Palladium-catalyzed intramolecular reactions of (E)-2,2-disubstituted 1-alkenyldimethylalanes with aryl triflates

Article abstract of DOI:10.1021/om900286x

A full account of the Pd-catalyzed intramolecular reactions of (E)-2,2-disubstituted 1-alkenyldimethylalanes with aryl triflates as an entry into polycarbocyclic structures displaying an ethyl - methyl-substituted all-carbon benzylic quaternary center is

Full text of DOI:10.1021/om900286x

3518
Organometallics 2009, 28, 3518–3531
Palladium-Catalyzed Intramolecular Reactions of
(E)-2,2-Disubstituted 1-Alkenyldimethylalanes with Aryl Triflates
†
‡
§
´
Eric Fillion,* Vincent E. Tre´panier, Jarkko J. Heikkinen, Anna A. Remorova,
Rebekah J. Carson,| Julie M. Goll, and Adam Seed
Department of Chemistry, UniVersity of Waterloo, Waterloo, Ontario N2L 3G1, Canada
ReceiVed April 15, 2009
A full account of the Pd-catalyzed intramolecular reactions of (E)-2,2-disubstituted 1-alkenyldimethyl-
alanes with aryl triflates as an entry into polycarbocyclic structures displaying an ethyl-methyl-
substituted all-carbon benzylic quaternary center is herein presented. It was found that the efficiency
of the Pd-catalyzed carbon-carbon bond forming process is highly affected by the structure of the
starting material, including tether length and aryl substitution pattern; substituting the position ortho
to the triflate is mandatory to obtain a good yield of the carbocycle. Moreover, the formation of
1-ethyl-1-methylindanes is facile in comparison to the case for the analogous tetrahydronaphthalenes,
for which the competing methyl cross-coupling reaction is equally competent. It was established
through labeling studies that the carbon-carbon bond forming events are stereospecific and proceed
though the intermediacy of a neopentylic sp3-gem-dimetallic palladio(II) dialkylaluminoalkane species,
from which a 1,2-methyl migration from aluminum to carbon occurs. Intramolecular palladium-
catalyzed reactions of 1-naphthyl triflates with (E)-2,2-disubstituted 1-alkenyldimethylalanes revealed
two competing reaction pathways: arylation with sequential 1,2-alkyl migration from aluminum to
carbon and intramolecular 1,2-diarylation, in which the catalytic cycle is terminated by direct arylation
of the C(sp3)-Pd(II) bond. Factors such as tether length, additives, solvent polarity, and C-H · · · Pd
interactions between the Pd(II) center and the hydrogen atom at the 8-position all influence not only
the pathway taken by the (σ-aryl)palladium(II) complexes but also the subsequent reactivity of the
(σ-alkyl)palladium(II) complexes.
other Pd-catalyzed C-C bond forming methods, are espe-
cially powerful for the assembly of complex carbocyclic
structures.3
Introduction
Palladium-catalyzed inter- and intramolecular arylation of
alkenes with aryl triflates and halides has been thoroughly
studied and exploited in synthesis.1 The key carbon-carbon
bond forming event proceeds through migratory insertion of
an olefin into a (σ-aryl)palladium(II) complex, accessed by
oxidative addition of Pd(0) catalysts into aryl halide and aryl
triflate bonds, and results in a (σ-alkyl)palladium(II) complex
intermediate. A multitude of bond-forming avenues are then
available for the newly formed palladium species. ꢀ-Hydride
elimination is a common pathway (Heck reaction) for (σ-
alkyl)palladium(II) species, generating alkene products.
Functionalization of the C-Pd bond has been successful
primarily for neopentylic (σ-alkyl)palladium(II) complexes,
in which the ꢀ-hydride elimination pathway is unavailable.2
Intramolecular olefin arylation reactions, when coupled with
There exists a vast body of studies on the reactivity of (σ-
aryl)palladium(II) complexes with alkenes. However, from a
synthetic and mechanistic point of view, little is known on their
reactivity with metalated alkenes aside from cross-coupling
reactions. Carbopalladation of metalated alkenes and the forma-
tion of Pd(II)-based dimetallic species have been proposed to
rationalize the formation of cine substitution products in cross-
coupling reactions.4 Our group has provided evidence that cine
substitution in the Stille coupling proceeds through sp3-gem-
dimetallic palladio(II)-trialkylstannylalkane complexes, which
exhibit carbenoid reactivity and undergo dimerization and alkene
cyclopropanation.5
As illustrated in Scheme 1, we further disclosed that (E)-
2,2-disubstituted 1-alkenyldimethylalanes react intramolecularly
with aryl triflates and iodides, undergoing arylation with
concomitant methyl migration from aluminum to carbon to form
ethyl-methyl-substituted benzylic all-carbon quaternary ste-
reocenters in benzocyclic structures.6
* To whom correspondence should be addressed. E-mail: efillion@
uwaterloo.ca.
† Current address: Institute of Chemical and Engineering Sciences,
Chemical Synthesis Lab@Biopolis, 11 Biopolis Way, Helios Block #03-
08, Singapore 138667.
A full account of our findings on the Pd-catalyzed intramo-
lecular reactions of (E)-2,2-disubstituted-1-alkenyldimethyl-
alanes with aryl triflates is herein presented. The preparation of
polycarbocyclic structures displaying an ethyl-methyl-substi-
tuted all-carbon benzylic quaternary center was investigated
‡ Current address: Department of Chemistry, University of Oulu, P.O.
Box 3000, Oulu FI-90014, Finland.
§ Current address: Toronto Research Chemicals, 2 Brisbane Road, North
York, Ontario M3J 2J8, Canada.
| Current address: De´partement de Chimie, Boehringer Ingelheim
(Canada) Ltd., Recherche et de´veloppement, 2100 rue Cunard, Laval,
Que´bec H7S 2G5, Canada.
(1) (a) Diedrich, F., Stang, P. J., Eds. Metal-Catalyzed Cross Coupling
Reactions; Wiley-VCH: Weinheim, Germany, 1998. (b) Farina, V.; Krish-
namurthy, V.; Scott, W. J. Org. React. 1998, 50, 1–657. (c) Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
McNeil Consumer Healthcare Division of Johnson & Johnson Inc.,
Manufacturing Site, 890 Woodlawn Road West, Guelph, Ontario N1K 1A5,
Canada.
10.1021/om900286x CCC: $40.75
2009 American Chemical Society
Publication on Web 05/20/2009

Pd-Catalyzed Reactions of 1-Alkenyldimethylalanes
Organometallics, Vol. 28, No. 12, 2009 3519
Scheme 1. Palladium-Catalyzed Alkene Arylation/1,2-Methyl
Migration Reaction
Scheme 3. Proposed Domino Sequence
thoroughly, and it was found that the efficiency of the Pd-
catalyzed process is highly affected by the structure of the
starting material, including tether length and aryl substitution
pattern. Substitution of the positions ortho to the triflate is
mandatory to obtain a good yield of the carbocycle. Morever,
the formation of 1-ethyl-1-methylindanes is facile in comparison
to the analogous tetrahydronaphthalenes. The scope and limita-
tions of the arylation/methyl shift reaction are presented, as well
as thorough mechanistic and stereochemical studies.
In addition, the intramolecular palladium-catalyzed reaction
of 1-naphthyl triflates with (E)-2,2-disubstituted 1-alkenyldi-
methylalanes revealed two competing reaction pathways: namely,
arylation with sequential 1,2-alkyl migration from aluminum
to carbon and intramolecular 1,2-diarylation, in which the
catalytic cycle is terminated by (σ-alkyl)palladium(II) complex
direct arylation (Scheme 2). Factors such as tether length,
additives, solvent polarity, and C-H · · · Pd interactions between
the Pd(II) center and the hydrogen atom at the 8-position all
influence not only the pathway taken by the (σ-aryl)palladium(II)
complexes but also the subsequent reactivity of the (σ-
alkyl)palladium(II) complexes.
Using either THF or toluene as solvent and Pd(PPh3)4 (25
mol %) at temperatures ranging between 70 and 100 °C, neither
tricycle 4 nor the dimeric species was detected. Instead, the
major product of the reaction, albeit in low yield, was an
inseparable 1:1 diastereomeric mixture of bicycles containing
an ethyl group (eq 1). The structure of 5 was elucidated by NMR
studies and GC-MS analysis. No products derived from the
anticipated Pd-carbene reactivity were observed.
A C(sp3)-C(sp3) coupling process was postulated in the
formation of the ethyl group at the all-carbon benzylic quater-
nary center, which deserved further investigation. Simplified
substrate 6 was designed to preclude diastereomer formation
upon cyclization, thereby facilitating product analysis and
reaction optimization.9 When alkyne 6 was methylaluminated
and then subjected to catalytic Pd(0) cyclization conditions, four
reaction products possessing molecular ions of m/z 158, 160,
172, and 174, respectively, were observed by GC-MS (Scheme
4), in a combined yield of 31%. Through synthesis via alternate
routes,10 their structures were ascertained unambiguously, and
the 8:9:10:11 ratio was determined to be 24:12:58:6 in the crude
mixture. Tricycle 8 was separated from the mixture and its
Scheme 2. Palladium-Catalyzed Alkene Arylation/1,2-Methyl
Migration Reaction or/and Alkene 1,2-Diarylation
11
1
structure assigned by H NMR. Three new carbon-carbon
bonds are formed in the overall process from 6 to 8, 10, and
11.
Scheme 4. Preparation and Carbocyclization of Alkene 7
Results and Discussion
For our initial examination of the reaction of (σ-aryl)palla-
dium(II) complexes with (E)-2,2-disubstituted 1-alkenyldim-
ethylalanes, the cyclization substrate 1 was first considered
(Scheme 3).7 The vinylalane 2 was generated by Negishi’s
methylalumination protocol.8 It was initially proposed that
intermediate 3 would originate from intramolecular migratory
insertion of the (σ-aryl)palladium(II) iodide species and that this
species would display Pd-carbenoid behavior as described by
our group for sp3-gem-dimetallic halo-Pd(II) trialkylstannyla-
lkanes. Subsequent C-H insertion of the Pd-carbene in the
isopropylic carbon-hydrogen bond would form tricycle 4, in a
one-pot sequence. Dimerization of the resulting carbene was
also envisaged as a significant competing pathway.
Strained tricycle 8 was proposed to arise from carbopalla-
dation of the vinylalane to yield a neopentylic sp3-gem-dimetallic
iodopalladio(II) dialkylaluminoalkane intermediate that subse-
quently takes part in intramolecular C-H bond arylation.12 The
gem-dimethyl compound 9 was of limited interest compared to
the arylation process, since no additional C-C bond was formed.
Carbocyclized products 10 and 11 incorporated an additional
methyl group, presumably from the dimethylalane moiety.13 It
remained to be determined if products 8, 10, and 11 resulted
from a common reactive intermediate and if both processes,
alkene arylation/C-H functionalization and alkene arylation/
methyl incorporation, could be independently optimized in order
to fully exploit the synthetic potential of these catalytic
transformations. Should these products arise from a common
(2) For examples of oxidative interception of Heck intermediates
outcompeting ꢀ-hydride elimination, see: (a) Kalyani, D.; Sanford, M. S.
J. Am. Chem. Soc. 2008, 130, 2150–2151. (b) Tong, X.; Beller, M.; Tse,
M. K. J. Am. Chem. Soc. 2007, 129, 4906–4907.
(3) For reviews, see: (a) Grigg, R.; Sridharan, V. J. Organomet. Chem.
1999, 576, 65–87. (b) Negishi, E.; Cope´ret, C.; Ma, S.; Liou, S.-Y.; Liu, F.
Chem. ReV. 1996, 96, 365–393.

3520 Organometallics, Vol. 28, No. 12, 2009
Fillion et al.
intermediate, reaction conditions that would allow selection of
either process would then be significant, both mechanistically
and synthetically.
opening of oxacyclobutane with (3-isopropyl-2-(methoxym-
ethyl)-1-phenyl)lithium15 furnished the corresponding 3-aryl-
1-propanol. The precursors to 14 and 17 were synthesized from
the parent benzaldehyde via stabilized Wittig olefination and
hydrogenation, followed by ester reduction (Scheme 6b).16 The
1-propanol derivatives were then converted to bromides and
homologated with lithium (trimethylsilyl)acetylide to the cor-
responding alkynylsilane. With the TMS-butynyl and TMS-
pentynyl compounds in hand, the substrates were obtained
following sequential deprotection and triflation.
In order to address these issues, third-generation substrates
possessing an alkyl substituent at the ortho position (12-15)
were synthesized, along with naphthalenyl triflates (16 and 17)
(Scheme 5). Ortho substitution would not only prevent the
competing C-H 1,4-insertion reaction but also favor C-H 1,5-
insertion into C(sp3)-H benzylic hydrogens in 12-15 and
C(sp2)-H aryl hydrogens in 16 and 17, affording more stable
five-membered-ring products. For an optimal comparison of the
reactivity of aryl triflates in the Pd-catalyzed multiple bond
forming reactions, the unsubstituted substrate 18 was also
prepared.
Scheme 6. Synthesis of Aryl Triflate Cyclization Substrates
Scheme 5. Third-Generation Substrates
Optimization Studies
With adequate supplies of cyclization precursors 12-18 in
hand, their reactivity was explored. Methylalumination of aryl
triflate 12 led to the desired 2,2-disubstituted 1-alkenyldi-
methylalane, using typical Negishi conditions (2.0 equiv of
Me3Al and 25 mol % of Cp2ZrCl2), with no interference of the
triflate substituent.17 Following evaporation of the volatiles,
heating the vinylalane for 24 h at 100 °C in acetonitrile with
Pd(PPh3)4 (25 mol %) provided a 79:8:13 ratio of cyclized
products 19, 20, and the methyl cross-coupled product 21.19
Indanes 19 and 20 were separated from 21 and isolated in a
combined 42% yield (eq 2). The separation of the nonpolar
products from PPh3 was tedious, which affected the isolated
yield. It was determined that acetonitrile was optimal (Table 2,
entry 1), as good conversion to products was observed and
competing formation of the gem-dimethyl compound was
hindered. The structure of 1-ethenyl-1,7-dimethylindane (20)
For the optimization studies, we required access to ample
amounts of 2-(3-butynyl)-tethered triflates 12, 13, 16, and 18.
Aryl triflates were selected, as they were readily prepared from
widely available 2-substituted phenols. Their synthesis was
realized by nucleophilic displacement of o-methoxymethyl-
protected benzylic bromides with 1-lithio-3-(trimethylsilyl)prop-
2-yne (Scheme 6). A one-pot three-transformation procedure,
wherein 3-substituted 2-methoxymethoxybenzyl alcohols were
transformed into the corresponding benzyl bromides by mesy-
lation followed by Finkelstein displacement with lithium
bromide, was devised (Scheme 6a).10 The resulting benzyl
bromides were reacted with lithiated TMS-propyne,14 furnish-
ing TMS-butynyl adducts in yields >70% for the overall
process. Conversely, 6-substituted 2-(4-pentynyl)-tethered aryl
and naphthyl triflates 14, 15, and 17 were accessed via
homologation of a 3-aryl-1-bromopropane derivative with
(trimethylsilyl)acetylene. En route to 15, nucleophilic ring
(7) Synthesized by coupling of 2-iodobenzyl bromide with the propargyl
anion of (5-methylhex-1-ynyl)trimethylsilane, followed by K2CO3 in MeOH
desilylation (64% yield over 2 steps). See the Supporting Information for
detailed experimental procedures.
(8) Negishi, E. Acc. Chem. Res. 1987, 20, 65–72.
(9) Substrate 6 was synthesized in six steps commencing with 2-iodo-
benzyl bromide displacement with the sodium anion of diethyl malonate
(THF, reflux, 70%), followed by Krapcho decarboxylation, to afford ethyl
3-(2-iodophenyl)propanoate in quantitative yield. Subsequent reduction with
excess DIBAL-H (THF,-30 °C, 93%) and then bromination of the alcohol
(CBr4, PPh3, 85%) resulted in 3-(2-iodophenyl)-1-bromopropane. Homolo-
gation of the latter with 1-lithiotrimethylsilylacetylene installed the requisite
alkyne functionality. Finally, desilylation of the terminal alkyne (K2CO3,
MeOH, 64% over two steps) provided 1-(2-iodophenyl)pent-4-yne (7) in
an overall 35% yield. See the Supporting Information for details.
(4) (a) Farina, V.; Hossain, M. A. Tetrahedron Lett. 1996, 37, 6997–
7000. (b) Busacca, C. A.; Swestock, J.; Johnson, R. E.; Bailey, T. R.; Musza,
L.; Rodger, C. A. J. Org. Chem. 1994, 59, 7553–7556.
(5) Fillion, E.; Taylor, N. J. J. Am. Chem. Soc. 2003, 125, 12700–12701.
´
(6) Fillion, E.; Carson, R. J.; Tre´panier, V. E.; Goll, J. M.; Remorova,
A. A. J. Am. Chem. Soc. 2004, 126, 15354–15355.

Pd-Catalyzed Reactions of 1-Alkenyldimethylalanes
Organometallics, Vol. 28, No. 12, 2009 3521
was confirmed by hydrogenation (H2, 5% Pd/C, EtOAc) of the
inseparable mixture to pure 1,7-dimethyl-1-ethylindane (19).
Further improvements to the reaction conditions were at-
tempted by revisiting the additives. As depicted in Table 1, entry
2, a poor 15% isolated yield of 19 from 12 was observed in the
absence of DABCO, with a 73:27 ratio of methyl shift 19 to
methyl cross-coupling adduct 21. The ratio became even worse
with respect to 19 using 1.0 equiv of cesium fluoride (Table 1,
entry 3). The addition of excess triethylamine gave a better ratio
of 94:6, yet product 19 was generated concomitantly with 8%
of methyl-vinyl side product 20 (entry 4). 4-(Dimethylamino)-
pyridine (DMAP) was inadequate at promoting this process
(entry 5), and DBU gave an incomplete conversion (entry 6).23
Table 1. Lewis Basic Additives
Conditions for the preparation of a single product, indane
19, and the elimination of the pathways leading to 20 and 21
were investigated. An array of ligands in combination with
Pd2(dba)3 was then examined, including dppb (1,4-diphe-
nylphosphinobutane), dppe (1,2-diphenylphosphinoethane), dppf
(1,1′-diphenylphosphinoferrocene), t-Bu3P, and Ph3As. Poor
results were obtained; either no reaction or decomposition
occurred when the methyl cross-coupled product 21 or gem-
dimethyl products were not preferentially formed.
entry
additive
DABCO
additive n (equiv)
ratioa (19:21)
yieldb (%)
1
2
3
4
5
6
6
>99:1
73:27
55:45
94:6c
77:23
67:33d
67
15
17
56
18
N/A
CsF
Et3N
DMAP
DBU
1
6
6
6
The electron-rich P(p-MeOC6H4)3 ligand was shown by Hii
and co-workers to improve (σ-aryl)palladium(II) migratory
insertion kinetics.20,18 Keay reported the superiority of 1,4-
diazabicyclo[2.2.2]octane (DABCO) in the asymmetric con-
struction of all-carbon benzylic quaternary centers through
intramolecular Heck reactions.21 Substituting Pd(PPh3)4 with
P(p-MeOC6H4)3 (40 mol %) and Pd2(dba)3 (5 mol %) as the
catalytic system, in the presence of a 6-fold excess of DABCO,
produced 19 exclusively in a reproducible 50-55% yield (eq
3). While product isolation and purification were also greatly
facilitated, compounds 20 and 21 were not formed, as deter-
a Determined by 1H NMR analysis of the crude reaction mixture.
b Isolated yield of compound 19. c Contaminated with 8% of
methyl-vinyl product 20. d Reaction 78% complete.
Solvent effects were also investigated. Among various aprotic
solvents compatible with vinylalanes, nonpolar and noncoor-
dinating solvents (1,2-dichloroethane and toluene) were found
to provide substantial amounts of the competing methyl cross-
coupled product 21 (Table 2). Lewis-basic ethereal solvents
(DME, 1,4-dioxane) improved the ratios of methyl-shift versus
cross-coupled adducts as well as yields (entries 4 and 5).
Benzonitrile (entry 6) did not possess the optimal properties of
acetonitrile (entry 1), despite their similar functionality.
1
mined by H NMR analysis of the crude mixture. Of note, a
6-fold excess of DABCO was required for complete eradication
of 20.
Table 2. Solvent Optimization
The objective of exclusively forming 19 was attained, but it
was observed that dibenzylideneacetone was consumed in the
course of the reaction, likely reacting with the substrate’s
alkenyldimethylaluminummoiety.Indeed,10mol%ofPdCl2[P(p-
MeOC6H4)3]222 in the presence of P(p-MeOC6H4)3 (20 mol %)
and Et3N (10 mol %) improved the yield to 67% (eq 4).
entry
solvent
ratioa (19:21)
yieldb (%)
1
2
3
4
5
6
CH3CN
PhCH3
(CH2Cl)2
DME
1,4-dioxane
PhCN
>99:1
67:33
30:70
90:10
90:10
52:48
67
45
N/A
58
48
28
a Determined by 1H NMR analysis of the crude mixture. b Isolated
yield of 19.
Having fully explored all reaction parameters selected for the
maximum yield of indane, these conditions were applied to
(10) See the Supporting Information for details.
(11) Decomposed upon standing.
(12) For reactivity of the neopentyl-Pd intermediate in C-H function-
alization, see: Liron, F.; Knochel, P. Tetrahedron Lett. 2007, 48, 4943–
4946.
(13) The asymmetric preparation of indanes bearing acetonitrile-alkyl
or acetonitrile-aryl benzylic all-carbon quaternary stereocenters was recently
reported; see: (a) Watson, M. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2008,
130, 12874–12875.
(14) Lipshutz, B. H.; Bulow, G.; Fernandez-Lazaro, F.; Kim, S.-K.;
Lowe, R.; Mollard, P.; Stevens, K. L. J. Am. Chem. Soc. 1999, 121, 11664–
11673.
(15) Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G. Tetrahedron
Lett. 1979, 20, 1503–1506.
(16) Substrate 17 was also prepared on a 100 mg scale by ring opening
´
of 1,4-epoxy-1,4-dihydronaphthalene; see: Fillion, E.; Tre´panier, V. E.;
Mercier, L. J.; Remorova, A. A.; Carson, R. J. Tetrahedron Lett. 2005, 46,
1091–1094.

3522 Organometallics, Vol. 28, No. 12, 2009
Fillion et al.
isopropyl-substituted 13 and unsubstituted 18 (eq 5). For 13,
the steric demands of the bulkier ortho substituent required
higher temperature (120 °C for 72 h) to give 22 as the sole
isolated product. Importantly, the requirement for an ortho
substituent was demonstrated by 18, which produced indane
23 in only 6% yield.
the triflate and on the length of the tether, and that trapping
of reactive intermediates through C-H insertion proceeds into
C(sp2)-H bonds only. The reactivity of substrates 16 and 17
and their derivatives was then studied, and the results are
presented in the next section.
Pd-Catalyzed 1,2-Diarylation of Vinyldimethylalanes
Vinylalane 27, derived from alkyne 17, was submitted to the
Pd-catalyzed carbocyclization at 120 °C for 24 h. In the absence
of DABCO, a nearly equimolar mixture of methyl shift 28 and
methyl cross-coupled 29 was obtained (Table 3, entry 1). As
previously observed, six-membered-ring formation was inef-
ficient, and tricycle 28 was isolated in a low 27% yield. The
amount of DABCO was then increased until, when 1.5 equiv
was used, the formation of 29 decreased to the benefit of
tetracyclic product 30 (entries 2-4). Compound 30 was
preferentially formed when 6.0 equiv of DABCO was utilized
and obtained in a 76% yield (entry 5), which underlined the
facile intramolecular transformation undergone by C(sp2)-H
aryl hydrogens in comparison to C(sp3)-H benzylic hydrogens.
The temperature was lowered to 100 °C without affecting the
ratio and yield of 30 (entry 6). Conversely, excess Et3N (6 equiv)
was ineffective at promoting the formation of tetracycle 30, as
a 28:29:30 ratio of 37:63:<1 ratio was observed after 24 h at
100 °C. A considerable solvent dependence on the outcome of
the reaction was determined, as nonpolar toluene favored
formation of tetracycle 30 versus tricycle 28 to a lesser extent
than acetonitrile (entry 7).
With optimized conditions in hand, the synthesis of tetrahy-
dronaphthalenes from the 1-carbon homologues 14, 15, and 17
was investigated. In contrast with the results obtained with aryl
iodide 6 (Scheme 4), alkyne 14 led to an unquantified mixture
of inseparable products when reacted under the optimal condi-
tions, which comprised a trace amount of the tetrahydronaph-
thalene 24 (eq 6). However, isopropyl derivative 15 gave a 28%
isolated yield of 25 accompanied by an equimolar quantity of
methyl cross-coupled product 26, obtained in 31% yield.24,25
Typically, six-membered-ring formation through carbocycliza-
tion is slower than that of the analogous five-membered ring.26
As a result, the relative cyclization rate of the (σ-aryl)palla-
dium(II) intermediate derived from 14 and leading to 24 was
slow, and side reactions dominated. Increasing steric bulk in
close vicinity to the C-Pd bond in the (σ-aryl)palladium(II)
intermediate hindered competing side reactions and allow the
formation of 25 from 15. From the cyclization precursors
discussed above, tricycles generated through C-H functional-
ization of the benzylic position were not observed.
Table 3. Effect of Solvent, Temperature, and DABCO on Methyl
Migration versus 1,2-Diarylation Product Distribution
entry solvent temp (°C) DABCO n(equiv) ratioa 28:29:30 yieldb (%)
1
2
3
4
5
6
7
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
PhMe
120
120c
120c
120
120
100
100
0
45:55:<1
50:50:<1
51:49:<1
55:30:15
6:<1:94
5:<1:95
36:1:63
27
29
29
27
76
82
21
Reaction conditions favoring the methyl shift reaction leading
to carbocycles bearing a benzylic ethyl-methyl-substituted
quaternary center were developed. The results suggest that
the reaction manifold depends on the nature of the substrate,
more specifically on the presence of a substituent ortho to
0.5
1.0
1.5
6.0
6.0
6.0
a Determined by 1H NMR analysis of the crude mixture. b Combined
(17) Typically, a 95:5 regioselectivity was observed.
(18) The yields were unaffected by the presence of Cp2ZrCl2 and its
removal by precipitation with hexanes was omitted for operational simplicity
Negishi, E.; Boardman, L. D. Tetrahedron Lett. 1982, 23, 3327–3330.
(19) For convenience, considering the difficulties in monitoring the
reaction time due to the presence of aluminum salts and the air sensitivity
of the protocol, the Pd-catalyzed reactions were typically heated for 18-
72 h (if unreacted triflate remained after 18 or 24 h) at 100 or 120 °C in a
resealable Schlenk tube, and the individual reaction times not determined.
(20) Qadir, M.; Mo¨chel, T.; Hii, K. K. Tetrahedron 2000, 56, 7975–
7979.
(21) Lau, S. Y. W.; Andersen, N. G.; Keay, B. A. Org. Lett. 2001, 3,
181–184.
(22) Decker, C.; Henderson, W.; Nicholson, B. K. J. Chem. Soc., Dalton
Trans. 1999, 3507–3513.
(23) Baidya, M.; Mayr, H. Chem. Commun. 2008, 1792–1794.
(24) 1H NMR analysis of the crude reaction mixture gave a 1:1.03 ratio
of 25 to 26.
(25) Bicycle 25 was isolated in 35% yield when the reaction was carried
out for 72 h at 120 °C.
yield of inseparable compounds 28 and 30. c Reaction time is 72 h.
This set of experiments determined the key role of DABCO
on product distribution and its influence on the pathway followed
by the (σ-aryl)palladium(II) complex and/or (σ-alkyl)palla-
dium(II) species. Next, we set out to explore electronic and steric
effects on the olefin 1,2-diarylation pathway. This was ac-
complished by preparing an array of naphthalene cyclization
precursors 31a-e, in which the ring participating in the direct
arylation reaction was substituted at various positions with
electron-donating groups.27 Triflate 31a, substituted with an
electron-donating group at the 5-position, provided diarylated
product 34a in excellent yield and selectivity (Table 4, entry
1). In contrast, substituting the naphthalene 6-position with the
same electron-donating methoxy group had a detrimental effect
on the selectivity (entry 2); triflate 31b yielded a 32b:34b ratio
(26) Link, J. T. Org. React. 2002, 60, 157–534.

Pd-Catalyzed Reactions of 1-Alkenyldimethylalanes
Organometallics, Vol. 28, No. 12, 2009 3523
of 17:83. A poor selectivity in favor of tetracycle 34c was
observed for substrate 31c, whereas 31d provided reverse
selectivity, yielding solely tricycle 32e (entries 3 and 4).
Substantial amounts of cross-coupled products 33c,d were
obtained from the 7-substituted naphthalene substrates. The
ethyl-methyl-substituted tricycles 32e,f were isolated in excel-
lent yields (entries 5 and 6), and no diarylation product was
detected from alkynes 31e and 16 bearing a shorter tether.28
It has been reported in the literature that methylaluminum
compounds add to CH3CN under thermal conditions.29 It was
therefore important to establish the alkenyldimethylalanes’
behavior in CH3CN. When 27 was heated in the presence of
DABCO (6.0 equiv) for 24 h at 100 °C in CD3CN, (E)-d1-37
was recovered as a single isomer in 77% yield and 72% D
incorporation after acid treatment (eq 8), indicating the con-
figurational stability of the organoaluminum species. No prod-
ucts derived from the addition of the alkenylalane to CH3CN
were detected. The fact that only 72% D incorporation was
observed after 24 h suggested that the relative rate of pro-
todealumination of the C(sp2)-Al bond ought to be much
smaller than that of the intramolecular C-C bond forming
reaction with the (σ-aryl)palladium(II) complex.
Table 4. Scope of the Pd-Catalyzed Diarylation Reaction
entry
R
n
ratioa 32:33:34
yieldb (%)
1
2
3
4
5
6
5-MeO (31a)
6-MeO (31b)
7-MeO (31c)
7-Me (31d)
5-MeO (31e)
H (16)
1
1
1
1
0
0
2:<1:98
17:<1:83
26:18 (33c):56
64:36 (33d):<1
>99:<1:<1
>99:<1:<1
91 (32a, 34a)
74 (32b, 34b)
70 (32c, 34c)
42 (32d)
90 (32e)
63-71 (32f)
The fate of the C(sp2)-Al bond during the Pd-catalyzed
carbon-carbon bond forming events leading to the tricycles was
then probed. Following the Pd-catalyzed reaction, if a C-Al
bond was present in the final species, treatment with an
electrophile would allow identification of its location. Unfor-
tunately, interception of the C-Al bond failed; from triflate 38,
only 39 was isolated after quenching the reaction with
CD3CO2D, which suggested premature protodealumination by
CH3CN (eq 9).
a Determined by 1H NMR analysis of the crude mixture. b Combined
yield of inseparable compounds 32 and 34.
The intramolecular palladium-catalyzed reaction of 1-naphthyl
triflates with (E)-2,2-disubstituted 1-alkenyldimethylalanes re-
vealed two competing reaction pathways: the previously ob-
served alkene arylation with sequential 1,2-alkyl migration from
aluminum to carbon and intramolecular olefin 1,2-diarylation.
In the latter multiple carbon-carbon bond forming sequence,
the second C-C bond was formed through intramolecular
functionalization of an arene C(sp2)-H bond following alkene
arylation. The reaction pathway undertaken by the (σ-aryl)pal-
ladium(II) complex was influenced by electronic and steric
factors, including tether length. Moreover, solvent polarity and
additives, namely DABCO, played a key role in product
distribution.
In view of the experimental data presented above, a thorough
mechanistic investigation of the palladium-catalyzed carbon-
carbon bond forming events and of the fate of the C-Al bond
via labeling studies was then undertaken.
In order to verify this hypothesis, the methyl shift reactions
were carried out in CD3CN, and in all cases, H, 13C, and H
NMR spectra showed a single indane diastereoisomer with
significant deuterium incorporation at the C-1 position of the
ethyl group (Scheme 7). The large chemical shift difference
between the two diastereotopic methylene hydrogens in the ethyl
group allowed for an easy assessment of the incorporation.
Substrate 12 furnished d1-19 in good yield, with a D incorpora-
tion of 86% (2H NMR 1.80 ppm). Methoxy-substituted triflate
38 provided similar results with a D incorporation of 91% for
d1-39 (2H NMR 1.81 ppm) (Scheme 7a).30 The configurational
stability of the carbon-aluminum bond was further confirmed
by preparing the deuterated alkyne analogues d1-12 and d1-38
1
2
Labeling Studies
The origin of the methyl group in the arylation/methyl shift
reaction was first verified by submitting terminal alkyne 35 to
methylalumination with d9-Me3Al, followed by Pd-catalyzed
C-C bond forming conditions. The hexadeuterated indane d6-
36 was isolated in 52% yield, thereby confirming that two of
the three new C-C bonds originate from d9-Me3Al (eq 7).
(29) (a) Timoshkin, A. Y.; Schaefer, H. F., III. J. Am. Chem. Soc. 2003,
125, 9998–10011, and references therein. (b) Kopp, M. R.; Neumu¨ller, B.
Z. Anorg. Allg. Chem. 1999, 625, 739–745. (c) Kuran, W.; Pasynkiewicz,
S.; Salek, A. J. Organomet. Chem. 1974, 73, 199–203. (d) Seale, S. K.;
Atwood, J. L. J. Organomet. Chem. 1974, 73, 27–34. (e) Atwood, J. L.;
Seale, S. K.; Roberts, D. H. J. Organomet. Chem. 1973, 72, 105–111. (f)
Jennings, J. R.; Lloyd, J. E.; Wade, K. J. Chem. Soc. 1965, 5083–5094.
(30) For the preparation of substrates 38 and d1-38, see the Supporting
Information.
(27) 2-(4-Pentyn-1-yl)-tethered triflates 31a-d were synthesized from
the parent 2-naphthaldehydes (Scheme 6b), and the 2-(3-butyn-1-yl)-tethered
1-naphthyl triflate 31e was obtained from the corresponding 2-naphthyl
bromide, as depicted in Scheme 6a. The synthesis of the naphthalene
substrates is described in detail in the Supporting Information.
(28) At 120 °C, 32f was obtained in 80% yield. Using Pd(PPh3)4 (10
mol %) in PhMe, 32f was formed in 48% yield at 100 °C and 52% yield
at 120 °C.

3524 Organometallics, Vol. 28, No. 12, 2009
Fillion et al.
(>95% D incorporation). On reaction under the previous
conditions using CH3CN as the solvent (Scheme 7b), exclusive
formation of the opposite diastereomeric products epi-d1-19 (2H
NMR 1.71 ppm, >95% D incorporation) and epi-d1-39 (2H NMR
1.71 ppm, >95% D incorporation) was observed. Therefore, the
carbon-carbon bond forming events were stereospecific and
the stereochemical information found in the vinylalane was
relayed into the final products.
furnished bicycles d1-25 and epi-d1-25, respectively, as single
diastereomers (Scheme 9).
Scheme 9. Labeling Experiments for the Six-Membered-
Ring Series
Scheme 7. Labeling Experiments for the Five-Membered-
Ring Series
A similar strategy was used to access epi-d1-25 and determine
its relative stereochemistry (Scheme 10). From alkyne 42,
trisubstituted alkene preparation by methylalumination and
trapping with ethyl chloroformate, followed by a reductive
carbopalladation reaction with subsequent methyl ether cleavage
and lactonization, yielded tricycle 43. The procedure developed
earlier was used to generate d1-43 with good D incorporation
and diastereoselectivity. The relative stereochemistry of d1-43
was determined by 1H and 2H NMR; by 1H NMR, the signal at
2.44 ppm disappeared, and by 2H NMR, a single signal appeared
at 2.46 ppm. From the tricyclic lactone d1-43, epi-d1-44 was
prepared, from which sequential phenol deprotection, triflation,
Stille cross-coupling, and hydrogenation furnished epi-d1-25.
The relative stereochemistry was confirmed by analysis of the
1H, 2H, and 13C spectra of epi-d1-25, which were identical with
those of epi-d1-25 formed via the Pd-catalyzed reaction depicted
in Scheme 9. The compound epi-d1-25 had the same relative
stereochemistry as epi-d1-39, suggesting an identical stereospe-
cific process for the five- and six-membered-ring series.
This stereospecific process was generalized by preparing the
5-naphthyl substrates 16 and d1-16 (>95% D incorporation)
(Scheme 11). The reactions gave a single diastereomer of the
corresponding benzocycle d1-32f (2H NMR 2.12 ppm, 80% D
incorporation) and epi-d1-32f (2H NMR 1.93 ppm, >95% D
incorporation).
The relative stereochemistry of the 1-deuterioethyl-methyl-
substituted indane products was ascertained by the synthesis of
epi-d1-39 via an alternate route (Scheme 8). Starting from the
known alkyne 40,6 the tricyclic lactone 41 was obtained through
a series of high-yielding steps. The carbonyl R-hydrogens were
easily distinguishable with chemical shifts of 2.54 and 2.97 ppm.
When the methyl group in 41 was irradiated, only one R-proton
of the lactone gave strong NOE enhancement. The hydrogen
atom at 2.97 ppm was then determined to be syn to the methyl
group. Tricyclic lactone 41 was used as a rigid template to
stereoselectively introduce a deuterium atom R to the carbonyl
group. Deuterium labeling was realized by forming the enolate
with TiCl4 and Et3N, which was trapped with 20% DCl in D2O
to give the anti-R-deuterated lactone d1-41 with dr >24:1. The
relative stereochemistry of d1-41 was determined by 1H and 2H
NMR; by 1H NMR, the signal at 2.54 ppm disappeared, and by
2H NMR, a single signal appeared at 2.59 ppm. From d1-41,
1
2
the synthesis of epi-d1-39 was completed, which had H, H,
and 13C spectra identical with those of epi-d1-39 formed via
the Pd-catalyzed reaction depicted in Scheme 7.
In the six-membered-ring series, identical stereospecificity
was observed starting with triflates 15 and d1-15, which
In the Pd-catalyzed transformation, switching from CH3CN to
a non-Brønsted acidic solvent, the integrity of the neopentylic C-Al
bond should be preserved until an electrophile is added. Using 16,
following methylalumination, the catalytic arylation/methyl shift
Scheme 8. Diastereoselective Synthesis of epi-d1-39

Pd-Catalyzed Reactions of 1-Alkenyldimethylalanes
Organometallics, Vol. 28, No. 12, 2009 3525
Scheme 10. Diastereoselective Synthesis of Tetrahydronaphthalene epi-d1-25
Scheme 11. Labeling Experiments for the Naphthalene
Series
to CH3CN. This suggests that the slower deuteriodealumination in
comparison to protiodealumination led to the formation of byprod-
ucts to a larger extent.
Similarly, deuterium labeling experiments with naphthalene
triflate 17 furnished mechanistic insights on the tetracycle
formation. As depicted in Table 5, in the absence of DABCO,
methyl shift d1-28 was the sole cyclized product along with an
equimolar amount of uncyclized (E)-d1-29 (entry 1). As for the
formation of the indene derivatives, a single diastereomer of
the monodeuterated tricycle was generated, with 71% D
incorporation at the C1 position of the ethyl group. The outcome
was similar upon using excess Et3N (entry 2). When the reaction
was performed in the presence of 6 equiv of DABCO, the
tricycle d1-28 was obtained over the tetracycle d1-30, with an
equimolar amount of uncyclized (E)-d1-29 (entry 3). This
contrasted strongly with the product ratio obtained in CH3CN
under identical conditions (Table 3, entry 5) and implied an
involvement of the solvent in the rate-determining step leading
to the cyclized materials. Due to overlapping signals in the 1H
NMR, D incorporation percentages for d1-28 could not be
determined. Doubling the amount of DABCO to 12 equiv did
not affect the amount of competing formation of (E)-d1-29,
although d1-28 and d1-30 were now generated in a 1:1 ratio,
with decreased D incorporation (entry 4).
reaction was carried out in THF, 1,4-dioxane, DME, toluene,
cyclohexane, 2,2,5,5-tetramethyltetrahydrofuran, and pivalonitrile
and then quenched with 10% DCl/D2O. All of the above, except
for cyclohexane, in which the catalyst was insoluble and no reaction
was observed, led to the cyclized product in variable yields and
conversions, but with no D incorporation. Gratifyingly, when the
Pd-catalyzed reaction was conducted in benzene and quenched with
10% DCl/D2O, triflate 16 yielded epi-d1-32f, albeit in a low 11%
yield (the methyl cross-coupled product being formed preferen-
tially) as a single diastereomer with 39% D incorporation in the
C1 position of the ethyl group (eq 10). All attempts to functionalize
the methylene group by trapping the C-Al bond with I2, N-
bromosuccinimide, methyl chloroformate, allyl bromide, and O2
were unsuccessful.
Table 5. 1,2-Diarylation in CD3CN
c
d
-
entry additive n (equiv) ratioa d1-28:(E)-d1-29:d1-30 yieldb (%)
-
Despite the intrinsically low reactivity of the C-Al bond,
following the key carbon-carbon bond forming events various
reaction pathways are available to the organometallic species in
benzene in the presence of a Pd catalyst, including protodealumi-
nation, as judged by the low yield and D incorporation. Similar
conclusions can be drawn for the reactions performed in CD3CN;
in all cases, lower yields were observed in CD3CN in comparison
1
2
3
4
45 (71):55 (62):<1
64 (71):36 (69):<1
29 (N/A):58 (>95):13 (82)
24 (N/A):54 (79):22 (48)
27
28
36
36
Et3N
DABCO
DABCO
6.0
6.0
12.0
a
Determined by H NMR analysis of the crude mixture. b Average of
1
two runs. c % D incorporations for 28-30 are in parentheses. d Isolated
yield of inseparable d1-28 and d1-30.

3526 Organometallics, Vol. 28, No. 12, 2009
Fillion et al.
Scheme 12. Synthesis of Authentic Samples of Tetracycles
As shown by the reaction of acetylene d1-17 in CH3CN, the
1,2-diarylation proceeded stereospecifically (eq 11). The tricycle
epi-d1-28 and the tetracycle epi-d1-30 were isolated in a 63:37
ratio and 35% combined yield, which differed from the
cyclization of unlabeled alkyne 17 that produced tetracycle 30
in 82% yield, with a trace quantity of 28 (Table 3, entry 5).
The significant change in product ratios was linked to a kinetic
isotope effect influencing selection between reaction pathways.
d1-30 and epi-d1-30
carbon triggered by electrophilic palladium triflate (or iodide)
46 forms palladacycle 48, which reductively eliminates to
49.32,33
There are reports that 5-exo-trig-carbopalladation is faster than
the analogous 6-exo-trig reaction26 and that formation of the
seven-membered-ring palladacycle is slower than that of the
six-membered ring.34 Thus, when n ) 2, cyclization of the (σ-
aryl)palladium(II) complex 46 to 47 and/or 48 competes with
cross-coupling with alkenyldimethylalane to furnish 50. The
slower cyclization rate leading to tetrahydronaphthalene deriva-
tives accounts for the lower yields obtained for the cyclization
of 14 versus 12 and of 15 versus 13.
To confirm the chemical shift of the individual hydrogens in
the five-membered ring of 30, and the stereochemistry of labeled
compounds d1-30 and epi-d1-30, NOE experiments were per-
formed on the unlabeled tetracycle. Upon irradiation of the
doublet at 3.11 ppm, enhancement of the benzylic methyl signal
was observed, establishing a syn relationship (Figure 1).
Absence of NOE between the proton at 3.33 ppm and the methyl
group validated the assignment.
It was also observed that, in the absence of Lewis basic
additives, intermediate 49 partially dehydroaluminated to byprod-
uct 51 (see eq 2).35 DABCO played a dual role in the preferential
and high-yielding formation of 52 by complexing with the
aluminum center, where it facilitated the 1,2-methyl migration
while suppressing dehydroalumination of 49 (Scheme 13).36,37
Furthermore, DABCO has been recently shown to be a highly
effective ligand for palladium-catalyzed transformations.38 The
intermediacy of 49 and CH3CN acting as a proton source in
the protodealumination step leading to 52 were confirmed when
the reaction was carried out in CD3CN, leading to deuterium
incorporation at the C-1 position of the ethyl group (Schemes
7, 9, and 11).39 Furthermore, replacing CH3CN by benzene in
the Pd-catalyzed step allowed for deuterolysis of the C(sp3)-Al
bond of intermediate 49 with 10% DCl in D2O, as exemplified
with 16 to furnish the tricycle d1-32f (eq 10). The in situ
protodealumination with CH3CN and the sequential Pd-catalyzed
reaction/Brønsted acid quench led to the same relative stereo-
Figure 1. NOE study of tetracycle 30.
Authentic samples of diastereomeric tetracycles d1-30 and epi-
d1-30 (>95% D incorporation) were synthesized from the
corresponding deuteropentenyl-tethered naphthyl triflates (E)-
d1-37 (>95% D incorporation) and (Z)-d1-37 (>95% D incor-
poration) via an intramolecular tandem carbopalladation termi-
nated with an aromatic cyclization (Scheme 12). Thereby, due
to the stereospecific nature of the carbopalladation reactions,
the chemical shift of the diastereotopic methylene hydrogens
in the five-membered-ring moiety was assigned unambiguously.
(32) Alkyl 1,2-migration from boron to carbon triggered by a Pd(II)
complex: (a) Ishikura, M.; Kato, H. Tetrahedron 2002, 58, 9827–9838. (b)
Ishikura, M.; Terashima, M. Tetrahedron Lett. 1992, 33, 6849–6852. (c)
Ishikura, M.; Terashima, M.; Okamura, K.; Date, T. J. Chem. Soc., Chem.
Commun. 1991, 1219–1221.
(33) Alkenylalanes as π-nucleophiles: (a) Negishi, E.; Boardman, L. D.;
Sawada, H.; Bagheri, V.; Stoll, A. T.; Tour, J. M.; Rand, C. L. J. Am.
Chem. Soc. 1988, 110, 5383–5396, and references cited thereinArPdIIOTf
as electrophiles: (b) Aoki, S.; Fujimura, T.; Nakamura, E.; Kuwajima, I.
J. Am. Chem. Soc. 1988, 110, 3296–3298. For a discussion on the
electrophilicity of ArPdII complexes: (c) Beletskaya, I. P.; Cheprakov, A. V.
Chem. ReV. 2000, 100, 3009–3066.
(34) Tietze, L. F.; Schimpf, R. Angew. Chem., Int. Ed. Engl. 1994, 33,
1089–1091.
(35) Dehydroalumination at elevated temperature has been reported: (a)
Eisch, J. J. Fichter, K. C. J. Organomet. Chem. 1983, 250, 63–81. The
authors also demonstrated the configurational stability at the C-Al bond
of trialkylaluminum derivatives in the presence of the Lewis bases diethyl
ether and N-methylpyrrolidine.
Proposed Mechanisms
Two mechanistic proposals accounting for the formation of
the arylation/methyl shift product from aryl iodides 1 and 6 and
aryl triflates 12-15, 18, 31, and 33 are outlined in Scheme 13.
In both pathways, the initial step is the formation of 46 by
oxidative insertion of Pd(0) into the aryl triflate C-O bond of
45, which is accessed through alkyne methylalumination.
Alkenylalane carbopalladation generates the dimetallic31 species
47, which undergoes 1,2-methyl migration from aluminum to
carbon, affording 49 and regenerating the Pd catalyst. Alterna-
tively, 1,2-migration of the methyl group from aluminum to
(31) For a review on sp3-gem-dimetallics: (a) Marek, I.; Normant, J.-F.
Chem. ReV. 1996, 96, 3241–3267.

Pd-Catalyzed Reactions of 1-Alkenyldimethylalanes
Organometallics, Vol. 28, No. 12, 2009 3527
Scheme 13. Postulated Mechanisms for the Arylation/Methyl Shift Reactiona
a
DABCO is omitted for clarity.
chemistry in the product, which strongly suggested a common
organoaluminum intermediate.
Indeed, if the methyl group was replaced by a hydrogen atom,
then the vicinal dimetallic mechanism would lead to 1-ethylin-
dane products, whereas the corresponding geminal dimetallic
pathway might give rise to products of competing ꢀ-hydride
elimination. The desired E-disubstituted vinylalane 53 was
obtained via hydrozirconation of 12 (Cp2Zr(H)Cl, CH2Cl2, room
temperature) followed by transmetalation with Me2AlCl.40
Submitting the latter to the optimized reaction conditions
afforded none of the 1,2-methyl shift adduct 56; instead, a
mixture of exo- and endocyclic olefin isomers of 1,7-dimethyl-
1-indenes 54 and 55 was isolated in 67% combined yield and
95:5 ratio (Scheme 14). The exocyclic alkene 54 partially
isomerized to 55 during purification by silica gel chromatog-
raphy. Thus, the experimental data support the carbopalladation
pathway, whereby the alkenyldimethylalane arylation occurs via
5-exo-trig carbometalation, affording intermediate 47. The
palladium(II) triflate/trialkylalane 47 then undergoes a 1,2-
methyl shift from the aluminum center to the neopentylic carbon
atom and yields the dialkylaluminum triflate 49 (Scheme 13).
The C-C bond forming methyl migration mechanism was
then studied. As determined through labeling experiments, the
process is stereospecific, and since the carbopalladation is a
concerted syn-addition process,41 the introduction of the methyl
group took place with retention of configuration. From dimetallic
47, 1,2-metalate rearrangement would proceed with inversion
of configuration of the sp3 carbenoid carbon,42 and subsequent
trapping of epi-49 with CD3CN would have furnished the
diastereomer epi-d1-52 (Scheme 15). Alternatively, transmeta-
lation or 1,3-methyl shift from aluminum to palladium with
retention of configuration at the dimetallic carbon center would
lead to the dialkylpalladium species 57.43 Subsequent reductive
The carbopalladation pathway is supported by both the low
yield obtained when attempting to cyclize 18 (eq 5) and the
yield enhancement for ortho-substituted aryl triflates, in addition
to the isolation of the tricycle 8 (Scheme 4). In order to further
distinguish between the two mechanisms leading to 49, the
requirement for the ꢀ-methyl group on the vinylalane was
probed (Scheme 14).
Scheme 14. Evidence for a Geminal Dimetallic Intermediate
(36) It is assumed that DABCO displaces the trifluoromethanesulfonate
group on the Pd(II) center.
(37) DABCO reacts with Me3Al to form the stable (Me3Al)2 · DABCO
complex, see: (a) Biswas, K.; Prieto, O.; Goldsmith, P. J.; Woodward, S.
Angew. Chem., Int. Ed. 2005, 44, 2232–2234. (b) Bradford, A. M.; Bradley,
D. C.; Hursthouse, M. B.; Motevalli, M. Organometallics 1992, 11, 111–
115.
(38) Pd(0)-catalyzed cross-coupling reactions with DABCO: (a) Li, J.-
H.; Zhu, Q.-M.; Xie, Y.-X. Tetrahedron 2006, 62, 10888–10895. (b) Li,
J.-H.; Deng, C.-L.; Liu, W.-J.; Xie, Y.-X. Synthesis 2005, 3039–3044. (c)
Li, J.-H.; Wang, D.-P.; Xie, Y.-X. Synthesis 2005, 2193–2197. (d) Li, J.-
H.; Zhang, X.-D.; Xie, Y.-X. Synthesis 2005, 804–808. (e) Li, J.-H.; Liang,
Y.; Wang, D.-P.; Liu, W.-J.; Xie, Y.-X.; Yin, D.-L. J. Org. Chem. 2005,
70, 2832–2834. (f) Li, J.-H.; Liu, W.-J. Org. Lett. 2004, 6, 2809–2811.
(39) Eisch, J. J.; Manfre, R. J.; Komar, D. A. J. Organomet. Chem.
1978, 159, C13–C19.
(40) Carr, D. B.; Schwartz, J. J. Am. Chem. Soc. 1979, 101, 3521–3531.
(41) For the isolation and characterization of stereodefined (σ-alkyl)pal-
ladium(II) complexes, see Burke, B. J.; Overman, L. E. J. Am. Chem. Soc.
2004, 126, 16820–16833.
(42) Randaishenvi, M. V.; Singram, B.; Brown, H. C. J. Org. Chem.
1991, 56, 3286–3294.
(43) An alkyne arylation/alkyl shift reaction with retention of config-
uration through the intermediacy of a sp2-1,1-palladium/trialkylsilylalkene
complex has been reported; see: Bishop, B. C.; Cottrell, I. F.; Hands, D.
Synthesis 1997, 131, 5–1320.

3528 Organometallics, Vol. 28, No. 12, 2009
Scheme 15. 1,2-Methyl Shift from Aluminum to Carbon Mechanismsa
Fillion et al.
a
DABCO is omitted for clarity.
elimination to 49 followed by deuterodealumination would
furnish the diastereomer d1-52.44 It is well-established that the
formation of a C-C bond by reductive elimination from the
Pd(II) center occurs with retention of configuration.45 Moreover,
the configurational stability of organoaluminum compounds in
the presence of trialkylamine Lewis base and subsequent
protodealumination with retention of configuration have been
reported.35
One additional piece of evidence in favor of the 1,3-methyl
shift from aluminum to palladium/reductive elimination mech-
anism arose from investigating an arylation/1,2-ethyl shift
reaction. It was postulated that the ethyl shift from dimetallic
species 58, through 1,2-metalate rearrangement, would cleanly
furnish the 1-methyl-1-propylindane 59. On the other hand, if
the C-C bond formation pathway involves 1,3-ethyl shift from
aluminum to palladium to the aryl ethylpalladium(II) species
60, then ꢀ-hydride elimination becomes an available competing
pathway (Scheme 16), and the 1,1-dimethylindane 61 and
1-methyl-1-propylindane 59 could be produced concurrently.
Alkyne 38 was transformed into E-trisubstituted alkenyldi-
ethylalane by a Negishi methylalumination reaction, followed
by redistribution of ligands with excess Et2AlCl and in vacuo
removal of volatile organometallic reagents. Treatment with Pd
catalyst led to an inseparable 9:1:9 mixture of 62, 39, and 63
in an unoptimized 15% yield (eq 12). The equimolar formation
of indanes 62 and 63, 39 being derived from incomplete ligand
redistribution, clearly suggested that the aluminum ethyl ligand
first underwent transmetalation, followed by ꢀ-hydride elimina-
tion and subsequent reductive elimination of Pd(0) to form 62.
From the same intermediate, competing C(sp3)-C(sp3) cross-
coupling with concomitant reductive elimination of Pd(0)
furnished 63.
Scheme 16. Proposed 1,2-Ethyl Migration Mechanisms
On the basis of labeling studies and other experimental data,
alkene arylation and 1,2-methyl shift mechanisms were postu-
lated (Schemes 13 and 15). Our attention then centered on
determining a mechanism rationalizing the 1,2-diarylation
reaction observed with the naphthalene substrates. That mech-
anism had to account for the high-yielding and facile formation
of tetracycle 30 and analogous tetracycles 34a-c from 17 and
triflates 31a-c, respectively. In contrast, formation of six-
membered-ring carbocycles from substrates 14 and 15 was
sluggish and competed with methyl cross-coupling, resulting
in low yields of the tetrahydronaphthalene products.
As depicted in Table 3, DABCO had a pronounced effect on
the domino pathway followed by the (σ-aryl)palladium(II)
complex: in its absence, alkene arylation/1,2-methyl migration
product 28 was formed in low yield, with an equimolar amount
of 29, a reactivity pattern comparable to that of 14 and 15 under
optimized conditions, while excess DABCO led to a reversal
of selectivity favoring the alkene 1,2-diarylation product 30.
Formation of tetracycle 30 was optimal in CH3CN, a polar
solvent. The selection of either domino process by simply
omitting or adding an additive is of mechanistic and synthetic
significance. In the presence of DABCO, the high-yielding 1,2-
diarylation pathway was rationalized in term of alkene insertion
aptitudes, which were enhanced by complexation of DABCO
with the Lewis acidic aluminum center, the formation of the
aluminate complex being favorable in a polar solvent. Conse-
quently, the olefin inserted more readily into the C-Pd(II) bond
(44) Transmetalation followed by reductive elimination is the typical
C-C bond forming reactive pathway in Pd-catalyzed cross-coupling
reactions. See, for example: Hegedus, L. S. In Organometallics in Synthesis:
A Manual; Schlosser, M., Ed. Wiley-VCH: West Sussex, U.K., 2002.
(45) Ridgway, B. H.; Woerpel, K. A. J. Org. Chem. 1998, 63, 458–
460.

Pd-Catalyzed Reactions of 1-Alkenyldimethylalanes
Organometallics, Vol. 28, No. 12, 2009 3529
to furnish a neopentylic sp3-gem-dimetallic palladio(II) dialky-
laluminoalkane species, assuming that 1,2-diarylation is initiated
by olefin carbopalladation. Without DABCO, the carbocycliza-
tion became slow enough that the kinetics of methyl cross-
coupling efficiently competed with dimetallic formation.
From 17, labeling studies depicted in Table 5 and eq 11
suggested a common reactive intermediate for the formation of
28 and 30, given the fact that both products display the same
relative stereochemistry. Furthermore, that relative stereochem-
istry correlated with that observed previously in the five-
membered-ring series (Schemes 7, 9, and 11), pinpointing a key
neopentylic sp3-gem-dimetallic palladio(II) dialkylaluminoalkane
intermediate. From that (σ-alkyl)palladium(II) complex, two
reactivity pathways were then available: methyl migration from
the aluminum center to carbon, as described previously to
furnish 28, and direct arylation to 30. Examples of intramo-
lecular direct arylation of (σ-alkyl)palladium(II) species are
scarce.46,47 Of note, the 1,2-diarylation process was only
operational in the six-membered series; triflates 16 and 31e,
bearing a shorter tether, provided exclusively the alkene
arylation/methyl migration products 32f and 32e, respectively
(Table 4). These observations suggested that geometrical
constraints imposed by the five-membered carbocycle modified
the kinetics of the direct arylation of the dimetallic intermediate.
suggested that such a mechanism was unique to naphthalenes
17 and 31a-c and was not operational for substrates 14 and
15.
The hypothesis on the role of C-H · · · Pd interactions
stabilizing the carbopalladation transition state and facilitating
the arylation process was verified by studying the reactivity of
6-phenyl-2-(4-pentyn-1-yl)-1-phenyl triflate 64. On submission
to the two-step one-pot sequence, only methyl migration and
methyl cross-coupling products 65 and 66 were obtained, in
yields typical for 1,2,3,4-tetrahydronaphthalene formation (eq
13). This observation suggested that the orientation of the
C(sp2)-H bond was crucial in accelerating migratory insertion
through interaction with the Pd(II) center of the (σ-aryl)palla-
dium species.
At this stage, the origin of the distinct reactivity of naphtha-
lene substrates 17 and 31a-c in the presence of DABCO
remained to be identified. When triflates 14, 15, and 17 are
compared, the only structural variable is the substituent at the
position ortho to the triflate. In alkynes 14 and 15, the methyl
and isopropyl groups are sp3-hybridized, while in 17, carbon-8
of the naphthalene moiety is ortho to the triflate and sp2-
hybridized. This hybridization difference positioned the
C(sp2)-H bond at the 8-position of the naphthalene in the
vicinity of the Pd(II) center following oxidative insertion of
Pd(0) into the triflate C-O bond, which might explain the
discrepancy in reactivity. In addition, the ortho group in 17 is
conformationally locked, being part of the naphthalene, contrast-
ing with the freely rotating methyl and isopropyl groups.
Further insights on the function played by the C(sp2)-H bond
at the naphthalene 8-position were obtained by replacing H(8)
with a deuterium (eq 14). This change brought about a
significant isotope effect; carbocyclization of d8-17 at 100 and
120 °C led mainly to tricycle d8-28 and cross-coupled product
d8-29.50 While deuterium was still present in the methyl
migration product, no deuterium label was found in tetracycle
30, which unequivocally ruled out the intermediacy of a
palladium carbene in the 1,2-diarylation process. Tricycle d8-
28 contained 7 and 10% of dehydroaluminated product at 100
and 120 °C, respectively, in which the ethyl group is replaced
by a vinyl group.
The fact that a large amount of d8-29 was produced and
tricycle d8-28 was formed preferentially over tetracycle 30
indicates that H(8) is involved in both C-C bond forming
events, namely alkene carbopalladation and direct arylation of
the (σ-alkyl)palladium(II) intermediate.
From these observations, it was then proposed that a
C-H · · · Pd interaction facilitated the migratory insertion step
in the naphthalene substrates. Synergetic enhancement of the
Lewis acidity of the square-planar Pd(II) center may be caused
by the C(8) proton occupying one of the axial positions that
then allows coordination of the trisubstituted olefin with the
second axially oriented empty valence orbital.48 From that
hexacoordinated species, migratory insertion proceeded to
furnish a neopentylic sp3-gem-dimetallic palladio(II) dialkyla-
luminoalkane species. In a few instances, interaction of a Pd(II)
center with a C-H bond has been invoked to assist or stabilize
the migratory insertion transition state.49 The pattern of reactivity
(46) (a) Jana, R.; Samanta, S.; Ray, J. K. Tetrahedron Lett. 2008, 49,
851–854. (b) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 12084–12085. (c) Grigg, R.; Sridharan, V.; Sukirthalingam, S.
Tetrahedron Lett. 1991, 32, 3855–3858. For related (σ-alkyl)palladium
species arylation strategies, see: (d) Catellani, M.; Motti, E.; Della Ca’, N.
Acc. Chem. Res. 2008, 41, 1512–1522. (e) Catellani, M.; Motti, E.; Della
Ca’, N.; Ferraccioli, R. Eur. J. Org. Chem. 2007, 4153–4165.
(47) For an example of Pd-catalyzed alkyl to aryl migration and
cyclization, see: Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock,
R. C. J. Am. Chem. Soc. 2004, 126, 7460–7461.
(48) Aullo´n, G.; Alvarez, S. Inorg. Chem. 1996, 35, 3137–3144.
(49) Alkyne carbopalladation: (a) Rubina, M.; Gevorgyan, V. J. Am.
Chem. Soc. 2001, 123, 11107–11108. (b) Hada, M.; Tanaka, Y.; Ito, M.;
Murakami, M.; Amii, H.; Ito, Y.; Nakatsuji, H. J. Am. Chem. Soc. 1994,
116, 8754–8765. Alkyl migration: (c) Danopoulos, A. A.; Tsoureas, N.;
Green, J. C.; Hursthouse, M. B. Chem. Commun. 2003, 756–757.
The nature of the interaction between the Pd(II) center and
H(8) was further investigated by preparing the (σ-aryl)palla-
dium(II) complex, bis(triphenylphosphino)naphthalen-1-ylpal-
ladium(II) iodide (68), from 1-iodonaphthalene and Pd(PPh3)4
(Scheme 17).
(50) Determined by analysis of the 1H NMR spectrum of the crude
reaction mixture.

3530 Organometallics, Vol. 28, No. 12, 2009
Fillion et al.
Scheme 17. Formation of Pd(II) Complexes 68-70
of the proposed 130-170° range for this type of interaction.
Of note, the C(8)-H(8) and the C(1)-Pd bonds are almost
perfectly eclipsed, deviating from the plane by only 2.2°.
1H NMR and crystal structures of square-planar Pd(II)
complexes have previously revealed intramolecular C-H · · · Pd
interactions.52 However,thenatureofthebondinginC-H · · · Pd(II)
complexes (agostic vs preagostic vs H bond) and its impact on
the migratory insertion of alkenes into C-Pd(II) bonds remain
elusive. In naphthalene systems 17 and 31a-c, the C-H · · · Pd
interaction, which may change its nature in the course of the
C-C bond forming events, likely stabilizes the transition state
of the migratory insertion, as suggested earlier.
To reinforce this postulate and for comparison, Pd(II)
complexes 69 and 70 were prepared and their solid-state
1
structures determined (Scheme 17 and Figure 2). H NMR
analysis of 69 showed an interaction of the Pd(II) center with
H(8a) with a downfield shift for H(8A) (7.21 f 7.66 ppm, ∆δ
) 0.45 ppm). The X-ray structure of 69 revealed that the Pd
and H(8A) atoms are in close proximity with a distance of 2.47
Å and a C-H(8) · · · Pd angle of 116.8°. As for 68, this
interaction was characterized as preagostic on the basis of the
downfield chemical shift of the hydrogen atom in comparison
to that of 2-iodobiphenyl and the H · · · Pd distance. Similarly
to 68, the C-H · · · Pd angle was not within the proposed
130-170° range. Of note, in Pd(II) complex 69, the C(8)-H(8A)
and C(1)-Pd bonds were gauche, with a deviation of 65.3°.
The high energy required for the diaryl template to eclipse the
C(8)-H(8A) and the C(1)-Pd bond for optimal interaction of
the Pd(II) center with H(8) is in line with the absence of a 1,2-
diarylation product for substrate 64.
1H NMR analysis of 68 revealed a downfield shift for H(8)
(8.14 f 8.83 ppm, ∆δ ) 0.79 ppm), implying an interaction
of the Pd(II) center with H(8), which was further confirmed by
X-ray crystallography (Figure 2). In the solid state, the Pd and
H(8) atoms are in close contact with a distance of 2.74 Å and
a C-H(8) · · · Pd angle of 113.3°. This interaction is characterized
as preagostic on the basis of the downfield chemical shift of
H(8) in comparison to that of naphthyl iodide and the short
H(8) · · · Pd distance.51 However, the C-H · · · Pd angle is outside
An interaction of the Pd(II) center with H(7) in 70 was
1
detected through H NMR analysis with a downfield shift for
H(7) (3.21 f 4.10 ppm, ∆δ ) 0.89 ppm) (Scheme 17). In the
solid state, the Pd and H(7) atoms are in close contact with a
distance of 2.68 Å and a C-H(7) · · · Pd angle of 141.9°,
corresponding to a C-H · · · Pd(II) preagostic interaction (Figure
2). The C(7)-H(7) and the C(1)-Pd bond are not eclipsed, with
a deviation of 23.3°. Despite the presence of a C-H · · · Pd
preagostic interaction in the solid state, it is presumed that the
lower acidity of the isopropyl C(sp3)-H bond versus a
C(sp2)-H bond in the naphthalene substrate may preclude an
efficient stabilization of the migratory insertion transition state,
explaining the reactivity difference and the low yield obtained
for tricycle 25 from 15.
The experimental evidence presented above suggest an
underlying C(sp2)-H · · · Pd(II) interaction in the formation of
tetracycle 30 from triflate 17 through dimetallic intermediate
71 (Figure 3). The latter, depending on reaction conditions, can
undertake two reaction pathways to yield either tricycle 28, via
the intermediacy of 72 following methyl migration, or orga-
noaluminum species 73 en route to tetracycle 30. Labeling
experiments supported the diastereospecific formation of 71-73
(Table 5 and eq 11).
A mechanism rationalizing the direct arylation of (σ-alkyl)-
palladium(II) species 71 to furnish 73 was then postulated. As
(51) (a) Zhang, Y.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A.; Oldfield,
E. Organometallics 2006, 25, 3515–3519. (b) Lewis, J. C.; Wu, J.; Bergman,
R. G.; Ellman, J. A. Organometallics 2005, 24, 5737–5746. (c) Yao, W.;
Eisenstein, O.; Crabtree, R. H. Inorg. Chim. Acta 1997, 254, 105–111.
(52) (a) Singh, A.; Sharp, P. R. J. Am. Chem. Soc. 2006, 128, 5998–
5999. (b) Blake, A. J.; Holder, A. J.; Roberts, Y. V.; Schroder, M. J. Chem.
Soc., Chem. Commun. 1993, 260–262. (c) Roe, D. M.; Bailey, P. M.;
Moseley, K.; Maitlis, P. M. J. Chem. Soc., Chem. Commun. 1972, 1273–
1274. (d) Bailey, N. A.; Jenkins, J. M.; Mason, R.; Shaw, B. L. J. Chem.
Soc., Chem. Commun. 1965, 237–238.
Figure 2. X-ray structures of trans-bis(triphenylphosphino)naph-
thalen-1-ylpalladium(II) iodide (68), trans-bis(triphenylphosphino)-
biphenyl-2-ylpalladium(II) iodide (69), and trans-bis(triphenylphos-
phino)(2-isopropylphenyl)palladium(II) iodide (70).

Pd-Catalyzed Reactions of 1-Alkenyldimethylalanes
Organometallics, Vol. 28, No. 12, 2009 3531
might not be a requirement for the functionalization of the arene
C(sp2)-H bond in the formation of d1-30 and epi-d1-30 from
17 and d1-17, respectively. On the other hand, the reactivity of
the (σ-aryl)palladium(II) and neopentylic sp3-gem-dimetallic
palladio(II) dialkylaluminoalkane were affected by either sub-
stituting the alkene with a deuterium atom or by carrying out
the domino reaction in CD3CN (eq 11 and Table 5), suggesting
that the suppression or promotion of the pathways followed by
the Pd(II) intermediates might be achieved by altering the
reaction conditions and substrate substitution pattern (aromatic
and alkyne moieties).
Figure 3. Plausible intermediates in the 1,2-diarylation process.
stated above, the C(8)-H · · · Pd interaction in naphthalene
substrates seems to account for not only the pathway taken by
the (σ-aryl)palladium(II) complexes but also the subsequent
reactivity of the (σ-alkyl)palladium(II) complexes. From that
observation, the intervention of an electrophilic aromatic
substitution mechanism and Heck-like process for the ring-
closing direct arylation were eliminated; the results obtained
with triflates d8-17 and 31a-d (Table 4) were not in accordance
with these two mechanisms.
Summary
We have established a novel and stereospecific synthesis of
sp3-gem-dimetallic palladio(II) dialkylaluminoalkane species via
the intramolecular Pd-catalyzed arylation of (E)-2,2-disubsti-
tuted-1-alkenyldimethylalanes with aryl triflates. In the presence
of DABCO, these unprecedented organodimetallics were con-
figurationally stable and underwent 1,2-alkyl migration from
aluminum to carbon with retention of configuration at the carbon
center, followed by reductive elimination of Pd(0). The Pd-
catalyzed domino process provided an entry into benzocyclic
structures containing an ethyl-methyl-substituted benzylic all-
carbon quaternary stereocenter. The same reaction pathway was
observed with 1-naphthyl triflates in the absence of DABCO.
Alternatively, the neopentylic sp3-gem-dimetallic palladio(II)
dialkylaluminoalkane complexes underwent direct arylation in
the presence of DABCO. The formation and reactivity of sp3-
gem-dimetallic palladio(II) dialkylaluminoalkane, direct aryla-
tion versus methyl migration from aluminum to carbon, was
determined by the C-H · · · Pd interaction between the Pd(II)
center and the hydrogen atom at the naphthalene 8-position.
The proposed mechanisms are consistent with thorough labeling
studies.
Thus, the consensual concerted metalation-deprotonation
mechanism rationalizing Pd-catalyzed direct arylation of (σ-
aryl)palladium(II) species53 was likely operating in the intramo-
lecular direct arylation of the (σ-alkyl)palladium(II) intermediate
observed with the naphthalene substrates. As depicted in Table
3, in the absence of DABCO, the 1,2-diarylation process was
hampered. In its presence, we propose that palladacycle 74
formed, followed by reductive elimination of Pd(0) to afford
73.46a The concerted metalation-deprotonation mechanism also
rationalizes the lack of reactivity of the (σ-alkyl)palladium(II)
complex toward direct arylation when substitution is introduced
at the 7-position of the naphthalene, as found in substrates 31c,d.
Increased steric hindrance around H(8) decreases both its ability
to interact with the Pd(II) center to promote the migratory
insertion, thus the formation of cross-coupled products 33c,d
from 31c,d, respectively (Table 4, entries 3 and 4), and with
the large DABCO-Pd catalyst complex, resulting in the
exclusive formation of 1,2-methyl migration product 32d from
31d, in addition to uncyclized 33d. For the sterically less
demanding 31c, a 2.1:1 ratio of tetracycle 34b to tricycle 32b
was isolated. When 31a and 31b are compared, electronic factors
play a role in the direct arylation pathway, as the ratio of tricycle
32 to tetracycle 34 significantly varied (Table 4, entry 2) by
modifying the position of the methoxy group.54
Acknowledgment. This work was supported by an
award from Research Corporation, the Natural Sciences
and Engineering Research Council of Canada (NSERC),
AstraZeneca Canada Inc., the Merck Frosst Centre for
Therapeutic Research, Boehringer Ingelheim (Canada) Ltd.,
the Canadian Foundation for Innovation, the Ontario In-
´
novation Trust, and the University of Waterloo. V.E.T.
acknowledges the NSERC (PGS-D2 scholarship), the Gov-
ernment of Que´bec (FCAR), and the Government of Ontario
(OGS). R.J.C. thanks the Government of Ontario for scholar-
ships (OGS and OGSST). J.J.H. thanks the Magnus Ehrn-
rooth Foundation, the Oulu University Scholarship Founda-
tion, and the Gust. Komppa Fund of the Alfred Kordelin
Foundation for scholarships. J.M.G. thanks the Government
of Ontario and the University of Waterloo for scholarships.
The late Dr. Nicholas J. Taylor, University of Waterloo, is
gratefully acknowledged for the X-ray structure determina-
tion of 68, Dr. Alan Lough, University of Toronto, for the
X-ray structure determinations of 69 and 70, and Cambridge
Isotope Laboratories, Inc., for donating the CD3I.
The participation of the dimethylaluminum moiety in the
direct arylation of the neopentylic sp3-gem-dimetallic palladio(II)
dialkylaluminoalkane intermediate cannot be ruled out. How-
ever, as illustrated in Scheme 12, olefin 1,2-diarylation pro-
ceeded in high yields for substrates (E)- and (Z)-d1-37, lacking
the dimethylaluminum moiety.55 These results suggested that
the presence of the dimethylaluminum moiety on the alkene
(53) (a) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 10848–10849. (b) Garc´ıa-Cuadrado, D.; de Mendoza, P.; Braga,
A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2007, 129,
6880–6886. (c) Garc´ıa-Cuadrado, D.; Braga, A. A. C.; Maseras, F.;
Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066–1067. (d) Lafrance,
M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
8754–8756.
(54) For a correlation between C-H acidity and C-H activation
regiochemistry, see: Campo, M. A.; Zhang, H.; Yao, T.; Ibdah, A.; McCulla,
R. D.; Huang, Q.; Zhao, J.; Jenks, W. S.; Larock, R. C. J. Am. Chem. Soc.
2007, 129, 6298–6307.
Supporting Information Available: Text, figures, tables, and
CIF files giving detailed experimental procedures, full characteriza-
tion data, NMR spectra for all new compounds, and crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
(55) This is additional evidence that direct arylation does not proceed
through the intermediacy of a Pd-carbene/C-H insertion pathway.
OM900286X