Highly regioselective intermolecular hydroacylations of enamides with salicylaldehydes

Article abstract of DOI:10.1021/ol201431c

Highly regioselective intermolecular hydroacylations of enamides under rhodium catalysis with monodentate phosphane ligands are reported for the first time. The presence of MeCN facilitates this novel C-C bond formation, and the electron-deficient phosphi

Full text of DOI:10.1021/ol201431c

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3900–3903
Highly Regioselective Intermolecular
Hydroacylations of Enamides with
Salicylaldehydes
Hui-Jun Zhang and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received May 26, 2011
ABSTRACT
Highly regioselective intermolecular hydroacylations of enamides under rhodium catalysis with monodentate phosphane ligands are reported for
the first time. The presence of MeCN facilitates this novel CꢀC bond formation, and the electron-deficient phosphine P(p-F-Ph)3 has proven most
effective for the direct hydroacylation of 1-vinyl-2-pyrrolidinone. Accordingly, an atom-economic synthetic route to R-amido ketones from readily
available substrates has been developed.
The transition metal-catalyzed hydroacylation of unsa-
turated hydrocarbons represents a powerful synthetic tool
for the construction of new carbonꢀcarbon bonds, and it
has become an important example for efficient and atom-
economic processes in organic synthesis.1 Expanding the
substratescopeproved challenging, particularly because of
theoccurrenceand facilenessofundesireddecarbonylation
reactions. So far, the reported examples mostly involve
reactive electron-poor or strained olefins as unsaturated
hydrocarbons, such as acrylate esters,2 acrylamides,3 1,5-
hexadienes,4 methylenecyclopropanes,5 cyclopropenes,6
or norbornenes.7,8 In contrast, hydroacylation reactions
of electron-rich olefins such as vinyl ethers and enamides
have remained unknown. Here, we present for the first
time a highly regioselective rhodium-catalyzed hydroacy-
lation of enamides with salicylaldehydes as carbonyl com-
ponents leading to a variety of R-amido ketones.9
For the initial reactivity screening of various rhodium/
ligand combinations (Table 1), we focused on the reaction
between salicylaldehyde (1a) and 1-vinyl-2-pyrrolidinone
(2a). First, cationic rhodium complex [Rh(dppb)]BF4
[formed in situ from [Rh(ndb)2]BF4 and dppb under
(1) (a) Fu, G. C. In Modern Rhodium-Catalyzed Reactions; Evan,
P. A., Ed.; Wiley-VCH: New York, 2005; pp 79ꢀ91. (b) Willis, M. C. Chem.
Rev. 2010, 110, 725–748. (c) Jun, C.-H.; Jo, E.-A.; Park, J.-W. Eur. J.
Org. Chem. 2007, 1869–1881.
(2) (a) Willis, M. C.; Sapmaz, S. Chem. Commun. 2001, 2558–2559.
(b) Willis, M. C.; McNally, J. S.; Beswick, P. J. Angew. Chem., Int. Ed.
2004, 43, 340–343. (c) Willis, M. C.; Randell-Sly, H. E.; Woodward,
R. L.; Currie, G. S. Org. Lett. 2005, 7, 2249–2251. (d) Willis, M. C.;
Randell-Sly, H. E.; Woodward, R. L.; McNally, S. J.; Currie, G. S.
J. Org. Chem. 2006, 71, 5291–5297.
(3) (a) Tanaka, K.; Shibata, Y.; Suda, T.; Hagiwara, Y.; Hirano, M.
Org. Lett. 2007, 9, 1215–1218. (b) Shibata, Y.; Tanaka, K. J. Am. Chem.
Soc. 2009, 131, 12552–12553.
(4) (a) Imai, M.; Tanaka, M.; Tanaka, K.; Yamamoto, Y.;
Imai-Ogata, N.; Shimowatari, M.; Nagumo, S.; Kawahara, N.;
Suemune, H. J. Org. Chem. 2004, 69, 1144–1150. (b) Tanaka, M.; Imai,
M.; Yamamoto, Y.; Tanaka, K.; Shimowatari, M.; Nagumo, S.;
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46, 6053–6056. (b) Stemmler, R. T.; Bolm, C. Adv. Synth. Catal. 2007,
349, 1185–1198.
(8) For hydroacylations of neutral alkenes, see: (a) Park, Y. J.; Park,
J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222–234. (b) Moxham,
G. L.; Randell-Sly, H. E.; Brayshaw, S. K.; Woodward, R. L.; Weller,
A. S.; Willis, M. C. Angew. Chem., Int. Ed. 2006, 45, 7618–7622.
(9) For synthetic methods toward R-amino ketones, see: (a) Reetz,
M. T. Chem. Rev. 1999, 99, 1121–1162. (b) Evans, D. A.; Johnson, D. S.
Org. Lett. 1999, 1, 595–598. (c) Minakata, S.; Ando, T.; Nishimura, M.;
Ryu, I.; Komatsu, M. Angew. Chem., Int. Ed. 1998, 37, 3392–3394. (d)
Kells, K. W.; Chong, J. M. J. Am. Chem. Soc. 2004, 126, 15666–15667.
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Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.;
Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696–9697. (g) Duthaler, R. O.
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r
10.1021/ol201431c
Published on Web 07/08/2011
2011 American Chemical Society

Table 1. Optimization of the Rhodium-Catalyzed Reaction
between Salicylaldehyde (la) and l-Vinyl-2-pyrrolidinone (2a)a
Table 2. Hydroacylations of Enamide 2a with Salicylaldehydes
1bꢀha
yieldb
entry
[Rh]
[Rh] mol %
ligand
dppb
of 3aa (%)
1c
2
3d
4
Rh(nbd)2BF4
RhCI(PPh3)3
[Rh(cod)CI]2
10
10
5
ꢀ
ꢀ
trace
12e
15e
21e
48
dppf
Rh(acac)(C2H4)2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
10
20
10
20
20
10
10
20
dppf
5
rac-BINAP
(R)-PhanePhos
(R)-PhanePhos
PPh3
6
7
62
8
9f
66
PPh3
64
10g Rh(acac)(CO)2
11g Rh(acac)(CO)2
P(p-F-Ph)3
P(p-F-Ph)3
70
90
a Standard conditions: [Rh] and ligand (ratio = 1:1) were stirred in
toluene (0.3 mL) for 1 h at room temperature, and then 1a (0.3 mmol)
and 2a (1.8 mmol) were added. The reaction mixture was heated to reflux
for 48 h. b Based on 1a. c H2 was introduced to form [Rh(dppb)]BF4.
d The addition of Na2CO3 (10 mol %) was necessary. e Ratios of 3aa:4aa:
1:0.4 (entry 3), 1:0.3 (entry 4), 1:0.1 (entry 5). f [Rh]:PPh3 = 1:1.5; MeCN
(6 equiv) was added. g [Rh]:P(p-F-Ph)3 = 1:1.3.
hydrogen] was tested,3 but no hydroacylation product was
observed (Table 1, entry 1). In the presence of Willkinson
catalyst RhCl(PPh3)3,4 only a trace amountofthe expected
product 3aa was formed (entry 2). The combination of
[Rh(cod)Cl]2, dppf, and Na2CO3 catalyzed the hydroacy-
lation, but the yield of 3aa was only 12% (entry 3). In
addition, decarbonylation product 4aa was formed, and
the ratio of 3aa/4aa was 1:0.4. No base had to be added in
hydroacylation reactions catalyzed by Rh(acac)(C2H4)2
and Rh(acac)(CO)2 (entries 4ꢀ11). Those two complexes
were combined with various mono- and bidentate phos-
phines, and the activities of the resulting in situ formed
catalysts were studied. Of particular interest were phos-
phines, which previously had successfully been applied as
ligands in hydroacylation reactions such as Chiraphos,10a,c
rac-Binap,10aꢀc Me-DuPhos,10bꢀd dppf,10e,f dppb,3a
DuanPhos,10g DPEphos,10h and Josiphos.6 In the pre-
sence of Rh(acac)(C2H4)2 and dppf neither the yield of
a Rh(acac)(CO)2 and ligand were stirred in toluene (0.3 mL) for
1 h at room temperature, and then 1 (0.3 mmol) and 2a (1.8 mmol)
were added. The reaction mixture was heated to reflux for 48 h.
b Condition A: use of Rh(acac)(CO)2 (10 mol %), PPh3 (15 mol %),
and MeCN (6 equiv). Condition B: use of Rh(acac)(CO)2 (10 mol %)
and P(p-F-Ph)3 (13 mol %).
3aa nor the ratio of 3aa/4aa was improved, and the
results were similar to those obtained in the catalysis
with [Rh(cod)Cl]2/dppf (Table 1, entry 4 vs entry 3). The
combination of Rh(acac)(CO)2 and rac-BINAP gave
3aa with an improved yield (21%), and less decarbony-
lation product 4aa was formed (entry 5). Finally, the use
of PhanePhos led to the best results in the series of the
tested bidentate ligands. Thus, with Rh(acac)(CO)2 and
PhanePhos (10 mol % each), 3aa was obtained in 48%
yield, and no decarbonylation was observed (entry 6).
Increasing the catalyst amount to 20 mol % gave 3aa in
62% yield (entry 7). Among the monodentate phosphines,
PPh3 gave complexes with good catalytic activity. For exam-
ple, in the presence of Rh(acac)(CO)2 and PPh3 (20 mol %
each) hydroacylation product 3aa was furnished in 66%
yield (entry 8). Pleasingly we found that the catalyst loading
(10) (a) Barnhart, R. W.; Wang, X.; Noheda, P.; Bergens, S. H.;
Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1994, 116, 1821–1830. (b)
Barnhart, R. W.; McMorran, D. A.; Bosnich, B. Inorg. Chem. Acta 1997,
263, 1–7. (c) Bosnich, B. Acc. Chem. Res. 1998, 31, 667–674. (d) Coulter,
M. M.; Dornan, P. K.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 6932–
6933. (e) Kokobu, K.; Matsumasa, K.; Miura, M.; Nomura, M. J. Org.
Chem. 1997, 62, 4564–4565. (f) Kokobu, K.; Matsumasa, K.; Nishinaka,
Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1999, 72, 303–311. (g)
Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Chem. Soc. 2010, 131,
15608–15609.
Org. Lett., Vol. 13, No. 15, 2011
3901

could be decreased upon addition of MeCN. Presumably,
the nitrile group coordinated to the rhodium center, thereby
stabilizing relevant catalytic intermediates.11 In this man-
ner, the yield of 3aa remained almost the same when only
10 mol % (each) of Rh(acac)(CO)2 and PPh3 were applied
(entry 9).
Table 3. Hydroacylations of Enamides 2bꢀe with Salicylalde-
hyde (1a)a
Commonly, an electron-rich ligand coordinated to a
metal center in low oxidation state can be expected to
positively affect a hydroacylation reaction because it
facilitates the CꢀH bond activation step.12 However, the
electronic properties of the ligand will also influence the
later stages of the catalysis. Assuming that complexes of
the type [(RCO)RhH(olefin)Ln]þ are formed, a positive
effect could result from the presence of an electron-
deficient ligand. This is particularly true for reactions
with electron-rich substrates, where the olefin insertion
barrier is reduced.13 On the basis of that hypothesis,
fluoro-substituted P(p-F-Ph)3 was employed, and to our
delight we found that with Rh(acac)(CO)2 and this
electron-deficient ligand the reactions furnished 3aa in
much better yields than before (up to 90%). Further-
more, the addition of MeCN was not necessary anymore
(Table 1, entries 10 and 11).
Next, various salicylaldehydes 1 were subjected to the
hydroacylation with 1-vinyl-2-pyrrolidinone (2a) in the
presence of Rh(acac)(CO)2 and PPh3 or P(p-F-Ph)3
(Table 2, conditions A and B, respectively). Electron-
donating substituents (methyl, tert-butyl, and methoxy)
in the 3 or 5 position had no significant effect on the
hydroacylation reaction, and reactions with salicylalde-
hydes 1bꢀe furnished addition products 3baꢀea in good
yields and high selectivity (entries 1ꢀ4). Salicylalde-
hydes 1f and 1g with 5-chloro and 5-fluoro substituents,
respectively, also reacted with 2a, but the yields of the
corresponding products, 3fa and 3ga, were lower (entries
5 and 6). This finding was attributed to their more
difficult CꢀH activation in the initial phase of the
catalysis. The hydroacylation of 2a with 2-hydroxy-1-
naphthaldehyde (1h) gave 3ha in high yield (entry 7).
Note that in all cases only the branched addition pro-
ducts were formed. The lack of linear products may be a
result of the electronic properties of the enamide moiety
which affectedthe carbonꢀcarbon double bond polarity.14
Unfortunately, under the same conditions, enamide 2a
did not react with benzaldehyde. Apparently, the phenolic
hydroxyl of the salicylaldehydes served as directing group
being crucial for the success of the transformations.
a Rh(acac)(CO)2 (10 or 20 mol %) and ligand (15 or 20 mol %) were
stirred in toluene (0.3 mL) for 1 h at room temperature, and then 1a
(0.3 mmol) and 2 (1.8 mmol) were added. The reaction mixture was
heated to reflux for 48 h. b MeCN (6 equiv) was added.
Analogous observations have also been made in hydro-
acylations of other substrates, where the presence of
coordinating groups proved essential as well.1ꢀ4,6,7
To further examine the scope of the reaction, enamides
2bꢀe were reacted with salicylaldehyde (1a). To our
surprise, the use of the rhodium complex derived from
Rh(acac)(CO)2 and P(p-F-Ph)3 as ligand did not lead to
satisfying results, and thus, for those reactions Phanephos
and PPh3 were selected as representative ligands. The
results are summarized in Table 3. Hydroacylations of
acyclic N-methyl-N-vinylacetamide (2b) with 1a in the
presence of the Rh(acac)(CO)2/PhanePhos catalyst furn-
ished 3ab in yields up to 69% (entries 1 and 2). Also in this
case, the addition of MeCN allowed reduction of the
rhodium loading from 20 to 10 mol %. Using PPh3 instead
of Phanephos as ligand lowered the yield (data not shown
in Table 3). N-Vinylacetamide (2c) having a hydrogen
atom at the amide nitrogen also reacted with 1a to afford
3ac in up to 75% yield (entries 3 and 4). The reaction of
N-vinylcaprolactam 2d with 1a gave 3ad in 47% yield. In
both cases, the best results were obtained by addition of MeCN
(6 equiv) to a catalyst prepared from 10 mol % of Rh(acac)-
(CO)2 and 15 mol % of PPh3 (Table 3, entries 4 and 5).
Finally, starting from N-vinylphthalimide (2e) and 1a the
formation of two regioisomeric products, 3ae and 3ae0, was
observed. In the absence of MeCN, they were isolated in
(11) Imai, M.; Tanaka, M.; Nagumo, S.; Kawahara, N.; Suemune, H.
J. Org. Chem. 2007, 72, 2543–2546.
(12) Dyker, G., Ed. Handbook of CꢀH Transformations; Wiley-VCH
Verlag: Weinheim, 2005 and references cited therein.
(13) (a) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751–760.
(b) Campeau, L.- C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am.
Chem. Soc. 2004, 126, 9186–9187.
(14) For reviews describing reactions of enamides, see: (a)
Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292–301. (b)
Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455–3460. (c) Dehli, J. R.;
Legros, J.; Bolm, C. Chem. Commun. 2005, 973–986. For an example of
regioselective hydroformylations of enamides, see: (d) McDonald, R. I;
Wong, G. W.; Neupane, R. P.; Stahl, S. S.; Landis, C. R. J. Am. Chem.
Soc. 2010, 132, 14027–14029.
3902
Org. Lett., Vol. 13, No. 15, 2011

54% overall yield with branched 3ae as the major product
(entry 6). However, when the standard conditions (with
10 mol % of Rh(acac)(CO)2, 15 mol % of PPh3 and 6 equiv
MeCN) were used the yield increased to 99%, but now,
linear 3ae0 became the major isomer. Presumably, the nitrile
coordinates to the metal altering the catalyst structure.
In summary, a rhodium-catalyzed regioselective inter-
molecular hydroacylation of enamides with salicylalde-
hydes has been developed. It represents an atom-
economic method for the synthesis of R-amido ketones.
Studies with the goal to further extend the substrate scope
and to develop asymmetric variants of this transformation
are in progress.
Acknowledgment. This paper is dedicated to Prof. Dr.
Christian Bruneau on the occasion of his 60th birthday.
The study was supported by the Fonds der Chemischen
Industrie and, in part, and by the Cluster of Excellence
(Tailor-Made Fuels from Biomass) funded by the Excel-
lence Initiative of the German federal and state govern-
ments. H.-J.Z. is grateful to the Alexander von Humboldt
Foundation for a postdoctoral fellowship.
Supporting Information Available. Experimental pro-
cedures and analytical data for all products. This material
is available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett., Vol. 13, No. 15, 2011
3903