Synthesis of Functionalized Pyridines via a Regioselective Oxazoline Promoted C-H Amidation Reaction

Article abstract of DOI:10.1021/acs.orglett.6b01612

The first Rh-catalyzed C-H amidation of pyridines is reported. The incorporation of a substituent at the C2 position both is crucial to the success of this transformation and provides considerable scope for further elaboration of the resulting products. Among these compounds, 2-chloropyridines allow access to a selection of intermediates including a versatile azaquinazoline scaffold.

Full text of DOI:10.1021/acs.orglett.6b01612

Letter
pubs.acs.org/OrgLett
Synthesis of Functionalized Pyridines via a Regioselective Oxazoline
Promoted C−H Amidation Reaction
Tracy M. M. Maiden,† Stephen Swanson,‡ Panayiotis A. Procopiou,‡ and Joseph P. A. Harrity*,†
†Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, U.K.
‡GlaxoSmithKline, Stevenage, Hertfordshire, SG1 2NY, U.K.
S
* Supporting Information
ABSTRACT: The first Rh-catalyzed C−H amidation of
pyridines is reported. The incorporation of a substituent at the
C2 position both is crucial to the success of this transformation
and provides considerable scope for further elaboration of the
resulting products. Among these compounds, 2-chloropyridines
allow access to a selection of intermediates including a versatile
azaquinazoline scaffold.
In spite of the successes in sp2 C−H activation, compatibility
nthranilic acid derivatives are an important class of
with heterocycles remains a significant challenge. While
Asubstrate, particularly for the synthesis of nitrogen-
impressive advances have been achieved with heterocycles
based on indoles,3d pyrroles,6 furans,7 and thiophenes,8
examples of pyridine functionalization are somewhat rare in
comparison. The propensity of pyridine itself to function as a
directing group in C−H activation chemistry is the likely cause
of the relatively slow progress made in the functionalization of
this highly important scaffold. Nonetheless, key contributions
by Yu and Daugulis have allowed significant advances in this
respect with elegant stoichiometric and catalytic copper
mediated C−H amidations having been achieved upon pyridine
scaffolds by utilizing bidentate directing groups such as the 8-
aminoquinoline or oxazoline tethered secondary amides
(Scheme 1B).9 Based on our observations that oxazolines can
function as effective promoters of benzene based C−H
amidation, we decided to explore their compatibility in the
functionalization of pyridines and report herein the successful
realization of this strategy.
containing heterocycles such as quinazolines, indoles, and
quinolines.1 Despite the broad synthetic utility of anthranilic
acids, access to highly functionalized examples of these 1,2-
disubstituted aromatic systems remains a significant challenge.
Many strategies rely upon multistep and often linear sequences
to circumvent the low reactivity of azines toward functionaliza-
tion via electrophilic aromatic substitution. In this regard, C−H
activation has emerged as an effective alternative, offering
simpler and more effective approaches to functionalized analogs
of this important scaffold.2 Contributions by Yu, Ackermann,
Glorius, and others have allowed for significant advancement in
this area (Scheme 1A).3 Our group has reported a mild Rh-
catalyzed oxazoline directed amidation that provides access to
highly functionalized quinazolines.4 Moreover, Ackermann
recently demonstrated the applicability of cobalt catalysis to
this particular method.5
Our initial studies began by exploring the reactivity of
substrates 1a−c where the directing group was positioned
around the parent pyridine ring. As shown in Scheme 2, these
substrates were inert to Rh-catalyzed amidation and increasing
both reaction temperature and time failed to result in any of the
desired amidopyridine products.10 Based on the hypothesis that
the lack of reactivity arises from catalyst deactivation by the
Lewis basic pyridine, we considered how this process could be
circumvented. In this regard, we were intrigued by a report
from Cossy which demonstrated that incorporation of a 2-Cl
group on a pyridine could result in efficient Ru-catalyzed cross-
metathesis, while the parent pyridine was unreactive in this
process.11 This approach seemed well suited to our C−H
amidation conditions, not only to attenuate the Lewis basicity
of the heterocycle, but by also offering the opportunity for
Scheme 1. C−H Amidation of (Hetero)aromatic
Compounds
Received: June 3, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b01612
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Letter
trifluoromethyl- and sulfone-substituted analogs 7 and 8, which
afforded the products in good yield with excellent regiocontrol.
Notably, the regioselectivity of C−H amidation in these cases
complimented that of the Cu-promoted systems developed by
Yu and Daugulis.9a,c However, switching the 6-substituent to an
electron-donating group had a marked effect on reaction
efficiency. 2-Methoxy-substituted pyridine afforded 9 in a low
yield while the 2-dimethylamino compound only provided a
trace amount of compound 10. Similarly, when alkyl and aryl
examples were examined only trace or low reactivity was
observed. Overall, although the efficiency of amination strategy
was found to be modest in some cases, especially as compared
to the analogous reaction of arenes,4 it represents an effective
alternative to traditional methods of pyridine functionalization
processes.
Scheme 2. Oxazoline Directed C−H Amidation of Pyridines
further derivatization. To probe our hypothesis, we prepared
substrate 1d and were delighted to find that amidation
proceeded in a promising yield of 61% under mild conditions.
Moreover, the reaction demonstrated respectable regioselectiv-
ity, with 2a being the major isomer observed (Scheme 2).
Pleased by the effectiveness of a 3-oxazoline to direct the C−
H amidation of 6-chloropyridine, we decided to explore the
scope of this process on a range of substrates, subjecting them
to the reaction conditions. Notably, we chose to confine our
studies to trifluoroacetamide, as the corresponding amidation
products can be readily hydrolyzed. As depicted in Scheme 3,
Having thoroughly explored the scope of 3-oxazoline
substituted pyridines, we turned our attention to the scope of
4-oxazoline substituted pyridines and our results are
summarized in Scheme 4. Interestingly, we found that 2-F
Scheme 4. 4-Oxazoline Directed C−H Amidation of
a
Pyridines
Scheme 3. 3-Oxazoline Directed C−H Amidation of
Pyridines
a
Regioisomers separable by column chromatography.
and 2-Cl pyridines underwent dichotomous regiochemical
insertion processes to afford isomeric major products 15 and
16. The trifluoromethyl substituted pyridine afforded 17 in
excellent yield and selectivity. Surprisingly, however, both 2-
methyl- and 2-aryl-substituted pyridines were also well tolerated
in this case, producing 18 and 19 in good yield. These results
are notable in light of the observations described earlier
(Scheme 3, compounds 11−14) and highlight that the position
of the directing group can have a profound effect on substrate
reactivity.
a
b
Reaction performed on 4.56 mmol scale. Reaction performed using
c
[RhCp*Cl2]2 (1 mol %) and AgSbF6 (4 mol %) for 24 h. Reaction
performed at 80 °C. Regioisomers separable by column chromatog-
d
We turned our attention to the 6-oxazoline substituted
pyridines in order to complete the scope of our studies.
Disappointingly, however, subjection of 2-halo-6-oxazoline-
substituted pyridines to the standard reaction conditions failed
to deliver the corresponding products, regardless of the
reaction temperature/time (Scheme 5). We suspect the lack
of reactivity arises from the ability of these substrates to act as
strong ligands, thereby deactivating the Rh-catalyst.12
raphy.
we observed a variety of functionalities were compatible with
these C−H amidation conditions. Both 2- and 6-halopyridines
underwent smooth amidation affording the desired products
2a−6 in good to excellent yields. Moreover, 3-oxazoline-6-
halopyridines underwent regioselective and consistent C−H
amidation at the 2-position. Additionally, we were able to lower
the Rh-catalyst loading to 1 mol % to deliver 2 with only a
modest drop in yield. We could extend this chemistry to
Having confirmed the importance of the 2-substituent for
catalyst reactivity, we wanted to highlight the potential of these
groups as valuable functional handles (Scheme 6). Hydrolysis
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The mild and efficient reaction conditions allow for the
introduction of a readily deprotectable amino source on a range
of pyridine scaffolds. Furthermore, the synthetic value of 2-halo
substituted pyridines is demonstrated by their successful late
stage derivatization into a variety of highly functionalized
scaffolds.
Scheme 5. 2-Oxazoline Substituted Pyridines
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 6. Post C−H Amidation Functionalization
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01612.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: j.harrity@sheffield.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge GlaxoSmithKline and the EPSRC
for financial support.
■
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■
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