Cobalt-catalyzed benzylzincation of alkynes

Article abstract of DOI:10.1002/chem.201001061

Chemical Equotion Present Carbometalation: Cobalt salts catalyze benzylzincation of alkynes to afford benzylated multisubstituted alkenes with high regio- and stereoselectivity. The scope of the reaction is wide enough to apply unfunctionalized alkynes as well as arylacetylenes. The reaction offers a new route to the regio- and stereoselective synthesis of an estrogen receptor antagonist (see scheme).

Full text of DOI:10.1002/chem.201001061

DOI: 10.1002/chem.201001061
Cobalt-Catalyzed Benzylzincation of Alkynes
Kei Murakami,[a] Hideki Yorimitsu,*[a, b] and Koichiro Oshima*[a]
Multisubstituted alkenes are among the most important
structures in organic chemistry. In particular, multisubstitut-
ed alkenes bearing a benzyl group are essential fragments
present in the key precursors of lignans[1] and in pharmaco-
logically important molecules.[2] Although there are numer-
ous methods for the preparation of alkenes, the regio- and
stereoselective synthesis of benzylated, multisubstituted al-
kenes is still challenging. Thus, development of general and
efficient routes to benzylated alkenes is in high demand.
Herein we wish to report cobalt-catalyzed[3] benzylzinca-
tion[4–7] of alkynes to afford benzylated multisubstituted al-
kenes. The reaction is applicable to the regio- and stereose-
lective synthesis of an estrogen receptor antagonist.
Scheme 1.
Table 1. Scope of benzylzinc reagents and aliphatic alkynes[a]
Treatment of 6-dodecyne (1a) with benzylzinc bromide
(2a) in the presence of cobalt(II) bromide and tris(4-me-
thoxyphenyl)phosphine in propionitrile at 258C for 1.5 h fol-
lowed by hydrolysis gave the corresponding benzylated
product 3a in 90% yield with high
E
selectivity
(Scheme 1).[8–10] The use of propionitrile as the solvent was
crucial and the use of acetonitrile significantly retarded the
reaction. When the reaction was carried out in THF, no ben-
zylated product was obtained.
1
2
3
Yield [%][b]
E/Z[c]
r.r.[d]
The scope of benzylzinc reagents and alkynes was studied,
and the results are summarized in Table 1. Symmetrical al-
kynes, such as 4-octyne (1b) and 1,4-dibenzyloxy-2-butyne
(1c), participated in the reaction in high yield and with high
stereoselectivity (Table 1, entries 1–3). The reaction of ter-
1
1b
1b
1c
1d
1e
1 f
1g
1h
1b
1b
1b
1b
1b
1b
1b
1b
2a
2a
2a
2b
2a
2a
2a
2a
2b
2c
2d
2e
2 f
2g
2h
2i
3b
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
86
94
88
94
60
89
83
trace
93
94
85
79
69
94
75
trace
96:4
95:5
<1:99
–
–
–
–
2[e]
3
4
5
6
7
>99:1
93:7
91:9
48:52
–
–
nd[f]
–
8[g]
9
–
–
–
–
–
–
–
–
–
[a] K. Murakami, Prof. Dr. H. Yorimitsu, Prof. Dr. K. Oshima
Department of Material Chemistry
97:3
96:4
97:3
>99:1
>99:1
97:3
96:4
–
10
11
12
13
Graduate School of Engineering, Kyoto University
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
Fax : (+81)75-383-2438
14[h]
15[i]
16
E-mail: oshima@orgrxn.mbox.media.kyoto-u.ac.jp
[b] Prof. Dr. H. Yorimitsu
Present address: Department of Chemistry
Graduate School of Science
Kyoto University, Sakyo-ku, Kyoto 606-8502 (Japan)
Fax : (+81)75-753-4010
[a] Performed on a 0.3 mmol scale. [b] Isolated yield. [c] Determined by
1H NMR spectroscopy. [d] Regioisomeric ratio determined by 1H NMR
spectroscopy. [e] Performed on
[g] Performed at 608C. [h] CoBr2 (10 mol%) and P(3,5-Me2-4-
MeOC6H2)3 (20 mol%) were used. [i] CoBr2 (10 mol%) and P(4-
MeOC6H4)3 (20 mol%) were used.
a 5 mmol scale. [f] Not determined.
E-mail: yori@kuchem.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001061.
7688
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Chem. Eur. J. 2010, 16, 7688 – 7691

COMMUNICATION
minal alkynes (1d–1 f) proceeded regioselectively to yield
gem-disubstituted alkenes (Table 1, entries 4–6). However,
the reaction of 2-octyne (1g) provided a 48:52 mixture of re-
gioisomers (Table 1, entry 7). Unfortunately, sterically hin-
dered 2-methyl-3-decyne (1h) failed to react (Table 1,
entry 8). The reactions with 4-methylbenzyl- and 3-methyl-
benzylzinc bromide afforded 3i and 3j in 93 and 94%
yields, respectively (Table 1, entries 9 and 10). A bulky 2-
methylbenzylzinc reagent also participated in the reaction
(Table 1, entry 11). The benzylzincation with 2-thienylme-
thylzinc bromide (2e) and 3-methoxybenzylzinc bromide
(2 f) occurred with perfect stereoselectivity (Table 1, en-
tries 12 and 13). The benzylzinc reagent bearing a chloro or
bromo group was also applicable to provide the correspond-
ing product without any observable side reactions (Table 1,
entries 14 and 15). Attempts on benzylzincation with elec-
tron-deficient 4-CF3C6H4CH2ZnBr (2i) failed and 1b was re-
covered (Table 1, entry 16). It is worth noting that no cyclo-
trimerization of the alkyne occurred owing to the mild reac-
tion conditions.[11]
The scope of dibenzylzinc reagents and aryl-substituted
alkynes is summarized in Table 3. The reaction of aryl-sub-
stituted alkynes bearing an electron-withdrawing group and
Table 3. Scope of dibenzylzinc reagents and aryl-substituted alkynes.[a]
4
5
6
Yield [%][b]
E/Z[c]
r.r.[d]
1
2
3
4
5
6
7
8
4b
4c
4d
4e
4 f
4 f
4 f
4 f
5a
5a
5a
5a
5b
5c
5d
5e
6b
6c
6d
6e
6 f
6g
6h
6i
71
50
96
61
66
62
63
40
>99:1
>99:1
>99:1
97:3
97:3
97:3
>99:1
90:10
>99:1
94:6
95:5
95:5
We next examined the reaction of the more reactive aryl-
substituted alkyne 4a with benzylzinc bromide (2a). Al-
though the reaction completed smoothly, the benzylated
product was a 41:59 mixture of regioisomers (Table 2,
97:3
92:8
95:5
89:11
[a] Performed on a 0.3 mmol scale. [b] Isolated yield. [c] E/Z ratio of the
major regioisomer 6 determined by 1H NMR spectroscopy. [d] Regioiso-
1
meric ratio determined by H NMR spectroscopy.
Table 2. Optimization of arylzincation of 1-phenyl-1-propyne.
an electron-donating group reacted smoothly (Table 3, en-
tries 1 and 2). The reaction of sterically hindered 1-(2-meth-
ylphenyl)-1-octyne (4d) provided the benzylated product 6d
in high yield. The ester group of 4e survived and 6e was ob-
tained in 61% yield (Table 3, entry 4). The reaction with 4-
methyl-, 4-fluoro-, and 4-methoxybenzylzinc reagents pro-
ceeded smoothly to give the corresponding benzylated prod-
ucts (Table 3, entries 5–7). The sterically hindered 2-methyl-
benzylzinc reagents reacted in moderate yield (Table 3,
entry 8).
Having the efficient protocols for the benzylzincation re-
action in hand, we examined the reaction of alkenylzinc in-
termediates with various electrophiles. The alkenylzinc inter-
mediate A, which was prepared by the reaction of 1b with
2a, reacted with D2O and I2 to afford 7a and 7b, respective-
ly (Scheme 2, top). As for the reaction of allyl bromide, the
addition of iPrMgCl·LiCl[12a] to the alkenylzinc intermediate
A was necessary due to the low reactivity of A. The alkenyl-
zinc intermediate B also reacted smoothly to afford tetra-
substituted alkenes 8a–8c regio- and stereoselectively in
good yields (Scheme 2, bottom).
Zinc reagent
Solvent T [8C] t [h] Yield [%][a] r.r.[b]
1
2
3
4
PhCH2ZnBr (2a)
PhCH2ZnBr·LiCl (2aa) EtCN
PhCH2ZnBr·LiBr (2ab) EtCN
PhCH2ZnBr·MgClBr
(2ac)
EtCN
25
60
60
60
1.5 78[c]
41:59
>99:1
>99:1
>99:1
12
12
12
33
40
27
EtCN
EtCN
none
none
5
6
7
G
25
25
25
12
12
12
54
>99:1
>99:1
>99:1
A
82
(5a)
PhCH2MgCl
13[d]
[a] 1H NMR yield. E/Z ratios of 6a was over 99:1 unless otherwise noted.
[b] Regioisomeric ratio determined by 1H NMR spectroscopy. [c] E/Z
ratio of 6a was 93:7. [d] E/Z ratio of 6a was 62:38.
entry 1). Interestingly, complexation of the zinc reagent with
lithium halide resulted in perfect regioselectivitiy, albeit the
yields of 6a were low (Table 2, entries 2 and 3).[12,13] The re-
action with PhCH2ZnBr·MgClBr (2ac), which was prepared
from PhCH2MgCl and ZnBr2, also afforded 6a with perfect
regioselectivity. Further investigation revealed that the use
of dibenzylzinc reagent 5a was effective and that the reac-
tion proceeded at 258C to give 6a in 54% yield. Finally, we
found that the addition of propionitrile was not crucial for
the reaction of aryl-substituted alkynes. Hence, the reaction
was carried out without propionitrile to give 6a in 82%
yield (Table 2, entry 6). It is worth noting that benzylmetala-
tion did not proceed when benzylmagnesium reagent was
employed (Table 2, entry 7).
Finally, we attempted to synthesize estrogen receptor an-
tagonist 11 (Scheme 3). Benzylzincation of 4g followed by
an addition of iodine gave the corresponding vinyl iodide 9
in 60% yield. Then, Negishi coupling of 9 with arylzinc re-
agent 10 afforded 11 in 60% yield. The efficient two-step
synthesis highlights the synthetic advantage of the benzyl-
A
ACHTUNGTRNEaNUNG tion.
Chem. Eur. J. 2010, 16, 7688 – 7691
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7689

H. Yorimitsu, K. Oshima and K. Murakami
afforded (E)-6-phenylmethyl-6-dodecene (3a, 70 mg, 0.27 mmol) in 90%
yield.
Typical procedure for the preparation of dibenzylzinc reagents: Anhy-
drous ZnBr2 (10 mmol) was placed in a 50 mL reaction flask and dried
for 20 min at 150–1708C under high vacuum. The flask was refilled with
argon and cooled to 08C. The corresponding benzylmagnesium chloride
(20 mmol, 20 mL, 1m in THF) was slowly added to the flask and the mix-
ture was stirred for 10 min. Then, the mixture was warmed to room tem-
perature.
Typical procedure for cobalt-catalyzed benzylzincation of arylacetylenes:
The reaction of 1-(2-methylphenyl)-1-octyne with dibenzylzinc reagent is
representative (Table 3, entry 3). CoBr2 (3.3 mg, 0.015 mmol) and
P(4-MeOC6H4)3 (10.7 mg, 0.03 mmol) were placed in a 20 mL reaction
flask under argon. Compound 4d (60 mg, 0.30 mmol) was added. Then,
dibenzylzinc reagent 5a (0.90 mmol, 1.8 mL, 0.5m in THF) was added.
The mixture was stirred at 258C for 12 h. A saturated aqueous solution
of NH4Cl (2 mL) was added. The organic compounds were extracted
with ethyl acetate three times. The combined organic part was dried over
Na2SO4 and concentrated in vacuo. Chromatographic purification on
silica gel by using hexane as an eluent afforded (E)-1-(2-methylphenyl)-
2-phenylmethyl-1-octene (6d, 84 mg, 0.29 mmol) in 96% yield.
Scheme 2. Reactions of alkenylzinc intermediates with electrophiles. Re-
agents and conditions: [a] CoBr2 (5 mol%), P(4-MeOC6H4)3 (10 mol%).
[b] 08C, 5 h. [c] i) iPrMgCl·LiCl/THF (3 equiv), 08C, 0.5 h; ii) CuCN·2-
LiCl (20 mol%), allyl bromide. [d] CuCN·2LiCl (20 mol%), MeI.
Acknowledgements
This work was supported by Grant-in-Aid for Scientific Research from
MEXT and JSPS. K.M. acknowledges JSPS for financial support.
Keywords: alkenes · benzylation · carbometalation · cobalt ·
zinc
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Scheme 3. Regio- and diastereoselective synthesis of estrogen receptor
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Experimental Section
Typical procedure for the preparation of benzylzinc reagents: Zn powder
(13 mmol) was placed in a 50 mL reaction flask. THF (10 mL) wad
added. TMSCl (0.01 mmol) and 1,2-dibromoethane (0.05 mmol) were
added subsequently. The mixture was stirred for 10 min at room tempera-
ture. Then, the corresponding benzyl bromide (10 mmol) was added
slowly to keep the solvent gently refluxed. After addition, the mixture
was stirred for 3 h at room temperature.
Typical procedure for cobalt-catalyzed benzylzincation of dialkylacety-
lenes and terminal acetylenes: The reaction of 6-dodecyne with benzyl-
zinc bromide is representative (Scheme 1). CoBr2 (3.3 mg, 0.015 mmol)
and P(4-MeOC6H4)3 (10.7 mg, 0.03 mmol) were placed in a 20 mL reac-
tion flask under argon. Propionitrile (1 mL) and benzylzinc bromide
(0.90 mmol, 0.90 mL, 1m solution in THF) were added. Then, 6-dodecyne
(1a, 50 mg, 0.30 mmol) was added. The mixture was stirred at 258C for
1.5 h. A saturated aqueous solution of NH4Cl (2 mL) was added. The or-
ganic compounds were extracted with ethyl acetate three times. The com-
bined organic part was dried over Na2SO4 and concentrated in vacuo.
Chromatographic purification on silica gel by using hexane as an eluent
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Benzylzincation of Alkynes
COMMUNICATION
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[9] Optimization of the reaction was noted in the Supporting Informa-
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Received: April 22, 2010
Published online: June 2, 2010
Chem. Eur. J. 2010, 16, 7688 – 7691
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7691