A new method for the synthesis of carboxamides and peptides using 1,1′-carbonyldioxydi[2(1H)-pyridone] (CDOP) in the absence of basic promoters

Article abstract of DOI:10.1016/S0040-4039(03)00063-7

Various carboxamides or peptides are synthesized from the corresponding carboxylic acids and amines or α-amino acids using 1,1′-carbonyldioxydi[2(1H)-pyridone]. The reaction proceeds in the absence of basic promoters such as triethylamine or 4-(dimethylamino)pyridine, therefore, the undesired racemization does not occur at all in the segment coupling producing Z-Gly-Phe-Val-OMe and Z-Phe-Val-Ala-OMe.

Full text of DOI:10.1016/S0040-4039(03)00063-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1951–1955
A new method for the synthesis of carboxamides and peptides
using 1,1%-carbonyldioxydi[2(1H)-pyridone] (CDOP)
in the absence of basic promoters
Isamu Shiina* and Yo-ichi Kawakita
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601,
Japan
Received 8 November 2002; revised 24 December 2002; accepted 27 December 2002
Abstract—Various carboxamides or peptides are synthesized from the corresponding carboxylic acids and amines or a-amino
acids using 1,1%-carbonyldioxydi[2(1H)-pyridone]. The reaction proceeds in the absence of basic promoters such as triethylamine
or 4-(dimethylamino)pyridine, therefore, the undesired racemization does not occur at all in the segment coupling producing
Z-Gly-Phe-Val-OMe and Z-Phe-Val-Ala-OMe. © 2003 Elsevier Science Ltd. All rights reserved.
The carboxamide moiety is one of the most important
ingredients in natural bioactive compounds such as
peptides, b-lactams and macrolactams. A new and use-
ful method for the synthesis of these components under
form the more active pyridinium salt B which caused
the racemization via the oxazolone intermediate.
Therefore, we have to investigate more efficient amida-
tion reagents which promote the segment coupling to
produce oligopeptides without the accompanying unde-
sirable racemization.
2
1
mild reaction conditions is now required. Although
many coupling reagents giving carboxamides have been
investigated, there remains the severe problem that a
frequent racemization occurs in the segment coupling
We would now like to report a novel method for the
synthesis of carboxamides using 1,1%-carbonyl-
2
for producing oligopeptides.
dioxydi[2(1H)-pyridone] (CDOP),
a new coupling
Recently, we reported an effective method for the syn-
thesis of carboxamides or dipeptides in high yields from
the corresponding carboxylic acids and amines or a-
amino acids by dehydration condensation using di(2-
pyridyl) carbonate (DPC) or O,O-di(2-pyridyl)
thiocarbonate (DPTC) in the presence of a catalytic
reagent related to DPC. Since this reaction proceeds in
the absence of basic promoters such as DMAP, it is
applied to the coupling of a-amino acids in order to
produce di- or tripeptides without any loss of the
chirality of the acid segments.
3,4
amount of 4-(dimethylamino)pyridine (DMAP).
It
was revealed there that 2-pyridyl esters A, reactive
acylating intermediates, were in situ formed from car-
boxylic acids upon treatment with DPC or DPTC by
the catalysis of DMAP (Scheme 1).
However, these methods were not effective for the
preparation of a tripeptide derived from Z-Gly-Phe and
Val-OMe since the undesired racemization proceeded to
form a mixture of nearly equal amounts of LL- and
5
DL-isomers. In this reaction, the pyridyl ester A
derived from Z-Gly-Phe would react with DMAP to
*
Corresponding author. Fax: (81)-3-3260-5609; e-mail: shiina@
ch.kagu.tus.ac.jp
Scheme 1. Carboxamide-forming reaction using DPC or
DPTC.
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00063-7

1
952
I. Shiina, Y. Kawakita / Tetrahedron Letters 44 (2003) 1951–1955
coupling reaction using CDOP instead of DPCO
according to the general procedure reported in the
3
,4
amidation reactions using DPC and DPTC.
A simple amidation reaction was chosen as a model
case for the first stage of the present research. 3-Phenyl-
propylamine (1.0 equiv.) was added to the reaction
mixture of CDOP (1.1 equiv.) and 3-phenylpropanoic
acid (1.1 equiv.) in dichloromethane at room tempera-
ture, and then the corresponding amide was obtained in
1
8
8% yield (Table 1, entry 1). The H NMR of the
reaction mixture in chloroform-d showed that 82%
2
(1H)-oxo-1-pyridyl ester D* was generated from
CDOP (1.2 equiv.) with 3-phenylpropanoic acid (1.0
equiv.) before adding 3-phenylpropylamine (entry 3).
9
Furthermore, the use of an excess amount of CDOP
1
(
1.5 equiv.) increased the ratio of D* (94%) in the H
NMR experiment (entry 4), and it was then revealed
that D* was completely formed when 1.8 equiv. of
CDOP was employed (entry 5). Actually, it was shown
that the greater molar amounts of CDOP used, higher
yields of the amide were attained by the successive
reactions (entries 3–6). In these cases, an equal amount
of amine to CDOP has to be used since an excess
amount of CDOP would directly react with the amine
to form the corresponding carbamate. It was deter-
mined that the use of not less than 1.8 equiv. molar
amounts of CDOP with an equal amount of 3-phenyl-
propylamine gave the desired carboxamide in quantita-
tive yields (entries 5 and 6).
Scheme 2. Attempted synthesis of DPCO and formation of
CDOP.
First, we tried to prepare di(2-pyridyl) carbonate N,N%-
dioxide (DPCO) because it might potentially produce
very active intermediates, 2-pyridyl ester N-oxides C,
by the reaction with carboxylic acids (Scheme 2). How-
ever, the reaction of 2-hydroxypyridine N-oxides (6
equiv.) with triphosgene (1 equiv.) in the presence of
pyridine (12 equiv.) did not produce the desired DPCO,
but CDOP, the corresponding tautomer of DPCO, was
unpredictably prepared in high yield, as shown in
The present reaction was performed in several polar
and nonpolar solvents such as DMF (41%), THF
6
,7
Scheme 2. The structure of CDOP was confirmed by
(74%), Et O (46%), toluene (93%) and benzene (94%) at
2
1
13
H and C NMR by comparison of all signals to those
room temperature, and the best yield was observed
when the reaction was carried out in CH Cl (quant.).
8
of a reference compound. It is also assumed that the
2
2
2
(1H)-oxo-1-pyridyl esters D generated from CDOP
with carboxylic acids might act as reactive intermedi-
ates to form the carboxamides by the reaction with
amines. Therefore, we then tried to develop a new
Table 2 shows the yields of a variety of carboxamides
including ones derived from bulky substrates. The reac-
tions of benzylamine, diphenylmethylamine, benzyl-
Table 1. Formation of an active 2(1H)-oxo-1-pyridyl ester and its reaction with amine
a
Yield of amide (%)b
Entry
x
y
z
Yield of D* (%)
1
2
3
4
5
6
1.1
1.2
1.0
1.0
1.0
1.0
1.1
1.2
1.2
1.5
1.8
2.0
1.0
1.0
1.2
1.5
1.8
2.0
Nd
Nd
82
94
Quant.
Quant.
88
82
88
90
Quant.
Quant.
a
Conversion yield. Determined by 1H NMR.9
Isolated yield.
b

I. Shiina, Y. Kawakita / Tetrahedron Letters 44 (2003) 1951–1955
1953
Table 2. Synthesis of carboxamides
Entry Acid Amine
PhCH CH CH NH Quant.
acids with CDOP to produce the corresponding 2(1H)-
oxo-1-pyridyl esters D in situ, Gly-OEt·HCl was added
to the mixture with an equal amount of triethylamine
Yield (%)a
(
Table 3, entries 1–6). All reactions proceeded smoothly
1
2
3
4
5
6
7
8
9
1
1
1
PhCH CH COOH
2 2
2
2
2
2
to afford the desired dipeptides in high yields and the
optical purities of the products were not reduced
through the successive reactions. Although facile
racemization has been observed for the synthesis of
peptides from Z-Gly-Phe with several amino acids
when using conventional coupling reagents (Anteunis’
PhCH CH COOH
PhCH NH
97
2
2
2
2
PhCH CH COOH
Ph CHNH
Quant.
97
2
2
2
2
PhCH CH COOH
PhCH NHMe
2
2
2
PhCH CH COOH
1-Adamantyl-NH2
Piperidine
90
91
2
2
PhCH CH COOH
2
2
PhCH CH COOH
PhNH2
90
2
2
1f,1h–l,12
PhMeCHCOOH
PhCOOH
PhCH CH CH NH 98
test),
the CDOP-mediated amidation proved to
2
2
2
2
PhCH CH CH NH 67
2
2
2
2
be quite effective for the preparation of the LL-type of
Z-Gly-Phe-Val-OMe without forming the DL-isomer
0
1
2
Me CCOOH
(E)-MeCHꢀCHCOOH
(Z)-MeCHꢀCMeCOOH PhCH CH CH NH 88
PhCH CH CH NH 83
PhCH CH CH NH 87
2 2 2 2
3
2 2 2 2
(
entry 7). Furthermore, the reaction of Z-Phe-Val with
2
2
2
2
Ala-OMe·HCl was also examined by employing the
present reaction (entries 8).
1g,13
1
a
The H NMR and
Isolated yield.
HPLC analyses of the formed crude product showed
that the undesired LDL-stereoisomer was not generated
in the least, and only the desired LLL-peptide was
obtained in high yield. It is noteworthy that these
segment couplings were performed without any loss of
chirality and the corresponding tripeptides were synthe-
sized in high yields with excellent purities. We further
methylamine, 1-adamantanamine and piperidine with
the 2(1H)-oxo-1-pyridyl ester D* derived from 3-
phenylpropanoic acid proceeded to form the corre-
sponding coupling products in quite high yields (entries
2
–6). A weak nucleophile such as aniline also reacted
with D* to form the desired anilide in good yield (entry
). Other 2(1H)-oxo-1-pyridyl esters were generated
7
from several carboxylic acids in situ, and the reaction
of the active intermediates D with 3-phenylpropylamine
gave the corresponding carboxamides in good to excel-
lent yields (entries 8–10). It is known that the reactions
of crotonic and angelic acids with nucleophiles pro-
moted by basic catalysts afford the E- and Z-mixtures
since the double bond easily isomerized under basic
Table 3. Synthesis of peptides and their LOC
Entry Acid
Amine
Yield (%)a LOCb (%)
d
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
Z-
Z-
Z-
Z-
Z-
Z-
L
L
L
L
L
L
-Leu
-ALa
-Phe
-Val
-Met
-Pro
Gly-OEt·HCl
Gly-OEt·HCl
Gly-OEt·HCl
Gly-OEt·HCl
Gly-OEt·HCl
Gly-OEt·HCl
99
99
90
93
91
Quant.
Nd
Nd
e
Ndf
g
Nd
Nd
Nd
1
0
conditions. For example, the EDC/DMAP-, 2-fluoro-
h
i
11
1-methylpyridinium 4-toluenesulfonate/triethylamine-
and DPC/DMAP-promoted amidation of the E-cro-
tonic and angelic acids with 3-phenylpropylamine gave
mixtures of two isomers (E- or Z-N-(3-phenyl-
propyl)crotonamide; E/Z=96/4, 93/7 and 93/7, respec-
tively; N-(3-phenylpropyl)angelamide or N-(3-phenyl-
propyl)tiglamide; Z/E=84/16, 95/5 and 10/90, respec-
tively); however, the CDOP method produced only the
corresponding E- or Z-isomer in high yield (entries 11
and 12) since the present reaction takes place without
any basic promoters such as tertiary amines or DMAP.
c
c
Z-Gly-
L
-Phe
-Val
L
L
L
L
L
L
L
L
L
-Val-OMe·HCl 78
B0.1
B0.1
Z- -Phe-
L
L
-Ala-OMe·HCl 89
-Val-OMe·HCl 58
-Val-OMe·HCl 56
-Val-OMe·HCl 62
-Val-OMe·HCl 77
-Val-OMe·HCl 60
-Val-OMe·HCl 46
-Val-OMe·HCl 76
j
c
Z-Gly-
Z-Gly-
Z-Gly-
Z-Gly-
Z-Gly-
Z-Gly-
Z-Gly-
L
L
L
L
L
L
L
-Phe
-Phe
-Phe
-Phe
-Phe
-Phe
-Phe
7.6
1.6
3.0
k
l
c
0
1
2
3
4
5
c
m
n
o
p
c
c
B0.1
B0.1
c
14.6
96.0
c
a
Isolated yield.
LOC=(diastereomeric
b
excess
of
acid)−(enantiomeric
or
A typical experimental procedure is described for the
synthesis of 3-phenyl-N-benzylpropanamide. To a solu-
tion of CDOP (54.8 mg, 0.221 mmol) in
dichloromethane (0.8 mL) at room temperature under
an argon atmosphere was added 3-phenylpropanonic
acid (18.4 mg, 0.123 mmol). After the reaction mixture
had been stirred for 1 h, complete consumption of the
diastereomeric excess of product).
Enantiomeric or diastereomeric excesses of acids and products were
c
1
4–16
determined by HPLC.
d
e
f
18
17
[
[
[
[
h] −26.3° (c 1.94, EtOH); cf. −26.3°.
h] −22.1° (c 1.81, EtOH); cf. −22.2°.
h] −16.7° (c 1.97, EtOH); cf. −16.9°.
h] −25.6° (c 0.973, EtOH); cf. −25.3°.
h] −19.7° (c 3.01, EtOH); cf. −19.8°.
[h] −60.4° (c 1.76, AcOEt); cf. −60.4°.
D
17
18
D
18
19
D
18
g
h
i
20
D
18
21
[
D
16
22
3
-phenylpropanonic acid was monitored by TLC, and
D
j
then a solution of benzylamine (23.6 mg, 0.221 mmol)
in dichloromethane (1.0 mL) was added at room tem-
perature. The reaction mixture was stirred for 30 min
and then the solvent was evaporated. The resulting
mixture was purified by preparative TLC on silica gel
TBTU (1.1 equiv.), NMM (2.0 equiv.), DMF, −18°C.
TBTU (1.1 equiv.), HOBt (1.1 equiv.), NMM (2.0 equiv.), DMF,
k
−
18°C.
l
TBTU (1.1 equiv.), DIEA (2.0 equiv.), DMF, −18°C.
TBTU (1.1 equiv.), HOBt (1.1 equiv.), DIEA (2.0 equiv.), DMF,
m
−
18°C.
(
hexane/ethyl acetate=1/1) to afford 3-phenyl-N-ben-
n
TBTU (1.1 equiv.), HOAt (1.1 equiv.), DIEA (2.0 equiv.), DMF,
zylpropanamide (28.4 mg, 97%) as a white solid.
−
18°C.
o
p
DCC (1.1 equiv.), TEA (1.1 equiv.), CH Cl , −18°C.
DPC (1.1 equiv.), DMAP (0.1 equiv.), CH Cl , rt, then TEA,
2
2
Next, we applied this protocol to the synthesis of the
2 2
di- and tripeptides. After treatment of several Z-amino
−18°C.

1
954
I. Shiina, Y. Kawakita / Tetrahedron Letters 44 (2003) 1951–1955
examined the Anteunis’ test using other effective
reagents for the formation of carboxamides, and each
LOC (loss of chirality) was found as shown in entries
Lett. 1994, 35, 9561–9564; (i) (BOMI, BDMP, BPMP,
DOMP, SOMP, FOMP, AOMP): Li, P.; Xu, J.-C. Tetra-
hedron 2000, 56, 4437–4445; (j) (BEP, FEP, BEPH,
FEPH): Li, P.; Xu, J.-C. Tetrahedron 2000, 56, 8119–
9–15.
9131; (k) (CMBI): Li, P.; Xu, J.-C. Tetrahedron 2000, 56,
A typical experimental procedure is described for the
synthesis of Z-Gly-Phe-Val-OMe. To a solution of
CDOP (77.0 mg, 0.310 mmol) in dichloromethane (1.3
mL) at 0°C under an argon atmosphere was added
Z-Gly-Phe (61.4 mg, 0.172 mmol) in dichloromethane
9949–9955; (l) (HOTT, TOTT, HODT, TODT): Alberi-
cio, F.; Bail e´ n, M. A.; Chinchilla, R.; Dodsworth, D. J.;
N a´ jera, C. Tetrahedron 2001, 57, 9607–9613.
2. (a) Williams, M. W.; Young, G. T. J. Chem. Soc. 1964,
3701–3708; (b) Williams, A. J. Chem. Soc., Perkin 2 1975,
947–953; (c) Curran, T. C.; Farrar, C. R.; Niazy, O.;
Williams, A. J. Am. Chem. Soc. 1980, 102, 6828–6837; (d)
Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; 3rd ed.; John Wiley & Sons: New
York, 1999; pp. 503–504.
(
0.8 mL). After the reaction mixture had been stirred
for 1 h at room temperature, complete consumption of
the Z-Gly-Phe was monitored by TLC, and then Val-
OMe·HCl (52.0 mg, 0.310 mmol) and a solution of
triethylamine
dichloromethane (1.2 mL) were successively added at
18°C. The reaction mixture was stirred for 5 min and
(31.4
mg,
0.310
mmol)
in
3. Shiina, I.; Suenaga, Y.; Nakano, M.; Mukaiyama, T.
−
Bull. Chem. Soc. Jpn. 2000, 73, 2811–2818.
then iced brine (10 mL) was added. The mixture was
extracted with dichloromethane, and the organic layer
was washed with 1 M HCl, water and brine, and dried
over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was
purified by preparative TLC on silica gel (hexane/ethyl
acetate=1/3) to afford Z-Gly-Phe-Val-OMe (63.2 mg,
4. Shiina, I.; Saitoh, K.; Nakano, M.; Suenaga, Y.;
Mukaiyama, T. Collect. Czech. Chem. Commun. 2000, 65,
621–630. See also: (b) Shiina, I.; Saitoh, K.; Fr e´ chard-
Ortuno, I.; Mukaiyama, T. Chem. Lett. 1998, 3–4; (c)
Saitoh, K.; Shiina, I.; Mukaiyama, T. Chem. Lett. 1998,
679–680; (d) Mukaiyama, T.; Shiina, I.; Iwadare, H.;
Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sakoh, H.;
Nishimura, K.; Tani, Y.; Hasegawa, M.; Yamada, K.;
Saitoh, K. Chem. Eur. J. 1999, 5, 121–161.
78%) as a white solid.
Thus, we developed a new reaction providing amides
and peptides in high yields via active intermediates,
5. For example, a mixture of the LL- and DL-isomers (48/52)
was obtained in 77% yield when using DPC (1.1 equiv.)
2(1H)-oxo-1-pyridyl esters D, using CDOP. Since this
with DMAP (0.1 equiv.) for the reaction of Z-Gly-
(1.1 equiv.) with -Val-OMe·HCl (1.0 equiv.) and trieth-
ylamine (1.0 equiv.).
L-Phe
reaction proceeds in the absence of basic promoters
such as tertiary amines or substituted pyridines, the
undesired racemization was completely prevented in the
segment coupling to afford oligopeptides. Further stud-
ies of the reaction using CDOP and other applications
of the present protocol for the syntheses of useful
complex molecules are now in progress.
L
6. CDOP was synthesized as follows. To a mixture of
2-hydroxypyridine N-oxide (1.00 g, 9.00 mmol) and
triphosgene (450 mg, 1.51 mmol) in dichloromethane (30
mL) at 0°C under an argon atmosphere was added
pyridine (1.5 mL). After the reaction mixture had been
stirred for 24 h at room temperature, the solvent was
evaporated. The residue was washed with ether three
times (each 30 mL) under an argon atmosphere. The
crude CDOP was dissolved in THF (50 mL) and the
suspension including pyridine·HCl salt was stirred for 2 h
at room temperature and then it was allowed to stand for
30 min. After filtration of the mixture under an argon
atmosphere and evaporation of the solvent at 45°C, THF
Acknowledgements
This work was partially supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Science, Sports and Culture, Japan.
(
50 mL) was added to the yellow residue, and then the
above operation was repeated three times.
References
Dichloromethane (each 3 mL) and ether (each 6 mL)
were successively added to the resulted mixture and the
yellow solution was separated from white precipitates
under an argon atmosphere, and then the above opera-
tion was repeated twice. The remaining solvent was
removed under reduced pressure at 45°C to produce
CDOP (1.02 g, 91%) as a white solid.
1
. (a) Benz, G. In Comprehensive Organic Synthesis; Trost,
B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6,
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1
1
972, 94, 6203–6205; Takuma, S.; Hamada, Y.; Shioiri,
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T. Chem. Pharm. Bull. 1982, 30, 3147–3153; (d) (DEPC):
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3
(2H, ddd, J=9.3, 6.9, 2.2 Hz, H-4), 6.73 (2H, dd, J=9.3,
1.8 Hz, H-3), 6.23 (2H, ddd, J=7.2, 6.9, 1.8 Hz, H-5);
1
973, 14, 1595–1598; (e) (BOP): Castro, B.; Dormoy, J.
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222; (f) (HBTU, TBTU): Knorr, R.; Trzeciak, A.; Ban-
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1
3
C NMR (CDCl ): l 156.3 (2), 150.2 (CꢀO), 140.0 (4),
3
1
134.5 (6), 122.9 (3), 105.5 (5).
8. 1-Methyl-2-pyridone: H NMR (CDCl ): l 7.35 (2H, dd,
1
3
1
J=8.1, 2.2 Hz, H-6), 7.34 (2H, ddd, J=9.7, 6.6, 2.2 Hz,
H-4), 6.54 (2H, dd, J=9.7, 1.4 Hz, H-3), 6.17 (2H, ddd,
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fonyl chloride): Cabaret, D.; Wakselman, M. Tetrahedron
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J=8.1, 6.6, 1.4 Hz, H-5), 3.54 (3H, s, Me); C NMR

I. Shiina, Y. Kawakita / Tetrahedron Letters 44 (2003) 1951–1955
1955
1
f,1i–l
(
(
CDCl ): l 162.9 (2), 139.7 (6), 138.8 (4), 120.2 (3), 105.8
15. Z-Gly-
D
/
L
-Phe-
L
-Val-OMe;
HPLC (Kromasil KR
3
5), 37.4 (Me).
100-10 C18 (4.6×25 cm), CH CN/H O (0.1% TFA)=48/
52, flow rate=1.5 mL/min, detect 220 nm): t =9.5 min
R
3 2
1
9
. We compared the integration of the H NMR peaks of
H-2 in 3-phenylpropanoic acid with those of H-3 in D*
(
LL form), t =10.6 min (DL form).
R
23
for the determination of the conversion yield. 3-Phenyl-
1
6. Z-L-Phe-D/L-Val-L-Ala-OMe; HPLC (Cosmosil 5C18
1
propanoic acid: H NMR (CD Cl ): l 7.35–7.23 (5H, m,
2
2
(4.6 I.D.×150 mm), MeOH/H O=60/40, flow rate=1.0
mL/min, detect 254 nm): t =15.2 min (LLL form), t =
2
Ph), 2.98 (2H, t, J=7.6 Hz, H-3), 2.71 (2H, t, J=7.6 Hz,
R
R
1
H-2). 2(1H)-Oxo-1-pyridyl 3-phenylpropanoate (D*): H
1
7.9 min (LDL form).
7. Fujino, M.; Hatanaka, C. Chem. Pharm. Bull. 1968, 16,
29–932.
8. Heslinga, L.; Arens, J. F. Recl. Trav. Chim. Pays-Bas
957, 76, 982–995.
NMR (CD Cl ): l 7.81–5.32 (9H, m, Ph, Py), 3.11–3.06
2
2
1
1
1
(2H, m, H-3), 2.99–2.93 (2H, m, H-2).
9
1
0. (a) Miyashita, M.; Shiina, I.; Miyoshi, S.; Mukaiyama, T.
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H O–H PO (pH 2)=40/60, flow rate=0.35 mL/min,
2
3
4
detect 220 nm): t =12.1 min (L form), t =13.8 min (
D
R
R
form).