Formal olefination and acylaziridination of imidazolones

Article abstract of DOI:10.1021/ol1007923

(Figure presented) The first formal olefination and acylaziridination of imidazolones were obtained by cycloaddition of cyclic nitrones with alkenes and alkynes, respectively.

Full text of DOI:10.1021/ol1007923

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2718-2721
Formal Olefination and Acylaziridination
of Imidazolones†
Xing Dai,* Michael W. Miller, and Andrew W. Stamford
Merck Research Laboratories, 2015 Galloping Hill Road,
Kenilworth, New Jersey 07033
xing.dai@merck.com
Received April 6, 2010
ABSTRACT
The first formal olefination and acylaziridination of imidazolones were obtained by cycloaddition of cyclic nitrones with alkenes and alkynes,
respectively.
The imidazolone and imidazolidinone skeletons are key
structural motifs that appear in the core structures of natural
products and drug candidates. For example, alkaloids Kot-
tamides A-C (1), isolated from the endemic ascidian
PycnoclaVella kottae, have exhibited anti-inflammatory and
antimetabolic activity as well as cytotoxicity toward tumor
cell lines (Figure 1).1 For recent pharmaceutical candidates,
the spiro-condensed imidazolone (2) is an example of a
glycine transporter inhibitor, a potential therapeutic agent
for Schizophrenia,2 while the 2,3,5-substituted imidazolidin-
4-one (3) is a ꢀ-secretase (BACE-1) inhibitor, which has
potential for treating Alzheimer’s disease.3 Despite the
importance of these molecules, very few methods have been
developed to functionalize these heterocycles,4 especially for
1H-imidazol-5(2H)-ones. In this paper, we describe the
preparation of two novel imidazolone derivatives 5 and 6
† This paper is dedicated to Professor Huw M. L. Davies on the occasion
of his 54th birthday.
Figure 1. Biologically active compounds.
(1) Appleton, D. R.; Page, M. J.; Lambert, G.; Berridge, M. V.; Copp,
B. R. J. Org. Chem. 2002, 67, 5402.
(2) (a) Blunt, R.; Cooper, D. G.; Porter, R. A.; Wyman, P. A. WO
2009034061, 2009. (b) Ahmad, N. M.; Lai, J. Y. Q.; Andreotti, D.; Marshall,
H. R.; Nash, D. J.; Porter, R. A. WO 2008092876, 2008. (c) Coulton, S.;
Porter, R. A. WO 2008092872, 2008.
that are made from the cycloaddition of heterocyclic nitrone
4 with alkenes and alkynes, respectively (Figure 2).
The 1,3-dipolar cycloaddition reaction of nitrones has
attracted considerable attention as one of the most important
methodologies for the construction of N-containing hetero-
cycles.5 For instance, the [3+2] cycloaddition of nitrones
with alkenes is a classic reaction for the synthesis of
(3) Barrow, J. C.; Rittle, K. E.; Ngo, P. L.; Selnick, H. G.; Graham,
S. L.; Pitzenberger, S. M.; McGaughey, G. B.; Colussi, D.; Lai, M.-T.;
Huang, Q.; Tugusheva, K.; Espeseth, A. S.; Simon, A. J.; Munshi, S. K.;
Vacca Jo, P. ChemMedChem 2007, 2, 995.
(4) Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T. HelV.
Chim. Acta 1987, 70, 237.
10.1021/ol1007923  2010 American Chemical Society
Published on Web 05/19/2010

Scheme 1. Formation of 11
Figure 2. Novel products from imidazolone nitrones.
isoxazolidines 7, which have been utilized to access
ꢀ-amino alcohols, and both pyrrolizidine and indolizidine
alkaloids (Figure 3). On the other hand, isoxazolines 8
that are cycloaddition products from nitrones and alkynes
tend to undergo rearrangement due to their thermal
instability.6
To the best of our knowledge, this is the first example of
a formal olefination reaction via a [3+2] cycloaddition of a
nitrone with an alkene. More interestingly, only the (E)-
isomer of the olefin product was formed. This result
prompted us to optimize the reaction conditions and study
its scope. As shown in Scheme 1, there are actually three
stages from the starting nitrone 9 to the final product (11).
However, a one-pot and practical procedure would be ideal.
Toward this goal, we determined that a mixture of nitrone 4
(1 equiv) and olefins 15 (5 equiv) in ethanol at 80 °C
provided the desired [3+2] adducts. The reaction mixture
was cooled to room temperature and then successively treated
with 1 N aqueous sodium hydroxide (2 equiv) and 1 N
aqueous hydrochloric acid (3 equiv) at 0 °C to generate the
desired products 5 (Table 1).10
Under the optimal reaction conditions, a range of terminal
olefins were screened (Table 1). The reaction of 4 with styrene
(15a) afforded the olefinated imidazolone 5a in 90% yield
(Table 1, entry 1). For styrene derivatives, a variety of
synthetically common functional groups, including electron-
withdrawing and electron-donating groups, such as ether (15b),
ester (15c), and halogen (15d,f) are tolerated (Table 1, entries
2-7). Ethyl acrylate (15h) showed comparable reactivity to
styrene (Table 1, entry 8). Reactions of aliphatic olefins (15i,j)
also produced the desired product, although the rate of [3+2]
cycloaddition is much slower than that observed for styrenes
(Table 1, entries 9 and 10). Interestingly, the reaction of ethyl
vinyl ether (15k) with nitrone 4 generated predominantly
imidazolidinone 5k under conditions without acidic workup.
Presumably, the ethoxy moiety, a good leaving group, played
a major role in the formation of this different product.11
Figure 3. Classic [3+2] cycloaddition of nitrones.
We have been interested in the synthesis of imidazolone
derivatives that could impact our current project targeting
type-II diabetes. One of our model studies was to test a 1,3-
dipolar reaction on spiro-imidazolone 9 (Scheme 1).7 When
the [3+2] adduct 108 was treated with base, trans-olefinated
product 11 was isolated after acidic workup in 80% yield,
along with a minor side product 14 (<5%).9 Presumably, the
proton adjacent to the carbonyl group is removed by the base
to form the anion 12, in which the N-O bond is subsequently
cleaved to afford the alcohol 13. Dehydration of 13 under
acidic conditions would generate the product 11.
(5) For reviews on nitrones and their cycloaddition reactions, see: (a)
Jones, R. C. F.; Martin, J. N. In Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products, The
Chemistry of Heterocyclic Compounds; Padwa, A., Pearson, W. H., Eds.;
Wiley: New York, 2002; Vol. 59, pp 1-81; (b) Feuer, H. Nitrile Oxides,
Nitrones, and Nitronates in Organic Synthesis, 2nd ed.; John Wiley & Sons,
Inc.: Hoboken, NJ, 2008. (c) Stanley, L. M.; Sibi, M. P. Chem. ReV. 2008,
108, 2887. (d) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863.
(e) Cardona, F.; Goti, A. Angew. Chem. 2005, 117, 8042. Cardona, F.; Goti,
A. Angew. Chem., Int. Ed. 2005, 44, 7832. (f) Nair, V.; Suja, T. D.
Tetrahedron 2007, 63, 12247. (g) Pellissier, H. Tetrahedron 2007, 63, 3235–
3285. (h) Bonin, M.; Chauveau, A.; Micouin, L. Synlett 2006, 15, 2349. (i)
Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem.sEur.
J. 2009, 15, 7808.
(6) For a review, see: (a) Freeman, J. P Chem. ReV. 1983, 83, 241. Also
see recent examples: (b) Heaney, F.; Fenlon, J.; O’Mahony, C.; McArdle,
P.; Cunningham, D. J. Chem. Soc., Perkin Trans. 1 2001, 3382. (c) Friebolin,
W.; Eberbach, W. Tetraheron 2001, 57, 4349.
(9) Possible mechanism to form 14
(7) See recent example of 1,3-dipolar cycloaddition of imidazolone
nitrones: (a) Cheng, S.; Wu, H.; Hu, X. Synth. Commun. 2007, 37, 297. (b)
Aouadi, K.; Jeanneau, E.; Msaddek, M.; Praly, J.-P. Tetrahedron: Asymmetry
2008, 19, 1145. (c) Aouadi, K.; Jeanneau, E.; Msaddek, M.; Praly, J.-P.
Synthesis 2007, 21, 3399. (d) Aouadi, K.; Vidal, S.; Msaddek, M.; Praly,
J.-P. Synlett 2006, 19, 3299. (e) Pernet-Poil-Chevrier, A.; Cantagrel, F.; Le
Jeune, K.; Philouze, C.; Chavant, P. Y. Tetrahedron: Asymmetry 2006, 17,
1969. (f) Cantagrel, F.; Pinet, S.; Gimbert, Y.; Chavant, P. Y. Eur. J. Org.
Chem. 2005, 70, 2694. (g) Pernet-Poil-Chevrier, A.; Cantagrel, F.; Jeune,
K. L.; Philouze, C.; Chavant, P. Y. Tetrahedron: Asymmetry 2006, 17,
1969. (h) Westermann, B.; Walter, A.; Florke, U.; Altenbach, H.-J. Org.
Lett. 2001, 3, 1375. (i) Baldwin, S. W.; Long, A. Org. Lett. 2004, 6, 1653.
(8) The sterochemistry of 10 was confirmed by NOESY. Also see
ref 7a.
(10) Other solvents (such as toluene, 1,2-dichloroethane, acetonitrile,
etc.), bases (such as NaH, KOtBu, etc.), and acids (CF3COOH, CH3COOH,
etc.) also work in these reactions. However, these combinations have not
been optimized.
(11) Possible mechanism to 5K:
Org. Lett., Vol. 12, No. 12, 2010
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Table 1. One-Pot Formal Olefination of Imidazolonea
Table 2. Formal Acylaziridination of Imidazolonea
a Reactions were performed with 5 equiv of alkyne in ethanol at 80 °C
for 18 h. b The reaction was performed with 5 equiv of alkyne and heated
for 2 days.
a Reactions were performed with 5 equiv of alkene in ethanol at 80 °C
for 18 h. b The reaction was performed with 10 equiv of alkene and heated
for 3 days. c The reaction was run without acidic workup.
4 was performed. The reaction afforded the single diastero-
meric cis-fused-acylaziridine 6a12 in 92% yield (Table 2,
entry 1). The first step of this process involves a concerted
cycloaddition to give the corresponding intermediate 17,
which likely immediately rearranges to the acyl-substituted
aziridine 6a (Scheme 2).
It is known that the [3+2] addition reactions of acetylenes
with nitrones usually generate rearranged products instead
of the normal product isoxazolines 8, which are often
thermally labile (Figure 3). The key intermediate in these
reactions is an acylaziridine.2a Having discovered this novel
formal olefination reaction of imidazolone, we wondered
what would form from the reaction of nitrone 4 with alkynes.
Thus, the cycloaddition of phenyl acetylene 16a with nitrone
(12) For other isolated acylaziridines, please see ref 6a and the references
cited therein.
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Org. Lett., Vol. 12, No. 12, 2010

As mentioned above, acylaziridines formed from isoxazo-
lines are usually not stable and rearrange to other products.
An obvious concern is the stability of this newly discovered
cis-fused-acylaridine core. Thus, 6a was treated with 20 equiv
of NaOH in methanol for 14 days, and it was found that 6a
was recovered in 99% yield without any rearrangement or
decomposition (eq 1). In contrast, under acidic conditions,
the aziridine was labile and generated the R-chloro ketone
19 as a single isomer in quantitative yield (eq 2). This result
indicates that the nucleophilic ring-opening reaction is highly
stereospecific and efficient. Subsequently, under basic condi-
tions, a conjugated product 20 was generated from 19 by a
simple elimination.
Scheme 2. Cycloaddition of Phenyl Acetylene with Nitrone 4
The significance of aziridines in organic synthesis has been
well recognized.13 This newly discovered fused-acylaziridine
core is unique and thus has the potential to be a very
interesting and useful structural element. To study the
reaction scope, the cycloadditions of 4 with various terminal
alkynes were performed and the results are summarized in
Table 2. Ortho- (16b, 16c, 16d), para- (16e), and meta-
substituted (16f) phenyl acetylenes are all tolerated (Table
2, entries 2-6).14 It should be pointed out that the o-bromo-
substituted product 6d could be easily derivatized to indazole
or benzoisoxazole under known conditions.15 Addition of
heteroaromatic acetylene (16g) afforded a moderate yield of
product (Table 2, entry 7). Primary (16h), secondary (16i),
and cyclic aliphatic acetylenes (16j,k) also could be ef-
ficiently added to nitrone 4 under these conditions to generate
the expected products in moderate to good yields (Table 2,
entries 8-11). Finally, 1-triethylsilyl acetylene (16l) pro-
duced the expected acylsilane 6l (Table 2, entries 12), which
is a very useful synthon in many reactions such as the silyl
benzoin reaction16 and sila-Stetter reaction17 by taking
advantage of the Brook rearrangement.
In summary, we report the first formal olefination of an
imidazolone via [3+2] cycloaddition of terminal alkenes with
an imidazolone N-oxide. This transformation provides trans-
olefinated imidazolones that would be difficult to prepare
by other methods. Through the [3+2] cycloaddition of
terminal alkynes with imidazalone N-oxide, we have also
developed the first formal acylaziridination of imidazolones.
Acknowledgment. We would like to thank Dr. William
Greenlee for strong support of this program, Mr. Ibrahim
Daaro for mass spectrometry assistance, Drs. Tze-Ming
Chan, Mary Senior, and Alexei Buevich for NMR studies,
Drs. Guoqing Li and Duane DeMong for helpful discussion,
and Dr. Robert Aslanian for insightful suggestions. We also
thank Drs. Jaemoon Yang and Jared Cumming for proof-
reading.
(13) For reviews on reactions of aziridines, see: (a) Mitunobu, O. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 6, Chapter 1.3. (b) Padwa, A. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 4, Chapter 4.9. (c) Thompson, D. J. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 3, Chapter 4.1. (d) Hudlicky, T.; Reed,
J. W. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 5, Chapter 8.1. (e) Tanner, D. Angew.
Chem., Int. Ed. Engl. 1994, 33, 599.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) After silica gel chromatograpgy, there is a minor side product (18)
isolated (<5%) for entry 2. The Z-isomer has been comfirmed by COSY
and J-resolved HMBC data. This type of side product has been found from
other substrates as well.
OL1007923
(16) (e) Xin, L.; Bausch, C. C.; Johnson, J. S. J. Am. Chem. Soc. 2005,
127, 1833, and references cited therein.
(15) Inamoto, K.; Katsuno, M.; Yoshino, T.; Arai, Y.; Hiroya, K.;
Sakamoto, T. Tetrahedron 2007, 63, 2695.
(17) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem.
Soc. 2004, 126, 2314.
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