Page 5 of 7
Journal of the American Chemical Society
This work was supported by Award No. R01 GM107204 from the
National Institute of General Medical Sciences.
Our results involving the reactions of alkyl iodides in the
1
2
3
4
5
6
7
8
presence of inhibitors, and in the absence of palladium, suggest
that an alternative mechanistic scenario may be involved. While
palladium is required to abstract an iodine atom to begin the
reaction, upon radical cyclization chain transfer with another
equivalent of substrate is viable (Scheme 2). Furthermore, pal-
ladium is not necessarily required for the dehydrohalogenation
of ATRC iodide products. While other pathways may contrib-
ute overall, in reactions of alkyl iodides involving palladium the
role of the metal as an initiator, rather than catalyst, must be
considered.
REFERENCES
(1) The Mizoroki-Heck Reaction; Oestrich, M., Ed.; John Wiley &
Sons: West Sussex, U.K., 2009.
(2) For reviews on metal-catalyzed cross-coupling reactions employ-
ing unactivated alkyl halides, see: (a) Luh, T.-Y.; Leung, M.-K.; Wong,
K.-T. Chem. Rev. 2000, 100, 3187. (b) Frisch, A. C.; Beller, M. Angew.
Chem. Int. Ed. 2005, 44, 674. (c) Kambe, N.; Iwasaki, T.; Terao, J.
Chem. Soc. Rev. 2011, 40, 4937.
(3) (a) Collman, J. P. Acc. Chem. Res. 1975, 8, 342. (b) Pearson, R.
G.; Figdore, P. E. J. Am. Chem. Soc. 1980, 102, 1541.
(4) (a) Ozawa, F.; Ito, T.; Yamamoto, A. J. Am. Chem. Soc. 1980, 102,
6457. (b) Hartwig, J. Organotransition Metal Chemistry: From Bond-
ing to Catalysis; University Science Books: Sausalito, CA, 2009; Chap-
ter 10, pp 398–402.
(5) Alkyl Mizoroki-Heck-type reactions with styrene: (a) Lebedev, S.
A.; Lopatina, V. S.; Petrov, E. S.; Beletskaya, I. P. J. Organomet. Chem.
1988, 344, 253. Alkyl Mizoroki-Heck-type reactions with alkyl halides
not prone to β-hydride elimination: (b) Bräse S.; Waegell, B.; de Mei-
jere, A. Synthesis 1997, 148.
(6) Alkyl-Mizoroki-Heck-type reactions with superstoichiometric al-
kylmagnesium reagents: (Titanocene catalysis) (a) Terao, J.; Watabe, H.;
Miyamoto, M.; Kambe, N. Bull. Chem. Soc. Jpn. 2003, 76, 2209. (b)
Terao, J.; Kambe, N. Bull. Chem. Soc. Jpn. 2006, 79, 663. (Cobalt cataly-
sis) (c) Affo, W.; Ohmiya, H.; Fujioka, T.; Ikeda, Y.; Nakamura, T.;
Yorimitsu, H.; Oshima, K.; Imamura, Y.; Mizuta, T.; Miyoshi, K. J. Am.
Chem. Soc. 2006, 128, 8068. (d) Wakabayashi, K.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2001, 123, 5374.
(7) Nickel catalysis: (a) Millán, A.; Álvarez de Cienfuegos, L.; Miguel,
D.; Campaña, A. G.; Cuerva, J. M. Org. Lett. 2012, 14, 5984. Gold
catalysis: (b) Xie, J.; Li, J.; Weingand, V.; Rudolph, M.; Hashmi, A. S.
K. Chem. Eur. J. 2016, 22, 12646. Cobalt catalysis: (c) Weiss, M. E.;
Kreis, L. M.; Lauber, A.; Carreira, E. M. Angew. Chem. Int. Ed. 2011,
50, 11125. (d) Busato, S.; Tinembart, O.; Zhang, Z.; Scheffold, R. Tet-
rahedron 1990, 46, 3155. (e) Bhandal, H.; Pattenden, G.; Russell, J. J.
Tetrahedron Lett. 1986, 27, 2299.
(8) Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 11340.
(9) Bloome, K. S.; McMahen, R. L.; Alexanian, E. J. J. Am. Chem.
Soc. 2011, 133, 20146.
(10) For a discussion of the role of metal reagents as catalysts or ini-
tiators in radical-mediated reactions, see: Studer, A.; Curran, D. P.
Angew. Chem. Int. Ed. 2016, 55, 58.
(11) Sargent, B. T.; Alexanian, E. J. J. Am. Chem. Soc. 2016, 138,
7520.
(12) Venning, A. R. O.; Bohan, P. T.; Alexanian, E. J. J. Am. Chem.
Soc. 2015, 137, 3731.
(13) Parasram, M.; Iaroshenko, V. O.; Gevorgyan, V. J. Am. Chem.
Soc. 2014, 136, 17926.
9
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
Scheme 2. Plausible mechanism for the palladium-initiated
carbocyclization of alkyl iodides involving an innate chain
reaction.
I
LnPd0
LnPdII
TsN
TsN
TsN
H
palladium-initiated
innate chain reaction
H
17
TsN
TsN
H
H
17
base or Pd cat.
H
H
I
16
51
n
CONCLUSIONS
In conclusion, we have developed an efficient second-
generation system for the carbocyclization of unactivated alkyl
halides with alkenes. This catalytic system promotes a general
carbocyclization of unactivated alkyl bromides for the first time,
and avoids the undesired use of the CO atmosphere previously
required. This reaction efficiently transforms an array of prima-
ry and secondary alkyl bromides in cyclizations with diverse
alkenes to form valuable 5- and 6-membered carbo- and hetero-
cycles. We propose the reactions of alkyl bromides involve auto-
tandem catalysis, involving the first examples of ATRC with
unactivated alkyl bromides. We anticipate this work will signifi-
cantly expand the use of these catalytic cyclizations in chemical
synthesis and provide important insights into the reactivity of
palladium catalysts with unactivated alkyl halides in new reac-
tion development.
ASSOCIATED CONTENT
Supporting Information
(14) For comparison, reactions involving the alkyl chloride or tosyl-
ate of substrate 8 proceeded with significantly lower yields than the
bromide, providing 6% and <2% 1H NMR yield, respectively, of cy-
clization products after 16 h with significant amounts of starting mate-
rial remaining. Additionally, reactions of the alkyl iodides in Table 2
using the current protocol provided carbocyclization products in gener-
ally poor yields. See the Supporting Information for details.
(15) (a) McMahon, C. M.; Alexanian, E. J. Angew. Chem. Int. Ed.
2014, 53, 5974. (b) Zou, Y.; Zhou, J. Chem. Commun. 2014, 50, 3725.
(16) (a) Liu, H.; Qiao, Z.; Jiang, X. Org. Biomol. Chem. 2012, 10,
7274. (b) Shen, Y.; Cornella, J.; Juliá-Hernández, F.; Martin, R. ACS
Catal. 2017, 7, 409. (c) Monks, B. M.; Cook, S. P. Angew. Chem. Int. Ed.
2013, 52, 14214.
Experimental procedures and spectral data for all new com-
pounds. This material is available free of charge via the Internet
AUTHOR INFORMATION
Corresponding Author
* eja@email.unc.edu
Notes
The authors declare no competing financial interest.
(17) Bissember, A. C.; Levina, A.; Fu, G. C. J. Am. Chem. Soc. 2012,
134, 14232.
ACKNOWLEDGMENT
ACS Paragon Plus Environment