Silver-catalyzed regioselective carbomagnesiation of alkynes with alkyl halides and Grignard reagents

Article abstract of DOI:10.1021/ol2018664

A silver-catalyzed carbomagnesiation of alkynes with alkyl halides and Grignard reagents afforded alkenyl Grignard reagents regioselectively, where the alkyl group of the alkyl halide, but not that of the Grignard reagent, was introduced into the alkyne.

Full text of DOI:10.1021/ol2018664

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4656–4659
Silver-Catalyzed Regioselective
Carbomagnesiation of Alkynes with Alkyl
Halides and Grignard Reagents
Nobuaki Kambe,*,† Yuusuke Moriwaki,† Yuuki Fujii,† Takanori Iwasaki,† and
Jun Terao‡
Department of Applied Chemistry, Graduate School of Engineering, Osaka University,
Suita, Osaka 565-0871 Japan, and Department of Energy, Hydrocarbon Chemistry,
Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku,
Kyoto 615-8510 Japan
kambe@chem.eng.osaka-u.ac.jp
Received July 11, 2011
ABSTRACT
A silver-catalyzed carbomagnesiation of alkynes with alkyl halides and Grignard reagents afforded alkenyl Grignard reagents regioselectively,
where the alkyl group of the alkyl halide, but not that of the Grignard reagent, was introduced into the alkyne. Application to δ-haloalkylacetylenes
yielded cyclopentanes or a tetrahydrofuran containing an exo-methylene substituent via 5-exo-dig cyclization.
The addition of Grignard reagents to alkynes, i.e.,
carbomagnesiation, yields vinyl Grignard reagents 1 with
the concomitant formation of a new CꢀC bond and a
CꢀMg bond (Scheme 1, route A).1 Combinations of this
reaction and subsequent trapping with electrophiles or
metal-catalyzed coupling provide a useful and practical
method for the synthesis of multisubstituted alkenes 2.
Although a variety of transition-metal catalysts, including
Zr,2 Cr,3 Mn,4 Fe,5 Fe/Cu,6 Ni,7 Cu,8 and Ag,9 have been
used in this carbomagnesiation, aryl, vinyl, methyl or allyl
Grignard reagents have often been employed.10 Primary
alkyl Grignard reagents have, in some cases, been reported
to work,2,5a,7b,8c,8eꢀ8i,9 but the reaction was inefficient2,7b
and/or restricted to alkynes having a directing heteroatom
group.5a,8c,8eꢀ8i Reactions for the introduction of
secondary8c,g or tertiary7b,9 alkyl groups to alkynes are
more limited, and sterically hindered alkyl Grignard re-
agents are less easily accessible. As a practical method for
† Osaka University.
‡ Kyoto University.
(1) For reviews, see: (a) Organomagnesium Methods in Organic
Synthesis; Wakefield, B. J., Ed.; Academic Press, Inc.: San Diego, 1995;
pp 73ꢀ86. (b) Dzhemilev, U. M.; Ibragimov, A. G. Russ. Chem. Rev.
2005, 74, 807–823. (c) Itami, K.; Yoshida, J.-I. Carbomagnesiation
Reactions. In The Chemistry of Organomagnesium Compounds; Rappo-
port, Z., Marek, I., Eds.; Wiley: Chichester, 2008; Chapter 14, pp 631ꢀ679.
(2) D’yakonov, V. A.; Makarov, A. A.; Dzhemilev, U. M. Russ. J.
Org. Chem. 2009, 45, 1598–1609.
(3) Murakami, K.; Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett.
2007, 9, 1569–1571.
(4) (a) Okada, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc. 1996,
118, 6076–6077. (b) Tang, J.; Okada, K.; Shinokubo, H.; Oshima, K.
Tetrahedron 1997, 53, 5061–5072. (c) Yorimitsu, H.; Tang, J.; Okada,
K.; Shinokubo, H.; Oshima, K. Chem. Lett. 1998, 11–12. (d) Shinokubo,
H.; Oshima, K. Cat. Sur. Asia 2003, 7, 39–46.
(7) (a) Duboudin, J. G.; Jousseaume, B. J. Organomet. Chem. 1972,
44, C1–C3. (b) Duboudin, J. G.; Jousseaume, B. J. Organomet. Chem.
1978, 162, 209–222. (c) Snider, B. B.; Karras, M.; Conn, R. S. E. J. Am.
Chem. Soc. 1978, 100, 4624–4626. (d) Murakami, K.; Ohmiya, H.;
Yorimitsu, H.; Oshima, K. Chem. Lett. 2007, 36, 1066–10067.
(8) (a) Xie, M.; Huang, X. Synlett 2003, 477–480. (b) Itami, K.;
Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670–14671. (c)
Chechik, H.; Marek, I. Org. Lett. 2003, 5, 5087–5089. (d) Xie, M.; Liu,
L.; Wang, J.; Wang, S. J. Organomet. Chem. 2005, 690, 4058–4062. (e)
Chechik-Lankin, H.; Livshin, S.; Marek, I. Synlet 2005, 2098–2100. (f)
Lu, Z.; Ma, S. J. Org. Chem. 2006, 71, 2655–2660. (g) Fang, G.-H.; Yan,
Z.-J.; Yang, J.; Deng, M.-Z. Synthesis 2006, 1148–1154. (h) Yasui, H.;
Yorimitsu, H.; Oshima, K. Chem. Lett. 2007, 32–33. (i) Yasui, H.;
Yorimitsu, H.; Oshima, K. Bull. Chem. Soc. Jpn. 2008, 81, 373–379.
(5) (a) Zhang, D.; Ready, J. M. J. Am. Chem. Soc. 2006, 128, 15050–
15051. (b) Yamagami, T.; Shintani, R.; Shirakawa, E.; Hayashi, T. Org.
Lett. 2007, 9, 1045–1048.
(6) Shirakawa, E.; Yamagami, T.; Kimura, T.; Yamaguchi, S.;
Hayashi, T. J. Am. Chem. Soc. 2005, 127, 17164–17165.
r
10.1021/ol2018664
Published on Web 08/01/2011
2011 American Chemical Society

overcoming these difficulties, we herein report a new
catalytic system which enables the regioselective carbo-
magnesiation of alkynes with secondary and tertiary
alkyl iodides and commercially available i-BuMgCl in the
amount of AgOTs and PPh3, the hydroalkylation product
4a was obtained exclusively in 88% yield after workup, in
which the t-Bu group of t-Bu-MgCl was introduced at the
terminal carbon by direct addition (entry 1, Table 1).
Interestingly, the reaction using t-C5H11Br and t-Bu-MgCl
gave 3b in 7% yield together with 4a in 85% yield (entry 2).
The yield of 3b could be improved to 21% by employing
Grignard reagents having a less branched alkyl group
(entries 2ꢀ4). When a tertiary alkyl iodide, t-C5H11I, was
employed instead of t-C5H11Br, the formation of 4c was
suppressed and 3b was selectively produced in 91% yield
(entry 5). The use of i-Bu-MgCl further improved the yield
of 3b to 96%.
Scheme 1. Carbomagnesiation of Alkynes
Table 1. Carbomagnesiation of Alkynes with Alkyl Halides and
Grignard Reagents
presence of a silver catalyst (Scheme 1, route B).11,12 In this
reaction, the alkyl group of an alkyl halide is transferred to
an alkyne carbon to give the corresponding vinyl Grignard
reagents 1, and sterically hindered alkyl Grignard reagents
(RMgX) do not have to be preformed.
We recently reported the silver-catalyzed regioselective
carbomagnesiation of terminal alkynes with alkyl
Grignard reagents by the combined use of a silver catalyst
and 1,2-dibromoethane, which functions as a reoxidizing
reagent.9 These successful results prompted us to examine
the use of other alkyl halides in this reaction, instead of 1,
2-dibromoethane.13 When phenylacetylene was reacted with
t-Bu-MgCl in the presence of n-C5H11Br and a catalytic
entry alkyl-X
R
yield of 3a (%) E/Zb yield of 4a (%) E/Zb
1
2
3
4
5
6
n-C5H11Br t-Bu 3a: nd
t-C5H11Br t-Bu 3b: 7
t-C5H11Br s-Bu 3b: 11
t-C5H11Br n-Bu 3b: 21
4a: 88
4a: 85
4b: 65
4c: 39
4c: nd
4d: nd
3/97
5/95
8/92
14/86
8/92
3/97
17/83
35/65
t-C5H11
I
I
n-Bu 3b: 91
t-C5H11
i-Bu 3b: 96 (85) 18/82
a GC yield. Isolated yield is in parentheses. b Determined by GC.
(9) Fujii, Y.; Terao, J.; Kambe, N. Chem. Commun. 2009, 1115–1117.
(10) Examples of the carbometalation of olefins and dienes using Ti:
(a) Akutagawa, S.; Otsuka, S. J. Am. Chem. Soc. 1975, 97, 6870–6871.
(b) Terao, J.; Kato, Y.; Kambe, N. Chem. Asian J. 2008, 3, 1472–1478.
Zr:(c) Dzhemilev, U. M.; Vostrikova, O. S. J. Organomet. Chem. 1985,
285, 43–51. (d) Hoveyda, A. H.; Xu, Z. J. Am. Chem. Soc. 1991, 113,
5079–5080. (e) Takahashi, T.; Seki, T.; Nitto, Y.; Saburi, M.; Rousset,
C. J.; Negishi, E. J. Am. Chem. Soc. 1991, 113, 6266–6268. (f) Lewis,
D. P.; Muller, P. M.; Whitby, R. J.; Jones, R. V. H. Tetrahedron Lett.
1991, 32, 6797–6800. (g) Bell, L.; Whitby, R. J.; Jones, R. V. H.; Standen,
M. C. H. Tetrahedron Lett. 1996, 37, 7139–7142. (h) Fischer, R.;
Using the optimized reaction conditions of entry 6 in
Table 1, we investigated the use of various alkynes and
alkyl iodides in the reaction (Table 2). Tertiary and
secondary butyl iodides reacted readily with phenylacety-
lene, and their alkyl groups were transferred into the
alkyne to afford 5a and 5b as the sole regioisomers in good
to excellent yields with E/Z ratios approaching 1/4 and 3/7,
respectively, although the reaction of n-Bu-I was less
efficient and less selective (entries 1ꢀ3). 1-Adamantyl
iodide and cyclohexyl iodide were also applicable (entries
4 and 5). In the latter case, the use of sterically bulky P-
(o-tol)3 improved the stereoselectivity to E/Z = 18/82
(entry 6). Tolylacetylenes also reacted efficiently and both
the yield and stereoselectivity increased in the order of
para-, meta-, and ortho-substituted compounds (entries
7ꢀ9). p-Methoxyphenylacetylene gave a 1:1 mixture of
stereoisomers, but the 4-CF3 compound afforded the Z-
isomer predominantly (entries 10 and 11). These results
indicate that the stereoselectivity of the reaction is con-
trolled, not only by steric effects but also by electronic
effects. Although alkyl substituted alkynes such as 1-octyne
(entry 12) or internal alkynes reacted sluggishly, silylacety-
lene reacted under the same reaction conditions (entry 13).
To demonstrate the synthetic utility of the reaction as a
convenient and practical route to preparing trisubstituted
alkenes, we investigated the reaction of the vinyl Grignard
€
Walther, D.; Gebhardt, P.; Gorls, H. Organometallics 2000, 19, 2532–
2540. (i) Dzhemilev, U. M.; D’yakonov, V. A.; Khafizova, L. O.;
Ibagimov, A. G. Tetrahedron 2004, 60, 1287–1290. Mn:(j) Nishikawa,
T.; Shinokubo, H.; Oshima, K. Org. Lett. 2003, 5, 4623–4626. Fe:(k)
Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2000, 122,
ꢀ
^
978–979. Ni:(l) Farady, L.; Bencze, L.; Marko, L. J. Organomet. Chem.
1969, 17, 107–116. Cu:(m) Simaan, S.; Masarwa, A.; Bertus, P.; Marech,
I. Angew. Chem., Int. Ed. 2006, 45, 3963–3965. (n) Todo, H.; Terao, J.;
Watanabe, H.; Kuniyasu, H.; Kambe, N. Chem. Commun. 2008, 1332–
1334. (o) Simaan, S.; Masarwa, A.; Zohar, E.; Stanger, A.; Bertus, P.;
Marek, I. Angew. Chem., Int. Ed. 2009, 15, 8449–8464.
(11) We have reported that titanocene catalyzes regioselective alkyla-
tion of styrenes and 1,3-dienes with alkyl halides in the presence of
n-Bu-MgCl: (a) Terao, J.; Saito, K.; Nii, S.; Kambe, N.; Sonoda, N. J.
Am. Chem. Soc. 1998, 120, 11822–11823. (b) Nii, S.; Terao, J.; Kambe,
N. J. Org. Chem. 2000, 65, 5291–5297. (c) Nii, S.; Terao, J.; Kambe, N.
J. Org. Chem. 2004, 69, 573–576.
(12) For alkenes, other groups reported on a Zr-catalyzed reaction.
See for the intra- and intermolecular carbomagnesiation of alkenes using
primary and secondary alkyl tosylates and Grignard reagents, see: (a) de
Armas, J.; Hoveyda, A. H. Org. Lett. 2001, 3, 2097–2100. (b) Cesati,
R. R.; de Armas, J.; Hoveyda, A. H. Org. Lett. 2002, 4, 395–398. For
intramolecular vinylmagnesiation of alkenes with vinyl ether, see: (c)
ꢀ
Barluenga, J.; Alvarez-Rodrigo, L.; Rodrı
~
guez, F.; Fananas, F. J.
ꢀ
´
Angew. Chem., Int. Ed. 2006, 45, 6362–6365.
(13) Ag-catalyzed homocoupling of alkyl Grignrd reagents pro-
moted by 1,2-dibromoethane has been reported; see: Nagano, T.;
Hayashi, T. Chem. Lett. 2005, 34, 1152.
Org. Lett., Vol. 13, No. 17, 2011
4657

GC analysis of the resulting mixture in entry 1 of Table 2
indicated that 0.99 mmol of i-Bu-I was produced, along
with 0.93 mmol of product 5a. To probe the mechanism of
this catalytic reaction, we carried out a stoichiometric
reaction of 9, generated by the reaction of equimolar
amounts of AgOTs, PPh3, and i-Bu-MgCl,15f with t-Bu-I
at ꢀ10 °C for 1 h and confirmed that i-Bu-I was formed in
73% yield (Scheme 3). In the absence of AgOTs and PPh3,
the direct reaction of t-Bu-I with i-Bu-MgCl was ineffi-
cient, and the yield of i-Bu-I was only 11%, suggesting that
9 generated in situ undergoes exchange reaction with t-Bu-
I to give i-Bu-I and Ph3PAg-t-Bu (10).
Table 2. Scope and Limitations of Alkynes and Alkyl Iodides
yield of 5a
yield of 6a
entry
1
R
alkyl
(%)
E/Zb
(%)
E/Zb
Ph
t-Bu 5a: 93(81) 22/78
s-Bu 5b: 80 (67) 30/70
nd
1
2c,d Ph
3c,d Ph
n-Bu 5c: 37
36/64
9
36/64
31/69
33/67
22/78
4e
Ph
1-Ad 5d: 61 (43) 32/68
4
5c,d Ph
6c,f Ph
Cy
Cy
5e: 80
5e: 58
30/70
18/82
4
Scheme 3. Stoichiometric Reaction of Complex 9 with t-BuI
2
7
8
4-MeC6H4
3-MeC6H4
2-MeC6H4
t-Bu 5f: 84 (76) 35/65
t-Bu 5g: 90 (79) 26/74
t-Bu 5h: 96 (85) 3/97
nd
nd
nd
nd
nd
nd
1
9
10
11
12g
4-MeOC6H4 t-Bu 5i: 79 (73) 50/50
4-CF3C6H4 t-Bu 5j: 68 (63) 11/89
n-Hex
t-Bu 5k: nd
13d,g PhMe2Si
t-Bu 51: 67 (52) 9/91
To reveal the relative reactivity of alkyl halides, we
performed a competitive experiment using equimolar
amounts of tert-, sec-, and n-butyl iodides under the same
conditions as entry 1 in Table 2 and obtained 5a, 5b, and 5c
in 62%, 4%, and <1% yields, respectively (Scheme 4).
This result suggests that the exchange reaction of 9 with an
alkyl iodide and/or the addition of alkyl silver complexes
10 to terminal alkynes proceed via alkyl radical inter-
mediates.
a GC yield. Isolated yield is in parentheses. b Determined by GC
analysis. c 3 h. d Slow addition of Grignard reagent; see the Supporting
Infomation. e 4 h. f P(o-tol)3 was used instead of PPh3. g 9 h.
Scheme 2. Further Transformations of Vinyl Grignard Reagent 7
Scheme 4. Competitive Reaction of Alkyl Iodides
Taking these results into account, a plausible reaction
pathway for this reaction is shown in Scheme 5. The
catalytic cycle is triggered by the reaction of AgOTs with
i-Bu-MgCl in the presence of PPh3 to generate the isobutyl
silver complex 9.15 Then, 9reacts with the alkyl-I to give i-Bu-
I and the alkyl silver complex 10. The addition of 10 to the
terminal alkyne, probably via homolitic cleavage of AgꢀC
bond of 10,15f affords vinyl silver complex 11,15h which then
reagent 7 prepared by the present procedure. The vinyl
Grignard reagent 7 can be trapped with various electrophiles
such as D2O, allyl iodide, I2, acetoaldehyde, and CO2 to
afford the corresponding trisubstituted alkenes 8aꢀe
(Scheme 2). Arylation has successfully been achieved by
submitting the vinyl Grignard reagent 7 to a Pd-catalyzed
cross-coupling reaction by the simple addition of a catalyst,
PhI and a phosphine to the resulting solution in a one-pot
operation, which results in the production of the trisubstituted
alkyne 8f in 77% yield as a sole regioisomer (Scheme 2).14
(15) For the formation and reactions of alkyl silver complexes, see:
(a) Gardner, J. H.; Borgstrom, P. J. Am. Chem. Soc. 1929, 51, 3375–
3377. (b) Tamura, M.; Kochi, J. K. Synthesis 1971, 303–305. (c) Tamura,
M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1483–1485. (d) Whitesides,
G. M.; Panek, E. J.; Stedronsky, E. R. J. Am. Chem. Soc. 1972, 94, 232–
239. (e) Tamura, M.; Kochi, J. K. Bull. Chem. Soc. Jpn. 1972, 45, 1120–
1127. (f) Whitesides, G. M.; Bergbreiter, D. E.; Kendall, P. E. J. Am.
Chem. Soc. 1974, 96, 2806–2813. (g) Organometallic Mechanisms and
Catalysis; Kochi, J. K., Ed.; Academic Press: New York, 1978; pp 263, 374.
(h) Westmijze, H.; Kleijm, H.; Vermeer, P. J. Organomet. Chem. 1979,
172, 377–383.
(14) (a) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc.
1972, 94, 4374–4376. (b) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc.,
Chem. Commun. 1972, 144. (c) Yamamura, M.; Noritani, I.; Murahashi,
S.-i. J. Organomet. Chem. 1975, 91, C39–C42.
4658
Org. Lett., Vol. 13, No. 17, 2011

Table 3. Intramolecular Carbomagnesiation of Haloalkynes 13
Scheme 5. Proposed Catalytic Cycle
entry 13 (X) temp (°C) time (h)
Eþ
E
yield (%)a
1
2
3
13a (I)
13a (I)
13b (Br)
ꢀ10
ꢀ10
25
4
4
7
3
Hþ
H
15a: 79
CO2 then Hþ COOH 15b: 75
CO2 then Hþ COOH 15b: 23
4b 13c (I)
25
Dþ
D
15c: 80c
undergoes transmetalation with i-Bu-MgCl to give the vinyl
Grignard reagent 12 and the regeneration of 9.16
a Isolation yields. b THF and dichloroethane were used as solvents in
the absence of PPh3. c 96% d, E/Z = 42/58.
We then attempted to construct a ring by way of
incorporating the 5-exo-dig cyclization process of 6-hexynyl
radicals17 into the present catalytic cycle. We employed
6-iodo-1-phenyl-1-hexyne (13a) as a substrate, and the
reaction was conducted under the same optimized condi-
tions as described above. The resulting Grignard reagent 14
was treated with NH4Cl or CO 2 to give 15a and 15b as the
sole cyclized products in 79% and 75% yield, respectively
(Table 3, entries 1 and 2). The use of 6-bromo-1-phenyl-1-
hexyne (13b) also gave the corresponding product 15b,
albeit in poor yield (23%, entry 3). This intramolecular
reaction can be applied to the construction of heterocyclic
rings, as exemplified by entry 4 in Table 3, in which an acetal
13c was treated with i-Bu-MgCl in the presence of AgOTs
to give a substituted THF 15c in 80% yield (E/Z = 42/58,
96% d) after quenching with D2O.
Finally, we attempted the carbomagnesiation of an
enyne (Scheme 6) and found that the t-Bu group was
introduced at the terminal carbon of the double bond to
give an allenyl Grignard reagent 18, which was efficiently
trapped with D2O to afford the trisubstituted allene 20 in
73% yield accompanied by a small amount of alkyne 19.
In conclusion, we report herein on the silver-catalyzed
regioselective carbomagnesiation ofterminalalkynesusing
i-Bu-MgCl and alkyl iodides. In this reaction, the alkyl
group of the alkyl iodide, and not that of the Grignard
reagent, is introduced into the terminal alkyne carbon to
give alkylated vinyl Grignard reagents. To the best of our
knowledge, this is the first example of the three-component
carbomagnesiation of alkynes in which an alkyl halide is
used as a coupling component. The reaction proceeds via a
Scheme 6. Formation of an Allenyl Grignard Reagent from 16
radical mechanism and affords vinyl Grignard reagents
efficiently when tertiary or secondary alkyl iodides are
employed. The reaction provides a useful and convenient
method for the synthesis of trisubstituted olefins by not
only the simple trapping of the resulting vinyl Grignard
reagents with electrophiles but also by further manipula-
tion catalyzed by transition metals such as cross-coupling.
The application of this reaction to δ-haloalkylalkynes led
to the synthesis of five-membered (hetero) cycles bearing
an exo-methylene substituent. Allenyl Grignard reagents
can be prepared when enynes are employed.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research (S) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Supporting Information Available. Additional data,
experimental details, and spectroscopic data. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(16) An alternative mechanism that alkyl radicals, generated by SH2
reaction of alkyl iodides with i-Bu radical from 9, directly attack alkynes
without forming 10 may also be operating.
(17) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41,
3925–3941.
Org. Lett., Vol. 13, No. 17, 2011
4659