Facile ring-opening of azabicyclic [3.1.0]-and [4.1.0]aminocyclopropanes to afford 3-piperidinone and 3-azepinone

Article abstract of DOI:10.1021/ol103105q

Azabicyclic [3.1.0] and [4.1.0] Kulinkovich products underwent a facile reduction/fragmentation to afford a variety of 3-piperidinones and 3-azepinones, respectively, in the presence of catalytic palladium on carbon and formic acid in an atmosphere of hyd

Full text of DOI:10.1021/ol103105q

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1083–1085
Facile Ring-Opening of Azabicyclic [3.1.0]-
and [4.1.0]Aminocyclopropanes to Afford
3-Piperidinone and 3-Azepinone
ꢀ
Jisun Lee, Simon Berritt, Christopher K. Prier, and Madeleine M. Joullie*
Department of Chemistry, University of Pennsylvania, 231 South 34th Street,
Philadelphia, Pennsylvania 19104, United States
mjoullie@sas.upenn.edu
Received December 22, 2010
ABSTRACT
Azabicyclic [3.1.0] and [4.1.0] Kulinkovich products underwent a facile reduction/fragmentation to afford a variety of 3-piperidinones and
3-azepinones, respectively, in the presence of catalytic palladium on carbon and formic acid in an atmosphere of hydrogen.
The Kulinkovich reaction1 has been generally utilized to
access a number of biologically and structurally interesting
cyclopropanols and aminocyclopropanes from simple start-
ing materials.2,3 We recently reported the synthesis of a
range of azabicyclic [3.1.0]cyclopropylamines derived from
amino acids,3 and we now wish to report the ring-opening of
these systems to afford piperidinone and azepinone deriva-
tives. Piperidinones are often used as intermediates in
organic synthesis,4 and azepinone moieties are found in
pharmaceuticals and biologically important compounds.5
Azepinones also pose synthetic challenges due to their
nitrogen-containing seven-membered ring.6
Ring-opening of cyclopropanols is a relatively facile
process compared to ring-opening of tertiary aminocyclo-
propanes,7 which require high temperatures,8 photooxida-
tive, or aerobic oxidative conditions.9 To the best of our
knowledge, no ring-opening reactions of azabicyclic ami-
nocyclopropanes have been reported under the conditions
presented.
(1) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A. Synthesis
1991, 234.
(2) (a) Ollero, L.; Mentink, G.; Rutjes, F.; Speckamp, W. N.; Hiemstra,
H. Org. Lett. 1999, 1, 1331. (b) Kulinkovich, O. G.; de Meijere, A. Chem.
Rev. 2000, 100, 2789. (c) Quan, L. G.; Kim, S. H.; Lee, J. C.; Cha, J. K.
Angew. Chem., Int. Ed. 2002, 41, 2160. (d) Tebben, G. D.; Rauch, K.;
Stratmann, C.; Williams, C. M.; de Meijere, A. Org. Lett. 2003, 5, 483. (e) de
Meijere, A.; Kozhushkov, S. I.; Savchenko, A. I. J. Organomet. Chem. 2004,
689, 2033. (f) Gensini, M.; de Meijere, A. Chem.;Eur. J. 2004, 10, 785. (g)
Lack, O.; Martin, R. E. Tetrahedron Lett. 2005, 46, 8207. (h) Faler, C. A.;
We began our studies by testing traditional (i.e., SiO2
and FeCl3, pyridine, DMF) oxidative ring-opening of the
strained aminocyclopropanes, which resulted in decom-
position of starting material.10 Hence, a different approach
(6) Dubinina, G. G.; Yoshida, W. Y.; Chain, W. J. Tetrahedron Lett.
2010, 51, 5325.
(7) Most recent review on Kulinkovich reaction and its applications:
ꢀ
Joullie, M. M. Tetrahedron Lett. 2008, 49, 6512. (i) Madelaine, C.; Buzas,
A. K.; Lowalska-Six, J. A.; Six, Y.; Crousse, B. Tetrahedron Lett. 2009, 50,
5367.
Wolan, A.; Six, Y. Tetrahedron 2010, 66, 15.
ꢀ
(3) (a) Cao, B.; Xiao, D.; Joullie, M. M. Org. Lett. 1999, 1, 1799. (b)
ꢀ
Faler, C. A.; Cao, B.; Joullie, M. M. Heterocycles 2006, 67, 519.
(4) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
(8) Kuehne, M. E.; King, J. J. Org. Chem. 1973, 38, 304.
(9) (a) Lee, J. W.; U, J. S.; Blackstock, S. C.; Cha, J. K. J. Am. Chem.
Soc. 1997, 119, 10241. (b) Lee, H. B.; Sung, M. J.; Blackstock, S. C.; Cha,
J. K. J. Am. Chem. Soc. 2001, 123, 11322.
(10) Faler, C. A. Ph.D. Dissertation, University of Pennsylvania,
Philadelphia, PA, 2007.
Tetrahedron 2003, 59, 2953.
(5) Most recent article on cathepsin K inhibitors: Wang, H.; Matsuhashi,
H.; Doan, B. D.; Goodman, S. N.; Ouyang, X.; Clark, W. M., Jr. Tetra-
hedron 2009, 65, 6291.
r
10.1021/ol103105q
2011 American Chemical Society
Published on Web 01/27/2011

was considered on the basis of the work by Schulte-
11
The ring-opening presumably occurs via debenzylation
followed by protonation of the cyclopropane ring and sub-
sequent hydrolysis of the intermediate imine to the ketone.
Based on this fortuitous result, we synthesized a variety
of azabicyclic [3.1.0]- and [4.1.0]aminocyclopropanes
using a modified procedure to test the scope of the reaction
(Scheme 3).
€
Wulwer et al.
Scheme 1. CuCl Approach to Radical-Induced Cleavage of
Cyclopropylamines
Scheme 3. Synthesis of 3-Piperidinone and 3-Azepinone Deriv-
atives
Formation of the highly reactive N-chloroaminocyclo-
propane derivative followed by reaction with CuCl
could induce a nitrogen radical formation/cleavage event
(Scheme 1). When previously synthesized phenylalanine
aminocyclopropane3 was employed in the proposed meth-
odology, selective monodeprotection of the N-methylben-
zylamine and subsequent chlorination were unsuccessful.
Traditional palladium-catalyzed hydrogenolysis showed
poor selectivity over the two secondary amines, and the
subsequent chlorination product was highly unstable upon
isolation. We therefore opted to protect the cyclic amine as
its benzenesulfonamide to establish orthogonality within
the route (Scheme 2).
Scheme 2. Pd/C-Catalyzed Hydrogenolysis/Fragmentation
The syntheses of allylsulfonamides (n = 1) 8, 10, 12, and
14 generally proceeded in good yield, whereas the homo-
allylsulfonamides (n = 2) were less reactive under the same
reaction conditions because of the reduced nucleophilicity
of the sulfonamide nitrogen12 and afforded the product in
lower yields but with recovery of starting materials. Other
bases such as n-BuLi, LiHMDS, and NaH were screened,
which resulted solely in the recovery of starting material.
Reductive alkylation with allyltributylstannane only af-
forded starting material, even after prolonged reaction
times. Saponification of the methyl ester followed by BOP
mediated coupling of the acid and N-methylbenzylamine
gave 16-23 in satisfactory yields considering this difficult
coupling (a two-step EDCI mediated coupling and sub-
sequent N-methylation procedure could also be utilized to
givethe desiredproduct). Exposure of the allylsulfonamide
or homoallylsulfonamide to stoichiometric ClTi(O-i-Pr)3
afforded corresponding aminocyclopropanes in moderate
to good yields. For certain homoallylsulfonamide sub-
strates it was necessary to replace ClTi(O-i-Pr)3 with
MeTi(O-i-Pr)3 to obtain the desired product, for the for-
mer resulted in no reaction.13 The general decrease in yield
for the synthesis of azabicyclic [3.1.0] ring system com-
pared to that of [4.1.0] system is likely due to increase in
ring-strain of five-membered compared to six-membered
ring formations. Finally, exposure of the aminocyclopro-
panes to 10% Pd/C and catalytic amount of formic acid
Upon synthesis of bicyclic [3.1.0]aminocyclopropane
sulfonamide (1) using previously reported methods3 with
minor changes in amine protecting group, we turned our
attention to hydrogenolysis of the benzylamine in order to
proceed with N-chlorination. Palladium-on-carbon cata-
lyzed hydrogenolysis of benzylamines is generally known
to be slow compared to hydrogenolysis of benzyl ethers,
but in the presence of a protic acid, this process can be
expedited. Thus, treatment of 1 with 10% Pd/C in the
presence of formic acid under a hydrogen atmosphere
provided the debenzylated product, but to our surprise,
the ring-opening of the aminocyclopropane also occurred
predominantly to afford piperidinone derivative 3 in
synthetically useful yield (Scheme 2).
(12) Bowman, W. R.; Coghlan, D. R. Tetrahedron 1997, 53, 15787.
(13) Gensini, M.; Kozhushkov, S. I.; Yufit, D. S.; Howard, J. A. K.;
Es-Sayed, M.; de Meijere, A. Eur. J. Org. Chem. 2002, 2002, 2499.
€
(11) Schulte-Wulwer, I. A.; Helaja, J.; Gottlich, R. Synthesis 2003,
1886.
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Org. Lett., Vol. 13, No. 5, 2011

in recovery of starting material, proving the need for
palladium (entry 10, Table 1). When the cyclopropylamine
was subjected under a hydrogen atmosphere with catalytic
amount of palladium without the addition of formic acid,
only insignificant amount of debenzylated amine was
formed over prolonged reaction time (entry 9, Table 1).
Furthermore, the importance of catalytic addition of
formic acid was evident when the cyclopropylamine
was exposed under a hydrogen atmosphere with cata-
lytic amount of palladium in neat formic acid (entry 11,
Table 1).
Table 1. Scope of Ring-Opening Reactions of Azabicyclic [3.1.0]
and [4.1.0] Kulinkovich Products
The ring-opening methodology on various azabicyclic
[3.1.0] and [4.1.0] substrates proved to be generally accep-
table, whereas in some cases the formation of 3-piperidi-
none is more favorable than 3-azepinone (Table 1). This
observation may be due to the well-accepted fact that six-
membered ring formations are more favorable than seven-
membered ring formations. For instance, 3-azepinone
formations of structurally more complex tryptophan and
leucine derivatives (entries 6 and 8, Table 1) were relatively
unsuccessful in comparison to the respective formations of
3-piperidinone (entries 5 and 7, Table 1).
In conclusion, we have provided a novel method to open
bicyclic aminocyclopropanes in good yields under mild
reaction conditions to provide a range of 3-piperidinone
and 3-azepinone derivatives. The use of a sulfonamide as a
protecting group may also provide interesting antimicro-
bial activities when coupled with the conformationally
constrained Kulinkovich products, which we will investi-
gate in due course.
Acknowledgment. This paper is dedicated to Professor
Harry H. Wasserman (Yale University) on the occasion of
his birthday. Financial support for this research was
provided by the NSF (CHE-0951394). Financial support
for the departmental instrumentation was provided by the
National Institutes of Health (1S10RR23444-1). An Eli
Lilly Undergraduate Research Fellowship to C.K.P. is
acknowledged. We also thank Dr. George Furst and Dr.
Rakesh Kohli (University of Pennsylvania) for NMR and
MS assistance, respectively.
a Silica gel chromatography yields. b Benzyl ether moiety of tyrosine
transformed to afford the corresponding alcohol under the reaction condi-
tions. c Reaction time was extended to 48 h. d Recovered starting material.
(88% solution) afforded 3-piperidinone and 3-azepinone
derivatives in satisfactory yields (Table 1).
When the scope of this interesting ring-expansion meth-
odology was investigated, the presence of catalytic
amounts of both palladium and formic acid proved to be
essential for the reaction (Table 1). Forinstance, subjecting
the cyclopropylamine to a solution of formic acid resulted
Supporting Information Available. General methods,
experimental procedures, spectroscopic data, and HRMS
of compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 5, 2011
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