Cobalt-catalyzed arylzincation of alkynes

Article abstract of DOI:10.1021/ol900883j

Cobalt(II) bromide catalyzes arylzincation of alkynes with arylzinc iodide·lithium chloride complexes in acetonitrile. The scope of the arylzincation is wide enough to use unfunctionalized alkynes, such as 6-dodecyne, as well as arylacetylenes. The inherent functional group compatibility of arylzinc reagents allows preparation of various functionalized styrene derivatives. The reaction is applicable to the efficient and stereoselective synthesis of a synthetic estrogen and its derivative.

Full text of DOI:10.1021/ol900883j

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2373-2375
Cobalt-Catalyzed Arylzincation of
Alkynes
Kei Murakami, 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 April 23, 2009
ABSTRACT
Cobalt(II) bromide catalyzes arylzincation of alkynes with arylzinc iodide•lithium chloride complexes in acetonitrile. The scope of the arylzincation
is wide enough to use unfunctionalized alkynes, such as 6-dodecyne, as well as arylacetylenes. The inherent functional group compatibility
of arylzinc reagents allows preparation of various functionalized styrene derivatives. The reaction is applicable to the efficient and stereoselective
synthesis of a synthetic estrogen and its derivative.
Carbometalation of alkynes is a useful reaction to synthesize
multisubstituted alkenes.1 In particular, carbozincation is one
of the most important reactions due to the high functional
group compatibility of organozinc reagents. Although there
are several reports on transition metal-catalyzed carbozin-
cation of propynoate derivatives,2 alkynyl sulfoxide,3 phe-
nylacetylenes,4 or ynamides,5 carbozincation of unfunction-
alized alkynes such as dialkylacetylene remains an important
challenge.6 Here we wish to report that simple cobalt salts7
can catalyze arylzincation of a wide range of alkynes
including unfunctionalized ones.8 In addition, the reaction
offers a new route to the key structure of various synthetic
estrogen derivatives.
Our investigation began with treatment of 6-dodecyne (1a)
with 4-methylphenylzinc iodide·lithium chloride complex (1
M in THF)9 in toluene at 100 °C in the presence of cobalt
bromide for 1 h. However, the reaction did not proceed
(Table 1, entry 1). Interestingly, the addition of acetonitrile
promoted the reaction to provide (E)-6-(4-methylphenyl)-6-
(6) There are few examples of carbometalation of dialkylacetylenes.
Carbomagnesiation: (a) Shirakawa, E.; Yamagami, T.; Kimura, T.; Yamagu-
chi, S.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 17164–17165. (b)
Murakami, K.; Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9,
1569–1571. Carboboration: (c) Suginome, M.; Shirakura, M.; Yamamoto,
A. J. Am. Chem. Soc. 2006, 128, 14438–14439. (d) Daini, M.; Suginome,
M. Chem. Commun. 2008, 5224–5226. Carbostannylation: (e) Shirakawa,
E.; Yamasaki, K.; Yoshida, H.; Hiyama, T. J. Am. Chem. Soc. 1999, 121,
10221–10222.
(1) (a) Knochel, P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: New York, 1991;
Vol. 4, Chapter 4.4, pp 865-911. (b) Marek, I.; Normant, J. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998; pp 271-337. (c) Negishi, E.; Huang, Z.;
Wang, G.; Mohan, S.; Wang, C.; Hattori, H. Acc. Chem. Res. 2008, 41,
1474–1485. (d) Flynn, A. B.; Ogilvie, W. W. Chem. ReV. 2007, 107, 4698–
4745. (e) Fallis, A. G.; Forgione, P. Tetrahedron 2001, 57, 5899–5913. (f)
Itami, K.; Yoshida, J. In The Chemistry of Organomagnesium Compounds;
Rappoport, Z., Marek, I., Eds.; John Wiley & Sons: Chichester, 2008;
Chapter 18.
(7) Recent reviews for cobalt-catalyzed reactions: (a) Yorimitsu, H.;
Oshima, K. Pure Appl. Chem. 2006, 78, 441–449. (b) Shinokubo, H.;
Oshima, K. Eur. J. Org. Chem. 2004, 2081–2091. (c) Oshima, K. Bull.
Chem. Soc. Jpn. 2008, 81, 1–24. (d) Gosmini, C.; Be´gouin, J.-M.;
Moncomble, A. Chem. Commun. 2008, 3221–3223. (e) Rudolph, A.;
Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656–2670. (f) Jeganmohan,
M.; Cheng, C.-H. Chem.-Eur. J. 2008, 14, 10876–10886. (g) Hess, W.;
Treutwein, J.; Hilt, G. Synthesis 2008, 3537–3562.
(2) (a) Shintani, R.; Yamagami, T.; Hayashi, T. Org. Lett. 2006, 8, 4799–
4801. (b) Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 2071–2073. (c) Xue,
S.; He, L.; Liu, Y.-K.; Han, K.-Z; Guo, Q.-X. Synthesis 2006, 666–674.
(3) (a) Sklute, G.; Bolm, C.; Marek, I. Org. Lett. 2007, 9, 1259–1261.
(b) Maezaki, N.; Sawamoto, H.; Yoshigami, R.; Suzuki, T.; Tanaka, T.
Org. Lett. 2003, 5, 1345–1347.
(8) Cobalt-catalyzed hydroarylation of alkynes with arylboronic acid was
reported. Most of alkynes used were propynoate esters and alkynes having
a directing group. The addition to 3-hexyne was found to afford a 1:1
mixture of stereoisomers. Lin, P.-S.; Jeganmohan, M.; Cheng, C.-H.
Chem.-Eur. J. 2008, 14, 11296–11299.
(4) (a) Stu¨demann, T.; Ibrahim-Ouali, M.; Knochel, P. Tetrahedron 1998,
54, 1299–1316. (b) Yasui, H.; Nishikawa, T.; Yorimitsu, H.; Oshima, K.
Bull. Chem. Soc. Jpn. 2006, 79, 1271–1274. The cobalt-catalyzed allylz-
incation reaction of 6-dodecyne afforded only an 18% yield of the
corresponding allylated product.
(9) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 6040–6044.
(5) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc. 2009, 131, 3802–3803.
10.1021/ol900883j CCC: $40.75
Published on Web 05/08/2009
 2009 American Chemical Society

Table 1. Optimization of the Arylzincation of 6-Dodecyne
Table 2. Scope of Arylzinc Reagents and Alkynesa
temp (° C),
time (h)
entry solvent 1
solvent 2
toluene
yield(%)a
1
THF
100, 1
100, 1
60, 4
60, 4
60, 4
60, 4
60, 4
-
2
3
4
5
THF
toluene/MeCN (3/1)
22
55
32
-
MeCN
EtCN
iPrCN
MeCO2Et
MeCN
-
-
-
-
-
entry
1
2
time (h)
3
yield (%)b
3:3′c
1d
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
2b
2c
2d
2e
2f
2g
2h
2b
2b
2b
2b
2b
2b
2b
2 (4)e
3
6
2
6
3
5
2
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
82 (77)e
71
trace
64
72
74
53
64
89
86
-
-
-
-
-
-
-
55:45
90:10
>99:1
-
>99:1
98:2
>99:1
6
-
7b
64c
a Yields were determined by 1H NMR. b PtBu3 (10 mol %) was added.
c Isolated yield.
dodecene (3a) stereoselectively in 22% yield (Table 1, entry
2). Hence we replaced THF and toluene with acetonitrile as
the next trial. Gratifyingly, the reaction proceeded smoothly
to provide 3a in 55% yield (Table 1, entry 3).10 The addition
of propionitrile was less effective, and isobutyronitrile
completely suppressed the reaction (Table 1, entries 4 and
5). Other polar solvents such as ethyl acetate are also
ineffective (Table 1, entry 6). Further investigation revealed
that the addition of PtBu3 improved the efficiency of the
reaction and afforded 3a in 64% yield (Table 1, entry 7).11,12
3
10d
11
12d
13d
1.5
1.5
2
2
2
trace
86
91
1g
1h
14d f
80
,
a Reaction was performed on a 0.3 mmol scale. b Isolated yield. c Ratio
of regioisomers was determined by 1H NMR. d PtBu3 (10 mol %) was added.
e Reaction was performed on a 5 mmol scale. f Reaction was performed at
room temperature.
The scope of arylzinc reagents and alkynes was studied,
and the results are summarized in Table 2. The reactions
with phenyl- and 3-methylphenylzinc reagents proceeded
smoothly to afford the corresponding products in high yields
(entries 1 and 2). However, sterically hindered 2-methylphe-
nylzinc reagent 2d failed to react (entry 3). Arylzinc reagents
bearing bromo and ethoxycarbonyl group were also ap-
plicable and provided the corresponding arylated products
in 64% and 72% yields, respectively (entries 4 and 5).
Whereas an arylzinc reagent having an electron-donating
methoxy group reacted smoothly, a trifluoromethyl-substi-
tuted arylzinc reagent was less reactive (entries 6 and 7).
Attempts to alkylate 1a with hexylzinc iodide•lithium
chloride under cobalt catalysis afforded (Z)-6-dodecene in
less than 20% yields, and none of the corresponding
hexylated product was observed.
The reaction of 2-octyne (1b) provided a 55:45 mixture
of regioisomers (entry 8). 1-Phenyl-1-propyne reacted smoothly
with high regioselectivity (entry 9). The phenylzincation of
phenylacetylene having a methoxy group at the ortho position
exhibited perfect regioselectivity to yield phenylation product
3k (entry 10). Unfortunately, 2-methyl-3-decyne (1e) failed
to react because of its steric hindrance (entry 11). Acetylene
having an ester group reacted without any observable side
reactions (entry 12). The reaction proceeded efficiently with
heteroaryl-substituted alkyne 1g (entry 13). The reaction of
alkynyl phosphonate 1h gave the corresponding product 3o
regioselectively (entry 14). Bulky triethylsilyl-substituted
alkyne was inert under the reaction conditions, and the
reaction of diyne 1i gave 3p selectively (eq 1). Attempts to
(10) Preparation of acetonitrile solutions of arylzinc reagents: Arylzinc
reagents in THF were prepared from zinc powder (Wako Pure Chemical
Industries, Ltd.), lithium chloride (Wako Pure Chemical Industries, Ltd.),
and the corresponding aryl iodides in THF.9 An arylzinc iodide•lithium
chloride complex in THF (1.0 M, 0.9 mmol, 0.9 mL) was placed in a 50-
mL round-bottomed flask under argon. The THF solvent was evaporated
in vacuo. Then, acetonitrile (0.5 mL) was added to the flask to afford an
acetonitrile solution of an arylzinc reagent. The solutions were prepared
immediately prior to use.
(11) Typical procedure for cobalt-catalyzed reactions: The reaction of
6-dodecyne with 4-methylphenylzinc iodide•lithium chloride complex is
representative. CoBr2 (3.3 mg, 0.015 mmol) was placed in a 20-mL reaction
flask under argon. 6-Dodecyne (50 mg, 0.30 mmol) and PtBu3 (1.0 M hexane
solution, 0.030 mL, 0.030 mmol) were added. Then, 4-methylphenylzinc
iodide•lithium chloride complex in acetonitrile (0.90 mmol) was added.
The mixture was stirred at 60 °C for 4 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)-6-(4-methylphenyl)-6-dodecene (47
(13) Negishi, E. Acc. Chem. Res. 1982, 15, 340–348.
(14) meso-Hexestrol is an effective inhibitor of microtubule assembly
of proteins. Thus, its derivatives have also been extensively studied.
However, it is difficult to synthesize asymmetrical meso-hexestrol derivatives
diastereoselectively. (a) Wilson, J. W.; Burger, A.; Turnbull, L. B.; Peters,
M.; Milnes, F. J. Org. Chem. 1953, 18, 96–105. (b) Angelis, M. D.;
Katzenellenbogen, J. A. Bioorg. Med. Chem. Lett. 2004, 14, 5835–5839.
mg, 0.19 mmol) in 64% yield
.
(12) The necessity of PtBu3 as an additive heavily depended on alkynes
and arylzinc reagents used. The addition of PtBu3 often retarded the reaction.
The exact role of PtBu3 is not clear
.
2374
Org. Lett., Vol. 11, No. 11, 2009

use terminal alkynes resulted in low yields (less than 20%)
as well as formation of 1:1 mixtures of regioisomers.
Scheme 1. Reactions of Alkenylzinc Intermediate 4a with
Various Electrophiles
With the reliable arylzincation reaction in hand, we
investigated the utility of the intermediary alkenylzinc
compounds. Intermediate 4a reacted with various electro-
philes, such as deuterium oxide, iodine, and allyl bromide,
to give the corresponding tetrasubstituted alkenes stereose-
lectively. As for trapping 4a with allyl bromide, the addition
of a catalytic amount of CuCN·2LiCl improved the yield of
the corresponding product 5c. Alkenylzinc intermediate 4a
participated in Negishi coupling reactions.13 The reactions
with iodobenzene and 4-iodobenzonitrile afforded the cor-
responding diarylethene derivatives 5d and 5e stereoselec-
tively.
a 20 mol % of CuCN•2LiCl was added. b 2.5 mol % of Pd2(dba)3 and
10 mol % of P(o-tol)3 were added.
Scheme 2. Diastereoselective Synthesis of meso-Hexestrol and
Its Derivative
Finally, we attempted to synthesize a synthetic estrogen,
meso-hexestrol, and its derivative.14 Treatment of 3-hexyne
(1j) with 4-benzyloxyphenylzinc reagent 2i yielded alkenylz-
inc intermediate 4b. Negishi coupling reactions of 4b
proceeded smoothly to yield cis-stilbestrol derivatives 6a and
6b. Reduction of 6a and 6b under hydrogen in the presence
of Pd(OH)2/C afforded meso-hexestrol (7a)15 and its deriva-
tive 7b, respectively.
In summary, the protocol described here provides a mild
and efficient method for the preparation of multisubstituted
a Reaction was performed in the presence of 10 mol % of Pd(OH)2/C
for 4 h. b Contained 4% of diastereomer. c Reaction was performed in the
presence of 100 mol % of Pd(OH)2/C for 0.5 h. d Contained 5% of
diastereomer.
(15) Synthesis of meso-hexestrol: CoBr2 (3.3 mg, 0.015 mmol) was
placed in a 20-mL reaction flask under argon. 3-Hexyne (25 mg, 0.30 mmol)
was added. Then, 4-benzyloxyphenylzinc iodide•lithium chloride complex
in acetonitrile (0.90 mmol) was added. The mixture was stirred at 60 °C
for 2 h. The mixture was cooled to 0 °C. A THF solution of 1-benzyloxy-
4-iodobenzene (372 mg, 1.2 mmol), Pd2(dba)3 (6.9 mg, 0.0075 mmol), and
PPh3 (7.9 mg, 0.030 mmol) was added to the solution. The mixture was
warmed to 25 °C and stirred for 3 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/ethyl acetate (20/1) as an eluent afforded (Z)-3,4-bis(4-benzylox-
yphenyl)-3-hexene contaminated with 4,4′-dibenzyloxybiphenyl. Further
purification by GPC afforded pure (Z)-3,4-bis(4-benzyloxyphenyl)-3-hexene
(81 mg, 0.18 mmol) in 60% yield. (Z)-3,4-Bis(4-benzyloxyphenyl)-3-hexene
(111 mg, 0.25 mmol) was reduced under hydrogen (0.1 MPa) in the presence
of Pd(OH)2/C (20 wt % of Pd, 13 mg, 0.025 mmol) in ethanol (10 mL).
The mixture was filtrated through a pad of Celite, and the filtrate was
concentrated in vacuo. Chromatographic purification on silica gel by using
hexane/ethyl acetate (5/1) as an eluent afforded meso-hexestrol (68 mg,
0.25 mmol) in quantitive yield (including 4% of diastereomer).
alkenes. The application to the synthesis of meso-hexestrol
and its derivative highlights the synthetic potential of this
reaction.
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research and GCOE Research from
JSPS. K.M. acknowledges JSPS for financial support.
Supporting Information Available: Experimental details,
characterization data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900883J
Org. Lett., Vol. 11, No. 11, 2009
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