Chemoselective Reductive Aminations in Aqueous Nanoreactors Using Parts per Million Level Pd/C Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c02156

Condensation in recyclable water between aldehydes or ketones and amines occurs smoothly within the hydrophobic cores of nanomicelles, resulting in imine formation that is subject to subsequent reduction leading, overall, to reductive amination. This micellar technology enables the synthesis of several types of pharmaceuticals, a new procedure that relies on only 2000 ppm (0.20 mol %) palladium from commercially available Pd/C. A broad range of substrates can be used under mild conditions, leading to high chemical yields of the desired secondary and tertiary amines.

Full text of DOI:10.1021/acs.orglett.0c02156

pubs.acs.org/OrgLett
Letter
Chemoselective Reductive Aminations in Aqueous Nanoreactors
Using Parts per Million Level Pd/C Catalysis
Ruchita R. Thakore, Balaram S. Takale,* Gianluca Casotti, Eugene S. Gao, Henry S. Jin,
and Bruce H. Lipshutz*
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ABSTRACT: Condensation in recyclable water between aldehydes or
ketones and amines occurs smoothly within the hydrophobic cores of
nanomicelles, resulting in imine formation that is subject to subsequent
reduction leading, overall, to reductive amination. This micellar technology
enables the synthesis of several types of pharmaceuticals, a new procedure
that relies on only 2000 ppm (0.20 mol %) palladium from commercially
available Pd/C. A broad range of substrates can be used under mild
conditions, leading to high chemical yields of the desired secondary and
tertiary amines.
conditions of use are often harsh (vide infra), resulting in
mines are an integral part of pharmaceuticals and
1
Aagrochemicals. Nucleophilic displacement of an aryl or low selectivity, and/or necessitate special equipment for the
heteroaryl halide (SNAr)2 by an amine via net stoichiometric
reaction.
Reductive aminations performed in water as the reaction
medium, at first glance, might be viewed as fraught with
potential problems,13 given that initial imine formation
produces stoichiometric water by dehydration and hence
requires a drying agent (e.g., MgSO4, molecular sieves, etc.)14
to shift this equilibrium. However, use of an aqueous micellar
medium such as that derived from the designer surfactant
TPGS-750-M, albeit typically composed of 98% water,
provides a hydrophobic inner pocket for each nanomicelle
that extrudes water of formation and therefore is self-drying.
We and others have shown that a wide range of reactions can
be performed under such conditions, including moisture
sensitive (e.g., Negishi couplings) and dehydration proces-
ses.13b,15,16
removal of HX is one, albeit limited, approach. The most
widely used entry, however, is the reduction of imines. Here,
reduction can be performed either on an isolated imine
prepared previously by condensation of a precursor carbonyl
and amine or via the one-pot, two-step process of reductive
amination (RA).1,3 However, competitive carbonyl reduction
can be challenging to avoid, leading to byproduct formation
from a lack of chemoselectivity. According to Roughley’s
analysis of reactions used in the synthesis of pharmaceuticals,
25% of C−N bond-forming reactions involve reductive
aminations.4 Popular reducing agents to effect reductive
amination involve NaBH4, NaBH3CN, and NaBH(OAc)3,
among others,5 while more specific options such as Leuckart6
and Eschweiler−Clarke7 reactions, while dated, remain
available for use under homogeneous conditions.
Each nanomicelle typically functions as a nanoreactor in
which reactions take place.17 Anticipating from prior studies
showing that the micellar interior, housing the newly formed
imine, would deliver the substrate to the Pd/C catalyst (i.e.,
the “nano-to-nano” effect),18 we examined reductive amina-
tions as a general, enabling tool applied to syntheses of targets
Alternatively, heterogeneous Pd catalysis,8 along with
reducing agents, have also been extensively used. Supported
Pd nanoparticles, however, require typically special exper-
imental techniques for their preparation, which almost
invariably raises questions regarding reproducibility (i.e., as
to their size, shape and hence, the reactivity). Moreover, high
loadings of endangered Pd together with limited substrate
scope can limit their applications to syntheses of highly
functionalized targets, and pharmaceuticals in particular. To
avoid use of Pd, other metal catalyst/reductant combina-
tions9−12 (e.g., H2 gas or transfer hydrogenating agents) have
been widely investigated (Scheme 1). However, their
Received: June 29, 2020
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© XXXX American Chemical Society
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A

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water” (i.e., in the absence of surfactant)20 was sluggish but did
lead to a 60% yield of the desired product (entry 10).
Scheme 1. Comparison: Traditional Reductive Aminations
in Organic Solvents versus In Aqueous Nanomicelles
These optimized conditions were then utilized in syntheses
of a wide range of pharmaceutical APIs or intermediates
involved in their preparation (Scheme 2). Piridebil (4), an
antiparkinsonian agent21 was obtained directly from its
precursors in 80% isolated yield. Given the low loading of
Pd used for these reactions, the level of residual Pd expected in
the final products is below FDA guidelines, in this case for Pd
being ≤10 ppm.22 An analysis for residual Pd on product 4
Scheme 2. Application of Reductive Amination in the
a
Synthesis of Pharmaceuticals and Intermediates
specifically in the pharmaceutical industry. Herein, we describe
not only new technology for reductive aminations to be run in
water, but a process that requires only inexpensive Et3SiH
together with 2000 ppm (0.20 mol %) of commercially
available 1 wt % Pd/C.
Initial optimization was performed under aqueous micellar
conditions using aldehyde 1 and amine 2 as a model system in
the presence of 2000 ppm (0.2 mol %) Pd/C.19 Several
sources of silanes were examined (Table 1, entries 1−7), with
inexpensive and readily available Et3SiH found to afford the
highest yield (90%) of desired product 3. Use of PMHS
(polymethylhydrosiloxane) did not lead to any resulting amine
(entry 7), while either a balloon of H2 or NaBH4 as reducing
agent led to only traces of the desired product 3 along with
reduced aldehyde (entries 8 and 9). A control reaction “on
Table 1. Optimization for Parts per Million Pd/C-Catalyzed
a
Reductive Aminations
b
entry
reductant
Et3SiH
PhSiH3
PhMeSiH2
Ph2SiH2
(EtO)3SiH
Me(EtO)2SiH
PMHS
yield (%)
1
2
3
4
5
6
7
8
9
90
40
27
20
<1
<1
<1
5
H2 balloon
NaBH4
Et3SiH
<1
60
c
a
10
Reaction conditions unless otherwise noted: 0.25 mmol of aldehyde/
ketone, 0.30 mmol of amine, 2000 ppm of 1 wt % Pd/C, 1.2 equiv of
a
Reaction conditions unless otherwise noted: 0.5 mmol of 1, 0.75
Et3SiH, stirred in 2 wt % TPGS-750-M/H2O, 45 °C (or 55 °C for
b
mmol of 2, 2000 ppm of 1 wt % Pd/C, reductant (1.5 equiv), stirred
ketones); 1.0 equiv glac. HOAc added for ketones. Isolated yield.
b
c
d
e
in 2 wt % TPGS-750-M/H2O at 45 °C for 4 h. Isolated yield.
0.38 mmol of amine. 1.5 equiv of Et3SiH. 1.8 equiv of Et3SiH.
f
c
Reaction was run “on water.”
8000 ppm (0.80 mol %) of 1 wt % Pd/C.
B
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using inductively coupled plasma (ICP-MS)23 indicated that
<1 ppm of Pd had been incorporated into piridebil (see
Supporting Information for other examples).
Scheme 3. Comparison between Pd/C versus Literature
Processes for RA
Other pharmaceuticals (Scheme 2) such as prozapine24 (5)
(an antispasmodic drug), cinacalcet25 (6) (hyperparathyroid-
ism medication), and fendiline26 (7) (an antiarrhythmic
agent), likewise, were obtained in 87, 88, and 90% yields,
respectively. Similarly, intermediates involved in the synthesis
of fentanyl27 (8) (a pain medication), Amgen’s hyper-
thyroidism drug (9),28 an agent for chronic obstructive
pulmonary disease (10),29 Pfizer’s cancer library (11),30
Ranbaxy’s 5-lipoxygenase inhibitors (12 and 13),31 GSK’s
schizophrenia library (14),32 AbbVie’s cancer library (15),33
an anticancer agent (16),34 and an anti-inflammatory agent
(17)35 could all be prepared using this chemistry in water.
Model compounds 18 and 20, mimicking intermediates
involved in antidiabetic agents,36 were also easily obtained in
high chemical yields. Additionally, reductive aminations that
show further functional group compatibility include amines
bearing a heteroaromatic (20), tertiary nitrogen (21), a
secondary aliphatic nitrogen (22), a primary aliphatic chain
(23), a cyclic array (from methyl estrone; 24), a bicyclic-
containing product (from norcamphor; 25), and an attached
secondary aliphatic carbon chain (26), all of which led
efficiently to the desired products.
While the results illustrated in Scheme 2 demonstrate that
reductive aminations readily proceed in water using minimal
amounts of palladium and afford targets of interest to the
pharmaceutical industry, they are also indicative of the mild
conditions needed and the inherent safety associated with use
of both water as the medium and Et3SiH as the source of
hydrogen on Pd.5 To further emphasize these salient features,
direct comparisons have been made with recently introduced
transition-metal-catalyzed reductive amination processes,
representing both heterogeneous and homogeneous catalysis.
As shown in Scheme 3, products 3 and 27, obtained in 90 and
92% yield, respectively, both proceeding in the presence of
only 0.2 mol % of Pd/C at 45 °C, otherwise require at least 25
times greater loadings of metal, high pressure, and hot organic
solvents.9,10 Similarly, compound 28 was obtained in 83% yield
using ppm Pd/C, but needed higher pressure and temperature
according to literature conditions.11 Interestingly, compound
29 could be obtained in 91% yield using our typical conditions
of 2000 ppm Pd/C, but required 4 mol % (i.e., 40,000 ppm) of
an iridium catalyst at 120 °C to realize a similar outcome.37
The mild reaction conditions associated with use of
nanomicelles in water for reductive aminations offer yet
another major benefit, in addition to the safety aspect:
chemoselectivity. Several potentially reducible or otherwise
sensitive functional groups, such as halide (30−33), nitro (13,
34, and 35), cyano (12, 15), and alkene (28) are tolerated
under these ppm level Pd/C-catalyzed conditions (Scheme 4).
Either replacing Et3SiH with its deuterated analogue or using
D2O in place of H2O led to the desired deuterated product 11′
with ∼70% deuterium incorporation. Incorporation of
deuterium using D2O is evidence that, in addition to the
silane supplying H/D to Pd/C, H-D gas generated during the
reaction in water undergoes heterolytic cleavage on Pd/C as
expected prior to subsequent addition to the C = N bond. Use
of both deuterated silane and D2O, as then expected, led to
100% D incorporation (Scheme 5, eq 1). These results
suggested that hydrogen gas itself might be a sufficient
alternative reductant toward an imine; indeed, aldimine 38
a
Scheme 4. Chemoselective Reductive Aminations in Water
a
Reaction conditions unless otherwise noted: 0.25 mmol aldehyde,
0.28 mmol amine, 1 wt % Pd/C (2000 ppm), 1.2 equiv Et3SiH, stirred
in 2 wt % TPGS-750-M/H2O, 45 °C. Isolated yields.
reacted readily to afford the desired amine 39 in 95% yield
(Scheme 5, eq 2).
Given that today there are many different types of reactions
amenable to chemistry in water, performing sequential
C
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Scheme 5. Deuterium Labeling (Eq 1) and Hydrogenation
of an Imine Using a Balloon of H2 (Eq 2)
Scheme 7. Larger Scale Reactions and Recycling and E-
Factor Calculation
In conclusion, nanoreactors derived from a readily available,
inexpensive surfactant can be used as a general methodology
for ppm Pd/C-catalyzed reductive aminations. The mild
reaction conditions involved lead to highly chemoselective
reductions of imines in the presence of otherwise competitively
reducible functionality. Using low loadings of heterogeneous
Pd/C (0.2 mol %), several syntheses of pharmaceuticals and/
or related compounds could be made with residual levels of Pd
found to be well below the FDA allowed limit. Both reaction
medium and catalyst can be recycled and reused without
significant loss of catalyst activity, even at scale. A telescoped
one-pot, three-step sequence demonstrates the potential of this
technology for use in industrial circles.
reactions in one pot is now becoming a very attractive,
environmentally responsible approach to synthesis. By
contrast, telescoping in organic solvents may be precluded
due to a need for different solvents for each reaction in a
sequence. We, and others, have recently shown that targets in
the pharma15a and agro15b,38 areas are amenable to this
strategy using aqueous micellar technology. Hence, we
combined a previously disclosed ppm Pd-catalyzed Suzuki−
Miyaura coupling16a with a reductive amination sequence,
followed by acylation (Scheme 6). This gave, in one pot, the
desired product 43 in 87% yield over three steps.
Scheme 6. Tandem Reactions in Aqueous Nanomicelles
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02156.
Experimental procedures and characterization data for
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Bruce H. Lipshutz − Department of Chemistry and
Biochemistry, University of California, Santa Barbara,
California 93106, United States; orcid.org/0000-0001-
9116-7049; Email: bhlipshutz@ucsb.edu
Balaram S. Takale − Department of Chemistry and
Biochemistry, University of California, Santa Barbara,
California 93106, United States; orcid.org/0000-0001-
8279-944X; Email: balaram_takale@ucsb.edu
Authors
Lastly, a combined reaction at scale together with recycling
of the entire reaction mixture was performed using 20 mmol of
aldehyde 1 using the optimized conditions outlined in Table 1.
Three total reactions with two recycles were performed
(Scheme 7). The first two reactions were performed with the
initially invested 2000 ppm Pd/C, and a fresh 500 ppm Pd/C
was added for last recycle (or 830 ppm Pd/C per reductive
amination). Product 3 was distilled from the reaction mixture
(see Supporting Information for details), and hence, no
organic solvent was used at any point in this sequence. This led
to a calculated E factor (based on the reaction medium) of 2.6
that, remarkably, includes water (ultimately, ∼39 g of
wastewater/14.85 g of product), which is orders of magnitude
lower than that typically observed in the pharmaceutical
industry,39 as originally put forth by Sheldon.40
Ruchita R. Thakore − Department of Chemistry and
Biochemistry, University of California, Santa Barbara,
California 93106, United States
Gianluca Casotti − Department of Chemistry and Biochemistry,
University of California, Santa Barbara, California 93106,
United States; Dipartimento di Chimica e Chimica Industriale,
́
Universita di Pisa, 56124 Pisa, Italy
Eugene S. Gao − Department of Chemistry and Biochemistry,
University of California, Santa Barbara, California 93106,
United States; Princeton International School of Mathematics
and Science, Princeton, New Jersey 08540, United States
Henry S. Jin − Department of Chemistry and Biochemistry,
University of California, Santa Barbara, California 93106,
United States; St. George’s School, Vancouver, British Columbia
V6S 1V1, Canada
D
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Nanoparticles Catalyze a General Synthesis of Amines. Science
2017, 358, 326−332.
(10) Takale, B. S.; Feng, X.; Lu, Y.; Bao, M.; Jin, T.; Minato, T.;
Yamamoto, Y. Unsupported Nanoporous Gold Catalyst for Chemo-
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Residual Silver on the Reaction. J. Am. Chem. Soc. 2016, 138, 10356.
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02156
Notes
The authors declare no competing financial interest.
̈
Gaillard, S.; Renaud, J.-L. Knolker’s Iron Complex: An Efficient In
ACKNOWLEDGMENTS
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Situ Generated Catalyst for Reductive Amination of Alkyl Aldehydes
and Amines. Angew. Chem., Int. Ed. 2012, 51, 4976−4980.
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Financial support provided by the NSF (CHE 18-56406),
Novartis, and PHT International (postdoctoral fellowship to
B.S.T.) is warmly acknowledged.
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