Phosphine-Catalyzed Divergent [4+3] Domino Annulations of CF3

8 hours ago - Phosphine-catalyzed divergent [4+3] domino annulations of fluorinated imidoyl chlorides with MBH carbonates were developed. Two classes ...
0 downloads 0 Views 1MB Size
Download PDF
Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Phosphine-Catalyzed Divergent [4+3] Domino Annulations of CF3‑Containing Imines with MBH Carbonates: Construction of Perfluoroalkylated Benzazepines Junlong Chen,† Zhongmo Yin,† and You Huang*,† †

State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China

Downloaded via NOTTINGHAM TRENT UNIV on August 23, 2019 at 02:52:39 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: Phosphine-catalyzed divergent [4+3] domino annulations of fluorinated imidoyl chlorides with MBH carbonates were developed. Two classes of perfluoroalkylated benzazepines were obtained in moderate to good yields via an interesting dearomatization/rearomatization sequence. Remarkably, the fluorinated imidoyl chlorides could be utilized for the first time as a new four-atom building block in phosphine catalysis. Moreover, the proposed mechanism is supported by capturing the intermediate.

B

Great progress has been made in phosphine-catalyzed domino cycloadditions for the versatile construction of carbo- and heterocyclic compounds over the past decades.4 Among these, imine derivatives as electrophilic components, which are widely used as versatile two-atom building blocks, could react with electron-deficient alkenes, alkynes, allenes, and their derivatives to afford five- and six-membered Nheterocyclic compounds via [2+3] or [2+4] cycloadditions (Scheme 1a). Despite these advances, phosphine-catalyzed intermolecular [4+3] reactions for the synthesis of densely substituted seven-membered N-containing heterocycles are still quite limited.5 In recent years, the group of Deng6a and Zhang6b succeeded in achieving an umpolung addition reaction of trifluoromethyl ketimines with enals or MBH carbonates to form trifluoromethyl amine derivatives. Recently, Huang7a and Lu7b developed a protocol using azadienes as effective four-atom building blocks reacted with MBH carbonates to generate a broad range of benzofuran-fused medium-sized N-heterocycles. Inspired by their excellent studies and our ongoing investigation of the phosphine-catalyzed domino reactions to construct N-containing heterocycles,8 we suggested a new

enzoaza nitrogen seven-membered heterocyclics are widely found in numerous natural products and marketed drugs (Figure 1).1 Nevertheless, relative to reactions for the

Figure 1. Selected natural products and pharmaceutical agents.

construction of five- and six-membered N-heterocycles, facile synthesis of such skeletons is still challenging due to the unfavorable transannular interactions and entropic factors.2 In view of the significance of the seven-membered N-heterocyclic compounds and the synthetic challenge, a series of [m+n] cycloadditions have been established for the synthesis of sevenmembered cyclic derivatives to date.3 Nevertheless, some shortcomings of these approaches are costly catalysts, tedious processes for purification, and intramolecular cyclizations that generally require multiple-step synthesis of substrates. Therefore, the development of expeditious strategies for the diverse construction of seven-membered N-heterocycles from readily accessible starting materials remains highly attractive and challenging. © XXXX American Chemical Society

Received: July 26, 2019

A

DOI: 10.1021/acs.orglett.9b02626 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

In an attempt to understand the generality of this process, the scope of PPh3-catalyzed [4+3] reactions was first investigated (Scheme 2). A wide range of trifluoroacetimidoyl

Scheme 1. Previous Works and This Work

Scheme 2. PPh3-Catalyzed [4+3] Reactionsa,b

reaction model could be achieved if the electrophiles could be carefully designed. Our reaction design involves CF3-containing imines that might be employed as new four-atom building blocks by means of introducing a Cl atom as a leaving group to react with MBH carbonates, thereby creating the challenging fluorine-containing benzazepines (Scheme 1b). Mechanistically, trifluoroacetimidoyl chlorides could be attacked by a nucleophile to generate intermediate I in which the N anion may delocalize to the ortho position of arenes. Then, the carbon anion is captured by the electrophile to afford intermediate II, and elimination of Cl anion leads to the N-containing heterocycles through a process of dearomatization and rearomatization. We herein report novel phosphine-catalyzed divergent [4+3] domino annulation reactions of trifluoroacetimidoyl chlorides with MBH carbonates under mild reaction conditions, affording various perfluoroalkylated benzazepines in moderate to good yields by changing the phosphine catalysts (Scheme 1c). It is highly significant that that CF3-containing imines as electrophiles serve as new four-atom building blocks in the phosphine-catalyzed intermolecular [4+3] cycloadditions for the first time. Meanwhile, the incorporation of fluorine atoms and perfluoroalkyl groups into products is an additional attractive feature of this approach, which is widely applied in the agrochemical and pharmaceutical industries.9 We commenced our studies by the treatment of trifluoroacetimidoyl chloride 1a and MBH carbonate 2a with 25 mol % PPh3 as the catalyst (see the Supporting Information). Unfortunately, no desired product was detected. Gratifyingly, when 1.0 equiv of Cs2CO3 was added as an additive, trace amounts of expected product 3a and 4a were indeed obtained in 10% and 8% yields, respectively. The structure of 3a was confirmed by X-ray analysis, and product 4a was assessed by DEPT and 2D NMR (HMQC and HMBC) shown in the Supporting Information. To improve the yield further, various temperatures, the ratio of 1a to 2a, and the additive loading were surveyed. Subsequently, a range of catalysts were explored; PPh3 and P(p-CH3OPh)3 proved to be the most efficient for products 3a and 4a, respectively. After much optimization, 3a and 4a were finally forged in 56% and 53% yields, respectively.

a Reactions were performed using 1a (0.15 mmol), 2a (0.23 mmol), PPh3 (25 mol %), and Cs2CO3 (1.5 equiv) in 1.5 mL of CHCl3 at 60 °C. bIsolated yields. cWith 2.0 equiv of Cs2CO3.

chlorides with either electron-withdrawing or electrondonating groups could smoothly assemble the corresponding annulation products 3a−3i in moderate yields. However, substrates 1 with increasing steric bulk groups gave products (3j−3l) with relatively lower yields. Interestingly, trifluoroacetimidoyl chlorides bearing a naphthyl group (1m−1o) underwent cyclization to deliver the desired products in good yields (62−86%).11 In addition, MBH carbonates 2 with various ester groups (CO2R2, where R2 = Me, n-Bu, i-Bu, or tBu) favored this reaction, and the corresponding products (3p−3s) were isolated in moderate yields. Moreover, substrate 1t with a longer perfluoroalkylated chain could also be transformed into the corresponding product 3t in 57% yield. The generality of the reaction with respect to P(pCH3OPh)3-catalyzed [4+3] reactions was also explored (Scheme 3). The substrates 1 with electron-poor groups could be converted to the corresponding products (4a−4d) in moderate yields, whereas the yields of products (4e−4j) were sharply reduced when trifluoroacetimidoyl chlorides (1e−1j) bearing electron-rich and steric bulk groups were used, which may come from the low reactivity of substrates. Further investigation showed that substrate 1h could generate the product 4h in 54% yield. In addition, good yields were obtained for products 4i−4k with different ester group sizes (CO2R2, where R2 = Me, n-Bu, or i-Bu). Moreover, product 4k could be obtained in moderate yield when 1.0 mmol of 1a was used. Substrate 1t containing a pentafluoroethyl group also reacted well to provide product 4t in 43% yield. To show the practicality of this method, a gram-scale reaction was performed and 1.04 g of 3m was obtained in 78% yield (Scheme 4a). The transformation of 3m was also B

DOI: 10.1021/acs.orglett.9b02626 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. P(p-CH3OPh)3-Catalyzed [4+3] Reactionsa,b

Scheme 5. Mechanistic Studies

a

Reactions were performed using 1a (0.15 mmol), 2a (0.38 mmol), P(p-CH3OPh)3 (25 mol %), and Cs2CO3 (1.5 equiv) in 1.5 mL of CHCl3 at 60 °C. bIsolated yields. cWith 2.0 equiv of Cs2CO3. dWith 1.0 mmol of 1a.

Scheme 4. Gram-Scale Synthesis and Further Transformation eq 5). These results suggest (1) product 3a might be derived from the imine/enamine tautomerism of intermediate 3a′ and (2) the organophosphine catalyst might play a crucial role in the construction of products 3a and 4a. Moreover, we carried out deuterium labeling investigations (Scheme 5c, eqs 6 and 7). Deuterated products D-3m and D-4a were obtained in 84% and 32% yields, respectively (see the Supporting Information for details). These results indicated that the possible carbanion intermediates were involved in the [4+3] cycloadditions. On the basis of the experimental results and previous reports mentioned above,10 we developed a plausible mechanism for the [4+3] reaction (Scheme 6). With respect to the formation Scheme 6. Proposed Mechanism conducted (Scheme 4b). The ester group of 3m could be selectively reduced by treatment with DIBAL-H, thus directly affording the corresponding alcohol 5a in 89% yield. Then, subjecting 5a to an oxidizing reaction delivered product 5b in 98% yield. Moreover, the imine moiety of 3m could be reduced by 1.5 equiv of LiAlH4 to yield product 5c. To gain some insight into the mechanism, intermediate 3a′ was captured in 42% yield in the presence of PPh3 and Cs2CO3 at room temperature (Scheme 5a, eq 1). The structure of 3a′ was confirmed by X-ray analysis (see the Supporting Information). Then, we conducted some controlled experiments with intermediate 3a′. Treatment of intermediate 3a′ with Cs2CO3 allowed smooth formation of 3a in 91% yield (Scheme 5b, eq 2). Additionally, no desired product 4a was obtained in the presence of Cs2CO3 without P(p-CH3OPh)3, and only product 3a was isolated in 61% yield (Scheme 5b, eq 3). When P(p-CH3OPh)3 participated in the reaction, intermediate 3a′ could further be transformed into the expected product in 96% yield (Scheme 4b, eq 4). In addition, when intermediate 3a′ was subjected to the standard reaction conditions with MBH carbonate 2a, the corresponding product 4a was facilely produced in 90% yield (Scheme 5b,

of product 3a, see the PPh3 catalysis cycle. The first step was the formation of phosphorus ylides I and II via the commonly accepted addition−elimination−deprotonation process. Next, nucleophilic attack of phosphorus ylide II on substrate 1a afforded intermediate A, and subsequent elimination of Cl anion gave intermediate B, which was deprotonated by tertC

DOI: 10.1021/acs.orglett.9b02626 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters butoxide anion to generate intermediate C. Then, intermediate C would isomerize into intermediate D, in which the N anion may delocalize to the ortho position of the benzene ring. Subsequently, intramolecular dearomatization afforded intermediate E and regenerated the phosphine catalyst to provide intermediate F, which underwent rearomatization to furnish intermediate 3a′. Finally, the imine/enamine tautomerism of intermediate 3a′ produced the corresponding product 3a in the presence of Cs2CO3. With respect to the formation of product 4a, see the P(p-CH3OPh)3 catalysis cycle. Intermediate 3a′ underwent deprotonation to give intermediate G followed by a H-shift of G to afford intermediate H, which attacked intermediate III to furnish product 4a and regenerated the phosphine catalyst. In conclusion, we have developed the first new method for the diverse construction of vital perfluoroalkylated benzazepines by means of phosphine-catalyzed divergent [4+3] domino annulations starting from readily accessible CF3containing imines with MBH carbonates under mild reaction conditions. In contrast to the traditional reactions of imines, the CF3-containing imines first served as a new kind of fouratom building block, which was realized through a dearomatization/rearomatization process. Notably, to the best of our knowledge, this work represents the first example of phosphine-catalyzed [4+3] annulations of imines. Synthetic transformations of the products were also showcased. The strategy discovered in this report affords a new protocol for synthetically valued benzazepine derivatives, which might be useful for organic synthesis and medicinal chemistry. Further investigation of the mechanism and synthetic applications is underway in our laboratory.

■

■

DEDICATION

■

REFERENCES

Dedicated to the 100th anniversary of Nankai University and the 100th anniversary of the birth of Academician Ruyu Chen.

(1) (a) Liu, S.; Qu, J.; Wang, B. Chem. Commun. 2018, 54, 7928. (b) Kang, G.; Yamagami, M.; Vellalath, S.; Romo, D. Angew. Chem., Int. Ed. 2018, 57, 6527. (c) Compiled and produced by the Njardarson group (University of Arizona): Smith, D. T.; Delost, M. D.; Qureshi, H.; Njarđarson, J. T. https://njardarson.lab.arizona.edu/ content/toppharmaceutical-poster. (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) Barnes, K. L.; Eickhoff, J. A.; Carson, C. R.; Jeffrey, C. S. J. Am. Chem. Soc. 2011, 133, 7688. (c) Shang, H.; Wang, Y.; Tian, Y.; Feng, J.; Tang, Y. Angew. Chem., Int. Ed. 2014, 53, 5662. (d) Schultz, E. E.; Lindsay, V.; Sarpong, R. Angew. Chem., Int. Ed. 2014, 53, 9904. (e) Gerstner, N. C.; Adams, C. S.; Tretbar, M.; Schomaker, J. M. Angew. Chem., Int. Ed. 2016, 55, 13240. (f) Zhu, C.; Feng, J.; Zhang, J. Angew. Chem., Int. Ed. 2017, 56, 1351. (g) Wu, X.; Zhou, L.; Maiti, R.; Mou, C.; Pan, L.; Chi, Y. R. Angew. Chem., Int. Ed. 2019, 58, 477. For selected examples of [5+2] cycloadditions, see: (h) Pedersen, T. M.; Scanio, M.; Wender, P. A. J. J. Am. Chem. Soc. 2002, 124, 15154. (i) Zhou, M.; Song, R.; Wang, C.; Li, J. Angew. Chem. 2013, 125, 11005. (j) Shenje, R.; Martin, M. C.; France, S. Angew. Chem. 2014, 126, 14127. (k) Lee, D.; Han, H.; Shin, J.; Yoo, E. J. Am. Chem. Soc. 2014, 136, 11606. (l) Feng, J.; Lin, T.; Wu, H.; Zhang, J. J. Am. Chem. Soc. 2015, 137, 3787. (m) Yang, Y.; Zhou, M.; Ouyang, X.; Pi, R.; Song, R.; Li, J. Angew. Chem., Int. Ed. 2015, 54, 6595. (n) Feng, J.; Lin, T.; Zhu, C.; Wang, H.; Wu, H.; Zhang, J. J. Am. Chem. Soc. 2016, 138, 2178. (o) Hu, C.; Song, R.; Hu, M.; Yang, Y.; Li, J.; Luo, S. Angew. Chem., Int. Ed. 2016, 55, 10423. (p) Zhao, C.; Glazier, D.; Yang, D.; Yin, D.; Guzei, I.; Aristov, M.; Liu, P.; Tang, W. Angew. Chem., Int. Ed. 2019, 58, 887. For selected examples of [3+2+2] cycloadditions, see: (q) Zhou, M.; Song, R.; Li, J. Angew. Chem., Int. Ed. 2014, 53, 4196. (r) Li, T.; Xu, F.; Li, X.; Wang, C.; Wan, B. Angew. Chem., Int. Ed. 2016, 55, 2861. (4) For selected reviews of phosphine catalysis, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b) Methot, J.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (c) Ye, L.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (d) Cowen, B. J.; Miller, S. Chem. Soc. Rev. 2009, 38, 3102. (e) Zhao, Q.; Lian, Z.; Wei, Y.; Shi, M. Chem. Commun. 2012, 48, 1724. (f) Liu, T.; Xie, M.; Chen, Y. Chem. Soc. Rev. 2012, 41, 4101. (g) Gomez, C.; Betzer, J.; Voituriez, A.; Marinetti, A. ChemCatChem 2013, 5, 1055. (h) Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659. (i) Xie, P.; Huang, Y. Eur. J. Org. Chem. 2013, 2013, 6213. (j) Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927. (k) Xie, P.; Huang, Y. Org. Biomol. Chem. 2015, 13, 8578. (l) Wang, T.; Han, X.; Zhong, F.; Yao, W.; Lu, Y. Acc. Chem. Res. 2016, 49, 1369. (m) Ni, H.; Chan, W.; Lu, Y. Chem. Rev. 2018, 118, 9344. (n) Guo, H.; Fan, Y. C.; Sun, Z.; Wu, Y.; Kwon, O. Chem. Rev. 2018, 118, 10049. (5) For selected examples of phosphine-catalyzed [4+3] cycloadditions, see: (a) Kumar, K.; Kapoor, R.; Kapur, A.; Ishar, M. P. S. Org. Lett. 2000, 2, 2023. (b) Zheng, S.; Lu, X. Org. Lett. 2009, 11, 3978. (c) Jing, C.; Na, R.; Wang, B.; Liu, H.; Zhang, L.; Liu, J.; Wang, M.; Zhong, J.; Kwon, O.; Guo, H. Adv. Synth. Catal. 2012, 354, 1023. (d) Zhou, R.; Wang, J.; Duan, C.; He, Z. Org. Lett. 2012, 14, 6134. (e) Zhan, G.; Shi, M.; He, Q.; Du, W.; Chen, Y. Org. Lett. 2015, 17, 4750. (f) Li, Z.; Yu, H.; Feng, Y.; Hou, Z.; Zhang, L.; Yang, W.; Wu, Y.; Xiao, Y.; Guo, H. RSC Adv. 2015, 5, 34481. (g) Yuan, C.; Zhou, L.; Xia, M.; Sun, Z.; Wang, D.; Guo, H. Org. Lett. 2016, 18, 5644. (h) Liu, H.; Lin, Y.; Zhao, Y.; Xiao, M.; Zhou, L.; Wang, Q.; Zhang, C.; Wang, D.; Kwon, O.; Guo, H. RSC Adv. 2019, 9, 1214.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02626. Experimental details, characterization data for new compounds, copies of NMR spectra, and X-ray crystal structures of 3a and 3a′ (PDF) Accession Codes

CCDC 1887997−1887998 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■

Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

You Huang: 0000-0002-9430-4034 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors thank the National Natural Science Foundation of China (21672109, 21871148 and 21472097) and the Natural Science Foundation of Tianjin (15JCYBJC20000). D

DOI: 10.1021/acs.orglett.9b02626 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters (6) (a) Wu, Y.; Hu, L.; Li, Z.; Deng, L. Nature 2015, 523, 445. (b) Chen, P.; Yue, Z.; Zhang, J.; Lv, X.; Wang, L.; Zhang, J. Angew. Chem., Int. Ed. 2016, 55, 13316. (7) (a) Chen, J.; Huang, Y. Org. Lett. 2017, 19, 5609. (b) Ni, H.; Tang, X.; Zheng, W.; Yao, W.; Ullah, N.; Lu, Y. Angew. Chem., Int. Ed. 2017, 56, 14222. (8) (a) Zhao, H.; Meng, X.; Huang, Y. Chem. Commun. 2013, 49, 10513. (b) Li, E.; Jia, P.; Liang, L.; Huang, Y. ACS Catal. 2014, 4, 600. (c) Liang, L.; Huang, Y. Org. Lett. 2016, 18, 2604. (d) Li, E.; Jin, H.; Jia, P.; Dong, X.; Huang, Y. Angew. Chem., Int. Ed. 2016, 55, 11591. (e) Zhang, Q.; Zhu, Y.; Jin, H.; Huang, Y. Chem. Commun. 2017, 53, 3974. (f) Jin, H.; Zhang, Q.; Li, E.; Jia, P.; Li, N.; Huang, Y. Org. Biomol. Chem. 2017, 15, 7097. (g) Zhu, Y.; Wang, D.; Huang, Y. Org. Lett. 2019, 21, 908. (h) Zhang, Q.; Jin, H.; Feng, J.; Zhu, Y.; Jia, P.; Wu, C.; Huang, Y. Org. Lett. 2019, 21, 1407. (9) (a) Wang, J.; Sańchez-Rosello, M.; Aceña, J.; Pozo, C.; Sorochinsky, A.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432. (b) Ilardi, E.; Vitaku, E.; Njardarson, J. J. Med. Chem. 2014, 57, 2832. (10) (a) Zheng, S. Q.; Lu, X. Org. Lett. 2008, 10, 4481. (b) Wang, H.; Zhang, J.; Tu, Y.; Zhang, J. Angew. Chem., Int. Ed. 2019, 58, 5422. (c) Li, K.; Goncalves, T.; Huang, K.; Lu, Y. Angew. Chem., Int. Ed. 2019, 58, 5427. (11) We think the different yields of 3j (37%) and 3m (86%) mainly come from the stability of intermediate D, and intermediate D (m) is more stable than intermediate D (j).

E

DOI: 10.1021/acs.orglett.9b02626 Org. Lett. XXXX, XXX, XXX−XXX