An efficient synthesis of 5-(or 6-)-arylbenzoindolizidine and - quinolizidine derivatives

Article abstract of DOI:10.1002/(SICI)1099-0690(199909)1999:9<2345::AID-EJOC2345>3.0.CO;2-P

A new methodology for the synthesis of (hetero)arylated benzomdolizidine and benzoquinolizidine derivatives through sequential reduction of pyrrolidine- and piperidine-based aromatic enamides, and ultimate cyclization, is reported.

Full text of DOI:10.1002/(SICI)1099-0690(199909)1999:9<2345::AID-EJOC2345>3.0.CO;2-P

FULL PAPER
An Efficient Synthesis of 5-(or 6-)Arylbenzoindolizidine
and -quinolizidine Derivatives
[a]
[a]
[a]
[a]
´
Stephane Lebrun, Axel Couture,* Eric Deniau, and Pierre Grandclaudon
Keywords: Horner reaction / Enamides / Reductions / Cyclizations / Alkaloids
A new methodology for the synthesis of (hetero)arylated
benzoindolizidine and benzoquinolizidine derivatives
based aromatic enamides, and ultimate cyclization, is
reported.
through sequential reduction of pyrrolidine- and piperidine-
The benzo[b]indolizidine and benzo[b]quinolizidine ring
systems represent the main structural subunit of a wide var-
iety of highly condensed alkaloids which have been shown
to display unique and interesting biological properties.[1]
When these fused heterocyclic models are further equipped
with a pendant aromatic unit at the 5 or 6 position of the
central nucleus, i. e. 1 (n ϭ 1) or 2 (n ϭ 2), these new skel-
etons constitute the framework of an array of tetrahydro-
protoberberine (berbine) alkaloids as exemplified by the 8-
phenyl derivatives of tetrahydrocoptisine 3,[2] tetrahydropal-
matine 4,[3] and the 8-phenyl analogues of coralydine 5[4]
and O-methylcorytenchirine 6[4] (Figure 1).
On the other hand 6-arylbenzo[b]quinolizidine deriva-
tives 2 (n ϭ 2) have been recently suggested as promising
alternative models to podophyllotoxin (7),[5] which has long
been known to display antitumour and mitotoxic activi-
ties[6] but also ill-fated toxic side effects.[7] Indeed, such
compounds in which the sp3 C-2 atom is replaced by an sp3
nitrogen atom embedded in the fused hydrocarbon rings of-
fer the double advantage of avoiding epimerization at this
site and eliminating any deleterious effects attributable to
the highly reactive nature of the γ-lactone moiety.
Paradoxically, the synthesis of the fused polyheterocyclic
compounds 1 (n ϭ 1), 2 (n ϭ 2) has not elicited great syn-
thetic efforts from the scientific community. An elegant and
skilful route to the benzoquinolizidine derivatives 2 by ap-
plication of the CN(RS) method involving alkylation of 2-
cyano-6-phenyloxazolopiperidine followed by reduction
and cyclization has been recently reported, but this route
has been confined to the six-membered models.[8]
In our continuing study aimed at the involvement of N-
acyl enamine derivatives in the elaboration of alkaloids and
natural products[9Ϫ12] we wish to report here a conceptually
and tactically new approach to benzoindolizidine and -qui-
nolizidine derivatives 1 and 2, arylated or heteroarylated at
the 5-(6-)position of the heterocyclic framework.
Figure 1
1 (n ϭ 1) or 2 (n ϭ 2), as well as various heterocyclic ana-
logues, should be accessible by a semisynthetic strategy
wherein the aromatic enamide 10 or 11 would be a key in-
termediate which could be derived from the Horner reac-
tion between the phosphorylated N-acylpyrrolidine or -pip-
eridine derivatives 12 (n ϭ 1) or 13 (n ϭ 2) and a suitably
substituted aromatic carboxaldehyde 14 or 15. The present
work, which offers a number of undoubted advantages,
originated from the following premises. The PictetϪS-
pengler cyclization of aromatic aldehydes, which enables ac-
cess to the isoquinoline framework, requires the presence of
a para-hydroxy group on the benzene ring.[13][14] When this
is not the case, the BischlerϪNapieralski reaction represents
an interesting alternative approach and, in this regard, N-
acyl-2-arylmethylpyrrolidine 8 (n ϭ 1) or -piperidine 9 (n ϭ
2) should be excellent candidates for this carboannulation
process. On the other hand, the scheme might be extended
to the preparation of heteroaryl derivatives 1 or 2 (Ar ϭ
Retrosynthetic analysis, depicted in Scheme 1, suggested
that the 5-(or 6-)arylbenzoindo(or quino)lizidine derivatives
[a]
Laboratoire de Chimie Organique Physique, UPRES A 8009,
UST Lille 1,
F-59655 Villeneuve dЈAscq Cedex, France
Fax: (internat.) ϩ33-3/20336309
E-mail: Axel.Couture@univ-lille1.fr
Eur. J. Org. Chem. 1999, 2345Ϫ2352
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
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2345

S. Lebrun, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
heteroaryl) owing to the ready accessibility of the phos- arylmethylene unit was strongly influenced by the size of
phorylated cyclic N-acylamines 12 or 13. Most interesting the aza heterocycle (Table 1). Thus, enamides 10a؊c were
of all, the possibility of controlling a priori the stereochem- invariably obtained as a mixture of (Z) and (E) isomers,
ical outcome of the appended arylmethylene unit of the en- with (E) isomers predominating, whereas a high degree of
amides 10 or 11 set the stage for an investigation of the stereoselectivity was observed with the piperidine deriva-
enantioselective reduction of these dehydro precursors tives 11a,b,d which were obtained exclusively in the (E)
which might address the problem of stereocontrol at the form. The (Z) and (E) isomers were in all cases separable
chiral centre adjacent to the nitrogen atom embedded in the by repeated flash chromatography on silica gel.
skeleton of the fused compounds 1 and 2.
Scheme 1. Retrosynthetic scheme
To establish the generality and versatility of the synthetic
approach depicted in Scheme 1, the elaboration of a num-
ber of aromatic and heteroaromatic models, contiguously
and differentially substituted by phenolic methoxy or
pyrrolidines and -piperidines
methylenedioxy groups on the aromatic moieties, was ex-
Scheme 2. Synthesis of 1-aroyl- and -heteroaroyl-2-arylmethylene-
plored.
The stereochemistry was unambiguously determined by
Initially, a variety of 1-aroyl- and -heteroaroyl-2-di- NMR spectroscopy. Thus, the signals of the N-aroyl pro-
phenylphosphinoylpyrrolidine and -piperidine derivatives, tons of the (Z) isomers occur at a higher field, owing to
12a؊c and 13a؊c, respectively, were easily and almost aromatic shielding, than those of the (E) isomers. The (Z)
quantitatively formed by SchottenϪBaumann reaction of stereochemistry was further confirmed by a one-dimen-
the appropriate carboxylic chlorides 21a؊c with the phos- sional difference nuclear Overhauser experiment wherein ir-
phorylated cyclic amines 19 and 20, readily obtained by ad- radiation of the vinylic proton led to an increased intensity
dition of diphenylphosphane oxide 18 to the triazines 16 of the allylic proton signal of the pyrrolidine ring.
and 17[10][15] (Scheme 2). Compounds 12a؊c and 13a؊c
Two different methods were then adopted to convert the
were then smoothly deprotonated at Ϫ78°C with nBuLi in dehydro precursors 10a؊c and 11a,b,d into the 1-aroyl-
THF and subsequently treated with suitably substituted al- and -heteroaroyl-2-arylmethylpyrrolidines 8a؊c and -pip-
dehydes 14 or 15. Warming of the reaction mixture to room eridines 9a,b,d (Scheme 3). Catalytic hydrogenation (H2,
temperature ensured completion of the reaction, and the 1- Rh/C, method A) afforded the desired aromatic and het-
aroyl- and -heteroaroyl-2-arylmethylenepyrrolidines 10a؊c eroaromatic carboxamides 8a؊c and 9a,b,d which were also
and -piperidines 11a,b,d were isolated in high yields accessible by a more rarely employed method, making use
(Scheme 2, Table 1). Curiously, the stereochemistry of the of Pd on C and ammonium formate[16][17] (method B). The
2346
Eur. J. Org. Chem. 1999, 2345Ϫ2352

An Efficient Synthesis of 5-(or 6-)Arylbenzoindolizidine and -quinolizidine Derivatives
FULL PAPER
Table 1. 1-Aroyl(heteroaroyl)-2-arylmethylenepyrrolidines 10a؊c and -piperidines 11a,b,d
Product Starting
amide
n
Ar
Starting aldehyde
R1
R2
R3
Yield (%)
(E)/(Z)
10a
10b
10c
11a
11b
11d
12a
12b
12c
13a
13b
13c
1
1
1
2
2
2
3,4-dimethoxyphenyl
3,4,5-trimethoxyphenyl
2-furyl
3,4-dimethoxyphenyl
3,4,5-trimethoxyphenyl
2-furyl
14
14
15
14
14
14
OϪCH2ϪO
OϪCH2ϪO
OCH3
OϪCH2ϪO
OϪCH2ϪO
OϪCH2ϪO
H
62
72
70
70
67
60
75:25
60:40
80:20
100:0
100:0
100:0
H
OCH3
OCH3
H
H
H
results of a representative series of compounds which we ever, these concepts have been mainly applied to the stereo-
have prepared following these two protocols are presented selective connection of arylmethyl groups via their halide
in Table 2, where it may be seen that these simple pro- or trifluoromethanesulfonate derivatives on N-benzylcarba-
cedures afford excellent yields of the 2-arylmethylpyrrolid- mates.[22][23]
ine and -piperidine derivatives 8a؊c and 9a,b,d, respec-
tively.
A survey of the literature revealed that since the pion-
eering work of Takaya and Noyori[24] only a few known
examples of N-acyl enamines have been successfully re-
duced with a high degree of enantioselectivity.[25][26] We
were then cautiously optimistic about the chances for suc-
cess of the asymmetric hydrogenation of the enamide de-
rivatives even though high enantioselectivities have been ob-
tained with models incorporating a styrene moiety.[24Ϫ27]
Initially, of crucial importance was the stereoselective prep-
aration of the (Z)-configured substrates because (E) stereo-
mers are inactive to the hydrogenation conditions. As-
suming that (Z)/(E) stereoselectivity might be strongly af-
fected by the Horner reaction conditions, namely the nature
of the counterion[28Ϫ32] in the primary adduct 22 (Figure
2), deprotonation of 12 or 13 with bases such as KHMDS,
nBuLi/tBuOK, KHMDS and 18-crown-6 ether, which
should maximize kinetic control and favour formation of
Scheme 3. Synthesis of 1-aroyl- and -heteroaroyl-2-arylmethylpyr-
rolidines and -piperidines
At this stage we focused our attention on the asymmetric the (Z) product, was examined.[28Ϫ32] These experiments re-
hydrogenation of the N-acyl enamines 10؊11 with asym- vealed that the phosphorylated amides 12a؊c or 13a؊c
metric Ru catalysts in order to solve the problem of stereo- were exclusively deprotonated with lithiated bases like
control of the chiral centre adjacent to the nitrogen atom nBuLi and LDA. Furthermore, all attempts to isolate the
in the five- or six-membered ring of 1 or 2. Enantioselective initially formed alcohols deriving from 22 (Figure 2, M ϭ
alkylation α to the nitrogen atom remains a challenging Li), which could be dephosphorylated with sodium or pot-
synthetic task, which has been tackled by several groups assium bases (Figure 2; 22, M ϭ Na or K), met with no
but which has been only partly addressed by adopting cat- success, probably due to the high degree of conjugation of
ion[18] or radical chemistry.[19] Methods based on carbanion the final compounds. Consequently, we opted to study the
chemistry have been developed in recent years and the cre- photoinduced (E) Ǟ (Z) interconversion. Exposure of a
ation of the asymmetric centre α to N is generally achieved solution of 10a؊c (n ϭ 1) in diethyl ether at 25°C for 4 h
either by stoichiometric chirality transfer from a chiral pre- to UV light resulted in the formation of a photostationary
cursor[20][21] or by performing the metallation-alkylation se- 3:2 mixture of the (E) and (Z) isomers, whereas the six-
quence in the presence of enantiopure inductors.[22] How- membered congeners were photochemically unreactive. The
Table 2. 1-Aroyl(heteroaroyl)-2-arylmethylpyrrolidines 8a؊c and -piperidines 9a,b,d
Product Starting
enamide
n
Ar
R1
R2
R3
Method AMethod B
Yield (%) Yield (%)
8a
8b
8c
9a
9b
9d
10a
10b
10c
11a
11b
11d
1
1
1
2
2
2
3,4-dimethoxyphenyl
3,4,5-trimethoxyphenyl
2-furyl
3,4-dimethoxyphenyl
3,4,5-trimethoxyphenyl
2-furyl
OϪCH2ϪO
OϪCH2ϪO
OCH3
OϪCH2ϪO
OϪCH2ϪO
OϪCH2ϪO
H
90
86
Ϫ
87
Ϫ
93
91
89
90
88
89
H
OCH3
OCH3
H
H
H
Ϫ
Eur. J. Org. Chem. 1999, 2345Ϫ2352
2347

S. Lebrun, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
formation of several minor by-products, arising probably tries 3, 4). Use of TolBINAPϪRu complexes as well as RuI-
from photo Fries rearrangement[33Ϫ35] or photocycli- IϪdicarboxylatoϪBINAP complexes (entries 5,6 and 7,8)
zation[36] of the highly conjugated parent models, was also decreased the selectivity to a great extent, as under 5 atm
observed but in negligible amounts. Repetition of this pro- the ee was lowered to 20%. These results confirm the erratic
cedure two times and separation by flash chromatography nature of the asymmetric hydrogenation of enamides, which
gave pure stereoisomeric (Z)-10a؊c.
can be performed exclusively on the rather sterically con-
strained (Z) stereoisomer, and which is strongly influenced
by the degree of aromatic substitution, the nature of the
substituents and the geometry of the parent models.
Compounds 8a؊c and 9a,b,d were then subjected to
BischlerϪNapieralski reaction conditions. Thus, treatment
of these compounds with POCl3 in toluene at reflux and
subsequent reduction of the intermediary iminium salts
with NaBH4 in methanol delivered fairly good yields of the
cyclocondensed products 1a؊c and 2a,b,d which were in-
Figure 2. Primary adduct of the Horner reaction
The efficiency of the catalyst and reaction conditions was
examined by hydrogenation of (Z)-10a as substrate giving
the 2-(benzo[1,3]dioxol-5-yl)methyl-1-(3,4-dimethoxyben-
zoyl)pyrrolidine 8a (Scheme 4). Table 3 lists the results of
the screening experiments. We first used the BINAP-Ru
complexes as catalysts which exhibited excellent chiral ef-
ficiency in asymmetric hydrogenation of 1-acyl-2-alkylid-
enetetrahydroisoquinolines.[27] Thus, the reaction of (Z)-
10a in a mixture of methanol and dichloromethane, which
appeared to be the best medium for the asymmetric re-
duction of related systems,[24] at 30°C under an initial hy-
drogen pressure of 5 atm gave 8a in 96% yield but with
modest enantioselectivity (entry 1). By increasing the hy-
drogen pressure and reducing the reaction time, the chiral
efficiency remained virtually unchanged. Variation of the
atropisomeric chiral ligands in freshly prepared [RuBr2(di-
phosphane)]-type catalysts led to comparable ee values (en-
Scheme 5. Synthesis of 5-(or-6-)arylbenzoindolizidines and -quino-
lizidines
Scheme 4. Enantioselective hydrogenation of (Z )-10a
Table 3. Asymmetric hydrogenation of enamide (Z)-10a into 8a[a]
Entry
Catalyst
p(H2) [atm]
t[b] [h]
Yield[c] (%)
ee[d] (%)
1
2
3
4
5
6
7
8
{RuCl2[(S)-BINAP]}2 · NEt3
{RuCl2[(S)-BINAP]}2 · NEt3
RuBr2[(S)-MeOBIPHEP]
RuBr2[(S)-MeOBIPHEP]
RuBr2[(S)-TolBINAP]
5
24
14
16
3
96
95
90
95
97
93
95
90
40 (Ϫ)
41 (Ϫ)
41 (Ϫ)
42 (Ϫ)
20 (Ϫ)
20 (Ϫ)
20 (ϩ)
18 (ϩ)
10
10
100
5
21
3
RuBr2[(S)-TolBINAP]
100
5
5
Ru(OAc)2[(R)-BINAP]
Ru(TFA)2[(R)-BINAP]
16
4
[a]
[b]
Reaction conditions: 30°C, substrate/catalyst, 200:1, ca. 0.5Ϫ1.0 mmol of substrate in 12 mL of MeOH/CH2Cl2 (5:1). Ϫ
optimized reaction times for quantitative conversion of (Z)-10a into 8a as determined by 1H-NMR and HPLC analysis. Ϫ
Non-
Yield
[c]
determined after purification by column chromatography. Ϫ [d] Enantiomeric excesses were determined by HPLC analysis with a Supelco-
sil (R)-DNBPG column (hexane/2-propanol, 95:5), 1 mL/min, UV detector 254 nm.
2348
Eur. J. Org. Chem. 1999, 2345Ϫ2352

An Efficient Synthesis of 5-(or 6-)Arylbenzoindolizidine and -quinolizidine Derivatives
FULL PAPER
Table 4. Arylated benzoindolizidines 1a؊c and benzoquinolizidines 2a,b,d
n
Ar
R1
R2
R3
Yield[a] (%)
1a
1b
1c
2a
2b
2d
1
1
1
2
2
2
3,4-dimethoxyphenyl
3,4,5-trimethoxyphenyl
2-furyl
3,4-dimethoxyphenyl
3,4,5-trimethoxyphenyl
2-furyl
OϪCH2ϪO
OϪCH2ϪO
OCH3
OϪCH2ϪO
OϪCH2ϪO
OϪCH2ϪO
H
H
70
75
65
68
72
65
OCH3
OCH3
H
H
H
[a]Yield determined before separation of diastereomers.
128.0 (d, JCP ϭ 11.5 Hz), 128.7 (d, JCP ϭ 11.5 Hz), 130.5 (d, JCP
ϭ
variably obtained as a mixture of diastereomers in the ratio
10:1 (Scheme 5, Table 4). The structure of the major dia-
stereomer was deduced from the H-NMR spectrum, na-
mely by the presence of long-range coupling between the
mono- and dibenzylic protons attributable to their axial re-
lationship.[13][14]
In conclusion, we have developed a general and versatile
method for the preparation of benzoindolizidines and quin-
olizidines flanked indifferently with aromatic or heteroaro-
matic units on the central heteroring unit. The enamide syn-
thesis, consecutive hydrogenation and subsequent cycliza-
tion reactions proceed in high yields even though the en-
antioselectivities of the hydrogenation products of enamides
are rather modest. The reported protocol could undoubt-
edly be broadened to include the synthesis of a variety of
alkaloids containing the 5-(or 6-)arylbenzoindo(or quino)li-
zidine skeleton.
95 Hz), 131.4 (d, JCP ϭ 8.5 Hz), 131.8 (d, JCP ϭ 3 Hz), 132.1 (d,
JCP ϭ 3 Hz), 148.4, 150.7, 170.2 (s, CϭO). Ϫ 31P NMR: δ ϭ 34.3.
Ϫ C25H26NO4P (435.5): calcd. C 68.96, H 5.98, N 3.22; found C
69.10, H 5.83, N 3.45.
1
Phosphorylated Amide 12b: 78%, m.p. 148Ϫ149°C. Ϫ IR (KBr):
1
ν˜ ϭ 1638 cmϪ1 (CO), 1168 (PO). Ϫ H NMR: δ ϭ 1.82Ϫ1.94 (m,
1 H, CH2), 1.97Ϫ2.15 (m, 1 H, CH2), 2.19Ϫ2.30 (m, 1 H, CH2),
2.45Ϫ2.60 (m, 1 H, CH2), 3.31Ϫ3.59 (m, 2 H, NCH2), 3.73 (s, 3
H, OCH3), 3.76 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 5.53Ϫ5.56
(m, 1 H, CH-P), 6.28 (s, 2 H, aromatic H), 7.31Ϫ7.45 (m, 3 H,
aromatic H), 7.47Ϫ7.55 (m, 3 H, aromatic H), 7.82Ϫ7.90 (m, 2 H,
aromatic H), 8.05Ϫ8.11 (m, 2 H, aromatic H). Ϫ 13C NMR: δ ϭ
24.9, 25.5, 50.6, 55.9 (s, OCH3), 56.0 (d, JCP ϭ 79 Hz), 60.8 (s,
OCH3), 104.6, 128.2 (d, JCP ϭ 10 Hz), 128.9 (d, JCP ϭ 9 Hz), 130.6,
131.4 (d, JCP ϭ 9 Hz), 131.5 (d, JCP ϭ 94 Hz), 131.8 (d, JCP
ϭ
8 Hz), 146.3, 152.8, 170.1 (s, CϭO). Ϫ 31P NMR: δ ϭ 34.6. Ϫ
C26H28NO5P (465.5): calcd. C 67.09, H 6.02, N 3.01; found C
67.18, H 5.93, N 2.88.
Phosphorylated Amide 12c: 77%, m.p. 147Ϫ148°C. Ϫ IR (KBr):
1
ν˜ ϭ 1635 cmϪ1 (CO), 1173 (PO). Ϫ H NMR: δ ϭ 1.72Ϫ2.08 (m,
Experimental Section
2 H, CH2), 2.36Ϫ2.51 (m, 2 H, CH2), 3.68Ϫ3.84 (m, 2 H, NCH2),
5.46 (br. s, 1 H, CH-P), 6.34 (br. s, 1 H, furanic H), 6.78 (br. s, 1
H, furanic H), 7.21Ϫ7.56 (m, 7 H, 6 aromatic H ϩ 1 furanic H),
7.66Ϫ7.79 (m, 2 H, aromatic H), 8.03Ϫ8.12 (m, 2 H, aromatic H).
General: Methanol was distilled from magnesium turnings.
Tetrahydrofuran (THF) and ether (Et2O) were predried with anhy-
drous Na2SO4 and distilled from sodium benzophenone ketyl un-
der Ar before use. CH2Cl2, NEt3 and toluene were distilled from
CaH2. Dry glassware was obtained by oven-drying and assembly
under dry Ar. The glassware was equipped with rubber septa and
reagent transfer was performed by syringe techniques. For flash
chromatography, Merck silica-gel 60 (230Ϫ400 mesh ASTM) was
used. The melting points were taken on a Reichert-Thermopan ap-
paratus and are not corrected. Ϫ NMR: Bruker AM 300 (300, 75
and 121 MHz, for 1H, 13C and 31P, respectively). For 1H and 13C
NMR, CDCl3 as solvent, TMS as internal standard; for 31P NMR,
CDCl3 as solvent, H3PO4 as external standard. Ϫ Microanalyses
were performed by the CNRS microanalysis centre. Ϫ Triazines
16,[37] 17[38] and diphenylphosphane oxide 18[39] were prepared ac-
cording to the literature methods.
Ϫ
13C NMR: δ ϭ 24.8, 26.4, 48.8, 57.3 (d, JCP ϭ 78 Hz), 111.3,
116.1, 127.9 (d, JCP ϭ 12 Hz), 128.7 (d, JCP ϭ 11 Hz), 130.3 (d,
J
CP ϭ 89 Hz), 131.3 (d, JCP ϭ 10 Hz), 131.6 (d, JCP ϭ 9 Hz), 132.0,
144.6, 159.8 (s, CϭO). Ϫ 31P NMR: δ ϭ 33.9. Ϫ C21H20NO3P
(365.4): calcd. C 69.04, H 5.48, N 3.83; found C 69.16, H 5.39,
N 3.88.
Phosphorylated Amide 13a: 76%, m.p. 156Ϫ157°C. Ϫ IR (KBr):
1
ν˜ ϭ 1621 cmϪ1 (CO), 1178 (PO). Ϫ H NMR: δ ϭ 1.26Ϫ1.43 (m,
1 H, CH2), 1.61Ϫ1.98 (m, 3 H, CH2), 2.06Ϫ2.18 (m, 1 H, CH2),
2.37Ϫ2.56 (m, 1 H, CH2), 3.47Ϫ3.55 (m, 1 H, NCH2), 3.71Ϫ3.73
(m, 4 H, OCH3 ϩ 1 H NCH2), 3.81 (s, 3 H, OCH3), 5.84 (br. s, 1
H, CH-P), 6.29 (s, 1 H, aromatic H), 6.37 (d, J ϭ 9.0 Hz, 1 H,
aromatic H), 6.68 (d, J ϭ 9.0 Hz, 1 H, aromatic H), 7.38Ϫ7.53 (m,
6 H, aromatic H), 7.88Ϫ8.05 (m, 4 H, aromatic H). Ϫ 13C NMR:
δ ϭ 20.5, 24.2, 26.2, 46.6, 48.1 (d, JCP ϭ 82.5 Hz), 55.8 (s, OCH3),
109.8, 110.5, 119.5, 127.5, 128.8 (d, JCP ϭ 10.5 Hz), 130.9 (d, JCP ϭ
9 Hz), 131.0 (d, JCP ϭ 9 Hz), 131.8 (d, JCP ϭ 15 Hz), 131.9 (d,
Phosphorylated Amides: The phosphorylated amines 19,[15] 20[10]
and amides 12a؊c, 13a؊c[9] were synthesized according to already
reported procedures.
Phosphorylated Amide 12a: 75%, m.p. 125Ϫ126°C. Ϫ IR (KBr):
1
ν˜ ϭ 1623 cmϪ1 (CO), 1172 (PO). Ϫ H NMR: δ ϭ 1.73Ϫ1.92 (m,
J
CP ϭ 92 Hz), 148.6, 150.0, 170.5 (s, CϭO). Ϫ 31P NMR: δ ϭ 31.8.
1 H, CH2), 1.97Ϫ2.35 (m, 2 H, CH2), 2.41Ϫ2.60 (m, 1 H, CH2),
3.42Ϫ3.51 (m, 1 H, NCH2), 3.58Ϫ3.66 (m, 1 H, NCH2), 3.81 (s, 3
H, OCH3), 3.86 (s, 3 H, OCH3), 5.51Ϫ5.59 (m, 1 H, CH-P),
6.68Ϫ6.81 (m, 3 H, aromatic H), 7.32Ϫ7.41 (m, 3 H, aromatic H),
7.45Ϫ7.58 (m, 3 H, aromatic H), 7.73Ϫ7.88 (m, 2 H, aromatic H),
8.06Ϫ8.13 (m, 2 H, aromatic H). Ϫ 13C NMR: δ ϭ 24.7, 25.8, 50.9,
55.7 (d, JCP ϭ 80 Hz), 55.9 (s, OCH3), 110.1, 110.8, 120.8, 127.9,
Ϫ C26H28NO4P (449.5): calcd. C 69.49, H 6.24, N 3.12; found C
69.61, H 6.38, N 3.01.
Phosphorylated Amide 13b: 75%, m.p. 131Ϫ132°C. Ϫ IR (KBr):
1
ν˜ ϭ 1637 cmϪ1 (CO), 1171 (PO). Ϫ H NMR: δ ϭ 1.23Ϫ1.41 (m,
1 H, CH2), 1.60Ϫ2.05 (m, 4 H, 2 CH2), 2.32Ϫ2.50 (m, 1 H, CH2),
3.54 (m, 1 H, NCH2), 3.66 (td, J ϭ 13.1, 2.4 Hz, 1 H, NCH2), 3.86
Eur. J. Org. Chem. 1999, 2345Ϫ2352
2349

S. Lebrun, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
(s, 6 H, 2 ϫ OCH3), 3.91 (s, 3 H, OCH3), 5.84 (br. s, 1 H, CH-P),
6.13 (s, 2 H, aromatic H), 7.32Ϫ7.55 (m, 6 H, aromatic H),
7.86Ϫ8.12 (m, 4 H, aromatic H). Ϫ 13C NMR: δ ϭ 20.8, 24.5, 26.3,
46.5, 49.1 (d, JCP ϭ 76.5 Hz), 56.1 (s, OCH3), 60.6 (s, OCH3),
104.3, 128.6 (d, JCP ϭ 9 Hz), 129.3 (d, JCP ϭ 8.5 Hz), 130.8 (d,
(s, CϭO); (Z) isomer, m.p. 108Ϫ109°C. Ϫ 1H NMR: δ ϭ
1.98Ϫ2.13 (m, 2 H, CH2), 2.66 (t, J ϭ 7.6 Hz, 2 H, ϭCCH2), 3.73
(s, 6 H, 2 ϫ OCH3), 3.82 (s, 3 H, OCH3), 3.87 (t, J ϭ 7.5 Hz, 2 H,
NCH2), 5.70 (s, 1 H, vinylic H), 5.85 (s, 2 H, OCH2O), 6.19 (s, 1
H, aromatic H), 6.43 (d, J ϭ 8.2 Hz, 1 H, aromatic H), 6.45 (s, 2
H, aromatic H), 6.57 (d, J ϭ 8.2 Hz, 1 H, aromatic H). Ϫ 13C
NMR: δ ϭ 20.8, 31.8, 49.0, 55.9 (s, OCH3), 60.7 (s, OCH3), 100.7,
105.2, 107.7, 107.9, 112.5, 121.0, 128.6, 130.5, 130.8, 138.5, 145.5,
147.3, 152.3, 168.6 (s, CϭO). Ϫ C22H23NO6 (397.4): calcd. C 66.50,
H 5.79, N 3.53; found C 66.41, H 5.70, N 3.69.
JCP ϭ 83 Hz), 131.2, 131.3 (d, JCP ϭ 8.5 Hz), 131.7 (d, JCP
ϭ
8 Hz), 147.1, 152.7, 169.9 (s, CϭO). Ϫ 31P NMR: δ ϭ 32.3. Ϫ
C27H30NO5P (479.5): calcd. C 67.64, H 6.26, N 2.92; found C
67.48, H 6.39, N 3.06.
Phosphorylated Amide 13c: 83%, m.p. 112Ϫ113°C. Ϫ IR (KBr):
1
1
ν˜ ϭ 1631 cmϪ1 (CO), 1177 (PO). Ϫ H NMR: δ ϭ 1.37Ϫ2.06 (m,
N-Acyl Enamine 10c: (E) isomer, oil. Ϫ H NMR: δ ϭ 1.78Ϫ1.92
(m, 2 H, CH2), 2.81 (td, J ϭ 7.3, 1.9 Hz, 2 H, ϭCCH2), 3.68 (t,
J ϭ 6.8 Hz, 2 H, NCH2), 3.89 (s, 9 H, 3 ϫ OCH3), 6.42 (dd, J ϭ
3.4, 1.5 Hz, 1 H, furanic H), 6.82 (s, 2 H, aromatic H), 7.04 (dd,
J ϭ 3.4, 0.8 Hz, 1 H, furanic H), 7.31 (s, 1 H, vinylic H), 7.42 (dd,
J ϭ 1.5, 0.8 Hz, 1 H, furanic H). Ϫ 13C NMR: δ ϭ 22.7, 30.6,
50.7, 56.0 (s, OCH3), 60.9 (s, OCH3), 102.4, 108.3, 111.6, 115.8,
130.6, 137.6, 141.3, 142.7, 147.4, 150.1, 169.7 (s, CϭO); (Z) isomer,
oil. Ϫ 1H NMR: δ ϭ 1.81Ϫ2.02 (m, 2 H, CH2), 2.65 (t, J ϭ 6.9 Hz,
2 H, ϭCCH2), 3.75 (s, 6 H, 2 ϫ OCH3), 3.80 (s, 3 H, OCH3), 3.86
(t, J ϭ 7.2 Hz, 2 H, NCH2), 5.78 (s, 1 H, vinylic H), 6.46 (d, J ϭ
3.3 Hz, 1 H, furanic H), 6.54 (s, 2 H, aromatic H), 7.08 (d, J ϭ
3.3 Hz, 1 H, furanic H), 7.45 (br. s, 1 H, furanic H). Ϫ 13C NMR:
δ ϭ 21.2, 31.7, 50.1, 55.6 (s, OCH3), 60.8 (s, OCH3), 102.6, 108.0,
111.2, 115.9, 130.9, 137.2, 141.2, 142.9, 147.8, 150.2, 169.6 (s, Cϭ
O). Ϫ C19H21NO5 (343.4): calcd. C 66.47, H 6.12, N 4.08; found
C 66.41, H 5.98, N, 4.16.
5 H, CH2), 2.38Ϫ2.55 (m, 1 H, CH2), 3.77 (br. t, J ϭ 12.7 Hz, 1
H, NCH2), 4.08 (br. d, J ϭ 12.7 Hz, 1 H, NCH2), 5.69 (br. s, 1 H,
CH-P), 6.37 (dd, J ϭ 3.8, 1.8 Hz, 1 H, furanic H), 7.14Ϫ7.46 (m,
7 H, 6 aromatic H ϩ furanic H), 7.65Ϫ7.98 (m, 5 H, 4 aromatic H
ϩ furanic H). Ϫ 13C NMR: δ ϭ 20.7, 24.6, 26.3, 45.7, 49.0 (d,
JCP ϭ 75.5 Hz), 110.9, 115.4, 128.2 (d, JCP ϭ 11.5 Hz), 128.8 (d,
JCP ϭ 11 Hz), 130.6 (d, JCP ϭ 90.5 Hz), 131.0 (d, JCP ϭ 8 Hz),
131.7 (d, JCP ϭ 13 Hz), 143.8, 145.8, 160.5 (s, CϭO). Ϫ 31P NMR:
δ ϭ 32.7. Ϫ C22H22NO3P (379.4): calcd. C 69.65, H 5.80, N 3.69;
found C 69.58, H 5.92, N 3.60.
General Procedure for the Synthesis of N-Acyl Enamines 10؊11: A
solution of nBuLi (1.6  in hexanes, 1.7 mL, 2.75 mmol) was added
dropwise to a solution of the phosphorylated amide 12؊13
(2.5 mmol) in THF (30 mL) at Ϫ78°C with stirring under Ar. The
orange solution was stirred for an additional 15 min and a solution
of the appropriate aldehyde 14 or 15 (2.5 mmol) in THF (5 mL)
was then slowly added. After being stirred at Ϫ78°C for 15 min the
reaction mixture was allowed to come to room temperature over
2 h. Aqueous NH4Cl was added and the organic layer was sepa-
rated, rinsed with brine, dried (MgSO4) and concentrated to dry-
ness. The crude products were analysed by 1H NMR in order to
determine the (E)/(Z) isomer ratio and compounds 10a؊c [(E) and
(Z) isomers] and 11a,b,d [(E) isomers] were finally purified by flash
column chromatography with AcOEt/hexane (60:40) as eluent and
recrystallized from hexane/toluene.
1
N-Acyl Enamine 11a: (E) isomer, m.p. 97Ϫ98°C. Ϫ H NMR: δ ϭ
1.65Ϫ1.82 (m, 4 H, CH2), 2.44 (t, J ϭ 5.8 Hz, 2 H, ϭCCH2), 3.65
(s, 3 H, OCH3), 3.70 (s, 3 H, OCH3), 3.74 (m, 2 H, NCH2), 5.63
(s, 1 H, vinylic H), 5.92 (s, 2 H, OCH2O), 6.21 (s, 1 H, aromatic
H), 6.25 (s, 1 H, aromatic H), 6.29Ϫ6.58 (m, 4 H, aromatic H). Ϫ
13C NMR: δ ϭ 25.2, 25.6, 28.2, 46.1, 56.0 (s, OCH3), 100.9, 107.2,
108.3, 108.7, 113.3, 122.1, 124.3, 124.5, 130.3, 130.5, 136.2, 147.7,
148.6, 150.7, 158.4, 170.2 (s, CϭO). Ϫ C22H23NO5 (381.4): calcd.
C 69.29, H 6.03, N 3.67; found C 69.41, H 5.95, N 3.59.
1
N-Acyl Enamine 10a: (E) isomer, m.p. 129Ϫ130°C. Ϫ 1H NMR:
δ ϭ 1.86Ϫ1.98 (m, 2 H, CH2), 2.83 (td, J ϭ 7.5, 2.0 Hz, 2 H, ϭ
CCH2), 3.71 (t, J ϭ 6.9 Hz, 2 H, NCH2), 3.86 (s, 3 H, OCH3), 3.88
(s, 3 H, OCH3), 5.91 (s, 2 H, OCH2O), 6.66Ϫ6.74 (m, 3 H, 2 aro-
matic H ϩ vinylic H), 6.83 (d, J ϭ 8.0 Hz, 1 H, aromatic H),
7.06Ϫ7.12 (m, 3 H, aromatic H). Ϫ 13C NMR: δ ϭ 22.8, 30.4, 51.9,
56.0 (s, OCH3), 100.9, 108.1, 108.4, 110.3, 110.8, 113.1, 120.3,
122.0, 130.5, 132.1, 139.8, 145.7, 147.5, 149.5, 151.6, 169.1 (s, Cϭ
O); (Z) isomer, oil. Ϫ 1H NMR: δ ϭ 1.81Ϫ1.99 (m, 2 H, CH2),
2.49 (t, J ϭ 7.3 Hz, 2 H, ϭCCH2), 3.62 (s, 3 H, OCH3), 3.68 (s, 3
H, OCH3), 3.71 (t, J ϭ 7.0 Hz, 2 H, NCH2), 5.55 (s, 1 H, vinylic
H), 5.67 (s, 2 H, OCH2O), 6.13 (s, 1 H, aromatic H), 6.28 (d, J ϭ
7.9 Hz, 1 H, aromatic H), 6.41 (d, J ϭ 7.9 Hz, 1 H, aromatic H),
6.52 (d, J ϭ 8.3 Hz, 1 H, aromatic H), 6.60 (s, 1 H, aromatic H),
6.81 (d, J ϭ 8.3 Hz, 1 H, aromatic H). Ϫ 13C NMR: δ ϭ 20.9,
31.8, 49.5, 55.4 (s, OCH3), 55.9 (s, OCH3), 100.6, 107.6, 107.7,
109.6, 111.3, 112.2, 120.5, 120.9, 129.1, 131.0, 138.3, 145.4, 147.2,
148.3, 150.7, 168.7 (s, CϭO). Ϫ C21H21NO5 (367.4): calcd. C 68.66,
H 5.72, N 3.81; found C 68.57, H 5.81, N 3.66.
N-Acyl Enamine 11b: (E) isomer, m.p. 92Ϫ93°C. Ϫ H NMR: δ ϭ
1.71Ϫ1.88 (m, 4 H, CH2), 2.53 (t, J ϭ 6.1 Hz, 2 H, ϭCCH2), 3.69
(t, J ϭ 7.0 Hz, 2 H, NCH2), 3.83 (s, 9 H, 3 ϫ OCH3), 5.71 (s, 1 H,
vinylic H), 5.93 (s, 2 H, OCH2O), 6.43Ϫ6.71 (m, 5 H, aromatic H).
Ϫ
13C NMR: δ ϭ 25.1, 25.7, 29.1, 46.5, 55.8 (s, OCH3), 60.1 (s,
OCH3), 100.8, 104.3, 108.1, 108.4, 113.2, 122.1, 130.5, 132.1, 133.0,
139.6, 145.6, 147.5, 153.1, 169.2 (s, CϭO). Ϫ C23H25NO6 (411.5):
calcd. C 67.15, H 6.08, N 3.41; found C 67.09, H 6.19, N 3.38.
1
N-Acyl Enamine 11d: (E) isomer, oil. Ϫ H NMR: δ ϭ 1.75Ϫ1.89
(m, 4 H, 2 CH2), 2.61 (t, J ϭ 6.5 Hz, 2 H, ϭCCH2), 3.58 (t, J ϭ
7.1 Hz, 2 H, NCH2), 5.77 (s, 1 H, vinylic H), 5.90 (s, 2 H, OCH2O),
6.25 (s, 1 H, aromatic H), 6.33Ϫ6.58 (m, 3 H, 2 aromatic H ϩ
furanic H), 7.08 (d, J ϭ 3.4 Hz, 1 H, furanic H), 7.45 (d, J ϭ
1.8 Hz, 1 H, furanic H). Ϫ 13C NMR: δ ϭ 24.9, 25.8, 29.3, 45.8,
100.9, 108.0, 108.8, 110.7, 111.8, 114.8, 122.2, 130.6, 131.8, 143.6,
147.3, 148.5, 148.7, 159.2 (s, CϭO). Ϫ C18H17NO4 (311.3): calcd.
C 69.45, H 5.47, N 4.50; found C 69.53, H 5.38, N 4.53.
General Procedure for the Photoisomerization Process: A solution
of the enamide (E)-10a؊c (2 mmol) in Et2O (200 mL) was purged
N-Acyl Enamine 10b: (E) isomer, m.p. 125Ϫ126°C. Ϫ 1H NMR: by bubbling Ar through it for 0.5 h. Photolyses were carried out in
δ ϭ 1.83Ϫ1.93 (m, 2 H, CH2), 2.84 (td, J ϭ 7.3, 1.8 Hz, 2 H, ϭ
CCH2), 3.68 (t, J ϭ 6.9 Hz, 2 H, NCH2), 3.84 (s, 9 H, 3 ϫ OCH3),
a water-cooled quartz reactor equipped with a dry Ar inlet and a
magnetic stirrer. The solution was placed in a Rayonet RPR 208
˚
5.91 (s, 2 H, OCH2O), 6.66Ϫ6.75 (m, 4 H, 3 aromatic Hϩ vinylic photochemical reactor containing eight RUL 2537 A lamps. Degas-
H), 7.18Ϫ7.27 (m, 2 H, aromatic H). Ϫ 13C NMR: δ ϭ 22.8, 30.4,
51.5, 56.2 (s, OCH3), 60.9 (s, OCH3), 100.9, 104.3, 108.2, 108.4,
113.2, 122.1, 130.7, 132.0, 133.0, 139.6, 145.6, 147.5, 153.1, 169.2
sing and stirring of the solution were maintained during ir-
radiation. The photostationary state [(Z)/(E) ϭ 2:3] was obtained
after 4 h. The solvent was evaporated under vacuum and the resi-
2350
Eur. J. Org. Chem. 1999, 2345Ϫ2352

An Efficient Synthesis of 5-(or 6-)Arylbenzoindolizidine and -quinolizidine Derivatives
due treated by flash column chromatography with AcOEt/hexanes 3.01Ϫ3.13 (m, 1 H), 3.80 (s, 6 H, 2 ϫ OCH3), 3.82 (s, 3 H, OCH3),
FULL PAPER
(3:7) as eluent. Compounds (Z)-10a؊c and (E)-10a؊c were iso- 5.89 (s, 2 H, OCH2O), 6.31 (s, 2 H, aromatic H), 6.51Ϫ6.78 (m, 3
lated and the photochemical protocol was repeated twice with the
(E) isomer.
H, aromatic H). Ϫ 13C NMR: δ ϭ 19.2, 25.6, 30.8, 35.2, 45.1, 54.3,
56.1 (s, OCH3), 60.9 (s, OCH3), 100.9, 103.6, 108.2, 109.6, 122.1,
129.8, 132.2, 145.7, 147.6, 148.3, 153.2, 169.8 (s, CϭO).
General Procedure for the Synthesis of N-Acylpyrrolidine and -pi-
peridine Derivatives 8a؊c and 9a,b,d. Ϫ Method A: A solution of
the N-acyl enamine 10 or 11 (2 mmol) in a mixture of methanol/
CH2Cl2 (5:1, 20 mL) was degassed by two freeze-thaw cycles and
then transferred on the catalyst Rh/C (5 ϫ 10Ϫ3 mmol) placed in a
Schlenk tube. The resulting mixture was transferred to a 100-mL
stainless steel autoclave. Hydrogen was introduced (25 atm) and the
reaction mixture was magnetically stirred at 30°C during 20 h. The
hydrogen was then removed and the solution was concentrated un-
der vacuum to leave an oily product, which was purified by flash
column chromatography with AcOEt/hexanes (1:1) as eluent. Ϫ
Method B: A suspension of compounds 10 or 11 (2 mmol) in meth-
anol (30 mL) was stirred with activated Pd/C (10%, 20 mg) and a
solution of HCOONH4 (640 mg, 10 mmol) in distilled water (5 mL)
was slowly added. The reaction mixture was refluxed for 2 h, fil-
tered through Celite and water was added. Extraction with
CH2Cl2 (3 ϫ 20 mL), drying with MgSO4 and concentration in va-
cuo left an oily product which was purified as described above.
1
N-Acylpiperidine 9d: Oil.[18] Ϫ H NMR: δ ϭ 1.42Ϫ1.75 (m, 6 H,
CH2), 2.70Ϫ2.76 (m, 1 H, CH2), 2.72 (dd, J ϭ 13.4, 8.8 Hz, 1 H),
2.98Ϫ3.13 (m, 1 H), 4.25Ϫ4.46 (br. s, 1 H), 4.58Ϫ4.73 (br. s, 1 H),
5.81 (s, 2 H, OCH2O), 6.38 (dd, J ϭ 3.4, 1.9 Hz, 1 H, furanic H),
6.56 (d, J ϭ 1.9 Hz, 1 H, furanic H), 6.58Ϫ6.67 (m, 3 H, aromatic
H), 7.41 (dd, J ϭ 1.9, 0.8 Hz, 1 H, furanic H). Ϫ 13C NMR: δ ϭ
19.1, 25.8, 26.9, 36.0, 43.9, 54.8, 100.8, 108.1, 111.0, 112.7, 115.2,
122.0, 132.3, 141.8, 147.6, 148.3, 148.6, 159.9 (s, CϭO).
Asymmetric Hydrogenation of (Z)-10a: The catalyst {RuCl2[(S)-
BINAP]}2 · NEt3 is commercially available and the catalysts
RuBr2[(S)-MeOBiPHEP],[40]
RuBr2[(S)-TolBINAP],[40]
Ru-
(OAc)2[(R)-BINAP][41] and Ru(TFA)2[(R)-BINAP][41] were freshly
prepared as previously described. For the determination of the en-
antiomeric excesses the oily residue obtained after the hydrogen-
ation experiment carried out as for Method A was analysed by
HPLC with a Supelcosil (R)-DNBPG column with hexane-2-pro-
panol (95:5) as eluent (flow rate 1 mL/min), UV detection at
254 nm, tR of 8a (Ϫ): 52.1 min and 8a (ϩ): 54.6 min.
1
N-Acylpyrrolidine 8a: Oil. Ϫ H NMR: δ ϭ 1.53Ϫ1.97 (m, 4 H, 2
CH2), 2.76 (dd, J ϭ 13.2, 8.4 Hz, 1 H, CH2Ar), 3.09 (br. d, J ϭ
13.2 Hz, 1 H, CH2Ar), 3.18Ϫ3.24 (m, 1 H, NCH2), 3.33Ϫ3.42 (m,
1 H, NCH2), 3.83 (s, 6 H, 2 ϫ OCH3), 4.31Ϫ4.39 (m, 1 H, NCH),
5.84 (s, 2 H, OCH2O), 6.65Ϫ6.78 (m, 4 H, aromatic H), 7.03Ϫ7.15
(m, 2 H, aromatic H). Ϫ 13C NMR: δ ϭ 20.9, 29.3, 38.4, 50.9, 55.9
(s, OCH3), 58.6, 100.7, 108.0, 110.0, 110.2, 111.0, 120.5, 122.6,
127.8, 129.7, 146.0, 147.5, 148.7, 150.4, 169.5 (s, CϭO). Ϫ
General Procedure for the Synthesis of the Cyclocondensed Products
1a؊c and 2a,b,d: A mixture of compound 8a؊c or 9a,b,d (2 mmol),
POCl3 (1.53 g, 10 mmol) in dry toluene (30 mL) was refluxed for
6 h under Ar with stirring. The solvent and excess reagent were
removed under vacuum and the residue was dissolved in dry meth-
anol (20 mL). Sodium tetrahydroborate (0.38 g, 10 mmol) was then
added portionwise until pH ϭ 9, AcOEt (50 mL) was added and
the organic layer washed with aqueous NaOH (10%) and dried
(MgSO4). Evaporation of the solvent left an oily residue, which was
analysed by 1H-NMR spectroscopy and finally purified by flash
column chromatography with acetone/petroleum ether (1:1) as elu-
ent and by recrystallization from Et2O/hexane.
C
21H23NO5 (369.4): calcd. C 68.29, H 6.23, N 3.79; found C 68.17,
H 6.36, N 3.19.
N-Acylpyrrolidine 8b: Oil. Ϫ 1H NMR: δ ϭ 1.38Ϫ1.66 (m, 2 H,
CH2), 1.73Ϫ1.85 (m, 2 H, CH2), 2.76 (dd, J ϭ 12.9, 8.1 Hz, 1 H,
CH2Ar), 2.96 (dd, J ϭ 12.9, 2.2 Hz, 1 H, CH2Ar), 3.03Ϫ3.15 (m,
1 H, NCH2), 3.22Ϫ3.33 (m, 1 H, NCH2), 3.71 (s, 3 H, OCH3), 3.73
(s, 6 H, 2 ϫ OCH3), 4.21Ϫ4.36 (m, 1 H, NCH), 5.76 (s, 2 H,
OCH2O), 6.41Ϫ6.65 (m, 5 H, aromatic H). Ϫ 13C NMR: δ ϭ 20.9,
24.8, 38.1, 50.8, 56.1 (s, OCH3), 58.4, 60.7 (s, OCH3), 100.7, 104.6,
107.9, 110.0, 122.7, 132.1, 132.5, 139.3, 146.0, 147.5, 152.9, 169.4
(s, CϭO). Ϫ C22H25NO6 (399.45): calcd. C 66.16, H 6.26, N 3.51;
found C 66.27, H 6.41, N 3.38.
Benzoindolizidine 1a: Major isomer, m.p. 147Ϫ148°C. Ϫ 1H NMR:
δ ϭ 1.54Ϫ1.78 (m, 4 H, CH2), 1.95Ϫ2.13 (m, 2 H, CH2Ar),
2.77Ϫ2.88 (m, 3 H, NCH2 ϩ NCH), 3.71 (s, 3 H, OCH3), 3.74 (s,
3 H, OCH3), 4.10 (s, 1 H, NCHAr), 5.75 (s, 2 H, OCH2O), 6.06 (s,
1 H, aromatic H), 6.73Ϫ6.83 (m, 3 H, aromatic H). Ϫ 13C NMR:
δ ϭ 21.1, 30.8, 35.9, 53.5, 55.8 (s, OCH3), 55.9 (s, OCH3), 61.2,
71.5, 100.6, 107.8, 108.0, 110.5, 111.8, 121.7, 128.1, 132.2, 135.9,
145.7, 145.9, 148.4, 149.1. Ϫ C21H23NO4 (353.4): calcd. C 71.39,
H 6.51, N 3.96; found C 71.58, H 6.33, N 3.82.
1
N-Acylpyrrolidine 8c: Oil. Ϫ H NMR: δ ϭ 1.66Ϫ2.03 (m, 4 H, 2
CH2), 2.76 (dd, J ϭ 12.9, 9.0 Hz, 1 H, CH2Ar), 3.17 (dd, J ϭ 12.9,
2.0 Hz, 1 H, CH2Ar), 3.61Ϫ3.96 (m, 11 H, 3 ϫ OCH3 ϩ NCH2),
4.41Ϫ4.45 (m, 1 H, NCH), 6.41 (s, 2 H, aromatic H), 6.44 (dd, J ϭ
3.3, 1.6 Hz, 1 H, furanic H), 7.02 (d, J ϭ 1.6 Hz, 1 H, furanic H),
7.46 (br. s, 1 H, furanic H). Ϫ 13C NMR: δ ϭ 24.5, 28.1, 38.9,
48.5, 56.0 (s, OCH3), 59.8, 60.8 (s, OCH3), 106.3, 111.4, 115.9,
134.6, 144.1, 148.8, 153.0, 158.0, 172.3 (s, CϭO). Ϫ C19H23NO5
(345.4): calcd. C 66.09, H 6.66, N 4.06; found C 65.91, H 6.83,
N 4.18.
N-Acylpiperidine 9a: Oil. Ϫ 1H NMR: δ ϭ 1.29Ϫ1.68 (m, 7 H,
CH2), 2.51Ϫ2.76 (m, 2 H, CH2), 2.78 (dd, J ϭ 13.6, 8.2 Hz, 1 H),
2.89Ϫ3.01 (m, 1 H), 3.64 (s, 3 H, OCH3), 3.67 (s, 3 H, OCH3), 5.68
(s, 2 H, OCH2O), 6.30Ϫ6.72 (m, 6 H, aromatic H). Ϫ 13C NMR:
δ ϭ 19.3, 25.8, 30.6, 35.7, 44.8, 54.9, 55.7 (s, OCH3), 55.8 (s,
OCH3), 100.7, 107.9, 109.4, 110.2, 110.3, 119.1, 121.9, 129.0, 132.1,
145.9, 147.5, 148.7, 149.7, 170.6 (s, CϭO). Ϫ C22H25NO5 (383.45):
calcd. C 68.93, H 6.53, N 3.65; found C 69.04, H 6.56, N 3.58.
Benzoindolizidine 1b: Major isomer, m.p. 163Ϫ164°C. Ϫ 1H NMR:
δ ϭ 1.54Ϫ1.80 (m, 3 H, CH2), 1.99Ϫ2.11 (m, 2 H, CH2), 2.54Ϫ2.54
(m, 1 H, CH2Ar), 2.69Ϫ2.91 (m, 3 H, NCH2 ϩ NCH), 3.83 (s, 3
H, OCH3), 3.85 (s, 6 H, 2 ϫ OCH3), 4.09 (s, 1 H, NCHAr), 5.82
(s, 2 H, OCH2O), 6.16 (s, 1 H, aromatic H), 6.51 (s, 2 H, aromatic
H), 6.54 (s, 1 H, aromatic H). Ϫ 13C NMR: δ ϭ 21.2, 31.0, 36.3,
53.7, 56.1 (s, OCH3), 60.8 (s, OCH3), 60.9, 72.1, 100.7, 106.0, 107.7,
108.1, 128.2, 132.3, 137.1, 139.7, 145.6, 145.8, 153.1. Ϫ C22H25NO5
(383.45): calcd. C 68.93, H 6.53, N 3.65; found C 69.08, H 6.71,
N 3.46.
Benzoindolizidine 1c: Major isomer, m.p. 78Ϫ79°C. Ϫ 1H NMR:
δ ϭ 1.58Ϫ1.92 (m, 3 H, 2 CH2), 2.01Ϫ2.36 (m, 2 H, CH2),
2.48Ϫ2.56 (m, 1 H, CH2Ar), 2.72Ϫ2.85 (m, 2 H, NCH2), 3.09 (td,
J ϭ 8.3, 2.6 Hz, 1 H, NCH), 3.74 (s, 3 H, OCH3), 3.82 (s, 6 H,
2 ϫ OCH3), 4.55 (s, 1 H, NCHAr), 6.17 (d, J ϭ 2.8 Hz, 1 H, fu-
ranic H), 6.31 (dd, J ϭ 2.8, 1.9 Hz, 1 H, furanic H), 6.43 (s, 1 H,
aromatic H), 7.27 (d, J ϭ 1.9 Hz, 1 H, furanic H). Ϫ 13C NMR:
1
N-Acylpiperidine 9b: Oil.[18] Ϫ H NMR: δ ϭ 1.56Ϫ1.83 (m, 7 H,
CH2), 2.61Ϫ2.84 (m, 2 H, CH2), 2.98 (dd, J ϭ 13.7, 8.4 Hz, 1 H),
Eur. J. Org. Chem. 1999, 2345Ϫ2352
2351

S. Lebrun, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
S. G. Weiss, M. Tin-Wa, R. E. Perdue, N. R. Farnsworth, J.
Pharm. Sci. 1975, 64, 95Ϫ98.
δ ϭ 21.1, 30.6, 36.6, 53.0, 55.8 (s, OCH3), 59.7 (s, OCH3), 59.8,
60.4, 106.1, 107.1, 110.1, 122.0, 132.0, 140.3, 140.5, 151.1, 152.3,
157.0. Ϫ C19H23NO4 (329.4): calcd. C 69.30, H 6.99, N 4.25; found
C 69.45, H 7.12, N 4.11.
[7]
[8]
F. Cortese, B. Bhattacharyya, J. Wolff, J. Biol. Chem. 1977,
252, 1134Ϫ1140.
P. Lienard, J. Royer, J. C. Quirion, H. P. Husson, Tetrahedron
Lett. 1991, 32, 2489Ϫ2492.
Benzoquinolizidine 2a: Major isomer, m.p. 132Ϫ133°C. Ϫ 1H
NMR: δ ϭ 1.24Ϫ1.91 (m, 7 H, CH2), 2.39 (td, J ϭ 10.8, 3.3 Hz,
1 H, NCH), 2.60 (dd, J ϭ 15.4, 3.3 Hz, 1 H, CH2Ar), 2.81 (m, 2
H, 1 H CH2Ar ϩ 1 H NCH2), 3.82 (s, 3 H, OCH3), 3.87 (s, 3 H,
OCH3), 4.04 (s, 1 H, NCHAr), 5.79 (dd, J ϭ 4.9, 1.3 Hz, 2 H,
OCH2O), 6.08 (s, 1 H, aromatic H), 6.49 (s, 1 H, aromatic H), 6.79
(d, J ϭ 8.0 Hz, 1 H, aromatic H), 6.80 (s, 1 H, aromatic H), 6.86
(dd, J ϭ 8.0, 1.9 Hz, 1 H, aromatic H). Ϫ 13C NMR: δ ϭ 24.3,
26.0, 33.8, 37.5, 53.8, 55.8 (s, OCH3), 55.9 (s, OCH3), 58.0, 71.8,
100.5, 107.1, 108.0, 110.5, 111.9, 121.8, 127.1, 131.7, 137.5, 145.5,
145.6, 149.1, 150.8. Ϫ C22H25NO4 (367.45): calcd. C 71.93, H 6.81,
N 3.81; found C 71.97, H 6.89, N 3.76.
[9]
A. Couture, E. Deniau, P. Grandclaudon, C. Hoarau, J. Org.
Chem. 1998, 63, 3128Ϫ3132.
[10]
[11]
[12]
A. Couture, E. Deniau, P. Grandclaudon, P. Woisel, Tetra-
hedron 1996, 52, 4433Ϫ4448.
A. Couture, E. Deniau, P. Grandclaudon, Tetrahedron 1997,
53, 10313Ϫ10330.
A. Couture, E. Deniau, P. Woisel, P. Grandclaudon, J. F. Carp-
entier, Tetrahedron Lett. 1996, 37, 3697Ϫ3700.
T. Kametani, K. Fukumoto, Heterocycles 1975, 3, 311Ϫ341.
L. E. Overman, M. Kakimoto, M. E. Okazaki, G. P. Meier, J.
Am. Chem. Soc. 1983, 105, 6622Ϫ6629.
[13]
[14]
[15]
[16]
[17]
A. Couture, E. Deniau, S. Lebrun, P. Grandclaudon, J. F. Carp-
entier, J. Chem. Soc., Perkin Trans. 1 1998, 1403Ϫ1407.
C. Sonesson, M. Larhed, C. Nyqvist, A. Hallberg, J. Org.
Chem. 1996, 61, 4756Ϫ4763.
C. Sonesson, H. Wikstroem, M. W. Smith, K. Svensson, A.
Carlsson, N. Waters, Bioorg. Med. Chem. Lett. 1997, 7,
241Ϫ246.
R. P. Polniaszek, S. E. Belmont, R. Alvarez, J. Org. Chem. 1990,
55, 215Ϫ223.
R. A. Ewin, K. Jones, C. G. Newton, J. Chem. Soc., Perkin
Trans. 1 1996, 1107Ϫ1111.
T. K. Highsmith, A. I. Meyers, in Advances in Heterocyclic
Natural Product Synthesis (Ed.: W. H. Pearson), JAI Green-
wich, CT, 1990, vol. 1, p. 95Ϫ135.
Benzoquinolizidine 2b: Major isomer, m.p. 124Ϫ125°C (ref.[18]
1
123°C). Ϫ H NMR: δ ϭ 1.31Ϫ1.90 (m, 7 H, CH2), 2.37 (td, J ϭ
[18]
[19]
[20]
10.5, 3.3 Hz, 1 H, NCH), 2.61 (dd, J ϭ 15.3, 3.3 Hz, 1 H, CH2Ar),
2.79 (m, 2 H, 1 H CH2Ar ϩ 1 H NCH2), 3.83 (s, 9 H, 3 ϫ OCH3),
4.03 (s, 1 H, NCHAr), 5.82 (s, 2 H, OCH2O), 6.15 (s, 1 H, aromatic
H), 6.50 (s, 1 H, aromatic H), 6.54 (s, 2 H, aromatic H). Ϫ 13C
NMR: δ ϭ 24.3, 26.1, 33.8, 37.5, 53.9, 56.1 (s, OCH3), 57.9, 60.9
(s, OCH3), 72.5, 100.5, 106.1, 107.2, 107.8, 127.1, 131.3, 136.8,
140.6, 145.5, 145.6, 153.1.
[21]
[22]
R. E. Gawley, P. Zhang, J. Org. Chem. 1996, 61, 8103Ϫ8112.
Y. S. Park, M. L. Boys, P. Beak, J. Am. Chem. Soc. 1996, 118,
3757Ϫ3758.
P. Beak, A. Basu, D. J. Gallagher, Y. S. Park, S. Thayumanavan,
Acc. Chem. Res. 1996, 29, 552Ϫ560.
Benzoquinolizidine 2d: Major isomer, m.p. 93Ϫ94°C (ref.[18] oil). Ϫ
1H NMR: δ ϭ 1.21Ϫ1.94 (m, 7 H, CH2), 2.34 (tt, J ϭ 10.8, 3.1 Hz,
1 H, NCH), 2.62 (dd, J ϭ 16.1, 3.1 Hz, 1 H, CH2Ar), 2.84 (m, 2
H, 1 H CH2Ar ϩ 1 H NCH2), 4.31 (s, 1 H, NCHAr), 5.83 (dd,
J ϭ 5.0, 0.9 Hz, 2 H, OCH2O), 6.19 (s, 1 H, aromatic H), 6.33 (m,
2 H, furanic H), 6.51 (s, 1 H, aromatic H), 7.36 (br. s, 1 H, furanic
H). Ϫ 13C NMR: δ ϭ 24.2, 25.8, 33.5, 37.1, 54.2, 58.2, 65.2, 100.6,
106.8, 107.5, 109.6, 109.7, 127.4, 128.1, 142.3, 145.8, 146.1, 154.9.
[23]
[24]
[25]
M. Kitamura, Y. Hsiao, M. Ohta, M. Tsukamoto, T. Ohta, H.
Takaya, R. Noyori, J. Org. Chem. 1994, 59, 297Ϫ310.
D. M. Tschaen, L. Abramson, D. Cai, R. Desmond, U. H. Dol-
ling, L. Frey, S. Karady, Y.-J. Shi, T. R. Verhoeven, J. Org.
Chem. 1995, 60, 4324Ϫ4330.
[26]
[27]
[28]
T. Morimoto, N. Nakajima, K. Achiwa, Tetrahedron: Asym-
metry 1995, 6, 75Ϫ78.
R. Noyori, M. Ohta, Y. Hsiao, M. Kitamura, T. Ohta, H.
Takaya, J. Am. Chem. Soc. 1986, 108, 7117Ϫ7119.
`
G. Lefebvre, J. Seyden-Penne, J. Chem. Soc., Chem. Commun.
Acknowledgments
1970, 1308Ϫ1309.
[29]
[30]
W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405Ϫ4408.
S. K. Thompson, C. H. Heathcock, J. Org. Chem. 1990, 55,
3386Ϫ3388.
We thank Dr. T. G. C. Bird (Zeneca Pharma) for helpful comments
on the manuscript and Dr. J.-F. Carpentier for valuable discussions.
This research was supported by the Centre National de la Recher-
che Scientifique and MENESR (grant to S. L.).
[31]
[32]
B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89, 863Ϫ927.
H. J. Hensel, P. L. Fuchs, Synth. Commun. 1986, 16,
1285Ϫ1295.
A. Couture, E. Deniau, P. Grandclaudon, S. Lebrun, Tetra-
hedron Lett. 1996, 37, 7749Ϫ7752.
N. C. Yang, G. R. Lenz, Tetrahedron Lett. 1967, 4897Ϫ4800.
D. Bellus, Adv. Photochem. 1978, 8, 109Ϫ113.
I. Ninomiya, T. Naito, Alkaloids 1983, 22, 189Ϫ279.
K. Ogawa, Y. Nomura, Y. Takeuchi, S. Tomoda, J. Chem. Soc.,
Perkin Trans. 1 1982, 3031Ϫ3035.
[33]
[1] [1a]
I. S. de la Lande, Aust. J. Exp. Biol. Med. Sci. 1948, 26,
[34]
[35]
[36]
[37]
181Ϫ187. Ϫ [1b] A. Al-Shamma, S. D. Drake, L. E. Guagliardi,
L. A. Mitscher, J. K. Swayze, Phytochemistry 1982, 21,
[1c]
485Ϫ487. Ϫ
E. Krmpotic, N. R. Farnsworth, W. M.
Messner, J. Pharm. Sci. 1972, 61, 1508Ϫ1509. Ϫ [1d] J. J. Hoff-
man, D. J. Luzbetak, S. J. Torrance, J. R. Cole, Phytochemistry
1978, 17, 1448.
[38]
G. P. Claxton, L. Allen, J. M. Grisar, Org. Synth. Coll. Vol. VI
1988, 968Ϫ971.
[2]
[3]
[4]
[5]
A. R. Battersby, R. J. Francis, M. Hirst, E. A. Ruveda, J. Staun-
ton, J. Chem. Soc., Perkin Trans. 1 1975, 1140Ϫ1147.
R. S. Mali, S. D. Patil, S. L. Patil, Tetrahedron 1986, 42,
2075Ϫ2082.
[39]
[40]
R. C. Miller, J. Org. Chem. 1959, 24, 2013Ϫ2015.
ˆ
J. P. Genet, C. Pinel, V. Ratovelomanana-Vidal, S. Mallart, X.
Pfister, M. C. Can˜o de Andrade, J. A. Laffite, Tetrahedron:
Asymmetry 1994, 5, 665Ϫ674.
´
N. Sotomayor, E. Domınguez, E. Lete, J. Org. Chem. 1996,
[41]
61, 4062Ϫ4072.
B. Heiser, E. A. Broger, Y. Crameri, Tetrahedron: Asymmetry
1991, 2, 51Ϫ62.
P. Lienard, J. C. Quirion, H. P. Husson, Tetrahedron 1993, 49,
3995Ϫ4006.
Received March 4, 1999
[6] [6a]
[6b]
S. B. Horwitz, J. D. Loike, Lloydia 1977, 40, 82Ϫ89. Ϫ
[O99149]
2352
Eur. J. Org. Chem. 1999, 2345Ϫ2352