Highly enantio-, regio- and diastereo-selective one-pot [2 + 3]-cycloaddition reaction via isomerization of 3-butynoates to allenoates,

Abstract

Phosphine-catalyzed one-pot isomerization and [2 + 3]-cycloaddition of 3-butynoates with electron-deficient olefins affords highly functionalized cyclopentenes with both good yields and excellent selectivities of up to 99%.

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Highly enantio-, regio- and diastereo-selective approach towards the synthesis of functionalized five-membered rings is highly sought-after, as these are featured widely in many natural products and synthetic building blocks.¹ Although, there are many methods available for the construction of five-membered rings,² Lu's phosphine-catalyzed [2 + 3]-cycloaddition reaction using electron-deficient allenoates/2-butynoates and electron-deficient double bonds is considered to be one of the most efficient methods.^3–5 This method has also been utilized in the synthesis of some natural products.⁶ Recently, asymmetric versions of this method have also been elegantly demonstrated by different groups.⁷ However, there are still limitations in the reported cases. For example, in some systems, the reported chiral phosphines are difficult to obtain and their substrate scope are relatively narrow. Another problem associated with this process is the need to use allenoates which can be difficult to make. Furthermore, the allenoates are sometime contaminated with the corresponding homo-propargylic equivalents.⁸ In this sense, usage of 3-butynoates which can be isomerized⁹ to the corresponding allenoates in situ for the [2 + 3]-cycloaddition reaction is highly desirable (Scheme 1). If successful, a mixture of propargylic and allenic esters can be directly employed in this reaction without the need for isolation.

Scheme 1 Proposed reaction pathways: isomerization and [2 + 3]-cycloaddition of 3-butynoates.

In this paper, we report the use of tributylphosphine which concurrently catalyzes the isomerization of 3-butynoates to allenoates, as well as subsequent Lu [2 + 3]-cyclization reaction of the latter. As we envisaged, in situ isomerization of 3-butynoates (1a) to allenoates led to the formation of formal [2 + 3]-cyclized product in 75% yield when trans-chalcone was stirred in a catalytic amount of tributylphosphine (Scheme 1). Notably, triphenylphosphine failed to catalyze the reaction. This is probably due to the comparatively lower nucleophilicity of triphenylphosphine as compared to aliphatic phosphines (e.g. tributylphosphine). Moreover, the reaction with triethylamine or 1,4-diazabicyclo[2.2.2]octane (DABCO) instead of tributylphosphine under the same reaction conditions, led to only isomerized product (allenoates) but not the cycloaddition or conjugate addition product.¹⁰

To define the generality of this method, various electron-deficient double bonds (Table 1, entries 1–8) and 3-butynoates (Table 2, entries 1–8) were screened. Both electron-withdrawing and electron-donating groups on the phenyl ring of 3-butynoates and enones furnished the products in moderate to good yields. Cycloaddition reaction with enoates such as diethyl fumarate also afforded the product (2h) in good yield (Table 1, entry 8).

Table 1 Phosphine-catalyzed [2 + 3]-cycloaddition reactions using 3-butynoate and various electron deficient double bonds.^a

Entry	R^1	R^2	Product^b	Yield^c (%)
a See ESI^1 for the detailed experimental procedure; 3-butynoates 1a contain 2% of the corresponding allenoates. b Single regio (α)- and diastereo-isomers were observed by crude NMR analysis. c Isolated yield. d Trace amount of minor diastereoisomers were observed in NMR analysis. e 10 equiv. of diethyl fumarate was used.
1	C6H5	C6H5	2a	75
2	4-BrC6H4	4-FC6H4	2b	72
3	4-MeC6H4	4-MeC6H4	2c	77
4	4-ClC6H4	4-FC6H4	2d	70
5	4-MeOC6H4	4-FC6H4	2e	80
6	C6H5	4-FC6H4	2f	68
7^d	C6H5CH=H	C6H5	2g	70
8^d^,^e	OEt	COOEt	2h	78

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Table 2 Phosphine-catalyzed [2 + 3]-cycloadditin using various 3-butynoates.^a

Entry	R	Product^b	Yield^c (%)
a See the ESI for the detailed experimental procedure; 3-butynoate 1e was contaminated with 35% of the corresponding allenoate and the remainder of the 3-butynoates contain 5% of the allenoates. b Single regio (α)- and diastereo-isomers were observed by crude NMR analysis. c Isolated yield. d Reaction required 28 h. e Product 2o was hydrolyzed to the corresponding acid (Scheme 2) and the relative stereochemistry was confirmed by X-ray analysis (CCDC 748921). f Corresponding allenoates were used. Compound 1i was synthesized using the procedure reported in the literature.^11
1	4-MeC6H41b	2i	77
2	4-MeOC6H41c	2j	82
3	(2-Me)(4-MeO)C6H31d	2k	88
4	4-CF3C6H41e	2l	71
5	3-Thienyl 1f	2m	78
6	6-MeO-2-naphthyl 1g	2n	80
7^d^,^e	Cyclopropyl 1h	2o	85
8^f	CH31i	2p	87

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Scheme 2 Hydrolysis of product 2o; X-Ray crystallographic structure of hydrolyzed product; 50% probability was chosen for the ellipsoids. Reagents and conditions: (a) LiOH·H₂O (5 equiv.), THF–H₂O (1 : 1), 60 °C, 8 h, 95%.

In addition, 3-butynoates bearing thiophene (1f), naphthalene (1g) and aliphatic substituents such as the cyclopropyl group (1h) also afforded the products in good yields (Table 2, entries 5–7).

Next, we focused on the asymmetric version of this reaction. On the basis of our studies as described above, we believed that aliphatic phosphines with stereogenic centers in close proximity to the reactive sites will be more promising for asymmetric cycloaddition reaction. With this in mind, various commercially available chiral phosphines were screened using a solution of 3-butynoate (1a) (0.26 mmol), trans-chalcone (0.29 mmol) and 10 mol% of phosphines in dry toluene (1.5 mL) at room temperature (Table 3, entries 1–8).

Table 3 Screening various commercially available chiral phosphines for asymmetric [2 + 3]-cycloaddition reactions.

Entry	Phosphine^a	t/h	Yield^b (%)	Ee^c (%)
a See Scheme 3 for the structure of commercially available chiral phosphines screened. b Isolated yield. c Ee (%) was determined using chiral HPLC.
1	(+)-DIOP	8	72	66
2	(R,R)-Et-BPE	8	78	63
3	(R,R)-DIPAMP	8	87	95
4	(R,R)-Et-DUPHOS	24	27	33
5	(S)-(−)-2-[2-(Diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline	24	—	—
6	(R)-BINAP	24	—	—
7	(R)-Tol-BINAP	24	—	—
8	(2S,3S)-CHIRAPHOS	24	58	34

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Scheme 3 Structure of commercially available chiral phosphines screened for asymmetric [2 + 3]-cycloaddition reaction.

The commercially available catalyst (R,R)-DIPAMP emerged as the best catalyst in terms of both yield and enantioselectivity. However, lower yield and enantioselectivity were observed when the catalyst loading was decreased to 5 mol%. Increasing the amount of catalyst loading to 20 mol% and decreasing the temperature of the reaction to 0 °C did not increase the yield or enantioselectivity of the product. Using the best chiral phosphine (R,R)-DIPAMP and optimized reaction conditions, asymmetric reactions were carried out with a series of electron-deficient enones (Table 4, entries 1–8). In all the cases, both excellent enantioselectivities and yields were observed. Notably, reaction with symmetrical dienone affords single [2 + 3]-cycloaddition product (2g′) with excellent enantioselectivity (Table 4, entry 7).

Table 4 Asymmetric [2 + 3]-cycloaddition reaction using (R,R)-DIPAMP^a,b

Entry	R^1	R^2	Product/yield^c (%)	Ee^d (%)
a See ESI^1 for the detailed experimental procedure. b Single regio (α)- and diastereo-isomers were observed by crude NMR analysis. c Isolated yield. d Ee was determined using chiral HPLC (see ESI^1 for more details). e Symmetrical dienone was used. No trace of double [2 + 3]-cyclized product was observed. f 10 equiv. of diethyl fumarate was used. g Reaction completed in 12 h.
1	C6H5	C6H5	2a′/87	95
2	4-BrC6H4	4-FC6H4	2b′/92	95
3	4-MeC6H4	4-MeC6H4	2c′/95	93
4	4-ClC6H4	4-FC6H4	2d′/88	95
5	4-MeOC6H4	4-FC6H4	2e′/82	98
6	C6H5	4-FC6H4	2f′/85	95
7^e	C6H5CH=CH	C6H5	2g′/90	99
8^f^,^g	OEt	COOEt	2h′/88	81

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To further explore the generality of this catalyst DIPAMP, electronically and sterically divergent 3-butynoates were screened (Table 5, entries 1–8). In all the cases, excellent yields and enantioselectivities were obtained. Interestingly, the catalyst (R,R)-DIPAMP afforded excellent enantioselectivities with butynoates containing thiophene (1f) (Table 5, entry 5) and naphthalene (1g) (Table 5, entry 6). However, (R,R)-DIPAMP failed to yield the desired product with cyclopropyl substituted 3-butynoate (1h) even after stirring for 3 days. It was gratifying to find that addition of a catalytic amount 10 mol% of triethylamine facilitated the isomerization to afford the cyclized product in good yield with high enantioselectivity (Table 5, entry 7). Interestingly, in all the cases, products were obtained as single regio- and diastereo-isomers, which was consistent with the results reported by Miller and Cowen.^7c

Table 5 Asymmetric [2 + 3]-cycloaddition reaction using (R,R)-DIPAMP: scope with respect to 3-butynoates.^a,b

Entry	R	Product/yield^c (%)	Ee^d (%)
a See ESI^1 for the detailed experimental procedure. b Single regio (α)- and diastereo-isomers were observed by crude NMR analysis. c Isolated yield. d Ee was determined using chiral HPLC (see ESI^1 for more details). e 3-Butynoate 1e contaminated with 35% of the corresponding allenoate and the remainder of the 3-butynoates contain 5% of allenoates. f 10 mol% of triethylamine was added and the reaction was completed in 12 h. g Absolute configuration was assigned by comparing with the optical rotation value reported in the literature.^7c h Corresponding allenoate was used (for the synthesis of allenoate see ref. 11).
1	4-MeC6H41b	2i′/82	97
2	4-MeOC6H41c	2j′/89	95
3	(2-Me)(4-OMe)C6H31d	2k′/93	84
4^e	4-CF3C6H41e	2l′/66	94
5	3-Thienyl 1f	2m′/90	96
6	6-OMe-2-naphthyl 1g	2n′/77	96
7^f	Cyclopropyl 1h	2o′/93	90
8^g^,^h	CH31i	2p′/87	99

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The absolute configuration of the product 2p′ was assigned by comparing the optical rotation of the corresponding benzyl ester with literature value.^7c The product (2p′) was transformed to the corresponding benzyl ester as described in Scheme 4.

Scheme 4 Determination of absolute stereochemistry; see ESI† for detailed experimental procedure. Reagents and conditions: (a) LiOH·H₂O (5 equiv.), THF–H₂O (1 : 1), 60 °C, 5 h, 92%; (b) PhCH₂Br, K₂CO₃, DMF, rt, 12 h, 95%.

A control experiment had been carried out by first isolating the (±)-allenoate intermediate before subjecting it to the asymmetric [2 + 3]-cycloaddition using trans-chalcone and 10 mol% of (R,R)-DIPAMP (Scheme 5).¹² The above reaction affords identical results with the one-pot [2 + 3]-cycloaddition of 3-butynoates using trans-chalcone and (R,R)-DIPAMP (Table 4, entry 1). This experiment indicated that the chirality of the allenoates played no significant role in the asymmetric induction of the reaction.

Scheme 5 A control experiment: isolation of intermediate.

In conclusion, we have demonstrated the direct applicability of 3-butynoates in the [2 + 3]-cycloaddition reaction. This one-pot procedure is an attractive alternative to the usual protocol reported for this type of reaction. In addition, we have identified a more efficient commercially available chiral phosphine, (R,R)-DIPAMP for this cycloaddition reaction, affording various cyclopentene derivatives in high optical purities. Further investigation of the scope, mechanism and application of this methodology to the synthesis of complex molecules are in progress.

Acknowledgements

We thank Dr Yong-Xin Li for X-ray analyses. We gratefully acknowledge the Nanyang Technological University and Biomedical Research Council (A*STAR Grant No 05/1/22/19/408) for the funding support of this research

Notes and references

1. (a) R. C. Hartley and S. T. Caldwell, J. Chem. Soc., Perkin Trans. 1, 2000, 477–501; (b) H. Wu, H. Zhang and G. Zhao, Tetrahedron, 2007, 63, 6454–6461.
2. For reviews, see: (a) B. J. Cowen and S. J. Miller, Chem. Soc. Rev., 2009, 38, 3102–3116 , and references therein; (b) T. Hudlicky and J. D. Price, Chem. Rev., 1989, 89, 1467–1486; (c) M. Lautens, W. Klute and W. Tam, Chem. Rev., 1996, 96, 49–92; (d) B. M. Trost, Angew. Chem., Int. Ed. Engl., 1986, 25, 1–20; (e) H. Li and T. P. Loh, J. Am. Chem. Soc., 2008, 130, 7194–7195; (f) S. G. Van Ornum and J. M. Cook, Tetrahedron Lett., 1997, 38, 3657–3658; (g) B. M. Trost, P. Seoane, S. Mignani and M. Acemoglu, J. Am. Chem. Soc., 1989, 111, 7487–7500; (h) A. Panossian, N. F. Bregeot and A. Marinetti, Eur. J. Org. Chem., 2008, 3826–3833.
3. (a) X. Lu and C. Zhang, J. Org. Chem., 1995, 60, 2906–2908. For phosphine catalyzed annulation reactions, see: (b) S. Zheng and X. Lu, Org. Lett., 2009, 11, 3978–3981; (c) Z. Lu, S. Zheng, X. Zhang and X. Lu, Org. Lett., 2008, 10, 3267–3270; (d) M. Sampath and T. P. Loh, Chem. Commun., 2009, 1568–1570; (e) J. L. Methot and W. R. Roush, Adv. Synth. Catal., 2004, 346, 1035–1050; (f) L.-W. Ye, J. Zhou and Y. Tang, Chem. Soc. Rev., 2008, 37, 1140–1152; (g) L. Jean and A. Marinetti, Tetrahedron Lett., 2006, 47, 2141–2145; (h) Y. Du, X. Lu and Y. Yu, J. Org. Chem., 2002, 67, 8901–8905; (i) Y. S. Tran and O. Kwon, J. Am. Chem. Soc., 2007, 129, 12632–12633; (j) X. F. Zhu, J. Lan and O. Kwon, J. Am. Chem. Soc., 2003, 125, 4716–4717; (k) G. S. Creech and O. Kwon, Org. Lett., 2008, 10, 429–432; (l) X. F. Zhu, C. E. Henry, J. Wang, T. Dudding and O. Kwon, Org. Lett., 2005, 7, 1387–1390; (m) X. F. Zhu, A. P. Schaffner, R. C. Li and O. Kwon, Org. Lett., 2005, 7, 2977–2980; (n) C. E. Henry and O. Kwon, Org. Lett., 2007, 9, 3069–3072; (o) Z. Xu and X. Lu, Tetrahedron Lett., 1999, 40, 549–552.
4. (a) Y. S. Tran and O. Kwon, Org. Lett., 2005, 7, 4289–4291; (b) V. Sriramurthy, G. A. Barcan and O. Kwon, J. Am. Chem. Soc., 2007, 129, 12928–12929; (c) R. P. Wurz and G. C. Fu, J. Am. Chem. Soc., 2005, 127, 12234–12235; (d) A. T. Ung, K. Schafer, K. B. Lindsay, S. G. Pyne, K. Amornraksa, R. Wouters, I. V. Linden, I. Biesmans, A. S. J. Lesage, B. W. Skelton and A. H. White, J. Org. Chem., 2002, 67, 227–233; (e) A. Scherer and J. A. Gladysz, Tetrahedron Lett., 2006, 47, 6335–6337; (f) X. Meng, Y. Huang and R. Chen, Org. Lett., 2009, 11, 137–140; (g) H. Guo, Q. Xu and O. Kwon, J. Am. Chem. Soc., 2009, 131, 6318–6319; (h) X. Meng, Y. Huang, H. Zhao, P. Xie, J. Ma and R. Chen, Org. Lett., 2009, 11, 991–994; (i) X.-Y. Guan and M. Shi, J. Org. Chem., 2009, 74, 1977–1981; (j) V. Nair, A. T. Biju, K. Mohanan and E. Suresh, Org. Lett., 2006, 8, 2213–2216; (k) D. J. Wallace, R. L. Sidda and R. A. Reamer, J. Org. Chem., 2007, 72, 1051–1054; (l) L.-W. Ye, X.-L. Sun, Q.-G. Wang and Y. Tong, Angew. Chem., Int. Ed., 2007, 46, 5951–5954.
5. For mechanistic investigation of [3 + 2]-cycloaddition reactions, see: (a) Y. Xia, Y. Liang, Y. Chen, M. Wang, L. Jiao, F. Huang, S. Liu, Y. Li and Z.-X. Yu, J. Am. Chem. Soc., 2007, 129, 3470–3471; (b) Y. Liang, S. Liu and Z.-X. Yu, Synlett, 2009, 905–909; (c) T. Dudding, O. Kwon and E. Mercier, Org. Lett., 2006, 8, 3643–3646; (d) E. Mercier, B. Fonovic, C. Henry, O. Kwon and T. Dudding, Tetrahedron Lett., 2007, 48, 3617–3620.
6. (a) Y. Du and X. Lu, J. Org. Chem., 2003, 68, 6463–6465; (b) J. C. Wang and M. J. Krische, Angew. Chem., Int. Ed., 2003, 42, 5855–5857; (c) T. Q. Pham, S. G. Pyne, B. W. Skelton and A. H. White, J. Org. Chem., 2005, 70, 6369–6377; (d) H. Mizuno, K. Domon, K. Masuya, K. Tanino and I. Kuwajima, J. Org. Chem., 1999, 64, 2648–2656.
7. (a) G. Zhu, Z. Chen, Q. Jiang, D. Xiao, P. Cao and X. Zhang, J. Am. Chem. Soc., 1997, 119, 3836–3837; (b) J. E. Wilson and G. C. Fu, Angew. Chem., Int. Ed., 2006, 45, 1426–1429; (c) B. J. Cowen and S. J. Miller, J. Am. Chem. Soc., 2007, 129, 10988–10989; (d) Y. Q. Fang and E. N. Jacobsen, J. Am. Chem. Soc., 2008, 130, 5660–5661; (e) A. Voituriez, A. Panossian, N. F. Bregeot, P. Retailleau and A. Marinetti, J. Am. Chem. Soc., 2008, 130, 14030–14031; (f) A. Voituriez, A. Panossian, N. F. Bregeot, P. Retailleau and A. Marinetti, Adv. Synth. Catal., 2009, 351, 1968–1976.
8. (a) M. J. Lin and T. P. Loh, J. Am. Chem. Soc., 2003, 125, 13042–13043; (b) F. Fu, L. M. Hoang and T. P. Loh, Org. Lett., 2008, 10, 3437–3439; (c) F. Sato, T. Nakagawa and A. Kasatkin, Tetrahedron Lett., 1995, 36, 3207–3210; (d) U. Maeorg and A. Jogi, Molecules, 2001, 6, 964–968; (e) W. L. Wu, Z. J. Yao, Y. L. Li, J. C. Li, Y. Xia and Y. L. Wu, J. Org. Chem., 1995, 60, 3257–3259; (f) M. Iyoda, Y. Kanao, M. Nishizaki and M. Oda, Bull. Chem. Soc. Jpn., 1989, 62, 3380–3382; (g) A. Suárez and G. C. Fu, Angew. Chem., Int. Ed., 2004, 43, 3580–3582; (h) K. Takami, S. Usugi, H. Yorimitsu and K. Oshima, Synthesis, 2005, 824–839; (i) J. A. Cabezas and L. X. Alvarez, Tetrahedron Lett., 1998, 39, 3935–3938; (j) W. Miao and T. H. Chan, Synthesis, 2003, 785–789.
9. For base-promoted isomerization, see: (a) M. E. Jung, M. Node, R. W. Pfluger, M. A. Lyster and J. A. Lowe III, J. Org. Chem., 1982, 47, 1150–1152; (b) D. Ma, Y. Yu and X. Lu, J. Org. Chem., 1989, 54, 1105–1109; (c) H. Liu, D. Leow, K. W. Huang and C. H. Tan, J. Am. Chem. Soc., 2009, 131, 7212–7213; (d) M. Oku, S. Arai, K. Katayama and T. Shioiri, Synlett, 2000, 493–494.
10. C. A. Evans and S. J. Miller, J. Am. Chem. Soc., 2003, 125, 12394–12395.
11. R. W. Lang and H. J. Hansen, Org. Synth., 1984, 62, 202.
12. For control experiment see ESI†.

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Footnotes

† Electronic supplementary information (ESI) available: Detailed experimental procedures and analytical data. CCDC reference number 748921. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c0sc00123f

‡ General procedure for the synthesis of 2a: To a stirred solution of 3-butynoate 1a (50 mg; 0.265 mmol) and trans-chalcone (61 mg, 0.292 mmol) in toluene (1.5 mL) was added (R,R-DIPAMP) (12 mg, 0.026 mmol; pre-dissolved in toluene) dropwise at 0 °C under nitrogen. After 8 h stirring at room temperature under N₂ atmosphere, the reaction mixture was concentrated and purified using flash column chromatography (10% ethyl acetate in hexane) to afford pure product 2a (89.5 mg, 87% yield, 95% ee).

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