Stereoselective synthesis of unsymmetrical β,β-diarylacrylates by a heck-matsuda reaction: Versatile building blocks for asymmetric synthesis of β,β-diphenylpropanoates, 3-Aryl-indole, and 4-Aryl-3,4-dihydro- quinolin-2-one and formal synthesis of (-)-indatraline

Article abstract of DOI:10.1021/jo102134v

β,β-Disubstituted R,β-unsaturated esters may serve as valuable derivatives for the preparation of other highly functionalized systems found in many natural products and marketed drugs. The stereoselective synthesis of unsymmetrical β,β-diarylacrylate compounds possessing two similar aromatic groups remains a substantial challenge. A simple and convenient stereoselective protocol for the preparation of β,β- disubstituted acrylates via a Heck-Matsuda reaction is reported. Good to high yields were accomplished by a "ligand-free" Pd-catalyzed arylation reaction of cinnamate esters with arenediazonium tetrafluoroborates. Both electron-deficient and electron-rich arenediazonium salts could be employed as arylating reagents, and cinnamate esters were generally more reactive when substituted with an electron-donating group. The overall methodology is highly stereoselective, and this attribute was taken advantage of in the asymmetric Cu-catalyzed 1,4 reduction reaction to provide β,β-diarylpropanoates in high enantioselectivities. The synthesis of a 3-aryl indole and a chiral 4-aryl-2-quinolone from β,β-diarylacrylates was achieved by cyclization in the presence of a diphosphine ligated CuH catalyst. A convenient route for the asymmetric formal synthesis of the psychoactive compound (-)-Indatraline is also presented.

Full text of DOI:10.1021/jo102134v

pubs.acs.org/joc
Stereoselective Synthesis of Unsymmetrical β,β-Diarylacrylates by a
Heck-Matsuda Reaction: Versatile Building Blocks for Asymmetric
Synthesis of β,β-Diphenylpropanoates, 3-Aryl-indole, and
4-Aryl-3,4-dihydro-quinolin-2-one and Formal Synthesis of (-)-Indatraline
Jason G. Taylor and Carlos Roque D. Correia*
´
Instituto de Quımica, Universidade Estadual de Campinas, UNICAMP, C.P.6154, CEP 13083-970,
~
Campinas, Sao Paulo, Brazil
roque@iqm.unicamp.br
Received October 27, 2010
β,β-Disubstituted R,β-unsaturated esters may serve as valuable derivatives for the preparation of other
highly functionalized systems found in many natural products and marketed drugs. The stereoselective
synthesis of unsymmetrical β,β-diarylacrylate compounds possessing two similar aromatic groups remains
a substantial challenge. A simple and convenient stereoselective protocol for the preparation of β,β-
disubstituted acrylates via a Heck-Matsuda reaction is reported. Good to high yields were accomplished
by a “ligand-free” Pd-catalyzed arylation reaction of cinnamate esters with arenediazonium tetrafluor-
oborates. Both electron-deficient and electron-rich arenediazonium salts could be employed as arylating
reagents, and cinnamate esters were generally more reactive when substituted with an electron-donating
group. The overall methodology is highly stereoselective, and this attribute was taken advantage of in the
asymmetric Cu-catalyzed 1,4 reduction reaction to provide β,β-diarylpropanoates in high enantioselec-
tivities. The synthesis of a 3-aryl indole and a chiral 4-aryl-2-quinolone from β,β-diarylacrylates was
achieved by cyclization in the presence of a diphosphine ligated CuH catalyst. A convenient route for the
asymmetric formal synthesis of the psychoactive compound (-)-Indatraline is also presented.
Introduction
organic synthesis.1 This methodology is particularly interesting
in the construction of complex arylated compounds. Among
those, the unsaturated diaryl substituted carbon centers are
The palladium-catalyzed coupling of arenediazonium salts to
olefins (often referred to as a Heck-Matsuda reaction (HM))
has attracted considerable interest as a convenient alternative to
traditional Heck protocols, and has been increasingly applied in
(1) (a) Kikukawa, K.; Matsuda, T. Chem. Lett. 1977, 159. For a review, see:
(b) Roglans, A.; Pla-Quintana, A.; Moreno-Manas Chem. Rev. 2006, 106, 4622.
DOI: 10.1021/jo102134v
r
Published on Web 01/11/2011
J. Org. Chem. 2011, 76, 857–869 857
2011 American Chemical Society

Taylor and Correia
JOCArticle
FIGURE 1. Unsaturated diaryl substituted carbon centers in natural products Kuhlmannene and Isocalophyllic Acid.
relevant frameworks because they are present in natural pro-
ducts like Kuhlmannene2a and Isocalophyllic acid2b (Figure 1),
and they can also be precursors for the synthesis of marketed
drugs such as Sertraline3a and Tolterodine.3b
Unsymmetrical β,β-diaryl cinnamic acids and esters have
been shown to be useful intermediates for the synthesis of
medicinal products as illustrated in two different reports where
the target compounds were accessed by a Heck arylation
reaction and thus exemplifying the utility of this strategy in
the construction of interesting molecules.9 However, when
traditional Heck protocols are employed for the synthesis of
β,β-diarylacrylates, they are often disadvantaged by the neces-
sity for long reaction times, an inert atmosphere, elevated
temperatures and often lacking high control in the stereochem-
istry of the process. On the other hand, arenediazonium salts
can be employed in the absence of phosphines as ligand and
thus negating the requirement for aerobic conditions, which
makes the reaction more practical and easier to handle.10
Additionally, the reaction can be performed with or without a
base and it is often faster than traditional Heck protocols.11
Recently, we reported the use of arenediazonium salts as
arylating agents for methyl cinnamate in a highly effective
and stereoselective Pd-catalyzed Heck-Matsuda reaction.3a
However, a new, mild, straightforward and highly selective
method that can provide unsymmetrical β,β-diarylacrylates is
still desired. We reasoned that applying the Heck-Matsuda
protocol toward the synthesis of unsymmetrical β,β-diarylacry-
lates would provide convenient access to these compounds and
expand the available methods for their synthesis.
β,β-Disubstituted R,β-unsaturated esters may serve as
valuable derivatives for the preparation of highly functiona-
lized olefin systems such as R,β -enals and -enones, and R,β-
unsaturated acrylamides. Although symmetrical β,β-diaryla-
crylates can be accessed by Wittig olefination of functionalized
benzophenones with a stabilized phosphorus ylide, unsymme-
trical substituted benzophenones typically afford the corre-
sponding R,β-unsaturated esters in poor stereoselectivities.4 In
comparison, the application of CuOAc as catalyst in the
conjugate addition of arylboronic acids to alkynoates was
shown to be a highly effective methodology for the stereoselec-
tive synthesis of trisubstituted cinnamates.5 In this study,
Yamamoto, Kirai and Harada demonstrated with 5 examples
that using 1-3 mol % CuOAc, electronically rich, poor and
neutral phenylboronic acids could be reacted with ethyl phe-
nylpropiolate to provide the corresponding β,β-diarylacrylates
in high yields as single stereoisomers.
Heck arylations of β-substituted R,β-unsaturated carbonyl
compounds have been the subject of several investigations, with
the achievement of a stereoselective synthesis being the main
challenge.6 Several studies have been reported for the Pd-
catalyzed arylation of cinnamic esters with aryl halides but
often lacking examples for unsymmetrical β,β-diarylacrylates
functionalized on both aromatic rings.7 Calo et al. demon-
strated that Pd nanoparticles could efficiently catalyze the
stereospecific coupling of cinnamates with aryl halides at
130 °C using tetrabutylammonium acetate as base, dissolved
in tetrabutylammonium bromide.8 The substrate scope was
explored and among the eleven examples presented, five were
derived from a substituted cinnamate ester but only in two cases
the product was functionalized on both aromatic rings.
Herein, we describe a method of synthesizing unsymme-
trical β,β-diarylacrylates in high stereoselectivity from cin-
namate ester derivatives via a Heck-Matsuda procedure.
The utility of this protocol is further exemplified by the
application toward the synthesis of optically enriched β,β-
diphenylpropanoates, a 4-aryl-3,4-dihydro-quinolin-2-one
and the formal asymmetric synthesis of Indatraline.
Results and Discussion
The present technique for producing β,β-diarylacrylates
relies on the efficient synthesis of cinnamate esters in stereo-
isomerically pure form. All of the cinnamate derivatives dis-
cussed in this paper were easily prepared by either a Wittig-
Horner reaction (using commercially available benzaldehydes)
or by a Heck Matsuda reaction with methylacrylate (Figure 2).
These substrates were purified by recrystallization or chroma-
tography, and were synthesized according to literature proce-
dures, which accentuates the usefulness of this method (see
Supporting Information for details).
(2) (a) Ollis; et al. Chem. Commun. 1968, 1392. (b) Alarcon, A. B.; Cuesta-
Rubio, O.; Perez, J. C.; Piccinelli, A. L.; Rastrelli, L. J. Nat. Prod. 2008, 71
(7), 1283.
(3) (a) Pastre, J. C.; Correia, C. R. D. Adv. Synth. Catal. 2009, 351, 1217.
(b) Gallagher, B. D.; Taft, R.; Lipshutz, B. H. Org. Lett. 2009, 11 (23), 5374.
(4) For examples see: (a) Malamas, M. S.; Palka, C. L. J. Heterocycl.
Chem. 1996, 33 (2), 475. (b) Almansa, C. A.; et al. J. Med. Chem. 1996, 39
(11), 2197. (c) Yu, K.-L.; et al. J. Med. Chem. 1996, 39 (12), 2411.
(5) Yamamoto, Y.; Kirai, N.; Harada, Y. Chem. Commun. 2008, 2010.
(6) For reports on Heck coupling reactions of aryl halides to R,β-
unsaturated carbonyl compounds, see: (a) Cacchi, S. Palmieri Synthesis
1984, 7, 575. (b) Baek, G. H.; et al. Bull. Korean Chem. Soc. 1999, 20 (2), 232.
(c) Bernini, R.; Cacchi, S.; Salve, I. D.; Fabrizi, G. Synlett 2006, 18, 2947.
(7) (a) Moreno-Manas, M.; Perez, M.; Pleixats, R. Tetrahedron Lett.
1996, 37, 7449. (b) Gurtler, C.; Buchwald, S. L. Chem.;Eur. J. 1999, 5, 3107.
(9) (a) Ikemoto, T.; et al. Tetrahedron Lett. 2004, 45, 7757. (b) Song, F.
et al J. Med. Chem. 2007, 50, 2807.
ꢀ
(c) Botella, L.; Carmen Najera, C. J. Org. Chem. 2005, 70 (11), 4360.
(10) Sengupta, S.; Bhattacharyya, S. Tetrahedron Lett. 2001, 42, 2035.
(11) (a) Kikukawa, K.; Nagira, K.; Wada, F.; Matsuda, T. Tetrahedron
1981, 37, 31. (b) Kikukawa, K.; Matsuda, T. Chem. Lett. 1977, 159.
(8) Calo, V.; Nacci, A.; Monopoli, A.; Laera, S.; Cioffi, N. J. Org. Chem.
2003, 68, 2929.
858 J. Org. Chem. Vol. 76, No. 3, 2011

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We were pleased to find that the catalyst loading could be
reduced to 5 mol % whereas 10 mol % of Pd(OAc)2 was
required in our previous study involving methyl cinnamate.3a In
the arylation of 1 with the 4-chloro substituted arenediazonium
salt (1.5 equiv), both trifluoroethanol and acetonitrile (under an
atmosphere of CO to reduce PdII to Pd0) as solvent failed to
afford the expected Heck adduct 5 and the olefin remained
unreacted (entries 1 and 2). The reaction proceeded well in
methanol, but as previously mentioned, the stereoselectivities
were modest and only marginally improved by conducting the
reaction at lower temperature (entries 3 and 4). Several bases
were screened and all found to have dramatically improved the
stereoselectivity of the reaction (entries 5-8). Although the
stereoselectivity for the Heck adduct was high when using
tBuNOAc as base, the yield was disappointingly poor. Electron
deficient arenediazonium salts are susceptible to nucleophilic
attack at the electrophilic nitrogen of the diazonium group and
can react competitively with the acetate anion, thus eliminating
the arylating reagent from the reaction. Barium carbonate was
slightly better (entry 6), but in this case, a sterically hindered
pyridine DTBMP (2,6-ditertbutyl-4-methyl-pyridine) gave sa-
tisfactory results in terms of E/Z ratio although this was also
accompanied by a significant decrease in product yield (entries 7
and 8).
In comparison, 2 could be coupled to the 4-methoxy
arenediazonium salt to provide 6 in high stereoselectivity with-
out the assistance of a base in the reaction medium (entry 9).
The catalytic performance was particularly sluggish when
performed in methanol solvent (entries 9 and 10) but was
improved when using a binary solvent mixture of methanol
and acetonitrile in a 1:1 ratio (entry 11). We attribute the
beneficial effect of acetonitrile to its ability in assisting the
stabilization of the cationic intermediate (formed upon oxida-
tive addition), and therefore, inhibiting the formation of palla-
dium black and consequently permitting higher catalytic
turnovers. The presence of sodium acetate was found to have
positive impact on stereoselectivity and did not result in any
FIGURE 2. Preparation of cinnamate ester substrates.
SCHEME 1. Monitoring of Competitive HM-Reaction by GC-MS
Using our previously reported procedure for the arylation
of methyl cinnamate, Pd(OAc)2 and methanol as solvent were
employed for the investigation of the 4-methoxy and 4-chloro
substituted cinnamate esters (1 and 2 respectively). To under-
stand how the electronic properties affect the reaction rate and
stereoselectivity of the process, a competitive experiment was
carried out. Using GC-MS to monitor the reaction outcome,
cinnamate esters 1 and 2 were both reacted in the same flask
with benzene diazonium tetrafluoroborate in equimolar ratios
(Scheme 1).
Although benzene diazonium tetrafluoroborate was not
particularly reactive in this initial investigation, this early result
indicated that electronically rich olefins were more reactive than
electronically poor cinnamate esters but they had a tendency to
be less stereoselective. Mindful of the fact that the electronic
properties of the olefin influence both its reactivity and stereo-
selectivity in the coupling reaction, substrates 1 and 2 were
utilized for optimization studies (Table 1).
TABLE 1. Reaction Conditions in the Pd-Catalyzed Reaction of Cinnamate Esters with Arenediazonium Saltsa
entry
R1
R2
4Cl
4Cl
4Cl
4Cl
4Cl
4Cl
4Cl
solvent
T/°C
t/h
base
yields/ %b
Z/E ratioc
1
2
3
4
5
6
7
8
4OMe
4OMe
4OMe
4OMe
4OMe
4OMe
4OMe
4OMe
4Cl
F3CCH2OH
MeCN/CO
MeOH
MeOH
MeOH
MeOH/MeCN 1:1
MeOH
MeOH
MeOH
MeOH
80
80
60
25
60
80
60
25
60
60
80
25
2
8
1
14
1
1
-
-
-
-
NR
NR
93
78
18
40
37
29
39
20
98
77
NR
NR
42/58
32/68
01/99
01/99
08/92
03/97
97/03
99/01
72/28
97/03
tBuNþ-OAc
BaCO3
DTBMP
DTBMP
-
1
4Cl
14
14
1
14
14
9
4OMe
4OMe
4OMe
4OMe
10
11
12
4Cl
4Cl
4Cl
-
MeOH/MeCN 1:1
MeOH/MeCN 1:1
-
NaOAc
aTypical reaction conditions: cinnamate ester (0.50 mmol), arenediazonium salt (1.5 equiv), Pd(OAc)2 (5 mol %), base (1.2 equiv), solvent (3 mL).
bIsolated yields and NR = No Reaction. cDetermined by 1H NMR integration.
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SCHEME 2. Pd-Catalyzed R-Arylation of Cinnamate Ester with Arenediazonium Salts
significant deterioration of yield (entry 12). Concerning the
improvement in stereoselectivity when base was utilized, we
have previously rationalized this observation and attributed
this result to the scavenging of PdH.3a Although methanol is
capable of acting as a weak base to reconstitute Pd0, it is not
effective in preventing the reinserting of PdH which is respon-
sible for isomerization of the Heck adducts.
Although sodium acetate was found to be an effective base
for the arylation of 2, surprisingly, the coupling of 4-chloro
arenediazonium tetrafluoroborate to 1 afforded an insepar-
able mixture of the expected β-arylated adduct 5 and another
unexpected byproduct in a ratio of 6:4. Upon exploration of
the reaction scope, we isolated exclusively R-arylated Heck
adduct 9 from the reaction of 1 with arenediazonium salt 8
(Scheme 2), and by inference, we concluded that the con-
taminant coeluting with 5 was 7.
Compound 9 was isolated in 53% yield and appears to be
formed by a reversible oxa-Michael addition of methanol to
the R-arylated Heck adduct and thus furnishing 9 as a single
diastereoisomer albeit in modest yield. In the case of 9, a
doublet resonance in the 1H NMR at 4.55 ppm with a
coupling constant of 10.5 Hz was observed and used as a
reference to identify 7 and future occurrences for the forma-
tion of the R-arylated adduct. An R-arylated Heck-adduct
was only observed when the cinnamate ester bearing an
electronically donating methoxy substituent was coupled
with arenediazonium salts in the presence of sodium acetate.
The absence of sodium acetate or use of other bases such as
BaCO3 and DTBMP did not have a similar effect. This
preliminary result is of interest and is currently under
investigation in our laboratory, but results disclosed from
here on will focus on the β-arylation of cinnamate ester
derivatives.
on these targets. Compared to the para-methoxy substituted
arenediazonium salt, coupling of the ortho-methoxy equiva-
lent was less reactive although good stereoselectivities were
still achievable in this case (entry 2). In contrast to the
synthesis of 11, the coupling of the 3,4-dimethoxy arenedia-
zonium salt proceeded more smoothly suggesting that the
electron withdrawing nature of the meta-methoxy group
(inductive effect) has less of an impact on the reaction
outcome than the steric interference provided by the ortho
methoxy substituent (entries 2 and 3). We envisioned that
switching the functional groups around on the reactants
would conveniently provide access to the opposite stereo-
isomers. Indeed, the present method enabled the stereose-
lective preparation of the opposite stereoisomer of 12 by
simply coupling 3,4-dimethoxy cinnamate ester with the
appropriate arylating reagent. Unfortunately, the synthesis
of 13 in the presence of sodium acetate was hampered by the
formation of the aforementioned R-arylated product as a minor
impurity (∼5%, see Supporting Information), which we were
unable to remove by column chromatography. Alternatively
when the reaction was carried out in the absence of sodium
acetate, it afforded cleanly one regioisomer although the stereo-
selectivity was very poor (entry 4). Interestingly, a sterically
more demanding cinnamate ester was equally as reactive as
other electron rich substrates and once again highlighting the
stronger influence that ortho substituted arenediazonium salts
have on product yield (entry 5). Finally, regarding electron rich
cinnamate esters, coupling could also be accomplished with
electronically poor arylating agents such as the para-nitro
arenediazonium salt which furnished 15 in excellent yield
(entry 6). Turning our attention to the arylation of electronically
poor cinnamate esters, we began by attempting the synthesis of
16 (entry 7). Gratifyingly, 16 was prepared in high yield and
stereoselectivity comparable with the related chloro Heck-
adduct 6 (Table 1, entry 12). Chloro substituted compounds
17, 18 and 19 were all synthesized in high stereoselectivities,
albeit in modest yield for 17 (entries 8-10). Furthermore, the
meta-chloro Heck adduct 18 was obtained in lower yield than 6.
The final example between an electron rich arenediazonium salt
and an electronically poor olefin involves the 2-fluoro substi-
tuted cinnamate ester (entry 11). Apparently, the electron
withdrawing effect of fluorine in close proximity the double
bond resulted in only modest yield of 20 but without negatively
With an understanding of the different factors affecting
the arylation of electron rich and poor cinnamate esters, an
investigation of the reaction scope was initiated. The results
are summarized in Table 2.
The symmetrical β,β-diarylacrylate 10 was synthesized
uneventfully in high yield using an operationally simple
procedure in comparison to traditional Heck protocols
(entry 1). Given the fact that the synthesis of unsymmetrical
β,β-diarylacrylates with high stereoselectivities is consider-
ably more challenging, our attention was primarily focused
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TABLE 2. Pd-Catalyzed Arylation of trans-Cinnamates with Arenediazonium Saltsa
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TABLE 2. Continued
862 J. Org. Chem. Vol. 76, No. 3, 2011

Taylor and Correia
JOCArticle
TABLE 2. Continued
aTypical reaction conditions: cinnamate ester (0.50 mmol), arenediazonium salt (1.5 equiv), Pd(OAc)2 (5 mol %), NaOAc (1.2 equiv), 1:1 MeOH/
MeCN (3 mL). bCorresponds to isolated yields after purification by column chromatography. cStereoselectivities were determined by 1H NMR
integration. dReaction performed in MeOH and in the absence of a base. e2,6-Ditert-butyl-4-methylpyridine was used as base (1.2 equiv). fMeCN and
EtOH (1:1) were used as solvent. gBnCN and EtOH (1:1) were used as solvent. hMeOH used as solvent. iBnCN and MeOH (1:1) were used as solvent.
jReaction performed in the absence of base.
impacting the stereoselectivity. Given the fact that electron
deficient cinnamate esters were more resistant to arylation
and that electronically poor diazonium salts are less able to
stabilize the cationic intermediate (generated upon oxidative
addition with Pd0), this combination of reactants unsurprisingly
presented a greater challenge to us. For example, products 21
and 22 were obtained in moderate to low yields (entries 12 and
13) and catalytic performance was particularly sluggish, requir-
ing16hinthecaseof21. Unfortunately, the attempted coupling
of 4-chloroarenediazonium tetrafluoroborate with 2 failed to
provide any Heck adducts and instead, starting material 2 was
recovered by column chromatography. Highly electron defi-
cient olefins were only reactive with electron rich arenediazo-
nium salts, as can be seen in the case of ortho-nitro and the para-
trifluoromethane substituted cinnamate esters (entries 14 and
15). In these two reactions, the corresponding arylated products
23 and 24 were isolated in 73 and 91% yield respectively. High
stereoselectivities were also realized and in the case of product
23, a combination of benzonitrile with ethanol was necessary
for the attainment of a synthetically useful yield. The evaluation
of the substrate scope was completed by the arylation of the
methyl substituted cinnamates. In agreement with our previous
results,3a the success of the arylation was dependent on the
arenediazonium salt and the electron rich reagents were once
again more reactive than their electronically poor counterparts
(entries 16 and 17). We were unsurprised to find that compound
26 could be obtained in high stereoselectivity without the
assistance of base. This remarkable dependence on the electro-
nic nature of the arenediazoinium salt was also observed in the
arylation of methyl cinnamate.3a The observation is also
reminiscent of that found in the Heck reaction of aryl iodides
with β-arylacrylamides.6c Last, but not least, the 3,4-dimethyl
substituted cinnamate ester was examined and found to be
highly reactive providing product 27 in high yield and stereo-
selectivity (entry 18). The utility of this methodology is exem-
plified by the fact that the introduction of an electron-rich aryl
group is considerably less efficient when employing traditional
Heck protocols,3a and in this study, the majority of β,β-
diarylacrylates presented bear this motif.
The generally accepted mechanism of the Heck reaction
dictates that the stereochemical outcome for the arylation
of disubstituted alkenes giving trisubstituted alkenes should
proceed in a stereospecific manner and therefore be predictable.
However, to alleviate any doubt and to confirm the stereochem-
istry of those products isolated with exclusive formation of one
stereoisomer, NOE experiments were carried out (Figure 3).
Three representative examples are shown in the figure
below and all exhibited a nuclear Overhauser enhancement
(NOE) of the aromatic resonance when the only olefinic hydro-
gen present was irradiated, that being the only resonance so
affected. Low stereoselectivities have been attributed to a well-
known elimination-reverse addition-elimination of a putative
cationic PdH species. However, the presence of a base is critical
in eliminating this PdH species and the beneficial effect on the
stereochemical outcome of the reaction has been rationalized
and discussed in our previous report.3a
Many of the olefinic compounds prepared herein are
prochiral and can be readily converted to enantiomerically
pure intermediates by asymmetric catalysis. The prochiral
alkenes presented in this work are conjugated systems and in
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Taylor and Correia
JOCArticle
FIGURE 3. Confirmation of stereochemistry by NOE experiment.
TABLE 3. Enantioselective Conjugate Reduction of β,β-Diaryl-substi-
tuted r,β-Unsaturated Estersa
particular, the R,β-unsaturated carbonyl compounds are capable
of undergoing asymmetric 1,4 additions with a variety of nucleo-
philes such as copper-hydride,12a anilines,12b,c phosphorus
nucleophiles,12d nitroalkanes,12e sulfur donors,12f organometallic
reagents,12g,h and various enolizable carbonyl compounds.12i,j
The asymmetric Cu-catalyzed 1,4-hydrosilylation of R,β-
unsaturated carbonyl compounds utilizes a diphosphine
ligated Cu(I) hydride species generated in situ from a copper
salt, phosphine ligand and poly(hydroxymethylsiloxane). When
the reaction is quenched with a proton source, for example,
alcohol, β,β-saturated carbonyl compounds are usually ob-
tained in high optical purity.12a The stereochemical purity of
the olefins employed in this reaction is critical to its success as
the other stereoisomer will give the opposite enantiomer.13 The
modern racemic version of this methodology was pioneered by
Stryker,14a-d and used by Buchwald14e for the first asymmetric
1,4 addition of Cu-H to β,β-disubstituted alkenyl substrates
including R,β-unsaturated esters using p-tol-BINAP as ligand.
Further developments were achieved by the group of Lipshutz12
in which ligands of the SEGPHOS and JOSIPHOS families of
nonracemic bis-phosphines were evaluated for the 1,4-reduction
of β,β-disubstituted enoates and found to exert a high degree of
facial selectivity to provide the corresponding propanoates.15
However, both reports lack examples of 1,4-reductions with β,β-
diaryl R,β-unsaturated esters, presumably due to the unavail-
ability of a convenient and stereoselective methodology for their
preparation. To further demonstrate the utility of the HM
reaction, a few Heck adducts synthesized in geometrically pure
form were selected for evaluation in the asymmetric Cu-cata-
lyzed 1,4-hydrosilylation reaction. Using Cu(OAc)2 (3 mol %)
and R-JOSIPHOS as ligand (JOSIPHOS = (R)-1-[(S)-2-
diphenylphosphino) ferrocenyl]ethyldicyclohexylphosphine) in
the presence of excess polymethylhydrosiloxane (PMHS), the
enantioselective synthesis of β,β-diaryl propanoates was inves-
tigated (Table 3).
entry
R1
R2
product
yield/%b
ee/%c,d
1
2
3
4
5
6
H
4-CF3
3,4-Me
4-Cl
3,4-OMe
2,4,5-OMe
3,4-Cl
29
30
31
32
33
34
96
77
89 (-)
90 (þ)
91 (-)
90 (þ)
72
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
96
94
22e
NRf
-
aTypical reaction conditions: β,β-diaryl enoate (0.50 mmol), Cu-
(OAc)2 (3 mol %), R-JosiPhos (4 mol %), PMHS (4 equiv), tBuOH (4
equiv), toluene (3 mL), 25 °C, 16 h. bCorresponds to isolated yields after
purification by column chromatography. cDetermined by chiral HPLC.
For details see Supporting Information. dOptical rotations are shown in
parentheses. eResult corresponds to % conversion as determined by 1H
NMR integration. fNo reaction observed.
FIGURE 4. The basic structure of 4-Aryl-3,4-dihydroquinolin-2-
ones.
Initially, the Cu-catalyzed asymmetric hydrosilylation
protocol was applied to the synthesis of 29 to evaluate a sub-
strate bearing an electron-withdrawing group. Employing 3 mol
% Cu(OAc)2 and 4 mol % of R-JOSIPHOS in the presence of
PHMS yielded saturated ester 29 at ambient temperature in high
yield and with good enantioselectivity (entry 1). Accordingly,
substrates bearing electron-neutral or -withdrawing substitu-
ents on one of the phenyl rings were converted to the corre-
sponding propanoates with similar enantioselectivities (entries 2
to 4) whereas a drop in ee was observed in the case of compound
33 (entry 5) bearing only electron donating groups. This result
indicates that electronic factors can indeed influence the en-
antioselectivity of the process. It is also noteworthy that high
conversions were difficult to achieve in the case of substrate 13
and that no reaction was observed for even more electron rich
substrates (entry 6). Products 30-33 are novel compounds
and no attempts were made to determine their absolute
configuration. However, it was possible to assign the absolute
(12) For selected reviews, see: (a) Deutsch, C.; Krause, N.; Lipshutz,
B. H. Chem. Rev. 2008, 108, 2916. (b) Hii, K. K. Pure Appl. Chem. 2006, 78,
341. (c) Enders, D.; Wang, C.; Liebich, J. X. Chem.;Eur. J. 2009, 15, 11058.
(d) Enders, D.; Saint-Dizier, A.; Lannou, M,-I.; Lenzen, A. Eur. J. Org.
Chem. 2006, 29. (e) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini,
M. Chem. Rev. 2005, 105, 933. (f) Enders, D.; Lttgen, K.; Narine, A. A.
Synthesis 2007, 7, 959. (g) Jerphagnon, T.; Pizzuti, M. G.; Minnaard, A. J.;
Feringa, B. L. Chem. Soc. Rev. 2009, 38, 1039–1075. (h) Harutyunyan, S. R.;
den Hartog, T.; Geurts, K.; Minnard, A. J.; Feringa, B. L. Chem. Rev. 2008,
108, 2824. (i) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (j) Chrisyoffers,
J.; Koripelly, G.; Rosiak, A.; Rssle, M. Synthesis 2007, 1279.
(13) Yoo, K.; Kim, H.; Yun, J. Chem.;Eur. J 2009, 15 (42), 11134.
(14) (a) Brestensky, D. M.; Huseland, D. E.; McGettigan, C.; Stryker, J.
M. Tetrahedron Lett. 1988, 29, 3749. (b) Mahoney, W. S.; Brestensky, D. M.;
Stryker, J. M. J. Am. Chem. Soc. 1988, 110, 291. (c) Brestensky, D. M.;
Stryker, J. M. Tetrahedron Lett. 1989, 30, 5677. (d) Koenig, T. M.; Daeuble,
J. F.; Brestensky, D. M.; Stryker, J. M. Tetrahedron Lett. 1990, 31, 3237. (e)
Appella, D. H. L.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9473.
(15) Lipshutz, B. H.; Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc. 2004,
126 (27), 8352.
(16) Quallich, G. J. U.S. Patent 5196607, March 23, 1993.
864 J. Org. Chem. Vol. 76, No. 3, 2011

Taylor and Correia
JOCArticle
SCHEME 3. Synthesis of a 3-Aryl Indole and a 4-Aryl-dihydroquinolinone from Heck Adducts
stereochemistry of 29 (S-enantiomer) by comparison of its
optical rotation with the literature value.16
To extend the utility of HM methodology, we then decided
to take advantage of the functional groups present in com-
pounds 23 and 28 for subsequent elaboration (Scheme 3).
Initially, the Cu-catalyzed 1,4 reduction of 23 was
attempted using the aforementioned conditions, but sur-
prisingly, indole 35 was isolated instead of the expected
β,β-diaryl propanoate. The structure of 35 was evidenced
These promising results prompted us to explore the appli-
cation of this chemistry for the preparation of a chiral 4-aryl-
2-quinolinone derivative (Figure 4), a class of compounds
salient in many biologically active compounds.17 There are
precedents in the literature for the asymmetric synthesis of
4-aryl-2-quinolinones, the first being the utilization of dy-
namic thermodynamic resolution of dilithioaniline to prepare
enantioenriched tetrahydroquinoline derivatives.18a An alter-
native approach involves the asymmetric conjugate addition
of aryl boronic acid nucleophiles to electron-deficient accep-
tors catalyzed by a Rh-diene complex.18b The ortho-nitro
adduct was subjected to hydrogenation (H2, Pd/C in MeOH)
to afford the desired lactam in high yield and ee.18b We
envisaged that the target compound could be prepared via a
process involving a HM reaction followed by asymmetric 1,4
reduction and finally an intramolecular carbon-nitrogen
bond-forming step.
1
by a sharp low field signal in the H NMR (10.71 ppm).
Furthermore, its spectral data were consistent with those
reported in the literature19 and mass spectrometry con-
firmed its molecular identity. This result implies that nitro
groups in the ortho position may be incompatible with this
methodology and we tentatively propose that the enolate
initially formed from addition of Cu-H may have undergone
an intramolecular nucleophilic substitution with the nitro group.
To circumvent formation of the indole structure, we attempted
the reduction of 28 using the same protocol, but once again our
target compound evaded us and we instead isolated the un-
saturated lactam 36 in almost quantitative yield. Interestingly,
an intramolecular amidation reaction took place in preference
to the 1,4 reduction but we were pleased to find that this
intermediate could be subjected to a second Cu-catalyzed 1,4-
reduction to provide 37 in a yield of 80% and with 75% ee. A
control reaction subjecting 28 to Cu(OAc)2, R-JOSIPHOS and
tBuOH and another control using only 4 equivalents of PHMS
in toluene were carried out, but the substrate was recovered and
no cyclization was observed. This result implies that formation
of 36 occurs only under catalytic conditions and we speculated
that 37 was not afforded directly in the first instance due to an
insufficient supply of the hydrosiloxane polymer. Also, upon
(17) For some recent references, see: (a) Dhanak, D.; Kaura, A. C.; Shaw, A.
WO 2001085172, 2001; Chem. Abstr. 2001, 135, 357951. (b) Norman, P. Curr.
Opin. Invest. Drugs 2002, 3, 313. (c) Venet, M.; End, D.; Angibaud, P. Curr. Top.
Med. Chem. 2003, 3, 1095. (d) van Cutsem, E.; van de Velde, H.; Karasek, P.;
Oettle, H.; Vervenne, W. L.; Szawlowski, A.; Schoffski, P.; Post, S.; Verslype, C.;
Neumann, H.; Safran, H.; Humblet, Y.; Perez, R. J.; Ma, Y.; von Hoff, D. J. Clin.
Oncol. 2004, 22, 1430. (e) Freeman, G. A.; Andrews, C. W., III; Hopkins, A. L.;
Lowell, G. S.; Schaller, L. T.; Cowan, J. R.; Gonzales, S. S.; Koszalka, G. W.;
Hazen, R. J.; Boone, L. R.; Ferris, R. G.; Creech, K. L.; Roberts, G. B.; Short,
S. A.; Weaver, K.; Reynolds, D. J.; Milton, J.; Ren, J.; Stuart, D. I.; Stammers,
D. K.; Chan, J. H. J. Med. Chem. 2004, 47, 5923. (f) Li, Q.; Woods, K. W.; Wang,
W.; Lin, N.-H.; Claiborne, A.; Gu, W.-Z.; Cohen, J.; Stoll, V. S.; Hutchins, C.;
Frost, D.; Rosenberg, S. H.; Sham, H. L. Bioorg. Med. Chem. Lett. 2005,15, 2033.
(18) (a) Kim, Y.; Shin, E.; Beak, P.; Park, Y. S. Synthesis 2006, 22, 3805.
(b) Paquin, J.-F.; Steptenson, C. R. J.; Defieber, C.; Carreira, E. M. Org.
Lett. 2005, 7, 3821.
(19) Hong, D.; Chen, Z.; Lin, X.; Wang., Y. Org. Lett. 2010, 12, 4608.
J. Org. Chem. Vol. 76, No. 3, 2011 865

Taylor and Correia
JOCArticle
SCHEME 4. Enantioselective Formal Synthesis of (-)-Indatraline
cyclization, an ethoxide anion is liberated and may possibly be
responsible for deactivation of the catalyst or the poly(hydroxy-
methylsiloxane), thus preventing the formation of Cu-H. The
synthesis of 37 was therefore reattempted but using 10 equiva-
lents of both PHMS and BuOH yielding the expected dihy-
droquinoline-2-one 37 in good yield and surprisingly with
higher ee than that obtained from substrate 36.
ging. Notably, formation of a single geometric isomer could be
guaranteed by simply conducting the reaction in the presence of
a base and thus further corroborates the hypothesis of isomer-
ization of the Heck adduct by a PdH readdition. Other
advantages that this methodology presents include the mild
reaction conditions, the fact that they can be easily carried out
under aerobic conditions and that they are often fast, requiring
only a few hours to go to completion. The ease of preparation
of the olefin substrates renders this methodology an attractive
alternative to the Cu-catalyzed conjugate addition of arylboro-
nic acids to alkynoates. Thus, the present methodology has
demonstrated broad scope and permitted structural diversity in
the synthesis of unsymmetrical β,β-diarylacrylates derivatives.
The methodological potential of the present technique was
demonstrated by the asymmetric Cu-catalyzed 1,4 reduction of
the Heck adducts to the corresponding β,β-diarylated saturated
esters with high enantioselectivities. In one isolated example, we
observed the formation of an 3-aryl indole during the at-
tempted Cu-catalyzed 1,4-reduction of the ortho-nitro Heck
adduct 23 which presumably proceeded by an intramolecular
cyclization between a copper-enolate and the nitro group.
Finally, we have successfully combined a highly stereo and
enantioselective catalytic methodology toward the asymmetric
formal synthesis of (-)-Indatraline and to a chiral 4-aryl-3,4-
dihydroquinolin-2-one.
t
We have previously shown that saturated β,β-diarylated
product 29 could be employed in a concise formal total
syntheses of (()-Indatraline.3a,20 One of our objectives was
to take advantage of the high degree of stereoselectivity of
this process and to explore the formal asymmetric synthesis of
Indatraline. Hitherto, only one catalytic enantioselective synth-
esis of (þ)-Indatraline has been reported and this strategy
utilized an enantioselective rhodium-catalyzed carbenoid
C-H insertion reaction as the key step.21 More recently, a
series of R,β-unsaturated nitriles were reduced enantioselec-
tively by a copper-Josiphos catalyst in the presence of hydro-
silane and applied to the enantioselective formal synthesis of
(-)-Indatraline.13 The enantioselectivity for the saturated ni-
trile intermediate was reported as 96% (S-enantiomer), but the
optical purity for the cyclic indanone intermediate which is a
key intermediate in the synthesis of Indatraline,22 was not
disclosed. A complementary approach to the key cyclic inda-
none intermediate 38, from the β,β-diarylated propanoate 29 is
shown above (Scheme 4).
Hydrolysis of the ester function with aqueous KOH and
subsequent cyclization using chlorosulfonic acid afforded the
known precursor 38 in 55% yield over 2 steps. More impor-
tantly, we have demonstrated that the optical purity of 29 does
not decrease during the hydrolysis and cyclization processes.
Experimental Section
General Procedure for the Heck Arylation of Cinnamate
Esters. A test tube (inside diameter 13 mm; length 100 mm),
equipped with a magnetic stir bar was charged with cinnamate
ester (0.5 mmol), Pd(OAc)2, (0.025 mmol), base (when used, 1.5
mmol) and solvent (3 mL). After vigorous stirring at room
temperature for 30 s, the diazonium salt (1.0 mmol) was added
in one portion and the reaction left to stir until complete consump-
tion of the starting material was indicated by TLC (Thin Layer
Chromatography). Upon completion, the reaction mixture was
concentrated under reduced pressure and loaded directly onto
silica gel (using a small amount of DCM to transfer the oily
residue) and chromatographed with ethyl acetate-hexanes to give
the desired Heck-adducts.
(Z)-Methyl 3-(4-chlorophenyl)-3-(4-methoxyphenyl)acrylate
(6). Product obtained as a pale-yellow oil (77% yield). Rf =
0.20 (Hexanes/EtOAc, 9:1) after visualization by vanillin; υmax
(thin film, cm-1): 3001, 2838, 1721, 1601, 1571, 1511, 1489, 1462,
1433, 1369, 1363, 1293, 1275, 1253, 1163, 1090, 1032, 1014, 974,
880, 832, 763; δH (250 MHz, CDCl3): 7.39 (2H, d, J 9.0),
7.13-7.26 (4H, m), 6.87 (2H, d, J 9.0), 6.32 (1H, s), 3.82 (3H,
s), 3.62 (3H, s); δC (62.5 MHz, CDCl3): 166.4, 160.9, 155.7,
137.4, 134.1, 132.7, 130.5, 129.7, 128.2, 115.0, 113.8, 55.4, 51.2;
MS m/z (EI): calcd for C17H15ClO3 302.0710, found 302.0729.
Methyl-3-methoxy-2-(3,4,5-trimethoxyphenyl)-3-(4-methoxy-
phenyl)propanoate (9). Product obtained as a white solid (53%
yield). mp. 118-119 °C; Rf = 0.18 (Hexanes/EtOAc, 4:1) after
visualization by vanillin; υmax (thin film, cm-1): 2946, 1732,
Conclusion
We have shown that Pd-catalyzed HM reaction is a highly
useful method for the formation of unsymmetrical β,β-diary-
lacrylates in excellent stereoselectivity. Trisubstituted olefins
with aryl groups having a variety of electronic and steric
properties were prepared in good to excellent yields. In general,
electronically rich cinnamate esters were more reactive sub-
strates in the HM reaction and coupling of electron deficient
alkenes with arenediazonium salts proved to be more challen-
(20) Indatraline (Lu 19-005) is a potent psychoactive compound with
high binding and inhibitory activity for neuronal monoamine reuptake sites,
including dopamine and serotonin transporters and is currently being
investigated as medication to treat cocaine addiction. For further informa-
tion, see: (a) Bogeso, K. P.; Christensen, A. V.; Hyttel, J.; Liljefors, T. J. Med.
Chem. 1985, 28, 1817. (b) Hyttel, J.; Larsen, J. J. Neurochem. 1985, 44, 1615.
(c) Arnt, J.; Christensen, A. V.; Hyttel, J. Naunyn-Schmiedeberg’s Arch.
Pharmacol. 1985, 329, 101. (d) Hurd, Y. L.; Ungerstedt, U. Eur. J. Pharma-
col. 1989, 166, 251. (e) Negus, S. S.; Brandt, M. R.; Mello, N. K.
J. Pharmacol. Exp. Ther. 1999, 291, 60–69.
(21) Davies, H. M. L.; Gregg, T. M. Tetrahedron Lett. 2002, 43, 4951.
(22) Froimowitz, M.; Wu, K. M.; Moussa, A.; Haidar, R. M.; Jurayj, J.;
George, C.; Gardner, E. L. J. Med. Chem. 2000, 43, 4981.
866 J. Org. Chem. Vol. 76, No. 3, 2011

Taylor and Correia
JOCArticle
1723, 1609, 1590, 1510, 1461, 1424, 1370, 1325, 1306, 1281, 1245,
1192, 1179, 1159, 1125, 1097, 1070, 1034, 1015, 971, 928, 841,
829, 806, 777, 734, 706, 672, 637, 618; δH (250 MHz, CDCl3):
6.94 (2H, d, J 8.5), 6.69 (2H, d, J 8.5), 6.23 (2H, s), 4.55 (1H, d, J
10.5), 3.76 (3H, s), 3.74 (3H, s), 3.72 (3H, s), 3.69 (6H, s), 3.21
(3H, s); δC (62.5 MHz, CDCl3): 173.1, 159.3, 152.8, 137.3, 130.3,
130.2, 128.5, 113.4, 105.8, 85.5, 60.7, 59.5, 56.8, 56.0, 55.1, 52.1;
MS m/z (EI): calcd for C21H26O7 390.1679, found 358.1412
(corresponds to expected mass of 390.1679 minus a molecule of
MeOH lost under GC-HRMS (EI) conditions; therefore, the
calcd value would be 358.1416).
cm-1): 3007, 1721, 1600, 1587, 1570, 1510, 1486, 1462, 1433, 1391,
1364, 1293, 1274, 1252, 1215, 1178, 1162, 1069, 1032, 1011, 973, 880,
832, 759; δH (250 MHz, CDCl3): 7.51 (2H, d, J 8.5), 7.20 (2H, d,
J9.0), 7.07 (2H, d, J8.5), 6.83 (2H, d, J9.0), 6.32 (1H, s), 3.82 (3H, s),
3.62 (3H, s); δC (62.5 MHz, CDCl3): 166.4, 161.0, 155.7, 138.0, 132.6,
131.1, 130.8, 129.7, 122.4, 115.0, 113.9, 55.4, 51.2; MS m/z (EI):calcd
for C17H15BrO3 346.0205, found 346.0216.
(E)-Methyl 3-(4-Chlorophenyl)-3-(3,4-dimethoxyphenyl)acry-
late (17). Product obtained as a pale-yellow oil (49% yield).
Rf = 0.31 (Hexanes/EtOAc, 9:1) after visualization by vanillin;
υ
max (thin film, cm-1): 3001, 2837, 1721, 1593, 1515, 1489, 1463,
1434, 1418, 1363, 1325, 1291, 1265, 1223, 1163, 1136, 1088, 1024,
920, 853, 810, 766, 735; δH (250 MHz, CDCl3): 7.39 (2H, d,
J 8.5), 7.17 (2H, d, J 8.5), 6.77-6.84 (3H, m), 6.32 (1H, s), 3.89
(3H, s), 3.83 (3H, s), 3.62 (3H, s); δC (62.5 MHz, CDCl3): 166.3,
155.9, 150.6, 148.8, 137.3, 134.2, 132.9, 130.6, 128.1, 122.1,
115.2, 110.7, 110.6, 55.9, 55.9, 51.3; MS m/z (EI): calcd for
C18H17ClO4 332.0815, found 332.0817.
(E)-Methyl 3-(2-Methoxyphenyl)-3-(4-methoxyphenyl)acrylate
(11). Product obtained as a pale-yellow oil (42% yield). Rf=
0.17 (Hexanes/EtOAc, 5:1) after visualization by vanillin; υmax (thin
film, cm-1): 3000, 1721, 1605, 1576, 1511, 1489, 1462, 1434, 1362,
1292, 1249, 1164, 1112, 1028, 971, 880, 834, 807, 788, 755, 736; δH
(250 MHz, CDCl3): 7.10-7.19 (3H, m), 6.81-6.95 (5H, m), 6.18
(1H, s), 3.81 (3H, s), 3.65 (3H, s), 3.64 (3H, s); δC (62.5 MHz,
CDCl3): 166.9, 159.4, 157.3, 154.2, 131.4, 131.0, 130.3, 129.9, 120.3,
118.8, 113.7, 112.8, 111.6. 55.6, 55.1, 51.2; MS m/z (EI): calcd for
C18H18O4 298.1205, found 298.1223.
(E)-Methyl 3-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)acry-
late (12). Product obtained as a pale-yellow oil (76% yield). Rf =
0.15 (Hexanes/EtOAc, 4:1) after visualization by vanillin; υmax (thin
film, cm-1): 3001, 2951, 2837, 1721, 1606, 1597, 1579, 1513, 1463,
1441, 1417, 1365, 1324, 1289, 1230, 1222, 1173, 1162, 1137, 1027,
977, 920,, 839, 812, 768, 733, 702; δH (250 MHz, CDCl3): 7.14 (2H,
d, J 9.0), 6.80-6.93 (5H, m), 6.24 (1H, s), 3.89 (3H, s), 3.85 (3H, s),
3.83(3H,s),3.63(3H,s);δC (62.5MHz,CDCl3): 170.0, 159.7, 157.0,
150.4, 148.7, 134.1, 130.9, 128.6, 122.2, 114.5, 113.2, 113.3, 110.6,
55.9, 55.8, 55.2, 51.1; MS m/z (EI): calcd for C19H20O5 328.1311,
found 328.1293.
(Z)-Ethyl 3-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)acrylate
(13). Product obtained as a pale-yellow oil (99% yield). Rf = 0.12
(Hexanes/EtOAc, 4:1) after visualization by vanillin; υmax (thin film,
cm-1): 2910, 1716, 1599, 1513, 1463, 1419, 1368, 1353, 1321, 1292,
1253, 1232, 1175, 1156, 1135, 1095, 1028, 834, 810, 766; δH (250
MHz, CDCl3): 7.23 (2H, d, J 8.75), 6.78-6.91 (4H, m), 6.70 (1H, d,
J 2.0), 6.23 (1H, s), 4.02 (2H, q, J 7.0), 3.91 (3H, s), 3.80 (6H, s), 1.10
(3H, t, J 7.0); δC (62.5 MHz, CDCl3): 166.4, 160.7, 156.0, 149.1,
148.3, 133.5, 131.6, 129.9, 122.2, 115.1, 113.7, 112.8, 110.4, 59.8,
55.9, 55.8, 55.3, 14.1; MS m/z (EI): calcd for C20H22O5 342.1467,
found 342.1472.
(Z)-Ethyl 3-(2,4,5-Trimethoxyphenyl)-3-(4-methoxyphenyl)acry-
late (14). Product obtained as a pale-yellow oil (96% yield). Rf =
0.26 (Hexanes/EtOAc, 3:1) after visualization by vanillin; υmax (thin
film, cm-1): 2936, 1719, 1601, 1573, 1511, 1464, 1441, 1420, 1397,
1366, 1351, 1251, 1215, 1207, 1171, 1156, 1113, 1033, 862, 834, 735;
(Z)-Methyl 3-(3-Chlorophenyl)-3-(4-methoxyphenyl)acrylate
(18). Product obtained as a pale-yellow oil (72% yield). Rf =
0.20 (Hexanes/EtOAc, 9:1) after visualization by vanillin; υmax (thin
film, cm-1): 2949, 1723, 1601, 1569, 1511, 1463, 1433, 1360, 1294,
1274, 1254, 1181, 1156, 1119, 1094, 1078, 1032, 977, 874, 833, 811,
795, 772, 737, 700; δH (250 MHz, CDCl3): 7.19-7.36 (5H, m),
7.09-7.12 (1H, m), 6.84 (2H, d, J9.0), 6.33 (1H, s), 3.82 (3H, s), 3.61
(3H, s); δC (62.5 MHz, CDCl3): 166.2, 161.0, 155.2, 140.8, 133.8,
132.3, 129.7, 129.2, 128.9, 128.2, 127.3, 115.2, 113.9, 55.4, 51.3; MS
m/z (EI): calcd for C17H15ClO3 302.0710, found 302.0718.
(Z)-Methyl 3-(3,4-Dichlorophenyl)-3-(4-methoxyphenyl)acrylate
(19). Product obtained as a pale-yellow oil (78% yield). Rf = 0.36
(Hexanes/EtOAc, 4:1) after visualization by vanillin; υmax (thinfilm,
cm-1): 2838, 1721, 1601, 1571, 1551, 1511, 1469, 1433, 1376, 1360,
1295, 1276, 1254, 1159, 1127, 1031, 979, 876, 833, 816, 759; δH (250
MHz, CDCl3): 7.47-7.48 (1H, m), 7.28 (1H, d, J 2.0), 7.19 (2H, d,
J 9.0), 7.04 (1H, dd, J 4.0, 8.0), 6.84 (2H, d, J 9.0), 6.33 (1H, s), 3.82
(3H, s), 3.63 (3H, s); δC (62.5 MHz, CDCl3): 166.1, 161.2, 154.3,
139.0, 132.2, 132.2, 132.0, 130.9, 129.9, 129.7, 128.6, 115.5, 114.0,
55.4, 51.3; MS m/z (EI): calcd for C17H14Cl2O3 336.0320, found
336.0299.
(Z)-Ethyl 3-(2-Fluorophenyl)-3-(4-methoxyphenyl)acrylate
(20). Product obtained as a pale-yellow oil (48% yield). Rf = 0.32
(Hexanes/EtOAc, 8:1) after visualization by vanillin; υmax (thinfilm,
cm-1): 2980, 1719, 1624, 1600, 1574, 1512, 1490, 1462, 1449, 1420,
1368, 132, 1254, 1221, 1159, 1117, 1099, 1021, 876, 8345, 793, 760;
δH (250 MHz, CDCl3): 7.33-7.44 (1H, m), 7.26 (2H, d, J 9.0),
7.09-7.21 (3H, m), 6.84 (2H, d, J 9.0), 6.84 (2H, d, J 9.0), 6.46 (1H,
s), 4.03 (2H, q, J 7.0), 3.81 (3H, s), 1.13 (3H, t, J 7.0); δC (62.5 MHz,
CDCl3): 165.6, 161.5 (d, J 245), 160.9, 149.4, 131.8, 130.7 (d, J 3.4),
129.8 (d, J 8.1), 129.0, 126.9 (d, J 16.4), 123.7 (d, J 3.5), 117.2, 115.5
(d, J 21.9), 113.9, 59.9, 55.3, 14.0; δF (235 MHz, CDCl3): -115.0;
MS m/z (EI): calcd for C18H17FO3 300.1162, found 300.1157.
(Z)-Methyl 3-(4-Chlorophenyl)-3-(4-nitrophenyl)acrylate
(21). Product obtained as a pale-yellow oil (65% yield). Rf =
0.31 (Hexanes/EtOAc, 9:1); υmax (thin film, cm-1): 3086, 1726,
1623, 1596, 1520, 1490, 1434, 1408, 1346, 1271, 1260, 1193, 1169,
1107, 1090, 1013, 973, 874, 854, 830, 760, 737, 699; δH (250 MHz,
CDCl3): 8.21 (2H, d, J 9.0), 7.38-7.45 (4H, m), 7.16 (2H, d,
J 8.5), 6.43 (1H, s), 3.66 (3H, s); δC (62.5 MHz, CDCl3): 165.5,
153.0, 148.2, 146.6, 135.8, 135.0, 130.5, 129.1, 128.6, 123.7, 120.4,
51.7; MS m/z (EI): calcd for C16H12ClNO4 317.0455, found
317.0471.
δH (250 MHz, CDCl3): 7.28 (2H, d, J 9.0), 6.82 (2H, d, J 9.0), 6.57
(1H, s), 6.55 (1H, s), 6.35 (1H, s), 4.02 (2H, q, J 7.0), 3.90 (3H, s),
3.77 (3H, s), 3.75 (3H, s), 3.65 (3H, s), 1.09 (3H, t, J 7.0); δC (62.5
MHz, CDCl3): 166.1, 160.6, 151.9, 1512.1, 149.5, 142.9, 132.8, 129.0,
119.8, 116.3, 113.9, 113.7, 98.0, 59.7, 56.8, 56.5, 55.9, 55.2, 14.1; MS
m/z (EI): calcd for C21H24O6 372.1573, found 372.1587.
(Z)-Methyl 3-(4-Methoxyphenyl)-3-(4-nitrophenyl)acrylate (15).
Product obtained as a pale-yellow solid after evaporation of the
volatiles (96% yield). mp. 88-89 °C; Rf = 0.31 (Hexanes/EtOAc,
9:1) after visualization by vanillin; υmax (thin film, cm-1): 3080,
3001, 2839, 1725, 1606, 1514, 1491, 1460, 1434, 1410, 1347, 1297,
1250, 1168, 1154, 1110, 1032, 973, 912, 872, 854, 834, 803, 762, 732;
δH (250 MHz, CDCl3): 8.19 (2H, d, J 9.0), 7.47 (2H, d, J 9.0), 7.15
(2H, d, J 9.0), 6.94 (2H, d, J 9.0), 6.33 (1H, s), 3.85 (3H, s), 3.66 (3H,
s); δC (62.5 MHz, CDCl3): 166.0, 160.2, 154.2, 148.1, 147.9, 130.9,
129.5, 129.4, 123.6, 119.2, 113.6, 55.3, 51.6; MS m/z (EI): calcd for
C17H15NO5 313.0950, found 313.0964.
(Z)-Methyl 3-(4-bromophenyl)-3-(4-methoxyphenyl)acrylate (16).
Product obtained as a pale-yellow oil (84% yield). Rf = 0.46
(Hexanes/EtOAc, 4:1) after visualization by vanillin; υmax (thin film,
(Z)-Methyl 3-(3-Chlorophenyl)-3-(4-nitrophenyl)acrylate (22).
Product obtained as a pale-yellow oil (25% yield). Rf=0.20
(Hexanes/EtOAc, 9:1) after visualization by vanillin; υmax (thinfilm,
cm-1): 2922, 1728, 1615, 1594, 1564, 1514, 1474, 1433, 1344, 1271,
1254, 1192, 1166, 1080, 1009, 972, 869, 851, 792, 760, 739; δH (250
MHz, CDCl3): 8.18 (2H, d, J 9.0), 7.36-7.46 (4H, m), 7.17-7.19
(4H, m), 7.08 (1H, dt, J 1.8 7.0), 6.84 (2H, d, J 9.0), 6.33 (1H, s), 3.82
J. Org. Chem. Vol. 76, No. 3, 2011 867

Taylor and Correia
JOCArticle
(3H, s), 3.61 (3H, s); δC (62.5 MHz, CDCl3): 165.4, 152.6, 146.2,
139.2, 134.3, 129.6, 129.0, 128.9, 128.3, 127.2, 124.4, 123.8, 120.7,
51.7; MS m/z (EI): calcd for C16H11ClNO4 317.0455, found
317.0479.
13.9; MS m/z (EI): calcd for C20H21NO5 355.1420, found
355.1432.
General Procedure for the Copper-Catalyzed Enantioselective
Reduction of β,β-Diarylacrylates. Cu(OAc)2 (0.015 mmol) and
(R)-1-[(S)-2-diphenylphosphino) ferrocenyl]ethyldicyclohexylphos-
phine) (0.020 mmol) were placed in an oven-dried Schlenk tube and
the air evacuated and backfilled with nitrogen four times. Next,
anhydrous toluene (0.5 mL) was added and the reaction mixture
was stirred for 15 min at room temperature. Polymethylhydrosilox-
ane (2.0 mmol) was added and the reaction was stirred for a further
5 min for catalyst activation. The unsaturated ester (0.5 mmol) in
toluene (1.0 mL) was added, followed by tBuOH (2.0 mmol). The
reaction was sealed, and stirred overnight at room temperature. The
reaction mixture was quenched with saturated NaHCO3 (5mL) and
transferred to a round-bottomed flask with the aid of EtOAc
(5 mL). The biphasic mixture was stirred vigorously for one hour.
The layers were separated and the aqueous layer was extracted with
EtOAc (2 ꢀ 10 mL). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo. The product
was purified by flash chromatography on silica gel.
(Z)-Ethyl 3-(4-Methoxyphenyl)-3-(2-nitrophenyl)acrylate (23).
Product obtained as a white solid after recrystallization with ethyl
acetate/hexanes (73% yield). mp. 96-98 °C, Rf = 0.13 (Hexanes/
EtOAc, 4:1) after visualization by vanillin; υmax (thin film, cm-1):
2981, 1715, 1638, 1601, 1572, 1525, 1513, 1456, 1443, 1367, 1346,
1291, 1273, 1253, 1179, 1031, 975, 856, 834, 787; δH (250 MHz,
CDCl3): 8.19 (1H, d, J 9.5), 7.66 (1H, t, J 7.5), 7.58 (1H, t, J 7.5),
7.27-7.29 (3H, m), 6.85 (2H, d, J 9.0), 6.43 (1H, s), 3.97 (2H, q, J
7.5), 3.82 (3H, s), 1.10 (3H, t, J 7.5); δC (62.5 MHz, CDCl3): 165.9,
161.2, 153.2, 148.2, 135.6, 133.4, 131.3, 130.9, 129.2, 128.9, 124.8,
115.2, 114.3, 60.3, 55.6, 19.2; MS m/z (EI): calcd for C18H17NO5
327.1107, found 327.1100.
(E)-Ethyl 3-(4-(Trifluoromethyl)phenyl)-3-(4-methoxyphenyl)-
acrylate (24). Product obtained as a pale-yellow oil (91% yield).
Rf = 0.38 (Hexanes/EtOAc, 9:1) after visualization by vanillin;
υ
max (thin film, cm-1): 2981, 1761, 1791, 1600, 1573, 1510, 1464,
1443, 1420, 1407, 1370, 1325, 1296, 1254, 1164, 1125, 1066, 1020,
876, 703, 623; δH (250 MHz, CDCl3): 7.64 (2H, d, J 8.0), 7.31 (2H,
d, J 8.0), 7.19 (2H, d, J 9.0), 6.84 (2H, d, J 9.0), 6.34 (1H, s), 4.03
(2H, q, J 7.0), 3.83 (3H, s), 1.11 (3H, t, J 7.0); δC (62.5 MHz,
CDCl3): 165.9, 161.1, 154.7, 143.1, 132.2, 129.6, 129.4, 124.7 (q, J
3.8), 116.0, 113.9, 60.1, 55.3, 13.9; δF (235 MHz, CDCl3): -62.5;
MS m/z (EI): calcd for C19H17F3O3 350.1130, found 350.1142.
(Z)-Methyl 3-(4-Methoxyphenyl)-3-o-tolylacrylate (25). Product
obtained as a pale-yellow oil (73% yield). Rf = 0.37 (Hexanes/
EtOAc, 4:1) after visualization by vanillin; υmax (thin film, cm-1):
3013, 2838, 1724, 1702, 1598, 1571, 1511, 1435, 1359, 1254, 1182,
1118, 1032, 973, 834, 762, 732; δH (250 MHz, CDCl3): 7.26-7.29
(5H, m), 7.04-7.07 (1H, m), 6.83 (2H, d, J 9.0), 6.48 (1H, s), 3.81
(3H, s), 3.59 (3H, s), 2.09 (3H, s); δC (62.5 MHz, CDCl3): 166.2,
160.9, 156.2, 138.7, 135.3, 131.6, 129.8, 128.9, 128.2, 127.7, 125.4,
114.6, 114.0, 55.3, 51.1, 19.5; MS m/z (EI): calcd for C18H18O3
282.1256, found 282.1276.
(Z)-Methyl 3-(4-Nitrophenyl)-3-o-tolylacrylate (26). Product
obtained as a pale-yellow oil (54% yield). Rf = 0.13 (Hexanes/
EtOAc, 9:1); υmax (thin film, cm-1): 3019, 1729, 1624, 1594, 1519,
1457, 1435, 1409, 1345, 1263, 1192, 1169, 1110, 1013, 973, 851, 767,
761, 731, 697; δH (250 MHz, CDCl3): 8.15 (2H, d, J9.0), 7.45 (2H, d,
J 9.0), 7.26-7.33 (3H, m), 7.05-7.08 (1H, m), 6.60 (1H, s), 3.62
(3H, s), 2.06 (3H, s); δC (62.5 MHz, CDCl3): 165.4, 153.8, 148.2,
145.6, 137.1, 130.2, 128.5, 125.8, 123.8, 120.5, 114.0, 51.6, 19.6; MS
m/z (EI): calcd for C17H15NO4 297.1001, found 297.0984.
(Z)-Ethyl 3-(4-Methoxyphenyl)-3-(3,4-dimethylphenyl)acrylate
(27). Product obtained as a pale-yellow solid (91% yield). mp.
55-56 °C; Rf = 0.29 (Hexanes/EtOAc, 5:1) after visualization by
vanillin; υmax (thin film, cm-1): 2976, 1720, 159, 1572, 1522, 1461,
1420, 1367, 1352, 1252, 1177, 1154, 1119, 1035, 873, 833; δH (250
MHz, CDCl3): 7.13-7.28 (3H, m), 6.95-6.98 (2H, m), 6.82 (2H, d,
J 9.0), 6.26 (1H, s), 4.02 (2H, q, J 7.0), 3.82 (3H, s), 2.31 (3H, s), 2.26
(3H, s), 1.12 (3H, t, J 7.0); δC (62.5 MHz, CDCl3): 166.4, 160.7,
156.7, 136.6, 136.5, 135.9, 133.9, 130.2, 129.8, 129.1, 126.7, 115.0,
113.7, 59.9, 55.3, 19.8, 19.7, 14.0; MS m/z (EI): calcd for C20H22O3
310.1569, found 310.1560.
Methyl-2-((Z)-2-(ethoxycarbonyl)-1-(4-methoxyphenyl)vinyl)-
phenylcarbamate (28). Product obtained as viscous a pale-yellow
oil (87% yield). Rf = 0.36 (Hexanes/EtOAc, 4:1); υmax (thin film,
cm-1): 3306, 1728, 1696, 1633, 1579, 1530, 1476, 1456, 1367,
1324, 1301, 1283, 1266, 1235, 1137, 1105, 1063, 1031, 992, 882,
862, 832, 759, 733, 713; δH (250 MHz, CDCl3): 7.99(1H, d, J 7.8),
7.35 (1H, t, J 8.5), 7.26 (2H, d, J 7.5), 7.08 (1H, t, J 7.3), 6.99 (1H,
dd, J 1.5 7.5), 6.83 (2H, d, J 9.0), 6.54 (1H, s), 6.52 (1H, br s),
3.98 (2H, q, J 7.5), 3.80 (3H, s), 3.65 (3H, s), 1.05 (3H, t, J 7.5);
δC (62.5 MHz, CDCl3): 165.7, 161.2, 154.0, 151.4, 135.1,
130.6, 129.0, 128.9, 128.8, 123.5, 117.2, 114.2, 60.3, 55.4, 52.2,
(S)-Methyl 3-(3,4-Dichlorophenyl)-3-phenylpropanoate (29).
Product obtained as a colorless viscous oil (96% yield). Rf = 0.24
(Hexanes/EtOAc, 9:1); δH (250 MHz, CDCl3): 7.18-7.36 (7H, m),
7.06 (1H, dd, J1.8, 8.3), 4.48 (1H, t, J8.0), 3.61 (3H, s), 3.02 (2H, d, J
8.0). NMR data were consistent with the literature values.3a The ee
(89% ee) was measured by chiral HPLC on an OD column (iPrOH/
hexane 1:99 to 15:85 over 10 min then 15:85 for 6 min, 0.8 mL/min,
λ = 235 nm): (S)-enantiomer tr = 10.44 min and (R)-enantiomer
tr = 13.44 min. [R]D -1.0 (c 1.2, DCM) [lit.16 value for the R
20
20
enantiomer:[R]D þ1.6 (c 10.6, DCM).
(þ)-Ethyl 3-(4-(Trifluoromethyl)phenyl)-3-(4-methoxyphenyl)-
propanoate (30). Product obtained as a colorless viscous oil (77%
yield). Rf = 0.22 (Hexanes/EtOAc, 9:1); υmax (thin film, cm-1):
2982, 2838, 1733, 1617, 1584, 1512, 1464, 1443, 1418, 1392, 1372,
1326, 1304, 1251, 1214, 1163, 1121, 1069, 1035, 1018, 964, 903, 878,
827, 810, 754; δH (250 MHz, CDCl3):7.54(2H, d,J8.0), 7.36 (2H, d,
J 8.0), 7.15 (2H, d, J 8.5), 6.82 (2H, d, J 8.5), 4.53 (1H, t, J 8.0), 4.02
(2H, q, J 7.0), 3.77 (3H, s), 3.01 (2H, d, J 8.0), 1.10 (3H, t, J 7.0); δC
(62.5 MHz, CDCl3): 171.4, 158.4, 147.9, 134.6, 128.6, 127.9, 125.4
(q, J 3.9), 122.3, 114.4, 114.1, 60.5, 55.2, 46.1, 40.6, 14.0; MS m/z
(EI): calcd for C19H19F3O3 352.1286, found 352.1292. The ee (90%
ee) was measured by chiral HPLC on an AD-H column (iPrOH/
hexane 1:99 to 2:98 over 15 min then 10:90 over 3 min and hold at
this ratio for a further 12 min, 0.8 mL/min, λ = 254 nm): (þ)-
20
enantiomer tr = 19.18 min and (-)-isomer tr = 20.27 min. [R]D
þ1.0 (c 2.2, DCM).
(-)-Ethyl 3-(4-Methoxyphenyl)-3-(3,4-dimethylphenyl)propa-
noate (31). Product obtained as a colorless viscous oil (96% yield).
Rf = 0.25 (Hexanes/EtOAc, 3:1); υmax (thinfilm, cm-1): 2975, 1734,
1611, 1583, 1511, 1456, 1369, 1302, 1250, 1179, 1151, 1111, 1034,
903, 832, 785; δH (250 MHz, CDCl3): 7.16 (2H, d, J 8.5), 6.94-7.07
(3H, m), 6.81 (2H, d, J 8.5), 4.28 (1H, t, J 8.0), 4.01 (2H, q, J 7.0),
3.77 (3H, s), 2.99 (2H, d, J8.0), 2.22 (3H, s), 2.21 (3H, s), 1.12 (3H, t,
J 7.0); δC (62.5 MHz, CDCl3): 171.9, 158.0, 141.4, 136.5, 136.0,
134.6, 129.7, 129.0, 128.6, 124.7, 113.9, 60.3, 55.2, 45.9, 41.1, 19.9,
19.3, 14.1; MS m/z (EI): calcd for C20H24O3 312.1725, found
312.1756. The ee (91% ee) was measured by chiral HPLC on an
AD-H column (iPrOH/hexane 1:99 to 2:98 over 15 min then 5:95
over 3 min and finally 10:90 over 11 min, 0.8 mL/min, λ = 254 nm):
(-)-enantiomer tr = 17.55 min and (þ)-enantiomer tr = 19.54 min.
[R]D20 -2.9 (c 4.0, DCM).
(þ)-Methyl 3-(4-Chlorophenyl)-3-(4-methoxyphenyl)propanoate
(32). Product obtained as a colorless viscous oil (94% yield). Rf =
0.28 (Hexanes/EtOAc, 9:1); υmax (thin film, cm-1): 2974, 1740,
1513, 1491, 1366, 1270, 1201, 1026, 903, 845, 783; δH (250 MHz,
CDCl3): 7.23 (2H, d, J 8.5), 7.10-7.17 (4H, m), 6.81 (2H, d, J 8.5),
4.45 (1H, t, J 8.0), 3.77 (3H, s), 3.59 (3H, s), 2.98 (2H, d, J 8.0); δC
(62.5 MHz, CDCl3): 172.1, 158.3, 142.3, 136.0, 132.3, 128.9, 128.6,
868 J. Org. Chem. Vol. 76, No. 3, 2011

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128.5, 114.0, 55.2, 51.7, 45.5, 40.6; MS m/z (EI): calcd for
C17H17ClO3 304.0866, found 304.0867. The ee (90% ee) was
measured by chiral HPLC on an AD-H column (iPrOH/hexane
1:99 to 1:98 over 26 min, 0.8 mL/min, λ = 254 nm): (þ)-enantiomer
(-)-Methyl 3,4-Dihydro-4-(4-methoxyphenyl)-2-oxoquinoline-
1(2H)-carboxylate (37). Product obtained as an amorphous beige
solid (80% yield). Rf = 0.18 (Hexanes/EtOAc, 4:1); υmax (thin
film, cm-1): 3418, 2975, 1777, 1698, 1663, 1608, 1557, 1511, 1494,
1455, 1436, 1417, 1366, 1305, 1270, 1246, 1179, 1111, 1030, 908,
838, 784, 759; δH (250 MHz, CDCl3): 6.98-7.10 (6H, m),
6.85 (2H, d, J 9.0), 4.23 (1H, t, J 6.8), 4.00 (3H, s), 3.79 (3H, s),
2.95 (2H, d, J 6.8); δC (62.5 MHz, CDCl3): 168.9, 159.1, 154.2,
136.9, 132.2, 130.4, 129.0, 128.4, 128.0, 125.2, 119.1, 114.6, 55.5,
55.2, 41.2, 40.6; MS m/z (EI): calcd for C18H17NO4 311.1158,
found 311.1271. The ee (75% ee) was measured by chiral HPLC
on an AD column (iPrOH/hexane 1:99 to 10:90 over 19 min then
20:80 over 5 min and hold for a further 11 min at this ratio,
0.8 mL/min, λ=254 nm): (þ)-enantiomer tr = 26.18 min and
(-)-enantiomer tr = 28.39 min. [R]D20 -13.0 (c 1.0, DCM).
(S)-3-(3,4-Dichlorophenyl)-2,3-dihydroinden-1-one (38). Pro-
duct obtained as a white solid (55% yield over 2 steps) following
the procedure reported in the literature.3a mp. 110-111 °C;
Rf = 0.32 (Hexanes/EtOAc, 8:1) after visualization by vanillin;
20
tr = 11.41 min and (-)-enantiomer tr = 13.85 min. [R]D þ0.4 (c
4.2, DCM).
Methyl 3-(4-Chlorophenyl)-3-(4-methoxyphenyl)propanoate
(33). Obtained as an inseparable mixture of starting material
and product after column chromatography. Conversion of 22%
1
as determined by H NMR integration by comparison of the
methine triplet (4.45 ppm) corresponding to 33 and the olefinic
hydrogen singlet (6.24 ppm) of 14 (see Supporting Information
for 1H NMR spectra). MS m/z (EI): calcd for C20H24O5
344.1624, found 344.1646. The ee (72% ee) was measured by
chiral HPLC on an OD-H column (iPrOH/hexane 1:99, 0.8 mL/
min, λ = 235 nm): Olefin tr = 43.55, (minor)-enantiomer tr =
56.90 min and (major)-enantiomer tr = 62.04 min.
Ethyl 3-(4-Methoxyphenyl)-1H-indole-2-carboxylate (35). After
mixing of the initial pale-yellow viscous oil with hexanes and
recrystallization of the subsequent pale-yellow solid with ethyl
acetate/hexanes a white solid was afforded (58% yield). mp. 109-
111 °C (lit. 115-116 °C);19 Rf = 0.43 (Hexanes/EtOAc, 4:1) after
visualization by vanillin; υmax (thin film, cm-1): 2977, 2165, 1655,
1620, 1572, 1503, 1471, 1430, 1387, 1366, 1329, 1307, 1272, 1241,
1199, 1176, 1124, 1035, 949, 907, 876, 848, 839, 811, 774, 755, 745;
δH (250 MHz, CDCl3): 10.71 (1H, s), 7.55 (2H, dd, J 4.0 9.0),
7.35-7.45 (3H, m), 7.08 (1H, t, J 8.0), 6.96 (2H, d, J 9.0), 4.28 (2H,
q, J 7.0), 3.89 (3H, s), 1.21 (3H, t, J 7.0); δC (62.5 MHz, CDCl3):
165.0, 159.2, 133.3, 132.2, 126.3, 125.7, 121.8, 121.1, 120.3, 118.3,
113.4, 109.8, 61.7, 55.6, 14.1; MS m/z (EI): calcd for C18H17NO3
295.1208, found 295.1218.
δH (250 MHz, CDCl3): 7.82 (1H, d, J 7.5), 7.58 (1H, td, J 1.3, 7.5),
7.37-7.49(2H,m),7.22-7.28 (2H, m), 6.93 (1H, dd, J2.0, 8.3), 4.52
(1H, dd, J 3.8, 8.0), 3.18 (1H, dd, J 8.3, 19.3), 2.57 (1H, dd, J 4.0,
19.3); δC (62.5 MHz, CDCl3): 204.9, 156.5, 143.9, 136.7, 135.4,
130.8, 129.7, 128.3, 126.9, 123.5, 46.5, 43.6. NMR data were
consistent with the literature values. The ee (89% ee) was measured
by chiral HPLC on an OD column (iPrOH/hexane 1:99 to 15:85
over 10 min then hold at this ratio for 6 min, 0.8 mL/min, λ = 254
nm): (R)-enantiomer tr = 11.30 min and (S)-enantiomer tr = 12.15
min. [R]D20 -50.0 (c = 1.1, CHCl3)
Acknowledgment. We thank the Research Supporting
Foundation of the State of Sao Paulo (FAPESP) for finan-
cial support and the Brazilian National Research Council
(CNPq) for financial support and fellowships
Methyl 4-(4-Methoxyphenyl)-2-oxoquinoline-1(2H)-carboxylate
(36). Product obtained as an amorphous pale-yellow solid (97%
yield). Rf = 0.12 (Hexanes/EtOAc, 4:1); υmax (thin film, cm-1):
3419, 2973, 1777, 1732, 1664, 1608, 1594, 1511, 1492, 1449, 1417,
1374, 1305, 1291, 1267, 1245, 1179, 1132, 1069, 1030, 908, 873, 838,
753; δH (250 MHz, CDCl3): 7.59 (1H, dd, J 1.5 8.3), 7.59 (1H, t, J
6.0), 7.59 (2H, d, J9.0), 7.11-7.23(2H, m), 6,57(1H, s), 4.18(3H, s),
3.89 (3H, s); δC (62.5MHz, CDCl3): 160.3, 159.9, 158.7, 152.9, 136.8,
130.9, 130.1, 128.7, 127.8, 123.2, 120.3, 119.7, 114.4, 114.1, 56.0, 55.4;
MS m/z (EI): calcd for C18H15NO4 309.1001, found 309.0977.
Supporting Information Available: General methods, Ex-
perimental details, characterization data and copies of 1H
and 13C NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 3, 2011 869