Use of 2,2′-dibenzothiazolyl disulfide-triphenylphosphine and Lawesson's Reagent in the cyclization of β-amino acids

Article abstract of DOI:10.1246/bcsj.79.1748

The disulfide reagents 2,2′-dithiobisbenzothiazole (MBTS) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's Reagent, LR) mediate the cyclization of β-amino acids with remarkable product yields. Compared to other cyclodehydrating agents, these have been found to be superior in terms of their cost, making them industrially viable. The advantageous properties of MBTS and LR make them useful and unique additions to the arsenal of cyclodehydrating agents.

Full text of DOI:10.1246/bcsj.79.1748

1748 Bull. Chem. Soc. Jpn. Vol. 79, No. 11, 1748–1752 (2006)
Ó 2006 The Chemical Society of Japan
Use of 2,20-Dibenzothiazolyl Disulfide-Triphenylphosphine and
Lawesson’s Reagent in the Cyclization of ꢀ-Amino Acids
ꢀ
Seema Kanwar and S. D. Sharma
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160 014, India
Received February 28, 2006; E-mail: sdsharmapu@yahoo.com
The disulfide reagents 2,20-dithiobisbenzothiazole (MBTS) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphos-
phetane 2,4-disulfide (Lawesson’s Reagent, LR) mediate the cyclization of ꢀ-amino acids with remarkable product
yields. Compared to other cyclodehydrating agents, these have been found to be superior in terms of their cost, making
them industrially viable. The advantageous properties of MBTS and LR make them useful and unique additions to the
arsenal of cyclodehydrating agents.
N
In addition to the utility of monocyclic ꢀ-lactams as antibi-
otic agents, such as norcardicines, and monobactams,1 their
value in designing new enzyme inhibitors has caused a renewed
interest in these compounds.2 Moreover, azetidin-2-ones are
important synthetic intermediates for the construction of highly
functionalized natural and unnatural products. Considerable ef-
forts have been focused on strategies for the de novo construc-
tion of the 4-membered ring system.3–5 Although there are a va-
riety of methods for the formation of ꢀ-lactam ring,6–8 one of
the most useful approaches is based on the dehydration of ꢀ-
amino acids by means of condensing agents.9–12 Several orga-
nophosphorus,13,14 and triphenylphosphine-based reagents15–18
have been used in ꢀ-lactam synthesis.
Recently, we demonstrated the utility of phosphoryl chlo-
ride19 and (chloromethylene)dimethylammonium chloride20
for the cyclodehydration of ꢀ-amino acids which proceeds
via a mixed anhydride and active ester formation, respectively.
In continuation of our work in this direction, we now wish to
report the utility of two more efficient reagents. The first one,
2,20-dithiobisbenzothiazole-triphenylphosphine (MBTS-TPP),
is well-known as being useful for peptide synthesis21 and amide
synthesis22 through oxidation–reduction condensation, intro-
duced in 1970. More recently, we employed this reagent in
the formation of azetidin-2-ones via a non concerted [2 þ 2] cy-
cloaddition.23 Though dipyridyl disulfide has been used exten-
sively for the cyclodehydration of ꢀ-amino acids,24–28 to the
best of our knowledge, there are no reports involving the use
of 2,20-dithiobisbenzothiazole to form ꢀ-lactam rings from a
ꢀ-amino acid by intramolecular condensation, except for its
use to prepare the carbapenem intermediate as mentioned in a
Japanese patent.29 The other reagent used in this study is
Lawesson’s reagent (LR), which is considered to be the most
powerful reagent for the thionation of a wide variety of carbon-
yl compounds.30 It is also useful as a racemization free coupling
reagent in peptide synthesis.31 Recently, this reagent has been
used to prepare azetidin-2-ones via enolate–imine condensation
reaction.32 However, use of this reagent for cyclodehydration of
ꢀ-amino acids to the corresponding azetidin-2-ones seems to
be so far unexplored and is thus reported herein (Chart 1).
N
S
S
C6H4OCH3-p
S
S
P
P
S S
p-H3COC6H4
S
S
2,2'-dithiobisbenzothiazole (MBTS)
Lawesson's Reagent (LR)
Chart 1.
Results and Discussion
Our success in using MBTS-TPP and LR for the synthesis
of azetidin-2-ones via [2 þ 2] cycloaddition reaction prompted
us to explore the possibility of using them for the intramolec-
ular cyclization of ꢀ-amino acids. In the MBTS-TPP mediated
reaction, MBTS acts as oxidant and TPP as reductant. The pro-
posed mechanism for the MBTS-TPP coupling reaction is
shown in Scheme 1. The reaction proceeds with the formation
of an addition adduct 1 of TPP and MBTS, which then reacts
with the carboxylic acid functional group of the amino acid to
generate the activated ester 3. The nucleophilic character of
the thiols makes them strong competitors for the amino group
of acylating agents. Thus, attack of benzothiazole sulfide anion
on the carbonyl carbon of 3 then leads to the formation of
ꢀ-amino thioester 4 as shown. Thioester 4 was isolated and
fully characterized by analytical and spectroscopic data. Final-
ly, intramolecular attack of the amino nitrogen at the highly
activated carbonyl carbon of thioester is facilitated by the
tertiary base triethylamine (TEA) to afford the ꢀ-lactam 5
(pathway a). Alternatively, in the one-pot reaction, the forma-
tion of ꢀ-lactam can go directly through the active ester 3
itself, as shown in the pathway b.
LR also works in a similar fashion, and the proposed mech-
anism is shown in Scheme 2. LR reacts with the carboxylate
anion forming the mixed anhydride 7, making the carboxylate
carbonyl more electrophilic. This facilitates attack of the
amino nitrogen in the presence of base to form the ꢀ-lactam.
While performing these reactions, we found that the order of
addition of reagents was critical to the success of the reaction.
If MBTS was added to a solution of ꢀ-amino acid in dichloro-
methane at 25–30 ꢁC followed by TPP, a homogenous solution
was obtained, but subsequent addition of triethylamine did not
Published on the web November 9, 2006; doi:10.1246/bcsj.79.1748

S. Kanwar et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 11 (2006) 1749
N
N
S
N
S
S
P+Ph3
S-
R
R
S S
R =
PPh3 +
S
1
(MBTS)
R2
R3
O
R4HN
OH
R1
2
Ph
Ph
R2
O
R3
R4HN
R2
O
P
R3
R4HN
HS
R
+
Ph
a
O
S R
R
S
O
P
Ph
R1
+
Ph
a
b
R1
Ph
3
S-
R
4
+
RSH
(C2H5)3N
b
(C2H5)3N
R2
R3
R1
R2
R3
R1
Ph
RSH +
N
O
P
RSH
+
R4
O
Ph
N
R4
O
Ph
5
5
Scheme 1. Proposed mechanism for MBTS-TPP-mediated coupling.
R2
O
R2
O
R3
R4HN
R3
R4HN
Dry DCM
O-
OH
(C2H5)3N
R2
R1
R1
O
R3
S
2
6
R4HN
O P C6H4OCH3-p
S- N+(C2H5)3
R1
S
S
7
p-H3COC6H4
P
C6H4OCH3-p
P
S
(C2H5)3N
S
(LR)
R2
R3
S-
R1
2(C2H5)3N+
O P C6H4OCH3-p
+
N
S-
8
R3
O
5
Scheme 2. Proposed mechanism for LR-mediated coupling.
afford the expected ꢀ-lactam product. Instead, starting mate-
rial was recovered unchanged. However, when MBTS was
added to the stirred solution of TPP and ꢀ-amino acid in di-
chloromethane, adduct 1 was formed which then reacted with
ꢀ-amino acid to form active ester 3, which in the presence of
triethylamine formed ꢀ-lactam 5.
Similarly, in the case of LR-mediated cyclization, product
formation was not observed if the ꢀ-amino acid was reacted
as such with LR, without initial formation of carboxylate anion
of ꢀ-amino acid. After formation of mixed anhydride 7 at 25–
30 ꢁC, triethylamine at 0 ꢁC completes the intramolecular cy-
clization process. When the reaction was examined in different
solvents, dichloromethane gave the best results in terms of
chemical yields, although acetonitrile, tetrahydrofuran, and
N,N-dimethylformamide were also effective. Furthermore, the
reaction temperature was also studied from reflux to ꢂ10 ꢁC.
The optimum reaction conditions for MBTS-TPP-mediated
cyclization are 25–30 ꢁC and for LR, the best conditions for
the formation of the mixed anhydride are 25–30 ꢁC, 0 ꢁC for
nucleophilic attack at the carbonyl carbon of the mixed anhy-
dride during the addition of triethylamine and finally stirring at
25–30 ꢁC for approximately 10–12 h to complete the reaction.
Both MBTS-TPP and LR react with almost equal efficiency.
To ascertain the reproducibility of these results, a variety of
ꢀ-amino acids33–36 were cyclized to the corresponding ꢀ-lac-
tams as shown in Table 1. The reaction works well with both
erythro- and threo-ꢀ-amino acids (1s–1v) to give the corre-
sponding cis and trans ꢀ-lactams respectively, in excellent
yields. The stereochemistry of the ꢀ-lactams was determined
by 1H NMR, based on the coupling constant values of the
C3–C4 hydrogens (Jcis > Jtrans). Normally erythro-ꢀ-amino
acid ring closure occurs in low yield;37–39 however, due to ster-
ic compression, the yield is higher with this method. The pres-
ent methods are compatible with amino acids containing elec-
tron donating, aromatic groups, and aliphatic side chains at any
position. Even the simplest ꢀ-amino acid, ꢀ-alanine cyclized
to azetidin-2-one in good yield. Moreover, the workup is
straightforward and involves just washing with sodium hydro-
gen carbonate and water.
Since the stereochemistry of the ꢀ-amino acids was pre-
served in the cyclization reaction, this procedure was used to
determine unambiguously the isomers that were produced in

1750 Bull. Chem. Soc. Jpn. Vol. 79, No. 11 (2006)
Two New Entries in Intramolecular Cyclization of ꢀ-Amino Acids
Table 1. ꢀ-Lactams Obtained in MBTS-TPP- and LR-Mediated Coupling
R2
N
(i) MBTS-TPP
R1
O
R2
or
R3
R3
LR
HOOC
NHR4
(ii) TEA/DCM
R4
R1
2
5
Entry
R1
R2
R3
R4
Yield/%a)
MBTS-TPP
LR
a.36
b.20
c.36
d.20
e.19
f.19
g.19
h.19
i.41
j.20
k.20
l.19
m.19
n.20
o.19
p.42
q.20
r.20
s.
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
54
80
83
85
75
82
83
79
85
86
73
81
82
84
80
54
50
51
79
75
73
70
76
80
79
82
81
78
79
82
85
81
82
80
83
84
81
82
80
79
75
70
69
77
CH2C6H5
CH2C6H5
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
CH2CH2C6H5
(CH2)3CH3
CH2CH(CH3)2
CH2CH2OH
CH2CH(OH)CH3
CH2C6H5
CH2CH2C6H5
(CH2)3CH3
CH2CH(CH3)2
CH2CH2OH
CH2CH(OH)CH3
CH2C6H5
H
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
C6H5
C6H5
Piperonyl
C6H4OCH3(p)
H
H
H
H
H
H
C6H4CH3(p)
CH3
C2H5
CH2C6H5
C6H5CH2O
C6H4CH3(p)
CH2C6H5
CH2C6H5
t.
u.
v.
CH3
CH3
C6H5
H
H
H
CH2C6H5
a) Yields based on the weight of isolated product; all ꢀ-lactams prepared were racemic mixtures; fully
characterized by their physical and spectroscopic data.
ꢀ-lactam 9 was formed as the sole reaction product. Similarly,
Table 2. ꢀ-Lactam Ring-Opening Reaction
12 afforded ꢀ-lactam 10, thus confirming the absence of epi-
merization during ꢀ-lactam ring opening (Scheme 3).
The noteworthy features of the present methodology can be
summarized as: (1) A variety of ꢀ-amino acids can be used
with the system, i.e., Ph3P-MBTS-TEA-DCM and LR-TEA-
DCM, under mild conditions. Hence, there is no need for the
protection of sensitive functional group like hydroxy substitu-
tents; (2) very ‘‘high dilutions’’ and high temperatures (reflux)
are not required and instead the reaction proceeds well in low
dilutions and at room temperature;28 (3) both N-substituted and
N-unsubstituted ꢀ-amino acids can be cyclized; (4) the order
of addition and also quantities of reactants play an important
role; (5) the efficiency of these condensing systems is indeed
remarkable, since the DCC method afforded ꢀ-lactams in 10–
30% yield in most cases and, the Ph3P-(PyS)2 method, though
yields are good, requires ‘‘high dilution’’ and reflux tempera-
tures; and (6) the stereochemistry of the ꢀ-amino acid was pre-
served in the cyclization. As well the commercial availability
and lower cost of the reagents, make these processes industri-
ally viable.
R2
R1
R2
R3
R3
LiOH-H2O, THF,
HOOC
NHR4
N
25 - 30°C, 12 - 14h
R1
O
R4
Entry R1
R2
R3
R4
Yield/%
11a. OC6H5 Piperonal
11b. OC6H5 CH=CHC6H5
12a. SC6H5
12b. Phth
H
H
C6H4OCH3
C6H4OCH3
H
80
75
82
78
H
H
Piperonal
C6H5 C6H4OCH3
a synthetic plan leading to ꢀ-amino acids. In connection with
the studies directed towards the synthesis of non proteinogenic
amino acids, a class of compounds that represents an important
group of natural products,40 we found that the treatment of
1,3,4-trisubstituted ꢀ-lactams with lithium hydroxide afforded
the desired ꢀ-amino acids without epimerization at any of the
two chiral centers. For this purpose, the starting ꢀ-lactams 9
and 10 were prepared by our recently developed titanium eno-
late–imine condensation.23,32 Pure cis and trans isomers were
subjected to treatment with lithium hydroxide in a tetrahydro-
furan–water mixture and after usual workup, the corresponding
ꢀ-amino acids were obtained in quantitative yields, Table 2.
When ꢀ-amino acid 11 was allowed to react with the MBTS-
TPP or LR in the presence of triethylamine, the corresponding
Conclusion
In conclusion, the present methods offer several advantages
over previously known methods in terms of simplicity, appli-
cability, mildness, high yields, and availability of the reagents,

S. Kanwar et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 11 (2006) 1751
H
R3
N
R2 R3
R1
R2
HOOC
ii
NHR4
R3
+
R4
R2
NR4
O
+
R1
O-TiCl3
H
9 (cis)
R3 = H
i
R3 = H
11
R1
Z
iii
N
R2 R3
or
Z =
S
H
R3
R2
R4
R1
HOOC
S
S
ii
NHR4
R1
N
O
R2 = H
12
O P C6H4OCH3-p
10 (trans)
R2 = H
S-
iii
Scheme 3. Reagents and conditions: (i) NEt3, DCM, ꢂ78 to 0 ꢁC, 6 h; (ii) LiOH H2O, THF–water, 25–30 ꢁC, 12–14 h; (iii) TPP,
ꢅ
MBTS, TEA, DCM, 25–30 ꢁC, 14–16 h, or TEA, LR, DCM, 0–25 ꢁC, 12–14 h.
30 ꢁC while stirring. After 5 min, the reaction mixture became
therefore, the present methods as useful additions to the known
methods.
homogenous. At this stage, triethylamine (19.7 mg, 0.195 mmol)
in dry dichloromethane (1.0 mL) was added dropwise. The reac-
tion mixture was stirred overnight and then quenched with a satu-
rated solution of sodium hydrogen carbonate (0.5 mL). The solu-
tion was washed with water (0.5 mL), and the organic phase was
separated and dried. The solvent was evaporated under reduced
pressure. Chromatography of the residue on silica gel using ethyl
acetate:hexane (2:8) as an eluent afforded pure azetidin-2-one.
Cyclization of ꢀ-Amino Acid Using LR General Procedure.
To a suspension of a ꢀ-amino acid (0.1 mmol) in dry dichloro-
methane (10 mL, 0.01 M) was added triethylamine (0.2 g, 1.77
mmol) and the mixture was stirred at 25–30 ꢁC for 30 min. LR
(20.2 mg, 0.050 mmol) was added to this mixture, and the mixture
was again stirred till it became homogenous (ꢃ30 min). Then, the
reaction mixture was cooled to 0 ꢁC, and triethylamine (0.4 g,
3.55 mmol) in dry dichloromethane (1.0 mL) was added dropwise
under stirring. The reaction mixture was stirred overnight at 25–
30 ꢁC and then quenched with water (5 mL). The organic phase
was separated and dried over anhydrous sodium sulphate, and
the solvent was evaporated under reduced pressure. Chromatogra-
phy of the residue on silica gel using ethyl acetate:hexane (1:9) as
the eluent afforded pure azetidin-2-one.
Experimental
ꢁ
Melting points (Mp, C) were determined on a Buchi SMP-20
Instrument and are uncorrected. The FT-IR spectra were recorded
on a Perkin-Elmer Model 1430 spectrophotometer and were cali-
brated against polystyrene. Only the principal peaks of interest are
1
reported and expressed in cmꢂ1. H NMR and 13C NMR spectra
were recorded on a 300 MHz Bruker AC 300F spectrometer.
Chemical shifts are expressed as ꢁ values (ppm) downfield from
tetramethylsilane (TMS). Elemental analysis (C, H, N) was per-
formed using a Perkin-Elmer 2400 (C, H, N) elemental analyzer.
Thin layer chromatography was performed using TLC grade Silica
gel (G) and was developed in an atmosphere of iodine vapors.
Acetonitrile was dried and purified by distillation over calcium
hydride. Tetrahydrofuran was distilled over sodium and benzophe-
none. Dichloromethane was shaken with concentrated sulfuric
acid, dried over potassium carbonate and distilled.
General Procedure for the Preparation of S-Benzothiazol-2-
yl Thiocarboxylate. To a stirred solution of amino acid (0.1
mmol) and triphenylphosphine (31.5 mg, 0.12 mmol) in dichloro-
methane (1.0 mL) was added di(benzothiazol-2-yl) disulfide (36.6
mg, 0.1 mmol), and the mixture was stirred for 24 h at 25–30 ꢁC.
The reaction was quenched by the addition of water (1.0 mL), and
the organic layer separated, washed with water (1.0 mL) and dried
over anhydrous sodium sulfate. The excess solvent was removed
under vacuum, and the remaining residue chromatographed over
silica gel to provide the S-benzothiazol-2-yl thiocarboxylate.
Procedure for the Cyclization of S-Benzothiazol-2-yl Thio-
carboxylate. To the thiocarboxylate (0.1 mmol) in dichlorometh-
ane (1.5 mL), triethylamine (0.2 mmol) in dichloromethane (1.0
mL) was added dropwise. The reaction mixture was stirred over-
night, and the progress was monitored by TLC. The reaction was
quenched with a saturated solution of sodium hydrogen carbonate
(0.5 mL) and washed with water (0.5 mL), and the organic phase
was separated and dried. The solvent evaporated under reduced
pressure. Chromatography of the residue on silica gel using ethyl
acetate:hexane (2:8) as an eluent afforded pure azetidin-2-one.
Cyclization of ꢀ-Amino Acid Using MBTS-TPP General
General Procedure for ꢀ-Lactam Ring Opening. To a solu-
tion of ꢀ-lactam (2 mmol) in tetrahydrofuran (7 mL) and water
(3 mL), LiOH–H2O (0.14 g, 3.5 mmol) was added, and the result-
ing mixture was stirred overnight at rt. The solution was extracted
with diisopropyl ether (2 ꢄ 20 mL), and after phase separation, the
aqueous layer was acidified to pH ꢃ 2 with saturated NaH2PO4
and then extracted with diisopropyl ether (20 mL) to yield after
crystallization (DIPE/hexane) the ꢀ-amino acid (80%).
erythro-3-p-Anisidino-3-(1,3-benzodioxol-5-yl)-2-phenoxy-
1
propanoic Acid (11a): FT-IR: 1600 cmꢂ1. H NMR (300 MHz,
CDCl3, 25 ꢁC): ꢁ 7.55–6.86 (m, 3H, ArH), 7.37–6.86 (m, 5H,
ArH), 6.90 (br s, 2H, NH and –COOH), 6.67–6.61 (m, 4H, ArH),
5.98 (d, J ¼ 2:78 Hz, 1H, OCH2O), 5.96 (d, J ¼ 2:78 Hz, 1H,
OCH2O), 5.15 (d, J ¼ 4:15 Hz, 1H, CHCO), 5.06 (d, J ¼ 4:15 Hz,
1H, CHNH), 3.65 (s, 3H, OCH3). 13C NMR: ꢁ 174.81, 157.54,
152.38, 149.46, 148.76, 141.72, 128.91 (2C), 127.24, 122.56,
122.37, 118.59 (2C), 117.12 (2C), 115.68 (2C), 111.36, 107.76,
101.30, 80.48, 55.57, 55.08. Anal. Found: C, 67.69; H, 5.30; N,
3.59%. Calcd for C23H21NO6: C, 67.80; H, 5.20; N, 3.44%.
erythro-3-p-Anisidino-2-phenoxy-5-phenyl-4-pentenoic Acid
Procedure.
TPP (31.5 mg, 0.12 mmol), followed by MBTS
(36.6 mg, 0.11 mmol), were added to a 0.07 M suspension of ꢀ-
amino acid (0.1 mmol) in dry dichloromethane (1.5 mL) at 25–

1752 Bull. Chem. Soc. Jpn. Vol. 79, No. 11 (2006)
Two New Entries in Intramolecular Cyclization of ꢀ-Amino Acids
(11b): FT-IR: 1603 cmꢂ1. 1H NMR (300 MHz, CDCl3, 25 ꢁC): ꢁ
7.40–6.86 (m, 5H, ArH), 7.35–7.19 (m, 5H, ArH), 6.90 (br s, 2H,
NH and –COOH), 6.75 (d, J ¼ 15:50 Hz, 1H, =CHPh), 6.65–6.57
(m, 4H, ArH), 5.98 (dd, J ¼ 15:50, 8.22 Hz, 1H, –CCH=), 4.70
(dd, J ¼ 8:22, 4.16 Hz, 1H, CHNH), 4.57 (d, J ¼ 4:16 Hz, 1H,
CHOPh), 3.63 (s, 3H, OCH3). 13C NMR: ꢁ 173.07, 156.99, 152.47,
144.02, 137.16, 133.00, 129.25 (2C), 129.15 (2C), 128.07 (2C),
127.28, 126.49, 122.37, 116.95 (2C), 116.86 (2C), 115.50 (2C),
81.12, 55.56, 52.95. Anal. Found: C, 74.29; H, 5.49; N, 3.48%.
Calcd for C24H23NO4: C, 74.02; H, 5.95; N, 3.60%.
10 S. Kim, K. Y. Yi, J. Y. Namkung, Heterocycles 1989, 29,
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103, 4582.
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2004, 34, 1855.
threo-3-p-Anisidino-3-(1,3-benzodioxol-5-yl)-2-phenylthio-
1
propanoic Acid (12a): FT-IR: 1610 cmꢂ1. H NMR (300 MHz,
CDCl3, 25 ꢁC): ꢁ 8.01 (br s, 2H, NH and –COOH), 7.50–7.17 (m,
5H, ArH), 7.37–7.07 (m, 3H, ArH), 6.84–6.80 (m, 5H, ArH), 5.99
(d, J ¼ 2:79 Hz, 1H, OCH2O), 5.97 (d, J ¼ 2:79 Hz, 1H, OCH2O),
4.85 (d, J ¼ 7:42 Hz, 1H, NHCH), 4.00 (d, J ¼ 7:42 Hz, 1H,
CHSPh), 3.49 (s, 3H, OCH3). 13C NMR: ꢁ 179.19, 152.26, 149.25,
148.12, 140.87, 133.90, 131.08 (2C), 129.36 (2C), 127.72, 126.68,
121.75, 117.09 (2C), 116.78 (2C), 110.73, 106.43, 101.30, 63.03,
55.50, 51.69. Anal. Found: C, 65.03; H, 5.21; N, 3.18%. Calcd
for C23H21NO5S: C, 65.23; H, 5.00; N, 3.31%.
20 S. Kanwar, S. D. Sharma, J. Chem. Res. 2005, 705.
21 T. Mukaiyama, R. Mutseda, M. Suzuki, Tetrahedron Lett.
1970, 11, 1901.
threo-3-p-Anisidino-2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-
yl)-3-phenylpropanoic Acid (12b): FT-IR: 1605 cmꢂ1. 1H NMR
(300 MHz, CDCl3, 25 ꢁC): ꢁ 7.77–7.71 (m, 4H, ArH), 7.56–7.09
(m, 5H, ArH), 6.92 (br s, 2H, NH and –COOH), 6.64–6.43 (m, 4H,
ArH), 4.79 (d, J ¼ 3:66 Hz, 1H, CHNH), 4.17 (d, J ¼ 3:66 Hz, 1H,
CHCOOH), 3.49 (s, 3H, OCH3). 13C NMR: ꢁ 173.46, 167.72 (2C),
152.26, 142.83, 134.43, 134.00 (2C), 131.61 (2C), 128.88 (2C),
128.26 (2C), 127.43, 124.09 (2C), 116.88 (2C), 116.56 (2C),
55.50, 52.86, 41.32, 40.40. Anal. Found: C, 69.61; H, 5.01; N,
6.40%. Calcd for C24H20N2O5: C, 69.23; H, 4.84; N, 6.73%.
22 K. Ito, T. Iida, T. Fujita, S. Tsuji, Synthesis 1981, 287.
23 S. D. Sharma, S. Kanwar, Synlett 2004, 2824.
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8, 658.
The authors are grateful to CSIR (New Delhi, India) for
financial assistance.
Supporting Information
The compounds that were prepared were characterized by
FT-IR, 1H NMR, 13C NMR, and elemental analysis, and details
are provided in the Supporting Information. This material is avail-
able free of charge on the web at http://www.csj.jp/journals/bcsj/.
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