Nickel-Catalyzed α-Allylation of Aldehydes and Tandem Aldol Condensation/Allylation Reaction with Allylic Alcohols

Article abstract of DOI:10.1002/anie.201703486

An additive-free nickel-catalyzed α-allylation of aldehydes with allyl alcohol is reported. The reaction is promoted by 1 mol % of in situ formed nickel complex in methanol, and water is the sole by-product of the reaction. The experimental conditions allow the conversion of various α-branched aldehydes and α,β-unsaturated aldehydes as nucleophiles. The same catalyst and reaction conditions enabled a tandem aldol condensation of aldehyde/α-allylation reaction.

Full text of DOI:10.1002/anie.201703486

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Accepted Article
Title: The Nickel Catalyzed α-Allylation of Aldehydes and Tandem
Aldol Condensation / Allylation Reaction with Allylic Alcohols.
Authors: Mathieu Sauthier, Brodie Thomson, Vincent Ferey, and yann
bernhard
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201703486
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http://dx.doi.org/10.1002/ange.201703486

Angewandte Chemie International Edition
10.1002/anie.201703486
COMMUNICATION
The Nickel Catalyzed α-Allylation of Aldehydes and Tandem Aldol
Condensation / Allylation Reaction with Allylic Alcohols.
[
a]
[a]
[b]
[a]
Yann Bernhard, Brodie Thomson, Vincent Ferey and Mathieu Sauthier *
[
9]
Abstract: An additive free nickel catalyzed α-allylation of aldehydes
with allyl alcohol is reported. The reaction is promoted by 1 mol % of
in situ formed nickel complex in methanol and water is the sole by-
product of the reaction. The experimental conditions allowed the
conversion of various α-branched aldehydes and α,β-unsaturated
aldehydes as nucleophiles. The same catalyst and reaction
conditions allowed promoting a tandem aldol condensation of
aldehyde / α-allylation reaction.
sulfones to form protected homoallylic amines.
Since recently, metal catalyzed α-allylation of aldehydes has
been increasingly studied, involving principally palladium based
catalysts. Most examples needed the use of additives like boron
brönsted acid, or in numerous cases amine to
activate the aldehyde (i.e. to form in situ the enamine) and
[
10]
[11]
derivatives,
[
12]
induce an enantioselectivity. With a similar methodology, such
[13]
[14]
allylations were also conducted with iridium, or rhodium. We
now wish to report the first Nickel-catalyzed allylation of
aldehyde with allyl alcohol performed in neutral conditions
Metal catalyzed allylic alkylation reactions represent
a
(
Scheme 1) with a broad scope of substrates. The developed
versatile and powerful tool for the formation of various homo- (C-
method is suitable for the allylation of various α-branched
aldehydes and α,β-insaturated aldehydes. Moreover, the nickel
based catalysis allows the tandem aldol condensation / allylation
of linear aldehydes for the one step construction of a quaternary
center. Moreover, the reaction does not request the use of
additives or bases.
[
1]
C) and hetero- (C-N, C-O, C-S) bonds. This family of reactions
involves a nucleophile and an allylic substrate that bears a
leaving group activated by a metal used in a catalytic amount.
The nature of the leaving group is particularly crucial and very
reactive allylic acetates, carbonates or halogens are typically
used. The reaction consequently suffers from the formation of
stoichiometric amounts of salts obtained from the release of the
leaving group and the base commonly used to generate a
reactive nucleophile. Modern organic chemistry requests the use
[
2]
of greener, atom economic and cheaper synthetic methods.
The direct use of more synthetically reliable allylic alcohols that
conduce to water as side-product are in this context particularly
[3]
attractive.
Nevertheless, that requests the use of an
appropriate metal, frequently associated with an activator, to
perform the initial oxidative addition. Nickel is a metal of choice
in this field as it is able to rapidly perform such an oxidative step
[4]
without any request of activators. Moreover, this metal is
attractive in comparison to the more commonly used palladium
because of its low cost and wide availability.
Scheme 1. Ni-catalyzed allylation of aldehyde with allyl alcohol.
Ni-catalyzed allylation has been conducted with several
[
4,5]
Our study began with the optimisation of the reaction, using
aldehyde 1a and allyl alcohol 2a as models (Table 1). The
catalyst was initially generated in situ from the combination of 2
equivalents of 1,4-bis(diphenylphosphino)butane (dppb) and
nucleophiles to form heteroatomic bonds, including amines,
phenols,
[
5a]
[6]
amides and sulfonamides. To date, the most
studied class of nucleophiles that lead to C-C bond formation
are activated methylene compounds (-ketoesters, -diketones,
Examples of nickel catalyzed allylation
reactions to form C-C bonds where outlined by Walsh's group
who performed an allylation of diarylmethane pronucleophiles,
and Weix's group who conducted the allylation of α-amido
[
5a,7]
[
Ni(cod)
with 42 % yield by reacting 1a with 3 eq. of allyl alcohol 2a in
toluene at 80°C for 15 hours (entry 1).The PPh ligand did not
2
] (2 mol %). The product of allylation 3aa was obtained
malonates, etc...),
[
8]
3
allow noticeable yield and among the diphosphines that have
been evaluated, the dppf (1,1'-bis(diphenylphosphanyl)
ferrocene) showed the highest efficiency (50 % GC yield, entry
7
) and was thus kept for the rest of the study. The nature of the
[
[
a]
b]
Dr. Y. Bernhard, B. Thomson, Prof. Dr. M. Sauthier
Univ. Lille, CNRS, Centrale Lille, ENSCL, Univ. Artois, UMR 8181 -
UCCS - Unité de Catalyse et Chimie du Solide, F-59000 Lille
solvent used for the reaction also proved to be a crucial
parameter. Apolar solvents gave rather limited yields whereas
isopropanol (entry 10, see the Supporting Information) conduced
(France).
E-mail:mathieu.sauthier@univ-lille1.fr
Dr. V. Ferey
[15]
to a complete GC conversion and a quantitative GC yield. The
use of the dppf ligand and an alcohol as solvent allowed: (1)
performing the reaction with a stoichiometric amount of allyl
alcohol 2a in respect to the amount of aldehyde 1a (92 % GC
yield with 1 eq. of 2a, entry 12); 2) reducing the catalytic charge,
with 1 mol % catalyst, the yield reaches 73 % in isopropanol
Chemistry and Biotechnology Development, SANOFI, 371 rue du
Professeur Blayac, 34184-Montpellier Cedex 04 (France)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under : http://...
(
entry 13) and a quantitative yield in methanol (entry 14).
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Angewandte Chemie International Edition
10.1002/anie.201703486
COMMUNICATION
Table 1. Optimization of the nickel-catalyzed α-allylation of cyclohexane
Table 2. Scope of the Ni-catalyzed allylation of α-branched aldehydes 1
with allylic alcohols 2.
[
a]
[a]
carboxaldehyde with allyl alcohol - selected conditions
[
Ni(COD)2]
O
O
Phosphine
+
OH
Solvent
8
0°C, 15 h
Eq
1
a
2a
3aa
[
b]
Entry
1
1
Product
Yield[%]
96
Entry
Ligand
Solvant
Cat.
Conv
Yield
charge
1a
3aa
O
O
2a
[
b]
[c]
[
%]
[%]
[%]
1a
1b
3aa
1
2
3
4
5
6
7
8
9
dppb
toluene
3
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
46
3
42
0
[
d]
PPh
3
toluene
3
3
2
3
3ba
3ca
95
97
dppp
toluene
2
0
O
dpppen
dppmb
toluene
3
22
31
7
12
29
1
1c
toluene
3
Xantphos
dppf
toluene
3
O
toluene
3
56
81
56
50
78
48
>99
96
92
73
>99
41
[c]
4
1d
1e
3da
3ea
78
86
dppf
acetonitrile
THF
3
O
dppf
3
5
6
7
10
11
12
13
14
15
dppf
isopropanol
isopropanol
isopropanol
isopropanol
methanol
allyl alcohol
3
>99
>99
92
O
dppf
2
1f
3fa
95
92
dppf
1
dppf
1
73
O
1g
3ga
dppf
1
>99
52
dppf
10
O
[
a] General reaction conditions: 1a (1.8 mmol), 2a (5.4 mmol, 3 equiv),
8
1h
3ha
91
Ni(cod) (10 mg, 2 mol%), ligand (4 mol%), solvent (0.5 mL), 80°C, 15 h, in
2
a sealed schlenk tube [b] Conversions determined by GC analysis using
anisole as a internal standard. [c] Yields determined by GC analysis using
[
(
a] Reaction conditions: 1 (1.8 mmol), 2a (1.8 mmol), Ni(cod)
20 mg), MeOH (0.5 mL), 80°C, 15 h, in a sealed schlenk tube [b] Yield of
2
(5 mg), dppf
anisole as a internal standard. [d] PPh
THF= tetrahydrofurane, dppp= 1,4-bis(diphenylphosphino)propane, dppb=
,4-bis(diphen-ylphosphino)butane, dppf= 1,1'- bis( diphenylphosphanyl)
ferrocene.
3
(8 mol %). cod=1,5-cyclooctadiene,
product isolated after chromatographic purification. [c] Isolated as the
DNPH adduct (crude mixture added to EtOH (5 mL)/ H O (1 mL)/ H SO (1
precipitate filtered,
2
2
4
1
mL)/2,4-DinitroPhenylHydrazine (0.3 g) mixture
washed (MeOH), dried.
-
Using the optimized conditions, we first extended the scope
of the Ni-catalyzed allylation with respect to the aldehyde 1
Table 2). A complete conversion of the starting material was
Table 3. Scope of the Ni-catalyzed allylation of hydratropic aldehyde 1g
with various allylic alcohols.
[
a]
(
observed in all cases. Starting from cyclohexane
carboxaldehyde 1a and unsaturated derivatives 1b and 1c, the
allylation method afforded compounds 3aa, 3ba and 3ca with 96
%, 95 % and 97 % isolated yield, respectively (entry 1-3). We
next examined the case of linear α-substituted aldehydes 1d-1f.
Because of low boiling point that prevents a simple purification
procedure., A derivatization with 2,4-DiNitropPhenylHydrazine
[
b]
Entry
2
Yield[%]
Product
OH
O
1
2
2b
83
61
3
gb
Ph
(
2,4-DNPH) in acidic media was thus performed. The weight of
OH
2c
2d
(Z/E 1:1)
the yellow precipitate gave the isolated yield (78 %)(entry 4).
Product 3ea and 3fa were isolated with 86% and 95% yields,
O
Ph
3
4
5
3gd
97
65
39
OH
respectively
phenylpropionaldehyde 1g gave the product with good yields (92
, entry 7). The more sterically hindered aldehyde 1h was also
(entry
5
and
6).
More
acidic
2-
O
OH
Ph
Ph
3ge
2e
2f
%
(Z/E 1:1)
efficiently converted (91 %, entry 8).
O
At this stage, we decided to examine the influence of the
allylic source (Table 3). Compound 3gb is obtained as unique
product from crotyl alcohol 2b and methylvinylcarbinol 2c (entry
Ph
OH
3gf
Ph
[
2
a] Reaction conditions: 1g (1.8 mmol), 2 (1.8 mmol), Ni(cod) (10 mg),
dppf (40 mg), MeOH (0.5 mL), 80°C, 15 h, in a sealed schlenk tube [b]
isolated yields.
1
and 2).The formation of the same product from 2b and 2c
shows that both reactants is consistent with the formation of the
same (π-allyl)nickel as intermediate in the allylation reaction.
The nucleophile (aldehyde) attacks preferentially the less
hindered allylic carbon and yields the linear product 3gb.
(
E)-pent-3-en-2-ol 2e, yielding the product 3ge with 65 % yield
as a Z/E statistical mixture.
It is noteworthy that there is no selectivity between E and Z
configurations, and the product is obtained as the statistical
When methallyl alcohol 2d is involved in the reaction, the
product 3gd is obtained with an excellent yield of 97 % (entry3).
Lower yields are obtained starting from cinnamyl alcohol 2f
1
13
mixture, as evidenced by H and C NMR analysis (see the
Supporting Information). A similar result was observed with
(
39 %, entry 5).
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Angewandte Chemie International Edition
10.1002/anie.201703486
COMMUNICATION
In comparison to classic aldehydes, examples of metal
Ni(COD)2 (1 mol %)
O
catalyzed α-allylation of α,β-unsaturated aldehydes are
O
dppf (2 mol %)
+
OH
eq
[
10a,16]
rare.
In this field, we prospected the possibility to perform
MeOH, 80°C, 15 h
1
such an allylation using the Ni-catalyzed procedure (Table 4).
91 % yield
6c
2a
5c
O
NaOH, H2O
0°C, 1 h
86 % yield
Ni(COD)2 (1 mol %) 88 % yield
8
dppf (2 mol %)
Table 4. Scope of the Ni-catalyzed allylation of αβ-insaturated aldehydes 4
[
a]
with allyl alcohol 2a.
MeOH, 80°C, 15 h
4c
Scheme 2.Synthesis of aldehyde 5c.
Table 5. Scope of the Ni-catalyzed tandem aldol condensation/α-allylation
of linears aldehydes 6 with allyl alcohol 2a.
[
b]
[a]
Entry
1
4
Product
Yield[%]
84
4a
4b
5a
2
3
5b
5c
93
88
[
b]
Yield[%]
82
Entry
1
6
Product
4c
4d
O
O
6a
5a
4
5d
85
[
a] Reaction conditions: 4 (1.8 mmol), 2a (1.8 mmol), Ni(COD)
2
(5 mg),
O
dppf (10 mg), MeOH (0.5 mL), 80°C, 15 h, in a sealed schlenk tube [b]
Yield of product isolated after chromatographic purification.
O
2
3
6b
6c
5b
5c
94
91
O
O
O
Starting from aldehydes 4a-c, the Ni-catalyzed allylation with
allyl alcohol, using the same experimental conditions as for the
allylation of α-branched aldehydes, gave products 5a, 5b and 5c
with respectively 84 %, 93 % and 88 % yields (entries 1-3). The
aldehyde 4d with a cyclic unsaturated structure proved to be a
suitable reactant and was converted in 5d with 85 % yield.
α,β-unsaturated aldehydes are typically obtained from an aldol
condensation under basic conditions between two aldehydes.
We thus anticipated that a tandem aldolisation / allylation
reaction could be promoted by nickel catalysts. To our delight,
the reaction between 2 equivalents of valeraldehyde 6c and one
equivalent of allyl alcohol straightforwardly yields 5c with 91%
yield under neutral conditions (Scheme 2). 5c can elsewhere be
obtained from a two steps procedure that involves the Aldol
Condensation reaction of valeraldehyde 6c to form 4c (86 %
yield) promoted by sodium hydroxide followed by a nickel
catalyzed allylation reaction of 4c with 2a (5c was obtained with
O
4
6f
5f
72
O
O
O
5
6
6g
6h
5g
5h
43
81
O
[
2
a] Reaction conditions: 6 (1.8 mmol), 2a (1.8 mmol), Ni(COD) (5 mg),
dppf (10 mg), MeOH (0.5 mL), 80°C, 15 h, in a sealed schlenk tube [b]
Yield of product isolated after chromatographic purification.
The role of the nickel in the Aldol Condensation step was
assessed from
Supporting Information). The Aldol Condensation of 6c is not
promoted by allyl alcohol nor the precursor [Ni(cod) ] /
diphosphine if used separately. The combination of the nickel
precursor with allyl alcohol leads to the formation of Aldol
Condensation products 4c which is then converted to the
allylated product 5c. This prompted us to propose a mechanism
that involves a hydroxynickelallyl intermediate as promoter of
both the Aldol Condensation and allylation steps.
a series of blank experiments (see the
88 % yield from the second step). The scope of this tandem
reaction was extended with respect to the starting linear
aldehyde 6 (Table 5). Note that for each case, the resultant
ramified double bond is obtained with an E configuration.
Starting from propionaldehyde 6a, butyraldehyde 6b and
valeraldehyde 6c, the products 5a, 5b and 5c were respectively
obtained with 82 %, 94 %and 91 % yields (entry 1-3). The
reaction performed with heptanal gave after 15 hours at 80°C
the product 5f with 72 % yield (entry 4). The more sterically
hindered isovaleraldehyde 6g gave the product 5g with 43 %
yield (entry 5). Starting from hydrocinnamaldehyde 6h, the
expected product is obtained with 81 % yield (entry 6).
2
The allylation of α-branched aldehydes would involve a
(dppf)Ni(0)(allyl aclohol)] complex
[
A
that forms the
pentacoordinated complex B through an oxidative addition step
[
4,5c,6a,7c]
(
Scheme 4).
The hydroxy ligand acts as a base and
reacts with the aldehyde thus generating the enolate. The
nucleophilic attack on the π-allyl ligand and coordination of the
allyl alcohol to the nickel yields the product and regenerates the
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Angewandte Chemie International Edition
10.1002/anie.201703486
COMMUNICATION
[
19]
initial complex A. The nucleophile can be an alpha-substituted
aldehyde or an -unsaturated aldehyde. Interestingly, complex
B is suitable to promote the aldol condensation that allows the in
situ formation of the -unsaturated aldehyde needed for the
tandem reaction. Although neutral intermediates can’t be
completely discarded, the involvement of cationic nickel
complexes is likely as a polar solvent, methanol, has been
74 % yield.
The compound 5e was obtained as a mixture of
two diastereoisomers R,R and R,S, in
highlighted by the NMR analysis of the compound ( H- C-NMR
spectrum, see the Supporting Information).
a 45/55 ratio as
1
13
In summary, we have developed the first nickel catalyzed α-
allylation of aldehyde with the construction of quaternary
carbons. The reaction is performed under neutral conditions,
without any additive and yields water as by-product. The scope
of the reaction has been extended to various α-branched and
α,β-unsaturated aldehydes and applied for the transformation of
natural products. Moreover, the optimized conditions also
allowed developing the tandem aldol-condensation /allylation of
simple linear aldehydes. The proposed mechanism involves
cationic allylic nickel complexes that are key intermediates in
both the allylation and Aldol Condensation steps.
shown as the best reaction medium.
O
2
O
6
c
4c
OH
Ni
OH
Ni
Ni(COD)2
P
P
P
P
+
2 dppf
B
H O
OH
2
2a
OH
Acknowledgements
O
P
P
Ni
Ni
P
P
A
C
Sanofi is gratefully acknowledged for financial support and for a
post-doctoral grant (Y.B.).
O
O
Keywords: Allylation • Aldehyde • Nickel • Allyl alcohol
5
c
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P
P
Ni
2
a
D
Scheme 4. Proposed mechanism for the Ni-catalyzed tandem aldol
condensation plus allylation of linear aldehydes 6c.
In comparison to the neutral forms, the ionic complex B with a
hydroxide counter anion appears as more suitable to promote an
aldol condensation.
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[
17]
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COMMUNICATION
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[
[
[
[
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This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201703486
COMMUNICATION
Nickel based catalysts efficiently promote the -allylation of -branched
aldehydes and -unsaturated aldehydes with allylic alcohols under additive
free conditions. The reaction proceeds with high yields and water is formed as
the only side product. The nickel catalysts proved to be suitable for the
promotion of the tandem aldolisation/allylation reaction of simple linear
aldehydes with allyl alcohol.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201703486
COMMUNICATION
This article is protected by copyright. All rights reserved.