2-Aryl-1,1-dicyano-3-phenylsulfonylpropenes in heterocyclic synthesis: A synthetic strategy towards heterocyclic sulfones

Article abstract of DOI:10.1007/PL00010115

The applicability and synthetic potency of the novel reagent 1-aryl-1,1-dicyano-3-phenylsulfonylpropene for the development of an expeditious synthetic approach to unique polyfunctionally substituted heterocyclic sulfone systems is reported. Chemical and spectroscopic evidences for the structures of the new compounds are presented.

Full text of DOI:10.1007/PL00010115

Monatshefte fuÈr Chemie 129, 1049±1056 (1998)
2-Aryl-1,1-dicyano-3-phenylsulfonylpropenes
in Heterocyclic Synthesis: A Synthetic
Strategy Towards Heterocyclic Sulfones
Ayman W. Erian
Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
Summary. The applicability and synthetic potency of the novel reagent 1-aryl-1,1-dicyano-3-
phenylsulfonylpropene for the development of an expeditious synthetic approach to unique
polyfunctionally substituted heterocyclic sulfone systems is reported. Chemical and spectroscopic
evidences for the structures of the new compounds are presented.
Keywords. Sulfonylheterocycles; Pyridines; Pyridazines; Pyridopyrimidines.
2-Aryl-1,1-dicyano-3-phenylsulfonylpropen in der Heterocyclensynthese:
Eine Synthesestrategie fuÈr heterocyclische Sulfone
Zusammenfassung. Die Anwendbarkeit und synthetische Brauchbarkeit des neuen Reagens 1-Aryl-
1,1-dicyano-3-phenylsulfonylpropen fuÈr eine rasch durchfuÈhrbare Synthese von polyfunktionell
substiuierten heterocyclischen Sulfonen wird vorgestellt. Die chemischen und spektroskopischen
È
Daten werden als Evidenz fuÈr die Stukturen der neuen Verbindungen prasentiert.
Introduction
Sulfones have proven to be valuable synthons for the synthesis of a wide variety of
biologically active heterocyclic systems [1±6]. As an extension of our efforts
directed towards the development of convenient synthetic approaches for the
construction of biological active heterocycles [7±10], I wanted to accentuate the
synthetic scope of the novel reagent 2-aryl-1,1-dicyano-3-phenylsulfonylpropene
(3) as a key precursor for the synthesis of some hitherto unreported poly-
functionally substituted sulfonylheterocycles and their fused systems with an
expected broad spectrum of bioresponses.
Results and Discussion
The reaction of equimolar amounts of each of the ꢀ-bromomethyl-ꢁ-cyanocinna-
monitriles 1a,b [11] with sodium benzenesul®nate (2) in boiling ethanol furnished
exclusively the corresponding 2-aryl-1,1-dicyano-3-phenylsulfonylpropenes 3a,b

1050
A. W. Erian
Scheme 1
in excellent yield (Scheme 1). The elemental and spectroscopic data of 3 are
consistent with the assigned structure.
Compound 3 is established as a versatile reagent for the construction of several
unique heterocyclic systems. The methylene group of 3 proved to be highly reactive
towards electrophilic reagents. Thus, 3a reacted with an equimolar amount of
arylidenemalonitriles 4 to yield the corresponding fully substituted benzene
derivatives 6. Formation of 6 is believed to proceed via a Michael addition of the
activated methylene group in 3 to the electron de®cient carbon in the ꢁ,ꢀ-
unsaturated system in 4, intramolecular cyclization, and autoaromatizations via
loss of HCN under the experimental reaction conditions (Scheme 1). Similar
autoaromatizations have been reported previously [11±13].
Compound 3a readily coupled with equimolar amounts of arenediazonium
chlorides to yield the corresponding coupling products which may be formulated as
the acyclic hydrazone form 7 or its cyclic pyridazine form 8. However, the
hydrazone structure was tentatively preferred over 8 for the reaction products on
the basis of spectroscopic data. Thus, as a representative example, the IR spectrum
of 7a reveals the presence of two absorption peaks at ꢂ ˆ 2222 and 2218 cmꢀ1
which are attributed to two CN functions. Its 13C NMR spectrum (DMSO-d6)
shows, in addition to the expected signals at ꢃ ˆ 162.63 (C-3), 143.9 (C-2), 136.9-
126.0 (aromatic carbons), and 69.67 (C-1) ppm, two signals at ꢃ ˆ 116.76 and
114.31 ppm attributed to the presence of two CN carbons. Furthermore, pyridazine
8 could be obtained upon heating hydrazone 7 in glacial acetic acid.

Heterocyclic Sulfones via 2-Aryl-1,1-dicyano-3-phenylsulfonylpropenes
1051
Scheme 2
Compound 3a reacted with an equimolar amount of triethyl orthoformate in
re¯uxing dioxane in the presence of acetic anhydride to provide the corresponding
ethoxymethylene derivative 9 in acceptable yield. Compound 9 exhibits a high
reactivity towards nucleophilic reagents. Thus, the reaction of 9 with equimolar
amounts of primary aromatic amines in re¯uxing dioxane solutions afforded the
corresponding N-arylpyridine derivatives 10 via EtOH elimination and sponta-
neous intramolecular heterocyclization (Scheme 2). The analytical and spectro-
scopic data are in accordance with the proposed structure. The 2-pyranone
derivative 11 was obtained in 55% yield upon boiling 9 with Ba(OH)2 in EtOH
solution. Likewise, the 2-aminopyridine-3-carbonitrile derivative 12 was obtained
by the action of an excess of ammonia on 9 at room temperature. Formation of 12
is assumed to proceed via EtOH elimination and spontaneous heterocyclization
via a Michael type nucleophilic addition of the NH2 protons to the neighbouring
C:N function. Structure 12 was established by a correct elemental analysis and
compatible spectra. Thus, its IR spectrum (KBr) revealed absorption peaks corres-
ponding to the presence of only one CN and of NH2 functions.
The 1-benzoyl-2-aminopyridine derivative 13 was obtained in 75% yield from
the reaction of 3a with an equimolar amount of benzoyl isothiocyanate in re¯uxing
acetonitrile solution (Scheme 3). Compound 13 could be annelated into fused
heterocyclic ring systems of an expected wide spectrum of biological activities.
Thus, compound 13 reacted with an equimolar amount of benzylidenemalononi-
trile (4a) to afford a single product with a pyrido[1,2-a]pyrimidine structure (15).
Formation of 15 was assumed to proceed via a Michael type addition of the NH2
group of 13 to the electron de®cient carbon atom in the ꢁ,ꢀ-unsaturated cin-
namonitrile system in 4a to form the intermediate acyclic 1:1 Michael adduct 14,
spontaneous intramolecular cyclization via loss of H2O from the amide carbonyl
group, and autoaromatization by loss of HCN to yield the ®nal product 15. Both
elemental and spectroscopic data of 15 are consistent with the assigned structure.
Thus, its mass spectrum revealed a molecular ion peak at m/z ˆ 580 corresponding
to the molecular formula C34H20N4O2S2. Its IR spectrum showed absorption peaks
corresponding to the presence of two CN and C=S functions at ꢂ ˆ 2225, 2220, and

1052
A. W. Erian
Scheme 3
1200 cmꢀ1. Alternatively, product 15 could be obtained via an independent
stepwise synthetic route involving the condensation of 13 with an equimolar
amount of benzaldehyde in the presence of a catalytic amount of Et3N to afford the
corresponding Schiff base 16. The latter, in turn, reacted with malononitrile in
dioxane containing a catalytic amount of Et3N under re¯ux to afford a single
product found to be identical with 15.
Finally, our methodology was applied to the synthesis of polyfunctionally
substituted fused pyridines accessible only with dif®culty otherwise. Thus,
compound 14 reacted with an equimolar amount of chloroacetonitrile in ethanol
in the presence of K2CO3 to afford the corresponding imidazo[1,2-a]pyridine
derivative 17 (Scheme 3).
In conclusion, it seems that the results extend and broaden the knowledge in the
area of heterocyclic sulfone systems obtainable only with dif®culty otherwise and
demonstrate a general applicable methodology for the construction of such ring
systems with reasonable yields.
Experimental
Melting points are uncorrected; IR spectra (KBr): Pye Unicam SP-1000, ꢂ in cmꢀ1; 1H and 13C NMR
spectra (DMSO-d6): Varian Gemini 200 MHz spectrometer, TMS as internal standard, chemical shifts
in ꢃ (ppm); mass spectra: AEI MS 30 mass spectrometer operating at 70 eV; elemental analysis:
Microanalytical Data Unit at Cairo University, their results agreed with the calculated values.
ꢀ-Bromomethyl-(ꢁ-cyanocinnamonitriles) 1a,b [11] were prepared according to the literature.

Heterocyclic Sulfones via 2-Aryl-1,1-dicyano-3-phenylsulfonylpropenes
1053
General procedure for the synthesis of 2-aryl-1,1-dicyano-3-phenyl-sulfonylpropenes
A mixture of 1a,b (0.01 mol) and sodium benzenesul®nate (2, 0.015 mol) in EtOH (30 ml) was boiled
under re¯ux for 4 h. The reaction mixture was left to cool at room temperature and poured onto cold
H2O. The solid product precipitated was collected by ®ltration, washed thoroughly with H2O, dried,
and crystallized.
1,1-Dicyano-2-phenyl-3-phenylsulfonylpropene (3a; C17H12N2O2S)
1
Yield: 2.59 g (84%); m.p.: 125ꢁC (EtOH); IR: 3010 (CH2), 2220, 2218 (2 CN), 1630 (C=C); H
NMR: 4.25 (s, 2H, CH2), 6.81±7.20 (m, 5H, arom. protons), 7.42±7.80 (m, 5H, arom. protons); MS:
‡
m/z (%) ˆ 308 (M , 12%).
2-(40-Chlorophenyl)-1,1-dicyano-3-phenylsulfonylpropene (3b; C17H11ClN2O2S)
Yield: 3.02 g (88%); m.p.: 136ꢁC (EtOH); IR: 3018 (CH2), 2222, 2215 (2 CN), 1635 (C=C).
2-Amino-4-(40-chlorophenyl)-3-cyano-6-phenyl-5-phenylsulfonylbenzonitrile
(6b; C26H16ClN3O2S)
To a suspension of 3a (0.003 mol) in dry dioxane (25 ml) containing Et3N (5 drops), ary-
lidenemalononitrile 4b (0.003 mol) was added. The reaction mixture was heated under re¯ux for 4 h,
poured into an ice/H2O mixture (30 ml), and neutralized with dilute HCl. The solid product was
®ltered off and crystallized.
Yield: 1.03 g (73%); m.p.: 223ꢁC (EtOH); IR: 3445±3310 (NH2), 2220, 2218 (2 CN), 1645
(C=C); 4.35 (br s, 2H, NH2, exchangeable), 6.78±7.21 (m, 5H, arom. protons), 7.34±7.82 (m, 9H,
arom. protons).
General procedure for the synthesis of 3-arylhydrazono-1,1-dicyano-2-phenyl-3-
phenylsulfonylpropenes
To a stirred solution of 3a (0.004 mol) in EtOH (50 ml) containing AcONa (3 g), the appropriate
arenediazonium chloride (prepared by adding NaNO2 (0.004 mol) to the primary aromatic amine
(0.004 mol) in concentrated HCl (3 ml) at 0±5ꢁC with stirring). The reaction mixture was then left at
room temperature for 6 h, triturated with cold H2O (15 ml) where the solid product formed was
®ltered off, washed thoroughly with H2O, dried, and crystallized.
1,1-Dicyano-2-phenyl-3-phenylhydrazono-3-phenylsulfonylpropene
(7a; C23H16N4O2S)
1
Yield: 1.15 g (70%); m.p.: 196ꢁC (CHCl3); IR: 3200 (NH), 2222, 2218 (2 CN), 1660 (C=C); H
NMR: 6.76±7.80 (m, 15H, arom. protons), 9.81 (br s, 1H, NH, exchangeable); 13C NMR: 162.63
(C-3), 143.9 (C-2), 136.9±126.0 (arom. carbons), 116.76, 114.13, (2 CN), 69.67 (C-1); MS: m/z
‡
(%) ˆ 412 (M , 24%).
3-(40-Chlorophenylhydrazono)-1,1-dicyano-2-phenyl-3-phenylsulfonylpropene
(7b; C23H15ClN4O2S)
Yield: 1.32 g (74%); m.p.: 180ꢁC (CHCl3); IR: 3200 (NH), 2222, 2219 (2 CN).

1054
A. W. Erian
General procedure for the synthesis of 2-aryl-3-imino-5-phenyl-6-
phenylsulfonylpyridazine-4-carbonitriles
A solution of 7a,b (0.002 mol) in glacial acetic acid (25 ml) was boiled under re¯ux for 1 h and the
solvent was evaporated in vacuo. The reaction mixture was triturated with cold H2O; the solid
product was ®ltered off, washed with cold H2O, dried, and crystallized.
1,4-Diphenyl-6-imino-3-phenylsulfonylpyridazine-5-carbonitrile (8a; C23H16N4O2S)
Yield: 0.54 g (66%); m.p.: 242ꢁC (AcOH); IR: 3250 (NH), 2222 (CN), 1660 (C=C); 1H NMR: 6.95±
7.81 (m, 15H, arom. protons), 12.80 (br s, 1H, NH, exchangeable); 13C NMR: 173.23 (C-3), 160.41
(C-6), 147.32 (C-5), 139.30±126.86 (arom. carbons), 122.51 (C-4), 116.76 (CN carbon); MS: m/z
‡
(%) ˆ 412 (M , 28%).
1-(40-Chlorophenyl)-6-imino-4-phenyl-3-phenylsulfonylpyridazine-5-carbonitrile
(8b; C23H15ClN4O2S)
Yield: 0.62 g (70%); m.p.: 230ꢁC (AcOH); IR: 3250 (NH), 2220 (CN), 1630 (C=C).
1,1-Dicyano-3-ethoxymethylene-3-phenyl-3-phenylsulfonylpropene (9; C20H16N2O3S)
A mixture of 3a (0.01 mol) and triethyl orthoformate (0.01 mol) in dioxane (30 ml) containing Ac2O
(15 ml) was boiled under re¯ux for 3 h. The reaction mixture was cooled at room temperature and
poured into cold H2O. The solid product that separated was ®ltered off, washed thoroughly with
H2O, dried, and crystallized from dioxane.
1
Yield: 2.22 g (61%); m.p.: 110ꢁC; IR: 3020 (CH2), 2225, 2219 (2 CN), 1660 (C=C); H NMR:
0.91 (t, 3H, J ˆ 8.0 Hz, CH3), 3.71 (q, 2H, J ˆ 8.3 Hz, CH2), 6.85±7.31 (m, 5H, arom. protons), 7.40±
‡
7.82 (m, 6H, arom. protons ‡ ole®nic CH); MS: m/z (%) ˆ 364 (M , 16%).
General procedure for the synthesis of 1-aryl-1,2-dihydro-2-imino-4-phenyl-5-
phenylsulfonylpyridine-3-carbonitriles
A solution of 9 (0.002 mol) and the appropriate primary aromatic amine (0.002 mol) in dry dioxane
(30 ml) was boiled under re¯ux for 3 h. The reaction mixture was evaporated in vacuo and triturated
with cold H2O. The solid product was ®ltered off, dried, and crystallized from an appropriate solvent.
1,2-Dihydro-1,4-diphenyl-2-imino-5-phenylsulfonylpyridine-3-carbonitrile (10a; C24H17N3O2S)
Yield: 0.53 g (64%); m.p.: 188ꢁC (EtOH); IR: 3220 (NH), 2225 (CN); 1H NMR: 6.71±7.82 (m, 16H,
‡
arom. protons ‡ pyridine H-6), 11.93 (br s, 1H, NH, exchangeable); MS: m/z (%) ˆ 411 (M , 28%).
1-(40-Chlorophenyl)-1,2-dihydro-2-imino-4-phenyl-5-phenylsulfonylpyridine-3-carbonitrile
(10b; C24H16ClN3O2S)
Yield: 0.59 g (66%); m.p.: 185ꢁC (dioxane); IR: 3250 (NH), 2222 (CN).
2-Oxo-4-phenyl-5-phenylsulfonyl-2H-pyran-3-carbonitrile (11; C18H11NO4S)
A mixture of 9 (0.002 mol) and Ba(OH)2 (0.002 mol) in EtOH (25 ml) was boiled under re¯ux for
2 h. The reaction mixture was poured into cold H2O; the solid product that separated was ®ltered off
and crystallized from EtOH.

Heterocyclic Sulfones via 2-Aryl-1,1-dicyano-3-phenylsulfonylpropenes
1055
Yield: 0.37 g (55%); m.p.: 135ꢁC; IR: 2220 (CN), 1675 (C=O), 1650 (C=C); 1H NMR: 6.71±7.82
‡
(m, 11H, arom. protons ‡ pyran H-6); MS: m/z (%) ˆ 337 (M , 16%).
2-Amino-4-phenyl-5-phenylsulfonylpyridine-3-carbonitrile (12; C18H13N3O2S)
A suspension of 9 (0.003 mol) in NH2OH (30 ml) was stirred at room temperature for 4 days. The
reaction mixture was evaporated in vacuo and triturated with cold H2O. The solid product was
®ltered off, washed thoroughly with H2O, dried, and crystallized from ethanol.
1
Yield: 0.56 g (56%); m.p.: 200ꢁC; IR: 3450±3400 (NH2), 2222 (CN); H NMR: 4.75 (br s, 2H,
NH2, exchangeable), 6.75±7.35 (m, 6H, arom. protons ‡ pyridine H-6), 7.41±7.80 (m, 5H, arom.
protons).
2-Amino-1,6-dihydro-1-benzoyl-4-phenyl-5-phenylsulfonyl-6-thioxopyridine-3-carbonitrile
(13; C25H17N3O3S2)
To a suspension of NH4SCN (0.005 mol) in acetonitrile (30 ml), benzoyl chloride (0.005 mol) was
added. The reaction mixture was boiled under re¯ux for 5 min and then treated with 3a (0.005 mol).
The mixture was boiled under re¯ux for 1 h, left aside to cool at room temperature, poured onto ice/
H2O mixture, and neutralized with NaOH (0.01 N). The solid product was collected by ®ltration,
washed thoroughly with H2O, dried, and crystallized from EtOH.
Yield: 1.77 g (75%); m.p.: 175ꢁC; IR: 3400±3350 (NH2), 2220 (CN), 1710 (C=O), 1200±1140
(C=S); 1H NMR: 7.52±7.65 (m, 11H, arom. protons), 8.16±8.36 (m, 4H, arom. protons), 9.71 (br s,
‡
2H, NH2, exchangeable); MS: m/z (%) ˆ 471 (M , 21%).
1,8a-Dihydro-2-phenylsulfonyl-1-thioxo-3,6,8-triphenylpyrido[1,2-a] pyrimidine-4,7-
dicarbonitrile (15; C34H20N4O2S2)
Method A. To a solution of 13 (0.002 mol) in dry dioxane (30 ml) containing piperidine (5 drops),
benzylidenemalononitrile (4a, 0.002 mol) was added. The reaction mixture was boiled under re¯ux
for 4 h,left to cool at room temperature, triturated with cold H2O, and neutralized with dilute HCl.
The solid product precipitated was collected by ®ltration and crystallized from EtOH.
Yield: 0.68 g (59%); m.p.: 245ꢁC; IR: 2225, 2219 (2 CN), 1200 (C=S); 1H NMR: 7.38±7.80 (m,
‡
12H, arom. protons), 7.91±8.26 (m, 8H, arom. protons); MS: m/z (%) ˆ 580 (M , 14%).
Method B via Schiff base (16; C32H21N3O3S2)
To a solution of 13 (0.004 mol) in dioxane (30 ml) containing Et3N (5 drops), benzaldehyde
(0.004 mol) was added. The reaction mixture was boiled under re¯ux for 3 h, poured onto cold H2O,
and neutralized with dilute HCl. The solid product obtained was ®ltered off, dried, and crystallized
from EtOH.
Yield: 1.34 g (60%); m.p.: 222ꢁC; IR: 2222 (CN), 1710 (C=O), 1200 (C=S); 1H NMR: 7.33±7.66
(m, 10H, arom. protons ‡ methylenic CH), 7.82±8.30 (m, 11H, arom. protons).
To a solution of 16 (0.002 mol) in dioxane (30 ml) containing Et3N (5 drops), malononitrile
(0.002 mol) was added. The reaction mixture was boiled under re¯ux for 4 h, poured onto cold H2O,
and neutralized with dilute HCl. The solid product precipitated was collected by ®ltration and
neutralized from EtOH. Yield: 0.68 g (59%); identical (m.p., mixed m.p., IR spectrum) with authentic
sample prepared according to method A.
1,7a-Dihydro-5-H-3,7-diphenyl-2-phenylsulfonyl-1-thioxoimidazo[1,2-a] pyridine-4,6-
dicarbonitrile (17; C27H16N4O2S2)
To a warm solution of 13 (0.002 mol) in EtOH (30 ml) containing K2CO3 (0.002 mol), chloro-
acetonitrile (0.002 mol) was added. The reaction mixture was boiled under re¯ux for 3 h and then

1056
A. W. Erian: Heterocyclic Sulfones via 2-Aryl-1,1-dicyano-3-phenylsulfonylpropenes
poured onto cold H2O. The solid product was collected by ®ltration, washed thoroughly with H2O,
dried, and crystallized from EtOH.
1
Yield: 0.54 g (55%); m.p.: 275ꢁC; IR: 3320 (NH), 2222, 2216 (2 CN), 1200 (C=S); H NMR:
7.38±7.80 (m, 9H, arom. protons), 7.90±8.18 (m, 6H, arom. protons), 11.69 (br s, 1H, NH,
‡
exchangeable); MS: m/z (%) ˆ 492 (M , 19%).
References
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vol 3. Pergamon Press, New York, p 885
[2] Sharma S (1989) Sulfur Rep 9: 328
[3] Mukerjee AK, Ashare R (1991) Chem Rev 91: 1
[4] Erian AW, Sherif SM (1998) Tetrahedron Rep (in press)
[5] Simpkins NS (1993) In: Baldwin JE, Magnus PD (eds) Tetrahedron Organic Chemistry Series,
vol 10. Pergamon Press, New York, p1
[6] Simpkins NS (1990) Tetrahedron 46: 6951
[7] Erian AW, Sherif SM (1995) Heterocycles 40: 1195
[8] Sherif SM, Erian AW (1996) Heterocycles 43: 1085
[9] Erian AW, Sherif SM, Alassar AA, ElKholy YM (1994) Tetrahedron 50: 1877
[10] Erian AW (1993) Chem Rev 93: 1991 and references cited therein
[11] Erian AW (1998) Synth Commun (in press)
[12] Yamanka H, Ohba S, Konnos (1987) Heterocycles 26: 2853
[13] Gupta RR, Kumar R (1987) Synth Commun 17: 229
Received March 11, 1998. Accepted (revised) May 14, 1998