Ethers as hydrogen sources in BF₃·OEt₂ promoted reduction of diphenylmethyl alcohols, ethers and esters to hydrocarbons

Abstract

A novel ether/BF₃ reductive system has been described, in which diphenylmethanols and their ether and ester derivatives are used as starting materials. Reductions are performed in ether under reflux and an argon atmosphere, and the addition of extra water is beneficial to this reduction. A series of alkanes are able to be prepared with good to excellent yields. A deuterated experiment exhibits that the reductive hydrogen is generated from ether. The mechanism is discussed in detail to explain the observed reactivity.

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The reduction of carbon–oxygen bonds to the corresponding carbon–hydrogen bonds plays a fundamental role in organic chemistry.^1,2 It is also widely applied in total synthesis chemistry, in which the C–H frame of natural products are constructed with high efficiency.³ Barton–McCombie deoxygenation is one of the most classic methods, and is well applied by transforming alcohols to their corresponding thiocarbonyl intermediates which undergo radical fragmentation.⁴ After Barton–McCombie deoxygenation, several alternative catalytic protocols have been developed employing metal hydrides such as organotin hydride.^5,6 In these strategies, a two-step procedure firstly converts alcohols into preactivated intermediates such as thionocarbonates that are capable of being cleaved readily in reductive steps.⁷ Subsequently, the application of a two-step procedure is preferred in the deoxygenation of alcohol derivatives such as aryl sulfonates (e.g. triflates, tosylates, mesylates), arylthiocarbonates, ethers and esters mediated by Pd-,⁸ Ni-^9a–c and Rh-based catalysts.^9d In the past decades, many direct dehydroxylation reactions have been reported as well.^10,11 Among these established methods, the combination of hydride reagents with Lewis acids such as LiAlH₄/AlCl₃,^11a LiAlH₄/TiCl₃,^11b and NaBH₄/AlCl₃ ^11c seems to increase the reactivity of hydride. Dehydroxylations of primary, secondary, and tertiary alcohols have been developed by employing hydrosilanes/metallic Lewis acids systems such as Ph₂SiHCl/InCl₃,^12a Et₃SiH/PdCl₂ ^12b and PMHS/PdCl₂.^12c Reduction processes in the presence of nonmetallic Lewis acid B(C₆F₅)₃ are also reported.¹³

BF₃·OEt₂, generated from the donor–acceptor action between BF₃ and Et₂O,¹⁴ has shown high activity in many synthetic procedures like alkylation,^15a–d cyclization,^15e rearrangement,^15f coupling,^15g cyanation^15h and etherification reactions.¹⁵ⁱ It was also utilized in the reduction of alcohols,^16a,b carbonyl compounds^16c and epoxides^16d via hydride transfer from hydrosilanes. Our studies have demonstrated that the superacid BF₃–H₂O promoted benzylation reaction via a carbonium intermediate.¹⁷ We found that when iodobenzene was involved as both arene and solvent, the benzylation product was not produced and the undesired diphenylmethane was obtained in 47% yield by a reductive mechanism. The source of hydrogen was thought to come from the diphenylmethanol or diethyl ether by disproportionation, accompanied with the generation of reductive hydrogen. However, no diphenylketone was detected, which indicated that hydrogen was released very probably from the selfoxidation of ether ligand of BF₃·OEt₂. To test this theory, control experiments were performed in which diphenylmethanol and BF₃·OEt₂ in dichloromethane led to a 22% yield (see ESI†) and the later deuterated experiment resulted in the D-labelled methene.

The studies on triphenylmethyl cation, in the stable form of trityl salt, can date back to one century ago.¹⁸ Due to its importance in polymer of ether, it was regarded as an excellent initiator of polymerization and kinetically studied extensively covering the hydride ion transfer between triphenylcarbonium and ether. However, for this H transfer, there is no report on relatively unstable diphenylcarbonium ion, due to the unavailability of the salt. Herein, we would like to report our work in BF₃·OEt₂-promoted reductive reaction of diphenylcarbonium, using diphenylmethanols as well as their ether and ester derivatives as substrates, to corresponding alkanes, employing various ethers as hydrogen sources (Scheme 1).

Scheme 1 Proposal in this work.

Considering the hydrogen generated from the ether, we chose initially tetrahydrofuran (THF) as a solvent for the reduction of diphenylmethanol (1a), and as a result the yield was improved by up to 53% (Table 1, entry 1). As mentioned before,¹⁷ mixing BF₃·OEt₂ with H₂O resulted in the formation of BF₃–H₂O which has shown elevated reactivity in the benzylation of arenes. We assessed the influence of different amounts of H₂O in BF₃·OEt₂ promotion. 0.48 equivalent of water gave the best result while lower or higher amount of water turned out to be detrimental to this reduction (Table 1, entries 2–4). Then, the treatment of diphenylmethanol with catalytic amount (20 mol%) of BF₃·OEt₂ gave rise to diphenylmethane 2a in 20% yield (Table 1, entry 5). Increasing the amount of BF₃·OEt₂ from 0.6 to 0.8 equivalent resulted in a large improvement of the yield up to 61% (Table 1, entries 6 and 7). 1.0 equivalent of BF₃·OEt₂ furnished the desired product in 63% yield with the same level of reactivity compared to 1.2 equivalents of BF₃·OEt₂ (Table 1, entry 8 vs. 3). However, a lower yield was observed when further increasing the amount of BF₃·OEt₂ (Table 1, entry 9). A solvent screening with diethyl ether, and 2-methyl tetrahydrofuran was conducted and gave moderate yields (Table 1, entries 10 and 11). When methyl tert-butyl ether (MTBE) and isopropyl ether were utilized as solvent, the reactions went complex and the attempt to separate the product failed (Table 1, entries 12 and 13). To our delight, employing butyl ether as solvent exhibited excellent reactivity (Table 1, entry 14). Variations of the temperature from 100 °C to 160 °C were tested, in which an excellent yield of 87% was obtained under 160 °C (Table 1, entries 15–17). The optimal reaction conditions were established: 1.0 mmol diphenylmethanol, 1.2 equivalents of BF₃·OEt₂ in 1 mL of butyl ether in argon atmosphere under reflux for 2 h (Table 1, entry 17).

Table 1 Optimization of reaction conditions^a

Entry	BF3·OEt2 (eq.)	H2O (eq.)	Solvent	Yield^b (%)
a Conditions: 1a (1.0 mmol), BF3·OEt2 (specified), H2O (specified) in solvent (1.0 mL) under argon and reflux (oil bath of 120 °C) for 2 h.b Isolated yields.c Complex reaction.d Oil bath of 100 °C.e Oil bath of 140 °C.f Oil bath of 160 °C.
1	1.2	—	THF	53
2	1.2	0.36	THF	55
3	1.2	0.48	THF	62
4	1.2	0.60	THF	52
5	0.2	0.48	THF	20
6	0.6	0.48	THF	52
7	0.8	0.48	THF	61
8	1.0	0.48	THF	63
9	1.5	0.48	THF	52
10	1.2	0.48	Et2O	53
11	1.2	0.48	2-Methyl THF	55
12	1.2	0.48	MTBE	—^c
13	1.2	0.48	Isopropyl ether	—^c
14	1.2	0.48	Butyl ether	83
15	1.2	0.48	Butyl ether	80^d
16	1.2	0.48	Butyl ether	84^e
17	1.2	0.48	Butyl ether	87^f

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Table 2 Substrate scope for diphenylmethanols^a

a Conditions: 1 (1.0 mmol), BF₃·OEt₂ (1.2 mmol), H₂O (0.48 mmol), oil bath of 160 °C, butyl ether (1.0 mL) under argon for 2 h. Isolated yields.^b THF as solvent. Oil bath of 120 °C.

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With the optimal reaction conditions in hand, diverse substituted diphenylmethanols bearing mono-/di-halo, methyl, and methoxyl groups were investigated with moderate to excellent yields Table 2. Considering the potential utilization of fluorine-containing compounds in pharmaceuticals and functionalized materials,¹⁹ fluoro-substituted diphenylmethanols were chosen as substrates such as 4-fluoro- (1b), 4,4′-difluoro- (1c), 3,4-difluoro- (1d) and 2-fluoro- (1e) substituents. As a result, the corresponding alkanes were obtained in yields of 72–93%. The ortho-fluoro substituent (1e) gave a relatively lower yield of 72% than the para-fluoro substitution, probably due to a large extend to the significant steric effects. The chloro- and bromo- substituted aromatics are capable of being further functionalized by S_NAr reactions, Grignard reactions and coupling reactions, etc. Structurally diverse chloro- and bromo- substituents (1f–j) were chosen as substrates, and the yields of 53–94% were obtained. It is worthwhile noting that ortho-substitution gave lower yields in the reduction process (1f vs. 1g, h and 1i vs. 1j). When compounds with different halogen groups such as 1k (F, Cl) and 1l (F, Br) were used as substrates, good yields of 68% and 59% were obtained. Diphenylmethanols bearing electron-donating methyl groups such as methyl (1m) and methoxyl (1n) gave the yields of 93% and 24%, respectively. However compared with methyl substituent 1m, dramatically decreased yields were observed by using diphenylmethanol bearing electron-withdrawing trifluoromethyl (1o) and ester (1p) groups. Naphthalene derivative (1q) worked well providing the corresponding product in 76% yield. Interestingly, triphenylmethanol (1r) and triphenylmethanthiol (1s) gave rise to triphenylmethane in 95% and 91%, which suggests that thiol possesses the similar reactivity in this case. Despites many attempts, aliphatic alcohols and aromatic primary or secondary alcohols, did not undergo any reduction process and only adamantanol (1t) generated the corresponding adamentane in an isolated yield of 29%. Heterocyclic substrates (1u and 1v) were disable to give the dehydroxylation products. It is notable that prop-1-ene-1,1-diyldibenzene (2w) was obtained with 99% yield through β-H elimination when 1,1-diphenylpropan-1-ol (1w) was used as substrate, and 1,1-diphenylethanol (1x) only gave ethene-1,1-diyldibenzene (2x) in 55% yield (Scheme 2).

Scheme 2 Investigation of 1,1-diphenylpropan-1-ol and 1,1-diphenylethanol.

A series of leaving groups has been investigated in reductive reactions as well, such as alkoxy, hydroxymethoxy, and acetyoxy groups (Table 3). The diphenylmethane was produced in yields ranging from 37 to 90% depending on the nature of the leaving group. Methoxy diphenylmethane 3a provided the diphenylmethane in 71% yield. Regardless of linear (3b, 3c), branched (3d) or cyclic (3e) alkoxy diphenylmethyl ethers employed, the reductive products were obtained in good yields. Benzyloxy (3f) and allyloxy (3g) substituted substrates gave similar levels of yields, 37% and 42% respectively, which was probably explained by the released benzylalcohol and allylalcohol which further trap the promoter BF₃·OEt₂ to form carbonium ion. Interestingly, when doubling the amount of BF₃·OEt₂ in these two cases, both yields were improved to 60% and 59%. The reaction of the hydroxyethyl substituted substrate (3h) led to 2a in 70% yield, close to the yields obtained for alkoxy substitutions. Both acetoxy (3i) and trifluoroacetoxy (3j) were better leaving groups which resulted in yields of 83% and 90%. Diphenyl ether 3k provided the diphenylmethane in 60% yield under standard conditions. Doubling the amount of BF₃·OEt₂ improved the yield to 86%.

Table 3 Substrate scope of diphenylmethyl ethers or esters^a

a Conditions: 3 (1.0 mmol), BF₃·OEt₂ (1.2 mmol), H₂O (0.48 mmol), oil bath of 160 °C, butyl ether (1.0 mL) under argon for 2 h. Isolated yields.b BF₃·OEt₂ (2.4 eq.), H₂O (0.96 eq.), butyl ether (2.0 mL).

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A large-scale experiment was carried out to demonstrate both the practicality and effectiveness of our method. 74% yield of diphenylmethane (2a) was obtained when treating 2 g of 1a under standard reaction conditions (Scheme 3).

Scheme 3 Gram-scale synthesis.

Further experiments were performed to gain a better understanding of the reaction mechanism. Deuterated experiments employing THF-d₈ were performed and the results showed the incorporation of the deuterium on the product 2m′ and 92% of D on 2m′, which was readily identified by ¹H NMR analysis after silica column chromatography (Scheme 4). It is well-known that the p-σ hyperconjugation exists between the σ electron of α-H of ether and the lone pair electron on oxygen and hence the α-H could be activated through this p-σ hyperconjugation probably resulting in the formation of reductive hydrogen (H⁻), accompanied with the formation of oxonium ion, which could react with another ether molecule to produce the resonance stabilized species.^18c–h Meanwhile, the diphenylmethyl cation could be produced in the presence of BF₃ from diphenylmethanol (1). The carbonium ion interacted with reductive hydrogen would give rise to alkane product (2) (Fig. 1).

Scheme 4 Deuterated experiment.

Fig. 1 Proposed mechanism for reduction.

In summary, we have developed a novel ether/BF₃ reductive system for diphenylmethanols and their ether and ester derivatives, presenting a metal-free strategy and affording the corresponding alkane products in good to excellent yields for most cases. The D-labelled experiment showed the reductive hydrogen was generated from ethers. The favourable safety profile, ease to handling and environmentally benign nature make this methodology particularly attractive and practical.

Acknowledgements

We are grateful for funding from the National Natural Science Foundation of China (No. 21372265 and No. 61271059) and sincerely thank Dr Vincent Coeffard for helpful discussions.

Notes and references

1. (a) A. Yamamoto, Advances in Organometallic Chemistry, ed. F. G. A. Stone and R. West, 1992, vol. 34, p. 111; (b) R. O. Hutchins, Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming, Oxford, 1991, vol. 8, p. 327; (c) S. W. McCombie, Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming, Oxford, 1991, vol. 8, p. 811.
2. (a) N. Kishner, J. Russ. Phys. Chem. Soc., 1911, 43, 582; (b) L. Wolff, Justus Liebigs Ann. Chem., 1912, 394, 86; (c) M. L. Huang, J. Am. Chem. Soc., 1946, 68, 2487.
3. (a) G. E. Veitch, E. Beckmann, B. J. Burke, A. Boyer, S. L. Maslen and S. V. Ley, Angew. Chem., Int. Ed., 2007, 46, 7629; (b) W. C. Liu and C. C. Liao, Chem. Commun., 1999, 117; (c) S. A. Frank and W. R. Roush, J. Org. Chem., 2002, 67, 4316.
4. (a) D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin Trans. 1, 1975, 1574; (b) D. H. R. Barton, D. Crich, A. Löbberding and S. Z. Zard, Tetrahedron, 1986, 42, 2329.
5. (a) R. M. Lopez, D. S. Hays and G. C. Fu, J. Am. Chem. Soc., 1997, 119, 6949; (b) P. Boussaguet, B. Delmond, G. Dumartin and M. Pereyre, Tetrahedron Lett., 2000, 41, 3377.
6. D. A. Spiegel, K. B. Wiberg, L. N. Schacherer, M. R. Medeiros and J. L. Wood, J. Am. Chem. Soc., 2005, 127, 12513.
7. J. M. Herrmann and B. König, Eur. J. Org. Chem., 2013, 7017.
8. Two step procedure by Pd-based catalysts: (a) K. Clauss and H. Jensen, Angew. Chem., Int. Ed., 1973, 12, 918; (b) G. A. Peterson, F. A. Kunng, J. S. McCallum and W. D. Wulff, Tetrahedron Lett., 1987, 28, 1381; (c) Q. Y. Chen, Y. B. He and Z. Y. Yang, J. Chem. Soc., Chem. Commun., 1986, 1452; (d) P. Sebök, T. Tímár and T. Eszenyi, J. Org. Chem., 1994, 59, 6318; (e) W. J. Musliner and J. W. Gates Jr., J. Am. Chem. Soc., 1966, 88, 4271; (f) H. Sajiki, A. Mori, T. Mizusaki, T. Ikawa, T. Maegawa and K. Hirota, Org. Lett., 2006, 8, 987; (g) A. Mori, T. Mizusaki, T. Ikawa, T. Maegawa, Y. Monguchi and H. Sajiki, Tetrahedron, 2007, 63, 1270; (h) J. M. Saá, M. Dopico, G. Martorell and A. García-Raso, J. Org. Chem., 1990, 55, 991; (i) Y. J. Pan and C. P. Holmes, Org. Lett., 2001, 3, 2769; (j) A. N. Cammidge and Z. Ngaini, Chem. Commun., 2004, 1914; (k) J. D. Revell and A. Ganesan, Chem. Commun., 2004, 1916; (l) H. Kotsuki, P. K. Datta, H. Hayakawa and H. Suenaga, Synthesis, 1995, 1348; (m) H. J. Kim, L. Su, H. Jung and S. Koo, Org. Lett., 2011, 13, 2682.
9. Two step procedure by Ni- and Rh-based catalysts: (a) M. Tobisu, K. Yamakawa, T. Shimasaki and N. Chatani, Chem. Commun., 2011, 47, 2946; (b) B. H. Lipshutz, B. A. Frieman, T. Butler and V. Kogan, Angew. Chem., Int. Ed., 2006, 45, 800; (c) P. Álvarez-Bercedo and R. Martin, J. Am. Chem. Soc., 2010, 132, 17352; (d) H. J. Liu and B. Y. Zhu, Synth. Commun., 1990, 20, 557.
10. (a) S. Sawadjoon, A. Lundstedt and J. S. M. Samec, ACS Catal., 2013, 3, 635; (b) X. H. Liu, G. Z. Lu, Y. L. Guo, Y. Guo, Y. S. Wang and X. H. Wang, J. Mol. Catal. A: Chem., 2006, 252, 176; (c) M. Dobmeier, J. M. Herrmann, D. Lenoir and B. König, Beilstein J. Org. Chem., 2012, 8, 330; (d) A. Aramini, M. R. Sablone, G. Bianchini, A. Amore, M. Fanì, P. Perrone, A. Dolce and M. Allegretti, Tetrahedron, 2009, 65, 2015; (e) P. E. Gordon and A. J. Fry, Tetrahedron Lett., 2001, 42, 831; (f) T. Ankner and G. Hilmersson, Tetrahedron, 2009, 65, 10856; (g) C. K. Lau, C. Dufresne, P. C. Bélanger, S. Piétré and J. Scheigetz, J. Org. Chem., 1986, 51, 3038; (h) M. A. Tandiary, Y. Masui and M. Onaka, Tetrahedron Lett., 2014, 55, 4160; (i) H. R. Diéguez, A. López, V. Domingo, J. F. Arteaga, J. A. Dobado, M. M. Herrador, J. F. Quílez del Moral and A. F. Barrero, J. Am. Chem. Soc., 2010, 132, 254; (j) G. W. Gribble, R. M. Leese and B. E. Evans, Synthesis, 1977, 172; (k) C. F. Nutaitis and J. E. Bernardo, Synth. Commun., 1990, 20, 487; (l) J. L. Huang, X. J. Dai and C. J. Li, Eur. J. Org. Chem., 2013, 6496; (m) K. A. Hope-Ross and J. F. Kadla, Can. J. Chem., 2010, 88, 1003; (n) J. L. Fry and M. G. Adlington, J. Am. Chem. Soc., 1978, 100, 7641.
11. (a) R. F. Nystrom and C. R. A. Berger, J. Am. Chem. Soc., 1958, 80, 2896; (b) J. E. McMurry, M. G. Silvestri, M. P. Fleming, T. Hoz and M. W. Grayston, J. Org. Chem., 1978, 43, 3249; (c) A. Ono, N. Suzuki and J. Kamimura, Synthesis, 1987, 736.
12. (a) M. Yasuda, Y. Onishi, M. Ueba, T. Miyai and A. Baba, J. Org. Chem., 2001, 66, 7741; (b) M. Mirza-Aghayan, R. Boukherroub and M. Rahimifard, Tetrahedron Lett., 2009, 50, 5930; (c) H. Wang, L. Li, X. F. Bai, W. H. Deng, Z. J. Zheng, K. F. Yang and L. W. Xu, Green Chem., 2013, 15, 2349.
13. V. Gevorgyan, M. Rubin, S. Benson, J. X. Liu and Y. Yamamoto, J. Org. Chem., 2000, 65, 6179.
14. A. W. Laubengayer and G. R. Finlay, J. Am. Chem. Soc., 1943, 65, 884.
15. (a) G. Schäfer and J. W. Bode, Angew. Chem., Int. Ed., 2011, 50, 10913; (b) G. K. S. Prakash, C. Panja, A. Shakhmin, E. Shah, T. Mathew and G. A. Olah, J. Org. Chem., 2009, 74, 8659; (c) G. K. S. Prakash, F. Paknia, T. Mathew, G. Mloston, J. P. Joschek and G. A. Olah, Org. Lett., 2011, 13, 4128; (d) X. F. Xu, Y. Xiong, X. G. Ling, X. M. Xie, J. Yuan, S. T. Zhang and Z. R. Song, Chin. Chem. Lett., 2014, 25, 406; (e) E. O. Onyango, L. F. Fu and G. W. Gribble, Org. Lett., 2014, 16, 322; (f) L. X. Shao, Y. P. Zhang, M. H. Qi and M. Shi, Org. Lett., 2007, 9, 117; (g) L. Shi, Y. Q. Tu, M. Wang, F. M. Zhang, C. A. Fan, Y. M. Zhao and W. J. Xia, J. Am. Chem. Soc., 2005, 127, 10836; (h) H. Sheng, J. Q. Li, Q. Liu, J. Pan, R. F. Huang and Y. Xiong, J. Org. Chem., 2015, 80, 7212; (i) J. Q. Li, X. H. Zhang, H. Shen, Q. Liu, J. Pan, W. Hu, Y. Xiong and C. G. Chen, Adv. Synth. Catal., 2015 DOI:10.1002/adsc.201500663 , in press.
16. (a) J. A. Cella, J. Org. Chem., 1982, 47, 2125; (b) M. G. Adlington, M. Orfanopoulos and J. L. Fry, Tetrahedron Lett., 1976, 34, 2955; (c) J. L. Fry, M. Orfanopoulos, M. G. Adlington, W. R. Dittman and J. S. B. Silverman, J. Org. Chem., 1978, 43, 374; (d) J. L. Fry and T. J. Mraz, Tetrahedron Lett., 1979, 10, 849.
17. (a) Y. Li, Y. Xiong, X. M. Li, X. G. Ling, R. F. Huang, X. H. Zhang and J. C. Yang, Green Chem., 2014, 16, 2976; (b) S. T. Zhang, X. H. Zhang, X. G. Ling, C. He, R. F. Huang, J. Pan, J. Q. Li and Y. Xiong, RSC Adv., 2014, 4, 30768; (c) R. F. Huang, X. H. Zhang, J. Pan, J. Q. Li, H. Shen, X. G. Ling and Y. Xiong, Tetrahedron, 2015, 71, 1540; (d) J. Pan, J. Q. Li, R. F. Huang, X. H. Zhang, H. Shen, X. G. Ling, Y. Xiong and X. M. Zhu, Synthesis, 2015, 47, 1101.
18. (a) D. W. A. Sharp and N. Sheppard, J. Chem. Soc., 1957, 674; (b) K. A. Hofman and H. Kirmreuther, Eur. J. Inorg. Chem., 1909, 42, 4856; (c) C. E. H. Bawn, R. M. Bell and A. Ledwith, Polymer, 1965, 6, 95; (d) C. E. H. Bawn, R. M. Bell, C. Fitzsimmons and A. Ledwith, Polymer, 1965, 6, 661; (e) I. Kuntz, J. Polym. Sci., Polym. Phys. Ed., 1966, 4, 427; (f) M. P. Dreyfuss, J. C. Westfahl and P. Dreyfuss, Macromolecules, 1968, 1, 437; (g) K. Din and P. H. Plesch, J. Chem. Soc., Perkin Trans. 2, 1978, 937; (h) Y. Yamashita, M. Hirota, H. Matsui, A. Hirao and K. Nobutoki, Polym. J., 1971, 2, 43; (i) M. Horn, L. H. Schappele, G. Lang-Wittkowski, H. Mayr and A. R. Ofial, Chem.–Eur. J., 2013, 19, 249.
19. (a) P. Kirsch, Modern fluoroorganic Chemistry, Wiley, Weinheim, 2004; (b) K. Uneyama, Organofluorine Chemistry, Blackwell, Oxford, 2006; (c) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Blackwell, Chichester, 2009.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra14775a

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