T3P (propylphosphonic anhydride) mediated conversion of carboxylic acids into acid azides and one-pot synthesis of ureidopeptides

Article abstract of DOI:10.1016/j.tetlet.2010.04.002

A general, mild, efficient, and environmentally benign protocol, which makes use of T3P as an acid activating agent for the direct synthesis of acid azides from carboxylic acids is described. Further, the protocol is employed for the one-pot synthesis of α-ureidopeptides starting from N-protected α-amino acids.

Full text of DOI:10.1016/j.tetlet.2010.04.002

Tetrahedron Letters 51 (2010) 3002–3005
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T3PÒ (propylphosphonic anhydride) mediated conversion of carboxylic
acids into acid azides and one-pot synthesis of ureidopeptides
*
Basavaprabhu, N. Narendra, Ravi S. Lamani, Vommina V. Sureshbabu
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi, Bangalore University, Bangalore 560 001, India
a r t i c l e i n f o
a b s t r a c t
A general, mild, efficient, and environmentally benign protocol, which makes use of T3PÒ as an acid acti-
vating agent for the direct synthesis of acid azides from carboxylic acids is described. Further, the proto-
Article history:
Received 4 March 2010
Revised 27 March 2010
Accepted 1 April 2010
Available online 8 April 2010
col is employed for the one-pot synthesis of
a
-ureidopeptides starting from N-protected
a-amino acids.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Propylphosphonic anhydride
Acid azides
Curtius rearrangement
Ureidopeptides
Acid azides are synthetically extremely valuable compounds.
They form the starting materials for a vast range of reactions in or-
ganic synthesis as well as in peptides and peptidomimetic synthe-
sis. Acid azides are extensively used for the preparation of amides,
nitriles, and a variety of heterocycles through cycloaddition reac-
tions.1 Curtius rearrangement of acid azides into isocyanates is of
profound importance in organic synthesis as this can be used for
the preparation of amines, ureas, carbamates, amides, and many
other class of compounds.2 In peptide chemistry, acid azides occu-
py an important place wherein they form the building blocks for
peptide as well as peptidomimetic synthesis. They have been em-
ployed as coupling agents for the racemization-free formation of
peptide bond. These are also employed for the synthesis of peptide
zide methods are not compatible with substrates having acid and
base sensitive groups, respectively. Further, the acid chloride
method is constrained with respect to storage and stability aspects
due to the moisture sensitivity of certain acid chlorides. Also, the
poor solubility of NaN3 in organic medium requires phase transfer
catalysts, ZnI2/Zn triflate7 to obtain acceptable yields. Acid hydra-
zides have to be synthesized through a multistep process starting
from acids. In case of acyl benzotriazoles, the reaction duration is
prolonged. For the direct synthesis of acid azides from acids,
several types of activating agents have been employed, but many
of them possess certain intrinsic limitations. Some of these
reagents are toxic (triphosgene),8 irritating (SOCl2/DMF),9 expen-
sive [diphenylphosphoryl azide (DPPA), deoxoflour],10 while a
few other reagents produce undesirable by-products which are
difficult to separate and toxic which in turn requires additional
handling costs and safety measures (i.e., cyanuric chloride,
tetramethylflouroformamidinium hexaflourophosphate, and phe-
nyl dichlorophosphate).11 Reagents like NCS–Ph3P and the recently
reported Cl3CCN–Ph3P12 have been employed, but the presence of
triphenyl phosphine unit in them disfavors the use of acid sensitive
reactants. The extensively employed mixed anhydride method13
mimics such as partially modified retro-inverso peptides, a/b-ure-
idopeptides, and amino acid derivatives like formamides and alkyl-
gem-diamines.3 The reactions of acid azides have been used to
advantage for the construction of a number of biologically valuable
compounds. In this regard, development of a new and improved
protocol for acid azide synthesis is significant.
Acid azides are synthesized mainly through two routes (i) a
two-step protocol in which carboxylic acids are converted into sta-
ble reactive intermediates such as acid chlorides,4 acid hydra-
zides,5 and acyl benzotriazoles6 followed by their treatment with
azide ion. (ii) One-pot protocols with in situ activation of carbox-
ylic acids in the presence of azide ion. The former approach lacks
universal applications, for instance acid chloride and acid hydra-
suffers from the problem of isomerization in case of
a,b-unsatu-
rated acids. Also, the mixed anhydride intermediates should be
generated by using chloroformates, which are corrosive and irri-
tants and harmful if inhaled, so pose handling problems.
a
Our group has described the first synthesis of stable N -Fmoc-
amino acid azides and demonstrated their application as peptide-
coupling agents. These acid azides were prepared via acid chloride
and mixed anhydride methods. Recently we also reported the
synthesis of acid azides using peptide-coupling agents EDC and
* Corresponding author. Tel.: +91 08 2296 1339/9986312937.
E-mail addresses: sureshbabuvommina@rediffmail.com, hariccb@hotmail.com
(V.V. Sureshbabu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.002

Basavaprabhu et al. / Tetrahedron Letters 51 (2010) 3002–3005
3003
Table 1
List of acid azides prepared via Schemes 1 and 2
Compd No.
Acid azide
Yielda (%)
Mp (°C) obsd (lit.)
O
O
P
O P
O
P
O
O
26–28 (27)14
(T3P)
1a
1b
92
82
N3
N3
O
NaN3, Et3N
0 º C, THF
R COOH
R CON3
1a-h
O
S
34–37 (35)14
81–84 (83)14
Scheme 1. Synthesis of acid azides 1a–h.
O
O
1c
81
72
N3
N3
HBTU.14 Due to the immense utility and wide applicability of acid
azides, we sought to develop a simple, alternative, and efficient
protocol for the synthesis of these useful class of compounds.
T3PÒ (propylphosphonic anhydride) is a highly reactive cyclic
anhydride, which has been employed for the conversion of carbox-
ylic acids, aldehydes, and amides to nitriles and formamides to iso-
nitriles. It has also been used in the preparation of heterocycles,
Weinreb amides, b-lactams, hydroxamic acids, thiohydroxamic
acid anhydrides, and in acylation reactions.15 It has been used as
a peptide-coupling agent, in the segment coupling and head to tail
cyclization of sterically hindered peptides.16 T3PÒ offers several
advantages over other reagents in terms of higher yields, shorter
reaction duration, ease of isolation of the products, minimal side
reactions including epimerization during peptide couplings, inex-
pensive, and non-toxic nature. Based on these qualities, we sought
to develop a simple and efficient method for the direct synthesis of
acid azides from carboxylic acids employing T3PÒ.
O2N
1d
104–106 (104–105)9
NO2
O
1e
1f
84
85
33–35 (35)12
N3
N3
O
Gum14
N
H
O
A typical reaction was carried using benzoic acid as acid compo-
nent. A solution of benzoic acid and T3PÒ in dry CH2Cl2 at 0 °C was
treated with NaN3 in DMSO in the presence of Et3N. Carboxyl group
underwent activation by the T3PÒ and readily reacted with the
azide ion to give corresponding benzoyl azide in 20 min in 92%
yield. The formation of acid azide was confirmed by the presence
of a strong IR peak around mmax 2140–2144 cmÀ1 and finally
through mass and NMR analyses. To explore the scope of this pro-
tocol, a series of aromatic acids substituted with electron-donating
as well as electron-withdrawing groups and long chain aliphatic
acids (hexanoic acid) were converted into corresponding acid
azides, 1a–h in good yield (Scheme 1).17 Table 1 summarizes the
results. In all these preparations, no column purification was
needed, as the protocol did not result in the formation of contam-
inants and hence the acid azides could be isolated in pure form
through simple work-up.
1g
86
Gum14
N3
N
O
1h
2a
76
94
Oil8
N3
N3
162 (162)1c
FmocHN
ZHN
O
162–164 (162)1c
177–178 (178)1c
N3
2b
2c
84
86
FmocHN
O
OtBu
N3
a
The protocol was extended to prepare N -Fmoc and Z-protected
a
FmocHN
S
amino acid azides from the corresponding N -protected amino
acids.17 Several Fmoc-amino acid azides 2a–f including the side
chain protected amino acids (2b and 2c) were prepared and iso-
lated as solids (Scheme 2). In all the cases, the reaction proceeded
smoothly and rapidly with quantitative yield (Table 1). Z-Phe-N3
O
2d
84
173–175 (172)1c
166–168 (168)1c
a
2g as well as the acid azide of N -Z-Asp-oxazolidin-5-one 2h was
N3
a
FmocHN
prepared similarly. Interestingly, when the unprotected N -Fmoc-
O
serine was subjected to the above-mentioned reaction conditions,
the corresponding acid azide 2f was obtained in good yield without
affecting the free hydroxyl group, despite the oxidation of alcohol
to aldehyde by T3PÒ is known.15c The acid azide formation requires
about 20 min for completion while oxidation requires the treat-
ment of alcohol with T3PÒ for overnight. Consequently, the synthe-
sis of Fmoc-Ser-N3 was possible.
2e
2f
89
70
N3
N3
FmocHN
HO
O
O
Finally, the utility of T3PÒ was applied for a three-step, one-pot
Gum
FmocHN
a
synthesis of ureidopeptides from N -urethane protected amino
acids. The one-pot protocols are of paramount importance for rapid
synthesis of biologically active compounds and a large number of
(continued on next page)

3004
Basavaprabhu et al. / Tetrahedron Letters 51 (2010) 3002–3005
The possibility of racemization during the synthesis of acid
azides and -ureidopeptides via the present protocol was as-
sessed following the reported method, and it was found that
the protocol was racemization-free and yielded optically pure
products.19,20
Table 1 (continued)
a
Compd No.
Acid azide
Yielda (%)
Mp (°C) obsd (lit.)
2g
91
148 (146)14
In conclusion, we have described an alternative protocol for di-
N3
rect conversion of acids to acid azides by employing T3PÒ. A series
ZHN
a
of carboxylic acids including N -Fmoc/Z/Boc amino acids have
O
O
been converted to their acid azides. The utility of the reagent has
been extended for the one-pot synthesis of ureidopeptides. This
protocol is mild, high yielding, economical and eco-friendly. The
synthesis of acid azides as well as a-ureidopeptides via the present
protocol was proved racemization free.
N3
O
2h
76
Gum14
ZHN
O
a
Yields correspond to the isolated pure acid azides.
Acknowledgments
We thank the Council of Scientific and Industrial Research
(CSIR), New Delhi (Grant No. 01(2323)/09/EMR-II) for the financial
assistance. One of the authors R.S.L. thanks University Grants Com-
mission, New Delhi, for the award of Dr. D. S. Kothari Postdoctoral
Fellowship.
R
R
T3P/ NaN3, Et3N
OH
N3
PgHN
0ºC, THF
PgHN
2a-g
O
O
Pg = Fmoc, Cbz
References and notes
a
Scheme 2. Synthesis of N -protected amino acid azides 2a–g.
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R1
O
R2
R1
T3P/ NaN , Et N
(i)
3
3
o
0 C, THF
R2
H2N COOMe
OH
PgHN
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H
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O
3a-f
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W. A. Synthesis 1985, 220–222; (c) Luedtke, A. E.; Timberlake, J. W. J. Org. Chem.
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Comp. Pg
No.
R1
R2
Yield
(%)
92
3a
3b
3c
3d
Fmoc
CH3
CH(CH3)2
(CH2)3
Fmoc
H
88
Z
Z
(CH2)3
CH2C6H5
CH2S(Bzl)
82
CH(CH3)CH2
CH3
87
3e
3f
Boc
Boc
CH2CH(CH3)2 CH(CH3)2
80
85
C6H5
CH2C6H5
a
Scheme 3. Synthesis of N -urethane protected ureidopeptides 3a–f.
their analogues. In case of the synthesis of N-protected-a-ureido-
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peptides using Boc and Z-amino acids as reactants, the one-pot
protocols tend to furnish higher yields as the isolation of corre-
sponding unstable acid azides can be circumvented.
a
The N -protected amino acid was converted to corresponding
acid azide in the presence of T3PÒ/NaN3 in dry THF followed by
in situ Curtius rearrangement in toluene under ultrasonic condi-
tions into isocyanates. The transformation of acid azide into isocy-
anate in toluene under ultrasonic conditions was previously
reported by our group.2f The formation of isocyanate was con-
firmed through the appearance of IR peak at around mmax 2252–
2256 cmÀ1. Further, to the solution of isocyanate, amino acid
methyl ester in dry CH2Cl2 was added and sonication was contin-
ued for an hour to obtain the corresponding ureidopeptide in good
a
yield. A series of ureidopeptides 3a–f were synthesized from N -
Fmoc/Z/Boc amino acids.18 In case of Boc-protected amino acids,
an additional equivalent of base was used to avoid decrease in
the yield, possibly due to the acidic by-product liberated.
15. (a) Llanes, A. L. Synlett 2007, 1328–1329. and references cited therein; (b)
Augustine, J. K.; Atta, R. N.; Ramappa, B. K.; Boodappa, C. Synlett 2009, 3378–

Basavaprabhu et al. / Tetrahedron Letters 51 (2010) 3002–3005
3005
3382; (c) Meudt, A.; Scherer, S.; Böhm, C. PCT Int. Appl. WO 2005102978, 2005;
Chem. Abstr. 2005, 143, 440908
1H NMR spectrum of the crude sample of 3g and 3h contained distinct methyl
group doublet at 1.41, 1.43; and 1.38, 1.40, respectively. The epimeric
d
16. (a) Wissmann, H.; Kleiner, H.-J. Angew. Chem., Int. Ed. Engl. 1980, 19, 133–134;
(b) Escher, R.; Bunning, P. Angew. Chem., Int. Ed. Engl. 1986, 25, 277–278; (c)
Glauder, J. Specialit. Chem. Mag. 2004, 24, 30. and references cited therein; (d)
Wehner, M.; Kirschbaun, B.; Deutcher, L.; Wagner, H. J.; Hoessl, H. PCT Int.Appl.
WO 2005014604, 2005; Chem. Abstr. 2005, 142, 198208; (e) Klose, J.; Bienert,
M.; Mollenkopf, C.; Wehle, D.; Zhang, C. W.; Carpino, L. A.; Henklein, P. Chem.
Commun. 1999, 1847–1848.
mixture showed –CH3 group signals at 1.38, 1.40, 1.42, 1.43 corresponding to
two doublets. These studies showed that the sample of ureidopeptides
analyzed contained
a single optically pure epimer. Consequently, it was
concluded that the synthesis of acid azides as well as the one-pot preparation
of ureidopeptides was free from racemization. The absence of racemization
was also confirmed by conducting NMR analysis of dipeptidyl ureas Fmoc-Phe-
w
[NHCONH]-L-Ala-OMe (3i) and Fmoc-Phe-w[NHCONH]-D-Ala-OMe (3j). The
17. General procedure for the synthesis of acid azides: (1, 2). To a solution of acid
(1.0 mmol) and T3PÒ (0.36 mL, 1.2 mmol) in dry THF (8.0 mL) was added Et3N
(0.20 mL, 1.5 mmol) at 0 °C followed by NaN3 (98 mg, 1.5 mmol) in DMSO (2–3
drops) and the reaction mixture was stirred for 15–20 min. Then the reaction
mixture was concentrated and diluted with CH2Cl2 (20 mL). The organic layer
was washed with 5% Na2CO3 (2 Â 10 mL), water (2 Â 10 mL), brine (10 mL) and
dried over anhydrous Na2SO4. Solvent was evaporated in vacuo to obtain acid
azide quantitatively.
18. Typical procedure for the synthesis of ureidopeptide 3d: To a solution of Z-Phe-OH
(0.30 g, 1.0 mmol) and T3PÒ (0.40 mL, 1.2 mmol) in dry THF (8.0 mL), Et3N
(0.25 mL, 1.5 mmol) was added at 0 °C followed by NaN3 (100.0 mg, 1.5 mmol)
in DMSO (2–3 drops) and the reaction mixture was stirred for 20 min. Toluene
was added to the reaction mixture which was subjected to ultrasonication at
45 °C for about 20 min followed by the addition of H-Ile-OMe (175.0 mg,
1.2 mmol). The reaction mixture was then sonicated for an hour. The solvent
was then evaporated and diluted with cold water. The solid was separated out
and washed with 20% Na2CO3 (10 mL) followed by 10% HCl (10 mL) and water
(20 mL). Finally, the crude product was recrystallized from DMSO:H2O.
19. Fmoc-Phe-N3 prepared via the present protocol was converted into two
sample of 3i showed distinct –CH3 group doublet at d 1.29 and 1.32 and 3j at
1.24 and 1.28. The equimolar mixture of 3i and 3j showed two doublets at d
1.24, 1.28, 1.32, 1.34, which confirmed that the samples analyzed contained a
single optically pure compound.
20. Characterization data for representative compounds:
Thiophene-2-carboxylic acid azide (1b): white solid; Rf 0.54 (hexane/EtOAc,
9:1), IR (KBr) m ;
max = 2148 cmÀ1 1H NMR (CDCl3, 400 MHz): d 7.08–7.20 (m,
1H), 7.62–7.70 (m, 1H), 7.78–7.90 (m, 1H) ppm; 13C NMR (CDCl3, 100 MHz): d
128.2, 134.1, 134.6, 135.0, 168.4 ppm; HRMS calcd for C5H3N3OS m/z: 175.9870
[M+Na], found 175.9873.
Fmoc-Val-N3 (2e): white solid; Rf 0.62 (hexane/EtOAc, 8:2), IR (KBr)
m
max = 2142 cmÀ1 1H NMR (CDCl3, 400 MHz): d 0.92–0.93 (br, 6H), 2.11 (m,
;
1H), 4.15–4.34 (m, 2H), 4.35 (d, J = 7.2 Hz, 1H), 4.41 (d, J = 6.4 Hz, 1H), 5.15 (m,
1H), 7.20–7.73 (m, 8H) ppm; 13C NMR (CDCl3, 100 MHz): d 17.75, 31.35, 47.59,
60.85, 67.43, 124.88, 126.24, 127.62, 130.11, 140.23, 145.02, 158.32,
183.21 ppm; HRMS calcd for C20H20N4O3 m/z: 387.1433 [M+Na], found
387.1437.
Boc-Leu-
w
[NHCONH]-Val-OMe (3e): white solid; Rf 0.4 (CHCl3/MeOH, 9:1); IR
(KBr)
m
max = 1649 cmÀ1
;
1H NMR (DMSO, 400 MHz): d 0.86 (br, 12H), 1.37 (s,
epimeric ureidopepitdes Fmoc-Phe-
and Fmoc-Phe- [NHCONH]-(S)-1-phenylethylamine (3h) as outlined in
Scheme by coupling separately with (R)- and (S)-1-phenylethylamine,
respectively. Further, an equimolar mixture of these two epimers was
obtained by coupling with the racemic mixture of 1-phenylethylamine. The
w
[NHCONH]-(R)-1-phenylethylamine (3g)
9H), 1.55 (br, 2H) 2.06 (br, 2H), 3.64 (s, 3H), 4.20 (m, 1H), 4.32 (m, 1H), 5.05 (br,
1H), 6.40-6.58 (m, 2H) ppm; 13C NMR (DMSO, 100 MHz): d 17.12, 17.88, 18.56,
27.15, 31.08, 48.11, 52.96, 55.14, 63.18, 76.31, 155.82, 156.33, 172.68 ppm;
HRMS calcd for C17H33N3O5 m/z: 382.2318 (M+Na), found 382.2316.
w
3