Convergent Synthesis of Diverse Nitrogen Heterocycles via Rh(III)-Catalyzed C-H Conjugate Addition/Cyclization Reactions

Article abstract of DOI:10.1021/acs.orglett.6b01611

The development of Rh(III)-catalyzed C-H conjugate addition/cyclization reactions that provide access to synthetically useful fused bi- and tricyclic nitrogen heterocycles is reported. A broad scope of C-H functionalization substrates and electrophilic olefin coupling partners is effective, and depending on the nature of the directing group, cyclic imide, amide, or heteroaromatic products are obtained. An efficient synthesis of a pyrrolophenanthridine alkaloid natural product, oxoassoanine, highlights the utility of this method.

Full text of DOI:10.1021/acs.orglett.6b01611

Letter
pubs.acs.org/OrgLett
Convergent Synthesis of Diverse Nitrogen Heterocycles via Rh(III)-
Catalyzed C−H Conjugate Addition/Cyclization Reactions
Adam B. Weinstein and Jonathan A. Ellman*
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, United States
S
* Supporting Information
ABSTRACT: The development of Rh(III)-catalyzed C−H
conjugate addition/cyclization reactions that provide access to
synthetically useful fused bi- and tricyclic nitrogen heterocycles
is reported. A broad scope of C−H functionalization substrates
and electrophilic olefin coupling partners is effective, and
depending on the nature of the directing group, cyclic imide,
amide, or heteroaromatic products are obtained. An efficient
synthesis of a pyrrolophenanthridine alkaloid natural product,
oxoassoanine, highlights the utility of this method.
Our interest in the synthetic utility of catalytic C−H
conjugate addition reactions prompted us to explore new
electrophilic olefin coupling partners.5w Here, we show that
addition to unsymmetrical 1,4-dicarbonyl derivatives leads to
useful heterocyclic structures through an addition and
cyclization cascade (Scheme 1b).8 This transformation
requires that high regioselectivity be achieved for olefin
addition based upon the electronic bias provided by the two
carbonyl substituents. We further show that this cyclative
cascade process can be applied to structurally diverse directing
groups to provide different types of pharmaceutically relevant
heterocycles. The utility of this method is showcased in a
synthesis of the pyrrolophenanthridine alkaloid oxoassoanine.
We began our studies by evaluating the reaction between
N-methyl benzamide (1a) and ethyl-3-benzoyl acrylate (2a)
under conditions for catalytic Cp*Rh(III) mediated C−H
functionalization (Table 1). The cationic Cp*Rh(III) catalyst
generated from [Cp*RhCl2]2 and AgSbF6 in 1,2-dichloro-
ethane (DCE) effected regioselective C−H addition of the
benzamide substrate into the olefin at room temperature
(entry 1). Addition product 3a, resulting from C−C bond
formation α to the ester and β to the more electron-
withdrawing acetophenone, was generated in moderate yield
and with complete regioselectivity. Increasing the temperature
of the reaction to 40 °C improved the yield of 3a (entry 2),
and further increasing the temperature resulted in cascade
cyclization to imide product 4a in good yield (entries 3−4).
Notably, related Cp*Co(III) and Cp*Ir(III) catalyst pre-
cursors were not effective for this transformation under these
conditions (entries 5−6).
yclopentadienyl-ligated Rh(III) complexes are proven
Ccatalysts for C−H functionalization reactions that enable
rapid generation of molecular complexity from simple starting
materials.1 In particular, these catalysts have been employed in
a range of reactions that couple sp2 C−H bonds with olefin
partners. Categories include Heck-type couplings,2 hydro-
arylations,3 allylic substitutions,4 and cascade difunctionaliza-
tions.5 The regioselectivity of olefin functionalization in these
transformations is sensitive to electronic, steric, and directing
effects,6,7 and in the case of insertion into α,β-unsaturated
carbonyl derivatives, the C−C bond typically forms distal to
the carbonyl group with high fidelity (i.e., conjugate additions,
Scheme 1a).
Scheme 1. Rhodium(III)-Catalyzed C−H Conjugate
Addition Cascade Reactions
Having identified viable catalytic conditions for selective
C−H addition/cyclization of N-methyl benzamide and ethyl-
3-benzoyl acrylate, we evaluated the scope of the reaction
Received: June 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01611
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
corresponding dihydroisoquinolinone products (4f, 4g, 4h)
in good yields. α-Methylbenzylamine and α-phenyl-
benzylamine were also evaluated as substrates but provided
the desired cyclic products in <20% yield (data not shown).
We next evaluated the scope of the reaction with respect to
the identity of the polarizing electron-withdrawing group β to
the ester substituent on the olefin coupling partner (Scheme
3). In addition to the parent phenyl ketone (4b), furyl and
Table 1. Reaction Discovery and Evaluation of Conditions
Scheme 3. Evaluation of Electrophilic Olefin Substrate
a
Scope
a
a
entry
[Cp*MCl2]2
temp (°C)
% 3a
% 4a
1
2
3
4
5
6
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*CoCl2]2
[Cp*IrCl2]2
23
40
60
90
90
90
40
61
40
0
0
2
16
75
0
0
2
9
a
Yields determined by 1H NMR spectroscopic analysis with
phenyltrimethylsilane added as an internal standard.
a
Scheme 2. Evaluation of Directing Group Substrate Scope
a
b
Isolated yields are reported. Reaction performed at 60 °C.
aliphatic ketones were well tolerated for regioselective
insertion α to the ester (4i, 4j, 4k). Acyl oxazolidinone also
proved effective in dictating efficient C−H addition (4l, 4m).9
A key aspect of the catalytic reactions described here is the
ability to install synthetically useful heterocyclic 1,4-dicarbonyl
functionality in a convergent manner. We showcase the utility
of this feature with a facile synthesis of oxoassoanine, a
member of the lycorine alkaloid family of natural products.10
Studies by Padwa11 and Boger12 demonstrated the reactivity
of 2-amidofurans in Diels−Alder reactions and the application
of these transformations in the synthesis of lycorine
alkaloids.13 Inspired by these works, we envisioned our
conjugate addition/cyclization process could provide rapid
access to amidofuran 5, which could be converted to the
desired pyrrolophenanthridinone alkaloid framework by an
intramolecular Diels−Alder reaction (Scheme 4). Amidofuran
5 could be obtained by Paal−Knorr cyclization of imide 6,
which in turn could be generated from C−H addition/
cyclization of N-homoallyl benzamide 7 with α,β-unsaturated
ketoester 8.
Our initial attempt to employ N-homoallyl benzamide
substrate 7 in the C−H functionalization reaction gave a low
yield of the desired conjugate addition product. Analysis of
the reaction mixture revealed side reactivity derived from
allylic C−H activation of the homoallyl group.14 Lowering of
the temperature and addition of AgOAc to the catalyst system
enabled conjugate addition product 9 to be obtained in
moderate yield, though cyclization to imide 6 did not occur
under these conditions (Scheme 5). Fortunately, treatment of
intermediate 9 with trifluoroacetic acid gave clean conversion
a
b
c
Isolated yields are reported. Reaction performed at 60 °C. 1.5 equiv
d
of 2-phenylpyridine was employed. The diastereomeric ratio was
determined by H NMR spectroscopic analysis of the crude reaction
mixture, and the diastereomers were separated on isolation and the
relative configurations were assigned by NOESY-1D spectroscopic
analysis.
1
with respect to the identity of the directing group (Scheme
2). Full analysis of the reaction of N-methyl benzamide
substrate 1a revealed minor side products arising from
difunctionalization of the arene. Installation of a blocking
methyl group at the meta position thus improved the overall
efficiency of the C−H addition/cyclization reaction (4b).
Modification to an N-methoxy benzamide substrate provided
a highly efficient reaction irrespective of the presence of a
meta blocking group (4c, 4d), probably due to rapid
cyclization of the more acidic N-methoxy amide prior to a
second C−H activation. The pyridyl directing group also
participated in the C−H addition/cyclization cascade process,
yielding fluorescent product 4e following aromatization.8a
Additionally, α,α-disubstituted benzylamines led to the
B
DOI: 10.1021/acs.orglett.6b01611
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Scheme 4. Retrosynthetic Analysis of Oxoassoanine
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01611.
Full experimental details and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jonathan.ellman@yale.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Scheme 5. Synthesis of Oxoassoanine
■
This work was supported by the National Institutes of Health
(F32-GM112454 to A.B.W. and R01-GM069559 to J.A.E.).
The authors thank Haya Jamali (Yale University) for
assistance with the acquisition of high-resolution mass
spectrometric data.
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