Cobalt-catalyzed benzyl-alkynyl coupling

Article abstract of DOI:10.1016/j.tetlet.2006.02.028

Benzylic halides coupled with 1-alkynylmagnesium halides in the presence of a catalytic amount of Co(acac)₃ to provide 1-aryl-2-alkynes in moderate to good yield.

Full text of DOI:10.1016/j.tetlet.2006.02.028

Tetrahedron Letters 47 (2006) 2591–2594
Cobalt-catalyzed benzyl–alkynyl coupling
Akiko Kuno, Naoko Saino, Taku Kamachi and Sentaro Okamoto*
Department of Applied Chemistry, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
Received 23 January 2006; revised 1 February 2006; accepted 6 February 2006
Available online 20 February 2006
Abstract—Benzylic halides coupled with 1-alkynylmagnesium halides in the presence of a catalytic amount of Co(acac)3 to provide
1-aryl-2-alkynes in moderate to good yield.
Ó 2006 Elsevier Ltd. All rights reserved.
Table 1.a
Reactions mediated or catalyzed by organometallic
3b
Trace 4%
Trace Trace Trace 98
4c
Recovered 1 (%)
compounds have enabled efficient carbon–carbon bond
formations between a variety of nucleophiles and
electrophiles.1 However, it is somewhat surprising that
coupling between benzylic sp3 electrophiles (ArCH2X)
and alkynyl sp carbanion (RC„Cꢀ) has not been nec-
essarily easy and has been limited to a few methods:
the reaction of alknyllithium compounds in the pres-
ence of DMPU,2 the CuX-catalyzed reaction with
RC„CMgX or RC„CLi under high concentrations
and/or high temperature conditions,3,4 Pd-catalyzed
coupling with (RC„C)3In4 or RC„CZnBr5 and
several reactions providing such coupling compounds
as a side product have been reported. Herein described
Catalyst (2 mol %)
2
PdCl2(PPh3)2
CuCN
Trace 96
Ni(acac)2
CO(acac)3
0%
39%
0%
6%
7%
94
59
90
2%
5%
d
Fe(acac)3
10%
15%
(AcO)2Mn(H2O)4
Trace Trace Trace 99
a After addition of water to the reaction mixture, the organic phase was
subjected to GC analysis using an internal standard.
b Based on consumption of 1 for formation of 3.
c Based on 1-hexyne used.
d The reaction was performed overnight.
is
a novel method for benzyl–alkynyl coupling,
which is catalyzed by cobalt compounds under mild
room temperature. The results summarized in Table 1
revealed that Co(acac)3 [acac = acetylacetonato] could
catalyze the coupling to give 39% of 1-phenyl-2-heptyne
(2) with production of a small amount of dibenzyl (3)
and diyne 4 as by-products. The reaction with other
metal complexes gave 3 and/or 4 but not the desired 2
at all.
conditions.6,7
First, we surveyed the possibility of several metallic
compounds as a catalyst for benzyl–alkynyl coupling
(Scheme 1). Thus, in the presence of 2 mol % of a metal-
lic compound benzyl bromide (1) (1.5 mmol) was treated
with 1-hexynylmagnesium bromide (2 mmol), prepared
from 1-hexyne and EtMgBr, in THF for 2 h at 0 °C to
With the results in hand, we investigated the reaction of
Scheme 1 with various Co-catalyst precursors to find the
better conditions for the production of 2 and the results
are summarized in Table 2. CoCl2 and CpCo(CO)2 as
well as Co(acac)3 could exhibit similar catalytic activity
(entries 1, 7 and 11). Regarding the catalysis with
Co(acac)3, elongation of reaction time (entry 2), increase
of temperature (entry 3) or a two-shot addition of the
Grignard reagent (entry 4) improved the yield of 2. A
bidentate ligand such as dppp, dppb and bipyridinyl
inhibited the formation of 2. Addition of a monodentate
ligand such as imidazolium carbene8 IPr (to CoCl2) and
PPh3 (to CpCo(CO)2) had little effect (entries 9, 10 and
PhCH2Br
PhCH2
Bu 2
1
+
+
catalyst
THF
PhCH2CH2Ph
+
3
BrMg
Bu
Bu
Bu
4
Scheme 1.
*
Corresponding author. Tel.: +81 45 481 5661; fax: +81 45 413
9770; e-mail: okamos10@kanagawa-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.028

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A. Kuno et al. / Tetrahedron Letters 47 (2006) 2591–2594
Table 2.a
Entry
Catalyst (2 mol %)
Conditions
Yield, %b
2
3c
4d
1
1
2
3
4
5
6
7
8
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3 + dpppf
Co(acac)3 + bipyridinylg
CoCl2
CoCl2 + dppbh
CoCl2 + Ipr
rt, 2 h
38
76
53
70
4
8
31
0
63
60
34
33
2
24
6
7
9
11
18
14
7
12
14
10
7
11
24
60
0
rt, 12 h
40 °C, 2 h
rt, 4 he
rt, 2 h
rt, 2 h
rt, 2 h
rt, 2 h
rt, 2 h
45 °C, 21 h
rt, 24 h
rt, 24 h
40
12
68
78
57
82
31
24
54
59
18
28
14
12
18
6
16
12
8
9
10
11
12
CoCl2 + Ipr
CpCo(CO)2
CpCo(CO)2 + 2PPh3
a To a mixture of 1 (1.0 mmol) and catalyst precursor (2 mol %) in THF (2 mL) was added a solution of n-BuC„CMgBr (1.5 mmol) in THF (5 mL)
at 0 °C and the mixture was stirred under the given conditions.
b Determined by GC analysis using an internal standard.
c Based on consumption of 1 for formation of 3.
d Based on 1-hexyne used.
e The reaction was started with 1.0 equiv of n-BuC„CMgBr. After 2 h, an additional 0.8 eqiv of n-BuC„CMgBr was added and the mixture was
stirred for an additional 2 h.
f 2 mol % of Co(acac)3 +3 mol % of dppp[1,3-bis(diphenylphosphino)propane].
g 2,20-Dipyridyl.
h 2 mol % of CoCl2 + 3 mol % of dppb[1,4-bis(diphenylphosphino)butane].
i-Pr i-Pr
N
N
i-Pr i-Pr
IPr
12). The reaction was specific for benzylic halides: the
reaction of n-BuC„CMgBr with other organic halides
such as cyclohexyl bromide, allyl bromide and
PhCH2CH2Br did not proceed (data not shown).
di-propargylated benzenes 10 and 11 in good yield,
respectively.
To discuss the reaction mechanism, we investigated the
time course of the present coupling reaction, which
was traced by GC analyses. Thus, PhCH2Br was treated
with n-BuC„CMgBr (1.5 equiv) in the presence of
2 mol % of Co(acac)3 and the time-course of the distri-
bution of 1, 2 and 3 is summarized in Figure 1. As
revealed from the figure, PhCH2CH2Ph (3) was rapidly
produced in the beginning 0.5–1 h and then it increased
no longer. In the period, the production of 2 was rela-
tively slow and, after this initiation time, the reaction
rate of formation of 2 increased and yield of 2 reached
>70% within 4 h. Although this switch of the reaction
course from the formation of 3 to production of 2 at
around 0.5–1 h of the reaction time is currently difficult
to explain, probably an active catalyst for the formation
of 2 would gradually be generated via the reaction(s)
affording 3 in the beginning 0.5–1 h. Since CpCo(CO)2
could catalyze the coupling similarly to Co(acac)3- and
CoCl2-based catalysis (entries 11 and 12 in Table 1), it
is likely that the reaction may involve the Co(I) species.
Therefore, Co(II) and Co(III) complexes may initially be
reduced by the reaction with R–C„CMgBr through the
formation of di- and/or tri-alkynyl cobalt complexe(s)
and the following elimination of diyne 4. Then, the reac-
tion may proceed via the oxidative addition10 with ben-
zylic halide and the following substitution with the
alkynyl anion and the reductive elimination of the coup-
ling compound to give a Co(I) compound(s) again.
The better reaction conditions thus found (entry 2 or 4
in Table 2) were subsequently utilized for the benzyl–
alkynyl coupling reaction of a series of representative
benzylic halides depicted in Table 3.9 As revealed from
the table, the reaction with Me3SiC„CMgBr afforded
the corresponding benzyl–alkynyl coupling product
in good to excellent yield, except for the reaction of
1-bromo-2-chloromethylbenzene (entry 6). Whereas the
coupling of benzyl bromide with n-BuC„CMgBr pro-
ceeded in a synthetically useful yield, the reaction with
other benzylic halides gave poor yield. The substituent
of the substrate halides affected the reaction electroni-
cally (entries 2–5) but, interestingly, opposite trends
were observed for the reactions with Me3SiC„CMgBr
and n-BuC„CMgBr.
Scheme 2 illustrates additional successful examples,
which are double-alkynylation of dibromide or
dichloride. Thus, o- or m-di(halomethyl)benzene could
smoothly couple with Me3SiC„CMgBr in the presence
of 2 mol % of Co(acac)3 at room temperature to provide
The reactions were performed under the conditions indicated in entry
4 of Table 2.

A. Kuno et al. / Tetrahedron Letters 47 (2006) 2591–2594
2593
Table 3.a
ArCH2X
+
Co(acac)3 (2 mol%)
ArCH2C≡C-R
THF
BrMgC≡C-R
room temperature
Entry
ArCH2X
Isolated yield, %b
R = n-Bu
R = SiMe3
1
2
2a: 70
2b: 71
Br
Cl
2a: (21)
5a: (14)
6a: (25)
7a: (38)
8a: (31)
2b: 82
5b: 98
6b: 80
7b: 63
8b: 40
MeO
Me
Cl
3
4
5
6
Cl
Cl
Figure 1. Time course of coupling reaction of PhCH2Br with
n-BuC„CMgBr.
Cl
Cl
Cl
Br
References and notes
c
1. Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 3, Dounay, A.
B.; Overman, L. E. Chem. Rev. 2003, 103, 2945–2964;
Metal-catalyzed Cross-coupling Reactions; Diederich, P.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998;
p 12; Cross-coupling Reactions: A practical Guide; Miya-
ura, N., Ed.; Topics in Current Chemistry Series 219;
Springer: New York, 2002.
7
—
9a: 93
OMe
a The reaction was performed under conditions indicated in entry 2 or
4 of Table 2.
b Yield in the parentheses was determined by GC analysis.
c Not carried out.
2. Takahashi, T.; Kitamura, M.; Shen, B.; Nakajima, K. J.
Am. Chem. Soc. 2000, 122, 12876.
3. Friary, R.; Seidl, V. J. Org. Chem. 1986, 51, 3214.
4. Gopalsamuthiram, V.; Wulff, W. D. J. Am. Chem. Soc.
2004, 126, 13936.
5. An efficient coupling of alkynylzinc reagents with benzylic
halides catalyzed by Pd(DPEphos)Cl2 has recently been
reported: Qian, M.; Negishi, E. Tetrahedron Lett. 2005, 46,
2927.
6. Cobalt-catalyzed cross-coupling reactions: Shukla, P.;
Hsu, Y.-C.; Cheng, C.-H. J. Org. Chem. 2006, 71, 655,
and references cited therein.
7. Cobalt-catalyzed cross-coupling with Grignard reagent:
Ohmiya, H.; Tsuji, T.; Yorimitsu, H.; Oshima, K. Chem.
Eur. J. 2004, 10, 5640; Kamachi, T.; Kuno, A.; Matsuno,
C.; Okamoto, S. Tetrahedron Lett. 2004, 45, 4677;
Fujioka, T.; Nakamura, T.; Yorimitsu, H.; Oshima, K.
Org. Lett. 2002, 4, 2257; Wakabayashi, K.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2001, 123, 5374;
Cahiez, G.; Avedissian, H. Tetrahedron Lett. 1998, 39,
6159.
Co(acac)3
(2 mol%)
Br
Br
Me3SiC≡CMgBr
SiMe3
SiMe3
(2 + 1.6 eq.)
THF, room temp.
4 h
10
69% isolated yield
Cl
Cl
SiMe3
as above
SiMe3
11
90% isolated yield
Scheme 2.
8. Arduengo, A. J., III; Dias, H. V. R.; Harlow, R. L.; Kline,
M. J. Am. Chem. Soc. 1992, 114, 5530; Arduengo, A. J.,
III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113,
361; Arduengo, A. J., III. Acc. Chem. Res. 1999, 32, 913.
9. Typical procedure: to a mixture of Co(acac)3 (7.13 mg,
0.02 mmol) and 4-methylbenzyl chloride (140 mg,
1.0 mmol) in THF (0.5 mL) was added dropwise a solution
of Me3SiC„CMgBr (1.5 mmol) in THF (3.5 mL) at 0 °C.
The resulting mixture was allowed to warm to room
temperature and stirred for 10 h. After addition of satd aq
In summary, we have demonstrated that cobalt
complexes such as Co(acac)3 could catalyze coupling
of benzylic halides with alkynyl Grignard reagents under
mild reaction conditions. Although generality of the
reaction is not necessarily high at this time, the several
cases presented here are synthetically useful and further
study for generalization of the reaction is underway in
our laboratory.

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A. Kuno et al. / Tetrahedron Letters 47 (2006) 2591–2594
NH4Cl, usual extractive workup gave a residue, which was
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provide 6b (162 mg) in 80% yield.
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