A rich array of reactions of cyanomonothiocarbonylmalonamides RNHCSCH(CN)CONHR′ and their thioenols RNHC(SH)=C(CN)CONHR′

Article abstract of DOI:10.1021/jo7022262

(Chemical Equation Presented) The thioenols derived from cyanomonothiocarbonylmalonamides and a cyanodithiocarbonylmalonamide were found to be very reactive species. They react under a variety of conditions such as crystallization, reaction with several c

Full text of DOI:10.1021/jo7022262

A Rich Array of Reactions of Cyanomonothiocarbonylmalonamides
RNHCSCH(CN)CONHR′ and Their Thioenols
RNHC(SH)dC(CN)CONHR′1
Ahmad Basheer and Zvi Rappoport*
Department of Organic Chemistry and the MinerVa Center for Computational Quantum Chemistry,
The Hebrew UniVersity, Jerusalem 91904, Israel
zr@Vms.huji.ac.il
ReceiVed October 17, 2007
The thioenols derived from cyanomonothiocarbonylmalonamides and a cyanodithiocarbonylmalonamide
were found to be very reactive species. They react under a variety of conditions such as crystallization,
reaction with several carbonyl compounds, and reactions with another thioenol molecule to give a variety
of products, mostly heterocycles, including substituted 2,3-dihydroisothiazole-3-ones and 3-thione,
2-substituted methylenethiazoles, 3,4-dihydro-1,3-thiazine-4-ones and 4-thiones, divinyl sulfides, a 1,2-
dithiolane radical, and a 3,7-diaza[3.3.0]bicyclooctane derivative. Mechanisms suggested for these reactions
include radical mechanisms, nucleophilic substitutions, and condensations.
Introduction
groups, EWGs) 1 and/or their tautomeric amides Y′YCH-
CONRR′ 2 and studied their properties, including the equilib-
rium constants KEnol between the two tautomers.1,2 Initial studies
on their functionalization included reactions with diazomethane,3
an intramolecular cyclization of derivatives prepared analogously
to the formation of 1 and 2,4 and their oxa-ene reactions with
4-phenyl-1,2,4-triazoline-3,5-dione.5 Fewer thio analogues of
these species are known,6,7 and an extensive series of “formal”8
cyanomonothiocarbonylmalonamides 4 were isolated.7 X-ray
In recent years, we prepared many enols of carboxylic acid
amides Y′YCdC(OH)NRR′ (Y, Y′ ) electron-withdrawing
(1) Preliminary report: Basheer, A.; Rappoport, Z. Kyushu International
Symposium on Physical Organic Chemistry (KISPOC XI), Fukuoka
September 12-15, 2005, Abstract O01.
(2) (a) Mukhopadhyaya, J. K.; Sklenak, S.; Rappoport, Z. J. Am. Chem.
Soc. 2000, 122, 1325. (b) Mukhopadhyaya, J. K.; Sklenak, S.; Rappoport,
Z. J. Org. Chem. 2000, 65, 6856. (c) Lei, Y. X.; Cerioni, G.; Rappoport, Z.
J. Org. Chem. 2000, 65, 4028. (d ) Lei, Y. X.; Cerioni, G.; Rappoport, Z.
J. Org. Chem. 2001, 66, 8379. (e) Lei, Y. X.; Casarini, D.; Cerioni, G.;
Rappoport, Z. J. Phys. Org. Chem. 2003, 16, 525. (f) Lei, Y. X.; Casarini,
D.; Cerioni, G.; Rappoport, Z. J. Org. Chem. 2003, 68, 947. (g) Basheer,
A.; Rappoport, Z. J. Org. Chem. 2004, 69, 1151. (h) Basheer, A.; Yamataka,
H.; Ammal, S. C.; Rappoport, Z. J. Org. Chem. 2007, 72, 5297. (i) Song,
J.; Yamataka, H.; Rappoport, Z. J. Org. Chem. 2007, 72, 7605.
(3) Lei, Y. X.; Rappoport, Z. J. Org. Chem. 2002, 67, 6971.
(4) Basheer, A.; Rappoport, Z. J. Org. Chem. 2006, 71, 9743.
(5) Basheer, A.; Rappoport, Z. J. Org. Chem. 2008, 73, 184.
(6) For examples of thioenols which were observed or investigated in
solution, see: Sklenak, S.; Apeloig, Y.; Rappoport, Z. J. Chem. Soc., Perkin
Trans. 2 2000, 2269, and ref 7.
10.1021/jo7022262 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/23/2008
1386
J. Org. Chem. 2008, 73, 1386-1396

Cyanomonothiocarbonylmalonamides and their Thioenols
CHART 1
structures of some of them in the solid state were determined,
and their simultaneous equilibria (KEnol and KThioenol) with the
tautomeric enols 3 or the thioenols 5 were determined in
solution.7
Species 3/4/5 carry several functional groups such as the
nucleophilic NHR, OH, or SH groups, the electrophilic CdC
bond, and Y/Y′, all of which are capable of undergoing a variety
of reactions. Coupled with the easy oxidation of the SH group,
they can potentially participate in a wide array of reactions,
making these species useful synthones.
In the present work, we investigated several reactions of the
3/4/5 systems, mostly reactions leading to heterocyclic systems.9
We found that a small structural variation can change the nature
of the products. Several reactions of the dithio analogues were
also studied.
oxidation products, where a dihydrogen was lost between the
cis-SH and NHR groups of the thioenols 5. The apparent oxidant
is air oxygen since, when 3e/4e/5e was crystallized from EtOAc
under nitrogen, the open-chain enol 3f (R1 ) Me, R2 ) H, R3
) 1-Np), whose X-ray structure and NMR data are known,7
was isolated. When formal 4j was kept for more than 40 h in
AcOEt, only signals for the 3j/4j/5j mixture were observed,
and reaction of formal 4i under nitrogen showed signals of 3i/
4i, whereas the cyclic 9c, 9d, and 9f were obtained under air.
A similar reaction of the formal cyanodithiocarbonylmalonamide
6 under air gave the analogous 5-anilido-4-cyano-2,3-dihy-
droisothiazole-3-thione 10 (eq 4).
Results and Discussion
Sixteen formal systems 3a-p/4a-p/5a-p whose equilibrium
constants in solution (Chart 1, eq 1) were determined earlier7
were investigated, and the structures of the various types of
products were determined. These are given below, and a
representative X-ray structure for each type of product is given
either in the text or in the Supporting Information. Few reaction
mechanisms are suggested. The reactions are divided into those
involving one or two molecules of 3/4/5. When available,
reactions of the formal cyanodithiocarbonylmalonamide ana-
logues 6/7/8 (Chart 1, eq 2) are given together with the
analogous reactions of 3/4/5.
a. Reactions Involving One Molecule of 3/4/5. 1. Formation
of 2,3-Dihydroisothiazole-3-one and 2,3-Dihydroisothiazole-
3-thione Derivatives. When formal compounds 4a-d,f,l where
R2 ) Me, were crystallized from EtOAc at rt, only one of the
corresponding precursors 3/4/5 was isolated.7 However, when
their analogues 5e (R1 ) Me, R3 ) 1-Np) and 5g-k (R1 ) H,
R3 ) Ph, p-An, 1-Np, i-Pr, t-Bu) were crystallized from EtOAc
in air, the five-membered substituted 4-cyano-2,3-dihydroisothi-
azole-3-ones 9a-f were formed (eq 3). These are formal cyclic
The structures of the two solid derivatives 9d and 9f were
determined by X-ray crystallography. Both ORTEP drawings
together with the full crystallographic data are given in the
Supporting Information. The C(1)-C(2), C(2)-C(3), C(3)-O,
and C(1)-S bond lengths of 9d are 1.384(2), 1.437(3), 1.233-
(3), and 1.7356(18) Å and of 9f are 1.386(3), 1.450(3), 1.237-
(2), and 1.7315(18) Å, respectively. The C(1)-C(2) bond
lengths are typical for those in push-pull ethylenes, as found
2a,b,d-i
in Y,Y′-activated enols
and thioenols.7 In 9d, where R1
) H, each molecule is intermolecularly hydrogen bonded by
N-H‚‚‚O and N-H‚‚‚N moieties to two other molecules, where
the N‚‚‚O and the N‚‚‚N nonbonding distances are 2.722(2) and
3.014(2) Å, respectively. In 9f, only two molecules are hydrogen
bonded by an N-H‚‚‚O moiety where the N‚‚‚O nonbonding
distance is 2.913(2) Å.
The compositions and structures of the six compounds were
consistent with the elemental analysis (Table S3 in the Sup-
porting Information) and with the NMR spectra in solution
(7) Basheer, A.; Rappoport, Z. Submitted for publication.
(8) “Formal” is used since in solution the three species 3, 4, and 5 are
simultaneously present for most systems and the solid-state structure is not
necessarily that in solution. When it seems reasonable that one of the species
participates in a reaction, its structure is given.
(9) Formation of a plethora of products, mostly heterocycles, from
thioamides including cyanothioacetamides was reviewed (Jagodzinski, T.
S. Chem. ReV. 2003, 103, 197; Litvinov, V. P. Russ. Chem. ReV. 1999, 68,
737). None of the precursors is written as the thioenol, and only
2-N-substituted thioamido-1,3-indanedione may have the thioenol structure.
J. Org. Chem, Vol. 73, No. 4, 2008 1387

Basheer and Rappoport
SCHEME 1. Suggested Mechanism for the Formation of 13
(Tables S1 and S2 in the Supporting Information). The 1H NMR
spectra show two NH signals for 9a-e (e.g., δ(NH) ) 7.95
and δ(NHR3) ) 10.19 for 9a) and 10 (two overlapping signals
at 9.83 ppm). Only one NH signal was observed for 9f, and the
Me signal appears as a singlet compared with the NHMe doublet
in the precursor 5e.7 The 13C NMR spectra show two low field
signals at 164.88-165.18 and 165.53-167.74 ppm ascribed to
CR (dC(NHR3)S) and the CdO groups.
We suggest that the thioenols 5, which are present in the 3/4/5
equilibria in solution,7 are oxidized by air to give 9 and water.
Although 9 can tautomerize to the heterocyclic isothiazole-3-
ol, this is not supported by our data.
The solid-state structures of 12, 13, and 14 were determined
by X-ray diffraction. The ORTEP drawing and the complete
data are given in the Supporting Information. On the basis of
the solid-state structures, especially the double bond lengths of
1.381(3) Å for 12, 1.402(2) Å for 13, and 1.414(7) Å for 14, it
seems that all derivatives had retained the push-pull moieties
of their precursors. Each derivative is intermolecularly hydrogen
bonded to a second molecule by an N-H‚‚‚O hydrogen bond
for 12 and an N-H‚‚‚N bond for 13 and 14.
Similar 2,3-dihydroisothiazole-3-ones, including 9a-d, were
recently reported, and their biological activity was investigated.10
However, although their synthesis formally resembles eq 3, it
differs from it in important details.10a Its first step is the reaction
of cyanoacetamide with ArNCS in the presence of aqueous KOH
to give the amide 4, R1 ) H, which cyclizes in the presence of
an added oxidant such as chloramine-T or Br2 to a product
written as the tautomer of 9-the substituted isothiazole-3-ol 11
(eq 5). No supporting X-ray data for structure 11 are
given.
1
The 2,3-dihydroisothiazole-3-thione 10 displays in the H
NMR spectrum Ph-H signals and two additional 1H singlets
at 8.57 (br) and 12.9 ppm in DMSO-d6 ascribed to the two NH
hydrogens. In the 13C NMR spectrum, each of the 10 carbons
appears separately. The highest field carbon is at 76.10 ppm
and the lowest field at 169.5 and 188.6 ppm, ascribed to CR
(dC(NHR3)S) and the CdS groups.
2. Formation of 2-Substituted Methylene Thiazoles. Crys-
tallization of 5e from acetone in air and of the dithio derivative
6/7/8 from acetonitrile yields the 2-substituted methylenenaph-
tho-2,3-dihydrothiazole and benzo-2,3-dihydrothiazole 12 and
13, respectively (eqs 6 and 7). When 5e was crystallized from
EtOAc under nitrogen, evaporation of the solvent after >30 h
gave no 12, and only the signals of the starting material were
observed. Crystallization of 7 from ethyl acetoacetate gave the
aliphatic 2,3-dihydrothiazole 14 (eq 8).
The 1H NMR spectra of 12 display two NH signals at 13.92
and 5.80 ppm in CDCl3 (12.87 and 7.32 ppm in DMSO-d6),
ascribed to the hydrogen-bonded N-H‚‚‚O moiety and the non-
hydrogen-bonded NHMe, respectively. Three NH signals were
observed for 13. The lowest field one at 12.97 ppm was ascribed
to the intramolecular hydrogen-bonded N-H‚‚‚S moiety, and
the other signals at 7.90 and 8.57 ppm belong to the NH2 group.
In 14, which has an E-configuration, an intramolecular hydrogen
bond is absent according to the solid-state structure. The 13C
spectrum of 12 displays two low field signals at 166.03 and
166.78 ppm which are ascribed to the CR and CdO groups.
For 13, the low field signals appear at 169.05 and 188.66 ppm
and are ascribed, as in 10, to the CR and CdS groups,
respectively. These signals of 12 and 13 resemble those of the
precursors 5e and 8.
(10) (a) Zhang, W.; Ricketts, W.; An, H.; Hong, Z. U.S. Patent 2004/
0039037, February 26, 2004. (b) Varaprasad, C. V. N. S.; Barawkar, D.;
El Abdellaoui, H.; Chakravarty, S.; Allan, M.; Chen, H.; Zhang, W.; Wu,
J. Z.; Tam, R.; Hamatake, R.; Lang, S.; Hong, Z. Bioorg. Med. Chem. Lett.
2006, 16, 3975.
A reasonable suggested mechanism for formation of 12 and
13 involves an intramolecular aromatic radical substitution. The
1388 J. Org. Chem., Vol. 73, No. 4, 2008

Cyanomonothiocarbonylmalonamides and their Thioenols
CHART 2
SCHEME 2. Suggested Mechanism for a Formation of 20
sulfur-centered thiyl radicals (5e• and 8•), formed by hydrogen
abstraction by air oxygen from 5e and 8, respectively, attack
an adjacent aromatic carbon to form the thiazoles after abstrac-
tion of hydrogen radical by oxygen from the intermediate radical
(Scheme 1).
It is suggested that the formation of 14 also begins by
abstraction of the S-H hydrogen of 6 by oxygen, followed by
attack of the thiyl radical on the vinylic Câ of the enol tautomer
of ethyl acetoacetate 15 to form a C-S bond. This is followed
by abstraction of the OH hydrogen by oxygen. An intramo-
J. Org. Chem, Vol. 73, No. 4, 2008 1389

Basheer and Rappoport
lecular nucleophilic attack of the NH2 on the adjacent formed
carbonyl, followed by intramolecular proton transfer and
elimination of water gives 14.
Additional data are given in Table S1 in the Supporting
Information. The spectra of 16 and 17 also display the signals
for R4 and R5 derived from the carbonyl compound 15. A new
signal observed in the spectra (also in 17) at ca. 62 ppm is
ascribed to the sp3 carbon R to the sulfur. The amido carbonyl
of 5, the thioamido carbonyl of 8, and their CR signals were
retained in 16 and 17 and appear at 164.55-165.19 and
165.53-168.65 ppm for 16a-p and at 186.95 and 161.80 ppm
for 17.
The suggested mechanism (Scheme 2) involves a nucleophilic
attack of the thioenol SH group or of its conjugate base on the
carbonyl group of the ketone or aldehyde. Proton transfer to
the alkoxide moiety is followed by protonation and water loss
and then by cyclization of the NH2 on the positive center. A
related route starting with NH2 attack on the carbonyl is also
possible. The formation of 17 takes place analogously. The
possibility that the reaction of 8 gives a dithioketal isomer of
17 is excluded by the observed 13C NMR CdS signal of 17 at
a low field.
3. Formation of 3,4-Dihydro-1,3-thiazine-4-one and 3,4-
Dihydro-1,3-thiazine-4-thione. When thioenols 5g-k, having
an unsubstituted amido nitrogen and monosubstituted thioamido
nitrogen (R3 ) Ph, p-An, 1-Np, i-Pr, t-Bu), were crystallized
from a ketonic solvent 15a-g (e.g., acetone, methyl ethyl
ketone) or from anisaldehyde 15h, the six-membered 2,2-dialkyl-
6-alkylamino- (or arylamino)-5-cyano-3,4-dihydro-1,3-thiazine-
4(1H)-one 16a-o or the 2-anisyl derivative 16p were obtained
in high yields by a condensation reaction with a loss of water
(Chart 2, eq 9). The structures of three products 16d, 16k, and
16p, derived from acetone, ethyl methyl ketone, and anisalde-
hyde, respectively, were determined by X-ray crystallography.
The ORTEPs and the full crystallographic data for the three
compounds are given in the Supporting Information. A similar
reaction, giving products 16 with different R3-R5 substituents
in the presence of a catalytic amount of p-toluenesulfonic acid,
was reported by Vovk and co-workers11 at about the same time
of our preliminary report.1 None of the products 16b-p are
identical with those reported by Vovk. An analogous reaction
took place with the dithio precursor analogue 8 to give the
unknown substituted 3,4-dihydrothiazine-4-thione 17 (Chart 2,
eq 10).
4. Formation of 3-Cyano-6-methyl-4-trifluoromethyl-2-
pyridone (19). The reaction of 5j with trifluoroacetylacetone
18 yields the 2-pyridone derivative 19 (eq 11).
The X-ray diffraction data of 16d, 16k, and 16p show the
dihydrothiazine-4-one structure. The ORTEP and the crystal-
lographic data are given in the Supporting Information. The
C(1)-C(2), C(2)-C(3), C(3)-O, and C(1)-S bond lengths are
1.3940(19), 1.4554(18), 1.2395(17), and 1.7452(14) Å for 16d,
1.388(4), 1.453(4), 1.234(4), and 1.743(3) Å for 16k, and 1.394-
(6), 1.459(6), 1.229(5), and 1.723(6) Å [1.758(4) Å] for 16p,
respectively. The C(1)-C(2) bond lengths are typical for push-
pull enol systems activated by EWGs,2a,b,d-i,7 similar to the enol/
thioenol systems. Each molecule in the three structures is
intermolecularly hydrogen bonded to two other molecules: to
the first molecule by an N-H‚‚‚O moiety where the N-H bond
length is 0.78(5)-1.02(6) Å, and the O‚‚‚H and the N‚‚‚O
nonbonding distances are 1.84(6)-2.08(5) and 2.828(6)-
2.8995(16) Å. The second molecule is hydrogen bonded by an
N-H‚‚‚N moiety where the N-H bond length is 0.65(5)-1.03-
(4) Å, and the N‚‚‚H and N‚‚‚O nonbonding distances are 2.03-
(6)-2.50(6) and 2.858(5)-3.091(7) Å.
This is the only product in this work that does not contain sulfur.
The structure of solid 19 was determined by X-ray crystal-
lography. The ORTEP (see numbering of atoms in 19) and the
crystallographic data are given in the Supporting Information,
and the structure is supported by the C1-C2, C2-C3, C3-
C4, C4-C5, C1-N, C5-N, and C5-O bond lengths of 1.366-
(3), 1.394(3), 1.382(3), 1.443(3), 1.351(3), 1.375(2) and 1.235(2)
Å, respectively.
2-Pyridone is the favorable tautomer in the solid12a and mostly
in solution.12b,13 However, preference of 2-hydroxypyridine
derivatives in solution is also known.13 The low field signal at
13.36 ppm in DMSO-d6 can be ascribed to either the NH of 19
or to the OH of the hydroxypyridine 20, whereas the signal at
6.65 ppm was ascribed to the vinylic hydrogen present in both
19 and 20.
The structures are consistent with the elemental analysis, the
1H and 13C spectra in solution, and the known structure of
compound 16a. Two NH signals were observed for all deriva-
tives 16a-p and 17, one for the cyclic NH at higher field and
another at a lower field for the NHR3 group when R3 ) Ar in
DMSO-d6 (e.g., δ ) 8.11 and 10.34 for 16c) and very close
shifts when R3 ) i-Pr (e.g., δ ) 7.94 and 7.97 for 16d).
(11) (a) Vovk, M.; Sukach, V. A.; Chernega, A. N.; Pyrozhenko, V. V.;
Bol’but, A. V.; Pinchuk, A. M. Heteroat. Chem. 2005, 16, 426. (b)
For an earlier work, see: Yokoyama, M. Bull. Chem. Soc. Jpn. 1971, 44,
1610.
(12) (a) Almof, J.; Kvick, A.; Olovsson, I. Acta Crystallogr. 1971, B27,-
1201. (b) Wheeler, G. L.; Ammon, H. L. Acta Crystallogr. 1974, B30, 680.
(c) Beak, P.; Fry, F. S., Jr. J. Am. Chem. Soc. 1973, 95, 1700.
(13) For discussion on the pyridine-2-one/2-hydroxypyridine tautomerism
in solution and the gas phase, see: (a) Beak, P. Acc. Chem. Res. 1977, 10,
186. (b) Katritzky, A. R.; Karelson, M.; Malhorta, N. Heterocycles 1991,
32, 127. (c) Katritzky, A. R.; Karelson, M.; Harris, P. A. Heterocycles 1991,
32, 329. (d) March’s AdVanced Organic Chemistry. Reactions, Mechanisms,
and Structure, 6th ed.; Smith, M. B., March, J., Eds. Wiley: Hoboken, NJ,
2007; p 103. (e) Forlani, L.; Cristoni, G.; Boga, C.; Todesco, P. E.; Del
Vecchio, E.; Selva, S.; Monari, M. ARKIVOC 2002, XI, 198.
1390 J. Org. Chem., Vol. 73, No. 4, 2008

Cyanomonothiocarbonylmalonamides and their Thioenols
SCHEME 3. Suggested Mechanism for a Formation of 21
We suggest that the 2-pyridone is formed from the reaction
of trifluoroacetylacetone with the anion of 2-cyanoacetamide
which was obtained in turn from decomposition of the thioenol
5j. Loss of an EWG from methane substituted by three EWGs
is known. For example, a CO2CH2CF3 group is lost on heating
PhNHC(OH)dC(CO2CH2CF3)22d or on attempted crystallization
at -20 °C of (MeO)2P(dO)CH(CO2CH2CF3)CONHAn-p,2i and
a CO2CH(CF3)2 group is lost on attempted crystallization at
-20 °C of (MeO)2P(dO)CH(CO2CH(CF3)2)-CONHC6F5.2i We
do not know the mechanism of this process, although attack of
a weak base (e.g., 19) on the i-PrNHCdS group can displace
the anion of cyanoacetamide. Indeed, condensation of 18 with
cyanoacetamide in the presence of NaOEt14a or piperidine14b
gave 19. The same synthesis, with the product written as 20,
was reported earlier.14c Condensation of 18 with malononitrile
also gave 19.14d
The structure of the sulfide 21b (R ) i-Pr) was determined
by X-ray diffraction. The ORTEP (see numbering in 21)
and the full crystallographic data are given in the Supporting
Information. The solid state 21b is symmetrical with
E,E-configuration, that is, with cis-CN and S moieties. The
cis-PhNHCO and i-PrNH groups are hydrogen bonded to one
another as shown in eq 12. The X-ray unit cell contains two
independent molecules with C(1)-C(2), C(2)-C(3), and C(3)-O
bond lengths of 1.403(3) (1.394(3)), 1.461(4) (1.463(3)), and
1.253(3) Å (1.228(3) Å), respectively. The N‚‚‚O nonbonding
distances are 2.597(3) and 2.606(3) Å.
Attempted crystallization of the t-Bu derivative 4m, which
displays the amide 4m (20%), the enol 3m (32%), and the
thioenol 5m (48%) in CDCl3 solution,7 from EtOAc yielded
elementary sulfur S8, indicating the high reactivity and instability
of the species.
The two NH signals of 21a-c in the 1H NMR spectra appear
at 7.56-8.18 ppm for the CONHPh group and at 10.73-12.07
ppm for the intramolecularly N-H‚‚‚O hydrogen-bonded CON-
HR3 group. The 13C NMR spectra showed the CR [(NR3)CS]
b. Reactions Involving Two Molecules of 3/4/5. 1. Forma-
tion of Divinyl Sulfide Derivatives. When the N-phenyl-N′-
substituted cyanomonothiocarbonylmalonamides 5n-p were
crystallized from EtOAc, the corresponding symmetrical sulfides
21a-c, formed by a loss of H2S between the thioenol groups
of two molecules, were isolated (eq 12).
1
and CdO signals at 160.2 and 165.27 ppm. The H and 13C
NMR spectra of 21a-c resemble those of their precursors 5n-
p,7 except for the absence of the SH signal.
The suggested mechanism for formation of 21 is given in
Scheme 3. The CN and CONHPh groups increase the acidity
of the SH, and its ionization gives the thiolate anion 5-.
Although 5- is less nucleophilic than a simple RS- due to the
EWGs, it is still sufficiently nucleophilic to attack the positive
CR of another molecule of 5 with displacement of an HS-
nucleofuge to give the divinyl sulfide. Such an SNV replacement
of a RS- nucleofuge by an R′S- nucleophile in a â-EWG system
was investigated kinetically by Bernasconi and co-workers.15
2. Formation of a 1,2-Dithiolane Heterocycle. On attempted
crystallization of 3j/4j/5j from acetonitrile or acetonitrile-d3, an
unusual product composed of three molecules is obtained. One
is a symmetrical five-membered 3,5-bis(isopropylamino)-[1,2]-
dithiolane-4-carbonitrile moiety 22, the second (4j•) is derived
from the amide 4j by loss of hydrogen, and both are hydrogen
bonded by a water molecule (Figure 1) whose one hydrogen is
hydrogen bonded to the oxygen of the latter and the oxygen is
(14) (a) Portnoy, S. J. Org. Chem. 1965, 30, 3377. (b) Narsaiah, B.;
Sivaprasad, A.; Venkatarnam, R. V. Org. Prep. Proced. Int. 1993, 25, 116.
(c) Greene, J. L.; Montgomery, J. A. J. Med. Chem. 1963, 6, 294. (d)
Maitraie, D. V.; Venkat Reddy, G.; Rama Rao, V. V. V. N. S.; Ravi Kanth,
S.; Shanthan Rao, P.; Narsaiah, B. J. Fluorine Chem. 2002, 118, 73.
(15) (a) Bernasconi, C. F.; Ketner, R. J.; Chen, X.; Rappoport, Z. Can.
J. Chem. 1999, 77, 584; ARKIVOC 2000, 161. (b) Bernasconi, C. F.; Ketner,
R. J.; Ragains, M. C.; Chen, X. Rappoport, Z. J. Am. Chem. Soc. 2001,
123, 2155.
J. Org. Chem, Vol. 73, No. 4, 2008 1391

Basheer and Rappoport
hydrogen bonded to one of the NH groups of 22 (eq 13). The
X-ray data are of high quality and reliable: all the hydrogens
were located and the R factor is 0.03.
FIGURE 1. The ORTEP drawing of the 22-H2O-4j• adduct.
A tentative mechanism of formation of radical 22 is given in
Scheme 4. As in the formation of 19, the CONH2 can be initially
lost, although the details are unclear, and the anion 23 formed
then attacks a molecule of 4j to form the cyanodithiocarbon-
ylmalonamide 24 by expulsion of the cyanoacetamide anion.
The latter undergoes thioenolization, followed by loss of the
SH hydrogen by air oxidation, and attack of the thiyl radical
on the CdS bond will lead to the radical 22. Other variants for
the S-S bond formation via the well-known20 oxidative
sulfhydryl-disulfide reaction can also be suggested. Thioeno-
lization and hydrogen abstraction by air oxygen can also lead
to the radical 4j•.
Formation of a 3,7-Diaza[3.3.0]bicyclooctane-4,8-dithione
Derivative (25). Crystallization of 3f/4f/5f from CDCl3 at rt
under air yielded mainly the enol 3f7,21 and few crystals of the
1,5-bis(methylcarbamoyl)-3,7-dimethyl-2,6-diimino-3,7-diaza-
[3.3.0]bicyclooctane-4,8-dithione 25 (eq 14). When the crystal-
lization was conducted under nitrogen, only a mixture of 3f/
4f/5f was recovered.
Compound 22 is completely symmetric: the C(11)-C(12)
and C(12)-C(13) bonds have bond lengths of 1.403(2) Å, the
C(11)-S(2) and C(13)-S(3) bond lengths are 1.7467(17) and
1.7438(16) Å, respectively, and the C(11)-N(5) and C(13)-
N(6) bond lengths are 1.309(2) and1.310(2) Å, respectively. The
ring is completely planar. The full crystallographic data are given
in the Supporting Information of ref 7. The absence of hydrogens
on the ring carbons of 22 and on the C-CN carbon of 4j•
indicates a valence deficiency in both moieties. Tentative
structures are therefore “long-lived intermediates”: a delocalized
allylic cation, anion, or radical for 22, and a complementary
delocalized anion, cation, or radical, respectively, for 4j•.
Comparison with X-ray data of structurally related neutral
amides7 shows that the C-S and C-C bonds are longer than
those in the amides. The two 4-cyano-1,2-dithiolane crystal
structures in the literature16a,b are not helpful in solving the
structural problems, as is the NMR spectrum in solution, which
does not have to be the same as that in the solid. In CDCl3, the
3j/4j/5j composition is 61/24/10,7 and several signals are broad
and overlap other signals.
There are arguments for and against each type of long-lived
intermediates, based on the stability of the systems and the
substituent effect. We believe that the most likely intermediates
are two radicals. This is based on the observed X-ray structures
of several 4-EWG-1,2-dithia-3,5-diazolyl radicals. These sys-
tems are the analogues of 22, where two nitrogens replace the
two carbons, and an EWG (e.g., Cl or fluoro-substituted phenyl
groups) replaces the cyano.17 There are few systems where the
5-nitrogen is replaced by a carbon.18 Moreover, even a radical
pair was observed by X-ray crystallography.19
(16) (a) Yokoyama, M.; Shiraishi, T.; Hatanaka, H.; Ogata, K. Chem.
Commun. 1985, 1704. (b) Cmelik, R.; Marek, J.; Pazdera, P. Heterocycl.
Commun. 2002, 8, 55.
(17) (a) Antorrrena, G.; Dabies, J. E.; Hartley, M.; Palacio, F.; Rawson,
J. M.; Smith, J. N. B.; Steiner, A. Chem. Commun. 1999, 1393. (b) Bond,
A. D.; Haynes, D. A.; Pask, C. M.; Rawson, J. M. J. Chem. Soc., Dalton
Trans. 2002, 2522. (c) Clarke, C. S.; Pascu, S. I.; Rawson, J. M.
CrystEngComm 2004, 6, 79. (d) Alberola, A.; Less, R. J.; Pask, C. M.;
Rawson, J. M.; Palacio, F.; Oliete, P.; Paulsen, C.; Yamaguchi, A.; Farley,
R. D.; Murphy, D. M. Angew. Chem., Int. Ed. 2003, 42, 4782. (e) Heams,
N. G. R.; Preuss, K. E.; Richardson, J. F.; Bin-Salamon, S. J. Am. Chem.
Soc. 2004, 126, 9942.
(18) (a) Beer, L.; Britten, J. F.; Clements, O. P.; Haddon, R. C.; Itkis,
M. E.; Maikovich, K. M.; Oakley, R. T.; Reed, R. W. Chem. Mater. 2004,
16, 1564. (b) Oakley, R. T.; Reed, R. W.; Robertson, C. M.; Richardson,
J. F. Inorg. Chem. 2005, 44, 1837. (c) Barclay, T. M.; Beer, L.; Cordes, A.
W.; Oakley, R. T.; Preuss, K. E.; Taylor, N. J.; Reed, R. W. Chem. Commun.
1999, 531.
The solid-state structure of 25 is given in Figure 2, and
the full crystallographic data are given in the Supporting
Information. It shows that 25 is intramolecularly hydro-
(20) Capozzi, G.; Modena, G. In The Chemistry of the Thiol Group; Patai,
S., Ed.; Wiley: Chichester, UK, 1974; Chapter 17, p 785.
(21) Basheer, A.; Rappoport, Z. Org. Lett. 2006, 8, 5931.
(19) Kaawano, M.; Sano, T.; Abe, J.; Ohashi, Y. J. Am. Chem. Soc. 1999,
121, 8106.
1392 J. Org. Chem., Vol. 73, No. 4, 2008

Cyanomonothiocarbonylmalonamides and their Thioenols
SCHEME 4. Suggested Mechanism for Formation of 22
SCHEME 5. Suggested Mechanism for a Formation of 25
gen bonded by an N(1)-H‚‚‚N(2) moiety and inter-
molecularly hydrogen bonded to two other molecules by an
N(2)-H‚‚‚O(2′) moiety (Figure 2). The N(1)-H and N(2)-H
bond lengths are 0.82(2)-0.83(3) and 0.84(3)-0.89(3) Å,
respectively, and the N(2)‚‚‚H and N(1)‚‚‚N(2) non-
bonding distances are 2.12(3)-2.16(3) and 2.815(3)-2.820(3)
Å, respectively. The O(1′)‚‚‚H and N(2)‚‚‚O(1′) non-
bonding distances are 2.21(3)-2.24(3) and 3.055(3)-3.069(2)
Å, respectively. The C(1)-C(2), C(2)-C(3), C(2)-C(2′),
C(1′)-C(2′), and C(2′)-C(3′) bond lengths are 1.535(3)-1.543-
(3) Å, typical lengths for a C-C single bond.22 The C(1)-
O(1) and C(1)-O(1′) bond lengths are 1.230(2) and 1.231(2)
Å, respectively, values close to that of a CdO double bond.22
Finally, the C(3)-S(1) and C(3′)-S(1′) bond lengths are 1.626-
(2) and 1.623(2) Å, respectively, slightly shorter than a CdS
double bond length.22 The amount of 25 was too small for
obtaining NMR spectra.
Attempts to obtain other compounds with a similar skeleton
from the structurally related 3a/4a/5a, EtNHCSCH(CN)CON-
HMe, or i-PrNHCSCH(CN)CONHPr-i failed, and only amide,
enol, and/or thioenol mixtures were obtained in solution, and
the amide structure was obtained for the first system in the solid
state.7
From its structure, 25 is the condensation product of
two identical molecules of 3f, 4f, or 5f with a loss of a H2
molecule. The most likely precursor is the thioenol 5f,
which exists as 7% in the isomer mixture in CDCl3.7,21
The first step in the suggested mechanism is hydrogen abstrac-
(22) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A.
G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1987, S1.
FIGURE 2. The ORTEP drawing of 25.
J. Org. Chem, Vol. 73, No. 4, 2008 1393

Basheer and Rappoport
SCHEME 6. The Various Products Formed from 4j/5j
SCHEME 7. Various Products Formed from the Dithio 7/8 System
tion by the air oxygen from the S-H bond of 5f to form
the thiyl radical 5f• whose electron is partially delocalized
on Câ of its double bond. Attack by this Câ radical on Câ
of a second molecule of 5f concerted with or followed by
expulsion of H• from the SH bond generates 26 containing the
future central bond of 25. Separate attacks of the NH nitrogens
on the adjacent carbons of the cyano groups (written to-
gether in Scheme 5), followed by proton transfers, complete
the formation of the two five-membered rings to give 25
(Scheme 5).
We did not find other 3,7-diaza[3.3.0]bicyclooctane systems
in the literature. However, an isomeric skeleton to 25 in which
the four double bonds are within the bicyclic systems (e.g., 1,4-
disubstituted amino-3,6-dithiomethyl-2,5-diazapentalenes) is
known.23
Since both 4 and 5 are present in a rapid equilibrium in solution,
we suggested in each case the most probable precursor which
fit a suggested reasonable mechanism. Several products are
formed from the same precursor under a variety or even similar
conditions, suggesting similar barriers to their formation. In
Scheme 6, the five- and six-membered ring systems formed from
4j/5j are summarized; in Scheme 7, the four types of products
formed from the dithio system 7/8 are shown, and in Scheme
8, the three products formed from 4e/5e are given. Due to this
variety, it is difficult to predict what will be the products of yet
unstudied substituted precursors 3/4/5 under certain conditions.
Experimental Section
1
General Methods. Melting points are uncorrected. H and 13C
NMR spectra were recorded as described previously.24
Solvents and Materials. The 3a-p/4a-p/5a-p and 6/7/8
systems were available from our previous work.7 The other
precursors and the deuteriated solvents were purchased from a
commercial supplier and used without further purification.
Isothiazole-3-ones 9a-f from Air Oxygen Oxidation of
Thioenols 5e and 5g-k. The procedure is demonstrated for the
reaction of the 1-naphthyl derivative 9f. Compound 5e (141 mg,
Conclusions
A main feature of the present work is the variety of products
formed from thioenol/amide systems. No product formed from
the enol 3 was observed, and thioenols display high reactivity.
(23) Closs, F.; Breimaier, W.; Frank, W.; Gompper, R.; Hohenester, A.
Synth. Met. 1989, 29, E537.
(24) Frey, J.; Rappoport, Z. J. Am. Chem. Soc. 1996, 118, 5169.
1394 J. Org. Chem., Vol. 73, No. 4, 2008

Cyanomonothiocarbonylmalonamides and their Thioenols
SCHEME 8. The Various Products Formed from Formal 4e
0.5 mmol) was dissolved in ethyl acetate (2 mL) with stirring for
5 min and then kept for 3 days at room temperature. The colorless
crystals that precipitated were dried at room temperature to give
75 mg (0.267 mmol, 53%) of the pure 2-methyl-5-(naphthalen-1-
ylamino)-3-oxo-2,3-dihydroisothiazole-4-carbonitrile 9f, mp 237-
238 °C. Anal. Calcd for C15H11N3OS: C, 64.06; H, 3.91; N, 14.95.
Found: C, 63.84; H, 3.95; N, 14.94. 1H NMR (DMSO-d6, 298 K,
400 MHz) δ: 3.01 (3H, s), 7.58 (1H, t, J ) 7.6 Hz), 7.32 (3H, m),
7.99-8.06 (3H, m), 11.12 (1H, s). 13C NMR (DMSO-d6, 298 K,
100.62 MHz) δ: 30.3, 72.6, 114.6, 122.6, 124.6, 126.2, 127.6,
127.8, 128.9, 129.2, 129.5, 134.3, 134.6, 166.7, 169.7.
7.90 (1H, br s), 8.57 (1H, br s), 12.97 (1H, s). 13C NMR (DMSO-
d6, 298 K, 100.62 MHz) δ: 76.1 (s), 113.9 (d, J ) 167 Hz), 117.7
(s), 122.6 (d, J ) 162 Hz), 124.2 (d, J ) 164 Hz), 127.1 (s), 127.6
(d, J ) 164 Hz), 138.8 (s), 169.1 (s), 188.7 (s).
5-[Cyano(phenylthiocarbamoyl)methylene]-3-methyl-2,3-di-
hydrothiazole-2-carboxylic Acid Ethyl Ester 14. When the formal
cyanodithiocarbonylmalonamide 7 (118 mg, 0.5 mmol) was dis-
solved in ethyl acetoacetate (2 mL) at rt and the solution stood
for 1 week, 5-[cyano(phenylthiocarbamoyl)methylene]-3-methyl-
2,3-dihydrothiazole-2-carboxylic acid ethyl ester 14 (74 mg, 0.32
mmol, 64%), mp 183-184 °C, was formed. Anal. Calcd for
C16H15N3O2S2: C, 55.65; H, 4.35; N, 12.17. Found: C, 55.28; H,
The spectral and analytical data for derivatives 9a-f, which were
obtained similarly, are given in Tables S1-S3 in the Supporting
Information.
1
4.60; N, 11.33. H NMR (DMSO-d6, 298 K, 400 MHz) δ: 1.28
(3H, t, J ) 7.1 Hz), 2.58 (3H, s), 4.27 (2H, q, J ) 7.0 Hz), 7.17
(1H, t, J ) 7.4 Hz), 7.34 (2H, t, J ) 7.9 Hz), 7.45 (2H, d, J ) 7.1
Hz), 10.07 (IH, s), 13.08 (1H, br s). 13C NMR (DMSO-d6, 298 K,
100.62 MHz) δ: 14.7, 30.5, 61.4, 78.8, 110.0, 117.4, 125.7, 128.7,
140.6, 147.5, 161.8, 167.2, 186.5.
5-Phenylamino-3-thioxo-2,3-dihydroisothiazole-4-carboni-
trile 10, mp 208-209 °C (89 mg, 0.39 mmol), was obtained from
the formal cyanodithiocarbonylmalonamide 7 (118 mg, 0.5 mmol)
in 76% yield by a procedure similar to that described for formation
of 9b. Anal. Calcd for C10H7N3S2: C, 51.50; H, 3.00; N, 18.02.
Found: C, 51.77; H, 2.86; N, 17.58. 1H NMR (DMSO-d6, 298 K,
400 MHz) δ: 7.25-7.49 (3H, m), 7.86-8.03 (2H, m), 9.83 (2H,
s). 13C NMR (DMSO-d6, 298 K, 100.62 MHz) δ: 88.9 (s), 116.4
(s), 125.7 (d, J ) 162 Hz), 128.3 (d, J ) 163 Hz), 130.0 (d, J )
163 Hz), 139.2 (t, J ) 9.3 Hz), 162.3 (s), 187.4 (s).
6-Substituted Amino-2,2-dialkyl-4-oxo-3,4-dihydro-2H-[1,3]-
thiazine-5-carbonitriles 16a-o. The procedure is demonstrated
for the reaction of 5j with acetone. When the thioenol 5j (185 mg,
1 mmol) was dissolved in acetone (2 mL) and the mixture was
stirred for 5 min and kept at room temperature overnight, colorless
crystals were precipitated. The crystals were filtered, washed with
ether, and dried at room temperature to give 211 mg (0.94 mmol,
94%) of the pure 6-isopropylamino-2,2-dimethyl-4-oxo-3,4-dihydro-
2H-[1,3]thiazine-5-carbonitrile 16d, mp 203-204 °C. Anal. Calcd
for 16d: C, 53.33; H, 6.67; N, 18.67. Found: C, 53.37; H, 6.74;
N, 18.56. 1H NMR (CDCl3, 298 K, 400 MHz) δ: 1.30 (6H, d, J )
6.6 Hz), 1.76 (6H, s), 3.86 (1H, oct, J ) 6.5 Hz), 5.90 (1H, d, J )
2-Cyano-N-methyl-2-(1H-naphtho[1,2-d]thiazol-2-ylidene)ac-
etamide 12. When a formal thioenol 5e (141 mg, 1 mmol) was
dissolved in ethyl acetate under air, it gave colorless crystals which
were filtered and dried in air at rt to give the pure 2-cyano-N-
methyl-2-(1H-naphtho[1,2-d]thiazol-2-ylidene)acetamide 12 (97 mg,
0.35 mmol, 70%), mp 258-260 °C. Anal. Calcd for C15H11N3OS:
C, 64.06; H, 3.91; N, 14.95. Found: C, 63.92; H, 4.00; N, 14.67.
1H NMR (CDCl3, 298 K, 400 MHz) δ: 2.98 (3H, d, J ) 4.8 Hz),
5.80 (1H, q, J ) 3.1 Hz), 7.12 (1H, d, J ) 8.7 Hz), 7.57-7.67
(3H, m), 7.95 (1H, d, J ) 8.0 Hz), 8.02 (1H, d, J ) 8.2 Hz), 13.92
1
8.3 Hz), 7.00 (1H, s). H NMR (DMSO-d6, 298 K, 400 MHz) δ:
1.20 (6H, d, J ) 6.5 Hz), 1.62 (6H, s), 3.86 (1H, oct, J ) 4.7 Hz),
7.94 (1H, s), 7.97 (1H, d, J ) 8.6 Hz). 13C NMR (DMSO-d6,
298 K, 100.62 MHz) δ: 22.8 (q, J ) 127 Hz), 29.9 (q, J ) 129
Hz), 48.2 (d, J ) 138 Hz), 61.4 (s), 72.5 (s), 117.7 (s), 165.2 (s),
165.5 (s).
1
(1H, s). H NMR (DMSO-d6) δ: 2.72 (3H, s), 7.32 (1H, br s),
7.53-7.67 (2H, m), 7.78 (1H, d, J ) 8.3 Hz), 7.89 (1H, d, J ) 8.3
Hz), 8.02 (1H, d, J ) 8.0 Hz), 8.77 (1H, d, J ) 7.8 Hz), 12.87
(1H, s). 13C NMR (DMSO-d6, 298 K, 100.62 Hz) δ: 26.9, 67.1,
118.5, 119. 9, 121.0, 123.1, 123.9, 124.1, 126.6, 127.0, 128.9, 132.4,
134.7, 166.0, 166.8.
The analogous 2-anisyl derivative 16p was prepared similarly
from 5j and anisaldehyde.
The spectral and analytical data for 16a-p are given in Tables
S1-S3 in the Supporting Information.
2-(3H-Benzothiazol-2-ylidene)-2-cyanothioacetamide 13. A
reaction similar to the formation of 12 took place when the formal
cyanodithiocarbonylmalonamide 7 (118 mg, 0.5 mmol) was dis-
solved in acetonitrile, and 2-(3H-benzothiazol-2-ylidene)-2-cyan-
othioacetamide 13, mp 221-222 °C, was obtained in 68% yield
(79 mg, 0.34 mmol). Anal. Calcd for C10H7N3S2: C, 51.50; H, 3.00;
N, 18.03. Found: C, 51.59; H, 2.99; N, 17.82. 1H NMR (DMSO-
d6, 298 K, 400 MHz) δ: 7.28 (1H, t, J ) 7.9 Hz), 7.43 (1H, t, J
) 7.2 Hz), 7.62 (1H, d, J ) 6.8 Hz), 7.86 (1H, d, J ) 7.8 Hz),
6-Phenylamino-2,2-dimethyl-4-thioxo-3,4-dihydro-2H-[1,3]-
thiazine-5-carbonitrile 17. Reaction of formal cyanodithiocarbo-
nylmalonamide 7 (59 mg, 0.25 mmol) in acetone (1 mL) under the
condition used for preparation 16a-p yielded the 6-phenylamino-
2,2-dimethyl-4-thioxo-3,4-dihydro-2H-[1,3]thiazine-5-carbonitrile
17, mp 232-233 °C, in 87% yield (51 mg, 0.218 mmol). Anal.
Calcd for 17: C, 56.73; H, 4.73; N, 15.27; S, 22.27. Found: C,
1
56.76; H, 4.89; N, 15.14; S, 22.83. H NMR (DMSO-d6, 298 K,
400 MHz) δ: 1.61 (6H, s), 7.27 (2H, d, J ) 7.3 Hz), 7.33 (1H, t,
J. Org. Chem, Vol. 73, No. 4, 2008 1395

Basheer and Rappoport
J ) 7.4 Hz), 7.42 (2H, t, J ) 7.8 Hz), 9.82 (1H, s), 10.30 (1H, s).
13C NMR (DMSO-d6, 298 K, 100.62 MHz) δ: 28.6 (q, J ) 130
Hz), 62.6 (s), 86.6 (s), 117.1 (s), 126.7 (d, J ) 163 Hz), 127.9 (d,
J ) 163 Hz), 129.5 (d, J ) 163 Hz), 138.0 (t, J ) 9.3 Hz), 161.8
(s), 187.0 (s).
Formation of 3,5-Bis(isopropylamino)-[1,2]-dithiolane-4-car-
bonitrile/4j•/H2O 22. Crystallization of 4j (185 mg, 1 mmol) from
acetonitrile or from acetonitrile-d3 (4 mL) at rt gives a three-
molecule associate: the radical 4j• which is intermolecularly
hydrogen bonded by one water molecule to the 3,5-bis(isopropy-
lamino)-[1,2]-dithiolane-4-carbonitrile radical 22. Anal. Calcd for
C17H28N6O2S3: C, 45.94; H, 6.38; N, 21.60. Found: C, 44.62; H,
3-Cyano-6-methyl-4-trifluoromethyl-2(1H)-pyridone, 19. Col-
orless crystals of 19 (65 mg, 0.32 mmol, 64%), mp 232-233 °C
(lit.14a,25 mp 232-234 °C, lit.14b,d mp 234 °C), were obtained after
dissolving 5j (93 mg, 0.5 mmol) in trifluoroacetylacetone 18 (2
mL) and keeping the mixture under air for 48 h at rt. Anal. Calcd
for C8H5F3N2O: C, 47.52; H, 2.48; N, 13.86. Found: C, 47.25; H,
1
6.07; N, 17.90. H NMR (DMSO-d6, 298 K, 400 MHz) δ: 1.09
(6H, br), 1.25 (12H, J ) 6.6 Hz), 3.35 (2.5H, br s), 3.69 (2.5H, s),
4.43 (1H, s), 5.02 (0.3H, s), 5.81 (1H, br s), 7.55 (0.5H, d, J ) 6.5
Hz), 9.96 (0.5H, s) 10.21 (1.6H, br s).
1
2.48; N, 13.88. H NMR (DMSO-d6, 298 K, 400 MHz) δ: 2.38
1,5-Bis(methylcarbamoyl)-3,7-dimethyl-2,6-diimino-3,7-diaza-
[3.3.0]bicyclooctane-4,8-dithione (25). When the formal cyano-
monothiomalonamide 4f (86 mg, 0.05 mmol) was dissolved in
chloroform (5 mL) and the solution was kept overnight, colorless
crystals of the enol 3f accompanied by few yellow crystals of 25,
mp 287-288 °C, were formed. The crystals of 25 were sufficient
only for X-ray diffraction but not for the NMR spectral measure-
ments.
(3H, s), 6.65 (1H, s), 13.36 (1H, s). 13C NMR (DMSO-d6, 298 K,
100.62 MHz) δ: 20.0, 96.6, 102.1, 114.0, 121.7 (q, J ) 276 Hz),
146.4 (q, J ) 32 Hz), 157.4, 161.0.
Divinyl Sulfides 21a-c from Thioenols 5n-p. The disulfides
21a-c were prepared similarly under the same condition as
demonstrated for formation of 21b. The thioenol 5o (261 mg, 1
mmol) was dissolved in ethyl acetate (2 mL), and the mixture was
kept at rt for 48 h. The orange crystals obtained were filtered and
dried in air at rt to give the pure bis[(2-cyano-2-phenylcarbamoyl-
1-isopropylamino)vinyl] sulfide 21b, mp 218-220 °C, in 79% yield
(192 mg, 0.39 mmol). Anal. Calcd for C26H28N6O2S: C, 63.93; H,
Reactions under Nitrogen. (a) Formal compound 4j was
dissolved in AcOEt under nitrogen, and the mixture was stirred
for 5 min and then kept for more than 40 h at rt. The solvent was
1
1
5.74; N, 17.21. Found: C, 64.15; H, 5.91; N, 17.33. H NMR
evaporated, and the remainder was dissolved in CDCl3 and its H
(CDCl3, 298 K, 400 MHz) δ: 1.37 (12H, d, J ) 6.5 Hz), 4.30
(2H, oct, J ) 6.5 Hz), 7.12 (2H, t, J ) 7.4 Hz), 7.33 (4H, t, J )
8.2 Hz), 7.47 (4H, d, J ) 7.7 Hz), 7.56 (2H, s), 11.22 (2H, q, J )
7.8 Hz). 13C NMR (CDCl3, 298 K, 100.62 MHz) δ: 23.6 (q, J )
128 Hz), 49.7 (d, J ) 140 Hz), 76.1 (d, J ) 3.6 Hz), 118.4 (s),
120.6 (d, J ) 163 Hz), 124.7 (d, J ) 162 Hz), 129.0 (d, J ) 162
Hz), 137.0 (t, J ) 7.9 Hz), 160.0 (d, J ) 4.1 Hz), 165.3(d, J ) 3.0
Hz).
NMR spectrum shows signals for the 3j/4j/5j mixture. In a similar
reaction of 4i under nitrogen, the spectrum in THF-d8 showed only
signals for the enol 3i. (b) Compound 4e was dissolved in acetone,
and the solution stood under nitrogen at rt for more than 30 h.
After evaporation of the solvent, the solid obtained showed in the
1H NMR spectrum signals for the enol 3e and the thioenol 5e. From
crystallization of 4e in EtOAc under nitrogen, crystals of 3e were
isolated. (c) Dissolution of 4f in CDCl3 under nitrogen for 24 h
showed only signals for the 3f/4f/5f mixture.
Bis[(2-cyano-2-phenylcarbamoyl-1-anilido)vinyl] Sulfide 21a.
Mp 236-7 °C. Anal. Calcd for C32H24N6O2S: C, 69.05; H, 4.35;
1
N, 15.10. Found: C, 69.29; H, 4.12; N, 15.20. H NMR (CDCl3,
Acknowledgment. We are indebted to the Israel Science
Foundation for support, to Dr. Shmuel Cohen for the X-ray
structure determination and discussions, and to Prof. Silvio Biali
for valuable suggestions.
298 K, 400 MHz) δ: 7.17-7.24 (6H, m), 7.29 (2H, d, J ) 7.8
Hz), 7.36-7.46 (12H, m), 7.75 (2H, s), 12.04 (2H, s). 13C NMR
(CDCl3, 298 K, 100.62 MHz) δ: 62.6, 72.1, 118.0, 124.5, 125.1,
125.8, 127.3, 129.07, 129.4, 136.0, 136.4, 160.5, 163.4.
Bis[(2-cyano-2-phenylcarbamoyl-1-ethylamino)vinyl] Sulfide
21c. Mp 220-221 °C. Anal. Calcd for C24H24N6O2S: C, 62.59;
Supporting Information Available: CIFs of compounds 9d,
9f, 12, 13, 14, 16d, 16k, 16p, 19, 21b, and 25, Tables S1 and S2
of 1H and 13C NMR of 9a-f and 16a-p and Table S3 of analytical
data of all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
H, 5.25; N, 18.25. Found: C, 62.41; H, 5.18; N, 17.95. H NMR
(CDCl3, 298 K, 400 MHz) δ: 1.36 (6H, t, J ) 7.2 Hz), 3.74 (4H,
pent, J ) 7.1 Hz), 7.12 (2H, t, J ) 7.3 Hz), 7.32 (4H, t, J ) 8.0
Hz), 7.45 (4H, d, J ) 7.9 Hz), 7.63 (2H, s), 10.73 (2H, s).
(25) Lang, R. W.; Wenk, P. F. HelV. Chim. Acta 1988, 71, 596.
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