Copper-catalyzed cross-coupling reaction of Grignard reagents with primary-alkyl halides: Remarkable effect of 1-phenylpropyne

Article abstract of DOI:10.1002/anie.200603451

(Chemical Equation Presented) A general get-together: The Cu-catalyzed cross-coupling reaction of primary-alkyl halides with primary-, secondary-, and tertiary-alkyl and phenyl Grignard reagents proceeds efficiently in THF under reflux in the presence of 1-phenylpropyne (see scheme). The reaction is also applicable to alkyl mesylates (OMs) and tosylates (OTs). The reactivities of alkyl-X with a Grignard reagent increase in the order X = Cl < F < OMs < OTs < Br.

Full text of DOI:10.1002/anie.200603451

Communications
DOI: 10.1002/anie.200603451
Cross-Coupling Reactions
Copper-Catalyzed Cross-Coupling Reaction of Grignard Reagents with
Primary-Alkyl Halides: Remarkable Effect of 1-Phenylpropyne**
Jun Terao,* Hirohisa Todo, Shameem Ara Begum, Hitoshi Kuniyasu, and Nobuaki Kambe*
[a]
À
À
Table 1: Cross-coupling reaction of nNon Cl with nBu MgCl.
The copper-catalyzed cross-coupling of alkyl halides or
sulfonates with Grignard reagents has become one of the
most straightforward methods for constructing methylene
chains.[1,2] Aserious drawback of this reaction is its non-
applicability toward alkyl chlorides, which are promising
alkylating reagents because of their wide availability and low
cost relative to their iodo and bromo analogues.[3,4] This lack
Entry
Additive
Product yield [%][b]
nonane
tridecane
nonenes
1
>98
91
93
3
<1
1
1
0
0
<1
0
2[c]
3[d]
4
none
2
5
16
26
4
À
of reactivity is probably due to the strong C Cl bond relative
6
7
8
4
66
13
19
44
5
10
20
12
10
5
10
18
<1
2
9
1
3
0
1
1
0
À
À
to the C I and C Br bonds. We have recently reported that
Cu catalyzes the cross-coupling reaction of non-activated
alkyl fluorides with Grignard reagents in the presence of
1,3-butadiene additives under mild conditions;[5] however, the
corresponding alkyl chlorides gave only poor yields of the
cross-coupling products.[6] We describe herein the first
example of a Cu-catalyzed cross-coupling reaction of alkyl
chlorides with Grignard reagents in the presence of
1-phenylpropyne as an additive [Eq. (1)].
9
10
11
12
13
12
95
À
[a] nNon Cl (1 mmol), CuCl2 (0.02 mmol), additive (0.1 mmol), and
nBu MgCl (1.5 mmol), THF (1.5 mL), reflux, 6 h; tol =tolyl. [b] GC yield
based on nNon Cl used. [c] Reaction was carried out at 258C for 48 h.
[d] CuCl was used as the catalyst.
À
À
recovered (Table 1, entry 4). 1,3-Butadiene and styrene are
far less effective as the ligand (Table 1, entries 5 and 6). We
then examined other alkynes in the reaction. The yield of
tridecane decreased as the length of the alkyl chain was
increased (Table 1, entries 1, 7, and 8). Torane, phenyl
acetylene, and 4-octyne gave moderate to poor yields of the
coupling product (Table 1, entries 9–11). The presence of an
o-methyl group on the aryl substituent resulted in a decreased
product yield; however, a p-methyl group did not affect the
reaction. These results suggest that the present cross-coupling
When n-nonyl chloride (1 mmol) was allowed to react
with nBuMgCl (1.5 mmol) in the presence of catalytic
amounts of CuCl2 (0.02 mmol) and 1-phenylpropyne
(0.1 mmol) in THF under reflux for 6 h, the cross-coupling
product, tridecane, was obtained in greater than 98% yield
along with a trace amount of a reduction product, nonane
(<1%; Table 1, entry 1). This reaction proceeds at room
temperature, but more slowly (Table 1, entry 2).[7] The use of
a CuCl catalyst also afforded tridecane in high yields (Table 1,
entry 3). In the absence of 1-phenylpropyne, tridecane was
obtained in only 3% yield, and 95% of n-nonyl chloride was
À
reaction is sensitive to the steric hindrance around the C C
triple bond of the alkynes.
We have recently reported an example of a Ni-catalyzed
cross-coupling reaction of a primary-alkyl chloride with
nBuMgCl in the presence of 1,3-butadiene at 258C for 20 h
which afforded dodecane in 96% yield.[4a] However, this
reaction cannot be applied to sec-butyl, tert-butyl, and phenyl
Grignard reagents as shown in Equation (2). On the other
hand, the Cu-catalyzed cross-coupling reaction proceeds
efficiently with these alkyl and phenyl Grignard reagents. It
should be noted that alkyl fluorides and mesylates (OMs)[8]
can also undergo the present cross-coupling reaction to give
rise to the corresponding products in almost quantitative
yields [Eq. (3)].
We next examined independent reactions of alkyl electro-
philes (alkyl-X; X = F, Cl, Br, OMs, OTs; OTs = tosylate)
with nBuMgCl in the presence of catalytic amounts of CuCl2
and 1-phenylpropyne in THF at 258C for 15 minutes to
determine the reactivity of these electrophiles in the reaction.
The corresponding coupling product was obtained in high
[*] Dr. J. Terao, H. Todo, S. A. Begum, Dr. H. Kuniyasu,
Prof. Dr. N. Kambe
Department of Applied Chemistry & Science and
Technology Center for Atoms, Molecules, and Ions Control
Graduate School of Engineering, Osaka University
Yamadaoka 2-1, Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-7390
E-mail: kambe@chem.eng.osaka-u.ac.jp
[**] This study was supported by the Industrial Technology Research
Grant Program in 2006 from the New Energy and Industrial
Technolgy Development Organization (NEDO) of Japan and a
Grant-in-Aid for Scientific Researchon Priority Areas from the
Ministry of Education, Culture, Sports, Science, and Technology,
Japan.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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formation of tetradecane in 98% yield along with a 2% yield
of dodecane [Eq. (5)]. Asimilar reaction using only alkyl
fluorides and chlorides resulted in the formation of dodecane
and tridecane in 95% and 5% yields, respectively. These
results indicate the reactivity of the alkyl halides to be in the
order chloride < fluoride < bromide. Theoretical calculation
À
À
of the strengths of the Me X and X MgCl bonds indicates
that the reactions of the alkyl fluorides are not disfavored
energetically relative to those of alkyl chlorides and alkyl
[9]
À
bromides because of the formation of a strong F Mg bond.
It is proposed that an interaction between Li and X plays an
À
important role in the fission of the C X bond for the related
reaction of alkyl-X with R2CuLi.[10]
These remarkable differences in reactivity, especially
between the alkyl chlorides and bromides, prompted us to
perform site-selective sequential cross-coupling reactions
using dihaloalkanes. Reaction of 1-bromo-6-chlorohexane
(1) with nBuMgCl (1.1 equiv) in the presence of catalytic
amounts of CuCl2 and 1-phenylpropyne at 08C for 15 minutes
followed by addition of tBuMgCl (1.3 equiv) afforded a
nearly quantitative yield of 2,2-dimethyldodecane (2) along
with less than 1% of tetradecane (3) [Eq. (6)].
yield from n-nonyl bromide and in moderate yields from n-
heptyl tosylate and n-heptyl mesylate. In contrast, n-nonyl
chloride and fluoride gave only small amounts of products
[Eq. (4)]. These results indicate the reactivities of the alkyl
Although the reaction of 2-octyl bromide with nBuMgCl
under identical conditions as used in entry 1 of Table 1
afforded the corresponding cross-coupling product in 40%
yield, no reaction took place with 2-octyl chloride. This
reactivity allows the successful synthesis of 2-octyl chloride
(4) in high yield by using 1,3-dichlorobutane [Eq. (7)].
electrophiles in the present cross-coupling reaction increase
in the order: chloride < fluoride < mesylate < tosylate < bro-
mide.
To examine these abnormal reactivities of the alkyl
halides (alkyl-X; X = F, Cl, Br) in this catalytic system we
also carried out the following competitive experiments: A
solution of nBuMgCl, CuCl2, and 1-phenylpropyne in THF
was added to a mixture of equimolar amounts of n-octyl
fluoride, n-nonyl chloride, and n-decyl bromide [Eq. (5)].
After stirring the reaction for 30 minutes in THF under reflux,
GC analysis of the resulting mixture indicated the selective
To examine the effect of 1-phenylpropyne in the present
reaction system we then carried out the reaction of n-nonyl
chloride with nBuMgCl in THF under reflux in the presence
of 2 mol% of CuCl2 and different amounts of 1-phenyl-
propyne. Agraph of the time course of the formation of
tridecane against the amount of additive is shown in Figure 1.
Interestingly, as the amount of additive was increased, the
reaction rate at the early stage decreased (see below). When
only 2 mol% of the additive was employed the catalyst
rapidly lost its activity and the reaction stopped.
It has been proposed that direct reaction of sec-alkyl
iodides with lithium diorganocuprates may proceed by a
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To gain insight into the stereochemistry of the present
coupling reaction[14] we treated diastereometrically pure a,b-
[D2]-b-adamantylethyl chloride (9) with PhMgBr [Eq. (10)].
1H NMR analysis of the products indicated that the cross-
coupling reaction occurs primarily with inversion of config-
uration, with approximately 10:1 selectivity. This result
suggests that the present cross-coupling reaction for pri-
mary-alkyl chlorides proceeds principally by an SN2 mecha-
nism.
Although the role of 1-phenylpropyne in the present
catalytic reaction has not yet been clarified, it is possible that
the coordination of alkynes to the copper(I) ion prevents
decomposition of thermally unstable alkylcopper(I) inter-
mediates 10,[15,16] which may exist in equilibrium with other
complexes 11–14 in the reaction media (Scheme 1). The
Figure 1. Time course of the Cu-catalyzed cross-coupling reaction
using different amounts of 1-phenylpropyne in THF under reflux.
radical pathway.[11] We then carried out the cross-coupling
reaction with 6-chloro-1-hexene [Eq. (8)]. Alkene 5 was
Scheme 1. A plausible reaction pathway.
coordination of alkynes to 10 then forms an alkyne–alkyl-
copper(I) complex 11.[17] Complexation of 11 with the
Grignard reagent forms an ate complex 12, which would be
a key species in the present cross-coupling reaction and react
with the alkyl halides.[18] Increasing the concentration of the
alkynes shifts the equilibrium toward the formation of
bis(alkyne)copper(I) complexes (13 and/or 14),[19] which
might be the resting states of the catalyst, thus resulting in a
lowering of the rate of the coupling process.
In conclusion, we have shown that the Cu-catalyzed alkyl–
alkyl cross-coupling reaction between alkyl chlorides and
Grignard reagents proceeds efficiently in the presence of 1-
phenylpropyne as an additive, and is applicable to alkyl
fluorides, mesylates, and tosylates.
obtained in 86% yield as the sole coupling product, without
formation of cyclic compound 6, which may arise from
intramolecular cyclization of a 5-hexenyl radical.[12] We also
carried out the coupling reaction of (chloromethyl)cyclopro-
pane with PhMgBr. Benzylcyclopropane (7) was obtained in
98% yield as the sole coupling product without formation of
4-phenyl-1-butene (8), which may arise from ring-opening of
the cyclopropylmethyl radical [Eq. (9)].[13] These results
would rule out a radical mechanism.
Experimental Section
2 (CAS registry number 49598-54-1): A solution of n-butylmagnesium
chloride (0.87m, 1.25 mL, 1.1 mmol) in THF was added to a mixture
of 1-bromo-6-chlorohexane (197 mg, 1.0 mmol) and catalytic
amounts of CuCl2 (2.9 mg, 0.02 mmol) and 1-phenypropyne
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Angewandte
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(11.8 mg, 0.1 mmol) at 08C under nitrogen. After stirring the mixture
for 15 min at 08C, a solution of tert-butylmagnesium chloride (0.9m,
1.45 mL, 1.3 mmol) in THF was added. After stirring the reaction
mixture for 3 h at 688C, 1m aqueous HCl was added. Asaturated
aqueous solution of NH4Cl (10 mL) was added, and the product was
extracted with diethyl ether (10 mL). The organic layer was dried
over MgSO4, and evaporated to give a yellow crude product (98%,
GC yield). Purification by HPLC with CHCl3 as the eluent afforded
180 mg (91%) of 2. IR (neat): 2926, 2855, 1468, 1392, 1364, 1250, 1014,
[7] In this reaction, 0.09 mmol of 1-phenylpropyne was recovered
=
and a trace amount of PhCH C(Me)nBu (< 0.01 mmol) was
formed, probably from a Cu-catalyzed carbomagnezation of 1-
phenylpropyne with nBuMgCl.
[8] Two examples of Cu-catalyzed cross-coupling reactions using
sec-alkyl mesylates have been reported, see D. H. Burns, J. D.
Miller, H. K. Chan, M. O. Delaney, J. Am. Chem. Soc. 1997, 119,
2125.
À
[9] The calculated bond energies of X MgCl obtained by using the
1
722 cmÀ1; H NMR (400 MHz, CDCl3): d = 1.26–1.14 (m, 18H), 0.88
G2 method of the Gaussian 98 program are 142, 112, 101 kcal
(t, J = 6.0 Hz, 3H), 0.86 ppm (s, 9H); 13C NMR (100 MHz, CDCl3):
d = 44.4, 32.1, 30.8, 30.4, 29.91, 29.87, 29.8, 29.6, 29.5, 24.7, 22.9,
14.3 ppm; MS (EI) m/z (relative intensity, %): 198 ([M]+, 1), 183 (6),
140 (6), 85 (9), 71 (12), 57 (100), 56 (53), 43 (10), 41 (13); HRMS calcd
for C14H30: 198.2347; found: 198.2357; elemental analysis calcd for
C14H30: C 84.76, H 15.24; found: C 84.47, H 15.02.
molÀ1, and those of X CH3 are 112, 85, 74 kcalmol for X = F,
À1
À
À
Cl, and Br, respectively. The energy differences between the X
À
MgCl and X CH3 bonds for X = F, Cl, and Br are similar (30, 28,
27 kcalmolÀ1, respectively), thus indicating that the reaction of
alkyl fluorides is not disfavored energetically.
[10] Atheoretical study led to a proposed cyclic transition state with
À
À
an RX Li interaction, which facilitates cleavage of the R X
bond in the rate-determining step: E. Nakamura, S. Mori, K.
Morokuma, J. Am. Chem. Soc. 2000, 122, 7294.
Received: August 23, 2006
Revised: December 21, 2006
Published online: February 5, 2007
[11] a) E. C. Ashby, R. N. Depriest, A. Tuncay, S. Srivastava,
Tetrahedron Lett. 1982, 23, 5251; b) E. C. Ashby, D. Coleman,
J. Org. Chem. 1987, 52, 4554.
Keywords: alkynes · copper · cross-coupling · Grignard reagents
[12] The rate constant k = 7.0 ” 105 sÀ1 (at 258C) for the isomerization
of the 5-hexenyl radical to the cyclopentylmethyl radical has
been reported, see A. Citterio, F. Minisci, J. Am. Chem. Soc.
1974, 96, 6355.
.
[1] B. H. Lipshutz, S. Sengupta, Organic Reactions, Vol. 41 (Ed.:
L. A. Paquette), Wiley, New York, 1992, p. 149.
[13] The rate constant k = 1.3 ” 108 sÀ1 (at 258C) for the isomerization
of the cyclopropylmethyl radical to the butenyl radical has been
reported, see B. Maillard, D. Forrest, U. K. Ingold, J. Am. Chem.
Soc. 1976, 98, 7024.
[2] For recent reviews on transition-metal-catalyzed cross-coupling
reactions using alkyl halides, see: a) D. J. Cµrdenas, Angew.
Chem. 1999, 111, 3201; Angew. Chem. Int. Ed. 1999, 38, 3018;
b) T.-Y. Luh, M.-K. Leung, K.-T. Wong, Chem. Rev. 2000, 100,
3187; c) D. J. Cµrdenas, Angew. Chem. 2003, 115, 557; Angew.
Chem. Int. Ed. 2003, 42, 384; d) M. R. Netherton, G. C. Fu, Adv.
Synth. Catal. 2004, 346, 1525; e) J. Terao, N. Kambe, J. Synth.
Org. Chem. Jpn. 2004, 62, 1192; f) A. C. Frisch, M. Beller,
Angew. Chem. 2005, 117, 680; Angew. Chem. Int. Ed. 2005, 44,
674.
[14] a) G. M. Whitesides, W. F. Fischer, J. San Filippo, R. W. Bashe,
H. O. House, J. Am. Chem. Soc. 1969, 91, 4871; b) C. R. Johnson,
G. A. Dutra, J. Am. Chem. Soc. 1973, 95, 7783; c) B. H. Lipshutz,
R. S. Wilhelm, J. Am. Chem. Soc. 1982, 104, 4696; d) E. Hebert,
Tetrahedron Lett. 1982, 23, 415; e) C.-y. Guo, M. L. Brownawell,
J. San Filippo, J. Am. Chem. Soc. 1985, 107, 6028; f) S. Mori, E.
Nakamura, K. Morokuma, J. Am. Chem. Soc. 2000, 122, 7294.
[15] It is known that alkylcopper(I) species are formed from both
CuCl and CuCl2 on reaction with alkyl Grignard reagents, see M.
Tamura, J. K. Kochi, J. Organomet. Chem. 1972, 42, 205.
[16] For thermal stabilities of alkylcopper(I) complexes, see A.
Miyashita, T. Yamamoto, A. Yamamoto, Bull. Chem. Soc. Jpn.
1977, 50, 1109, and references therein.
[17] For alkynecopper(I) complexes, see P. Schulte, U. Behrens, J.
Organomet. Chem. 1998, 563, 235, and references therein.
[18] a) J. K. Kochi, Organometallic Mechanisms and Catalysis, Aca-
demic Press, New York, 1978, p. 372; b) J. M. Klunder, G. H.
Posner, Comprehensive Organic Synthesis, Vol. 3 (Eds.: B. M.
Trost, I. Fleming), Pergamon, Oxford, 1991, p. 207; c) E.
Nakamura, S. Mori, K. Morokuma, J. Am. Chem. Soc. 1998,
120, 8273.
[3] a) G. Cahiez, S. Marquais, Synlett 1993, 45; b) G. Cahiez, C.
Chaboche, M. Jezequel, Tetrahedron 2000, 56, 2733.
[4] For transition-metal-catalyzed cross-coupling reactions using
alkyl chlorides, see a) J. Terao, H. Watanabe, A. Ikumi, H.
Kuniyasu, N. Kambe, J. Am. Chem. Soc. 2002, 124, 4222; b) J. H.
Kirchhoff, C. Dai, G. C. Fu, Angew. Chem. 2002, 114, 2025;
Angew. Chem. Int. Ed. 2002, 41, 1945; c) A. C. Frisch, N. Shaikh,
A. Zapf, M. Beller, Angew. Chem. 2002, 114, 4218; Angew.
Chem. Int. Ed. 2002, 41, 4056; d) J. Zhou, G. C. Fu, J. Am. Chem.
Soc. 2003, 125, 12527; e) M. Nakamura, K. Matsuo, S. Ito, E.
Nakamura, J. Am. Chem. Soc. 2004, 126, 3686.
[5] J. Terao, A. Ikumi, H. Kuniyasu, N. Kambe, J. Am. Chem. Soc.
2003, 125, 5646.
[6] It is known that stoichiometric cuprates such as Li2CuMe3 react
with alkyl chlorides and fluorides, see E. C. Ashby, J. J. Lin, J.
Org. Chem. 1977, 42, 2805.
[19] For bis(alkyne)copper(I) complexes, see G. Grꢀger, U. Behrens,
F. Olbrich, Organometallics 2000, 19, 3354.
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