Synthesis of α,β-unsaturated aldehydes based on a one-pot phase-switch dehydrogenative cross-coupling of primary alcohols

Article abstract of DOI:10.1021/ol500916g

An efficient one-pot ruthenium-catalyzed hydrogen-transfer strategy for a direct access to α,β-unsaturated aldehydes has been developed. The employment of enolates prepared in situ from alcohols avoided handling unstable aldehydes and provided a very appealing route to different cinnamaldehydes substituted in position 2. A silica-grafted amine was used as phase-switch tag leading to a selective one-pot process in favor of cross-dehydrogenative coupling products.

Full text of DOI:10.1021/ol500916g

Letter
pubs.acs.org/OrgLett
Synthesis of α,β-Unsaturated Aldehydes Based on a One-Pot Phase-
Switch Dehydrogenative Cross-Coupling of Primary Alcohols
Manuel G. Mura,† Lidia De Luca,† Maurizio Taddei,‡ Jonathan M. J. Williams,§ and Andrea Porcheddu*,†
†Dipartimento di Chimica e Farmacia, Universita
̀
degli Studi di Sassari, via Vienna 2, 07100 Sassari, Italy
di Siena, Via A. Moro 2, 53100 Siena, Italy
‡Dipartimento di Biotecnologie, Chimica e Farmacia, Universita
̀
§Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
S
* Supporting Information
ABSTRACT: An efficient one-pot ruthenium-catalyzed hydro-
gen-transfer strategy for a direct access to α,β-unsaturated
aldehydes has been developed. The employment of enolates
prepared in situ from alcohols avoided handling unstable
aldehydes and provided a very appealing route to different
cinnamaldehydes substituted in position 2. A silica-grafted amine was used as phase-switch tag leading to a selective one-pot
process in favor of cross-dehydrogenative coupling products.
oday, the forging of new carbon−carbon (C−C) bonds
through the addition of active C−H nucleophiles to C-
aliphatic aldehydes and nonenolizable aldehydes in the
presence of an amine represents a very useful approach to
α,β-unsaturated aldehydes (Scheme 1, eq 2).7 In this regard,
the development of a synthetic process that employs enolates
prepared in situ with high effectiveness and in low
concentrations from a noncarbonyl precursor would avoid the
handling of sensitive aldehydes.8
Following our previous interest in hydrogen transfer (HT)
and borrowing hydrogen strategies,9 we now focused our
attention on the development of a rapid access to α,β-
unsaturated aldehydes, through the cross-dehydrogenative
coupling of two different primary alcohols behaving as latent
aldehydes (Scheme 1, eq 3). We designed a cascade reaction
where a nonenolizable aldehyde is first generated in situ by the
removal of a “hydrogen molecule” from an alcohol and then
temporarily trapped as an imine. The following Mannich-type
condensation between the imine species and the other transient
aldehyde should give us the target compounds.10
In order to establish the optimal reaction conditions for
imine synthesis, benzyl alcohol 1 and methylamine11 2 were
chosen as model substrates and reacted with various
ruthenium-based catalysts12 in the presence of crotononitrile,
used as a hydrogen trap (Table S1, Supporting Information).
Among various Ru catalysts screened, we found that RuH2CO-
(PPh3)3 (4 mol %) in combination with Xantphos ligand (4
mol %) gave an almost complete conversion of alcohol 1 into
imine 3 (Scheme 2).
T
heteroatom double bonds is widely recognized as one of the
most important topics in organic chemistry.1 In this area, the
aldol2 and Mannich3 reactions are highly efficient synthetic
strategies that allow expedient access to versatile molecules
such as α,β-unsaturated aldehydes, among others.4 Because of
their bifunctionality, substituted α,β-unsaturated aldehydes are
used in the manufacture of a wide range of products including
detergents, plasticizers, fragrances, pharmaceuticals, and cos-
metics.5
Typical approaches to the preparation of these compounds
involve condensation reactions between two aldehydes over
basic or acidic catalysts (Scheme 1, eq 1). Although aldol
reactions provide an attractive synthetic route to α,β-
unsaturated aldehydes, the cross-aldol condensation between
two different enolizable aldehydes continues to be a challenge
that has found no general solution.6 To prevent or reduce any
unwanted side reactions, the Mannich-type reaction between
Scheme 1. Different Approaches to α,β-Unsaturated
Aldehydes
In the absence of an added hydrogen scavenger molecule, the
imine intermediate 3 was reduced to N-methylbenzylamine as
the major product. Interestingly, microwave (MW) dielectric
heating cut down the reaction times from 24 h to a mere 1 h,
highlighting the beneficial effect of MW in this process (Table
S1, Supporting Information, compare entries 12 and 13).
Received: February 2, 2014
Published: May 2, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Scheme 2. Synthesis of Imine 3: An Assessment of the
Reaction Conditions
Table 1. Dehydrogenative Cross-Coupling of Benzyl Alcohol
1 with Heptanol 6 via a One-Pot Reaction Sequence
a
a
a
1
Conversion into imine 3 determined by H NMR analysis.
b
c
c
d
entry
amine
1/6
conv 6 (%)
7/8
7
(%)
With an efficient procedure for preparing imines in hand, we
1
2
3
4
MeNH2 (2.0 mmol)
MeNH2 (0.5 mmol)
2:1
2:1
2:1
3:1
<10
100
>90
100
investigated whether the same catalytic system could also
promote the synthesis of α,β-unsaturated aldehydes by reacting
in situ generated imines with aliphatic primary alcohols. To test
our hypothesis, once the formation of 3 was completed, 1 equiv
of heptanol 6 and 1.1 equiv of crotononitrile were added into
the previously prepared imine solution containing the
ruthenium catalyst, which was then heated in a MW oven at
120 °C for 2 h (Scheme 3). To our delight, the ruthenium−
76:24
83:17
90:10
40
e
(Si)-NH2 (0.9 mmol)
60
75
e
(Si)-NH2 (0.9 mmol)
a
Reaction performed under MWI at 120 °C using RuH2CO(PPh3)3/
Xantphos (4 mol %) as catalyst and crotononitrile (5.0 mmol) as
b
c
hydrogen acceptor. Heptanol (1.0 mmol). Determined by 1H NMR
d
spectroscopy analysis. Yields of isolated product 7 after column
chromatography. Reaction performed by using amine-grafted silica gel
with particle size 40−63 μm.
e
Scheme 3. Chemoselective Dehydrogenative Cross-Coupling
Reaction of the Benzyl Alcohol with Heptanol via a Cascade
Catalytic Sequence
phase13 would allow us to perform a more efficient trans-
formation.
a,b
In order to achieve this goal, a new phase-switching
strategy14 was designed using a silica-grafted primary amine
(Table S3, Supporting Information, entries 5−16) as phase-
switch tag. This brought a noteworthy change in the outcome
of the one-pot reaction, leading to the preparation of
compound 7 in acceptable 60% yields (Table 1, entry 3).
Optimization of the reaction parameters showed that mixing
benzyl alcohol 1 and heptanol 2 in the ratio 3:1 with
RuH2CO(PPh3)3 (4 mol %) and Xantphos (4 mol %) in the
presence of silica-immobilized amine (0.9 mmol), at 120 °C
under MW dielectric heating for 3 h without solvent, afforded a
75% yield of the desired cross-coupling product 7 (Table 1,
entry 4). Interestingly, when catalyst loading was halved (2 mol
%), the activity and selectivity of the catalyst system remained
unchanged (Table S3, Supporting Information, entry 11).
Notably, silica-immobilized amine can be recovered by simple
filtration, and it remained active, even after the fifth use (Table
S4, Supporting Information). Several analyses showed the
absence of any residual unsaturated aldehyde 7 on the solid
support at the end of the cross-coupling reactions (see section
7, Supporting Information).
To better understand the substrate scope and limitations of
this procedure, different aromatic alcohols and heptanol were
reacted under the optimized reaction conditions (Scheme 4,
products 9−22). In general, substituents at different positions
on the phenyl ring did not have a significant effect on the
efficiency and selectivity of this procedure (Scheme 4, products
10−12). Electron-withdrawing groups on the aromatic ring
provided slightly better results than electron-donating sub-
stituents (Scheme 4, compare, for example, products 14 and
16).
a
b
Ratio determined by 1H NMR spectroscopy analysis. Reaction
performed by adding 100 mg of silica gel, particle size 40−63 μm.
Xantphos system was indeed able to carry out both the
transient oxidation of the alcohols 1 and 6 to the corresponding
aldehydes and the subsequent Mannich-type reaction.
However, despite the complete conversion of heptanol 6, we
recovered a 6:4 mixture of the expected α,β-unsaturated
aldehyde 7 and byproduct 8 derived from homocondensation
(Scheme 3, entry 1). Improved selectivity was obtained
doubling the imine to 1-heptanol ratio (Scheme 3, entry 2).
Further increasing this molar ratio had no significant impact on
either conversion or selectivity (Scheme 3, entry 3).
Interestingly, the addition of 100 mg of silica gel exerted a
beneficial effect on chemoselectivity (Scheme 3, entry 4), with
up to 85% improvement toward the heterocoupling product 7
(see Table S2, Supporting Information, for acid catalyst
screening). It must also be pointed out that the presence of a
sacrificial hydrogen acceptor in this second step was mandatory
both to promote hydrogen extraction from heptanol
(RCH2OH) and to avoid the over-reduction of the α,β-
unsaturated aldehydes formed.
The combination of imine synthesis and Mannich con-
densation was then attempted in a one-pot reaction sequence.
The desired product 7 was obtained, but a very low conversion
(<10%) of alcohol 6 was observed (Table 1, entry 1), even after
prolonged reaction time. However, reducing the amount of
methylamine from 2 down to 0.5 mmol yielded 40% of α,β-
unsaturated aldehyde 7 (Table 1, entry 2). Any attempt to
reduce MeNH2 below this threshold resulted in a slower
reaction rates (see Table S3, Supporting Information, for a fine-
tuning of the reaction conditions). We hypothesized that amine
excess might inhibit or reduce the catalytic activity of the one-
pot process. Thus, the use of an amine in heterogeneous
The reaction proceeded successfully even with benzylic
alcohols bearing halogen moieties on the aromatic ring, leading
to good yields of halogenated cinnamaldehydes 16−18 (65−
73%, Scheme 4). p-Nitrobenzylic alcohol afforded the
corresponding aldehyde 19 in a still acceptable yield (50%,
Scheme 4). We were delighted to notice that base-sensitive
residues as carboxymethyl ester or phenol were well tolerated
under these conditions (Scheme 4, products 20 and 21).
To assess the versatility of the reaction, the cascade catalytic
sequence between benzyl alcohol 1 and a broad range of
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Letter
Scheme 4. Catalyzed Dehydrogenative Cross-Coupling
Reactions of Primary Alcohols under Solvent-Free MWI
Conditions
Scheme 5. Plausible Reaction Mechanism
a
in the absence of crotononitrile. These results highlight the key
role of hydrogen transfer and how crotononitrile was able to
intercept the dihydrogen molecule much more strongly than
other unsaturated species (imine and α,β-unsaturated alde-
hyde) involved in the mechanism.
In summary, we have developed an efficient one-pot synthesis
of α,β-unsaturated aldehydes by a ruthenium-catalyzed
procedure, which uses alcohols instead of aldehydes as starting
material. The employment of enolates derived from a
noncarbonyl precursors avoided handling unstable aldehydes
and provided a very appealing and interesting alternative route
to α,β-unsaturated aldehydes. The addition of a silica-grafted
primary amine led to a selective one-pot process in favor of
cross-dehydrogenative coupling products, which were obtained
in good yields and with high chemoselectivity.
a
b
Yield of isolated product. Mixture of E/Z isomers: 65/35.
aliphatic alcohol partners was also investigated (Scheme 4,
products 23−35). The reaction proceeded smoothly to give the
corresponding products 23−35 in 47−72% yields. This
protocol has also proven fruitful with various primary alcohols
containing pyridyl and indolyl motifs, thus allowing the
introduction of different heterocyclic rings into the α,β-
unsaturated aldehydes skeleton (Scheme 4, products 30 and
31). In addition, a variety of functional moieties offering
versatile synthetic functionality for further transformations were
successfully incorporated (Scheme 4, products 32−35). We
were pleased to find that this catalytic system could also be
extended to a few examples of reaction between α-branched
and linear aliphatic alcohols (Scheme 4, products 36 and 37).
All the products, with the only exception of aldehyde 33, were
isolated as E-isomers (>98%), showing an excellent selectivity
for the reaction. We were pleasantly surprised by the high rate
of unknown compounds prepared (Scheme 4, products 9, 10,
12, 13, 16, 17, 20−22, 25, and 29−37) using this method,
suggesting that our approach could help in solving a synthetic
problems still opened for α,β-unsaturated aldehyde synthesis.
As expected, although this reaction may be applicable to the
coupling between two linear aliphatic alcohols, a mixture of
inseparable unsaturated aldehydes was recovered. In particular,
if both reaction partners are enolizable and have a similar steric
environment the most abundant products comes from the self-
condensation.
A plausible mechanism that accounts for this ruthenium-
promoted transfer-hydrogenation/Mannich-type domino reac-
tion is proposed in Scheme 5. More reactive benzyl alcohol is
first oxidized by the ruthenium-mediated hydrogen transfer
from the substrate to crotononitrile. The formed benzaldehyde
is probably caught by the supported amine leaving the restored
catalyst to oxidize the aliphatic alcohol via a second hydrogen
transfer with crotononitrile. Finally, the Mannich-type reaction
between the grafted imine species and the second aldehyde
gives the α,β-unsaturated coupling product.15 To gain further
insight into this catalytic mechanism, we checked the same
reaction without the hydrogen acceptor. No reaction occurred
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra and experimental procedures for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: anpo@uniss.it.
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Regione Autonoma della Sardegna
(Grant No. F71J11001240002) and Fondazione Banco di
Sardegna (Prot. U640.2013/AI.564.MGB, Prat.2013.1194).
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