Direct conversion of aldehydes to acyl azides using tert-butyl hypochlorite

Article abstract of DOI:10.1016/j.tetlet.2007.06.020

A general method, for the direct conversion of aldehydes to acyl azides using tert-butyl hypochlorite and sodium azide is described. The method is simple and occurs under mild conditions.

Full text of DOI:10.1016/j.tetlet.2007.06.020

Tetrahedron Letters 48 (2007) 5661–5664
Direct conversion of aldehydes to acyl azides using
tert-butyl hypochlorite
Nitin D. Arote and Krishnacharya G. Akamanchi*
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
Received 21 April 2007; revised 29 May 2007; accepted 6 June 2007
Available online 9 June 2007
Abstract—A general method, for the direct conversion of aldehydes to acyl azides using tert-butyl hypochlorite and sodium azide is
described. The method is simple and occurs under mild conditions.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Acyl azides are widely utilized in industry and act as a
chemical feedstock for a range of useful materials in
organic chemistry1 and especially in pharmaceuticals,2
dyes3 and agrochemicals.4 They are very useful for the
preparation of amides and heterocyclic compounds
and also undergo facile rearrangement to isocyanates
from which amines, urethanes, thiourethanes, keteni-
mines, carbodiimides and ureas can be obtained.1c
pare. It has been used for many oxidative transforma-
tions including oxidation of alcohols13 and sulfides.14
Recently, we reported a reaction of 1,3-dithiolanes and
1,3-dithianes with t-BuOCl to afford dihydro-1,4-dithi-
ins and dihydro-1,4-dithiepines in high yield.15 As a part
of our ongoing programme on the development of new
methodologies in organic synthesis, we report a new
method for direct conversion of aldehydes to acyl azides.
During the course of our studies, we found that treat-
ment of 4-methoxybenzaldehyde with t-BuOCl and
NaN3 gave the corresponding acyl azide in good yield
(87%) (Scheme 1).
Acyl azides are usually prepared from acid derivatives
such as acid chlorides and acid hydrazides.5 There are
a few reports on the direct conversion of carboxylic
acids to acyl azides using acid activators such as ethyl
chloroformate,6a DDPA,6b NCS-TPP,6c triphosgene6d
and cyanuric chloride.6e Aldehydes have also been di-
rectly converted into acyl azides. Various reagents and
reagent systems have been reported in the literature
for this purpose, and include chromic anhydride–tri-
In a preliminary study, experiments were carried out to
optimize the reaction conditions.
To optimize the mole ratio of t-BuOCl and NaN3 with
respect to the aldehyde, experiments were carried out
as shown in Table 1. The best result was obtained when
the mole ratio of aldehyde: t-BuOCl:NaN3 was 1:2:2 in
CCl4 as solvent (Table 1, entry 3). These conditions were
used for subsequent reactions. In acetonitrile, the reac-
tion was slow and gave only a 32% yield of the acyl azide
(Table 1, entry 5). Solvents such as chloroform, dichlo-
romethane and cyclohexane afforded high yields. In tert-
butanol the reaction was faster, however, 20% of 4-
methyl silylazide,7 PhI(OAc)2,8 triazidochlorosilane–
activated MnO2,9 IN3
and Dess–Martin period-
10
inane.11a Modified methods in which carbamoyl azides
were formed directly from aldehydes via acyl azides in
one-pot12 have also been reported.
Despite these, additional methods for this conversion
are still valuable.
tert-Butyl hypochlorite (t-BuOCl) is a versatile reagent,
is readily available at low cost and is also easy to pre-
O
O
H
t-BuOCl, NaN3
Solvent , RT
N3
Keywords: Aldehyde; Acyl azide; tert-Butyl hypochlorite; Sodium
H3CO
azide.
H3CO
*
Corresponding author. Tel.: +91 22 2414 5616; fax: +91 22 2414
5614; e-mail: kgap@rediffmail.com
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.020

5662
N. D. Arote, K. G. Akamanchi / Tetrahedron Letters 48 (2007) 5661–5664
Table 1. Optimization of the reaction conditions for the conversion of
We next examined the scope and generality of the meth-
od. Various aldehydes were studied and the results are
summarized in Table 2.16
4-methoxybenzaldehyde to the corresponding acyl azidea
Entry
t-BuOCl:NaN3
Conditions (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
1:1
1.5:1.5
2:2
2.5:2.5
2:2
2:2
2:2
2:2
2:2
CCl4, 24
CCl4, 24
CCl4, 24
CCl4, 24
42
68
87
85
32c
78
75
69d
80
As can be seen from the results in Table 2, a wide variety
of substrates including aromatics, heteroaromatics and
aliphatic aldehydes (entries 1–12), furnished the desired
acyl azides in good yields.17
ACN, 24
CHCl3, 24
CH2Cl2, 24
tert-Butanol, 6
Cyclohexane, 24
In the case of aliphatic aldehydes, when the reactions
were carried out at room temperature, some rearrange-
ment to the corresponding isocyanate was observed.10
Hence, reactions were carried out at low temperature
(Table 2, entries 9–12).
a Reactions were carried out on 5 mmol scale at room temperature.
b Isolated yield.
c 60% starting material was recovered.
d 4-Methoxybenzoic anhydride was isolated in 20% yield.
In summary, we have developed a general method for
direct conversion of aldehydes to acyl azides using t-but-
yl hypochlorite and sodium azide. The method is simple
and occurs under mild conditions. Further applications
methoxybenzoic anhydride was obtained as a side prod-
uct (Table 1, entry 8).
Table 2. t-BuOCl/NaN3 mediated conversion of aldehydes to acyl azidesa
t
-BuOCl, NaN3
5-10 0
RCHO
RCON3
C
CCl4, RT /
R = alkyl or aryl
Entry
1
Substrate
Productb,c
Yieldc (%)
84
Mp (ꢁC) (lit.)
O
O
H
N3
25–27 (27)11b
O
O
O
H
H
N3
N3
2
3
87
72
70 (70–71)11b
H3CO
H3CO
H3CO
H3CO
O
74–76
H3CO
H3CO
OCH3
O
OCH3
O
N3
43–44 (43)11b
65–67 (65)11b
H
4
5
80
83
Cl
Cl
O
O
H
N
3
O2N
O2N
O
O
H
N3
6
7
8
9
80
78
85
80
68–7011b
NO2
NO2
H
N3
Oil
S
S
O
O
CH3
N
CH3
O
O
N
105–107
Oil (—)d,6e
O
O
Ph
Ph
H
N3
O
O
H
N3
O
O

N. D. Arote, K. G. Akamanchi / Tetrahedron Letters 48 (2007) 5661–5664
5663
Table 2 (continued)
Entry
Substrate
Productb,c
Yieldc (%)
79
Mp (ꢁC) (lit.)
O
O
Oil (—)d,10
10
H
N3
O
O
11
12
78
80
Oil (—)d,7a
Oil (—)d,6d
N3
N3
H
H
O
O
H3C
H3C
4
4
a Reactions were carried out on 1–5 mmol scale using 2.0 equiv of t-BuOCl and 2.0 equiv of NaN3 in 20 ml of CCl4 for 24 h at rt (entries 1–8)16a or at
5–10 ꢁC (entries 9–12).16b
b Structures confirmed by IR, 1H NMR and 13C NMR (spectral details are provided).17
c Isolated yield.
d The aliphatic acyl azides decompose upon standing in air at room temperature. Spectra were thus recorded at low temperature (0–5 ꢁC) under
nitrogen.10
5. Laszlo, P.; Polla, E. Tetrahedron Lett. 1984, 25, 3701.
6. (a) Kobayasi, S.; Kamiyama, K.; Limori, T.; Ohno, M.
Tetrahedron Lett. 1984, 25, 2557; (b) Shao, H.; Colucci,
M.; Tong, S.; Zhang, H.; Castelhano, A. L. Tetrahedron
Lett. 1998, 39, 7235; (c) Froeyen, P. Phosphorus Sulfur
Silicon Relat. Elem. 1994, 89, 57; (d) Gumaste, V. K.;
Bhawal, B. M.; Deshmukh, A. R. Tetrahedron Lett. 2002,
43, 1345; (e) Bandgar, B. P.; Pandit, S. S. Tetrahedron
Lett. 2002, 43, 3413.
of tert-butyl hypochlorite in organic transformations are
currently being investigated in our laboratory.
Acknowledgement
The authors thank the Council of Scientific and Indus-
trial Research (CSIR), New Delhi, India, for financial
support.
7. (a) Lee, J. G.; Kwak, K. H. Tetrahedron Lett. 1992, 33,
3165; (b) Reddy, P. S.; Yadgiri, P.; Lumin, S.; Falck, J. R.
Synth. Commun. 1988, 18, 545.
8. Chen, D. J.; Chen, Z. C. Tetrahedron Lett. 2000, 41, 7361.
9. Elmorsy, S. S. Tetrahedron Lett. 1995, 36, 1341.
10. Marinescu, L.; Thinggaard, J.; Thomsen, I. B.; Bols, M. J.
Org. Chem. 2003, 68, 9453.
11. (a) Bose, S. D.; Reddy, A. V. N. Tetrahedron Lett. 2003,
44, 3543; (b) Yukawa, Y.; Tsuno, Y. J. Am. Chem. Soc.
1957, 79, 5530.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2007.06.020.
12. (a) Pedersen, M. C.; Marinescu, L. G.; Bols, M. Org.
Biomol. Chem. 2005, 3, 816; (b) Marinescu, L. G.;
Pedersen, M. C.; Bols, M. Tetrahedron 2005, 61, 123.
13. Milovanovic, J. N.; Vasojevic, M.; Gojkovic, S. J. Chem.
Soc., Perkin Trans. 2 1988, 533.
14. Jalsovszkey, I.; Ruff, F.; Kajtar-Peredy, M.; Kucsman, A.
Synthesis 1990, 1037.
15. Arote, N. D.; Telvekar, V. N.; Akamanchi, K. G. Synlett
2005, 2595.
16. (a) General experimental procedure (entries 1–8): To a
stirred suspension of t-BuOCl (1.1 g, 10 mmol) and NaN3
(0.65 g, 10 mmol) in CCl4 (20 ml), aldehyde (5 mmol) was
added at room temperature. The reaction mixture was
stirred at the same temperature until complete consump-
tion of starting material as indicated by TLC. The reaction
mixture was diluted with dichloromethane and the organic
layer was washed successively with 5% sodium thiosul-
phate solution (2 · 15 ml), 5% sodium bicarbonate solu-
tion (2 · 15 ml), water (2 · 15 ml) and brine (15 ml). The
organic layer was dried over sodium sulfate and concen-
trated in vacuo. Purification by silica gel column chroma-
tography (5% EtOAc/n-hexane) afforded the pure acyl
azide; (b) General experimental procedure (entries 9–12):
To a stirred and cooled (5–10 ꢁC) suspension of t-BuOCl
(1.1 g, 10 mmol) and NaN3 (0.65 g, 10 mmol) in CCl4
(20 ml), aldehyde (5 mmol) was added. The reaction
mixture was stirred at the same temperature until complete
consumption of starting material as indicated by TLC.
The reaction mixture was diluted with cold dichlorometh-
ane and worked-up using cold solutions. The organic layer
References and notes
1. (a) Patai, S. The Chemistry of the Azido Group; Chichester
Interscience: New York, 1971; p 397; (b) Scriven, E. F. V.;
Turnbull, K. Chem. Rev. 1988, 88, 297; (c) Brase, S.; Gil,
C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed.
2005, 44, 5188.
2. (a) Valiaeva, N.; Bartley, D.; Konno, T.; Coward, J. K. J.
Org. Chem. 2001, 66, 5146; (b) Chiyoda, T.; Iida, K.;
Takatori, K.; Kajiwara, M. Synlett 2000, 1427; (c) Kubo,
K.; Kohara, Y.; Imamiya, E.; Sugiura, Y.; Inada, Y.;
Furukawa, Y.; Nishikawa, K.; Naka, T. J. Med. Chem.
1993, 36, 2182; (d) Burger, A.; Yost, W. L. J. Am. Chem.
Soc. 1948, 70, 2198.
3. Mallakpour, S.; Nasr-Isfahani, H. Indian J. Chem. 2002,
41B, 169.
4. (a) Wang, Y. G.; Wang, Z. Y.; Zhao, X. Y.; Song, X. J.
Youji Huaxue 2004, 24, 1606; Wang, Y. G.; Wang, Z. Y.;
Zhao, X. Y.; Song, X. J. Chem. Abstr. 2005, 143, 326296c;
(b) Kudis, S.; Baumann, E.; Von Deyn, W.; Langemann,
K.; Mayer, G.; Misslitz, U.; Neidlein, U.; Witschel, M.;
Westphalen, K.-O.; Walter, H. WO0140200; Kudis, S.;
Baumann, E.; Von Deyn, W.; Langemann, K.; Mayer, G.;
Misslitz, U.; Neidlein, U.; Witschel, M.; Westphalen,
K.-O.; Walter, H. Chem. Abstr. 2001, 135, 5609w; (c)
Crews Jr., A. D.; Harrington, P. M.; Karp, G. M.; Gill, S.
D.; Dieterich P. US 5,519,133; Crews, A. D., Jr.;
Harrington, P. M.; Karp, G. M.; Gill, S. D.; Dieterich,
P. Chem. Abstr. 1996, 125, 114718v.

5664
N. D. Arote, K. G. Akamanchi / Tetrahedron Letters 48 (2007) 5661–5664
was washed successively with 5% sodium thiosulphate
9H), 7.17 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz): d
55.28, 61.01, 106.66, 125.52, 143.53, 153.06, 171.82
(–CON3) ppm. Elemental analysis: Calculated for
C10H11N3O4: C, 50.63; H, 4.64; N, 17.72. Found: C,
50.60; H, 4.66; N, 17.69. Entry 7: Thiophene-2-carbonyl
solution (2 · 15 ml), 5% sodium bicarbonate solution
(2 · 15 ml), water (2 · 15 ml) and brine (15 ml). The
organic layer was dried over sodium sulfate and concen-
trated in vacuo without heating. Purification by silica gel
column chromatography (n-hexane) afforded the pure acyl
azide. Caution!: tert-Butyl hypochlorite decomposes exo-
thermically when exposed to UV light to give acetone and
chloromethane. Glass containers have burst because of
pressure build up after exposure to fluorescent lighting or
daylight. It reacts violently with rubber and should not be
heated to its boiling point. Caution!: During reactions and
isolations, we have not observed any explosive hazards but
it is known that azido compounds may represent an
explosion hazard when being concentrated under vacuum
or stored neat. A safety shield and appropriate handling
procedures are recommended.
azide IR (neat)
m ;
max = 2155, 1680 cmÀ1 1H NMR
(CDCl3, 60 MHz): d 7.02–7.80 (m, 3H) ppm; 13C NMR
(CDCl3, 75 MHz): d 128.47, 134.49, 134.85, 153.06, 166.61
(–CON3) ppm. Elemental analysis: Calculated for
C5H3N3OS: C, 39.21; H, 1.96; N, 27.45. Found: C,
39.19; H, 1.99; N, 27.42. Entry 8: 4-[2-(N-Methyl-N-
phenyl)amino-2-oxo-ethoxy]benzoyl azide IR (KBr)
m
max = 2127, 1684 cmÀ1 1H NMR (CDCl3, 60 MHz): d
;
3.26 (s, 3H), 4.43 (s, 2H), 6.71 (d, 2H, J = 8.82 Hz), 7.33
(m, 5H), 7.81–7.94 (d, 2H, J = 8.82 Hz) ppm; 13C NMR
(CDCl3, 75 MHz): d 37.62, 66.07, 114.52, 123.78, 126.92,
128.72, 130.24, 131.64, 162.97, 166.72, 171.59 (–CON3)
ppm. Elemental analysis: Calculated for C16H14N4O3: C,
61.93; H, 4.51; N, 18.06. Found: C, 61.95; H, 4.49; N,
18.09.
17. Spectral data for novel acyl azides (Table 2): Entry 3:
3,4,5-Trimethoxybenzoyl azide IR (KBr) mmax = 2137,
1
1679 cmÀ1; H NMR (CDCl3, 60 MHz): d 3.83–3.88 (m,