Synthesis of tetrahydrochromenes and dihydronaphthofurans via a cascade process of [3 + 3] and [3 + 2] annulation reactions: mechanistic insight for 6-endo-trig and 5-exo-trig cyclisation期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索


Synthesis of tetrahydrochromenes and dihydronaphthofurans via a cascade process of [3 + 3] and [3 + 2] annulation reactions: mechanistic insight for 6-endo-trig and 5-exo-trig cyclisation

Authors:	Yeruva Pavankumar Reddy V. Srinivasadesikan Rengarajan Balamurugan M. C. Lin Shaik Anwar

Affiliation:	^a Department of Chemistry, School of Applied Sciences and Humanities, Vignan''s Foundation for Science Technology and Research-VFSTR (Deemed to be University), Vadlamudi-522213, Guntur Andhra Pradesh India, , +91-8632344700 ; ^b School of Chemistry, University of Hyderabad, Gachibowli, Hyderabad India, 500046 ; ^c Department of Applied Chemistry, National Yang Ming Chiao Tung University, Hsinchu 30010 Taiwan

Abstract:	Substituted tetrahydrochromenes and dihydronaphthofurans are easily accessible by the treatment of β-tetralone with trans-β-nitro styrene derived Morita–Baylis–Hillman (MBH) acetates through a formal [3 + 3]/[3 + 2] annulation. The reaction proceeds through a cascade Michael/oxa-Michael pathway with moderate to good yields. A DFT study was carried out to account for the formation of the corresponding six and five-membered heterocycles via 6-endo-trig and 5-exo-trig cyclization. A [3 + 3] and [3 + 2] annulation strategy using nitrostyrene derived MBH primary and secondary nitro allylic acetate for the construction of tetrahydrochromenes and dihydronaphthofurans at room temperature. The ability to synthesize diverse molecules utilizing nitro allylic MBH acetates in various cascade reactions has received considerable interest.¹ A few molecules synthesized using nitro allylic acetates have shown promising cytotoxic, trypanocidal and AchE inhibition² activity in pharmaceutical and medicinal chemistry. Nitro allylic MBH acetates have been used as main precursors in organocatalysis³ and heterocyclic chemistry,⁴ and as bicyclic skeletons⁵ for the construction of elegant building blocks like tetrahydro-pyranoquinolinones,⁶ sulfonyl furans,⁷ pyranonaphthoquinones,⁸ arenopyrans/arenylsulfanes,⁹ triazoles,^10a tetrasubstituted furans,^10b fused furans,^10c,d tetrasubstituted pyrroles,^11a benzofuranones,^11b and tetrahydropyrano scaffolds/pyranocoumarins.¹² The nitro allylic MBH-acetates can also undergo asymmetric benzylic^13a and allylic alkylation^13b reactions as well as kinetic resolution [KR]^13c,d under normal conditions. These acetates undergo a range of cascade [2 + 3],¹⁴ [3 + 2]¹⁵ and [3 + 3]¹⁶ ring annulation reactions using different substrates. They have been widely utilized in [3 + 2]^17a and [3 + 3]^17b annulation reactions due to their unique nature of 1,2-/1,3-biselectrophilic reactivity to form either five or six membered rings depending on the nature of nucleophiles employed in the reaction^17c,d These adducts are also stable under NHC catalytic conditions to yield cyclopentanes.¹⁸Peng-Fei Xu et al. (Scheme 1, eqn (a)) synthesised tetrahydropyranoindoles through organocatalytic asymmetric C–H functionalization of indoles via [3 + 3] annulation through 6-endo trig cyclization.¹⁹ The Namboothiri group recently developed a metal free regioselective synthesis of α-carbolines via [3 + 3] annulation involving secondary MBH acetate (Scheme 1, eqn (b)).²⁰ Previously, our group carried out a [3 + 3] cyclization reaction of β-naphthol with primary MBH acetate to study the scope of S_N2′ vs. S_N2 reaction.²¹ With our ongoing interest in using nitro styrene derived MBH adducts²² explored the reactivity of primary and secondary MBH acetate with β-tetralone 1 as our model reaction. Initially, the reaction carried out using β-tetralone 1 with primary MBH-acetate 2, predominantly gave a tetrahydrochromene 3via [3 + 3] annulation involving 6-endo trig cyclization through Michael/oxa-Michael cascade process. The possible dihydronaphthofuran product was not observed under the present conditions as primary MBH acetate 2 acts as 1,3-biselectrophile instead of 1,2-biselectrophile (Scheme 1, eqn (c)).Open in a separate window Scheme 1[3 + 3] and [3 + 2] annulation reactions using 1°- and 2°-nitro allylic MBH acetate.On the other hand, the reaction of β-tetralone 1 with secondary MBH acetate 4 gave dihydronaphthofuran instead of the possible tetrahydrochromene product due to the 1,2-biselectrophile nature of secondary MBH acetate (Scheme 1, eqn (d)). The formation of dihydronaphthofuran 5 occurs in an S_N2′ fashion via [3 + 2] annulation involving 5-exo-trig cyclization through Michael followed by intramolecular oxa-Michael reaction with the elimination of HNO₂. Subsequently, we have carried out a DFT calculation to prove the formation of tetrahydrochromene 3 using primary MBH acetate 2 and dihydronaphthofuran 5 in the case of secondary MBH acetate 4.Initially, we carried out the optimization conditions for constructing tetrahydrochromenes 3a using β-tetralone 1 with MBH nitro allylic primary acetate 2a with different bases and solvents. Reaction with organic base, i.e. DABCO using a polar aprotic solvent such as acetonitrile at room temperature gave the desired product in 27% (23 (CCDC-2149875) (
Entry	Base	Solvent	Time (h)	Yield (%)	dr^b
1	DABCO	CH₃CN	5	27	99 : 1
2	DABCO	CH₂Cl₂	5	22	99 : 1
3	DABCO	CHCl₃	5	19	99 : 1
4	DMAP	THF	5	40	99 : 1
5	TEA	THF	5	45	99 : 1
6	PPh₃	THF	5	44	99 : 1
7	K₂CO₃	THF	4	60	99 : 1
8	Cs ₂ CO ₃	THF	4	77	99 : 1
9^c	Cs₂CO₃	THF	8	50	99 : 1
10^d	Cs₂CO₃	THF	5	61	99 : 1
11^e	Cs₂CO₃	THF	4	65	99 : 1
12^f	Cs₂CO₃	THF	4	60	n.d

Open in a separate window^aUnless otherwise noted, reactions were carried out by and (0.11 mmol) of 1 with (0.11 mmol) of 2a using 0.22 mmol of a base in 1 ml of THF solvent.^bDetermined by ¹H-NMR analysis of crude reaction mixture.^cReaction was carried out using 0.5 equiv. of Cs₂CO₃.^dReaction was carried out using 1.0 equiv. of Cs₂CO₃.^eReaction was carried out using 1.5 equiv. of Cs₂CO₃.^fReaction was carried out using 3.0 equiv. of Cs₂CO₃.Substrate scope for tetrahydrochromenes 3a–f

Open in a separate windowBased on the best optimized conditions, we studied the scope of different nitro allylic MBH primary acetates (2a–e) with β-tetralone 1. The reaction accommodates various electron rich substituents on the primary MBH acetates (2a–e). The electron rich substituent contaning 2b gave 76% yield for the benzyloxy product 3b. The substrate having meta-OMe and para–OMe gave the desired product 3c and 3d with 71 & 68% of yield, respectively. Furthermore, using fluoro substituent at para position of the MBH adduct gave the product 3e with 72% yield. Reaction carried out using 6-bromo tetralone 1b gave the corresponding product 3f in 68% of yield. Notably, remarkable diastereoselectivity of 99 : 1 dr was observed in all the cases of base screening and substrate scope of MBH primary acetate.Encouraged, by the high diastereoselectivity for various tetrahydrochromenes derivatives 3a–e, we pursued our studies towards asymmetric synthesis of 3a using different chiral catalysts (I–IV). We observed the poor ee for the product formation in the presence of cinchona based squaramide catalyst I & BINAM based urea catalyst II (

Entry

Catalyst

Time (h)

Yield (%)

ee (%)

III

Open in a separate window^aAll the reactions were carried out with (0.11 mmol) of 1, (0.11 mmol) of 2a, (0.22 mmol) of base and 10 mol% in 1 ml of THF solvent.We next focused our studies on understand the reactivity of secondary MBH acetate 4a using β-tetralone 1. Interestingly, the reaction followed an S_N2′ Michael/intramolecular oxa-Michael pathway to form dihydronaphthofuran 5avia [3 + 2] annulation instead of an alternate path resulting in the formation of chromene product via 3 + 3 annulation (i.e., Scheme 1; eqn (d)). To recognize the optimal reaction condition, we carried out the reaction in the presence of Cs₂CO₃ in THF solvent to get the desired dihydronaphthofuran 5a in 35% yield ( EntryBaseSolventTime (h)Yield (%)1Cs₂CO₃THF6352Cs₂CO₃CH₂Cl₂4.5313Cs₂CO₃CHCl₃4.5274Cs₂CO₃CCl₄4.5165TEATHF5466DABCOCH₃CN6417PPh₃CH₃CN527 8 K ₂ CO ₃ CH ₃ CN 4 72 9^bK₂CO₃CH₃CN75910^cK₂CO₃CH₃CN66311^dK₂CO₃CH₃CN56812^eK₂CO₃CH₃CN465 Open in a separate window^aUnless otherwise noted, reactions were carried out with (0.11 mmol) of 1 with (0.11 mmol) of 4a using 0.22 mmol% of base in 1 ml of acetonitrile solvent.^bReaction was carried out using 0.5 equiv. of K₂CO₃.^cReaction was carried out using 1.0 equiv. of K₂CO₃.^dReaction was carried out using 1.5 equiv. of K₂CO₃.^eReaction was carried out using 3.0 equiv. of K₂CO₃.The reaction with reduced base equivalents, led to reduced yields confirming that 2.0 equiv. of K₂CO₃ is desirable to yield dihydronaphthofuran 5a at room temperature within 4 h ( Open in a separate windowTo further demonstrate our protocol''s practical and scalable utility, we have carried out the gram scale preparation of tetrahydrochromene 3a and dihydronaphthofuran 5a in 66 and 70% of yield. We observed the retention of diastereoselectivity i.e., 99 : 1 of tetrahydrochromene 3a, even at the gram scale condition (Scheme 2).Open in a separate window Scheme 2Gram scale synthesis of tetrahydrochromene 3a and dihydronaphthofuran 5a.We have successfully applied the synthetic utility for dihydronaphthofuran 5a. Reduction of the ester group in 5a was feasible using LAH in THF to afford the desired alcohol product 6 with 60% of yield. Using KOH, the ester group in dihydronaphthofuran 5a was hydrolysed to the corresponding acid derivative 7 in 70% yield. The amidation reaction of 7 with aniline accomplished oxidation of the tetralone ring providing the N-phenyl-2-(1-phenylnaphtho[2,1-b]furan-2-yl)acetamide product 8 in 67% of yield (Scheme 3).Open in a separate window Scheme 3Synthetic utility for the dihydronaphthofuran 5a. Keywords:

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