An improved synthesis of N-Boc protected aryl amines

Article abstract of DOI:10.1081/SCC-100106036

There are several known methods of protecting amines as their Boc derivatives. For less nucleophilic amines such as aryl amines these methods often give poor yields and are generally not satisfactory. Here, Boc aryl amines are obtained by first introducing two Boc groups followed by selective removal of one of them. This procedure works well for a number highly sterically hindered substrates as well as electron deficient and electron rich aryl amines.

Full text of DOI:10.1081/SCC-100106036

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AN IMPROVED SYNTHESIS OF N-BOC PROTECTED ARYL
AMINES
Shelley Darnbrough a , Miljenko Mervic a , Stephen M. Condon b & Christopher J. Burns a
a Department of Medicinal Chemistry, Aventis Pharmaceuticals, 500 Arcola Road,
Collegeville, PA, 19426, U.S.A.
b Millennium Pharmaceuticals, Inc., 75 Sidney St., Cambridge, MA, 02139, U.S.A.
Version of record first published: 20 Aug 2006.
To cite this article: Shelley Darnbrough, Miljenko Mervic, Stephen M. Condon & Christopher J. Burns (2001): AN
IMPROVED SYNTHESIS OF N-BOC PROTECTED ARYL AMINES, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:21, 3273-3280
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SYNTHETIC COMMUNICATIONS, 31(21), 3273–3280 (2001)
AN IMPROVED SYNTHESIS OF
N-BOC PROTECTED ARYL AMINES
Shelley Darnbrough,* Miljenko Mervic,
Stephen M. Condon,y and Christopher J. Burns
Department of Medicinal Chemistry,
Aventis Pharmaceuticals, 500 Arcola Road,
Collegeville, PA 19426
ABSTRACT
There are several known methods of protecting amines as
their Boc derivatives. For less nucleophilic amines such as
aryl amines these methods often give poor yields and are
generally not satisfactory. Here, Boc aryl amines are obtained
by first introducing two Boc groups followed by selective
removal of one of them. This procedure works well for
a number highly sterically hindered substrates as well as
electron deficient and electron rich aryl amines.
The Boc group has been used extensively for the protection of amines
due to its ease of formation, stability under basic conditions and ease of
removal.1 Boc-protected aryl amines are important intermediates in organic
*Corresponding author.
yCurrent Address: Millennium Pharmaceuticals, Inc. 75 Sidney St., Cambridge,
MA 02139.
3273
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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DARNBROUGH ET AL.
Figure 1.
synthesis and have been used for the directed lithiation of aromatic rings2
and the preparation of unsymmetrical ureas3 amongst others. Our interest in
mono-Boc protected anilines arose from our desire to prepare a series of
2-halo-N-Boc-anilines as substrates in the well-documented Pd-mediated
coupling/cyclization with terminal alkynes.4
Aryl amines are particularly difficult to protect with the Boc-group
because of the reduced nucleophilicity of the nitrogen atom when compared
to primary of secondary aliphatic amines. Thus, their synthesis often
requires the Curtius rearrangement of acyl azides followed by trapping
with t-butyl alcohol.5 However, recent reports have demonstrated that the
reaction of aryl amines with one equivalent of di-t-butyldicarbonate
(Boc2O) using extended reaction times,6 elevated temperatures,7 or the addi-
tion of a base (DMAP,8 aq. NaOH9 or pyridine10) can be successful in
certain cases. In addition, Kelly and McNeil published a general method
for the mono-N-Boc-protection of aryl amine derivatives using Boc2O and
sodium hexamethyldisilazide (NaHMDS).11 This new procedure addressed
many of the problems associated with mono-N-Boc-protection of aryl
amines but was limited by steric effects, especially when the amine was
flanked by two ortho-substituents.
Since our aryl amines all contained a halogen in the ortho-position and
several were highly sterically hindered, they appeared to be very reluctant to
undergo direct mono-Boc protection using one equivalent of Boc2O. Using
all of the conditions described above, including the NaHMDS method, the
reactions proceeded in all cases to afford only di-Boc product (4) and recov-
ered starting material (3, Scheme 1). It is thought that mono-Boc protection
of these derivatives is very slow but once the first Boc group is incorporated,
the carbamate NH is then sufficiently acidic to allow deprotonation and
Scheme 1.

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N-BOC PROTECTED ARYL AMINES
3275
fast incorporation of a second Boc-group. We anticipated that one might
exploit this phenomenon by purposefully exhaustively protecting the aryl
amines and then performing a selective deprotection to afford the required
mono-Boc-derivatives (Scheme 1).
Treatment of each ortho-halo aryl amine with a 3-fold excess of Boc2O
in the presence of a catalytic amount of DMAP in refluxing THF rapidly
formed the di-Boc derivatives (4) in quantitative yield. The selective removal
of one Boc-group is not well-precedented in the literature although isolated
reports using TFA have appeared.12,13 The deprotection of different carba-
mate groups in the presence of a Boc-group under basic conditions, is
however, well-documented.14,15 These conditions have been applied, again
in isolated examples, to the selective deprotection of di-Boc amines.16,17
We therefore chose to use potassium carbonate in methanol at reflux
as the conditions to selectively remove one Boc-group and provide the
required derivatives (1). The reactions were generally complete in 2–12 h
and provided 70–90% yields of the required products after purification by
flash silica gel chromatography. This method was successfully applied to
a number of highly electron-deficient and sterically hindered substrates
(Table 1).
As can be seen in Table 1, entries 4–11 show that this method is
applicable to ortho-halo substituted aryl amines containing both activating
and deactivating functional groups in the aromatic ring. Entries 12–15
clearly demonstrate that unprecedented sterically hindered amines where
the amine is flanked by two substituents are also accessible using this
method. Entries 16–21 are examples which were made to test whether
this method is limited to ortho-halo substituted aryl amines. Entry 17 is of
particular interest since this highly sterically hindered compound could not
be synthesized using the NaHMDS method yet was obtained in good yield
using this route. Entry 18 showed a limitation to the method in that upon
subjecting the di-Boc derivative to the deprotection conditions, both
Boc-groups were removed and only the starting aniline was recovered.
However, if the deprotection was performed at ambient temperature, the
required mono-Boc derivative was successfully obtained. Entry 20 demon-
strates that the acid functionality is not stable to the reaction conditions.
The reaction proceeded to afford some of the required product plus the
corresponding methyl ester. This problem could be countered by using
the methyl ester derivative (Entry 21) which was stable to the reaction
conditions with no hydrolysis of the ester being observed.
In an attempt to convert this method into a one-pot synthesis, it was
found that by concentrating the THF after the first reaction and using the
material directly in the next reaction, good yields could be obtained. This led
us to merely add potassium carbonate and methanol to the THF solution

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DARNBROUGH ET AL.
Table 1.
Product
R1
R2
R3
R4R5
Yield (%)
4
5
6
I
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
F
H
NO2
H
t-Butyl
F
F
Cl
NO2
H
H
H
Cl
H
NO2
H
CF3
H
H
F
H
H
Cl
H
H
MeO
H
H
H
H
H
H
H
H
H
H
F
76
88
88
86
85
75
69
74
82
72
73
81
83
78/97a
0b
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
F
Cl
Cl
H
NO2
MeO
H
NO2
H
H
H
H
H
H
NO2
H
CO2H
CO2Me
MeO
MeO
H
79
H
H
29c
72
H
aSecond yield reflects results from one-pot reaction procedure; bComplete removal of
both Boc groups observed to afford only starting material. Mono-Boc deprotection
c
successful if reaction performed at ambient temperature; Reaction complicated by
esterification of the acid functionality during Boc-deprotection step.
after completion of Boc-protection and proceed with the reaction. This
method also worked well and even provided improved yields in one case
(Entry 17).
In conclusion we have presented an improved general method to
prepare inaccessible Boc-protected aryl amines using a simple two-step
exhaustive Boc-protection/selective deprotection procedure which can also
be used as a one-pot procedure. The method works well on several different

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N-BOC PROTECTED ARYL AMINES
3277
substrates and is of particular use when highly sterically hindered aryl
amines are employed.
General Procedure: To a solution of the aryl amine (9.69 mmol) in
anhydrous THF (100 mL) was added Boc2O (29 mmol) followed by
DMAP (0.97 mmol). The solution was stirred at reflux for 2–12 h then
concentrated to dryness and partitioned between 0.5 N HCl (100 mL) and
EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2 ꢀ 50 mL)
and the combined organic phases were washed with brine (50 mL), dried
over NaSO4, filtered and concentrated to afford the crude di-Boc product
usually as a solid.
The crude material was dissolved in methanol (100 mL), treated with
potassium carbonate (29 mmol) and stirred at reflux for 2–12 h. The mixture
was concentrated to dryness and partitioned between 0.5 N HCl (100 mL)
and EtOAc (100 mL). The aqueous phase was extracted with EtOAc
(2 ꢀ 50 mL) and the combined organic phases were washed with brine
(50 mL), dried over Na2SO4, filtered and concentrated to afford the crude
product. This was purified by flash silica gel column chromatography elut-
ing with hexane/EtOAc mixtures to afford the products as white solids or
colourless oils in 70–90% overall yield.
(2-Iodo-phenyl)-carbamic acid tert-butyl ester (4): 1H NMR (300 MHz,
CDCl3) d 8.02 (dd, J ¼ 8.3, 1.3 Hz, 1H), 7.73 (dd, J ¼ 7.9, 1.3 Hz, 1H), 7.27
(m, 1H), 6.80 (br. s, 1H), 6.75 (m, 1H), 1.56 (s, 9H) ppm. Mass Spectrum:
(ESI) m/z 320 (M þ H)+.
1
(2-Bromo-4-chloro-phenyl)-carbamic acid tert-butyl ester (5): H NMR
(300 MHz, CDCl3) d 8.10 (dd, J ¼ 8.9 Hz, 1H), 7.49 (d, J ¼ 2.4Hz, 1H), 7.24
(dd, J ¼ 8.9, 2.4Hz, 1H), 6.94(br. s, 1H), 1.52 (s, 9H) ppm. Mass Spectrum:
(EI) m/z 307 (M+).
1
(2-Bromo-5-chloro-phenyl)-carbamic acid tert-butyl ester (6): H NMR
(300 MHz, CDCl3) d 8.25 (d, J ¼ 2.4Hz, 1H), 7.40 (d, J ¼ 8.5 Hz, 1H), 6.99
(br. s, 1H), 6.87 (dd, J ¼ 8.5, 2.5 Hz, 1H), 1.55 (s, 9H) ppm. Mass Spectrum:
(EI) m/z 307 (M+).
1
(2-Bromo-4-fluoro-phenyl)-carbamic acid tert-butyl ester (7): H NMR
(300 MHz, CDCl3) d 8.07 (dd, J ¼ 9.1, 5.5 Hz, 1H), 7.23 (m, 1H), 6.97 (m, 1H),
6.83 (br. s, 1H), 1.55 (s, 9H) ppm. Mass Spectrum: (EI) m/z 290 (M þ H)+.
1
(2-Bromo-5-nitro-phenyl)-carbamic acid tert-butyl ester (8): H NMR
(300 MHz, CDCl3) d 9.10 (d, J ¼ 2.6 Hz, 1H), 7.75 (dd, J ¼ 8.7, 2.6 Hz,
1H), 7.67 (d, J ¼ 8.7 Hz, 1H), 7.15 (br. s, 1H), 1.55 (s, 9H) ppm. Mass
Spectrum: (ESI) m/z 319 (M þ H)+.
1
(2-Bromo-4-nitro-phenyl)-carbamic acid tert-butyl ester (9): H NMR
(300 MHz, CDCl3) d 9.10 (d, J ¼ 2.6 Hz, 1H), 7.75 (dd, J ¼ 8.7, 2.6 Hz,
1H), 7.67 (d, J ¼ 8.7 Hz, 1H), 7.15 (br. s, 1H), 1.55 (s, 9H) ppm. Mass
Spectrum: (ESI) m/z 319 (M þ H)+.

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3278
DARNBROUGH ET AL.
(2-Bromo-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (10):
1H NMR (300 MHz, CDCl3) d 8.50 (s, 1H), 7.61 (d, J ¼ 8.4Hz, 1H), 7.13
(dd, J ¼ 8.4, 1.9 Hz, 1H), 7.09 (br. s, 1H), 1.54 (s, 9H) ppm. Mass Spectrum:
(EI) m/z 340 (M þ H)+.
(2-Bromo-4-tert-butyl-phenyl)-carbamic acid tert-butyl ester (11):
1H NMR (300 MHz, CDCl3) d 7.99 (d, J ¼ 8.7 Hz, 1H), 7.48 (d, J ¼ 2.2 Hz,
1H), 7.28 (d, J ¼ 8.7, 2.2 Hz, 1H), 6.88 (br. s, 1H), 1.59 (s, 9H), 1.33 (s, 9H)
ppm. Mass Spectrum: (EI) m/z 327 (M)+.
(2-Bromo-4,6-difluoro-phenyl)-carbamic acid tert-butyl ester (12):
1H NMR (300 MHz, CDCl3) d 7.16 (m, 1H), 6.86 (m, 1H), 5.09 (br. s, 1H),
1.56 (s, 9H) ppm. Mass Spectrum: (EI) m/z 307 (M)+.
(2-Bromo-4,5,6-trifluoro-phenyl)-carbamic acid tert-butyl ester (13):
1H NMR (300 MHz, CDCl3) d 7.25 (m, 1H), 6.02 (br. s, 1H), 1.59 (s, 9H)
ppm. Mass Spectrum: (EI) m/z 326 (M þ H)+.
(2-Bromo-4,6-dichloro-phenyl)-carbamic acid tert-butyl ester (14):
1H NMR (300 MHz, CDCl3) d 7.53 (d, J ¼ 2.3 Hz, 1H), 7.41 (d, J ¼
2.3 Hz, 1H), 6.08 (br. s, 1H), 1.50 (s, 9H) ppm. Mass Spectrum: (EI) m/z
341 (M)+.
(2-Bromo-6-chloro-4-nitro-phenyl)-carbamic acid tert-butyl ester (15):
1H NMR (300 MHz, CDCl3) d 8.39 (d, J ¼ 2.5 Hz, 1H), 8.27 (d, J ¼ 2.5 Hz,
1H), 6.38 (br. s, 1H), 1.39 (s, 9H) ppm. Mass Spectrum: (EI) m/z 350
(M þ H)+.
(5-Chloro-phenyl)-carbamic acid tert-butyl ester (16): 1H NMR
(300 MHz, CDCl3) d 7.52 (s, 1H), 7.20 (m, 2H), 6.96 (m, 1H), 6.45 (br. s, 1H),
1.50 (s, 9H) ppm. Mass Spectrum: (EI) m/z 227 (M)+.
(2,6-Dinitro-phenyl)-carbamic acid tert-butyl ester (17): 1H NMR
(300 MHz, CDCl3) d 8.95 (br. s, 1H), 8.25 (d, J ¼ 8.2 Hz, 2H), 7.35 (t,
J ¼ 8.2 Hz, 1H), 1.54(s, 9H) ppm. Mass Spectrum: (EI) m/z 283 (M)+.
(2,5-Dimethoxy-4-nitro-phenyl)-carbamic acid tert-butyl ester (18):
1H NMR (300 MHz, CDCl3) d 7.45 (s, 1H), 6.85 (s, 1H), 3.90 (s, 3H),
3.80 (s, 3H), 147 (s, 9H) ppm. Mass Spectrum: (EI) m/z 298 (M)+.
1
(3,5-Dimethoxy-phenyl)-carbamic acid tert-butyl ester (19): H NMR
(300 MHz, CDCl3) d 6.58 (d, J ¼ 2.1 Hz, 2H), 6.45 (br. s, 1H), 6.15 (m,
1H), 3.76 (s, 6H), 1.42 (s, 9H) ppm. Mass Spectrum: (ESI) m/z 254
(M þ H)+.
4-tert-Butoxycarbonylamino-benzoic acid (20): 1H NMR (300 MHz,
CDCl3) d 8.03 (d, J ¼ 8.7 Hz, 2H), 7.45 (d, J ¼ 8.7 Hz, 2H), 6.75 (br. s,
1H), 1.59 (s, 9H) ppm. Mass Spectrum: (ESI) m/z 252 (M þ H)+.
1
4-tert-Butoxycarbonylamino-benzoic acid methyl ester (21): H NMR
(300 MHz, CDCl3) d 7.95 (d, J ¼ 8.7 Hz, 2H), 7.42 (d, J ¼ 8.7 Hz, 2H),
6.63 (br. s, 1H), 3.88 (s, 3H), 1.54(s, 9H) ppm. Mass Spectrum: (ESI) m/z
252 (M þ H)+.

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N-BOC PROTECTED ARYL AMINES
3279
One-Pot Procedure: To a solution of 2,6-dinitroaniline (100 mg,
0.55 mmol) in anhydrous THF (5 mL) was added Boc2O (358 mg,
1.64mmol) followed by DMAP (6.8 mg, 0.054mmol). The mixture was stir-
red at reflux for 3 h then cooled to ambient temperature. Potassium carbo-
nate (228 mg, 1.64mmol) and methanol (5 mL) were added and the mixture
was stirred at reflux for 3 h. The mixture was cooled to ambient temperature,
concentrated and the residue purified by flash silica gel column chromato-
graphy (hexane : EtOAc, 4:1), to afford 150 mg (97%) of (2,6-dinitro-
phenyl)-carbamic acid tert-butyl ester (17) as a white solid with identical
MS and NMR to a sample prepared by the general two-step procedure.
ACKNOWLEDGMENT
The authors wish to thank Dr. Sheng-Yuh Tang for obtaining mass
spectral data for all of the compounds.
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Received in the USA January 21, 2001

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