A selective synthesis of enamines versus aziridines

Article abstract of DOI:10.1002/jhet.529

The reaction of 10-azidoacetyl-10H-phenothiazine with olefinic dipolarophiles depends on the reaction temperature. In refluxing toluene, a mixture of enamine and aziridine is formed in 3:1 ratio. The reaction mechanism appears to involve a Michael-type addition of the nucleophilic N¹ azide atom to the olefinic double bond. In chloroform, a cycloaddition reaction takes place with the formation of a 4,5-dihydro-1,2,3-triazole. The heating of dihydrotriazoles in toluene is accompanied by nitrogen elimination leading to a mixture of enamine and aziridine in 1:3 ratio.

Full text of DOI:10.1002/jhet.529

January 2011
A Selective Synthesis of Enamines versus Aziridines
129
Dalila Belei,a Elena Bicu,a Peter G. Jones,b and M. Lucian Birsaa*
aDepartment of Organic Chemistry, ‘Al. I. Cuza’ University of Iasi, 700506 Iasi, Romania
bInstitute of Inorganic and Analytical Chemistry, Technical University of Braunschweig,
Hagenring 30, D-38106 Braunschweig, Germany
*E-mail: lbirsa@uaic.ro
Received January 6, 2010
DOI 10.1002/jhet.529
Published online 9 September 2010 in Wiley Online Library (wileyonlinelibrary.com).
The reaction of 10-azidoacetyl-10H-phenothiazine with olefinic dipolarophiles depends on the reac-
tion temperature. In refluxing toluene, a mixture of enamine and aziridine is formed in 3:1 ratio. The
reaction mechanism appears to involve a Michael-type addition of the nucleophilic N1 azide atom to the
olefinic double bond. In chloroform, a cycloaddition reaction takes place with the formation of a 4,5-
dihydro-1,2,3-triazole. The heating of dihydrotriazoles in toluene is accompanied by nitrogen elimina-
tion leading to a mixture of enamine and aziridine in 1:3 ratio.
J. Heterocyclic Chem., 48, 129 (2011).
INTRODUCTION
only retention of the azide unit but also cleavage of the
nitrogenAnitrogen single bond, as in the case of nitrene
chemistry [29–32]. The mechanistically simplest case,
addition, has been extensively used in cycloaddition
reactions. The Huisgen reaction of dipoles to dipolaro-
philes has been successfully applied with azides as
dipoles [33].
Phenothiazines and related compounds have shown
diverse biological activities, e.g., as tranquilizers [1],
antimalarial [2], antipsychotropic [3], antimicrobial [4],
antitubercular [5–7], or antitumor agents [8–10], revers-
ers of multidrug resistance and potential activity in treat-
ment of Alzheimer’s and Creutzfeldt-Jakob diseases
[11,12]. A slight variation in the substitution pattern of
the phenothiazine often causes a marked difference in
activities and therefore phenothiazines with various sub-
stituents are being synthesized and tested for activities
in search of better medicinal agents. An important modi-
fication of the parent phenothiazine structure is the
introduction of a substituent at the thiazine nitrogen
atom. This substituent may contain an azide moiety, a
grouping that leads to energy-rich and flexible inter-
mediates and has enjoyed considerable interest since its
discovery in 1864 [13–16]. Industrial interest in organic
azide compounds began with the use of azides for the
synthesis of heterocycles such as triazoles and tetra-
zoles, and other applications include use as blowing
agents and as functional groups in pharmaceuticals.
Azides can react very differently under different reac-
tion conditions [17–19]. In principle, they react with
electron-deficient compounds at N1 [20–24] and elec-
tron-rich compounds at N3 [25–28]. There can be not
RESULTS AND DISCUSSION
Following our interest for the synthesis of new pheno-
thiazine derivatives with biological activities, we report
here the chemical behavior of 10-azidoacetyl-10H-phe-
nothiazine 1 toward olefinic dipolarophiles. Compound
1 was obtained from 10-chloroacetyl-10H-phenothiazine
[34] and sodium azide using tetrabutylammonium bro-
mide as phase-transfer catalyst (Scheme 1).
Among dipolarophiles, terminal olefines and N-substi-
tuted maleinimides were used. The uncatalyzed thermal
cycloaddition of azide 1 to acrylonitrile and ethyl acry-
late allows the synthesis of 4,5-dihydro-1,2,3-triazoles
2a,b (Scheme 2). The structure of triazoles 2a,b has
been proved by mass spectrometry and nuclear magnetic
resonance (NMR) analysis. As expected, the reactions
with terminal alkenes took place slowly, even in boiling
chloroform. To shorten the reaction time, we decided to
C
V
2010 HeteroCorporation

130
D. Belei, E. Bicu, P. G. Jones, and M. Lucian Birsa
Vol 48
Scheme 1
increase the reaction temperature up to the boiling point
of toluene. Surprisingly, thin-layer chromatography
monitoring of the reaction progress did not reveal a
shorter reaction time. However, the reaction output was
completely different, a mixture of enamine 3 and aziri-
dine 4 being obtained in a ratio of 3:1 and total yield of
80% (Scheme 2, path ‘‘a" and Table 1). For both com-
pounds, mass spectrometric analysis showed molecular
ions of m/z with 28 amu less than that in the corre-
sponding triazoles. Nitrogen elimination was also indi-
cated by the IR spectra of the enamine, which showed
an intense absorption characteristic of a nitrogenAhy-
drogen bond (3349 cmꢀ1). The coupling constants of
the vinylic hydrogens (13.8 Hz) indicated a selective
synthesis of the trans-enamine.
Detailed structural information was obtained from X-
ray analysis of 3a (Fig. 1) and 4a (Fig. 2). From the
mechanistic point of view, we may assume that formation
of enamine and aziridine takes place by thermal decom-
position of 4,5-dihydro-1,2,3-triazole 2. To check this
assumption, the triazoles were heated in toluene for 36 h
(Scheme 2, path ‘‘b’’). Although the same compounds
were identified in the reaction mixture, the ratio of enam-
ine and aziridine is 1 : 3 (Table 1), which is in sharp con-
trast to the ratio obtained through pathway ‘‘a.’’ The
structure of aziridines obtained via pathway ‘‘b’’ was
proved to be identical with those reported above.
The uncatalyzed thermal cycloaddition of azide 1 to
N-substituted maleinimides proceeds in a similar manner
to that described above. Thus, in chloroform, the
Scheme 2
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A Selective Synthesis of Enamines versus Aziridines
131
Table 1
Products ratio and total isolated yields.
Compounds
Method
Ratio
Yield
3a þ 4a
3b þ 4b
6a þ 7a
6b þ 7b
3a þ 4a
3b þ 4b
6a þ 7a
6b þ 7b
Path a
Path a
Path a
Path a
Path b
Path b
Path b
Path b
3:1
3:1
80
81
70
72
85
88
92
90
2.8:1
2.8:1
1:3
1:3
1:3
1:3
corresponding fused 4,5-dihydro-1,2,3-triazoles 5a,b
have been obtained in 80% isolated yield (Scheme 3).
The structure of these compounds has been confirmed
by mass spectrometry (MS) and NMR analysis.
The latter has revealed a coupling constant of 11 Hz
for the syn-vicinal hydrogen atoms of the fused bridge.
By changing the temperature to the boiling point of tol-
uene, a mixture of enamine 6 and aziridine derivative 7
have been obtained in 70% total isolated yield (Scheme
3, path ‘‘a’’). As described in Table 1, the ratio of
enamine and aziridine is again ca. 3 : 1. The formation
of enamines 6 has been confirmed by the IR spectra
which revealed a strong absorption band at 3319 cmꢀ1
for NAH bond. Both structures have been fully charac-
terized by mass spectrometry and NMR analysis.
Figure 2. Molecular structure of aziridine 4a. Ellipsoids represent
50% probability levels.
nucleophilic N1 atom to the olefinic double bond (path
‘‘a’’). A simultaneous or subsequent elimination of mo-
lecular nitrogen opens the way for the aziridine ring clo-
sure or for a 1,2-hydride shift to the nitrogen atom. The
latter process, which leads to the enamines 3, appears to
be favored. The formation of a nitrene compound before
the Michael type interaction of azide with the olefinic
dipolarophiles was ruled out by heating the azide 1
alone in toluene. Regardless of the concentration (10ꢀ3
or 1M), after 72 h reflux, the azide was recovered in
quantitative yields. Moreover, the prolonged heating of
aziridines 4 and 7 in boiling toluene has ruled out their
conversion to enamine compounds 3 and 6.
In conclusion, we report here a temperature-dependent
interaction between 10-azidoacetyl-10H-phenothiazine
and olefinic dipolarophiles. In refluxing toluene, a mix-
ture of enamine and aziridine is formed in 3:1 ratio. The
reaction mechanism appears to involve a Michael type
addition of nucleophilic N1 azide atom to the olefinic
double bond. In chloroform, a cycloaddition reaction
takes place with the formation of a 4,5-dihydro-1,2,3-tri-
azole. The heating of the 4,5-dihydro-1,2,3-triazoles in
toluene is accompanied by nitrogen elimination leading
to a mixture of enamine and aziridine in 1:3 ratio. It
seems that by tuning the reaction temperature the selec-
tive synthesis of enamine or aziridine can be realized.
Thermal decomposition of 4,5-dihydro-1,2,3-triazoles
5 (Scheme 3, path ‘‘b’’) has provided again a mixture of
enamine and aziridine derivative with the latter as major
compound (Table 1). These facts suggest two different
mechanistic pathways for the formation of enamine/azir-
idine mixture. By controlling the reaction temperature
the formation and subsequent thermal decomposition of
4,5-dihydro-1,2,3-triazole 2 was allowed (path b). Alter-
natively, in refluxing toluene, the 10-azidoacetyl-10H-
phenothiazine 1 undergoes a Michael-type addition of
EXPERIMENTAL
General remarks. Melting points: Bu¨chi 510, uncorrected.
IR: Bruker Tensor 27. 1H and 13C NMR: Bruker DRX
400 with tetramethylsilane as internal standard at room
Figure 1. Molecular structure of enamine 3a. Ellipsoids represent 50%
probability levels.
Journal of Heterocyclic Chemistry
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132
D. Belei, E. Bicu, P. G. Jones, and M. Lucian Birsa
Vol 48
Scheme 3
temperature. Chemical shifts are reported in ppm downfield
from tetramethylsilane. MS: Finnigan MAT 90X, electron
impact (EI). All reagents were commercially available and
used without further purification.
mmol) in chloroform (30 mL) was heated under reflux for
72 h. The solvent was evaporated and the residue purified by
column chromatography on silica gel with ethyl acetate : hex-
ane 1 : 1 as eluent (Rf ¼ 0.35). Colorless crystals 1.3 g, 78%,
mp 160–161ꢂC; IR (ATR): 2103, 1664, 1458, 1381, 1260,
10-Azidoacetyl-10H-phenothiazine (1). To a solution of
10-chloroacetyl-10H-phenothiazine (2.75 g, 10 mmol) in chlo-
roform (30 mL) sodium azide (0.72 g, 11 mmol), water (15
mL), and tetrabutylammonium bromide (0.04 g, 0.12 mmol)
were added. The reaction mixture was stirred vigorously at
room temperature for 48 h and then separated. The organic
layer was washed with water (3 ꢁ 20 mL), dried off
(Na2SO4), and concentrated in vacuo. The residue was titrated
with ethanol and the resulting solid recrystallized from ethanol
(40 mL) to give 1 as colorless crystals; 2.4 g, 85%, mp 110–
111ꢂC; IR (attenuated total reflection [ATR]): 2105, 1682,
1
1115, 755, 735 cmꢀ1; H-NMR (dimethyl sulfoxide [DMSO]-
2
3
2
d6): d 3.45 (dd, J ¼ 9.6, J ¼ 10 Hz, 1 H, H5), 3.58 (dd, J
3
¼ 9.6, J ¼ 12.4 Hz, 1 H, H5), 4.82 (bs, 2 H, CH2), 5.52 (dd,
3J ¼ 10, 12.4 Hz, 1 H, H4), 7.32–7.75 (m, 8 H, 8 ꢁ CHar);
13C-NMR (DMSO-d6): d 48.4 (t), 50.4 (t), 63.7 (d), 117.1 (s),
127.1 (d), 127.4 (d), 128.0 (d), 132.1 (s), 137.3 (s), 166.3 (s);
MS (EI): m/z (%) 335 (24) [Mþ], 307 (72), 254 (8), 199 (100),
167 (20), 154 (18). Anal. Calcd. for C17H13N5OS: C, 60.88;
H, 3.91; N, 20.88. Found: C, 61.07; H, 4.14; N, 21.10.
4,5-Dihydro-1,2,3-triazole 2b. Following the typical proce-
dure after 72 h reflux, compound 2b (Rf ¼ 0.31) was obtained
as colorless crystals; 1.43 g, 75%, mp 130–131ꢂC. IR (ATR):
1
1459, 1367, 1253, 1178, 764 cmꢀ1; H-NMR (CDCl3): d 3.95
(bs, 2 H, CH2), 7.21–7.50 (m, 8 H, 8 ꢁ CHar); 13C-NMR
(CDCl3): d 50.9 (t), 126.6 (d), 127.3 (d), 127.4 (d), 128.2 (d),
133.0 (s), 137.5 (s), 166.7 (s); MS (EI): m/z (%) 282 (45)
[Mþ], 199 (100), 154 (12). Anal. Calcd. for C14H10N4OS: C,
59.56; H, 3.57; N, 19.85. Found: C, 59.84; H, 3.68; N, 20.06.
4,5-Dihydro-1,2,3-triazole 2a: Typical procedure. A solu-
tion of 1 (1.41 g, 5 mmol) and acrylonitrile (0.33 mL, 5
1736, 1680, 1462, 1299, 1104, 756 cmꢀ1
;
1H-NMR (CDCl3):
3
2
3
d 1.26 (t, J ¼ 7.2 Hz, 3 H, CH3), 3.42 (dd, J ¼ 9.6, J ¼ 11
Hz, 1 H, H5), 3.55 (dd, 2J ¼ 9.6, 3J ¼ 12.4 Hz, 1 H, H5),
3
4.24 (q, J ¼ 7.2 Hz, 2 H, OCH2), 4.90 (bs, 2 H, CH2), 5.05
(dd, 3J ¼ 11, 12.4 Hz, 1 H, H4), 7.24–7.55 (m, 8 H, 8 ꢁ
CHar); 13C-NMR (CDCl3): d 14.1 (q), 47.1 (t), 51.7 (t), 62.0
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A Selective Synthesis of Enamines versus Aziridines
133
(t), 79.5 (d), 126.7 (d), 126.9 (d), 127.2 (d), 127.3 (d), 127.4
(d), 128.1 (d), 128.2 (d), 133.0 (s), 137.5 (s), 137.6 (s), 166.6
(s), 168.2 (s); MS (EI): m/z (%) ¼ 382 (14) [Mþ], 354 (79),
199 (100), 154 (24). Anal. Calcd. for C19H18N4O3S: C, 59.67;
H, 4.74; N, 14.65. Found: C, 59.88; H, 4.55; N, 14.81.
Enamine 3b. Following the typical procedure after 72 h
reflux, compound 3b (Rf ¼ 0.28) was obtained as colorless
crystals: 1.07 g, 61%, mp 175–176ꢂC. IR (ATR): 3358, 1696,
1671, 1608, 1148, 978, 760, 623 cmꢀ1
;
1H-NMR (CDCl3): d
3
1.24 (t, J ¼ 6.4 Hz, 3 H, CH3), 3.82 (bs, 2 H, CH2), 4.11 (m,
3
4,5-Dihydro-1,2,3-triazole 5a. Following the typical proce-
dure after 48 h reflux, compound 5a (Rf ¼ 0.26) was obtained
as colorless crystals; 1.82 g, 80%, mp 180–181ꢂC. IR (ATR):
3 H, OCH2 þ CH), 4.47 (d, J ¼ 12.8 Hz, 1 H, CH), 5.59 (bs,
1 H, NH), 7.29–7.57 (m, 8 H, 8 ꢁ CHar); 13C-NMR (CDCl3):
d ¼ 14.5 (q), 49.9 (t), 59.1 (t), 87.0 (d), 126.8 (d), 127.1 (d),
127.2 (s), 127.3 (d), 128.2 (d), 128.4 (d), 133.2 (s), 137.7 (s),
147.3 (d), 167.3 (s), 169.0 (s); MS (EI): m/z (%) 354 (11)
[Mþ], 309 (5), 199 (100), 167 (16). Anal. Calcd. for
C19H18N2O3S: C, 64.39; H, 5.12; N, 7.90. Found: C, 64.58; H,
5.26; N, 8.12.
1
1715, 1712, 1459, 1384, 1256, 1183, 765, 692 cmꢀ1; H-NMR
3
(DMSO-d6): d 4.55 (d, J ¼ 11 Hz, 1 H, CH), 5.02 (bs, 2 H,
CH2), 5.81 (d, 3J ¼ 11 Hz, 1 H, CH), 7.12 (m, 2 H, 2 ꢁ
CHar), 7.39 (m, 7 H, 7 ꢁ CHar), 7.60 (m, 2 H, 2 ꢁ CHar),
7.73 (m, 2 H, 2 ꢁ CHar); 13C-NMR (DMSO-d6): d 49.4 (t),
57.2 (d), 82.8 (d), 126.6 (d), 126.9 (s), 127.1 (s), 127.5 (d),
128.0 (d), 128.6 (d), 128.8 (d), 131.5 (s), 132.1 (s), 137.0 (s),
167.1 (s), 170.5 (s), 171.8 (s); MS (EI): m/z (%) 455 (15)
[Mþ], 427 (85), 350 (34), 199 (100), 154 (25). Anal. Calcd for
C24H17N5O3S: C, 63.29; H, 3.76; N, 15.38. Found: C, 63.51;
H, 3.82; N, 15.62.
Aziridine 4b. Following the typical procedure after 72 h
reflux, compound 4b (Rf ¼ 0.11) was obtained as yellow crys-
tals: 0.35 g, 20%, mp 107–108ꢂC. IR (ATR): 1676, 1458,
1
3
1116, 766, 749, 657 cmꢀ1; H-NMR (CDCl3): d 1.24 (t, J ¼
7.2 Hz, 3 H, CH3), 2.14 (m, 1 H, CH), 3.52 (bs, 2 H, CH2),
3
3.61 (m, 2 H, CH2), 4.21 (q, J ¼ 7.2 Hz, 2 H, OCH2), 7.22–
7.58 (m, 8 H, 8 ꢁ CHar); 13C-NMR (CDCl3): d 14.5 (q), 44.1
(t), 50.0 (t), 60.75 (d), 60.8 (t), 126.9 (d), 127.1 (d), 128.1 (d),
133.2 (s), 138.0 (s), 166.8 (s), 170.3 (s); MS (EI): m/z (%) 354
(14) [Mþ], 199 (100), 167 (24). Anal. Calcd. for
C19H18N2O3S: C, 64.39; H, 5.12; N, 7.90. Found: C, 64.64; H,
5.31; N, 8.14.
4,5-Dihydro-1,2,3-triazole 5b. Following the typical proce-
dure after 48 h reflux, compound 5b (Rf ¼ 0.26) was obtained
as colorless crystals; 1.63 g, 80%, mp 167–168ꢂC. IR (ATR):
1
1705, 1682, 1462, 1395, 1257, 1223, 1131, 752, 598 cmꢀ1; H
3
NMR (DMSO-d6): d 0.97 (t, J ¼ 7.1 Hz, 3 H, CH3), 3.37 (q,
3J ¼ 7.1 Hz, 2 H, OCH2), 4.40 (d, 3J ¼ 10.6 Hz, 1 H, CH),
4.75 (bs, 1 H, CH2), 5.01 (bs, 1 H, CH2), 5.63 (d, 3J ¼ 10.6
Hz, 1 H, CH), 7.34–7.73 (m, 8 H, 8 ꢁ CHar); 13C NMR
(DMSO-d6): d ¼ 12.1 (q), 33.3 (t), 49.5 (t), 57.4 (d), 82.7 (d),
126.9 (d), 127.3 (d), 127.9 (d), 132.0 (s), 137.1 (s), 166.4 (s),
170.9 (s), 172.4 (s); MS (EI): m/z (%) ¼ 407 (18) [Mþ], 379
(57), 352 (28), 199 (100), 154 (28). Anal. Calcd. for
C20H17N5O3S: C, 58.96; H, 4.21; N, 17.19. Found: C, 59.12;
H, 4.38; N, 17.43.
Enamine 6a. Following the typical procedure after 48 h
reflux compound 6a (Rf ¼ 0.41) was obtained as yellow crys-
tals: 1.1 g, 51%, mp 193–194ꢂC. IR (ATR): 3318, 1704, 1686,
1
1636, 1388, 1178, 767 cmꢀ1; H-NMR (CDCl3): d 4.01 (bs, 2
H, CH2), 4.83 (s, 1 H, CH), 6.34 (bs, 1 H, NH), 7.20–7.58 (m,
13 H, 13 ꢁ CHar); 13C-NMR (CDCl3): d 45.9 (t), 86.2 (d),
125.8 (d), 126.4 (d), 126.6 (d), 127.2 (d), 127.3 (d), 127.4 (d),
127.8 (d), 128.0 (d), 128.4 (d), 128.5 (d), 128.8 (d), 129.0 (d),
129.1 (d), 131.7 (s), 137.0 (s), 137.6 (s), 147.9 (s), 165.6 (s),
166.1 (s), 170.3 (s); MS (EI): m/z (%) ¼ 427 (34) [Mþ], 350
(35), 199 (100). Anal. Calcd. for C24H17N3O3S: C, 67.43; H,
4.01; N, 9.83. Found: C, 67.61; H, 4.21; N, 10.12.
Enamine 3a and aziridine 4a: Path ‘‘a’’—Typical
procedure. A solution of 1 (1.41 g, 5 mmol) and acrylonitrile
(0.33 mL, 5 mmol) in toluene (30 mL) was heated under
reflux for 72 h. The solvent was evaporated and the residue
purified by column chromatography on silica gel with ethyl ac-
etate : hexane 1 : 1 as eluent.
Aziridine 7a. Following the typical procedure after 48 h
reflux compound 7a (Rf ¼ 0.33) was obtained as yellow pale
crystals: 0.39 g, 19%, mp 196–197ꢂC. IR (ATR): 1718, 1687,
Enamine 3a. Colorless crystals 0.92 g, 60%, mp 194–
195ꢂC, Rf ¼0.3. IR (ATR): 3349, 2191, 1672, 1624, 1441,
1461, 1362, 1181, 765, 749, 693 cmꢀ1
;
1H-NMR (CDCl3): d
1
1384, 1258, 766, 748, 602 cmꢀ1; H-NMR (CDCl3): d 3.68 (d,
3
4.59 (d, J ¼ 11.2 Hz, 1 H, CH), 5.03 (bs, 2 H, CH2), 5.74 (d,
3J ¼ 11.2 Hz, 1 H, CH), 7.17–7.57 (m, 13 H, 13 ꢁ CHar);
13C-NMR (CDCl3): d 50.1 (t), 57.3 (d), 82.8 (d), 125.8 (d),
126.3 (d), 126.7 (d), 127.2 (d), 127.5 (d), 128.2 (d), 128.9 (d),
129.0 (d), 129.2 (d), 130.8 (s), 137.0 (s), 167.0 (s), 169.2 (s),
171.5 (s); MS (EI): m/z (%) 427 (31) [Mþ], 350 (25), 199
(100). Anal. Calcd. for C24H17N3O3S: C, 67.43; H, 4.01; N,
9.83. Found: C, 67.68; H, 4.18; N, 10.08.
3J ¼ 13.8, 1 H, CH), 3.78 (bs, 2 H, CH2), 5.67 (m, 1 H, NH),
7.00 (dd, 3J ¼ 7.1, 13.8 Hz, 1 H, CH), 7.27–7.56 (m, 8 H,
8 ꢁ CHar); 13C-NMR (CDCl3): d ¼ 44.9 (t), 63.3 (d), 120.9
(s), 126.5 (d), 127.4 (d), 127.8 (d), 128.4 (d), 133.0 (s),
149.4 (d), 166.8 (s); MS (EI): m/z (%) 307 (29) [Mþ], 199
(100), 198 (76), 167 (21), 154 (15). Anal. Calcd. for
C17H13N3OS: C, 66.43; H, 4.26; N, 13.67. Found: C, 66.51; H,
4.47; N, 13.82.
Enamine 6b. Following the typical procedure after 48 h
reflux compound 6b (Rf ¼ 0.4) was obtained as yellow pale
crystals: 1.0 g, 53%, mp 178–179ꢂC. IR (ATR): 3319, 1706,
Aziridine 4a. Colorless crystals 0.3 g, 20%, mp 177–178ꢂC,
Rf ¼0.24. IR (ATR): 2245, 1684, 1460, 1378, 1258, 1183,
1
3
754, 655 cmꢀ1; H-NMR (DMSO-d6): d 1.89 (d, J ¼ 6.4 Hz,
1 H, CH2), 2.25 (d, 3J ¼ 3.2 Hz, 1 H, CH2), 2.61 (dd, 3J ¼
3.2, 6.4 Hz, 1 H, CH), 3.28 (bs, 1 H, CH2), 3.42 (bs, 1 H,
CH2), 7.31–7.64 (m, 8 H, 8 ꢁ CHar); 13C-NMR (DMSO-d6): d
¼ 22.7 (d), 33.1 (t), 59.2 (t), 119.5 (s), 127.1 (s), 127.3 (s),
127.4 (d), 128.0 (d), 132.2 (s), 137.6 (s), 167.2 (s); MS (EI):
m/z (%) 307 (27) [Mþ], 199 (62), 198 (100), 167 (19), 154
(12). Anal. Calcd. for C17H13N3OS: C, 66.43; H, 4.26; N,
13.67. Found: C, 66.56; H, 4.42; N, 13.76.
1
3
1684, 1392, 1175, 760 cmꢀ1; H-NMR (CDCl3): d 0.99 (t, J
3
¼ 6.9 Hz, 3 H, CH3), 3.34 (q, J ¼ 6.9 Hz, 2 H, OCH2), 4.11
(bs, 2 H, CH2), 4.80 (s, 1 H, CH), 6.11 (bs, 1 H, NH), 7.24–
7.53 (m, 8 H, 8 ꢁ CHar); 13C-NMR (CDCl3): d 12.0 (q), 33.1
(t), 46.2 (t), 87.5 (d), 126.8 (d), 127.4 (d), 127.9 (d), 132.1 (s),
137.3 (s), 165.7 (s), 166.5 (s), 170.1 (s); MS (EI): m/z (%) 379
(61) [Mþ], 350 (35), 199 (100). Anal. Calcd. for
C20H17N3O3S: C, 63.31; H, 4.52; N, 11.07. Found: C, 63.57;
H, 4.78; N, 11.33.
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DOI 10.1002/jhet

134
D. Belei, E. Bicu, P. G. Jones, and M. Lucian Birsa
Vol 48
[5] Viveros, M.; Amaral, L. Int J Antimicrob Agents 2001, 17,
[6] Amaral, L.; Kristiansen, J. E. Int J Antimicrob Agents
Aziridine 7b. Following the typical procedure after 48 h
reflux, compound 7b (Rf ¼ 0.3) was obtained as yellow pale
225.
crystals: 0.36 g, 19%, mp 185–186ꢂC. IR (ATR): 1711, 1684,
1461, 1374, 1154, 760, 691 cmꢀ1
;
1H-NMR (CDCl3): d 0.98
2000, 14, 173.
[7] Trivedi, A. R.; Siddiqui, A. B.; Shah, V. H. ARKIVOC
2008, (ii), 210.
[8] Motohasho, N.; Kurihara, T.; Satoh, K.; Sakagami, H. H.;
3
3
(t, J ¼ 6.9 Hz, 3 H, CH3), 3.30 (q, J ¼ 6.9 Hz, 2 H, OCH2),
3
4.51 (d, J ¼ 11.2 Hz, 1 H, CH), 4.98 (bs, 2 H, CH2), 5.72 (d,
3J ¼ 11.2 Hz, 1 H, CH), 7.19–7.48 (m, 8 H, 8 ꢁ CHar); 13C-
NMR (CDCl3): d 12.5 (q), 32.8 (t), 49.8 (t), 57.1 (d), 82.3 (d),
126.9 (d), 127.5 (d), 127.9 (d), 132.4 (s), 137.2 (s), 167.1 (s),
169.5 (s), 171.8 (s); MS (EI): m/z (%) 379 (45) [Mþ], 350
(31), 199 (100). Anal. Calcd. for C20H17N3O3S: C, 63.31; H,
4.52; N, 11.07. Found: C, 63.55; H, 4.81; N, 11.29.
Mucsi, I.; Pusztai, R.; Szabo, M; Molnar, J. Anticancer Res 1999, 19,
1837.
[9] Motohasho, N.; Kawase, M.; Saito, S.; Sakagami, H. Curr
Drug Targets 2000, 1, 237.
[10] Kurihara, T.; Motohasho, N.; Pang, G. L.; Higano, M.;
Kiguchi, K.; Molnar, J. J Anticancer Res 1996, 16, 2757.
[11] Mayur, Y. C.; Jagadeesh, S.; Thimmaiah, K. N. Mini Rev
Med Chem 2006, 6, 1383.
Enamines
and
aziridines:
Path
‘‘b’’—Typical
procedure. A solution of 4,5-dihydro-1,2,3-triazole (1 mmol)
in toluene (30 mL) was heated at reflux for 36 h. The solvent
was evaporated and the residue purified by column chromatog-
raphy on silica gel with ethyl acetate:hexane 1:1 as eluent.
Products ratio and total yields are described in Table 1.
[12] Amaral, L.; Martins, M.; Viveiros, M. J Antimicrob Chemo-
ther 2007, 59, 1237.
[13] Grieb, P. Philos Trans R Soc London 1864, 13, 377.
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Crystal structure determination of 3a. Crystal data: mono-
clinic, space group P21/n, a ¼ 12.4076(3), b ¼ 8.8927(2), c ¼
¨
[16] Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew
ꢂ
˚
Chem Int Ed 2005, 44, 5188.
¨
[17] Brase, S.; Banert, K. Organic Azides: Synthesis and Appli-
13.7600(3) A, b ¼ 105.076(3) , Z ¼ 4, T ¼ 100(2) K. Data
collection: a crystal ca. 0.3 ꢁ 0.25 ꢁ 0.1 mm3 was used to re-
cord 44,648 intensities on a Oxford Diffraction Xcalibur E dif-
cations; Wiley: New York, 2009; pp113.
[18] Sha C. K.; Mohanakrishnan A. K. Synthetic Application of
1,3-Dipolar Cycloaddition Chemistry towards Heterocycles and Natural
Products; Padwa A., Pearson W. H., Eds.; Wiley, New York, 2003; pp
623.
˚
fractometer using Mo Ka radiation (k ¼ 0.71073 A). Structure
refinement: the structure was refined anisotropically on F2
(program SHELXL-97 [35]) to wR2 ¼ 0.0856, R1 ¼ 0.0308
for 203 parameters and 4254 unique reflexions. The NH hydro-
gen was refined freely, other hydrogens using a riding model.
Data have been deposited in Cambridge under the number
CCDC-753518.
[19] Markidis, T.; Mikros, E.; Kokotos, G. Heterocycles,2003,
60, 2637.
´
[20] Milligan, G. L.; Mossman, C. J.; Aube, J. J Am Chem Soc
1995, 117, 10449.
´
[21] Forsee J. E.; Aube, J. J Org Chem 1999, 64, 4381.
Crystal structure determination of 4a. Crystal data: mono-
clinic, space group P21/c, a ¼ 12.6700(3), b ¼ 8.4297(2), c ¼
[22] Sahasrabudhe K.; Gracias. V.; Furness K.; Smith B. T.;
´
Katz C. E.; Reddy S. D.; Aube, J. J Am Chem Soc 2003, 125, 7914.
ꢂ
˚
13.7418(3) A, b ¼ 91.868(3) , Z ¼ 4, T ¼ 100(2) K. Data col-
lection: a crystal ca. 0.3 ꢁ 0.2 ꢁ 0.1 mm3 was used to record
52,950 intensities as above. Structure refinement: the structure
was refined as above to wR2 ¼ 0.0869, R1 ¼ 0.0305 for 211
parameters and 4364 unique reflexions. The aziridine hydro-
gens were refined freely, other hydrogens using a riding
model. Data have been deposited in Cambridge under the
number CCDC-753519.
[23] Lang S.; Kennedy A. R.; Murphy J. A.; Payne A. H. Org
Lett 2003, 5, 3655.
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Ed 2004, 43, 478.
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1054.
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1281.
Acknowledgment. Part of this work has been supported by the
Romanian PN II (IDEI 2643) program.
[29] Kedrowski B. L.; J Org Chem 2003, 68, 5403.
[30] Kuramochi K.; Osada Y.; Kitahara T. Tetrahedron 2003,
59, 9447.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet