Predictable and site-selective functionalization of poly(hetero)arene compounds by palladium catalysis

Article abstract of DOI:10.1021/jo102081a

The challenge of achieving selective and predictable functionalizations at C-H bonds with complex poly(hetero)aromatic substrates was addressed by two different approaches. Site-selectivity can be obtained by applying various reaction conditions that are (hetero)arene specific to substrates that contain indoles, pyridine N-oxide, and polyfluorinated benzenes. An experimental classification of electron-rich heteroarenes based on their reactivity toward palladium-catalyzed C-Hfunctionalization was established, the result of which correlated well with the order of reactivity predicted by the DFT-calculated concerted metalation-deprotonation (CMD) pathway. Model substrates containing two reactive heteroarenes were then reacted under general reaction conditions to demonstrate the applicability this reactivity chart in predicting the regioselectivity of the palladium-catalyzed direct arylation and benzylation reactions.

Full text of DOI:10.1021/jo102081a

pubs.acs.org/joc
Predictable and Site-Selective Functionalization of Poly(hetero)arene
Compounds by Palladium Catalysis
David Lapointe,* Thomas Markiewicz, Christopher J. Whipp, Amy Toderian, and
Keith Fagnou†
Center for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa,
10 Marie Curie, Ottawa ON K1N 6N5, Canada
dlapo063@uottawa.ca
Received October 23, 2010
The challenge of achieving selective and predictable functionalizations at C-H bonds with complex
poly(hetero)aromatic substrates was addressed by two different approaches. Site-selectivity can be
obtained by applying various reaction conditions that are (hetero)arene specific to substrates that
contain indoles, pyridine N-oxide, and polyfluorinated benzenes. An experimental classification of
electron-rich heteroarenes based on their reactivity toward palladium-catalyzed C-H functionaliza-
tion was established, the result of which correlated well with the order of reactivity predicted by the
DFT-calculated concerted metalation-deprotonation (CMD) pathway. Model substrates contain-
ing two reactive heteroarenes were then reacted under general reaction conditions to demonstrate the
applicability this reactivity chart in predicting the regioselectivity of the palladium-catalyzed direct
arylation and benzylation reactions.
Introduction
of some organometallic substrates.1 With the prevalence of
multiple arenes, aromatic heterocycles as well as biaryl
linkages in medicinally relevant molecules (Figure 1), effi-
cient methods to directly functionalize complex poly(hetero)-
arenes through transition-metal catalysis would be of great
value.
A large number of arenes have been functionalized by
direct arylation and alkylation methods, including a wide
variety of electron-rich, electron-deficient, and simple
(hetero)arenes.1 The substrate scopes for the arylation of
Transition-metal-catalyzed direct functionalization of
(hetero)arene C-H bonds has emerged in the past decade
as a rapidly broadening and increasingly viable alternative to
traditional cross-coupling reactions. In these reactions, the
organometallic coupling partner used in conventional cross-
coupling methods is replaced by a simple arene, thus minimizing
the number of synthetic steps prior to the cross-coupling event
and avoiding the limitations associated with the preparation
(1) (a) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.-N.;
Lazareva, A. Synlett 2006, 3382. (b) Campeau, L.-C.; Fagnou, K. Chem.
Commun. 2006, 1253. (c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev.
2007, 107, 174. (d) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36,
1173. (e) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200. (f ) Campeau, L.-C.;
Stuart, D. R.; Fagnou, K. Aldrichim. Acta 2007, 40, 35. (g) Li, B.-J.; Yang,
S.-D.; Shi, Z.-J. Synlett 2008, 949. (h) Kakiuchi, F.; Kochi, T. Synthesis 2008,
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2009, 48, 5094. (k) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 24, 4087.
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Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (n) Roger,
J.; Gottumukkala, A. L.; Doucet, H. ChemCatChem 2010, 2, 20.
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Chen, B. J. Med. Chem. 2009, 52, 7503. (b) Gavai, A. V.; Fink, B. E.; Fairfax,
D. J.; Martin, G. S.; Rossiter, L. M.; Holst, C. L.; Kim, S.-H.; Leavitt, K. J.;
Mastalerz, H.; Han, W.-C.; Norris, D.; Goyal, B.; Swaminathan, S.; Patel,
B.; Mathur, A.; Vyas, D. M.; Tokarski, J. S.; Yu, C.; Oppenheimer, S.;
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J. Med. Chem. 2009, 52, 6527. (c) Brak, K.; Kerr, I. D.; Barrett, K. T.; Fuchi,
N.; Debnath, M.; Ang, K.; Engel, J. C.; McKerrow, J. H.; Doyle, P. S.;
Brinen, L. S.; Ellman, J. A. J. Med. Chem. 2010, 53, 1763. (d) Lumeras, W.;
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DOI: 10.1021/jo102081a
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Published on Web 12/01/2010
J. Org. Chem. 2011, 76, 749–759 749
2010 American Chemical Society

Lapointe et al.
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arylated in the presence of electron-rich arenes by applying
mild (hetero)arene specific conditions. In contrast, electron-
rich arenes can also be selectively arylated in the presence of
electron-deficient (hetero)arenes by applying different mild
(hetero)arene specific conditions. In parallel, we establish the
first reactivity chart for a range of heteroarenes based on
their relative reactivity toward C-H functionalization. This
reactivity chart is in good agreement with the predicted reactivity
obtained from the concerted metalation-deprotonation (CMD)
barriers of activation calculated by DFT.5 From this, we
demonstrate that by using general/nonspecific conditions,
we can predict the outcome of the C-H bond functionaliza-
tion with substrates containing two reactive C-H bonds on
two different electron-rich heteroarenes.
Results and Discussion
Conditions-Based Site-Selectivity. Our attention was first
directed toward the use of mild reaction conditions selective
for specific classes of (hetero)arenes. In a previous report,6
6- and 7-azaindoles were selectively functionalized at either the
azine or the azole rings by utilizing two specific sets of mild
conditions, one which was developed to functionalize azine
N-oxides7 and another set that was developed by Larrosa
et al.8 to arylate at the C2 position of indoles. We envisioned
extending the scope of conditions-based selectivity to include
perfluorinated arenes.9 We also opted to employ additional
site-selective conditions such as Gaunt’s Cu-catalyzedmethod
for the C3 arylation of indoles10 and the conditions devel-
oped for the palladium-catalyzed C2 arylation of pyridine
N-oxides using aryl triflates.7b
Preliminary test reactions showed that the targeted con-
ditions were specific for their respective class of substrates,
although of the two electron-poor arenes we investigated
(i.e., the pentafluorobenzene and the pyridine N-oxide), the
polyfluorinated arene reacted preferentially over the pyr-
idine N-oxide regardless of the conditions. Consequently,
substrates 1 to 5 (Table 1) were prepared using known direct
arylation methods in order to test the site-selectivity of the
various sets of conditions with actual substrates containing
two different (hetero)arenes.11
FIGURE 1. Examples of drugs and drug candidates containing
multiple functionalizable C-H bonds.2
electron-deficient and simple (hetero)arenes are often limited
to either a specific heteroarene or a set of chemically similar
(hetero)arenes. For electron-rich heteroarenes, however, two
general direct arylation methods capable of accommodating
a large range of arenes have been developed.3,4 The condi-
tions reported by Daugulis et al. employed a palladium
acetate/adamantylphosphine precatalyst to couple aryl
chlorides with a variety of electron-rich heteroarenes.3 The
method our group developed was based on advances made
on the functionalization of simple arenes employing pivalate
additives to increase the reactivity of the system.4 To date,
there have been very few reports, if any, on the direct function-
alization of complex substrates containing multiple (hetero)-
arenes and functionalizable at multiple C-H bonds, similar
to the examples depicted in Figure 1.
The underlying challenges of functionalizing complex
substrates containing multiple reactive C-H bonds are (1)
to achieve site-selectivity in the transformation by choosing
the appropriate conditions and (2) to predict the outcome of
the transformation when general/nonspecific conditions are
applied. Being able to select and/or predict the outcome of
such reactions would greatly improve the applicability of
C-H bond functionalization methods in the late stage of the
synthesis of biologically active analogues. As part of a program
dedicated to site-selective functionalization of aromatic C-H
bonds, we were interested in addressing these challenges.
Herein, we present a systematic evaluation of reaction
conditions and heteroarene reactivity to obtain selective and
predictable functionalization at various positions on sub-
strates containing multiple functionalizable C-H bonds. We
show that electron-deficient (hetero)arenes can be selectively
Gratifyingly, we were able to selectively arylate each of the
molecules at the desired position in the presence of other
potentially reactive site(s). Starting with substrate 1, bearing
an electron-rich indole ring and an electron-deficient per-
fluorinated arene ring, we achieved the selective arylation at
(5) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
10848.
(6) Huestis, M. P.; Fagnou., K. Org. Lett. 2009, 11, 1357.
(7) (a) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle,
M.; Villemure, E.; Sun, H.-Y.; Laserre, S.; Guimond, N.; Lecavallier, M.;
Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291. (b) Schipper, D. J.; El-Salfiti,
M.; Whipp, C. J.; Fagnou, K. Tetrahedron 2009, 65, 4977. (c) Schipper, D. J.;
Campeau, L.-C.; Fagnou, K. Tetrahedron 2009, 65, 3155. (d) Campeau
L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3266.
(e) Campeau, L.-C.; Bertrand-Laperle, M.; Leclerc, J.-P.; Villemure, E.;
Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3276. (f ) Leclerc
J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45, 7781. (g) Campeau, L.-C.;
Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020.
(8) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926.
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(9) (a) Rene, O.; Fagnou, K. Org. Lett. 2010, 12, 2116. (b) Lafrance, M.;
Shore, D.; Fagnou, K. Org. Lett. 2006, 8, 5097. (c) Lafrance, M.; Rowley,
C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754.
(10) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 8172.
(3) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449.
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(4) (a) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K.
J. Org. Chem. 2009, 74, 1826. (b) Liegault, B.; Petrov, I.; Gorelsky, S. I.;
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Fagnou, K. J. Org. Chem. 2010, 75, 1047.
(11) See the Supporting Information for details.
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TABLE 1. Site-Selective Direct Arylation Based on Mild
(Hetero)arene Specific Conditions
position of the indole to give the arylated product 9 in 53%
(entry 5, Table 1) and the C3 arylated indole 11 in 55% (entry 7,
Table 1). Unfortunately, we were not able to functionalize
both the C2 and C3 positions of the indole when we used
substrate 3 containing an unactivated azine in place of the
activated azine N-oxide (entries 6 and 8, Table 1).12 We
believe that the pyridine moiety in 3 coordinated the metals
and potentially formed a stable metallacycle with the adja-
cent ring, which would prevent any further reaction. Also,
the C2 position of the pyridine N-oxide 2 could also be
functionalized selectively to afford 13 in 24% yield using an
aryl bromide (conditions E);7a,g however, the yield could be
increased to 51% when an aryl triflate was used instead
(conditions F)7b (entries 9 and 10, Table 1, respectively).
Substrate 4, which contains both a polyfluorinated phenyl
group and a pyridine N-oxide, was found to be incompatible
with conditions C. However, substrate 5, which contains a
nonactivated pyridine, reacted with the perfluorinated ring
affording product 15 in 85% yield (entries 11 and 12, Table 1).
For all the examples presented using the conditions-based
site-selectivity approach, we only isolated the targeted regio-
isomer each time, and generally, the remaining mass balance
was recovered starting material and/or decomposition prod-
ucts. Even though we cannot rule out the formation of
undesired regioisomers in small amounts, the examples shown
in Table 1 demonstrate the applicability of this approach. It
would also be beneficial to further expand the breath of the
known reaction conditions that are (hetero)arene selective.
Predicted Selectivity with the DFT-Calculated CMD Path-
way. The second main challenge with the selective function-
alization of polyaromatic compound is to be able to predict
the outcome of a reaction when two (or more) different C-H
bonds can react under the same reaction conditions.
In a combined experimental and computational study, we
demonstrated that for a wide range of electron-poor, -neutral,
and -rich (hetero)arenes which undergo direct arylation reac-
tions catalyzed by a PdII/carboxylate combination, the most
accessible pathway for the C-H bond cleavage was the
concerted metalation-deprotonation (CMD) pathway
(Scheme 1).5,13 Computationally, the CMD pathway was
able to accurately predict the regioselectivity observed ex-
perimentally for the palladium-catalyzed direct arylation of
each (hetero)arene evaluated. In addition to accurately pre-
dicting the site-selectivity on individual arenes, the calculated
barriers of activation for the CMD mechanism should also
reflect the relative reactivity of the various studied arenes. As
a result, one could utilize these values to determine the site-
selectivity of a reaction where two or more heteroarenes are
present on a single substrate.
aConditions A8 (Larrosa’s protocol): indole (1.0 equiv), aryl iodide
(2.0 equiv), Pd(OAc)2 (5 mol %), 2-nitrobenzoic acid (1.5 equiv),
Ag2O (0.75 equiv) in DMF (0.5 M) at 45 °C. Conditions B10 (Gaunt’s
protocol): indole (1.0 equiv), diaryliodonium triflate (1.3 equiv), Cu-
(OTf)2 (10 mol %), 2,6-di-tert-butylpyridine (1.0 equiv) in DCM (0.1 M)
at 50 °C. Conditions C:9b perfluorinated arene (1 equiv), aryl bromide
(1.0 equiv), Pd(OAc)2 (5 mol %), SPhos (10 mol %), PivOH (30 mol %),
K2CO3 (2 equiv) in isopropyl acetate (1.0 M) at 80 °C; Conditions D:9a
perfluorinated arene (1 equiv), aryl iodide (1.1 equiv), Pd(OAc)2
(5 mol %), MePhos (10 mol %), Ag2CO3 (0.50 equiv), K2CO3 (2 equiv)
in ethyl acetate/water (2.5:1, 0.35 M) at ambient temperature. Condi-
tions E:7a,g pyridine N-oxide (1.0 equiv), aryl bromide (1.5 equiv),
Pd(OAc)2 (5 mol %), PtBu3 HBF4 (15 mol %), K2CO3 (2 equiv) in
3
toluene (0.30 M) at reflux. Conditions F:7b pyridine N-oxide (1.0 equiv),
aryl triflate (2.0 equiv), Pd(OAc)2 (5 mol %), PtBu2Me HBF4
3
(10 mol %), PivOH (30 mol %), K2CO3 (2 equiv) in toluene (0.50 M)
at reflux. bNo reaction observed.
To evaluate experimentally the accuracy of the site-selec-
tivity prediction obtained from the calculated CMD barrier
of activation,5 a series of competition experiments were
the C2 position of the indole ring to yield product 6 in 65%
yield (entry 1, Table 1) using Larrosa’s protocol8 (conditions A).
Starting from the same substrate (1), the C3 position of the
indole ring was arylated to give 7 in 64% yield (entry 2,
Table 1) using Gaunt’s Cu-catalyzed protocol10 (conditions B).
Using two different sets of conditions developed in our
group9 (conditions C9b and D9a), we were able to selectively
arylate the fluorinated arene 1 using both an aryl bromide
and an aryl iodide affording 8 in acceptable yields of 54%
and 58%, respectively (entries 3 and 4, Table 1). Similarly,
compound 2 could be selectively functionalized at the C2
(12) Contrary to the report on azaindoles (see ref 6), in which the
functionalization of the azole ring gave better yields when the unactivated
azine ring was used compared to the yields obtained when the azine ring was
activated as the N-oxide.
(13) For a review on the mechanistic work done on the CMD mechanism,
see: (a) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118. For the
ꢀ
seminal mechanistic studies in catalytic settings, see: (b) Gonzalez, J. J.;
ꢀ
Garcıa, N.; Gomez-Lor, B.; Echavarren, A. M. J. Org. Chem. 1997, 62, 1286.
´
(c) Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem.
Soc. 2004, 126, 9186. (d) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K.
J. Am. Chem. Soc. 2006, 128, 581. (e) Garcıa-Cuadrado, D.; Braga, A. A. C.;
´
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066.
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SCHEME 1. Example of the CMD Transition State in a Direct
Arylation Reaction
be reliable.4a The results of these competitions are summar-
ized in Figure 1, and the theoretical product distributions are
shown in parentheses. The theoretical values were obtained
using the difference in free energy of activation (ΔΔGq) at
373 K for each substrate. In addition, it is important to
mention that we have limited our study mostly to hetero-
cycles that were previously examined computationally and
restricted our attention to their single most reactive C-H
bond instead of examining the reactivity of each potentially
reactive position.
performed using a range of electron-rich heteroarenes to
determine their relative reactivity. The competition experi-
ments consisted of measuring the product distribution using
19F NMR spectroscopy14 in the reaction of p-CF3-bromo-
benzene (0.125 equiv) with two heteroarenes (0.5 equiv each),
using palladium acetate (5 mol %) and tricyclohexylpho-
sphonium tetrafluoroborate (10 mol %) as the precatalyst,
pivalic acid (30 mol %) as a rate enhancing additive and
potassium carbonate (1.5 equiv) as the base in N,N-dimethy-
lacetamide (0.3 M) at 100 °C. These conditions have already
been proven to be applicable for the direct arylation of a wide
variety of electron-rich heteroarenes and have been shown to
The aim of this reactivity chart (Figure 2) is to obtain a
comprehensive estimate of the reactivity for a range of
heteorarenes regardless of the effects of the substituents in
order to apply it to the functionalization of complex sub-
strates. With substrates for which the CMD barrier of
activation have been calculated by DFT,5 we can see that
the computationally predicted site-selectivity accurately
matches the selectivity observed experimentally. Moreover,
considering the sum of the various approximations made in
the DFT calculations (such as ligand and solvent approx-
imations and the lack of substituents on the heteroarenes)
and the inherent experimental variability of these competition
FIGURE 2. Relative reactivity of various heteroarenes toward direct arylation. (a) Conditions: heteroarene 1 (0.50 equiv), heteroarene
2 (0.50 equiv), 4-bromotrifluorotoluene (0.125 equiv), Pd(OAc)2 (5 mol %), PCy3 HBF4 (10 mol %), PivOH (30 mol %), K2CO3 (1.5 equiv) in
3
DMA (0.3 M) at 100 °C. (b) Experimental product ratios (19F NMR) in parentheses are the theoretical product ratios obtained from DFT-
calculated barriers of activation of the CMD pathway.5
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TABLE 2. Direct Arylation of Aromatic Heterocyclesa
reactions (e.g., the choice of reactions conditions, high
volatility, or low solubility of some heteroarenes and the
precision of the product peak integration), a good overall
agreement between the experimental and theoretical results
was observed. Imidazopyrimidine (A) and thiazoles (B) were
the most reactive substrates, which is in agreement with the
DFT-predicted reactivity. The presence of C2 substituents
on thiazole (B) had a significant effect on the reactivity.
Indeed, 2-phenylthiazole reacted 2.5 times faster than the
2-isobutylthiazole (B2-Ph vs B2-i-Bu), although the difference
in the reactivity of the two analogues remains relatively small
so that the general order of reactivity of the heteroarenes
is not affected. Similarly, the effect of substituents at the
C2 position of indolizine (C) has been reported previously
by Gevorgyan et al. in the context of mechanistic studies,
where the authors found small reactivity changes when the
2-methyl is abstracted or replaced by an ester functionality.15
Furthermore, the relative reactivity of N-benzyl-1,2,3-tria-
zole (D) has not been evaluated computationally, but was
found experimentally to be situated in between the indolizine
(C) and the benzothiophene (E). Finally, benzothiophene
(E), thiophene (F), and furan (G) were the least reactive
substrates that were evaluated, conforming with the DFT
predictions.16
With the results of these competitions in hand, our efforts
were directed toward using them as a reactivity guideline in
the functionalization of model substrates bearing two poten-
tially reactive heteroarenes. We first prepared substrate 16
(Table 2) to test the difference in reactivity between the C5
C-H bond of 2-arylthiazole and the C5 C-H bond of C2-
substituted furan. We chose to use a slight excess (1.1 equiv)
of 16 in the reaction in order to limit the formation of double
arylation product that we observed in our initial attempts
(∼10 mol %) using equimolar amounts of both coupling
partners. Although this is not the ideal reagent to use in
excess, the formation of double arylation product is very
undesirable since it results in the consumption of both the
desired final product and the starting aryl bromide partner.
Moreover, the unreacted starting material could, in principle, be
recovered at the end of the reaction. Using the conditions of the
general method of direct arylation developed by our group4
with 1.1 equiv of 16, we were able to isolate the monoarylated
product 20 in 80% yield (entry 1, Table 2), the double
arylation was still observed in approximately 5 mol %.
Substrate 16 could also be sequentially and selectively func-
tionalized with two different aryl bromides, and the thiazole
moiety was first selectively functionalized with methyl
p-benzoate to afford 17 in 69% yield, followed by a second
arylation at the furan ring with a p-tolyl bromide yielding the
aConditions: bis-heteroarene (1.1 equiv), aryl bromide (1.0 equiv),
Pd(OAc)2 (5 mol %), PCy3 HBF4 (10 mol %), PivOH (30 mol %),
3
K2CO3 (1.5 equiv), DMA (0.3 M), 100 °C. bBis-heteroarene (1.0 equiv),
aryl bromide (1.2 equiv).
highly conjugated product 21 in 76% yield (entries 2 and 3,
Table 2). Similarly, a substrate containing both an imidazo-
pyrimidine ring and a N-aryl-1,2,3-triazole (18) was pre-
pared. The imidazopyrimidine ring could be selectively
functionalized in an acceptable yield (65%, entry 4, Table 2).
Lastly, the combination of an indolizine arene and a thio-
phene was also evaluated. As expected, substrate 19 was
selectively functionalized in 75% yield on the indolizine
arene (entry 5, Table 2).
The reactivity guidelines we established in Figure 2 can
also be used for other types of C-H bond functionalization
reactions, since the relative reactivity of the heteroarenes was
based on the C-H bond cleaving step and should not be
affected significantly by the nature of the coupling partner.
To illustrate this point, we applied these guidelines for the
benzylation of bis-heteroarene 24, 18, and 19, shown in Table 3.
From 24, we were able to selectively benzylate the C5
position of the thiazole arene in 69% yield using a slightly
modified variation of previously reported conditions (entry 1,
Table 3).17 For this reaction, the bis-heteroarene was used in
slight excess (1.1 equiv) compared to the benzyl chloride in
order to minimize formation of the double-benzylation
products. Alternatively, the direct benzylation of substrates
24, 18, and 19 could also be achieved in acceptable yields
(entries 2-4, Table 3) using Pd(OAc)2/PPh3 as precatalyst
and potassium carbonate since they are easily accessible and
cheaper compared to the reagents previously employed
(palladium pivalate, 2-Ph2P-20-(Me2N)biphenyl, and cesium
carbonate).
(14) For examples of studies utilizing p-trifluromethylphenyl groups and
19F NMR spectroscopy, see: (a) Geyer, A. M.; Wiedner, E. S.; Gary, J. B.;
Gdula, R. L.; Kuhlmann, N. C.; Johnson, M. J. A.; Dunietz, B. D.; Kampf,
J. W. J. Am. Chem. Soc. 2008, 130, 8984. For other recent examples of
mechanistic studies utilizing 19F NMR spectroscopy, see: (b) Viciu, M. S.;
Gupta, L.; Collum, D. B. J. Am. Chem. Soc. 2010, 132, 6361. (c) De Vries,
T. S.; Goswami, A.; Liou, L. R.; Gruver, J. M.; Jayne, E.; Collum, D. B.
J. Am. Chem. Soc. 2009, 131, 13142. (d) Gupta, L.; Hoepker, A. C.; Singh,
K. J.; Collum, D. B. J. Org. Chem. 2009, 74, 2231.
Conclusion
(15) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan,
V. Org. Lett. 2004, 6, 1159.
In this paper, we showed that the site-selective direct
arylation of substrates containing two different classes of
(16) As one of our reviewers pointed out, a close examination of the
various product ratios reveals that the ratios are not always cumulative when
the reactivity of the heteroarenes are compared. Certainly, it is a very
interesting observation, and it would be worth examining in detail; however,
at the moment we cannot propose an explanation.
(17) Lapointe, D.; Fagnou, K. Org. Lett. 2009, 11, 4160.
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TABLE 3. Benzylation of Aromatic Heterocyclesa
(60 mg, 0.268 mmol, 1 equiv), (4-methylphenyl)(2,4,6-triisopropyl-
phenyl)iodonium triflate (180 mg, 0.2942 mmol, 1.1 equiv),
Cu(OTf) (10.8 mg, 0.026 mmol, 10 mol %), and 4-methyl-2,6-di-
tert-butylpyridine (62 mg, 0.294 mmol, 1.1 equiv). 1,2-Dichlor-
oethane (DCE, 3 mL) was added via syringe. The reaction was
stirred for 24 h at 50 °C. The crude product was filtered through
a plug of silica gel, and the solvent was removed under reduced
pressure. The crude residue was purified by silica gel chroma-
tography using 2% methanol in dichloromethane. 2-(3-(4-
(Methoxycarbonyl)phenyl)-1-methyl-1H-indol-5-yl)pyridine
1-oxide (11) was isolated as a pale brown solid in 55% yield.
Procedure for Conditions C (Table 1)9b. In a 2 mL screw cap
vial were added potassium carbonate (104 mg, 0.750 mmol,
1.5 equiv), SPhos (20.5 mg, 0.050 mmol, 10 mol %), N-methyl-
5-(2,3,5,6-tetrafluorophenyl)indole (1) (139.7 mg, 0.500 mmol,
1 equiv), pivalic acid (15.3 mg, 0.150 mmol, 0.3 equiv), and
palladium(II) acetate (5.6 mg, 0.025 mmol, 5 mol %). The vial
was purged with argon before a solution of ethyl 4-bromo-
benzoate (172 mg, 0.75 mmol, 1.5 equiv) in isopropyl acetate
(1 mL, 0.5 M) was added via syringe. The reaction was stirred for
15 h at 80 °C. The crude product was filtered through Celite, and
the solvent was removed under reduced pressure. The crude
residue was purified by silica gel chromatography using 5%
ether in petroleum ether. Ethyl N-methyl-5-(2,3,5,6-tetrafluoro-
40-carboxylatebiphenyl-4-yl)indole (8) was isolated as a white
solid in 54% yield.
aConditions: bis-heteroarene (1.1 equiv), benzyl chloride (1.0 equiv),
Pd(OAc)2 (5 mol %), PPh3 (10 mol %), PivOH (20 mol %), K2CO3
(1.5 equiv) in toluene (0.5 M) at 110 °C. bBis-heteroarene (1.1 equiv),
benzyl chloride (1.0 equiv), Pd(OPiv)2 (2 mol %), 2-Ph2P-20-(Me2N)-
biphenyl (4 mol %), PivOH (20 mol %), Cs2CO3 (1.5 equiv) in toluene
(0.5 M) at 110 °C.
Procedure for Conditions D (Table 1)9a. In a 2 mL screw cap
vial were added potassium carbonate (83 mg, 0.60 mmol,
2 equiv), silver carbonate (41 mg, 0.15 mmol, 0.5 equiv), MePhos
(10.9 mg, 0.030 mmol, 10 mol %), palladium(II) acetate (3.4 mg,
0.015 mmol, 5 mol %), N-methyl-5-(2,3,5,6-tetrafluorophenyl)-
indole (1) (83.8 mg, 0.30 mmol, 1 equiv), and ethyl 4-iodobenzo-
ate(91mg, 0.33 mmol, 1.1 equiv). The vial was purgedwithargon,
and 0.6 mL of ethyl acetate and 0.3 mL of water (0.35 M in total)
were added via syringe. The reaction was stirred for 15 h at
ambient temperature. The crude product was filtered through
Celite, and the solvent was removed under reduced pressure. The
crude residue was purified by silica gel chromatography using 5%
ether in petroleum ether. Ethyl N-methyl-5-(2,3,5,6-tetrafluoro-
40-carboxylatebiphenyl-4-yl)indole (8) was isolated as a white
solid in 58% yield.
arenes was possible using mild methods developed for spe-
cific types of arenes. In addition, the results of competition
reactions among electron-rich heteroarenes allowed for the
first experimental classification of these heteroarenes based
on their reactivities toward C-H bond functionalization.
The presented order of reactivity of those heteroarenes was
in good agreement with the order predicted by the DFT-
calculated concerted metalation-deprotonation (CMD)
pathway promoted by palladium/carboxylate complexes.
Importantly, the ability to achieve predictable and selective
C-H bond functionalization (without organometallic pre-
activation) of more challenging substrates was achieved,
which will serve to be an invaluable tool given the demand
of the preparation of these types of molecules. Continued
studies toward a better understanding of the relationship
between substituents and their effect on substrate reactivity
should be pursued to ultimately help achieve the establish-
ment of a comprehensive set of predictive guidelines for the
C-H bond functionalization of an even broader scope of
heteroarenes.
Procedure for Conditions E (Table 1)7a,g. In a round-bottom
flask equipped with a condenser and a stir bar were added
potassium carbonate (83 mg, 0.6 mmol, 2.0 equiv), tri-tert-
butylphosphonium tetrafluoroborate (11.2 mg, 0.045 mmol,
15 mol %), palladium(II) acetate (3.4 mg, 0.015 mmol, 5 mol %),
2-(N-methylindol-5-yl)pyridine N-oxide (2) (66 mg, 0.294 mmol,
1 equiv), and pivalic acid (9.2 mg, 0.09 mmol, 0.3 equiv). The
condenser was fitted with a septum and purged with argon
before a solution of 5-bromo-m-xylene (82 mg, 0.45 mmol,
1.5 equiv) in toluene (1 mL, 0.3 M) was added. The septum was
heated to reflux (∼115 °C) and stirred for 18 h. Upon cooling,
the reaction was diluted with dichloromethane and filtered over
Celite. The filtrate was concentrated, and the residues were
purified by silica gel chromatography using 3% methanol and
5% acetone in chloroform as the eluent. 2-(3,5-Dimethylphenyl)-
6-(N-methylindol-5-yl)pyridine N-oxide (13) was isolated as an
off-white solid in 24% yield. The poor yield could be explained
by the decomposition of the final product on silica gel as
mentioned in the previous report.7g
Experimental Section
Procedure for Conditions A (Table 1)8. In a 2 mL screw cap vial
were added silver(I) oxide (87 mg, 0.375 mmol, 0.75 equiv),
2-nitrobenzoic acid (125 mg, 0.750 mmol, 1.5 equiv), N-methyl-
5-(2,3,5,6-tetrafluorophenyl)indole (1) (139.7 mg, 0.50 mmol,
1 equiv), palladium(II) acetate (5.6 mg, 0.025 mmol, 5 mol %),
and 4-iodotoluene (164 mg, 0.75 mmol, 2.0 equiv). The vial was
purged with argon before DMF (1 mL) was added via syringe.
The reaction was allowed to run for 15 h at 45 °C. The crude
product was filtered through a plug of silica gel, and the solvent
was removed under reduced pressure. The crude residue was
purified by silica gel chromatography using 2% ether in petro-
leum ether. N-Methyl-5-(2,3,5,6-tetrafluorophenyl)-2-p-tolylindole
(6) was isolated as a white solid in 64% yield.
Procedure for Conditions F (Table 1)7b. In a 2 mL screw cap
vial were added palladium(II) acetate (3.5 mg, 0.016 mmol,
5 mol %), pivalic acid (9.6 mg, 0.094 mmol, 0.3 equiv), potas-
sium carbonate (86 mg, 0.624 mmol, 2 equiv), di-tert-butyl-
methyl phosphonium tetrafluoroborate (7.7 mg, 0.031 mmol,
10 mol %), and 2-(N-methylindol-5-yl)pyridine N-oxide (2) (70 mg,
0.31 mmol, 1 equiv). The vial was purged with argon before a
stock solution of 3,5-dimethylphenyl trifluoromethanesulfonate
Procedure for Conditions B (Table 1)10. In a 4 mL screw
cap vial were added 2-(N-methylindol-5-yl)pyridine N-oxide (2)
754 J. Org. Chem. Vol. 76, No. 3, 2011

Lapointe et al.
JOCFeatured Article
(119 mg, 0.47 mmol, 1.5 equiv) in toluene (1.1 mL, 0.3 M) was
added. The reaction was heated to 110 °C and stirred overnight.
Upon cooling, the reaction was diluted with dichloromethane
and filtered over Celite. The filtrate was concentrated and the
residues were purified by silica gel chromatography using 3%
acetone in chloroform as the eluent. 2-(3,5-Dimethylphenyl)-
6-(N-methylindol-5-yl)pyridine N-oxide (13) was isolated as an
off-white solid in 51% yield.
General Procedure for the Direct Arylation of Heterocycles.
Pd(OAc)2 (5 mol %), tricyclohexylphosphonium tetrafluorobo-
rate (10 mol %), K2CO3 (1.5 equiv), and PivOH (30 mol %) were
weighed to air and placed in a screw-cap vial equipped with a
magnetic stir bar. The heterocycle (1.1 equiv) and the aryl bromide
(1.0 equiv), if a solid, were then added. The vial was purged with
argon, and a solution of the coupling partners, if liquid, in
dimethylacetamide (DMA) (0.3 M) was added to the mixture.
The reaction mixture was then stirred vigorously at 100 °C for 16 h.
The solution was then cooled to ambient temperature and loaded
directly on the column or was diluted with ethyl acetate, filtered,
and evaporated under reduced pressure. The crude product was
purified by silica gel column chromatography to afford the
corresponding product.
General Procedure for the Direct Benzylation of Heterocycles.
Pd(OAc)2 (5 mol %), triphenylphosphine (10 mol %), K2CO3
(1.5 equiv), and PivOH (20 mol %) were weighed in air and
placed in a screw-cap vial equipped with a magnetic stir bar. The
heterocycle (1.1 equiv) was then added at that point. The vial
was purged with argon, and a solution of the benzyl chloride
(1.0 equiv) in toluene (0.5 M) was added to the mixture. The
reaction mixture was then stirred vigorously at 110 °C for 16 to
24 h. The solution was then cooled to ambient temperature,
diluted with ethyl acetate, filtered, and evaporated under reduced
pressure. The crude product was purified by silica gel column
chromatography to afford the desired product.
General Procedure for the Competition Experiments. Pd(OAc)2
(6.7 mg, 0.030 mmol, 5 mol %), tricyclohexylphosphonium tetra-
fluoroborate (22.1 mg, 0.060 mmol, 10 mol %), K2CO3 (124 mg,
0.90 mmol, 1.5 equiv), and PivOH (18.4 mg, 0.18 mmol, 30 mol %)
were weighed in air and placed in a screw-cap vial equipped with a
magnetic stir bar. The heteroarenes (0.30 mmol, 0.5 equiv each), if a
solid, were then added at that point. The vial was purged with argon,
and a solution of the p-CF3-bromobenzene (16.9 mg, 0.075 mmol,
0.125 equiv) and the heteroarenes (0.30 mmol, 0.5 equiv each),
if liquid, in dimethylacetamide (2.0 mL, 0.3 M) was added to the
mixture. The reaction mixture was then stirred vigorously at 100 °C
overnight. The solution was then cooled to ambient temperature
and then filtered and evaporated under reduced pressure. The
remaining solvent was then removed under reduced pressure using
a Kugelrohr apparatus. The crude mixture was then analyzed by 19F
NMR spectroscopy.
(dd, J = 8.7, 1.9 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.04 (d, J =
3.1 Hz, 1H), 6.41 (dd, J = 3.1, 0.8 Hz, 1H), 3.76 (s, 3H).
N-methyl-5-(2,3,5,6-tetrafluorophenyl)indole (1). In a 4 mL
screw cap vial were added potassium carbonate (658 mg, 4.76 mmol,
2 equiv), SPhos (98 mg, 0.24 mmol, 10 mol %), and palladium-
(II) acetate (26.7 mg, 0.119 mmol, 5 mol %). The vial was purged
with argon before a stock solution of 5-bromo-N-methylindole
(500 mg, 2.38 mmol, 1 equiv) in isopropyl acetate (2.4 mL) was
added. The solution was stirred for 1 min before 1,2,4,5-tetra-
fluorobenzene (1,07 g, 7.14 mmol, 3 equiv) was added. The
reaction was heated to 80 °C and stirred for 18 h. Upon cooling,
the reaction was diluted with ethyl acetate and filtered over Celite.
The filtrate was concentrated, and the residues were purified by
silica gel chromatography using 2% ether in petroleum ether as
the eluent. The product was isolated as a white solid in 52%
yield. Mp: 125-128 °C (CHCl3). Rf: 0.55 (2% ether, petroleum
ether); 1H NMR (400 MHz, CDCl3, 296K, TMS): δ 7.74-7.71
(m, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.30 (dddd, J = 8.5, 1.5, 1.5,
1.5 Hz, 1H), 7.12 (d, J = 3.1 Hz, 1H), 7.03 (dddd, J = 9.7, 9.7,
7.3, 7.3 Hz, 1H), 6.56 (dd, J = 3.1, 0.8 Hz, 1H), 3.84 (s, 3H); 13
C
NMR (100 MHz, CDCl3, 297K, TMS): δ 147.7-144.80 (m),
145.4-142.5 (m), 136.7, 129.8, 128.5, 123.3 (t, J = 1.8 Hz), 123.0
(t, J = 1.9 Hz), 122.9 (t, J = 16.7 Hz), 118.2 (t, J = 2.3 Hz),
109.4, 103.9 (t, J = 22.8 Hz), 101.6, 32.9. IR (νmax /cm-1): 2931,
1515, 1506, 1487, 1170, 931, 887, 738, 708. HRMS calcd for
C15H9F4N (Mþ) 279.0671, found 279.0665.
2-(N-Methylindol-5-yl)pyridine N-Oxide (2). In a test tube
were added potassium carbonate (214 mg, 1.55 mmol, 1.3 equiv),
tri-tert-butylphosphonium tetrafluoroborate (20.7 mg, 0.071 mmol,
10 mol %), palladium(II) acetate (13.36 mg, 0.060 mmol, 5 mol %),
and pyridine N-oxide (453 mg, 4.76 mmol, 4 equiv). The tube
was fitted with a septum and purged with argon before a
solution of 5-bromo-N-methylindole (250 mg, 1.19 mmol,
1 equiv) in toluene (4 mL, 0.3 M) was added. The septum was
covered in parafilm, and the reaction was heated to 110 °C and
stirred for 18 h. Upon cooling, the reaction was diluted with
dichloromethane and filtered over Celite. The filtrate was con-
centrated, and the residues were purified by silica gel chroma-
tography using 3% methanol and 5% acetone in chloroform as
the eluent. The product was isolated as an off-white solid in 63%
yield. Mp: 138-142 °C (CHCl3). Rf: 0.25 (3% MeOH, 5%
1
Me2CO, CHCl3). H NMR (400 MHz, CDCl3, 296K, TMS):
δ 8.35 (d, J = 5.6 Hz, 1H), 8.05 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H),
7.48 (dd, J = 7.8, 1.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.28
(dd, J = 7.6, 7.6 Hz, 1H), 7.17 (dd, J = 5.7, 5.7 Hz, 1H), 7.09
(d, J = 3.1 Hz, 1H), 6.55 (d, J = 3.1 Hz, 1H), 3.81 (s, 3H). 13C
NMR (100 MHz, CDCl3, 298K, TMS): δ 150.7, 140.6, 137.1,
129.6, 128.2, 127.6, 125.7, 123.8, 123.6, 122.8, 122.5, 109.0, 101.9,
33.0. IR (νmax /cm-1): 3102, 2948, 1606, 1513, 1476, 1421, 1339,
1245, 842, 763, 734. HRMS: calcd for C14H12N2O (Mþ)
224.0950, found 224.0930.
Synthesis and Characterization of Starting Coupling Partners.
5-Bromo-N-methylindole. the compound was synthesized fol-
lowing a literature procedure.18 To a solution of 5-bromoindole
(3.00 g, 15.3 mmol, 1 equiv) in acetone (46.0 mL, 0.33 M) cooled
to 0 °C was added freshly powdered potassium hydroxide
(4.29 g, 77 mmol, 5 equiv). After the mixture was stirred at 0 °C
for 30 min, iodomethane (4.34 g, 30.6 mmol, 2 equiv) was added
dropwise while the solution was vigorously stirred. The reaction
temperature was slowly raised to room temperature and stirred
overnight. The reaction mixture was filtered and the solvent
removed under reduced pressure. The crude product was pur-
ified by distillation on a Kugelrhor apparatus (115-125 °C) and
isolated as a pale yellow solid in 94% yield and exhibited spectral
data identical to previous reports.18 1H NMR (400 MHz,
CDCl3, 297K, TMS): δ 7.74 (dd, J = 1.9, 0.5 Hz, 1H), 7.29
N-Methyl-5-(pyridin-2-yl)indole (3). In a round-bottom flask
was dissolved the pyridine N-oxide in methanol, to the solution
was added palladium on carbon, the flask was purged with hydro-
gen gas, and the solution was vigorously stirred under hydrogen
atmosphere until the reaction was judged complete by TLC.
Alternatively, 3 was prepared by mixing in a flask equipped
with a stir bar, zinc dust <10 μm (∼4 to 5 equiv), the starting
pyridine N-oxide, and a 1:1 mixture of THF and a saturated
aqueous solution of NH4Cl. The mixture was vigorously stirred
at ambient temperature for ∼30 min. The crude was extracted
with ethyl acetate and purified by silica gel chromatography.
Pale yellow solid. Mp: 54-58 °C. Rf: 0.49 (MeOH/DCM 5/95).
1H NMR (400 MHz, CDCl3) δ 8.68 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H),
8.26 (dd, J=1.7, 0.6 Hz, 1H), 7.92 (dd, J = 8.6, 1.6 Hz, 1H),
7.78 (dt, J = 8.0, 1.1 Hz, 1H), 7.72 (ddd, J = 8.0, 7.3, 1.8 Hz,
1H), 7.40 (dt, J = 8.6, 0.7 Hz, 1H), 7.16 (ddd, J = 7.3, 4.8,
1.2 Hz, 1H), 7.08 (d, J= 3.1 Hz, 1H), 6.56 (dd, J=3.1, 0.8Hz,1H),
(18) Soll, R. M.; Parks, J. A.; Rimele, T. J.; Heaslip, R. J.; Wojdan, A.;
Oshiro, G.; Grimes, D.; Asselin, A. Eur. J. Org. Chem. 1990, 25, 191.
J. Org. Chem. Vol. 76, No. 3, 2011 755

Lapointe et al.
JOCFeatured Article
3.82 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.9, 149.6, 137.4,
136.7, 131.1, 129.7, 128.9, 121.15, 121.0, 120.5, 119.8, 109.5,
102.0, 33.1. IR (νmax /cm-1): 3086, 3002, 2939, 1583, 1512, 1462,
1422, 1341, 1304, 1247, 1150, 777, 761, 686. HRMS: calcd for
C14H12N2 (Mþ) 208.1000, found 208.0975.
to a reaction flask equipped with a magnetic stir bar. The
reaction mixture was stirred vigorously and heated to reflux
until judged complete by TLC. The solution was then evapo-
rated under reduced pressure and the crude product purified by
silica gel column chromatography in 10-20% ethyl acetate/
petroleum ether to afford 4-(furan-2-yl)-2-(3-nitrophenyl)-
thiazole (16) in 92% yield. Yellow solid. Mp: 116-118 °C. Rf:
0.47 (petroleum ether/ethyl acetate 80/20). 1H NMR (400 MHz,
CDCl3): δ 8.85 (t, J = 2.0 Hz, 1H), 8.33 (ddd, J = 7.8, 1.7, 1.0
Hz, 1H), 8.28 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 7.65 (t, J = 8.0 Hz,
1H), 7.51 (s, 1H), 7.49 (dd, J = 1.8, 0.8 Hz, 1H), 6.94 (dd, J =
3.4, 0.5 Hz, 1H), 6.53 (dd, J = 3.4, 1.8 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 165.5, 149.9, 148.8, 148.7, 142.7, 135.1, 132.3,
130.1, 124.6, 121.6, 113.0, 111.8, 107.9. IR (νmax /cm-1): 3116,
3093, 1531, 1348, 1024. HRMS: calcd for C13H8N2O3S (Mþ)
272.0256, found 272.0271.
4-(Furan-2-yl)-2-phenylthiazole (24). Synthesized using the
same procedure as compound 16, isolated in 74% yield. Orange
solid. Mp: 56-57 °C. Rf: 0.44 (petroleum ether/ethyl acetate
90/10). 1H NMR (400 MHz, CDCl3) δ 8.01-7.99 (m, 2H),
7.46-7.43 (m, 4H), 7.40 (s, 1H), 6.89 (dd, J = 3.2, 0.5 Hz, 1H),
6.50 (dd, J = 3.3, 1.8 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ 168.6, 150.4, 148.1, 142.4, 133.5, 130.3, 129.1, 126.8, 112.0,
111.7, 107.4. IR (νmax /cm-1): 3115, 3066, 3025, 1616, 1515,
1469, 1201, 1007, 763, 743, 688. HRMS: calcd for C13H9NOS
(Mþ) 227.0405, found 227.0387.
2-(2,3,5,6-Tetrafluorophenyl)pyridine (5). Pd(OAc)2 (5 mol %),
di-tert-butylmethylphosphonium tetrafluoroborate (10 mol %),
and K2CO3 (1.1 equiv) were weighed to air and placed in a screw-
cap vial equipped with a magnetic stir bar. 2-Bromopyridine
(1.0 equiv) was added at this point. The vial was purged with argon,
and a solution of 1,2,4,5-tetrafluorobenzene (3.0 equiv) in dimethy-
lacetamide (DMA) (3.0 M) was added to the mixture. The reaction
mixture was then stirred vigorously at 120 °C for 16 h. The solution
was then cooled to ambient temperature, diluted with ethyl acetate,
filtered, and evaporated under reduced pressure. The crude product
was purified by silica gel column chromatography to afford
the corresponding product. Yellow solid. Mp: 74-76 °C. Rf: 0.36
(petroleum ether/ethyl acetate 80/20). 1H NMR (400 MHz, CDCl3):
δ 8.79 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H),
7.51 (dt, J = 7.9, 1.2 Hz, 1H), 7.39 (ddd, J = 7.7, 4.9, 1.2 Hz, 1H),
7.14 (tt, JHF =9.6, 7.3 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ 150.2, 147.9, 146.3 (dddd, JCF = 248.2, 14.6, 10.2, 4.2 Hz), 144.4
(dtd, JCF = 249.5, 9.3, 5.2 Hz), 136.8, 126.0, 123.9, 120.9 (t, JCF
=
16.3 Hz), 106.2 (t, JCF = 22.6 Hz). IR (νmax /cm-1): 3032, 2926,
1590, 1572, 1511, 1499, 1297, 1198, 939. HRMS: calcd for
C11H5NF4 (Mþ) 227.0358, found 227.0349.
2-(2,3,5,6-Tetrafluorophenyl)pyridine N-Oxide (4). 2-(2,3,5,6-
Tetrafluorophenyl)pyridine (5) was dissolved in DCM (∼0.3 M),
and few milligrams of MeReO4 was added to the solution. A
50% solution of H2O2 in water (approximately 1/5 of the volume of
DCM) was added, and the mixture was stirred vigorously at
ambient temperature until the reaction was judge completed
by TLC. The solution was then extracted with ethyl acetate,
dried over anhydrous magnesium sulfate, filtered, and evapo-
rated under reduced pressure. The crude product was purified by
silica gel column chromatography to afford the corresponding
product. White solid. Mp: 167-168 °C. Rf: 0.36 (MeOH/DCM
5/95). 1H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 6.4 Hz, 1H),
7.43-7.34 (m, 3H), 7.21 (quin, J = 8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 146.3 (dm, JC-F = 252 Hz), 144.5 (dm,
2-(4-(4-Butyl-1H-1,2,3-triazole)phenyl)imidazo[1,2-a]pyrim-
idine (18). 2-Bromo-1-(4-iodophenyl)ethanone was synthesized
following the same procedure described for 2-bromo-1-(furan-
2-yl)ethanone, isolated in 72% yield. White solid. Mp: 102-
106 °C. Rf: 0.47 (petroleum ether/diethyl ether 90/10). 1H NMR
(400 MHz, CDCl3): δ 7.89-7.86 (m, 2H), 7.71-7.68 (m, 2H),
4.39 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 190.9, 138.4, 133.3,
130.4, 102.4, 30.4. IR (νmax /cm-1): 2997, 2948, 1692, 1580, 1395,
1196, 803. HRMS: calcd for C8H6NBrI (Mþ) 323.8647, found
323.8657. 2-(4-Iodophenyl)imidazo[1,2-a]pyrimidine was synthe-
sized following a literature procedure.21 In a round-bottom flask
were mixed 2-aminopyrimidine (1.0 equiv) and 2-bromo-1-(4-
iodophenyl)ethanone. Acetone (0.4 M) was added, and the
mixture was heated to reflux for 2-3 h. At this point, a sig-
nificant amount of precipitate had formed, and the mixture was
cooled down to ambient temperature and decanted. Then a 1.5:1
mixture of ethanol and water (∼0.4 M) was added to the precipitate
as well as NaHCO3 (∼1.4equiv). Theresultingsolution was heated
to 80 °C for an additional 2-3 h. The reaction mixture was then
cooled to ambient temperature and extracted with dichloro-
methane. The combined organic layers were dried over anhy-
drous magnesium sulfate, filtered, and evaporated under reduced
pressure. The crude product was purified using silica gel column
chromatography to afford 2-(4iodophenyl)imidazo[1,2-a]pyrimidine
as a pale brown solid in 50 to 78% yield. No melting point was
J
C-F = 252 Hz), 140.5, 138.5 129.2, 126.9, 124.9, 107.7 (m). IR
(νmax /cm-1): 3052, 3024, 3007, 1500, 1432, 1257, 1188, 940, 896,
763. HRMS: calcd for C11H5NOF4 (Mþ) 243.0307, found
243.0327.
4-(Furan-2-yl)-2-(3-nitrophenyl)thiazole (16). A solution of
2-acetylfuran (1.0 equiv) in ethyl acetate (0.1 M) was added to
a reaction flask equipped with a magnetic stir bar, followed by
the addition of copper(II) bromide (1.7 equiv). The reaction
mixture was then stirred vigorously and heated to reflux. When
the reaction reached completion, as judged by TLC, the reaction
mixture was allowed to cool to room temperature, filtered, and
evaporated under reduced pressure. The crude product was
purified using silica gel column chromatography to afford
2-bromo-1-(furan-2-yl)ethanone as a white solid in 70% yield.
Rf: 0.21 (petroleum ether/ethyl acetate 90/10). 1H NMR
matched the previously reported spectrum.19 1H NMR (400
MHz, CDCl3, 296 K, TMS): δ 7.65 (dd, J=1.7, 0.8 Hz, 1H),
7.35 (dd, J = 3.6, 0.8 Hz, 1H), 6.61 (dd, J=3.6, 1.7 Hz, 1H),
4.33 (s, 2H). 4-(Furan-2-yl)-2-(3-nitrophenyl)thiazole (16) was
synthesized following a literature procedure.20 To a solution of
2-bromo-1-(furan-2-yl)ethanone (1.0 equiv) and 3-nitroben-
zothioamide (1.0 equiv) in tetrahydrofuran (1.0 M) was added
1
found: ∼270 °C dec. Rf: 0.53 (MeOH/DCM 5/95). H NMR
(400 MHz; DMSO-d6): δ 8.96 (dd, J = 6.8, 1.9 Hz, 1H), 8.54 (dd,
J = 4.1, 1.9 Hz, 1H), 8.42 (s, 1H), 7.85-7.80 (m, 4H), 7.06 (dd,
J = 6.7, 4.2 Hz, 1H). 13C NMR (101 MHz; 383 K; DMSO):
δ 149.9, 144.4, 144.1, 137.1, 134.4, 132.8, 127.4, 108.4, 107.3,
93.2. IR (νmax /cm-1): 3114, 3073, 2922, 2854, 1499, 1469, 1350,
1200. HRMS: calcd for C12H8N3I (Mþ) 320.9763, found
320.9780. 2-(4-(4-Butyl-1H-1,2,3-triazole)phenyl)imidazo[1,2-a]-
pyrimidine (18) was synthesized following a literature pro-
cedure.22 In a flask equipped with a stir bar were mixed (1.0
equiv), sodium azide (1.05 equiv), CuI (10 mol %), and sodium
ascorbate (10 mol %). To this mixture was added a solution of
(19) Taikyun, R.; Lankin, M. E.; Shih, D. H.; Lankin, C. M. Synthesis of
2-(2-furoyl)-4(5)-(2-furanyl)-1H-imidazole and analogs thereof. U.S. Patent
4665192, May 1987.
(21) Rivall, Y.; Grassy, G.; Taudou, A.; Ecalle, R. J. Med. Chem. 1991,
26, 13.
(20) Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew. Chem., Int. Ed.
2007, 46, 7996.
(22) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596.
756 J. Org. Chem. Vol. 76, No. 3, 2011

Lapointe et al.
JOCFeatured Article
DMF (0.3 M) containing 1-hexyne (1.05 equiv) and N,N0-
dimethylethane-1,2-diamine (15 mol %). The mixture was stir-
red at ambient temperature until it was judged complete by
TLC. Water and dichloromethane were added to the reaction
mixture, and the aqueous layer was extracted a few times with
dichloromethane. The combined organic layers were dried over
anhydrous magnesium sulfate, filtered, and evaporated under
reduced pressure. The crude product was purified using silica gel
column chromatography to afford 18 as a pale brown solid in
82-90% yield. Pale brown solid; ∼270 °C dec.Rf: 0.20 (MeOH/
DCM 5/95). 1H NMR (400 MHz, CDCl3): δ 8.57 (dd, J = 4.1,
2.0 Hz, 1H), 8.47 (dd, J = 6.7, 2.0 Hz, 1H), 8.20-8.15 (m, 2H),
7.89 (s, 1H), 7.84-7.81 (m, 2H), 7.77 (s, 1H), 6.90 (dd, J = 6.7,
4.1 Hz, 1H), 2.82 (t, J = 7.7 Hz, 2H), 1.74 (dt, J = 15.3, 7.6 Hz,
Synthesized according to the general procedure for the direct
arylation.4a White solid. Mp: 183-184 °C. Rf: 0.45 (dichloro-
methane/methanol 95/5). 1H NMR (400 MHz, CDCl3): δ 8.61 (dd,
J = 4.1, 2.0 Hz, 1H), 8.28 (dd, J = 6.9 and 2.0 Hz, 1H), 7.81 (d, J =
8.0 Hz, 2H), 7.72-7.69 (m, 2H), 7.61 (d, J= 8.0 Hz, 2H), 7.36-7.30
(m, 3H), 6.87 (dd, J = 6.9, 4.1 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 150.4, 148.3, 144.8, 133.1, 132.8, 131.2 (q, JC-F = 33.0
Hz), 131.0, 130.6, 128.6, 128.6, 128.5, 126.8 (q, JC-F = 3.7 Hz),
123.9 (q, JC-F = 272.3 Hz), 117.9, 109.1. 19F NMR (377 MHz,
CDCl3): δ -65.954. IR (νmax /cm-1): 3065, 2929, 2857, 1616, 1496,
1392, 1324, 1167, 1125, 1066, 766. HRMS: calcd for C19H12F3N3
(Mþ) 339.0983, found 339.1000.
5-(4-(Trifluoromethyl)phenyl)-2-phenylthiazole] (B2-Ph, Figure 2).
Synthesized according to the general procedure for the direct
arylation.4a Light yellow solid. Mp: 142-143 °C. Rf: 0.65
(petroleum ether/ethyl acetate 80/20). 1H NMR (400 MHz,
CDCl3): δ 8.10 (s, 1H), 8.00-7.97 (m, 2H), 7.70 (dd, J =
8.3 Hz, 4H), 7.51-7.45 (m, 3H). 13C NMR (100 MHz, CDCl3):
δ 168.6, 140.5, 137.7, 135.1, 133.5, 130.6, 130.2 (q, JC-F = 33.0 Hz),
2H), 1.45 (dq, J = 14.9, 7.4 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13
C
NMR (100 MHz, 383 K, DMSO-d6): δ 150.0, 147.9, 147.7,
144.0, 136.1, 134.4, 133.1, 126.6, 119.8, 119.3, 108.4, 107.5, 30.3,
24.2, 21.1, 12.9. IR (νmax /cm-1): 3131, 2953, 2923, 2856, 1614,
1521, 1492, 1225, 762. HRMS: calcd for C18H18N4 (Mþ - N2)
290.1531, found 290.1525.
129.2, 126.9, 126.6, 126.3 (q, JC-F = 3.7 Hz), 124.1 (q, JC-F
=
Ethyl 2-(Thiophene-2-yl)indolizine-1-carboxylate (19). (E)-Ethyl
3-(thiophene-2-yl)acrylate was synthesized following a literature
procedure.23 1H NMR of the final product matched the previously
reported spectrum.23 Light sensitive clear oil. Rf: 0.279 (petroleum
272.3 Hz). 19F NMR (377 MHz, CDCl3): δ -65.856. IR
(νmax /cm-1): 3085, 2920, 2853, 1453, 1167, 1112, 833, 764,
686, 631. HRMS: calcd for C16H10F3NS (Mþ) 305.0486, found
305.0496.
1
ether/ethyl acetate 90/10). H NMR (400 MHz, CDCl3): δ 7.78
5-(4-(Trifluoromethyl)phenyl)-2-isobutylthiazole(B2-i-Bu,Figure2).
Synthesized according to the general procedure for the direct
arylation.4a Brown oil. Rf: 0.60 (petroleum ether/ethyl acetate
80/20). 1H NMR (400 MHz, CDCl3): δ 7.92 (s, 1H), 7.64 (s, 4H),
2.90 (d, J = 7.3 Hz, 2H), 2.15 (nonet, J = 6.8 Hz, 1H), 1.03
(d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 171.2,
139.0, 137.0, 135.3, 129.9 (q, JC-F = 32.9 Hz), 126.8, 126.2
(q, JC-F = 3.7 Hz), 124.1 (q, JC-F = 271.8 Hz), 42.7, 30.0,
22.4. 19F NMR (377 MHz, CDCl3): δ -65.798. IR (νmax /cm-1):
3084, 2961, 2875, 1615, 1449, 1410, 1327, 1161, 1121, 1066, 1015,
841, 596 cm-1. HRMS: calcd for C14H14F3NS (Mþ) 285.0799,
found 285.0802.
(d, J = 15.7 Hz, 1H), 7.37 (d, J = 5.1 Hz, 1H), 7.25-7.24 (m, 1H),
7.05 (dd, J = 5.1, 3.6 Hz, 1H), 6.24 (d, J = 15.7 Hz, 1H), 4.25
(q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 166.9, 139.6, 137.1, 130.9, 128.4, 128.1, 117.1, 60.5, 14.4.
IR (νmax /cm-1): 3106, 2981, 2903, 1709, 1627, 1370, 1267, 1170,
1043, 706. HRMS: calcd for C9H10O2S (Mþ) 182.0402, found
182.0383. 1-(Carboxymethyl)pyridinium chloride was synthesized
following a literature procedure.24 To a solution of pyridine
(1.0 equiv) in ethyl acetate (0.66 M) was added R-chloroacetic acid,
and the mixture was stirred at ambient temperature overnight.
A white precipitate was formed. The solution was filtered, washed
with ethyl acetate, and dried under vacuum. The product was used
crude. 1H NMR of the final product matched the previously
reported spectrum.24 1H NMR (400 MHz; DMSO-d6): δ 9.09
(dd, J = 6.7, 1.3 Hz, 2H), 8.67 (tt, J = 7.8, 1.3 Hz, 1H), 8.20 (dd,
J = 7.8, 6.8 Hz, 2H), 5.58 (s, 2H). Ethyl 2-(thiophene-2-yl)-
indolizine-1-carboxylate (19) was synthesized following a literature
procedure.24 In a round-bottom flask equipped with a stir bar were
added 1-(carboxymethyl)pyridinium chloride (1.0 equiv), MnO2
(∼8 equiv), and 1,4-dioxane (0.25 M). To the suspension were
added triethylamine (3.0 equiv) and (E)-ethyl 3-(thiophene-2-yl)-
acrylate (4.0 equiv). The resulting mixture was stirred at 120 °C
overnight. After the mixture was cooled to ambient temperature, it
was filtered and washed with ethyl acetate. The filtrate was evapo-
rated, and the crude residue was purified by silica gel column chro-
matography. The remaining starting olefin was recovered along
with the desired product in 25% yield. Pale green and light sensitive
solid. Mp: 62-66 °C. Rf: 0.19 (petroleum ether/ethyl acetate 90/10).
1H NMR (400 MHz, CDCl3): δ 8.22 (d, J= 9.1 Hz, 1H), 7.96
(d, J= 6.8 Hz, 1H), 7.43 (dd, J= 3.6, 1.1 Hz, 1H), 7.39 (s, 1H), 7.31
(dd, J = 5.1, 1.1 Hz, 1H), 7.08 (t, J = 4.4 Hz, 1H), 7.06 (ddd, J =
9.3, 6.9, 1.0 Hz, 1H), 6.73 (td, J = 6.8, 1.1 Hz, 1H), 4.35 (q, J = 7.1
Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 164.9, 137.0, 135.7, 127.8, 127.1, 125.5, 125.4, 125.0, 122.7, 120.6,
114.2, 113.0, 101.6, 59.7, 14.6. IR (νmax /cm-1): 3111, 2979, 2903,
1696, 1507, 1437, 1419, 1237, 1218, 1103, 782. HRMS: calcd for
C15H13NO2S (Mþ) 271.0667, found 271.0697.
3-(4-(Trifluoromethyl)phenyl)-2-methylindolizine (C, Figure 2).
Synthesized according to the general procedure for the direct
arylation.4a Off-white solid (light sensitive). Mp: 58-60 °C.
Rf: 0.55 (petroleum ether/ethyl acetate 98/2). 1H NMR (400 MHz,
CDCl3): δ 8.01 (d, J = 7.3 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.58
(d, J = 8.0 Hz, 2H), 7.33 (d, J = 9.0 Hz, 1H), 6.72-6.64 (m, 1H),
6.45-6.38 (m, 2H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 135.7, 133.2, 129.8, 128.9 (q, JC-F = 32.5 Hz), 126.0 (q, JC-F
=
3.7 Hz), 124.4 (q, JC-F = 271.8 Hz), 124.2, 122.0, 121.1, 118.7,
117.8, 110.4, 101.4, 12.6. 19F NMR (377 MHz, CDCl3): δ-65.665.
IR (νmax /cm-1): 3058, 2929, 2857, 1615, 1324, 1166, 1123, 1068,
836, 768, 728 cm-1. HRMS: calcd for C16H12F3N (Mþ) 275.0922,
found 275.0947.
1-Benzyl-5-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazole
(D, Figure 2). Synthesized according to the general procedure
for the direct arylation.4a White solid. Mp: 98-100 °C. Rf:
0.55 (petroleum ether/ethyl acetate 65/35). 1H NMR (400 MHz,
CDCl3): δ 7.80 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.0
Hz, 2H), 7.31-7.29 (m, 3H), 7.08-7.06 (m, 2H), 5.57 (s, 2H).
13C NMR (100 MHz, CDCl3): δ 136.9, 135.3, 133.9, 131.7
(q, JC-F = 33.0 Hz), 130.7, 129.4, 129.1, 128.5, 127.2, 126.1
(q, JC-F = 3.7 Hz), 123.8 (q, JC-F = 272.2 Hz), 52.2. 19F NMR
(377 MHz, CDCl3): δ -66.107. IR (νmax /cm-1): 3141, 3073,
3035, 2991, 2738, 2403, 1935, 1624, 1497, 1456, 1326, 1162, 1125,
1066, 844, 724. HRMS: calcd for C16H12F3N3 (Mþ) 303.0983,
found 303.0964.
Synthesis and Characterization of Coupling Products. 3-(4-(Tri-
fluoromethyl)phenyl)-2-phenylimidazo[1,2-a]pyrimidine (A, Figure2).
2-(4-(Trifluoromethyl)phenyl)benzo[b]thiophene (E, Figure 2).
Synthesized according to the general procedure for the direct
arylation.4a Off-white solid. Mp: 214-216 °C. Rf: 0.70 (petroleum
1
ether/toluene 95/5). H NMR (400 MHz, CDCl3): δ 7.89-7.81
(23) Bonini, C.;Chiummiento, L.;DeBonis, M.;Funicello, M.;Lupattelli, P.;
Pandolfo, R. Tetrahedron: Asymmetry 2006, 17, 2919.
(24) Zhang, L.; Liang, F.; Sun, L.; Hu, Y.; Hu, H Synthesis 2000, 12, 1733.
(m, 2H), 7.82 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.64
(s, 1H), 7.42-7.32 (m, 2H). 13C NMR (100 MHz, CDCl3)
J. Org. Chem. Vol. 76, No. 3, 2011 757

Lapointe et al.
JOCFeatured Article
δ 142.6, 140.7, 140.1, 138.1, 130.3 (q, JC-F = 32.8 Hz), 126.8,
126.1 (q, JC-F = 3.8 Hz), 125.2, 125.0, 124.3 (q, JC-F = 272 Hz)
124.1, 122.5, 121.3. 19F NMR (377 MHz, CDCl3): δ -65.799. IR
(νmax /cm-1): 3065, 2919, 2853, 1411, 1327, 1166, 1113, 843, 823,
750, 723. HRMS: calcd for C15H9F3S (Mþ) 278.0377, found
278.0395.
129.7, 129.9, 130.3 (dd, JC-F=2.0, 2.0 Hz), 130.9, 132.3 (dd,
J
C-F = 2.0, 2.0 Hz), 136.8, 145.4-142.6 (m), 145.8-143.0 (m),
166.1. IR (νmax /cm-1): 2958, 2908, 1710, 1479, 1271, 1100, 979,
711. HRMS: calcd for C24H17F4NO2 (Mþ) 427.1195, found
427.1180.
2-(N-Methyl-2-p-tolylindol-5-yl)pyridine N-Oxide (9). Synthe-
sized according to the general procedure of conditions A. The
product was isolated as a white solid in 53% yield. Beige solid.
5-(4-(Trifluoromethyl)phenyl)furan-2-carbaldehyde (F, Figure 2).
Synthesized according to the general procedure for the direct
arylation.4a Orange solid. Mp: 101-102 °C. Rf: 0.24 (petroleum
1
Mp: 156-160 °C. Rf: 0.27 (MeOH/acetone/DCM 5:30:65). H
1
ether/ethyl acetate 80/20). H NMR (400 MHz, CDCl3): δ 9.71
NMR (400 MHz, CDCl3): δ 8.42-8.40 (m, 1H), 8.06 (d, J =
0.8 Hz, 1H), 7.78-7.74 (m, 1H), 7.54-7.40 (m, 4H), 7.36-7.18
(m, 4H), 6.60 (s, 1H), 3.77 (s, 3H), 2.43 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 150.9, 142.6, 140.7, 138.8, 138.1, 132.5,
129.6, 129.4 (2 carbons), 127.8, 126.4, 124.2, 123.7, 122.9, 122.1,
109.4, 102.2, 31.4, 21.4. IR (νmax /cm-1): 3024, 2950, 2920, 1616,
1472, 1233, 759. HRMS: calcd for C21H18N2O (Mþ) 314.1419,
found 314.1391.
(s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.35
(d, J = 3.7 Hz, 1H), 6.96 (d, J = 3.7 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 177.6, 157.5, 152.7, 132.3, 131.3 (q, JC-F = 32.9 Hz),
126.1 (q, JC-F = 3.7 Hz), 125.5, 123.9 (q, JC-F = 272.4 Hz), 123.2,
109.4. 19F NMR (377 MHz, CDCl3): δ -66.011. IR (νmax /cm-1):
3123, 2845, 1668, 1490, 1324, 1160, 1107, 966, 841, 802. HRMS:
calcd for C12H7F3O2 (Mþ) 240.0398, found 240.0373.
2-(3-(4-(Methoxycarbonyl)phenyl)-1-methyl-1H-indol-5-yl)-
pyridine 1-Oxide (11). Synthesized according to the general
procedure of conditions B. The product was isolated as a white
solid in 55% yield. Yellow solid. Mp: ∼210 °C dec. Rf: 0.58
(MeOH/DCM 2/98). 1H NMR (400 MHz, CDCl3): δ 8.69
(d, J = 4.7 Hz, 1H), 8.17 (d, J = 1.1 Hz, 1H), 7.99 (dd, J =
8.7, 1.6 Hz, 1H), 7.74 (td, J = 8.0, 1.7 Hz, 1H), 7.72 (d, J =
1.4 Hz, 1H), 7.52 (d, J = 10.2 Hz, 2H), 7.42 (d, J = 8.6 Hz, 1H),
7.20 (ddd, J = 6.5, 4.7, 1.9 Hz, 1H), 6.98 (s, 1H), 6.43 (d, J =
10.2 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 185.1, 170.2, 158.3, 149.7, 147.6, 143.4, 138.0, 136.8,
132.0, 128.7, 127.4, 125.6, 122.0, 121.5, 120.5, 117.9, 110.9,
110.4, 53.6, 33.2. IR (νmax /cm-1): 3057, 2961, 2871, 1714,
1589, 1466, 1278, 1162, 773. HRMS: calcd for C22H18N2O3
(Mþ) 358.1317, found 358.1310.
2-(3,5-Dimethylphenyl)-6-(N-methylindol-5-yl)pyridine N-Oxide
(13). Synthesized according to the procedure of conditions E
and F. The product was isolated as a white solid in 24% yield
with conditions E and in 51% yield with conditions F. Off-white
solid. Mp: 195-198 °C (CHCl3). Rf: 0.45 (3% Me2CO, CHCl3).
1H NMR (400 MHz, CDCl3, 296 K, TMS): δ 8.10 (dd, J = 1.6,
0.4 Hz, 1H), 7.78 (dd, J = 8.7, 1.6 Hz, 1H), 7.47-7.42 (m, 3H),
7.37 (d, J = 8.7 Hz, 1H), 7.33 (dd, J = 7.8, 2.4 Hz, 1H), 7.28
(dd, J =7.7, 7.7 Hz, 1H), 7.05 (m, 2H), 6.52 (dd, J = 3.1, 0.8 Hz,
1H), 3.80 (s, 3H), 2.36 (s, 6H). 13C NMR (100 MHz, CDCl3, 298
K, TMS): δ 151.1, 150.2, 137.5, 137.0, 133.6, 130.8, 129.4, 128.1,
127.3, 126.2, 125.3, 124.8, 124.5, 123.2, 122.8, 108.6, 101.8, 32.9,
21.3. IR (νmax /cm-1): 3005, 2951, 1556, 1476, 1358, 1246, 1226,
786, 721. HRMS: calcd for C22H20N2O (Mþ) 328.1576, found
328.1556.
2-(2,3,5,6-Tetrafluoro-30,40-dimethoxybiphenyl-4-yl)pyridine
(15). Synthesized according to the general procedure of condi-
tions C. White solid. Mp: 154-156 °C. Rf: 0.21 (petroleum
ether/ethyl acetate 80/20). 1H NMR (400 MHz, CDCl3): δ 8.81
(ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.86 (td, J = 7.8, 1.8 Hz, 1H),
7.56 (dt, J = 7.9, 1.0 Hz, 1H), 7.39 (ddd, J = 7.7, 4.9, 1.1 Hz,
1H), 7.11 (dq, J = 8.3, 1.6 Hz, 1H), 7.03 (q, J = 1.6 Hz, 1H), 7.01
(d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 150.2, 149.9, 149.0, 148.0, 136.7, 126.1,
123.7, 123.3, 120.8 (t, JCF = 16.7 Hz), 119.6, 118.6 (t, JCF = 16.2
Hz), 113.3, 111.2, 56.1, 56.0. IR (νmax /cm-1): 3015, 2987, 2949,
2914, 2844, 1586, 1524, 1482, 1456, 1261, 980; HRMS calcd for
C19H13NO2F4 (Mþ) 363.0882, found 363.0887.
4-(Furan-2-yl)-2-(3-nitrophenyl)-5-(4-(trifluoromethyl)phenyl)-
thiazole (20). Synthesized according to the general procedure for
the direct arylation. Pale brown solid. Mp: 157-159 °C. Rf: 0.41
(petroleum ether/ethyl acetate 80/20). 1H NMR (400 MHz,
CDCl3): δ 8.83 (t, J = 1.9 Hz, 1H), 8.31 (dddd, J = 7.8, 7.8,
1.5, 1.0 Hz, 2H), 7.71-7.64 (m, 5H), 7.38 (dd, J = 1.7, 0.7 Hz,
1H), 6.79 (dd, J = 3.4, 0.7 Hz, 1H), 6.48 (dd, J = 3.4, 1.8 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 164.1, 149.1, 148.9, 143.0,
2-(4-(Trifluoromethyl)phenyl)-5-propylthiophene (G, Figure 2).
Synthesized according to the general procedure for the direct
arylation.4a Exhibited identical spectral data according to a
previous report.4a 1H NMR (400 MHz, CDCl3): δ 7.64 (d,
J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 3.6 Hz,
1H), 6.78 (d, J = 3.5 Hz, 1H), 2.81 (t, J = 7.5 Hz, 2H), 1.74
(sext, J = 7.5 Hz, 2H), 1.01 (t, J = 7.3 Hz, 3H).
N-Methyl-5-(2,3,5,6-tetrafluorophenyl)-2-p-tolylindole (6).
Synthesized according to the general procedure of conditions A.
The product was isolated as a white solid in 64% yield. Mp:
152-155 °C (CHCl3). Rf: 0.45 (2% ether, petroleum ether). 1H
NMR (400 MHz, CDCl3, 296 K, TMS): δ 7.72 (d, J = 0.9 Hz,
1H), 7.46 (d, J = 8.5 Hz, 1H), 7.43-7.40 (m, 2H), 7.33-7.28
(m, 3H), 7.03 (dddd, JH-F = 9.7, 9.7, 7.3, 7.3 Hz, 1H), 6.60 (d,
J = 0.7 Hz, 1H), 3.78 (s, 3H), 2.44 (s, 3H). 13C NMR (100 MHz,
CDCl3, 298 K, TMS): δ 147.9-144.6 (m), 145.4-142.8 (m),
142.7, 138.3, 138.2, 129.5, 129.3 (two overlapping carbon
signals), 128.0, 123.3 (dd, J = 1.8, 1.8 Hz), 122.9 (dd, J =
17.3, 17.3 Hz), 122.5 (dd, J = 1.8, 1.8 Hz), 118.6 (dd, J = 2.4, 2.4
Hz), 109.7, 103.9 (dd, J = 22.5, 22.5 Hz), 101.7, 31.3, 21.3. IR
(νmax /cm-1): 3075, 2928, 1493, 1171, 939, 801, 709. HRMS:
calcd for C22H15F4N (Mþ) 369.1141, found 369.1116.
N-Methyl-3-phenyl-5-(2,3,5,6-tetrafluorophenyl)indole (7).
Synthesized according to the procedure of conditions B. Yellow
solid. Mp: 123-125 °C (CHCl3). Rf: 0.27 (2% ether, petroleum
ether). 1H NMR (400 MHz, CDCl3, 296 K, TMS): δ 8.01 (d, J =
0.7 Hz, 1H), 7.63 (dd, J = 8.3, 1.2 Hz, 2H), 7.49-7.41 (m, 3H),
7.35 (ddd, J = 8.5, 2.9, 1.4 Hz, 1H), 7.30-7.26 (m, 1H), 7.29
(s, 1H), 7.04 (dddd, J = 9.7, 9.7, 7.3, 7.3 Hz, 1H), 3.89 (s, 3H).
13C NMR (100 MHz, CDCl3, 297 K, TMS): δ 147.8-144.7
(m), 145.4-142.4 (m), 137.5, 135.0, 128.9, 127.4, 127.4, 126.2,
126.1, 123.8 (dd, JC-F = 1.7, 1.7 Hz), 122.8 (dd, JC-F = 17.1,
17.1 Hz), 122.1 (dd, JC-F = 1.8, 1.8 Hz), 118.8 (dd, JC-F = 2.2,
2.2 Hz), 109.7, 117.4, 104.0 (dd, JC-F = 22.9, 22.9 Hz), 33.0. IR
(νmax /cm-1): 3075, 2948, 1604, 1491, 1456, 1223, 1171, 939, 751,
710. HRMS: calcd for C21H13F4N (Mþ) 355.0984, found
355.0990.
Ethyl
N-Methyl-5-(2,3,5,6-tetrafluoro-40-carboxylatebiphenyl-
4-yl)indole (8). Synthesized according to the procedure of con-
ditions C and D. The product was isolated as a white solid in
54% yield with conditions C and in 58% yield with conditions
D. Mp: 177-179 °C (CHCl3). Rf: 0.21 (5% ether, petroleum
ether). 1H NMR (400 MHz, CDCl3, 296 K, TMS): δ 1.43 (t, J =
7.1 Hz, 3H), 3.86 (s, 3H), 4.43 (q, J = 7.1 Hz, 2H), 6.58 (dd, J =
3.1, 0.7 Hz, 1H), 7.14 (d, J = 3.1 Hz, 1H), 7.36 (ddd, J = 8.4, 2.9,
1.4 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.62 (ddd, J = 8.6, 1.4,
1.4 Hz, 2H), 7.79 (d, J = 0.8 Hz, 1H), 8.19 (ddd, J = 8.6, 1.8 Hz,
2H). 13C NMR (100 MHz, CDCl3, 298 K, TMS): δ 14.3, 33.0,
61.2, 101.7, 109.4, 117.6 (dd, JC-F = 16.5, 16.5 Hz), 118.0
(dd, JC-F = 2.0, 2.0 Hz), 121.9 (dd, JC-F = 16.8, 16.8 Hz), 123.1
(dd, JC-F = 1.7, 1.7 Hz), 123.4 (dd, JC-F = 1.6, 1.6 Hz), 128.5,
758 J. Org. Chem. Vol. 76, No. 3, 2011

Lapointe et al.
JOCFeatured Article
142.9, 134.7, 132.2, 131.6, 130.9 (q, JC-F = 32.8 Hz), 130.4,
130.2, 125.6 (q, JC-F = 3.8 Hz), 124.9, 124.0 (q, JC-F = 272 Hz),
121.4, 111.6, 110.6. IR (νmax /cm-1): 3094, 2932, 1534, 1353, 1324,
1168, 1125, 1068, 1013, 734. HRMS: calcd for C20H11N2O3SF3
(Mþ) 416.0442, found 416.0398.
131.9, 130.0, 129.1, 126.5, 126.3, 125.5, 123.9, 123.5, 123.3,
123.1, 122.7, 120.7, 113.7, 104.3, 59.7, 14.3. IR (νmax /cm-1):
3077, 2981, 1685, 1534, 1507, 1348, 1199, 1129, 739. HRMS:
calcd for C21H16N2O4S (Mþ) 392.0831, found 392.0847.
5-Benzyl-4-(furan-2-yl)-2-phenylthiazole (25). Synthesized ac-
cording to the general procedure for the direct benzylation.
Beige solid. Mp: 120-121 °C. Rf: 0.46 (petroleum ether/ethyl
acetate 90/10). 1H NMR (400 MHz, CDCl3): δ 7.93-7.90
(m, 2H), 7.52 (dd, J = 1.1, 0.5 Hz, 1H), 7.41-7.39 (m, 3H),
7.33-7.25 (m, 5H), 6.85 (d, J = 3.3 Hz, 1H), 6.53 (dd, J = 3.4,
1.9 Hz, 1H), 4.50 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 165.8,
150.8, 142.9, 142.2, 140.1, 133.6, 133.2, 130.1, 128.9, 128.9,
128.7, 126.9, 126.5, 111.5, 108.8, 33.1. IR (νmax /cm-1): 3062,
3027, 2919, 2852, 1680, 1601, 1494, 1474, 1310, 1253, 1171, 1009,
762. HRMS: calcd for C20H15NOS (Mþ) 317.0874, found
317.0864.
Ethyl 3-Benzyl-2-(thiophene-2-yl)indolizine-1-carboxylate (26).
Synthesized according to the general procedure for the direct
benzylation. Yellow solid. Mp: 154-156 °C. Rf: 0.48 (petroleum
ether/ethyl acetate 90/10). 1H NMR (400 MHz, CDCl3): δ 8.29
(dt, J = 9.1, 1.1 Hz, 1H), 7.64 (dt, J = 7.0, 0.9 Hz, 1H), 7.37
(dd, J = 4.6, 1.8 Hz, 1H), 7.31-7.18 (m, 3H), 7.08-7.04
(m, 5H), 6.64 (td, J = 6.8, 1.3 Hz, 1H), 4.25 (q, J = 7.1 Hz,
2H), 4.24 (s, 2H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 164.9, 137.3, 136.2, 135.7, 128.9, 128.0, 127.9, 126.8,
126.6, 126.1, 123.4, 123.3, 123.1, 122.4, 120.3, 112.9, 102.9,
59.4, 30.4, 14.4. IR (νmax /cm-1): 3105, 3026, 2979, 2928, 2901,
1683, 1501, 1243, 1038. HRMS: calcd for C22H19NO2S (Mþ)
361.1136, found 361.1138.
3-Benzyl-2-(4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl)imidazo-
[1,2-a]pyrimidine (27). Synthesized according to the general
procedure for the direct benzylation. Pale yellow solid. Mp:
178-180 °C. Rf: 0.11 (MeOH/DCM 2/98). 1H NMR (400 MHz,
CDCl3): δ 8.58 (dd, J = 4.1, 2.0 Hz, 1H), 8.03 (td, J = 7.0, 2.8
Hz, 1H), 8.02 (d, J = 8.7 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.76
(s, 1H), 7.36-7.29 (m, 3H), 7.16 (d, J = 6.8 Hz, 2H), 6.81 (dd,
J = 6.8, 4.1 Hz, 1H), 4.55 (s, 2H), 2.81 (t, J = 7.7 Hz, 2H), 1.74
(q, J = 6.8 Hz, 2H), 1.44 (sext, J = 7.4 Hz, 2H), 0.97 (t, J =
7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 149.9, 149.4,
148.2, 144.3, 137.0, 135.8, 134.2, 131.1, 129.7, 129. 5, 127.7,
127.5, 120.6, 118.8, 116.9, 108.8, 31.6, 29.8, 25.5, 22.5, 14.0. IR
(νmax /cm-1): 2958, 2932, 2864, 1507, 1498, 1346, 1225, 1097,
1042, 843. HRMS: calcd for C25H24N6 (Mþ) 408.2062, found
408.2072.
Methyl 4-(2-(3-Nitrophenyl)-4-(furan-2-yl)thiazol-5-yl)benzoate
(17). Synthesized according to the general procedure for the
direct arylation. Yellow solid. Mp: 166-168 °C. Rf: 0.42 (petroleum
ether/ethyl acetate 80/20). 1H NMR (400 MHz, CDCl3): δ 8.83
(t, J = 1.9 Hz, 1H), 8.32 - 8.26 (m, 2H), 8.10 (d, J = 8.6 Hz,
2H), 7.67 (t, J = 7.9 Hz, 1H), 7.60 (d, J = 8.6 Hz, 2H), 7.37
(dd, J = 1.8 and 0.8 Hz, 1H), 6.76 (dd, J = 3.4 and 0.8 Hz, 1H),
6.46 (dd, J = 3.4 and 1.8 Hz, 1H), 3.96 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 166.7, 164.1, 149.0, 148.7, 142.8, 142.6,
135.5, 134.7, 132.2, 132.0, 130.3, 130.1, 129.9, 129.7, 124.7, 121.3,
111.5, 110.4, 52.3. IR (νmax /cm-1): 3094, 2952, 2857, 1724, 1607,
1534, 1353, 1279, 736. HRMS: calcd for C21H14N2O5S (Mþ)
406.0623, found 406.0618.
Methyl 4-(2-(3-Nitrophenyl)-4-(5-p-tolylfuran-2-yl)thiazol-5-yl)-
benzoate (21). Synthesized according to the general procedure
for the direct arylation. Bright yellow solid. Mp: 194-202 °C.
Rf: 0.26 (petroleum ether/ethyl acetate 80/20). 1H NMR
(400 MHz, CDCl3): δ 8.86 (t, J = 1.8 Hz, 1H), 8.34-8.29
(m, 2H), 8.16-8.13 (m, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.67
(t, J = 8.0 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 8.0 Hz,
2H), 7.00 (d, J = 3.5 Hz, 1H), 6.67 (d, J = 3.5 Hz, 1H), 4.00
(s, 3H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.8,
164.1, 154.5, 148.9, 148.7, 142.9, 137.8, 136.1, 134.8, 132.2, 131.2,
130.3, 130.3, 130.2, 129.8, 129.5, 127.6, 124.8, 123.7, 121.4, 112.7,
106.2, 52.5, 21.4. IR (νmax /cm-1): 3028, 2957, 2921, 2859, 1716,
1532, 1351, 1277, 1112. HRMS: calcd for C28H20N2O5S (Mþ)
496.1093, found 496.1104.
2-(4-(4-Butyl-1H-1,2,3-triazol-1-yl)phenyl)-3-p-tolylimidazo-
[1,2-a]pyrimidine (22). Synthesized according to the general
procedure for the direct arylation. Yellow solid. Mp: 192-194 oC.
Rf: 0.50 (MeOH/DCM 5/95). 1H NMR (400 MHz, CDCl3):
δ 8.58 (dd, J = 4.0, 2.0 Hz, 1H), 8.24 (dd, J = 6.9, 2.0 Hz, 1H),
7.92 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H),
7.40-7.33 (m, 4H), 6.83 (dd, J = 6.9, 4.1 Hz, 1H), 2.80 (t, J =
7.6 Hz, 2H), 2.49 (d, J = 2.4 Hz, 3H), 1.76-1.66 (m, 2H),
1.49-1.36 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 150.3, 149.3, 148.0, 142.2, 140.0, 136.7,
134.0, 131.0, 130.8, 130.5, 129.5, 125.4, 120.2, 120.1, 118.7, 108.9,
31.6, 25.5, 22.4, 21.6, 14.0. IR (νmax /cm-1): 2956, 2927, 2869, 2859,
1617, 1525, 1517, 1496, 1223, 1203. HRMS: calcd for C25H24N6
(Mþ) 408.2062, found 408.2053.
Ethyl 3-(3-Nitrophenyl)-2-(thiophene-2-yl)indolizine-1-car-
boxylate (23). Synthesized according to the general procedure
for the direct arylation. Bright yellow solid. Mp: 136-137 °C.
Rf: 0.18 (petroleum ether/ethyl acetate 90/10). 1H NMR
(400 MHz, CDCl3): δ 8.36 (dt, J = 9.1, 1.2 Hz, 1H), 8.27 (t,
J = 1.8 Hz, 1H), 8.20 (ddd, J = 8.2, 2.3, 1.2 Hz, 1H), 8.00 (dt,
J = 7.1, 1.1 Hz, 1H), 7.64 (dt, J = 7.7, 1.4 Hz, 1H), 7.56 (t, J =
7.9 Hz, 1H), 7.28 (dd, J = 5.0, 1.4 Hz, 1H), 7.16 (ddd, J = 9.2,
6.7, 1.1 Hz, 1H), 6.96-6.92 (m, 2H), 6.77 (td, J = 6.9, 1.3 Hz,
1H), 4.26 (q, J = 7.1 Hz, 2H), 1.22 (d, J = 14.3 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 164.6, 148.7, 137.0, 136.5, 134.5,
Acknowledgment. This paper is dedicated to the memory
of Keith Fagnou. We thank Ho-Yan Sun, Louis-Charles
ꢀ
Campeau, and Professors Louis Barriault and Andre Beau-
chemin for their critical review and help in the preparation of
this manuscript. We thank NSERC, the University of Ottawa,
Eli Lilly, Amgen, and Astra Zeneca for support of this work.
D.L. thanks NSERC for a postgraduate scholarship (PGS-D).
Supporting Information Available: General considerations
and copies of NMR spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 3, 2011 759