Ring-chain tautomerism in organic synthesis: Synthesis of heterocyclic enamines from a novel and practical formal ring transformation reaction of lactones

Article abstract of DOI:10.1021/jo026560t

A novel approach to heterocyclic enamines has been developed from the formal ring transformation reaction of lactones. The synthesis comprises consecutive Reformatsky reaction of lactones and mesylation of the resulting mixture of ring-chain tautomers in

Full text of DOI:10.1021/jo026560t

Rin g-Ch a in Ta u tom er ism in Or ga n ic Syn th esis: Syn th esis of
Heter ocyclic En a m in es fr om a Novel a n d P r a ctica l F or m a l Rin g
Tr a n sfor m a tion Rea ction of La cton es
Mei-Xiang Wang,*,† Yong Liu,† Hong-Yun Gao,† Yan Zhang,† Chu-Yi Yu,†
Zhi-Tang Huang,† and George W. J . Fleet‡
Laboratory of Chemical Biology, Center for Molecular Science, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China, and Dyson Perrins Laboratory,
Department of Chemistry, Oxford University, South Parks Road, Oxford, United Kingdom
mxwang@mail.iccas.ac.cn
Received October 12, 2002
A novel approach to heterocyclic enamines has been developed from the formal ring transformation
reaction of lactones. The synthesis comprises consecutive Reformatsky reaction of lactones and
mesylation of the resulting mixture of ring-chain tautomers in a one-pot reaction, followed by
cyclocondensation reaction with primary amines. The synthetic application of this method was
demonstrated by a straightforward preparation of indolizidine compounds via N-(3-bromopropyl)-
substituted enamine intermediates. The use of cheap and readily available materials and reagents
under very mild conditions renders this formal ring transformation method practical and applicable
in the preparation of various heterocyclic enamines that are the precursors for (poly)hydroxylated
alkaloid derivatives.
In tr od u ction
ample, employed the reaction of a thiolactam with a bro-
momethyl ketone or ester, followed by sulfur extrusion
in the presence of triphenylphosphine. The condensation
reaction between active methylene or methyl compounds
and lactim ethers,5 pioneered by Eshenmoser and co-
workers6 during the synthetic study of corrin, and lactam-
derived iminium salts7,8 or acetals7 has been developed
into another popular approach to heterocyclic enamines.
Other methods reported comprise coupling reactions of
organometallic reagents with lactams9 and thiolactames10
and their derivates.11 In contrast, the synthesis of
heterocyclic enamines by constructing the N-heterocyclic
ring moiety has only been reported in a few cases. The
reaction of ω-mesylated alkylnitriles with methyl bro-
moacetate, developed by Kishi,12 provided an efficient
route to pyrroline-containing heterocyclic enamines. Car-
rie and co-workers13 reported a more general approach
utilizing the intramolecular aza-Wittig reaction of ω-azi-
do â-dicarbonyl intermediates that were prepared through
Heterocyclic enamines, also known as exo-cyclic enam-
ino esters, are powerful and versatile intermediates in
the preparation of natural products1,2 and fused hetero-
cyclic compounds.1,3 The syntheses of heterocyclic enam-
ines have been extensively studied mainly utilizing
N-heterocyclic compounds as starting materials.1 The
Eshenmoser synthesis,4 a widely used method, for ex-
* To whom correspondence should be addressed. Phone: +86-10-
62554628. Fax: +86-10-62539564.
† Chinese Academy of Sciences.
‡ Oxford University.
(1) For useful reviews, see: (a) Lue, P.; Greenhill, J . V. Enaminones
in Heterocyclic Synthesis. In Adv. Heterocycl. Chem. 1997, 67, 209-
343. (b) Granik, V. G.; Makarov, V. A. Enamines as Synthons in the
Synthesis of Heterocycles. In Adv. Heterocycl. Chem. 1999, 72, 283-
349.
(2) For selected examples, see: (a) Taguchi, H.; Yazawa, H.; Arnett,
J . F.; Kishi, Y. Tetrahedron Lett. 1977, 627-630. (b) Danishefsky, S.;
Etheredge, S. J . J . Org. Chem. 1974, 39, 3430-3432. (c) Shen, W.;
Coburn, C. A.; Bornmann, W. G.; Danishefsky, S. J . Org. Chem. 1993,
58, 611-617. (d) Snyder, L.; Shen, W.; Bornmann, W. G.; Danishefsky,
S. J . Org. Chem. 1994, 59, 7033-7037. (e) Luly, J . R.; Rapoport, H. J .
Am. Chem. Soc. 1983, 105, 2859-2866. (f) Pinnick, H. W.; Chang, Y.-
H. J . Org. Chem. 1978, 43, 4662-4663. (g) Buchanan, J . G.; J igajinni,
V. B.; Singh, G.; Wightman, R. T. J . Chem. Soc., Perkin Trans. 1 1987,
2377-2384. (h) Paulvannan, K.; Stille, J . R. J . Org. Chem. 1994, 59,
1613-1620. (i) Saliou, C.; Fleurant, A.; Celerier, J . P.; Lhommet, G.
Tetrahedron Lett. 1991, 32, 3365-3368. (j) Fleurant, A.; Celerier, J .
P.; Lhommet, G. Tetrahedron: Asymmetry 1993, 4, 1429-1430. (k)
Thanh, G. V.; Celerier, J . P.; Lhommet, G. Tetrahedron: Asymmetry
1996, 7, 2211-2212.
(3) For recent examples, see: (a) Cheng, Y.; Yang, H.-B.; Wang, M.-
X.; Williams, D. J . Tetrahedron 2002, 58, 2821-2829. (b) Wang, M.-
X.; Miao, W. S.; Cheng, Y.; Huang, Z.-T. Tetrahedron 1999, 55, 14611-
14622. (c) Folmer, J . J .; Acero, C.; Thai, D. L.; Rapoport, H. J . Org.
Chem. 1998, 63, 8170-8182.
(4) (a) Roth, M.; Dubs, P.; Go¨tschi, E.; Eschenmoser, A. Helv. Chim.
Acta 1971, 54, 710-734. (b) Michael, J . P.; Gravestock, D. J . Chem.
Soc., Perkin Trans. 1 2000, 1919-1928 and references therein.
(5) Celerier, J .-P.; Deloisy, E.; Lhommet, G.; Maitte, P. J . Org. Chem.
1979, 17, 3089.
(6) Bertele, E.; Boos, H.; Dinitz, J . D.; Elsinger, F.; Eschenmoser,
A.; Felner, I.; Gribi, H. P.; Gshwend, H.; Meyer, E. F.; Pesaro, M.;
Scheffold, R. Angew. Chem., Int. Ed. Engl. 1964, 3, 490-496.
(7) Gugelchuk, M. M.; Hart, D. J .; Tsai, Y.-M. J . Org. Chem. 1981,
46, 3671-3675.
(8) Celerier, J . P.; Richaud, M. G.; Lhommet, G. Synthesis 1983,
195-197.
(9) Yamaguchi, M.; Hirao, I. J . Org. Chem. 1985, 50, 1975-1977.
(10) Lee, H. K.; Kim, J .; Pak, C. S. Tetrahedron Lett. 1999, 40, 2173-
2174.
(11) (a) Matsumura, Y.; Fujiwara, J .; Maruoka, K.; Yamamoto, H.
J . Am. Chem. Soc. 1983, 105, 6312-6314. (b) J ain, S.; J ain, R.; Singh,
J .; Anand, N. Tetrahedron Lett. 1994, 35, 2951-2954.
(12) Hannick, S. M.; Kishi, Y. J . Org. Chem. 1983, 48, 3833-3835.
(13) Lambert, P. H.; Vaultier, M.; Carrie, R. J . Org. Chem. 1985,
50, 5352-5356.
10.1021/jo026560t CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/22/2003
J . Org. Chem. 2003, 68, 3281-3286
3281

Wang et al.
SCHEME 1. P r ep a r a tion of Heter ocyclic
En a m in es via th e Rin g Tr a n sfor m a tion of
La cton es
the γ-alkylation of â-dicarbonyl dianions with R,ω-diha-
loalkane compounds followed by a nucleophilic substitu-
tion by sodium azide. The reaction was extended by
Michael and co-workers14 to synthesize alkyl (E)-(1-aryl-
2-pyrrolidinylidene)acetates by reacting anilines bearing
electron-donating substituent(s) with 6-chloro-3-oxohex-
anoate.
In the course of synthetic study of (poly)hydroxylated
pyrrolizidine, indolizidine, and quinolizidine alkaloids
including swainsonine and castanospermine,3 we require
a general and practical method to produce (poly)hydroxy-
lated chiral heterocyclic enamines starting from cheap
and readily available materials. Considering the easy
accessibility to sugar lactones15 that are derived easily
from the naturally abundant sugar compounds, it ap-
pears desirable to explore the transformation of lactones
into heterocyclic enamines. As a prelude to studying the
synthesis of hydroxylated chiral heterocyclic enamines,
we have systematically undertaken the current study and
here we report a formal ring transformation of lactones
into the corresponding heterocyclic enamines utilizing
ring-chain tautomerism as the key step.
Resu lts a n d Discu ssion
TABLE 1. Syn th esis of Meth ylsu lfon a te Com p ou n d s 3
fr om La cton es 1
Ring-chain tautomerism has been known for a long
time. The tautomerism between hydroxyketones and
hemiketals, the simplest ring-chain tautomerism, for
example, has been fully studied. Surprisingly, however,
most of the tautomerim has been used only for the
construction of heterocycles, and its application in the
synthesis of chain compounds has been rarely reported.16
Our synthesis was devised on the basis that the hemiket-
als 2 resulting from the Reformatsky reaction of lactones
could co-exit in tautomeric equilibrium with their chain
isomers 2′ and 2′′. Subsequent mesylation of the ω-hy-
droxy group of the chain tautomers would drive the
equilibrium into the side of methylsulfonate compounds
3 and 3′, which are the key precursors of heterocyclic
enamines (Scheme 1).
In the presence of activated zinc dust and a catalytic
amount of copper dust, the Reformatsky reaction of
lactones 1 with tert-butyl bromoacatate proceeded ef-
fectively in warm tetrahydrofuran (THF) under argon
atmosphere. The 1H NMR spectra of the isolated products
2a -c appeared to be chaos. However, a careful inspection
revealed that the products were indeed an equilibrium
mixture of ring and chain tautomers, which was evi-
denced by the observation of two or three singlet peaks
around 1.48 ppm corresponding to tertiary butyl protons
and a vinyl proton signal around 4.9 ppm corresponding
to the enol structure. Mesylation of the Reformatsky
products with methylsulfonyl chloride using pyridine as
an acid scavenger afforded methylsulfonate derivatives
3a -c in moderate to good yield. The tidy 1H NMR spectra
indicated that the products were also a mixture of ketone
and enol tautomers, but with the former being a domi-
nant isomer. To improve the overall chemical yield of
methylsulfonates from lactones and to avoid somewhat
3 (overall yield
3 (yield by
one-pot
2
3
by two-step
entry
1
n
R1 (%)a (%)a synthesis, %)a synthesis, %)a
1
2
3
4
5
1a
1b
1c
1d
1e
1
1
1
1
2
H
70
56
61
85
39
44
69
58
66
MeO 72
AllO 81
BzO
53
49
H
a
Isolated yield.
tedious chromatographic isolation of the Reformatsky
adducts 2, the Reformatsky reaction and mesylation were
conducted consecutively in a one-pot manner, without
isolation and purification of intermediates 2. Gratifyingly,
this simple and convenient experimental operation led
to a much higher overall yield of 3 (Table 1).
Being reactive toward almost all types of primary
amines, methylsulfonates 3 appeared as excellent inter-
mediates for the preparation of heterocyclic enamines
(Scheme 1). As illustrated in Table 2, 3 reacted with
aliphatic amines including glycine ethyl ester smoothly
at ambient temperature in dichloromethane to afford
N-alkyl heterocyclic enamines 6 (Method A). The pres-
ence of molecular sieves (4 Å) was found to facilitate
cyclocondensation (Method B). Efficient synthesis of
N-aryl heterocyclic enamines 6 was achieved from the
reaction of methylsulfonates with anilines when a polar
solvent such as ethanol was used (Methods C and D),
albeit the ester interchange was observed in some cases.
It was also noticeable that the synthesis was not limited
to anilines bearing an electron-donating substituent.14 In
other words, all anilines that bear either an electron-
donating or electron-withdrawing group readily reacted
with methylsulfonates to furnish heterocyclic enamine
products. It should be noted that, during the course of
reaction between o-bromoaniline and methylsulfonates,
a trace amount of unstable ω-(o-bromoanilino)-â-oxoal-
kanoate intermediates 5 and 5′ was observed from mass
(14) Michael, J . P.; Hosken, G. D.; Howard, A. S. Tetrahedron 1988,
44, 3025-3036.
(15) Lundt, I. Top. Curr. Chem. 1997, 187, 117-156.
(16) Valters, R. E.; Flitsch, W. Ring-chain Tautomerism; Katritzky,
A. R, Ed.; Plenum Press: New York, 1985.
3282 J . Org. Chem., Vol. 68, No. 8, 2003

Synthesis of Heterocyclic Enamines
TABLE 2. Com p ou n d s 6 P r ep a r ed fr om th e Rea ction betw een Meth ylsu lfon a tes 3 a n d Am in es 4
entry
6
n
R1
R2
R3
reaction conditionsa
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
H
H
H
H
H
H
H
H
H
H
H
H
PhCH2
But
But
But
Et
Method A
Method B
Method B
Method C
Method C
Method C
Method C
Method C
Method C
Method C
Method C
Method D
Method C
Method A
Method A
Method C
Method B
Method B
Method A
Method B
Method B
Method B
Method C
Method C
Method C
57
44
42
80
69
75
75
71
42
62
63
40
66
66
57
85
44
41
61
68
75
78
75
61
53
CH2dCHCH2
EtO2CCH2
Ph
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
o-MeC6H4
m-BrC6H4
p-BrC6H4
p-ClC6H4
p-NO2C6H4
Naph
Me
PhCH2
Ph
PhCH2
EtO2CCH2
Me
PhCH2
CH2dCHCH2
EtO2CCH2
Ph
But
But
But
But
But
Et
Et
Et
H
But
But
But
But
But
But
But
But
But
But
But
But
But
MeO
MeO
MeO
CH2dCHCH2O
CH2dCHCH2O
PhCH2O
PhCH2O
PhCH2O
PhCH2O
PhCH2O
H
6s
6t
6u
6v
6w
6x
6y
PhCH2
CH2dCHCH2
H
a
Reactions, which were not optimized, were terminated in about 24 h. Method A: Dichloromethane was used as the solvent and
reaction was carried out at room temperature. Method B: Same as Method A but with molecular sieves (4 Å). Method C: Ethanol was
b
used as the solvent. Method D: Reaction was carried out in warm ethanol (35-45 °C) solution. Isolated yield.
SCHEME 2. P r ep a r a tion of In d olizid in e
Der iva tives
and reagents were required, the reaction conditions were
mild and experimental operations were very simple and
convenient, the synthesis appeared practical and ap-
plicable in the preparation of various heterocyclic enam-
ines. The synthetic potential of this new transformation
was demonstrated by a facile and straightforward prepa-
ration of indolizidine compounds, using 3-bromopropyl-
amine as the amine reactant. The method would open a
new venue to synthetically versatile heterocyclic enam-
ines from sugar lactones. Application of this method in
the total synthesis of (poly)hydroxylated indolizidine
alkaloids is under investigation in this laboratory.
spectra. This suggests that the substitution reaction of
methylsulfonate by an amine proceeded prior to conden-
sation with the ketone moiety, a reaction pathway dif-
ferent from the reaction of anilines with 6-chloro-3-
oxohexanoate,14 which also explains high reactivity of
methylsulfonates 3 toward anilines including p-nitro-
aniline of low nucleophilicity.
Since the formation of heterocyclic enamines via the
ring transformation of lactones was general, being not
limited to amine structures, we attempted the prepara-
tion of N-bromoalkyl-substituted enamine intermediates
for indolizidine synthesis. Both methylsulfonates 3a and
3b reacted effectively with 3-bromopropylamine hydro-
bromide to afford the desired enamines 7a and 7b in
moderate yield. Reflux of 7 in ethanol led to the formation
of indolizidine product 8 in a yield of 60-65% (Scheme
2). To our knowledge, this is the shortest route to the
indolizidine structure.
Exp er im en ta l Section
Melting points are uncorrected. Elemental analyses were
performed at the Analytical Laboratory of the Institute. All
chemicals were dried or purified according to standard pro-
cedures prior to use, and molecular sieves (4 Å) were ground
into fine powder.
Gen er a l P r oced u r e for th e Refor m a tsk y Rea ction of
La cton es. A mixture of lactone (20 mmol), tert-butyl bromoac-
etate (30-36 mmol), activated zinc dust (20-30 mmol), and
copper dust (2 mmol) in dry THF was refluxed gently under
argon. After the starting lactone was consumed, which was
monitored by TLC, the mixture was cooled and the solvent
was removed under vacuum. The residue was stirred vigor-
ously with a mixture of ethyl acetate (50 mL) and water (2
mL) for 5 min and then was filtrated through a Celite pad.
The filtrate was washed with brine and dried with anhydrous
Na2SO4. After removal of solvent and column chromatography,
product 2 was obtained as colorless liquid. 1H NMR spectra
showed that it was a mixture of ring and chain tautomers (see
Supporting Information). Without column chromatography,
the crude product can be used directly for mesylation reaction.
Con clu sion
In summary, we have provided a novel approach to
heterocyclic enamines from the formal ring transforma-
tion of lactones, which comprised consecutively the
Reformatsky reaction of lactones, mesylation of the
resulting mixture of ring and chain tautomers, followed
by cyclocondensation reaction with primary amines. Since
only the readily available and cheap starting materials
Gen er a l P r oced u r e for th e P r ep a r a tion of Meth ylsu l-
fon a te Com p ou n d s 3. To a mixture of isolated Reformatsky
adducts 2 (5 mmol) or the crude 2 (obtained from 5.5 mmol of
lactone) without purification by column chromatography and
J . Org. Chem, Vol. 68, No. 8, 2003 3283

Wang et al.
pyridine (3 equiv) in dichloromethane (12 mL) under argon
was added methanesulfonyl chloride (3 equiv) dropwise with
continued stirring and cooling at 0 C°. After 3 h, the reaction
mixture was warmed gradually to room temperature and
stirred for another day. A saturated NaHCO3 aqueous dichlo-
romethane (15 mL) solution was added and the organic
mixture was washed with brine and then dried with anhydrous
Na2SO4. After removal of solvent, the residue was purified by
flash chromatography with use of a silica gel column and a
mixture of petroleum ether and ethyl acetate (2:1) as an eluent
to give methylsulfonate derivatives 3. All methylsulfonates 3
were not very stable and were used immediately after isolation.
Gen er a l P r oced u r e for th e P r ep a r a tion of Heter ocy-
clic En a m in es 6 fr om th e An n u la tion Rea ction of Meth -
ylsu lfon a tes 3 w ith P r im a r y Am in es. A mixture of a meth-
ylsulfonate with 1 equiv of an amine or ammonium was stirred
for a period of time at room temperature in dichloromethane
(Method A) with 4 Å molecular sieves (Method B), or in ethanol
(Method C) or in warm ethanol (35-45 °C) (Method D). After
completion of the reaction, the precipitated was filtrated and
the filtrate was concentrated and chromarographied to give
heterocyclic enamines 6.
1-Ben zyl-2-[(ter t-b u t oxyca r b on yl)m et h ylid en e]p yr -
r olid in e (6a ). White solid, mp 116 °C; 1H NMR (CDCl3) δ
7.35-7.25 (m, 3H), 7.17 (d, J ) 7.3 Hz, 2H), 4.63 (s, 1H), 4.34
(s, 2H), 3.29 (t, J ) 7.1 Hz, 2H), 3.20 (t, J ) 7.7 Hz, 2H), 1.94
(quin, J ) 7.4 Hz, 2H), 1.45 (s, 9H); 13C NMR (CDCl3) δ 169.2,
164.3, 136.1, 128.5, 127.2, 127.0, 80.0, 77.4, 52.0, 49.7, 32.3,
28.5, 21.0; IR (KBr) 1680 (CdO), 1602 cm-1 (CdC); MS (FAB)
m/z 274 (M + H). Anal. Calcd for C17H23NO2: C, 74.69; H, 8.48;
N, 5.12. Found: C, 74.52; H, 8.57; N, 4.82.
3H), 3.68 (t, J ) 6.9 Hz, 2H), 3.27 (t, J ) 7.7 Hz, 2H), 2.05
(quin, J ) 7.3 Hz, 2H), 1.44 (s, 9H); 13C NMR (CDCl3) δ 169.3,
162.6, 160.3, 142.8, 130.0, 116.8, 111.0, 110.4, 83.5, 77.7, 55.3,
54.3, 32.4, 28.6, 21.5; IR (KBr) 1675 (CdO), 1618 cm-1 (CdC);
MS (EI) m/z 289 (M+, 12%), 233 (18), 216 (17), 188 (100). Anal.
Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C,
70.73; H, 8.13; N, 4.65.
1-(4-Met h oxyp h en yl)-2-[(ter t-b u t oxyca r b on yl)m et h -
1
ylid en e]p yr r olid in e (6g). White solid, mp 101 °C; H NMR
(CDCl3) δ 7.16 (d, J ) 8.8 Hz, 2H), 6.93 (d, J ) 8.8 Hz, 2H),
4.66 (s, 1H), 3.82 (s, 3H), 3.66 (t, J ) 7.0 Hz, 2H), 3.28 (t, J )
7.7 Hz, 2H), 2.07 (quin, J ) 7.3 Hz, 2H), 1.44 (s, 9H); 13C NMR
(CDCl3) δ 168.9, 163.4, 157.1, 133.8, 125.9, 114.1, 81.8, 54.9,
54.3, 31.8, 28.1, 21.1; IR (KBr) 1677 (CdO), 1599 cm-1 (CdC);
MS (EI) m/z 289 (M+, 42%), 233 (100), 216 (53), 189 (48), 188
(51), 174 (36). Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01;
N, 4.84. Found: C, 70.60; H, 8.08; N, 4.67.
1-(2-Me t h ylp h e n yl)-2-[(t er t -b u t oxyca r b on yl)m e t h -
ylid en e]p yr r olid in e (6h ). White solid, mp 130 °C; 1H NMR
(CDCl3) δ 7.40-7.10 (m, 4H), 4.20 (s, 1H), 3.56 (t, J ) 7.0 Hz,
2H), 3.70-3.25 (m, 2H), 2.15 (s, 1H), 2.14-2.00 (m, 2H), 1.40
(s, 9H); 13C NMR (CDCl3) δ 169.4, 164.1, 139.6, 135.9, 131.3,
127.8, 127.4, 82.0, 77.5, 54.2, 31.9, 28.6, 22.1, 17.5; IR (KBr)
1675 (CdO), 1608 cm-1 (CdC); MS (EI) m/z 273 (M+, 6%), 200
(17), 172 (13), 158 (100). Anal. Calcd for C17H23NO2: C, 74.69;
H, 8.48; N, 5.12. Found: C, 74.67; H, 8.53; N, 4.86.
1-(3-Br om op h e n yl)-2-[(t er t -b u t oxyca r b on yl)m e t h -
1
ylid en e]p yr r olid in e (6i). White solid, mp 100-101 °C; H
NMR (CDCl3) δ 7.34 (s, 1H), 7.29-7.15 (m, 4H), 4.88 (s, 1H),
3.63 (t, J ) 6.9 Hz, 2H), 3.23 (t, J ) 7.6 Hz, 2H), 2.02 (quin,
J ) 7.3 Hz, 2H), 1.41 (s, 9H); 13C NMR (CDCl3) δ 169.0, 162.1,
143.1, 130.6, 128.5, 127.3, 123.1, 122.8, 84.4, 78.0, 54.1, 32.3,
28.6, 21.6; IR (KBr) 1670 (CdO), 1610 cm-1 (CdC); MS (EI)
m/z 339 (M + 2, 15), 337 (M+, 18%), 283 (48), 281 (51), 266
(36), 264 (17), 238 (41), 237 (43), 236 (54), 157 (100). Anal.
Calcd for C16H20BrNO3: C, 56.82; H, 5.96; N, 4.14. Found: C,
56.92; H, 5.85; N, 3.84.
1-Ally l-2-[(t er t -b u t o x y c a r b o n y l)m e t h y lid e n e ]p y r -
r olid in e (6b). White solid, mp 42-43 °C; 1H NMR (CDCl3) δ
5.82-5.66 (m, 1H), 5.17 (d, J ) 8.4 Hz, 1H), 5.13 (d, J ) 15.7
Hz, 1H), 4.48 (s, 1H), 3.74 (d, J ) 5.4 Hz, 2H), 3.32 (t, J ) 7.0
Hz, 2H), 3.13 (t, J ) 7.7 Hz, 2H), 1.92 (quin, J ) 7.4 Hz, 2H),
1.45 (s, 9H); 13C NMR (CDCl3) δ 169.3, 164.0, 131.1, 117.2,
79.9, 77.4, 52.0, 48.7, 32.4, 28.7, 21.1; IR (KBr) 1676 (CdO),
1600 cm-1 (CdC); MS (EI) m/z 223 (M+, 12%), 167 (16), 166
(12), 150 (20), 122 (100). Anal. Calcd for C13H21NO2: C, 69.92;
H, 9.48; N, 6.27. Found: C, 70.10; H, 9.77; N, 6.17.
1-(4-Br om op h en yl)-2-[(eth oxyca r bon yl)m eth ylid en e]-
p yr r olid in e (6j). White solid, mp 111-112 °C; 1H NMR
(CDCl3) δ 7.46 (d, J ) 8.6 Hz, 2H), 7.10 (d, J ) 8.6 Hz, 2H),
4.89 (s, 1H), 4.04 (q, J ) 7.1 Hz, 2H), 3.66 (t, J ) 7.1 Hz, 2H),
3.27 (t, J ) 7.0 Hz, 2H), 2.05 (quin, J ) 7.3 Hz, 2H), 1.19 (t,
J ) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 169.2, 163.2, 140.5, 132.5,
126.0, 118.8, 82.0, 58.5, 54.3, 32.4, 21.5, 14.6; IR (KBr) 1687
(CdO), 1604 cm-1 (CdO); MS (EI) m/z 311 (M + 2, 56), 309
(M+, 58%), 266 (52), 264 (52), 239 (64), 238 (72), 237 (74), 236
(65), 185 (65), 157 (100). Anal. Calcd for C14H16BrNO3: C,
54.21; H, 5.20; N, 4.52. Found: C, 54.55; H, 5.26; N, 4.06.
1-(4-Ch lor op h en yl)-2-[(eth oxyca r bon yl)m eth ylid en e]-
p yr r olid in e (6k ). White solid, mp 79 °C; 1H NMR (CDCl3) δ
7.38 (d, J ) 6.9 Hz, 2H), 7.22 (d, J ) 6.9 Hz, 2H), 4.92 (s, 1H),
4.11 (q, J ) 7.1 Hz, 2H), 3.72 (t, J ) 7.0 Hz, 2H), 3.33 (t, J )
7.7 Hz, 2H), 2.12 (quin, J ) 7.4 Hz, 2H), 1.25 (t, J ) 7.2 Hz,
2H); 13C NMR (CDCl3) δ 169.1, 163.3, 139.8, 130.9, 129.4,
125.6, 81.6, 58.4, 54.2, 32.3, 21.3, 14.4; IR (KBr) 1688 (CdO),
1608 cm-1 (CdC); MS (EI) m/z 267 (M + 2, 16), 265 (M+, 51%),
222 (29), 220 (89), 195 (21), 194 (41), 193 (70), 192 (100). Anal.
Calcd for C14H26NO2Cl: C, 63.28; H, 6.07; N, 5.27. Found: C,
63.14; H, 5.90; N, 5.19.
1-(E t h oxyca r b on ylm et h yl)-2-[(ter t-b u t oxyca r b on yl)-
1
m eth ylid en e]p yr r olid in e (6c). H NMR (CDCl3) δ 4.43 (s,
1H), 4.38 (q, J ) 7.1 Hz, 2H), 3.92 (s, 2H), 3.47 (t, J ) 7.1 Hz,
2H), 3.19 (t, J ) 7.7 Hz, 2H), 2.00 (quin, J ) 7.4 Hz, 2H), 1.49
(s, 9H), 1.32 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 168.8,
168.5, 164.1, 81.1, 77.6, 61.3, 53.1, 47.6, 32.0, 28.6, 21.3, 14.1;
IR (KBr) 1748 (CdO), 1683 (CdO), 1600 cm-1 (CdC); MS (EI)
m/z 269 (M+, 35%), 213 (43), 196 (54), 140 (100). HRMS calcd
for C14H23NO4 (M + 1) 270.1704. Found 270.1700.
1-P h e n y l-2-[(e t h o x y c a r b o n y l)m e t h y li d e n e ]p y r -
r olid in e (6d ). White solid, mp 62 °C; 1H NMR (CDCl3) δ 7.42-
7.19 (m, 5H), 4.91 (s, 1H), 4.07 (q, J ) 7.1 Hz, 2H), 3.74 (t, J
) 7.0 Hz, 2H), 3.32 (t, J ) 7.7 Hz, 2H), 2.10 (quin, J ) 7.4 Hz,
2H), 1.22 (t, J ) 7.1 Hz, 2H); 13C NMR (CDCl3) δ 169.2, 163.7,
141.2, 129.2, 125.7, 124.3, 80.8, 58.2, 54.3, 32.4, 21.3, 14.4; IR
(KBr) 1686 (CdO), 1608 cm-1 (CdC); MS (EI) m/z 231 (M+,
43%), 186 (70), 158 (100). Anal. Calcd for C14H17NO2: C, 72.70;
H, 7.41; N, 6.06. Found: C, 72.74; H, 7.25; N, 6.11.
1-(2-Met h oxyp h en yl)-2-[(ter t-b u t oxyca r b on yl)m et h -
ylid en e]p yr r olid in e (6e). White solid, mp 113-114 °C; H
1-(4-Nitr oph en yl)-2-[(eth oxycar bon yl)m eth yliden e]pyr -
r olid in e (6l). White solid, mp 90-92 °C; H NMR (CDCl3) δ
1
1
NMR (CDCl3) δ 7.29-6.94 (m, 4H), 4.34 (s, 1H), 3.80 (s, 3H),
3.70 (br, 2H), 3.25 (t, J ) 7.7 Hz, 2H), 2.08 (quin, J ) 7.3 Hz,
2H), 1.41 (s, 9H); 13C NMR (CDCl3) δ 169.4, 165.0, 155.3, 129.4,
129.1, 128.6, 121.1, 112.4, 81.8, 77.2, 55.6, 53.4, 32.0, 28.6, 22.0;
IR (KBr) 1680 (CdO), 1610 cm-1 (CdC); MS (EI) m/z 289 (M+,
9%), 216 (13), 174 (100). Anal. Calcd for C17H23NO3: C, 70.56;
H, 8.01; N, 4.84. Found: C, 70.78; H, 8.09; N, 4.76.
8.25 (d, J ) 9.1 Hz, 2H), 7.40 (d, J ) 8.8 Hz, 2H), 5.40 (s, 1H),
4.12 (q, J ) 7.1 Hz, 2H), 3.80 (t, J ) 6.9 Hz, 2H), 3.34 (t, J )
7.6 Hz, 2H), 2.12 (quin, J ) 7.3 Hz, 2H), 1.25 (t, J ) 7.1 Hz,
3H); 13C NMR (CDCl3) δ 169.2, 161.2, 148.0, 143.7, 125.4,
122.6, 86.7, 59.5, 54.0, 32.8, 21.6, 15.0; IR (KBr) 1684 (CdO),
1615 (CdC), 1578, 1325 cm-1; MS (EI) m/z 276 (M+, 68%), 247
(15), 231 (59), 204 (74), 203 (100), 185 (61). HRMS Calcd for
C
14H17N2O4 (M + 1) 277.1183. Found 277.1183.
1-(2-Na p h th yl)-2-[(ter t-bu toxyca r bon yl)m eth ylid en e]-
1-(3-Met h oxyp h en yl)-2-[(ter t-b u t oxyca r b on yl)m et h -
ylid en e]p yr r olid in e (6f). White solid, mp 94-95 °C; 1H NMR
(CDCl3) δ 7.29 (t, J ) 8.0 Hz, 1H), 6.84 (d, J ) 8.0 Hz, 1H),
6.78 (s, 1H), 6.74 (d, J ) 8.3 Hz, 1H), 4.91 (s, 1H), 3.80 (s,
p yr r olid in e (6m ). White solid, mp 185-186 °C; 1H NMR
(CDCl3) δ 7.88-7.31 (m, 7H), 4.20 (s, 1H), 3.75-3.48 (m, 3H),
3284 J . Org. Chem., Vol. 68, No. 8, 2003

Synthesis of Heterocyclic Enamines
3.37-3.28 (m, 1H), 2.20 (quin, J ) 7.3 Hz, 2H), 1.38 (s, 9H);
13C NMR (CDCl3) δ 169.3, 165.4, 137.9, 134.8, 129.7, 128.6,
128.2, 126.8, 126.5, 126.1, 125.2, 122.9, 83.2, 77.5, 55.4, 32.2,
28.6, 22.4; IR (KBr) 1677 (CdO), 1602 cm-1; MS (EI) m/z 309
(M+, 31%), 253 (60), 252 (52), 236 (36), 209 (52), 208 (100),
207 (88). Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49; N, 4.53.
Found: C, 77.58; H, 7.42; N, 4.39.
3-Me t h oxy-1-m e t h yl-2-[(t er t -b u t oxyca r b on yl)m e t h -
ylid en e]p yr r olid in e (6n ). Colorless oil: 1H NMR (CDCl3) δ
5.30 (d, J ) 5.3 Hz, 1H), 4.48 (s, 1H), 3.60 (dt, J ) 6.1, 9.5 Hz,
1H), 3.47 (s, 3H), 3.20 (t, J ) 9.0 Hz, 1H), 2.80 (s, 3H), 2.09-
2.02 (m, 1H), 1.98-1.69 (m, 1H), 1.49 (s, 9H); 13C NMR (CDCl3)
δ 168.1, 161.3, 81.5, 79.0, 77.6, 57.2, 52.1, 33.0, 28.6, 28.4. IR
(KBr) 1685 (CdO), 1614 cm-1 (CdC); MS (EI) m/z 227 (M+,
5%), 197 (8), 154 (16), 141 (53), 41 (100). HRMS calcd for
(CDCl3) δ 7.38-7.17 (m, 10H), 5.72 (d, J ) 5.1 Hz, 1H), 4.80
(d, J ) 11.1 Hz, 1H), 4.69 (d, J ) 10.7 Hz, 1H), 4.68 (s, 1H),
4.37 (s, 2H), 3.62 (dt, J ) 6.3, 9.2 Hz, 1H), 3.20 (t, J ) 8.3 Hz,
1H), 2.13-1.97 (m, 2H), 1.48 (s, 9H); 13C NMR (CDCl3) δ 168.4,
161.2, 138.9, 135.8, 128.5, 128.0, 127.8, 127.3, 127.2, 126.8,
82.1, 78.1, 77.7, 71.7, 50.2, 49.4, 29.2, 28.5; IR (KBr) 1682
(CdO), 1608 cm-1 (CdC); MS (EI) m/z 306 (M - 73, 4%), 273
(14), 217 (46), 170 (9), 91 (100). HRMS calcd for C24H29NO3
(M + 1) 380.2222. Found 380.2220.
1-Allyl-3-b e n zyloxy-2-[(t er t -b u t oxyca r b on yl)m e t h -
ylid en e]p yr r olid in e (6u ). Oil; 1H NMR (CDCl3) δ 7.36-7.20
(m, 5H), 5.77-5.64 (m, 1H), 5.63 (d, J ) 5.3 Hz, 1H), 5.18-
5.11 (m, 2H), 4.75 (d, J ) 11.1 Hz, 1H), 4.66 (d, J ) 11.1 Hz,
1H), 4.54 (s, 1H), 3.76 (s, 2H), 3.60 (dt, J ) 15.4, 8.8 Hz, 1H),
3.22 (s, br, 1H), 2.10-1.93 (m, 2H), 1.47 (s, 9H); 13C NMR
(CDCl3) δ 168.5, 161.0, 139.1, 130.8, 128.2, 128.0, 127.4, 117.0,
81.9, 78.4, 77.7, 72.0, 50.2, 48.5, 29.3, 28.7; IR (KBr) 1683
(CdO), 1609 cm-1 (CdC); MS (EI) m/z 329 (M+, 4%), 256 (11),
223 (23), 167 (100), 91 (72). HRMS calcd for C20H29NO3 (M +
1) 330.2065. Found 330.2064.
3-Be n zyloxy-1-(e t h oxyca r b on ylm e t h yl)-2-[(t er t -b u -
toxyca r bon yl)m eth ylid en e]p yr r olid in e (6v). White solid,
mp 68-69 °C; 1H NMR (CDCl3) δ 7.38-7.21 (m, 5H), 5.63 (d,
J ) 4.6 Hz, 1H), 4.75 (d, J ) 11.0 Hz, 1H), 4.66 (d, J ) 11.1
Hz, 1H), 4.48 (s, 1H), 4.20 (q, J ) 7.1 Hz, 2H), 3.93 (d, J )
17.8 Hz, 1H), 3.76 (d, J ) 17.8 Hz, 1H), 3.68 (dt, J ) 15.8, 9.0
Hz, 1H), 3.33 (t, J ) 8.2 Hz, 2H), 2.14-2.01 (m, 2H), 1.48 (s,
9H), 1.24 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 168.5, 167.9,
160.9, 139.0, 128.2, 128.0, 127.4, 83.3, 78.0, 77.8, 71.9, 61.4,
51.2, 47.6, 29.6, 28.6, 14.2; IR (KBr) 1754 (CdO), 1687
(CdO), 1607 cm-1 (CdC); MS (EI) m/z 302 (M - 73, 8%), 269
(23), 213 (36), 140 (100). HRMS calcd for C21H29NO5 (M + 1)
376.2120. Found 376.2118.
C
12H21NO3 (M + 1) 228.1597. Found 228.1594.
1-Be n zyl-3-m e t h oxy-2-[(t er t -b u t oxyca r b on yl)m e t h -
ylid en e]p yr r olid in e (6o). Solid, mp 84-85 °C; 1H NMR
(CDCl3) δ 7.38-7.25 (m, 3H), 7.19 (d, J ) 7.3 Hz, 2H), 5.42 (d,
J ) 5.1 Hz, 1H), 4.66 (s, 1H), 4.35 (s, 2H), 3.62-3.52 (m, 1H),
3.49 (s, 3H), 3.20 (t, J ) 9.0 Hz, 1H), 2.13-2.07 (m, 1H), 2.01-
1.93 (m, 1H), 1.46 (s, 9H); 13C NMR (CDCl3) δ 168.3, 160.9,
135.8, 128.6, 127.2, 126.8, 82.3, 78.9, 77.7, 57.1, 50.1, 49.5, 28.5;
IR (KBr) 1677 (CdO), 1610 cm-1 (CdC); MS (EI) m/z 303 (M+,
12%), 273 (26), 261 (38), 230 (73), 217 (84), 216 (75), 215 (63),
170 (99), 91 (100). Anal. Calcd for C18H25NO3: C, 71.26; H,
8.31; N, 4.62. Found: C, 71.32; H, 8.43; N, 4.49.
3-Me t h oxy-1-p h e n yl-2-[(t er t -b u t oxyca r b on yl)m e t h -
ylid en e]p yr r olid in e (6p ). White solid, mp 75-76 °C; 1H
NMR (CDCl3) δ 7.42-7.14 (m, 5H), 5.49 (d, J ) 5.0 Hz, 1H),
5.00 (s, 1H), 3.97-3.89 (m, 1H), 3.62 (t, J ) 9.0 Hz, 1H), 3.54
(s, 3H), 2.22-2.00 (m, 2H), 1.45 (s, 9H); 13C NMR (CDCl3) δ
168.3, 159.2, 141.5, 129.4, 125.6, 124.3, 86.0, 78.7, 78.1, 57.3,
52.1, 28.7, 28.5; IR (KBr) 1682 (CdO), 1616 cm-1 (CdC); MS
(EI) m/z 289 (M+, 9%), 259 (22), 216 (21), 203 (100). Anal. Calcd
for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.54;
H, 8.05; N, 4.98.
3-Allyloxy-1-b e n zyl-2-[(t er t -b u t oxyca r b on yl)m e t h -
ylid en e]p yr r olid in e (6q). Oil; 1H NMR (CDCl3) δ 7.37-7.25
(m, 3H), 7.18 (d, J ) 7.5 Hz, 2H), 6.06-5.94 (m, 1H), 6.01 (d,
J ) 5.0 Hz, 1H), 5.31 (d, J ) 17.2 Hz, 1H), 5.17 (d, J ) 10.4
Hz, 1H), 4.67 (s, 1H), 4.38 (s, 2H), 4.25 (s, br, 2H), 3.62 (dt, J
) 6.1, 9.7 Hz, 1H), 3.20 (t, J ) 8.9 Hz, 1H), 2.13-1.97 (m,
2H), 1.48 (s, 9H); 13C NMR (CDCl3) δ 168.4, 161.3, 136.0, 135.5,
128.7, 127.3, 126.9, 116.5, 82.2, 77.8, 77.6, 70.7, 50.3, 49.5, 29.5,
28.6; IR (KBr) 1684 (CdO), 1611 cm-1 (CdC); MS (EI) m/z 329
(M+, 3%), 273 (12), 256 (8), 232 (6), 217 (42), 91 (100). HRMS
calcd for C20H27NO3 (M + 1) 330.2062. Found 330.2064.
3-Allyloxy-1-(et h oxyca r b on ylm et h yl)-2-[(ter t-b u t oxy-
ca r bon yl)m eth ylid en e]p yr r olid in e (6r ). 1H NMR (CDCl3)
δ 6.00-5.85 (m, 1H), 5.46 (d, J ) 4.6 Hz, 1H), 5.24 (d, J )
17.2 Hz, 1H), 5.09 (d, J ) 10.4 Hz, 1H), 4.42 (s, 1H), 4.20-
4.14 (m, 4H), 3.89 (d, J ) 15.0 Hz, 1H), 3.80 (d, J ) 15.0 Hz,
1H), 3.69-3.61 (m, 1H), 3.28 (t, J ) 8.3 Hz, 2H), 2.07-1.96
(m, 2H), 1.42 (s, 9H), 1.25 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3)
δ 168.4, 167.7, 160.8, 135.4, 116.4, 83.2, 77.9, 77.1, 70.6, 61.3,
51.0, 47.5, 29.6, 28.5, 14.1; IR (KBr) 1748 (CdO), 1688
(CdO), 1614 cm-1 (CdC); MS (EI) m/z 325 (M+, 3%), 269 (11),
252 (11), 228 (5), 213 (23), 196 (19), 140 (100). HRMS calcd
for C17H27NO5 (M + 1) 326.1964. Found 326.1962.
3-Ben zyloxy-1-p h en yl-2-[(ter t-b u t oxyca r b on yl)m et h -
1
ylid en e]p yr r olid in e (6w ). White solid, mp 110-111 °C; H
NMR (CDCl3) δ 7.41-7.14 (m, 10H), 5.77 (d, J ) 5.0 Hz, 1H),
5.04 (s, 1H), 4.83 (d, J ) 11.0 Hz, 1H), 4.72 (d, J ) 11.0 Hz,
1H), 3.98 (dt, J ) 6.1, 9.5 Hz, 1H), 3.31 (t, J ) 8.6 Hz, 1H),
2.23-2.07 (m, 2H), 1.46 (s, 9H); 13C NMR (CDCl3) δ 168.5,
159.5, 141.5, 139.0, 129.4, 128.2, 128.0, 127.5, 125.5, 124.2,
86.0, 78.1, 72.2, 52.2, 29.4, 28.6; IR (KBr) 1685 (CdO), 1612
cm-1 (CdC); MS (EI) m/z 292 (M - 73, 6%), 259 (31), 203 (100).
Anal. Calcd for C22H27NO3: C, 75.59; H, 7.45; N, 3.83. Found:
C, 75.73; H, 7.36; N, 3.83.
1-Be n zyl-2-[(t er t-b u t oxyca r b on yl)m e t h ylid e n e ]p ip -
1
er id in e (6x). White solid, mp 110-111 °C; H NMR (CDCl3)
δ 7.34-7.13 (m, 5H), 4.62 (s, 1H), 4.36 (s, 2H), 3.20-3.13 (m,
4H), 1.75-1.67 (m, 4H), 1.40 (s, 9H); 13C NMR (CDCl3) δ 169.2,
162.0, 136.4, 128.7, 127.1, 126.8, 84.5, 77.4, 55.0, 49.6, 28.7,
26.8, 23.4, 19.9; IR (KBr) 1673 (CdO), 1566 cm-1; MS (EI) m/z
287 (M+, 12%), 231 (32), 230 (22), 214 (17), 186 (37), 91 (100).
Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found:
C, 75.26; H, 8.86; N, 4.71.
1-Ally l-2-[(t er t -b u t o x y c a r b o n y l)m e t h y lid e n e ]p ip -
er id in e (6y). Oil; 1H NMR (CDCl3) δ 5.74-5.66 (m, 1H), 5.12
(d, J ) 11.5 Hz, 1H), 5.06 (d, J ) 18.6 Hz, 1H), 4.47 (s, 1H),
3.69 (s, 2H), 3.11 (t, J ) 5.3 Hz, 2H), 3.00 (t, J ) 5.4 Hz, 2H),
1.69 (quin, J ) 4.9 Hz, 2H), 1.57 (quin, J ) 5.1 Hz, 2H), 1.37
(s, 9H); 13C NMR (CDCl3) δ 168.9, 161.1, 131.1, 116.8, 84.0,
54.2, 49.1, 28.6, 26.6, 23.3, 19.7; IR (KBr) 1679 (CdO), 1569
cm-1; MS (EI) m/z 237 (M+, 11%), 181 (20), 164 (21), 149 (7),
136 (100), 122 (30). HRMS calcd for C14H23NO2 (M + 1)
238.1804. Found 238.1801.
P r ep a r a tion of Eth yl 1,2,3,5,6,7-Hexa h yd r oin d olizin e-
8-ca r boxyla te (8a ). The reaction of 3a with 3-bromopropyl-
amine hydrobromide following the procedure described above
(Method B) gave 1-(3-bromopropyl)-2-[(tert-butoxycarbonyl)-
methylidene]pyrrolidine (7a ): 30%; oil; 1H NMR (300 MHz,
CDCl3) δ 4.48 (s, 1H), 3.42-3.34 (m, 6H), 3.13 (t, J ) 7.6 Hz,
2H), 2.14 (quin, J ) 6.5 Hz, 2H), 1.95 (quin, J ) 7.3 Hz, 2H),
1.57 (s, 9H); 13C NMR (CDCl3) δ 169.1, 163.9, 80.0, 77.6, 53.0,
44.6, 32.4, 30.8, 29.1, 28.7, 21.2. Compound 7a was then
3-Ben zyloxy-1-m et h yl-2-[(ter t-b u t oxyca r b on yl)m et h -
ylid en e]p yr r olid in e (6s). Oil; 1H NMR (CDCl3) δ 7.41-7.24
(m, 5H), 5.62 (d, J ) 5.3 Hz, 1H), 4.80 (d, J ) 10.9 Hz, 1H),
4.68 (d, J ) 10.9 Hz, 1H), 4.50 (s, 1H), 3.64 (dd, J ) 15.8, 9.4
Hz, 1H), 3.21 (t, J ) 8.9 Hz, 1H), 2.80 (s, 3H), 2.12-1.74 (m,
2H), 1.54 (s, 9H); 13C NMR (CDCl3) δ 168.3, 161.8, 139.0, 128.2,
128.1, 127.5, 81.3, 78.6, 77.6, 72.3, 52.3, 33.1, 29.1, 28.7; IR
(KBr) 1682 (CdO), 1613 cm-1 (CdC); MS (EI) m/z 230 (M -
73, 8%), 197 (26), 141 (100), 140 (33), 91 (37). HRMS calcd for
C
18H25NO3 (M + 1) 304.1906. Found 304.1907.
1-Ben zyl-3-b en zyloxy-2-[(ter t-b u t oxyca r b on yl)m et h -
ylid en e]p yr r olid in e (6t). White solid, mp 66-67 °C; 1H NMR
J . Org. Chem, Vol. 68, No. 8, 2003 3285

Wang et al.
refluxed in ethanol for 5 h. After removal of the solvent,
dichloromethane was added, and the mixture was washed with
saturated sodium carbonate aqueous solution and brine suc-
cessively. Column chromatography gave ethyl 1,2,3,5,6,7-
hexahydroindolizine-8-carboxylate (8a ): 65%; oil; 1H NMR
(300 MHz, CDCl3) δ 4.14 (t, J ) 7.1 Hz, 2H), 3.31 (t, J ) 7.0
Hz, 2H), 3.18 (t, J ) 5.7 Hz, 2H), 3.09 (t, J ) 7.7 Hz, 2H), 2.39
(t, J ) 6.3 Hz, 2H), 1.95 (quin, J ) 7.4 Hz, 2H), 1.87 (quin, J
) 6.0 Hz, 2H), 1.29 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3) δ
169.3, 159.6, 87.9, 58.8, 53.4, 45.4, 33.1, 22.0, 21.4, 15.2; IR
(KBr) 1675, 1594 cm-1; MS (EI) m/z 195 (M+, 54%), 166 (61),
150 (90), 122 (100). HRMS calcd for C11H18NO2 (M + 1)
196.1334. Found 196.1332.
P r ep a r a tion of Eth yl 3-Meth oxy-1,2,3,5,6,7-h exa h y-
d r oin d olizin e-8-ca r boxyla te (8b). The reaction of 3b with
3-bromopropylamine hydrobromide following the procedure
described above (Method B) gave 1-(3-bromopropyl)-3-methoxy-
2-[(tert-butoxycarbonyl)methylidene]pyrrolidine (7b): 32%; oil;
1H NMR (300 MHz, CDCl3) δ 5.28 (d, J ) 5.1 Hz, 1H), 4.49 (s,
1H), 3.59-3.52 (m, 1H), 3.41 (s, 3H), 3.36 (t, J ) 6.4 Hz, 2H),
3.29 (q, J ) 6.4 Hz, 1H), 3.21 (t, J ) 9.0 Hz, 1H), 2.14-1.98
(m, 1H), 1.91-1.80 (m, 1H), 1.43 (s, 9H); 13C NMR (CDCl3) δ
168.0, 160.4, 82.2, 78.9, 77.8, 57.2, 51.2, 44.3, 30.7, 28.9, 28.6,
28.5. Following the procedure for the preparation of 8a ,
compound 7b was transformed into ethyl 3-methoxy-1,2,3,5,6,7-
hexahydroindolizine-8-carboxylate (8b): 60%; oil; 1H NMR (300
MHz, CDCl3) δ 5.05 (d, J ) 5.5 Hz, 1H), 4.05 (t, J ) 7.1 Hz,
2H), 3.47-3.30 (m, 1H), 3.36 (s, 1H), 3.12-3.06 (m, 3H), 2.41-
2.21 (m, 2H), 2.00-1.68 (m, 4H), 1.18 (t, J ) 7.1 Hz, 2H); 13
C
NMR (CDCl3) δ 168.3, 156.5, 89.9, 80.7, 59.1, 57.7, 51.2, 45.3,
28.2, 22.1, 21.4, 15.2; IR (KBr) 1677, 1606 cm-1; MS (EI) m/z
225 (M+, 61%), 210 (15), 195 (100), 180 (74), 152 (28). HRMS
calcd for C12H20NO2 (M + 1) 226.1439. Found 226.1438.
Ack n ow led gm en t. We are grateful to the Major
State Basic Research Development Program of China
(Grant No. G2000077502) and the National Natural
Science Foundation of China for financial support. M.-
X. Wang and G. W. J . Fleet also thank the Chinese
Academy of Sciences and the Royal Society, London for
supporting a joint research project between China and
UK groups.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 2 and 3, and 1H NMR and 13C NMR spectra of
compounds 6a , 6d , 6g, 6j, 6m , 6o, 6s, 6x, and 6y. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O026560T
3286 J . Org. Chem., Vol. 68, No. 8, 2003