Synthesis of 1,3-selenazines and 1,3-selenazolidines via intramolecular addition of N-allylselenoureas

Article abstract of DOI:10.1246/cl.2006.626

The regiochemistry of intramolecular addition of N-allylselenoureas leading to 2-imino-5-methyl-1,3-selenazolidines or 2-amino-5-iodo-4H-5,6-dihydro-1,3- selenazines depends on the treatment of hydrogen chloride or iodine: treatment of hydrogen chloride w

Full text of DOI:10.1246/cl.2006.626

626
Chemistry Letters Vol.35, No.6 (2006)
Synthesis of 1,3-Selenazines and 1,3-Selenazolidines via Intramolecular Addition
of N-Allylselenoureas
Mamoru Koketsu,ꢀ1 Takashi Kiyokuni,2 Tsutomu Sakai,2 Hiromune Ando,1 and Hideharu Ishiharaꢀ2
1Division of Instrumental Analysis, Life Science Research Center, Gifu University, Gifu 501-1193
2Department of Chemistry, Faculty of Engineering, Gifu University, Gifu 501-1193
(Received March 16, 2006; CL-060322; E-mail: koketsu@cc.gifu-.ac.jp)
The regiochemistry of intramolecular addition of N-allyl-
R
Se
selenoureas leading to 2-imino-5-methyl-1,3-selenazolidines or
2-amino-5-iodo-4H-5,6-dihydro-1,3-selenazines depends on the
treatment of hydrogen chloride or iodine: treatment of hydrogen
chloride with N-allylselenoureas affords preferentially 2-imino-
5-methyl-1,3-selenazolidines through 5-endo closure, whereas
treatment of iodine affords preferentially 2-amino-5-iodo-4H-
5,6-dihydro-1,3-selenazines through 6-exo closure.
Se
HCl/ EtOAc
reflux / 2 h
N
R
N
H
N
H
HN
1
2
Yield / %
R
C6H5
81 (2a)
Quant. (2b)
4-CH3C6H4
4-ClC6H4
2-Naphthyl
95 (2c)
92 (2d)
cyclo-C6H11 Quant. (2e)
Selenium–nitrogen heterocycles such as 1,3-selenazines and
1,3-selenazoles have enthusiastically been studied in the fields of
chemistry1 and pharmaceutical science, because they biological-
ly act as antioxidants and can inhibit human fibro sarcoma DNA
fragmentation, eukaryotic elongation factor-2 kinase and induci-
ble nitric oxide production.2 Several reactions using N-allyl-
thioureas, N-homoallyl-thioamides and -thioureas have been re-
ported. For example, N-allylthioureas by enzymic treatment3 or
active manganese dioxide4 converted to the corresponding ureas.
By an iodocyclization of N-allylthioureas, 4,5-dihydro-1,3-thia-
zoles were obtained.5 The 6-iodomethyl-5,6-dihydro-4H-1,3-
thiazines were prepared by iodocyclization of N-homoallylthio-
amides.6 2-Amino- or 2-imino-1,3-thiazole derivatives were
obtained by cyclization of N-allylthioureas with hydrogen
chloride.7 In contrast, there are few reports on the synthesis of
selenium–nitrogen heterocycles using N-allylselenoureas8 by
iodocyclization and cyclization with hydrogen chloride. Herein,
preparation of 1,3-selenazine and 1,3-selenazole derivatives
from N-allylselenoureas has been described.
Scheme 2.
(Scheme 2). The driving force, in this case, is the formation of
the more stable carbonium ion. This behavior is in agreement
with the cyclization of imidates, amides, and carbonates, which
afford five-membered heterocyclic rings exclusively.11
Crystal structure of the 2-(2-naphthyl)imino-5-methyl-1,3-
selenazolidine (2d) was determined by X-ray diffraction analysis
(Figure 1).12 Though the isomeric 2-amino-5-methyl-4,5-dihy-
dro-1,3-selenazole is a possible product, the structure of 2 was
confirmed to be 2-imino-5-methyl-1,3-selenazolidine by crystal
analysis of 2d.
Furthermore, we studied iodocyclization of N-allylselenour-
eas 1. Reaction of N-allyl-N0-phenylselenourea (1a) with iodine
afforded 5-iodo-2-phenylamino-4H-5,6-dihydro-1,3-selenazine
(3a) in 90% yield at room temperature (Scheme 3).13 The struc-
ture of 3a was elucidated by studies of IR, H, 13C, 77Se NMR,
1
COSY, HMQC, and HMBC data, MS, and HRMS. Under the
same reaction conditions, four kinds of N-allylselenoureas 1
were treated with iodine to give the corresponding 2-amino-5-
iodo-1,3-selenazine 3 in moderate to high yields (Scheme 3). Re-
action at ꢂ40 ꢁC also resulted in the formation of only six-mem-
bered ring compound 3 while formation of five-membered ring
compound has not been observed. Previously, reactions of intra-
molecular iodocyclization of allylureas and allylthioureas gave
the corresponding five-membered ring 4,5-dihydro-1,3-oxazoles
and 4,5-dihydro-1,3-thiazoles, respectively.5,14 Reactions with
N-homoallyl-thioamides and -thioamides afforded six-mem-
Five kinds of N-allylselenoureas 1 were prepared by reac-
tions of isoselenocyanates with allylamine (Scheme 1).9
Next, we investigated synthesis of selenium–nitrogen het-
erocycles via intramolecular addition using obtained N-allylsele-
noureas 1. Reaction of N-allyl-N0-p-tolylselenourea (1b) with
dry hydrogen chloride under reflux conditions (bath temp:
80 ꢁC) gave 5-methyl-2-p-tolylimino-1,3-selenazolidine (2b)
in quantitative yield (Scheme 2). Under the optimal reaction
conditions, five kinds of five-membered ring 2-imino-5-meth-
yl-1,3-selenazolidines 2a–2e10 were prepared by reactions using
N-allylselenoureas 1 with hydrogen chloride in high yields
Se
THF
R
+
R
NCSe
H2N
N
H
N
H
rt / 1 h
R
C6H5
4-CH3C6H4
4-ClC6H4
2-Naphtyl
cyclo-C6H11
Yield (%)
95 (1a)
89 (1b)
98 (1c)
95 (1d)
97 (1e)
1
Figure 1. ORTEP diagram (50% thermal ellipsoids) of 2-(2-
naphthyl)imino-5-methyl-1,3-selenazolidine (2d).
Scheme 1.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.6 (2006)
627
8
9
There are limited numbers of papers regarding N-allylseleno-
ureas, themselves. The reports do not include cyclization
reaction using N-allylselenoureas. N. Kagawa, H. Takiguchi,
Jpn. Patent 84-4850, 1985; Chem. Abstr. 1986, 104, 59340; T.
Tarantelli, C. Furlani, J. Inorg. Nucl. Chem. 1972, 34, 999; T.
Tarantelli, D. Leonesi, Ann. Chim. 1963, 53, 1113.
Typical spectral data for 1. N-Allyl-N0-(2-naphthyl)selenourea
(1d): IR (KBr): 1634, 1536 cmꢂ1; 1H NMR (500 MHz, CDCl3):
ꢀ 4.37 (2H, s), 5.13–5.18 (2H, m), 5.82–5.91 (1H, m), 6.45 (1H,
br), 7.33–7.91 (7H, m), 9.19 (1H, br); 13C NMR (125 MHz,
CDCl3): ꢀ 50.2, 117.2, 123.1, 123.3, 126.5, 126.9, 127.5,
127.6, 130.2, 131.8, 132.6, 132.8, 133.4, 178.6; 77Se NMR
(95 MHz, CDCl3): ꢀ 211.6; MS (FAB): m=z 291 [Mþ þ 1];
Anal. Calcd for C14H14N2Se: C, 58.14; H, 4.88; N, 9.69%.
Found: C, 58.52; H, 5.13; N, 9.58%.
H
N
Se
Se
l / CH Cl
2
2
2
R
R
N
H
N
H
rt / 1.5 h
N
I
1
3
Yield / %
90 (3a)
76 (3b)
53 (3c)
96 (3d)
R
C6H5
4-CH3C6H4
4-ClC6H4
cyclo-C6H11
Scheme 3.
bered ring 6-iodomethyl-4H-5,6-dihydro-1,3-thiazines.5,6 The
present reactions with N-allylselenoureas 1 gave six-membered
ring 5-iodo-4H-5,6-dihydro-1,3-selenazines 3 by iodocycliza-
tion.
In this letter, we confirmed intramolecular addition of N-al-
lylselenoureas afforded five-membered ring 1,3-selenazolidines
through 5-endo closure or six-membered ring 1,3-selenazines
through 6-exo closure by treatment of hydrogen chloride or
iodine, respectively.
10 Synthesis procedure and spectral data of selected compounds.
2-p-Tolylimino-5-methyl-1,3-selenazolidine (2b): 1 M Hydro-
gen chloride in diethyl ether solution (0.52 mL, 0.52 mmol)
was added to an ethyl acetate solution (5 mL) of N-allyl-
N0- p-tolylselenourea (1b) (25.4 mL, 0.10 mmol). The reaction
mixture was stirred for 2 h in an oil bath kept at 80 ꢁC. The
mixture was extracted with dichloromethane, washed with
aqueous saturated sodium carbonate. The organic layer was
dried over sodium sulfate and evaporated to dryness. The
residue was purified by flash chromatography on silica gel with
dichloromethane/methanol (30/1) as the eluent to give 2b (25.2
This work was supported by a Grant-in-Aid for Science Re-
search from the Ministry of Education, Culture, Sports, Science
and Technology of Japan (Nos. 15550030 and 17550099) to
which we are grateful.
mg, quantitative yield). IR (KBr): 1600 cmꢂ1 1H NMR (500
;
MHz, CDCl3): ꢀ 1.54 (3H, d, J ¼ 6:9 Hz), 2.30 (3H, s), 3.32
(1H, dd, J ¼ 6:6, 10.9 Hz), 3.72 (1H, dd, J ¼ 5:7, 10.9 Hz),
3.91–3.98 (1H, m), 6.75 (1H, brs), 6.91 (2H, d, J ¼ 8:6 Hz),
7.08 (2H, d, J ¼ 8:6 Hz); 13C NMR (125 MHz, CDCl3): ꢀ
20.8, 20.9, 39.1, 55.9, 121.2, 129.5, 132.8, 147.9, 161.0;
77Se NMR (95 MHz, CDCl3): ꢀ 411.5; MS (FAB): m=z 255
[Mþ þ 1]; Anal. Calcd for C11H14N2Se: C, 52.18; H, 5.57; N,
11.06%. Found: C, 52.03; H, 5.62; N, 10.79%.
References and Notes
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12 For 2d. CCDC 601464 contains the supplementary crystallo-
graphic data for this letter. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data request/cif.
13 Synthesis procedure and spectral data of selected compounds.
5-Iodo-2-p-tolylamino-4H-5,6-dihydro-1,3-selenazine (3b):
Iodine (76.3 mg, 0.30 mmol) was added to a dichloromethane
solution (13.0 mL) of N-allyl-N0- p-tolylselenourea (1b) (76.0
mg, 0.30 mmol). The reaction mixture was stirred at room tem-
perature for 1.5 h. The mixture was extracted with dichloro-
methane, washed with aqueous saturated sodium carbonate.
The organic layer was dried over sodium sulfate and evaporated
to dryness. The residue was purified by flash chromatography
on silica gel with dichloromethane/ether (25/1) as the eluent
3
4
5
6
7
to give 3b (86.6 mg, 76%). IR (KBr): 1626 cmꢂ1 1H NMR
;
There is only one example for the synthesis of thiazoles deriv-
atives using allylthioureas. S. T. Cholpankulova, L. A. Tsoi,
A. D. Salimbaeva, G. A. Ryskieva, N. N. Alekseeva, L. T.
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(500 MHz, CDCl3): ꢀ 2.31 (3H, s), 3.53 (1H, dd, J ¼ 4:0,
9.7 Hz), 3.60 (1H, m), 3.77 (1H, dd, J ¼ 5:7, 12.0 Hz), 3.85
(1H, dd, J ¼ 2:9, 12.0 Hz), 4.11–4.17 (1H, m), 6.93 (2H, d,
J ¼ 8:6 Hz), 7.09 (2H, d, J ¼ 8:6 Hz), 7.35 (1H, brs); 13C NMR
(125 MHz, CDCl3): ꢀ 9.3, 20.9, 44.5, 54.4, 121.2, 129.8, 133.9,
145.8, 159.7; MS (EI): m=z 380 [Mþ]; HRMS: m=z 379.9289,
calcd for C11H13IN2Se, found 379.9301.
14 A. Bongini, G. Cardillo, M. Orena, S. Sandri, C. Tomasimi,
J. Org. Chem. 1986, 51, 4905; J. W. Lown, A. V. Joshua,
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Published on the web (Advance View) May 20, 2006; doi:10.1246/cl.2006.626