Metal-Free Reduction of Aromatic and Aliphatic Nitro Compounds to Amines: A HSiCl3-Mediated Reaction of Wide General Applicability

Article abstract of DOI:10.1021/acs.orglett.5b01698

A new, mild, metal-free, HSiCl₃-mediated reduction of both aromatic and aliphatic nitro groups to amines that is of wide general applicability, tolerant of many functional groups, and respectful of the stereochemical integrity of stereocenters is reported.

Full text of DOI:10.1021/acs.orglett.5b01698

Letter
pubs.acs.org/OrgLett
Metal-Free Reduction of Aromatic and Aliphatic Nitro Compounds to
Amines: A HSiCl3‑Mediated Reaction of Wide General Applicability
M. Orlandi, F. Tosi, M. Bonsignore, and M. Benaglia*
̀
Dipartimento di Chimica, Universita degli Studi di Milano, Via Golgi 19, I-20133 Milano, Italy
S
* Supporting Information
ABSTRACT: A new, mild, metal-free, HSiCl3-mediated reduction of both aromatic
and aliphatic nitro groups to amines that is of wide general applicability, tolerant of
many functional groups, and respectful of the stereochemical integrity of
stereocenters is reported.
eduction of nitro groups represents one of the most
straightforward entries to aliphatic or aromatic amines.1
generated,19 which was demonstrated to be reactive toward
R
carbonyls,20 alkyl halides,21 and acid chlorides, typically under
harsh reaction conditions (Scheme 1).22 Here we report that
Among the numerous available methodologies, reductions via
hydrogenation with classical or revisited protocols (Pd/C,
PtO2, Raney nickel, or transition-metal catalysts)2 or under
transfer hydrogenation conditions3 are largely employed.
However, these protocols sometimes lack functional group
compatibility, often requiring high-pressure equipment, and
may suffer from the use of hazardous reagents (e.g., hydrazine)
or the presence of potentially toxic transition metals. Similar
Scheme 1. Use of the HSiCl3/R3N Mixture in Reduction
Reactions
4
considerations can be made for reductions with SnCl2 or for
metal-dissolving reductions involving Zn, Fe, In, or Sm,5−7
which were reported to be poorly compatible with the presence
of halogen atoms.8 Efforts have been made to discover new
green methodologies that would avoid the use of metal
catalysts, but only few new protocols have been reported to
date. Some representative examples of metal-free transfer
hydrogenations, limited to reduction of nitroarenes, include the
use of 9,10-dihydroanthracene,9 1,4-dihydropyridines,10 thi-
ols,11 (2-pyridyl)phenylmethanol,12 and vasicine.13 However, a
real application is hampered by the formation of difficult-to-
remove organic byproducts. An alternative is provided by the
use of sodium dithionite, Na2S2O4.14 Despite the fact that its
use on a large scale results in highly exothermic reactions,15 this
reagent has been used for the synthesis of benzimidazoles via
reductive cyclization of 2-nitroanilines on a multigram scale.16
However, the reaction scope is restricted to the synthesis of
aromatic amines only.
Hence, a green, efficient, mild, and widely general method-
ology for the nitro-to-amine conversion is still strongly
required. Here we report an innovative metal-free reduction
of both aliphatic and aromatic nitro derivatives to the
corresponding amines that is efficient, chemoselective, and
compatible with a plethora of functional groups.
HSiCl3 is a green, cheap waste byproduct of the silicon
industry that may be activated as a reducing agent in
combination with Lewis bases17 and employed in enantiose-
lective catalytic reductions of ketoimines.18 However, it is
likewise known that when HSiCl3 is used in combination with a
tertiary amine, a formally nucleophilic silicon species is
the combination of HSiCl3 and a tertiary amine allows efficient
reduction of both aliphatic and aromatic nitro compounds
using a simple experimental protocol under mild reaction
conditions (Scheme 1).23
The reduction of 4-nitrotoluene was selected as a model
reaction and was performed in the presence of 3.5 equiv of
HSiCl3 and 5 equiv of a tertiary amine. The solvent of choice
appeared to be either dichloromethane or acetonitrile,
providing the reduction of 1a in full conversion (see Table
S1 in the Supporting Information). Among the screened
tertiary amines, the aliphatic ones provided optimum results
(Table S1). It is noteworthy that in the presence of Lewis bases
such as pyridines, DABCO, and DMF, the reaction did not
occur.24
The scope of the reaction was then explored (Scheme 2). In
most cases, complete conversion of the nitro derivative into the
corresponding amine was observed. Isolated yields after a quick
chromatographic purification were in good agreement with the
Received: June 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01698
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Cl3Si− ion pair (Scheme 4). Almost 30 years later, Karsch
proposed that this equilibrium may further evolve toward the
Scheme 2. Scope of the Reaction
Scheme 4. Generation of SiCl3− and SiCl2 from HSiCl3 in the
Presence of Tertiary Amines
formation of dichlorosilylene, SiCl2 (Scheme 4).26 More
recently it was reported that the reaction of HSiCl3 with an
organic base may generate SiCl2 in situ.27
In proposing a plausible mechanism for the reaction, it
−
should be considered that either SiCl3 or SiCl2 may be the
effective reducing agent. While the former, an anionic species,
might act as a nucleophile toward the electrophilic nitrogen
atom, SiCl2 could react with NO bonds through a
cheletropic mechanism. The two mechanistic hypotheses are
a
Standard reaction conditions: to a solution of the nitro compound
(0.7 mmol) and the base (5 equiv) in acetonitrile (7 mL) was added
HSiCl3 (3.5 equiv) at 0 °C; the reaction mixture was then allowed to
warm to rt in 18 h. The yield column shows the reaction conversion
based on the 1H NMR spectrum of the crude mixture, with the
isolated yield in parentheses.
−
depicted in Scheme 5. In Scheme 5a, SiCl3 is involved, while
−
Scheme 5. Hypothesized Mechanisms Involving SiCl3 or
SiCl2
1H NMR-determined conversions. Allylic and benzylic
protecting groups on both O and N atoms survived the
reduction reaction conditions (1c−g and 1n). Moreover,
cyanides, amides, ketones, alcohols, and carboxylic moieties
were tolerated (1h−n). Nitropyridines can be efficiently
reduced (1r−s), as well as nitroalkanes (1t−v); remarkably,
halogenated nitro compounds can be converted to amines
without any detectable traces of dehalogenated products (1o−q
and 1s).
Furthermore, the metal-free reduction protocol was success-
fully employed in the reduction of nitrolactone 1z in the total
synthesis of aliskiren. The very mild procedure afforded the
enantiopure aminolactone in 99% isolated yield without
altering the stereochemical integrity of the four stereocenters
of the molecule (Scheme 3).25 Indeed, the new metal-free
reduction methodology allowed the development of a novel
and straightforward route for the synthesis of this important
pharmaceutical product.
The first studies reporting the use of HSiCl3 in combination
with a tertiary amine date back to 1969.19 On the basis of NMR
experiments, it was hypothesized that the combination of
HSiCl3 with a base could lead to the formation of the R3NH+/
Scheme 3. Metal-Free Reduction of a Functionalized Chiral
Nitro Derivative
in Scheme 5b, SiCl2 behaves as the reducing species. It is
important to point out that the proposals offer only a general
picture and that variations are possible; for example, although
the mechanism involving a naked SiCl2 is reported here for
simplicity, this reacting species likely could be stabilized by an
amine molecule.28 Further studies devoted to the determination
of the correct reaction mechanism are ongoing in our
laboratories.29
B
DOI: 10.1021/acs.orglett.5b01698
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 919.
In conclusion, we have reported a new HSiCl3-mediated
reduction of both aromatic and aliphatic nitro groups to
amines. The methodology has several positive features, as it is
of general applicability, chemoselective, tolerant of many
functional groups, and respectful of the stereochemical integrity
of stereocenters. Moreover, the reduction protocol relies on the
use of inexpensive and nonhazardous chemicals, features a
simple experimental procedure, and is performed under mild
conditions. Since the new method will offer the opportunity to
redesign ex novo the synthetic plans of several important
molecules or key intermediates, it is expected that the metal-
free protocol could possibly find useful applications also in
industrially relevant processes.
(8) (a) Kasparian, A. J.; Savarin, C.; Allgeier, A. M.; Walker, S. D. J.
Org. Chem. 2011, 76, 9841. (b) Armitage, M.; Bret, G.; Choudary, B.
M.; Kingswood, M.; Loft, M.; Moore, S.; Smith, S.; Urquhart, M. W. J.
Org. Process Res. Dev. 2012, 16, 1626.
(9) Coellen, M.; Ruchardt, C. Chem. - Eur. J. 1995, 1, 564.
(10) Maslov, K. V.; Egorov, A. G.; Akimova, T. I.; Kaminski, A. V.
Chem. Heterocycl. Compd. 2002, 38, 560.
(11) Duan, Z.; Ranjit, S.; Liu, X. Org. Lett. 2010, 12, 2430.
(12) Giomi, D.; Alfini, R.; Brandi, A. Tetrahedron 2011, 67, 167.
(13) Sharma, S.; Kumar, M.; Kumar, V.; Kumar, N. J. Org. Chem.
2014, 79, 9433.
(14) Park, K. K.; Oh, C. H.; Joung, W. K. Tetrahedron Lett. 1993, 34,
7445.
(15) Bretherick’s Handbook of Reactive Chemical Hazards, 7th ed.;
Urben, P., Ed.; Elsevier: Amsterdam, 2007.
ASSOCIATED CONTENT
* Supporting Information
■
(16) Oda, S.; Shimizu, H.; Aoyama, Y.; Ueki, T.; Shimizu, S.; Osato,
H.; Takeuchi, Y. Org. Process Res. Dev. 2012, 16, 96.
(17) For reviews, see: (a) Guizzetti, S.; Benaglia, M. Eur. J. Org.
Chem. 2010, 2010, 5529. (b) Jones, S.; Warner, C. J. A. Org. Biomol.
Chem. 2012, 10, 2189.
(18) For the most recent contributions of our group in the field, see:
(a) Genoni, A.; Benaglia, M.; Massolo, E.; Rossi, S. Chem. Commun.
2013, 49, 8365. (b) Barrulas, P.; Genoni, A.; Benaglia, M.; Burke, A.
Eur. J. Org. Chem. 2014, 2014, 7339.
(19) Bernstein, C. S. J. Am. Chem. Soc. 1970, 92, 699.
(20) Benkeser, R. A.; Smith, W. E. J. Am. Chem. Soc. 1969, 91, 1556.
(21) (a) Benkeser, R. A.; Smith, W. E. J. Am. Chem. Soc. 1968, 90,
5307. (b) Benkeser, R. A.; Gaul, J. M.; Smith, W. E. J. Am. Chem. Soc.
1969, 91, 3666.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01698.
Experimental procedures for both nitro reduction
1
reactions and mechanistic studies, H and 29Si NMR
spectra, and theoretical details (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*Maurizio.Benaglia@unimi.it
Notes
(22) Benkeser, R. A.; Foley, K. M.; Gaul, J. M.; Li, G. S.; Smith, W. E.
J. Am. Chem. Soc. 1969, 91, 4578.
(23) The methodology is described in a patent, See: Bonsignore, M.;
The authors declare no competing financial interest.
̀
Benaglia, M. (Universita degli Studi di Milano, Milano, Italy).
International Patent Application PCT/EP/2013/0683; now owned
by DexLeChem GmbH (Berlin, Germany).
(24) This may be explained by the HSAB theory: soft bases such as
Lewis bases prefer to interact with the soft acidic site of HSiCl3 (Si),
while harder bases such as amines prefer to interact with the harder
acidic site (the hydrogen).
ACKNOWLEDGMENTS
■
M.B. thanks Universita
̀
degli Studi di Milano and ZaCh System
SpA (Zambon Chemicals) for financial support; M.O. thanks
Universita
̀
degli Studi di Milano for a Ph.D. fellowship.
(25) Rossi, S.; Benaglia, M.; Porta, R.; Cotarca, L.; Maragni, P.;
Verzini, M. Eur. J. Org. Chem. 2015, 2015, 2531.
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DOI: 10.1021/acs.orglett.5b01698
Org. Lett. XXXX, XXX, XXX−XXX