Palladium-catalyzed carbon - Carbon bond-forming 1,2-ligand migration of organoalanes

Article abstract of DOI:10.1021/ja045783t

A one-pot, two-step process that transforms terminal alkynes into ethyl methyl-substituted benzylic quaternary carbon centers is described. (E)-2,2-Disubstituted-1-alkenyldimethylalanes have been shown to participate in 1,2-alkyl migration from aluminum to carbon with concomitant arylation at the 2-position to furnish ethyl methyl-substituted benzylic quaternary carbon centers, when reacted intramolecularly with aryl halides and triflates in the presence of a Pd(0) catalyst. The protocol is initiated with Cp₂ZrCl₂-catalyzed methylalumination of terminal alkynes followed by palladium-catalyzed intramolecular arylation of the resulting (E)-2,2-disubstituted-1-alkenyldimethylalanes, leading to 1,2-methyl shift from aluminum to carbon. In that sequence, a total of three new C-C single bonds are made, and two of the three alkyl groups on Me₃Al transferred to the substrate on vicinal carbons. This method was applied to a variety of substrates, and the mechanism was investigated by deuterium-labeling experiments, which revealed that protodealumination of the final dialkylaluminum triflate or halide intermediates by CH₃CN results in the formation of the fourth bond in the course of the transformation. Copyright

Full text of DOI:10.1021/ja045783t

Published on Web 11/05/2004
Palladium-Catalyzed Carbon-Carbon Bond-Forming 1,2-Ligand Migration of
Organoalanes
Eric Fillion,* Rebekah J. Carson, Vincent E. Tr e´ panier, Julie M. Goll, and Anna A. Remorova
Department of Chemistry, UniVersity of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Received July 14, 2004; E-mail: efillion@uwaterloo.ca
8
1
,2-Alkyl migration reactions are common in organoboron,
yield of 5c and 6c was obtained. Complete conversion was attained
organocopper, and organozinc chemistry and represent powerful
methods for forming multiple carbon-carbon bonds and generating
structural complexity in a single synthetic operation.1 Scarce
examples of this type of migratory insertion have been described
for organoalanes, and catalytic strategies remain unexplored.2
We report herein that (E)-2,2-disubstituted-1-alkenyldimethyl-
alanes participate in 1,2-alkyl migration from aluminum to carbon
with concomitant arylation at the 2-position when reacted intra-
molecularly with aryl halides and triflates in the presence of a Pd(0)
catalyst to furnish ethyl methyl-substituted benzylic quaternary
carbon centers. From terminal alkynes, a total of three new C-C
with Pd[P(p-MeOPh)
the presence of P(p-MeOPh)
3
]
2
Cl
2
(10 mol %), reduced in situ by Et
3
N in
3
(20 mol %). This catalyst provided
9
superior results in terms of yields and reproducibility. To
circumvent the formation of vinyl byproduct 5c, Lewis basic
additives were investigated. After an extensive survey of amines,
it was found that 6 equivalents of DABCO cleanly led to 6c in 67%
yield from 1c and that the formation of 5c was entirely suppressed
(Table 1, entry 2).
Table 1. Scope of the Pd-Catalyzed 1,2-Ligand Transfer Reaction
3
single bonds are made, and two of the three alkyl groups on Me Al
are transferred to the substrate on vicinal carbons (Scheme 1).3
Scheme 1
E-Vinylalane 2a, prepared from alkyne 1a following Negishi’s
4
alkyne methylalumination protocol, was initially subjected to Pd-
3 4
(PPh ) in toluene at 85 °C. Four major cyclic compounds were
generated in a 6:24:12:58 ratio and a 31% combined yield and were
identified as tricycle 3 and bicycles 4a, 5a, and 6a (Scheme 2).5
The incorporation of additional methylene and methyl groups,
presumably from the alane moiety, to provide 5a and 6a, respec-
tively, induced us to explore that unprecedented catalytic C-C
bond-forming transformation.
,6
a
See the Supporting Information for details. b Compounds 6b-g, 6i, and
Scheme 2
6
6
j were contaminated with <6% of the gem-dimethyl byproduct. Bicycle
h contained 19% of the gem-dimethyl byproduct. c Using Pd(PPh3)4
(25 mol %) in PhMe at 100 °C.
Having established a high-yielding protocol, we set out to define
the scope of the methodology (Table 1). As expected, aryl triflate
b afforded a low yield of 6b. Sterically demanding substrate 1d
1
required higher temperatures and longer reaction times to give
bicycle 6d (entry 3), while DABCO greatly reduced the formation
of gem-dimethyl byproduct 4d.10 Alternatively, TMS substrate 1f
smoothly reacted in 24 h at 100 °C (entry 5). Heteroatom-containing
substrates 1g-i were tolerated (entries 6-8), but aryl iodide 1h
provided a lower yield of 6g compared to that of triflate 1g, and
thioether 1i necessitated harsher conditions than 1g. In contrast to
1d and 1j, substrates 1e and 1k were resilient to the cyclization
reaction and resulted in the formation of the corresponding
desulfonylated uncyclized byproducts in equimolar amounts (entries
4 and 10).
Synthetically useful yields of 5a and 6a would be obtained by
preventing formation of both 4a and thermally unstable tricycle 3.
2,6-Disubstituted aryl triflates and iodide 1b-k were prepared and
subjected to the two-step, one-pot procedure. Alkyne methylalu-
minations provided the key alkenylalanes that were isolated by
7
removal of the volatiles and used without further purification. For
3
the subsequent step, CH CN was found to be the optimal solvent,
giving good yields of the ligand transfer product. When 1c was
1
treated with Pd(PPh
NMR analysis showed a 9:1 mixture of 1-ethyl-1,7-dimethylindan
6c) and 1,7-dimethyl-1-vinylindan (5c), in addition to the un-
cyclized and desulfonylated uncyclized products. A 42% combined
3 4
) (25 mol %) for 22 h at 100 °C, crude H
Two mechanistic proposals accounting for the formation of
products 6 are outlined in Scheme 3. Starting from 2, formation of
7 by oxidative insertion of Pd(0) into the aryltriflate (or iodide) is
(
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9
J. AM. CHEM. SOC. 2004, 126, 15354-15355
10.1021/ja045783t CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
the initial step in both pathways. Alkenylalane carbopalladation
generates dimetallic11 species 8 that undergoes 1,2-methyl migration
from aluminum to carbon with concomitant regeneration of Pd(0),
leading to 9. Alternatively, 1,2-migration of the methyl group from
aluminum to carbon triggered by electrophilic palladium-triflate 7
forms palladacycle 10 that reductively eliminates to 9.1 5-exo-
trig-Carbopalladation is faster than the analogous 6-exo-trig reac-
tion,14 and formation of seven-membered ring palladacycle is slower
than that of six-membered. Thus, competition between ring closure
and alkenylalane cross-coupling, leading to oligomerization, may
explain the lower yields obtained for 6e and 6j. Yield enhancement
for 2,6-disubstituted aryltriflates and isolation of 3 support the
carbopalladation pathway.
2-position to furnish benzylic all-carbon quaternary centers. Further
results of our studies on this reaction will be reported in due course.
Acknowledgment. We are grateful to the Natural Sciences and
Engineering Research Council of Canada (NSERC), the Canadian
Foundation for Innovation (CFI), the Ontario Innovation Trust
2,13
(OIT), and the University of Waterloo for financial support. This
research was supported by an award from Research Corporation.
The authors thank the Chong group for generously sharing their
GC-MS equipment, and Dr. V. Farina, Dr. C. A. Busacca, and
Dr. M. C. Eriksson for sharing unpublished results. R.J.C. thanks
the Government of Ontario for scholarships (OGS and OGSST).
V.E.T. thanks the Government of Qu e´ bec (FCAR) and the
Government of Ontario (OGS) for fellowships, and J.M.G. thanks
NSERC for an USRA. Cristina Quinn is acknowledged for
preliminary experiments.
15
Scheme 3
Supporting Information Available: Experimental procedures and
NMR spectra. This material is available free of charge via the Internet
at http://pubs.acs.org. See any current masthead page for ordering
information and Web access instructions.
References
(
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2
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1
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1
,4-insertion into the arene C-H bond. For other mechanisms, see:
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2 2
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1
(
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(
(
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(
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(
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1
1
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integration of the H NMR spectrum, and 70% to >95% from alane
2
h. Similarly, the cyclization of alane 2j in CD
with 70-80% deuterium incorporation at the C-1 position of the
ethyl group. Furthermore, replacing CH CN by benzene in the Pd-
catalyzed step allowed for deuteriolysis of the C-Al bond of
intermediate 9i with 10% DCl in D O to furnish tricycle d -6i, for
3 1
CN yielded d -6i,
3
(
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2
1
(
which a 39% deuterium incorporation at the C1-position of the ethyl
group was determined.
In summary, we demonstrated that Pd(0) catalyzes the 1,2-ligand
migration of 2,2-disubstituted-1-alkenyldimethylalanes from alu-
minum to carbon with concomitant intramolecular arylation at the
(
16) Dehydroalumination at elevated temperature has been reported: Eisch, J.
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