(Arylsulfonyl)acetones and -acetonitriles: New activated methylenic building blocks for synthesis of 1,2,3-triazoles

Article abstract of DOI:10.1055/s-0029-1216850

β-Keto sulfones and b-nitrile sulfones were used as building blocks for 1,2,3-triazole synthesis in the Dimroth cyclization. It was shown, that sulfone reagents undergo base-catalyzed cyclization under mild conditions (at room temperature) to give 1,2,3-triazoles in moderate to excellent yields. This fact has confirmed the high nucleophilicity of sulfonylmethylenic compounds and allows new synthetic applications. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216850

SHORT PAPER
2321
(Arylsulfonyl)acetones and -acetonitriles: New Activated Methylenic Building
Blocks for Synthesis of 1,2,3-Triazoles
1
-Aryl-4-(arylsulfo
a
nyl)-1
H
-1,
z
2,3-triazole
a
s
riy T. Pokhodylo,* Vasyl S. Matiychuk, Mykola D. Obushak
Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya St. 6, Lviv 79005, Ukraine
Fax +380(322)971668; E-mail: pokhodylo@gmail.com
Received 6 March 2009; revised 23 March 2009
sulfones.8 Efforts in the direction of anti-HIV-1 agents
Abstract: b-Keto sulfones and b-nitrile sulfones were used as
have led us to the design of 1,2,3-triazole derivatives with
an aryl sulfone fragment.
building blocks for 1,2,3-triazole synthesis in the Dimroth cycliza-
tion. It was shown, that sulfone reagents undergo base-catalyzed cy-
clization under mild conditions (at room temperature) to give 1,2,3-
It is well known, that organic azides undergo base-cata-
triazoles in moderate to excellent yields. This fact has confirmed the
high nucleophilicity of sulfonylmethylenic compounds and allows
compounds.9 Stabilized and nonstabilized carbanions re-
new synthetic applications.
lyzed condensation reactions with activated methylenic
act with organic azides to form triazenyl anions, which
Key words: azides, triazoles, sulfones, Dimroth reaction
can then be trapped regioselectively with electrophiles un-
der appropriate reaction conditions. The triazenyl anions
that are formed in the presence of an internal electrophile
Synthetic strategies that provide rapid and efficient library
undergo ring closure to give triazoles (Dimroth reac-
generation are of increasing importance.1 In the current
work we report the synthesis of aryl hetaryl sulfones. Such
compounds are very attractive targets for the study of
biological activity, as a few of them are anti-HIV agents.
Following the discovery of 2-nitrophenyl phenyl sulfone
(NNPS),2,3 as a non-nucleoside inhibitor of HIV-1 reverse
transcriptase, several articles have been dedicated to the
synthesis of compounds of this class. For example, new
derivatives, such as L-737126 and aryl 1H-pyrrol-1-yl
sulfones (PASs), have been synthesized by substitution of
the nitrophenyl moiety for 2-carbamoyl-5-chloro-1H-in-
dol-3-yl or pyrrol-1-yl fragments (Figure 1). Subsequent-
ly, optimization of the indole-containing compound L-
737126 has led to potent inhibitors4 with equivalent anti-
HIV-1 reverse transcriptase activity, but improved physi-
cochemical properties.
tion).10 Malonic, cyanoacetic, and related esters can be
used as substrates. Furthermore, in b-keto sulfones or b-
nitrile sulfones the internal electrophile can be a carbonyl
or cyano group. Moreover, the sulfonyl azides are used for
diazo transfer to CH-acid compounds, especially for acti-
vated b-keto esters and b-keto sulfones.11,12 In this case,
the enolate or enol attacks the organic azide with forma-
tion of a triazene, which reacts after tautomerization and
forms the diazo compound and the sulfonamide.
Herein, azides and sulfones were used as starting materi-
als for the synthesis of 1,2,3-triazoles, prepared from
commercially available aromatic amines. Diazotization of
anilines 1a–g with sodium nitrite and followed by reaction
with sodium azide led to aryl azides 3a–e in 67–83%
yields. The reaction of diazonium salts 2a–c,e with sulfur
dioxide in acetone gave arenesulfonyl chlorides 4a–d in
79–91% yields. Reduction of compounds 4a–d with zinc
gave sodium sulfinates 5a–d and their subsequent reac-
tion with one equivalent of chloromethylenic compounds
6a,b yielded the corresponding b-keto sulfones 7a–d or b-
nitrile sulfone 7e. Finally, reaction of sulfones 7a–e with
aryl azides 3a–e occurred to yield triazoles 8a–l
(Scheme 1).
OR
NH2
O
Cl
O
O
O
S
NH
O
S
N
S
O
O
O
NH2
O2N
R = Et, i-Pr
Cl
NPPS
L-737126
PASs
It was established that cyclization of azides 3 with sul-
fones 7 was rapid at room temperature or within a short re-
action time after heating and gave triazoles 8a–l in good
yields without formation of byproducts (Table 1). Com-
pounds 8a–c,e–g,i–l were precipitated from methanol so-
lution and were obtained with satisfactory purity. In the
case of compounds 8d,h, the initial product was heated
with alkaline water leading to ester hydrolysis and then
the carboxylic was acid crystallized.
Figure 1 Aryl sulfones anti-HIV agents
The importance of the diaryl sulfone moiety for the design
of new potential anti-HIV-1 agents is confirmed by stud-
ies of novel aryl pyrrolyl sulfones and related indole sul-
fones.5–7 Recently, three-dimensional quantitative
structure–activity relationship (3-D QSAR) studies and
docking simulations have been developed on aryl indolyl
A new synthesis of aryl 1H-1,2,3-triazol-4-yl sulfones has
been developed. It was shown, that b-keto sulfones or b-
nitrile sulfones are useful building blocks for the synthesis
of heterocyclic products. Thus, the approach proposed can
SYNTHESIS 2009, No. 14, pp 2321–2323
x
x.
x
x
.
2
0
0
9
Advanced online publication: 29.05.2009
DOI: 10.1055/s-0029-1216850; Art ID: Z03509SS
© Georg Thieme Verlag Stuttgart · New York

2322
N. T. Pokhodylo et al.
SHORT PAPER
mode. The evolution of the reactions and purity of the synthesized
compounds were monitored chromatographically on Silufol UV-
254 plates. Starting azides 3a–e13 and sulfonyl chlorides 4a–d14
were prepared from commercially available amines 1a–g according
to the procedures described in the literature. The sodium sulfinates
5a–d, b-keto sulfones 7a–d, and b-nitrile sulfone 7e were prepared
following the two-step literature procedure.15,16
NH2
+Cl–
SO2Cl
N2
SO2
NaNO2
HCl
acetone
CuCl
R
R
R
2a–g
1a–g
4a–d
4,5a: R = H
b: R = 3-Me
c: R = 4-Me
d: R = 4-Cl
1,2a: R = H
b: R = 3-Me
c: R = 4-Me
d: R = 4-F
e: R = 4-Cl
f: R = 4-Br
Zn
H2O
NaN3
4-(Arylsulfonyl)-1H-1,2,3-triazoles 8a–l; General Procedure
To a soln of MeONa (540 mg, 10.0 mmol) in anhyd MeOH (20 mL)
was added substituted sulfone 7 (10.0 mmol). To this soln the ap-
propriated aryl azide 3 (10.0 mmol) in anhyd MeOH (2 mL) was
added dropwise and the solid started to precipitate. The mixture was
stirred for several hours (r.t. for 2–5 h) until completion. The result-
ing suspension was filtered and the solid product was washed with
MeOH to give the corresponding aryl 1H-1,2,3-triazol-4-yl sulfones
8a–c,e–g,i–l.
SO2Na
N3
g: R = 4-COOEt
R
5a–d
R
3a–e
3a: R = H
Cl
EWG
b: R = Me
c: R = F
d: R = Br
6a: EWG = COMe
b: EWG = CN
6a, b
i-PrOH
e: R = COOEt
For extraction of compounds 8d,h, to the resulting suspension was
added hot H2O (20 mL) and a soln of NaOH to pH 11–12. The mix-
ture was heated under reflux for 1 h. The hot soln was poured into
concd HCl (10 mL) and left crystallize. The obtained solid was fil-
tered, washed with H2O (2 ×) and recrystallized (MeOH).
O
O
EWG
S
R2
N
N
3a–e
S
O
O
MeONa
MeOH
r.t.
N
R
7a–e
R3
8a–l
7a: R = H, EWG = COMe
b: R = 3-Me, EWG = COMe
c: R = 4-Me, EWG = COMe
d: R = 4-Cl, EWG = COMe
e: R = 4-Cl, EWG = CN
5-Methyl-1-phenyl-4-(phenylsulfonyl)-1H-1,2,3-triazole (8a)
White crystals; yield: 70%; mp 165–166 °C (MeOH).
R1
1H NMR: d = 2.59 (s, 3 H, CH3), 7.58–7.74 (m, 8 HPh), 8.04 (d, J =
8.4 Hz, 2 HPh).
Scheme 1 A synthetic route to aryl 1H-1,2,3-triazol-4-yl sulfones
8a–l
MS (CI): m/z (%) = 300 (100, [M + 1]+).
Anal. Calcd for C15H13N3O2S: C, 60.18; H, 4.38; N, 14.04. Found:
C, 60.09; H, 4.45; N, 13.91.
Table 1 Aryl 1H-1,2,3-Triazol-4-yl Sulfones 8a–l
Triazole
8a
R1
R2
R3
Yielda (%)
5-Methyl-1-(4-methylphenyl)-4-(phenylsulfonyl)-1H-1,2,3-tri-
azole (8b)
White crystals; yield: 63%; mp 134–135 °C (MeOH).
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
NH2
NH2
70
63
75
81
67
86
91
74
61
83
54
71
1H NMR: d = 2.45 (s, 3 H, CH3), 2.56 (s, 3 H, CH3), 7.39 (d, J = 8.4
Hz, 2 H, HAr-3,5), 7.44 (d, J = 8.4 Hz, 2 H, HAr-2,6), 7.64 (t, J = 7.2
Hz, 2 H, HPh-3,5), 7.71 (t, J = 7.2 Hz, 1 H, HPh-4), 8.02 (d, J = 7.2
Hz, 2 H, HPh-2,6).
8b
8c
Me
Br
H
H
8d
8e
CO2H
H
H
MS (CI): m/z (%) = 314 (100, [M + 1]+).
4-Me
4-Me
4-Me
4-Me
3-Me
4-Cl
4-Cl
4-Cl
Anal. Calcd for C16H15N3O2S: C, 61.32; H, 4.82; N, 13.41. Found:
C, 61.46; H, 4.73; N, 13.59.
8f
Me
Br
8g
1-(4-Bromophenyl)-5-methyl-4-(phenylsulfonyl)-1H-1,2,3-tri-
azole (8c)
White crystals; yield: 75%; mp 154–155 °C (MeOH).
8h
8i
CO2H
H
1H NMR: d = 2.58 (s, 3 H, CH3), 7.58 (d, J = 8.8 Hz, 2 H, HAr-3,5),
7.64 (t, J = 7.2 Hz, 2 H, HPh-3,5), 7.71 (t, J = 7.2 Hz, 1 H, HPh-4),
7.76 (d, J = 8.8 Hz, 2 H, HAr-2,6), 8.03 (d, J = 7.2 Hz, 2 H, HPh-2,6).
8j
H
MS (CI): m/z (%) = 378 (82, [M + 1]+), 380 (100, [M + 1]+).
8k
8l
H
Anal. Calcd for C15H12BrN3O2S: C, 47.63; H, 3.20; N, 11.11.
Found: C, 47.48; H, 3.01; N, 11.02.
F
a Isolated yields are based on a single experiment and the yields were
not optimized.
4-[5-Methyl-4-(phenylsulfonyl)-1H-1,2,3-triazol-1-yl]benzoic
Acid (8d)
White crystals; yield: 81%; mp 247–248 °C (MeOH).
be used for the creation of compound libraries for biolog-
ical activity testing.
1H NMR: d = 2.62 (s, 3 H, HH3), 7.62–7.69 (m, 3 H, HPh-3,4,5),
7.72 (d, J = 8.4 Hz, 2 H, HAr-3,5), 8.03 (d, J = 7.2, 2 H, HPh-2,6),
8.16 (d, J = 8.4 Hz, 2 H, HAr-2,6), 13.10 (br s, 1 H, CO2H).
MS (CI): m/z (%) = 343 (100, [M+]).
All melting points were determined in capillary tubes in a Thiele ap-
1
paratus and are uncorrected. H NMR spectra were recorded on a
Anal. Calcd for C16H13N3O4S: C, 55.97; H, 3.82; N, 12.24. Found:
C, 55.80; H, 3.61; N, 12.30.
Varian Mercury 400 instrument (400 MHz for 1H) with the deuter-
ated solvent as the internal reference. Mass spectra were run using
Agilent 1100 series LC/MSD with an API-ES/APCI ionization
Synthesis 2009, No. 14, 2321–2323 © Thieme Stuttgart · New York

SHORT PAPER
1-Aryl-4-(arylsulfonyl)-1H-1,2,3-triazoles
2323
5-Methyl-4-[(4-methylphenyl)sulfonyl]-1-phenyl-1H-1,2,3-tri-
azole (8e)
White crystals; yield: 67%; mp 157–158 °C (MeOH).
4-[(4-Chlorophenyl)sulfonyl]-1-phenyl-1H-1,2,3-triazol-5-
amine (8k)
White crystals; yield: 54%; mp 164–165 °C (MeOH).
1H NMR: d = 2.44 (s, 3 H, CH3), 2.56 (s, 3 H, CH3), 7.44 (d, J = 8.0
Hz, 2 H, HAr-3,5), 7.56–7.64 (m, 5 HPh), 7.90 (d, J = 8.0 Hz, 2 H,
HAr-2,6).
1H NMR: d = 6.55 (s, 2 H, NH2), 7.50–7.62 (m, 5 HPh), 7.63 (d, J =
8.8 Hz, 2 H, HAr-3,5), 8.03 (d, J = 8.8 Hz, 2 H, HAr-2,6).
MS (CI): m/z (%) = 335 (100, [M + 1]+).
MS (CI): m/z (%) = 314 (100, [M + 1]+).
Anal. Calcd for C14H11ClN4O2S: C, 50.23; H, 3.31; N, 16.74.
Found: C, 50.06; H, 3.23; N, 16.88.
Anal. Calcd for C16H15N3O2S: C, 61.62; H, 4.82; N, 13.41. Found:
C, 61.74; H, 4.61; N, 13.45.
4-[(4-Chlorophenyl)sulfonyl]-1-(4-fluorophenyl)-1H-1,2,3-tri-
azol-5-amine (8l)
White crystals; yield: 71%; mp 182–183 °C (MeOH).
5-Methyl-1-(4-methylphenyl)-4-[(4-methylphenyl)sulfonyl]-
1H-1,2,3-triazole (8f)
White crystals; yield: 86%; mp 140–141 °C (MeOH).
1H NMR: d = 6.56 (s, 2 H, NH2), 7.34 (t, 3J = 8.8 Hz, 2 H, HAr-3,5),
4
1H NMR: d = 2.43 (s, 3 H, CH3), 2.44 (s, 3 H, CH3), 2.54 (s, 3 H,
CH3), 7.37–7.48 (m, 6 HAr), 7.90 (d, J = 8.0 Hz, 2 H, HAr-2,6).
7.56 (dd, 3J = 8.8 Hz, J = 4.8 Hz, 2 H, HAr-2,6), 7.62 (d, 3J = 8.8
Hz, 2 H, HAr-3,5), 8.02 (d, 3J = 8.8 Hz, 2 H, HAr-2,6).
MS (CI): m/z (%) = 328 (100, [M + 1]+).
MS (CI): m/z (%) = 353 (100, [M + 1]+).
Anal. Calcd for C17H17N3O2S: C, 62.37; H, 5.23; N, 12.83. Found:
C, 62.28; H, 5.14; N, 12.99.
Anal. Calcd for C14H10ClFN4O2S: C, 47.67; H, 2.86; N, 15.88.
Found: C, 47.52; H, 2.69; N, 15.64.
1-(4-Bromophenyl)-5-methyl-4-[(4-methylphenyl)sulfonyl]-1H-
1,2,3-triazole (8g)
White crystals; yield: 91%; mp 151–152 °C (MeOH).
References
(1) Terrett, N. K. Combinatorial Chemistry; Oxford University
Press: New York, 1998.
1H NMR: d = 2.44 (s, 3 H, CH3), 2.57 (s, 3 H, CH 3), 7.44 (d, J = 8.0
Hz, 2 H, HAr-3,5), 7.58 (dd, 3J = 8.4 Hz, 4J = 1.2 Hz, 2 H, HAr-3,5),
7.78 (dd, 3J = 8.4 Hz, 4J = 1.2 Hz, 2 H, HAr-2,6), 7.90 (d, J = 8.0 Hz,
2 H, HAr-2,6).
(2) McMahon, J. B.; Gulakowsky, R. J.; Weislow, O. S.;
Schultz, R. J.; Narayanan, V. L.; Clanton, D. J.; Pedemonte,
R.; Wassmundt, F. W.; Buckheit, R. W. Jr.; Decker, W. D.;
White, E. L.; Bader, J. P.; Boyd, M. R. Antimicrob. Agents
Chemother. 1993, 37, 754.
MS (CI): m/z (%) = 392 (80, [M + 1]+), 394 (100, [M + 1]+).
Anal. Calcd for C16H14BrN3O2S: C, 48.99; H, 3.60; N, 10.71.
Found: C, 49.07; H, 3.76; N, 10.54.
(3) Williams, T. M.; Ciccarone, T. M.; Mac Tough, S. C.;
Rooney, C. S.; Balani, S. K.; Condra, J. H.; Emini, E. A.;
Goldman, M. E.; Greenlee, W. J.; Kauffman, L. R.; O’Brien,
J. A.; Sardana, V. V.; Schleif, W. A.; Theoharides, A. D.;
Anderson, P. S. J. Med. Chem. 1993, 36, 1291.
(4) Young, S. D.; Amblard, M. C.; Britcher, S. F.; Grey, V. E.;
Tran, L. O.; Lumma, W. C.; Huff, J. R.; Schleif, W. A.;
Emini, E. E.; O’Brien, J. A.; Pettibone, D. J. Bioorg. Med.
Chem. Lett. 1995, 5, 491.
4-{5-Methyl-4-[(4-methylphenyl)sulfonyl]-1H-1,2,3-triazol-1-
yl}benzoic Acid (8h)
White crystals; yield: 74%; mp 209–210 °C (MeOH).
1H NMR: d = 2.45 (s, 3 H, CH3), 2.61 (s, 3 H, CH3), 7.44 (d, J = 8.0
Hz, 2 H, HAr-3,5), 7.76 (d, J = 8.8 Hz, 2 H, HAr-3,5), 7.91 (d, J = 8.0
Hz, 2 H, HAr-2,6), 8.19 (d, J = 8.8 Hz, 2 H, HAr-2,6).
(5) Artico, M.; Silvestri, R.; Stefancich, G.; Massa, S. R.;
Pagnozzi, E.; Musiu, E.; Scintu, E.; Pinna, E.; Tinti, P.;
La Colla, P. Arch. Pharm. (Weinheim, Ger.) 1995, 328, 223.
(6) Artico, M.; Silvestri, R.; Massa, S.; Loi, A. G.; Corrias, S.;
Piras, G.; La Colla, P. J. Med. Chem. 1996, 39, 522.
(7) Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.;
Massa, S.; Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.;
La Colla, P. J. Med. Chem. 2003, 46, 2482.
MS (CI): m/z (%) = 357 (100, [M+]).
Anal. Calcd for C17H15N3O4S: C, 57.13; H, 4.23; N, 11.76. Found:
C, 57.17; H, 4.14; N, 11.60.
5-Methyl-4-[(3-methylphenyl)sulfonyl]-1-phenyl-1H-1,2,3-tri-
azole (8i)
White crystals; yield: 61%; mp 157–158 °C (MeOH).
1H NMR: d = 2.47 (s, 3 H, CH3), 2.58 (s, 3 H, CH3), 7.51–7.54 (m,
2 HAr), 7.58–7.65 (m, 5 HAr), 7.81–7.85 (m, 2 HAr).
(8) Ragno, R.; Artico, M.; De Martino, G.; La Regina, G.;
Coluccia, A.; Di Pasquali, A.; Silvestri, R. J. Med. Chem.
2005, 48, 213.
(9) Krivopalov, V. P.; Shkurko, O. P. Russ. Chem. Rev. (Engl.
Transl.) 2005, 74, 339.
(10) Wamhoff, H.; Wambach, W. Chem.-Ztg. 1989, 113, 11.
(11) Davies, H. M. L.; Cantrell, W. R. Jr.; Romines, K. R.; Baum,
J. S. Org. Synth. 1992, 70, 93.
(12) Hughes, C. C.; Kennedy-Smith, J. J.; Trauner, D. Org. Lett.
2003, 5, 4113.
MS (CI): m/z (%) = 314 (100, [M + 1]+).
Anal. Calcd for C16H15N3O2S: C, 61.32; H, 4.82; N, 13.41. Found:
C, 61.18; H, 4.73; N, 13.55.
4-[(4-Chlorophenyl)sulfonyl]-5-methyl-1-phenyl-1H-1,2,3-tri-
azole (8j)
White crystals; yield: 83%; mp 125–126 °C (MeOH).
(13) Smith, P. A. S.; Boyer, J. H. Org. Synth. 1951, 31, 14.
(14) Hoffman, R. V. Org. Synth. 1981, 60, 121.
(15) Tietze, L. F.; Eicher, T. Reaktionen und Synthesen im
organisch-chemischen Praktikum und
1H NMR: d = 2.58 (s, 3 H, CH3), 7.58–7.64 (m, 5 HPh), 7.68 (d, J =
8.8 Hz, 2 H, HAr-3,5), 8.05 (d, J = 8.8 Hz, 2 H, HAr-2,6).
MS (CI): m/z (%) = 334 (100, [M + 1]+).
Forschungslaboratorium; Georg Thieme Verlag: Stuttgart,
1991, 511.
Anal. Calcd for C15H12ClN3O2S: C, 53.97; H, 3.62; N, 12.59.
Found: C, 54.14; H, 3.52; N, 12.45.
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Chem. 1962, 27, 1251.
Synthesis 2009, No. 14, 2321–2323 © Thieme Stuttgart · New York