Effect of iminic nitrogen substituents on [4+2] versus [3+2] cycloaddition pathways in reactions of nitrosoalkenes with simple acyclic imines: An experimental and theoretical investigation

Article abstract of DOI:10.1016/j.tetlet.2005.08.142

The results of experimental and theoretical investigations on the mechanism of competitive [3+2] versus [4+2] cycloaddition reactions of simple acyclic imines with nitrosoalkenes are reported. The effect of substituents on the iminic nitrogen in influencing the cycloaddition pathways has been meticulously explored.

Full text of DOI:10.1016/j.tetlet.2005.08.142

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8253–8256
Effect of iminic nitrogen substituents on [4+2] versus
[3+2] cycloaddition pathways in reactions of nitrosoalkenes
with simple acyclic imines: an experimental and
theoretical investigation
Alka Marwaha,a P. V. Bharatamb and M. P. Mahajana,*
aDepartment of Applied Chemistry, Guru Nanak Dev University, Amritsar 143 005, Punjab, India
bDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER),
Phase X, S.A.S. Nagar, Mohali 160 062, India
Received 13 April 2005;revised 5 August 2005;accepted 23 August 2005
Available online 10 October 2005
Abstract—The results of experimental and theoretical investigations on the mechanism of competitive [3+2] versus [4+2] cyclo-
addition reactions of simple acyclic imines with nitrosoalkenes are reported. The effect of substituents on the iminic nitrogen in
influencing the cycloaddition pathways has been meticulously explored.
ꢀ 2005 Elsevier Ltd. All rights reserved.
a-Nitrosoalkenes are widely known as 4p components in
cycloaddition reactions with a variety of polarized
and unpolarized alkenes,1a–c allenes,1d dienes,1e enam-
ines1f–h and enol ethers1i either via a concerted or a step-
wise process involving a zwitterionic intermediate.
Recently, the formation of an unusual [3+2] cycload-
duct has also been observed in the reactions of a-nitro-
sostyrenes with a carbon–carbon double bond attached
to a pyrimidinone ring.2 In contrast, there are fewer
reports of such reactions with substrates having carbon–
nitrogen double bonds.3 Mackay and co-workers
reported an unusual [3+2] cycloaddition of a-nitroso-
alkenes with the carbon–nitrogen double bond of
oxazines and failed to observe any reaction with various
other cyclic and acyclic models bearing a carbon–nitro-
gen double bond.3 Since such a cycloaddition mode
could not be generalized, it was concluded that the core
requirements for such reactions to take place are: (i) an
oxazine oxygen and (ii) an allene or alkene function
allylic to this oxygen in a rigid bicyclic system.
Subsequent reports from our laboratories have shown
a generalized and unusual [3+2] cycloaddition mode
with the carbon–nitrogen double bond of polarized
1,3-diazabuta-1,3-dienes resulting in a useful access to
synthetically and biologically significant heterocyclic
N-oxides.4 Further, the predominance of the products
from such cycloadditions was explained on the basis of
the preferred conformations of the nitrosoalkenes, in
turn governed by the electronic nature of the substitu-
ents present on them.3
Recent reports by Tahdi and co-workers5 regarding the
role of substituents present on nitrosoalkenes in control-
ling their conformational preferences and in turn the
nature of products formed via [3+2] and [4+2] cycload-
dition pathways are not generalized.6 In view of these
contradictions and bearing in mind that the conforma-
tional preferences of 1,3-diazabuta-1,3-dienes play a pivo-
tal role in determining the mode of cycloaddition
followed in their reactions with ketenes,6 it was felt that
the nature of substituents on the iminic nitrogen of sim-
ple imines might be crucial in influencing the pathways
followed and hence the distribution of the products
formed in these reactions. Accordingly, the present com-
munication describes experimental and theoretical inves-
tigations to examine the influence of substituents on
iminic nitrogen on the mode of cycloadditions in the
Keywords: SchiffÕs bases;Nitrosoalkenes;Nitrones;Oxazines;Guassian
94W.
*
Corresponding author. Tel.: +91 183-2258802-09x3320;fax: +91 183
2258819/20;e-mail: mahajanmohinderp@yahoo.co.in
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.142

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A. Marwaha et al. / Tetrahedron Letters 46 (2005) 8253–8256
reactions of various N-alkyl/aryl-substituted imines
(SchiffÕs bases) with nitrosoalkenes.
product 3a, for example, analyzed for C21H23N3O3,
exhibited an intense M-16 peak (m/z = 349) diagnostic
of a nitrone,3a while the mass spectrum of 4a exhibited
a molecular ion peak at m/z = 365 for C21H23N3O3. In
The acyclic aryl and alkyl imines 1 derived from conden-
sation of alkyl/aryl amines and aldehydes reacted with
nitrosoalkenes 2, generated in situ from a-bromo oximes
and sodium bicarbonate, in methylene chloride to give
either nitrones 3 or a mixture of nitrones 3 and oxazines
4 in good yields (70–80%).7 The reactions of N-aryl imi-
nes led to the exclusive formation of cyclic nitrones 3.
There was no evidence for the formation of oxazine 4
as co-product with 3, even when the crude products were
examined by high-resolution 1H NMR spectroscopy.
However, the reactions of N-alkyl imines with a-nitro-
soalkenes resulted in the competitive formation of both
[3+2] and [4+2] adducts, the latter being formed in high-
er proportions ꢀ60:40 (Scheme 1).
1
the H NMR of 3a, the methylene protons exhibited
two doublets of doublets at d 3.98 (J = 14.7 and
3.6 Hz, Ha) and 4.62 (J = 14.7 and 4.2 Hz, Hb) corre-
sponding to a CH2 of a nitrone, downfield from the
position d 3.62 typical of oxazines 4a. A doublet of
doublets (J = 3.6 and 4.2 Hz, Hc) corresponding to the
CH of nitrone 3a appeared at d 5.72, while that for
oxazine 4a appeared as a singlet at d 6.00. The 13C
NMR spectra were also in agreement with the nitrone
and oxazine structures assigned above to 3a and 4a.
The nitrones 3 and oxazines 4 are formed in competition
and are not in equilibrium, these were separately shown
to be stable to the reaction conditions, though rear-
rangements of oxazines to nitrones9 and nitrones to oxa-
zines10 are well documented in the literature. The
complete absence of oxazines in the reactions of aryl
imines with nitrosoalkenes bearing an electron-with-
drawing nitro group again contradicts the earlier pro-
posal that the electronic nature of the substituents on
nitrosoalkenes controls the preferred conformation of
nitrosoalkenes and in turn, the nature of the products
in the title reactions.3a
The products 3a and 4a were characterized as 1-cyclo-
hexyl-4-(4-nitrophenyl)-2-phenyl-2,5-dihydro-1H-imid-
azole-3-oxide and 5-cyclohexyl-3-(4-nitrophenyl)-6-
phenyl-5,6-dihydro-4H-[1,2,5]oxadiazine on the basis
of analytical and spectral data.8 The mass spectrum of
R
Hc
Ha
N
Hb
R1
R=aryl
Ph
N
Ph
H
H
H
O
dry DCM
R.T./stir
+
A plausible mechanism for the formation of nitrones
and oxazines is illustrated in Scheme 2. The addition
of nitrosoalkene to a C@N bond is less likely to proceed
via a concerted single step as reported earlier.1,11 The
reaction appears to lead unusually to the resonance-sta-
bilized zwitterionic intermediates 5A and 6A, which are
formed from the transoid and cisoid conformations of
the nitrosoalkenes. These two intermediates 5A and 6A
are interconvertible into other intermediates 5B and
6B, respectively. However, interconversion between the
zwitterionic intermediates 5 and 6 does not seem to be
credible as suggested earlier,11,3,4 since this requires rota-
tion around a C@N–O bond, which becomes stronger
after nucleophilic attack, that is changes from a partial
double bond in the nitrosoalkene to a typical double
R1
N
3
N
R
R
N
Ha
Hb
O
R
N
R=alkyl Hc
Ha
Ph
Hc
O
2
1
b
+
H
Ph
N
N
R1
R1
O
3
4
f. R = phenyl, R1 =-C6H5
g. R = cyclohexyl, R1 = -C6H4-CH3(p)
a. R = cyclohexyl; R1 = -C6H4-NO2(p)
b. R = benzyl,
R1 = -C6H4-NO2(p)
R1 = -C6H4-NO2(p)
h. R = benzyl,
i. R = phenyl,
R1 = -C6H4-CH3(p)
R1 =-C6H4-CH3(p)
c. R = phenyl,
d. R = cyclohexyl; R1 =-C6H5
e. R = benzyl;
R1 =-C6H5
Scheme 1.
H
Ph
R
R
C
H
N
N
H
N
Ph
R
Ph
N
N
N
R1
R1
R1
O
R= Aryl
path I
O
O
3
H
H
5A
5B
H
Ph
+
ON
R1
N
H
Ph
H
Ph
C
R
R=Alkyl
C
N
N
1
2
R
+
R
O
R1
N
N
R1
O
6A
5A
R
N
R
R
N
R
H
Ph
H
N
H
N
H
Ph
Ph
Ph
O
O
N
N
N
4
R1
N
R1
R1
O
R1
O
5B
3
6B
Scheme 2.

A. Marwaha et al. / Tetrahedron Letters 46 (2005) 8253–8256
8255
bond in the zwitterionic intermediate. Finally, the inter-
30
28.6
27.6
mediates 5B and 6B cyclize to form the nitrones 3 and
oxazines 4, respectively. It seems that formation of the
intermediate 6A is discouraged in the case of aryl substi-
tuted imines because of the steric repulsions between the
oxygen lone pairs and the p electron cloud on the aryl
substituent. In the case of alkyl substituted imine;the
formation of intermediates 5A as well as 6A is possible
because of the reduced steric repulsion between the alkyl
group and the nitrogen or oxygen of the nitrosoalkenes.
The above mechanistic rationale is in agreement with the
formation of both [4+2] and [3+2] cycloadducts in the
case of alkyl imines and exclusively the [3+2] adduct
in the case of aryl imines.
15
17.6
0
0
I
II
IV
-15
-30
-45
-20.2
-21.1
The experimental observations and the mechanistic
rationale proposed above is further supported by theo-
retical studies performed at semi-empirical AM1 and
ab initio12 HF/6-31G* levels of computational analysis
implemented in the Gaussian series of programs.13
Gilchrist1a have proposed a concerted [4+2] cycloaddi-
tion mechanism for the formation of the six-membered
ring. However, all attempts to locate a transition state
for such a concerted process between H2C@NH and
H2C@CH–N@O at AM1 and HF/6-31+G* levels led
invariably to the zwitterionic intermediate. Complete
optimizations carried out at HF/6-31+G* theory level
on the reaction path involving H2C@NMe and the cis-
and trans-conformers of H2C@CH–N@O showed that
the initial nucleophilic attack occurs in such a way so
as to form intermediates having the geometry as shown
in I and II, respectively (Fig. 1). The intermediates I and
II were found to be 17.6 and 27.6 kcal/mol higher in en-
ergy than the corresponding starting materials, respec-
tively. The resultant final products are stable by À37.6
and À20.2 kcal/mol as compared to the starting materi-
als (Fig. 2) indicating that the formation of a six-mem-
bered ring, in the subsequent ring closure step, is more
favourable from kinetic as well as thermodynamic
aspects.
-37.6
Zwitterionic intermediates
Figure 2. Potential energy surface showing the relative energy of
zwitterionic intermediates on the reaction path between nitrosoalkene
and imine. The path involving intermediate I leads to the formation of
an oxazine, the path involving intermediates II and IV leads to the
formation of nitrones. The path involving III, which should have led to
an oxazine, could not be traced due to the instability of intermediate
III on the PE surface.
that the formation of a zwitterionic intermediate is fea-
sible for the s-trans arrangement of nitrosoethylene.
However, such an intermediate could not be located
for the s-cis arrangement. This may be due to the repul-
sive interactions operating between the approaching
phenyl (p-electrons) and oxygen (non-bonding elec-
trons) during the initial nucleophilic attack. Due to these
repulsive forces, the formation of the corresponding
zwitterionic intermediate is avoided. However, in the
case of an s-trans arrangement of nitrosoethylene, the
formation of intermediate IV is conceivable after a twist
in the C–C–N–C angle, probably because of the
decreased repulsive interactions. The relative energies
of the intermediate IV and the nitrone are 28.6 and
À21.1 kcal/mol with respect to the corresponding start-
ing materials. Thus, the presence of a phenyl group on
nitrogen does not allow the formation of zwitterionic
intermediate 6, thereby justifying the absence of the
six-membered oxazine in the reactions of imines bearing
aryl substituents. This rationale is further substantiated
by the formation of nitrones and oxazines in the reac-
tions of 1b with nitrosoalkenes 2, where the above
referred electronic repulsions and steric interactions
are supposedly decreased, the phenyl ring being one
carbon away from the nitrogen of the imine due to the
insertion of a methylene group.
Further, HF/6-31+G* calculations for the reaction path
involving H2C@N–Ph and H2C@CH–N@O indicated
O
N
N
O
Me
Me
II
I
O
Solvent effects, not taken into account here, might also
change the chemoselectivity of the reaction. However,
the solvent used experimentally is dichloromethane,
which is a non-polar solvent and hence would not have
any influence on the activation energies.
N
N
O
III
IV
In conclusion, iminic nitrogen substituents have been
found to play a crucial role in influencing the cycloaddi-
tion path followed in the reactions of various alkyl/aryl
Figure 1. Schematic representation of the conformations of the
intermediates on the reaction path between nitrosoalkenes and imines.

8256
A. Marwaha et al. / Tetrahedron Letters 46 (2005) 8253–8256
filtrates were washed with water, dried over Na2SO4 and
concentrated under reduced pressure. The nitrones 3 and
oxazines 4 were isolated and purified with the help of
column chromatography on 60–120-mesh silica gel. The
nitrones and oxazines were recrystallized from benzene–
hexane (2:1) and EtOAc–hexane (1:5), respectively.
% Yields: 3a: 34%; 4a: 51%; 3b: 36%; 4b: 54%; 3c: 79%; 3d:
35%; 4d: 53%; 3e: 37%; 4e: 55%; 3f: 82%; 3g: 32%; 4g: 48%;
3h: 30%; 4h: 50%; 3i: 80%.
substituted imines with a-nitrosoalkenes. These cycload-
dition reactions offer a practical access to a diversity of
functional and synthetically flexible nitrogen-containing
molecular assemblies (cyclic nitrones14 and oxazines).
References and notes
8. (a) 1-Cyclohexyl-4-(4-nitrophenyl)-2-phenyl-2,5-dihydro-
1H-imidazole 3-oxide 3a: mp 115–117 ꢁC;yield: 34%; 1H
NMR (200 MHz, CDCl3, Me4Si): d 1.18–1.95 (m, 10H,
cyclohexyl);2.65–2.66 (m, 1H, –CH–, cyclohexyl);3.98
(dd, J = 14.7 and 3.6 Hz, 1H, Ha, –CH2–);4.62 (dd,
J = 14.7 and 4.2 Hz, 1H, Hb, –CH2–);5.72 (dd, J = 3.6
and 4.2 Hz, 1H, Hc, methine);7.43–7.61 (m, 5H, ArH);
8.27 (d, J = 8 Hz, 2H, ArH);8.42 (d, J = 8 Hz, 2H, ArH).
13C NMR (50 MHz, CDCl3, Me4Si): 25.4;25.7;25.8;31.1;
31.5;38.9;53.2 (–CH 2);89.2 (–CH);120.2;123.6;127.3;
1. (a) Gilchrist, T. L. Chem. Soc. Rev. 1983, 12, 53;(b)
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127.8;128.1;129.7;129.9;134.3;151.2;MS:
m/z = 365
+
(M+);349 (M À16). Anal. Calcd for C21H23O3N3
requires: C, 69.02;H, 6.34;N, 11.50. Found: C, 69.78;
H, 6.22;N, 11.26.;(b) 5-Cyclohexyl-3-(4-nitrophenyl)-5,6-
dihydro-4H-[1,2,5]-oxadiazine 4a: mp 168–169 ꢁC;yield:
51%. 1H NMR (200 MHz, CDCl3, Me4Si): d 1.21–2.05 (m,
10H, cyclohexyl);2.85–2.87 (m, 1H, –CH–, cyclohexyl);
3.62 (s, 2H, –CH2–, oxazine);6.00 (s, 1H, –CH–, methine);
7.30–7.57 (m, 5H, ArH);7.73 (d, J = 8 Hz, 2H, ArH);8.19
(d, J = 8 Hz, 2H, ArH). 13C NMR (50 MHz, CDCl3,
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Me4Si): 25.5;25.6;25.7;31.1;31.4;38.9;61.1 (–CH
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7. General procedure for the preparation of nitrones and
oxazines: A solution of SchiffÕs base 1 (4 mmol) and a-
bromooxime 2 (4.2 mmol) in dry CH2Cl2 was stirred at
room temperature in the presence of anhydrous sodium
bicarbonate (6 mmol) for 24–25 h. The deposited salt and
the excess sodium bicarbonate were filtered off and washed
with small portions (2 · 10 ml) of CH2Cl2. The combined