Process Development of CuI/ABNO/NMI-Catalyzed Aerobic Alcohol Oxidation

Article abstract of DOI:10.1021/acs.oprd.5b00179

An improved Cu/nitroxyl catalyst system for aerobic alcohol oxidation has been developed for the oxidation of functionalized primary and secondary alcohols to aldehydes and ketones, suitable for implementation in batch and flow processes. This catalyst, which has been demonstrated in a >50 g scale batch reaction, addresses a number of process limitations associated with a previously reported (^MeObpy)Cu^I/ABNO/NMI catalyst system (^MeObpy = 4,4′-dimethoxy-2,2′-bipyridine, ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl, NMI = N-methylimidazole). Important catalyst modifications include the replacement of [Cu(MeCN)₄]OTf with a lower-cost Cu source, CuI, reduction of the ABNO loading to 0.05-0.3 mol%, and use of NMI as the only ligand/additive (i.e., without a need for ^MeObpy). Use of a high flash point solvent, N-methylpyrrolidone, enables safe operation in batch reactions with air as the oxidant. For continuous-flow applications compatible with elevated gas pressures, better performance is observed with acetonitrile as the solvent.

Full text of DOI:10.1021/acs.oprd.5b00179

Article
pubs.acs.org/OPRD
Process Development of CuI/ABNO/NMI-Catalyzed Aerobic Alcohol
Oxidation
Janelle E. Steves,† Yuliya Preger,‡ Joseph R. Martinelli,§ Christopher J. Welch,∥ Thatcher W. Root,*,‡
Joel M. Hawkins,*,⊥ and Shannon S. Stahl*,†
†Department of Chemistry, University of WisconsinMadison, Madison, Wisconsin 53706, United States
‡Department of Chemical and Biological Engineering, University of WisconsinMadison, Madison, Wisconsin 53706, United States
§Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
∥Department of Process & Analytical Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, United States
⊥Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: An improved Cu/nitroxyl catalyst system for aerobic alcohol oxidation has been developed for the oxidation of
functionalized primary and secondary alcohols to aldehydes and ketones, suitable for implementation in batch and flow
processes. This catalyst, which has been demonstrated in a >50 g scale batch reaction, addresses a number of process limitations
associated with a previously reported (MeObpy)CuI/ABNO/NMI catalyst system (MeObpy = 4,4′-dimethoxy-2,2′-bipyridine,
ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl, NMI = N-methylimidazole). Important catalyst modifications include the
replacement of [Cu(MeCN)4]OTf with a lower-cost Cu source, CuI, reduction of the ABNO loading to 0.05−0.3 mol%, and use
of NMI as the only ligand/additive (i.e., without a need for MeObpy). Use of a high flash point solvent, N-methylpyrrolidone,
enables safe operation in batch reactions with air as the oxidant. For continuous-flow applications compatible with elevated gas
pressures, better performance is observed with acetonitrile as the solvent.
(Table 1),2g and both have been demonstrated in continuous
INTRODUCTION
■
flow.4a,b The latter applications achieved residence times as low
Alcohol oxidation to produce aldehydes and ketones is one of
as 1 min for diverse alcohols bearing a variety of functional
groups.
the most frequently encountered oxidation reactions in the
synthesis of complex organic molecules. Despite the breadth of
reagents available for this transformation,1 aerobic alcohol
oxidation has been the focus of considerable attention due to its
use of O2 as a near-ideal oxidant that typically forms only water
as a stoichiometric byproduct.2 The application of many
homogeneous and heterogeneous catalytic aerobic oxidation
methods to production-scale pharmaceutical synthesis, how-
ever, has been constrained by safety concerns associated with
the combination of flammable organic solvents with O2. In
addition, the scope and selectivity of most previously reported
aerobic methods do not compete with other viable, though less
green, protocols for the oxidation of complex pharmaceutical
intermediates (e.g., TEMPO/NaOCl, pyridine·SO3).3
Continuous-flow reaction methods are well equipped to
address many of the safety issues associated with the
combination of O2 and organic solvents: smaller reactor
volume, effective and reproducible gas−liquid mixing, and the
ability to operate at high gas pressures can promote faster
aerobic oxidation on large scale.4−6 We recently reported two
different Cu/nitroxyl catalyst systems for aerobic alcohol
oxidation, composed of a CuI source, such as [Cu(MeCN)4]-
OTf; a 2,2′-bipyridyl (bpy) ligand; an organic nitroxyl, such as
2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl (TEMPO) or 9-
azabicyclo[3.3.1]nonane N-oxyl (ABNO); and N-methyl-
imidazole (NMI).7,8 The synthetic scope, selectivity, and
functional group compatibility of these catalyst systems rival
or surpass those of most traditional alcohol oxidation methods
The Cu/TEMPO catalyst system is selective for primary
alcohols and displays faster reaction rates with activated
substrates, while Cu/ABNO exhibits fast reaction rates with
both primary (1°) and secondary (2°) alcohols. These Cu/
nitroxyl systems tolerate functionalities such as thioethers,
alkenes, internal alkynes, heterocycles, amines, and halogenated
arenes. Despite the practical advantages that these Cu/nitroxyl
protocols offer on laboratory scale (i.e., simple setup and
workup, open to air, room temperature), they have features that
could limit large-scale applications, such the cost of some of the
catalyst components (e.g., bpy, ABNO). In addition, it would
be preferred to avoid a requirement for continuous processing
equipment, which may not be available at all manufacturing
sites. Herein, we describe the development of less expensive
Cu/ABNO-catalyzed aerobic alcohol oxidation methods that
are more amenable to safe and scalable oxidation of
functionalized 1° and 2° alcohols under both batch and flow
conditions.
Special Issue: Oxidation and Oxidative Reactions
Received: June 4, 2015
© XXXX American Chemical Society
A
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Table 1. Representative Scope of Copper/TEMPO and
Copper/ABNO-Catalyzed Aerobic Alcohol Oxidation
Scheme 1. Proposed Modifications for Cu/ABNO-Catalyzed
Aerobic Alcohol Oxidation
Table 2. Optimization of Cu/ABNO-Catalyzed Alcohol
a
Oxidation
entry
Cu salt
T (°C)
NMI (%)
nitroxyl (%)
yield (%)
bc
,
1
Cu(OTf)
Cu(OTf)
CuCl
CuBr
Cul
22
22
22
22
22
22
60
60
60
60
60
60
20
20
20
20
20
5
1.0
1.0
0.2
0.2
0.2
0.2
0.2
0.3
0.3
0.3
0.3
0.0
20
b
2
28
10
13
19
32
68
82
3
RESULTS AND DISCUSSION
■
4
Assessment of Process Challenges. The principal goal of
this study was to identify a “process-friendly” catalyst system for
Cu/nitroxyl-catalyzed aerobic oxidation of alcohols that could
facilitate larger-scale applications. An ABNO-based catalyst
system was of particular interest because of its broad substrate
scope. The following benchmarks, summarized in Scheme 1,
were identified as important criteria:
5
6
Cul
7
Cul
5
8
Cul
5
d
9
Cul
5
89
d
10
11
12
none
Cul
5
0
d
0
24
d
Cul
5
0
1. Copper source. [Cu(MeCN)4]OTf should be replaced
with an inexpensive copper halide salt to lower the
catalyst cost and avoid fluorine-containing waste from
the triflate counterion.
a
Reactions were performed on a 0.5 mmol scale in 1 mL of NMP,
unless otherwise noted. GC yields, internal standard = biphenyl.
b
Reaction performed with 0.1 mmol of substrate in 1 mL of MeCN.
c
d
2. Ligand. The MeObpy ligand should be replaced with a
low-cost alternative, such as bpy or, preferably, a
monodentate nitrogenous ligand.
Ambient air used as O2 source without bubbling. 10 mL/min air
bubbling rate.
3. ABNO loading. The ABNO loading should be reduced
from 1 mol% to minimize operating costs.
solvents were tested under the conditions in entry 6, such as
DMF, DMA, dimethylimidazolidinone, and γ-valerolactone, but
NMP was chosen for its good performance, excellent solubility
of reaction components, and high potential operating temper-
ature. Alternate solvents, such as DMF and DMA, also led to
good product yields, but they have lower flashpoints that limit
the available temperature for performing the reactions.
Increasing the NMI loading to 20 mol% in propylene carbonate
provided excellent results with a different substrate (see
Supporting Information, Scheme S1), but again, NMP was
chosen for further study due to the improved solubility of many
substrates in this solvent. The reaction was ineffective when
CuI, NMI, or ABNO was not present (entries 10−12). The
CuII/ABNO/NMI conditions identified from these tests (i.e.,
entry 9) met most of the criteria we established (cf. Scheme 1)
and provided the basis for subsequent investigation of other
substrates.
A variety of 1° and 2° benzylic and aliphatic alcohols
underwent efficient oxidation on 10 mmol scale with the CuII/
ABNO/NMI system, and the functional group compatibility
aligns with previous results obtained with the (MeObpy)CuI/
ABNO/NMI catalyst system7b (Table 3). The catalyst system
also mediated efficient oxidation of the densely functionalized
precursor to rosuvastatin (Scheme 2, 10 mmol scale).10 For
electron-rich benzylic alcohols, ABNO can be lowered to 0.05
4. Solvent and concentration. For batch reaction applications,
acetonitrile should be replaced with a water-soluble, high
flash point solvent to permit the use of air as the source
of oxidant. As a starting point, reactions should be
performed at least 25 °C below the solvent flash point
under 1 atm of air, with the understanding that a full
safety assessment would be required prior to scale-up.9 In
addition, the reaction concentration should be increased
from 0.1 M to ≥0.5 M to maximize throughput and
minimize waste.
Catalyst Optimization for Batch Reactions. The studies
were initiated by examining NMI as ligand replacement for bpy
on the basis of a promising lead result obtained in the course of
developing the previous Cu/ABNO system7b (Table 2, entry
1). Bubbling air through the reaction with a gas dispersion tube
(entry 2) afforded slightly higher yield. Employing a high flash
point solvent (NMP = N-methylpyrrolidone, flash point = 90
°C) and switching from [Cu(MeCN)4]OTf to CuI halide salts
provided lower product yields, with the exception of CuI (entry
5). Reducing the NMI loading to 5 mol% (entry 6) in NMP
boosted reactivity, and increasing the temperature to 60 °C and
ABNO loading to 0.3 mol% provided the best results for a 2°
aliphatic alcohol (entry 9). Numerous other high flash point
B
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Table 3. Scope of (NMI)CuI/ABNO-Catalyzed Aerobic
Alcohol Oxidation
removal of ABNO from the product without using silica gel
column chromatography are ongoing in our laboratory.
Catalyst Optimization for Flow Reactors. Acetonitrile is
the solvent of choice for many Cu/nitroxyl-catalyzed aerobic
oxidation reactions,14 and can be safely employed by using a
slug flow reactor4b with elevated pressures of dilute O2 (e.g., 9%
in N215) or in a membrane reactor using elevated pressures of
pure O2.4c,16 A direct comparison of MeCN and NMP as
solvents showed that the CuII/ABNO/NMI-catalyzed aerobic
alcohol oxidation performs better in MeCN (Figure 1). Since
O2 solubility is slightly higher in NMP than in MeCN,17 the
higher reaction rate in MeCN is attributed to a solvent effect on
the reaction, rather than O2 solubility. Consequently, we
elected to use MeCN as the solvent for testing the CuII/
ABNO/NMI catalyst system under continuous-flow conditions.
The (bpy)Cu/TEMPO/NMI catalyst was demonstrated
previously in a stainless steel slug flow reactor;4b however,
the new CuI-based system led to noticeable stainless steel
corrosion in less than 24 h when operated at representative
reaction conditions (35 bar 9% O2 in N2 at 100 °C). As a result,
a PTFE membrane reactor4c (Figure 2) was used to test the
CuII/ABNO/NMI catalyst in flow. To avoid contact with
stainless steel, a solution of CuII/ABNO/NMI in MeCN was
stored in a PTFE loop and was delivered to the reactor using an
HPLC pump that contained acetonitrile. A PTFE Luer lock
attachment to the PTFE loop allowed for facile loading of the
catalyst solution via gastight glass syringe.
a
a
Isolated yields. All reactions were performed on a 10 mmol scale in
b
20 mL of NMP in purged reaction vessel, unless otherwise noted. 250
mmol scale in a 500 mL cylindrical vessel (see Experimental Section),
c
1
air flow = 2.5 L/min, H NMR yield. 5 mol% bpy used instead of
NMI. >99% ee.
d
Scheme 2. Oxidation of a Rosuvastatin Precursor
In the initial attempts to use the CuII/ABNO/NMI catalyst
in flow, a solid precipitated from the stock solution of CuI,
ABNO, and NMI in MeCN. The solid was not characterized
but was presumed to consist of insoluble Cu species. Increasing
the NMI loading threefold (i.e., 15 mol% under the reaction
conditions) prevented solid formation in the catalyst solution.
This catalyst system was then tested in the conversion of 1-Boc-
3-hydroxyazetidine to the corresponding ketone. A 6 min
residence time provided the highest product yield (Figure 3A),
and a steady state yield of ≥98% was maintained over a 3 h
period, corresponding to the oxidation of 9 mmol of 1-Boc-3-
hydroxyazetidine (Figure 3B).
mol% without loss of activity. More sterically hindered or
electron-deficient benzylic alcohols and aliphatic substrates
require ABNO loadings of 0.2−0.3 mol% in order to achieve
quantitative conversion. In the case of a substrate with a basic
functional group near the alcohol (cf. 2, Table 3), the use of
bpy led to better performance than NMI (98% vs 28%,
respectively). The bidentate ligand is believed to disfavor CuII
chelation and deactivation by the substrate.
This new process-friendly method proved to be scalable in
batch mode. A 250 mmol (59 g) scale oxidation of 2-
iodobenzyl alcohol afforded the aldehyde in quantitative yield
in under 2 h with 0.05 mol% ABNO. Isolation of the product
on a 10 mmol scale was accomplished with aqueous extraction
to remove CuI, NMI, and NMP. The product may be isolated
from most of the catalytic components by partitioning the
reaction between water and ethyl acetate, then washing the
combined organic layers with sodium bisulfite or passing the
layers through activated carbon to remove yellow color.
Complete separation of NMP from the product required
additional washing of the organic layer with water. Removal of
ABNO from the product may be accomplished with silica gel
column chromatography on the laboratory scale, or crystal-
lization of the product or subsequent intermediates on a larger
scale. (The presence of residual ABNO is unlikely to affect the
performance of many subsequent reactions.11) Polymer-
immobilized or other supported ABNO12 or water-soluble
ABNO13 derivatives could facilitate separation of the nitroxyl
from the product on a large scale, and efforts to achieve efficient
CONCLUSION
■
The results presented here showcase a new CuII/ABNO/NMI
reaction system that exhibits many advantageous features for
large-scale aerobic alcohol oxidation reactions. This catalyst
appears to retain all of the favorable characteristics of the
previously reported Cu/nitroxyl catalyst systems, including
Figure 1. Kinetic profiles of CuII/NMI/ABNO-catalyzed aerobic
alcohol oxidation in NMP and MeCN.
C
DOI: 10.1021/acs.oprd.5b00179
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EXPERIMENTAL SECTION
■
1
General Considerations. H and 13C{1H} NMR spectra
were recorded on a Bruker Avance 400 MHz spectrometer.
Chemical shifts (δ) are given in parts per million and are
referenced to tetramethylsilane (all 1H NMR spectra) or
residual solvent signal (all 13C NMR spectra). All coupling
constants are reported in Hz. GC analyses were performed
using a DB-Wax column installed on a Shimadzu GC-17 with
FID.
Figure 2. Diagram of PTFE membrane flow reactor (BPR = back
pressure regulator).
All commercial reagents were purchased from Aldrich and
used as received. 4-(4-Fluorophenyl)-6-isopropyl-2-[(N-meth-
yl-N-methylsulfonyl)amino]pyrimidin-5-yl methanol was do-
nated by DSM. CuI was purchased at 98% purity, NMP at
≥99% purity (Chromasolv Plus, for HPLC), and NMI at 99%
purity (ReagentPlus). CH3CN was taken from a solvent system
which passes the solvent through a column of activated
molecular sieves, but no precautions to exclude water or air
from the solvent or reaction mixtures were taken. Reactions
1
were monitored by GC or H NMR spectroscopy.
Representative Procedure for 10 mmol Scale Batch
Reactions. A solution of ABNO (0.7−4.2 mg, 0.005−0.03
mmol) in NMP (1 mL) and a solution of CuI (95 mg, 0.5
mmol) and NMI (40 μL, 0.5 mmol) in NMP (4 mL) were
added to a solution of the alcohol (10 mmol) in NMP (15 mL)
in a 25 × 150 mm test tube with oval (15.9 × 6.35 mm) stirbar.
The vessel was fitted with a rubber septum with a hole in the
center holding a Tygon tube attached to an Ace glass gas
dispersion tube (7 mm × 135 mm, 4−8 μm porosity; see
Figure 4). A vent needle leading to a bubble meter (Supelco 25
mL manual bubble flow meter, standard version) was attached
to the septum. Air was bubbled (120 mL/min) from a tank of
compressed air and the reaction was stirred at 700 rpm and
1
heated to 60 °C. Reactions were monitored by H NMR
spectroscopy; aliquots (50 μL) were removed via syringe,
diluted with EtOAc (1 mL), and filtered through SiO2 plugs in
pipets. The plugs were flushed with additional EtOAc (3 mL),
and the filtrate was concentrated in vacuo and taken up in
1
CDCl3 for H NMR analysis. When the reaction was deemed
1
complete by H NMR spectroscopy, the vessel was cooled to
Figure 3. Flow reaction yields for aerobic oxidation of 1-Boc-3-
hydroxyazetidine with the CuII/ABNO/NMI catalyst system.
Residence-time scan (A) and yields obtained during continuous
operation with a 6 min residence time (B). Yields determined by H
NMR spectroscopy with biphenyl as an internal standard.
room temperature. The reaction was quenched with H2O (100
mL) and brine (50 mL), and the aqueous layer was extracted
with EtOAc (3 × 150 mL). The organic layers were combined
and washed with 10% aqueous Na2S2O3 (250 mL) to remove
yellow color and water (3 × 300 mL) to remove NMP. The
organic layer was dried over MgSO4 and concentrated in vacuo
to afford the corresponding aldehyde or ketone as the sole
product.
1
broad substrate scope with both benzylic and aliphatic alcohols
as well as excellent functional group compatibility. Expensive
CuI salts and bpy-based ligands have been replaced with CuII
and NMI, respectively, and ABNO loadings as low as 0.05
mol% have been demonstrated successfully. Use of NMP as a
high flash point solvent (flash point = 90 °C) provides the basis
for the safe use of air as an oxidant under batch reaction
conditions, while use of MeCN as the solvent provides optimal
performance in continuous-flow applications under elevated gas
pressures. Reactions performed in batch mode exhibited 1−6 h
reaction times, and oxidation of an aliphatic substrate in flow
mode was achieved with a residence time of 6 min. The low
cost and flexible implementation of this catalyst are attractive
features compared to our previous catalysts, and these results
have important implications for implementation of large-scale
aerobic alcohol oxidation reactions in the pharmaceutical and
fine chemicals industries.
Figure 4. Representative reaction vessel for 10 mmol aerobic alcohol
oxidation reactions.
D
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Isolation of 1-Boc-3-azetidinone. After washing with
10% aqueous Na2S2O3, the organic layer was washed with
saturated aqueous NH4Cl (pH = 8) to remove blue color. The
organic layer was then washed with water (2 × 300 mL) to
remove NMP and dried over MgSO4. Solvent was removed in
vacuo, yielding 1-Boc-3-azetidinone as the sole product.
pump flow rates were varied to identify the lowest residence
time that led to the highest yield.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all
products. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.oprd.5b00179.
250 mmol Scale Oxidation of 2-Iodobenzyl Alcohol. A
solution of ABNO (17.5 mg, 0.125 mmol), CuI (2.38 g, 12.5
mmol), and NMI (996 μL, 12.5 mmol) in NMP (20 mL) was
added to a solution of 2-iodobenzyl alcohol (58.5 g, 250 mmol)
and biphenyl (internal standard; 19.3 g, 125 mmol) in NMP
(480 mL) in a cylindrical vessel with gas dispersion tube and
stir bar (19.1 × 9.5 mm, “+” shape; see Figure 5). The vessel
was fitted to a compressed air tank and rotameter, and then was
stirred and heated to 60 °C. Air was bubbled through the vessel
(2.5 L/min). At 1.75 h, an aliquot was removed (200 μL),
diluted with EtOAc (1 mL), and filtered through a pipet SiO2
plug. The plug was flushed with additional EtOAc (3 mL), and
the filtrate was concentrated in vacuo. The residue was taken up
in CDCl3 for 1H NMR analysis, and the acquired spectrum was
consistent with 2-iodobenzaldehyde as the sole product (100%
yield based on internal standard).
Representative Procedure for Alcohol Oxidation in
Flow. The substrate (15 mmol, 1 M) and biphenyl internal
standard (7.5 mmol, 0.5 M) were prepared as a stock solution
in MeCN. The solution was delivered to the reactor by a
Hitachi L6200 HPLC pump. A Hamilton gastight syringe was
used to inject the catalyst solution into a 30 mL PTFE sample
loop filled with MeCN through a six way, two-position valve (in
“load” position). A gastight syringe was then used to push
MeCN through the sample loop, moving the green catalyst
solution through the sample loop until it reached the end of the
six-way valve. A clear boundary between the two phases was
observed. The six-way valve was switched to the “run” position
to connect the sample loop to the reactor and a Hitachi L6200
HPLC pump containing pure MeCN. The MeCN pump was
used to push the catalyst solution through the loop and into the
reactor, avoiding contact between the stainless steel pump and
CuI. The oven was set to 100 °C and allowed to equilibrate at
temperature for 1 h. The liquid back pressure regulator was set
3 atm higher than the gas pressure. The O2 tank was set to the
17 atm by a gas pressure regulator. The solutions were pumped
through the system, with each HPLC pump providing half of
the total flow. The EtOAc quench pump flow rate was
maintained at 6 times the liquid feed flow rate from the reactor.
The product (diluted with EtOAc) was collected at the exit of
the liquid back pressure regulator. For the residence time scan,
AUTHOR INFORMATION
Corresponding Authors
*E-mail: thatcher@engr.wisc.edu.
*E-mail: joel.m.hawkins@pfizer.com.
*E-mail: stahl@chem.wisc.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Dr. Paul Alsters (DSM) for supplying a
sample of the rosuvastatin precursor. We thank Dr. David
Mannel for insightful discussion, and Dr. Eric Cordi (Pfizer) for
calculation of O2 solubility values in MeCN and NMP.
Financial support for this work was provided by the ACS
GCI Pharmaceutical Roundtable, a consortium of pharmaceut-
ical companies (Eli Lilly, Pfizer, and Merck), and the NSF
(predoctoral fellowship to J.E.S.). NMR spectroscopy facilities
were partially supported by the NSF (CHE-9208463) and NIH
(S10 RR08389).
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DOI: 10.1021/acs.oprd.5b00179
Org. Process Res. Dev. XXXX, XXX, XXX−XXX