Stable TEMPO and ABNO Catalyst Solutions for User-Friendly (bpy)Cu/Nitroxyl-Catalyzed Aerobic Alcohol Oxidation

Article abstract of DOI:10.1021/acs.joc.5b01950

Two solutions, one consisting of bpy/TEMPO/NMI and the other bpy/ABNO/NMI (bpy =2,2′-bipyridyl; TEMPO = 2,2,6,6-tetramethylpiperidine N-oxyl, ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl; NMI = N-methylimidazole), in acetonitrile are shown to have good long-term stability (≥1 year) under air at 5 °C. The solutions may be combined in appropriate quantities with commercially available [Cu(MeCN)₄]OTf to provide a convenient catalyst system for the aerobic oxidation of primary and secondary alcohols.

Full text of DOI:10.1021/acs.joc.5b01950

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Note
Stable TEMPO and ABNO Catalyst Solutions for User-
Friendly (bpy)Cu/Nitroxyl-Catalyzed Aerobic Alcohol Oxidation
Janelle E. Steves, and Shannon S. Stahl
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01950 • Publication Date (Web): 12 Oct 2015
Downloaded from http://pubs.acs.org on October 17, 2015
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Stable TEMPO and ABNO Catalyst Solutions for
User-Friendly (bpy)Cu/Nitroxyl-Catalyzed Aerobic
Alcohol Oxidation
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Janelle E. Steves and Shannon S. Stahl*
Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706
Email: stahl@chem.wisc.edu
RECEIVED DATE
ABSTRACT
Two solutions, one consisting of bpy/TEMPO/NMI and the other bpy/ABNO/NMI (bpy = 2,2'-
bipyridyl; TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy, ABNO = 9-azabicyclo[3.3.1]nonane
N-oxyl; NMI = N-methylimidazole), in acetonitrile are shown to have good long-term stability (≥
1 year) under refrigeration. The solutions may be combined in appropriate quantities with
commercially available [Cu(MeCN)4]OTf to provide a convenient catalyst system for the aerobic
oxidation of primary and secondary alcohols.
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Alcohol oxidation is one of the most frequently used oxidation reactions in organic
chemistry, and molecular oxygen is widely recognized as an ideal oxidant. Aerobic alcohol
oxidations have been studied extensively,1 but they are rarely used in preparative organic
synthesis. Recent advances in Cu/nitroxyl catalyst systems,1d,e,g,2-4 however, have led to aerobic
alcohol oxidation methods that rival the scope, selectivity, and practicality of traditional
oxidation protocols. These methods have emerged as some of the most versatile bench scale
methods for aerobic alcohol oxidation.
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In recent years, we have reported two highly practical catalyst systems for aerobic
alcohol oxidation: (bpy)CuI/TEMPO/NMI3 and (MeObpy)CuI/ABNO/NMI4 (Figure 1). These
Cu/nitroxyl-catalyzed aerobic alcohol oxidation methods exhibit a broad scope of benzylic,
allylic, and aliphatic alcohols as well as high functional group tolerance. The first generation
(bpy)CuI/TEMPO/NMI catalyst displays high chemoselectivity for unhindered primary alcohols
over hindered primary alcohols and secondary alcohols. Mechanistic insights into this
(bpy)CuI/TEMPO/NMI catalyst system5 led to the development of a (MeObpy)CuI/ABNO/NMI
catalyst system, which exhibits much faster rates for aliphatic alcohol oxidation and readily
oxidizes secondary alcohols. Reactions with both catalyst systems typically can be performed in
an open flask at room temperature, and the product often may be used in subsequent reactions
without purification.6
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R
R
4
5
6
7
N
N
O
N
N
N
N
O
bpy (R = H)
MeObpy (R = OMe)
NMI
TEMPO
ABNO
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Cu/TEMPO: CHEMOSELECTIVE FOR 1° ALCOHOLS
9
5 mol% [Cu(MeCN)4]OTf, 5 mol% bpy
5 mol% TEMPO, 10 mol% NMI
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R
OH
R
O
MeCN, r.t., ambient air, 2-24 h
H2N
O
O
O
O
Cl
96%
>98%
>98%
Cu/ABNO: BROAD SCOPE 1° AND 2° ALCOHOLS
5 mol% [Cu(MeCN)4]OTf, 5 mol% MeObpy
1 mol% ABNO, 10 mol% NMI
O
OH
R1 R2
O
R1 R2
O
MeCN, r.t., ambient air, 1 h
O
S
O
Ph
N
N
NHBoc
95%
88%
>98%
91%
Figure 1. Cu/nitroxyl-catalyzed aerobic alcohol oxidation methods.3,4
In spite of the utility of these methods, their use can be somewhat cumbersome,
especially for small-scale applications, because small quantities (sometimes submilligram) of the
four different catalyst components must be independently weighed or dispensed into the reaction
mixture. This feature can present a barrier to the use of the catalytic methods relative to easily
dispensed stoichiometric reagents, such as chromium oxides or Dess-Martin periodinane. To
address this issue, we sought to identify shelf-stable mixtures of the catalyst components that
would improve the utility of the methods. Here, we show that solutions of bpy, nitroxyl, and
NMI (nitroxyl = TEMPO or ABNO) are stable in acetonitrile solution for ≥ 1 year at 5 °C. This
solution may be dispensed as a single catalyst component, together with solid [Cu(MeCN)4]OTf,
as a convenient means to perform air oxidation of diverse functionalized 1° and 2° alcohols.
We initially targeted a solid catalyst mixture containing all catalyst components needed
for alcohol oxidation. In this case, NMI would be replaced by a solid alternative; however, all
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combinations of the solid components, [Cu(MeCN)4]OTf, bpy, and nitroxyl, led to
decomposition and poor catalyst activity as a result of deleterious interactions between the
components in the solid state.
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We then elected test solutions of the catalytic reagents in acetonitrile, the preferred
reaction solvent. The electron-rich bpy derivative, MeObpy, was shown to have among the best
activity for the Cu/ABNO catalyst system,4 but this bpy derivative is sparingly soluble in MeCN
and ligand precipitation was observed from solutions stored in a refrigerator. Thus, we chose to
test bpy as a ligand for both of the alcohol oxidation solutions (i.e., with TEMPO and ABNO).
Oxidation of cyclohexanemethanol was used to assess catalyst performance because aliphatic
alcohols are less reactive than allylic and benzylic alcohols and, therefore, would provide a
sensitive assay of catalyst stability (Table 1). Solutions of [Cu(MeCN)4]OTf, bpy, nitroxyl, and
NMI (0.05-0.2 M in [Cu(MeCN)4]OTf and bpy) under air or N2 were unstable on the basis of
their loss of activity for cyclohexanemethanol oxidation after being stored at 5 °C for a 1–2
month period (Table 1, entries 1, 3, 5, 7). This problem was solved by removing
[Cu(MeCN)4]OTf. Solutions of bpy, nitroxyl, and NMI in acetonitrile (0.2 M bpy/0.2 M
TEMPO/0.4 M NMI or 0.2 M bpy/0.04 M ABNO/0.4 M NMI) were stable over the same periods
(Table 1, entries 2, 4, 6, 8). Full activity for cyclohexanemethanol oxidation was observed when
this catalyst solution was combined with solid [Cu(MeCN)4]OTf. The most reliable catalyst
activity and stability was observed when bpy/nitroxyl/NMI solutions were stored in a refrigerator
(5 °C), and minimal differences in activity were observed from solutions prepared under air or
N2 (cf. entries 2 vs 4 and 6 vs 8). Very good activity was also observed over a two-month period
with bpy/nitroxyl/NMI solutions stored under air at room temperature (22 °C) (entries 9 and 10).
Solid [Cu(MeCN)4]OTf has indefinite stability when stored under N2 in a dry environment, but
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can be stored at room temperature (22 °C) on a lab shelf for at least six months without
appreciable activity loss.
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Table 1. Stability Testing of Catalyst Solutions.a
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Cu(OTf)/bpy/nitroxyl/NMI solution
-or-
bpy/nitroxyl/NMI solution
Cy
OH
Cy
O
MeCN, r.t., ambient air, 1-22 h
storage
atmosphere
% yield
(1 month)
% yield
(2 month)
entry
[Cu(MeCN)4]OTf?
nitroxyl
1
2
N2
N2
yes
no
TEMPO
TEMPO
TEMPO
TEMPO
ABNO
73
63
98
83
95
71
94
77
94
100
92
97
81
98
83
99
79
98
98
97
yes
no
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air
air
4
5
N2
N2
air
air
air
air
yes
no
6
ABNO
7
yes
no
ABNO
8
ABNO
9b
10b
no
TEMPO
ABNO
no
a GC yields vs internal standard. Catalyst solutions stored in a refrigerator at 5 °C when not in
use. Reactions were performed on a 0.2 mmol scale in 2 mL of MeCN. b Catalyst solutions
stored at 22 °C when not in use.
Among the successful catalyst solutions in Table 1, the solutions under air in a
refrigerator (entries 4 and 8) offer a convenient storage option and should minimize catalyst
decomposition over time, so we proceeded with further testing of these mixtures. A solution
concentration of 0.2 M in bpy, 0.04-0.2 M in nitroxyl, and 0.4 M in NMI was selected for long-
term testing because these concentrations allow for convenient dispensing of the catalyst into a
reaction vessel via syringe. For example, 250 µL of catalyst solution is required for a 1 mmol
reaction, and 2.5 mL of catalyst solution is required for a 10 mmol reaction. These solutions
were stored at 5 °C for six months and tested in the oxidation of a collection of alcohols bearing
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diverse functional groups (Figure 2). The reactions proceeded with essentially the same
efficiency as reported previously using freshly prepared catalysts (Figure 2).3,4 As observed
previously, various halides, ethers, amines, and heterocycles are well tolerated, a cis-allylic
alcohol is oxidized without significant isomerization, and a Boc-protected aminoalcohol is
oxidized without racemization.
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5 mol% [Cu(MeCN)4]OTf
bpy/TEMPO/NMI or bpy/ABNO/NMI solution
OH
O
(0.2 M/0.2 M/0.4 M)
(0.2 M/0.04 M/0.4 M)
MeCN, r.t.-50 °C, open air
R1 R2
R1 R2
F
O
O
NH2
Cl
1
2
2.5 h, 94% (TEMPO)
1.75 h, >99% (TEMPO)
O
O
O
O
3
2.5 h, 94% (TEMPO)
>20:1 Z:E
4
4 h, 97% (TEMPO)
F
O
O
O
O
O
NHBoc
O
O
5
6
N
O
2 h, >99% (ABNO)
no loss in enantiopurity
3 h, 95% (ABNO)
O
N
N
SO2Me
7
2 h, >99% (ABNO)
Cl
NO2
8
4 h, 95% (ABNO)
50 °C
Figure 2. Isolated product yields from oxidation of functionalized alcohols with
[Cu(MeCN)4]OTf in combination of bpy/TEMPO/NMI or bpy/ABNO/NMI catalyst solutions
stored for six months under air at 5 °C.
These bpy/ABNO/NMI and bpy/TEMPO/NMI solutions were then tested over a one-year
period for the oxidation of cyclohexanemethanol to gauge catalyst stability (Figure 3). Time-
course data were acquired, rather than just analysis of the final yield, in order to increase the
sensitivity of the assay. ABNO and TEMPO solutions afforded >92%
cyclohexanecarboxaldehyde within 2 h (ABNO, Figure 3A) or 24 h (TEMPO, Figure 3B) when
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the reactions were performed open to air at room temperature, and no loss of catalyst activity
was observed during the one-year trial.
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5 mol% Cu(MeCN)4OTf
bpy/ABNO/NMI solution
(0.2 M/0.04 M/0.4 M)
A.
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Cy
OH
Cy
O
MeCN, r.t., ambient air, 2 h
5 mol% Cu(MeCN)4OTf
bpy/TEMPO/NMI solution
(0.2 M/0.2 M/0.4 M)
B.
Cy
OH
Cy
O
MeCN, r.t., ambient air, 24 h
Figure 3. Time course of cyclohexanemethanol oxidation with [Cu(MeCN)4]OTf and
bpy/nitroxyl/NMI solutions stored under air at 5 °C over a one-year period.
A typical protocol for use of these catalyst solutions is as follows. For a 1 mmol reaction,
a 25 mL round bottom flask is equipped with a stir bar and charged with alcohol (1 mmol),
[Cu(MeCN)4]OTf (19 mg), and MeCN (10 mL). The bpy/nitroxyl/NMI solution (250 µL; 0.2 M
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bpy/0.2 M TEMPO/0.4 M NMI or 0.2 M bpy/0.04 M ABNO/0.4 M NMI) is added, which results
in a red-brown solution. The reaction is stirred rapidly at room temperature open to air.7 The
reaction may be monitored by TLC, and upon completion (often accompanied by a color change
to green or blue), the crude reaction mixture is purified via aqueous extraction or flash
chromatography to afford the desired carbonyl compound.
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The catalyst solutions described here are now commercially available through Sigma-
Aldrich.8
CONCLUSION
Shelf-stable solutions of several catalyst components have been developed for the
Cu/TEMPO- and Cu/ABNO-based alcohol oxidation catalysts that are capable of operating
efficiently at room temperature with air as the oxidant. These solutions should make these
methods more convenient for bench-scale applications of aerobic alcohol oxidation. In short,
these bpy/[Cu(MeCN)4]OTf/nitroxyl/NMI catalysts represent a compelling alternative to
traditional stoichiometric oxidants for alcohol oxidation.
EXPERIMENTAL SECTION
General Considerations.
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1H and C{1H} NMR spectra were recorded on a 400 MHz spectrometer. Chemical shifts (δ)
13
are given in parts per million and are referenced to the residual solvent signal (all C NMR
spectra) or tetramethylsilane (all 1H NMR spectra in CDCl3). All coupling constants are reported
in Hz. GC analyses were performed using a DB-Wax column installed on a GC with FID. Silica
gel plugs used 40-63 µm (230-400 mesh) 60 Å silica gel.
All commercial reagents were purchased and used as received unless otherwise noted.
[Cu(MeCN)4]OTf is commercially available, but can be prepared according to literature
procedure.9 1,2:4,5-di-O-isopropylidene-β-D-(-)-fructopyranose was prepared according to
literature procedure.10 CH3CN was taken from a solvent system which passes the solvent through
a column of activated molecular sieves, but no precautions to exclude air or water from the
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solvent or reaction mixtures were taken. Reaction mixtures were monitored by GC or TLC using
a UV lamp or KMnO4 stain to visualize the plate.
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General Method for Screening Catalyst Combinations.
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Preparation of Catalyst Mixtures
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Testing of solid catalyst mixtures.
[Cu(MeCN)4]OTf, 2,2'-bipyridine, and TEMPO were each separately ground to a fine powder
with a pestle in a ceramic mortar. The finely ground powders of [Cu(MeCN)4]OTf (0.6 mmol),
bpy (0.6 mmol), and TEMPO (0.6 mmol) were then dispensed into a glass vial and shaken for 20
s to form a homogeneous mixture. The vial was closed with a Teflon cap and stored at 22 °C, 5
°C, or -20 °C for 1 week. All combinations of the three components resulted in a sticky black
solid and were not tested for activity.
For catalyst solutions:
Under air:
2,2'-Bipyridine (0.6 mmol), nitroxyl (TEMPO: 0.6 mmol, ABNO: 0.12 mmol), NMI (1.2 mmol),
and [Cu(MeCN)4]OTf (0.6 mmol) were added to a glass vial, then MeCN (3 mL) was added. The
glass vial was sealed with a Teflon cap, and the solutions were stored at 22 °C, 5 °C, or -20 °C.
For copper-free solutions, [Cu(MeCN)4]OTf was omitted.
Under N2:
2,2'-Bipyridine (0.6 mmol), nitroxyl (TEMPO: 0.6 mmol, ABNO: 0.12 mmol), NMI (1.2 mmol),
and [Cu(MeCN)4]OTf (0.6 mmol) were added to a flame-dried glass vial. The vial was sealed
with a rubber septum and purged with N2 for 30 min. At this point, anhydrous and degassed
MeCN (3 mL) was added via syringe, and the solutions were stored at 22 °C, 5 °C, or -20 °C.
For copper-free solutions, [Cu(MeCN)4]OTf was omitted.
General Procedure for Evaluation of Catalyst Solution Activity
Cyclohexanemethanol (25 µL, 0.2 mmol. 1 equiv) was added to a 13x100 mm test tube with 5x3
mm stirbar. Solid [Cu(MeCN)4]OTf (3.8 mg, 0.01 mmol, 0.05 equiv) was added if the catalyst
solution employed lacked [Cu(MeCN)4]OTf. The material was dissolved in MeCN (2 mL), then
bpy/nitroxyl/NMI or (bpy)CuI/nitroxyl/NMI catalyst solution (50 µL, 0.01 mmol bpy, 0.01 mmol
TEMPO or 0.002 mmol ABNO, 0.02 mmol NMI; 0.05 equiv bpy, 0.05 equiv TEMPO or 0.01
equiv ABNO, 0.1 equiv NMI) was added via syringe. The resulting red-brown solution was
stirred rapidly open to air and monitored by TLC until no further conversion was observed.
Internal standard (trimethyl(phenyl)silane, 0.1 mmol) was then added, and the reaction was
diluted with EtOAc (1 mL) and filtered through a pipet SiO2 plug. The plug was flushed with
EtOAc (2 mL), and filtrate was taken up for GC analysis.
Representative Procedure for the Aerobic Oxidation of Alcohols.
Neat substrate (1 mmol) and solid [Cu(MeCN)4]OTf (18.8 mg, 0.05 mmol, 0.05 equiv) were
added to a 25 mL round-bottom flask with an oval (0.625 x 0.25 in) stirbar. MeCN (10 mL) and
bpy/TEMPO/NMI or bpy/ABNO/NMI solution (250 µL) were then added, and the dark
red/brown solution was stirred rapidly (ca. 950 RPM) open to air at room temperature until no
starting material remained by TLC analysis. Reaction completion is often accompanied by a
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change in color to blue or green. Preliminary experiments indicate that stir rate impacts the rate
of reaction for reactions with ABNO. The order of addition of reaction components does not
affect product yield.
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The concentration of the reaction may be adjusted depending on the type of substrate:
For primary aliphatic alcohols, substrate concentration should be ≤0.1 M in MeCN
For primary benzylic, allylic, and propargylic alcohols and all secondary alcohols, substrate
concentration can be increased to 0.2 M in MeCN without loss of reactivity.
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Larger scale reactions should be performed in an appropriately sized round bottom flask:
10 mmol reactions should be performed with 50-100 mL MeCN in a 250 mL round bottom flask.
50 mmol reactions should be performed with 250-500 mL MeCN in a 1-2 L round bottom flask.
Large scale reactions should be concentrated in vacuo to ~10% of the original volume prior to
performing purification as described below.
Purification Method A: for most products
Upon completion by TLC, the reaction was diluted (10 mL) with an appropriate organic solvent
(e.g. EtOAc, Et2O, pentane, CH2Cl2) and filtered through a SiO2 plug. The plug was rinsed with
additional solvent (80 mL), and the filtrate was concentrated in vacuo to yield the product
carbonyl compound. Residual nitroxyl (<1 mol%) is observed by GC analysis, and can be
removed by SiO2 column chromatography.
Purification Method B: for racemizeable products
Upon completion by TLC, the reaction was diluted with H2O (50 mL) and the product was
extracted with an appropriate organic solvent (e.g. EtOAc, Et2O, pentane, CH2Cl2, 3x50 mL).
The organic layers were combined, washed with brine (100 mL), and dried over MgSO4. The
solvent was removed in vacuo to yield the product carbonyl compound. Residual nitroxyl (<1
mol%) is observed by GC analysis, and can be removed by SiO2 column chromatography.
Purification Method C: for volatile products
Upon completion by TLC, the reaction was diluted with H2O (50 mL) and the product was
extracted with an appropriate low-boiling organic solvent (e.g. Et2O or pentane, 3x50 mL). The
organic layers were combined, washed with brine (100 mL), and dried over MgSO4. The solvent
was removed in vacuo at 0 °C (rotary evaporation in an ice bath) to yield the product carbonyl
compound.
Product Characterization.
2-chloro-6-fluorobenzaldehyde (1)
The product was purified according to Method A (EtOAc eluent), and was isolated as a yellow
1
solid (151 mg, 94%). H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 7.49 (td, J = 8.2, 5.7 Hz,
1H), 7.30 – 7.28 (m, 1H), 7.13 – 7.08 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 187.0 (d, JC–F
=
2.0 Hz), 163.4 (d, JC–F = 265.6 Hz), 137.2 (d, JC–F = 4.0 Hz), 135.3 (d, JC–F = 11.0 Hz), 126.9 (d,
JC–F = 4.0 Hz), 121.9 (d, JC–F = 10.1 Hz), 115.8 (d, JC–F = 20.2). Spectral properties are consistent
with literature values.11
2-aminobenzaldehyde (2)
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The product was purified according to Method A (Et2O eluent), and was isolated as a yellow oil
1
(121 mg, >99%). H NMR (400 MHz, CDCl3): δ 9.87 (s, 1H), 7.48 (dd, J = 7.8, 1.5 Hz, 1H),
7.40 – 7.21 (m, 1H), 6.74 (t, J = 7.8 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.11 (s, 2H). 13C NMR
(101 MHz, CDCl3) δ 194.0, 149.8, 135.7, 135.2, 118.8, 116.3, 116.0. Spectral properties are
consistent with literature values.12
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(Z)-4-benzyloxy-but-2-enal (3)
The reaction was performed in a flask covered with black electrical tape in a fume hood with
hood lights turned off. It is unnecessary to turn auxiliary laboratory lights off during the reaction.
Upon completion by TLC analysis, the product was purified according to Method A (EtOAc
eluent) with fume hood lights off. Rotary evaporation was performed in normal lab lighting. The
product was isolated as a pink oil (165 mg, 94%) and was stored in a glass vial covered with
black electrical tape. >20:1 Z:E by 1H NMR spectroscopy. 1H NMR (400 MHz, CDCl3) δ 10.05
(d, J = 6.8 Hz, 1H), 7.34 (m, 5H), 6.64 (dt, J = 11.2, 5.6 Hz, 1H), 6.06 (ddt, J = 11.2, 6.8, 2.0 Hz,
13
1H), 4.59 (s, 2H), 4.53 (dd, J = 5.6, 2.0 Hz, 2H). C NMR (101 MHz, CDCl3) δ 191.6, 147.7,
137.5, 129.9, 128.8, 128.2, 128.0, 73.3, 67.2.
Spectral properties are consistent with literature values.13
3-benzyloxy-propionaldehyde (4)
The product was purified according to Method A (Et2O eluent), and was isolated as a pink oil
1
(159 mg, 97%). H NMR (400 MHz, CDCl3) δ 9.80 (q, J = 1.5 Hz, 1H), 7.88 – 6.35 (m, 5H),
4.54 (s, 2H), 3.82 (td, J = 6.1, 1.3 Hz, 2H), 2.70 (t, J = 6.1 Hz, 2H). 13C NMR (101 MHz, CDCl3)
δ 201.3, 137.9, 128.6, 127.9, 127.8, 73.4, 64.0, 44.0. Spectral properties are consistent with
literature values.14
Boc-L-tert-leucinal (5)
The product was purified according to Method B (EtOAc organic layer), and was isolated as a
1
white solid (195 mg, 97%). H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 5.15 (s, 1H), 4.18 (d, J
13
= 8.7 Hz, 1H), 1.45 (s, 9H), 1.05 (s, 9H). C NMR (101 MHz, CDCl3) δ 201.4, 156.3, 80.2,
67.8, 35.9, 28.6, 27.1. >99% ee based on HPLC analysis. Analysis of % ee is shown in the
HPLC traces of (S)-2-((Boc)amino)-3,3-dimethylbutyl-4-nitrobenzoate (see Supporting
Information). (S)-2-((Boc)amino)-3,3-dimethylbutyl-4-nitrobenzoate was synthesized according
to literature procedure.4 Spectral properties are consistent with literature values.4
1,2:4,5-Di-O-isopropylidene-β-D-erythro-2,3-hexodiulo-2,6-pyranose (6)
The product was purified according to Method A (EtOAc eluent), and was isolated as a white
crystalline solid (246 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 4.73 (d, J = 5.6 Hz, 1H), 4.62 (d,
J = 9.5 Hz, 1H), 4.55 (ddd, J = 5.6, 2.2, 1.0 Hz, 1H), 4.39 (dd, J = 13.5, 2.2 Hz, 1H), 4.12 (d, J =
13.5 Hz, 1H), 4.00 (d, J = 9.5 Hz, 1H), 1.55 (s, 3H), 1.47 (s, 3H), 1.40 (s, 6H). 13C NMR (101
MHz, CDCl3) δ 197.3, 114.2, 111.0, 104.5, 78.3, 76.2, 70.3, 60.4, 27.5, 26.9, 26.41, 26.36.
Spectral properties are consistent with commercially available product.
N-[4-(4-Fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide
(7)
The product was purified according to Method A (CH2Cl2 eluent), and was isolated as a white
1
solid (351 mg, >99%). H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.68 – 7.58 (m, 2H), 7.26 –
7.19 (m, 2H), 4.01 (hept, J = 6.7 Hz, 1H), 3.64 (s, 3H), 3.55 (s, 3H), 1.32 (d, J = 6.7 Hz, 6H). 13C
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NMR (101 MHz, CDCl3) δ 190.9, 179.4, 170.2, 164.8 (d, JC–F = 253.5 Hz), 159.2, 133.0 (d, JC–F
= 9.1 Hz), 132.5 (d, JC–F = 3.0 Hz), 119.9, 116.4 (d, JC–F = 21.0 Hz), 42.9, 33.5, 32.4, 22.1.
Spectral properties are consistent with literature values.15
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4-Chloro-2-nitrobenzaldehyde (8)
The product was purified according to Method A (EtOAc eluent), and was isolated as a light
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yellow solid (175 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 10.39 (d, J = 0.7 Hz, 1H), 8.11 (d, J
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= 2.0 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.77 (ddd, J = 8.3, 2.0, 0.7 Hz, 1H). C NMR (101
MHz, CDCl3) δ 187.2, 150.1, 140.6, 134.5, 131.3, 129.6, 125.1. Spectral properties are consistent
with literature values.16
ASSOCIATED CONTENT
Supporting Information. Spectral data for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
stahl@chem.wisc.edu
ACKNOWLEDGMENT
Financial support for this work was provided by the ACS GCI Pharmaceutical Roundtable, a
consortium of pharmaceutical companies (Eli Lilly, Pfizer, and Merck), the DOE (DE-FG02-
05ER15690), and the NSF (predoctoral fellowship to J.E.S.). We thank Sigma-Aldrich for
donation of ABNO. NMR spectroscopy facilities were partially supported by the NSF (CHE-
9208463) and NIH (S10 RR08389).
REFERENCES
(1) For reviews of aerobic alcohol oxidation, see: (a) Zhan, B.-Z.; Thompson, A. Tetrahedron
2004, 60, 2917−2935. (b) Schultz, M. J.; Sigman, M. S. Tetrahedron 2006, 62, 8227−8241.
(c) Parmeggiani, C.; Cardona, F. Green Chem. 2012, 14, 547−564. (d) Cao, Q.; Dornan, L.
M.; Rogan, L.; Hughes, N. L.; Muldoon, M. J. Chem. Commun. 2014, 50, 4524–4543. (e)
Ryland, B. L.; Stahl, S. S. Angew. Chem. Int. Ed. 2014, 53, 8824–8838. (f) Sheldon, R. A.
Catal. Today 2015, 247, 4–13. (g) Miles, K. C.; Stahl, S. S. Aldrichim. Acta 2015, 48, 8-10.
(2) For leading references, see: (a) Semmelhack, M. F.; Schmid, C. R.; Cortés, D. A.; Chou, C.
S. J. Am. Chem. Soc. 1984, 106, 3374–3376. (b) Ragagnin, G.; Betzemeier, B.; Quici, S.;
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Knochel, P. Tetrahedron 2002, 58, 3985–3991. (c) Gamez, P.; Arends, I. W. C. E.; Reedijk,
J.; Sheldon, R. A. Chem. Commun. 2003, 2414–2415. (d) Gamez, P.; Arends, I. W. C. E.;
Sheldon, R. A.; Reedijk, J. Adv. Synth. Catal. 2004, 346, 805−811. (e) Jiang, N.; Ragauskas,
A. J. J. Org. Chem. 2006, 71, 7087−7090. (f) Kumpulainen, E. T. T.; Koskinen, A. M. P.
Chem. Eur. J. 2009, 15, 10901−10911. (g) Figiel, P. J.; Sibaouih, A.; Ahmad, J. U.; Nieger,
M.; Raïsänen, M. T.; Leskelä, M.; Repo, T. Adv. Synth. Catal. 2009, 351, 2625−2632. (h)
Sasano, Y.; Nagasawa, S.; Yamazaki, M.; Shibuya, M.; Park, J.; Iwabuchi, Y. Angew. Chem.
Int. Ed. 2014, 53, 3236–3240.
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(3) (a) Hoover, J. M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 16901−16910. (b) Hoover, J. M.;
Steves, J. E.; Stahl, S. S. Nat. Protoc. 2012, 7, 1161−1166.
(4) Steves, J. E.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 15742–15745.
(5) (a) Hoover, J. M.; Ryland, B. L.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 2357–2367. (b)
Hoover, J. M.; Ryland, B. L; Stahl, S. S. ACS Catal. 2013, 3, 2599–2605.
(6) For representative examples of tandem reactions employing Cu/nitroxyl aerobic oxidation
catalysts, see: (a) Li, C. M.; Bardhan, S.; Pace, E. A.; Liang, M. C.; Gilmore, T. D.; Porco, J.
A. Org. Lett. 2002, 4, 3267–3270. (b) Nonappa; Maitra, U. Eur. J. Org. Chem. 2007, 3331–
3336. (c) Brioche, J.; Masson, G.; Zhu, J. Org. Lett. 2010, 12, 1432–1435. (d) Ho, X.-H.; Oh,
H.-J.; Jang, H.-Y. Eur. J. Org. Chem. 2012, 5655–5659. (e) Könning, D.; Hiller, W.;
Christmann, M. Org. Lett. 2012, 14, 5258–5261. (f) Dornan, L. M.; Cao, Q.; Flanagan, J. C.
A.; Crawford, J. J.; Cook, M. J.; Muldoon, M. J. Chem. Commun. 2013, 49, 6030–6032. (g)
Tao, C.; Liu, F.; Zhu, Y.; Liu, W.; Cao, Z. Org. Biomol. Chem. 2013, 11, 3349–3354. (h)
Yin, W.; Wang, C.; Huang, Y. Org. Lett. 2013, 15, 1850–1853.
(7) Vigorous stirring and a headspace:liquid ratio of ≥ 1:1 is recommended to achieve optimal
gas-liquid mixing. Round-bottom flasks are suitable for most bench scale reactions.
Alternative reaction vessels and/or bubbling of air into the reaction mixture can be beneficial
for larger scale reactions. For additional discussion, see: Steves, J. E.; Preger, Y.; Martinelli,
J. R.; Welch, C. J.; Root, T. W.; Hawkins, J. M.; Stahl, S. S. Org. Process Res. Dev. 2015,
ASAP. DOI: 10.1021/acs.oprd.5b00179
(8) Sigma-Aldrich product numbers: bpy/TEMPO/NMI – #796549, bpy/ABNO/NMI – #796557.
(9) Jenkins, C. L.; Kochi, J. K. J. Am. Chem. Soc. 1972, 94, 843–855.
(10) Kang, J.; Lim, G. J.; Yoon, S. K.; Kim, M. Y. J. Org. Chem. 1995, 60, 564–577.
(11) Wang, G.; Li, Z.; Ha, C.; Ding, K. Synth. Commun. 2008, 38, 1629–1637.
(12) Maddani, M. R.; Moorthy, S. K.; Prabhu, K. R. Tetrahedron 2010, 66, 329–333.
(13) Nielson, L.; Lindsay, K. B.; Faber, J.; Nielson, N. C.; Skrydstrup, T. J. Org. Chem. 2007,
72, 10035–10044.
(14) Fournier, J.-F.; Mathieu, S.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 13140–13141.
(15) Šterk, D.; Časar, Z.; Jukič, M.; Košmrlj, J. Tetrahedron 2012, 68, 2155–2160.
(16) Naffziger, M. R.; Ashburn, B. O.; Perkins, J. R.; Carter, R. G. J. Org. Chem. 2007, 72,
9857–9865.
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TOC GRAPHIC
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Catalyst Solution A
chemoselective for 1° alcohols
1. Solid CuI(OTf)
2. Catalyst Solution A or B
N
3. Alcohol
OH
O
N
N
N
N
NMI
R1
R2
bpy
O
R1
R2
TEMPO
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room temp.
open to air
Catalyst Solution B
high rates with 1° and 2° alcohols
N
N
N
N
ABNO
N
NMI
bpy
O
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