Chemoselective reductions of nitroaromatics in water at room temperature

Article abstract of DOI:10.1021/ol403079x

A robust and green protocol for the reduction of functionalized nitroarenes to the corresponding primary amines has been developed. It relies on inexpensive zinc dust in water containing nanomicelles derived from the commercially available designer surfactant TPGS-750-M. This mild process takes place at room temperature and tolerates a wide range of functionalities. Highly selective reductions can also be achieved in the presence of common protecting groups.

Full text of DOI:10.1021/ol403079x

Letter
pubs.acs.org/OrgLett
Chemoselective Reductions of Nitroaromatics in Water at Room
Temperature
Sean M. Kelly and Bruce H. Lipshutz*
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
ABSTRACT: A robust and green protocol for the reduction of
functionalized nitroarenes to the corresponding primary amines has
been developed. It relies on inexpensive zinc dust in water containing
nanomicelles derived from the commercially available designer
surfactant TPGS-750-M. This mild process takes place at room
temperature and tolerates a wide range of functionalities. Highly
selective reductions can also be achieved in the presence of common
protecting groups.
romatic and heteroaromatic primary amines have proven
to be important building blocks in the synthesis of a wide
impressive chemoselectivity and functional group tolerance but
have limitations due to their cost and complexity.7 Additional
exotic solutions, such as the use of copper,8a iron,8b or precious
metal8c nanoparticles or other engineered nanomaterials,9 have
demonstrated good activity but may suffer from a similar lack of
selectivity.
A
range of pharmaceuticals, polymers, and fine chemicals, with
particular utility in cross-coupling reactions.1 However, the
inherent reactivity of this functional group often requires
protection from premature participation in multistep syntheses.
While a wide range of protecting groups are available to limit
amine reactivity, one popular strategy involves their masking as
nitroarenes. This approach provides multiple benefits, including
facile nitrogen introduction via early stage nitration, excellent
atom economy, good stability of the nitro group under
numerous reaction conditions, and directed arene functional-
ization resulting from the associated electronics of the nitro
moiety. Unfortunately, this protection strategy introduces a
new challenge: the required chemoselective reduction of
nitroarenes in the presence of other functional groups,
including those that may be competitively reduced.
Classically, such reductions have been achieved under harsh
conditions, including strong acids and various metals, such as
iron or tin.2 Although effective in scaled industrial processes,3
these reductions tend to suffer from a limited substrate scope
due to their severity and present significant safety and
environmental issues associated with their use. Several
protocols have been reported in recent years to address these
concerns. Catalytic hydrogenation using transition metal
catalysis has received high interest, but this approach exhibits
limited selectivity in the presence of other reducible functional
groups.4 Even when chemoselectivity is not an issue, this route
still requires specialized equipment, pressurized hydrogen gas,
and flammable organic solvents, decreasing its safety and
ultimate appeal. Additionally, the known energetic nature5 of
intermediates from nitro group reductions often makes working
in organic solvent under a pressurized atmosphere of hydrogen
particularly undesirable.
One classical solution involves the use of elemental zinc as a
reducing agent in various reaction environments, including
acetic acid or methanol mixtures, or more recently in biphasic
solutions.10 While chemoselectivity is impressively high,
especially when acidic pH can be avoided, literature methods
all require the use of organic solvents or ionic liquids11 in order
to solvate nitroarene substrates and often require heating.2
Standard protocols generally call for 10−20 equiv of zinc dust,
increasing material costs, waste disposal, investment in energy,
and limitations in reaction throughput. It follows that if the
virtues of zinc could be leveraged by its utilization at ambient
temperatures while eliminating organic solvents as the reaction
media, a greener and more robust protocol would result,
providing a solution to this important and timely synthetic
problem.
Our work continues to focus, in part, on the design of
nonionic surfactants that enable transition-metal-catalyzed
reactions to be performed in water at room temperature (rt),
rather than in traditional organic solvents.12 Several applica-
tions of micellar technology to an array of valued organic
transformations have already been developed. To further
expand the scope of these micellar surfactant conditions, zinc-
mediated reductions of nitroarenes and nitroheteroarenes have
been studied; we now report the results of this investigation.
A representative hydrophobic nitroarene was examined in a 2
wt % aqueous solution of the designer surfactant TPGS-750-M,
which is an item of commerce (Sigma-Aldrich cat. no.
733857).13 Addition of zinc dust and ammonium chloride to
Transfer hydrogenation processes of nitroarenes eliminate
the use of pressurized hydrogen gas but often show a decrease
in yields in the presence of other reducible groups.6 Most
recently, MO3S4 cluster catalysts have been developed that offer
Received: October 25, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol403079x | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a solution of 4-nitrobenzophenone 1 resulted in clean
conversion to 4-aminobenzophenone 1b upon stirring for 6 h
at room temperature (Scheme 1).
but also created inherently limited functional group compat-
ibility and poor surfactant emulsion stability. Additionally, these
highly acidic conditions resulted in a significant exotherm upon
introduction of zinc dust, necessitating slow batch-wise addition
and potentially limiting scalability. Basic additives (TMEDA,
NH4OH, Et3N) completely shut down the reduction and
returned only unreduced starting material.
Scheme 1. Initial Study: Reduction of 4-Nitrobenzophenone
The test reaction was also run in a 1 M potassium phosphate-
buffered solution of 2% TPGS-750-M adjusted to various levels
of pH. Adequate conversion was observed with no additional
additive when the starting pH was set to 6.0 or lower, albeit at
significantly slower rates. No activity was seen above a starting
pH of 8.0. Final conditions were set at 0.5−1.0 M nitroarene, 5
equiv of fresh zinc dust, and 1.2 equiv of ammonium chloride.
Using these optimized conditions, a series of functionalized
nitroarenes was subjected to this reduction protocol to evaluate
its scope and chemoselectivity (Figure 1). Reductions
Monitoring the reaction products by GCMS revealed no
residual nitroso or hydroxylamine intermediates and no
unwanted reduction of the carbonyl group at full conversion.
A simple workup including filtration through a silica gel plug
followed by rinsing with a minimal volume of ethyl acetate
afforded the amino product 1b in 94% yield. Alternately,
extraction with a minimal volume of organic solvent led to
isolated product of similar purity and yield.
Following this initial success, experiments were conducted to
optimize the reaction protocol (Table 1). Zinc dust loading was
Table 1. Optimization of Zinc-Mediated Reductions
zinc (equiv) additive (2 equiv) conc (M) time (h) conversion (%)
3
5
NH4Cl
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.5
2
2
60
84
NH4Cl
10
5
NH4Cl
2
87
NH4Cl
4
100
62
a
5
NH4Cl only
acetic acid
formic acid
TMEDA
4
b
5
b
2
100
100
0
5
2
5
24
4
5
pH 6 phosphate
pH 8 phosphate
93
5
24
4
0
c
5
NH4Cl
100
72
c
5
NH4Cl
4
a
b
c
Figure 1. Substrate scope: Zn-mediated reductions of aromatic nitro
groups in TPGS-750-M/water at room temperature: (a) yield after
workup; (b) 2 equiv of NH4Cl used.
“On water”, no surfactact. Two batchwise zinc additions. 1.2 equiv.
varied from the required 3 equiv up to 10 equiv suggested by
prior literature.11 While limiting zinc loading to 3 equiv slowed
reaction rates and failed to achieve 100% conversion, with
significant amounts of partially reduced hydroxylamine as an
impurity, 5 equiv resulted in clean, complete conversion. The
global reaction concentration was established at 0.5 M,
affording a reasonable reaction rate. Increasing the concen-
tration to 1 M resulted in a similar rate, while higher
concentrations showed poor substrate solubility and failed to
reach complete conversion. Attempting the reaction “on-water”
without the aid of TPGS-750-M resulted in low and
inconsistent yields.
proceeded smoothly in the presence of both electron-
withdrawing as well as electron-donating groups. Functional
group tolerance was shown to include aldehydes, ketones,
esters, amides, allenes, sulfides, and various halogens, suggestive
of a strong preference for selective nitro group reduction.
In contrast to classical hydrogenation,5 no complications
were encountered due to the presence of other reducible
functionalities, including alkenes, alkynes, and carbonyls
groups. Nitroarenes bearing halogen reacted particularly
cleanly, yielding a variety of potentially synthetically useful
building blocks. Most substrates showed complete reduction in
1−4 h.
Several alternative additives were screened, with none
showing better overall performance than that seen with
NH4Cl. Acids (HOAc, HCOOH) resulted in rapid conversion
B
dx.doi.org/10.1021/ol403079x | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Orthogonal blocking group strategies were evaluated using
protected nitroanilines and nitrophenols, subjecting each to our
standard nitro group reduction conditions (Figure 2).
Carbamate 21, benzylic amine 22, and benzyl ether 23 were
all found to be stable over a period of 48 h.
could be applied to reduce reaction times to <4 h, if desired.
However, sensitive substrates, e.g., a substituted aryl iodide,
showed increased lability upon heating, so a balance between
throughput, energy input, and product stability should be taken
into consideration.
Lastly, this methodology was applied to a two-step synthesis
of the antiarrhythmic agent procainamide (Scheme 2). The
amide bond was constructed in aqueous 2 wt % TPGS-750-M
with 4-nitrobenzoic acid 27 and N,N-diethylethylenediamine
28, utilizing EDCI/HOBt at room temperature. After isolation,
the resulting nitrobenzamide 29 was reduced under standard
conditions, producing the final API 1-chloro-4-methyl-2-
nitrobenzene 30 in 83% yield over two steps. E factors,14
comparing the mass ratio of organic solvent used to product
produced, could be dramatically reduced relative to those
associated with the patented route that relies on organic
solvents.15 This approach also obviated the need for specialized
hydrogenation equipment, thereby eliminating this particular
process safety risk and its costs associated with such nitro group
reductions.
Figure 2. Screening of protecting group stability.
Selected heteroaromatic natural products were nitrated and
then subjected to reduction (Figure 3). The protocol
successfully yielded clean amino derivatives 24b−26b, demon-
strating its potential utility for unmasking an NH2 moiety in
advanced intermediates in pharmaceutical or natural product
synthesis or other heteroaromatic targets of interest.
In summary, a robust, cost-effective, and environmentally
friendly method has been developed for chemoselective
reductions of nitroaromatic compounds in the presence of a
wide range of functional groups. Full conversion was achieved
in water and at room temperature, enabled by TPGS-750-M-
derived nanomicelles. Compatibility with orthogonal protecting
groups and heteroaromatic substrates has been demonstrated,
highlighting the potential utility of this protocol in multistep
complex molecule synthesis.
Figure 3. Reductions of natural products/heteroaromatics.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization information for
all new compounds. This information is available free of charge
via the Internet at http://pubs.acs.org.
■
S
To demonstrate the ease of use and flexibility of this
protocol, a few modifications were attempted with a focus on
robustness and potential scalability. To eliminate the use of
silica gel filtration on scale, the reaction was instead extracted
with a minimum amount of ethyl acetate. As demonstrated in
previous publications from our group,7 a standard in-flask
extraction leads to clean product, while leaving the surfactant
behind in the aqueous phase to be recycled. As alluded to
previously (vide supra), substrate concentration could be
increased from 0.5 to 1.5 M to minimize the investment in
water, with a slight reduction in rate. Mild heating (60 °C)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lipshutz@chem.ucsb.edu.
Notes
The authors declare no competing financial interest.
Scheme 2. Procainamide Synthesis: Comparison of Route in Organic Solvents vs in Water at Room Temperature
C
dx.doi.org/10.1021/ol403079x | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ACKNOWLEDGMENTS
■
We warmly thank the NIH for supporting our research in green
chemistry (GM 86485). Support provided by a New Leaf Grant
from UCSB to B.H.L. is also appreciated.
REFERENCES
■
(1) Downing, R. S.; Kunkeler, P. J.; van Bekkum, H. Catal. Today
1997, 37, 121.
(2) Vogel, A. I. et al. Textbook of Practical Organic Chemistry, 5th ed.;
Addison Wesley Longman Ltd.: Edinburgh Gate, England, 1989;
Chapter 6, p 953.
(3) Weissermel, K.; Arpe, H. J. Industrial Organic Chemistry, 4th ed.;
John Wiley & Sons: Darmstadt, 2003; Chapter 13, p 376.
(4) Pandarus, V.; Ciriminna, R.; Beland, F.; Pagliaro, M. Catal. Sci.
Technol. 2011, 1, 1616.
(5) Figueras, F.; Coq, B J. Mol. Catal. A: Chem. 2001, 173, 223.
(6) Taleb, A. B.; Jenner, G. J. Mol. Catal. 1994, 91, 149.
(7) (a) Sorribes, I.; Wienhofer, G.; Vicent, C.; Junge, K.; Llusar, R.;
̈
Beller, M. J. Am. Chem. Soc. 2011, 133, 12875. (b) Sorribes, I.;
Wienhofer, G.; Vicent, C.; Junge, K.; Llusar, R.; Beller, M. Angew.
̈
Chem., Int. Ed. 2012, 21, 7794.
(8) (a) Dey, R.; Mukherjee, N.; Ahammed, S.; Ranu, B. C. Chem.
Commun. 2012, 48, 7982. (b) Kim, S.; Kim, E.; Kim, B. M. Chem.
Asian J. 2011, 6, 1921. (c) Zhang, L.; Zhang, S.; Kang, D. E.; Shin, J.
Y.; Suh, H.; Kim, I. RSC Adv. 2013, 3, 4692.
(9) (a) Rahman, A.; Jonnalagadda, S. B. Catal. Lett. 2008, 123, 264.
(b) Wang, H. C.; Li, B. L.; Zheng, Y. J.; Wang, W. Y. Bull. Korean
Chem. Soc. 2012, 33, 2961. (c) Kaur, B.; Tumma, M.; Srivastava, R.
Ind. Eng. Chem. Res. 2013, 52, 11479. (d) Tumma, M.; Srivastava, R.
Catal. Commun. 2013, 37, 64.
(10) Kabalka, G. W.; Varma, R. S. Comprehensive Organic Synthesis,
1st ed.; Trost, B. M., Fleming, I., Eds.; Elsevier Ltd.: Kidlington,
Oxford, 1991; Vol. 8, Chapter 2.1, p 363.
(11) Khan, F. A.; Dash, J.; Sudheer, C.; Gupta, R. K. Tetrahedron Lett.
2003, 42, 7783.
(12) Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta 2012, 45, 3.
(13) Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.; NIshikata,
T.; Duplais, C.; Krasovskiv, A.; Gaston, R. D.; Gadwood, R. C. J. Org.
Chem. 2011, 76, 4379.
(14) (a) Sheldon, R. A. Green Chem. 2007, 9, 1273. (b) Lipshutz, B.
H.; Isley, N. A.; Fennewald, J. C.; Slack, E. D. Angew. Chem., Int. Ed.
2013, 52, 10952.
(15) Wurster, J. A.; Wang, E. H.; Yee, R. C (Allergan Inc.). Kinase
Inhibitors. US Patent 20070032478, Feb 8, 2007.
D
dx.doi.org/10.1021/ol403079x | Org. Lett. XXXX, XXX, XXX−XXX