3,3-dichloro-1,2-diphenylcyclopropene (CPICL)-mediated synthesis of n α-protected amino acid azides and α-ureidopeptides

Article abstract of DOI:10.1055/s-0033-1340864

Rapid synthesis of acid azides via in situ generation of acid chlorides using CPICl as chlorinating agent from the corresponding N^α- protected amino acids is described. Also the conversion of acid azides into ureidopeptides through the Curtius rearrangement under ultrasonication is delineated. The mildness of the protocol renders the acid-sensitive substrates to afford the corresponding amino acid azides and ureidopeptides in good yields. Diphenylcyclopropenone has also been recovered from the reaction mixture and reused. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340864

LETTER
▌1001
letter
3,3-Dichloro-1,2-diphenylcyclopropene (CPICl)-Mediated Synthesis of
Nα-Protected Amino Acid Azides and α-Ureidopeptides
Synthesis of Nα-Protected Amino Acid Azides
Nageswara Rao Panguluri, M. Samarasimhareddy, C. Madhu, Vommina V. Sureshbabu*
109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi, Bangalore
University, Bangalore 560 001, India
Fax +91(80)22292848; E-mail: hariccb@gmail.com; E-mail: hariccb@hotmail.com; E-mail: sureshbabuvommina@rediffmail.com
Received: 05.12.2013; Accepted after revision: 04.02.2014
method has disadvantages such as preparation and storage
Abstract: Rapid synthesis of acid azides via in situ generation of
of acid chloride itself. The HCl generated with the usage
acid chlorides using CPICl as chlorinating agent from the corre-
sponding Nα-protected amino acids is described. Also the conver-
sion of acid azides into ureidopeptides through the Curtius
of chlorinating reagents render them incompatible with
acid-sensitive substrates (Boc/Z). Moreover, acid chlo-
rearrangement under ultrasonication is delineated. The mildness of rides are sensitive to moisture, which require care in han-
the protocol renders the acid-sensitive substrates to afford the cor-
responding amino acid azides and ureidopeptides in good yields.
Diphenylcyclopropenone has also been recovered from the reaction
quires the usage of phase-transfer catalyst to improve the
mixture and reused.
Keywords: Nα-protected amino acids, CPICl, acid chlorides, acid
dling with sodium azide in aqueous conditions. Also the
poor solubility of NaN3 in organic reaction medium re-
yield of acid azides.11 Mixed anhydride method involves
the use of alkyl chloroformates which are inconvenient to
handle. For the synthesis of acid azides, acyl hydrazides
azides, Curtius rearrangement, ureidopeptides
need to react with nitrosyl ions or their precursors. Acyl
benzotriazoles preparation proceeded with longer reaction
In recent years acid azides have gained more importance
duration. Aldehydes have also been directly converted
in peptide chemistry, combinatorial chemistry, and het-
into acid azides using chromic anhydride and trimethylsi-
lylazide,12a (diacetoxyiodo)benzene (DIB),12b triazido-
chlorosilane-activated MnO2,12c IN3,12d tert-butyl
hypochlorite,12e Dess–Martin periodinane,12f 1,3-dimeth-
yltriazolium iodide–diazabicycloundecane (DBU).12g
erocyclic synthesis. The Curtius rearrangement of acid
azides lead to isocyanates, from which amines, urethanes,
thiourethanes, ketenimines, carbodiimides, carbamates,
and ureas can be easily obtained.1 Accordingly, there has
been a significant amount of effort directed at developing
efficient methods for the synthesis of acid azides either di-
rect or indirectly from carboxylic acids.
Since acid chlorides are attractive to accomplish activa-
tion of a carboxylic group towards acylation, it is desir-
able to develop a newer protocol devoid of sulfur- or
phosphorus-based catalysts, aqueous and harsh conditions
including elevated temperature. In continuation of our
works, herein we report a mild and highly efficient proce-
dure using CPICl/TMSN3 for the synthesis of Nα-protect-
ed amino acid azides from the corresponding carboxylic
acids and their conversion into ureidopeptides. Signifi-
cantly, the protocol is compatible with acid-labile protect-
ing groups.
Direct conversion of carboxylic acids into acid azides is
achieved using acid activators such as phenyl dichloro-
phosphate,2a SOCl2-DMF,2b ethyl chloroformate,2c NCS-
Ph3P,2d diphenylphosphoryl azide (DPPA),2e cyanuric
chloride,2f triphosgene,2g POCl3-DMF,2h bis(2-methoxy-
ethyl)aminosulfur
trifluoride
benzotriazole-1-yl-oxy-tris(dimethyl-
(Deoxo-Fluor),2i
Cl3CCN/Ph3P,2j
amino)phosphonium hexafluorophosphate (BOP),2k 2-az-
ido-1,3-dimethyl-imidazolinium chloride (ADMC),2l
Ph2PCl/I2,2m 3,4,5-trifluorobenzeneboronic acid,3 di-tert-
butyl dicarbonate,4 trichloroisocyanuric acid/Ph3P5 in the
presence of NaN3/TMSN3. These protocols often suffer
from several limitations, which include harsh reaction
conditions, substrate limitations, elevated temperatures,
prolonged reaction duration, offensive byproduct forma-
tion, etc.
The cyclopropenium cation is the smallest member of the
Hückel aromatic systems, and numerous investigations
have been carried out on this class of cation since the first
synthesis of triphenylcyclopropenylium perchlorate by
Breslow.13 Particularly in organometallic chemistry these
cations have been developed in various applications.14 Re-
cently, Lambert et al. developed the reactions involving
cyclopropenium intermediates, for the rapid conversion of
alcohols and carboxylic acids into the corresponding alkyl
chlorides15a and acid chlorides.15b The similar strategy
was applied for the dehydrative cyclization of diols to cy-
clic ethers and nucleophilic substitution of alcohols by
methane sulfonate ion with inversion of configuration by
the same group.16 The concept of cyclopropenium activa-
tion has been extended to Beckman rearrangement of ke-
toximes to amides/lactams.17 Bennett et al. described
dehydrative glycosylation reactions using deoxy- and di-
Acid azides can also be prepared from acid derivatives
such as acid chlorides,6 mixed anhydrides,7 acyl hydra-
zides,8 and acyl benzotriazoles.9 Synthesis of Fmoc-α-
amino acid azides using acid chlorides and mixed anhy-
drides had been reported by our group.10 The acid chloride
SYNLETT 2014, 25, 1001–1005
Advanced online publication: 14.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340864; Art ID: ST-2013-B1110-L
© Georg Thieme Verlag Stuttgart · New York

1002
N. R. Panguluri et al.
LETTER
Table 1 List of Nα-Fmoc/Cbz-Amino Acid Azides 2
deoxy-sugar donors mediated by dichlorodiphenylcyclo-
propene which is tolerant of acid- and base-sensitive
substrates.18
Compound Acid azide 2
Yield (%)a mp (°C)
Attracted by the unique reactivity profile of the cyclopro-
penium ion, we envisioned that cyclopropenium activa-
tion might be the rapid and mild process for the
conversion of carboxylic acids into acid azides via the in-
termediacy of acid chlorides. In a typical reaction, to the
in situ generated 3,3-dichloro-1,2-diphenylcyclopropene
(generated by the treatment of 2,3-diphenylcycloprope-
none with oxalyl chloride in CH2Cl2),19 a solution of
Fmoc-Ile-OH (1a) and diisopropylethylamine (DIPEA) in
dry CH2Cl2 was added at –15 °C. After five minutes,
TMSN3 was added to the reaction mixture. As monitored
by TLC, the desired acid azide was obtained within 5–10
minutes and was confirmed by IR analysis showing strong
absorbance at 2141 cm–1. A simple workup led to Fmoc-
Ile-CON3 (2a) and diphenylcyclopropenone. Other sol-
vents such as MeCN, THF, 1,4-dioxane, and EtOAc were
tried and found to be inefficient in affording the desired
product in good yields. Dichloromethane in the presence
of DIPEA was found to be the best reaction medium for
the easier isolation of acid azides at lower temperatures.
The crude residue was purified by flash chromatography
(20% EtOAc in hexane) to obtain pure Fmoc-Ile-CON3
(2a).20,27 Diphenylcyclopropenone was recovered quanti-
tatively (Scheme 1).
2a
94
152
FmocHN
CON3
2b
96
93
175
178
FmocHN
CON3
CON3
t-BuO
2c
FmocHN
t-BuO
2d
92
173
FmocHN
CON3
CO2t-Bu
2e
2f
90
93
168
135
FmocHN
CON3
BnO2C
FmocHN
CbzHN
CON3
CON3
Since acid azides are valuable synthetic intermediates in
peptide chemistry, we further explored them for the syn-
thesis of ureidopeptides through the Curtius rearrange-
ment. Fmoc-Ile-CON3 (2a) was subjected to
ultrasonication using our reported procedure.21 Subse-
quently, the formed isocyanate was treated with methyl
glycinate, and the ultrasonication was continued till com-
pletion of the reaction. After a simple workup, the solvent
was removed in vacuo. The crude product was recrystal-
lized (DMSO–H2O, 8:2) to obtain the ureidopeptide 3a
(Scheme 1). To explore the scope and generality of the
method, various Nα-Fmoc/Cbz-amino acids were tested
for the nucleophilic substitution with TMSN3 via in situ
generation of acid chlorides, and their application for the
synthesis of ureidopeptides through the Curtius rearrange-
ment. The results are summarized in Table 1 and Table 2.
2g
2h
91
93
67
123
CbzHN
CbzHN
CON3
CON3
2i
2j
92
94
130
134
CbzHN
CON3
a Yields correspond to the isolated pure acid azides.
et al. reported the one-pot conversion of N-Boc-protected β-
amino acids to acyl azides and then to carbamates.22
Sureshbabu and his coworkers prepared ureas and carba-
mates from the corresponding carboxylic acids using EDC
One-pot processes that allow the direct conversion of car-
boxylic acids into ureas have become attractive. Guichard
O
Cl
Cl
Ph
Ph
R1
O
R2
R1
R1
Ph
i-Pr2NEt
Ph
OH
N3
PGHN
N
N
CO2Me
PGHN
PGHN
R2
H
H
CH2Cl2, –15 °C
TMS-N3
O
O
,
2
1
H2N
CO2Me
3
PG = Fmoc/Cbz
R1, R2 = amino acid side chain
Scheme 1 Synthesis of Nα-Fmoc/Cbz-amino acid azides 2 and their conversion into the corresponding ureidopeptides 3
Synlett 2014, 25, 1001–1005 © Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Nα-Protected Amino Acid Azides
1003
Table 2 List of Nα-Fmoc/Cbz-Ureidopeptides 3
corresponding α-amino acids in reasonably good yields.
The present protocol is an advantageous and alternative to
the reported one-pot synthesis of ureidopeptides since
phosphorous residues resulted from DPPA25a renders the
product isolation a tedious process, T3P25b is moisture-sen-
sitive and requires careful handling to obtain ureidopep-
tides. Unlike in situ generated acid chloride protocols for
the synthesis of acid azides and then to ureidopeptides, the
present protocol is compatible with Fmoc/Boc/Cbz chemis-
try. The 1H NMR spectroscopy of the diastereomeric α-ure-
Compound PG
R1
R2
Yield (%)
3a
3b
3c
3d
3e
3f
Fmoc
CH(Me)Et
Bn
H
92
89
90
92
91
93
89
91
92
93
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Cbz
Me
H
CH2Ot-Bu
CH2C6H4Ot-Bu
CH2CH2CO2t-Bu
CH2CO2Bn
H
i-Pr
H
idopeptides,
Boc-(L)-Phe-Ψ(NH-CO-NH)-(R)-(+)-1-
i-Pr
i-Pr
H
phenylethylamine (5k), Boc-(L)-Phe-Ψ(NH-CO-NH)-(S)-
(–)-1-phenylethylamine (5l), and Boc-(L)-Phe-Ψ(NH-CO-
NH)-(R,S)-(±)-1-phenylethylamine (5k + 5l) prepared by
the present methodology, was found to be free from race-
mization.26
3g
3h
3i
Cbz
Me
Cbz
i-Pr
Me
Me
Table 3 List of Nα-Boc-Ureidopeptides 5
3j
Cbz
CH2CHMe2
Compound
R1
R2
Yield (%)
and HBTU.23 Due to the instability of Nα-Boc-amino acid
azides, we further investigated the optimized reaction con-
ditions for the one-pot synthesis of α-ureidopeptides start-
ing from Boc-amino acids. The process involves the
formation of acid azides via the intermediacy of acid chlo-
ride and their in situ Curtius rearrangement to an isocyanate
followed by coupling with amino acid methyl ester under
ultrasonication. The Boc-Phe-OH (4d) was treated with
CPICl/TMSN3 and DIPEA at –15 °C in CH2Cl2. After
completion of reaction as monitored by IR (νmax = 2140 cm–
1), the reaction mixture was subjected to ultrasonication for
about 20 minutes. Subsequently, L-methyl alaninate was
added, and the ultrasonication was continued till comple-
tion of the reaction. The solvent was evaporated, and the
residue was washed with citric acid and NaHCO3 solutions
and triturated with diethyl ether and then filtered. The solid
thus obtained was recrystallized (DMSO–H2O) to obtain
pure ureidopeptide24 5d in good yield (Scheme 2). The di-
phenylcyclopropenone was also recovered from the ether
layer. As summarized in Table 3, the reaction proceeded
well with various Nα-Boc-amino acids to afford the corre-
sponding α-ureidopeptides in good yields. The Curtius re-
arrangement was monitored through IR by observing the
disappearance of the azide peak at 2140 cm–1 and the ap-
pearance of the characteristic isocyanate peak at 2250 cm–1.
The same protocol holds good even for the one-pot syn-
thesis of Fmoc/Cbz-protected α-ureidopeptides from the
5a
5b
5c
5d
5e
5f
i-Pr
Me
Bn
H
89
88
87
89
90
88
86
87
90
87
Me
i-Pr
Bn
Me
Bn
Bn
Me
i-Pr
Me
H
i-Pr
CH2CH2SMe
CH(Me)OBn
CH2CH2CO2Bn
Ph
5g
5h
5i
5j
CH2OBn
In conclusion, we have developed a mild and convenient
protocol for the synthesis of Nα-protected amino acid
azides from the corresponding carboxylic acids using
CPICl/TMSN3 and their application for the synthesis of
ureidopeptides through the Curtius rearrangement was
found to be racemization-free. Using this protocol, several
ureidopeptides were synthesized from Boc-, Cbz-, and
Fmoc-amino acids including Asp, Glu, Ser, and Tyr pos-
sessing tert-butyl, benzyl, and Boc groups in the side
chain.
Cl
Cl
Ph
Ph
O
R1
O
R2
R1
i-Pr2NEt, CH2Cl2, –15 °C
+
OH
TMS-N3
BocHN
N
N
CO2Me
BocHN
Ph
Ph
R2
H
H
O
,
5
4
H2N
CO2Me
R1, R2 = amino acid side chain
Scheme 2 Synthesis of Nα-Boc-ureidopeptides 5
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1001–1005

1004
N. R. Panguluri et al.
LETTER
(15) (a) Kelly, B. D.; Lambert, T. H. J. Am. Chem. Soc. 2009,
Acknowledgement
131, 13930. (b) Hardee, D. J.; Kovalchuke, L.; Lambert, T.
H. J. Am. Chem. Soc. 2010, 132, 5002. (c) Vanos, C. M.;
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(b) Nacsa, E. D.; Lambert, T. H. Org. Lett. 2013, 15, 38.
(17) (a) Vanos, C. M.; Lambert, T. H. Chem. Sci. 2010, 1 705.
(b) Srivastava, V. P.; Patel, R.; Garima; Yadav, L. D. S.
Chem. Commun. 2010, 46, 5808. (c) Tian, B. X.; An, N.;
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(18) Nogueira, J. M.; Nguyen, S. H.; Bennett, C. S. Org. Lett.
2011, 13, 2814.
We thank the Department of Science and Technology (DST) (Grant
NO.SR/S1/OC-52/2011) New Delhi, India, for financial assistance.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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(20) General Procedure for the Synthesis of Nα-Fmoc/Cbz-
Amino Acid Azides 2
Oxalyl chloride (1.0 equiv) was added to a solution of
diphenylcyclopropenone (1.1 equiv) in CH2Cl2 at r.t. After
gas evolution had ceased, a solution of Nα-protected amino
acid (1.0 equiv) and DIPEA (2.2 equiv) in CH2Cl2 was added
at –15 °C followed by stirring for 5 min and then TMSN3
(1.5 equiv) was added. After stirring for an additional 5–10
min, the reaction mixture was diluted with CH2Cl2, washed
with citric acid (10%), sat. NaHCO3 (10%), and sat. NaCl
solutions. The organic phase was dried over anhydrous
Na2SO4 and concentrated. The crude residue was purified by
flash chromatography (20% EtOAc in hexane) to obtain pure
acid azide. Diphenylcyclopropenone was recovered in
approximately the same yield.
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(24) General Procedure for the Synthesis of
Nα-Boc/Cbz/Fmoc-Ureidopeptides 5
Oxalyl chloride (1.0 equiv) was added to a solution of
diphenylcyclopropenone (1.1 equiv) in CH2Cl2 at r.t. After
gas evolution had ceased, a solution of Nα-protected amino
acid (1.0 equiv) and DIPEA (2.2 equiv) in CH2Cl2 was added
at –15 °C followed by stirring for 5 min, TMSN3 (1.5 equiv)
was added to the reaction mixture. After stirring for an
additional 5–10 min, toluene was added to the reaction
mixture which was subjected to ultrasonication at 45 °C for
about 20 min followed by addition of amino acid methyl
ester, and the ultrasonication was continued until completion
of the reaction. The solvent was removed in vacuo. The
residue was washed with citric acid (10%) and NaHCO3
(10%) solutions and triturated 2–3 times with Et2O (5 mL)
and filtered. The solid obtained was then recrystallized using
DMSO–H2O (8:2). The diphenylcyclopropenone was also
recovered from ether layer and reused.
(25) (a) Sureshbabu, V. V.; Chennakrishnareddy, G.; Narendra,
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(26) The possibility of the epimerization for the two epimeric
ureidopeptides was analyzed through 1H NMR
spectroscopy, which were prepared from Boc-(L)-Phe-OH
and optically pure (R)-(+)- and (S)-(–)-1-phenylethylamine
using the present method. The 1H NMR spectra of Boc-
Synlett 2014, 25, 1001–1005
© Georg Thieme Verlag Stuttgart · New York

LETTER
(L)-Phe-Ψ(NHCONH)-(R)-(+)-1-phenylethylamine (5k)
Synthesis of Nα-Protected Amino Acid Azides
1005
(27) Selected Spectroscopic Data
andBoc-(L)-Phe-Ψ(NHCONH)-(S)-(–)-1-phenylethylamine
(5l) contained the (R)- and (S)-1-phenylethylamine methyl
group doublet at δ = 1.28, 1.30 and 1.25, 1.27 ppm,
respectively. Whereas Boc-(L)-Phe-Ψ(NHCONH)-(R,S)-
(±)-1-phenylethylamine (5k + 5l) contained two separate
doublets at δ = 1.25, 1.27, 1.28, 1.30 ppm for (R,S)-(±)-1-
phenylethylamine methyl groups (Figure 1). This clearly
indicates that the present protocol is free of epimerization.
Fmoc-Ile-N3 (2a)23
Yield 94%; mp 152 °C. 1H NMR (400 MHz, DMSO-d6): δ =
0.88–0.92 (m, 3 H), 1.02–1.37 (m, 5 H), 1.87–1.99 (m, 1 H),
4.45–4.49 (m, 2 H), 4.54 (d, J = 6.3 Hz, 2 H), 5.14 (s, 1 H),
7.29–7.80 (m, 8 H). 13C NMR (100 MHz, DMSO-d6): δ =
11.62, 15.10, 25.71, 30.03, 47.57, 55.82, 67.09, 120.49,
125.76, 127.67, 128.29, 141.58, 144.27, 156.63, 180.03.
HRMS: m/z calcd for C21H22N4NaO3: 401.1590; found:
401.1596 [M + Na]+.
(Z)-Ala-Ψ[NH-CO-NH]-Gly-OMe (3h)23
Yield 91%; mp 141–143 °C. 1H NMR (400 MHz, DMSO-
d6): δ = 1.40 (d, J = 7.7 Hz, 3 H), 3.57 (s, 3 H), 4.45 (d,
J = 6.5 Hz, 2 H), 5.13 (s, 2 H), 5.01–5.06 (m, 1 H), 5.66 (br,
1 H), 6.50 (br, 2 H), 7.22–7.38 (m, 5 H). 13C NMR (100
MHz, DMSO-d6): δ = 21.56, 41.23, 51.49, 59.78, 64.94,
127.43, 127.61, 128.57, 137.22, 155.07, 156.28, 171.75.
HRMS: m/z calcd for C14H19N3NaO5: 332.1222; found:
332.1225 [M + Na]+.
O
O
BocHN
N
H
N
BocHN
N
N
H
H
H
5l
5k
Boc-Ser(Bn)-Ψ[NH-CO-NH]-Gly-OMe (5j)24
Yield 87%; mp 133 °C. 1H NMR (400 MHz, DMSO-d6): δ =
1.34 (s, 9 H), 3.44–3.48 (m, 2 H), 3.62 (s, 3 H), 3.84 (d,
J = 6.9 Hz, 2 H), 4.49 (s, 2 H), 4.94–4.97 (m, 1 H), 5.78 (br,
O
BocHN
N
N
H
H
1 H), 6.48 (br, 1 H), 6.54 (br, 1 H), 7.26–7.38 (m, 5 H). 13
C
NMR (100 MHz, DMSO-d6): δ = 28.63, 45.51, 53.56, 71.57,
76.61, 77.45, 78.77, 126.61, 127.36, 128.53, 138.14, 156.38,
157.25, 171.35. HRMS: m/z calcd for C18H27N3NaO6:
404.1798; found: 404.1797 [M + Na]+.
5k + 5l
Figure 1
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1001–1005

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