S. El Kazzouli et al. / Tetrahedron Letters 47 (2006) 8575–8577
8577
CO2Et
The reaction conditions are mild and compatible with
acidic and basic sensitive groups. The method is used
for deprotecting various N-Boc protected compounds
and offers a good selectivity for amine deprotection.
BocO
Me
N
7
Boc
References and notes
Na2CO3
DME/H2O, reflux
BocO
1. Bose, D. S.; Kumar, K. K.; Reddy, A. V. N. Synth.
Commun. 2003, 33, 445.
CO2Et
CO2Et
2. Greene, T. W.; Wuts, P. G. M. Protective groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons, 1999, and
references cited therein; Philip, J. K. Protecting Groups,
3rd ed.; Georg Thieme: Stuttgart, New york, 2005, and
references cited therein.
HO
Me
Me
N
N
H
H
3. Wasserman, H. H.; Berger, G. D.; Cho, K. R. Tetrahedron
Lett. 1982, 23, 465.
+
7a
7b
4. Tom, N. J.; Simon, W. M.; Frost, H. N.; Ewing, M.
Tetrahedron Lett. 2004, 45, 905.
5. Kuttan, A.; Nowshudin, S.; Rao, M. N. A. Tetrahedron
Lett. 2004, 45, 2663.
Na2CO3 (1.2 equiv.)
Na2CO3 (2.4 equiv.)
40%
96%
48%
0%
Scheme 2. Results of Na2CO3 cleavage of 7.
6. Marcantoni, G.; Massccesi, M.; Torregiani, E.; Bar-
toli, G.; Bosco, M.; Sambri, L. J. Org. Chem. 2001, 66,
4430.
corresponding deprotected amines in excellent yields
(Table 1, entries 1–4), except for 1-N-Boc pyrazole 5,
which conducted to the corresponding pyrazole 5a in a
moderate yield of 60% (Table 1, entry 5).
7. Jackson, R. W. Tetrahedron Lett. 2001, 42, 5163.
´
´
8. Routier, S.; Sauge, L.; Ayerbe, N.; Coudert, G.; Merour,
J.-Y. Tetrahedron Lett. 2002, 43, 589.
´ ´
9. Jacquemard, U.; Beneteau, V.; Lefoix, M.; Routier, S.;
Acid and/or basic sensitive groups (Table 1, entries 6–8)
were not affected. Thus, the treatment of compounds
6–8 with Na2CO3 gave the desired products 6a–8a in
70–98% yields. It is noticed that with 1.2 equiv of
Na2CO3, the reaction using 7 was not complete and
compounds 7a and 7b10 were produced in 40% and
48% yields, respectively. However, when increasing the
quantity of Na2CO3 (2.4 equiv), compound 7 was recov-
ered to 7a in a 100% conversion and in an excellent yield
(Scheme 2, Table 1).
´
Merour, J.-Y.; Coudert, G. Tetrahedron 2004, 60, 10039.
10. Compound 7b is prepared from 7 as described for 1a.
Analytical data for 7b is described as follows. 5-tert-
Butoxycarbonyloxy-2-methyl-1H-indole-3-carboxylic acid
ethyl ester. Yield 48%; 1H NMR (250 MHz, DMSO-d6): d
11.92 (1H, s, 1-NH), 7.61 (1H, d, J = 2.2 Hz, ArH), 7.35
(1H, d, J = 8.8 Hz, ArH), 6.92 (1H, dd, J = 2.2, 8.8 Hz,
ArH), 4.26 (2H, q, J = 7.2 Hz, OCH2), 2.64 (3H, s, CH3),
1.48 (9H, s, –C(CH3)3), 1.32 (3H, t, J = 7.2 Hz,
OCH2CH3); 13C NMR (62.5 MHz, DMSO-d6): d 164.8
(CO), 152.1 (CO), 146.0 (C), 145.5 (C), 132.5 (C), 127.1
(CH), 115.6 (C), 112.3 (CH), 111.6 (CH), 103.0 (C), 82.7
(C), 58.9 (CH2), 27.3 ((CH3)3), 14.4 (CH3), 13.8 (CH3). MS
(IS) 320 (M+1)+.
Surprisingly, 1-N-Boc indole 9, 1-N-Boc-3-methylindole
10 and 1-N-Boc 2-phenylethylamine 11 afford only the
starting material (Table 1, entries 9–11).
11. Compound 12 is prepared from 5-aminoindazole as
described in the literature: Bouissane, L.; El Kazzouli,
´
S.; Leonce, S.; Pfeiffer, B.; Rakib, E. M.; Khouili, M.;
It is noteworthy that the selectivity of the N-Boc depro-
tection by Na2CO3 was also studied using compound 12,
which bears both aromatic and indazolic N-Boc protec-
tion11 (Table 1, entry 12). The reaction was performed
with 1.2 equiv of Na2CO3 in DMF/H2O at 85 °C (the
starting material was not very soluble in DME/H2O).
In these conditions, only the indazolic deprotection
was observed. The structure of 12a was established by
the comparison between 1H NMR, 13C NMR, mass
spectroscopy data of 12 and 12a (see analytical data of
12 and 12a).11,12 We observed, in particular, in 1H
NMR spectra of 12a, recorded in DMSO-d6, the appear-
ance of NH signal of 1-NH at 12.90 ppm. The 1H NMR
spectra of 12 and 12a also showed a singlet at d 9.56
(5-NH) for 12 and a singlet at d 9.26 (5-NH) for 12a.
These results serve to confirm the structure of 12a.
Guillaumet, G. Bioorg. Med. Chem. 2006, 14, 1078.
Analytical data for 12 is as follows. 5-tert-Butoxycarbon-
ylamino-indazole-1-carboxylic acid tert-butyl ester. Yield
85%; 1H NMR (250 MHz, DMSO-d6): d 9.56 (1H, s, 5-
NHAr), 8.34 (1H, s, ArH), 8.04 (1H, ArH), 7.94 (1H, d,
J = 9.10 Hz, ArH), 7.57 (1H, d, J = 9.10 Hz, ArH), 1.63
(9H, s, –C(CH3)3), 1.49 (9H, s, –C(CH3)3); 13C NMR
(62.5 MHz, DMSO-d6): d 153.3 (CO), 148.8 (CO), 140.1
(CH), 136.1 (C), 135.2 (C), 126.3 (C), 121.6 (CH), 114.4
(CH), 109.2 (CH), 84.6 (C), 79.6 (C), 28.5 ((CH3)3), 28.0
((CH3)3). MS (IS) 334 (M+1)+.
12. Compound 12a is obtained from 12 as described for 1a.
Analytical data for 12a is described as follows. (1H-
Indazol-5-yl)-carbamic acid tert-butyl ester. Yield 95%; 1H
NMR (250 MHz, DMSO-d6): d 12.90 (1H, s, 1-NH), 9.26
(1H, s, 5-NHAr), 7.97 (1H, s, ArH), 7.88 (1H, ArH), 7.33–
7.45 (2H, m, ArH), 1.49 (9H, s, –C(CH3)3); 13C NMR
(62.5 MHz, DMSO-d6): d 153.8 (CO), 137.2 (C), 133.6
(CH), 133.1 (C), 123.5 (C), 120.5 (CH), 110.7 (CH), 108.8
(CH), 79.4 (C), 28.9 ((CH3)3). MS (IS) 234 (M+1)+.
In conclusion, we found a simple and efficient method
for the cleavage of Boc protected amines using Na2CO3.