Tandem Pd-catalyzed double C-C bond formation: Effect of water

Article abstract of DOI:10.1021/jo900053b

A highly efficient water-accelerated palladium-catalyzed reaction of gem-dibromoolefins with a boronic acid via a tandem Suzuki-Miyaura coupling and direct arylation is reported. A wide range of aryl, alkenyl, and alkyl boronic acids, as well as a variety

Full text of DOI:10.1021/jo900053b

Tandem Pd-Catalyzed Double C-C Bond Formation:
Effect of Water
David I. Chai and Mark Lautens*
DaVenport Research Laboratory, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, Canada, M5S 3H6
mlautens@chem.utoronto.ca
ReceiVed January 10, 2009
A highly efficient water-accelerated palladium-catalyzed reaction of gem-dibromoolefins with a boronic
acid via a tandem Suzuki-Miyaura coupling and direct arylation is reported. A wide range of aryl,
alkenyl, and alkyl boronic acids, as well as a variety of substitution patterns on the phenyl ring, are
tolerated. Additionally, mechanistic studies were conducted to ascertain the order of the couplings as
well as the role(s) of water. Results from this study indicate that the major pathway is a Suzuki-Miyaura
coupling/direct arylation sequence and that water accelerates the Pd(0) formation and Suzuki-Miyaura
coupling.
Introduction
It has been our aim to develop new tandem processes and
now report a Suzuki-Miyaura coupling-direct arylation,5 using
catalytic palladium. To the best of our knowledge, this combina-
tion has not yet been explored, despite the fact that these two
transformations have thoroughly been studied and expanded in
recent times. This combination can increase the efficiency and
modularity of the reactions by reducing the number of chemical
transformations and chemical waste.
As a part of our research in Pd-catalyzed tandem reactions,
we have reported on the utility of gem-dihalovinyl systems for
syntheses of heterocycles (Scheme 1).6 This system has
important features:7 (1) the gem-dihalovinyl system is more
reactive toward Pd complexes compared to the corresponding
mono halo-compound, thereby rendering cross-coupling more
The development of efficient strategies for the C-C bond-
forming processes continues to be of major importance in synthetic
organic chemistry1 with many efficient C-C bond forming
processes developed in the field of organopalladium-catalyzed
reactions.2 The most reliable class of C-C bond formation is
via the use of the Pd-catalyzed coupling reaction of an aryl or
vinyl halide with an organometallic reagent.3 Examples include
Suzuki-Miyaura coupling (organoboron),3a-c Stille coupling
(organostannane),3d,e Negishi coupling (organozinc),3f or Hiya-
ma coupling (organosilane).3g An attractive alternative to this
method is the use of direct arylation, which does not require
the creation of a reactive functionality prior to the coupling (i.e.,
metalation).4 In the last two decades, this area has undergone
tremendous growth and new types of direct arylation have been
developed.4
(4) For recent reviews on direct arylation, see: (a) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174. (b) Miura, M.; Nomura, M. Top. Curr.
Chem. 2002, 219, 211. (c) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schultz, E.;
Lemaire, M. Chem. ReV. 2002, 102, 1359. (d) Kakiuchi, F.; Chatani, N. AdV.
Synth. Catal. 2003, 345, 1077. (e) Handbook of C-H Transformations; Dyker,
G., Ed.; Wiley-VCH: Weinheim, Germany, 2005; Vols. 1 and 2. (f) Schnu¨rch,
M.; Flasik, R.; Farooq Khan, A.; Spina, M.; Mihovilovic, M. D.; Stanetty, P.
Eur. J. Org. Chem. 2006, 3283. (g) Campeau, L.-C.; Fagnou, K. Chem. Commun.
2006, 1253. (h) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichim. Acta 2007,
40, 35. (i) Seregin, I. V.; Gevorgyan, J. Chem. Soc. ReV. 2007, 36, 1173, and
references cited therein. (j) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem.
Soc. 2005, 127, 8050–8057. (k) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003,
125, 5274–5275. (l) Ackermann, L. Top. Organomet. Chem. 2007, 24, 35–60.
(m) Ackermann, L.; Althammer, A. Angew. Chem., Int. Ed. 2007, 46, 1627–
1629.
(1) For a recent general review, see: Joule, J. A.; Mills, K. In Heterocyclic
Chemistry, 4th ed.; Blackwell Science Ltd.: Cambridge, MA, 2000.
(2) (a) Stanforth, S. P. Tetrahedron 1998, 54, 263. (b) Hassan, J.; Se´vignon,
M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (c)
Anastasia, L.; Negishi, E. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley: New York, 2002; pp 311-334.
(3) (a) Suzuki, A. J. Organomet. Chem. 2002, 653, 83. (b) Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457. (c) Suzuki, A. In Boronic Acids; Hall,
D. G., Ed.; Wiley-VCH: Weinheim, Germany, 2005; p 123. (d) Milstein, D.;
Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636. (e) Farina, V.; Krishnamurthy,
V.; Scott, W. J. The Stille Reaction; Wiley: New York, 1998. (f) Knochel, P.;
Perea, J. J. A.; Jones, P. Tetrahedron 1998, 54, 8275. (g) Hiyama, T.; Shirakawa,
E. Top. Curr. Chem. 2002, 219, 62.
(5) For the first Tandem direct arylation/Suzuki coupling, see: Fang, Y.-Q.
Ph.D. Thesis, The University of Toronto, Canada, 2006.
3054 J. Org. Chem. 2009, 74, 3054–3061
10.1021/jo900053b CCC: $40.75 2009 American Chemical Society
Published on Web 03/25/2009

Tandem Pd-Catalyzed Double C-C Bond Formation
SCHEME 1. Transformations with the Dihalovinyl System
SCHEME 2. Initial Synthesis of Pyrrolo[1,2-a]quinoline
SCHEME 3. Our Strategy for the Synthesis of Substitued Pyrrolo[1,2-a]quinoline
facile, and (2) the oxidative addition to Pd is usually trans-
selective due to steric effects of substituents in the ꢀ-position.
caspases and inducing apoptosis9a-d in addition to electron
transport properties.9e
The direct arylation/Suzuki-Miyaura coupling sequence
provides an interesting heterocyclic system via consecutive C-C
bond formation. We chose the dihalovinyl pyrrole system 1
as a model substrate to synthesize pyrrole[1,2-a]quinoline 2b,
since we have shown8a that direct arylation on a pyrrole ring is
a facile process to construct the pyrrolo[1,2-a]quinoline skeleton
2a8b-f (Schemes 2 and 3). This product and its derivatives are
known to exhibit biological activities including activation of
Results and Discussion
Optimization of the Tandem Suzuki/Direct Arylation
Reaction. Our first attempt to effect the reaction of dibromovinyl
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A.; Suzuki, K.; Tamao, K. J. Am. Chem. Soc. 1987, 109, 1257. (c) Minato, A.
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Zeng, X. Tetrahedron. 2005, 61, 9886. (i) Shen, W.; Wang, L. J. Org. Chem.
1999, 64, 8873.
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2003, 125, 5274. (d) Rieth, R. D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P.
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Lautens, M. Org. Lett. 2005, 7, 3549. (c) Fayol, A.; Fang, Y.-Q.; Lautens, M.
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Org. Lett. 2008, 10, 4633.
J. Org. Chem. Vol. 74, No. 8, 2009 3055

Chai and Lautens
TABLE 1. Ligand Screening for the Tandem Reaction between 1
and PhB(OH)2
found to afford good to excellent yield for the desired product for
electron-rich and electron-poor boronic acids (Table 2, entries 2-9)
though very electron-poor (Table 2, entry 10) or electron-rich
boronic acids (Table 2, entry 4) resulted in no reaction or reduced
yield under the optimized conditions. In some substances, a
significant improvement was realized by using 3 equiv of aryl
boronic acid, presumably due to a competitive deboronation or
homocoupling of aryl boronic acids (Table 2). In fact, the
homocoupled biaryl product was sometimes observed when
electron-rich or neutral boronic acids were used.
This methodology could also be extended to alkenyl and alkyl
boronic acids affording the desired product in good yield though
the addition of water was not necessary (Table 2, entries 13 and
16). The product of the reaction with alkenyl boronic acids was
isolated as a single (E)-isomer under the optimized conditions.
Coupling of sterically hindered boronic acids has historically proven
to be a difficult task; however, with the dibromovinyl system 1,
the coupling proceeded in moderate to excellent yields with ortho-
substituted boronic acids as hindered as 2-phenylboronic acid
(Table 2, entries 12, 17, and 18). Heterocycles such as thiophene
were compatible with this reaction (Table 2, entry 11). Usually,
systems employing pinacol boranes in Pd-catalyzed reactions result
in borylation products from aryl halides.13 However, the use of 1
provided the reduced product 2v, presumably via a transmetalation
with the borane (Table 2, entry 21).
We could extend this method to include a variety of
substituents on the dibromo alkene partner (Table 3). Both
electronic and steric variation on the aromatic substituents
afforded moderate to excellent yields. Interestingly, a substituent
on the vinyl position did not affect the yield (Table 3, entry 2).
Given the success of direct arylation on pyrroles, we wished
to extend this methodology to include other heteroaromatic ring
systems. We found that the indole derivative 4 gave the desired
product 5 in good yield (Scheme 4), while attempts to
incorporate other aromatic ring systems such as furans, thiophenes,
pyrazoles, and tetrazoles failed. Fortunately, we were pleased
to see pyridine derivative 6 reacted under the optimized
condition (Scheme 5) since a variety of substituted pyridine
derivatives exhibit interesting biological activities.14
entry
ligand
yield (%)a
1
2
3
4
5
PPh3
55
65
90
85
68
P(p-tol)3
S-Phos
X-Phos
dppf
a Isolated yield.
system 1 with phenyl boronic acid was promising in that the
desired product 2 was obtained in 50% yield with Pd(OAc)2
and PPh3 in toluene at reflux. Among several parameters
modified, the combination of Pd(OAc)2, P(o-tolyl)3, and Cs2CO3
at 100 °C in toluene was more effective. More significant
improvement in reaction yields could be achieved by using
Buchwald-type biphenyl ligands10 such as S-Phos, leading to
the desired product 2 in 75% yield. S-Phos was somewhat more
effective than the hindered X-Phos ligand (Table 1). Further-
more, it was found that bidentate phosphine ligands such as
dppf were slightly less reactive. The addition of water had a
dramatic effect not only on the reactivity of diboromovinyl
system 1, but also on minimizing the formation of side products.
Further improvement in reaction yield was realized by decreas-
ing the reaction concentration. Further optimization showed that
the desired product 2 was obtained in 90% yield with phenyl-
boronic acid (1.5 equiv), toluene (0.04 M), Pd(OAc)2 (4 mol
%), S-Phos (8 mol %), Cs2CO3 (2 equiv), and water (5 equiv).
Scope of the Tandem Reaction. To establish the scope of
this reaction, the effects of changing the boronic acid and the
substituents at the aromatic ring were tested (Tables 2 and 3). Well-
tolerated functional groups at different positions of the boronic acid
include methyl, methoxy, Boc-protected amine, trifluoromethyl,
fluoro, chloro, and TMS groups, which are useful for postmodifica-
tions11,12 (Table 2, entries 1-19). In particular, the reaction was
(12) For example, see: (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am.
Chem. Soc. 1996, 118, 10333. (b) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc.
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Soc. 1997, 119, 3395. (d) Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L.
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(h) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc.
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J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369.
(13) For other systems employing pinacol borane in Pd-catalyzed borylations
of aryl iodides and bromides, see:(a) Baudoin, O.; Guenard, D.; Gueritte, F. J.
Org. Chem. 2000, 65, 9268–9271. (b) Murata, M.; Oyama, T.; Watanabe, S.;
Masuda, Y. J. Org. Chem. 2000, 65, 164–168. For a system employing pinacol
borane in Pd-catalyzed borylations of aryl bromides, see:(c) Broutin, P.-E.; Cerna,
I.; Campaniello, M.; Leroux, F.; Colobert, F. Org. Lett. 2004, 6, 4419–4422.
(14) (a) Elhakmoui, A.; Gueiffier, A.; Milhavet, J. C.; Blache, Y.; Chapat,
J. P. Bioorg. Med. Chem. Lett. 1994, 4, 1937. (b) Gueiffier, A.; Lhassani, M.;
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Clercq, E.; Chapat, J. P. J. Med. Chem. 1996, 39, 2856. (c) Lhassani, M.;
Chavignion, O.; Chezal, J. M.; Teulade, J. C.; Chapat, J. P.; Snoeck, R.; Andrei,
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Gudmundsson, K. S.; Drach, J. C.; Townsend, L. B. J. Org. Chem. 1997, 62,
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Nat. Prod. Rep. 1994, 11, 581–590. (i) Daly, J. W.; Pinder, A. R. Nat. Proc.
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A. R., Rees, C. W., Scriven, E. S. V., Eds.; Pergamon: New York, NY, 1996;
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in Heterocyclic Chemistry; Gribble, G. W., Joule, J. A., Eds.; Pergamon:
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Patent WO 2004055163, 2004. (e) Leontie, L.; Druta, I.; Danac, R.; Rusa, G. I.
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J. P. Curr. Org. Synth. 2004, 1, 211–226.
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Tandem Pd-Catalyzed Double C-C Bond Formation
TABLE 2. Reaction Scope with Different Boronic Acids
a Isolated yield. b 3 equiv of boronic acid was used. c Without water. d Reaction with HBpin
.
We next examined other organoboron reagents including aryl
pinacol borane, alkenyl boronate ester, and trialkyl boron reagents
(Table 4). Coupling under the optimized conditions gave the desired
products 8 in moderate yields. In particular, the pinacol borane
species showed no reactivity in the absence of water, indicating
that the boron species involved in the transmetalation step should
contain one or more hydroxyl groups, in accord with the observa-
tion made by Batey and co-workers in coupling between organ-
otrifluoroborate salts and aryl halides.15
We also explored the reactivity of the products to undergo
subsequent transformations. For instance, treatment of 2b with
BuLi, followed by quenching with ethyl chloroformate afforded
2-ethyl ester 9 in 60% yield, indicating that the proton next to
the pyrrole nitrogen is the most acidic (Scheme 6). This result
led us to examine the Pd-catalyzed direct arylation to compare
the regioselectivity. Under conditions described by Seregin et
(15) Batey, R. A.; Quach, T. D. Tetrahedron Lett. 2001, 42, 9099.
J. Org. Chem. Vol. 74, No. 8, 2009 3057

Chai and Lautens
TABLE 3. Reaction Scope of the Tandem Reaction Varying Phenyl Substituents
a Isolated yield.
SCHEME 4. Tandem Reaction of the Dibormovinyl Indole
System
observed and further experiments with deuterated starting
material 14 gave 15 with 100% deuterium remaining (Scheme
8).
Eliminating alkynes such as 11 from the reaction pathway
indicated that the reaction must proceed via a sequential
replacement of the halogens. Accordingly, there are two possible
pathways (Scheme 9). The first is one that proceeds with direct
arylation, followed by Suzuki-Miyaura coupling. The second
pathway reverses the order of events such that Suzuki-Miyaura
coupling precedes the direct arylation. Further experiments were
performed to elucidate the order of coupling by subjecting
possible intermediates to the reaction conditions. Intermediate
12 quantitatively led to production of 2b (Scheme 10), in accord
with path A. However, the formation of intermediate 12 is
unfavored due to steric effects that disfavor the oxidative
addition to the C-Br bond cis to the aryl group.7 On the other
hand, the direct arylation of 13 in the presence of 0.5 equiv of
PhB(OH)2 gave a mixture of the desired product 2b and bis-
Suzuki coupling product 16 (Scheme 11). The double Suzuki
coupling product 16 has been observed as a side product when
more than 1.5 equiv of boronic acids was used with 1, suggesting
that 13 is a possible intermediate under the reaction conditions
(Scheme 9, path B). Unfortunately, intermediate 13 could not
be detected during the reaction probably because the second
step is too fast.
SCHEME 5. Tandem Reaction of the Dibormovinyl
Pyridine System
al.,16 the pyrroloquinoline 2b was regioselectively coupled with
trimethylsilyl acetyl bromide to give 10 in 67% yield (Scheme
6).
Mechanistic Considerations. Furstner reported the formation
of pyrrole[1,2-a]quinolines using an alkyne precursor,17 which
suggested products 2b were formed via an intermediate alkyne
(Scheme 7). This process could happen through base-induced
elimination17 or through an initial oxidative addition of Pd into
the C-Br bond trans to the aryl group, followed by ꢀ-hydride
elimination.18 To test this possibility, alkynes 11a,b were
subjected to the reaction conditions with phenyl boronic acid
in the presence of palladium. The desired product was not
It was found that the addition of water has a dramatic effect
on the reaction rate. A recent report19 by Buchwald suggested
that water could serve as a promoter of Pd(0) formation by
removing the phosphonium salt formed during reduction of
Pd(II), thus resulting in increased rates of reactions. In our case,
performing the reaction in the absence of water resulted in 95%
conversion and moderate yields after 6 h (Table 5, entry 1),
while water preactivated catalytic reactions (Table 5, entry 2)
experienced 100% conversion and somewhat higher yields in
(16) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 7742.
(17) Mamane, V.; Hannen, P.; Furstner, A. Chem. Eur. J. 2004, 10, 4556.
(18) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873.
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Tandem Pd-Catalyzed Double C-C Bond Formation
SCHEME 6. Synthetic Utility of Substrate 2b
TABLE 4. Reaction Scope of the Tandem Reaction Varying
Organoboron Reagents
SCHEME 9. Possible Mechanistic Pathways for the Tandem
Reaction
SCHEME 10. Possible Reaction Intermediate 12 Subjected
to the Reaction Condition
SCHEME 11. Possible Reaction Intermediate 13 Subjected
to the Reaction Condition
a Isolated yield. b Without water.
SCHEME 7. Possible Alkyne Intermediates Subjected to the
Reaction Condition
Suzuki coupling (Table 5, entry 2 vs. entry 3). Thus, we believe
that water has dual roles: the preactivation of catalyst and the
acceleration of the Suzuki coupling.
These results lead us to propose that the dominant process is
the Suzuki coupling/direct arylation sequence (Scheme 12, path
B) accompanied by a minor process involving the intermediate
12 (Scheme 12, path A). The Pd(II) source is first converted to
Pd(0) in the presence of a ligand promoted by water. Pd(0) then
undergoes oxidative addition into the trans-C-Br bond. The
resulting intermediate 17 couples with a boronic acid to give
the intermediate 13, which subsequently undergoes coupling by
direct arylation, presumably via an electrophilic substitution
mechanism,20 to give the desired product 2b.
SCHEME 8. Deuterium Labeling Study
Conclusions
6 h. In addition, the formation of Pd(0) is easily monitored by
a color change (yellow to dark green) in this system. Additional
study showed that the direct arylation of 13 is not affected by
water, suggesting the acceleration of the Suzuki coupling by
water. Further studies demonstrated that water not only increased
the reactivity (Table 5, entry 1 vs. entry 2), but also reduced
the formation of byproduct perhaps via the acceleration of the
The synthetic utility of gem-dibromovinyl substrates 1 is
illustrated by the sequential Suzuki-Miyaura coupling/direct
arylation tandem reaction and represents an attractive method
for the synthesis of N-fused heterocycles. This methodology
is compatible with a variety of aryl, alkenyl, and alkyl boronic
acids, as well as boronic esters, providing products that
require multiple chemical transformations to match existing
J. Org. Chem. Vol. 74, No. 8, 2009 3059

Chai and Lautens
TABLE 5. Effect of Water
entry
water
no
0.1 equiv
5 equiv
x, equiv
yield (%)a
70-80b c d
,
,
1
2
3
1.5
1.5
1.5
75-82c e
,
90f
a NMR yield. b 5% 1 remained. c Several byproducts found. d Slow color change within 3 h. e Preactivation of catalyst system by water. f Fast color
change within 5 min.
SCHEME 12. Proposed Mechanism for the Tandem Reaction
details and characterization data for the compounds. The information
for all other compounds can be found in the Supporting Information.
General Procedure for the Tandem Reaction. In a sealable
microwave tube with a PTFE faced silicone septum cap gem-
dibromoolefin (0.3 mmol, 1.0 equiv), boronic acid (1.5 equiv),
Cs2CO3 (2 equiv), Pd(OAc)2 (4 mol %), and S-Phos (8 mol %)
were added. After the flask was purged with argon for 10 min,
toluene (7.5 mL) and water (5 equiv) were successfully added, and
the sealed reaction tube (caution: build-up of pressure is possible;
use a safety shield) was heated at 100 °C in a preheated oil bath.
After 12 h, the mixture was diluted with Et2O (5 mL) and filtered
methods. In general, yields for this reaction were good to
excellent, allowing it a versatile approach. Mechanistic
investigation indicates that Suzuki-Miyaura coupling occurs
prior to direct arylation. In particular, water has a dramatic
effect on both the reactivity of the substrate and the reduction
of the byproduct.
Experimental Section
The following represents experimental procedures toward the
synthesis of products 2i, 3a, 9, and 10, including experimental
3060 J. Org. Chem. Vol. 74, No. 8, 2009

Tandem Pd-Catalyzed Double C-C Bond Formation
through Celite. The crude material was purified by flash chroma-
tography with EtOAc:hexanes system containing 5% Et3N to afford
a corresponding product.
(1H, s), 6.59 (1H, d, J ) 4.4 Hz), 4.43 (2H, q, J ) 7.2 Hz), 1.44
(3H, t, J ) 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 162.3, 138.5,
138.1, 133.3, 132.2, 128.9, 128.7, 128.5, 127.6, 125.5, 124.9, 124.9,
123.4, 121.0, 120.0, 104.3, 60.9, 14.7; νmax/cm-1 (CHCl3) 3103.6,
3057.3, 3032.2, 2980.1, 1699.3, 1608.7, 1537.3, 1537.3, 1489.1,
1456, 1438.9, 1398.4, 1363.7, 1329.0, 1317.4, 1292.4, 1261.5,
1244.1, 1170.8, 1145.8, 1116.8, 1035.8, 977.9, 879.6, 788.9, 756.1,
740.7, 702.1, 669.3; m/z (EI) calcd for C21H17NO2 315.1259, found
315.1259; mp 75-77 °C.
4-(2-Fluorophenyl)pyrrolo[1,2-a]quinoline (2i). 2i was syn-
thesized according to the general procedure with 1-[2-(2,2-
dibromovinyl)phenyl]-1H-pyrrole and 2-fluoromethylphenyl boronic
acid (1.5 equiv) by flash column chromatography (pentane:triethyl
amine, 95:5) as a green solid (36.1 mg, 46%): 1H NMR (400 MHz,
CDCl3) δ 7.91 (1H, m), 7.89 (1H, d, J ) 5.6 Hz), 7.67 (1H, dd, J
) 7.6 Hz, J ) 1.2 Hz), 7.60 (1H, dt, J ) 7.6 Hz, J ) 2.0 Hz), 7.52
(1H, dt, J ) 7.2 Hz, J ) 1.6 Hz), 7.43-7.37 (1H, m), 7.33 (1H,
dt, J ) 8.4 Hz, J ) 1.2 Hz), 7.26-7.19 (2H, m), 7.04 (1H, s), 6.79
(1H, dd, J ) 4.0 Hz, J ) 3.2 Hz), 6.39 (1H, dt, J ) 4.0 Hz, J )
1.6 Hz); 13C NMR (100 MHz, CDCl3) δ 161.6, 159.1, 133.1, 131.5,
131.4, 130.9, 130.0, 129.9, 129.0, 128.2, 126.8, 126.5, 124.3, 124.3,
124.2, 124.0, 123.9, 120.0, 116.9, 116.4, 116.1, 114.3, 113.0, 112.7,
103.4, 103.3; νmax/cm-1 (CHCl3) 3142, 3106, 3061, 1718, 1612,
1576, 1539, 1490, 1457, 1448, 1419, 1364, 1341, 1318, 1301, 1259,
1247, 1219, 1164, 1097, 1038, 993, 938, 925, 870, 841, 798, 756,
696; m/z (EI) calcd for C18H12FN 261.0954, found 261.0961; mp
80-82 °C.
4-Phenylpyrrolo[1,2-a]quinoline-7-carboxylic Acid Methyl
Ester (3a). 3a was synthesized according to the general procedure
with 3-(2,2-dibromovinyl)-4-pyrrol-1-yl-benzoic acid methyl ester
and phenyl boronic acid (1.5 equiv) by flash column chromatog-
raphy (5% ethyl acetate in pentane:triethyl amine, 95:5) as a pale
yellow solid (63.3 mg, 70%): 1H NMR (400 MHz, CDCl3) δ 8.39
(1H, d, J ) 1.6 Hz), 8.15 (1H, dd, J ) 8.8 Hz, J ) 2.0 Hz), 7.95(1H,
dd, J ) 2.8 Hz, J ) 1.2 Hz), 7.90 (1H, d, J ) 8.8 Hz), 7.70 (2H,
m), 7.50-7.40 (3H, m), 7.03 (1H, s), 6.84 (1H, dd, J ) 4.0 Hz, J
) 2.8 Hz), 6.65 (1H, dd, J ) 3.6 Hz, J ) 1.2 Hz), 3.97 (3H, s);
13C NMR (100 MHz, CDCl3) δ 166.9, 138.7, 135.6, 133.8, 131.4,
131.1, 128.9, 128.7, 128.5, 125.6, 124.1, 118.1, 114.3, 114.0,
113.5, 104.6, 52.4; νmax/cm-1 (CHCl3) 3128.9, 2066.7, 3019.2,
2948.1, 1708.9, 1612.5, 1490.2, 1442.9, 1351.4, 1310.0, 1296.8,
1279.7, 1266.7, 1200.5, 1157.3, 1111.9, 783.6, 764.8, 737.2,
700.3; m/z (EI) calcd for C20H15NO2 301.1103, found 301.1107;
mp 120-121 °C.
Procedure for the Synthesis of 4-Phenyl-1-trimethylsilanyl-
ethynyl Pyrrolo[1,2-a]quinoline (10). In a 5.0 mL microwave tube
equipped with a PTFE faced silicone septum cap were added
phenylpyrrolo[1,2-a]quinoline (2b) (1 equiv, 0.3 mmol), 5 mol %
of PdCl2(PPh3)2, and 2 equiv of KOAc. Then, bromoalkyne (1.5
equiv) and anhydrous toluene (0.01 M) were successively added
and the mixture was stirred for 12 h at 60 °C. The mixture was
concentrated under reduced pressure and the residue was purified
by flash-column chromatography (pentane:triethylamine, 95:5) to
afford pure alkynyl-heterocycles 10 as a yellow solid (68.2 mg,
1
67%): H NMR (400 MHz, CDCl3) δ 9.30 (1H, d, J ) 8.4 Hz),
7.33-7.27 (3H, m), 7.14-7.05 (4H, m), 7.01 (1H, t, J ) 8.4 Hz),
6.72 (1H, d, J ) 4.4 Hz), 6.70 (1H, s), 6.17 (1H, d, J ) 4.4 Hz),
0.00 (9H, s); 13C NMR (100 MHz, CDCl3) δ 138.7, 135.1, 133.0,
132.6, 128.8, 128.7, 128.7, 128.3, 126.8, 125.3, 124.4, 122.5, 120.6,
116.5, 111.0, 103.9, 102.0, 100.4, 0.000; νmax/cm-1 (CHCl3) 3059.2,
2045.7, 3032.2, 2957.0, 2897.2, 2139.1, 1601.0, 1537.3, 1489.1,
1452.5, 1440.9, 1375.3, 1317.4, 1290.4, 1249.9, 1184.3, 1184.3,
1051.2, 1033.9, 997.2, 902.7, 856.4, 842.9, 779.3, 758.1, 740.7,
700.2, 669.3, 648.1; m/z (EI) calcd for C23H21NSi 339.1443, found
339.1443; mp 85-86 °C.
Acknowledgment. We would like to thank Dr. Yuan-Qing
Fang for initial experimental contributions and helpful sugges-
tions. We also thank the Natural Sciences and Engineering
Research Council (NSERC) of Canada, the Merck Frosst Center
for Therapeutic Research for an Industrial Research Chair, and
the University of Toronto for supporting this research.
Procedure for the Synthesis of 4-Phenylpyrrolo[1,2-a]quino-
line-1-carboxylic Acid Ethyl Ester (9). To a solution of 4-Phe-
nylpyrrolo[1,2-a]quinoline (2b) (1 equiv, 0.3 mmol) in hexane was
added BuLi (1.1 equiv, 1.6 M in hexane) dropwise at -78 °C. After
1 h at this temperature, ethyl chloroformate (1 equiv) was added
dropwise at -78 °C, then the mixture was warmed to ambient
temperature. Next, the reaction was quenched by water and the
layers were separated. The aqueous layer was then extracted with
ether. The combined organic layers were next dried (MgSO4),
filtered, and concentrated in vacuo. The crude product was purified
by column chromatography (pentane:triethylamine, 95:5) to yield
Supporting Information Available: Experimental details and
characterization data for all compounds and their precursors.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO900053B
(19) Fros, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008,
10 (16), 3505.
(20) For examples supporting the electrophilic palladation pathway for direct
heteroarylation, see: (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem.
Soc. 2005, 127, 8050–8057. (b) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek,
A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159–1162. (c) Li, W.; Nelson, D. P.;
Jensen, M. S.; Hoerner, R. S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett.
2003, 5, 4835–4837.
1
the desired product 9 as a green solid (56.8 mg, 60%): H NMR
(400 MHz, CDCl3) δ 8.40 (1H, d, J ) 8.8 Hz), 7.71 (1H, dd, J )
7.6 Hz, J ) 1.6 Hz), 7.65-7.62 (2H, m), 7.56-7.38 (6H, m), 7.26
J. Org. Chem. Vol. 74, No. 8, 2009 3061