Copper-catalyzed rearrangement of tertiary amines through oxidation of aliphatic C-H bonds in air or oxygen: Direct synthesis of α-amino acetals

Article abstract of DOI:10.1002/anie.201003646

A surprising turn of events: Mechanistic studies, including trapping, control, and isotope-labeling experiments, led to the proposal of a rearrangement mechanism involving oxidation of aliphatic C-H bonds (see scheme; TMEDA=tetramethylethylenediamine).

Full text of DOI:10.1002/anie.201003646

Angewandte
Chemie
DOI: 10.1002/anie.201003646
Oxidative Rearrangement
Copper-Catalyzed Rearrangement of Tertiary Amines through
À
Oxidation of Aliphatic C H Bonds in Air or Oxygen: Direct Synthesis
of a-Amino Acetals**
Jie-Sheng Tian and Teck-Peng Loh*
Table 1: Optimization of the reaction conditions.[a]
Many natural products or biomolecules contain a-amino acid
or b-amino alcohol units in their structures.[1] Although these
units may be obtained from naturally occurring a-amino
acids, general methods for the synthesis of other non-natural
a-amino acids are highly sought after. Among many reported
Entry
Catalyst
R
t [h]
Product
Yield [%][b]
approaches, the direct synthesis of a-amino acids in air by
means of biomimetic methods has been regarded as one of the
most challenging tasks.[2] The biological method involving the
activation of dioxygen by copper enzymes has attracted
considerable attention owing to the existence of important
copper monooxygenases.[3] This system has been mimicked in
many studies for the investigation of copper–dioxygen
interactions[4] and further applications of dioxygen–copper
1
–
Me
Me
Me
Me
Et
nPr
iPr
48
48
5
2a
2a
2a
2a
2b
2c
2d
2e
0
11
66
58
25
19
0
2[c]
3
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
4[d]
5
6
7
8
6
24
48
48
48
n-pentyl
12
systems in organic synthesis, especially in the development of
[a] Reaction conditions: 1a (0.5 mmol), copper catalyst (0.25 equiv),
TMEDA (0.5 equiv), MeOH (0.5 mL, 25 equiv), MeCN (2.0 mL), O2
(1 atm), 408C. [b] Yield of the isolated product. [c] The reaction was
carried out without TMEDA; the by-product N,N-dicyclohexylformamide
was obtained in 62% yield. [d] The reaction was carried out in air.
[5]
À
À
oxidation reactions of aliphatic C H bonds. For C H bond
activation, dioxygen–copper systems[6] provide an alternative
to the commonly employed methods based on the use of
expensive metal catalysts and stoichiometric metal oxidants.[7]
Herein we report a novel rearrangement of tertiary amines
À
through oxidation of aliphatic C H bonds with dioxygen–
copper catalytic systems for the direct synthesis of a-amino
acetals. Furthermore, a mechanism to account for the product
observed is proposed on the basis of trapping, control, and
isotope-labeling experiments.
nitrogen donor ligands play an important role in dioxygen
activation,[3a] we tested a series of these ligands in the
reaction. We obtained the best result with N,N,N’,N’-tetra-
methylethylenediamine (TMEDA). When this ligand was
used with copper(II) bromide in a 2:1 ratio, the formation of
N,N-dicyclohexylformamide was suppressed, and the desired
a-amino acetal 2a was isolated in 66% yield (Table 1,
entry 3). The reaction proceeded even in air without a
significant decrease in yield (Table 1, entry 4). Primary
alcohols, such as ethanol, were suitable for this reaction,
although the yields were low, whereas secondary alcohols,
such as 2-propanol, did not yield the desired product (Table 1,
entries 5–8). Therefore, the optimal reaction conditions found
for the rearrangement of tertiary amines involved treatment
with methanol in acetonitrile (1:4, v/v) under an oxygen
atmosphere (1 atm) at 408C in the presence of copper(II)
bromide (25 mol%) and TMEDA (50 mol%) as the catalytic
system.
We next investigated the scope of this oxidative rear-
rangement with respect to the tertiary amine (Table 2).
Almost all substrates containing R1 = R2 = Cy provided the
desired products in moderate yields under the standard
reaction conditions (Table 2, entries 1–8). A tertiary amine
with a long carbon chain was also suitable for this reaction,
although the reaction time was much longer (Table 2,
entry 3). The reaction tolerated a wide array of functional
groups, including ester groups (Table 2, entries 4 and 8), a
bromo group (Table 2, entry 5), a double bond (Table 2,
When we treated N,N-dicyclohexyl-n-butylamine (1a)
with copper(II) bromide and oxygen in methanol/acetonitrile
(1:4, v/v) at 408C, we were surprised to obtain the a-amino
acetal 2a in low yield (11%; Table 1, entry 2). The structure of
2a was confirmed by single-crystal X-ray analysis (see the
Supporting Information). Interestingly, most of substrate 1a
was converted into N,N-dicyclohexylformamide[8] (62%).
During optimization of the reaction conditions (see the
Supporting Information), we found that the reaction did not
proceed without the copper catalyst (Table 1, entry 1). Since
[*] J.-S. Tian, Prof. Dr. T.-P. Loh
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371 (Singapore)
Fax: (+65)65158229
E-mail: teckpeng@ntu.edu.sg
[**] We gratefully acknowledge Nanyang Technological University and
the Singapore Ministry of Education Academic Research Fund Tier 2
(T206B1221, 207B1220RS) for the financial support of this research.
We also thank Dr. Yong-Xin Li for X-ray crystallographic support, and
Prof. K. Narasaka, Prof. S. Kim, Prof. S. Chiba, and Prof. J. (Steve)
Zhou for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003646.
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Table 2: Oxidative rearrangement of tertiary amines.[a]
Entry
R1
R2
R3
2
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
9
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
H
Et
2a
2 f
2g
2h
2i
2j
2k
2l
5
6
24
12
6
24
20
20
24
72
72
66
65
61
60
54
61
56
55
45
12
0
n-octyl
CO2Me
CH2CH2Br
CH CH2
CH2NPhth
Scheme 2. Control experiments.
=
CH2OAc
To explore how the rearrangement occurred, which
Cy
nBu
tBu
iPr
nBu
tert-pentyl
H
H
H
2m
2n
2o
À
carbon atom was involved in the reaction, and which C H
10
11
bonds of the long carbon chain were activated, we carried out
isotope-labeling experiments (Scheme 3). From three such
experiments [Scheme 3, Eqs. (1)–(3)] we could conclude that
the a and b carbon atoms of the aliphatic chain were involved
in the reaction. The use of 13C-labeled methanol in the
experiment [Scheme 3, Eq. (2)] showed that methanol was
[a] Reaction conditions: 1 (0.5 mmol), CuBr2 (0.25 equiv), TMEDA
(0.5 equiv), MeOH (0.5 mL), MeCN (2.0 mL). [b] Yield of the isolated
product. Cy=cyclohexyl, Phth=phthalimidyl.
entry 6), and an imido group (Table 2, entry 7). Substrates
containing R1 and R2 groups with more branched carbon
chains (Table 2, entries 1 and 9) showed better reactivity in
this reaction than those with linear carbon chains (Table 2,
entry 10). Unfortunately, when tert-butyl-tert-pentyl-n-butyl-
amine (1k), with substituents that are bulkier than the
cyclohexyl group, was tested as a substrate for this rearrange-
ment, none of the desired product was obtained (Table 2,
entry 11).
The tertiary amine 1l with a stereogenic center underwent
this reaction to afford the desired product in a moderate yield
of 52% as two diastereomers, which could be separated
readily by silica-gel column chromatography (Scheme 1).
Scheme 1. Oxidative rearrangement of a chiral tertiary amine.
TBS=tert-butyldimethylsilyl.
During our investigations of this rearrangement, we made
several observations of mechanistic interest. First, we isolated
a white solid with the molecular structure Cy2NH2Br (as
confirmed by X-ray crystallographic analysis; see the Sup-
porting Information) from the reaction mixture in about 8%
yield by a simple filtration. The results of trapping and control
experiments [Scheme 2, Eq. (1)] supported the involvement
of the reversible step a (Scheme 5) in the reaction mechanism.
Second, to prove the intermediacy of an enamine, we
synthesized enamine 1m[9] as a substrate for this reaction.
The desired rearrangement occurred to give 2q in 62% yield
[Scheme 2, Eq. (2)].
Scheme 3. Isotope-labeling experiment (see Scheme 5 for where
steps b and d occur in the proposed mechanism).
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not oxidized in the reaction. Under the standard reaction
conditions, compound 1n gave product 2r in about 48% yield.
Of particular interest was the observation at 74% intensity of
molecular oxygen, and the bidentate ligand TMEDA.[3,4]
After electron-transfer, deprotonation, and electron-transfer
processes, iminium ion C is produced. Iminium ion C is then
converted into enamine D by deprotonation. Next, electron
transfer yields the cationic radical species E and F. Nucleo-
philic attack by methanol on intermediate F and subsequent
electron transfer give the corresponding aziridinium ion H.
Following opening of the three-membered ring to form
oxocarbenium ion I, attack by an additional methanol
molecule generates the observed product.
1
the hydrogen atom indicated in bold in 2r in the H NMR
spectrum. Similar results were observed for the experiments
shown in Equations (4) and (5) in Scheme 3. The reason for
H/D exchange may be due to deprotonation and protonation
in the reversible steps b and d in the reaction mechanism
(Scheme 5).
When compound 2a was treated with CD3OD under
similar reaction conditions, only 67% of 2a was recovered,
and the three expected by-products were produced, albeit in
very low yield (Scheme 4). This result showed that most steps
in this oxidative rearrangement were reversible, which may be
one of the reasons why these by-products were produced.
In conclusion, we have described a novel rearrangement
À
of tertiary amines through the oxidation of aliphatic C H
bonds with a dioxygen–copper catalytic system for the direct
synthesis of synthetically useful a-amino acetals. In compar-
ison with the use of expensive metal catalysts and stoichio-
À
metric metal oxidants in traditional methods for C H bond
oxidation, this catalytic system has the clear advantages of
mild reaction conditions and the use of air or oxygen as the
oxidant. The development of other methods for the direct
synthesis of a-amino acetals from secondary amines and
aliphatic aldehydes or enamines, as well as further studies on
the scope and mechanism of this reaction, the development of
an asymmetric version, and the application of this method-
ology to the synthesis of complex molecules, are in progress.
Experimental Section
Scheme 4. Deuterium-labeling experiment.
Typical procedure: N,N-Dicyclohexyl-n-butylamine (1a; 0.118 g,
0.5 mmol) was added to a mixture of CuBr2 (28 mg, 0.125 mmol)
and TMEDA (29 mg, 0.25 mmol) in methanol (0.5 mL)/acetonitrile
(2.0 mL) in air at room temperature. The mixture was stirred at 408C
under an O2 atmosphere (1 atm) until the conversion of 1a was
complete (TLC). The reaction mixture was then mixed with a small
amount of silica gel and concentrated. Purification of the crude
product by flash column chromatography (silica gel; triethylamine/
ethyl acetate/hexane 0.1:1:100, v/v/v) afforded 2a (98 mg, 66%).
A possible rationalization of this rearrangement on the
basis of the trapping, control, and isotope-labeling experi-
ments is shown in Scheme 5.[10] In this proposed mechanism, a
series of copper–dioxygen species function as one-electron
oxidizing agents toward the tertiary amine, enamine D, and
intermediates B and G. Initially, the copper species [LCun+1] is
formed in the catalytic system composed of the copper salt,
Received: June 15, 2010
Revised: August 25, 2010
Published online: September 28, 2010
Keywords: a-amino acetals · copper · oxidative rearrangement ·
.
oxygen · tertiary amines
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