A simple key for benzylic mono- and gem-dibromination of primary aromatic amine derivatives using molecular bromine1

Article abstract of DOI:10.1055/s-2002-19812

Quantitative benzylic mono- and gem-dibromination on primary aromatic amine derivatives have been achieved using molecular bromine and by protecting the amino group as a succinimide moiety. The reactions of N-(o/m/p-tolyl)succinimides 5a-c with 1.25 equiv

Full text of DOI:10.1055/s-2002-19812

PAPER
221
A Simple Key for Benzylic Mono- and gem-Dibromination of Primary
Aromatic Amine Derivatives Using Molecular Bromine1
B
romination of Pri
n
mary Aroma
i
tic
A
m
r
ine
D
eriv
b
a
tive
s
an Kar, Narshinha P. Argade*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Fax +91(20)5893153; E-mail: argade@dalton.ncl.res.in
Received 25 September 2001; revised 12 November 2001
Dedicated to Honourable Professor Kenji Mori, Science University of Tokyo, Tokyo, Japan
bioactive natural products.7 During these studies,6–9 we
noticed that the lone pair of electrons on nitrogen atom in
N-aryl cyclic imides has no influence on the aryl ring. We
reasoned and planned to take advantage of this futuristic
Abstract: Quantitative benzylic mono- and gem-dibromination on
primary aromatic amine derivatives have been achieved using mo-
lecular bromine and by protecting the amino group as a succinimide
moiety. The reactions of N-(o/m/p-tolyl)succinimides 5a–c with
1.25 equivalents of molecular bromine in CCl4 at room temperature observation to add a new useful concept in the chemistry
furnished the corresponding benzylic monobrominated products
6a–c in 92–94% yields, while with 2.5 equivalents of molecular
bromine in refluxing CCl4 gem-dibromo products 7a–c were ob-
of primary aromatic amines.
The N-phenylsuccinimide (1)10 on reaction with molecu-
lar bromine in refluxing CCl4 and with bromine in acetic
acid at room temperature remained completely unreacted
proving that the lone pair of electrons on nitrogen atom in
phenyl succinimide 1 is fully engaged with two imide car-
bonyls and loses its mesomeric connectivity with aromat-
ic ring and the phenyl ring behaves like benzene
(Scheme). The reaction of the corresponding p-methoxy
derivative 3 with bromine in acetic acid at room tempera-
ture exclusively furnished the desired nuclear brominated
product 4 in 100% yield (Scheme), thus rendering the
electrophilic substitution at an alternate site, dictated by a
secondary activating OCH3 group (as compared to NH2).
With suitable manipulations in substrate structures and re-
action conditions, several electrophilic substitution reac-
tions will be possible to generate an avenue of new and
useful aniline derivatives. Like toluene,2c the N-(o/m/p)-
tolylsuccinimides 5a–c on treatment with 1.25 equiva-
lents of molecular bromine in CCl4 at room temperature,
underwent a smooth monobenzylic bromination to yield
the products 6a–c respectively, in 92–94% yields, while in
refluxing CCl4 with 2.50 equivalents of bromine they fur-
nished the corresponding gem-dibromo derivatives 7a–c
respectively, in 94–96% yields (Scheme). Both these
mono- and gem-dibenzylic bromination reactions must be
following a radical pathway and the ortho-, meta- and
para-isomers reacted in a similar manner revealing that
only the benzylic relay may be operational at the reaction
sites. Moreover these compounds 6a–c and 7a–c are clean
solid materials and do not show any noticeable lachrymal
properties. Thus for the first time benzylic monobromina-
tions and gem-dibrominations have been achieved on the
toluidine nucleus by using molecular bromine and pro-
tecting the free amino group as succinimide moiety and
this concept will be amply useful for benzylic mono/gem-
dihalogenations of several other primary aromatic amine
derivatives. The monobrominated products 6a–c will pro-
tained in 94–96% yields. It is also possible to carry out nuclear bro-
mination in these N-protected primary aromatic amines at an
alternate site by using suitably substituted aniline derivatives. Thus
the reaction of 3 with 1.25 equivalents of molecular bromine in ace-
tic acid gave the desired monobrominated product 4 in nearly 100%
yield.
Key words: primary aromatic amines, succinimide derivatives,
molecular bromine, benzylic mono-/gem-dibromination
Large numbers of primary aromatic amine derivatives
(aniline derivatives) with a variety of substituents and
substituent patterns are well known in the literature and
their utilities have been also well proved in practice.2
They are generally obtained by electrophilic or nucleo-
philic aromatic substitution reactions and these synthetic
operations are performed directly on free aniline deriva-
tives,2c N-nitrosoaniline derivatives,2c N-haloaniline de-
rivatives,3 N-hydroxyaniline derivatives4 or N-protected
aniline derivatives.2c The free NH2 group protections are
generally done by converting it into (a) N-acyl derivatives
(b) N-protonated salts (c) carbamates, and (d) phthalim-
ides. The latter two protecting groups have been mostly
used in the chemistry of amino acids.2c There is no direct
method to obtain aniline derivatives, wherein the electro-
philic substitutions are directed by a secondary activating
group on the phenyl ring, and also for benzylic halogena-
tions on aniline derivatives. To date, both these aims have
been achieved in a stepwise fashion by carrying out the
various reactions on the corresponding less reactive nitro
derivatives, followed by reduction of the nitro group to an
amino group.5 This process is quite cumbersome and may
not be feasible for all the cases. For the past several years
we have been using cyclic anhydrides and imides as po-
tential starting materials for the synthesis of structurally
interesting and biologically important heterocycles6 and
vide
a new simple, clean and efficient approach to
ortho-, meta- and para-aminobenzyl nitrile,11,12 benzyl
amine,13 benzyl alcohol,14 benzyl thiol15 derivatives and
several other products, while gem-dibromo products 7a–c
Synthesis 2002, No. 2, 01 02 2002. Article Identifier:
1437-210X,E;2002,0,02,0221,0224,ftx,en;Z11001SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

222
A. Kar, N. P. Argade
PAPER
will be potential starting materials for corresponding o/m/
p-amino gem-diamine/imine,2d gem-diol,16 gem-dithiol,17
benzaldehyde,18 acetal,19 1,3-dithiane20 derivatives and
several other products. These new potential approaches to
the above mentioned compounds will be highly useful in
practice and depending on the substrate structure, the pro-
tecting group can be detached by using hydrazine or acid-
ic/basic reaction conditions.
Melting points are uncorrected. Ac2O was obtained from Aldrich
Chemical Co. Freshly prepared succinic anhydride and freshly pu-
rified amines were used.
Succinanilic acids
To a stirred solution of succinic anhydride (5 g, 50 mmol) in a mix-
ture of benzene and 1,4-dioxane (60 mL, 2:1) was added a solution
of primary aromatic amine (50 mmol) in Et2O (40 mL) in a drop-
wise fashion at r.t. over a period of 20 min and the mixture was fur-
ther stirred for 2 h. The formed solid product was filtered, washed
with Et2O (25 mL) and vacuum dried to obtain succinanilic acids in
quantitative yield, which were used for the next step without any
further purification.
N-Arylsuccinimides 1, 3 and 5; General Procedure
A mixture of succinanilic acid (45 mmol), Ac2O (30 mL) and fused
NaOAc (500 mg) was heated on a water bath at 60 °C for 2 h. The
mixture was cooled to r.t. and poured into ice-cold water. The pre-
cipitated product was filtered, washed with H2O and dried in vacuo
to obtain succinimides 1, 3 and 5 in 90–95% yield.
1
Mp 158–159 °C.
IR (Nujol): 1776, 1709, 1595 cm–1.
1H NMR (CDCl3, 200 MHz): = 2.91 (s, 4 H), 7.20–7.60 (m, 5 H).
3
Mp 165–167 °C.
IR (Nujol): 1770, 1705, 1607 cm–1.
1H NMR (CDCl3, 200 MHz): = 2.88 (s, 4 H), 3.82 (s, 3 H), 6.99
(d, J = 10 Hz, 2 H), 7.20 (d, J = 10 Hz, 2 H).
5a
Mp 99–102 °C.
IR (Nujol): 1770, 1705, 1600 cm–1.
1H NMR (CDCl3, 200 MHz): = 2.15 (s, 3 H), 2.93 (s, 4 H), 7.08
(d, J = 6 Hz, 1 H), 7.25–7.45 (m, 3 H).
5b
Mp 103–105 °C.
IR (Nujol): 1767, 1705, 1607 cm–1.
1H NMR (CDCl3, 200 MHz): = 2.39 (s, 3 H), 2.88 (s, 4 H), 7.00–
7.50 (m, 4 H).
5c
Scheme Reagents and conditions: (i) Br2 (1.25 mmol), CCl4, reflux,
24 h; (ii) Br2 (1.25 mmol), HOAc, r.t., 6 h (aqueous workup); (iii) Br2
(1.25 mmol), CCl4, r.t., 4 h; (iv) Br2 (2.50 mmol), CCl4, reflux, 8 h;
(v) Br2 (1.25 mmol), CCl4, reflux, 8 h
Mp 158-160 °C.
IR (Nujol): 1770, 1705, 1600 cm–1.
1H NMR (CDCl3, 200 MHz): = 2.38 (s, 3 H), 2.87 (s, 4 H), 7.15
(d, J = 6 Hz, 2 H), 7.28 (d, J = 6 Hz, 2 H).
In summary, for the first time N-arylsuccinimides have
been treated as an aniline derivatives rather than succinic N-(3-Bromo-4-methoxy)phenylsuccinimide (4)
To a stirred solution of imide 3 (2.84 g, 10 mmol) in HOAc (20 mL)
anhydride derivatives to demonstrate the simple method
for nuclear bromination at an alternate site and benzylic
mono/gem-dibrominations using molecular bromine. In
future this concept will be highly useful to demonstrate
plenty of new applications in the subject. Starting from
compound 6a and 7a, we plan to develop new synthetic
routes to mitomycins21 and their congeners via reactivity
umpolung.
was added Br2 (2.00 g, 12.5 mmol) and the mixture was stirred at r.t.
for 6 h. Aqueous workup, followed by filtration of the formed pre-
cipitate and vacuum drying gave pure 4 (3.62 g, 100%); mp 178–
180 °C (CCl4).
IR (CHCl3): 1782, 1717, 1603 cm–1.
1H NMR (CDCl3, 200 MHz): = 2.89 (s, 4 H), 3.93 (s, 3 H), 6.99
(d, J = 10 Hz, 1 H), 7.24 (dd, J = 10, 2 Hz, 1 H), 7.51 (d, J = 4 Hz,
1 H).
MS: m/z = 285, 283, 270, 268, 257, 255, 240, 239, 214, 212, 204,
186, 158, 140, 132, 106, 90, 76, 63.
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Bromination of Primary Aromatic Amine Derivatives
223
Anal. Calcd for C11H10BrNO3 (284.1): C, 46.50; H, 3.55; N, 4.93.
Found: C, 46.62; H, 3.41; N, 5.01.
7b
Waxy solid.
IR (Nujol): 1780, 1715, 1607 cm–1.
1H NMR (CDCl3, 200 MHz): = 2.93 (s, 4 H), 6.65 (s, 1 H), 7.29
Benzylic Monobromination and gem-Dibromination of 5a–c
To a stirred solution of the appropriate succinimide 5a–c (5 mmol)
in CCl4 (40 mL) was added dropwise a solution of Br2 (6.25 mmol)
in CCl4 (10 mL) at r.t. over a period of 10 min to 15 min and the
mixture was further stirred for 4 h at r.t. The mixture was concen-
trated in vacuo and the residue was dissolved in EtOAc (50 mL).
The organic layer was washed with H2O, 5% aq NaHSO3, H2O,
brine and dried (Na2SO4). Concentration of the organic layer in vac-
uo furnished the desired monobromo products 6a–c in 92–94%
yields. Similarly the starting materials 5a–c (5 mmol) with Br2 (12.5
mmol) on refluxing in CCl4 (50 mL) for 8 h gave the gem-dibromo
compounds 7a–c in 94–96% yields. The 1H NMR spectra of isolat-
ed monobromo products 6a–c revealed that 2–3% of starting mate-
rials remain unreacted and/or the formation of corresponding gem-
dibromo products. The analytically pure products were obtained by
further recrystallisation.
(d, J = 8 Hz, 1 H), 7.40–7.70 (m, 3 H).
MS: m/z = 349, 347, 345, 268, 266, 210, 187, 158, 130, 117, 103, 89.
Anal. Calcd for C11H9Br2NO2 (347.0): C, 38.07; H, 2.61; N, 4.04.
Found: C, 37.88; H, 2.43; N, 4.02.
7c
Mp 212–213 °C (EtOAc).
IR (Nujol): 1774, 1707, 1603 cm–1.
1H NMR (CDCl3, 200 MHz): = 2.93 (s, 4 H), 6.65 (s, 1 H), 7.35
(d, J = 8 Hz, 2 H), 7.69 (d, J = 8 Hz, 2 H).
13C NMR (acetone-d6, 50 MHz): = 29.2, 41.6, 127.8, 127.9, 135.2,
142.8, 177.0.
MS: m/z = 349, 347, 345, 268, 266, 210, 184, 158, 130, 104, 77, 63.
6a
Anal. Calcd for C11H9Br2NO2 (347.0): C, 38.07; H, 2.61; N, 4.04.
Found: C, 37.97; H, 2.58; N, 3.76.
Mp 126–128 °C (CCl4).
IR (Nujol): 1782, 1717, 1595 cm–1.
1H NMR (CDCl3, 200 MHz): = 2.96 (d, J = 2 Hz, 4 H), 4.38 (s, 2
H), 7.17 (d, J = 6 Hz, 1 H), 7.30–7.65 (m, 3 H).
Acknowledgements
A. K. thanks CSIR, New Delhi, for the award of a research fel-
lowship. N. P. A. thanks Department of Science and Technology,
New Delhi, for financial support. We thank Dr. K. N. Ganesh, Head,
Division of Organic Chemistry (Synthesis), for constant encourage-
ment.
MS: m/z = 269, 267, 188, 160, 142, 132, 118, 104, 91, 77, 63.
Anal. Calcd for C11H10BrNO2 (268.1): C, 49.28; H, 3.76; N, 5.23.
Found: C, 49.11; H, 3.58; N, 5.08.
6b
Mp 97–100 °C (CHCl3).
IR (CHCl3): 1782, 1718, 1610 cm–1.
References
1H NMR (CDCl3, 200 MHz): = 2.90 (s, 4 H), 4.50 (s, 2 H), 7.20–
7.55 (m, 4 H).
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MS: m/z = 269, 267, 188, 160, 146, 132, 106, 91, 77, 65.
Anal. Calcd for C11H10BrNO2 (268.1): C, 49.28; H, 3.76; N, 5.23.
Found: C, 49.15; H, 3.82; N, 5.36.
6c
Mp 186-187 °C (EtOAc).
IR (Nujol): 1778, 1700, 1600 cm–1.
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(d, J = 8 Hz, 2 H), 7.51 (d, J = 8 Hz, 2 H).
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138.1, 175.9.
MS: m/z = 269, 267, 188, 132, 106, 89, 77.
Anal. Calcd for C11H10BrNO2 (268.1): C, 49.28; H, 3.76; N, 5.23.
Found: C, 49.16; H, 3.70; N, 5.19.
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IR (Nujol): 1771, 1709, 1595 cm–1.
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1H NMR (CDCl3, 200 MHz): = 2.99 (d, J = 2 Hz, 4 H), 6.55 (s, 1
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J = 8, 2 Hz, 1 H), 8.12 (dd, J = 10, 2 Hz, 1 H).
MS: m/z = 349, 347, 345, 268, 266, 186, 158, 130, 103, 76.
Anal. Calcd for C11H9Br2NO2 (347.0): C, 38.07; H, 2.61; N, 4.04.
Found: C, 37.93; H, 2.55; N, 3.81.
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224
A. Kar, N. P. Argade
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Synthesis 2002, No. 2, 221–224 ISSN 0039-7881 © Thieme Stuttgart · New York