Palladium-catalyzed heck-type cross-couplings of unactivated alkyl iodides

Article abstract of DOI:10.1002/anie.201311323

A palladium-catalyzed, intermolecular Heck-type coupling of alkyl iodides and alkenes is described. This process is successful with a variety of primary and secondary unactivated alkyl iodides as reaction partners, including those with hydrogen atoms in t

Full text of DOI:10.1002/anie.201311323

Angewandte
Chemie
DOI: 10.1002/anie.201311323
Synthetic Methods
Palladium-Catalyzed Heck-Type Cross-Couplings of Unactivated Alkyl
Iodides**
Caitlin M. McMahon and Erik J. Alexanian*
Abstract: A palladium-catalyzed, intermolecular Heck-type
coupling of alkyl iodides and alkenes is described. This process
is successful with a variety of primary and secondary
unactivated alkyl iodides as reaction partners, including those
with hydrogen atoms in the b position. The mild catalytic
transition metals (e.g., Ni, Ti, Co) have been developed to
facilitate intermolecular alkyl-Heck processes.[6] However,
these methods commonly rely on stoichiometric amounts of
alkylmetal reductants, limiting the general applicability of
these reactions in synthesis. Furthermore, these processes
have been solely limited to cross-coupling with styrenes.
Recent studies have demonstrated the potential for
palladium-and nickel-catalyzed alkyl-Heck-type carbocycli-
zations of alkyl halides.[3,7] We have also obtained promising
preliminary results involving the intermolecular alkyl-Heck
coupling of cyclohexyl iodide with a small sample of styrenes,
albeit in moderate yield.[7a] Herein, we report the develop-
ment of a general protocol for the palladium-catalyzed, alkyl-
Heck-type cross-coupling. This process is applicable to
a range of alkyl iodides and alkenes, and represents the first
intermolecular alkyl-Heck coupling of any kind involving
non-styrenyl substrates.
À
conditions enable intermolecular C C bond formations with
a diverse set of alkyl iodides and alkenes, including substrates
containing base- or nucleophile-sensitive functionality.
P
alladium-catalyzed cross-couplings are invaluable to an
array of disciplines that involve chemical synthesis, ranging
from pharmaceuticals to materials science.[1] Among the most
useful reactions of this type are Heck cross-couplings, which
À
form an intermolecular C C bond between a halide or
sulfonate electrophile and an alkene under mild conditions.[2]
However, this reaction has been largely limited to aryl or
vinyl electrophiles, and palladium-catalyzed Heck-type reac-
tions involving unactivated alkyl halides are considered
a major challenge (Scheme 1).[3] This issue is commonly
attributed to the decreased rates of oxidative addition using
sp3-hybridized electrophiles,[4] and the predisposition of
putative alkylpalladium species to undergo dehydrohaloge-
nation.[5] A number of catalytic systems involving first-row
We commenced our studies by evaluating the intermo-
lecular coupling of cyclohexyl iodide and acrylonitrile
(Table 1). The use of an organic base (Cy2NMe), as in our
previously developed alkyl-Heck-type reactions,[7a] led to
a large amount of undesired reductive product 2 (Table 1,
entry 2). Fortunately, this problem could be mitigated by the
Table 1: Palladium-catalyzed cross-coupling of cyclohexyl iodide and
acrylonitrile.
Entry Deviation from conditions described above
Yield of 1 (2)
[%][a]
1
2
3
4
5
6
7
none
72
18 (24)
57
24
54
Cy2NMe instead of K3PO4
Cs2CO3 instead of K3PO4
808C instead of 1008C
1.0 equiv of alkene, 2.0 equiv of iodide
[Pd(PPh3)4] (10 mol%) instead of [PdCl2(dppf)]
Pd(OAc)2 (10 mol%) and BINAP (20 mol%)
instead of [PdCl2(dppf)]
Scheme 1. Palladium-catalyzed Heck cross-couplings.
55 (5)
17
[*] C. M. McMahon, Prof. E. J. Alexanian
Department of Chemistry
8
9
Pd(OAc)2 (10 mol%) and dppe (20 mol%)
instead of [PdCl2(dppf)]
Pd(OAc)2 (10 mol%) and dppf (20 mol%) instead 73
of [PdCl2(dppf)]
no [PdCl2(dppf)]
reaction in the dark, 24 h
<2
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599 (USA)
E-mail: eja@email.unc.edu
[**] This work was supported by UNC Chapel Hill, and a Burroughs-
Wellcome Graduate Fellowship (C.M.M.).
10
11
<2
69
Supporting information for this article (including experimental
procedures and data) is available on the WWW under http://dx.doi.
org/10.1002/anie.201311323.
[a] Calculated by 1H NMR spectroscopy of the crude reaction mixtures
using an internal standard.
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Table 2: Scope of palladium-catalyzed alkyl-Heck-type cross-couplings
use of inorganic bases instead of Cy2NMe (Table 1, entries 1
and 3), with K3PO4 most effective. We determined that the
use of solvents that lack abstractable hydrogen atoms limited
the production of by-product 2, and PhCF3 was found to be
a suitable choice. Lowering the reaction temperature to 808C
resulted in a marked decrease in reaction efficiency (Table 1,
entry 4). A slight excess of acrylonitrile was preferable in this
cross-coupling (1.5 equiv), however, reactions using a slight
excess of alkyl iodide proceeded in lower yield (Table 1,
entry 5). Other palladium-based catalytic systems, including
[Pd(PPh3)4], which we used in our previous studies, were
inferior to [PdCl2(dppf)] (Table 1, entry 6–8). The combina-
tion of Pd(OAc)2 (10 mol%) and dppf (20 mol%) was
a suitable substitute for [PdCl2(dppf)] (10 mol%; Table 1,
entry 9). No product was formed in the absence of [PdCl2-
(dppf)] (Table 1, entry 10), and the reaction proceeded in the
dark (entry 11). The success of this cross-coupling is partic-
ularly intriguing with regard to the potential for an undesired
polymerization of acrylonitrile.[8]
with respect to the alkene.[a]
Upon the identification of a viable reaction system, we
first surveyed the cross-coupling of a variety of alkenes. As
with acrylonitrile cross-coupling (Table 1), the use of [PdCl2-
(dppf)] was crucial to obtain a high yield. An electronically
diverse set of styrenes, including those with base- and
nucleophile-sensitive functionality, are viable coupling part-
ners (Table 2, entries 1–9). In styrenyl cross-couplings,
Cy2NMe was used as base, because reductive by-products
were not problematic. 2-Vinyl pyridine participates in the
cross-coupling, albeit in modest yield (Table 2, entry 10).
Electron-poor alkenes, such as methyl vinyl ketone (Table 2,
entry 11) and acrylonitrile (entries 12 and 13), afforded the
products in moderate to good yields. In the case of the highly
polymerizable methyl vinyl ketone, substitution of [PdCl2-
(dppf)] for [{Pd(allyl)Cl}2] (5 mol%) and PPh2tBu (40 mol%)
was required. We studied the reaction of trans-2-(tert-
butyldimethylsilyloxy)-1-iodocyclohexane in order to probe
the diastereoselectivity of the reaction with simple cyclic
substrates (Table 2, entry 13). The cross-coupling of this
substrate with acrylonitrile delivered the product with
a 50:50 ratio of cis- and trans-substituted cyclic diastereomers.
Alkenes containing substituents in the b position also react
efficiently (Table 2, entries 14–16) with either cyclohexylio-
dide or the heterocyclic 4-iodo-1-tosylpiperidine as coupling
partners. In analogy to the standard Heck reaction using aryl
electrophiles, the cross-couplings of b-substituted alkenes
gave mixtures of geometric isomers as products, with the
predominate isomer containing the incoming alkyl electro-
phile and the electron-withdrawing group in trans position to
each other.[9] In the cross-couplings of b-disubstituted alkenes,
we determined that [Pd(PPh3)4] was superior to [PdCl2(dppf)]
as catalyst.
[a] Reactions run using 1.0 equiv alkyl iodide and 1.5 equiv alkene 0.5m
in PhCF3 at 1008C in the presence of 10 mol% [PdCl2(dppf)] and
2.0 equiv Cy2NMe for 14 h. [b] Yields of isolated product. [c] Product
ratios were determined by 1H NMR spectroscopy of crude reaction
mixtures. [d] Yield calculated by 1H NMR spectroscopy of the crude
reaction mixture using an internal standard. [e] 2.0 equiv K3PO4 used as
base. [f] 5 mol% [{Pd(allyl)Cl}2] and 40 mol% PPh2tBu used as catalyst,
5 h. [g] 10 mol% [Pd(PPh3)4] used as catalyst. [h] 2.0 equiv alkyl iodide
and 1.0 equiv enone. [i] 3.0 equiv crotononitrile. TBS=tert-butyldime-
thylsilyl, Ts=toluene-p-sulfonyl.
the reactions of 1-iodooctane and 2-iodononane (Table 3,
entries 4 and 5). Sterically congested 6-iodo-1,4-dioxaspiro-
[4.5]decane was an excellent substrate, and coupled with
styrene in 79% yield (Table 3, entry 6). The reactions of alkyl
iodide substrates containing nucleofuges in the a position are
À
We next examined the scope of the reaction with a variety
of alkyl iodides using styrene as the coupling partner
(Table 3). Cyclopentyl and cycloheptyliodide reacted with
similar efficiency to cyclohexyl iodide (Table 3, entries 1 and
2).[10] The cross-coupling of exo-2-norbornyl iodide provided
the styrylation product with high diastereoselectivity (> 95:5
d.r.; Table 3, entry 3). The cross-coupling is also applicable to
acyclic primary and secondary iodides, as demonstrated by
also useful intermolecular C C bond-forming transforma-
tions, as demonstrated by the reactions of an iodo-g-lactone
and enantiopure TBS-protected (S)-1-iodododecan-2-ol
(Table 3, entries 7 and 8). With regard to the array of useful
methods for the asymmetric synthesis of such substrates,[11] we
view this as a particularly attractive approach to the
enantioselective preparation of highly functionalized small
molecules.
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Table 3: Scope of palladium-catalyzed alkyl-Heck-type cross-couplings
with respect to the alkyl halide.[a]
Scheme 2. Plausible catalytic cycle for the palladium-catalyzed alkyl-
Heck-type cross-coupling.
À
transformation holds promise as an enabling tool for C C
bond formation in complex synthesis.
We hypothesize that this cross-coupling proceeds through
single-electron oxidative addition of the alkyl iodide substrate
followed by alkene addition of the carbon-centered radical, as
shown in Scheme 2.[15–17] The exclusive formation of the exo-
substituted coupling product with exo-2-norbornyl iodide
(Table 3, entry 3),[18] and the stereoablation observed in the
reaction of a diastereomerically pure cyclic substrate (Table 2,
entry 13) is consistent with a single-electron pathway. Addi-
tionally, the reaction of styrene with a radical-clock substrate
(6-iodo-1-hexene) provided the cyclic coupling product in
38% yield [Eq. (2)], with no linear coupling product
observed.
[a] Reactions run using 1.0 equiv alkyl iodide and 1.5 equiv alkene 0.5m
in PhCF3 at 1008C in the presence of 10 mol% [PdCl2(dppf)] and
2.0 equiv Cy2NMe for 14 h. [b] Yields of isolated product. [c] Product
ratios were determined by 1H NMR spectroscopy of the crude reaction
mixtures. [d] Reaction run at 1308C. [e] Yield calculated by 1H NMR
spectroscopy of the crude reaction mixture using an internal standard.
Notable features of Heck cross-couplings are the mild
catalytic conditions and simple substrates involved, which are
À
ideal for late-stage intermolecular C C bond formation in
synthesis. For an initial demonstration of this concept with
a substrate derived from a complex natural product, we
prepared an iodide substrate in straightforward fashion from
cholic acid.[12] The intermolecular alkyl-Heck coupling with
crotononitrile delivered the alkenylation product in a highly
stereoselective fashion with respect to the cyclohexyl ring
[Eq. (1)].[13] In light of the many methods available for the
preparation of alkyl iodides directly from alcohols,[14] this
Following the addition step, the alkylpalladium(II) species
is formed, and b-hydride elimination delivers the cross-
coupling product. We hypothesize that the lack of significant
amounts of polymer in reactions involving reactive monomers
(e.g., methyl vinyl ketone, acrylonitrile) may be due to the
unique reactivity of the PdI species, which may exhibit
persistent radical-like character.[16] However, at this stage
we cannot rule out pathways involving organometallic
insertion.
In conclusion, we have developed a general strategy for
the palladium-catalyzed intermolecular alkyl-Heck reaction.
The approach includes the first examples of alkyl-Heck cross-
couplings using non-styrenyl substrates. The observed reac-
tivity is consistent with a hybrid organometallic–radical
pathway, which may be crucial to avoiding undesired dehy-
drohalogenation of the simple alkyl halide substrates. A
notable feature of the current process is the easy access to the
involved substrates, which combined with the mild reaction
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Cuerva, Org. Lett. 2012, 14, 5984 – 5987; for a very recent study
of palladium-catalyzed cross-couplings of alkyl halides and
styrenes, see: Y. Zou, J. Zhou, Chem. Commun. 2014, 50,
3725 – 3728.
conditions makes this approach attractive for complex syn-
thesis.
Received: December 31, 2013
Revised: February 17, 2014
Published online: && &&, &&&&
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Keywords: alkenes · alkyl halides · cross-coupling ·
.
homogeneous catalysis · palladium
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Synthetic Methods
C. M. McMahon,
E. J. Alexanian*
&&&& — &&&&
Palladium-Catalyzed Heck-Type Cross-
Couplings of Unactivated Alkyl Iodides
Success with palladium: A variety of
unactivated alkyl iodides, including those
with hydrogen atoms in the b position,
were successfully coupled with different
alkenes in Pd-catalyzed Heck-type reac-
tions. The mild catalytic conditions
enable the formation of intermolecular
À
C C bonds, with applications to sub-
strates that contain base- or nucleophile-
sensitive functionality.
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