An efficient one-pot synthesis of azidoformates from alcohols using triphosgene: Synthesis of N-carbobenzyloxy azetidin-2-ones

Article abstract of DOI:10.1055/s-2002-33512

An efficient use of triphosgene for the preparation of various azidoformates from alcohols and sodium azide is described. The method is applied to various chiral alcohols including glucose diacetonide to get the corresponding azidoformates. One of these azidoformates has been successfully utilized for the synthesis of N-carbobenzyloxy-β-lactams.

Full text of DOI:10.1055/s-2002-33512

LETTER
1455
An Efficient One-Pot Synthesis of Azidoformates from Alcohols Using
Triphosgene: Synthesis of N-Carbobenzyloxy Azetidin-2-ones
Efficient
O
ne-Pot
.
S
ynthesis
o
T
f
A
zidoformates. Patil, Ghazala Parveen, V. K. Gumaste, B. M. Bhawal, A. R. A. S. Deshmukh*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune - 411 008, India
Fax +91(20)5893153; E-mail: arasd@dalton.ncl.res.in
Received 30 May 2002
carbazates using sodium nitrite and acetic acid. The carba-
zates are prepared from alcohols, acid chloride and hydra-
zine.7 The azidoformates are also prepared by reacting
alcohol with hazardous phosgene8 to generate correspond-
Abstract: An efficient use of triphosgene for the preparation of var-
ious azidoformates from alcohols and sodium azide is described.
The method is applied to various chiral alcohols including glucose
diacetonide to get the corresponding azidoformates. One of these
azidoformates has been successfully utilized for the synthesis of N- ing chloroformate which is further reacted with alkali
carbobenzyloxy- -lactams.
metal azide or hydrazoic acid.
Key words: azidoformate, alcohol, sodium azide, triphosgene,
azetidin-2-one
Triphosgene has been employed for the one-pot prepara-
tion of azidoformates.9 Various alcohols were reacted
with triphosgene in the presence of sodium azide and tri-
ethylamine at 0 °C followed by stirring at room tempera-
ture for 24 h afforded azidoformates in very good yields
(Table 1). The in situ generated chloroformate or carbon-
ate reacts directly with sodium azide to get azidoformate
(Scheme 1).
Over the last few years triphosgene [bis(trichlorometh-
yl)carbonate] has emerged as a versatile synthetic auxilia-
ry for the synthesis of some important classes of organic
compounds.1 This white crystalline compound has proved
to be safe and advantageous in comparison with its gas-
eous congener, phosgene. In our recent publication2 we
have reported an efficient use of triphosgene as an acid ac-
tivator in the construction of -lactam rings by ketene-
imine cycloaddition reactions. We have also used triphos-
gene for the preparation of acylazides from acids and so-
dium azide.3 In this communication we wish to report the
application of triphosgene as a reagent for one pot prepa-
ration of various azidoformates from alcohols and sodium
azide under very mild reaction conditions. The utility of
azidoformates for the synthesis of N-carbobenzyloxy- -
lactams is also described in this communication.
The reaction conditions are very mild and can be em-
ployed for the synthesis of various chiral azidoformates
starting from chiral alcohols (see entries 4–10, Table 1).
The diacetonide, readily available from D-glucose,10 was
also efficiently transformed to its azidoformate in very
good yield (see entry 5, Table 1).
Methoxy alcohol was prepared from (+)-3-carene, natu-
rally occurring monoterpene, by our reported procedure.2b
This alcohol also gave azidoformate in excellent yield
when reacted with triphosgene and sodium azide (see en-
try 8, Table 1).
After developing an efficient method for azidoformate we
were interested in the application of these azidoformates
for their synthetic utility. We have successfully used ben-
zylazidoformate for the synthesis of N-carbobenzyloxy- -
lactams (Scheme 2). This application was a part of our on
going research program on the synthesis -lactams.11
Interest in the synthesis of azidoformates stems from their
increasing use as protecting agents for amino groups in
peptide synthesis.4 They are valuable synthetic intermedi-
ates for many heterocyclic compounds.5
Azidoformates are generally prepared by reacting corre-
sponding chloroformates with alkali metal azides.6 The
other method for azidoformates involves nitrosation of
Scheme 1
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1455,1458,ftx,en;G15202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1456
R. T. Patil et al.
LETTER
Table 1 Preparation of Various Azidoformates from Alcohols and Sodium Azide Using Triphosgene
Entry No.
Alcohol
Azidoformate
Yield (%)
1
2
3
4
Benzyl alcohol
Cyclohexyl alcohol
CH3(CH2)6CH2OH
L-Menthol
Benzyl azidoformate
Cyclohexyl azidoformate
CH3(CH2)6CH2OCON3
Menthyl azidoformate
77
90
81
64
5
65
6
7
8
69
66
86
9
86
78
10
The iminophosphorane, which is readily generated from Table 2 Synthesis of N-Carbobenzyloxy azetidin-2-ones (4a–f)
benzyl azidoformate and triphenyl phosphine, was treated
Entry
No.
Com-
pound
R1
R2
Yield
(%)a,b
Mp (°C)
with benzaldehyde to get aza-Wittig reaction product in
very good yield. This product was used further for the
cycloaddition reaction with ketene, generated from acid
chloride, using Staudinger reaction conditions to get N-
carbobenzyloxy- -lactams (4a–f)12 in good yields
(Table 2).
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
-Ph
-OPh
-OPh
-OBz
-OPh
-OBz
78
80
73
56
65
84
128
-PMP
-PMP
-Styryl
-Styryl
106
95
In summary, we have demonstrated a general one-pot
method for the preparation of azidoformates from alco-
hols and sodium azide using triphosgene. We have also
shown the utility of azidoformate for the synthesis of N-
carbobenzyloxy- -lactams. The work on further applica-
tion of azidoformates as well as chiral azidoformates for
asymmetric synthesis is in progress.
Thick oil
Thick oil
109
-Furfuryl -OPh
a Isolated yields.
b All the compounds gave satisfactory elemental analyses and spec-
tral data.
Synlett 2002, No. 9, 1455–1458 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Efficient One-Pot Synthesis of Azidoformates
1457
Scheme 2
brine (10 mL) and dried (Na2SO4). The solvent was removed
and the residue was purified by column chromatography to
get pure azidoformate in good yield (Table 1). [CAUTION:
We did not observe any untoward incidence while working
with azidoformates. However, the use of hood and safety
shield is recommended as tert-butyl azidoformate is known
to decompose above 80 °C with apparent detonation.13].
Spectral data for benzyl azidoformate 1H NMR (CDCl3,
200MHz): 5.25 (s, 2 H), 7.45 (s, 5 H); IR (KBr, CHCl3)
2166, 2140, 1736, 1498, 1456, 1377, 1236 cm–1; Anal. Calcd
for C8H7N3O2: C, 54.23; H, 3.98; N, 23.71. Found: C, 54.47;
H, 3.95; N, 23.67.
Acknowledgement
RTP thanks CSIR for the award of research fellowship.
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(12) General Experimental Procedure for the Synthesis of N-
Carbobenzyloxy- -lactams (4a–f): To a solution of benzyl
azidoformate (1 mmol) in toluene (10 mL) was added
triphenyl phosphine (1 mmol) and the reaction mixture was
stirred at room temperature for 3 h. Aldehyde (1 mmol) was
added to the reaction and refluxed for 8–10 h. Solvent was
removed under reduced pressure and dry diethyl ether
(15 mL) was added to the residue. The solid triphenyl
phosphineoxide separated was removed by filtration and the
solvent was removed to get imine 3. These imines were
found to be unstable and used further without purification.
A solution of above imine (1 mmol) in dichloromethane
(15 mL) and triethylamine (4 mmol) was cooled to 0 °C and
(9) General Experimental Procedure for the Preparation of
Azidoformates: To a stirred solution of alcohol (1 mmol) and
sodium azide (2 mmol) in acetone (10 mL) was added
triethylamine (1.5 mmol) at 0 °C. The reaction mixture was
stirred at this temperature for 15 min and a solution of
triphosgene (0.5 mmol) in acetone (5 mL) was added
dropwise at 0 °C over about 15 min. The reaction mixture
was stirred at this temperature for 1 h and slowly allowed to
warm up to room temperature. It was stirred for 24 h at room
temperature. The reaction mixture was filtered to remove
insoluble salts and the filtrate was diluted with an equal
volume of water. It was extracted with EtOAc (3 20 mL)
and the organic extract was washed with water (10 mL) and
Synlett 2002, No. 9, 1455–1458 ISSN 0936-5214 © Thieme Stuttgart · New York

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R. T. Patil et al.
LETTER
a solution of acid chloride in CH2Cl2 (10 mL), was added
slowly with stirring in about 20 min. The reaction mixture
was allowed to warm up to room temperature and stirred for
18 h. It was washed with water (15 mL), saturated sodium
bicarbonate solution (10 mL), brine (10 mL) and dried over
sodium sulfate. Solvent was removed under reduced
pressure and the crude product was purified by column
chromatography to get -lactams 4a–f in good yield.
Spectral data for -lactam (4a): 1H NMR (CDCl3, 200
MHz): 3.87 (d, J = 14.7 Hz, 1 H), 4.75 (d, J = 4.4 Hz, 1 H),
4.91 (d, J = 14.7 Hz, 1 H), 5.40 (d, J = 4.4 Hz, 1 H), 6.70 (d,
J = 7.8 Hz, 2 H), 6.85 (t, J = 7.8 Hz, 1 H), 7.10–7.33 (m, 12
H); 13C NMR (CDCl3, 50.3 MHz) 44.10, 61.34, 82.04,
115.45, 121.84, 127.84, 128.13, 128.53, 128.76, 129.05,
132.61, 134.67, 156.80, 159.56, 165.48; IR (KBr, CHCl3)
1758, 1596, 1494, 1236 cm–1; Anal. Calcd for C23H19NO4: C,
73.98; H, 5.12; N, 3.75. Found: C, 73.79; H, 4.98; N, 3.77.
(13) (a) Feyen, P. Angew. Chem. 1977, 89, 119. (b) Koppel, H.
C. Chem. Eng. News 1976, 54, 5; Chem. Abstr 1977, 86,
19144.
Synlett 2002, No. 9, 1455–1458 ISSN 0936-5214 © Thieme Stuttgart · New York