Iron-catalyzed heterocycle and arene deprotonative alkylation

Article abstract of DOI:10.1021/ol101684u

Figure Presented. A method for iron-catalyzed deprotonative alkylation of arene C-H bonds by alkyl iodides and bromides has been developed. In the presence of an amide base, both primary and secondary alkyl halides can be coupled with furans, thiophenes, pyridine derivatives, and some electron-withdrawing-group containing arenes.

Full text of DOI:10.1021/ol101684u

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4277-4279
Iron-Catalyzed Heterocycle and Arene
Deprotonative Alkylation
Ly Dieu Tran and Olafs Daugulis*
Department of Chemistry, UniVersity of Houston, Houston, Texas 77204-5003
olafs@uh.edu
Received July 21, 2010
ABSTRACT
A method for iron-catalyzed deprotonative alkylation of arene C-H bonds by alkyl iodides and bromides has been developed. In the presence
of an amide base, both primary and secondary alkyl halides can be coupled with furans, thiophenes, pyridine derivatives, and some electron-
withdrawing-group containing arenes.
Direct arylation of heterocycle and directing-group containing
arene sp2 C-H bonds has resulted in many synthetically
useful procedures.1 However, transition-metal-catalyzed alkyl-
ation of C-H bonds is not common, and the need for new
methodology still exists. Several methods have been devel-
oped for converting an sp2 C-H bond to a C(sp2)-C(sp3)
functionality. An industrially important Friedel-Crafts alkyl-
ation suffers from carbocation isomerization, polyalkylation,
and regioselectivity problems that may limit its synthetic
applicability.2 More recent methodology involves directing-
group-containing arene and heterocycle alkylation by alkenes
that employs ruthenium, rhodium, or cobalt catalysis. While
regioselectivity is excellent with respect to the arene coupling
component, the scope of alkenes that can be employed is
often limited by double-bond isomerization.3 The third
method employs an alkyl halide coupling partner. Pioneering
reports by Tremont and Liebeskind describe palladium-
promoted alkylation of anilides and imines.4 More recently,
methods for heterocycle and benzoic acid alkylation under
ruthenium and palladium catalysis have been developed.5 A
rare example that employs abundant first-row transition-metal
catalysis was recently reported by Knochel. An iron amide
base was used to deprotonate a variety of ester and-/or
fluorine-containing arenes. Trace nickel-catalyzed coupling
with alkyl halides subsequently afforded the alkylated
aromatic species.6 While iron-catalyzed Grignard alkylation
reactions have been developed by Fu¨rster and Nakamura,7
iron-catalyzed deprotonative alkylation of arene C-H bonds
has not been reported.
We have recently developed a method for copper-catalyzed
arylation of acidic arene sp2 C-H bonds.8 An in situ
(4) (a) Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984, 106,
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D. Acc. Chem. Res. 2009, 42, 1074. (g) Alberico, D.; Scott, M. E.; Lautens,
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E.; Della Ca’, N. Acc. Chem. Res. 2008, 41, 1512. (h) Rudolph, A.;
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(2) Roberts, R. M.; Khalaf, A. A. Friedel-Crafts Alkylation Chemistry:
A Century of DiscoVery; Marcel Dekker: New York, 1984.
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Brookhart, M. J. Am. Chem. Soc. 1999, 121, 6616. (c) Lewis, J. C.;
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10.1021/ol101684u  2010 American Chemical Society
Published on Web 09/08/2010

deprotonation/transmetalation is followed by the reaction
with an aryl halide to afford a biaryl (Scheme 1). Both Li
Table 1. Alkylation Scope with Respect to Arenea
Scheme 1. Arene Deprotonative Functionalization
and Cu bases are competent metalating agents under the
reaction conditions.8c Unfortunately, most alkylations at-
tempted were not successful. Only benzylation afforded
product in modest yield.8b A combination of deprotonation
with an iron-catalyzed alkylation7 would allow for the
development of a method for arene regioselective direct
alkylation.
We report here a method for iron-catalyzed deprotonative
alkylation of furan, thiophene, pyridine, as well as ester- and
cyano group-containing arene derivatives. Both primary and
secondary alkyl halide electrophiles can be employed.
A short optimization showed that iron-catalyzed cross-
coupling of 2-lithiobenzothiophene with cyclohexyl bromide
is inefficient (<20% yield), and that the corresponding
Grignard reagent couples with improved yields. The best
ligands were found to be HMTA/TMEDTA9 and trans-N,N′-
dimethylcyclohexane-1,2-diamine10 with the latter affording
slightly higher yields. Iron(III) chloride catalyst was shown
to be superior to other Fe sources. The optimized conditions
involve TMPMgCl·LiCl base, 10 mol % of FeCl3, 25 mol
% of trans-N,N′-1,2-dimethylcyclohexane-1,2-diamine ligand,
and THF solvent at room temperature.
The scope with respect to the arene coupling component
is shown in Table 1. Five-membered heterocycles such as
benzofuran (entry 1), 2-methylthiophene (entry 2), and
benzothiophene (entry 3) can be coupled with cyclohexyl
bromide in moderate to good yields. Various pyridines are
also reactive. Pyridine can be cyclohexylated in a reasonable
yield (entry 4). 3-Methoxy and 3-fluoropyridines react at the
2-position (entries 5 and 6), in contrast to our previous
copper-catalyzed arylation methodology where arylation at
a Cy ) cyclohexyl. Substrate (1.3-3 equiv), cyclohexyl bromide (1
equiv), FeCl3 (5-10 mol %), ligand (13-25 mol %), TMPMgCl·LiCl
(1.6-2.6 equiv), THF, rt. b Cy2NMgCl·LiCl base. c Benzothiophene (1
equiv), CyBr (2 equiv). d TMP2Zn·2MgCl2·LiCl/TMPMgCl·LiCl mixed base.
4-position was observed.8b Isoquinoline is alkylated at the
1-position (entry 7), while 4-methylquinoline reacts at the
methyl group (entry 8), presumably due to the high acidity
of benzylic sp3 protons. Arenes such as 1-cyano-3-methoxy-
benzene and 4-fluorobenzoic acid ethyl ester are also reactive
(entries 9 and 10). In some cases, cheaper dicyclohexylamide
base can be used (entries 3 and 8). For several arenes,
addition of zinc amide base11 is beneficial. Interestingly,
several substrates that were shown to be efficiently arylated
under copper catalysis were unreactive in the alkylation.
Alkylation is not successful for relatively acidic substrates
(7) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem.
Soc. 2004, 126, 3686. (b) Martin, R.; Fu¨rstner, A. Angew. Chem., Int. Ed.
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J. Am. Chem. Soc. 2008, 130, 5858.
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Int. Ed. 2007, 46, 4364.
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Org. Lett., Vol. 12, No. 19, 2010

such as tetrafluoroanisole, 3,5-dichloropyridine, and N-butyl-
1,2,4-triazole. It appears that there is both lower and upper
limit of C-H bond acidity that is acceptable for alkylation.12
The scope with respect to alkyl halides is presented in
Table 2.13 Primary alkyl iodides and bromides are reactive
is more efficient, thus showing that it is the most likely
deprotonating agent (Scheme 2). At longer reaction times
Scheme 2. Deprotonation
Table 2. Alkylation Scope with Respect to Halidea
(t > 10 min), extensive decomposition of benzothiophene
was observed if TMP2Fe·2MgCl2·4LiCl base was employed.
It was also shown that the coupling reaction is rapid, and
64% conversion to 2-cyclohexylbenzothiophene is observed
in 10 min.14
Control experiments were run to determine if a trace of
another transition metal catalyzes the dimerization (Scheme
3).15 With reagent-grade or ultrapure FeCl3 nearly identical
Scheme 3. Control Experiments
results were obtained, showing that reactivity by contami-
nants is unlikely. If iron salt was omitted, no product was
obtained.
In conclusion, we have developed a method for iron-
catalyzed deprotonative alkylation of arene C-H bonds by
alkyl iodides and bromides. Both primary and secondary
alkyl halides can be coupled with furans, thiophenes, pyridine
derivatives, and some electron-withdrawing-group containing
arenes.
a 3-Methoxypyridine (1.4-1.8 equiv), halide (1 equiv), FeCl3 (10 mol
%), ligand (25 mol %), TMPMgCl·LiCl (1.5-2.0 equiv), THF, rt.
(entries 1 and 2). Some functionality, such as alkene (entry
3), ω-chloride (entry 4), and trifluoromethyl (entry 5), is
tolerated. If cyclopropylmethyl bromide is employed (entry
6), ring-opening product is obtained, signifying possible
radical intermediacy.7e Other secondary alkyl halides such
as cyclopentyl bromide (entry 7) also afford product in a
good yield.
The identity of metalating reagent was determined by
subjecting benzothiophene to deprotonation by either
TMPMgCl·LiCl or Knochels′ TMP2Fe·2MgCl2·4LiCl re-
agent6a followed by quench with D2O. The magnesium base
Acknowledgment. We thank the Welch Foundation (Grant
No. E-1571), NIGMS (Grant No. R01GM077635), A. P.
Sloan Foundation, Camille and Henry Dreyfus Foundation,
and Norman Hackerman Advanced Research Program for
supporting this research.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron
2007, 63, 1568. (b) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(13) A reviewer asked us to evaluate several other alkyl halides for the
alkylation. We have checked the reactivity of benzyl bromide with
3-methoxypyridine and obtained a 28% isolated yield of 2-benzyl-3-
methoxypyridine. Allyl bromide and tert-butyl 2-bromoisobutyrate did not
afford significant conversion to the desired alkylation products. It was also
suggested to check the reactivity of toluene derivatives. Attempted reaction
of mesitylene with cyclohexyl bromide afforded no alkylation product. See
the Supporting Information for details.
OL101684U
(14) See the Supporting Information for details.
(15) (a) Buchwald, S. L.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48,
5586. (b) Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.; Williams, V. A.;
Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70, 161.
Org. Lett., Vol. 12, No. 19, 2010
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