Unexpected ring size effect of the annulation reaction of heterocyclic secondary enamines with dicarboxylic acid dichlorides

Article abstract of DOI:10.1016/S0040-4020(02)00177-1

Heterocyclic enamines are versatile ambident nucleophilic reagents able to react with both aliphatic and aromatic dicarboxylic acid dichlorides in diverse manners. The reaction outcome was strongly dependent upon the heterocyclic structure of the enamines

Full text of DOI:10.1016/S0040-4020(02)00177-1

TETRAHEDRON
Pergamon
Tetrahedron 58 32002) 2821±2829
Unexpected ring size effect of the annulation reaction
of heterocyclic secondary enamines with
dicarboxylic acid dichlorides
a,p
Ying Cheng, Hai-Bo Yang, Mei-Xiang Wang and David J. Williams
a
b,p
c
a
Department of Chemistry, Beijing Normal University, Beijing 100875, People's Republic of China
Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, People's Republic of China
b
c
Department of Chemistry, Imperial College, London SW7 2AY, UK
Received 8 November 2001; revised 14 January 2002; accepted 14 February 2002
AbstractÐHeterocyclic enamines are versatile ambident nucleophilic reagents able to react with both aliphatic and aromatic dicarboxylic
acid dichlorides in diverse manners. The reaction outcome was strongly dependent upon the heterocyclic structure of the enamines and the
nature of the diacid dichlorides employed. q 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
Much attention has been given to the annulation reactions
between heterocyclic enamines and a,b-unsaturated
1
6,17
Heterocyclic secondary enamines 1, also known as exo-
cyclic enaminoesters, enaminones, and enamino nitriles
when the electron-withdrawing group 3EWG) is ester,
acyl, and cyano, respectively, are versatile intermediates
for the synthesis of natural products and heterocyclic
compounds in the past decades
gation of the reaction of exo-cyclic enamino esters with
and a systematic investi-
1
8
electrophilic alkynes has appeared very recently. Surpris-
ingly, however, no reaction of heterocyclic secondary
enamines with dicarboxylic acid dichlorides, simple and
strong biselectrophilic species, has yet been reported. We
envisaged that annulation of enamines 1 through diacylation
using dicarboxylic acid dichlorides should produce poly-
functionalized fused heterocyclic derivatives that would
1
compounds. In the 1960s, Eschenmoser and his co-workers
pioneered the chemistry of heterocyclic enamines during
their synthetic studies of corrin. They used the reaction of
an enamino nitrile with iminoether as one of the key steps in
the construction of the corrin ring system. Since the late
1
9
be valuable precursors to hydroxylated pyrrolizidine and
2
0
1
Kishi, Danishefsky,
970s, heterocyclic enamines have been investigated by
indolizidine alkaloids such as rosmarinecine and castano-
spermine and their analogues. By systematically examining
the reactions of heterocyclic secondary enamines with both
aliphatic and aromatic dicarboxylic acid chlorides, we have
been astonished by the unexpected diversity of reaction
patterns which are strongly dependent upon the structures
2
ꢀ±5
6
Rapoport and others in the
synthesis of saxitoxin, camptothecin, mitomycins and
alkaloids.
7
±12
Recently, a synthesis of carbacephems, a
1
ꢀ
new class of b-lactam antibiotics, has been reported by
reducing the double bond of exo-cyclic enaminoesters
followed by intramolecular cyclization.
2
1
of both reactants. Herein we wish to report our results.
One of the most intriguing features of heterocyclic
secondary enamines 1 is their ambident bisnucleophilicity;
nucleophilic reaction can take place at the site of enaminic
carbon and/or the secondary amino nitrogen. This has been
2. Results and discussion
Initially, we chose the cheap and commercially available
oxalyl chloride as the biselectrophilic reagent, expecting
formation of pyrrol-2,ꢀ-dione-fused heterocycles. In the
presence of pyridine as an acid scavenger, enamines of
different heterocyclic ring size 31a±c) reacted smoothly
and ef®ciently with oxalyl chloride at 215 to 2108C in
methylene chloride. Surprisingly, however, the reaction
produced completely different heterocyclic ring systems,
depending on the structure of the starting heterocyclic
enamines. Whilst the ®ve-membered enamine 1a gave the
C-acylated product 2 in 62% yield, the six-membered
1
4,15
exempli®ed
by the acylation reaction using simple
carboxylic acid chlorides, which gave rise to C- and/or
N-acylated products depending upon both the heterocyclic
structure of enamines and the structure of carboxylic acids.
Keywords: annulation; heterocyclic secondary enamines; dicarboxylic acid
dichlorides.
p
Corresponding authors. Tel.: 18610-6220558;
e-mail: mxwang@infocꢀ.icas.ac.cn; Tel.: 18610-62564628; fax: 18610-
62569564; e-mail: yincheng@95777.com
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020302)00 177-1

2822
Y. Cheng et al. / Tetrahedron 58 ꢀ2002) 2821±2829
It is worth noting that in all the aforementioned cases, no
N-acylated products were obtained, regardless of both the
ring size of the heterocyclic enamines and the structure of
dicarboxylic acid dichlorides. This is different from the
acylation reactions of enamines 1 using mono-carboxylic
1
4
acid halides, which have been reported to yield C- and/
or N-acylated products depending on the heterocyclic
structure of the enamine.
Apparently, compound 2 has resulted from the hydrolysis of
the initially formed C-acylated intermediate 8 3nˆ1), while
the formation of product 4 was probably effected by the
cyclization of the intermediate 8 3nˆꢀ). The energy gained
from both aromatization and intramolecular hydrogen bond
formation between the hydroxy and carbonyl groups
stabilizes the hydroxylated pyrrol-2-one structure, giving 5
as the major isomer in equilibrium. The formation of 7 most
probably stemmed from a similar C-acylation, cycloconden-
sation followed by aromatization. To account for the forma-
tion of the pyranone product from the six-membered
enamine 1b, a reaction mechanism comprising proton-
assisted cyclisation and oxidative aromatization is
proposed. As depicted in Scheme ꢀ, intermediate 8 3nˆ2)
isomerizes to form the tetrahydropyridine 9. It has been
Scheme 1. Reaction of enamines 1a±c with oxalyl chloride.
1
4,17
analog 1b afforded a totally unexpected pyranone 3 as the
sole product in 76% yield. Only in the case of the seven-
membered enamine 1c, did the reaction form the expected
condensed heterocyclic product 4 in 67% yield. The use of
diethyl ether instead of methylene chloride as the solvent
did not affect the formation of 2 and 3, but improved the
reported
that six-membered exo-cyclic enamine
derivatives tend to shift their double bond from the exo- to
endo-position. Being an amino acid, the hydrolysis inter-
mediate 10 would tautomerize into its zwitterionic form
11 thus facilitating cyclization of the carboxylic anion to
1
1ꢀ
yield of 4 from 67 to 82%. As evidenced by both H and C
NMR data, each of which showed two sets of signals,
product 4 co-existed as an equilibrium mixture with the
hydroxylated pyrrol-2-one-fused azepine compound 5.
1
The ratio of 4 to 5, determined roughly by H NMR, was
about 1:1.8. 3Scheme 1).
Intrigued by the diversity of reactions with oxalyl chloride,
we then examined reaction of heterocyclic enamines 1a±c
with other dicarboxylic acid dichlorides. It has been
2
2
reported that only at an elevated temperature 31558C),
does 2-pyrrolidylidene acetate 1a undergo annulation with
substituted di-2,4,6-trichlorophenyl malonates. Under
similar conditions as that for oxalyl chloride, we found
that malonyl chloride reacted rapidly and effectively
with all enamines 1a±c tested to afford hydroxylated
2-pyridinone-fused heterocycles 7 as the sole products in
good yields 3Scheme 2).
Scheme 3. Proposed reaction pathways between enamines and oxalyl
chloride.
Scheme 2. Reaction of enamines 1a±c with malonyl chloride.

Y. Cheng et al. / Tetrahedron 58 ꢀ2002) 2821±2829
282ꢀ
Scheme 4. Reaction of enamines with succinyl chloride.
the enaminium double bond to form lactone 12. Oxidative
aromatization of 12, caused by atmospheric oxygen, would
then lead to the formation of the product 3 3Scheme ꢀ).
unambiguously by the X-ray crystallography. It is interest-
ing to note that in the H NMR spectra almost all the
methylene protons of the heterocyclic rings in 16b and
1
16c gave broad peaks at room temperature and they became
sharpened at 808C.
When the bis-electrophiles were extended to succinyl
chloride, the reaction became very sluggish at low tempera-
ture. Only under the conditions of re¯uxing in methlyene
chloride, did the reaction proceed effectively. However, a
very different chemistry was encountered. In all cases,
N-acylation took place. For example, the ®ve-membered
heterocyclic enamine 1a gave succinamide 13 in moderate
yield while the six- and seven-membered heterocyclic
enamines 1b and 1c led to the formation of the lactone-
bearing succinamide derivatives 16b and 16c in the yield
of 50and 24%, respectively 3Scheme 4). Spectroscopic data
and microanalysis con®rmed the structure of compound 13.
The structures of 16b and 16c were determined
As illustrated in Scheme 4, heterocyclic enamines 1a±c
reacted with succinyl chloride in a different fashion. Instead
of the C-acylation and subsequent cyclisation observed for
the reaction with malonyl chloride, di-N-acylation took
place ®rst between one succinyl chloride and two enamine
molecules to give succinamide 13. The dif®culty of forming
fused seven-membered ring products may account for the
di-N-acylation reaction rather than annulation in these
cases. Being more reactive than the ®ve-membered analog
13a, the six- and seven-membered heterocyclic inter-
mediates 13b±c underwent further diacylation at their
Figure 1. The molecular structure of 16b.
Figure 2. The molecular structure of 16c.

2824
Y. Cheng et al. / Tetrahedron 58 ꢀ2002) 2821±2829
Scheme 5. Reaction of enamines with phthaloyl dichloride.
enaminic carbons to form intermediate 14 which enolised
and lactonised to afford the ®nal product 16 3Scheme 4). The
spectroscopic data were insuf®cient to elucidate the struc-
ture of 16 and therefore their structures were determined by
single crystal X-ray analysis. These analyses showed both
16b and 16c to have inversion symmetry and established
unambiguously the patterns of bonding present in these two
compounds and the conformations that they adopt in the
solid state. The X-ray structures of 16b and 16c are shown
in Figs. 1 and 2, respectively.

Y. Cheng et al. / Tetrahedron 58 ꢀ2002) 2821±2829
2825
5.52 ppm suggested a dihydropyrrole moiety. The spectro-
scopic data were not suf®cient enough to elucidate the
structures of compounds 18 and 19, and their structures
were ®nally established by single crystal X-ray diffraction
1
analysis. Similar to compound 16, H NMR spectrum of
compounds 18 and 19 showed broad peaks corresponding
to the heterocyclic protons at room temperature and these
peaks sharpened as the probe temperature increased. The
tautomeric equilibrium between secondary enamine ketone
1
9a and imine enol 19b in solution was also observed, as the
1
H NMR spectrum of 19 gave two sets of signals. The
tautomeric ratio of 19a to 19b, which varied with tempera-
ture, was not determined because of the dif®culty in assign-
ing the peaks. The X-ray structures of compounds 18 and
19a are shown in Figs. ꢀ and 4, respectively.
The formation of different products 17±19 from the reaction
of heterocyclic enamines 1a±c and phthaloyl dichloride can
be best interpreted by the reaction pathways depicted in
Scheme 5. The C-acylation of enamines followed by intra-
molecular N-acylation led to the intermediate 21 3nˆ1, 2)
which underwent intermolecular condensation with the
secondary amino group of enamines 1a±b to yield 17.
Further acylation of 17b 3nˆ2) by secondary phthaloyl
dichloride resulted in the intermediate 23 which isomerized
and lactonized to furnish product 18 3nˆ2). In contrast to its
®ve- and six-membered analogs, the C-acylated seven-
membered heterocyclic intermediate 20 acted as an
acylating agent to react secondary amino group of the
second enamine molecule 1c with the formation of 25.
Further acylation at the enaminic carbon followed by
isomerization and lactonization yielded product 19.
Figure 3. The molecular structure of 18.
In order to construct a new azepine ring through the annula-
tion, we thought a rigid dicarboxylic acid dihalide such as
phthaloyl dichloride might help, as the initially formed
mono-C-acylation or mono-N-acylation intermediate
would bring the rest of the carboxylic acid chloride group
proximal to the secondary amino N atom or the enaminic
carbon atom. The idea worked, but in a more complicated
manner; the reaction outcome was again determined by the
heterocyclic structure of enamines 1 3Scheme 5). Whilst the
lactone-containing benzo[d]pyridino[1,2-a]azepinone 18
was isolated in moderate yield from the reaction of the
six-membered heterocyclic enamine 1b with phthaloyl
dichloride in re¯uxing methylene chloride, the
The results obtained from this study clearly indicate that the
reaction between heterocyclic enamines 1a±c and both
aliphatic and aromatic dicarboxylic acid dichlorides is
strongly dependent upon the structures of both reactants.
Being an ambident nucleophile, heterocyclic enamines
1a±c appeared extremely sensitive towards the dicarboxylic
acid dichlorides used. This was exempli®ed by the forma-
tion of different types of compounds such as 3, 7 and 14
from one enamine species 1b when treated with
dicarboxylic acid dichloride homologs. More strikingly,
heterocyclic enamines exhibited an unexpected ring size
effect on the enaminic and secondary amino reactivity, the
®
ve-membered heterocyclic enamine 1a gave the enam-
ine-substituted benzo[d]pyrrolo[1,2-a]azepinone product
7a, albeit in low yield. In the case of the seven-membered
1
heterocyclic enamine 1c, most surprisingly, compound 19
was produced in good yield. The structure of 17 was
evidenced by its spectroscopic data. The observation of a
singlet vinyl proton peak at 4.40ppm indicated the presence
of an enamine moiety whilst a triplet vinyl proton peak at
®
ve-, six- and seven-membered heterocyclic enamine
analogs producing diverse types of products when they
were allowed to react with the same dicarboxylic acid
dichloride. In most cases, both ®ve- and six-membered
heterocyclic enamines 1a±b displayed greater enaminic
reactivity than secondary amino group while for the
N-acylated enamines, the enaminic reactivity of the six-
and seven-membered compounds appeared higher than
that of the ®ve-membered analog. In addition, the six-
membered compound showed the highest tendency to shift
its exo-cyclic double bond to the endo position during the
course of the reaction. However, it should be noted that
the precise reason for the various reaction pathways for
the enamines of the different heterocyclic ring structures
remains unclear. This may arise from a combined effect of
the ambident conjugation system comprising a secondary
amino nitrogen, a double bond and an ester carbonyl within
a molecule, and the tendency for double bond migration
Figure 4. The molecular structure of 19a.

2826
Y. Cheng et al. / Tetrahedron 58 ꢀ2002) 2821±2829
from the exo- to the endo-position together with the ring
strain generated from the formation of fused heterocycles.
In other words, the ring size of heterocyclic secondary
enamines 1 plays an important and subtle part in determin-
ing the reaction outcome.
was performed in toluene, the product was obtained in
80±92%. The compounds 4 and/or 5 were sensitive to
heat. If the solvent was removed by heating during the
work-up, dark oil was resulted.
4.2.1. 3-Ethoxy-2,4-dioxo-3-ꢀ2-pyrrolidin-2-yl)butanoic
acid 2. White crystals: mp 1ꢀ9±1408C; H NMR 3CDCl )
d 11.4031H, s, OH), 9.82 31H, s, br, NH), 4.2032H, q,
1
ꢀ
3. Conclusion
Jˆ6.9 Hz, OCH ), ꢀ.75 32H, t, Jˆ6.8 Hz, NCH ), ꢀ.ꢀ1
2
2
2
In conclusion, we have demonstrated that heterocyclic
enamines 1a±c are versatile ambident nucleophilic reagents
able to react with both aliphatic and aromatic dicarboxylic
acid dichlorides. It has also been revealed that the reaction
outcome was strongly dependent upon the heterocyclic
structure of the enamines and the nature of the diacid
dichlorides employed. By reacting heterocyclic enamines
with dicarboxylic dichlorides we have provided simple,
convenient and powerful methods for the synthesis of a
wide arrange of heterocyclic compounds such as g-, d-
and 1-lactam-fused heterocycles, g- and d-lactone deriva-
tives that are not easily prepared from other means. The
novel products obtained from this study could serve as the
potential precursors to the indolizidine and quinolizidine
alkaloids and their analogs, the research being actively
studied in this laboratory.
32H, t, Jˆ7.6 Hz, CH
2
CvC), 2.1032H, m, CH
), 1.29
1
ꢀ
3ꢀH, t, Jˆ7.0Hz, CH ); C NMR 3CDCl ) d 184.7,
ꢀ
ꢀ
177.1, 170.4, 166.8, 94.2, 60.4, 48.6, ꢀ5.2, 20.4, 1ꢀ.8. IR
3KBr) ꢀꢀ00, ꢀ000, 2800, 2620, 1720, 1670, 1610 cm ; MS
2
1
1
3EI) m/z: 227 3M , 2%), 209 320), 182 3100), 154 390), 1ꢀ6
370), 1ꢀ5 360), 110 380), 109 3100). Anal. Calcd for
C H1ꢀNO : C, 52.86; H, 5.77; N, 6.16. Found: C, 52.69;
10 5
H, 5.86; N, 6.19.
4.2.2. Ethyl 3-hydroxy-2-oxo-5,6,7,8-tetrahydro-2H-
pyrano[3,2-b]pyridine-4-carboxylate 3. Pale yellow
1
crystals: mp 194±1958C; H NMR 3CDCl
) d 11.85 31H,
),
), 2.54 32H, t, Jˆ6.2 Hz,
), 1.44 3ꢀH, t, Jˆ7.0Hz,
) d 167.ꢀ, 158.4, 150.ꢀ, 148.6,
ꢀ
s, OH), 9.64 31H, s, br, NH), 4.47 32H, q, Jˆ7.0Hz, OCH
2
ꢀ.75 32H, t, Jˆ5.6 Hz, NCH
2
CH
CH
CvC), 2.05 32H, m, CH
2
ꢀ
2
1
); C NMR 3CDCl
ꢀ
ꢀ
1
ꢀ
10.1, 104.1, 62.8, ꢀ8.ꢀ, 27.5, 27.1, 14.ꢀ; IR 3KBr) ꢀ550,
2
1
1
400, 2960, 1650, 1460 cm ; MS 3EI) m/z 2ꢀ9 317%, M ),
: C, 55.2ꢀ; H, 5.48; N,
.85. Found: C, 55.26; H, 5.49; N, 5.87.
4. Experimental
19ꢀ 3100). Anal. Calcd for C11H1ꢀNO
5
5
4
.1. General
4
.2.3. Ethyl 2,3-dioxo-2,5,6,7,8,9-hexahydro-3H-pyrrolo-
1 1ꢀ
Melting points are uncorrected. H and C NMR spectra in
[1,2-a]azepine-1-carboxylate 4 and ethyl 2-hydroxy-3-
oxo-5,6,7,8-tetrahydro-3H-pyrrolo[1,2-a]azepine-1-car-
boxylate 5. Yellow powder from the reaction of 1c and
oxalyl chloride in ethyl ether): mp 84±908C; two sets of
CDCl or DMSO-d were obtained on Varian 200, Varian
ꢀ
6
ꢀ
00 and Avance 500 Bruker spectrometers. IR spectra were
obtained on a HITACHI-260-50 spectrometer as liquid ®lms
or KBr discs. Mass spectra were measured on a KYKY-
ZHT-5 mass spectrometer. Elemental analyses were
performed on a GMBH Vario EL instrument.
1
1
1ꢀ
H and C NMR corresponding to 4 and 5 were observed.
H NMR 3CDCl ) d 9.54 30.64H, s, br, OH), 6.27 30.64H, t,
), 4.28
ꢀ
Jˆ6.1 Hz, CHvC), 4.ꢀ9 31.28H, q, Jˆ7.1 Hz, OCH
2
3
0.72H, q, Jˆ7.1 Hz, OCH ), ꢀ.88±ꢀ.81 32H, m, NCH ),
2
2
All reagents were obtained from commercial suppliers. The
reaction solvent dichloromethane was dried with phos-
phorus pentoxide, and the ethyl ethane was dried with
sodium, respectively. Column chromatography was
performed using 200±ꢀ00 mesh silica gel. The enamines
ꢀ.ꢀ9 30.72H, br, CH
1.88 34H, m, 2CH ), 1.703 .07 2H, m, CH
CvC), 2.5031.28H, m, CH
2
CvC),
2
), 1.42±1.ꢀ1
2
2
1
ꢀ
); C NMR 3CDCl ) d 185.5,
3ꢀH, dt, Jˆ7.1 Hz, CH
ꢀ
ꢀ
178.1, 165.9, 162.4, 162.0, 156.5, 1ꢀꢀ.ꢀ, 115.9, 105.6,
10ꢀ.6, 101.0, 61.6, 60.5, 4ꢀ.2, 41.ꢀ, ꢀ0.1, 28.5, 27.7, 27.4,
26.6, 26.4, 25.7, 14.ꢀ, 14.ꢀ; IR 3KBr) ꢀ150, 1720, 1710,
2
ꢀ
1
a±c were prepared followed the literature method.
2
1
1
1
620cm ; MS 3EI) m/z 2ꢀ7 349%, M ), 191 3100), 16ꢀ
361). Anal. Calcd for C H NO : C, 60.75; H, 6.ꢀ7; N, 5.90.
Found: C, 60.48; H, 6.ꢀ8; N, 5.58.
4.2. General procedure for the reactions between 1a±c
and oxalyl chloride
12 15
4
Under nitrogen atmosphere, the oxalyl chloride 310mmol)
in dichloromethane 310mL) was added dropwise to the
mixture of enamine 1a±c 310mmol) and dry pyridine
4.3. Reaction with malonyl chloride
4.3.1. Reactions of 1a with malonyl chloride. Under
nitrogen atmosphere, the malonyl chloride 3ꢀ.5 mmol) in
dichloromethane 315 mL) was added dropwise to the solu-
tion of enamine 1a 3ꢀ.5 mmol) in dichloromethane 315 mL)
cooled in an ice±salt bath. The resulting orange mixture
with some white precipitates was stirred at 215 to 2108C
for about ꢀ h. After removal of the precipitates through
®ltration, the mother liquid was neutralised with 5%
NaOH solution. Extraction with chloroform, followed by
column chromatography and recrystallisation gave ethyl
7-hydroxy-5-oxo-1,2,ꢀ,5-tetrahydro-8-indolizinecarboxyl-
3
20mmol) in dichloromethane3ꢀ0mL) cooled in an ice±
salt bath to form a yellow solution. After the reaction
proceeded in ꢀ h at 215 to 2108C, silica gel 35±10g)
was added to the mixture and the solvent was removed
under vacuum. The product absorbed on silica gel was
column chromatographed, followed by recrystallisation
from ethyl acetate±petroleum ether to give pure product
2
, 3 or 4. When the reaction of 1c with oxalyl chloride
was carried out in dichloromethane, it gave an oil product
in 67% yield. However, the same reaction in ethyl ether
afforded a yellow solid product in 82% yield. If the reaction
2
4
ate 7a as white crystals, mp 1ꢀꢀ±1ꢀ58C 3lit. mp 1ꢀ18C).

Y. Cheng et al. / Tetrahedron 58 ꢀ2002) 2821±2829
2827
4
.3.2. Reactions of 1b with malonyl chloride. Under
32H, t, Jˆ7.7 Hz, CH COO), 2.41 32H, br, CH CO), 2.16
32H, br, CH CvC), 1.77 32H, br, CH ), 1.15 3ꢀH, t,
2 2
2
2
nitrogen atmosphere, the malonyl chloride 3ꢀ.5 mmol) in
dichloromethane 315 mL) was added dropwise to the solu-
tion of enamine 1b 3ꢀ.5 mmol) and dry triethylamine
1
Jˆ7.0Hz, CH ); H NMR 3DMSO-d ) 3808C) d 5.19 31H,
ꢀ
6
t, Jˆꢀ.7 Hz, CvCH), 4.07 32H, q, Jˆ7.1 Hz, OCH ), ꢀ.55
2
3
7 mmol) in dichloromethane 315 mL) cooled in an ice±
32H, t, Jˆ5.5 Hz, NCH ), ꢀ.2ꢀ 32H, t, Jˆ8.0Hz, CH CvC),
2
2
salt bath to form a orange mixture with white solid 3triethyl-
amine hydrogen chloride salt) precipitating. The mixture
was stirred at 215 to 2108C for ꢀ h. After removal of the
precipitates, the ®ltrate was concentrated to give after
column chromatography the pure ethyl 8-hydroxy-6-oxo-
2.7ꢀ 32H, t, Jˆ8.ꢀ Hz, CH COO), 2.42 32H, s, CH CO),
2 2
2
2
2.15 32H, m, CH CvC), 1.78 32H, m, CH ), 1.16 3ꢀH, t,
1
ꢀ
Jˆ7.1 Hz, CH ); C NMR 3CDCl ) d 175.4, 169.8, 166.1,
ꢀ
ꢀ
1ꢀ1.6, 122.7, 118.7, 109.6, 60.5, 44.7, 42.5, 29.4, 27.2, 26.ꢀ,
2ꢀ.2, 14.2; IR 3KBr) 1820, 1710, 1640, 16ꢀ0 cm ; MS 3EI)
2
1
1
m/z 584 3M , 2%), ꢀꢀ5 360), ꢀꢀ4 3100), 288 36ꢀ), 252 355),
1,ꢀ,4,6-tetrahydro-2H-9-quinolizinecarboxylate 7b as
white crystals, mp 154±1558C 3lit. mp 152±1548C).
2
5
251 395). Anal. Calcd for C H N O : C, 61.6ꢀ; H, 6.21;
10
ꢀ
0
ꢀ6
2
N, 4.79. Found: C, 61.4ꢀ; H, 6.42; N, 4.80. Crystal data for
16b: C H N O , Mˆ584.6, monoclinic, P2 =c 3no. 14),
4
.3.3. Reactions of 1c with malonyl chloride. Under
ꢀ
0
ꢀ6
2
10
1
Ê
nitrogen atmosphere, the malonyl chloride 3ꢀ.5 mmol) in
dry toluene 310mL) was added dropwise to the solution
of enamine 1c 3ꢀ.5 mmol) in toluene 310mL) cooled in an
ice±salt bath to form a yellow solution with white solid
precipitating. The mixture was stirred at 215 to 2108C
for about 1 h. After the removal of toluene under vacuum,
the residue was chromatographed to give ethyl 2-hydroxy-4-
aˆ10.40231), bˆ9.ꢀ5231), cˆ15.56931) A, bˆ105.6731)8,
Ê
i c
ꢀ
2ꢀ
Vˆ1458.231) A , Zˆ2 3C symmetry), D ˆ1.ꢀꢀ1 g cm ,
2
1
m 3Cu Ka)ˆ0.84 mm , Tˆ29ꢀ K, pale yellow prisms;
2
2415 independent measured re¯ections, F re®nement,
R ˆ0.04ꢀ, wR ˆ0.108, 2056 independent observed re¯ec-
1
2
tions [uF u.4s3uF u), 2u#1288], 19ꢀ parameters. CCDC
o
o
172562.
oxo-4,6,7,8,9,10-hexahydropyrido[1,2-a]azepine-1-carboxyl-
ate 7c as white crystals. Mp 175±1778C; H NMR 3CDCl )
1
4.4.3. Compound 16c. White crystals from methanol±ethyl
acetate±petroleum: mp 221±22ꢀ8C; H NMR 3DMSO-d )
ꢀ
1
d 11.2031H, br, OH), 6. 09 31H, s, C vCH), 4.5032H, bs,
NCH ), 4.4ꢀ 32H, q, Jˆ6.8 Hz, OCH ), ꢀ.2ꢀ 32H, bs,
6
3258C) d 5.81 31H, t, Jˆ6.5 Hz), 4.1032H, q, Jˆ7.1 Hz),
2
2
CH CvC), 1.79 36H, bs, ꢀCH ), 1.403ꢀH, t, Jˆ6.8 Hz,
ꢀ.ꢀ2 32H, s), ꢀ.21 32H, br), 2.74 32H, t, Jˆ7.7 Hz), 2.21 34H,
2
2
1
CH ); C NMR 3CDCl ) d 169.1, 165.7, 16ꢀ.4, 159.2,
ꢀ
1
br), 1.61 34H, br), 1.17 3ꢀH, t, Jˆ7.1 Hz); H NMR 3DMSO-
ꢀ
ꢀ
1
01.6, 97.ꢀ, 62.1, 42.8, ꢀ1.4, 28.6, 27.0, 25.0, 14.0. IR
KBr) 2950, 1720, 1660, 1620, 1560 cm ; MS 3EI) m/z
d ) 3808C) d 5.77 31H, br, CvCH), 4.1ꢀ 32H, q, Jˆ7.1 Hz,
6
2
1
3
OCH ), ꢀ.52 32H, br, NCH ), ꢀ.2ꢀ 32H, t, Jˆ7.9 Hz,
2
2
1
51 3M , 88%), 205 3100), 177 381); Anal. Calcd for
2
C H NO : C, 62.14; H, 6.81; N, 5.57. Found: C, 61.90;
H, 7.04; N, 5.67.
CH CvC), 2.7ꢀ 32H, t, Jˆ8.ꢀ Hz, CH COO), 2.ꢀ032H,
2 2
2
2
br, CH CO), 2.2032H, q, Jˆ6.5 Hz, CH CvC), 1.66 32H,
1
ꢀ
17
4
br, CH ), 1.46 32H, br, CH ), 1.203ꢀH, t, Jˆ7.1 Hz, CH );
2
2
ꢀ
1
ꢀ
C NMR 3CDCl ) d 175.5, 171.0, 166.7, 165.1, 1ꢀ6.8,
ꢀ
1
1
6
ꢀ2.0, 109.0, 61.2, 47.8, 29.5, 29.4, 28.ꢀ, 27.7, 26.9, 24.6,
4.4. General procedure for the reaction between 1a±c
and succinyl chloride
2
4.9; IR 3KBr) 1840, 1720, 1660, 1650 cm ; MS 3EI) m/z
1
1
12 3M , 6%), ꢀ48 3100), ꢀ49 3ꢀ0). Anal. Calcd for
C H N O : C, 62.7ꢀ; H, 6.58; N, 4.57. Found: C, 62.46;
10
Under nitrogen atmosphere, succinyl chloride 35.7 mmol) in
dry dichloromethane 320mL) was added dropwise to the
solution of enamine 1a±c 34.7 mmol) and pyridine
ꢀ2 40
2
H, 6.26; N, 4.ꢀ9. Crystal data for 16c: C H N O ,
ꢀ2 40
2
10
ꢀ
Mˆ612.7, triclinic, P1 3no. 2), aˆ9.64ꢀ36), bˆ9.74431),
Ê
Ê
cˆ10.4453ꢀ) A, aˆ112.ꢀ732), bˆ116.903ꢀ), gˆ92.8ꢀ32)8,
3
11.4 mmol) in dichloromethane 315 mL) cooled in an ice-
ꢀ
2ꢀ
Vˆ779.635) A , Zˆ1 3C symmetry), D ˆ1.ꢀ05 g cm , m
salt bath. The white solid precipitated and the colour of the
solution turned red. The mixture was stirred under re¯uxing
for about 20±22 h, and then silica gel 35±10 g) was added.
After removal of the solvent under vacuum, the pure
products 13, 16b±c absorbed on silica gel were obtained
after column chromatography and further recrystallisation.
i
c
2
1
3
Cu Ka)ˆ0.81 mm , Tˆ29ꢀ K, colourless rhombs; 248ꢀ
2
independent measured re¯ections,
F
re®nement,
R ˆ0.05ꢀ, wR ˆ0.14ꢀ, 2218 independent observed re¯ec-
1
2
tions [uF u.4s3uF u), 2u#1288], 204 parameters. CCDC
o
o
17256ꢀ.
4.4.1. Bis-2-ethoxycarbonylmethylenepyrrolidyl suc-
cinamide 13. White crystals from ethyl acetate and
4.5. General procedure for the reaction of 1a±c with
phthaloyl dichloride
1
petroleum ether: mp 205±2068C; H NMR 3CDCl ) d
ꢀ
6
.9031H, s, C vCH), 4.11 32H, q, Jˆ7.1 Hz, OCH ), ꢀ.84
Under a nitrogen atmosphere, the phthaloyl dichloride
315 mmol) was added to the solution of DABCO
315 mmol) in dry dichloromethane 320mL) at 2158C to
form a white mixture. To it was added dropwise the solution
of enamines 1a±c in dichloromethane 340mL) cooled in an
ice-bath. The colour of the reaction mixture turned yellow.
After being stirred under re¯uxing for about 20±22 h, the
mixture was poured into water 3about ꢀ0mL) and
2
3
2
2H, t, Jˆ7.1 Hz, NCH ), ꢀ.19 32H, t, Jˆ7.6 Hz, CH CvC),
2
2
.81 32H, s, CH CO), 2.00 32H, m, CH ), 1.24 3ꢀH, t,
2 2
1
ꢀ
Jˆ7.1 Hz, CH ); C NMR 3CDCl ) d 171.7, 168.9, 156.7,
ꢀ
ꢀ
1
1
48.6, 99.6, 59.4, 49.7, ꢀ1.ꢀ, 21.6, 14.4. IR 3KBr) 1700,
620cm ; MS 3FAB) m/z: ꢀ9ꢀ 3M11, 2%), 2ꢀ8 3100);
2
1
Anal. Calcd for C H N O : C, 61.21; H, 7.19; N, 7.1ꢀ.
2
Found: C, 61.02; H, 7.0ꢀ; N, 7.1ꢀ.
0
28
2
6
neutralised with saturated NaHCO solution. The products
ꢀ
4
.4.2. Compound 16b. Pale yellow crystals from ethyl
were extracted by chloroform and dried over MgSO . After
4
1
acetate and petroleum ether: mp 1ꢀ5±1ꢀ78C; H NMR
DMSO-d ) 3258C) d 5.14 31H, br, CvCH), 4.05 32H, br,
OCH ), ꢀ.5032H, br, NCH ), ꢀ.2032H, br, CH CvC), 2.74
removal of the solvent under vacuum, the pure products
17±19 were obtained from column chromatography and
further recrystallisation.
3
6
2
2
2

2828
Y. Cheng et al. / Tetrahedron 58 ꢀ2002) 2821±2829
4.5.1. 11-Ethoxycarbonyl-10-ꢀ2-ethoxycarbonylmethyl-
enepyrrolidin-1-yl)-2,3-dihydro-5H-pyrrolo[1,2-b][2]-
32H, t, Jˆ4.2 Hz), 2.61 32H, br), 2.45 32H, m), 1.54±1.78
310H, m), 1.ꢀ1 3ꢀH, t, Jˆ7.0Hz), 0. 74 3ꢀH, t, Jˆ7.2 Hz);
1
ꢀ
benzazepine-5-one 17a. Yellow crystals from ethyl
acetate±petroleum ether: mp 168±1708C;
C NMR 3DMSO-d ) d 174.8, 170.ꢀ, 166.2, 166.1, 165.7,
6
1
H
NMR
148.7, 147.1, 1ꢀ7.5, 1ꢀ7.1, 1ꢀ6.2, 1ꢀ5.7, 1ꢀ2.9, 1ꢀ2.5,
1ꢀ2.ꢀ, 128.8, 128.ꢀ, 127.8, 126.ꢀ, 126.1, 125.7, 125.6,
116.0, 62.4, 62.0, 59.9, 50.7, 47.8, 44.ꢀ, 44.1, ꢀ0.2, ꢀ0.0,
29.8, 28.8, 28.ꢀ, 27.6, 25.0, 24.0, 14.7, 14.6, 14.1; IR 3KBr)
3
DMSO-d ) d 8.2ꢀ 31H, d, Jˆ6.7 Hz), 7.5ꢀ 31H, t,
6
Jˆ7.ꢀ Hz), 7.48 31H, t, Jˆ7.4 Hz), 6.96 31H, d,
Jˆ7.8 Hz), 5.52 31H, t, Jˆꢀ.4 Hz, CvCH), 4.4031H, s,
2
1
CvCH), 4.14 32H, q, Jˆ7.1 Hz, OCH ), 4.21 and 4.05
1800, 1720, 1700, 1660, 1640, 1600 cm ; MS 3FAB) m/z:
627 3M11, 4%), ꢀ14390), 96 3100). Anal. Calcd for
C H N O : C, 69.00; H, 6.11; N, 4.47. Found: C, 68.91;
2
3
m, NCH ), ꢀ.1032H, m, CH CvC), 2.58 32H, m,
2H, m, NCH ), ꢀ.9032H, q, Jˆ7.1 Hz, OCH ), ꢀ.47 32H,
2 2
2
2
ꢀ6 ꢀ8
2
8
CH CvC), 2.10and 1.9032H, m, CH
2
), 1.19 3ꢀH, t,
H, 6.08; N, 4.51. Crystal data for 19a: C H N O ,
ꢀ6 ꢀ8 2 8
2
1
ꢀ
Jˆ7.1 Hz, CH ) 1.103ꢀH, t, Jˆ7.0Hz, CH ); C NMR
Mˆ626.7, monoclinic, P2 /n 3no. 14), aˆ9.59531),
ꢀ
ꢀ
1
ꢀ
Ê
Ê
3
DMSO-d ) d 168.4, 165.1, 164.8, 162.2, 1ꢀ5.ꢀ, 1ꢀ4.5,
6
bˆ1ꢀ.ꢀ7031), cˆ25.47931) A, bˆ9ꢀ.ꢀ831)8, Vˆꢀ262.832) A ,
2
ꢀ
21
1
8
ꢀꢀ.8, 1ꢀꢀ.4, 1ꢀ2.4, 1ꢀ1.6, 1ꢀ0.9, 129.6, 128.6, 120.7,
ꢀ.0, 62.6, 58.6, 54.0, 52.0, ꢀ1.8, 27.1, 22.5, 15.ꢀ, 14.5.
Zˆ4, D ˆ1.276 g cm , m 3Cu Ka)ˆ0.74 mm , Tˆ29ꢀ K,
c
colourless platy prisms; 5079 independent measured
2
MS 3FAB) m/z 42ꢀ 3M11, ꢀ8%), ꢀ49 3100); IR 3KBr)
1
re¯ections, F re®nement, R ˆ0.072, wR ˆ0.197, ꢀ88ꢀ
1
2
2
1
7ꢀ0, 1680, 1620, 1610, 1590 cm . Exactly MS:
2ꢀ.1909, C H N O requires 42ꢀ.1914.
independent
2u#1248], 420parameters. CCDC 172565.
observed
re¯ections
[uF u.4s3uF u),
o
o
4
2
4
27
2
5
4.5.2. Compound 18. Yellow crystals from ethyl acetate±
petroleum ether: mp 198±2008C; H NMR 3DMSO-d )
1
6
5. Supporting material
3
7
258C) d 7.99 31H, d, Jˆ7.2 Hz), 7.84 31H, t, Jˆ7.5 Hz),
.7ꢀ 32H, t, Jˆ7.2 Hz), 7.65 31H, d, Jˆ7.ꢀ Hz), 7.6031H, t,
X-Ray data for compounds 16b, 16c, 18 and 19.
Jˆ7.1 Hz), 7.5ꢀ 31H, d, Jˆ7.4 Hz), 7.49 31H, bs), 5.41 31H,
s), 5.25 31H, s), 4.24 31H, m), 4.103ꢀH, m), ꢀ.26 31H, br),
ꢀ.17 31H, br), 2.99±ꢀ.ꢀ4 32H, br), 2.ꢀ2 32H, br), 1.98 3ꢀH,
br), 1.85 31H, br), 1.67 31H, br), 1.6031H, br) 1.21 3ꢀH, t,
Acknowledgements
1
Jˆ7.1 Hz), 1.06 3ꢀH, t, Jˆ6.8 Hz); H NMR 3DMSO-d )
We thank the National Natural Science Foundation of China
and SRF for ROCS, SEM for ®nancial support.
6
3
7
808C) d 7.92 31H, d, Jˆ7.6 Hz), 7.8031H, t, Jˆ8.1 Hz),
.67±7.72 3ꢀH, m), 7.58 31H, d, Jˆ7.8 Hz), 7.55 31H, t,
Jˆ7.1 Hz), 7.42 31H, t, Jˆ7.9 Hz), 5.ꢀ4 31H, t, Jˆ4.0Hz,
CHvC), 5.ꢀ1 31H, t, Jˆ4.2 Hz, CHvC), 4.2032H, q,
Jˆ7.1 Hz, OCH ), 4.16 32H, q, Jˆ7.2 Hz, OCH ), ꢀ.61
References
2
2
3
2H, br, NCH ), ꢀ.ꢀꢀ 32H, t, Jˆ5.ꢀ Hz, NCH ), 2.ꢀ5 32H,
1. Bertele, E.; Boos, H.; Dunitz, J. D.; Elsinger, F.; Eschenmoser,
A.; Felner, I.; Gribi, H. P.; Gschwend, H.; Meyer, E. F.;
Pesaro, M.; Scheffold, R. Angew. Chem., Int. Ed. Engl.
1964, 3, 490±496.
2
2
m, CH CvC), 2.00 34H, m, CH CvC and CH ), 1.68 32H,
2
2
2
m, CH ), 1.24 3ꢀH, t, Jˆ7.2 Hz, CH ), 1.14 3ꢀH, t,
2
ꢀ
1
ꢀ
Jˆ7.2 Hz, CH ); C NMR 3DMSO-d ) d 167.ꢀ, 166.2,
ꢀ
6
1
1
1
2
1
65.8, 165.2, 150.4, 149.1, 1ꢀ7.8, 1ꢀ7.1, 1ꢀ6.1, 1ꢀ5.5,
ꢀ4.2, 1ꢀ2.5, 1ꢀ1.6, 1ꢀ1.0, 1ꢀ0.9, 1ꢀ0.2, 126.2, 125.6,
24.6, 12ꢀ.5, 117.0, 115.ꢀ, 114.8, 62.8, 61.1, 52.0, 24.2,
4.1, 2ꢀ.ꢀ, 22.ꢀ, 14.9, 14.2. IR 3KBr) 1800, 1740, 1650,
2. Taguchi, H.; Yazawa, H.; Arnett, J. F.; Kishi, Y. Tetrahedron
Lett. 1977, 627±6ꢀ0.
ꢀ. Danishefsky, S.; Etheredge, S. J. J. Org. Chem. 1974, 39,
ꢀ4ꢀ0±ꢀ4ꢀ2.
2
1
600 cm ; MS 3FAB) m/z 581 3M11, 40%), 507 3100).
4. Shen, W.; Coburn, C. A.; Bornmann, W. G.; Danishefsky, S.
J. Org. Chem. 1993, 58, 611±617.
Anal. Calcd for C H N O : C, 70.ꢀꢀ; H, 5.55; N, 4.82.
7
ꢀ
4
ꢀ2
2
Found: C, 70.25; H, 5.54; N, 4.89. Crystal data for 18:
ꢀ
5. Snyder, L.; Shen, W.; Bornmann, W. G.; Danishefsky, S.
J. Org. Chem. 1994, 59, 70ꢀꢀ±70ꢀ7.
C H N O , Mˆ580.6, triclinic, P1 3no. 2), aˆ9.78832),
ꢀ
4
ꢀ2
2
7
Ê
Ê
bˆ10.67232), cˆ15.60032) A, aˆ109.1932), bˆ102.6532),
6. Luly, J. R.; Rapoport, H. J. Am. Chem. Soc. 1983, 105, 2859±
2866 and references cited therein.
ꢀ
2ꢀ
gˆ92.4ꢀ31)8, Vˆ1490.135) A , Zˆ2, D ˆ1.294 g cm , m
c
2
1
3
Mo Ka)ˆ0.09 mm , Tˆ29ꢀ K, yellow blocks; 51ꢀ5 inde-
7. Pinnick, H. W.; Chang, Y.-H. J. Org. Chem. 1978, 43, 4662±
466ꢀ.
2
pendent measured re¯ections, F re®nement, R ˆ0.049,
1
wR ˆ0.11ꢀ, ꢀ58ꢀ independent observed re¯ections
8. Buchanan, J. G.; Jigajinni, V. B.; Singh, G.; Wightman, R. T.
J. Chem. Soc., Perkin Trans. 1 1987, 2ꢀ77±2ꢀ84.
2
[
uF u.4s3uF u), 2u#508], ꢀ87 parameters. CCDC 172564.
o
o
9
. Paulvannan, K.; Stille, J. R. J. Org. Chem. 1994, 59, 161ꢀ±
1620.
4.5.3. Compound 19. White crystals from acetone±ethyl
acetate±petroleum ether: mp 195±1978C;
1
H
DMSO-d ) 3ꢀ58C) d 7.11±8.08 38H, m), 6.07 30.55H, t,
NMR
10. Saliou, C.; Fleurant, A.; Celerier, J. P.; Lhommet, G.
Tetrahedron Lett. 1991, 32, ꢀꢀ65±ꢀꢀ68.
3
6
Jˆ6.4 Hz), 5.87 30.45H, t, Jˆ5.9 Hz), 4.42 31.1H, q,
11. Fleurant, A.; Celerier, J. P.; Lhommet, G. Tetrahedron:
Asymmetry 1993, 4, 1429±14ꢀ0.
Jˆ7.1 Hz), 4.1ꢀ 30.9H, q, Jˆ7.0Hz), ꢀ.64±ꢀ.75 32H, m),
ꢀ
.40±ꢀ.48 34H, m), 2.40±2.69 34H, m), 1.55±1.87 310H,
12. Thanh, G. V.; Celerier, J. P.; Lhommet, G. Tetrahedron:
Asymmetry 1996, 7, 2211±2212.
m), 1.ꢀ2 31.65H, t, Jˆ7.1 Hz), 1.2031.ꢀ5H, t, Jˆ6.9 Hz),
1
.60±0.68 3ꢀH, m). H NMR 3DMSO-d ) 3908C) d 7.9ꢀ±
0
7
1ꢀ. Folmer, J. J.; Acero, C.; Thai, D. L.; Rapoport, H. J. Org.
Chem. 1998, 63, 8170±8182.
6
.8032H, m), 7.81 31H, t, Jˆ7.ꢀ Hz), 7.7031H, t,
Jˆ7.4 Hz), 7.15±7.4034H, m), 5.94 31H, t, Jˆ5.5 Hz),
14. Brunerie, P.; Celerier, J. P.; Petit, H.; Lhommet, G. J. Hetero-
cycl. Chem. 1986, 23, 118ꢀ±1188.
4
.ꢀ2 32H, br), ꢀ.75 32H, q, Jˆ7.1 Hz), ꢀ.71 32H, br), ꢀ.44

Y. Cheng et al. / Tetrahedron 58 ꢀ2002) 2821±2829
2829
1
1
1
1
1
2
5. Bahaji, El.H.; Refouvelet, B.; Couquelet, J.; Tronche, P. C. R.
Acad. Sci. II 1986, 303, 455±458.
Lett. 1994, 35, 949±952. Cicchi, S.; Goti, A.; Brandi, A.
J. Org. Chem. 1995, 60, 474ꢀ±4748.
6. Nagasaka, T.; Inoue, H.; Ichimura, M.; Hamaguchi, F.
Synthesis 1982, 848±850.
21. Part of this work appeared as preliminary communications:
Cheng, Y.; Yang, H.-B.; Hung, Z.-T.; Wang, M.-X.
Tetrahedron Lett. 2001, 42, 1757±1759.
7. Brunerie, P.; Celerier, J. P.; Huche, M.; Lhommet, G.
Synthesis 1985, 7ꢀ5±7ꢀ8.
22. Dannhardt, G.; Meindl, W.; Gussmann, S.; Ajili, S.; Kappe,
T.; Eur J. Med. Chem. 1987, 22, 505±510.
8. Wang, M.-X.; Miao, W.-S.; Cheng, Y.; Huang, Z.-T.
Tetrahedron 1999, 55, 14611±14622.
9. For a useful review, see: Roeder, E. Curr. Org. Chem. 1999, 3,
2ꢀ. Celerier, J. P.; Deloisy, E.; Lhommet, G.; Maitte, P. J. Org.
Chem. 1979, 44, ꢀ089.
5
57.
24. Celerier, J. P.; Eskenazi, C.; Maitte, P.; Lhommet, G.
J. Heterocycl. Chem. 1979, 16, 95ꢀ±955.
0. For the synthesis of hydroxylated indolizidine alkaloidal
compounds, see: Maggini, M.; Prato, M.; Ranelli, M.;
Scorrano, G. Tetrahedron Lett. 1992, 33, 65ꢀ7±6540.
Cordero, F. M.; Cicchi, S.; Goti, A.; Brandi, A. Tetrahedron
25. Kappe, T.; Hariri, M.; Soliman, F. S. G. Arch. Pham. 1976,
309, 684±687.