Mild and efficient palladium-catalyzed intramolecular direct arylation reactions

Article abstract of DOI:10.1016/j.tet.2008.01.057

The influence of ligand, stoichiometric base, and additive has been evaluated in the context of intramolecular direct arylation reactions. Under the optimal conditions, arylation of simple arenes can be performed under very mild conditions, with heating to 50 °C. The role of the pivalic acid additive is rationalized by invoking a concerted palladation-deprotonation pathway where the pivalate is behaving as either an intramolecular base from the palladium metal or through an intermolecular deprotonation in a similar manner as that previously described by Echavarren and Maseras.

Full text of DOI:10.1016/j.tet.2008.01.057

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 6015e6020
www.elsevier.com/locate/tet
Mild and efficient palladium-catalyzed intramolecular
direct arylation reactions
*
Marc Lafrance, David Lapointe, Keith Fagnou
Center for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
Received 11 October 2007; received in revised form 20 November 2007; accepted 21 November 2007
Available online 17 January 2008
Abstract
The influence of ligand, stoichiometric base, and additive has been evaluated in the context of intramolecular direct arylation reactions. Under
the optimal conditions, arylation of simple arenes can be performed under very mild conditions, with heating to 50 ꢀC. The role of the pivalic
acid additive is rationalized by invoking a concerted palladationedeprotonation pathway where the pivalate is behaving as either an intramo-
lecular base from the palladium metal or through an intermolecular deprotonation in a similar manner as that previously described by Echavarren
and Maseras.
Ó 2008 Published by Elsevier Ltd.
Type 1: Both Arenes are Pre-Activated as a Halide (X) and an
1. Introduction
Organometallic (M)
R2
The synthesis of biaryl molecules has been greatly
X
M
Catalyst
R1
R2
+
facilitated through the development of palladium-catalyzed
cross-coupling reactions, of which the Suzuki reaction is
undoubtedly the most renown (Scheme 1, Type 1).1 Suzuki
couplings occur between aryl halide and an arylboronic acid
in the presence of a palladium catalyst and base. While wide-
spread, it is important to recognize that both of the arene com-
ponents must be prepared prior to cross-coupling to install the
organometallic and halide moieties. This can involve several
steps and ultimately leads to the formation of additional waste
subsequent to biaryl formation.
Recognizing both the value of biaryl molecules and the po-
tential for improvement, several research groups have been
searching for ways to reduce our reliance on substrate pre-
activation. One approach involves the replacement of the
one of the two pre-activated arenes. In the context of Type 3
biaryl cross-coupling reactions, tremendous success has been
achieved with the use of electron-rich heteroaromatic
R1
Type 2: One Arene Pre-Activated as an Organometallic (M)
R2
H
M
Catalyst
R1
R2
+
R1
Type 3: One Arene Pre-Activated as a Halide (X)
R2
X
H
Catalyst
R1
R2
+
R1
Scheme 1. Strategies for biaryl synthesis.
compounds.3 This can be attributed to the growing apprecia-
tion and application of electrophilic aromatic substitution (or
metalation) reaction pathways in reaction design. Indeed,
from a strategic perspective, replacement of the nucleophilic
aryl organometallic component may best be done with
electron-rich, p-nucleophilic aromatic compounds whose
latent reactivity might mimic that of the organometallic at
the transmetalation step of the catalytic cycle. For this reason,
* Corresponding author. Tel.: þ1 613 562 5800x6055; fax: þ1 613 562
5170.
E-mail address: keith.fagnou@uottawa.ca (K. Fagnou).
0040-4020/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.01.057

6016
M. Lafrance et al. / Tetrahedron 64 (2008) 6015e6020
much less progress has been realized with simple arenes such
as benzene or with electron-deficient arenes/heteroarenes as
coupling partners with the simple, unfunctionalized arene it-
self (Scheme 1, Types 2 and 3).2 Since more waste and chal-
lenge is associated with the preparation and use of the aryl
organometallic fragment, it has been most commonly this
component which has been removed (Type 3).
products are isolated in good to excellent yields and a mecha-
nistic proposal is advanced to explain the enhancement in
reactivity.
During the course of our investigations on benzene aryl-
ation,9 we found that the combined use of a catalytic amount
of pivalic acid (30 mol %) when used in conjunction with an
excess of K2CO3 provided vastly superior outcomes when
compared to the use of K2CO3 alone. These observations
prompted us to reevaluate the intramolecular direct arylation
processes to determine if any benefits would be revealed. Re-
action development efforts focused on the appropriate choice
of ligand in the reaction of 1a to give the biaryl 2a. A variety
of ligands were screened in conjunction with Pd(OAc)2
(5 mol %), pivalic acid (30 mol %), K2CO3 (3 equiv) in
DMA at 45 ꢀC (Scheme 3). From these experiments, two li-
gands were found to give the highest yields, triphenylphos-
phine 12 and tri(4-fluorophenyl)phosphine 19. Since 19 gave
slightly superior yield, it was taken on for further optimization
work. The observation that electron-deficient phosphines can
provide the optimal outcomes in direct arylation has previ-
ously been noted by Itami et al.,10 Baudoin et al.,11 and by
us.12 It is plausible that the use of such ligands may facilitate
arene binding by creating a more electron-deficient palladium
metal atom or by providing for a vacant site for arene binding
by undergoing more facile displacement from the metal center.
Employing Pd(OAc)2 with ligand 19 a variety of carbox-
ylic acid additives were evaluated in conjunction with
K2CO3 as the stoichiometric base (Table 1). There is a marked
increase in conversion as the steric encumbrance of the acid
increases from acetic acid to pivalic acid (entries 2e5). In
contrast the use of adamantylcarboxylic acid results in an in-
ferior conversion (entry 6). The use of more acidic additives,
such as with trifluoroacetic acid does not influence the reac-
tion outcome compared to a control when no additive is em-
ployed (entry 7 vs entry 1). The selection of stoichiometric
base also has a profound effect on the transformation. For
example, use of sodium carbonate provides slightly lower
2. Results and discussion
During the course of our methodological work on intramo-
lecular direct arylation reactions, an intriguing effect of fluo-
rine substituents was observed, which appeared incompatible
with an SEAr pathway.4 To rationalize the reactivity, we in-
voked concerted palladationedeprotonation pathways where
the acidity of the CeH bond might influence both site selectiv-
ity and reactivity. Such pathways have been proposed and
evaluated by others, including Davies et al.,5 Echavarran
et al.,6 and Sakaki et al.7 (Scheme 2). The viability of this al-
ternative pathway as well as computed information regarding
the potential transition states played a large role in reaction de-
velopment efforts, leading to the development of fluorobenz-
ene8 and benzene9 arylation reactions. As part of these
studies, the beneficial effects associated with the use of a cata-
lytic quantity of pivalic acid in conjunction with a stoichiomet-
ric and insoluble inorganic base was noted. These results were
rationalized by similar transition states as those proposed for
the intramolecular variants.
Herein, we describe our work in applying these new condi-
tions to the original source of our inspiration, intramolecular
direct arylation reactions of simple arenes. The new conditions
permit a dramatic reduction in reaction temperature. While it
is not atypical to require forcing conditions with heating in ex-
cess of 120 ꢀC for these types of reactions, our new conditions
permit intramolecular direct arylation reactions of simple are-
nes to occur at temperatures as low as 50 ꢀC. The biaryl
O
O
O
H
H
HO
O
H
X
H
O
O
HO
O
Pd
O
Pd
O
Pd NMe2
OAc
Pd
O
PR3
PR3
Acetate Assisted
Acetate Assisted
Carbonate Assisted
Palladation
Carbonate Assisted
Palladation
Benzene Palladation
Palladacycle Formation
Sakaki
Davies, Macgregor
Echavarren, Maseras
F
F
F
F
O
O
H
H
HO
F
O
O
Pd
Pd
PR3
PR3
Carbonate and Pivalate Assisted Intermolecular
Palladation of Simple and Electron-Deficient
Benzenes
Scheme 2. Mechanistic possibilities for arene palladation in the context of biaryl synthesis.

M. Lafrance et al. / Tetrahedron 64 (2008) 6015e6020
6017
5 mol% Pd(OAc)2
Br
5 mol% Ligand
30 mol% PivOH
O
3.0 eq. K2CO3
DMA, 45 °C
O
2a
1a
100
75
50
25
0
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19
H
BF4
R2
R4
H
BF4
N
N+
Cl-
Ar
Ar
P
R1
R3
R2
P
O
H
PPh2
PPh2
3
4
8: Ar=2,4,6-MePh
P
10
3
12: R1,R2,R3,R4=H
O
O
R
PPh2
PPh2
H
BF4
P
R
13: R1,R2,R3,R4=F
Fe
O
P
P
Me2N
14: R1,R3,R4=H, R2=CF3
15: R1,R3,R4=H, R2=Me
16: R1,R2,R3=H, R4=Me
17: R1,R2,R4=H, R3=CF3
18: R1,R2,R4=H, R3=OMe
19: R1,R2,R4=H, R3=F
6: R = Cy
7: R = Ph
9
5
11
Scheme 3. Ligand evaluation in intramolecular direct arylation reactions.
conversions than the potassium salt while use of cesium car-
bonate results in very low conversions after the same reaction
time (Table 2, entries 1e3). The use of a catalytic quantity of
pivalic acid (which generates potassium pivalate in situ when
treated with potassium carbonate) is also superior to simply em-
ploying potassium pivalate as the terminal stoichiometric base
as illustrated by entries 4 and 5. The enhanced reactivity associ-
ated with the presence of 30 mol % potassium pivalate in the
reaction mixture can be partially gained through the use of
a palladium pivalate catalyst precursor. With Pd(OPiv)2 and
potassium carbonate as the base, a 71% conversion is observed
after 12 h compared to the use of Pd(OAc)2, which provides
only 32% (entry 7 vs entry 2).
Table 1
Effect of carboxylic acid additives on direct arylationa
Br
Pd(OAc)2, P(p-FPh)3
Additive, K2CO3,
O
DMA, 45 °C
O
1a
2a
Entry
1
Additive
None
Conv.b (%)
31
Entry
5
Additive
Conv.b (%)
100
Table 2
Influence of stoichiometric base on direct arylationa
O
OH
Br
Pd(OR)2, P(p-FPh)3,
Additive, Base,
O
CO2H
O
DMA, 45 °C
O
1a
2
3
32
36
63
6
7
56
28
2a
OH
Entry
Pd source
Additive
Base
Conv.b (%)
O
1
2
3
4
5
6
7
a
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OPiv)2
Pd(OPiv)2
None
None
None
None
PivOH
None
PivOH
Na2CO3
K2CO3
Cs2CO3
KOPiv
K2CO3
K2CO3
K2CO3
22
32
O
F
F
OH
OH
5
22
F
O
100
71
4
OH
100
a
Conditions: substrate 1a, Pd(OR)2 (5 mol %), P(p-FPh)3 (5 mol %), addi-
tive (30 mol %), and base (3.0 equiv) are dissolved in DMA (0.25 M) and
heated to 45 ꢀC for 12 h.
Conditions: substrate 1a, Pd(OAc)2 (5 mol %), P(p-FPh)3 (5 mol %), addi-
tive (30 mol %), and K2CO3 (3.0 equiv) are dissolved in DMA (0.25 M) and
heated to 45 ꢀC for 12 h.
b
b
Determined by GCeMS.
Determined by GCeMS.

6018
M. Lafrance et al. / Tetrahedron 64 (2008) 6015e6020
the absence of pivalic acid provides approximately 30% con-
5% Pd(OR)2, 5% (p-FPh)3P
version while an identical reaction performed with 30 mol %
pivalic acid reached 100% conversion. A similar, albeit less
pronounced, acceleration is also observed using palladium piva-
late as the catalyst precursor in place of palladium acetate.
Application of these optimized reaction conditions to
a range of substrates is included in Table 3. A variety of acti-
vated and deactivated aryl bromides are compatible including
reactions for the formation of sterically encumbered biaryls.
These are rare examples where the arylation of a broad range
of simple arenes can be achieved under such mild conditions.
A range of substitution patterns are compatible including elec-
tron-donating (entries 3, 5, and 6) and withdrawing groups
(entries 4, 9, and 10). Reaction at more sterically encumbered
positions can also occur in high yield (entries 1, 3, and 5).
More highly functionalized substrates can also be employed
as illustrated by the use of a precursor for aporphine synthesis
in entry 5.
3.0 eq. K2CO3, 30% Additive,
Br
DMA, 50 °C
O
O
2a
1a
100
90
80
70
60
50
40
30
20
10
0
Pd(OPiv)2 + PivOH
Pd(OPiv)2
Pd(OAc)2
0
1
2
3
4
Time (h)
5
6
7
8
9
Scheme 4. Ligand evaluation in intramolecular direct arylation reactions.
The presence of primary kinetic isotope effects is strong
evidence for a mechanism where the CeH bond cleavage is a ki-
netically significant step in the catalytic cycleda feature, which
is inconsistent with electrophilic aromatic substitution path-
ways. Under the current reaction conditions, reaction of 1l re-
veals the presence of a pronounced primary intramolecular
The acceleration in product formation over time resulting
from the addition of pivalic acid is illustrated in Scheme 4. Af-
ter 6 h, a reaction performed under the standard conditions in
Table 3
Substrate scope in intramolecular direct arylationa
Entry
Substrate
Product
Yieldb (%) Entry
Substrate
Product
Ratioc Yieldb (%)
1
96d
6
7
>30:1 99
Br
1b
Br
1g
2b
O
O
O
O
O
O
O
O
2g
Br
1c
2
3
4
97
>30:1 98
15:1 96
1.2:1 93
Br
O
O
O
O
O
1h
2h
2c
O
O
95
94
8
9
Br
Br
1d
1i
2i
Cl
Cl
O
2d
O
O
O
O
F
O2N
O2N
Br
O
O
O
F
1e
1j
2j
2e
Br
O
O
O
O
N
O
N
O
70e
10
>30:1 92
Br
5
O
O
MeO2C
O
MeO2C
1f
1k
2k
2f
Br
a
Conditions: substrate, Pd(OPiv)2 (5 mol %), P(p-FPh)3 (5 mol %), PivOH (30 mol %), and K2CO3 (3.0 equiv) are dissolved in DMA (0.25 M) and heated to
50 ꢀC for 12 h.
b
Isolated yield.
Ratio of regioisomers formed at the ortho positions.
Reaction performed at 60 ꢀC.
Reaction performed at 70 ꢀC.
c
d
e

M. Lafrance et al. / Tetrahedron 64 (2008) 6015e6020
6019
1a
Pd(PR3)n
O
O
H
X
20
Pd
PR3
PivOK
KBr
O
O
O
O
O
H
X
Pd
23
O
PR3
Pd
H
Pd
O
PR3
24
PivOH
21
PR3
PivOH
K2CO3
O
O
O
H
PivOK + KHCO3
Pd
PR3
22
Scheme 5. Proposed catalytic cycle.
hydrogen/deuterium kinetic isotope effect of 5.4. This magni-
tude of KIE is in line with our previously observed KIE of
3.512 for similar reactions performed in the absence of pivalic
acid and of 3.08 and 5.59 for intermolecular direct arylation
reactions with perfluorobenzenes and benzene, respectively. It
is also consistent with KIEs reported by Echavarren and Maseras
with similar substrates for intramolecular reactions.6 Pro-
nounced KIEs are compatible with, and characteristic of, mech-
anisms where CeH bond cleavage is occurring simultaneously
with carbonepalladium bond formation.13
In line with Echavarren’s and Maseras’s proposed mecha-
nism for intramolecular direct arylation6 and our own work
in intermolecular processes4 we favor the involvement of a cata-
lytic cycle similar to that illustrated in Scheme 5. Subsequent
to oxidative insertion into the carbonehalide bond, two path-
ways may be followed. The first involves an anion exchange of
a pivalate for the bromide ligand to give 21. This species can
then undergo a concerted deprotonationepalladation to give
the biarylpalladium(II) intermediate 23, which will reductively
eliminate to give the observed product and regenerate the cata-
lyst. Alternatively, the pivalate may be acting as an external
base at the CeH bond cleaving transition state via 24 to inter-
cept intermediate 23 of the other pathway. The reason for the
superior reactivity of pivalic acid as an additive in these reac-
tions compared to other carboxylic acids may be related to
both its steric bulk and the increased basicity of its conjugate
base. The ability to control the amount of pivalate present is
crucial to achieve maximal reactivity. It is also noteworthy
that some bidentate ligands such as 9 and 10 exhibited moder-
ate reactivity under these conditions. This may indicate the in-
volvement of a pentacoordinate pathway16 or a cationic
manifold may be operating with an intermolecular deprotona-
tion such as that illustrated by 24.
While evidence points to the involvement of concerted
palladationedeprotonation pathways in the present reactions,
insufficient data exists to state whether one, the other, or
both of these pathways are responsible for the observed reac-
tivity. Indeed, as previously pointed out,6 the intimate reaction
mechanism may change from reaction to reaction as the sub-
strate, solvent, base, and additives are changed. If accurate,
such a flat thermodynamic landscape can make a detailed un-
derstanding of the exact mechanism for any precise reaction
elusive. Nonetheless, we have, and are continuing, to use these
transition states and reaction pathways as an enabling technol-
ogy in the development of other, novel carbonecarbon bond
forming processes.
3. Conclusion
These reactions, and more importantly, the reaction condi-
tions that enable them should be of use in the synthetic com-
munity for the preparation of biaryl molecules. The particular
mildness of these conditions with respect to the base and tem-
perature should enable an application to more complex mole-
cules that may be prone to decomposition under more forcing
reaction conditions and the commonly employed elevated re-
action temperatures that are commonly associated with direct
arylation protocols.
4. Experimental section
4.1. General methods
N,N-Dimethylacetamide was purchased from commercial
sources and degassed with argon prior to every use. Pd(OPiv)2
was synthesized according to the known literature procedure.14

6020
M. Lafrance et al. / Tetrahedron 64 (2008) 6015e6020
All other solvents or chemical were purchased from commercial
sources and used as received. Experiments were carried out un-
der an atmosphere of argon. 1H, 19F, and 13C NMR were
recorded in CDCl3 solutions using a Bruker AVANCE 400 or
500 MHz spectrometer. 1H and 13C chemical shifts were deter-
mined relative to internal tetramethylsilyl at d¼0. NMR
high-resolution mass spectra were obtained on a Kratos
Concept IIH. Infra red analysis was performed with a Bruker
EQUINOX 55.
Rf¼0.23 (SiO2, 3% ether/hexane); IR (nmax/cmꢁ1): 2982,
1
1518, 1339, 1266, 1106; H NMR (400 MHz, CDCl3, 293 K,
TMS): 1.67 (6H, s), 7.00 (1H, d, J¼8.9 Hz), 7.25e7.27 (1H,
m), 7.36e7.43 (2H, m), 7.76e7.79 (1H, s), 8.10 (1H, dd,
J¼8.9, 2.7 Hz), 8.64 (1H, d, J¼2.7 Hz); 13C NMR
(100 MHz, CDCl3, 293 K, TMS): 27.9, 79.5, 118.4, 118.9,
122.4, 122.5, 123.4, 124.9, 126.3, 128.2, 129.4, 138.7,
142.2, 158.2; HRMS calcd for C15H13O3N (Mþ) 255.0895,
found: 255.0873.
Bromoether 1a,4 1b,4 1c,12 1d,4 1f,15 1g,4 1h,4 1i,4 1j,4 1k4
were prepared accordingly and exhibited spectral data identi-
cal to literature. Tricyclic compound 2a,4 2b,4 2c,12 2d,4
2f,15 2g,4 2h,4 2i,4 2j,4 2k4 were prepared using the general cy-
clization procedure and exhibited spectral data identical to
literature.
Acknowledgements
We thank NSERC for support of this work. The Research
Corporation (Cottrell Scholar Award; K.F.), the Ontario gov-
ernment (Premier’s Research Excellence Award; K.F.), Merck
Frosst, Astra Zeneca, Amgen, Eli Lilly, and Boehringer Ingel-
heim are thanked for additional unrestricted financial support.
M.L. thanks NSERC for a CGS-D.
4.2. 1-(2-(2-Bromo-5-nitrophenoxy)propan-2-yl)benzene 1e
To a flask containing a suspension of potassium hydride
(0.27 g, 2.0 mmol, 1.1 equiv) in THF (3 mL) at 0 ꢀC was
added slowly the 2-phenylpropan-2-ol (0.4 g, 2.0 mmol,
1.1 equiv) and the solution was stirred for 10 min. This solu-
tion was then added slowly to a solution of 2-bromo-1-
fluoro-4-nitrobenzene (0.4 g, 1.8 mmol, 1.0 equiv) in THF
(9 mL) at 0 ꢀC. The solution was then allowed to warm to
room temperature and was stirred for an additional 2 h. Satu-
rated aqueous ammonium chloride was then added and the so-
lution was extracted with DCM and dried over magnesium
sulfate. Compound 1e was then purified by column chroma-
tography on silica gel using 3% ether/hexanes as the eluant.
References and notes
1. For reviews on this topic, see: (a) Metal-catalyzed Cross-coupling Reac-
tions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, NY,
1998; (b) Hassan, J.; Se’vignon, M.; Gozzi, C.; Shulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359.
2. For recent reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
Rev. 2007, 107, 174; (b) Seregin, I. V.; Gevorgyan, V. J. Chem. Soc.,
Chem. Rev. 2007, 36, 1173; (c) Campeau, L.-C.; Stuart, D. R.; Fagnou,
K. Aldrichimica Acta 2007, 40, 35.
3. (a) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476; (b)
Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc.
2006, 128, 4972; (c) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc.
2005, 127, 4996; (d) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897; (e)
Lewis, J. C.; Wiedemann, S. H.; Bergmann, R. G.; Ellman, J. A. Org. Lett.
2004, 6, 35; (f) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.;
Gevorgyan, V. Org. Lett. 2004, 6, 1159; (g) Li, W.; Nelson, D. P.; Jensen,
M. S.; Hoerrner, R. S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett.
2003, 5, 4835; (h) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M.
J. Am. Chem. Soc. 2002, 124, 5286; (i) Kakiuchi, F.; Kan, S.; Igi, K.;
Chatani, N.; Murai, S. J. Am. Chem. Soc. 2003, 125, 1698; (j) McClure,
M. S.; Glover, B.; McSorley, E.; Millar, A.; Osterhout, M. H.; Roschangar,
F. Org. Lett. 2001, 3, 1677.
Yield 83%: Rf¼0.30 (SiO2, 5% ether/hexane); IR (nmax
/
cmꢁ1): 2984, 1516, 1473, 1341, 1275, 1138; 1H NMR
(400 MHz, CDCl3, 293 K, TMS): 1.85 (6H, s), 6.36 (1H, d,
J¼9.2 Hz), 7.28e7.41 (5H, m), 7.80 (1H, dd, J¼9.2,
2.8 Hz), 8.42 (1H, d, J¼2.8 Hz); 13C NMR (100 MHz,
CDCl3, 293 K, TMS): 29.3, 83.9, 114.5, 116.8, 123.4, 124.9,
127.8, 128.9, 128.9, 141.0, 144.1, 158.4; HRMS calcd for
C15H14O3NBr (Mþ) 335.0157, found: 335.0105.
4. Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, F. J. Am. Chem. Soc.
2006, 128, 581.
4.3. General cyclization procedure
5. Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc.
2005, 127, 13754.
K2CO3 (1.7 mmol, 3.0 equiv), Pd(OPiv)2 (0.03, 0.05 equiv),
P(p-FPh)3 (0.03 mmol, 0.05 equiv), andpivalic acid(0.17 mmol,
0.3 equiv) were weighed to air and placed in a screw capped
vial (4 mL) with a magnetic stir bar. The reaction vessel was
evacuated and backfilled with argon three times. The cyclization
precursor (0.57 mmol, 1.0 equiv) was then added to the reaction
vesselas a solution in N,N-dimethylacetamide (3 mL). Thereac-
tion was heated to 50e60 ꢀC for 12 h. Upon completion, the
reaction was cooled to room temperature. The products were
loaded directly onto a silica gel packed column and eluted using
ether/hexane mixtures.
6. (a) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
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The compound was prepared following the general cycliza-
tion procedure at 50 ꢀC. Yield 94%; mp¼92e95 ꢀC(ether);