Catalytic reductive dehydration of tertiary amides to enamines under hydrosilylation conditions

Article abstract of DOI:10.1021/ol403302g

Tertiary amides are efficiently reduced to their corresponding enamines under hydrosilylation conditions, using a transition-metal-free catalytic protocol based on t-BuOK (5 mol %) and (MeO)₃SiH or (EtO) ₃SiH as the reducing agent. The enamines were formed with high selectivity in good-to-excellent yields.

Full text of DOI:10.1021/ol403302g

Letter
pubs.acs.org/OrgLett
Catalytic Reductive Dehydration of Tertiary Amides to Enamines
under Hydrosilylation Conditions
Alexey Volkov, Fredrik Tinnis, and Hans Adolfsson*
Department of Organic Chemistry, Stockholm University, The Arrhenius Laboratory, SE-106 91 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: Tertiary amides are efficiently reduced to their corresponding
enamines under hydrosilylation conditions, using a transition-metal-free
catalytic protocol based on t-BuOK (5 mol %) and (MeO)3SiH or (EtO)3SiH
as the reducing agent. The enamines were formed with high selectivity in
good-to-excellent yields.
namines are important organic compounds that can
participate in a variety of essential transformations such
direct transformation of amides to enamines. In their successful
study, IrCl(CO)(PPh3)2 (0.05 mol %) was employed together
with 1,1,3,3-tetramethyldisiloxane (TMDS) or polymethylhy-
drosiloxane (PMHS) as hydride sources to reduce aliphatic and
benzylic tertiary amides to enamines at room temperature.13 To
the best of our knowledge this is the only catalytic system that
can carry out the direct transformation of tertiary amides to
enamines via hydrosilylation in high selectivity and yield.
Recently we developed an efficient NHC/iron-based catalytic
system for the reduction of tertiary benzamides to their
corresponding amines under hydrosilylation conditions.14,15 In
this protocol, benzylic tertiary amide 1a proved difficult to
reduce. Instead of the expected amine product 2a′ we noticed
the formation of enamine 2a in trace amounts (Scheme 1), the
rest being unreacted starting material.
E
as alkylation, acylation, conjugate addition, formation of
heterocycles, and cycloaddition reactions.1 Enamines can,
through asymmetrical hydrogenation, give rise to chiral amines,
which are important building blocks for the drug industry and
can also serve as organocatalysts or chiral ligands.2 The main
route to enamines involves the direct condensation of an
aldehyde or ketone with a secondary amine under Brønsted or
Lewis acid catalysis.1 However, this approach usually requires
high reaction temperature, water scavengers, or azeotropic
distillation, which prevents the use of heat-sensitive substrates
and restricts the use of some functional groups.
́
Recently Belanger and co-workers reported a mild method
for obtaining aldehyde-derived enamines.3 They were able to
carry out the reaction at low temperature (0 °C) in the
presence of a large amount of molecular sieves (1.16 g/mmol of
carbonyl compound). Katritzky et al. developed a mild two-step
procedure for the formation of enamines with benzotriazole
assistance.4 Furthermore, a large amount of transition-metal-
mediated cross-coupling reactions based on Buchwald−
Hartwig-type amination with Pd or Cu catalysts have been
reported for enamine formation.5−8 Beller and co-workers
demonstrated the use of Rh(CO)2(acac) (0.1 mol %) together
with naphos (0.2 mol %) in the hydroaminomethylation of a
variety of alkenes at relatively high CO/H2 pressure to obtain
enamines in high yields and selectivity.9
Scheme 1. Direct Catalytic Transformation of Amides to
Enamines
In an attempt to facilitate the reduction of substrate 1a, the
reaction temperature was increased from 65 to 120 °C. Still,
this did not give any conversion to the amine; instead, an 87%
selective conversion to enamine 2a was observed.16 Inspired by
this interesting result we started to optimize the conditions. By
varying the NHC (N-heterocyclic carbene) ligand, a 95%
conversion to the enamine was obtained. However, high
reaction temperature was still necessary. Investigation of
various additives, surprisingly, showed that 20 mol % of lithium
chloride could catalyze the reaction without addition of the iron
catalyst.16 More importantly, simple butyllithium could be used
as a catalyst for the reduction of tertiary amides to enamines at
a reaction temperature of 65 °C (Table 1, entry 1). Evaluation
The catalytic reduction of amides with hydrosilanes is well-
known in the literature, and this transformation usually leads to
the formation of amines.10 The direct formation of enamines
from amides under hydrosilylation conditions is a reaction
much less explored. Buchwald and co-workers developed a
hydrosilylation protocol for the reduction of amides to
aldehydes, where the initial product was characterized as an
enamine.11 The hydrosilylation was promoted by stoichio-
metric quantities of Ti(OiPr)4 in combination with Ph2SiH2.
The group of Nagashima has developed several catalytic
hydrosilylation protocols for the reduction of amides and, in
some cases, noticed that small amounts of enamines were
formed as undesired byproducts.12 Intrigued by this observa-
tion, they set out to find a selective catalytic method for the
Received: November 18, 2013
© XXXX American Chemical Society
A
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Organic Letters
Letter
Table 1. Reduction of 2-Phenyl-1-(piperidin-1-yl)ethanone
Scheme 2. Scope of the Catalytic Reduction of Amides to
Enamines
a
(1a) to (E)-1-Styrylpiperidine (2a) under Hydrosilylation
a
Conditions
b
entry
catalyst
silane
solvent
conv (%)
1
nBuLi
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(MeO)3SiH
(MeO)3SiH
(MeO)3SiH
(MeO)3SiH
(MeO)3SiH
THF
THF
toluene
DCM
MeCN
THF
THF
THF
THF
THF
THF
37
>95
80
0
2
3
4
5
6
7
8
9
KOBut
KOBut
KOBut
KOBut
KOBut
KOBut
KOBut
KOBut
KOBut
0
c
c
c
c
43
63
74
90
>95
0
,
,
d
d
,
e
c
c
,
,
d,e,f
10
11
e,f
a
Reaction conditions: amide (1.0 mmol), dry solvent (3 mL), silane 3
b
equiv, catalyst (10 mol %), 65 °C, 14 h. Conversion determined by
c
d
1H NMR spectroscopy; 5 mol % KOBut. KOBut 99.99% purity was
e
f
used. 2 mL of dry solvent was used. (MeO)3SiH 4 equiv.
of different bases that could catalyze the reaction showed that
potassium tert-butoxide was the most active and led to the
highest conversion (Table 1, entry 2). Changing the solvent to
CH2Cl2 or MeCN led to no conversion of the starting amide,
while in toluene we observed a slightly lower conversion in
comparison to reactions run in THF (Table 1, entries 2−5).
Different silanes were compared as reducing agents (PMHS,
TMDS, Ph2SiH2, (EtO)2MeSiH),16 and it was established that
only triethoxy- and trimethoxysilane were active enough to
perform the reaction (Table 1, entries 6 and 7).17 To confirm
that the catalyst (t-BuOK) is responsible for carrying out the
reaction, we set up a blank experiment that resulted in zero
conversion of the starting compound (Table 1, entry 11). To
avoid the potential influence of transition metal impurities in
the base, extra pure potassium tert-butoxide (99.99%) was
employed in all further reduction reactions. The use of t-BuOK
of higher purity also increased the conversion to enamine
(Table 1, entries 7 and 8). Further investigation of silane
equivalents and concentration dependence revealed the optimal
conditions for this reaction (Table 1, entry 10). In order to
simplify the process, a stock solution of the catalyst (t-BuOK
99.99%) in THF (0.2 M) was used.
a
Isolated yields.
Scheme 3. Plausible Mechanism of Reduction of Amides to
Enamines
To investigate the scope of the reaction, a variety of different
tertiary amides were reduced to enamines using the optimized
reaction conditions (Scheme 2). As can be seen in Scheme 2,
aromatic, heteroaromatic, and aliphatic enamines were formed
from the corresponding tertiary amides in good-to-excellent
selectivity and yields. The reaction with substrate 2a was also
carried out in 2-methyltetrahydrofuran as a more environ-
mentally friendly solvent, without any decrease in yield.18
Synthetically important aromatic halides that are sensitive to
reduction remained untouched under the reaction conditions
(2e and 2f). Furthermore, enamine 2i, derived from
thiophenol-substituted amide, can be of great value in synthesis
since it can lead to a more functionalized compound. Alkoxide-
catalyzed hydrosilylation of aldehydes, ketones, and imines
toward alcohols and amines has previously been reported,19,20
and amides containing such functionalities were not compatible
with the current protocol. However, we found that olefins could
endure under these conditions, and (E)-1-(piperidin-1-yl)hex-
3-en-1-one was reduced to the corresponding enamine 2j in
86% yield.
A plausible reaction path for the conversion of tertiary
amides to enamines is shown in Scheme 3. Previously, it has
been proposed that the base activates the silane via formation of
a pentacoordinated intermediate, which facilitates the transfer
of the hydride to the amide carbonyl to generate the tetrahedral
intermediate A (Scheme 3).20 Presumably, the intermediate
alkoxide is immediately trapped by the silane. In contrast to
amide reductions to amines, the α-proton is removed followed
by elimination of the silyl ether, which leads to the enamine.
There is also a possibility for deprotonation of an initially
formed iminium intermediate; however, this is unlikely due to
the high reactivity of iminium species toward reducing agents.
B
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Significant gas evolution was observed during the reaction,
which suggests the possibility of hydride acting as a base in the
deprotonation step. The latter could also explain the need for
more equivalents of the silane reagent.
In the reduction of compound 1l, a byproduct was formed
and characterized as amino amide 3 (Scheme 4). Evidently,
To conclude, we have developed an efficient transition-
metal-free method for the reductive dehydration of benzylic
and aliphatic tertiary amides to give enamines with high
selectivity and in good-to-excellent yields. In almost all of the
cases studied, trans-enamines were selectively formed. The
enamine formation was performed under hydrosilylation
conditions with trimethoxy- or triethoxysilane as hydride
source in the presence of catalytic amounts of t-BuOK. The
possibility of in situ trapping of the generated enamines was
demonstrated by the formation of amino amide 3. Further-
more, addition of benzyl bromide to the enamine formed from
tertiary amide 1a gave aldehyde 4 in good isolated yield after
hydrolytic workup. Additionally, highly reactive aliphatic
enamines difficult to isolate were efficiently converted to
amino alcohols using a hydroboration/oxidation protocol. We
were also able to run the reaction in 2-methyltetrahydrofuran,
also known as “green THF”, without any loss in efficiency in
the reduction of model substrate 1a. The combination of a
transition-metal-free catalytic hydrosilylation protocol per-
formed in 2-methylTHF allows for a more environmentally
friendly reduction. Alkoxides have previously been known as
catalysts for the hydrosilylation of aldehydes, ketones, and
imines19,20 and recently for amides;22 however, to our
knowledge this is the first example of an alkoxide being used
as catalyst for the transformation of amides to enamines.
Scheme 4. Unexpected in Situ Trapping of the Formed
Enamine
after the initial formation of the enamine, this nucleophilic
species attacked remaining starting amide, and after elimination
of a stabilized anion, imine intermediate B was formed (Scheme
4). The fact that diphenylmethane was isolated in 78% yield
further supports the suggested mechanism. Subsequent
reduction of the imine generated amino amide 3. It is possible
that the amide functionality in the final product remained
untouched due to severe sterical hindrance around that group.
Interestingly, if trimethoxysilane was replaced with the slightly
more sterically hindered triethoxysilane, compound 3 became
the major product with an isolated yield of 82%.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
The above-described methodology for the synthesis of
different enamines can be successfully extended to generate
more complex compounds. Aldehyde 4 was successfully
generated from 1a, via site-selective alkylation of the
intermediate enamine 2a followed by hydrolysis (Scheme
5).21 The target aldehyde 4 was isolated in 77% yield.
*E-mail: hansa@organ.su.se.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the Swedish Research
Council and the K & A Wallenberg Foundation.
■
Scheme 5. Enamine Formation Followed by Site-Selective
Alkylation
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