A facile CAN-mediated transformation of acetoacetamides to oxamates

Full text of DOI:10.1021/jo9904359

6
898
J . Org. Chem. 1999, 64, 6898-6900
A F a cile CAN-Med ia ted Tr a n sfor m a tion of
Acetoa ceta m id es to Oxa m a tes†
dimerization reactions of 1,3-dicarbonyl compounds have
been reported. The reaction requires 2 equiv of CAN,
14
and on using 1 equiv of CAN only half of the starting
material was consumed. A number of other acetoacetani-
lides were subjected to the CAN oxidation under oxygen-
ated conditions, and in all cases the oxamate was
obtained in high yields. The results are summarized in
Scheme 2.
Vijay Nair* and V. Sheeba
Organic Chemistry Division, Regional Research Laboratory,
Trivandrum-19, India
Received March 10, 1999
In tr od u ction
Sch em e 2
Carbon-carbon bond-forming reactions mediated by
one-electron oxidants have been of considerable topical
interest.1 Early investigations by Heiba and Dessau,
-4
5
6
,7
Baciocchi, and the more recent studies in our labora-
tory8 and elsewhere have convincingly demonstrated
that cerium(IV) ammonium nitrate (CAN) is an excep-
tionally useful reagent for accomplishing intermolecular
C-C bond formation. In this context, it was of interest
to probe the usefulness of CAN in intramolecular reac-
tions. With this objective and with the expectation that
an oxindole derivative 2 would result from acetoacet-
anilide 1, the latter was treated with CAN in methanol.
Surprisingly, no cyclization occurred, and instead the
corresponding oxamate 3 was obtained as the only
isolable product in 51% yield.
-12
13
It appears that acetoacetamides derived from aliphatic
amines are also susceptible to the oxidative transforma-
tion. For instance, cyclohexyl acetoacetamide when treated
with CAN under the conditions described above trans-
formed smoothly into the oxamate in 88% yield. A similar
result was obtained with benzyl acetoacetamide also
Sch em e 1
(Scheme 3). All the new compounds were characterized
on the basis of spectral and analytical data.
Sch em e 3
Although the expected reaction did not occur, the
facility of formation of the oxamate 3 prompted us to
examine the generality of the reaction from the vantage
point of using it as a synthetic method for oxamates.
Resu lts a n d Discu ssion s
With the reasonable assumption that oxygen takes part
in the reaction leading to the oxamate 3, the reaction of
1
with CAN was repeated in an atmosphere of oxygen.
In this case, the yield of the oxamate increased to 70%.
When the experiment was performed in the absence of
oxygen, oxamate formation was not observed; instead, a
product identified as a dimer of 1 was isolated. Similar
A mechanistic rationale for the transformation de-
scribed here may be presented as in Scheme 4. Oxidation
Sch em e 4
*
To whom correspondence should be addressed. Fax: +91-471-
4
91712. E-mail: gvn@csrrltrd.ren.nic.in.
†
This paper is dedicated with best regards to Professor Edward Piers
on the occasion of his 60th birthday.
(
(
(
(
(
(
(
(
(
(
(
1) Dalko, P. I. Tetrahedron 1995, 51, 7579.
2) Snider, B. B. Chem. Rev. 1996, 96, 339.
3) Melikyan, G. G. Synthesis 1993, 833.
4) Iqbal, J .; Bhatia, B.; Nayyar, N. K. Chem. Rev. 1994, 94, 519.
5) Heiba, E. I.; Dessau, R. M. J . Am. Chem. Soc. 1972, 94, 2888.
6) Baciocchi, E.; Ruzziconi, R. J . Org. Chem. 1986, 51, 1645.
7) Baciocchi, E.; Casu, A.; Ruzziconi, R. Synlett 1990, 679.
8) Nair, V.; Mathew, J .; Prabhakaran, J . Chem. Soc. Rev. 1997, 127.
9) Nair, V.; Mathew, J . J . Chem. Soc., Perkin Trans. 1 1995, 187.
10) Nair, V.; Mathew, J . J . Chem. Soc., Perkin Trans. 1 1995, 1881.
11) Nair, V.; Mathew, J .; Radhakrishnan, K. V. J . Chem. Soc.,
Perkin Trans. 1 1996, 1487.
12) Nair, V.; Mathew, J .; Kanakamma, P. P.; Panicker, S. B.;
Sheeba, V.; Zeena, S.; Eigendorf, G. K. Tetrahedron Lett. 1997, 38,
(
of the dicarbonyl system by CAN would conceivably lead
to the radical 6. The latter can trap oxygen leading to
15
2
191.
(
13) Linker, T.; Sommermann, T.; Kahlenberg, F. J . Am. Chem. Soc.
1
997, 119, 9377.
(14) Cho, L. Y.; Romero, J . R. Tetrahedron Lett. 1995, 36, 8757.
1
0.1021/jo9904359 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/04/1999

Notes
J . Org. Chem., Vol. 64, No. 18, 1999 6899
the hydroperoxide 8, which in turn can yield the dioxet-
ane 9. Fragmentation of the dioxetane to the aldehyde
and oxidation of the latter in methanol can ultimately
lead to the oxamate. The peroxy radical 7, in principle,
can abstract a hydrogen from the substrate, thus allowing
a catalytic cycle to operate. However, there is no evidence
for a catalytic process, and it has been confirmed that 2
equiv of CAN is required for the completion of the
reaction. In experiments using less than 2 equiv of CAN,
a proportionate amount of substrate remains unchanged.
This may be rationalized by invoking the possibility that
the peroxy radical is more likely to abstract the C-H
proton from methanol, in a process assisted by CAN that
is known to form a complex with methanol.16
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Oxa m a t e
3a ). To a solution of 1a (500 mg, 2.82 mmol) in methanol
saturated with oxygen was added an oxygenated solution of CAN
3.86 g, 7.05 mmol) in methanol while the reaction mixture was
(
(
continuously being purged with oxygen. After 15 min, the
reaction mixture was diluted with distilled water, extracted with
dichloromethane (3 × 30 mL), washed with saturated brine, and
dried over sodium sulfate. The residue obtained after the
removal of solvent was chromatographed on a silica gel column
to afford a white crystalline solid.
Sp ectr a l d a ta of m eth yl N-p h en yloxa m a te28 (3a ): white
crystals; recrystallized from CH
2
Cl
2
-hexane; mp 111-113 °C;
-1
1
IR (KBr) νmax 3351, 1708 cm ; H NMR (CDCl -CCl , v/v, 3:1)
3
4
δ 8.889 (s, 1H, NH), 7.660-7.633 (d, 2H, J ) 8.1 Hz, ArH),
7.415-7.363 (m, 2H, ArH), 7.229-7.204 (m, 1H, ArH), 3.981 (s,
3H, OCH ); 13C NMR (CDCl -CCl , v/v, 3:1) δ 161.449, 153.779,
3
3
4
+
1
1
36.355, 129.166, 125.546, 119.983, 53.953; EIMS m/z M
Such oxidative fragmentation of 1,3-dicarbonyl systems
79.17.
is well precedented.1
7,18
Meth yl N-(4-m eth ylp h en yl)oxa m a te (3b): white crystals,
recrystallized from CH Cl -hexane; mp 145-147 °C; IR (KBr)
νmax 3337, 1729, 1700 cm ; H NMR (CDCl -CCl , v/v, 3:1) δ
The potential application of the reaction as a synthetic
method for oxamates is worthy of note. It may be recalled
that the existing methods for the synthesis of oxamates,
2
2
-
1
1
3
4
8.874 (s, 1H, NH), 7.542-7.514 (d, 2H, J ) 8.3 Hz, ArH), 7.184-
7
.158 (d, 2H, J ) 8 Hz, ArH), 3.954 (s, 3H, OCH
3
), 2.334 (s, 3H,
, v/v, 3:1) δ 161.523, 153.348,
viz., (i) carbonylation of amino alcohols using Pd (II)
1
3
catalyst,19 (ii) reaction of amines with oxalyl chloride,20,21
ArCH
3
); C NMR (CDCl
3
-CCl
4
1
35.123, 133.817, 129.620, 119.789, 53.753, 20.920. Anal.Calcd
for C10 : C, 62.15; H, 5.74; N, 7.25. Found: C, 62.17; H,
.49; N, 7.2.
Meth yl N-(4-m eth oxyp h en yl)oxa m a te (3c): white crystals,
recrystallized from CH Cl -hexane; mp 145-147 °C; IR (KBr)
max 3353, 3332, 1729, 1697, 1547 cm ; H NMR (CDCl
v/v, 3:1) δ 8.861 (s, 1H, NH), 7.581-7.551 (d, 2H, J ) 8.88 Hz,
),
, v/v, 3:1) δ
61.623, 157.184, 153.242, 129.274, 121.369, 114.303, 55.349,
2
2
and (iii) reaction of trichloroacetyl chloride or diisopro-
pyl oxalate,23 all have certain limitations. It is therefore
anticipated that the present method may serve as an
alternative in the synthesis of oxamates. It is noteworthy
H
11NO
3
5
2
2
-
1 1
ν
3
4
-CCl ,
that oxamate functionality is present in a number of
therapeutically important compounds.2
4,25
In addition,
ArH), 6.909-6.879 (d, 2H, J ) 8.9 Hz, ArH), 3.946 (s, 3H, OCH
3
oxamates serve as key intermediates in the synthesis of
1
3
3
1
.799 (s, 3H, ArOCH
3
); C NMR (CDCl
3
-CCl
4
bioactive 2,3-diketopiperazines.26
In conclusion, we have uncovered a facile conversion
of acetoacetamides to oxamates that may serve as a
convenient alternative to at least some of the conven-
tional procedures for the latter.
53.827. Anal. Calcd for C10H11NO : C, 57.41; H, 5.3; N, 6.7.
Found: C, 57.51; H, 5.1; N, 6.68.
Meth yl N-(4-ch lor op h en yl)oxa m a te (3d ): white crystals,
4
recrystallized from CH
2
Cl
2
-hexane; mp 164-166 °C; IR (KBr)
-
1 1
ν
max 3349, 1745, 1690, 1599 cm ; H NMR (CDCl
:1) δ 8.885 (s, 1H, NH), 7.622-7.592 (d, 2H, J ) 8.8 Hz, ArH),
3
4
-CCl , v/v,
3
13
Exp er im en ta l Section
7.336-7.326 (d, 2H, J ) 8.8 Hz, ArH), 3.975 (s, 3H, OCH
NMR (CDCl
3
);
C
3
4
-CCl , v/v, 3:1) δ 161.303, 153.455, 134.862,
1
Gen er a l Meth od s. NMR spectra were recorded at 300 ( H)
1
30.794, 129.349, 121.041, 54.068. Anal. Calcd for C
C, 50.6; H, 3.77; N, 6.56. Found: C, 50.77; H, 3.56; N 6.53.
Meth yl N-(2-m eth ylp h en yl)oxa m a te (3e): white crystals,
recrystallized from CH Cl -hexane; mp 76-78 °C; IR (KBr) νmax
9 8 3
H NO Cl:
1
3
and 75 ( C) MHz. Chemical shifts are reported (δ) relative to
1
13
3
TMS ( H) and CDCl ( C) as the external standards. Mass
spectra were recorded under EI/HRMS (at 5000 resolution) using
an Auto Spec. M mass spectrometer. Column chromatography
was performed on silica gel (100-200 mesh). Solvents were
distilled prior to use. The CAN used for the reactions was
purchased from Aldrich Co. and was used without purification.
Substituted acetoacetamides except 1a and 1g were prepared
2
-1
2
1
3
(
7
382, 1716, 1535 cm ; H NMR (CDCl
s, 1H, NH), 8.019-7.993 (d, 1H, J ) 7.86 Hz, ArH), 7.279-
.204 (m, 2H, ArH), 7.151-7.128 (d, 1H, J ) 7.05 Hz, ArH), 3.977
3
-CCl
4
, v/v, 3:1) δ 8.83
13
(
s, 3H, OCH
v/v, 3:1) δ 161.765, 153.565, 134.427, 130.690, 128.307, 127.182,
11
26.000, 121.792, 54.036, and 17.596; HRMS calcd for C10H -
3
), 2.328 (s, 3H, ArOCH
3
); C NMR (CDCl
3
-CCl
4
,
2
7
from substituted amines. 1a and 1g were purchased from E.
Merck. Co.
1
+
+
NO
93 (45).
Meth yl N-(2-m eth oxyp h en yl)oxa m a te (3f): white crystals,
recrystallized from CH Cl -hexane; mp 72-74 °C; IR (KBr) νmax
391, 1785, 1713 cm ; H NMR (CDCl -CCl , v/v, 3:1) δ 9.483
s, 1H, NH), 8.420-8.390 (dd, 1H, J ) 7.9 Hz, J ) 1.1 Hz ArH),
3
193.073893, found 193.075254; EIMS M + 1 194 (5), M
1
(
15) Nair, V.; Mathew, J .; Nair. L. G. Synth. Commun. 1996, 26,
4
531.
2
2
(
(
16) DuttaGupta, A.; Singh, R.; Singh, V. K. Synlett 1996, 69.
17) Brimble, M. A.; Elliott, R. J . R.; Turner, P. Tetrahedron 1998,
-1 1
3
3
4
(
5
4, 14053.
18) (a) Feringa, B. L.; Butselaar, R. J . Tetrahedron Lett. 1983, 24,
193. (b) Adam, W.; Catalini, L. H.; Saha-Moller, C. R.; Will, B.
7
6
.135-7.109 (m, 1H, ArH), 7.025-6.999 (m, 1H, ArH), 6.934-
), 3.923 (s, 3H,
, v/v, 3:1) δ 161.352, 153.429,
(
.907 (d, 1H, J ) 8 Hz, ArH), 3.97 (s, 3H, OCH
3
1
1
3
Synthesis 1989, 121.
19) (a) Murahashi, S.; Mitsue, Y.; Ike, K. J . Chem. Soc., Chem.
Commun. 1987, 125. (b) Fenton, D. M.; Steinwand, P. J . J . Org. Chem.
974, 39, 701. (c) Tam, W. J . Org. Chem. 1986, 51, 2977. (d) Pri-bar,
I.; Alper, H. Can. J . Chem. 1990, 68, 1544.
20) (a) Sokol, P. E. Org. Synth. 1964, 44, 69. (b) Psiorz, M.; Schmid,
R. Chem. Ber. 1987, 120, 1825.
21) (a) Stoffel, P. J . J . Org. Chem. 1964, 29, 2794. (b) McDonald,
R. N. J . Org. Chem. 1959, 24, 1580.
22) Richardson, A. G.; Pierce, J . S.; Ried, E. E. J . Am. Chem. Soc.
952, 74, 4011.
23) Neveux, M.; Bruneau, C.; Lecolier, S.; Dixneuf, P. H. Tetrahe-
dron 1993, 49, 2629.
24) Yokoyama, N.; Walker, G. N.; Main, A. J .; Stanton, J . L.;
OCH
3
); C NMR (CDCl
3
-CCl
4
(
148.490, 126.037, 125.374, 121.107, 119.973, 110.146, 55.813,
5
C H11NO
10 4
+
+
3.925; EIMS M + 1 210 (38) M 209 (100). Anal. Calcd for
1
: C, 57.4; H, 5.3; N, 6.7. Found: C, 56.99; H, 5.32; N,
6
.08.
Meth yl N-(2-ca r bom eth oxyp h en yl)oxa m a te (3g): white
crystals, recrystallized from CH Cl -hexane; mp 150-152 °C;
(
(
2
-
2
1 1
IR KBr νmax 3259, 1729, 1702 cm ; H NMR (CDCl
3
-CCl
4
, v/v,
(
3
:1) δ 12.591 (s, 1H, NH), 8.761-8.733 (d, 1H, J ) 8.25 Hz, ArH),
1
(
(27) Amine was taken in dry xylene along with 2,2,6-trimethyl-1,3-
(
dioxin-4-one and refluxed at 140 °C for 3 h. The reaction mixture was
chromatographed on a silica gel column to afford the acetoacetamide
in quantitative yield. Wentrup, C.; Heilmayer, W.; Kollenz, G. Synthesis
1994, 1219 and the references therein.
(28) Izawa, Y.; Ishiguro, K.; Tomioka, H. Bull. Chem. Soc., J pn.
1983, 56, 951.
Morrissey, M. M.; Boehm, C.; Engle, A.; Neubert, A. D.; Wasvary, J .
M.; Stephan, Z. F.; Steele, R. E. J . Med. Chem. 1995, 38, 695.
(
25) Kees, K. L.; Musser, J . H.; Chang, J .; Skowronek, M.; Lewis,
A. J . J . Med. Chem. 1986, 29, 2329.
26) Dinsmore, C. J .; Bergman, J . M. J . Org. Chem. 1998, 63, 4131.
(

6
900 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
8
1
.098-8.068 (dd, 1H, J ) 1.2, 7.9 Hz, ArH), 7.637-7.581 (m,
32.657, 25.447, 24.720; HRMS calcd for C
found 185.106430; M 185 (2.3).
9
H
15NO
3
185.105194,
+
H, ArH), 7.218-7.165 (m, 1H, ArH), 4.00 (s, 3H, OCH
3
), 3.985
, v/v, 3:1) δ 168.067,
61.060, 154.335, 139.638, 134.708, 131.086, 123.993, 120.593,
16.221, 53.858, 52.592. Anal. Calcd for C NO : C, 55.7; H,
.67; N, 5.9. Found: C, 55.69; H, 4.71; N, 6.04.
Meth yl N-(3-br om op h en yl)oxa m a te (3h ): white crystals,
recrystallized from CH Cl -hexane; mp 110-111 °C; IR (KBr)
1
3
(s, 3H, OCH
3
); C NMR (CDCl
3
-CCl
4
Meth yl N-ben zyloxa m a te (5b): white crystals, recrystal-
lized from CH Cl -hexane; mp 116-118 °C; IR (KBr) νmax 3270,
2952, 1738, 1682 cm ; H NMR (CDCl
(s, 1H, NH), 7.371-7.265 (m, 5H, ArH), 4.522-4.502 (d, 2H, J
1
1
4
2
2
-
1 1
9
H
8
5
3
4
-CCl , v/v, 3:1) δ 7.395
1
3
) 6 Hz, CH
2
NH), 3.890 (s, 3H, OCH
3
); C NMR (CDCl
3
4
-CCl ,
2
2
-
v/v, 3:1) δ 161.120, 156.070, 136.728, 128.874, 127.960, 53.409,
1 1
ν
8
7
max 3337, 1729, 1706, cm ; H NMR (CDCl
.881 (s, 1H, NH), 7.850 (s, 1H, ArH), 7.610-7.584 (d, 1H, J )
.7 Hz, ArH), 7.335-7.214 (m, 2H, ArH), 3.794 (s, 3H, OCH );
, v/v, 3:1) δ 161.319, 153.591, 137.640,
30.643, 128.729, 123.008, 122.895, 118.420, 104.907,54.205;
3
-CCl
4
, v/v, 3:1) δ
43.956.
Ack n ow led gm en t. V.S. thanks the CSIR for Senior
Research Fellowship. Thanks are due to Mr. C. Sree-
kumaran Nair, VSSC, for elemental analyses, Dr. G.
Anilkumar, University of Nijmegen, The Netherlands,
for mass spectra, and Saumini Mathew for spectral
data.
3
1
3
C NMR (CDCl
3
-CCl
4
1
+
+
LRMS M + 2 259 (80), M 257 (77); HRMS (EI) calcd for C
NO Br 258.966708, found 258.966958.
Meth yl N-cycloh exyloxa m a te (5a ): white crystals, recrys-
tallized from CH Cl -hexane; mp 77-79 °C; IR (KBr) νmax 3267,
935, 2854, 1742 cm ; H NMR (CDCl
s, 1H, NH), 3.894 (s, 3H, OCH ), 3.843-3.744 (m, 1H, >CHNH),
), 1.774-1.629 (m, 3H, CH ), 1.461-
9 8
H -
3
2
2
-
1 1
2
(
1
1
3
4
-CCl , v/v, 3:1) δ 6.963
Su p p or tin g In for m a tion Ava ila ble: Copies of carbon
NMR spectra of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
3
.969-1.930 (m, 2H, CH
.340 (m, 2H, CH ), 1.293-1.138 (m, 3H, CH
-CCl , v/v, 3:1) δ 161.555, 155.211, 53.491, 48.901,
2
2
1
3
2
2
); C NMR
(CDCl
3
4
J O9904359