A cascade approach to cyclic aminonitrones: reaction discovery, mechanism and scope

Article abstract of DOI:10.1021/ol9010147

Treatment of ω-epoxynitriles with hydroxylamine affords cyclic aminonitrones in a single step and with high stereoselectivity. The scope of this novel transformation was explored in a series of examples. The aminonitrone products were shown to be useful s

Full text of DOI:10.1021/ol9010147

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3194-3197
A Cascade Approach to Cyclic
Aminonitrones: Reaction Discovery,
Mechanism, and Scope
Rojita Sharma,† Paul G. Bulger,*,† Michael McNevin,‡ Peter G. Dormer,†
Richard G. Ball,‡ Eric Streckfuss,§ James F. Cuff,† Jingjun Yin,† and
Cheng-yi Chen†
Departments of Process Research, Pharmaceutical Research and DeVelopment, and Medicinal
Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065
paul_bulger@merck.com
Received May 10, 2009
ABSTRACT
Treatment of ω-epoxynitriles with hydroxylamine affords cyclic aminonitrones in a single step and with high stereoselectivity. The scope of
this novel transformation was explored in a series of examples. The aminonitrone products were shown to be useful substrates for further
selective elaboration.
Raltegravir (1, Figure 1) is the first HIV antiretroviral drug
to be approved by the FDA that targets and inhibits integrase,
the enzyme that catalyzes insertion of viral DNA into the
host cell genome.1,2 In patients with multidrug-resistant
strains of HIV-1, and otherwise limited treatment options,
combination of raltegravir with existing antiretrovirals has
proven to be highly successful in reducing the viral load.3
† Department of Process Research.
‡ Department of Pharmaceutical Research and Development.
§ Department of Medicinal Chemistry.
(1) Raltegravir was approved by the FDA in October 2007 for the
treatment of HIV/AIDS and is marketed under the trademark Isentress.
(2) (a) Meadows, D. C.; Gervay-Hague, J. ChemMedChem 2006, 1, 16.
(b) Craigie, R. J. Biol. Chem. 2001, 276, 23213. (c) Hazuda, D. J.; Felock,
P.; Witmer, M.; Wolfe, A.; Stillmock, K.; Grobler, J. A.; Espeseth, A.;
Gabryelski, L.; Schleif, W.; Blau, C.; Miller, M. D. Science 2000, 287,
646.
(3) (a) Steigbigel, R. T.; Cooper, D. A.; Kumar, P. N.; Eron, J. E.;
Schechter, M.; Markowitz, M.; Loufty, M. R.; Lennox, J. L.; Gatell, J. M.;
Rockstroh, J. K.; Katlama, C.; Yeni, P.; Lazzarin, A.; Clotet, B.; Zhao, J.;
Chen, J.; Ryan, D. M.; Rhodes, R. R.; Killar, J. A.; Gilde, L. R.; Strohmaier,
K. M.; Meibohm, A. R.; Miller, M. D.; Hazuda, D. J.; Nessly, M. L.;
DiNubile, M. J.; Isaacs, R. D.; Nguyen, B.-Y.; Teppler, H. New. Engl.
J. Med. 2008, 359, 339. (b) Grinsztejn, B.; Nguyen, B.-Y.; Katlama, C.;
Gatell, J. M.; Lazzarin, A.; Vittecoq, D.; Gonzalez, C. J.; Chen, J.; Harvey,
C. M.; Isaacs, R. D. Lancet 2007, 369, 1261.
Figure 1. Raltegravir (1).
In an ongoing drug discovery program in these laborato-
ries, a series of fused bicyclic pyrimidones were developed
as potent and selective integrase inhibitors, of which MK-
0396 (2, Scheme 1) is a representative example.4,5 These
analogues were prepared from cyclic amidoximes 5 through
a dimethyl acetylenedicarboxylate (DMAD) addition/thermal
rearrangement sequence6 to give the core bicyclic pyrimidone
scaffolds 6, followed by further elaboration.7 The preparation
(4) (a) Muraglia, E.; Kinzel, O.; Gardelli, C.; Crescenzi, B.; Donghi,
M.; Ferrara, M.; Nizi, E.; Orvieto, F.; Pescatore, G.; Laufer, R.; Gonzalez-
Paz, O.; Di Marco, A.; Fiore, F.; Monteagudo, E.; Fonsi, M.; Felock, P. J.;
Rowley, M.; Summa, V. J. Med. Chem. 2008, 51, 861. (b) Kinzel, O. D.;
Monteagudo, E.; Muraglia, E.; Orvieto, F.; Pescatore, G.; Ferreira, M. R. R.;
Rowley, M.; Summa, V. Tetrahedron Lett. 2007, 48, 6552. (c) Ferrara,
M.; Crescenzi, B.; Donghi, M.; Muraglia, E.; Nizi, E.; Pesci, S.; Summa,
V.; Gardelli, C. Tetrahedron Lett. 2007, 48, 8379.
10.1021/ol9010147 CCC: $40.75
Published on Web 07/02/2009
 2009 American Chemical Society

rather straightforward, such a reaction has, to the best of
our knowledge, not been reported in the literature.
As an initial test of the feasibility of the proposed cascade
reaction, epoxide 1112 was treated with 50% aqueous
hydroxylamine (1.1 equiv) in MeOH at 55-60 °C for 24 h
(Scheme 3). Unexpectedly, this resulted in the formation of
Scheme 1. MK-0396 (2) and Synthesis of Amidoximes 5
Scheme 3. Cyclization of Epoxide 11
of amidoximes 5, in turn, required multistep syntheses from
ω-halonitriles 4 and bis-protected hydroxylamine deriva-
tive 3.
As part of a general strategy toward novel bicyclic
pyrimidone structures, we envisaged a more concise, atom-
economical route to the key cyclic amidoxime precursor
motif. As shown in Scheme 2, treatment of ω-epoxynitriles
Scheme 2. Proposed Cascade Approach to Amidoximes 10
two major products, 13 and 14, neither of which was the
anticipated 7-membered amidoxime structure 15. Aminoni-
trones 13 and 14 (which can also be considered to be amidine
N-oxides) were formed in a ratio of 2.3:1 and 57% combined
assay yield.13 Separation and purification of the highly polar,
water-soluble product mixture was achieved by preparative
HPLC, giving 13 and 14 in a modest overall isolated yield
of 42%.
The formation of 13 and 14 would be consistent with either
of the two mechanisms depicted in Scheme 2. Attempts to
observe the putative intermediates 12 or 12a/b by HPLC-MS
7 with hydroxylamine could potentially generate amidoxime
10 in a single operation. The resulting adducts (10) would
bear a secondary hydroxyl group, which could subsequently
be removed or, more purposefully, serve later as a handle
for further diversification.
Hypothetically, two mechanistic pathways could exist for
this transformation. The intermolecular addition of hydroxy-
lamine to nitriles is well established,8 and precedent exists
for two of the other three elementary steps illustrated.9-11
While the conversion of 7 to 10 is therefore conceptually
(8) For examples, see: (a) Ref 7a. (b) Di Francesca, M. E.; Pace, P.;
Fiore, F.; Naimo, F.; Bonelli, F.; Rowley, M.; Summa, V. Bioorg. Med.
Chem. Lett. 2008, 18, 2709. (c) Ismail, M. A.; Arafa, R. K.; Brun, R.;
Wenzler, T.; Miao, Y.; Wilson, W. D.; Generaux, C.; Bridges, A.; Hall,
J. E.; Boykin, D. W. J. Med. Chem. 2006, 49, 5324.
(9) Intermolecular opening of terminal epoxides by hydroxylamine
(7f8): (a) Kliegel, W. Chem. Ber. 1969, 102, 1776. (b) Da¸bkowska, K.;
Da¸browska, P.; Drabik, J.; Kopczuk, D.; Plenkiewicz, J.; Strosznajder, J. B.;
WielechowskaM., Synth. Commun. 2005, 1455. (c) Palmer, A. M.; Ja¨ger,
V. Synlett 2000, 1405.
(10) Intramolecular cyclizsation of unsubstituted hydroxylamines, gener-
ated in situ by reduction of nitro groups, onto nitriles (8 f 10): (a) Buckley,
G. D.; Elliot, T. J. J. Chem. Soc. 1947, 1508. (b) Munshi, K. L.; Kohl, H.;
de Souza, N. J. J. Heterocycl. Chem. 1977, 14, 1145. (c) Belley, M.; Sauer,
E.; Beaudoin, D.; Duspara, P.; Trimble, L. A.; Dube´, P. Tetrahedron Lett.
2006, 47, 159.
(5) The related unsaturated heterocyclic pyridopyrimidine scaffold has
also been reported; see: Kinzel, O. D.; Ball, R. G.; Donghi, M.; Maguire,
C. K.; Muraglia, E.; Pesci, S.; Rowley, M.; Summa, V. Tetrahedron Lett.
2008, 49, 6556.
(6) (a) Pye, P. J.; Zhong, Y.-L.; Jones, G. O.; Reamer, R. A.; Houk,
K. N.; Askin, D. Angew. Chem., Int. Ed. 2008, 47, 4134. (b) Zhong, Y.-L.;
Zhou, H.; Gauthier, D. R., Jr.; Askin, D. Tetrahedron Lett. 2006, 47, 1315.
(c) Culbertson, T. P. J. Heterocycl. Chem. 1979, 1423.
(11) The intermolcular opening of epoxides by hydroxyamidines (an
intermolecular variant of 9 f 10) has been discussed in a hypothetical
context in a Japanese patent, but no examples were reported; see: Katoh,
S.; Sayama, S.; Shibata, S.; Uchida, I. Preparation of Benzopyran Derivatives
as Antihypertensives and Vasodilators. PCT Int. Appl. WO 9219611, 1992.
(12) de Raadt, A.; Klempier, N.; Faber, K.; Griengl, H. J. Chem. Soc.,
Perkin Trans. 1 1992, 137.
(7) For a more recent, scalable synthesis of 2, see: (a) Zhong, Y.-L.;
Pipik, B.; Lee, J.; Kohmura, Y.; Okada, S.; Igawa, K.; Kadowaki, C.;
Takezawa, A.; Kato, S.; Conlon, D. A.; Zhou, H.; King, A. O.; Reamer,
R. A.; Gauthier, D. R., Jr.; Askin, D. Org. Proc. Res. DeV. 2008, 12, 1245.
(b) Zhong, Y.-L.; Krska, S. W.; Zhou, H.; Reamer, R. A.; Lee, J.; Sun, Y.;
Askin, D. Org. Lett. 2009, 11, 369.
(13) “Assay yield” refers to a nonisolated solution yield of product as
determined by comparison of product UV absorbance with that of pure,
authentic product standard using HPLC analysis.
Org. Lett., Vol. 11, No. 15, 2009
3195

or NMR spectroscopy were unsuccessful. This suggests that
the intermolecular step may be rate-limiting under these
conditions but does not enable distinction between the
possible sequences of events.
Table 1. Further Examples of the Cascade Cyclization
The structural determination of products 13 and 14
warrants further comment, using 13 as an example. As shown
in Figure 2, there are four potential structures for a
Figure 2. Aminonitrone 13 and other structures considered.
7-membered cyclization product; note that 13 and 15 are
tautomers, as are 16 and 17. NMR spectroscopy (including
1H-15N HMBC)14 confirmed the C-N connectivity and
location of the double bond in an endocyclic position, thus
ruling out 15 and 17, but could not unequivocally establish
the site of N-oxidation, i.e., distinguish between aminonitrone
13 and hydroxyamidine 16. Previous reports have highlighted
the difficulty in rigorously differentiating these two structural
motifs.15 Assignment of structure 13 rather than 16 to the
7-membered product was ultimately made by analogy with
related derivatives (vide infra).
The substrate scope of this cascade reaction was then
expanded with a small series of examples (Table 1). The
isolated yields were uniformly moderate, although a single
set of reaction conditions was used, which was not optimized
for each individual case. Furthermore, all of the products
were isolated by crystallization, with no requirement for
aqueous workup or chromatography.16 The observed cy-
clization products were formed with high selectivity for the
6-membered ring17 and in each case were isolated as single
regioisomers with the double bond located within the ring.
If the reaction proceeds via an intermolecular nitrile addition/
intramolecular epoxide-opening pathway, then examination
of molecular models provides a convenient explanation for
this selectivity. By this simple analysis, the transition state
for 5-exo epoxide opening would be considerably more
strained than for the corresponding 6-endo process (Table
1, entries 1-3 and 7). Conversely, compared to the acyclic
a Isolated yield. b ee of the crude product before isolation.
example in Scheme 3, the rigidity imposed by incorporation
of two more sp2 carbon atoms into the tether in entries 4-6
of Table 1 now favors the 6-exo over the 7-endo mode of
cyclization. An alternative explanation would be that inter-
molecular epoxide opening by hydroxylamine occurs first
at the less hindered carbon in each case, followed by
cyclization onto the nitrile group.
The data currently available unfortunately does not allow
for a definitive assessment of which of these two overall
mechanistic scenarios is indeed operative. However, evidence
for an SN2-based mechanism of epoxide opening could be
(14) See the Supporting Information for details.
(15) (a) Nicholas, G. M.; Blunt, J. W.; Munro, M. H. G. J. Nat. Prod.
2001, 64, 341. (b) Forrester, A. R.; Irikawa, H.; Thomson, R. H.; Woo,
S. O.; King, T. J. J. Chem. Soc., Perkin Trans. 1 1981, 1712. (c) Forrester,
A. R.; Thomson, R. H. Spectrochim. Acta 1963, 19, 1481.
(16) Byproducts in the reaction mixtures, tentatively identified by
HPLC-MS as resulting from competing nitrile hydrolysis or epoxide
opening by MeOH or H2O, were generally observed but were efficiently
rejected during crystallization of the aminonitrone products.
(17) Determined by HPLC and/or 1H NMR analysis of the crude reaction
mixtures.
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Org. Lett., Vol. 11, No. 15, 2009

established; trans-1,2-disubstituted epoxides (()-26 and (()-
28 gave the corresponding trans-disubstituted products (()-
27 and (()-29, respectively, as single diastereoisomers (Table
1, entries 6 and 7), and cyclization of optically active
substrate (-)-24 proceeded with no erosion of stereochemical
integrity (Table 1, entry 5).
Scheme 4. Manipulation of Aminonitrone 23
Crystals of cyclization products 19 and 23 suitable for
X-ray single-crystal analysis were grown by slow evaporation
from EtOAc/MeOH and MeCN/MeOH, respectively, provid-
ing rigorous proof of the proposed aminonitrone structures
for these two compounds (Figure 3).18-20 By analogy,
strated that the aminonitrone structure can be utilized in the
same manner as the tautomeric amidoximes employed
previously (cf. Scheme 1).4b,c Alternatively, acylation of 23
with isobutyl chloroformate followed by thermal cyclization
generated 1,2,4-oxadiazolone 32 in good overall yield.
In summary, we have discovered and developed a new
cascade reaction between ω-epoxynitriles and hydroxylamine
that offers a concise, stereocontrolled route to novel func-
tionalized cyclic aminonitrones. The reaction is generally
selective for the formation of 6-membered rings over the
corresponding 5- or 7-membered products. The large number
of methods for enantioselective epoxide synthesis make this
an attractive approach to chiral, cyclic aminonitrones that
would be difficult to access by other methods.22 Finally, the
cascade products are themselves amenable to further ma-
nipulation.
Figure 3
23 (right).
. X-ray crystal structures of aminonitrones 19 (left) and
therefore, the other cascade products were assigned the
corresponding aminonitrone structures illustrated in Scheme
3 and Table 1.
Literature reports on aminonitrones have focused largely
on the preparation or spectroscopic properties of these
compounds; they have found only sporadic use as reagents
in organic synthesis themselves.19a,c To add to the repertoire
of synthetically useful transformations that these species
undergo, aminonitrone 23 was treated with DMAD in MeOH,
leading to the formation of 1,2,4-oxadiazoline 30 in excellent
yield (Scheme 4).21 Refluxing a solution of 30 in PhMe then
provided polycyclic pyrimidone 31. This sequence demon-
Acknowledgment. We thank the following individuals
from Merck Research Laboratories: W. A. Schafer, T.
Brkovic, and Z. Pirzada for chiral SFC analysis, T. J. Novak
for assistance with HRMS. We also thank the reviewers for
constructive comments.
(18) CCD deposition codes: 730722 (19) and 730723 (23).
(19) The X-ray analysis revealed extensive intermolecular hydrogen
bonding within the crystal lattice of both 19 and 23. For examples of X-ray
structure analysis of other aminonitrones and discussion of potential solid/
solution-phase tautomerism, see: (a) Trzewik, B.; Ciez˙, D.; Hodorowicz,
M.; Stadnicka, K. Synthesis 2008, 2977. (b) Giumanini, A. G.; Toniutti,
N.; Verardo, G.; Merli, M. Eur. J. Org. Chem. 1999, 141. (c) Branco, P. S.;
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Prabhakar, S.; Lobo, A. M.; Williams, D. J. Tetrahedron 1992, 48, 6335
.
OL9010147
(20) Selected interatomic distances (Å) for 19: O1-N2 1.3611(16),
O2-C4 1.4251(18), N1-C1 1.3322(19), N2-C5 1.4694(19), N2-C1
1.304(2), C1-C2 1.498(2), C2-C3 1.531(2), C3-C4 1.518(2), C4-C5
1.519(2).
(22) Cyclic aminonitrones have generally been prepared by the reductive
cyclization of ω-nitronitriles. For examples, see refs 10a and 15a. For a
discussion of synthetic routes to acyclic aminonitrones, see ref 19a.
(21) Naidu, B. N.; Sorensen, M. E. Org. Lett. 2005, 7, 1391.
Org. Lett., Vol. 11, No. 15, 2009
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