Palladium-catalyzed hydroarylation of propiolamides. A regio- and stereocontrolled method for preparing 3,3-diarylacrylamides

Article abstract of DOI:10.1021/jo980235h

A general regio- and stereoselective synthesis of 3,3-diarylacrylamides is reported. Palladium-catalyzed coupling reactions of propiolamides with aryl provides arylpropiolamides. A subsequent hydroarylation reaction of these arylpropiolamides with aryl halides, catalytic palladium, an amine base, and formic acid in refluxing ethyl acetate provides 3,3- diarylacrylamides regio- and stereoselectively. The unique stereo- and regiocontrol is presumed to proceed through careful reaction parameters that allow intramolecular coordination of the propiolamide amide functionality to the transient palladium-alkyne complex. Palladium-catalyzed hydroarylation of propiolamides has not been studied; however, preliminary results from related systems suggest that regioselective addition can be achieved. The methodology as a synthesis tool is demonstrated in an efficient route to previously difficult-to-prepare potent, benzimidazole antiviral targets. In addition, the synthesis scope is explored where, by judicious choice of reaction sequence and aryl iodide, either the Z- or E-geometric isomer of a given pair of 3,3-diarylacrylamides is independently prepared.

Full text of DOI:10.1021/jo980235h

5050
J . Org. Chem. 1998, 63, 5050-5058
P a lla d iu m -Ca ta lyzed Hyd r oa r yla tion of P r op iola m id es. A Regio-
a n d Ster eocon tr olled Meth od for P r ep a r in g 3,3-Dia r yla cr yla m id es
Lynne A. Hay, Thomas M. Koenig, Francis O. Ginah, J ames D. Copp, and David Mitchell*
Chemical Process R&D, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly
Corporate Center, Indianapolis, Indiana 46285-4813
Received February 9, 1998
A general regio- and stereoselective synthesis of 3,3-diarylacrylamides is reported. Palladium-
catalyzed coupling reactions of propiolamides with aryl halides provide arylpropiolamides.
A
subsequent hydroarylation reaction of these arylpropiolamides with aryl halides, catalytic palladium,
an amine base, and formic acid in refluxing ethyl acetate provides 3,3-diarylacrylamides regio-
and stereoselectively. The unique stereo- and regiocontrol is presumed to proceed through careful
reaction parameters that allow intramolecular coordination of the propiolamide amide functionality
to the transient palladium-alkyne complex. Palladium-catalyzed hydroarylation of propiolamides
has not been studied; however, preliminary results from related systems suggest that regioselective
addition can be achieved. The methodology as a synthesis tool is demonstrated in an efficient
route to previously difficult-to-prepare potent, benzimidazole antiviral targets. In addition, the
synthesis scope is explored where, by judicious choice of reaction sequence and aryl iodide, either
the Z- or E-geometric isomer of a given pair of 3,3-diarylacrylamides is independently prepared.
In tr od u ction
establish the geometric 3,3-diarylacrylamide relationship.
This convergent approach involved preparation of 2-ami-
nobenzimidazole 7 or 8 and propiolamides 4-6. The
palladium-catalyzed hydroarylation reaction between 7
or 8 and 4-6 would provide 3,3-diarylacrylamides 1-3.
The 3,3-diarylacrylamide structure is present in a
variety of biologically active molecules. When one of the
aryl units is substituted with a carboxyalkanamide or a
carboxyalkenamido group, these derivatives are effective
in antagonizing the spasmogenic activity of the slow-
reacting substance of anaphylaxis (SRS-A) in human
subjects.1 Therefore, this class of compounds is useful
for preventing and treating certain obstructive airway
diseases, notably allergic bronchial asthma and allergic
rhinitis. Additionally, a variety of 3,3-diarylacrylamides
are active fungicides in various microbicidal composi-
tions.2 Specifically, 3-aryl-3-benzimidazole acrylamides
can function as agents to treat viral growth.3
Since one geometric isomer is usually more active than
the other (or at times the other stereoisomer is totally
inactive), versatile, stereoselective syntheses of these
targets are advantageous. Thus far, 3,3-diarylacryl-
amides have been prepared by methods such as the
Wittig and related reactions, Peterson olefination, Heck
reaction, or simply by dehydration of a carbinol. While
these reactions are suitable methods, many of them
produce mixtures of the (E)- and (Z)-isomers.
In conjunction with projected syntheses of antirhinovi-
ral agents 1-3 (eq 1), our need to develop a practical
route to stereospecific 3,3-diarylacrylamides led to an
investigation of the palladium-catalyzed hydroarylation
reaction4-7 of propiolamides. The synthesis strategy was
to incorporate a key hydroarylation reaction step to
Hydroarylation reactions of substituted acetylenes with
aryl iodides in the presence of palladium catalyst, formic
acid, and base are known to result in high stereo- and
regioselective formation of trisubstituted olefins. In
particular, variations of this methodology have found
wide use in the palladium-catalyzed annulation of func-
tionalized carbo- and heterocycles.8,9 Among the acety-
lene systems that have been reported are dialkylacety-
lenes, diarylacetylenes, arylethynylcarbinols, arylethynyl-
silanes, alkylethynylsilanes, and alkyl 4-hydroxy-2-
alkynoates. We have recently investigated the applica-
* To whom correspondence should be addressed. Tel.: (317) 276-
1384. Fax: (317) 276-4507. E-mail: mitchell•david•nmn@lilly.com.
(1) Kadin, S. B. U.S. Patent 4,342,781, Aug 3, 1982.
(2) Curtz, J .; Gunter Krummel, M. U.S. Patent 4,912,217, March
27, 1990.
(3) Morwick, T. M.; Paget, C. J . U.S. Patent 4,420,479, Dec 13, 1983.
(4) Cacchi, S.; Felici, M.; Pietroni, B. Tetrahedron Lett. 1984, 25,
3137.
(5) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron 1985, 41, 5121.
(6) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1986, 42,
6397.
(7) Arcadi, A.; Bernocchi, E, Burini, A.; Cacchi, S.; Marinelli, F.;
Pietroni, B. Tetrahedron 1988, 44, 481.
(8) Arcadi A.; Cacchi S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F.
J . Org. Chem. 1996, 61, 9280.
(9) Cacchi, S.; Fabrizi, G.; Moro, L. J . Org. Chem. 1997, 62, 5327.
S0022-3263(98)00235-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/27/1998

Pd-Catalyzed Hydroarylation of Propiolamides
J . Org. Chem., Vol. 63, No. 15, 1998 5051
tion of palladium-catalyzed hydroarylation to the propi-
olamide system for preparing 3,3-diarylacrylamides.10
Unlike most other acetylene systems where steric factors
control the regiochemistry, we reasoned that the amide
functionality would play a key role in the regiochemical
outcome due to possible coordination of the amide to the
transient-metal complex. Herein, we report the use of
propiolamides in the palladium-catalyzed hydroarylation
reaction. The methodology is developed in terms of the
synthesis for antiviral 3,3-diarylacrylamide targets 2 and
3, which is further extended to include the scope of the
general reaction in preparing regio- and stereoselective
3,3-diarylacrylamides.
coupling of 11 and 12 in the presence of 6 mol % Pd-
(Ph3P)2OAc2, 20 mol % CuI, and triethylamine in ethyl
acetate at ambient temperature for 6 h provided the
coupled product 5 in 82% yield (eq 3). On the other hand,
propiolamide 13 reacted with the triflate 14 in the
presence of 7 mol % Pd(Ph3P)2Cl2, 5 mol % CuI, triethyl-
amine, and LiCl in DMSO at 55 °C for 1 h to provide 3
in 81% yield (eq 4).
Resu lts a n d Discu ssion
Bu ild in g Block s. The heterocycles 7 and 8 were
prepared from readily available 2-aminobenzimidazole
according to eq 2. First, the sulfonamide functionality
was introduced by reaction of 9 with isopropylsulfonyl
chloride in a solution of acetonitrile and sodium hydrox-
ide. Iodination using N-iodosuccinimide in acetic acid
provided 6-iodo-2-aminobenzimidazole 7 in an overall
yield of 76% from 9.
Hyd r oa r yla tion of P r op iola m id es. Modifying a
literature procedure4 for the palladium-catalyzed hy-
droarylation reaction, 5 and 1 equiv of the aryl halide 7
were heated in DMF at 50 °C with Pd(Ph3P)2(OAc)2,
formic acid, and an amine (diethylamine, piperidine, or
triethylamine) (eq 5). No reaction occurred with triethyl-
amine, while the reaction with diethylamine provided low
yields of the reduced propiolamide, cis-alkene 17. Using
piperidine as base provided 10% of 15 as a mixture of
geometric isomers in addition to an equal amount of the
structural regioisomer 16 also as a mixture. The re-
mainder of the material isolated from this reaction was
the dehalogenated benzimidazole 18. To minimize de-
halogenation, 7 was added slowly to the reaction mixture.
This approach did not decrease the amount of 18 formed
but resulted in an increase of the alkene product 17.
Employing bromobenzimidazole 8 gave similar results.
Other hydroarylation conditions were investigated using
the same catalyst and replacing the amine/formic acid
combination with tetrapropylammonium bromide/sodium
formate or potassium carbonate, lithium chloride/formic
acid. Neither of these conditions provided the desired
product, and only starting materials were recovered.
Although excess aryl halide was used in the noted
literature reaction, our system was limited to 1 equiv due
to the complex nature of the aryl halide. This deviation
may have contributed to the outcome of our experimenta-
tion.
Initial attempts at preparing various arylpropiolamides
by the Castro-Stephens11,12 reaction or its modi-
fications13-15 employing aryl iodides or aryl triflates with
methyl propiolate followed by amination of the ester
functionality were not successful due to the low-yielding
coupling reaction step. It has been documented that
terminal acetylenes containing an electron-withdrawing
group directly attached to the ethynyl carbon atom react
poorly with aryl halides.16 With the obvious difference
between the ester functionality and amide, we turned our
efforts toward cross-coupling reactions of propiolamides
and aryl halides or aryl triflates.
Propiolamide and N-methylpropiolamide were pre-
pared from methyl propiolate 17-20 in 88% and 95% yield,
respectively. Both propiolamides were subjected to cross-
coupling reaction conditions with a variety of aryl iodides,
aryl bromides, and aryl triflates. Unlike methyl propi-
olate or ethyl propiolate, the propiolamides provide
arylpropiolamides in good yields. For example, the
(10) Hay, L. A.; Mitchell, D. Tetrahedron Lett. 1997, 38, 6533.
(11) Stephens, R. D.; Castro, C. E. J . Org. Chem. 1963, 28, 3313.
(12) Burdon, J .; Coe, P. L.; March, C. R.; Tatlow, J . C. J Chem. Soc.,
Chem. Commun. 1967, 1259.
(13) Guillerm, D.; Linstrumelle, G. Tetrahedron Lett. 1985, 26, 3811.
(14) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
(15) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic
Press: San Diego, CA, 1985.
(16) Sakamoto, T.; Shiga, F.; Yasuhara, A.; Uchiyama, D.; Kondo,
Y.; Yamanaka, H. Synthesis 1992, 746.
(17) Crow, W. D.; Leonard, N. J . Tetrahedron Lett. 1964, 23, 1477.
(18) Crow, W. D.; Leonard, N. J . J . Org. Chem. 1965, 30, 2660.
(19) Truce, W. E.; Tichenor, G. J . W. J . Org. Chem. 1972, 37, 2391.
(20) J ung, M. E.; Buszek, K. R. J . Am. Chem. Soc. 1988, 110, 3965.
In an effort to optimize the palladium-catalyzed hy-
droarylation reaction to provide 2, several catalysts were
examined. The results are summarized in Table 1.

5052 J . Org. Chem., Vol. 63, No. 15, 1998
Hay et al.
Ta ble 3. Solven t Effect on Isom er Ra tio a t 0.02 Ma
Ta ble 1. P a lla d iu m -Ca ta lyzed Hyd r oa r yla tion in DMF a
isomer
isomer ratio
dielectric
constant (ꢀ)
time yield (%) yield (%) yield (%) ratio
solvent
T (°C)
(2:19)b
catalyst
(h)
of 15b
of 16b
of 18b
(15:16)
EtOAc
THF
CHCl3
MeOH
DMF
77
66
61
65
60
82
17:1
20:1
5.8:1
3.5:1
2:1
6.02
7.6
4.9
32.7
36.7
37.5
Pd(Ph3P)2(OAc)2
Pd(MeCN)2Cl2
Pd(OAc)2/(o-tol)3P
>24
52
48
7
31
7
27
29
<5
1:1
1.1:1
2:1
trace amounts
a
Reactions run using 6-7% catalyst, 3.3 equiv of piperidine,
2.6 equiv of formic acid in DMF at 50-55 °C. bReversed-phase
HPLC area percents.
MeCN
1:1
a
Reactions run using 6-7% Pd(dba)2, 3.3 equiv of piperidine,
2.6 equiv of formic acid. Reversed-phase HPLC area percents.
b
Ta ble 2. P a lla d iu m -Ca ta lyzed Hyd r oa r yla tion in Eth yl
Aceta tea
overall yield of products. In palladium-catalyzed hy-
droarylation, there is evidence that switching the ligand
from triphenylphosphine to the more sterically demand-
ing tri-o-tolylphosphine ligand affects the regioselectivity
and yield.7 In our system, eliminating the bulky ligand
altogether gave higher yields and a major reduction in
the amount of dehalogenation byproduct. The phosphine
ligand may hinder the requisite palladium-propiolamide
coordination, giving rise to an increase in the palladium-
catalyzed dehalogenation pathway. Trost and Li21 also
reported that a palladium-catalyzed addition across a
carbon-carbon triple bond occurred much more readily
and with less decomposition in the absence of ligands.
The absence of phosphine ligand on the palladium metal
may decrease steric hindrance and increase the potential
of the ligandless metal to coordinate with the substrate.
However, on the basis of our data, one would therefore
expect that PdCl2 would give significantly better yields
and improved isomer ratios since it has the least steri-
cally demanding substituents. Although this catalyst
gave fairly good yields of product 2 relative to the amount
of byproducts 19 and 18, its selectivity was not much
better than that obtained using Pd(PPh3)2(OAc)2. Ap-
parently, there may be other factors in the reaction that
can account for the success of Pd(dba)2 and Pd(MeCN)2-
Cl2.
Another parameter that contributed significantly to the
optimization of this reaction was concentration. Most of
the reactions during the optimization studies were
conducted at concentrations of 0.1 M following literature
procedures for palladium-catalyzed hydroarylation. Un-
der dilute conditions, such as 0.02 M, an improved isomer
ratio was observed. For example, the hydroarylation
reaction in refluxing ethyl acetate and Pd(dba)2 at 0.02
M gave a regioisomer ratio of 17:1 (2:19). Other catalysts
also showed improved regioisomer ratios in dilute ethyl
acetate. For example, Pd(PhCN)2Cl2, PdCl2, and Pd-
(OAc)2 all gave ratios of >6:1 (2:19). Concentrations less
than 0.02 M showed no further improvements.
isomer
time yield (%) yield (%) yield (%) ratio
catalyst
(h)
of 2b
of 19b
of 18b
(2:19)
Pd(MeCN)2Cl2
Pd(dba)2
Pd(OAc)2
PdCl2
Pd(TFA)2
2
1
1.5
2
3
47
55
43
50
44
36
20
11
15
18
19
22
15
9
4
11
12
10
12
6
4.4:1
3.7:1
2.4:1
2.6:1
2:1
Pd(BnCN)2Cl2
Pd(Ph3P)2(OAc)2
1
1
2.5:1
2.2:1
16
a
Reactions run using 6-7% catalyst, 3.3 equiv of piperidine,
2.6 equiv of formic acid in ethyl acetate at reflux. bReversed-phase
HPLC area percents.
Forming the catalyst in situ using Pd(OAc)2 and (o-tol)3P
gave the best isomer ratio; however, the rate of reaction
was very slow. Pd(MeCN)2Cl2 was used to screen for
optimal reaction conditions since it gave higher yields of
15 with fewer byproducts.
We started the optimization study with Pd(MeCN)2Cl2
as catalyst, piperidine as base, formic acid, and the
solvent as the variable. At this stage, our goal was to
find a solvent that would provide increased yields and a
high regioisomer ratio of 15. Among the solvents inves-
tigated, ethyl acetate gave the best isomer ratio of 4.4:1
(15:16) with decreased reaction time and byproduct
formation. Additionally, these conditions minimized
formation of geometric isomers for both 15 and 16 where
only the Z-isomer was observed for both regioisomers.
Acetone, 2-butanone, chloroform and toluene, also inves-
tigated, were poor solvents for the reaction.
Therefore, ethyl acetate was chosen as the solvent for
reinvestigation of the various catalysts since the initial
catalyst work was performed with DMF. On the basis
of our prior study, we focused on phosphine-free pal-
ladium catalysts (Table 2) since these catalysts provided
higher yields of 15 relative to regioisomer 16 (see Table
1).
Pd(MeCN)2Cl2 and Pd(dba)2 gave higher yields, lower
byproduct formation, and increased rate of reaction.
Both catalysts also gave ratios of the two regioisomers
of 2 and 19 in a ratio of approximately 4:1, favoring the
desired regioisomer 2. It is unclear why phosphine-free
catalysts gave such significant improvements in the
Since ethyl acetate has a lower dielectric constant than
DMF and possesses different coordinating ability, the
possibility of a relationship between dielectric constant
of the solvent and regiochemical outcome was examined.
Table 3 lists six of the solvents that were investigated
at 0.02 M. The temperature was held at 60 °C for DMF
and at reflux for the other solvents, giving a range of
approximately 60-82 °C.22 Although dilute refluxing
THF provided a similar ratio as ethyl acetate, this
reaction progressed much more slowly.
(21) Trost, B. M.; Li, Y. J . Am. Chem. Soc. 1996, 118, 28, 6625.
(22) Lange’s Handbook of Chemistry, 13th ed.; Dean, J . A., Ed.;
McGraw-Hill: St. Louis, 1985. Although the dielectric constants used
were derived at 25 °C for a given solvent, the reactions in Table 3 were
conducted at 60-82 °C.

Pd-Catalyzed Hydroarylation of Propiolamides
J . Org. Chem., Vol. 63, No. 15, 1998 5053
Sch em e 1a
a
Reaction conditions: (a) ) 3-FC6H4I, Pd(Ph3P)2Cl2, CuI, Et3N, EtOAc; (b) ) 7, Pd(dba)2, piperidine, HCOOH, EtOAc, 70 °C; (c) ) 7,
Pd(Ph3P)2OAc2, CuI, Et3N, EtOAc; (d) ) 3-FC6H4I, Pd(dba)2, piperidine, HCOOH, EtOAc, 70 °C.
As anticipated, it appears that a general trend does
exist between the ratio of regioisomers and the dielectric
constant of the reaction solvent. For the most part, as
the dielectric constant of the solvent decreased, the
isomer ratio increased in favor of 2. Methanol, DMF, and
acetonitrile, all with high dielectric constants, provided
poor regioisomer ratios, while ethyl acetate and THF with
low dielectric constants provided high regioisomeric
ratios.
Combining data from the optimization studies, the
optimum reaction conditions that were developed in-
cluded Pd(dba)2 or Pd(MeCN)2Cl2 as catalyst; diethyl-
amine or piperidine as base; formic acid; and 0.02 M of
propiolamide 5 in refluxing ethyl acetate. Using these
conditions, 2 was obtained in 81% yield. The success of
the process development is evident when one compares
the optimized reaction conditions to the reaction param-
eters established in the literature for the palladium-
catalyzed hydroarylation of acetylenes. The reaction time
was reduced from >24 to 2 h. Significantly less byprod-
uct formation occurred under the optimized conditions,
and the regioisomeric ratio of 2 was improved from 1:1
to >17:1 in favor of 2. These improvements also in-
creased the yield from 10% to 81%.
Similar reaction conditions used for the preparation
of 2 were applied to the formation of 3. Thus, 6 was
reacted with 7 to provide 3 in 75% isolated yield with a
regioisomer23 ratio of 4.2:1. Although the reaction for
preparing 3 was not optimized, we were somewhat
disappointed that the reaction conditions developed for
preparing 2 did not give higher isomeric ratios for this
target.
F igu r e 1. Coupling partners used in the palladium-catalyzed
hydroarylation reactions.
general scope for the palladium-catalyzed hydroarylation
of propiolamides.
Rea ction Scop e. For consistency and ease in product
1
analysis by H NMR, the N-methyl derivative of propi-
olamide was used in the study. Therefore, in addition
to 5, four other aryl-N-methylpropiolamides were pre-
pared in an attempt to explore the effect of electron
density or steric influence in the hydroarylation reaction.
N-Methylpropiolamide 11 was reacted with anisyl iodide
(22), methyl 4-iodobenzoate (23), 2-iodotoluene (24), and
9-iodophenanthrene (25) using the procedure similar to
eq 3 to give N-methyl-3-arylpropiolamides 26-29 in 76-
95% yield (Figure 1). These various arylpropiolamides
were then reacted with the same selection of aryl iodides
to produce pairs of geometric isomers (Table 4). The
palladium-catalyzed hydroarylation reaction of arylpro-
piolamides 5 and 26-29 with aryl iodides 12 and 22-35
proceeded cleanly with few exceptions to provide each of
the geometric isomers.23
Another area where the optimized reaction conditions
for preparing 2 did not perform as expected was in the
attempted preparation of the opposite geometric isomer
21 (Scheme 1) by simply reversing the order of propiol-
amide preparation and hydroarylation reaction. Thus,
7 was coupled to N-methylpropiolamide in the presence
of Pd(Ph3P)2(OAc)2 to give 20 in 96.2% yield. Reaction
of 20 with 3-fluoroiodobenzene under various hydroary-
lation conditions provided no significant amount of 21.
This difference in the outcome of the two types of
hydroarylation reaction approaches coupled with the low
isomeric ratio in the formation of 3 led to a study of the
The results summarized in Table 4 indicate that
electron density in either coupling partner had very little
effect on the reaction’s yield or regioselectivity. For
example, aryl groups with electron-donating substituents
such as 22 and 26 gave results similar to those of groups
with electron-withdrawing substituents such as 23 and
27. Large aromatic rings such as phenanthrene in 25
and 29 also provided excellent yields and regioselectivi-
ties. In the cases where the aromatic ring of the
propiolamide was substituted at the 2-position, the
reactions proceeded smoothly. However, in two reactions
examined where 2-iodotoluene (24) was used as a cou-
pling partner, the attempted hydroarylation reaction was
very slow, providing only traces of the 3,3-diarylacryl-
amide 34 or 44. In these cases, reduction of the acetylene
to the cis olefin product occurred.
(23) Structural assignments were made on the basis of spectroscopic
analyses (NMR), and X-ray crystallographic analyses were also
obtained for compound 3 and (Z)-N-methyl-3-(1-naphthyl)-3-(9-phenan-
thryl)-2-propenamide.

5054 J . Org. Chem., Vol. 63, No. 15, 1998
Ta ble 4. P a lla d iu m -Ca ta lyzed Hyd r oa r yla tion of P r op iola m id esa
Hay et al.
a
All reactions were carried out with 1 equiv of arylpropiolamide and aryl iodide, Pd(dba)2 (7 mol %) in refluxing ethyl acetate (0.02
mmol of arylpropiolamide/L of solvent).
Taking into consideration the key features of the
optimized reaction for preparing regioselective 3,3-dia-
rylacrylamides, i.e., the phosphine-free catalysts, low-
coordinating solvents, and low reaction concentrations,
we can propose that the high regioselective hydroaryla-
tion reaction of arylpropiolamides is mediated by a key
coordinated amide complex (Figure 2). Therefore, the
regioselectivity of insertion for this process appears to

Pd-Catalyzed Hydroarylation of Propiolamides
J . Org. Chem., Vol. 63, No. 15, 1998 5055
under a dry nitrogen atmosphere unless specified otherwise.
Reaction progress was monitored by thin-layer chromatogra-
phy (TLC) or HPLC analyses. TLC analyses were performed
with 0.25 mm silica gel plates containing F-254 indicator and
visualized using UV light (254 nm) or phosphomolybdic acid
indicator. Flash column chromatography was performed with
32-63 µm silica gel packing.27
F igu r e 2. Possible transient palladium-propiolamide complex.
Melting and boiling points are uncorrected. 1H NMR and
13C NMR spectra were recorded as specified for each experi-
ment with chemical shift recorded as parts per million.
Combustion analyses were performed by Eli Lilly and Co.
Physical Chemistry Microanalytical Laboratory.
follow the pattern established by others24-26 in which the
aryl group adds to the less hindered carbon of the alkyne
functionality and the palladium group adds to the more
hindered carbon. Using this rationale, the amide func-
tionality would be viewed as larger than a phenyl.
However, this explanation does not fully account for
instances where one geometric isomer forms readily while
the other does not. This is illustrated in the attempted
formation of 21, 34, and 44. The rationale also does not
explain the low regioselectivity observed in the formation
of 3. In these reactions, a combination of coordination
and steric influences may play a major role in the overall
reaction outcome.
Hydroxyl coordination has been proposed to affect the
palladium-catalyzed reaction of aryl iodides with allylic
alcohols.7 In our case, the results suggest that the amide
functionality coordinates to the palladium center. Phos-
phine ligands, coordinating solvents, and high concentra-
tion of amide may all compete with the possible transient
palladium complex to provide reactions that are nonse-
lective or nonhydroarylation reactions. In an attempt to
form either geometric isomer by judicious choice of aryl
iodide in the arylpropiolamide formation and the hy-
droarylation reaction, two very different transient pal-
ladium complexes are formed. The two complexes be-
come more distinct when the arypropiolamide is a
heteroaryl such as 20, which contains other coordinating
sites in addition to the carbon-carbon triple bond.
P r ep a r a tion of 2. To a reaction vessel were added 7 (7.94
g, 21.8 mmol), 5 (5.00 g, 28.2 mmol), and ethyl acetate (750
mL) to form a solution at ambient temperature. To this
solution were added Pd(MeCN)2Cl2 (0.40 g, 1.5 mmol) and
piperidine (7.1 mL, 71.8 mmol) followed by formic acid (2.10
g, 55.7 mmol). This mixture was heated to reflux for 5 h,
adding additional 5 (0.445 g) after 1 h before the mixture was
cooled to room temperature. About half of the solvent was
removed under vacuum before dilution with water. The layers
were separated and the organics washed two times with water
and once with brine, dried over MgSO4, and concentrated to a
residue. This material was crystallized from EtOAc to obtain
purified product (5.75 g, 60.0% yield): IR (CHCl3) 1638, 1610,
1580, 1546, 1442, 1360 cm-1; 1H NMR (250 MHz; DMSO-d6) δ
7.98 (d, J ) 4.50 Hz, 1H), 7.41-6.93 (m, 9H), 6.43 (s, 1H),
3.85 (m, 1H), 2.57 (d, J ) 4.75 Hz, 3H), 1.24 (d, J ) 7.00, 6H);
13C NMR (63 MHz, DMSO-d6) δ 165.3, 163.6, 159.7, 153.7,
148.2, 143.2, 142.1, 133.2, 132.2, 131.6, 129.5, 125.5, 124.5,
121.0, 116.0, 114.1, 111.2, 55.9, 25.4, 15.7; MS (FD+) calcd for
C
C
20H21FN4O3S 416.47, found 416.0 (M+, 100). Anal. Calcd for
20H21FN4O3S: C, 57.68; H, 5.08; F, 4.56; N, 13.45; S, 7.70.
Found: C, 58.29; H, 5.07; F, 4.69; N, 12.99; S, 7.15.
P r ep a r a tion of 3. Compound 7 (6.185 g, 0.0169 mol),
Pd(dba)2 (0.388 g, 0.675 mmol), and diethylamine (5.8 mL, 56.1
mmol) were dissolved in ethyl acetate (750 mL). Into an
addition funnel was placed 6 (3.07 g, 0.0169 mol) in ethyl
acetate (60 mL). Formic acid (1.5 mL, 39.8 mmol) was added
all at once to the addition funnel. The contents of the reaction
vessel were heated to reflux before the solution of 6, and formic
acid was slowly added to the reaction mixture over several
hours. The mixture was refluxed overnight. Additional 6
(0.705 g) in ethyl acetate (15 mL) was added along with formic
acid (0.09 mL) as a means to drive the reaction to completion.
After being refluxed overnight again, the mixture was cooled
to room temperature, and half of the solvent was removed
under vacuum. The remaining solution was washed with
water, 1.0 N NaOH, and brine, dried (MgSO4), and concen-
trated to 8.282 g (53%) of a yellow solid: IR (CH2Cl2) 3461,
3386, 3148, 1677, 1645, 1594, 1544, 1490, 1426, 1269, 1255,
Con clu sion
The palladium-catalyzed hydroarylation reaction be-
tween an aryl propiolamide and an aryl iodide has proven
to be a practical means for preparing 3,3-diarylacryl-
amides. In most cases, regio- and stereocontrol was
obtained when the reaction was performed under dilute
conditions employing phosphine-free Pd(0) catalyst and
low-coordinating solvents such as ethyl acetate. The
methodology was applied to a variety of arylpropiola-
mides and aryl iodides for which the reaction was found
to be generally regio- and stereoselective. Among the
exceptions is 2-iodotoluene, where no hydroarylation
reaction took place. The methodology is particularly
useful since either the (Z)- or (E)-isomer of a given 3,3-
diarylacrylamide could be prepared by judicious choice
of the arylpropiolamide coupling reaction and the hy-
droarylation reaction. Finally, the utility of the meth-
odology was demonstrated with a convergent synthesis
of antirhinoviral agents 2 and 3.
1
1153, 1042, 832, 687, 512 cm-1; H NMR (250 MHz, DMSO-
d6) δ 7.55 (s, 1H), 7.44 (s, 1H), 7.26-6.96 (m, 8H), 6.63 (s, 1H),
3.85 (m, 1H), 1.25 (d, J ) 6.75 Hz, 6H); 13C NMR (63 MHz,
DMSO-d6) δ 165.9, 153.8, 143.5, 142.9, 131.8, 131.6, 129.4,
129.1, 128.9, 123.7, 122.2, 116.5, 116.2, 110.4, 56.0, 15.7; MS
(FD+) calcd for C19H18N4O3F2S 420.437, found 420.1 (M+, 100).
Anal. Calcd for C19H18N4O3F2S: C, 54.28; H, 4.32; N, 13.33;
S, 7.63; F, 9.04. Found: C,54.02; H, 4.44; N, 13.18; S, 7.40; F,
9.31.
2-(3-F lu or op h en yl)p r op iola m id e (4). Propiolamide 13
(1.75 g, 25.3 mmol), 1-fluoro-3-iodobenzene (3.76 g, 16.9 mmol),
Pd(Ph3P)2(OAc)2 (0.941 g, 1.26 mmol), copper(I) iodide (0.649
g, 3.40 mmol), and triethylamine (7.11 mL, 50.9 mmol) were
stirred in ethyl acetate (25 mL) at room temperature. Ad-
ditional propiolamide (1.07 g) was added after several hours.
The mixture was allowed to stir at room temperature for
another 6 h before dilution with water, and the layers were
separated. The organics were washed with water and brine,
dried over MgSO4, and concentrated to tan solid (2.109 g,
76.3%): IR (CHCl3) 3522, 3403, 3015, 2221, 1672, 1582, 1367,
Exp er im en ta l Section
Gen er a l Meth od s. All reagents and solvents were ob-
tained from Aldrich, Fluka, or J ohnson Matthey and were used
without further purification. All reactions were performed
(24) Pfeffer, M.; Rotteveel, M. A.; LeBorgne, G.; Fischer, J . J Org.
Chem. 1992, 57, 2147.
(25) Spencer, J .; Pfeffer, M.; DeCian, A.; Fischer, J . J . Org. Chem.
1995, 60, 1005.
1
1582, 1367, 1278 cm-1; H NMR (300 MHz, DMSO-d6) δ 8.25
(26) Larock, R. C.; Yum, E. K.; Doty, M. J .; Sham, K. K. J . Org.
Chem. 1995, 60, 3270.
(27) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

5056 J . Org. Chem., Vol. 63, No. 15, 1998
Hay et al.
(br s, 1H), 7.8 (br s, 1H), 7.6-7.3 (m, 4H); 13C NMR (75 MHz,
DMSO-d6) δ 163.6, 160.4, 153.9, 131.2, 128.6, 118.8, 117.7,
85.1, 81.6; MS (FD+) calcd for C9H6NOF 163.15, found 163.1
(M+, 100). Anal. Calcd for C9H6NOF: C, 66.26; H, 3.71; N,
8.59; F, 11.64. Found: C, 64.30; H, 3.73; F, 10.28; N, 7.39.
N-Meth yl 2-(3-flu or oph en yl)pr opiolam ide (5). 1-Fluoro-
3-iodobenzene (20.0 g, 90.1 mmol), triethylamine (37.5 mL,
269.0 mmol), Pd(Ph3P)2(OAc)2 (4.0 g, 5.35 mmol), and copper-
(I) iodide (3.4 g, 17.98 mmol) were stirred in ethyl acetate (250
mL) at room temperature. N-Methylpropiolamide 11 (14.1 g,
170.0 mmol) was added in portions over several hours as the
mixture was stirred at room temperature, monitoring by
HPLC. This mixture was diluted with water and additional
ethyl acetate, and the layers were separated. The aqueous
layer was extracted with additional ethyl acetate, and the
combined organic layers were washed twice with water and
once with brine, dried over anhydrous MgSO4, and concen-
trated to give a dark solid. Reslurrying in cold toluene gave
the purified product (13.09 g, 82.0% yield): mp 91-93 °C; IR
(CHCl3) 3449, 3008, 2222, 1612, 1584, 1521, 1488, 1437, 1428,
940, 776, 730, 681 cm-1; H NMR (300 MHz, CDCl3) δ 7.6 (d,
J ) 8.01 Hz, 1 H), 7.33 (d, J ) 7.84 Hz, 1 H), 7.21 (t, J ) 7.70
Hz, 1 H), 7.07 (t, J ) 7.77 Hz, 1 H), 6.95 (br s, 2 H), 3.65 (m,
1 H), 1.39 (d, J ) 6.86 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ
152.7, 141.1, 130.9, 124.3, 121.0, 116.2, 111.8, 55.6, 15.7; MS
m/e (rel int) 239 (M+, 100). Anal. Calcd for C10H13N3O2S: C,
50.19; H, 5.48; N, 17.56. Found: C, 49.43; H, 5.41; N, 16.80.
N-Meth ylp r op iola m id e (11). Methylamine (40% in water,
22.0 mL) in an equal volume of methanol was cooled to -78
°C for the dropwise addition of methyl propiolate (20.1 g, 0.238
mol) over 15 min via an addition funnel. The reaction mixture
was stirred for 3 h at -78 °C before being warmed to room
temperature. The solvent was removed at 25 °C under
vacuum, and the resulting solid was slurried in methanol to
remove any water. The slightly yellow solid was slurried in
diethyl ether and cooled to -30 °C before being filtered to
obtain a white crystalline solid (18.7, 95%): mp 88 °C; IR
(CHCl3) 3691, 3450, 3303, 3025, 3016, 2948, 2338, 2113, 1164,
1523, 1416, 1359, 1252, 1205, 1164, 1051, 1003, 868 cm-1; 1H
NMR (300 MHz, DMSO-d6) δ 8.56 (br s, 1 H), 4.0 (s, 1 H), 2.56
(d, J ) 4.89 Hz, 3 H); 13C NMR (75 MHz, DMSO-d6) δ 25.67,
75.23, 78.24, 152.05. Anal. Calcd for C4H5NO: C, 57.82; H,
6.07; N, 16.86. Found: C, 57.88; H, 6.12; N, 16.99.
1
1
1415, 1299, 1266, 1250, 1235, 1167, 1150, 951, 875 cm-1; H
NMR (300 MHz, DMSO-d6) δ 8.79 (br d, J ) 4.05 Hz, 1H),
7.54-7.39 (m, 4H), 2.70 (d, J ) 4.78 Hz, 3H); 13C NMR (75
MHz, DMSO-d6) δ 25.80, 81.28, 84.57, 117.54, 118.57, 128.41,
131.14, 152.38, 160.14, 163.39; MS (FD+) calcd for C10H8FNO
177.18, found 177 (M+, 100). Anal. Calcd for C10H8FNO: C,
67.79; H, 4.55; F, 10.72; N, 7.91. Found: C, 67.64; H, 4.57; F,
10.68; N, 7.69.
P r op iola m id e (13). Aqueous ammonia (14.0 mL, 29% in
water) was cooled to -78 °C for the dropwise addition of
methyl propiolate (4.2 g, 50.2 mmol) over 15 min via an
addition funnel. The mixture was stirred for 1 h at -78 °C
before being warmed to room temperature. The solvent was
removed at 25 °C under vacuum to obtain 3.04 g (87.7%)
product: mp 60.5-62 °C; IR (CHCl3) 3295, 2111, 1664, 1614,
P r ep a r a tion of 6. DMSO (50 mL), 2,5-difluorophenyltri-
flate (10.5 g, 40 mmol), propiolamide 13 (3.0 g, 44 mmol), Pd-
(Ph3P)2Cl2 (2.0 g, 2.85 mmol), copper iodide (381 mg, 2 mmol),
lithium chloride (5.08 g, 120 mmol), and triethylamine (10.10
g, 100 mmol) were combined and heated to 80 °C in a 250 mL
round-bottom flask with reflux condenser. TLC analysis
(silica, 100% ethyl ether, UV) was used to monitor the
reaction’s progress. After 3 h, additional propiolamide (∼300
mg) was added to the reaction. After an additional 2 h, the
reaction was cooled to room temperature, diluted with water
(20 mL), and filtered through a pad of silica gel using ethyl
ether. The resulting filtrate was diluted with water and the
organic portion separated. The combined organic extracts
were washed with 1 N NaOH, 1 N HCl, and brine before being
dried over anhydrous MgSO4. After drying, the solution was
concentrated and purified by crystallization from toluene (4.9
g, 68%): mp 92-93 °C; IR (KBr) 3409, 3190, 3049, 2218, 1651,
1605, 1498, 1396, 1282, 1200, 1138, 1098, 900, 852, 761, 696,
1384, 1134, 657, 592, 543 cm-1; H NMR (300 MHz, CDCl3/
1
DMSO-d6) δ 7.1 (br s, 1H), 6.9 (br s, 1H), 3.0 (s, 1H); 13C NMR
(75 MHz, CDCl3/DMSO-d6) δ 154.3, 77.8, 74.3. Anal. Calcd
for C3H3NO: C, 52.17; H, 4.38; N, 20.28. Found: C, 52.26; H,
4.61; N, 20.48.
P r ep a r a tion of 14. To a flask were added 2,5-difluorophe-
nol (30.0 g, 230 mmol) and methylene chloride (150 mL) to
form a solution. The solution was cooled to 0 °C, and pyridine
(20.0 g, 253 mmol) was added. A methylene chloride solution
of trifluoromethanesulfonyl anhydride (84.5 g, 300 mmol) was
added dropwise to the reaction mixture at 0 °C. After addition,
the resulting reaction mixture was stirred at room temperature
for 4 h. Workup involved filtering the reaction mixture to
remove the corresponding pyridine salt and the filtrate washed
with 0.5 N HCl solution followed by a brine wash. After being
dried over anhydrous MgSO4, the methylene chloride solution
was concentrated to a residue. The residue was purified by
vacuum distillation to provide 52 g (84%) of pure product as a
colorless liquid: bp 70 °C (13 mmHg); IR (CHCl3) 1616, 1511,
600 cm-1 1H NMR (300 MHz,CDCl3) δ 7.31-7.15 (m, 1 H),
;
7.15-7.00 (m, 2 H), 6.90-6.5 (br s, 1 H), 6.40-6.90 (m, 1 H);
13C NMR (75 MHz, CDCl3) δ 161.5, 120.3, 119.9, 119.2, 118.9,
117.0, 116.6, 87.4, 77.8; MS m/e (rel int) 181 (M+, 100). Anal.
Calcd for C9H5F2NO: C, 59.68; H, 2.78; F, 20.98; N, 7.73.
Found: C, 59.78; H, 2.77; F, 20.69, N, 7.74.
1476, 1420, 1301, 1246, 1135, 1003, 790, 780, 748, 682 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.33-7.18 (m, 1 H), 7.17-7.0
(m, 2 H); 13C NMR (75.5 MHz, CDCl3) δ 111.2, 111.6, 116.0,
116.4, 116.5, 117.7, 118.0; MS m/e (rel int) 262 (M+, 100). Anal.
Calcd for C7H3F5O3: C, 32.07; H, 1.15; F, 36.24. Found: C,
31.87; H, 1.15; F, 36.37.
P r ep a r a t ion of 7. Compound 10 (520 g, 2.18 mol) was
added to acetic acid (3.9 L) to form a solution. N-Iodosuccin-
imide (488.8 g, 2.2 mol) was added and the reaction mixture
heated to 55 °C. After 5 h, the reaction mixture was cooled to
ambient temperature and the product crystallized from solu-
tion. Water was used to dilute the slurry before filtering to
collect 674 g (84%) of compound 7: IR (CHCl3) 3516, 3482,
3401, 3022, 1628, 1556, 1450, 1383, 1361, 1290, 1228, 1192,
P r ep a r a tion of 20. The iodobenzimidazole 7 (6.63 g, 18.2
mol), Pd(Ph3P)2(OAc)2 (1.09 g, 1.46 mmol), copper(I) iodide
(0.702 g, 3.69 mmol), and N-methylpropiolamide 11 (2.08 g,
25.1 mmol) were taken up in DMSO (140 mL). Triethylamine
(7.26 mL, 52.1 mmol) was added and the mixture stirred at
room temperature. Additional 11 (3.24 g) was added in
portions. After 4 h, water was added, and the resulting solid
was filtered off. This solid was reslurried in toluene to give
5.17 g of product. The filtrate was extracted with methylene
chloride, washed with water and then brine, dried over MgSO4,
and concentrated under vacuum to give another 0.433 g of
product. The combined crude material was crystallized from
ethyl acetate (5.5 g, 96.2%): IR (CH2Cl2) 3437, 3087, 2982,
2211, 1673, 1610, 1554, 1474, 1445, 1358, 1275, 1259, 1235,
1
1176, 1049, 776, 730, 681 cm-1; H NMR (300 MHz, DMSO-
d6) δ 7.74 (d, J ) 1.48 Hz, 1 H), 7.44 (dd, J ) 8.2, 1.58 Hz, 1
H), 7.10 (br s, 2 H), 7.50 (dd, J ) 8.34, 1.65 Hz, 1 H), 3.90 (m,
1 H), 1.21 (d, J ) 6.72 Hz, 6 H); 13C NMR (75 MHz, DMSO-d6)
δ 152.9, 142.1, 132.9, 132.7, 119.9, 118.2, 82.5, 55.7, 15.6; MS
m/z (rel int) 365 (M+, 100). Anal. Calcd for C10H12IN3O2S:
C, 32.89; H, 3.31; N, 11.38. Found: C, 33.07; H, 3.39; N, 11.38.
P r ep a r a tion of 10. Acetonitrile (44 mL), water (4.0 mL),
sodium hydroxide (1.92 g, 45.1 mmol), and 2-aminobenzimi-
dazole (3.0 g, 22.5 mmol) were stirred at room temperature to
form a solution. At ambient temperature, 2-propanesulfonyl
chloride (3.2 g, 22.5 mmol) was added. After 2 h, the reaction
was diluted with water and cooled to 15 °C and then filtered
to isolate 10 (6.4 g, 90%): IR (CHCl3) 3516, 3481, 3400, 3022,
1682, 1556, 1450, 1383, 1361, 1256, 1228, 1192, 1176, 1049,
1176, 1154, 1038, 688, 606, 592 cm-1 1H NMR (300 MHz,
;
DMSO-d6) δ 8.65 (m, 1H), 7.65-7.25 (m, 5H), 3.95 (m, 1H),
2.67 (d, J ) 4.78 Hz, 3H), 1.33 (d, J ) 6.9 Hz, 6H); 13C NMR
(75 MHz, DMSO-d6) δ 154.3, 153.0, 144.3, 131.2, 129.0, 116.2,
115.5, 110.8, 84.2, 82.9, 55.7, 25.8, 15.5; MS (FD+) calcd for
C
14H16N4O3F 320.37, found 320.3 (M+, 100). Anal. Calcd for

Pd-Catalyzed Hydroarylation of Propiolamides
J . Org. Chem., Vol. 63, No. 15, 1998 5057
C14H16N4O3F: C, 52.49; H, 5.03; N, 17.49; S, 10.01. Found:
C, 51.14; H, 4.95; N, 16.76; S, 9.58.
(Z)-3-(4-An isyl)-3-(3-flu or op h en yl)-N-m eth yl-2-p r op e-
n a m id e (30): yield 80%; mp 165-168 °C; IR (CHCl3) 3460,
3008, 1653, 1606, 1582, 1512, 1255, 1179 cm-1; 1H NMR (300
MHz, DMSO-d6) δ 7.88 (d, J ) 4.5 Hz, 1H), 7.37-7.32 (q, J )
7.2 Hz, 1H), 7.16-7.11 (m, 3H), 6.93-6.89 (m, 4H), 6.38 (s,
1H), 3.75 (s, 3H), 2.53 (d, J ) 4.5 Hz, 3H); 13C NMR (75 MHz,
DMSO-d6) δ 165.2, 159.8, 147.2, 141.9, 141.8, 132.9, 129.5,
128.8, 125.3, 120.7, 116.1, 115.8, 113.9, 55.2, 25.3; MS (FD+)
calcd for C17H16NO2F 285.32, found 285.1 (M+, 100). Anal.
Calcd for C17H16NO2F: C, 71.56; H, 5.65; N, 4.91; F, 6.66.
Found: C, 71.51; H, 5.63; N, 4.95; F, 6.38.
3-(4-An isyl)-N-m eth ylp r op iola m id e (26). Gen er a l P r o-
ced u r e A. N-Methylpropiolamide (6.1 g, 72.8 mmol), 4-io-
doanisole (13.58 g, 58.04 mmol), Pd(Ph3P)2(OAc)2 (3.4 g, 4.5
mmol), copper iodide (2.2 g, 11.6 mmol), and triethylamine
(24.2 mL, 173.6 mmol) were stirred in ethyl acetate (200 mL)
at room temperature. After 1 h (7.1 g, 85.9 mmol), N-
methylpropiolamide was added in portions, along with water
(75 mL). After another hour, additional water (75 mL) was
added, and the mixture was separated into the two layers. The
organic layer was washed with water and brine, dried over
MgSO4, and concentrated under vacuum at room temperature
to a solid, which was reslurried in ethyl acetate and cooled to
-10 °C and then filtered to provide 8.4 g (76%) of product:
mp 123-124 °C; IR (CHCl3) 2222, 1649, 1606, 1511, 1288,
(E)-3-(4-An isyl)-3-(3-flu or op h en yl)-N-m eth yl-2-p r op e-
n a m id e (31): yield 85%, mp 118-122 °C; IR (CHCl3) 3460,
3007, 1652, 1608, 1583, 1511, 1485, 1440, 1292, 1267, 1250,
1
1177 cm-1; H NMR (300 MHz, DMSO-d6) δ 7.83 (d, J ) 4.5
Hz, 1H), 7.38 (q, J ) 7.4 Hz, 1H), 7.20-7.14 (m, 1H), 7.08-
6.99 (m, 4H), 6.90 (d, J ) 8.7 Hz, 2H), 6.35 (s, 1H), 3.77 (s,
3H), 2.54 (d, J ) 4.5 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ
165.6, 158.9, 146.7, 144.6, 144.5, 130.7, 130.4, 130.3, 124.0,
1
1252, 1173, 835 cm-1; H NMR (250 MHz, DMSO-d6) δ 8.61
(d, J ) 4.75 Hz, 1H), 7.51 (d, J ) 9.01 Hz, 2H), 7.01 (d, J )
8.76 Hz, 2H), 3.81 (s, 3H), 2.68 (d, J ) 4.50 Hz, 3H); 13C NMR
(63 MHz, DMSO-d6) δ 160.6, 153.1, 133.9, 114.6, 111.7, 83.4,
83.2, 55.4, 25.8; MS (FD+) calcd for C11H11NO2 189.22, found
189.0 (M+, 100). Anal. Calcd for C11H11NO2: C, 69.83; H, 5.86;
N, 7.40. Found: C, 69.83; H, 6.10; N, 7.44.
123.0, 115.0, 114.1, 113.1, 55.0, 25.4; MS (FD+) calcd for C17H16
-
-
NO2F: 285.32, found 285.1 (M+, 100). Anal. Calcd for C17H16
NO2F: C, 71.56; H, 5.65; N, 4.91; F, 6.66. Found: C, 70.99;
H, 5.99; N, 4.71; F, 6.28.
N-Meth yl-3-(9-p h en a n th r yl)p r op iola m id e (29). Gen -
er a l P r oced u r e B. N-Methylpropiolamide (1.96 g, 23.56
mmol), 9-iodophenanthrene (5.93 g, 19.49 mmol), Pd(Ph3P)2-
(OAc)2 (1.15 g, 1.54 mmol), copper iodide (0.743 g, 3.90 mmol),
and triethylamine (6.0 mL, 43.05 mmol) were stirred at room
temperature in 130 mL of DMSO overnight. The mixture was
diluted with water and extracted with ethyl acetate. The
organics were washed with water and brine, dried over MgSO4,
and concentrated to a tan solid. This solid was reslurried in
toluene and filtered to give 4.13 g (82% yield) of product: mp
140-142 °C; IR (CHCl3) 3450, 2219, 2205, 1651, 1520, 1494,
(Z)-3-[4-(r,r,r-Tr iflu or om eth yl)p h en yl]-3-(3-flu or op h e-
n yl)-N-m eth yl-2-p r op en a m id e (32): yield 75%; mp 122-
125 °C; IR (CHCl3) 3454, 3008, 1658, 1614, 1583, 1523, 1411,
1326, 1277, 1266, 1247, 1225, 1171, 1114, 1069, 1017, 841
cm-1 1H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J ) 4.5 Hz,
;
1H), 7.74 (d, J ) 8.3 Hz, 2H), 7.44-7.35 (m, 3H), 7.20-7.17
(m, 1H), 7.00-6.93 (m, 2H), 6.57 (s, 1H), 2.55 (d, J ) 4.5 Hz,
3H); 13C NMR (75 MHz, DMSO-d6) δ 164.9, 160.1, 145.7, 144.7,
140.8, 140.7, 129.9, 129.7, 128.3, 125.5, 125.41, 125.37, 125.3,
116.2, 114.6, 25.4; MS (FD+) calcd for C17H13NOF4 323.29,
found 323 (M+, 100). Anal. Calcd for C17H13NOF4: C, 63.16;
H, 4.05; N, 4.33; F, 23.52. Found: C, 64.11; H, 4.11; N, 4.25;
F, 23.27.
1
1453, 1264, 1242 cm-1; H NMR (250 MHz, DMSO-d6) δ 8.98
(d, J ) 4.50 Hz, 1H), 8.96-7.70 (m, 9H), 2.81 (d, J ) 4.75 Hz,
3H); 13C (63 MHz, DMSO-d6) δ 152.8, 134.0, 130.4, 130.3,
130.0, 129.6, 129.0, 128.8, 127.9, 127.8, 127.5, 126.2, 123.5,
123.0, 116.3, 88.4, 81.0, 26.0; MS (FD+) calcd for C18H13NO
259.31, found 259.1 (M+, 100). Anal. Calcd for C18H13NO: C,
83.38; H, 5.05; N, 5.40. Found: C,83.30; H, 5.05; N, 5.52.
3-[4-r,r,r-Tr iflu or om et h yl)p h en yl]-N-m et h ylp r op iol-
a m id e (27). Product was obtained as a white crystalline solid
in 85% yield: mp 160-162 °C; IR (CHCl3) 3449, 2232, 1656,
1617, 1532, 1524, 1510, 1415, 1405, 1284, 1173, 1135, 1107,
(E)-3-[4-(r,r,r-Tr iflu or om eth yl)p h en yl]-3-(3-flu or op h e-
n yl)-N-m eth yl-2-p r op en a m id e (33): yield 64%; IR (CHCl3)
3440, 3008, 1662, 1618, 1584, 1522, 1320, 1170, 1133, 1110,
1
1067 cm-1; H NMR (250 MHz, DMSO-d6) δ 8.07 (d, J ) 4.5
Hz, 1H), 7.71 (d, J ) 8.3 Hz, 2H), 7.43-7.33 (m, 3H), 7.25-
7.18 (m, 1H), 7.09-6.98 (m, 2H), 6.59 (s, 1H), 2.55 (d, J ) 4.5
Hz, 3H); 13C NMR (63 MHz, DMSO-d6) δ 168.8, 160.3, 146.4,
143.1, 132.9, 130.7, 130.6, 130.0, 124.7, 124.62, 124.57, 123.90,
123.85, 115.5, 113.9, 25.4; MS (FD+) calcd for C17H13NOF4
323.29, found 323.4 (M+, 100). Anal. Calcd for C17H13NOF4:
C, 63.16; H, 4.05; N, 4.33; F, 23.52. Found: 62.86; H, 4.04; N,
4.45; F, 23.71.
1
1070, 1018, 844 cm-1; H NMR (250 MHz, DMSO-d6) δ 8.85
(d, J ) 4.5 Hz, 1H), 7.85 (m, 4H), 2.72 (d, J ) 5.0 Hz, 3H); 13
C
NMR (63 MHz, DMSO-d6) δ 152.3, 132.8, 125.92, 125.87, 125.7,
124.3, 85.9, 81.1, 25.9; MS (FD+) calcd for C11H8F3NO 227.19,
found 227 (M+, 100). Anal. Calcd for C11H8F3NO: C, 58.16;
H, 3.55; N, 6.17; F, 25.09. Found: C, 58.12; H, 3.52; N, 6.17;
F, 24.87.
(Z)-3-(3-F lu or op h en yl)-N-m eth yl-3-(2-tolyl)-2-p r op en -
a m id e (35): yield 68%; IR (CHCl3) 3436, 3007, 1651, 1610,
1596, 1583, 1529, 1485, 1442, 1268 cm-1; 1H NMR (500 MHz,
DMSO-d6) δ 7.84 (d, J ) 4.5 Hz, 1H), 7.42-7.35 (m, 1H), 7.28-
7.17 (m, 4H), 7.03-6.98 (m, 3H), 6.67 (s, 1H), 2.54 (d, J ) 4.6
Hz, 3H), 2.00 (s, 3H); 13C NMR (63 MHz, DMSO-d6) δ 164.9,
146.8, 142.6, 138.5, 135.2, 130.7, 130.6, 129.6, 128.7, 127.3,
125.3, 123.3, 122.8, 115.5, 113.3, 25.4, 19.4; MS (FD+) calcd
for C17H16NOF 269.32, found 269 (M+, 100). Anal. Calcd for
N-m et h yl-3-(2-t olyl)p r op iola m id e (28). Product was
obtained as a white solid in 95% yield: mp 52-55 °C; IR
(CHCl3) 3451, 3012, 2222, 1650, 1523, 1487, 1415, 1295, 1283,
1
1278 cm-1; H NMR (250 MHz, CDCl3) δ 7.44 (d, J ) 7.5 Hz,
1H), 7.32-7.10 (m, 3H), 6.07 (br s, 1H), 2.91 (d, J ) 4.9 Hz,
3H), 2.44 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 154.2, 141.3,
132.7, 129.8, 129.6, 125.7, 120.0, 86.7, 83.5, 26.5, 20.5; MS
(FD+) calcd for C11H11NO 173.22, found 173.0 (M+, 100). Anal.
Calcd for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C,
76.04; H, 6.42; N, 8.15.
C
17H16NOF: C, 75.82; H, 5.99; N, 5.20; F, 7.05. Found: C,
76.10; H, 6.00; N, 5.14; F, 6.98.
(E)-3-(3-F lu or op h en yl)-N-m eth yl-3-(9-p h en a n th r yl)-2-
p r op en a m id e (36): yield 77%; mp 199-201 °C; IR (CHCl3)
3454, 3010, 1658, 1611, 1582, 1521, 1494, 1486, 1268 cm-1
;
Gen er a l P r oced u r e for th e Hyd r oa r yla tion of Ar yl-
p r op iola m id es. Arylpropiolamide, aryl iodide (1 equiv), and
Pd(dba)2 (7 mol %) were dissolved in ethyl acetate (0.02 mmol
of arylpropiolamide/L of solvent). Diethylamine (3.3 equiv)
was added, followed by formic acid (2.6 equiv), and the solution
was heated to reflux until reaction completion. The reaction
was then cooled to room temperature and washed with dilute
HCl, dilute NaOH, and finally brine. The organics were dried
over anhydrous MgSO4, and the solvent was removed under
vacuum. Product was isolated from the crude mixture by
either flash column chromatography (3% MeOH/CHCl3; silica)
or crystallization (1:1 EtOAc/Et2O). All products were isolated
as solids.
1H NMR (250 MHz, DMSO-d6) δ 8.84 (t, J ) 7.5 Hz, 2H), 8.19
(d, J ) 5.0 Hz, 1H), 8.06 (d, J ) 7.5 Hz, 1H), 7.86-7.84 (m,
2H), 7.73-7.52 (m, 4H), 7.31-7.10 (m, 4H), 6.36 (s, 1H), 2.66
(d, J ) 4.5 Hz, 3H); 13C NMR (63 MHz, DMSO-d6) δ 165.7,
145.6, 138.1, 130.9, 130.2, 129.80, 129.77, 129.7, 128.9, 127.6,
127.4, 127.2, 127.0, 126.9, 126.4, 124.82, 124.79, 123.4, 122.9,
115.6, 115.3, 114.9, 114.6, 25.6; MS (FD+) calcd for C24H18
-
-
NFO 355.42, found 355.1 (M+, 100). Anal. Calcd for C24H18
NFO: C, 81.10; H, 5.11; N, 3.94; F, 5.35. Found: C, 81.12; H,
5.02; N, 3.91; F, 5.23.
(Z)-3-(3-F lu or op h en yl)-N-m eth yl-3-(9-p h en a n th r yl)-2-
p r op en a m id e (37): yield 83%; mp 124 °C; IR (CHCl3) 3444,
3009, 1653, 1611, 1583, 1529, 1493, 1486, 1451, 1289, 1266

5058 J . Org. Chem., Vol. 63, No. 15, 1998
Hay et al.
1
cm-1; H NMR (300 MHz, CDCl3) δ 8.75 (t, J ) 8.7 Hz, 2H),
127.5, 127.3, 127.2, 127.0, 126.3, 123.1, 122.6, 122.3, 113.9,
55.2, 26.1; MS (FD+) calcd for C25H21NO2 367.45, found 367.01
(M+, 100). Anal. Calcd for C25H21NO2: C, 81.72; H, 5.76; N,
3.81. Found: C, 81.76; H, 6.02; N, 3.49.
7.90 (dd, J 1 ) 7.7 Hz, J 2 ) 1.3 Hz, 1H), 7.78-7.62 (m, 5H),
7.55-7.50 (m, 1H), 7.26-7.14 (m, 2H), 7.06-6.96 (m, 2H), 6.80
(s, 1H), 5.38 (br s, 1H), 2.39 (d, J ) 4.9 Hz, 3H); 13C NMR
(300 MHz, CDCl3) δ 166.3, 146.2, 142.2, 142.1, 133.7, 131.0,
130.6, 130.4, 130.1, 130.0, 129.9, 128.9, 127.8, 127.4, 127.3,
127.11, 127.07, 126.0, 125.3, 123.2, 122.7, 122.6, 114.1, 26.1;
MS (FD+) calcd for C24H18NOF 355.42, found 355.18 (M+, 100).
Anal. Calcd for C24H18NOF: C, 81.11; H, 5.10; N, 3.94.
Found: C, 80.99; H, 5.17; N, 3.94.
(Z)-3-[4-(r,r,r-Tr iflu or om eth yl)p h en yl]-N-m eth yl-3-(2-
tolyl)-2-p r op en a m id e (45): yield 85%; IR (CHCl3) 1653,
1618, 1529, 1411, 1326, 1171, 1131, 1116, 1069, 1016, 844
cm-1 1H NMR (250 MHz, DMSO-d6) δ 7.95 (d, J ) 4.5 Hz,
;
1H), 7.72 (d, J ) 8.3 Hz, 2H), 7.41 (d, J ) 8.0 Hz, 2H), 7.27-
6.99 (m, 4H), 6.72 (s, 1H), 2.54 (d, J ) 4.8 Hz, 3H), 1.99 (s,
3H); 13C NMR (63 MHz, DMSO-d6) δ 164.8, 146.8, 144.2, 138.3,
135.2, 129.7, 128.8, 127.44, 127.38, 125.63, 125.57, 125.5,
125.4, 124.4, 25.4, 19.4; MS (FD+) calcd for C18H16NOF3 319.33,
found 319.1 (M+, 100). Anal. Calcd for C18H16NOF3: C, 67.71;
H, 5.05; N, 4.39. Found: C, 67.54; H, 5.13; N, 4.36.
(Z)-3-(4-An isyl)-3-[r,r,r-t r iflu or om e t h yl)p h e n yl]-N -
m eth yl-2-p r op en a m id e (38): yield 50%; IR (CHCl3) 3450,
3004, 1653, 1606, 1510, 1325, 1251, 1171, 1131, 1068 cm-1
;
1H NMR (250 MHz, DMSO-d6) δ 7.94 (d, J ) 5.0 Hz, 1H), 7.73
(d, J ) 8.5 Hz, 2H), 7.44 (d, J ) 8.3 Hz, 2H), 7.09 (d, J ) 8.5
Hz, 2H), 6.92 (d, J ) 8.8 Hz, 2H), 6.40 (s, 1H), 3.79 (s, 3H),
2.57 (d, J ) 4.5 Hz, 3H); 13C NMR (63 MHz, DMSO-d6) δ 165.6,
159.1, 146.7, 146.2, 130.9, 130.4, 128.9, 128.6, 125.4, 125.3,
125.2, 124.0, 113.3, 55.1, 25.4; MS (FD+) calcd for C18H16NO2F3
335.53, found 335.1 (M+, 100). Anal. Calcd for C18H16NO2F3:
C, 64.47; H, 4.81; N, 4.18; F, 16.99. Found: C, 64.35; H, 4.79;
N, 4.19; F, 17.22.
(E)-3-[4-(r,r,r-Tr iflu or om eth yl)p h en yl]-N-m eth yl-3-(9-
p h en a n th r yl)-2-p r op en a m id e (46): yield 89%; mp 209-210
°C; IR (CHCl3) 3450, 3000, 1660, 1617, 1521, 1325, 1170, 1131,
1115, 1074, 1068, 1017, 856 cm-1; 1H NMR (250 MHz, DMSO-
d6) δ 8.85 (t, J ) 7.9 Hz, 2H), 8.23 (d, J ) 4.5 Hz, 1H), 8.06 (d,
J ) 7.8 Hz, 1H), 7.88-7.83 (m, 2H), 7.76-7.53 (m, 8H), 6.43
(s, 1H), 2.66 (d, J ) 4.5 Hz, 3H); 13C NMR (63 MHz, DMSO-
d6) δ 165.4, 146.1, 143.3, 138.0, 130.8, 130.3, 128.8, 129.7,
129.5, 128.9, 128.3, 127.8, 127.7, 127.5, 127.3, 127.1, 127.0,
126.3, 124.7, 124.6, 123.5, 122.9, 25.6; MS (FD+) calcd for
(E)-3-(4-An isyl)-3-[r,r,r-t r iflu or om et h yl)p h en yl]-N-
m eth yl-2-p r op en a m id e (39): yield 22%; IR (CHCl3) 3458,
3020, 1660, 1603, 1510, 1325, 1254, 1170, 1131, 1109, 1066,
1034, 1020, 833 cm-1; H NMR (300 MHz,CDCl3) δ 7.63 (d, J
1
C
C
25H18F3NO 405.42, found 405.1 (M+, 100). Anal. Calcd for
25H18F3NO C, 74.07; H, 4.48; N, 3.46; F, 14.06. Found: C,
) 8.3 Hz, 2H), 7.36 (d, J ) 7.9 Hz, 2H), 7.14 (dd, J ) 6.8, 1.9
Hz, 2H), 6.84 (dd, J ) 6.8, 2.3 Hz, 2H), 6.30 (s, 1H), 5.44 (d, J
) 3.8 Hz, 1H), 3.80 (s, 3H), 2.69 (d, J ) 4.9 Hz, 3H); 13C NMR
(75 MHz,CDCl3) δ 166.3, 160.3, 149.0, 142.8, 132.6, 129.6,
129.2, 125.13, 125.08, 125.03, 124.97, 120.3, 113.8, 55.2, 26.1;
MS (FD+) calcd for C18H16NO2F3 335.53, found 335.14 (M+,
100). Anal. Calcd for C18H16NO2F3: C, 64.47; H, 4.81; N, 4.18.
Found: C, 64.33; H, 4.85; N, 4.23.
74.21; H, 4.53; N, 3.59; F, 14.16.
(Z)-3-[4-(r,r,r-Tr iflu or om eth yl)p h en yl]-N-m eth yl-3-(9-
p h en a n th r yl)-2-p r op en a m id e (47): yield 77%; mp 138-139
°C; IR (CHCl3) 3010, 1654, 1617, 1529, 1325, 1171, 1132, 1070,
1016, 842 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.76 (t, J ) 9.2
Hz, 2H), 7.91 (dd, J 1 ) 7.7 Hz, J 2 ) 1.3 Hz, 1H), 7.76-7.62
(m, 5H), 7.55-7.45 (m, 5H), 6.84 (s, 1H), 5.44 (d, J ) 4.1 Hz,
1H), 2.40 (d, J ) 4.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
166.2, 146.0, 143.3, 133.5, 131.0, 130.6, 130.4, 129.8, 128.9,
127.9, 127.5, 127.4, 127.3, 127.2, 127.1, 126.1, 125.9, 125.6,
125.54, 125.49, 123.3, 122.6, 118.4, 26.1; MS (FD+) calcd for
(E)-3-(4-An isyl)-N-m eth yl-3-(2-tolyl)-2-pr open am ide (40):
yield 82%; IR (CHCl3) 3453, 3008, 1654, 1606, 1511, 1294,
1251, 1179, 1033, 838 cm-1; H NMR (250 MHz, DMSO-d6) δ
1
7.87 (d, J ) 4.5 Hz, 1H), 7.25-7.11 (m, 4H), 7.08 (d, J ) 8.5,
2H), 6.83 (d, J ) 8.8 Hz, 2H), 5.85 (s, 1H), 3.74 (s, 3H), 2.58
(d, J ) 4.5 Hz, 3H), 1.97 (s, 3H); 13C NMR (63 MHz, DMSO-
d6) δ 166.2, 158.9, 147.9, 142.7, 135.3, 131.0, 130.4, 130.3,
129.4, 127.8, 125.8, 123.3, 113.0, 55.1, 25.5, 19.7; MS (FD+)
calcd for C18H19NO2 281.36, found 281.2 (M+, 100). Anal.
Calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C,
76.61; H, 6.79; N, 5.20.
C
C
25H18F3NO 405.42, found 405.1 (M+, 100). Anal. Calcd for
25H18F3NO: C, 74.07; H, 4.48; N, 3.46. Found: C, 73.98; H,
4.73; N, 3.72.
(E)-N-Meth yl-3-(9-p h en a n th r yl)-3-(2-tolyl)-2-p r op en a -
m id e (48): yield 90%; mp 247-248 °C; IR (CHCl3) 3008, 1651,
1528 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 8.88 (d, J ) 7.87
Hz, 1H), 8.80 (d, J ) 8.17 Hz, 1 H), 8.23 (dd, J ) 7.94 Hz, J )
0.85 Hz, 1H), 8.00-7.89 (m, 2H), 7.74-7.56 (m, 5H), 6.39 (s,
1H), 2.60 (d, J ) 4.60 Hz, 3H), 2.20 (s, 3H); 13C NMR (63 MHz,
DMSO-d6) δ 165.1, 147.2, 140.0, 138.5, 135.5, 130.9, 130.6,
130.5, 130.0, 129.7, 129.5, 129.1, 128.8, 127.7, 127.4, 127.3,
127.2, 127.0, 126.9, 126.1, 125.2, 123.5, 122.8, 25.5, 20.1; MS
(FD+) calcd for C25H21NO 351.47, found 351.1 (M+, 100). Anal.
Calcd for C25H21NO: C, 85.44; H, 6.02; N, 3.99. Found: C,
85.17; H, 5.95; N, 4.21.
(Z)-N-Meth yl-3-(9-p h en a n th r yl)-3-(2-tolyl)-2-p r op en a -
m id e (49): yield 62%; mp 144 °C; IR (CHCl3) 3450, 3011, 2219,
2205, 1652, 1521, 1494, 1452, 1415, 1265, 1242 cm-1; 1H NMR
(350 MHz, CDCl3) δ 8.77-8.60 (m, 3 H), 8.11 (d, J ) 7.62 Hz,
1 H), 7.80 (dd, J ) 7.83, 1.1 Hz), 7.70-7.50 (m, 4 H), 7.29 (s,
1 H), 7.25-7.0 (m, 3 H), 6.45 (s, 1H), 2.35 (d, J ) 4.52 Hz,
3H), 2.32 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 166.9, 147.4,
141.3 128.9 127.1, 126.9, 126.8, 122.7, 26.0, 21.2; MS (FD+)
calcd for C25H21NO 351.47, found 351.1 (M+, 100). Anal. Calcd
for C25H21NO: C, 85.44; H, 6.02; N, 3.99. Found: C, 85.36;
H, 5.87; N, 4.41.
(Z)-3-(4-An isyl)-N-m eth yl-3-(2-tolyl)-2-pr open am ide (41):
yield 88%; IR (CHCl3) 3007, 1646, 1605, 1573, 1530, 1512,
1291, 1279, 1254, 1181, 1034, 834 cm-1; H NMR (250 MHz,
1
DMSO-d6) δ 7.77 (d, J ) 4.8 Hz, 1H), 7.20-7.10 (m, 5H), 6.95-
6.88 (m, 3H), 6.52 (s, 1H), 3.74 (s, 3H), 2.52 (d, J ) 4.5 Hz,
3H), 1.98 (s, 3H); 13C NMR (63 MHz, DMSO-d6) δ 165.2, 159.7,
146.2, 139.4, 135.1, 132.3, 129.4, 128.6, 128.0, 126.9, 125.2,
119.8, 114.1, 55.2, 25.4, 19.4; MS (FD+) calcd for C18H19NO2
281.36, found 281.1 (M+, 100). Anal. Calcd for C18H19NO2:
C, 76.84; H, 6.81; N, 4.98. Found: C, 76.60; H, 6.84; N, 5.08.
(E)-3-(4-An isyl)-N-m eth yl-3-(9-p h en a n th r yl)-2-p r op en -
a m id e (42): yield 72%; mp 156-158 °C; IR (CHCl3) 3452,
1653, 1606, 1494, 1451, 1413, 1294, 1252, 1176, 1032, 845
cm-1 1H NMR (250 MHz, DMSO-d6) δ 8.83 (m, 2H), 8.07-
;
8.02 (m, 2H), 7.82-7.50 (m, 6H), 7.26 (d, J ) 9.0 Hz, 2H), 6.80
(d, J ) 8.5 Hz, 2H), 6.21 (s, 1H), 3.70 (s, 3H), 2.66 (d, J ) 4.5
Hz, 3H); 13C NMR (63 MHz, DMSO-d6) δ 166.3, 159.1, 146.5,
139.0, 131.1, 131.0, 130.3, 130.2, 130.1, 129.7, 128.8, 127.3,
127.2, 126.8, 126.74, 126.68, 124.5, 123.3, 122.8, 113.3, 55.1,
25.6; MS (FD+) calcd for C25H21NO2 367.45, found 367.0 (M+,
100). Anal. Calcd for C25H21NO2: 81.72; H, 5.76; N, 3.81.
Found: C, 81.81; H, 5.62; N, 3.94.
Ack n ow led gm en t. We are thankful to Drs. Lou
J ungheim, Wayne Spitzer, and Mark Tebbe and Profes-
sors Marvin Miller, Leo Paquette, Bill Roush, Ted
Taylor, and Paul Wender for helpful discussions during
the course of this work. We are also grateful to Mr. Dave
Robbins and the Lilly Physical Chemistry group for
obtaining analytical data.
(Z)-3-(4-An isyl)-N-m eth yl-3-(9-p h en a n th r yl)-2-p r op en -
a m id e (43): yield 83%; mp 176-179 °C; IR (CHCl3) 3435,
3010, 1648, 1604, 1529, 1512, 1274, 1254, 1180 cm-1; 1H NMR
(250 MHz, DMSO-d6) δ 8.81 (m, 2H), 8.05-7.77 (m, 2H), 7.76-
7.50 (m, 6H), 7.26 (d, J ) 9.0 Hz, 2H), 6.80 (d, J ) 8.5 Hz,
2H), 6.75 (s, 1H), 5.29 (br s, 1 H), 3.72 (s, 3H), 2.39 (d, J ) 4.5
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.9, 160.3, 146.9,
134.6, 132.2, 131.1, 130.6, 130.2, 129.0, 128.9, 128.4, 128.1,
J O980235H