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Selective difluoroalkylation of alkenes by using visible light photoredox catalysis† Chunghyeon Yu, Naeem Iqbal, Sehyun Park and Eun Jin Cho*
Received 16th July 2014, Accepted 30th August 2014 DOI: 10.1039/c4cc05467a www.rsc.org/chemcomm
A visible light-induced process for selective difluoroalkylation of unactivated alkenes has been developed. The choice of base is crucial for governing the chemoselectivity of the process to produce difluoroalkylated alkanes and alkenes.
Perfluoroalkylated organic compounds play significant roles in the pharmaceutical, agrochemical and material sciences owing to the substantial influence that fluorine substitution has on the physical and chemical properties of substances.1 The incorporation of various difluoroalkyl groups (–CF2R) into organic compounds is particularly interesting not only because these groups alter molecular properties, but also because it introduces the possibility of functional group modification of the appended alkyl groups. While significant advances have been made in carrying out difluoro alkylation reactions of arenes,2 similar transformations of alkenes are relatively underdeveloped despite their potential importance [Fig. 1(1)].3 In addition, many methods devised thus far for difluoro alkylation of alkenes have narrow scope and they require multi-step prefunctionalization procedures. Recent developments made in the studies of visible light photoredox catalysis have attracted substantial attention because the processes serve as environmentally friendly methods for promoting selective radical reactions.4 Included in the group of new photoredox catalyzed processes are radical mediated perfluoroalkylation reactions of various organic substrates.5 In the investigation described below, we have devised a new, selective, photoredox catalyzed difluoroalkylation reaction of unactivated alkenes.6 The process is promoted by visible light irradiation of a mixture of an alkene, ethyl 2-bromo-2,2-difluoroacetate (BrCF2CO2Et) and bases in the presence of a photoredox catalyst [Fig. 1(2)]. The choice of base is crucial for guiding selective formation of difluoro-alkene or -alkane products. Importantly, this
Department of Bionanotechnology and Department of Applied Chemistry, Hanyang University, Republic of Korea. E-mail: [email protected]; Fax: +82-31-400-5457; Tel: +82-31-400-5496 † Electronic supplementary information (ESI) available: Experimental details and NMR spectra. See DOI: 10.1039/c4cc05467a
12884 | Chem. Commun., 2014, 50, 12884--12887
Fig. 1
Difluoroalkylation reactions of alkenes.
process does not require prefunctionalization steps and proceeds under mild environmentally benign conditions. The mechanistic pathway followed in the difluoroalkylation reactions involves initial visible light photoredox catalyzed formation of the CF2 radical, which adds to the alkene to form the CF2-substituted alkyl radical intermediate 2. Depending on the base present, intermediate 2 reacts by direct hydrogen atom abstraction to produce alkane product 3 or by either bromine abstraction6 from BrCF2CO2Et followed by HBr elimination or oxidation of 2 followed by deprotonation to yield 6 [Fig. 1(2)]. In the initial phase of this effort, dodecene (1a) was used as a model alkene and BrCF2CO2Et as the difluoroalkyl donor along with different bases, solvents, triscyclometalated ruthenium
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Table 1
ChemComm
Optimization of the conditions for the difluoroalkylation reaction of alkenesa
Yieldb (%) Entry
Photocatalyst (1 mol%)
Base (2 equiv.)
Solvent (0.1 M)
3a
4a
6a
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
[Ru(bpy)3]Cl2 [Ru(phen)3]Cl2 fac-[lr(dFppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] — fac-[lr(ppy)3](no light) fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3]
DBU DBU DBU DBU TMEDA K2CO3 DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) — DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) K2CO3/DBU (2eq : 2eq) K2CO3; DBU (2eq : 2eq)d K2CO3; DBU (2eq : 2eq)d K2CO3; DBU (2eq : 2eq)d
MeCN MeCN MeCN MeCN MeCN MeCN MeCN DMF DMSO THF 1,4-Dioxane MeOH DCM DCM DCM DCM MeCN MeCN 1,4-Dioxane DMF
30 25 35 55 40 — 59 41 Trace 34 75 80c 86 Trace — — 49 — Trace Trace
— — — — 39 99 Trace Trace — Trace 8 3 — — — — — — (35e) —
Trace Trace Trace Trace Trace — 7 Trace — Trace 8 10 11 — — — 15 95(16e) 96(58e) 97(96e)
a Conditions: 1a (0.1 mmol), BrCF2CO2Et (0.15 mmol), 24 h. b Yields were determined by using gas chromatography and 19F NMR spectroscopy with internal standards dodecane and 4-fluorotoluene, respectively. c CF2CO2Me substituted alkane was formed. d DBU was added after complete conversion of 1a to 4a. e In parentheses are yields after 1 h reaction time.
and iridium photocatalysts, including [Ru(bpy)3]Cl2, [Ru(phen)3]Cl2, fac-[Ir(dFppy)3], and fac-[Ir(ppy)3], and visible light irradiation with blue LEDs (7 W) (Table 1). Interestingly, reactions using DBU in MeCN were observed to generate only the difluoroalkane product 3a despite incomplete alkene conversion (entries 1–4).7,8 Because fac-[Ir(ppy)3] displayed the highest reactivity it was used as the photocatalyst in further optimization studies. The results showed that the nature of the base strongly influences the product distribution. For example, reaction of 1a employing TMEDA takes place to complete conversion to generate a mixture of difluroalkane 3a and bromodifluoroalkane 4a while that using K2CO3 produces only the bromodifluoroalkylated product 4a (entries 5 and 6).6 Importantly, a reaction using a mixture of DBU and TMEDA as base takes place selectively to form 3a as the major product with complete conversion (entry 7).9 Moreover, a change of the solvent to dichloromethane increases the yield of 3a to 86% (entries 8–13). Reaction in MeOH also efficiently generates hydrodifluoroalkylation product 3a, which is then transformed into the CF2CO2Me substituted alkane by consecutive transesterification (entry 12). A further exploratory effort was carried out to uncover optimal conditions for production of the difluoroalkene product 6a. The finding that the use of K2CO3 leads to quantitative formation of the bromodifluoroalkane 4a (entry 6 in Table 1) prompted the evaluation of a tandem process to generate 6a, in which HBr elimination is carried out following difluoroalkylation. Irradiation of a dichloromethane solution of fac-[Ir(ppy)3] in the presence of 1a and a mixture of K2CO3 and DBU produces both 3a and 6a due to the multiple roles played by DBU (entry 17). However, the addition of DBU to the reaction mixture after complete conversion of 1a to 4a leads to selective formation of 6a (entry 18). In this
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process, DBU acts solely as a base for the elimination reaction. Surprisingly, the use of DMF as solvent causes a decrease in time (1 h) needed to bring about complete conversion (entry 20). The substrate scope of the difluoroalkylation process was examined next using the optimized conditions described above (Table 2). The results show that difluoroalkene forming reactions of a variety of aliphatic alkenes, containing a range of functional groups including amide (3b, 3c, 3d), ester (3f, 3g), silyl ether (3e), and aryl halide (3b, 3c), take place efficiently. Reaction of the amine substrate 1i generates the CF2-containing lactam 3i owing to intramolecular amide formation occurring between the amine and ester moieties in the initially formed product (entry 9). In these processes, the alkenyl-CF2CO2Et product 6 together with 3 are produced as minor products. Compared to those with terminal alkene substrates, reactions of internal alkenes take place more slowly and generate mixtures of hydro- (3), bromo- (4), and alkenyl (6) products with different selectivities. Reactions of trans-5-decene and cyclohexene are presented in Scheme S2 of the ESI.† Interestingly, reaction of an alkenyl-alcohol 1j generates a mixture of difluoroalkylated products, 3j, 3j0 , and 3j00 (Scheme 1). In this process, 3j0 and 3j00 are produced by consecutive nucleophilic acyl substitution reactions between the ester and hydroxyl groups in 3j. The ethoxy group acts as the leaving group in the formation of lactone product 3j0 while CF2R is the leaving group10 in the generation of 3j00 . The results of studies exploring the scope of the alkenyldifluoroalkylation process showed that both aliphatic and aromatic alkenes are suitable substrates for transformations that efficiently yield alkenyl-CF2CO2Et products 6 (Table 3). These reactions take place with excellent levels of regio- and
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Table 2
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Hydrodifluoroalkylation reactions of aliphatic alkenesa
Entry
Product
Table 3
Yieldb (%)
Ratio (3 : 6)c
1
3a
85
4 : 1d
2
3b
70
11 : 1
3
3c
75
8:1
4
3d
80
8:1
5
3e
65
4 : 1d
6
3f
90
5:1
7
3g
85
6:1
8
3h
67
11 : 1
9
3i
70
7:1
Alkenyl-difluoroalkylation reactions of alkenesa,b,c
a Conditions: 1 (1.0 mmol), BrCF2CO2Et (1.5 mmol), 2 h. b Isolated yields based on an average of two runs. c The E/Z ratios were determined by using gas chromatography and 1H NMR spectroscopy. d Reactions proceed without DBU addition (with 3 equiv. K2CO3 and 5 h reaction time).
a Conditions: 1 (0.5 mmol), BrCF2CO2Et (0.75 mmol), 18–24 h. b Isolated yields based on an average of two runs. c Ratios of 3 and 6 (alkenylCF2CO2Et) were determined by using gas chromatography and 19F NMR spectroscopy. d Reactions on 40.5 mmol scales produce greater amounts of 6 than those on a 0.1 mmol scale.
Fig. 2
Scheme 1
Reaction of alkenyl–alcohol 1j.
E/Z stereoselectivity. Interestingly, electron rich styrene derivatives undergo alkenyl-difluoroalkylation to form 6p, 6q and 6r completely in the absence of DBU despite the need for longer reaction times. Based on the results of the studies described above, it is possible to propose the plausible mechanism outlined in Fig. 2 for the processes. Photoexcitation of fac-[IrIII(ppy)3] produces the metalto-ligand charge-transfer excited state [IrIVppy (ppy)2], which is oxidatively quenched by single electron transfer to BrCF2CO2Et to
12886 | Chem. Commun., 2014, 50, 12884--12887
Proposed mechanism for the difluoroalkylation reaction.
produce the key intermediate CF2CO2Et, [IrIV(ppy)3]+ and the bromide ion. Addition of the electron deficient carbon-centered radical CF2CO2Et to the alkene generates the difluoroalkylated radical species 2, which participates in several reactions depending on the base present. First, hydrodifluoroalkylated product 3 is generated by direct hydrogen abstraction by 2 from amminium radical cations [NR3] + produced by one electron transfer from the corresponding tertiary amines to [IrIV(ppy)3]+ [pathway (a) in Fig. 2]. The direct H abstraction mechanism for conversion of 2 to 3 is supported by the results of an experiment in which bromide 4a is subjected to the conditions used for the hydrodifluoroalkylation reaction. In this process, only the alkene product 6a and not the debromonated product 3a is formed through E2 elimination [Scheme 2].11 Alternatively, alkenyl-difluoroalkyl product formation from 2 can take place by either pathway (b) or (c) shown in Fig. 2. In the
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3
Scheme 2
Selective conversion of 4a to 6a.
presence of K2CO3, radical 2 can abstract a bromine atom from BrCF2CO2Et to generate the CF2CO2Et and bromodifluoroalkylated product 4, which then undergoes E2 elimination to form E-alkenyl product 6 [pathway (b)]. Although this pathway is considered to be the one most likely followed, the alternative pathway (c) is possible especially in reactions of aromatic alkenes. In this route radical 2 donates one electron to [IrIV(ppy)3]+ to produce the cationic complex 5 which loses a proton to produce alkene product 6. In the investigation described above, we have developed an efficient and selective method for difluoroalkylation of alkenes. Difluoroalkylated alkanes and alkenes are produced in these reactions, which use ethyl 2-bromo-2,2-difluoroacetate as the difluoroalkyl donor, fac-Ir(ppy)3 as the photoredox catalyst and visible light irradiation. The choice of base is crucial for governing the chemoselectivity of the process. For example, reactions in dichloromethane in which TMEDA and DBU serve as the base form CF2-substituted alkanes while those in DMF where K2CO3 and DBU12 are bases generate alkene products. The new protocol represents a practical and environmentally benign method for promoting efficient difluoroalkylation reactions of alkenes, a process that has potential applications in the preparation of various CF2-containing compounds. This work was supported by the National Research Foundation of Korea [NRF-2014R1A1A1A05003274, NRF-2014-011165, and NRF-2012M3A7B4049657] and the TJ Science Fellowship of the POSCO TJ Park Foundation.
Notes and references 1 (a) H. R. Hope, D. Heuvelman, K. Duffin, C. Smith, J. Zablocki, R. Schilling, S. Hegde, L. Lee, B. Witherbee, M. Baganoff, C. Bruce, A. R. Tall, E. Krul, K. Glenn and D. T. Connolly, J. Lipid Res., 2000, 40, 1604; (b) V. D. Romanenko and V. P. Kukhar, Chem. Rev., 2006, ¨ller, C. Faeh and F. Diederich, Science, 2007, 106, 3868; (c) K. Mu 317, 1881; (d) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Blackwell, 2009; (e) T. Liang, C. N. Neumann and T. Ritter, Angew. Chem., Int. Ed., 2013, 52, 8214. 2 For examples of aryl-difluoroalkylations, see: (a) Y. Ohtsuka and T. Yamakawa, Tetrahedron, 2011, 67, 2323; (b) G. K. S. Prakash, S. K. Ganesh, J.-P. Jones, A. Kulkarni, K. Masood, J. K. Swabeck and G. A. Olah, Angew. Chem., Int. Ed., 2012, 51, 12090; (c) Y. Fujiwara, J. A. Dixon, R. A. Rodriguez, R. D. Baxter, D. D. Dixon, M. R. Collins, D. G. Blackmond and P. S. Baran, J. Am. Chem. Soc., 2012, 134, 1494; (d) Q. Zhou, A. Ruffoni, R. Gianatassio, Y. Fujiwara, E. Sella, D. Shabat and P. S. Baran, Angew. Chem., Int. Ed., 2013, 52, 3949; (e) A. Hafner, ¨se, J. Org. Chem., 2013, A. Bihlmeier, M. Nieger, W. Klopper and S. Bra 78, 7938; ( f ) V. P. Mehta and M. F. Greaney, Org. Lett., 2013, 15, 5036; (g) Q. Lin, L. Chu and F.-L. Qing, Chin. J. Chem., 2013, 31, 885; (h) Z. Feng, Q.-Q. Min, Y.-L. Xiao, B. Zhang and X. Zhang, Angew.
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4
5
6 7
8 9 10 11
12
Chem., Int. Ed., 2014, 53, 1669; (i) Y.-M. Su, Y. Hou, F. Yin, Y.-M. Xu, Y. Li, X. Zheng and X.-S. Wang, Org. Lett., 2014, 16, 2958. For examples of difluoroalkylations of alkenes, see: (a) V. Reutrakul, T. Thongpaisanwong, P. Tuchinda, C. Kuhakarn and M. Pohmakotr, J. Org. Chem., 2004, 69, 6913; (b) K. Sato, M. Omote, A. Ando and I. Kumadaki, J. Fluorine Chem., 2004, 125, 509; (c) F. Xiao, F. Wu, Y. Shen and L. Zhou, J. Fluorine Chem., 2005, 126, 63; (d) S. Murakami, H. Ishii, T. Tajima and T. Fuchigami, Tetrahedron, 2006, 62, 3761; (e) Y. Li, J. Liu, L. Zhang, L. Zhu and J. Hu, J. Org. Chem., 2007, 72, 5824; ( f ) X. Yang, Z. Wang, Y. Zhu, X. Fang, X. Yang, F. Wu and Y. Shen, J. Fluorine Chem., 2007, 128, 1046; (g) L. Leung and B. Linclau, J. Fluorine Chem., 2008, 129, 986; (h) J. D. Nguyen, J. W. Tucker, M. D. Konieczynska and C. R. J. Stephenson, J. Am. Chem. Soc., 2011, 133, 4160; (i) C. J. Wallentin, J. D. Nguyen, P. Finkbeiner and C. R. J. Stephenson, J. Am. Chem. Soc., 2012, 134, 8875; ( j) M.-C. Belhomme, T. Poisson and X. Pannecoucke, Org. Lett., 2013, 15, 3428. For some recent reviews on visible light photoredox catalysis, see: (a) T. P. Yoon, M. A. Ischay and J. Du, Nat. Chem., 2010, 2, 527; (b) J. M. R. Narayanam and C. R. J. Stephenson, Chem. Soc. Rev., 2011, 40, 102; (c) J. Xuan and W.-J. Xiao, Angew. Chem., Int. Ed., 2012, 51, 6828; ¨ler and A. G. Griesbeck, Adv. Synth. Catal., 2013, (d) M. Reckentha 355, 2727; (e) C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013, 113, 5322; ( f ) T. Koike and M. Akita, Top. Catal., 2014, 57, 967; (g) J. Xie, H. Jin, P. Xu and C. Zhu, Tetrahedron Lett., 2014, 55, 36. For examples of visible light-induced perfluoroalkylations, see ref. 2g, i, 3h, i and (a) D. A. Nagib and D. W. C. MacMillan, Nature, 2011, 480, 224; (b) N. Iqbal, S. Choi, E. Ko and E. J. Cho, Tetrahedron Lett., 2012, 53, 2005; (c) N. Iqbal, S. Choi, E. Kim and E. J. Cho, J. Org. Chem., 2012, 77, 11383; (d) Y. Yasu, T. Koike and M. Akita, Angew. Chem., Int. Ed., 2012, 51, 9567; (e) E. Kim, S. Choi, H. Kim and E. J. Cho, Chem. – Eur. J., 2013, 19, 6209; ( f ) Y. Yasu, T. Koike and M. Akita, Chem. Commun., 2013, 49, 2037; ( g) S. Mizuta, S. Verhoog, K. M. Engle, T. Khotavivattana, M. O’Duill, K. Wheelhouse, ´debielle and V. Gouverneur, J. Am. Chem. Soc., G. Rassias, M. Me 2013, 135, 2505; (h) J.-B. Xia, C. Zhu and C. Chen, J. Am. Chem. Soc., 2013, 135, 17494; (i) N. Iqbal, J. Jung, S. Park and E. J. Cho, Angew. ´, Chem., Int. Ed., 2014, 53, 539; ( j) M. Rueda-Becerril, O. Mahe M. Drouin, M. B. Majewski, J. G. West, M. O. Wolf, G. M. Sammis and J.-F. Paquin, J. Am. Chem. Soc., 2014, 136, 2637; (k) N. J. W. Straathof, H. P. L. Gemoets, X. Wang, J. C. Schouten, V. Hessel and ¨l, ChemSusChem, 2014, 7, 1612; (l) X. Sun and S. Yu, Org. Lett., T. Noe 2014, 16, 2938; (m) W. Li, X. Zhu, H. Mao, Z. Tang, Y. Cheng and C. Zhu, Chem. Commun., 2014, 50, 7521. The Stephenson group reported the visible light-inudced synthesis of bromo-difluoroalkylated products from alkenes and BrCF2CO2Et, see ref. 3h and i. The [NR3] + species formed by the photocatalytic pathway bears acidic a-hydrogen atoms, and it can also serve as a hydrogen donor, see: (a) J. Du, L. R. Espelt, I. A. Guzei and T. P. Yoon, Chem. Sci., 2011, 2, 2115; (b) H. Kim and C. Lee, Angew. Chem., Int. Ed., 2012, 51, 12303. DBU showed a good reactivity as the hydrogen atom source for hydrotrifluoromethylation of alkynes, see ref. 5i. In the process, the difluoroalkylatedalkene 6a was also obtained as a minor product probably through an elimination reaction of the bromodifluroalkane intermediate 4a. See Scheme S1 in ESI†. It is likely that the presence of two fluorine atoms makes CF2R act as a good leaving group due to the ability of the highly electronegative fluorine atom to stabilize the carbanion. These results exclude the possibility of cascade catalysis where hydrodifluoroalkylation occurs by bromodifluoroalkylation followed by debromonation under visible light photoredox catalysis. For dehalogenation of alkenyl-halides, see ref. 7b and J. D. Nguyen, E. M. D’Amato, J. M. R. Narayanam and C. R. J. Stephenson, Nat. Chem., 2012, 4, 854. The addition of DBU was not required for the reaction of electronrich aromatic alkenes.
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Cite this: Chem. Commun., 2014, 50, 12884
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Selective difluoroalkylation of alkenes by using visible light photoredox catalysis† Chunghyeon Yu, Naeem Iqbal, Sehyun Park and Eun Jin Cho*
Received 16th July 2014, Accepted 30th August 2014 DOI: 10.1039/c4cc05467a www.rsc.org/chemcomm
A visible light-induced process for selective difluoroalkylation of unactivated alkenes has been developed. The choice of base is crucial for governing the chemoselectivity of the process to produce difluoroalkylated alkanes and alkenes.
Perfluoroalkylated organic compounds play significant roles in the pharmaceutical, agrochemical and material sciences owing to the substantial influence that fluorine substitution has on the physical and chemical properties of substances.1 The incorporation of various difluoroalkyl groups (–CF2R) into organic compounds is particularly interesting not only because these groups alter molecular properties, but also because it introduces the possibility of functional group modification of the appended alkyl groups. While significant advances have been made in carrying out difluoro alkylation reactions of arenes,2 similar transformations of alkenes are relatively underdeveloped despite their potential importance [Fig. 1(1)].3 In addition, many methods devised thus far for difluoro alkylation of alkenes have narrow scope and they require multi-step prefunctionalization procedures. Recent developments made in the studies of visible light photoredox catalysis have attracted substantial attention because the processes serve as environmentally friendly methods for promoting selective radical reactions.4 Included in the group of new photoredox catalyzed processes are radical mediated perfluoroalkylation reactions of various organic substrates.5 In the investigation described below, we have devised a new, selective, photoredox catalyzed difluoroalkylation reaction of unactivated alkenes.6 The process is promoted by visible light irradiation of a mixture of an alkene, ethyl 2-bromo-2,2-difluoroacetate (BrCF2CO2Et) and bases in the presence of a photoredox catalyst [Fig. 1(2)]. The choice of base is crucial for guiding selective formation of difluoro-alkene or -alkane products. Importantly, this
Department of Bionanotechnology and Department of Applied Chemistry, Hanyang University, Republic of Korea. E-mail: [email protected]; Fax: +82-31-400-5457; Tel: +82-31-400-5496 † Electronic supplementary information (ESI) available: Experimental details and NMR spectra. See DOI: 10.1039/c4cc05467a
12884 | Chem. Commun., 2014, 50, 12884--12887
Fig. 1
Difluoroalkylation reactions of alkenes.
process does not require prefunctionalization steps and proceeds under mild environmentally benign conditions. The mechanistic pathway followed in the difluoroalkylation reactions involves initial visible light photoredox catalyzed formation of the CF2 radical, which adds to the alkene to form the CF2-substituted alkyl radical intermediate 2. Depending on the base present, intermediate 2 reacts by direct hydrogen atom abstraction to produce alkane product 3 or by either bromine abstraction6 from BrCF2CO2Et followed by HBr elimination or oxidation of 2 followed by deprotonation to yield 6 [Fig. 1(2)]. In the initial phase of this effort, dodecene (1a) was used as a model alkene and BrCF2CO2Et as the difluoroalkyl donor along with different bases, solvents, triscyclometalated ruthenium
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Table 1
ChemComm
Optimization of the conditions for the difluoroalkylation reaction of alkenesa
Yieldb (%) Entry
Photocatalyst (1 mol%)
Base (2 equiv.)
Solvent (0.1 M)
3a
4a
6a
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
[Ru(bpy)3]Cl2 [Ru(phen)3]Cl2 fac-[lr(dFppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] — fac-[lr(ppy)3](no light) fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3] fac-[lr(ppy)3]
DBU DBU DBU DBU TMEDA K2CO3 DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) — DBU/TMEDA (2eq : 2eq) DBU/TMEDA (2eq : 2eq) K2CO3/DBU (2eq : 2eq) K2CO3; DBU (2eq : 2eq)d K2CO3; DBU (2eq : 2eq)d K2CO3; DBU (2eq : 2eq)d
MeCN MeCN MeCN MeCN MeCN MeCN MeCN DMF DMSO THF 1,4-Dioxane MeOH DCM DCM DCM DCM MeCN MeCN 1,4-Dioxane DMF
30 25 35 55 40 — 59 41 Trace 34 75 80c 86 Trace — — 49 — Trace Trace
— — — — 39 99 Trace Trace — Trace 8 3 — — — — — — (35e) —
Trace Trace Trace Trace Trace — 7 Trace — Trace 8 10 11 — — — 15 95(16e) 96(58e) 97(96e)
a Conditions: 1a (0.1 mmol), BrCF2CO2Et (0.15 mmol), 24 h. b Yields were determined by using gas chromatography and 19F NMR spectroscopy with internal standards dodecane and 4-fluorotoluene, respectively. c CF2CO2Me substituted alkane was formed. d DBU was added after complete conversion of 1a to 4a. e In parentheses are yields after 1 h reaction time.
and iridium photocatalysts, including [Ru(bpy)3]Cl2, [Ru(phen)3]Cl2, fac-[Ir(dFppy)3], and fac-[Ir(ppy)3], and visible light irradiation with blue LEDs (7 W) (Table 1). Interestingly, reactions using DBU in MeCN were observed to generate only the difluoroalkane product 3a despite incomplete alkene conversion (entries 1–4).7,8 Because fac-[Ir(ppy)3] displayed the highest reactivity it was used as the photocatalyst in further optimization studies. The results showed that the nature of the base strongly influences the product distribution. For example, reaction of 1a employing TMEDA takes place to complete conversion to generate a mixture of difluroalkane 3a and bromodifluoroalkane 4a while that using K2CO3 produces only the bromodifluoroalkylated product 4a (entries 5 and 6).6 Importantly, a reaction using a mixture of DBU and TMEDA as base takes place selectively to form 3a as the major product with complete conversion (entry 7).9 Moreover, a change of the solvent to dichloromethane increases the yield of 3a to 86% (entries 8–13). Reaction in MeOH also efficiently generates hydrodifluoroalkylation product 3a, which is then transformed into the CF2CO2Me substituted alkane by consecutive transesterification (entry 12). A further exploratory effort was carried out to uncover optimal conditions for production of the difluoroalkene product 6a. The finding that the use of K2CO3 leads to quantitative formation of the bromodifluoroalkane 4a (entry 6 in Table 1) prompted the evaluation of a tandem process to generate 6a, in which HBr elimination is carried out following difluoroalkylation. Irradiation of a dichloromethane solution of fac-[Ir(ppy)3] in the presence of 1a and a mixture of K2CO3 and DBU produces both 3a and 6a due to the multiple roles played by DBU (entry 17). However, the addition of DBU to the reaction mixture after complete conversion of 1a to 4a leads to selective formation of 6a (entry 18). In this
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process, DBU acts solely as a base for the elimination reaction. Surprisingly, the use of DMF as solvent causes a decrease in time (1 h) needed to bring about complete conversion (entry 20). The substrate scope of the difluoroalkylation process was examined next using the optimized conditions described above (Table 2). The results show that difluoroalkene forming reactions of a variety of aliphatic alkenes, containing a range of functional groups including amide (3b, 3c, 3d), ester (3f, 3g), silyl ether (3e), and aryl halide (3b, 3c), take place efficiently. Reaction of the amine substrate 1i generates the CF2-containing lactam 3i owing to intramolecular amide formation occurring between the amine and ester moieties in the initially formed product (entry 9). In these processes, the alkenyl-CF2CO2Et product 6 together with 3 are produced as minor products. Compared to those with terminal alkene substrates, reactions of internal alkenes take place more slowly and generate mixtures of hydro- (3), bromo- (4), and alkenyl (6) products with different selectivities. Reactions of trans-5-decene and cyclohexene are presented in Scheme S2 of the ESI.† Interestingly, reaction of an alkenyl-alcohol 1j generates a mixture of difluoroalkylated products, 3j, 3j0 , and 3j00 (Scheme 1). In this process, 3j0 and 3j00 are produced by consecutive nucleophilic acyl substitution reactions between the ester and hydroxyl groups in 3j. The ethoxy group acts as the leaving group in the formation of lactone product 3j0 while CF2R is the leaving group10 in the generation of 3j00 . The results of studies exploring the scope of the alkenyldifluoroalkylation process showed that both aliphatic and aromatic alkenes are suitable substrates for transformations that efficiently yield alkenyl-CF2CO2Et products 6 (Table 3). These reactions take place with excellent levels of regio- and
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Table 2
Communication
Hydrodifluoroalkylation reactions of aliphatic alkenesa
Entry
Product
Table 3
Yieldb (%)
Ratio (3 : 6)c
1
3a
85
4 : 1d
2
3b
70
11 : 1
3
3c
75
8:1
4
3d
80
8:1
5
3e
65
4 : 1d
6
3f
90
5:1
7
3g
85
6:1
8
3h
67
11 : 1
9
3i
70
7:1
Alkenyl-difluoroalkylation reactions of alkenesa,b,c
a Conditions: 1 (1.0 mmol), BrCF2CO2Et (1.5 mmol), 2 h. b Isolated yields based on an average of two runs. c The E/Z ratios were determined by using gas chromatography and 1H NMR spectroscopy. d Reactions proceed without DBU addition (with 3 equiv. K2CO3 and 5 h reaction time).
a Conditions: 1 (0.5 mmol), BrCF2CO2Et (0.75 mmol), 18–24 h. b Isolated yields based on an average of two runs. c Ratios of 3 and 6 (alkenylCF2CO2Et) were determined by using gas chromatography and 19F NMR spectroscopy. d Reactions on 40.5 mmol scales produce greater amounts of 6 than those on a 0.1 mmol scale.
Fig. 2
Scheme 1
Reaction of alkenyl–alcohol 1j.
E/Z stereoselectivity. Interestingly, electron rich styrene derivatives undergo alkenyl-difluoroalkylation to form 6p, 6q and 6r completely in the absence of DBU despite the need for longer reaction times. Based on the results of the studies described above, it is possible to propose the plausible mechanism outlined in Fig. 2 for the processes. Photoexcitation of fac-[IrIII(ppy)3] produces the metalto-ligand charge-transfer excited state [IrIVppy (ppy)2], which is oxidatively quenched by single electron transfer to BrCF2CO2Et to
12886 | Chem. Commun., 2014, 50, 12884--12887
Proposed mechanism for the difluoroalkylation reaction.
produce the key intermediate CF2CO2Et, [IrIV(ppy)3]+ and the bromide ion. Addition of the electron deficient carbon-centered radical CF2CO2Et to the alkene generates the difluoroalkylated radical species 2, which participates in several reactions depending on the base present. First, hydrodifluoroalkylated product 3 is generated by direct hydrogen abstraction by 2 from amminium radical cations [NR3] + produced by one electron transfer from the corresponding tertiary amines to [IrIV(ppy)3]+ [pathway (a) in Fig. 2]. The direct H abstraction mechanism for conversion of 2 to 3 is supported by the results of an experiment in which bromide 4a is subjected to the conditions used for the hydrodifluoroalkylation reaction. In this process, only the alkene product 6a and not the debromonated product 3a is formed through E2 elimination [Scheme 2].11 Alternatively, alkenyl-difluoroalkyl product formation from 2 can take place by either pathway (b) or (c) shown in Fig. 2. In the
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3
Scheme 2
Selective conversion of 4a to 6a.
presence of K2CO3, radical 2 can abstract a bromine atom from BrCF2CO2Et to generate the CF2CO2Et and bromodifluoroalkylated product 4, which then undergoes E2 elimination to form E-alkenyl product 6 [pathway (b)]. Although this pathway is considered to be the one most likely followed, the alternative pathway (c) is possible especially in reactions of aromatic alkenes. In this route radical 2 donates one electron to [IrIV(ppy)3]+ to produce the cationic complex 5 which loses a proton to produce alkene product 6. In the investigation described above, we have developed an efficient and selective method for difluoroalkylation of alkenes. Difluoroalkylated alkanes and alkenes are produced in these reactions, which use ethyl 2-bromo-2,2-difluoroacetate as the difluoroalkyl donor, fac-Ir(ppy)3 as the photoredox catalyst and visible light irradiation. The choice of base is crucial for governing the chemoselectivity of the process. For example, reactions in dichloromethane in which TMEDA and DBU serve as the base form CF2-substituted alkanes while those in DMF where K2CO3 and DBU12 are bases generate alkene products. The new protocol represents a practical and environmentally benign method for promoting efficient difluoroalkylation reactions of alkenes, a process that has potential applications in the preparation of various CF2-containing compounds. This work was supported by the National Research Foundation of Korea [NRF-2014R1A1A1A05003274, NRF-2014-011165, and NRF-2012M3A7B4049657] and the TJ Science Fellowship of the POSCO TJ Park Foundation.
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6 7
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12
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Chem. Commun., 2014, 50, 12884--12887 | 12887
