Iron-Catalyzed arylation of heterocycles via directed c-h bond activation

Article abstract of DOI:10.1021/ol403634b

The iron-catalyzed arylation of aromatic heterocycles, such as pyridines, thiophenes, and furans, has been achieved. The use of an imine directing group allowed for the ortho functionalization of these heterocycles with complete conversion in 15 min at 0

Full text of DOI:10.1021/ol403634b

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed Arylation of Heterocycles via Directed C−H Bond
Activation
John J. Sirois, Riley Davis, and Brenton DeBoef*
Department of Chemistry, University of Rhode Island, 51 Lower College Road, Kingston, Rhode Island 02881, United States
S
* Supporting Information
ABSTRACT: The iron-catalyzed arylation of aromatic hetero-
cycles, such as pyridines, thiophenes, and furans, has been
achieved. The use of an imine directing group allowed for the
ortho functionalization of these heterocycles with complete
conversion in 15 min at 0 °C. Yields up to 88% were observed
in the synthesis of 15 heterocyclic biaryls.
Scheme 1. Comparison of C−H Arylation Methods
here is an increasing need in both the fine chemical and
pharmaceutical industries for the development of new
T
methods that easily provide substituted heterocycles. One of
the methods that have been extensively explored for this
function is the direct conversion of carbon−hydrogen (C−H)
bonds into carbon−carbon (C−C) bonds.1 This process is
considered a “green” synthetic pathway because it eliminates
the prefunctionalization steps required in modern coupling
reactions and, therefore, directly reduces time, expenses, and
hazardous waste. In fact, the ACS Green Chemistry Roundtable
described C−H functionalizations of heterocycles as the most
desirable new reactions that could benefit the pharmaceutical
industry.2,3
For decades, precious metals, namely palladium, have been
the primary catalysts used for both traditional coupling and C−
H arylation reactions.4 Iron catalysts, which are readily
available, cheap, and nontoxic, have been relatively unexplored
for coupling reactions. However, new methods are emerging
that suggest an important role for this transition metal in
modern organic synthesis.5 Notably, Nakamura has recently
developed an iron-catalyzed C−H arylation reaction.6 Compar-
ison of the metallic catalyst used in two similar methods for the
direct C−H arylation of 2-phenylpyridine shows that the iron-
catalyzed reaction proceeds at lower temperatures and is higher
yielding and the catalyst is 22 times cheaper (Scheme 1).4b,6b,7
Though the utility of iron-catalyzed C−H arylation reactions is
apparent, the scope of these potentially transformative reactions
has yet to be expanded to include the arylation of highly desired
heterocycles, and the mechanism is still not fully understood.
Herein, we describe the ability to perform directed C−H
arylations of heterocyclic substrates using cheap and nontoxic
iron catalysts.
reaction’s yield, possibly as a consequence of reduction of the
imine; on a few occasions, the corresponding amine was
isolated as a minor product.
Careful control of reaction conditions allowed for complete
conversion in 15 min. Notable difficulty arose with regards to
the drop rate of the Grignard reagent and the stir rate of the
reaction.6b It appears that the size of the reaction vessel can also
dramatically alter yield. Dropwise Grignard addition into small,
narrow vials provided almost no reaction, with exclusive
homocoupling of the Grignard reagent resulting in biphenyl
formation. This is likely caused by a combination of small
surface area for substrate reactivity and inadequate stir rates.
Larger flasks (e.g., 35−50 mL round-bottom flasks for a 0.55
mmol reaction), providing more surface area, and high stir rates
proved to be the best choice (see Supporting Information for
details.)
The reactions were very clean; the only compounds that
could be observed by GCMS were the starting materials, the
biaryl product and biphenyl, arising from homocoupling of the
Grignard reagent. To minimize the aerobic iron-catalyzed
homocoupling, an inert atmosphere and excess Grignard
reagent were required.8 Additionally, we employed additives
Our initial studies commenced with the pyridine substrate
shown in Table 1. Nakamaura’s conditions that were previously
shown in Scheme 1 were not optimal, producing only a 67%
yield (entry 3). Also in contrast to Nakamura’s work, the
monoarylated product was exclusively obtained; the diarylated
product was never observed for any of the reactions presented
herein. Extended reaction times led to deterioration of the
Received: December 16, 2013
© XXXX American Chemical Society
A
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Table 1. Optimization of Pyridine Arylation
a
b
entry
catalyst (loading)
ligand (loading)
additive
% conversion
1
Fe(acac)3 (20 mol %)
Fe(acac)3 (10 mol %)
Fe(acac)3 (10 mol %)
Fe(acac)3 (5 mol %)
Fe(acac)3 (10 mol %)
Fe(acac)3 (10 mol %)
Fe(acac)3 (10 mol %)
Fe(acac)3 (10 mol %)
FeF3·3H2O (10 mol %)
FeCl3 (10 mol %)
dtbpy (20 mol %)
dtbpy (20 mol %)
dtbpy (10 mol %)
dtbpy (20 mol %)
bpy (20 mol %)
DMPU
DMPU
DMPU
DMPU
DMPU
DMPU
KF
73
90
2
3
67
4
58
5
15
6
bphen (20 mol %)
dtbpy (20 mol %)
dtbpy (20 mol %)
dtbpy (20 mol %)
dtbpy (20 mol %)
37
7
100
100
18
8
none
9
KF
10
11
KF
76
Fe(acac)2 (10 mol %)
dtbpy (20 mol %)
KF
7
a
b
dtbpy = 4,4′-di-tert-butyl-2,2′-dipyridyl, bpy = 2,2′-bipyridine, bathophenanthroline. All reactions were performed on a 0.55 mmol substrate scale.
Conversion was calculated by subtracting Astarting material/Aproduct from 100%, where Astarting material and Aproduct were calculated using the areas of the
corresponding peaks in the gas chromatogram.
such as DMPU9 or KF10 which have been previously shown to
minimize Grignard homocoupling.
Table 2. Directing Group Optimization
The best conversion was achieved with a catalyst/ligand ratio
of 1:2 (Table 1, entry 2). As shown by Nakamura, 4,4′-di-tert-
butyl bipyridine (dtbpy) appeared to be the optimal ligand
(entries 2, 5, and 6). Interestingly, the use of FeF3·3H2O
showed 18% product formation, with no biphenyl present
(entry 9); but the optimal catalyst was Fe(acac)3 (entries 7 and
8), so this was used for subsequent experiments. We ultimately
chose to perform the reactions in the presence of the KF
additive (entry 7) due to a slight suppression of the biphenyl
byproduct. Interestingly, an iron(II) catalyst was ineffective
(entry 11). Future research efforts in our laboratory will be
directed toward identifying the catalytic intermediates in this
reaction, including the oxidation state of the iron in this
process. Further screening of solvents and oxidants showed that
our original choices, chlorobenzene and 1,2-dichloro-2-methyl-
propane, were optimal. When our optimized conditions were
applied to the nonheterocyclic substrate derived from
acetophenone, diarylated products were observed, as previously
shown by Nakamura (not shown).6
A screen of directing groups was performed (Table 2). Use
of the para-methoxyphenyl (PMP) directing group showed
promising conversion (entry 3), but complete conversion was
achieved using aniline derivatives (entry 1). Comparison of the
imines derived from heterocyclic aldehydes and ketones
(entries 1 and 4) showed drastic steric requirements for
reaction conversion. Oxime ethers and alkyl imines completely
inhibited the reaction (entries 2 and 5), possibly by strong
coordination to the iron catalyst.
Our optimized reaction conditions were then applied to a
variety of heterocyclic substrates (Table 3). In most cases, the
imine group could be easily hydrolyzed to the ketone.11 Several
nitrogen-containing heterocyclic biaryls could only be isolated
as imines (entries 1 and 3) because the hydrolysis of these
compounds proved more difficult than expected, presumably
due to protonation of the heterocycle’s basic nitrogen. For
reactions that did not reach complete conversion, the isolated
yields were reduced considerably due to difficult chromato-
graphic separations.
a
All reactions were performed on a 0.55 mmol substrate scale.
Conversion was calculated by subtracting Astarting material/Aproduct from
100%, where Astarting material and Aproduct were calculated using the areas
of the corresponding peaks in the gas chromatogram. Isolated yields
obtained after flash chromatography. Trace starting material detected
b
c
1
by H NMR but not by GC.
B
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Table 3. Substrate Scope
Table 4. Grignard Reagent Scope
a
All reactions performed on a 0.55 mmol scale. Conversion was
calculated by subtracting Astarting material/Aproduct from 100%, where
Astarting material and Aproduct were calculated using the areas of the
b
corresponding peaks in the gas chromatogram. Yields obtained after
hydrolysis of imine and purification by flash chromatography.
nonreactive, indicating a decrease in reactivity with increasing
steric hindrance.
Analysis of the oxygen-containing heterocycles shows that
conversions and yields increased with steric constraints (entries
6−8). Azole substrates appear to be more robust (entries 1−4).
Notably, chlorinated pyridines can be readily substituted,
allowing for subsequent functionalization (entry 3). A quinoline
substrate was nonreactive (entry 5); however, this could be
attributed to the aldehyde-derived directing group described in
Table 2, entry 3.
As the thiophene substrate provided the highest yields, it was
used to generate a brief Grignard scope (Table 4). Halogen-
substituted aromatic Grignard reagents reduced the conversion
and decreased the overall yield (entries 2 and 3). Electron-
donating groups also appeared to slightly decrease the yield
(entries 1 and 4). Methyl and cyclohexyl Grignard reagents
afforded no reaction. The elucidation of the seemingly
contradictory electronic and steric trends for this reaction will
be the subject of future studies.
a
All reactions performed on a 0.55 mmol scale. Conversion was
calculated by subtracting Astarting material/Aproduct from 100%, where
Astarting material and Aproduct were calculated using the areas of the
corresponding peaks in the gas chromatogram. Yields obtained after
hydrolysis of imine and purification by flash chromatography, unless
otherwise noted. Isolated as imine with trace starting material
b
c
d
1
detected by H NMR. Based on recovered starting material.
In summary, we have shown that iron-catalyzed arylation via
C−H bond activation can be successfully carried out on a
variety of N-, S-, and O-containing heterocycles at 0 °C, over 15
min. Future work will involve insight into the reaction
mechanism to provide further understanding and reaction
control.
The yields of the arylations were sterically dependent, and
opposing trends were observed for pyridines, thiophenes, and
furans. Comparison of sulfur-containing compounds shows that
benzothiophene was less reactive than thiophene (entries 10
and 9), and 3-methyl thiophene (entry 11) was completely
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures as well as characterization of
previously unknown compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bdeboef@chm.uri.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CAREER 0847222), and the National Institutes of Health
(NIGMS, 1R15GM097708-01). B.D.B. is the recipient of a
Pfizer Green Chemistry Award.
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