Merging organocatalysis with transition metal catalysis and using O 2 as the oxidant for enantioselective C-H functionalization of aldehydes

Article abstract of DOI:10.1039/c3cc44214d

A new catalytic Saegusa oxidation-Michael addition cascade reaction has been developed for the enantioselective β-functionalization of aldehydes. The feature of this research is the combination of organocatalysis and transition-metal catalysis for the asymmetric C-H functionalization which remains an underdeveloped research topic.

Full text of DOI:10.1039/c3cc44214d

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Merging organocatalysis with transition metal
catalysis and using O2 as the oxidant for
enantioselective C–H functionalization of aldehydes†
Cite this: Chem. Commun., 2013,
49, 7555
Received 5th June 2013,
Accepted 27th June 2013
Yong-Long Zhao,z Yao Wang,z Xiu-Qin Hu and Peng-Fei Xu*
DOI: 10.1039/c3cc44214d
www.rsc.org/chemcomm
A new catalytic Saegusa oxidation–Michael addition cascade reaction made important complementation to the limitations associated
has been developed for the enantioselective b-functionalization of with this research field, the ‘‘Oxidant Problem’’ arose due to the
aldehydes. The feature of this research is the combination of organo- use of IBX or DDQ as a stoichiometric oxidant in the above
catalysis and transition-metal catalysis for the asymmetric C–H function- reactions. To this end, we aimed at (1) developing an example
alization which remains an underdeveloped research topic.
of C–H functionalization reaction by using the strategy of merging
organocatalysis with transition metal catalysis and (2) employing an
Enantioselective catalytic C–C bond formation via C–H bond economical and green oxidant. Oxygen will be an ideal oxidant to
activation, being one of the most challenging fields in organic solve the ‘Oxidant Problem’ since water was the only by-product.8
synthesis, is at the forefront of current chemical research.1,2 As a result, our proposed strategy for C–H functionalization of
Although significant progress has been made in transition- aldehydes is outlined in Scheme 1.
metal-catalyzed enantioselective C–H functionalization, most
With the strategy in hand, we next focused our attention on
of these reactions need complex chiral ligands and neighboring realizing this idea. Recently, the amine/Pd(OAc)2 co-catalyzed
directing groups that can tolerate harsh reaction conditions.3 Saegusa-type reactions and Heck–Saegusa cascade reaction
As a result, the development of efficient methods using easily were reported by the Wang group,9a–c however, to date, owing
accessible catalysts and/or substrates is highly desired. On the to the restrictions such as solvent and reaction temperatures these
other hand, with the advent of generic modes of the activation, Saegusa-type reactions have only been used as methods for the
it is now commonly accepted that organocatalysis is one of the synthesis of a,b-unsaturated aldehydes.6g To the best of our knowl-
main branches of enantioselective synthesis.4 However, to date, edge, there is no report on the enantioselective b-functionalization
organocatalytic activation of C–H bonds still remains one of aldehydes via Saegusa oxidation–Michael addition cascade
specific challenge in this field.4a,6 In recent years, the concept reaction. We envisaged that the merging of these fields could
of combining transition metal catalysis and organocatalysis has provide new opportunities for C–H functionalization of aldehydes
received considerable attention since it can potentially realize and allow desirable levels of stereocontrol and efficiency in a range
unprecedented transformations which are currently impossible of new transformations. Therefore, we would like to report our
using the transition metal complex or the organocatalyst alone.5 progress in developing a highly enantioselective b-functionalization
In this context, it is reasonable to anticipate that the combination
of organocatalysis and transition metal catalysis for asymmetric
C–H functionalization may become a promising research field,
which yet remains to be developed.6f,i,j
So far, despite significant advances in b-functionalization of
carbonyl compounds,7 however, the enantioselective routes have
been challenging and rare. In 2011, two examples of enantioselective
b-functionalization of aldehydes were reported by Wang et al.6g
and Hayashi et al.6h Although these elegant approaches have
State Key Laboratory of Applied Organic Chemistry and College of Chemistry &
Chemical Engineering, Lanzhou University, Lanzhou 730000, P.R. China.
E-mail: xupf@lzu.edu.cn; Fax: +86-931-8915557
Scheme 1 Proposed strategy of combining organocatalysis and transition
metal catalysis using O2 as the oxidant for asymmetric C–H functionalization of
aldehydes.
† Electronic supplementary information (ESI) available: Experimental procedures
and spectra of all new compounds. See DOI: 10.1039/c3cc44214d
‡ These authors contributed equally to this work.
c
This journal is The Royal Society of Chemistry 2013
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Table 1 Screening of the reaction conditionsa
of EtOH (Table 1, entries 15–17). Finally, we examined the effect
of catalyst loading and reaction time on this cascade reaction,
and found that this process could be finished in 28 hours in
the presence of the secondary amine catalyst C (10 mol%)
and Pd(OAc)2 (10 mol%). Accordingly, a cooperative catalytic
system that consists of secondary amine C (10 mol%) and
Pd(OAc)2 (10 mol%), with DMSO as the solvent and an O2
atmosphere at room temperature are the optimal conditions for
this cascade reaction.
With the optimal reaction conditions established, the scope
of substrates for the chiral amine–Pd(OAc)2 co-catalyzed Saegusa
oxidation–Michael cascade reaction was then studied. In general, it
was found that all the reactions afforded the corresponding chiral
aldehydes 3 in moderate to good yields (45–72%) and with good to
excellent enantioselectivities (87–99% ee). However, the reaction
using aliphatic aldehydes is not successful under the optimal
reaction conditions (Table 2, entry 17). The reaction proceeded
well for malonate derivatives with ethyl, methyl, benzyl and iso-
propyl esters (Table 2, entries 1–4). A range of b-aryl substituted
aldehydes 1a–m were examined, and they all reacted smoothly to
afford the desired products 3a–p. As shown in Table 2, the aldehyde
1 allowed installation of a wide range of diverse molecules regard-
less of the substituents on the aryl moiety; aromatic groups bearing
electron withdrawing or donating groups were tolerated. Further
analysis of these results implied that both the electronic feature
and steric interaction have a certain degree of influence on this
cascade process. Owing to steric interaction of the ortho substitu-
ents (1c, 1d, 1f, 1j), the yields of products (3f, 3j, 3i, 3m) decreased
slightly (Table 2, entries 6, 7, 9 and 13). Compared with the
electron-donating aldehydes (1b, 1e), the electron-withdrawing
aldehydes (1l, 1m) gave relatively lower yields.
Entry
Cat.
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
A (20 mol%)
B (20 mol%)
C (20 mol%)
D (20 mol%)
E (20 mol%)
F (20 mol%)
G (20 mol%)
C (20 mol%)
C (20 mol%)
C (20 mol%)
C (20 mol%)
C (20 mol%)
C (20 mol%)
C (20 mol%)
C (20 mol%)
C (20 mol%)
C (20 mol%)
C (15 mol%)
C (10 mol%)
C (10 mol%)
C (10 mol%)
C (20 mol%)
C (5 mol%)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
THF
MeOH
EtOH
CH3CN
Toluene
Dioxane
DMSO : EtOH (2 : 1)
DMSO : EtOH (1 : 1)
DMSO : EtOH (1 : 2)
DMSO
Trace
55
65
n.d.f
93
96
Trace
n.d.
n.d.
n.d.
n.d.
89
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
97
96
n.d.
95
95
96
27d
nd
nd
24d
9
o5d
Trace
Trace
Trace
Trace
Trace
52
10
11
12
13
14
15
16
17
18
19
20e
21i
22g
23h
39
o10d
66
DMSO
DMSO
DMSO
DMSO
64
58
61
67
96
94
96
DMSO
48
a
Unless otherwise specified, all reactions were carried out with 1a
(0.4 mmol), 2a (0.2 mmol), solvent (0.50 mL), Pd(OAc)2 (10 mol%) and
organocatalyst at room temperature under an O2 (balloon) atmosphere
Table 2 The scope of the chiral amine-palladium acetate cocatalyzed Saegusa
oxidation–Michael cascade reactiona
b
for 28 h. Unless otherwise specified, all yields are isolated yields after
flash chromatography. Determined by HPLC analysis on a chiral
c
d
phase after oxidation to the corresponding ethyl ester. Determined
by 1H NMR analysis. Reaction time: 24 h. n.d. = not determined.
e
f
g
h
i
Pd(OAc)2 (20 mol%). Pd(OAc)2 (5 mol%). Reaction time: 32 h.
Entry R1
R2
Products Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
4-MeOC6H4 (1b)
2-MeOC6H4 (1c)
2,4-DiMeOC6H3 (1d) Et (2a)
4-MeC6H4 (1e)
2-MeC6H4 (1f)
4-C6H5C6H4 (1g)
2-Naphthyl (1h)
4-FC6H4 (1i)
Et (2a)
3a
64
59
57
66
72
51
53
64
61
65
47
63
55
53
45
47
—
95
94d
89
94
94
95
87
of aldehydes via Saegusa–Michael cascade reaction by combining
chiral amine and Pd(OAc)2 catalysis and using O2 as the oxidant.
Initially, a feasibility study of our hypothesis revealed that
3-phenylpropanal 1a and diethyl malonate 2a reacted smoothly
in the presence of the secondary amine catalyst B (20 mol%) and
Pd(OAc)2 (10 mol%) in DMSO and under an O2 (balloon) atmo-
sphere at room temperature to furnish the desired product 3a
in 55% yield and 93% ee (Table 1, entry 2). Next, we screened
various secondary amines, and C was found to be the most
promising organocatalyst for this cascade reaction (Table 1,
entry 3). For secondary amine catalyst A, D, F or G, no desired
product was obtained (Table 1, entries 1, 4, 6 and 7). We then
tested the effect of solvents on this cascade reaction. Some
common solvents such as DMSO, DMF, THF, MeOH, EtOH,
Me (2b) 3b
Bn (2c) 3c
iPr (2d) 3d
Et (2a)
Et (2a)
3e
3f
3g
3h
3i
3j
3k
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
>99
9
94
95
94
94
96
95
94
94
10e
11
12e
13
14
15e
16
17
3l
2-FC6H4 (1j)
3m
3n
3o
3p
3q
4-ClC6H4 (1k)
4-EtOCOC6H4 (1l)
4-CF3C6H4 (1m)
CH3CH2 (1n)
—
a
Unless otherwise specified, the reaction was performed on a 0.2 mmol
toluene, dioxane and CH3CN were used, and DMSO was found scale at room temperature for 28 h. b Isolated yields after flash chromato-
c
graphy. The enantioselective excess was determined by HPLC analysis
to be the optimal choice (Table 1, entry 3). We also tested the
on a chiral phase after oxidation to the corresponding ethyl ester.
d
effect of mixed solvents (DMSO–EtOH) on this cascade reaction,
Determined by HPLC analysis on a chiral phase after oxidation to the
e
and found that the yield decreased with the increase in loading corresponding methyl ester. The reactions were carried out for 32 h.
c
7556 Chem. Commun., 2013, 49, 7555--7557
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We are grateful for the NSFC (21032005, 21172097), the Inter-
national S&T Cooperation Program of China (2013DFR70580), ICP
(1204WCGA015) from Gansu province, the National Basic Research
Program of China (2010CB833203) and the ‘‘111’’ program of MOE
of P. R. China.
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 7555--7557 7557