Sustainable and Scalable Fe/ppm Pd Nanoparticle Nitro Group Reductions in Water at Room Temperature

Article abstract of DOI:10.1021/acs.oprd.6b00410

An operationally simple and general process for the safe and selective reduction of nitro groups utilizing ppm Pd supported on Fe nanomaterials in aqueous solution of designer surfactant TPGS-750-M has been developed and successfully carried out at a 100 mmol scale. Preferred use of KBH₄ as the hydride source, at ambient temperature and pressure, lends this process suitable for a standard reaction vessel alleviating the need for specialized hydrogenation equipment. Calorimetry data parallel those expected for a classical nitro group reduction when measuring the heat of reaction (-896 to -850 kJ/mol).

Full text of DOI:10.1021/acs.oprd.6b00410

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Full Paper
Sustainable and Scalable Fe/ppm Pd Nanoparticle
Nitro Group Reductions in Water at Room Temperature
Christopher Michael Gabriel, Michael Parmentier, Christian Riegert,
Marian Lanz, Sachin Handa, Bruce H. Lipshutz, and Fabrice Gallou
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00410 • Publication Date (Web): 27 Jan 2017
Downloaded from http://pubs.acs.org on January 27, 2017
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Sustainable and Scalable Fe/ppm Pd Nanoparticle Nitro Group Re-
ductions in Water at Room Temperature
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Christopher M. Gabriel†, Michael Parmentier‡, Christian Riegert‡, Marian Lanz‡, Sachin Handa§, Bruce H. Lip-
shutz†, and Fabrice Gallou*‡
†Department of Chemistry & Biochemistry, University of California, Santa Barbara 93106, United States
‡ Novartis Pharma AG, CH-4057 Basel, Switzerland
§ Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States
Supporting Information Placeholder
Table of Contents Graphic
ABSTRACT: An operationally simple and general process for the safe and selective reduction of nitro groups utilizing ppm Pd supported on
Fe nanomaterials in aqueous solution of designer surfactant TPGS-750-M has been developed and successfully carried out at a 100 mmol
scale. Preferred use of KBH4 as the hydride source, at ambient temperature and pressure, lends this process suitable for a standard reaction
vessel alleviating the need for specialized hydrogenation equipment. Calorimetry data parallels that expected for a classical nitro group reduc-
tion when measuring the heat of reaction (-896 to -850 kJ/mol).
Keywords: green chemistry, KBH4, micellar catalysis, nanoparticles, reduction, chemistry in water.
century,9 the need, especially at scale, for a safer, more environmen-
tally responsible method remains.
INTRODUCTION
The reduction of a nitro group to the corresponding amine
Recently, a new reagent has been developed that can be uti-
represents one of the most widely utilized transformations in or-
lized under conditions that meet many of these concerns associated
ganic synthesis. With aromatic compounds, this transformation
with the reduction of aromatic and heteroaromatic nitro com-
represents, by far, the most common procedure for the synthesis of
pounds to their corresponding amines. Using nanoparticles (NPs)
aryl amines due to the ease, low cost, and predictability by which
derived from FeCl3 that contain ppm levels Pd, along with NaBH4
such aryl derivatives can be generated.1,2 Most often, hydrogenation
as the source of hydrogen under aqueous micellar conditions at
conditions are employed utilizing a transition metal catalyst such as
room temperature, reductions take place in good to exceptional
5
Pd/C,3 Rainey-Ni,4 or PtO2 . Less expensive, alternative metals
yields (80-98% isolated) within short reaction times (typically 2-4
such as Fe,6 Zn,7 and Sn,8 have been widely employed for these
hours).10 These NPs and associated conditions have been found to
reductions as well; however, they oftentimes require stoichiometric
be highly general, tolerating a variety of other potentially reducible
(or super stoichiometric) amounts of metals, and/or harsh reaction
functional groups, including aryl halides, alkenes, alkynes, esters,
conditions. Moreover, such reduction methods may stop at inter-
amides, nitriles, and ketones, as well as benzyl protected alcohols
mediate stages, and/or go through accumulation of highly energet-
and amines which would otherwise be cleaved under Pd-catalyzed
ic intermediates. While this transformation has been ubiquitous in
hydrogenation conditions.11 Encouraged by this success, develop-
the synthesis of pharmaceuticals, dyes, explosives, agrochemicals,
ment of a scale-up process for this method was pursued, as was a
functional materials, and bioactive natural products for well over a
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study of several other reaction parameters, the results from which Table 1. Comparison of various co-solvents
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are described herein.
Our standard procedure for Fe/ppm Pd-catalyzed reduction
of nitro compounds calls for generating Fe nanoparticles (≥80 ppm
Pd) in a 2 wt % solution of designer surfactant TPGS-750-M in
water (Figure 1).10 NaBH4 (1.5-3.0 equiv) is then transferred to the
catalyst solution to arrive at the active nanomaterial catalyst (acti-
vation), as well as to charge the reaction mixture with the hydride
source for the subsequent reductions. In a separate vessel, the nitro
group-containing starting material is dispersed in 2 wt % TPGS-
750-M/H2O prior to its addition into the reaction mixture. Once
added, the reaction is allowed to stir at room temperature until full
conversion of starting material and intermediates is observed, as
monitored by TLC. Amine isolation/purification is carried out via
extraction with ethyl acetate or t-butyl methyl ether (MTBE) from
the reaction mixture, followed by column chromatography or, more
favorably (and feasible) via direct recrystallization as the corre-
sponding HCl salt.
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We next focused on understanding the role of NaBH4 as the
reductant. Upon addition of NaBH4 to the homogeneous catalyst
solution, the iron(III) salt is quickly reduced, as it precipitates as
fine black particles while the reaction mixture foams due to gas
evolution. A hydrogenation study was done in order to assess
whether NaBH4 acts as the direct hydride source or as an H2 pre-
cursor (Table 2). Consistent with the initial report,10 when NaBH4
is directly replaced with H2, only a negligible amount of product is
detected even at a pressure of 2 bars (entry 3). Under hydrogena-
tion conditions, no visual change in catalyst solution was observed,
indicating that the catalyst was not activated. When only a catalytic
amount of NaBH4 was added to the reaction for catalyst activation,
the reduced Fe/Pd catalyst was readily observed. Even under 10
bar H2, only trace amounts of product was observed along with the
appearance of condensation and dehalogenated by-products.
O
O
O
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O
O
O
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Figure 1. Structure of TPGS-750-M
RESULTS AND DISCUSSION
The reduction of 1-chloro-4-nitrobenzene (2) to 4-chloro-
aniline, 3, was investigated as the model system for scalable
Fe/ppm Pd-catalyzed nitro group reductions. We began by consid-
ering the physical aspects of the system. Materials containing nitro
functionality are typically highly crystalline solids, oftentimes unfa-
vorable for reactions in which water is used as the reaction medium.
While the use of surfactants at or above their critical micellar con-
centrations (CMC) can be used to stabilize a biphasic mixture as a
microemulsion, this is often not sufficient to liberate material from
its energetically more favorable crystalline state, especially at rela-
tively high solute concentrations. As a result, heterogeneous mix-
tures containing undissolved solids can provide challenges on scale.
For this reason, we sought to employ the use of a cosolvent that
would aid in dissolving crystalline material and stabilize the starting
material emulsion. Consistent with our previous efforts,10,12 THF
was found to be the cosolvent of choice showing, for this specific
transformation based on observations highlighted below, slightly
better conversion on a 78 mg scale than literature conditions (Ta-
ble 1). While PEG-200 was found to work equally as well, solubility
of 2 in this solvent was poor resulting in an unstable emulsion.
Table 2. Fe/ppm Pd-catalyzed nitro group reduction of 1-
chloroaniline under hydrogenation conditions
At this stage, we envisioned that a more dissociated borohy-
dride might impact the outcome of the reduction. When NaBH4 is
replaced by other metal borohydride salts, a pronounced effect is
observed depending on the nature of the counterion (Table 3). In
comparison to NaBH4, KBH4 reacts far faster both in terms of start-
ing material conversion and in the final slow step of the reduction;
i.e., from hydroxylamine 5 to aniline 3 (Scheme 1).
When a solution of 2 in THF was added directly to the reac-
tion mixture, the progress of the reaction suffered significantly as
only 18% product was observed after 18 hours (entry 6), showing
that the dispersion of the nitro compound in surfactant solution is
in fact necessary for high conversion. In forming an emulsion for a
given starting material, it was found that dissolution in THF prior
to addition to 2 wt % TPGS-750-M/H2O achieves the desired
‘milky’ appearance much faster than other addition sequences. This
should be done at high stirring rates (>800 rpm). Water-miscible
alcohols such as methanol and isopropanol were not considered as
co-solvents due to their inability to dissolve 2 prior to addition of
the aqueous surfactant solution.
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completion. Upon our second attempt, quantitative conversion to
Table 3. Initial MBH4 screening
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product was achieved by charging the reaction with 3.0 additional
equivalents KBH4 prior to adding the second portion of starting
material. We have found that portion-wise addition of materials can
be continued up to at least ten additional times without effecting
reaction conversion, however, precipitation of product leads to a
decrease in homogeneity of the reaction mixture which may not be
desirable for this process at a larger scale. These results translated
well when the identical procedure was carried out on a 100 mmol
scale affording 3 in 94% isolated yield (as its HCl salt).
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Reaction work-up via acidification of the mixture with HCl
under air achieves the quenching of KBH4, deactivation and solu-
bilization of the catalyst, as well as solubilization of the product
amine in water. It should be investigated that all KBH4 has been
decomposed before continuing further work-up and purification.
Also, it should be noted that the catalyst will not be solubilized if
the reaction quench is performed under oxygen-free conditions. At
this point, extraction with a minimal amount of heptanes is used to
remove impurities arising from the condensation pathway outlined
in Scheme 1. Noteworthy is that isolation of all impurities associat-
ed with this pathway represented less than 0.1% of the total crude
mass at the 100 mmol scale. Product isolation is then achieved via
neutralization with aqueous NaOH solution, extraction of the
product with i-PrOAc (isopropyl acetate), and passing the organic
extracts through a plug of filter aide (Celite). After reducing the
volume of filtrate with recovery of much of the solvent, recrystalli-
zation of the product as the corresponding HCl salt followed from
the dropwise addition of 1 M HCl solution in ethyl acetate to afford
3 as white crystals. ICP analysis was carried out on the purified
material revealing < 1 ppm of residual Pd content.
It has been well studied that aromatic nitro reductions may be
achieved via two pathways, both of which go through nitroso- and
hydroxylamine intermediates (Scheme 1). In order to further un-
derstand this system, isolated intermediates and by-products were
submitted to standard reaction conditions including the corre-
sponding hydroxylamine 5, azoxy 6, and diazo compound 7 (Table
4). Complete conversion of 5 to 3 was achieved while only trace
amounts of azoxy 6 were reduced to 7, and no conversion of 7 to 8
was detected rendering the condensation reaction pathway a dead
end under our conditions. The condensation of 4 and 5 to 6 is not
only a concern in terms of overall conversion to product, but also in
terms of safety, as these by-products be both genotoxic and car-
cinogenic.13 Therefore, conditions were required for avoiding this
pathway so as to ultimately arrive at a safer, more efficient process.
Scheme 1. Reaction pathways for nitro group reductions
Scheme 2. Conditions for avoiding the condensation pathway
Table 4. Intermediate and by-product formation under stand-
ard conditions
In terms of the physical aspects characteristic of the system, it
is apparent that the majority of gas evolved for all processes of this
reaction occurs during catalyst activation upon addition the initial
portion of KBH4. Foaming has been observed to increase the reac-
tion volume up to four times the original solvent level during cata-
lyst activation (for example, 200 mL of catalyst solution can gener-
ate ~600 mL of foam). This is a result of the high surface tension of
the surfactant solution and gas generated in-situ. Investigations
were conducted to counteract/diminish the amount of foam pre-
sent during catalyst activation. Upon addition of the 1-chloro-4-
nitrobenzene emulsion, the foam will collapse completely, which
can also be effected by the introduction of the solute 2 and THF,
not merely THF alone. Addition of KBH4 that is charged to the
system after the substrate is present will not lead to the generation
of any significant amount of foam.
A careful kinetic study led us to a simple process that prevents
formation of the unproductive by-products and minimizes accumu-
lation of problematic intermediates. First, to increase reaction rate,
we changed the nature of the hydride source from NaBH4 (1.5
equiv) to the more reactive KBH4, and increased its loading (3.0
equiv). Additionally, catalyst loading was increased to 200 ppm Pd
loading. Next, we considered the entropic factor of condensation
by diluting the system from 0.5 to 0.25 M. Within one hour, 100%
conversion of 2 was achieved and by two hours the reaction had
gone to completion free of by-products (Scheme 2). The reaction
was then charged with an additional equivalent of starting material,
and although full consumption of 2 was achieved, the remaining
hydride in the system was not sufficient to bring the reaction to
In order to investigate the limitations of our conditions, cata-
lyst loading was decreased (Table 5, entry 2), as were the equiva-
lents of reductant (entry 3). The resulting rate of the reaction was
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slower from both modifications, and the undesired azoxy by- tude for classical nitro reduction per hydrogenation; the heat of
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product 6 was observed yet again. To further generalize this revised
system, we also examined the effect of added KCl in the presence of
other less reactive hydride sources, such as LiBH4 and NaBH4.
While the reactivity of LiBH4 was only marginally affected, identical
results to our optimized system were realized when NaBH4 (3
equiv) was used in the presence of 1.0 equivalent KCl salt (entry
6). Due to the lower cost of NaBH4 in comparison to other boro-
hydride salts, use of KCl as additive may serve as a viable alternative
to KBH4 on scale.14
reaction approximately after each addition being in the range of -
896 to -850 kJ/mol. As expected, the heat of reaction in kJ/kg de-
pends on the concentration of the nitro compound in the reaction
mixture; the reaction is strongly exothermic [ca. -153 kJ/kg FRM
(final reaction mass), corresponding to theoretical adiabatic tem-
perature increase of about 37 °C] in the first portion and ca -115
kJ/kg FRM corresponding to theoretical adiabatic temperature
increase of about 29 °C in the second portion. About 50% of the
whole energy is accumulated at the end of the addition correspond-
ing to a theoretical adiabatic temperature increase of about 18 °C to
15 °C. Even in a worst case scenario, in the case of an undetected
loss of cooling, a maximum temperature of about 62 °C (IT + ΔTad
= 25 + 37°C = 62 °C) could theoretically be reached. This is well
below the boiling point of the solvent (water) and would not be
safety matter; however, a potential increase in gas release can be
expected. The dynamic SEDEX thermostability test of the reaction
mixture after addition of the second portion of 2 at 20 °C within 10
minutes shows no significant exothermal decomposition reaction
up to 160 °C.15 The expected H2 evolution based on a 3:1 stoichi-
ometry of KBH4 to nitro compound is calculated at 36.7 L / kg
FRM16 and much of the remaining KBH4 portion is decomposed
upon workup. Potential accumulation of KBH4 should be evaluated
as this may lead to potential higher gas release and the entire pro-
cess should be performed under argon flow to ensure good conver-
sion. This process alleviates the occurrence of pressure build-up
which can be expected after several portion additions and elimi-
nates the requirement for specialized equipment.
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Table 5. Limitations and effects of added KCl
Additional representative examples using this technology are
illustrated in Table 6, with each being run in water at ambient tem-
perature. These are meant to be suggestive of the functional group
compatibility associated with this process, where an aryl bromide, a
dihalocyclopropane, a protected acylhydrazine derivative, and an
α,β-unsaturated ester all survive these conditions and afford the
targeted anilines in good isolated yields.
• approximate heat of reaction from -896 to - 850 kJ/mol
• 50% of the energy accumulated at the end of the addition
• an undetected loss of cooling could result in an increase to only 62 °C
• no significant exothermal decomposition reaction up to 160°C
Figure 2. Key results from a calorimetry study
Table 6. Additional examples using KBH4
SUMMARY & CONCLUSIONS
In conclusion, we have developed a safe scale-up process for
the Fe/ppm Pd-catalyzed reduction of nitro compounds in water at
room temperature. This process benefits from the use of an aque-
ous solution of TPGS-750-M as the gross reaction medium, mini-
mal levels of palladium (80-200 ppm), and minimal by-product
accumulation. Furthermore, this process allows for reductions
which typically require high pressure equipment to be run in a
standard reactor without significant safety concerns as determined
by calorimetry studies. As the result of the aqueous nature of this
process, reaction work up and product purification is operationally
simple. In addition, we envision this process to be well suited for
late stage reduction of aryl and heteroaryl nitro groups due to the to
the high functional group tolerance of these conditions, as well as
the low levels of residual metal catalyst in the final product.
EXPERIMENTAL SECTION
CALORIMETRY
General. Unless otherwise noted, all reactions were per-
formed under an atmosphere of argon. A solution of 2 wt % TPGS-
750-M/H2O solution was prepared by dissolving TPGS-750-M in
degassed Millipore purified water. All commercially available rea-
gents and solvents were used without further purification including
TPGS-750-M (CAS-No. 1309573-60-1). Thin layer chromatog-
raphy (TLC) was done using Silica Gel 60 F254 plates (Merck, 0.25
mm thick). The developed chromatogram was analyzed by UV
These results translated well when this procedure was carried
out on a 40 mmol scale in a 0.5 L RC1 reactor by charging KBH4
and 2 stepwise and portion-wise; with each portion of KBH4 and 2
only being added once full conversion of the precedent portion was
confirmed, considering each portion as a separate process. Calori-
metric analysis measured the energy for each portion correspond-
ing to the nitro reduction and the decomposition of KBH4. The
measured heat of reaction in kJ/mol is in the same order of magni-
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lamp (254 nm). Flash chromatography was performed using a Bio-
Teflon coated stir bar was charged with 5-bromo-2-nitropyridine
tage IsoleraTM Four using prepacked Biotage® SNAP Ultra cartridg-
es. Hydrogenation experiments utilized Argonaut Technologies
(203 mg, 1.0 mmol), 0.4 mL THF, followed by the slow addition of
1.5 mL 2 wt % TPGS-750-M/H2O. The mixture was mixed via
vortex and stirred at high speed (>1000 rpm) and approx. half of
the mixture was transferred to the catalyst reaction. After ca. 4 h,
the reaction was charged with KBH4 (162 mg, 3.0 mmol) and the
remaining portion of the starting material mixture. After ca. 16 h
(reaction time not optimized), the crude product was extracted
with 3 x 3 mL EtOAc, dried over anhydrous Na2SO4, and purified
via flash chromatography to yield 5-bromopyridin-2-amine as a
yellow solid (157.6 mg, 91%). Spectroscopic data was in agreement
with literature values.17 1H NMR (500 MHz, CDCl3) δ 7.85(dd,
1H, J = 2.60, 0.52 Hz), 7.21 (dd, 1H, J = 8.56, 0.52 Hz), 6.88 (dd,
1H J = 8.56, 3.11 Hz). 13C NMR (125 MHz, CDCl3) δ 142.06,
137.01, 129.48, 127.75, 124.68.
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EndeavorTM Katalysator Screening system. H and 13C NMR were
recorded at 297.8 K on a Bruker® 400 MHz spectrometer. The FID
was processed using ACD Labs NMR analysis software. Chemical
1
shifts in H NMR spectra are reported in parts per million (ppm)
on the δ scale from an internal standard of residual CDCl3 (7.260
ppm) or the central peak of DMSO-d6 (2.50 ppm). Data are re-
ported as follows: chemical shift, multiplicity (s = singlet, d = dou-
blet, t = triplet, q = quartet, quin = quintet), and integration. Chem-
ical shifts in 13C chemical spectra are reported in ppm on the δ scale
from the central peak of residual CDCl3 (77.16 ppm) or the central
peak of DMSO-d6 (39.51 ppm). ICP-OES measurements were
conducted by Solvias AG. Reaction profile based on analysis of
UPLC/MS data using Acquity HSS T3 1.8 µm 2.1 x 50 mm at 60°C
with the following eluent system: (A: water + 0.05 % formic acid +
3.75 mM ammonium acetate; B: acetonitrile + 0.04% formic acid);
gradient from 5 to 98 % B in 1.4 min; flow 1.0 mL/min.
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(2,2-Dibromo-3,3-dimethylcyclopropyl)methyl
4-amino-
benzoate (10). Prepared as described for 5-bromopyridin-2-amine
from (2,2-dibromo-3,3-dimethylcyclopropyl)methyl 4-nitrobenzo-
ate (484.0 mg, 1.2 mmol) to yield the product as a white solid
1
Preparation of 4-chloroaniline hydrochloride (3). In a three-
neck round bottom flask with overhead stirring at 200 rpm, 1.117 g
Fe nanomaterial (11.4 μmol Pd) was dissolved in 200.0 mL 2 wt %
TPGS-750-M/H2O. KBH4 (8.091 g, 150 mmol) was slowly
charged to the catalyst solution resulting in catalyst precipitation as
black solids, foaming, and gas evolution. In a separate 500 mL
round bottom flask with Teflon coated stir bar, 1-chloro-4-
nitrobenzene 1 (15.76 g, 100 mmol), was dissolved in 40 mL THF
followed by the slow addition of 100.0 mL 2 wt % TPGS-750-
M/H2O while stirring at 1000 rpm. A milky emulsion was achieved
after stirring ca. 30 min. Chloro-4-nitrobenzene emulsion (70 mL)
was then transferred dropwise (1 drop/sec) via addition funnel to
the center of the reaction mixture. Upon reaction completion (as
determined by TLC), the reaction was charged with an additional
KBH4 (8.091 g, 150 mmol) followed by the remaining 70 mL of the
chloro-4-nitrobenzene emulsion as described above. Upon comple-
tion ca. 11 h, the reaction was exposed to air and quenched with
37% HCl to pH = 3 and stirred for ca. 1 h. The quenched reaction
mixture was then extracted with 50 mL n-heptane to remove con-
densation by-products. The aqueous phase was then separated,
charged back into the reaction flask and neutralized with 11 M
NaOH, precipitating 4-chloroaniline (3). The mixture was then
extracted with 3 x 50 mL isopropyl acetate, the organic layers were
combined, filtered through Celite into a 500 mL round bottom
flask, concentrated under reduced pressure to ~75 mL and 75 mL
n-heptane was charged into the flask. The flask was then charged
with a Teflon coated stir bar and 1 M HCl solution in EtOAc (110
mL, 110 mmol) was transferred via addition funnel at a rate of 1
drop / sec while stirring at 200 rpm leading to the precipitation of
4-chloroaniline hydrochloride as white crystals. Stirring continued
for an additional 1 h after complete addition of HCl solution, the
solid was collected via vacuum filtration and dried at 45 °C and 0
(400.5 mg, 88%). H NMR (500 MHz, CDCl3) δ 7.88 (dt, 2H),
6.66 (m, 2H), 4.38 (m, 2H), 4.12 (s, 2H), 1.78 (t, 1.78), 1.45 (s,
3H), 1.33 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 166.37, 151.02,
131.69, 119.24, 113.74, 103.67, 99.03, 63.20, 43.73, 37.25, 28.96,
27.12, 19.67.
t-Butyl 2-(3-aminobenzoyl)hydrazine-1-carboxylate (11).
Prepared as described for 5-bromopyridin-2-amine from t-butyl 2-
(3-nitrobenzoyl)hydrazine-1-carboxylate (281.3 mg, 1.0 mmol) to
yield the product as a yellow solid (233.0 mg, 93%). 1H NMR (500
MHz, DMSO-d6) δ 9.91 (d, 1H, J = 1.30 Hz), 8.78 (s, 1H), 7.08 (t,
1H, J = 7.79 Hz), 7.03 (s, 1H), 6.95 (d, 1H, J = 7.53), 6.71 (ddd,
1H, J = 7.79, 2.34, 0.78 Hz), 5.29 (s, 2H), 1.42 (s, 9H). 13C NMR
(125 MHz, DMSO-d6) δ 166.73, 155.45, 148.49, 133.49, 128.72,
116.97, 114.46, 113.05, 79.01, 28.11.
ethyl (E)-3-(4-aminophenyl)acrylate (12). Prepared as de-
scribed for 5-bromopyridin-2-amine from ethyl (E)-3-(4-
nitrophenyl)acrylate (221.2 mg, 1.0 mmol) to yield the product as
a yellow oil as an inseparable mixture of 12 and the corresponding
alkane (181.9 mg, 93%, 17:3 alkene:alkane). Spectroscopic data
was in agreement with literature values.18 1H NMR (500 MHz,
CDCl3) δ 7.60 (d, 1H, J = 16.09 Hz), 7.36 (m, 2H), 6.65 (m, 2H),
6.24 (d, 1H, J = 15.8 Hz), 4.25 (q, 2H), 1.33 (t, 3H). 13C NMR
(125 MHz, CDCl3) δ 167.65, 148.60, 144.79, 129.82, 124.76,
114.80, 113.75, 60.13, 14.37.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization data, 1H and 13C NMR
spectra, and calorimetry data. This material is available free of charge
via the internet at http://pubs.acs.org
1
AUTHOR INFORMATION
torr for 18 h to afford 15.49 grams (94%). H NMR (500 MHz,
DMSO-d6) δ 10.12 (brs, 3H), 7.53 (dt, 2H), 7.39 (dt, 2H). 13C
NMR (125 MHz, DMSO-d6) δ 132.02, 131.66, 129.58, 124.68.
Corresponding Author
*E-mail: fabrice.gallou@novartis.com
Preparation of 5-bromopyridin-2-amine (9). A 50 mL round
bottom flask with Teflon-coated stir bar was charged with 16 mg Fe
nanomaterial (0.11 μmol Pd) and was suspended in 1.5 mL 2 wt %
TPGS-750-M/H2O. KBH4 (162 mg, 3.0 mmol) was slowly charged
to the catalyst solution resulting in catalyst precipitation as black
solids, foaming, and gas evolution. A separate 8 mL dram vial with a
Author Contributions
This work was performed in large measure at Novartis in Basel, carried
out predominantly by Chris Gabriel. The manuscript was written
through contributions of all authors. All authors have given approval to
the final version of the manuscript.
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Page 6 of 6
Synth. Commun. 1998, 28, 1139. (i) Kumbhar, P. S.; Valnte, J.
ACKNOWLEDGMENT
S.; Figueras, F. Tetrahedron Lett. 1998, 39, 2573. (j) Marlic, C.
A.; Motamed, S.; Quinn, B. J. Org. Chem. 1995, 60, 3365. (k) B.
A. Fox B. A.; Threlfall T. L. Org. Synth. 1964, 44, 34. (l) Mahood
S. A.; Schaffner P. V. L. Org. Synth. 1931, 11, 32. (m) Béchamp,
A. J. Ann. Chim. Phys., 1854, 42, 186.
1
2
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Financial support provided by Novartis and the NSF (GOALI; Sus-
ChEM 1566212) is warmly acknowledged. The authors would like to
thank Pascale Hoehn for compilation of the calorimetric report, and
Darija Dedic for miscellaneous experimental support.
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(14) Price comparaison for (ACROS Organics, 98+% pure powder):
NaBH4
$597.70/2.5
kg
($9.04/mol)
ACD
code
MFCD00003518; KBH4 $751.00/2.5 kg ($16.20/mol) ACD
code MFCD00011396.
(15) See supporting information for SEDEX thermostability plot.
(16) H2 evolution determined from a 20 mmol portion of 60 mmol
KBH4 and 20 mmol nitro compound. 60 mmol 3KBH4 = 240
mmol H- and H- consumed by the nitro compound = 20 mmol x
3 reductions = 60 mmol (scheme 1) leaves an excess of 240
mmol – 60 mmol = 180 mmol H- for the conversion to H2. From
the ideal gas law (PV=nRT) at STP (P = 1 atm; T = 298 K), 4.40
L of gas evolved for a 0.120 kg reaction arrives at 36.7 L / kg.
(17) Leboho, T. C.; Giri, S.; Popova, I.; Cock, I.; Michael, J. P.; de Ko-
ning C. B. Bioorg. Med. Chem. 2015, 23, 4943.
(18) Hagiwara, H.; Sato, K.; Hoshi, T.; Suzuki, T. Synlett 2011, 2905.
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