Reductive bromine atom-transfer reaction

Article abstract of DOI:10.1021/ol4011536

Atom-transfer radical (ATR) reactions of alkenes with R-X usually give products having new C-C and C-X bonds at the adjacent carbons. However, when the reaction was carried out under irradiation using a low-pressure Hg lamp, addition/reduction products were obtained in good yield. Hydrogen bromide, formed by H-abstraction of a bromine radical from alkenes, is likely to play a key role in the reductive ATR reaction.

Full text of DOI:10.1021/ol4011536

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Reductive Bromine
Atom-Transfer Reaction
000–000
Shuhei Sumino, Akira Fusano, and Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University,
Sakai, Osaka 599-8531, Japan
ryu@c.s.osakafu-u.ac.jp
Received April 24, 2013
ABSTRACT
Atom-transfer radical (ATR) reactions of alkenes with RÀX usually give products having new CÀC and CÀX bonds at the adjacent carbons.
However, when the reaction was carried out under irradiation using a low-pressure Hg lamp, addition/reduction products were obtained in good
yield. Hydrogen bromide, formed by H-abstraction of a bromine radical from alkenes, is likely to play a key role in the reductive ATR reaction.
1
Ever since Kharasch’s work published in 1940s, atom-
transfer radical (ATR) reactions have found widespread
radical initiators, some ATR reactions of alkyl iodides
are known to proceed under light irradiation conditions in
the absence of radical initiators.
2
3
7
uses in organic synthesis and polymer synthesis. ATR
reactions of alkenes and alkynes provide a useful tool to
create CÀC and CÀX bonds across CÀC double and triple
4À6
bonds.
Whereas archetypal ATR reactions require
Scheme 1. Concept: Reductive ATR Reaction of RBr
(
1) (a) Kharasch, M. S.; Skell, P. S.; Fisher, P. J. Am. Chem. Soc.
1
1
948, 70, 1055. (b) Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science
945, 102, 128.
(
2) (a) Curran, D. P. Synthesis 1988, 489. (b) Jasperse, C. P.; Curran,
D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237. (c) Byers, J. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001; Vol. 1, Chapter 1.5.
(3) Pintauer, T.; Matyjaszewiski, K. In Encyclopedia of Radicals in
Chemistry, Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.;
Wiley-VCH: Weinheim, 2012; Vol. 4, Chapter 62.
(4) (a) Curran, D. P.; Chen, M. H.; Spletzer, E.; Seong, C. M.; Chang,
C. T. J. Am. Chem. Soc. 1989, 111, 8872. (b) Curran, D. P.; Seong, C. M.
J. Am. Chem. Soc. 1990, 112, 9401. (c) Curran, D. P.; Tamine, J. J. Org.
Chem. 1991, 56, 2746.
Generally, ATR reactions of alkyl bromides require
more forcing conditions for the initiation than that of alkyl
iodides due to the stronger CÀX bond. To cleave CÀBr
bonds, photoirradiation with a low pressure mercury
lamp is known to be effective and we recently applied this
methodology to the radical addition reaction of alkyl
(5) (a) Nakamura, T.; Yorimitsu, H.; Shinokubo, H.; Oshima, K.
Synlett 1998, 1351. (b) Yorimitsu, H.; Nakamura, T.; Shinokubo, H.;
Oshima, K.; Omoto, K.; Fujimoto, H. J. Am. Chem. Soc. 2000, 122,
1
1041. (c) Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima, K.;
Omoto, K.; Fujimoto, H. J. Org. Chem. 2001, 66, 7776.
6) (a) Renaud, P.; Ollivier, C.; Panchaud, P. Angew. Chem., Int. Ed.
002, 41, 3460. (b) Panchaud, P.; Ollivier, C.; Renaud, P.; Zigmantas, S.
(
2
8
J. Org. Chem. 2004, 69, 2755. (c) Chabaud, L.; Landais, Y.; Renaud, P.
Org. Lett. 2005, 7, 2587. (d) Sch €a r, P.; Renaud, P. Org. Lett. 2006, 8,
bromides to formaldehyde. In this paper, the radical
addition reaction of R-bromo esters and ketones 1 onto
alkenes 2 was studied under photoirradiation conditions
using a low pressure mercury lamp. The reaction proceeded
1
569. (e) Weidner, K.; Giroult, A.; Panchaud, P.; Renaud, P. J. Am.
Chem. Soc. 2010, 132, 17511.
7) (a) Davies, T.; Haszeldine, R. N.; Tipping, A. E. J. Chem. Soc.,
(
Perkin Trans. 1 1980, 927. (b) Tsuchii, K.; Imura, M.; Kamada, N.;
Hirao, T.; Ogawa, A. J. Org. Chem. 2004, 69, 6658. (c) Slodowicz, M.;
Barata-Vallejo, S.; V ꢀa zquez, A.; Nudelman, N. S.; Postigo, A.
J. Fluorine Chem. 2012, 135, 137.
(8) Kawamoto, T.; Fukuyama, T.; Ryu, I. J. Am. Chem. Soc. 2012,
134, 875.
1
0.1021/ol4011536 r XXXX American Chemical Society

well, but to our surprise it gave the reduced addition
products 4 rather than 3 as major product (Scheme 1, eq 2).
A literature survey showed that only one precedence exists
for “reductive” ATR reaction, which was found in the
reaction of 1-bromo-1-chloro-2,2,2-trifluoroethane and
a
Table 2. Reaction of R-Bromo Carbonyl Compounds and Olefins
allylaromatics with sodium dithionite in MeCN/H O solu-
2
9
tion. In this paper, we present the unusual reductive ATR
reaction, which serves as the hydroalkylation of alkenes.
a
Table 1. Reductive ATR Reaction
yield (%)
b
c
entry conc of 1a (M)
solvent (mL)
filter
3a
4a
1
2
3
4
5
6
7
0.1
C
C
C
6
6
6
H
H
H
6
6
6
(5)
(5)
(5)
quartz 16
Pyrex
quartz 18
quartz
59
0
0.1
0
d
0.1
54
b
0.1
MeCN (5)
hexane (5)
4
52
62
69
74
0.1
quartz 21
0.1
hexane/H
hexane/H
2
O (5/0.05) quartz 16
0.025
2
O (10/0.1) quartz
4
a
Conditions: 1a (0.5 mmol), 2a (5 mmol), solvent (5 mL), hν
low-pressure mercury lamp, 6 W, quartz), 6 h. NMR yield. Isolated
yield. The reaction was performed for 12 h under irradiation of 500 W
xenon lamp.
b
c
(
d
We examined the reaction of ethyl R-bromoacetate (1a)
and 1-hexene (2a) as a model reaction under a variety of
conditions (Table 1). When a benzene solution of 1a
(
0.1 M) and 2a (10-fold excess) was irradiated using a
low-pressure mercury lamp (6 W) through a quartz glass
tube, ethyl caprylate (4a) was obtained in a 59% yield
together with 16% yield of the brominated ATR product
3
a (Table 1, entry 1). The photoirradiation reaction did not
proceedwhena Pyrexfilterwas used(Table 1, entry2). The
suitability of a xenon lamp (500 W) was also tested and
gave a similar result to that of the mercury lamp (Table 1,
entry 3). Among the solvents tested, hexane plus a small
amount of water gave the best yield (Table 1, entry 6).
Reducing the concentration of [1a] = 0.025 M also con-
tributed to increase the yield up to 74% (Table 1, entry 7).
With optimized reaction conditions (Table 1, entry 7) in
hand, we then examined the generality of the reductive
ATR reaction using a variety of alkyl bromides 1 and
alkenes 2, the results of which are summarized in Table 2.
The reaction of 1a and terminal alkenes 2a, 2b, 2c, and 2d
gave good to modest yields of the expected reductive ATR
products 4a, 4b, 4c, and 4d, respectively (Table 2, entries
1
À4). The reaction of 1a with methylenecyclohexane (2e)
proceeded smoothly to give the adduct 4e quantitatively
Table 2, entry 5). Disubstituted alkene 2f gave 4f in 71%
yield (Table 2, entry 6). Vinyl ether 2g and 1-octyne (2h)
a
The reaction was performed by using 1 (0.25 mmol), 2 (2.5 mmol),
O (10 mL/100 μL) for 6 h under photoirradiation
conditions. Isolated yield. 25 mmol of 2a was used.
and hexane/H
2
b
c
(
also participated in the reductive ATR reaction, giving 4g
and 4h respectively in modest yields (Table 2, entries
(
9) (a) Ignatowska, J.; Dmowski, W. J. Fluorine Chem. 2006, 127,
7
20. (b) Dmowski, W. J. Fluorine Chem. 2011, 132, 504.
B
Org. Lett., Vol. XX, No. XX, XXXX

7
1
and 8). Cyclic R-bromo ester 1b and R-bromo-malonate
c also gave the corresponding addition/reduction prod-
To further support this scenario, we were able to detect
dimer 6 formed from 2-cyclooctenyl radical, in the reaction
of 1a with 2f (Scheme 2, eq 3).
ucts (Table 2, entries 9À11). Reaction of methyl bromo-
difluoroacatate (1d) with 2a and 2f gave 4l and 4m,
respectively (Table 2, entries 12 and 13). On the other
hand, the reaction of R-bromo acetophenone (1e) with
Taking these observations together, we propose a non-
chain radical reaction mechanism for the unusual reduc-
tive ATR reaction (Figure 1). First, photoinduced
homolysis of CÀBr bond of 1a would take place to give
alkyl radical A and Br radical. While A would add to
alkene to form a new radical B, Br radical would abstract
hydrogen from the allylic position of alkene to give HBr
and allyl radical C, which would then undergo dimeriza-
1
-hexene under standard conditions gave 4n in very low
yield due to the formation of acetophenone, the directly
reduced product. When a large excess of 1-hexene (100
fold) was used, 4n was obtained in a 58% yield (Table 2,
entry 14). Under the same conditions, R-bromo ketone 1f
gave 4o in 62% yield (Table 2, entry 15).
1
1
tion to giveD. Radical B abstracts hydrogen from HBr to
give the product E and the liberated Br radical would again
abstract hydrogen from another molecule of alkene. In
this reaction, the addition of water suppressed the reaction
Scheme 2. Experiments To Investigate the Reaction Mechanism
1
2
of alkene with HBr. Recently, the Wood group and
1
3
the Renaud group reported that trialkylborane/water
or B-alkylcatecholborane/methanol complexes, respectively,
can serve as effective H atom donors. In this regard, we are
now curious about the possibility of using a HBr/water
14
complex, such as F, to serve as a good hydrogen donor.
To gain some insight into the reaction mechanism, we
conducted several experiments whose results are shown in
Scheme 2. The addition of of 2,2,6,6-tetramethyl-1-piper-
idinyloxy (TEMPO) to the reaction of 1a with 2a comple-
tely suppressed the formation of product (4a), instead
giving the TEMPO adduct 5 in 69% yield (Scheme 2,
eq 1). This suggested that homolysis of the CÀBr bond by
photoirradiation worked well in the present system. To
determine the source of hydrogen at the 3-position, we
carried out deuterium-labeling experiments (Scheme 2,
eq 2). Whereas no deuterium incorporation was observed
from cyclohexane-d , added as the solvent, the addition of
Figure 1. Possible reaction mechanism.
1
2
In summary, we have demonstrated the unusual reductive
atom-transfer addition of RÀBr to alkenes under photo-
irradiation conditions. The interplay of CÀC bond-form-
ing reaction and reduction in the absence of any reducing
reagent is an interesting feature of the present reaction. We
propose a nonchain radical mechanism involving CÀBr
homolysis and rapid conversion of the resulting bromine
radical to HBr by H-abstraction of alkenes. We are now
exploring other applications of bromine radical mediated
deuterium oxide caused the deuteration at the 3-position
with a D/H ratio of 90:10. On the basis of these ob-
servations, we speculated that HBr would be generated
by abstraction of the allylic hydrogen of the alkene by
1
0
bromine radical which acts as radical scavenger, given
that the D/H scrambling of HBr by D O is quite rapid.
2
(
10) Matsubara, H.; Tsukida, M.; Ishihara, D.; Kuniyoshi, K.; Ryu,
I. Synlett 2010, 2014.
11) For bromine radical abstraction of hydrogen from the allylic
(
position, see; Kharasch, M. S.; Schwartz, D.; Nudenberg, W. J. Org.
Chem. 1953, 18, 337.
(13) (a) Pozzi, D.; Scanlan, E. M.; Renaud, P. J. Am. Chem. Soc.
2005, 127, 14204. (b) Povie, G.; Marzorati, M.; Bigler, P.; Renaud, P.
J. Org. Chem. 2013, 78, 1553.
(12) Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros,
M. R.; Wood, J. L. J. Am. Chem. Soc. 2005, 127, 12513.
(14) We thank a reviewer for calling our attention to this possibility.
Org. Lett., Vol. XX, No. XX, XXXX
C

reductive CÀC bond-forming reactions and the precise
Supporting Information Available. Experimental proce-
dure and compound characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
role of water in this reaction.
Acknowledgment. I.R. acknowledges MEXT and JSPS
for funding of this work.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX