Polyfunctional tetrazolic thioethers through electrooxidative/Michael-type sequential reactions of 1,2- and 1,4-dihydroxybenzenes with 1-phenyl-5- mercaptotetrazole

Article abstract of DOI:10.1021/jo702327m

(Chemical Equation Presented) In the presence of 1-phenyl-5- mercaptotetrazole as a nucleophile, electrochemical oxidations of 1,2- and 1,4-dihydroxybenzenes have been investigated in aqueous solution using cyclic voltammetry and controlled-potential coulometry. The voltammetric results indicate that an electrooxidative/Michael-type sequential reaction occurs between the mercaptide anion and the electrochemically generated benzoquinones leading to the corresponding polyfunctional tetrazolic thioethers. The mechanism of electrochemical reaction is proved as an EC pathway using controlled-potential coulometry. In addition, the electrosyntheses of tetrazolic thioethers have been successfully performed in ambient conditions in an undivided cell using an environmentally friendly method with high atom economy.

Full text of DOI:10.1021/jo702327m

Polyfunctional Tetrazolic Thioethers through Electrooxidative/
Michael-Type Sequential Reactions of 1,2- and
1,4-Dihydroxybenzenes with 1-Phenyl-5-mercaptotetrazole
Mohammad M. Khodaei,* Abdolhamid Alizadeh,* and Narges Pakravan
Chemistry Department & Nanoscience and Nanotechnology Research Center (NNRC), Razi UniVersity,
Kermanshah, 67149 Iran
ahalizadeh2@hotmail.com
ReceiVed NoVember 12, 2007
In the presence of 1-phenyl-5-mercaptotetrazole as a nucleophile, electrochemical oxidations of 1,2- and
1,4-dihydroxybenzenes have been investigated in aqueous solution using cyclic voltammetry and controlled-
potential coulometry. The voltammetric results indicate that an electrooxidative/Michael-type sequential
reaction occurs between the mercaptide anion and the electrochemically generated benzoquinones leading
to the corresponding polyfunctional tetrazolic thioethers. The mechanism of electrochemical reaction is
proved as an EC pathway using controlled-potential coulometry. In addition, the electrosyntheses of
tetrazolic thioethers have been successfully performed in ambient conditions in an undivided cell using
an environmentally friendly method with high atom economy.
Tetrazolic thioethres have found widespread use in the
modern approach to the synthesis of biologically active com-
pounds and various drugs. Despite their scarcity in natural
systems, tetrazoles are important aromatic heterocyclic com-
pounds because of their diverse applications in medicine,
biochemistry, agriculture, photography, information recording
systems, and others.1,2 For instance, it was determined that
1-aryl-5-alkylthiotetrazoles (I) have well-known antiviral and
anti-inflammatory properties,3 1-aryl-thiotetrazolyl acetanilides
(II, III) have demonstrated activities as HIV-1 non-nucleoside
reverse transcriptase inhibitors,4 and 1-phenyl-5-arylthiotetrazole
(IV) is used as activating reagent in RNA synthesis5 (Figure
1). Bearing a 5-arylthio moiety, compound IV is a significantly
better activator than the corresponding 5-aryl- or 5-alkyltetra-
(1) Sosnowska, N. S. J. Org. Chem. 2001, 66, 8737.
FIGURE 1. Structures of biologically active molecules with thiotet-
razolyl moieties.
(2) Koldobskii, G. I.; Ostrovskii, V. A. Russ. Chem. ReV. 1994, 63, 797.
(3) (a) Steven, J. W. Org. Prep. Proced. Int. 1994, 26, 499. (b) Hrabalek,
A.; Myznikov, L.; Kunes, J.; Vavrova, K.; Koldobskii, G. Tetrahedron Lett.
2004, 45, 7955.
(4) (a) Muraglia, E.; Kinzel, O. D.; Laufer, R.; Miller, M. D.; Moyer,
G.; Munshi, V.; Orvieto, F.; Palumbi, M. C.; Pescatore, G.; Rowley, M.;
Williamsd, P. D.; Summa, V. Bioorg. Med. Chem. Lett. 2006, 16, 2748.
(b) Thevelein, J.; Van Dijck, P. WO 01/16357 A2, 2001. (c) Shaw-reid, C.
A.; Miller, M.; Hazuda, D. J.; Ferrer, M.; Sur, S. M.; Summa, V.; Lyle, T.
A.; Kinzel, O.; Pescatore, G. WO 2005/115147 A2, 2005.
zoles. Interestingly, in the context of peptidomimetic chemistry,
it has long been recognized that the tetrazole moiety can serve
as a metabolically stable surrogate for the carboxylic acid moiety
(5) Welz, R.; Mu¨ller, S. Tetrahedron Lett. 2002, 43, 795.
10.1021/jo702327m CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/04/2008
J. Org. Chem. 2008, 73, 2527-2532
2527

Khodaei et al.
and this ability of tetrazole compounds has motivated the
incorporation of tetrazole derivatives into biologically active
molecules.6
o- and p-dihydroxybenzenes are ubiquitous in nature. Their
functionalized derivatives are extensively used in the chemical
and pharmaceutical industries as well as synthetic intermediates
in the manufacturing of food antioxidants and antioxidants.7-9
A literature survey revealed that despite their promising
biological features, the synthesis of polyfunctional adducts
bearing dihydroxybenzene and thiotetrazolyl moieties have not
been subjected to detailed investigations and only a ∼ 40-year-
old study of Porter and co-workers has reported the 1,4-addition
of 1-phenyl-5-mercaptotetrazole to p-benzoquinone resulting in
tetrazolic thioether-substituted hydroquinones via a chemical
oxidative route.10 Similar to most conventional chemical
transformations, the oxidative routes to produce active inter-
mediates like benzoquinones involve toxic oxidizing agents and/
or metal additives. Here we demonstrate an alternative procedure
for synthesizing novel tetrazolic thioether-substituted dihy-
droxybenzenes using electrochemically initiated oxidative cou-
pling reactions of dihydroxybenzenes with 1-phenyl-5-mercap-
totetrazole that avoids organic solvents, metal-based reagents,
catalysts, and stoichiometric oxidants. Electrochemical reactions
work based on the electron transfer in the Helmholtz layer at
the electrode-solution interface,11 and through these reactions
conditions, highly reactive intermediates (i.e., benzoquinones)
can be generated under very mild conditions, such as ambient
temperatures, normal pressure, and often in non-halogenated
solvents.12 Direct electrochemical oxidations/reductions of
substrates utilize practically mass-free electrons as the only
reagents. In this sense, electrochemistry is frequently referred
to as one of the prototypical green procedures for synthesizing
various organic molecules and structures.13
FIGURE 2. Cyclic voltammograms of 1.0 mM catechol (1a) in the
absence (a) and presence (b) of 1.0 mM of 1-phenyl-5-mercaptotetrazole
(3) and 1.0 mM of 3 in the absence of 1a at glassy carbon electrode
versus SCE in water/acetonitrile (90/10) solution containing 0.2 M
sodium acetate. Scan rate: 50 mV s-1; t ) 25 ( 1 °C.
benzenes (1a-f) (Schemes 1 and 3) to their corresponding
benzoquinones in the presence of 1-phenyl-5-mercaptotetrazole
(3) as a very acidic nucleophile (a desirable property in ionic
addition reactions to unsaturated compounds).15
The present study describes a straightforward, environmen-
tally friendly, and reagentless protocol with high atom economy
and safe waste, for the synthesis of a series of new polyfunc-
tional tetrazolic thioethrs (5a-f) via an EC electrochemical
mechanism pathway in a sequential fashion. The electro-
syntheses of 5a-f, in high yields and purity, have been
successfully performed in ambient conditions in an undivided
cell using graphite electrode. To the best of our knowledge,
this is the first report aimed at the synthesizing of polyfunctional
tetrazolic thioethers.
Although o-benzoquinones are extremely reactive and often
difficult to isolate, they can be easily generated in situ by
oxidation of the corresponding catechols and then trapped by
sulfur nucleophiles. Cyclic voltammogram of a 1 mM solution
of catechol (1a) in water/acetonitrile (90/10) solution containing
0.2 M sodium acetate shows one anodic peak (A1) and a
corresponding cathodic peak (C1), which correspond to the
transformation of 1a to o-benzoquinone (2a) and vice versa
through a quasi-reversible two-electron process (Figure 2, curve
a). A peak current ratio (IpC1/IpA1) of nearly unity, particularly
during the repetitive recycling of potential, can be considered
as a criterion for the stability of o-benzoquinone produced at
the surface of electrode, under the experimental conditions. In
other words, any side reactions such as hydroxylation and/or
dimerization reactions are too slow to be observed at the time
scale of cyclic voltammetry.16-19 To get further support on the
electrochemical oxidation of 1a, it was studied in the presence
of 1-phenyl-5-mercaptotetrazole (3) as a nucleophile. The proton
of thiol 3 is acidic enough so it seems that its ionic 1,4-addition
to various quinones can proceed in a quick and simple way.
Figure 2, curve b, shows the cyclic voltammogram obtained
In continuation of our efforts to develop more versatile and
convenient chemical and electrochemical synthesis of highly
functionalized dihyroxybenzenes,14 we envisaged that the
incorporation of thiotetrazolyl moiety into the biologically active
dihydroxybenzene structures might lead to a series of tetrazolic
thioethers with even better biological activities. This idea
prompted us to investigate the anodic oxidation of dihydroxy-
(6) (a) Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379. (b) Koldobskii,
G.; Hrabalek, A.; Esikov, K. A. Russ. J. Org. Chem., 2004, 40, 447.
Translated from Zh. Org. Khim. 2004, 40, 479.
(7) Ganapati, D. Y.; Salim, A. R.; Navinchandra, S. A. Ind. Eng. Chem.
Res. 2005, 44, 7969.
(8) Lau, S. S.; Monks, T. J.; Everitt, J. I.; Kleymenova, E.; Walker, C.
L. Chem. Res. Toxicol. 2001, 14, 25.
(9) Abdel-Lateff, A.; Konig, G. M.; Fisch, K. M.; Holler, U.; Jones, P.
G.; Wright, A. D. J. Nat. Prod. 2002, 65, 1605.
(10) Porter, R. F.; Rees, W. W.; Frauenglass, E.; Wilgus, H. S.; Nawn,
G. H.; Chiesa, P. P.; Gates, Jr., J. W. J. Org. Chem. 1964, 29, 588.
(11) Bard, A. J.; Faulkner, L. K. Electrochemical Methods: Fundamen-
tals and Applications, 2nd ed.; John Wiley & Sons: New York, 2001;
Chapter 1.
(12) (a) Lund, H.; Baizer, M. M. Organic Electrochemistry: An
Introduction and a Guide, 3rd ed.; M. Dekker: New York, 1991. (b) Torii,
S. NoVel Trends in Electroorganic Synthesis; Springer-Verlag: New York,
1998. (c) Little, R. D.; Norman, L. Electroorganic Synthesis; M. Dekker:
New York, 1991.
(13) Steckhan, E.; Arns, T.; Heineman, W. R.; Hilt, G.; Hoormann, D.;
Jorissen, J.; Kroner, L.; Lewall, B.; Putter, H. Chemosphere 2001, 43, 63.
(14) (a) Alizadeh, A.; Nematollahi, D.; Habibi, D.; Hesari, M. Synthesis
2007, 10, 1513. (b) Shamsipur, M.; Kazemi, S. H.; Alizadeh, A.; Mousavi,
M. F.; Workentin, M. S. J. Electroanal Chem. 2007, 610, 218. (c)
Nematollahi, D.; Habibi, D.; Alizadeh, A. Phosphorus, Sulfur Silicon Relat.
Elem. 2006, 181, 1391. (d) Habibi, D.; Nematollahi, D.; Alizadeh, A.;
Hesari, M. Heterocycl. Commun. 2005, 11, 145. (e) Nematollahi, D.; Habibi,
D.; Alizadeh, A.; Hesari, M. J. Heterocycl. Chem. 2005, 42, 289.
(15) Cunneen, J. I. J. Chem. Soc., 1947, 36, 134.
(16) Papouchado, L.; Petrie, G.; Adams, R. N. J. Electroanal. Chem.
1972, 38, 389.
(17) Papouchado, L.; Petrie, G.; Sharp, J. H.; Adams, R. N. J. Am. Chem.
Soc. 1968, 90, 5620.
(18) Young, T. E.; Griswold, J. R.; Hulbert, M. H. J. Org. Chem. 1974,
39 1980.
(19) Rayn, M. D.; Yueh, A.; Wen-Yu, C. J. Electrochem. Soc. 1980,
127 1489.
2528 J. Org. Chem., Vol. 73, No. 7, 2008

Polyfunctional Tetrazolic Thioethers
FIGURE 4. Cyclic voltammogram of (a) 1 mM catechol (1a), (b)
saturated solution of obtained product (5a) at glassy carbon electrode
versus SCE in water/acetonitrile (50/50) solution containing 0.2 M
sodium acetate. Scan rate: 50 mV s-1; t ) 25 ( 1 °C.
FIGURE 3. Typical cyclic voltammograms of 1.0 mM catechol (1a)
in the presence of 1.0 mM 1-phenyl-5-mercaptotetrazole (3) at a glassy
carbon electrode versus SCE in water/acetonitrile (90/10) solution
containing 0.2 M sodium acetate. Scan rates for a-f are: 20, 50, 100,
200, 500, 1000 mV s-1, respectively. (g) Variation of peak current ratio
(IpA1/IpC1) versus scan rate, t ) 25 ( 1 °C.
obtained results, the electrochemical efficiency is >80%. The
preparative synthesis was performed in potentiostatic condition
by oxidation of 1a in the presence of 3 at 0.20 V versus SCE
potential on a graphite rode anode electrode in an undivided
cell. More detail is described in the Experimental Section.
for a 1 mM solution of 1a in the presence of 1 mM of 3. The
voltammogram exhibits one anodic peak (A1) and two cathodic
peaks (C1 and C2). The comparison of C1 peaks in the absence
and presence of 3 shows a considerable decrease of the current
density for the latter and this obviously indicates the reactivity
of electrochemically derived highly active o-benzoquinone (2a)
toward mercaptide anion 3a. The observed negative shift of the
C1 peak in curve b, relative to curve a, is probably due to the
formation of a thin film of product at the surface of the electrode,
inhibiting to a certain extent the performance of the electrode
process.20 The cyclic voltammogram of a 1 mM solution of 3
is shown in Figure 2, curve c, for comparison. The cathodic
peak (C2) that can be seen in both curves b and c is probably
corresponding to the reduction of product of dimerization of 3.
Furthermore, we examined the effects of potential scan rate
and concentration of 3 on the peak current ratio (IpA1/IpC1) in
cyclic voltammograms of 1a in the presence of 3. It is seen
that, proportional to the increasing of the potential scan rate
(Figure 3, curves a-f) or decreasing of 3 to 1a concentration
ratio, the peak current ratio (IpA1/IpC1) decreases. A plot of the
peak current ratio (IpA1/IpC1) versus the scan rate for a mixture
of 1a and 3 confirms the reactivity of o-benzoquinone (2a)
toward 3 (Figure 3, curve g). Meanwhile, the peak current
function for A1 peak (IpA1/IpC1) decreases with increasing scan
rate, which is adapted as indication of an EC mechanism.21
Similar to the oxidation of 2-mercaptobenzoxazole, which
leads to the formation of bis(benzoxazolyl) disulfide,22 1-phenyl-
5-mercaptotetrazole (3) can be oxidized to the corresponding
disulfide. Considering the closeness of oxidation potential peaks
of 1a and 3 (Figure 2, curves a and c), to minimize the oxidation
of 3 and hence, achieving higher selectivity, we applied 0.20 V
potential versus SCE in both coulometry and preparative
synthesis processes. To determine electrochemical efficiency,
controlled potential coulometry of catechol (1a) in the presence
of 3 was performed at 0.20 V versus SCE. On the basis of
The aforementioned coulometry and voltammetry results
allow us to propose the pathways shown in Scheme 1 for the
electro-oxidation of catechol (1a) in the presence of 3. Accord-
ing to our results, it seems that upon anodic oxidation of 1a to
o-benzoquinone 2a (Scheme 1, eq 1), an intermolecular Michael-
type reaction of mercaptide anion (3a) (Scheme 1, eq 2) with
2a occurs in a sequential fashion and this reaction seems to
occur much faster than other side reactions, leading to the
formation of N-arylthiotetrazolyl catechol (5a) (Scheme 1, eq
3). The overoxidation of 5a was circumvented during the
preparative reaction because of the presence of a thiotetrazolyl
moiety with electron-withdrawing character on the catechol ring
(Figure 4) as well as the insolubility of 5a in reaction medium.
As can be seen, there is an electrooxidative/Michael-type
addition sequence in this one-pot coupling reaction of 1a with
3 leading to the formation of novel arylthiotetrazolyl catechol
5a as a final product in excellent yield (Scheme 1).
In examining the scope and generality of the developed
protocol as well as the influence of structural variation of
catechol ring on the reactivity of electrochemically derived
o-benzoquinones toward 3, we studied the electrochemically
induced reaction of 1-phenyl-5-mercaptotetrazole (3) with some
other catechols bearing methyl, methoxy, or 4-tert-butyl groups
at the C-3 or C-4 positions (1b-e) in the conditions similar to
that of 1a. The electro-oxidation of 3-methylcatechol (1b) and
3-methoxycatechol (1c) in the presence of 3 proceed in a way
similar to that of 1a. The existence of a methyl or methoxy
group at the C-3 position of 1b or 1c may has subtle electronic
and steric effects on the reactivity of their relevant o-bezo-
quinones (2b,c) and would probably cause these Michael
acceptors (2b,c) to be attacked by 3a at the C-4 or C-5 positions
to yield two types of product in each case (5b,c or 6b,c, Scheme
2). Because the methyl and methoxy groups are both electron-
donating substituents, we suggest that o-benzoquinones 2b and
2c are more electropositive at C-5 position and therefore, can
be selectively attacked from C-5 position by the mercaptide
anion 3a leading to the formation of 5b,c, respectively, and not
(20) Nematollahi, D.; Goodarzi, H. J. Org. Chem. 2002, 67, 5036.
(21) Bard, A. J.; Faulkner, L. R. Electrochemical Methods, 2nd ed.;
Wiley: New York, 2001; p 497.
(22) Berlich, A.; Flemmig, B.; Wittstock, G. J. Solid State Electrochem.
2001, 6, 29.
J. Org. Chem, Vol. 73, No. 7, 2008 2529

Khodaei et al.
SCHEME 1
TABLE 1. Experimental and Calculated 13CNMR Data for Methyl
and Methoxy Carbons in Catechol Ring
SCHEME 2. Schematic Possible Structures of 5b,c and 6b,c
compd
exptl δ (ppm)
calcd δ (ppm)
product obtained from 1b
14.05
5b
6b
14.00
7.01
product obtained from 1c
56.08
5c
6c
56.20
50.80
of the methyl and methoxy carbons in the catechol rings for
the suggested possible structures (Table 1) can support the
formation of 5b,c instead of 6b,c. According to these results, it
is obvious that o-benzoquinones 2b,c are selectively attacked
from C-5 position by 3a. Therefore, these sequential electrooxi-
dative/Michael-type one-pot coupling reactions of 1b and 1c
with 3 lead to the formation of novel tetrazolic thioether-
substituted catechols 5b and 5c as final products in high yields
(Scheme 1).
Furthermore, the effect of a group located at the reactive site
of o-quinones (C-4 or â-position to carbonyl group) on their
reactivity toward mercaptide anion 3a was investigated in some
details. The electrochemical oxidations of 4-methylcatechol (1d)
and 4-tert-butylcatechol (1e) bearing methyl and tert-butyl
groups at the C-4 position were studied in the presence of 3 in
water/acetonitrile (90/10) solution containing 0.20 M sodium
acetate. As mentioned earlier, any decrease observed in the
current density for the cathodic peak in cyclic voltammograms
of catechols obviously relates to the reactivity of electrochemi-
cally derived o-benzoquinones toward mercaptide anion 3a.
Comparison of the cyclic voltammograms of 1d and 1a in the
presence of 3, shows less decrease in the current density for
the cathodic part of 1d which means o-benzoquinone 2d has
less reactivity in the Michael-addition reaction toward mercap-
6b,c. The accuracy of theses suggestions was proved by
comparing the calculated23 and experimentally obtained 1H and
13CNMR data of the possible structures 5b,c and 6b,c. Spec-
troscopic characterization of the product obtained from (1b) by
1H NMR indicated the presence of two doublets at 6.70 and
w
6.94 ppm with small coupling constant value (4J or J) which
is in a good agreement with two aromatic protons in the meta
position24 and supports the addition of 3a to the C-5 position.
The addition to C-4 in the generation of more complex feature,
once ortho hydrogens, would couple, which would result in a
doublet with a coupling constant, J, of about 10 Hz. Also,
comparison of the calculated and experimental 13CNMR data
(23) CS ChemDraw Ultra, Version 8.0, CambridgeSoft Corp., 100
Cambridge Park Dr., Cambridge, MA.
(24) Silverstein, R. M.; Webster, F. M. Spectrometric Identification of
Organic Compounds, 6th ed.; Wiley: New York, 1998; p 212.
2530 J. Org. Chem., Vol. 73, No. 7, 2008

Polyfunctional Tetrazolic Thioethers
SCHEME 3
FIGURE 5. Cyclic voltammograms of 1.0 mM hydroquinone (1f).
(a) In the absence and (b) in the presence of 1.0 mM of 1-phenyl-5-
mercaptotetrazole (3), (c) 1.0 mM 1-phenyl-5-mercaptotetrazole in the
absence of 1f at glassy carbon electrode versus SCE in water/acetonitrile
(90/10) solution containing 0.2 M sodium acetate. Scan rate: 100 mV
s-1; t ) 25 ( 1 °C.
tide anion 3a, appearing as an increase in peak current ratio
(IpC1/IpA1). In addition, comparing the cathodic peaks of cyclic
voltammograms of 1e and 1a in the presence of 3, suggests
that the presence of tert-butyl group, a bulky substituent, at the
C-4 position of 2e would probably cause a streic inhibition of
the accessibility of C-5 position to the mercaptide anion 3a and
therefore, this Michael acceptor (2e) will be attacked by 3a at
the C-5 position in a difficult and slower process. The
considerable increase in peak current ratio (IpC1/IpA1) for 1e
clearly supports this suggestion. Except longer reaction time
and lower yield, other electrochemical investigations for 1d and
1e, including cyclic voltammetry and controlled potential
coulometry showed a behavior similar to that of 1a. These one-
pot oxidative coupling reactions of 1d and 1e with 3 lead to
the formation of tetrazolic thioether-substituted catechols 5d-e
in high yields (Scheme 1).
Finally, the electrochemical oxidation of p-dihydroxybenzene
(1f) (hydroquinone) in the presence of 3 was studied in some
detail. Cyclic voltammogram of a 1 mM solution of hydro-
quinone (1f) in water/acetonitrile (90/10) solution containing
0.2 M sodium acetate shows one anodic peak (A1) and a
corresponding cathodic peak (C1), which correspond to the
transformation of hydroquinone (1f) to p-benzoquinone (2f) and
vice versa through a quasi-reversible two-electron process
(Figure 5, curve a). The cyclic voltammogram obtained for a 1
mM solution of 1f in the presence of 1 mM of 3 is shown in
Figure 5, curve b. This voltammogram exhibits one anodic peak
(A1) and compared to the curve a, shows a nearly complete
decrease of the current density for cathodic peak (C1). This
observation is in a good agreement with the reactivity of the
electrochemically derived highly active o-benzoquinone (2a)
toward mercaptide anion 3a. The cyclic voltammogram of a 1
mM solution of 3 is shown in Figure 5, curve c, for comparison
and the cathodic peak (C2) that can be seen in both curves b
and c is probably corresponding to the reduction of product of
dimerization of 1-phenyl-5-mercaptotetrazole (3).
type reaction of mercaptide anion (3a) (Scheme 3, eq 2) with
2f occurs in a domino fashion and this sequential reaction seems
to occur much faster than other side reactions, leading to the
formation of tetrazolic thioether-substituted hydroquinone (5f)
(Scheme 3, eq 3).
Conclusion
The results of this work show that 1,2- and 1,4-dihydroxy-
benzenes are electrochemically oxidized to their corresponding
benzoquinones and these benzoquinones can be attacked by
1-phenyl-5-mercaptotetrazole leading to the novel polyfunctional
tetrazolic thioethers. In addition, our results suggest that the
electronic and steric nature of the substituents attached to
benzoquinones rings have important effects on their reactivity
toward nucleophile and also control the structures of final
products. In conclusion, we have described a general, conve-
nient, environmentally friendly and reagent-less protocol for the
preparation of a series of polyfunctional tetrazolic thioethers
through a sequential oxidation/Michael addition reaction of
commercially available starting materials.
We believe that this easy and selective electrooxidative
coupling reaction with its advantages of complementary reactiv-
ity and mild reaction conditions and using electrons as reagent
instead of oxidative ones (only 2F charge consumption per each
mol of dihydroxybenzene is needed), working in ambient
conditions, technical feasibility, and especially dramatically high
atom economy (>99%) may find potential applications in
synthetic organic chemistry and more importantly, can compli-
ment the existing chemical strategies.
The obtained coulometry and voltammetry results allow us
to propose the pathways shown in Scheme 3 for the electro-
oxidation of hydroquinone (1f) in the presence of 1-phenyl-5-
mercaptotetrazole (3). According to our results, it seems that
similar to the case of 1a, upon anodic oxidation of 1f to
p-benzoquinone 2f (Scheme 3, eq 1), an intermolecular Michael-
In addition, we hope that because of the diversity of this
method, it can be adopted in organic heterocyclic chemistry to
synthesize and screen libraries of related biologically important
polycyclic thiotetrazoles.
J. Org. Chem, Vol. 73, No. 7, 2008 2531

Khodaei et al.
(5), 171 (100), 156 (10), 118 (65), 84 (38), 77 (8), 65 (6); HRMS
(EI) calcd for C14H12 O3N4S 316.0630, found 316.0625.
Experimental Section
Apparatus and Reagents. Electrolysis equipment is described
in the Supporting Information. All chemicals were of reagent-grade
and used without further purification. Throughout all experiments
distilled water was used and all the experiments were done at room
temperature.
4-Methyl-5-(1-phenyl-1H-tetrazol-5-ylthio)benzene-1,2-diol (5d):
mp 169-171 °C; yield 65%; IR (dropcast on NaCl) 690, 715, 723,
821, 874, 1050, 1098, 1130, 1198, 1250, 1450, 1490, 1529, 1601,
1
2902, 3075, 3480 cm-1; H NMR δ ppm (200 MHz DMSO-d6)
2.16 (s, 3H), 6.76 (s, 1H), 6.95 (s, 1H), 7.66-7.70 (m, 5H), 9.22-
9.48 (broad, 2H); 13C NMR δ ppm (50 MHz DMSO-d6) 19.5, 113.1,
117.9, 122.6, 124.9, 129.9, 130.7, 133.2, 133.3, 144.0, 148.0, 154.3;
MS (EI, 70 eV) 300 (M+, 46), 267 (21), 155 (64), 118 (100), 93
(17), 91 (18), 77 (12), 65 (16); HRMS (EI) calcd for C14H12 O2N4S
300.0681, found 300.0686.
Electroorganic Synthesis of 5a-f. In a typical procedure, a
solution (ca. 100 mL) of water/acetonitrile (90/10), containing 0.2
M acetate sodium, 1.0 mmol of dihydroxybenzene (1a-f) and 1.0
mmol of 1-phenyl-5-mercaptotetrazole (3), was electrolyzed in an
undivided cell equipped with a carbon anode (an assembly of four
rods, 6-mm diameter, and ∼10-cm length), and a large platinum
gauze cathode at 0.20 V vs SCE, at 25 °C. The electrolysis was
terminated when the decay of the current became more than 95%.
The process was interrupted during the electrolysis and the graphite
anode was washed in acetone in order to reactivate it. At the end
of electrolysis, a few drops of acetic acid were added to the solution
and the cell was placed in a refrigerator overnight. The precipitated
solid was collected by filtration, washed copiously with distilled
4-tert-Butyl-5-(1-phenyl-1H-tetrazol-5-ylthio)benzene-1,2-di-
ol (5e): mp 181-183 °C; yield 57%; IR (dropcast on NaCl) 560,
610, 691, 700, 725, 880, 943, 1055, 1090, 1155, 1287, 1340, 1355,
1401, 1490, 1539, 1599, 2902, 3088, 3510 cm-1; 1H NMR δ ppm
(200 MHz DMSO-d6) 1.12 (s, 9H), 6.80 (s, 1H), 6.91 (s, 1H), 7.63-
7.80 (m, 5H), 9.08 (broad, 1H), 9.56 (broad, 1H); 13C NMR δ ppm
(50 MHz DMSO-d6) 31.1, 33.8, 112.1, 114.8, 120.8, 124.8, 129.7,
130.5, 133.3, 142.0, 143.8, 145.4, 153.2; MS (EI, 70 eV) 342 (M+,
100), 298 (9), 283 (10), 255 (7), 197 (22), 180 (35), 164 (24), 135
(14), 118 (46), 91 (15), 77 (14), 65 (9); HRMS (EI) calcd for
C17H18O2N4S 342.1150, found 342.1152.
2-(1-Phenyl-1H-tetrazol-5-ylthio)benzene-1,4-diol (5f): mp
217-218 °C (lit.10 mp 216-217 °C); yield 96%; 1H NMR δ ppm
(200 MHz DMSO-d6): 6.87-6.97 (m, 3H), 7.76-7.92 (m, 5H),
9.25 (s, 1H), 9.72 (s, 1H); 13C NMR δ ppm (50 MHz DMSO-d6)
113.3, 116.7, 118.0, 119.3, 124.6, 124.9, 129.8, 130.6, 133.2, 149.3,
150.1; MS (EI, 70 eV) 286 (M+, 45), 243 (8), 141 (29), 118 (100),
112 (28), 91 (16), 77 (21), 65 (11); HRMS (EI) calcd for
C13H10O2N4S 286.0524, found 286.0512.
water and characterized by: FT-IR, H NMR, 13C NMR and HR-
MS. The final products (5a-f) were obtained purely and no extra
purification was needed.
1
4-(1-Phenyl-1H-tetrazol-5-ylthio)benzene-1,2-diol (5a): mp
1
135-136 °C; yield 92%; H NMR δ ppm (200 MHz DMSO-d6)
4.51 (broad, 2H), 6.79-7.01 (m, 3H), 7.58-7.69 (m, 5H); 13C NMR
δ ppm (50 MHz DMSO-d6) 114.3, 116.4, 121.4, 125.1, 126.1,
129.9, 130.7, 133.1, 146.2, 147.8, 154.5; MS (EI, 70 eV) 286 (M+,
23), 141 (48), 118 (100), 91 (10), 77 (10), 65 (6); HRMS (EI) calcd
for C13H10O2N4S 286.0524, found 286.0512.
3-Methyl-5-(1-phenyl-1H-tetrazol-5-ylthio)benzene-1,2-diol (5b):
mp 160-161 °C; yield 76%; IR (dropcast on NaCl) 653, 695, 710,
810, 847, 910, 1083, 1302, 1428, 1490, 1520, 1610, 2993, 3050,
3450 cm-1; 1H NMR, δ ppm (200 MHz DMSO-d6): 2.16 (s, 3H),
6.70 (d, J ) 8.34, 1H), 6.94 (d, J ) 8.34, 1H), 7.66-7.74 (m, 5H),
8.67 (broad, 1H), 9.86 (broad, 1H); 13C NMR δ ppm (50 MHz
DMSO-d6) 14.0, 113.2, 114.6, 124.9, 127.3, 129.2, 130.0, 130.7,
133.2, 144.4, 147.7, 154.5; MS (EI, 70 eV) 300 (M+, 45), 230 (9),
213 (6), 155 (80), 118 (100), 93 (17), 77 (17), 65 (21); HRMS
(EI) calcd for C14H12 O2N4S 300.0681, found 300.0675.
3-Methoxy-5-(1-phenyl-1H-tetrazol-5-ylthio)benzene-1,2-di-
ol (5c): mp 82-83 °C; yield 58%; H NMR δ ppm (200 MHz
DMSO-d6) 3.69 (s, 3H), 6.61-670 (m, 2H), 7.62-7.69 (m, 5H),
8.75-9.40 (broad); 13C NMR δ ppm (50 MHz DMSO-d6) 56.0,
109.7, 113.8, 115.4, 124.9, 125.1, 129.9, 130.7, 133.2, 136.5, 146.4,
148.6, 149.7, 154.3; MS (EI, 70 eV) 316 (M+, 32), 256 (4), 230
Acknowledgment. Financial support for this work from
Research Affairs, Razi University, Kermanshah, Iran, is grate-
fully acknowledged. We also thank Professor Mark S. Worken-
tin (Department of Chemistry, The University of Western
Ontario, Canada) for the use of the HR-mass spectrometer.
1
Supporting Information Available: Copies of H, 13C NMR,
FT-IR, and HR-MS of all compounds (5a-f) as well as general
information for cyclic voltammetry, controlled-potential coulometry,
and preparative electrolysis procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
JO702327M
2532 J. Org. Chem., Vol. 73, No. 7, 2008