An efficient synthetic route to substituted tetrahydropyrimidines by Cu(OTf)2-mediated nucleophilic ring-opening followed by the [4+2] cycloaddition of N-tosylazetidines with nitriles

Article abstract of DOI:10.1016/j.tetlet.2008.12.035

A highly efficient strategy for Cu(OTf)₂-mediated S_N2 type nucleophilic ring-opening followed by the [4+2] cycloaddition reactions of a number of 2-aryl-N-tosylazetidines with nitriles to afford a variety of substituted tetrahydropyr

Full text of DOI:10.1016/j.tetlet.2008.12.035

Tetrahedron Letters 50 (2009) 1105–1109
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An efficient synthetic route to substituted tetrahydropyrimidines
by Cu(OTf)2-mediated nucleophilic ring-opening followed by the [4+2]
cycloaddition of N-tosylazetidines with nitriles
*
Manas K. Ghorai , Kalpataru Das, Amit Kumar
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient strategy for Cu(OTf)2-mediated SN2 type nucleophilic ring-opening followed by the
[4+2] cycloaddition reactions of a number of 2-aryl-N-tosylazetidines with nitriles to afford a variety
of substituted tetrahydropyrimidines in excellent yields is reported. The resulting tetrahydropyrimidines
could easily be transformed into synthetically important 1,3-diamines by acid-catalyzed hydrolysis. The
strategy has been extended to the synthesis of enantiomerically pure tetrahydropyrimidines from enan-
tiopure disubstituted azetidines. The reaction proceeds through an SN2 type mechanism as proposed by
us earlier.
Received 8 November 2008
Revised 2 December 2008
Accepted 4 December 2008
Available online 13 December 2008
Keywords:
Azetidine
[4+2] cycloaddition
Cu(OTf)2
Ó 2008 Elsevier Ltd. All rights reserved.
SN2
Tetrahydropyrimidine
1,3-Diamine
Small-ring aza-heterocycles are valuable building blocks in or-
ganic synthesis.1 Cycloaddition reactions of four-membered aza-
heterocycles with various dipolarophiles are of contemporary
interest due to the potential biological activities of the resulting
heterocycles.2 There are only a few successful reports for the cyclo-
addition of azetidines with different dipolarophiles employing
BF3ÁOEt2 and a Pd(II)complex as the catalysts.3 We recently re-
ported Zn(OTf)2-mediated cycloaddition of 2-aryl-N-tosylazeti-
asymmetric conjugate additions,9 asymmetric Mannich-type reac-
tions,10 oxidative couplings,11 asymmetric Friedel–Craft reac-
tions,12 and cycloaddition reactions.13 Moreover, Cu(OTf)2 can
easily be prepared by following a known method,7 and can be han-
dled in air for quick transfer. In continuation of our research activ-
ities in Lewis acid-mediated SN2 type ring-opening of small-ring
aza-heterocycles, we found Cu(OTf)2 an efficient LA for the [4+2]
cycloaddition reaction of N-tosylazetidine with nitriles.14 We
report, herein, Cu(OTf)2-mediated SN2 type nucleophilic ring-open-
ing followed by [4+2] cycloaddition reactions of a number of
2-aryl-N-tosylazetidines with nitriles to afford a variety of substi-
tuted tetrahydropyrimidines in excellent yields.
We initially examined the cycloaddition of 2-phenyl-N-tosylaz-
etidine 1 with acetonitrile as the solvent in the presence of
Cu(OTf)2. When 1 was treated with acetonitrile in the presence of
1.0 equiv of Cu(OTf)2 at 80 °C, the corresponding tetrahydropyrim-
idine 2 was obtained in excellent yield within 10 mins.15 The
progress of the reaction was comparatively slow when the reaction
was performed at lower temperatures, or by taking smaller
amounts of LA. Under optimal conditions,16 1 was reacted with var-
ious nitriles (Scheme 1) to give the corresponding tetrahydropyrim-
idines 2–5 in good to excellent yields (Table 1). The reaction was
studied with an equivalent amount of acetonitrile in DCM, THF,
CHCl3, and benzene as the solvent. In all these cases, azetidine 1
underwent a competitive ring-opening rearrangement to produce
allylamine 6 as a byproduct with a poor yield of cycloaddition
dines with
a variety of nitriles to synthesize substituted
tetrahydropyrimidines.4 However, the Zn(OTf)2-mediated reaction
was found to be sluggish especially with 2-aryl-N-tosylazetidines
having electron-withdrawing substituents in the aryl ring com-
pared to that of 2-phenyl-N-tosylazetidine. We have recently
found Cu(OTf)2 an efficient Lewis acid (LA) to effect the [4+2] cyclo-
addition of carbonyls with enantiopure 2-phenyl-N-tosylazetidine
to give non-racemic oxazinanes in moderate to high enantiomeric
excess.5 Based on the experimental results, we proposed an alter-
native SN2 type of mechanism for this transformation in contrast
to the earlier proposed mechanism involving a 1,4-dipole.3a–c Sim-
ilar results were obtained for the [3+2] cycloaddition of N-sulfony-
laziridines with nitriles6a and carbonyls.6b Cu(OTf)2 is an efficient
catalyst in the organic synthesis for effecting several transforma-
tions, for example, oxidations of alkyl radicals,7 aziridinations,8
* Corresponding author. Tel.: +91 512 2597518; fax: +91 512 2597436.
E-mail address: mkghorai@iitk.ac.in (M.K. Ghorai).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.035

1106
M. K. Ghorai et al. / Tetrahedron Letters 50 (2009) 1105–1109
SN2 pathway,5 the mechanism of the cycloaddition reaction with
R
nitriles was further investigated. Enantiomerically pure (S)-1 was
reacted with acetonitrile as the solvent in the presence of Cu(OTf)2
at rt for 1 h to produce non-racemic tetrahydropyrimidine 2 in 38–
40% ee with 10% isolated yield (95% brsm). When the reaction was
continued for 4 h, 2 was obtained in 23% ee with 60% isolated yield
indicating the decrease in ee of 2 with increasing time. These obser-
vations are in support of our earlier proposed mechanism for the
cycloaddition reaction as shown in Scheme 3. Cu(OTf)2 is coordi-
nated to the nitrogen atom of heterocycle 18 and generates a highly
reactive species 19. Subsequently, it undergoes a [4+2] cycloaddi-
tion reaction with the nitrile to provide non-racemic tetrahydro-
pyrimidine 22. We rationalized the reduced enantioselectivity of
2 due to the partial racemization of (S)-1 (through the interconver-
sion of 19 and 21) before the nucleophilic ring-opening step, as
shown in Scheme 3. Convincing evidence to support this mechanis-
tic proposal has been provided in our earlier work.18
The cycloaddition products were found to be very labile, and
gave hydrolyzed products 1,3-diamines under acidic conditions.
Various tetrahydropyrimidines on treatment with 1(N) HCl pro-
duced corresponding 1,3-diamines 23–26 in good yields (Table
3).19 1,3-diamines are useful intermediates in organic synthesis.20
Moreover, 1,3-diamines are important structural units present in
a number of peptidomimetic inhibitors of the HIV-1 protease, used
for the treatment of AIDS.21
RCN, Cu(OTf)2
80 oC
Ph
Ts
Ts
N
N
N
Ph
2-5
1
65 - 79%
R = CH3, Ph, CH2Ph, 4-EtC6H4
Scheme 1. Cu(OTf)2-mediated [4+2] cycloaddition of 2-aryl-N-tosylazetidine with
nitriles.
product 2 as shown in Scheme 2. The Cu(OTf)2-mediated rearrange-
ment of 2-aryl-N-tosylazetidine leading to allylamine has been de-
scribed in our earlier work.17
Further, to study the effect of the 2-aryl group on the Cu(OTf)2-
mediated [4+2] cycloaddition with nitriles, a number of azetidines
7–10 with different aryl groups were prepared following our re-
ported procedure4 and studied for a cycloaddition reaction with ni-
triles. Under optimal conditions, all azetidines underwent
a
smooth cycloaddition reaction with nitriles to give tetrahydropyr-
imidine derivatives 11–17. The results are shown in Table 2. When
2-(4-methoxyphenyl)-1-(phenylsulfonyl)azetidine 10 (Table 2, en-
try 7) was reacted with benzonitrile under the same conditions,
tetrahydropyrimidine derivative 17 was produced within 1 min
or even at rt within 10 min. In contrast, 2-(3-bromophenyl)-1-
tosylazetidine 9 (Table 2, entry 5) reacted with acetonitrile slowly
under the same conditions to provide tetrahydropyrimidine 15 in
63% yield along with the corresponding allylamine (15%).
The scope of the methodology was further extended for the
cycloaddition of enantiomerically pure cis-disubstituted azeti-
dines22 27a–b with acetonitrile to give highly substituted enantio-
pure tetrahydropyrimidines 28a–b and 29a–b in 80% combined
yield with 4,6-trans geometry (28a–b) as the major diastereomer
in both the cases (Scheme 4). The diastereomers 28 and 29 were
obtained in pure forms by simple column chromatography. The
Although we have demonstrated earlier that the LA-mediated
nucleophilic ring-opening of 2-phenyl-N-tosylazetidine follows an
Table 1
Cu(OTf)2-mediated [4+2] cycloaddition of 2-phenyl-N-tosylazetidine with different nitrilesa
Entry
Azetidine
Nitrile
Product (2–5)
Time (min)
10
Yieldb (%)
79 (95%)c
Ph
Ph
Ph
N
CH3
2
Ts
Ph
N
Ts
Ts
Ts
Ts
1
CH3CN
N
N
N
N
Ph
3
Ts
Ph
N
2
3
PhCN
10
10
10
72
68
65
N
Ph
N
Ph
Ph CH2CN
4-EtC6H4CN
4
Ts
Ts
Ph
N
N
5
Ph
4
-
4 EtC6H4
N
a
In all the cases nitrile was served as solvent.
b
c
Isolated yield after column chromatographic purification.
Yield was determined by 1H NMR analysis of the crude reaction mixture.
Ph
N
CH3
Ts
Ph
Ts
Cu(OTf)2
N
Ph
NHTs
+
+
CH3CN
N
DCM, reflux
2h
1
6
2
Scheme 2. Competitive ring-opening reaction of 2-phenyl-N-tosylazetidine with acetonitrile in DCM as a solvent.

M. K. Ghorai et al. / Tetrahedron Letters 50 (2009) 1105–1109
1107
Table 2
Cu(OTf)2-mediated [4+2] cycloaddition of 2-aryl-N-tosylazetidine with acetonitrile and benzonitrilea
R
RCN, Cu(OTf)2
80 oC
Ar
Ts
Ts
N
N
N
Ar
11-17
7-10
Entry
1
Azetidine (7–10)
Nitrile
Product (11–17)
Time (min)
30
Yieldb (%)
68
2-ClC6H4
2-ClC6H4
4-ClC6H4
4-ClC6H4
N
CH3
11
Ts
2ClC6H4
Ts
CH3CN
PhCN
N
N
N
N
N
N
7
N
N
N
N
N
Ph
12
Ts
2ClC6H4
Ts
Ts
2
3
4
5
6
20
62
72
70
63
70
55
N
7
CH3
13
Ts
4ClC6H4
N
8
CH3CN
PhCN
10
Ph
14
Ts
4ClC6H4
N
8
Ts
10
-
3 BrC6H4
CH3
15
Ts
3Br-C6H4
Ts
CH3CN
PhCN
180
20
N
9
-
3 BrC6H4
Ph
16
Ts
3Br-C6H4
Ts
N
N
N
N
9
-
4 MeOC6H4
Ph
4MeO-C6H4
Ts
7
PhCN
17
Ts
10c
N
10
a
In all the cases nitrile was served as solvent.
Isolated yield after column chromatographic purification.
Reaction was performed at rt.
b
c
R
C
R
C
N
N
Cu(OTf)2
R
Ar
Ts
Cu(OTf)2
Ts
Ar
Ts
N
Ts
*
Cu(OTf)2
N
N
*
N
N
Ar
Ar
18
19
20
22
RCN
Ph
N
Ts
21
Scheme 3. Proposed mechanism for the [4+2] cycloaddition of 2-aryl-N-tosylazetidine with nitriles.
diastereomeric ratio was determined by the isolated yields of both
the diastereomers (28 and 29) from column chromatography and
1H NMR of the crude reaction mixture. The relative stereochemis-
try of the chiral substituted tetrahydropyrimidines (28a and 29a)
was determined by NOE measurements. The relative stereochemis-
try of the starting azetidines 27a–b at C4 had been inverted in the
major cycloaddition products (28a–b), which clearly supports the
involvement of an SN2 type pathway during a cycloaddition
reaction.
In conclusion, we have demonstrated a novel Cu(OTf)2-medi-
ated [4+2] cycloaddition of 2-aryl-N-tosyl azetidines with nitriles
for a direct one-step synthesis of substituted tetrahydropyrimi-
dines. The cycloaddition reaction proceeds through an SN2 type
pathway as we proposed earlier. The strategy has been extended
for the synthesis of enantiomerically pure tetrahydropyrimidines.
Acid-catalyzed hydrolysis of tetrahydropyrimidines leads to the
formation of 1,3-diamines. Further synthetic and mechanistic
investigations are currently underway in our laboratory.

1108
M. K. Ghorai et al. / Tetrahedron Letters 50 (2009) 1105–1109
Table 3
Hydrolysis of tetrahydropyrimidines with 1 (N) HCl
O
Ar
N
R
1(N) HCl / THF
HN
R
N
rt
Ts
Ar
NHTs
Entry
1
Tetrahydropyrimidine
Time (h)
Product
Yielda (%)
75
Ph
N
CH3
2
Ts
NHCOCH3
NHTs
NHCOPh
NHTs
12
12
8
N
N
Ph
Ph
23
Ph
N
Ph
3
Ts
2
3
73
66
63
24
2-ClC6H4
4-ClC6H4
N
CH3
NHCOCH3
12
2-ClC6H4
NHTs
N
N
25
Ts
N
CH3
14
NHCOCH3
4
15
-
4 ClC6H4
NHTs
26
Ts
a
Isolated yield after column chromatographic purification.
Ph
+
N
R
CH3
Ts
Ph
N
R
CH3
Ts
Ph
Ts
R
Cu(OTf)2
N
N
N
+
CH3CN
80 °C, 30 min
27
28
29
a: (R = Et)
b: (R = n-Pr)
80% (28a : 29a 71 : 29)
80% (28b : 29b 69 : 31)
Scheme 4. Cycloaddition of 2,4-disubstituted-N-tosylazetidines with acetonitrile.
6. (a) Ghorai, M. K.; Ghosh, K.; Das, K. Tetrahedron Lett. 2006, 47, 5399–5403;
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Acknowledgments
M.K.G. is grateful to IIT-Kanpur and DST, India for financial sup-
port. K.D. and A.K. thank IIT-Kanpur and CSIR, India, respectively,
for research fellowships.
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References and notes
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14, 2006.; (b) Part of the work is included in the Ph.D. thesis of Kalpataru Das
(2007, IIT Kanpur, India).
15. After screening of several Lewis acids under optimized reaction conditions,
Cu(OTf)2 was found to be a better and more efficient catalyst to effect the
reaction.
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16. Representative experimental procedure:
A
mixture of 2-phenyl-N-
tosylazetidine 1 (0.35 mmol) and acetonitrile (1 mL) was added to anhyd
Cu(OTf)2 (0.35 mmol) under argon and heated at 80 °C for 10 mins. TLC indicated
complete consumption of the starting azetidine 1. Then the reaction mixture was
quenched with a saturated aq NaHCO3 solution (1 mL) and extracted with ethyl
acetate three times. The combined organic layers were washed with brine, dried
over anhyd Na2SO4, filtered, and the solvent was removed under vacuum. The
crude product was purified by flash column chromatography on deactivated
silica gel (deactivated with 1% NEt3) using ethyl acetate/petroleum ether to
provide the corresponding tetrahydropyrimidine 2. 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.
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M. K. Ghorai et al. / Tetrahedron Letters 50 (2009) 1105–1109
1109
19. Experimental procedure of the hydrolysis of 2-methyl-4-phenyl-1-tosyl-1,4,5,6-
tetrahydropyrimidine (2): 1 (N) solution of HCl (0.34 mmol) was added to a
solution of 2 (0.17 mmol) in THF (1 mL), and the mixture was stirred at rt
overnight. Later, a saturated aq NaHCO3 solution was added, and the aq layer
was extracted with ethyl acetate (3 Â 4.0 mL) and dried over anhyd Na2SO4.
The crude product was purified by flash column chromatography on silica gel
(230–400 mesh) using 60% ethyl acetate in petroleum ether to provide the
pure product 23. Characterization data of 23: 1H NMR (400 MHz, CDCl3) d 1.79–
1.97 (m, 2H), 1.89 (s, 3H), 2.33 (s, 3H), 2.71–2.79 (m, 1H), 3.01–3.09 (m, 1H),
4.91–4.97 (m, 1H), 5.81 (br s, 1H, NH), 6.02 (d, J = 7.8 Hz, 1H, NH), 7.11–7.26
(m, 7H), 7.66 (d, J = 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 21.4, 23.0, 36.0,
40.1, 51.0, 126.5, 127.0, 127.9, 128.9, 129.6, 137.3, 140.7, 143.2, 170.7; HRMS
(ES+) for C18H23N2O3S (M+H), calcd 347.1429; found 347.1427.
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22. For the synthesis of cis-disubstituted azetidines 27a–b: Ghorai, M. K.; Das, K.;
Kumar, A. Tetrahedron Lett. 2007, 48, 2471–2475.