Hydrated nickel (II) halides mediated ring opening reaction with N-tosylaziridines

Article abstract of DOI:10.1016/j.cclet.2011.12.005

An efficient and water tolerant method for the synthesis of β-haloamines is described utilizing hydrated nickel (II) halides (NiX ₂·nH₂O X = Cl, Br, I) and aziridines as starting materials. N-Tosylaziridines reacted with NiCl₂

Full text of DOI:10.1016/j.cclet.2011.12.005

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 285–288
www.elsevier.com/locate/cclet
Hydrated nickel (II) halides mediated ring opening
reaction with N-tosylaziridines
*
Wan Xuan Zhang , Wei Gang Hu, Li Su, Li Qin Liu
Ministry of Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules,
Hubei University, Wuhan 430062, China
Received 9 October 2011
Available online 28 January 2012
Abstract
An efficient and water tolerant method for the synthesis of b-haloamines is described utilizing hydrated nickel (II) halides
(NiX2ÁnH2O X = Cl, Br, I) and aziridines as starting materials. N-Tosylaziridines reacted with NiCl2Á6H2O or NiI2Á6H2O giving b-
chloro- or b-iodoamines in high yields (73–99%) within a short time, but 10 mol% of n-Bu4NBr should be added in the reactions of
N-tosylaziridines with NiBr2Á3H2O in order to obtain the high yields of corresponding b-bromoamines. Solvent played an important
role in the reactions. The proper solvent for the reaction of NiCl2Á6H2O was DMF, while NiBr2Á3H2O or NiI2Á6H2O proceeded well
in 1,4-dioxane.
# 2011 Wan Xuan Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: N-Tosylaziridines; Hydrated nickel (II) halides; Ring opening reaction; b-Haloamines
Aziridines are important intermediates in organic synthesis because they can react with various nucleophiles
leading to highly regio- and stereoselective ring opened products. Methods have been documented for the cleavage of
aziridines with heteroatoms such as O, N, S, Se, and halogen [1–4]. Nucleophilic halogen addition to aziridines leads
to the formation of b-haloamines, which serve as important precursors for the synthesis of medicinally important
compounds [5,6]. Therefore, there is significant current interest in the halogen ring opening reactions of aziridines.
Reagents employed in the reaction of nucleophilic halogen ring opening to aziridines are mainly halides such as
hydrogen halides, metal halides, quaternary ammonium halides [1,2,7–9]. Almost all the halides reacted with
aziridines under strongly acidic condition; this limits their application in the reactions of aziridines bearing acid
sensitive functional groups. CeCl3Á7H2O could react with aziridines or catalyze the reaction of aziridines with NaI
affording b-chloro- or b-iodoamines under nearly neutral condition, but b-bromoamines was not obtained by the
protocol [10]. On the other hand, the reactions using some non-ionic compounds, such as Me3SiX (X = Cl, I) and
Ph3P/X2 (X = Cl, Br, I), as substrates suffered from harsh reaction conditions or high toxicity of halogen (X2) [11]. So
the development of a mild, convenient and general method is desired for the synthesis of b-haloamines. We here
describe a new approach using hydrated nickel (II) halides (NiX2ÁnH2O, X = Cl, Br, I), an inexpensive, non-toxic and
* Corresponding author.
E-mail address: zhangwx@hubu.edu.cn (W.X. Zhang).
1001-8417/$ – see front matter # 2011 Wan Xuan Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.12.005

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W.X. Zhang et al. / Chinese Chemical Letters 23 (2012) 285–288
2
1
1
2
2
1
3
R
R
R
R
R
R
R
.
NiX nH O
2
2
3
3
R
+
R
N
X
TsHN
NHTs
X
Ts
1
2
3
1
2
3
X = Cl, Br, I; R = alkyl, Ph; R , R = H, alkyl
Scheme 1. The ring opening reaction of aziridines with hydrated nickel (II) halides.
ready available salts as halogen sources for the reactions. The reactions smoothly proceeded under convenient
condition (Scheme 1).
The reactions were performed by heating the mixture of aziridine 1 and NiX2ÁnH2O (60 mol%) in a proper solvent,
but 10 mol% of n-Bu4NBr (TBAB) should be added as a catalyst in the reactions of NiBr2Á3H2O. Control experiments
were carried out for the discussion of reaction conditions.
The best yield of 2a [12] (99%; R1, R2 = –(CH2)4–; R3 = H, X = Cl) was obtained by heating the mixture of 7-
(toluene-4-sulfonyl)-7-azabicyclo[4.1.0]heptane 1a and NiCl2Á6H2O (60 mol%) at 70 8C within 15 min in DMF.
However, when 1,4-dioxane was used as a solvent in stead of DMF under above conditions, the reaction could not
occur. In the case of NiI2Á6H2O (60 mol%), the high yield of 2a (98%, X = I) was obtained in 1,4-dioxane (reflux, 3 h).
If DMF and 1,4-dioxane were used as solvents respectively in the reaction of NiBr2Á3H2O (60 mol%) with 1b
(R1 = Ph; R2 = H) in the absence of TBAB, the low total yields of 2b and 3b (DMF, 70 8C, 46%; 1,4-dioxane, reflux,
40%) were obtained, and two undetermined side-products were formed. However when 10 mol% of TBAB was added
to the reaction of 1b with NiBr2Á3H2O in 1,4-dioxane, a high yield (97%) of bromides 2b and 3b (R1 = Ph; R2, R3 = H,
X = Br) was obtained within 4 h. These results indicated that the proper reaction conditions were different depending
on various nickel (II) halides (Table 1).
Results for the reactions of aziridines (1a–1e) with nickel (II) halides under specified conditions as shown in Table 1
are summarized in Table 2. The aziridines (1a–1e) gave moderate to excellent yields (66–99%) of corresponding b-
haloamines. The regioselectivities of the reactions depended on the structure of aziridines and the type of halogen
anions. Cyclic aziridines 1a afforded trans-b-haloamines in high yields (96–99%; entries 1–3 in Table 2). Phenyl
aziridine 1b or trimethyl aziridine 1c reacted with these three nickel (II) halides (NiX2ÁnH2O, X = Cl, Br, I)
respectively leading to two isomers 2b (or 2c) and 3b (or 3c) (entries 4–9 in Table 2), while the isomer with a halogen
atom at secondary or tertiary carbon was the main product, as expected for a charge-controlled ring-opening process.
The reactions of terminal n-butyl aziridine 1d afforded two products 2d and 3d in the ratios of 93/7 (X = Cl), 75/25
(X = Br) and 90/10 (X = I) (entries 10–12 in Table 2); however, for the terminal n-hexadecyl aziridine 1e, one
regioisomer 2e incorporating the halogen atom at the less substituted carbon were obtained due to the increased steric
hindrance (entries 13–15 in Table 2).
In the eye of the nickel (II) halide, NiBr2Á3H2O/TBAB led to relatively low regioselectivities (entries 5, 8 and 11 in
Table 2) and took the longest time (4–12 h) among these three nickel (II) halides when they reacted with a same
aziridine respectively (entries 2, 5, 8, 11 and 14 in Table 2). The lowest yield (66%) also provided by the reaction of
NiBr2Á3H2O/TBAB with 1c, giving 2c and 3c (entry 8, Table 2), while 26% of 3-methyl-N-tosylbut-3-en-2-amine 4
(Fig. 1) was isolated as a side-product. It was indicated that the carbon cation such as 5 (Fig. 1) might be involved in the
reaction of 1c with NiBr2Á3H2O catalyzed by TBAB. These results reflect the differences between NiBr2Á3H2O and
NiCl2Á6H2O or NiI2Á6H2O.
In conclusion, aziridines could react with hydrated nickel (II) halides (NiX2ÁnH2O X = Cl, Br, I) leading to
corresponding b-haloamines in moderate to excellent yields and regioselectivities, which provided a new convenient
Table 1
The optimized reaction conditions of aziridines 1 with different nickel (II) halides.
Entry
Nickel (II) halide
Ratio of 1/NiX2ÁnH2O
Solvent
T (8C)
Catalyst
1
2
3
NiCl2Á6H2O
NiBr2Á3H2O
NiI2Á6H2O
1:0.6
1:0.6
1:0.6
DMF
70
–
1,4-dioxane
1,4-dioxane
Reflux
Reflux
10 mol% TBAB
–

W.X. Zhang et al. / Chinese Chemical Letters 23 (2012) 285–288
287
Table 2
The results of the reactions of aziridines with hydrated nickel (II) halides.
b
Entry
Aziridine
NiX2ÁnH2O
Product
Time
Yield (%)
Ref. c
1
2
3
NiCl2Á6H2O
NiBr2Á3H2O
NiI2Á6H2O
X = Cl
X = Br
X = I
35 min
4 h
99
96
98
[12]
[13]
[10]
NHTs
X
a
a
N
Ts
3 h
2a
1a
4
5
6
NiCl2Á6H2O
NiBr2Á3H2O
NiI2Á6H2O
X = Cl
X = Br
X = I
1.5 h
90(2b/3b = 23/77)
97(2b/3b = 32/68)
96(2b/3b ꢀ 5/95)
[13]
TsHN
NTs
4 h
3 h
[13,14]
[14]
2b
X
Ph
X
1b
NHTs
3b
Ph
7
8
9
NiCl2Á6H2O
NiBr2Á3H2O
NiI2Á6H2O
X = Cl
X = Br
X = I
2 h
12 h
1 h
85(2c/3c = 8/92)
66(2c/3c = 31/67)
73(2c/3c = 5/95)
[16]
[16]
[16]
TsHN
a
2c
3c
X
NTs
1c
X
NHTs
10
11
12
NiCl2Á6H2O
NiBr2Á3H2O
NiI2Á6H2O
X = Cl
X = Br
X = I
1 h
97(2d/3d = 93/7)
96(2d/3d = 75/25)
94(2d/3d = 90/10)
[15]
TsHN
TsN
a
4.5 h
[12,13]
[14]
X
2d
3d
1.5 h
X
1d
TsHN
13
14
15
NiCl2Á6H2O
NiBr2Á3H2O
NiI2Á6H2O
X = Cl
X = Br
X = I
1.5 h
9.5 h
99
99
84
[16]
[16]
[16]
NHTs
TsN
a
X
(CH2)15CH3
(CH2)15CH3
7 h
2e
1e
a
10 mol% of TBAB was added as catalyst.
Isolated yield. Ratios of the two regioisomers 2 and 3 were determined by 600 MHz 1H NMR.
The products were identified by comparison with the authentic sample or spectra.
b
c
NHTs
NHTs
4
5
Fig. 1. The structures of compound 4 and cation 5.
way to synthesize b-haloamines. n-Bu4NBr (TBAB) should be added as a catalyst in the reaction of aziridines with
NiBr2Á3H2O to obtain the high yields of corresponding b-bromoamines, while any catalysts were needless for
NiCl2Á6H2O and NiI2Á6H2O. The inexpensive, non-toxic, ready available and water tolerant inorganic salts might be
used as general reagents for the preparations of b-haloamines.
Acknowledgments
This research was financially supported by the National Natural Science Foundation of China (No. 20872031) and
Hubei Provincial Department of Education (No. T200701).
References
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[16] Spectral data of new compounds: [3c] (X = Cl, entry 7 in Table 2): 1H NMR (600 MHz, CDCl3): d 1.08 (d, 3H, J = 6.6 Hz), 1.52 (s, 3H), 1.53 (s,
3H), 2.43 (s, 3H), 3.35 (m, 1H), 4.62 (d, 1H, J = 9.0 Hz), 7.31 (d, 2H, J = 7.8 Hz), 7.76 (d, 2H, J = 7.8 Hz). Anal. Calcd. for C12H18ClNO2S: C
52.26, H 6.58, N 5.08. Found: C 52.23, H 6.55, N 5.07. 2c/3c (X = Br, entry 8 in Table 2): 1H NMR (600 MHz, CDCl3): d 1.10 (d, 3H,
J = 6.6 Hz, 3c), 1.29 (s, 3H, 2c), 1.32 (s, 3H, 2c), 1.66 (d, 3H, J = 6.6 Hz, 2c), 1.69 (s, 3H, 3d), 1.69 (s, 3H, 3c), 1.72 (s, 3H, 3c), 2.43 (s, 3H, 3c),
2.43 (s, 3H, 2c), 3.10 (m, 1H, 3c), 4.28 (m, 1H, 2c), 4.60 (d, 1H, J = 8.4 Hz, 3c), 4.92 (brs, 1H, 2c), 7.30 (d, 2H, J = 8.4 Hz, 2c), 7.31 (d, 2H,
J = 8.4 Hz, 3c), 7.76 (d, 2H, J = 8.4 Hz, 3c), 7.78 (d, 2H, J = 8.4 Hz, 3c); EI-MS m/z 319(M+, 1), 240(4), 198(100), 155(96), 91(95). Anal.
1
Calcd. for C12H18BrNO2S: C 45.01, H 5.67, N 4.37. Found: C 45.03, H 5.70, N 4.35. 3c (X = I, entry 9 in Table 2): H NMR (600 MHz,
CDCl3): d 1.10 (d, 3H, J = 6.6 Hz), 1.85 (s, 3H), 1.92 (s, 3H), 2.25 (m, 1H), 2.43 (s, 3H), 4.60 (d, 1H, J = 9.6 Hz), 7.31 (d, 2H, J = 7.8 Hz), 7.76
(d, 2H, J = 7.8 Hz). Anal. Calcd. for C12H18INO2S: C 39.25, H 4.94, N 3.81. Found: C 39. 26, H 4.96, N 3.83. 2e (X = Cl, entry 13 in Table 2):
1H NMR (600 MHz, CDCl3): d 0.88 (t, 3H, J = 6.6 Hz), 1.03–1.34 (m, 28H), 1.40–1.56 (m, 2H), 2.43 (s, 3H), 3.42–3.54 (m, 3H), 4.70 (d, 1H,
J = 7.8 Hz), 7.31 (t, 2H, J = 7.8 Hz), 7.77 (d, 2H, J = 7.8 Hz). EI-MS m/z 457 (M+, 1), 408 (58), 232 (37), 155 (100), 91 (88). Anal. Calcd. for
C25H44ClNO2S: C 65.54, H 9.68, N 3.06. Found: C 65.57; H, 9.69, N 3.07. 2e (X = Br, entry 14 in Table 2): 1H NMR (600 MHz, CDCl3): d 0.88
(t, 3H, J = 6.6 Hz), 1.03–1.32 (m, 28H), 1.41–1.56 (m, 2H), 2.43 (s, 3H), 3.30–3.36 (m, 1H), 3.37–3.43 (m, 2H), 4.69 (d, 1H, J = 8.4 Hz), 7.31
(t, 2H, J = 7.8 Hz), 7.77 (d, 2H, J = 7.8 Hz). Anal. Calcd. for C25H44BrNO2S: C 59.74, H 8.82, N 2.79. Found: C 59.77, H 8.83, N 2.79. 2e
(X = I, entry 15 in Table 2): 1H NMR (600 MHz, CDCl3): d 0.88 (t, 3H, J = 7.2 Hz), 1.00–1.34 (m, 28H), 1.35–1.48 (m, 2H), 2.43 (s, 3H), 2.93
(m, 1H), 3.14–3.25 (m, 2H), 4.61 (d, 1H, J = 8.4 Hz), 7.31 (t, 2H, J = 7.8 Hz), 7.77 (d, 2H, J = 7.8 Hz). Anal. Calcd. for C25H44INO2S: C 54.63,
H 8.07, N 2.55. Found: C 54.61, H 8.05, N 2.54. 4: 1H NMR (600 MHz, CDCl3): d 1.17 (d, 3H, J = 7.2 Hz), 1.56 (s, 3H), 2.42 (s, 3H), 3.84 (m,
1H), 4.44 (d, 1H, J = 7.2 Hz), 4.72 (s, 1H), 4.80 (s, 1H), 7.28 (d, 2H, J = 9.0 Hz), 7.74 (d, 2H, J = 8.4 Hz); EI-MS m/z 239 (M+, 1), 155 (8.1), 91
(21), 84 (100). Anal. Calcd. for C12H17NO2S: C 60.22, H 7.16, N 5.85. Found: C 60.23, H 7.19, N 5.86.