Page 3 of 4
RSC Advances
DOI: 10.1039/C3RA42887G
studies indicated Et3N was used as base only, which prompted the
use of excess DMAP instead of Et3N, reducing the sets of 31P
NMR spectrum peaks. The starting POCl3 in CH2Cl2 showed
signal in the 31P NMR spectrum at δ = 4.7 ppm. After DMAP (2.4
problems, such as separation of product from reagent derived
coproducts, racemization, poor recovery of product, high cost,
instability of the reagent, etc. The “in situ” activation of the
carboxylic acid makes our method an excellent alternative to the
5
eq.) was added to the solution of POCl3, the peak of POCl3 was 40 known acylation procedures, useful for the synthesis of peptides,
decreasing while a new peak at ꢀ15.8 ppm corresponding to
intermediate 6 emerged (A in Figure 1). When CbzꢀPhe (1k) was
added to the mixture, two sets of new signals appear at –5.8 and –
particularly complex natural products. The suggested possible
mechanism is supported by the 31P NMR spectrum analyses.
10.4 ppm (B in Figure 1), which indicated the forming of the
Acknowledgment.
10 mixed phosphoricꢀcarboxylic anhydride 719b 20 that subsequent 45 We acknowledge financial support from the Chinese National
,
react with DMAP to give the more reactive intermediate 8.
Although no spectroscopic data for intermediate 8 are available,
Natural Science Foundation (21173178, 21232005), Program for
Changjiang Scholars and Innovative Research Team in
University, Collaborative Innovation Center of Chemistry for
Energy Materials, and Anhui (KJ2012B145, 2012rcjj03)
21
PO2Cl2 (−5.8 ppm) has been previously studied by 31P NMR,
showing chemical shifts at −7.5 ppm in MeCN, similar to that
15 observed for our proposed intermediate. However, addition of
LeuꢀOMe resulted in a peak (–10.4 ppm) rapidly decrease (C in
Figure 1), meanwhile the peak at −5.8 ppm was gradually
increased, indicating the existence of the intermediate 7 again. In
addition, a new peak at −19.5 ppm was assigned as the byꢀ
20 product 9, which was proved by mix of acetylpyridinium
intermediate 6 with LeuꢀOMe.
ꢀ
50 Notes and references
a
Department of Chemistry, College of Chemistry and Chemical
Engineering, and the Key Laboratory for Chemical Biology of Fujian
Province, Xiamen University, Xiamen, Fujian 361005, China.E-mail:
b
55
Department of Chemistry and Chemical Engineering, Hefei Normal
† Electronic Supplementary Information (ESI) available: See
DOI:10.1039/b000000x/
60
65
70
75
80
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Scheme 1. Possible reaction mechanism
-
PO2Cl2
8
9
9
25 min
20 min
15 min
10 min
C
5 min
20 min
10 S. T. Heller, R. Sarpong, Org. Lett., 2010, 8, 4572–4575.
85 11 J. Tian, W. C.Gao, D. M. Zhou, C. Zhang, Org. Lett., 2012, 14,
3020–3023.
15 min
10 min
B
5 min
5 min
12 J. R. Dunetz, Y. Xiang, A. Baldwin, J. Ringling, Org. Lett., 2011,
13, 5048–5051.
A
POCl3
6
7
13 H. W. Horn, G. O. Jones, D. S. Wei, K. Fukushima, J. M. Lecuyer,
90
95
D. J. Coady, J. L. Hedrick, J. E. Rice, J. Phys. Chem. A, 2012, 116,
12389–12398.
25
Figure 1. 31P NMR spectra for the synthesis of 5l.
14 (a) J. K. Twibanire, T. B. Grindley, Org. Lett., 2011, 13, 2988–2991;
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10852; (e) K. Thalluri, K. C. Nadimpally, M. P. Chakravarty, A.
Paul, B. Mandal, Adv. Synth. Catal., 2013, 355, 448 – 462.
15 K. Sakamoto, K. Sato, A. Shigenaga, K. Tsuji, S. Tsuda, H.
Hibino,Y. Nishiuchi, A. Otaka, J. Org. Chem., 2012, 71, 6948ꢀ6958;
(b) A.Bach, N. StuhrꢀHansen, T. S. Thorsen, N. Bork, I. S. Moreira,
K. Frydenvang, S. Padrah, S. B. Christensen, K. L. Madsen, H.
Weinstein, U. Gether, K. Stromgaard, Org. Biomol. Chem., 2010, 8,
A: POCl3 (1.0 mmol), DMAP (2.4 mmol), CH2Cl2 (1 mL).
B: CbzꢀPhe(1.5 mmol) in CH2Cl2 (2 mL) was added to A.
C: LeuꢀOMe(1.5 mmol) in CH2Cl2 (2 mL) was added to B.
30
In summary, we have developed a mild, safe, and economic
oneꢀpot protocol for the conversion of carboxylic acids into esters,
amides, as well as peptides without racemization through
carboxyl activation by the reagent combination of POCl3 and
100
35 DMAP. The method eliminates some commonly encountered
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