Air-assisted addition of grignard reagents to olefins. A simple protocol for a three-component coupling process yielding alcohols

Article abstract of DOI:10.1021/ja055732b

Silylmethyl, tertiary-alkyl, alkenyl, and aryl Grignard reagents underwent intermolecular addition to olefins, such as styrenes, conjugated dienes, and enynes under an air atmosphere to give homologated alcohols. For example, (trimethylsilyl)methylmagnesi

Full text of DOI:10.1021/ja055732b

Published on Web 12/01/2005
Air-Assisted Addition of Grignard Reagents to Olefins. A Simple Protocol for
a Three-Component Coupling Process Yielding Alcohols
Youhei Nobe, Kyohei Arayama, and Hirokazu Urabe*
Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of
Technology, 4259-B-59 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
Received August 22, 2005; E-mail: hurabe@bio.titech.ac.jp
Scheme 1. Confirmation of the O2-Assisted Mechanism
Oxidation of Grignard reagents with O2 is well-known to yield
alcohols via a radical mechanism (eq 1).1 However, to our best
knowledge, application of the intermediate radicals (R•) has not
been fully investigated from the synthetic point of view.1a,2,3
Grignard reagents are generally reluctant to add to olefins, and
methods to execute this type of reaction are still limited.4,5 Herein
we report a new and simple entry to Grignard addition to olefins,
which takes advantage of the radical species generated by the aerial
oxidation of Grignard reagents and enables a one-pot, three-
component coupling process of a Grignard reagent, olefin, and O2
(air), directly yielding alcohols according to eq 2.
Table 2. Air-Assisted Addition of Grignard Reagents to Various
Olefinsa
The feasibility of intermolecular addition of various Grignard
reagents 1-8 according to eq 2 was first evaluated with R-methyl-
styrene (9) (eq 3, Table 1). An attempted addition of butyl or
i-propyl Grignard reagents to this olefin failed (entries 1 and 2).
This is in accord with a precedent that exposure of 5-hexenyl
Grignard reagent to O2 gave cyclopentylmethanol as a minor
component, showing that the addition of the transient alkyl radical
to olefin is not a preferable path even in an intramolecular manner.1a
However, gratifyingly, we found that certain Grignard reagents,
such as those having tertiary-alkyl, alkenyl, and aryl groups (3-
6), nicely undergo the intermolecular addition to 9 followed by
the oxygenation with O2 to yield alcohols 12-15 (entries 3-6). In
addition, silylmethyl Grignard reagent 7 or 8 is an exceptional
primary-alkyl reagent that participates in the present reaction (entries
7 and 8).6-8 As far as the solvents are concerned, both ether and
THF, common solvents for the preparation of Grignard reagents,
are acceptable for this process (Table 1).9,10
That the above reaction is actually assisted by O2 and does not
involve the carbomagnesiation/oxidation sequence has been evi-
Table 1. O2(Air)-Assisted Intermolecular Addition of Grignard
Reagents
a For reaction conditions, see eq 3. b Me3SiCH2MgCl (7) in Et2O or
H2CdC(Me)MgBr (5) in THF. c Isolated yields. d Four equivalents of 7 was
used.
entry
RMgX
solvent
product
yield (%)
1
2
3
4
5
6
7
8
BuMgBr
i-PrMgCl
t-BuMgCl
Me2CdC(H)MgBr
H2CdC(Me)MgBr
PhMgBr
Me3SiCH2MgCl
Me2PhSiCH2MgCl
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
Et2O
Et2O
Et2O
THF
THF
THF
Et2O
Et2O
10
11
12
13
14
15
16
17
<10
<10
74
72
70
denced by the following experiments (Scheme 1). When a mixture
of Grignard reagent 7 and olefin 9 was stirred under argon with
rigorous exclusion of O2, nearly complete recovery of 9 and the
absence of a coupling product resulting from carbomagnesiation
were observed.11 To the contrary, it is interesting to note that a
similar reaction under a (pure) O2 atmosphere did not give the
desired product 16 due perhaps to much accelerated oxygenation
of the Grignard reagent itself.12
75
72-90a
74b
a Range of yields in different scales. See Supporting Information.
b Me2PhSiCH2OH (2.0 equiv) was also produced.
9
18006
J. AM. CHEM. SOC. 2005, 127, 18006-18007
10.1021/ja055732b CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Regioselective Addition of Grignard Reagents to
Supporting Information Available: Experimental procedures,
structural determinations, and spectroscopic properties of products
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
Enynesa
References
(1) (a) Lamb, R. C.; Ayers, P. W.; Toney, M. K.; Garst, J. F. J. Am. Chem.
Soc. 1966, 88, 4261-4262. (b) Walling, C.; Buckler, S. A. J. Am. Chem.
Soc. 1953, 75, 4372-4373. (c) Kharasch, M. S.; Reynolds, W. B. J. Am.
Chem. Soc. 1943, 65, 501-504. For review, see: (d) Wakefield, B. J.
Organomagnesium Methods in Organic Synthesis; Academic Press:
London, 1995; pp 197-199.
(2) For reviews on synthetic application of radicals, see: (a) Renaud, P., Sibi,
M. P., Eds. Radicals in Organic Synthesis; Wiley-VCH: Weinheim,
Germany, 2001; Vols. 1 and 2. (b) Giese, B.; Kopping, B.; Go¨bel, T.;
Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F. In Organic Reactions;
Paquette, L. A., Ed.; John Wiley & Sons: New York, 1996; Vol. 48, pp
301-850. (c) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds; Pergamon Press: Oxford, 1986.
Enyne
entry
R 1MgX
R2
R3
product yield (%)b
1
2
3
4
5
6
PhMe2SiCH2MgCl (8) C10H21
Me3SiCH2MgCl
PhMe2SiCH2MgCl (8)
H2CdC(Me)MgBr (5)
PhMgBr
H
Me
"
"
"
(32)
(33)
(33)
(33)
(33)
35
36
37
38
39
40
71
70
76
55
48
88
(7)
"
"
"
"
(6)
PhMe2SiCH2MgCl (8) SiMe3 C9H19 (34)
a Reaction conditions are the same as those of eq 3. b Isolated yields.
(3) For a review on O2-induced radical reactions, see: (a) Ollivier, C.; Renaud,
P. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, Germany, 2001; Vol. 2, pp 93-112. O2-assisted
addition of an organometallic compound to olefin was precedented by
alkylboranes to R,â-unsaturated carbonyl compounds: (b) Brown, H. C.;
Kabalka, G. W. J. Am. Chem. Soc. 1970, 92, 714-716. For preparation
of alcohols via the addition of radicals, generated from organic halides,
to olefins followed by O2 trap, see: (with tin reagents) (c) Yoshida, M.;
Ohkoshi, M.; Aoki, N.; Ohnuma, Y.; Iyoda, M. Tetrahedron Lett. 1999,
40, 5731-5734. (d) Mayer, S.; Prandi, J. Tetrahedron Lett. 1996, 37,
3117-3120. (e) Nakamura, E.; Inubushi, T.; Aoki, S.; Machii, D. J. Am.
Chem. Soc. 1991, 113, 8980-8982. (with Co complex) (f) De´sire´, J.;
Prandi, J. Tetrahedron Lett. 1997, 38, 6189-6192. See also: (g)
Chowdhury, F. A.; Nishino, H.; Kurosawa, K. Tetrahedron Lett. 1998,
39, 7931-7934.
Table 4. Dual Grignard System Decreasing the Stoichiometry of
Precious Grignard Reagent
entry
7 (equiv)
1 (equiv)
yield of 42 (%)
1
2
3
4
3
0
0
1.2
0.8
78
32
64
65
1.2
1.2
1.5
(4) For addition of Grignard reagents to olefins, see: Lindsell, W. E. In
ComprehensiVe Organometallic Chemistry; Wilkinson, G., Stone, F. G.
A., Abel, E. W., Eds.; Pergamon Press: Oxford, 1982; Vol. 1, pp 167-
169.
This reaction shows reasonable generality not only to styrenes
18-20 but also to conjugated dienes 21-24 (Table 2). Good
diastereoselectivity was observed in entry 2, where the protection
of the free hydroxy group of 19 is not necessary. As this reaction
does not involve an unstable R-furfuryl carbanion13 arising from
carbomagnesiation, furfuryl alcohol 27 was obtained without
difficulty (entry 3). In all cases, the first radical addition to olefins
took place at the unsubstituted methylene moiety in a highly
regioselective manner. Although the successive oxygenation of the
resulting pseudo-symmetrical allyl radicals gave a regioisomeric
mixture of allyl alcohols (entries 4-6), a suitably substituted diene
24 nicely afforded a single isomer 31 (entry 7).14 A more dependable
regiochemical control of both Grignard addition and oxygenation
was achieved in the reaction of conjugated enynes, such as 32-
34,15 giving solely propargyl alcohols 35-40 unaccompanied by
isomeric unsaturated ketones and allenyl alcohol (Table 3).16
Throughout the above transformations, excess use of Grignard
reagent is mandatory because at least 1 equiv of the reagent was
consumed for the reduction of the resultant hydroperoxide, yielding
nonhomologated alcohols, as mentioned in footnote b to Table 1.
To save the precious Grignard reagent, we tried the reaction in the
presence of a second Grignard reagent that does not add to olefin,
but solely decomposes the intermediate hydroperoxide. To our
satisfaction, BuMgBr works quite well as the second Grignard
reagent, and, in its presence, a slight excess Grignard reagent 7
and olefin 41 now afforded the product 42 in good yield (entry 3
or 4 as compared to entry 2, Table 4), close to that of the original
reaction conditions (entry 1).
(5) For transition-metal-mediated addition of Grignard reagents to olefins,
see: (a) Sato, F.; Urabe, H. In Handbook of Grignard Reactions;
Silverman, G. S., Rakita, P. E., Eds.; Marcel Dekker: New York, 1996;
pp 23-52. (b) Urabe, H.; Sato F. In Handbook of Grignard Reactions;
Silverman, G. S., Rakita, P. E., Eds.; Marcel Dekker: New York, 1996;
pp 577-632. (c) Sato, F.; Urabe, H. In Grignard ReagentssNew
DeVelopments; Richey, H. G., Jr., Ed.; Wiley: Chichester, U.K., 2000;
pp 65-105. (d) Hoveyda, A. H.; Heron, N. M.; Adams, J. A. In Grignard
ReagentssNew DeVelopments; Richey, H. G., Jr., Ed.; Wiley: Chichester,
U.K., 2000; pp 107-137. (e) Wakefield, B. J. Organomagnesium Methods
in Organic Synthesis; Academic Press: London, 1995; pp 73-79.
(6) For radical stabilization with an R-silyl group, see: Negishi, E. Organo-
metallics in Organic Synthesis; John Wiley & Sons: New York, 1980;
Vol. 1, p 398.
(7) For review on synthetic utility of alkylsilanes, see: (a) Jones, G. R.;
Landais, Y. Tetrahedron 1996, 52, 7599-7662. (b) Weber, W. P. Silicon
Reagents for Organic Synthesis; Springer-Verlag: Berlin, 1983. (c) Colvin,
E. W. Silicon in Organic Synthesis; Butterworth: London, 1981.
(8) For comparison, yields of 16 obtained with Me3SiCH2M under the
conditions of eq 3 are as follows: M ) Li, 42%; MgCl, 90%; ZnCl 13%.
Thus, the Grignard reagent gave the most satisfactory result.
(9) Although THF often blocks a desired radical reaction via its hydrogen
radical abstraction, this was not observed.
(10) Caution: Although, in these reactions, hydroperoxide was not produced
in an isolable amount in our hands, care must be taken in the formation
of peroxides particularly in a large-scale preparation. For more details,
see Supporting Information.
(11) The same recovery of olefinic substrates under pure argon was further
confirmed in other reactions of entry 6 of Table 2, and entries 2, 4, and
5 of Table 3.
(12) This means that, although we used dry air throughout this study owing to
its convenience and economy, careful optimization of the partial pressure
of O2 may lead to higher product yields with less equivalents of Grignard
reagent.
(13) (a) Takanishi, K.; Urabe, H.; Kuwajima, I. Tetrahedron Lett. 1987, 28,
2281-2282. (b) Atsumi, K.; Kuwajima, I. J. Am. Chem. Soc. 1979, 101,
2208-2210.
(14) The double stabilization of the radical center by tert-alkyl and benzylic
positions in the intermediate to 31 may account for the highly regio-
selective oxygenation. The structure 31 represents a carbon framework
of aromatic sesquiterpenes. Devon, T. K.; Scott, A. I. Handbook of
Naturally Occurring Compounds; Academic Press: New York, 1972; Vol.
II, pp 100-102.
(15) Thio-radical addition to enynes was reported. (a) Back, T. G.; Lai, E. K.
Y.; Muralidharan, K. R. J. Org. Chem. 1990, 55, 4595-4602. (b) Wang,
X.; Ni, Z.; Lu, X.; Hollis, A.; Banks, H.; Rodriguez, A.; Padwa, A. J.
Org. Chem. 1993, 58, 5377-5385.
(16) A nonconjugated olefin, such as 1-octene, did not participate in the present
radical addition.
In conclusion, the above reaction provides a very simple three-
component coupling process, free of additional or toxic reagents,
such as transition metal salts or organotin and related reagents, to
yield alcohols.
Acknowledgment. This work was supported, in part, by a
Grant-in-Aid for Scientific Research on Priority Areas 16073208
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
JA055732B
9
J. AM. CHEM. SOC. VOL. 127, NO. 51, 2005 18007