S. Narayana Murthy, Y. V. D. Nageswar / Tetrahedron Letters 52 (2011) 4481–4484
4483
Berlin, 2006. Vol. 1; For a review on IBX: see (c) Satam, V.; Harad, A.; Rajule, R.;
Pati, H. Tetrahedron 2010, 66, 7659–7706.
OEt
OH
IBX
N
N
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O
Ph P=CH COOEt
3
2
β-CD, H O,
2
C
0
70-80
OEt
OH
IBX
N
N
O
Ph P=CH COOEt
3
2
O
O
O
O
β-CD, H O,
2
0
70-80
C
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Scheme 2.
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ble 1, entry 8) did not hamper the reaction and gave corresponding
N-benzylpyrrole in moderate yield.
While applying this interesting research work toward the natu-
rally occurring L-proline derivatives, L-proline ester hydrochloride
was subjected to the IBX oxidation reaction in water medium med-
iated by b-CD under optimized reaction conditions, resulting in
methyl 1H-pyrrole-2-carboxylate in 89% (Table 2, entry 1). Encour-
aged by this result this reaction was extended to prepare a wide
variety of N-protected
L-proline derivatives such as N-benzyl, N-
ethyl, N-propargyl, N-allyl-L-proline methyl esters and the reactiv-
8. Bratton, L. D.; Cheng, X-M.; Lee, C.; Miller, S. R.; Pfefferkorn, J. A.; Poel, T-J.;
Sorenson, R. J.; Song, Y.; Sun, K-L.; Trivedi, B. K.; Unangst, P. C. U.S. Patent
US2005154042 (A1).
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ity pattern was examined toward this novel transformation. The
corresponding results were tabulated (Table 2, entries 2, 3, 4, 5).
In L-proline methyl ester, when N-was protected with Boc anhy-
dride, acetic anhydride, the corresponding N-protected pyrrol-
idines failed to undergo aromatization to give pyrrole derivatives,
instead starting materials were recovered.
When N-benzyl-L-prolinol was treated with IBX under opti-
mized reaction conditions. 1-benzyl-1H-pyrrole-2-carbaldehyde
was obtained in moderate yield (Table 2, entry 6). However, the
same N-benzyl-L-prolinol was subjected to Wittig’s reaction with
ylide (Ph3P@CH2COOEt) in presence of IBX and b-cyclodextrin in
water which resulted in (E)-ethyl 3-(1-benzyl-1H-pyrrol-2-yl)
acrylate in excellent yield (Scheme 2). Moreover, the correspond-
10. (a) Le, Z.-G.; Chen, Z.-C.; Hu, Y.; Zheng, Q.-G. Synthesis 2004, 12, 1951–1954; (b)
Jorapur, Y. R.; Jeong, J. M.; Chi, D. Y. Tetrahedron Lett. 2006, 47, 2435–2438.
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P.; Kumar, A. V.; Rao, K. R. Tetrahedron Lett. 2011, 52, 777–780; (c) Sridhar, R.;
Srinivas, B.; Kumar, V. P.; Reddy, V. P.; Kumar, A. V.; Rao, K. R. Adv. Synth. Catal.
2008, 350, 1489–1492.
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Reddy, V. P.; Rao, K. R.; Nageswar, Y. V. D. Tetrahedron Lett. 2009, 50, 6025–
6028; (c) Murthy, S. N.; Madhav, B.; Kumar, A. V.; Rao, K. R.; Nageswar, Y. V. D.
Tetrahedron 2009, 65, 5251–5256; (d) Murthy, S. N.; Madhav, B.; Kumar, A. V.;
Rao, K. R.; Nageswar, Y. V. D. Helv. Chim. Acta 2009, 92, 2118–2124; (e) Murthy,
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ing N-Boc-protected L-prolinol failed to undergo aromatization
and instead gave only the Wittig product (Scheme 2). All the prod-
ucts were characterized by 1H, 13C NMR, mass spectra and com-
pared with authentic samples.16
14. Surendra, K.; Krishnaveni, N. S.; Reddy, M. A.; Nageswar, Y. V. D.; Rao, K. R. J.
Org. Chem. 2003, 68, 9119–9121.
In conclusion, we have demonstrated for the first time a mild
and highly efficient protocol for the synthesis of N-benzylpyrroles
under neutral conditions, using IBX as an oxidizing agent mediated
by b-cyclodextrin in water. To the best of our knowledge, this is the
first report on the synthesis of N-benzylpyrroles under supramo-
lecular catalysis in water medium. This simple, convenient and
practical approach may have wide applicability in both synthetic
and medicinal chemistry.
15. General procedure for the synthesis of N-benzylpyrroles. To an aqueous solution
of b-cyclodextrin (1.0 mmol of b-CD in 5 mL of water), IBX (2.0 mmol), N-
benzylpyrrolidine (1.0 mmol) was added while stirring, and stirring was
continued for the stipulated reaction time as shown in the Table at room
temperature. After completion of reaction as indicated by TLC, the reaction
mixture was extracted with ethyl acetate (3 Â 5 mL), the combined organic
layers were washed with saturated brine solution, dried and concentrated in
vacuum. The crude product was purified by column chromatography on Silica
gel using hexane/ethyl acetate (9:1) as an eluent.
16. Data for the representative examples of synthesized compounds. 1-Benzyl-1H-
pyrrole4 (entry 1, Table 1): 86 %, light yellow oil, 1H NMR (300 MHz; CDCl3;
TMS) 5.27 (s, 2H, CH2), 6.38 (t, 2H, J = 2.0 Hz, CH), 6.89 (t, 2H, J = 1.8 Hz, CH),
7.29–7.39 (m, 2H, Ph), 7.44–7.55 (m, 3H, Ph). 13C NMR (75 MHz; CDCl3; TMS)
53.30, 108.45, 121.12, 126.95, 127.59, 128.67, 138.10.
Acknowledgment
We Thank CSIR, New Delhi, India for awarding fellowship to
SNM.
Methyl 1H-pyrrole-2-carboxylate (entry 1, Table 2): 89 %, pale yellow solid, 1H
NMR (300 MHz; CDCl3; TMS) 3.85 (s, 3H, OMe), 6.19–6.22 (m, 1H), 6.83–6.85
(m, 1H), 6.91–6.93 (m, 1H), 9.53 (br s, 1H, NH). 13C NMR (75 MHz; CDCl3; TMS)
51.45, 110.45, 115.74, 122.35, 123.39, 162.18.
Supplementary data
Methyl 1-benzyl-1H-pyrrole-2-carboxylate (entry 2, Table 2): 84 %, pale yellow
oil, 1H NMR (300 MHz; CDCl3; TMS) 3.74 (s, 3H, OMe), 5.53 (s, 2H), 6.10–6.12
(m, 1H), 6.81 (t, 1H, J = 2.2 Hz, CH), 6.91–6.92 (m, 1H), 7.04–7.09 (m, 2H), 7.18–
7.28 (m, 3H). 13C NMR (75 MHz; CDCl3; TMS) 50.83, 51.97, 108.53, 118.35,
121.98, 126.95, 127.40, 128.58, 138.27, 161.13.
Supplementary data associated with this article can be found, in
Methyl 1-allyl-1H-pyrrole-2-carboxylate (entry 3, Table 2): 73 %, yellow oil, 1H
NMR (300 MHz; CDCl3; TMS) 3.78 (s, 3H, OMe), 4.93–4.98(m, 3H), 5.10 (d, 1H,
J = 10.1 Hz), 5.91–6.04 (m, 1H), 6.09 (t, 1H, J = 2.6 Hz), 6.78 (t, 1H, J = 1.8 Hz),
6.87–6.89 (m, 1H). 13C NMR (75 MHz; CDCl3; TMS) 50.80, 50.91, 108.28,
116.54, 118.10, 121.67, 128.13, 134.76, 161.10.
References and notes
1. (a) Tojo, G.; Fernandez, M. Oxidation of Primary Alcohols to Carboxylic Acids. In
Basic Reactions in Organic Synthesis Series; Tojo, G., Ed.; Springer: Berlin, 2007.
Vol. 2; (b) Tojo, G.; Fernandez, M. Oxidation of Alcohols to Aldehydes and
Ketones. In Basic Reactions in Organic Synthesis Series; Toji, G., Ed.; Springer:
(E)-ethyl 3-(1-benzyl-1H-pyrrol-2-yl)acrylate: 88 %, yellow oil, 1H NMR
(300 MHz; CDCl3; TMS) 1.27 (t, 3H, J = 6.7 Hz), 4.14 (q, 2H, J1 = 14.3 Hz,