DAST-mediated cyclization of α,α-disubstituted-α- acylaminoketones: Efficient and divergent synthesis of unprecedented heterocycles

Article abstract of DOI:10.1021/ol102454e

The design of a new potent nonsteroidal ecdysone agonist led to the discovery of a diethylaminosulfur trifluoride (DAST)-mediated cyclization of α,α-disubstituted-α-acylaminoketones. The resulting fluorooxazolines can be ring-opened or selectively substit

Full text of DOI:10.1021/ol102454e

ORGANIC
LETTERS
2011
Vol. 13, No. 2
192-195
DAST-Mediated Cyclization of
r,r-Disubstituted-r-acylaminoketones:
Efficient and Divergent Synthesis of
Unprecedented Heterocycles
Aure´lien Bigot,† Judith Blythe,‡ Chirag Pandya,‡ Trixie Wagner,§ and
Olivier Loiseleur*,†
Syngenta Crop Protection Mu¨nchwilen AG, Schaffhauserestrasse,
CH-4332 Stein, Switzerland
oliVier.loiseleur@syngenta.com
Received October 11, 2010
ABSTRACT
The design of a new potent nonsteroidal ecdysone agonist led to the discovery of a diethylaminosulfur trifluoride (DAST)-mediated cyclization
of r,r-disubstituted-r-acylaminoketones. The resulting fluorooxazolines can be ring-opened or selectively substituted by a range of nucleophiles
to provide in high yields a diverse array of unprecedented heterocyclic frameworks.
The constant need for small molecules able to disrupt
biological pathways continues to drive efforts toward efficient
sequences leading to diverse scaffolds.1 A particularly
relevant chemotype is represented by nitrogen-containing
heterocycles since they are ubiquitous in biologically active
compounds.2 Therefore the development of general methods
to access original N-heterocycles with unexplored properties
from simple common intermediates is of great interest for
pharmaceutical and agrochemical purposes. We report herein
a diethylaminosulfur trifluoride (DAST)-mediated two-step
sequence from readily available acylaminoketones affording
highly functionalized and unprecedented heterocycles in an
efficient and divergent fashion.
As part of a program directed toward the discovery of new
insecticide leads, we became interested in the recently
reported R,R-disubstituted-R-acylaminoketone chemotype3
as a central scaffold to design new bioisosters. This class of
ligands has been identified as potent analogues of the
(3) (a) Tice, C. M.; Michelotti, E. L.; Mata, E. G.; Nicolas, E.; Garcia,
J.; Albericio, F. Tetrahedron Lett. 2002, 43, 7491. (b) Garcia, J.; Nicolas,
E.; Albericio, F.; Michelotti, E. L.; Tice, C. M. Tetrahedron Lett. 2002,
43, 7495. (c) Tice, C. M.; Hormann, R. E.; Thompson, C. S.; Friz, J. L.;
Cavanaugh, C. K.; Saggers, J. A. Bioorg. Med. Chem. Lett. 2003, 13, 1883.
(d) Tice, C. M.; Hormann, R. E.; Thompson, C. S.; Friz, J. L.; Cavanaugh,
C. K.; Michelotti, E. L.; Garcia, J.; Nicolas, E.; Albericio, F. Bioorg. Med.
Chem. Lett. 2003, 13, 475. (e) Garcia, J.; Mata, E. G.; Tice, C. M.; Hormann,
R. E.; Nicolas, E.; Albericio, F.; Michelotti, E. L. J. Comb. Chem. 2005, 7,
843, and references therein.
† Syngenta Crop Protection Mu¨nchwilen AG.
‡ Syngenta, Jealott’s Hill International Research Centre.
§ Novartis Institute for Biomedical Research.
(1) (a) Strausberg, R. L.; Schreiber, S. L. Science 2003, 300, 294. (b)
Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008, 47, 48.
(2) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell:
Oxford, 2000. (b) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles;
Wiley-VCH: Weinheim, 2003. (c) Katrizky, A. R.; Pozharskii, A. F.
Handbook of Heterocyclic Chemistry, 2nd ed.; Pergamon: Amsterdam, 2000.
10.1021/ol102454e  2011 American Chemical Society
Published on Web 12/08/2010

bisacylhydrazine family of commercial insecticides4 and was
used to control gene expression in systems based on
engineered ecdysone receptors.5 The generation of a small
library3e allowed the identification of 1a (Scheme 1),
the oxazoline scaffold10 and the numerous methods of
preparation.11 We envisioned that 2a could be directly
synthesized from 1a by the use of a deoxofluorinating agent
such as DAST.12 The cyclodehydration of ꢀ-hydroxyamide
to 4,5-unsubstituted oxazolines is known;11c nevertheless this
reagent was never applied to ketone counterparts. Gratify-
ingly the treatment of 1a with an excess of DAST at low
temperature promoted smoothly the desired cyclization
affording 2a in very good isolated yields (Scheme 2).
Scheme 1
.
Design of a Conformationally Restricted Analogue
Based on X-ray Structure of 1aa
Scheme 2. DAST-Mediated Cyclization of 1a
a X-ray structure from ref 3c.
synthetically derived from 1-aminocyclohexyl-1-carboxylic
acid, displaying micromolar range affinity close to that of
the commercial product Tebufenozide.6
The cyclization is proposed to follow two SN1 pathways
involving prior activation of the carbonyl by DAST to allow
intramolecular attack of the amide oxygen.13 Subsequent
formation of the stabilized benzylic R-oxycarbenium ion,
which is trapped by a fluoride, provides the desired fluo-
rooxazoline.
The biological evaluation of 2a was performed on an
ecdysone reporter gene assay.14 It displayed a high potency
similar to that of 1a (EC30(2a) ) 1.21 µM; EC30(1a) ) 1.33
µM). Oxazoline 2a represents therefore a potential new class
of nonsteroidal ecdysone agonists based on a conformation
analogue of 1a.
The X-ray structure of 1a displays a folded shape that
particularly attracted our attention and was used as a starting
point for our design. This conformation is induced to
minimize steric clashes with the cyclohexyl substituent and
is further stabilized by an additional carbonyl-carbonyl
attractive interaction, recently thoroughly studied by Raines
et al. and named n-π* interaction.7,8 We assumed that this
conformation was responsible for the biological activity, and
conformationally restricted analogue oxazoline 2a was
designed to assess this hypothesis. Indeed 2a mimics the
X-ray structure of 1a while displaying a similar electronic
distribution. The (sp3)C-F bond is of particular importance,
replacing the pyramidalized and elongated ketone of 1a due
to n-π* delocalization.
Encouraged by these results we embarked on investigating
the scope of the DAST-mediated cyclization process (Table
1). The substrates acylaminoketones 1b-j were readily
available in 2-3 steps from commercially available building
Surprisingly oxazolines bearing a heteroatom at C5 are
scarcely found in the literature9 despite the importance of
(10) For examples of naturally occuring oxazoline, see: (a) Portmann,
C.; Blom, J. F.; Gademann, K.; Jttner, F. J. Nat. Prod. 2008, 71, 1193. (b)
Wipf, P.; Fritch, P. C.; Geib, S. J.; Sefler, A. M. J. Am. Chem. Soc. 2009,
131, 16758. For a review on insecticidal oxazolines, see: Stevenson, T. M.;
Amoo, V. E.; Chiang, G. C.; Keskeny, E.; Long, J. K.; Crouse, B. A.;
Sharpe, P.; Hillegass, K.; Jones, L.; Yatsko, C. Synthesis and Chemistry of
Agrochemicals VI; ACS Symposium Series 800; American Chemical
Society: Washington, DC, 2001; pp 188-198. For a review on recent
applications of oxazoline-containing ligands, see: Hargaden, G. C.; Guiry,
P. J. Chem. ReV. 2009, 109, 2505.
(4) Dhadialla, T. S.; Ross, R. Modern Crop Protection Compounds;
Wiley-VCH: Weinheim, 2003; pp 773-797.
(5) (a) Laudet, V.; Gronemeyer, H. The Nuclear Receptor Facts Book;
Academic Press: San Diego, CA, 2002; pp 181-191. (b) Dhadialla, T. S.;
Carlson, G. R.; Le, D. P. Annu. ReV. Entomol. 1998, 43, 545.
(6) see the Supporting Information.
(7) (a) Choudhary, A.; Gandla, D.; Krow, G. R.; Raines, R. T. J. Am.
Chem. Soc. 2009, 131, 7244. (b) Jakobsche, H. E.; Choudhary, A.; Miller,
S. J.; Raines, R. T. J. Am. Chem. Soc. 2010, 132, 6651
.
(8) The criteria for n-π* delocalization are fulfilled (see ref 7a): the
distance between the oxygen of the amide and the carbon of the carbonyl
is 2.62 Å which is less than the sum of their van der Waals radii (rS + rC
< 3.50 Å). The angle O-CdO is 104.9°, and the carbonyl presents a slight
pyramidalization.
(11) For recent exemples, see: (a) Fan, L.; Lobkovsky, E.; Ganem, B.
Org. Lett. 2007, 9, 2015. (b) Schwekendiek, K.; Glorius, F. Synthesis 2006,
2996. (c) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R.
Org. Lett. 2000, 2, 1165.
(12) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(9) (a) Hassner, A.; Burke, S. S.; Cheng-fan, I, J. J. Am. Chem. Soc.
1975, 97, 4692. (b) Morwick, T.; Hrapchak, M.; DeTuri, M.; campbell, S.
Org. Lett. 2002, 4, 2665.
(13) The n-π* delocalization increases the negative charge on the ketone
oxygen, which possibly becomes more prone to react with DAST.
(14) See Supporting Information.
Org. Lett., Vol. 13, No. 2, 2011
193

of DAST to afford 2c in high yields, and higher temperature
was necessary to provide 2d in moderate yields. The reaction
proceeded smoothly in the presence of an aldehyde or a
variety of ketone substituents such as alkyl, alkene, and
alkyne (Table 1, entries 5-8). Heteroaryls were also tolerated
together with variations at the gem-disubstituted position
(Table 1, entry 9). All oxazolines 2b-j were purified by
column chromatography and proved to be stable over several
weeks upon storage at 4 °C.
Table 1. Scope of the Reaction
With the aim to further fonctionalize the fluorooxazolines
2, we subsequently studied their chemical stability perform-
ing hydrolysis experiments with 2b at several pH values
(Scheme 3). As expected 2b proved to be almost unaltered
Scheme 3. Hydrolysis of 2b
after a week at pH ) 7, but complete hydrolysis to 1b was
observed after 1 h at pH ) 2. The hydrolysis is assumed to
be triggered by activation through protonation of the nitrogen
with subsequent attack of the water at C2 rather than at the
congested yet potentially reactive C5 bearing the fluorine.
Subsequent ring opening with extrusion of HF provides
acylaminoketone 1b.
Thus we envisioned that addition of other nucleophiles
could selectively lead to a derivatization of the amide
functionality of acylaminoketones 1 through a DAST-
mediated cyclization/ring-opening sequence. At first 2b was
subjected to an excess of sodium sulfide in acidic methanol
(Scheme 4). As expected, thioamide 3 was isolated as the
a Isolated yields. b As a 1:1 mixture of diastereoisomers according to
1H NMR. c Reaction performed in a sealed tube under microwave irradiation.
d
1
As a 85:15 mixture of diastereoisomers according to H NMR.
Scheme 4
.
Ring Opening of 2b with Na2S and Subsequent
Cyclization
blocks through modified known procedures.15 Initially 1b
was chosen for optimization study and showed that only a
slight excess of DAST (1.2 equiv) was required to promote
the cyclization in almost quantitative yield.16 The process
proved tolerant of variation of the amide with heteroaryl,
ester, or alkyl substituents (Table 1, entries 2-4). Amide 1c
bearing an electron-withdrawing group required an excess
(15) See Supporting Information.
sole sulfur-containing isomer in 73% yield after 48 h.
Subsequent treatment with DAST afforded smoothly the
fluorothiazoline 4 in excellent yield.
(16) The addition of a catalytic amount of an alcohol is usually required
for the difluorination of ketones with DAST but was unnecessary in this
case.
194
Org. Lett., Vol. 13, No. 2, 2011

The versatility of this process was further investigated by
reacting 2b with hydrazine. We anticipated that upon opening
of the ring, the formed hydrazonamide would condense onto
the ketone to form cyclic triazines.
Scheme 6. Synthesis of 5,5-Disubstituted-1,2,4-oxadiazinols 7
To our delight we found after some optimization that
heating 2b in the microwave for 1 h at 90 °C in methanol in
the presence of excess hydrazine hydrochloride provided 5b
in excellent yield (Scheme 5).17 The same conditions were
Scheme 5. Synthesis of 5,5-Disubstituted-1,2,4-triazines 5 and 6
Scheme 7. Regioselective Functionalization of 2b at C5
In summary, an efficient two-step process was developed
to afford a series of structurally distinct and unprecedented
heterocyclic frameworks in a divergent fashion. Further
investigations toward the use of other nucleophiles in order
to expand the scope of this process together with the
generation of a library for biological evaluation is currently
underway and will be reported in due course.
applied to oxazolines 2c/h, affording the corresponding
triazines in good to excellent yields. Addition of methyl
hydrazine furnished under optimized conditions N-methyl-
triazine 6 in high yield as the sole isomer. To our knowledge,
this represents the first general synthesis of this rare class of
5,5-disubstituted-1,2,4-triazines18 accessible in two steps
from R,R-disubstituted-R-acylaminoketones of type 1. It is
noteworthy that the direct condensation of hydrazine to 1b
failed to give triazine 5b even at high temperature for
extended reaction time.
The addition of another simple binucleophile was next
envisaged, and we found that addition of a slight excess of
hydroxylamine hydrochloride to 2b/f/i afforded the corre-
sponding unprecedented oxadiazinols 7b/f/i in good yields
(Scheme 6).19
Finally the regioselective functionalization of fluoroox-
azolines 2 at C5 was addressed. We have found that Brønsted
acids catalyze the nucleophilic ring opening of the oxazoline
with regioselective attack at C2. We then speculated that
fluorophilic Lewis acids could possibly lead to the formation
of a transient carbocation at C5 allowing the direct substitu-
tion of the fluorine atom by nucleophiles.
Gratifyingly, microwave irradiation of 2b in EtOH in the
presence of BF3·OEt2 allowed the formation of 8 in 55%
isolated yields. This result opens the door for further
regioselective functionalization at C5.
Acknowledgment. We thank Dr. L. Hagman and M.
Hellstern (Syngenta) for analytical support and technical
assistance. P. Drayton and H. Gates (Syngenta) are acknowl-
edged for the maintenance and supply of the mammalian
cell line for the ecdysone assay. We are also grateful to Dr.
J. Cassayre, Dr. A. De Mesmaeker, Dr. R. Dumeunier, Dr.
E. Godineau, Dr. D. Stierli, Dr. S. Sulzer-Mosse and Dr. S.
Wendeborn (Syngenta) for fruitful scientific discussions.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and CIF files. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL102454E
(17) The structure of 5b was undoubtedly assigned by X-ray analysis.
See Supporting Information.
(18) Rare exemples are found through addition to aromatic triazines
under harsh conditions: (a) Konno, S.; Ohba, S.; Sagi, M.; Yamanaka, H.
Hererocycles 1986, 2, 1243. (b) Benson, S. C.; Gross, J. L.; Snyder, J. K.
J. Org. Chem. 1990, 55, 3257.
(19) The structure of 7b was undoubtedly assigned by X-ray analysis.
See Supporting Information.
Org. Lett., Vol. 13, No. 2, 2011
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