Regioselective ring opening of aziridines with activated DMF complexes: A facile synthesis of β-haloamines

Article abstract of DOI:10.1016/j.tetlet.2004.10.161

A wide variety of aziridines were converted to the corresponding β-haloamines using activated DMF complexes in good to excellent yields with high regioselectivity.

Full text of DOI:10.1016/j.tetlet.2004.10.161

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9661–9663
Regioselective ring opening of aziridines with activated
DMF complexes: a facile synthesis of b-haloamines
Manoj K. Pandey, Alakesh Bisai and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 26 January 2004; revised 20 October 2004; accepted 28 October 2004
Abstract—A wide variety of aziridines were converted to the corresponding b-haloamines using activated DMF complexes in good
to excellent yields with high regioselectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
Table 1.
Aziridines are versatile intermediates for the synthesis of
nitrogen-containing biologically active compounds.1–3
NHTs
-10 °C - r.t.
Extensive studies have been carried out on opening of
aziridines with a variety of nucleophiles such as amines,4
alcohols,5 azides,6 Wittig reagents,7 and organometallic
reagents.8 Very few reports are known for the synthesis
of b-haloamines, which are versatile building blocks in
the field of organic and medicinal chemistry. In the liter-
ature, these have been synthesized via the amino halo-
genation of olefins9 and aziridine ring opening using
halides as nucleophiles.10 In continuation of our studies
in this area,5,11 we were interested in the synthesis of b-
haloamines from aziridines. At the outset, we envisaged
that an activated DMF complex should work well for
the proposed reaction based on mechanistic concepts
(vide infra). Various reagents such as POCl3, (COCl)2,
triphosgene, N3P3Cl6, SOCl2, SO2Cl2, cyanuric chloride,
(PhO)2POCl, Ph3PCl2, Ph3PBr2, PBr3 are known to acti-
vate DMF and all of them should give the required b-
haloamine compound. Although activated DMF com-
plexes are known for formylation, haloformylation, halo-
genation and ring annulation reactions,12 they have not
been used for the synthesis of b-haloamines. In this
letter, we describe our work on the synthesis of b-halo-
amines from aziridines using activated DMF complexes.
NTs
+
Reagents
X = Cl, Br
X
Entry Reagents
Products Time Isolated
(h)
yield (%)
1
POCl3/DMF
X = Cl
X = Cl
X = Cl
X = Cl
X = Cl
X = Cl
6
3
91
98
99
95
89
84
77
99
85
88
93
2
(COCl)2/DMF
Triphosgene/DMF
N3P3Cl6/DMF
SOCl2/DMF
3
2
4
12
6
5
6
SO2Cl2/DMF
6
7
Cyanuric chloride/DMF X = Cl
12
6
8
(PhO)2POCl/DMF
Ph3PCl2/DMF
3PBr2/DMF
X = Cl
X = Cl
X = Br
X = Br
9
6
10Ph
11
12
12
PBr3/DMF
reaction (time indicated in Table 1), the reaction mixture
was added to ice-cold water and extracted with ethyl
acetate. Work-up and purification by silica gel column
chromatography gave the desired b-haloamines in good
to excellent yields (Table 1). All the activated DMF
complexes gave ring-opened products in high yields.
The same experimental procedure was followed for all
other activated aziridines.
A solution of N-tosylcyclohexyl aziridine (1mmol) was
added to the freshly prepared activated DMF complex
(2mmol) at À10°C. The reaction mixture was gradually
warmed to room temperature. After completion of the
The ring cleavage reaction was extended to a variety of
cyclic and acyclic N-tosylaziridines using oxalyl chlo-
ride, triphosgene and phosphorous tribromide as the
activating agents in combination with DMF. The results
are summarized in Table 2. Cyclic N-tosylaziridines gave
quantitative yields of products (entries 1, 2 and 3). In the
*
Corresponding
vinodks@iitk.ac.in
author.
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+91
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597436; e-mail:
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doi:10.1016/j.tetlet.2004.10.161

9662
M. K. Pandey et al. / Tetrahedron Letters 45 (2004) 9661–9663
Table 2.
Entry
Substrate
Products
Isolated yield, % (time, h)
(COCl)2/DMF (X = Cl)
CO(OCCl3)2/DMF (X = Cl)
PBr3/DMF (X = Br)
NHTs
1
1a: 98 (3)
99 (2)
1b: 93 (12)
NTs
X
NHTs
2
3
2a: 91 (12)
3a: 87 (12)
95 (12)
98 (12)
2b: 93 (12)
3b: 92 (12)
NTs
NTs
X
NHTs
X
X
NTs
NHTs
4
5
6
7
4a: 95 (12)
5a: 84 (20)
6a: 86 (24)
7a: 97 (18)
70(12)
96 (20)
82 (24)
86 (18)
4b: 91 (8)
5b: 87 (12)
6b: 90(12)
7b: 97 (12)
X
NHTs
NTs
NHTs
NTs
NTs
X
X
3
7
3
NHTs
7
N
X
N
N
X
N
X
X
Workup
X
H
O
O
S
O
O
O
O
H
- HX
N
S
Ar
Ar
N
S
Ar
H
O
O
X
X
N
X
+ DMF
NHTs
NTs
Scheme 1.
case of phenyl substituted N-tosylaziridine (entry 4), we
obtained a single regioisomer due to internal attack at
the benzylic position. Acyclic terminal aziridines (entries
5, 6 and 7) gave the product resulting from terminal at-
tack at the less hindered position. In all cases, the reac-
tion was highly regioselective as only one product was
formed and the yields were good to excellent.
Acknowledgements
V.K.S. thanks DST for a research grant. A.B. thanks
CSIR for a junior research fellowship.
References and notes
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dron Lett. 2000, 41, 10079; (b) Wu, J.; Hou, X.-L.; Dai,
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In order to ascertain whether the activated DMF com-
plex is activating the aziridines or is only the source of
halide, we performed the ring cleavage reaction in the
presence of ionic nucleophiles (LiBr and NaCl)13 in
DMF at room temperature, but no trace of the desired
b-haloamine was obtained. This indicates that the acti-
vated DMF complex facilitates the cleavage reaction
by coordination with the aziridine. A possible reaction
mechanism is shown in Scheme 1.
In conclusion, we have demonstrated a very simple, effi-
cient and highly regioselective synthesis of b-haloamines
via the ring cleavage of N-tosylaziridines using various
activated DMF complexes in good to excellent yields.14

M. K. Pandey et al. / Tetrahedron Letters 45 (2004) 9661–9663
9663
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14. General procedure: In an oven dried round bottom flask,
the activated DMF complex (2mmol) was prepared by
adding the activating reagent (2mmol) in DMF (1mL) at
À10°C. To this solution of N-tosylaziridine (1mmol) in
DMF (0.5mL) was added at the same temperature and the
reaction mixture was allowed to warm to room tempera-
ture. After completion, the reaction mixture was added to
ice-cold water and extracted with ethyl acetate. Work-up
and purification by silica gel column chromatography gave
the corresponding b-haloamines in good to excellent yields.
Spectral data of N-(2-chlorocyclohexyl)-4-methylbenzene-
sulfonamide (Table 2, entry 1a):10 1H NMR (400MHz,
CDCl3): d 1.25–1.32 (m, 3H), 1.50–1.78 (m, 3H), 2.04–2.26
(m, 2H), 2.43 (s, 3H, CH3), 3.00–3.17 (m, 1H) 3.68–3.72 (m,
1H), 4.94 (d, 1H, NH), 7.31 (d, J = 8.1Hz, 2H), 7.78
(d, J = 8.1Hz, 2H); 13C NMR (100MHz, CHCl3): d 21.5,
23.4, 24.5, 32.6, 35.0, 58.8, 62.2, 127.3, 129.6, 137.1, 143.5.
12. Amaresh, R. R.; Perumal, P. T. Tetrahedron Lett. 1995,
36, 7287.