Journal of the American Chemical Society
Page 4 of 5
Table 3. Examination of alternative reductantsa
hydrogen-atom abstraction mechanism. Complete results of our
1
2
3
4
5
6
7
8
mechanistic studies will be reported in due course.
O
Br
Br
Acknowledgement. Support was provided by NIHGMS (R01
GM078201-05) and gifts from Merck and Abbvie.
Ir
Ni
O
MeO2C
MeO2C
reductant
Supporting Information Available. Experimental procedures
and spectral data are provided. This material is available free of
base, DME
sp3–sp2 product
alkyl halide
aryl halide
yieldb
entry
reductant
photocatalyst
References
9
1
2
3
4
5
6
7
Hantzsch ethyl ester
(MeO)3SiH or Et3SiH
TTMSS
1
0%c
0%
(1) (a) de Meijere, A.; Diederich, F. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004. (b) Jana, R.; Pathak, T. P.;
Sigman, M. S. Chem. Rev. 2011, 111, 1417.
(2) For some reviews on the use of nickel in cross-coupling methods: (a) Tasker,
S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299. (b) Netherton,
M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346, 1525. (c) Frisch, A. C.; Beller,
M. Angew. Chem. Int. Ed. 2005, 44, 674. (d) Rudolph, A.; Lautens, M. Angew.
Chem. Int. Ed. 2009, 48, 2656. (e) Nakamura, M.; Ito, S. In Modern Arylation
Methods; Ackermann, L., Ed.; Wiley: Weinheim, 2009.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Ir(ppy)3
0%
TTMSS
Ru(bpy)3(PF6)2
0%
TTMSS
Ru(phen)3Cl2
0%
Ph3SiH
1
1
50%
18%
Me2(TMS)SiH
(3) Knappke, C. E. I.; Grupe, S.; Gärtner, D.; Corpet, M.; Gosmini, C.; Jacobi von
Wangelin, A. Chem. Eur. J. 2014, 20, 6828.
aAll reactions followed the general conditions described in SI. bYields were
obtained by 1H NMR of the crude reaction mixture with mesitylene as internal
standard. cYielded 80% of the homocoupled biaryl product.
(4) (a) Czaplik, W. M.; Mayer, M.; Jacobi von Wangelin, A. Synlett 2009, 18,
2931. (b) Czaplik, W. M.; Mayer, M.; Jacobi von Wangelin, A. Angew. Chem.
Int. Ed. 2009, 48, 607. (c) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am.
Chem. Soc. 2009, 131, 15592. (d) Lipshutz, B. H.; Ghorai, S.; Yi Leong, W.
W.; Taft, B. R. J. Org. Chem. 2011, 76, 5061. (e) Duplais, C.; Krasovskiy, A.;
Lipshutz, B. H. Organometallics 2011, 30, 6090. (f) Gosmini, C.; Bassene-
Ernst, C.; Durandetti, M. Tetrahedron 2009, 65, 6141. (g) Amatore, M.;
Gosmini, C. Chem. Eur. J. 2010, 16, 5848.
(5) (a) Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010, 132,
920. (b) Everson, D. A.; Jones, B. A.; Weix, D. J. J. Am. Chem. Soc. 2012,
134, 6146. (c) Biswas, S.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 16192.
(d) Wang, S.; Qian, Q.; Gong, H. Org. Lett. 2012, 14, 3352. (e) Xu, H.; Zhao,
C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci. 2013, 4, 4022. (f) Molander, G.
A.; Traister, K. M.; O’Neill, B. T. J. Org. Chem. 2014, 79, 5771. (g)
Molander, G. A.; Traister, K. M.; O’Neill, B. T. J. Org. Chem. 2015, 80,
2907. (h) Bhonde, V. R.; O’Neill, B. T.; Buchwald, S. L. Angew. Chem. Int.
Ed. 2016, 55, 1849.
(6) Terrett, J. A.; Cuthbertson, J. D.; Shurtleff, V. W.; MacMillan, D. W. C.
Nature 2015, 524, 330.
(7) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.; MacMillan, D.
W. C. Science 2014, 345, 437.
(8) (a) Tellis, J. C.; Primer, D. N.; Molander, G. A. Science 2014, 345, 433. (b)
Chu, L.; Lipshultz, J. M.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2015,
54, 7929.
(9) (a) Noble, A.; McCarver, S. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2015,
137, 624. (b) Zuo, Z.; Cong, H.; Li, W.; Choi, J.; Fu, G. C.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2016, 138, 1832. (c) Gutierrez, O.; Tellis, J. C.; Primer,
D. N.; Molander, G. A.; Kozlowski, M. C. J. Am. Chem. Soc. 2015, 137, 4896.
(10) (a) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188. (b) Chatgilialoglu, C.;
Lalevée, J. Molecules 2012, 17, 527. (c) Chatgilialoglu, C. Organosilanes in
Radical Chemistry; Wiley: Chichester, 2004. (d) Ballestri, M.; Chatgilialoglu,
C. J. Org. Chem. 1991, 56, 678.
(11) For Si–Br BDE, see: Walsh, R. Acc. Chem. Res. 1981, 14, 246. For C–Br
BDE, see: Gordon, A. J.; Ford, R. A. The Chemist’s Companion: A Handbook
of Practical Data, Techniques, and References; Wiley: New York, 1972.
(12) dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-trifluoromethylpyridine, dtbbpy = 4,4'-
di-t-Bu-2,2'-bipyridine
technologies, performed well under these conditions (entries 23
and 24, 60% and 66% yield, respectively).19
We next examined the generality of the photoredox silyl-
abstraction coupling with respect to the alkyl halide fragment. In
addition to the 6-membered tetrahydropyran model substrate, 7-
and 5-membered cyclic systems were also tolerated (entries 25–
27, 66–80% yield), along with an acyclic secondary alkyl halide
(entry 28, 75% yield). Moreover, smaller strained ring systems
such as cyclobutane, cyclopropane, azetidine, and oxetane
bromides were shown to work in good measure (entries 29–32,
32–92% yield). Primary alkyl bromide precursors were indeed
highly successful reaction partners (entries 33 and 34, 82% and
92% yield), and notably, methoxymethyl-chloride was viable to
deliver an α-oxy adduct in 58% yield (entry 35). Sterically-
encumbered primary bromides were shown to be competent
substrates, with the neopentylarene product being readily
generated (entry 36, 77% yield). Interestingly, methylation of
aryl bromides was successfully achieved with easy-to-handle
reagents, methyl tosylate and LiBr, (entry 37, 62% yield), a
result that we believe will have ramifications for isotopic
labeling protocols.20 We were also delighted to find that tertiary
alkyl bromides readily couple with aryl halides as entries 38 and
39 demonstrate to incorporate tert-butyl and 1-adamantyl
moieties with synthetically useful 52% and 62% yields,
respectively. Given the generality demonstrated in these studies,
we expect this light-mediated cross-electrophile coupling to be
useful for fragment-couplings towards a large range of medicinal
agents and complex targets.
(13) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal, R. A., Jr.;
Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005, 17, 5712.
(14) The oxidation potential of lithium bromide was measured in DME following
the methods in: (a) Andrieux, C. P.; Gonzalez, F.; Saveant, J. J. Electroanal.
Chem. 2001, 498, 171. (b) Galicia M.; Gonzalez, F. J. J. Electrochem. Soc.
2002, 149, D46. See Supporting Information for cyclic voltammogram. (c) For
other potential mechanisms to generate the halogen radical, see: Hwang, S. J.;
Power, D. C.; Maher, A. G.; Anderson, B. L.; Hadt, R. G.; Zheng, S.-L.; Chen,
Y.-S.; Nocera, D. G. J. Am. Chem. Soc. 2015, 137, 6472.
(15) On the lability of halides on nickel salts: (a) Klein, A.; Kaiser, A.; Sarkar, B.;
Wanner, M.; Fiedler, J. Eur. J. Inorg. Chem. 2007, 965. (b) Klein, A.;
Budnikova, Y. H.; Sinyahsin, O. G. J. Organomet. Chem. 2007, 692, 3156.
(16) Biswas, S.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 16192.
(17) For Stern-Volmer data of the bromide, see Supporting Information.
(18) Piva da Silva, G.; Ali, A.; César da Silva, R.; Jiang, H.; Paixão, M. W. Chem.
Commun. 2015, 51, 15110.
Preliminary experiments were carried out to gain a deeper
understanding of the role of TTMSS. As shown in Table 3,
replacement of the silane with Hantzsch ethyl ester gave no
desired product and only formation of the homocoupled biaryl
product was observed (entry 1).21 In addition, other commonly
used silanes for reduction of Ni intermediates to Ni0 resulted in
no observable efficiency (entry 2).22 Moreover, the use of
photocatalysts with diminished oxidizing capacity also failed to
give the desired coupled adduct (entries 3–5). Together, these
observations suggest that our coupling strategy does not operate
via a direct reduction of either the photocatalyst or the nickel
catalyst. While further studies are currently being carried out to
confirm the presence of a silyl radical during the course of the
reaction, we were encouraged to observe a correlation between
the reaction efficiency and the Si–H BDEs (entries 6 and 7).10
We believe the dependence on the Si–H strength is in line with a
(19) Su, M.; Buchwald, S. L. Angew. Chem. Int. Ed. 2012, 51, 4710.
(20) Miller, P. W.; Long, N. J.; Vilar, R.; Gee A. D. Angew. Chem. Int. Ed. 2008,
47, 8998.
(21) The formation of biaryl product instead of the desired cross-coupled product
may be attributed to the replacement of a silicon-based hydrogen atom source
by
a carbon-based hydrogen atom source. Elimination of the silicon
component, while maintaining the reducing ability of the system,
demonstrates the non-innocent role of the silane.
(22) Jackson, E. P.; Montgomery, J. J. Am. Chem. Soc. 2015, 137, 958.
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