Lithiation of aryl bromides possessing α-proton of carbonyl groups

Article abstract of DOI:10.1055/s-2002-22727

A new methodology for metalation of aryl bromide possessing an active methylene adjacent to carbonyl groups is described. In order to avoid self-quenching, selective deprotonation was necessary prior to halogen-metal exchange reaction. For this purpose, m

Full text of DOI:10.1055/s-2002-22727

LETTER
561
Lithiation of Aryl Bromides Possessing -Proton of Carbonyl Groups
Lithiation of
Aryl
uBromides hei Yamamoto,* Kenji Maeda, Koji Tomimoto, Toshiaki Mase
Process Research, Process R&D, Laboratories for Technology Development, Banyu Pharmaceutical Co., Ltd., Kamimutsuna 3-
chome-9-1, Okazaki, Aichi 444-0858, Japan
Fax +81(564)517086; E-mail: yammtoyh@banyu.co.jp
Received 27 December 2001
(Scheme 1).4 Herein we wish to report metal-halogen ex-
change reaction of aryl bromide possessing an active
methylene adjacent to carbonyl groups, and its application
to the lithiation of -(4-bromophenyl)alanine side struc-
Abstract: A new methodology for metalation of aryl bromide pos-
sessing an active methylene adjacent to carbonyl groups is de-
scribed. In order to avoid self-quenching, selective deprotonation
was necessary prior to halogen-metal exchange reaction. For this
purpose, mesityllithium was found to be the best choice. Subse- ture 3.
quent treatment with n-BuLi resulted in the lithium-bromine ex-
change to generate the dianion, which was successfully trapped
with some electrophiles in good yield. This method was applied to
NH2
CONH2
the efficient synthesis of a novel carbapenem.
HO
H
H
N
Key words: aryllithium, active methylene, lithium-bromine ex-
change reaction, intramolecular protonation, enolate, mesityllithi-
um
S
NH
O
·
CO2H
XHCl
1
Metal-halogen exchange reaction is an important transfor-
mation, which mediates functionalization of aryl and vi-
nyl compounds in synthetic organic chemistry. Metalation
of a variety of functionalized aryls and vinyls using Zn
and Mg have been reported to date.1 However, there is no
report on metal-halogen exchange reaction of aryl halides
possessing an acidic proton at the carbon adjacent to func-
tional groups such as carbonyl, nitrile, and sulfonyl
groups, which stabilize their -carbanions, probably due
to the self protonation/deprotonation.2 In the course of
studies toward a practical and large scale synthesis of our
drug candidate, carbapenem 1 (Figure 1),3 we required a
clean metalation of -(4-bromophenyl)alanine side struc-
ture 3 for an efficient synthesis of the thiol side chain 2
Figure 1
Reactions of tert-butyl 3-(4-bromophenyl)propionate 5a
as a representative of aryl halide having a proton to an
ester group with various metalating agents are summa-
rized in the Table. Treatment of 5a with sec-BuLi at –78
°C, followed by quenching with water gave the protonated
product 7a in 53% yield, indicating that the bromine-lith-
ium exchange reaction certainly took place.5,6 Attack of
sec-BuLi on the ester was observed as a major side reac-
tion. To our surprise, quenching with DMF instead of wa-
ter did not give the formylated product 6a, and the
protonated product 7a was obtained (Figure 3) in a similar
NH2
NR2
CONH2
COOtBu
O
TBSO
NBoc
HS
Br
NH
2
3
4
Scheme 1
O-Li+
O-Li+
R
COR
n-BuLi
Base
R
Br
Br
Li
Figure 2
Synlett 2002, No. 4, 29 03 2002. Article Identifier:
1437-2096,E;2002,0,04,0561,0564,ftx,en;Y25901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

562
Y. Yamamoto et al.
LETTER
yield as above (entry 1). It is most likely that the aryllith-
ium generated from the bromine-lithium exchange reac-
tion was quenched with the acidic proton(s) on the carbon
adjacent to the ester group. Therefore, we desired a new
methodology to obviate the intramolecular quenching.
Our initial concept involved deprotonation of an acidic
proton first with a non-nucleophilic base (which is not ca-
pable of metal-halogen exchange reaction) and subse-
quent metal-halogen exchange on the aromatic ring with
n-BuLi (Figure 2).7
Table Reactions of tert-Butyl 3-(4-Bromophenyl)propionate 5a
with Various Metalating Agents
Entry
R
Base/Metalating
Agent
5
6
7
1
2
t-BuO
t-BuO
sec-BuLi
n.d.a
n.d.
n.d.
18
53
64
LDA (1.1 equiv)/
n-BuLi (2.6 equiv)
3
4
5
t-BuO
t-BuO
t-BuO
MeLi (1.2 equiv)/
n-BuLi (2.2 equiv)
16
n.d.
n.d.
74
21
13
<5
Lithium amides such as LDA was not valuable for this
purpose since the resulting amine can act as a proton
source (entry 2). Metal hydride such as sodium hydride
might be useful, however, evolution of hydrogen gas is
not amenable to large-scale synthesis. Alkyllithiums like
as MeLi and PhLi ended in competition with attack at the
ester group (entries 3 and 4). It has been reported that
bulky, non-nucleophilic mesityllithium is able to cleanly
produce enolates of carbonyl compounds.8 In addition, the
resulting mesitylene no longer acts as a proton source. In
this regard, the combination of mesityllithium (as a base
to generate the ester enolate) and n-BuLi (as an agent to
raise the bromine-metal exchange reaction) seemed to be
of the best choice. In fact, treatment of 5a with 1.1 equiv-
alents of mesityllithium, followed by 1 equivalent of n-
BuLi generated the dianion, which was trapped with DMF
to afford the desired the formylated product in 74% yield
(entry 5).9 Mesityllithium has been recently reported to
undergo iodine-lithium exchange reaction, but such reac-
tion was not observed in this case.10 Even when 2 equiva-
lents of mesityllithium were used, the second
mesityllithium left the bromide intact (entry 6). Mesityl-
lithium did not attack a smaller alkyl ester such as ethyl
ester 5b (entry 7) and tolerated the diethylamide 5c (entry
8). Thus, mesityllithium was found to be a very useful
base for the enolate formation, with no reaction with aryl-
bromide and regeneration of a proton donor.
PhLi (1.2 equiv)/
n-BuLi (1.3 equiv)
10
Mesityllithium
(1.1 equiv)/n-BuLi
(1 equiv)
n.d.
6
7
t-BuO
Mesityllithium
(2 equiv)
95
n.d.
71
n.d.
<5
EtO
Mesityllithium
(1.1 equiv)/n-BuLi
(1 equiv)
n.d.
8
NEt2
Mesityllithium
(1.1 equiv)/n-BuLi
(1 equiv)
n.d.
67
<5
a n.d. = not determined
Next, we applied this methodology to the synthesis of the
thiol side chain of novel carbapenem 1. -Amino acid
fragment 11 was prepared as shown in Scheme 2. 4-Bro-
mobenzaldehyde (8) was converted to , -unsaturated t-
butyl ester 9 by Horner–Emmons reaction (96%). Subse-
quent asymmetric Michael reaction using (R)-N-( -meth-
ylbenzyl)benzylamine (10) gave 11 in good yield and
selectivity (95%, 94% de).11,12
1) Base and/or
Metalating agent
COR
COR
COR
+
2) BuLi
3) DMF
4) H2O
Br
OHC
H
R = OtBu, 5a
= OEt, 5b
= NEt2, 5c
6a-c
7a-c
Figure 3
(R)
Ph
N
Ph
Ph
N
H
Ph
COOtBu
COOtBu
CHO
(a)
10
(S)
(b)
Br
Br
Br
11
9
8
Scheme 2 Reagents and conditions: (a) (EtO)2P(O)CH2COO-t-Bu, NaH, toluene (b) 10 (2 equiv), n-BuLi (2 equiv), THF, –78 °C.
Synlett 2002, No. 4, 561–564 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Lithiation of Aryl Bromides
563
With the desired -(4-bromophenyl)alanine fragment 11
in hand, we then implemented our protocol. Treatment of
11 with mesityllithium followed by treatment with n-BuLi
generated the dianion 12 (Figure 4), which was quenched
with DMF to afford the desired formylated product 13
(Figure 4) in 87% yield.
References
(1) (a) Boudier, A.; Bromm, O. D.; Lotz, M.; Knochel, P.
Angew. Chem. Int. Ed. 2000, 39, 4414. (b) Inoue, A.;
Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem.
2001, 66, 4333. (c) Kitagawa, K.; Inoue, A.; Shinokubo, H.;
Oshima, K. Angew. Chem. Int. Ed. 2000, 39, 2481.
(d) Uchiyama, M.; Kameda, M.; Mishima, O.; Yokoyama,
N.; Koike, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc.
1998, 120, 4934.
(2) Lithium-halogen exchange reaction of aryl halides bearing
more acidic functionalities has been reported: (a) Beak, P.;
Musick, T. J.; Liu, C.; Cooper, T.; Gallaher, D. J. J. Org.
Chem. 1993, 58, 7330. (b) Narasimhan, N. S.; Sunder, N.;
Liu, C.; Ammanamanchi, R.; Bonde, B. D. J. Am. Chem.
Soc. 1990, 112, 4431. (c) Beak, P.; Musick, T. J.; Chen, C.-
W. J. Am. Chem. Soc. 1988, 110, 3538.
(3) (a) Imamura, H.; Ohtake, N.; Shimizu, A.; Sato, H.;
Sugimoto, Y.; Sakuraba, S.; Kiyonaga, H.; Suzuki-Sato, C.;
Nakano, M.; Nagano, R.; Yamada, K.; Hashizume, T.;
Morishima, H. Bioorg. Med. Chem. Lett. 2000, 10, 115.
(b) Nagano, R.; Shibata, K.; Adachi, Y.; Imamura, H.;
Hashizume, T.; Morishima, H. Antimicrob. Agents
Chemother. 2000, 44, 489. (c) Hashizume, T.; Morishima,
H. Drugs of the Future 2001, 25, 833.
Ph
1)
Ph
N
O-Li+
OtBu
Ph
N
Ph
Li
COOtBu
2) n-BuLi
Li
Br
11
12
Ph
N
Ph
1) DMF
2) H2O
COOtBu
OHC
13
(4) (a) Maeda, K.; Yamamoto, Y.; Tomimoto, K.; Mase, T.
Synlett 2001, 1808. (b) Sugimoto, Y.; Imamura, H.; Sako,
H.; Yamada, K.; Morishima, H. Synlett 2001, 1747.
(c) Imamura, H.; Shimizu, A.; Sato, H.; Sugimoto, Y.;
Sakuraba, S.; Nakajima, S.; Abe, S.; Miura, K.; Nishimura,
I.; Yamada, K.; Morishima, H. Tetrahedron 2000, 56, 7705.
(d) Sugimoto, Y.; Imamura, H.; Shimizu, A.; Nakano, M.;
Nakajima, S.; Abe, S.; Yamada, K.; Morishima, H.
Tetrahedron: Asymmetry 2000, 11, 3609.
(5) The reaction with n-BuLi resulted in attack on the ester.
(6) Magnesium- or zinc-based approaches were all
unsuccessful: i-PrMgCl, (i-Pr)2Mg, Bu3MgLi, Me4ZnLi2
and Rieke Mg–Zn left the substrate unreacted.
Figure 4
As we confirmed that the mesityllithium/n-BuLi protocol
successfully produced the dianion 12, the reaction with 4-
TBSoxy-N-Boc-pyrrolidin-2-one (4) was finally attempt-
ed. Addition of the dianion 12 to 4 proceeded cleanly and
the desired coupling adduct 14 was obtained in 74% yield
(Figure 5). Compound 14 could be converted to the thiol
side chain 2 for the synthesis of a novel carbapenem 1.
The whole synthetic work will be reported elsewhere as a
full article.
(7) n-BuLi should be used because thus any nucleophiles would
not attack the enolate thus formed.
(8) (a) Beck, K. A.; Hoekstra, M. S.; Seeback, D. Tetrahedron
Lett. 1977, 1187. (b) Vedejs, E.; Lee, N. J. Am. Chem. Soc.
1995, 117, 891.
In conclusion, it was found that mesityllithium could act
as a non-nucleophilic base without reaction with aryl bro-
mide and regeneration of a proton donor. Combination of
mesityllithium with n-BuLi allowed us to develop a new
synthetic technique for metalation of aryl bromides pos-
sessing active methylene adjacent to carbonyl groups.
(9) Typical experimental procedure: To a solution of mesityl
bromide (876 mg, 4.4 mmol) in THF (15 mL) at –78 °C was
added dropwise n-BuLi (2.9 mL of 1.5 M solution in
heptane, 4.40 mmol) to form white suspension. The mixture
was stirred for 30 min at the same temperature. Arylbromide
5a (1.14 g, 4.40 mmol, dissolved in 7.8 mL of THF) was
added to the mixture at –78 °C to form yellow solution which
indicated enolate was formed, and stirred for 30 min at the
same temperature. n-BuLi (2.7 mL of 1.5 M solution in
heptane, 4.0 mmol) was added dropwise at –78 °C and
stirred for additional 30 min at the same temperature to
complete the reaction. DMF (0.37 mL, 4.8 mmol) was added
dropwise to the solution and was stirred for 30 min at the
Acknowledgement
We are indebted to Prof. H. Yamamoto at Nagoya University for his
helpful advise on this work. We also thank Drs. H. Imamura and Y.
Sugimoto at Banyu Tsukuba Research Institute for their technical
assistance.
1) Mesityllithium
2) n-BuLi
Ph
N
Ph
COOtBu
Ph
N
Ph
COOtBu
4
12
BocHN
14
Br
11
OTBS O
Figure 5
Synlett 2002, No. 4, 561–564 ISSN 0936-5214 © Thieme Stuttgart · New York

564
Y. Yamamoto et al.
LETTER
same temperature. Aq NH4Cl was added to the solution and
the product was extracted with EtOAc. The organic layer
was washed with water, dried over anhyd Na2SO4 and was
concentrated in vacuo to yield crude product which was
purified by column chromatography using silica to afford 6a
(690 mg, 2.95 mmol) in 74% yield.
H2
Pd/C
AcOH
NH2
Ph
N
Ph
COOtBu
COOtBu
(S)
•AcOH
11
15
Br
(10) Kondo, Y.; Asai, M.; Miura, T.; Uchiyama, M.; Sakamoto,
T. Org. Lett. 2001, 3, 13.
(11) Davies, G. S.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2,
183.
(12) The diastereoselectivity was determined after conversion of
11 to amine 15 (Figure 6) by hydrogenation using Pd/C.
Enantiomeric purity was determined by HPLC with
comparison of a standard sample 17, which was prepared
from conjugated ester 9.
H2
NH2
Ph
N
Ph
COOtBu
Pd/C
N
Ph
Ph
Br
COOtBu
AcOH
Li
9
•AcOH
16
17
Figure 6
Synlett 2002, No. 4, 561–564 ISSN 0936-5214 © Thieme Stuttgart · New York