Photooxygenation of 5-dialkylamino-4-pyrrolin-3-ones. Synthesis of highly functionalized ureas, 2-oxazolidinones, and 2-oxazolinones

Article abstract of DOI:10.1021/jo801192z

(Chemical Equation Presented) 5-Dialkylamino-4-pyrrolin-3-ones, available from cyclocondensation of amidines with dimethyl acetylenedicarboxylate (DMAD), undergo rapid singlet oxygenation to give highly functionalized ureas by way of a 1,2-dioxetane cleavage of the initially formed [2 + 2] cycloadducts. These latter compounds undergo cyclization to 2-oxazolidinones in MeOH. Catalytic hydrogenation of the ureas in EtOAc gives 2-oxazolinones. The DBU-DMAD adduct undergoes photooxygenation by an entirely different pathway to give a large ring heterocycle.

Full text of DOI:10.1021/jo801192z

SCHEME 1. Amidine-DMAD Cyclocondensations
Photooxygenation of
5-Dialkylamino-4-pyrrolin-3-ones. Synthesis of
Highly Functionalized Ureas, 2-Oxazolidinones,
and 2-Oxazolinones†
¨
Ihsan Erden,* Galip Ozer, Christophe Hoarau, Weiguo Cao,
Jiangao Song, and Christian Ga¨rtner
transfer mechanism to 1,2-dioxetanes before the latter collapse
to carbonyl fragments. Exocyclic enaminoketones and lactones
have been reported by Wasserman and Ives to react with O2
Department of Chemistry and Biochemistry, San Francisco
State UniVersity, 1600 Holloway AVenue,
San Francisco, California 94132
1
to give 1,2-diones, presumably by way of a 1,2-dioxetane.9-11
We have extensively studied the singlet oxygenations of CdN-
containing compounds in the past and found that in contrast to
enaminoketones R-oximinoketones undergo in the presence of
base oxidative C-C cleavage to give esters and carboxylic
acids.12-16 We recently reported the synthesis of 5-dialkyl-
amino-4-pyrrolin-3-ones of the type 3 (Scheme 1) through a
cyclocondensation of amidines with dimethyl acetylenedicar-
boxylate (DMAD).17 We also showed that the 4-demethyl
analog serves as an excellent precursor of 2-acyltetramic acids,
a naturally occurring class of antibiotics and antitumor agents,18
and now report the singlet oxygenations of these compounds.
Singlet oxygenations of the enaminoketones (or vinylogous
amides) 4 at -78 °C in CH2Cl2 using a high-pressure sodium
lamp and tetraphenylporphyrin as sensitizer proceeded rapidly,
resulting in quantitative formation of a single product in each
Ingmar Baumgardt‡ and Holger Butenscho¨n‡
Institut fu¨r Organische Chemie, Leibniz UniVersita¨t
HannoVer, Schneiderberg 1B, D-30167 HannoVer, Germany
ierden@sfsu.edu
ReceiVed June 23, 2008
1
case. On the basis of H and 13C NMR, as well as elemental
analysis, MS spectra and FT-IR data, the products were
identified as the vinylogous ureas of the type 6 (Table 1).
The urea structure 6a was further confirmed by X-ray
crystallography (Figure 1, Supporting Information).
Ureas 6 underwent cyclization to the 2-oxazolidinones 9 when
stirred in MeOH at room temperature. Alternatively, when the
photooxygenations of 4a and 4c were conducted in methanol
solution instead of CH2Cl2, the corresponding ureas immediately
underwent cyclization to the 2-oxazolidinone derivatives 9a and
9c, respectively. Scheme 2 depicts the mechanism that appears
to be plausible for the intramolecular cyclization pathway in
the presence of methanol.
5-Dialkylamino-4-pyrrolin-3-ones, available from cyclocon-
densation of amidines with dimethyl acetylenedicarboxylate
(DMAD), undergo rapid singlet oxygenation to give highly
functionalized ureas by way of a 1,2-dioxetane cleavage of
the initially formed [2 + 2] cycloadducts. These latter
compounds undergo cyclization to 2-oxazolidinones in
MeOH. Catalytic hydrogenation of the ureas in EtOAc gives
2-oxazolinones. The DBU-DMAD adduct undergoes pho-
tooxygenation by an entirely different pathway to give a large
ring heterocycle.
Upon catalytic hydrogenation of the ureas in an aprotic
solvent such as ethyl acetate, the sole products that were
obtained after chromatography on silica gel were the 4-oxazolin-
2-ones 11a-c in yields of 74-82%. These results are in accord
with the expectation that once the exocyclic double bond in 6
is reduced, the resulting saturated 1,2-dione would undergo
Introduction
The reactions of enamines with singlet oxygen have been
extensively studied and the mechanisms involved elucidated.1-8
In these reactions it has been shown that singlet oxygen
combines with enamines by way of an electron transfer or charge
† This paper is dedicated to Professor Dieter Kaufmann on the occasion of
his 60th birthday.
(9) Wasserman, H. H.; Ives, J. L. J. Am. Chem. Soc. 1976, 98, 7868.
(10) Wasserman, H. H.; Ives, J. L. J. Org. Chem. 1978, 43, 3238.
(11) Wasserman, H. H.; Ives, J. L. J. Org. Chem. 1985, 50, 3573.
(12) Castro, C.; Dixon, M.; Erden, I.; Ergonenc, P.; Keeffe, J. R.; Sukhovitsky,
A. J. Org. Chem. 1989, 54, 3732.
(13) Erden, I.; Griffin, A.; Keeffe, J. R.; Brinck-Kohn, V. Tetrahedron Lett.
1993, 34, 793.
(14) Ocal, N.; Erden, I. Tetrahedron Lett. 2001, 42, 4765.
(15) Ocal, N.; Yano, L. M.; Erden, I. Tetrahedron Lett. 2003, 44, 6947.
(16) Erden, I.; Ergonenc-Alscher, P.; Keeffe, J. R.; Mercer, C. J. Org. Chem.
2005, 70, 4389.
‡ Authors to whom correspondence regarding the X-ray crystallography should
be addressed.
(1) Martin, N. H.; Jefford, C. W. HelV. Chim. Acta 1982, 65, 762.
(2) Foote, C. S.; Lin, J. W.-P. Tetrahedron Lett. 1968, 9, 3267.
(3) Huber, J. E. Tetrahedron Lett. 1968, 9, 3271.
(4) Foote, C. S.; Dzakpasu, A. A.; Lin, J. W.-P. Tetrahedron Lett. 1975, 16,
1247.
(5) Wasserman, H. H.; Stiller, K.; Floyd, M. B. Tetrahedron Lett. 1968, 9,
3277.
(6) Matsuura, T.; Saito, I. Tetrahedron 1969, 25, 557.
(7) Ando, W.; Saiki, T.; Migita, T. J. Am. Chem. Soc. 1975, 97, 5028.
(8) Bartlett, P. A.; Landis, M. E. In Singlet Oxygen; Wasserman, H. H.,
Murray, R. W. Eds.; Academic Press: New York, NY, 1979; pp 243-286.
(17) Erden, I.; Ozer, G.; Hoarau, C.; Cao, W. J. Heterocycl. Chem. 2006,
43, 395.
(18) (a) Erden, I.; Cao, W. Unpublished results, 1995. (b) Ma, L.; Dolphin,
D. J. Chem. Soc., Chem. Commun. 1995, 2251.
10.1021/jo801192z CCC: $40.75
Published on Web 08/05/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6943–6945 6943

TABLE 1. Singlet Oxygenation of 5-Dimethylamino-4-pyrrolin-3-
ones
SCHEME 4. Photooxygenation of the DBU-DMAD
Cyclocondensation Product
entry
substrate
R1
Me
Me
Ph
Me
n-Hex
n-Hex
R2
Bn
Ph
Bn
n-Bu
Bn
n-Bu
product
yield, %a
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
6a
6b
6c
6d
6e
6f
85
86
90
83
89
92
a Isolated yields by chromatography and/or crystallization.
SCHEME 2. Mechanism of 2-Oxazolidinone Formation
from 3
SCHEME 5. Similar Photooxidation Mechanism
13a disappeared within a short time, and the singlet oxygenation
was terminated, the solvent removed in vacuo, to give a colorless
product. To our surprise, the product from this reaction did not
exhibit any of the characteristic features in the NMR spectrum
displayed by the 2-oxazolidinones obtained from the monocyclic
analogs. On the basis of all spectral data as well as elemental
analysis, the product turned out to be the bridged heterocycle
18. It obviously stems from an alternative singlet oxygenation
pathway; the initial 1,2-dioxetane undergoes a “walk” to the
alternative dioxetane 14, and after C-C cleavage, the resulting
tricyclic heterocycle 15 suffers ring opening in the presence of
H2O. Intramolecular conjugate addition of the enol 17 onto the
remote R,ꢀ-unsaturated ester group delivers the interesting
macrocyclic compound 18 containing a 1,3-oxazolidin-4-one
unit. Scheme 4 depicts a plausible mechanism for the afore-
mentioned transformation.
Compound 18 is formally an amino acid and is soluble in
H2O as well as organic solvents. Although intermediate 15 was
never observed spectroscopically, a white solid appeared upon
rotary evaporation of the solvent from the photooxygenation
mixture, and as soon as vacuum was cut off and moist air was
let in, the crystals melted and a waxy solid was formed. We
postulate that at that stage compound 15 was converted to 18
by way of 16 and 17. The characteristic AB doublets at 3.3
and 3.4 (JAB ) 17.4 Hz) for the CH2 group attached to the
carbomethoxy group and the triplet at 6.0 ppm for the olefinic
SCHEME 3. 2-Oxazolinone Formation from 6 or 12
intramolecular cyclization in a manner similar to that shown in
Scheme 2, by way of attack of adventitious H2O at the carbonyl
group; the resulting 5-hydroxy-2-oxazolidinone would undergo
spontaneous dehydration to give the 4-oxazolin-2-one derivatives
11 as outlined in Scheme 3. Alternatively, the cyclization to 11
could occur directly via the enol derived from 10. In one case,
the starting 4-pyrrolin-3-one 4a was selectively reduced at the
exocyclic double bond (Pd/H2, EtOAc), and the resulting
4-pyrrolin-3-one 12 was photooxygenated in CH2Cl2 at -78
°C. Under these conditions, the 2-oxazolinone 11a was directly
formed and was isolated by column chromatography. Com-
pounds of the type 11 with the substitution pattern shown are
unknown.
In one case the reduced urea intermediate 10b was identified
in the crude 1H NMR spectrum of the hydrogenolysis mixture.
Compound 10b exhibited a caharacteristic triplet at 4.8 ppm (J
) 6.75 Hz) for the tertiary hydrogen R to the carbonyl group,
an AB system at 2.9 and 2.6 ppm (dd, J ) 6.75 and 16.0 Hz)
for the diastereotopic hydrogens adjacent to the carbomethoxy
group, and singlets at 2.5 ppm for the NMe2 group and 2.3 ppm
for the acetyl group, respectively. Upon chromatography on
silica gel, urea 10b underwent cyclization followed by dim-
ethylamine elimination to give oxazolidinone 11b.
(20) In our hands, this compound is formed as a mixture of both E (13b)
and Z (13a) isomers (separable by column chromatography), depending on the
reaction temperature and solvent used. Moreover, we cannot account for the
singlet at 3.33 ppm for the methoxy group as reported in ref 18b; rather, it appears
at 3.71 ppm in the case of the (Z) isomer (13a) and 3.82 ppm in the case of 13b.
Both (Z) and (E) isomers afford 18 upon photooxygenation. Upon catalytic
hydrogenation, both yield the same partially reduced product (19). The
experimental details are given in Supporting Information.
The question was whether the tricyclic 4-pyrrolin-3-one 13a
derived from the cyclocondensation between DBU and dimethyl
acetylenedicarboxylate19,20 would undergo a similar transforma-
tion reaction upon singlet oxygenation. Under the same condi-
tion (-78 °C, CH2Cl2), the crimson color of the starting material
(19) (a) Boyles, B. J. L. Chem. ReV. 1995, 95, 1981. (b) Lewis, J. R. Nat.
Prod. Rep. 1994, 11, 329.
6944 J. Org. Chem. Vol. 73, No. 17, 2008

hydrogen in the 1H NMR spectrum were of diagnostic value in
the characterization of the 18. Endoperoxide-dioxetane rear-
rangements are relatively common;21-25 however, dioxetane-
dioxetane rearrangements are extremely rare. To our knowledge,
there is one other case similar to the one described herein, where
an enaminoketone undergoes with 1O2 an analogous dioxetane-
dioxetane rearrangement and oxidative C-C cleavage giving
rise to a ketolactone, analogous to the intermediate 15.26 This
transformation was implemented in a total synthesis of a
rhoeadin alkaloid by the authors. Whereas the spirolactone 21
was stable, in our case, the strained tricyclic nature of 15 as
well as the presence of the additional nitrogen facilitates the
fragmentation of the 1,3-oxazolidin-5-one unit.
In conclusion, we have shown that 5-dialkylamino-4-pyrrolin-
2-ones, readily available by our amidine-DMAD cycloconden-
sation reactions, exhibit exceptional reactivity toward singlet
oxygen. The 1,2-dioxetane cleavage products from these reac-
tions serve as precursors of uniquely functionalized ureas as
well as 2-oxazolidinones and 2-oxazolinones. The tricyclic
analog 13 (Z and E isomers) exhibits divergent behavior in the
photooxygenation due to strain reasons and undergoes C-C
cleavage followed by rearrangement to large ring heterocycles.
Currently we are investigating the cycloadditions of pyrrolinones
of the type 3 toward a variety of other cycloaddends, and will
shortly disclose our results from these reactions.
Experimental Section
Typical Procedure for the Photooxygenations of 5-Dimethyl-
amino-4-pyrroline-3-ones. A 100 mg (0.35 mmol) portion of 4 was
dissolved in 5 mL of CH2Cl2, 3 mg of the sensitizer (TPP,
tetraphenylporphyrin) was added, and the solution was irradiated
with a 250 W high-pressure Na vapor lamp at -78 °C under a
positive pressure of dry oxygen. The reaction was monitored by
TLC, and in most cases it was over after 20 min of irradiation.
The solvent was rotary evaporated to give a quantitative yield of
the urea 6 (by NMR). Further purification for analytical samples
was achieved by either recrystallization in the case of solid products
or column chromatography on silica gel, eluting with EtOAc/MeOH
(99:1).
Acknowledgment. This work was supported by funds from
the National Institutes of Health, MBRS-SCORE Program-
NIGMS (Grant No. GM52588). We also ackonwledge funding
from the National Science Foundation (DBI 05213242 and
DUE-9451624) for the acquisition of the 500 and 300 MHz
NMR spectrometers. Support for the MS analyses was provided
by a grant from the National Science Foundation (Grant No.
CHEM-0619163). We also thank Mr. Wee Tam, SFSU, for
recording most of our NMR spectra.
(21) Adam, W.; Ahnweiler, M.; Sauter, M. Angew. Chem., Int. Ed. 2003,
32, 80.
(22) Adam, W.; Erden, I. Tetrahedron Lett. 1979, 20, 1975.
(23) Schaap, A. P.; Burns, P. A.; Zaklika, K. A. J. Am. Chem. Soc. 1977,
99, 1270.
(24) LeRoux, J. P.; Goasdoue, C. Tetrahedron 1975, 31, 2761.
(25) Schaap, A. P.; Zaklika, K. A. In Singlet Oxygen; Wasserman, H. H.,
Murray, R. W. Eds.; Academic Press: New York, NY, 1979; pp 173-242.
(26) Orito, K.; Manske, R. H.; Rodrigo, R. J. Am. Chem. Soc. 1974, 96,
1944.
Supporting Information Available: Synthetic procedures;
analytical and spectral data for the ureas 6e-f, 2-oxazolidinones
9a-d, 2-oxazolinones 11a-c, and compounds 12a, 13a,b, 18
and 19; and X-ray crystallography data for 6a. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO801192Z
J. Org. Chem. Vol. 73, No. 17, 2008 6945