Iron-catalyzed chemoselective cross-coupling of α-bromocarboxylic acid derivatives with aryl grignard reagents

Article abstract of DOI:10.1246/cl.2011.1012

We have developed a simple and effective synthetic method of α-arylcarboxylic acid derivatives based on the iron-catalyzed cross-coupling reaction of α-bromocarboxylic acid derivatives with aryl Grignard reagents. The reaction proceeds smoothly at -78 °C in a chemoselective manner to produce the coupling product in good to excellent yields.

Full text of DOI:10.1246/cl.2011.1012

doi:10.1246/cl.2011.1012
1012
Published on the web September 5, 2011
Iron-catalyzed Chemoselective Cross-coupling of ¡-Bromocarboxylic Acid Derivatives
with Aryl Grignard Reagents
Masayoshi Jin1,2 and Masaharu Nakamura*2
1Process Technology Research Laboratories, Pharmaceutical Technology Division, Daiichi Sankyo Co., Ltd.,
1-12-1 Shinomiya, Hiratsuka, Kanagawa 254-0014
2International Research Center for Elements Science (IRCELS), Institute for Chemical Research,
Kyoto University, Uji, Kyoto 611-0011
(Received June 28, 2011; CL-110540; E-mail: masaharu@scl.kyoto-u.ac.jp, m.jin@at2.ecs.kyoto-u.ac.jp)
We have developed a simple and effective synthetic method
of ¡-arylcarboxylic acid derivatives based on the iron-catalyzed
cross-coupling reaction of ¡-bromocarboxylic acid derivatives
with aryl Grignard reagents. The reaction proceeds smoothly at
¹78 °C in a chemoselective manner to produce the coupling
product in good to excellent yields.
Table 1. Cross-coupling of bromoacetate 1a with aryl Grignard
reagents
catalyst
R
R
O
(1.0 mol%)
O
+
Br
Ot-Bu
THF
–78 °C, 1 h
MgBr
Ot-Bu
1a
2
3
+
R
R
4
¡-Arylcarboxylic acids and their derivatives are useful
synthetic intermediates of pharmaceuticals, or important bio-
active compounds themselves, such as loxoprofen or lumira-
coxib.1 Due to their significance, a number of synthetic methods
for this class of compounds have been already developed,2
however, further effort is needed to establish more practical
methods to overcome several drawbacks associated with the
classical methods: for example, the use of toxic reagents such as
NaCN, the requirement of multistep transformations and/or
harsh reaction conditions, just to name a few. Catalytic cross-
coupling reactions have been recognized as a straightforward
strategy to synthesize ¡-arylcarboxylic acid derivatives from
aryl halides with preformed or in situ generated enolates by a
single-step operation. The most popular metal catalysts utilized
are palladium3 and nickel.3a,4 However, the disadvantages are
the usage of toxic and expensive catalysts, the need for the
preparation of the enolate substrate, undesired side reactions
such as multiple arylation, and racemization at the ¡-carbon
atom of the carbonyl group. We envisioned that iron catalysts
can solve the above problems since iron makes low-toxic,
economical, and environmentally friendly catalysts. In addition,
we anticipated that the easily available ¡-bromocarboxylic acid
derivatives5 could be used as the electrophilic substrate due to
the distinctive reactivity of the iron catalyst toward alkyl halide
electrophiles.5,6 Herein we report the cross-coupling reaction of
¡-bromocarboxylic acid derivatives with aryl Grignard reagents
in the presence of a catalytic amount of Fe(acac)3.
For the purpose of catalyst screening, tert-butyl bromo-
acetate (1a) was coupled with p-tolylmagnesium bromide in the
presence of various metal catalysts (Table 1). To minimize the
undesired nucleophilic attack of the Grignard reagent to the
carbonyl group, we chose the bulky tert-butyl ester, and the
reactions were carried out at ¹78 °C. In the absence of a
transition-metal catalyst, the desired product 3 was formed in
15% yield along with 42% recovery of 1a after 1 h; it is
noteworthy that, after 24 h, the coupling product 3 was obtained
in a decreased yield (5%) despite the further consumption of 1a
(Entries 1 and 2). Conceivably, side-reactions including nucle-
ophilic attack to the ester group and halogen-metal exchange
reaction competed with the coupling reaction, and several
Products RSM
(Yield/%)b /%
Entry ArMgBr (equiv)
Catalysta
3
4c
1a
1
p-tolMgBr (2.0)
none
none
15 <1
42
21
2d p-tolMgBr (2.0)
5
<1
12
8
8
11
8
9
9
8
5
e
3
4
5
6
7
8
9
p-tolMgBr (2.0)
p-tolMgBr (2.0)
p-tolMgBr (2.0)
p-tolMgBr (2.0)
p-tolMgBr (2.0)
p-tolMgBr (1.5)
p-tolMgBr (1.2)
FeCl2(dppbz)2 74
Fe complex 5e 77
Fe complex 6e 84
<1
<1
<1
<1
<1
<1
10
<1
<1
47
FeCl3
77
85
84
62
82
84
5
Fe(acac)3
Fe(acac)3
Fe(acac)3
Co(acac)2
Ni(acac)2
Cu(acac)2
Pd(acac)2
Fe(acac)3
(0.1 mol %)
Co(acac)2
(0.1 mol %)
Ni(acac)2
(0.1 mol %)
10 p-tolMgBr (2.0)
11 p-tolMgBr (2.0)
12 p-tolMgBr (2.0)
13 p-tolMgBr (2.0)
5
<1
5
49
14 p-anisylMgBr (1.5)
15 p-anisylMgBr (1.5)
16 p-anisylMgBr (1.5)
85
32
34
4
1
1
<1
36
37
a1.0 mol % catalyst was used unless otherwise noted. Yields
were determined by NMR using 1,1,2,2-tetrachloroethane as
an internal standard. Based on the amount of the ArMgBr 2
used. dThe reaction was carried out for 24 h. eStructures of iron
complexes are shown below.
b
c
R
R
Ph2
P
Ph2
P
Cl
Fe
Cl
R
R
R
R
P
P
P
P
Ph2
Ph2
Fe
5: R = t-Bu
6: R = TMS
[FeCl2(dppbz)2]
Cl
Cl
R
R
unidentified by-products were obtained under the reaction
conditions. On the other hand, the desired cross-coupling
reaction proceeded smoothly in the presence of 1 mol % iron
catalyst regardless of the forms of the precatalyst used (Entries
Chem. Lett. 2011, 40, 1012-1014
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1013
Table 2. Cross-coupling of ¡-bromocarboxylic acid deriva-
tives with aryl Grignard reagents
3-7): p-tolylacetate 3 was obtained in 74-85% yield, accom-
panied by the formation of the by-product 4,4¤-dimethylbiphenyl
(4) in 8-12% yield. Fe(acac)3 gave the coupling product in the
highest yield (85%) with the minimum amount of by-product 4
(Entry 7).7 The coupling product was obtained in 84% even
when the amount of the Grignard reagent was reduced to 1.5
equivalents (Entry 8). The reaction proceeded in a chemo-
selective manner, and none of the alcohol or ketone by-products,
potentially formed by the Grignard addition reaction, was
O
O
Fe(acac)3 (1.0 mol%)
Br
+
X
X
MgBr
R2
THF
–78 °C, 1 h
R2
R1
R1
1
2
3
Entry
1
Electrophile
ArMgBra
Coupling product
O
Yieldb/%
1a
78
(R1 = H, X = Ot-Bu)
MgBr
Ot-Bu
2a
2a
3a
3b
1
detected by GC or H NMR. The yield of the cross-coupling
O
O
<1c
15c
product significantly depends on the experimental procedure,8,9
and the best result was obtained by the representative procedure
described in note 8.
2
3
1b
(R1 = H, X = OMe)
OMe
1c
2a
2a
Oi-Pr
Ot-Bu
The catalytic activities of the other transition metals were
also studied by using the corresponding acetylacetonato com-
plexes as in Entries 10-13:10 Co(acac)2 and Ni(acac)2 showed
a comparable catalytic activity with Fe(acac)3 to give the
product in 82% and 84% yields, respectively (Entries 10 and
11). The yields were substantially lower with the Cu(acac)2 or
Pd(acac)2 catalyst (Entries 12 and 13). The reaction of 1a
with p-tolylmagnesium bromide was equally catalyzed by the
acetylacetonato complexes of iron, cobalt, and nickel. On the
other hand, clear difference among these metals was observed in
the cross-coupling of 1a with p-anisylmagnesium bromide at a
lower catalyst loading; only 0.1 mol % of Fe(acac)3 gave the
coupling product in 85% yield (Entry 14), while 0.1 mol % of
Co(acac)2 and Ni(acac)2 gave the product in 32% and 34%
yields, respectively (Entries 15 and 16). The results of the side-
by-side experiments with various transition metals suggest that a
trace metal contaminant, if any, is not likely to be acting as the
true effective catalyst for the present iron-catalyzed coupling
reaction.10 Because of the high catalytic activity as well as the
economical and operational advantages of the iron complex, we
chose Fe(acac)3 as the precatalyst for the following studies.
Table 2 summarizes the scope of the present arylation
reaction of ¡-bromocarboxylic acid derivatives. The size of the
ester alkoxy substituent is critical for maximizing the yield of
the desired coupling products. The larger substituents gave the
better yields: the reaction with methyl bromoacetate (1b) did not
give the coupling product due to the competitive nucleophilic
addition of the Grignard reagent to the ester group, only to afford
a mixture of the alcohol and ketone by-products (Entry 2). When
isopropyl bromoacetate (1c) was subjected to the same reaction
conditions, the coupling product was obtained in 15% yield
along with the formation of several by-products (Entry 3). tert-
Butyl ¡-bromopropionate (1d), a secondary alkyl bromide, gave
low yield even when the reaction was carried out according to
Fürstner’s conditions (Entry 4). It should be noted that Fürstner
reported the reaction of ethyl ¡-bromobutyrate with phenyl-
magnesium bromide gave the coupling product in 87% yield in
the presence of [Li(tmeda)]2[Fe(C2H4)4].5 Our result suggests the
low-valent iron species proposed in Fürstner’s report are not
likely to be involved as the catalytically active species in the
present coupling reaction. A moderate yield was obtained
when N,N-diethylbromoacetamide (1e) was used as a substrate
(Entry 5).
(R1 = H, X = Oi-Pr)
3c
O
16c, 26c,d
4
1d
(R1 = Me, X = Ot-Bu)
3d
3e
3f
O
5
1e
44
84
2a
(R1 = H, X = NEt2)
NEt2
MeO
MeO
O
6e,f
1a
1a
1a
1a
1a
MgBr
Ot-Bu
2b
2c
F
F
O
O
7
8
90
81
70
41
MgBr
Ot-Bu
Ot-Bu
3g
Cl
Cl
MgBr
2d
2e
3h
3i
O
O
9
MgBr
MgBr
Ot-Bu
Ot-Bu
10
2f
3j
F
F
O
O
11
12
1a
1a
90
70
MgBr
Ot-Bu
Ot-Bu
2g
2h
3k
3l
F
F
F
MgBr
F
O
O
13
14
1a
1a
53
MgBr
MgBr
Ot-Bu
Ot-Bu
2i
2j
3m
3n
18c
O
O
37c
82
15
16
1a
1a
MgBr
Ot-Bu
2k
2l
3o
3p
MgBr
Ot-Bu
a1.5 equivalents of Grignard reagents were used in Entries 1-8,
and 3.0 equivalents of Grignard reagents were used in Entries
b
c
9-16. Isolated yields unless otherwise noted. NMR yields.
dReaction was carried out according to the Fürstner’s
conditions (see note 5): Fe(acac)3 (5 mol %), ArMgBr (1.2
Reactions of 1a with a variety of arylmagnesium bromides
were studied next: p-substituted aryl Grignard reagents such as
p-tolyl (2a), p-anisyl (2b), p-fluorophenyl (2c), and p-chloro-
phenyl (2d) Grignard reagents gave the desired products in high
e
equiv), THF, ¹20 °C, 0.5 h. 0.1 mol % of Fe(acac)3 was used.
f20 mmol scale see note 8.
Chem. Lett. 2011, 40, 1012-1014
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1014
coupling partners under iron catalysis: R. Martin, A. Fürstner,
Angew. Chem., Int. Ed. 2004, 43, 3955.
yields (Entries 1 and 6-8). m-Tolyl (2e) and o-tolyl (2f) Grignard
reagent gave the corresponding arylation products in fair to
modest yields (Entries 9 and 10). Disubstituted aryl Grignard
reagents including 4-fluoro-3-methylphenyl (2g),11 3,4-difluoro-
phenyl (2h),12 and 3,5-xylyl (2i)13 Grignard reagents afforded
the coupling products in moderate to high yields (Entries 11-
13). In contrast, a low yield (18%) was obtained when
mesitylmagnesium bromide (2j), a trisubstituted aryl Grignard
reagent, was used (Entry 14). This result suggested that the
present reaction is sensitive to the steric hindrance of aryl
Grignard reagents. The reactions of 1a with 1-naphthylmagne-
sium bromide (2k) and 2-naphthylmagnesium bromide (2l)
further support this conclusion: the more sterically demanding
reagent 2k gave the product in 37% yield, while the less
demanding reagent 2l gave the product in 82% yield (Entries 15
and 16). Although the reaction mechanism remains unclear at
the current stage of the study, we suppose that bare ferrate
species, which do not bear any auxiliary ligand, are responsible
for the coupling reaction based on the observation that all the
iron complexes examined in this study gave comparable results
despite the ligands on the precatalyst, and also that extra
additives did not affect the coupling reactions.14 In order to
expand the substrate scope of the present reaction and also to
develop an asymmetric variant of the ¡-arylation reaction,
detailed mechanistic studies will be needed to clarify the
catalytically active species. Further investigation along this line
is ongoing in our laboratory and will be reported in due course.
6
a) T. Nagano, T. Hayashi, Org. Lett. 2004, 6, 1297. b) R. B.
Bedford, D. W. Bruce, R. M. Frost, J. W. Goodby, M. Hird, Chem.
Commun. 2004, 2822. c) M. Nakamura, K. Matsuo, S. Ito, E.
Nakamura, J. Am. Chem. Soc. 2004, 126, 3686. d) R. B. Bedford,
D. W. Bruce, R. M. Frost, M. Hird, Chem. Commun. 2005, 4161. e)
R. B. Bedford, M. Betham, D. W. Bruce, A. A. Danopoulos, R. M.
Frost, M. Hird, J. Org. Chem. 2006, 71, 1104. f) G. Cahiez, V.
Habiak, C. Duplais, A. Moyeux, Angew. Chem., Int. Ed. 2007, 46,
4364.
7
8
Fe(acac)3 was purchased from Aldrich Chemical Co. and readily
applied to the coupling reaction without purification.
A representative procedure (Table 2, Entry 6): Under a positive
pressure of argon, to a solution of tert-butyl bromoacetate (3.89 g,
19.9 mmol) in dry THF (40.0 mL) was dropwise added a p-
anisylmagnesium bromide solution (1.0 M in THF, 30.0 mL,
1.5 equiv) at ¹78 °C. To the mixture was slowly added a solution
of Fe(acac)3 (7.1 mg, 0.1 mol %) in dry THF (4.0 mL) over 1 h, and
the resulting mixture was stirred at ¹78 °C for 1 h. After quenching
with 3 M aqueous solution of hydrochloric acid, the mixture was
extracted with EtOAc, passed through a pad of Florisilμ, and
concentrated in vacuo. The residue was chromatographed on silica
gel (n-hexane/toluene = 4/1, 2/1, 1/1) to give the desired product
(3.74 g, 84%, colorless oil).
The yields of the desired coupling products decreased dramatically
when the reaction was carried out under the procedure described as
follows: to a pre-cooled mixture of a bromoacetate and an iron
catalyst was slowly added a THF solution of a Grignard reagent, the
corresponding ¡-arylated ester was obtained in less than 30% yield.
9
10 a) S. L. Buchwald, C. Bolm, Angew. Chem., Int. Ed. 2009, 48, 5586.
b) R. B. Bedford, M. Nakamura, N. J. Gower, M. F. Haddow, M. A.
Hall, M. Huwe, T. Hashimoto, R. A. Okopie, Tetrahedron Lett.
2009, 50, 6110.
This research is granted by the Japan Society for the
Promotion of Science (JSPS) through the “Funding Program for
Next Generation World-Leading Researchers (NEXT Program),”
initiated by the Council for Science and Technology Policy
(CSTP). Financial support from Daiichi Sankyo Co., Ltd. is
gratefully acknowledged.
11 Compound data of the corresponding product, tert-butyl (4-fluoro-3-
methylphenyl)acetate (3k): IR (neat, cm¹1): ¯ 2978, 1728, 1607,
1
1367, 1295, 1254, 1136, 1038, 954, 851, 796, 753, 688; H NMR
(392 MHz, CDCl3): ¤ 1.44 (s, 9H), 2.25 (d, J = 1.8 Hz, 3H), 3.45 (s,
2H), 6.89-6.99 (m, 1H), 7.00-7.11 (m, 2H); 13C NMR (99 MHz,
CDCl3): ¤ 14.5 (d, J = 3.8 Hz), 28.0 (3C), 41.7, 80.9, 114.9 (d,
J = 22.5 Hz), 124.7 (d, J = 16.9 Hz), 127.9 (d, J = 7.5 Hz), 130.0
(d, J = 3.8 Hz), 132.3 (d, J = 4.7 Hz), 160.4 (d, J = 244 Hz), 171.0;
HRMS m/z: M+ calcd for C13H17FO2 224.1213; found, 224.1213;
Anal. Calcd for C13H17FO2: C, 69.62; H, 7.64; F, 8.47%. Found: C,
69.66; H, 7.69; F, 8.38%.
This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
12 Compound data of the corresponding product, tert-butyl (3,4-
difluorophenyl)acetate (3l): IR (neat, cm¹1): ¯ 2978, 1731, 1501,
1367, 1252, 1209, 1136, 957, 884, 799, 753, 711; 1H NMR (392
MHz, CDCl3): ¤ 1.44 (s, 9H), 3.48 (s, 2H), 6.95-7.02 (m, 1H), 7.09-
7.15 (m, 2H); 13C NMR (99 MHz, CDCl3): ¤ 28.0 (3C), 41.7, 81.3,
117.1 (d, J = 16.9 Hz), 118.2 (d, J = 17.8 Hz), 125.3 (dd, J = 5.6,
3.8 Hz), 131.5 (dd, J = 5.6, 3.8 Hz), 149.4 (dd, J = 247, 12.2 Hz),
150.2 (dd, J = 248, 12.2 Hz), 171.2; HRMS m/z: M+ calcd for C12-
H14F2O2, 228.0962; found, 228.0957; Anal. Calcd for C12H14F2O2:
C, 63.15; H, 6.18; F, 16.65%. Found: C, 63.12; H, 6.23; F, 16.68%.
13 Compound data of the corresponding product, tert-butyl (3,5-
xylyl)acetate (3m): IR (neat, cm¹1): ¯ 2979, 1728, 1610, 1517,
1437, 1368, 1283, 1208, 1136, 968, 873, 791, 767, 753, 710;
1H NMR (392 MHz, CDCl3): ¤ 1.44 (s, 9H), 2.30 (s, 6H), 3.45 (s,
2H), 6.88 (s, 3H); 13C NMR (99 MHz, CDCl3): ¤ 21.5 (2C), 28.1
(3C), 42.4, 80.7, 127.0 (2C), 128.5, 134.4, 137.9 (2C), 171.2;
HRMS m/z: M+ calcd for C14H20O2, 220.1463; found, 220.1468;
Anal. Calcd for C14H20O2: C, 76.33; H, 9.15; O, 14.52%. Found: C,
76.25; H, 9.23; O, 14.78%.
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14 The iron-catalyzed coupling reaction of tert-butyl bromoacetate
with o-tolylmagnesium bromide was carried out in the presence of
the following additives: the ¡-arylated ester was obtained in 42%,
6%, and 1% yield in the presence of 1,4-dioxane (10 equiv),
N-methylpyrrolidone (NMP, 10 equiv), and N,N,N¤,N¤-tetramethyl-
ethylenediamine (TMEDA, 3.0 equiv), respectively.
4
5
K. Tamao, M. Zembayashi, M. Kumada, Chem. Lett. 1976, 1239.
There is only sporadic reported literature example of utilizing
¡-bromocarboxylic acid derivatives and arylmetal reagents as the
Chem. Lett. 2011, 40, 1012-1014
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/