Journal of the American Chemical Society
Communication
(2) For example, see Figure 1 in: Brown, D. G.; Bostrom, J. J. Med.
Tunge, J. A. Chem. Rev. 2011, 111, 1846−1913) and have been
demonstrated in photoredox chemistry (e.g., Le, C.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2015, 137, 11938−11941).
̈
Chem. 2016, 59, 4443−4458.
(3) For leading references, see: Ahmad, N. M. Name Reactions for
Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley
& Sons: Hoboken, NJ, 2007; pp 438−450.
(15) For examples of metal-catalyzed intermolecular decarboxylative
C−N couplings, see: Lang, S. B.; Cartwright, K. C.; Welter, R. S.;
Locascio, T. M.; Tunge, J. A. Eur. J. Org. Chem. 2016, 2016, 3331−3334.
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(16) For examples of intramolecular decarboxylative C−N couplings,
see: (a) Jin, Y.; Yang, H.; Fu, H. Org. Lett. 2016, 18, 6400−6403. (b) Liu,
Z.-J.; Lu, X.; Wang, G.; Li, L.; Jiang, W.-T.; Wang, Y.-D.; Xiao, B.; Fu, Y.
J. Am. Chem. Soc. 2016, 138, 9714−9719. (c) Dai, Q.; Li, P.; Ma, N.; Hu,
C. Org. Lett. 2016, 18, 5560−5563.
(17) While our study was underway, H. Fu reported that thiophenols
can catalyze photoinduced decarboxylative C−N couplings of the type
illustrated in eq 3, wherein the NHP ester is derived from an α-amino
acid, via an N-acylimine intermediate (Reference 16a); however,
application of these conditions (CFL irradiation, 10 mol % 4-
trifluoromethylthiophenol, 0.5 equiv Cs2CO3, DMF, r.t.) to the NHP
ester illustrated in eq 4 furnishes none of the desired product (<1%).
(18) Deprotection of the product under conventional conditions
affords cyclohexylamine in 83% isolated yield.
(19) For reports of the use of [Cu(dmp)(xantphos)]BF4 as a
photocatalyst in organic chemistry, see: (a) Hernandez-Perez, A. C.;
Collins, S. K. Angew. Chem., Int. Ed. 2013, 52, 12696−12700. (b) Xiao,
P.; Dumur, F.; Zhang, J.; Fouassier, J. P.; Gigmes, D.; Lalevee, J.
Macromolecules 2014, 47, 3837−3844.
(20) When the mixture of CuCN, dmp, and xantphos shown in Table 1
is replaced with 10 mol % [Cu(dmp)(xantphos)]BF4, essentially none
of the desired product is formed (<1% yield). We hypothesize that
[Cu(dmp)(xantphos)]+, which we have identified by UV−vis spectros-
copy and ESI−MS under the reaction conditions, is serving as the
photoreductant (e.g., see Reference 19), but that an independent copper
complex is involved in the C−N bond-forming step.
(21) Notes: (a) A number of variations in this mechanistic outline can
be envisioned, including fragmentation of the NHP ester through
copper-bound intermediates, as well as C−N bond formation via
reductive elimination from a copper(III) complex that bears R and phth
as ligands. (b) In Figure 1, the copper(II)−phthalimide complex that
engages in C−N bond formation is not formed from the same copper(I)
complex that undergoes excitation. Diffusion out of the solvent cage,
ligand exchange, etc. occur in between (vide infra).
(22) For a non-photoinduced, copper-catalyzed intermolecular C−H
phthalimidation of unactivated alkanes, see: Tran, B. L.; Li, B.; Driess,
M.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 2555−2563.
(23) For leading references on photoredox catalysis, see: (a) Prier, C.
K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322−
5363. (b) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116,
10035−10074.
(4) For leading references to related processes, including the Lossen
rearrangement, see: Aube, J.; Fehl, C.; Liu, R.; McLeod, M. C.; Motiwala,
H. F. In Comprehensive Organic Synthesis; Knochel, P., Molander, G. A.,
Eds.; Elsevier: Amsterdam, 2015; Vol. 6, pp 598−635.
(5) For recent illustrative examples, see: (a) Zuo, Z.; Ahneman, D. T.;
Chu, L.; Terrett, J. A.; Doyle, A. G.; MacMillan, D. W. C. Science 2014,
345, 437−440. (b) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J.
T.; Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. Science
2016, 352, 801−805.
(6) For a recent example and discussion, see: Marsini, M. A.; Buono, F.
G.; Lorenz, J. C.; Yang, B.-S.; Reeves, J. T.; Sidhu, K.; Sarvestani, M.;
Tan, Z.; Zhang, Y.; Li, N.; Lee, H.; Brazzillo, J.; Nummy, L. J.; Chung, J.
C.; Luvaga, I. K.; Narayanan, B. A.; Wei, X.; Song, J. J.; Roschangar, F.;
Yee, N. K.; Senanayake, C. H. Green Chem. 2017, 19, 1454−1461.
(7) For pioneering studies of photoinduced activation of NHP esters,
see: (a) Okada, K.; Okamoto, K.; Oda, M. J. Am. Chem. Soc. 1988, 110,
8736−8738. (b) Okada, K.; Okamoto, K.; Morita, N.; Okubo, K.; Oda,
M. J. Am. Chem. Soc. 1991, 113, 9401−9402.
(8) For an early application of photoinduced activation of NHP esters
to achieve C−C bond formation in total synthesis, see: Schnermann, M.
J.; Overman, L. E. Angew. Chem., Int. Ed. 2012, 51, 9576−9580.
(9) For representative examples of recent studies, see: (a) Edwards, J.
T.; Merchant, R. R.; McClymont, K. S.; Knouse, K. W.; Qin, T.; Malins,
L. R.; Vokits, B.; Shaw, S. A.; Bao, D.-H.; Wei, F.-L.; Zhou, T.; Eastgate,
M. D.; Baran, P. S. Nature 2017, 545, 213−218. (b) Fawcett, A.;
Pradeilles, J.; Wang, Y.; Mutsuga, T.; Myers, E. L.; Aggarwal, V. K.
Science 2017, 357, 283−286. (c) Tlahuext-Aca, A.; Garza-Sanchez, R. A.;
Glorius, F. Angew. Chem., Int. Ed. 2017, 56, 3708−3711. (d) Suzuki, N.;
Hofstra, J. L.; Poremba, K. E.; Reisman, S. E. Org. Lett. 2017, 19, 2150−
2153. (e) Huihui, K. M. M.; Caputo, J. A.; Melchor, Z.; Olivares, A. M.;
Spiewak, A. M.; Johnson, K. A.; DiBenedetto, T. A.; Kim, S.; Ackerman,
L. K. G.; Weix, D. J. J. Am. Chem. Soc. 2016, 138, 5016−5019.
(10) (a) arylation of nitrogen nucleophiles: Creutz, S. E.; Lotito, K. J.;
Fu, G. C.; Peters, J. C. Science 2012, 338, 647−651. (b) alkylation of
nitrogen nucleophiles: Bissember, A. C.; Lundgren, R. J.; Creutz, S. E.;
Peters, J. C.; Fu, G. C. Angew. Chem., Int. Ed. 2013, 52, 5129−5133. (c)
arylation of sulfur nucleophiles: Uyeda, C.; Tan, Y.; Fu, G. C.; Peters, J.
C. J. Am. Chem. Soc. 2013, 135, 9548−9552. (d) arylation, alkenylation,
and alkynylation of nitrogen nucleophiles: Ziegler, D. T.; Choi, J.;
Munoz-Molina, J. M.; Bissember, A. C.; Peters, J. C.; Fu, G. C. J. Am.
Chem. Soc. 2013, 135, 13107−13112. (e) alkylation of nitrogen
nucleophiles: Do, H.-Q.; Bachman, S.; Bissember, A. C.; Peters, J. C.; Fu,
G. C. J. Am. Chem. Soc. 2014, 136, 2162−2167. (f) arylation of oxygen
nucleophiles: Tan, Y.; Munoz-Molina, J. M.; Fu, G. C.; Peters, J. C.
Chem. Sci. 2014, 5, 2831−2835. (g) alkylation of carbon nucleophiles:
Ratani, T. S.; Bachman, S.; Fu, G. C.; Peters, J. C. J. Am. Chem. Soc. 2015,
137, 13902−13907. (h) enantioconvergent alkylation of nitrogen
nucleophiles: Kainz, Q. M.; Matier, C. M.; Bartoszewicz, A.; Zultanski, S.
L.; Peters, J. C.; Fu, G. C. Science 2016, 351, 681−684.
(24) For a method that employs [Ru(bpy)3]Cl2 for photoactivation
and copper for C−C bond formation, see: Zhang, H.; Zhang, P.; Jiang,
M.; Yang, H.; Fu, H. Org. Lett. 2017, 19, 1016−1019.
(25) Hilborn, J. W.; Pincock, J. A. J. Am. Chem. Soc. 1991, 113, 2683−
2686.
(26) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science Books: Sausalito, CA, 2006; p 156.
(27) For leading references on radical clocks, see: Newcomb, M. In
Encyclopedia of Radicals in Chemistry, Biology and Materials;
Chatgilialoglu, C., Studer, A., Eds.; John Wiley & Sons: Chichester,
2012; Vol. 1, pp 107−124.
(28) This discussion is based on the assumption that ring opening and
ring formation are proceeding through radical, rather than organo-
metallic, pathways.
(29) An EPR study of a C−N coupling after 30 min at 10 °C showed a
weak signal that is consistent with a copper-containing radical.
(30) For the C−N coupling illustrated in Table 1, ethylcyclohexane
and vinylcyclohexane, which may form via the disproportionation of R·,
comprise the majority of the mass balance (15%).
(11) For mechanistic studies, see: (a) Johnson, M. W.; Hannoun, K. I.;
Tan, Y.; Fu, G. C.; Peters, J. C. Chem. Sci. 2016, 7, 4091−4100. (b) Ahn,
J. M.; Ratani, T. S.; Hannoun, K. I.; Fu, G. C.; Peters, J. C. J. Am. Chem.
(12) For leading references to the use of copper complexes in
photocatalysis, see: Paria, S.; Reiser, O. ChemCatChem 2014, 6, 2477−
2483.
(13) For reviews of decarboxylative reactions, see: (a) C−C bond
formation: Patra, T.; Maiti, D. Chem. - Eur. J. 2017, 23, 7382−7401.
Rodriguez, N.; Goossen, L. J. Chem. Soc. Rev. 2011, 40, 5030−5048. (b)
photoredox processes: Jin, Y.; Fu, H. Asian J. Org. Chem. 2017, 6, 368−
385.
(14) Decarboxylative reactions that involve the net extrusion of CO2
from a substrate are well-known (e.g., transition metal-catalyzed
allylation and benzylation: Weaver, J. D.; Recio, A.; Grenning, A. J.;
D
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX