Domino reactions of 1,2-diimidoyl-1,2-dichloroethanes. Synthesis of 3-imino-1,2-dithia-3H-cyclopent-4-enes, 3-amino-2-thioxo-2,5H-pyrrol-5-ones, 2,3-diamino-4-thioxo-4H-thiopyrans, and 6-imino-6H-1,3-oxazines

Article abstract of DOI:10.1021/jo052450l

The reaction of mono- and dilithiated ethyl thioglycolate with 1,2-diimidoyl-1,2-dichloroethanes, azaanalogues of oxalyl chloride, afforded (depending on the reaction conditions) 3-imino-1,2-dithia-3H-cyclopent-4-enes, 3-amino-2-thioxo-2,5H-pyrrol-5-ones,

Full text of DOI:10.1021/jo052450l

Domino Reactions of 1,2-Diimidoyl-1,2-dichloroethanes.
Synthesis of 3-Imino-1,2-dithia-3H-cyclopent-4-enes,
3-Amino-2-thioxo-2,5H-pyrrol-5-ones,
2,3-Diamino-4-thioxo-4H-thiopyrans, and
6-Imino-6H-1,3-oxazines
Esen Bellur,†,‡ Helmar Go¨rls,§ and Peter Langer*,†,|
Institut fu¨r Chemie, UniVersita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany, Institut fu¨r
Chemie und Biochemie, UniVersita¨t Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany, Institut fu¨r
Anorganische und Analytische Chemie, UniVersita¨t Jena, August-Bebel-Str. 2, 07740 Jena, Germany, and
Leibniz-Institut fu¨r Katalyse e. V. an der UniVersita¨t Rostock, Albert-Einstein-Str. 29a,
18059 Rostock, Germany
peter.langer@uni-rostock.de
ReceiVed NoVember 28, 2005
The reaction of mono- and dilithiated ethyl thioglycolate with 1,2-diimidoyl-1,2-dichloroethanes, aza-
analogues of oxalyl chloride, afforded (depending on the reaction conditions) 3-imino-1,2-dithia-3H-
cyclopent-4-enes, 3-amino-2-thioxo-2,5H-pyrrol-5-ones, and 2,3-diamino-4-thioxo-4H-thiopyrans. The
reaction of the dianion of ethyl hippurate with 1,2-diimidoyl-1,2-dichloroethanes afforded 6-imino-6H-
1,3-oxazines.
Introduction
1,2-Dithiacyclopent-4-ene-3-thiones represent an important
class of anticarcinogenes, which selectively induce the cellu-
lar production of chemoprotective phase II detoxification
enzymes.1a-d For example, synthetic oltipraz (Figure 1) pos-
FIGURE 1. Oltipraz.
* To whom correspondence should be addressed. Fax: +381 4986412.
† Universita¨t Rostock.
sesses potent anticarcinogenic properties based on the cleavage
of DNA and has been used as a cancer-preventive agent.1d The
related 1,2-dithiacyclopentane-3-thiones occur in cruciferous
vegetables (e.g., broccoli and cauliflower) and exhibit anticar-
cinogenic activity.1a,e,2 Low molecular weight 1,2-dithiacyclo-
pentan-3-one 1-oxides also exhibit antitumor activity based on
DNA-cleaving properties;3a their heterocyclic core structure is
present, for example, in the antitumor natural product leinamycin
(Figure 2),3 which is produced by Streptomyces atrooliVaceous
‡ Universita¨t Greifswald.
§ Universita¨t Jena.
| Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock.
(1) Kim, W.; Gates, K. S. Chem. Res. Toxicol. 1997, 10, 296 and
references therein. (a) Kensler, T. W.; Groopman, J. D.; Roebuck, B. D.;
Curphey, T. J. In Food Phytochemicals for Cancer PreVention; Huang, M.-
T., Osawa, T., Ho, C.-T., Rosen, R. T., Eds.; ACS Symposium Series 546;
American Chemical Society: Washington, DC, 1994; Vol. I, p 154. (b)
Egner, P. A.; Kensler, T. W.; Prestera, T.; Talalay, P.; Libby, A. H.; Joyner,
H. H.; Curphey, T. J. Carcinogenesis 1994, 15, 177. (c) Wattenberg, L.
W.; Bueding, E. Carcinogenesis 1986, 7, 1379. (d) Kensler, T. W.;
Helzsouer, K. J. J. Cell. Biochem. Suppl. 1995, 22, 101. (e) Reddy, B. S.;
Rao, C. V. In Food Phytochemicals for Cancer PreVention; Huang, M.-T.,
Osawa, T., Ho, C.-T., Rosen, R. T., Eds.; ACS Symposium Series 546;
American Chemical Society: Washington, DC, 1994; Vol. I, p 164.
(2) Maxuitenko, Y. Y.; Libby, A. H.; Joyner, H. H.; Curphey, T. J.;
MacMillan, D. L.; Kensler, T. W.; Roebuck, B. D. Carcinogenesis 1998,
19, 1609.
10.1021/jo052450l CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/15/2006
2332
J. Org. Chem. 2006, 71, 2332-2338

Domino Reactions of 1,2-Diimidoyl-1,2-dichloroethanes
opening-ring-closing reactions of 2-alkylidene-4-oxothiazo-
lidines with Lawesson’s reagent has been reported.10 3-Amino-
2-thioxopyrrol-5-ones and 3-aminopyrrol-2,5-dithiones have
been prepared by transformation of the carbonyl groups of
3-aminopyrrol-2,5-diones into thiocarbonyl groups.11 To the best
of our knowledge, 2,3-diamino-4-thioxo-4H-thiopyrans have not
yet been prepared. Synthetic approaches to 2-amino-4-thioxo-
4H-thiopyrans have only scarcely been reported in the litera-
ture.12,13 The reactions reported herein are useful, due to their
operational simplicity. In addition, the starting materials are
readily available.
FIGURE 2. Leinamycin.
S-140.3b,c 1,2-Dithia-3H-cyclopent-4-enes are also found in
nature, e.g., in the antibiotic natural product thiolutine.4
Therefore, the synthesis of unsaturated 1,2-dithiacyclopentane
derivatives is attractive from both a synthetic and medicinal
standpoint. 1,5-Dihydropyrrol-2-ones also represent important
synthetic building blocks which are found in a wide range of
natural compounds with different biological activities.5 For
example, synthetic imrecoxib (also known as BAP-909) repre-
sents inhibitory effects on cyclooxygenase 1 and 2, and its
antiinflammatory effect in vivo has been described.6
1,2-Dimidoyl-1,2-dichloroethanes7 represent useful C2-build-
ing blocks in cyclization reactions8 with various dinucleophiles.
Some years ago, we reported the synthesis of a 2,3-diiminothi-
etane and of 1,2-dithia-3H-3-iminocyclopent-4-enes by cycliza-
tion of dilithiated ethyl thioglycolate with 1,2-diimidoyl-1,2-
dichloroethanes.9 Herein, we wish to report full details and
studies related to the scope. With regard to our preliminary
communication, the scope was significantly extended; in addi-
tion, it was found that the reaction conditions (amount of base,
stoichiometry, concentration) have a dramatic influence on the
course of the reaction and on the product distribution. In fact,
the reaction of ethyl thioglycolate with 1,2-diimidoyl-1,2-
dichloroethanes afforded (depending on the conditions) 3-imino-
1,2-dithia-3H-cyclopent-4-enes, 3-amino-2-thioxo-2,5H-pyrrol-
5-ones, or 2,3-diamino-4-thioxo-4H-thiopyrans. Recently, the
synthesis of 3-imino-1,2-dithiacyclopent-4-enes based on ring-
Results and Discussion
Treatment of 1,2-diimidoyl-1,2-dichloroethane 2a with dil-
ithiated benzyl mercaptane (1)14 gave a complex reaction
mixture from which 1,2-dithiane 3 was isolated in low yield
(Scheme 1). The formation of 3 can be explained by initial
condensation of 2a with 2 equiv of 1 and subsequent oxidative
cyclization. The yield of 3 was improved by employment of 2
rather than only 1 equiv of the dianion. However, a change of
the reaction conditions (slow addition of the dianion to 2a) and
of the workup procedure (filtration under inert atmosphere rather
than aqueous workup) did not provide the expected 1:1
cyclization product. The reaction of the dianion of allyl
mercaptane with 2a gave a complex mixture.
SCHEME 1. Synthesis of 1,2-Dithiane 3a
(3) (a) Gates, K. S. Chem. Res. Toxicol. 2000, 13, 953. (b) Hara, M.;
Yoshida, M.; Asano, K.; Kawamoto, I.; Morimoto, M.; Nakano, H. J.
Antibiot. 1989, 42, 333. (c) Hara, M.; Asano, K.; Kawamoto, I.; Takiguchi,
T.; Katsumata, S.; Takahashi, K.-I.; Nakano, H. J. Antibiot. 1989, 42, 1768.
(d) Hirayama, N.; Matsuzawa, E. S. Chem. Lett. 1993, 1957. (e) Nakano,
H.; Tamaoki, T. Proc. Int. Biotechnol. Symp. Expos. 9th 1992, 72. (f) Hara,
M.; Saitoh, Y.; Nakano, H. Biochemistry 1990, 29, 5676. (g) Kanda, Y.;
Fukuyama, T. J. Am. Chem. Soc. 1993, 115, 8451. (h) Chatterji, T.; Kizil,
M.; Keerthi, K.; Chowdhury, G.; Posp´ısil, T.; Gates, K. S. J. Am. Chem.
Soc. 2003, 125, 4996.
a Key: (i) 1 (2.0 equiv), THF; (ii) n-BuLi (4.4 equiv), -78 °C, 4 h; (iii)
addition to 2a (1.0 equiv), THF, -78 °C, -78 f +20 °C, 14 h, then at 20
°C, 2 h.
(4) Stachel, H.-D.; Zeiler, K. Liebigs Ann. 1995, 2011.
(5) (a) Mattern, R.-H. Tetrahedron Lett. 1996, 37, 291. (b) Merino, P.;
Castillo, E.; Franco, S.: Merchan, F. L.; Tejero, T. Tetrahedron: Asymmetry
1998, 9, 1759. (c) Dittami, J. P.; Xu, F.; Qi, H.; Martin, M. W. Tetrahedron
Lett. 1995, 36, 4201. (d) Miller, S. L.; Tinto, W. F.; Yang, J.-P.; McLean,
S.; Reynolds, W. F. Tetrahedron Lett. 1995, 36, 5851. (e) Boger, D. L.;
Baldino, C. M. J. Org. Chem. 1991, 56, 6942. (f) Wasserman, H. H..;
Frechette, R.; Rotello, V. M. Tetrahedron Lett. 1991, 32, 7571. (g)
Wasserman, H. H.; DeSimone, R. W.; Boger, D. L.; Baldino, C. M. J. Am.
Chem. Soc. 1993, 115, 8457. (h) Boger, D. L.; Baldino, C. M. J. Am. Chem.
Soc. 1993, 115, 11418. (i) Decicco, C. P.; Grover, P. J. Org. Chem. 1997,
62, 3534. (j) Andrus, M. B.; Li, W.; Keyes, R. F. J. Org. Chem. 1997, 62,
5542. (k) Benbow, J. W.; McClure, K. F.; Danishefsky, S. J. J. Am. Chem.
Soc. 1993, 115, 12305.
Synthesis of 3-Imino-1,2-dithia-3H-cyclopent-4-enes. The
reaction of 1,2-diimidoyl-1,2-dichloroethane 2a with the dianion
of ethyl thioglycolate (4), generated according to a literature
procedure,15 resulted in formation of 3-imino-1,2-dithia-3H-
cyclopent-4-ene 5a (23%) and of side product 5a′ (9%) (Scheme
2, Table 1). The reaction was carried out by addition of the
(10) Markovic, R.; Baranac, M.; Jovetic, S. Tetrahedron Lett. 2003, 44,
7087.
(6) Chen, X.-H.; Bai, J.-Y.; Shen, F.; Bai, A.-P.; Guo, Z.-R.; Cheng,
G.-F. Acta Pharmacol. Sin. 2004, 25, 927.
(7) For a review of oxaldiimidoyl dichlorides, see: Langer, P.; Do¨ring,
M. Eur. J. Org. Chem. 2002, 221.
(11) Augustin, M.; Ko¨hler, M.; Kazandji, S. Tetrahedron 1984, 40, 3499.
(12) Dibo, A.; Stavaux, M.; Lozac’h, N. Bull. Soc. Chim. Fr. 1980, 539.
(13) Goerlitzer, K.; Hoelscher, D. Arch. Pharm. (Weinheim) 1986, 319,
120.
(8) For a review of cyclization reactions of dianions, see: Langer, P.;
Freiberg, W. Chem. ReV. 2004, 104, 4125.
(9) Langer, P.; Do¨ring, M. Chem. Commun. 1999, 2439.
(14) Geiss, K. H.; Seebach, D.; Seuring, B. Chem. Ber. 1977, 110, 1833.
(15) Tanaka, K.; Yamagishi, N.; Tanikaga, R.; Kaji, A. Chem. Lett. 1977,
471.
J. Org. Chem, Vol. 71, No. 6, 2006 2333

Bellur et al.
SCHEME 2. Cyclization of Lithiated Ethyl Thioglycolate with Oxaldiimidoyl Dichlorides
TABLE 1. Product and Yields
(path A), proton shift (intermediate E), cyclization with extrusion
of lithiated ethyl acetate and subsequent protonation during the
aqueous workup. Alternatively, a direct formation of intermedi-
ate D by addition of A onto B is possible (path B). However,
path A is supported by the fact that the 2,3-diiminothietane
(intermediate C, R ) p-Tol, 30%) rather than 5a could be
isolated when the reaction mixture was warmed to 20 °C within
15 min (rather than 14 h), stirred for 2 h, concentrated, and
directly purified by chromatography. Due to their ring strain,
four-membered ring lactams and lactones readily undergo ring-
expansion or -opening reactions16,17 and the synthesis of
iminothietanes has been previously reported.18,19 Side product
5a′ was presumably formed by fragmentation of intermediate
B by extrusion of lithiated ethyl acetate and hydrolysis of the
imidoyl chloride upon aqueous workup.
yield (%) (5)a yield (%) (6)a yield (%) (7)a
5, 6, 7
R
procedure 1b
procedure 2c
procedure 3d
a
b
c
d
e
f
4-MeC6H4
Ph
23e
32
28
0f
30
28
27
-
41g
40
55
55
38
63
40
52
79
62
78
46
69
54
-
2-MeC6H4
2-(MeO)C6H4
4-(MeO)C6H4
1-naphthyl
2,4-Me2C6H3
3,5-Me2C6H3
g
h
-
a Yields of isolated products. b Procedure 1: (i) (1) LDA (2.3 equiv),
TMEDA, 4 (1.0-1.2 equiv), THF, -40 f 0 °C, 1 h, (2) 0 °C, 1 h; (ii)
addition to 2 (1.0 equiv, in THF), -78 °C, -78 f +20 °C, 14 h, then 20
°C, 2 h. c Procedure 2: (i) (1) LDA (5.0-5.5 equiv), TMEDA, 4 (2.0-2.2
equiv), THF, -40 f 0 °C, 1 h, (2) 0 °C, 1 h; (ii) addition to 2 (1.0 equiv,
in THF), -78 °C, -78 f +20 °C, 14 h, then 20 °C, 24 h. d Procedure 3:
(i) (1) LDA (6.0-9.0 equiv), TMEDA, 4 (5.0-7.0 equiv), THF, -40 f 0
°C, 1 h, (2) 0 °C, 1 h; (ii) addition to 2 (1.0 equiv, in THF), -78 °C, -78
f +20 °C, 14 h, then 20 °C, 48 h. e Besides, 5a′ (structure given below)
was isolated (9%). f Only 5d′ was isolated (31%). g Product 5a was isolated
as a side product (24%).
The 1,2-dithia-3H-cyclopent-4-enes 5b-d were prepared,
according to the procedure as given for 5a, from 1,2-diimid-
oyl-1,2-dichloroethanes 2b-d. The reaction of 2e with 4
gave N-(2-methoxyphenyl)-2-(2-methoxyphenylamino)-2-thi-
(16) (a) Pono, J. A.; Schreiber, S. L. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, p 151.
(b) Mattay, J.; Conrads, R.; Hoffmann, R. In Houben-Weyl, 4th ed.;
Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.;
Thieme: Stuttgart, 1995; Vol. E21c, p 3133.
(17) (a) Paquette, L. A.; Rothhaar, R. R.; Isaac, M.; Rogers, L. M.;
Rogers, R. D. J. Org. Chem. 1998, 63, 5463. (b) Buynak, J. D.; Borate, H.
B.; Lamb, G. W.; Khasnis, D. D.; Husting, C.; Isom, H.; Siriwardane, U.
J. Org. Chem. 1993, 58, 1325.
(18) For 2,3-diiminooxetane, see: H.-J. Kabbe, Angew. Chem. 1968, 80,
406; Angew. Chem., Int. Ed. Engl. 1968, 7, 389.
(19) For 2-iminothietanes, see: (a) Dondoni, A.; Batagha, A.; Giorgianni,
P.; Gilli, G.; Sacerdoti, M. J. Chem. Soc., Chem. Commun. 1977, 43. (b)
Mulzer, J.; Kerkmann, T. Angew. Chem. 1980, 92, 470; Angew. Chem.,
Int. Ed. Engl. 1980, 19, 466. (c) Schaumann, E.; Mo¨ller, M.; Adiwidjaja,
G. Chem. Ber. 1988, 121, 689. (d) Sakamoto, M.; Ishida, T.; Fujita, T.;
Watanabe, S. J. Org. Chem. 1992, 57, 2419. For the preparation of a
triiminothietane: (e) L’abbe´, G.; Huybrechts, L. J. Chem. Soc., Chem.
Commun. 1979, 161. For 2,4-diiminothietanes: (f) L’abbe´, G.; Dekerk, J.-
P. Tetrahedron Lett. 1979, 3213. (g) Bestmann, H. J. Angew. Chem. 1977,
89, 370; Angew. Chem., Int. Ed. Engl. 1977, 16, 358.
dianion (1.2 equiv) to a THF solution of 2a (1.0 equiv) at -78
°C, warming of the reaction mixture to 20 °C within 14 h, and
finally, addition of hydrochloric acid (10%) (procedure 1). The
formation of 5a can be explained by nucleophilic attack of the
sulfur atom of the dianion (intermediate A) onto 2 to give
intermediate B, cyclization to give 2,3-diiminothietane C, ring
opening by attack of a second molecule of 4 (intermediate D)
2334 J. Org. Chem., Vol. 71, No. 6, 2006

Domino Reactions of 1,2-Diimidoyl-1,2-dichloroethanes
SCHEME 3. Synthesis of 6-Imino-6H-1,3-oxazines 9a,ba
oxoacetamide (5e′) rather than the expected 1,2-dithia-3H-
cyclopent-4-ene (5e). The reaction of 1,2-diimidoyl-1,2-dichlo-
roethanes 2f,g with 4 afforded the 1,2-dithia-3H-cyclopent-4-
enes 5f,g. Unfortunately, the isolated yields of 5a-g were rather
low, due to incomplete conversion of the starting materials. In
fact, significant amounts of diaryloxalamides (formed by
hydrolysis of 2 during the aqueous workup) were isolated. In
addition, the formation of side products of the type of 5a′ was
observed in all reactions.
a Key: (i) (1) LDA (2.3 equiv), TMEDA, 8 (1.0 equiv), THF, -40 f
0 °C, 1 h, (2) 0 °C, 1 h; (ii) added into 2 (in THF), -78 °C, -78 f +20
°C, 14 h, then at 20 °C, 24 h.
Synthesis of 3-Amino-2-thioxo-2,5H-pyrrol-5-ones. Studies
related to the optimization of the cyclization of ethyl thiogly-
colate (4) with 1,2-diimidoyl-1,2-dichloroethanes 2 revealed that
the reaction conditions (concentration, reaction time, stoichi-
ometry) and the substituents of the 1,2-diimidoyl-1,2-dichloro-
ethanes have a major influence on the mechanism and the course
of the reaction. In fact, the employment of a 2-fold excess of
ethyl thioglycolate (procedure 2) resulted in the formation of a
new type of product rather than an increase of the yield of 1,2-
dithia-3H-cyclopent-4-enes 5. The reaction of dilithiated ethyl
thioglycolate (2.0-2.2 equiv) with 1,2-diimidoyl-1,2-dichloro-
ethane 2a (1.0 equiv) afforded the 3-amino-2-thioxo-2,5H-
pyrrol-5-one 6a (41%) and 1,2-dithia-3H-cyclopent-4-ene 5a
(24%) (Scheme 2, Table 1). Likewise, the 3-amino-2-thioxo-
2,5H-pyrrol-5-ones 6b-h were prepared by reaction of 4 with
1,2-diimidoyl-1,2-dichloroethanes 2b-h. In these reactions the
respective 1,2-dithia-3H-cyclopent-4-enes 5b-h were formed
only in small quantities. The formation of 6a-h can be
explained by formation of intermediate C, reductive ring opening
(to give intermediate F), protonation-deprotonation (intermedi-
ate G), and subsequent cyclization by attack of the nitrogen
atom onto the ester group.
philicity of the oxygen compared to the sulfur atom. In contrast,
the reaction of 2a,b with the dianion of ethyl hippurate (8)20
afforded the 6-imino-6H-1,3-oxazines 9a,b by regioselective
cyclization via the carbon and the oxygen atom of the dianion
(Scheme 3). A four-membered ring was not formed. Notably,
a Dimroth rearrangement of the iminoether into an amide group
was not observed.
The structure of 9a was independently confirmed by crystal
structure analysis (see the Supporting Information). Two out
of three aryl groups are in plane with the heterocyclic core
structure. The ester and the amino group are involved in an
intramolecular hydrogen bond N-H‚‚‚O.
In conclusion, the reaction of mono- and dilithiated ethyl
thioglycolate with 1,2-diimidoyl-1,2-dichloroethanes afforded,
depending on the reaction conditions, 3-imino-1,2-dithia-3H-
cyclopent-4-enes, 3-amino-2-thioxo-2,5H-pyrrol-5-ones, and 2,3-
diamino-4-thioxo-4H-thiopyrans. The reaction of the dianion
of ethyl hippurate with bis(imidoyl)dichlorides afforded 6-imino-
6H-1,3-oxazines.
An independent and unambiguous proof of the structure was
established by crystal structure analysis of 6g (see supplementary
information). All 3-amino-2-thioxo-2,5H-pyrrol-5-ones 6a-h
showed characteristic 13C NMR resonances for OdC in the
range of δ 173.5-174.0 and for SdC in the range of δ 194.5-
195.7.
Experimental Section
Synthesis of 4,5-Bis[(4-methylphenyl)imino]-3,6-diphenyl-1,2-
dithiane (3). To a THF (20 mL) solution of benzyl mercaptane (1)
(0.72 mL, 6.0 mmol) was added n-BuLi (8.25 mL, 13.2 mmol, 1.6
M in n-hexane) at -78 °C, stirred for 4 h, and subsequently
transferred into a THF (80 mL) solution of oxaldi(4-tolylimidoyl)
dichloride (2a) (0.90 g, 3.0 mmol) at -78 °C. The temperature
was allowed to rise to 20 °C over 14 h, and the mixture was stirred
at 20 °C for 2 h. To the reaction mixture was added an aqueous
solution of HCl (10%, 100 mL) and extracted with diethyl ether
(5 × 100 mL). The combined organic extracts were dried (Na2SO4)
and filtered, and the filtrate was concentrated in vacuo. The resi-
due was purified by column chromatography (silica gel, petroleum
ether/Et2O ) 10:1 f 3:1) to give 3 as a slightly brownish solid
Synthesis of 2,3-Diamino-4-thioxo-4H-thiopyrans. During
the variation of the reaction conditions, it was observed that
the employment of a mono- rather than a dianion of ethyl
thioglycolate again resulted in the formation of a different
product. The reaction of a high excess of the monoanion of ethyl
thioglycolate (5.0-7.0 equiv) with 2a (procedure 3) afforded
the 3-hydroxy-5,6-di(arylamino)-4-thioxo-4H-thiopyran-2-car-
boxylate 7a (Scheme 2, Table 1). Likewise, heterocycles 7b-f
were prepared by reaction of lithiated ethyl thioglycolate with
1,2-diimidoyl-1,2-dichloroethanes 2b-c,e-g. The formation of
7a-f can be explained by formation of the open-chained
intermediate A and subsequent cyclization. During the optimiza-
tion, the use of an excess of monolithiated ethyl thioglycolate
(5.0-7.0 equiv) proved to be important.
1
(0.717 g, 50%). H NMR (THF-d8, 200 MHz): δ 2.29 (s, 6 H, 2
× CH3), 5.24 (s, 2 H, 2 × CH-S), 6.80-7.25 (m, 18 H, 18 × CH).
13C NMR (THF-d8, 50 MHz): δC 20.9, 54.5, 120.7, 128.6, 129.0,
129.6, 130.1, 138.1, 147.8, 156.8, 162.9. IR (KBr, cm-1): ν˜ )
3027 (w), 2921 (w), 1590 (s), 1502 (s), 1408 (m), 1218 (m),
1205 (m), 1114 (m), 824 (m). MS (CI, H2O): m/z 479 ([M + 1]+,
100).
The structure of 7c was unambiguously and independently
confirmed by crystal structure analysis (see the Supporting
Information). The SdC and the hydroxy group are involved in
Synthesis of Ethyl 2,3-Bis(p-tolylimino)thietane-4-carboxy-
late.9 A THF solution of LDA was prepared by addition of n-BuLi
(9.4 mL, 15.0 mmol, 1.6 M in n-hexane) to a THF (15 mL) solution
of diisopropylamine (2.1 mL, 15.0 mmol) at 0 °C. To this solution
were added TMEDA (2.3 mL, 15.0 mmol) and ethyl thioglycolate
(4) (0.54 mL, 6.0 mmol) at -40 °C. The solution was stirred at
0 °C for 2 h and subsequently transferred into a THF (80 mL)
solution of oxaldi(4-tolylimidoyl) dichloride (2a) (1.80 g, 6.0 mmol)
at -78 °C. The temperature was allowed to rise to 20 °C within
an intramolecular hydrogen bond O-H‚‚‚S. Characteristic 13
C
NMR resonances in the range of δ 174.9-176.7 were observed
for the CdS group of all 4-thioxo-4H-thiopyrans 7a-f.
Synthesis of 6-Imino-6H-1,3-oxazines. The influence of the
heteroatoms of the 1,2-dianion on the regiochemistry of cy-
clization was next studied. No cyclization could be induced in
the reaction of 1,2-diimidoyl-1,2-dichloroethane 2a with the
dianion of ethyl lactate, presumably due to the lower nucleo-
(20) Krapcho, A. P.; Dundulis, E. A. Tetrahedron Lett. 1976, 2205.
J. Org. Chem, Vol. 71, No. 6, 2006 2335

Bellur et al.
15 min, and the mixture was stirred at 20 °C for 2 h. The solvent
was removed in vacuo, and the residue was purified by column
chromatography (silica gel, petroleum ether/Et2O ) 10:1 f 3:1)
to give the product as a yellowish solid (0.634 g, 30%). Mp ) 110
°C dec. 1H NMR (CDCl3, 200 MHz): δ 0.98 (t, J ) 7.2 Hz, 3 H,
OCH2CH3), 2.32 (s, 3 H, CH3), 2.34 (s, 3 H, CH3), 4.94 (m, 2 H,
cm-1): ν˜ 3249 (m), 2966 (w), 2940 (w), 2839 (w), 1684 (s), 1600
(m), 1533 (s), 1529 (s), 1480 (s), 1464 (s), 1437 (m), 1397 (w),
1322 (w), 1294 (w), 1253 (s), 1113 (m), 1054 (w), 1043 (w), 1024
(m), 813 (w), 755 (s), 740 (m), 514 (w). MS (EI, 70 eV): m/z 316
(M+, 21), 285 (23), 252 (35), 148 (100), 134 (35), 123 (76), 107
(52), 77 (21), 72 (22). HRMS (ESI): calcd for C16H16N2O3S [M+]
316.08816, found 316.08681.
OCH2), 5.33 (s, 1 H, CHCO2Et) 6.95-7.25 (m, 8 H, 8 × CH). 13
C
NMR (CDCl3, 50 MHz): δC 13.6, 21.0, 21.2, 54.5, 62.2, 121.4,
122.4, 129.8, 130.0, 136.7, 137.3, 143.0, 143.3, 157.0, 159.0, 167.4.
IR (KBr, cm-1): ν˜ 2980 (w), 1738 (s), 1655 (m), 1641 (m), 1505
(s), 1268 (s), 1235 (m), 1125 (m), 1030 (m), 823 (m). MS
(CI, H2O): m/z 353 ([M + 1]+), 236 ([M + 1]+ - TolNtC), 203
([M + 1]+ - TolNdCdS). Anal. Calcd for C20H20N2O2S
(352.450): C, 68.16; H, 5.72; N, 7.94. Found: C, 68.51; H, 5.79;
N, 8.07.
General Procedure for the Synthesis of 3-Imino-1,2-dithia-
3H-cyclopent-4-enes (5). A THF solution of LDA was prepared
by addition of n-BuLi (2.5-3.0 equiv) to a THF (5 mL/mmol of
6) solution of diisopropylamine (2.5-3.0 equiv) at 0 °C. To this
solution were added TMEDA (2.5-3.0 equiv) and ethyl thiogly-
colate (6) (1.0-1.2 equiv) at -40 °C. The solution was warmed to
0 °C during 1 h, stirred at 0 °C for 1 h, and subsequently transferred
into a THF (20 mL/mmol of 2) solution of oxaldiimidoyl dichloride
2 (1.0 equiv) at -78 °C. The temperature was allowed to rise to
ambient over 14 h, and the mixture was stirred at 20 °C for 2 h.
To the reaction mixture was added an aqueous solution of HCl
(10%, 25 mL/mmol) and the mixture extracted with diethyl ether
(5 × 25 mL/mmol). The combined organic extracts were dried (Na2-
SO4) and filtered, and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
n-hexane/EtOAc) to give 5.
Ethyl 4-(4-Methoxyphenylamino)-3-(4-methoxyphenylimino)-
1,2-dithia-3H-cyclopent-4-ene-5-carboxylate (5e). Starting with
ethyl thioglycolate (4) (0.54 mL, 6.0 mmol), diisopropylamine (2.1
mL, 15.0 mmol), n-BuLi (9.4 mL, 15.0 mmol, 1.6 M in n-hexane),
TMEDA (2.3 mL, 15.0 mmol), and N,N′-bis(4-methoxyphenyl)-
ethane-bis(imidoyl) dichloride (2e) (2.02 g, 6.0 mmol) in THF
(30 + 100 mL), 5e was isolated after chromatography (silica gel,
n-hexane/EtOAc ) 100:1 f 5:1) as a yellowish oil (0.748 g, 30%).
1H NMR (CDCl3, 250 MHz): δ 1.16 (t, J ) 7.2 Hz, 3 H,
OCH2CH3), 3.76 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 4.15 (q, J
) 7.2 Hz, 2 H, OCH2), 6.78 (d, J ) 11 Hz, 2 H, 2 × CH), 6.90 (d,
J ) 11 Hz, 2 H, 2 × CH), 6.98 (d, J ) 11 Hz, 2 H, 2 × CH), 7.12
(d, J ) 11 Hz, 2 H, 2 × CH), 7.95 (broad s, 1 H, NH). 13C NMR
(CDCl3, 75 MHz): δC 13.4, 55.37, 55.41, 61.8, 113.7, 114.5, 121.5,
121.9, 124.2, 134.8, 141.1, 142.1, 155.7, 157.3, 161.0, 162.1. IR
(KBr, cm-1): ν˜ 3360 (w), 2980 (w), 2928 (w), 1702 (s), 1638 (s),
1605 (s), 1532 (s), 1232 (s), 1130 (m), 1075 (s), 1043 (m). MS
(EI, 70 eV): m/z 416 (M+, 100). The exact molecular mass m/z )
416.0864 ( 2 ppm [M+] for C20H20N2O4S2 was confirmed by
HRMS (EI, 70 eV).
General Procedure for the Synthesis of 3-Amino-2-thioxo-
2,5H-pyrrol-5-ones (6). A THF solution of LDA was prepared by
addition of n-BuLi (5.0-5.5 equiv) to a THF (10 mL/mmol of 4)
solution of diisopropylamine (5.0-5.5 equiv) at 0 °C. To this
solution were added TMEDA (5.0-5.5 equiv) and ethyl thiogly-
colate (4) (2.0-2.2 equiv) at -40 °C. The solution was warmed to
0 °C during 1 h, stirred at 0 °C for 1 h, and subsequently transferred
into a THF (20 mL/mmol of 2) solution of the N,N′-diarylethane-
bis(imidoyl) dichloride 2 (1.0 equiv) at -78 °C. The temperature
was allowed to rise to ambient over 14 h, and the mixture was
stirred at 20 °C for 24 h. To the reaction mixture was added an
aqueous solution of HCl (10%, 30 mL/mmol), and the mixture was
extracted with diethyl ether (2 × 30 mL/mmol) and then dichlo-
romethane (4 × 30 mL/mmol). The combined organic extracts were
dried (Na2SO4) and filtered, and the filtrate was concentrated in
vacuo. The residue was purified by column chromatography (silica
gel, n-hexane/EtOAc) to give 6.
1-(2-Methoxyphenyl)-3-(2-methoxyphenylamino)-2-thioxo-
2,5H-dihydropyrrol-5-one (6d). Starting with ethyl thioglycolate
(4) (0.10 mL, 0.90 mmol), diisopropylamine (0.30 mL, 2.1 mmol),
n-BuLi (1.32 mL, 2.1 mmol, 15% in n-hexane), TMEDA (0.32
mL, 2.1 mmol), and N,N′-bis(2-methoxyphenyl)ethane-bis(imidoyl)
dichloride (2d) (0.100 g, 0.30 mmol) in THF (10 + 10 mL), 6d
was isolated after chromatography (silica gel, n-hexane/EtOAc )
50:1 f 1:1) as an orange solid (0.056 g, 55%). Mp ) 140 °C. 1H
NMR (CDCl3, 300 MHz): δ 3.79 (s, 3 H, OCH3), 3.95 (s, 3 H,
OCH3), 5.64 (s, 1 H, CHdC), 6.94-7.14 (m, 5 H, 5 × CH), 7.23-
7.31 (m, 2 H, 2 × CH), 7.41-7.45 (m, 1 H, CH), 8.55 (broad s, 1
H, NH). 13C NMR (CDCl3, 150 MHz): δC 56.0, 56.2, 84.5, 111.0,
112.5, 117.2, 121.0, 121.3, 122.9, 124.6, 128.5, 130.3, 130.9, 144.4,
150.1, 155.7, 174.0, 195.7. IR (KBr, cm-1): ν˜ ) 3274 (w), 2963
(w), 1723 (m), 1635 (s), 1596 (m), 1530 (s), 1509 (m), 1485 (w),
1463 (m), 1437 (w), 1411 (m), 1304 (m), 1280 (m), 1247 (s), 1175
(w), 1116 (w), 1052 (w), 1024 (m), 749 (m). UV-vis (CH2Cl2,
nm): λmax (log ꢀ) 225 (4.16), 251 (4.18), 274 (4.13), 312 (4.09),
470 (3.52). MS (EI, 70 eV): m/z 340 (M+, 68), 309 (100), 294
(8), 92 (20), 77 (25). The exact molecular mass m/z ) 340.0882 (
2 ppm [M+] for C18H16N2O3S was confirmed by HRMS (EI, 70
eV).
Ethyl 4-(o-Tolylamino)-3-(o-tolylimino)-1,2-dithia-3H-cyclo-
pent-4-ene-5-carboxylate (5c). Starting with ethyl thioglycolate
(4) (0.22 mL, 1.97 mmol), diisopropylamine (0.70 mL, 4.92 mmol),
n-BuLi (2.0 mL, 4.92 mmol, 2.5 M in n-hexane), TMEDA (0.74
mL, 4.92 mmol), and N,N′-bis(2-methylphenyl)ethane-bis(imidoyl)
dichloride (2c) (0.500 g, 1.64 mmol) in THF (15+35 mL), 5c was
isolated after chromatography (silica gel, n-hexane/EtOAc ) 100:1
1
f 3:1) as a brownish oil (0.178 g, 28%). H NMR (CDCl3, 300
MHz): δ 1.15 (t, J ) 7.2 Hz, 3 H, OCH2CH3), 2.07 (s, 3 H, CH3),
2.37 (s, 3 H, CH3), 4.15 (q, J ) 7.2 Hz, 2 H, OCH2), 6.94-7.09
(m, 4 H, 4 × CH), 7.16-7.31 (m, 4 H, 4 × CH), 7.86 (broad s, 1
H, NH). 13C NMR (CDCl3, 75 MHz): δC 13.8, 17.7, 18.0, 61.9,
115.8, 117.4, 120.5, 123.7, 125.4, 125.8, 126.8, 129.7, 129.9, 130.4,
131.0, 140.0, 141.2, 148.7, 162.5, 162.7. IR (neat, cm-1): ν˜ 3293
(w), 3065 (w), 3018 (w), 2974 (m), 2961 (m), 2928 (m), 2870 (w),
1722 (m), 1686 (s), 1587 (s), 1574 (s), 1516 (s), 1497 (s), 1484
(s), 1459 (s), 1418 (m), 1394 (m), 1378 (m), 1329 (m), 1289 (m),
1243 (s), 1210 (s), 1185 (s), 1114 (s), 1098 (w), 1073 (m), 1049
(s), 1010 (w), 1000 (w), 760 (s), 749 (s), 724 (m), 715 (m), 587
(w). UV-vis (CH2Cl2, nm): λmax (log ꢀ) 229 (4.28), 420 (3.87).
MS (EI, 70 eV): m/z 385 ([M + 1]+, 5), 384 (M+, 34), 351 (11),
311 (11), 291 (30), 284 (43), 251 (18), 193 (10), 161 (12), 148
(34), 118 (63), 91 (100), 77 (10). HRMS (ESI): calcd for
C20H20N2O2S2 [M+] 384.09662, found 384.09606.
N-(2-Methoxyphenyl)-2-(2-methoxyphenylamino)-2-thioxo-
acetamide (5d′). Starting with ethyl thioglycolate (4) (0.24 mL,
2.14 mmol), diisopropylamine (0.75 mL, 5.34 mmol), n-BuLi (2.2
mL, 5.34 mmol, 2.5 M in n-hexane), TMEDA (0.81 mL, 5.34
mmol), and N,N′-bis(2-methoxyphenyl)ethane-bis(imidoyl) dichlo-
ride (2d) (0.600 g, 1.78 mmol) in THF (15 + 35 mL), 5d′ was
isolated after chromatography (silica gel, n-hexane/EtOAc ) 100:1
1
f 10:1) as a yellowish solid (0.173 g, 31%). H NMR (CDCl3,
300 MHz): δ 3.97 (s, 3 H, OCH3), 3.98 (s, 3 H, OCH3), 6.92-
7.17 (m, 5 H, 5 × CH), 7.24-7.30 (m, 1 H, CH), 8.44 (dd, J )
8.1, 1.8 Hz, 1 H, CH), 9.26 (dd, J ) 8.1, 1.8 Hz, 1 H, CH), 10.90
(broad s, 1 H, NH), 12.00 (broad s, 1 H, NH). 13C NMR (CDCl3,
75 MHz): δC 55.95, 56.00, 110.3, 110.4, 119.3, 120.3, 120.4, 120.9,
125.2, 126.6, 127.39, 127.44, 149.5, 150.2, 156.5, 180.6. IR (KBr,
1-Naphthalen-1-yl-3-(naphthalen-1-ylamino)-2-thioxo-2,5H-
dihydropyrrol-5-one (6f). Starting with ethyl thioglycolate (4) (0.18
mL, 1.6 mmol), diisopropylamine (0.6 mL, 4.0 mmol), n-BuLi (2.5
2336 J. Org. Chem., Vol. 71, No. 6, 2006

Domino Reactions of 1,2-Diimidoyl-1,2-dichloroethanes
mL, 4.0 mmol, 15% in n-hexane), TMEDA (0.6 mL, 4.0 mmol),
and N,N′-bis(1-naphthyl)ethane-bis(imidoyl) dichloride (2f) (0.300
g, 0.80 mmol) in THF (20 + 20 mL), 6f was isolated after
chromatography (silica gel, n-hexane/EtOAc ) 100:1 f 5:1) as
doyl) dichloride (2e) (0.200 g, 0.59 mmol) in THF (30 + 35 mL),
7e was isolated after chromatography (silica gel, n-hexane/EtOAc
) 50:1 f 1:1) as a reddish solid (0.186 g, 69%). 1H NMR (CDCl3,
300 MHz): δ ) 1.37 (t, J ) 7.2 Hz, 3 H, CH3), 3.76 (s, 3 H,
OCH3), 3.84 (s, 3 H, OCH3), 4.40 (q, J ) 7.2 Hz, 2 H, OCH2),
6.83 (d, J ) 8.7 Hz, 4 H, 4 × CH), 6.95 (dd, J ) 6.6, 2.2 Hz, 2 H,
2 × CH), 7.15 (dd, J ) 6.6, 2.2 Hz, 2 H, 2 × CH), 7.33 (broad s,
1
an orange solid (0.190 g, 63%). Mp ) 175 °C. H NMR (CDCl3,
300 MHz): δ 5.63 (s, 1 H, CHdC), 7.48-7.67 (m, 9 H, 9 × CH),
7.76-7.79 (m, 1 H, CH), 7.93-8.06 (m, 4 H, 4 × CH), 8.50 (broad
s, 1 H, NH). 13C NMR (CDCl3, 75 MHz): δC 83.9, 116.9, 120.6,
122.5, 125.3, 125.5, 125.9, 126.5, 126.8, 126.9, 127.1, 127.1, 128.6,
128.8, 128.9, 129.9, 130.1, 130.7, 133.8, 134.30, 134.33, 146.0,
173.8, 195.5. IR (KBr, cm-1): ν˜ 3285 (w), 2983 (w), 1738 (s),
1635 (s), 1596 (w), 1576 (w), 1549 (w), 1503 (s), 1468 (w), 1444
(w),1420 (m), 1393 (w), 1370 (w), 1347 (w), 1288 (s), 1207 (w),
1183 (w), 1161 (m), 1124 (w), 1107 (w), 1028 (m), 1012 (w), 806
(w), 781 (m), 765 (m), 602 (w). UV-vis (CH2Cl2, nm): λmax (log
ꢀ) 228 (4.67), 305 (4.31), 475 (3.53). MS (EI, 70 eV): m/z 380
(M+, 100), 252 (11), 210 (12), 194 (51), 166 (55), 154 (35), 143
(24), 127 (82), 77 (12). The exact molecular mass m/z ) 380.0983
( 2 ppm [M+] for C24H16N2OS was confirmed by HRMS (EI, 70
eV).
1 H, NH), 10.51 (broad s, 1 H, OH), 12.68 (broad s, 1 H, NH). 13
C
NMR (CDCl3, 75 MHz): δC ) 14.3, 55.5, 55.6, 62.5, 99.2, 114.8,
115.4, 118.8, 121.9, 127.2, 132.6, 134.3, 135.1, 153.3, 155.48,
155.53, 164.1, 174.9. IR (neat, cm-1): ν˜ ) 3447 (w), 3441 (w),
3274 (w), 2977 (w), 1726 (w), 1677 (w), 1509 (s), 1464 (w), 1440
(w), 1420 (w), 1407 (w), 1369 (m), 1349 (m), 1298 (m), 1244 (s),
1186 (m), 1113 (w), 1031 (m). UV-Vis (CH2Cl2, nm): λmax (log
ꢀ) ) 229 (4.26), 381 (3.97), 456 (3.96). MS (EI, 70 eV): m/z 458
(M+, 22), 428 (29), 386 (8), 353 (17), 340 (73), 324 (13), 279 (14),
222 (9), 208 (37), 192 (22), 174 (74), 160 (20), 146 (44), 134 (100),
121 (82), 107 (62), 92 (34). The exact molecular mass m/z )
458.0970 ( 2 ppm [M+] for C22H22N2O5S2 was confirmed by
HRMS (EI, 70 eV).
General Procedure for the Synthesis of 2,3-Diamino-4-thioxo-
4H-thiopyrans (7). A THF solution of LDA was prepared by
addition of n-BuLi (6.0-9.0 equiv) to a THF (5 mL/mmol of 4)
solution of diisopropylamine (6.0-9.0 equiv) at 0 °C. To this
solution were added TMEDA (6.0-9.0 equiv) and ethyl thiogly-
colate (4) (5.0-7.0 equiv) at - 40 °C. The solution was warmed
to 0 °C during 1 h, stirred at 0 °C for 1 h, and subsequently
transferred into a THF (50 mL/mmol of 2) solution of N,N′-
diarylethane-bis(imidoyl) dichloride (2) (1.0 equiv) at - 78 °C.
The temperature was allowed to rise to ambient over 14 h, and the
mixture was stirred at 20 °C for 48 h. To the reaction mixture was
added an aqueous solution of HCl (10%, 30 mL/mmol), and the
mixture was extracted with diethyl ether (2 × 50 mL/mmol) and
then dichloromethane (4 × 50 mL/mmol). The combined organic
extracts were dried (Na2SO4) and filtered, and the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, n-hexane/EtOAc) to give 7.
General Procedure for the Synthesis of 6-Imino-6H-1,3-
oxazines (9). A THF solution of LDA was prepared by addition of
n-BuLi (2.5 equiv) to a THF (3 mL/mmol of 8) solution of
diisopropylamine (2.5 equiv) at 0 °C. To this solution were added
TMEDA (2.5 equiv) and ethyl hippurate (8) (1.0 equiv) at - 40
°C. The solution was warmed to 0 °C during 1 h, stirred at 0 °C
for 1 h, and subsequently transferred into a THF (13 mL/mmol of
2) solution of N,N′-diarylethane-bis(imidoyl) dichloride (2) (1.0
equiv) at - 78 °C. The temperature was allowed to rise to ambient
over 14 h, and the mixture was stirred at 20 °C for 2 h. To the
reaction mixture was added an aqueous solution of HCl (10%, 20
mL/mmol of 8) and the mixture extracted with diethyl ether (5 ×
20 mL/mmol). The combined organic extracts were dried (Na2-
SO4) and filtered, and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
petroleum ether/Et2O) to give 9.
Ethyl 2-Phenyl-5-(p-tolylamino)-6-(p-tolylimino)-6H-1,3-oxa-
zine-4-carboxylate (9a). Starting with ethyl hippurate (8) (1.24 g,
6.0 mmol), diisopropylamine (2.1 mL, 15.0 mmol), n-BuLi (9.4
mL, 15.0 mmol, 1.6 M in n-hexane), TMEDA (2.3 mL, 15.0 mmol),
and N,N′-bis(4-methylphenyl)ethane-bis(imidoyl) dichloride (2a)
(1.80 g, 6.0 mmol) in THF (15 + 80 mL), 9a was isolated after
chromatography (silica gel, petroleum ether/Et2O ) 10:1 f 3:1)
as a yellowish solid (1.08 g, 41%). 1H NMR (THF-d8, 200 MHz):
δ 1.10 (t, J ) 7.2 Hz, 3 H, OCH2CH3), 2.26 (s, 3 H, CH3), 2.32 (s,
3 H, CH3), 3.92 (q, J ) 7.2 Hz, 2 H, OCH2), 6.95-7.45 (m, 11 H,
11 × CH), 7.95 (m, 2 H, 2 × CH), 8.60 (broad s, 1 H, NH). 13C
NMR (THF-d8, 50 MHz): δC 14.4, 20.9, 21.1, 61.2, 119.1, 122.0,
123.6, 127.5, 129.2, 129.7, 130.0, 131.6, 131.7, 132.0, 133.4, 134.8,
140.1, 143.0, 144.9, 148.7, 166.2. IR (KBr, cm-1): ν˜ 3335 (m,
br), 2980 (w), 1703 (s), 1680 (s), 1612 (w), 1512 (s), 1482 (m),
1380 (m), 1337 (m), 1100 (m), 1028 (m), 818 (m). MS (CI, H2O):
m/z 441 ([M+2]+, 100), 440 ([M + 1]+, 47). Anal. Calcd for
C27H25N3O3 (439.506): C, 73.79; H, 5.73; N, 9.56. Found: C,
71.92; H, 6.33; N, 8.95. The structure was confirmed by X-ray
crystallography.
Ethyl 5-Hydroxy-4-thioxo-2,3-di(o-tolylamino)-4H-thiopyran-
6-carboxylate (7c). Starting with ethyl thioglycolate (4) (0.88 mL,
8.0 mmol), diisopropylamine (1.41 mL, 10 mmol), n-BuLi (6.3 mL,
10.0 mmol, 15% in n-hexane), TMEDA (1.5 mL, 10.0 mmol), and
N,N′-bis(2-methylphenyl)ethane-bis(imidoyl) dichloride (2c) (0.500
g, 1.64 mmol) in THF (30 + 70 mL), 7c was isolated after
chromatography (silica gel, n-hexane/EtOAc ) 100:1 f EtOAc)
1
as a dark reddish solid (0.542 g, 78%). Mp ) 151 °C. H NMR
(CDCl3, 300 MHz): δ 1.37 (t, J ) 7.2 Hz, 3 H, CH3), 2.17 (s, 3
H, CH3), 2.48 (s, 3 H, CH3), 4.39 (q, J ) 7.2 Hz, 2 H, OCH2),
6.51 (d, J ) 8.1 Hz, 1 H, CH), 6.65 (broad s, 1 H, NH), 6.91 (dt,
J ) 7.5, 0.6 Hz, 1 H, CH), 7.08 (dt, J ) 7.5, 0.9 Hz, 1 H, CH),
7.19 (broad s, 1 H, NH), 7.22 (d, J ) 7.2 Hz, 1 H, CH), 7.27-
7.32 (m, 4 H, 4 × CH), 10.53 (broad s, 1 H, OH). 13C NMR (CDCl3,
75 MHz): δC 14.2, 17.7, 17.9, 62.5, 99.7, 114.1, 122.1, 126.7,
126.8, 127.2, 127.7, 129.2, 131.0, 131.9, 131.9, 134.5, 135.3, 139.9,
153.4, 155.5, 164.0, 175.8. IR (KBr, cm-1): ν˜ ) 3438 (m), 3267
(w), 3228 (w), 3193 (w), 2978 (w), 1729 (w), 1675 (s), 1581 (m),
1498 (s), 1476 (s), 1461 (s), 1442 (m), 1377 (m), 1365 (s), 1349
(s), 1301 (m), 1290 (m), 1249 (s), 1232 (m), 1211 (s), 1186 (m),
1161 (w), 1130 (w), 1117 (m), 1094 (w), 1063 (m), 921 (w), 755
(m), 745 (m). UV-vis (CH2Cl2, nm): λmax (log ꢀ) ) 269 (4.14),
317 (4.02), 381 (3.89), 442 (3.91). MS (EI, 70 eV): m/z 426 (M+,
100), 352 (15), 319 (17), 91 (27). The exact molecular mass m/z )
426.1072 ( 2 ppm [M+] for C22H22N2O3S2 was confirmed by
HRMS (EI, 70 eV). The structure was confirmed by X-ray
crystallography.
Ethyl 2-Phenyl-5-phenylamino-6-phenylimino-6H-1,3-oxazine-
4-carboxylate (9b). Starting with ethyl hippurate (8) (1.24 g, 6.0
mmol), diisopropylamine (2.1 mL, 15.0 mmol), n-BuLi (9.4 mL,
15.0 mmol, 1.6 M in n-hexane), TMEDA (2.3 mL, 15.0 mmol),
and N,N′-diphenylethane-bis(imidoyl) dichloride (2b) (1.67 g, 6.0
mmol) in THF (15 + 80 mL), 9b was isolated after chromatography
(silica gel, petroleum ether/Et2O ) 10:1 f 3:1) as a yellowish solid
1
(0.937 g, 38%). H NMR (DMSO-d6, 200 MHz): δ 0.98 (t, J )
Ethyl 5-Hydroxy-2,3-di(4-methoxyphenylamino)-4-thioxo-4H-
thiopyran-6-carboxylate (7e). Starting with ethyl thioglycolate (4)
(0.45 mL, 4.15 mmol), diisopropylamine (0.75 mL, 5.34 mmol),
n-BuLi (3.4 mL, 5.34 mmol, 15% in n-hexane), TMEDA (0.81
mL, 5.34 mmol), and N,N′-bis(4-methoxyphenyl)ethane-bis(imi-
7.2 Hz, 3 H, OCH2CH3), 3.78 (q, J ) 7.2 Hz, 2 H, OCH2), 6.95-
7.55 (m, 13 H, 13 × CH), 7.82 (m, 2 H, 2 × CH), 8.72 (broad s,
1 H, NH). 13C NMR (DMSO-d6, 50 MHz): δC 13.7, 60.6, 119.4,
119.9, 120.4, 122.29, 122.30, 124.5, 126.3, 128.5, 128.8, 131.4,
129.5, 130.0, 141.8, 144.8, 145.1, 148.2, 164.8. IR (KBr, cm-1):
J. Org. Chem, Vol. 71, No. 6, 2006 2337

Bellur et al.
ν˜ 3307 (w), 3060 (w), 2980 (w), 1740 (m), 1668 (s), 1590 (s),
1570 (s), 1520 (s), 1495 (m); 1450 (m); 1269 (s), 1210 (s), 1196
(m), 1138 (m), 1028 (m). MS (FAB): m/z 412 ([M + 1]+, 100).
Anal. Calcd for C25H21N3O3 (411.453): C, 72.98; H, 5.14; N, 10.21.
Found: C, 72.52; H, 5.48; N, 9.90.
Wirkstoffe und Screeningverfahren”), and from the Deutsche
Forschungsgemeinschaft is gratefully acknowledged.
Supporting Information Available: Copies of the NMR
spectra, experimental procedures, and details of the crystal structure
determinations. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the DAAD
(scholarship for E.B.), from the BASF AG, from the state of
Mecklenburg-Vorpommern (Landesforschungsschwerpunkt “Neue
JO052450L
2338 J. Org. Chem., Vol. 71, No. 6, 2006