Efficient N-tert-butoxycarbonylation of indoles with di-tert-butyl dicarbonate catalyzed by cesium fluoride

Article abstract of DOI:10.1055/s-2007-1000869

An environmentally friendly process for the tert-butoxycarbonylation of indoles with di-tert-butyl dicarbonate has been developed. Catalytic amount of cesium fluoride can accelerate this tert-butoxycarbonylation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000869

294
LETTER
Efficient N-tert-Butoxycarbonylation of Indoles with Di-tert-butyl Dicarbonate
Catalyzed by Cesium Fluoride
Efficient
N-
tert-Bu
o
toxycarbony
b
lation of Ind
u
oles yuki Inahashi, Ayako Matsumiya, Tsuneo Sato*
Department of Life Science, Kurashiki University of Science and the Arts, Kurashiki 712-8505, Japan
Fax +81(86)4401062; E-mail: sato@chem.kusa.ac.jp
Received 29 October 2007
Table 1 Reaction of Indole with Boc2O in the Presence of Alkali
Abstract: An environmentally friendly process for the tert-butoxy-
carbonylation of indoles with di-tert-butyl dicarbonate has been de-
veloped. Catalytic amount of cesium fluoride can accelerate this
tert-butoxycarbonylation.
Metal Fluoridesa
MF
+
Boc2O
N
H
N
Key words: catalysis, cesium fluoride, di-tert-butyl dicarbonate,
indoles, protecting groups
Boc
Entry
1
M
Solvent
Yield (%)b
Cs
DMF
100 (93)
For protection of indole nitrogen, tert-butoxycarbonyl
(Boc) group is extensively used1 since it can be easily re-
moved under mild reaction conditions.2 Although the di-
tert-butyl dicarbonate (Boc2O) and 4-(dimethylamino)pyr-
idine (DMAP) protocol3,4 is used routinely for N-tert-bu-
toxycarbonylation, the high toxicity of DMAP (LD50 in
the rat, intravenous: 56 mg/kg)5 restricts its use. Thus, de-
velopment of an efficient, safe and environmentally
friendly method of N-tert-butoxycarbonylation is still in
demand. Herein, we report a novel methodology for N-
tert-butoxycarbonylation of indole with Boc2O using CsF
as nontoxic catalyst under mild conditions (Scheme 1).
2c
3d
4
Cs
–
DMF
100 (94)
DMF
0
15
33
64
26
29
32
66
24
8
Cs
Cs
Cs
Cs
Cs
Cs
Rb
K
MeCN
EtOAc
acetone
THF
5
6
7
8
CH2Cl2
toluene
DMF
9
CsF
10
11
12
13
(20 mol%)
Boc2O
+
r.t.
DMF
N
N
R
R
H
Boc
Na
DMF
Scheme 1
Li
DMF
0
a Reaction conditions: indole (1.0 mmol), Boc2O (1.3 mmol), MF (0.2
mmol), solvent (1 mL), r.t., 6 h, unless otherwise mentioned.
b Based on 1H NMR. Isolated yields are given in the parentheses.
c CsF (0.05 mmol), 19 h.
First, the reaction of indole with Boc2O (1.3 equiv) was
carried out in the presence of various alkali metal fluo-
rides (20 mol%) at room temperature (25–30 °C)
(Table 1). After screening various reaction conditions, we
found that CsF in DMF was the most effective catalyst for
conversion of indole to the desired N-tert-butyl carbamate
(entry 1).
d The reaction was carried out in the absence of CsF (control experi-
ment).
N-tert-butoxycarbonylation did not proceed at all (entry
3).
When other less polar solvents such as MeCN, acetone,
THF and toluene were used, it was found that the yield
was considerably lower (entries 4–9). Among alkali metal
fluorides screened, we found CsF to be indeed effective,
while inferior results were obtained with LiF, NaF, KF
and RbF (entries 10–13).6 Even with 5 mol% of CsF, this
N-tert-butoxycarbonylation proceeded almost quantita-
tively, but longer reaction time was required (entry 2).
When this reaction was attempted in the absence of CsF,
On the basis of these results, we settled on the following
standard conditions: indole/Boc2O/CsF ratio of 1:1.3:0.2,
DMF as solvent, room temperature. The results of N-tert-
butoxycarbonylation of various indoles by use of the
Boc2O and CsF protocol are summarized in Table 2. The
desired tert-butyl carbamates were generally obtained in
reasonable yields.
No restrictions were found with regard to the nature of the
indole substrates. A variety of acid- (entries 12–14) and
base-sensitive (entries 15 and 16) functional groups re-
mained intact under our reaction conditions. Interestingly,
SYNLETT 2008, No. 2, pp 0294–0296
Advanced online publication: 21.12.2007
DOI: 10.1055/s-2007-1000869; Art ID: U10407ST
x
x.
x
x.
2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient N-tert-Butoxycarbonylation of Indoles
295
the tert-butyldimethylsilyl group survived under these re-
action conditions (entry 17).8 The optical purity of the
chiral indole was completely retained [98% ee determined
by 500 MHz 1H NMR in the presence of Eu(hfc)3] (entry
18).
Table 2 N-tert-Butoxycarbonylation of Indoles with Boc2O Cata-
lyzed by CsFa
Entry
17
2
Indole
Time (h) Yield (%)b
indole
6
2
93
80
80
80
82
87
83
83
80
80
82
Finally, we examined selective N-tert-butoxycarbonyla-
tion of indoles bearing an hydroxyl group such as 3-(3-hy-
droxybutyl)indole utilizing our protocol (Scheme 2).
When the indole was allowed to react with Boc2O and CsF
under the usual conditions, only N-Boc derivative was ob-
tained in 81% yield. 1H NMR analysis of the crude prod-
uct showed no formation of N,O-di(Boc) derivative. In
contrast to this result, when tert-butoxycarbonylation was
carried out by the DMAP method, a considerable amount
of N,O-di(Boc) derivative was formed.
2-methylindole
ethyl indole-2-carboxylate
3-methylindole
3-formylindole
methyl indole-3-carboxylate
5-methoxyindole
5-bromoindole
5-cyanoindole
5-nitroindole
3
1
4
19
1
5
6
1
7
6
8
1
In conclusion, we have demonstrated an efficient N-tert-
butoxycarbonylation of indoles with di-tert-butyl dicar-
bonate catalyzed by cesium fluoride. Further study on
CsF-catalyzed reaction is currently underway in our labo-
ratory.
9
1
10
11
1
7-methylindole
R
1
References and Notes
(1) Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic
Synthesis, 4th ed.; Wiley: New York, 2007, Chap. 7.
(2) Ravinder, K.; Reddy, A. V.; Mahesh, K. C.; Narasimhulu,
M.; Venkateswarlu, Y. Synth. Commun. 2007, 37, 281; and
references cited therein.
(3) (a) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl.
1984, 23, 296. (b) Franzen, H.; Grehn, L.; Ragnarsson, U. J.
Chem. Soc., Chem. Commun. 1984, 1699. (c) Ragnarsson,
U.; Grehn, L. Acc. Chem. Res. 1998, 31, 494. For recent
examples using this protocol for the N-tert-
N
H
12
13
R = (CH2)2NHBoc
20
19
80
80
R =
O
O
(CH2)2
butoxycarbonylation of indoles, see: (d) Baran, P. S.;
Shenvi, R. A.; Mitsos, C. A. Angew. Chem. Int. Ed. 2005, 44,
3714. (e) Roy, S.; Gribble, G. W. Synth. Commun. 2006, 36,
3487. (f) Pedras, M. S. C.; Zheng, Q.-A.; Sarwar, M. G. Org.
Biomol. Chem. 2007, 5, 1167.
14
15
16
17
R = (CH2)2CH(OTHP)Me
R = (CH2)2CH(OAc)Me
R = (CH2)2CH(OTs)Me
R = (CH2)2CH(OTBS)Me
R =
30
20
24
24
81
83
83
82
(4) For other methods for the N-tert-butoxycarbonylation of
indoles, see: (a) NaH + BocN3: Hasan, I.; Marinelli, E. R.;
Lin, L.-C. C.; Fowler, F. W.; Levy, A. B. J. Org. Chem.
1981, 46, 157. (b) NaH + BocOC6H5: Dhanak, D.; Reese, C.
B. J. Chem. Soc., Perkin Trans. 1 1986, 2181.
18
4
80
(5) (a) Sweet, D. V. Registry of Toxic Effects of Chemical
Substances 1985-86; U. S. Govt. Printing Office:
Washington D. C., 1988, 3336. (b) Sweet, D. V. Registry of
Toxic Effects of Chemical Substances 1985-86; U. S. Govt.
Printing Office: Washington DC, 1988, 4049.
(6) CsF was the best catalyst among the cesium salts examined
under the identical conditions: CsCl (0%), CsBr (6%), CsI
(0%).
H2C
CO2Me
NHAc
a Reaction conditions: indole (1.0 mmol), Boc2O (1.3 mmol), CsF (0.2
mmol), DMF (1 mL), r.t.
b Isolated yield.
OH
OH
OBoc
Boc2O (1.3 equiv)
r.t.
+
N
H
N
N
Boc
Boc
CsF (20 mol%), DMF, 17 h
DMAP (10 mol%), MeCN, 1 h
81%
17%
0%
47%
Scheme 2
Synlett 2008, No. 2, 294–296 © Thieme Stuttgart · New York

296
N. Inahashi et al.
LETTER
(7) Typical Procedure (Table 2, entry 1): Boc2O (284 mg, 1.3
mmol) was added dropwise to a stirred mixture of indole
(117 mg, 1.0 mmol) and CsF9 (30 mg, 0.2 mmol) in DMF (1
mL) at r.t. The reaction was complete in 6 h at the same
temperature. The reaction mixture was poured into H2O and
extracted with EtOAc. The organic layer was dried (Na2SO4)
and evaporated. Column chromatography of the residue on
silica gel (7% EtOAc–hexane) afforded tert-butyl indole-1-
carboxylate (202 mg, 93%).10
Butyl 3-[3-(tert-Butyldimethylsilanyloxy)butyl]indole-1-
carboxylate: 1H NMR (CDCl3): d = 0.08 (s, 3 H), 0.09 (s, 3
H), 0.92 (s, 9 H), 1.20 (d, J = 6.1 Hz, 3 H), 1.67 (s, 9 H),
1.76–1.89 (m, 2 H), 2.61–2.70 (m, 1 H), 2.75–2.82 (m, 1 H),
3.88–3.96 (m, 1 H), 7.23 (t, J = 7.9 Hz, 1 H), 7.30 (t, J = 7.9
Hz, 1 H), 7.34 (s, 1 H), 7.52 (d, J = 7.9 Hz, 1 H), 8.12 (br, 1
H). 13C NMR (CDCl3): d = –4.7, –4.3, 18.1, 21.1, 23.8, 25.9,
28.2, 39.0, 68.2, 83.2, 115.2, 119.0, 121.2, 122.1, 122.2,
124.2, 130.7, 149.9. tert-Butyl 3-[2-Acetylamino-2-
(methoxycarbonyl)ethyl]indole-1-carboxylate: 1H NMR
(CDCl3): d = 1.67 (s, 9 H), 1.98 (s, 3 H), 3.23 (dd, J = 5.2,
14.7 Hz, 1 H), 3.30 (dd, J = 5.5, 14.7 Hz, 1 H), 3.71 (s, 3 H),
4.95 (dt, J = 5.2, 7.7 Hz, 1 H), 6.02 (d, J = 7.7 Hz, 1 H), 7.23
(t, J = 7.6 Hz, 1 H), 7.31 (t, J = 7.6 Hz, 1 H), 7.36 (s, 1 H),
7.47 (d, J = 7.6 Hz, 1 H), 8.11 (d, J = 7.6 Hz, 1 H). 13C NMR
(CDCl3): d = 22.7, 27.0, 27.9, 52.1, 52.3, 83.4, 114.9, 115.0,
118.5, 122.3, 123.7, 124.2, 130.3, 135.0, 149.3, 169.7,
172.0. tert-Butyl 3-(3-Hydroxybutyl) indole-1-
(8) CsF-promoted desilylation of tert-butyldimethylsilyl ethers
was reported: Cirillo, P. F.; Panek, J. S. J. Org. Chem. 1990,
55, 6071.
(9) Purchased from Mitsuwa Chemicals Co., Ltd.
(10) The selected spectroscopic data are shown as follows:
tert-Butyl 3-Formylindole-1-carboxylate: 1H NMR
(CDCl3): d = 1.71 (s, 9 H), 7.38 (t, J = 8.3 Hz, 1 H), 7.42 (t,
J = 8.3 Hz, 1 H), 8.15 (d, J = 8.3 Hz, 1 H), 8.24 (s, 1 H), 8.29
(d, J = 8.3 Hz, 1 H), 10.11 (s, 1 H). 13C NMR (CDCl3): d =
28.0, 85.6, 115.1, 121.5, 122.1, 124.6, 126.0, 126.1, 135.9,
136.4, 148.8, 185.7. tert-Butyl 7-Methylindole-1-
carboxylate: 1H NMR (CDCl3): d = 1.63 (s, 9 H), 2.64 (s, 3
H), 6.53 (d, J = 4.0 Hz, 1 H), 7.09 (d, J = 7.6 Hz, 1 H), 7.14
(t, J = 7.6 Hz, 1 H), 7.38 (d, J = 7.6 Hz, 1 H), 7.51 (d, J = 4.0
Hz, 1 H). 13C NMR (CDCl3): d = 22.1, 28.0, 83.2, 107.3,
118.5, 123.1, 125.3, 127.5, 128.0, 131.9, 134.7, 149.5. tert-
carboxylate: 1H NMR (CDCl3): d = 1.26 (d, J = 6.1 Hz, 3
H), 1.37 (br, 1 H), 1.67 (s, 9 H), 1.83–1.89 (m, 2 H), 2.72–
2.80 (m, 1 H), 2.80–2.88 (m, 1 H), 3.91 (br s, 1 H), 7.23 (t,
J = 7.6 Hz, 1 H), 7.31 (t, J = 7.6 Hz, 1 H), 7.37 (s, 1 H), 7.54
(d, J = 7.6 Hz, 1 H), 8.12 (br, 1 H). 13C NMR (CDCl3): d =
21.0, 23.5, 28.1, 38.4, 67.4, 83.2, 115.1, 118.9, 120.7, 122.2,
124.2, 130.6, 135.5, 149.7.
Synlett 2008, No. 2, 294–296 © Thieme Stuttgart · New York

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