N-Heterocyclic carbene catalyzed tail-to-tail oligomerization of N,N-dimethylacrylamide (DMAA) and the search for the Stetter reaction of DMAA with benzaldehyde

Article abstract of DOI:10.1016/j.tetlet.2015.09.104

The tail-to-tail oligomerization of N,N-dimethylacrylamide catalyzed by N-heterocyclic carbenes (NHCs) was investigated, giving the dimerization and trimerization products in a moderate combined yield. Reaction intermediates involved in the new oligomerization have been observed by NMR and ESI-MS. We showed the first NHC-catalyzed cross coupling of methyl methacrylate and N,N-dimethylacrylamide, and the reaction of benzaldehyde/benzoin with N,N-dimethylacrylamide.

Full text of DOI:10.1016/j.tetlet.2015.09.104

Accepted Manuscript
N-Heterocyclic Carbene Catalyzed Tail-to-Tail Oligomerization of N,N-Di-
methyl-acrylamide (DMAA) and the Search for the Stetter Reaction of DMAA
with Benzaldehyde
Oue-artorn Rajachan, Mathias Paul, Veera Reddy Yatham, Jörg-M. Neudörfl,
Kwanjai Kanokmedhakul, Somdej Kanokmedhakul, Albrecht Berkessel
PII:
S0040-4039(15)30146-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.104
TETL 46776
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
25 July 2015
21 September 2015
23 September 2015
Please cite this article as: Rajachan, O-a., Paul, M., Yatham, V.R., Neudörfl, Jörg-M., Kanokmedhakul, K.,
Kanokmedhakul, S., Berkessel, A., N-Heterocyclic Carbene Catalyzed Tail-to-Tail Oligomerization of N,N-
Dimethyl-acrylamide (DMAA) and the Search for the Stetter Reaction of DMAA with Benzaldehyde, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.09.104
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
N-Heterocyclic Carbene-Catalyzed Tail-to-
Tail Oligomerization of N,N-Dimethyl-
acrylamide (DMAA), and the Search for the
Stetter Reaction of DMAA with
Benzaldehyde
Leave this area blank for abstract info.
Oue-artorn Rajachan, Mathias Paul, Veera Reddy Yatham, Jörg-M. Neudörfl, Kwanjai
*
Kanokmedhakul, Somdej Kanokmedhakul, and Albrecht Berkessel

1
Tetrahedron Letters
N-Heterocyclic Carbene Catalyzed Tail-to-Tail Oligomerization of N,N-Dimethyl-
acrylamide (DMAA) and the Search for the Stetter Reaction of DMAA with
Benzaldehyde
a
b
b
b,c
Oue-artorn Rajachan, Mathias Paul, Veera Reddy Yatham, Jörg-M. Neudörfl, Kwanjai
a
a
b
Kanokmedhakul, Somdej Kanokmedhakul, and Albrecht Berkessel *
a
Natural Products Research Unit, Department of Chemistry, and Center of Excellence for Innovation in Chemistry, Faculty of Science,
Khon Kaen University, Khon Kaen, 40002, Thailand.
b
Department of Chemistry, Cologne University, Greinstrasse 4, Cologne, 50939, Germany
c
x-Ray crystallography, Cologne University, Greinstrasse 4, Cologne, 50939, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The tail-to-tail oligomerization of N,N-dimethylacrylamide catalyzed by N-heterocyclic
carbenes (NHCs) was investigated, giving the dimerization and trimerization products in
moderate combined yield. Reaction intermediates involved in the new oligomerization have
been observed by NMR and ESI-MS. We showed the first NHC-catalyzed cross coupling of
methyl methacrylate and N,N-dimethylacrylamide, and the reaction of benzaldehyde/benzoin
with N,N-dimethylacrylamide.
Available online
Keywords:
2
015 Elsevier Ltd. All rights reserved.
N-Heterocyclic carbene
Michael acceptor
Umpolung
Tail-to-tail oligomerization
Organocatalysis
1
The use of N-heterocyclic carbenes (NHCs) as organocatalysts
of several acrylate derivatives, e.g. methyl methacrylate (MMA,
Scheme 2). In addition, the Matsuoka group also reported the
NHC-catalyzed cyclotetramerization of acrylates.
is based on their ability to invert the inherent polarity of
functional groups. The Umpolung of aldehydes catalyzed by
NHCs gives the Breslow intermediate which can react with a
8
2
3
second aldehyde to produce benzoin products, and with a
4
Michael system to form the Stetter products (Scheme 1).
Recently, the NHC-catalyzed Umpolung of Michael acceptors
involving deoxy-Breslow intermediates has been developed. The
first successful transformation was reported by Fu and co-
5
workers, in the synthesis of cyclopentenones. The groups of
6
7
Glorius and Matsuoka have reported the tail-to-tail dimerization
Scheme 2. NHC-catalyzed tail-to-tail dimerization of acrylic
acid derivatives.
According to the literature, there is no report on the NHC-
catalyzed tail-to-tail oligomerization of N,N-dimethylacrylamide
(DMAA). There appears to be only one report on the catalytic
dimerization of DMAA, which is metal-based. Sakakibara et al.
reported the Ru catalyzed dimerization of DMAA, along with the
9
formation of a small amount of a non-characterized trimer.
In recent years, our group has studied intermediates of the
1
0
Scheme 1. Overview of NHC-catalyzed reactions of aldehydes
and Michael systems.
NHC-catalyzed Umpolung of aldehydes. Herein we report the
tail-to-tail oligomerization of DMAA, the NHC-catalyzed cross
coupling of DMAA with MMA, and the attempted Stetter
reaction of benzaldehyde with DMAA.

Corresponding author. Tel.: +49-221-470-3283; fax: +49-221-470-5102; e-mail: berkessel@uni-koeln.de

2
Tetrahedron
I. Screening of the oligomerization of acrylamide derivatives in
Table 1. Optimization of the tail-to-tail oligomerization of
DMAA.
the presence of the triphenyl triazolylidene carbene A
First, we screened the reaction of acrylamides and the NHC A by
NMR experiments (Scheme 3). The reaction of acrylamide (1a)
and NHC A (2:1 molar ratio) in THF-d was performed in an
8
NMR tube and monitored by NMR spectroscopy. For the N-
unsubstituted acrylamide 1a, the spirocyclic lactam 2a was
1
observed. For example, characteristic H NMR signals of 2a are a
multiplet at δ=2.84-2.78 ppm (1H, H2b), a multiplet at δ=2.41-
2
.30 ppm (2H, H2a and H3b), and a multiplet at δ=1.96-1.91
13
ppm (1H, H3a). C NMR signals are 173.5 (C4), 99.5 (C1),
9.85 (C2), and 29.4 (C3). Analogously, the N-monosubstituted
acrylamide 1b (1:1 molar ratio) furnished the spiro-lactam 2b.
2
1
[Selected H NMR: 2.89-2.84 (m, 1H, H2b), 2.68-2.63 (m, 1H,
13
H3b), 2.36-2.32 (m, 1H, H2a), 2.25-2.20 (m, 1H, H3a) and
C
NMR: 170.98 (1C, C4), 102.62 (1C, C1), 29.21 (1C, C3), and
7.12 (1C, C2)]. When DMAA was investigated in benzene-d
1:1 molar ratio), NMR monitoring revealed a mixture of the E/Z
2
6
(
isomers of the deoxy-Breslow intermediate II (Scheme 3), the
second addition intermediate IV (Scheme 3), as well as the
unreacted carbene. The ESI-MS analysis showed the cor-
responding peaks at m/z=397.2, m/z=496.3, and m/z=298.1,
respectively. When two equivalent of DMAA were employed,
instead only a mixture of the E/Z isomers of the secondary
a
entry
catalyst
solvent temperature
yield
[%]
E/Z
3
o
[ C]
3
4
1
2
3
4
5
6
7
8
A
A
A
A
A
toluene
THF
105
80
46 11 94/6
20
9
-
-
-
-
-
-
93/7
11
d
addition intermediate IV was observed.
DCE
90
tr
-
-
-
-
-
-
Ph
d
O
Ph
N
R
N
DMSO
105
90
tr
N
O
N
R
N
N
4
d
THF-d8
CH
CN
tr
N
3
+
1
(1)
b
N
H
3
Ph
A
-
105
105
-
-
-
Ph
2
Ph
Ph
2a, R = H
2b, R = m-methoxybenzene
B
toluene
A
1a, R = H
c
C-I/DIPEA
toluene
a
105
1
1b, R = m-methoxybenzene
b
Dipp = 2,6-di-iso-propylphenyl, calculated from H NMR spectrum, 1 mol %
c
d
Ph
N
O
A, 1 mol% DIPEA, trace, detected by GC.
Ph
N
O
N
N
A
N
N
+
(2)
N
O
benzene-d6
N
N
H
Ph
Ph
Ph
N
Ph
O
[
II+H]+ m/z 397.2
[IV+H]+ m/z 496.3
Scheme 3. The screening reaction of acrylamides catalyzed by A
Solvent effects on this reaction catalyzed by A are
summarized in Table 1. Best results in the tail-to-tail oligo-
merization of DMAA were obtained when toluene was used as
the solvent. The reaction was followed by GC and ESI-MS
analysis, which showed that the reaction was not completed after
o
2
1
4 h (90 C). The DMAA oligomerization could be completed at
o
05 C within 24 h to give the dimer 3 in 47% yield with a 94:6
E/Z ratio and the trimer 4 in 11% isolated yield. When using
THF as the solvent, the reaction generated 3 and 4 (20 and 9%
o
yield) at 80 C, and DMAA was recovered (12%). With other
solvents, including DCE, DMSO, acetonitrile, or under solvent
free conditions, no product formation was observed. We then
investigated the catalytic activities of various NHCs and NHC
precursors in the presence of DIPEA (di-iso-propylethylamine) at
o
1
05 C in toluene. In contrast to carbene A, all other NHCs/
azolium salts B-I did not induce product formation.
Scheme 4. Proposed mechanism for the tail-to-tail dimerization
and trimerization of DMAA, effected by NHC A.
II. Proposed mechanism
From the NMR and ESI-MS analyses, a reaction mechanism is
proposed (Scheme 4). The addition of carbene A to the Michael
acceptor DMAA generates the enolate I, followed by proton
transfer to give the deoxy-Breslow intermediate II, which was
detected by NMR spectroscopy and ESI-MS analysis
intermediate IV (detected by NMR and ESI-MS, m/z =496.3). A
formal 1,2-proton shift in IV followed by elimination of NHC A
from intermediate V gives the dimer 3. Alternatively, inter-
mediate IV can react with a third molecule of DMAA leading to
the intermediate VI. Proton transfer in VI generates the inter-
mediate VII (detected by ESI-MS, m/z =595.3). The elimination
of carbene A from VII produces the DMAA trimer 4.
(m/z=367.2). Addition of this intermediate II to a second mole-
cule of DMAA leads to tail-to-tail dimerization, forming the
intermediate III, and a second proton transfer gives the

3
Scheme 5. Homo- and cross-coupling of DMAA and MMA, catalyzed by NHC A.
Scheme 6. The reaction of benzaldehyde and DMAA catalyzed by NHC A.
III. The NHC-catalyzed cross-coupling of DMAA and MMA
Acknowledgments
The NHC-catalyzed cross-coupling of DMAA and MMA (1:1)
was investigated under the conditions optimized for DMAA-
oligomerization (Scheme 5). It was found that the tail-to-tail
dimerization (3) and trimerization (4) products of DMAA were
obtained in 26 and 7 % yield, whereas the mixed cross coupling
products 5 and 6 were formed in 26 and 6 % yield. Additionally,
This work was supported by the Thailand Research Fund via the
Royal Golden Jubilee Ph.D. program, Khon Kaen University
(0353/2551), and by BASF SE.
References and notes
1
8
6 % of the MMA homodimer 7 were isolated (combined yield
1%).
1.
(a) Grossmann, A.; Enders, D. Angew. Chem. Int. Ed. 2012, 51, 314-
25; Angew. Chem. 2012, 124, 320-332. (b) Douglas, J.; Churchill, G.;
3
Smith, A. D. Synthesis 2012, 44, 2295-2309. (c) Mahatthananchai, J.;
Bode, J. W. Acc. Chem. Res. 2014, 47, 696-707. (d) Bugaut, X.;
Glorius, F. Chem. Soc. Rev. 2012, 41, 3511-3522. (e) Hopkinson, M.
N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014, 510, 485-496.
(f) D. M. Flanigan, F. Romanov-Michailidis, N. A. White, T. Rovis,
Chem. Rev. 2015, 115, 9307-9387.
IV. The reaction of DMAA with benzaldehyde catalyzed by NHC
A
The NHC-catalyzed reaction of DMAA with benzaldehyde (1:1)
was performed as shown in Scheme 6. In the presence of
1
mol % of carbene A and 1 mol % of benzoic acid as co-
catalyst, benzoin (8), the Michael addition product of benzoin to
2.
3.
(a) Breslow, R. J. Am. Chem. Soc. 1957, 79, 1762-1763. (b) Breslow,
R. J. Am. Chem. Soc. 1958, 80, 3719-3726.
Ukai,T.; Tanaka, R.; Dokawa, T. J. Pharm. Soc. Jpn. 1943, 63, 296-
300.
(a) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407-496. (b)
Stetter, H.; Schreckenberg, M. Angew. Chem. Int. Ed. Engl. 1973, 12,
12
DMAA (9), and the lactone (10) were formed. The molecular
structure of the Michael product 9 was unambiguously proven by
13
X-ray crystallography (Figure 1). In the absence of the benzoic
acid co-catalyst, no product formation was observed. As a control
experiment, a mixture of preformed benzoin and DMAA was
exposed to DBU. Again, the formation of the Michael addition
products 9 and 10 was detected by GC-MS. From this result, we
conclude that the NHC A promotes both benzoin formation from
benzaldehyde (as Umpolung catalyst), and subsequent Michael
addition of the latter to DMAA (as Brønsted base).
4
.
8
1.
Fischer, C.; Smith, S. W.; Powell, D. A.; Fu, G. C. J. Am. Chem. Soc.
006, 128, 1472-1473.
5
6
.
.
2
(a) Biju, A. T.; Padmanaban, M.; Wurz, N. E.; Glorius, F. Angew.
Chem. Int. Ed. 2011, 50, 8412-8415; Angew. Chem. 2011, 123, 8562-
8
565. (b) Schedler, M.; Wurz, N. E.; Daniliuc, C. G.; Glorius, F. Org.
In conclusion, our studies on the first organocatalytic tail-to-
tail oligomerization of DMAA gave the dimer 3 and the new
trimer 4. The reaction mechanism and the intermediates were
proposed based on NMR and ESI-MS analyses. Furthermore, we
report the first example of a NHC-catalyzed cross coupling of
DMAA and MMA, and the reaction of benzaldehyde/benzoin
with DMAA catalyzed by a NHC.
Lett. 2014, 16, 3134-3137.
7
.
(a) Matsuoka, S.; Ota, Y.; Washio, A.; Katada, A.; Ichioka, K.; Takagi,
K.; Suzuki, M. Org. Lett. 2011, 13, 3722-3725. (b) Kato, T.; Ota, Y.;
Matsuoka, S.; Takagi, K.; Suzuki, M. J. Org. Chem. 2013, 78, 8739-
8
4
747. (c) Kato, T.; Matsuoka, S.; Suzuki, M. J. Org. Chem. 2014, 79,
484-4491.
8
9
.
.
Matsuoka, S.; Namera, S.; Washio, A.; Takagi, K.; Suzuki, M. Org.
Lett. 2013, 15, 5916-5919.
Higashimura, M.; Imamura, K.; Yokogawa, Y.; Sakakibara, T. Chem.
Lett. 2004, 33, 728-729.
1
0. (a) Berkessel, A.; Elfert, S.; Etzenbach-Effers, K.; Teles, J. H. Angew.
Chem. Int. Ed. 2010, 49, 7120-7124; Angew. Chem. 2010, 122, 7275-
279. (b) Berkessel, A.; Elfert, S.; Yatham, V. R.; Neudörfl, J.-M.;
Schlörer, N. E.; Teles, J. H. Angew. Chem. Int. Ed. 2012, 51, 12370-
2374; Angew. Chem. 2012, 124, 12537-12541. (c) Berkessel, A.;
Yatham, V. R.; Elfert, S.; Neudörfl, J.-M. Angew. Chem. Int. Ed. 2013,
2, 11158-11162; Angew. Chem. 2013, 125, 11364-11369. (d)
7
1
5
Figure 1. X-ray crystal structure of the alkylated benzoin 9.

4
Tetrahedron
Berkessel, A.; Elfert, S. Adv. Synth. Catal. 2014, 356, 571-578. (e)
Yatham, V. R.;. Neudörfl, J.-M.; Schlörer, N. E.; Berkessel, A. Chem.
Sci. 2015, 6, 3706-3711.
1
1. ESI-MS analysis of the crude reaction mixture also points to the
+
formation of a DMAA tetramer [m/z = 419.3 (+Na )], see Supporting
Information (Figure 74S).
1
2. Ye, W.; Cai, G.; Zhuang, Z.; Jia, X.; Zhai, H. Org. Lett. 2005, 7, 3769-
3
771.
1
3. CCDC 1406034 (9) contains supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/ cif.

5
Graphical abstract