Synthesis of 1H-2,3-dihydropyrrolizine derivatives as precursors of bifunctional alkylating agents

Article abstract of DOI:10.1016/S0040-4020(02)01419-9

Two 1H-2,3-dihydropyrrolizine derivatives bearing a nitro group at the 6 position have been synthesized and an improved method for nitrating pyrroles using potassium nitrate in trifluoroacetic acid was developed. An efficient, two-step synthesis of the butterfly pheromone, Danaidone, was also developed with an overall 33% yield.

Full text of DOI:10.1016/S0040-4020(02)01419-9

Tetrahedron 58 (2002) 10407–10412
Synthesis of 1H-2,3-dihydropyrrolizine derivatives as precursors
of bifunctional alkylating agents
*
Shanthi Rajaraman and Leslie S. Jimenez
Department of Chemistry and Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854-8087, USA
Received 31 July 2002; accepted 30 October 2002
Abstract—Two 1H-2,3-dihydropyrrolizine derivatives bearing a nitro group at the 6 position have been synthesized and an improved
method for nitrating pyrroles using potassium nitrate in trifluoroacetic acid was developed. An efficient, two-step synthesis of the butterfly
pheromone, Danaidone, was also developed with an overall 33% yield. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
drawing group (e.g. the nitro group) at the 6-position of the
1H-2,3-dihydropyrrolizine ring system would provide a way
to attenuate the leaving ability of appropriate groups at
positions 1 and 8 until the electron-withdrawing group was
reduced thereby unmasking the reactive bisalkylating agent
(Scheme 1).
Bifunctional, pyrrole-based alkylating agents have the
ability to form interstrand cross-links within the DNA
double helix and are often useful as antitumor agents. The
anticancer drug, mitomycin C, and the structurally related
natural product, FR900482, are reductively activated inside
cells to the mitosene intermediates, 1 and 2, respectively.
These highly reactive intermediates bind to the minor
groove and selectively form interstrand cross-links between
adjacent deoxyguanosine residues at 50-CpG sites.1 Another
class of bifunctional alkylating agents which preferentially
alkylate this site are the oxidatively activated pyrrolizine
alkaloids (e.g. 3, the dehydropyrrolizidine intermediate
derived from retrorsine), which share the same reactive,
pyrrole substructure as the mitomycin and FR900482
active intermediates.1f,i,2 Interestingly, the simple pyrrole
derivative 4 also exhibited a marked preference for forming
deoxyguanosine-deoxyguanosine 0 interstrand cross-links
at the dinucleotide sequence 5 -CpG over 50-GpC.1f,3
Molecular modeling revealed that the distance between
the adjacent deoxyguanosine amino groups (N2) at the
50-CpG sites was nearly the same as the distance in the
cross-linked adduct, while the amino group separation at
the 50-GpC sites was substantially larger in the starting DNA
than in the adduct.4 Proximity at CpG sites appears to
greatly accelerate the second step (alkylation at C-10) of the
cross-linking reaction.
Nitro compounds that are activated by a bioreductive
mechanism to form the cytotoxic species have been the
subject of investigation for nearly a decade. It is known that
the hypoxia-dependent activation of nitroheterocyclic drugs
by cellular nitroreductases leads to the formation of
intracellular adducts between the drugs and cellular
macromolecules.5 There has been considerable interest in
designing potent and selective nitro compounds by using the
nitro group as an electronic switch to activate a latent
reactive moiety elsewhere in the molecule.6 Some simple
Diacetate 4 lacks any kind of triggering mechanism which
could modify its alkylating ability unlike the mitomycins
and pyrrolizidine alkaloids. Introducing an electron-with-
Keywords: dihydropyrrolizine; bifunctional alkylating agents; antitumor
agents.
*
Corresponding author. Tel.: þ1-732-445-0641; fax: þ1-732-445-5312;
e-mail: jimenez@rutchem.rutgers.edu
Scheme 1.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01419-9

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S. Rajaraman, L. S. Jimenez / Tetrahedron 58 (2002) 10407–10412
Scheme 3.
Two six-step syntheses have been previously reported for
Danaidone, both with low overall yield.8 In an attempt to
improve the overall yield, N-cyanoethyl-3-methylpyrrole
was synthesized by reducing dimethyl methyl succinate in
situ with DIBAL to form the corresponding dialdehyde and
reacting it with 3-aminopropionitrile.9 This procedure
resulted in moderate yields (41%) on a small scale to a
reasonably high yield (66%) on a multigram scale.
However, the cyclization of N-cyanoethyl-3-methyl pyrrole
using gaseous HCl8a seemed to be capricious in our hands.
The yield varied anywhere between 0 and 25% (Scheme 3).
The failure of this reaction was probably because there was
no accurate way to control the concentration of HCl in the
reaction mixture and it is known that pyrroles are prone to
polymerization under acidic conditions.
pyrrole-derived bifunctional electrophiles have also been
shown to form cross-links in synthetic DNA duplexes.1f
Studies on pyrrolic alkylating agents have shown the
following: (1) pyrrolic esters are more reactive than the
corresponding alcohols, (2) the position of the leaving group
determines the leaving group ability; thus, when two
alkylating functional groups are present, they may differ
considerably in alkylating reactivity, (3) reactivity of esters
depends on the structure of the acid moiety; thus, acetate
esters are more reactive than the corresponding pivaloyl
esters, and (4) reactivity is enhanced by electron donating
substituents on the pyrrole ring.7
After ruling out the possibility of using hydrogen chloride to
effect the cyclization, the use of boron tribromide as a Lewis
acid for the cyclization of the pyrrole ester 5 seemed most
promising.10 As a modification of the first step, b-alanine
ethyl ester hydrochloride was used in place of 3-amino-
propionitrile to form the appropriate pyrrole ester 5 in a 44%
yield (Scheme 4). Like the N-cyanoethyl-3-methylpyrrole, 5
was also found to be light-sensitive. Using BBr3, the
cyclization yield of 5 to form Danaidone was 75%. Having
solved the cyclization problem, nitration of Danaidone was
examined next.
We report here the synthesis of two 1H-2,3-dihydropyrro-
lizine derivatives bearing a nitro group at the 6 position
(EWG¼NO2). It is anticipated that such a compound would
only become a good bisalkylating agent after reduction of
the nitro group. Because of the similarity between the
geometry of the C1 and C8 carbons of this reductively
activated compound and the C1 and C10 carbons of the
active intermediates of mitomycin C and FR900482, it is
expected that these derivatives might also display a
preference for forming cross-links at the 50-CpG site.
2. Results and discussion
Looking at the structure of the target molecule, the known
insect pheromone, Danaidone, seemed to be a good starting
point for us. Pyrroles undergo electrophilic substitution at
the 2-position preferentially. Since our target has an
electron-withdrawing nitro group at the 6-position of the
1H-2,3-dihydropyrrolizine skeleton, we realized that we
could rely on the directing effect of the keto group in
Danaidone to effect that electrophilic aromatic substitution
(Scheme 2).
Scheme 4.
It is well known that the high reactivity of pyrroles allows
substitution by electrophilic reagents to proceed readily
even under mild conditions. In addition to substituted
pyrroles, the products usually include resinous substances
formed by side reactions. It has been reported that the
reactivities of the 2- and 3-positions of the pyrrole ring are
estimated at 130000 and 30000 (with respect to
benzene¼1), respectively.11 Bromination of 2-pyrrole-
carboxaldehyde occurs primarily at the 4-position,12 so it
seemed reasonable to assume Danaidone’s keto group might
direct nitration to the 6-position.
Pyrrole is usually nitrated in acetic anhydride at low
Scheme 2.

S. Rajaraman, L. S. Jimenez / Tetrahedron 58 (2002) 10407–10412
10409
the highest yield known for nitrating pyrroles. The best yield
obtained for this step was 60% on a 100 mg scale. Nitration
using nitric acid in acetic anhydride yields the 5-nitro
isomer 6 as the major product while potassium nitrate in
trifluoroacetic acid exhibits better selectivity for the 6-nitro
isomer 7 (Scheme 5).
With the deactivating nitro group in place, functionalization
of the methyl group by bromination was attempted.
Bromination on the unsubstituted pyrrole derivative,
Danaidone, even under free radical conditions resulted in
bromination of the pyrrole nucleus. Nitration attenuates the
reactivity of the pyrrole ring so bromination of 7 using NBS
and 2,20-azobisisobutyronitrile (AIBN) proceeded smoothly
to give the desired bromo derivative 8.16 Hydrolysis of 8
yielded alcohol 9 in a quantitative yield. Reduction of
alcohol 9 with sodium borohydride yielded the diol 10, in
an 87% yield. Acetylation of the diol 10 gave the diacetate
11 in a 70% yield. Ethanolysis of the bromo derivative 8
resulted in formation of 12 in a 93% yield. Reduction of the
ether 12 with sodium borohydride, followed by acetylation,
gave the acetate 13 in a 92% overall yield for the two steps
(Scheme 5).
Acetates 11 and 13 were unchanged by stirring in methanol
at rt overnight. In an attempt to see whether reduction of the
nitro group resulted in solvolysis of the acetoxy groups at
C-1 and C-8, catalytic hydrogenation on Pd/C in methanol17
was carried out on both 11 and 13. However, this resulted in
a mixture of very polar products which were very difficult to
isolate and purify on a milligram scale.
Scheme 5.
temperatures.11 Nitration with nitric acid in acetic anhydride
resulted in the 5-nitro isomer 6 in ,30% yield (Scheme 5)
while the 6-nitro isomer 7 was a minor product (,5%
yield). The strongly acidic reaction conditions probably
resulted in the protonation of the keto carbonyl group which
promoted formation of a hemiketal (or ketal) with acetic
acid; this species then proceeded to nitrate the 5-position in
the absence of the directing effect of the keto functionality.
Nitration under neutral conditions was attempted next.
The use of nitronium tetrafluoroborate13 in acetonitrile
proceeded as expected to yield primarily the desired 6-nitro
isomer 7. The yield was 30–35%, which is common for
pyrrolic systems. With the nitro group in place, it was
decided to proceed forward with the functionalization of the
methyl side chain.
3. Conclusion
Two 1H-2,3-dihydropyrrolizine derivatives bearing a nitro
group at the 6 position have been synthesized and an
improved method for nitrating pyrroles using potassium
nitrate in trifluoroacetic acid was developed. Results from
reducing the nitro acetates 11 and 13 by Pd-catalyzed
hydrogenation were inconclusive. An efficient, two-step
synthesis of the butterfly pheromone, Danaidone, was also
developed with an overall 33% yield.
4. Experimental
4.1. General
In an attempt to effect oxidation of the methyl group to the
corresponding aldehyde, ceric ammonium nitrate (CAN) in
acetic acid or trifluoroacetic acid was used since this reagent
has been shown to oxidize a-methyl groups of pyrroles to
aldehydes and ethers14 as well as b-alkyl groups.15
However, no reaction of the deactivated nitropyrrole 7
occurred even under refluxing reaction conditions. There-
fore, the order of reactions was changed and oxidation was
attempted using CAN on Danaidone, prior to nitration.
To our surprise, CAN in trifluoroacetic acid gave the 6-nitro
isomer 7 as the major product. However, when the reaction
was scaled up, CAN seemed to give a mixture of products
and it was difficult to control the equivalents of the active
nitrating species. This led to the replacement of CAN with
potassium nitrate. As expected, KNO3 gave a better yield
(45% on a 0.500 g scale), which is, to our best knowledge,
Melting points were uncorrected and were recorded on a
Thomas Hoover melting point apparatus. All chemicals
were obtained from commercial suppliers and used without
further purification, unless otherwise mentioned. All reac-
tions were carried out under nitrogen. Thin layer chroma-
tography (TLC) was carried out on pre-coated plates and
visualized under UV light. Flash column chromatography
was performed with silica (Merck 230–400 mesh), unless
mentioned otherwise. Elemental analyses were processed
by Quantitative Technologies Inc., Whitehouse, NJ. Mass
spectra were processed by the University of California Mass
Spectroscopy Facility, Riverside, CA, and the Center for
Advanced Food Technology, Rutgers University, New
Brunswick, NJ. Infrared spectra were recorded by using a

10410
S. Rajaraman, L. S. Jimenez / Tetrahedron 58 (2002) 10407–10412
Matteson Genesis FT-IR spectrometer. H and 13C NMR
were recorded on Varian-Gemini 200 MHz, Varian Unity
300 MHz and Varian Unity 400 MHz spectrometers using
commercially available CDCl3 as the solvent, unless
otherwise noted. Proton and carbon chemical shifts are
expressed in parts per million (ppm) downfield relative to
internal tetramethylsilane. 1H NMR spectra are reported on
the d scale with splitting patterns, coupling constants, and
relative integral areas. The letter designates the multiplicity
of the signal: s, singlet; bs, broad singlet; d, doublet; dd,
doublet of doublet; t, triplet, q, quartet; m, multiplet. 13C
NMR spectra are proton decoupled spectra unless otherwise
mentioned. Dry solvents were either freshly distilled
over calcium hydride under nitrogen or bought from
commercially available sources.
the solvent system. A total of 0.179 g (75%) of Danaidone
was obtained as pale yellow crystals. Mp 68–708C. (lit.8a
1
72–748C). IR: 3053, 2926, 1681, 1389 cm21 1H NMR
.
(CDCl3): d 2.33 (s, 3H), 3.05 (t, 2H, J¼6.3 Hz), 4.23 (t, 2H,
J¼6.3 Hz), 6.28 (d, 1H, J¼2 Hz), 6.90 (d, 1H, J¼2 Hz).
4.1.3. 7-Methyl-5-nitro-2,3-dihydro-1H-pyrrolizin-1-one
(6). Compound 6 is obtained as a side product from the
synthesis of 7 in ,5% yield. It is a pale yellow crystalline
solid. Mp 132–1348C. Rf 0.67 (1:1 petroleum ether/ethyl
1
acetate). IR: 3064, 2248, 1721 cm21. H NMR (CDCl3): d
2.32 (s, 3H), 3.11 (t, 2H, J¼6.0 Hz), 4.66 (t, 2H, J¼6.0 Hz),
7.04 (s, 1H). 13C NMR (CDCl3): d 11.2, 38.9, 44.9, 116.4,
116.6, 121.1, 132.3, 190.5. MS (EI): m/z 180 (Mþ). Anal.
calcd for C8H8N2O3: C, 53.33; H, 4.44; N, 15.55. Found: C,
53.48; H, 4.43; N, 15.55.
4.1.1. 3-(3-Methyl-pyrrol-1-yl)-propionic acid ethyl ester
(5). A total of 9.23 mL (62 mmol) of dimethyl methyl-
succinate was added to a 250 mL 3-necked round-bottomed
flask fitted with a mechanical stirrer and flushed with
nitrogen. A total of 20 mL of freshly distilled dichloro-
methane was added to the reaction flask, which was then
cooled to 2788C. A total of 217 mL of DIBAL (217 mmol,
1 M solution in dichloromethane) was then added to the
reaction flask. The reaction mixture was stirred for about
40 min. A solution of 19.0 g (124 mmol) of b-alanine ethyl
ester hydrochloride in 150 mL of deionized water was then
added slowly to the reaction flask. It was further stirred for
3 h at rt. The reaction mixture was yellow in color with a
white fluffy emulsion-like solid floating on the top. The
white solid was filtered off and washed with dichloro-
methane. The combined organic layer was dried over
anhydrous sodium sulfate and the solvent was evaporated in
vacuo. The product was purified by flash chromatography
using neutral alumina in 80:20 petroleum ether/ethyl acetate
as the solvent system (significant loss of product occurred if
purified on silica gel). A total of 4.91 g (44%) of 2 was
obtained a pale yellow oil. It can be stored for up to a
maximum of 2 months in the freezer without decompo-
4.1.4. 7-Methyl-6-nitro-2,3-dihydro-1H-pyrrolizin-1-one
(7). A total of 0.100 g (0.741 mmol) of Danaidone was
placed in a 10 mL round-bottomed flask with a stir bar and
the reaction vessel was flushed with nitrogen. To this,
0.187 g (1.85 mmol) of potassium nitrate was added and
the reaction flask was cooled to 08C. A total of 2 mL of
trifluoroacetic acid was added dropwise and the temperature
was maintained between 4 and 68C. The reaction was
monitored by TLC (1:1 petroleum ether/ethyl acetate). After
45 min, the reaction was complete and was quenched with
2 mL of deionized water, then the solvent was evaporated
in vacuo and purified by flash chromatography using 1:1
petroleum ether/ethyl acetate (Rf 0.15) as the solvent
system. A total of 0.080 g (60%) of 7 was obtained as
yellow crystalline solid. Mp 72–748C. IR: 3071, 2250,
1
1726 cm21. H NMR (CDCl3): d 2.60 (s, 3H), 3.08 (t, 2H,
J¼6.6 Hz), 4.35 (t, 2H, J¼6.6 Hz), 7.79 (s, 1H). 13C NMR
(CDCl3): d 11.4, 39.0, 43.4, 119.0, 122.4, 122.7, 146.2,
191.7. MS (EI): m/z 180 (Mþ). Anal. calcd for C8H8N2O3: C,
53.33; H, 4.44; N, 15.55. Found: C, 53.46; H, 4.42; N, 15.53.
4.1.5. 7-Bromomethyl-6-nitro-2,3-dihydro-1H-pyrroli-
zin-1-one (8). A total of 0.081 g (0.45 mmol) of 7 was
placed in a 50 mL round-bottomed flask, which was fitted
with a reflux condenser and flushed with nitrogen. A total of
20 mL of anhydrous carbon tetrachloride and 160 mg
(1.01 mmol) of N-bromosuccinimide were added to the
reaction flask. It was heated to reflux by irradiating with a
660 W sunlamp. A total of 0.030 g (catalytic amount) of
AIBN was added quickly when refluxing. It was then
refluxed for 3 h. At the end of 3 h, succinimide was found
floating in the reaction mixture as a white fluffy solid. It was
filtered, washed with carbon tetrachloride (succinimide is
soluble in dichloromethane and hence carbon tetrachloride
is used for the work-up). Isobutyronitrile was formed from
AIBN and was removed from the product by azeotroping
with toluene. The product was then purified by flash
chromatography using 99.5:0.5 CH2Cl2/CH3OH. A total
of 0.094 g (80%) of 8 was obtained as a pale yellow oil. IR:
1
sition. IR: 2985, 2253, 1730, 1267, 1161 cm21. H NMR
(CDCl3): d 1.26 (t, 3H, J¼7.1 Hz), 2.09 (s, 3H), 2.74 (t, 2H,
J¼7.0 Hz), 4.14 (t, 2H, J¼7.0 Hz), 4.17 (q, 2H, J¼7.1 Hz),
5.96 (d, 1H, J¼2 Hz), 6.44 (s, 1H), 6.56 (d, 1H, J¼2 Hz).
13C NMR (CDCl3): d 12.3, 14.6, 37.1, 45.3, 61.3, 110.0,
119.0, 119.5, 120.9, 171.6. MS (EI): m/z 181 (Mþ), 108
(Mþ2CO2CH2CH3), 94 (Mþ2CH2CO2CH2CH3). HRMS,
m/z (Mþ, C10H15NO2) calcd 181.1103, obsd 181.1104.
4.1.2. 7-Methyl-2,3-dihydro-1H-pyrrolizin-1-one
(Danaidone). A total of 0.320 g (1.76 mmol) of 2 was
placed in a 50 mL round-bottomed flask, which was flushed
with nitrogen. A total of 15 mL of freshly distilled
dichloromethane was added and the reaction flask was
cooled to 08C. A total of 2.5 mL of BBr3 (2.5 mmol, 1 M
solution in dichloromethane) was added and stirred at rt
overnight. The reaction was then quenched with 1 mL of
deionized water. Saturated sodium bicarbonate solution was
added until pH¼8. The phases were separated and the
aqueous layer was extracted with dichloromethane
(2£10 mL). The combined organic layer was then dried
over anhydrous sodium sulfate, and the solvent was
evaporated in vacuo. The product was purified by flash
chromatography using 1:1 petroleum ether/ethyl acetate as
1
3054, 2305, 1721, 1422, 1265 cm21. H NMR (CDCl3): d
3.14 (t, 2H, J¼6.5 Hz), 4.42 (t, 2H, J¼6.5 Hz), 4.93 (s, 2H),
7.82 (s, 1H). 13C NMR (CDCl3): d 19.1, 38.8, 43.8, 117.2,
120.0, 122.3, 128.9, 190.0. MS (CI): m/z 261 (Mþþ3), 259
(Mþþ1), 165 (Mþ2CH2Br). Anal. calcd for C8H7N2O3Br:
C, 37.06; H, 2.70; N, 10.81; Br, 30.88. Found: C, 37.15; H,
2.47; N, 10.83; Br, 31.03.

S. Rajaraman, L. S. Jimenez / Tetrahedron 58 (2002) 10407–10412
10411
4.1.6. 7-Hydroxymethyl-6-nitro-2,3-dihydro-1H-pyrroli-
zin-1-one (9). A total of 0.0207 g (0.0799 mmol) of 8 was
dissolved in 10 mL of deionized water and refluxed for 3 h
under nitrogen. A total of 0.0156 g (100%) of 9 was
obtained as a colorless oil and is used without further
(CDCl3): d 1.24 (t, 3H, J¼7.1 Hz), 3.11 (t, 2H, J¼
6.5 Hz), 3.65 (q, 2H, J¼7.1 Hz), 4.39 (t, 2H, J¼6.5 Hz),
4.88 (s, 2H), 7.83 (s, 1H). 13C NMR (CDCl3): d 15.6, 39.1,
43.6, 60.6, 67.0, 117.9, 122.4, 129.9, 140.2, 190.6. MS: m/z
224 (Mþ). Anal. calcd for C10H12N2O4: C, 53.57; H, 5.36;
N, 12.50. Found: C, 53.26; H, 5.72; N, 12.22.
1
purification. IR: 3427, 2900, 2250, 1280 cm21. H NMR
(CDCl3): d 3.16 (t, 2H, J¼6.5 Hz), 4.46 (t, 2H, J¼6.5 Hz),
5.07 (s, 2H), 7.84 (s, 1H). 13C NMR (CDCl3): d 37.6, 44.5,
68.2, 116.2, 120.8, 125.4, 139.6, 191.0. MS: m/z 196 (Mþ).
Anal. calcd for C8H8N2O4: C, 48.97; H, 4.02; N, 14.28.
Found: C, 48.73; H, 4.02; N, 14.20.
4.1.10. 7-Ethoxymethyl-6-nitro-2,3-dihydro-1H-pyrroli-
zin-1-ol. A total of 0.020 g (0.0892 mmol) of 12 was placed
in a 10 mL round-bottomed flask, which was maintained at
08C using an ice bath. A total of 0.006 g (0.188 mmol) of
NaBH4 and 1 mL of anhydrous methanol were added. The
reaction was stirred for 30 min at 08C. The solvent was
evaporated in vacuo and purified by flash chromatography
using 98:2 CH2Cl2/CH3OH. A total of 0.019 g (95%) of the
product was obtained as a pale yellow oil. IR: 3459, 2983,
4.1.7. 7-Hydroxymethyl-6-nitro-2,3-dihydro-1H-pyrroli-
zin-1-ol (10). A total of 0.0204 g (0.104 mmol) of 9 was
placed in a 50 mL round-bottomed flask with a stir bar under
nitrogen. A total of 0.030 mg (0.938 mmol) of NaBH4 and
1 mL of anhydrous methanol was syringed into the reaction
flask. The reaction mixture was stirred at 08C for 1 h. The
solvent was evaporated in vacuo and the product was purified
by flash chromatography using 98:2 CH2Cl2/ CH3OH. A
total of 0.0179 g (87%) of 10 was obtained as a pale yellow
oil. IR: 3480, 2965, 2249, 1279 cm21. 1H NMR (CDCl3): d
2.35–2.50 (m, 1H), 2.7–2.9 (m, 1H), 3.90–4.05 (m, 1H),
4.15–4.30 (m, 1H), 4.79 (d, 1H, J¼ 14 Hz), 4.97 (d, 1H,
J¼14 Hz), 5.2–5.3 (m, 1H), 7.49 (s, 1H). 13C NMR
(CDCl3): d 34.3, 46.0, 67.8, 68.9, 112.5, 113.6, 117.9,
135.2. MS: m/z 198 (Mþ). Anal. calcd for C8H10N2O4: C,
48.48; H, 5.05; N, 14.14. Found: C, 49.08; H, 4.95; N, 13.85.
1
2253, 1506, 1267, 909 cm21. H NMR (CDCl3): d 1.25 (t,
3H, J¼7.0 Hz), 2.35–2.50 (m, 1H), 2.75–2.85 (m, 1H),
3.56 (q, 2H, J¼7.0 Hz), 3.95–4.05 (m, 1H), 4.15–4.25 (m,
1H), 4.79 (d, 1H, J¼14 Hz), 4.97 (d, 1H, J¼14 Hz), 5.2–5.3
(m, 1H), 7.49 (s, 1H). 13C NMR (CDCl3): d 15.7, 35.7, 46.7,
67.6, 67.8, 68.2, 112.3, 112.8, 116.5, 137.8. MS: m/z 226
(Mþ). Anal. calcd for C10H14N2O4: C, 53.09; H, 6.19; N,
12.39. Found: C, 52.71; H, 6.48; N, 11.97.
4.1.11. 1-Acetoxy-7-ethoxymethyl-6-nitro-2,3-dihydro-
1H-pyrrolizine (13). A total of 0.020 g (0.0884 mmol) of
the preceding alcohol was placed in a 10 mL round-
bottomed flask fitted with a stir bar, to which a pre-mixed
solution of 1 mL acetic anhydride and 1 mL pyridine was
added at rt. The reaction mixture was stirred for 3 h and then
quenched with 1:1 water/ethyl acetate (2 mL), after which,
it was stirred for another hour to hydrolyze any acetic
anhydride present. The reaction mixture was washed with
deionized water and ethyl acetate, followed by 1N HCl (to
remove traces of pyridine), then neutralized with saturated
sodium bicarbonate solution until pH¼7 and finally washed
with saturated brine solution. The combined organic layer
was then dried over anhydrous sodium sulfate, filtered, and
the solvent was evaporated in vacuo. The product was
purified by flash chromatography using 98:2 CH2Cl2/
CH3OH. A total of 0.023 g (97%) of 13 was obtained as a
pale yellow oil. 1H NMR (CDCl3): d 1.21 (t, 3H, J¼7.0 Hz),
2.07 (s, 3H), 2.4–2.55 (m, 1H), 2.75–2.95 (m, 1H), 3.60 (q,
2H, J¼7.0 Hz), 3.95–4.30 (m, 2H), 4.74 (s, 2H), 6.23 (d,
1H, J¼6.3 Hz), 7.59 (s, 1H). 13C NMR (CDCl3): d 15.7,
30.2, 35.9, 46.1, 65.0, 66.9, 69.8, 114.1, 117.9, 128.7, 133.7,
170.6. MS: m/z 268 (Mþ). Anal. calcd for C12H16N2O5: C,
53.73; H, 5.97; N, 10.45. Found: C, 54.03; H, 6.27; N, 10.67.
4.1.8. 1-Acetoxy-7-acetoxymethyl-6-nitro-2,3-dihydro-
1H-pyrrolizine (11). A total of 0.0179 g (0.0904 mmol)
of 10 was placed in a 25 mL round-bottomed flask under
nitrogen. A total of 2 mL of a pre-mixed solution of acetic
anhydride and pyridine (1:1) was added to the reaction flask.
The reaction mixture was stirred at rt for 3 h and then
quenched with 1:1 water/ethyl acetate (2 mL), after which,
it was stirred for another hour to hydrolyze any acetic
anhydride present. The reaction mixture was washed with
deionized water and ethyl acetate, followed by 1N HCl (to
remove traces of pyridine), then neutralized with saturated
sodium bicarbonate solution until pH¼7 and finally washed
with saturated brine solution. The combined organic layer
was then dried over anhydrous sodium sulfate, filtered, and
the solvent was evaporated in vacuo. The product was
purified by flash chromatography using dichloromethane as
the eluent. A total of 0.018 g (70%) of 11 was obtained as a
1
pale yellow oil. H NMR (CDCl3): d 2.06 (s, 3H), 2.07 (s,
3H), 2.45–2.55 (m, 1H), 2.75–3.0 (m, 1H), 4.0–4.3 (m,
2H), 5.35 (s, 2H), 6.15–6.25 (m, 1H), 7.62 (s, 1H). 13C
NMR (CDCl3): d 30.0, 34.3, 46.2, 46.5, 64.9, 69.2, 112.2,
114.4, 117.9, 120.0, 170.1, 172.1. MS: m/z 282 (Mþ). Anal.
calcd for C12H14N2O6: C, 51.06; H, 4.96; N, 9.93. Found: C,
51.45; H, 4.88; N, 9.68.
Acknowledgements
We gratefully acknowledge the National Science Foundation
(CHE-0074836), the Charles and Johanna Busch Memorial
Fund, and Schering-Plough Research Institute, Kenilworth,
NJ for support of this research.
4.1.9. 7-Ethoxymethyl-6-nitro-2,3-dihydro-1H-pyrroli-
zin-1-one (12). A total of 0.030 g (0.116 mmol) of 8 was
placed in a 25 mL round-bottomed flask, which was fitted
with a reflux condenser and flushed with nitrogen. A total of
15 mL of absolute ethanol (200 proof) was then added to the
reaction flask and the reaction mixture was refluxed for 3 h.
A total of 0.024 g (93%) of 12 was obtained. The product
was a colorless oil and used without further purification. IR:
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