Palladium-catalyzed heck-type reactions of alkyl iodides

Article abstract of DOI:10.1021/ja2091883

A palladium-catalyzed Heck-type reaction of unactivated alkyl iodides is described. This process displays broad substrate scope with respect to both alkene and alkyl iodide components and provides efficient access to a variety of cyclic products. The reaction is proposed to proceed via a hybrid organometallic-radical mechanism, facilitating the Heck-type process with alkyl halide coupling partners. Initial intermolecular studies are also reported, demonstrating the potentially wide applicability of this approach in synthesis.

Full text of DOI:10.1021/ja2091883

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Palladium-Catalyzed Heck-Type Reactions of Alkyl Iodides
Kayla S. Bloome, Rebecca L. McMahen, and Erik J. Alexanian*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S Supporting Information
b
Scheme 1. Challenges in Developing Alkyl-Heck Processes
ABSTRACT: A palladium-catalyzed Heck-type reaction of
unactivated alkyl iodides is described. This process displays
broad substrate scope with respect to both alkene and alkyl
iodide components and provides efficient access to a variety
of cyclic products. The reaction is proposed to proceed via a
hybrid organometallic-radical mechanism, facilitating the
Heck-type process with alkyl halide coupling partners. Initial
intermolecular studies are also reported, demonstrating the
potentially wide applicability of this approach in synthesis.
Our efforts commenced with the study of iodide 1. We
examined this substrate in order to test whether a noncarbony-
lative 5-exo alkyl-Heck-type process would outcompete a possi-
ble 6-exo carbonylative cyclization. Substrate 1 was subjected to
identical conditions from our previous study comprised of 10
mol % Pd(PPh3)4 and 2.0 equiv of iPr2EtN under 50 atm of CO
pressure at 130 °C in PhMe. Cyclopentene 2 was formed in good
yield from an alkyl-Heck-type process, and no formation of any
carbonylative cyclization products was observed (eq 1).9
he palladium-catalyzed Heck reaction is a fundamental
synthetic transformation in chemical synthesis, enabling
T
the direct cross-coupling of simple alkenes with aryl or vinyl
halides (or sulfonates).1 The utility of this process with aryl or
vinyl coupling partners has been well demonstrated in synthesis.
However, extending the Heck reaction to simple alkyl halide
substrates has been a major challenge.2 The difficulty is attributed
to two main factors: the general reluctance of sp3-hybridized alkyl
halides to undergo oxidative addition processes with low-valent
transition metals,3 and the predisposition of putative alkylmetal
species to undergo β-hydride elimination,4 resulting in overall
dehydrohalogenation (Scheme 1).
Despite these significant challenges, useful strategies have
emerged to facilitate alkyl-Heck-type transformations in selected
cases. The development of reactions catalyzed by transition
metals other than palladium has shown promise, but these
processes require the use of superstoichiometric amounts of
highly reactive alkylmagnesium reagents, greatly limiting poten-
tial applications in organic synthesis.5 Seminal work by Fu
demonstrated the possibility of a palladium-catalyzed intramo-
lecular alkyl-Heck-type process.6 However, the scope of this
process is strictly limited to cyclopentene synthesis utilizing only
primary alkyl halides and terminal alkenes as substrates.7
Alkyl-Heck-type processes of broad substrate scope, capitaliz-
ing on the mild conditions afforded by palladium(0) catalysis
while leveraging the synthetic accessibility of alkenes and alkyl
halides, would constitute powerful transformations for organic
synthesis. We recently reported our initial efforts toward the
development of alkyl-Heck-type processes in the form of a
palladium(0)-catalyzed carbonylative cyclization of simple un-
saturated alkyl iodides, providing expedient access to numerous
classes of cycloalkenones.8 Herein, we demonstrate that a similar
catalytic system also facilitates the direct alkyl-Heck-type reac-
tion of a wide variety of alkyl iodides and alkenes. The pro-
cess employs mild reaction conditions using Pd(PPh3)4 as a
catalyst and holds high potential in both intra- and intermole-
cular settings.
Following this promising initial result, we continued with
further study of substrate 1 in order to determine whether CO
played any role in this noncarbonylative cyclization process.
Interestingly, while the cyclization did proceed in the absence of
CO (76% yield), increasing CO pressure up to 10 atm greatly
minimized the formation of alkene isomers of 2.10 Reaction of
substrate 1 under optimized reaction conditions employing 10
mol % Pd(PPh3)4 and 2.0 equiv of 1,2,2,6,6-pentamethylpiper-
idine (PMP) under 10 atm of CO pressure at 110 °C in PhH
delivered cyclopentene 2 in 80% yield (Table 1, entry 1).11
We next aimed to explore the substrate scope of the carbocy-
clization using a wide variety of unsaturated alkyl halides
(Table 1). In order to test the potential of the alkyl-Heck-type
process to construct quaternary stereocenters, we examined the
reaction of substrate 3 containing a trisubstituted alkene (entry 2).
This substrate efficiently formed pyrrolidine 4, demonstrating
Received: October 7, 2011
Published: November 18, 2011
r
2011 American Chemical Society
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Table 1. Palladium-Catalyzed Carbocyclizationsa
Scheme 2. Plausible Catalytic Cycle for the Carbocyclization
Alkyl halides are known to react with palladium(0) via both
SN213 and single-electron transfer pathways.14 In order to probe
for the potential intermediacy of carbon-centered radicals in the
current reaction, we have attempted a cyclization in the presence
of TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl).15 The reac-
tion of substrate 11 with 1 equiv of added TEMPO produced
adduct 18 in 24% yield, with a significant amount of unreacted
starting material, and no alkyl-Heck-type products were observed
(1H NMR analysis) (eq 2).16
a Reactions run 0.5 M in PhH at 110 °C under 10 atm of CO in the
Although the determination of a precise reaction pathway for
this process requires further studies, our preliminary mechanistic
hypothesis is outlined in Scheme 2 (with 3 as the substrate). We
hypothesize that palladium(0) initiates this process via single-
electron transfer to generate a carbon-centered free-radical 19
which then cyclizes onto the pendant alkene to deliver a second
carbon-centered radical 20.17 After interception of this radical
species by a putative palladium(I) species, β-hydride elimination
of an alkylpalladium(II) compound 21 provides product and
regenerates the catalyst. Substrate dehydrohalogenation was not
a significant side reaction in the carbocyclization, which is con-
sistent with this proposal. At this time, the exact role of CO
in increasing the efficiency of the present reaction with a number
of substrates (Table 1, entries 1À5) is unclear. It is possible that
the formation of less electron-rich Pd(PPh3)x(CO)y species,
which are formed under CO pressure,18 results in a more efficient
hybrid organometallic-radical process. Studies to further eluci-
date the mechanistic pathway are underway.
presence of 10 mol % Pd(PPh3)4 and 2.0 equiv of PMP. b Yields of
c
1
isolated product. Product ratios were determined by H NMR spec-
troscopy of crude reaction mixtures. d Yield calculated by H NMR
1
spectroscopy of crude reaction mixtures using internal standard. e Reac-
tion temperature: 130 °C. f Reactions performed under Ar.
the ability of the carbocyclization to form quaternary centers
(70% yield). Notably, the CO atmosphere was critical to the
success of this reaction, as reaction under Ar led to the forma-
tion of a number of unidentified byproducts in addition to 4.
Cyclization of iodide 5 was also successful, providing substituted
tetrahydrofuran 6 containing a quaternary stereocenter. This
carbocyclization is capable of constructing bicyclic architectures,
as demonstrated by the cyclization of cyclohexenyl substrate 7.
Importantly, this reaction is not limited to five-membered ring
synthesis. For instance, alkyl iodide 11 delivered products 12 and
13 in 70% yield via 6-exo cyclization.
We also explored the potential of the palladium-catalyzed
carbocyclization using secondary alkyl iodides. Our studies
commenced with substrate 14, which cyclized to afford product
15.12 Notably, CO does not have a significant effect on the
efficiency of reactions using secondary iodides as substrates. The
reaction of secondary iodide 16 was also successful, delivering 17
with high stereoselectivity.
Initial studies have also demonstrated the potential of the
present catalytic system to facilitate an intermolecular variant of
the palladium-catalyzed alkyl-Heck-type reaction. For example,
the direct cross-coupling of styrene (22a) (1.0 equiv) and
cyclohexyl iodide (2.0 equiv) delivers β-cyclohexyl styrene 23a
in 55% isolated yield (eq 3). The reactions of substituted styrenes
22b and 22c containing ketone and alcohol functional groups,
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respectively, serve to demonstrate the functional group compat-
ibility of this process. Future efforts will target the development
of an efficient, general intermolecular variant of this fundamental
transformation employing mild palladium(0)-catalyzed conditions.
(7) Following the submission of our manuscript, Carreira et al. have
reported a cobalt-catalyzed intramolecular alkyl-Heck-type cyclization of
alkyl iodides using alkyl or stannyl cobaloximes and blue LEDs: Angew.
Chem., Int. Ed. 2011, 50, 11125À11128.
(8) Bloome, K. S.; Alexanian, E. J. J. Am. Chem. Soc. 2010,
132, 12823–12825.
1
(9) The reaction yields determined by H NMR were calculated
from crude reactions using 1,3,5-trimethoxybenzene as an internal
standard.
(10) For further details, including experiments run at other pressures
of CO, see the Supporting Information.
(11) No product formed under these conditions in the absence of
Pd(PPh3)4.
In conclusion, we have developed a palladium-catalyzed Heck-
type reaction of alkyl iodides of broad substrate scope. This
process is applicable to the synthesis of many types of common
cyclic frameworks and tolerates a variety of substituted alkenes
and alkyl iodides. We have also demonstrated the potential of this
process in an intermolecular direct palladium-catalyzed alkyl-
Heck-type cross-coupling reaction. We propose that the wide
scope of this transformation results from the hybrid organome-
tallic-radical nature of the process, successfully overcoming the
major challenges inherent in the development of palladium-
catalyzed Heck reactions employing alkyl halide substrates.
(12) Reaction of the alkyl bromide of substrate 14 was substantially
slower, providing a 26% 1H NMR yield of cyclization products after 24 h,
with significant amounts of starting material remaining.
(13) (a) Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2002,
41, 3910–3912. (b) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu,
G. C. J. Am. Chem. Soc. 2002, 124, 13662–13663.
(14) For a survey of the mechanisms of oxidative addition of
palladium(0) to alkyl halides, see: Stille, J. K.; Lau, K. S. Y. Acc. Chem.
Res. 1977, 10, 434–442.
(15) TEMPO has been previously utilized to trap radical intermedi-
ates in Ni-catalyzed reactions involving alkyl iodides: Phapale, V. B.;
Bu~nuel, E.; García-Iglesias, M.; Cꢀardenas, D. J. Angew. Chem., Int. Ed.
2007, 46, 8790–8795.
(16) No TEMPO-trapped product (18) formed under these condi-
tions in the absence of Pd(PPh3)4.
(17) Examples of palladium(0)-catalyzed reactions of alkyl iodides
proposed to involve hybrid organometallic-radical mechanisms:
(a) Stadtm€uller, H.; Vaupel, A.; Tucker, C. E.; St€udemann, T.; Knochel,
P. Chem.—Eur. J. 1996, 2, 1204–1220. (b) Ryu, I.; Kreimerman, S.;
Araki, F.; Nishitani, S.; Oderaotoshi, Y.; Minakata, S.; Komatsu, M. J. Am.
Chem. Soc. 2002, 124, 3812–3813. (c) Ishiyama, T.; Murata, M.; Suzuki,
A.; Miyaura, N. J. Chem. Soc., Chem. Commun. 1995, 295–296.
(d) Ishiyama, T.; Miyaura, N.; Suzuki, A. Tetrahedron Lett. 1991,
32, 6923–6926.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and spectral data for all new compounds are provided. This
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
eja@email.unc.edu
(18) (a) Cavinato, G.; Toniolo, L.; Vavasori, A. J. Mol. Catal. A:
Chem. 2004, 219, 233–240. (b) Ozawa, F.; Sugimoto, T.; Yuasa, Y.;
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3, 683–692. (c) Hidai, M.; Kokura, M.; Uchida, Y. J. Organomet. Chem.
1973, 52, 431–435.
’ ACKNOWLEDGMENT
This work was supported by generous start-up funds provided
by UNC Chapel Hill.
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