Iron-catalyzed highly regio- and stereoselective conjugate addition of 2,3-allenoates with grignard reagents

Article abstract of DOI:10.1021/ja075750o

An efficient highly regio- and stereoselective iron-catalyzed conjugate addition of 2,3-allenoates with primary or secondary alkyl, phenyl, or vinyl Grignard reagents to synthesize multi-substituted β,γ-unsaturated enoates has been reported. The in situ f

Full text of DOI:10.1021/ja075750o

Published on Web 11/07/2007
Iron-Catalyzed Highly Regio- and Stereoselective Conjugate Addition of
2,3-Allenoates with Grignard Reagents
Zhan Lu,† Guobi Chai,† and Shengming Ma*,†,‡
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry, Zhejiang UniVersity, Hangzhou
310027, Zhejiang, PR China, and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, PR China
Received August 1, 2007; E-mail: masm@mail.sioc.ac.cn
Table 1. Effects of Solvent and the Amount of Catalyst on
Iron-Catalyzed Conjugate Addition of 2,3-Allenoate 1a
Iron, one of the most inexpensive metals, has recently attracted
great attention in organic synthesis.1 Iron catalysts have been applied
to various reactions, such as addition,2 oxidation,3 coupling,4
cyclization,5 allylic alkylation,6 etc.7 We know that it is not so easy
to prepare â,γ-unsaturated alkenoates due to the possible migration
of the C-C double bond to the conjugated R,â-position. In
principle, conjugate addition of 2,3-allenoates would be the most
convenient method.8 Addition reactions of lithium dialkylcuprates
or dialkenylcuprate with simple 2,3-allenoate9a or 2,3-allenoates
with functional groups, such as hydroxyl,9b methoxycarbonyl,9c or
4-ethylthio groups,9d afforded â,γ-unsaturated alkenoates with good
regio- and stereoselectivity; the reaction of organolithium with 2,3-
allenoates using CuCN‚2LiCl (0.5 equiv) also afforded â,γ-
unsaturated alkenoates with high regio- and moderate stereoselec-
tivity (86/14).9e,f However, these reactions require a stoichiometric
or substoichiometric amount of organocuprate reagents. To the best
of our knowledge, there is no report on the catalytic conjugate
addition of 2,3-allenoates with easily available organometallic
reagents. Herein, we wish to report an iron-catalyzed conjugate
addition of 2,3-allenoates with Grignard reagents in excellent regio-
and stereoselectivity.
First, we used ethyl 2-(n-propyl)-4-phenylbutadienoate 1a as
the substrate. The results of its reaction with methyl magnesium
chloride (3 equiv) at -78 °C in different solvents are summarized
in Table 1. With 20 mol % of Fe(acac)3, ethyl 2-(n-propyl)-3-
methyl-4-phenylbut-3-enoate (Z)-2a was afforded in 78% yield
with a Z/E ratio of 96/4 in THF; the yield of 2-(n-propyl)-3-methyl-
4-phenylbut-2-enoate 3a was at the extent of 0.5% (entry 2,
Table 1). In the absence of Fe(acac)3, no reaction occurred (entry
1, Table 1). However, when CH2Cl2 or n-hexane was used as the
solvent, the yield of 2a was lower with a poor stereoselectivity
(entries 3 and 4, Table 1). Fortunately, it was found that Et2O or
toluene is a very nice solvent for this reaction (entries 5 and 7,
Table 1). With 5 mol % of the catalyst, the yield and stereoselec-
tivity of the reaction in toluene were somewhat higher than those
in Et2O (compare entries 6, 8, and 9, Table 1). It was also quite
interesting to note that the reaction with 1.2 equiv of methyl
magnesium chloride afforded 2a with a lower stereoselectivity (Z/E
) 91/9) (entry 10, Table 1).10 Furthermore, the reaction could
even afford 2a in 73% yield with just 0.5 mol % of Fe(acac)3 (entry
12, Table 1). In the absence of Fe(acac)3, the reaction in toluene
was very slow (entry 13, Table 1). It should be noted that under
the catalysis of 20 mol % of CuCl2 the reaction in toluene afforded
(Z)-2a and 3a in 82 and 3% yields, respectively (entry 14, Table
1).
mol % of
catalyst
yield of (Z)-2a (%)
1a recoveredc
yieldc of
entry
solvent
(Z/E)c
(%)
3a (%)
1
2
3
4
5
6
7
8
9
-
20
20
20
20
5
20
10
5
5
2
0.5
-
20
THF
THF
CH2Cl2
n-hexane
Et2O
-
77
-
2
-
0.5
3
78 (96/4)
50 (74/26)
50 (83/17)
81 (98/2)
77 (99/1)
71 (98/2)
75 (99/1)
81 (>99/1)
76 (91/9)
82 (>99/1)
73 (>99/1)
29 (>99/1)
82 (>99/1)
6
1.5
1.1
0.4
1
0.4
0.8
1.5
0.3
1.5
2
-
-
-
-
-
-
2
6
56
-
Et2O
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
10a
11
12b
13
14d
3
a CH3MgCl (1.2 equiv) was applied. b The reaction time was 5 h.
c Determined by NMR. d CuCl2 used instead of Fe(acac)3.
reaction conditions. The typical results shown in Table 2 indicated
that the reaction is quite general, forming â,γ-unsaturated alkenoates
with very high regio- and stereoselectivity. R1 may be alkyl or aryl;
R2 may be H, alkyl, or benzyl; R3 may be alkyl or Bn. In addition
to primary alkyl Grignard reagent, secondary alkyl Grignard reagent
may also be applied to afford corresponding products in good yields
(entries 10-13, Table 2). The reaction of 1i and 1j with phenyl
magnesium chloride afforded the products in the same yields (63%)
(entries 14 and 15, Table 2). Vinyl magnesium chloride may also
be used in the reaction (entries 16 and 17, Table 2).
In terms of mechanism, the reaction of Fe(acac)3 with Grignard
reagent R4MgX may form the iron-magnesium ate complex 4.4d,f
The subsequent conjugate addition with the electron-deficient R,â-
carbon-carbon double bond in 2,3-allenoates would form 1,3-
dienolate intermediate 7 highly stereoselectively, probably due to
the steric interaction between the R1 and R4 group in the transition
state 6. Upon transmetalation of 7 with R4MgX, magnesium 1,3-
dienolate 82g was formed with the regeneration of the catalytically
active species 4 (Scheme 1).
Thus, we defined 2 mol % of Fe(acac)3, 3 equiv of Grignard
reagents, and toluene as the solvent at -78 °C as the standard
The in situ formation of magnesium dienolate may be trapped
with D2O to afford the 2-D-3-methyl-4-phenyl-2-propyl-3-butenoate
9 in 89% yield with a D incorporation of 97% (Scheme 2).
† Zhejiang University.
‡ Chinese Academy of Sciences.
9
14546
J. AM. CHEM. SOC. 2007, 129, 14546-14547
10.1021/ja075750o CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Iron-Catalyzed Carbomagnesiation of 2,3-Allenoatesa
Scheme 3
time
(h)
yieldd of
entry
R1
R2
R3
R4
2 (%)
1b
2c
Ph
Ph
Ph
Ph
p-BrC6H4
p-BrC6H4
n-C7H15
n-C4H9
Ph
Ph
n-C7H15
Ph
n-C7H15
n-C4H9
n-C7H15
Ph
n-Pr
n-Pr
n-Pr
Me
n-Pr
Me
n-Pr
Bn
n-Pr
n-Pr
n-Pr
Me
n-Pr
H
H
n-Pr
n-Pr
Et (1a)
Me (1b)
Bn (1c)
Et (1d)
Et (1e)
Et (1f)
Et (1g)
Me (1h)
Et (1a)
Et (1a)
Et (1g)
Et (1d)
Et (1g)
Et (1i)
Me
Me
Me
Me
Me
Me
Me
Me
n-Bu
c-Hex
c-Hex
c-Hex
s-Bue
Ph
Ph
vinyl
vinyl
2
3
2
1.5
1
1.5
5
1.5
1
1.7
1
1
77 (2a)
86 (2b)
84 (2c)
88 (2d)
88 (2e)
88 (2f)
85 (2g)
85 (2h)
70 (2i)
86 (2j)
90 (2k)
78 (2l)
94 (1m)
63 (2n)
63 (2o)
82 (1p)
86 (1q)
3b
4
5
6c
Acknowledgment. Financial support from the international
program issued by National Natural Science Foundation of China,
theMajorStateBasicResearchDevelopmentProgram(2006CB806105),
and Cheung Kong Scholar Programme is greatly appreciated. This
work was conducted at Zhejiang University. We thank Mr. Guofei
Chen in this group for reproducing the results presented in entries
3 and 6 of Table 2.
7b
8
9b
10b
11b
12b
13b
14
15b
16b
17b
1
2
1
1
Et (1j)
Et (1a)
Et (1g)
Supporting Information Available: Spectroscopic data and general
procedure (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
n-C7H15
1
a The reaction was conducted using 0.4 mmol of 2,3-allenoates, 3 equiv
of the Grignard reagents (solution in THF), and 2 mol % of Fe(acac)3 in 5
mL of toluene at -78 °C. b Fe(acac)3 (5 mol %) was used. c Fe(acac)3 (0.5
mol %) was used. d Isolated yield. e s-Butyl magnesium bromide was used.
References
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Scheme 2
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(Scheme 3).
In summary, we have developed an efficient regio- and ste-
reospecific iron-catalyzed conjugate addition of 2,3-allenoates with
1°- and 2°-alkyl, phenyl, or vinyl Grignard reagents. This protocol
introduces the R4 group from the Grignard reagents to the â-position
of the ester group with the R4 group trans to the R1 group at the
4-position in the remaining â,γ-carbon-carbon double bond. The
in situ formed magnesium dienolate may also react with different
electrophiles to prepare a series of compounds containing an allylic
quaternary carbon at the R-position of the ester group. Further
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(10) For details, see Table S1 in the Supporting Information.
JA075750O
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J. AM. CHEM. SOC. VOL. 129, NO. 47, 2007 14547