Cycloaddition of synthetic equivalent of nonstabilized aminonitrile ylides: A new route to amino-substituted aΔ2-imidazolines and Δ3-1,2,4-triazolines

Article abstract of DOI:10.3987/COM-00-9121

The N-unsubstituted nonstabilized azomethine ylides generated from the desilylation of N-[(trimethylsilyl)methyl]iminium triflates undergo successful cycloaddition to strongly polarized sulfonylimines and diethyl azodicarboxylate to produce the corresponding Δ²-imidazolines and Δ³-1,2,4-triazolines together with the initial cycloadducts. The initial cycloadducts are converted to the corresponding aminonitrile ylide cycloadducts. Thus the present process provides a new route to amino-substituted Δ²-imidazolines and Δ³-1,2,4-triazolines that are otherwise relatively inaccessible.

Full text of DOI:10.3987/COM-00-9121

HETEROCYCLES, Vol. 55, No. 2, 2001, pp. 243 - 248, Received, 24th November, 2000
CYCLOADDITION OF SYNTHETIC EQUIVALENT OF NON-
STABILIZED AMINONITRILE YLIDES: A NEW ROUTE TO
2
3
∆
∆
-1,2,4-TRI-
AMINO-SUBSTITUTED
AZOLINES
-IMIDAZOLINES AND
Otohiko Tsuge,* Taizo Hatta, Hideki Tashiro, and Hironori Maeda
Department of Applied Chemistry, Sojo University,
Ikeda, Kumamoto 860-0082, Japan
Abstract - The N-unsubstituted nonstabilized azomethine ylides generated from
the desilylation of N-[(trimethylsilyl)methyl]iminium triflates undergo successful
cycloaddition to strongly polarized sulfonylimines and diethyl azodicarboxylate to
2
3
produce the corresponding ∆ -imidazolines and ∆ -1,2,4-triazolines together with
the initial cycloadducts. The initial cycloadducts are converted to the corresponding
aminonitrile ylide cycloadducts. Thus the present process provides a new route to
2
3
amino-substituted ∆ -imidazolines and ∆ -1,2,4-triazolines that are otherwise
relatively inaccessible.
The 1,3-dipolar cycloaddition of azomethine ylides to dipolarophiles is an important method for the
1
2
construction of five-membered ring nitrogen heterocycles. We recently reported the generation of
nonstabilized N-unsubstituted azomethine ylides (A) from the desilylation of N-[(trimethylsilyl)methyl]-
iminium triflates (1) and their 1,3-dipolar cycloaddition reactions with electron-deficient alkenes, alkynes
and aldehydes in which 2-amino-substituted pyrrolines, pyrroles and 2-oxazolines are formed,
respectively: thus, A can be synthetic equivalents of nonstabilized aminonitrile ylides (B) that are otherwise
relatively inaccessible.
+
+
+
-
-
TMSCH2NH C NRR'
CH2N C NRR'
CH2N CNRR'
H
-
OTf
SMe
SMe
1
A
B
3
Nitrile ylides are also one of the interesting members of 1,3-dipole family. Although the cycloaddition of
aryl-substituted nitrile ylides ArC=NCHR has been widely studied, nitrile ylides without aromatic
4-6
substitution are rare. Particularly, the generation and cycloaddition of nonstabilized aminonitrile ylides
7
such as B are little known. Thus, in an effort to expand the synthetic utility of nonstabilized azomethine
ylides (A) that are synthetic equivalent of aminonitrile ylides (B), we have investigated on cycloaddition
reactions of A with 1,3-dipolarophiles other than electron-deficient alkenes, alkynes and aldehydes. The

present communication describes the cycloaddition of A to imines and azo compounds.
Cycloaddition Reactions with Imines. Although imines were first employed in cycloadditions with
8
azomethine ylides as early as 1963, there is only a limited number of reports concerning the imine
8,9
cycloadditions. Azomethine ylides generated through 3,4-dihydroisoqunolinium salts,
and
10,11
aziridines,
reacted with imines to give the corresponding imidazolidines. It would be no exaggeration
to say that most imine cycloadditions have been discovered unexpectedly during investigations on the
12
13
generation of azomethine ylides from imines. In recent years, it has been reported that the ester-
stabilized imidate ylide, derived from the condensation of ethyl acetimidate with dimethyl aminomalonate,
2
reacted with benzylidenealkylamines to give ∆ -imidazolines with the loss of ethanol; thus the imidate ylide
can be a synthetic equivalent of ester-stabilized nitrile ylide. To the best of our knowledge little has been
investigated on the reaction of nonstabilized azomethine ylides with imines.
On the other hand, cycloadditions of nitrile ylides to imines are also little employed as useful routes of
14-16
heterocyclic synthesis.
If the cycloaddition of azomethine ylides (A) generated from iminium salts (1) to imines occurs in the
2
similar manner to those with electron-deficient carbon-carbon multiple bonds and aldehydes, a novel and
general route to amino-substituted imidazolidines and/or imidazolines is offered through the cycloaddition
and elimination sequence. Unfortunately the imines such as arylidenealkylamines and -arylamines were
very sluggish to the azomethine ylides from 1. However, we have eventually found that the strongly
17
polarized sulfonylimines such as benzylidene- (2), p-chlorobenzylidene- (3) and p-nitrobenzylidene-p-
toluene-sulfonamide (4) are reactive to the intended cycloaddition reaction.
H
SMe
NRR'
Ts
N
N
NRR'
F -
SMe
+
and/or
1
Ar CH N Ts
Me N
N
N
NRR'
2 - 4
Ar
Ar
Ts
11
8 - 10
5 - 7
in toluene
100%
H
SMe
N
NRR'
2, 5, 8: Ar = Ph; 3, 6, 9: Ar = p-ClC6H4;
4, 7, 10: Ar = p-NO2C6H4
N
Ts
Ar
5'
a: R = H, R' = Ph; b: RR' = -(CH2)5-; c: RR' = -(CH2)2O(CH2)2-
Scheme 1
The reaction of anilino-substituted N-[(trimethylsilyl)methyl]iminium triflate (1a) with imine (2) in the
presence of cesium fluoride (CsF) at room temperature gave a single product, whose molecular formula
corresponded to that of initial cycloadducts, 2-anilino-2-methylthio- (5a) or 5-anilino-5-methylthio-4-
phenyl-3-tosyl-imidazolidine (5'a). On the basis of chemical shifts and splitting pattern of methine and
1
methylene protons of its imidazolidine ring in H NMR spectrum, however, the product was concluded to

be 5a.
Similar reactions of 1a with imines (3) and (4) afforded the corresponding initial cycloadducts, 2-anilino-
2-methylthio-substituted 4-(p-chlorophenyl)- (6a) and 4-(p-nitrophenyl)-3-tosylimidazolidine (7a),
2
although the aminonitrile cycloadduct, 2-anilino-5-(p-chlorophenyl)-1-tosyl-∆ -imidazoline (9a) was
18
formed as a by-product in the reaction with 3 (Scheme 1, Table 1). In the cycloaddition of azomethine
ylides (A) to carbon-carbon and carbon-oxygen multiple bonds the initial cycloadducts could not be
isolated, but instead the products that are one oxygen state higher than initial cycloadducts were directly
2
obtained. It is thus noteworthy that imidazolidines (5a, 6a and 7a) are the first example of stable initial
cycloadducts of A to multiple bonds. The initial cycloadducts (5a, 6a and 7a) were quantitatively
2
converted to the corresponding 2-anilino-4-aryl-1-tosyl-∆ -imidazolines (8a, 9a and 10a), when refluxed
in toluene.
a
Table 1. Cycloaddition Reaction with Imines (2 - 4)
b
c
Entry
Precursor
Imine
Molar ratio
Products (yield, %)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1c
1c
1c
2
3
4
3
3
4
3
4
4
1/1/1.2
1/1/1.2
1/1/1.2
1/1/1.2
1/2/1.2
1/1/1.2
1/1/1.2
1/1/1.2
1/2/1.2
5a (42), 11a (31)
6a (55), 9a (7)
7a (70)
9b (50), 11b (21)
9b (66)
10b (58)
9c (31), 11c (24)
10c (32), 11c (21)
10c (52)
a
The reactions were carried out in dry DME at room temperature for 6 h under
b
c
argon. Molar ratio of 1/imine/CsF. Isolated yield based on the precursor (1).
The reaction of N-[(trimethylsilyl)methyl]iminium triflates (1b) and (1c) bearing cyclic amine moiety with
more reactive imines (3) and (4) was next investigated under similar conditions, since the reactions with 2
were very sluggish. Some selected runs are listed in Table 1 (Entries 4-9). The azomethine ylides generated
from 1b and 1c were somewhat less reactive than that from 1a. In contrast with 1a, the corresponding
initial cycloadducts (6b, 6c or 7b, 7c) could not be isolated, but instead the formal aminonitrile ylide
cycloadducts (9b, 9c or 10b, 10c) were directly obtained, respectively.
In the reaction between rather inactive two reagents, imine (11) which was probably derived from the
19
azomethine ylide through a 1,2-proton migration was obtained as the by-product.
Cycloaddition Reaction with Diethyl Azodicarboxylate. Although only limited examples are
known, the electron-deficient nitrogen-nitrogen double bond of azodicarboxylates is also reactive to
20
21
azomethine ylides and nitrile ylides. Azomethine ylides generated through the aziridine, tautomerization

22
and decarboxylation routes are captured as the corresponding triazolidine cycloadducts. A variety of
23
5
nitrile ylides generated from the photolysis of 2H-azirines, and thermolysis of 2,3-dihydro-1,4,2λ -
24
3
oxazaphospholes have been found to react with diethyl azodicarboxylate to yield the corresponding ∆ -
1,2,4-triazolines. It has also been reported that azobenzene reacted with nitrilio hexafluoro-2-propanides to
3
25
yield the ∆ -1,2,4-triazolines.
The reaction of azomethine ylides generated from 1 was thus investigated with the electron-deficient
nitrogen-nitrogen double bond of diethyl azodicarboxylate (1 2). This reaction was particularly interesting,
since isolation of the initial cycloadducts, 1,2,4-triazolidines, might be expected in analogy with the
reaction of imines (2-4) described above.
The reaction of 1a with 1 2 in DME at room temperature gave the expected initial cycloadducts, 3-anilino-
1,2-bis(ethoxycarbonyl)-3-methylthio-1,2,4-triazolidines (13a) in good yields, but the same reaction in
refluxing DME afforded a mixture of 13a and the corresponding aminonitrile cycloadduct, 3-anilino-1,2-
3
bis(ethoxycarbonyl)-∆ -1,2,4-triazoline (14a). Similarly, 1b or 1c reacted with 1 2 to give the
3
corresponding initial cycloadduct (13b) or (13c) and/or ∆ -1,2,4-triazoline (14b) or (14c), whose
relative yields depended on the reaction temperature. Elimination of methanethiol from initial cycloadduct
(1 3) was more sluggish than that from the imine-initial cycloadducts. When heated in refluxing toluene for
3
8 h, however, the initial cycloadducts (1 3) were converted into the corresponding ∆ -1,2,4-triazolines
(1 4) in 57-75% yields, together with recovery of 1 3.
a
Table 2. Cycloaddition Reaction with Diethyl Azodicarboxylate (1 2)
H
SMe
N
N
NRR'
F -
1 +
and/or
E N N E
NRR'
N N
N N
12
E
E
E
E
14
13
in toluene
57-75%
E = COOEt
a: R = H, R' = Ph; b: RR' = -(CH2)5-; c: RR' = -(CH2)2O(CH2)2-
b
Entry
Precursor
Temp.
Products (yield, %)
1
2
3
4
5
6
1a
1a
1b
1b
1c
1c
rt
13a (73)
reflux
rt
13a (8), 14a (49)
13b (54)
reflux
rt
13b (20), 14b (31)
13c (74)
reflux
13c (51), 14c (19)
a
The reactions (molar ratio of 1/1 2/CsF=1/1/1.2) were carried
b
out in dry DME at room temperature or reflux for 8 h. Isolated
yield based on the precursor (1).

Hydrolysis of 14a-14c with 10% aqueous sodium hydroxide in refluxing ethanol for 1 h afforded the
1
corresponding amino-substituted 1,2,4-triazoles in good yields. On the basis of H NMR spectra in which
the proton at 5-position appeared as a singlet, the triazoles were assigned as 3-amino-2H-1,2,4-triazoles
(15a-15c), but not 1H isomers (1 5 ') (Scheme 2).
N
N
NaOH aq.
NRR'
NRR'
14
N NH
HN N
15a (78%)
15b (74%)
15c (79%)
15'
a: R = H, R' = Ph; b: RR' = -(CH2)5-; c: RR' = -(CH2)2O(CH2)2-
Scheme 2
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6a,6b
7. Recently, two research groups
reported that in the reactions of carbonyl compounds 2-azaallyl
anions generated through the desilylation of certain N-(silylmethyl)isothioureas served as synthetic
equivalents of aminonitrile ylides such as B.
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-1
example, 6a: colorless needles (CHCl ), mp 174-175 ˚C (decomp). IR 3412, 1584, 1334, 1162 cm ;
3
1
H NMR (DMSO-d ) δ 2.10, 2.33 (each s, 3H), 3.25-3.46 (m, 2H), 4.58 (dd, J = 6.8, 13.5 Hz,
6
1H), 6.42 (br s, 1H), 6.58-6.61 (m, 2H), 6.90-6.96 (m, 1H), 7.17-7.32 (m. 8H), 7.56-7.60 (m,
13
2H), 8.31 (d, J = 6.7 Hz, 1H); C NMR (DMSO-d ) δ 13.15, 20.86, 47.42, 55.76, 121.99, 126.40,
6
127.83, 128.41, 128.64, 129.32, 131.53, 137.70, 139.39, 142.41, 149.52, 152.58; MS m/z (relative
+
+
intensity) 475 (M , 0.5), 473 (M , 1), 427 (8), 425 (19), 272 (23), 270 (66), 152 (5), 150 (17), 133
(100). Anal. Calcd for C H N O ClS : C, 58.27; H, 5.10; N, 8.86. Found: C, 58.21; H, 5.11; N,
23 24 3 2
2
8.86. However, the stereochemisty of initial cycloadducts (5a, 6a and 7a) was not clear yet.
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2
obtained as the by-product.
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