Oxidation of primary amines to ketones

Article abstract of DOI:10.1055/s-0028-1083541

A simple method for the oxidation of primary amines to the corresponding ketones that proceeds in the presence of both moisture and air is described. Treatment of an amine with benzoyl peroxide in the presence of caesium carbonate, followed by warming of the hydroxylamine product to 50-70°C leads directly to the ketone. The method is shown to be effective for both benzylic and aliphatic substrates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083541

LETTER
2769
Oxidation of Primary Amines to Ketones
a
b
a
A
D
mine
O
xidation eborah A. Knowles, Christopher J. Mathews, Nicholas C. O. Tomkinson*
a
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Fax +44(2920)874030; E-mail: tomkinsonnc@cardiff.ac.uk
b
Chemistry Department, Syngenta, Jealotts Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, UK
Received 2 June 2008
and air, offering a practical alternative to existing method-
ology.
Abstract: A simple method for the oxidation of primary amines to
the corresponding ketones that proceeds in the presence of both
moisture and air is described. Treatment of an amine with benzoyl As part of our investigations into the chemistry of
peroxide in the presence of caesium carbonate, followed by warm-
ing of the hydroxylamine product to 50–70 °C leads directly to the
ketone. The method is shown to be effective for both benzylic and
aliphatic substrates.
17–21
hydroxylamines
we reacted N-cyclohexyl-O-benzoyl
hydroxylamine hydrochloride (2) with one equivalent of
heptan-4-one (1) and were surprised to observe the a-
functionalised cyclohexanone 7 as the major product. Ra-
tionalising that this could have arisen through decomposi-
tion of the reagent to give the imine 5 followed by
condensation with a second molecule of hydroxylamine 2
to give the intermediate enamine 6. Subsequent [3,3]-sig-
matropic rearrangement followed by hydrolysis of the re-
sulting imine then led to the observed product 7
Key words: amine, oxidation, hydroxylamine, benzoyl peroxide,
ketone
The ability of the chemist to manipulate the carbonyl
group in a chemo-, stereo- and enantioselective manner
has bestowed upon it a central role in synthetic chemis-
(
Scheme 1). Intrigued that if we were able to stop this pro-
1
try. New methods with which to prepare this functional-
cess at the intermediate imine 5 the transformation would
represent a new method for amine oxidation we sought to
examine this reaction further.
ity from readily available precursors are therefore of great
use to the synthetic chemist.
Amines represent a significant class of available building
blocks as well as fundamental synthetic intermediates
which are readily accessible. There have been a number of
reports describing the oxidation of amines to a wide vari-
ety of functional groups including imines, amides, nitriles,
aldehydes and ketones. Early methods reported for these
transformations include the use of stoichiometric transi-
O
O
1
DMSO, 50 °C
+
Ph
O
2
4 h
Ph
O
N
O
H
3
2
3
4
tion metal reagents including nickel-, mercury-, lead-,
O
⋅HCl
5
6
7
manganese-, iron-, and zinc-derived species. More re-
cently, catalytic methods have been described using
2
8
9
10
11
palladium as well as tungsten, rhodium ruthenium
and manganese salts. Stoichiometric methods avoiding
the use of transition metals have also been developed us-
O
1
2
Cy
O
Ph
N
OBz
2
[3,3]
BzOH +
O
1
3
14
+ H O
– CyNH2
–
NH
NH3
2
ing iodosobenzene, 2-iodoxybenzoic acid (IBX), sul-
1
5
16
fonyl peroxides, and benzoquinones. These methods
represent important alternatives to perform the overall ox-
idation of primary amines, with varied levels of scope and
limitations in substrate tolerance and reaction conditions.
Of the transition-metal free methods each optimised
method requires anhydrous reaction conditions and the
use of an inert atmosphere. Circumventing these practical
considerations would represent an advance in the methods
available for the overall transformation. Within this letter
we describe a simple method for the oxidation of primary
amines to the corresponding ketones that proceeds under
mild reaction conditions in the presence of both moisture
4
5
7
6
Scheme 1
Preparation of the substrates for the development of this
transformation used a robust and convenient method
reported by Phanstiel for the conversion of amines to
O-benzoyl hydroxylamines. Our key transformation was
optimised with the phenethylamine-derived hydroxyl-
amine 8 (Table 1). Use of 8·HCl in chloroform at 50 °C
proved to be inefficient (<10%) and resulted in a number
of unidentified by-products (entry 1). Heating of the free
base 8 resulted in recovery of starting material after a 48-
hour reaction period (entry 2). Addition of DBU (1 equiv)
significantly accelerated the reaction and provided the
product in an encouraging 30% yield (entry 3). Examina-
tion of alternative solvents showed polar solvents to be
2
2
2
3
SYNLETT 2008, No. 18, pp 2769–2772
1
4
.1
1
.2
0
0
8
Advanced online publication: 15.10.2008
DOI: 10.1055/s-0028-1083541; Art ID: D20008ST
©
Georg Thieme Verlag Stuttgart · New York

2
770
D. A. Knowles et al.
LETTER
more effective with DMF emerging as the optimal reac- Table 2 Scope of Conversion
tion medium (entries 3–5). Changing the base to caesium
carbonate improved the yield further with acetophenone
Entry Hydroxylamine
Product
Yield (%)
84
(
9) being isolated in an excellent 84% yield (entry 7). It
1a
was also found that catalytic quantities of caesium carbon-
ate could be used with 0.5 equivalent (entry 8) and 0.1
equivalent (entry 9) giving the product in 76% and 71%
isolated yields, respectively.
NHOBz
O
2a
3a
72
90
NHOBz
O
Table 1 Optimisation of Key Bond Formationa
OBz
Ph
N
Ph
O
H
NHOBz
O
8
9
F
F
4a
5a
6a
90
70
Entry
Reagent Base
Solvent
CHCl3
CHCl3
CHCl3
toluene
DMF
Temp (°C) Yield (%)e
<10f
NHOBz
O
1
8·HCl
none
none
DBU
DBU
DBU
DBU
50
50
50
50
50
70
50
50
50
MeO
MeO
2
8
8
8
8
8
8
8
8
0
30
34
66
70
84
76
71
3
NHOBz
O
4
5
NHOBz
O
75
6b
DMF
7
Cs CO
DMF
2
3
3
3
7b
8c
41
8c
Cs CO
DMF
NHOBz
2
O
9d
Cs CO
DMF
2
53d
NHOBz
O
a
All reactions were performed at 0.5 M concentration in the presence
of base (1 equiv) for 24 h unless stated otherwise.
b
Base (2 equiv) was added.
Base (0.5 equiv) was added.
Reaction was carried out for 48 h with base (0.1 equiv).
Isolated yield.
9c
0c
29
63
c
NHOBz
NHOBz
O
O
d
e
f
1
Estimated from H NMR.
1
1
Having established efficient conditions for the conversion
of 8 to acetophenone (9) we examined a series of alterna-
tive O-benzoyl hydroxylamines to determine some of the
scope of this transformation (Table 2). The reaction
1c
68
53
NHOBz
O
O
worked efficiently for both benzylic (entries 1–7) and ali- 12
phatic (entries 8–12) amines. Both electron-donating (en-
tries 2 and 4) and electron-withdrawing (entry 3)
NHOBz
a
substituents were tolerated on the aromatic ring as well as
increased steric crowding around the reactive nitrogen
Reaction was performed at 50 °C.
Reaction was performed at 25 °C.
Reaction was performed at 70 °C.
b
c
(
entries 5 and 6). The conversion of N-benzyl-O-benzoyl
d
Product isolated as the 2,4-dinitrophenylhydrazine (2,4-DNPH)
derivative.
hydroxylamine to benzaldehyde was particularly facile,
the reaction proceeding at room temperature, however,
this was accompanied by significant decomposition lead-
ing to a reduced isolated yield of the product (41%; entry
tively leading to the expected product, suggesting the re-
action should have a reasonable scope.
7
). It was expected that enolisable aldehydes would be in-
Finally, having developed effective conditions for the
conversion of O-benzoyl hydroxylamines to the corre-
sponding ketone we sought to discover if a one-pot meth-
od for the direct conversion of primary amines to ketones
could also be established. The synthesis of O-benzoyl hy-
droxylamines from primary amines has been shown to be
most efficient under basic reaction conditions. Reported
herently unstable to the basic reaction conditions required
for this transformation; therefore these substrates were not
examined. The conditions are mild enough to be able to
carry out the reaction on substrates that lead to enolisable
ketones (entries 8–12) with all substrates examined effec-
Synlett 2008, No. 18, 2769–2772 © Thieme Stuttgart · New York

LETTER
Amine Oxidation
2771
2
2
bases for this transformation include sodium carbonate,
References and Notes
2
4
25
sodium hydroxide, tert-butylamine and disodium hy-
(
1) Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH:
Weinheim, 2000.
2
6
drogen phosphate. Pleasingly, caesium carbonate was
found to be effective in the reaction of primary amines
with benzoyl peroxide allowing for the direct conversion
of primary amines to ketones. Treatment of a cooled DMF
solution of caesium carbonate (1.5 equiv) and benzoyl
peroxide (1.0 equiv) with the primary amine (1.2 equiv)
followed by warming of the reaction mixture led directly
to the corresponding ketone (Table 3). The reaction was
effective for both benzylic (entries 1–4) and aliphatic (en-
try 5) primary amines and provides a convenient alterna-
tive for this overall transformation.
(2) Nakagawa, K.; Onoue, H.; Sugita, J. Chem. Pharm. Bull.
1964, 12, 1135.
(3) Orito, K.; Hatakeyama, T.; Takeo, M.; Uchiito, S.; Tokuda,
M.; Suginome, H. Tetrahedron 1998, 54, 8403.
4) Stephens, F. F.; Bower, J. D. J. Chem. Soc. 1949, 2971.
5) (a) Rawalay, S. S.; Shechter, H. J. Org. Chem. 1967, 32,
(
(
3129. (b) Noureldin, N. A.; Bellegarde, J. W. Synthesis
1
999, 939.
(
6) Audette, R. J.; Quail, J. W.; Smith, P. J. Tetrahedron Lett.
1971, 279.
(7) Chen, H. G.; Knochel, P. Tetrahedron Lett. 1988, 29, 6701.
(8) Miyazawa, A.; Tanaka, K.; Sakakura, T.; Tashiro, M.;
Table 3 One-Pot Transformation27
Tashiro, H.; Prakash, G. K. S.; Olah, G. A. Chem. Commun.
2005, 2104.
R2
R2
Bz O , Cs CO
2
2
2
3
(9) Hamamoto, H.; Suzuki, Y.; Takahashi, H.; Ikegami, S.
Tetrahedron Lett. 2007, 48, 4239.
10) Choi, H.; Doyle, M. P. Chem. Commun. 2007, 745.
11) Murahashi, S.-I.; Komiya, N. In Modern Oxidation
Methods; Backvall, J.-E., Ed.; Wiley-VCH: Weinheim,
2004, 175–179.
R1
NH2
DMF, 0 °C then ∆
R1
O
(
(
Entry Amine
1
Ketone
Yield (%)
59
(
(
(
12) Larsen, J.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 2
NH2
O
1992, 1213.
13) Moriarty, R. M.; Vaid, R. K.; Duncan, M. P. Tetrahedron
Lett. 1988, 29, 6913.
14) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am.
Chem. Soc. 2004, 126, 5192.
2
3
66
57
NH2
O
(
(
(
15) Hoffman, R. V. J. Am. Chem. Soc. 1976, 98, 6702.
16) Corey, E. J.; Achiwa, K. J. Am. Chem. Soc. 1969, 91, 1429.
17) For the a-oxyacylation of carbonyl compounds, see:
(a) Beshara, C. S.; Hall, A.; Jenkins, R. L.; Jones, K. L.;
Jones, T. C.; Killeen, N. M.; Taylor, P. H.; Thomas, S. P.;
Tomkinson, N. C. O. Org. Lett. 2005, 7, 5729. (b) Beshara,
C. S.; Hall, A.; Jenkins, R. L.; Jones, T. C.; Parry, R. T.;
Thomas, S. P.; Tomkinson, N. C. O. Chem. Commun. 2005,
NH2
O
F
F
4
69
59
NH2
O
1478. (c) Jones, T. C.; Tomkinson, N. C. O. Org. Synth.
2007, 233.
MeO
MeO
(
(
(
(
18) For the formation of carbamates, see: Hall, A.; Huguet, E. P.;
Jones, K. L.; Jones, T. C.; Killeen, N. M.; Yau, S. C.;
Tomkinson, N. C. O. Synlett 2007, 293.
19) For the formation of carbonates, see: Hall, A.; Jones, K. L.;
Jones, T. C.; Killeen, N. M.; Porzig, R.; Taylor, P. H.; Yau,
S. C.; Tomkinson, N. C. O. Synlett 2006, 3435.
5
NH2
O
20) For the a-oxysulfonylation of carbonyl compounds, see:
John, O. R. S.; Killeen, N. M.; Knowles, D. A.; Yau, S. C.;
Tomkinson, N. C. O. Org. Lett. 2007, 9, 4009.
21) For the N-arylation of hydroxylamines, see: Jones, K. L.;
Porzelle, A.; Hall, A.; Woodrow, M. D.; Tomkinson, N. C.
O. Org. Lett. 2008, 10, 797.
In summary, we have shown that O-benzoyl hydroxyl-
amines can efficiently be converted into the correspond-
ing ketones by treatment with caesium carbonate.27 The
reactions are simple to perform in the presence of both
moisture and air and lead to the product in good to excel-
lent yield. A direct method for the conversion of primary
amines to ketones was also shown to be possible by reac-
tion of a primary amine and benzoyl peroxide under basic
reaction conditions. The reactions are effective for both
benzylic and aliphatic primary amines and a variety of
substitution patterns on the parent amine.
(22) Wang, Q. X.; King, J.; Phanstiel, O. I. V. J. Org. Chem.
997, 62, 8104.
23) All the known ketones prepared in this study were
1
(
1
13
characterised by H NMR, C NMR, IR and LRMS.
24) Roy, R. B.; Swan, G. A. J. Chem. Soc. C 1968, 80.
25) Alewood, P. F.; Calder, I. C.; Richardson, R. L. Synthesis
(
(
1
981, 121.
26) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126,
680.
(
(
5
Acknowledgment
27) Typical Procedure for Conversion of N-Alkyl-O-benzoyl
Hydroxylamines to Ketones: N-a-Methyl benzyl-O-
benzoyl hydroxylamine (100 mg, 0.41 mmol) was dissolved
in DMF (0.59 mL) at ambient temperature. Caesium
carbonate (135 mg, 0.41 mmol) was added and the resulting
reaction mixture was heated at 50 °C overnight. The
resulting reaction mixture was allowed to cool and purified
The authors thank Dr Tom Sheppard for insightful discussions, the
EPSRC and Syngenta for financial support and the Mass Spectro-
metry Service, Swansea for high-resolution spectra.
Synlett 2008, No. 18, 2769–2772 © Thieme Stuttgart · New York

2
772
D. A. Knowles et al.
LETTER
directly by column chromatography, eluting with 20%
EtOAc–PE, to give acetophenone (42 mg, 84%) as a clear
colourless oil. IR (thin film): 1683, 1599, 1582, 1449, 1359,
mL, 1.21 mmol). The resulting reaction mixture was stirred
at 0 °C for 2 h before warming to r.t. TLC was used to
confirm complete consumption of benzoyl peroxide before
heating at 50 °C overnight. The resulting reaction mixture
was purified directly by column chromatography, eluting
with 20% EtOAc–PE, to give cyclohexyl methyl ketone
(75 mg, 59%) as a clear colourless oil. IR (thin film): 2931,
–
1 1
1266, 1180, 1078, 1025, 955, 760, 690 cm . H NMR (400
MHz, CDCl ): d = 7.85 (d, J = 7.2 Hz, 2 H), 7.45 (t, J = 7.3
3
1
3
Hz, 1 H), 7.40–7.30 (m, 2 H), 2.50 (s, 3 H). C NMR (100
MHz, CDCl ): d = 198.1, 137.1, 133.1, 128.6, 128.3, 26.6.
3
+
–1 1
MS (EI): m/z = 120.06 [M] .
2854, 1706 cm . H NMR (400 MHz, CDCl ): d = 2.3–2.1
3
Typical Procedure for the One-Pot Conversion of
Primary Amines to Ketones: Benzoyl peroxide (326 mg,
(m, 1 H), 2.05 (s, 3 H), 1.80–1.85 (m, 2 H), 1.70–1.75 (m,
1
3
2 H), 1.55–1.65 (m, 1 H), 1.05–1.30 (m, 5 H). C NMR (100
1
.01 mmol, 75%) was dissolved in DMF (2.53 mL) and
MHz, CDCl ): d = 212.2, 51.4, 28.4, 27.8, 25.8, 25.6. MS
3
+
cooled to 0 °C. Caesium carbonate (493 mg, 1.51 mmol) was
added with stirring followed by cyclohexyl ethylamine (0.18
(EI): m/z = 126.22 [M] .
Synlett 2008, No. 18, 2769–2772 © Thieme Stuttgart · New York

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