Palladium(II)-catalyzed direct alkenylation of nonaromatic enamides

Article abstract of DOI:10.1021/ol301249n

A mild and efficient method for the direct alkenylation of nonaromatic enamides was achieved through a palladium(II)-catalyzed C-H functionalization. The reaction scope includes cyclic and acyclic enamides and a range of activated alkenes. This approach represents the first successful direct C(3)-functionalization of nonaromatic cyclic enamides.

Full text of DOI:10.1021/ol301249n

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3304–3307
Palladium(II)-Catalyzed Direct
Alkenylation of Nonaromatic Enamides
Nicolas Gigant and Isabelle Gillaizeau*
Institut de Chimie Organique et Analytique, UMR 7311 CNRS, rue de Chartres,
ꢀ
Universite d’Orleans, F-45067 Orleans Cedex 2, France
ꢀ
ꢀ
isabelle.gillaizeau@univ-orleans.fr
Received May 9, 2012
ABSTRACT
A mild and efficient method for the direct alkenylation of nonaromatic enamides was achieved through a palladium(II)-catalyzed CÀH
functionalization. The reaction scope includes cyclic and acyclic enamides and a range of activated alkenes. This approach represents the
first successful direct C(3)-functionalization of nonaromatic cyclic enamides.
Transition-metal-catalyzed regioselective CÀC bond
formationsviaCÀH bond activation haverecentlybecome
one of the most attractive research subjects in organic
synthesis.1 Indeed, atom economy, nontoxic and inexpen-
sive solvents, catalytic reagents, and readily available
substrates without preliminary functionalization are fun-
damental criteria for accessing clean reactions.2 Among
these earlier studies, particularly noteworthy is the MizorokiÀ
Heck reaction which involves aryl halides and alkenes
in the presence of transition-metal catalysts to yield
π-conjugated aromatic compounds.3 Alternatively, the
Fujiwara and Moritani4 reaction has recently been widely
used to link various aromatic cores directly with activated
alkenes via a dehydrogenative process.5 It constitutes a
powerful halogen-free strategy to explore the scope of the
alkenylation method. However it is noteworthy that to
date only a few studies have reported the direct CÀC bond
functionalization of nonaromatic substrates with alkenes.6
In connection with our ongoing project on the develop-
ment of efficient methodologies to generate an original
collection of small nitrogen-containing molecules,7 we
focused on the direct C-3 functionalization of enamides I
(Figure 1).8 While the C-2 functionalization was recently
developed by direct arylation, especially in the case of
acyclic compounds II,9 the regioselective C-3 functionali-
zation of nonsubstituted enamides of type I has not yet
been described. We therefore envisaged examining the
(1) For recent reviews on transition-metal-catalyzed CÀH activa-
tion, see: (a) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev.
2011, 40, 5068–5083. (b) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev.
2011, 40, 1976–1991. (c) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem.
Soc. Rev. 2011, 40, 1885–1898. (d) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147–1169. (e) Messaoudi, S.; Brion, J. D.; Alami, M.
Eur. J. Org. Chem. 2010, 6495–6516. (f) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624–655. (g) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792–9826.
(2) For recent reviews, see: (a) Dunn, P. J. Chem. Soc. Rev. 2012, 41,
1452–1461. (b) Sheldon, R. A. Chem. Soc. Rev. 2012, 41, 1437–1451. (c)
Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301–312. (d) New-
house, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38,
3010–3021. (e) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H.
Acc. Chem. Res. 2008, 41, 40–49. (f) Horvath, I. T.; Anastas, P. T. Chem.
Rev. 2007, 107, 2167–2168.
(3) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4442–4489. (b) Dounay, A. B.; Overman, L. E. Chem. Rev.
2003, 103, 2945–2963. (c) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev.
2000, 100, 3009–3066.
(4) (a) Moritani, I.; Fujiwara, Y. Tetrahedron Lett. 1967, 8, 1119–
1122. (b) Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S.
J. Am. Chem. Soc. 1969, 91, 7166–7169.
(5) For recent or significant examples, see: (a) Ackermann, L.; Wang,
L.; Wolfram, R.; Lygin, A. V. Org. Lett. 2012, 14, 728–731. (b) Li, Z.;
Zhang, Y.; Liu, Z.-Q. Org. Lett. 2012, 14, 74–77. (c) Zhang, Y.; Li, Z.;
Liu, Z.-Q. Org. Lett. 2012, 14, 226–229. (d) Xiang, S.-K.; Zhang, B.;
Zhang, L.-H.; Cui, Y.; Jiao, N. Chem. Commun. 2011, 47, 8097–8099. (e)
Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170–1214. (f) Yeung, C. S.;
Dong, V. M. Chem. Rev. 2011, 111, 1215–1292. (g) Kim, D.; Hong, S.
Org. Lett. 2011, 13, 4466–4469. (h) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 6964–6967. (i) Garcia-Rubia, A.; Fernandez-
Ibanez, M.; Gomez Arrayas, R.; Carretero, J. C. Chem.;Eur. J. 2011,
17, 3567–3570. (j) Nishikata, T.; Lipshutz, B. H. Org. Lett. 2010, 12,
1972–1975. (k) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc.
2008, 130, 9254–9256. (l) Beck, E. M.; Grimster, N. P.; Hatley, R.;
Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528–2529. (m) Grimster,
M. P.; Gaunlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int.
Ed. 2005, 44, 3125–3129.
r
10.1021/ol301249n
Published on Web 06/13/2012
2012 American Chemical Society

direct alkenylation of the appropriate CÀH bond to gen-
erate conjugated enamides III. We report herein our
successful results on the direct regio- and stereoselective
Pd-catalyzed alkenylation of a range of enamides and
demonstrate the cost-effective and high reaction efficiency,
excellent functionalgroup compatibility, and mildreaction
conditions of our methodology.
isolated as an E-isomer in 56% yield (entry 1).10 No
beneficial effect was observed by changing the nature of
the acidic source (entries 2 and 3). Owing to the sensitivity
of enamides in acidic media, the quantity of acetic acid was
reduced by half by using dimethylacetamide as cosolvent; a
slight increase in the yield of 3a (71%) was thus observed
(entry 4). The absence of acid dramatically reduced the
yield of the reaction (entry 5) by affecting the electrophi-
licity of the metal ions, highlighting the importance of
balancing the two factors. Further optimizing the reaction
conditions, we found that satisfying yields could also be
achieved by using Ag2CO3 as additive (entries 6 and 7). As
expected, when the additive was removed, no conversion
occurred and starting material is recovered (entry 8). A
trace quantity of 3a was obtained when the reaction was
conducted under air rather than a pure oxygen atmosphere
(entry 9); in this case the conversion was extremely slow.
Moreover, catalytic activity decreased by using lower
catalyst loading (entries 10 and 11) or by modifying the
copper source (entry 12).
Figure 1. Pd(II) direct functionalization strategy.
Optimized conditions using inexpensive copper salt in
association with dioxygen as a co-oxidant, an inexhausti-
ble and nonpolluting resource (Table 1, entry 4), can be
applied to different alkene partners (Scheme 1). Electron-
deficient alkenes 2 that display a range of functional motifs
were investigated, providing conjugated enamides 3aÀi in
good to excellent yields (70À90%). These newly formed
enamides were obtained with absolute regio- and stereo-
selectivity (E-isomers)10 and polar functional groups were
tolerated. To our knowledge this is the first report on the
catalytic direct alkenylation in beta position of enamide.6a,b
In light of recent advances in this area, we began this
study by performing the direct alkenylation of enamide 1a
in the presence of 2 equiv of ethyl acrylate 2a, 10 mol % of
Pd(OAc)2 as a catalyst, and 1 equiv of Cu(OAc)2 H2O as
3
oxidant in acetic acid under a slow bubbling of oxygen at
70°C (Table1).6c Asreported inthe literature, a co-oxidant
(O2) and an acidic source are both required to carry out
the Pd-catalyzed direct alkenylation in good yields.5g Under
these conditions, the desired conjugated enamide 3a was
Table 1. Optimization of the Direct Coupling of Enamidesa
entry
oxidant
solvent
AcOH
co-oxidant
timeb (h)
yieldc (%)
1
2
Cu(OAc)2 H2O
O2
3
4
2
5
6
4
8
8
8
7
7
3
56d
28
3
Cu(OAc)2 H2O
PivOH
O2
3
3
Cu(OAc)2 H2O
TFA
O2
14
3
4
Cu(OAc)2 H2O
AcOH/DMA (1:1)
DMA
O2
71
3
5
Cu(OAc)2 H2O
O2
46
3
6
Cu(OAc)2 H2O
AcOH/DMA (1:1)
PivOH
Ag2CO3
Ag2CO3
none
air
67
3
7
Cu(OAc)2 H2O
72
3
8
Cu(OAc)2 H2O
AcOH/DMA (1:1)
AcOH/DMA (1:1)
AcOH/DMA (1:1)
AcOH/DMA (1:1)
AcOH/DMA (1:1)
0
3
9
Cu(OAc)2 H2O
trace
46e
0f
67g
3
10
11
12
Cu(OAc)2 H2O
O2
3
Cu(OAc)2 H2O
O2
3
Cu(OTf)2
O2
a Reaction conditions unless otherwise specified: enamide 1a (1 equiv), ethyl acrylate 2 (2 equiv), oxidant (1 equiv), Pd(OAc)2 (0.1 equiv), and additive
(bubbling or 2 equiv) at 70 °C. b Reactions were carried out until disappearance of the starting material. c Yield of pure product after purification by
column chromatography. d By using 0.5 equivalent of Cu(OAc)2 H2O, 3a was isolated in 47% yield. e Pd(OAc)2 (0.05 equiv) was used. f Reaction
3
conducted without palladium catalyst. g Cu(OTf)2 was used as oxidant.
Org. Lett., Vol. 14, No. 13, 2012
3305

In addition, it is noticeable that in the presence of a
simple unactivated alkene as cyclohexene, homocoupling
compounds 3ka and 3kb were isolated. The reaction was
accordingly conducted without additional alkene and the
inseparable unconjugated dimers 3ka and 3kb were thus
isolated in 52% yield as a 87:13 ratio. The nature of 3ka
and 3kb was demonstrated by NMR. On the basis of the
preliminary studies and observations, an electrophilic
palladation pathway involving an alkenyl Pd complex
was envisaged (Scheme 2). Nucleophilic attack of this
palladium species onto the enamide bond and subsequent
β-hydride elimination furnished the homocoupling pro-
duct 3ka, and reoxidation by Cu(II) regenerated Pd(II).
3kb was provided from 3ka through PdÀH insertion and
immediate β-H elimination.11 As previously noted,5i un-
conjugated dienes were favored.
Scheme 1. Direct Coupling of Enamides with Different
Alkenesa,b
Scheme 2. Plausible Mechanism for the Homocoupling
Reaction
a Reaction conditions: 1a (1 equiv), 2 (2 equiv), Cu(OAc)2.H2O
(1 equiv), Pd(OAc)2 (0.1 equiv), and O2 (bubbling) at 70 °C in AcOH/
DMA (1:1) for 2À8 h. b Yield of pure product after purification by column
chromatography. c Ratio determined by 1H NMR.
Interestingly, conducting the coupling with methyl metha-
crylate provided compounds 3ja and 3jb, isolated in 57%
yield as inseparable 49:51 regioisomers.11 The β-hydride
elimination derivative 3jb was in fact observed when the
methyl group was present at the R-position of the acrylate.
Different enamide derivatives 1 were then screened
under these optimized alkenylation conditions in the pre-
sence of benzyl acrylate 2b (Scheme 3). Modifications
concerning both the protecting grouponthe nitrogen atom
and the size of the heterocycle were thus envisaged. Con-
jugated enamides 3lÀn were isolated with good yields.
Endoenamides furnished the desired dienes 3o,p in excel-
lent yields. However, the introduction of a C2-electron-
rich phenyl substituent to the cyclic enamide significantly
decreased the yield (of 3q); pleasingly, in this case, the use
of Ag2CO3 in pure pivalic acid gave 3q in 60% yield. These
conditions were amenable to other electron-rich enamides
substituted with a heteroatom (O or S) in the beta position.
Substrates 3r,s were thus isolated in moderate yields.
(6) (a) Pankajakshan, S.; Xu, Y.-H.; Chang, J. K.; Low, M. T.; Loh,
T. P. Angew. Chem., Int. Ed. 2012, 51, 1–6. (b) Yu, Y.-Y.; Niphakis,
M. J.; Georg., G. I. Org. Lett. 2011, 13, 5932–5935. (c) Bai, Y.; Zeng, J.;
Cai, S.; Liu, X.-W. Org. Lett. 2011, 13, 4394–4397. (d) Yu, H.; Jin, W.;
Sun, J.; Du, W.; He, S.; Yu, Z. Angew. Chem., Int. Ed. 2010, 49, 5792–
5797. (e) Xu, Y.-H.; Wang, W.-J.; Wen, Z.-K.; Hartley, J. J.; Loh, T.-P.
Tetrahedron Lett. 2010, 51, 3504–3507. (f) Xu, Y.-H.; Lu, J.; Loh, T.-P.
J. Am. Chem. Soc. 2009, 131, 1372–1373.
(7) For recent examples, see: (a) Gigant, N.; Claveau, E.; Bouyssou,
P.; Gillaizeau, I. Org. Lett. 2012, 14, 844–847. (b) Gigant, N.; Dequirez,
G.; Retailleau, P.; Gillaizeau, I.; Dauban, P. Chem.;Eur. J. 2012, 18,
90–94. (c) Claveau, E.; Gillaizeau, I.; Kalinowska, J.; Bouyssou, P.;
Coudert, G. J. Org. Chem. 2009, 74, 2911–2914. (d) Claveau, E.;
Gillaizeau, I.; Bruel, A.; Coudert, G. J. Org. Chem. 2007, 72, 4832–
ꢀ
4836. (e) Mousset, D.; Gillaizeau, I.; Sabatie, A.; Bouyssou, P.; Coudert,
(9) (a) Liu, Y.; Li, Dan.; Park, C.-M. Angew. Chem., Int. Ed. 2011, 50,
7333–7336. (b) Ruan, J.; Iggo, J. A.; Berry, N. G.; Xiao, J. J. Am. Chem.
Soc. 2010, 132, 16689–16699. (c) Hyder, Z.; Ruan, J.; Xiao, J. Chem.;
Eur. J. 2008, 14, 5555–5566. (d) Mo, J.; Xiao, J. Angew. Chem., Int. Ed.
2006, 45, 4152–4157. (e) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005,
127, 751–760.
G. J. Org. Chem. 2006, 71, 5993–5999.
(8) For recent reviews, see: (a) Gopalaiah, K.; Kagan, H. B. Chem.
Rev. 2011, 111, 4599–4657. (b) Matsubara, R.; Kobayashi, S. Acc. Chem.
Res. 2008, 41, 292–301. (c) Carbery, D. R. Org. Biomol. Chem. 2008, 6,
3455–3460.
3306
Org. Lett., Vol. 14, No. 13, 2012

by both a greater encumbrance and the increased basicity
of its conjugate base.12 Moreover, the use of pivalic acid in
conjunction with oxygen proved to be inefficient, showing
the good and unique correlation between the carboxylic
acid and the silver salt. Finally, acyclic enamide was found
toperformdirect alkenylation (3t) albeit inlow yield (21%)
and with slow conversion.13
Scheme 3. Direct Coupling of Different Enamides 1 with Benzyl
Acrylate 2ba
An attempt was also made with the macrocyclic enamide
4 (Scheme 4). Interestingly, the acyclic R,ω-aminoaldehyde
5, which could be considered as a useful linker,14 was
isolated because of the high sensitivity of this enamide to
oxidative conditions.15
In summary, we have developed an efficient methodol-
ogy for the direct palladium(II)-catalyzed alkenylation of
nonaromatic enamides. The generality of this approach
provides a useful access to C-3 functionalized enamides,
stable enamine surrogates, with absolute regio- and stereo-
selectivity and good functional group compatibility.
Further applications of this methodology for the genera-
tion of suitably functionalized key scaffolds are in progress
and the results of these investigations will be reported
in due course.
Scheme 4. Synthesis of R,ω-Aminoaldehyde 5
a a
Reaction conditions: 1 (1 equiv), 2b (2 equiv), Cu(OAc)2.H2O
(1 equiv), Pd(OAc)2 (0.1 equiv) and O2 (bubbling) at 70 °C in AcOH/
DMA (1:1) for 2À8 h. b Reaction conditions: 1 (1 equiv), 2b (2 equiv),
Cu(OAc)2 H2O (1 equiv), Pd(OAc)2 (0.1 equiv), and Ag2CO3 (2 equiv)
3
at 70 °C in PivOH for 3À8 h. c Yield of pure product after purification by
column chromatography.
ꢁ
Acknowledgment. The MESR (Ministere de l’Enseigne-
ment Superieur et de la Recherche) is gratefully acknowl-
edged for the doctoral fellowship to N.G.
ꢀ
Recent reports have proposed that carboxylate-assisted
CÀH bond transformations proceed via a deprotonative
metalation mechanism leading to a decrease of the transi-
tion-state energy.12 The preference for pivalic acid com-
pared to acetic acid, which is less voluminous, is explained
Supporting Information Available. Full characteriza-
1
tion details including H and 13C NMR, IR, MS, and
HRMS. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) The E configuration of the alkenes was confirmed from the
NOESY spectra and/or the trans coupling constants (J = 15À16 Hz)
(see the Supporting Information for details). It is noteworthy that traces
of homocoupling compounds were also oberved.
(11) Ozawa, F.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi,
K.; Moriguchi, K. Organometallics 1993, 12, 4188–4196.
(12) (a) Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron 2008,
64, 6015–60220. (b) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am.
Chem. Soc. 2007, 129, 14570–14571. (c) Lafrance, M.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 16496–16497. (d) Ackermann, L. Chem. Rev.
2011, 111, 1315–1345.
(13) 62% of the starting material was recovered after 8 h.
(14) For one recent example, see: Kim, I.-H.; Nishi, K.; Tsai, H.-J.;
Bradford, T.; Koda, Y.; Watanabe, T.; Morisseau, C.; Blanchfield, J.;
Toth, I.; Hammock, D. D. Bioorg. Med. Chem. 2007, 15, 312–323.
(15) Kumagai, T.; Tokida, A.; Kidoura, K.; Seshimoto, O.; Mukai,
T. Tetrahedron Lett. 1982, 23, 873–876.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3307