Efficient synthesis of highly functionalized cyclic aminimides

Article abstract of DOI:10.1021/ol051270v

(Chemical Equation Presented) Simple condensation reactions of various α,β-epoxy or α,β-aziridinyl methyl esters with 1,1-dialkyl hydrazines provided cyclic aminimides (1,1-dialkyl-3-oxopyrazolidines) with a heteroatom substituent at the 4-position in good yields. The reaction proceeds smoothly, without any coreagent, providing the product as an easily isolable precipitate. The reaction is expected to be a good candidate for combinatorial synthesis of a highly functionalized five-membered ring scaffold. The scope and limitations of this reaction were investigated by varying the substituents R¹-R⁵.

Full text of DOI:10.1021/ol051270v

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3359-3361
Efficient Synthesis of Highly
Functionalized Cyclic Aminimides
Bongjin Moon,* Sangbae Han, and Dohyung Kim
Department of Chemistry, Sogang UniVersity, Seoul 121-742, Korea
bjmoon@sogang.ac.kr
Received May 31, 2005
ABSTRACT
Simple condensation reactions of various
r,â-epoxy or r,â-aziridinyl methyl esters with 1,1-dialkyl hydrazines provided cyclic aminimides
(1,1-dialkyl-3-oxopyrazolidines) with a heteroatom substituent at the 4-position in good yields. The reaction proceeds smoothly, without any
coreagent, providing the product as an easily isolable precipitate. The reaction is expected to be a good candidate for combinatorial synthesis
of a highly functionalized five-membered ring scaffold. The scope and limitations of this reaction were investigated by varying the substituents
R1 R5.
−
As the combinatorial approach continues to gain prevalence
in drug discovery, the demand for efficient procedures for
generating a scaffold with high functionality is increasing.1
Among the various scaffold-generating strategies, multicom-
ponent reactions have drawn a lot of attention because they
quickly provide relatively complex and biologically interest-
ing core structures with high degrees of functionalization
under mild conditions.2 In this respect, the three-component
reaction of an ester, a 1,1-dialkyl hydrazine, and an epoxide
(Scheme 1)3 is undoubtedly an attractive one for molecular
mixing the substrates in a protic solvent or polar aprotic
solvent such as DMSO without any coreagent) and purifica-
tion procedure (simple filtration) make this reaction a
powerful tool for building combinatorial libraries. The
importance of variable substituents and simple conditions
for combinatorial synthesis has been demonstrated by Ruten-
ber and co-workers.4 They noticed that hydroxyaminimide
1 resembles the peptide hydrolysis transition state. Accord-
ingly, they constructed a peptide isostere library using this
three-component reaction (Scheme 1) in search of effective
HIV-1 protease inhibitors. Additionally, Ringe and co-worker
demonstrated that a peptidomimetic aminimide could be an
effective inhibitor of porcine pancreatic elastase (PPE) by
showing the X-ray structure of the PPE-inhibitor complex.5
To expand the utility of this powerful reaction, we envision-
ed integrating the ester and epoxide functionalities into one
molecule to provide a cyclic aminimide as shown in Scheme
2. Although linking two components into one molecule may
Scheme 1 Three-Component Reaction of an Ester, a
1,1-Dialkyl Hydrazine, and an Epoxide
library construction because the reaction has up to five
variable sites: R1 (ester), R2 and R3 (hydrazine), and R4 and
R5 (epoxide). Most of all, the simple reaction conditions (just
Scheme 2. Cyclic Aminimide Formation with an Epoxy Ester
and a 1,1-Dialkyl Hydrazine
(1) (a) Ivachtchenko, A. V.; Il’yin, A. P.; Kobak, V. V.; Zolotarev, D.
A.; Boksha, L. V.; Trifilenkov, A. S.; Ugoleva, D. M. J. Comb. Chem.
2002, 419. (b) Wunberg, T.; Kallus, C.; Opatz, T.; Henke, S.; Schmidt,
W.; Kunz, H. Angew. Chem., Int. Ed. 1998, 37, 2503.
(2) Weber, L. Curr. Med. Chem. 2002, 9, 2085.
(3) Slagel, R. C. J. Org. Chem. 1968, 33, 1374.
10.1021/ol051270v CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/22/2005

reduce the number of variable sites, this drawback is com-
pensated by the potential advantages of the newly generated
cyclic skeleton, which may be an interesting pharmacophore.
Table 1. Reactions of Epoxy Esters with Various 1,1-Dialkyl
Hydrazines
A review of the literature revealed the work of Sucrow
and co-workers (Scheme 3).6 In the late 1970s, the Sucrow
Scheme 3 Reaction of 3-Phenylglycidyl Methyl Ester (5) and
1,1-Dimethyl Hydrazine (6) Described in Ref 6
group reported that trans-1,1-dimethyl-4-hydroxy-5-phenyl-
pyrazolidin-3-one (7) was obtained in 42% yield from the
reaction of trans-3-phenylglycidic acid ethyl ester (5) and
1,1-dimethyl hydrazine (6) in methanol at room temperature.
The corresponding cis-glycidic ester afforded the cis-cyclic
aminimide under the same conditions. To the best of our
knowledge, these are the only examples of this type of
reaction in the literature.
In this article, we wish to report the scope and limitations
of this reaction for cyclic aminimide library synthesis by
screening the utility of combining various epoxy or aziridinyl
esters and 1,1-dialkyl hydrazines.
Initially, we prepared epoxy esters 8-11 following
literature procedures7 and reacted these esters with com-
mercially available 1,1-dialkyl hydrazines A-D (Figure 1).
Figure 1. 1,1-Dialkyl hydrazines used in this study.
a All reactions were carried out in iPrOH at room temperature. b Isolated
yields.
The structures and yields of the products are provided in
Table 1. All the reactions proceeded smoothly in a protic
solvent (iPrOH), and the products precipitated during the
reaction. In most cases, simple filtration of the reaction
mixture yielded the desired cyclic aminimides in high purity
(>95%) as judged by 1H NMR and elemental analyses (EA).
probably due to the higher solubility of the products in these
solvents compared to their solubility in i-PrOH.
The reaction of glycidic acid methyl ester 8 with dimethyl
hydrazine (A) yielded the corresponding cyclic aminimide
12 in high yield (95%). When ester 8 was reacted with cyclic
hydrazines such as B-D, the cyclic aminimides were
obtained in somewhat lower yields. This trend was valid for
other 2- or 3-substituted glycidic acid methyl esters such as
9-11. Although alkyl substitution at the ester 2-position
yielded the desired cyclic aminimides in reasonable yields
as shown in entries 5-8, alkyl substitution at 3-position did
not provide any product. Only â-aryl-substituted ester 11
yielded the condensed product as shown in entry 9.
When the reactions were carried out in more polar protic
solvents such as methanol or ethanol, the yields were lower,
(4) Rutenber, E. E.; McPhee, F.; Kaplan, A. P.; Gallion, S. L.; Hogan,
J. C., Jr.; Craik, C. S.; Stroud, R. M. Bioorg. Med. Chem. 1996, 4, 1545.
(5) Peisach, E.; Casebier, D.; Gallion, S. L.; Furth, P.; Petsko, G. A.;
Hogan, J. C., Jr.; Ringe, D. Science 1995, 269, 66.
(6) Sucrow, W.; Slopianka, M.; Vetter, H-.J. Chem. Ber. 1978, 111, 791.
(7) (a) Nemes, A.; Czibula, L.; Visky, G.; Farkas, M.; Kredl, J.
Heterocycles 1991, 32, 2329. (b) Glabe, A. R.; Sturgeon, K. L.; Ghizzoni,
S. B.; Musker, W.; Takahashi, J. N. J. Org. Chem. 1996, 61, 7212.
All of the resulting cyclic aminimides were water-soluble
white solids with high melting points (>200 °C).8 Each
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Org. Lett., Vol. 7, No. 15, 2005

showed a characteristic aminimide absorption at 1570∼1600
cm-1 in their IR spectra.3 Formation of the cyclic aminimide
skeleton was also confirmed by X-ray crystallographic
analysis of the spirocyclic aminimide 14 (Figure 2).9
Table 2. Reactions of Aziridinyl Esters with Various
1,1-Dialkyl Hydrazines
Figure 2. Single-crystal X-ray structure of compound 14.
To expand the scope of this reaction, we next investigated
the analogous reactions with aziridinyl methyl esters 21-
23 (Table 2). In contrast to the epoxy ester series, aziridinyl
esters exhibited more sluggish reactivity and required harsher
conditions. At room temperature, the reactions were rather
slow. As a result, the reactions were carried out in i-PrOH
under reflux conditions. When the substituent on the aziri-
dinyl nitrogen is an electron-withdrawing group such as
p-toluenesulfonyl (Ts) or methanesulfonyl group (Ms), the
reaction proceeds smoothly. In these cases, the desired
products could be isolated as a white precipitate in reasonably
high yields (74-83%). However, when the substituent is a
simple alkyl group such as a phenethyl group (entry 7 in
Table 2) or a benzyl group, no desired product is observed
even under reflux conditions. Several attempts to promote
the reactions using a protic acid (TsOH) or Lewis acids [Ti-
(OiPr)4, Ce(OTf)4, InCl3] failed to provide the desired results.
Similar to the reactions of epoxy esters, extra substitution at
the â-position of the aziridinyl esters also inhibited the
reaction.
i
a All reactions were carried out in PrOH at 80 °C. b Isolated yields.
washing. Although the reactions of â-substituted derivatives
were limited to aryl substitution, we expect that this reaction
might be useful in generating pharmaceutically interesting
scaffolds. We are currently investigating the bioactivity of
these compounds, and the results will be reported in due
course.
Acknowledgment. This work was supported by Grant
R14-2002-045-01002-0 from the Advanced Basic Research
Laboratory (ABRL) Program and Center for Bioactive
Molecular Hybrid (CBMH) of the Korea Science & Engi-
neering Foundation. We thank Mr. Sangwoo Park and
Professor M. K. Choi for X-ray crystallographic analysis of
compound 14 and Dr. Michael Haukaas for his editorial
contributions to the manuscript.
In summary, we have investigated the condensation
reactions of epoxy esters with various 1,1-dialkyl hydrazines.
Additionally, we have found that the scope of the reaction
can be extended to the use of aziridinyl methyl esters. These
reactions provide highly functionalized cyclic aminimides.
The reactions proceeded smoothly in iPrOH, yielding the
cyclic aminimides as precipitates in good yields. No purifica-
tion procedures were required other than filtration and
Supporting Information Available: Synthetic procedures
and characterization data for all new compounds (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(8) Melting points and IR spectral data of the individual compounds are
listed in Supporting Information.
(9) X-ray data for compound 14 are available in Supporting Information.
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