Novel method for the synthesis of β-lactams by the reaction of α-bromocarboxylic acids with imines mediated by triphenylphosphine

Article abstract of DOI:10.3987/COM-05-10661

The useful and simple method for the formation of the β-lactams by the reaction between α-bromo carboxylic acids and imines is described. This reaction was effectively mediated by triphenylphosphine or polystyryl-diphenylphosphine to given the β-lactams i

Full text of DOI:10.3987/COM-05-10661

HETEROCYCLES, Vol. 68, No. 3, 2006
453
HETEROCYCLES, Vol. 68, No. 3, 2006, pp. 453 - 457. © The Japan Institute of Heterocyclic Chemistry
Received, 27th December, 2005, Accepted, 20th February, 2006, Published online, 21st February, 2006. COM-05-10661
NOVEL METHOD FOR THE SYNTHESIS OF β-LACTAMS BY THE
REACTION OF α-BROMOCARBOXYLIC ACIDS WITH IMINES
MEDIATED BY TRIPHENYLPHOSPHINE
Satoshi Kikuchia and Yukihiko Hashimoto*
Department of Chemistry and Biotechnology, School of Engineering, The
University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. E-mail:
hashimoto@chiral.t.u-tokyo.ac.jp
Abstract – The useful and simple method for the formation of the β-lactams by
the reaction between α-bromo carboxylic acids and imines is described. This
reaction was effectively mediated by triphenylphosphine or polystyryl-
diphenylphosphine to give the β-lactams in good yields with high trans-
selectivity.
β-Lactams are one of the most important heterocycles in medicinal chemistry as skeletons of antibiotics,
such as penicillins, cephalosporins and carbapenems etc.1 Therefore, until now, many useful methods
for constructing β-lactam rings were developed and the numerous articles and accounts have been
published.2
For example, the Staudinger reaction is one of the most versatile means to get β-lactams, which is a [2+2]
cycloaddition between imines and ketenes.2a, c Moreover, it is known that the cyclization of the β-amino
acid derivatives is one of the other useful means. This reaction is convenient to get both trans- and cis-
isomers, because the stereochemistry of β-lactams depends upon the β-amino acid derivatives that can be
synthesized diastereoselectively.2b, c
In recent years, we have been interested in the study of the reaction using phosphines and have already
reported that several reactions were promoted by the combination of phosphine and Lewis acid
effectively.3 For example, it has been already reported that the Reformatsky-type reaction of α-bromo
Current address; Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University,
Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan

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HETEROCYCLES, Vol. 68, No. 3, 2006
carbonyl compounds was mediated by the (o-tolyl)3P/TiCl4 combination in good yields with high
diastereoselectivity.3b, c In addition, it was also found that these composite reagents smoothly promoted
the Mannich-type reaction of the α-bromo thioesters with imines.3f
This time, we found that the β-lactams were formed by the reaction between α-bromo carboxylic acids
and imines in the presence of triphenylphosphine. Thus, in this manuscript, we would like to describe
the convenient method for the synthesis of β-lactams with trans-selectivity in one step.
Initially, we examined the reaction of 2-bromo-2-phenylacetic acid with N-(4-chlorobenzylidene)-p-
anisidine in benzene at 70 °C using various phosphines, such as tributylphosphine, tri-o-tolylphosphine,
triphenylphosphine and so on. Then it was found that the desired β-lactam, 4-(4-chlorophenyl)-1-(4-
methoxyphenyl)-3-phenyl-2-azetidinone, was obtained with trans-selectivity in any cases and that
triphenylphosphine was the best promoter of this reaction among phosphines examined.
Next, we investigated the effects of solvents, such as MeCN, THF, DMF, toluene and benzene, in the
same reaction using triphenylphosphine. The desired β-lactam was obtained in moderate yield
(30%-67%) in any solvents and among solvents examined, the highest yield was achieved in benzene.
Moreover, it was found that the reaction proceeded more smoothly under benzene reflux condition.4
Then, under the optimized reaction conditions,5 the reaction of 2-bromoacetic acid derivatives with
Table 1.a The reaction of !-bromocarboxylic acids with several imines under the optimized
conditions.
OMe
OMe
O
O
Ph3P
N
R1
N
OH
Benzene, reflux
R2
R1
R2
Br
trans : cis c
R1
R2
Entry
Time (h)
24
Yield (%) b
100 :
95 :
91 :
0
5
9
1
2
3
4
5
6
7
82
98
Ph
Ph
Ph
Ph
Ph
p-MeOC6H4
Ph
18
12
100
100
27
p-ClC6H4
p-NO2C6H4
PhCH=CH2
p-ClC6H4
p-ClC6H4
88 : 12
100 :
12
0
12
85 : 15
79 : 21
12
93
p-BrC6H4S
Me
24
26
a Molar ratio of acid:imine:Ph3P=1.2:1.0:2.4. b Isolated yield. c The stereochemistry of these
products was assigned by the vicinal coupling constants of C3 and C4 protons: trans-Isomers; 1.8-
2.6 Hz. cis-Isomers; 6.0-6.5 Hz.

HETEROCYCLES, Vol. 68, No. 3, 2006
455
several imines was carried out. The results are summarized in Table 1.
As can be seen from Table 1, the reaction of 2-bromo-2-phenylacetic acid and imines derived from
aromatic aldehydes proceeded in high yields with good trans-selectivity (Entries 1-4). Moreover, it
should be noted that when the imine had an electron-donating group on the 4-position of aldehyde moiety,
the diastereoselectivity of the product became higher and that an electron-withdrawing group, in contrast,
made the yield higher. Although the yield was low in the reaction with the imine derived from
cinnamaldehyde, it was confirmed that the corresponding β-lactam was obtained as a single trans-isomer
(Entry 5).
Moreover, the reaction of 2-bromo-2-(4-bromophenylthio)acetic acid6 with N-(4-
chlorobenzylidene)-p-anisidine proceeded in good yield with high trans-selectivity (Entry 6). In
addition, the reaction of 2-bromopropionic acid (Entry 7) was also achieved with trans-selectivity.
However, in this case, both the yield and the stereoselectivity were lower.
The mechanism of this reaction was thought as follows; first, a little amount of α-bromo carboxylic acid
reacted with triphenylphosphine to give triphenylphosphonium bromide.
Next, this triphenyl-
phosphonium bromide reacted with other α-bromo carboxylic acid and the compound (1), which had a
good leaving group, was formed. Then, the reaction of this compound (1) with imines proceeded in the
presence of triphenylphosphine and the corresponding β-lactam was obtained through the formation of
the intermediate (3).7 The substituent on the 4-position of aldehyde moiety had an effect on the rate of
O
O
R
OH
R
OH
Br
HBr
Br
Ph3P
O
Ph3PBr
R
PPh3
O
Ar1
Ar2
O
O
R
Br
N
R
Ar1
Ar1
1
N
N
Ar2
Ar2
4
Ph3P=O
Ph3P
Ar1
Ar2
O
O
R
Ar1
Ar2
N
N
R
Br
Br
3
2
Scheme 1

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HETEROCYCLES, Vol. 68, No. 3, 2006
the isomerization between (2) and (3); that is, the electron-donating group made the rate faster.
A typical procedure for the synthesis of 4-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-phenyl-2-azetidinone
(Entry 1) is as follows: Under an argon atmosphere, a benzene (4 mL) solution of N-(4-
chlorobenzylidene)-p-anisidine (51.5 mg, 0.21 mmol), triphenylphosphine (132.1 mg, 0.50 mmol) and 2-
bromo-2-phenylacetic acid (54.1 mg, 0.25 mmol) was stirred under reflux for 12 h. The reaction was
quenched with water (10 mL), and the reaction mixture was extracted with CH2Cl2 (3×10 mL). The
combined organic layer was dried over MgSO4. This organic layer was filtered and concentrated under
reduced pressure, and then the crude product was purified by preparative TLC (SiO2, ethyl
acetate/hexane=1:5) to give the desired β-lactam.8
Furthermore, it was found that the polymer-supported phosphine could be used instead of
triphenylphosphine and that the polystyryl-diphenylphosphine9 could promote the reaction in good yield
with high trans-selectivity (Scheme 2). In this case, the by-product, the polystyryl-diphenylphosphine
oxide, could be separated by filtration, so that the purification became much easier.
n
OMe
OMe
O
O
PPh2
N
N
Ph
OH
Benzene, reflux
Br
Ph
12 h
Cl
Cl
Yield 72 %, trans : cis = 90 : 10
Scheme 2
In summary, we found that the several β-lactams were smoothly constructed in one step by
triphenylphosphine in good yields with high trans-selectivity. Moreover, the polystyryl-
diphenylphosphine was also found to promote the same reaction effectively. These reactions are very
versatile reactions in organic synthesis because the operations are very simple, the starting materials are
easily available and β-lactams are obtained with the high trans-selectivity. Further examination for
clarification of mechanism is now in progress.
REFERENCES AND NOTES
1. (a) G. I. Georg, ‘The Organic Chemistry of β-lactams,’ VCH, New York, 1993. (b) L. Ghosez and
J. Marchand-Brynaert, ‘Comprehensive Organic Synthesis,’ Vol. 5, ed. by B. M. Trost and I.
Fleming, Pergamon, Oxford, 1991, p. 85.
2. For reviews, see; (a) C. Palomo, J. M. Aizpurua, I. Ganboa, and M. Oiarbide, Eur. J. Org. Chem.,

HETEROCYCLES, Vol. 68, No. 3, 2006
457
1999, 3223. (b) M. Benaglia, M. Cinquini, and F. Cozzi, Eur. J. Org. Chem., 2000, 563. (c) G. S.
Singh, Tetrahedron, 2003, 59, 7631. (d) P. M. P. Gois and C. A. M. Afonso, Eur. J. Org. Chem.,
2004, 3773. (e) S. France, A. Weatherwax, A. E. Taggi, and T. Lectka, Acc. Chem. Res., 2004, 37,
592. (f) E. C. Lee, B. L. Hodous, E. Bergin, C. Shih, and G. C. Fu, J. Am. Chem. Soc., 2005, 127,
11586.
3. (a) H. Kagoshima, Y. Hashimoto, D. Oguro, T. Kutsuna, and K. Saigo, Tetrahedron Lett., 1998, 39,
1203. (b) H. Kagoshima, Y. Hashimoto, and K. Saigo, Tetrahedron Lett., 1998, 39, 8465. (c) Y.
Hashimoto and S. Kikuchi, Chem. Lett., 2002, 126. (d) Y. Hashimoto, H. Konishi, and S. Kikuchi,
Synlett, 2004, 1264. (e) S. Kikuchi and Y. Hashimoto, Synlett, 2004, 1267. (f) S. Kikuchi, T.
Kobayashi, and Y. Hashimoto, Tetrahedron. Lett., 2006, in press.
4. The reaction was also carried out under reflux conditions in other solvents, toluene and MeCN.
However, the best results were obtained under benzene reflux condition.
5. We investigated the effects of the several substituents on the nitrogen atom of the imine. Then,
p-methoxyphenyl group was found to be the best substituent to achieve the highest yield and
selectivity.
6. D. Walker and J. Leib, J. Org. Chem., 1962, 27, 4455.
7. Although there was the possibility that the reaction proceeded via the formation of ketenes, the
product was obtained with trans-selectivity even in the reaction of 2-bromopropionic acid (Entry 7).
So, this reaction mechanism was thought as that illustrated in Scheme 1. The cis-selective β-lactam
formation of alkyl ketenes with imines was reported; C. Palomo, J. M. Ontoria, J. M. Odriozola, J. M.
Alzpurua, and I. Ganboa, J. Chem. Soc., Chem. Commun., 1990, 248.
8. 1H-NMR (300 MHz, CDCl3): trans-isomer; δ 7.25-7.38 (m, 11H), 6.84 (d, 2H, J = 8.7 Hz), 4.88 (d,
1H, J = 1.8 Hz), 4.21 (d, 1H, J = 1.8 Hz), 3.74 (s, 3H). cis-isomer; δ 7.33 (d, 2H, J = 9.0 Hz),
6.98-7.12 (m, 9H), 6.83 (d, 2H, J = 9.3 Hz), 5.39 (d, 1H, J = 6.3Hz), 5.00 (d, 1H, J = 6.3 Hz), 3.77 (s,
3H). IR(KBr): 3100-2900, 1740, 1510, 1490, 830, 820.
9. (a) S. L. Regen and D. P. Lee, J. Org. Chem., 1975, 40, 1669. (b) M. Bernard and W. T. Ford, J.
Org. Chem., 1983, 48, 326.