Predictably selective (sp3)C-O bond formation through copper catalyzed dehydrogenative coupling: Facile synthesis of dihydro-oxazinone derivatives

Article abstract of DOI:10.1021/ol500670h

An intramolecular dehydrogenative (sp³)C-O bond formation in salicylamides can be initiated by an active Cu/O₂ species to generate pharamaceutically relevant dihydro-oxazinones. Experimental findings suggest that stereoelectronic parameters in both coupling partners are controlling factors for site selectivity in bond formation. Mechanistic investigations including isotope labeling, kinetic studies helped to propose a catalytic cycle. The method provides a convenient synthesis of an investigational new medicine CX-614, which has potential in finding treatment for Parkinson's and Alzheimer's diseases.

Full text of DOI:10.1021/ol500670h

Letter
pubs.acs.org/OrgLett
Predictably Selective (sp3)C−O Bond Formation through Copper
Catalyzed Dehydrogenative Coupling: Facile Synthesis of Dihydro-
oxazinone Derivatives
Atanu Modak,† Uttam Dutta,† Rajesh Kancherla,† Soham Maity,† Mohitosh Bhadra,† Shaikh M. Mobin,‡
and Debabrata Maiti*,†
†Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
‡Discipline of Chemistry, School of Basic Sciences, Indian Institute of Technology Indore, Indore 452017, India
S
* Supporting Information
ABSTRACT: An intramolecular dehydrogenative (sp3)C−O
bond formation in salicylamides can be initiated by an active
Cu/O2 species to generate pharamaceutically relevant dihydro-
oxazinones. Experimental findings suggest that stereoelectronic
parameters in both coupling partners are controlling factors for
site selectivity in bond formation. Mechanistic investigations
including isotope labeling, kinetic studies helped to propose a
catalytic cycle. The method provides a convenient synthesis of an investigational new medicine CX-614, which has potential in
finding treatment for Parkinson’s and Alzheimer’s diseases.
Scheme 1. Synthetic Design
ver the past decade, substantial research interest has been
Ofocused on developing selective C−C bond formation
reactions through Cu-catalyzed cross-dehydrogenative cou-
pling.1 The basis of this waste-minimized approach, popularized
by the Chao-Jun Li group,2 lies in the oxidative C−H activation
of both of the coupling partners. In most of the cases, a tertiary
amine has been used as one of the partners where a C−H bond
next to the heteroatom has been activated.3 During the course of
these reactions, an iminium intermediate formed, which is sub-
sequently trapped by a carbon-centered nucleophile.4 Despite
the significant advances made in this greener side of the cross-
coupling chemistry, application of this strategy in intramolecular
C−heteroatom bond formation to synthesize pharmaceutically
important and synthetically challenging heterocycles is far less
studied.5
produced cyclic compound 2b (isolated, 80%; GC yield, 85%) by
employing active Cu/O2 species.
In this context, we planned to study cross-dehydrogenative sp3
C−O bond formation involving an amide and phenol under
an O2 atmosphere with a Cu-based small molecule catalyst
(Scheme 1). Formation of an iminiun ion from amide, which is
essential to implement such a strategy, is challenging due to
delocalization of the nitrogen lone pair to the carbonyl oxygen
(Scheme 1). To overcome this difficulty, we thought to develop a
highly reactive catalyst system, which will generate an iminiun
ion transiently, followed by an intramolecular phenolic moiety
intercepting this intermediate to generate medicinally relevant
heterocyclic scaffolds (Scheme 1). The power of this strategy is
described herein by generating an exemplary set of dihydro-
oxazinone compounds (38 examples), most of which represent
new chemical entities. The dihydro-oxazinone moiety is found in
a number of pharmaceutically relevant scaffolds such as CX-6146
and DRF-2519.7 Optimized conditions8 with the diethyl amide
of salicylic acid in the presence of 5 mol % of CuCl2 in m-xylene
The scope of the reaction was investigated by varying both
the amine and the acid part. A gram scale reaction gave a 75%
isolated yield (2b) of the cyclized product. Amides synthesized
from cyclic amines such as pyrrolidine (2d, 83%), piperidine
(2e, 77%), and azepane (2f, 71%) also underwent C−O bond
formation in preparatively useful yields. The relative ease of
product formation observed upon varying substituents at the 5-
position of the salicylic acid unit (e.g., 2a, 2i−2l, and 2n) suggests
that stereoelectronic parameters are strong contributing factors
in these C−O bond formation reactions. Specifically a strong
electron-withdrawing group, such as nitro, in a salicylic acid
moiety deactivates the nucleophile, thereby decreasing the
efficiency of the cyclization reaction considerably (2i and 2n).
Received: March 5, 2014
© XXXX American Chemical Society
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Letter
Scheme 2. Cyclization with Symmetric Amines
Scheme 3. Cyclization with Unsymmetric Amines (SM,
Starting Material)
a
b
c
10 mol % Cu. 20 mol % Cu. 10% 2a isolated as side product.
To examine the site selectivity aspect of this C−O coupling, a
number of unsymmetrical amides were tested (Scheme 3).
Despite having two possible N-methylene sites for cross-
dehydrogenative sp3 C−O bond formation in 3a-SM, we
observed cyclization only at the benzylic position in the presence
of an N-ethyl moiety (3a). Specifically, complete selectivity for
C−O bond formation was observed at the benzylic side of
tetrahydroisoquinoline while incorporated either in salicylamide
(3c) or in 2-hydroxy-1-naphthamide (3d). Consistent with this
observation, not even a trace of C−O bond formation at the N-
phenethyl arm was detected in the presence of a N-benzyl group
(3b). A lower product yield in the case of 3b (66%) can be
attributed to the formation of ketone product 3b′ (21%) via an
oxygen rebound step (vide infra) originating from the active Cu/
O2 species.
Cyclization occurred preferentially at the more electron-rich
(2°) C−H bonds (3e) compared to (1°) C−H bonds (3e′). But,
in the case of ethyl (2°) vs isopropyl (3°) (3f-SM) or methyl (1°)
vs isopropyl (3g-SM), the steric factor dominated over the elec-
tronic factor. The Cu catalyst even recognized subtle electronic
differences in N-picolylamine versus N-benzylamine. Therefore,
salicylamides generated from either 2-picolyl or 4-picolyl amine
yielded the C−O coupled product exclusively at the pyridine
end (3h, 94%, X-ray;9 3i, 92%) in the presence of the N-benzyl
moiety. Consistent with this observation, cyclization in 3j-SM
and 3k-SM preferentially occurred at the heterocyclic end.
Encouraged by these results, we probed the electronic de-
pendence of the method by incorporating either an electron-
donating or -withdrawing group in the amine part (Scheme 4). A
noticeable electronic bias was evident, as preferential cyclization
occurred on the electron-rich side.8,9 Consistent with this,
regioselectivity followed the order of electron donating ability on
phenyl substitution (OMe > H > Cl > CN > NO2) of the
dibenzylamine part (4a−4d).
a
b
c
Yield based on recovered starting materials. 20 mol % Cu. Total
yield of two isomers.
Subsequently we tested the salicylamide of N-methyl aniline,
which was found to be unreactive (5a) under the standard
reaction conditions (Scheme 5). Even the corresponding
N-phenyl benzyl salicylamide failed to provide the desired cyclic
product (5b, 3%). This lack of reactivity of N-phenyl amides may
be attributed to the additional delocalization of the nitrogen lone
pair into the phenyl ring, which in turn failed to stabilize the
B
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Letter
Scheme 4. Electronic Dependence
Scheme 6. O-18 Labeling Experiment
Scheme 7. Kinetic Isotope Effect Study
Scheme 5. Reactivity Depends on C−H Bond Strength
Scheme 8. Proposed Mechanism
incipient iminium intermediate. To validate this hypothesis, an
allylic moiety was incorporated (5c) into one end of the amine, as
allylic C−H bonds are comparably weaker than the rest. In this
case, C−O bond formation occurred in 33% yield without an
allylic C−H shift in the cyclized product (X-ray).9
To elucidate mechanistic details, a crossover experiment was
performed. A mixture of two amides, generated from piperidine
and pyrrolidine, did not produce even a trace amount of the
crossover compounds in either the starting materials or product.8
Control experiments carried out under N2 failed to produce the
cyclized product.8 Formation of 2b decreased from 85% to 20%
upon addition of TEMPO.8 Furthermore, the detection of the
homocoupling product from 2,4-di-tert-butyl phenol indicates
that a radical is likely.8
Replacement of the hydroxyl moiety with a methyl group
resulted in formation of the keto product 6a, (Scheme 6; also
see 3c-SM, Scheme 3). A labeling study with 18O2 further con-
firmed the Cu/O2 species as being the active intermediate since
∼98% O-18 incorporation was observed in the product 8a.
As anticipated, a similar experiment with 3a-SM and Cu/18O2
resulted in >99% O-18 labeling in 3a′-18O (Scheme 6). Please
note that the O-18 labeling experiment was carried out upon
evacuating the reaction flask and subsequent injection of 18O2 by
syringe. Under these conditions (compared to the reaction under
air), cyclized product 3a formation decreased to 26% and the
keto product 3a′ increased to 56%. A first-order rate dependence
(rate order = 1.33)8 on N,N′-diethylsalicylamide (2b-SM) was
established which is consistent with an intramolecular reaction.
Further insights came by setting up an intramolecular substrate
competition, −N(CH2Ph) versus −N(CD2Ph) cross-dehydro-
genative sp3 C−O cyclization in 2a-SM-D2 (Scheme 7). It
has been observed that the C−H bond is more facile for
cyclization over the C−D bond with a resultant product ratio of
4.2 (Scheme 7).4d
B.4d,10 Subsequently, Cu(II)-superoxo species C is formed via
Cu(I)/O2 interaction.11,12 This reactive intermediate C can
abstract an H atom from the oxidized amide residue to form
Cu(II)-hydroperoxo complex D along with generation of an
iminium ion intermediate.11 Subsequently, nucleophilic attack of
the phenolate oxygen at the iminium carbon center provided the
desired cyclic product. A resultant Cu(II)-hydroperoxo complex
is thought to undergo an anion exchange with the substrate, and
thereby, the catalyst center can be regenerated.
A minor amount of keto-product, as observed in 3a′ and 3b′,
may be caused by the adventitious water present in the solvent or
by the Cu(II)-hydroperoxo species. No O-18 incorporation into
the ketone product (e.g., 3a′, Scheme 6) was observed upon
addition of H218O either in trace amount or in excess. Therefore,
water may be ruled out as the source of ketonic oxygen. Further,
the 18O2 labeling studies suggested involvement of a Cu/O2
reactive intermediate for the ketone product as well as the cross-
dehydrogenative sp3 C−O bond formation.
Based on these findings and from literature precedence,1b,2b,4c,d
a probable mechanism has been depicted in Scheme 8. A
substrate-bound Cu(II) center A is likely to be responsible for
the single electron oxidation of the amide-nitrogen to form
Investigational new medicine CX-614, developed by Cortex
Pharmaceuticals, and its derivatives have attracted extensive
C
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attention because of their activity on AMPA receptor and their
ability to increase the synthesis of the brain-derived neurotrophic
factor.6 We have designed a four-step synthesis (Scheme 9);
which resulted in a 44% (overall) yield of CX-614.8,9
In conclusion we have synthesized medicinally relevant
dihydro-oxazinone derivatives through a Cu-based small mole-
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Scheme 9. Synthesis of CX-614
cule catalyst that uses O2 to promote a direct and operationally
simple cross-dehydrogenative coupling. The site of sp3 C−O
bond formation can be predicted based on electronic differences
between the amide N-substituents. This scalable method uses
an inexpensive catalyst and is applicable to a broad range of
substrates.13 Mechanistic studies including O-18 labeling, kinetic
experiments, and deuterium labeling suggested that a Cu/O2
based active species is responsible for the chemistry described
herein. Such a method has potential to enable cross-dehydrogen-
ative sp3 C−O bond formation as a tool to synthesize complex
heterocyclic compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
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Marrs, C.; Rachwal, S.; Ulas, J.; Nielsson, L.; Rogers, G. Bioorg. Med.
Chem. Lett. 2011, 21, 3923. (b) Mueller, R.; Rachwal, S.; Tedder, M. E.;
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Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dmaiti@chem.iitb.ac.in.
Notes
The authors declare the following competing financial
interest(s): A provisional patent on this work has been filed.
(7) Madhavan, G. R.; Chakrabarti, R.; Reddy, K. A.; Rajesh, B. M.;
Balraju, V.; Rao, P. B.; Rajagopalan, R.; Iqbal, J. Bioorg. Med. Chem. 2006,
14, 584.
ACKNOWLEDGMENTS
■
(8) See Supporting Information for detailed description.
This activity is supported by DST-India. Financial support
received from CSIR-India (fellowships to A.M. and S.M.) and
DST Fast Track Scheme (R.K.) is gratefully acknowledged.
(9) CCDC-976164 (entry 3h), CCDC-978672 (entry 4cA), CCDC-
976163 (entry 4dB), CCDC-976165 (entry 5c) and CCDC-978671
(CX-614) contain the supplementary crystallographic data for this
paper,8 and data can be obtained via http://www.ccdc.cam.ac.uk/data_
request/cif.
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D
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