New and simple synthesis of acid azides, ureas and carbamates from carboxylic acids: Application of peptide coupling agents EDC and HBTU

Article abstract of DOI:10.1039/b920290k

Conversion of carboxylic acids into acid azides using peptide coupling agents, EDC and HBTU is described. The procedure is efficient, practical and applicable to a diverse range of carboxylic acids including N-protected amino acids. Using the same reagents, one-pot synthesis of ureas, dipeptidyl urea esters and carbamates from acids has also been achieved. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b920290k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
New and simple synthesis of acid azides, ureas and carbamates from
carboxylic acids: application of peptide coupling agents EDC and HBTU†
Vommina V. Sureshbabu,* H. S. Lalithamba, N. Narendra and H. P. Hemantha
Received 29th September 2009, Accepted 6th November 2009
First published as an Advance Article on the web 8th December 2009
DOI: 10.1039/b920290k
Conversion of carboxylic acids into acid azides using peptide coupling agents, EDC and HBTU is
described. The procedure is efficient, practical and applicable to a diverse range of carboxylic acids
including N-protected amino acids. Using the same reagents, one-pot synthesis of ureas, dipeptidyl urea
esters and carbamates from acids has also been achieved.
Acyl azides, in general, and N-protected a-amino acid azides
in particular, have occupied a place of their own importance in
organic1 and peptide as well as peptidomimetic2 syntheses. They
are extensively used in the preparation of amides and peptides,
and a wide range of other compounds such as nitriles, and
several classes of heterocycles.1,3 The Curtius rearrangement of
acyl azides into isocyanates is of paramount value in synthetic
chemistry. It is widely used in the preparation of amines, ureas
and carbamates. A number of natural products and pharma-
cologically important compounds containing uriedo linkages,4
ureidopeptidomimetics,5 partially modified retro-inverso (PMRI)
peptides, formamides and unnatural amino acids have been
prepared via this rearrangement.2,6 Due to such vast utility of
acid azides, the development of efficient routes for their synthesis
is important.
reactive intermediates.15Acid azides, such as Boc/Z-amino acid
azides, have also been prepared through a multi-step route
starting from acids by hydrazinolysis of the methyl/ethyl esters
followed by reaction of the resultant hydrazide with nitrosyl
donors like HNO2.6a,b,16 A few other reported protocols involve
treatment of acids with diphenylphosphoryl azide (DPPA) or
17
Deoxo-Fluor/NaN3 and that of aldehydes with Dess–Martin
reagent/NaN3.18 But most of these methods either involve lengthy
procedures or expensive reagents (e.g., DPPA) or are less com-
monly used.
Peptide coupling agents, starting from carbodiimides19 to
uronium reagents such as 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-
tetramethyluroniumhexafluorophosphate (HATU)19a,20 are versa-
tile reagents for activation of the carboxylic group. They have
enabled the execution of an acid–amine coupling in a single step
without the requirement for pre-activation of the acids. Their
main advantages include a practically convenient procedure, rapid
in situ activation, minimal side reactions, commercial availabil-
ity, stability, solubility in a wide range of solvents including
water and easy removal of the byproducts of coupling.21 Their
high practical utility is also marked by the availability of a
plethora of reagents for applications in a diverse range of
conditions which has resulted in their successful application in
organic synthesis including natural products synthesis.22 In the
case of carbodiimide mediated couplings, the use of additives
1-hydroxybenzotriazole (HOBt),23 1-hydroxy-7-azabenzotriazole
(HOAt),20 N-hydroxysuccinimide,24 and 3-hydroxy-3,4-dihydro-4-
oxo-1,2,3-benzotriazine25 significantly improves the yield and also
suppresses epimerization when a-amido acids are activated.
In view of these advantages, we envisaged employing peptide
coupling agents for the first time for the general synthesis of acyl
azides. This paper describes the direct conversion of a diverse
range of carboxylic acids including Fmoc/Z-a-amino acid into
acyl azides using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
The two well known routes for the preparation of acid azides
are the reaction of NaN3 with an acid chloride7 or mixed
anhydride.8 The acid chloride method offers disadvantages at
the preparation of acid chloride itself. These include prolonged
reaction duration, incompatibility with acid cleavable groups,
and storage and stability problems associated with moisture
sensitive acid chlorides. Also the poor solubility of NaN3 in
organic reaction medium requires the usage of a phase transfer
catalyst,9 or catalysts such as ZnI2 to improve the yield of
10
acid azides. Alternately, protocols for the in situ generation
of acid chlorides using SOCl2/DMF–NaN3,11 cyanuric chlo-
ride/N-methylmorpholine,12 triphosgene/triethylamine,13 N,N-
chloromethylenedimethylammonium chloride,14 followed by cou-
pling with an azide have also been reported. But these methods
are not suitable for acids such as N-Boc/Z-a-amino acids
whose acid chlorides are unstable. Preparation of acid azides
via mixed anhydrides has been used to advantage. Yet, this
method uses chloroformates which are inconvenient for handling.
Katritzky et al., recently prepared acid azides from acids in a
two step route involving N-acyl benzotriazoles as stable and
(EDC)
and
2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyl-
uroniumhexafluorophosphate (HBTU). In addition, application
of these reagents in the one pot synthesis of ureas, ureidopeptides
and carbamates is also presented.
Our initial objective was to convert acids into acid azides using
carbodiimides. For this purpose, to a solution of pyridine 3-
carboxylic acid 1a in dry CH2Cl2 at 0 ◦C was added EDC and
then NaN3 in DMSO (or in CH3CN with a drop of water). The
O-acylisourea generated readily reacted with NaN3 leading to the
Peptide Research Laboratory, Department of Studies in Chemistry, Central
College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi,
Bangalore – 560 001, India. E-mail: sureshbabuvommina@rediffmail.com,
hariccb@hotmail.com
† Electronic supplementary information (ESI) available: Spectral char-
acterization data for all the compounds and copies of mass and NMR
spectra; references for the known ureas and carbamates. See DOI:
10.1039/b920290k
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Scheme 1 Synthesis of acid azides 2.
Table 1 Reagents and conditions for the preparation of 2a
Table 3 List of N-Fmoc/Z-amino acid azides prepared via Scheme 2
Entry Reagent
Base/additive
—
HOBt (1.1 eq) CH2Cl2 20
HOAt (1.1 eq) CH2Cl2 15
—
—
DIPEA
DIPEA
DIPEA
Solvent Time/min Yield (%)
HRMS: Found/
Compd.2c R1
Yield (%) M.p./◦C Calcd. (M + Na)+
1
2
3
4
5
6
7
8
EDC
EDC
EDC
DCC
CH2Cl2 20
80
83
85
79
76
73
84
77
4a
4b
4c
4d
4e
4f
CH3
CH(CH3)2
82
81
85
163
169
122
152
175
74
359.1126/359.1120
387.1423/387.1433
401.1573/401.1590
401.1596/401.1590
451.1615/451.1172b
385.1133/385.1277
347.1098/347.1120
327.1/327.0 [ESMS
calcd. for (M + Na)+]
THF
THF
THF
THF
THF
25
25
30
05
25
CH2CH(CH3)2
DCI
CH(CH3)CH2CH3 78 (70a)
PyBOP
HATU
(Boc)2O
CH2C6H5
-(CH2)3-[proline] 81
CH2C6H5
82 (80c)
4g
4h
85
80
146
gum
formation of the corresponding acid azide 2a (Scheme 1). The
reaction was completed in 20 min (TLC). A simple work-up led to
the isolation of 2a in 83% yield, which was initially characterized
by the IR (strong peak at 2135 cm-1 corresponding to the azido
group) and then confirmed through mass and NMR analysis.
Encouraged by the result, the usefulness of other popular
coupling agents for the preparation of acid azides from acids
was studied. Boc-anhydride,26 a reagent originally introduced
for the preparation of tert-butyl carbamates from amines, has
also been used as carboxylic activator in reactions such as the
macrolactonization of w-hydroxy acids27 and in peptide coupling
for the preparation of dipeptides.28 Further, the Boc2O/NaN3
system has been used for the in situ generation of acid azides that
have been converted into carbamates without isolation.29 In the
present study, treatment of 1a with Boc2O and NaN3 resulted in
the acid azide 2a which was isolated in 77% yield. The other widely
used coupling agent HATU was also studied. A comparative study
of the preparation of 2a employing different coupling agents is
summarized in Table 1. Carbodiimides resulted in higher yields of
2a and EDC was especially useful due to the easy removal of the
water soluble urea byproduct. Although HATU could provide
an increased yield, its extensive application was limited by its
significantly higher cost than EDC. Hence EDC was further used
to prepare a series of diversely functionalized acyl azides 2a–i
(Table 2) in 78–84% yield.
a Reaction carried out using HATU. b Mass calculated for (M + K)+.
c Reaction carried out using EDC-HOBt system.
We then focused on preparing N-protected a-amino acid
azides which are the common precursors for peptide as well as
peptidomimetic synthesis. Our group has reported the synthesis
of Fmoc-a-amino acid azides using acid chlorides and mixed
anhydrides.2c These azides were isolated as shelf stable compounds
and were used as peptide coupling agents. In the present study,
for the conversion of a-amino acids into acid azides, HBTU was
used, although better results were obtained with EDC in our
above study. Usage of EDC alone causes an appreciable degree
of racemization during activation, which has to be minimized by
using additives like HOBt. This generates the same -OBt active
ester as the acylating agent as that of HBTU. Hence HBTU was
directly used for the preparation of amino acid azides rather than
EDC-HOBt. HBTU is also familiar to peptide chemists, involves a
simple operational procedure and is less expensive than HATU. In
a typical reaction, Fmoc-Phe-OH in THF at 0 ◦C was treated with
an equivalent each of HBTU and diisopropylethylamine (DIEA)
followed by the addition of NaN3 in DMSO. Formation of the
acyl azide was completed in about 15 min. A simple work-up led
to the isolation of Fmoc-Phe-N3 4e in 82% yield (EDC-HOBt
system also yielded 4e in a similar yield; Table 3). The reaction
was repeated to prepare several Fmoc amino acid azides 4a–d and
4f, g and also Z-Phe-N3. Acid azide 4h which is the product of
Table 2 List of acid azides prepared via Scheme 1
Compd. R-CON3
Yield (%) Ref. M.p./◦C
2a
2b
2c
2d
2e
2f
2g
2h
2i
pyridine-3-carboxylic acid azide 83
pyridine-2-carboxylic acid azide 80
15
15
15
15
—
13
13
13
—
gum
gum
64
35
gum
83
88
68
gum
furan-2-carboxylic acid azide
thiophene-2-carboxylic acid
2-(1H-indol-3yl)acetyl azide
cinnamoyl azide
84
79
80
78
83
82
79
phenylacetyl azide
p-nitrobenzoyl azide
p-(Fmoc-amino)benzoyl azide
Scheme 2 Synthesis of N-protected a-amino acid azides 4.
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conversion of the b-COOH of Z-Asp-OH was prepared similarly
from Z-Asp-5-oxazolidinone (Table 3).
One-pot synthesis of the ureas and carbamates was also carried
out under ultrasonication. Ureas 5a, 5c–e and carbamates 6a
and 6e were synthesized via the rearrangement of acid azides as
well as the coupling of the resulting isocyanates at rt under the
influence of ultrasonic waves (Scheme 3; method c). The yields of
the compounds thus prepared were comparatively higher (Table 4)
and also the reaction could be carried out at rt with the same
reaction duration.
In conclusion, we have demonstrated the first application of the
peptide coupling agents for the direct conversion of acids into acid
azides. The use of carbodiimide EDC and the uronium reagent
HBTU as carboxylic activator has resulted in a mild, facile and
racemization free synthesis32 of acid azides from a diverse range
of acids including N-Fmoc/Z-protected a-amino acids. All the
azides have been obtained in good yields. The coupling agents
have also been successfully employed for the one-pot synthesis of
ureas and carbamates from acids.
One pot synthesis of ureas and carbamates
We could successfully synthesize, isolate and characterize a series
of acid azides using HBTU and EDC. But several classes of
acid azides such as N-Boc and Z protected a-amino acid azides
are not stable towards isolation. Syntheses involving such acid
azides can be efficiently carried out through one-pot synthetic
procedures which involve the chemical transformation of the acid
azides generated in situ without isolation. These one pot protocols
are also highly useful for rapid synthesis of biologically active
analogues which are required in large numbers for screening. An
example of such kind is the single-pot synthesis of ureas and
carbamates starting from acids which involves the formation of
acid azides and their in situ Curtius rearrangement followed by
coupling of the isocyanates with amines and alcohols. Procedures
for generating acid azides using NaN3 and chloroformates or
Boc2O, and the rearrangement and trapping of the isocyanates
in presence of n-Bu4NBr and zinc triflate, have been reported.29,30
A continuous flow reactor designed for the sequential execu-
tion of the generation and rearrangement of acid azides, and
coupling of isocyanates has also been used to prepared ureas
and carbamates.31 DPPA and Deoxo-Fluor-TMS-N3 have been
employed in the preparation of peptidyl and sugar ureas.17b,17d
However, application of the peptide coupling agents for this
purpose has not been demonstrated. We extended the utility of
EDC and HBTU to the one-pot synthesis of ureas and alkyl
carbamates. Accordingly, Fmoc-Phe-OH was treated with HBTU
in THF for 30 min and then refluxed till the complete formation
of isocyanate (IR), followed by coupling with the ester H-Ala-
OMe. This yielded the dipeptidyl urea 5b which was purified by
recrystallization with DMSO-water and characterized. Using this
procedure, several dipeptidyl ureas 5a, 5c–f were synthesized from
Fmoc, Boc and Z-amino acids (Scheme 3, Table 4). Urea-peptide
hybrids, Fmoc-Val-Ala-y[NH-CO-NH]-Val-OMe (5f) and Fmoc-
Pro-Val-y[NH-CO-NH]-Val-OMe (5g) were also obtained from
the corresponding Fmoc-dipeptide acids. Further, when the in
situ generated isocyanates were treated with 2.0 equivalents of
methanol, methyl carbamates 6a–e were obtained in 75–93% yield
(Table 4). Similarly, when, p-nitrobenzoic acid and thiophene-2-
carboxylic acid were reacted with NaN3, EDC at 0 ◦C in CH2Cl2
for 20 min followed by refluxing in the presence of ethanol and
toluene, the ethyl carbamates 6g and 6f were obtained. Addition
of amines under similar condition resulted in ureas 5h–n from
diversely functionalized acids (Table 4).
Experimental section
General procedure for the preparation of acyl azides 2
To a solution of an acid (1.0 mmol) in dry CH2Cl2 (10.0 mL)
was added EDC (1.1 mmol, 210.2 mg) at 0 ◦C followed by NaN3
(97.5 mg, 1.5 mmol) in DMSO (1 mL). The reaction mixture was
stirred for 20 min. It was diluted with CH2Cl2 and the organic layer
(15.0 mL) was washed with 5% sodium carbonate (2 ¥ 10 mL),
water (2 ¥ 10 mL), and brine (10 mL) and dried over anhydrous
Na2SO4. Solvent was evaporated in vacuo to obtain the products.
General procedure for the preparation of Fmoc/Z amino acid
azides 4
To a solution of Fmoc/Z-amino acid (1.0 mmol) in dry THF
(10.0 mL) were added DIEA (1.3 mmol) and HBTU (1.1 mmol,
148.5 mg) at 0 ◦C followed by NaN3 (97.5 mg, 1.5 mmol) in DMSO
(1 mL). The reaction mixture was stirred for 20 min, concentrated
in vacuo and the residue was flash chromatographed (20% EtOAc
in hexane) to obtain pure acid azides.
General procedure for the synthesis of ureas and carbamates 5h–n
and 6f, g
To a solution of acid (1.0 mmol) in dry CH2Cl2, EDC (1.1 mmol,
210.2 mg) was added at 0 ◦C followed by NaN3 (1.5 mmol) in
DMSO (1 mL) and stirred for 15 min. Toluene was added to the
reaction mixture which was then refluxed for 30 min followed
by the addition of 1.0 mmol of an amine or ethanol, and the
refluxing was continued till the completion of the reaction. The
Scheme 3 Synthesis of ureas and carbamates.
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Table 4 List of ureas and carbamates prepared via Scheme 3
Compd.
Ureas/carbamates
Yield (%)
M.p./◦C
HRMS: Found/Calcd. (M + Na)+
5aa
5ba
5ca
5da
5ea
5fa
Fmoc-Ala-y[NHCONH]-Val-OMe
Fmoc-Phe-y[NHCONH]-Ala-OMe
Boc-Val-y[NHCONH]-Ala-OMe
Boc-Leu-y[NHCONH]-Val-OMe
Cbz-Ala-y[NHCONH]-Gly-OMe
Fmoc-Val-Ala-y[NHCONH]-Leu-OMe
Fmoc-Pro-Val-y[NHCONH]-Val-OMe
80 (88)
81
76 (85)
79 (86)
75 (90)
73
181
186
168
175
142
170
gum
125
462.2008/462.2005
510.2010/510.2005
340.1825/340.1848
382.2313/382.2318
332.1/332.1 (ESMS calcd. for M + Na)
575.2853/575.2846
5ga
5hb
81
75
559.2539/559.2533
280.1445/280.1450c
5ib
5jb
79
77
245
320.9506/320.9435
229.1321/229.1317
gum
5kb
83
82
gum
261.0797/261.0794c
363.0943/363.0932c
5lb
184
5mb
5nb
72
74
174
188
478.2114/478.2107
294.0852/294.0855
6aa
6ba
6ca
6da
6ea
6fa
Fmoc-Gly-[NHCOCH3]
Fmoc-Leu-[NHCOOCH3]
Fmoc-Phe-[NHCOOCH3]
Z-Val-[NHCOOCH3]
75 (88)
80
78
75
79 (84)
78
145
172
190
138
130
gum
349.1168/349.1164
405.1793/405.1790
439.1620/439.1634
303.1341/303.1433
335.1039/335.1041
172.0428/172.0432c
Z-Met-[NHCOOCH3]
6ga
86
93
233.0542/233.0538
a Prepared by method A in Scheme 3. b Prepared by method B in Scheme 3; values in parenthesis are the yields for method C in Scheme 3. c Mass calcd.
for (M + H)+.
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solvent was evaporated and the residue was dissolved in EtOAc.
The organic layer was washed with 20% Na2CO3 followed by HCl,
water and brine, dried with anhydrous Na2SO4 and evaporated
in vacuo to obtain the crude product which was purified through
column chromatography (30% EtOAc in hexane)
2 For peptide synthesis using acid azides see: (a) J. Lutz, H.-J. Musiol, and
L. Moroder, Vol. E22a, pp 427 in Houben-Weyl: Synthesis of Peptides &
Peptidomimetics, M. Goodman, A. Felix, L. Moroder and C. Toniolo,
ed.; Georg Thieme Verlag: Stuttgart, New York; For the utility of
Boc/Z-amino acid azides in total synthesis of ribonuclease in solution,
see: (b) N. Fujii and H. J. Yajima, J. Chem. Soc., Perkin Trans. 1, 1981,
831–841 and references cited therein; For Fmoc-acid azides as peptide
coupling agents see: (c) V. V. Suresh Babu, K. Ananda and G. R.
Vasanthakumar, J. Chem. Soc., Perkin Trans. 1, 2000, 4328–4331; For
applications of acids azides in peptidomimetics synthesis see: (d) M.
Chorev, Biopolymers Peptide Sci, 2005, 80, 67–84; (e) M. D. Fletcher
and M. M. Campbell, Chem. Rev., 1998, 98, 763–795.
General procedure for the synthesis of ureas and carbamates 5a–g
and 6a–e
To a solution of acid (1.0 mmol) in dry THF, DIEA (1.0 mmol)
and HBTU (1.1 mmol, 148.5 mg) were added at 0 ◦C followed
by NaN3 (1.5 mmol) in DMSO (1 mL) and stirred for 25 min.
It was then refluxed or ultrasonicated for 30 min followed by the
addition of 1.0 mmol of an amino acid ester or an alcohol and
the refluxing or ultrasonication was continued till the completion
of the reaction. The solvent was then evaporated and resultant
residue was washed with water. The crude product was purified
through recrystallization from DMSO-water.
3 C. O. Kangani, B. W. Day and D. E. Kelley, Tetrahedron Lett., 2008,
49, 914–918.
4 (a) A. Palani, S. Shapiro, M. D. McBriar, J. W. Clader, W. J. Greenlee,
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Chem., 2003, 68, 7274–7280; (b) V. V. Sureshbabu, B. S. Patil and R.
Venkataramanarao, J. Org. Chem., 2006, 71, 7697–7705; (c) L. Fischer,
V. Semetey, J.-M. Lozano, A.-P. Schaffner, J.-P. Briand, C. Didierjean
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610–620; (b) M. Chorev and M. Goodman, Int. J. Pept. Prot. Res., 1983,
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6, 213–215.
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1984, 49, 2231–2235.
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9 J. R. Pfister and W. E. Wymann, Synthesis, 1983, 38–39.
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Characterization data for representative compounds
2-(1H-Indol-3-yl)acetyl azide, 2e. Rf 0.4 (n-hexane–AcOEt
8 : 2); IR (KBr) nmax = 2138 cm-1; 1H NMR (CDCl3, 400 MHz) d:
3.86 (2H, s), 7.02 (1H, d, J = 2.0 Hz), 7.05–7.59 (4H, m), 8.84 (1H,
s); 13C NMR (CDCl3,100 MHz) d 31.84, 111.81, 111.93, 120.03,
122.50, 123.74, 123.89, 127.69, 136.69, 172.83; HRMS Calc’d for
C10H8N4O m/z: 201.0776 (M+ + H), found 201.0781
(S)-Methyl
2-(3-((R)-1-((S)-2-(((9H-fluoren-9-yl)methoxy)-
carbon-yl)-3-methylbutanamido)ethyl)ureido)-4-methylpentanoate
{Fmoc-Val-Ala-w[NHCONH]-Leu-OMe}, 5f. Rf 0.4 (CHCl3–
1
MeOH 9 : 1); IR (KBr) nmax = 1652 cm-1; H NMR (DMSO-d6,
400 MHz) d: 0.81 (6H, br), 1.08 (6H, br), 1.18 (2H, m), 2.52–2.63
(2H, br), 3.53 (3H, s), 4.23 (1H, m) 4.41–4.52 (2H, m), 4.62 (2H,
d, J = 7.0 Hz), 5.09 (1H, m), 6.32 (1H, br), 7.89–7.21 (8H, m); 13
C
NMR (DMSO-d6, 100 MHz) d 18.99, 20.20, 24.18, 25.30, 31.00,
35.00, 47.55, 55.34, 56.17, 61.03, 66.60, 126.27, 128.02, 128.60,
129.88, 141.58, 144.76, 156.30, 157.10, 171.35, 174.39; HRMS
Calc’d for C30H40N4O6 m/z: 575.2846 (M+ + Na), found 575.2853
Ethyl thiophen-2-ylcarbamate, 6f. Rf 0.4 (n-hexane–AcOEt
7 : 3); IR (KBr) nmax = 1728 cm-1; 1H NMR (DMSO-d6, 400 MHz)
d 1.25 (3H, t, J = 7.24 Hz), 4.21 (2H, q, J = 6.8 Hz), 6.60–6.78
(3H, m), 8.10 (1H, s); 13C NMR (DMSO-d6, 100 MHz) d 14.98,
62.37, 112.80, 117.68, 125.15, 140.69, 154.59, HRMS Calc’d for
C7H9NO2S m/z: 172.0432 (M+ + H), found 172.0428
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Acknowledgements
We thank Department of Science and Technology (Grant no.
SR/S1/OC/26/2008) and Council of Scientific and Industrial
Research, Govt. of India for financial support. H. S. L. thanks
Siddaganga Institute of Technology, Tumkur, India for research
leave.
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32 Optical purities of the ureas were determined by the NMR analy-
sis of compounds, Boc-Phe-y[NHCONH]-(R)-1-phenylethylamine 7a
and Boc-Phe-y[NHCONH]-(S)-1-phenylethylamine 7b prepared by
reacting Boc-Phe-OH with (R) and (S) 1-phenylethylamine separately
via method A in Scheme 3, contained the methyl group doublets at
d = 1.27, 1.29; and 1.24, 1.26 respectively. The equimolar mixture
of these compounds obtained by reacting racemic 1-phenylethylamine
with Boc-Phe-OH had -CH3 peaks at 1.24, 1.26, 1.27, 1.29 ppm,
corresponding to the presence of two epimers. These studies confirmed
that the sample 7a and 7b contained a single and optically pure
compound. Thus using the present method, acid azides as well as
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840 | Org. Biomol. Chem., 2010, 8, 835–840
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