Efficient and novel synthesis of benzoxazole derivatives in the presence of zinc dust under solvent-free conditions

Article abstract of DOI:10.1080/00397910903320621

A mild and efficient method has been developed for the synthesis of 2-cyclic amine-substituted benzoxazole derivatives using zinc dust under microwave irradiation in the absence of solvent is described. A comparative study was performed under conventional and microwave heating conditions. Zinc dust can be reused several times after reactivation. The significant feature of this method is the isolation of the pure product by simple workup in a short reaction time with high purity.

Full text of DOI:10.1080/00397910903320621

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Efficient and Novel Synthesis of
Benzoxazole Derivatives in the Presence
of Zinc Dust Under Solvent-Free
Conditions
M. S. R. Murty a , Kesur R. Ram a , Rayudu Venkateswara Rao a & J.
S. Yadav a
a Organic Chemistry Division I , Indian Institute of Chemical
Technology , Hyderabad, India
Published online: 25 Aug 2010.
To cite this article: M. S. R. Murty , Kesur R. Ram , Rayudu Venkateswara Rao & J. S. Yadav (2010)
Efficient and Novel Synthesis of Benzoxazole Derivatives in the Presence of Zinc Dust Under Solvent-
Free Conditions, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:19, 2844-2849, DOI: 10.1080/00397910903320621
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Synthetic Communications1, 40: 2844–2849, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903320621
EFFICIENT AND NOVEL SYNTHESIS OF BENZOXAZOLE
DERIVATIVES IN THE PRESENCE OF ZINC DUST
UNDER SOLVENT-FREE CONDITIONS
M. S. R. Murty, Kesur R. Ram, Rayudu Venkateswara Rao,
and J. S. Yadav
Organic Chemistry Division I, Indian Institute of Chemical Technology,
Hyderabad, India
A
mild and efficient method has been developed for the synthesis of 2-cyclic
amine-substituted benzoxazole derivatives using zinc dust under microwave irradiation in
the absence of solvent is described. A comparative study was performed under conventional
and microwave heating conditions. Zinc dust can be reused several times after reactivation.
The significant feature of this method is the isolation of the pure product by simple workup
in a short reaction time with high purity.
Keywords: Benzoxazole; cyclic amine; microwave; solvent free; zinc dust
INTRODUCTION
Benzoxazole derivatives are biologically significant compounds and known to
exhibit various biological activities such as anticancer,[1,2] antimicrobial,[1,3]
anti-HIV,[3] and dopamine D4 agonists.[4] The substitution at second position in
the benzoxazole skeleton is influential for the biological activity of the molecule.
Similarly, several nitrogen heterocycles containing piperazine moieties have been
described as potent chemotherapeutic agents. This cyclic amine moiety is also found
in drug candidates displaying antiallergic,[5] antibacterial,[6] antianxiety, antiemetic,
antimigraine,[7] and anti-inflammatory[8,9] activities.
Microwave reactions under solvent-free conditions have attracted much
attention in organic synthesis. They possess many advantages over conventional
methods such as milder reaction conditions, shorter reaction times, simple workup,
and excellent yields.[10,11] They are environmentally benign and economical.
In recent times, metal- and metal-salt-catalyzed reactions have been extensively
studied because of their reusability and easy workup. Among them, zinc[12] has
drawn the attention of many researchers because it is easily available, inexpensive,
and nontoxic. Recently, we reported Zn-dust-promoted alkylation[13] and sulfonyla-
tion[14] of amines.
Received May 30, 2009.
Address correspondence to M. S. R. Murty, Organic Chemistry Division I, Indian Institute of
Chemical Technology, Hyderabad 500607, India. E-mail: msrmurty@ymail.com
2844

SYNTHESIS OF BENZOXAZOLE DERIVATIVES
2845
As a part of our project work on the synthesis of biomolecules, the pharmaco-
logical potency of cyclic amines (e.g., piperazines, morpholine, and piperadine) as
well as the biological activity of benzoxazole analogs has drawn our attention to
the synthesis of new cyclic amine-substituted benzoxazole derivatives. Because of
their importance, it is essential to develop an efficient and economical method for
the synthesis of cyclic amine-substituted benzoxazoles. In the present article, we
report the application of zinc dust as a reusable reagent in the synthesis of 2-cyclic
amine-substituted benzoxazoles under microwave irradiation conditions in the
absence of a solvent. Zinc dust can be reused after activation.
DISCUSSION
2-Chlorobenzoxazole[15] was treated with various cyclic amines (Table 1) under
conventional and microwave irradiation conditions. In the conventional procedure,
ꢀ
2-chlobenzoxazole was treated with various cyclic amines in acetonitrile at 0 C to
Table 1. Synthesis of 2-cyclic amine substituted benzoxazoles
Yield (%)b
Reaction time
Conventional MW
(Min)
Entry
Cyclic amine
2-Cyclic amine-benzoxazolea
Conventional MW
(Sec)
1
70
87
30
65
2
3
4
65
75
80
89
92
90
45
35
40
70
60
55
5
6
78
68
94
96
50
50
70
60
(Continued )

2846
M. S. R. MURTY ET AL.
Table 1. Continued
Yield (%)b
Reaction time
Conventional MW
(Min)
Entry
7
Cyclic amine
2-Cyclic amine-benzoxazolea
Conventional MW
(Sec)
78
85
95
97
30
60
8
9
35
35
55
50
82
69
96
88
10
50
75
11
12
74
70
95
85
45
55
60
70
aAll the products were characterized by 1H NMR, IR and mass spectroscopy.
bIsolated and optimized yields.
obtain the product for an appropriate time as mentioned in Table 1. The presence of
zinc dust did not improve the reaction time or yield of the product. When the reac-
tion was carried out under microwave irradiation, the product was obtained with less
purity in poor yield in the absence of zinc dust. The microwave irradiation experi-
ments were carried out using a focused microwave instrument, Discover (CEM)
model, at 2450 MHz and 450 W. Improvement in yields was not obtained even by
increasing the irradiation time and voltage. On other hand, when the reaction was
Scheme 1. Synthesis of 2-cyclic amine substituted benzoxazoles (1). X ¼ N-Me, N-Et, N-benzyl, N-phenyl,
CH2, O, N-pyridyl, N-pyrimidyl, N-(3-chlorophenyl), N-(2-hydroxyethyl). entry 10: 2-(30-methylpiperazine)-
benzoxazole. entry 11: 2-homopiperazinyl benzoxazole.

SYNTHESIS OF BENZOXAZOLE DERIVATIVES
2847
Table 2. Recyclability studies of Zn dust for 1c and 1g under microwave conditions
Compound
Parameter
Run 1
Run 2
Run 3
Run 4
Run 5
1c
Time (s)
Yield (%)
Time (s)
Yield (%)
60
92
60
95
65
92
70
95
80
90
75
93
90
89
85
90
120
85
1g
100
87
carried out under microwave conditions in the presence of activated zinc, the pro-
duct was obtained in excellent yield with high purity, and the reaction time decreased
from minutes to seconds. This is a remarkable achievement over the existing conven-
tional method. We also investigated the possibility of using zinc dust in catalytical or
less than stoichiometric quantities. However, excellent yields of the products with
good purity were obtained with 1 equivalent of zinc dust (for compound 1h: with
0.25 mmol, 55%; with 0.5 mmol, 67%; with 0.75 mmol, 85%; with 1 mmol, 97%;
with 1.5 mmol, 97%). A mixture of 2-chlorobenzoxazole and cyclic amine was sub-
jected to microwave irradiation in the presence of zinc dust for an appropriate time
as described in Table 1 (Scheme 1). The reaction is remarkably fast and led to very
good yields of the products with good purity. Comparison of the yields and the
reaction times under conventional and microwave condition are listed in Table 1.
Reusability of zinc dust under microwave conditions was also studied for 1c
and 1g (Table 2). The zinc dust was reactivated[16] and used for subsequent runs.
It showed nearly the same activity after each use. This makes the process more
economical.
In conclusion, the synthesis of 2-cyclic amine benzoxazole derivatives was
achieved with good conversion in a short reaction time using zinc dust under
solvent-free microwave irradiation. The advantage of the present method over the
conventional methods is the use of zinc dust as a recyclable catalyst. This is remark-
able and makes the method environmentally friendly and economically valuable.
EXPERIMENTAL
Melting points were determined on a Buchi capillary melting-point apparatus.
The 1H NMR spectra were recorded on Varian Gemini 200-MHz spectrometer using
tetramethylsilane (TMS) as an internal standard. Mass spectra were recorded on a
VG Auto Spec mass spectrometer, and infrared (IR) spectra were recorded on a
Fourier transform (FT)–IR Perkin-Elmer 1310 spectrometer using KBr pellets.
Elemental analyses were performed on an Elementar Vario EL elemental analyzer.
Synthesis of 2[4[2-Pyrimidyl]-piperizinyl]-benzoxazole (1h) as a
Typical Procedure
Conventional procedure. The 2-chlorobenzoxazole (1 mmol, 150 mg) was
added to a solution of 1-(2-pyrimidyl) piperazine (1 mmol, 165 mg) in dry acetonitrile
(10 ml) at 0 ꢀC. The mixture was stirred at 0 ꢀC–rt for 35 min, quenched in ice water
(20 ml), extracted with ethyl acetate (3 ꢁ 20 ml), and dried over Na2SO4. After

2848
M. S. R. MURTY ET AL.
concentration, the residue was purified by flash chromatography to obtain the pure
product and was crystallized from methanol.
Microwave procedure. The 2-chlorobenzoxazole (1 mmol, 150 mg) was
added to a mixture of 1-(2-pyrimidyl) piperazine (1 mmol, 165 mg) and activated zinc
dust (1 mmol, 65 mg). The mixture was subjected to microwave irradiation at 450 W
for 55 s. The experiment was performed in a 10-mL pressure tube. After the reaction
was completed in the stipulated time (see Table 1), ethyl acetate was added to the
reaction mixture, and the zinc dust was filtered off and washed with ethyl acetate.
The combined organic layer was concentrated, and the residue was purified by flash
chromatography and crystallized from methanol to obtain the pure product: mp
183–185 ꢀC; IR (KBr) n (cmꢂ1): 2911, 2860, 1651, 1581, 1542, 1490, 1451, 1393.
1H NMR (200 MHz, CDCl3) d: 3.76 (t, 4H, J ¼ 5.9 Hz); 3.99 (t, 4H, J ¼ 5.9 Hz);
6.51 (t, 1H, J ¼ 5.0 Hz); 6.99 (t, 1H, J ¼ 7.6 Hz); 7.13 (t, 1H, J ¼ 7.6 Hz); 7.23 (d,
1H, J ¼ 7.6 Hz); 7.33 (d, 1H, J ¼ 7.6 Hz); 8.30 (d, 1H, J ¼ 5.0 Hz). EIMS (m=z):
281 (Mþ). Anal. calcd. for C15H15N5O (281): C, 64.04; H, 5.37; N, 24.89. Found:
C, 64.08; H, 5.41; N, 24.94. IR (n, cmꢂ1) and 1H NMR (d, ppm) spectroscopic data
of the representative compounds are given next.
Selected Data
Compound 1f. Mp 205–206 ꢀC; IR (KBr) n 3057, 2966, 2920, 2863, 1637,
1
1578, 1525, 1454, 1398. H NMR (200 MHz, CDCl3) d: 3.64 (t, 4H, J ¼ 4.5 Hz);
3.77 (t, 4H, J ¼ 4.5 Hz); 6.98 (t, 1H, J ¼ 7.9 Hz); 7.13 (t, 1H, J ¼ 7.9 Hz); 7.21 (d,
1H, J ¼ 7.9 Hz); 7.32 (d, 1H, J ¼ 7.9 Hz). EIMS (m=z): 204 (Mþ). Anal. calcd. for
C11H12N2O2 (204): C, 64.69; H, 5.92; N, 13.72. Found: C, 64.63; H, 5.94: N, 13.66.
Compound 1g. Mp 186–188 ꢀC; IR (KBr) n 2993, 2917, 2846, 1635, 1576,
1
1480, 1459, 1435. H NMR (200 MHz, CDCl3) d: 3.70 (m, 4H); 3.81 (m, 4H); 6.64
(m, 2H); 6.99 (t, 1H, J ¼ 7.7 Hz); 7.13 (t, 1H, J ¼ 7.7 Hz); 7.23 (d, 1H, J ¼ 7.7 Hz);
7.33 (d, 1H, J ¼ 7.7 Hz); 7.47 (m, 1H); 8.17(m, 1H). EIMS (m=z): 280 (Mþ). Anal.
calcd. for C16H16N4O (280): C, 68.55; H, 5.75; N, 19.99. Found: C, 68.59; H,
5.78; N, 19.93.
Compound 1j. Mp 51–52 ꢀC; IR (KBr) n 3321, 3057, 2958, 2921, 2856, 1638,
1
1578, 1458, 1400. H NMR (200 MHz, CDCl3) d: 1.11 (d, 3H, J ¼ 8.3 Hz); 1.80 (s,
1H); 2.71 (t, 1H, J ¼ 8.3 Hz); 2.91 (t, 2H, J ¼ 9.0 Hz); 3.07 (t, 2H, J ¼ 9.0 Hz); 4.11
(d, 2H, J ¼ 11.3 Hz); 6.95 (t, 1H, J ¼ 7.6 Hz); 7.11 (t, 1H, J ¼ 7.6 Hz); 7.19 (d, 1H,
J ¼ 7.6 Hz); 7.30 (d, 1H, J ¼ 7.6 Hz). EIMS (m=z): 217 (Mþ). Anal. calcd. for
C12H15N3O (217): C, 66.34; H, 6.96; N, 19.34. Found: C, 66.36; H, 6.99; N, 19.28.
ACKNOWLEDGMENT
K. R. R. and R. V. R thank the Council of Scientific and Industrial Research
(CSIR, New Delhi, India) for the award of fellowships.

SYNTHESIS OF BENZOXAZOLE DERIVATIVES
2849
REFERENCES
1. Kumar, D.; Jacob, M. R.; Reynoldsa, M. B.; Kerwina, S. M.; Kumar, D.; Jacob, M. R.;
Reynoldsa, M. B.; Kerwina, S. M. Synthesis and evaluation of anticancer benzoxazoles
and benzimidazoles related to UK-1. Bioorg. Med. Chem. 2002, 10, 3997–4004.
2. Easmon, J.; Puerstinger, G.; Roth, T.; Fiebig, H. H.; Jenny, V.; Jaeger, W.; Heinsch, G.;
Hofmann, J. 2-Benzoxazolyl and 2-benzimidazolyl hydrazones derived from 2-acetylpyr-
idine: A novel class of antitumor agents. Int. J. Cancer. 2001, 94, 89–96.
3. Temiz-Arpacı, O.; Ozdemir, A.; Yalcin, I.; Yıldız, I.; Akı-Sener, E.; Altanlar, N. Synthesis
and antimicrobial activity of some 5-[2-(morpholin-4-yl)acetamido] and=or 5-[2-(4-
substituted piperazin-1-yl)acetamido]-2-(p-substituted phenyl)benzoxazoles. Arch. Pharm.
2005, 338, 105–111.
4. Wang, X.; Bhatia, P. A.; Daanen, J. F.; Latsaw, S. P.; Rohde, J.; Kolasa, T.; Hakeem,
A. A.; Matulenko, M. A.; Nakane, M.; Uchic, M. E.; Miller, L. N.; Chang, R.; Moreland,
R. B.; Brioni, J. D.; Stewart, A. O. Synthesis and evaluation of 3-aryl piperidine analogs
as potent and efficacious dopamine D4 receptor agonists. Bioorg. Med. Chem. 2005, 13,
4667–4678.
5. Piwinski, J. J.; Wong, J.; Green, M. J.; Seidl, V.; Friary, R. Pyridine and pyridine N-oxide
derivatives of diaryl methyl piperidines or piperazines, and compositions and methods of
use thereof. US Patent 5432175, 1995; Chem. Abstr. 1995, 123, 228218.
6. Antoine, M.; Barreau, M.; Desconclois, J. F.; Girard, P.; Picaut, G. Benzo[1,8]naphthyr-
idine derivatives, their preparation, and compositions containing them. US Patent
5053509, 1991; Chem. Abstr. 1992, 116, 6538.
7. Castro Pineiro, J. L.; Chambers, M. S.; Hobbs, S. C.; Reeve, A. J.; Showell, G. A.; Street,
L. J.; Matassa, V. G. Piperazine, piperidine, and tetrahydropyridine derivative of indol-3-
alkyl as 5-HT1D-a agonists. US Patent 5807857, 1998; Chem. Abstr. 1996, 124, 232488.
8. Dogruer, D. S.; Unlu, S.; Sahin, M. F.; Yqilada, E. Anti-nociceptive and anti-
inflammatory activity of some (2-benzoxazolone-3-yl and 2-benzothiazolone-3-yl) acetic
acid derivatives. Farmaco. 1998, 53, 80–84.
9. Gulcan, H. O.; Kupeli, E.; Unlu, S.; Yesilada, E.; Sahin, M. F. 4-(5-Chloro-2(3H)-
benzoxazolon-3-yl) butanoic acid derivatives: Synthesis, antinociceptive, and
anti-inflammatory properties. Arch. Pharm. 2003, 336, 477–482.
10. Paul, S.; Nanda, P.; Gupta, R. PhCOCl-Py=basic alumina as a versatile reagent for
benzoylation in solvent-free conditions. Molecules. 2003, 8, 374–380.
11. Kidwai, M. Dry media reactions. Pure Appl. Chem. 2001, 73, 147–151.
12. Arora, R.; Paul, S.; Gupta, R. A mild and efficient procedure for the conversion of
aromatic carboxylic esters to secondary amides. Can. J. Chem. 2005, 83, 1137–1140.
13. Murty, M. S. R.; Jyotirmayi, B.; Krishna, P. R.; Yadav, J. S. Zinc-mediated alkylation of
cyclic secondary amines. Synth. Commun. 2003, 33, 2483–2486.
14. Murty, M. S. R.; Rami Reddy, N.; Yadav, J. S. Zinc-mediated novel and efficient method
for N-sulfonylation of amines in the absence of base. J. Sulfur Chem. 2006, 27, 589–593.
15. Yamada, M.; Sato, Y.; Kobayashi, K.; Konno, F.; Soneda, T.; Watanable, T. A new
5-HT3 receptor ligand II: Structure–activity analysis of 5-HT3 receptor agonist action in
the gut. Chem. Pharm. Bull. 1998, 46, 445–451.
16. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook of
Practical Organic Chemistry, 5th ed.; Pearson Education: Singapore, 1989; p. 467.