Carbonyl Iron Powder: A Reagent for Nitro Group Reductions under Aqueous Micellar Catalysis Conditions

Article abstract of DOI:10.1021/acs.orglett.7b03216

An especially mild, safe, efficient, and environmentally responsible reduction of aromatic and heteroaromatic nitro-group-containing educts is reported that utilizes very inexpensive carbonyl iron powder (CIP), a highly active commercial grade of iron powder. These reductions are conducted in the presence of nanomicelles composed of TPGS-750-M in water, a recyclable aqueous micellar reaction medium. This new technology also shows broad scope and scalability and presents opportunities for multistep one-pot sequences involving this reducing agent.

Full text of DOI:10.1021/acs.orglett.7b03216

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Carbonyl Iron Powder: A Reagent for Nitro Group Reductions under
Aqueous Micellar Catalysis Conditions
Nicholas R. Lee,† Agata A. Bikovtseva,† Margery Cortes-Clerget,† Fabrice Gallou,‡
and Bruce H. Lipshutz*,†
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
‡Chemical & Analytical Development, Novartis Pharma AG, 4056 Basel, Switzerland
S
* Supporting Information
ABSTRACT: An especially mild, safe, efficient, and environ-
mentally responsible reduction of aromatic and heteroaromatic
nitro-group-containing educts is reported that utilizes very
inexpensive carbonyl iron powder (CIP), a highly active
commercial grade of iron powder. These reductions are
conducted in the presence of nanomicelles composed of
TPGS-750-M in water, a recyclable aqueous micellar reaction
medium. This new technology also shows broad scope and
scalability and presents opportunities for multistep one-pot
sequences involving this reducing agent.
eveloping, modifying, and optimizing methodologies for
Dnitro group reductions has a rich history in organic
chemistry.1 Most existing methods have undesirable aspects,
such as high pressures and/or temperatures, pyrophoric
materials, toxic or dangerous reagents, high-boiling or egregious
dipolar, aprotic solvents, precious or toxic metals, long reaction
times, expensive ligands, commercially unavailable materials,
Figure 1. Carbonyl iron powder (CIP).
lack of selectivity, and highly variable yields. The more
common traditional approaches oftentimes focus on catalytic
hydrogenation utilizing a variety of catalysts or stoichiometric
reducing agents such as formic acid,2 hydrazine,3 and silanes.4
Various metals have also played an important role, including
tin, zinc, platinum, and nickel.5 Iron-based reagents, in
particular, have been fundamental to these reductions, with
Fe/HCl and Fe/NH4Cl as textbook cases.6 Nonetheless, these
reagents are considered relatively harsh and may be functional-
group-intolerant; from a modern perspective, they are certainly
not environmentally friendly. Herein we describe the use of
commercially available, inexpensive, and safe carbonyl iron
powder (CIP), which can be used under micellar catalysis
conditions in water for the facile and efficient reduction of
functionalized aryl and heteroaryl nitro-group-containing
compounds.
CIP (Figure 1) is a free-flowing powder produced in large
quantities by BASF via thermal decomposition of liquid
Fe(CO)5.7 That process affords the reagent as uniform
spherical particles (2−3.5 μm average diameter) suitable for
direct use. Bulk quotes for one metric ton range from $5000 to
$8000 (i.e., $5−8/kg),8 which categorizes this reagent as
inexpensive as well as practical. Its high purity makes it also
suitable for a variety of industrial uses, such as in electronic
parts, in the synthesis of industrial diamonds, and as an
absorber of microwave radiation. Its use in organic synthesis,
and specifically for nitro-group-containing intermediates en
route to active pharmaceutical ingredients, however, has not
been tested, notwithstanding reports on other types of iron
powders that have been applied for similar purposes.6
The use of CIP is remarkably straightforward, as none of the
typical additives are needed for this reduction; no ligands,
hydride, external gases and resulting pressure, or special
equipment is required. Only NH4Cl is needed, (presumably)
to clean the CIP surface during the reaction. Reductions take
place in water containing nanoreactors composed of the
designer surfactant TPGS-750-M (2 wt %) between rt and 45
°C, typically with high functional group tolerance and in
excellent isolated yields.
By way of comparison, other reagents, in particular
alternative processes based on iron metal6 (e.g., Fe/NH4Cl),
required refluxing aqueous EtOH under dilute conditions. Such
conditions lead to considerable waste generation upon workup,
as this is not a recyclable reaction mixture. Attempts to use
commonly available 325 mesh iron powder under the same
aqueous nanomicellar conditions at 45 °C gave highly variable
and unreliable results, with some substrates going to
Received: October 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03216
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
completion while others were only partially reduced. Moreover,
this form of iron is rather abrasive, as was evident from its
impact on Teflon-coated stir bars. While not a major issue in an
academic setting, this could be troublesome and costly at scale.
No such problem was observed using CIP.
Pd NPs,12a those with electron-donating residues appear to be
the most receptive to reduction with CIP. Thus, these reagents
appear to be complementary.
As the examples in Scheme 1 show, several functional groups
are unaffected under the standard reaction conditions. These
include, notably, a free hydroxyl group as in product 3, aryl
fluorides, chlorides, and bromides (e.g., products 1, 7 and 14),
CF3 residues (e.g., 1), amides, esters, ketones, and carbamates.
Several pyridyl- or pyridyl-like-containing educts were also
studied, affording products 18−22 (Scheme 2), documenting
The addition of cosolvents9 such as THF and EtOAc
improved the reaction processability and stirring on occasion
and frequently shortened the reaction time (Scheme 1). Some
Scheme 1. Substrate Scope for CIP-Mediated Nitro Group
Reductions
Scheme 2. CIP-Mediated Reductions of Pyridyl and Pyridyl-
like Substrates To Arrive at Products 18−22
that this important heteroaromatic ring remains unaffected (i.e.,
not reduced) using CIP under these conditions. In general,
therefore, the functional group compatibility appeared to be
excellent. By contrast, the use of CIP under identical conditions
but in organic solvents (MeOH, THF, EtOAc, or DMF) led to
no product formation. All attempts to extend this methodology
to analogous alkyl nitro compounds met with failure, as in
several cases none of the anticipated primary amines were
observed.
Increasing the scale of a reduction under our standard
conditions was performed, going in this case from the typical
100 mg reaction to one that generates ca. 3.5 g of amine
product (Scheme 3). Unlike the use of Zn/NH4Cl, which
Scheme 3. Scale-Up Reaction: (a) Ammonium Chloride,
CIP, and Nitro Compound; (b) After Addition of EtOAc
Cosolvent and 2 wt % TPGS-750-M/H2O; (c) After Stirring
for 20 min at 45 °C
substrates (e.g., precursors to products 2, 6, and 19) were fully
reduced at ambient temperature, although the reaction times
were notably longer than for those treated with CIP at 45 °C.
In comparison to earlier processes developed using micellar
catalysis conditions, the CIP method is similar to that based on
zinc;10 however, iron is a notable improvement from a
sustainability perspective in terms of earth abundance11 and
presents no complications with stirring in large-scale reactions.
No aggregation of solids using CIP was noted at any point,
including during the scale-up experiment (vide infra). Use of
prior technology based on Fe/ppm Pd nanoparticles (NPs) for
similar reductions, while not leading to any solids of
consequence, can lead to foaming due to hydrogen gas
evolution from NaBH4 (or KBH4) being added to the aqueous
mixture, which can present difficulties when scaling reac-
tions.12,13 Introduction of a cosolvent can decrease the extent of
foaming but may necessitate the use of a larger vessel to ensure
that any foaming can be accommodated. CIP, on the other
hand, with no gas evolution involved, obviates these practical
considerations. Furthermore, while educts bearing electron-
withdrawing groups proved to be very reactive toward Fe/ppm
produces copious amounts of solids that can inhibit stirring,10
no notable changes in either physical appearance or reaction
outcome were seen, suggesting that this is a scalable method.
On the basis of the multitude of processes that can now be
run in the same aqueous medium containing TPGS-750-M,14
a
tandem series of three reactions was run in a single pot
(Scheme 4). The sequence was designed with special emphasis
B
DOI: 10.1021/acs.orglett.7b03216
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Tandem Three-Step, One-Pot Sequence: (A)
Completed SNAr Reaction; (B) Completed Suzuki−Miyaura
Coupling; (C) Completed Nitro Group Reduction
Table 3. Recycling Using Repeated Addition of CIP and
NH4Cl
first
recycle
second
recycle
third
recycle
reaction
isolated yield (%)
reaction time (h)
94
93
2
93
2
96
2.5
2.5
3
2
equiv of CIP added
equiv of NH4Cl added
none
none
2.5
3
2.5
3
gram scale and beyond, under environmentally responsible
reaction conditions. The reagent and reaction medium are both
recyclable and can be applied to sequential processes in a one-
pot sequence. This new technology relies on iron, the one
element among the transition metals that is both of great
synthetic value and not endangered. While many alternative
processes exist, including those with iron, few are of recent
vintage and cognizant of the importance of the selection of
reagents, the energy invested, and the avoidance of organic
solvents from the perspective of sustainability.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03216.
on the use of the nitro group to aid in an SNAr reaction,15
followed by a Suzuki−Miyaura cross-coupling, and finally
reduction of the nitro group. The nitro reduction proved to be
robust for this step and was unaffected by the complex mixture
present from the previous two steps, leading to amine 24 in a
global yield of 89% over three steps.
1
Experimental procedures, characterization data, and H
and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
The aqueous reaction medium containing nanoreactors
composed of TPGS-750-M is fully recyclable (Table 1), with
Corresponding Author
*E-mail: lipshutz@chem.ucsb.edu
ORCID
Table 1. Recycling of Aqueous TPGS-750-M
Margery Cortes-Clerget: 0000-0002-8358-1925
Bruce H. Lipshutz: 0000-0001-9116-7049
Notes
The authors declare no competing financial interest.
reaction
first recycle
second recycle
isolated yield (%)
95
93
96
ACKNOWLEDGMENTS
Financial support provided by the NSF (GOALI SusChEM
1566212) and Novartis is warmly acknowledged with thanks.
■
E factor (organic solvent)
E factor (including water)
5.5
16.5
5.5
5.5
5.5
5.5
no loss in reaction yield. Moreover, as expected, the E Factors16
associated with this chemistry as a measure of greenness are
low.17 In addition, the CIP present retains enough residual
reactivity to mediate a second reduction, but only upon
addition of NH4Cl (Table 2). Adding more CIP and NH4Cl to
the reaction vessel containing the same TPGS-750-M allows for
the continued use of the aqueous reaction mixture for three
consecutive recycles (Table 3).
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■
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94
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5
NR
N/A
3
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equiv of NH4Cl added
none
3
C
DOI: 10.1021/acs.orglett.7b03216
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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D
DOI: 10.1021/acs.orglett.7b03216
Org. Lett. XXXX, XXX, XXX−XXX