Regioselective synthesis of 2-iminooxazinones from dioxinones and carbodiimides

Article abstract of DOI:10.1016/j.tetlet.2012.07.100

Iminooxazinones are readily formed via microwave heating of dioxinones in the presence of carbodiimides. Unsymmetrically substituted carbodiimides generally react with high or complete regioselectivity, allowing for assembly of the target ring systems wit

Full text of DOI:10.1016/j.tetlet.2012.07.100

Tetrahedron Letters 53 (2012) 5479–5482
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective synthesis of 2-iminooxazinones from dioxinones
and carbodiimides
⇑
Jeffrey R. Johnston, F. G. West
Department of Chemistry, University of Alberta, E3-43 Gunning-Lemieux Chemistry Centre, Edmonton, AB T6G 2G2, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Iminooxazinones are readily formed via microwave heating of dioxinones in the presence of carbodii-
mides. Unsymmetrically substituted carbodiimides generally react with high or complete regioselectiv-
ity, allowing for assembly of the target ring systems with full control of substitution pattern under
convenient conditions.
Received 28 June 2012
Revised 20 July 2012
Accepted 24 July 2012
Available online 28 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Iminooxazinone
Carbodiimide
Microwave heating
Acylketene
Cycloaddition
Scaffolds based on nitrogen-containing heterocycles are com-
mon in many classes of bioactive substances, such as pharmaceu-
ticals and agricultural chemicals. Methods for convergent
generation of such skeletons in a single step are especially attrac-
tive, both from a step-economy standpoint and as an approach
for the preparation of structurally diverse compound libraries.
Oxidized oxazine derivatives such as amino- and iminooxazinones
(Fig. 1) possess heteroatom-rich structures with multiple attach-
ment points for variable side-chains and several hydrogen bond
acceptors and/or donors. Compounds with these substructures
have been described, pertaining to anti-cancer, analgesic, and fun-
gicidal activities.1 Moreover, iminooxazinones are versatile inter-
mediates in the construction of other heterocyclic classes, such
as 4-oxooxazinones or uracils.2
reaction is presumed to proceed through initial DCC-mediated
dehydration to give the acylketene intermediate 3a, followed by
Figure 1. Representative iminooxazinones.
Iminooxazinones can be prepared in one step from cycloaddition
or cyclocondensation of simple carbodiimides with allene-contain-
ing carboxylic acids,3 salicylic acids,4 or acylketenes derived from
precursors such as diketenes,2 diazocarbonyls,5 furandiones,6 or
dioxinones.7 Persistent acylketenes also undergo this process.8
Acylketenes are generated in situ from malonic acid monoesters
in the presence of DCC, and in one case this intermediate was
trapped in a subsequent cycloaddition with a second equivalent
of the carbodiimide.9 We encountered a similar result during the
preparation of b-ketoester 2 from ketoacid 1, a process that was fre-
quently complicated by the competing formation of iminooxazi-
none 4a, especially on attempted scale-up (Scheme 1). This
⇑
Corresponding author.
E-mail address: frederick.west@ualberta.ca (F.G. West).
Scheme 1. Formation of iminooxazinone 4a from 1 and DCC.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.100

5480
J. R. Johnston, F. G. West / Tetrahedron Letters 53 (2012) 5479–5482
Before addressing the question of regioselectivity, we first
sought to develop a procedurally simple method for effecting the
cycloaddition to afford the iminooxazinone products. Keto-acid
starting materials such as 1 require the use of 2 equiv of carbodi-
imide: one for dehydration to generate the transient acylketene
(with consequent formation of urea by-product), and one to partic-
ipate in the subsequent cycloaddition process. As noted above,
there are several alternative routes to acylketenes, and we were
particularly attracted to the dioxinone method,7 given its proce-
dural simplicity, the innocuous by-product (acetone), and the po-
tential for structural modification of the commercially available
2,2,6-trimethyldioxinone 5a.
Initial experiments utilized 5a and either diisopropylcarbodiim-
ide 6a or dicyclohexylcarbodiimide 6b (Scheme 2). Extended heat-
ing in toluene at reflux furnished known iminooxazinones 7a 2 and
7b7 in good yield, comparable to previously described cases
employing dioxinones with either 6b or diphenylcarbodiimide in
xylene or mesitylene at reflux. In an effort to shorten the reaction
time, the effect of microwave heating10 on the reaction with DCC
6b was investigated on a small scale with % conversion determined
via 1H NMR analysis. In the event, 100% conversion was observed
after 30 min at 130 °C, while only 5 min was required at 150 °C. Gi-
ven these results, subsequent preparative scale experiments were
carried out with microwave heating at either 150 °C or 200 °C.
Several unsymmetrically substituted carbodiimides11 were pre-
pared (Fig. 2). Phenyl cyclohexyl carbodiimide 6c was prepared by
the method of Palomo and Mestres via dehydration of the corre-
sponding mixed urea.11a The known 11e–g phenyl allyl carbodiimide
6d and t-butyl cyclohexyl carbodiimide 6e were prepared using the
same method. Regioisomeric allylation products 5b 12 and 5c 13 are
both available from 5a, and were prepared by a variation on these
procedures.
Scheme 2. Initial experiments with dioxinone 5a.
Figure 2. Unsymmetrical substrates.
Using the microwave heating conditions worked out with 5a
and 6b, dioxinones 5a–c were treated with unsymmetrical carbo-
diimides 6c–e to afford iminooxazinones 7c–i in moderate to good
yields (Table 1). In most cases, reactions were carried out at both
150 °C and 200 °C, and the higher yielding conditions are included
in the table. In most cases, the higher temperature furnished 7 in
higher yield, though in the case of 5a and 6c, a shorter reaction
time was required (entry 2). A higher temperature was consis-
tently desirable in the case of more substituted dioxinones 5b
and 5c, whose expulsion of acetone is slow at 150 °C. With dioxi-
cycloaddition with a second equivalent of DCC. As noted above,
there is ample precedent for the construction of iminooxazinones
from simple carbodiimides and ketene equivalents; on the other
hand, relatively little is known regarding regiochemical outcomes
in cases involving unsymmetrical partners. With this in mind, we
set out to prepare a series of unsymmetrical carbodiimides and acy-
lketene precursors and evaluate their cycloaddition behavior. Here
we describe the results of this study, including convenient reaction
conditions using microwave heating, and complete regioselectivity
in the cycloaddition process.
Table 1
Cycloaddition of dioxinones with carbodiimidesa
Entry
Dioxinone
Carbodiimide
R1
R2
R3
R4
Iminooxazinone
T (°C)
Yield 7b (%)
1
2
3
4
5a
5a
5a
5a
5b
5b
5b
5c
6c
6c
6d
6e
6c
6d
6e
6c
Me
Me
Me
Me
H
H
H
H
H
H
H
Allyl
Cy
Cy
Allyl
Cy
Cy
Allyl
Cy
Cy
Ph
Ph
Ph
t-Bu
Ph
Ph
t-Bu
Ph
7c
7c
7d
7e
7f
7g
7h
7i
150
200c
200
150
200
200
200
200
71
75
93
82
75
68
71
42
5d
6d
7d
8d
(CH2)2CH@CH2
(CH2)2CH@CH2
(CH2)2CH@CH2
Me
a
Standard conditions: Dioxinone 5 (0.22 mmol) and carbodiimide 6 (0.27 mmol) were dissolved in DCE (0.5 mL) in a microwave reaction vial, then subjected to microwave
heating at 150 °C or 200 °C for 5 min. Solvent was removed and the crude reaction mixture purified by column chromatography.
b
Yields given are for isolated material after chromatographic purification, and reflect average values taken from at least two runs.
Reaction time was reduced to 10 s.
Acetone (5 lL, 0.07 mmol) was added to the reaction mixture.
c
d

J. R. Johnston, F. G. West / Tetrahedron Letters 53 (2012) 5479–5482
5481
nones 5b and 5c, it was found beneficial to include a small amount
of added acetone to the reaction mixture to enhance the rate of
microwave heating.14
Importantly, in all examples only one regioisomer was detected.
While regioselectivity has been described in a few early examples
involving unsymmetrical reactants,2 these results indicate a here-
tofore unappreciated generality of this phenomenon for this trans-
formation. Evidence for the indicated regiochemistry includes the
following. In the case of DCC adduct 7b, a characteristic difference
in chemical shift (4.68 vs 3.60 ppm) for the cyclohexyl methine
protons was noted (Fig. 3) allowing for tentative determination
of the location of the cyclohexyl substituent in adducts derived
from 6c and 6e. Thus, in the case of 7c, the single cyclohexyl
methine resonance appears at 4.82 ppm, consistent with substitu-
tion on the ring nitrogen. Furthermore, a 3-bond HMBC correlation
was detected between the cyclohexyl methine proton and the car-
bonyl carbon (possible for 7c but not for its hypothetical regio-
isomer 8c) and an NOE correlation was observed between the
ortho phenyl protons and the methyl protons. Regiochemistry in
other cases was assigned by analogy. It should be noted that the
NOE correlation mentioned above not only supported the regio-
chemical assignment, but also strongly suggested a (Z) geometry
for the exocyclic imino group. This geometry for a C@NPh moiety
was also observed in the X-ray crystal structure for diphenylcarbo-
diimide adduct 7j,2b,7,15 and likely arises from avoidance of unfa-
vorable steric interactions between the two nitrogen substituents.
The mechanism of the cycloaddition process remains uncertain
at this time. Two mechanistic extremes are concerted [4+2]-cyclo-
addition and stepwise nucleophilic attack by one nitrogen atom at
the electrophilic ketene carbon, followed by electrocyclic ring-clo-
sure (Scheme 3). In the case of alkyl aryl carbodiimides 6c and 6d,
the alkyl-substituted nitrogen is consistently incorporated into the
ring (R3). Preferential bonding between this more nucleophilic
nitrogen and the former ketene carbon atom suggests that the
cycloaddition may proceed with a significant polar component.
On the other hand, the difference in relative nucleophilicity of
the two carbodiimide nitrogens of 6e is likely to be negligible,
and selective placement of the t-butyl substituent on the exocyclic
Scheme 3. Mechanism and regioselectivity.
imino nitrogen may result from avoidance of unfavorable steric
interactions in the transition state for addition. Reaction of 1-t-bu-
tyl-3-phenylcarbodiimide11f,g,16 would provide an opportunity to
more fully explore the relative importance of the electronic and
steric factors that appear to influence regioselectivity, and these
studies are planned for future publication.
Cycloaddition of thermally generated acylketenes with carbo-
diimides offers a convergent and expedient route to the iminoox-
azinone skeleton. Examination of a series of unsymmetrically
substituted reaction partners has shown that high levels of regiose-
lectivity can be expected from this process, with the nitrogen atom
that is less nucleophilic or more sterically encumbered occupying a
position on the exocyclic imino group. Microwave heating allows
for clean conversion in relatively short reaction times. Further
applications of this work, including the examination of other
mixed carbodiimides and the exploration of alternative acylketene
precursors, will be described in due course.
Acknowledgements
The authors thank NSERC for generous funding of the project,
and Dr. Michael Ferguson (University of Alberta X-ray Crystallogra-
phy Laboratory) for obtaining the structure of 7j.
References and notes
1. (a) March, L. C.; Romanchick, W. A.; Bajwa, G. S.; Joulié, M. M. J. Med. Chem.
1973, 16, 337–342; (b) Bereznak, J. F.; Marshall, PCT Int. Appl. (2000), WO
2000051992 A1 20000908.
2. (a) Lacey, R. N. J. Chem. Soc. 1954, 845–849; (b) Lacey, R. N.; Ward, W. R. J. Chem.
Soc. 1958, 2134–2141.
3. Trifonov, L. S.; Orahovats, A. S. Helv. Chim. Acta 1986, 69, 1585–1587.
4. May, E. L. J. Med. Chem. 1967, 10, 505–506.
5. Capuano, L.; Kirn, H. R.; Zander, R. Chem. Ber. 1976, 109, 2456–2461.
6. Lisovenko, N. Y.; Maslivets, A. N.; Aliev, Z. G. Russ. J. Org. Chem. 2007, 43, 117–
120.
7. Sato, M.; Ogasawara, H.; Kato, T. Chem. Pharm. Bull. 1984, 32, 2602–2608.
8. (a) Kappe, C. O.; Färber, G.; Wentrup, C.; Kollenz, G. J. Org. Chem. 1992, 57,
7078–7083; (b) Saidi, K.; Shaterian, H.; Aghaei, D. Heterocycl. Commun. 2000, 6,
93–96.
9. Shelkov, R.; Nahmany, M.; Melman, A. J. Org. Chem. 2002, 67, 8975–8992.
10. Gudipati, I. R.; Sadasivam, D. V.; Birney, D. M. Green Chem. 2008, 10, 275–
277.
11. (a) Palomo, C.; Mestres, R. Synthesis 1981, 373–374; (b) Schlama, T.;
Gouverneur, V.; Mioskowski, C. Tetrahedron Lett. 1996, 37, 7047–7048; (c)
Babcock, J. R.; Sita, L. R. J. Am. Chem. Soc. 1998, 120, 5585–5586; (d) Anderson, J.
C.; Bou-Moreno, R. Tetrahedron 2010, 66, 9182–9186; (e) Kong, K. H.; Tan, C. K.;
Lin, X.; Lam, Y. Chem. Eur. J. 2012, 18, 1476–1486; (f) Kim, S.; Yi, K. Y.
Tetrahedron Lett. 1985, 26, 1661–1664; (g) Olimpieri, F.; Volonterio, A.;
Bellucci, M. C.; Zanda, M. Eur. J. Org. Chem. 2009, 6179–6188.
12. Cramer, N.; Buchweitz, M.; Laschat, S.; Frey, W.; Baro, A.; Mathieu, D.; Richter,
C.; Schwalbe, H. Chem. Eur. J. 2006, 12, 2488–2503.
13. Vu, V. A.; Bérillon, L.; Knochel, P. Tetrahedron Lett. 2001, 42, 6847–6850.
Figure 3. Evidence for regiochemical assignment.

5482
J. R. Johnston, F. G. West / Tetrahedron Letters 53 (2012) 5479–5482
14. Note that commercially available 5a contains 5% acetone. The role of acetone in
promoting the effectiveness of microwave heating is unclear, since the solvent
(DCE) has a significantly higher loss factor (tand) than acetone. See Kappe, C. O.
Angew. Chem. Int. Ed. 2004, 43, 6250–6284.
formed in low yield, arose from preferential reaction with traces of the more
reactive diphenylcarbodiimide, which appears to have been formed
inadvertently during the preparation of the mixed 3-benzyl-1-
phenylcarbodiimide.
15. Compound 7j was obtained unexpectedly from the attempted reaction of 5a
with crude 3-benzyl-1-phenylcarbodiimide. We postulate that this product,
16. Larksarp, C.; Alper, H. J. Org. Chem. 1998, 63, 6229–6233.