The development of a scalable, chemoselective nitro reduction

Article abstract of DOI:10.1021/op3002239

We have demonstrated a scalable chemoselective reduction of a nitro functional group in the presence of an aryl imine using (NH₄) ₂S/EtOH or hydrogenation (Sponge Nickel) to afford the corresponding amino-imines in moderate to excellent yields. Other reducible groups such as aryl halides, styryl olefins, and ether linkages survived as well.

Full text of DOI:10.1021/op3002239

Technical Note
pubs.acs.org/OPRD
The Development of a Scalable, Chemoselective Nitro Reduction
William P. Gallagher,* Mark Marlatt, Robert Livingston, Susanne Kiau, and Jale Muslehiddinoglu
Chemical Development, Bristol-Myers Squibb Co., 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
S
* Supporting Information
ABSTRACT: We have demonstrated a scalable chemoselective reduction of a nitro functional group in the presence of an aryl
imine using (NH4)2S/EtOH or hydrogenation (Sponge Nickel) to afford the corresponding amino-imines in moderate to
excellent yields. Other reducible groups such as aryl halides, styryl olefins, and ether linkages survived as well.
65−68%17 after isolation. Higher yields (75−80%) were
INTRODUCTION
■
possible in a TiCl4/Mg0 system18 with <1% hydroxylamine or
The reduction of nitro compounds to amines is a useful
over-reduction products remaining. However, due to the large
synthetic transformation for which vast arrays of reagents and
reaction conditions have been developed.1 Typically employed
excess of TiCl4 required, this method was not considered
methods utilize iron,2 zinc,3 or tin4 and reductions using
practical due to slow filtration of the inorganic salts
catalytic hydrogenation.5 However, selectivity versus the
encountered during the isolation.
A scalable method was developed by the use of (NH4)2S.19
reduction of other sensitive functionalities in the substrate
remains a challenge in modern6 synthetic methodology.
During the development work for a recent drug candidate,
When a 40 wt % (NH4)2S solution in water was added to 1 in
IPA at 80 °C, gas rapidly evolved, and the reaction was
complete after ∼3 h. To minimize the hazard of gassing, we
observed that simply stirring the suspension of the reaction
mixture for 2 h at 20 °C20 afforded a 4:1 mixture of
hydroxylamine 3 and aniline 2. Once the nitro compound
was consumed, the reaction was heated to 70 °C for 2.5 h to
complete the reduction of the hydroxylamine 3. The reaction
was diluted with water, cooled to 20 °C, and filtered, and upon
recrystallization, 75−80% of the desired aniline 2 was obtained
in >98% purity (Scheme 2). Disappointingly, at >20-kg scale
the yield fell to 53% as the reduction was highly dependent on
the particular batch and source of (NH4)2S.
we had a need to develop an efficient, chemoselective method
for the reduction of nitro functionality in the presence of other
reducible functional groups (Scheme 1). Limitations associated
with the reduction of the nitro functionality in 17 were the acid-
sensitive/reductive nature of an imine, an aryl ether linkage,
and the presence of two aryl halides. Nevertheless, there exist at
least two examples of such a transformation. Levacher8 has
demonstrated that Na2S·H2O selectively reduced a nitro group
in the presence of an aldimine. However, our system was not
tolerant of these conditions, as concomitant ether cleavage
occurred.9 Similarly, Lemaire10 utilized a Pd-catalyzed hydro-
genation to perform a nitro reduction; however, when 1 was
subjected to these conditions, uncontrolled reduction leading to
a mixture of 2−5 occurred (Scheme 1).
As it seemed we had sufficiently explored low-valent
elements for reduction, we began a more in-depth investigation
of transition metal catalyzed hydrogenation conditions using
23
Pd,21 and Pt22 or Rh
and Ni24 catalysts with varying
pressures of H2, temperatures and solvents. Unfortunately, we
did not observe a selective reduction to aniline 2 using Pd, Pt,
or Rh. Of general interest is that Pd/C in EtOAc afforded the
benzhydryl-aniline 4 exclusively25 in 90% yield and >99%
purity.
RESULTS AND DISCUSSION
■
Subsequently, we screened a variety of reduction protocols
under basic or neutral conditions. See Table 1 which shows
promising results of this initial screen. The use of sodium
dithionite11 or Zn/NH4OH12 afforded reduction to aniline 2
with variable amounts of the hydroxylamine 3 produced. Efforts
to further reduce the hydroxylamine 3 were unsuccessful. Sulfur
(S8) can be a mild reductant13 but failed with our system.
Transfer14 hydrogenation yielded, as expected, over-reduction
products 4 and 5. FeSO4/NH4OH15 afforded the desired
aniline 2 in 85% yield with only a few impurities (<1%), but
purity was dependent on the batch/source of FeSO4.16
Our best procedures were promising in that the only
impurity remaining was hydroxylamine 3. As 3 could not be
easily purged or further reduced under the reaction conditions,
we considered the use of sequential FeSO4/Na2S to address the
half-reduced substrate. Following reduction with FeSO4/
NH4OH to produce a 7:1 mixture of aniline 2/hydroxylamine
3, the batch was treated with Na2S to further reduce
hydroxylamine 3 to aniline 2, producing consistent yields of
However, Sponge Nickel26 in 2-MeTHF produced a mixture
of aniline 2 as the major product (99%), with hydroxylamine 3
(<1%) as a minor impurity. A variety of solvents were screened
and were found to be less optimal than 2-MeTHF (CH2Cl2,
EtOAc, toluene, and THF). Optimization led us to the
following conditions: 2-MeTHF (10 mL/g), 125 mg/g·LR27
Sponge Nickel, 40 °C, and 25 psig H2. To attenuate28 the
activity of the catalyst, the commercial Sponge Nickel was
washed sequentially with 5% AcOH, water, and MeOH. The
water washes ensure that any residual acid is gone, as its
presence could induce imine hydrolysis. The sponge Nickel29
obtained after this wash sequence was then utilized under the
Received: August 13, 2012
Published: September 4, 2012
© 2012 American Chemical Society
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Organic Process Research & Development
Technical Note
Scheme 1. Desired selective reduction of a nitro group
Table 1. Initial screen of reductants
Table 2. Summary of processes
a
b
entry
reductant
Na2S2O4
yield (%)
2:3:4:5
scale
(kg)
yield
(%)
process
comments
problematic filtration
1
2
65
53
1:1:0:0
1:0:0:0
FeSO4/
NH4OHNa2S
2
65
Na2S
Pd/C
aq (NH4)2S/IPA
25
22
53
88
yield dependent on batch of (NH4)2S
3
67
0:0:1:1
NH4HCO2
Zn/NH4Cl
Zn/NaOH
FeSO4/NH4OH
FeSO4/NH4OH
then Na2S
TiCl4/Mg0
Sponge Nickel
(A-5001)
reproducibly performed with various
lots of sponge nickel
4
5
6
68
72
85
3:1:0:0
2:1:0:0
7:1:0:0
substrates to test the scope of our protocols (Scheme 3).
Utilizing either Na2S, (NH4)2S, or Sponge Nickel, aryl
ketimines as well as aryl aldimines31 survived the reduction
sequence to exclusively afford the corresponding imino-anilines
with high selectivity. Remarkably, little to no reduction32 of
vinyl, alkynyl, and halogen substituents were observed, and the
products were isolated in 48−86% yields.
7
65
1:0:0:0
8
9
75
90
1:0:0:0
1:0:0:0
(NH4)2S
a
b
Isolated yields of mixtures. HPLC ratios.
optimized conditions which completed the reaction after ∼8 h
at 25 °C. The benzhydryl-aniline 4 would form after prolonged
reaction times (>48 h), but only after the complete
consumption of hydroxylamine 3. Using the optimized
conditions B (Scheme 2) with the commercially available
Sponge Nickel A-500128 (from Johnson-Matthey), we success-
fully carried out a 22-kg campaign30 in 88% yield. While
different batches of FeSO4, and (NH4)2S had led to variable
reductions, all lots (four separate lots) of Sponge Nickel (type
A-5001) performed identically (Table 2). Lab-scale (<25 g)
experiments have demonstrated that the catalyst could be
reused up to five times (filtered off catalyst and recharged to a
separate flask) with no loss in reactivity or chemoselectivity.
Further exploration of recycling the Sponge Nickel is needed to
demonstrate the reproducibility and scalability.
CONCLUSIONS
■
In summary, we have shown that a chemoselective reduction of
a nitro group with Sponge Nickel (type A-5001) or sulfide can
occur in the presence of an aryl imine, aryl fluorides and
chlorides, and aryl ether functionalities. Both methods were
scaled to >22 kg scale in good yield and selectivity.
Reproducibly good yields and selectivity were obtained with
both reagents for a variety of substrates, suggesting these will be
useful for selective nitro group reduction in the presence of
groups prone to reduction.
EXPERIMENTAL SECTION
■
General Methods. Reagents were used as received, unless
otherwise noted. Solvents were reagent grade. Reactions were
stirred and monitored by HPLC. Yields refer to recrystallized
and spectroscopically pure compounds unless noted otherwise.
Melting points were determined on a Thomas-Hoover melting
point apparatus and are uncorrected. 1H and 13C were recorded
GENERALITY OF REDUCTION METHODOLOGY
■
With both the Sponge Nickel hydrogenation and sulfide
((NH4)2S or Na2S) conditions in hand, we screened a variety of
Scheme 2. Optimized (NH4)2S protocol (A) and Sponge Nickel protocol (B)
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Organic Process Research & Development
Technical Note
a
chloro-N-(diphenylmethylene)pyridin-2-amine (2). To a
2000-L stainless-steel hydrogenator was added Sponge Nickel
(type A-5001) (2.75 kg), 2-MeTHF (733 L) and 3-chloro-N-
(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-
amine (1) (22 kg, 49.12 mol). The vessel was purged with N2
(30 psig, 3×), followed by purging with H2 (30 psig, 3×). The
vessel was pressurized with H2 (25 psig) and was then heated
to 25 °C. Once complete (6 h, HPLC analysis), the solution
was filtered over Celite, followed by a cake wash of 2-MeTHF
(180 L). The combined organics were passed through a 0.20
μm cartridge filter. The filtered organics were concentrated to
approximately one-quarter volume. n-Butyl acetate (154 L) was
added, heated to 80 °C, and held until complete dissolution
was obtained. At 80 °C, heptane (154 L) was added over 3 h
and then was cooled to 20 °C over 3 h. The slurry was aged for
15 h at 20 °C. The solids were filtered, washed with heptanes
(75 L), and then dried (50 °C, 25 mmHg) to afford 4-(4-
amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)-
pyridin-2-amine (2) (17.42 kg, 85% yield) as a yellow solid. See
above for spectroscopic data.
Scheme 3. Chemoselective reduction of nitro functionality
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures for intermediates and copies of H
and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*william.gallagher@bms.com
■
a
All reactions are unoptimized, and all yields listed are of isolated
material
Notes
The authors declare no competing financial interest.
on either a 400 or 500 MHz spectrometer. Chemical shifts are
ACKNOWLEDGMENTS
■
1
relative to either CDCl3 (δ 7.26 for H and δ 77.0 for 13C) or
We thank Drs. Rajendra P. Deshpande, David R. Kronenthal,
Xinhua Qian, Yi Xiao, Michael Randazzo, and Robert E.
Waltermire for helpful discussions.
1
d6-DMSO (δ 2.50 for H and δ 39.51 for 13C).
Use of (NH4)2S as the Reductant. Preparation of 4-(4-
A m i n o - 2 - fl u o r o p h e n o x y ) - 3 - c h l o r o - N -
(diphenylmethylene)pyridin-2-amine (2). To a reactor was
added 3-chloro-N-(diphenylmethylene)-4-(2-fluoro-4-
nitrophenoxy)pyridin-2-amine (1) (22.00 kg, 44.20 mol),
isopropanol (200 L), and (NH4)2S (60 L, 442 mol). This
solution was allowed to stir at 20 °C for 1 h. This solution was
then heated to 70 °C and held for 2.5 h. Water (200 L) was
added, and the solution was cooled to 20 °C. After holding at
20 °C for 3 h, the slurry was filtered. The solids were dissolved
into butyl acetate (110 L) by heating to 80 °C. At 80 °C,
heptane (110 L) was added and the solution was cooled to 20
°C over 1 h. The slurry was aged for 2 h at 20 °C. The solids
were filtered, washed with heptanes (110 L), and then dried
(50 °C, 25 mmHg) to afford 4-(4-amino-2-fluorophenoxy)-3-
chloro-N-(diphenylmethylene)pyridin-2-amine (2) (9.82 kg,
REFERENCES
■
(1) Kabalka, G. W.; Varma, R. S. Reduction of Nitro and Nitroso
Compounds. In Comprehensive Organic Synthesis, 1st ed., Trost, B. M.,
Fleming, I., Eds. Pergamon Press: Oxford, 1991; Vol. 8, p 363.
(2) (a) Macleod, C.; McKiernan, G. J.; Guthrie, E. J.; Farrugia, L. J.;
Hamprecht, D. W.; Macritchie, J.; Hartley, R. C. J. Org. Chem. 2003,
68, 387−401. (b) Ramadas, K.; Srinivasan, N. Synth. Commun. 1992,
́
22, 3189−3195. (c) Perzyna, A.; Marty, C.; Facompre, M.; Goossens,
J.-F.; Pommery, N.; Colson, P.; Houssier, C.; Houssin, R.; Henichart,
J.-P.; Bailly, C. J. Med. Chem. 2002, 45, 5809−5812. (d) Wang, S.; Li,
Z.; Hua, W. Synth. Commun. 2002, 32, 3339−3345. (e) Messeri, T.;
Pentassuglia, G.; Fabio, R. D. Tetrahedron. Lett. 2001, 42, 3227−3230.
(f) Desai, D. G.; Swami, S. S.; Dabhade, S. K.; Ghagare, M. G. Synth.
Commun. 2001, 31, 1249−1251. (g) Desai, D. G.; Swami, S. S.;
Hapase, S. B. Synth. Commun. 1999, 29, 1033−1036. (h) Wang, L.; Li,
P.; Wu, Z.; Yan, J.; Wang, M.; Ding, Y. Synthesis 2003, 2001−2004.
(i) Awad, W. I.; Hassan, S. S. M.; Zaki, M. T. M. Anal. Chem. 1972, 44,
911−915.
1
53% yield) as a yellow solid (mp =151−153 °C). H NMR
(500 MHz, DMSO-d6) δ = 7.97 (d, J = 5.7 Hz, 1H), 7.81−7.15
(m, 10H), 6.96 (t, J = 9.0 Hz, 1H), 6.52 (d, J = 13.2 Hz, 1H),
6.43 (d, J = 8.5 Hz, 1H), 6.28 (d, J = 5.7 Hz, 1H), 5.52 (s, 2H).
13C NMR (126 MHz, DMSO-d6) δ = 170.5, 161.3, 160.9,
154.9, 152.9, 148.7, 147.4, 137.7, 135.6, 131.8, 129.3, 129.1,
128.5, 128.0, 123.5, 109.9, 107.9, 105.6, 101.4, 101.3. HRMS EI
(m/z): [M + H] Calcd C24H18ClFN3O, 418.1122; Found [M +
H] 418.1127.
(3) (a) Matthews, J. M.; Greco, M. N.; Hecker, L. R.; Hoekstra, W. J.;
Andrade-Gordon, P.; de Garavilla, L.; Demarest, K. T.; Ericson, E.;
Gunnet, J. W.; Hageman, W.; Look, R.; Moore, J. B.; Maryanoff, B. E.
Bioorg. Med. Chem. Lett. 2003, 13, 753−756. (b) Kim, Y.; Nam, N.-H.;
You, Y.-J.; Ahn, B.-Z. Bioorg. Med. Chem. Lett. 2002, 12, 719−722.
(c) Edwards, J. P.; Zhi, L.; Pooley, C. L. F.; Tegley, C. M.; West, S. J.;
Wang, M.-W.; Gottardis, M. M.; Pathirana, C.; Schrader, W. T.; Jones,
T. K. J. Med. Chem. 1998, 41, 2779−2785. (d) Neidlein, R.; Christen,
D. Helv. Chim. Acta 1986, 69, 1623−1626.
Use of Sponge Nickel (type A-5001) on a 22-kg-Scale
Run. Preparation of 4-(4-Amino-2-fluorophenoxy)-3-
1667
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Organic Process Research & Development
Technical Note
(4) (a) Xing, W. K.; Ogata, Y. J. Org. Chem. 1982, 47, 3577.
(b) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839−842.
(5) (a) Rylander, P. In Catalytic Hydrogenation in Organic Synthesis;
Academic Press: New York, 1979; p 112. (b) Baumeister, P.; Studer,
M.; Roessler, F. In Handbook of Heterogeneous Catalysis; Ertl, G.,
2001, 66, 2480−2483. (F) Barrero, A. F.; Alvarez-Manzaneda, E. J.;
Chahboun, R.; Meneses, R. Synlett 2000, 197−200. (G) Barrero, A. F.;
Alvarez-Manzaneda, E. J.; Chahboun, R.; Meneses, R. Synlett 1999,
1663−1666. (I) Bui, T. K.; Arcelli, A. J. Org. Chem. 1989, 54, 949−
953. (J) Ishiyama, J.; Maeda, S.; Takahashi, K.; Senda, Y.; Imaizumi, S.
Bull. Chem. Soc. Jpn. 1987, 60, 1721−1726. (K) Yuste, F.; Saldana, M.;
Walls, F. Tetrahedron Lett. 1982, 23, 147−148.
Knozinger,H., Weitkamp, J., Eds.; Wiley-VCH: Weinheim, 1997; pp
̈
2186−2209. (c) Blaser, H.-U.; Siegrist, U.; Steiner, H.; Studer, M. In
Fine Chemicals through Heterogeneous Catalysis; Sheldon, R. A., van
Bekkum, H., Eds.; Wiley-VCH: Weinheim, 2001; p 389.
(6) (a) Blackie, J. A.; Turner, N. J.; Wells, A. S. Tetrahedron Lett.
1997, 38, 3043−3046. (b) Guibellina, N.; Stabile, P.; Laval, G.;
Perboni, A. D.; Cimarosti, Z.; Westerduin, P.; Cooke, J. W. B. Org.
Process Res. Dev. 2010, 14, 859−867. (c) Boros, E. E.; Burova, S. A.;
Erickson, G. A.; Johns, B. A.; Koble, C. S.; Kurose, N.; Sharp, M. J.;
Tabet, E. A.; Thompson, J. B.; Toczko, M. A. Org. Process. Res. Dev.
2007, 11, 899−902. (d) Whritenour, D. C.; Brenek, S. J.; Tom, N. J.
Org. Process Res. Dev. 2001, 5, 539−541. (e) Junge, K.; Wendt, B.;
Shaikh, N.; Beller, M. Chem. Commun. 2010, 46, 1769−1771.
(7) Livingston, R. C.; Gallagher, W. P., Process for preparation of
pyridyloxyphenyl oxodihydropyridinecarboxamides via amidation of
oxopyridinecarboxylates with protected pyridyloxyphenylamines. WO/
2009/094427, July 30, 2009. This material was prepared in four steps
from 2,3-dichloropyridine. See Supporting Information for details.
(8) Leleu, S.; Papamicael, C.; Marsais, F.; Dupas, G.; Levacher, V.
Tetrahedron: Asymmetry 2004, 15, 3919−3928.
(27) mg/g·LR = mg per g of limiting reagent (LR).
(28) If the standard nickel was not treated with the wash sequence,
variable amounts of hydroxylamine 3 (1−15%) were observed. This
wash was applied to remove any residual NaOH.
(29) Sponge Nickel (A-5001 from Johnson-Matthey) is the
commercially available form that is prewashed with washed with 5%
AcOH, water, and then MeOH. It is supplied as a slurry in water.
(30) We utilized multiple lots of Sponge Nickel A-5001, and all lots
performed as expected.
(31) When using aldimines, yields listed are for the isolated TFA-
derivatives. The anilines were found to be unstable during isolation
(they degraded to the bis-imine upon recrystallization or chromatog-
raphy).
(32) LC/MS analysis of the crude reaction mixtures showed <5% of
over-reduced impurities.
(9) Draper, W. M.; Casida, J. E. J. Agric. Food Chem. 1983, 31, 227−
231. We postulate that Na2S was undergoing nucleophilic aromatic
substitution with the nitro compound 1, as this cleavage was not seen
when aniline 2 was subjected to the reaction conditions.
(10) Karame, I.; Tommasino, M. L.; Faure, R.; Lemaire, M. Eur. J.
Org. Chem. 2003, 1271.
(11) Park, K. K.; Oh, C. H.; Sim, W.-J. J. Org. Chem. 1995, 60, 6202−
6204.
(12) Hirata, Y.; Nakata, H.; Yamada, K.; Okuhara, K.; Naito, T.
Tetrahedron 1961, 14, 252−274.
(13) McLaughlin, M. A.; Barnes, D. M. Tetrahedron Lett. 2006, 47,
9095−9097.
(14) Ram, S.; Ehrenkaufer, R. E. Tetrahedron Lett. 1984, 25, 3415−
3418.
(15) Raiford, L. C.; Stroesser, W. C. J. Am. Chem. Soc. 1928, 50,
2556−2563.
(16) Each batch of FeSO4 was analyzed with standard techniques,
and no differences were observed.
(17) This protocol was scaled to 2 kg, but the filtration of the Fe salts
proved to be extremely problematic on scale; thus, this system was not
further studied.
(18) Malinowski, M.; Kaczmarek, L. J. Prakt. Chem. 1988, 330, 154−
158.
(19) Plattner, A.; Armstrong, E. C. Dehydrogenation with Sulfur,
Selenium, and Platinum Metals: Newer Methods of Preparative Organic
Chemistry; Interscience: New York, 1948; p 21.
(20) Even after prolonged reaction times (>48 h) at 20 °C, the
hydroxylamine was not reduced further.
(21) Takasaki, M.; Motoyama, Y.; Higashi, K.; Yoon, S.-H.;
Nagashima, H. Org. Lett. 2008, 10, 1601−1604 and references cited
therein..
(22) Voorhees, V.; Adams, R. J. Am. Chem. Soc. 1922, 44, 1397−
1405.
(23) Akao, A.; Sato, K.; Nonoyama, N.; Mase, T.; Yasuda, N.
Tetrahedron Lett. 2006, 47, 969−972 and references cited therein..
(24) Sarmah, B. K.; Barua, N. C. Tetrahedron 1991, 47, 8587−8600.
(25) See Supporting Information for experimental details.
(26) Chemoselective uses of Sponge Nickel see: (a) Gowda, N. B.;
Rao, G. K.; Ramakrishna, R. A. Tetrahedron Lett. 2010, 51, 5690−5693.
(b) Koso, S.; Furikado, I.; Shimao, A.; Miyazawa, T.; Kunimori, K.;
Tomishige, K. Chem. Commun. 2009, 2035−2037. (c) Kukula, P.;
Koprivova, K. J. Catal. 2005, 234, 161−171. (D) Barrero, A. F.;
Alvarez-Manzaneda, E. J.; Chahboun, R.; Meneses, R.; Romera, J. L.
Synlett 2001, 485−488. (E) Klenke, B.; Gilbert, I. H. J. Org. Chem.
1668
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