Amide-directed arylation of sp3 C-H bonds using Pd(II) and Pd(0) catalysts

Article abstract of DOI:10.1016/j.tet.2010.03.111

Protocols to effect β-arylation of sp³ C-H bonds via Pd(II)/(IV) and Pd(0)/(II) catalytic cycles have been achieved using a newly developed monodentate CONHC₆F₅ directing group. These reactions provide an unprecedented means to functionalize sp³ C-H bonds in aliphatic carboxylic acid-derived substrates.

Full text of DOI:10.1016/j.tet.2010.03.111

Tetrahedron 66 (2010) 4811e4815
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Tetrahedron
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Amide-directed arylation of sp3 CeH bonds using Pd(II) and Pd(0) catalysts
*
Masayuki Wasa, Jin-Quan Yu
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Protocols to effect b
-arylation of sp3 CeH bonds via Pd(II)/(IV) and Pd(0)/(II) catalytic cycles have been
Article history:
Received 19 January 2010
Received in revised form 26 March 2010
Accepted 29 March 2010
Available online 9 April 2010
achieved using a newly developed monodentate CONHC6F5 directing group. These reactions provide an
unprecedented means to functionalize sp3 CeH bonds in aliphatic carboxylic acid-derived substrates.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Amide
Palladium
Arylation
sp3 CeH activation
1. Introduction
accommodates organophosphine or NHC ligands and aryl halides
(Scheme 1).1,2
Pd-catalyzed CeH activation/functionalization reactions have
emerged as powerful synthetic tools for converting ubiquitous sp2
and sp3 CeH bonds into desired chemical functional groups.1,2d
Methods for effecting the functionalization of aryl and heteroaryl
sp2 CeH bonds have been extensively investigated and have found
impressive applications in natural products synthesis and drug
discovery.2 In contrast, the functionalization of more inert sp3 CeH
bonds still represents a tremendous challenge in organic synthesis
and remains at an early stage of development.
Ar
H
Ar
Pd(II)/(IV)
Pd(0)/(II)
DG
DG
DG
R1 R2
R1 R2
R1 R2
ArI, oxidant
ArX
PR3 or NHC
1
1a
1a
Scheme 1. Two catalytic cycles to effect Pd-mediated arylation of sp3 CeH bonds.
The redox chemistry involving Pd(IV) has been poorly understood
in its early stage and gained much attention in recent years.10
A
The majority of sp3 CeH activation methods utilize heteroatom-
containing functional groups that can coordinate the metal and
direct CeH insertion.1a,3 Indeed, reactions that proceed via cleavage
of sp3 CeH bonds directed by heteroatom-directing groups such as
oximes,4 oxazolines,5 and pyridines6,13b have been well-docu-
mented. Recent investigations in the area of directed CeH func-
tionalization focus on utilizing more synthetically practical
functional groups, such as amino,7 amide,8 and carboxyl9 groups as
directing groups. Using the directing group approach, a number of
sp3 CeH activation/CeC bond forming reactions have been repor-
ted.2 One important class of these reactions concerns the Pd-cata-
lyzed arylation of unactivated sp3 CeH bonds with aryl halides,
which was developed via two distinct catalytic pathways: Pd(II)/
(IV) catalysis, which uses aryl iodides and requires external oxidant
for reoxidation, and Pd(0)/(II) homogeneous catalysis, which
number of reactions have been developed using the Pd(II)/(IV) ca-
talysis, which includes acetoxylation, amination, arylation, haloge-
nation, among others.1,2 For instance, Chen reported an interesting
arylation of aldehydic CeH bonds with [Ph2I]Br, which could involve
the Pd(II)/(IV) catalysis.11 Sanford and Daugulis independently de-
veloped general approaches using directed CeH activation and [Ph2I]
PF612 or [Ph2I]BF46d for arylation of sp2 CeH bonds. Building on these
studies, Daugulis and et al. went on to develop a highly efficient CeH
arylation reaction using readily available aryl iodides and applied
these conditions to effect arylation of sp3 CeH bonds (Scheme 2).6b,c
Pd(OAc)2
AgOAc
ArI
Pd(OAc)2
AgOAc
N
N
N
N
H
NH
ArI
Ar
NH
H
Ar
2a
R
O
3
R
O
3a
2
* Corresponding author. Tel.: þ1 858 784 7942; fax: þ1 858 784 7949; e-mail
Scheme 2. Arylation of sp3 CeH bonds using aryl iodides.
address: yu200@scripps.edu (J.-Q. Yu).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.111

4812
M. Wasa, J.-Q. Yu / Tetrahedron 66 (2010) 4811e4815
Ar
O
H
Ar
O
Notably, despite numerous evidence for Pd(II)/Pd(IV) catalysis
reportedinliterature,1e4 theinvolvementofPd(II)/Pd(III)catalysis has
also been invoked with substantial experimental support.13 It is
possible that the competition between these two catalytic pathways
may vary with substrates.
O
Pd(0)/PR3
ArI
Pd(II)
NHC6F5
NHC6F5
NHC6F5
ArI, AgOAc
R(H)
R(H)
R(H)
10a
10
10a
Scheme 5. Amide-directed arylation of sp3 CeH bonds via two modes of catalysis.
Their initial reports described the arylation of an sp3 CeH bond
in 2-ethylpyridine (2) using catalytic amounts of Pd(OAc)2 and
stoichiometric AgOAc.6b A subsequent report by the same group
2. Results and discussion
demonstrated impressive examples of b-arylation using an effec-
2.1. Arylation of sp3 CeH bonds via Pd(II)/(IV) catalysis
tive bisdentate directing group such as (3).6c Notably, this reaction
represents a rare example of catalytic methylene CeH activation in
Pd chemsitry. Corey et al. have used this directing group and these
reaction conditions to functionalize sp3 CeH bonds in natural
amino acid derivatives (4) (Scheme 3).14 A related investigation by
In 2007, we reported that the b-methyl groups of aliphatic carboxylic
acids could be cross-coupled with aryl iodides via sp3 CeH bond acti-
vation in the presence of stoichiometric Ag2CO3 (Scheme 3).9b However,
the carboxylate moiety proved to be a poor directing group for activa-
tion of inert sp3 CeH bonds, as it required high reaction temperatures
and gave low yields. Additionally, we found that this reaction was in-
our group described b-arylation of simple aliphatic acids without
installing a directing group (5); however the yields were low
(40e70%) and the reaction temperature was higher (130 ꢀC).9b We
found, by converting the carboxylic acids into structurally analo-
gous hydroxamic acids (6), the yields could be greatly improved
(>80%), and the reaction could be carried out at lower temperature
compatible with aliphatic carboxylic acids that contained a-hydrogen
atoms, a problem that could not be remedied by converting the car-
boxylate to other directing groups, such as oxazoline5 or hydroxamic
acid (6).8d Thus, the substrate scope was limited to compounds that
(60 ꢀC).15 However, substrates containing
reactive with either carboxylic acids or this directing group.
a-hydrogens were not
contained quaternary a-carbon atoms. In an effort to overcome both of
these issues, we sought to develop a novel directing group that would
enhance the reactivity and broaden the substrate scope.
Based on previous reports, we were aware that bis-coordinating
pyridine-containing directing groups such as 3 and 4 were capable
H
Pd(OAc)2
Ag2CO3
Ar
Pd(OAc)2
AgOAc
N
N
R1
R2
R1
R2
HN
Ar
O
H
HN
O
OH
OH
ArI
NaOAc, ArI
of directing CeH activation with substrates that contained
drogen atoms.6c,14 However, we thought that a simpler mono-
dentate directing group could provide both the reactivity and
a-hy-
H
H
O
O
NPth
H
NPth
iPr
4a
iPr
a
-
4
5
5a
hydrogen tolerance that we sought. Based on the high reactivity
observed with hydroxamic acids (6),8d we hypothesized that
replacing the methoxy group with functional group in which the
steric and electronic properties could be readily adjusted could
prove to be highly useful in developing an improved directing
group. Given that a wide variety of substituted anilines are com-
mercially available, we identified N-aryl amides as a class of po-
tential directing groups that would be easily tunable. To test this
idea, we initially converted pivalic acid into several N-arylpivala-
mides to examine whether the amide group was capable of
directing CeH activation (Scheme 6 and Table 1).
H
Ar
Pd(OAc)2
AgOAc
ArI
R1
R2
R1
R2
H
H
N
N
OMe
OMe
O
O
6a
6
Scheme 3. Pd(II)/Pd(IV) catalysis for sp3 CeH arylation.
Pd(0)-catalyzed arylation of CeH bonds using phosphine or NHC
ligands and aryl halides represents another class of CeH activation/
arylation reactions that has been extensively studied in recent
decades.9c,16e18 Compared to the aforementioned Pd(II)/Pd(IV) CeH
arylation reactions, this mode of catalysis does not require stoi-
chiometric silver salts, which is a significant practical advantage.
Both intra- and intermolecular arylation of aryl and heteroaryl sp2
CeH bonds has proven to be highly successful.9c,16e18 On the other
hand, only a limited number of sp3 CeH arylation reactions via Pd
(0)/Pd(II) catalysis have been achieved to date (Scheme 4).19In this
manuscript, we describe Pd-catalyzed sp3 CeH arylation protocols
using a recently developed amide directing group and two modes
of catalysis, Pd(0)/(II) and Pd(II)/(IV). (Scheme 5). Notably, the use of
this particular directing group allowed for a significant expansion
in substrate scope such that carboxylic acid derivatives containing
Ar
O
H
O
O
Pd(OAc)2
AgOAc
1. (COCl)2
2. ArNH2
Me
NHAr
NHAr
OH
ArI
Me Me
Me Me
Me Me
11b
11
11a
Scheme 6. Preparation of amide substrates.
We were encouraged by the initial observation of trace amount
of the desired arylation products using simple aniline-derived
amide with Cs2CO3 in neat PhI (Table 1, entry 2). Further screening
revealed that electron-withdrawing, fluorine-substituted directing
groups showed dramatically higher reactivity (Table 1, entries 3 and
5). The addition of base was found to be crucial for the arylation
reaction (as no product was obtained in absence of base) (Table 1,
entries 1 and 4) with Cs2CO3 giving the highest yield.
a
-hydrogen atoms could be tolerated.
CO2Et
EtO2C
Me
Me
Me
Me
Pd(0)/PR3
Pd(0)/PR3
O
O
Me
Me
To test if the reaction would be compatible with substrates
containing a-hydrogen atoms, we converted isobutyric acid to an
H
Br
Br
H
array of different N-arylisobutyramides. Gratifyingly, we obtained
a mixture of mono- and di-arylation products in high yields. The
reaction was optimized using various directing groups. Among
those screened, CONHC6F5 gave the best results (Table 2).
A variety of carboxylic acid derivatives were arylated in rea-
sonable to excellent yields under the optimized reaction conditions
7
7a
8
8a
Me Me
Me Me
Pd(0)/PR3
PhB(OH)2
H
Ph
Br
9
9a
Scheme 4. Arylation of sp3 CeH bonds via Pd(0)/(II) catalysis.
(Table 3). b-Amino acid substrate 15, as well as substrates derived

M. Wasa, J.-Q. Yu / Tetrahedron 66 (2010) 4811e4815
4813
Table 1
from commercial drugs, such as 16 (from Gemfibrozil) and 17 (from
Ibuprofen), were also compatible. For substrate 17, both -arylation
of the methyl group and -arylation of the arene were observed in
Arylation of N-phenylpivalamidesa,b
b
g
the major product. For substrate 14, it was possible to reduce the
reaction temperature to 100 ꢀC, though the yield decreased to 64%
even after 12 h.
Entry
Ar
Ph
Base
Yield (%)
sm
2.2. Arylation of sp3 CeH bonds via Pd(0)/(II) catalysis
mono
di
tri
Despite the remarkable efficiency of these Pd(II)/(IV)-catalyzed
arylation reactions, the need for superstoichiometric amount of
AgOAc is a major drawback. In contrast, Pd(0)-catalyzed homoge-
neous reactions accommodates phosphine or NHC ligands and do
not require a co-oxidants or silver salts, which are significant
practical advantages. Miura and Daugulis have previously reported
pioneering examples of Pd(0)/PR3-catalyzed sp2 CeH arylation re-
actions directed by amides18a and carboxylic acids,9c respectively.
We have recently reported CONHC6F5-directed arylation of sp3 CeH
bonds (Scheme 7).8f This work will be summarized briefly here to
allow for comparison to our Pd(II)/(IV) CeH arylation data, as both
reactions rely upon the same directing group.
1
2
3
None
100
91
0
7
0
0
0
8
Cs2CO3
Cs2CO3
2
39
41
12
4
5
None
100
12
0
0
0
Cs2CO3
32
40
16
a
Reaction conditions: 0.2 mmol substrate, 10 mol % Pd(OAc)2, 4 equiv AgOAc,
1.2 equiv Cs2CO3, 0.5 mL iodobenzene, 130 ꢀC, 3 h, air.
b
Yield was determined by 1H NMR analysis of crude product using CH2Br2 as the
Ar
H
O
O
internal standard.
Pd(0)/PR3
ArI
NHC6F5
NHC6F5
R(H)
R(H)
10
10a
Scheme 7. Pd(0)/PR3-catalyzed arylation of sp3 CeH bonds.
Table 2
Screening of directing groups for a
-hydrogen-containing substratesa
Based on the successful development of Pd(II)/(IV)-catalyzed
arylation directed by CONHC6F5 group, we initiated our in-
vestigation of Pd(0)-catalyzed activation of sp3 CeH bonds. Our
initial experiment using substrate 12 gave trace quantities of the
desired mono-arylated product with PPh3 as the ligand and Cs2CO3
as the base (Scheme 8). To improve this result, systematic screening
of ligands, bases, solvents, and coupling partners was undertaken.
H
O
Ph
Ph
Pd(0)/PPh3
Cs2CO3, PhI
H
NHC6F5
NHC6F5 Ph
NHC6F5
Me
Toluene
120 °C, N2
24h
H
H
H
a
The reaction conditions are identical to those described in Table 1.
O
O
12
12a 3%
12b 0%
Scheme 8. Initial experiments with Pd(0)/PR3-catalyzed sp3 CeH arylation.
Among the bases tested, only CsF gave appreciable amounts of
Table 3
Arylation of N-phenylpivalamidesa,b
the desired product. Buchwald ligands, protected as HBF4 salts
using Fu’s strategy,20 were found to give considerably better yield
than PPh3. To our surprise, the reaction was only found to proceed
when aryl iodides were used; aryl bromides, chlorides, triflates, and
tosylates did not give any of the desired product. The oxidative
insertion of Pd(0) into an arylehalide bond is the most facile for aryl
iodides. However, Fagnou and others have established that the use
of aryl iodides typically results in poor reactivity due to the accu-
mulation of iodide anions in reaction mixture, which ultimately
leads to catalyst poisoning.21 Indeed, higher catalyst and ligand
loadings (10 and 20 mol %, respectively) were needed to obtain high
product yields, which could be attributed to the poisoning phe-
nomenon. With the optimized conditions in hand, we obtained 12a
in 34% and 12b in 54% yield (Scheme 9).
Through the development of sp3 CeH arylation protocols via Pd
(0)/(II) and Pd(II)/(IV) catalysis, we learned there are inherent ad-
vantages and disadvantages of both catalytic cycles. CeH arylation
reactions via Pd(II)/(IV) catalysis went to completion in shorter
reaction times (<3 h) and gave generally higher product yields than
a
The reaction conditions are identical to those described in Table 1.
Isolated yield.
b

4814
M. Wasa, J.-Q. Yu / Tetrahedron 66 (2010) 4811e4815
Pd(0)/PR3
H
O
Ph
O
Ph
CsF, PhI
PCy2•HBF4
H
NHC6F5
NHC6F5 Ph
NHC6F5
54 %
PR3
=
Me
H
H
3Å MS
H
O
Toluene, N2
100 °C, 24 h
12a
12
34 %
12b
Scheme 9. Optimized conditions.
did Pd(0)/(II) catalysis for the same set of substrates. Nevertheless,
Pd(0)/(II)-catalyzed CeH arylation was found to proceed under
milder reaction conditions and did not require stoichiometric silver
salts, though the current conditions did require higher catalyst and
ligand loadings due to potential catalyst poisoning. Further opti-
mization is currently underway for the Pd(0)/(II) reaction, in an
effort to utilize other aryl halides in order to suppress catalyst
poisoning.
in a rotary evaporator. The purification was done by silica gel col-
umn chromatography using 1e5% diethyl ether/hexane as an
eluting solvent.
4.3.1. 2-Methyl-N-(perfluorophenyl)-3-phenylpropanamide (12a).
Substrate 12 was arylated following the general procedure. After
purification by column chromatography, 12a was obtained as
a
colorless solid (27.1 mg, 41%). 1H NMR (400 MHz, CDCl3)
d
7.34e7.10 (m, 5H), 6.72 (br s,1H), 3.10e2.97 (m,1H), 2.83e2.71 (m,
2H), 1.31 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 174.7, 139.3,
3. Conclusions
129.2, 129.0, 127.0, 44.1, 40.7, 18.1; IR (neat)
n 3256, 2927, 1682,
1498 cmꢂ1
;
HRMS (ESI-TOF) calcd for C16H12F5NO (MHþ):
b
-Arylation of inert sp3 CeH bonds via two catalytic pathways
330.0912; found: 330.0907.
has been achieved using a newly developed monodentate amide
directing group. These studies have allowed for the discovery of an
unprecedented CeH activation reaction of carboxylic acid-derived
4.3.2. 2-Benzyl-N-(perfluorophenyl)-3-phenylpropanamide (12b).
Substrate 12 was arylated following the general procedure. After
purification by column chromatography, 12b was obtained as
substrates that contain
a-hydrogen atoms. Follow-up studies to
further tune the directing group and to develop asymmetric sp3
CeH arylation of gem-dimethyl groups using chiral phosphine li-
gands are underway in our laboratory.
a
colorless solid (36.6 mg, 45%). 1H NMR (400 MHz, CDCl3)
d
7.32e7.20 (m, 8H), 6.12 (br s, 1H), 3.12e3.05 (m, 2H), 2.95e2.79
(m, 3H); 13C NMR (100 MHz, CDCl3)
d 173.2, 139.2, 129.2, 129.0,
127.1, 53.4, 39.5; IR (neat)
n ;
3231, 2919, 1674, 1526, 1450 cmꢂ1
4. Experimental
HRMS (ESI-TOF) calcd for C22H16F5NO (MHþ): 406.1225; found:
406.1235.
4.1. General experimental
4.3.3. N-(Perfluorophenyl)-3-phenylpropanamide (13a). Substrate
13 was arylated following the general procedure. After purification
by column chromatography, 13a was obtained as a colorless solid
Solvents were obtained from SigmaeAldrich and used directly
without further purification. 1H and 13C NMR spectra were recorded
on a Varian instrument (400 MHz and 100 MHz, respectively) and
internally referenced to the SiMe4 signal. Exact mass spectra for
new compounds were recorded on a VG 7070 high resolution mass
(43.0 mg, 68%). 1H NMR (400 MHz, CDCl3)
d 7.32e7.20 (m, 4H), 6.89
(br s, 1H), 3.05 (t, J¼7.6 Hz, 2H), 2.75 (t, J¼7.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3)
d 171.1, 143.3, 129.0, 128.6, 126.9, 38.3, 31.6; IR
spectrometer. Analytical GCeMS was performed on
a Hew-
(neat)
n
3264, 2921, 1680, 1530, 1495 cmꢂ1; HRMS (ESI-TOF) calcd
lettePackard G1800C instrument connected to an electron ioniza-
tion detector using a MS-5 GC column (30ꢁ0.25 mm). Infrared
spectra were recorded on a PerkineElmer FT-IR Spectrometer.
Carboxylic acids, anilines, and phosphine ligands were pur-
chased from Aldrich, Acros, and Strem and were used as received
without further purification. Pd(OAc)2 was received from Alfa
Aesar.
for C15H10F5NO (MHþ): 316.0755; found: 316.0755.
4.3.4. 2-Benzyl-N-(perfluorophenyl)pentanamide (14a). Substrate
14 was arylated following the general procedure. After purification
by column chromatography, 14a was obtained as a colorless solid
(62.3 mg, 84%). 1H NMR (400 MHz, CDCl3)
d 7.39e7.15 (m, 4H), 6.49
(br s, 1H), 2.95e2.82 (m, 1H), 2.82e2.80 (m, 1H), 2.61e2.54 (m, 1H),
2.04e1.99 (m, 1H), 1.88e1.68 (m, 1H), 1.53e1.32 (m, 4H), 0.93 (t,
4.2. Preparation of amide substrates
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
176.6,139.5,129.1,129.0,
3274, 2901,
126.9, 105.1, 44.2, 39.7, 36.2, 33.1, 23.0, 14.25; IR (neat)
n
An acid chloride (20 mmol), prepared from the corresponding
carboxylic acid and oxalyl chloride, was added to a vigorously
stirred solution of 2,3,4,5,6-pentafluoroaniline (22 mmol) in tolu-
ene (50 mL). The reaction mixture was stirred for 12 h under reflux,
and then stirred at room temperature for 4 h. The product mixture
was concentrated under vacuum and was recrystallized from ethyl
acetate/hexane (100 ꢀC to 0 ꢀC) to give the amide.
1650, 1520 cmꢂ1; HRMS (ESI-TOF) calcd for C19H18F5NO (MHþ):
371.1309; found: 371.1310.
4.3.5. 2-Benzyl-3-(1,3-dioxoisoindolin-2-yl)-N-(perfluorophenyl)
propanamide (15a). Substrate 15 was arylated following the gen-
eral procedure. After purification by column chromatography, 15a
was obtained as a colorless solid (62.7 mg, 66%). 1H NMR (400 MHz,
CDCl3)
4.18e4.13 (m, 1H), 3.92e3.86 (m, 1H), 3.51e3.39 (m, 1H), 3.15e3.09
(m, 1H), 2.96e2.91 (m, 1H); 13C NMR (100 MHz, CDCl3)
171.2,
168.6,138.1,134.6, 134.6, 129.1,127.2,123.8, 48.1, 40.6, 37.2; IR (neat)
d 7.86e7.73 (m, 4H), 7.30e7.16 (m, 4H), 6.74 (br s, 1H),
4.3. General procedure for palladium-catalyzed arylation of
sp3 CeH bonds via Pd(II)/(IV) catalysis
d
Substrate (0.2 mmol), aryl iodide (0.5 mL), AgOAc (0.8 mmol),
and Cs2CO3 (0.24 mmol) were added in a 25 mL glass pressure
vessel. Pd(OAc)2 (0.02 mmol) was added to the reaction mixture,
tightly capped and heated to 130 ꢀC with vigorous stirring. The
reaction was stopped after it completely turned black (typically
3 h). The black solid was filtered off, and the solvent was removed
n
3268, 2918, 2850, 1716, 1522, 1495 cmꢂ1; HRMS (ESI-TOF) calcd
for C24H15F5N2O (MHþ): 475.1076; found: 475.1075.
4.3.6. 2-Benzyl-6-(2,5-dimethylphenyl)-2-methyl-N-(per-
fluorophenyl)hexanamide (16a). Substrate 16 was arylated

M. Wasa, J.-Q. Yu / Tetrahedron 66 (2010) 4811e4815
4815
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; (e) Seregin, I. V.; Gevorgyan,
V. Chem. Soc. Rev. 2007, 36, 1173; (f) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013.
3. (a) Ryabov, A. D. Chem. Rev. 1990, 90, 403; (b) Ackermann, L. Top. Organomet.
Chem. 2007, 24, 35; (c) Kalyani, D.; Sanford, M. S. Top. Organomet. Chem. 2007,
24, 85.
4. (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542; (b)
Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048; (c) Desai, L. V.;
Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141.
following the general procedure. After purification by column
chromatography, 16a was obtained as a colorless solid (33.5 mg,
34%). 1H NMR (400 MHz, CDCl3)
d 7.42 (s, 1H), 7.30e7.24 (m, 5H),
6.98 (d, J¼7.6 Hz, 1H), 6.77 (s, 1H), 6.65 (d, J¼7.6 Hz, 1H), 3.99 (t,
J¼6.0 Hz, 3H), 3.16 (d, J¼13.2 Hz, 2H), 2.80 (d, J¼13.2 Hz, 2H), 2.80
(s, 3H), 2.10 (s, 3H) 1.98e1.40 (m, 6H), 1.30 (s, 3H); 13C NMR
5. (a) Giri, R.; Liang, J.; Lei, J. G.; Li, J. J.; Wang, D. H.; Chen, X.; Naggar, I. C.; Guo, C.;
Foxman, B. M.; Yu, J. Q. Angew. Chem., Int. Ed. 2005, 44, 7420; (b) Giri, R.; Chen,
X.; Hao, X.-S.; Li, J.-J.; Liang, J.; Fan, Z.-P.; Yu, J.-Q. Tetrahedron: Asymmetry 2005,
16, 3502; (c) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44, 2112; (d)
Giri, R.; Wasa, M.; Breazzano, S. P.; Yu, J.-Q. Org. Lett. 2006, 8, 5685; (e) Chen, X.;
Li, J. J.; Hao, X. S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78.
6. (a) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149; (b) Shabashov, D.; Dau-
gulis, O. Org. Lett. 2005, 7, 3657; (c) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J.
Am. Chem. Soc. 2005, 127, 13154; (d) Kalyani, D.; Deprez, N. R.; Desai, L. V.;
Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330; (e) Chen, X.; Goodhue, C. E.; Yu,
J.-Q. J. Am. Chem. Soc. 2006, 128, 12634; (f) Hull, K. L.; Lanni, E. L.; Sanford, M. S. J.
Am. Chem. Soc. 2006, 128, 14047.
(100 MHz, CDCl3)
123.8, 121.3, 112.5, 92.6, 68.0, 48.3, 46.7, 36.6, 25.1, 21.5, 16.1 cmꢂ1
IR (neat)
3296, 2924, 2869, 1675, 1523, 1490 cmꢂ1; HRMS (ESI-
TOF) calcd for C27H26F5NO2 (MHþ): 492.1956; found: 492.1959.
d 175.4, 157.0, 137.1, 137.0, 130.7, 130.6, 127.2,
;
n
4.3.7. 2,2-Dibenzyl-6-(2,5-dimethylphenyl)-N-(perfluorophenyl)hex-
anamide (16b). Substrate 16 was arylated following the general
procedure. After purification by column chromatography, 16b was
obtained as a colorless solid (44.3 mg, 39%). 1H NMR (400 MHz,
CDCl3)
d
7.30e7.21 (m, 10H), 6.93 (d, J¼8.0 Hz, 1H), 6.76e6.59 (m,
7. Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211.
8. (a) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156; (b) Yang, S.; Li,
B.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066; (c) Shabashov, D.; Daugulis,
O. J. Org. Chem. 2007, 72, 7720; (d) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am.
Chem. Soc. 2008, 130, 7190; (e) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130,
14058; (f) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 9886.
9. (a) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org. Chem. 1998,
63, 5211; (b) 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; (c) Chiong, H. A.; Pham, Q.-N.;
Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879; (d) Giri, R.; Yu, J.-Q. J. Am. Chem.
Soc. 2008, 130, 14082; (e) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2008,
130, 17676; (f) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
6097; (g) Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654; (h) Wang, D.-
H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2009, ASAP; (i) Shi, B.-F.; Zhang, Y.-
H.; Lam, J. K.; Wang, D.-H.; Yu, J.-.Q. J. Am. Chem. Soc. 2009, ASAP.
10. (a) For early proposal of formation of Pt(IV) complexes, see: Pope, W. J.; Peachy,
S. J. Proc. Chem. Soc., London 1907, 23, 86; (b) For oxidation of Pt(II) to Pt(IV) by
O2 see: Rostovtsev, V. V.; Henling, L. M.; Labinger, J. A.; Bercaw, J. E. Inorg. Chem.
2002, 41, 3608; (c) Uson, R.; Fornies, J.; Navarro, R. J. Organomet. Chem. 1975, 96,
307; (d) Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1987, 109, 4753; (e) Canty, A.
J. Acc. Chem. Res. 1992, 25, 83.
3H), 4.00 (t, J¼5.6 Hz, 2H), 3.27 (d, J¼13.6 Hz, 2H), 2.94 (d,
J¼13.6 Hz, 2H), 2.28 (s, 3H), 2.20e2.08 (m, 2H), 1.96 (s, 3H),
1.87e1.77 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 174.6, 156.8, 137.0,
137.0, 130.6, 130.6, 128.7, 127.2, 123.7, 121.5, 112.4, 105.1, 67.8, 42.9,
30.1, 28.5, 21.7, 16.1; IR (neat) 3299, 2924, 2856, 1676, 1523,
1453 cmꢂ1 HRMS (ESI-TOF) calcd for C33H30F5NO2 (MHþ):
n
;
568.2269; found: 568.2269.
4.3.8. 2-(5-Isobutylbiphenyl-2-yl)-N-(perfluorophenyl)-3-phenyl-
propanamide (17a). Substrate 17 was arylated following the gen-
eral procedure. After purification by column chromatography, 17a
was obtained as a colorless solid (67.0 mg, 64%). 1H NMR (400 MHz,
CDCl3)
d 7.59e7.16 (m, 9H), 6.99e6.93 (m, 4H), 6.28 (s, 1H), 3.97 (t,
J¼7.6 Hz, 1H), 3.49e3.45 (m, 1H), 3.06e3.03 (m, 1H), 2.47 (d,
J¼7.2 Hz, 2H), 1.90e1.85 (m, 1H), 0.93 (d, J¼2.8 Hz, 6H); 13C NMR
(100 MHz, CDCl3)
d 172.1, 142.5, 141.4, 141.4, 139.4, 133.4, 131.2,
11. Xia, M.; Chen, Z.-C. Synth. Commun. 2000, 30, 531.
12. Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046.
13. (a) McAuley, A.; Whitcombe, T. W. Inorg. Chem. 1988, 27, 3090; (b) Hull, K. L.;
Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134; (c) Cotton, F. A.;
Koshevoy, I. O.; Lahuerta, P.; Murillo, C. A.; Sanaú, M.; Ubeda, M. A.; Zhao, Q. L. J.
Am. Chem. Soc. 2006, 128, 13674; (d) Kaspi, A. W.; Yahav-Levi, A.; Goldberg, I.;
Vigalok, A. Inorg. Chem. 2008, 47, 5; (e) Furuya, T.; Ritter, T. J. Am. Chem. Soc.
2008, 130, 10060; (f) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
10806.
129.6, 129.5, 129.4, 128.8, 128.6, 127.8, 127.6, 126.7, 50.7, 45.3, 39.8,
30.5, 22.7; IR (neat)
n 3260, 2950, 2929, 1700, 1512, 1489,
1411 cmꢂ1; HRMS (ESI-TOF) calcd for C31H26F5NO (MHþ): 523.1945;
found: 523.1944.
Acknowledgements
14. Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391.
15. Unpublished results.
We gratefully acknowledge The Scripps Research Institute, the
National Institutes of Health (NIGMS, 1 R01 GM084019-02), Amgen
and Eli Lilly for financial support. We thank the A.P. Sloan Foun-
dation for a fellowship (J.-Q.Y.), and the Bristol Myers Squibb for
graduate fellowships (M.W.).
16. For arylation of heterocycles see: (a) Nakamura, N.; Tajima, Y.; Sakai, K. Het-
erocycles 1982, 17, 235; (b) Akita, Y.; Ohta, A. Heterocycles 1982, 19, 329; (c)
Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc.
Jpn. 1998, 71, 467; (d) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.;
Gevorgyan, V. Org. Lett. 2004, 6, 1159.
17. For pioneering work on Pd(0)-catalyzed arylation of arenes see: (a) Hennings,
D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997, 62, 2; (b) Satoh, T.; Kawamura, Y.;
Miura, M.; Nomura, M. Angew. Chem., Int. Ed. 1997, 36, 1740.
18. For Pd(0)-catalyzed intermolecular arylation of sp2 CeH bonds see: (a) Ka-
metani, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2000, 41, 2655; (b)
Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
References and notes
1. For reviews, see; (a) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041;
(b) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439; (c) Daugulis, O.;
Zaitsev, V. G.; Shabashov, D.; Pham, Q.-N.; Lazareva, A. Synlett 2006, 3382; (d)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
5094.
2. For reviews, see; (a) Hassan, J.; Sévignon, M.; Gozzi, C.; Shultz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359; (b) Kakiuchi, F.; Murai, S. Acc.Chem. Res. 2002, 35,
826; (c) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253; (d) Alberico, D.;
19. (a) Dyker, G. Angew. Chem., Int. Ed. 1992, 31, 1023; (b) Baudoin, O.; Herrbach, A.;
Guéritte, F. Angew. Chem., Int. Ed. 2003, 42, 5736; (c) Zhao, J.; Campo, M.; Larock,
R. C. Angew. Chem., Int. Ed. 2005, 44, 1873; (d) Barder, T. E.; Walker, S. D.;
Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685; (e) Lafrance,
M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 14570.
20. Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
21. Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581.