New Perspectives in Oxazole Chemistry. 2. One-Pot Efficient Access to Polyfunctionalized Nitroenamines by Nucleophilic Ring Opening of 4-Nitro Derivatives

Full text of DOI:10.1021/jo9804893

6050
J . Org. Chem. 1998, 63, 6050-6052
Sch em e 1
New P er sp ectives in Oxa zole Ch em istr y.
2.1 On e-P ot Efficien t Access to
P olyfu n ction a lized Nitr oen a m in es by
Nu cleop h ilic Rin g Op en in g of 4-Nitr o
Der iva tives
Rodolfo Nesi,* Donatella Giomi,* and Stefania Turchi
Dipartimento di Chimica Organica “Ugo Schiff”, Centro di
Studio del CNR sulla chimica e la struttura dei composti
eterociclici e loro applicazioni, Universita` di Firenze,
Via Gino Capponi 9, I-50121 Firenze, Italy
Sch em e 2
Received March 13, 1998
In tr od u ction
The use of heterocycles in organic synthesis has
impressively grown over the past decades,2 and in this
respect, aromatic oxazoles emerged as excellent synthons
in diverse standard protocols.3 Valuable heterodienes for
the preparation of pyridine and furan products with
alkenes and alkynes, respectively,4 they were also widely
employed as masked acylating agents for the build-up of
macrocyclic lactones, through the oxazole-triamide rear-
rangement with singlet oxygen.5
After a systematic investigation on the cycloaddition
chemistry of 4-nitroisoxazoles,6 we more recently focused
our attention on the corresponding oxazoles, and obtain-
ment of the 4-nitro-2-phenyl derivative 4 paved the way
for an evaluation of the synthetic potentialities of this
unexplored system. Although a remarkable activation
of the C(4)dC(5) double bond by the NO2 group enabled
4 to enter as a very reactive partner into hitherto
unknown, normal [2 + 4] cycloadditions with several 4π
counterparts, a quite different reaction course was ob-
served with 6-[(dimethylamino)methylene]amino-1,3-
dimethyluracil, involving a polyfunctionalized nitroalk-
ene as key intermediate.1
Resu lts a n d Discu ssion
Since conversion of 4-nitro-3-phenylisoxazole (1) into
4 with a trace amount of concentrated HCl in xylene at
155 °C suffered from a modest absolute yield (29%) and
recycling of the unreacted starting material rested on a
tedious chromatographic workup,1 we repeatedly tried to
improve this procedure.
When thermolysis was carried out under the same
conditions but the above catalyst was replaced with the
anhydrous FeCl3-SiO2 reagent, previously employed as
an effective Lewis acid for different purposes,8 compound
1 completely disappeared after 35 h and the desired
product 4 was easily isolated in 42% yield; furthermore,
we succeeded in this way in obtaining for the first time
in reasonable yields (54% and 44%) the difunctionalized
nitrooxazoles 5 and 6 from the corresponding isomers 2
and 3, respectively (Scheme 1).
In light of this finding and bearing in mind the role of
nitroenamines in both theoretical and synthetic studies,7
we decided to gain better insight into the possibility of
exploiting the same system as a source of the title
compounds with primary and secondary amines.
(1) Part 1: Nesi, R.; Turchi, S.; Giomi, D. J . Org. Chem. 1996, 61,
7933.
(2) (a) Kozikowski, A. P. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, U.K., 1984;
Vol. 1, Chapter 16. (b) Lipschutz, B. H. Chem. Rev. 1986, 86, 795. (c)
Ho, T.-L. Symmetry: A Basis for Synthesis Design; Wiley: New York,
1995; Chapter 9.
(3) (a) Maryanoff, B. E. Oxazoles, The Chemistry of Heterocyclic
Compounds; Turchi, I. J ., Ed.; Wiley: New York, 1986; Vol. 45, Chapter
5. (b) Hartner, F. W., J r. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon:
Oxford, U.K., 1996; Vol. 3, p 271.
(4) Boger, D. L.; Weinreb, S. N. Hetero Diels-Alder Methodology in
Organic Synthesis; Academic Press: New York, 1987; p 301.
(5) Wasserman, H. H.; McCarthy, K. E.; Prowse, K. S. Chem. Rev.
1986, 86, 845.
(6) Turchi, S.; Giomi, D.; Nesi, R.; Paoli, P. Tetrahedron 1995, 51,
7085, and references therein.
Treatment of 4 with a very small excess of propylamine
(7a ) and phenethylamine (7b) in chloroform at room
temperature afforded almost quantitatively the nitro-
enamines 10a and 10b through a nucleophilic attack at
position 5, followed by ring cleavage of the resulting
dipolar oxazolines 8a and 8b, respectively (Scheme 2).
While compounds 5 and 6 gave complex mixtures of
inseparable products with the same reagents, very clean
reactions of the three nitrooxazoles 4-6 with pyrrolidine
(11a ) allowed us to isolate the enamines 12-14 in 97-
98% yields (Scheme 3); noteworthily, a total selectivity
was now observed for the interaction of 11a on the
(7) (a) Rajappa, S. Tetrahedron 1981, 37, 1453. (b) Perekalin, V. V.;
Lipina, E. S.; Berestovitskaja, V. M.; Efremov, D. A. In Nitroalkenes.
Conjugated Nitro Compounds; Wiley: New York, 1994; p 210. (c)
Chiara, J . L.; Gomez-Sanchez, A. In The chemistry of enamines;
Rappoport, Z., Ed.; Wiley: New York, 1994; Part 2, Chapter 5.
(8) For
a few typical examples, see: (a) Fadel, A.; Salau¨n, J .
Tetrahedron 1985, 41, 413. (b) Fadel, A.; Salau¨n, J . Tetrahedron 1985,
41, 1267. (c) Fadel. A.; Yefsah, R.; Salau¨n, J . Synthesis 1987, 37.
S0022-3263(98)00489-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/25/1998

Notes
J . Org. Chem., Vol. 63, No. 17, 1998 6051
F igu r e 1.
Sch em e 3
F igu r e 2.
F igu r e 3.
remarkably electrophilic C-5 ring carbon of the nitroester
5. The growing interest in chiral nitroenamines as
attractive substrates for enantioselective reactions9
prompted us to test the reactivity of the above oxazoles
toward (S)-2-methoxymethylpyrrolidine (SMP) (11b);
these reactions, too, gave very satisfactory results and
the desired products 15-17 were obtained in excellent
yields (Scheme 3).
The structures of the new nitro compounds 5, 6, 10a ,b,
and 12-17 were determined from analytical and spectral
evidence (Experimental Section). Particularly, upon
going from 4-6 to the open-chain derivatives, the IR NO2
stretching vibrations at 1530-1570 and 1360-1374 cm-1
were replaced by strong absorptions at 1208-1261 cm-1
for the nitronate moiety;10 in addition, whereas the IR
patterns of the latter were also characterized by the
“enamine band” at 1570-1655 cm-1, the corresponding
13C NMR spectra showed resonances at δ 115.2-118.6
for the C-2 carbons, strongly shielded by the push-pull
electron drift (Figure 1).
F igu r e 4.
for the most crowded benzoyl derivative 14, involving
both E and Z isomers; the E configuration, firmly
established for 12 on the basis of the diagnostic12 H-1
value (δ ) 8.66) also appeared to be preferred for the
nitro ester 13, better ensuring an effective delocalization
between amino and nitro groups.
Replacement of pyrrolidine with the asymmetrical
SMP well accounts for the existence of compound 15 in
two forms (ca. 50%) arising from a common E configu-
ration with different conformations around the C(1)-N
bond (Figure 3), as supported by the presence of two
singlets of comparable intensities at δ 8.62 and 8.65 for
the olefinic proton. Whereas a conformational equilib-
rium between similar forms can be also taken into
consideration for the ester 16, giving rise to a severe
The stereochemical behavior of the nitroenamines,
1
inferred from their H and 13C NMR spectra, was notably
broadening for some H and 13C resonances, the presence
1
influenced by the nature of the substituents at position
1. Compounds 10a ,b, containing a secondary amino
group, were shown to exist as mixtures of E,E and Z,E
isomers (Figure 2),11 whose proportions (ca. 5:1) were
deduced from the relative intensities of the amide NH
singlets at δ 9.57-9.80; on the other hand, while the
predominant forms are characterized by doublets at δ
8.50 and 8.43, respectively, for the more deshielded H-1
protons,12 the corresponding signals of the minor ones
were evidenced at lower frequencies (δ 7.55 and 7.57) by
HETCOR experiments with the C-1 resonances at δ
146.8-149.0. With regard to the pyrrolidino enamines,
partial duplications of NMR signals were only observed
of both E and Z configurations for 17 is strongly sug-
gested by its 13C NMR pattern showing well-resolved
triads of signals for different carbons (Experimental
Section).
In conclusion, a satisfactory preparation has been
accomplished for the 4-nitrooxazoles 4-6 that can be
regarded as attractive synthetic equivalents of the ni-
trovinyl cations 18-20 (Figure 4), for a new simple and
efficient access to polyfunctionalized nitroenamine sys-
tems by ring opening with amine nucleophiles.
Exp er im en ta l Section 13
Th er m a l Isom er iza tion of th e Nitr oisoxa zoles 1-3 in to
th e Oxa zoles 4-6. Gen er a l P r oced u r e. A mixture of the
(9) Fuji, K.; Node, M. Synlett 1991, 603.
(10) Reference 7b, p 220.
(11) The symbols indicate, in the order shown, the “configuration”
around the C(1)dC(2) double bond and the “conformation” around the
C(1)-N single bond.
(12) Ostercamp, D. L.; Taylor, P. J . J . Chem. Soc., Perkin Trans. 2
1985, 1021.
(13) Instruments and general techniques are described in ref 1. The
NMR spectra of the nitrooxazoles and nitroenamines were recorded
in CDCl3 and DMSO-d6 solutions, respectively. The values in square
brackets refer to the most evident resonances of the minor isomer(s).

6052 J . Org. Chem., Vol. 63, No. 17, 1998
Notes
nitroisoxazole (1 mmol) and the anhydrous FeCl3-SiO2 reagent8a
(0.010 g) in xylene (3 mL) was stirred in a screw-capped tube
(Pyrex N. 18) at 155 °C until the starting material disappeared
(TLC, 1H NMR). After dilution with dichloromethane (5 mL)
and removal of the catalyst by filtration, the residue left by
evaporation to dryness was subjected to flash chromatography
with petroleum ether/ethyl acetate (10:1 v/v) as eluent.
A. The reaction product from the thermolysis of 1 (35 h) gave
compound 4 (Rf ) 0.32, 0.080 g, 42%), identical with a specimen
previously described.1
crystallized from ether as yellow needles: mp 148-149 °C; IR
3341, 1746, 1667, 1586, and 1252 cm-1 1H NMR δ 1.80-1.92
;
(m, 4H), 3.25-3.46 (br m, 2H), 3.52-3.74 (br m, 2H), 3.89 (s,
3H), 7.50-7.70 (m, 3H), 7.93-8.02 (m, 2H), 10.05 (s, 1H); 13C
NMR δ 24.8 (sbr t), 50.9 (sbr t), 53.5 (q), 117.7 (s), 128.1 (d),
129.0 (d), 132.6 (d), 133.0 (s), 147.7 (s), 162.7 (s), 167.1 (s). Anal.
calcd for C15H17N3O5: C, 56.42; H, 5.37; N, 13.16. Found: C,
56.38; H, 5.60; N, 12.87.
E. Treatment of 6 with 11a afforded 1-benzoyl-2-benzoy-
lamino-2-nitro-1-(pyrrolidin-1-yl)ethylene (14) (0.179 g, 98%): an
analytical sample, obtained as ivory-colored needles by crystal-
lization from acetone, gradually darkened above 185 °C and
melted with decomposition at 198 °C; IR 3314, 1665, 1578, and
1261 cm-1; 1H NMR δ 1.80-1.98 (vbr s), 3.0-3.18 (vbr s), 3.30-
3.55 (vbr m), 3.78-3.98 (vbr s), 7.55-7.78 (m), 7.98-8.08 (m),
8.25-8.33 (m), [10.18 (sbr s)], 10.24 (sbr s); 13C NMR δ 24.8 (br
t), 51.2 (br t), 118.4 (s), [118.6 (s)], 127.8 (d), 128.0 (d), 128.2 (d),
128.25 (d), 129.0 (d), 129.6 (d), 132.6 (d), 132.7 (d), 132.8 (s),
133.1 (s), 134.3 (d), 134.4 (d), 134.45 (s), 134.6 (s), [153.3 (s)],
153.45 (s), [167.0 (s)], 167.3 (s), [186.2 (s)], 186.7 (s). Anal. calcd
for C20H19N3O4: C, 65.74; H, 5.24; N, 11.50. Found: C, 65.50;
H, 5.30; N, 11.60.
B. Chromatographic workup of the crude product from 2 (38
h) afforded methyl 4-nitro-2-phenyloxazole-5-carboxylate (5) (Rf
) 0.25, 0.135 g, 54%) that was crystallized from ether as yellow
needles: mp 139-140 °C; IR 1739, 1534, and 1366 cm-1 1H
;
NMR δ 4.03 (s, 3H), 7.48-7.61 (m, 3H), 8.13-8.18 (m, 2H); 13
C
NMR δ 53.4 (q), 124.3 (s), 127.6 (d), 129.1 (d), 133.05 (d), 134.9
(s), 148.5 (s), 155.5 (s), 160.9 (s). Anal. calcd for C11H8N2O5:
C, 53.23; H, 3.25; N, 11.29. Found: C, 53.46; H, 3.32; N, 11.33.
C. The residue from 3 (48 h) yielded 5-benzoyl-4-nitro-2-
phenyloxazole (6) as a pale yellow solid (Rf ) 0.35, 0.130 g,
44%): mp 133-134 °C (from ethanol); IR 1661, 1523, and 1372
1
cm-1; H NMR δ 7.42-7.78 (m, 6H), 7.92-7.98 (m, 2H), 8.12-
8.19 (m, 2H); 13C NMR δ 124.5 (s), 127.5 (d), 129.1 (d), 129.2
(d), 129.5 (d), 132.9 (d), 134.9 (s), 135.0 (d), 142.5 (s), 147.3 (s),
160.6 (s), 181.2 (s). Anal. calcd for C16H10N2O4: C, 65.31; H,
3.43; N, 9.52. Found: C, 65.56; H, 3.50; N, 9.42.
F . Reaction of 4 with SMP (11b) (0.059 g, 0.063 mL) gave
(E)-2-benzoylamino-1-[(S)-2-methoxymethylpyrrolidin-1-yl]-2-ni-
troethylene (15) (0.148 g, 97%) that was crystallized from ethyl
acetate as pale yellow needles: mp 138-139 °C dec; [R]29
)
D
Syn th esis of th e Nitr oen a m in es 10a ,b a n d 12-17. Gen -
er a l P r oced u r e. A mixture of the nitrooxazole (0.5 mmol) and
the amine (0.51 mmol) in chloroform (1.5 mL) was stirred at
room temperature in a screw-capped tube (Pyrex N. 13) for 24
h. The residue left by removal of the solvent and prolonged
evacuation under reduced pressure was taken up in n-pentane,
filtered, and dried.
(-)12.1 (c 0.925, CHCl3); IR 3277, 1661, 1632, and 1269 cm-1
;
1H NMR δ 1.57-1.75 (br m), 1.78-2.02 (br m), 3.22-3.55 (br
m), 3.32 (s), [3.34 (s)], 3.60-3.78 (br m), 4.03-4.18 (br m), 7.45-
7.65 (m), 7.90-7.98 (m), 8.62 (s), [8.65 (s)], [9.78 (sbr s)], 9.81
(sbr s); 13C NMR δ 23.7 (t), 26.4 (t), [26.6 (t)], 47.7 (t), [48.1 (t)],
58.7 (d), 63.8 (q), 74.3 (t), [74.5 (t)], 118.6 (s), 128.0 (d), 128.8
(d), 132.3 (d), 133.4 (s), 143.1 (d), [166.8 (s)], 167.7 (s). Anal.
calcd for C15H19N3O4: C, 59.01; H, 6.27; N, 13.76. Found: C,
58.83; H, 6.27; N, 14.10.
A. Treatment of 4 with propylamine (7a ) (0.030 g, 0.042 mL)
afforded 2-benzoylamino-2-nitro-1-propylaminoethylene (10a ) as
yellow flakes (0.124 g, 99%): mp 131-132 °C dec (from dichlo-
G. Ring cleavage of 5 with 11b yielded (E)-methyl 3-benzoy-
lamino-2-[(S)-2-methoxymethylpyrrolidin-1-yl]-3-nitroacrylate (16)
as a yellow solid (0.174 g, 96%): an analytical sample, obtained
by crystallization from n-pentane/ether, wrinkled above 70 °C
romethane); IR 3243, 1678, 1655, and 1208 cm-1 1H NMR δ
;
0.88 (t, J ) 7.3 Hz), [0.90 (t, J ) 7.3 Hz)], 1.45-1.70 (m), 3.20-
3.43 (m), 7.42-7.68 (m), 7.85-8.25 (m), 8.50 (d, J ) 14.0 Hz),
9.45-9.58 (br m), 9.60 (s), [9.80 (s)]; 13C NMR δ 10.9 (q), 23.8
(t), 50.2 (t), [50.8 (t)], [115.2 (s)], 118.4 (s), 127.9 (d), 128.3 (d),
128.4 (d), 128.7 (d), 132.0 (d), 132.2 (d), 133.6 (s), 133.85 (s),
147.15 (d), [149.0 (d)], 165.9 (s), [167.2 (s)]. Anal. calcd for
C12H15N3O3: C, 57.82; H, 6.07; N, 16.86. Found: C, 57.56; H,
6.13; N, 16.77.
and melted at 90-91 °C; [R]21 ) (-)68.4 (c 1.85, CHCl3); IR
D
3296, 1741, 1666, 1579, and 1268 cm-1
;
1H NMR δ 1.75-2.08
(br m, 4H), 3.15-3.70 (br m, 4H), 3.42 (sbr s, 3H), 3.87 (sbr s,
3H), 3.95-4.30 (vbr s, 1H), 7.55-7.70 (m, 3H), 7.97-8.02 (m,
2H), 10.16 (br s, 1H); 13C NMR δ 22.7 (sbr t), 27.7 (sbr t), 51.6
(sbr t), 53.4 (q), 58.6 (sbr q), 60.3 (sbr d), 73.4 (vbr t), 119.0 (vbr
s), 128.0 (d), 128.8 (d), 132.5 (d), 132.9 (s), 146.8 (br s), 162.6
(s), 166.9 (vbr s). Anal. calcd for C17H21N3O6: C, 56.19; H, 5.83;
N, 11.56. Found: C, 55.94; H, 6.01; N, 11.84.
B. Reaction of 4 with phenethylamine (7b) (0.062 g, 0.064
mL) gave 2-benzoylamino-2-nitro-1-(2-phenylethylamino)ethyl-
ene (10b) (0.154 g, 99%) that was crystallized from ethanol as
pale yellow needles: mp 124-125 °C; IR 3275, 1676, 1648, and
1210 cm-1; 1H NMR δ 2.81 (t, J ) 7.4 Hz), [2.92 (t, J ) 7.4 Hz)],
3.43-3.70 (m), 7.18-7.38 (m), 7.42-7.65 (m), 7.90-8.05 (m),
8.08-8.22 (br m), 8.43 (d, J ) 14.9 Hz), 9.57 (s), [9.75 (s)]; 13C
NMR δ [36.6 (t)], 36.8 (t), 49.8 (t), [50.3 (t)], [115.2 (s)], 118.3
(s), 126.4 (d), 127.7 (d), 128.1 (d), 128.3 (d), 128.5 (d), 128.6 (d),
128.9 (d), 129.0 (d), 129.3 (d), 131.9 (d), 132.0 (d), 133.4 (s), 133.6
(s), 138.3 (s), 138.4 (s), 146.8 (d), [148.5 (d)], 165.9 (s), [167.1
(s)]. Anal. calcd for C17H17N3O3: C, 65.58; H, 5.50; N, 13.50.
Found: C, 65.39; H, 5.55; N, 13.76.
C. Ring opening of 4 with pyrrolidine (11a ) (0.036 g, 0.042
mL) yielded (E)-2-benzoylamino-2-nitro-1-(pyrrolidin-1-yl)eth-
ylene (12) as a yellow solid (0.128 g, 98%): mp 179 °C dec (from
acetone); IR 3310, 1672, 1634, 1256, and 1217 cm-1; 1H NMR δ
1.72-1.97 (m, 4H), 3.14-3.36 (m, 1H), 3.54-3.76 (m, 3H), 7.50-
7.68 (m, 3H), 7.92-7.99 (m, 2H), 8.66 (s, 1H), 9.81 (s, 1H); 13C
NMR δ 24.1 (t), 25.5 (t), 47.4 (t), 54.9 (t), 118.2 (s), 128.0 (d),
128.9 (d), 132.4 (d), 133.4 (s), 143.5 (d), 167.3 (s). Anal. calcd
for C13H15N3O3: C, 59.76; H, 5.79; N, 16.08. Found: C, 59.41;
H, 5.76; N, 16.37.
H. Treatment of 6 with 11b afforded 1-benzoyl-2-benzoylam-
mino-1-[(S)-2-methoxymethylpyrrolidin-1-yl]-2-nitroethylene (17)
(0.200 g, 98%) that was crystallized from n-pentane/ether as
yellow needles: it gradually wrinkled above 90 °C and melted
at 108-109 °C; [R]22 ) (+)44.5 (c 1.05, CHCl3); IR 3301, 1681,
D
1
1573, and 1254 cm-1; H NMR δ 1.70-1.98 (vbr m), 2.70-3.70
(vbr m), 4.02-4.15 (br m), 7.52-7.78 (sbr m), 7.90-8.10 (sbr m),
8.35-8.42 (br m), [10.15 (sbr s)], 10.30 (sbr s); 13C NMR δ 22.1
(t), [22.3 (t)], [22.7 (t)], 27.4 (br t), [51.7 (sbr t)], 52.3 (t), [58.0
(q)], [58.4 (q)], 58.7 (q), 60.0 (br d), 72.3 (vbr t), [118.6 (s)], 119.1
(s), 127.7 (d), 127.9 (d), 128.0 (d), 128.1 (d), 128.2 (d), 128.85 (d),
128.9 (d), 129.3 (d), 129.6 (d), 132.6 (d), 132.7 (d), 132.9 (s), 133.1
(s), 133.3 (s), 134.2 (d), 134.7 (s), 152.8 (br s), 166.3 (vbr s), [185.8
(s)], [186.3 (s)], 186.9 (s). Anal. calcd for C22H23N3O5: C, 64.54;
H, 5.66; N, 10.26. Found: C, 64.46; H, 5.68; N, 10.47.
Ack n ow led gm en t. We wish to thank Mrs. Brunella
Innocenti for the analytical data. Prof. J acques Salau¨n
is gratefully acknowledged for the fruitful suggestions.
D. Reaction of 5 with 11a gave (E)-methyl 3-benzoylamino-
3-nitro-2-(pyrrolidin-1-yl)acrylate (13) (0.155 g, 97%) that was
J O9804893