Auxiliary-assisted palladium-catalyzed arylation and alkylation of sp 2 and sp3 carbon-hydrogen bonds

Article abstract of DOI:10.1021/ja910900p

We have developed a method for auxiliary-directed, palladium-catalyzed β-arylation and alkylation of sp³ and sp² C-H bonds in carboxylic acid derivatives. The method employs a carboxylic acid 2-methylthioaniline- or 8-aminoquinoline amide substrate, aryl or alkyl iodide coupling partner, palladium acetate catalyst, and an inorganic base. By employing 2-methylthioaniline auxiliary, selective monoarylation of primary sp³ C-H bonds can be achieved. If arylation of secondary sp ³ C-H bonds is desired, 8-aminoquinoline auxiliary may be used. For alkylation of sp³ and sp² C-H bonds, 8-aminoquinoline auxiliary affords the best results. Some functional group tolerance is observed and amino- and hydroxy-acid derivatives can be functionalized. Preliminary mechanistic studies have been performed. A palladacycle intermediate has been isolated, characterized by X-ray crystallography, and its reactions have been studied.

Full text of DOI:10.1021/ja910900p

Published on Web 02/22/2010
Auxiliary-Assisted Palladium-Catalyzed Arylation and
Alkylation of sp2 and sp3 Carbon-Hydrogen Bonds
Dmitry Shabashov and Olafs Daugulis*
Department of Chemistry, UniVersity of Houston, Houston, Texas 77204-5003
Received December 26, 2009; E-mail: olafs@uh.edu
Abstract: We have developed a method for auxiliary-directed, palladium-catalyzed ꢀ-arylation and alkylation
of sp3 and sp2 C-H bonds in carboxylic acid derivatives. The method employs a carboxylic acid
2-methylthioaniline- or 8-aminoquinoline amide substrate, aryl or alkyl iodide coupling partner, palladium
acetate catalyst, and an inorganic base. By employing 2-methylthioaniline auxiliary, selective monoarylation
of primary sp3 C-H bonds can be achieved. If arylation of secondary sp3 C-H bonds is desired,
8-aminoquinoline auxiliary may be used. For alkylation of sp3 and sp2 C-H bonds, 8-aminoquinoline auxiliary
affords the best results. Some functional group tolerance is observed and amino- and hydroxy-acid
derivatives can be functionalized. Preliminary mechanistic studies have been performed. A palladacycle
intermediate has been isolated, characterized by X-ray crystallography, and its reactions have been studied.
activation of sp2 C-H bonds is favored by precoordination of
the arene π system to the transition metal as well as the
subsequent formation of aryl-metal bond that is typically
stronger than the corresponding alkyl-metal bond.5 In contrast,
benzylic or R to heteroatom sp3 carbon-hydrogen bonds
undergo functionalization relatively easily, presumably due to
weakness of those C-H bonds and proximity of aromatic system
or electron lone pair. Consequently, transition-metal-catalyzed
functionalization of activated sp3 C-H bonds is quite common
and many examples have been recently described in literature.6
On the other hand, catalytic functionalization of nonactivated,
alkane sp3 C-H bonds is rare. Most of the examples published
so far report functionalization of sp3 C-H bonds adjacent to
quarternary centers which is the easiest case due to entropic
considerations and impossibility of ꢀ-hydride elimination from
the metalated intermediates.7 Notable exceptions include Ohno’s
synthesis of indoline derivatives from N-protected 2-bromoa-
1. Introduction
In the past decade, transition-metal-catalyzed functionalization
of carbon-hydrogen bonds has emerged as an efficient method
for carbon-carbon and carbon-heteroatom bond formation.1
Most of the developed methodology centers on the functional-
ization of sp2 C-H bonds. Electron-rich heterocycles can be
predictably and regioselectively arylated under palladium,
rhodium, iridium, copper, and nickel catalysis.2 Functionalization
of directing-group-containing arenes has been extensively
investigated. Palladium- and ruthenium-catalyzed arylation of
imines, anilides, 2-arylpyridine derivatives, benzamides, benzoic
acids, and nitroarenes has been demonstrated allowing short
syntheses of the corresponding biaryls.3 These arylations are
highly ortho-selective; however, in some cases, meta selectivity
has been achieved.4
For both kinetic and thermodynamic reasons, metal-catalyzed
functionalization of unactivated sp3 C-H bonds is more difficult
than that of sp2 hybridized carbon-hydrogen bonds. The
(3) Selected examples: (a) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.;
Murai, S. J. Am. Chem. Soc. 2003, 125, 1698. (b) Oi, S.; Fukita, S.;
Inoue, Y. Chem. Commun. 1998, 2439. (c) Bedford, R. B.; Coles,
S. J.; Hursthouse, M. B.; Limmert, M. E. Angew. Chem., Int. Ed. 2003,
42, 112. (d) Caron, L.; Campeau, L.-C.; Fagnou, K. Org. Lett. 2008,
10, 4533. (e) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc.
2008, 130, 9254. (f) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.;
Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78. (g) Chiong, H. A.; Pham,
Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. (h) Desai,
L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130,
13285. (i) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin,
C.; Wang, Y. Angew. Chem., Int. Ed. 2007, 46, 5554.
(1) (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008,
41, 1013. (b) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253.
(c) Ackermann, L. Synlett 2007, 507. (d) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (e)
Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (f)
Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (g) Daugulis,
O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (h)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174.
(2) Selected examples: (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura,
M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467. (b) Park, C.-
H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org.
Lett. 2004, 6, 1159. (c) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi,
R.; Viel, S. J. Org. Chem. 2005, 70, 3997. (d) Flegeau, E. F.; Popkin,
M. E.; Greaney, M. F. Org. Lett. 2008, 10, 2717. (e) Chiong, H. A.;
Daugulis, O. Org. Lett. 2007, 9, 1449. (f) Liegault, B.; Lapointe, D.;
Caron, L.; Vlassova, A.; Fagnou, K. J. Org. Chem. 2009, 74, 1826.
(g) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009,
11, 1737. (h) Canivet, J.; Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett.
2009, 11, 1733. (i) Yotphan, S.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2009, 11, 1511. (j) Do, H.-Q.; Khan, R. M. K.; Daugulis, O.
J. Am. Chem. Soc. 2008, 130, 15185. (k) Dwight, T. A.; Rue, N. R.;
Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137.
(4) (a) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (b) Zhang,
Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072.
(5) Jones, W. D. Inorg. Chem. 2005, 44, 4475.
(6) Selected examples: (a) Dong, C.-G.; Hu, Q.-S. Angew. Chem., Int.
Ed. 2006, 45, 2289. (b) Campeau, L.-C.; Schipper, D. J.; Fagnou, K.
J. Am. Chem. Soc. 2008, 130, 3266. (c) Ren, H.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 3462. (d) Dyker, G. Angew. Chem., Int. Ed.
1992, 31, 1023. (e) Ishii, Y.; Chatani, N.; Kakiuchi, F.; Murai, S.
Organometallics 1997, 16, 3615. (f) Jun, C.-H.; Hwang, D.-C.; Na,
S.-J. Chem. Commun. 1998, 1405. (g) DeBoef, B.; Pastine, S. J.;
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Kasagawa, M.; Endo, K.; Shibata, T. Org. Lett. 2009, 11, 1821.
9
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A R T I C L E S
Shabashov and Daugulis
Scheme 1. Auxiliaries for sp3 C-H Bond Arylation
Depending on the attachment of the auxiliary, either ꢀ-ary-
lation of carboxylic acids or γ-arylation of amines could be
achieved. After the arylation, auxiliary could be removed by
hydrolysis. We successfully demonstrated the concept and a
preliminary account has been published.9b Corey has used this
methodology to arylate protected R-amino acid derivatives.10a
Chen has employed the arylation in context of celogentin total
synthesis, demonstrating that C-H activation methodology is
compatible with complex molecular environment.10b Pyridine
and quinoline auxiliary directed acetoxylation of sp2 C-H bonds
has been recently reported.11
We report here a method for auxiliary-directed, palladium-
catalyzed arylation and alkylation of unactivated sp3 C-H
bonds. Alkylation of sp2 C-H bonds is also demonstrated.
Arylation of sp2 C-H bonds was not investigated since
benzylamines and simple N-isopropyl benzamides can be
arylated without the requirement of an auxiliary.12 Mechanistic
studies are also described.
2. Results
nilines, Yu’s 2-substituted pyridine alkylation, and ꢀ-arylation
of carboxylic acid pentafluoroanilides.8
2.1. Auxiliary Optimization Studies. A successful auxiliary
requires a nitrogen or sulfur coordinating group and a com-
paratively acidic NH group.13 The initial optimization experi-
ments were directed toward using stoichiometric additives other
than AgOAc to promote arylation. For the arylation of 8a, a
combination of inorganic base and a hydroxylic solvent was
discovered to be successful.14 Subsequently, propionamides of
a number of readily available auxiliaries were subjected to the
optimized arylation conditions (Table 1). The conditions for the
arylation involve heating substrate with iodobenzene in tert-
amyl alcohol/water mixture in the presence of K2CO3 or K3PO4
base at 90-110 °C. 2-Methylthio-N-propionylaniline was ef-
ficiently arylated at 90 °C affording the monoarylation product
predominately (entries 1 and 2). Better selectivity for the
monophenylation was observed in mixed water/alcohol
solvent. Increase of the coordinating group size from thi-
omethyl to thioisopropyl resulted in slight lowering of yield
(entry 3). tert-Butyl derivative 8c was shown to be inefficient
and less than 20% conversion to the product was observed
(entry 4). 2-Dimethylamino-N-propionylaniline 8d was phe-
nylated affording a reasonable conversion to the products.
Use of the previously reported 8-aminoquinoline derivative
resulted in formation of mono/diarylation product mixture
(entry 6). Aliphatic auxiliaries such as 2-ethylthioethylamine
and 2-dimethylaminoethylamine are not effective and the
corresponding propionamides were arylated with low conver-
sions (entries 7 and 8).
We reported in 2005 that 2-substituted pyridines are arylated
by employing a combination of palladium acetate catalyst,
stoichiometric silver acetate, and aryl iodide coupling partner.9a
While most examples involve arylation of sp2 C-H bonds,
p-tolylation of 2-ethylpyridine was also demonstrated in moder-
ate yield (eq 1). Unfortunately, 2-ethylpyridine was the only
substrate that underwent clean arylation of unactivated sp3 C-H
bonds. Other substrates afforded either a mixture of mono- and
poly-arylation products or stilbene derivatives that can arise from
ꢀ-hydride elimination from palladated intermediates.
We reasoned that the generality of the method could be
improved by using pyridine or other chelating group as a
removable auxiliary (Scheme 1). The reaction mechanism most
likely involves cyclopalladation to afford 3 and step where Pd(II)
is converted to a high-energy Pd(IV) species 3a (Scheme 1).
An additional chelating group should stabilize Pd(IV) species
and facilitate the cyclometalation step. Additionally, ꢀ-hydride
elimination should be retarded by saturating the coordination
sites on palladium.
2.2. Arylation of Primary C-H Bonds: 2-Methylthio-
aniline Auxiliary. The optimization results show that the
arylations are successful if commercially available 2-methylth-
ioaniline and 8-aminoquinoline auxiliaries are employed (Table
1). Furthermore, 2-isopropylthioaniline and 2-dimethylamino-
aniline auxiliaries are also efficient; however, these compounds
are not commercially available. 2-Methylthioaniline auxiliary
affords the best selectivity for monoarylation of primary
carbon-hydrogen bonds (entry 2 vs entry 6, Table 1). Arylation
scope by employing 2-methylthioaniline auxiliary is shown in
(7) (a) Dyker, G. Angew. Chem., Int. Ed. 1994, 33, 103. (b) Barder, T. E.;
Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 4685. (c) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce,
J.; Peglion, J.-L.; Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008, 130,
15157. (d) Chaumontet, M.; Piccardi, R.; Baudoin, O. Angew. Chem.,
Int. Ed. 2009, 48, 179. (e) Lafrance, M.; Gorelsky, S. I.; Fagnou, K.
J. Am. Chem. Soc. 2007, 129, 14570. (f) Lie´gault, B.; Fagnou, K.
Organometallics 2008, 27, 4841. (g) Giri, R.; Maugel, N.; Li, J.-J.;
Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am.
Chem. Soc. 2007, 129, 3510. (h) Wang, D.-H.; Wasa, M.; Giri, R.;
Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190.
(8) (a) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10,
1759. (b) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 12634. (c) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem.
Soc. 2009, 131, 9886.
(11) Gou, F.-R.; Wang, X.-C.; Huo, P.-F.; Bi, H.-P.; Guan, Z.-H.; Liang,
Y.-M. Org. Lett. 2009, 11, 5726.
(9) (a) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657. (b) Zaitsev,
V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127,
13154.
(12) (a) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211. (b) Shabashov,
D.; Daugulis, O. Org. Lett. 2006, 8, 4947.
(10) (a) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8,
3391. (b) Feng, Y.; Chen, G. Angew. Chem., Int. Ed. 2010, 49, 958.
(13) See footnote 13, ref 9a.
(14) See Supporting Information for optimization data.
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A R T I C L E S
Table 1. Auxiliary Optimization Studiesa
arylation of phthaloyl-protected amino acids by employing
8-aminoquinoline auxiliary, palladium acetate catalyst, and
stoichiometric silver acetate.10a However, clean ꢀ-monoary-
lation of methyl groups was elusive.
We also showed that directing group can be removed under
base hydrolysis affording a phenylpropionic acid derivative
(eq 2). Thus, p-bromophenylpropionic acid 2-methylthioa-
nilide was heated with NaOH in ethanol to afford 90% of
the hydrolysis product.
Secondary C-H bond arylation proceeds with a moderate
yield even for a weak benzylic bond (entry 7) and requires the
presence of catalytic pivalic acid additive employed by Larock
and Fagnou.16 It has been suggested that pivalate anion acts as
a catalytic proton shuttle between the substrate and inorganic
base.16a To efficiently arylate methylene groups one needs to
employ another auxiliary as shown below.
2.3. Arylation of Secondary C-H Bonds: 8-Aminoquino-
line Auxiliary. Efficient arylation of secondary C-H bonds is
possible by employing 8-aminoquinoline auxiliary. Optimal
conditions involve heating substrate with aryl iodide and Cs3PO4
base in tert-amyl alcohol solvent. The arylation is highly
selective for the ꢀ-position of the alkyl chain. Butyric acid
derivative is arylated in good yield with both electron-rich and
electron-poor aryl iodides (Table 3, entries 1 and 2).
Cyclohexanecarboxylic acid amide can be arylated by
p-methoxyiodobenzene and 3-bromoiodobenzene affording
diarylation products in reasonable yields. The diastereose-
lectivity depends on the aryl iodide. p-Methoxyphenylation
affords about 4/1 isomer ratio (entry 3) or about 5/1 ratio if
previously reported conditions9b that use AgOAc are em-
ployed with all-cis isomer predominating in both cases.
m-Bromophenylation results in the formation of all-cis isomer
(entry 5). m-Methoxyphenylation of cyclopentanecarboxylic
acid derivative affords monoarylation product cis isomer
(entry 6). ω-Phthaloyl-protected amino group is compatible
with the arylation conditions as shown in entry 7. 6-Ami-
nohexanoic acid derivative is p-tolylated in good yield.
Finally, alkenylation of sp2 C-H bonds was shown to be
successful (entry 8). 2-Methoxybenzoic acid amide was
reacted with iodostyrene affording the product in good yield
if AgOAc halide removing agent was employed.
a Amide (1 equiv), Pd(OAc)2 (0.05 equiv), base (2.5 equiv), and PhI
(3 equiv). Yields are NMR yields against dichloroethane internal
standard. See the Supporting Information for details. b Base used -
K3PO4.
Table 2. The arylation of propionyl derivative 8a with p-
bromoiodobenzene is successful in tert-amyl alcohol/water
mixture by employing K2CO3 base. Monoarylation product was
obtained in 60% yield accompanied with 9% of diarylated
species (entry 1). Reaction in acetonitrile is somewhat slower
and afforded clean monoarylation (entry 2). 2-Methylbutyric
acid amide was selectively arylated at ꢀ-position and the product
was isolated in 60% yield (entry 3). Some functionality is
tolerated on the amide.15
Thus, benzyl protected lactic acid derivative 11 was
arylated with 4-iodo-tert-butylbenzene affording the product
11a in 65% yield (entry 4). If 11 with 81% ee was employed
in arylation, partial racemization was observed and 11a was
obtained with 75% ee. Phthaloyl protected alanine amide can
be arylated by electron-rich 3,4-dimethyliodobenzene (entry
5) and electron-poor 4-chloroiodobenzene (entry 6). In this
case, highest conversion was obtained if toluene solvent and
cesium acetate base were employed. Corey has reported
2.4. Alkylation of C-H Bonds. The previously described
conditions that involve use of AgOAc for iodide removal
were not successful for C-H bond alkylation. Silver acetate
reaction with alkyl iodides competes with the C-alkylation
resulting in low catalytic turnover. The new conditions should
(16) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
(b) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am.
Chem. Soc. 2004, 126, 7460.
(17) (a) Lapointe, D.; Fagnou, K. Org. Lett. 2009, 11, 4160. (b) Zhang,
Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 6097.
(c) Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N. Angew.
Chem., Int. Ed. 2009, 48, 6045. (d) Catellani, M.; Frignani, F.;
Rangoni, A. Angew. Chem., Int. Ed. 1997, 36, 119. (e) Martins, A.;
Lautens, M. Org. Lett. 2008, 10, 5095. (f) McCallum, J. S.; Gasdaska,
J. R.; Liebeskind, L. S.; Tremont, S. J. Tetrahedron Lett. 1989, 30,
4085.
(15) While simple arylpropionic acids may be obtained by a condensation
of acetic anhydride with an aromatic aldehyde followed by hydrogena-
tion, aliphatic or aromatic ketones as well as aliphatic aldehydes are
not generally suitable substrates for the Perkins reaction. Rosen, T.
The Perkin Reaction. In: ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, U.K.,
1991; Vol. 2, pp 395-408.
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A R T I C L E S
Shabashov and Daugulis
Table 2. Arylation of Primary C-H Bondsa
directing group was also demonstrated affording the dialky-
lated benzoic acid in excellent yield (eq 3). Several examples
of transition-metal-catalyzed sp2 C-H bond alkylation have
been reported.17
2.5. Mechanistic Considerations. 2.5.1. Synthesis of Pal-
ladium Complexes. Several complexes that are related to
potential reaction intermediates were synthesized and character-
ized (Scheme 2). Reaction of 8-aminoquinoline pivalamide with
palladium acetate in nitrile solvents afforded the corresponding
acetonitrile and pivalonitrile complexes 13 and 14 in quantitative
yields. Notably, the cyclometalated complexes are easily formed
in high yields under conditions where catalytic reaction is
successful (entry 2, Table 2). Nitrile ligands are labile and can
be easily replaced by tert-butyl isonitrile to afford complex 15
in quantitative yield (Scheme 2). Complexes 13-15 were fully
characterized by 1H and 13C NMR as well as elemental analyses.
Palladated methylene group signals appear in 1H NMR spectra
at 1.80-1.94 ppm (CDCl3 solvent). The complexes exist as
yellow-brownish, crystalline solids that are stable at room
temperature in air. They are soluble in most common organic
solvents except pentane.
The structure of the complex 13 was verified by single-crystal
X-ray diffraction analysis. The ORTEP diagram of 13 is shown
in Figure 1. Interestingly, 13 crystallizes in two different forms,
orange blocks and yellow, thin plates. Both crystals were formed
simultaneously upon slow diffusion of pentane into CH2Cl2
solution of 13 at -20 °C. Orange material is 13 that crystallizes
j
in triclinic space group P1, while the yellow plates is 13 that
crystallizes in the orthorhombic space group Cmca. Structure
shown in Figure 1 is the orange material that has two
independent molecules in the asymmetric unit, one of which is
depicted. The Pd(1)-N(1)-C(9)-C(8)-N(2) five-membered
ring is planar within four degrees. The other ring, Pd(1)-N(2)-
C(10)-C(11)-C(12), assumes a puckered geometry, with C(11)
forming the flap of an envelope and N(2)-Pd(1)-C(12)-C(11)
dihedral angle is 18.3(5)°. The N(2)-Pd(1)-C(12) angle is
83.3(2)°, showing distortion from an idealized square planar
geometry at the palladium center. Several related crystalographi-
cally characterized palladium complexes that possess dianionic
NNC ligands have been described in literature. Amino acid-
derived (NNC)Pd complexes have been described by Beck.18
Espinet19 and an Italian group20 have also reported several ortho-
palladated species resulting from NNC ligands. Layh has shown
that facile cyclometalation of sp3 C-H bonds is observed in a
monoanionic (NN)Pd system, affording an interesting PdNSiC
heterocycle.21
a Amide (1 equiv), Pd(OAc)2 (0.05 equiv), base (2.5 equiv), and ArI
(3-4 equiv) Yields are isolated yields. See the Supporting Information
for details. b Diarylated product also isolated (9%). In all other cases,
<5% diarylation was observed.
be successful since the competitive destruction of alkyl
iodides is expected to be slower. It was determined that the
optimal auxiliary for alkylation of C-H bonds is 8-amino-
quinoline. Alkylation conditions involve heating of the
substrate with alkyl iodide or benzyl bromide to 100-110
°C in tert-amyl alcohol in the presence of K2CO3 base and
catalytic amount of pivalic acid (Table 4). ꢀ-Alkylation of
propionic acid amide can be performed with branched (entry
1) or straight-chain primary alkyl iodides (entry 2). The yields
are moderate. Benzoic acid derivatives, in contrast, can be
alkylated in good yields by alkyl iodides (entry 3) and benzyl
bromides (entries 4 and 5). Acid-catalyzed removal of the
(18) (a) Schreiner, B.; Urban, R.; Zorgafidis, A.; Su¨nkel, K.; Polborn, K.;
Beck, W. Z. Naturforsch. B 1999, 54, 970. (b) Bo¨hm, A.; Schreiner,
B.; Steiner, N.; Urban, R.; Su¨nkel, K.; Polborn, K.; Beck, W. Z.
Naturforsch. B 1998, 53, 191.
(19) Espinet, P.; Alonso, M. Y.; Garcia-Herbosa, G.; Ramos, J. M.; Jeannin,
Y.; Philoche-Levisalles, M. Inorg. Chem. 1992, 31, 2501.
(20) Bacchi, A.; Carcelli, M.; Costa, M.; Pelagatti, P.; Pelizzi, C.; Pelizzi,
G. J. Chem. Soc., Dalton Trans. 1996, 4239.
(21) Bowen, R. J.; Fernandes, M. A.; Layh, M. J. Organomet. Chem. 2004,
689, 1230.
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A R T I C L E S
Table 3. Arylation of Secondary C-H Bondsa
a Amide (1 equiv), Pd(OAc)2 (0.05 equiv), base (1.5-3.3 equiv), and ArI (2-4 equiv) Yields are isolated yields. See the Supporting Information for
details.
The reaction of 13 and 15 with bromine was investigated. If
of palladated methylene group is shifted downfield compared
13 was treated with Br2 at -78 °C, an unstable product that
decomposed in solution at -40 °C within minutes was obtained.
Reaction of 15 with bromine at -78 °C in CH2Cl2 afforded a
green solution, from which palladium(IV) dibromide 16 was
isolated in 85% yield after recrystallization from dichlo-
romethane-pentane at -20 °C (eq 4). Complex 16 decomposes
at 0 °C within hours in solution and within days in solid state.
Relative stability of 16 may be explained by strong binding of
the isonitrile ligand to palladium. It is known that d6 octahedral
complexes often require dissociation of one ligand to decompose
by reductive elimination pathways.22 Interestingly, the signal
with the corresponding signals for 13-15 and appears at 4.80
1
ppm in H spectrum.
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A R T I C L E S
Shabashov and Daugulis
Table 4. Alkylation of C-H Bondsa
Figure 2. ORTEP view of 16. Selected interatomic distances (Å) and angles
(deg): Pd-N(2) ) 1.981(3), Pd-C(15) ) 1.993(4), Pd-C(12) ) 2.072(3),
Pd-N(1) ) 2.171(3), Pd-Br(1) ) 2.4411(5), Pd-Br(2) ) 2.4690(5),
N(1)-Pd-N(2)-C(8) ) 2.0(2), Pd-N(2)-C(10)-C(11) ) -5.5(4).
analysis. The five-membered Pd-N(2)-C(10)-C(11)-C(12)
ring adopts an envelope conformation with C(11) forming the
flap of the envelope (torsion angle Pd-N(2)-C(10)-C(11) )
-5.5(4)°). An octahedral arrangement of ligands around Pd(IV)
center is observed. The bromide ligands assume trans arrange-
ment about the palladium center. While Pd(IV) complexes have
been investigated quite extensively in recent years,23 it appears
that no alkylpalladium(IV) dibromides have been crystallo-
graphically characterized. Some Pd(IV) dibromides possessing
polydentate nitrogen or sulfur ligands have been described.24 It
appears that the dianionic, tridentate NNC ligand stabilizes
Pd(IV) oxidation state allowing for an efficient catalytic
functionalization of C-H bonds and also for isolation of unusual
and typically unstable high-valent Pd complexes. Unfortunately,
attempts to replace the bromide substituent with an aryl or alkyl
group have not been successful so far.
a Amide (1 equiv), Pd(OAc)2 (0.05 equiv), base (2.5-3.5 equiv),
pivalic acid (0.2 equiv), and RI or RBr (3-4 equiv) Yields are isolated
yields. See the Supporting Information for details.
Scheme 2. Synthesis of Nitrile and Isonitrile Complexes
2.5.2. Mechanistic Studies. Upon dissolution of 13 in
CD3CO2D, complete H/D exchange of the aliphatic hydrogens
was observed within minutes at room temperature. The loss of
alkyl hydrogen resonances in 13 with respect to time was
measured by NMR at -35 °C in CD2Cl2 containing 40 equiv
of CD3CO2D. First-order rate constant k ) 2.0 × 10-4 s-1 was
obtained corresponding to ∆Gq ) 18 kcal/mol.
Complexes 13 and 15 were reacted with p-tolyl iodide and
iodomethane, respectively, in acetone solvent at room temper-
ature (Scheme 4). Following the treatment with HI to remove
palladium, reaction mixture was either separated by preparative
TLC (for arylation of 13) or analyzed by 1H NMR (for
methylation of 15). A mixture of mono- and disubstitution
products was obtained in addition to the recovered unreacted
amide. This result shows that monomeric palladated complexes
are capable of reacting with alkyl and aryl halides and are thus
competent intermediates in the catalytic cycle.
The dibromide 16 was isolated as dark-green crystalline
blocks. Its structure was verified by X-ray crystallographic
(22) Williams, B. S.; Holland, A. W.; Goldberg, K. I. J. Am. Chem. Soc.
1999, 121, 252.
(23) (a) Canty, A. J. Acc. Chem. Res. 1992, 25, 83. (b) Racowski, J. M.;
Dick, A. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 10974. (c)
Sobanov, A. A.; Vedernikov, A. N.; Dyker, G.; Solomonov, B. N.
MendeleeV Commun. 2002, 1, 14. (d) Amatore, C.; Catellani, M.;
Deledda, S.; Jutand, A.; Motti, E. Organometallics 2008, 27, 4549.
(e) Guo, R.; Portscheller, J. L.; Day, V. W.; Malinakova, H. C.
Organometallics 2007, 26, 3874.
Figure 1. ORTEP view of 13. Selected interatomic distances (Å) and angles
(deg): Pd(1)-N(2) ) 1.969(4), Pd(1)-C(12) ) 2.012(6), Pd(1)-N(3) )
2.013(5), Pd(1)-N(1) ) 2.124(5), N(2)-Pd(1)-C(12)-C(11) ) 18.3(5),
N(2)-Pd(1)-C(12) ) 83.3(2).
(24) (a) Yamashita, M.; Ito, H.; Toriumi, K.; Ito, T. Inorg. Chem. 1983,
22, 1566. (b) Blake, A. J.; Kathirgamanthan, P.; Toohey, M. J. Inorg.
Chim. Acta 2000, 303, 137.
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3970 J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010

Palladium-Catalyzed Arylation and Alkylation
A R T I C L E S
Scheme 3. H/D Exchange Studies
Scheme 4. Arylation and Alkylation of Palladated Intermediates
Scheme 5. Reaction Mechanism
Pivalonitrile exchange was studied in CD2Cl2 solution at -35
°C by treatment of 14 with a large excess of CH3CN. The first-
order rate constant obtained by using 10 equiv of CH3CN (kobs
) 4.6 × 10-5 s-1) is about twice lower than the rate constant
obtained using 20 equiv (kobs ) 1.1 × 10-4 s-1). Thus it is clear
that ligand displacement proceeds by an associative mechanism,
consistent with the prevailing ligand substitution mechanism at
square planar Pd(II) centers.
At this point a generalized mechanism for the auxiliary-
directed arylation of C-H bonds can be proposed (Scheme 5).
Palladium acetate reaction with 8-pivaloylaminoquinoline af-
fords the palladium amide 17. The next step involves a rapid
cyclometalation of tert-butyl group resulting in the formation
of 18. We have shown that only amides possessing an NH group
are reactive;9b hence, formation of 17 is essential for the success
of reaction. Oxidative addition of alkyl or aryl iodide to 18
produces 19. However, intermediacy of Pd(III) can not be
excluded25 although formation of dimeric species is unlikely
in strongly coordinating acetonitrile solvent. Reductive elimina-
tion followed by ligand exchange releases 21 and regenerates
palladium amide.
3. Summary
We have developed a method for auxiliary-directed, pal-
ladium-catalyzed arylation and alkylation of sp3 and sp2 C-H
bonds. Stoichiometric silver additives are not required in contrast
with our previously reported procedure.9b Instead, simple
inorganic bases can be employed and some reactions can be
performed in alcohol/water mixtures. By employing 2-meth-
ylthioaniline auxiliary, selective monoarylation of primary sp3
C-H bonds can be achieved. If arylation of secondary sp3 C-H
bonds is desired, 8-aminoquinoline auxiliary may be used. For
alkylation of sp3 and sp2 C-H bonds, 8-aminoquinoline
auxiliary affords the best results. A cyclometalated reaction
intermediate has been isolated, structurally characterized, and
its conversion to a Pd(IV) species investigated. A general
reaction mechanism has been proposed involving formation of
palladium amide, cyclometalation, oxidative addition, and
reductive elimination steps. Detailed mechanistic studies of
separate catalytic steps will be reported in future.
(25) (a) Powers, D. C.; Geibel, M. A. L.; Klein, J. E. M. N.; Ritter, T.
J. Am. Chem. Soc. 2009, 131, 17050. (b) Deprez, N. R.; Sanford, M. S.
J. Am. Chem. Soc. 2009, 131, 11234.
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J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010 3971

A R T I C L E S
Shabashov and Daugulis
4. Experimental Section
7.58-7.43 (m, 3H) 2.55 (t, 2H, J ) 7.6 Hz) 1.89-1.77 (m, 2H)
1.63 (septet, 2H, J ) 6.7 Hz) 1.37-1.28 (m, 2H) 0.92 (d, 6H, J )
6.7 Hz). 13C NMR (75 MHz, CDCl3, ppm) δ 172.1, 148.3, 138.5,
136.5, 134.8, 128.1, 127.6, 121.7, 121.5, 116.6, 38.7, 28.1, 23.8,
22.7. Signal for one aliphatic carbon could not be detected. FT-IR
(neat, cm-1) ν 3353, 1687. Anal. Calcd for C16H20N2O: C 74.97,
H 7.86, N 10.93. Found: C 74.83, H 7.91, N 10.93.
General Procedure for Alkylation of C-H Bonds. A 2-dram
screw-cap vial was charged with Pd(OAc)2 (5 mol %), K2CO3 (2.5
equiv), substrate (1 equiv), pivalic acid (20 mol %), and alkyl iodide
(3-4 equiv). The tert-amyl alcohol (0.7 mL) solvent was added
and the resulting mixture was stirred and heated at 100-110 °C
for 12-26 h. The conversion was monitored by GC. After
completion of reaction, ethyl acetate was added to reaction mixture
followed by extraction with water. Aqueous layer was washed once
with ethyl acetate. Combined organic extracts were dried over
MgSO4. Filtration and evaporation under reduced pressure followed
by purification by flash chromatography gave products.
Acknowledgment. We thank the Welch Foundation (Grant No.
E-1571), National Institute of General Medical Sciences (Grant No.
R01GM077635), A. P. Sloan Foundation, and Camille and Henry
Dreyfus Foundation for supporting this research. We thank Dr.
James Korp for collecting and solving the X-ray structures of 13
and 16.
N-(5-Methylhexanoyl)-8-aminoquinoline (Table 4, entry 1).
The general procedure was followed using N-propionyl-8-amino-
quinoline (140 mg, 0.7 mmol), Pd(OAc)2 (7.8 mg, 0.035 mmol),
K2CO3 (242 mg, 1.75 mmol), pivalic acid (14 mg, 0.14 mmol),
and 2-methyliodopropane (240 µL, 2.1 mmol). Resulting mixture
was heated for 22 h at 110 °C. Flash chromatography (toluene/
EtOAc 50/1 to 25/1) gave 104 mg (58%) of a colorless oil, Rf )
Supporting Information Available: Detailed experimental
procedures, characterization data for new compounds, and X-ray
crystallography data for 13 and 16. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
0.19 (toluene/EtOAc 50/1). H NMR (300 MHz, CDCl3, ppm) δ
9.82 (s, 1H) 8.83-8.78 (m, 2H) 8.17 (dd, 1H, J ) 8.3, 1.7 Hz)
JA910900P
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3972 J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010