Regio- and stereoselective thiocyanatothiolation of alkynes and alkenes by using NH4SCN and N-thiosuccinimides

A highly regioselective thiocyanatothiolation of alkynes and alkenes assisted by hydrogen bonding under simple and mild conditions is developed. Our thiocyanatothiolation reagents are readily available ammonium thiocyanate and N-thiosuccinimides. This metal-free system offers good chemical yields for a wide range of alkyne and alkene substrates with good functional group tolerance.

A highly regioselective thiocyanatothiolation of alkynes assisted by hydrogen bonding under simple and mild conditions is developed.

Sulfur-containing molecules are ubiquitous structural motifs and widely exist in natural products,^1,2 pharmaceuticals^3,4 and agrochemicals.^5–7 Examples include the nonsteroidal anti-inflammatory drug Sulindac,⁸ the basal-cell carcinoma treatment drug Vismodegib,⁹ and drugs for the treatment of Parkinson''s disease.¹⁰ Therefore, efficient introduction of sulfur into organic molecules has drawn much attention.^11–15 And numerous approaches for the formation of C–S bonds have been developed.^16–20 The most used organosulfur sources for the formation of C–S bonds are thiols and thiophenols, which have an unpleasant smell. Recently, inorganic metal sulfides have been extensively used to construct C–S bonds, such as sodium metabisulfite,²¹ K₂S,²² Na₂S²³ and Na₂S₂O₃.²⁴ Compared to thiols and thiophenols, inorganic metal sulfides are cheaper and generally stable. Thus, introduction of sulfur-containing groups into molecules by using inorganic metal sulfides is one of the desired approaches. Among them, thiocyanates commonly serve as important precursors for the preparation of thioethers,²⁵ trifluoromethyl sulfides,²⁶ heteroaromatic compounds.²⁷ In general, the sources of SCN used to introduce a sulfur-containing group into molecules are thiocyanate salts^28–35 such as KSCN, NaSCN, AgSCN and NH₄SCN. For example, thiocyanate salts were employed in thiocyanation of bromoalkenes via photocatalysis (Scheme 1a).³⁶ Besides, the vinyl thiocyanates could be also obtained by thiocyanation of haloalkynes (Scheme 1b),³⁷ iodothiocyanation of alkynes (Scheme 1c).³⁸ Obviously, difunctionalization of alkynes is the most straightforward protocol to prepare vinyl thiocyanates.Open in a separate windowScheme 1Methods for thiocyanatothiolation of alkynes and alkenes.Recently, our group has focused on hydrogen-bonding network or cluster³⁹ assisted transformations such as hydrofluorination of ynamides⁴⁰ and alkenes,⁴¹ the addition of sulfonic acids to haloalkynes,⁴² fluorothiolation of alkenes,²⁰ dihalogenation of alkynes⁴³ and hydrochlorination of alkynes,^44–46halothiolation of alkynes.⁴⁷ Along this line, herein, we are glad to report a hydrogen bond network-enabled regio- and stereoselective thiocyanatothiolation of alkynes using NH₄SCN and N-thiosuccinimides.Initially, according to the previous report,²⁰ we started the investigation of thiocyanatothiolation protocol using NH₄SCN and N-(phenylthio)succinimide as thiolation reagents in DCM under air and carried out the reaction at 60 °C (48 In order to enhance the H-bond interaction between the hydroxyl and 2, so AcOH was chosen to compare with HFIP (

Palladium-catalyzed one-pot synthesis of 2-substituted quinazolin-4(3H)-ones from o-nitrobenzamide and alcohols

Palladium-catalyzed 2-substituted quinazolin-4(3H)-one formation from readily available o-nitrobenzamides and alcohols using hydrogen transfer is described. Various quinazolin-4(3H)-ones were obtained in good to high yields. The cascade reaction including alcohol oxidation, nitro reduction, condensation, and dehydrogenation occurs without any added reducing or oxidizing agent.

Palladium-catalyzed 2-substituted quinazolin-4(3H)-one formation from readily available o-nitrobenzamides and alcohols using hydrogen transfer is described. Various quinazolin-4(3H)-ones were obtained in good to high yields.

The quinazolinones and their derivatives are a family of privileged heterocyclic structures commonly found in a wide variety of natural products, biologically active molecules, and functional organic materials.¹ Due to quinazolinone''s important value, various conventional methods have been developed for the synthesis of these molecules in both academic and industrial settings.² The most common approaches utilize 2-aminobenzoic acid and its derivatives as the starting materials along with aldehydes,³ acyl chlorides or their analogues⁴ to obtain the corresponding structural motifs. These methods usually have the disadvantages of multistep reactions,⁵ low yields,⁶ long reaction times,⁷ and the use of stoichiometric amounts of strong or toxic oxidants.⁸In the past decade, direct coupling methods of C–N bonds⁹ through which o-aminobenzamides react with benzylic alcohols by metal-catalyzed cascade reactions have been recognized as an attractive methods for the synthesis of 2-substituted quinazolinone derivatives. For example, Yokoyama and coworkers reported the synthesis of quinazolin-4(3H)-ones via a palladium-catalyzed domino reaction of o-aminobenzamides with benzylic alcohols.¹⁰ Wang et al. also reported the one-pot oxidative cyclization of o-aminobenzamide with alcohols to quinazolin-4(3H)-ones catalyzed by MnO₂ under hydrogen transfer conditions.¹¹ The groups of Watson,¹² Paul,¹³ and some others¹⁴ also independently reported the Ru-, Ni-, and Cu-catalyzed synthesis of quinazolin-4(3H)-ones via the acceptorless dehydrogenative coupling of o-aminobenzamides with alcohols. Considering that aniline is prepared from the corresponding nitroarenes,¹⁵ and that nitroarenes are cheaper and commercially available, the direct use of nitroarenes as amino sources for quinazolinone synthesis features their atom-economic advantage over anilines. However, methodologies for the synthesis quinazolinone derivatives via the acceptorless dehydrogenative coupling of nitroarenes with alcohols are relatively scarce.¹⁶Herein, we report a new approach for directly synthesizing 2-substituted quinazolin-4(3H)-ones from o-nitrobenzamides with alcohols via a hydrogen transfer methodology.¹⁷Initially, a model reaction of o-nitrobenzamide (1a) and benzyl alcohol (2a) was chosen to optimize the reaction conditions ( EntryCatalystSolvent t (h)Yield (%)1CuClToluene802CuCl₂Toluene803dppfToluene8284FeCl₃Toluene8225Cu(OAc)₂Toluene806CuBr₂Toluene8Trace7CuBrToluene8Trace8PdCl₂Toluene8149Pd(OAc)₂Toluene84210Pd(dppf)Cl₂Toluene85911Pd(dppf)Cl₂DMF87712Pd(dppf)Cl₂DMSO85613Pd(dppf)Cl₂PhCl88014Pd(dppf)Cl₂^bPhCl88715Pd(dppf)Cl₂^cPhCl88016Pd(dppf)Cl₂^dPhCl57917Pd(dppf)Cl₂^ePhCl87818Pd(dppf)Cl₂^fPhCl88719Pd(dppf)Cl₂^gPhCl880Open in a separate window^aReaction conditions: 1 mmol of 1a, 2.5 equiv. of 2a, catalyst and 1 mL of solvent in a 10 mL sealed tube at 150 °C under Ar for 8 h. Yield of the isolated product based on 1a.^bAt 140 °C under Ar for 8 h.^cAt 130 °C under Ar for 8 h.^dAt 140 °C under Ar for 5 h.^ePd (dppf) Cl₂, 5%.^fPd (dppf) Cl₂, 15%.^gAt 140 °C under air for 8 h.After optimized reaction conditions (Pd(dppf)Cl₂, chlorobenzene, 140 °C, argon) were established, the reaction scope and generality of various primary alcohols were tested, as shown in Open in a separate window^aReaction conditions: 1 mmol of 1a, 2.5 equiv. of 2a, catalyst and 1 mL of solvent in a 10 mL sealed tube at 140 °C under Ar for 8 h.^bIsolated yield.Next, substituent effects on the o-nitrobenzamide were also evaluated. Not surprisingly, o-nitrobenzamide with either electron-donating or electron-withdrawing groups could be successfully coupled with benzyl alcohol 2a to provide the corresponding products in high yields (84–87%) ( Open in a separate window^aReaction conditions: 1 mmol of 1, 2.5 equiv. of 2a, catalyst and 1 mL of solvent in a 10 mL sealed tube at 140 °C under Ar for 8 h.^bIsolated yield.Reaction of 2t with substituted amides^a,b

Association of liquid-assisted grinding with aging accelerates the inherently slow slipping-on of a dibenzo-24-crown-8 over the N-hydroxysuccinimide ester of an ammonium-containing thread

Solvent-free and solvent-less slipping-on of the dibenzo-24-crown-8 (DB24C8) over the N-hydroxysuccinimide end of an ammonium-containing thread has been studied and compared to the same reaction operated in solution. Slippage proved to be possible in solvent-free conditions, but the fastest slippage was obtained under heating when preliminary Liquid-Assisted Grinding (LAG) conditions were applied to the reactants followed by aging under an atmosphere of acetonitrile.

Very efficient slipping-on of the dibenzo-24-crown-8 over the NHS end of an ammonium-containing molecular axle was carried out through a solvent-less procedure.

The recently awarded 2016 Nobel Prize in chemistry¹ has put a light on molecular machines.² Some of these machines benefit from their interlocked molecular architecture³ so that the relative displacement of one interlaced element among others becomes possible and controllable. Hence, the straightforward synthesis of interlocked molecules is appealing in order to access novel molecular machines. Using the slippage strategy,⁴ we recently reported the preparation of an insulated and storable, albeit activated, N-hydroxysuccinimide (NHS) ester-containing [2]rotaxane building block (Scheme 1 and entry 1 of 5 This compound is a valuable activated building block for post-interlocking elongation of the encircled axle using bulky amino compounds.⁶ As the mechanism of such aminolysis reactions preserves the mechanical bond, it allowed the efficient and straightforward preparation of more sophisticated interlocked compounds such as [2] and [3]rotaxane molecular shuttles.^5,6 Improving the access to the NHS ester-containing [2]rotaxane building block 2 is therefore of real interest. This is particularly justified since in acetonitrile solution, the slipping-on of the DB24C8 (3 equiv.) over the NHS extremity of an ammonium-containing thread (at a concentration of 3 × 10⁻² M) is very slow and necessitates heating (13 days and 333 K, respectively). In this paper, we wondered if this slipping-on process could be possible, nay improved, by drastically reducing the amount of solvent. Since solvent-free/solvent-less conditions are highly prone to induce mass transfer limitations, utilisation of ball-milling was envisaged. Indeed it was previously shown that ball-milling could improve the speed of inherently slow reactions.⁷ A few examples of solvent-free/solvent-less synthesis of rotaxanes have been reported to date,⁸ and to the best of our knowledge, only three of these examples are related to slippage process through a co-melting process⁹ or an immediate solvent evaporation method.¹⁰ Herein, different experimental procedures were considered to yield the activated [2]rotaxane 2: solvent-free grinding,¹¹ Liquid-Assisted Grinding (LAG),¹² and aging by heating with or without an acetonitrile atmosphere.¹³ LAG is defined as the use of small amounts of a non-reactive liquid during grinding.¹⁴ It has been shown by us and by other research groups to have a considerable effect on the course of reactions run under mechanical forces.¹⁵ Besides, aging is the action of letting the reaction take place in the absence of any mechanical agitation. This reactivity is based on the inherent mobility of molecules and can be accelerated by the presence of vapours and/or a slight heating in the presence, or not, of a catalyst.¹⁶ Both LAG and aging are processes that are using generally much lower quantities of solvents compared to traditional solvent-based syntheses, and therefore are generally qualified as “solvent-less” processes. The results of these slipping-on experiments are shown in Fig. 1 and Open in a separate windowScheme 1Slippage process of the NHS ester-containing molecular axle 1 by the DB24C8.Experimental conditions relative to the slippage of thread 1

Fe-catalyzed esterification of amides via C–N bond activation

An efficient Fe-catalyzed esterification of primary, secondary, and tertiary amides with various alcohols for the preparation of esters was performed. The esterification process was accomplished with FeCl₃·6H₂O, which is a stable, inexpensive, environmentally friendly catalyst with high functional group tolerance.

An efficient Fe-catalyzed esterification of primary, secondary, and tertiary amides with various alcohols was performed. Esterification was accomplished with inexpensive, environmentally friendly FeCl₃·6H₂O, and with high functional group tolerance

The amide bond is not only employed as an important natural peptide skeleton in biological systems, but also as a versatile functional group in organic transformations.^1,2 Among amide transformations,^3,4 transamidation and esterification of amides have attracted widespread attention from organic chemists.^5–11 In contrast to transamidation of amides, esterification of amides is relatively difficult because of the low nucleophilicity of alcohols compared with amines.¹² To overcome this shortcoming, various processes for the esterification of amides have been developed, such as using an activating agent,⁶ employing twisted amides,⁷ and forming intramolecular assisted groups.⁸ For increasing the synthetic flexibility of esterification of amides, new catalytic systems Zn(OTf)₂ and Sc(OTf)₃ were developed by Mashima and Williams for the esterification of amides.⁹ Shimizu et al. reported CeO₂ catalyzed esterification of amides.¹⁰ Off late, progress of the significant Ni-catalyzed esterification of amides has gained precedence.¹¹ Although this approach produces satisfactory yield, the drawbacks such as the use of an expensive catalyst, generation of reagent waste, high temperature and the limited scope of the substrate still persists. Herein, under mild reaction conditions, we report a novel and efficient Fe-catalyzed esterification of amides for the synthesis of esters (eqn (1)). Compared to conventional methods, this esterification procedure is distinguished by using a stable, inexpensive, environment-friendly catalyst, i.e., FeCl₃·6H₂O with a low toxicity solvent. The catalytic system has wide functional group compatibility. The reactions of several primary, secondary, and tertiary amides with various alcohols have been well tolerated in this process. Moreover, esters were also as effective as esterification reagents for the esterification of amides by the acyl–acyl exchange process. In the course of our present study, a Co-catalyzed amide C–N cleavage to form esters was reported by Danoun et al.¹³ However, an additional additive (Bipy) and Mn (3 equiv.) were needed and the scope of the reaction was limited to only tertiary amides; primary or secondary amides were not compatible with this catalytic oxidation system.1We initially selected benzamide 1a and ethanol 2a as model substrates to screen the reaction conditions, and the results are summarized in EntryCatalyst (20%)Additive (40%)Yield^b1FeCl₂—312FeCl₃—313FeBr₃—254FeSO₄·7H₂O—205Fe(NO₃)₃·9H₂O—206FeCl₃·6H₂O—357CuCl₂—Trace8PdCl₂—Trace9Ni₂Cl·6H₂O—Trace10———12FeCl₃·6H₂OPyridineTrace13FeCl₃·6H₂O1,10-PhenanthrolineTrace14FeCl₃·6H₂OFormic acidTrace15FeCl₃·6H₂O l-ProlineTrace16FeCl₃·6H₂OH₂SO₄2217FeCl₃·6H₂OHNO₃2518FeCl₃·6H₂OHCl9119—HCl3520^cFeCl₃·6H₂OHClTrace21^dFeCl₃·6H₂OHCl3622^eFeCl₃·6H₂OHCl2823^fFeCl₃·6H₂OHCl40Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.1 mL), catalyst (0.04 mmol, 20 mol%), H₂SO₄ (concentrated, 0.24 mmol), HNO₃ (concentrated, 0.24 mmol), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 °C, 14 h.^bGC yield using hexadecane as internal standard.^cDMF was used as a solvent.^d1,4-Dioxane was used as solvent.^eToluene was used as solvent.^fCH₃CN was used as solvent.The substrate scope of esterification with alcohols was investigated under the optimized reaction conditions. As shown in EntryAlcoholProductsYield^b1Ethanol 2a 3a, 85%2 n-Propanol 2b 3b, 88%3 n-Octanol 2c 3c, 82%4 i-Propanol 2d 3d, 91%5 t-Butyl alcohol 2e 3e, 81%6Cyclohexanol 2f 3f, 80%7Phenethanol 2g 3g, 83%8Phenethanol 2h 3h, 81%9Trifluoroethanol 2i 3i, 81%10Ethane-1,2-diol 2j 3j, 85%Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.1 mL), 2b–2j (0.24 mmol), FeCl₃·6H₂O (0.04 mmol, 20 mol%), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 °C, 14 h.^bIsolated yield.We then examined the generality of amides and the results are compiled in EntryAmidesProducts and yield^b1 3k, 86%2 3l, 85%3 3m, 78%4 3n, 75%5 3o, 86%6 3p, 84%7 3q, 90%8 3r, 86%9 3s, 84%10 3t, 55%11 3u, 88%12 3v, 85%13 3w, 81%Open in a separate window^aReaction conditions: 1b–1n (0.2 mmol), 2a (0.1 mL), FeCl₃·6H₂O (0.04 mmol, 20 mol%), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 °C, 14 h.^bIsolated yield.In addition to alcohols, esters were also used as substrates for esterification of amides through the acyl–acyl exchange process under the optimal reaction conditions.¹⁴ As shown in EntryAmidesEstersProducts and yield^b11a 21a 31a 41a 51b 61c 71h Open in a separate window^aReaction conditions: 1a–1h (0.2 mmol), 2k, 2l (0.1 mL), 2m–2o (0.24 mmol), FeCl₃·6H₂O (0.04 mmol, 20 mol%), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 °C, 14 h.^bIsolated yield.The substrate scope of this iron-catalyzed esterification of secondary and tertiary amides with alcohols was investigated. Remarkably, when a secondary amide, viz., N-methylbenzamide (1o) and a tertiary amide, viz., N,N-diethylbenzamide (1p) were used as substrates, the corresponding esters 3a and 3v were afforded in high yield (Scheme 1).Open in a separate windowScheme 1Reaction of secondary and tertiary amides 1o and 1p with ethanol.In addition to aromatic primary, secondary and tertiary amides, the esterification of aliphatic primary, secondary and tertiary amides was also investigated under the optimal reaction conditions, the corresponding esters were afforded in good to excellent yield and the results are shown in Scheme 2. 2-Phenylacetamide (1q) participated in this catalytic reaction to form the ester 3y in 86% yield. N-Acetylaniline 1r and N,N-dimethylformamide 1s were also applicable to this catalytic system, and transformed into the corresponding esters 3z and 3z¹ in 79% and 82% yield respectively.Open in a separate windowScheme 2Reaction of aliphatic amides 1q, 1r and 1s with different alcohols.To demonstrate the effect of iron salt in the current catalytic system, several control experiments were carried out as shown in Scheme 3. When 1 equivalent FeCl₃·6H₂O was used as the catalyst in the absence of HCl, 3a was obtained in 90% yield. This result indicated that the catalytic cycle of the iron salt was hindered in the present reaction conditions. When the stronger bidentate ligands such as 2,2-bipyridine was used, 3a was not obtained and trace amounts of 3a were detected on using ferrocene as the catalyst, indicating that the iron salt catalyst showed low efficiency in the presence of the stronger ligand. Thus, it was deduced that free Fe(ii or iii) was effective for this reaction.Open in a separate windowScheme 3Control experiments.According to the reported literature^5d and our experimental results, the catalytic reaction pathways for the Fe-catalyzed esterification of amides by alcohols are proposed as shown in Scheme 4. The first step is the generation of the amidate complex A, which can be formed from free Fe(iii) and amide 1. The complex A reacts with alcohol 2 to produce an unstable intermediate B. The interaction between the alcohol oxygen and the carbonyl results in cyclic intermediate C, which is in equilibrium with its isomer D. Intermediate E can also be produced from Dvia C–N bond cleavage. Through the reaction of HCl and a new molecule amide, intermediate E produces the desired ester 3, ammonium chloride (colorless crystal, which was detected after the reaction), and the amidate complex A.Open in a separate windowScheme 4Plausible reaction mechanism for Fe-catalyzed esterification of amides by alcohols.     

Palladium-catalyzed cross-coupling reaction of alkenyl aluminums with 2-bromobenzo[b]furans

Highly efficient and simple cross-coupling reactions of 2-bromobenzo[b]furans with alkenylaluminum reagents for the synthesis of 2-alkenylbenzo[b]furan derivatives using PdCl₂ (3 mol%)/XantPhos (6 mol%) as catalyst are reported. Excellent yields (up to 97%) were obtained for a wide range of substrates at 80 °C for 4 h in DCE.

PdCl₂ (3 mol%)/XantPhos (6 mol%) complexes was found to be a highly efficient catalyst for the synthesis of 2-alkenylbenzo[b]furans from 2-bromobenzo[b]furans and alkenylaluminums. The reaction was also found to be effective in gram-scale synthesis.

2-Substituted benzo[b]furans are important structural scaffolds found in many natural products and pharmaceutical products.¹ Some of these compounds have been known to exhibit anti-inflammatory,² antitumor,³ anticancer,⁴ and anti-fungal,⁵ antiplasmodial,⁶ antioxidant,⁷ anti-HIV,⁸ and estrogenic activities.⁹ In addition, they serve as building blocks for many organic transformations.¹⁰ Thus, their synthesis and applications have attracted considerable attention in the chemical and pharmaceutical industries over the past decades.¹¹ Until now numerous effective synthetic methodologies of synthesis 2-substituted benzo[b]furans have been reported.^12,13 Among these methods hitherto developed, the metal-catalyzed 2-halobenzo[b]furans coupling with organometallic nucleophiles is one of the most effective methods (Scheme 1).¹³ However, in most cases generally suffer from one or more drawbacks such as requirement co-catalyst like Cu salts, limited substrate scope, high catalyst loading, high temperature and poor chemoselectivity etc. Therefore, the development of more efficient and atom economical approaches for the preparation of 2-substituted benzo[b]furans remains as desirable work. Previous studies show that organoaluminum reagents are highly efficient nucleophiles for cross-coupling reactions with aromatic halides¹⁴ or benzylic halides,¹⁵ and the investigations have demonstrated that palladium is a good catalytic metal.¹⁶Open in a separate windowScheme 1Palladium-catalyzed cross-coupling reactions of 2-halobenzo[b]furans derivatives with organometallic nucleophiles.At present, a variety of methods have been developed to prepare compounds containing olefin functional groups through hydrocarbon activation of olefins.¹⁷ To continue our effort to develop coupling reactions using reactive organoaluminum reagents,¹⁸ we herein report a palladium(ii)-catalyzed, base free cross-coupling reactions of 2-bromo benzo[b]furans with alkenylaluminum reagents at 80 °C in short reaction time with good to excellent isolated yields for 2-alkenyl benzo[b]furans. The process was simple and easily performed, and it provides an efficient method for the synthesis of 2-alkenyl benzo[b]furans derivatives. Notably, in our procedure palladium is used as the single catalyst and base free.Our initial studies used 2-bromo-6-methoxybenzo[b]furan (2e) with diethyl(oct-1-enyl)aluminum (1a) as model substrates. Treatment of compound 2e with the alkenylaluminum (1a) using PdCl₂ (3 mol%)/XantPhos (6 mol%) as catalyst in toluene at 60 °C for 4 h, the coupled product 6-methoxy-2-(oct-1-enyl)benzo[b]furan (3ae) was obtained in 46% isolated yield ( EntryPd salt.1a (equiv.)Base (x equiv.)Solvent3ae^b yield (%)1PdCl₂1.0—Toluene462Pd(OAc)₂1.0—Toluene193Pd(acac)₂1.0—Toluene104PdCl₂1.0Et₃N (2.0)Toluene275PdCl₂1.0K₂CO₃ (2.0)TolueneNR6PdCl₂1.0TMEDA (2.0)TolueneNR7PdCl₂1.0—Hexane478PdCl₂1.0—THF519PdCl₂1.0—DCE7410^cPdCl₂1.0—DCE8511^cPdCl₂0.8—DCE8412^cPdCl₂0.6—DCE5313^c,dPdCl₂0.8—DCE49Open in a separate window^a1a/2a/PdCl₂/XantPhos = 1.0/0.5/0.03/0.06 mmol, 60 °C, 3 mL solvent, 4 h, Ar₂.^bIsolated yield of 3ae.^c80 °C.^d1a/2a/PdCl₂/XantPhos = 0.8/0.5/0.02/0.04 mmol.Under the optimized conditions, coupling reactions of aliphatic alkenylaluminum reagents, such as di-sec-butyl(oct-1-enyl)aluminum (1a) and di-sec-butyl(dec-1-enyl)aluminum (1b), proceed with electron-neutral, electron rich and electron-deficient 2-bromo benzo[b]furans derivatives affording the products in good yields ( Open in a separate window^a1/2/PdCl₂/XantPhos = 0.8/0.5/0.03/0.06 mmol, 80 °C, 4 h. Isolated yield of 3, two runs.The reaction was also found to be effective in gram-scale synthesis, which indicated its potential for practical application (Scheme 2). 2-Substituted benzo[b]furans derivatives 3ah was synthesized in 1.31 gram using this methodology.Open in a separate windowScheme 2Preparative scale synthesis of compound 3ah.In order to further explore the reaction mechanism, control experiments were carried out (see the ESI^†). We performed the reaction between 2-bromobenzo[b]furan (2a, 0.5 mmol) with di-sec-butyl(oct-1-enyl)aluminum (1a, 0.8 mmol) in the presence of PdCl₂ (3 mol%)/XantPhos (6 mol%) in DCE at 80 °C for 4 h. The reaction mixture was analyzed by ³¹P NMR, it was found that the characteristic peak of ³¹P NMR appeared around at 22.98 ppm and 30.98 ppm. However, ³¹P NMR peak of pure XantPhos is −18.03 ppm. The results show that XantPhos work as a ligand of the palladium center. Thus, a proposed possible reaction mechanism for the cross-coupling reaction is shown in Scheme 3. The first step is the oxidative addition of 2-bromobenzo[b]furans (2) to Pd(0) phosphine complex (4) (which in turn from PdCl₂ and RAlMe₂ (1) reagents) to form the organopalladium(ii) bromide intermediate (5). Transmetalation of RAlMe₂ (1) with complex 5 gives R''PdR(ii) intermediate (6) and Me₂AlBr. Finally, complex 6 under goes reductive elimination to afford the desired coupling product of 2-alkenylbenzo[b]furans (3) and regenerate the active Pd(0) species for the next catalytic cycle.Open in a separate windowScheme 3The proposed mechanism for the formation of coupled product 3.     

Microwave-assisted iodine-catalyzed oxidative coupling of dibenzyl(difurfuryl)disulfides with amines: a rapid and efficient protocol for thioamides

An efficient protocol for synthesis of thioamides was developed via the microwave-assisted iodine-catalyzed oxidative coupling of dibenzyl(difurfuryl)disulfides with amines. This process is scalable and tolerates a wide spectrum of amines to deliver the corresponding products in moderate to excellent yields in 10 minutes, providing a cheap and rapid approach to thioamides.

Rapid and efficient protocol for thioamides via microwave-assisted iodine-catalyzed oxidative coupling of dibenzyl(difurfuryl)disulfides with amines.

Thioamides have become an attractive synthetic goal in organic chemistry,¹ because thioamide skeletons are widely present in drugs and natural products,² such as cycasthioamide,³ 6-thioyuanine,⁴ 2-thiocytidine⁵ and closthioamide^2a (Scheme 1), and their application as useful precursors and versatile building blocks for construction of a range of heterocyclic compounds has also been studied.^1a,6 In addition, thioamides also can be used as a synthetic isostere for amides in peptide backbones,⁷ and their application as directing groups has also been reported.^8,1c Furthermore, the application of thioamides in developing novel a fluorophore/quencher pair for monitoring the unfolding of a small protein was also explored.⁹Open in a separate windowScheme 1Structures of natural products bearing thiocarbonyl group.Because of their wide application, efforts are devoted toward their generation.¹⁰ The Willgerodt–Kindler reaction is a well-known method for construction of thioamides by using aldehydes and secondary amines as starting materials.¹¹ However, this thioamidation always suffers from the problems of low conversions and harsh conditions. Though, modified variations in Willgerodt–Kindler reaction were also reported,^1a,12 the use of excessive amounts of elemental sulphur makes it a less economical method. Lawesson''s reagent was also used as common sulfur reagent for synthesis of thioamides,¹³ however, this reaction was also occur under harsh conditions. Another thioamidation, where elemental sulfur was used as sulfur reagent, was also reported by Savateev''s groups via a photoinitiated reaction (Scheme 2a).^11a However, this transformation was only suitable for special thioamides with the same structure of amines. Thiols can also be used as sulfur reagent for construction of thioamides,^13b,c but its pungent smell makes this reaction difficult to carry out (Scheme 2b). Recently, Nguyen''s group described a novel process to thioamides by using sulfur as catalyst.¹⁴ This method was suitable for a large range of amines for giving the corresponding products in good to excellent yields at 80 °C for a long time of 16 h.Open in a separate windowScheme 2General methods for synthesis of thioamides.Other methods for thioamides were also reported,¹⁵ but challenges still exist in developing more convenient and efficient ways to these important scaffolds. In our previous work, thioamides were synthesized via the iodine-promoted thioamidation of several of amines.¹⁶ However, this reaction must be performed under high temperature, for a long time (100 °C, 8.0 h), and 0.5 equiv. of I₂ must to be used to promote the thioamidation effectively (Scheme 2c).As one of the efficient and clean procedures in modern synthetic organic chemistry, microwave-assisted organic synthesis (MAOS) has aroused wide interest among scientists, which are suited to the increased demands in industry with the advantages of short reaction times and expanded reaction range.¹⁷ Herein, we reported an efficient method for synthesis of thioamides via the microwave-assisted iodine-catalyzed oxidative coupling of dibenzyl(furan-2-ylmethyl) disulfides with amines (Scheme 2d).We initiated our studies with the reaction of dibenzyldisulfide (1a) with N-methylpiperazine (2a) catalyzed by 10 mol% of I₂ in DMSO under microwave radiation (100 °C) for 10 minutes, and the desired product (3a) was obtained in the yield of 36% ( EntryI₂ (mol%)SolventTemp. (°C)Time (min)Yield^b (%)1I₂ (10 mol%)DMSO1001036%2I₂ (10 mol%)DMSO1101048%3I₂ (10 mol%)DMSO1201065%4I₂ (10 mol%)DMSO1301088%5I₂ (10 mol%)DMSO1401088%6I₂ (10 mol%)DMSO1301588%7I₂ (10 mol%)DMF1301074%8I₂ (10 mol%)1,4-Dioxane1301067%9I₂ (10 mol%)THF1301065%10I₂ (10 mol%)CH₃CN1301070%11I₂ (10 mol%)HOAc1301062%12I₂ (10 mol%)Chlorobenzene1301074%13I₂ (10 mol%)Toluene1301063%14I₂ (10 mol%)Solvent-free1301021% 15 I ₂ (5 mol%) DMSO 130 10 88% (86%) ^c 16I₂ (3 mol%)DMSO1301073%17I₂ (3 mol%)DMSO1301578%18^dI₂ (5 mol%)DMSO1301088%19^eI₂ (5 mol%)DMSO1301018%Open in a separate window^aReaction conditions: dibenzyldisulfide 1a (0.2 mmol), N-methylpiperazine 2a (0.4 mmol), I₂, solvent (2.0 mL).^bGC yields based on dibenzyldisulfide 1a.^cIsolated yields based on dibenzyldisulfide 1a.^d0.6 mmol of N-methylpiperazine 2a was used.^eWithout microwave radiation.With the optimal conditions in hand, the scope of the amines and disulfides were investigated, and results were summarized in Open in a separate window^aReaction conditions: dibenzyldisulfide 1a (0.5 mmol), amines 2 (1.0 mmol), I₂ (0.025 mmol), DMSO (2.0 mL), 130 °C, 10 min.^bIsolated yields based on dibenzyldisulfide 1a.In subsequent studies, we examined the reaction of various amines with difurfuryl disulfide under the optimal conditions, and the results were summarized in Open in a separate window^aReaction conditions: difurfuryldisulfide (1b) (0.5 mmol), amines 2 (1.0 mmol), I₂ (0.025 mmol), DMSO (2.0 mL), 130 °C, 10 min.^bIsolated yields based on difurfuryldisulfide (1b).The thioamidation can also be carried out on a larger scale reaction, and the desired product (3a) were obtained in the yields of 87%, when 5 mmol of dibenzyldisulfide (1a) was treated with 10 mmol of N-methylpiperazine (2a) under the standard conditions (Scheme 3a). To shed light on the mechanism of the reaction, dibenzyldisulfide (1a) was treated with N-methylpiperazine (2a) under standard conditions by using 2.0 equiv. of TEMPO or BHT as radical scavengers (Scheme 3b), and desired product 3a was obtained in the yields of 86% and 80% respectively, suggesting that no single-electron transfer process was involved through the whole reaction. In addition, thioamides have been used as important intermediates for the construction of heterocycles and other compounds containing both nitrogen and sulfur in their backbones (Scheme 3c).¹⁸Open in a separate windowScheme 3(a) Larger-scale synthesis of 3a. (b) Control experimental for mechanism study. (c) Selected transformation of thioamides.On the basis of the above experimental results and previous works,^16,19 a possible mechanism has been depicted in Scheme 4. The first step of the thioamidation is the generation of the intermediate A by the reaction of dibenzyldisulfide (1a) with I₂, with concomitant loss of HI and BnS⁻. Then intermediate A react with N-methylpiperazine (2a) to yield intermediate B, which was converted to species Cvia coupling with BnS⁻ in the presence of DMSO. Finally, species C decomposed to desired product (3a) and BnSH, which was then converted to dibenzyldisulfide (1a) via oxidation reaction. During the whole reaction, the catalyst (I₂) was regenerated by the cycle of HI in the presence of DMSO, which catalyzed the thioamidation effectively.Open in a separate windowScheme 4Proposed mechanism of the thioamidation.     

Enantioselective Nozaki–Hiyama–Kishi allylation-lactonization for the syntheses of 3-substituted phthalides

We report the synthesis of bipyridyl ligands and these ligands were applied in the chromium-catalyzed enantioselective Nozaki–Hiyama–Kishi allylation of substituted (2-ethoxycarbonyl)benzaldehydes and subsequently lactonized to synthesize phthalides with an optimal enantioselectivity of 99%. This approach was applied to synthesize (S)-cytosporone E at a 71% yield in three steps.

A chromium-catalyzed enantioselective Nozaki–Hiyama–Kishi allylation of substituted (2-ethoxycarbonyl)benzaldehydes and subsequent lactonization to synthesize phthalides with an optimal enantioselectivity of 99%.

The addition of organochromium reagents to carbonyl compounds was pioneered by Nozaki et al.¹ and is a versatile reaction forming carbon–carbon bonds for use with various building blocks to synthesize complex natural products and pharmaceuticals.² Organochromium reagents are formed in situ through the oxidative addition of Cr(ii) species to allyl, propargyl halides, and triflates (aryl, vinyl halides, and triflates requiring catalytic amounts of Ni(ii) salt)^3a,b and can be added to aldehydes and ketones to produce the corresponding alcohols.³ The major disadvantage of the original NHK allylation method is the excessive amount of Cr(ii) salts necessary for the formation of the organochromium reagent.^1,4 Fürstner and Shi⁵ reported NHK allylation that requires only catalytic amounts of active Cr(ii) species; Mn is used as the reducing agent, and trimethylchlorosilane prolongs the catalytic cycle. These improvements have driven chemists to improve the enantioselectivity of this reaction. Several chiral ligands have been used as enantioselective catalysts for the allylation of aldehydes.⁶ A chiral bipyridyldiol was used as the efficient enantioselective catalyst in an asymmetric NHK reaction to provide the corresponding homoallylic alcohol and simultaneously form lactone in high enantiomeric excess (90% ee).⁶ⁿ The successful application of these ligand systems motivated us to investigate the NHK allylation of (2-ethoxycarbonyl)benzaldehydes and simultaneous lactonization to produce phthalides. This approach was then employed to enantioselectively synthesize (S)-cytosporone E.Pineno-bipyridyl alcohols are readily obtainable from (+)-α-pinene in four steps (Scheme 1); these steps include the stereoselective alkylation of chiral bipyridine with ketones to obtain desired products 4–7.^6o In a previous work, we used benzaldehyde, allyl chloride, and ligand 6 under Fürstner''s reaction conditions to obtain the corresponding product with 70% yield and 75% ee.⁶ⁿ In the same study, a bipyridyldiol was applied under Fürstner''s reaction conditions to prepare phthalide 8 with 92% yield and 90% ee. To improve the enantioselectivity of the NHK reaction using ligand 6 under Fürstner''s reaction conditions, we obtained the optimal reaction conditions using benzaldehyde, allyl bromide, CrCl₃ (10 mol%), ligand 6 (30 mol%), and Et₃N (60 mol%) to provide a product with 83% yield and 90% ee.^6oOpen in a separate windowScheme 1Ligand synthesis.^6oInitial evaluation of non-symmetrical bipyridine ligands (4–7) in the Cr(ii)-catalyzed addition of allyl bromide to (2-ethoxycarbonyl)-3,5-dimethoxybenzaldehyde revealed that ligand 6 has excellent reactivity and enantioselectivity (†) Reactions performed at 0 °C in THF afforded better results than all of screened conditions ( EntryLigandSolventTemp [°C]Yield^a [%]ee^b [%]14THFr.t.868325THFr.t.898936THFr.t.899347THFr.t.859054THF0888765THF0898976THF0869787THF0879296CH₂Cl₂r.t.5886106DMFr.t.3684116Toluener.t.NR—126Etherr.t.NR—136CH₂Cl₂06889146DMF01582156Toluene0NR—166Ether0NR—Open in a separate window^aIsolated yield.^bThe ee% were determined on a Chiracel OJ HPLC column.Ligands 4 and 5, which had less steric hindrance, showed slightly lower enantioselectivity than ligands 6 and 7. The reaction conducted at room temperature resulted in a product with less enantioselectivity than the reaction at 0 °C. †).Catalytic enantioselective synthesis of phthalides

I2-mediated Csp2–P bond formation via tandem cyclization of o-alkynylphenyl isothiocyanates with organophosphorus esters

A novel, I₂-mediated tandem cyclization of o-alkynylphenyl isothiocyanates with organophosphorus esters has been developed under mild conditions. Different kinds of 4H-benzo[d][1,3]thiazin-2-ylphosphonate could be synthesized in moderate to excellent yields. This method has the advantages of easy access to raw materials, free-metal catalyst, simple operation, high yield and high functional group tolerance.

A highly efficient molecular-iodine-catalyzed cascade cyclization reaction has been developed, creating a series of 4H-benzo[d][1,3]thiazin-2-yl phosphonates in moderate to excellent yields. This approach benefits from metal-free catalysts and available raw materials.

As an important class of organic products, organophosphorus compounds have received considerable attention because they have broad application in the field of materials science,¹ medicinal chemistry,² organic synthesis,³ natural products,⁴ and ligand chemistry.⁵ Phosphorus-containing compounds are valuable precursors of many biologically active molecules which can act as antibiotics,⁶ anti-tumor agents⁷ and enzyme inhibitors.⁸ Traditionally, the preparation of organophosphorus compounds relies on a transition-metal-catalyzed cross-coupling of phosphine reagents with electrophilic aryl halides (Ar-X),⁹ aryl boronic acids (Ar-B),¹⁰ aryl diazonium salts (Ar-N),¹¹ and so on.¹² Recently, the construction of a Csp²–P bond on heterocycles is another powerful method to synthesize the organophosphorus compounds.¹³ For instance, the Duan group and the Ackermann group reported a Ag-mediated C–H/P–H functionalization method to construct a Csp²–P bond by using arylphosphine oxides and internal alkynes as the substrates^13a,b (Scheme 1a). In 2014, Studer and co-workers reported a pioneering radical cascade reaction for the synthesis of 6-phosphorylated phenanthridines from 2-isocyanobiphenyls and diphenylphosphine oxides (Scheme 1b).^13c Before long, Ji and Lu''s group described two similar radical process with excess of PhI(OAc)₂ or K₂S₂O₈ as the oxidant (Scheme 1c).^13d,e Recently, Liang and co-works developed two cases of cascade functionalization to construct phosphorylated heterocycles via the ionic pathway (Scheme 1d and 1e).^13f,g Meanwhile, Li and coworkers reported a Mn(ii)-promoted tandem cyclization reaction of 2-biaryl isothiocyanates with phosphine oxides which went through the same mechanism(Scheme 1f).^13h Despite the usefulness of the above methods, common problems, such as complex reaction substrates, relatively high temperature, excess amounts of oxidants, limited their applications. Furthermore, transition metals are required in these reactions, thereby resulting in limitations in reactants. Therefore, the development of a simple and transition-metal-free method for the formation of the Csp²–P bond from easily prepared starting materials is highly desirable.Open in a separate windowScheme 1Synthesis of P-containing heterocycles through Csp²–P bond formation. o-Alkynylphenyl isothiocyanates are easily prepared organic synthons with versatile chemical reactivity,¹⁴ and they could be used as electrophiles,¹⁵ nucleophiles,¹⁶ and radical receptors¹⁷ due to the N C S moiety in the structure. Recently, the rapid development of the transition-metal-catalyzed cascade cycloaddition of o-alkynylphenyl isothiocyanates with various nucleophiles provides a new and powerful synthetic strategy to synthesize different heterocycles. Very recently, we have developed a tandem cyclization process for the synthesis of 4H-benzo[d][1,3]thiazin-2-yl)phosphonates by using this strategy.¹⁸ As part of our continuing interest in the transformation of o-alkynylphenyl isothiocyanates,¹⁹ we describe herein a novel I₂-promotedtandem reaction to construct Csp²–P bond from o-alkynylphenyl isothiocyanates and phosphine oxides(Scheme 1g).The starting o-alkynylphenyl isothiocyanates were prepared via the Sonogashira coupling of 2-iodoanilines with terminal alkynes,²⁰ followed by the treatment with thiophosgene according to the literature procedure.²¹ We commenced our studies with the reaction of o-phenylethynylphenyl isothiocyanate (1a, 0.2 mmol) and diethyl phosphonate (2a, 0.6 mmol) in the presence of I₂ (0.5 equiv.) as the catalyst, 8-diazabicyclo[5,4,0]undec-7-ene (DBU, 3.0 equiv.) as the base, in dichloromethane (DCM, 2 mL) at 0 °C for 12 h in air atmosphere. Gratifyingly, the desired product diethyl (Z)-(4-benzylidene-4H-benzo[d][1,3] thiazin-2-yl)phosphonate 3a was obtained in 75% yield (Schemes 1–4)Optimization of the reaction conditions^a

[3 + 2] cycloaddition of nonstabilized azomethine ylides and 2-benzothiazolamines to access imidazolidine derivatives

A simple and practical method for the construction of 1,3,5-trisubstituted imidazolidine derivatives via [3 + 2] cycloaddition reaction has been developed. This reaction could smoothly proceed between nonstabilized azomethine ylides generated in situ and 2-benzothiazolamines to deliver a wide scope of differently substituted imidazolidines in high yields (up to 98%). The structure of one example was confirmed by X-ray single-crystal structure analysis.

An effective method for the synthesis of functionalized imidazolidine derivatives via a [3 + 2] cycloaddition reaction from nonstabilized azomethine ylides generated in situ from 2-benzothiazolamines in high yields (up to 98%) has been developed.

Heterocyclic compounds are important structural motifs that are frequently discovered in natural products and biologically active molecules, with wide applications and potency in the field of medicinal chemistry.¹ Among them, the 2-aminobenzothiazole scaffolds, which contain a core of isothiourea motifs as a privileged scaffold, are ubiquitous in natural products, drugs and bioactive compounds.² Some examples of biologically active molecules and pharmaceuticals containing benzothiazoles are shown in Fig. 1. These compounds display a variety of important biological activities, such as anti-HIV, anticancer, antineoplastic and anticonvulsant activity, and so on.³Open in a separate windowFig. 1Selected examples of biologically active compounds containing a 2-aminobenzothiazole scaffolds.Due to their momentous and potent biological activities and structural diversifications, more organic and medicinal chemists have been significantly attracted to developing effective and advanced methodologies for the construction of benzazole scaffolds.⁴ The 2-benzothiazolamines could serve as alternative C4 synthons with various reaction partners in [4 + 2] cycloadditions for the straightforward and convenient access to 2-aminobenzothiazole scaffolds, and this type of reaction has been well established (Scheme 1a).⁵ By contrast, the 2-benzothiazolamines which acted as C2 synthons in cycloaddition reactions have been very limited.⁶ Therefore, the development of efficient cycloaddition between the 2-benzothiazolamines as C2 synthons and suitable reaction partners to provide diverse functionalized heteroarenes molecules is always in great demand.Open in a separate windowScheme 1Previous reports and our protocol.On the other hand, the 1,3-dipole cycloaddition is recognized one of the most efficient and powerful methods for building five membered heterocyclic rings from simple starting materials.⁷ In particular, the nonstabilized azomethine ylides generated in situ from N-benzyl-substituted compounds were a highly reactive intermediate with unsaturated compounds, such as activated alkenes,⁸ aromatic ketones,⁹ aromatic aldehydes,¹⁰ phthalic anhydrides,¹¹ imines,¹² cyano compounds¹³ or stable dipoles,¹⁴ to build various N-containing heterocycles via [3 + 2] or [3 + 3] cycloaddition reactions (Scheme 1b). Despite the progress were well developed via 1,3-dipolar cycloadditions employing nonstabilized azomethine ylides as the substrates, challenges still remain. Herein, we would like to present an effective process to furnish functionalized 1,3,5-trisubstituted imidazolidine derivatives via [3 + 2] cycloaddition strategy from 2-benzothiazolamines with nonstabilized azomethine ylides generated in situ (Scheme 1c). In contrast, the desired product was not obtained via [4 + 3] cycloaddition reaction.Initially, we used 2-benzothiazolimine 1a and N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl amine 2a which could in situ form azomethine ylide in the presence of acid as model substrates to optimize the reaction conditions. The results were shown in EntryAdditiveSolventTimeYield of 3a^b (%)1AcOHCHCl₃12482TfOHCHCl₃12513TFACHCl₃3904HClCHCl₃12205TFACH₂Cl₂1986TFADCE3827TFAEtOAc6758TFAToluene12709TFAMeOH123110TFACH₃CN37111TFADioxane125912TFAEt₂O124613TFATHF1262Open in a separate window^aReaction conditions: 2-benzothiazolimine 1a (0.1 mmol, 1.0 equiv.), N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl-amine 2a (0.12 mmol, 1.2 equiv.), addition (0.01 mmol, 0.1 equiv.) and solvent (1.0 mL) in a test tube at room temperature.^bYield of the isolated product.After establishing the optimal reaction conditions, the scope and limitations of this [3 + 2] cycloaddition reaction for formation of 1,3,5-trisubstituted imidazolidines were examined. The results were shown in †)¹⁵ was unequivocally confirmed by X-ray crystallographic analysis (see ESI^†). On the other hand, when the R² groups were heteroaromatic substituted group, such as 2-furanyl, 3-thienyl, 1-naphthyl and 2-naphthyl, the cycloaddition reaction were well tolerated and could also proceed smoothly without obvious interference to produce corresponding pyrazoles 3k–3n in 92–96% yields. Meanwhile, substituted substrates at the C4 or C6-position of the 2-aminobenzothiazole, such as Me and Cl were also reacting smoothly to afford the corresponding products in 95%, 96% yields (3o–3p), respectively. Notably, the 2-benzoxazolimine as substrate also reacted smoothly with azomethine ylides 2a to deliver the corresponding product 3q in high yield (94%). Especially, when using (R)-nonstabilized azomethine ylide as the chiral substrate in the cycloaddition reaction, the reaction could proceed smoothly under the standard conditions to afford the corresponding chiral product 3r in 95% yield as single diastereomer only. The chiral center was determined by NOESY analysis (see ESI^†). Nevertheless, as for the R² group, when it was changed from an aryl group to an alkyl group, the reaction did not take place (3s). The possible reason may be due to the low activity of alkyl substituted substrate.Substrate scopes for the formation of 1,3,5-trisubstituted imidazolidine derivatives 3^a

N-Heterocyclic carbene (NHC)-catalyzed oxidation of unactivated aldimines to amides via imine umpolung under aerobic conditions

Herein, we disclose an NHC-catalyzed aerobic oxidation of unactivated aldimines for the synthesis of amides via umpolung of imines proceeding through an aza-Breslow intermediate. We have developed an eco-friendly method for the conversion of imines to amides by using molecular oxygen in air as the sole oxidant and dimethyl carbonate (DMC) as a green solvent under mild reaction conditions. Broad substrate scope, high yields and gram scale syntheses expand the practicality of the developed method.

A general NHC-catalyzed conversion of imines to amides proceeding through umpolung–oxidation under aerobic conditions in green solvent is reported.

NHCs have emerged as an important class of organocatalysts for unconventional organic transformations due to their unique property of umpolung i.e. essentially reversing the polarity of electrophilic carbon centers. NHC-catalyzed umpolung reactivity has been extensively exploited over the past two decades for the construction of carbon–carbon and carbon–heteroatom bonds.¹ NHC-catalytic transformations proceeding through umpolung reactivity, via Breslow intermediate, have been well established using aldehydes.^1,2 Despite imines being considered to be potentially important building blocks, the obvious use of imines as reactants for the same is still an under developed area, probably due their lower reactivity. The umpolung of imine came into existence after the isolation of a nitrogen containing Breslow intermediate (known as aza-Breslow intermediate) by the Douthwaite and Rovis groups from the reaction of stoichiometric amounts of NHC and imine or iminium salt, respectively.³ For the first time, our group⁴ and the Biju group,⁵ independently, reported the NHC-catalyzed imine umpolung transformations. Recently, a few other groups including our group,⁶ the Wei–Fu–Huang,⁷ Biju,⁸ Lupton⁹ and Tian–Zhang–Chi¹⁰ groups reported NHC-catalyzed imine C–H functionalization or oxidation of imines. In continuation of our ongoing research on NHC-catalyzed umpolung transformations,^4,6,11 herein, we present the development of NHC-catalyzed aerobic oxidation of aldimines to amides, via imine umpolung without using any additive. We became interested to access the amide functionality because amide is a very crucial functional group due its ubiquitous presence in life-processes in the form of peptide bond in protein molecules as well as its appearance in several of the drug molecules.¹² For example, imatinib^13a and ponatinib^13a are used in the chemotherapy treatment of chronic myelogenous leukemia (CML) in cancer disease (Fig. 1). Betrixaban containing two amide functional groups is an oral anticoagulant drug (Fig. 1).^13bOpen in a separate windowFig. 1Selected amide containing therapeutic molecules.The scientific community has been showing great interest to develop new and efficient methods for the construction of amide bond. Coupling of carboxylic acid with amine is one of the most common methods used for the construction of amide molecule.¹⁴ However, this method requires stoichiometric amounts of peptide coupling reagents such as carbodiimides and 1-hydroxy benzotriazoles or activated carboxylic acid derivatives.¹⁵ The Schmidt reaction¹⁶ and Beckmann rearrangement¹⁷ are classical examples for the synthesis of amides. However, there are considerably a few reports available for the oxidation of imine to amide. Palladium-catalyzed oxidation of imines to amides was reported by using excess tert-butyl hydroperoxide (TBHP) as an oxidant.¹⁸ Methods for the oxidation of imines to amides were reported by using peroxy acids in the presence of strong Lewis acid and Brønsted acid, which generate stoichiometric amount of by-products.¹⁹ Cheon and co-workers reported the oxidation of imines to amides by using sodium cyanide (NaCN) in stoichiometric amounts. High toxic nature of NaCN is the limitation of this methodology (Scheme 1a).^20a Recently, Fu and Huang group reported the oxidation of imines, limited to the imines derived from heteroaryl amines, to amides by using NHC catalysis with the assistance of excess lithium chloride as Lewis acid (Scheme 1b).^7a Recently, we reported an NHC-catalyzed tandem aza-Michael oxidation of β-carboline cyclic imines in the presence of external Michael acceptors (Scheme 1c).⁶ Besides the limitations associated with the above transformations, those were performed in non-green solvent media. However, to the best of our knowledge, there are no reports for the conversion of imines to amides under NHC-catalysis without using an external additive/assistance.²¹ On the other hand, the development of new methods to access amide functionality inclusive of green chemistry principles such as organocatalysis, air as the sole oxidant and use of green solvent medium under ambient conditions is highly desirable. Herein, we report an NHC-catalyzed conversion of aldimines to amides, proceeding through imine umpolung–oxidation, in the presence of air in a green solvent such as DMC²² under mild conditions.Open in a separate windowScheme 1Prior work and this work.Initially, we began our investigation with the reaction of aldimine 3a, derived from benzaldehyde 1a and aniline 2a, in the presence of NHC A1 catalyst under open air conditions at room temperature in a green solvent such as DMC. Gratifyingly, we observed the formation of the corresponding amide 4a in 53% yield († for an extensive optimization survey). We conducted an experiment in presence of LiCl (1.2 equiv.), and it did not help to improve the yield of the product.Optimization study

Iodine-catalyzed sulfonylation of sulfonyl hydrazides with tert-amines: a green and efficient protocol for the synthesis of sulfonamides

This study provides a direct, sustainable and eco-friendly method for the synthesis of various sulfonamides via the sulfonylation of sulfonyl hydrazides with tert-amines. The method utilizes sulfonyl hydrazides to oxidize and couple with tertiary amines through selective cleavage of C–N bonds. In this reaction, molecular iodine was used as the catalyst and t-butyl hydroperoxide was used as the oxidant.

Sustainable and eco-friendly method for the synthesis of various sulfonamides.

Sulfonamides commonly serve as synthetic intermediates to produce various drugs and industrial compounds (Scheme 1).¹ They also commonly act as a N-sulfonyl protecting group for easy removal under mild conditions.² There have been many efforts devoted to synthesizing these compounds. Among the methods developed, nucleophilic substitution of an amine with a sulfonyl chloride or sulfonamides with organic halides in the presence of a base is frequently utilized.³ Over the past few years, transition metal catalysis has been proved a powerful tool to synthesize sulfonamides. For example, a cross-coupling reaction of primary sulfonamides with aryl halide or boronic acids,⁴ a Chan-Lam type coupling reaction of sulfonyl azides with boronic acids,⁵ or an oxidative coupling reaction of sulfinate salts with amines were developed.⁶ However, the use of non-stable, hazardous and mutagenic starting materials and toxic high boiling polar solvents in these reactions resulted in a larger amount of toxic waste. Furthermore, the use of stoichiometric amounts of bases or transition metals makes reactions with a slow reactivity and poor functional group tolerability. Therefore, a novel, sustainable, efficient, and eco-friendly method is desired to synthesize sulfonamides.Open in a separate windowScheme 1Examples of important sulfonamide drugs in top 200 pharmaceuticals of 2018.Iodine and its salts have been reported as very efficient catalysts in CDC reactions in which transition metals are used as catalysts.⁷ In recent years, many methods have been reported for synthesis of sulfonamides under metal-free conditions.⁸ As a source of sulfonyl groups, sulfonyl hydrazides are readily accessible solid. They are stable in air and under moisture conditions, and can be easily prepared and stored. Most importantly, only water and nitrogen were obtained as by-products during the reactions using sulfonyl hydrazides as starting materials. Iodine catalyzed oxidative coupling of sulfonyl hydrazides with secondary amines have been developed (Scheme 2(a)).⁹Tert-amines can donate an amine group via a C–N cleavage in place of primary or secondary amines. Compared to the high reactivity of primary or secondary amines, tert-amines are less nucleophilic and non-destructive for some amine-sensitive functional groups. Recently, Yuan et al. and Gui''s have developed a new method to sulfonamides using I₂-mediated or catalyzed C–N bond cleavage of tert-amines (Scheme 2(b)).¹⁰ Meanwhile, Sheykhan et al. reported a novel electrochemical oxidative sulfonylation¹¹ of tert-amines (Scheme 2(c)).¹² Moreover, catalytic reactions in the aqueous phase have also been recently developed,¹³ and sulfonylation of sulfonyl hydrazides has caused wide interest recently.¹⁴ In this study, we will report a new method to synthesize sulfonamides using iodine-catalyzed oxidative coupling of sulfonyl hydrazides with tert-amines (Scheme 2(d)). This approach avoids use of metal catalysts and hazardous regents; the materials, sulfonyl hydrazides and tert-amines, are versatile intermediates in commercial.Open in a separate windowScheme 2Methods for the synthesis of sulfonamides.Commercially available sulfonyl hydrazide 1a was selected as a sulfonyl source to synthesize sulfonamides. When 1a was mixed with 1 equiv. of N-ethyl pyrrolidine under various solvents at 80 °C, an 80% yield of the corresponding sulfonamide 3a was obtained after 4 hours in the aqueous phase (Scheme 3).Optimization of the reaction conditions^a

A formal intermolecular [4 + 1] cycloaddition reaction of 3-chlorooxindole and o-quinone methides: a facile synthesis of spirocyclic oxindole scaffolds

Herein, we developed an efficient and straightforward method for the rapid synthesis of spirocyclic oxindole scaffolds via the [4 + 1] cyclization reaction of 3-chlorooxindole with o-quinone methides (o-QMs), which were generated under mild conditions. The products could be obtained in excellent yields with numerous types of 3-chlorooxindole. This methodology features mild reaction conditions, high atom-economy and broad substrate scope.

Herein, we developed an efficient and straightforward method for the rapid synthesis of spirocyclic oxindole scaffolds via the [4 + 1] cyclization reaction of 3-chlorooxindole with o-quinone methides (o-QMs), which were generated under mild conditions.

The structural diversity of spirocyclic oxindole scaffolds is a reason for their frequent occurrence in many relevant natural products and medicinal agents (Fig. 1).¹ In particular, natural spirocyclic-2-oxindole scaffolds have been proven to exhibit a broad range of biological activities and have attracted increasing attention in the synthetic field. For instance, XEN 907 is a novel pentacyclic spirooxindole with excellent activities as sodium channel blockers.² Due to their unique structure and intriguing biological activity, numerous methodologies have been developed for the construction of these privileged frameworks.³ For example, in the past few years, transition-metal catalyzed or organocatalytic [3 + 2] cycloaddition reactions have been developed for the synthesis of spirocyclic oxindole scaffolds.⁴ Despite the emergence of these elegant approaches, exploiting new strategies for the construction of spirocyclic oxindole derivatives is still highly desirable.Open in a separate windowFig. 1Examples of biologically active spirocyclic oxindole scaffolds. Ortho-quinone methides (o-QMs) as highly reactive versatile intermediates have been of great interest to the chemical and biological community.⁵o-QMs react with various classes of reagents by three typical reaction pathways: 1,4-addition of nucleophiles, [4 + 2] cycloaddition with dienophiles and oxa-6π-electrocyclization.⁶ Because most o-QMs are unstable, these reactions generally depend on the reaction conditions used for the generation of o-QMs in situ. Rokita et al. reported that o-silylated phenols when exposed to fluoride could also produce o-QMs under mild reaction conditions.⁷Because of the dual nature (nucleophilic/electrophilic) of the C-3 position, 3-chlorooxindole serves as a highly reactive starting material in the synthesis of spirocyclic oxindole scaffolds. The introduction of a chloro group at the C-3 position of indoles serves as an excellent leaving group in favour of the subsequent cyclization. In addition, this also increases the acidity of the C–H bond for directly entering the C-3 quaternary centers.⁸ Inspired by this reactivity profile, 3-chlorooxindoles have been successfully utilized for [2 + 1]⁹ and [4 + 1]¹⁰ cyclization to synthesize spirocyclic oxindole scaffolds (Fig. 2).Open in a separate windowFig. 2Representation of the synthesis and applications of 3-chlorooxindoles.We designed an efficient and straightforward method for the rapid synthesis of spirocyclic oxindoles via the [4 + 1] cyclization reaction of 3-chlorooxindole with o-QMs, which were generated under mild conditions. In this study, using TBAF as the fluoride source and base ensures that the one-pot domino reaction will occur in mild reaction conditions, with high atom-economy and broad substrate scope.Initially, we carried out optimization studies by examining the reaction between O-silylated phenol 2a and 3-chlorooxindole 1a. Indeed, when TBAF was employed as the fluoride source, a smooth [4 + 1] cyclization reaction occurred, affording the spirocyclic oxindole product 3a with 75% yield (entry 1, EntryF⁻ source X Y SolventTemp (°C)Yield^b1TBAF^c1.24.0DCMrt75%2TBAF1.54.0DCMrt87%3TBAF2.04.0DCMrt85%4CsF1.54.0DCMrt11%5TBAF1.53.0DCMrt80%6TBAF1.54.0CHCl₃rt83%7TBAF1.54.0THFrt94%8TBAF1.54.0Toluenert90%9TBAF1.54.0DMFrt72%10TBAF1.54.0MeCNrt84%11TBAF1.54.0MeOHrtNDOpen in a separate window^aReaction conditions: 1a (0.3 mmol), solvent (3.0 mL), 6 h.^bIsolated yield.^cTBAF (1 M in THF solution).With the optimal conditions known, we next investigated the substrate scope of substituted 3-chlorooxindole 1 using O-silylated phenol 2a as a representative ( Open in a separate window^aReaction conditions: 1 (0.3 mmol), 2a (1.5 eq.), TBAF (4.0 eq.), THF (3.0 mL), 6 h.^bIsolated yields.Next, we also explored the substrate scope of substituted 3-chlorooxindole 1 using O-silylated phenols 2a′ ( Open in a separate window^aReaction conditions: 1 (0.3 mmol), 2a′ (1.5 eq.), TBAF (4.0 eq.), THF (3.0 mL), 6 h.^bIsolated yields.On the basis of above-mentioned results, a plausible mechanism for this formal [4 + 1] cycloaddition reaction is depicted in Scheme 1. Initially, the highly reactive o-QMs are generated via the desilylation/elimination reaction. Then, 3-chlorooxindole 1a as a nucleophile attacks the external carbon of o-QMs, affording zwitterion Int-1. Finally, the zwitterion Int-1 loses one molecular HCl through a nucleophilic attack, yielding the spirocyclic oxindole product 3a.Open in a separate windowScheme 1Possible mechanism.     

Highly stereoselective spirocyclopropanation of various diazooxindoles with olefins catalyzed using Ru(ii)-complex

Optically active spirocyclopropyloxindole derivatives were efficiently synthesized from diazooxindoles and olefins in the presence of a Ru(ii)-Pheox catalyst. Among a series of Ru(ii)-Pheox catalysts, Ru(ii)-Pheox 6e was determined to be the best catalyst for spirocyclopropanation reactions of diazooxindoles with various olefins in high yields (up to 98%) with high diastereoselectivities (up to trans:cis = >99:1<) and enantioselectivities (up to 99% ee). Furthermore, as the first catalytic asymmetric synthesis, anti-HIV active candidate 4a and a bioactive compound of AMPK modulator 4c were easily synthesized from the corresponding diazooxindoles 1i and 1b, respectively, in high yields with high enantioselectivities (4a: 82% yield, 95% ee, 4b: 99% yield, 93% ee).

Optically active spirocyclopropyloxindole derivatives were efficiently synthesized from diazooxindoles and olefins in the presence of a Ru(ii)-Pheox catalyst.

The discovery of a new class of optically active cyclopropyl oxindoles, as shown below (Fig. 1), has stimulated intensive research interest in the development of biologically active new organic molecules in both academia and industry.^1,2 These compounds were observed to be pharmacologically important substrates with potentially interesting biological activities—e.g., potent HIV inhibitors,³ and anti-cancer⁴ and inotrope agents.⁵ Furthermore, chiral spirocyclopropyl oxindoles are useful key intermediates for the ring-expansion reaction of spirocyclopropane rings via a concerted mechanism in the presence of a Lewis acid catalyst.⁶ As for the synthetic methodology, the transition-metal-catalyzed asymmetric cyclopropanation of diazooxindoles with olefins has been reported, which is one of the most direct and efficient pathways for the synthesis of chiral spirocyclopropyl oxindoles. After the first report by Arai⁷ and Zhou⁸ independently with Rh and Hg catalysts, Ding and co-workers reported the asymmetric cyclopropanation of diazooxindoles with alkenes using a C₂-symmetric spiroketal bisphosphine/Au(i) complex with good enantioselectivity.⁹ More recently, Xu and co-workers reported efficient dirhodium catalysts, which exhibited good to excellent enantioselectivity control with alkyl alkenes.¹⁰ Although effective catalysts and catalytic systems have been reported for the asymmetric cyclopropanation of diazooxindoles with olefins, the development of effective and powerful methodologies to prepare the unique structural motif of a spirocyclopropyloxindole remains an active research area.Open in a separate windowFig. 1Bioactive spirocyclopropyl oxindoles.We reported a series of Ru(ii) phenyloxazoline catalysts (Ru(ii)-Pheox) in 2010, which effectively promoted the asymmetric intra- and intermolecular carbene transfer reactions to olefins, C–H, N–H, and Si–H bonds in high yields with high enantioselectivities.¹¹ Based on this study, we employed Ru(ii)-Pheox catalyst to synthesize a spirocyclopropanated oxindole from 5-bromo-3-methylene-indolin-2-one and diazoacetate.¹² However, in this study, the reactivities and stereoselectivities were reported with moderate, or even high, diastereoselectivities. To improve the yield and enantioselectivity, we initially used Ru(ii)-Pheox for the reaction of a diazooxindole of an olefin (Fig. 2).Open in a separate windowFig. 2Synthetic strategies of optically active spirocyclopropyl oxindole.First, we attempted a catalytic asymmetric cyclopropanation of diazooxindole 1a with styrene 2a catalyzed by authorized complexes such as 4¹³ and 5¹⁴ and a series of Ru(ii)-Pheox catalysts. The results are summarized in ii)-Pheox catalysts was also tested for the spirocyclopropanation reaction. The reaction of diazooxindole 1a proceeded smoothly at room temperature to afford the desired cyclopropane product 3a in high yield with moderate enantioselectivity ( EntryCatalystTime [h]Yield^b [%] trans/cis^cee^d [%]14109069:31−92254 days7581:194836a69595:55046b3 day9597:34656c249395:54966d59195:56176e69194:692Open in a separate window^aReaction condition: catalyst (1 mol%) and styrene 2a (5.0 equiv., 1 mmol) were dissolved in CH₂Cl₂ (2.0 mL), and diazooxindole 1a (0.2 mmol) in CH₂Cl₂ (2 mL) was added.^bIsolated yield.^cDetermined by NMR.^dDetermined by chiral HPLC analysis.To improve the enantioselectivity, the Ru(ii)-Pheox 6a catalyst was modified in terms of electron density on the aromatic ring connecting with Ru(ii) and a chiral environment (6b–e). Catalyst screening of various Ru(ii)-Pheox 6 catalysts is shown in ii)-Pheox 6d having an electron-withdrawing group such as NO₂ (ii)-Pheox 6e15 having an indane-derived chiral environment, was observed to have higher activity and enantioselectivity than the other Ru(ii)-Pheox 6a catalysts, resulting in the corresponding product in high yield (98%) with excellent diastereoselectivity (94:6) and high enantioselectivity (92% ee) (ii)-Pheox 6e. The effect of temperature on the reaction was also investigated ( EntrySolvent T [°C]Time [h]Yield^b [%] trans/cis^cee^d [%]1THFrt77796:4942CH₂Cl₂rt69194:6923Acetonert68794:6914CH₃CNrt425377:23765^eToluene : CH₂Cl₂rt69791:9956Toluenert249597:3947Toluene0249494:6968Toluene−10249298:2929Toluene−20249292:891Open in a separate window^aReaction condition: catalyst (1 mol%) and styrene 2a (5.0 equiv., 1 mmol) were dissolved in CH₂Cl₂ (2.0 mL), and diazooxindole 1a (0.2 mmol) in CH₂Cl₂ (2 mL) was added.^bIsolated yield.^cDetermined by NMR.^dDetermined by chiral HPLC analysis.^eToluene : CH₂Cl₂ = 1 : 1.Subsequently, we briefly examined the effect of N-substituted group under these optimized conditions. The result is summarized in EntryR¹ProductYield^b [%] trans/cis^cee^d [%]1^eH3b9893:7922Et3c9497:3973iPr3d8696:4954Bn3e97>99:1<98Open in a separate window^aReaction condition: catalyst (1 mol%) and styrene 2 (5.0 equiv., 1 mmol) were dissolved in CH₂Cl₂ (2.0 mL), and diazooxindole 1 (0.2 mmol) in CH₂Cl₂ (2 mL) was added.^bIsolated yield.^cDetermined by NMR.^dDetermined by chiral HPLC analysis.^eCH₂Cl₂ was used as the solvent.We subsequently explored the scope and generality of the catalytic system (ii)-Pheox 6e. Most of the vinyl arenes provided the corresponding spirocyclopropanation products in high yields (up to 98% yields) with high diastereoselectivities and enantioselectivities 93–99% ee ( EntryR¹R²R³ProductYield^b [%] trans/cis^cee^d [%]1PhHH3a9494:6962 o-MeC₆H₄HH3f9292:8953 m-MeC₆H₄HH3g80>99:1<994 p-MeC₆H₄HH3h96>99:1<965 p-tBuC₆H₄HH3i97>99:1<956^eNpHH3j83>99:1<967^fPhMeH3k9398:2978^e p-NO₂C₆H₄HH3l8596:4949 p-BrC₆H₄HH3m9896:49410 p-ClC₆H₄HH3n9896:49311 p-OMeC₆H₄HH3o79>99:1<9712 p-NMe₂C₆H₄HH3p74>99:1<2413PhH5-Br3q9389:118714PhH6-Cl3r9896:49915^ePhH6-OMe3s9398:295Open in a separate window^aReaction condition: catalyst (1 mol%) and styrene 2 (5.0 equiv., 1 mmol) were dissolved in CH₂Cl₂ (2.0 mL), and diazooxindole 1 (0.2 mmol) in CH₂Cl₂ (2 mL) was added.^bIsolated yield.^cDetermined by NMR.^dDetermined by chiral HPLC analysis.^eToluene : CH₂Cl₂ was used as the solvent.^fSlow addition for 4 h, and stirring for 20 h.Furthermore, various oxindoles examined under similar conditions resulted in high yields and stereoselectivities, except 5-Br group ( EntryR¹ProductYield^b [%] trans/cis^cee^d [%]1^e,f 3t8498:2902^e,f 3u85>99:1<923 3v9292:8784^e,f,g 3w3786:1493Open in a separate window^aReaction condition: catalyst (1 mol%) and styrene 2 (5.0 equiv., 1 mmol) were dissolved in CH₂Cl₂ (2.0 mL), and diazooxindole 1 (0.2 mmol) in CH₂Cl₂ (2 mL) was added.^bIsolated yield.^cDetermined by NMR.^dDetermined by chiral HPLC analysis.^eToluene : CH₂Cl₂ was used as the solvent.^fSlow addition for 4 h, and stirring for 20 h.^g98% conversion.When the substrate has low solubility in toluene, a mixed solvent system such as CH₂Cl₂ : toluene = 1 : 1 is efficient to improve the reactivity without decreasing the stereoselectivity (ii)-Pheox catalyst (Table S1, Fig. 3 and S1–S3^†).^17–19 The computational chemical analysis shows the Ru-oxindole carbene complex, which suggests that π–π interaction between oxindole and the indane aromatic ring controls the chiral environment to induce high enantioselectivity. Thus, an olefin may approach from only one side to provide high stereoselectivity as shown in Fig. 3. The absolute stereochemistry was determined using X-ray analysis (Scheme 1).Open in a separate windowFig. 3Plausible transition state of spirocyclopropanation.Open in a separate windowScheme 1Synthesis of bioactive compounds.To demonstrate the utility of our direct enantioselective cyclopropyloxindole synthesis, we demonstrated the first catalytic asymmetric synthesis of bioactive compounds such as anti-HIV activity candidate 4a and AMPK modulator 4c from diazooxindoles 1i and 1b, respectively. Both spirocyclopropanations proceeded smoothly, resulting in high yield with high enantioselectivity (4a: 82% yield, 95% ee, 4b: 99% yield, 93% ee as it is methyl ester).^2e,16In summary, the catalytic asymmetric cyclopropanation reaction of diazooxindoles and olefins by a series of Ru(ii)-Pheox catalysts is very effective for the synthesis of optically active spirocyclopropyloxindole derivatives. The stereoselectivity is good to excellent in most cases and optically active spirocyclopropyloxindole derivatives can be synthesized under a mild reaction condition in a short step. Furthermore, this strategy could be applied for the first synthesis of optically active bioactive compounds such as anti-HIV candidates and an AMPK modulator.     

Enantioselective amination of 4-alkylisoquinoline-1,3(2H,4H)-dione derivatives

A mild and efficient enantioselective amination of 4-alkylisoquinoline-1,3(2H,4H)-dione derivatives was established, which is compatible with a broad range of substrates and delivers the final products in excellent yields (up to 99%) and ee values (up to 99%) with low catalyst loading (down to 1 mol%). The synthetic potential of this methodology was also demonstrated in the gram scale level.

A mild and efficient enantioselective amination of 4-alkylisoquinoline-1,3(2H,4H)-dione derivatives was established and a broad range of amination products were prepared in excellent yields and ee values with low catalyst loading.

Isoquinolinedione, bearing the carbon skeleton of tetrahydroisoquinoline (THIQ), is an important structural motif present in bioactive compounds and natural products with a broad array of biological properties.¹ However, the construction of isoquinolinedione, particularly the chiral version, is currently underdeveloped,² and the reported methods heavily rely on the radical-initiated addition–cyclization of activated alkenes to prepare this structural motif that hard to be further diversified.³ From a pharmaceutical point of view, the presence of heteroatoms (such as nitrogen) is essential for their biological activity (Fig. 1).⁴ Therefore, the introduction of other functional groups or heteroatoms into this framework is a pressing issue to be addressed.Open in a separate windowFig. 1Bioactive compounds bearing isoquinolinedione or tetrahydroisoquinoline core structure.On a different note, amine attached to a stereogenic center is a ubiquitous structure in natural products and bioactive compounds and becomes impetus for continuous exploration.⁵ Using azodicarboxylates or nitrosoarenes as electrophilic amine sources,⁶ activated substrates such as 1,3-dicarbonyl compounds and pyrazolones could be readily transformed into the corresponding amination products in high ee and yields.⁷ With the pioneering work of List and Jørgensen, the α-amination of aldehydes could be realized through enamine activation.⁸ The α-amination of less activated substrates such as nitroisoxazole derivatives could be realized via phase-transfer catalysis.⁹ Recently, cyclic ketones or vinyl ketones were transformed into the corresponding amination products via organo- or metal catalysis.¹⁰ Surprisingly, reports on the amination of heterocyclic compounds are very limited, and they majorly focus on the oxindole scaffold.¹¹ Therefore, the construction of other pharmaceutical relevant α-amination heterocyclic compounds would be a meaningful work.¹² In addition, the organo-catalyzed asymmetric amination reactions generally require relatively high catalyst loading to achieve the optimal yields and enantioselectivities; for this reason, the development of an efficient amination protocol would still be highly desirable.Recently, our group reported the amination of 4-arylisoquinolinedione via organo-catalysis.¹³ However, due to the attenuated reactivity at low temperatures, high catalyst loading is required for satisfactory yields and enantioselectivities, and the substrate scope is limited to 4-aryl substituents. To further expand the scope of this reaction, we tried to extend this amination methodology to 4-alkylisoquinolinedione derivatives.Our study commenced with 2-benzyl-4-butylisoquinoline-1,3(2H,4H)-dione 4a and di-tert-butyl azodicarboxylate 5 as model substrates for condition optimization ( Entry^a7 (mol%)SolventYield 6a^b (%)ee^c (%)1^d10CHCl₃5098210CHCl₃7197310Toluene8274410Ether9580510THF9921610DCM9990710Chlorobenzene8594810CH₂ClCH₂Cl999895CH₂ClCH₂Cl979710^e2CH₂ClCH₂Cl999711^f,g1CH₂ClCH₂Cl839512^f,g1CH₂ClCH₂Cl8893Open in a separate window^aAll reaction was conducted with 0.2 mmol compound 4a, 0.44 mmol compound 5, in 0.5 mL solvent and reacted at 25 °C for 24 h.^bIsolated yield.^cThe ee was determined by HPLC analysis.^dReaction was conducted at 5 °C and reacted for 24 h.^eReaction was run for 35 h.^fReaction was reacted for 72 h.^gReaction was conducted at 40 °C.Further solvent optimization reveals that DCM gives the best yield along with very good ee (14Substrate scope for the amination reaction

Highly efficient construction of an oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton and ring-opening of the bridged ring via C–O bond cleavage

We report herein a highly efficient strategy for construction of a bridged oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton through [3 + 2] IMCC (intramolecular [3 + 2] cross-cycloaddition), and the substituents and/or stereochemistries on C-4, C-6, C-7 and C-10 fully match those in the rhamnofolane, tigliane and daphnane diterpenoids. Furthermore, ring-opening of the bridged oxa-[3.2.1]octane via C–O bond cleavage was also successfully achieved.

We reported a highly efficient construction of an oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton with a full match of the substituents and stereochemistries on C-4/-6/-7/-10 with those in the rhamnofolane/tigliane/daphnane diterpenoids.

Rhamnofolane, tigliane, and daphnane are three families of diterpenoids displaying a broad range of biological activities such as antiviral, anticancer, anti-HIV, immunomodulatory and neurotrophic activities.¹ Three representative members are neoglabrescin A² and curcusones I/J.³ The unique structural features of these three compounds include a 5–7–6 tricyclic carbon skeleton with a trans-fused 5–7 bicyclic skeleton, a 4,7-bridged oxa-[3.2.1]octane skeleton and a methylene (methyl) group at C-6 (Fig. 1). Some other related natural products include crotophorbolone,⁴ phorbol,⁵ prostratin,⁶ resiniferatoxin⁷ and curcusone A.⁸Open in a separate windowFig. 1Representative rhamnofolane/tigliane/daphnane diterpenes with a trans-fused 5–7 bicyclic skeleton, a 4,7-bridged oxa-[3.2.1]octane skeleton (corresponding structures with a ring-opening of the oxa-[3.2.1]octane via C–O cleavage) and a methylene (methyl) group at C-6.Due to their remarkable biological activities and unique and complex structures, these types of diterpenoids have drawn considerable attention from organic chemists, and many creative strategies have been developed for construction of the 5–7–6 tricycles with desirable substituents and stereochemistries on C-4, C-6, C-7 and C-10.⁹ Dai et al. reported the total syntheses of curcusones I and J by using an intramolecular Au-catalysed [4 + 3] cycloaddition for construction of the oxa-[3.2.1]octane-embedded 5–7-fused carbon skeleton and Diels–Alder [4 + 2] cycloaddition for construction of the additional 6-membered carbocycle (Scheme 1).^10a Some other natural products have been reported by the groups of Wender (phorbol, resiniferatoxin and prostratin),¹¹ Cha (phorbol),¹² Baran (phorbol),¹³ Xu/Li (prostratin),¹⁴ Liu (crotophorbolone),¹⁵ Inoue (crotophorbolone, resiniferatoxin, prostratin and related molecules)¹⁶ and Dai/Adibekian (curcusones A–D).^10b The groups of West^9c and Maimone^9h have reported attempts toward the total syntheses of related molecules through construction of a 4,7-bridged oxa-[3.2.1]octane skeleton respectively (Scheme 2).Open in a separate windowScheme 1Representative total syntheses of rhamnofolane/tigliane/daphnane diterpenes containing a 5–7–6 tricyclic carbon skeleton with a trans-fused 5–7 bicyclic skeleton and a 4,7-bridged oxa-[3.2.1]octane skeleton.Open in a separate windowScheme 2Representative synthetic strategies for construction of a bridged oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton with desirable substituents and stereochemistries.We have previously reported a highly efficient construction of 5–7–6 tricyclic carbon skeleton with an intramolecular [4 + 3] IMPC (intramolecular [4 + 3] parallel-cycloaddition) of cyclopropane with dendralene/Diels–Alder [4 + 2] cycloaddition strategy.¹⁷ With this strategy, the fused 5–7 bicycle was efficiently constructed which matched the trans-stereochemisty, however a C-4 oxygen atom was not be direct. Following our previously developed [3 + 2] IMCC strategy,^18a–h we have recently reported a novel and efficient construction of a bridged aza-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton with desirable substituents and stereochemistries toward total syntheses of calyciphylline D-type Daphniphyllum alkaloids (Scheme 3).¹⁸ⁱ Herein, we report the application of the [3 + 2] IMCC strategy for efficient construction of the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle with stereochemistries on C-4, C-7 and C-10, as well as a methylene (methyl) group at C-6 matching those in neoglabrescin A, curcusones I/J and related rhamnofolane/tigliane/daphnane diterpenes.Open in a separate windowScheme 3Proposed [3 + 2] IMCC strategy for construction of the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle with suitable substituents and stereochemistries on C-4, C-6, C-7 and C-10.We started the research from benzyl bromide 2 which was prepared from a known compound 1 according to our recently reported method (Scheme 4).¹⁸ⁱ Compound 2 was then oxidized with NMO to afford aldehyde 3 which was used directly in the next step without further purification. Under catalysis of Sc(OTf)₃ (0.2 equiv.), the [3 + 2] IMCC of aldehyde 3 was successfully carried out to afford compound 4 in 82% yield over two steps. The structure of 4 was confirmed by X-ray crystal structure analysis.¹⁹ Hereto, the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle have been successfully constructed, the substituents and stereochemistries on C-4, C-6, C-7 and C-10 fully match those in the corresponding natural products.Open in a separate windowScheme 4Construction of the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle.With compound 4 in hand, we started to investigate the ring-opening of the bridged oxa-[3.2.1]octane via C–O bond cleavage (Scheme 5). Krapcho decarboxylation of 4 afforded monoester 5 in 88% yield as a mixture of two diastereoisomers in a ratio of nearly 1 : 1. Reduction of 5 with DIBAL-H at −78 °C afforded aldehyde 6 in 85% yield. To our delight, the oxa-bridge was opened under catalysis of TMSOTf²⁰ at −5 °C and a dehydration product 7 was obtained in 16% yield (brsm 53%) (21 conditions (Open in a separate windowScheme 5Ring-opening of the oxa-[3.2.1]octane via C–O bond cleavage.Ring-opening of the compound 6

Enantioselective bromination of axially chiral cyanoarenes in the presence of bifunctional organocatalysts

Enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts is reported. Sequential addition of a brominating reagent in several portions at an optimized temperature was effective in accomplishing high enantioselectivities.

Enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts is reported.

Axially chiral biaryls are privileged structures in pharmaceuticals,¹ asymmetric catalysts,² functional materials,³etc. Thus, the development of efficient methods for their synthesis is desirable to advance research in these scientific fields. Among recent accomplishments on catalytic atroposelective transformations⁴ toward the synthesis of densely substituted axially chiral biaryls, powerful strategies include organocatalytic dynamic kinetic resolution involving ortho-functionalization of existing biaryls via the introduction of additional rotational barriers.⁵ In this method, substrates should in principle have rotational barriers low enough to enable fast rotation about the biaryl axis, leading to their rapid racemization. Therefore, it is difficult to employ biaryl substrates bearing intrinsic rotational barriers, which impede their racemization. In 2015, the Miller group reported an elegant example of this type of dynamic kinetic resolution via bromination of 3-arylquinazolin-4(3H)-ones, the rotational barrier of which is ∼19 kcal mol⁻¹, by slow addition of a brominating agent.^5e Here, we present enantioselective bromination of axially chiral cyanoarenes bearing intrinsic rotational barriers exceeding 18 kcal mol⁻¹ (Scheme 1). To the best of our knowledge, there has been no report of a catalytic asymmetric reaction affording axially chiral cyanoarenes,⁶ despite their prevalence in bioactive agents⁷ and the rich chemistry of cyano compounds as synthetic intermediates.⁸Open in a separate windowScheme 1Enantioselective bromination of axially chiral cyanoarenes using bifunctional organocatalysts. 9 Other catalysts 3d and 3e, bearing a cyclohexanediamine framework, and 3f, bearing a binaphthyl framework, resulted in poor enantioselectivities (10 Using 3a and 3c, lower reaction temperatures were investigated (Fig. 1) were also investigated; NBA (4a) still afforded the best enantioselectivities ( EntryCatalystBrominating reagentSolventTemp. (°C)Yield^b (%)ee (%)13aNBA (4a)CH₂Cl₂25812623bNBA (4a)CH₂Cl₂2587633cNBA (4a)CH₂Cl₂25891843dNBA (4a)CH₂Cl₂2583653eNBA (4a)CH₂Cl₂2585363fNBA (4a)CH₂Cl₂2579373aNBA (4a)CH₂Cl₂−40822083aNBA (4a)CH₂Cl₂−60<1—93cNBA (4a)CH₂Cl₂−408341103cNBA (4a)CH₂Cl₂−60<1—113cNBA (4a)CHCl₃−402154123cNBA (4a)Toluene−4018−10133cNBA (4a)THF−4013−2143cNBA (4a)Et₂O−4046−20153cNBA (4a)EtOAc−4068−4163cNBA (4a)EtOH−40<5—173cDBH (4b)CH₂Cl₂−40791183cNBS (4c)CH₂Cl₂−408220193cNBP (4d)CH₂Cl₂−4079−520^c,d3cNBA (4a)CH₂Cl₂−40854921^c,e3cNBA (4a)CH₂Cl₂−40515922^c,f3cNBA (4a)CH₂Cl₂−40336623^c,g3cNBA (4a)CH₂Cl₂−401771 Open in a separate window^aReactions were run using 1a (0.10 mmol), the brominating reagent (0.30 mmol), and the catalyst (0.010 mmol) in the solvent (10 mL).^bIsolated yields.^cReactions were run using 3c (0.0050 mmol).^dReaction was run for 48 h.^eReaction was run for 24 h.^fReaction was run for 12 h.^gReaction was run for 6 h.Open in a separate windowFig. 1Brominating reagents.Subsequently, to improve the efficiency of dynamic kinetic resolution by retarding the enantiodetermining bromination,^5e4a was added sequentially in five portions (Fig. 2).¹¹ Although the procedure hardly affected the results at −40 °C, the enantioselectivity was greatly improved for reactions carried out at −20 °C and −30 °C. Such effects were smaller at temperatures above −10 °C.Open in a separate windowFig. 2Investigations of temperatures and procedures. Blue bar: reactions were run with 4a added in 1 portion. Red bar: reactions were run with 4a added in 5 portions. Green values represent yields of 2a isolated after silica gel column chromatography. At 0, −10, −20, and −30 °C, reactions were run for 24 h; at −40 °C, reactions were run for 72 h.Next, at −30 °C and −40 °C, respectively, the relationships between enantioselectivity and yield were investigated (Fig. 3). Reactions were carried out using various amounts of 4a. At both temperatures, the enantioselectivity decreased as the yield increased; however, the quantitative reactions also exhibited some enantioselectivity (−30 °C: 99% yield, 50% ee; −40 °C: 99% yield, 47% ee), implying the presence of the characteristics of dynamic kinetic resolution. In addition, although the enantioselectivity was better at −40 °C than −30 °C when the yield was low, the relationship became reversed as the yield increased; hence, the efficiency of dynamic kinetic resolution was revealed to be better at −30 °C than at −40 °C. Furthermore, when 1.5 equiv. of 4a were used at −30 °C affording 2a in 22% yield with 65% ee, the ortho-monobrominated product 1a-Br (Fig. 4) was also obtained with 75% ee (see Scheme S1 in the ESI^† for details). It shows that the bromination at one of the ortho-positions introduces a rotational barrier high enough to set the chiral axis, which is consistent with the rotational barriers calculated at the M06-2X/6-311++G(2d,3p)//B3LYP/6-31+G(d,p) level of theory (Fig. 4).Open in a separate windowFig. 3Relationships between ee and yield. Red line: reactions were run at −30 °C for 24 h with 4a added in 5 portions. Blue line: reactions were run at −40 °C for 72 h with 4a added in 5 portions. Red and blue values represent amounts of 4a used for each reaction.Open in a separate windowFig. 4Rotational barriers of substrate, intermediate, and product calculated at the M06-2X/6-311++G(2d,3p)//B3LYP/6-31+G(d,p) level of theory.Under the conditions of using 3c as the catalyst at −30 °C with 3 equiv. of 4a added sequentially in five portions, other substrates bearing substituted phenols were also investigated (Scheme 2).¹² First, substrates 1b–1e bearing a substituent at the meta-position were investigated. While the electron-deficient substrate 1b resulted in poor enantioselectivity, 1c and 1d bearing aliphatic substituents gave improved enantioselectivities; however, substrate 1e with a methoxy group resulted in low enantioselectivity. In addition, substrates 1f–1i bearing substituents at the para-positions of the biaryl axis were then examined; phenol 2h bearing a methyl group resulted in higher enantioselectivities than phenols 2f and 2g bearing electron-withdrawing groups and 2i bearing a methoxy group. These results suggest that aliphatic substituents might efficiently facilitate the racemization of 1 during bromination, leading to dynamic kinetic resolution with greater enantioselectivity. Utilizing this methodology with the characteristics of dynamic kinetic resolution, the reactions of 1c and 1g were also carried out using a sub-stoichiometric amount of 4a (Scheme 3); higher enantioselectivities were accomplished albeit with lower yields.¹³ The absolute configuration of 2c was determined by X-ray crystallography (see the ESI^† for details), and the configurations of all other products were assigned analogously.Open in a separate windowScheme 2Reactions of substrates with substituted phenols. ^aReaction was run for 72 h.Open in a separate windowScheme 3Reactions with a substoichiometric amount of 4a.In summary, we present enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts. The sequential addition of 4a in several portions at the optimized temperature was effective in improving the enantioselectivity. Although the enantioselectivities are still moderate using the current catalytic system, the guidelines for designing catalytic asymmetric syntheses of axially chiral cyanoarenes were established. Further studies on the additional optimization and application of this methodology to the construction of densely substituted axially chiral biaryls are currently underway.     

Brønsted acid-promoted thiazole synthesis under metal-free conditions using sulfur powder as the sulfur source

A Brønsted acid-promoted sulfuration/annulation reaction for the one-pot synthesis of bis-substituted thiazoles from benzylamines, acetophenones, and sulfur powder has been developed. One C–N bond and multi C–S bonds were selectively formed in one pot. The choice of the Brønsted acid was the key to the high efficiency of this transformation under metal-free conditions.

A Brønsted acid-promoted protocol for the synthesis of 2,4-disubstituted thiazoles from benzylamines, acetophenones, and sulfur powder under metal-free conditions is described.

At least 50% of the biologically active compounds have a heterocyclic skeleton.¹ Among these, the thiazole ring is an important five-membered aromatic heterocycle with nitrogen and sulfur atoms, and the unique structure has led to many applications in different pharmaceuticals and biological processes.² For example (Fig. 1), antimicrobial (Abafungin),³ antihypertension (Arotinolol),⁴ anti-inflammatory (Meloxicam),⁵ and immunomodulatory (Fanetizole)⁶ drugs are prevalent among the drugs based on thiazole that have reached the marketplace.⁷Open in a separate windowFig. 1Selected commercial drugs based on thiazole.In view of this, great efforts have been invested in the development of novel synthetic protocols to facilitate the construction of thiazole derivatives. The typical procedure for the synthesis of thiazoles involves the reaction of α-haloketones with thioureas/thioamides using catalysts such as cyclodextrin,⁸ iodine,⁹ silica chloride,¹⁰ baker''s yeast,¹¹ and others¹² (Scheme 1a). Besides, Wu¹³ and co-workers developed a catalyst-free protocol for the construction of polysubstituted thiazoles from α-haloketones and thioureas/thioamides. Togo¹⁴ reported the efficient synthesis of thiazoles via a base-promoted 1H-1-(1′-alkynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-dioxide reaction with thioamides. Recently, Kshirsagar¹⁵ and co-workers developed NIS-mediated intermolecular cyclization of styrenes and thioamides using water as the solvent. On the other hand, the transition metal-catalyzed direct coupling of pre-existing thiazole compounds provides an alternative approach (Scheme 1b).¹⁶ Very recently, Jiao¹⁷ and co-workers developed a novel Cu-catalyzed aerobic oxidative approach to obtain thiazoles using elemental sulfur as the sulfur source via a multiple Csp³–H bond cleavage strategy (Scheme 1c). In spite of synthetic efficiency, these methods suffer from limitations with respect to special substrates and transition-metal catalysts. Therefore, the development of efficient methods for the synthesis of thiazoles from simple and readily available substrates under metal-free conditions is highly desirable. It is well-known that the sulfur element is cheap, stable, and easy to handle and thus, it is an ideal sulfur source for C–S bond construction.¹⁸ In our continuing efforts on using elemental sulfur for the synthesis of sulfur-containing heterocycles under simple conditions,¹⁹ we describe a three-component strategy for thiazole formation from readily available acetophenones, benzylamines, and sulfur powder under metal-free conditions (Scheme 1d).Open in a separate windowScheme 1Synthesis of 2,4-disubstituted thiazoles.We commenced our investigation using acetophenone (1a), benzylamine (2a), and sulfur powder as the model system ( EntryAcidSolventYield^b (%)1Formic acidDMSO242HOAcDMSO333TFADMSOn.d.4TsOHDMSOn.d.5MsOHDMSOn.d.6PivOHDMSO457Benzoic acidDMSO288Nicotinic acidDMSO549Isonicotinic acidDMSO6610Isonicotinic acidDMFn.d.11Isonicotinic acidDMAcn.d.12Isonicotinic acidNMPn.d.13Isonicotinic acidToluenen.d.14Isonicotinic acidPhCln.d.15Isonicotinic acid1,4-DioxaneTrace16^cIsonicotinic acidDMSO5817^dIsonicotinic acidDMSO4718^eIsonicotinic acidDMSO6219^fIsonicotinic acidDMSO3420DMSO13Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), acid (0.2 mmol), S (0.4 mmol), solvent (0.6 mL), 130 °C, 8 h, under air atmosphere.^bGC yield using dodecane as the internal standard. n.d. means not detected.^cS (0.6 mmol, 3 equiv.).^d120 °C.^eUnder an argon atmosphere.^fUnder an oxygen atmosphere.Under the optimized reaction conditions, the generality of the sulfuration/annulation reaction cascade to the synthesized thiazoles was investigated ( Open in a separate window^aReaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), S (0.4 mmol), isonicotinic acid (0.2 mmol), DMSO (0.6 mL), 130 °C, 8 h, under an air atmosphere, isolated yield based on 1.^bYield of 10 mmol scale reaction.Subsequently, various substituted benzylamines were examined under the optimized reaction conditions ( Open in a separate window^aReaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), S (0.4 mmol), isonicotinic acid (0.2 mmol), DMSO (0.6 mL), 130 °C, 8 h, under an air atmosphere, isolated yield based on 1a.In order to understand the reaction mechanism, several control experiments were designed under different conditions (Scheme 2). The reaction of acetophenone 1a and benzothioamide 5 only yielded a trace amount of the desired product under the optimal conditions. No reaction occurred in the absence of sulfur powder (Scheme 2a). Similarly, the replacement of benzothioamide with benzamide 6 did not give the thiazole product (Scheme 2b). The treatment of N-(1-phenylethyl)benzothioamide 7, (E)-1-phenyl-N-(1-phenylethylidene)methanamine 8 and (E)-N-benzylidene-1-phenylethanamine 9 under the optimal reaction conditions did not afford the target product (Scheme 2c–e). However, imines 8 and 9 under the optimal conditions without isonicotinic acid provided the target product with 37% and trace amount yields, respectively (Scheme 2d and e).Open in a separate windowScheme 2Control experiments.On the basis of the experimental observations and previous reports,^17,18f,19d a possible reaction mechanism is proposed (Scheme 3). The dehydrative condensation of acetophenone (1a) and benzylamine (2a) should be the initial step, which affords the imine intermediate 8. The tautomerization of the intermediate 8 generates enamine A. Subsequently, the interaction of A and elemental sulfur delivers the poly-sulfur intermediate B through Willgerodt–Kindler type oxidation.²⁰ Further oxidation and deprotonation of B affords the intermediate C. Then, intramolecular attack occurs to release S_n−1 and generate the intermediate D, which finally furnishes the product 3aa by the oxidation process.Open in a separate windowScheme 3Possible reaction mechanism.In summary, we have developed a novel Brønsted acid-promoted protocol for the synthesis of 2,4-disubstituted thiazoles from benzylamines, acetophenones, and sulfur powder under metal-free conditions. The cheap and readily available sulfur powder acted as the sulfur source to selectively assemble the thiazole derivatives. This reaction represents effective access to thiazoles from readily available starting materials with good functional group tolerance. Further studies on the mechanism are ongoing in our laboratory.     

Copper-catalyzed three-component reaction to synthesize polysubstituted imidazo[1,2-a]pyridines

An efficient three-component one-pot and operationally simple cascade of 2-aminopyridines with sulfonyl azides and terminal ynones is reported, providing a variety of polysubstituted imidazo[1,2-a]pyridine derivatives in moderate to excellent yields. In particular, the reaction goes a through CuAAC/ring-cleavage process and forms a highly active intermediate α-acyl-N-sulfonyl ketenimine with base free.

Three-component one-pot synthesis of polysubstituted imidazo[1,2-a]pyridine derivatives through a base free CuAAC/ring-cleavage process.

Polysubstituted imidazo[1,2-a]pyridines are well established as privileged scaffolds which are commonly encountered in many bioactive natural products and biological molecules that may be good drug candidates.¹ Most imidazo[1,2-a]pyridines possess various biological activities, like antibacterial,² antiinflammatory,³ antiviral,⁴ and anticancer.⁵ Some of the imidazo[1,2-a]pyridine derivatives are commercially available drugs, including Saripidem,⁶ Alpidem,⁷ Zolpidem,⁸ Zolimidine,⁹ Miroprofen¹⁰ and drug candidates GSK812397 (Fig. 1).¹¹ Therefore, the development of novel methods for the synthesis of these imidazo[1,2-a]pyridines is important in the field of synthetic organic and pharmaceutical chemistry.Open in a separate windowFig. 1Some imidazo[1,2-a]pyridine drugs or drug candidates.In the past few years, reactions utilizing Cu,¹² Pd,¹³ Mn,¹⁴ TEMPO-mediated,¹⁵ I₂ (ref. 16) and a few other catalysts¹⁷ have provided attractive and valuable routes for the construction of imidazo[1,2-a]pyridines. However, most reactions can only produce monosubstituted imidazo[1,2-a]pyridines or halogenated intermediates (Scheme 1a)¹⁸ which can undergo one more steps of coupling reaction leading to polysubstituted products. Therefore, developing one-pot synthetic reactions will provide a direct and powerful tool to meet these challenges. To the best of our knowledge, imidazo[1,2-a]pyridines can be synthesized from 2-aminopyridines, terminal alkyne and aldehyde in a three-component coupling reaction, catalyzed by copper, in one pot (Scheme 1b).¹⁹ However, aldehydes are unstable and easily oxidized. They are environmentally unfriendly for synthesis or complex procedures. Under this background, the development of multicomponent one-pot synthetic strategies for the preparation of polysubstituted imidazo[1,2-a]pyridines still remains highly desirable.Open in a separate windowScheme 1Synthesis of polysubstituted imidazo[1,2-a]pyridines.Previous studies reported that the copper-catalyzed multicomponent reactions (MCRs) of sulfonyl azides, terminal alkynes and other components (CuAAC/ring-cleavage reaction) has been applied to synthesize numerous oxygen- and nitrogen-containing heterocyclic compounds.²⁰ However, the reaction generally carried out under strong base conditions, and limited the application of some substrates, such as terminal ynones, which will take a self-condensation under the base conditions.²¹ Thus, the neutral or weak acidic conditions have developed by our group and the terminal ynones successfully used in CuAAC/ring-cleavage reaction to form a highly active intermediate α-acyl-N-sulfonyl ketenimines.²² Accordingly, an efficient one-pot and operationally three-component reaction of 2-aminopyridines, sulfonyl azides and terminal ynones is reported (Scheme 1c).Our initial study began with an examination of the synthesis of imidazo[1,2-a]pyridine 4a from 2-aminopyridine (1a), ethyl propiolate (2a) and p-tosyl azide (3a). Initial screenings involved using CuI as catalyst and no additive with a variety of solvents in a range of standard solvents. These results revealed that the desired conversion could be effected in most solvents ( EntryCat.SolventYield^b (%) 4a1CuICHCl₃742CuIDCE773CuIToluene784CuIMeCN805CuITHF626CuI1,4-Dioxane447CuIDMSO268CuIDMF359 CuI EtOH 83 10CuClEtOH7511CuBrEtOH7312CuBr₂EtOH7013Cu(OAc)₂EtOH5014Cu(OTf)₂EtOH3215AgOAcEtOHnd^c16CuIEtOH80^d17CuIEtOH76^eOpen in a separate window^aReaction conditions: 1a (1.0 mmol), cat. (10 mol%) in the solvent (3 mL) was added 2a (1.5 mmol) and 3a (1.5 mmol) stirring at 80 °C for 6 h.^bIsolated yields.^cnd = not detected the target product.^dThe reaction temperature was 70 °C.^eThe temperature was 90 °C.Under the optimized conditions ( Open in a separate window^aUnless otherwise noted, the reaction conditions were as follow: 1 (1.0 mmol), CuI (10 mol%) in the MeCN (3 mL) was added 2 (1.5 mmol), 3 (1.5 mmol) stirring at 80 °C for 6 h.Next, the scope and limitation of the terminal ynone 2 and sulfonyl azide 3 substrates were tested. It is noteworthy that the sulfonyl azide substrates showed slight influences on this reaction. With R³ changed by aromatic or aliphatic substituents, such as –Ph, –(4-ClC₆H₄), –(4-CF₃C₆H₄), –(4-OMeC₆H₄), –Me and –n-Bu, the reaction could smoothly give the anticipated products (4f–4n) in comparable yields. The substrates R² bearing the –OMe, –O^tBu, –Me and other alkyl group also can obtain 4o–4r in good yields.In order to broaden the suitability of substrates, we also investigated other terminal alkynes, such as aryl acetylenes. The experiments revealed that some aryl acetylene such as 3-methyl phenylacetylene can obtain imidazo[1,2-a]pyridine 4u with low yield of 26% and an uncyclized linear product 4v (Scheme 2a). Most aryl acetylenes such as 4-methoxy phenylacetylene only obtain uncyclized products (Scheme 2b). It shows that the reactivity of terminal ynones is higher than that of traditional terminal alkyne.Open in a separate windowScheme 2Investigation the reaction of 2-aminopyridine (1a), aryl acetylenes (2f, 2g) and p-tosyl azide (3a).None of the product imidazo[1,2-a]pyridines 4a–4r have been reported previously, which were subject to full spectroscopic characterization (see ESI^† for details) and the derived data were in complete accord with the assigned structures. And 4a was confirmed by single-crystal X-ray analysis (Fig. 2).Open in a separate windowFig. 2Single-crystal X-ray analysis of 4a (CCDC 2121234).^†A possible reaction pathway for the formation of imidazo[1,2-a]pyridine (4a) from precursors 1a, 2a and 3a is shown in Scheme 3. Thus, in keeping with earlier proposals,^19,21 the substrates 2a and 3a are expected to react, in the presence of the copper(i) catalyst to form the metallated triazole A through the CuAAC procedure. Then, the complex A undergo a ring-cleavage rearrangement leading to a highly active intermediate N-sulfonyl-α-acylketenimine B. This last species B is captured by 1avia nucleophilic addition to generate the intermediate C, which deliver the observed product 4a by intramolecular oxidative coupling similar to literature.²³ Otherwise, due to the poor activity, most of the traditional terminal alkynes involved in the reaction will stop in the intermediate C leading the uncyclized products.Open in a separate windowScheme 3Plausible reaction mechanism.In summary, we have developed an original approach for the synthesis of polysubstituted imidazo[1,2-a]pyridines from a mixture of the corresponding 2-aminopyridines, sulfonyl azides and terminal ynones, through CuAAC/ring-cleavage process and generated a highly active intermediate α-acyl-N-sulfonyl ketenimines. More detailed novel reactions and the investigation of new applications of this intermediate are now being undertaken in our laboratory.     

A sustainable innovation for the tandem synthesis of sugar-containing coumarin derivatives catalyzed by lipozyme TL IM from Thermomyces lanuginosus in continuous-flow microreactors

We developed an efficient and environmentally friendly two-step tandem methodology for the synthesis of sugar-containing coumarin derivatives catalyzed by lipozyme TL IM from Thermomyces lanuginosus in continuous-flow microreactors. Compared to those observed for other methods, the salient features of this work including green reaction conditions, short residence time (50 min), and catalysts are more readily available and the biocatalysis reaction process is efficient and easy to control. This two-step tandem synthesis of coumarin derivatives using the continuous-flow technology is a proof of concept that opens the use of enzymatic microreactors in coumarin derivative biotransformations.

An effective and environmentally friendly two-step tandem protocol for the synthesis of sugar-containing coumarin derivatives catalyzed by lipozyme TL IM in continuous-flow microreactors has been developed.

Coumarins and their derivatives have attracted considerable attention due to their extensive biological activities such as anti-bacterial, antiviral, anticancer, and antioxidant properties.¹ Numerous studies including the separation and purification of naturally occurring coumarins from a variety of plants as well as the chemical synthesis of coumarin compounds with novel structures and properties have been conducted for the research and development of coumarins as potential drugs.² So far, some coumarins, for example, warfarin,³ an anticoagulant that acts as a vitamin K antagonist, have been widely used in the treatment of thrombosis. Armillarisin A and novobiocin are commonly used as antibiotics (Fig. 1).⁴Open in a separate windowFig. 1Drugs containing coumarin structures.As important coumarin derivatives, sugar-containing coumarin compounds have attracted special interest in organic synthesis and medicinal research due to their excellent physicochemical and pharmacokinetic characteristics.⁵ Thorson et al.⁶ reported that the glycosylation of the classical pharmacophore warfarin fundamentally alters the drug''s mechanism of action, leading to a dramatic reduction in the anticoagulant function and a concomitant marked increase in anticancer cytotoxicity. In the past few years, several works on the synthesis of sugar-containing coumarins have been reported. Supuran et al.⁷ synthesized a series of glycosyl coumarin carbonic anhydrase IX and XII inhibitors, which strongly attenuated the growth of primary breast tumors. In 2016, Nilsson et al.⁸ reported a selective galactose-coumarin-derived galectin-3 inhibitor, which displayed efficacy similar to that of a known nonselective galectin-1/galectin-3 inhibitor.The construction of sugar-containing coumarin derivatives can be achieved by basic synthetic approaches, and the most common synthesis strategy is the chemical method,⁹ which always needs several “protection–deprotection” steps. Recently, visible light has been used in the glycosylation reaction; however, most of the protocols for photoinduced glycosylation require transition metal catalysts in combination with expensive additives for the reaction to proceed.¹⁰Enzymes are the most efficient catalysts, offering much more competitive processes compared to chemical catalysts.¹¹ The use of enzymes as catalysts for the preparation of novel compounds has received increasing attention over the past few years. Some enzymes, such as the engineered C-glycosyltransferase MiCGTb-GAGM, were applied for the synthesis of coumarin C-glycosides, and two of them exhibited potent SGLT2 inhibitory activities.¹² Nidetzky synthesized a new sugar-containing coumarin catalyzed by O-glycosyltransferase.¹³ Some other enzymes such as BLAP (alkaline protease from Bacillus licheniformis) have also been used to synthesize coumarin.¹⁴ The reactions catalyzed by enzymes are relatively mild; however, they always require a longer reaction time (24 h or more) to achieve the desired yields, and the enzymes needed for the reaction are difficult to obtain.¹⁵Continuous-flow microreactors coupled with enzymes have become an efficient way to increase the reaction efficiency and improve the yield.¹⁶ Modern synthetic chemistry faces the challenge of providing the society with high-performing, valuable products that are environmentally benign, cost-effective, safe, and atom-efficient. Due to a high surface-to-volume ratio, better heat exchange, and efficient mixing, the continuous-flow microreactor technology (MRT) has become increasingly popular as an alternative to conventional batch chemistry synthesis.¹⁷ In particular, with respect to the 12 principles of green chemistry, MRT can play a major role in improving chemical processes.¹⁸ To explore novel, eco-friendly and highly efficient protocols for sugar-containing coumarins and also as part of our ongoing study on the tandem microreaction technology, herein, we have reported a two-step tandem synthesis process of sugar-containing coumarin derivatives catalysed by lipozyme TL IM from Thermomyces lanuginosus in continuous-flow microreactors. The aim of this paper is to investigate using a two-step tandem continuous-flow microreactor the effect of various reaction parameters on the reaction yield. Furthermore, we hope to quickly build the related compound library through a new synthesis method for future drug screening (Scheme 1).Open in a separate windowScheme 1Synthesis of sugar-containing coumarin derivatives in continuous-flow microreactors.First, in order to determine whether lipozyme TL IM can be used to catalyze coumarin intermediates or sugar-containing coumarin synthesis reactions, we chose salicylaldehyde (1a) and diethyl malonate (2a) to react at 50 °C for 24 h in a shaker reactor (Fig. 2. It was found that the rate of the reaction catalyzed by the mixed catalyst was faster than that of the reaction catalyzed by K₂CO₃, especially in the range of 0–8 h. After 16 h, the product 3a catalyzed by the mixed catalyst reached equilibrium. Although the yield of 3a after catalysis by 25 mg K₂CO₃ peaked after 24 hours, it was not as high as the yield obtained after catalysis by the mixed catalyst.Effect of reaction solvents and catalysts on the synthesis of coumarin under shaker reactors^a

Synthesis of six-membered spirooxindoles via a chiral Brønsted acid-catalyzed asymmetric intramolecular Friedel–Crafts reaction

By means of the direct condensation of N-aminoethylpyrroles and isatins, followed by a chiral phosphoric acid-catalyzed asymmetric intramolecular Friedel-Crafts reaction, a new class of valuable chiral 3′,4′-dihydro-2′H-spiro[indoline-3,1′-pyrrolo[1,2-a]pyrazin]-2-ones bearing a quaternary carbon stereocenter were successfully synthesized in good to excellent yields and with moderate to good enantioselectivities under mild reaction conditions.

A chiral phosphoric acid-catalyzed asymmetric intramolecular Friedel–Crafts reaction for the synthesis of 3′,4′-dihydro-2′H-spiro[indoline-3,1′-pyrrolo[1,2-a]pyrazin]-2-ones.

Spirooxindoles, containing a spirocyclic system, are unique structural motifs found in a wide range of natural products and bioactive compounds.¹ For instance, Spirotryprostatin B (Fig. 1) was isolated from the fermentation broth of Aspergillus fumigatus and was shown to completely inhibit the G2/M progression of cell division in mammalian tsFT210 cells.²Gelsemium alkaloids (e.g. gelsenicine, gelsedine and gelsedilam) were isolated from the ancient medicine Yakatsu stored in the Shosoin Repository and exhibit a wide range of biological activities, including analgesic, anti-inflammatory, and antitumor effects.³ Besides, a considerable number of spirooxindoles display anticancer activity. For example, APG-115 and MI77301, which can effectively block the MDM2-p53 protein–protein interaction in cells as MDM2 inhibitors, are under clinical trials as promising anticancer drugs.⁴Open in a separate windowFig. 1Selected examples of natural and artificial spirooxindoles.Consequently, the unique structure of those compounds has attracted much attention from synthetic chemists.⁵ Some investigated strategies to access this skeleton include intramolecular reactions of imines via Pictet–Spengler reaction synthesized from tryptamines or tryptophans with isatin (Scheme 1a),⁶ oxidative rearrangement of tetrahydro-β-carbolines prepared via Pictet–Spengler reaction (Scheme 1b),⁷ metal or small-molecule catalyzed 1,3-dipolar cycloaddition of imino esters with methyleneindolinones (Scheme 1c),⁸ Rh-catalyzed [4 + 1] cycloaddition of azocompound with vinyl isocyanates (Scheme 1d),⁹ chiral iodoarene catalytic oxidative spirocyclization (Scheme 1e),¹⁰ Pd-catalyzed intramolecular addition and domino spirocyclization,¹¹ intramolecular nucleophilic addition¹² and so on.¹³ Despite of several methods developed for the construction of this skeleton, however, less work finished catalytic asymmetric synthesis and preparation of novel chiral spirooxindoles are warmly anticipated. Herein, we report an efficient protocol via an intermolecular condensation/intramolecular Friedel–Crafts reaction to synthesize a new class of 3′,4′-dihydro-2′H-spiro[indoline-3,1′-pyrrolo[1,2-a]pyrazin]-2-ones in an asymmetric way.Open in a separate windowScheme 1Catalytic synthesis of spirooxindoles.At the outset of this study, we envisaged that reaction of N-aminoethylpyrroles with isatins catalyzed by chiral phosphoric acids might undergo direct condensation, followed by intramolecular Friedel–Crafts reactions under very mild reaction conditions.¹⁴ We first began our investigation with 1-benzylindole-2,3-dione (1.0 equiv.) and N-aminoethylpyrrole (1.2 equiv.) as the substrates, BINOL-derived chiral phosphoric acid 4a as the catalyst, dichloromethane (DCM) as the solvent, 4 Å MS as a desiccant. The reaction was performed at room temperature (20 °C). To our delight, the cascade reaction proceeded smoothly providing 3′,4′-dihydro-2′H-spiro[indoline-3,1′-pyrrolo[1,2-a]pyrazin]-2-one 3aa in 99% yield but with a poor enantioselectivity (5% ee, 15 we turned to employ another kind of spiro catalysts¹⁶ and investigated their function. Delightingly, catalyst (R)-PA 5a was found to significantly improve the ee from 49% to 88% and product 3aa was given in 85% yield under mild reaction conditions in DCM. Then we evaluated the feasibility of the reaction in other solvents ( EntrySubstrate(R)-PASolventTemp. [°C]Yield^b [%]ee^c [%]11a4aDCMr.t.99521a4bDCMr.t.99031a4cDCMr.t.72541a4dDCMr.t.99051a4eDCMr.t.992161a4fDCMr.t.99071a4gDCMr.t.99081a4hDCMr.t.97091a4iDCMr.t.9649 10 1a5a DCM r.t. 85 88 111a5bDCMr.t.7019121a5aTHFr.t.9980131a5aMeCNr.t.6862141a5aDMFr.t.2844151a5aEt₂Or.t.8179161a5aCHCl₃r.t.9078171a5a1,4-Dioxaner.t.8383181a5aDCEr.t.8487191b5aDCMr.t.8939201c5aDCMr.t.6868211d5aDCMr.t.9774221e5aDCMr.t.8474231f5aDCMr.t.9269241a5aDCM07179251a5aDCM309080Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (1.2 equiv.), (R)-PA (10 mol%), 4 Å MS (50 mg), 2.0 mL of solvent, r.t. = 20 °C, overnight.^bIsolated yield.^cee was determined by chiral HPLC.With the set of optimized reaction conditions in hand, we focused our attention on the substrate scope of this catalytic asymmetric intramolecular Friedel–Crafts reaction. At first, substituted isatin derivatives were screened as the substrates in combination with N-aminoethyl pyrrole 2a, affording chiral products 3′,4′-dihydro-2′H-spiro[indoline-3,1′-pyrrolo[1,2-a]pyrazin]-2-ones in moderate to excellent yields ( Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (1.2 equiv.), (R)-PA 5a (10 mol%), 4 Å MS (50 mg), 2.0 mL of solvent, overnight.^bIsolated yield.^cee was determined by chiral HPLC.Next, the substrate scope of N-aminoalkylpyrroles was also investigated. As shown in Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (1.2 equiv.), (R)-PA 5a (10 mol%), 4 Å MS (50 mg), 2.0 mL of solvent, overnight.^bIsolated yield.^cee was determined by chiral HPLC.Furthermore, a scale up reaction of 1a and 2a was performed, generating product 3aa in 89% yield and 82% ee (Fig. 2).Open in a separate windowFig. 2Scale-up reaction.Finally, based on the experimental results, together with related studies on CPA-catalyzed reactions,^5f–5i we proposed a possible reaction pathway to explain the stereochemistry of the formation of spirooxindoles 3 (Scheme 2). Isatins 1 initially participated in a Mannich reaction with N-aminoethylpyrroles 2, affording transient intermediates 6 under the catalysis of Brønsted acid. Through the dual-hydrogen-bond, (R)-CPA 5a interacted with intermediates 6 to realize their catalysis and stereocontrol. The enantioenriched spirooxindoles 3 were subsequently yielded via the intramolecular Friedel–Crafts reaction of intermediates 6.Open in a separate windowScheme 2Proposed reaction pathway and activation mode.