Cycloaddition of new N-unsubstituted azomethine ylides generated from N-(trimethylsilylmethyl)thioureas to electron-deficient olefins, acetylenes and aldehydes, synthetic equivalents of nonstabilized aminonitrile ylides

Article abstract of DOI:10.1016/S0040-4020(00)00688-8

The S-methylation of N-(trimethylsilylmethyl)thioureas and the subsequent desilylation of the silylmethyl group generates N-unsubstituted azomethine ylides having both methylthio and amino groups at the ylide carbon. These azomethine ylides undergo succes

Full text of DOI:10.1016/S0040-4020(00)00688-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7723±7735
Cycloaddition of New N-Unsubstituted Azomethine Ylides
Generated from N-(Trimethylsilylmethyl)thioureas to
Electron-De®cient Ole®ns, Acetylenes and Aldehydes, Synthetic
Equivalents of Nonstabilized Aminonitrile Ylides1
a
a
a
a
Otohiko Tsuge,a, Taizo Hatta, Hideki Tashiro, Yoshikazu Kakura, Hironori Maeda and
*
Akikazu Kakehib
aDepartment of Applied Chemistry, Sojo University, Ikeda, Kumamoto 860-0082, Japan
bDepartment of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Wakasato, Nagano 380-8553, Japan
Received 10 July 2000; accepted 4 August 2000
AbstractÐThe S-methylation of N-(trimethylsilylmethyl)thioureas and the subsequent desilylation of the silylmethyl group generates
N-unsubstituted azomethine ylides having both methylthio and amino groups at the ylide carbon. These azomethine ylides undergo
successful cycloaddition to electron-de®cient ole®ns, acetylenes and aldehydes. As the methylthio group is eliminated under the reaction
conditions to produce the corresponding pyrrolines, pyrroles and 2-oxazolines bearing the amino group at 2-position, these azomethine ylides
can be synthetic equivalents of nonstabilized aminonitrile ylides that are otherwise relatively inaccessible. q 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
cycloaddition products which are one oxidation state higher
than those expected from simple azomethine ylides.
The importance of 1,3-dipoles such as azomethine ylides in
organic synthesis has grown rapidly by the development of
mild and versatile methods for the generation.2 A particu-
larly mild method for the generation of nonstabilized
azomethine ylides involves the desilylation, usually under
the in¯uence of ¯uoride, of N-(silylmethyl)iminium salts.3
The resultant azomethine ylides can be trapped with
electron-de®cient ole®ns and acetylenes to give a variety
of pyrrolidines, pyrrolines, and pyrroles.
The present research is aiming at opening a new and general
route to N-unsubstituted azomethine ylides A carrying
alkylthio and amino moieties, both of which serve as a
leaving group, at the ylide carbon and also aiming at
establishing their utility as synthetic equivalents of non-
stabilized nitrile ylides. Our approach to azomethine ylides
A consists of initial S-alkylation of N-(trimethylsilyl-
methyl)thioureas leading to N-(trimethylsilylmethyl)iminium
salts, and subsequent desilylation with ¯uoride. Elimination
of the leaving alkylthio group or amino group from the
cycloadducts of azomethine ylides A gives formal cyclo-
adducts of nonstabilized aminonitrile ylides B9 or alkylthio-
nitrile ones C10, whose generation is little known heretofore,
respectively. The most important step in this sequence is
regioselective alkylation at the sulfur atom, not at the
thiourea nitrogen.
Water-induced desilylation of N-(trimethylsilylmethyl)-
imines,4,5 or thioimidates,6 and ¯uoride-mediated desilylation
after the in situ S- or N0-alkylation of N-(trimethylsilyl-
methyl)thioamides7 or amidines,7,8 are synthetically valuable
since they can lead to novel 1,3-dipoles, N-unsubstituted
azomethine ylides. It should be emphasized that the
N-unsubstituted azomethine ylides carrying a leaving group
such as alkylthio6,7 or amino moiety7,8 at the ylide carbon can
be synthetic equivalents of nonstabilized nitrile ylides. This is
important because such azomethine ylides directly afford
N-(Trimethylsilylmethyl)thioureas were chosen as starting
compounds, and cycloadditions of the resulting ylides to
electron-de®cient ole®ns, acetylenes, and aldehydes are
described.
Keywords: azomethine ylides; 1,3-dipolar cycloadditions; nonstabilized
aminonitrile ylide.
* Corresponding author. Tel.: 196-326-3111-2126; fax: 196-326-3000;
e-mail: hatta@chem.sojo-u.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00688-8

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O. Tsuge et al. / Tetrahedron 56 (2000) 7723±7735
Results and Discussion
Preparation of N-(trimethylsilylmethyl)thioureas and
their S-methylation
The reaction of (trimethylsilyl)methyl isothiocyanate (1)11
with aniline or cyclic secondary amines such as pyrrolidine,
piperidine and morpholine in benzene under re¯ux furn-
ished the corresponding N-(trimethylsilylmethyl)thioureas
2a±2d in excellent yields. The next step is selective S-alkyl-
ation of thioureas 2 leading to N-(trimethylsilylmethyl)-
iminium salts. In analogy with N-(trimethylsilyl-
methyl)thioamides,7 the selective S-methylation of 2 with
methyl tri¯ate proceeded smoothly to give the correspond-
ing N-(trimethylsilylmethyl)iminium tri¯ates 3a±3d as
precursors of azomethine ylides A (Scheme 1).
Scheme 1.
Generation of N-unsubstituted azomethine ylides and
their cycloaddition to maleimides
Although 2-azaallyl anions9 generated from certain N-(silyl-
methyl)isothioureas can be viewed as synthetic equivalents
of aminonitrile ylides, little has been investigated on their
reactions with electron-de®cient ole®ns, except for the reac-
tion with dimethyl fumarate in which a Michael adduct was
formed but not formal [312] cycloadduct.9a Thus, genera-
tion of N-unsubstituted azomethine ylides A by desilylation
of precursors 3 and subsequent cycloaddition to N-methyl-
maleimide (4) as an electron-de®cient ole®n were ®rst
investigated (Scheme 2). The reaction of N-(trimethylsilyl-
methyl)iminium tri¯ate 3a with 4 was examined in the
presence of cesium ¯uoride (CsF) under a variety of condi-
tions, some of which are listed in Table 1 (entries 1±3,9,10).
In all cases the initial cycloadduct D (RˆMe, R1ˆH,
R2ˆPh) could not be isolated, but instead methanethiol
Scheme 2.
Table 1. Cycloaddition with maleimides 4, 8 and 12 (The reactions were carried out in dry solvent at room temperature (entries 1-3, 9,10, 17-23) or at re¯ux
(entries 4-8, 11-16) for 10 h under nitrogen or argon.)
Entry
Precursor
Maleimide
Solventa
Molar ratiob
Product: yield/%
1
2
3
4
5
6
7
8
3a
3a
3a
3b
3c
3c
3c
3d
3a
3a
3b
3b
3c
3c
3d
3d
3a
3d
3d
3a
3c
3d
3d
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
8
8
8
12
12
12
12
DME
AN
THF
DME
DME
AN
1/1/1
5a (83)
5a (75)
5a (74)
5b (24), 6 (2)
5c (51), 6 (26)
5c (39), 6 (41)
5c (45), 6 (27)
5d (49), 6 (7)
5a (90)
5a (90)
5b (41), 6 (60), 7b (14)
6 (52), 7b (48)
5c (45), 6 (65), 7c (17)
6 (30), 7c (60)
5d (32), 6 (49), 7d (17)
6 (43), 7d (51)
9a (59), 10 (23)
9d (41), 10 (23), 11d (6)
9d (8), 11d (38)
13a 1 14a (70)c, 15 (26)
13a 1 14a (58)c, 15 (36)
13c 1 14c (62)c, 15 (34)
13d 1 14d (54)c, 15 (37)
1/1/1.2
1/1/1.2
1/1/1
1/1/1
1/1/1
THF
1/1/1
1/1/1
DME
DME
THF
9
1/2/1.2
1/2/1.2
1/2/1.2
1/2.5/1.2
1/2/1.2
1/2.5/1.2
1/2/1.2
1/2.5/1.2
1/1/1
1/1/1.2
1/2/1.3
1/1/1.3
1/1/1.3
1/1/1.3
1/2/1.3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
a DME: 1,2-dimethoxyethane; AN: acetonitrile; THF: tetrahydrofuran.
b Molar ratio of 3/maleimide/CsF.
c In all cases the ratio 13/14 was determined to be ca. 2.3/1 by 1H NMR.

O. Tsuge et al. / Tetrahedron 56 (2000) 7723±7735
7725
Figure 1.
was eliminated from D and formal aminonitrile ylide
cycloadduct 5a was obtained in good yield.
The reaction of N-(trimethylsilylmethyl)iminium tri¯ates
3b±3d bearing cyclic amine moiety with an equivalent of
4 in the presence of CsF was next investigated (entries 4±8).
In contrast with 3a, the corresponding aminonitrile ylide
cycloadduct 5b±5d (hereinafter abbreviated as 1:1 adduct)
was formed in low to moderate yield, together with
N-methyl-2-methylthiosuccinimide (6) whose structure
corresponds to the Michael adduct of eliminated
methanethiol to the unreacted 4. The formation of 6 indi-
cates that the reactivity of azomethine ylides generated from
3b±3d toward 4 is lower than that of the ylide from 3a and
elimination of methanethiol occurs rapidly as soon as initial
cycloadducts D (RˆMe) are formed.12 Thus, the reactions
of 3b±3d with excess 4 were investigated. In contrast to the
reaction of 3a giving a high yield of 5a as the sole product
(entries 9, 10), interestingly, the reactions of 3b±3d gave a
Scheme 3.
Table 2. Cycloaddition with acyclic ole®ns 16±19
Entry
Precursor
Ole®n
Molar ratioa
Temp.
Time/h
Product: Yield/%
1
2
3
4
5
6
7
8
3a
3c
3c
3d
3a
3c
3d
3a
3b
3c
3d
3a
3c
3d
3a
3a
16
16
16
16
17
17
17
18
18
18
18
18
18
18
19
19
1/1/1
1/1/1
1/1/1
1/1/1
1/1/1
1/1/1
1/1/1
1/1/1
1/1/1
1/1/1
1/1/1
1/1/2
1/1/2
1/1/2
1/1/1.2
1/5/1.2
r.t.
r.t.
re¯ux
re¯ux
r.t.
re¯ux
re¯ux
r.t.
r.t.
r.t.
20
20
10
10
20
10
10
10
10
10
10
10
10
10
5
20a (71)
20c (38)
20c (52)
20d (57)
20a (52)
20c (35)
20d (30)
21a (61)
21b (48)
21c (46)
21d (48)
21a (35), 22a (23)
21c (24), 22c (25)
22d (46)
9
10
11
12
13
14
15
16
r.t.
re¯ux
re¯ux
re¯ux
re¯ux
re¯ux
23a (31)
23a (42)
10
a Molar ratio of 3/ole®n/CsF.

7726
O. Tsuge et al. / Tetrahedron 56 (2000) 7723±7735
mixture of the corresponding 1:1 adduct 5, Michael adduct 6
and/or novel product 7b±7d whose relative yields depended
on the reaction conditions (entries 11±16).
reacted with acyclic ole®ns to give the formal [312]
cycloadduct of amino nitrile ylides, since it has been
reported that the 2-azaallyl anion generated from an
N-(silylmethyl)isothiourea reacted with 16 to form Michael
adduct in low yield.9a
On the basis of spectral data and X-ray crystallographic
analysis of 7d whose ORTEP drawing is shown in Fig. 1,
the structure of 7 corresponded to an addition product of 5
to 4, and was determined as 6-amino-2-methyl-6a-[3-(1-
methyl-2,5-dioxopyrrolidinyl)]-1,2,3,3a,4,6a-hexahydro-
pyrrolo[3,4-c]pyrrole-1,3-dione; the product 7 is hereinafter
abbreviated as 1:2 adduct. However, no 1:2 adducts 7b±7d
were formed in the reaction of the corresponding 1:1 adduct
5 with 4 in the presence or absence of CsF in re¯uxing 1,2-
dimethoxyethane (DME). The reaction pathway for the
formation of 7 is not clear yet.
It has been found that 1-pyrroline 20a underwent air-oxida-
tion to give 3-hydroxy-1-pyrroline 24; such air oxidation of
1-pyrrolines has been observed previously.14
Cycloadditions to dimethyl acetylenedicarboxylate
(DMAD)
The above results clearly show that the azomethine ylides
generated from precursors 3 serve as synthetic equivalents
of nonstabilized aminonitrile ylides through a cycloaddition
and elimination sequence. Cycloaddition of these
azomethine ylides to acetylenic dipolarophiles is, therefore,
expected to be a convenient route to N-unsubstituted
2-aminopyrroles. Unfortunately, the reactivity of diaroyl-
and aroylarylacetylenes toward azomethine ylides gener-
ated from 3 was low and the reaction under more forced
conditions resulted in the formation of intractable materials.
The reaction of 3 with DMAD under the in¯uence of CsF,
however, furnished the corresponding 1:1 adduct, 2-amino-
pyrrole 25, and a mixture of two isomeric 1:2 adducts 26 and
27 whose relative yields depended on the amount of used
DMAD (Scheme 4, Table 3)
The reaction of 3 with N-phenylmaleimide (8) under similar
conditions afforded a mixture of the corresponding amino-
nitrile ylide 1:1 cycloadduct 9, Michael adduct, 2-methyl-N-
phenylsuccinimide (10), and/or 1:2 adduct 11, whose
relative yields depended on the nature of 3 as well as
reaction conditions. The 1:2 adduct 11d was formed even
in the reaction of 3d with an equivalent of 8. The results are
listed in entries 17±19 in Table 1.
In order to study the regioselectivity of cycloaddition, the
reaction with 2-methyl-N-phenylmaleimide (12) expected
to suppress the formation of 1:2 adduct was investigated
(entries 20±23 in Table 1). Although the formation of 1:2
adduct such as type 7 or 11 was completely inhibited,
azomethine ylides generated from 3 did not exhibited high
regioselectivity in cycloaddition reaction with 12. In all the
reactions the less crowed 3a-methyl-substituted 1:1 adduct
13 was more formed than the crowed 6a-methyl-substituted
one 14 (13/14ˆca. 2.3/1) along with Michael adduct,
2-methyl-2-methylthio-N-phenylsuccinimide (15).
The reaction of 25 with DMAD in the presence of a base
gave a mixture of two isomers 26 and 27 in good yield. On
the basis of spectral data and X-ray crystallographic analysis
of 26d whose ORTEP drawing is shown in Fig. 2, the
compounds 26 and 27 were assigned as stereoisomeric
Michael adducts of 25 to DMAD; 26d was determined as
Cycloadditions to acyclic ole®ns
Next, the reaction of precursors 3 with electron-de®cient
acyclic ole®ns such as dimethyl fumalate (16), dimethyl
maleate (17), fumaronitrile (18), and 2-chloroacrylonitrile
(19) in the presence of CsF in dry DME (Scheme 3, Table
2). Although these acyclic dipolarophiles were somewhat
less reactive than the cyclic dipolarophile 4, the correspond-
ing aminonitrile ylide cycloadducts were obtained in all
cases.
The reaction of cis-ole®n 17 gave the thermodynamically
stable trans-bis(methoxycarbonyl)-1-pyrroline 20, which
was identical with the cycloadduct from trans-ole®n 16.
Exclusive formation of 3,4-trans-1-pyrroline 20 from both
16 and 17 is due to a ready imine/enamine tautomerism (or a
1-pyrroline/2-pyrroline isomerization).7 On the other hand,
3 reacted with 18 to give a mixture of 2-pyrroline 2113 and
3-cyanopyrrole 22 whose relative yields depended upon
reaction conditions: when 21a or 21c was heated with CsF
in DME for 24 h, 22a or 22c was obtained in good yield.
The reaction of 3a with unsymmetrically substituted ole®n
19 furnished exclusively the 1-pyrroline 23a with electron-
withdrawing groups in 3-position, though its yield was low.
Scheme 4.
Table 3. Cycloaddition with DMAD (The reactions were carried out in dry
DME at room temperature for 6 h)
Entry
Precursor
Molar ratioa
Products (yield, %)
1
2
3
4
5
6
3a
3b
3c
3c
3d
3d
1/1/1
1/2/1.2
1/1/2
1/2/1
1/1/1
1/2/1
25a (71)
26b 1 27b (34)
25c (41), 26c 1 27c (14)
25c (7), 26c 1 27c (34)
25d (41), 26d 1 27d (16)
25d (10), 26d 1 27d (32)
a Molar ratio of 3/DMAD/CsF.
It should be noted that azomethine ylides generated from 3

O. Tsuge et al. / Tetrahedron 56 (2000) 7723±7735
7727
Figure 2.
Scheme 5.
Table 4. Cycloaddition with aldehydes 28±33
(Z)-1,2-bis(methoxycarbonyl)-1-[3,4-bis(methoxycarbonyl)-
2-(morpholino)pyrrolyl]ethene.
Entry
Precursor
Aldehyde
Molar ratioa
Product (yield, %)
1
2
3
4
5
6
7
8
9
10
3a
3a
3a
3a
3a
3c
3d
3a
3a
3a
28
28
29
29
30
30
30
31
32
33
1/1/1.2
1/5/1.2
1/1/1.2
1/5/1.2
1/5/1.2
1/5/1.2
1/5/1.2
1/5/1.2
1/5/1.2
1/5/1.2
34a (15), 40 (30)
34a (39), 40 (48)
35a (30), 40 (46)
35a (54), 40 (29)
36a (70)
36c (90)
36d (77)
37a (71)
38a (63)
39a (76)
It has been reported that the nitrile ylide generated from
N-(tosylmethyl)methylthioimidoyl chloride reacted with
DMAD under severe conditions (in re¯uxing THF, 40 h)
to lead to the formation of a mixture of two isomeric
N-vinyl pyrroles such as 26 and 27.15
Cycloadditions to aldehydes
Nitrile ylides generated by the photolysis of azirines
undergo cycloaddition with aldehydes to give 3-oxazolines,16,17
a Molar ratio of 3/Aldehyde/CsF.

7728
O. Tsuge et al. / Tetrahedron 56 (2000) 7723±7735
and similar reactions of related ylides generated from
the dehydrochlorination of imidoyl chlorides leading to
3-oxazolines, with a few exceptions,18 are also known.19
In contrast to the above observations, azomethine ylides
generated from the desilylation of N-(trimethylsilyl)-
methyl-N0-methyl-N0-phenylamidinium tri¯ates show fairly
high reactivity toward aromatic and heteroaromatic alde-
hydes to give moderate yields of 2,5-disubstituted 2-oxazo-
lines by a sequence of cycloaddition and spontaneous
elimination of N-methylaniline.7 By contrast, related
azomethine ylides generated by the action of water on
N-(trimethylsilylmethyl)thioimidates are totally inert to
carbonyl compounds.6 Instead, on treatment with ¯uoride
ion, the thioimidates generate 2-azaallyl anions, which are
highly reactive to aromatic aldehydes and produce 2-oxazo-
lines. More recently, two research groups9 have found that
2-azaallyl anions generated by desilylation of certain
N-(silylmethyl)isothioureas served as synthetic equivalent
of aminonitrile ylides and reacted with carbonyl compounds
to produce 2-amino-2-oxazolines.
energy. (Trimethylsilyl)methylisothiocyanate (1) was
prepared according to the reported method.10 Cesium ¯uo-
ride was dried under vacuum prior to its use. Acetonitrile
and 1,2-dimethoxyethane were distilled over P2O5 and CaH,
respectively, and stored on molecular sieves 5A. Other
reagents are commercially available. Column chromato-
graphy was carried out on silica gel BW 200, BW 300 or
NH DM-1020 (Fuji Silisya Chem. Ltd.).
General procedure for the preparation of N-(trimethyl-
silylmethyl)thioureas 2a±2d
The typical procedure is given with an example for the
synthesis of 1-phenyl-3-(trimethylsilylmethyl)thiourea
(2a). A solution of aniline (1.89 g, 20 mmol) and (trimethyl-
silyl)methylisothiocyanate (1) (2.91 g, 20 mmol) in dry
benzene (30 mL) was re¯uxed under argon for 3 h. The
solvent was evaporated in vacuo and the residue was
recrystallized from cyclohexane to give 4.46 g (93%) of
2a as colorless needles.
1
2a. Mp 125±1268C; IR 3288, 1251, 857 cm21; H NMR d
If the cycloaddition of azomethine ylides generated from 3
to carbonyl compounds occurs in the same manner as those
from amidinium salts,7 the route to 2-amino-substituted
2-oxazolines via the elimination of methanethiol from initial
cycloadducts, 2-amino-5-aryl-2-methylthiooxazolidines E,
would become available. In fact, the azomethine ylides
generated from 3a reacted with aromatic and heteroaromatic
aldehydes 28±33 in a regioselective manner to give
the expected 2-anilino-5-aryl(heteroaryl)-2-oxazolines
34a±39a in low to high yields depending on the nature of
aldehydes (Scheme 5, Table 4).
0.05 (s, 9H), 3.15 (d, Jˆ5.4 Hz, 2H), 5.99 (br s, 1H), 7.21±
7.46 (m, 5H), 8.39 (br s, 1H); 13C NMR d 22.55, 35.71,
125.14, 125.21, 127.04, 130.06, 181.26; MS m/z (relative
intensity) 238 (M1, 66), 223 (100). Anal. Calcd for
C11H18N2SSi: C, 55.41; H, 7.61; N, 11.75. Found: C,
55.16; H, 7.63; N, 11.47.
1-[N-(Trimethylisilylmethyl)thiocarbamoyl]pyrrolidine
(2b). Yield 98%; colorless needles (hexane); mp 58.5±
598C; IR 3342, 1247, 853 cm21; H NMR d 0.12 (s, 9H),
1
1.9±2.1 (m, 4H), 3.18 (d, Jˆ5.1 Hz, 2H), 3.59 (br s, 4H),
5.05 (br s, 1H); 13C NMR d 22.55, 25.41, 35.83, 49.38,
179.98; MS m/z (relative intensity) 216 (M1, 37), 70
(100). Anal. Calcd for C9H20N2SSi: C, 49.95; H, 9.31; N,
12.94. Found: C, 49.71; H, 9.35; N, 12.89.
In the reaction with rather inactive dipolarophiles such as
benzaldehyde 28 and p-chlorobenzaldehyde 29 (entries 1±4
in Table 4),20 the imine 40 which was probably derived from
the azomethine ylide through a 1,2-proton migration was
obtained as the by-product. Similar reactions of 3c and 3d
with p-nitrobenzaldehyde 29 afforded the corresponding
2-oxazolines 36c and 36d in good yield, respectively.
1-[N-(Trimethylsilylmethyl)thiocarbamoyl]piperidine
(2c). Yield 97%; colorless needles (cyclohexane); mp 73±
1
748C; IR 3352, 1253, 857 cm21; H NMR d 0.12 (s, 9H),
In conclusion, azomethine ylides readily generated by the
desilylation of N-(trimethylsilylmethyl)iminium tri¯ates 3
react with electron-de®cient ole®ns, acetylenes and
aromatic and heteroaromatic aldehydes to give formal
nonstabilized aminonitrile ylides cycloadducts, novel
2-amino-pyrrolines, 2-amino-pyrrole, and 2-amino-2-
oxazolines, which are otherwise relatively inaccessible.
1.6±1.8 (m, 6H), 3.09 (d, Jˆ2.5 Hz, 2H), 3.65 (br s, 4H),
5.34 (br s, 1H); 13C NMR d 22.39, 24.31, 25.39, 36.50,
48.95, 182.84; MS m/z (relative intensity) 230 (M1, 13),
84 (100). Anal. Calcd for C10H22N2SSi: C, 52.12; H, 9.62;
N, 12.12. Found: C, 52.24; H, 9.44; N, 12.14.
1-[N-(Trimethylsilylmethyl)thiocarbamoyl]morpholine
(2d). Yield 97%; colorless needles (hexane); mp 73±748C;
IR 3376, 1249, 843 cm21; 1H NMR d 0.12 (s, 9H), 3.23 (d,
Jˆ5.3 Hz, 2H), 3.55±4.02 (m, 8H), 6.50 (br s, 1H); 13C
NMR d 22.35, 36.59, 47.53, 66.14, 184.24; MS m/z
(relative intensity) 232 (M1, 37), 86 (100). Anal. Calcd
for C9H20N2OSSi: C, 46.51; H, 8.67; N, 12.05. Found: C,
46.49; H, 8.54; N, 12.02.
Experimental
General procedures
Melting points were determined on a hot-plate microscope
apparatus and are not corrected. IR spectra were measured
1
as KBr pellets unless otherwise noted. H and 13C NMR
General procedure for the S-methylation of thioureas (2)
spectra were recorded at 270 and 67.5 MHz, respectively,
in CDCl3 unless otherwise mentioned. Chemical shifts are
expressed in parts per million down®eld from TMS. 13C
NMR resonance assignments were aided by the use of the
DEPT technique to determine number of attached hydro-
gens. Mass spectra were measured at 70 eV of ionization
The typical procedure is given with an example for the
preparation of N-(trimethylsilylmethyl)iminium tri¯ate 3a.
To a solution of the thiourea 2a (2.38 g, 10 mmol) in dry
dichloromethane (30 mL) was added methyltri¯ate (1.80 g,
11 mmol). The reaction mixture was re¯uxed for 2 h under

O. Tsuge et al. / Tetrahedron 56 (2000) 7723±7735
7729
argon. The solvent was evaporated in vacuo and recrystal-
lization of the residue from benzene gave 3.83 g (95%) of 3a
as colorless plates.
gen. The mixture was concentrated in vacuo and extracted
with dichloromethane (50 mL). The organic layer was
washed with water, dried over anhydrous MgSO4, and
evaporated in vacuo. The residue was chromatographed
(NH DM-1020) to give Michael adduct 6 (382 mg, 60%),
1:1 adduct 5b (362 mg, 41%) and 1:2 adduct 7b (184 mg,
14%) from elution of hexane±benzene (1:1), benzene±ethyl
acetate (1:4) and ethyl acetate, respectively (entry 11 in
Table 1).
1
3a. Mp 122±1238C; IR 3268, 1620, 1257, 859 cm21; H
NMR (a mixture of E and Z isomers) d 0.12 (s, 2.25H),
0.17 (s, 6.75H), 2.46 (s, 2.25H), 2.54 (0.75H), 3.01 (d,
Jˆ5.9 Hz, 0.5H), 3.31 (d, Jˆ6.7 Hz, 1.5H), 7.2±7.47 (m,
5H), 7.88 (br s, 0.25H), 8.19 (br s, 0.75H), 9.57 (br s,
0.75H), 9.90 (br s, 0.25H); 13C NMR d 22.61, 22.53,
14.00, 14.70, 36.62, 36.78, 124.87, 127.13, 128.75,
128.98, 129.45, 130.47, 134.32, 134.77, 166.92, 169.95.
Anal. Calcd for C13H21N2O3F3S2Si: C, 38.78; H, 5.26; N,
6.96. Found: C, 38.83; H, 5.20; N, 6.93.
The other reactions were carried out under the conditions
summarized in Table 1.
Anilino-substituted 1:1 adduct 5a. Mp 190±190.58C, IR
3278, 1702, 1601 cm21; 1H NMR d 2.97 (s, 3H), 3.45±4.30
(m, 4H), 6.9±7.6 (m, 6H); 13C NMR d 25.18, 43.44, 54.21,
59.70, 118.46, 122.83, 129.00, 139.97, 154.66, 174.69,
178.41; MS m/z (relative intensity) 243 (M1, 41), 242
(100). Anal. Calcd for C13H13N3O2: C, 64.17; H, 5.40; N,
17.28. Found: C, 63.96; H, 5.38; N, 17.06.
1-Pyrrolidinyl-substituted N-(trimethylsilylmethyl)imi-
nium tri¯ate 3b. Yield 98%; colorless oil; IR (neat)
1
3244, 1611, 1257, 857 cm21; H NMR d 0.15 (s, 9H),
2.0±2.2 (m, 4H), 2.59 (s, 3H), 3.26 (d, Jˆ5.9 Hz, 2H),
3.70±3.84 (m, 4H), 8.27 (br s, 1H); 13C NMR d 22.53,
16.28, 25.18, 39.01, 52.08, 163.88 Anal. Calcd for
C11H23N2O3F3S2Si: C, 34.74; H, 6.05; N, 7.37. Found: C,
34.89; H, 5.98; N, 7.29.
1-Pyrrolidinyl-substituted 1:1 adduct 5b. Colorless
1
viscous oil; IR (neat) 1696, 1618 cm21; H NMR d 1.85±
2.20 (m, 4H), 2.97 (s, 3H), 3.2±4.3 (m, 8H); 13C NMR d
25.06, 25.48, 45.45, 48.57, 53.11, 58.67, 158.65, 173.92,
178.37; MS m/z (relative intensity) 221 (M1, 7), 137
(100). Anal. Calcd for C11H15N3O2: C, 59.71; H, 6.83; N,
18.99. Found: C, 59.54; H, 6.97; N, 19.06.
Piperidino-substituted N-(trimethylsilylmethyl)iminium
tri¯ate 3c. Yield 95%; colorless prisms (benzene±hexane
1
(1:1)); mp 87±888C; IR 3236, 1609, 1249, 855 cm21; H
NMR d 0.15 (s, 9H), 1.74 (br s, 6H), 2.54 (s, 3H), 3.29
(d, Jˆ5.9 Hz, 2H), 3.73 (br s, 4H), 8.93 (br s, 1H); 13C
NMR d 22.41, 17.09, 23.53, 25.82, 39.26, 52.27, 169.13.
Anal. Calcd for C12H25N2O3F3S2Si: C, 36.52; H, 6.40; N,
7.10. Found: C, 36.73; H, 6.56; N, 6.98.
Piperidino-substituted 1:1 adduct 5c. Colorless plates
(cyclohexane), mp 127±1288C; IR 1688, 1607 cm21
;
1H NMR d 1.62 (br s, 6H), 2.97 (s, 3H), 3.40±4.30
(m, 8H); 13C NMR d 24.36, 25.09, 25.51, 45.30,
48.09, 51.51, 58.18, 160.69, 173.71, 178.32; MS m/z
(relative intensity) 235 (M1, 100). Anal. Calcd for
C12H17N3O2: C, 61.26; H, 7.28; N, 17.86. Found: C,
61.54; H, 7.41; N, 17.81.
Morpholino-substituted N-(trimethylsilylmethyl)iminium
tri¯ate 3d. Yield 96%; colorless prisms (benzene); mp
1
65.5±668C; IR 3226, 1607, 1245, 857 cm21; H NMR d
0.16 (s, 9H), 2.57 (s, 3H), 3.32 (d, Jˆ5.9 Hz, 2H), 3,82
(br s, 8H), 9.17 (br s, 1H); 13C NMR d 22.39, 17.11,
39.68, 51.21, 66.14, 169.59. Anal. Calcd for
C11H23N2O4F3S2Si; C, 33.22; H, 5.85; N, 7.06. Found: C,
33.36; H, 5.87; N 6.97.
Morpholino-substituted 1:1 adduct 5d. Colorless prisms
1
(cyclohexane), mp 142±1438C, IR 1694, 1613 cm21; H
NMR d 2.98 (s, 3H), 3.25±4.28 (m, 12H); 13C NMR d
25.15, 45.16, 47.15, 51.41, 58.27, 66.47, 160.80, 173.57,
178.04; MS m/z (relative intensity), 237 (M1, 60), 236
(100). Anal. Calcd for C11H15N3O3: C, 55.68; H, 6.37; N,
17.71. Found: C, 55.61; H, 6.39; N, 17.86.
General procedure for the generation of azomethine
ylides from N-(trimethylsilylmethyl)iminium tri¯ates 3
and their cycloaddition reactions with N-methylmale-
imide (4)
N-Methyl-2-methylthiosuccinimide (6). Pale yellow oil;
1
IR (neat) 1702 cm21; H NMR d 2.32 (s, 3H), 2.55 (dd,
Each typical procedure for the reaction of iminium tri¯ate
3a with an equivalent of 4 or 3b with an excess of 4 is shown
below: (i) to a suspension of CsF (76 mg, 0.5 mmol) in dry
DME (3 mL) was added a solution of 3a (201 mg,
0.5 mmol) and 4 (55.5 mg, 0.5 mmol) in dry DME
(5 mL), and the resulting mixture was stirred at room
temperature under nitrogen for 10 h, and then concentrated
in vacuo. The residue was extracted with dichloromethane
(15 mL) and organic layer was washed with water (5 mL),
dried over anhydrous MgSO4, and evaporated in vacuo. The
residue was recrystallized from benzene to give 101 mg
(83%) of 1:1 adduct 5a as colorless needles (entry 1 in
Table 1). (ii) To a suspension of CsF (608 mg, 4.0 mmol)
in dry DME (10 mL) was added a solution of 3b (1.52 g,
4.0 mmol) and 4 (890 mg, 8.0 mmol) in dry DME (10 mL),
and the resulting mixture was re¯uxed for 10 h under nitro-
Jˆ3.6, 18.6 Hz, 1H), 3.01 (s, 3H), 3.17 (dd, Jˆ8.9,
18.6 Hz, 1H), 3.77 (dd, Jˆ3.6, 8.9 Hz, 1H); 13C NMR d
14.65, 25.05, 35.76, 40.63, 174.82, 176.46; MS m/z (relative
intensity) 159 (M1, 29), 113 (100). Anal. Calcd for
C6H9NO2S: C, 45.28; H, 5.70; N, 8.80. Found: C, 45.06;
H, 5.86; N, 8.58.
1-Pyrrolidinyl-substituted 1:2 adduct 7b. Colorless
needles, mp 255±2568C; IR 1696, 1609 cm21; H NMR d
1
1.7±2.0 (m, 4H), 2.98, 3.06 (each s, 3H), 3.70±4.05 (m, 4H),
2.0±4.25 (m, 6H); 13C NMR d 25.11, 25.61, 25.33, 31.24,
41.87, 48.56, 49.75, 56.72, 63.12, 158.02, 174.37, 174.71,
175.97, 176.73; MS m/z (relative intensity) 332 (M1, 58),
221 (100). Anal. Calcd for C16H20N4O4: C, 57.82; H, 6.07;
N, 16.86. Found: C, 57.93; H, 5.87; N, 17.04.

7730
O. Tsuge et al. / Tetrahedron 56 (2000) 7723±7735
Piperidino-substituted 1:2 adduct 7c. Colorless needles
(s, 1H), 6.99±7.05 (m, 1H), 7.25±7.50 (m, 7H), 7.58 (d,
Jˆ7.6 Hz, 2H); 13C NMR d 43.50, 54.29, 60.57, 118.40,
122.91, 126.34, 128.93, 129.04, 129.25, 131.26, 139.64,
154.53, 173.76, 177.39; MS m/z (relative intensity) 305
(M1, 50), 304 (100). Anal. Calcd for C18H15N3O2; C,
70.80; H, 4.95; N, 13.76. Found: C, 70.81; H, 5.07; N, 13.70.
1
(ethyl acetate), mp 249±2508C; IR 1702, 1603 cm21; H
NMR (pyridine-d5) d 1.3±1.8 (m, 6H), 2.87, 3.04 (each s,
3H), 2.25±4.50 (m, 6H,), 3.78 (br s, 4H); 13C NMR (pyri-
dine-d5) d 24.61, 24.76, 24.55, 26.12, 32.13, 43.81, 48.03,
50.81, 56.63, 63.88, 160.31, 175.28, 175.65, 177.10, 177.56;
MS m/z (relative intensity) 346 (M1, 82), 235 (100). Anal.
Calcd for C17H22N4O4: C, 58.94; H, 6.41; N, 16.18. Found:
C, 58.83; H, 6.32; N, 15.97.
Morpholino-substituted 1:1 adduct 9d. Colorless needles
(hexane±benzene (1:1)), mp 133±1348C; IR 1713 cm21; 1H
NMR d 3.45±3.83 (m, 9H), 4.07±4.17 (m, 1H), 4.21 (d,
Jˆ9.3 Hz, 1H), 4.29 (d, Jˆ8.4 Hz, 1H), 7.20±7.29 (m,
2H), 7.37±7.52 (m, 3H); 13C NMR d 45.14, 47.22, 51.34,
58.81, 66.47, 126.40, 128.86, 129.22, 131.41, 160.77,
172.49, 177.01; MS m/z (relative intensity) 299 (M1, 78),
298 (100). Anal. Calcd for C16H17N3O3: C, 64.20; H, 5.72,
14.04. Found: C, 64.28; H, 5.87; N, 13.92.
Morpholino-substituted 1:2 adduct 7d. Colorless needles
(DME), mp.3008C; IR 1694, 1605 cm21; 1H NMR d 2.05±
3,70 (m, 6H), 2.98, 3.08 (each s, 3H), 3.50±3.70 (m, 4H),
3.85±4.05 (m, 4H); 13C NMR d 25.12, 25.79, 31.40, 42.84,
47.27, 50.05, 56.22, 63.43, 66.65, 160.35, 174.04, 175.58,
176.16; MS m/z (relative intensity) 348 (M1, 72), 347 (100).
Anal. Calcd for C16H20N4O5: C, 55.16; H, 5.79; N, 16.08.
Found: C, 55.35; H, 5.88; N, 16.09.
2-Methylthio-N-phenylsuccinimide (10). Colorless plates
(benzene), mp 95±968C; IR 1713 cm21; 1H NMR d 2.38 (s,
3H), 2.68 (dd, Jˆ3.4, 18.6 Hz, 1H), 3.27 (dd, Jˆ8.9,
18.6 Hz, 1H), 3.76 (dd, Jˆ3.4, 8.9 Hz, 1H), 7.26±7.37 (m,
2H), 7.37±7.52 (m, 3H); 13C NMR d 14.91, 35.87, 40.65,
126.41, 128.79, 129.22, 131.61, 173.71, 175.27; MS m/z
(relative intensity) 221 (M1, 32), 175 (100). Anal. Calcd
for C11H11NO2S: C, 59.72; H, 5.01; N, 6.33. Found: C,
59.58; H, 5.32; N, 6.54.
Crystallography of 7d
A single crystal (0.18£0.38£0.80 mm3) grown from a
mixture of hexane±benzene (1/1) was used for the unit-
cell determinations and the data collections of a Rigaku
AFC5S four-circle diffractometer, with graphite-mono-
Ê
chromated MoKa radiation (lˆ0.71069 A). This crystal
Ê
was monoclinic, space group P21 (#4), aˆ10.375 (1) A,
Ê
Ê
Morpholino-substituted 1:2 adduct 11d. Colorless
bˆ6.482 (1) A, cˆ12.292 (1) A, bˆ102.304 (8)8, Vˆ
1
needles (EtOH), mp 255±2568C; IR 1715, 1605 cm21; H
807.6 (2) A , Zˆ2, Dcalcdˆ1.432 g/cm3. All calculations
Ê 3
were performed using texsan program.21 The structure
was solved by a direct method (MITHRIL).22 The non-
hydrogen atoms were re®ned anisotropically and the hydro-
gen atoms were re®ned anisotropically and the hydrogen
atoms isotoropically. The ®nal R-factors after full-matrix
least-squares re®nements were 0.045 for 1487 observed
re¯ections.
NMR d 2.46 (dd, Jˆ7.2, 18.1 Hz, 1H), 3.12 (dd, Jˆ9.7,
18.1 Hz, 1H), 3.37 (dd, Jˆ3.0, 9.3 Hz, 1H), 3.6±3.8 (m,
8H), 4.07 (dd, Jˆ9.3, 15.9 Hz, 1H), 4.20 (dd, Jˆ3.0,
9.3 Hz, 1H), 4,26 (dd, Jˆ7.2, 9.7 Hz, 1H); 7.25±7.52 (m,
10H); 13C NMR d 31.50, 43.41, 47.26, 50.01, 56.68, 63.34,
66.63, 126.09, 126.68, 129.16, 129.22, 129.27, 129.41,
130.89, 131.50, 160.14, 172.99, 173.83, 174.86, 175.24;
MS m/z (relative intensity) 472 (M1, 100). Anal. Calcd
for C26H24N4O5: C, 66.09; H, 5.12; N, 11.86. Found: C,
65.87; H, 5.31; N, 11.75.
Cycloaddition reaction of azomethine ylides with
N-phenylmaleimide (8)
Each typical procedure for the reaction of 3a or 3d is shown
below. (i) A solution of 3a (1.40 g, 3.5 mmol) and 8 (0.60 g,
3.5 mmol) in dry DME (10 mL) was stirred with CsF
(0.53 g, 3.5 mmol) at room temperature for 10 h under
argon. The mixture was concentrated in vacuo and extracted
with dichloromethane (40 mL). The organic layer was
washed with water, dried over anhydrous MgSO4 and
evaporated in vacuo. Flash chromatography (BW-300) of
the residue gave 1:1 adduct 9a (0.63 g, 59%) and Michael
adduct 10 (0.14 g, 23%) from elution of benzene±ethyl
acetate (1:1) (entry 17 in Table 1). (ii) A solution of 3d
(1.2 g, 3.0 mmol) and 8 (1.1 g, 6.0 mmol) in dry DME
(10 mL) was re¯uxed with CsF (0.59 g, 3.9 mmol) for
10 h under nitrogen. Flash chromatography of the reaction
mixture obtained by the same procedure as above gave 1:1
adduct 9d (72 mg, 8%) and 1:2 adduct 11d (536 mg, 38%)
from elution of hexane±benzene (1:1) and benzene±ethyl
acetate (1:4), respectively (entry 19 in Table 1).
Cycloaddition reaction of azomethine ylides with
2-methyl-N-phenylmaleimide (12)
(1) A solution of 3a (2.01 g, 5.0 mmol) and 12 (0.94 g,
5.0 mmol) in dry DME (10 mL) was stirred with CsF
(1.0 g, 6.5 mmol) at room temperature for 10 h under
argon. Flash chromatography (BW 300, benzene±ethyl
acetate (9:1)) of the reaction mixture obtained by the
same procedure as above gave 0.31 g (26%) of Michael
adduct 15 and 1.12 g (70%) of a 2.3:1 mixture of 3a-methyl-
substituted 13a and 6a-methyl substituted 1:1 adduct 14a
(estimated by 1H NMR), respectively (entry 20 in Table 1).
Although chromatographic separation of this mixture of 13a
and 14a was unsuccessful, the mixture was washed with
ethanol (15 mL) to leave 380 mg (24%) of 13a as an
insoluble compound.
13a114a (2.3:1). Colorless viscous oil; IR (neat) 3380,
1715, 1664 cm21 1H NMR d 1.62 (s, 2.1H), 1.73 (s,
;
Anilino-substituted 1:1 adduct 9a. Colorless needles
(benzene±cyclohexane (1:1)), mp 140±1418C; IR 3370,
0.9H), 3.34 (t, Jˆ5.5 Hz, 0.3H), 3.75 (s, 0.7H), 3.92 (d,
Jˆ15.2 Hz, 0.7H), 4.32 (d, Jˆ5.5 Hz, 0.6H), 4.43 (d,
Jˆ5.5 Hz, 0.7H), 6.63±6.75 (m, 11H); MS m/z (relative
intensity) 319 (M1, 52), 318 (100).
1705 cm21
;
1H NMR d 3.70 (ddd, Jˆ5.5, 6.7, 8.9 Hz,
1H), 4.11 (d, Jˆ8.9 Hz, 1H), 4.33 (d, Jˆ6.7 Hz, 2H), 6.86

O. Tsuge et al. / Tetrahedron 56 (2000) 7723±7735
7731
3a-Methyl-substituted 1:1 adduct 13a. Colorless needles
(cyclohexane), mp 102±1038C; IR (KBr) 3374, 1711,
13d114d (2.3:1). Colorless viscous oil, IR (neat) 1717,
1
1620 cm21; H NMR d 1.60 (s, 2.1H), 1.71 (s, 0.9H), 3.21
1
1644 cm21; H NMR d 1.63 (s, 3H), 3.78 (d, Jˆ1.7 Hz,
(dd, Jˆ2.5, 8.1 Hz, 0.3H), 3.45±3.83 (m, 8.7H), 3.91 (d,
Jˆ1.3 Hz, 0.7H), 4.02 (dd, Jˆ8.1, 14.8 Hz, 0.3H), 4.14
(dd, Jˆ2.5, 14.8 Hz, 0.3H), 4.22 (d, Jˆ1.3 Hz, 0.7H),
7.20±7.55 (m, 5H).
1H), 3.91 (d, Jˆ15.2 Hz, 1H), 4.42 (dd, Jˆ1.7, 15.2 Hz,
1H), 6.99±7.06 (m, 1H), 7.25±7.57 (m, 10H); 13C NMR d
21.36, 50.21, 60.56, 67.47, 118.63, 122.98, 126.34, 128.89,
129.05, 129.22, 131.30, 139.84, 154.41, 172.97, 180.190;
MS m/z (relative intensity) 319 (M1, 56), 318 (100). Anal.
Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found:
C, 71.20; H, 5.40; N, 13.03.
6a-Methyl-substituted 1:1 adduct 14d. Colorless needles
1
(cyclohexane), mp 186±1878C; IR 1715, 1605 cm21; H
NMR d 1.72 (s, 3H), 3.36 (dd, Jˆ2.5, 8.0 Hz, 1H), 3.52±
3.74 (m, 8H), 4.02 (dd, Jˆ8.0, 15.2 Hz, 1H), 4.14 (dd,
Jˆ2.5, 15.2 Hz, 1H), 7.26±7.30 (m, 2H), 7.40±7.51 (m,
3H); 13C NMR d 19.69, 47.01, 55.26, 55.54, 58.01, 66.72,
126.29, 128.77, 129.18, 131.64, 163.57, 176.31, 176.39; MS
m/z 313 (M1, 100). Anal. Calcd for C17H19N3O3: C, 65.16;
H, 6.11; N, 13.41. Found: C, 65.37; H, 6.24; N, 13.16.
2-Methyl-2-methylthio-N-phenylsuccinimide (15). Color-
less needles (cyclohexane); mp 84.5±85.58C; IR
1
1705 cm21; H NMR d 1.74, 2.29 (each s, 3H), 2.86, 2.99
(each d, Jˆ18.5 Hz, 1H), 7.26±7.52 (m, 5H); 13C NMR d
12.92, 21.83, 43.61, 45.35, 126.40, 128.68, 129.18, 131.77,
173.03, 176.87; MS m/z (relative intensity) 235 (M1, 25),
189 (100). Anal. Calcd for C12H13NO2S: C, 61.25; H, 5.57;
N, 5.95. Found: C, 61.24; H, 5.63; N, 5.98.
Cycloaddition reactions of azomethine ylides with di-
methyl fumarate (16) or dimethyl maleate (17)
(2) A solution of 3c (1.58 mg, 4.0 mmol) and 12 (750 mg,
4.0 mmol) in dry DME (10 mL) was stirred with CsF
(790 mg, 5.2 mmol) at room temperature for 10 h under
argon. Flash chromatography of the residue obtained by
the same procedure as above gave 338 mg (36%) of Michael
adduct 15 and 722 mg (58%) of a 2.3:1 mixture of 3a-
methyl-substituted 13c and 6a-methyl-substituted 1:1
As a typical example, the reaction of 3a with 16 is shown
below. A solution of 3a (201 mg, 0.5 mmol) and 16 (72 mg,
0.5 mmol) in dry DME (7 mL) was stirred with CsF (76 mg,
0.5 mmol) at room temperature for 20 h under nitrogen, and
then concentrated in vacuo. The residue was extracted with
dichloromethane (13 mL) and organic layer was washed
with water (5 mL), dried over anhydrous MgSO4 and then
evaporated in vacuo. Flash chromatography of the residue
on silica gel (BW 300) with a mixture of benzene±ethyl
acetate (4:1) gave 98 mg (71%) of aminonitrile cycloadduct
20a (entry 1 in Table 2).
1
adduct 14c (estimated by H NMR) (entry 21 in Table 1).
Although chromatographic separation of the mixture of 13c
and 14c was unsuccessful, the mixture was washed with
ethyl acetate (5 mL) to leave the minor adduct 14c
(137 mg, 11%).
13c114c (2.3:1). Colorless viscous oil; IR (neat) 1717,
The reaction of 3a with 17 under similar reaction conditions
furnished the same cycloadduct 20a in 52% yield (entry 5 in
Table 2). The other reactions of 3 with 16 or 17 are listed in
Table 2.
1615 cm21 1H NMR d 1.48±1.85 (m, 9H), 3.22 (dd,
;
Jˆ2.1, 8.0 Hz, 0.3H), 3.45±3.65 (m, 4H), 3.76 (d,
Jˆ14.8 Hz, 0.7H), 3.93 (d, Jˆ1.3 Hz, 0.7H), 3.95±4.12
(m, 0.6H), 4.17 (dd, Jˆ1.3, 14.8 Hz, 0.7H), 7.26±7.30 (m,
2H), 7.34±7.50 (m, 3H).
(E)-2-Anilino-3,4-bis(methoxycarbonyl)-1-pyrroline (20a).
Colorless viscous oil, IR (neat) 3378, 1738, 1647 cm21; 1H
NMR d 3.64±3.75 (m, 2H), 3.80, 3.83 (each s, 3H), 4.20±
4.35 (m, 2H), 6.79±6.88 (m, 1H), 6.97±7.37 (m, 3H), 7.55±
7.62 (m, 2H); 13C NMR d 44.51, 52.47, 53.12, 54.21, 59.35,
118.54, 122.59, 128.96, 139.93, 155.56, 169.83, 173.35; MS
m/z (relative intensity) 276 (M1, 60), 275 (100). HRMS
Calcd for C14H16N2O4 276.1110. Found: 276.1129.
6a-Methylated 1:1 adduct 14c. Colorless needles (cyclo-
1
hexane), mp 197±1988C; IR 1715, 1595 cm21; H NMR d
1.42±1.70 (m, 6H), 1.71 (s, 3H), 3.33 (dd, Jˆ2.1, 8.0 Hz,
1H), 3.52±3.66 (m, 4H), 4.01 (dd, Jˆ8.0, 14.8 Hz, 1H), 4.14
(dd, Jˆ2.1, 14.8 Hz, 1H), 7.26±7.30 (m, 2H), 7.36±7.51
(m, 3H); 13C NMR d 19.60, 24.42, 25.91, 47.78, 54.99,
55.85, 58.11, 126.32, 128.62, 129.13, 131.84, 163.50,
176.53; MS m/z 311 (M1, 100). Anal. Calcd for
C18H21N3O2: C, 69.43; H, 6.80; N, 13.49. Found: C,
69.35; H, 6.85; N, 13.40.
(E)-3,4-Bis(methoxycarbonyl)-2-piperidino-1-pyrroline
1
(20c). Colorless oil, IR (neat) 1738 cm21; H NMR d 1.57
(br s, 6H) 3.38 (br s, 4H), 3.72, 3.75 (each s, 3H), 3.96±4.24
(m, 4H); 13C NMR d 24.44, 25.54, 47.78, 47.87, 51.21,
52.41, 52.63, 59.30, 163.09, 170.86, 173.62; MS m/z
(relative intensity) 268 (M1, 44), 209 (100). Anal. Calcd
for C13H20N2O4: C, 58.19; H, 7.51; N, 10.44. Found: C,
57.87; H, 7.62, N, 10.58.
(3) A solution of 3d (1.58 g, 4.0 mmol) and 12 (751 mg,
4.0 mmol) in dry DME (10 mL) was stirred with CsF
(791 mg, 5.2 mmol) at room temperature for 10 h under
argon. Flash chromatography of the residue obtained by
the same procedure as above gave 319 mg (34%) of 15
and 776 mg (62%) of a 2.3:1 mixture of 3a-methyl-substi-
tuted 13d and 6a-methyl-substituted 1:1 adduct 14d
(E)-3,4-Bis(methoxycarbonyl)-2-morpholino-1-pyrroline
1
(20d). Pale yellow oil, IR (neat) 1738 cm21; H NMR d
1
(estimated by H NMR) (entry 22 in Table 1). Although
3.30±3.80 (m, 8H), 3.73, 3.78 (each s, 3H), 3.30±4.30 (m,
4H); 13C NMR d 47.08, 47.51, 52.05, 52.48, 52.73, 59.39,
66.46, 163.18, 170.41, 173.45; MS m/z (relative intensity)
270 (M1, 60), 211 (100). Anal. Calcd for C12H18N2O5: C,
53.32; H, 6.71; N, 10.37. Found: C, 53.03; H, 6.83; N, 10.59.
chromatographic separation of the 1:1 adducts was again
unsuccessful, washing of the mixture with ethanol (5 mL)
gave the minor adduct 14d (125 mg, 10%) as an insoluble
compound.

7732
O. Tsuge et al. / Tetrahedron 56 (2000) 7723±7735
Cycloaddition reactions of azomethine ylides with
fumaronitrile (18)
(ethyl acetate±hexane (1:1)), mp 172±1738C; IR (KBr)
1
3258, 2198 cm21; H NMR d 1.85±2.15 (m, 4H), 3.4±3.6
(m, 4H), 6.13, 6.17 (each d, Jˆ3.4 Hz, 1H), 8.13 (br s, 1H);
13C NMR d 25.48, 48.55, 68.34, 110.35, 110.69, 120.75,
147.47; MS m/z (relative intensity) 161 (M1, 100). Anal.
Calcd for C9H11N3: C, 67.06; H, 6.88; N, 26.07. Found: C,
66.78; H, 6.82; N, 25.80.
As a typical run, the reaction of 3a with 18 in DME under
re¯ux is shown below (entry 12 in Table 2). A solution of 3a
(403 mg, 1.0 mmol) and 18 (78 mg, 1.0 mmol) in dry DME
(25 mL) was re¯uxed with CsF (304 mg, 2.0 mmol) for 10 h
under nitrogen, and then concentrated in vacuo. Flash chro-
matography of the residue obtained by the same procedure
as above gave 22a (42 mg, 23%) and 21a (73.5 mg, 35%)
from elution of a mixture of benzene±ethyl acetate (9:1) and
AcOEt, respectively.
3-Cyano-2-piperidinopyrrole (22c). Colorless needles
(ethyl acetate±hexane (1:1)), mp 90±90.58C; IR (KBr)
1
3272, 2206 cm21; H NMR d 1.42±1.72 (m, 6H), 3.27±
3.31 (m, 4H), 6.17, 6.28 (each dd, Jˆ2.5, 3.4 Hz, 1H),
8.59 (br s, 1H); 13C NMR d 23.79, 25.37, 50.53, 73.98,
110.56, 111.89, 119.51, 149.67; MS m/z (relative intensity)
175 (M1, 100). Anal. Calcd for C10H13N3: C, 68.54; H, 7.48;
N, 23.98. Found: C, 68.82; H, 7.43; N, 23.99.
The other reactions were performed under the conditions
listed in Table 2 (entries 8±11, 13 and 14).
2-Anilino-3,4-dicyano-2-pyrroline (21a).13 Pale yellow
viscous oil. IR (neat) 3346, 3146, 2252, 2174, 1656 cm21
;
3-Cyano-2-morpholinopyrrole (22d). Purple needles
(benzene±hexane (1:1)), mp 127±1288C; IR 3276,
MS m/z (relative intensity) 210 (M1, 10), 77 (100). HRMS
Calcd for C12H10N4 210.0905. Found: 210.0885.
1
2210 cm21; H NMR d 3.25±3.35 (m, 4H), 3.80±3.85 (m,
4H), 6.22, 6.34 (each dd, Jˆ2.5, 3.3 Hz, 1H), 8.62 (br s,
1H); 13C NMR d 49.45, 66.31, 75.22, 110.92, 112.47,
113.76, 148.48; MS m/z (relative intensity) 177 (M1, 78),
119 (100). Anal. Calcd for C9H11N3O: C, 61.00; H, 6.26; N,
23.72. Found: C, 61.07; H, 6.29; N, 23.65.
3,4-Dicyano-2-(1-pyrrolidinyl)-2-pyrroline (21b). Color-
less needles (benzene±hexane (1:1)), mp 135±1368C; IR
3270, 2242, 2160, 1595 cm21 1H NMR (DMSO-d6) d
;
1.75±2.0 (m, 4H), 3.36±3.40 (m, 4H), 3.49 (dd, Jˆ2.1,
4.6 Hz, 1H), 3.55 (dd, Jˆ2.1, 9.3 Hz, 1H), 4.11 (dd,
Jˆ4.6, 9.3 Hz, 1H), 6.39 (s, 1H); 13C NMR (DMSO-d6) d
24.78, 31.88, 45.61, 47.55, 47.96, 121.58, 122.10, 160.91;
MS m/z (relative intensity) 188 (M1, 72), 160 (100). Anal.
C10H12N4: C, 63.81; H, 6.43; N, 29.76. Found: C, 63.85; H,
6.33; N, 29.46.
Dehydrocyanation of pyrroline 21a leading to pyrrole
22a
A solution of 21a (294 mg, 1.4 mmol) in dry DME (5 mL)
was re¯uxed with CsF (205 mg, 1.4 mmol) under nitrogen
for 24 h, and then concentrated in vacuo to leave the residue.
Flash chromatography of the residue obtained by the same
procedure as above gave 218 mg (85%) of 22a by using a
mixture of benzene±ethyl acetate (1:1) as eluent.
3,4-Dicyano-2-piperidino-2-pyrroline (21c). Colorless
needles (cyclohexane), mp 125±1268C; IR (KBr) 3272,
2236, 2166, 1603 cm21 1H NMR (DMSO-d6) d 1.40±
;
1.70 (m, 6H), 3.32±3.44 (m, 4H), 3.48 (dd, Jˆ2.1, 4.6 Hz,
1H), 3.52 (dd, Jˆ2.1, 9.7 Hz, 1H), 4.12 (dd, Jˆ4.6, 9.7 Hz,
1H), 6.51 (s, 1H); 13C NMR (DMSO-d6) d 23.32, 25.07,
32.02, 46.43, 46.61, 47.67, 121.47, 121.69, 162.78; MS
m/z (relative intensity) 202 (M1, 7), 175 (100). Anal.
Calcd for C11H14N4: C, 65.32; H, 6.98; N, 27.70. Found:
C, 65.41; H, 7.05; N, 27.48.
The similar dehydrocyanation of 20c gave a 79% yield of
21c.
Cycloaddition reaction of azomethine ylide with
2-chloroacrylonitrile (19)
A solution of 3a (1.2 g, 3.0 mmol) and 19 (1.31 g, 15 mmol)
in dry DME (10 mL) was re¯uxed with CsF (547 mg,
3.6 mmol) for 10 h under argon. Chromatography (BW-
200, benzene±ethyl acetate (9:1)) of the reaction mixture
obtained by the same procedure as above gave 277 mg
(42%) of 2-anilino-3-chloro-3-cyano-1-pyrroline (23a)
(entry 16 in Table 2).
3,4-Dicyano-2-morpholino-2-pyrroline (21d). Colorless
prisms (benzene), mp 153±154.58C; IR (KBr) 3282, 2234,
1
2170 cm21; H NMR (DMSO-d6) d 3.28±3.45 (m, 4H),
3.46±3.67 (m, 6H), 4.16 (dd, Jˆ5.1, 9.3 Hz, 1H), 6.64 (br
s, 1H); 13C NMR (DMSO-d6) d 31.90, 46.61, 46.67, 47.39,
65.34, 121.27, 163.27; MS m/z (relative intensity) 204 (M1,
63), 177 (100). Anal. Calcd for C10H12N4O: C, 58.81; H,
5.92; N, 27.44. Found: C, 58.84; H, 5.98; N, 27.27.
1
23a. Pale brown oil, IR (neat) 3360, 2240, 1680 cm21; H
NMR d 2.68 (dt, Jˆ6.4, 14.3 Hz, 1H), 2.84 (dt, Jˆ7.2,
14.3 Hz, 1H), 3.91 (br s, 2H), 7.02±7.12 (m, 1H), 7.28±7.38
(m, 4H), 7.48 (br s, 1H); 13C NMR d 41.31, 58.15, 77.29,
116.15, 123.74, 128.35, 129.23, 155.01; MS m/z (relative
intensity) 221 (M1, 25), 220 (40), 219 (M1, 80), 218 (100).
HRMS Calcd for C11H10N3Cl 219.0564. Found: 219.0560.
2-Anilino-3-cyanopyrrole (22a). Colorless needles (ethyl
acetate±hexane (1:1)), mp 92.5±93.58C; IR (KBr) 3358,
1
3270, 2216 cm21; H NMR d 5.89 (br s, 1H), 6.32, 6.44
(each dd, Jˆ2.5, 3.4 Hz, 1H), 6.87±6.92 (m, 2H), 6.95±
7.02 (m, 1H), 7.26±7.33 (m, 2H), 8.20 (br s, 1H); 13C
NMR d 80.74, 110.04, 113.51, 116.28, 116.98, 121.63,
129.68, 139.91, 142.50; MS m/z (relative intensity) 183
(M1, 100). Anal. Calcd for C11H9N3: C, 72.11; H, 4.95;
N, 22.94. Found: C, 71.88; H, 5.01; N, 22.77.
Air oxidation of 20a leading to 2-anilino-3,4-bis(methoxy-
carbonyl)-3-hydroxy-1-pyrroline (24). A solution of 20a
(314 mg, 1.15 mmol) in ethanol (10 mL) was stirred at room
temperature under air atmosphere for 10 days. The solvent
was evaporated in vacuo and the residue was triturated with
3-Cyano-2-(1-pyrrolidinyl)pyrrole (22b). Gray needles

O. Tsuge et al. / Tetrahedron 56 (2000) 7723±7735
7733
benzene to give solid which was recrystallized from
benzene to give 72 mg (22%) of 24 as colorless plates.
nitrogen. The reaction mixture was evaporated in vacuo, and
¯ash chromatography (BW 300) of the residue with a
mixture of benzene±ethyl acetate (4:1) gave 205 mg
(78%) of a 3:1 mixture of isomeric Michael adducts 26d
1
Mp 71±728C; IR 3550, 3296, 1738, 1715 cm21; H NMR
d 3.72, 3.81 (each s, 3H), 3.5±4.1 (m, 4H), 7.05±7.38 (m,
6H); MS m/z (relative intensity) 292 (M1, 60), 291 (100).
Anal, Calcd for C14H16N2O5: C, 57.53; H, 5.52; N, 9.59.
Found: C, 57.67; H, 5.42; N, 9.48.
1
and 27d (estimated by H NMR). Although quantitative
separation of the isomers was very dif®cult, pure 26d and
27d were obtained by further chromatography and recrys-
tallization. The structure of (Z)-Michael adduct 26d was
determined by the X-ray crystallographic analysis.
The cycloaddition reactions of azomethine ylides with
DMAD
(Z)-1,2-Bis(methoxycarbonyl)-1-[3,4-bis(methoxycar-
bonyl)-2-(morpholino)pyrrolyl]ethane (26d). Pale yellow
prisms (hexane±benzene (1:1)) mp 147±1488C; IR 1738,
As typical examples, the reactions of entries 1 and 6 in
Table 3 are shown, respectively. (i) A solution of 3a
(423 mg, 1.05 mmol) and DMAD (150 mg, 1.05 mmol) in
dry DME (3 mL) was stirred with CsF (160 mg, 1.05 mmol)
at room temperature for 6 h under argon. The reaction
mixture was concentrated in vacuo and the residue was
extracted with dichloromethane (20 mL). The organic
layer was washed with water, dried over anhydrous
MgSO4, and evaporated in vacuo. Flash chromatography
(BW 300) of the residue with a mixture of benzene±ethyl
acetate (4:1) gave 204 mg (71%) of aminonitrile cyclo-
adduct 25a. (ii) A solution of 3d (0.98 g, 2.5 mmol) and
DMAD (0.71 g, 5.0 mmol) in dry DME (10 mL) was stirred
with CsF (0.38 g, 2.5 mmol) at room temperature for 6 h.
Flash chromatography of the residue obtained from the
same procedure as above with a mixture of benzene±ethyl
acetate (5:1) gave 327 mg (32%) of a 2:1 mixture of 26d and
1
1705 cm21; H NMR d 2.97±3.05 (m, 4H), 3.58±3.61 (m,
4H), 3.73, 3.79, 3.84, 3.89 (each s, 3H), 6.91 (s, 1H), 7.01 (s,
1H); 13C NMR d 51.45, 51.64, 51.91, 52.47, 53.21, 67.22,
107.83, 115.09, 123.02, 123.90, 137.57, 144.63, 163.27,
163.66, 263.75, 165.49. MS m/z (relative intensity) 410
(M1, 60), 319 (100). Anal. Calcd for C18H22N2O9: C,
52.68; H, 5.40; N, 6.83. Found: C, 52.79; H, 5.49; N, 6.73.
Crystallography of 26d
A single crystal (0.18£0.32£0.36 mm) grown from a
mixture of hexane±benzene (1:1) was used for the unit-
cell determination and the data collections of a Rigaku
AFC5S diffractometer. This crystal was monoclinic, space
Ê
Ê
group P21 (#14), Zˆ4 with aˆ8.20(3) A, bˆ8.980(6) A,
1
Ê
Ê 3
27d (estimated by H NMR) and 68 mg (10%) of 25d,
respectively.
cˆ27.13(1) A, bˆ96.64(9)8, Vˆ1985(8) A , and Dcalcd
ˆ
1.373 g/cm3. All calculations were performed using the
texsan program,21 and the structure was solved by a direct
method (MITHRIL).22 The ®nal R-factors after full-matrix
least-squares re®nement were 0.087 for 1149 observed
re¯ections.
2-Anilino-3,4-bis(methoxycarbonyl)pyrrole (25a). Color-
less prisms (benzene), mp 148±1498C; IR 3352, 3296,
1
1713 cm21; H NMR d 3.74, 3.75 (each s, 3H), 6.8±7.4
(m, 6H), 8.32, 9.06 (each br s, 1H); 13C NMR d 51.09,
51.45, 93.40, 114.19, 118.64, 119.67, 129.93, 139.94,
143.89, 164.63, 166.35; MS m/z (relative intensity) 274
(M1, 44), 210 (100). Anal. Calcd for C14H14N2O4: C,
61.31; H, 5.15; N, 10.21. Found: C, 61.44; H, 5.28; N, 10.05.
(E)-Morpholino isomer 27d. Colorless needles (hexane±
1
benzene (1:1)), mp 104±1058C; IR 1738, 1717 cm21; H
NMR d 2.90±3.15 (m, 4H), 3.55±3.75 (m, 4H), 3.80,
3.81, 3.88, 3.89 (each s, 3H), 6.25 (s, 1H), 7.14 (s, 1H);
13C NMR d 50.82, 51.70, 52.30, 52.51, 53.05, 66.69,
111.09, 116.37, 118.59, 121.81, 139.03, 141.61, 162.73,
163.19, 163.89, 165.06; MS m/z (relatively intensity) 410
(M1, 56), 319 (100). Anal. Calcd for C18H22N2O9: C, 52.68,
H, 5.40, N, 6.83. Found: C, 52.79; H, 5.49; N, 6.73.
3,4-Bis(methoxycarbonyl)-2-piperidinopyrrole
(25c).
Pale yellow viscous oil, IR (neat) 3296, 1711 cm21; H
NMR d 1.45±1.70 (m, 6H), 3.02±3.15 (m, 4H), 3.77, 3.80
(each s, 3H), 6.91 (d, Jˆ3.0 Hz, 1H), 9.30 (br s, 1H); 13C
NMR d 23.95, 25.88, 51.48, 51.52, 100.47, 115.13, 118.83,
147.081, 165.35, 166.68; MS m/z (relative intensity) 266
(M1, 100). HRMS Calcd for C13H18N2O4 266.1267.
Found: 266.1275.
1
A similar reaction of pyrrole 25b or 25c with DMAD gave a
mixture of the corresponding Michael adducts 26b (Z
isomer) and 27b (E isomer) or 26c (Z isomer) and 27c (E
isomer) in 72 or 74% yield, respectively. However, pure 26b
could not be isolated.
3,4-Bis(methoxycarbonyl)-2-morpholinopyrrole (25d).
Colorless prisms (ethyl acetate±hexane (1:1)), mp 127±
1
1288C; IR 3284, 1711 cm21; H NMR d 3.10±3.25 (m,
(E)-1,2-Bis(methoxycarbonyl)-1-[3,4-bis(methoxycar-
bonyl)-2-(1-pyrrolidinyl)pyrrolyl]ethene (27b). Colorless
needles (hexane±ethyl acetate (1:1)), mp 107±1088C; IR
4H), 3.7±3.8 (m, 4H), 3.78 (d, Jˆ2.9 Hz, 1H), 9.57 (br s,
1H); 13C NMR d 51.20, 51.60, 51.63, 66.85, 101.70, 115.30,
119.27, 145.48, 165.26, 165.51; MS m/z (relative intensity)
268 (M1, 100). Anal Calcd for C12H16N2O5: C, 53.72, H,
6.01; N, 10.44. Found: C, 53.80; H, 6.01; N, 10.50.
1
1720, 1710 cm21; H NMR d 1.72±2.12 (m, 4H), 2.96±
3.31 (m, 4H), 3.72, 3.78, 3.83, 3.89 (each s, 3H), 6.25 (s,
1H), 7.15 (s, 1H); MS m/z (relative intensity) 394 (M1, 57),
303 (100). Anal. Calcd for C18H22N2O8: C, 54.82; H, 5.62;
N, 7.10. Found: C, 54.75; H, 5.52; N, 6.94.
Reaction of pyrrole 25d with DMAD
A solution of 25d (172 mg, 0.64 mmol) and DMAD (91 mg,
0.64 mmol) in dry benzene (3 mL) was stirred with triethyl-
amine (72 mg, 0.71 mg) at room temperature for 4 h under
(Z)-1,2-Bis(methoxycarbonyl)-1-[3,4-bis(methoxycar-
bonyl)-2-(piperidino)-pyrrolyl]ethene (26c). Pale yellow
viscous oil; IR (neat) 1734, 1714 cm21; 1H NMR d 1.47 (br

7734
O. Tsuge et al. / Tetrahedron 56 (2000) 7723±7735
s, 6H), 2.90 (br s, 4H), 3.73, 3.78, 3.82, 3.87 (each s, 3H),
6.84 (s, 1H), 7.01 (s, 1H); 13C NMR d 23.76, 26.15,
51.64, 51.45, 51.91, 52.47, 53.21, 107.83, 115.09,
123.07, 123.07, 123.90, 137.51, 144.63, 163.27, 163.66,
163.75, 165.50; MS m/z (relative intensity) 408 (M1, 67),
317 (100). HRMS Calcd for C19H24N2O8 408.1533. Found:
408.1539.
2H), 6.97±7.03 (m, 1H), 7.22±7.29 (m, 2H); 13C NMR
13.87, 30.01, 122.32, 122.60, 128.95, 149.63, 154.57.
Anal. C9H12N2S: C, 59.97; H, 6.71; N, 15.54. Found: C,
60.09; H, 6.82; N, 15.50.
(ii) As a typical example of the reaction with p-nitrobenzal-
dehyde (30), the reaction of 3c is shown (entry 6 in Table 4).
A solution of 3c (1.5 g, 3.8 mmol) and 30 (2.87 g,
19.0 mmol) in dry DME (15 mL) was stirred with CsF
(703 mg, 4.6 mmol) at room temperature for 10 h under
argon. The reaction mixture was concentrated in vacuo
and the residue was extracted with chloroform (30 mL).
Flash chromatography of the extract on silica gel
(BW-300) with a mixture of ethyl acetate±ethanol (10:1)
gave 943 mg (90%) of 2-oxazoline 36c.
(E)-Piperidino isomer 27c. Colorless needles (hexane); mp
1
109±1108C; IR 1751, 1721 cm21; H NMR d 1.50 (br s,
6H), 2.89±2.92 (m, 4H), 3.79, 3.81 (each s, 3H), 3.87 (s,
6H), 6.24 (s, 1H), 7.12 (s, 1H); 13C NMR d 23.45, 25.51,
51.82, 51.64, 52.20, 52.47, 52.87, 110.21, 116.06, 117.99,
121.42, 139.33, 143.56, 162.60, 163.39, 164.11, 165.55; MS
m/z (relative intensity) 408 (M1, 70), 317 (100). Anal. Calcd
for C19H24N2O8: C, 55.87; H, 5.92; N, 6.86. Found: C,
55.82; H, 6.04; N, 6.76.
Reactions of 3a and 3d with 30 under similar conditions
gave the corresponding 2-oxazolines 36a and 36d, respec-
tively (entries 5 and 7 in Table 4).
Cycloaddition reactions of azomethine ylides with
aldehydes 28±33
2-Anilino-5-(p-nitrophenyl)-2-oxazoline (36a). Colorless
prisms (benzene), mp 189.5±1908C, IR 3236, 1657, 1518,
(i) Reaction with benzaldehyde (28). After a solution of 3a
(1.5 g, 3.73 mmol) and 28 (1.98 g, 18.7 mmol) in dry DME
(10 mL) was stirred with CsF (679 mg, 4.5 mmol) at room
temperature for 10 h under argon, the reaction mixture was
concentrated in vacuo. The residue was extracted with ether
(30 mL) and ¯ash chromatography (BW-300) of the extract
furnished imine 40 (324 mg, 48%) and 2-oxazoline 34a
(342 mg, 39%) from elution of a mixture of benzene±
ethyl acetate (9:1) and ethyl acetate, respectively (entry 2
in Table 4).
1354 cm21
;
1H NMR (DMSO-d6) d 3.34 (dd, Jˆ6.7,
12.7 Hz, 1H), 4.34 (dd, Jˆ9.3, 12.7 Hz, 1H), 5.76 (dd,
Jˆ6.7, 9.3 Hz, 1H), 6.90±6.96 (m, 1H), 7.23±7.30 (m,
2H), 7.63±7.67 (m, 4H), 8.29 (d, Jˆ8.9 Hz, 2H); 9.45 (br
s, 1H); 13C NMR (DMSO-d6) d 60.95, 77.07, 117.45,
121.15, 123.90, 126.47, 128.55, 140.38, 147.04, 148.87,
155.54; MS m/z (relative intensity) 283 (M1, 81), 119
(100). Anal. Calcd for C15H13N3O3: C, 63.59; H, 4.63; N,
14.83. Found: C, 63.62; H, 4.67; M, 14.76.
5-(p-Nitrophenyl)-2-piperidino-2-oxazoline (36c). Color-
less needles (hexane), mp 86±878C, IR 1649, 1522,
The similar reaction of 3a with p-chlorobenzaldehyde (29)
gave a mixture of 2-oxazoline 35a and imine 40 (entries 3
and 4 in Table 4).
1
1340 cm21, H NMR d 1.62 (br s, 6H), 3.44 (br s, 4H),
3.65 (dd, Jˆ7.2, 12.2 Hz, 1H), 4.28 (dd, Jˆ9.3, 12.2 Hz,
1H), 5.57 (dd, Jˆ7.2, 9.3 Hz, 1H), 7.45±7.51 (m, 2H),
8.21±8.27 (m, 2H); 13C NMR d 24.19, 25.37, 46.68,
61.28, 79.99, 123.99, 126.14, 147.56, 148.68, 161.22; MS
m/z (relative intensity) 275 (M1, 36), 84 (100). Anal. Calcd
for C14H17N3O3: C, 61.08; H, 6.22; N, 15.26. Found: C,
60.89; H, 6.28; N, 15.42.
2-Anilino-5-phenyl-2-oxazoline (34a). Colorless needles
1
(cyclohexane), mp 127±1288C. IR 3240, 1657 cm21; H
NMR d 3.78 (dd, Jˆ7.6, 11.8 Hz, 1H), 4.24 (dd, Jˆ8.9,
11.8 Hz, 1H), 5.55 (dd, Jˆ7.6, 8.9 Hz, 1H), 6.79 (br s,
1H), 6.94±7.01 (m, 1H), 7.21±7.38 (m, 9H); 13C NMR d
58.76, 80.86, 119.19, 122.35, 125.86, 128.48, 128.82,
128.96, 140.02, 140.64, 157.19; MS m/z (relative intensity)
238 (M1, 40), 134 (100). Anal. Calcd for C15H14N2O:
C, 75.59; H, 5.93; N, 11.76. Found: C, 75.81; H, 6.05; N,
11.46.
2-Morpholino-5-(p-nitrophenyl)-2-oxazoline (36d). Color-
less needles (benzene±hexane (1:1)), mp 89±908C; IR
1
1663, 1521, 1344 cm21; H NMR d 3.40±3.52 (m, 4H),
3.68 (dd, Jˆ7.6, 12.7 Hz, 1H), 4.29 (dd, Jˆ9.3, 12.7, 1H),
5.62 (dd, Jˆ7.6, 9.3 Hz, 1H), 5.70±5.80 (m, 4H), 7.49 (d,
Jˆ8.9 Hz, 2H), 8.22±8.27 (m, 2H); 13C NMR d 45.88,
61.06, 66.32, 80.38, 124.06, 126.20, 147.69, 148.03,
160.95; MS m/z (relative intensity) 277 (M1, 34), 86
(100). Anal. Calcd for C13H15N3O4: C, 56.31; H, 5.45; N,
15.15. Found: C, 56.20; H, 5.41; N, 15.18.
2-Anilino-5-(p-chlorophenyl)-2-oxazoline (35a). Color-
less needles (benzene), mp 156±1578C, IR 3240,
1651 cm21
;
1H NMR (DMSO-d6) d 3.62 (dd, Jˆ6.7,
12.2 Hz, 1H), 4.24 (dd, Jˆ9.3, 12.2 Hz, 1H), 5.58 (dd,
Jˆ6.7, 9.3 Hz, 1H), 6.88±6.94 (m, 1H), 7.40, 7.47 (each
d, Jˆ8.4 Hz, 2H), 7.51 (d, Jˆ7.2 Hz, 2H), 9.13 (br s, 1H);
13C NMR (DMSO-d6) d 60.65, 77.67, 117.48, 121.00,
127.40, 128.50, 128.64, 132.52, 140.14, 140.64, 155.59;
MS m/z (relative intensity) 274 (M1, 5), 272 (M1, 17),
134 (100), 132 (47). Anal. Calcd for C15H13N2OCl:
C, 66.03; H, 4.81; N, 10.27. Found: C, 66.31; H, 4.87; N,
10.35.
(iii) Reaction of 3a with 2-pyridinecarboxaldehyde (31).
After a solution of 3a (1.5 g, 3.73 mmol) and 31 (1.99 g,
18.6 mmol) in dry DME (10 mL) was stirred with CsF
(673 mg, 4.4 mmol) at room temperature for 10 h under
argon, the reaction mixture was concentrated in vacuo.
The residue was extracted with ether (30 mL), and ¯ash
chromatography of the extract on silica gel (BW-300)
with ethyl acetate furnished 635 mg (71%) of 2-oxazoline
37a (entry 8 in Table 4).
2,3-Dimethyl-1-phenylisothiourea (40). Colorless needles
(hexane); mp 59.5±60.58C; IR 3342, 1603 cm21; 1H NMR d
2.25 (s, 3H), 2.91 (s, 3H), 4.40 (br s, 1H), 6.89±6.91 (m,

O. Tsuge et al. / Tetrahedron 56 (2000) 7723±7735
7735
6. Tsuge, O.; Kanemasa, S.; Yamada, T.; Matsuda, K. J. Org.
Chem. 1987, 52, 2523.
A similar reaction of 3a with 3-(32) or 4-pyridinecarboxal-
dehyde (33) afforded the corresponding 2-oxazolines 38a or
39a, respectively (entries 9, 10 in Table 4).
7. Tsuge, O.; Kanemasa, S.; Matsuda, K. J. Org. Chem. 1986, 51,
1997.
8. Tsuge, O.; Kanemasa, S.; Matsuda, K. Chem. Lett. 1985, 1411.
9. Recently, two research groups demonstrated that in the reac-
tions 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. (a) Kohra,
S.; Ueda, K.; Tominaga, Y. Chem. Pharm. Bull. 1995, 43, 204.
(b) Oba, M.; Yoshihara, M.; Nishiyama, K. Heterocycles 1997, 45,
1405.
2-Anilino-5-(2-pyridyl)-2-oxazoline (37a). Colorless
needles (benzene), mp 138.5±139.58C, IR 3370,
1
1688 cm21; H NMR d 3.95 (dd, Jˆ6.7, 11.8 Hz, 1H),
4.35 (dd, Jˆ9.3, 11.8 Hz, 1H), 5.67 (dd, Jˆ6.7, 9.3 Hz,
1H), 6.4±7.2 (br s, 1H), 6.99 (t, Jˆ7.6 Hz, 1H), 7.21±7.44
(m, 6H), 7.70 (t, Jˆ7.6 Hz, 1H), 8.59 (d, Jˆ5.1 Hz, 1H); 13C
NMR d 57.32, 80.34, 119.21, 119.82, 122.42, 123.04,
128.98, 137.03, 140.77, 149.49, 156.92, 159.49; MS m/z
(relative intensity) 239 (M1, 14), 93 (100). Anal. Calcd
for C14H13N3O: C, 70.28; H, 5.48; N, 17.56. Found: C,
70.33; H, 5.56; N, 17.44.
10. It has been reported that 2-azaallyl anion generated from
N-(silylmethyl)iminodithiocarbonate reacted with carbonyl
compounds to give the formal [312] cycloadducts of the alkyl-
thionitrile ylide such as C: Oba, M.; Yoshihara, M.; Nagatsuka, J.;
Nishiyama, K. Heterocycles 1997, 45, 1913.
2-Anilino-5-(3-pyridyl)-2-oxazoline (38a). Colorless
needles (benzene), mp 127.5±1288C, IR 3238, 1653 cm21
;
11. Tsuge, O.; Kanemasa, S.; Matsuda, K. J. Org. Chem. 1984, 49,
2688.
1H NMR d 3.84 (dd, Jˆ7.6, 12.2 Hz, 1H), 4.35 (dd, Jˆ9.3,
12.2 Hz, 1H), 5.25 (br s, 1H), 5.59 (dd, Jˆ7.6, 9.3 Hz, 1H),
6.99±7.06 (m, 1H), 7.25±7.42 (m, 5H), 7.70±7.73 (m, 1H),
8.59±8.65 (m, 2H); 13C NMR d 59.42, 78.20, 118.87,
122.55, 123.79, 129.04, 133.42, 135.85, 140.07, 147.49,
149.77, 156.94; MS m/z (relative intensity) 239 (M1, 65),
93 (100). Anal. Calcd for C14H13N3O: C, 70.28; H, 5.48; N,
17.56. Found: C, 70.36; H, 5.54; N, 17.56.
12. The initial azomethine ylide adducts could be isolated as stable
compounds in the reaction of 3 with electron-de®cient CvN and
NvN double bonds in the presence of CsF. The results will be
reported elsewhere in the near future.
13. Position of double bond in each cycloadduct has been found to
depend upon th e electronic nature and the steric size of the sub-
stituents (Ref. 5). The double bond in pyrrolines presumably
migrates to the thermodynamically most stable location. Dicyano-
pyrrolines 21b±21d except for 21a exist only as 2-pyrrolines in
neat state and DMSO-d6 solution, but exist in a mixture of 1- and 2-
pyrrolines in CDCl3 solution. However, 21a whose IR exhibited
two NH absorption bands showed a complex 1H NMR spectrum of
a mixture of 1- and 2-pyrrolines even in DMSO-d6.
14. Tsuge, O.; Ueno, K.; Kanemasa, S.; Yorozu, K. Bull. Chem.
Soc. Jpn 1986, 59, 1809.
2-Anilino-5-(4-pyridyl)-2-oxazoline (39a). Colorless
needles (hexane±benzene (1:1)), mp 134.5±1358C, IR
1
3254, 1680 cm21; H NMR d 3.76 (dd, Jˆ7.2, 12.2 Hz,
1H), 4.36 (dd, Jˆ9.3, 12.2 Hz, 1H), 5.23 (dd, Jˆ7.2,
9.3 Hz, 1H), 6.97±7.05 (m, 1H), 7.20±7.45 (m, 7H),
8.55±8.65 (m, 2H); 13C NMR d 59.55, 78.62, 118.78,
120.11, 122.64, 129.07, 139.82, 149.32, 150.20, 156.91;
MS m/z (relative intensity) 239 (M1, 86), 104 (100). Anal.
Calcd for C14H13N3O: C, 70.28; H, 5.48; N, 17.56. Found:
C, 70.27; H, 5.55: N, 17.45.
15. Berree, F.; Marchand, E.; Morel, G. Tetrahedron Lett. 1992,
33, 6155.
16. Giezendanner, H.; Heimgartner, H.; Jackson, B.; Winkler, T.;
Hansen, H. -J.; Schmid, H. Helv. Chim. Acta 1973, 56, 2611.
17. As reviews: Padwa, A. Acc. Chem. Res. 1976, 9, 371; Gilgen,
P.; Heimgartner, H.; Schmid, H.; Hansen, H.-J. Heterocycles 1977,
6, 143.
References
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20. Relative reactivity of nonstabilized C-unsubstituted
azomethine ylide, N-benzylmethylene methylide, toward benzal-
dehyde, dimethyl fumarate and N-phenylmaleimide has been
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