α-amination of aldehydes catalyzed by in situ generated hypoiodite

Article abstract of DOI:10.1002/anie.201204215

The metal-free amination of different aldehydes is catalyzed by hypoiodite, which is generated by employing commercially available sodium percarbonate as the co-oxidant. This approach has several advantages: it is a metal-free oxidation that works under m

Full text of DOI:10.1002/anie.201204215

Angewandte
Chemie
DOI: 10.1002/anie.201204215
Oxidative Amination
a-Amination of Aldehydes Catalyzed by In Situ Generated
Hypoiodite**
Jie-Sheng Tian, Kang Wai Jeffrey Ng, Jiun-Ru Wong, and Teck-Peng Loh*
Direct functionalization of organic molecules using metal-
free oxidative transformations has long been one of the most
challenging research targets.[1] Over the past two decades,
immense research interests were directed toward the appli-
cation of hypervalent iodine compounds in organic synthesis.
The interest was partly due to the low toxicity, simple
handling, commercial availability, and mild reactivity of
hypervalent iodine reagents.[2] The most notable feature of
such iodine compounds is their catalytic activity; they work
effectively in combination with stoichiometric amounts of
common co-oxidants, as evidenced in the development of new
reactions.[3,4] Recent progress has focused on the construction
Therefore, we aimed to realize the synthesis of a-amino
acetals catalyzed by an active cationic iodine species that is
generated in situ. This process is mainly carried out with
readily available and environmentally benign co-oxidants,
such as molecular oxygen or hydrogen peroxide, which were
already used in similar oxidation processes.[7] We herein
report a method for the a-amination of a divergent group of
aldehydes. The reaction utilizes secondary amines as the
nucleophilic nitrogen source, and is catalyzed by in situ
generated hypoiodite, which is prepared with commercially
available hydrogen peroxide (30 wt% in water) or sodium
percarbonate (H2O2 20–30%). Sodium percarbonate is
regarded as a “solid form” or “dry carrier” of hydrogen
peroxide and is used for the preparation of hypervalent iodine
compounds.[8] This novel approach has a number of advan-
tages, which include being a metal-free system, working under
milder reaction conditions, accommodating a wide scope of
substrates, which include bulky aldehydes or secondary
amines, and avoiding the generation of toxic by-products
derived from the co-oxidant.
In an initial study, which was aimed at optimizing the
reaction conditions as well as the choice of the co-oxidant,
dibenzylamine 1a and phenylacetaldehyde 2a were used as
the substrates in the presence of molecular iodine and
methanol (Table 1). Interestingly, each reaction afforded the
desired product 3a in moderate to good yield. According to
the results of reactions in which molecular oxygen and
hydrogen peroxide (30 wt% in water) were used as the
co-oxidants (Table 1, entries 1–7), methanol was a better
solvent than 1,2-dichloroethane with regard to product
formation and yield. Even at 208C, product 3a was generated
in 50–67% yield in methanol (Table 1, entries 3 and 7).
Gratifyingly, desired product 3a was obtained in 83% yield
when the co-oxidant was changed to sodium percarbonate
and dichloroethane was used as the solvent (Table 1, entry 8).
Further exploration of the reaction with sodium percarbonate
showed that it proceeded smoothly, even at room temper-
ature, although the yield decreased slightly (Table 1, entry 9).
Increasing the temperature to 808C resulted in a significantly
lower yield (61%; Table 1, entries 10 vs. 8 and 9). Thus, the
optimal temperature was established to be 408C. The nature
of the solvent also played an important role in the reaction.
Using the sodium percarbonate system, (CH2Cl)2 was the
most suitable solvent, giving isolated compound 3a with the
highest yield of 83% (Table 1, entry 8). However, use of
methanol, MeCN, and 1,4-dioxane as solvents provided the
desired product in low to moderate yields of 46, 74, and 68%,
respectively (Table 1, entries 11–13). These initial studies
showed that the ideal ratio of 1a:2a was 1:1.5 (Table 1,
entries 9, 14, and 15). Based on these results, the optimized
À
À
of C O and C N bonds by employing in situ generated
hypervalent iodine as the catalyst. Examples include
a-oxygenation reaction of ketones reported by Ochiai and
co-workers,[3b] dearomatization of phenols by Kita and
co-workers,[3h] and the oxidative cycloetherification of keto-
phenols by Ishihara and co-workers[3l] for the installation of
À
C O bonds and the spirocyclization of amides by Kita and
co-workers,[4a] the cross-amination of unactivated arenes by
Antonchick and co-workers,[4b] and the oxidative amination of
heteroarenes by Nachtsheim and co-workers[4c] for the con-
À
struction of C N bonds. Despite the progress made in forming
À
À
C O or C N bonds, the development of methods for the
À
formation of C N bonds of a-amino acid derivatives has
lagged behind, even though there is a significant interest in
doing so, because
a-amino acid derivatives are central building blocks for
pharmaceutical agents and natural products with biological
activities.[5] Accordingly, novel methodologies to install C N
À
bonds still remain a hot research topic. For instance, a new
methodology has been reported for the synthesis of a-amino
acetals, involving the use of a copper catalyst.[6] However, this
approach was plagued by major problems that needed to be
solved, especially in regard to its narrow substrate scope.
[*] Prof. T. P. Loh
Department of Chemistry, University of Science and Technology of
China, Hefei, 230026 (China)
J. S. Tian, K. W. J. Ng, J. R. Wong, Prof. T. P. Loh
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: teckpeng@ntu.edu.sg
[**] We gratefully acknowledge Nanyang Technological University and
the Singapore Ministry of Education Academic Research Fund AcRF
Tier 2 (MOE2010-T2-2-067) for the funding support, and Prof.
Moses N. F. Lee (Hope College (USA)) for his proofreading and
valuable discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204215.
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Table 1: Optimization of the reaction conditions.[a]
Entry Oxidant (equiv)
Solvent
T [oC] t [h] Yield [%][b]
1
2
3
4
5
6
7
8
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
30% H2O2 (1.5)
30% H2O2 (1.5)
30% H2O2 (1.5)
(CH2Cl)2
(CH2Cl)2
MeOH
(CH2Cl)2
(CH2Cl)2
MeOH
40
20
20
40
20
40
20
40
20
80
40
40
16
24
24
16
24
24
24
16
24
24
16
16
16
24
24
45
40
50
41
39
64
67
83
79
61
46
74
68
74
61
30% H2O2 (1.5)
MeOH
.
Na2CO3 1.5H2O2(1.0) (CH2Cl)2
.
9
Na2CO3 1.5H2O2(1.0) (CH2Cl)2
.
10
11
12
13
14[c]
15[d]
Na2CO3 1.5H2O2(1.0) (CH2Cl)2
.
Na2CO3 1.5H2O2(1.0) MeOH
.
Na2CO3 1.5H2O2(1.0) MeCN
.
Na2CO3 1.5H2O2(1.0) 1,4-dioxane 40
.
Na2CO3 1.5H2O2(1.0) (CH2Cl)2
40
40
.
Na2CO3 1.5H2O2(1.0) (CH2Cl)2
[a] Reaction conditions: dibenzylamine 1a (0.5 mmol, 1.0 equiv), phe-
nylacetaldehyde 2a (0.75 mmol), iodine (0.2 equiv), oxidant (1.0 equiv),
MeOH (0.5 mL), solvent (2.0 mL). [b] Isolated yields based on diben-
zylamine. [c] Dibenzylamine 1a (0.5 mmol, 1.0 equiv), phenylacetalde-
hyde (0.5 mmol). [d] Dibenzylamine 1a (0.75 mmol), phenylacetalde-
hyde (0.5 mmol, 1.0 equiv). The entry hightlighted in bold marks
optimized reaction conditions.
Scheme 1. Scope of aldehydes and secondary amines. Reaction con-
ditions: secondary amines 1 (0.5 mmol, 1.0 equiv), aldehydes
(0.75 mmol), iodine (0.2 equiv), sodium percarbonate (1.0 equiv),
MeOH (0.5 mL), (CH2Cl)2 (2.0 mL). Yields of isolated products based
on secondary amines 1. Compound numbers of corresponding starting
materials given in brackets underneath the products.
conditions for the synthesis of a-amino acetals employing our
method include: use of sodium percarbonate as the
co-oxidant, conduction of the reaction at 408C, use of
(CH2Cl)2 as the solvent, use of secondary amine and aldehyde
in a ratio of 1:1.5, adjustment of the solvent ratio of
MeOH/(CH2Cl)2 to 1:4 (v/v), and use of 0.2 equivalents of
molecular iodine as the precatalyst.
hexane carbaldehyde 2h also worked well in this reaction,
Next, our studies focused on the investigation of the scope
of our a-amination reaction by employing aldehydes that
contain a short carbon chain or a bulky group. A dozen
reactions were carried out using the optimized reaction
conditions (Scheme 1).
The bulky mono-a-substituted acetaldehydes 2a–g
reacted smoothly to afford the corresponding a-amino
acetals. When di-a-substituted acetaldehyde 2h was used,
which directly created a new quaternary carbon center that
À
bears a C N bond. We further expanded the scope of this
reaction by investigating the effects of different functional-
ities on secondary amines. Secondary amines that contain an
allylic substituent or ester functionality were also suitable for
this reaction, affording the corresponding a-amino acetals 3i–
k in moderate yields. The secondary amine 1e, which features
a stereogenic center, was also applied to this reaction, and
furnished the desired product 3l in a good yield of 78% as
a mixture of two diastereomers (1:1). The two optically active
a-amino acetals were easily separated by column chromatog-
raphy on silica gel.
À
a new C N bond was directly constructed at the tertiary
carbon center. For the single-ring-substituted phenylacetal-
dehydes with a substituent such as a methoxy or halo group,
the reaction provided the a-amino acetals 3b–d in good yields
(75–78%). An aldehyde with a larger aromatic group, such as
naphthyl, was also suitable for this reaction and the desired
product 3e was obtained in a moderate yield of 62%. It is
worth noting that, as a result of the mild reaction conditions,
the reaction showed good tolerance for heteroaromatic
substituents. For example, the amination of 2-(thiophen-3-
yl)acetaldehyde afforded a-amino acetal 3 f in a moderate
yield of 54%. The reaction was also very effective with
branched aldehydes, such as 2g, which contains an isopropyl
group at the a-position. The substrate was aminated to
provide the desired product 3g in a good yield of 82%. It is
gratifying that di-a-substituted acetaldehydes, such as cyclo-
À
This newly discovered approach to prepare C N bonds
also provides a route to critical intermediates needed to
construct complex molecules or to improve biological activ-
ities by introducing novel functional groups to natural
products or drugs. For example, a Diels–Alder adduct[9] and
a Claisen rearrangement adduct[10] were readily converted to
the desired a-amino acetals 3m and 3n in 38% and 79%
yields, respectively (Scheme 2). It is especially noteworthy
that aldehydes derived from natural sources, such as (S)-(À)-
b-citronellol and deoxycholic acid, were also suitable for this
reaction. Furthermore, the diastereoselectivity of the forma-
tion of a-amino acetals 3p was 91:9, and the two diastereo-
2
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and 3). Only a trace amount of product was detected when
sodium periodate (NaIO4) was used (Table 2, entry 4). In
contrast, when a mixture of molecular iodine and two
equivalents of potassium hydroxide was employed in this
reaction, the desired product was obtained in a good yield of
70% (Table 2, entry 2). As a result, an in situ generated
hypoiodite (IOÀ) or iodite (IO2 )[12] was suggested to be the
À
active intermediate (see the Supporting Information).
3) When the reaction was carried out in the absence of
methanol [Scheme 4, Eq. (1)], no a-amino aldehyde was
detected and only a-iodo aldehyde was isolated. This showed
Scheme 2. Functionalization of complex molecules. Reaction condi-
tions: dibenzylamine 1a (0.5 mmol, 1.0 equiv), aldehydes (0.75 mmol),
iodine (0.2 equiv), sodium percarbonate (1.0 equiv), MeOH (0.5 mL),
(CH2Cl)2 (2.0 mL). Yields of isolated products based on dibenzylamine
1a.
mers were easily separated by column chromatography on
silica gel (Scheme 2).
In order to better understand the reaction mechanism and
to determine the active intermediates involved, the following
control experiments were conducted: 1) The enamine 4a
(N,N-diallyl-3-methylbut-1-en-1-amine)[11] was utilized for
this reaction, affording the desired product 3q in 70% yield
(Scheme 3). This showed that an enamine is a possible
Scheme 4. Control experiment. Reaction in the absence of methanol.
that a) dibenzylamine serves as the catalyst and not a reactant
in the reaction; b) the reaction of hypoiodite acid (from the
oxidation of molecular iodine) with enamine led to the
formation of the a-iodo iminium ion intermediate, and
c) hypoiodite (IOÀ) is possibly the active intermediate.
Meanwhile, further reaction of dibenzylamine with a-iodo
aldehyde 5a in the presence of methanol afforded the desired
a-amino acetal [Scheme 4, Eq. (2)]. 4) To clarify how a-iodo
aldehyde was converted into the corresponding a-amino
acetal, three possible pathways were proposed: a) configu-
ration inversion of the product through intermolecular
nucleophilic substitution, b) configuration retention of the
product through double nucleophilic substitution, or c) intra-
molecular amino migration (see the Supporting Information).
Studying the stereochemical outcome of the reaction may
provide a clue to the mechanism. Therefore, the easily
available optically active a-bromo aldehyde 5b (86% ee)
was treated with dibenzylamine and methanol, and the
desired a-amino acetal 3r was obtained in 85% yield.
However, the enantioselectivity of the resulting product was
only 28% ee (Scheme 5). This result showed that a reversible
step involving the stereogenic center may exist in the reaction
process, thus supporting the amino migration mechanism.
Scheme 3. Control experiment. Use of an enamine.
intermediate in this a-amination. 2) The reaction of 1a and 2a
was also studied in (CH2Cl)2 and methanol at 408C using
iodized salts of different oxidation states (Table 2). The use of
molecular iodine (I2) or sodium iodate (NaIO3) did not result
in the formation of the desired product 3a (Table 2, entries 1
Table 2: Control experiments. Use of iodized salts at different oxidations
states.[a]
Entry
Additive [equiv]
Yield [%][b]
1
2
3
4
I2 (1.0)
I2 (1.0)+KOH (2.0)
NaIO3 (1.0)
0
70
0
NaIO4 (1.0)
trace
[a] Reaction conditions: Dibenzylamine 1a (0.5 mmol, 1.0 equiv), phe-
nylacetaldehyde (0.75 mmol), additive (1.0 equiv), MeOH (0.5 mL),
(CH2Cl)2 (2.0 mL) at 408C for 16 h. [b] Isolated yields based on
dibenzylamine 1a.
Scheme 5. Control experiment. Use of an optically active a-bromo
aldehyde.
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ethane (2.0 mL) at room temperature. The mixture was stirred at
408C until 1a was completely consumed, according to TLC analysis of
the reaction mixture. A small amount of silica gel was added to the
mixture, which was subsequently concentrated. The crude product
was purified by flash chromatography (silica gel; ethyl acetate or
diethyl ether/hexane = 1:100, v/v) to afford the desired product 3a as
a light-yellow oil (0.150 g, 83%).
Received: May 30, 2012
Published online: && &&, &&&&
Keywords: a-amino acetal · amination · aldehydes · hypoiodite ·
.
sodium percarbonate
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Scheme 6. Proposed mechanism for a-amination of aldehydes cata-
lyzed by in situ generated hypoiodite.
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which is thought to function as a one-electron oxidizing
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iodine (I2) or iodide (IÀ) with hydrogen peroxide. In the
second step, the hypoiodite reacts with enamine A to provide
iminium ion B, the existence of which was confirmed by the
control experiment shown in Scheme 4, in which the hydrol-
ysis of the intermediate B led to the corresponding a-iodo
aldehyde. In the third step, methanol attacks iminium ion B to
give the iodo-substituted intermediate D, which undergoes
intramolecular cyclization to afford aziridinium ion E. Finally,
an additional methanol molecule captures the ring-opened
intermediate F to afford the desired product.
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Experimental Section
Typical procedure for the a-amination of aldehydes catalyzed by
in situ generated hypoiodite (for dibenzylamine 1a and phenylace-
taldehyde 2a as a model system): Iodine (25 mg, 0.1 mmol) was added
to a mixture of sodium percarbonate (79 mg, 0.5 mmol), 1a (98 mg,
0.5 mmol), and 2a (90 mg, 0.75 mmol) in methanol (0.5 mL)/dichloro-
4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Oxidative Amination
J. S. Tian, K. W. J. Ng, J. R. Wong,
T. P. Loh*
&&&& — &&&&
a-Amination of Aldehydes Catalyzed by
In Situ Generated Hypoiodite
The metal-free amination of different
aldehydes is catalyzed by hypoiodite,
which is generated by employing com-
mercially available sodium percarbonate
as the co-oxidant. This approach has
several advantages, it is a metal-free
oxidation that works under mild reaction
conditions, furthermore, it has a wide
substrate scope, and does not give toxic
by-products from the co-oxidant that is
used.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!