Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Phosphine-Catalyzed [8 + 2]-Annulation of Heptafulvenes with Allenoates and Its Asymmetric Variant: Construction of Bicyclo[5.3.0]decane Scaffold Zhenzhen Gao,†,‡ Chang Wang,† Leijie Zhou,† Chunhao Yuan,† Yumei Xiao,† and Hongchao Guo*,†,§ †
Department of Applied Chemistry, China Agricultural University, Beijing 100193, P. R. China School of Pharmacy, Liaocheng University, Liaocheng 252000, Shandong, P. R. China § State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China Downloaded via UNIV OF CALIFORNIA SANTA BARBARA on July 3, 2018 at 21:12:56 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
‡
S Supporting Information *
ABSTRACT: In this paper, a phosphine-catalyzed [8 + 2]annulation of heptafulvene with allenoates has been achieved under mild conditions, giving functionalized bicyclo[5.3.0]decane derivatives in moderate to excellent yields. Using chiral phosphine as the catalyst, optically active products were obtained in moderate to high yields with excellent enantioselectivities. he higher-order cycloadditions involving more than six π electrons have emerged as highly reliable tools for the construction of important medium-sized ring-fused polycyclic scaffolds.1 In the past two decades, various phosphinecatalyzed annulation reactions have been achieved.2 Under phosphine catalysis conditions, a few higher-order cycloadditions had been accomplished. In 2000, Ishar and coworkers reported a Ph3P-catalyzed [8 + 2]-annulation reaction of tropone with allenic esters/ketones to give 8-oxa-bicyclo[5.3.0]deca-1,3,5-trienes (Scheme 1, eq 1).3 In 2005, Lu and co-workers developed a phosphine-catalyzed [6 + 3]-
T
annulation reaction of tropone with modified allylic compounds including acetates, bromides, chlorides, or tert-butyl carbonates derived from the Morita−Baylis−Hillman (MBH) reaction, affording bridged nine-membered carbocycles (Scheme 1, eq 2).4 In 2011, Yao, Yuan and co-workers grafted triphenylphosphine groups in the 2D structure of layered aminophenylsilica dodecyl sulfate.5 With the use of this type of phosphine, an [8 + 3]-annulation of tropone with allyl halides was achieved to produce bicyclic 2,6-dihydrocyclohepta[b]pyran derivative (Scheme 1, eq 3).5 However, there has been no report on phosphine-catalyzed all-carbon higher-order cycloadditions involving heptafulvene and chiral phosphinecatalyzed asymmetric higher-order cycloaddition. In continuation of our interest in developing phosphine-catalyzed asymmetric cycloaddition reactions,6 we became interested in phosphine-promoted higher-order cycloaddition reactions. Herein, we report the phosphine-catalyzed [8 + 2]-annulation of heptafulvenes with allenoates and its asymmetric variant, which provides a practical, regiospecific, and enantioselective approach to functionalized bicyclo[5.3.0]decane derivatives (Scheme 1, eq 4). To the best of our knowledge, this represents the first example of phosphine-catalyzed enantioselective higher-order [8 + 2]-annulation of allenoates. Initially, with the use of barbiturate-heptafulvene 1,7 which has not been used as an 8π component in an [8 + 2]cycloaddition before, we carried out our study by examining the reaction with α-benzyl allenoate (2aa) to probe the feasibility of the reaction in toluene at rt in the presence of 20 mol % of Me2PPh (Table 1). To our delight, a new product 3aa was isolated in 55% yield (Table 1, entry 1). A subsequent screening of solvents indicated that only THF and toluene are
Scheme 1. Phosphine-Catalyzed Higher-Order Formal Cycloaddition Reactions
Received: June 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01734 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
Table 2. Scope of Allenoatesa
entry
PR3
solvent
temp (°C)
t (h)
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12c 13d 14c,e 15c,f
Me2PPh Me2PPh Me2PPh Me2PPh Me2PPh Me2PPh Me2PPh Me2PPh PPh3 MePPh2 PBu3 Me2PPh Me2PPh Me2PPh Me2PPh
toluene CH2Cl2 DCE THF CH3OH Et2O toluene toluene toluene toluene toluene toluene toluene toluene toluene
25 25 25 25 25 25 40 60 40 40 40 40 40 40 40
48 48 48 48 48 48 5 5 10 10 10 5 5 12 24
55 trace trace 45 NR 10 90 63 40 trace 53 93 85 76 60
a Unless otherwise indicated, all reactions were performed with 1 (0.1 mmol) and 2aa (0.12 mmol) in 2 mL of solvent. bIsolated yield. c Using 3 Å MS (100 mg). dUsing 4 Å MS (100 mg). e15 mol % of catalyst was used. f10 mol % catalyst was used.
compatible with this phosphine catalysis, providing the desired product in moderate 45% and 55% yield, respectively (Table 1, entries 2−6). Satisfactorily, increasing the reaction temperature to 40 °C remarkably increased the conversion rate, giving the product in 90% yield within 5 h (Table 1, entry 7). A further increase of the temperature to 60 °C did not offer better results (Table 1, entry 8). Despite employing other phosphines as the catalyst, the yield could not be increased (Table 1, entries 9− 11). To further improve the reaction efficiency, the additives were next screened. The 3 Å MS displayed a favorable effect, leading to an increase of the yield to 93% (Table 1, entries 12). When the loading of Me2PPh was decreased to 15 mol % and 10 mol %, the yields decreased to 76% and 60%, respectively (Table 1, entries 14−15). Other heptafulvenes such as 2(cyclohepta-2,4,6-trien-1-ylidene)malononitrile (1′) and diethyl 2-(cyclohepta-2,4,6-trien-1-ylidene)malonate (1′′) had also been attempted in this reaction. Unfortunately, both heptafulvenes 1′ and 1′′ did not work. According to the above screening, the optimal conditions were determined as using Me2PPh (20 mol %) as the catalyst and 3 Å MS (100 mg) as the additive in toluene at 40 °C. With the optimal conditions in hand, we then investigated the substrate scope of the allenoates 2 in the [8 + 2]annulation (Table 2). A variety of allenoates 2aa−2ra and 2ta−2va bearing electron-rich, -neutral, and -deficient groups on the benzene ring provided the corresponding products 3aa−3ra and 3ta−3va in moderate to excellent yields (61− 93%) (Table 2, entries 1−18, 20−22). The allenoate 2sa bearing a 2-naphthyl group was also compatible with the reaction to give the product 3sa in 91% yield (Table 2, entry 19). In addition, the α-(ethoxycarbonylmethyl)allenoate 2wa
entry
2, R1/R2
t (h)
3
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
2aa, Bn/Et 2ba, 2-MeC6H4CH2/Et 2ca, 3-MeC6H4CH2/Et 2da, 4-MeC6H4CH2/Et 2ea, 3-OMeC6H4CH2/Et 2fa, 4-t-BuC6H4CH2/Et 2ga, 2-FC6H4CH2/Et 2ha, 3-FC6H4CH2/Et 2ia, 4-FC6H4CH2/Et 2ja, 2-ClC6H4CH2/Et 2ka, 3-ClC6H4CH2/Et 2la, 4-ClC6H4CH2/Et 2ma, 2-BrC6H4CH2/Et 2na, 3-BrC6H4CH2/Et 2oa, 4-BrC6H4CH2/Et 2pa, 3-CF3C6H4CH2/Et 2qa, 4-CF3C6H4CH2/Et 2ra, 4-CO2MeC6H4CH2/Et 2sa, 2-naphthylCH2/Et 2ta, 3,5-OMe2C6H3CH2/Et 2ua, 2-F-5-ClC6H3CH2/Et 2va, 3-F-4-ClC6H3CH2/Et 2wa, CH2CO2Et/Et 2xa, CH3/Et 2ya, H/Et 2ab, Bn/Me 2ac, Bn/Ph
5 12 12 15 15 12 20 20 12 12 15 12 12 12 12 15 20 12 15 12 12 12 15 24 24 15 12
3aa 3ba 3ca 3da 3ea 3fa 3ga 3ha 3ia 3ja 3ka 3la 3ma 3na 3oa 3pa 3qa 3ra 3sa 3ta 3ua 3va 3wa 3xa 3ya 3ab 3ac
93 74 78 61 84 84 79 73 85 76 80 81 78 83 87 88 81 67 91 63 67 68 60 0 0 85 78
a All reactions were performed with 1a (0.1 mmol), 2 (0.12 mmol), 3 Å MS (100 mg), and PMe2Ph (0.02 mmol) in 2 mL of toluene at 40 °C. bIsolated yield.
underwent the reaction to give the product 3wa in 60% yield (Table 2, entry 23). The α-methyl allenoate (2xa) and ethyl buta-2,3-dienoate (2ya) were inert in this reaction, and no desired products were observed (Table 2, entries 24−25). Changing the ester moieties in allenoates with Me and Ph groups has no significant influence on the reactivity. These allenoates led to the desired products in 85% and 78% yields (Table 2, entries 26−27). The structure of the annulation products was confirmed by single crystal X-ray analysis of the product 3sa (CCDC 1587408). With chiral phosphine as the catalyst, we attempted to develop an asymmetric variant of this phosphine-catalyzed [8 + 2]-annulation of heptafulvene with allenoates (Table 3). In the initial exploration, various chiral phosphines including cyclic and multifunctional phosphines were screened (Table 3, entries 1−6). Kwon’s endo phosphine P1 catalyzed the reaction to give the desired product 3aa with 90% ee, albeit in 24% yield. In contrast, the exo isomer P2 of the phosphine P1 only led to a trace amount of the product (Table 3, entry 2). Thus, we next examined two of Kwon’s endo phosphines P3 and P4. In the presence of phosphine P3, the yield was slightly increased to 30% (Table 3, entry 3). The phosphine P4 displayed similar activity to that of P3, leading to the product in 35% yield, but the ee decreased to 84% (Table 3, entry 4). B
DOI: 10.1021/acs.orglett.8b01734 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 3. Evaluation of Asymmetric [8 + 2]-Annulation Reaction Conditionsa
entry
Px
R
solvent
3
yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11d
P1 P2 P3 P4 P5 P6 P3 P3 P3 P3 P3
Et Et Et Et Et Et Me Ph Ph Ph Ph
toluene toluene toluene toluene toluene toluene toluene toluene PhCF3 PhF PhF
3aa 3aa 3aa 3aa 3aa 3aa 3ab 3ac 3ac 3ac 3ac
24 trace 30 35 trace 5 30 70 70 72 64
90 − 90 84 − −60 87 82 88 88 90
Table 4. Scope of Allenoates in Asymmetric [8 + 2]Annulationa
entry
R1/R2
3
yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11 12 13d
2ac, Ph/Ph 2bc, 2-MeC6H4/Ph 2cc, 3-MeC6H4/Ph 2dc, 4-MeC6H4/Ph 2gc, 2-FC6H4/Ph 2hc, 3-FC6H4/Ph 2ic, 4-FC6H4/Ph 2xc, 1-naphthyl/Ph 2ad, Ph/CH2CHF2 2gd, 2-FC6H4/CH2CHF2 2jd, 2-ClC6H4/CH2CHF2 2md, 2-BrC6H4/CH2CHF2 2ae, Ph/CH2CCl3
3ac 3bc 3cc 3dc 3gc 3hc 3ic 3xc 3ad 3gd 3jd 3md 3ae
64 59 63 64 61 60 65 65 60 61 65 67 55
90 90 90 90 92 91 88 86 92 92 94 92 97
a
Unless otherwise indicated, all reactions were carried out with 1 (0.1 mmol), 2 (0.12 mmol), P3 (20 mol %) and 3 Å MS (100 mg) in 2 mL of PhF at rt. bIsolated yield. cDetermined by HPLC analysis using a chiral stationary phase. dThe reaction was performed at 0 °C.
To further evaluate the synthetic utility of the current reaction, the reaction on the gram scale was investigated (Scheme 2). The reaction of the heptafulvene 1 (0.73 g) with
a
Unless otherwise indicated, all reactions were carried out with 1 (0.1 mmol) and 2a (0.12 mmol) in the presence of 3 Å MS (100 mg) in 2 mL of solvent. bIsolated yield. cDetermined by HPLC analysis using a chiral stationary phase. dThe reaction was performed at rt for 72 h.
Scheme 2. Scale-up and Further Transformations Spirocyclic chiral phosphine P5 was noneffective, giving only a trace amount of the product 3aa (Table 3, entry 5). The multifunctional phosphine P6 showed extremely weak activity, resulting in the product in approximately 5% yield with 60% ee (Table 3, entry 6). With the use of chiral phosphine P3, we then investigated the influence of the variation of the ester moiety in allenoate (Table 3, entries 7−8). The results indicate the phenyl ester proved to be superior to other esters, and the yield and ee of the product could be increased to 70% yield and 82% ee, respectively (Table 3, entry 8). Concise solvent screening revealed that fluorobenzene is the optimal solvent, resulting in the product 3ac in 72% yield with 88% ee (Table 3, entries 9−10). Decreasing the temperature to rt slightly enhanced the ee to 90% (Table 3, entry 11). Under the optimized conditions, and in the presence of chiral phosphine P3, the substrate scope of the asymmetric [8 + 2]-cycloaddition of heptafulvene 1 with allenoate 2 was examined (Table 4). The allenoates substituted with an aryl bearing either an electron-rich or electron-deficient group smoothly underwent the reaction, delivering the corresponding products in 59−65% yields with 88−92% ee (3bc−3ic). The 2-naphthyl substituted allenoate 2xc was also a suitable reaction partner, affording the product 3xc in 65% yield with 86% ee. Several halo-substituted ethyl allenoates worked well under the optimal conditions, providing the product with acceptable yields and enantioselectivities (Table 4, entries 9− 13). The absolute configuration of chiral product was confirmed by single crystal X-ray analysis of the product 3ad (CCDC 1587409).
allenoate 2aa proceeded smoothly to give the product 3aa in 73% yield. Treatment of 3aa with 1.5 equiv of DDQ (2,3dichloro-5,6-dicyano-1,4-benzoquinone) at rt for 12 h produced the oxidized product 4 in 88% yield. In the presence of Pd(Ph3P)4, the cycloadduct 3oa underwent a Suzuki coupling reaction to afford the derivative 5 in 80% yield. More interestingly, a novel tetrabromo derivative 6 (CCDC C
DOI: 10.1021/acs.orglett.8b01734 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters ORCID
1587410) was obtained in 82% yield through treatment of the cycloadduct 3ac with NBS at rt. A plausible reaction mechanism has been proposed in Scheme 3. The phosphine undergoes conjugate addition to
Hongchao Guo: 0000-0002-7356-4283 Notes
The authors declare no competing financial interest.
■
Scheme 3. A Plausible Reaction Mechanism for the Annulation
ACKNOWLEDGMENTS This work is supported by the NSFC (21372256 and 21572264), the State Key Laboratory of Chemical Resource Engineering, the Program for Changjiang Scholars and Innovative Research Team Project IRT1042, and the Shandong Provincial Natural Science Foundation of China (ZR2018BB028).
■
(1) For reviews, see: (a) Rigby, J. H. Acc. Chem. Res. 1993, 26, 579. (b) Rigby, J. H. Tetrahedron 1999, 55, 4521. (c) Harmata, M. Acc. Chem. Res. 2001, 34, 595. (d) Harmata, M. Adv. Synth. Catal. 2006, 348, 2297. (e) Nair, V.; Abhilash, K. G. Synlett 2008, 2008, 301. (f) Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev. 2010, 39, 2791. (g) Lohse, A. G.; Hsung, R. P. Chem. - Eur. J. 2011, 17, 3812. (h) Pellissier, H. Adv. Synth. Catal. 2011, 353, 189. (i) Ylijoki, K. E. O.; Stryker, J. M. Chem. Rev. 2013, 113, 2244. (2) For selected reviews see: (a) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (b) Zhao, Q.-Y.; Lian, Z.; Wei, Y.; Shi, M. Chem. Commun. 2012, 48, 1724. (c) Fan, Y. C.; Kwon, O. Chem. Commun. 2013, 49, 11588. (d) Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927. (e) Xiao, Y.; Sun, Z.; Guo, H.; Kwon, O. Beilstein J. Org. Chem. 2014, 10, 2089. (f) Xiao, Y.; Guo, H.; Kwon, O. Aldrichimica Acta 2016, 49, 3. (g) Wang, T.; Han, X.; Zhong, F.; Yao, W.; Lu, Y. Acc. Chem. Res. 2016, 49, 1369. (h) Li, W.; Zhang, J. Chem. Soc. Rev. 2016, 45, 1657. (i) Li, H.; Lu, Y. Asian J. Org. Chem. 2017, 6, 1130. (j) Wei, Y.; Shi, M. Org. Chem. Front. 2017, 4, 1876. (3) (3) Kumar, K.; Kapur, A.; Ishar, M. P. S. Org. Lett. 2000, 2, 787. (4) Du, Y.; Feng, J.; Lu, X. Org. Lett. 2005, 7, 1987. (5) Chen, C.; Shao, X.; Yao, K.; Shangguan, W.; Kawaguchi, T.; Shimazu, K. Langmuir 2011, 27, 11958. (6) (a) Na, R.; Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.; Zhong, J.; Wang, M.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Guo, H.; Kwon, O. J. Am. Chem. Soc. 2011, 133, 13337. (b) Zhang, L.; Liu, H.; Qiao, G.; Hou, Z.; Liu, Y.; Xiao, Y.; Guo, H. J. Am. Chem. Soc. 2015, 137, 4316. (c) Yuan, C.; Zhou, L.; Xia, M.; Sun, Z.; Wang, D.; Guo, H. Org. Lett. 2016, 18, 5644. (d) Liu, H.; Liu, Y.; Yuan, C.; Wang, G.P.; Zhu, S. F.; Wu, Y.; Wang, B.; Sun, Z.; Xiao, Y.; Zhou, Q.-L.; Guo, H. Org. Lett. 2016, 18, 1302. (e) Zhou, L.; Yuan, C.; Zhang, C.; Zhang, L.; Gao, Z.; Wang, C.; Liu, H.; Wu, Y.; Guo, H. Adv. Synth. Catal. 2017, 359, 2316. (f) Yang, W.; Sun, W.; Zhang, C.; Wang, Q.; Guo, Z.; Mao, B.; Liao, J.; Guo, H. ACS Catal. 2017, 7, 3142. (g) Zhou, L.; Yuan, C.; Zeng, Y.; Liu, H.; Wang, C.; Gao, X.; Wang, Q.; Zhang, C.; Guo, H. Chem. Sci. 2018, 9, 1831. (h) Wang, C.; Gao, Z.; Zhou, L.; Wang, Q.; Wu, Y.; Yuan, C.; Liao, J.; Xiao, Y.; Guo, H. Chem. Commun. 2018, 54, 279. (7) (a) Naya, S.-i.; Nitta, M. Tetrahedron 2003, 59, 3709. (b) Naya, S.-i.; Yamaguchi, Y.; Nitta, M. Tetrahedron 2008, 64, 3225.
allenoate 2aa to form the β-phosphonium dienolate intermediate B, which attacks heptafulvene 1 to give the enolate intermediate C. Subsequent intramolecular Michael addition affords the intermediate D. The product 3aa is produced through elimination of phosphine from the intermediate D. In the asymmetric reaction, the β-phosphonium dienolate intermediate performs an Si-face attack to heptafulvene, leading to (S)-tricyclic products. In conclusion, we have achieved a phosphine-catalyzed [8 + 2]-annulation of heptafulvene with allenoates under mild conditions to provide pharmaceutically interesting bicyclo[5.3.0]decane-fused spirobarbiturates in moderate to excellent yields. With the use of Kwon’s phosphine as the chiral catalyst, enantioenriched products were obtained in moderate to high yields with excellent enantioselectivities. This represents the first example of phosphine-catalyzed enantioselective allcarbon [8 + 2]-annulation of allenoates. Moreover, the reaction could be performed on the gram scale, and further conversions of tricyclic products provided some useful compounds with interesting structures.
■
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.8b01734. Experimental procedures, characterization data, HPLC analysis dada, NMR spectra and X-ray crystallographic data (PDF) Accession Codes
CCDC 1587408−1587410 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.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. D
DOI: 10.1021/acs.orglett.8b01734 Org. Lett. XXXX, XXX, XXX−XXX
