Zinc-mediated facile and efficient chemoselective s-alkylation of 5-aryl-1,3,4-oxadiazole-2-thiols in the absence of base

Article abstract of DOI:10.1080/00397910903340660

Zinc-mediated facile and efficient chemoselective S-alkylation of 5-aryl 1,3,4-oxadiazole-2-thiols in the presence of a catalytic amount of tetra butyl ammonium iodide was described. The reaction was performed under neutral conditions. The chemoselectivity of the alkylation was confirmed by NMR spectroscopy and x-ray crystallography.

Full text of DOI:10.1080/00397910903340660

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Zinc-Mediated Facile and Efficient
Chemoselective S-Alkylation of 5-
Aryl-1,3,4-oxadiazole-2-thiols in the
Absence of Base
M. S. R. Murty a , Rayudu Venkateswara Rao a , Kesur R. Ram a , N.
Rami Reddy a , J. S. Yadav a & B. Sridhar b
a Organic Chemistry Division I, Indian Institute of Chemical
Technology, Hyderabad, India
b Laboratory of X-ray Crystallography, Indian Institute of Chemical
Technology, Hyderabad, India
Published online: 25 Aug 2010.
To cite this article: M. S. R. Murty , Rayudu Venkateswara Rao , Kesur R. Ram , N. Rami Reddy ,
J. S. Yadav & B. Sridhar (2010) Zinc-Mediated Facile and Efficient Chemoselective S-Alkylation
of 5-Aryl-1,3,4-oxadiazole-2-thiols in the Absence of Base, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:19, 2914-2921,
DOI: 10.1080/00397910903340660
To link to this article: http://dx.doi.org/10.1080/00397910903340660
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Synthetic Communications1, 40: 2914–2921, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903340660
ZINC-MEDIATED FACILE AND EFFICIENT
CHEMOSELECTIVE S-ALKYLATION OF
5-ARYL-1,3,4-OXADIAZOLE-2-THIOLS IN THE
ABSENCE OF BASE
M. S. R. Murty,1 Rayudu Venkateswara Rao,1 Kesur R. Ram,1
N. Rami Reddy,1 J. S. Yadav,1 and B. Sridhar2
1Organic Chemistry Division I, Indian Institute of Chemical Technology,
Hyderabad, India
2Laboratory of X-ray Crystallography, Indian Institute of Chemical
Technology, Hyderabad, India
Zinc-mediated facile and efficient chemoselective S-alkylation of 5-aryl 1,3,4-oxadiazole-2-
thiols in the presence of a catalytic amount of tetra butyl ammonium iodide was described.
The reaction was performed under neutral conditions. The chemoselectivity of the
alkylation was confirmed by NMR spectroscopy and x-ray crystallography.
Keywords: Alkylation; chemoselectivity; oxadiazole; piperazines; zinc
INTRODUCTION
The 1,3,4-oxadiazole derivatives are useful in the fields of medicinal and
pesticide chemistry as well as in polymer science.[1–4] The 1,3,4-oxadiazole ring is
associated with many types of biological activities such as HIV integrase inhibi-
tory,[5] anti-inflammatory,[6–8] antibacterial and antifungal,[9–11] and hypoglycemic[12]
activities. In particular, mercapto substituted-1,3,4-oxadiazole derivatives are found
to show anti-hepatitis B virus (HBV) activity.[13]
N-Arylpiperazines are considered ‘‘privileged’’ templates in drug discovery.[14]
Piperazines are important pharmacophores found in many drugs, such as the Merck
HIV protease inhibitor Crixivan.[15] Aryl piperazines are regarded as potential
therapeutics for anxiety and depression.[16]
The S-alkylation of 5-substituted-1,3,4-oxadiazole-2-thiols has been
reported with various bases such as K2CO3,[17] NaOH,[18] KOH,[19] Et3N,[20]
NaOMe,[21] and NaOAc.[22] The synthetic utility of zinc is well established in
the literature for various chemical reactions. Zinc has drawn the attention of
many researchers because it is easily availabile, inexpensive, and nontoxic.[23]
As a part of our continuing efforts to develop simple, efficient, economical,
Received June 12, 2009.
Address correspondence to M. S. R. Murty, Organic Chemistry Division I, Indian Institute of
Chemical Technology, Hyderabad 500 607, India. E-mail: msrmurty@ymail.com
2914

SYNTHESIS OF 5-ARYL-2-S-ALKYLATED-1,3,4-OXADIAZOLE
2915
and environmentally benign synthetic methods using zinc dust,[24] we have
demonstrated a convenient zinc-mediated method for the S-alkylation of
5-aryl-1,3,4-oxadiazole-2-thiol with 1-(3-chloropropyl)-4-substituted piperazines
in the absence of base.
RESULTS AND DISCUSSION
We have carried out zinc-mediated S-alkylation of 5-aryl-1,3,4-
oxadiazole-2-thiols with 1-(3-chloropropyl)-4-substituted piperazines in the
absence of base (Scheme 1). The products were obtained in excellent yields
and high purity.
The oxadiazole thiol was alkylated with 1-(3-chloropropyl)-4-substituted
piperazines using K2CO3 and a catalytic quantity of tetra butyl ammonium iod-
ide (TBAI), which in acetonitrile solvent gave the product in good yield. The
same reaction in the presence of zinc dust did not form the alkylated product.
Equimolar quantities of various 5-substituted-1,3,4-oxadiazole-2-thiols were
reacted with 1-(3-chloropropyl)-4-substituted piperazines in the presence of zinc
dust and catalytic amounts of TBAI in tetrahydrofuran (THF) solvent, which
produced exclusively the S-alkylated product in excellent yield with high purity
(Table 1). The reaction was also investigated for the possibility of using zinc
dust in catalytical or less than stoichiometric quantities. High yields of the pro-
ducts with excellent purity were obtained with 1 equivalent of zinc dust. The
products were characterized by their spectral data. The 1H NMR spectrum is
the indicative for the determination of the S-alkylated isomer. The 1H NMR
of the compound in entry 5 showed a chemical shift at d 3.37, which is typi-
cal[25] for S-CH2 protons.
X-ray crystallography was undertaken on a representative compound
(entry 5) to further confirm the structural isomer. A crystal of compound
(entry 5) was grown by slow evaporation from hexane and the chloroform
mixture, and the S-alkylated isomer was proved by single-crystal x-ray analysis
of the compound (entry 5, Fig. 1).
The reusability of zinc dust was studied for entries 3 and 8 (Table 2). The zinc
dust was reactivated and reused in further runs, and no remarkable loss in activity
was observed. (Used zinc was treated with 10% HCl, washed with water and acetone,
and dried in an oven for 2 h at 120–130 ꢀC.) This makes the process more
economical.
Scheme 1. Synthesis of 5-aryl-2-S-alkylated-1,3,4-oxadiazole.

2916
M. S. R. MURTY ET AL.
Table 1. 5-Substituted-2-[3-(4-arylpiperazinyl)] propylthio-1,3,4-oxadiazoles
Oxadiazole
thiol
Time Yield
(min) (%)b
Entry
Piperazine
Producta
1
2
3
X ¼ o-Me
X ¼ p-Me
X ¼ p-Cl
X ¼ o-Me, Y ¼ Ph
X ¼ p-Me, Y ¼ Ph
X ¼ p-Cl, Y ¼ Ph
55
55
45
85
95
90
4
5
6
X ¼ o-Me
X ¼ p-Me
X ¼ p-Cl
X ¼ o-Me, Y ¼
X ¼ p-Me, Y ¼
X ¼ p-Cl, Y ¼
50
40
40
88
92
90
7
8
9
X ¼ o-Me
X ¼ p-Me
X ¼ p-Cl
X ¼ o-Me, Y ¼ Bn
X ¼ p-Me, Y ¼ Bn
X ¼ p-Cl, Y ¼ Bn
60
60
55
84
88
90
aAll products were characterized by 1H NMR, ESI-HRMS, and IR spectroscopy.
bIsolated yields after column chromatography.
Figure 1. X-ray crystal structure (entry 5). Displacement ellipsoids are drawn at the 30% probability level,
and H atoms are shown as small spheres of arbitrary radii.
Table 2. Recyclability studies of zinc dust for entries 3 and 8
Run
Yield (%) of 3
Yield (%) of 8
1
2
3
4
5
90
87
86
84
84
88
88
85
82
82

SYNTHESIS OF 5-ARYL-2-S-ALKYLATED-1,3,4-OXADIAZOLE
2917
CONCLUSION
In conclusion, we have demonstrated an easy, convenient, and highly efficient
approach for the chemoselective synthesis of 5-aryl-2-S-alkylated-1,3,4-oxadiazole
derivatives. The reaction was performed using zinc dust as a recyclable catalyst with
a catalytic amount of TBAI under neutral conditions. The products were obtained in
good yields with excellent purity, and the workup is easy, thus making the process
simple, economical, environmentally benign, and useful in organic synthesis.
EXPERIMENTAL
Melting points were determined on a Buchi capillary melting-point apparatus.
The 1H NMR (200MHz and 300 MHz) were recorded on Varian Gemini and Bruker
Avance spectrometers using tetramethylsilane (TMS) as an internal standard. Electro-
spray ionization–mass spectra (EIS-MS) were recorded on an Agilent Technologies
LC=MSD SL single quadrupole (Agilent ChemStation software). High-resolution
mass spectra (HRMS) were recorded on a high-resolution QSTAR XL hybrid MS=
MS system (Applied Biosystems) under ESI conditions with sample solutions prepared
in MeOH. Infrared (IR) spectra were recorded on a Perkin-Elmer IR 683.
X-Ray Crystallographic Analysis
The crystal system was monoclinic, and the space group was P21=c. The unit
˚
˚
˚
cell dimension were as follows: a ¼ 12.2372(10) A, b ¼ 10.3618(9) A, c ¼ 14.4945 A,
and b ¼ 105.853(1)ꢀ. Data collection yielded 19845 reflections, resulting in 3741
unique, averaged reflections, 2761 with I > 2r(I), and h range: 1.73–25.00ꢀ. The
structure was solved by direct methods using SHELXS-97[26] and refined by
full-matrix least-squares refinement using SHELXL-97[26], leading to a final
R ¼ 0.0472, wR ¼ 0.1182, and GOF ¼ 1.034. Intensity data were measured on a
Bruker Smart Apex with CCD area detector. CCDC 713379 contains supplementary
crystallographic data for the structure.
Typical Procedure for the Synthesis of 2-[3-(4-
(4-Fluorophenyl)piperazinyl)] Propylthio-5-[4-methylphenyl]-
1,3,4-oxadiazoles (Entry 5)
In a typical procedure, 5-(4-methylphenyl)-1,3,4-oxadiazole-2-thiol (1.0 g,
5.2 mmol) and 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine (1.39 g, 5.2 mmol)
were taken in THF (20 ml) and mixed well for 5 min. Zinc dust (0.34 g, 5.2 mmol)
and a catalytic amount of TBAI (0.0192 g, 0.052 mmol) were added. The reaction
mixture was refluxed for 40 min. After completion, the reaction mixture was filtered,
and the solid was washed with THF (2 ꢁ 5 ml). The combined filtrate was concen-
trated, and the product was purified by flash-column chromatography.
Characterization Data for the Products, Entries 1–9
Entry 1. Brown viscous liquid; 1H NMR (CDCl3, 200 MHz) d: 7.85 (d,
J ¼ 7.3 Hz,1H), 7.45–7.12 (m, 5H), 6.92–6.72 (m, 3H), 3.38 (t, J ¼ 7.3 Hz, 2H),

2918
M. S. R. MURTY ET AL.
3.24–3.10 (m, 4H), 2.69 (s, 3H), 2.67–2.51 (m, 6H), 2.09 (quintet, J ¼ 7.3 Hz, 2H). IR
(KBr): 3059, 2930, 2818, 1598, 1548, 1470, 1380, 1234, 1188, 1133, 1041, 998, 951,
761, 725, 692 cmꢂ1; ESI-MS: m=z 395.0 (M þ 1).
Entry 2. Light yellow solid; mp 90–92 ꢀC; 1H NMR (CDCl3, 200 MHz) d: 7.87
(d, J ¼ 7.8 Hz, 2H), 7.30–7.13 (m, 4H), 6.90–6.73 (m, 3H), 3.37 (t, J ¼ 7.0 Hz, 2H),
3.22–3.11 (m, 4H), 2.65–2.50 (m, 6H), 2.42 (s, 3H), 2.08 (quintet, J ¼ 7.0 Hz, 2H).
IR (KBr): 3026, 2923, 2817, 1569, 1501, 1472, 1291, 1235, 1179, 1064, 951, 824,
754, 692 cmꢂ1; ESI-MS: m=z 395.0 (M þ 1); ESI-HRMS for C22H26N4OS: found:
394.1840; calcd: 394.1827.
Entry 3. White solid; mp 113–115 ꢀC; 1H NMR (CDCl3, 200 MHz) d: 7.94 (d,
J ¼ 8.8 Hz, 2H), 7.46 (d, J ¼ 8.8 Hz, 2H), 7.26–7.14 (m, 2H), 6.90–6.75 (m, 3H), 3.39
(t, J ¼ 6.6 Hz, 2H), 3.24–3.13 (m, 4H), 2.73–2.53 (m, 6H), 2.11 (quintet, J ¼ 6.6 Hz,
2H). IR (KBr): 3047, 2938, 1598, 1462, 1238, 1190, 1008, 847, 753 cmꢂ1; ESI-MS:
m=z 416 (M þ 1). ESI-HRMS for C21H23N4OSCl: found: 414.9498; calcd: 414.9500.
Entry 4. Yellow oily liquid; 1H NMR (CDCl3, 300 MHz) d: 7.87 (d, J ¼ 7.6 Hz,
1H), 7.42–7.26 (m, 3H), 6.97–6.77 (m, 4H), 3.38(t, J ¼ 6.8 Hz, 2H), 3.14–3.04 (m, 4H),
2.71 (s, 3H), 2.65–2.50 (m, 6H), 2.10 (quintet, J ¼ 6.8 Hz, 2H). IR (KBr): 2930, 2817,
1604, 1548, 1509, 1470, 1381, 1231, 1189, 1042, 1002, 951, 821, 771, 724, 671 cmꢂ1
;
ESI-MS: m=z 413 (M þ 1).
Entry 5. White solid; mp 131–133 ꢀC; 1H NMR (CDCl3, 300 MHz) d: 7.88 (d,
J ¼ 7.6 Hz, 2H), 7.26 (d, J ¼ 7.6 Hz, 2H), 6.94–6.86 (m, 2H), 6.85–6.78 (m, 2H), 3.37
(t, J ¼ 6.8 Hz, 2H), 3.13–3.03 (m, 4H), 2.64–2.50 (m, 6H) 2.43 (s, 3H), 2.08 (quintet,
J ¼ 6.8 Hz, 2H). IR (KBr): 2947, 2818, 1612, 1508, 1473, 1238, 1179, 1063, 828,
720 cmꢂ1; ESI-MS: m=z 413.2 (M þ 1); ESI-HRMS for C22H26N4OFS: found
413.1806; calcd. 413.1811.
1
Entry 6. Pale yellow solid; mp 133–134 ꢀC; H NMR (CDCl3, 200 MHz) d:
7.94 (d, J ¼ 8.5 Hz, 2H), 7.46 (d, J ¼ 8.5 Hz, 2H), 6.96–6.78 (m, 4H), 3.38 (t,
J ¼ 7.0 Hz, 2H), 3.15–3.06 (m, 4H), 2.67–2.53 (m, 6H), 2.08 (quintet, J ¼ 7.0 Hz,
2H). IR (KBr): 3089, 2938, 2818, 2776, 1603, 1510, 1459, 1356, 1238, 1184, 1087,
1007, 951, 816, 721, 693 cmꢂ1; ESI-MS: m=z 432.8 (M þ 1). ESI-HRMS for
C21H22ClFN4OS: found 432.1193; calcd. 432.1187.
Entry 7. Brown viscous liquid; 1H NMR (CDCl3, 200 MHz) d: 7.86 (d,
J ¼ 6.8 Hz, 1H), 7.40–7.15 (m, 8H), 3.47 (s, 2H), 3.34 (t, J ¼ 6.8 Hz, 2H), 2.71 (s,
3H), 2.54–2.39 (m, 10H), 2.04 (quintet, J ¼ 6.8 Hz, 2H). IR (KBr): 3060, 2937,
2810, 1605, 1550, 1471, 1350, 1189, 1156, 1042, 1007, 950, 729, 700 cmꢂ1; ESI-MS:
m=z 409.0 (M þ 1); ESI-HRMS for C23H28N4OS: found 408.1997; calcd. 408.1983.
1
Entry 8. Brown solid; mp 54–56 ꢀC. H NMR (CDCl3, 300 MHz) d: 7.84 (d,
J ¼ 8.3 Hz, 2H), 7.31–7.15 (m, 7H), 3.49 (s, 2H), 3.31 (t, J ¼ 7.6 Hz, 2H), 2.58–2.42
(m, 10H), 2.39 (s, 3H), 2.03 (quintet, J ¼ 7.6 Hz, 2H). IR (KBr): 3028, 2941, 2803,
2768, 1962, 1654, 1613, 1556, 1468, 1407, 1344, 1286, 1179, 1136, 1066, 1006, 940,
821, 738, 694 cmꢂ1; ESI-MS: m=z 409 (M þ 1).
Entry 9. Light yellow solid; mp 68–69 ꢀC. 1H NMR (CDCl3, 200 MHz) d: 7.93
(d, J ¼ 8.3 Hz, 2H), 7.45 (d, J ¼ 8.3 Hz, 2H), 7.32–7.15 (m, 5H), 3.48 (s, 2H), 3.34

SYNTHESIS OF 5-ARYL-2-S-ALKYLATED-1,3,4-OXADIAZOLE
2919
(t, J ¼ 6.8 Hz, 2H), 2.56–2.36 (m, 10H), 2.03 (quintet, J ¼ 6.8 Hz, 2H). IR (KBr):
2922, 2803, 1605, 1470, 1403, 1089, 830, 727 cmꢂ1; ESI-MS: m=z 429.8 (M þ 1);
ESI-HRMS for C22H25ClN4OS: found 429.1500; calcd. 429.1515.
ACKNOWLEDGMENT
R. V. R., K. R. R., and N. R. R are grateful to the Council of Scientific and
Industrial Research (CSIR), New Delhi, India, for the research fellowships.
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