Improved yields of meta-amination and symmetrical and unsymmetrical diamination of benzenes

Article abstract of DOI:10.1016/S0040-4039(01)00582-2

Much higher yields were found after shorter reaction times for the meta-substituted amination of benzenes in DMPU with microwave heating in a sealed tube (180°C, 5 h), e.g. piperidine and m-fluorobenzonitrile 1 gave the m-substituted 3 in 92% yield. These

Full text of DOI:10.1016/S0040-4039(01)00582-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3917–3919
Improved yields of meta-amination and symmetrical and
unsymmetrical diamination of benzenes
George R. Brown,* Alan J. Foubister, Craig A. Roberts, Stuart L. Wells and Robin Wood
AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Received 30 January 2001; revised 27 March 2001; accepted 6 April 2001
Abstract—Much higher yields were found after shorter reaction times for the meta-substituted amination of benzenes in DMPU
with microwave heating in a sealed tube (180°C, 5 h), e.g. piperidine and m-fluorobenzonitrile 1 gave the m-substituted 3 in 92%
yield. These modified reaction conditions also afforded a new synthesis of unsymmetrical diamines in >80% yield. © 2001 Elsevier
Science Ltd. All rights reserved.
There are two main strategies for the nucleophilic ami-
nation of benzenes.1 Palladium-catalysed amination
proceeds in good yields with a range of substrates and
is often the synthetic method of choice. Alternatively, a
benzene substituted by a leaving group may be reacted
with an amine, but the benzene must also contain an
ortho or para electron-withdrawing group (EWG).
Another limitation of direct substitution is that syn-
thetic yields in meta-substitution have been very poor.1
Recently we described2 improved yields of these meta-
substitutions, but the best yields were obtained only
with a strong EWG. Yields in primary amine substitu-
tions were modest, and substitution of a second amine
group into dihalo-substituted compounds proceeded in
poor yield. Herein, we report an investigation aimed at
a significant yield improvement for the direct amination
reaction, enabling a wider substrate scope to be used.
could not be improved2 by variation of the reaction
conditions, including increasing the reaction tempera-
ture to 130°C. A more significant increase in reaction
temperature was examined with a sealed glass tube
(Carius tube) and with a microwave oven, where recent
developments3 allow for sealed tube reactions.
Piperidine substitution in benzenes with a para-substi-
tuted EWG has been reported4 (without any yield
improvement) in a microwave oven with external reflux.
We anticipated, however, that much higher reaction
temperatures would be attainable with a Carius tube or
in a sealed reaction tube in a microwave oven, and that
this might improve the yields of our more difficult
meta-aminations. Due to the potential for decomposi-
tion of DMSO at these higher reaction temperatures
(with the risk of a pressure build up), alternative sol-
vents to DMSO were examined for the amination in
Scheme 1 (Table 1). The amination yield of 2 obtained
with morpholine in sulpholane was much poorer than
that found in DMSO (18 versus 62%), but in
sulpholane in a sealed tube in a microwave oven at
Amination of 3-fluorobenzonitrile 1 with 5.5 equiva-
lents of morpholine (Scheme 1) in DMSO at 100°C for
60 h (under conventional atmospheric pressure reaction
conditions) had given2 a 62% yield of 2. This yield
Scheme 1.
Keywords: amination; aryl halides; substituent effects.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00582-2

3918
G. R. Brown et al. / Tetrahedron Letters 42 (2001) 3917–3919
Table 2. Reactions of primary amines under microwave
reaction conditions
Table 1. Variation in morpholine aminations of 1 with
solvent and heating conditions
Conditions
Solvent
°C
Time (h)
Yield of 2
(%)
Conventional Sulpholane
Microwave Sulpholane
Conventional DMPU
100 60
180
100 60
180
180 18
18
30
51
63
51
41
80
2
Compound
R
Amine R%NH2 Conditions
Yield (%)
Carius tube
Carius tube
Microwave
Microwave
DMPU
DMPU
DMPU
DMPU
5
8
8
CN MeS(CH2)3NH Conventional 31
180
180
2
5
2
CN MeS(CH2)3NH Microwave
56
2
9
9
10
10
CN Allylamine
CN Allylamine
CN Benzylamine
CN Benzylamine
Conventional 19
Microwave 29
Conventional 33
Microwave 42
180°C for only 2 h the yield was improved (30%).
Reactions in DMPU gave a small yield improvement in
the Carius tube, but decomposition occurred in the 18
h reaction. In a sealed tube in the microwave oven an
80% yield of 2 was obtained after 5 h, compared with
62% in 60 h previously.2 Under the same reaction
conditions, but with piperidine or N-methylpiperazine
in place of morpholine, the amination yields were 92%
of 3 and 93% of 4 (Scheme 1), respectively (originally2b
68 and 69% in DMSO at 100°C for 60 h). Thus with
DMPU as solvent and shorter reaction times, large
yield improvements were found with microwave heat-
ing, but in the Carius tube decomposition was
observed. These microwave reaction conditions were
applied generally to: benzenes with other EWGs; ben-
zenes with a chloro-leaving group; primary amines and
disubstitution reactions with difluorobenzenes. The
observed yields were compared to those previously
obtained2b under conventional reaction conditions in
DMSO at atmospheric pressure and 100°C for 60 h.
not proceed at all2b under the conventional DMSO
reaction conditions, but under the microwave condi-
tions a 12% yield of 2 and a 14% yield of 7 was
isolated. Under the microwave oven conditions primary
amines consistently afforded better yields in reactions
with 1 (Table 2).
For palladium-catalysed diamination of m-dibromo-
benzenes good yields (45–83%) have been reported5 by
Beletskaya with morpholine and piperidine, but the
desired symmetrical diamines had to be separated from
dehydrohalogenation products. By contrast, our
microwave conditions in DMPU with an EWG present
gave high disubstitution yields (Table 3) of the symmet-
rical compounds 12 and 14. Unsymmetrical diamines
were not described by Beletskaya,5 and we have pre-
pared these in two ways. Firstly, we used the rare6
chemical 15 (Scheme 2) with our conventional DMSO
conditions for introduction of the first amino group to
afford 16 (under microwave conditions, mixtures were
obtained due to some amide formation). Introduction
of the second amine group to give 18, and separately
19, was then effected via palladium-catalysed
amination1 with bromide as the leaving group. Sec-
ondly, we re-examined in DMSO, the diaminations of
m-difluorobenzenes containing EWGs under milder
Sealed tube reactions in DMPU in a microwave oven at
180°C for 5 h
Morpholine gave only a modest yield improvement
during displacement of m-fluorobenzenes containing
weaker EWGs than cyano; e.g. with m-difluorobenzene
(structures in Scheme 1), 13% of 5 versus 8% in DMSO;
with m-trifluoromethyl fluorobenzene 28% of 6 versus
19% in DMSO. Chlorine replacement with morpholine
in m-chlorobenzonitrile and m-chloronitrobenzene did
Table 3. Reaction of excess morpholine with difluorobenzenes
Compounds
R
Reaction conditions
% Mono substitution
% Di substitution
11 and 12
11 and 12
11 and 12
13 and 14
13 and 14
13 and 14
CN
CN
CN
NO2
NO2
NO2
Conventional rt
Conventional 100°C
Microwave
Conventional rt
Conventional 100°C
Microwave
98a
62
5
0
37
65
0
16
76
91a
78
7
a Reaction allowed to reach completion by TLC.

G. R. Brown et al. / Tetrahedron Letters 42 (2001) 3917–3919
3919
Scheme 2.
reaction conditions. Introduction of the first amino
group proceeded regioselectively at room temperature
over 3–10 days (Table 3) or in a period of hours at
100°C to afford 11, and 13. Substitution of the second
amino group had previously proceeded2b in poor yield,
making access to unsymmetrical diamines difficult.
Now, unsymmetrical substitution was achieved via the
monosubstituted 11 (Scheme 2) in >80% yield. Pipe-
ridine was introduced as the second amino group under
the microwave conditions to give the unsymmetrical
diamine 20 in 88% yield.
References
1. Belfield, A. J.; Brown, G. R.; Foubister, A. J. Tetra-
hedron 1999, 55, 11399–11428. (Tetrahedron report num-
ber 503).
2. (a) Brown, G. R.; Foubister, A. J.; Ratcliffe, P. D. Tet-
rahedron Lett. 1999, 40, 1219–1222; (b) Belfield, A. J.;
Brown, G. R.; Foubister, A. J.; Ratcliffe, P. D. Tetra-
hedron 1999, 55, 13285–13300 and corrigendum 2000, 56,
4107.
3. MARS-X™ microwave system at power level 300 W in
PTFE cells with magnetic stirring; CEM (Microwave
Technology) Ltd., Buckingham Industrial Park, Bucking-
ham MK18 1WA, UK.
4. Salmoria, G. V.; Dall’Oglio, E.; Zucco, C. Tetrahedron
Lett. 1998, 39, 2471–2474.
In summary, microwave heating
at 180°C in a sealed tube raised all of the m-amination
yields in a shorter reaction time than with the conven-
tional DMSO reaction conditions for 60 h. Diamina-
tions were achieved in high yield for symmetrical and
unsymmetrical substrates without the use of transition
metals.
5. Beletskaya, I. P.; Bessmertnykh, A. G.; Guilard, R. Tet-
rahedron Lett. 1999, 40, 6393–6397.
6. Butt Park Ltd., Braysdown, Bath BA2 8LL, UK.
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