Synthesis of Tertiary Enamides by Ag2CO3-Promoted Pd-Catalyzed Alkenylation of Acyclic Secondary Amides

Article abstract of DOI:10.1021/acs.orglett.6b02305

A Pd-catalyzed methodology for the preparation of tertiary enamides from acyclic secondary amides and bromo acrylates under mild reaction conditions has been developed using [Pd₂(dba)₃], XantPhos, and Ag₂CO₃ as a base. The reaction occurs through a stereospecific metal-mediated oxidative-insertion mechanism.

Full text of DOI:10.1021/acs.orglett.6b02305

Letter
pubs.acs.org/OrgLett
Synthesis of Tertiary Enamides by Ag2CO3‑Promoted Pd-Catalyzed
Alkenylation of Acyclic Secondary Amides
Arnaud Delforge,† Irene Georgiou,† Adrian Kremer,† Johan Wouters,† and Davide Bonifazi*,†,‡
†Namur Research College and Department of Chemistry, University of Namur, Rue de Bruxelles 61, B-5000 Namur, Belgium
‡School of Chemistry, Cardiff University, Park Place, Main Building, CF10 3AT Cardiff, U.K.
S
* Supporting Information
ABSTRACT: A Pd-catalyzed methodology for the preparation of tertiary enamides from acyclic secondary amides and bromo
acrylates under mild reaction conditions has been developed using [Pd2(dba)3], XantPhos, and Ag2CO3 as a base. The reaction
occurs through a stereospecific metal-mediated oxidative-insertion mechanism.
n the past decade, metal-catalyzed C(sp2)−N and C(sp)−N
Apart from the alkylation of secondary enamides, methods
for directly accessing to tertiary enamides through direct
Ibond-forming reactions with amines and amides have been
under great development.1 In particular, the elaboration of
alkenylation of acyclic amides under mild conditions are
deficient (Scheme 1b, eq 3).19 This limits the versatility of
tertiary enamides as valuable stable variants of enamines to be
employed in the synthesis of natural products and heterocyclic
compounds of biological relevance.18,19 Here, we thus describe
the synthesis of tertiary N-alkyl and N-arylenamides through a
metal-catalyzed alkenylation reaction between acyclic secondary
amides and β-halo acrylates and β-halo acrylonitriles (Scheme
1b-ii). As a matter of fact, this method is an effective strategy
for synthesizing trisubstituted vinylogous imides and vinylogous
N-acylaminonitriles.
novel alkenylation reactions affording enamides2 has attracted a
lot of attention, as these functional groups are fundamental
components of a large variety of natural products3 and versatile
precursors of β-amino acids, the latter being important building
blocks for preparing biologically active peptides, small-molecule
pharmaceuticals, and chiral synthons.4 With respect to metal-
free protocols (e.g., acid-catalyzed condensation of amides and
aldehydes,5 acylation of imines,6 Curtius rearrangement of α,β-
unsaturated acyl azides,7 addition of amides to alkynes,8
condensation of aldehydes or ketones with nitriles,4f elimi-
nation of β-hydroxy-α-silyl amides,9 and electroorganic syn-
thesis,10 Scheme 1a), metal-catalyzed alkylenation reactions
have provided access to substituted enamides in high yields
with full stereocontrol on the double bond (Scheme 1b).11
Among the recently described methods, Pd- and Cu-catalyzed
coupling of alkenyl halides with amides is certainly very
efficient. Following the first report by Ogawa and Suzuki12
describing the stereospecific synthesis of enamides and
enimides from vinyl bromides and potassium amides in the
presence of a stoichiometric amount of CuI, the groups of
Buchwald,13 Porco,14 and Ma15 have developed efficient Cu(I)-
catalyzed variants that dramatically increase the scope and the
chemical compatibility of these coupling reactions (Scheme 1b,
eq 1) also starting from lactams (Scheme 1b, eq 2). Following
the first protocols by Mori and Kozawa describing intra-
molecular Pd-catalyzed vinylation of β-lactams,16 versatile Pd-
catalyzed variants have been also developed by Wallace and co-
workers17a and later by Willis,17b who reported the synthesis of
tertiary enamides (Scheme 1b, eq 2) through a coupling
reaction between an enol triflate and amides, carbamates, or
sulfonamides.
Thus, our studies commenced by examining the general
Cu(I)-catalyzed method14 (i.e., CuI (5 mol %), DMEDA (20
mol %), K2CO3, toluene, 110 °C) between N-methyl
propionamide and (E)-3-bromomethyl acrylate. Unfortunately,
under these reaction conditions, only starting materials were
observed. The use of different ligands (1,10-phenanthroline,
N,N-dimethylglycine) or changing the solvent, temperature, or
base did not lead to any improvements. Therefore, our
attention was turned toward Pd-catalyzed methodologies.
Taking into consideration the Pd-catalyzed reaction conditions
used for the coupling of β-lactams to vinyl halides16 (i.e.,
Pd(OAc)2 (10 mol %), DPEPhos (15 mol %), K2CO3, toluene,
110 °C) and applying them to the substrates of our interest,
only degradation of the starting material was observed. The
same observation was noted when XantPhos was used.
On the other hand, after the catalyst precursor was changed
to [Pd2(dba)3] in the presence of XantPhos and Cs2CO3 under
dry conditions at 65 °C for 16 h, 100% conversion was
observed, affording after purification the desired enamide (E)-1
Received: August 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
From these results, one could presume a marked activation
action of the Ag(I) ions on the halo methyl acrylate. However,
when the reaction was performed in the presence of AgBF4 or
AgOTf, no traces of the product were observed. This supports
the idea for which a synergistic effect between the Ag(I) ions
and the basic counterion improves the efficiency of the C−N
coupling. Furthermore, when other Pd sources, such as
[PdCl(C3H5)]2 (Table 1, entry 5), or microwave irradiation
at 100 °C for 2 h were used, yields higher than 80% were
obtained. No formation of enamide (E)-1 was observed (a) in
the absence of either [Pd2(dba)3] or Ag2CO3 (Table 1, entries
7 and 8) or (b) when the ligand was changed to JackiePhos,20
notorious to be effective for the formation of sterically
demanding substrates. Examination of a variety of other
ligands, including DPEPhos and XPhos, proved to be also
ineffective. Changing the solvent from THF to toluene or 1,4-
dioxane had only a minor effect in the outcome of the reaction,
and hence, THF was used. The conditions disclosed in Table 1,
entry 4, on the (E)-3-bromomethyl acrylate have been
successfully extended to its (Z)-stereoisomer, stereospecifically
producing related (Z)-enamide 2 by retention of the
configuration at the substituted vinylic carbon (Table 2, entry
3). This was further confirmed with δ-valerolactam, for which
the reaction with (Z)-3-bromomethyl acrylate also yielded
molecule 3 as the (Z)-isomer (Scheme 2).
Scheme 1. Metal-Free (a) and Metal-Catalyzed (b) Synthetic
Approaches for Preparing Enamides
Table 2. Effect of the Halide on the Cross-Coupling
Reaction Using and (Z)-3-Haloethylacrylate
in 64% yield (Table 1, entry 1). The use of weaker bases
(K2CO3 and Na2CO3) resulted in reduced yield or no
formation of enamide (E)-1 at all, respectively (Table 1,
entries 2 and 3). Instead, in the presence of Ag2CO3, an
improvement of the yield to 83% was noted (Table 1, entry 4).
X
conv (%)
yield (%)
F
0
100
100
100
0
62
70
79
Cl
Br
I
Table 1. Optimization of the Pd-Catalyzed Cross-Coupling
Reaction between N-Methyl Propionamide and (E)-3-
a
Bromomethylacrylate
When the acryl bromide was switched to the chloro and iodo
analogues (Table 2), enamide (Z)-2 was formed in 62% and
79% yield, respectively. In contrast, the fluoro precursor gave
no sign of desired enamide (Z)-2. Taken together, these results
promoted us to exclude an addition−elimination mechanism
and are fully consistent with a metal-mediated oxidative-
insertion mechanism. Having in hand the optimized reaction
conditions and the fundamental mechanistic insights, the
attention was then focused in examining the generality of this
method, by varying both the vinyl and the amide substrates.
As outlined in Scheme 2 (the E and Z notations are omitted
for clarity reasons), a variety of tertiary N-alkyl and N-aryl
enamides have been prepared employing the Ag2CO3-
promoted Pd-catalyzed conditions from moderate to good
yields. N-Methyl-, -phenyl-, and -pentyl-substituted amides
were all successfully coupled to acrylic bromides, and the
obtained yield confirmed the steric trend, with the N-pentyl
substrate being the less reactive. For example, when (E)-3-
bromomethyl acrylate was reacted with the relevant amide,
enamides 1, 5, and 6 were obtained in 83%, 63%, and 33%
yield, respectively. In general, when the N-pentyl-based amide
is coupled with any acyclic acrylic substrate, tertiary enamides
b,c
entry
catalyst
base
yield (%)
1
2
3
4
5
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[PdCl(C3H5) ]2
[Pd2(dba)3]
Cs2CO3
K2CO3
64
15
0
Na2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
83
81
85
0
d
6
7
8
[Pd2(dba)3]
0
a
Reaction conditions: N-methylpropionamide (0.3 mmol), (E)-3-
bromomethyl acrylate (0.25 mmol), catalyst (5 mol %), ligand (15 mol
%), base (0.35 mmol), MS 3 Å, THF. All yields refer to the isolated
compound (SI). All gave full conversion. Microwave irradiation, 100
b
c
d
°C, 2 h.
B
DOI: 10.1021/acs.orglett.6b02305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Pd-Catalyzed Ag2CO3-Promoted Formation of Acyclic Tertiary Enamides
a
Starting from (a) cis-3-bromoethyl acrylate; (b) trans-3-bromomethyl acrylate; (c) methyl-(E)-3-bromo-methyl acrylate; (d) methyl-(Z)-3-bromo-
2-methoxyacrylate; (e) 1:1 mixture of cis- and trans-3-bromo-2-methylacrylonitrile. All yields refer to the isolated and purified compounds.
with modest yields at around 30% were obtained (enamides 6,
11, 16, and 17). As observed for (E)-1 and (Z)-2, the geometry
of the double bond in the acryl halides has a modest effect on
the yield. In particular, when (Z)-3-bromoethyl acrylate was
used instead of (E)-3-bromomethyl acrylate, the E isomer of
the relevant enamide was obtained vs the Z isomer in the
second case, with only slightly higher yield ((E)-1 83% vs (Z)-2
70%). This is further confirmed when comparing the outcome
of the reaction leading to the formation of enamides 3 vs 4 and
6 vs 19. Notably, the protocol is also effective for the
electronically rich acrylic derivatives, such as 3-methyl and 3-
methoxy substrates, which gave rise to enamides 8−11 and 12−
16, respectively. It is worth pointing out that these reaction
conditions are certainly compatible with the majority of
thermally unstable and volatile vinyl bromides. The method
could be extended to functional substrates as 5-(bromo-
methylene)-1,3-dioxolan-4-one (molecule 22; see the SI for its
synthesis), a potential precursor for preparing β-amino α-
ketoacids. When the 1,3-dioxolan-4-one was reacted with N-
Figure 1. ORTEP representation of (E)-20 and cyclobutyl derivative
21 as determined by X-ray analysis (space group: P21/c). Atomic
displacement parameters, obtained at 223 K, are drawn at the 30%
probability level.
pentylamide, enamide 20 was isolated in 66% yield.
In our attempt to elucidate the double-bond configuration of
one of the tertiary enamides bearing a trisubstituted vinyl
group, two types of crystals (rod- and rhombic-like) deriving
from the crystallization of product 20 (being the only solid
derivative) were obtained and analyzed by single X-ray
diffraction (Figure 1). The first proved to be the Z isomer of
enamide 20 ((Z)-20, Scheme 3), and to our surprise, the
second crystals resulted from dispiro derivative 21 featuring a
central cyclobutane ring (Figure 1). Notably, no crystals of
isomer (E)-20 were found. Redissolution of the crystals in
suggesting that the dispiro derivative perishes in solution and
can be isolated only at the solid state. Complementary variable-
temperature (VT) 1H NMR investigations of a CDCl3 solution
containing 20 show coalescence between 5 and −10 °C of the
proton resonances in the diagnostic enamidic chemical shift
region, suggesting the presence of a dynamic equilibrium (see
Figure SI.5). Unfortunately, the overlap with the aromatic
proton resonances hampers the univocal assignment of the
coalescing peaks (see Figure SI.5). However, when similar VT
1
nonacidic CDCl3 gave the same H NMR spectrum as that
obtained before crystallization, namely that of 20 with no sign
of the typical proton resonances of the cyclobutyl ring,
C
DOI: 10.1021/acs.orglett.6b02305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Proposed E/Z Isomerization in Solution
Mediated by a Dispirocyclobutane Intermediate
ACKNOWLEDGMENTS
■
We gratefully acknowledge the EU through the ERC Starting
Grant “COLORLANDS” and the FRS-FNRS. We thank Prof.
A. Krief (University of Namur) for the useful discussion.
REFERENCES
■
(1) (a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48,
6954. (b) Beletskaya, I. P.; Cheprakov, A. V. Organometallics 2012, 31,
7753. (c) Evano, G.; Theunissen, C.; Pradal, A. Nat. Prod. Rep. 2013,
30, 1467. (d) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008,
108, 3054. (e) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett
2003, 1379. (f) Lu, T.; Hsung, R. P. ARKIVOC 2014, 127.
(2) Tracey, M. R.; Hsung, R. P.; Antoline, J.; Kurtz, K. C. M.; Shen,
L.; Slafer, B. W.; Zhang, Y. In Science of Synthesis, Houben-Weyl Methods
of Molecular Transformations; Weinreb, S. M., Ed.; Georg Thieme
Verlag KG, 2005; Chapter 21.4.
(3) (a) Kuranaga, T.; Sesoko, Y.; Inoue, M. Nat. Prod. Rep. 2014, 31,
514. (b) Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman, B. J.; Porco, J.
A. Org. Lett. 2002, 4, 3103. (c) Shen, R.; Porco, J. A. Org. Lett. 2000, 2,
1333. (d) Wu, Y.; Seguil, O. R.; De Brabander, J. K. Org. Lett. 2000, 2,
4241.
investigations were performed with enamide 13 (Figures SI.1,
see also 9, Figure SI.6), the 1H NMR spectrum in CD3CN at rt
displayed a vinylic proton resonance at 7.52 ppm that, upon
cooling to −40 °C, shifts and clearly splits into two peaks
centered at 7.76 and 7.29 ppm, respectively. Likely, this trend
has been observed for the vinylic proton resonances of isomers
(E)-20 and (Z)-20 (Figure SI.5). In contrast, the VT 1H NMR
spectra of all enamides bearing doubly substituted acryl (e.g., 5,
Figure SI.7) and of the Br-derived acrylate precursors (see
Figures SI.3 and SI.4) displayed no coalescence of the vinylic
proton resonances. These observations promoted us to
hypothesize that the enamides bearing acryl moieties decorated
with EDGs (Me or OMe) undergo E/Z isomerization in
solution, and therefore, the products are obtained as isomeric
mixtures at rt. Likely, this could hypothetically occurs through
the formation of a dispiro cyclobutane species that serve as
intermediate of a fast dynamic equilibrium possibly involving
sequential ring-opening and ring-closure reactions (Scheme 3).
On the contrary, all enamides bearing a vinyl moiety substituted
with only EWGs are thermally stable at rt and can be
stereospecifically prepared by this procedure.
In conclusion, we have demonstrated an Ag2CO3-promoted
Pd-catalyzed alkenylation procedure providing access to acyclic
tertiary enamides starting from acryl bromides and sterically
encumbered N-substituted amides. A wide range of enamides
was synthesized, proving the versatility of the method. The
reaction likely undergoes through a stereospecific oxidative-
insertion mechanism favored by the presence of Ag2CO3. VT
1H NMR experiments showed that the enamides bearing acryl
moieties decorated with EDGs undergo E/Z isomerization in
solution. The ease of access toward trisubstituted vinylogous
imides and N-acyl amino-nitriles,21 makes this Pd-catalyzed
alkenylation method appealing to organic chemists.
́
(4) (a) Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard, A. J.;
Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656. (b) Bode, J. W.; Fox, R.
M.; Baucom, K. D. Angew. Chem., Int. Ed. 2006, 45, 1248.
(c) Pattabiraman, V.; Bode, J. W. Nature 2011, 480, 471. (d) Courant,
T.; Dagousset, G.; Masson, G. Synthesis 2015, 47, 1799. (e) Carbery,
D. R. Org. Biomol. Chem. 2008, 6, 3455. (f) Rappoport, Z. The
Chemistry of Enamines. In The Chemistry of Functional Groups; John
Wiley and Sons: New York, 1994.
(5) Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron Lett.
1993, 34, 1479.
(6) Boeckman, R. K.; Goldstein, S. W.; Walters, M. A. J. Am. Chem.
Soc. 1988, 110, 8250.
(7) (a) Kuramochi, K.; Watanabe, H.; Kitahara, T. Synlett 2000,
2000, 397. (b) Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407.
(8) Kondo, T.; Tanaka, A.; Kotachi, S.; Watanabe, Y. J. Chem. Soc.,
Chem. Commun. 1995, 413.
(9) Furstner, A.; Brehm, C.; Cancho-Grande, Y. Org. Lett. 2001, 3,
̈
3955.
(10) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.; Yamane,
S.; Kanazawa, T.; Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697.
(11) (a) Panda, N.; Jena, A. K.; Raghavender, M. ACS Catal. 2012, 2,
539. (b) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973.
(12) Ogawa, T.; Kiji, T.; Hayami, K.; Suzuki, H. Chem. Lett. 1991, 20,
1443.
(13) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. S. L. Org. Lett.
2003, 5, 3667.
(14) Han, C.; Shen, R.; Su, S.; Porco, J. A. Org. Lett. 2004, 6, 27.
(15) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809.
(16) Kozawa, Y.; Mori, M. J. Org. Chem. 2003, 68, 3064.
(17) (a) Wallace, D. J.; Klauber, D. J.; Chen, C.; Volante, R. P. Org.
Lett. 2003, 5, 4749. (b) Willis, C.; Brace, G. N.; Holmes, I. P. Synthesis
2005, 3229.
(18) (a) Zhu, W.; Zhao, L.; Wang, M.-X. J. Org. Chem. 2015, 80,
12047. (b) Bai, X.-Y.; Wang, Z.-X.; Li, B.-J. Angew. Chem., Int. Ed.
2016, 55, 9007. (c) Xu, X.-M.; Zhao, L.; Zhu, J.; Wang, M.-X. Angew.
Chem., Int. Ed. 2016, 55, 3799.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02305.
(19) Wang, M.-X. Chem. Commun. 2015, 51, 6039.
(20) Hicks, J. D.; Hyde, A. M.; Cuezva, A. M.; Buchwald, S. L. J. Am.
Chem. Soc. 2009, 131, 16720.
(21) Nicolaou, K. C.; Mathison, C. J. N. Angew. Chem., Int. Ed. 2005,
44, 5992.
Synthetic protocols and spectroscopic data, relevant X-
ray data for molecules (E)-20 and 21, and VT H NMR
spectra of all enamides (PDF)
1
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bonifazid@cardiff.ac.uk.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.6b02305
Org. Lett. XXXX, XXX, XXX−XXX