ZrCl 4-catalyzed synthesis of β-aminosulfides from aziridines and thiols

Article abstract of DOI:10.1080/00397911.2011.553698

A simple and efficient synthesis of-aminosulfides has been introduced by ring opening of aziridine rings with aromatic thiols in the presence of zirconium(IV) chloride under solvent-free conditions at room temperature.

Full text of DOI:10.1080/00397911.2011.553698

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ZrCl4-Catalyzed Synthesis of β-
Aminosulfides from Aziridines and Thiols
Barahman Movassagh a & Amir Rakhshani a
a Department of Chemistry , K. N. Toosi University of Technology ,
Tehran , Iran
Accepted author version posted online: 27 Oct 2011.Published
online: 26 Mar 2012.
To cite this article: Barahman Movassagh & Amir Rakhshani (2012) ZrCl4-Catalyzed Synthesis
of β-Aminosulfides from Aziridines and Thiols, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:14, 2121-2130, DOI:
10.1080/00397911.2011.553698
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Synthetic Communications1, 42: 2121–2130, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.553698
ZrCl4-CATALYZED SYNTHESIS OF b-AMINOSULFIDES
FROM AZIRIDINES AND THIOLS
Barahman Movassagh and Amir Rakhshani
Department of Chemistry, K. N. Toosi University of Technology,
Tehran, Iran
GRAPHICAL ABSTRACT
Abstract A simple and efficient synthesis of b-aminosulfides has been introduced by ring
opening of aziridine rings with aromatic thiols in the presence of zirconium(IV) chloride
under solvent-free conditions at room temperature.
Keywords b-Aminosulfides; aziridines; thiols; zirconium(IV) chloride
INTRODUCTION
Aziridines are versatile precursors for the synthesis of various nitrogen-
containing bioactive molecules, such as amino acids,[1] alkaloids,[2] heterocycles,[3]
aza sugars,[1b,4] and natural products.[1b] Because of their ring strain and high reac-
tivity, reactions of aziridines with various nucleophiles lead to highly regio- and
stereoselective ring-opened products. Therefore, there is significant current interest
in the ring-opening reactions of aziridines. In particular, the cleavage of aziridines
with thiols is interesting because the resultant b-aminosulfides are important building
blocks for the synthesis of many bioactive molecules.[5] These compounds have been
prepared previously by ring opening of aziridines with thiols, Lewis acids, bases, and
catalysts.[6] However, many of these procedures involve the use of strongly acidic or
basic conditions, harsh conditions, the use of stoichiometric amounts of catalysts,
and an excess amount of thiols and anhydrous conditions. Thus, the development
of an efficient and mild catalytic process for the synthesis of b-aminosulfides is in
demand.
Received November 19, 2010.
Address correspondence to Barahman Movassagh, Department of Chemistry, K. N. Toosi
University of Technology, P.O. Box 16315-1618, Tehran, Iran. E-mail: bmovass1178@yahoo.com
2121

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B. MOVASSAGH AND A. RAKHSHANI
Scheme 1. ZrCl4-catalyzed reaction of N-tosyl aziridine and thiophenol.
RESULTS AND DISCUSSION
Recently, zirconium(IV) chloride has been used as a safe, stable, inexpensive,
environmentally friendly, and efficient Lewis acid in many organic transforma-
tions.[7] Therefore, we investigated a simple, mild, and efficient method for ZrCl4-
catalyzed ring opening of N-substituted aziridines under solvent-free conditions.
To the best of our knowledge, this is the first report on the use of zirconium(IV)
chloride as a catalyst for the synthesis of b-aminosulfides.
Initially, a model reaction of N-tosyl aziridine 1a (1.0 mmol) and thiophenol
(1.2 mmol) in the presence of ZrCl4 under dry air and solvent-free conditions at room
temperature was planned (Scheme 1); various solvents such as PhCH3, CH2Cl2,
tetrahydrofuran (THF), CH3CN, and CHCl3 were also screened for this reaction.
The best results were observed under solvent-free conditions.
Furthermore, to study the catalyst loading in our model reaction, the procedure
was optimized using different molar concentrations of zirconium tetrachloride under
solvent-free conditions at room temperature (Table 1). A good yield of the product
was observed using 20 mol% of the catalyst. Increased concentration of the catalyst
did not improve the result to any greater extent. In one case (Table 1, entry 5), after
completion of the reaction, the catalyst was recovered by diluting the reaction mixture
with CH2Cl2 (6 mL) and reused in subsequent reactions; a gradual decrease in activity
was observed, affording 90% and 81% yields over two more cycles.
To probe the generality and scope of this method, a variety of N-tosyl aziri-
dines were treated with different thiols in the presence of 20 mol% of ZrCl4 under
solvent-free conditions at room temperature (Scheme 2). The reaction conditions
are mild, and no side products or decomposition of the products were observed.
The results are shown in Table 2. As can be seen from Table 2, while treatment of
aromatic thiols with various N-tosyl aziridines in general are fast (25–85 min) and
Table 1. Effect of catalyst loading on the model reaction of 1 and thiophenola
Entry
ZrCl4 (mol %)
Yield of 2a (%)
1
2
3
4
5
6
7
—
5
38b
35
39
51
95
92
90
10
15
20
25
30
aReaction conditions: 1 (1 mmol), thiophenol (1.2 mmol), reaction time 60 min, rt.
bReaction time ¼ 6 h.

SYNTHESIS OF b-AMINOSULFIDES
2123
Scheme 2. ZrCl4-promoted synthesis of b-aminosulfides.
give the corresponding b-aminosulfides in good to excellent yields, aliphatic thiols
give the corresponding products in trace amounts under the same conditions
(Table 2, entries 5 and 6). All the reactions with bicyclic aziridines (Table 2, entries
1–6) gave products with anti-stereochemistry, which were confirmed by the coupling
constants (J ¼ 9.9 Hz) of the two cyclic methine hydrogens at the trans positions
(d ¼ 3.01). The reactions of styrene- and 4-methylstyrene N-tosyl aziridines with
thiols were completely regioselective with the attack of thiols on the more hindered
(benzylic) position (Table 2, entries 7–13); this is due to stabilization of developing
positive charge at the benzylic position of aziridine. In the cleavage of N-tosyl-2-
alkyl aziridines (Table 2, entries 14–17), minor (4–8%) preferential cleavage at low
hindered (terminal) aziridine-ring carbon was observed. A proposed mechanism is
depicted in Scheme 3.
In conclusion, ZrCl4 is found to be a useful and efficient alternative to other
conventional Lewis acids for the ring-opening reactions of aziridines with aromatic
thiols, leading to the synthesis of b-aminosulfides in good to excellent yields. The
specific advantages of this methodology are that the reactions are performed under
mild and solvent-free conditions within short times. The lack of appreciable toxicity
[LD50 (ZrCl4, oral rat) ¼ 1688 mg ꢀ Kg
]
ꢁ1 [8] and low cost of ZrCl4 are consistent with
increasing environmental concerns.
EXPERIMENTAL
Chemicals were purchased from Merck. Preparative thin-layer chromato-
graphy (TLC) was used for purification of b-aminosulfides using silica gel
60 PF254 þ 366 coated on 20 ꢂ 20-cm glass plates. Melting points were recorded on a
Buchi B-540 apparatus and are uncorrected. Infrared (IR) spectra were recorded
on an ABB FTLA 2000 instrument. NMR spectra were recorded with either a
Bruker AQS-300 or Bruker DRX-500 spectrometer with nominal frequencies of
300 and 500 MHz for proton or 75 and 125 MHz for carbon, respectively, in CDCl3
using tetramethylsilane (TMS) as an internal standard.
Typical Procedure: Preparation of 2-(4-Methoxyphenylthio)-2-p-
tolyl-N-tosylethanamine (Table 2, Entry 13)
N-(p-Toluenesulfonyl)-2-p-tolyl aziridine (287 mg, 1.0 mmol) and 4-methoxy-
benzenethiol (168 mg, 1.2 mmol) were mixed together, and anhydrous ZrCl4
(47 mg, 20 mol%) was added. The solution was stirred at room temperature under
a dry air atmosphere for 40 min. After the completion of the reaction, monitored

2124

2125

2126

2127

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B. MOVASSAGH AND A. RAKHSHANI
Scheme 3. Plausible mechanism for the Zrcl4-catalyzed synthesis of b-aminosulfides.
by TLC, the reaction mixture was subjected to preparative TLC (silica gel, eluent
n-hexane=EtOAc ¼ 3:1) to obtain the pure product (412 mg, 96%) as colorless
1
crystals, mp 99–101 ꢃC; IR (KBr): nmax ¼ 3291, 3019, 2927, 1591, 1494 cm ꢁ1; H
NMR (300 MHz, CDCl3): d ¼ 2.32 (s, 3H), 2.45 (s, 3H), 3.33 (t, J ¼ 7.5 Hz, 2H),
3.79 (s, 3H), 3.92 (t, J ¼ 7.5 Hz, 1H), 4.74 (t, J ¼ 6.1 Hz, 1H), 6.73 (d, J ¼ 8.6 Hz,
2H), 6.93 (d, J ¼ 8.1 Hz, 2H), 7.06 (d, J ¼ 7.9 Hz, 2H), 7.14 (d, J ¼ 8.6 Hz, 2H),
7.27 (d, J ¼ 7.9 Hz, 2H), 7.63 (d, J ¼ 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d ¼ 21.1, 21.6, 46.7, 53.0, 55.3, 114.5, 122.9, 127.1, 127.7, 129.4, 135.2, 136.0,
136.9, 137.7, 143.5, 159.9.
Supplementary Data
2-(Phenylthio)-N-tosylcyclohexanamine (Table 2, Entry 1)
White crystals; mp 130–131 ꢃC; IR (KBr): nmax ¼ 3276 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.18–1.43 (m, 4H), 1.55–1.61 (m, 2H), 1.99–2.04 (m, 1H),
2.12–2.41 (m, 1H), 2.42 (s, 3H), 2.91–3.04 (m, 2H), 5.46 (d, J ¼ 4.4 Hz, 1H),
7.22–7.37 (m, 7H), 7.76 (d, J ¼ 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3): d ¼ 21.6,
23.2, 24.4, 31.5, 32.1, 51.2, 55.2, 127.3, 127.6, 128.9, 129.6, 129.7, 132.9, 137.3, 143.3.
2-Phenyl-2-(phenylthio)-N-tosylethanamine (Table 2, Entry 7)
1
Light yellow oil; IR (neat): nmax ¼ 3291 cmꢁ1; H NMR (300 MHz, CDCl3):
d ¼ 2.44 (s, 3H), 3.40 (t, J ¼ 7.6 Hz, 2H), 4.16 (t, J ¼ 7.6 Hz, 1H), 4.86 (t, J ¼ 6.7 Hz,
1H), 7.12-7.33 (m, 12H), 7.64 (d, J ¼ 9.8 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d ¼ 21.6, 47.1, 52.5, 127.1, 127.8, 127.9, 128.1, 128.9, 129.0, 129.8, 132.6, 133.1,
136.9, 138.3, 143.6.

SYNTHESIS OF b-AMINOSULFIDES
2129
2-(4-Chlorophenylthio)-2-phenyl-N-tosylethanamine (Table 2, Entry 8)
1
Light yellow oil; IR (neat): nmax ¼ 3291 cmꢁ1; H NMR (500 MHz, CDCl3):
d ¼ 2.47 (s, 3H), 3.39–3.44 (m, 2H), 4.17 (t, J ¼ 7.5 Hz, 1H), 4.71 (t, J ¼ 6.3 Hz,
1H), 7.15–7.33 (m, 11H), 7.67 (d, J ¼ 8.2 Hz, 2H).
2-(Phenylthio)-2-p-tolyl-N-tosylethanamine (Table 2, Entry 11)
Yellow oil; IR (neat): nmax ¼ 3289 cmꢁ1; 1H NMR (300 MHz, CDCl3): d ¼ 2.32
(s, 3H), 2.44 (s, 3H), 3.29–3.44 (m, 2H), 4.13 (t, J ¼ 7.7 Hz, 1H), 4.80 (t, J ¼ 6.3 Hz,
1H), 7.03 (d, J ¼ 8.2 Hz, 2H), 7.09 (d, J ¼ 8.2 Hz, 2H), 7.23–7.28 (m, 7H), 7.64 (d,
J ¼ 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) d: 21.1, 21.6, 47.2, 52.1, 127.1, 127.7,
127.8, 129.0, 129.6, 129.8, 132.4, 133.3, 135.1, 136.9, 137.9, 143.5.
2-(4-Chlorophenylthio)-2-p-tolyl-N-tosylethanamine (Table 2, Entry 12)
Yellow oil; IR (neat): nmax ¼ 3294 cmꢁ1; 1H NMR (300 MHz, CDCl3): d ¼ 2.31
(s, 3H), 2.40 (s, 3H), 3.27 (t, J ¼ 7.1 Hz, 2H), 4.09 (t, J ¼ 7.1 Hz, 1H), 4.58 (t,
J ¼ 7.1 Hz, 1H), 6.96–7.18 (m, 8H), 7.27 (d, J ¼ 8.2 Hz, 2H), 7.59 (d, J ¼ 8.2 Hz, 2H).
1-(4-Chlorophenylthio)-N-tosyloctan-2-amine (Table 2, Entry 15)
Yellow oil; IR (neat): nmax ¼ 3280 cmꢁ1; 1H NMR (300 MHz, CDCl3): d ¼ 0.80
(t, J ¼ 7.1 Hz, 3H), 1.12–1.33 (m, 8H), 1.37–1.62 (m, 2H), 2.43 (s, 3H), 2.61 (dd,
J ¼ 10.4, 7.0 Hz, 1H), 3.05 (dd, J ¼ 10.3, 4.2 Hz, 1H), 3.22–3.35 (m, 1H), 4.71 (d,
J ¼ 4.5 Hz, 1H), 7.13 (d, J ¼ 8.0 Hz, 2H), 7.26 (d, J ¼ 8.2 Hz, 2H), 7.39 (d, J ¼ 8.2 Hz,
2H), 7.68 (d, J ¼ 8.0 Hz, 2H); 13C NMR (75 MHz, CDCl3): d ¼ 14.3, 21.6, 22.7, 25.4,
28.6, 31.9, 33.6, 39.8, 52.8, 114.4, 122.8 127.0, 129.7, 132.3, 137.8, 144.4, 159.9.
ACKNOWLEDGMENT
We thank the K. N. Toosi University of Technology Research Council for
financial support of this work.
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