Synthesis and characterization of chiral nitronic esters via O-alkylation of (4S*,5R)-(+)-4-(1′-nitro-1′-carbethoxymethyl)-5-[(1R)- menthyloxy]-3,4-dihydro-2(5H)-furanone with alkyl halides

Article abstract of DOI:10.1021/jo951902z

A series of stable and enantiomerically pure alkyl nitronic esters are synthesized in good to excellent yields via O-alkylation of (4S*,5R)-(+)-4-(1′-nitro-1′-carbethoxymethyl)-5-[(1R)- menthyloxy]-3,4-dihydro-2(5H)-furanone (4a) with alkyl halides in the presence of K₂CO₃ and DMF at room temperature. Thus, nitronic esters are obtained for the first time from the alkali metal salt of a nitro compound and various alkyl halides, which refutes the traditionally held view that the reaction of alkyl halides with alkali metal derivatives of nitro compounds gives a carbonyl compound and an oxime, rather than a nitronic ester. Secondary alkyl nitronic esters are found to partially decompose into O-alkyloximes. The configurations of the nitronic esters and O-alkyloximes were assigned to be Z on the basis of the NOE experiments. The synthesis of the nitro furanone 4a and its enolization to form a six-membered intramolecular hydrogen bond structure are described.

Full text of DOI:10.1021/jo951902z

J . Org. Chem. 1996, 61, 5523-5527
5523
Syn th esis a n d Ch a r a cter iza tion of Ch ir a l Nitr on ic Ester s via
O-Alk yla tion of (4S*,5R)-(+)-4-(1′-Nitr o-1′-ca r beth oxym eth yl)-
5-[(1R)-m en th yloxy]-3,4-d ih yd r o-2(5H)-fu r a n on e w ith Alk yl Ha lid es
Fu-An Kang and Cheng-Lie Yin*
Department of Chemistry, Beijing Normal University, Beijing 100875, PRC
Shi-Wang She
Sino-German J oint Institute (J iangxi-OAI), J iangxi 330047, PRC
Received October 25, 1995X
A series of stable and enantiomerically pure alkyl nitronic esters are synthesized in good to excellent
yields via O-alkylation of (4S*,5R)-(+)-4-(1′-nitro-1′-carbethoxymethyl)-5-[(1R)-menthyloxy]-3,4-
dihydro-2(5H)-furanone (4a ) with alkyl halides in the presence of K2CO3 and DMF at room
temperature. Thus, nitronic esters are obtained for the first time from the alkali metal salt of a
nitro compound and various alkyl halides, which refutes the traditionally held view that the reaction
of alkyl halides with alkali metal derivatives of nitro compounds gives a carbonyl compound and
an oxime, rather than a nitronic ester. Secondary alkyl nitronic esters are found to partially
decompose into O-alkyloximes. The configurations of the nitronic esters and O-alkyloximes were
assigned to be Z on the basis of the NOE experiments. The synthesis of the nitro furanone 4a and
its enolization to form a six-membered intramolecular hydrogen bond structure are described.
Sch em e 1a
In tr od u ction
R1R2CHNO2
Nitronic esters are a relatively little studied group of
compounds formally derived from aci-nitro compounds
(or nitronic acids). Nitronic esters have been obtained
mainly by three methods: (1) reaction of nitro compounds
that are comparatively strong acids with diazomethane,1
(2) treatment of the silver salts of nitro compounds with
alkyl iodides,2 utility being strained due to the observed
instability of these silver salts,3 and (3) alkylation of the
alkali metal salts of nitro compounds with trialkyloxo-
nium fluoroborates4 and dimethyl sulfate1a,5 (Scheme 1).
In addition, two special approaches are used for the
preparation of nitronic esters from 2,6-di-tert-butyl-4-
nitro phenol6 and trinitro methyl iodide.7
CH2N2
RI
R1R2C NO2H
M = Ag
R1R2C NO2R
(RO)3BF4
R1R2C NO2–M+
M = K, Na
(CH3)2SO4
R3R4CHX
R1R2C NOH + R3COR4
a
R1, R2, R3, R4 ) H, alkyl, aryl.
product.9 Indeed, this is a widely accepted method for
the synthesis of aldehydes and ketones10 (Scheme 1).
Given the scarcity of silver and the inconvenience of
using diazomethane, trialkyloxonium fluoroborates, and
dimethyl sulfate, it seems ideal to prepare nitronic esters
from alkali metal salts of nitro compounds and alkyl
halides. The application of alkyl halides to this alkyla-
tion has thus been a matter of considerable research.
Unfortunately, it seems that all of the attempts have
failed to produce a nitronic ester but rather gave an
oxime and a carbonyl compound,8 or a C-alkylated
Recently, during the study of an asymmetric synthesis
of a natural product, we synthesized a key intermediate,
the nitro furanone 4a , which is obtained by a three-step
procedure from furfural (Scheme 2).
In an attempt to obtain a chiral nitro compound (C-
alkylated product), we treated 4a with 1-bromobutane
in the presence of K2CO3 and DMF. A white crystalline
substance was eventually afforded, which to our surprise
was not the expected tertiary nitro compound but was
characterized as a butyl nitronic ester of 4a (O-alkylated
product) by its IR, 1H NMR, 13C NMR spectra and
elemental analysis (Figure 1).
We thus obtained an enantiomerically pure nitronic
ester, which was the first example of a nitronic ester
produced via O-alkylation of the alkali metal salt of a
nitro compound with an alkyl halide. Subsequently, we
prepared a series of chiral nitronic esters of 4a . The
yields ranged between 63 and 96% (Table 1).
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) (a) Arndt, F.; Rose, J . D. J . Chem. Soc. 1935, 1. (b) Shechter, H.;
Conrad, F. J . Am. Chem. Soc. 1954, 76, 2716. (c) Severin, T.; Bruck,
B. Chem. Ber. 1965, 98, 3847. (d) Meek, J . S.; Fowler, J . S.; Monroe,
P. A.; Clark, T. J . J . Org. Chem. 1968, 33, 223.
(2) (a) Parker, C. O.; Emmons, W. D.; Pagano, A. S. Tetrahedron
1962, 17, 89. (b) Reich, W. S.; Rose, G. G.; Wilson, W. J . Chem. Soc.
1947, 1234. (c) Thurston, J . T.; Shriner, R. L. J . Org. Chem. 1937, 2,
183. (d) Severin, T.; Bruck, B.; Adhikary, P. Chem. Ber. 1966, 99, 3097.
(e) Thurston, J . T.; Shriner, R. L. J . Am. Chem. Soc. 1935, 57, 2163.
(3) Shechter, H.; Kaplan, R. B. J . Am. Chem. Soc. 1953, 75, 3980.
(4) (a) Kornblum, N.; Brown, R. A. J . Am. Chem. Soc. 1963, 85, 1359.
(b) Kornblum, N.; Brown, R. A. J . Am. Chem. Soc. 1964, 86, 2681.
(5) Auwers, K. V.; Ottens, R. Chem. Ber. 1924, 57, 446.
(9) (a) Hass, H. B.; Berry, E. J .; Bender, M. L. J . Am. Chem. Soc.
1949, 71, 2290. (b) Russell, G. A.; Danen, W. C. J . Am. Chem. Soc.
1966, 88, 5663.
(10) (a) Hass, H. B.; Bender, M. L. Organic Syntheses; Wiley: New
York, 1963; Collect. Vol. IV, p 932. (b) Hass, H. B.; Bender, M. L. Org.
Synth. 1950, 30, 99. (c) Lieberman, S. V. J . Am. Chem. Soc. 1955, 77,
1114. (d) Bersohn, M. J . Am. Chem. Soc. 1961, 83, 2137.
(6) Meek, J . S.; Fowler, J . S. J . Org. Chem. 1968, 33, 226.
(7) Tartakovskii, V. A.; Nikonova, L. A.; Novikov, S. S. Izv. Akad.
Nauk SSSR Ser. Khim. 1966, 1290; Chem. Abstr. 1966, 65, 16808.
(8) (a) Weisler, L.; Helmkamp, R. W. J . Am. Chem. Soc. 1945, 67,
1167. (b) Montavon, M.; Lindler, H.; Marbet, R. Helv. Chim. Acta. 1957,
40, 1250. (c) McCoy, R. E.; Gohlke, R. E. J . Org. Chem. 1957, 22, 286.
S0022-3263(95)01902-5 CCC: $12.00 © 1996 American Chemical Society

5524 J . Org. Chem., Vol. 61, No. 16, 1996
Kang et al.
reaction mixture was extracted with a solvent, a colored
polar oil of 4b15 was ultimately obtained. However, when
it was quenched with ice and water, a white solid of the
completely enolized isomer 4a was isolated. It was also
observed that 4a spontaneously reverted to 4b when it
was left in a solvent for a period of time.16
In the presence of K2CO3, 4a was converted to the
potassium nitronate 5; then a nucleophilic substitution
occurred when 5 was treated with RX, yielding the
nitronic ester 6, whose IR spectrum as compared to that
of 4a showed a strong absorption at 1640 cm-1 (CdN),
with the absence of the absorption at 3225 cm-1 (O-H)
(Scheme 3). During the course of the reaction and after
the workup, we noticed that there were in fact two close
spots on our TLC plates, with the upper spot being
moderately weak for secondary alkyl nitronic esters (6h
and 6i) and very weak for primary alkyl nitronic esters
(6a -g). Careful column chromatography of crude 6h and
6i gave a colorless oil as the first species and white
crystals as the second species, while recrystallization of
crude 6a -g afforded white crystals. The purity of the
products was demonstrated by TLC. The crystalline
nitronic esters 6 gave a satisfactory elemental analysis
and 1H NMR and 13C NMR data consistent with their
structures. The carbon of nitronate was first observed
to resonate at ca. 103 ppm. In principle, two stereoiso-
mers could be obtained considering the resonance of the
nitronate anion 5, upon attack by RX. Indeed, stereo-
isomerism in nitronic esters has been noticed previously,4
but the designation of the two isomers could not be made.
The configuration of the nitronic esters obtained herein
was confirmed to be Z by means of NOE experiments. In
the case of cyclohexyl nitronic ester 6i, when irradiated
at the frequency of the C18 methylene proton signal (δ
4.33), a notable NOE decrease (16%) was observed in the
F igu r e 1.
Ta ble 1
nitronic ester
alkyl halide
time,a
d
yield,b %
configc
6a
6b
6c
6d
6e
6f
CH3I
C2H5I
1.5
2
96
96
85
74
86
72
70
66
63
12
6
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
n-C3H7Br
n-C4H9Br
C6H5CH2Cl
n-C9H19Br
n-C12H25Br
c-C5H9Br
c-C6H11Br
c-C5H9Br
c-C6H11Br
2
2
2.5
4
3.5
2.5
5
6g
6h
6i
7a d
7bd
2.5
5
a
Reaction was generally run once and no optimization was
made. Isolated yield. c On the basis of the NOE experiments.d O-
b
Alkyloxime.
Resu lts a n d Discu ssion
5-Hydroxy-2(5H)-furanone (2) was readily prepared by
sensitized photo-oxidation of furfural.12 By employing
(-)-menthol as a chiral auxiliary, 5-[(1R)-menthyloxy]-
2(5H)-furanone (3) was formed via esterification.11 It was
a mixture of two diastereoisomers, 3a and 3b (60:40
ratio). Crystalline, enantiomerically pure 3a was ob-
tained after three recrystallizations from light petroleum
ether (30-60 °C), and its absolute configuration at the
acetal center has been assigned to be R on the basis of
X-ray analysis.11b
H
20 signal (δ 5.19). On the other hand, irradiation of the
H20 frequency showed an NOE decrease (18%) of the C18
methylene proton signal and NOE enhancement (6%) of
the C19 methyl proton signal (δ 1.35).
The reason that the nitronic esters 6 were obtained
exclusively as Z stereoisomers is probably that there is
a considerable difference in the chemical surroundings
in which the two delocalized N-O bonds of the nitronate
anion reside (Scheme 3). Conformational analysis made
it clear that the N-O bond trans to the carbethoxy is
highly blocked by the plane of the furanone ring and the
hydrogen atoms linked to it, leaving the other N-O bond
to be attacked preferentially by RX.17
The oily products mentioned above were at last identi-
fied as O-alkyloximes 7 by elemental analyses. They
probably resulted from the partial decomposition of the
nitronic esters, an assumption that is in agreement with
previous observations.18 Although they had 1H NMR
patterns similar to those of the nitronic esters, a striking
difference was seen in their 13C NMR spectra, where the
signal at ca. 103 ppm for 4a and nitronic esters 6 shifted
downfield to ca. 153 ppm, which just falls in the range
(145-165 ppm) for oximes.19 The configuration of the
O-alkyloximes 7 was also assigned to be Z on the basis
of the NOE experiments. In the case of O-cyclopentyl-
The nitro furanone 4a was successfully synthesized via
Michael addition to the furanone 3a by ethyl nitroacetate.
On the basis of the fact that 3a underwent π-face
selective cycloadditions with a variety of dienes,11 ni-
trones, nitrile oxides, and azides13 and Michael additions
with such Michael donors as amines and mercaptans,14
we deduced that a similar enantioselective Michael
addition resulting in an asymmetric carbon-carbon bond
formation also took place here. This was confirmed by
the 1H NMR and 13C NMR spectra. A six-membered
intramolecular hydrogen bond structure (or a chelating
nitronic acid) was inferred by characteristic spectroscopic
data such as IR 3225 cm-1 (O-H), 1680 cm-1 (CdO), and
1635 cm-1 (C)N) and H NMR 9.70 ppm (O-H). It was
soon found that the state and structure of the Michael
adduct depended on the method of workup. When the
1
(11) (a) Feringa, B. L.; De J ong, J . C. J . Org. Chem. 1988, 53, 1125.
(b) De J ong, J . C.; Bolhuis, F. V.; Feringa, B. L. Tetrahedron:
Asymmetry 1991, 2, 1247.
(12) Gollnick, K.; Griesbeck, A. Tetrahedron 1985, 41, 2057.
(13) (a) De Lange, B.; Feringa, B. L. Tetrahedron Lett. 1988, 29,
5317. (b) Shu, R. Q. M.S. Thesis, Beijing Normal University, 1990.
(14) (a) Feringa, B. L.; De Lange, B. Tetrahedron Lett. 1988, 29,
1303. (b) Feringa, B. L.; De Lange, B. Tetrahedron 1988, 44, 7213.
(15) In principle, it should be comprised of two stereoisomers and
an effort to isolate and characterize them is underway at present.
(16) There seems to be no such an equilibrium of a nitro compound
and its enolized isomer in solution since the latter tends spontaneously
to tautomerize to the former. Kohler, E. P.; Stone, J . F. J . Am. Chem.
Soc. 1930, 52, 761.
(17) Further evidences including X-ray analysis to strengthen this
conclusion are in progress.
(18) (a) Barberger, E. Chem. Ber. 1898, 31, 2626. (b) Donaruma, L.
G. J . Org. Chem. 1957, 22, 1024.

Characterization of Nitronic Esters via O-Alkylation
J . Org. Chem., Vol. 61, No. 16, 1996 5525
Sch em e 2
epimerization
H
O
1O2
(–)-menthol
O
H
O
+
O
CHO
O
OH
O
O
O
O
1
2
3a
3b
enolization
in solution
crystallization
H
O
O
NO2
O
N
CO2Et
NO2CH2CO2Et
H
+
H
3a
OEt
H
H
O
O
O
O
O
O
4a
4b
Sch em e 3
OR
OR
H
O
N
K+–
N
O
N
CO2Et
H
H
CO2Et
CO2Et
O
H
H
+
K2CO3
DMF
H
H
O
RX
4a
H
O
O
O
O
O
O
O
O
(Z)-7
(Z)-6
5
R = primary alkyl 70–96%
R = secondary alkyl 63–66%
6–12%
oxime 7a , upon irradiation at the C18 methylene proton
frequency (δ 4.36), notable NOE decrease (33%) was
observed in the H20 signal (δ 5.18). On the other hand,
irradiation at the H20 frequency showed considerable
NOE decrease (46%) of the C18 methylene proton signal
and NOE enhancement (11%) of the C19 methyl proton
signal (δ 1.38).
alkyl halides. O-Alkyloximes were obtained as byprod-
ucts in concert with the production of secondary alkyl
nitronic esters. The molecular structures of the new
compounds were assigned and identified by means of
NMR analyses and NOE experiments. The carbon signal
for nitronate was first observed at ca. 103 ppm by 13C
NMR spectroscopy. Application of this methodology to
other nitro compounds and the use of the chiral nitronic
esters obtained herein in asymmetric synthesis are
currently under investigation.
Two geminal couplings at C3 and C20 were observed in
1
the H NMR spectra of most of the nitronic esters 6 and
2
O-alkyloximes 7, with the coupling constants J 3a,3b
)
2
16.6 Hz and J 20c,20d ) 1.5-2.0 Hz (Figure 1). Interest-
ingly, the small coupling constant characteristic of a trans
relationship between H4 and H5 varied slightly from J )
0 Hz (for 4a and nitronic esters 6) to J ) 1.8 Hz (for
O-alkyloximes 7). Moreover, the signals for the R and
R′ carbons of C20 in the cycloalkyl nitronic esters (6h and
6i) and the O-cycloalkyloximes (7a and 7b) were unusu-
ally differentiated at ca. 32.6 ppm with 0.08 ppm in
between, with a 200 MHz spectrometer, revealing their
unequivalent chemical environments.
Exp er im en ta l Section
Ma ter ia ls. All reagents were the best commercial grades
available and were not purified further unless otherwise
indicated. Ethyl nitroacetate was prepared according to S.
Sifniades′ method20 (bp 78-80°C/6 mmHg, lit.20 bp 70 °C/1.5
mmHg). 1H and 13C NMR spectra were performed at 200 MHz
in CDCl3 with chemical shifts in ppm downfield from TMS and
coupling constants (J ) in hertz. Melting points were measured
using a micro melting point apparatus and are uncorrected.
5-Hyd r oxy-2(5H)-fu r a n on e (2). A solution of freshly
distilled furfural (200 mL, 2.4 mol) and rose bengal (5 g, 4.9
mmol) in 95% ethanol (2000 mL) was exposed to a tungsten-
iodine lamp for 42 h, with the internal temperature main-
tained at 25 °C, while oxygen was bubbled through the reaction
vessel with effective stirring.11b,13b The mixture was concen-
trated by rotary evaporation to a red residue, which solidified
in a freezer to give a light pink solid (164 g, 68%) of 2 that
was used directly in the next step. Recrystallization from
methanol generated white crystals of 2: mp 55-56 °C
(lit.12,11b,21,22 mp 49-53, 55, 57.3-59.2, 58-60 °C).
From the literature,1,2,4 it is apparent that nitronic
esters are usually unstable and there is no defined
relationship between structure and stability. Most of the
reported nitronic esters decompose within minutes to
weeks upon storage at room temperature. Therefore, it
is noteworthy that the nitronic esters prepared in the
present study showed a remarkable stability. All turned
out to be quite stable for prolonged periods at ambient
temperature, and it made no difference if they were in
pure state or in solution.
(R)-(-)-5-[(1R)-Men t h yloxy]-2(5H )-fu r a n on e
(3a ).
In conclusion, using a very mild and versatile proce-
dure, stable chiral alkyl nitronic esters were synthesized
for the first time via asymmetric O-alkylation of the
alkali metal salt of the nitro furanone 4a with various
(1R,2S,5R)-(-)-Menthol (39 g, 0.25 mol) and compound 2 (25
g, 0.25 mol) were added to benzene (170 mL) followed by a
drop of concentrated H2SO4. The resulting mixture was stirred
and refluxed for 22 h with continuous removal of water by
(19) Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric
Identification of Organic Compounds, 4th ed.; J ohn Wiley: New York,
1981.
(20) Sifniades, S. J . Org. Chem. 1975, 40, 3562.
(21) Schlenck, O. G. Liebigs Ann. Chem. 1953, 584, 156.
(22) Yuste, F.; Sanchez-Obrgon, R. J . Org. Chem. 1982, 47, 3665.

5526 J . Org. Chem., Vol. 61, No. 16, 1996
Kang et al.
azeotropic distillation.11b,13b Removal of solvent gave a residue
which solidified on standing. Recrystallization three times
from light petroleum ether led to white crystals (33 g, 56%) of
3a : mp 79.5-80.5 °C (lit.11b,13b mp 70.5-70.7, 76-77 °C);
+60.9° (c 1.0, CHCl3); IR (KBr) 1760, 1730, 1650 cm-1; 1H NMR
δ 0.77-1.28 (m, 17H), 1.35 (m, 5H), 1.63 (m, 4H), 2.17 (m, 2H),
2.56 (dd, 1H, J ) 16.6, 11.2), 2.83 (dd, 1H, J ) 16.6, 3.6), 3.41
(ddd, 1H, J ) 10.6, 4.4), 3.75 (dd, 1H, J ) 11.2, 3.6), 4.12 (ddd,
2H, J ) 6.6, 1.7), 4.33 (q, 2H, J ) 7.1), 5.38 (s, 1H); 13C NMR
δ 13.7, 14.2, 16.1, 19.1, 21.0, 22.1, 23.1, 25.5, 30.6, 31.7, 33.3,
34.1, 43.0, 47.2, 48.2, 61.9, 65.1, 81.9, 103.2, 109.7, 158.6, 170.1.
Anal. Calcd for C22H37NO7: C, 61.83; H, 8,67; N, 3.28.
Found: C, 61.58; H, 8.66; N, 3.20.
[R]25
-139.5° (c 1.0, CHCl3) [lit.11b [R]D -136.4° (c 1.0,
578
absolute ethanol)]; IR (KBr) 3110, 1795, 1765, 1610 cm-1
.
(4S*,5R)-(+)-4-(1′-Nit r o-1′-ca r b et h oxym et h yl)-5-[(1R)-
m en th yloxy]-3,4-d ih yd r o-2(5H)-fu r a n on e (4a ). To a well-
stirred solution of ethyl nitroacetate (0.6 mL, 5.5 mmol) in
DMF (4 mL) was added 2 N NaOEt (0.8 mL). To this white
emulsion was then added 3a (1.2 g, 5 mmol) dissolved in DMF
(4 mL). The stirring was continued at rt for 24 h. Soon after
the completion of the reaction, the mixture was quenched with
ice and water (80 mL) and a white solid was precipitated on
standing. Recrystallization from ether and acetone afforded
(Z)-(+)-Ben zyl n itr on ic ester of (4S*,5R)-4-(1′-n itr o-1′-
ca r b e t h oxym e t h yl)-5-[(1R )-m e n t h yloxy]-3,4-d ih yd r o-
2(5H)-fu r a n on e (6e): white crystals; mp 97-98 °C; [R]25
578
+48.4° (c 1.0, CHCl3); IR (KBr) 1755, 1725, 1640 cm-1; 1H NMR
δ 0.75-1.25 (m, 14H), 1.33 (t, 3H, J ) 7.1), 1.64 (m, 2H), 2.17
(m, 2H), 2.61 (dd, 1H, J ) 16.6, 11.0), 2.89 (dd, 1H, J ) 16.6,
3.4), 3.39 (ddd, 1H, J ) 10.6, 4.2), 3.78 (dd, 1H, J ) 11.0, 3.4).
4.31 (q, 2H, J ) 7.1), 5.16 (d, 2H, J ) 2.0), 5.39 (s, 1H), 7.36
(s, 5H); 13C NMR δ 14.2, 16.1, 21.0, 22.1, 23.1, 25.5, 31.7, 33.3,
34.1, 43.0, 47.2, 48.2, 61.9, 67.0, 82.0, 103.2, 109.7, 128.4, 128.5,
128.7, 135.3, 158.5, 169.9. Anal. Calcd for C25H35NO7: C,
65.08; H, 7.59; N, 3.04. Found: C, 65.05; H, 7.54; N, 2.95.
(Z)-(+)-n -Non yl n itr on ic ester of (4S*,5R)-4-(1′-n itr o-
1′-ca r beth oxym eth yl)-5-[(1R)-m en th yloxy]-3,4-d ih yd r o-
white crystals (1.7 g, 92%) of 4a : mp 146-147 °C (dec); [R]25
578
+52.3° (c 1.0, CHCl3); IR (KBr) 3225, 1745, 1725, 1680, 1635
cm-1 1H NMR δ 0.71-1.23 (m, 14H), 1.33 (t, 3H, J ) 7.1),
;
1.62 (m, 2H), 2.14 (m, 2H), 2.64 (dd, 1H, J ) 17.4, 11.5), 2.94
(dd, 1H, J ) 17.4, 3.3), 3.38 (ddd, 1H, J ) 10.5, 4.3), 3.73 (dd,
1H, J ) 11.5, 3.3), 4.31 (q, 2H, J ) 7.1), 5.37 (s, 1H), 9.70 (br
s, 1H); 13C NMR δ 14.3, 16.1, 21.0, 22.2, 23.1, 25.5, 31.8, 33.0,
34.2, 43.1, 46.9, 48.3, 62.0, 82.3, 103.4, 109.3, 158.7, 176.5.
Anal. Calcd for C18H29NO7: C, 58.21; H, 7.87; N, 3.77.
Found: C, 57.99; H, 8.15; N, 3.83.
2(5H)-fu r a n on e (6f): white crystals; mp 54-55 °C; [R]25
578
+52.5° (c 1.0, CHCl3); IR (KBr) 1750, 1730, 1640 cm-1; 1H NMR
δ 0.77-1.15 (m, 16H), 1.18-1.50 (m, 16H), 1.63 (m, 4H), 2.16
(m, 2H), 2.57 (dd, 1H, J ) 16.6 11.2), 2.84 (dd, 1H, J ) 16.6,
3.5), 3.41 (ddd, 1H, J ) 10.3, 4.2), 3.75 (dd, 1H, J ) 11.2, 3.5),
4.11 (ddd, 2H, J ) 6.8, 2.0), 4.33 (q, 2H, J ) 7.1), 5.39 (s, 1H);
13C NMR δ 14.1, 14.2, 16.1, 21.0, 22.1, 22.7, 23.1, 25.5, 25.7,
28.6, 29.2, 29.5, 31.7, 31.9, 33.4, 34.1, 43.0, 47.2, 48.2, 61.9,
Gen er a l P r oced u r e for P r ep a r a tion of Alk yl Nitr on ic
Ester s 6. Compound 4a (0.74 g, 2 mmol) and finely ground
anhydrous K2CO3 (0.28 g, 2 mmol) were mixed in DMF (9 mL).
To this well-stirred suspension was added an alkyl halide (2
mmol). The progress of the reaction was monitored by TLC.
After being stirred at rt for the indicated time, the reaction
mixture was dissolved in ether and washed with water and
brine and then dried (Na2SO4). Removal of solvent furnished
the corresponding alkyl nitronic ester, which was further
purified by recrystallization from light petroleum ether or by
column chromatography on silica gel using a mixture of light
petroleum ether and ethyl acetate (8:1) as the eluent.
(Z)-(+)-Meth yl n itr on ic ester of (4S*,5R)-4-(1′-n itr o-1′-
ca r b e t h oxym e t h yl)-5-[(1R )-m e n t h yloxy]-3,4-d ih yd r o-
65.5, 82.0, 103.3, 109.9, 158.6, 170.2. Anal. Calcd for C27H47
-
NO7: C, 65.19; H, 9.46; N, 2.82. Found: C, 65.06; H, 9.58; N,
2.72.
(Z)-(+)-n -Dod ecyl n itr on ic ester of (4S*,5R)-4-(1′-n itr o-
1′-ca r beth oxym eth yl)-5-[(1R)-m en th yloxy]-3,4-d ih yd r o-
2(5H)-fu r a n on e (6g): white crystals; mp 53.5-55.5 °C; [R]25
578
+49.8° (c 1.0, CHCl3); IR (KBr) 1750, 1720, 1635 cm-1; 1H NMR
δ 0.77-1.00 (m, 17H), 1.00-1.50 (m, 21H), 1.64 (m, 4H), 2.17
(m, 2H), 2.56 (dd, 1H, J ) 16.6, 11.3), 2.83 (dd, 1H, J ) 16.6,
3.4), 3.41 (ddd, 1H, J ) 10.6, 4.4), 3.75 (dd, 1H, J ) 11.3, 3.4),
4.10 (ddd, 2H, J ) 6.8, 1.7), 4.33 (q, 2H, J ) 7.1), 5.39 (s, 1H);
13C NMR δ 14.1, 14.2, 16.1, 21.0, 22.1, 22.7, 23.1, 25.4, 25.9,
28.5, 29.2, 29.3, 29.5, 29.6, 29.6, 31.7, 31.9, 33.3, 34.1, 43.0,
47.2, 48.2, 61.8, 65.4, 81.9, 103.2, 109.7, 158.5, 170.1. Anal.
Calcd for C30H53NO7: C, 66.79; H, 9.83; N, 2.60. Found: C,
66.57; H, 10.01; N, 2.54.
2(5H)-fu r a n on e (6a ): white crystals; mp 93-94 °C; [R]25
578
+63.8° (c 1.0, CHCl3); IR (KBr) 1750, 1725, 1640 cm-1; 1H NMR
δ 0.78-1.28 (m, 14H), 1.35 (t, 3H, J ) 7.1), 1.65 (m, 2H), 2.18
(m, 2H), 2.58 (dd, 1H, J ) 16.6, 11.5), 2.86 (dd, 1H, J ) 16.6,
3.4), 3.41 (ddd, 1H, J ) 10.5, 4.2), 3.79 (s, 3H), 3.80 (dd, 1H,
J ) 11.5, 3.4), 4.33 (q, 2H, J ) 7.1), 5.39 (s, 1H); 13C NMR δ
14.2, 16.1, 21.0, 22.1, 23.1, 25.4, 31.6, 33.1, 34.1, 43.0, 47.1,
48.2, 52.1, 61.9, 82.0, 103.2, 109.6, 158.5, 170.4. Anal. Calcd
for C19H31NO7: C, 59.22; H, 8.05; N, 3.64. Found: C, 59.04;
H, 7.94; N, 3.47.
(Z)-(+)-Cyclop en tyl n itr on ic ester of (4S*,5R)-4-(1′-
n it r o-1′-ca r b et h oxym et h yl)-5-[(1R)-m en t h yloxy]-3,4-d i-
h yd r o-2(5H)-fu r a n on e (6h ): white crystals; mp 80-81 °C;
(Z)-(+)-Eth yl n itr on ic ester of (4S*,5R)-4-(1′-n itr o-1′-
ca r b e t h oxym e t h yl)-5-[(1R )-m e n t h yloxy]-3,4-d ih yd r o-
[R]25 +65.8° (c 1.0, CHCl3); IR (KBr) 1750,1725, 1640 cm-1
;
578
2(5H)-fu r a n on e (6b): white crystals; mp 71.5-72.5 °C; [R]25
1H NMR δ 0.77-1.23 (m, 13H), 1.35 (t, 3H, J ) 7.1), 1.5-2.0
(m, 13H), 2.16 (m, 2H), 2.56 (dd, 1H, J ) 16.6, 10.7), 2.76 (dd,
1H, J ) 16.6, 3.6), 3.41 (ddd, 1H, J ) 10.6, 4.4), 3.75 (dd, 1H,
J ) 10.7, 3.6), 4.33 (q, 2H, J ) 7.1), 5.19 (m, 1H), 5.38 (s, 1H);
13C NMR δ 14.2, 16.1, 21.0, 22.1, 23.1, 23.7, 25.5, 31.7, 32.6,
32.7, 33.7, 34.1, 43.0, 47.2, 48.2, 61.8, 78.0, 81.9, 103.1, 109.8,
158.6, 169.8. Anal. Calcd for C23H37NO7: C, 62.87; H, 8.43;
N, 3.19. Found: C, 62.47; H, 8.13; N, 3.03.
578
+68.0° (c 1.0, CHCl3); IR (KBr) 1750, 1725, 1640 cm-1; 1H NMR
δ 0.77-1.20 (m, 14H), 1.32 (quintet, 6H, J ) 7.1), 1.66 (m,
2H), 2.16 (m, 2H), 2.55 (dd, 1H, J ) 16.6, 11.2), 2.83 (dd, 1H,
J ) 16.6, 3.4), 3.41 (ddd, 1H, J ) 10.7, 4.4), 3.75 (dd, 1H, J )
11.2, 3.4), 4.18 (dddd, 2H, J ) 7.1, 1.5), 4.33 (q, 2H, J ) 7.1),
5.39 (s, 1H); 13C NMR δ 14.1, 14.2, 16.1, 21.0, 22.1, 23.0, 25.4,
31.6, 33.3, 34.1, 43.0, 47.1, 48.1, 61.1, 61.8, 81.9, 103.2, 109.7,
158.5, 170.0. Anal. Calcd for C20H33NO7: C, 60.15; H, 8.27;
N, 3.51. Found: C, 60.07; H, 8.01; N, 3.33.
(Z)-(+)-Cycloh exyl n itr on ic ester of (4S*,5R)-4-(1′-n i-
tr o-1′-ca r beth oxym eth yl)-5-[(1R)-m en th yloxy]-3,4-d ih y-
d r o-2(5H)-fu r a n on e (6i): white crystals; mp 73-75 °C;
(Z)-(+)-n -P r op yl n itr on ic ester of (4S*,5R)-4-(1′-n itr o-
1′-ca r beth oxym eth yl)-5-[(1R)-m en th yloxy]-3,4-d ih yd r o-
[R]25578 +64.2° (c 1.0, CHCl3); IR (KBr) 1750, 1725, 1640 cm-1
;
2(5H)-fu r a n on e (6c): white crystals; mp 81-82 °C; [R]25
1H NMR δ 0.77-1.25 (m, 14H), 1.35 (t, 3H, J ) 7.1), 1.5-2.0
(m, 12H), 2.17 (m, 2H), 2.56 (dd, 1H, J ) 16.6, 10.7), 2.78 (dd,
1H, J ) 16.6, 3.4), 3.42 (ddd, 1H, J ) 10.6, 4.4), 3.75 (dd, 1H,
J ) 10.7, 3.4), 4.33 (q, 2H, J ) 7.1), 5.19 (m, 1H), 5.38 (s, 1H);
13C NMR δ 14.2, 16.1, 21.0, 22.1, 23.1, 23.7, 25.5, 31.7, 32.6,
32.7, 33.7, 34.1, 43.0, 47.3, 48.2, 61.8, 78.0, 81.9, 103.1, 109.8,
158.6, 169.8. Anal. Calcd for C24H39NO7: C, 63.58; H, 8.61;
N, 3.09. Found: C, 63.49; H, 8.33; N, 2.97.
578
+66.3° (c 1.0, CHCl3); IR (KBr) 1750, 1730, 1640 cm-1; 1H NMR
δ 0.77-1.28 (m, 17H), 1.35 (t, 3H, J ) 7.1), 1.65 (m, 4H), 2.15
(m, 2H), 2.57 (dd, 1H, J ) 16.6, 11.2), 2.84 (dd, 1H, J ) 16.6,
3.4), 3.41 (ddd, 1H, J ) 10.6, 4.4), 3.74 (dd, 1H, J ) 11.2, 3.4),
4.08 (ddd, 2H, J ) 6.8, 1.5), 4.33 (t, 2H, J ) 7.1), 5.39 (s, 1H);
13C NMR δ 10.2, 14.1, 16.0, 20.9, 21.8, 22.0, 22.0, 23.0, 25.4,
31.6, 33.3, 34.1, 43.0, 47.1, 48.1, 61.8, 66.7, 81.9, 103.2, 109.7,
158.5, 170.0. Anal. Calcd for C21H35NO7: C, 61.02; H, 8.47;
N, 3.39. Found: C, 61.25; H, 8.61; N, 3.46.
(Z)-(+)-O-Cyclop en tyloxim e of (4S*,5R)-4-(1′-n itr oso-
1′-ca r beth oxym eth yl)-5-[(1R)-m en th yloxy]-3,4-d ih yd r o-
(Z)-(+)-n -Bu tyl n itr on ic ester of (4S*,5R)-4-(1′-n itr o-1′-
2(5H)-fu r a n on e (7a ): a colorless oil; [R]25 +104.0° (c 2.18,
578
1
ca r b e t h oxym e t h yl)-5-[(1R )-m e n t h yloxy]-3,4-d ih yd r o-
hexane); IR (neat) 1796, 1724, 1582 cm-1; H NMR δ 0.65-
2(5H)-fu r a n on e (6d ): white crystals; mp 89-90 °C; [R]25
1.32 (m, 13H), 1.38 (t, 3H, J ) 7.1), 1.67 (m, 11H), 2.20 (m,
578

Characterization of Nitronic Esters via O-Alkylation
J . Org. Chem., Vol. 61, No. 16, 1996 5527
2H), 2.36 (dd, 1H, J ) 16.0, 10.8), 2.76 (dd, 1H, J ) 16.0, 3.7),
3.45 (ddd, 1H, J ) 10.4, 4.2), 3.60 (dddd, 1H, J ) 10.8, 3.7,
1.8), 4.36 (q, 2H, J ) 7.1), 5.18 (m, 1H), 5.53 (d, 1H, J ) 1.8);
13C NMR δ 14.0, 16.0, 20.9, 22.0, 23.0, 23.5, 25.3, 31.5, 32.4,
32.5, 32.8, 34.1, 42.8, 48.1, 49.6, 61.9, 77.8, 81.5, 110.6, 153.4,
159.9, 169.7. Anal. Calcd for C23H37NO6: C, 65.25; H, 8.75;
N, 3.31. Found: C, 65.65; H, 9.03; N, 3.28.
32.5, 32.6, 32.9, 34.2, 42.8, 48.2, 49.6, 62.0, 77.9, 81.5, 110.7,
153.5, 160.0, 169.8. Anal. Calcd for C24H39NO6: C, 65.90; H,
8.92; N, 3.20. Found: C, 65.57; H, 9.28; N, 3.15.
Ca u tion . Care should be exercised when handling nitronic
acids or their salts, for they have been reported to explode
when allowed to stand for a period of time or when heated.10c,23
Ack n ow led gm en t. Financial support provided by
the National Science Foundation, the Doctoral Research
Foundation of the State Education Commission, and the
Allied Analyses Center of Beijing Zhongguancun is
gratefully acknowledged.
(Z)-(+)-O-Cycloh exyloxim e of (4S*,5R)-4-(1′-n itr oso-1′-
ca r b e t h oxym e t h yl)-5-[(1R )-m e n t h yloxy]-3,4-d ih yd r o-
2(5H)-fu r a n on e (7b): a colorless oil; [R]25 +94.2° (c 0.72,
578
1
hexane); IR (neat) 1795, 1720, 1580 cm-1; H NMR δ 0.70-
1.30 (m, 14H), 1.37 (t, 3H, J ) 7.1), 1.71 (m, 12H), 2.19 (m,
2H), 2.36 (dd, 1H, J ) 16.0, 10.8), 2.76 (dd, 1H, J ) 16.0, 3.7),
3.45 (ddd, 1H, J ) 10.6, 4.4), 3.60 (dddd, 1H, J ) 10.8, 3.7,
1.8), 4.35 (q, 2H, J ) 7.1), 5.18 (m, 1H), 5.53 (d, 1H, J ) 1.8);
13C NMR δ 14.1, 16.1, 21.0, 22.1, 23.1, 23.6, 25.4, 31.6, 31.8,
J O951902Z
(23) Hantzsch, A.; Kissel, H. Chem. Ber. 1899, 32, 3137.