Conjugate addition of RMgX-3MeLi to α,β-unsaturated amides and α,β-unsaturated carboxylic acids

Article abstract of DOI:10.1246/cl.2007.736

In the presence of 3 equivalents of MeLi, various Grignard reagents reacted with secondary α,β-unsaturated amides and α,β-unsaturated carboxylic acids to give the corresponding Michael adducts in good yields. Copyright

Full text of DOI:10.1246/cl.2007.736

736
Chemistry Letters Vol.36, No.6 (2007)
Conjugate Addition of RMgX–3MeLi to ꢀ,ꢁ-Unsaturated Amides
and ꢀ,ꢁ-Unsaturated Carboxylic Acids
Mikiko Kikuchi, Satomi Niikura, Nao Chiba, Nahoko Terauchi, and Morio Asaokaꢀ
Department of Chemical and Biological Sciences, Faculty of Science, Japan Women’s University,
2-8-1 Mejirodai, Bunkyo-ku, Tokyo 112-8681
(Received March 29, 2007; CL-070341; E-mail: asaoka-m@fc.jwu.ac.jp)
In the presence of 3 equivalents of MeLi, various Grignard
species is difficult, it can be pointed out that the formation of
higher order ate complexes, RMenMgLi
important role in this conjugate addition.9 It is noteworthy
that in all the above cases, n-Bu group of the complex was
preferentially transferred and no Me group-transferred product
was found.
reagents reacted with secondary ꢀ,ꢁ-unsaturated amides and
ꢀ,ꢁ-unsaturated carboxylic acids to give the corresponding
Michael adducts in good yields.
(n ꢃ 3), plays an
ðnꢂ1Þ
Conjugate additions of three RMgX–3MeLi reagents
to some secondary ꢀ,ꢁ-unsaturated amides were surveyed
(Table 2). The reactions were carried out with 4 equiv. of
RMgX–3MeLi since lack of reproducibility was observed when
2.5–3 equiv. of RMgX–3MeLi was used. In all the cases no ad-
dition product was obtained without MeLi under the same reac-
tion conditions. As long as judged from the reaction temperature,
the order of their reactivity is suggested as follows: t-BuMgCl–
3MeLi > n-BuMgCl–3MeLi > PhMgBr–3MeLi. Addition of
t-BuMgCl–3MeLi to crotonamide gave the Michael-adduct
in good yield (Entry 4).
On the contrary, t-BuMgCl–3MeLi gave the corresponding
contra-Michael adducts (2-t-butyl derivatives)1 by the reaction
with 3-trimethylsilyl- and 3-phenyl-substituted acrylamide
derivatives (Entries 2 and 7). PhMgBr–3MeLi (Entries 1, 5,
and 8) and n-BuMgCl–3MeLi (Entries 3 and 6) reagents gave
the corresponding Michael-adducts in fair to good yields. In
these cases also no Me group-transferred product was found.
The results in Table 2 in conjunction with those reported by
us1 led us to the conclusion that RMgX–3MeLi reagents are
more reactive than the corresponding Grignard reagents but
less reactive than RLi.
In the course of our studies on the regioselective additions of
RLi to 3-(trimethylsilyl)acrylamide and cinnamamide deriva-
tives,1 we have found that conjugate addition of MeLi is extra-
ordinary sluggish compared with other alkyl- and aryl-lithium
reagents.2
On the other hand, it is well-known fact that Grignard
reagents are easily prepared and handled, however, one of the
drawbacks of the reagents is their low reactivity compared with
the corresponding organolithium reagents.3 Thus, we envisioned
to activate Grignard reagents with MeLi in the conjugate addi-
tion to secondary ꢀ,ꢁ-unsaturated amides and ꢀ,ꢁ-unsaturated
carboxylic acids. Generally none of these Michael acceptors
reacts with organocuprates or Grignard reagents.3–6
Actually, no Michael adduct 2a was obtained by the reaction
of n-BuMgCl with 3-(trimethylsilyl)acrylamide 1a at 20 ꢁC for
2 h (Entry 1 in Table 1). Then, the reaction was carried out
in the presence of MeLi. When the reacion was carried out by
sequential addition of the Grignard reagent and MeLi to 1a,
the yields of adduct were often variable and low. Thus, in the
following reactions, n-BuMgCl and MeLi was mixed at 0 ꢁC
and stirred at that temperature for 20 min before use.7
In the presence of 1 equiv. of MeLi,8 n-BuMgCl gave only a
small amount of the Michael adduct 2a under the same reaction
conditions (Entry 2). Good yields of 2a were obtained in the
presence of 2–5 equiv. of MeLi (Entries 3–6, in Table 1). There
was no remarkable difference when more than 3 equiv. of MeLi
was used (Entries 4–6). Though the identification of actual active
Table 2. Conjugate addition of R00MgX–3MeLi to secondary
ꢀ,ꢁ-unsaturated amides
Table 1. Effect of MeLi in the addition of n-BuMgCl to 1a
Temp/Time Yields/%a
Entry
R
R0
R00MgX
ꢁC/h
2
1
2
3
4
5
6
7
8
Me3Si Me PhMgBr
t-BuMgCl
rt/2
rt/2
0/5
ꢂ10=1
rt/3
ꢂ10=2
ꢂ30=1
rt/3
77
69b
40
66
43
74
59b
59
Yield/%a
2a
Entry
Molar ratio (n-BuMgCl:MeLi)a
Me
Ph
Ph n-BuMgCl
t-BuMgCl
PhMgBr
Ph n-BuMgCl
t-BuMgCl
PhMgBr
1
2
3
4
5
6
—
—
7
54
82
78
83
1:1
1:2
1:3
1:4
1:5
aIsolated yield. bThe product was not the Michael adduct 2 but
the contra-Michael adduct (2-t-butyl derivative).1
aMolar ratio of 1a:n-BuMgCl is 1:4. bIsolated yield.
Copyright ꢀ 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.6 (2007)
737
Table 3. Conjugate addition of R0MgX–3MeLi to ꢀ,ꢁ-unsatu-
rated carboxylic acids
1986, 25, 947; Y. Yamamoto, S. Yamamoto, H. Yatagai,
Y. Ishihara, K. Maruyama, J. Org. Chem. 1982, 47, 119;
Y. Yamamoto, K. Maruyama, J. Am. Chem. Soc. 1978,
100, 3240.
6
7
Under harsh reaction conditions, Grignard reagents react
with some ꢀ,ꢁ-unsaturated carboxylic acids to give low
yields of adducts: J. H. Wotiz, J. S. Matthews, H. Greenfield,
J. Am. Chem. Soc. 1953, 75, 6342; J. Klein, Tetrahedron
1964, 20, 465; J. Klein, N. Aminadav, J. Chem. Soc. C
1970, 1380; J. Klein, S. Zitrin, J. Org. Chem. 1970, 35, 666.
A typical procedure for secondary ꢀ,ꢁ-unsaturated amides:
To a solution of n-BuMgCl (0.89 M in THF, 2.3 mL, 2 mmol)
was added MeLi (1.13 M in Et2O, 5.3 mL, 6 mmol) at 0 ꢁC.
After stirring for 20 min at that temperature, 1a (75 mg,
0.5 mmol) in THF (5 mL) was added and the reaction
mixture was stirred under Ar at 20 ꢁC for 2 h. Quenching
with aqueous NH4Cl (2 mL), extraction with ethyl acetate,
and purification by silica gel TLC (hexane:AcOEt = 1:1)
gave 2a in 82% yield as a colorless oil.
Temp/Time Yields/%a
Entry
R
R0MgX
ꢁC/h
4
1
2
3
4
5
6
Ph
n-BuMgCl
s-BuMgCl
PhMgBr
ꢂ15=1:5
ꢂ15=1:5
40=3:5
ꢂ15=1:5
ꢂ30=1:5
rt/3
60
60
58
50b
67b
36b
PhCH2CH2 n-BuMgCl
t-BuMgCl
PhMgBr
aIsolated yield. bIsolated as the corresponding methyl ester.
Conjugate addition of RMgX–3MeLi reagents to ꢀ,ꢁ-unsat-
urated carboxylic acids was also demonstrated (Table 3). In
some cases, esterification with DMF dimethylacetal (at 80 ꢁC
for 2 h) was carried out to facilitate the purification of addition
products by p-TLC.11
Though the conjugate addition of t-BuMgCl–3MeLi to cin-
namic acid was unsuccessful, n-BuMgCl–3MeLi, s-BuMgCl–
3MeLi, and PhMgCl–3MeLi reacted with cinnamic acid to give
the corresponding Michael adducts in good yields (Entries 1–3).
The reaction of n-BuMgCl–3MeLi, t-BuMgCl–3MeLi,
PhMgCl–3MeLi with 5-phenyl-2-pentenoic acid gave Michael
adducts in good yields (Entries 4–6). In the above cases
also, no Michael adduct was obtained without MeLi under the
same reaction conditions and transfer of Me group from
RMgX–3MeLi reagents was not observed.
8
9
Presumably, the following equilibration presents under the
reaction conditions.
2n-BuMeMg ꢀ (n-Bu)2Mg þ Me2Mg
The equilibration of methyl groups in mixtures of MeMgX
and MeLi is believed to proceed via the formation of a series
of complexes as illustrated below.10
MeLi
ꢂꢂ!
MeLi
ꢂꢂ!
MeMgX
Me Mg
2
Me MgLi
3
ꢂꢂ
ꢂꢂ
MeLi
ꢂꢂ!
MeLi
ꢂꢂ!
Me MgLi
4
Me MgLi
5 3
ꢂꢂ
ꢂꢂ
2
For 1,2-addition of RMe2MgLi to carbonyl compounds, see:
H. Hatano, T. Matsumura, K. Ishihara, Org. Lett. 2005, 7,
573; For the chemistry of R3MgLi, see: S. Dumouchel,
F. Mongin, F. Trecourt, G. Queguinter, Tetrahedron Lett.
2003, 44, 2033; A. Inoue, J. Kondo, H. Shinokubo, K.
Oshima, Chem. Eur. J. 2002, 8, 1730; A. Inoue, K. Kitagawa,
H. Shinokubo, K. Oshima, J. Org. Chem. 2001, 66, 4333,
and references therein.
In conclusion, though the mechanistic investigations still
remain, activation of Grignard reagents with 3 equiv. of MeLi
was demonstrated.
We are grateful to Dr. K. Takenaka, of this university, for
measurement of MS spectra.
10 L. M. Seitz, T. L. Brown, J. Am. Chem. Soc. 1966, 88, 4140;
H. O. House, R. A. Latham, G. M. Whitesides, J. Org. Chem.
1967, 32, 2481.
References and Notes
1
T. Hinago, N. Teshima, S. Kenmoku, T. Kamata, N.
Terauchi, N. Chiba, C. Satoh, A. Nakamura, M. Asaoka,
Chem. Lett. 2007, 36, 54.
Similar behavior of MeLi has already been reported: M. J.
Aurell, R. Mestres, E. Munoz, Tetrahedron Lett. 1998, 39,
6351.
V. J. Lee, in Comprehensive Organic Synthesis, ed. by B. M.
Trost, I. Fleming, Pergamon, Oxford, 1991, Vol. 4, p. 74.
G. B. Mpango, K. K. Mahalanabis, Z. Mahadavi-Damghani,
V. Snieckus, Tetrahedron Lett. 1980, 21, 4823.
11 A typical procedure for ꢀ,ꢁ-unsaturated carboxylic acid: To
a solution of t-BuMgCl (1.01 M in THF, 1.0 mL, 1.0 mmol)
was added MeLi (1.13 M in Et2O, 2.7 mL, 3 mmol) at 0 ꢁC.
After stirring for 30 min at that temperature, the mixture
was cooled to ꢂ30 ꢁC. 5-Phenyl-2-pentenoic acid (45 mg,
0.25 mmol) in THF (4 mL) was added and the reaction mix-
ture was stirred under Ar at ꢂ30 ꢁC for 1.5 h. Quenching
with 2 M HCl (4 mL), extraction with ethyl acetate, and
concentration gave a crude oil which was treated with N,N-
dimethylformamide dimethyl acetal (300 mL) at 80 ꢁC
for 2 h. Condensation and purification by silica gel TLC
(hexane:AcOEt = 10:1) gave methyl 3-t-butyl-5-phenyl-2-
pentenoate in 67% yield as a colorless oil.
2
3
4
5
.
Organocuprous–boron trifluoride complexe, BuCu BF3,
gave 1,4-adducts by the reactions with crotonic acid and
tiglic acid: Y. Yamamoto, Angew. Chem., Int. Ed. Engl.
Published on the web (Advance View) May 9, 2007; doi:10.1246/cl.2007.736