Molybdenum hexacarbonyl and DBU reduction of nitro compounds under microwave irradiation

Article abstract of DOI:10.1055/s-2007-986628

An ethanolic mixture of molybdenum hexacarbonyl and DBU mediates the reduction of nitroarenes to the corresponding anilines in excellent yields in 15-30 minutes under microwave irradiation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-986628

LETTER
2557
Molybdenum Hexacarbonyl and DBU Reduction of Nitro Compounds under
Microwave Irradiation
M
olybde
n
o
um
H
exacar
h
neduction of Nitro
S
C
ompounds pencer,* Nazira Anjum, Hiren Patel, Rajendra P. Rathnam, Jason Verma
School of Science, University of Greenwich at Medway, Chatham Maritime, Kent, ME4 4TB, UK
Fax +44(208)3319805; E-mail: j.spencer@gre.ac.uk
Received 5 July 2007
Table 1 Reduction of Nitrobenzene 1a to Aniline 2a
Abstract: An ethanolic mixture of molybdenum hexacarbonyl and
DBU mediates the reduction of nitroarenes to the corresponding
anilines in excellent yields in 15–30 minutes under microwave
irradiation.
NO2
NH2
Mo(CO)6
1a
Key words: amines, microwave, molybdenum, nitroarenes, reduc-
2a
tions
Reagent equiv
Entrya Solvent
Mo(CO)6 1a
DBU Conversion (%)b
The high cost of drug development and the capabilities of
high throughput screening (HTS) dictate the need for a
medicinal chemist to synthesise libraries of molecules in
high yields and purities, with minimal bottlenecks. In this
respect, microwave-assisted organic synthesis (MAOS) is
a particularly useful tool since many thermal processes
can be accelerated and performed in minutes.1
1
2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
1
1
1
0
2
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
3
3
3
33
20c
0d
3
4
0
5
50
60
The aniline motif is ubiquitous in medicinal chemistry as
both a side chain in bioactive molecules or as a precursor
to other functional groups including amides, sulfon-
amides, substituted amines and heterocycles. Anilines can
be prepared by the reduction of nitro compounds using
catalytic or transfer-hydrogenation routes or stoichio-
metric reducing agents.2 Many of these processes employ
microwave reactors,3 although the use of a monomodal
system is preferable for safety and reproducibility.4
6
7
<10
e
8
THF
9
EtOH
DMF
93
0
10
11
diglyme–H2O
(1:1)
75
The molybdenum hexacarbonyl mediated reduction of ni-
tro compounds to anilines, via thermal energy, is limited
to a handful of substrates and requires long reaction times
(24 h).5 We were interested in preparing a library of
anilines from their corresponding nitroarenes via MAOS
a General conditions: 150 °C, 30 min, 5 mL solvent, CEM Discover
Unit ( P = 300 W).
b By 1H NMR.
c At 125 °C.
inspired by reports that demonstrated the use of Mo(CO)6 d At 200 °C; tube cracks.
e Reproducibility problems.
as a convenient source of CO in aminocarbonylation
processes.1a,6 Our brief initial optimisation studies fo-
cused on the reduction of nitrobenzene 1a to aniline 2a
with Mo(CO)6 by varying the following parameters:
temperature, solvent, reaction time, metal carbonyl
stoichiometry, and the use of additives {1,8-diazabi-
cyclo[5.4.0]undec-7-ene, (DBU)}.6
N,N-Dimethylformamide (DMF), tetrahydrofuran (THF),
diglyme/water, used for aminocarbonylations,6 and neat
water were found to be inferior to EtOH as solvent (entries
7–11). In terms of stoichiometry, when zero equivalents
of Mo(CO)6 were used, in EtOH (control, entry 4), there
was no reaction. Increasing the number of equivalents of
Mo(CO)6 led to an increase in the conversion of nitro-
benzene into aniline at the given temperature (150 °C,
33%, 1 equiv; 50%, 2 equiv, 60%, 3 equiv; entries 5 and
6) although the use of excess reducing agent is un-
desirable. The benefit of adding DBU, known to facilitate
CO liberation from Mo(CO)6, is evident from entry 9.6b
Given that the original thermal process used EtOH as
solvent, we examined the effect of temperature on the
reduction process. From Table 1, 150°C appears to be the
optimal temperature since higher temperatures (200 °C)
often led to cracking of the microwave tube and at 125 °C
lower conversions were observed (entries 1–3).
SYNLETT 2007, No. 16, pp 2557–2558
Advanced online publication: 23.08.2007
DOI: 10.1055/s-2007-986628; Art ID: D19807ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.1
0
.2
0
0
7
We employed the latter conditions to prepare a library of
anilines from nitroarenes (Table 2).7

2558
J. Spencer et al.
LETTER
Table 2 Reduction of Nitrobenzene Derivatives
the microwave-mediated route. The reduction of
nitroheteroaromatics8 proceeds smoothly under micro-
wave or thermal conditions; 5-aminoquinoline could be
synthesised in excellent yields (5 mmol scale, unopti-
mised) within two hours in refluxing EtOH (Scheme 1).
H
H
Mo(CO)6, EtOH
3 equiv DBU
H
NH2
R1
H
NO2
R1
R3
R3
MW, 150 °C,
15–30 min
R2
R2
In summary, we have developed a general, convenient,
expedited microwave-mediated method for the synthesis
of a series of anilines from their corresponding nitro pre-
cursors, which displays excellent chemoselectivity.9
Current work in our group is exploring the generalization
of this reduction process towards the synthesis of poly-
substituted aniline intermediates found in bioactive mole-
cules.10
1
2
Product R1
R2
R3
Yield of 2 (%)a
2b
2c
2d
2e
2f
H
H
OMe
Me
Me
H
85
H
H
89,b,c 50d
66b
F
H
C(O)Me
H
50b
References and Notes
H
H
H
H
H
H
Br
H
H
Cl
C(O)Me
H
77b
(1) Reviews: (a) Larhed, M.; Hallberg, A. Drug Discovery
Today 2001, 6, 406. (b) Kappe, C. O. Angew. Chem. Int. Ed.
2004, 43, 6250. (c) Lidstrom, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225. (d) Collins, J. M.;
Leadbeater, N. E. Org. Biomol. Chem. 2007, 5, 1141.
(e) Mavandadi, F.; Lidstrom, P. Curr. Top. Med. Chem.
2004, 4, 773. (f) Hayes, B. L. Aldrichimica Acta 2004, 37,
66. (g) Mavandadi, F.; Pilotti, A. Drug Discovery Today
2006, 11, 165.
(2) (a) Larock, R. C. Comprehensive Organic Transformations;
VHC Publishers: New York, 1987. (b) Clayden, J.;
Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry;
Oxford University Press: New York, 2006.
(3) (a) Chapman, N.; Conway, B.; O’Grady, F.; Wall, M. D.
Synlett 2006, 1043. (b) Meshram, H. M.; Ganesh, Y. S. S.;
Sekhar, K. C.; Yadav, J. S. Synlett 2000, 993. (c) Vass, A.;
Dudas, J.; Toth, J.; Varma, R. S. Tetrahedron Lett. 2001, 42,
5347.
(4) Vidal, T.; Petit, A.; Loupy, A.; Gedye, R. N. Tetrahedron
2000, 56, 5473.
(5) Suresh, I.; Kulkarni, G. M. Synth. Comm. 2004, 34, 721.
(6) (a) Wannberg, J.; Larhed, M. J. Org. Chem. 2003, 68, 5750.
(b) Lagerlund, O.; Larhed, M. J. Comb. Chem. 2006, 8, 4;
and references cited therein.
2g
2h
2i
H
C(O)Me
71b
I
H
89b
H
CN
71b
2j
H
C(O)NH2
81b
2k
2l
CH=CH2
H
81b
H
Br
H
H
H
89,a 52b
93
2m
2n
2o
H
Br
79
CH2OH
90
a Isolated yield after column chromatography. General conditions:
150 °C, 300 W (power), 30 min, EtOH (solvent), 1 equiv Mo(CO)6,
3 equiv DBU.
b Reaction time = 15 min.
c Quantitative conversion by 1H NMR.
d 0.5 Equiv Mo(CO)6, 1.5 equiv DBU; conversion determined by
1H NMR; 15 min reaction time.
(7) (a) Typical Work-up
Mo(CO)6,
3 equiv DBU
R
R
After solvent concentration, the resulting crude product is
passed over a short SiO2 plug (6 cm × 3 cm). Typical eluent:
neat CH2Cl2 to 5:1 CH2Cl2–acetone gradient. All products
were characterised by 1H NMR, 13C NMR, GC-MS, or MS
and correspond to commercial samples or literature values
(see ref. 7b and also ref. 9). Compound 2o: 1H NMR (270
MHz): d = 3.67 (2 H, br s), 4.67 (2 H, s), 6.54 (1 H, d, J = 8.4
Hz), 6.78 (1 H,s), 7.07 (1 H, s), 7.11 (1 H, s). 13C NMR (67
MHz): d = 62.9, 115.1, 121.1, 129.8, 138.7, 145.4. (b) The
Aldrich Library of 13C and 1H FT NMR Spectra, 1st ed.;
Pouchert, C. J.; Behnke, J., Eds.; Aldrich Chemical
Company: USA, 1993.
O2N
H2N
EtOH
1
2
NH2
O
H2N
N
2g
2p
isolated yield of products 71%; MW, 15 min
75%; thermal, 2 h
92%; MW, 15 min
82%; thermal, 2 h
Scheme 1 Microwave-mediated vs. thermal-mediated reductions
(8) Spencer, J.; Rathnam, R. P.; Patel, H.; Anjum, N.,
manuscript in preparation.
(9) Similar ‘multifunctional’ nitro analogues were selectively
reduced with H2 in the presence of catalytic gold
nanoparticles: (a) Corma, A.; Serna, P. Science 2006, 313,
332. (b) See also: Blaser, H. U. Science 2006, 313, 312; and
references cited therein.
(10) For example; kinase inhibitors: (a) Knesl, P.; Roseling, D.;
Jordis, U. Molecules 2006, 11, 286; and references cited
therein. (b) CNS active molecules: Adams, D. R.; Duncton,
M. A. J.; Roffey, J. R. A.; Spencer, J. Tetrahedron Lett.
2002, 43, 7581.
The reduction process is rather general, rapid and gives a
high yield of product. It operates for electron-rich and
electron-poor nitroarenes and tolerates ortho substituents,
halides, and other functional groups such as ketones, alco-
hols, vinyl, nitrile, and benzamides. We have also been
able to reduce the reaction times to 15 minutes (e.g.,
Table 2, 2c–l). This reaction can also be carried out
thermally with yields comparable to those observed for
Synlett 2007, No. 16, 2557–2558 © Thieme Stuttgart · New York