Short and simple preparation of N-Boc-protected anthranilic acid tert-butyl esters from 2-bromo-anilines

Article abstract of DOI:10.1055/s-2005-921910

A novel two-step procedure for the preparation of diprotected anthranilic acid derivatives from ortho-bromoanilines is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-921910

LETTER
3107
Short and Simple Preparation of N-Boc-Protected Anthranilic Acid tert-Butyl
Esters from 2-Bromo-Anilines
P
reparationof
i
N
-Boc
l
-Protec
v
ted
A
nthrani
i
lic Acid
a
tert-Butyl
E
ster
s
Herzig, Stéphane Kritter, Thomas Lübbers,* Nadine Marquardt, Jens-Uwe Peters, Silja Weber
F. Hoffmann-La Roche Ltd., Division Pharma, Discovery Chemistry, 4070 Basel, Switzerland
Fax +41(61)6886459; E-mail: thomas.luebbers@roche.com
Received 4 October 2005
Table 1 Synthesis of Anthranilic Acid Derivatives 3 via Protected
Aniline Derivative 2
Abstract: A novel two-step procedure for the preparation of dipro-
tected anthranilic acid derivatives from ortho-bromoanilines is
described.
Entry
1
Substituent
Yield of 2 (%)a Yield of 3 (%)a
Key words: alkyl halides, carboxylic acids, metalations, rearrange-
ments, protecting groups
5-Cl
74
Quant.
95
77
66
99
69
53
58
44
0
2
5-OCF3
5-CF3
94
3
77
Anthranilic acid derivatives are widely used as starting
materials in organic syntheses. A variety of anthranilic
acids are commercially available, and numerous synthetic
accesses of anthranilic acids have been described.1 In the
course of a medicinal chemistry discovery programme,
we worked out a novel access to anthranilic acids, which
we found to be complementary to already existing proce-
dures. This novel synthesis uses ortho-bromoanilines
(which are readily available, either commercial or e.g. by
bromination of aromatic amines) as starting materials to
obtain diprotected anthranilic acid derivatives in two
steps. The obtained N-Boc-protected anthranilic acid tert-
butyl esters can, for instance, be selectively deprotected,2
and can be envisaged to be versatile building blocks for
organic syntheses.
4
5-CN
68
5
4-CF3
96
6
4-Cl
Quant.
88
7
H (unsubst.)
5-F
8
62
9
4-F
81
10
11
12
5-CH3
3-COOMe
3-NO2, 5-F
80
32
51
0
93
a Isolated yield. The yield was not optimized.
O
6
6
6
Br
a
Br
N
5
5
5
4
similarity to reported O-aryl-carbamate rearrangements4
and rearrangements of trialkylsilyl ethers and esters.5 The
ease of the reaction encouraged us to investigate the scope
of this novel rearrangement. The precursors for this rear-
rangement, di-Boc-substituted ortho-bromoanilines, were
prepared by a reliable, published procedure that is appli-
cable to a wide range of anilines.6 The n-BuLi initiated re-
arrangement was then found to be generally applicable for
the preparation of anthranilic acids that were of interest
for us. In the case of 2-[5-Cl], 1.1 equivalents of n-BuLi
afforded a ‘spot-to-spot’ reaction, as monitored by TLC
within less than 15 minutes. The fast rate of the reaction
allows adding n-BuLi in small, sub-equivalent amounts
until all starting material is consumed, as monitored by
TLC or HPLC. The latter option is useful in the case of
very small-scale reactions, when it is difficult to accurate-
ly dose the amount of the added n-BuLi. High yields of
diprotected anthranilic acids 3 were obtained when elec-
tron-withdrawing substituents such as Cl, OCF3, CF3, or
CN were present in positions 4 and 5 (Table 1, entries
1–6). The unsubstituted anthranilic acid derivative 3-[H]
or compounds with fluoro substituents {3-[5-F], 3-[4-F]}
were obtained in somewhat reduced yields (Table 1,
O
O
O
O
b
R
R
R
4
4
O
NH
NH2
3
3
3
O
O
1
2
3
Scheme 1 Reagents and conditions: a) Boc2O, THF, reflux; b)
n-BuLi, –78 °C, argon, THF.3 For clarity, the atom numbering of
anthranilic acid derivatives 3 was also applied to 1 and 2.
This novel access to anthranilic acid derivatives was
found when we reacted bromoarene 2-[5-Cl] (Table 1, en-
try 1) with n-BuLi to obtain a metalloaryl intermediate,
which was intended to be trapped with an electrophile
such as CO2. However, a rapid and preparatively useful
aza-metallo equivalent of a Fries rearrangement took
place after the addition of n-BuLi at –78 °C, leading to 3-
[5-Cl] in quantitative yield.3 This rearrangement has some
SYNLETT 2005, No. 20, pp 3107–3108
Advanced online publication: 04.11.2005
DOI: 10.1055/s-2005-921910; Art ID: G32005ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.1
2
.2
0
0
5

3108
S. Herzig et al.
LETTER
entries 7–9). p-Fluoro substituents are expected to have no at –78 °C. The rearrangement works especially well with
or an only weak electron-withdrawing effect7 and thus be- electron-deficient arene derivatives. Preliminary results
haves in terms of its electronic nature similar to a hydro- indicate that the reaction proceeds by an intramolecular
gen atom. Consequently, these latter findings suggest that mechanism.
the reaction is slightly less efficient, but still useful, with
non-electron-deficient arenes. Product 3-[5-CH3] with an
electron-donating methyl group could not be isolated
References
(1) For other procedures that involve metalloarene
intermediates, see: (a) Reed, J. N.; Snieckus, V. Tetrahedron
Lett. 1984, 25, 5505. (b) Bengtsson, S.; Hogbert, T. J. Org.
Chem. 1989, 54, 4549. (c) Zhang, P. W.; Zhang, W. J.; Liu,
R. Y.; Harris, B.; Skolnick, P.; Cook, J. M. J. Med. Chem.
1995, 38, 1679.
(2) Tillu, V. H.; Wakharkar, R. D.; Pandey, R. K.; Kumar, P.
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
2004, 43, 1004.
from the reaction mixture (Table 1, entry 10). The reac-
tion proceeded in the presence of a nitrile and ester func-
tionality, which are not generally regarded as being
compatible with lithium organic reagents (Table 1, entries
4 and 11). However, the presence of a nitro group led to
decomposition of 2-[3-NO2, 5-F], and the corresponding
product 3-[3-NO2, 5-F] could not be isolated (Table 1,
entry 12).
(3) General Procedure – Preparation of 2-tert-butoxy-
carbonylamino-5-chlorobenzoic acid tert-butyl ester
(3a).
Br
COOt-Bu
O
a
t-Bu
A solution of n-BuLi in hexane (340 mL of 1.6 M) were
added dropwise at –78 °C under argon to a solution of N,N-
di-tert-butyloxycarbonyl-2-bromo-4-chloroaniline (203 mg,
0.5 mmol) in THF (5 mL). The reaction turned yellow, was
stirred for 15 min at –78 °C and treated with sat. aq NH4Cl
solution. The reaction was warmed to r.t., diluted with H2O
and extracted twice with Et2O. The combined organic layers
were washed with sat. aq NaCl solution, dried over Na2SO4,
filtered and the solvent was evaporated to yield 169 mg (0.5
mmol) of 2-tert-butoxycarbonylamino-5-chlorobenzoic acid
tert-butyl ester as a white crystalline solid.
IR (CHCl3): 3289, 2924, 2854, 1736, 1723, 1683, 1586,
1512, 1457, 1367, 1320, 1249, 1167, 1048, 1025, 898, 824,
786, 772, 717, 653, 532, 498 cm–1. 1H NMR (250 MHz,
CDCl3): d = 10.28 (br s, 1 H), 8.41 (d, 1 H), 7.88 (d, 1 H),
7.41 (dd, 1 H), 1.61 (s, 9 H), 1.43 (s, 9 H). 13C NMR (75
MHz, CDCl3): d = 166.2, 152.8, 140.8, 133.7, 130.6, 125.9,
120.2, 117.2, 82.9, 80.7, 28.3, 28.2. MS (EI): m/z = 327 (25),
271 (20), 215 (90), 171 (100), 153 (40). HRMS (EI, Q-TOF):
m/z calcd for C16H21ClNO4 [M – H]–: 326.1159; found:
326.1175.
N
O
+
O
O
F
F
t-Bu
4
5
6
Scheme 2 Reagents and conditions: a) n-BuLi, –78 °C, THF, argon.
In order to investigate the mechanistic aspects of the reac-
tion, we tried to perform an intermolecular reaction
(Scheme 2). p-Fluoro-bromobenzene 4 was metallated
with n-BuLi and reacted with di-Boc-aniline 5 as a tert-
butyl-carboxylating reagent. This did not lead to para-
fluorobenzoic acid tert-butyl ester 6 under these reaction
1
conditions (the H NMR of the crude reaction mixture
showed, that reagent 5 was not consumed and therefore no
Boc-group was transferred; in addition comparison of the
HPLC chromatogram of the reaction mixture with an au-
thentic sample of 6 revealed that the intermolecular Boc-
transfer reaction did not take place). This finding indicates
that the rearrangement described in Scheme 1 might be
an intramolecular reaction. This interpretation is in ac-
cordance with previously reported, similar rearrange-
ments of trialkylsilyl ethers, for which an intramolecular
mechanism has been demonstrated.5
(4) (a) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1937.
(b) Hajduk, P. J.; Shuker, S. B.; Nettesheim, D. G.; Craing,
R.; Augeri, D. J.; Betebenner, D.; Albert, D. H.; Guo, Y.;
Meadows, R. P.; Xu, L.; Michaelides, M.; Davidsen, S. K.;
Fesik, S. W. J. Med. Chem. 2002, 45, 5628.
(5) (a) Miller, J. A. J. Org. Chem. 1987, 52, 322.
(b) Hardcastle, I. R.; Quayle, P. Tetrahedron Lett. 1994, 35,
1749. (c) Billedeau, R. J.; Sibi, M. P.; Snieckus, V. J.
Tetrahedron Lett. 1983, 24, 4515. (d) Simchen, G.;
Pfetschinger, J. Angew. Chem., Int. Ed. Engl. 1976, 15, 428.
(e) Habich, D.; Effenberger, F. Synthesis 1979, 841.
(6) Darnbrough, S.; Mervic, M.; Condon, S. M.; Burns, C. J.
Synth. Commun. 2001, 31, 3273.
In summary, di-boc-substituted ortho-bromoanilines,
which are readily available from ortho-bromoanilines,
can be converted into N-Boc-protected anthranilic acid
tert-butyl esters by an aza-metallo equivalent of a Fries re-
arrangement after the addition of 1 equivalent of n-BuLi
(7) Schlosser, M. Angew. Chem. Int. Ed. 1998, 110, 1496.
Synlett 2005, No. 20, 3107–3108 © Thieme Stuttgart · New York