A convenient synthetic route to 2-aryl-N-tosylazetidines and their ZnX2 (X = I, OTf) mediated regioselective nucleophilic ring opening reactions: synthesis of γ-iodoamines and tetrahydropyrimidines

Article abstract of DOI:10.1016/j.tetlet.2006.05.058

A general and convenient synthetic route to various 2-aryl-N-tosylazetidines has been described. Their ZnX₂ (X = I, OTf) mediated nucleophilic ring opening with halides and [4+2] cycloaddition reactions with various nitriles have been achieved

Full text of DOI:10.1016/j.tetlet.2006.05.058

Tetrahedron Letters 47 (2006) 5393–5397
A convenient synthetic route to 2-aryl-N-tosylazetidines and their
ZnX2 (X = I, OTf) mediated regioselective nucleophilic
ring opening reactions: synthesis of c-iodoamines and
tetrahydropyrimidines
Manas K. Ghorai,* Kalpataru Das, Amit Kumar and Animesh Das
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 19 March 2006; revised 8 May 2006; accepted 11 May 2006
Available online 12 June 2006
Abstract—A general and convenient synthetic route to various 2-aryl-N-tosylazetidines has been described. Their ZnX2 (X = I, OTf)
mediated nucleophilic ring opening with halides and [4+2] cycloaddition reactions with various nitriles have been achieved to afford
c-iodoamines and substituted tetrahydropyrimidines, respectively, in good to excellent yields. A mechanism for the cycloaddition
reaction is proposed.
Ó 2006 Elsevier Ltd. All rights reserved.
Synthetic organic chemistry has witnessed extensive re-
search activity in nucleophilic ring opening and ring
expansion reactions of N-activated aziridines1 over the
years. However, the similar chemistry of N-activated
azetidines has not been explored extensively probably
due to the lack of availability of easy methods for their
preparation. In the course of our studies on ZnX2
(X = Cl, Br, I) mediated regioselective ring opening
and [3+2] cycloaddition of N-tosylaziridine with nitr-
iles,2 we were attracted towards the regioselective nucleo-
philic ring opening of N-tosylazetidine with a variety of
nucleophiles. There are only a few reports on regioselec-
tive ring opening of azetidines3 and azetidinium ions4 in
the literature, and so far, there has been no report on
regioselective nucleophilic ring opening of N-tosylazet-
idine with halide ions to give c-haloamines. Such halo-
amines could be utilized as important precursors in
organic synthesis, for example, as alkylating agents for
the synthesis of antimalarial drugs.5 The synthesis of
six-membered nitrogen-containing heterocycles is of im-
mense research interest as these frameworks are found in
various natural products.6 Though azetidines are less
reactive in ring opening reactions due to their excep-
tional stability,7 N-tosylazetidines have been used as
1,4 masked dipoles for cycloaddition reactions,8 and
ring opening reactions with allylsilane9 to synthesize
N-heterocycles. Azetidines have been used for cyclo-
addition reactions with various dipolarophiles using a
Pd(II) complex as the catalyst.10 In spite of the broad
range of pharmacological and biological applications
of tetrahydropyrimidines,11 only a limited number of
methods are available for their direct synthesis via the
[4+2] cycloaddition reaction of azetidines with nitriles
employing BF3ÆOEt2 as the catalyst.12
In most of these cases the reaction suffers from several
disadvantages such as the use of a highly moisture
sensitive catalyst, poor yield, etc. Hence, it is desirable
to develop an easy and economically viable method
for the [4+2] cycloaddition of N-tosylazetidines with
nitriles.
Herein, we report the ZnX2 (X = I, OTf) mediated
nucleophilic ring opening of a number of 2-aryl-N-tosyl-
azetidines with halides and their [4+2] cycloaddition
reactions with various nitriles to produce c-iodoamines
and tetrahydropyrimidines, respectively. For our study
it was necessary to develop a general and convenient
method for the synthesis of 2-aryl-N-tosylazetidines.
Although a few procedures exist for the syntheses of
N-tosylazetidines,12a,13 those methods are not suitable
because of poor yields and formation of undesired
Keywords: 2-Aryl-N-tosylazetidine; [4+2] Cycloaddition; ZnX2 (X = I,
OTf); c-Iodoamines; Tetrahydropyrimidine.
*
Corresponding author. Tel.: +91 512 2597518; fax: +91 512
2597436; e-mail: mkghorai@iitk.ac.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.058

5394
M. K. Ghorai et al. / Tetrahedron Letters 47 (2006) 5393–5397
Ts
Ar
R
O
NH
O
RCN, Zn(OTf)2
Ts
Ar
Ts
i
R1
R1
N
N
N
O
O
80 ºC
Ar
1
R
1 = tBu, Et
3
6
ii
61 - 76%
Ts
Ar
Ar Ts
iii
NH
N
Scheme 3. Zn(OTf)2 mediated [4+2] cycloaddition of 2-aryl-N-tosyl-
azetidines 3a–c with nitriles.
OH
2
3
Ar = a: Ph; b: 2-ClC6H4; c: 4-ClC6H4; d: 3-BrC6H4; e: 4-MeOC6H4
Our study began with the nucleophilic ring opening
reaction of 2-phenyl-N-tosylazetidine 3a in the presence
of Zn(II) halides in DCM at room temperature. How-
ever, ZnCl2 or ZnBr2 gave a very complex mixture as
Scheme 1. Synthesis of various 2-aryl-N-tosylazetidines from tert-
butyl acetate and aryl-N-tosylaldimines. Reagents and conditions: (i)
LDA/THF, À78 °C, 1 h, Ar–CH@N–Ts, THF, À78 °C, 2 h, 100% (1);
(ii) LAH, THF, 0 °C–rt, 1 h, 100% (2); (iii) TsCl/KOH, THF, reflux,
30 min, 92–98% (3).
1
indicated by the H NMR spectrum of the crude reac-
tion mixture. Compound 3a, when subjected to our
reaction conditions15 employing ZnI2 as the halogen
source gave ring opened product 4a as the only product
in good yield. In order to generalize this approach, a
number of N-tosylazetidines 3b–d were studied and all
of them underwent regioselective ring opening with
ZnI2 to produce c-iodoamines16 4b–d smoothly; the
other possible regioisomers 5 (Scheme 2) were not been
observed. The results of the ring opening studies are
listed in Table 1. The azetidines are activated towards
nucleophilic ring opening by iodide ions when the nitro-
gen atom of the ring is coordinated to ZnI2. Regioselec-
tivity in all these cases probably arises due to
preferential intramolecular nucleophilic attack of the
iodide ion at the benzylic position as it is more electro-
philic in nature compared to the less substituted
position.
products. We also introduce in this report an easy meth-
od for the syntheses of various 2-aryl-N-tosylazetidines
using an imino aldol reaction14 as the key step.
We synthesized a variety of 2-aryl-N-tosylazetidines
(3a–e) using simple chemistry from easily available start-
ing materials in almost quantitative yields (Scheme 1).
Ester enolates were generated from tert-butyl acetate
upon treatment with one equivalent of LDA in THF
at À78 °C and were reacted with an N-tosylarylaldimine
to afford substituted N-tosyl-b-aminoesters 1 in quanti-
tative yields (Scheme 1). When ethyl acetate was used as
the enolate source, lower yields of 1 (65–70%) were
observed. N-Tosyl-b-aminoesters 1 were reduced to the
corresponding c-amino alcohols 2 by treatment with
LAH. Subsequently, compounds 2 were easily converted
to 2-aryl-N-tosylazetidines 3a–e in excellent yields by
treatment with TsCl/KOH in THF at reflux for 30 min.
Similar to our earlier report on ZnX2 mediated ring
opening reaction of aziridines2 in acetonitrile as a sol-
vent, when 2-phenyl-N-tosylazetidine 3a was treated
with ZnX2 (X = Cl, Br, I) at reflux in acetonitrile, a
[4+2] cycloaddition reaction was observed to furnish
substituted tetrahydropyrimidine 6a, however, the reac-
tion was found to be very slow. To overcome this prob-
lem we performed the same reaction in the presence of
1 equiv of Zn(OTf)2, and obtained 6a rapidly and in
excellent yield (Scheme 3, Table 2). It was found that
the use of 1 equiv of catalyst and a nitrile as the solvent
were necessary for completion of the reaction. The pro-
ZnI2, DCM
rt
Ar
Ts
Ar
I
Ar
NHTs
N
+
NHTs
I
3
4
5
Ar = a: Ph; b: 2-ClC6H4; c: 4-ClC6H4; d: 3-BrC6H4
Scheme 2. Regioselective ring opening of 2-aryl-N-tosylazetidines 3a–d
with ZnI2.
Table 1. Regioselective ring opening of 2-aryl-N-tosylazetidines 3a–d with ZnI2
Entry
1
Azetidine 3
Product 4
Time (h)
1.5
Yielda (%)
74
Ph
NHTs
Ph
Ts
N
I
2-ClC6H4
NHTs
NHTs
NHTs
2-ClC6H4
4-ClC6H4
3-BrC6H4
Ts
Ts
Ts
2
3
4
14
2
72
N
N
N
I
I
I
4-ClC6H4
3-BrC6H4
67 (84)b
62
12
a Isolated yield after column chromatographic purification.
b Yield was determined by 1H NMR analysis of the crude reaction mixture.

M. K. Ghorai et al. / Tetrahedron Letters 47 (2006) 5393–5397
5395
Table 2. Zn(OTf)2 mediated [4+2] cycloaddition of 2-aryl-N-tosylazetidines 3a–c with nitrilesa
Entry
Azetidine 3
Nitrile
Product 6
Time
1.5 h
Yieldb (%)
76 (90%)c
Ts
N
Ph
Ts
Ts
N
N
1
CH3CN
N
6a
Ph
Ts
N
Ph
2
PhCN
1 h
72
Ph
N
6b
Ph
Ts
N
Ph
Ph
Ts
Ts
3
4
5
6
7
PhCH2CN
4-EtC6H4CN
CH3CN
20 min
20 min
18 h
65
62
67
61
71
N
N
PhH2C
N
Ph
6c
Ts
N
4 EtC6H4
N
Ph
6d
Ts
N
N
N
2 ClC6H4
2 ClC6H4
4 ClC6H4
Ts
Ts
Ts
N
N
N
2 ClC6H4
2 ClC6H4
4 ClC6H4
N
6e
Ts
PhCN
18 h
N
Ph
Ts
6f
CH3CN
3 h
N
6g
Ts
Ph
N
4 ClC6H4
Ts
8
PhCN
2.5 h
69
N
4 ClC6H4
N
6h
a In all the cases the nitrile served as the solvent.
b Isolated yield after column chromatographic purification.
c Yield was determined by 1H NMR analysis of the crude reaction mixture.
gress of the reaction was comparatively slow when the
reaction was performed at room temperature or when
using 0.3–0.5 equiv of catalyst. We also studied the reac-
tion with 1 equiv of acetonitrile in DCM, THF, CHCl3
and benzene, in all cases 3a gave a poor yield of 6a.
When the reaction of 3a–c with different nitriles was car-
ried out under optimal conditions,17 tetrahydropyrimi-
dines 6a–c were obtained in good yields and the results
are summarized in Table 2.
cause the intermediate 7 (Scheme 4) is more stabilized
in an arylnitrile solvent compared to acetonitrile.
To investigate the mechanism of the cycloaddition reac-
tion we carried out the reaction with chiral (R)-2-phenyl-
1-(toluene-4-sulfonyl)-azetidine 3a. When this substrate
was reacted with acetonitrile as solvent non-racemic tet-
rahydropyrimidine 6a (R = Me) was obtained. From
this observation we have proposed a mechanism for the
cycloaddition reaction as shown in Scheme 4 where
Zn(OTf)2 is coordinated to the nitrogen atom of the het-
erocycle 3a and activates the ring generating a highly
reactive species 7. Subsequently, it undergoes a [4+2]
cycloaddition reaction with the nitrile to provide non-
racemic tetrahydropyrimidine 6a. We have proposed a
similar mechanism for the [3+2] cycloaddition of N-tosyl-
aziridine with nitriles using ZnBr2 as the Lewis acid.2
Interestingly, the ring opening and cycloaddition reac-
tions were found to be very dependent on the substituent
pattern of the azetidine ring. 2-(2-Chlorophenyl)-1-tosyl-
azetidine 3b (entries 5 and 6, Table 2) reacted very
slowly with different nitriles compared to 3a or 3c (en-
tries 1–4, 7 and 8, Table 2). Typically, arylnitriles reacted
faster with azetidines than acetonitrile presumably be-
R
C
R
Zn(OTf)2
R
N
C
N
Ar
Ts
Ts
Ts
N
Ar
Ts
Zn(OTf)2
N
N
N
N
Zn(OTf)2
Ar
Ar
7
8
3
6
Scheme 4. Proposed mechanism for the [4+2] cycloaddition of 2-aryl-N-tosylazetidines with nitriles in the presence of Zn(OTf)2.

5396
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In conclusion, we have developed a general and conve-
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using simple reagents and conditions in excellent over-
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ZnX2 (X = I, OTf) mediated nucleophilic ring opening
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Acknowledgements
M.K.G. is grateful to IIT-Kanpur and DST, India for
financial support. K.D. and A.K. thank IIT-Kanpur
and CSIR, India, respectively, for research fellowships.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.05.058.
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15. General procedure for the regioselective ring opening of
N-tosylazetidines with ZnI2: A solution of 2-phenyl-N-
tosylazetidine (0.174 mmol) in DCM (1.0 ml) was added to
anhydrous ZnI2 (0.348 mmol) under argon and stirred for
the appropriate amount of time at rt until complete
consumption of the substrate (monitored by TLC). The
reaction mixture was quenched with saturated aq NH4Cl
solution (1.0 ml) and extracted with DCM three times.
The organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and the solvent was removed
under vacuum. The crude product was purified by column
chromatography on silica gel (using ethyl acetate/petro-
leum ether eluent) to provide the corresponding c-
iodoamines. All products were characterized by 1H
NMR, 13C NMR and mass spectral analysis.
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2.14 (m, 1H), 2.33–2.42 (m, 1H), 2.36 (s, 3H), 2.90–3.04
(m, 2H), 4.46 (t, J = 6.36 Hz, 1H, NH), 5.05 (dd, J = 6.36,
8.8 Hz, 1H), 7.16–7.25 (m, 7H), 7.65 (d, J = 8.32 Hz, 2H);
13C NMR (100 MHz, CDCl3): d 21.5, 29.4, 40.8, 42.9,
127.0, 127.1, 128.2, 128.8, 129.8, 136.5, 142.9, 143.6; ESI
mass: m/z 416 (M++1).
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M. K. Ghorai et al. / Tetrahedron Letters 47 (2006) 5393–5397
5397
17. The procedure described in Ref. 15 was followed except,
(a) the nitrile was used as the solvent instead of DCM,
(b) Zn(OTf)2 was used as the Lewis acid. The crude
product was purified by flash column chromatography
using ethyl acetate/petroleum ether as eluent to provide
the tetrahydropyrimidines. All products were character-
Spectral data of 6a12a (R = CH3) 1H NMR (400 MHz,
CDCl3): d 1.65–1.74 (m, 1H), 2.06–2.13 (m, 1H), 2.35 (d,
J = 1.48 Hz, 3H), 2.38 (s, 3H), 3.65–3.78 (m, 2H), 4.40
(m, 1H), 7.07–7.29 (m, 7H), 7.66 (d, J = 8.28 Hz, 2H).
13C NMR (100 MHz, CDCl3): d 21.5, 25.2, 30.2, 44.0,
57.4, 126.4, 126.8, 126.9, 128.4, 130.0, 137.1, 143.1, 144.4,
149.2; FAB mass: m/z 329 (M++1).
1
ized by H NMR, 13C NMR, and mass spectral analysis.
The tetrahydropyrimidines isolated were sensitive to
moisture and may give hydrolyzed products. In cases
where higher boiling nitriles were used, a modified
purification method was followed. The reaction mixture
was directly charged on a deactivated basic alumina
column followed by washing with petroleum ether to
remove and recover excess nitriles. Pure compounds
were obtained using ethyl acetate/petroleum ether as
eluent.
Spectral data of 6b12a (R = Ph) 1H NMR (400 MHz,
CDCl3): d 1.56–1.61 (m, 1H), 2.03–2.08 (m, 1H), 2.35 (s,
3H), 3.70–3.76 (m, 1H), 3.84–3.90 (m, 1H), 4.39 (dd,
J = 5.12 Hz, 9.04, 1H), 7.06 (d, J = 6.84 Hz, 2H), 7.13–
7.36 (m, 8H), 7.45 (d, J = 8.32 Hz, 2H), 7.50 (d,
J = 7.08 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 21.5,
31.3, 44.1, 58.6, 126.5, 126.8, 127.4, 127.6 128.3, 128.6,
129.6, 129.8, 136.4, 137.7, 142.9, 144.3, 152.9; FAB mass:
m/z 391 (M++1).