Palladium-Catalyzed, Ring-Forming Aromatic C-H Alkylations with Unactivated Alkyl Halides

Article abstract of DOI:10.1021/jacs.5b01365

A catalytic C-H alkylation using unactivated alkyl halides and a variety of arenes and heteroarenes is described. This ring-forming process is successful with a variety of unactivated primary and secondary alkyl halides, including those with β-hydrogens. In contrast to standard polar or radical cyclizations of aromatic systems, electronic activation of the substrate is not required. The mild, catalytic reaction conditions are highly functional group tolerant and facilitate access to a diverse range of synthetically and medicinally important carbocyclic and heterocyclic systems.

Full text of DOI:10.1021/jacs.5b01365

Communication
pubs.acs.org/JACS
Palladium-Catalyzed, Ring-Forming Aromatic C−H Alkylations with
Unactivated Alkyl Halides
Alexander R. O. Venning, Patrick T. Bohan, and Erik J. Alexanian*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
S
* Supporting Information
Scheme 1. Palladium-Catalyzed Cyclizations of Unactivated
Alkyl Halides
ABSTRACT: A catalytic C−H alkylation using unac-
tivated alkyl halides and a variety of arenes and
heteroarenes is described. This ring-forming process is
successful with a variety of unactivated primary and
secondary alkyl halides, including those with β-hydrogens.
In contrast to standard polar or radical cyclizations of
aromatic systems, electronic activation of the substrate is
not required. The mild, catalytic reaction conditions are
highly functional group tolerant and facilitate access to a
diverse range of synthetically and medicinally important
carbocyclic and heterocyclic systems.
ment of such a palladium-catalyzed ring-forming C−H
alkylation, amenable to a diverse array of simple unactivated
alkyl halide electrophiles, arenes, and heteroarenes.
he cyclization of aromatic substrates with simple alkyl
Thalides is an important approach to polycyclic carbocycles
and heterocycles, most notably via Friedel−Crafts reactions.1
While these are valuable transformations in synthesis, the
substrate scope is limited owing to the requirement of electron-
rich aromatic substrates and the utilization of stoichiometric (or
super-stoichiometric) amounts of strong Lewis acids. Radical-
mediated homolytic aromatic substitutions offer an alternative
approach, but often necessitate electron-poor aromatic
substrates for efficient reactivity, with reductive dehalogenation
commonly observed.2 Substitution of alkyl halides for alkyl
xanthates (dithiocarbonates) in homolytic aromatic substitu-
tions is an excellent option for addressing these limitations
owing to the persistent radical effect, however this requires
additional synthetic effort to access desired substrates and
involves stoichiometric amounts of reactive peroxides (e.g.,
DLP, dilauroyl peroxide).3 Transition metal catalysts have
proven useful in select aromatic C−H alkylations involving the
cyclization of activated alkyl halides (α-halocarbonyls),4,5 or
intermolecular reactions between aromatic substrates contain-
ing appended directing groups and unactivated alkyl halides.6,7
A general, catalytic ring-forming C−H alkylation of arenes and
heteroarenes using unactivated alkyl halides has not been
reported, yet would be highly enabling in the synthesis of
polycyclic compounds.
Our efforts commenced with the construction of a range of
tetrahydronapthalenes and indanes via the catalytic alkylation of
arenes using alkyl bromides and iodides (Table 1). The
cyclizations of both unactivated alkyl bromides and alkyl
iodides were successful using 10 mol % Pd(PPh3)4 as catalyst,
although the reactions of alkyl bromides required elevated
temperatures (130 °C) as compared to the alkyl iodides (100
°C). As demonstrated in entries 1−8, there are no limitations
with respect to the electronic characteristics of the aromatic
substrate, which is an important advantage over prior
approaches to ring-forming C−H alkylations. Reactions
involving alkyl bromides and iodides proceeded with similar
efficiencies, and the tetrahydronapthalene products were
isolated in good to excellent yield (59−92%, entries 1−8).
While a number of substrates in Table 1 feature a malonate
tether to assist in their preparation, this reaction does not
require the Thorpe−Ingold effect to favor cyclization (entries 9
and 10). The reaction of ortho-substituted aromatic substrate
16 was successful, although a 50:50 mixture of product 17 and
rearrangement product 18 was produced (entry 11).9 The
indane framework was also easily accessed via 5-exo cyclization
(entries 12−15). However, with neopentyl substrates (entries
12−14) PhtBu was substituted for dioxane as solvent to reduce
the amount of undesired reductive dehalogenation byproducts
formed.
We have recently reported a general approach to the
palladium-catalyzed alkyl-Heck-type cross-coupling that our
initial studies indicated proceeds via a hybrid organometallic-
radical pathway (Scheme 1).8 We hypothesized that this
approach to C−C bond formation using unactivated alkyl
halides could be extended to aromatic substrates, constituting a
mild, catalytic C−H alkylation with distinct advantages over
Friedel−Crafts or standard radical-mediated homolytic aro-
matic substitutions. Herein we report the successful develop-
We next applied the catalytic C−H alkylation to the synthesis
of a diverse set of synthetically and medicinally valuable
heterocycles (Table 2). Cyclization of N-methanesulfonyl
protected aniline substrates 27 (alkyl bromide) and 29 (alkyl
Received: September 3, 2014
© XXXX American Chemical Society
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DOI: 10.1021/jacs.5b01365
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Journal of the American Chemical Society
Communication
Table 1. Palladium-Catalyzed C−H Alkylations Accessing
Tetrahydronapthalenes and Indanes
Table 2. Synthesis of Diverse Polycyclic Heterocycles Using
the Catalytic C−H Alkylation
All reactions were performed with [substrate]0 = 0.5 M and 10 mol %
Pd(PPh3)4 as catalyst. The reactions of alkyl bromides were performed
in PhtBu at 130 °C with 2 equiv PMP (1,2,2,6,6-pentamethylpiper-
idine) as base. The reactions of alkyl iodides were performed in
a
dioxane at 100 °C with 2 equiv K3PO4 as base. Isolated yields.
b
c
d
K3PO4 used as base. PhtBu used as solvent. Calculated by 1H NMR
spectroscopy of crude reaction mixtures using an internal standard.
iodide) delivered indoline product 28 in good yield (entries 1
and 2). As observed in the C−H alkylations of Table 1, these
reactions did not require particular electronic modulation of the
aromatic substrate as demonstrated in entries 1−4. The
excellent functional group tolerance of this protocol is further
exemplified by the successful reactions of entries 5−8, with
substrates containing a boronic acid pinacol ester, ketone,
alcohol, and alkene. We studied the ortho:para selectivity of the
reaction using meta-substituted anilines 40 and 42 (entries 9
and 10). In both instances, the reactions produced a mixture of
indoline products in high yield, with modest selectivity for the
ortho functionalization products (2.4:1 and 2.0:1, ortho:para,
respectively). Simple extension of the tether unit enabled access
to the tetrahydroquinoline framework, as the reaction of
substrate 44 provided N-methanesulfonyl 4-methyl-1,2,3,4-
tetrahydroquinoline 45 in moderate yield (57%, entry 11).
Changing the site of N-substitution in the tether permits facile
access to the tetrahydroisoquinoline derivative (entry 12).10
The catalytic C−H alkylation was also successful using indole
and pyrrole heterocycles (entries 13−18). Reactions involving
both primary and secondary alkyl iodides proceeded in good
yields in these transformations. The reactions of indoles 48 and
50 afforded dihydro-1H-pyrrolo[1,2-a]indoles via 5-exo cycliza-
tion (entries 13 and 14). Extension of the methylene tether
provided access to tetrahydropyrido[1,2-a]indoles via a 6-exo
All reactions were performed with [substrate]0 = 0.5 M in dioxane at
100 °C with 10 mol % Pd(PPh3)4 and 2 equiv K3PO4 as base.
a
b
Isolated yields. The reaction was performed at 130 °C in PhtBu.
c
Calculated by 1H NMR spectroscopy of crude reaction mixtures using
an internal standard.
process (entries 15 and 16). The cyclizations of pyrrole
substrates 56 and 58 successfully delivered tetrahydroindoli-
zines 57 and 59 in 64% and 95% yield, respectively.
Importantly, electronic activation of the indole or pyrrole
nucleuscommon to prior stoichiometric metal- or peroxide-
mediated protocols for efficient cyclizationwas not required
using our mild, palladium-catalyzed approach.2,3d
Following our synthetic studies, we performed a number of
experiments to gain insight into the reaction mechanism
(Scheme 2). The reaction of substrate 29 under standard
conditions with 1 equiv of the persistent radical TEMPO
(2,2,6,6-tetramethylpiperidine 1-oxyl) yielded 60% of adduct 60
B
DOI: 10.1021/jacs.5b01365
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Journal of the American Chemical Society
Communication
In conclusion, we have developed a palladium-catalyzed
approach to the direct ring-forming C−H alkylation of aromatic
substrates using unactivated alkyl halides. The reaction is
successful with both primary and secondary alkyl bromides and
iodides, and efficiently delivers a diverse range of valuable
carbocyclic and heterocyclic products. Electronic activation of
the aromatic substrates is not required, significantly increasing
the potential substrate scope of this process with respect to
prior polar or radical-mediated ring-forming C−H alkylations.
Furthermore, the mild, catalytic reaction conditions involved
offer an attractive alternative to known stoichiometric Lewis
acid or peroxide-mediated processes.
Scheme 2. Studies Probing the Reaction Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
and no C−H alkylation product, consistent with the
intermediacy of carbon-centered radicals. We additionally
prepared enantioenriched (R)-29, which produced indoline
28 as a racemate, also consistent with a single-electron pathway
rather than an SN2-type activation of the alkyl halide. This
reaction was stopped at partial conversion to determine the
enantiopurity of the remaining starting material. Interestingly,
recovered 29 was also completely racemic. The observed
stereoablation of 29 is consistent with a reversible single-
electron activation of the alkyl halide substrate prior to
cyclization. We have also performed an intermolecular
competition experiment involving deuterated substrate 29-d5.
No kinetic isotope effect was observed, demonstrating that C−
H bond cleavage is not involved in the rate-determining step of
the reaction.
AUTHOR INFORMATION
Corresponding Author
*eja@email.unc.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Award No. R01 GM107204 from
the National Institute of General Medical Sciences and a UNC
Chapel Hill SURF fellowship (P.T.B.).
REFERENCES
■
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C
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Journal of the American Chemical Society
Communication
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rearomatization. For a proposed mechanism, see the Supporting
Information.
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example, in this particular reaction tetrahydroisoquinoline 47 is
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1
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spectroscopy of the crude reaction mixture using an internal standard).
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(b) electron transfer to the substrate from a radical anion, formed from
deprotonation of the cyclohexadienyl radical (base-promoted homo-
lytic aromatic substitution, HAS). We consider the former unlikely
owing to the highly endergonic electron transfer involved. Oxidation
potential of the cyclohexadienyl radical, −0.1 V versus SCE, see:
Bhatia, K.; Schuler, R. H. J. Phys. Chem. 1974, 78, 2335. Reduction
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With respect to a base-mediated HAS, these reactions typically require
either a strong base (e.g., KOtBu) or appreciably electron-poor
aromatic substrates, neither of which are characteristic of the reactions
herein. For further discussion, see: Studer, A.; Curran, D. P. Angew.
Chem., Int. Ed. 2011, 50, 5018. We thank a reviewer for suggesting
these mechanistic variants.
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DOI: 10.1021/jacs.5b01365
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX