Silver-catalyzed cross-coupling reactions of alkyl bromides with alkyl or aryl Grignard reagents

Article abstract of DOI:10.1016/j.tetlet.2009.02.040

Treatment of secondary or tertiary alkyl bromides with alkyl Grignard reagents in the presence of catalytic amounts of silver bromide and potassium fluoride in CH₂Cl₂ afforded the corresponding cross-coupling products in reasonable yields. Moreover, silver showed catalytic activity for the cross-coupling reactions of alkyl bromides with aryl Grignard reagents.

Full text of DOI:10.1016/j.tetlet.2009.02.040

Tetrahedron Letters 50 (2009) 3270–3272
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Tetrahedron Letters
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Silver-catalyzed cross-coupling reactions of alkyl bromides with alkyl
or aryl Grignard reagents
*
*
Hidenori Someya, Hideki Yorimitsu , Koichiro Oshima
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of secondary or tertiary alkyl bromides with alkyl Grignard reagents in the presence of cata-
lytic amounts of silver bromide and potassium fluoride in CH2Cl2 afforded the corresponding cross-cou-
pling products in reasonable yields. Moreover, silver showed catalytic activity for the cross-coupling
reactions of alkyl bromides with aryl Grignard reagents.
Received 6 January 2009
Revised 3 February 2009
Accepted 6 February 2009
Available online 10 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Transition-metal-catalyzed cross-coupling reactions of alkyl ha-
lides with Grignard reagents are very useful methods for carbon–
carbon bond formation in organic synthesis.1 Among them, the
use of unactivated secondary or tertiary alkyl halides as substrates
is more difficult than that of primary alkyl halides, due to the faster
b-hydride elimination from the corresponding alkyl transition-me-
tal intermediates. Recently, the cross-coupling reactions of unacti-
vated secondary alkyl halides with aryl,2 alkenyl,3 or alkynyl3a
Grignard reagents have been achieved. However, the cross-cou-
pling reactions of unactivated secondary alkyl halides with alkyl
Grignard reagents are still rare, and have to be established.1,4
Recently, we have reported silver-catalyzed coupling reactions
of alkyl halides with benzyl and allyl Grignard reagents.5 In these
reactions, secondary and tertiary alkyl halides can be employed
as substrates. Along the line of our studies on silver-catalyzed cou-
pling reactions, here we wish to report silver-catalyzed cross-cou-
pling reactions of alkyl bromides with alkyl or aryl Grignard
reagents.6
yield (entry 5). AgF was not effective (entry 6).10 Even though both
AgF and LiBr were added, the product 2a was obtained in only 23%
yield (entry 7). Although the role of KF is not clear at this stage, KF
would dissociate the aggregation of AgBr or stabilize alkylsilver
intermediates by coordination to the silver metal.11
The silver-catalyzed alkylation reactions (10 mol % AgBr/KF) of
various substrates are summarized in Table 2.12 Both cyclic and
acyclic secondary alkyl bromides underwent the alkylation reac-
tions (Table 2, entries 1–4). The reaction of tertiary alkyl halide
1e suffered from a moderate yield (entry 5). In this case, 2-meth-
yldecane was mainly obtained. Although the reaction of 1-bromo-
adamantane (1f) was slow, it resulted in a reasonable yield of 2f
(entry 6). It is quite interesting that tertiary alkyl bromides can
be used as reaction partners.1 The substrates having functional
groups such as THP ether and sulfonamide could be also employed
(entries 7 and 8). The reaction of 1-bromooctane (1i) resulted in
low yield (entry 9).
Treatment of 2-bromooctane (1a) with 3-phenylpropylmagne-
sium bromide in the presence of a catalytic amount of AgCl in
Et2O afforded the cross-coupling product 2a in 34% yield (Table
1, entry 1). When we used PdCl2, NiCl2, FeCl3, or CuCl without
any ligands instead of AgCl, only trace amounts of 2a were de-
tected. After optimizing reaction conditions, we found that AgBr
was the most effective catalyst (entry 2). Using CH2Cl2 as a solvent
improved the yield slightly (entry 3).7 We thought that the low
yields were due to the decomposition of alkylsilver intermediates
at room temperature, because octane, propylbenzene, and allyl-
benzene were mainly produced.8,9 Indeed, the better yield was
achieved at À10 °C (entry 4). The reaction in entry 4 showed poor
reproducibility. When 10 mol % KF was added, we could reproduce
the result and obtain the corresponding coupling product 2a in 68%
Table 1
Optimization of conditions
Mtl (10 mol %)
BrMg
Ph
Ph
nC6H13
1a
Br
nC6H13
15 h
3
3
2.0 equiv
Solvent
2a
Entry
Mtl
Temp (°C)
Yielda (%)
1
2
3
4
5
6
7
AgCl
AgBr
AgBr
AgBr
Et2O
Et2O
25
25
34b
45
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
47
À10
À10
À10
À10
44–62
68
AgBr/KF
AgF
AgF/LiBr
<5c
23d
a
b
c
Based on NMR analysis.
3% of 1a was recovered.
26% of 1a was recovered.
11% of 1a was recovered.
* Corresponding authors. Tel.: +81 75 383 2441; fax: +81 75 383 2438 (K.O.).
E-mail addresses: yori@orgrxn.mbox.media.kyoto-u.ac.jp (H. Yorimitsu), oshima
@orgrxn.mbox.media.kyoto-u.ac.jp (K. Oshima).
d
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.040

H. Someya et al. / Tetrahedron Letters 50 (2009) 3270–3272
3271
Table 2
refluxing hexane afforded the cross-coupling product 3c in 81%
yield (Table 3, entry 2).14,15 Acyclic alkyl bromides as well as cyclic
ones underwent the reactions (entry 1). The reaction of 1-bromo-
adamantane (1f) took 10 h for completion (entry 3). Primary alkyl
bromide 1i underwent the phenylation to give 3i in high yield (en-
try 4).
Silver-catalyzed alkylation of alkyl bromidesa
AgBr (10 mol %)
KF (10 mol %)
BrMg
Ph
Alkyl
Ph
Alkyl Br
3
CH2Cl2/Et2O
3
1
2
1.8 equiv
º
10 C, 15 h
—
o-Tolyl Grignard reagent can be also employed to afford the cor-
responding product 4 in 90% yield (Scheme 2).
Entry
Alkyl-Br
2
Yieldb (%)
Treatment of 1,10-dibromoundecane (1j) with pentylmagne-
sium bromide under the AgBr/KF-catalyzed alkylation conditions
afforded monoalkylated product 5a in 55% yield (Scheme 3). Dial-
kylated product 5b was not detected. The reaction of 1j with phen-
ylmagnesium bromide under the AgBr/P(OPh)3-catalyzed arylation
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
2a
62
nC6H13
Br
2b
2c
2d
2e
2f
57
66
69
36
69c
Br
Br
Table 3
Silver-catalyzed phenylation of alkyl bromidesa
AgBr (10 mol %)
P(OPh)3 (10 mol %)
BrMg
Alkyl
Br
Alkyl Br
Hexane/Et2O
reflux, 5 h
1.6 equiv
1
3
nC8H17
Br
Entry
Alkyl-Br
3
Yieldb (%)
63
1
2
3
4
1a
1c
1f
1i
3a
nC6H13
Br
Br
Br
O
O
7
1g
2g
58
3c
3f
3i
81
9
Br
Br Ts
61c
88
8
9
1h
1i
2h
2i
44
20
N
Br
9
nC8H17 Br
nC8H17 Br
a
b
c
The Grignard reagent was 2.0 M Et2O solution.
Isolated yields.
Performed with 3.0 equiv of the Grignard reagent at 25 °C for 64 h.
a
b
c
The Grignard reagent was 1.0 M Et2O solution.
Isolated yields.
Performed for 10 h.
AgBr (10 mol %)
P(OPh)3 (10 mol %)
An alkyl Grignard reagent bearing a terminal alkene moiety re-
BrMg
acted with secondary alkyl bromide 1d smoothly to afford 2j in
63% yield (Scheme 1). Although KF was added in this alkylation
reaction, the reaction conditions were compatible with a tert-
butyldimethylsiloxy group. Unfortunately, the reactions with sec-
ondary and tertiary alkyl Grignard reagents afforded only trace
amounts of the corresponding coupling products under these reac-
tion conditions.13
1c
Hexane/Et2O
reflux, 5 h
1.6 equiv
4 90%
Scheme 2. Reaction with o-tolyl Grignard reagent.
Next, we applied the silver catalysis to the cross-coupling reac-
tions with phenyl Grignard reagent. Under the conditions with KF,
we could not obtain the phenylated product and the starting mate-
rial was recovered. After reoptimization of reaction conditions, we
found that treatment of bromocyclohexane (1c) with phenylmag-
nesium bromide in the presence of 10 mol % AgBr/P(OPh)3 in
AgBr (10 mol %)
KF (10 mol %)
Br
1j 9
BrMg nC5H11
1.8 equiv
Br
CH2Cl2/Et2O
—10 ºC, 15 h
nC5H11
nC5H11
1j
Br
nC5H11
5b not 9detected 0%
9
5a 55%
AgBr (10 mol %)
KF (10 mol %)
BrMg
1.8 equiv
AgBr (10 mol %)
P(OPh)3 (10 mol %)
1d
1d
3
CH2Cl2/Et2O
—10 ºC, 15 h
2j 63%3
1j
BrMg Ph
1.6 equiv
Hexane/Et2O
reflux, 5 h
Ph
Ph
same as above
BrMg
1.8 eq6uiv
OSitBuMe2
1j
OSitBuMe2
6
2k 68%
Br
Ph
9
6a 439%
11%
6b 16%
Scheme 1. Scope of alkyl Grignard reagents.
Scheme 3. Comparison of the reactivities of primary and secondary alkyl bromides.

3272
H. Someya et al. / Tetrahedron Letters 50 (2009) 3270–3272
2. (a) Martin, R.; Fürstner, A. Angew. Chem., Int. Ed. 2004, 43, 3955–3957; (b)
Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126,
3686–3687; (c) Ohmiya, H.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2006,
128, 1886–1889; (d) Cahiez, G.; Habiak, V.; Duplais, C.; Moyeux, A. Angew.
Chem., Int. Ed. 2007, 46, 4364–4366; (e) Yasuda, S.; Yorimitsu, H.; Oshima, K.
Bull. Chem. Soc. Jpn. 2008, 81, 287–290; (f) Cahiez, G.; Chaboche, C.; Duplais, C.;
Moyeux, A. Org. Lett. 2009, 11, 277–280.
3. (a) Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2006, 8, 3093–3096; (b)
Guérinot, A.; Reymond, S.; Cossy, J. Angew. Chem., Int. Ed. 2007, 46, 6521–6524;
(c) Cahiez, G.; Duplais, C.; Moyeux, A. Org. Lett. 2007, 9, 3253–3254.
4. (a) Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu, H.; Kambe, N. Angew. Chem., Int.
Ed. 2007, 46, 2086–2089; (b) Cahiez, G.; Chaboche, C.; Duplais, C.; Giulliani, A.;
Moyeux, A. Adv. Synth. Catal. 2008, 350, 1484–1488.
conditions yielded monophenylated product 6a and diphenylated
product 6b in 43% and 16% yields, respectively. The fact that sec-
ondary alkyl bromide reacted faster than primary one suggested
that these reactions would involve the generation of the corre-
sponding carbocation or carbon-centered radical intermediates
from alkyl bromides.
In summary, we have developed the silver-catalyzed coupling
reaction of alkyl bromides with alkyl or aryl Grignard reagents,
where secondary and tertiary alkyl bromides can be used as sub-
strates. The present results unveil the new catalytic potential of silver.
5. Someya, H.; Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2008, 10, 969–971.
6. Silver is an effective catalyst for the coupling reaction of alkyl Grignard reagent
R1MgX with alkyl halide R2MgX when the alkyl groups are the same (R1 = R2). (a)
Kochi, J. K. J. Organomet. Chem. 2002, 653, 11–19; (b) Tamura, M.; Kochi, J. K.
Synthesis 1971, 303–305.
Acknowledgments
This work was supported by Grants-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science
and Technology, Government of Japan. H.S. acknowledges JSPS
for financial support.
i
7. The reactions in hexane, toluene, Pr2O, and THF resulted in lower yields (10–
30%).
8. Whitesides, G. M.; Bergbreiter, D. E.; Kendall, P. E. J. Am. Chem. Soc. 1974, 96,
2806–2813.
9. Alkylsilver intermediates would be generated from alkyl halides and/or alkyl
Grignard reagents.
10. Hatakeyama, T.; Nakamura, M. J. Am. Chem. Soc. 2007, 129, 9844–9845.
11. Westmijze, H.; Kleijn, H.; Vermeer, P. J. Organometal. Chem. 1979, 172, 377–
383.
12. We also detected alkenes and alkanes in these reactions. The alkanes were the
main byproducts.
13. The reactions of 3-bromo-1-phenylbutane with cyclopentylmagnesium
bromide and with tert-butylmagnesium bromide afforded the corresponding
coupling products in 13% and 5% yields, respectively.
14. The reactions in CH2Cl2, Et2O, and THF resulted in lower yields. The reaction in
pentane resulted in a similar yield with a prolonged reaction time of 11 h.
15. When pyridine, dppe, P(OMe)3, and KF were used as additives in refluxing
hexane, 3c was obtained in 44%, 16%, 54%, and 56% yields, respectively. When
no additive was used, 3c was obtained in 41% yield.
Supplementary data
Supplementary data (experimental details, and characterization
data of 1g, 1h, 1j, and the products) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2009.02.040.
References and notes
1. (a) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674–688; (b) Terao, J.;
Kambe, N. Acc. Chem. Res. 2008, 41, 1545–1554.