Modular strategy for the synthesis of functionalized aryl-fused azabicyclo[2.2.2]octanes via radical-mediated cascade cyclization

Article abstract of DOI:10.1016/j.tetlet.2014.05.001

A two-step synthesis of rare 2-azabicyclo[2.2.2]octanes is described. N-propargyl amides obtained via Cu(I)-catalyzed three-component coupling, underwent radical-mediated cascade cyclization to afford 5,6-aryl-fused 2-azabicyclo[2.2.2]octanes with arylidene functionality on the two-carbon bridge in 43-62% yields. Phenylidene and 1-naphtylidene derivatives were obtained exclusively as Z diastereomers, whereas electron rich groups in the arylidene substituent afforded product mixtures favoring the Z diastereomer by 2.3:1 M ratio.

Full text of DOI:10.1016/j.tetlet.2014.05.001

Accepted Manuscript
Modular Strategy for the Synthesis of Functionalized Aryl-Fused Azabicy-
clo[2.2.2]octanes via Radical-Mediated Cascade Cyclization
Helena C. Malinakova, Sandeep N. Raikar, Lucas F. McCormick
PII:
S0040-4039(14)00777-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.001
TETL 44591
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 April 2014
30 April 2014
2 May 2014
Please cite this article as: Malinakova, H.C., Raikar, S.N., McCormick, L.F., Modular Strategy for the Synthesis of
Functionalized Aryl-Fused Azabicyclo[2.2.2]octanes via Radical-Mediated Cascade Cyclization, Tetrahedron
Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.001
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Modular Strategy for the Synthesis of Functionalized Aryl-Fused
Azabicyclo[2.2.2]octanes via Radical-Mediated Cascade Cyclization
Helena C. Malinakova,* Sandeep N. Raikar† and Lucas F. McCormick‡
Department of Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence,
Kansas 66045, United States
Center of Excellence in Chemical Methodologies and Library Development, The University
of Kansas, 2034 Becker Drive, Lawrence, Kansas, 66047, United States
ABSTRACT
A two-step synthesis of rare 2-azabicyclo[2.2.2]octanes is described. N-propargyl amides
obtained via Cu(I)-catalyzed three-component coupling, underwent radical-mediated cascade
cyclization to afford 5,6-aryl-fused 2-azabicyclo[2.2.2]octanes with arylidene functionality
on the two-carbon bridge in 43-62% yields. Phenylidene and 1-naphtylidene derivatives were
obtained exclusively as Z diastereomers, whereas electron rich groups in the arylidene
substituent afforded product mixtures favoring the Z diastereomer by 2.3 : 1 molar ratio.
* Corresponding author e-mail: hmalina@ku.edu; phone: 1-785-864-4743; FAX; 785-864-
5396
† Present address: Emory University, Atlanta, GA 30322, USA
‡ Present address: Bethany College, Lindsborg, KS 67456, USA

The 2-azabicyclo[2.2.2]octane represents the structural core of variety of synthetic
and naturally occurring compounds that possess significant biological activities, including
iboga and iboga-bisindole alkalods1 and alkalois like grandisine B2 or dioscorine3 (Figure 1).
Among the synthetic approaches developed for the construction of the 2-
azabicyclo[2.2.2]octane cores,4,5 Diels-Alder reactions of dihydropyridines are the most
prominent.6-8
Figure 1. 2-Azabicyclo[2.2.2]octane core in biologically active natural products
To date, synthetic methodologies available for the preparation of 5,6-aryl-fused
derivatives of 2-azabicyclo[2.2.2]octanes remain limited to Diels-Ader reactions of benzyne
dienophiles.9-11 Consequently, only a few such heterocycles have been isolated or

synthesized and made available for studies of their biological activities.12-16 Recently,
radical-mediated cyclization methodology17 has been applied to tetrahydropyridines to afford
aryl-fused 2-azabicyclo[2.2.2]octanes.18 A particular synthetic challenge is to design a
procedure that would easily incorporate functional groups or diverse substituents into the
two-carbon bridge of the 2-azabicyclooctanes.
Recently, we reported Pd-catalyzed intramolecular Heck cyclization of allyl amides I
that afforded in one step 5,6-aryl-fused 2-azabicyclo[2.2.2]octanes II.19 The 2-
azabicyclooctanes II were diversified by functionalization of the two-carbon bridge via two
subsequent steps, including cross-metathesis and nucleophilic substitution reactions (Figure
1).19 We have envisioned that an alternative variant of this methodology would employ
functionalized building blocks to construct an acyclic substrate primed for the construction of
the bridged bicyclic skeleton in one step, thus introducing substituents into the two-carbon
bridge in a more direct fashion. A brief screening of different types of propargyl amides and
cyclization conditions revealed that a radical-initiated cyclization20 of N-allyl-N-benzoyl
propargyl amides III afforded the desired 5,6-aryl-fused 2-azabicyclo[2.2.2]octanes IV
functionalized by an arylidene group in the two-carbon bridge in one step in moderate to
good yields.
Herein, the initial development of this new methodology is described. Our results are
notable by the complementary structural features of 5,6-aryl-fused 2-
azabicyclo[2.2.2]octanes IV delivered by the presented three-component coupling/radical
cyclization protocols to 2-azabicyclooctanes prepared in our prior studies.19 The availability
of both these protocols provides an access to more diverse libraries of functionalized 5,6-
aryl-fused 2-azabicyclo[2.2.2]octanes maximizing the likelihood of positive outcomes from

future biological screening efforts (Figure 2). Specifically heterocycles IV feature the amide
carbonyl transposed outside of the bridged bicyclic structure, and the two-carbon bridge
possesses an exocyclic double bond with opposite stereochemistry carrying an aryl, instead
of an alkyl substitution.
Figure 2. Comparison of complementary synthetic strategies
The acyclic propargyl amide precursors I used in our prior work were prepared by
Cu(I)-catalyzed three-component coupling using tributylvinylstannane.19 For the present
study, we have opted to employ a modified three-component coupling protocol21 and to
replace the single vinyl stannane component with a variety of environmentally friendly
terminal alkynes. Attempts to apply the Pd-catalyzed annulation conditions to the cyclization
of N-benzyl-N-methacryloyl propargyl amide 1 failed to afford the desired 2-
azabicyclo[2.2.2]octane structure. In contrast, successful annulation process was realized
when N-allyl-N-benzoyl propargyl amide 2a was subjected to radical-initiated cascade
cyclization20 that delivered 2-azabicyclo[2.2.2]octane heterocycle 3a as a single product in
47% unoptimized yield (Scheme 1). The relative stereochemistry was unequivocally

established by X-ray crystallographic analysis21 indicating the Z-configuration of the
exocyclic olefin (Figure 3).
Scheme 1
Figure 3. Molecular structure of 3a determined by X-ray crystallographic analysis

The diastereoselectivity of the initial 6-exo-trig cyclization step is critical for the
success of this synthetic protocol. The conformations of the initial aryl radical that possess
sterically demanding N-benzoyl and phenylethyne groups in a close proximity are not likely
to be represented to a significant extent. In contrast, conformations A and B with
phenylethyne group in a pseudoaxial position rather than pseudoequatorial positions will be
present in equilibrium under the reaction conditions (Figure 4). Only the 6-exo-trig
cyclization of the conformation A delivers the methylene radical C that is capable of
undergoing a subsequent 6-exo-dig cyclization yielding a vinylic radical poised to afford the
heterocycles IV after the hydrogen transfer from n-Bu3SnH (Figure 4). The selectivity
observed in our experimental studies can be ascribed to a faster rate of cyclization of the aryl
radical in conformation A than in conformation B. Alternatively, the selectivity can be
rationalized by the excess of the conformation A present in equilibrium with conformation B,
a situation that would become important if the rate of cyclization is significantly slower than
the interconversion of the conformations A and B under the reaction conditions.

Figure 4. Rationale for the observed diastereoselectivity
To evaluate the scope of the new synthetic protocol and to explore the possibilities for
optimization of the reaction conditions, a series of N-allyl-N-benzoyl propargyl amides 2a-e
was prepared by a Cu(I)-catalyzed three-component coupling protocol.19,21 In this initial
phase of method development, the structural variations remained limited to substitution of
the aryl ring of the terminal alkynes and a comparison between the performance of N-allyl
derivatives of benzaldehyde (2a, 2c-e) and 3,4-dioxymethylene-benzaldehyde (2b). Synthesis
of propargyl amides 2a and 2c was previously reported in the context of a distinct
methodology developed in our laboratories.23 N-allyl imines (1.0 equiv.), benzoyl chloride
(1.2 equiv.) and terminal alkynes (1.5 equiv.) were stirred in acetonitrile (0.34 M) at room
temperature before a solution of CuCl (20 mol%) in acetonitriile (0.67 M) and neat DIPEA

(1.5 equiv.) were added simultaneously dropwise. The amides 2a-e were isolated after
column chromatography on silica in good yields (69-81%) (Scheme 2).
Scheme 2
In an effort to optimize the yield of the radical-mediated cyclization of amide 2a, the
overall concentration, equivalents of AIBN and n-Bu3SnH employed as well as reaction
times and temperature were varied. Ultimately, an improvement in the yield of 2-
azabicyclooctane 3a from 47% yield (Scheme 1) to 55% yield (Table 1) has been achieved
by increasing the amounts of n-Bu3SnH from 1.5 equiv. to 2.0 equiv, AIBN from 0.1 equiv.
o
to 0.5 equiv. and by extending the reaction time at 100 C from 1 h to 3 h at an overall
concentration of 16 mM. However, a more significant increase in the reaction yields could
not be achieved by additional variations in the reagent system chosen. The optimized
conditions have been applied towards the cyclization of propargyl amides 2a-e to afford the
corresponding 2-azabicyclooctanes 3a-e (Table 1).

Table 1. Radical cyclization of propargyl amides to 2-azabicyclo[2.2.2]octanes

aIsolated yield of a single diastereomer, or a combined isolated yield of the mixture of
Z and E isomers. bMolar ratio of Z : E isomers determined by 1H NMR.
The treatment of propargyl amides 2a, 2b and 2e possessing phenyl and naphthyl-
substituted alkyne functionality afforded the anticipated 2-azabicyclooctanes 3a (55%), 3b
(62%) and 3e (56%) as single stereoisomers in moderate, but synthetically useful yields (55-
62%). No other cyclized products could be isolated from the crude reaction mixtures,
although notably less polar organic compounds coeluted from the chromatographic column
along with the excesss of n-Bu3SnH and could not be isolated and characterized. The Z
stereochemistry of the double bond in the products 3a, 3b and 3c was assigned based on the
results of the X-ray crystallographic analysis of the heterocycle 3a, and further confirmed by
1H NOE experiment performed on the sample of heterocycle 3b (Figure 5). Thus, selective
1
irradiation of the vinylic proton at 6.29 ppm in H NMR spectra of 3b resulted in the
enhancement of the signal for the methylene protons at 2.46 ppm and 2.78 ppm. The
comparison of the yields of azabicyclooctanes 3a and 3b appear to suggest that an increase in
the electron density in the aromatic ring of the N-allyl imines stabilizes the initially generated
aryl radical and may be contributing to the somewhat increased yields of heterocycle 3b
1
(compare entries 1 and 2, Table 1). Inspection of the H NMR spectra of azabicyclooctanes
featuring electron donating substituents in the aromatic ring of the terminal alkynes revealed
that the corresponding azabicyclooctanes were obtained as approximately 2 : 1 mixtures (by
1H NMR) of Z and E stereoisomers 3c/3c’ and 3d/3d’ in 63% and 43% combined yields,
respectively (entries 3 and 4, Table 1). 1H NOE experiment performed on the sample of the 2

: 1 mixture of azabicyclooctanes 3d/3d’ revealed that the minor stereoisomer possessed the E
configuration (Figure 5). Thus, irradiation of the methine proton at 5.11 ppm assinged to the
minor stereoisomer resulted in the enhancement of the vinylic proton at 6.12 ppm, also
assigned to the minor isomer. Although the preference for the formation of the Z isomer has
been retained, the electron donating substituents (methoxy or dimethyl amine) could increase
the life-time of the vinyl radical and therefore the likelihood of the inversion of its
configuration24 prior to the termination with n-Bu3SnH.
Figure 5. Assignment of E/Z configuration of olefins 3b and 3d’ by 1H NMR
In conclusion, initial development of a modular methodology for a two-step
construction of rare 5,6-aryl-2-azabicyclo[2.2.2]octanes substituted with arylidene
functionality on the two-carbon bridge has been described. The protocol expands the scope of
radical-mediated cascade reactions to the synthesis of bridged N-heterocycles. The resulting
heterocycles posses structures complementary to compounds that can be access by our
recently disclosed19 three-component coupling/Heck cyclization protocol. The availability of
this methodology magnifies the potential that screening of assemblies of 5,6-aryl-2-
azabicyclo[2.2.2]octanes constructed by both these protocols uncovers compounds with
significant biological activities.
Suplementary Data

Detailed descriptions of the preparative protocols for amides 2a-e and azabicyclooctanes 3a-
1
e, as well as copies of H NMR and 13C NMR spectra for compounds 2b, 2d-e, 3a-e and
results of the NOE experiments on compounds 3b and 3d’ are provided.
Acknowledgments
Support from the NIH via the KU Center for Methodology and Library Development (P 50
GM063966) is acknowledged. We thank our University of Kansas colleagures Dr. Justin
Douglas for his assistance with NMR spectroscopy and Dr. Victor D. Day for X-ray
crystallographic analysis.
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