Oxidation of secondary amines catalyzed by dirhodium caprolactamate

Article abstract of DOI:10.1039/b615805f

The dirhodium caprolactamate [Rh₂(cap)₄] catalyzed oxidation of secondary amines to imines by tert-butyl hydroperoxide (TBHP) occurs with high chemo- and regioselectivity. The Royal Society of Chemistry.

Full text of DOI:10.1039/b615805f

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Oxidation of secondary amines catalyzed by dirhodium
caprolactamate{
Hojae Choi and Michael P. Doyle*
Received (in Bloomington, IN, USA) 31st October 2006, Accepted 8th December 2006
First published as an Advance Article on the web 9th January 2007
DOI: 10.1039/b615805f
The dirhodium caprolactamate [Rh
of secondary amines to imines by tert-butyl hydroperoxide
TBHP) occurs with high chemo- and regioselectivity.
2
(cap)
4
] catalyzed oxidation
Table 1 Optimization of the conditions for the oxidation of
benzylphenylamine
a
(
The dehydrogenation of secondary amines to imines is of current
1
and intense interest. Stoichiometric methods in synthetic applica-
2
tions using hypervalent iodine reagents, phenylselenic anhydride,
3
b
Conv. (%) 2 : 3
b
Entry
R
Conditions
4
and N-tert-butylphenylsulfinimidoyl chloride have generally
1
2
3
4
5
6
7
8
a
Ph CH
Ph CH
Ph CH
Ph CH
Ph MeOH
Cy MeOH
Ph CH CN
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
, NaHCO
3
(50 mol %) . 95
. 95
48 : 52
80 : 20
90 : 10
90 : 10
. 95 : 5
—
replaced older methods using metal salts. Catalytic processes that
employ tert-butyl hydroperoxide (TBHP) have been reported with
˚
, 4 A MS (50 wt %)
, MgSO (1 equiv)
4
28
56
. 95
0
. 95 (94)c
. 95 (90)
5
6
ruthenium(II) chloride and with a cobalt Schiff base complex, but
these early examples were optimally performed in benzene or
DMSO and were limited in scope. Other metal–oxidant combina-
c
3
. 95 : 5
. 95 : 5
7
tions have been described with mixed results, but the developing
Cy CH CN
3
successes with ruthenium-catalyzed aerobic oxidations of B a¨ ckvall
8
and coworkers are worthy of note. We have recently reported
2 4
Reactions were performed using Rh (cap) (1.0 mol %), amine
(
room temperature for 16 hours.
1.0 equiv), t-BuOOH (6.5 M in decane, 2.0 equiv), and solvent at
b 1
Determined by
H NMR.
highly efficient hydrocarbon oxidations by tert-butyl hydroper-
9
oxide catalyzed by rhodium(II) caprolactamate. When extended
c
Isolated yield of analytically pure compound.
10
to oxidations of selected tertiary amines, this oxidation provided
a means for functionalization on the carbon adjacent to nitrogen,
presumably through an iminium ion intermediate (eqn. 1). The
potential of this mild methodology that uses low catalyst loading
to oxidize secondary amines generally (eqn. 2) was suggested by
these results.
1
0
choice for the oxidation of N-aryl tertiary amines, was found be
effective (entry 5); however, when N-cyclohexylbenzylamine was
submitted to reaction under the same conditions, no imine product
was obtained at room temperature (entry 6), and only trace
amounts were obtained at temperatures up to 60 uC. However, the
use of acetonitrile as the solvent gave optimal results for both
N-phenyl- and N-cyclohexylbenzylamine substrates (entries 7 and
ð1Þ
8
) with quantitative conversion, chromatographically pure product
in high yield, and the absence of hydrolysis. We assume that steric
effects in the two solvents are responsible for the difference in
reaction outcomes (entries 6 and 8).
ð2Þ
Results from the oxidation of representative secondary amines
under conditions optimized for 1 are reported in Table 2. In
N-Phenylbenzylamine (1) was selected to determine suitable
contrast to the ruthenium-catalyzed oxidation process of B a¨ ckvall
8
conditions for oxidation with TBHP catalyzed by Rh (cap)
2
4
at
and coworkers,
the dirhodium-catalyzed oxidation of
1
.0 mol % catalyst loading (Table 1). Previously described
N-phenylbenzylamines with electronically diverse substituents at
the para position (entries 1–3) gives the corresponding imines in
nearly quantitative yield. The reaction conditions employed allow
the same transformation to occur with the furanyl analog (entry 4).
N-Phenylcinnamylamine is oxidized to the a,b-unsaturated imine
in high yield despite the potential for allylic oxidative amidation
9
b
conditions for benzylic oxidation (entry 1) gave complete
conversion of 1, but benzylideneaniline (2) was accompanied by
its hydrolysis product benzaldehyde (3). Benzaldehyde formation
with complete substrate conversion was diminished in the absence
of NaHCO3 (entry 2). Attempts to decrease the extent of
hydrolysis even further using molecular sieves or anhydrous
(entry 6). Regioselective oxidation is observed for N-benzyl-N-1-
MgSO
4
were unsuccessful (entries 3 and 4) because they
phenethylamine which yielded aldimine to the exclusion of
ketimine (entry 7). In addition, the presence of a pendant alcohol
does not interfere with amine oxidation, indicating a high degree of
functional group tolerance (entries 8 and 9). Moreover, complete
retention of configuration at the benzylic position adjacent to
nitrogen is observed for the oxidation of (R)-N-benzyl-
significantly limited the oxidation of 1. Methanol, the solvent of
Department of Chemistry and Biochemistry, University of Maryland,
College Park, MD, 20742, USA. E-mail: mdoyle3@umd.edu;
Fax: 301-314-2779; Tel: 301-405-8388
{ Electronic supplementary information (ESI) available: Experimental
details and NMR data for 7. See DOI: 10.1039/b615805f
11
phenylglycinol (entry 9). N-Alkylbenzylamines (entries 10 and
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a
4
Table 2 Oxidation of secondary amines with Rh
2
(cap)
Pyrrolo[2,1-c][1,4]benzodiazepine (PBD)-based compounds have
b
received considerable attention as potential antitumor and gene
Entry Amine
Imine
yield
13
targeted drugs. A member of this class, DC-81 analog 7 (62%)
was obtained via amine oxidation of 6 using stoichiometric PIFA
1
4
(
PhI(O CCF ) ) in CF CH OH or (CF ) CHOH. Catalysis with
2 3 2 3 2 3 2
Rh (cap) and t-BuOOH in CH CN gave rapid conversion to the
2
4
3
desired eneamine tautomer exclusively (not shown). We surmised
that tautomerization was likely the result of using a polar solvent
1
2
3
4
R = H
R = OMe
R = NO
R = H
R = OMe
R = NO
2
94
92
93
84
2
and mildly acidic t-BuOOH. Therefore, using CH
buffered with K CO as a mild base, imine 7 was obtained
exclusively in 80% yield (eqn. 4).
2 2
Cl sufficiently
2
3
5
6
95
87
ð3Þ
ð4Þ
7
81
8
9
74
90
In summary, we have developed a mild, efficient, and selective
oxidation of 2u amines catalyzed by Rh (cap) . Further investiga-
2
4
tions are currently underway to develop new transformations as
well and to gain insight into the mechanism of dirhodium
catalyzed oxidations.
1
1
0
1
90
We are grateful to the National Science Foundation and the
National Institutes of Health for their support of this research.
85
85
Notes and references
1
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2
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a
Reactions were performed at room temperature for 16 h using
(cap) (1.0 mol %), substrate (1.0 equiv), and t-BuOOH
2.0 equiv) in CH
Rh
(
2
4
b
3
CN (0.27 M/[substrate]). Isolated yield after
c
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5
6
7
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1
1) and heterocyclic amines (entries 12–14) are oxidized to the
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(
1
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8 (a) J. S. M. Samec, A. H. E´ ll and J.-E. B a¨ ckvall, Chem.–Eur. J., 2005,
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has been observed previously,
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´
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Since this oxidative methodology exhibited significant prefer-
ence for the benzylic position, its potential for oxidative
deprotection was examined. As an example, benzyl protected
phenylalanine methyl ester 4 was transformed to amino acid ester
hydrochloride 5 in 78% yield without epimerization using 4.0 equiv
TBHP (eqn. 3).
9
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1
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46 | Chem. Commun., 2007, 745–747
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Chem. Commun., 2007, 745–747 | 747