Evaluation of electron-deficient phosphine ligands for direct arylation of heterocycles

Article abstract of DOI:10.1002/adsc.201000397

New electron-deficient biarylphosphine ligands were studied and proved to be efficient for the direct arylation of heteroarenes with aryl iodides. The ability of a more electron-deficient palladium centre to accelerate the arylation of heterocycles that remained unreactive with aryl iodides in the past has been validated and these heteroarenes can now be smoothly reacted in the presence of a new electrophilic catalyst. Experimental evidence suggests a viable concerted metalation-deprotonation pathway for the C-H bond cleavage step with an electron-deficient palladium centre.

Full text of DOI:10.1002/adsc.201000397

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DOI: 10.1002/adsc.201000397
Evaluation of Electron-Deficient Phosphine Ligands for Direct
Arylation of Heterocycles
Olivier Renꢀa,* and Keith Fagnoua,b
a
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa,
Ontario, Canada, K1N 6N5
Fax : (+1)-613-562-5633; phone: (+1)-613-562-5800 ext 6083; e-mail: orene088@uottawa.ca
Prof. Keith Fagnou passed away unexpectedly on November 11, 2009.
b
Received: May 19, 2010; Published online: September 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000397.
Abstract: New electron-deficient biarylphosphine li-
gands were studied and proved to be efficient for
the direct arylation of heteroarenes with aryl io-
dides. The ability of a more electron-deficient palla-
dium centre to accelerate the arylation of heterocy-
cles that remained unreactive with aryl iodides in
the past has been validated and these heteroarenes
can now be smoothly reacted in the presence of a
new electrophilic catalyst. Experimental evidence
suggests a viable concerted metalation–deprotona-
As part of a program dedicated to the study of the
direct arylation mechanism and the development of
broadly applicable reaction conditions, we became in-
terested in investigating the effect of electron-defi-
cient phosphine ligands[7] on the C H bond cleavage
À
step of this process under Pd(0) catalysis. Whilst most
of the focus has traditionally been on the study of
electron-rich ligands, few studies on the effect of elec-
tron-deficient phosphine ligands are described in the
literature.[4] Reports by Baudoin,[8] Gevorgyan[9] as
well as our group[10] have validated the efficiency of
electron-deficient ligands in intramolecular processes
with Pd(0) catalysts. Additionally, new intermolecular
reactions using p-accepting phosphite ligands have
also been observed by Itami and co-workers under
Rh(I) catalysis.[11]
À
tion pathway for the C H bond cleavage step with
an electron-deficient palladium centre.
Keywords: concerted metalation–deprotonation;
direct arylation; heterocycles; palladium; phosphine
ligands
Herein, we report the development of a new class
of electron-poor fluoroarylphosphine ligands that is
compatible with a broad variety of heterocycles. We
demonstrate that a more electron-deficient metal
Heterocyclic biaryl compounds are predominant in centre accelerates the direct arylation reaction and
natural products[1] and medicinal compounds.[2] Al- also report evidence that a concerted metalation–
though the traditional methods to prepare these val- deprotonation (CMD) mechanism[12] is operative.
uable motifs necessitate the use of a stoichiometric These results should encourage further investigation
amount of organometallic coupling partner through of electron-deficient ligands in new transition metal-
transition metal catalysis,[3] more efficient processes in catalyzed transformations.
which the organometallic species can be replaced by a
In our initial ligand design studies, we focused our
simple heteroarene have proven to be a viable alter- efforts toward the synthesis of biaryl-type phosphine
native for the preparation of heteroatom-containing ligands bearing electron-withdrawing fluoro and tri-
biaryls.[4,5] However, general conditions that are fluoromethyl groups (Figure 1). “Buchwald-type”
À
widely compatible with all classes of heterocyclic cou- biaryl ligands have shown to be efficient for C H
pling partners are only sparsely reported[6] and the bond functionalization reactions[13] as well as several
use of a different set of conditions for each class of other processes[14] and were therefore selected as a
substrate remains the norm. In order to further im- starting point for our studies. We were pleased to ob-
prove direct arylation and establish more broadly ap- serve that substitution of the cyclohexyl groups by
plicable reaction conditions, a better understanding of electron-deficient arenes on the S-Phos ligand[14d] pro-
the reaction mechanism and the development of vided promising results.
novel high-performance ligands are essential.
These electron-deficient variants of S-Phos could
be easily obtained via a straightforward phosphonite
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Evaluation of Electron-Deficient Phosphine Ligands for Direct Arylation
Figure 1. Electron-deficient ligands derived from S-Phos.
intermediate approach (Scheme 1).[15] Thus, biaryl
bromide 4, which was obtained by a nucleophilic aro-
matic substitution reaction, underwent lithium-halo-
gen exchange and reacted with triphenyl phosphite at
low temperature (À958C) to afford phosphonite inter-
mediate 5. This intermediate was immediately reacted
with an excess of a second aryllithium reactant bear-
ing the electron-withdrawing substituent to provide
the desired ligands 1 to 3 in moderate yields.
Ligands 1, 2 and 3 were then applied to the direct
arylation of benzothiophene and the results were
compared to those obtained with the electron-rich S-
Phos ligand. Interestingly, provided that a silver car-
Figure 2. Reaction profiles for the arylation of benzothio-
phene using electron-deficient ligands.
bonate additive was added to the reaction, the use of yield after 4 h and was therefore selected as our opti-
aryl iodides,[16] which are typically incompatible in mal ligand.
direct arylation due to potential catalyst poisoning,
Illustrative examples of the applicability of ligand 3
led to very promising results.[17] Furthermore, in the for the direct arylation of electron-rich heterocycles
previously reported broadly applicable conditions for are shown in Table 1. The transformation proceeds
direct arylation, aryl iodides remained unreactive smoothly and selectively with various sulfur-, oxygen-
even in the presence of silver additives.[6a]
and nitrogen-containing heterocycles. For example,
For example, the use of the electron-rich S-Phos benzothiophene (entry 1), 2-propylthiophene (entry 2)
ligand led to very low conversion after 4 h (Figure 2). and 2-isobutylthiazole (entry 3) led to the coupling
In contrast, ligand 1 and ligand 2 gave rise to substan- products using electron-rich and electron-poor aryl io-
tially more promising results, providing heterobiaryl dides in yields ranging from 78% to 89%. Furan het-
product in 33% and 39% yield, respectively. Ulti- erocycles bearing electron-withdrawing (entry 4) and
mately, the more electron-deficient ligand 3, bearing slightly electron-donating groups (entry 5) are also
two p-trifluoromethylphenyl substituents, led to the compatible providing heterobiaryl products, albeit in
best results, affording the desired product in 75% GC modest yields. Moreover, several nitrogen-containing
Scheme 1. Synthesis of the ligands.
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Table 1. Scope of the direct arylation.
by a kinetic isotope effect (kH/kD) of 1 measured in a
one-pot competition, indicating a kinetically insignifi-
À
cant C H bond cleavage step.
To better assess the mechanism of this transforma-
tion in the presence of our electron-deficient palladi-
um catalyst, a kinetic isotope effect was measured by
À
comparing the initial rate of C H bond functionaliza-
tion of benzothiophene vs. benzothiophene-d in side-
by-side experiments (Scheme 2). A pronounced pri-
Scheme 2. Kinetic isotope effect.
mary KIE of 5.6 was obtained, thereby implicating
À
C H bond cleavage at the rate-determining step. The
magnitude of the KIE is in line with previously ob-
served KIEs of 3.08 and 5.59 for intermolecular direct
arylation reactions with polyfluoroarenes[12b] and ben-
zene,[13e] respectively, both known to proceed via the
À
CMD mechanism for C H bond cleavage. It is also
consistent with large KIEs reported by Echavarren
and Maseras with the intramolecular variant of the
direct arylation reaction.[18]
To provide additional evidence for a CMD path-
way, a one-pot competition experiment performed
with an equimolar mixture of 2-methylthiophene and
2-chlorothiophene was conducted. This experiment
demonstrated that arylation of the more electron-
deficient 2-chlorothiophene was favoured over the
more nucleophilic 2-methylthiophene in a 3.9:1 ratio
(Scheme 3). This outcome is in agreement with previ-
ous results for a reaction demonstrated to proceed
through a CMD mechanism for which arylation of the
heterocycles such as pyrazole (entry 6), triazole
(entry 7), imidazole (entry 8), and pyrrole (entry 9)
proved to be efficient coupling partners, providing the
desired product in a regioselective fashion in yields
up to 93%. It is noteworthy to mention that iodides
bearing electron-donating (entries 2 and 6) and elec-
tron-withdrawing substituents (entry 3, 5 and 7) as
well as sterically encumbered iodides (entries 8 and 9)
are tolerated with these heterocycles.
In a previous report on the effect of electron-defi-
cient ligands, Itami and co-workers described a trend
similar to ours for the Rh(I)-catalyzed arylation of
thiophene wherein more electron-deficient ligands
[11b]
À
better facilitated C H bond cleavage.
They pro-
posed that p-accepting phosphite ligands render the
rhodium centre more electron-deficient, thereby facil-
itating electrophilic metalation. This was supported Scheme 3. Competition experiment.
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Evaluation of Electron-Deficient Phosphine Ligands for Direct Arylation
less nucleophilic 2-chlorothiophene was favoured in 2-p-Tolylbenzo[b]thiophene (6)
an 11:1 ratio.[12c] In contrast, Vilsmeier–Haack formy-
Prepared according to general procedure. The title com-
lation competition (which is know to proceed via an
SEAr mechanism)[19] with the same system reacts pref-
erentially with the more nucleophilic 2-methylthio-
phene in a 17:1 ratio.[12c]
pound was obtained as a white solid; yield: 78%. It exhibit-
ed spectral data in accordance with those of a previous re-
port.[6a] 1H NMR (400 MHz, CDCl3): d=7.84 (br d, J=
7.8 Hz, 1H), 7.75 (br d, J=7.6 Hz, 1H), 7.60 (d, J=8.0 Hz,
2H), 7.45 (d, J=0.5 Hz, 1H), 7.33 (ddd, J=6.8, 6.8, 1.6 Hz,
1H), 7.29 (ddd, J=6.8, 6.8, 1.6 Hz, 1H), 7.22 (br d, J=
8.0 Hz, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
144.5, 140.9, 139.4, 138.4, 131.6, 129.7, 126.5, 124.5, 124.2,
123.5, 122.3, 118.9, 21.4.
This experimental evidence is in agreement with a
CMD mechanism where metalation of the heterocycle
À
and C H bond cleavage occur simultaneously at the
turnover-limiting step of the reaction.[12] It also indi-
cates that electrophilic aromatic palladation is unlike-
ly to occur even in the presence of an electrophilic
catalyst system. It is plausible that a more electrophil-
ic palladium centre might facilitate interaction with
the heterocycle by promoting binding through p orbi-
tals between the arene and the metal.[20] Additionally,
a more facile displacement of a labile electron-defi-
cient ligand from a palladium centre bearing two li-
gands might liberate a vacant coordination site on the
metal for arene binding.
Acknowledgements
We thank NSERC, the University of Ottawa, AstraZeneca,
Amgen, and Eli Lilly for financial support. O.R. thanks
OGS and FQRNT for graduate student scholarships. We also
thank the Fagnou group for their help throughout the prepa-
ration of this manuscript.
In conclusion, we have developed a new electron-
deficient fluoroarylphosphine ligand that promotes
C H bond functionalization of a broad variety of het-
References
À
erocycles. The demonstrated ability of these types of
[1] For examples, see: a) D. J. Faulkner, Nat. Prod. Rep.
2001, 18, 1; b) R. J. Davies, P. D. Kane, C. J. Moody,
A. M. Z. Slawin, J. Org. Chem. 2005, 70, 5840; c) C.-G.
Yang, H. Huang, B. Jiang, Curr. Org. Chem. 2004, 8,
1691.
[2] For examples, see: a) F. Chimenti, E. Maccioni, D.
Secci, A. Bolasco, P. Chimenti, A. Granese, S. Carra-
dori, S. Alcaro, F. Ortuso, M. YꢂÇez, F. Orallo, R. Ciril-
li, R. Ferretti, F. La Torre, J. Med. Chem. 2008, 51,
4874; b) S. C. Goodacre, L. J. Street, D. J. Hallett, J. M.
Crawforth, S. Kelly, A. P. Owens, W. P. Blackaby, R. T.
Lewis, J. Stanley, A. J. Smith, P. Ferris, B. Sohal, S. M.
Cook, A. Pike, N. Brown, K. A. Wafford, G. Marshall,
J. L. Castro, J. R. Atack, J. Med. Chem. 2006, 49, 35;
c) D. M. Armistead, M. C. Badia, G. W. Bemis, R. S.
Bethiel, C. A. Frank, P. M. Novak, S. M. Ronkin, J. O.
Saunders, Patent WO9740028, 1997.
[3] For selected reviews on traditional cross-coupling reac-
tions, see: a) Metal-Catalyzed Cross-Coupling Reac-
tions, (Eds.: F. Diederich, P. J. Stang), Wiley-VCH, New
York, 1998; b) J. Hassan, M. Sꢀvignon, C. Gozzi, E.
Shulz, M. Lemaire, Chem. Rev. 2002, 102, 1359; c) O.
Baudoin, Eur. J. Org. Chem. 2005, 20, 4223.
[4] For selected reviews on direct arylation, see: a) D. Al-
berico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107,
174; b) L.-C. Campeau, D. R. Stuart, K. Fagnou, Aldri-
chimica Acta 2007, 40, 35; c) L.-C. Campeau, K.
Fagnou, Chem. Commun. 2006, 1253; d) T. Satoh, M.
Miura, Chem. Lett. 2007, 36, 200; e) B.-J. Li, S.-D.
Yang, Z.-J. Shi, Synlett 2008, 949; f) S. Pascual, P. de
Mendoza, A. M. Echavarren, Org. Biomol. Chem.
2007, 5, 2727; g) M. Catellani, E. Motti, N. Della Ca’,
R. Ferraccioli, Eur. J. Org. Chem. 2007, 4153; h) G. P.
McGlacken, L. M. Bateman, Chem. Soc. Rev. 2009, 38,
2447; i) L. Ackermann, R. Vicente, A. R. Kapdi,
Angew. Chem. 2009, 121, 9976; Angew. Chem. Int. Ed.
2009, 48, 9792.
À
ligands to facilitate the C H bond cleavage step of
this process has been assessed and experimental evi-
dence suggests a concerted metalation–deprotonation
mechanism in the presence of an electrophilic metal
centre. These results should prompt interest amongst
the scientific community in pursing the development
of electron-deficient ligands in an ever-widening
range of transition metal-catalyzed transformations.
Experimental Section
General Procedure for the Direct Arylation of
Heterocycles
K2CO3 (62.2 mg, 0.45 mmol, 1.5 equiv.), Ag2CO3 (41.4 mg,
0.15 mmol, 0.5 equiv.), phosphine 3 (16.0 mg, 0.03 mmol,
10 mol%), PdACHTUNGTRENNUNG(OAc)2 (3.4 mg, 0.015 mmol, 5 mol%) and piv-
alic acid (9.2 mg, 0.09 mmol, 30 mol%) were weighed to air
in a screw cap vial equipped with a magnetic stir bar. The
aryl iodide (0.3 mmol, 1.0 equiv.) and the heterocycle
(0.33 mmol, 1.1 equiv.) were introduced at this moment if
solid. The vial was purged with argon for 10 min. DMA
(1 mL, 0.3M) was then added to the reaction mixture using
a syringe and a 23G1 needle. The aryl iodide and the hetero-
cycle were introduced at this moment if liquid. The reaction
mixture was stirred at 1008C for 16 h. Upon completion of
the reaction, the mixture was filtered and concentrated
under reduced pressure. The crude material was purified by
silica gel column chromatography to afford the correspond-
ing product.
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Olivier Renꢀ and Keith Fagnou
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[5] For selected examples of direct arylation of heteroar-
enes, see: a) L.-C. Campeau, M. Bertrand-Laperle, J.-P.
Leclerc, E. Villemure, S. Gorelsky, K. Fagnou, J. Am.
Chem. Soc. 2008, 130, 3276; b) M. Nakano, H. Tsurugi,
T. Satoh, M. Miura, Org. Lett. 2008, 10, 1851; c) F. Bel-
lina, S. Cauteruccio, A. Di Fiore, C. Marchetti, R.
Rossi, Tetrahedron 2008, 64, 6060; d) J. X. Wang, J. A.
McCubbin, M. Jin, R. S. Laufer, Y. Mao, A. P. Crew,
M. J. Mulvihill, V. Snieckus, Org. Lett. 2008, 10, 2923;
e) F. Jafarpour, S. Rahiminejadan, H. Hazrati, J. Org.
Chem. 2010, 75, 3109; f) H. Hachiya, K. Hirano, T.
Satoh, M. Miura, Angew. Chem. Int. Ed. 2010, 49, 2202;
g) F. Shibahara, E. Yamaguchi, T. Murai, Chem.
Commun. 2010, 2471.
[6] a) B. Liꢀgault, D. Lapointe, L. Caron, A. Vlassova, K.
Fagnou, J. Org. Chem. 2009, 74, 1826; b) H. A. Chiong,
O. Daugulis, Org. Lett. 2007, 9, 1449.
[7] For a review on electron-deficient fluoroarylphosphine
ligands, see: C. L. Pollock, G. C. Saunders, E. C. M. S.
Smyth, V. Sorokin, J. Fluorine Chem. 2008, 129, 142.
[8] a) J. Hitce, O. Baudoin, Adv. Synth. Catal. 2007, 349,
2054; b) J. Hitce, P. Retailleau, O. Baudoin, Chem. Eur.
J. 2007, 13, 792.
Petrov, S. I. Gorelsky, K. Fagnou, J. Org. Chem. 2010,
75, 1047.
[13] For selected examples of biaryl phosphine ligands used
in direct arylation, see: a) O. Renꢀ, K. Fagnou, Org.
Lett. 2010, 12, 2116; b) L. Ackermann, A. Althammer,
S. Fenner, Angew. Chem. 2009, 121, 207; Angew. Chem.
Int. Ed. 2009, 48, 201; c) M. P. Huestis, K. Fagnou, Org.
Lett. 2009, 11, 1357; d) T. Watanabe, S. Oishi, N. Fujii,
H. Ohno, J. Org. Chem. 2009, 74, 4720; e) M. Lafrance,
K. Fagnou, J. Am. Chem. Soc. 2006, 128, 16496.
[14] For selected examples of biarylphosphine ligands used
in other processes, see: a) B. P. Fors, D. A. Watson,
M. R. Biscoe, S. L. Buchwald, J. Am. Chem. Soc. 2008,
130, 13552; b) J. P. Wolfe, R. A. Singer, B. H. Yang,
S. L. Buchwald, J. Am. Chem. Soc. 1999, 121, 9550;
c) J. D. Hicks, A. M. Hyde, A. M. Cuezva, S. L. Buch-
wald, J. Am. Chem. Soc. 2009, 131, 16720; d) S. D.
Walker, T. E. Barder, J. R. Martinelli, S. L. Buchwald,
Angew. Chem. 2004, 116, 1907; Angew. Chem. Int. Ed.
2004, 43, 1871; e) D. A. Watson, M. Su, G. Teverovskiy,
Y. Zhang, J. Garcꢃa-Fortanet, T. Kinzel, S. L. Buchwald,
Science 2009, 325, 1661.
[15] J. Keller, C. Schlierf, C. Nolte, P. Mayer, B. F. Straub,
Synthesis 2006, 354.
[9] C. Huang, V. Gevorgyan, Org. Lett. 2010, 12, 2442.
[10] a) L.-C. Campeau, M. Parisien, M. Leblanc, K. Fagnou,
J. Am. Chem. Soc. 2004, 126, 9186; b) M. Lafrance, D.
Lapointe, K. Fagnou, Tetrahedron 2008, 64, 6015.
[11] a) S. Yanagisawa, T. Sudo, R. Noyori, K. Itami, J. Am.
Chem. Soc. 2006, 128, 11748; b) S. Yanagisawa, T.
Sudo, R. Noyori, K. Itami, Tetrahedron 2008, 64, 6073;
c) S. Yanagisawa, K. Ueda, H. Sekizawa, K. Itami, J.
Am. Chem. Soc. 2009, 131, 14622.
[12] For an analysis of the concerted metalation–deprotona-
tion mechanism (CMD), see: a) S. I. Gorelsky, D. La-
pointe, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 10848;
b) M. Lafrance, C. N. Rowley, T. K. Woo, K. Fagnou, J.
Am. Chem. Soc. 2006, 128, 8754; c) B. Liꢀgault, I.
[16] Preliminary results with aryl chlorides and bromides
were unsatisfactory due to presumed slow oxidative in-
À
sertion into the carbon halogen bond.
[17] Silver additives have shown to overcome the inhibitory
effect of iodide on direct arylation by sequestering the
iodide anion, see: L.-C. Campeau, M. Parisien, A. Jean,
K. Fagnou, J. Am. Chem. Soc. 2006, 128, 581.
[18] D. Garcia-Cuadrado, P. de Mendoza, A. A. C. Braga, F.
Maseras, A. M. Echevarren, J. Am. Chem. Soc. 2007,
129, 6880.
[19] A. Vilsmeier, A. Haack, Ber. Dtsch. Chem. Ges. 1927,
60, 119.
[20] B. Biswas, M. Sugimoto, S. Sakaki, Organometallics
2000, 19, 3895.
2120
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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