Facile access to chiral ketones through metal-free oxidative C-C bond cleavage of aldehydes by O2

Article abstract of DOI:10.1002/anie.201107473

Giving the metal the boot: The title reaction provides facile access to functionalized chiral ketones from chiral α,α′-disubstituted aldehydes in the presence of molecular oxygen (see scheme). The C-C bond-cleavage approach offers an alternative or better method relative to the typical bond-forming strategies used in synthesizing chiral ketones.

Full text of DOI:10.1002/anie.201107473

Angewandte
Chemie
DOI: 10.1002/anie.201107473
À
C C Cleavage
À
Facile Access to Chiral Ketones through Metal-Free Oxidative C C
Bond Cleavage of Aldehydes by O2**
Bhoopendra Tiwari, Junmin Zhang, and Yonggui Robin Chi*
Functionalized chiral ketones, such as a-amino ketones, b-
nitro ketones, and their derivatives, are prevalent building
blocks and ubiquitous subunits present in natural products
and pharmaceutical lead compunds.[1] The synthesis of chiral
ketones can be achieved through direct a substitution. For
example, the synthesis of a-amino ketones has been devel-
oped by Jørgensen and co-workers using an elegant catalytic
amination of ketones by diethyl diazenedicarboxylate
(DEAD).[2] Despite the success, some drawbacks of this
method lie in the unsatisfactory and undesired regioselectiv-
ities for unsymmetric ketones, and to a certain extent the
nitro ketones. Given the large number of enantioselective
methods available for the preparation of chiral aldehydes,
especially the recent success with inexpensive amino catal-
ysis,[6] we expect this approach to be applicable for the
synthesis of a wide range of useful molecules. Our method
may also stimulate new synthetic approaches to building
complex molecules.
À
The C C bond cleavage holds tremendous potential in
synthesis, but has remained underdeveloped in part due to the
inherent inert nature of the C C bonds.[7] The impressive yet
À
still limited studies have mainly relied on transition-metal
demanding reaction conditions required for subsequent N N
reagents or catalysts.[8,9] Recently, Yamamoto et al. designed a
À
À
bond cleavage. Another approach for chiral ketone synthesis
employs N-heterocyclic carbene catalysis.[3] Rovis and co-
workers have recently reported excellent asymmetric Stetter
reactions of aldehydes to nitroalkenes to afford b-nitro
ketones.[4] The aldehyde substrates are restricted to (hetero)-
aryl aldehydes and enals as the acyl anion precursors, and
usually only aliphatic nitroalkenes can behave as effective
Michael acceptors. We envisioned that limitations[5] associ-
ated with current new bond-forming reactions for chiral
ketone synthesis could be substantially overcome by a less
very efficient metal-free nitrosobenzene-mediated C C bond
cleavage for esters and 1,3-diketo compounds.[10] The C C
À
bond-cleaving transformation for achiral aldehydes has been
studied since the 1950s, and involves the oxidation of the
corresponding preformed enamines in the presence of strong
metal oxidants or catalysts.[11] However, nearly all the
À
reported reactions for C C bond cleavage of aldehydes
were sluggish and multiple side products (or even large
amounts of undesired products) were formed as a result of the
nonselective reaction conditions. In addition, these methods
have only dealt with achiral and simple aldehydes bearing no
useful functional groups.
À
common C C bond-breaking approach (Scheme 1).
We first used the Mannich adduct 2a as a model substrate
to develop an oxidative cleavage approach to furnish the a-
amino ketone 1a as the desired product (Table 1). The
Mannich adduct was prepared in essentially pure form
without column chromatography starting from readily avail-
able materials (aldehydes and aryl imines) and the inexpen-
sive proline catalyst using the protocol reported by List and
co-workers.[6a] We decided to form enamine intermediates
in situ for operational simplicity and to avoid complications in
preparing preformed enamines of these chiral aldehydes
containing functional groups. An initial survey of cyclic
secondary amines [pyrrolidene, piperidine, and morpholine
(A)] known in the literature[11] for enamine oxidation did not
lead to detectable amounts of the ketone product 1a when
using metal-based oxidants or metal catalysts under a range of
reaction conditions (Table 1, entries 1–4; also see the Sup-
porting Information). Additional studies revealed that the use
of primary amines (B–G) in the presence of O2 at 508C could
afford the ketone product 1a in 12–34% yield upon isolation,
and electron-rich phenyl amines performed better than alkyl
amines (Table 1, entries 5–10). We then chose to use the
inexpensive p-methoxy aniline (F) for additional optimization
of the reaction. In the presence of one equivalent of the
aniline F under ten atmospheres of O2 at 508C in toluene, the
ketone product 1a could be obtained in 91% yield and
99% ee (Table 1, entry 12). It was very fortunate to observe
Scheme 1.
À
Reported herein is the C C bond cleavage of chiral
aldehydes by O2 for facile access to optically enriched a-
amino ketones, a,a’-diamino ketones, and a-substituted b-
[*] Dr. B. Tiwari, Dr. J. Zhang, Prof. Dr. Y. R. Chi
Division of Chemistry & Biological Chemistry, School of Physical &
Mathematical Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: robinchi@ntu.edu.sg
Homepage: http://chigroupweb.org
[**] We are grateful for the generous financial support from the
Singapore National Research Foundation (NRF), the Singapore
Economic Development Board (EDB), GlaxoSmithKline (GSK), and
the Nanyang Technological University (NTU); Dr. Y. Li and Dr. R.
Ganguly (X-ray structure, NTU). We also appreciate the thoughtful
suggestions from the referees.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107473.
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Table 1: Model reaction optimization.[a]
Table 2: Synthesis of a-amino ketones.
Entry[a]
R
R’
1
t
[h]
Yield
[%][b]
ee
[%][c]
1[d]
2[d]
3
4
5
6
7
8
9
10
11
12
13
14
15
Me
Ph
Ph
Ph
Ph
1b
1c
1d
1e
1 f
1a
1g
1h
1i
1j
1k
1l
1m
1n
1o
1
4
83
92
89
83
88
91
71
76
74
81
86
87
91
94
81
92
99
97
92
99
99
99
95
88
91
96
98
99
99
97
nBu
7-octenyl
iPr
Bn
nBu
iPr
14
36
16
24
36
48
48
24
30
24
24
24
20
Entry[b]
Conditions
Yield
[%][c]
ee
Ph
[%][d]
4-MOeC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
4-BrC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-naphthyl
1[e]
2[e]
3[e]
4[e]
5
6
7
8
9
10
11
12
13[g]
14
15
A, CuCl, 1 atm O2, CH3CN, 708C
A, CuI, 1 atm O2, CH3CN, 708C
A, CuCl2, 1 atm O2, CH3CN, 708C
A, CuCl2, 1 atm O2, toluene, 708C
B, 1 atm O2, toluene, 508C
C, 1 atm O2, toluene, 508C
D, 1 atm O2, toluene, 508C
E, 1 atm O2, toluene, 508C
F, 1 atm O2, toluene, 508C
G, 1 atm O2, toluene, 508C
F, 10 atm O2, toluene, RT
0[e]
0[e]
0[e]
0[e]
12
15
0[e]
23
32
34
0[f]
91
88
43
12
–
–
–
–
nBu
iPr
nBu
nBu
nBu
nBu
nBu
nBu
n.d.
n.d.
–
n.d.
n.d.
n.d.
–
99
97
n.d.
n.d.
[a] Reaction conditions: 2 (0.15 mmol; ee>97% and d.r. >20:1), F
(0.15 mmol), toluene (1.5 mL), O2 (10 atm). [b] Yield of isolated 1.
[c] Determined HPLC analysis using a chiral stationary phase. [d] Reac-
tion at RT. Bn=benzyl.
F, 10 atm O2, toluene, 508C
F, 10 atm O2, toluene, 508C
F, 10 atm O2, CH3CN, 508C
F, 10 atm O2, CH3Cl, 508C
[a] Special caution should be taken when using toluene as solvent under
O2 especially at elevated temperatures. [b] Reaction conditions: Alde-
hyde 2a (0.15 mmol; 99% ee, >20:1 d.r.) and amine (0.15 mmol) in
solvent (1.5 mL) for 24 h. [c] Yield of isolated product. [d] Determined by
HPLC analysis using a chiral stationary phase. [e] 20 mol% of metal
catalyst. [f] Determined by TLC and 1H NMR analysis of the crude
reaction mixture. [g] 2.0 equiv of amine was used. n.d.=not determined.
effects on the outcome of the reaction (Table 2, entries 12–
14).
To further demonstrate the simplicity of this method, we
combined protocol from List and co-wrokers for the catalytic
Mannich reaction[6a] and our oxidative cleavage in a single-pot
operation on a gram scale synthesis to yield the ketone
product 1a with 72% overall yield and 96% ee (see the
Supporting Information).
We then extended this oxidative cleavage approach for
the asymmetric synthesis of a,a’-diamino ketones (Scheme 2).
The precursor aldehyde 4a (R = H)[6b] was first subjected to
no apparent erosion on the chiral center of the ketone
product 1a. Increasing the loading of the amine reagent
beyond 100 mol% did not show additional improvements
(Table 1, entry 13). A brief solvent screening (Table 1,
entries 14–15) indicated toluene to be the solvent of choice.
À
Mechanistically, the C C cleaving reaction likely proceeds
through the decomposition of a dioxetane intermediate
resulting from oxidation of the enamine by oxygen.[12]
We next examined the scope of the amino aldehydes 2
with various R and R’ substituents (Table 2). When R is a
methyl (Table 2, entry 1) or n-alkyl group (entry 2) and R’ is a
phenyl group, the reactions are complete within 1–4 hours at
room temperature and give the corresponding ketone prod-
ucts with excellent yields and optical purities. With other R
substituents, such as alkenyl, branched alkyl, or benzyl
groups, a longer reaction time (14–36 h) and higher temper-
ature (508C) are necessary (Table 2, entries 3–5). The effects
of the electronic nature R’ when it is aryl were then studied
(Table 2, entries 6–11). The reactions proceeded to comple-
tion within 24–48 hours, thus giving products with excellent
yields and optical purities; both electron-donating (Table 2,
entries 6–7, 12–14) and electron-withdrawing substituents
(entries 8–11) were tolerated. When R’ is aryl, the substitu-
tion patterns (ortho, meta, and para) showed no observable
Scheme 2. Synthesis of a,a’-diamino ketones. Reaction conditions:
4 (0.10 mmol; ee>99%; d.r.>20:1), F (0.07 mmol), O2 (10 atm),
toluene (1.5 mL). Yields are for the isolated product. The d.r. values
were determined by 1H NMR spectroscopy and the ee values were
determined by HPLC analysis using a chiral stationary phase. [a] Reac-
tion time was 16 h.
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the standard reaction conditions used in Table 2 (1 equiv F,
10 atm O2). To our disappointment, the ketone product 3a
was obtained as a diastereomeric mixture (d.r. ꢀ 7:3). Addi-
tional studies showed that the residual amine F could mediate
the epimerization of the ketone product. By lowering the
amount of the amine F to 0.7 equivalents, the product 3a
could be obtained with acceptable yield and essentially as a
single diastereomer with 97% ee. The a,a’-diamino ketone
products can be easily transformed into optically pure
diamino alcohols [Eq. (1)], analogues of which are key
fragments in HIV-1 protease inhibitors.[1f]
ketone product racemization). The scope of the reaction was
briefly examined (Scheme 3). The aldehydes 7 having R as
both n-alkyl and branched alkyl substituents could give the
products with good ee values and yields (6b and 6c). The R’
substituents could be either aryls or alkyls. However with R’
being an electron-deficient aryl substituent, the initial b-nitro
À
ketone product (stable during the C C cleaving reaction and
crude H NMR analysis) underwent subsequent E2 elimina-
1
tion (6e) during SiO2 column chromatography. It is worth
noting that the aldehyde substrates 7 having relatively low
d.r. values could be used to give the ketone products 6 with
high ee values.
In conclusion, we have developed a metal-free approach
À
using molecular O2 as the sole oxidant for the C C bond
cleavage of chiral aldehydes through in situ formed enamine
intermediates. By using this method, a-amino ketones, a-
substituted b-nitro ketones, and unprecedented a,a’-diamino
ketones with high optical purities can be prepared from
readily available substrates. Todayꢀs synthetic chemistry has
primarily focused on the design of bond-forming strategies. It
is expected that the inverse process of chemical bond
cleavages will provide unique opportunities for organic
syntheses and materials fabrications.
To further demonstrate the applicability of our methods in
preparing other chiral a-functionalized ketones, we sought to
À
synthesize the b-nitro ketones 6 through C C bond cleavage
of the corresponding and readily available g-nitro aldehy-
des[6c] (Scheme 3). The use of metal-based oxidants or
catalysts was again not successful (see the Supporting
Information). The metal-free conditions, run with molecular
O2, used above worked effectively here after a very slight
modification (e.g., using 0.9 equivalents of amine F, to avoid
Received: October 24, 2011
Revised: November 17, 2011
Published online: January 17, 2012
À
Keywords: C C cleavage · enamines · ketones · oxygen ·
synthetic methods
.
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