heated under reflux for 1 h to give phenyl tert-butyl carbonate
(4a) quantitatively. Similar reactions of p-methoxy- and
p-nitorophenol (3b and 3c) afforded the corresponding
carbonates 4b and 4c in high yields, respectively (Table 1).
Table 2. tert-Butoxycarbonylation of Anilines by BBDI
Table 1. tert-Butoxycarbonylation of Phenols by BBDI
entry
R
solvent
product
yield (%)a
1
2
3
4
H
H
benzene
DME
DME
6a
6a
6b
6c
81
97
98
97
OMe
CH2CH2OH
DME
entry
R
temp
time (h)
product
yield (%)a
a Isolated yield.
1
2
3
4
H
OMe
NO2
CH2OH
reflux
reflux
rt
1
1
3
3
4a
4b
4c
4d
99
92
96
91
acid was undertaken. Screening experiments were made with
L-Met-OMe‚HCl as a model compound using the quantity
of 2 in DME. It was found the use of 3 equiv of 2 gave the
best yield (93%), whereas those of 2 and 1.2 equiv resulted
in 82% and 33% yields, respectively. Use of diethyl ether
as a solvent provided a similar result (95%) with reflux. On
the basis of these results obtained, the standard condition
for the tert-butoxycarbonylation of several amino acid ester
hydrochlorides with 2 (3 equiv) was in DME at room
temperature or in diethyl ether under reflux. Thus the tert-
butoxycarbonylation of various amino acids in this study was
normally performed, and the corresponding N-Boc L-amino
acid esters were obtained in high yields as shown in Table
3. The identification of N-Boc L-amino acid esters was
reflux
a Isolated yield.
tert-Butoxycarbonylation of p-hydroxymethylphenol (3d)
took place chemoselectively to give 4d without any contact
with hydroxymethyl. Surprisingly, although tert-butoxy-
carbonylation of phenols in alkali media has been reported,7
this example of that in the absence of bases is first.
However, under this condition tert-butoxycarbonylation
of aniline did not occur, resulting in the recovery of 2. On
the other hand, it was found tert-butoxycarbonylation of 3c
(pKa ) 10.8)8 proceeds in more mild condition compared
with those of 3a (pKa ) 18.0).8 With these results in hand,
we considered that this reactivity is proportional to the acidity
order of the substrates. Because a conjugate acid (pKa )
3.6)8 of aniline (pKa ) 30.6)8 is stronger acid than 3a, we
tried tert-butoxycarbonylation using the aniline hydrochloride
(5a). Treatment of 5a with 2 in benzene at room temperature
expectedly afforded N-Boc aniline 6a in 81% yield (Table
2, entry 1). The employment of dimethoxyethane (DME)
instead of benzene as solvent dramatically increased the yield
of 6a (entry 2). Similar treatment of p-methoxyaniline (5b)
with 2 afforded N-Boc aniline 6b in high yield (entry 3).
The high chemoselectivity was also demonstrated by the
coexistence of an aliphatic hydroxyl group as shown in entry
4.
Table 3. tert-Butoxycarbonylation of Amino Acids by BBDIa
starting
yield
(%)c
entry
compound
methodb
product
1
2
3
4
5
6
7
8
9
Met-OMe‚HCl
Met-OMe‚HCl
Ala-OEt‚HCl
Leu-OEt‚HCl
Val-OMe‚HCl
Phe-OMe‚HCl
Pro-OMe‚HCl
Glu(OEt)-OEt‚HCl
Ser-OMe‚HCl
Cys-OMe‚HCl
Tyr-OMe‚HCl
A
B
B
B
A
A
A
B
A
A
A
Boc-Met-OMe10
Boc-Met-OMe10
Boc-Ala-OEt11
Boc-Leu-OEt11
Boc-Val-OMe10
Boc-Phe-OMe12
Boc-Pro-OMe13
93
95
87
91
86
97
98
Next, the tert-butoxycarbonylation of amino acids ester
hydrochlorides (pKa ) 7.6-8.7)9 as the weaker conjugate
(5) (a) Kunieda, T.; Higuchi, T.; Abe, Y.; Hirobe, M. Chem. Pharm.
Bull. 1984, 32, 2174-2181. (b) Grapsas, I.; Cho, Y. G.; Mobashery, S. J.
Org. Chem. 1994, 59, 1918-1922.
Boc-Glu(OEt)-OEt14 98
Boc-Ser-OMe15
Boc-Cys-OMe16
Boc-Tyr-OMe17
92
87
76d
(6) Synthesis of BBDI (2). A solution of di-tert-butyl dicarbonate (1,
7.86 g, 36 mmol) in benzene (10 mL) was added dropwise to a stirred
solution of isoquinoline (3.87 g, 30 mmol) in benzene (20 mL), and the
mixture was stirred for 6 h at room temperature. After concentration in
vacuo, the residue was purified by recrystallization from pentane or distilled
under reduced pressure to give 2 (8.36 g, 92%) as colorless prisms: bp
134-136 °C (1.0 mmHg); mp 114-115 °C; IR (KBr) cm-1 1712; 1H NMR
(400 MHz, CDCl3) δ 1.29 (s, 9Η), 1.52 (s, 9Η), 6.10 (d, 1H, J ) 7.5 Hz),
6.66 (s, 1H), 6.88 (d, 1H, J ) 7.3 Hz), 7.18-7.29 (m, 4H); MS (EI) m/z
303 (M+). Anal. Calcd for C18H25NO3: C, 71.26; H, 8.31; N, 4.62. Found:
C, 71.38; H, 8.02; N, 4.54.
10
11
a The reactions were performed with 3 equiv of BBDI. b Method A: in
1,2-dimethoxyethane at room temperature for overnight. Method B: in
diethyl ether heated under reflux for overnight. c Isolated yield. d Small
amount of Boc-Tyr(OBoc)-OMe was also obtained.
confirmed by comparison of 1H NMR and IR data and [R]D
values with the reported data.10-17
As an application, the chemoselectivity of tert-butoxy-
carbonylation for amino and hydroxyl groups on a benzene
(7) (a) Houlihan, F.; Bouchard, F.; Frechert, J. M. J.; Wilson, C. G. Can.
J. Chem. 1985, 63, 153-162. (b) Hansen, M. M.; Riggs, J. R. Tetrahedron
Lett. 1998, 39, 2705-2706.
(8) pKa values were measured in dimethyl sulfoxide. Bordwell, F. G.
Acc. Chem. Res. 1988, 21, 456-463.
586
Org. Lett., Vol. 4, No. 4, 2002