Synthesis of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands for use in palladium-catalyzed cross-coupling reactions

3-Aryl-2-phosphinoimidazo[1,2-a]pyridine ligands were synthesized from 2-aminopyridine via two complementary routes. The first synthetic route involves the copper-catalyzed iodine-mediated cyclizations of 2-aminopyridine with arylacetylenes followed by palladium-catalyzed cross-coupling reactions with phosphines. The second synthetic route requires the preparation of 2,3-diiodoimidazo[1,2-a]pyridine or 2-iodo-3-bromoimidazo[1,2-a]pyridine from 2-aminopyridine followed by palladium-catalyzed Suzuki/phosphination or a phosphination/Suzuki cross-coupling reactions sequence, respectively. Preliminary model studies on the Suzuki synthesis of sterically-hindered biaryl and Buchwald–Hartwig amination compounds are presented with these ligands.

3-Aryl-2-phosphoimidazo[1,2-a]pyridine ligands were prepared via two complimentary synthetic routes and were evaluated in the Suzuki–Miyaura and Buchwald–Hartwig amination cross-coupling reactions.

Palladium-catalyzed cross-coupling reactions have revolutionized the formation of C–C and C–X bond formation in the academic and industrial synthetic organic chemistry sectors.^1,2 Applications such as synthesis of natural products,³ active pharmaceutical ingredients (API),⁴ agrochemicals,⁵ and materials for electronic applications⁶ are showcased. Snieckus described in his 2010 Nobel Prize review that privileged ligand scaffolds represented the “third wave” in the cross-coupling reactions where the “first wave” was the investigation of the metal catalyst-the rise of palladium and the “second wave” was the exploration of the organometallic coupling partner.¹ In the last twenty years, it was recognized that the choice of ligand facilitated the oxidative addition and reductive-elimination steps of the catalytic cycle of transition metal-catalyzed cross-coupling reactions, increasing the overall rate of the reaction. For example, bulky trialkylphosphines facilitated the oxidative addition processes of electron-rich, unactivated substrates such as aryl chlorides.^7,8 Sterically demanding ligands also provided enhanced rates of reductive elimination from [(L)_nPd(aryl)(R), R = aryl, amido, phenoxo, etc.] species by alleviation of steric congestion.⁹ Privileged ligands such as Buchwald''s biarylphosphines,^10,11 Fu''s trialkylphosphines,^7,8,12 Nolan–Hermann''s N-heterocyclic carbenes (NHC),^13–15 Hartwig''s ferrocenes,^16,17 Beller''s bis(adamantyl)phosphines^18,19 and N-aryl(benz)imidazolyl or N-pyrrolylphosphines,^20,21 Zhang''s ClickPhos ligands,^22,23 and Stradiotto''s biaryl P–N phosphines,^24,25 to mention a few, have found wide-spread use in Suzuki–Miyaura, Corriu–Kumada, Heck, Negishi, Sonogashira, C–X (X = S, O, P) cross-coupling and Buchwald–Hartwig amination reactions (Fig. 1). Preformed catalysts with these ligands attached to the palladium metal center are also recognized as well-defined entities in cross-coupling reactions.²⁶Open in a separate windowFig. 1Privileged ligands for palladium-catalyzed cross-coupling reactions.The term privileged structure was first coined by Evans et al. in 1988 and was defined as “a single molecular framework able to provide ligands for diverse receptors”.²⁷ In the last three decades, it is clear that privileged structures are exploited as opportunities in drug discovery programs.^28–31 For example, imidazo[1,2-a]pyridines are privileged structures in medicinal chemistry programs (Fig. 2).³² Imidazo[1,2-a]pyridines are a represented motif in several drugs on the market such as zolpidem, marketed as Ambien™ for the treatment of insomnia,³³ minodronic acid, marketed as Bonoteo™ for oral treatment of osteoporosis,³⁴ and olprinone, sold as Coretec™ as a cardiotonic agent.³⁵Open in a separate windowFig. 2Imidazo[1,2-a]pyridines as privileged structures in medicinal chemistry and in our cross-coupling reactions approach.Our group is interested in a long-term research program directed at the use of key privileged structures that are employed in drug discovery programs as potential phosphorus ligands for cross-coupling reactions. In our entry into the use of privileged structures from the medicinal chemistry literature for our investigation into new phosphorus ligands, we have developed two complementary synthetic routes for the preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands from 2-aminopyridine as our initial substrate.Our first synthetic route for the preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands 3a–3l required the copper(ii) acetate iodine-mediated double oxidative C–H amination of 2-aminopyridine (1) with arylacetylenes under an oxygen atmosphere to give 3-aryl-2-iodoimidazo[1,2-a]pyridines 2a–2d (Scheme 1).^36,37Open in a separate windowScheme 1Preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands 3a–3l from 2-aminopyridine via copper-catalyzed arylacetylene cyclizations/palladium-catalyzed phosphination reactions sequences.Phenylacetylene and 2-/3-/4-methoxyphenylacetylenes were commercially available reagents. With intermediates 2a–d in hand, we explored several cross-coupling phosphination reactions and we found that palladium-catalyzed phosphination with DIPPF ligand in the presence of cesium carbonate as the base in 1,4-dioxane under reflux provided twelve new ligands 3a–3l as shown in 38 Moderate to good yields were obtained under these cross-coupling conditions. There are few commercially available dimethoxyphenylacetylenes, and most are prohibitively expensive, and so an alternative synthetic strategy was explored.Palladium-catalyzed phosphination of 3-aryl-2-iodoimidazo[1,2-a]pyridines 2a–2d^a

Oxidative cyanation of N-aryltetrahydroisoquinoline induced by visible light for the synthesis of α-aminonitrile using potassium thiocyanate as a “CN” agent

A novel method for the synthesis of α-aminonitrile through visible-light-induced oxidative cyanation of N-aryltetrahydroisoquinoline with potassium thiocyanate has been developed. The process does not require the use of a photocatalyst, transition metal reagent, strong oxidizing agent, or toxic cyano-containing compound, which makes the reaction simple and green.

A novel method for the synthesis of α-aminonitrile, through visible-light-induced oxidative cyanation of N-aryltetrahydroisoquinoline with potassium thiocyanate, has been developed.

α-Aminonitriles are versatile intermediates which can be readily converted into a range of multifunctional organics,¹ such as α-aminocarbonyl compounds, α-amino acids, 1,2-diamines and many others. Moreover, many nitrile-containing compounds have been widely used as drugs for treating various diseases.² For example, amphetaminil³ is a stimulant that can be employed to treat obesity and narcolepsy; others like Saxagliptin,⁴ NVP-DPP728 (ref. 5) and Vildagliptin⁶ are potent reversible inhibitors of dipeptidyl peptidase-4 (DPP-4), and can be applied as novel antidiabetic drugs. Therefore, the development of novel, efficient and clean methods for the synthesis of α-aminonitriles has attracted wide attention.Traditionally, α-aminonitriles are synthesized through the Strecker reaction.⁷ Another momentous strategy for synthesis of α-aminonitriles is oxidative cyanation of tertiary amines with the involvement of transition metal reagents (such as Ru,⁸ Au,⁹ Cu,¹⁰ Fe,¹¹ Co,¹² V,¹³ Mo,¹⁴etc.) and non-metallic reagents (such as PhI(OAc)₂,¹⁵ tropylium salt,¹⁶ AIBN,¹⁷ TBAI,¹⁸ AcOH,¹⁹ PIFA,²⁰ TBHP,²¹ thiourea,²² DDQ,²³ TBPB,^24aetc.). Among the reported cyanidation of tertiary amines, the cyano sources mainly includes (i) metal-cyanides such as NaCN,^8a–8c,10c KCN,¹⁶ K₃[Fe(CN)₆],²⁵ KSCN,²¹etc., (ii) organic cyanides such as trimethylcyanosilane,^{9a,10e,11a–11c,11f} malononitrile,^10a,15,23 ethyl cyanoformate,^{11d,8e,11d,12} benzoyl cyanide,^11e phenylacetonitrile,^18a cyanoacetic acid,^18b tetrabutylammonium cyanide,¹⁹ cyanobenziodoxolones,²⁴ AIBN,²⁶etc., and (iii) combined cyano source such as the combination of 1,2-dichloroethane and trimethylsilyl azide.^10b (Scheme 1). However, most of these methods require transition metal reagents, strong oxidizing agents, and cyano sources that are highly toxic and difficult to obtain. Therefore, it is necessary to find a cyanide source that is easily available and of low toxicity for the cyanidation of tertiary amines.Open in a separate windowScheme 1Cyano sources for cyanidation reactions of tertiary amine.In organic synthesis, thiocyanate has received extensive attention due to its low toxicity, low cost and easy availability.²⁷ Using the thiocyano group of thiocyanate, thiocyanation of organic molecules can be achieved by nucleophilic substitution or through a free radical pathway.²⁸ More importantly, thiocyanate can be utilized as a clean and safe source of cyano group.^21,29 However, these methods have the following disadvantages: using a transition metal catalyst, or a strong oxidizing agent, or heating. The utilization of light energy in organic synthesis is highly commendable because it is sustainable, clean, environmentally benign, as well as widely and easily available. In recent years, great progresses have been made in the formation of carbon–carbon bond that is induced by visible light,³⁰ among which the oxidative cyanation of tertiary amine is a good example.³¹ However, to the best of our awareness, the cyanidation of tertiary amine with thiocyanate induced by visible light has not been documented yet. Herein, we report the visible-light-induced oxidative cyanation reaction of tertiary amines with potassium thiocyanate.We began our investigation with the use of N-phenyltetrahydroisoquinoline (1a) and potassium thiocyanate (2a) as the model reaction ( EntryOxidantLightSolventYield^b (%)1Air30 W CFLC₂H₅OH502O₂30 W CFLC₂H₅OH553TBHP30 W CFLC₂H₅OH254H₂O₂30 W CFLC₂H₅OH175K₂S₂O₈30 W CFLC₂H₅OH196DDQ30 W CFLC₂H₅OH37PhI(OAc)₂30 W CFLC₂H₅OH58O₂30 W red LEDsC₂H₅OH69O₂30 W green LEDsC₂H₅OH6810O₂30 W blue LEDsC₂H₅OH7411O₂30 W purple LEDsC₂H₅OH8312O₂30 W purple LEDsCH₃OH1113O₂30 W purple LEDsDMSO814O₂30 W purple LEDsPhMe1115O₂30 W purple LEDsCH₃CN9216^cO₂30 W purple LEDsCH₃CN7117—30 W purple LEDsC₂H₅OH018O₂—C₂H₅OH0Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), oxidant (1.5 equiv.), solvent (1.5 mL), rt, 24 h.^bIsolated yields based on 2a.^cNH₄SCN was used instead of KSCN.With the optimized conditions, we explored the substrate scope of this visible-light-induced cyanation reaction between N-aryltetrahydroisoquinoline (1) and potassium thiocyanate (2a) (Scheme 2). The N-aryltetrahydroisoquinolines with either an electron-withdrawing or electron-donating group reacted well with potassium thiocyanate to afford the desired products in moderate to good yields. Specifically, when the benzene ring attached to the nitrogen atom had an electron donating group (Me, Et, and Ph) at the para position, the desired products were in 79%, 86% and 62% yields, respectively (3b–d). In the cases of having an electron-withdrawing group (F, Cl, Br, CN, CF₃, and OCF₃) attached to the benzene ring at para position, the desired products were obtained in moderate to good yields, and the highest one was up to 88% (3e–j). Besides, ortho- and meta-substituted N-aryltetrahydroisoquinolines also exhibited high reactivity, and the target products were obtained in moderate yields (3k–n).Open in a separate windowScheme 2Substrate scope for cyanation of N-aryltetrahydroisoquinolines (1) with potassium thiocyanate (2a)^a. ^aConditions: 1 (0.2 mmol), 2a (0.1 mmol), CH₃CN (1.5 mL), 24 h, isolated yields of column chromatography based on 2a. ^bThe yield was based on 1 mmol of KSCN. ^cNo product was detected by GC-MS.What''s more, the substrates with two identical or different substituents on the phenyl ring were also suitable for this reaction, and the yields of the products vary from 60% to 80% (3o–q). Regrettably, dialkyl substituted aromatic amine (such as N,N-dimethylaniline) was not suitable for this reaction (3r).To gain reasonable insight into the reaction mechanism, we conducted the following control experiments (Scheme 3). When 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT), both are radical quenchers, was added to the reaction under the standard conditions, the product 3a was obtained in 3% and 9% yield, respectively, detected by GC. The results reveal that the reaction may proceed with the participation of free radicals.Open in a separate windowScheme 3Control experiments.Based on our experimental results and those of previous reports,^19,21,32,33 a mechanism for this visible-light-induced oxidative cyanation reaction is proposed as illustrated in Scheme 4. Initially, substrate 1 is transformed into cationic radical I in the presence of visible light and oxygen, and anionic superoxide radical O₂˙⁻ is generated simultaneously. Then, cationic radical I reacts with O₂˙⁻ to generate radical II which loses an electron to form intermediate V. Under the action of HOO⁻, thiocyanate is converted to cyano anion which then reacts with intermediate V to generate the desired product 3. At the same time, the intermediate II is combined with HOO˙ to form III, and the latter III is dehydrated to form a by-product IV.Open in a separate windowScheme 4Possible mechanism.     

Correction: Droplet microfluidics: fundamentals and its advanced applications

Correction for ‘Droplet microfluidics: fundamentals and its advanced applications’ by Somayeh Sohrabi et al., RSC Adv., 2020, 10, 27560–27574, DOI: 10.1039/D0RA04566G.

The authors regret the omission of a funding acknowledgement in the original article. This acknowledgement is given below.The authors would like to acknowledge the financial support of the Iran National Science Foundation (INSF), grant number 98017171.In addition, the authors regret that incorrect reference numbers were given in Geometry and materialContinuous phaseSize/μmFrequency/HzRef. in original article reference listRef. in this CorrectionWater in oilChannel array in siliconKerosene with monolaurate21∼5300 (est.)— 1 T-junction in acrylated urethaneDecane, tetradecane, and hexadecane with Span 8010 to 3520 to 80— 2 T-junction in PMMAHigh oleic sunflower oil100 to 35010 to 2500— 3 T-junction in PDMSC₁₄F₁₂ with (C₆F₁₃)(CH₂)₂OH7.5 nl (plug flow)255 4 Shear-focusing in PDMSOleic acid13 to 35 (satellites <100 nm)15–10049 5 Oil in waterChannel array in siliconWater with SDS22.5∼5300 (est.)— 1 Sheath flow in glass capillaryWater with SDS2 to 200100 to 10 000— 6 Gas in liquidFlow-focusing in PDMSWater with Tween 2010 to 1000>100 000— 7 Shear-focusing in PDMSWater with phospholipids5 to 50>1 000 000— 8 Liquid in airDEP on hydrophobic insulatorAir10 pl∼8 (est.)57 9 EWOD on hydrophobic insulatorAir∼700 nl∼1 (est.)28 10 Open in a separate windowThe Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

ortho-Naphthoquinone-catalyzed aerobic oxidation of amines to fused pyrimidin-4(3H)-ones: a convergent synthetic route to bouchardatine and sildenafil

A facile access to fused pyrimidin-4(3H)-one derivatives has been established by using the metal-free ortho-naphthoquinone-catalyzed aerobic cross-coupling reactions of amines. The utilization of two readily available amines allowed a direct coupling strategy to quinazolinone natural product, bouchardatine, as well as sildenafil (Viagra™) in a highly convergent manner.

Fused pyrimidin-4(3H)-one derivatives have been accessed by using the ortho-naphthoquinone-catalyzed aerobic cross-coupling reactions of amines.

N-Heterocyclic compounds with a pyrimidin-4(3H)-one core constitute a large number of natural products and biologically active molecules. For example, quinazolinone alkaloids possess a phenyl-fused pyrimidin-4(3H)-one structure and display a wide spectrum of pharmacological activities (Scheme 1a).¹ Sildenafil (Viagra™), a potent and selective inhibitor of type 5 phosphodiesterases on smooth muscle cell, is based on the pyrazole-fused pyrimidin-4(3H)-one structure and marketed for erectile dysfunction.² The synthetic approaches to the phenyl-fused pyrimidin-4(3H)-ones, quinazolinones, typically involve the condensation between anthranilamides and aldehydes to give aminal intermediates that in turn oxidized to quinazolinones under oxidation conditions (Scheme 1b). The oxidation catalysts include Cu,³ Fe,⁴ Ga,⁵ Ir,⁶ Mn,⁷ iodine,⁸ peroxide,⁹ however the aerobic oxidation of aminal intermediates is also known at 150 °C.¹⁰ The utilization of alcohols also effects the one-pot synthesis of quinazolinones through in situ oxidation to aldehydes in the presence of Fe,¹¹ Ir,¹² Mn,¹³ Ni,¹⁴ Pd,¹⁵ Ru,¹⁶ V,¹⁷ Zn,¹⁸ and iodine catalysts.¹⁹ Other precursors to aldehydes have been also identified using alkynes,²⁰ benzoic acids,²¹ indoles,²² α-keto acid salts,²³ β-keto esters,²⁴ styrenes,²⁵ sulfoxides,²⁶ and toluenes.²⁷ Non-aldehyde approaches to quinazolinones have been also demonstrated in the cross coupling of amidines,²⁸ amines,²⁹ benzamides,³⁰ isocyanides,³¹ and nitriles.³² In 2013, the Nguyen group disclosed the synthesis of four quinazolinones, utilizing the autooxidation of benzylamines to imines that subsequently condensed with anthranilamides.³³ While a closed system at 150 °C was necessary, the use of 40 mol% AcOH without solvent provided the quinazolinones in 46–75% yields. The Nguyen group also developed the FeCl₃·6H₂O-catalyzed condensation of 2-nitroanilines and benzylamines in the presence of 20 mol% of S₈, where six quinazolinones were obtained in 68–75% yields.³⁴ While the cross condensation of anthranilamides and benzylamines was accomplished, there exists a significant knowledge gap due to the limited substrate scope combined with less optimal reaction conditions (i.e. high reaction temperature, closed system in neat conditions and excess use of amines). In addition, it is not entirely clear if the cross condensation of amide-containing amines and benzylamines would work for other fused pyrimidin-4(3H)-one derivatives.³⁵ To address such shortcomings in the cross condensation of amines, the ortho-naphthoquinone (o-NQ)-catalyzed aerobic cross amination strategy was investigated (Scheme 1c).³⁶ Herein, we report a highly general approach to fused pyrimidin-4(3H)-one derivatives in the presence of o-NQ catalyst, culminating to the direct aerobic coupling of two amines to bouchardatine and sildenafil.Open in a separate windowScheme 1Biologically active fused pyrimidin-4(3H)-one derivatives and their synthetic methods.Given that the o-NQ-catalyzed aerobic cross coupling of benzylamines and aniline derivatives such as o-phenylenediamines provided a facile approach to heterocyclic compounds including benzoimidazoles,³⁷ the use of anthranilamide 1a and benzylamine 2a was examined as a model study (38 The reaction in DMSO lowered down the ratio of 1a and 2a from 1.0 : 1.5 to 1.0 : 1.2 (entry 12) and the catalyst loading to 5 mol% without affecting the overall reaction efficiency (entry 13). The control experiments confirmed the critical roles of both o-NQ1 and TFA (entries 15–18), and the reaction utilized molecular oxygen as a terminal oxidant (entries 19 and 20). Piecing together the experimental data, the employment of 5 mol% o-NQ1 and 20 mol% TFA in DMSO at 100 °C was selected for further studies.Optimization of o-NQ-catalyzed aerobic cross-coupling of amines to quinazolinone^a

Rapid and halide compatible synthesis of 2-N-substituted indazolone derivatives via photochemical cyclization in aqueous media

Indazolone derivatives exhibit a wide range of biological and pharmaceutical properties. We report a rapid and efficient approach to provide structurally diverse 2-N-substituted indazolones via photochemical cyclization in aqueous media at room temperature. This straightforward protocol is halide compatible for the synthesis of halogenated indazolones bearing a broad scope of substrates, which suggests a new avenue of great importance to medicinal chemistry.

A straightforward protocol for the rapid construction of privileged indazolone architectures suggests a new avenue of great importance to medicinal chemistry.

The indazolone ring system constitutes the core structural element found in a large family of nitrogen heterocycles as exemplified by those shown in Scheme 1.¹ Indazolone derivatives have been receiving much attention due to their promising pharmacological activities. Given the unique bioactive core skeleton, indazolone derivatives exhibit a wide range of biological and pharmaceutical properties such as antiviral and antibacterial activities (1–4),² new prototypes for antichagasic drugs (5),³ antihyperglycemic properties (6),⁴ TRPV1 receptor antagonists for analgesics (7),⁵ anti-flammatory agents (8),⁶ angiotensin II receptor antagonists (9),⁷ highly potent CDKs inhibitors for anticancer (10)⁸ and so on.⁹ The privileged indazolone structures have high potential as core components for the development of related compounds leading to medicinal agents.Open in a separate windowScheme 1Biologically active molecules containing indazolone skeletons.Due to their versatility in pharmaceutical applications, many synthetic approaches have been developed for the construction of indazolone skeletons (Scheme 2), including CuO-mediated coupling of 2-haloarylcarboxylic acids with methylhydrazine,¹⁰ cyclization of N-aryl-o-nitrobenzamides through Ti(vi) reagent or Zn(ii) reagent,¹¹ Cu(i)-mediated intramolecular C–N bond formation or a base-mediated intramolecular SNAr reaction of 2-halobenzohydrazides,¹² Cu(i)-catalyzed oxidative C–N cross-coupling and dehydrogenative N–N formation sequence,¹³ Rh-catalyzed C–H activation/C–N bond formation and Cu-catalyzed N–N bond formation between azides and arylimidates,¹⁴ Friedel–Crafts cyclization of N-isocyanates using Masked N-isocyanate precursors,¹⁵ PIFA-mediated intramolecular oxidative N–N bond formation by trapping of N-acylnitrenium intermediates,¹⁶ and recently reported reaction of o-nitrobenzyl alcohol with primary amines in basic conditions.¹⁷ These approaches are complementary providing avenue to access various substitution patterns,¹⁸ however most methods rely on the requirements for transition-metal catalysts. In fact, the procedures for synthesis indazolone skeletons from Friedel–Crafts cyclization of N-isocyanates and Davis–Beirut derived reaction still suffer from harsh reaction conditions such as high reaction temperature (i.e. more than 150 °C or 20 equiv. of KOH at 100 °C for 24 h).^15,17b Very recently, one photochemical route was reported for preparation of indazolone skeletons from o-nitrobenzyl alcohols and primary amines,¹⁹ however, this approach still need long reaction time (24 hours) and halogen substituted substrate could not be compatible in the reaction conditions.^19b Thus, the efficient and general methods tolerating a wide scope of readily available starting materials for synthesis of indazolones without a transition-metal catalyst involved are still in great demand.Open in a separate windowScheme 2Representative approaches for the preparation of indazolone skeletons. o-Nitrobenzyl alcohol derivatives have shown many applications in material science and chemical biology area as a photolabile protecting group (Scheme 3a).²⁰ Upon UV light-activation, o-nitrobenzyl alcohol derivatives generate corresponding aryl-nitroso compounds via photoisomerization.²¹ Based on the distinguishing feature of highly reactive of these photogenerated intermediates, we assumed that the reaction conditions would be crucial for the photoisomerization,^20,22 thus the reactive intermediates should spontaneously and rapidly form indazolone structures via cyclization in the presence of primary amines in suitable reaction conditions (Scheme 3b). Herein, we report a rapid and efficient approach to provide structural diversity 2-N-substituted indazolones via photochemical cyclization in aqueous media at room temperature. This photochemical cyclization reaction is halide compatible for synthesis of halogen substituted indazolones, bearing a broad scope of substrates. This straightforward protocol for rapid construction of halogenated indazolone architectures suggests a new avenue of great importance to medicinal chemistry.Open in a separate windowScheme 3Synthesis of indazolone derivatives via photochemical cyclization.The initial investigation to develop a method for synthesis of indazolone derivatives via photochemical cyclization started with 4-(hydroxymethyl)-3-nitro-N-propylbenzamide 11 and heptan-1-amine 12 upon UV light-activation in methanol, smoothly leading to the formation of indazolone 13 in 52% yield ( EntrySolvent11 : 12Time (h)Yield^f (%)1MeOH2.5 : 13522THF2.5 : 13583 n-BuOH2.5 : 13574CH₃CN2.5 : 13615CH₃CN : H₂O = 3 : 12.5 : 13676CH₃CN : PBS = 3 : 12.5 : 1361 7 n-BuOH : H ₂ O = 3:1 2.5 : 1 3 82 8 n-BuOH : PBS = 3 : 12.5 : 13569MeOH : H₂O = 3 : 12.5 : 133810i-PrOH : H₂O = 3 : 12.5 : 136311 tBuOH : H₂O = 3 : 12.5 : 135512THF : H₂O = 3 : 12.5 : 134913DMF : H₂O = 3 : 12.5 : 134514Dioxane : H₂O = 3 : 12.5 : 136715^b n-BuOH : H₂O = 3 : 12.5 : 13<1016^c n-BuOH : H₂O = 3 : 12.5 : 132217^d n-BuOH : H₂O = 3 : 11.5 : 134518^e n-BuOH : H₂O = 3 : 12.5 : 132819 n-BuOH : H₂O = 3 : 12.5 : 168520PBS2.5 : 131921 n-BuOH : H₂O = 3 : 11 : 2.5346Open in a separate window^aReaction conditions: heptan-1-amine (12, 0.3 mmol), 4-(hydroxymethyl)-3-nitro-N-propylbenzamide (11, 0.75 mmol), solvent 6 mL, exposed to UV lamp with 365 nm, at R.T.^bUV lamp with 254 nm.^cUsing blue light.^dThe ratio of 11/12 = 1.5/1.^eReaction carried out at 50 °C.^fIsolated yield.With the optimal conditions in hand, we investigated the generality for the scope of o-nitrobenzyl alcohols and primary amines ( Open in a separate window^aReaction conditions: primary amines (15, 0.3 mmol), o-nitrobenzyl alcohols derivatives (14, 0.75 mmol), solvent 6 mL, isolated yield.Many drug candidates and drugs are halogenated structures. In drug discovery, insertion of halogen atoms on hit or lead compounds was predominantly performed, with the aim to exploit their steric effects and structure–activity relationship, to form halogen bonds in ligand–target complexes, to optimize the ADME/T property.²³ Given the versatility of halogen atom on bioactive molecules, we next investigated the halogen substituted o-nitrobenzyl alcohols as starting materials for construction of indazolone skeletons (17b as well as aniline failed to give product in the recently reported photochemical approach (see ESI, Fig. S1^†).^19b Of note, in the recently reported photochemical approach, the reaction of chloride substituted o-nitrobenzyl alcohol with alkylamine gave indazolone with low yield, possibly because photocleavage of aryl halide bond is involved in that reaction conditions.^19b These outcomes are significant in view of the challenges in construction of indazolone skeletons, in which additional halogen substitution on substrates is incompatible for indazolones synthesis.^10,19b Importantly, our reaction condition is compatible with halide substrates, suggests a new protocol of importance to photochemical reactions, in which dehalogenation of aryl halide is known to be radical-mediated and exist in some reaction conditions.²⁴Scope of halogen substituted o-nitrobenzyl alcohols for indazolone formation^a

Pd-catalyzed [3 + 2] cycloaddition of vinylcyclopropanes with 1-azadienes: synthesis of 4-cyclopentylbenzo[e][1,2,3]oxathiazine 2,2-dioxides

The palladium-catalyzed [3 + 2] cycloaddition of vinylcyclopropanes and 1-azadienes has been developed under mild reaction conditions, giving the multisubstituted cyclopentane derivatives in good to excellent yields with moderate to good diastereoselectivities. The relative configuration of both diastereomers of the products have been determined through X-ray crystallographic diffraction.

Pd-catalyzed [3 + 2] cycloaddition of vinylcyclopropanes with 1-azadienes gave highly functionalized cyclopentane derivatives in high yields.

The cyclopentane framework is ubiquitous in nature and it is also an important structural moiety in many pharmaceuticals, agrochemicals, and materials.¹ The development of simple, fast and efficient synthetic methods for highly substituted cyclopentanes has attracted much attention. Among various methods for synthesis of cyclopentane structure, the cycloaddition reaction is a very attractive one.²Under palladium catalysis conditions, vinylcyclopropane derivatives underwent a ring-opening reaction to generate the zwitterionic allylpalladium intermediate, which reacted with carbon–carbon, carbon–oxygen, carbon–nitrogen double bonds and diazo compounds to provide a variety of five-membered cyclic compounds.³ In the past decades, this type of annulation reactions has emerged as a powerful tool for the synthesis of carbocyclic and heterocyclic compounds.² Diverse substrates including isocyanates,⁴ aldehydes,⁵ isatins,⁶ 3-diazooxindoles,⁷ electron-deficient alkenes such as para-quinone methides,⁸ α,β-unsaturated aldehydes,⁹ β,γ-unsaturated α-keto esters,¹⁰ nitroolefins,¹¹ azlactone- and Meldrum''s acid alkylidenes,¹² and α-nucleobase substituted acrylates,¹³ have been exploited in palladium-catalyzed [3 + 2] cycloadditions of vinyl cyclopropane, delivering biologically interesting functionalized heterocyclic compounds and cyclopentane derivatives. In 2015, Liu and He reported a palladium-catalyzed [3 + 2] cycloaddition of vinyl cyclopropane and α,β-unsaturated imines generated in situ from aryl sulfonyl indoles, providing the optically enriched spirocyclopentane-1,3′-indolenines with high diastereoselectivity.¹⁴ This is the only example where α,β-unsaturated imines were employed in Pd-catalyzed [3 + 2] cycloaddition reaction of vinyl cyclopropane.As a type of α,β-unsaturated imines, cyclic 1-azadienes such as (E)-4-styrylbenzo[e][1,2,3]oxathiazine 2,2-dioxides 2 are easily accessible and stable (Scheme 1). In particular, they contain the sulfonate-moiety, which is an interesting biologically important motif, and has a great potential in the synthesis of bioactive molecules.¹⁵ The cyclic 1-azadienes have been used in a series of annulation reactions such as [2 + n],^16–18 [3 + n],¹⁹ and [4 + n]²⁰ annulation reactions. Based on the electron-deficient nature of the carbon–carbon double bond in these cyclic 1-azadienes, in 2016, Chen and Ouyang developed cinchona-derived tertiary amine-catalyzed asymmetric [3 + 2] annulation of isatin-derived Morita–Baylis–Hillman (MBH) carbonates with cyclic 1-azadienes to form spirooxindole.¹⁷ In the same year, our group demonstrated a phosphine-catalyzed [3 + 2] annulation of MBH carbonates with cyclic 1-azadienes.¹⁸ Considering that the 1-azadiene 2 is an electron-deficient alkene with good reactivity, its reaction with a zwitterionic π-allyl Pd complex formed via ring-opening of vinylcyclopropane may be feasible. However, this type of cyclic 1-azadienes have never been used in Pd-catalyzed annulation reactions involving vinylcyclopropanes. As our continuing interest on cycloaddition reactions,²¹ herein we disclose a [3 + 2] cycloaddition of palladium-catalyzed vinyl cyclopropane with cyclic 1-azadienes to afford the multisubstituted cyclopentane derivatives (Scheme 1).Open in a separate windowScheme 1[3 + 2] Cycloaddition of 1,3-zwitterions with cyclic 1-azadienes.We carried out an initial screening with 2-vinylcyclopropane-1,1-dicarbonitrile 1a and (E)-4-styrylbenzo[e][1,2,3]oxathiazine 2,2-dioxide 2a in CH₂Cl₂ (DCM) at room temperature in the presence of Pd₂(dba)₃·CHCl₃ (2.5 mol%) (22 Under the optimized reaction conditions, we attempted to develop asymmetric variant of this reaction. Unfortunately, the two enantiomers of the product could not be resolved at present stage.²³Optimization of the reaction conditions^a

Metal free C-3 chalcogenation (sulfenylation and selenylation) of 4H-pyrido[1,2-a]pyrimidin-4-ones

An expeditious metal free C-3 chalcogenation of 4H-pyrido[1,2-a]pyrimidin-4-one has been devised to synthesize diversely orchestrated 3-ArS/ArSe derivatives in high yields (up to 95%). This operationally simple reaction proceeds under mild reaction conditions, can be executed in gram scale, and also highlights broad functional group tolerance. Preliminary experimental investigation suggests a radical mechanistic pathway for these transformations.

We have discovered an unprecedented metal-free route for the direct C-3 chalcogenation of various 4H-pyrido[1,2-a]pyrimidin-4-ones under mild conditions in good to excellent yields.

Organosulfur species and derivatives thereof, have garnered a prominent position in contemporary organic synthesis.¹ They also have widespread applications in pharmaceuticals, bioactive compounds and polymer materials.² In addition, carbon-selenium-carbon skeletons are high value core structures for their extensive use as therapeutically active agents, such as antioxidant, antihypertensive, antimicrobial, antibacterial, antiviral, anticancer agents etc.³ Moreover, organoselenium species have been identified as non-toxic compounds.⁴ Some of the biologically active C–S/C–Se linkage containing scaffolds is outlined in Fig. 1. Consequently, numerous efforts have been devoted to develop facile and reliable methods for the installation of a sulfenyl/selenyl group into organic frameworks.⁵ Apart from the cross-coupling approach, an alternative protocol for the transition-metal-catalyzed C–S bond formation via C–H bond functionalization has been established, which is known as a sulfenylation reaction.⁶ In this reaction, aryl sulfonyl hydrazides,⁷ arylsulfonyl chlorides,⁸ sulfinic acids,⁹ and sodium sulfinates¹⁰, thiols¹¹ are mostly used as the sulfenylating agents. Although, these methods are advantageous, certain limitations comprising the use of metal catalyst and toxic reagents still persist. Complete removal of trace amounts of transition-metal residues from the anticipated bioactive products is quite challenging task, and this contamination of a transition metal also inhibits the sustainable development.¹² Despite these accomplishments, development of an efficient and practical method for transition-metal-free C–S/Se bond forming reactions using thiols/diselenide as the sulfenylation/selenation reagent is an attractive and synthetically desirable.Open in a separate windowFig. 1Representative examples of some biologically active 4H-pyrido[1,2-a]pyrimidin-4-one and diarylsulfide/diselenide scaffold.On the other hand, N-fused bicyclic heterocycles¹³ has received enormous interest from synthetic chemists as well as medicinal researchers due to their profound impact in agrochemicals, pharmaceuticals and material sciences.¹⁴ In this family, 4H-pyrido[1,2-a]pyrimidin-4-one (Fig. 1) exhibits versatile biological activities,¹⁵ such as CXCR3 antagonism,¹⁶ HLE inhibition,¹⁷ MexAB-OprM specific efflux pump inhibition,¹⁸ potent 5-HT6 antagonists,¹⁹ and acetylcholinesterase inhibition.²⁰ Meanwhile, Pd catalyzed direct arylation and alkenylation of 4H-pyrido[1,2-a]pyrimidin-4-one through C–H bond functionalization has already been reported in the literature.²¹ Rather, only a single report for the insertion of –SAr group in 4H-pyrido[1,2-a]pyrimidin-4-one molecule using sulfonyl hydrazides as thiol surrogates is documented by Wang et al.²² Nevertheless, this protocol is effective at elevated temperature. Based on our research interests on the structural diversification of heterocyclic scaffolds, we recently reported different methodologies for the metal free direct C–H bond functionalization.²³ Herein, we envisaged to disclose a straightforward and efficient protocol of sulfenylation/selenylation for 4H-pyrido[1,2-a]pyrimidin-4-one in the presence of iodine under mild conditions. Pleasingly, several thiols/organodiselenides are smoothly coupled with 4H-pyrido[1,2-a]pyrimidin-4-one and furnished the desired anticipated products in good to excellent yields (Scheme 1).Open in a separate windowScheme 1Previous approaches and the present route of C–H bond functionalization of 4H-pyrido[1,2-a]pyrimidin-4-ones.We commenced our studies with the optimization of the sulfenylation reaction where 2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (1a) and thiophenol were used as a model coupling partner ( EntryReagent (equiv.)Oxidant (equiv.)Temperature (°C)Solvent (ml)Time (h)Yield^b (%)1NaI (3)TBHP (3)100DMSO24NR2NaI (3)TBHP (3)100CH₃CN24NR3TBAI (2)K₂S₂O₈ (2)70H₂O24504TBAI (1)K₂S₂O₈ (2)70CH₃CN12675I₂ (1)K₂S₂O₈ (2)70CH₃CN12916KI (1)K₂S₂O₈ (2)70CH₃CN12NR7NaI (1)K₂S₂O₈ (2)70CH₃CN12NR8NH₄I (1)K₂S₂O₈ (2)70CH₃CN12609NIS (1)K₂S₂O₈ (2)70CH₃CN126310I₂ (1)TBHP (2)70CH₃CN128511I₂ (1)DTBP (2)70CH₃CN12NR12I₂ (1)TBPB (2)70CH₃CN12NR13I₂ (1)H₂O₂ (2)70CH₃CN127114I₂ (1)K₂S₂O₈ (2)50CH₃CN125315I₂ (1)K₂S₂O₈ (2)30CH₃CN12NR16I₂ (1)—70CH₃CN12NR 17 I ₂ (50 mol%) K ₂ S ₂ O ₈ (2) 70 CH ₃ CN 12 92 18I₂ (50 mol%)K₂S₂O₈ (2)70Toluene123519I₂ (50 mol%)K₂S₂O₈ (2)70Dioxane124120I₂ (50 mol%)K₂S₂O₈ (2)70DCE126621I₂ (50 mol%)K₂S₂O₈ (2)70EtOH128122I₂ (50 mol%)K₂S₂O₈ (2)70DMF12NROpen in a separate window^aReaction condition: 2-phenyl substituted 4H-pyrido[1,2-a]pyrimidin-4-ones (0.125 mmol, 1 equiv.), benzene thiol (0.1875 mmol, 1.5 equiv.), inducer (equiv./mol%), solvent (2 ml), oxidant (3 equiv.).^bIsolated yields based on the reactants 1a, the reaction was run for 12–24 h.Having assimilated the robust reaction conditions for the C–S coupling of 4H-pyrido[1,2-a]pyrimidin-4-one, we sought to explore the scope and general applicability of this protocol (Scheme 1; entries 2b–2h). Noticeably, a crucial effect in the product yield was surveyed with the substituents present at the benzene thiol. 4-Methoxybenzene thiol furnished much lower yield of the corresponding coupled product (2b), compared to electron-withdrawing group, probably due to the generation of a more stable dimer [disulphide]. However, the yield of the anticipated product [2b] could further be enhanced upon/on using stoichiometric amount of catalyst (I₂). To our delight, maximum productivity of the product was obtained in the case of F-substituted benzenethiol compare to the other halogens. Notably, ortho bromo-substituted benzene thiol delivered in a higher yield of the corresponding product (2h) than the corresponding chloro derivative (2c). 2,5-Dimethylbenzene thiol was endured under the current reaction conditions to provide 88% yield of 2e. Importantly, the bulkier naphthalene thiol also effectively participated in this transformation to give 82% yield of the C–S coupled product (2g). For adorning the synthetic potentiality further, we investigated the reactivity of various thiols with diverse 4H-pyrido[1,2-a]pyrimidin-4-one. Employment of both electron-neutral (–Me) and electron-deficient (–Cl) functional group substituted parent scaffold provided synthetically useful yields of the desired sulfenylated products with a wide spectrum of benzene thiols (entries 2i–2p). In this context, a suitable choice of benzene thiols is also important, since electronic bias plays a pivotal role in this transformation (entries 2i–2p). Comparatively, a higher yield of the desired ArS derivatives was always obtained in the presence of an electron-withdrawing group (–F, –Cl) at the para position of benzene thiol (entries 2k, 2m, 2n and 2p). Exposure of 2-alkyl substituted 4H-pyrido[1,2-a]pyrimidin-4-one with thiophenol and 4-chlorothiophenol was also fruitful to give intended products in acceptable yields (entries 2q and 2r). Unfortunately, benzyl thiol, 1-pentane thiol and heterocyclic congener of thiol (2-mercapto benzimidazole) did not respond under the optimal reaction conditions (entries 2s, 2t and 2u). Especially, upscale synthesis of 2a was also achieved, illuminating potential capabilities to assemble specialized 3-ArS substituted 4H-pyrido-[1,2-a]pyrimidin-4-ones. It was remarkable that PhSSPh was also amenable instead of PhSH with this catalytic system.Scope of different substituted 4H-pyrido[1,2-a]pyrimidin-4-ones and thiol derivatives for I₂ mediated sulfenylation^a

Rh(iii)-catalyzed regioselective C–H activation dialkenylation/annulation cascade for rapid access to 6H-isoindolo[2,1-a]indole

6H-isoindolo[2,1-a]indoles were accessed via a Rh(iii)-catalyzed N–H free indole directed C–H activation dialkenylation/annulation cascade in moderate to excellent yields. This protocol also features: reaction procedures that are insensitive to air and moisture, excellent regioselectivity and good functional group tolerance.

6H-isoindolo[2,1-a]indoles were accessed via a Rh(iii)-catalyzed N–H free indole directed C–H activation dialkenylation/annulation cascade in moderate to excellent yields.

The indole motif, which widely occurs in many natural products, pharmaceuticals and other functional molecules (Fig. 1), is evidently one of the most important skeletons.¹ Over the past few decades, people have developed numerous synthetic routes towards indole.² Among them, direct modification of indoles by transition-metal catalysis through a C–H activation strategy is quite interesting and is undoubtedly of great significance in consideration of atom economy and step simplicity, thus attracting much attention from both academia and industry.^2b,3,4Open in a separate windowFig. 1Compounds containing indole motif.Transition-metal catalyzed oxidative cross-coupling via a C–H activation pathway eliminating the need for preactivated reaction partners, has become one of the most powerful tools for molecule manipulation.^2c,5 Since the pioneering work of Murai,^6a Fujiwara and Moritani,^6b,c this research area has undergone rapid developments. Generally, in order to achieve good reactivity and controlled selectivity, a directing group is usually needed.⁷ In this regard, various directing groups have been gradually designed and reported, including amides,^8a amines,^8b alcohols,^8c carboxylic acids,^8d esters,^8e ketones,^8f aldehydes,^8g triazenes^8h and N–H free indoles.⁹Meanwhile, in contrast to the well-reported C–H arylation of indoles,¹⁰ direct selective alkenylation of 2-position of N–H free indole is still limited and challenging due to the electrophilic nature of the C-2 position.¹¹ In 2005, Gaunt et al. reported Pd-catalyzed selective C-2 alkenylation of indoles,^11b but the reaction efficiency is low and high catalyst loading is required (Scheme 1a). Another most effective strategy is pre-installing a directing group into the indole structure to control the selectivity (Scheme 1b).¹² For example, Miura et al. disclosed Pd-catalyzed C-2 alkenylation reaction using carboxylic acid as a blocking and directing group.^12a Carretero and co-workers explored N-pyridylsulfonyl as a directing group to functionalize indole at the C-2 position employing excess of alkenes in the presence of Pd(ii) catalyst.^12bOpen in a separate windowScheme 1Transition-metal catalyzed C-2 alkenylation of indole.In the above-mentioned examples, high catalyst loading^11b (as much as 20 mol%, Scheme 2a) or pre-installed directing groups were generally required.¹² These directing groups, possessing functional groups containing a metal-binding heteroatom, remain part of the products after reaction. Such groups can rarely be conveniently removed under ambient conditions or undergo versatile cyclization reactions,^12c-f which have greatly limited the structural diversity of the products and subsequent applications to complex molecule synthesis. Therefore, the need for exploration of traceless or easily removable directing groups that can address these drawbacks remains urgent. Recently, Huang et al. reported a N–H indole directed sequential cascade olefination/cyclization reaction (Scheme 1c).¹³ However, the substrate scope of this transformation is limited, stepwise operation procedure is required, thus make this process tedious. Herein, we reported a Rh-catalyzed N–H free indole directed dialkenylation followed by an intramolecular cascade cyclization reaction leading to the efficient synthesis of 6H-isoindolo[2,1-a]indole.Open in a separate windowScheme 2Reaction under air.Our initial study was carried out by examining 2-phenyl indole 1a and ethyl acrylate 2a in the presence of [RhCp*Cl₂]₂ and Cu(OAc)₂·H₂O in DMF under argon atmosphere ( EntrySolventCatalystAdditiveYield1 o-xylene[Cp*RhCl₂]₂Na₂CO₃10%2DMF[Cp*RhCl₂]₂—54%3^b t-AmylOH[Cp*RhCl₂]₂AgSbF₆Trace4DMF[Cp*RhCl₂]₂CsOAc55%5DMF[Cp*RhCl₂]₂K₃PO₄·3H₂O23%6DMF[Cp*RhCl₂]₂ t-BuOK—7^cDMF[Cp*RhCl₂]₂CsOAcTrace8^dDMF[Cp*RhCl₂]₂CsOAcTrace9^eDMF—CsOAc—10DMF[RuCl₂(p-cymene)]₂CsOAcTrace11DMFRhCl(PPh₃)₃CsOAcTrace12DMF[Cp*RhCl₂]₂Cu(acac)₂Trace13^fDMF[Cp*RhCl₂]₂CsOAc86%Open in a separate window^aReaction on a 0.2 mmol scale, using 1a (1.0 equiv.), 2a (1.5 equiv.), additive (2.0 equiv.), Cu(OAc)₂·H₂O (2.0 equiv.), [TM] (3 mol%), solvent (1.5 mL), under N₂, 21 h, isolated yield.^bAdditive (0.15 equiv.).^cWithout oxidant.^d10 mol% [Cu] under O₂.^eWithout [Rh].^fUsing 2a (2.5 equiv.), [Rh] (5 mol%), 41 h.With the optimized conditions in hand, we next tend to investigate the scope of this transformation (14 also smoothly participated in this reaction. Currently, no electron-biased alkenes (for example: 1-octene) failed to afford the desired products for some unknown reasons.Substrates scope^a

A mild one-pot synthesis of 2-iminothiazolines from thioureas and 1-bromo-1-nitroalkenes

A mild method to access functionalized 2-iminothiazolines in a facile and efficient manner has been developed. The reaction started from 1,3-disubstituted thioureas and 1-bromo-1-nitroalkenes in the presence of triethylamine in THF and proceeded smoothly in air to afford 2-iminothiazoline derivatives in moderate to good yields.

A mild method to access functionalized 2-iminothiazolines in a facile and efficient manner has been developed.

Functionalized 2-iminothiazoline has been an important building block in organic chemistry.¹ Its derivatives show significant pharmacological activities such as bactericidal and fungicidal activity.² In addition, they are found in drug applications for treatment of allergies, hypertension, inflammations, bacterial and HIV infections.³ Pifithrin (Pft-α) (Fig. 1), isolated by screening of chemical libraries using 2-iminothiazoline skeleton, is a lead compound for p53 inactivation and has received increasing attention due to its possible applications in therapy of Alzheimer''s disease, Parkinson''s disease, stroke and other pathologies related to various signalling pathways.⁴ Hence, its utility and applicability are widely recognized in organic and biological areas.Open in a separate windowFig. 1Pharmacologically important molecules consisting of 2-iminothiazoline core structure. (a) p53 inactivator; (b) skin whitening agent; (c) anti-inflammatory agent.The classical synthesis of 2-aminothiazole moiety involves the Hantzsch condensation reaction of thioureas and α-haloketones.⁵ Birkinshaw et al. reported the synthesis of N-alkylated imino-thiazolines by replacing thioureas with mono-N-substituted thioureas.⁶ Also, several alternative strategies have been devised, which include synthesis of highly functionalized thiazoles and 2-iminothiazolines by replacing α-haloketone with 2,2-dicyano-3,3-bis(trifluoromethyl)oxirane⁷ and 2-chlorooxirane,⁸ treatment of α-bromoketimines with potassium thiocyanate,⁹ reaction of N-monoalkylated thioureas with 3-bromomethyl-2-cyanocinnamonitrile,¹⁰ cycloadditions followed by elimination of 5-imino-1,2,4-thiazolidin-3-ones with enamines and ester enolate,¹¹ ring transformation of 1-arylmethyl-2-(thiocyanomethyl)aziridines in the presence of TiCl₄ and acyl chloride,¹² reaction of N-propargylaniline with acyl isothiocyanates.¹³ Less general approaches towards the synthesis of these compounds involve the reaction of ketone either with N-alkyl rhodanamine or bisbenzyl formamidine disulfide¹⁴ or the reaction of α-chloroketones with thiosemicarbazide in an acidic medium,¹⁵ condensation of α-haloketones with N-benzoyl-N′-arylthioureas or N,N′-disubstituted thioureas.¹⁶Although some of the methods used for preparing 2-iminothiazolines are convenient and effective, most procedures reported in literatures require arduous preparation of precursor substrates or harsh reaction conditions. Till now, only a few procedures on the one-pot synthesis of 2-iminothiazoline from N,N′-dialkylthiourea and in situ generated α-bromoketones have been reported.¹⁷ Herein, we reported a novel and efficient methodology for the synthesis of 2-imino-5-nitrothiazolines using 1,3-diarylthioureas and 1-bromo-1-nitroalkenes as starting materials.The β-bromo-β-nitrostyrenes, with β-disubstituted styrene structure, showed versatile reactivity as a trifunctional synthon. Previous literatures showed their activity as Michael acceptors and [3 + 2] and [4 + 2] cycloaddition partners.¹⁸ In our preliminary experiments, the reaction of 1,3-diphenylthiourea and β-bromo-β-nitrostyrene 1a was studied, while the latter one could easily be prepared according to the reported procedure.^18e We found that when these two reactants were treated with base such as K₂CO₃ in THF at room temperature under atmospheric air, a red crystalline product was obtained ( Entry^aBaseSolventTemperature (°C)Time (h)Yield (%)1K₂CO₃THFrt24622^bK₂CO₃THF7010603Et₃NTHFrt24724^bEt₃NTHF7010655DBUTHFrt24636^bDBUTHF7010587KHCO₃THFrt24558^bKHCO₃THF7010609DIPEATHFrt246810NoneTHFrt242911^cEt₃NTHFrt246412^dEt₃NTHFrt245813^eEt₃NTHFrt241714Et₃NCH₂Cl₂rt244515Et₃NToluenert244216^bEt₃NToluene110540Open in a separate window^aReactions were performed with β-bromo-β-nitrostyrene 1a (0.10 mmol) and 1,3-diphenylthiourea 2a (0.11 mmol) with base (0.02 mmol) in the indicated solvent (2.0 mL) under atmospheric air.^bβ-Bromo-β-nitrostyrene was completely consumed.^cReaction was carried out with 0.04 mmol of base.^dReaction was carried out with 0.01 mmol of base.^eReaction was carried out with 0.1 mmol of base.This structure was later confirmed by single crystal X-ray analysis as shown in Fig. 2. When the reaction temperature was increased to 70 °C, the reaction was completed in shorter time. However, the yield was lower due to an increase of side products (Open in a separate windowFig. 2X-ray crystallography of compound 3a.Several other bases were tested such as K₂CO₃, Et₃N, DBU, KHCO₃, DIPEA, and Et₃N was found to give the best results ( Open in a separate window^aReactions were performed with 1-bromo-1-nitroalkenes 1a–1n (0.10 mmol) and 1,3-diarylthioureas 2 (0.11 mmol) with Et₃N (0.02 mmol) in THF (2.0 mL) at room temperature in the air for 24 hours.A plausible mechanism for this reaction has been proposed as shown in Scheme 1. Initially, a typical Michael addition happens with the β-bromo-β-nitrostyrene 1a,¹⁹ which is initiated by the attack of lone pair of nitrogen atom in 1,3-diphenylthiourea 2a, affording intermediate II. The successive tautomerism of thiourea structure and nucleophilic substitution in intermediate II generates five-membered ring intermediate III. Deprotonation of intermediate III by preceding bromide ion affords intermediate IV which subsequently undergoes aromatization with aid of atmospheric oxygen,²⁰ yielding final product 3a.Open in a separate windowScheme 1Plausible reaction pathway.     

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

Dual C–H activation: Rh(iii)-catalyzed cascade π-extended annulation of 2-arylindole with benzoquinone

A rhodium-catalyzed, N–H free indole directed cyclization reaction of benzoquinone via a dual C–H activation strategy is disclosed. This protocol has a good functional group tolerance and affords useful indole-fused heterocylces. Besides, it is insensitive to moisture, commercially available solvent can be directly used and work quite well for this transformation.

A Rh-catalyzed cascade annulation of N–H free 2-arylindole with benzoquinone via dual C–H activation strategy was reported.

Quinones are widely distributed in nature, and commonly occur in bacteria, flowering plants and arthropods (Fig. 1). They have a wide range of applications, including diverse important pharmacological properties, involvement in redox reactions and development for advanced electrochemical energy storage.¹ Among varied reported quinones, benzoquinone (BQ) is the simplest and most important one. It has been well reported that BQ has a significant and unique role in oxidative palladium(ii)-catalyzed coupling reactions.² The chemistry of benzoquinone has been extensively explored in detail, including nucleophilic addition and cycloaddition reactions, photochemistry and oxidative coupling.^1b,c,2 Although great achievements have been obtained, only a few examples are disclosed about BQ as a reactant applying to transition-metal catalyzed C–H functionalization.^1e Among the examples reported, cyclization or BQ direct functionalization products were mainly afforded (Scheme 1a).Open in a separate windowFig. 1Selected examples of bioactive molecules containing the benzoquinone moiety.Open in a separate windowScheme 1Transition-metal catalyzed C–H functionalization of BQ.Transition-metal catalyzed C–H functionalization has undergone great progresses in the past two decades.³ In order to get a better reactivity and controlled selectivity, a directing group is usually needed for this process. Therefore, various directing groups have been developed.⁴ However, many of them (e.g. various nitrogen-containing heterocycles) remained parts of products after reaction, therefore increasing the procedures and difficulty for structure further modification and manipulation.⁵ As a result, it is highly demanded to explore traceless or easily removable directing groups.⁶ In this context, N–H free indole moiety has gradually emerged as a versatile functionalizable directing group in transition-metal catalyzed cyclization reaction.⁷On the other hand, although the above-mentioned great breakthrough obtained in C–H functionalization, there are few examples reported for dual C–H activation reactions.⁸ During our research program exploring transition-metal catalysis and heterocyclic synthesis,⁹ we intended to prepare the indole-containing heterocycles based on the consideration of their potential biological activity. Herein, we report a rhodium-catalyzed N–H free indole directed annulation reaction with BQ through dual C–H activation strategy (Scheme 1b).Our initial study was carried out by examining 2-phenyl indole 1a and benzoquinone 2a in the presence of [{Cp*RhCl₂}₂] and Cu(OAc)₂·H₂O in commercial available N,N-dimethylformamide under argon atmosphere. To our delight, the desired 9H-dibenzo[a,c]carbazol-3-ol product 3a was isolated in 55% yield ( EntrySolventCatalystAdditiveYield1DMF[Cp*RhCl₂]₂Cu(OAc)₂·H₂O55%2DMF[Cp*RhCl₂]₂—<5%3DMF—Cu(OAc)₂·H₂O—4 t-Amyl-OH[Cp*RhCl₂]₂Cu(OAc)₂·H₂O—5DMAc[Cp*RhCl₂]₂Cu(OAc)₂·H₂O<5%6DMSO[Cp*RhCl₂]₂Cu(OAc)₂·H₂OTrace7DMF[RuCl₂(p-cymene)]₂Cu(OAc)₂·H₂O—8DMFPd(OAc)₂Cu(OAc)₂·H₂O—9DMFRhCl(PPh₃)₃Cu(OAc)₂·H₂O<5%10DMF[Cp*RhCl₂]₂AgOAc—11DMF[Cp*RhCl₂]₂Ag₂O—12DMF[Cp*RhCl₂]₂Cu(acac)₂Trace 13 ^{bb , cc} DMF/DCE[Cp*RhCl₂]₂Cu(OAc)₂·H₂O 84% Open in a separate window^aReaction on a 0.2 mmol scale, using 1a (1.0 equiv.), 2a (1.0 equiv.), additive (2.0 equiv.), CsOAc (2.0 equiv.), [TM] (5 mol%), solvent (1.0 mL), under N₂, isolated yield.^b1a (1.5 equiv.), solvent (0.3 M).^cNaOAc was used instead of CsOAc.With the optimized conditions in hand, we next tend to examine the substrates scope of this reaction. Various 2-aryl indoles with electron-rich substituted groups were tested and worked well for this reaction (10 Finally, an interesting S, N-fused heterocycle 3m was obtained when 2-thienyl indole was employed. Other derivatives of benzoquinone such as 1,4-naphthaquinone or methyl-p-benzoquinone currently failed to produce the related cyclization products with proper yields.Substrates scope^a

Sodium borohydride-nickel chloride hexahydrate in EtOH/PEG-400 as an efficient and recyclable catalytic system for the reduction of alkenes

An efficient, safe and one-pot convenient catalytic system has been developed for the reduction of alkenes using NaBH₄–NiCl₂·6H₂O in EtOH/PEG-400 under mild conditions. In this catalytic system, a variety of alkenes (including trisubstituted alkene α-pinene) were well reduced and the Ni catalyst could be recycled.

An efficient, safe and one-pot convenient catalytic system has been developed for the reduction of alkenes using NaBH₄–NiCl₂·6H₂O in EtOH/PEG-400 under mild conditions.

The reduction of alkenes is an important transformation in organic synthesis, widely used particularly in petrochemical, pharmaceutical, and fine chemical processes. Traditionally, direct hydrogenation,^1–4 catalytic hydrogen transfer ^5–7and hydride reduction methods^8–10 have been employed for the reduction of alkenes. Among the reported methods, the utility of sodium borohydride for the reduction of simple alkenes first described by Brown in 1962 is well known.¹¹ In recent years, several related catalytic systems on modification of Brown''s approach have been developed. These catalytic systems include NaBH₄/NiCl₂·6H₂O/moist alumina in hexane,¹² InCl₃–NaBH₄ reagent system,¹³ NaBH₄/RuCl₃ under aqueous conditions,¹⁴ NaBH₄/CH₃COOH in the presence of Pd/C¹⁵ and NaBH₄-RANEY® nickel system in water.¹⁶ Nevertheless, most of these systems require costly transition metal catalyst, long reaction time and a large excess of NaBH₄. In addition to this, little has been done to recycle the catalyst for the reduction of alkenes using NaBH₄. Thus, a very simple, efficient and recyclable system for the reduction of alkenes by NaBH₄ would be highly desirable.In the reduction of alkenes by NaBH₄, the in situ generated metal nanoparticles (NPs) from the combination of appropriate metal salts and NaBH₄ catalyze the reduction of alkene.¹⁵ In general, metal NPs tend to agglomerate during the catalytic processes and therefore need to be protected by stabilizers.¹⁷ Castro et al. ever noticed the aggregation of NPs after just one time in the reduction of alkenes by NaBH₄ without use of a stabilizer.¹⁸ Immobilized nanoparticles (NPs) on insoluble solid supports were generally used for this process in the past literature.^12,15,16 One significant example was that Takashi Morimoto and coworkers reached 90% yield of ethylbenzene within 3 h using NiCl₂·6H₂O on moist alumina reducted by NaBH₄ in hexane at 30 °C.¹² Unfortunately, heterogeneous catalysts of NPS on solid supports are often more inert than corresponding soluble NPs catalysts.¹⁹ In view of the above, we wanted to explore the use of soluble NPs generated in situ for this process. PEG-400 is known to be an excellent dispersion agent and stabilizer for soluble metal NPs.^20,21 Abdul Rahman Mohamed et al. found that iron metal NPs formed in an ethanol-PEG-400 solution displayed a more uniform distribution.²² In this work, we introduce NaBH₄/NiCl₂·6H₂O in EtOH/PEG-400 to the reduction of alkenes, to the best of our knowledge, the system is novel for the reaction. The novel system was expected to show the following advantages (Scheme 1): (a) NaBH₄ not only reduces Ni²⁺ to soluble Ni (0) NPs in situ, but also serves as hydrogen donation for the reduction of alkenes with ethanol; (b) the in situ generated soluble Ni (0) NPs catalyst stabilized by PEG-400 is stable, efficient and recyclable for the reduction of alkenes.Open in a separate windowScheme 1Reduction of alkenes using NaBH₄–NiCl₂·6H₂O in EtOH/PEG-400 system.We first chose the reduction of styrene as model reaction (12,15,23,24 This is possibly because the hydrogen source for the reduction can be sufficiently derived from the B–H of NaBH₄ and the O–H of ethanol in our catalytic system (ideally 1 molar of NaBH₄ can reduce 4 molar of alkenes with ethanol), as recently reported by Bai et al. for the semihydrogenation of alkynes with NaBH₄ in methanol.²⁵ The activity of the in situ generated Ni (0) NPs catalyst in EtOH/PEG-400 (3/2 ratio) had also been compared with the commercial RANEY® nickel catalyst. The results revealed that the in situ generated Ni (0) NPs exhibited a higher activity for the reduction of styrene (entries 4, 20). Thus, we can conclude that the EtOH/PEG-400 using NiCl₂·6H₂O–NaBH₄ is a very simple and efficient system for the reduction of styrene.Optimization of reaction conditions for the reduction of styrene^a

Organic dye-catalyzed radical ring expansion reaction

Herein, we reported an attractive method for synthesizing medium-sized rings that are catalyzed by erythrosine B under fluorescent light irradiation. This synthetic approach featured mild conditions, a facile procedure, a broad substrate scope, and moderate-to-good yields.

Herein, we reported an attractive method for synthesizing medium-sized rings that are catalyzed by erythrosine B under fluorescent light irradiation.

Medium-sized rings are present in numerous important natural products and pharmaceuticals.¹ Therefore, several researchers have strived to develop various methods, including olefin metathesis,² fragmentation,³ and pericyclic reactions⁴ (Scheme 1(a)), for synthesizing these materials. Nevertheless, unfavorable transannular interactions and entropic factors typical of rings of this size make this task quite challenging.⁵ Thus, we believe that new methods need to be developed to solve these problems.Open in a separate windowScheme 1(a) Examples of conventional approaches for the synthesis of medium-sized rings. (b) Beckwith–Dowd ring expansion reaction.More than 30 years ago, the Beckwith–Dowd ring expansion reaction⁶ was introduced as a novel method to form medium-sized rings (Scheme 1(b)). This approach can be an attractive alternative to conventional strategies for synthesizing the abovementioned structures. Actually, the fact that no new unsaturated C–C bonds are formed as part of this method renders hydrogenation processes unnecessary, thereby minimizing the impact of transformation on the substrate. Certainly, this approach could be applicable to the synthesis of natural products.⁷ However, the original method requires reagents, e.g., azobisisobutyronitrile (AIBN) or tributyltin hydride (Bu₃SnH), that are difficult to handle. Some related methods that employ other reagents, including Sm,⁸ Zn or In,⁹ B₁₂–TiO₂ hybrid catalyst,¹⁰ silane,¹¹ and amines,¹² have been reported. Recently, a few synthetic approaches based on photo-induced reactions have been developed.^12b,12d,13 A previous study reported that even α-(ω-carboxyalkyl) β-keto esters could be employed as relevant substrates.¹³In this context, we aimed to establish a more efficient and facile method than conventional ones to prepare a broad range of medium-sized rings via a ring expansion reaction. We continuously investigated various photo-initiated reactions by employing a photosensitizer and a fluorescent lamp as a light source.¹⁴ For example, the CDC cross-coupling reaction^14a and 1,3-dipolar cycloaddition/aromatization reaction^14d under photooxidative reaction conditions have been reported. While investigating these reactions, we found that organic dyes induced electron transfer from amine substrates to molecular oxygen.^14a,14d Thus, we envisioned that C–halogen bonds can be cleaved in the presence of a sacrificial amine using photosensitized substrates as a springboard. Herein, we reported a convenient and environmentally friendly method that employs a photo-induced reaction as part of the Beckwith–Dowd ring expansion route to synthesize medium-sized rings.We initiated our study with the optimization of the reaction conditions (15 This result can be explained by two facts: (a) the maximum absorption of EB (∼520 nm)¹⁶ coincides with the wavelength of the fluorescent lamp and (b) ⁱPr₂NEt is an effective reductive quencher (E_ox(ⁱPr₂NEt˙⁺/ⁱPr₂NEt) = +0.68 V vs. SCE; e.g., E_ox(NEt₃˙⁺/NEt₃) = +0.99 V vs. SCE).^17a,17b In fact, when we employed other combinations of photocatalysts, amines, and solvents, 2a was obtained in a relatively lower yield. Furthermore, in our experiments, we recovered 1a and/or its undesired hydrogenation product 1a′ from the reaction mixture in substantial amounts (entries 2–9).Optimization of the reaction conditions

TfOH mediated intermolecular electrocyclization for the synthesis of pyrazolines and its application in alkaloid synthesis

TfOH mediated easy access to interesting pyrazolines starting from an aldehyde, phenylhydrazine and styrene has been developed. The scope of this synthetic methodology has been explored by synthesizing various 1,3,5-trisubstituted pyrazolines in very good yields with very high regioselectivity. The origin of regioselectivity has been explained by comparing the stability of possible intermediate carbocations. The synthetic utility of a green solvent has been explored by synthesizing some of pyrazolines in a DES medium. The synthetic application of the present methodology is employed in the synthesis of a pyrazoline alkaloid.

A metal free and green synthetic methodology employing aldehydes, phenylhydrazine and styrene mediated by TfOH has been developed to access 1,3,5-trisubstituted pyrazolines. The synthetic application of the methodology is demonstrated in the synthesis of a pyrazoline alkaloid.

Pyrazoles and pyrazolines are known to exhibit interesting biological and photo-physical behaviours. The biological activities of pyrazoles/pyrazolines have been discussed in several reviews.^1–4 A few representative examples of biologically and medicinally important pyrazoles and pyrazolines are given in Fig. 1.^5–7 In particular, considerable interest has been focused on 1,3,5-trisubstituted pyrazoline derivatives due their potential pharmacological activities including (i) antitubercular activity against the H37Rv strain of Mycobacterium,⁹ (ii) antiproliferative activity,^8,10 (iii) antibacterial activity,^11–13 (iv) antiobesity effect in an animal model of the potent cannabinoid CB1 receptor antagonist,¹⁴ (v) pre-emergent herbicide activity against various kinds of weeds,¹⁵ and (vi) ACE-inhibitory activity with 0.123 mM IC504.¹⁶ Pyrazoline derivatives show enhanced biological activity compared with their corresponding pyrazoles.¹⁷ In addition, the pyrazoline motif is known to exhibit photo-luminescent behaviour due to intra-molecular charge transfer (ICT) in the excited state and also shows hole transport behaviour.^18–24Open in a separate windowFig. 1Representative examples of medicinally important 1,3,5-trisubstituted pyrazolines and pyrazoles.Various synthetic approaches have been developed to access these biologically important 1,3,5-trisubstituted pyrazoline/pyrazole compounds.^25–28 The most general synthetic approach proceeding via a reaction of 1,3-dicarbonyl compounds with arylhydrazines results in poor regioselectivity.^3,29,30 A synthetic method which employs appropriate chalcones and arylhydrazines has been considered to be the most widely accepted method for accessing pyrazolines, but this method falls behind due to a greater number of synthetic steps involved.^31–34 Recently Wang et al. disclosed a methodology proceeding via a three component [3 + 2] cycloaddition using 20 mol% Cu(OTf)₂ at elevated temperature.³⁵ The development of synthetic methodology to prepare active pharmaceutical ingredients (APIs) would preferably involve (i) high regioselectivity, (ii) diversity in substrates, (iii) the least number of synthetic steps involved and (iv) attaining target compounds, free of metal traces. Hence, a regioselective tandem one-pot intermolecular electrocyclization reaction under metal free condition to access 1,3,5-trisubstituted pyrazolines would be of great importance.In this regard, we are disclosing a general, metal free and green synthetic methodology to access diverse pyrazoline derivatives with various functionalities including –NO₂, –OH and aliphatic groups using arylhydrazines, aldehydes and styrenes. We have obtained the corresponding pyrazoline products in very good yields with enhanced regioselectivity. In addition, we have employed this synthetic methodology in the synthesis of a pyrazoline alkaloid (1,5-diphenyl-3-styryl-2-pyrazoline).In our initial studies to attempt metal free conditions, iodine mediated intermolecular electrocyclization of tolualdehyde 1a, phenylhydrazine 2a and styrene 3 was explored (l-proline, CH(OMe)₃, TFA, p-TSA and MeSO₃H (Scheme 1).^36,37 The use of other solvents such as H₂O, DMF, DMSO and ethanol did not result in product formation, as TfOH might be deactivated by these solvents (see ESI, Table S1^†).Optimization of reaction conditions in the synthesis of pyrazoline 4a^a

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

Access to 1-amino-3,4-dihydroisoquinolines via palladium-catalyzed C–H bond aminoimidoylation reaction from functionalized isocyanides

Efficient access to 1-amino-3,4-dihydroisoquinolines, through palladium-catalyzed intramolecular C–H bond aminoimidoylation of α-benzyl-α-isocyanoacetates, has been developed. Consecutive isocyanide insertion and C–H bond activation were realized with C–N and C–C bonds formation in one step under redox neutral conditions, employing O-benzoyl hydroxylamines as electrophilic amino sources.

Efficient and practice access to 1-amino-3,4-dihydroisoquinolines, through palladium-catalyzed intramolecular C–H bond aminoimidoylation of α-benzyl-α-isocyanoacetates, has been developed.

As a class of cyclic amidine compounds, 1-amino-3,4-dihydroisoquinolines are essential six-membered heterocycles which can be found in numerous natural products, functional chemicals and pharmaceutical agents (Scheme 1).¹ For example, piperazine tethered dihydroisoquinoline and benzocyclic amide I was found to be an efficient cardiovascular agent.^1a Phenylalanine-derived and arylamine or cyclic aliphatic-amine-containing 1-amino-3,4-dihydroisoquinolines (II–V) show outstanding BACE-1 inhibition, kinase VEGFR-2 inhibition, phosphodiesterase IV inhibition and hydrogen ion-sodium exchanger NHE-3 inhibition activities, respectively.^1b–e Traditional preparation of such 1-amino-3,4-dihydroisoquinoline scaffolds is mainly based on nucleophilic substitution of readily prepared 3,4-dihydroisoquinolines² and Bischler-Napieralski reaction starting from urea.³ Most of these methods suffer from multiple-step synthesis, harsh conditions or the use of toxic reagents. Thus, developing an efficient and practical method for the construction of 1-amino-3,4-dihydroisoquinoline derivatives remain an attractive synthetic task.Open in a separate windowScheme 1(a) Representative bioactive molecules containing the 1-amino-3,4-dihydroisoquinoline moiety. (b) Traditional synthetic methods.In recent decades, isocyanides have been extensively studied in multicomponent reactions,⁴ imidoyl radical-involved transformations⁵ and transition-metal-catalyzed insertion reactions⁶ due to their diverse and unique reactivities. A variety of acyclic imine derivatives were synthesized via palladium-catalyzed imidoylation reactions.⁷ For the construction of biorelevant nitrogen-containing heterocycles via Pd-catalyzed non-functionalized isocyanide insertion reactions, a nucleophilic group is usually preinstalled to the substrates containing C–X (C–H) bonds, followed by Pd-catalyzed oxidative addition (C–H bond activation)/isocyanide insertion/ligand substitution/reductive elimination sequence.⁸ For example, Maes and coworkers developed an efficient palladium-catalyzed synthesis of 4-aminoquinazolines from N-(2-bromoaryl)amidines using amidine as an internal nucleophile.^8a Access to the same scaffold through palladium-catalyzed amidine-directed C–H bond imidoylation/cyclization reaction was reported by Zhu group.^8c Isocyanide acted as a C1 synthon in these cyclization reactions, with the terminal carbon of isocyanide being used in the ring formation.⁹ Considering the diversity of R group on the nitrogen atom of isocyanide, the so-called functionalized isocyanide strategy was widely developed as well, with various N-heterocycles such as oxazoles,¹⁰ indoles,¹¹ phenanthridines,¹² 9H-pyrido[3,4-b]indoles¹³ and nonaromatic azepines¹⁴ being synthesized efficiently. Zhu and coworkers developed the first asymmetric C–H bond imidoylation reaction from easily accessible α,α-dibenzyl-α-isocyanoacetates with chiral quaternary-carbon-containing 3,4-dihydroisoquinolines being generated (Scheme 2a).¹⁵ Recently, a catalytic system controlled regioselective C–H bond imidoylation was realized for the selective synthesis of 5 or 6-membered cyclic imines (Scheme 2b).¹⁶ Aryl halides were mostly used in these transformations while N–O compounds were rarely reported as electrophiles in Pd-catalyzed isocyanide insertion reactions.¹⁷ Zhu group reported the synthesis of phenanthridin-6-amine derivatives from O-benzoyl hydroxylamines and commonly used biaryl isocyanides.^17c However, a methyl or methoxyl carbonyl group was needed at the ortho position of isocyano group, which critically limited the application of the reaction. Herein, we developed an efficient and practical synthesis of 1-amino-3,4-dihydroisoquinolines, through palladium-catalyzed intramolecular C–H bond aminoimidoylation reaction of α-benzyl-α-isocyanoacetates. Consecutive isocyanide insertion and C–H bond activation were realized with C–N and C–C bonds being constructed in one step, employing O-benzoyl hydroxylamines as electrophilic amino sources.Open in a separate windowScheme 2Palladium-catalyzed imidoylative cyclization of α-benzyl-ethylacetates.The reaction conditions were optimized with ethyl 2-benzyl-2-isocyano-3-phenylpropanoate (1a) and morpholino benzoate (2a) as model substrates, and ethyl 3-benzyl-1-morpholino-3,4-dihydroisoquinoline-3-carboxylate (3a) was obtained in 34% yield in the presence of Pd(OAc)₂ (1.5 equiv.), PPh₃ (20 mol%), Cs₂CO₃ (1.0 equiv.) and PivOH (0.6 equiv.) in toluene at 80 °C (entry 1, EntryCatalystLigandSolventYield^b1Pd(OAc)₂PPh₃Toluene342Pd(OAc)₂PPh₃THFTrace3Pd(OAc)₂PPh₃DCE294Pd(OAc)₂PPh₃Dioxane765Pd(OAc)₂PPh₃MeCNTrace6Pd(OAc)₂PPh₃DMSOTrace7Pd(OPiv)₂PPh₃Dioxane318Pd(TFA)₂PPh₃Dioxane269PdCl₂(MeCN)₂PPh₃Dioxane3811Pd(PPh₃)₄Dioxane5612Pd(OAc)₂BINAPDioxane3013Pd(OAc)₂dppbDioxane2614Pd(OAc)₂dpppDioxane2815Pd(OAc)₂XantPhosDioxane4216Pd(OAc)₂SPhosDioxane3417Pd(OAc)₂XPhosDioxane2418^cPd(OAc)₂PPh₃Dioxane84 (80)^d19^cNonePPh₃Dioxane020^cPd(OAc)₂NoneDioxane5621^c,ePd(OAc)₂PPh₃Dioxane022^c,fPd(OAc)₂PPh₃Dioxane4123^c,gPd(OAc)₂PPh₃Dioxane2424^c,hPd(OAc)₂PPh₃Dioxane3125^c,iPd(OAc)₂PPh₃Dioxane61Open in a separate window^aReaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), Pd-catalyst (0.01 mmol, 10 mol%), ligand (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 80 °C, Ar. A solution of 1a was added via a syringe pump within 1 h.^bNMR yield with 1-iodo-4-methoxybenzene as an internal standard.^c T = 110 °C.^dIsolated yield.^eWithout Cs₂CO₃ and PivOH.^fCsOPiv was used as the base.^gK₂CO₃ was used as the base.^hNa₂CO₃ was used as the base.ⁱ5 mol% of catalyst was used.With the optimized conditions in hand, the scope of functionalized isocyanide was investigated first, using morpholino benzoate 2a as the coupling partner (Scheme 3). Both electron rich and withdrawing substituents such as Me, t-Bu, F, Cl, CF₃, CO₂Me and NO₂ at the para position of aromatic ring can tolerate the reaction conditions, and generate the corresponding products in good to excellent yields (3a–3h). Isocyanides bearing ortho substituents on the phenyl ring underwent the reaction smoothly, generating the products 3i and 3j in 58% and 82% yields respectively. Even substrates bearing two substituents were well suited to the reaction conditions, affording the aminoimidoylation products without loss of efficiency (3k–3l). Compound 3m was delivered with excellent regioselectivity in 63% yield when m-Cl substituted starting material was employed in the reaction, which indicated the hindrance sensitivity of this reaction. Modifying the ester moiety in 1 to a methyl ester or an amide did not impede the reaction, giving 3n and 3o with excellent yields. Changing one of the benzyl groups to alkyl substituents didn''t decrease the reaction efficiency, generating products 3p and 3q in moderate yields.Open in a separate windowScheme 3Scope of isocyanides. Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 110 °C, Ar. A solution of 1 was added via a syringe pump within 1 h. Isolated yields.Then we moved our attention to the investigation of substrate scope of aminating partners (Scheme 4). It was found that various O-benzoyl hydroxylamines derived from piperidines could be smoothly employed in the reaction (4a–4e). Substituents such as Me, CO₂Et, OMe and ketal group on the piperidines were well tolerated (4b–4e). Aminating reagent derived from Boc-protected piperazine was also compatible with this reaction, generating the product 4f in 99% yield. Fortunately, acyclic aminated product 4g was obtained as well in moderate yield.Open in a separate windowScheme 4Substrate scope of aminating agents. Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 110 °C, Ar. A solution of 1a was added via a syringe pump within 1 h. Isolated yields.When ethyl 2-isocyano-2,3-diphenylpropanoate was conducted in the reaction with 2a, the 3,4-dihydroisoquinoline product 6 was generated exclusively, albeit in only 37% yield (Scheme 5a). To examine if isoindoline could be afforded by this aminoimidoylation reaction, ethyl 2-isocyano-4-methyl-2-phenylpentanoate (7) was selected as the substrate with 2a (Scheme 5b). However, no desired product was generated under the standard conditions, showing different site-selectivity with the previous imidoylation reaction developed by Zhu and coworkers.¹⁶Open in a separate windowScheme 5Reaction conditions: 5(7) (0.1 mmol), 2a (0.15 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 110 °C, Ar. A solution of 5(7) was added via a syringe pump within 1 h. Isolated yields.Gram-scale preparation of 3a was carried out smoothly under standard conditions (Scheme 6a). The reduction reaction of 3a was carried out using LiAlH₄ and the corresponding product 8 was generated in 70% yield (Scheme 6b). The ester group was successfully transformed to tertiary alcohol (9) in moderate yield with Grignard reagent.Open in a separate windowScheme 6Gram-scale preparation and diversifications of 3a.In order to get further insight into the reaction mechanism, a radical trapping reaction with 0.1 equivalents of TEMPO was carried out (Scheme 7a). The product 3a was generated without loss of efficiency, which indicated that the radical-involved pathway could be ruled out. A plausible mechanism was then proposed in Scheme 7b. The reaction was initiated with oxidative addition of O-benzoyl hydroxylamine 2a to the in situ generated Pd(0) species. Migratory isocyanide insertion to intermediate B afforded aminoimidoyl Pd(ii) intermediate C. The following intramolecular C–H bond activation and reductive elimination viaE yielded the final product 3a and regenerated Pd(0) to complete the catalytic cycle.Open in a separate windowScheme 7Proposed mechanism.In conclusion, we have developed an efficient and practical method to prepare 1-amino-3,4-dihydroisoquinolines via palladium-catalyzed intramolecular C–H bond aminoimidoylation of α-benzyl-α-isocyanoacetates under redox-neutral conditions. Consecutive isocyanide insertion and C–H bond activation were realized with C–N and C–C bonds formation in one step, employing O-benzoyl hydroxylamines as electrophilic amino sources. A broad range of substrates were applicable to the reaction in good to excellent yields.     

Diastereoselective synthesis of chroman bearing spirobenzofuranone scaffolds via oxa-Michael/1,6-conjugated addition of para-quinone methides with benzofuranone-type olefins

A simple and convenient cyclization of ortho-hydroxyphenyl-substituted para-quinone methides with benzofuran-2-one type active olefins via oxa-Michael/1,6-conjugated addition has been developed, which afforded an easy access to enriched functionalized chroman-spirobenzofuran-2-one scaffolds with good to excellent yields (up to 90%) and diastereoselectivities (up to >19 : 1 dr). This reaction provided an efficient method for constructing desired spirocyclic compounds combining both well-known heterocyclic pharmacophores chroman and benzofuran-2-one.

Highly diastereoselective synthesis of spirocyclic compounds combining both well-known heterocyclic pharmacophores chroman and benzofuran-2-one.

The chroman framework represents a privileged heterocyclic core commonly found within a wide variety of biologically active natural products¹ and synthetic compounds of medicinal interest (Fig. 1).² Owing to the wide application of these heterocyclic molecules, over the past few decades, numerous efforts have been devoted to the efficient synthesis of chroman nucleus motifs.^3,4 In particular, incorporating chroman into spiro-bridged and spiro-fused heterocyclic systems is appealing due to its fascinating molecular architecture and proven biological activity.⁵ Among the existing methods, the [4 + m] cycloaddition of para-quinone methides (p-QMs) is found to be an efficient pathway to access these valuable spirocyclic skeletons.⁶ For instance, the Enders group synthesized functionalized chromans with an oxindole motif by the asymmetric organocatalytic domino oxa-Michael/1,6-addition reaction.⁷ After that, the Hao,^8a Peng,^8b Shi,^8c,d Zhou,^8e Liang^8f and Wang^8g groups developed convenient methods to construct chromans bearing spirocyclic skeletons from p-QMs, respectively. Despite all these shining achievements, however, it is still very challenging to simply and conveniently construct chromans bearing quaternary carbon spirals for organic chemical or drug discovery among these [4 + m] cycloaddition reactions.Open in a separate windowFig. 1Representative chroman compounds.Benzofuran-2-(3H)-ones as one of the important oxygen-containing heterocycles that exist in a broad array of natural products⁹ and potential medicines.¹⁰ The streamlined synthesis of benzofuran-2-ones pose considerable challenge due to their quaternary carbon centers at the C-3 position,¹¹ especially those featuring relatively congested spirocyclic motifs represent challenging synthetic targets.^12,13 In our continuous interests in developing efficient method for the synthesis of spirocyclic compounds based on cyclization reaction,¹⁴ we wish to report a cycloaddition of para-quinone methides with benzofuranone derived olefins, affording the spiro-cycloadducts in good to excellent yields and diastereoselectivities. This cyclization features the simultaneous formation of chroman and spirobenzofuran-2-one skeletons in a single step (Scheme 1), which may be potentially applied as pharmaceutical agents.Open in a separate windowScheme 1Strategy for the synthesis of chroman-spirobenzofuran-2-one.We initiated our investigations with the readily available ortho-hydroxyphenyl-substituted para-quinone methides 1a and 3-benzylidenebenzofuran-2-one 2a in toluene at room temperature in the presence of base. Unfortunately, no desired chroman derivatives bearing spirobenzofuranone scaffolds 3a was isolated in the presence of 2 eq. Na₂CO₃ after stirring at room temperature for 48 h (entry 1, EntryBaseSolventYield^b (%)Dr^c1Na₂CO₃Toluene——2DMAPToluene——3K₂CO₃Toluene253 : 14CsFToluene525 : 15Cs₂CO₃Toluene706 : 16Cs₂CO₃THF68>19 : 17Cs₂CO₃Et₂O608 : 18Cs₂CO₃Dioxane537 : 19Cs₂CO₃CH₃CN50>19 : 110Cs₂CO₃DMF3115 : 111^dCs₂CO₃THF65>19 : 112^eCs₂CO₃THF75>19 : 113^fCs₂CO₃THF64>19 : 1Open in a separate window^aReaction conditions: p-QMs 1a (0.1 mmol), benzofuranones 2a (0.12 mmol) and base (0.2 mmol) in 2 mL of solvent for 6–48 h.^bIsolated yields.^cDetermined by crude ¹H NMR analysis.^dPerformed at 30 °C.^ePerformed at 10 °C.^fPerformed at 0 °C.With the optimized reaction conditions in hand, we explored the substrate scope of this cyclization reaction with a selection of benzofuranones. The results are shown in EntryR3Yield^b (%)Dr^c1C₆H₅3a75>19 : 122-ClC₆H₄3b69>19 : 132-BrC₆H₄3c6715 : 142-CH₃C₆H₄3d64>19 : 153-CH₃C₆H₄3e75>19 : 163-MeOC₆H₄3f72>19 : 173-NO₂C₆H₄3g71>19 : 183-BrC₆H₄3h75>19 : 194-CH₃C₆H₄3i7310 : 1104-MeOC₆H₄3j86>19 : 1114-CF₃C₆H₄3k8212 : 1124-NO₂C₆H₄3l8512 : 1134-ClC₆H₄3m83>19 : 1144-BrC₆H₄3n8112 : 1152-Naphthyl3o74>19 : 1163,4,5-(OMe)₃C₆H₂3p8812 : 1173-Pyridinyl3q79>19 : 1183-Thiophenyl3r80>19 : 1Open in a separate window^aReaction conditions: p-QMs 1a (0.1 mmol), benzofuranones 2 (0.12 mmol) and Cs₂CO₃ (0.2 mmol) in 2 mL of THF.^bIsolated yields for 4–48 h.^cDetermined by crude ¹H NMR analysis.Subsequently, the generality of this cyclization reaction was further evaluated through varying p-QMs 1. As shown in EntryR4Yield^b (%)Dr^c15-Cl4a73>19 : 125-Br4b65>19 : 135-CH₃4c90>19 : 145-OCH₃4d8010 : 154-CH₃4e72>19 : 164-OCH₃4f6610 : 1Open in a separate window^aReaction conditions: p-QMs 1 (0.1 mmol), benzofuranones 2a (0.12 mmol) and Cs₂CO₃ (0.2 mmol) in 2 mL of THF for 6–48 h.^bIsolated yields.^cDetermined by crude ¹H NMR analysis.The structure and relative configuration of 3a were determined by HRMS, NMR spectroscopy and single-crystal X-ray analysis.¹⁵ The relative configuration of other cycloadducts were tentatively assigned by analogy (Fig. 2 and see ESI^†).Open in a separate windowFig. 2X-ray crystal structure of 3a.     

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.     

Direct phosphorylation of benzylic C–H bonds under transition metal-free conditions forming sp3C–P bonds

Direct phosphorylation of benzylic C–H bonds was achieved in a biphasic system under transition metal-free conditions. A selective radical/radical sp³C–H/P(O)–H cross coupling was proposed, and various substituted toluenes were applicable. The transformation provided a promising method for constructing sp³C–P bonds.

Direct phosphorylation of benzylic C–H bonds with secondary phosphine oxides was first realized. The reaction was performed in organo/aqueous biphasic system and under transition metal-free conditions, proceeding via the cross dehydrogenative coupling.

To construct C–P bonds is of great significance in modern organic synthesis,¹ because organophosphorus compounds play varied roles in medical,^2,3 materials,⁴ and synthetic chemistry fields.⁵ Traditionally, the C–P bonds were formed from P–Cl species via nucleophilic substitutions with organometallic reagents,⁶ P–OR species via Michaelis–Arbusov reactions,⁷ or P–H species via the alkylation in the present of a base or a transition metal.⁸Over the past decades, cross dehydrogenative coupling reactions (CDC reactions) have become a powerful and atom-economic methodology for constructing chemical bonds.⁹ By using this strategy, C–H bonds can couple with Z–H bonds without prefunctionalization and thus short-cut the synthetic procedures (Scheme 1a).Open in a separate windowScheme 1Cross dehydrogenative coupling reactions and direct phosphorylation of benzylic C–H bonds.A similar construction of C–P bonds via CDC was also realized.^10,11 Among these methods, the phosphorylation of sp³C–H having an adjacent N or O atom, or the carbonyl group was well-developed.¹¹ Relatively, the formation of benzylic sp³C–P bond was less reported,^11w which was mainly limited to the sp³C–H of xanthene or 8-methylquinoline (Scheme 1b).¹² In these reported processes, transition metal catalysts or photo-, electro-catalysts were usually involved,^11v and an excess of P(O)–H compounds was usually employed.^11,13 To the best of our knowledge, the phosphorylation of non-active benzylic C–H bonds has scarcely been reported.Considering both benzylic and phosphorus radicals could be generated by oxidation,¹⁴ which might subsequently couple, the phosphorylation of benzylic sp³C–H bonds would be achieved (Scheme 1c). Herein, we disclosed the construction of benzylic C–P bonds from toluene and P–H species. The reaction was carried out under transition metal-free reaction conditions,¹⁵ and exhibited high regio-selectivity. The aromatic C–H remained intact during the reaction.We began our investigation by exploring the reaction of toluene 1a and diphenylphosphine oxide 2a in the presence of an oxidant (16 Other persulfates could also be used as an oxidant albeit with decreasing yields ( EntryOxidantToluene/water (v/v)Additive3a yield^b (%)3a/4^c1K₂S₂O₈1 : 0—Trace—2K₂S₂O₈1 : 1—1216 : 843K₂S₂O₈1 : 1SDS3726 : 744Na₂S₂O₈1 : 1SDS3127 : 735(NH₄)₂S₂O₈1 : 1SDS2723 : 776Oxone1 : 1SDSNone—7—1 : 1SDSNone—8—1 : 1—None—9K₂S₂O₈1 : 1SDBS4136 : 6410K₂S₂O₈1 : 2SDBS4628 : 7211K₂S₂O₈1 : 3SDBS3524 : 7612^dK₂S₂O₈1 : 2SDBS4632 : 6813^eK₂S₂O₈1 : 2SDBS2621 : 7914^fK₂S₂O₈1 : 2SDBS2926 : 7415^gK₂S₂O₈1 : 2SDBS4838 : 6216^g,hK₂S₂O₈1 : 2SDBS0—Open in a separate window^aReaction condition: 1a (1 mL), 2a (0.2 mmol), oxidant (2 equiv.), additive (1 equiv.) and H₂O, 120 °C, 3 h. under N₂.^bGC yields using n-dodecane as an internal standard.^cThe ratio of 3a/4 was determined by GC analysis.^d50 mol% SDBS was used.^e20 mol% SDBS was used.^fAt 100 °C.^g1 (0.8 mL) and H₂O (1.6 mL), 3 equiv. K₂S₂O₈ was used, 120 °C for 15 min.^h3 equiv. TEMPO was added.Based on the above results, we can easily find that a serious amount of 1,2-diphenylethane 4 was formed. These results suggest that the homocoupling rate of 1a was very quick. Thus, the choice of the phase transfer reagent and oxidant is the key to cross-coupling of toluene and diphenylphosphine oxide in this biphasic solvent system.Excessive P–H species were usually employed in reported CDC reactions to form C–P bonds, because of their facile oxidation.¹³ In our procedure, toluene was excessive, thus the yields were calculated based on 2a. The yields looked like low, which did not indicate the poorer conversion rate of P–H species. With the optimized conditions in hand, the substrate scope of the CDC reactions was explored ( Open in a separate window^aReaction conditions: 1 (0.8 mL), 2 (0.2 mmol), K₂S₂O₈ (3 equiv.), SDBS (50%) and H₂O (1.6 mL), 120 °C, under N₂, the reactions were monitored by TLC and/or GC until 2 work out.^b1 mmol scale, 30 min.^c130 °C.^d100 °C.In addition to toluene, o-xylene, m-xylene, p-xylene, mesitylene, and 1,2,4,5-tetramethylbenzene all coupled with 2a to give the expected 3b–f in moderate yields. Methoxy substituted toluene gave relatively lower yields of 3g and 3h. para-Halo substituted toluene exhibited good reactivity, furnishing the coupling products 3i and 3j in moderate yields. Comparing to toluene, a decreasing order of reactivity was observed for ethyl benzene (3l, 30% yield), isobutyl benzene (3m, 27% yield), isopropyl benzene (3n, <10% yield), and diphenyl methane (3o, trace). The order was probably controlled by the steric hindrance around the benzylic carbon. 1-Methylnaphthalene and 2-methylnaphthalene also gave low yields (3p and 3q). However, 2-methylquinoline served well and coupled with 2a, affording the product 3r in 49% yield, which could be ascribed to the activation of the nitrogen atom. Besides of 2a, diaryl phosphine oxides having methyl, F, and Cl substituents could also be employed as the substrate, producing 3s–3u in moderate yields under similar reaction conditions.Although the mechanism of the direct phosphorylation of benzyl C–H bond in aqueous solution is not quite clear, some aspects could be grasped based on experimental results. Firstly, the desired product 3a was not detected when the 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added, implying that a radical pathway might be possible in this reaction (entry 16). Secondly, the reaction only occurred in aqueous phase, and relied on the presence of PTC (phase transfer catalyst), as seen in that 3a was difficultly formed in entries 1 and 2 of 17We supposed 1 is converted to benzyl radical 5 by SO₄⁻ radical that is generated via hemolytic cleavage of potassium persulfates.¹⁸ Meanwhile, phosphorus radical 6 is similarly formed from 2. Because potassium persulfate was water soluble, both 1 and 2 had to be transferred into aqueous solution to react with potassium persulfates.¹⁹ This proposal is also in accord with the experimental results that no products of sp²C–H phosphorylation are detected, which are the main products in the previous radical systems.²⁰ Finally, cross couplings between 5 and 6 produce 3 (Scheme 2).Open in a separate windowScheme 2Proposed mechanism for the direct phosphorylation of benzylic C–H bonds under transition metal-free reaction conditions.