A novel and efficient oxidation of 1,2-amino alcohols to dialkylamides

Article abstract of DOI:10.1055/s-2002-35602

The oxidation of 1,2-amino alcohols and α-amino ketones can be efficiently performed using potassium hydroxide in the presence of air. This novel procedure affords carboxylic derivatives in excellent yields and high purity.

Full text of DOI:10.1055/s-2002-35602

LETTER
2092
A Novel and Efficient Oxidation of 1,2-Amino Alcohols to Dialkylamides
a
b
b
E
M
fficient oxidation of
1
a
,2-amino a
r
lcohols ía García-Valverde,* Rafael Pedrosa,* Martina Vicente
a
Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Bañuelos s/n 09001-Burgos, Spain
Fax +34(947)258087; E-mail: magaval@ubu.es
b
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n 47011-Valladolid, Spain
Received 22 August 2002
Table 1 Oxidation of 1,2-Amino Alcohols9
Abstract: The oxidation of 1,2-amino alcohols and -amino ke-
tones can be efficiently performed using potassium hydroxide in the
presence of air. This novel procedure affords carboxylic derivatives
in excellent yields and high purity.
R1
R2
R3
R4
R5
Amino
alcohol
T
(h)
Amide
(%)
10
11
1
1
1
1
1
1
a
b
c
d
e
f
H
H
Me
Me
Et
Me
Bn
Me
Bn
90
2a (73)
Key words: 1,2-amino alcohols -amino ketones, oxidations, po-
tassium hydroxide, radical reactions
H
H
90
90
54
90
90
68
2b (68)a
H
H
Me
Me
Me
Me
Bn
Me
Me
Me
Me
Bn
2c (84)
Several procedures have been employed in the oxidation
of compounds such as 1,2-diamines, 1,2-amino alco-
2d (69)a
H
H
Ph
1
,2
3
4
5
Me
Ph
Ph
Ph
H
H
H
2e (74)
2f (92)
2g (72)a
2h (91)
–b
hols, cyanoamines, enamines and enol-ethers with
concomitant cleavage of the central carbon-carbon bond.
These processes involved different oxidants such as
H
Me
Me
Me
Me
Me
1
3,4
4
dioxiranes , O with catalyst, potassium dichromate, or 1g
H
2
2
electron-transfer reactions induced by radiation or by cat-
1
h
H
n-Bu
Bn
n-Bu 90
Bn 90
Me 240
Me 90
5
alyst. The usefulness of these procedures in organic syn-
thesis needs cheap and environmentally acceptable 1i
Me
Me
H
methods of wider scope. In the course of our research6
,7
1
j
H
Me
–c
we were looking for some efficient methods for the cleav-
age of amino alcohol auxiliaries that were useful for chiral 1k
H
–(CH ) -
2k (87)
2
4
deprotection. In this paper, we wish to report a new and ef-
ficient way to perform the oxidation of amino alcohols
and amino ketones to dialkylamides and carboxylic acids.
a
The easy debenzylation could explain the lower yields obtained,
benzylamines were obtained as sub-products.
Benzylamine is obtained as the only product.
b
c
The starting amino alcohol was recovered unchanged.
Amino alcohols 1a–k were treated with an excess of po-
tassium hydroxide in different solvents under aerobic
8
conditions in vigorously stirred heterogeneous media
tion of intermediate enamines resulting from dehydration
of the starting amino alcohols, because the photooxidation
(
Scheme 1). The method works well with N,N-dialkyl-
amino alcohols and all sorts of solvents (hexane, THF, di-
ethyl ether, toluene, benzene…), except protic and
halogenated solvents. Table 1 shows the reagents and
products obtained by this method.
of enamines with C-C bond cleavage is a well-known pro-
4,12
cess.
Nevertheless, when the reaction was performed
by using enamines as the starting material, we did not ob-
tain amides in good yields (the enamine corresponding to
the amino alcohol 1g treated with KOH under air atmo-
sphere yielded the amide 2g in only 4% yield).
R1
R2
OH
N
R5
R1
O
OH
1
. KOH, air
R4
R4
2. H O+
R3
+
O
The reaction progress was followed by GC/MS, showing
that amino ketones were formed as intermediates in all of
the cases studied; although the amino ketone is more reac-
tive than the starting amino alcohol, this intermediate
could undoubtedly be detected by HPLC using reference
substances. To test the mechanism we then subjected the
3
N
R3
R5
1a-k
2a-k
3
Scheme 1
1
,2-amino ketones 4e–h,l to reaction with an excess of
A requirement for the process, is the presence of at least
one hydrogen in the -position to the amino group. We
thought that the reaction could initially involve the forma-
KOH under the same reaction conditions (Scheme 2). Of
course, when we employed amino ketones the reaction
was faster but with comparable yields (Table 2).
To accelerate the reaction we added benzophenone as hy-
dride acceptor to favor an Oppenauer-like process from
the starting amino alcohols to the intermediate -amino
ketones 4, expecting that diphenylmethanol could be ob-
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,2092,2094,ftx,en;G24502ST.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Efficient oxidation of 1,2-amino alcohols
2093
R1
R1
In summary, we have discovered a powerful and efficient
oxidation procedure for the conversion of 1,2-amino alco-
hols into amides and the oxidative decarbonylation of
-aminocarbonyl compounds to the corresponding carb-
oxylic derivatives. The main advantages are the simplicity
of the procedure, which involves only cheap potassium
hydroxide, and the high yields.
O
N
O
OH
1
. KOH, air
R4
R4
R5
2. H O+
R3
R3
+
O
3
N
R5
4
e,f,h,l
2e,f,h,l
3
Scheme 2
Table 2 Oxidation of 1,2-Amino Ketones
Acknowledgment
Amino R1
ketone13
R3
R4
R5
T (h) Amide
We gratefully acknowledge financial support from the University of
Burgos (Project FWF P-11994-CHE).
11
(%)
4
4
4
4
e
Me
Ph
Ph
Ph
H
Me
Me
Me
Me
40
30
2e (79)
2f (90)
2h (87)
2l (92)
References
f
Me
Me
Ph
(
1) Camps, P.; Muñoz-Torrero, D.; Muñoz-Torrero, V.
Tetrahedron Lett. 1995, 36, 1917.
h
l
nBu
nBu 30
30
4
(
2) (a) Burton, R. D.; Bartberger, M. D.; Zhang, Y.; Eyler, J. R.;
Schanze, K. S. J. Am. Chem. Soc. 1996, 118, 5655.
–(CH ) -
2
(
b) Chen, L. H.; Farahat, M. S.; Gaillard, E. R.; Farid, S.;
Whitten, D. G. J. Photochem. Photobiol. A: Chem. 1996, 95,
tained as by-product. Instead we isolated triphenylmetha-
nol and benzoic acid besides the carboxylic derivatives 2
and 3 (Scheme 3).
21. (c) Kellett, M. A.; Whitten, D. G. Res. Chem. Intermed.
1995, 21, 587. (d) Gan, H.; Kellett, M. A.; Leon, J. W.;
Kloeppner, L.; Leinhos, U.; Gould, I. R.; Farid, S.; Whitten,
D. G. J. Photochem. Photobiol. A: Chem. 1994, 82, 211.
3) Yuste, F.; Origel, A. E.; Breña, L. J. Synthesis 1983, 109.
4) (a) Benhaliliba, H.; Derdour, A.; Bazureau, J.-P.; Texier-
Boullet, F.; Hamelin, J. Tetrahedron Lett. 1998, 39, 541.
(b) Harris, C. E.; Lee, L. Y.; Dorr, H.; Singaram, B.
Tetrahedron Lett. 1995, 36, 2921; and references therein.
5) Lopez, L.; Troisi, L. Tetrahedron Lett. 1992, 48, 7321.
6) García-Valverde, M.; Pedrosa, R.; Vicente, M.; García-
Granda, S.; Gutiérrez-Rodríguez, A. Tetrahedron 1996, 52,
10761.
A careful examination of the literature showed that these
derivatives are typically produced in radical reactions.14
Indeed, EPR studies of reaction mixtures at different
reaction times confirmed the radical mechanism of the re-
actions of amino alcohols and amino ketones when they
(
(
1
5
(
(
were treated with KOH in the presence of air.
In order to evaluate the synthetic advantages of this meth-
od we then applied the reaction to a chiral amino alcohol.
The cleavage of chiral amino alcohols has been reported16
but the scope of these methods is limited because of the
structural requirements of the substrates. The substrate
employed in this study was obtained from the bicyclic lac-
(7) García-Valverde, M.; Nieto, J.; Pedrosa, R.; Vicente, M.
Tetrahedron 1999, 55, 2755.
(
8) For oxidations under air in strongly basic solutions, see:
a) Elkik, E. Bull. Soc. Chim. Fr. 1959, 933. (b) Russell, G.
A.; Bemis, A. G. J. Am. Chem. Soc. 1966, 88, 5491.
c) Gersmann, H. R.; Bickel, A. F. J. Chem. Soc. B 1971,
(
1
7
tam 5, which was in turn obtained by a known proce-
(
6
dure. Thus, the treatment of 5 with LiAlH /AlCl3
4
2230. (d) Neumann, R.; Sasson, Y. J. Org. Chem. 1984, 49,
followed by an acidic work-up led to the amonium salt 1m
as a pure enantiomer. Treatment of 1m with KOH in the
presence of air afforded the N-acetylpyrrolidine 2m18 in
almost quantitative yield with no epimerization at the ste-
reogenic center of the pyrrolidine moiety (Scheme 4).
1282.
(9) Typical experimental procedure: The amino alcohol (1a–k)
0.1 g) was added to a stirred suspension of KOH (1.0 g) in
(
diethyl ether (20 mL). The stirring was continued for the
proper time (Table 1) at room temperature. The solid was
filtered off and washed with ether. The solvent was removed
to yield the amide. The solid was dissolved in water and the
OH
O
R1
R2
OH
O
O
R1
OH
KOH
+
+
+
+
R2
NR4
Ph
Ph Ph
OH
NR42
Ph
Ph
O
2
Ph
1
2
3
Scheme 3
Ph
Me
O
N
Ph
OH
N
O
H
1. LiAlH4, AlCl3
1. KOH, air
+
–
10 °C
2
r.t., 2h
. H O+
2. H O
3
Me
N
Me
3
H
Bn
Bn
Bn
O
5
1m
2m
Scheme 4
Synlett 2002, No. 12, 2092–2094 ISSN 0936-5214 © Thieme Stuttgart · New York

2
094
M. García-Valverde et al.
LETTER
solution acidified with HCl and extracted with ether. The
organic layer was dried and the solvent was removed to yield
the corresponding carboxylic acid.
4h (67%). Colorless liquid. bp 82–84 (0.2 mmHg). IR (neat,
–
1
1
cm ): 1685. H NMR (CDCl , 200 MHz): 0.79 (t, 6 H, J =
3
12 Hz); 1.04–1.21 (m, 7 H), 1.22–1.38 (m, 4 H); 2.40 (t, 4 H,
(
10) The starting amino alcohols were purchased from the usual
J = 12 Hz); 4.31 (q, 1 H, J = 9.0 Hz); 7.22–7.50 (m, 3 H);
1
3
suppliers (1e: 1-dimethylamino-2-propanol, 1f: N-
methylephedrine, 1j: 2-dimethylamino-2-methyl-1-
propanol, 1k: 1-methyl-2-piperidinemethanol) or
synthesized by literature procedures: (a) 1a (2-
dimethylamino-1-propanol): Rosnati, V. Gazz. Chim. Ital.
7.94–8.00 (m, 2 H). C NMR (CDCl , 50 MHz): 9.2 (CH );
3
3
14.0 (CH ); 20.4 (CH ); 30.7 (CH ); 50.7 (CH ); 60.4 (CH);
3
2
2
2
128.1 (CH );128.9 (CH ); 132.4 (CH ); 137.0 (C ); 201.8
Ar
Ar
Ar
Ar
+
(CO). MS (m/z, %): 260 (M – 1, 1), 156(100). Anal. Calcd
for C H NO: C, 78.11; H, 10.41; N, 5.36. Found: C, 78.22;
1
7
27
1
(
950, 80, 663. (b) 1b (2-Dibenzylamino-1-propanol) and 1i
2-Dibenzylamino-2-methyl-1-propanol): Kerwin, J. F.;
Ullyot, G. E.; Fuson, R. C.; Zirkle, C. L. J. Am. Chem. Soc.
947, 69, 2961. (c) 1c (2-Dimethylamino-1-butanol):
H, 10.63; N, 5.27.
(14) (a) Turaeva, D. A.; Kurbatov, Y. V. Russ. J. Org. Chem.
1999, 1092. (b) Turaeva, D. A.; Kurbatov, Y. V.; Kurbatova,
A. S. Russ. J. Org. Chem. 1995, 739.
1
Halverstadt, I. F.; Hardie, W. R.; Willians, A. R. J. Am.
Chem. Soc. 1959, 81, 3618. (d) 1d (2-Dimethylamino-2-
phenylethanol): Miyano, S.; Lu, L. D.-L.; Viti, S. M.;
Sharpless, K. B. J. Org. Chem. 1985, 50, 4350. (e) 1g (2-
Dibenzylamino-1-phenyl-1-propanol): Schwan, T. J.;
Lougheed, G. S.; Burrous, S. E. J. Heterocyclic Chem. 1974,
(15) The EPR studies were made on the reaction mixtures without
filtration. Moreover, the evolution of the EPR spectra taken
at different reaction times showed the presence of mixtures
of radicals as intermediates in these reactions.
(16) (a) Neelakantan, L. J. Org. Chem. 1971, 36, 2256.
(b) Alcaide, B.; López-Mardomingo, C.; Pérez-Ossorio, R.;
Plumet, J. J. Heterocyclic Chem. 1982, 19, 45. (c) Wu, M.
J.; Pridgen, L. N. Synlett 1990, 636. (d) Aylward, J. B.
Quart. Rev. 1971, 25, 407. (e) Royer, J.; Hüsson, H. P. J.
Org. Chem. 1985, 50, 636.
1
1, 807. (f) 1h (2-Butylamino-1-phenyl-1-propanol): Soai,
K.; Yokoyama, S.; Hayasaka, T. J. Org. Chem. 1991, 56,
264.
11) The resulting amides 2a, 2f (dimethylacetamide); 2b, 2g
dibenzylacetamide); 2h (dibutylacetamide); 2c (dimethyl-
4
(
(
(17) NOESY experiments showed that the angular oxazolidine
proton at C-7a was trans to the proton at C-6, indicating an
S configuration at this carbon. (2S,3R,6S,7aR)-6-Benzyl-2-
phenyl-3-methyl-5-oxo-2,3,5,6,7,7a-hexahydro-pyrrolo-
propanamide); 2d (dimethylbenzamide); 2e (dimethyl-
formamide); 2k (1-methyl-2-piperidone) are commercial
products or described in literature; 2l (1-acetylpyrrol-idine):
Al-Sehemi, A. G.; Atkinson, R. S.; Fawcett, J. J. Chem. Soc.,
Perkin Trans 1 2002, 257.
2
3
[2,1-b]-oxazole (5). White solid, mp 101–103 ºC. [ ]
D
–
1
1
+34.6 (c 1.6, CHCl ). IR (neat, cm ) 1700. H NMR
3
(
(
12) (a) Huber, J. E. Tetrahedron Lett. 1968, 3271. (b) Foote, C.
S.; Dzakpasu, A. A.; Lin, J. W.-P. Tetrahedron Lett. 1975,
(CDCl , 300 MHz): 1.00 (d, J = 6.8 Hz, 3 H), 2.19–2.23 (m,
3
2 H), 2.88 (dd, J = 13.2 Hz, 8.2 Hz, 1 H), 3.06–3.18 (m, 2 H),
3.95 (qd, J = 6.9 Hz, 6.8 Hz, 1 H), 4.95 (t, J = 5.4 Hz, 1 H),
1247. (c) Wasserman, H. H.; Terao, S. Tetrahedron Lett.
1
3
1975, 1735.
5.19 (d, J = 7.1 Hz, 1 H), 7.20–7.37 (m, 5 H, HAr). C NMR
13) (a) The starting amino ketones were purchased from the
usual suppliers (4e: 1-dimethylamino-2-propanone);
(CDCl , 75 MHz): 13.4 (CH ), 30.7 (CH ), 37.6 (CH ), 48.6
3
3
2
2
(CH), 54.7 (CH), 85.3(CH), 91.2 (CH), 126.6 (CH ), 128.0
Ar
synthesized by literature procedures. 4f (2-dimethylamino-
(CH ), 128.3 (CH ), 128.5 (CH ), 129.1 (CH ), 136.3
Ar
Ar
Ar
Ar
1
-phenyl-1-propanone): Welle, F.; Verevkin, S. P.; Keller,
M.; Beckhaus, H.-D.; Ruechardt, C. Chem. Ber. 1994, 127,
97. (b) 4l ( -Phenyl- -pyrrolidinoacetophenone):
Heinzelman, R. V.; Aspergren, B. D. J. Am. Chem. Soc.
953, 75, 3409; or synthesized by known methods. (c) 4h:
2-Dibutylamino-1-phenyl-1-propanone): Pyridinium
(C ), 138.5 (C ), 175.5 (CO). Anal.calcd for C H NO : C,
78.15; H, 6.89; N, 4.56. Found: C, 77.77; H, 7.08; N, 4.35.
Ar Ar 20 21 2
6
(18) Two isomers were observed at room temperature. (R)-1-
2
3
Acetyl-2-benzyl pyrrolidine (2m). Colorless oil. [ ]
D
–
1
1
(
+25.54 (c 1.1, CHCl ), IR (neat, cm ) 1650. MS (m/z, %):
203 (M , 32), 91(28), 43(100). H NMR (CDCl , 300 MHz):
3
+
1
3
chlorochromate (1.29 g, 6 mmol) was added in small
portions to a stirred solution of amino alcohol 1h (0.39 g, 1.5
mmol) in CH Cl (30 mL) over 4 Å sieves. The resulting
1.53–1.75 (m, 2 H), 1.95–2.05 (m, 8 H), 2.41–2.52 (m, 2 H),
2.62–2.69 (m, 4 H), 3.03–3.12 (m, 2 H), 3.33–3.58 (m, 4 H),
1
3
3.61–3.68 (m, 2 H), 7.14–7.33 (m, 5 H, HAr). C NMR
(CDCl , 75 Mz): 22.2 (CH ), 22.4 (CH ), 30.4 (CH ), 31.7
2
2
mixture was stirred at r.t. for 6 h and filtered. The solvent
was evaporated under reduced pressure. The residue was
dissolved in an aqueous solution of NaOH (15% w/v, 10 mL)
and extracted with ether. The organic layer was separated,
washed with brine and dried (Na SO ). Removal of the
3
3
3
2
(CH ), 39.0 (CH ), 39.6 (CH), 41.1 (CH), 45.1 (CH ), 46.9
2
2
2
(CH ), 50.7 (CH ), 52.5 (CH ), 126.2 (CH ), 126.3 (CH ),
2
2
2
Ar
Ar
128.4 (CH ), 128.5 (CH ), 128.6 (CH ), 139.9 (C ),
Ar
Ar
Ar
Ar
169.2 (CO). Anal. Calcd for C H NO: C, 76.81; H, 8.43; N,
2
4
13 17
solvent left a residue, which was purified by column
6.89. Found: C, 76.70; H, 8.62; N, 6.76.
chromatography (hexane/EtOAc, 6:1) to yield amino ketone
Synlett 2002, No. 12, 2092–2094 ISSN 0936-5214 © Thieme Stuttgart · New York