Effect of the trifluoromethyl group on torquoselectivity in the 4π ring-opening reaction of oxetenes: stereoselective synthesis of tetrasubstituted olefins

Abstract

A highly stereoselective synthesis of tetrasubstituted olefins bearing a trifluoromethyl group via the thermal 4π electrocyclic ring-opening reaction of oxetenes, simply prepared by the Pd-catalyzed [2+2] cycloaddition reaction of various alkynes with trifluoropyruvate, is achieved. In this reaction process, the trifluoromethyl group prefers inward rotational torquoselectivity because of the orbital interactions between the breaking C–O σ orbital on the oxetene moiety and the C–F σ* orbital in the transition state.

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Introduction

The development of reliable synthetic approaches to trifluoromethylated compounds, which are widespread in pharmaceuticals and agrochemicals, has become a hot topic in organic synthesis.¹ The trifluoromethylation of (hetero)aromatic compounds has been intensively investigated and excellent progress has been made in recent years.² A number of synthetic approaches to disubstituted olefins bearing a trifluoromethyl (CF₃) group have been reported so far.³ However, stereoselective synthetic methods for tri- and tetrasubstituted olefins bearing a CF₃ group are still extremely limited.^4,5 These olefins are essential for the development of the catalytic enantioselective construction of trifluoromethylated tertiary and quaternary stereogenic carbon centers using asymmetric catalytic hydrogenations and addition reactions (Scheme 1).⁶

Scheme 1 Stereoselective synthesis of tetra-substituted alkenes containing a CF₃ group.

On the other hand, the 4π electrocyclic ring-opening reaction of cyclobutene derivatives has received much attention, both synthetically and theoretically. The selectivity of the inward or outward rotation of the substituent in the 2-position is termed “torquoselectivity”. Houk and co-workers have unveiled the stereoelectronic effects of various substituents including CF₃, on torquoselectivity in the ring-opening reaction of cyclobutenes.⁷ Murakami and co-workers also reported the preferences for inward rotation of silyl-, stannyl-, and boryl-substituents in the ring-opening reaction.⁸ Furthermore, Shindo and co-workers clarified the substituent effects on torquoselectivity in the ring-opening reaction of lithium oxetenoides as the reaction intermediates, which were generated from lithium ynolates and ketones.^9,10 In a cyclobutene system, although it has already been demonstrated that the CF₃ group of 3-(trifluoromethyl)cyclobutene exhibits a small preference for outward rotation,^7a,e,11 the stereoelectronic effects of the CF₃ group on torquoselectivity have never been investigated in an oxetene system. We have recently discovered the synthesis of stable oxetenes via the [2+2] cycloaddition reaction of various alkynes with ethyl trifluoropyruvate.¹² We proposed that the unprecedented stability of oxetenes containing a CF₃ group in the 2-position is attributed to the perfluoroalkyl effect,¹³ in which a perfluoroalkyl group can increase not only the kinetic but also the thermodynamic stability of a compound. In this communication, we disclose a reliable synthetic approach to tetrasubstituted olefins with the CF₃ group through the highly stereoselective 4π electrocyclic ring-opening reaction, using the isolated oxetenes not as reaction intermediates. The stereoselective construction of tetrasubstituted olefins, as well as quaternary stereogenic carbon centers bearing the CF₃ group, remains an extremely challenging task due to the unique stereoelectronic effect of the fluorine atom.

Results and discussion

Initially, oxetene derivatives were synthesized employing the procedure illustrated in Scheme 2. The catalytic [2+2] cycloaddition of ethyl trifluoropyruvate 2 with alkyne 1a in the presence of the dicationic rac-BINAP–Pd complex (5 mol%) provided the corresponding oxetene 3a in 95% yield. Subsequent reduction of the ester group by LiAlH₄, followed by protections (Nbz, Bz, and TBS) of the alcohol group led to oxetenes 5 in good yields. All the oxetenes could be easily purified by silica-gel column chromatography, without undergoing the 4π ring-opening reaction.

Scheme 2 Synthesis of oxetene derivatives: (a) rac-BINAP–Pd (5 mol%), CH₂Cl₂, −20 °C, 12 h; (b) LiAlH₄, THF, 0 °C, 30 min; (c) 4-NO₂C₆H₄COCl (NbzCl), NEt₃, CH₂Cl₂, RT, 2 h (95%); BzCl, NEt₃, CH₂Cl₂, RT, 2 h (89%); TBSCl, imid., DMF, RT, 6 h (76%).

When heating in toluene-d₈, the electrocyclic ring-opening reaction of oxetene 3a proceeded to give a mixture of the corresponding Z- and E-isomers, with the Z-isomer predominating in a ratio of 81 : 19 (Table 1, entry 1). The half-life (t_1/2) of the oxetene at 70 °C was 138 hours, demonstrating the extremely stable nature of the CF₃-oxetenes at elevated temperatures, compared to the oxetenes obtained previously.¹⁴ Of particular note, it was found that the use of oxetene 5a, with a methylene group, dramatically increased the stereoselectivity (entry 2). The structures of 5a and (Z)-6a were unequivocally determined by single crystal X-ray analysis (Fig. 1). Replacing 5a by 5a-Bz and 5a-TBS gave similar stereoselectivities (entries 3 and 4), but the more electron-donating R³-substituent decreased the thermal stability of the oxetenes. While the reaction of the unprotected oxetene 4a provided the corresponding olefin 6a-OH with complete stereoselectivity, many by-products were also obtained (entry 5). Increased temperature (100 °C) accelerated the reaction, but the stereoselectivity of the olefins remained almost the same regardless of temperature. In addition, the ratio of Z/E was constant during the course of the reaction, even after heating for a longer period of time. These results indicate that the ratio of Z/E was kinetically determined. The reactions gave almost quantitative yields, except for entry 5.

Table 1 Stereoselective 4π ring-opening reaction of oxetenes^a

Entity	Oxetene	R^3 (olefin)	t 1/2 [h]	k [h^−1]	Z : E^d^,^e
a Toluene-d8 (1.0 M) was used as a solvent. b Half-life of oxetenes at 70 °C. c At 70 °C. d Z/E stereoselectivity at 70 °C, and at 100 °C in parentheses. e Determined by ^19F NMR analysis. f Many by-products were obtained. g Purification by silica-gel chromatography gave only (Z)-6a-OH in 36% yield.
1	3a	CO2Et (6a-CO2Et)	138	5.0 × 10^−3	81 : 19 (77 : 23)
2	5a	CH2ONbz (6a)	134	5.2 × 10^−3	97 : 3 (96 : 4)
3	5a-Bz	CH2OBz (6a-Bz)	80	8.7 × 10^−3	97 : 3 (97 : 3)
4	5a-TBS	CH2OTBS (6a-TBS)	43	1.6 × 10^−2	98 : 2 (98 : 2)
5^f	4a	CH2OH (6a-OH)	—	—	100 : 0^g

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Fig. 1 X-Ray structures of oxetene and olefin.

In contrast to oxetene 4a, the reaction of unprotected oxetene 7, easily prepared from ethynylbenzene and ethyl trifluoropyruvate in two steps, was executed to give the trisubstituted olefin (Z)-8 quantitatively and with complete stereoselectivity (Scheme 3, eqn (1)). This Z-isomer bearing a CF₃ group cannot be synthesized through a Wittig reaction, which leads to the E-isomer.^4b,c Unprotected oxetene 9 also reacted to provide the desired cyclic product 10 in quantitative yield (Scheme 3, eqn (2)).

Scheme 3 Reactions of unprotected oxetenes.

In a cyclobutene system, Houk and co-workers showed that the CF₃ group of 3-(trifluoromethyl)cyclobutene exhibits a slight preference for outward rotation because of electrostatic repulsion between the CF₃ group and the π-system of cyclobutene.^7e Therefore, we carried out computational studies (B3LYP/6-31G(d) level calculations) to clarify the counterintuitive inward rotation of the CF₃ group in the oxetene system (Table 2). The activation energy for inward rotation in TSZa of oxetene A, with CO₂Me as an R³-substituent, was slightly lower than that in TSEa for outward rotation, because the two electron-accepting groups would be simultaneously substituted in the 2-positions (entries 1 and 2). In the case of oxetenes B and C with methoxymethyl and methyl substituents, the activation energies in TSZb and TSZc were 2.7 and 4.1 kcal mol⁻¹ lower than those for outward rotation, respectively (entries 3–6). These theoretical stereoselectivities agreed well with our experimental results (Table 1). On the other hand, oxetenes D and E bearing CHF₂ and CH₂F groups instead of a CF₃ group also indicated a preference for the inward rotation of these groups, although this was only demonstrated by the theoretical results (entries 7–10). Interestingly, it was found the preference for inward rotation follows the order: CHF₂ (ΔΔE^≠ = 5.8 kcal mol⁻¹), CF₃ (4.1 kcal mol⁻¹), CH₂F (1.0 kcal mol⁻¹).¹⁵ As shown in Fig. 2a, the C1–F1 and C3–H1 bonds, which are almost anti-periplanar to the breaking C–O bond, were found to be slightly longer than the other bonds in TSZ and TSE of oxetenes C, D, and E. In sharp contrast to the same bond lengths of C3–H1 (1.101 Å) in TSE, the C1–F1 bonds of TSZ were longer in the order of CH₂F (1.404 Å), CHF₂ (1.381 Å), CF₃ (1.366 Å), because the positive charge developed on the C1 carbon would be better stabilized by C1–H4 and C1–H5 bonds compared with C1–F2 and C1–F3 bonds. In the case of TSZ, it was also found that the C3–H3 bond is almost syn-periplanar to the breaking C–O bond.

Table 2 Calculated activation energies of TSE and TSZ at the B3LYP/6-31G(d) level

Entity	Oxetene	Transition state	ΔE^≠ (kcal mol^−1)	ΔΔE^≠ (kcal mol^−1)
1	A	TSEa	28.1	+1.0
2	A	TSZa	27.1	0
3	B	TSEb	29.0	+2.7
4	B	TSZb	26.3	0
5	C	TSEc	30.3	+4.1
6	C	TSZc	26.2	0
7	D	TSEd	30.0	+5.8
8	D	TSZd	24.2	0
9	E	TSEe	24.3	+1.0
10	E	TSZe	23.3	0

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Fig. 2 Effect of fluoromethyl groups on torquoselectivity. (a) Selected bond lengths and torsion angle of TSZ and TSE of oxetenes C, D, and E; (b) representative secondary interactions (I–III) between the NBOs of TSZc and TSEc, and the energies of these interactions in kcal mol⁻¹.

Next, NBO (natural bond orbital) analysis was carried out for TSZc and TSEc of oxetene C, referring to the approach reported by Shindo and Mori⁹ (Fig. 2b).¹⁶ The NBO analysis disclosed the secondary orbital interactions between the breaking C–O σ orbital and the C–F σ* orbital (I).¹⁷ The orbital interaction I_Z in TSZc was much larger in energy than I_E in TSEc, by 5.6 kcal mol⁻¹. The interactions III_Z and III_E between the nonbonding orbital of oxygen on the oxetene moiety and the C–F σ* orbital were much smaller.^9d In contrast, the interactions II_Z and II_E between the breaking C–O σ* orbital and the C–H σ orbital indicated favorability towards E-selectivity, i.e. outward rotation of the CF₃ group, but the difference was much smaller. These results show that the orbital interaction I_Z (8.2 kcal mol⁻¹) is the dominant factor in determining the torquoselectivity for inward rotation of the CF₃ group, with the assistance of the orbital interaction II_Z (6.1 kcal mol⁻¹).¹⁸

The effect of the R¹-substituent on the torquoselectivity and the thermal stability of oxetenes 5b–h, with n-Bu in the 3-position, were investigated under the same reaction conditions (Table 3). Oxetenes 5b–e with electron-withdrawing and -donating aromatic substituents, gave excellent stereoselectivities (entries 1–4). Importantly, it was clarified that the R¹-substituent in the 4-position does not electronically affect torquoselectivity in the 4π ring-opening reaction, due to the same stereoselectivities being observed regardless of temperature. In contrast, the R¹-substituent electronically influences the thermal stability of oxetenes; more electron-donating aromatic substituents facilitated the 4π ring-opening reaction (entry 4), while more electron-withdrawing substituents suppressed the reaction (entry 1). Interestingly, in spite of there being no change in stereoselectivity, the thermal stability of oxetenes 5f and 5g, with electron-donating mesityl substituents, was dramatically enhanced (entries 5 and 6). The stability of oxetenes would be increased when the conjugation between the π-system of oxetene and the R¹-substituent was not extended; as can be seen from the X-ray structures (Fig. 3), the torsion angle (C1–C2–C3–C4) of oxetene 5l was found to be significantly more acute than that of 5g-CO₂Et (ref. 12) (3.2° vs. 79.7°) (also 5a, 1.5°). The distortion of 5g-CO₂Et from planar geometry obviously stems from the steric repulsion between methyl groups in the 2,6-positions of the mesityl and tert-butyl substituents. The C2–C3 bond lengths of 5g-CO₂Et (1.468 Å) were also found to be somewhat longer than those of 5l (also 5a) (1.446 (1.453) Å). On the other hand, not only aromatic but also alkenyl substituents gave the corresponding tetrasubstituted olefin 6h in excellent stereoselectivity (entry 7).

Table 3 Effect of substituent R¹ on torquoselectivity^a

Entity	R^1		t 1/2 [h]	k [h^−1]	Z : E^d^,^e
a Toluene-d8 (1.0 M) was used as a solvent. b Half-life of oxetenes at 70 °C. c At 70 °C. d Z/E stereoselectivity at 70 °C, and at 100 °C in parentheses. e Determined by ^19F NMR analysis. f t-Bu was used instead of n-Bu in the 3-position of oxetene 5f. g At 100 °C. h Reaction did not proceed at 70 °C.
1	m-MeOC6H4	(b)	140	5.0 × 10^−3	98 : 2 (96 : 4)
2	Ph	(c)	137	5.1 × 10^−3	98 : 2 (96 : 4)
3	p-MeC6H4	(d)	106	6.6 × 10^−3	98 : 2 (96 : 4)
4	p-MeOC6H4	(e)	51	1.4 × 10^−2	98 : 2 (96 : 4)
5	Mes	(f)	354	2.0 × 10^−3	96 : 4 (96 : 4)
6^f	Mes	(g)	275^g	2.5 × 10^−3^g	—^h (98 : 2)
7		(h)	137	5.1 × 10^−3	97 : 3 (96 : 4)

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Fig. 3 X-Ray structures of oxetenes.

The effect of the R²-substituent on the torquoselectivity and thermal stability of oxetenes 5i–o with a para-methoxypheny group in the 4-position was also examined under the same reaction conditions (Table 4). Similarly to the effect of the R¹-substituent (Table 3, entries 1–4), the reaction of oxetenes 5i–k with electron-withdrawing and -donating aromatic substituents afforded the corresponding Z-isomers with the same stereoselectivities (entries 1–3). While more electron-donating aromatic substituents decreased the thermal stability of the oxetenes, their influence was lower than that of the corresponding R¹-substituents. Oxetenes 5l and 5m underwent the 4π ring-opening reaction with inward rotation to provide the E-isomers exclusively (entries 4 and 5). This complete torquoselectivity contributes to inhibition of the formation of the Z-isomer, due to the dipole repulsion in the TS between the strong electron-withdrawing R²-substituent (CF₃ and ester) and the CF₃ group (Fig. 4). The stereoselectivity of the reaction of oxetene 5n bearing a sterically demanding SiMe₂Ph substituent, was similar to that of the reaction of unsubstituted 5o (entries 6 and 7). This result clearly shows that the stereoelectronic effect on the torquoselectivity of R¹- and R²-substituents in the 3,4-positions of oxetene is extremely small, while the electronic properties strongly affect the thermal stability of oxetene. All of the reactions shown in Tables 3 and 4 provided the corresponding olefins 6 in almost quantitative yields.

Table 4 Effect of substituent R² on torquoselectivity^a

Entity	R^2		t 1/2 [h]	k [h^−1]	Z : E^d^,^e
a Toluene-d8 (1.0 M) was used as a solvent. b Half-life of oxetenes at 70 °C. c At 70 °C. d Z/E stereoselectivity at 70 °C, and at 100 °C in parentheses. e Determined by ^19F NMR analysis. f Decomposition of 5n was observed at 100 °C. g Ph group was used instead of p-MeOC6H4 group in the 4-position of oxetene.
1	p-NO2C6H4	(i)	3.2	2.2 × 10^−1	99 : 1 (98 : 2)
2	Ph	(j)	2.7	2.6 × 10^−1	99 : 1 (98 : 2)
3	p-MeOC6H4	(k)	2.5	2.8 × 10^−1	99 : 1 (98 : 2)
4	CF3	(l)	15	4.8 × 10^−2	0 : 100 (0 : 100)
5	CO2Et	(m)	10	6.9 × 10^−2	0 : 100 (0 : 100)
6	SiMe2Ph	(n)	50	1.4 × 10^−2	1 : 99 (— ^f)
7^g	H	(o)	3.9	1.8 × 10^−1	99 : 1 (99 : 1)

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Fig. 4 Effect of dipole repulsion on torquoselectivity.

Conclusions

In conclusion, we have succeeded in the highly stereoselective synthesis of tetrasubstituted olefins bearing a CF₃ group via the thermal 4π electrocyclic ring-opening reaction of various oxetenes. In this oxetene system, a remarkable inward rotation of the CF₃ group was observed. It was suggested that the inward rotation originates from the orbital interactions between the breaking C–O σ orbital and the C–F σ* orbital in the transition state. It was demonstrated that the R¹- and R²-substituents in the 3- and 4-positions of oxetenes scarcely affect the torquoselectivity, but rather affect the thermal stability of oxetenes in the reaction. Thus obtained, these tetrasubstituted olefins are essential as CF₃-containing building blocks for pharmaceuticals and agrochemicals. The development of the catalytic asymmetric construction of trifluoromethylated tertiary and quaternary stereogenic carbon centers using these olefins is ongoing in our laboratory.

Acknowledgements

This research was supported by Japan Science and Technology Agency (JST) (ACT-C: Creation of Advanced Catalytic Transformation for the Sustainable Manufacturing at Low Energy, Low Environmental Load), JSPS KAKENHI Grant Number 23750104, and Mizuho Foundation for the Promotion of Sciences. We thank Central Glass Co., Ltd. for the gift of ethyl trifluoropyruvate.

Notes and references

1. For recent reviews, see: (a) Z. Jin, G. B. Hammond and B. Xu, Aldrichimica Acta, 2012, 45, 67; (b) O. A. Tomashenko and V. V. Grushin, Chem. Rev., 2011, 111, 4475; (c) T. Furuya, A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470; (d) K. M. Engle, T.-S. Mei, X. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2011, 50, 1478; (e) J. Nie, H.-C. Guo, D. Cahard and J.-A. Ma, Chem. Rev., 2011, 111, 455; (f) K. Mikami, Y. Itoh and M. Yamanaka, Chem. Rev., 2004, 104, 1.
2. For selected recent examples, see: (a) M. Oishi, H. Kondo and H. Amii, Chem. Commun., 2009, 1909; (b) E. J. Cho, T. D. Senecal, T. Kinzel, Y. Zhang, D. A. Watson and S. L. Buchwald, Science, 2010, 328, 1679; (c) N. D. Ball, J. W. Kampf and M. S. Sanford, J. Am. Chem. Soc., 2010, 132, 2878; (d) X. Wang, L. Truesdale and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 3648; (e) L. Chu and F.-L. Qing, Org. Lett., 2010, 12, 5060; (f) T. D. Senecal, A. T. Parsons and S. L. Buchwald, J. Org. Chem., 2011, 76, 1174; (g) A. Zanardi, M. A. Novikov, E. Martin, J. Benet-Buchholz and V. V. Grushin, J. Am. Chem. Soc., 2011, 133, 20901; (h) H. Morimoto, T. Tsubogo, N. D. Litvinas and J. F. Hartwig, Angew. Chem., Int. Ed., 2011, 50, 3793; (i) D. A. Nagib and D. W. C. MacMillan, Nature, 2011, 480, 224; (j) Y. Fujiwara, J. A. Dixon, F. O'Hara, E. D. Funder, D. D. Dixon, R. A. Rodriguez, R. D. Baxter, B. Herlé, N. Sach, M. R. Collins, Y. Ishihara and P. S. Baran, Nature, 2012, 492, 95.
3. For selected recent examples, see: (a) A. T. Parsons, T. D. Senecal and S. L. Buchwald, Angew. Chem., Int. Ed., 2012, 51, 2947; (b) M. Omote, M. Tanaka, A. Ikeda, S. Nomura, A. Tarui, K. Sato and A. Ando, Org. Lett., 2012, 14, 2286; (c) G. K. S. Prakash, H. S. Krishnan, P. V. Jog, A. P. Iyer and G. A. Olah, Org. Lett., 2012, 14, 1146.
4. For examples of trisubstituted olefins bearing a CF₃ group, see: (a) J. Duan, W. R. Dolbier, Jr and Q.-Y. Chen, J. Org. Chem., 1998, 63, 9486; (b) M. Kimura, T. Yamazaki, T. Kitazume and T. Kubota, Org. Lett., 2004, 6, 4651; (c) T. Konno, T. Takehana, M. Mishima and T. Ishihara, J. Org. Chem., 2006, 71, 3545; (d) E. J. Cho and S. L. Buchwald, Org. Lett., 2011, 13, 6552; (e) Z. He, T. Luo, M. Hu, Y. Cao and J. Hu, Angew. Chem., Int. Ed., 2012, 51, 3944; (f) K. Zine, J. Petrignet, J. Thibonnet and M. Abarbri, Synlett, 2012, 755; (g) L. Debien, B. Quiclet-Sire and S. S. Zard, Org. Lett., 2012, 14, 5118; (h) P. G. Janson, I. Ghoneim, N. O. Ilchenko and K. J. Szabó, Org. Lett., 2012, 14, 2882.
5. For examples of tetrasubstituted olefins bearing a CF₃ group, see: (a) M. Shimizu and T. Hiyama, Angew. Chem., Int. Ed., 2005, 44, 214; (b) X. Liu, M. Shimizu and T. Hiyama, Angew. Chem., Int. Ed., 2004, 43, 879; (c) Y. Takeda, M. Shimizu and T. Hiyama, Angew. Chem., Int. Ed., 2007, 46, 8659; (d) M. Shimizu, Y. Takeda and T. Hiyama, Bull. Chem. Soc. Jpn., 2011, 84, 1339.
6. (a) H. Kawai, S. Okusu, E. Tokunaga, H. Sato, M. Shiro and N. Shibata, Angew. Chem., Int. Ed., 2012, 51, 4959; (b) Q.-H. Deng, H. Wadepohl and L. H. Gade, J. Am. Chem. Soc., 2012, 134, 10769; (c) H. Kawai, S. Okusu, Z. Yuan, E. Tokunaga, A. Yamano, M. Shiro and N. Shibata, Angew. Chem., Int. Ed., 2013, 52, 2221; (d) J.-R. Gao, H. Wu, B. Xiang, W.-B. Yu, L. Han and Y.-X. Jia, J. Am. Chem. Soc., 2013, 135, 2983.
7. (a) W. R. Dolbier, Jr, H. Koroniak, K. N. Houk and C. Sheu, Acc. Chem. Res., 1996, 29, 471; (b) W. R. Dolbier, Jr, H. Koroniak, D. J. Burton, A. R. Bailey, G. S. Shaw and S. W. Hansen, J. Am. Chem. Soc., 1984, 106, 1871; (c) W. Kirmse, N. G. Rondan and K. N. Houk, J. Am. Chem. Soc., 1984, 106, 7989; (d) N. G. Rondan and K. N. Houk, J. Am. Chem. Soc., 1985, 107, 2099; (e) P. S. Lee, X. Zhang and K. N. Houk, J. Am. Chem. Soc., 2003, 125, 5072; (f) Y.-h. Lam, S. J. Stanway and V. Gouverneur, Tetrahedron, 2009, 65, 9905.
8. (a) M. Murakami, Y. Miyamoto and Y. Ito, Angew. Chem., Int. Ed., 2001, 40, 189; (b) M. Murakami, Y. Miyamoto and Y. Ito, J. Am. Chem. Soc., 2001, 123, 6441; (c) M. Murakami and M. Hasegawa, Angew. Chem., Int. Ed., 2004, 43, 4874; (d) M. Murakami, M. Hasegawa and H. Igawa, J. Org. Chem., 2004, 69, 587; (e) M. Murakami, I. Usui, M. Hasegawa and T. Matsuda, J. Am. Chem. Soc., 2005, 127, 1366.
9. (a) M. Shindo and S. Mori, Synlett, 2008, 2231; (b) M. Shindo and S. Mori, J. Synth. Org. Chem., Jpn., 2008, 66, 28; (c) M. Shindo, K. Matsumoto, S. Mori and K. Shishido, J. Am. Chem. Soc., 2002, 124, 6840; (d) S. Mori and M. Shindo, Org. Lett., 2004, 6, 3945; (e) M. Shindo, T. Yoshikawa, Y. Itou, S. Mori, T. Nishii and K. Shishido, Chem.–Eur. J., 2006, 12, 524; (f) T. Yoshioka, S. Mori and M. Shindo, Tetrahedron, 2009, 65, 8832; (g) T. Yoshikawa, S. Mori and M. Shindo, J. Am. Chem. Soc., 2009, 131, 2092.
10. For examples of the ring opening reaction with amidines, see: (a) N. Shindoh, Y. Takemoto and K. Takasu, Chem.–Eur. J., 2009, 15, 7026; (b) N. Shindoh, K. Kitaura, Y. Takemoto and K. Takasu, J. Am. Chem. Soc., 2011, 133, 8470.
11. (a) W. R. Dolbier, Jr, T. A. Gray, J. J. Keaffaber, L. Celewicz and H. Koroniak, J. Am. Chem. Soc., 1990, 112, 363; (b) W. R. Dolbier, Jr, H. Koroniak, D. J. Burton and P. Heinze, Tetrahedron Lett., 1986, 27, 4387; (c) W. R. Dolbier, Jr, H. Koroniak, D. J. Burton, P. Heinze, A. R. Bailey, G. S. Shaw and S. W. Hansen, J. Am. Chem. Soc., 1987, 109, 219.
12. K. Aikawa, Y. Hioki, N. Shimizu and K. Mikami, J. Am. Chem. Soc., 2011, 133, 20092.
13. Perfluoroalkyl effect, see: (a) D. M. Lemal and L. H. Dunlap, Jr, J. Am. Chem. Soc., 1972, 94, 6562; (b) D. M. Lemal, J. Org. Chem., 2004, 69, 1.
14. (a) W. J. Middleton, J. Org. Chem., 1965, 30, 1307; (b) Y. Kobayashi, Y. Hanzawa, W. Miyashita, T. Kashiwagi, T. Nakano and I. Kumadaki, J. Am. Chem. Soc., 1979, 101, 6445; (c) P. C. Martino and P. B. Shevlin, J. Am. Chem. Soc., 1980, 102, 5429; (d) L. E. Friedrich and P. Y.-S. Lam, J. Org. Chem., 1981, 46, 306; (e) M. Oblin, J.-L. Parrain, M. Rajzmann and J.-M. Pons, Chem. Commun., 1998, 1619.
15. Theoretical studies on torquoselectivity of various oxetenes bearing fluoromethyl groups are ongoing in our laboratory in more detail.
16. I. V. Alabugin and T. A. Zeidan, J. Am. Chem. Soc., 2002, 124, 3175.
17. Representative secondary orbital interactions are shown in Fig 2b. See ESI† for more details.
18. In perfluoro systems, such as perfluoro-3-methyl- and -3,4-dimethylcyclobutenes, Dolbier and co-workers have already reported that the inward rotation of the CF₃ group proceeded with the support of a dramatic outward preference of the fluorine substituents in the 3- and 4-positions; see ref. 7b and 11.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 948159–948162. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3sc52548a

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