Mild Cu-Catalyzed Oxidation of Benzylic Boronic Esters to Ketones

Article abstract of DOI:10.1021/acscatal.9b00992

The oxidation of benzylic boronic esters directly to the ketone is reported. This mild Cu-catalyzed method uses an ambient atmosphere of air as the terminal oxidant and is notably chemoselective. Oxidation of the C-B bond occurs selectively, even in the presence of unprotected alcohols. Initial investigation suggests the reaction proceeds through an alkylboron to Cu transmetalation, peroxide formation, and rearrangement to give the carbonyl.

Full text of DOI:10.1021/acscatal.9b00992

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Letter
Mild Cu-Catalyzed Oxidation Of Benzylic Boronic Esters To Ketones
James Grayson, and Benjamin Michael Partridge
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 10 Apr 2019
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ACS Catalysis
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Mild Cu-Catalyzed Oxidation Of Benzylic Boronic Esters To Ketones
James D. Grayson and Benjamin M. Partridge*
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Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, UK
ABSTRACT: The oxidation of benzylic boronic esters directly to the ketone is reported. This mild Cu-catalyzed method uses an
ambient atmosphere of air as the terminal oxidant and is notably chemoselective. Oxidation of the C-B bond occurs selectively,
even in the presence of unprotected alcohols. Initial investigation suggests the reaction proceeds through an alkylboron to Cu
transmetallation, peroxide formation, and rearrangement to give the carbonyl.
KEYWORDS: Boron, catalysis, copper, ketones, oxidation
Organoboron reagents are versatile synthetic building blocks
used in a broad range of applications from medicinal
chemistry to materials science.1 Recent advances mean that
alkylboronic esters can be readily prepared and transformed
through a growing number of C-C and C-heteroatom bond-
forming processes.2 Oxidation of such boronic esters using
basic H2O2 to give the corresponding alcohol is widely used
(Scheme 1),3 including in the synthesis of complex natural
products.4 If access to the carbonyl in one step is desired,5
oxidation of either an alkenyl- or α-heteroatom-substituted
alkylboron is required. However, respectively these reagents
are susceptible to protodeboronation and are often non-trivial
to prepare. The oxidation of alkylboronic acids to the
carboxylic acid has been achieved using chromic acid.6
However, mild and direct conditions for boronic ester-to-
carbonyl oxidation are desirable to increase functional group
tolerance and improve sustainability.
conditions on the oxidation of benzylic boronic ester 1a. Initial
findings showed that 1a could be oxidized to give a mixture of
ketone 2 and alcohol 3 in the presence of Cu(OAc)2,
bipyridine (L1) and aniline under air at ambient pressure
(Table 1, entry 1). Key to the efficient formation of 2 was the
use of a solvent mixture of MeCN, AcOH and pyridine.11-13
Evaluation of other ligands in place of L1 showed that
dinitrogen ligands best promoted ketone formation (entries 2-
4). Diamine L2 gave 2 in high yield alongside 3 as a side
product. Though the yield of 2 was lower when using diimine
ligands L3 and L4, these reactions selectively gave ketone 2
with only traces of alcohol 3 observed. The absence of aniline
from the reaction mixture had a negative effect when using L2
(entry 5) but a beneficial effect when using L3 (entry 6).
Pleasingly, the loading of both Cu(OAc)2 and L3 could be
lowered, and the temperature decreased to 60 °C (entry 7).
Presumably, at lower temperatures, decomposition of 1a
through protodeboronation is reduced, leading to a higher
yield of 2, even at substoichiometric catalyst loadings. A
catalyst loading of 20 mol% was chosen as it gave consistently
high yields across a range of substrates. Finally, the reaction
could be run in the absence of molecular sieves without
decrease in yield (entry 8). Reaction of trifluoroborate salt 1b
under these conditions gave 2 selectively, but in low yield
(entry 9).
Herein, we report a mild Cu-catalyzed oxidation of
alkylboronic esters. This highly functional group tolerant
reaction oxidizes the C-B bond selectively to give the
corresponding carbonyl, using air as the terminal oxidant.
Furthermore, oxidation of the boronic ester is highly
chemoselective, even in the presence of unprotected alcohols.
Our method therefore complements other chemoselective
oxidation methods, including Wacker oxidation7 and the
selective oxidation of primary,8 secondary9 and benzylic
alcohols.10
Table 1. Evaluation of Reaction Conditionsa
B(pin)
O
OH
Cu(OAc)2, Ligand
a) Standard Peroxide Oxidation of C-B bond
MeCN/AcOH/pyr (1:2:2)
4 Å MS, air, T, 16 h
Ph
Me
Ph
Me
Ph
Me
B(OR)2
OH
H2O2
1a
2
3
R1
R2
R1
R2
NaOH
Entry
L
Catalyst
loadingb
Additive
(equiv.)
T
Yield Yield
b) Oxidation of alkenyl- and -heteroatom-substituted alkylborons:
(°C) of 2c
of 3c
2%
8%
<5%
<5%
<5%
<5%
<5%
<5%
<5%
B(OR)2
B(OR)2
R2
O
O
H2O2
H2O2
1
2
3
4
5
6
7
8d
9d,e
L1
L2
L3
L4
L2
L3
L3
L3
L3
100 mol% aniline (2) 80
100 mol% aniline (2) 80
100 mol% aniline (2) 80
100 mol% aniline (2) 80
47%
77%
64%
61%
33%
70%
74%
96%
34%
R2
R1
R2
X
R1
R1
R1
R2
NaOH
NaOH
c) This work:
 Chemoselective oxidation
 Air (1 atm.) as terminal oxidant
 Tolerates unprotected alcohols
B(pin)
O
Cu cat.
O2
100 mol%
100 mol%
15 mol%
20 mol%
20 mol%
-
-
-
-
-
80
80
60
60
60
R1
R2
R1
R2
Scheme 1: Oxidation of alkylboronic esters. pin = pinacol.
As part of ongoing investigations into the transformation of
alkylboronic esters, we evaluated the effect of various
1
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reductant. Under our oxidation conditions, 10 reacted to give a
Page 2 of 6
Ar
Ar
H
N
1
2
3
4
5
6
7
8
BF3K
N
HN
mixture of ketone 11 and alcohol 12 (eq 5). The presence of
both the alcohol and sulfoxide groups in alcohol 12 provides
strong evidence that a peroxide is formed during the reaction
pathway.
tBu
tBu
N
H
N
N
Ph
Me
L3: Ar = 2-MeOC6H4
L4: Ar = 2,6-Me2C6H3
L1
L2
1b
Cu(OAc)2 (20 mol%)
OH
[a] Reactions conducted using 0.05 mmol of 1a. [b] Loading of
both Cu(OAc)2 and ligand (1:1 ratio). [c] Determined by 1H NMR
analysis of the crude mixture using 1,3,5-trimethoxybenzene as an
internal standard. [d] Without 4 Å MS. [e] Reaction using 1b in
place of 1a. pyr = pyridine, MS = molecular sieves.
B(pin)
O
L3 (20 mol%)
Ph
(5)
Ph
SPh
S
Ph
SPh
Ph
MeCN/AcOH/pyr
air, 60 °C, 17 h
O
10
20%
60%
11
12
9
Next, we performed a radical clock experiment using
Intrigued by the mechanism of ketone formation, we
performed several competition experiments (see equations 1-
3). We considered the possibility of sequential oxidation of the
boronic ester to the alcohol and then ketone, given the
precedent of Cu-catalyzed oxidation of alcohols.14 To test this,
a 1:1 mixture of boronic ester 4 and alcohol 3 were subjected
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cyclopropyl boronic ester 13 to test if a radical mechanism
was under operation (eq 4). Ketone 14 was isolated in 81%
yield, with possible products from opening of the
cyclopropane not observed by either mass spectrometry or
NMR analysis of the crude mixture. This suggests that
peroxide formation is unlikely to occur through the
combination of O2 with a benzylic radical intermediate
(potentially formed through either homolytic C-B bond
cleavage or H-abstraction alpha to B). Instead, we propose that
B-to-Cu transmetallation17 leads to an alkyl Cu(II) species,
that can combine with O2 to form a peroxide.15e Presumably,
initial binding of O2 to Cu occurs through an η1-end-on
coordination due to steric congestion at Cu.18 However, the
process of insertion of O2 into the Cu-C bond requires further
study.
1
to our standard oxidation conditions (eq 1). H NMR analysis
of the crude showed that boronic ester 4 had been oxidized to
ketone 5 but alcohol 3 was recovered unreacted. Also,
subjecting alcohol 3 to the reaction conditions in the absence
of boronic ester, resulted in recovery of 3.12 This suggests that
sequential oxidation of the boronic ester to the ketone, via the
alcohol, does not occur. Similar competition experiments with
ethylbenzene (eq 2) and 2-vinylnaphthalene (eq 3) also gave
selective oxidation of the boronic ester to ketone. This
suggests that the reaction does not proceed through either
protodeboronation followed by benzylic oxidation15 or
elimination then Wacker oxidation.7
Cu(OAc)2 (20 mol%)
L3 (20 mol%)
B(pin)
O
products from
cyclopropane ring
opening not observed
(4)
Ph
Ph
MeCN/AcOH/pyr
air, 60 °C, 16 h
B(pin)
O
13
81%
14
OH
OH
O
Cu cat.
[O]
MeO
MeO
Ph
Ph
Ar
Ph
Ph
(1)
(2)
(3)
Given these results, we propose the following reaction
3
4
3
85%
2
0%
5
82%
mechanism (Scheme 3). Cu complex 15, which forms through
ligation of L3 with Cu(OAc)2, facilitates B-to-Cu
transmetallation to give intermediate 16. The combination of
O2 with 16 leads to the formation of a peroxide species 17,
which can be protonated by AcOH to form peroxide 9 and
regenerate Cu complex 15. Ketone 2 is formed through
pyridine-mediated elimination of peroxide 9.
B(pin)
O
OH
O
Cu cat.
[O]
MeO
MeO
Ph
Ph
6
4
3
0%
2
0%
5
>95%
Cu(OAc)2
L3
B(pin)
O
O
Cu cat.
[O]
OH
O
O
B(pin)
pyridine
Ar
Ar
Ph
Ph
Ph
7
Ar = 1-naphthyl
2
9
1a
1a
7
80%
8
0%
2
92%
N
Ar
H2O
N
Cu
OAc
AcOB(pin)
HOAc
N
Ar
Next, we hypothesized that a peroxide may be an
intermediate in the reaction. Peroxide 9 was independently
prepared, and subjected to both our reaction conditions and the
solvent mixture without catalyst (Scheme 2). In both cases
ketone 2 was formed in high yield. This suggests that while
the Cu-catalyst may be required to form a peroxide,
breakdown of the peroxide to the ketone is mediated by a
mixture of pyridine and acetic acid, presumably through an
E2-like elimination process.16
15
Ar = 2-MeOC6H4
Ar
O
N
Ar
Cu
N
O
N
Cu
Ar
Ar
Ph
Ph
16
O2
17
Scheme 3. Proposed mechanism for the Cu-catalyzed
oxidation reaction.
OH
Cu(OAc)2 (15 mol%)
L3 (15 mol%)
O
O
O
MeCN/AcOH/pyr
air, 60 °C, 16 h
Ph
Ph
Ph
Scheme 4 presents the oxidation of various benzylic boronic
esters. The reaction was found to be mild and functional group
tolerant. Compatible functionality includes aryl halide, methyl
ether, and trifluoromethyl groups. Steric hindrance from ortho-
methyl (19h) and 1-naphthyl (19i) groups is tolerated without
issue. Heterocycle-containing boronic esters were also
oxidized successfully (18j-18l). Primary benzylic boronic
esters reacted to give the corresponding aldehyde (19m-n).
MeCN/AcOH/pyr
air, 60 °C, 16 h
2
94%
2
95%
9
1
Scheme 2. Reaction of peroxide 9. Yields determined by H
NMR analysis of the crude reaction using 1,3,5-
trimethoxybenzene as an internal standard.
In an attempt to trap a peroxide intermediate in situ, boronic
ester 10 was prepared with a sulfide group that could act as a
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ACS Catalysis
However, a current limitation is that non-benzylic boronic
Cu(OAc)2 (20 mol%)
L3 (20 mol%)
Ar
Ar
B(pin)
O
N
HN
1
2
3
4
5
6
7
8
esters do not react, with primary alkylboronic ester 20 returned
unreacted. The alkyl chain could be extended beyond Me, with
tetralone (19o), phenylpropyl (19p) and isobutyl chains
tolerated (19q). The more sterically hindered isopropyl-
substituted boronic ester 18r reacted slowly, with 10-20% of
19r observed after 72 h. Reaction of tertiary boronic ester 21
under our conditions proceeded, albeit slowly. The products,
acetophone and alcohol 23, were presumably formed through
decomposition of alkylperoxide 22.19
Ph
R1
MeCN/AcOH/pyr (1:2:2)
air, 60 C, 16-48 h
Ph
R1
25a-i
L3: Ar = 2-MeOC6H4
24a-i
O
O
O
O
O
O
O
Ph
OEt
Ph
Ph
Ph
Me
Ph
OBn
71%a
65%b
67%c
62%b
25a
25b
25c
25d
O
9
O
Cu(OAc)2 (20 mol%)
L3 (20 mol%)
Ar
Ar
O
O
Bn
B(pin)
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
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N
HN
Ph
N
N3
N
Ph
Ph
R1
R2
MeCN/AcOH/pyr (1:2:2)
R1
R2
Boc
79%c
81%b,d
62%c
25f
air, 60 C, 16 h
L3: Ar = 2-MeOC6H4
18a-r
18a-r
25g
25e
2
R = H: 75%
O
O
19f R = Cl: 73%
19g R = Br: 70%
5 R = OMe: 89%
N
N
19a R = OMe: 86%
19b R = Me: 86%
19c R = Ph: 92%
19d R = F: 69%
OH
O
N
O
N
Ph
Me
Me
N
N
Ph
Ph
85%c,d
64%c,d
R
19e R = CF3: 89%
25h
25i
R
Scheme 5. Oxidation of difunctional alkylboronic esters, with
the newly formed ketone highlighted in red. Reactions were
conducted on a 0.60 mmol scale. Yields reported are of
isolated material. [a] Reaction time of 24 h. [b] Reaction time
of 48 h. [c] Reaction time of 16 h. [d] 0.30 mmol scale.
O
O
O
O
Me
Me
Me
Me
N
Me
87%
19h
N
Boc
82%
19i
87%a
76%a
19j
19k
To further explore the compatibility of our method, we
oxidized boronic ester 1a in the presence of a variety of
additives (Table 2).20 Pleasingly, the conditions were
compatible with secondary amine, amide, carboxylic acid,
aldehyde and alcohol functionality without decrease in yield of
ketone 2 and a ≥80% recovery of the additive (entries 1-6). In
the cases of benzaldehyde and anisyl alcohol, no oxidation of
the additive to the corresponding benzoic acid was observed
by NMR or mass spectroscopy analysis. Alkynes are also
tolerated (entries 7 and 8). In the presence of phenyl acetylene,
oxidation of 1a preceded in high yield but the additive was
returned in only 46%. In comparison, the yield of 2 was
reduced to 67% in the presence of 1-phenyl-1-hexyne, despite
the alkyne being returned unreacted. An amino acid reduced
the efficiency of oxidation, with significant portion of starting
material 1a returned (entry 9). The corresponding Fmoc-
protected amino acid was compatible, albeit with small
amount of additive decomposition (entry 10). Styrene oxide
did not interfere with the oxidation reaction but decomposed
under the reaction conditions (entry 11). The heterocycles
benzofuran and indole were also found to be compatible
without significant decrease in yield of 2 (entries 12 and 13).
O
O
O
Me
H
H
Ph
B(pin)
N
boronic ester
returned
20
76%
89%
86%b
Cl
19l
19m
19n
O
O
O
Me
O
Ph
Me
Ph
Ph
Me Ph
Me
56%c
63%c
69%
19q
<20%d
19o
19p
19r
O
OH Me
RO
B(pin) Me
O
Me
Cu cat.
[O]
Ph
Me Ph
Me
Ph
Me
Me
16%
23
Ph
Me
Me
Me
22
33%
21
2
+ 35% 21 returned
Scheme 4. Oxidation of various alkylboronic esters. Reactions
were conducted on a 0.60 mmol scale. Yields reported are of
isolated material. [a] Reaction conducted on a 0.30 mmol
scale. [b] Reaction conducted on a 0.05 mmol, and the yield
Table 2. Examining Functional Group Compatibilitya
1
determined by H NMR analysis of the crude reaction using
1,3,5-trimethoxybenzene as an internal standard. [c] Reaction
time of 48 h. [d] Reaction time of 72 h.
Cu(OAc)2 (20 mol%)
L3 (20 mol%)
Ar
Ar
B(pin)
O
N
HN
Ph
MeCN/AcOH/pyr (1:2:2)
air, 60 C, 16h
Ph
We next explored the reaction of more complex boronic esters
(Scheme 5). Boronic esters containing ester (24a), ketone
(24b-24c), and ether (24d) functionality reacted in good yield.
Nitrogen functionality is also tolerated, as shown by substrates
containing Boc-protected amine (25e), azide (25f), morpholine
(25g) and triazole groups (25h). Reaction of boronic ester 24i
demonstrates that oxidation of the C-B bond occurs
selectively, even in the presence of an unprotected alcohol.
Some substrates did require longer reaction times to achieve
good conversion.
1a
2
L3: Ar = 2-MeOC6H4
Additive (1 equiv.)
Entry Additive
Yield
Returned
1ab
Returned
Additiveb
84%
of 2b
Ph
1
85%
0%
HN
Ph
H
N
2
85%
0%
90%
O
F3C
3
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alkylboronic esters are in development and will be reported in
Page 4 of 6
CO2H
3
79%
0%
80%
1
2
3
4
5
6
7
8
due course.
Me
Ph
O
4
5
88%
82%
0%
0%
80%
83%
ASSOCIATED CONTENT
H
Supporting
Information.
Experimental
details
and
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
OH
MeO
Ph
6
7
83%
67%
0%
0%
46%
86%
AUTHOR INFORMATION
C4H9
Corresponding Author
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
Ph
* Email: b.m.partridge@sheffield.ac.uk.
CO2H
NH2
8
35%
52%
3%
Notes
The authors declare no competing financial interests
9
10
Fmoc-Phe-OH
74%
91%
0%
0%
59%
0%
O
ACKNOWLEDGMENT
Ph
11
12
72%
82%
9%
0%
84%
90%
We thank the University of Sheffield, the EPSRC and the Royal
Society (RSG\R1\180065) for financial support.
O
REFERENCES
N
H
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[a] Reactions conducted using 0.05 mmol of 1a and 0.05 mmol
of additive. [b] Values reported are the average of 3 experiments,
and determined by H NMR analysis of the crude mixture using
1,3,5-trimethoxybenzene as an internal standard.
1
Finally, we trialed 1,3-diboronic ester 26 under our
oxidation conditions (Scheme 6). We found that the benzylic
boronic ester was selectively oxidized to give ketone 27 in
36% yield after 16 h. Unfortunately, decomposition of 27 over
time led to a reduced yield and prohibited extending the
reaction time. Although 27 could be isolated, to more
accurately determine the mass balance after Cu-catalyzed
oxidation, the crude mixture was subjected to oxidation using
basic H2O2. This gave both ketone 28 and diol 29, formed
from the remaining diboronic ester 26. This shows that unlike
homologation chemistry,21 the regioselectivity of our method
appears to be dictated by the electronics of the C-B bond
undergoing functionalization rather than the steric
environment at boron.
(3) Chinnusamy, T.; Feeney, K.; Watson, C. G.; Leonori, D.;
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Morken, J. P. A Boron Alkylidene–Alkene Cycloaddition Reaction:
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Aggarwal, V. K. Stereocontrolled Total Synthesis of (−)-
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(5) A two-step oxidation protocol via the alcohol was recently
reported: Gerleve, C.; Kischkewitz, M.; Studer, A. Synthesis of α-
Chiral Ketones and Chiral Alkanes Using Radical Polar Crossover
Reactions of Vinyl Boron Ate Complexes. Angew. Chem., Int. Ed.
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(6) Brown, H. C.; Kulkarni, S. V.; Khanna, V. V.; Patil, V. D.;
Racherlazd, U. S. Organoboranes for Synthesis. 14. Convenient
Procedures for the Direct Oxidation of Organoboranes from Terminal
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(7) For reviews see: (a) Baiju, T. V.; Gravel, E.; Doris, E.;
Namboothiri, I. N. N.; Recent developments in Tsuji-Wacker
oxidation. Tetrahedron Lett. 2016, 57, 3993-4000; (b) Mann, S. E.;
Benhamou, L.; Sheppard, T. D.; Palladium(II)-Catalysed Oxidation of
Alkenes. Synthesis 2015, 47, 3079-3117; (c) Michel, B. W., Steffens,
L. D. and Sigman, M. S. The Wacker Oxidation, Organic Reactions,
2014, doi:10.1002/0471264180.or084.02. For selected examples of
the oxidation of styrenes, see: (d) Chai, H.; Cao, Q.; Dornan, L. M.;
Hughes, N. L.; Brown, C. L.; Nockemann, P.; Li, J.; Muldoon, M. J.
Cationic Palladium(II) Complexes for Catalytic Wacker‐Type
O
B(pin)
O
OH
B(pin) B(pin)
OH
OH
Cu cat.
[O]
H2O2
Ar
Ar
Ar
Ar
NaOH
THF
BnO
27
36%a (18%b)
BnO
40%
28
BnO
BnO
38%
29
26
Ar = 4-MeOC6H4
Scheme 6. Cu-catalyzed oxidation of 1,3-diboronic ester 26.
Cu cat. conditions: Cu(OAc)2 (20 mol%), L3 (20 mol%),
MeCN/AcOH/pyr (1:2:2), air, 60 °C, 16 h. The reaction was
conducted on a 0.30 mmol scale and yields reported are of
isolated material. [a] Yield determined by 1H NMR analysis of
the crude mixture using 1,3,5-trimethoxybenzene as an
internal standard from a 0.05 mmol scale reaction. [b] Isolated
yield.
In conclusion, we report a mild Cu-catalyzed oxidation of
alkylboronic esters to the corresponding ketone. The mild
conditions use ambient air as the terminal oxidant, and
chemoselective oxidation of the C-B bond is achieved even in
the presence of unprotected alcohols. Experimental evidence
suggests that the mechanism of reaction proceeds by B-to-Cu
transmetallation, peroxide formation, and rearrangement to
give the ketone. Further oxidative transformations of
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ACS Catalysis
Oxidation of Styrenes to Ketones Using O2 as the Sole Oxidant. Eur.
Precursor into a Highly Active Aerobic Oxidation Catalyst. ACS Cent.
Sci. 2017, 3, 314-321.
J. Inorg. Chem. 2017, 2017, 5604-5608; (e) Naik, A.; Meina, L.;
Zabel, M.; Reiser, O. Efficient Aerobic Wacker Oxidation of Styrenes
Using Palladium Bis(isonitrile) Catalysts. Chem. Eur. J. 2010, 16,
1624-1628; (f) Cornell, C. N.; Sigman, M. S. Discovery Of And
Mechanistic Insight Into A Ligand-Modulated Palladium-Catalyzed
Wacker Oxidation Of Styrenes Using TBHP. J. Am. Chem. Soc. 2005,
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(8) (a) Doi, R.; Shibuya, M.; Murayama, T.; Yamamoto, Y.;
Iwabuchi, Y. Development of an azanoradamantane-type nitroxyl
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Practical Copper(I)/TEMPO Catalyst System for Chemoselective
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(15) For a review see: (a) Díaz-Requejo, M. M.; Pérez, P. J. Coinage
Metal Catalyzed C−H Bond Functionalization of Hydrocarbons.
Chem. Rev. 2008, 108, 3379–3394. For selected examples see: (b) Deꢀ
Houwer, J.; AbbaspourꢀTehrani, K.; Maes, B. U. W. Synthesis of
Aryl(di)azinyl Ketones Through Copper- and Iron-catalyzed
Oxidation of the Methylene Group of Aryl(di)azinylmethanes. Angew.
Chem., Int. Ed. 2012, 51, 2745–2748; (c) Velusamy, S.;
Punniyamurthy, T. Copper(II)-catalyzed C-H Oxidation of
Alkylbenzenes and Cyclohexane with Hydrogen Peroxide.
Tetrahedron Lett. 2003, 44, 8955–8957; (d) Costas, M.; Llobet, A.
Copper(I)-induced Activation of Dioxygen for the Oxidation of
Organic Substrates Under Mild Conditions. An Evaluation of Ligand
Effects. J. Mol. Catal. A Chem. 1999, 142, 113–124; (e) Barton, D. H.
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Functionalisation of Saturated Hydrocarbons. Part XXI. The Fe(III)-
catalyzed and the Cu(II)-catalyzed Oxidation of Saturated
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A
Designer Catalyst for
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Hydrocarbons by Hydrogen Peroxide:
A Comparative Study.
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(16)
Kornblum, N.; DeLaMare, H. E. The Base Catalyzed
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17) The transmetallation of alkylboronic esters to Cu has only been
reported in a few instances previously, see: (a) Mori-Quiroz, L. M.;
Shimkin, K. W.; Rezazadeh, S.; Kozlowski, R. A.; Watson, D. A.
Copper-Catalyzed Amidation of Primary and Secondary Alkyl
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Kuninobu, Y. Copper-Catalyzed N- and O-Alkylation of Amines and
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(c) Zhu, M.; Qiu, Z.; Zhang, Y.; Du, H.; Li, J.; Zou, D.; Wu, Y.; Wu,
Y. Synthesis of (E)-Prop-1-ene-1,3-diyldibenzene Derivatives Via
Direct Decarboxylative Coupling Of α,β-Unsaturated Carboxylic
Acids With Benzyl Boronic Acid Pinacol Ester. Tetrahedron Lett.
2017, 58, 2255-2257.
(18) For reviews, see: (a) Esguerra, K. V. N.; Lumb, J.-P. Cu(III)-
Mediated Aerobic Oxidations. Synthesis 2019, 51, 334-358.; (b)
Rolff, M.; Tuczek, F. How Do Copper Enzymes Hydroxylate
Aliphatic Substrates? Recent Insights from the Chemistry of Model
Systems. Angew. Chem., Int. Ed. 2008, 47, 2344-2347. For selected
examples, see: (c) Reynolds, A. M.; Gherman, B. F.; Cramer, C. J.;
Tolman, W. B. Characterization Of A 1:1 Cu−O2 Adduct Supported
By An Anilido Imine Ligand. Inorg. Chem. 2005, 44, 6989-6997; (d)
Osako, T.; Nagatomo, S.; Kitagawa, T.; Cramer, C. J.; Itoh, S.
Kinetics And DFT Studies On The Reaction Of Copper(II)
Complexes And H2O2. J. Biol. Inorg. Chem. 2005, 10, 581-590. (e)
Aboelella, N. W.; Kryatov, S. V; Gherman, B. F.; Brennessel, W. W.;
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Dioxygen Activation At A Single Copper Site:ꢁ Structure, Bonding,
And Mechanism Of Formation Of 1:1 Cu−O2 Adducts. J. Am. Chem.
Soc. 2004, 126, 16896-16911.
(9) (a) Attoui, M.; Vatèle, J.-M. TEMPO/NBu4Br-Catalyzed Selective
Alcohol Oxidation with Periodic Acid. Synlett 2014, 25, 2923–2927;
(b) Dong, J. J.; Unjaroen, D.; Mecozzi, F.; Harvey, E. C.; Saisaha, P.;
Pijper, D.; deꢀBoer, J. W.; Alsters, P.; Feringa, B. L.; Browne, W. R.
Manganese-Catalyzed Selective Oxidation of Aliphatic C-H groups
and Secondary Alcohols to Ketones with Hydrogen Peroxide.
ChemSusChem 2013, 6, 1774–1778; (c) Painter, R. M.; Pearson, D.
M.; Waymouth, R. M. Selective Catalytic Oxidation of Glycerol to
Dihydroxyacetone. Angew. Chem., Int. Ed. 2010, 49, 9456–9459.
(10) (a) Yan, Q.; Fang, Y. C.; Jia, Y. X.; Duan, X. H. Chemoselective
hydrogen peroxide oxidation of primary alcohols to aldehydes by a
water-soluble and reusable iron(iii) catalyst in pure water at room
temperature New J. Chem. 2017, 41, 2372–2377; (b) Ray, R.;
Chandra, S.; Maiti, D.; Lahiri, G. K. Simple and Efficient Ruthenium-
Catalyzed Oxidation of Primary Alcohols with Molecular Oxygen
Chem. Eur. J 2016, 22, 8814–8822; (c) Devari, S.; Rizvi, M. A.;
Shah, B. A. Visible Light Mediated Chemo-selective Oxidation of
Benzylic Alcohols. Tetrahedron Lett. 2016, 57, 3294-3297; (d) Liu,
C.; Fang, Z.; Yang, Z.; Li, Q.; Guo, S.; Guo, K. Highly Practical
Oxidation of Benzylic Alcohol in Continuous-flow System with
Metal-free Catalyst. Tetrahedron Lett. 2015, 56, 5973–5976; (e)
Lipshutz, B. H.; Hageman, M.; Fennewald, J. C.; Linstadt, R.; Slack,
E.; Voigtritter, K. Selective Oxidations of Activated Alcohols in
Water at Room Temperature. Chem. Commun. 2014, 50, 11378–
11381; (f) Fernandes, R. A.; Bethi, V. An Expedient
Osmium(v)/K3Fe(CN)6-mediated Selective Oxidation of Benzylic,
Allylic and Propargylic Alcohols RSC Adv. 2014, 4, 40561–40568.
(11) AcOH was important to improve selectivity of oxidation to the
ketone; in its absence, greater proportions of alcohol 3 were observed.
Pyridine is likely to play a dual role; acting both as a base and as a
coordinating ligand to help break up Cu aggregates.
(19) Gephart, R. T.; McMullin, C. L.; Sapiezynski, N. G.; Jang, E. S.;
Aguila, M. J. B.; Cundari, T. R.; Warren, T. H. Reaction Of CuI With
Dialkyl Peroxides: CuII-Alkoxides, Alkoxy Radicals, And Catalytic
C–H Etherification. J. Am. Chem. Soc. 2012, 134, 17350-17353.
(20) Collins, K. D.; Glorius, F. A Robustness Screen for the Rapid
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(21) Fawcett, A.; Nitsch, D.; Ali, M.; Bateman, J. M.; Myers, E. L.;
Aggarwal, V. K. Regio- and Stereoselective Homologation of 1,2-
Bis(Boronic Esters): Stereocontrolled Synthesis of 1,3-Diols and
Schꢁ725674. Angew. Chem., Int. Ed. 2016, 55, 14663–14667.
(12) See supporting information for more details.
(13) The use of mixtures of pyridine/AcOH has been also been
important for other Cu-catalyzed oxidation reactions. For example:
Barton, D. H. R.; Csuhai, E.; Doller, D.; Geletti, Y. V. The
Functionalization Of Saturated Hydrocarbons. Part XIX. Oxidation Of
Alkanes By H2O2 In Pyridine Catalyzed By Copper(II) Complexes. A
Gif-Type Reaction. Tetrahedron 1991, 47, 6561-6570.
(14) For a recent review: (a) Ryland, B. L.; Stahl, S. S. Practical
Aerobic Oxidations of Alcohols and Amines with Homogeneous
Copper/TEMPO and Related Catalyst Systems. Angew. Chem., Int.
Ed. 2014, 53, 8824–8838. For a recent example: (b) McCann, S. D.;
Lumb, J.-P.; Arndtsen, B. A.; Stahl, S. S. Second-Order Biomimicry:
In Situ Oxidative Self-Processing Converts Copper(I)/Diamine
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B(pin)
R
Cu cat. (20 mol%)
O
MeCN/AcOH/pyr
air (1 atm), 60 C
Ar
Ar
R
28 examples
56-92% yield
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• Chemoselective oxidation
• Terminal oxidant = O2 from air
• Functional group tolerant
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