Ruthenium- and rhodium-catalyzed cross-coupling reaction of acrylamides with alkenes: Efficient access to (Z,E)-dienamides

Article abstract of DOI:10.1039/c2cc36137j

Ruthenium- and rhodium-catalyzed direct oxidative cross-coupling reactions of acrylamides with alkenes were developed. These methods provide an efficient route for the synthesis of (Z,E)-dienamides in excellent yields with good stereoselectivity. The catalytic systems allowed oxidative olefination of a wide range of alkenes bearing different functional groups, such as CO₂R, COMe, SO₂Ph, aryl, CONHBn, CN, PO(OEt)₂, as well as Weinreb amide.

Full text of DOI:10.1039/c2cc36137j

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COMMUNICATION
Ruthenium- and rhodium-catalyzed cross-coupling reaction of
acrylamides with alkenes: efficient access to (Z,E)-dienamidesw
Jian Zhanga and Teck-Peng Loh*ab
Received 23rd August 2012, Accepted 30th September 2012
DOI: 10.1039/c2cc36137j
Ruthenium- and rhodium-catalyzed direct oxidative cross-coupling
reactions of acrylamides with alkenes were developed. These methods
provide an efficient route for the synthesis of (Z,E)-dienamides in
excellent yields with good stereoselectivity. The catalytic systems
allowed oxidative olefination of a wide range of alkenes bearing
different functional groups, such as CO2R, COMe, SO2Ph, aryl,
CONHBn, CN, PO(OEt)2, as well as Weinreb amide.
Scheme 1 Direct cross-coupling reaction of acrylamides with alkenes
Butadiene is an important structural motif present in a large class
of pharmaceutically active molecules and complex natural
products,1 such as naphthomycin A,2 rifabutine,3 (+)-dactyl-
olide,4 etc. Thus, development of efficient, selective and
practical synthetic methodology would be highly desirable.
To our knowledge, carbonyl olefination5 such as Wittig reaction
and cross-coupling reactions6 such as Heck coupling reactions
represents two general approaches for the synthesis of butadienes.
However, direct alkenylation via vinylic C–H bond activation
remains highly desirable as it minimizes waste formation and
obviates pre-functionalization steps. To date, only several research
groups, such as Ishii,7 Loh,8 Yu,9 Glorius10 and Liu11 reported
that certain classes of butadienes can be synthesized by Pd- or
Rh-catalyzed olefination between simple alkenes, although the
substrate scope is often limited. Recently, ruthenium has
emerged as an efficient catalyst for C–H bond activation,
olefination and alkynylation reaction.12 However, to the best
of our knowledge, the use of inexpensive ruthenium catalyst12c
for direct cross-coupling reaction of olefins to form butadienes
has not been reported. During our studies on oxidative olefination
of vinylic C–H bond,8 we developed a ruthenium-catalyzed direct
cross-coupling reaction between acrylamides and electron-
deficient alkenes to produce (Z,E)-dienamides in high efficiency.13a
The same transformation also could be achieved by rhodium
catalyst (Scheme 1).13b The catalytic systems allowed oxidative
olefination of a wide range of alkenes bearing different functional
groups, such as CO2R, SO2Ph, aryl, CONHBn, CN, PO(OEt)2, as
well as Weinreb amide, which opens up new possibilities for the
providing (Z,E)-dienamides.
synthesis of a series of complex natural products and drugs. At
the outset of our studies, the reaction of methacrylamide with
n-butyl acrylate was explored to screen the catalytic conditions,
employing [RuCl2(p-cymene)]2 as the catalyst14 (Table 1).
The cross-coupling reaction exhibited low conversion in the
absence of additive (entry 1).14 Usage of KPF6 or AgSbF6 as
an additive led to the desired product in moderate yield
Table 1 Optimization of catalytic conditionsa
Entry Catalyst Oxidant
Solvent
Yield (%)
1
[Ru]
[Ru]
[Ru]
[Ru]
[Ru]
[Ru]
[Ru]
[Rh]
[Rh]
[Rh]
[Rh]
[Rh]
Cu(OAc)2ꢀH2O t-AmOH
Cu(OAc)2ꢀH2O Dioxane
Cu(OAc)2ꢀH2O Dioxane
Cu(OAc)2ꢀH2O Dioxane/H2O
28
50
44
55
2b
3c
4b,d
5b,e
6b,f
7b
Cu(OAc)2ꢀH2O Dioxane/H2O/AcOH 83
Cu(OAc)2ꢀH2O Dioxane/H2O
57
Dioxane/H2O/AcOH 21
MeCN
AgOAc
Ag2CO3
8
0
63
68
85
83
9b
Cu(OAc)2ꢀH2O DME
10
11
12g
Cu(OAc)2ꢀH2O t-AmOH
Cu(OAc)2ꢀH2O Acetone
Cu(OAc)2ꢀH2O Acetone/H2O
a
Reaction conditions unless otherwise specified: 1a (0.1 mmol,
1.0 equiv.), 2a (0.15 mmol, 1.5 equiv.), Ru or Rh (5 mol%), and an
oxidant (2.0 equiv.) in a specific solvent (0.6 mL), at 100 1C, under
nitrogen, 18 h. The yields indicated in the table are isolated yields.
a Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore, 637616. E-mail: teckpeng@ntu.edu.sg;
Fax: +65 6515 8229; Tel: +65 6513 8475
b Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui, 230026, P. R. China
b
c
KPF6 (20 mol%) was used as an additive. AgSbF6 (20 mol%) was
d
used as an additive. Dioxane/H2O = 2/1(v/v). Dioxane/H2O/
e
f
AcOH = 8/4/1(v/v/v). 2.0 equiv. AcOH added. Acetone/H2O =
g
w Electronic supplementary information (ESI) available: Detailed
experimental procedures analytical data, See DOI: 10.1039/c2cc36137j
2/1 (v/v). [Ru] = [RuCl2(p-cymene)]2; [Rh] = [RhCp*Cl2]2.
c
11232 Chem. Commun., 2012, 48, 11232–11234
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(entries 2 and 3).15 To optimize the catalytic conditions, the
effect of solvents was subsequently examined (see ESIw).
To our delight, a mixed solvent system of dioxane/H2O/
AcOH (v/v/v = 8/4/1) dramatically improved the reaction,
and the yield was increased to 83% with good stereoselectivity
(Z/E = 96/4) (entry 5). The intramolecular cyclization
reaction towards unsaturated lactam was not observed.10,14a
Other oxidant, such as AgOAc, led to low yield. Simple
ruthenium salts such as RuCl3 were also examined but were
ineffective (see ESIw). The same model reaction was chosen to
screen the Rh-catalyzed olefination conditions. Different
reaction parameters, such as solvent and oxidant, were
explored (Table S2 in ESIw). Optimal yields of dienamide
were obtained with [RhCp*Cl2]2, along with Cu(OAc)2ꢀH2O
as an oxidant, and acetone as the solvent (entry 11).
Table 3 Exploration of the scope of acrylamides towards direct
cross-coupling with various functionalized alkenes by rhodiumab
With the two optimised catalytic systems in hand, we firstly
explored the scope of Ru-catalyzed oxidative olefination by
employing differently substituted acrylamides and alkenes
(Table 2). Acrylamides 1 bearing different alkyl groups or no
substituent on the nitrogen atom were smoothly reacted.
However, the cross-coupling reaction between N-aryl metha-
crylamides with acrylate showed low conversion even at
elevated temperature, and the desired products were isolated in
a
The reactions were carried out as follows: acrylamide 1 (0.2 mmol),
acrylate 2 (0.3 mmol), [RhCp*Cl2]2 (2.5 mol%), Cu(OAc)2ꢀH2O
Table 2 Exploration of the scope of various acrylamides towards
direct cross-coupling with alkenes by ruthenium catalystab
b
(0.4 mmol) in acetone (0.6 mL) at 100 1C, 18 h. The yields
indicated in the table are isolated yields. The reaction was
c
d
performed at 120 1C, 12 h. The reactions were performed at 80 1C
for 6 h. 5.0 equiv. acrylonitrile used.
e
31–39% yield (3fa–3ja).12c Further structural modifications at the
a-position slightly influenced the catalytic process (3ka, 3la, 3ma).16
It is worthy to note that N-benzyl-2,3-dimethylpropenamide also
led to the tetra-substituted diene in low yield (3na). This is due to
the degradation of the starting material under the acidic conditions.
If a methyl group was introduced into the b-position of the
acrylamide, the reaction was sluggish and the corresponding
product was isolated in 23% yield (3oa).14d,18b Also, acrylamide
with an un-substituted olefin unit reacted with low conversion,
and a mixture of isomers (Z/E = 1/1) was obtained in only
31% yield (3pa).14d a-Methylacrylate also showed low conversion
and a by-product (3ac0) was formed in 22% yield during
the catalytic process.17c The catalytic system was not only
restricted to the usage of acrylates, but also allowed for a series
of differently functionalized alkenes, and the functional groups
could be CONHBn (3ad), PO(OEt)2 (3ae), CN (3af), SO2Ph
(3ag) and 4-Cl phenyl (3ah).17 To our delight, Weinreb
acrylamide was efficiently converted as well (3ai and 3ki).
Next, we examined the scope of Rh-catalyzed cross-coupling
reaction of acrylamides with alkenes. This catalytic system also
proved to be tolerant of a series of functional groups (Table 3).
In addition, competition experiments between differently
substituted styrenes with acrylamide as limiting reagent was
performed, showing that electron-deficient styrene reacted
preferentially.10,17a In contrast, intermolecular competition experi-
ments between differently N-substituted and a-substituted acryl-
amides revealed that the electron-rich substrate was more efficiently
converted, hence indicating an electrophilic C–H bond activation
(see ESIw). To obtain some further mechanistic insight, we
a
The reactions were carried out as follows: acrylamide 1 (0.1 mmol),
acrylate 2a (0.15 mmol), [RuCl2(p-cymene)]2 (2.5 mol%), KPF6
(20 mol%), Cu(OAc)2ꢀH2O (0.2 mmol) in dioxane/H2O/AcOH =
b
8/4/1 (0.6 mL) at 100 1C, 18 h. The yields indicated in the table
c
are isolated yields. The reaction was performed at 120 1C.
5.0 equiv. acrylonitrile used. 1.2 equiv. alkene used.
d
e
c
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4 (a) J. Tanaka and T. Higa, Tetrahedron Lett., 1996, 37,
5535; (b) A. Cutignano, I. Bruno, G. Bifulco, A. Casapullo,
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2010, 132, 5018.
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2001, 34, 633; (b) V. Ritleng, C. Sirlin and M. Pfeffer, Chem.
Rev., 2002, 102, 1731; (c) T. W. Lyons and M. S. Sanford,
Chem. Rev., 2010, 110, 1147; (d) J. Le Bras and J. Muzart, Chem.
Rev., 2011, 111, 1170; (e) E.-I. Negishi, Z. Huang, G. Wang,
S. Mohan, C. Wang and H. Hattori, Acc. Chem. Res., 2008,
41, 1474.
7 Y. Hatamoto, S. Sakaguchi and Y. Ishii, Org. Lett., 2004, 6, 4623.
8 (a) Y.-H. Xu, J. Lu and T.-P. Loh, J. Am. Chem. Soc., 2009,
131, 1372; (b) Y.-H. Xu, W.-J. Wang, Z.-K. Wen, J.-J. Hartley and
T.-P. Loh, Tetrahedron Lett., 2010, 51, 3504; (c) Y.-H. Xu,
Y.-K. Chok and T.-P. Loh, Chem. Sci., 2011, 2, 1822.
Scheme 2 Isotopically labeled experiment.
performed some control experiments with isotopically labeled
solvents. Both of the catalytic conditions led to Z-selective
olefinic H/D exchange on methacrylamide 1a in the absence of
acrylate, thus indicating reversible cyclometallation modes
(Scheme 2a).19 In contrast, if the same reaction is performed
in the presence of acrylate 2a, no deuterium incorporation is
observed in unreacted 1a, and no H/D scrambling between the
b-olefinic proton of the product 3aa and the solvent was
observed (Scheme 2b).
9 H. Yu, W. Jin, C. Sun, J. Chen, W. Du, S. He and Z. Yu, Angew.
Chem., Int. Ed., 2010, 49, 5792.
10 T. Besset, N. Kuhl, F. W. Patureau and F. Glorius, Chem.–Eur. J.,
2011, 17, 7167.
11 Y. Zhang, Z. Cui, Z. Li and Z.-Q. Liu, Org. Lett., 2012, 14, 1838.
12 (a) L. Ackermann, Chem. Rev., 2011, 111, 1315; (b) L. Ackermann and
R. Vicente, Top. Curr. Chem., 2010, 292, 211; (c) L. Ackermann,
A. V. Lygin and N. Hofmann, Angew. Chem., Int. Ed., 2011, 50, 6379.
13 (a) In 2010, Hirano reported a Ru-catalyzed cross-coupling reaction
of butadiene with acrylate, see: M. Hirano, Y. Arai, N. Komine and
S. Komiya, Organometallics, 2010, 29, 5741(b) Glorius’ group
reported a similar work, but our method provided many advantages:
without additive (AgSbF6), usage of less expensive and more
environmentally benign solvent (acetone vs. dioxane), lower
reaction temperature, better stereoselectivity etc. See ref. 10.
14 Ruthenium complex [RuCl2(p-cymene)]2 has emerged as an
efficient catalyst for C–H bond activation, see selected references:
(a) L. Ackermann, L. Wang, R. Wolfram and A. V. Lygin, Org.
Lett., 2012, 14, 728; (b) K. Padala and M. Jeganmohan, Org. Lett.,
2011, 13, 6144; (c) L. Ackermann, J. Pospech, K. Graczyk and
K. Rauch, Org. Lett., 2012, 14, 930; (d) L. Ackermann, A. V. Lygin
and N. Hofmann, Org. Lett., 2011, 13, 3278.
Based on these experiments we proposed the possible
mechanism. The reaction is presumably initiated by cyclometala-
tion of acrylamide 1 by amide-directing C–H bond activation.
Coordination of alkene 2 to the metal center, and followed by
insertion of the carbon–carbon double bond forms a 7-membered
ruthacycle or rhodacycle species. Subsequent b-elimination occurs
to afford the desired (Z,E)-dienamide 3.
In summary, we have developed Ru- and Rh-catalytic
systems for the direct cross-coupling of acrylamides with
electron-deficient alkenes forming (Z,E)-dienamides. Both of the
two transformations exhibit wide functional group compatibility
and substrate flexibility, and thus would have potential broad
application in organic synthesis.
15 (a) M. A. Bennett and A. K. Smith, J. Chem. Soc., Dalton Trans.,
1974, 233; (b) S. Fernandez, M. Pfeffer, V. Ritleng and C. Sirlin,
´
Organometallics, 1999, 18, 2390.
We gratefully acknowledge the Nanyang Technological
University, Ministry of Education Tier 2 Grant (MOE 2011-
T2-1-013) for the funding of this research.
16 The electron-rich acrylamide was easier to be reacted, thus revealed
an electrophilic activation manifold. This result is in agreement
with intermolecular competition experiments (see ESIw).
17 For the two catalytic conditions: (a) Styrene and 4-methoxy
styrene were also tested, but both of them led to low conversion,
and the desired dienamide was obtained in o20% yield. Also,
alkyl olefin, such as, 5-methoxy pentene, couldn’t be well reacted,
and only trace product was observed. These results indicated that
electron-deficient alkene was reacted preferentially. (See competition
experiment and ref. 14b and 18a); (b) moreover, alkenes with an
internal olefin unit, such as methyl trans-2-hexenoate, was totally
inactive, and the starting materials were mostly recovered; (c) homo-
coupling by-product originated from acrylamide could be detected
(o10% yield) when less reactive substrates were utilized.
18 (a) F. Wang, G.-Y. Song and X.-W. Li, Org. Lett., 2010, 12, 5430;
(b) Y. Su, M. Zhao, K. Han, G. Song and X. Li, Org. Lett., 2010,
12, 5462.
Notes and references
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19 A related references about Z-selective vinylic C–H bond activation
see: J. Wencel-Delord, C. Nimphius, F. W. Patureau and F. Glorius,
Chem.–Asian J., 2012, 7, 1208.
c
11234 Chem. Commun., 2012, 48, 11232–11234
This journal is The Royal Society of Chemistry 2012