A tandem reaction of 4-bromoalkyl aldehydes with sodium azide: Synthesis of 5,6,7,7a-tetrahydro-pyrrolo[1,2-d]-[1.2.3.4]oxatriazole

Article abstract of DOI:10.1002/hc.10035

5,6,7,7a-Tetrahydro-pyrrolo[1,2-d]-[1.2.3.4]oxatriazoles were synthesized through a nucleophilic substitution-cycloaddition tandem reaction of 4-bromoalkyl aldehydes with sodium azide.

Full text of DOI:10.1002/hc.10035

Heteroatom Chemistry
Volume 13, Number 4, 2002
A Tandem Reaction of 4-Bromoalkyl
Aldehydes with Sodium Azide: Synthesis
of 5,6,7,7a-Tetrahydro-pyrrolo[1,2-d]-
[1.2.3.4]oxatriazole
Yuan Ma
Bioorganic Phosphorus Chemistry Laboratory, Department of Chemistry, School of Life Science,
Tsinghua University, Beijing 100084, People’s Republic of China
Received 20 July 2001; revised 2 September 2001
through various reaction sequences [3,4]. Function-
ABSTRACT: 5,6,7,7a-Tetrahydro-pyrrolo[1,2-d]-
alized pyrrolidines are compounds of considerable
importance. They occur in a variety of natural prod-
ucts and pharmaceutically active compounds, either
as isolated ring systems or embedded in more com-
plex structures, which often possess widely rang-
ing biological activity [5]. The development of the
methodology for the preparation of highly func-
[1.2.3.4]oxatriazoles were synthesized through a nu-
cleophilic substitution–cycloaddition tandem reac-
tion of 4-bromoalkyl aldehydes with sodium azide.
C
2002 Wiley Periodicals, Inc. Heteroatom Chem 13:307–
309, 2002; Published online in Wiley Interscience (www.
interscience.wiley.com). DOI 10.1002/hc.10035
tionalized pyrrolidines has attracted considerable
interest recently [5–8]. Herein, I report a nucle-
ophilic substitution–cycloaddition tandem reaction
of 4-bromoalkyl aldehydes with sodium azide. It can
be used to synthesize 5,6,7,7a-tetrahydro-pyrrolo[1,
2-d][1.2.3.4]oxatriazoles.
INTRODUCTION
The development of tandem reaction processes has
been a rapidly growing area of synthetic organic
chemistry during recent years [1–4]. Tandem re-
actions, sometimes also called domino, sequential,
cascade, consecutive, iterative, zipper, and one-pot
reactions, link several transformations together in
a single synthetic step. Typically, an initial reac-
tion produces an intermediate that undergoes fur-
ther transformations with strategically positioned
reactive centers in the same molecule, with other
compounds in the reaction mixture, or with addi-
tional reagents introduced after the initial trans-
formation takes place. Over the last decade, tan-
dem reactions have been widely used in syntheses
of biologically active agents and natural products
RESULTS AND DISCUSSION
When a nucleophilic substitution reaction of 4-
bromobutyraldehyde with sodium azide was carried
out at room temperature, in addition to the desired
product 4-azidobutyraldehyde (2a) [9], another col-
orless oil was also obtained. In its 1H NMR, 13C NMR,
and IR spectra, no signal of a carbonyl group of an
aldehyde was found. Its structure was assigned as
a bicyclic compound, 5,6,7,7a-tetrahydro-pyrrolo[1,
2-d][1.2.3.4]oxatriazole (3a). When the reaction tem-
perature was reduced to 0 C, only 2a was obtained.
However, when the reaction temperature was in-
creased to 50 C, compound 3a was the sole product.
And 2a can convert to 3a at 50 C. It is rationalized
Correspondence to: Yuan Ma; e-mail: yuan ma 99@yahoo.com.
Contract grant sponsor: Tsinghua University.
2002 Wiley Periodicals, Inc.
c
307

308 Ma
and sodium azide. It can be used to synthesize
5,6,7,7a-tetrahydro-pyrrolo[1,2-d][1.2.3.4]oxatria-
zole derivatives.
EXPERIMENTAL
SCHEME 1 Reaction of bromo/toluenesulfonyloxy aldehy-
Melting points were obtained on a Yanaco melt-
ing point apparatus and are uncorrected. Elemen-
tal analyses were carried out on an Elementar Vario
des and ketones with sodium azide.
1
that a nucleophilic substitution–cycloaddition tan-
dem reaction takes place between the 4-bromoalkyl
aldehyde and sodium azide. 4-Bromobutyraldehyde
and sodium azide first undergo a nucleophilic sub-
stitution to yield 2a, which then undergoes an in-
tramolecular [2 + 3] cycloaddition reaction to form
3a (Scheme 1). According to my knowledge, this is
the first synthesis of this kind of a bicyclic hetero-
cyclic compound.
EL elemental analyzer. The H NMR spectra were
recorded on a Varian Inova 300 spectrometer with
TMS as an internal standard in CDCl3. The IR spectra
were taken on a Brucker Vector 22 FT-IR spectropho-
tometer in KBr. Mass spectra were obtained on a VG
ZAB-HS mass spectrometer. TLC separations were
performed on silica gel G plates with petroleum ether
(60–90 C)/ethyl acetate (10:1), and the plates were vi-
sualized with UV light.
In order to extend this tandem reaction, a variety
of bromo aldehydes have been tested (Table 1). It was
found that both 4-toluenesulfonyloxybutyraldehyde
[10] and 4-bromo-4-methylvaleraldehyde could
undergo this tandem reaction to produce 5,6,7,7a-
tetrahydro-pyrrolo[1,2-d][1.2.3.4]oxatriazoles 3a
and 3b, respectively. However, 5-toluenesulfonyloxy-
2-hexanone did not undergo this tandem reaction; it
just gave 5-azido-2-hexanone. Even if it were refluxed
in toluene, still no bicyclic product could be found.
All of the other bromo aldehydes and ketones did not
undergo this tandem reaction; they just gave nucle-
ophilic substitution products, azido aldehydes, and
ketones. The proposed mechanism for the formation
of compounds 3 is presented in Scheme 2.
Reaction of Bromo/Toluenesulfonyloxy
Aldehydes and Ketones with Sodium Azide
General Procedure. A mixture of bromo/tolue-
nesulfonyloxy aldehyde or ketone 1 (2.5 mmol) and
sodium azide (230 mg, 3.75 mmol) in DMF (5 ml)
was stirred in an oil bath at 50 C overnight. The re-
action mixture was diluted with ether/hexane (1:1,
25 ml), washed twice with water and twice with
brine, dried over Na2SO4, and concentrated. Flash
column chromatography on a silica gel column with
a mixture of petroleum ether (60–90 C)/ethyl ac-
etate (10:1) as the eluant gave colorless oils, azido
aldehyde (or ketone) 2, and/or 5,6,7,7a-tetrahydro-
pyrrolo[1,2-d][1.2.3.4]oxatriazole 3.
The proposed structures for unknown com-
pounds 3a,b are based on 1H NMR, 13C NMR, mass
spectral, and elemental analyses.
5,6,7,7a-Tetrahydro-pyrrolo[1,2-d][1.2.3.4]oxa-
1
triazole (3a): Colorless oil: H NMR : 4.92 (t, J =
In conclusion,
a nucleophilic substitution–
24.5 Hz, 1H, CH), 3.44 (t, J = 6.9 Hz, 2H, CH2), 2.03
(m, 2H, CH2), 1.84 (m, 2H, CH2). 13C NMR : 26.8,
32.9, 33.5, 100.4. MS/FAB m/z: 114 (MH+). Anal.
cycloaddition tandem reaction can take place be-
tween 4-bromo/toluenesulfonyloxy alkyl aldehydes
TABLE 1 Reaction of Bromo/ Toluenesulfonyloxy Aldehydes and Ketones with Sodium Azide
Entry
n
R1
R2
R3
X
Reaction Temperature ( C)
Yield of 2 (%)
Yield of 3 (%)
a
2
H
H
H
Br
0
RT
50
50
84
36
–
–
–
79
81
83
86
72
63
70
94
–
52
87
85
89
–
–
–
–
–
TsO
Br
Br
TsO
TsO
TsO
Br
Br
Cl
Br
b
c
d
e
f
g
h
i
2
2
2
3
4
1
0
0
0
H
Me
Me
H
H
H
H
Me
Ph
Me
H
H
H
H
H
H
H
H
Me
H
Me
H
H
H
H
H
H
50
RT to 110
RT to 110
RT to 110
RT to 110
RT to 110
RT to 110
RT to 110
RT to 110
–
–
–
j

Tandem Reaction of 4-Bromoalkyl Aldehydes with Sodium Azide 309
SCHEME 2 The proposed mechanism for the formation of compounds 3.
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Calcd. for C4H7N3O (113.06): C, 42.47; H, 6.24; N,
37.15. Found: C, 42.52; H, 6.30; N, 37.00.
5,6,7,7a-Tetrahydro-5,5-dimethyl-pyrrolo[1,2-d]-
1
[1.2.3.4]oxatriazole (3b): Colorless oil. H NMR
:
4.92 (t, J = 4.5 Hz, 1H, CH), 2.03 (m, 2H, CH2), 1.82
(m, 2H, CH2), 1.09 (s, 6H, 2Me). 13C NMR : 26.7,
30.2, 32.8, 33.4, 100.5. MS/FAB m/z: 142 (MH+).
Anal. Calcd. for C6H11N3O (141.17): C, 51.05; H,
7.85; N, 29.77. Found: C, 51.12; H, 7.79; N, 29.83.
[7] Bailey, J. H.; Cherry, D. T.; Crapnell, K. M.; Moloney,
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Leech, M.; Moloney, M. G.; Muller, M.; Prout, C. K. J
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Seoane, A.; Kwart, L. D.; Beal, C. J Am Chem Soc
1986, 108, 3755.
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