Ynamide Preactivation Allows a Regio- and Stereoselective Synthesis of α,β-Disubstituted Enamides

Article abstract of DOI:10.1002/anie.201709128

A novel ynamide preactivation strategy enables the use of otherwise incompatible reagents and allows preparation of α,β-disubstituted enamides with high regio- and stereoselectivity. Mechanistic analysis reveals the intermediacy of a triflate-bound intermediate as a solution-stable, effective keteniminium reservoir, whilst still allowing subsequent addition of organometallic reagents.

Full text of DOI:10.1002/anie.201709128

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Accepted Article
Title: Ynamide Preactivation Allows a Regio- and Stereoselective
Synthesis of α,β-disubstituted Enamides
Authors: Lucas Loss Baldassari, Aurelien de la Torre, Jing Li, Diogo
Seibert Lüdtke, and Nuno Maulide
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709128
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10.1002/anie.201709128
Angewandte Chemie International Edition
COMMUNICATION
Ynamide Preactivation Allows a Regio- and Stereoselective
Synthesis of -disubstituted Enamides
Lucas L. Baldassari,[a] Aurélien de la Torre,[b] Jing Li,[b] Diogo S. Lüdtke*[a] and Nuno Maulide*[b]
Abstract: A novel ynamide preactivation strategy enables the
use of otherwise incompatible reagents and allows preparation
of -disubstituted enamides with high regio- and
stereoselectivity. Mechanistic analysis reveals the intermediacy
of a triflate-bound intermediate as a solution-stable, effective
keteniminium reservoir, whilst still allowing subsequent addition
of organometallic reagents.
The enamide motif is a very significant functionality in organic
molecules. Not only is it widespread in many bioactive natural
products,[1] but its electron-rich double bond presents a broad
palette of reactivity. Indeed, enamides are common substrates
for asymmetric hydrogenations, epoxidations, cyclopropanations
or cycloadditions, among others.[2],[3] Enamides can be
classically obtained by condensation of a carbonyl derivative
with the corresponding amide (Scheme 1A),[4] a route that is
typically plagued by regio- and stereoselectivity issues whenever
unsymmetrical dialkyl ketones are employed. Other approaches
include the isomerization of allylamides,[5] hydroamidation of
alkynes,[6] or transition metal-catalyzed N-alkenylation.[7]
Recently, the functionalization of ynamides has emerged as a
particularly appealing alternative. Indeed, several methods were
developed for the preparation of functionalized enamides
carrying heteroatomic substituents.[8],[9] Carbon-carbon bond
formation can also be achieved, notably by the carbometallation
of ynamides, regioselectively affording a wide range of -
disubstituted enamides (Scheme 1B).[10],[11] Strikingly,
methods to access -disubstituted enamides are much more
scarce (Scheme 1C). In 2011, Sato developed a Ru-catalyzed
coupling of ynamides limited to ethylene as a partner, affording
2-aminobuta-1,3-diene.[12] Subsequently, Zhu and co-workers
reported
a
Pd-catalyzed arylation and alkynylation of
ynamides.[13] In 2015, Reddy et al. proposed a similar Pd-
catalyzed alkynylation of ynamides.[14] Finally, the same year,
Hou described an alkylative carboxylation of ynamides.[15]
Despite these remarkable advances, to date there is no direct
method to access -alkyl enamides from ynamides.
Scheme 1. Synthesis of and-substituted enamides.
We aimed at filling this methodology gap by exploiting the
chemistry of acid-mediated activation of ynamides.[16] We
reasoned that the keteniminium ion resulting from acidic
activation could be trapped by an organometallic nucleophile,
effectively achieving
a
regioselective -functionalization
(Scheme 1D). Although this approach would provide a new
efficient and straightforward access to -disubstituted
enamides, we were conscious that two important challenges
needed to be addressed, namely: (1) The use of a Brønsted acid
activator along with a Brønsted basic organometallic nucleophile
was bound to result in self-quenching of the two species. In
addition, keteniminium ions are known to be highly unstable
species and their generation from ynamides under acidic
conditions was, to the best of our knowledge, never performed
without having a nucleophile directly present in the reaction
mixture[17]; and (2) To be of synthetic interest, the addition
should lead to high E/Z stereoselectivity. In this Communication
[a]
[b]
L. L. Baldassari, Prof. Dr. D. S. Lüdtke
Institute of Chemistry, Universidade Federal do Rio Grande do Sul
Av. Bento Gonçalves 9500, 91501-970, Porto Alegre, RS, Brazil
E-mail: dsludtke@iq.ufrgs.br
Dr. A. de la Torre, Dr. J. Li, Prof. Dr. N. Maulide
Institute of Organic Chemistry, University of Vienna
Währinger Straße 38, 1090 Vienna (Austria)
E-Mail: nuno.maulide@univie.ac.at
Homepage: http://maulide.univie.ac.at
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201709128
Angewandte Chemie International Edition
COMMUNICATION
(Scheme 1E), we describe the unprecedented Brønsted acid-
intermediate (entry 12). Increasing slightly the amount of TfOH
to 1.2 equiv. (entry 15) led us to the best result for the formation
of the enecarbamate 2a. The use of alkyl-Grignard and alkylzinc
halides as the organometallic species was also tested but
results were inferior (entries 16 and 17). Notably, a single
diastereomer of the product 2a was consistently observed in
these experiments (vide infra).
mediated preactivation of ynamides as
a tool to allow
organometallic addition. This enables the synthesis of -
disubstituted enamides, formally derived from unsymmetrical
dialkyl ketones, in a regio- and stereoselective fashion.
At the outset, we elected to decouple the acid-mediated
activation and the nucleophilic addition events. Thus, our initial
attempts at the envisioned reaction were carried out on the
model substrate ynamide 1a. This substrate was reacted with a
Brønsted acid, followed by addition of the mild nucleophile
Et2Zn,[18] in hope of obtaining the enamide 2a. Selected results
of these studies are summarized in Table 1.[19] Initial results
using para-toluenesulfonic acid, methanesulfonic acid, acetic
acid or trifluoroacetic acid were disappointing and no trace of
product was detected (entries 1-4).
With suitable conditions in hand, we investigated the scope of
the reaction using a broader range of ynamides (Scheme 2). A
number of alkyl ynamides with linear, branched and cyclic
chains led to the corresponding enamides 2a-i in good yields
and excellent diastereoselectivity. Importantly, an alkyl chloride
was tolerated and the corresponding product 2f was obtained in
79% yield, as a single diastereoisomer. Aryl ynamides were also
competent substrates for the enamide synthesis, and phenyl
(2k), naphthyl (2l) and substituted aryl moieties (2m-u) were well
tolerated in the reaction conditions.
Table 1. Optimization of the reaction conditions for the reaction of ynamide 1a
with Et2Zn.
O
1) TfOH, DCM, 15 min., 0 o
C
O
O
N
pre-activation
O
R
O
N
R
Et
2a-v
2) Et2Zn (2.5 equiv.), 0 oC to rt, 3h
1a-u
Entry
1
HA (x equiv)
TsOH (1.1)
MsOH (1.1)
AcOH (1.1)
CF3CO2H (1.1)
Tf2NH (1.1)
TfOH (1.1)
TfOH (1.1)
TfOH (1.1)
TfOH (1.1)
TfOH (1.1)
TfOH (1.1)
TfOH (1.1)
TfOH (1.1)
TfOH (1.1)
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
toluene
DCE
Time (min)
R-M
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
EtMgBr
EtZnBr
Yield (%)a
40
40
60
60
20
20
20
20
20
5
0
0
O
N
O
O
2
O
O
O
O
N
N
N
3
0
4
0
2c 71%
2a 78%
2b 69%
2d 80%
5
0
O
N
O
O
O
6
66
0
O
O
O
O
N
O
N
Cl
N
7
8
57
0
2h 81%
2g 80%
2f 79%
2e 75%
9
THF
O
10
11
12
13c
14b
DCM
DCM
DCM
DCM
DCM
56
68
41
73
64
O
N
O
O
O
O
15
30
15
15
N
N
O
O
N
2j 72%
Z/E: 4.5/1
2k 86%
2l 62%
2i 68%
O
O
O
O
Br
F
Cl
O
O
O
N
N
N
N
15c
16
TfOH (1.2)
TfOH (1.1)
TfOH (1.1)
DCM
DCM
DCM
15
20
20
78
29
15
Cl
2p 81%
2n 82%
2o 71%
2m 44%
O
17
O
O
O
Cl
Cl
Me
a
F3C
O
O
O
O
N
- Yields refer to pure, isolated material. All reactions run at r.t. unless
N
N
N
indicated. b – reaction at -78 °C. c – reaction at 0 °C.
Me
2q 79%
2s 76%
2t 80%
2r 78%
The use of triflimide (Tf2NH)[20] was also unfruitful in this
transformation (entry 5), and a dramatic improvement was
brought about by the action of triflic acid (entry 6) which enabled
for the first time the preparation of enamide 2a. Additionally, a
solvent screening was performed and the best yields were
achieved using dichloromethane (cf. entries 6-9). To further
optimize the yield of the reaction, we studied the pre-activation
time and temperature (entries 10-15), and we found that keeping
the reaction at 0 oC for 15 minutes prior to organometallic
addition (entry 15) led to optimal results. Attempts using lower
temperatures did not result in any improvement, (entry 14) and
longer generation times led to noticeable decomposition of the
O
N
O
MeO2C
O
O
N
Me
2v 84%
2u 74%
Scheme 2. Substrate scope for the reaction between ynamides and diethyl- or
dimethylzinc. Yields refer to pure, isolated products.
As depicted, aryl-enamides substituted with chlorine, bromine,
fluorine, trifluoromethyl and ester functional groups have been
obtained selectively. In addition, enamide 2v, resulting from
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10.1002/anie.201709128
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COMMUNICATION
addition of Me2Zn was also obtained in very good yield.[21] In all
cases, the stereoconfiguration of the enamide was assigned
based on NOESY NMR experiments and, with the exception of
cyclopropyl-substituted 2j, Z-configured, trisubstituted products
were exclusively (> 20:1 ratio) obtained in all cases.[19]
Additionally, enamides 2g (R=C4H9, 79% yield) and 2k (R=Ph,
88% yield) were prepared in gram-scale reactions, without any
drop in yield.
We next turned our attention to the use of different
organometallic species. After some experimentation, we found
that trialkylaluminum reagents are competent nucleophiles,
expanding the breadth of this transformation (Scheme 3).[22]
Both aryl and alkyl ynamides could be subjected to the reaction
with trialkylaluminum reagents affording the corresponding
enamides in good to excellent yields, with complete regio- and
stereoselectivity. Reactions of phenyl-substituted ynamide with
Me3Al, Et3Al, i-Bu3Al, and (C8H17)3Al afforded the corresponding
enamides 2v, 2k, 2w, and 2x in excellent yields. In addition,
alkyl-substituted ynamides led to products 2y, 2z, and 2za in
good yields.
Figure 1. 1H NMR (400 MHz, CD2Cl2) spectra for: a) ynamide 1k, and b) vinyl
triflates (E)-3 and (Z)-3, obtained 15 min after the addition of TfOH.
Assignment of HA and HB was made based on a NOESY experiment (see SI
for details).
Scheme 4. Origin of the stereoselectivity
In summary, we herein present a new methodology for the
synthesis of disubstituted enamides, relying upon a triflic-
acid mediated preactivation. This preactivation event enables
the use of otherwise incompatible reagents and allows
preparation of the title products with high regio- and
stereoselectivity, in good to very good yields. Mechanistic
analysis reveals the intermediacy of triflate-bound keteneaminal
3 as a solution-stable keteniminium reservoir, whilst showcasing
the unique role of triflate in allowing subsequent addition of an
organometallic species. As this constitutes (to the best of our
knowledge) the first time that keteniminium ions are generated
without the desired nucleophile already present in the reaction
mixture, we believe this work will open new vistas for the
understanding and exploiting of sequential addition of
nucleophiles to those highly reactive species.
Scheme 3. Substrate scope for the reaction between ynamides and
trialkylaluminum reagents. Yields refer to pure, isolated products.
To obtain further insight on the mechanism of the reaction,
we performed in situ NMR studies (Figure 1). Addition of triflic
acid to a solution of ynamide 1k in CD2Cl2 led to the formation of
two new compounds, whose structures were assigned as the
1
vinyl triflates (E)-3 and (Z)-3 by H NMR (Figure 1, bottom) and
NOESY (cf. SI for details). Importantly, the 1.5:1 ratio between
vinyl triflates (E)-3 and (Z)-3 is not reflected in the
stereoselectivity of the final product obtained upon the addition
of the organometallic reagent to the reaction mixture. We thus
believe that the high stereoselectivity observed is the result of a
stereoconvergent process in which the stereoisomeric vinyl
triflates behave as a metastable keteniminium ion reservoir. The
organometallic reagent then approaches the least hindered face
of the highly reactive keteniminium, thus delivering the (Z)-
enamide 2 as the major product (Scheme 4).[23]
Acknowledgements
We thank Dr. H. Kählig (Univ. Vienna) and Prof. F. P. Santos (UFRGS) for
expert assistance with NMR experiments. Generous support of this research
by the EU (VINCAT CoG 682002 to N.M.), the DFG (MA 4861/4-2), the
Brazilian agencies CAPES (CAPES-PVE PVE 88881.030400/2013-01), CNPq,
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10.1002/anie.201709128
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COMMUNICATION
[11] For carbometalation of ynamides, followed by trapping of the resulting
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and the University of Vienna is acknowledged. L.L.B. thanks CAPES for a
Sandwich PhD fellowship.
Keywords: ynamide • preactivation • regioselectivity •
stereoselectivity • keteniminium
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10.1002/anie.201709128
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Lucas L. Baldassari, Aurélien de la
Torre, Jing Li, Diogo S. Lüdtke* and
Nuno Maulide*
Page No. – Page No.
Ynamide Preactivation Allows a
Regio- and Stereoselective Synthesis
of -disubstituted Enamides
Activate first, attack later: a novel ynamide preactivation strategy enables the use
of otherwise incompatible reagents and allows preparation of -disubstituted
enamides with high regio- and stereoselectivity. Mechanistic analysis reveals the
intermediacy of a triflate-bound species as a solution-stable, effective keteniminium
reservoir, whilst still allowing subsequent addition of organometallic reagents.
This article is protected by copyright. All rights reserved.