Allylic

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Cite This: Org. Lett. 2017, 19, 5609-5612

Phosphine-Catalyzed Sequential [4 + 3] Domino Annulation/Allylic Alkylation Reaction of MBH Carbonates: Efficient Construction of Seven-Membered Heterocycles Junlong Chen† and You Huang*,†,‡ †

State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China

‡

S Supporting Information *

ABSTRACT: Phosphine-catalyzed intermolecular sequential [4 + 3] domino annulation/allylic alkylation of MBH carbonates and N-tosyl azadienes is reported. A series of functionalized benzofuran-fused seven-membered nitrogen-heterocyclic compounds with one quaternary center were obtained in good to excellent yields. In this sequential reaction, three new bonds were formed in one pot, and the MBH carbonates serve as 1,2,3-C3 synthon and C1 synthon at the same time.

T

With the rapid development of organocatalysis, phosphinecatalyzed domino reactions have emerged as one of the most powerful strategies in the construction of carbo- and heterocycles.9 In particular, MBH carbonates have been reported as a kind of versatile C3 synthons that led to fruitful [3 + n] (n = 2, 3, 4, 6) reactions.10 Despite these impressive contributions, phosphine-catalyzed intermolecular [3 + 4] reactions for the synthesis of densely substituted seven-membered N-containing heterocycles are quite limited. In all of the [3 + 4] reactions, MBH carbonates serve as 1,3-dipolar C3 synthons (Scheme 1, eq 1).10i−l In previous years, MBH carbonates acting as 1,1dipolar C1 synthons was developed independently by our and Zhang’s group.11 Subsequently, MBH carbonates serving as C2

he seven-membered nitrogen−heterocycle compound exists widely in various natural products and pharmaceuticals. For instance, ibogamine, which is derived from the root bark of the African shrub Tabernanthe iboga, could be used to cure human addiction to multiple drugs.1a CID755673 isolated from marine sponge is a protein kinase D(PKD) inhibitor.1b (S)-Stemoamide has been employed in Chinese and Japanese folk medicine for respiratory disorders and also as an antihelminthic (Figure 1).1c−e On the other hand, compared

Scheme 1. Previous Work and This Work

Figure 1. Representative seven-membered heterocycles possessing biological activities.

to five- and six-membered rings, the seven-membered ring skeleton is difficult to construct due to the unfavorable transannular interactions and entropic factors.2 Inspired by the importance of the seven-membered nitrogen−heterocyclic compounds and the synthetic challenge, a number of approaches have been developed for the synthesis of sevenmembered cyclic derivatives over the past decades, such as (1) cycloaddition reaction,3 (2) ring-closing metathesis,4 (3) Heck coupling,5 (4) intramolecular α-alkenylation of furans,6 (5) radical additions,7 and others.8 Despite these achievements, most of those methods require multiple-step syntheses and costly catalysts. Moreover, these strategies mainly focused on the intramolecular cyclization. Therefore, the development of a general and facile method with readily available starting materials and inexpensive catalyst to construct seven-membered heterocycle frameworks remains highly desirable. © 2017 American Chemical Society

Received: September 3, 2017 Published: October 2, 2017 5609

DOI: 10.1021/acs.orglett.7b02742 Org. Lett. 2017, 19, 5609−5612

Letter

Organic Letters Table 1. Substrate Scopea

synthons for the synthesis of 2H-pyrans was discovered.12 Recently, our group has successfully developed a method using MBH carbonates as 1,2,3-C3 synthons to generate functionalized [4.1.0]bicycloalkenes13a and aza-benzobicyclo[4.3.0] derivatives13b (Scheme 1, eq 2). Intrigued by these elegant studies, we believe the complex functionalized medium-sized ring, especially the seven-membered ring, could be constructed using MBH carbonates. More recently, Zhao and co-workers employed the azadiene to construct six- and nine-membered heterocycles.14 Inspired by their previous work and on the basis of our continuous interest in exploring phosphine-catalyzed domino reactions, herein we report a phosphine-catalyzed intermolecular sequential [4 + 3] domino annulation/allylic alkylation of azadienes with MBH carbonates that produce multifunctionalized benzofuran-fused seven-membered heterocycle derivatives (Scheme 1, eq 2). To the best of our knowledge, this is the first example of MBH carbonates as 1,2,3-C3 synthons and C1 synthons in the construction of benzofuran-fused sevenmembered heterocycles. At the outset of this investigation, we employed the azadiene 1a with MBH carbonate 2a in the presence of PPh3 in CH2Cl2 at 30 °C (see the S-Table 1). To our delight, the desired product was isolated in 30% yield. To optimize the performance of the reaction, various catalysts and solvents were investigated. We found that CHCl3 and CH2Cl2 delivered a comparable yield (31% and 35% yield, respectively), and P(pCH3OPh)3 led to a better yield (37% yield). Meanwhile, screening of the ratio of 1a/2a revealed that 1a/2a (1:3) gave the desired product in 59%. When the catalyst loading was improved to 25 mol %, the reaction proceeded smoothly to give the corresponding [4 + 3] cycloaddition adduct in 68% yield, whereas further improvement of the catalyst loading diminished the yield. Considering CH2Cl2 and CHCl3 gave equal results, we used CHCl3 as solvent, and a better yield of product was obtained. When the temperature was raised to 60 °C, the desired product was obtained in 73% yield. To further improve the yield, additives were surveyed, and the yield of 3a could sharply increase to 99% when PhCO2H (25 mol %) was added to the reaction. Accordingly, the best reaction conditions were established as P(p-CH3OPh)3 (25 mol %) and PhCO2H (25 mol %) at 60 °C in CHCl3. In addition, the structure and stereochemistry of 3a was determined by a combination of NMR spectroscopy, high-resolution mass spectrometry (HRMS), and single-crystal X-ray analysis15 (see the SI). With the optimized reaction conditions in hand, we next examined the substrate generality of this domino annulation between azadienes and MBH carbonates (Table 1). It was found that a wide range of seven-membered nitrogen− heterocycles could be constructed smoothly in good to excellent yields. With regard to para-substituents, we found electron-withdrawing groups afforded products in a slightly higher yields than electron-donating groups (Table 1, entries 1−7). Notably, the para substituents of R1 with a phenyl group was also transformed into the corresponding product (Table 1, entry 8). While the steric bulk of aryl groups was increased, reduced yields were obtained and a significantly longer reaction time was required (Table 1, entries 9−12). It is obvious that the increased steric hindrance resulted in a significant decrease in efficiency. Moreover, as for the substitution of the aromatic ring of the benzofuran, we found 5-Br of the R1 could deliver a better yield than 4-Br of the R1, and R1 with a strong electrondonating group could furnish the desired product in a better

entry

R1

R2

R3

time (min)

3, yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

H H H H H H H H H H H H 5-Br 4-Br 4-CH3O H H H H

Ph 4-BrC6H4 4-ClC6H4 4-FC6H4 4-CF3C6H4 4-CH3C6H4 4-CH3OC6H4 4-biphenyl 3-BrC6H4 2-BrC6H4 2,4-Cl2C6H3 1-naphthyl 4-ClC6H4 4-ClC6H4 4-ClC6H4 Ph Ph Ph Ph

CO2Et CO2Et CO2Et CO2Et CO2Et CO2Et CO2Et CO2Et CO2Et CO2Et CO2Et CO2Et CO2Et CO2Et CO2Et CO2Me CO2-n-Bu CO2-t-Bu CN

45 45 45 60 45 60 60 60 60 360 180 720 45 45 45 180 180 720 20

3a, 99 3b, 97 3c, 98 3d, 98 3e, 96 3f, 87 3g, 69 3h, 95 3i, 98 3j, 69 3k, 75 3l, 58 3m, 98 3n, 76 3o, 98 3p, 93 3q, 93 3r, 81 3s, 88

a Reactions were performed using 1a (0.1 mmol), 2a (0.3 mmol), P(pCH3OPh)3 (25 mol %), and PhCO2H (25 mol %) in 1 mL of CHCl3 at 60 °C. bIsolated yields.

yield (Table 1, entries 13 vs 14 and 14 vs 15). Furthermore, the size of the ester substituent of R3 had a minor effect on the domino process albeit with a prolonged reaction time (Table 1, entries 16−18). In addition, when a cyano group was introduced to R3, the reaction could also give a promising result (Table 1, entry 19). To demonstrate the practicality of our method, a gram-scale version of the reaction using substrate 1b and 2a was carried out. Compound 3b was obtained in 97% yield (Scheme 2). It is Scheme 2. Gram-Scale Synthesis

noteworthy to point out that this reaction was easy to scale up and generated the product without diminish of yield. The asymmetric variant of this domino reaction was also investigated preliminarily, and a promising 50% ee value and 26% yield of 2a were obtained with chiral phosphine derived from L-isoleucine (see S-Table 2). To gain insight into the reaction mechanism, we conducted the domino reaction with 1a and 2a in the presence of 20 equiv of D2O under the optimized reaction conditions (Scheme 3). The deuterated product D-3a was obtained in a yield of 93%. 1 H NMR analysis showed 59% deuterium incorporation at the A-position, 65% deuterium incorporation at the B-position, 70% deuterium incorporation at the C-position, and 64% 5610

DOI: 10.1021/acs.orglett.7b02742 Org. Lett. 2017, 19, 5609−5612

Letter

Organic Letters

Experimental details, characterization data for new compounds, copies of NMR spectra, and X-ray crystal structure of 3a (PDF)

Scheme 3. Mechanism Study

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. deuterium incorporation at the D-position, indicating the possibility of the involvement of a carbanion intermediate. On the basis of our experimental results and previous studies,10a,b,h a plausible reaction mechanism for the domino reaction was proposed (Scheme 4). The reaction was initiated

ORCID

Scheme 4. Proposed Mechanism

ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21472097, 21672109, and 21421062), the Natural Science Foundation of Tianjin (15JCYBJC20000).

You Huang: 0000-0002-9430-4034 Notes

The authors declare no competing financial interest.

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(1) For selected examples, see: (a) Jana, G. K.; Sinha, S. Tetrahedron Lett. 2010, 51, 1994. (b) Torres-Marquez, E.; Sinnett-Smith, J.; Guha, S.; Kui, R.; Waldron, T.; Rey, O.; Rozengurt, E. Biochem. Biophys. Res. Commun. 2010, 391, 63. (c) Götz, M.; Edwards, O. E. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1967; Vol. 9, pp 545−551. (d) Sakata, K.; Aoki, K.; Chang, C. F.; Sakurai, A.; Tamura, S.; Murakoshi, S. Agric. Biol. Chem. 1978, 42, 457. (e) Ye, Y.; Qin, G. W.; Xu, R. S. Phytochemistry 1994, 37, 1205. (2) Anslyn, E. V., Dougherty, D. A., Eds. Modern Physical Organic Chemistry; Higher Education Press: Beijing, 2009. (3) For selected examples of [4 + 3] cycloadditions, see: (a) Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 9244. (b) Jeffrey, C. S.; Barnes, K. L.; Eickhoff, J. A.; Carson, C. R. J. Am. Chem. Soc. 2011, 133, 7688. (c) Liu, H.; Li, X.; Chen, Z. L.; Hu, W. X. J. Org. Chem. 2012, 77, 5184. (d) Acharya, A.; Eickhoff, J. A.; Jeffrey, C. S. Synthesis 2013, 45, 1825. (e) Shang, H.; Wang, Y. H.; Tian, Y.; Feng, J.; Tang, Y. F. Angew. Chem., Int. Ed. 2014, 53, 5662−5666. (f) Schultz, E. E.; Lindsay, V.; Sarpong, R. Angew. Chem., Int. Ed. 2014, 53, 9904. (g) Tian, Y.; Wang, Y.; Shang, H.; Xu, X. D.; Tang, Y. F. Org. Biomol. Chem. 2015, 13, 612. (h) Gerstner, N. C.; Adams, C. S.; Tretbar, M.; Shomaker, J. M. Angew. Chem., Int. Ed. 2016, 55, 13240−13243. For selected examples of [5 + 2] cycloadditions, see: (i) Wender, P. A.; Pedersen, T. M.; Scanio, M. J. Am. Chem. Soc. 2002, 124, 15154. (j) Zhou, M. B.; Song, R. J.; Wang, C. Y.; Li, J. H. Angew. Chem. 2013, 125, 11005. (k) Iqbal, N.; Fiksdahl, A. J. Org. Chem. 2013, 78, 7885. (l) Shenje, R.; Martin, M. C.; France, S. Angew. Chem. 2014, 126, 14127. (m) Yang, Y.; Zhou, M. B.; Ouyang, X. H.; Pi, R.; Song, R. J.; Li, J. H. Angew. Chem. 2015, 127, 6695. (n) Hu, C.; Song, R. J.; Hu, M.; Yang, Y.; Li, J. H.; Luo, S. L. Angew. Chem. 2016, 128, 10579− 10582. For selected examples of [3 + 2 + 2] cycloadditions, see: (o) Cui, L.; Ye, W. L.; Zhang, L. M. Chem. Commun. 2010, 46, 3351. (p) Zhou, M. B.; Song, R. J.; Li, J. H. Angew. Chem. 2014, 126, 4280. (q) Li, T. F.; Xu, F.; Li, X. C.; Wang, C. X.; Wan, B. S. Angew. Chem., Int. Ed. 2016, 55, 2861. (4) (a) Hunt, J. C.; Laurent, P.; Moody, C. J. Chem. Commun. 2000, 1771. (b) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073. (c) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199. (d) Gradillas, A.; Javier, P. C. Angew. Chem., Int. Ed. 2006, 45, 6086. (e) van Otterlo, W. A. L.; de Koning, C. B. Chem. Rev. 2009, 109, 3743. (f) Schurgers, B.; Brigou, B.; Urbanczyk-Lipkowska, Z.; Tourwé, D.; Ballet, S.; De Proft, F. D.; Van Lommen, G. V.; Verniest, G. Org. Lett. 2014, 16, 3712. (5) Qadir, M.; Cobb, J.; Sheldrake, P. W.; Whittall, N.; White, A. J. P.; Hii, K. K.; Horton, P. N.; Hursthouse, M. B. J. Org. Chem. 2005, 70, 1545. (6) Dong, Z.; Liu, C. H.; Wang, Y.; Lin, M.; Yu, Z. X. Angew. Chem., Int. Ed. 2013, 52, 14157.

by the formation of phosphorus ylide A (A-1 or A-2) via the commonly accepted addition−elimination−deprotonation process. Subsequently, conjugate addition of the ylide A-2 via α-carbon to the electron-deficient azadiene 1a generated the intermediate I, which underwent an intramolecular umpolung addition to generate intermediate II. Then, H-shift of II led to intermediate III. Finally, the anion of intermediate III attack the intermediate A-3 to furnished the corresponding product 3a and regenerated the phosphine catalyst to complete the catalytic cycle. In conclusion, we have developed a phosphine-catalyzed intermolecular sequential [4 + 3] domino annulation/allylic alkylation of N-tosyl azadienes with MBH carbonates for the first time. MBH carbonates serve as 1,2,3-C3 synthon and C1 synthon to generate benzofuran-fused seven-membered heterocycles with good to excellent yields. In this reaction, one quaternary center, two C−C bonds, and one C−N bond were formed. Readily available starting materials, inexpensive catalyst, and gram-scale synthesis make this reaction valuable in synthetic chemistry. Further studies about the asymmetric version of this reaction are underway in our laboratory.

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REFERENCES

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02742. Crystallographic data for 3a (CIF) 5611

DOI: 10.1021/acs.orglett.7b02742 Org. Lett. 2017, 19, 5609−5612

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Organic Letters (7) (a) Yet, L. Tetrahedron 1999, 55, 9349. (b) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442−6445. (8) Huang, L.; Dai, L. X.; You, S. L. J. Am. Chem. Soc. 2016, 138, 5793−5796. (9) For selected reviews on phosphine-promoted annulations, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (c) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 39, 520. (d) Ye, L. M.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (e) Aroyan, C. E.; Dermenci, A.; Miller, S. J. Tetrahedron 2009, 65, 4069. (f) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev. 2009, 38, 3102. (g) Marinetti, A.; Voituriez, A. Synlett 2010, 2010, 174. (h) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005. (i) Wang, S. X.; Han, X. Y.; Zhong, F. R.; Wang, Y. Q.; Lu, Y. X. Synlett 2011, 2011, 2766. (j) Zhao, Q. Y.; Lian, Z.; Wei, Y.; Shi, M. Chem. Commun. 2012, 48, 1724. (k) Xie, P.; Huang, Y. Eur. J. Org. Chem. 2013, 2013, 6213. (l) Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927. (m) Xiao, Y. M.; Sun, Z. H.; Guo, H. C.; Kwon, O. Beilstein J. Org. Chem. 2014, 10, 2089. (n) Xie, P.; Huang, Y. Org. Biomol. Chem. 2015, 13, 8578. (10) MBH carbonates serve as C3 synthons. For selected examples of phosphine-catalyzed [3 + 2] cycloadditions, see: (a) Du, Y.; Lu, X. Y.; Zhang, C. Angew. Chem., Int. Ed. 2003, 42, 1035. (b) Zheng, S. Q.; Lu, X. Y. Org. Lett. 2008, 10, 4481. (c) Han, X.; Ye, L. W.; Sun, X. L.; Tang, Y. J. Org. Chem. 2009, 74, 3394. (d) Zhou, R.; Wang, J.; Song, H.; He, Z. Org. Lett. 2011, 13, 580. (e) Deng, H. P.; Wei, Y.; Shi, M. Org. Lett. 2011, 13, 3348. (f) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. X. Angew. Chem., Int. Ed. 2011, 50, 7837. (g) Tan, B.; Candeias, N. R.; Barbas, C. F. J. Am. Chem. Soc. 2011, 133, 4672. (h) Zhang, L.; Yu, H.; Yang, Z. L.; Liu, H.; Guo, J.; Xiao, Y.; Guo, H. C. Org. Biomol. Chem. 2013, 11, 8235−8240. For an example of phosphine-catalyzed [3 + 3] cycloadditions, see: (i) Zheng, S.; Lu, X. Y. Tetrahedron Lett. 2009, 50, 4532. For examples of phosphine-catalyzed [3 + 4] cycloadditions, see: (j) Zheng, S.; Lu, X. Org. Lett. 2009, 11, 3978. (k) Zhou, R.; Wang, J.; Duan, C.; He, Z. Org. Lett. 2012, 14, 6134. (l) Zhan, G.; Shi, M.; He, H.; Du, W.; Chen, Y. Org. Lett. 2015, 17, 4750. (m) Liu, J.; Lu, H.; Li, C.; Liang, Y.; Xu, P. Synlett 2016, 27, 1287. For an example of phosphine catalyzed [3 + 6] cycloadditions, see: (n) Du, Y. S.; Feng, J. Q.; Lu, X. Y. Org. Lett. 2005, 7, 1987. (11) (a) Xie, P.; Huang, Y.; Chen, R. Org. Lett. 2010, 12, 3768. (b) Chen, Z.; Zhang, J. Chem. - Asian J. 2010, 5, 1542. (c) Tian, J.; Zhou, R.; Sun, H.; Song, H.; He, Z. J. Org. Chem. 2011, 76, 2374. (d) Zhang, X. N.; Deng, H. P.; Huang, L.; Wei, Y.; Shi, M. Chem. Commun. 2012, 48, 8664. (12) Xie, P.; Yang, J.; Zheng, J.; Huang, Y. Eur. J. Org. Chem. 2014, 2014, 1189. (13) (a) Zheng, J.; Huang, Y.; Li, Z. Chem. Commun. 2014, 50, 5710. (b) Zhang, Q. L.; Zhu, Y. N.; Jin, H. X.; Huang, Y. Chem. Commun. 2017, 53, 3974−3977. (14) (a) Rong, Z. Q.; Wang, M.; Chow, C. H. E.; Zhao, Y. Chem. Eur. J. 2016, 22, 9483−948. (b) Yang, L. C.; Rong, Z. Q.; Wang, Y. N.; Tan, J. Y.; Wang, M.; Zhao, Y. Angew. Chem., Int. Ed. 2017, 56, 2927. (15) CCDC 1561334 (3a) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/services/structure_deposit/cif.

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DOI: 10.1021/acs.orglett.7b02742 Org. Lett. 2017, 19, 5609−5612