Dual amine- and bronsted acid-catalyzed α-allylic alkylation of aldehydes

Article abstract of DOI:10.1002/adsc.201000071

A very simple method was developed for the direct, palladium-free catalytic α-allylic alkylation of aldehydes. The direct organocatalytic intermolecular α-allylic alkylation reaction was mediated by a simple combination of Bronsted acid and enamine catalysis which furnished α-allylic alkylated aldehydes and cyclohexanone in high yields and chemoselectivities. The reaction conditions are mild and environmental friendly, the process is conducted under an atmosphere of air without the need for dried solvents, and water is the only side product of the allylic alkylation reaction.

Full text of DOI:10.1002/adsc.201000071

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DOI: 10.1002/adsc.201000071
Dual Amine- and Brønsted Acid-Catalyzed a-Allylic Alkylation
of Aldehydes
Li-Wen Xu,a,* Guang Gao,a Feng-Lei Gu,a Hao Sheng,a Li Li,a,b Guo-Qiao Lai,a,*
and Jian-Xiong Jianga
a
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal
University, Hangzhou 310014, Peopleꢀs Republic of China
Fax : (+86)-571-2886-5135; phone: 86-571-2886-7756; e-mail: liwenxu@hznu.edu.cn or laiguoqiao@yahoo.com.cn
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310014, Peopleꢀs
b
Republic of China
Received: January 28, 2010; Published online: June 8, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000071.
Abstract: A very simple method was developed for
the direct, palladium-free catalytic a-allylic alkyla-
tion of aldehydes. The direct organocatalytic inter-
molecular a-allylic alkylation reaction was mediat-
ed by a simple combination of Brønsted acid and
enamine catalysis which furnished a-allylic alkylat-
ed aldehydes and cyclohexanone in high yields and
chemoselectivities. The reaction conditions are mild
and environmental friendly, the process is conduct-
ed under an atmosphere of air without the need for
dried solvents, and water is the only side product of
the allylic alkylation reaction.
aldol condensations, Cannizzaro or O-allylation reac-
tions in the catalytic direct a-allylation of non-stabi-
lized aldehyde and ketones.[6] Attempts to overcome
this limitation have focused mainly on the develop-
ment of the combinational use of palladium with
amino organocatalysts. Since 2006, a direct catalytic
intermolecular a-allylic alkylation of aldehydes and
cyclic ketones has been successfully developed by the
combination of enamine/Pd catalysis.[7] A related
study employing Brønsted acids as co-catalysts in the
palladium-catalyzed allylic allylation was reported by
List and co-workers in 2007.[8] In metal-free organoca-
talysis, a direct catalytic intermolecular a-allylic alky-
lation of aldehydes is still a difficult challenge. To the
best of our knowledge, there is only one example re-
ported on organocatalyzed a-allylation of aldehydes,[9]
in which allylic silane was used as substrate with
SOMO activation. Although amino (enamine and
iminium) catalysis[10] has been used as an efficient
Keywords: aldehydes; allylic alkylation; Brønsted
acids; enamine catalysis; organocatalysis
À
Allylic alkylations are important C C bond forming strategy for various transformations, include aldol,
reactions in organic synthesis.[1] During the last 30 Michael, cycloaddition, Mannich, a-functionalization
years, palladium-catalyzed allylic alkylation has and domino reactions, allylic alcohols other than allyl-
become an attractive and mature synthetic method.[2,3] ic acetates or allylic amines have not been investigat-
These processes inevitably produce a stoichiometric ed in the metal-free organocatalyzed a-allylic alkyla-
amount of alcohols or organic waste. The substitution tion of aldehydes. Therefore, we herein report the
of the halides and related compounds also produces first dual amine- and Brønsted acid-catalyzed a-allylic
salts waste and requires a stoichometric amount of a alkylation of aldehydes using allylic alcohols
base.[4] In this respect, the use of allylic alcohols as (Scheme 1).
substrates will be highly attractive since only water
The initial studies of the organocatalytic allylic al-
would be generated as an environmental benign by- kylation focused on the screening of different amines
product.[5] However, most of a-allylic alkylations of and Brønsted acids as catalyst for the reaction of al-
carbonyl compounds with allylic alcohols were limited dehyde 1a and allylic alcohol 2a. The results from
to activated dicarbonyl compounds, such as b-keto these investigations are presented in Table 1. l-Pro-
esters or diketones. The alternative intermolecular line and other primary amino acids were first evaluat-
direct ketone or aldehyde allylation is more difficult ed but gave no conversion (entries 1–3). We then
because there are competing side reactions such as screened different Brønsted acids in the presence of
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catalyst for the allylic alkylation of isobutyraldehyde
with 1,3-diphenylprop-2-en-1-ol. The reaction was
highly chemoselective, and we were able to isolate
the corresponding alkylated aldehyde derivative
easily in 83% of yield. In addition, we found that the
combination of other acyclic or cyclic secondary
amines with organic carboxylic acids or CSA used as
catalysts for the direct allylic alkylation reactions be-
tween aldehyde and allylic alcohol resulted in lower
conversion and chemoselectivity. However, the
amount of TsOH was crucial for the process of allylic
alkylation. The reason for an excess of TsOH in this
reaction is easily provided: one equivalent of TsOH
and Et2NH are involved in the formation enamine in-
termediate, the excess of TsOH generated the allylic
cation, thus there is a merging of two powerful cata-
lytic cycles with activation via different mechanisms,
which make the allylic alkylation proceed smoothly
(Scheme 2).
Encouraged by these initial results, we decide to in-
vestigate the dual amine- and Brønsted acid-catalyzed
direct a-allylic alkylation reactions for a set of simple
aldehydes and aromatic allylic alcohols. As shown in
Table 2, the reactions proceeded smoothly to give the
corresponding a-allylic alkylated aldehydes in moder-
ate to excellent yields (54–91%). It should be noted
that different aldehydes give a mixture of diastereo-
mers under the optimal conditions. The diastereose-
lectivity is increased with smaller substituted group in
aliphatic aldehyde: i-Pr<n-Pr<Et<Me (dr ranging
from 1:1 to 15:1, Table 2, entries 1–5). In addition, the
functional groups present on aromatic allylic alcohols
have a strong impact on the diastereoselectivity (en-
tries 11–13). It is remarkable that this methodology
gives rise selectively to a-allylic alkylated aldehydes
without formation of self-aldol adducts. However,
non-phenyl ring substituted allylic alcohols shut down
the allylic alkylation reaction and no conversion is ob-
served (entry 16).
Scheme 1. Metal-free organocatalyzed a-allylic alkylation of
isobutyraldehyde.
Table 1. Screening of different amines and Brønsted acids as
catalysts for the a-allylic alkylation of isobutyraldehyde.
Entry Amines
Brønsted acids Time Yield [%][a]
1
2
3
4
5
6
7
8
4 (10 mol%)
5 (10 mol%)
6 (10 mol%)
–
–
–
48
48
48
24
24
24
24
24
24
24
24
24
24
24
48
0
0
0
0
0
0
0
32
7 (10 mol%) 10 (20 mol%)
7 (10 mol%) 11 (20 mol%)
7 (10 mol%) 12 (20 mol%)
7 (10 mol%) 13 (20 mol%)
7 (10 mol%) 14 (20 mol%)
7 (10 mol%) 15 (20 mol%)
8 (10 mol%) 14 (20 mol%)
9 (10 mol%) 14 (20 mol%)
4 (10 mol%) 14 (15 mol%)
5 (10 mol%) 14 (15 mol%)
6 (10 mol%) 14 (15 mol%)
8 (10 mol%) 14 (10 mol%)
9
31
10
11
12
13
14
15
95 (83)[b]
27
33
45
70
0
The reaction is not restricted to the use of aldehyde
but can be transferred to the use of ketones under the
same mild conditions. The a-allylation of cyclohexa-
none employing the same catalyst system with the
combination of Brønsted acid and enamine catalysis
furnished the corresponding a-allylic alkylated cyclo-
[a]
[b]
NMR yield.
Isolated yield in parenthesis.
pyrrolidine (entries 4–9), and surprisingly, p-toluene- hexanone derivative in excellent yield (90%)
sulfonic acid (TsOH, 14) or camphorsulfonic acid (Scheme 3). We also investigated a catalytic asymmet-
(CSA, 15) proved to be an effective Brønsted acid co- ric version of the a-allylic alkylation. In preliminary
catalyst in this reaction (entries 8 and 9). Obviously, studies, several cheap and available amino catalysts
in the absence of a Brønsted acid or base, isobutyral- provide the a-allylic alkylated ketone in good yield
dehyde (1a) did not react with 1,3-diphenylprop-2-en- but with poor enantioselectivity (up to 7% ee)[11]. Al-
1-ol (2a) respectively. Therefore the presence of both though our explorations in the asymmetric a-allylic
a secondary amine and Brønsted acidic functions si- alkylation of aldehydes or ketones were unsuccessful,
multaneously are essential prerequisites for the a-al- further deep studies and screening of effective chiral
lylic alkylation to proceed. After the next screening amines are expected to result in improvements of the
of different amines in this reaction, the combination enantio- and diastereoselectivities in this allylic alky-
of Et2NH and TsOH turned out to be an excellent lation.
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Dual Amine- and Brønsted Acid-Catalyzed a-Allylic Alkylation of Aldehydes
Scheme 2. Combined Brønsted acid and enamine catalysis.
Table 2. Metal-free organocatalyzed a-allylic alkylation of
aldehydes.[a]
Scheme 3. Dual amine- and Brønsted acid-catalyzed a-allylic
alkylation of cyclohexanone.
Entry R1
R2
R3
Yield [%][b] dr
1
2
3
4
5
6
7
8
CH3 CH3 Ph
3a: 83
3b: 61
3c: 85
3d: 91
3e: 85
3f: 75
3g: 79
3h: 68
3i: 66
3k: 84
3l: 63
3m: 58
3n: 59
3o: 54
–
cally pure chiral amino catalysts did not allow us to
achieve a high level of enantioinduction during this
alkylation. Thus, we expect that the combination of
chiral Brønsted acid and asymmetric enamine cataly-
sis can possibly be a step in the direction leading to
the development of enantioselective reactions.
H
H
H
H
CH3 Ph
Et Ph
n-Pr Ph
15:1
10:1
2:1
–
–
–
–
–
–
2:1
1:1
5:2
–
–
-
i-Pr
-(CH2)5-
Ph
Ph
CH3 CH3 o-Br-C6H4
CH3 CH3 o-CH3-C6H4
CH3 CH3 p-Cl-C6H4
CH3 CH3 p-F-C6H4
9
10
11
12
13
14
15
16
Experimental Section
H
H
H
Et
Et
Et
o-CH3-C6H4
p-Br-C6H4
p-F-C6H4
General Remarks
All reaction flask and solvent were dried according to stan-
dard methods prior to use. Flash column chromatography
was performed over silica (100–200 mesh). NMR spectra
were recorded on a 400 MHz spectrometer (Avance 400).
13C NMR spectra were obtained with broadband proton de-
coupling. For spectra recorded in CDCl3, unless otherwise
noted, chemical shifts were recorded relative to the internal
TMS (tetramethylsilane) reference signal. GC-MS was per-
formed on a TRACE DSQ. IR spectra were recorded using
an FT-IR apparatus (Nicolot 5700). Thin layer chromatogra-
phy was performed using silica gel.
CH3 CH3 p-CH3-C6H4
CH3 CH3 m-OCH3-C6H4 3p: 75
CH3 CH3 NR
H
[a]
[b]
See Experimental Section for the reaction conditions.
Yield of the isolated product of the corresponding prod-
uct after column chromatography on silica gel.
In summary, we have developed a very simple
method for the direct, palladium-free organocatalytic
a-allylic alkylation of aldehydes. The direct catalytic
intermolecular a-allylic alkylation reaction is mediat-
ed by a simple combination of Brønsted acid and en-
amine catalysis which furnished a-allylic alkylated al-
dehydes and cyclohexanone in good yields and prom-
ising diastereoselectivities (up to 15:1 dr). Control ex-
periments show the importance of the presence of an
excess amount of Brønsted acid in the enamine-pro-
moted a-allylic alkylation reaction of aldehydes. Un-
General Procedure for a-Allylic Alkylation of
Aldehydes
Et2NH (0.1 mmol) and TsOH (0.2 mmol) were added into a
solution of aldehyde (2.0 mmol) and allylic alcohol
(1.0 mmol) in CH3CN (4 mL). After stirring at room tem-
perature for 24 h, the mixture was diluted with H2O (10 mL)
and extracted with EtOAc (3ꢂ15 mL). The combined or-
fortunately, employing several known enantiomeri- ganic layers were dried (Na2SO4), concentrated under
Adv. Synth. Catal. 2010, 352, 1441 – 1445
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Li-Wen Xu et al.
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vacuum, and purified by column chromatography on silica
gel (EtOAc-petroleum ether, 1:8) to gain the pure product.
All the products were confirmed by GC-MS, NMR, and
IR, and characterization data for compounds 3 are listed in
the Supporting Information.
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Acknowledgements
Partial financial support by the National Natural Science
Foundation of China (No. 20973051) and Zhejiang Provin-
cial Natural Science Foundation of China (Y4090139) is ap-
preciated. XLW is greatly indebted to Prof. Shibasaki Masa-
katsu, Graduate School of Pharmaceutical Sciences, The Uni-
versity of Tokyo, and Prof. Chun-Gu Xia, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences, for their
help.
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Dual Amine- and Brønsted Acid-Catalyzed a-Allylic Alkylation of Aldehydes
512; c)
(R,R)-1,2-diphenylethylenediamine (DPEN),
ic alkylation of cyclohexanone, in which most of the
amino catalysts gave no enantioselectivity and 7% ee
was the best result for the l-tryptophan-catalyzed a-al-
lylic alkylation of cyclohexanone in the presence of
TsOH.
Ts-DPEN, l-proline, l-serine, and l-tryptophan, l-
threonine, quinine-derived primary amines, and other
simple and commercial available secondary amino or-
ganocatalysts have been used in the asymmetric a-allyl-
Adv. Synth. Catal. 2010, 352, 1441 – 1445
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