Silver-catalyzed benzylation and allylation reactions of tertiary and secondary alkyl halides with grignard reagents

Article abstract of DOI:10.1021/ol800038a

Treatment of alkyl halides, including tertiary alkyl bromides, with benzylic or allylic Grignard reagent in the presence of a catalytic amount of silver nitrate in ether yielded the corresponding cross-coupling products in high yields. The coupling reactions of tertiary alkyl halides provide efficient access to quaternary carbon centers.

Full text of DOI:10.1021/ol800038a

ORGANIC
LETTERS
2008
Vol. 10, No. 5
969-971
Silver-Catalyzed Benzylation and
Allylation Reactions of Tertiary and
Secondary Alkyl Halides with Grignard
Reagents
Hidenori Someya, Hirohisa Ohmiya, Hideki Yorimitsu,* and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
yori@orgrxn.mbox.media.kyoto-u.ac.jp; oshima@orgrxn.mbox.media.kyoto-u.ac.jp
Received January 8, 2008
ABSTRACT
Treatment of alkyl halides, including tertiary alkyl bromides, with benzylic or allylic Grignard reagent in the presence of a catalytic amount of
silver nitrate in ether yielded the corresponding cross-coupling products in high yields. The coupling reactions of tertiary alkyl halides provide
efficient access to quaternary carbon centers.
Recent researches in transition-metal-catalyzed cross-
coupling reactions pursue much wider scope for establishing
universal cross-coupling methodology and new catalysts that
exhibit extremely high catalytic activity and/or unique
reactivity. Among them, replacement of palladium and nickel
catalysts by other transition metal catalysts has been attracting
increasing attention. The replacement does not only offer
economical and environmental advantages but also results
in discovery of new reactivity. The success of copper,1
manganese,2 cobalt,3 and iron4 catalysts in cross-coupling
reactions prompted us to survey other transition metals
further, the catalytic performance of which remains unex-
plored in the field of cross-coupling reactions. Here we report
that silver salts can efficiently catalyze cross-coupling
reactions of alkyl halides5,6 including tertiary alkyl halides
with benzyl or allyl Grignard reagent. Use of tertiary alkyl
halides as a coupling partner is still challenging7 and has to
be established.
Treatment of 2-methyl-2-bromodecane (1a) with benzyl-
magnesium bromide in the presence of a catalytic amount
of silver nitrate in ether afforded the cross-coupling product
2a in high yield (Table 1, entry 1).8-11 The silver-catalyzed
(4) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem.
Soc. 2004, 126, 3686. (b) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297.
(c) Fu¨rstner, A.; Martin, R. Angew. Chem., Int. Ed. 2004, 43, 3955. (d)
Hatakeyama, T.; Nakamura, M. J. Am. Chem. Soc. 2007, 129, 9844. (e)
Cahiez, G.; Habiak, V.; Duplais, C.; Moyeux, A. Angew. Chem., Int. Ed.
2007, 46, 4364. (f) Gue´rinot, A.; Reymond, S.; Cossy, J. Angew. Chem.,
Int. Ed. 2007, 46, 6521. (g) Bedford, R. B.; Betham, M.; Bruce, D. W.;
Danopoulos, A. A.; Frost, R. M.; Hird, M. J. Org. Chem. 2006, 71, 1104.
(5) Silver is an effective catalyst for the coupling reaction of alkyl
Grignard reagent and alkyl halide when the alkyl groups are the same. (a)
Kochi, J. K. J. Organomet. Chem. 2002, 653, 11. (b) Tamura, M.; Kochi,
J. K. Synthesis 1971, 303.
(6) Silver-catalyzed oxidative homocoupling reactions of Grignard
reagents were reported. (a) Nagano, T.; Hayashi, T. Chem. Lett. 2005, 34,
1152. (b) Tamura, M.; Kochi, J. K. Bull. Chem. Soc. Jpn. 1972, 45, 1120.
(7) (a) Tsuji, T.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2002,
41, 4137. (b) Ohmiya, H.; Tsuji, T.; Yorimitsu, H.; Oshima, K. Chem. Eur.
J. 2004, 10, 5640.
(1) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 149. (b) Do,
H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404. (c) Terao, J.;
Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646.
(d) Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu, H.; Kambe, N. Angew.
Chem., Int. Ed. 2007, 46, 2086. (e) Burns, D. H.; Miller, J. D.; Chan, H.
K.; Delaney, M. O. J. Am. Chem. Soc. 1997, 119, 2125. (f) Cahiez, G.;
Chaboche, C.; Jezequel, M. Tetrahedron 2000, 56, 2733. (g) Herber, C.;
Breit, B. Eur. J. Org. Chem. 2007, 3512.
(2) (a) Cahiez, G.; Marquais, S. Synlett 1993, 56. (b) Kang, S.-K.; Kim,
J.-S.; Choi, S.-C. J. Org. Chem. 1997, 62, 4208. (c) Rueping, M.;
Ieawsuwan, W. Synlett 2007, 247.
(3) (a) Cahiez, G.; Avedissian, H. Tetrahedron Lett. 1998, 39, 6159. (b)
Yorimitsu, H.; Oshima, K. Pure Appl. Chem. 2006, 78, 441.
10.1021/ol800038a CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/02/2008

Secondary alkyl bromides and iodide underwent the
benzylation, although a higher catalyst loading was necessary
(entries 7-9). The reaction of primary alkyl halides suffered
from low yields (entries 10 and 11). Secondary and primary
alkyl chlorides resisted the reaction.
Table 1. Silver-Catalyzed Benzylation of Alkyl Halidesa
A benzylic Grignard reagent having a methyl group at the
ortho position reacted with tertiary alkyl bromide 1a
smoothly to yield 2i in good yield (Scheme 1). Methoxy and
Scheme 1. Scope of Benzylic Grignard Reagents
fluoro groups did not retard the reaction significantly. The
steric as well as electronic factor of the benzylic Grignard
reagents is thus moderate. Under similar reaction conditions,
attempted phenylation, methylation, and butylation failed to
afford the corresponding coupling products.
We reported cobalt-catalyzed benzylation reaction of alkyl
halides with benzylmagnesium bromide.7b The present silver-
catalyzed reaction is much more efficient in terms of catalyst
loading, reactivity, yield, and scope of the substrates. For
instance, the cobalt-catalyzed reaction was not useful for
benzylation of tertiary alkyl halides.
a Conditions: 1 (0.50 mmol), benzylmagnesium bromide (0.65 mmol,
1.0 M in ether), ether (2 mL). b Performed in refluxing ether for 10 h.
c Performed for 24 h. d trans/cis ) 81:19. e trans/cis ) 66:34. f Performed
in refluxing ether for 4 h.
Treatment of a mixture of tertiary 1a (0.50 mmol) and
secondary 1i (0.50 mmol) with benzylmagnesium bromide
(0.30 mmol) in the presence of silver nitrate afforded 0.25
mmol of 2a and 0.03 mmol of 2g (Scheme 2). The
benzylation features facile creation of quaternary carbon
centers (entries 1-6). Tertiary alkyl chloride 1b reacted
smoothly in refluxing ether (entry 2). Tertiary alkyl iodide
was likely to be too reactive under the reaction conditions
(entry 3). The reaction of 1-bromoadamantane (1d) was slow,
and the completion of the reaction took 24 h (entry 4). The
reaction of 1e was not stereospecific (entry 5), which is
highly suggestive of the existence of an intermediate having
an sp2-hybridized carbon center. Proper protective groups
such as a benzyloxy group were compatible under the highly
basic conditions (entry 6). The conversions of the tertiary
alkyl halides were quantitative, and the byproducts were the
corresponding alkenes and alkane.
Scheme 2. Comparison of the Reactivity of Secondary and
Tertiary Alkyl Bromides
predominant conversion of 1a suggests that the reaction
would include generation of an sp2-hybridized carbon center
from 1. Furthermore, the silver-catalyzed benzylation reac-
tions of exo- and endo-bromonorbornanes (exo- and endo-
1l) yielded 2l with the same exo/endo selectivity (Scheme
3), which indicates the existence of a planar carbon center
with no original stereochemical information.
When (2-iodocyclohexyloxy)vinylsilane 3 was subjected
to the silver-catalyzed benzylation reaction, bicyclic com-
pound 4 was obtained (Scheme 4). Since 4 readily underwent
(8) General procedure for Ag-catalyzed benzylation of tert-alkyl
halides: Silver nitrate (0.8 mg, 0.005 mmol) was placed in a 20-mL reaction
flask. Anhydrous diethyl ether (2 mL) and substrate 1a (117.6 mg, 0.50
mmol) were added under argon. Benzylmagnesium bromide (1.0 M diethyl
ether solution, 0.65 mL, 0.65 mmol) was then added to the reaction mixture
at 25 °C. While the Grignard reagent was being added, the mixture turned
to a black suspension. After the mixture was stirred for 3 h at 25 °C, black
precipitations appeared at the bottom of the reaction flask, and the
supernatant solution became colorless. Then the reaction mixture was poured
into a saturated ammonium chloride solution (20 mL). The products were
extracted with hexane (20 mL × 3). The combined organic layer was dried
over Na2SO4 and concentrated. Silica gel column purification (hexane) of
the crude product provided the corresponding benzylated product 2a (107
mg, 0.44 mmol) in 87% isolated yield.
(9) The reactions in hexane, toluene, and THF resulted in lower yields
(ca. 70%).
(10) 1,2-Diphenylethane (0.12 mmol) was detected.
(11) The reaction was slow when performed in the presence of 0.1 mol%
of silver nitrate. After 5 h, 2a was obtained in 79% yield, along with 5%
of 1a and 10% of the dehydrobrominated products.
970
Org. Lett., Vol. 10, No. 5, 2008

silver15 and diphenylethane (Steps A and B). The zerovalent
silver would effect single electron-transfer to alkyl halide to
form the corresponding alkyl radical and silver halide (Step
C). The alkyl radical would immediately couple with another
zerovalent silver to yield the corresponding alkylsilver (Step
D). Silver halide formed by the single electron-transfer would
react with benzylmagnesium bromide to generate benzylsil-
ver (Step E). Reductive coupling of the benzylsilver with
the alkylsilver affords the benzylated product and regenerates
the zerovalent silver (Step F). The details of the reductive
coupling, especially the reason for the predominant cross-
coupling reaction over possible homocoupling reaction of
the benzylsilver, are not clear at this stage.
Scheme 3. Benzylation of Bromonorbornane
hydrolysis and 4 was hence difficult to handle, 4 was
converted to diacetate 5 by Tamao-Fleming oxidation
The silver-catalyzed conditions were applicable not only
to the benzylation but also to the coupling reactions with
allylic Grignard reagents. Allylation and methallylation
reactions of tertiary and secondary alkyl bromides proceeded
smoothly (Table 2). Unfortunately, silver-catalyzed preny-
Scheme 4. Cyclization of Iodoacetal 3
Table 2. Allylation and Methallylation of Alkyl Halides
entry
1
cat. /mol %
Grignard reagent
8
yield /%
followed by acetylation. Although the yield of 5 was low,
the formation of 5 suggests that the silver-catalyzed benzy-
lation reaction would proceed via radical intermediates 6 and
7,12 not via cationic ones.13
1
2
3
4
1a
1i
1a
1i
1.0
2.5
1.0
2.5
R ) H (1.3 equiv)
R ) H (1.3 equiv)
R ) Me (1.5 equiv) 8c
R ) Me (1.5 equiv) 8d
8a
8b
83
80
80
79
On the basis of the mechanistic study on silver-catalyzed
reactions by Tamura and Kochi,5a,14 we propose a draft
lation and crotylation of alkyl halide resulted in poor
regioselectivity (Table 3).
Scheme 5. Plausible Mechanism
Table 3. Reactions with Crotyl and Prenyl Grignard Reagents
entry
1
cat. /mol % R1
R2 yield /%
9/10
1
2
3
4
1a
1i
1a
1i
1.0
2.5
1.0
2.5
Me
Me
Me Me
Me Me
H
H
77
76
46
48
9a/10a ) 65:35
9b/10b ) 70:30
9c/10c ) 76:24
9d/10d ) 82:18
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Government
of Japan. H.O. acknowledges JSPS for financial support.
mechanism as outlined in Scheme 5. Benzylmagnesium bro-
mide would first react with silver nitrate to yield zerovalent
Supporting Information Available: Characterization
data of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) Someya, H.; Ohmiya, H.; Yorimitsu, H.; Oshima, K. Tetrahedron
2007, 63, 8609.
(13) Terao, J.; Begum, S. A.; Shinohara, Y.; Tomita, M.; Naitoh, Y.;
Kambe, N. Chem. Commun. 2007, 855.
OL800038A
(14) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1483.
(b) Kochi, J. K. Organometallic Mechanisms and Catalysis; Academic Press:
New York, 1978; p 374.
(15) The zero-valent silver can be multi-atomic or clustered and might
not be single atom.
Org. Lett., Vol. 10, No. 5, 2008
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