A multi-component reaction to 5-cyanouracils: Synthesis and mechanistic study

Article abstract of DOI:10.1016/j.bmc.2005.12.059

Acetonitrile as a solvent, excess of primary amines as general bases, and a reflux condition make the multi-component reactions of (2-cyanoacetyl) carbamate 1, ethyl orthoformate, and primary amines form 5-cyanouracils 4a-c feasibly. Mechanistic studies o

Full text of DOI:10.1016/j.bmc.2005.12.059

Bioorganic & Medicinal Chemistry 14 (2006) 3399–3404
A multi-component reaction to 5-cyanouracils: Synthesis
and mechanistic study
Bo-Ren Zhuang, Gien-Jow Hsu and Kuangsen Sung*
Department of Chemistry, National Cheng Kung University, Tainan, Taiwan, ROC
Received 9 November 2005; revised 11 December 2005; accepted 27 December 2005
Available online 23 January 2006
Abstract—Acetonitrile as a solvent, excess of primary amines as general bases, and a reflux condition make the multi-component
reactions of (2-cyanoacetyl) carbamate 1, ethyl orthoformate, and primary amines form 5-cyanouracils 4a–c feasibly. Mechanistic
studies of the multi-component reaction were carried out by proton NMR spectrometer. Acetonitrile as a solvent makes the reaction
of 1 with ethyl orthoformate produce E-ethyl (2-cyano-3-ethoxyacryloyl) carbamate E-2 without a catalyst of acetic anhydride. The
reactions of E-2 with primary amines produce the corresponding Z-3a–c as the only stable isomers eventually in CDCl or CD CN.
3
3
3
General-base-catalyzed intramolecular cyclizations of Z-3a–c at a reflux condition in CD CN generated the corresponding 5-cyano-
uracils 4a–c.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
(Scheme 1). The drawback of Shaw’s method is that
the reaction of 2 with a primary amine sometimes gener-
ates a non-cyclized product, instead of 5-cyanouracil,
Modified nucleosides are widely distributed naturally.
All species of tRNA contain unusual minor bases and
many bacteria and fungi provide rich sources of nucleo-
sides modified in the base, in the sugar, or in both base
and sugar residues. Modification of nucleosides some-
times shows a wide and useful biological activity due
to inhibition of nucleic acid metabolism. For example,
5-fluorouracil kills cancer cells, AZT acts as an inhibitor
of HIV reverse transcriptase, and 5-iodouridine is valu-
able for treating Herpes simplex infections. Therefore,
modern syntheses have been aimed at producing nucle-
4
c
4. In this article, we try to solve this problem and
search for optimal conditions of a multi-component
5
reaction (MCR) for synthesis of 5-cyanouracils.
1
5-Fluorouracil (5-FU) is an effective antitumor agent
6a
with a strong toxicity and poor tumor affinity. A lot
of efforts have been made to chemically modify 5-FU
by adding lipophilic substituents in order to reduce tox-
1
6b
icity and increase antitumor activity. It was reported
that 5-FU was prepared from 5-cyanouracil by one step
2
7
oside analogues.
easily. Therefore, the MCR to 5-cyanouracil derivatives
in this article provides an alternative way for synthesis
of the masked 5-FU.
Uracil is one of bases in nucleosides. Its analogues are
usually prepared by base-promoted condensation of
urea or its analogues with b-ketoesters, 3-alkoxyacry-
O
O
N
3
4a,b
O
O
lates, or 3-dialkylaminoacrylates. Shaw’s method
N
N
OEt
Ac O
2
H
for synthesis of 5-cyanouracils involved two steps: (1)
reaction of ethyl (2-cyanoacetyl) carbamate, 1, with eth-
yl orthoformate in the presence of acetic anhydride pro-
duced ethyl (2-cyano-3-ethoxyacryloyl) carbamate, 2,
whose configuration was not characterized. (2) Reaction
of 2 with a primary amine generated a 5-cyanouracil, 4
+
HC(OEt)3
N
OEt
H
EtO
2
1
O
O
O
N
N
NH
N
OEt
H
H2NR
N
O
R
EtO
2
Keywords: Multi-component reaction; Uracil.
*
4
Corresponding author. Tel.: +886 6 2757575; fax: +886 6 2740552;
e-mail: kssung@mail.ncku.edu.tw
Scheme 1.
0
968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.12.059

3400
B.-R. Zhuang et al. / Bioorg. Med. Chem. 14 (2006) 3399–3404
O
N
Development of synthetic oligonucleotides in the recog-
nition of specific DNA and RNA sequences for the anti-
sense or antigene therapy has grown explosively in last
N
O
O
N
+
HC(OEt)3
+
H2NR
NH
CH3CN
8
0 years. In addition to that, polyamide nucleic acids
PNA), where a polyamide replaced DNA backbone,
N
OEt
1
(
H
O
1
successfully recognized their complementary double-
stranded DNA by strand displacement, and this opened
R
4a : R = n-Bu; 4b : R = t-Bu; 4c : R = Ph
4a~c
9
up a new era in molecular biology. The MCR to
5
Scheme 3.
-cyanouracil derivatives in this article may provide an
alternative way to prepare the modified bases in
oligonucleotides or PNA.
O
O
N
N
OEt
2
. Results and discussion
H
H2NR
O
O
E-3a~c
RHN
We found that 1 hardly reacts with ethyl orthoformate
in chloroform but acetic anhydride may catalyze the
N
1
0a
N
OEt
reaction to get E-2 exclusively.
E-2 is much more stable than Z-2 due to resonance effect
We also found that
H
O
O
1
0b
EtO
N
and steric hindrance.
excess n-BuNH at room temperature, a 5-cyanouracil
When E-2 was treated with
E-2
2
H NR
2
N
H
OEt
4
a was generated. Then we attempted to combine these
two reactions together to become a multi-component
reaction (MCR) for synthesis of 5-cyanouracils 4, so
we mixed 1, ethyl orthoformate, and primary amine
together in the presence of acetic anhydride. What we
found was that acetic anhydride reacted with primary
amines at first before it could catalyze the reaction. To
solve this problem, we discarded acetic anhydride and
used a better solvent for this reaction. Due to good
solubility of 1 in acetonitrile, we replaced chloroform
with acetonitrile as a solvent for the reaction of 1 with
ethyl orthoformate without any catalyst at a reflux
condition, and it worked very well (Scheme 2). Presum-
ably the polar acetonitrile solvent helps stabilize the
polar transition state, and that makes this reaction work
without a catalyst of acetic anhydride. Then acetonitrile
was also used as a solvent for this MCR involving 1,
ethyl orthoformate, and primary amines without any
catalyst. Strangely, sometimes cyclized products of
3a : R = n-Bu; 3b : R = t-Bu; 3c : R = Ph
NHR
Z-3a~c
Scheme 4.
E-2 with one equivalent of t-BuNH
CD CN generated Z-3b at a much slower rate, because
bulky t-butylamine retarded its nucleophilic attack.
Similarly, due to less nucleophilicity of aniline, reaction
of E-2 with one equivalent of aniline in CDCl
CD CN produced Z-3c at a slow rate, too.
in CDCl or
3
2
3
or
3
3
When Z-3a was heated at a reflux condition in CD
no intramolecular cyclization occurred. The solvent of
CDCl was not used in the reaction because of limited
solubility of 4a–c in CDCl . Similarly, we did not obtain
any intramolecular cyclization product when Z-3b or
Z-3c was heated at a reflux condition in CD CN.
CN,
3
3
3
5
-cyanouracils 4 were generated, but sometimes non-
3
cyclized products Z-3 were produced (Scheme 3). This
inspired us to study its reaction mechanism and find
out the key point to control this MCR.
When Z-3a was treated with excess NEt in CD CN at
3 3
1
room temperature, the doublet signal for the H NMR
absorption of the vinyl hydrogen of Z-3a turned to a
singlet immediately and 5-cyanouracil 4a was generated
in 4 h (Scheme 5). This reaction was monitored by a
proton NMR spectrometer and the result is shown in
When E-2 was treated with one equivalent of n-BuNH2
in CDCl , both E-3a and Z-3a were formed at a ratio of
3
5
0:50 at 5 min, 25:75 at 30 min, and 0:100 at 24 h after
the reaction (Scheme 4). This reaction was monitored
by a proton NMR spectrometer, and the results are
shown in Figure 1. Eventually, Z-3a, instead of E-3a,
Figure 2. This result implies that NEt
1
3
works as a
to remove the proton on enamine
1
general base
nitrogen and enhances nucleophilicity of the enamine
for the intramolecular attack on carbonyl group of ester.
During this general-base-promoted intramolecular
cyclization, a small amount of E-3a was found because
is the only stable isomer in CDCl , indicating that there
3
is an intramolecular hydrogen bonding in Z-3a, which
makes Z-3a more stable than E-3a. Similar result was
found with the same reaction in CD CN. Reaction of
of NEt -promoted isomerization.
3
3
O
O
On the other hand, when Z-3b was treated with excess
NEt in CD CN at room temperature, we found that
N
O
O
3
3
N
N
OEt
1
CH3CN
HC(OEt)a
H
the doublet signal for the H NMR absorption of the vi-
nyl hydrogen of Z-3b became a singlet. However, no
intramolecular cyclization occurred at all until the reac-
tion temperature was increased to 80 °C. Clearly the
bulky t-Bu group retarded the ring-closure reaction.
+
N
OEt
H
EtO
E-2
1
Scheme 2.

B.-R. Zhuang et al. / Bioorg. Med. Chem. 14 (2006) 3399–3404
3401
1
Figure 1. Part of H NMR (CDCl
3
) spectra for the reaction of E-2 with n-BuNH
2
2
at 25 °C (A) before adding n-BuNH , (B) at 5 min, (C) at 30 min,
and (D) at 24 h after mixing the solution.

3402
B.-R. Zhuang et al. / Bioorg. Med. Chem. 14 (2006) 3399–3404
O
O
O
In comparison with the original Shaw’s method for the
N
N
synthesis of 4, our modified Shaw’s method has the fol-
lowing advantages. (1) Shaw’s method used acetic anhy-
dride to catalyze the first step of reaction. Our modified
method discarded acetic anhydride as a catalyst but used
acetonitrile as a solvent. (2) Shaw’s method is a two-pot
reaction. Our modified method is a one-pot MCR with
high yield. (3) We found that the second step of the reac-
tion in Shaw’s method is general-base catalyzed, so ex-
cess amine is needed to accelerate the ring-closure
reaction to 4.
N
OEt
H
NH
NEt3
H
NH
R
H
N
O
Z-3a~c
R
NEt3
4a~c
O
O
+
N
HOCH2CH3
N
H
OEt
3
a, 4a : R = n-Bu; 3b, 4b : R = t-Bu; 3c, 4c : R = Ph
HN
R
H
E-3a~c
3. Conclusion
Scheme 5.
Acetonitrile as a solvent makes the reaction of 1 with
ethyl orthoformate produce E-2 without a catalyst of
acetic anhydride. The reactions of E-2 with primary
amines produce the corresponding Z-3a–c as the only
stable isomers eventually in CDCl or CD CN. Intra-
Similarly, the reaction of Z-3c with excess NEt3 in
CD CN at room temperature made the doublet signal
3
1
for the H NMR absorption of the vinyl hydrogen of
3
3
Z-3c become a singlet. The ring-closure product Z-4c
was not generated until the reaction temperature was
raised to 80 °C, indicating that N-phenyl group reduced
nucleophilicity of the enamine.
molecular cyclizations of Z-3a–c, which form the corre-
sponding 5-cyanouracils 4a–c, work in CD CN at a
3
reflux condition and in the presence of a general base
like NEt . Acetonitrile as a solvent, excess of primary
3
amines as general bases, and a reflux condition make
the MCR of 1, ethyl orthoformate, and primary amines
form 5-cyanouracils 4a–c feasibly.
According to the mechanistic studies we just mentioned,
there are three key points in carrying out the MCR of 1,
ethyl orthoformate, and primary amines to form the
5-cyanouracils 4. (1) Acetonitrile as a solvent in the
MCR may eliminate the use of acetic anhydride as a cat-
4. Experimental
4.1. General
alyst. (2) A general base like NEt is needed for the
3
intramolecular cyclization to form the 5-cyanouracils
4
, and primary amines in the MCR can be used for this
purpose. (3) To overcome the barrier of the ring-closure
reactions, reflux is needed for some of this type of reac-
tions. Therefore, to do the MCR to 5-cyanouracils 4, we
mixed 1 and ethyl orthoformate with excess of primary
amine like n-BuNH , t-BuNH , or aniline in acetonitrile
All the reagents were obtained from commercial suppli-
ers and used as received. Ethyl (2-cyanoacetyl) carba-
mate 1 was prepared according to the literature
4
method.
2
2
and heated the reaction mixture at a reflux condition for
4.2. E-Ethyl (2-cyano-3-ethoxyacryloyl) carbamate (E-2)
4
5
h. By following this method, isolated yields of
-cyanouracils 4a–c were good. Aliphatic, aromatic,
To a solution of 1 (0.312 g, 2 mmol) in 2 mL of acetoni-
trile was added ethyl orthoformate (1 mL, 6 mmol). The
mixture was refluxed at 80 °C under nitrogen atmo-
sphere for 4 h. After the reaction was complete, the reac-
tion mixture was cooled down and concentrated by
rotary evaporator. Ether was poured into the reaction
mixture and the mixture kept in a refrigerator for
12 h. After filtration of the mixture, white powder was
collected and recrystallized from chloroform/ether.
Yield: 92%; its characterization is the same as in the
and bulky primary amines are suitable for this MCR.
However, primary amines with other active functional
groups like aldehyde, carboxylic acid, etc., are not suit-
able for this MCR, so these active functional groups
need to be protected before running this MCR.
Configuration assignment of E-3a–c and Z-3a–c is based
on two findings. (1) Proton NMR absorption of the vi-
nyl hydrogen (d 8.17) of E-2 is 0.37 ppm more downfield
than that (d 7.80) of Z-2. The vinyl hydrogen of 3 is
subjected to almost the same electronic environment as
that of 2, so proton NMR absorption of the vinyl
hydrogen of E-3a–c should be a more downfield than
that of Z-3a–c. (2) Theoretically, only Z-3a–c can under-
go intramolecular cyclization to form the corresponding
1
0a
10a
literature.
4.3. General method to prepare Z-3a–c
To a solution of 2 (0.2 g, 1 mmol) in 1 mL of CDCl was
3
added 1 mmol of n-butylamine, t-butylamine, or aniline.
The mixture was monitored by a proton NMR spectrom-
eter. At the beginning, both cis and trans isomers of 3a–c
were found, but 1 day later the cis isomer is the only prod-
uct. The solvent and byproducts were removed from the
solution by rotary evaporator to get crude Z-3a–c, which
were purified by column chromatography with a mobile
phase of hexane/ethyl acetate (3:1).
5
(
-cyanouracils 4a–c. In these proton NMR experiments
Figs. 1 and 2), proton NMR absorption of the vinyl
hydrogen of the one that does intramolecular cyclization
is more upfield. It means that proton NMR absorptions
of the vinyl hydrogens of Z-3a–c are more upfield than
those of E-3a–c, and this is consistent with the first
finding.

B.-R. Zhuang et al. / Bioorg. Med. Chem. 14 (2006) 3399–3404
3403
1
Figure 2. Part of H NMR (CD
3
CN) spectra for the intramolecular cyclization of Z-3a at 25 °C (A) before adding excess NEt
3
, (B) at 5 min, (C) at
3
10 min, and (D) at 4 h after adding excess NEt .
4
.3.1. Z-Ethyl [2-cyano-3-(n-butylamino) acryloyl] carba-
14.14, 19.41, 32.17, 50.04, 62.09, 71.26, 118.77, 150.31,
159.42, 165.03; IR (thin film) 2199 (CN), 1762, 1671
1
mate (Z-3a). Yield: 95%; yellow oil; H NMR (CDCl ) d
0
CH ), 1.38 (2H, m, CH ), 1.57 (2H, m, CH ), 3.36
3
À1
.94 (3H, t, J = 7.3 Hz, CH ), 1.31 (3H, t, J = 7.1 Hz,
(C@O) cm ; HRMS (ESI) m/z calcd for C H N O
3
11 17
3
3-
+
Na ([M + Na] ) 262.1168, found 262.1170.
3
2
2
(
CH ), 7.32 (1H, d, J = 13.9 Hz, CH ), 7.74 (1H, s,
2H, t, J = 6.7 Hz, CH ), 4.23 (2H, t, J = 7.1 Hz,
2
4.3.2. Z-Ethyl [2-cyano-3-(t-butylamino) acryloyl] carba-
2
2
1
3
1
NH), 9.81 (1H, s, NH); C NMR (CD CN) d 13.41,
mate (Z-3b). Yield: 92%; yellow oil; H NMR (CDCl ) d
3
3

3404
B.-R. Zhuang et al. / Bioorg. Med. Chem. 14 (2006) 3399–3404
1
.31 (3H, t, J = 7.0 Hz, CH ), 1.35 (9H, s, CH ), 4.24
3
4.5. Multi-component reaction to 5-cyanouracils (4a–c)
3
(
CH ), 10.17 (1H, d, J = 13.9 Hz, NH); C NMR
2H, q, J = 7.0 Hz, CH ), 7.46 (2H, d, J = 13.9 Hz,
2
1
3
To a solution of 1 (0.156 g, 1 mmol) and ethyl orthofor-
mate (1 mL, 6 mmol) in 1.5 mL of acetonitrile was add-
ed 7 mmol of n-butylamine, t-butylamine, or aniline.
The mixture was refluxed at 60 °C under nitrogen atmo-
sphere for 4 h. The reaction mixture was cooled down
and concentrated by rotary evaporator. The solid resi-
due was recrystallized by chloroform/acetonitrile to get
4a–c. Yields to 4a, 4b, and 4c were 87%, 90%, and
95%, respectively.
2
(
CD CN) d 14.13, 29.50, 54.55, 62.05, 70.86, 119.11,
3
1
1
50.32, 155.29, 165.06; IR (thin film) 2200 (CN), 1766,
667 (C@O) cm
À1
; HRMS (ESI) m/z calcd for
+
C H N O Na ([M + Na] ) 262.1168, found 262.1167.
1
1
17
3
3
4
.3.3. Z-Ethyl [2-cyano-3-anilinoacryloyl] carbamate
1
(
Z-3c). Yield: 96%; yellow oil; H NMR (CDCl ) d
3
1
J = 7.1 Hz, CH ), 7.12 (2H, m, PhH), 7.25 (1H, m,
.32 (3H, t, J = 7.1 Hz, CH3), 4.27 (2H, q,
2
PhH), 7.41 (2H, m, PhH), 7.89 (1H, d, J = 13.3 Hz,
CH), 7.91 (1H, s, NH), 11.62 (1H, d, J = 13.3 Hz,
Acknowledgment
1
3
NH);
C NMR (CD CN) d 14.13, 62.38, 75.17,
3
1
1
1
17.34, 117.96, 126.29, 130.06, 137.85, 150.06,
52.37, 164.56; IR (thin film) 2203 (CN), 1765,
Financial support from the National Science Council
of Taiwan (NSC 94-2113-M-006-009) is gratefully
acknowledged.
À1
665 (C@O) cm
; HRMS+ (ESI) m/z calcd for
([M + Na] ) 282.0855, found
C H N O Na
82.0855.
1
3
13
3
3
2
References and notes
4.4. General method for intramolecular cyclizations of
Z-3a–c
1
2
. Blackburn, G. M.; Gait, M. J. Nucleic Acids in Chemistry
and Biology, 2nd ed.; Oxford University Press: Oxford,
1
996.
. (a) Hanessian, S.; Machaalani, R. Tetrahedron Lett. 2003,
4, 8321; (b) Yokoyama, M.; Ikenogami, T.; Togo, H. J.
To a solution of Z-3a–c (0.2 mmol) in 1 mL of CD CN
3
was added triethylamine (0.2 g, 2 mmol). The mixture
was kept for 4 h at room temperature for Z-3a and at
4
Chem. Soc., Perkin Trans. 1 2000, 2055; (c) Momotake,
A.; Togo, H.; Yokoyama, M. J. Chem. Soc., Perkin Trans.
1 1999, 1193.
8
0 °C for Z-3b and Z-3c. The whole process was moni-
tored by a proton NMR spectrometer. The solution was
concentrated by a rotary evaporator and the solid prod-
uct was recrystallized by chloroform/acetonitrile to af-
ford 4a–c.
3. (a) Shi, G.-Q.; Wang, Q.; Schlosser, M. Tetrahedron 1996,
2, 4403; (b) Sato, T.; Hayakawa, Y.; Noyori, R. Bull.
5
Chem. Soc. Jpn. 1984, 57, 2515; (c) Sato, T.; Kobayashi,
H.; Noyori, R. Tetrahedron Lett. 1980, 21, 1971.
4
. (a) Atkinson, M. R.; Shaw, G.; Warrener, R. N. J. Chem.
Soc. 1956, 4118; (b) Shaw, G. J. Chem. Soc. 1955, 1834; (c)
By following Shaw’s method, the reaction of 2 with a
primary amine sometimes generates a non-cyclized prod-
uct, instead of 5-cyanouracil, in our laboratory.
4
.4.1. 1-n-Butyl-5-cyanouracil (4a). Yield: 93%; white
1
solid; mp: 181 °C; H NMR (CD CN) d 0.93 (3H, t,
J = 7.3 Hz, CH ), 1.34 (2H, m, CH ), 1.63 (2H, m,
CH ), 3.74 (2H, t, J = 7.3 Hz, CH ), 8.12 (1H, s,
3
3
2
2
2
1
3
CH);
5
C NMR (CD CN) d 13.84, 20.13, 31.48,
5. Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
6. (a) Daher, G. C.; Harris, B. E.; Diasio, R. B. Pharmacol.
Ther. 1990, 48, 189; (b) Ozaki, S. Med. Res. Rev. 1996, 16,
3
0.16, 89.14, 114.73, 153.00, 154.92, 161.29; IR (thin
film) 2235 (CN), 1726, 1704 (C@O) cm ; HRMS
À1
+
5
1.
(ESI) m/z calcd for C H N O ([M] ) 194.0929,
9 11 3 2
found 194.0931.
7
8
9
. Miyashita, O.; Matsumura, K.; Shimadzu, H.; Hashimoto,
N. Chem. Pharm. Bull. 1981, 29, 3181.
. (a) Uhlmann, E.; Payman, A. Chem. Rev. 1990, 90, 543;
4
.4.2. 1-t-Butyl-5-cyanouracil (4b). Yield: 95%; white sol-
(
b) Kool, E. T. Chem. Rev. 1997, 97, 1473.
1
id; mp: 241 °C; H NMR (CD CN) d 1.52 (9H, s, CH ),
8
8
2
calcd for C H N O Na ([M + Na] ) 216.0749, found
3
2
3
3
. (a) Egholm, M.; Berg, R. H.; Buchardt, O. Science 1991,
254, 1497; (b) Egholm, M.; Buchardt, O.; Christensen, L.;
Behrens, C.; Freier, S. M.; Driver, D.; Berg, R. H.; Kim, S.
K.; Norden, B.; Nielsen, P. E. Nature 1993, 365, 566; (c)
Wittung, P.; Nielsen, P. E.; Buchardt, O.; Egholm, M.;
Norden, B. Nature 1994, 368, 561.
1
3
.18 (1H, s, CH); C NMR (CD CN) d 28.49, 64.41,
3
8.41, 115.21, 150.41, 152.59, 161.14; IR (thin film)
234 (CN), 1734, 1704 (C@O) cm ; HRMS (ESI) m/z
À1
+
9
11
2
16.0751.
1
0. (a) Sung, K.; Lin, M.-C.; Huang, P.-M.; Zhuang, B.-R.;
Sung, R.; Wu, R.-R. Ark. Org. Chem. (ARKIVOC) 2005,
xiii, 131; (b) Sung, K.; Lin, M.-C.; Huang, P.-M.; Zhuang,
B.-R.; Sung, R.; Wu, R.-R. J. Phys. Org. Chem. 2005, 18,
4
.4.3. 5-Cyano-1-phenyluracil (4c). Yield: 96%; white sol-
1
id; mp: 278 °C; H NMR (CD CN) d 7.35 (2H, m,
3
1
3
PhH), 7.54 (3H, m, PhH), 8.22 (1H, s, CH); C NMR
CD CN) d 90.25, 114.43, 118.37, 127.79, 130.51,
1
183.
(
1
3
1
1. (a) Carey, F. A.; Sundberg, R. J. Advanced Organic
Chemistry Part A: Structure and Mechanism, 2nd ed.;
Plenum Press: New York, 1984; (b) Isaacs, N. Physical
Organic Chemistry, 2nd ed.; Longman Scientific & Tech-
nical: Essex, 1995.
38.90, 150.13, 154.88, 161.21; IR (thin film) 2238
À1
(CN), 1721, 1713 (C@O) cm ; HRMS (ESI) m/z calcd
for C H N O Na ([M + Na] ) 236.0436, found
2
+
1
1
7
3
2
36.0437.