Highly efficient Cu(I)-catalyzed oxidation of alcohols to ketones and aldehydes with diaziridinone

Article abstract of DOI:10.1021/ol303431h

A novel and efficient Cu(I)-catalyzed oxidation of alcohols has been achieved with di-tert-butyldiaziridinone as the oxidant under mild conditions. A wide variety of primary and secondary alcohols with various functional groups can be oxidized to aldehydes and ketones in high yields. The reaction proceeds under neutral conditions making it compatible with acid- or base-sensitive substrates, and it is amenable to gram scale.

Full text of DOI:10.1021/ol303431h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Highly Efficient Cu(I)-Catalyzed Oxidation
of Alcohols to Ketones and Aldehydes
with Diaziridinone
Yingguang Zhu, Baoguo Zhao, and Yian Shi*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
United States
yian@lamar.colostate.edu
Received December 16, 2012
ABSTRACT
A novel and efficient Cu(I)-catalyzed oxidation of alcohols has been achieved with di-tert-butyldiaziridinone as the oxidant under mild conditions.
A wide variety of primary and secondary alcohols with various functional groups can be oxidized to aldehydes and ketones in high yields. The
reaction proceeds under neutral conditions making it compatible with acid- or base-sensitive substrates, and it is amenable to gram scale.
The oxidation of alcohols to the corresponding ketones
or aldehydes is one of the most fundamental and widely
utilized transformations in organic synthesis.1 Various
effective reagents and methods have been developed,
including chromium reagents,2 manganese(IV) oxide,3
activated DMSO,4 hypervalent iodine reagents,5 ruthenium
reagents,6 osmium(VIII) oxide,7 metal-8À16 or TEMPO-
catalyzed17,18 oxidation, etc. Due to the importance of this
transformation in organic synthesis, the development of
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r
10.1021/ol303431h
XXXX American Chemical Society

new, efficient, safe, and mild oxidation processes is still
highly desirable and valuable.
Table 1. Studies on Reaction Conditionsa
We have previously reported that readily prepared di-
tert-butyldiaziridinone (1)19,20 is a highly effective nitrogen
sourceforthe Pd(0)21 and Cu(I)22 catalyzed diamination of
olefins. In our efforts to further explore the reactivity of
diaziridinone and expand its synthetic utility, we have found
that alcohols can be efficiently oxidized to the correspond-
ing carbonyl compounds with di-tert-butyldiaziridinone (1)
in the presence of a Cu(I) catalyst under mild reaction
time
(h)
conv
(%)b
yield
(%)c
entry
catalyst
CuCN
solvent
(10) For leading references on ruthenium-catalyzed oxidation of
alcohols, see: (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White,
A. D. J. Chem. Soc., Chem. Commun. 1987, 1625. (b) Morris, P. E.;
Kiely, D. E. J. Org. Chem. 1987, 52, 1149. (c) Ley, S. V.; Norman, J.;
Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639. (d) Fung, W.-H.; Yu,
1
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CH2Cl2
DCE
4
0
À
2
CuI
4
47
93
97
57
65
99
99
100
42
89
0
38
78
87
49
53
82
80
94
29
79
À
3
CuCl
4
4
CuBr
4
ꢀ
W.-Y.; Che, C.-M. J. Org. Chem. 1998, 63, 2873. (e) Csjernyik, G.; Ell,
5
CuBr2
CuBr-P(nBu)3 (1:1)
CuBr
4
€
A. H.; Fadini, L.; Pugin, B.; Backvall, J.-E. J. Org. Chem. 2002, 67, 1657.
6
4
(f) Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2002, 41, 4538.
(g) Gonsalvi, L.; Arends, I. W. C. E.; Sheldon, R. A. Org. Lett. 2002, 4,
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Doucet, R. J.; Rao, K. V. R.; Robertson, K. N.; Cameron, T. S.
J. Am. Chem. Soc. 2003, 125, 2195.
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see: (a) Tsunoyama, H.; Sakurai, H.; Negishi, Y.; Tsukuda, T. J. Am.
Chem. Soc. 2005, 127, 9374. (b) Guan, B.; Xing, D.; Cai, G.; Wan, X.;
Yu, N.; Fang, Z.; Yang, L.; Shi, Z. J. Am. Chem. Soc. 2005, 127, 18004.
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Green Chem. 2009, 11, 756.
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Chem. 1986, 51, 2661. (b) Sato, K.; Aoki, M.; Takagi, J.; Noyori, R.
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alcohols, see: (a) Son, Y.-C.; Makwana, V. D.; Howell, A. R.; Suib,
S. L. Angew. Chem., Int. Ed. 2001, 40, 4280. (b) Bagherzadeh, M.
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K.-C.; Lau, T.-C. Chem. Commun. 2011, 4273.
7
4
8
CuBr
4
9
CuBr
CuBr
CH3CN
DMF
2
10
11
12d
13e
4
CuBr
THF
4
none
CH3CN
CH3CN
24
24
CuBr
0
À
a All reactions were carried out with alcohol 2a (0.30 mmol), di-tert-
butyldiaziridinone (1) (0.33 mmol), and Cu catalyst (0.030 mmol) in
solvent (0.6 mL) at rt under Ar unless otherwise stated. b The conversion
was based on alcohol 2a and determined by the 1H NMR. c Isolated
yield. d The reaction was carried out at rt or 60 °C under Ar. e The
reaction was carried out at 60 °C under air in the absence of 1.
conditions. Herein we wish to report our preliminary
studies on this subject.
Our initial studies were carried out with 2,2-dimethyl-1-
phenyl-1-propanol (2a) as a test substrate. Several copper
catalysts were first screened in CDCl3 at room temperature
(Table 1, entries 1À5). High conversions were obtained
with CuCl and CuBr (Table 1, entries 3 and 4). In the case
of CuBr, ketone 3a was isolated in 87% yield. The yield
decreased to 53% when P(nBu)3 was added (Table 1, entry 6).
Among the solvents examined (Table 1, entries 7À11),
CH3CN gave the highest yield (94%) for ketone 3a
(Table 1, entry 9). No reaction occurred in the absence of
the Cu catalyst (Table 1, entry 12) or di-tert-butyldiaziri-
dinone (1) under air (Table 1, entry 13), suggesting that
both the Cu catalyst and di-tert-butyldiaziridinone (1) are
required for the reaction.
(14) For leading references on iron-catalyzed oxidation of alcohols,
see: (a) Pearson, A. J.; Kwak, Y. Tetrahedron Lett. 2005, 46, 5417. (b)
€
Shi, F.; Tse, M. K.; Pohl, M.-M.; Bruckner, A.; Zhang, S.; Beller, M.
€
Angew. Chem., Int. Ed. 2007, 46, 8866. (c) Schroder, K.; Junge, K.;
Bitterlich, B.; Beller, M. Top. Organomet. Chem. 2011, 33, 83. (d)
Kunisu, T.; Oguma, T.; Katsuki, T. J. Am. Chem. Soc. 2011, 133, 12937.
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hols, see: (a) Tovrog, B. S.; Diamond, S. E.; Mares, F.; Szalkiewicz, A.
J. Am. Chem. Soc. 1981, 103, 3522. (b) Iwahama, T.; Yoshino, Y.;
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R. J. Mol. Catal. A: Chem. 2012, 353À354, 156.
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alcohols, see: (a) Li, C.; Zheng, P.; Li, J.; Zhang, H.; Cui, Y.; Shao,
Q.; Ji, X.; Zhang, J.; Zhao, P.; Xu, Y. Angew. Chem., Int. Ed. 2003, 42,
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J. Coord. Chem. 2010, 63, 3849. (d) Alagiri, K.; Prabhu, K. R. Tetra-
hedron 2011, 67, 8544.
With the optimal reaction conditions in hand, the gen-
erality for the oxidation was subsequently investigated
with various secondary alcohols. As shown in Table 2,
high yields were obtained for a wide range of alcohols.
(17) For leading reviews on TEMPO-catalyzed oxidation of alcohols,
€
see: (a) Adam, W.; Saha-Moller, C. R.; Ganeshpure, P. A. Chem. Rev.
2001, 101, 3499. (b) Sheldon, R. A.; Arends, I. W. C. E. Adv. Synth.
Catal. 2004, 346, 1051.
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see: (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987,
52, 2559. (b) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org.
Chem. 1996, 61, 7452. (c) Rychnovsky, S. D.; Vaidyanathan, R. J. Org.
Chem. 1999, 64, 310. (d) Bolm, C.; Magnus, A. S.; Hildebrand, J. P. Org.
Lett. 2000, 2, 1173. (e) Liu, R.; Liang, X.; Dong, C.; Hu, X. J. Am. Chem.
Soc. 2004, 126, 4112. (f) Shibuya, M.; Osada, Y.; Sasano, Y.; Tomizawa,
M.; Iwabuchi, Y. J. Am. Chem. Soc. 2011, 133, 6497.
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Chemistry of Heterocyclic Compounds; Hassner, A., Ed.; John Wiley &
Sons, Inc: New York, 1983; p 547.
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Greene, F. D.; Stowell, J. C.; Bergmark, W. R. J. Org. Chem. 1969, 34,
2254. (b) Du, H.; Zhao, B.; Shi, Y. Org. Synth. 2009, 86, 315.
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Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762. (b) Du, H.; Yuan,
W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 11688. (c) Du, H.;
Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496. (d) Du,
H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 8590. (e) Zhao, B.; Du,
H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
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Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9, 2589. (b) Du, H.; Zhao, B.;
Yuan, W.; Shi, Y. Org. Lett. 2008, 10, 4231. (c) Wen, Y.; Zhao, B.; Shi,
Y. Org. Lett. 2009, 11, 2365. (d) Zhao, B.; Du, H.; Shi, Y. J. Org. Chem.
2009, 74, 8392. (e) Zhao, B.; Peng, X.; Cui, S.; Shi, Y. J. Am. Chem. Soc.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Oxidation of Secondary Alcoholsa
a All reactions were carried out with alcohol 2 (0.60 mmol), di-tert-butyldiaziridinone (1) (0.66 mmol), and CuBr (0.060 mmol) in CH3CN (1.2 mL) at
rt under Ar unless otherwise stated. b Isolated yield. c The reaction was carried out on 10 mmol scale of 2c under open air. d The reaction was carried out at
60 °C. e The reaction was carried out with 0.90 mmol of 1 at 60 °C. f The reaction was carried out on 0.90 mmol scale of 2p. g The reaction was carried out
in CH3CN (2.0 mL) at 60 °C. h The reaction was carried out in CDCl3 (1.5 mL) at 60 °C. i The reaction was carried out with 1.14 mmol of 1 in CDCl3
(1.5 mL) at 60 °C. j The reaction was carried out in CH3CN (2.4 mL) at 60 °C.
Various acyclicand cyclicsecondarybenzylicalcoholswith
alkyl, cyclopropyl, vinyl, allyl, alkynyl, and thioether
groups were effectively oxidized to ketones in 73À99%
yields (Table 2, entries 1À13). As illustrated in the oxida-
tion of benzhydrol (2c) (Table 2, entry 3), the method is
amenable to gram scale. The oxidation can also be ex-
tended to a variety of nonbenzylic secondary alcohols,
giving the corresponding ketones in 74À99% yields
(Table 2, entries 14À28). Acyclic aliphatic alcohol 2o was
oxidized to ketone 3o in 99% yield (Table 2, entry 15).
Cyclic alcohols with variable ring sizes and substituents were
found to be effective substrates (Table 2, entries 16À28).
Acid-sensitive groups such as silyl ethers and ketal can be
tolerated (Table 2, entries 20 and 27). The mildness of
Org. Lett., Vol. XX, No. XX, XXXX
C

aldehydes in 63À96% yields (Table 3, entries 1À10).
Heterocyclic primary alcohols were smoothly oxidized to
give the aldehydes in good yields (Table 3, entries 11 and
12). In addition, allylic and aliphatic alcohols were also
effective substrates, giving the corresponding aldehydes in
70À90% yields (Table 3, entries 13À16).
Table 3. Oxidation of Primary Alcoholsa
While a precise understanding of the reaction mechanism
awaits further study, a plausible catalytic pathway is pro-
posed in Scheme 1. The CuBr first reductively cleaves the
NÀN bond of di-tert-butyldiaziridinone (1) to form four-
membered Cu(III) species A and/or Cu(II) nitrogen radical
B,22e,f which reacts with alcohol 2to generate alkoxy Cu(III)
species C. The β-H elimination of intermediate C affords
ketone 3 and Cu(III) species D, which undergoes reductive
elimination to form urea and regenerate the CuBr catalyst.
Scheme 1. Proposed Catalytic Cycle for the Oxidation
In summary, we developed a novel oxidation of alcohols
with CuBr as the catalyst and di-tert-butyldiaziridinone (1) as
the oxidant. Various primary and secondary alcohols can be
efficiently oxidized under mild conditions to the correspond-
ing aldehydes and ketones in high yields. The present process
exhibits the following favorable features: (1) the procedure is
effective for a wide range of substrates bearing various
functional groups, such as, alkenyl, alkynyl, thioether, silyl
ether, amide, carbamate, ketal, ester, and heterocycles; (2) the
reaction proceeds under neutral and mild conditions (no acid
or base required) making it compatible with acid- or base-
sensitive substrates; (3) the method is amenable to gram scale
with no special precautions to exclude air or moisture.
Further development of other reaction processes with diaziri-
dinones and related compounds is currently underway.
a All reactions were carried out with alcohol 4 (0.60 mmol), di-tert-
butyldiaziridinone (1) (0.66 mmol), and CuBr (0.060 mmol) in CH3CN
(1.2 mL) at 60 °C under Ar unless otherwise stated. b Isolated yield. c The
reaction was carried out with 0.72 mmol of 1. d The reaction was carried
out in CDCl3 (1.2 mL).
the reaction conditions was further demonstrated in the
oxidation of (1R,2S)-trans-2-phenyl-1-cyclohexanol (2bb)
(Table 2, entry 28). Ketone 3bb was obtained in 98%
yield, and no racemization of the R-stereocenter occurred
during the oxidation.
Acknowledgment. We are grateful for the generous
financial support from the General Medical Sciences of
the National Institutes of Health (GM083944-05).
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Primary alcohols were also found to be effective sub-
strates but generally less reactive than secondary alcohols.
To shorten the reaction time, the reaction temperature was
raised to 60 °C. Under these reaction conditions, various
benzylic alcohols with different substituents on the phenyl
ring can be efficiently oxidized to the corresponding
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX