Letter pubs.acs.org/OrgLett
CuCl/Et3N‑Catalyzed Synthesis of Indanone-Fused 2‑Methylene Pyrrolidines from Enynals and Propargylamines Shaotong Qiu,† Lianfen Chen,† Huanfeng Jiang,† and Shifa Zhu*,†,‡ †
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China ‡ State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China S Supporting Information *
ABSTRACT: An efficient CuCl/Et3N-catalyzed tandem reaction for the synthesis of indanone-fused pyrrolidine was developed. In this process, two rings and four bonds are generated in one pot with high atom-economy and step-efficiency. The addition of Et3N was found as the key factor for the success of the tandem reaction.
N
unexpected 1,2-dihydropyridine 4a was obtained in low yield instead, which should come from the Michael addition/ cyclization process (Scheme 1, eq 2).6 When CuCl was applied as the catalyst, the yield of 4a could even be improved to 58%, with the desired product 3a being detected only in trace amount. The preliminary results indicated that there obviously existed a competition between the intramolecular addition of carbonyl (Scheme 2, path a) and intermolecular addition of propargyl-
itrogen-containing polycyclic compounds are ubiquitous in nature and many biologically active compounds and are important for the agrochemical, pharmaceutical, and fine chemical industries.1,2 Therefore, the development of new methodologies to rapidly construct the nitrogen-containing polycyclic molecules is highly important.3 Recently, we reported an indium-catalyzed cascade reaction of enynals with propynols to synthesize a series of indanone-fused tetrahydrofurans, which was proposed to proceed through an efficient one-pot tandem process involving hydrolysis, Knoevenagel condensation, Michael addition, and Conia-ene reaction (Scheme 1, eq 1).4 As part of our continuous efforts in
Scheme 2. Strategy for Synthesis of Pyrrolidine
Scheme 1. Efforts for Synthesis of Pyrrolidine from AcceptorEnynal and Propargylamine
amine (path b). The stronger nucleophilicity of propargylamine makes the undesired path b process dominate in this reaction. To depress the intermolecular reaction (path b), a synergistic catalysis by metal and Lewis base was designed to switch the reaction selectivity in which the Lewis base with higher nucleophilicity initially attacked the metal-activated alkyne to lead the intermediate I, followed by the intramolecular addition/ elimination to give the key intermediate III. In the presence of propargylamine 2, it might produce the desired product 3 (Scheme 2). With this design in mind, initial efforts were then made to systematically investigate various combinations of Lewis acid and Lewis base to tune the reaction selectivity with enynal 1a and
developing highly efficient tandem reactions based on enynal/ enynone chemistry,5 we envisioned that indanone-fused 2methylene pyrrolidines could also be rapidly accessed through a cascade process from enynals and propargylamines. However, no desired product 3a could be detected under the standard reaction conditions. Take the reaction of enynal 1a and benzyl propargylamine 2a as an example: In(OTf)3 and AgNTf2, which were typically good catalysts to promote the reaction of enynals, failed to give the desired product 3a. However, an © 2017 American Chemical Society
Received: July 12, 2017 Published: August 21, 2017 4540
DOI: 10.1021/acs.orglett.7b02121 Org. Lett. 2017, 19, 4540−4543
Letter
Organic Letters Scheme 3. Substrate Scopea
propargylamine 2a as substrates (Table 1). First, PBu3 and PPh3 were tested as the Lewis base because they were typically Table 1. Optimization of Reaction Conditionsa
yield (%)b entry
cat. (mol %)
additive (1 equiv)
3a
4a
1 2 3 4 5 6d 7 8 9 10
CuCl (20) CuCl (20) CuCl (20) CuCl (20) CuCl (20) CuCl (20) CuCl2 (20) In(OTf)3 (20) AgNTf2 (5)
PBu3 PPh3 DMAP DABCO Et3N Et3N Et3N Et3N Et3N Et3N
ND 8 5 50c 82c 8 32 20 23 ND
ND 36 27 25 11 60c ND ND ND ND
a Reaction was performed with 1a (0.25 mmol) and 2a (0.5 mmol) in MeCN (2 mL), 18 h, under N2 atmosphere. DMAP = 4dimethylaminopyridine. DABCO = 1,4-diazabicyclo[2.2.2]octane. b NMR yield. cIsolated yield. d20 mol % of Et3N was added.
regarded as good nucleophilic organocatalysts in organic synthesis.7 As shown in Table 1, PBu3 completely depressed the CuCl-catalyzed reaction, in which both products 3a and 4a were not detected (Table 1, entry 1). The less nucleophilic PPh3 produced the products 3a and 4a in 8 and 36% yield, respectively (Table 1, entry 2). DMAP gave a result similar to that with PPh3 (Table 1, entry 3). An obvious positive effect was observed when DABCO was used as the additive; the yield of 3a could be greatly improved to 50% (Table 1, entry 4). The yield of 3a could be further enhanced to 82% when the additive was Et3N, in which reaction yield with side product 4a was lowered to 11% (Table 1, entry 5). Catalytic amount of Et3N was not able to promote the reaction as the yield was sharply decreased to 8% using 20 mol % of Et3N (Table 1, entry 6). As a comparison with CuCl, CuCl2 was an inferior catalyst (Table 1, entry 7). Further experiments showed that Et3N was capable of promoting the catalytic performance of In(OTf)3 and AgNTf2, as well, albeit in relatively lower yields (Table 1, entries 8 and 9). Et3N alone could not catalyze the formation of products 3a and 4a (Table 1, entry 10) (see Supporting Information for more details). Based on the optimized reaction conditions (Table 1, entry 5), the substrate scope of this synergistic catalysis was then examined. As shown in Scheme 3, in addition to benzylprotected propargylamine 2a, the phenyl-protected 2b could be used as an efficient substrate, as well, giving the desired product 3b in 88% yield. The reaction could be scaled up to 10 mmol, with the yield almost remaining unaffected. Propargylamines with different aryl groups could be transferred to the desired products 3c−h in excellent yields (80−94%). Attempts to extend this reaction either to p-tosyl-protected propargylamine 2c or to acetyl 2d failed (3i,j). The low nucleophilicity of tosyl- and acetyl-substituted propargylamines may account for these negative results. In addition to enynal 1a, the enynals substituted with different groups on the CC triple bond and phenyl ring were also tested for this reaction (3k−p). For example, enynal with an acyl group on the CC triple bond reacted with
a
The reaction was performed with 1 (0.25 mmol) and 2 (0.5 mmol) in CH3CN (2 mL) for 18 h, under N2 atmosphere; isolated yield. b60 °C.
propargylamine 2b smoothly, leading to the desired product 3k in 81% yield. Furthermore, enynals bearing different substituents at the phenyl ring could also be effectively converted into the corresponding products (3l−p) in good yields (64−80%). To further investigate the robustness of this Cu/Et3N synergistic catalysis system, the internal propargylamines, which represent the challenging substrates for the Conia-ene reaction,4,8 were also investigated. To our surprise, various internal alkyne derivatives containing different aryl groups could be applied as the effective substrate (3q−z). The yields were typically higher than 70%. For example, in addition to phenyl alkyne, various alkyne derivatives containing groups at different ring positions could be effectively cyclized. Alkynes with both electronwithdrawing and -donating substituents at the aryl groups could afford the desired products in satisfactory yields. In most cases, Z-isomers of the products were selectively formed (3q−w, 3z). It was noteworthy that the alkynes substituted with electrondeficient aryl groups gave a mixture of Z- and E-isomers (3x,y), which implies that there may exist two different reaction pathways for the alkynes with electron-deficient aryl groups.9 This reaction has excellent functional group tolerance. The heterocycles, such as pyridine and thiophene, were very compatible with the catalytic condition, converting to the products 3y and 3z in 83 and 96% yields, respectively. Attempts to extend this reaction to alkyl-substituted internal alkynes failed (3aa). The product structure of 3r and 3y was further confirmed by the X-ray diffraction analysis. 4541
DOI: 10.1021/acs.orglett.7b02121 Org. Lett. 2017, 19, 4540−4543
Letter
Organic Letters
Et3N was essential for the cyclization reaction. Moreover, a stable ethylamine indenol 5′ could be produced in 91% yield when propargylamine 2a was replaced with ethylamine 2a′ (Scheme 4, eq 3). Enynal 1a remained intact in the absence of propargylamine (Scheme 4, eq 4). With these results in hand, a possible reaction mechanism was then proposed (Scheme 5). Initially, CuCl formed a 1:1 Et3N− CuCl complex with triethylamine,10 which might be the real catalyst for the reaction. The catalytic reaction commenced with the formation of the [Cu]-alkyne complex A, where the copper center coordinated to the alkyne and formyl group. After that, Et3N nucleophilically attacked the copper-activated alkyne to form the quaternary ammonium salt B with subsequent intramolecular attack of the formyl group and intermolecular attack of propargylamine to give the 5-exo-trig intermediate C. Release of Et3N produced the benzoisofuran D, and then ringopening resulted in the formation of enol E. Followed by the iminium-type Knoevenagel condensation from E, the key intermediate indenone F was then formed. There might be two possible reaction pathways9 from intermediate F in the presence of Et3N. Path a proceeds through the formation of a Cuenolate, by direct cupration of the β-ketoester F, followed by a ciscarbocupration of the alkyne to produce vinyl-Cu intermediate H. The proto-decupration then led to the product (Z)-3. Path b involves a nucleophilic anti-attack on the Cu(I)-alkyne complex by the enol anion, forming the (E)-vinyl-Cu intermediate H′. The proto-decupration of H′ eventually produced product (E)3. These two proposed pathways would give opposite configurations of the double bond if a substituted propargylamine (R′ ≠ H) was employed. The electron-deficient aryl group R′, such as 3x,y, reduced the electronic density of the Cu(I)alkyne complex, thus making the nucleophilic anti-attack on the Cu(I)-alkyne complex (path b) easier and then led to the formation of (E)-3. With the indanone-fused pyrrolidines in hand, we explored their further chemical transformations. Taking 3b as an example, four different transformations were performed (Scheme 6). The ester group of product 3b could be easily removed under basic conditions, producing indanone-dihydropyrrole 6. Additionally, the ester and the carbonyl groups of 3b could be selectively
To better understand the reaction mechanism, several control reactions were then conducted (Scheme 4). When the reaction of Scheme 4. Control Reactions
enynal 1a and benzyl propargylamine 2a was quenched after 10 min, an indenol 5, tethered with a propargylamine, was obtained in 17% yield (Scheme 4, eq 1). Indenol 5 was unstable and might be the potential intermediate for the reaction. Intriguingly, no desired product 3a could be detected when the solution of indenol 5 was subjected to the CuCl-catalyzed condition in the absence of Et3N. The product 3a could be obtained in 25% yield when 0.2 equiv of Et3N was added. The yield could be significantly improved to 82% when 1.0 equiv of Et3N was added (Scheme 4, eq 2). These results indicated that the addition of Scheme 5. Proposed Reaction Mechanism
4542
DOI: 10.1021/acs.orglett.7b02121 Org. Lett. 2017, 19, 4540−4543
Letter
Organic Letters Scheme 6. Further Transformation of 3ba
nology Program of Guangzhou (201707010316), and the Fundamental Research Funds for the Central Universities, SCUT.
■
a
The reactions were carried out in 0.25 mmol scale. b5 equiv. c1.1 equiv.
reduced, furnishing the corresponding alcohols 7, 8, and 9 in good to excellent yields. In summary, an efficient CuCl/Et3N-catalyzed tandem reaction for the synthesis of indanone-fused pyrrolidine was developed. The addition of Et3N was found as the key factor for the success of the tandem reaction. The presence of Et3N not only depressed the side reaction but also switched the reaction pathway. Et3N might function as both the ligand for CuCl and the Lewis base to initiate the reaction in the first step as well as to promote the cyclization in the late stage of the reaction. The reaction has very broad substrate scope, in which the substrates with heteroaryl substituents were compatible with the reaction conditions. Moreover, the reaction proceeded smoothly even for the propargylamine substrates with an internal alkyne, which represents challenging substrates for the Conia-ene reaction. Owing to good substrate scope, mild reaction conditions, and high step-economy, this tandem reaction holds considerable potential for the construction of natural or bioactive compounds containing an indanone-fused pyrrolidine moiety.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02121. Typical experimental procedure, characterization for all products (PDF) Crystallographic data for 3r (CIF) Crystallographic data for 3y (CIF) Crystallographic data for 7 (CIF) Crystallographic data for 8 (CIF)
■
REFERENCES
(1) (a) Hu, J.; Fan, H.; Xiong, J.; Wu, S. Chem. Rev. 2011, 111, 5465. (b) Sridharan, V.; Suryavanshi, P. A.; Menéndez, J. C. Chem. Rev. 2011, 111, 7157. (c) Pilli, R. A.; Rosso, G. B.; de Oliveira, M. C. F. Nat. Prod. Rep. 2010, 27, 1908. (d) Walker, S. R.; Carter, E. J.; Huff, B. C.; Morris, J. C. Chem. Rev. 2009, 109, 3080. (2) (a) Zhao, Y.; Gu, Q.; Morris-Natschke, S. L.; Chen, C.; Lee, K. J. Med. Chem. 2016, 59, 9262. (b) Kuhnert, M.; Blum, A.; Steuber, H.; Diederich, W. E. J. Med. Chem. 2015, 58, 4845. (3) (a) Leonardi, M.; Villacampa, M.; Menendez, J. C. J. Org. Chem. 2017, 82, 2570. (b) Vessally, E.; Soleimani-Amiri, S.; Hosseinian, A.; Edjlali, L.; Bekhradnia, A. RSC Adv. 2017, 7, 7079. (c) Cao, Z.; Zhu, H.; Meng, X.; Guan, J.; Zhang, Q.; Tian, L.; Sun, X.; Chen, G.; You, J. Chem. - Eur. J. 2016, 22, 16979. (d) Royo, S.; Chapman, R. S. L.; Sim, A. M.; Peacock, L. R.; Bull, S. D. Org. Lett. 2016, 18, 1146. (e) Ye, C.; Chen, Z.; Wang, H.; Wu, J. Tetrahedron 2012, 68, 5197. (f) Huang, Q.; Hunter, J. A.; Larock, R. C. Org. Lett. 2001, 3, 2973. (4) Liang, R.; Chen, K.; Zhang, Q.; Zhang, J.; Jiang, H.; Zhu, S. Angew. Chem., Int. Ed. 2016, 55, 2587. (5) (a) Zheng, M.; Chen, K.; Zhu, S. Synthesis 2017, DOI: 10.1055/s0036-1588416. (b) Zhang, C.; Jiang, H.; Zhu, S. Chem. Commun. 2017, 53, 2677. (c) Chen, K.; Zhu, S. Synlett 2017, 28, 640. (d) Luo, H.; Chen, K.; Jiang, H.; Zhu, S. Org. Lett. 2016, 18, 5208. (e) Zhang, J.; Xiao, Y.; Chen, K.; Wu, W.; Jiang, H.; Zhu, S. Adv. Synth. Catal. 2016, 358, 2684. (f) Zhu, D.; Ma, J.; Luo, K.; Fu, H.; Zhang, L.; Zhu, S. Angew. Chem., Int. Ed. 2016, 55, 8452. (g) Ma, J.; Chen, K.; Fu, H.; Zhang, L.; Wu, W.; Jiang, H.; Zhu, S. Org. Lett. 2016, 18, 1322. (h) Ma, J.; Zhang, L.; Zhu, S. Curr. Org. Chem. 2015, 20, 102. (i) Zhu, S.; Zhang, Q.; Chen, K.; Jiang, H. Angew. Chem., Int. Ed. 2015, 54, 9414. (j) Liang, R.; Jiang, H.; Zhu, S. Chem. Commun. 2015, 51, 5530. (k) Liang, R.; Ma, T.; Zhu, S. Org. Lett. 2014, 16, 4412. (l) Ma, J.; Jiang, H.; Zhu, S. Org. Lett. 2014, 16, 4472. (6) (a) Mizoguchi, H.; Watanabe, R.; Minami, S.; Oikawa, H.; Oguri, H. Org. Biomol. Chem. 2015, 13, 5955. (b) Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. 2008, 10, 2629. (7) (a) Xiao, Y.; Sun, Z.; Guo, H.; Kwon, O. Beilstein J. Org. Chem. 2014, 10, 2089. (b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (8) (a) Hack, D.; Blumel, M.; Chauhan, P.; Philipps, A. R.; Enders, D. Chem. Soc. Rev. 2015, 44, 6059. (b) Sladojevich, F.; Fuentes de Arriba, Á . L.; Ortín, I.; Yang, T.; Ferrali, A.; Paton, R. S.; Dixon, D. J. Chem. - Eur. J. 2013, 19, 14286. (c) Deng, C.; Zou, T.; Wang, Z.; Song, R.; Li, J. J. Org. Chem. 2009, 74, 412. (d) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 9140. (e) Deng, C.; Song, R.; Guo, S.; Wang, Z.; Li, J. Org. Lett. 2007, 9, 5111. (9) (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526. (b) Clique, B.; Monteiro, N.; Balme, G. Tetrahedron Lett. 1999, 40, 1301. (10) (a) Weiss, J. F.; Tollin, G.; Yoke, J., III Inorg. Chem. 1964, 3, 1344. (b) Yoke, J. T., III; Weiss, J. F.; Tollin, G. Inorg. Chem. 1963, 2, 1210.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Huanfeng Jiang: 0000-0002-4355-0294 Shifa Zhu: 0000-0001-5172-7152 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We are grateful to Ministry of Science and Technology of the People’s Republic of China (2016YFA0602900), the NSFC (21372086, 21422204, and 21672071), Guangdong NSF (2014A030313229, 2016A030310433), the Science and Tech4543
DOI: 10.1021/acs.orglett.7b02121 Org. Lett. 2017, 19, 4540−4543
