Direct Synthesis of Thioethers from Carboxylates and Thiols Catalyzed by FeCl3

Article abstract of DOI:10.1021/acs.joc.5b02143

A new and efficient method has been developed for the synthesis of thioethers from carboxylates and thiols. The reaction proceeds via a Fe(III)-catalyzed direct displacement of carboxylates from benzylic or allylic esters by heterocyclic thiols. Short rea

Full text of DOI:10.1021/acs.joc.5b02143

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Note
Direct Synthesis of Thioethers from
Carboxylates and Thiols Catalyzed by FeCl3
Kunuru Venkatesham , Chitturi Bhujanga Rao, Chanti Babu
Dokuburra, Richard A. Bunce , and Yenamandra Venkateswarlu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02143 • Publication Date (Web): 24 Oct 2015
Downloaded from http://pubs.acs.org on October 27, 2015
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Direct Synthesis of Thioethers from Carboxylates and Thiols Catalyzed
by FeCl3
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Kunuru Venkatesham,a Chitturi Bhujanga Rao,*,a Chanti Babu Dokuburra,a Richard A. Bunce b
and Yenamandra Venkateswalu a,†
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aNatural Products Laboratory, Natural Products Division, Indian Institute of Chemical Technology,
Hyderabad, India, 500007; Fax: 91-40-27160512; Tel: +91-40-27193167. bDepartment of
Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078-3071.
ABSTRACT:
A new and efficient method has been developed for the synthesis of thioethers from
carboxylates and thiols. The reaction proceeds via a Fe(III)-catalyzed direct displacement of
carboxylates from benzylic or allylic esters by heterocyclic thiols. Short reaction times, good to
excellent yields of products, and few side reactions are the significant features of the new protocol.
_________________________
†This paper is dedicated to the memory to our late mentor Dr. Yenamandra Venkateswarlu, who
passed away suddenly on July 17, 2013.
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Organosulfur compounds are versatile intermediates for the synthesis of bioactive natural
products, and often possess significant pharmaceutical activities.1,2 Among this class of compounds,
thioethers3 (e.g. Cephalosporin analogues), their derived sulfones4 (e.g. Dapsone) and some
sulfoxides5 (e.g. Omeprazole, Armodafinil and Ajoene) have been used extensively in human health
care as well as in medicinal chemistry research.3-5 All of these compounds have been prepared by
several routes.6 A wide range of thioethers and their derived sulfones are being used as synthons for
the preparation of lead compounds and novel materials for human needs.7
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In the past, several other methods have been employed for the synthesis of thioethers,8 but
these transformations required stoichiometric or near-stoichiometric amounts of catalyst. Although
these techniques have shown great promise, in practice, they are characterized by various limitations
such as tedious reaction procedures, contamination by side products, low yields and expensive
reagents and catalysts. These requirements render them commercially as well as ecologically
untenable. Consequently, they are restricted from extensive industrial applications. To circumvent
these problems, the development of more reliable and convenient procedures using readily accessible
and inexpensive materials is a continuing goal. For example, in 2002, Hidai and co-workers9 reported
that ruthenium complexes catalyzed the direct synthesis of thioethers from propargyl alcohols and
thiols. Recently, Wu et al.10 reported that Ga(OTf)3 also catalyzed the one-pot synthesis of thioethers
from benzylic and allylic alcohols.
In the recent past, Fe-based catalysts have become a powerful tool in organic synthesis.11
Interest in Fe(III)-catalyzed transformations has blossomed because of their environmentally benign
characteristics, significant reactivity and low cost. Furthermore, it is one of the most abundant metals
in the Earth's crust. Metal-catalyzed C-O, C-S, C-C and C-N bond formations have also gained much
recent attention,12 since they have vast potential in organic synthesis and material chemistry. In this
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connection, we wish to advance a simple and efficient Fe(III)-catalyzed protocol for the synthesis of
thioethers.
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Scheme 1. Direct displacement of benzylic and allylic carboxylates by using heterocyclic thiols
As an extension of our previous work on the pivaloylation of alcohols13a and Fe(III)-catalyzed
synthesis of esters,13b we herein report our recent work on the development of an inexpensive and
efficient approach to the synthesis of thioethers. Direct displacement of carboxylates from benzyl or
allyl esters by thiols has been achieved to generate the corresponding thioethers in the presence of
anhydrous FeCl3 in MeCN at 80 oC (Scheme 1).
Scheme 2: Reaction of 1 with 4-9
To optimize the required displacement of carboxylates with thiols, we selected the reaction of
p-methoxybenzyl pivalate (4) with 1-phenyl-1H-tetrazole-5-thiol (1) as a model system. This
transformation was evaluated under a variety of conditions to identify the optimum protocol, and the
results are summarized in Table 1. These experiments demonstrated that the reaction performed in
MeCN using anhydrous FeCl3 (10 mol%) at 80 oC gave superior results, affording 96% of product 4a
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in 1 h (Scheme 2). This same reaction (Table 1) afforded almost equal yields of 4a (>95%) in the
presence of Fe(OTf)3 (10 mol%, 1 h), and gave slightly diminished yields (91%) of the required
product in the presence of FeCl3·6H2O (10 mol%, 6 h).
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Table 1. Optimized conditions for the reaction of 1 with 4 to give 4a
Entry Catalyst
Conditions
MeCN/80 oC
MeCN/25 oC
H2O/80 oC
Time (h) Yield (%)a
1
2
3
4
5
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8
FeCl3
FeCl3
FeCl3
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6
96b
00
6
trace
91
FeCl3·6H2O MeCN/80 oC
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Fe(OTf)3
BiCl3
MeCN/80 oC
MeCN/80 oC
MeCN/80 oC
MeCN/80 oC
1
96
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12
6
80
AlCl3
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None
00
Reaction conditions: Thiol 1 (1 eq), ester 4 (1.1 eq), catalyst (10 mol%), 2.5 mL MeCN, 80 °C.
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Table 2. Reaction of different esters with thiol 1 in the presence of FeCl3 in MeCN at 80 oC
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After initial refinement of the reaction conditions, we turned our attention to evaluating the
leaving group characteristics of the different carboxylate groups. We studied a series of carboxylates
in place of the pivalyloxy group in 4, and performed reactions with thiol 1 under the same reaction
conditions (10 mol% FeCl3/MeCN/ꢀ, 1 h). Indeed, we did not perceive any significant change in the
reactivity of esters 5, 6 and 7 which contain acetyloxy, benzoyloxy or p-methoxybenzoyloxy,
respectively, as leaving groups. In each case, the reaction proceeded smoothly with thiol 1 under the
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optimized conditions to furnish similar yields of 4a (>94%). However, the use of ester 8, with p-
nitrobenzoyloxy as the leaving group, afforded only moderate yields of 4a (~74%), and 9, with m-
nitrobenzoyloxy as the leaving group, did not give any product.
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To further validate our method, we investigated the scope and limitations of this novel
transformation (Table 2). In this study, we used different benzylic and allylic pivalates in combination
with 1. The benzylic esters with electron-donating groups (e.g. -OMe) at C-4 of the benzene ring
afforded excellent yields in most instances. The benzylic esters with electron-withdrawing groups
(e.g. -NO2) at C-4 afforded moderate to good yields (Table 2). Impressively, polycyclic aromatic and
heteroaromatic esters furnished stunning (>99%) yields of the thioether products within 30 minutes
(Table 2) under our standard reaction conditions. The allylic esters also gave high yields as shown in
the Table 2. On the other hand, esters 28, 30 and 32 did not react with 1 to any appreciable extent
under the optimized conditions. We suspect, this may be due to steric hindrance present in one or both
of the reacting partners (ester or thiols) in these reactions.
To extend the substrate scope, we have employed three additional thiols: 1-methyl-1H-
tetrazole-5-thiol (2), benzo[d]thiazole-2-thiol (3) and pyridine-2-thiol, as nucleophiles in combination
with various esters that were reacted with 1 (Table 3). In assessing the expected reactivity of the
various thiols, 1 and 2 should exhibit very similar nucleophilicities, with 2 being slightly more
nucleophilic. Additionally, Ph- substitution adjacent to the thiol in 1 should make it more hindered
than 2. Thus, one might expect that 2 would react with more esters since it is less influenced by these
two limiting factors. Thiol 3, while not sterically hindered, potentially suffers from resonance
deactivation and should show reduced nucleophilicity. Finally, the more highly delocalized pyridine-
2-thiol should be even less reactive.
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Table 3. Reaction of 2 with different esters in the presence of FeCl3 in MeCN at 80 oC
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In practice, thiol 1 reacted with a large number of esters, including those with electron-rich
benzylic esters, such as 6 and 7, and more hindered benzylic and allylic systems such as 16 and 27.
However, it failed to react with extended chain esters like 28, 30 and 32. Thiol 2 also reacted
smoothly with a broad selection of esters. In contrast to 1, however, 2 did not react with electron-rich
esters like 6 and 7 or hindered systems such as 16 and 27, but did react with the three esters 28, 30
and 32. The results with 16, 27, 28, 30 and 32 support our assumptions regarding the importance of
steric and electronic factors in the reactivity. Thiol 2 would be expected to fail when steric hindrance
is close to the reaction site, as in 16 and 27, since the methyl group cannot rotate to avoid the steric
interaction as phenyl can. For the chain-extended esters, the site bearing the ester leaving group is
less congested and reaction occurs faster with the less hindered more nucleophilic thiol 2. The
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importance of thiol nucleophilicity was further substantiated by examination of the remaining thiols.
As expected, resonance deactivated 3 (Scheme 3) reacted with fewer esters under the optimized
reaction conditions and afforded products in only moderate yields. Finally, the more highly
delocalized thiol in pyridine-2-thiol did not react with any of the esters used in the current study.
Hence, the nucleophilicity of the four thiols 1, 2, 3 and pyridine-2-thiol is in the order
2>1>3>>pyridine-2-thiol.
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Scheme 3. Reaction of thiol 3 with esters 4, 14 and 23
Sulfides are most commonly prepared by the Mitsunobu reaction of an alcohol with a thiol in
the presence of excess diisopropyl azodicarboxylate and triphenylphosphine.14 This route, however,
generally leads to a higher impurity profile (requiring chromatographic purification) and lower yields
of the desired product. In contrast, the only by-product generated in the current method is pivalic acid
and it can be easily removed from the reaction mixture by washing with aq NaHCO3. Thus, our new
method affords these sulfides in higher yields and with greater purities than most of the previously
reported methods.
In conclusion, we have developed a convenient and efficient method for the conversion of
benzyl and allyl pivalate (acetate and some benzoate) esters to sulfides by treatment with catalytic
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anhydrous FeCl3 in MeCN at 80 C. The reaction proceeds in high yield for activated benzyl and
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allyl pivalates as well as substrates incorporating polycyclic aromatic and heteroaromatic rings. The
conversion is rapid (generally ≤6 h) and generates the target sulfides with fewer side reactions than
are observed by other approaches. The level of success in the reaction is somewhat dependent on the
nucleophilicity of the sulfide nucleophile and the steric hindrance in proximity to the ester leaving
group. It was also found that nitro substitution on the benzoate esters diminished the yields in the
reaction. Nevertheless, the direct carboxylate-to-thioether conversion constitutes a powerful method
for the high yield synthesis of a wide range of thioethers. These compounds are widely distributed in
many commercial drugs, and thus, the current method could have broad applications in the synthesis
of natural products and medicinal agents.
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EXPERIMENTAL SECTION
General Procedure: The reaction was carried out by simple addition of the heterocyclic thiol (1.1
mmol) to the solution of ester (1.0 mmol) in MeCN (2.5 mL) in a 10-mL round-bottomed flask
o
followed by the catalyst [FeCl3, 16 mg (10 mol%)]. The reaction mixture was stirred at 80 C and
monitored by TLC. Upon completion, the crude mixture was diluted with EtOAc (5 mL) and washed
with saturated aq NaHCO3 (5 mL). The aqueous phase was extracted with EtOAc (1 × 10 mL) and
the combined organic layers were dried over Na2SO4. The mixture was then concentrated under
vacuum to yield the corresponding product. Purification of the final products, when necessary, was
performed by chromatography through a short column of silica gel using hexane/EtOAc as the mobile
phase.
5-(4-Methoxybenzylthio)-1-phenyl-1H-tetrazole10 (4a, Scheme 2): Yield: 283 mg (95%), 1.0 mmol
reaction scale; 1H NMR (300 MHz, CDCl3): δ 7.50 (m, 5H), 7.29 (d, 2H, J = 8.0 Hz), 6.78 (d, 2H, J =
8.0 Hz), 4.56 (s, 2H), 3.76 (s, 3H); C {1H} NMR (75 MHz, CDCl3): δ 159.4, 153.9, 133.6, 130.5
13
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(2C), 130.0, 129.7 (2C), 127.0, 123.7 (2C), 114.2 (2C), 55.2, 37.3; IR: 2933, 2837, 1730, 1608, 1508,
5
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1246, 1032, 761 cm-1; MS (ESI): m/z 321 (M+Na).
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5-(4-Ethylbenzylthio)-1-phenyl-1H-tetrazole (10a, Table 2): Yield: 140 mg (94%), 0.5 mmol
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1
reaction; H NMR (300 MHz, CDCl3): δ 7.52 (m, 5H), 7.32 (d, 2H, J =8.0 Hz), 7.15 (d, 2H, J = 8.0
Hz), 4.60 (s, 2H), 2.62 (q, 2H, J = 7.4 Hz), 1.21 (t, 3H, J = 7.4 Hz); C {1H} NMR (75 MHz,
13
CDCl3): δ 153.9, 144.3, 133.5, 132.2, 129.9, 129.6 (2C), 129.1 (2C), 128.2 (2C), 123.7 (2C), 37.4,
29.6, 15.4; IR: 2962, 2853, 1724, 1499, 1385, 1238, 1082, 760 cm-1; MS (ESI): m/z 319 (M+Na);
HRMS: m/z Calcd: 319.0988 (C16H16N4S+Na); Found: 319.1008.
1-Phenyl-5-(4-propylbenzylthio)-1H-tetrazole (11a, Table 2): Yield: 148 mg (95%), 0.5 mmol
reaction scale; 1H NMR (300 MHz, CDCl3): δ 7.52 (m, 5H), 7.32 (d, 2H, J = 8.0 Hz), 7.12 (d, 2H, J =
8.0 Hz), 4.60 (s, 2H), 2.56 (t, 2H, J = 7.6 Hz), 1.6 (m, 2H), 0.92 (t, 3H, J = 7.3 Hz); 13C {1H} NMR
(75 MHz, CDCl3): δ 153.9, 142.8, 133.6, 132.2, 130.0, 129.6 (2C), 129.0 (2C), 128.8 (2C), 123.7
(2C), 37.6, 37.4, 24.3, 13.7; IR: 2960, 2851, 1720, 1499, 1385, 1239, 1081, 760 cm-1; MS (ESI): m/z
333 (M+Na); HRMS: m/z Calcd: 333.1144 (C17H18N4S+Na); Found: 333.1162.
5-(4-Nitrobenzylthio)-1-phenyl-1H-tetrazole (12a, Table 2): Yield: 263 mg (84%), 1.0 mmol
reaction scale; 1H NMR (300 MHz, CDCl3): δ 8.23 (d, 2H, J = 8.9 Hz), 7.60 (m, 5H), 7.53 (d, 2H, J =
8.9 Hz), 5.20 (s, 2H); C {1H} NMR (75 MHz, CDCl3): δ 170.4, 151.4, 143.1, 132.9, 130.9, 129.9
13
(2C), 128.2 (2C), 124.5, 124.4, 123.7 (2C), 64.7; IR: 2927, 1605, 1483, 1351, 1229, 770 cm-1; MS
(ESI): m/z 314 (M+H); HRMS: m/z Calcd: 314.0706 (C14H11N5O2S+H); Found: 314.0729.
5-(3-Nitrobenzylthio)-1-phenyl-1H-tetrazole (13a, Table 2): Yield: 144 mg (92%), 0.5 mmol
reaction scale; 1H NMR (300 MHz, CDCl3): δ 8.25 (s, 1H), 8.15 (d, 1H, J = 8.0 Hz), 7.71 (d, 1H, J =
7.4 Hz), 7.59 (m, 5H), 7.53 (t, 1H, J = 8.0 Hz), 4.83 (s, 2H); C {1H} NMR (75 MHz, CDCl3): δ
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152.2, 132.9, 132.6, 130.8 (2C), 129.9 (3C), 129.3, 124.3 (2C), 122.2, 121.4, 63.7; IR: 2921, 1595,
1498, 1350, 1234, 762 cm-1; MS (ESI): m/z 314 (M+H); HRMS: m/z Calcd: 314.0706
(C14H11N5O2S+H); Found: 314.0729.
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5-(3,4-Dimethoxybenzylthio)-1-phenyl-1H-tetrazole (14a, Table 2): Yield: 158 mg (96%), 0.5
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mmol reaction scale; H NMR (300 MHz, CDCl3): δ 7.54-7.48 (m, 5H), 6.95 (dd, 1H, J = 8.0, 2.1
Hz), 6.94 (m, 1H), 6.79 (d, 1H, J = 7.7 Hz), 4.59 (s, 2H), 3.86 (s, 3H), 3.86 (s, 3H); C {1H} NMR
13
(75 MHz, CDCl3): δ 153.7, 149.0, 148.8, 133.4, 129.9, 129.5 (2C), 127.4, 123.6 (2C), 121.5, 112.0,
111.0, 55.7 (2C), 37.6; IR: 2934, 2836, 1706, 1596, 1337, 1264, 1026, 762 cm-1; MS (ESI): m/z 351
(M+Na); HRMS: m/z Calcd: 351.0886 (C16H16N4O2S+Na); Found: 351.0903.
5-(2,4-Dimethylbenzylthio)-1-phenyl-1H-tetrazole (15a, Table 2): Yield: 260 mg (88%), 1.0 mmol
1
reaction scale; H NMR (300 MHz, CDCl3): δ 7.51 (m, 5H), 7.25 (d, 1H, J = 6.7 Hz), 6.98 (m, 2H),
4.63 (s, 2H), 2.36 (s, 3H), 2.29 (s, 3H); C {1H} NMR (75 MHz, CDCl3): δ 154.0, 138.4, 136.9,
13
131.4, 130.3, 129.9 (2C), 129.6 (3C), 127.0, 123.6 (2C), 35.7, 21.0, 19.0; IR: 2922, 2854, 1731, 1595,
1499, 1384, 1235, 761 cm-1; MS (ESI): m/z 319 (M+Na); HRMS: m/z Calcd: 319.0988
(C16H16N4S+Na); Found: 319.1008.
1-Phenyl-5-(1-phenylethylthio)-1H-tetrazole10 (16a, Table 2): Yield: 274 mg (97%), 1.0 mmol
1
reaction scale; H NMR (300 MHz, CDCl3): δ 7.56-7.42 (m, 5H), 7.39 (m, 2H), 7.35-7.26 (m, 2H),
5.20 (q, 1H, J = 6.8 Hz), 1.89 (d, 3H, J = 6.8 Hz); 13C {1H} NMR (75 MHz, CDCl3): δ 153.4, 140.7,
133.5, 129.9, 129.5 (2C), 128.7 (2C), 128.1, 127.1 (2C), 123.9 (2C), 47.8, 22.1; IR: 2973, 2867,
1596, 1497, 1385, 1222, 1087, 762 cm-1; MS (ESI): m/z 305 (M+Na).
5-(Furan-2-ylmethylthio)-1-phenyl-1H-tetrazole10 (18a, Table 2): Yield: 256 mg (99%), 1.0 mmol
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reaction scale; H NMR (300 MHz, CDCl3): δ 7.96 (d, 2H, J = 7.9 Hz), 7.60-7.47 (m, 3H), 7.44 (m,
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1H), 6.61 (d, 1H, J = 3.2 Hz), 6.39 (m, 1H), 5.55 (s, 2H); 13C {1H} NMR (75 MHz, CDCl3): δ 153.4,
143.5, 142.8, 130.1 (2C), 129.7, 129.1, 123.7 (2C), 110.7, 109.7, 44.1; IR: 2923, 2852, 1729, 1596,
1499, 1219, 772 cm-1; MS (ESI): m/z 281 (M+Na).
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1-Phenyl-5-(thiophen-2-ylmethylthio)-1H-tetrazole10 (20a, Table 2): Yield: 136 mg (99%), 0.5
1
mmol reaction scale; H NMR (300 MHz, CDCl3): δ 7.52 (m, 5H), 7.22 (dd, 1H, J = 5.0, 1.1 Hz),
7.11 (d, 1H, J = 3.5 Hz), 6.92 (dd, 1H, J = 3.5, 1.1 Hz), 4.86 (s, 2H); C {1H} NMR (75 MHz,
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CDCl3): δ 153.4, 137.2, 133.4, 130.1, 129.7 (2C), 128.1, 127.0, 126.2, 123.7 (2C), 32.2; IR: 2927,
2850, 1733, 1595, 1497, 771 cm-1; MS (ESI): m/z 297 (M+Na), 292 (M+NH4).
5-(Naphthalen-1-ylmethylthio)-1-phenyl-1H-tetrazole (22a, Table 2): Yield: 157 mg (99%), 0.5
mmol reaction scale; 1H NMR (300 MHz, CDCl3): δ 8.06 (d, 1H, J = 8.5 Hz), 7.87 (dd, 1H, J = 7.3,
1.4 Hz), 7.82 (d, 1H, J = 8.2 Hz), 7.62 (d, 1H, J = 7.0 Hz), 7.57-7.49 (m, 2H), 7.46 (m, 5H), 7.41 (d,
1H, J = 8.4 Hz), 5.13 (s, 2H); 13C {1H} NMR (75 MHz, CDCl3): δ 154.1, 133.9, 133.5, 131.2, 130.3,
130.0, 129.6 (2C), 129.3, 128.9, 128.5, 126.7, 126.1, 125.4, 123.7 (2C), 123.2, 35.6; IR: 2924, 2852,
1745, 1499, 1386, 1234, 762 cm-1; MS (ESI): m/z 319 (M+H); HRMS: m/z Calcd: 319.1012
(C18H14N4S+H); Found: 319.1026.
5-(Cinnamylthio)-1-phenyl-1H-tetrazole10 (23a, Table 2): Yield: 141 mg (96%), 0.5 mmol reaction
scale; 1H NMR (300 MHz, CDCl3): δ 7.56 (m, 5H), 7.36 (d, 2H, J = 7.4 Hz), 7.30 (t, 2H, J = 7.3 Hz),
7.24 (t, 1H, J = 6.7 Hz), 6.72 (d, 1H, J = 15.5 Hz), 6.35 (m, 1H), 4.2 (d, 2H, J = 7.4 Hz); C {1H}
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NMR (75 MHz, CDCl3): δ 153.6, 135.9, 135.1, 133.5, 130.0, 129.7 (2C), 128.5 (2C), 128.0, 126.5
(2C), 123.8 (2C), 122.3, 35.8; IR: 2973, 2873, 1728, 1599, 1479, 1281, 1151, 965, 744 cm-1; MS
(ESI): m/z 317 (M+Na).
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(E)-5-(3-(4-Methoxyphenyl)allylthio)-1-phenyl-1H-tetrazole10 (24a, Table 2): Yield: 160 mg
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(99%), 0.5 mmol reaction scale; H NMR (300 MHz, CDCl3): δ 7.55 (m, 5H), 7.30 (d, 2H, J = 8.9
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Hz), 6.82 (d, 2H, J = 8.9 Hz), 6.65 (d, 1H, J = 15.9 Hz), 6.20 (m, 1H), 4.19 (d, 2H, J = 7.4 Hz), 3.80
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(s, 3H); C {1H} NMR (75 MHz, CDCl3): δ 159.5, 151.7, 134.6, 133.6, 130.0, 129.6 (2C), 128.7,
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127.7 (2C), 123.8 (2C), 119.9, 113.9 (2C), 55.2, 36.1; IR: 2924, 2852, 1725, 1603, 1507, 1386, 1550,
1032, 760 cm-1; MS (ESI): m/z 325 (M+H), 347 (M+Na).
(E)-5-(2-Methyl-3-phenylallylthio)-1-phenyl-1H-tetrazole (25a, Table 2): Yield: 152 mg (98%),
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0.5 mmol reaction scale; H NMR (300 MHz, CDCl3): δ 7.60-7.53 (m, 5H), 7.32 (m, 2H), 7.23 (m,
3H), 6.63 (s, 1H), 4.22 (d, 2H, J = 0.9 Hz), 1.97 (d, 3H, J = 1.4 Hz); C {1H} NMR (75 MHz,
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CDCl3): δ 153.9, 136.7, 133.6, 131.4, 130.5, 130.0, 129.6 (2C), 128.7 (2C), 128.1 (2C), 126.8, 123.8
(2C), 43.6, 16.9; IR: 2921, 2852, 1736, 1595, 1497, 1385, 1237, 757 cm-1; MS (ESI): m/z 309 (M+H);
HRMS: m/z Calcd: 309.1168 (C17H16N4S+H); Found: 309.1193.
5-((2E,4E)-Hexa-2,4-dienylthio)-1-phenyl-1H-tetrazole (26a, Table 2): Yield: 253 mg (98%), 1.0
mmol reaction scale; 1H NMR (300 MHz, CDCl3): δ 7.56 (m, 5H), 6.32 (m, 1H), 5.99 (m, 1H), 5.79-
5.63 (m, 2H) 4.05 (d, 2H, J = 7.6 Hz), 1.74 (d, 3H, J = 6.6 Hz); 13C {1H} NMR (75 MHz, CDCl3): δ
153.8, 135.7, 131.4, 130.1, 130.05, 129.8, 129.7 (2C), 123.8 (2C), 122.7, 29.6, 18.1; IR: 2963, 2855,
1724, 1597, 1388, 1242, 1016, 760 cm-1; MS (ESI): m/z 281 (M+Na); HRMS: m/z Calcd: 281.0831
(C13H14N4S+Na); Found: 281.0842.
5-(Cyclohex-2-enylthio)-1-phenyl-1H-tetrazole10 (27a, Table 2): Yield: 251 mg (92%), 1.0 mmol
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reaction scale; H NMR (300 MHz, CDCl3): δ 7.61-7.51 (m, 5H), 5.96 (m, 1H), 5.84 (m, 1H), 4.75
(m, 1H), 2.23-2.02 (m, 1H), 2.12-2.02 (m, 3H), 1.85-1.66 (m, 2H); 13C {1H} NMR (75 MHz, CDCl3):
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δ 154.1, 133.7, 133.0, 129.9, 129.7 (2C), 124.8, 123.9 (2C), 44.7, 29.0, 24.8, 19.1; IR: 2923, 2854,
1729, 1595, 1498, 1385, 1239, 758 cm-1; MS (ESI): m/z 281 (M+Na).
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5-(4-Methoxybenzylthio)-1-methyl-1H-tetrazole (4b, Table 3): Yield: 232 mg (98%), 1.0 mmol
reaction scale; 1H NMR (300 MHz, CDCl3): δ 7.44 (d, 2H, J = 8.7 Hz), 6.88 (d, 2H, J = 8.7 Hz), 5.39
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(s, 2H), 3.88 (s, 3H), 3.79 (s, 3H); C {1H} NMR (75 MHz, CDCl3): δ 163.9, 159.7, 130.2 (2C),
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125.4, 114.0 (2C), 55.1, 50.9, 34.6; IR: 2921, 2832, 1611, 1511, 1366, 1210, 1028, 747 cm-1; MS
(ESI): m/z 259 (M+Na); HRMS: m/z Calcd: 259.0624 (C10H12N4OS+Na); Found: 259.0642.
5-(2,4-Dimethylbenzylthio)-1-methyl-1H-tetrazole (15b, Table 3): Yield: 106 mg (90%), 0.5 mmol
reaction scale; 1H NMR (300 MHz, CDCl3): δ 7.20 (d, 1H, J = 7.5 Hz), 7.15 (d, 1H, J = 7.8 Hz), 6.94
(d, 1H, J = 7.5 Hz), 4.53 (s, 2H), 3.78 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H); 13C {1H} NMR (75 MHz): δ
; IR: 2923, 2853, 1736, 1502, 1461, 1386, 1278, 1170, 1027, 699 cm-1; MS (ESI): m/z 257 (M+Na);
HRMS: m/z Calcd: 257.0831 (C11H14N4S+Na); Found: 257.0850.
5-(Furan-2-ylmethylthio)-1-methyl-1H-tetrazole (18b, Table 3): Yield: 99 mg (100%), 0.5 mmol
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reaction scale; H NMR (300 MHz, CDCl3): δ 7.36 (dd, 1H, J = 1.6, 1.0 Hz), 6.30 (m, 2H), 4.56 (s,
2H), 3.85 (s, 3H); C {1H} NMR (75 MHz, CDCl3): δ 164.0, 148.5, 142.9, 110.8, 109.7, 34.0, 30.4;
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IR: 2923, 2793, 1721, 1504, 1353, 1039, 174 cm-1; MS (ESI): m/z 219 (M+Na); HRMS: m/z Calcd:
219.0311 (C7H8N4OS+Na); Found: 219. 0322.
1-Methyl-5-(thiophen-2-ylmethylthio)-1H-tetrazole (20b, Table 3): Yield: 105 mg (100%), 0.5
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mmol reaction scale; H NMR (300 MHz, CDCl3): δ 7.29 (d, 1H, J = 5.2 Hz), 7.27 (d, 1H, J = 3.2
Hz), 6.98 (t, 1H, J = 3.2 Hz), 5.62 (s, 2H), 3.88 (s, 3H); C {1H} NMR (75 MHz, CDCl3): δ 163.7,
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134.3, 128.8, 126.9, 126.8, 45.6, 34.6; IR: 3104, 2945, 1730, 1611, 1454, 1360, 1308, 1193, 1090,
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772 cm-1; MS (ESI): m/z 235 (M+Na); HRMS: m/z Calcd: 235.0083 (C7H8N4S2+Na); Found:
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1-Methyl-5-(naphthalen-1-ylmethylthio)-1H-tetrazole (22b, Table 3): Yield: 127 mg (99%), 0.5
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mmol reaction scale; H NMR (300 MHz, CDCl3): δ 8.05 (d, 1H, J = 8.2 Hz), 7.89 (d, 1H, J = 8.1
Hz), 7.83 (d, 1H, J = 8.2 Hz), 7.59 (td, 1H, J = 8.1, 1.4 Hz), 7.54 (m, 2H), 7.39 (td, 1H, J = 8.1 Hz),
5.02 (s, 2H), 3.70 (s, 3H); C {1H} NMR (75 MHz, CDCl3): δ 153.6, 133.7, 130.8, 130.5, 129.2,
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128.9, 128.1, 126.6, 126.0, 125.2, 123.0, 35.7, 33.1; IR: 3051, 3011, 2926, 2853, 1736, 1596, 1511,
1467, 1389, 1227, 1170, 1020, 778 cm-1; MS (ESI): m/z 257 (M+H); HRMS: m/z Calcd: 257.0855
(C13H12N4S+H); Found: 257.0869.
5-(Cinnamylthio)-1-methyl-1H-tetrazole (23b, Table 3): Yield: 111 mg (95%), 0.5 mmol reaction
scale; 1H NMR (300 MHz, CDCl3): δ 7.30 (m, 5H), 6.66 (d, 1H, J = 15.6 Hz), 6.33 (p, 1H, J = 15.6,
7.5 Hz), 4.16 (dd, 2H, J = 7.5, 0.7 Hz), 3.91 (s, 3H); C {1H} NMR (75 MHz, CDCl3): δ 153.5,
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135.8, 134.9, 128.5 (2C), 128.0, 126.4 (2C), 122.4, 35.9, 33.3; IR: 3028, 2927, 1734, 1597, 1450,
1389, 1279, 1230, 1171, 967, 752 cm-1; MS (ESI): m/z 233 (M+H); HRMS: m/z Calcd: 233.0855
(C11H12N4S+H); Found: 233.0863.
(E)-5-(3-(4-Methoxyphenyl)allylthio)-1-methyl-1H-tetrazole (24b, Table 3): Yield: 130 mg
(99%), 0.5 mmol reaction scale; 1H NMR (300 MHz, CDCl3): δ 7.29 (d, 2H, J = 8.7 Hz), 6.83 (d, 2H,
J = 8.7 Hz), 6.60 (d, 1H, J = 15.5 Hz), 6.18 (p, 1H, J = 15.5, 7.6 Hz), 4.13 (dd, 2H, J = 7.6, 1.0 Hz),
3.91 (s, 3H), 3.80 (s, 3H); C {1H} NMR (75 MHz, CDCl3): δ 159.5, 153.7, 134.5, 128.6, 127.7
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(2C), 119.9, 113.9 (2C), 55.4, 36.3, 33.4; IR: 2924, 2852, 1725, 1507, 1386, 1250, 1032, 760 cm-1;
MS (ESI): m/z 285 (M+Na); HRMS: m/z Calcd: 285.0781 (C12H14N4OS+Na); Found: 285.0803.
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(E)-1-Methyl-5-(2-methyl-3-phenylallylthio)-1H-tetrazole (25b, Table 3): Yield: 118 mg (96%),
0.5 mmol reaction scale; 1H NMR (300 MHz, CDCl3): δ 7.32 (t, 2H, J = 7.4 Hz), 7.23 (tt, 1H, J = 7.4,
1.2 Hz), 7.21 (d, 2H, J = 7.4 Hz), 6.54 (s, 1H), 4.13 (s, 2H), 3.93 (s, 3H), 2.01 (d, 3H, J = 1.3 Hz); 13C
{1H} NMR (75 MHz, CDCl3): δ 153.7, 136.6, 131.5, 130.4, 128.7 (2C), 128.1 (2C), 126.9, 43.9, 33.4,
16.7; IR: 3059, 3021, 2949, 2792, 1598, 1513, 1354, 1219, 1171, 1037, 757 cm-1; MS (ESI): m/z 247
(M+H); HRMS: m/z Calcd: 247.1012 (C12H14N4S+H); Found: 247.1017.
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5-((2E,4E)-Hexa-2,4-dienylthio)-1-methyl-1H-tetrazole (26b, Table 3): Yield: 192 mg (98%), 1.0
mmol reaction scale; 1H NMR (300 MHz, CDCl3): δ 6.24 (q, 1H, J = 14.9, 10.4 Hz), 5.98 (t, 1H, J =
14.9 Hz), 5.69 (m, 2H), 4.00 (d, 2H, J = 7.5 Hz), 3.90 (s, 3H), 1.72 (d, 3H, J = 6.7 Hz); C {1H}
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NMR (75 MHz, CDCl3): δ 153.7, 135.5, 131.5, 130.0, 122.8, 35.9, 33.4, 18.1; IR: 2926, 1719, 1473,
1391, 1220, 1022, 772 cm-1; MS (ESI): m/z 219 (M+Na); HRMS: m/z Calcd: 219.0675
(C8H12N4S+Na); Found: 219.0688.
1-Methyl-5-((2E,4E)-5-phenylpenta-2,4-dienylthio)-1H-tetrazole (28b, Table 3): Yield: 253 mg
(98%), 1.0 mmol reaction scale; 1H NMR (300 MHz, CDCl3): δ 7.41-7.28 (m, 5H), 6.71 (dd, 1H, J =
15.6, 10.5 Hz), 6.56 (d, 1H, J = 15.6 Hz), 6.47 (dd, 1H, J = 15.6, 10.5 Hz), 5.92 (p, 1H, J = 15.6, 7.6
Hz), 4.08 (dd, 2H, J = 7.6, 0.6 Hz), 3.92 (s, 3H); C {1H} NMR (75 MHz, CDCl3): δ 153.6, 136.7,
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135.5, 133.9, 128.6 (2C), 127.8, 127.2, 126.4 (2C), 126.1, 35.9, 29.6; IR: 2924, 2853, 1721, 1451,
1389, 1171, 1076, 755, 697 cm-1; MS (ESI): m/z 281 (M+Na); HRMS: m/z Calcd: 281.0831
(C13H14N4S+Na); Found: 281.0849.
(E)-1-Methyl-5-(3-(naphthalen-1-yl)allylthio)-1H-tetrazole (30b, Table 3): Yield: 140 mg (99%),
0.5 mmol reaction scale; 1H NMR (300 MHz, CDCl3): δ 8.00 (d, 1H, J = 8.4 Hz), 7.82 (d, 1H, J = 8.7
Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.54-7.46 (m, 4H), 7.42 (t, 1H, J = 7.9 Hz), 6.32 (p, 1H, J = 7.4 Hz),
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4.27 (dd, 2H, J = 7.4, 1.0 Hz), 3.92 (s, 3H); 13C {1H} NMR (75 MHz, CDCl3): δ 153.4, 133.5, 133.3,
132.2, 130.8, 128.3 (2C), 126.1, 125.7, 125.4, 125.3, 123.8, 123.4, 36.0, 33.3; IR: 3052, 2925, 2854,
1741, 1591, 1465, 1390, 1228, 1170, 966, 778 cm-1; MS (ESI): m/z 305 (M+Na); HRMS: m/z Calcd:
305.0831 (C15H14N4S+Na); Found: 305.0846.
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(E)-5-(3,7-Dimethylocta-2,6-dienylthio)-1-methyl-1H-tetrazole (32b, Table 3): Yield: 242 mg
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(96%), 1.0 mmol reaction scale; H NMR (300 MHz, CDCl3): δ 5.38 (td, 1H, J = 8.0, 1.3 Hz), 5.03
(tt, 1H, J = 6.7, 1.3 Hz), 3.98 (d, 2H, J = 8.0 Hz), 3.90 (s, 3H), 2.05 (m, 4H), 1.71 (s, 3H), 1.66 (s,
3H), 1.58 (s, 3H); 13C {1H} NMR (75 MHz, CDCl3): δ 154.2, 143.1, 131.9, 123.4, 116.9, 39.4, 33.4,
31.7, 26.2, 25.6, 17.7, 16.2; IR: 2965, 2924, 2855, 1728, 1663, 1449, 1385, 1277, 1228, 1170, 770
cm-1; MS (ESI): m/z 253 (M+H); HRMS: m/z Calcd: 253.1481 (C12H20N4S+H); Found: 253.1497.
2-(4-Methoxybenzylthio)benzo[d]thiazole10 (4c, Scheme 3): Yield: 238 mg (83%), 1.0 mmol
reaction scale; 1H NMR (300 MHz, CDCl3): δ 7.43 (dd, 1H, J = 7.1, 1.7 Hz), 7.23 (m, 4H), 7.07 (dd,
1H, J = 7.1, 1.7 Hz), 6.82 (d, 2H, J = 8.5 Hz), 5.59 (s, 2H), 3.75 (s, 3H); C {1H} NMR (75 MHz,
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CDCl3): δ 189.9, 159.1, 141.3, 128.5 (2C), 127.5, 126.8 (2C), 126.3, 124.7, 121.2, 114.2, 113.0, 55.2,
48.9; IR: 2925, 1679, 1511, 1366, 1254, 1026, 741 cm-1; MS (ESI): m/z 288 (M+H).
2-(3,4-Dimethoxybenzylthio)benzo[d]thiazole (14c, Scheme 3): Yield: 253 mg (80%), 1.0 mmol
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reaction scale; H NMR (300 MHz, CDCl3): δ 7.89 (d, 1H, J = 8.1 Hz), 7.72 (d, 1H, J = 7.7 Hz),
7.45-7.25 (m, 2H), 7.07 (d, 1H, J = 8.3 Hz), 6.83 (dd, 2H, J = 8.3, 6.6 Hz), 4.54 (s, 2H), 3.77 (s, 6H);
13C {1H} NMR (75 MHz, CDCl3): δ 153.0, 148.9, 148.6, 135.2, 128.4, 127.0, 126.0, 124.2, 121.4
(2C), 120.9, 112.2, 111.1, 55.8, 55.8, 37.7; IR: 3003, 2964, 2933, 2841, 1703, 1588, 1460, 1421,
1260, 1025, 761 cm-1; MS (ESI): m/z 340 (M+Na); HRMS: m/z Calcd: 340.0436 (C16H15NO2S2+Na);
Found: 340.0443.
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2-(Cinnamylthio)benzo[d]thiazole (23c, Scheme 3): Yield: 210 mg (74%), 1.0 mmol reaction scale;
1H NMR (300 MHz, CDCl3): δ 7.88 (d, 1H, J = 8.1 Hz), 7.76 (d, 1H, J = 7.9 Hz), 7.50-7.17 (m, 7H),
6.68 (t, 1H, J = 15.8 Hz), 6.43-6.21 (m, 1H), 4.16 (d, 2H, J = 7.3 Hz); C {1H} NMR (75 MHz,
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CDCl3): δ 166.1, 153.1, 136.2, 134.2, 133.5, 128.5 (2C), 127.8, 126.5, 126.4, 125.9, 124.2, 123.4,
121.4, 120.9, 36.0; IR: 3028, 2967, 2929, 1726, 1458, 1426, 1280, 1152, 995, 751 cm-1; MS (ESI):
m/z 284 (M+H).
Corresponding Author
*C/O Dr. U.V. Mallavadhani, Principal Scientist, Natural Products Chemistry Division, Indian
Institute of Chemical Technology, Taranaka, Hyderabad, Telangana. India-500007. Corresponding
author: E-Mail: cbrchem@gmail.com.
ACKNOWLEDGMENT
The authors are thankful to CSIR, New Delhi for the financial support and thankful to the Director,
IICT for constant encouragement.
ASSOCIATED CONTENT
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13
Supporting Information. NMR, IR and Mass spectral data of all compounds, H and CNMR copies
of all compounds are available in supplementary information. This material is available free of charge
via the Internet at http://pubs.acs.org/
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