Metalation vs Nucleophilic Addition in the Reactions of N-Phenethylimides with Organolithium Reagents. Ready Access to Isoquinoline Derivatives via N-Acyliminium Ions and Parham-Type Cyclizations

Article abstract of DOI:10.1021/jo962155o

Sequential carbophilic addition of organolithium reagents and N-acyliminium ion cyclization of N-phenethylimides 1 affords the substituted isoquinolones 3 in high yields, with the possibility of varying the substituent at the C-1 position of the isoquinoline ring by changing the organolithium reagent. Ready access to the isoquinoline nucleus via Parham-type cyclization of imides 2 is also described. We have shown that iodinated imides 2 tolerate the metal-halogen exchange in the presence of the imide group, and the intramolecular cyclization of the so-obtained aromatic organometallic derivatives leads to the corresponding enamides 4. Both approaches have allowed the efficient preparation of various types of the isoquinoline class of alkaloids, just by changing the substitution pattern on the readily available starting imides. Thus, we have developed convenient alternative routes for the synthesis of benzo[a]quinolizidones and their 2-oxa analogs, isoindoloisoquinolones, dibenzo[a,h]quinolizidones, and thiazolo- and oxazolo[4,3-a]isoquinolones.

Full text of DOI:10.1021/jo962155o

2080
J . Org. Chem. 1997, 62, 2080-2092
Meta la tion vs Nu cleop h ilic Ad d ition in th e Rea ction s of
N-P h en eth ylim id es w ith Or ga n olith iu m Rea gen ts. Rea d y Access
to Isoqu in olin e Der iva tives via N-Acylim in iu m Ion s a n d
P a r h a m -Typ e Cycliza tion s
M. Isabel Collado, Izaskun Manteca, Nuria Sotomayor, Mar´ıa-J esu´s Villa, and Esther Lete*
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad del Pa´ıs Vasco, Apdo. 644,
48080 Bilbao, Spain
Received November 18, 1996X
Sequential carbophilic addition of organolithium reagents and N-acyliminium ion cyclization of
N-phenethylimides 1 affords the substituted isoquinolones 3 in high yields, with the possibility of
varying the substituent at the C-1 position of the isoquinoline ring by changing the organolithium
reagent. Ready access to the isoquinoline nucleus via Parham-type cyclization of imides 2 is also
described. We have shown that iodinated imides 2 tolerate the metal-halogen exchange in the
presence of the imide group, and the intramolecular cyclization of the so-obtained aromatic
organometallic derivatives leads to the corresponding enamides 4. Both approaches have allowed
the efficient preparation of various types of the isoquinoline class of alkaloids, just by changing
the substitution pattern on the readily available starting imides. Thus, we have developed
convenient alternative routes for the synthesis of benzo[a]quinolizidones and their 2-oxa analogs,
isoindoloisoquinolones, dibenzo[a,h]quinolizidones, and thiazolo- and oxazolo[4,3-a]isoquinolones.
In tr od u ction
carbophilic addition-N-acyliminium ion cyclization se-
quence could be performed on N-phenethylimides 1,
leading to the substituted isoquinolones 3 through a
preferential attack to the imidic carbonyl group (Scheme
1). The key step involves N-acyliminium ion-mediated
carbon-carbon bond-forming reactions, which have found
an impressive number of synthetic applications.7 N-
Acyliminium ions have demonstrated significant utility
as intermediates in various types of cyclization reactions
using different types of π nucleophiles.8 In our strategy,
the appropriate choice of the organolithium reagent at
the first step would allow the introduction of functionality
on the pendant side chain of 3, giving rise to useful
precursors for the construction of more complex isoquino-
line alkaloids, such as the Erythrina type.9 The second
approach relied on assembling the isoquinoline nucleus
via Parham-type cyclization of imides 2, since haloge-
nated imides 2 could tolerate the metal-halogen ex-
change in the presence of the imide group, and the
intramolecular cyclization of the so-obtained aromatic
organometallic derivatives would lead to the correspond-
ing enamides 4 (Scheme 1). In view of the ready
availability of a wide array of substituted imides, both
approaches seemed well suited to provide access to a wide
variety of isoquinoline alkaloids.
Within the scope of the aromatic directed metalation
reaction, a protocol which is enjoying increasing utility
in organic synthesis, the intramolecular capture of the
aryllithium intermediate by internal electrophiles (ortho-
lithiation-cyclization strategy) has proven to be an
effective method for the construction of carbocyclic and
heterocyclic systems.1,2 However, certain electrophilic
groups, such as ketones and imides, do not remain
passive during the metalation process, and competitive
nucleophilic attack by organolithium base may occur.
Advantage can be taken of the very fast rate of metal-
halogen exchange compared with nucleophilic addition
to carbonyl groups to allow survival of acidic sites and
other electrophilic groups under low-temperature RLi
conditions.3 In their work on Parham-type cyclizations,3
Wolfe4 reported that the N-acyl groups of N-acyl-2-
bromobenzamides tolerated metal-bromine exchange
when the imide nitrogen was either deprotonated by
sodium hydride or carried an alkyl substituent. The
resulting ortho-lithium intermediates underwent cycliza-
tion to yield 3-alkylidenephthalimidines. Narasimhan5
has described a novel synthesis of 1-arylbenzocyclobutenols
and benzocyclobutenes from deoxybenzoins using a simi-
lar metal-halogen exchange strategy.
Here we detail6 the utility of the reactions of N-
phenethylimides with organolithium compounds for the
synthesis of different isoquinoline alkaloids using two
basic strategies. First, it was expected that a tandem
(7) Reviews: (a) Speckamp, W. N. Rec. Trav. Chim. Pays-Bas 1981,
100, 345. (b) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,
4367. (c) Hiemstra, H.; Speckamp, W. N. In The Alkaloids; Academic
Press: New York, 1988; Vol. 32, p 271. (d) Hiemstra, H.; Speckamp,
W. N. Additions to N-Acyliminium ions. In Comprehensive Organic
Chemistry; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 2, p 1047. (e) Maryanoff, B. E.; Rebarchak, M. C. Synthesis
1992, 1245-1248 and references therein.
X Abstract published in Advance ACS Abstracts, March 1, 1997.
(1) Snieckus, V. Chem. Rev. 1990, 90, 879.
(2) Snieckus, V. Pure Appl. Chem. 1994, 66, 2155.
(3) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300.
(4) Hendi, M. S.; Natalie, K. J .; Hendi, S. B.; Campbell, J . A.;
Greenwood, T. D.; Wolfe, J . F. Tetrahedron Lett. 1989, 30, 275.
(5) Aidhen, I. S.; Narasimhan, N. S. Tetrahedron Lett. 1991, 32,
2171.
(6) For preliminary communications: Lete, E.; Eguiarte, A.; Soto-
mayor, N.; Vicente, T.; Villa, M. J . Synlett 1993, 41. Collado, M. I.;
Sotomayor, N.; Villa, M. J .; Lete, E. Tetrahedron Lett. 1996, 37, 6193.
Manteca, I.; Sotomayor, N.; Villa, M. J .; Lete, E. Tetrahedron Lett.
1996, 37, 7841.
(8) For representative examples of π-nucleophiles, see: ref 7. For
some recent examples, see: (a) Heaney, H.; Shuhaibar, K. F. Synlett
1995, 47. (b) Lee, Y. S.; Kang, D. W.; Lee, S. J .; Park, H. J . Org. Chem.
1995, 60, 7149. (c) Li, W. H.; Hanau, C. E.; Davignon, A.; Moeller, K.
D. J . Org. Chem. 1995, 60, 8155. (d) Logers, M.; Overman, L. E.;
Welmalker, G. S. J . Am. Chem. Soc. 1995, 117, 9139. (e) Marson, C.
M.; Pink, J . H.; Smith, C. Tetrahedron Lett. 1995, 36, 8107. (f) Rigo,
B.; Elghammarti, S.; Couturier, D. Tetrahedron Lett. 1996, 37, 485.
(g) Yamada, H.; Aoyagi, S.; Kibayashi, C. J . Am. Chem. Soc. 1996,
118, 1054.
(9) Bentley, K. W. Nat. Prod. Rep. 1994, 555.
S0022-3263(96)02155-X CCC: $14.00 © 1997 American Chemical Society

Reactions of N-Phenethylimides with Organolithium Reagents
J . Org. Chem., Vol. 62, No. 7, 1997 2081
Sch em e 1
Sch em e 3
Ta ble 2. P r od u cts fr om th e RLi Ca r bop h ilic Ad d ition
Step of th e Sequ en ce w ith 3a
products
Ta ble 1. On e P ot Ad d ition -Cycliza tion of 1a w ith
n -Bu Li
entry
RLi
n-BuLi
MeLi
s-BuLi
t-BuLi
Me3SiCH2Li
PhLi
PhCtCLi
CH2dCHCH2Li g, CH2dCHCH2
R
yielda (%) ratio 5/6b
1
2
3
4
5
6
7
8
a , n-Bu
b, Me
c, s-Bu
d , t-Bu
b, Me
e, Ph
61
87
52
53
60
95
61
e
4.2/1
c
d
conditionsa
entry n-BuLi (equiv) quenching agent yieldb (%) of product 3a
d
1
2
3
1.1
2.2
2.2
12 M HCl
12 M HCl
TFA
26
40
92
4.8/1
1/3
d
f, PhCtC
1.9/1
a
b
Reactions carried out in THF at -78 °C for 6 h. Yields of
a
b
isolated products.
Yields of the mixture of tautomers 5 and 6. Determined by
d
1H NMR. c Only the hydroxy lactam 5 was isolated. Only the oxo
amide 6 was isolated. e Yields could not be accurately calculated
due to contamination with the stannane derivative formed in the
transmetalation.
Sch em e 2
formation of the N-acyliminium ion, which is probably
the rate-determining step.
In order to study the influence of steric and electronic
effects in both the addition and cyclization reactions,
succinimide 1a was treated with a range of organolithium
reagents. Allyllithium was prepared by transmetalation
of allyltriphenyltin with PhLi, according to literature
procedures.10 Addition reactions were thus carried out
with 2 equiv of the organolithium reagent at -78 °C over
6 h and quenched by addition of water at low tempera-
ture. After workup, equilibrium mixtures of the hydroxy
lactams 5, and the corresponding tautomeric oxo amides
6 were obtained, as summarized in Table 2 (Scheme 3).
The fact that no open-chain hydroxy amides resulting
from RLi attack to the ketone carbonyl in 6 have been
detected suggests that these oxo amides 6 are formed
during aqueous workup, and not by ring opening of the
intermediate lithium alkoxide. In cases a and b (R )
Bu, Me, entries 1 and 5, Table 2), the tautomers 5 and 6
could be chromatographically separated and identified
by NMR, while in the other cases decomposition occurred
during the purification processes. However, since the
subsequent cyclization of both compounds leads to the
same pyrroloisoquinolone, no previous separation is
required and NMR resonances can be used in the
determination of the tautomers ratio from the mixture.
The most significant signals were the NH triplet for the
oxo amides 6 (i.e.: 5.67 ppm for 6a ) in the 1H NMR
spectrum and the 13C NMR shift of the carbinolic or
ketonic carbon (i.e.: 92.2 ppm for 5a and 210.1 for 6a ,
respectively).
Resu lts a n d Discu ssion
Ca r bop h ilic Ad d ition -N-Acylim in iu m Ion Cy-
cliza tion . A preliminary study of the reaction conditions
for the tandem one-pot addition-cyclization reaction was
carried out using succinimide 1a as substrate, prepared
by condensation of 3,4-dimethoxyphenethylamine with
succinic anhydride. Representative results are sum-
marized in Table 1 (Scheme 2).
When 1a was treated with 1 equiv of n-BuLi at -78
°C for 6 h, quenching the reaction mixture with 12 M
HCl once at room temperature, complete conversion was
not accomplished, and the cyclization product 3a was
isolated in low yield (26%), together with starting mate-
rial (entry 1). A better yield of 3a (40%) was obtained
using 2 equiv of n-BuLi under the same conditions (entry
2). However, treatment with 2 equiv of n-BuLi at -78
°C for 6 h, followed by TFA quench at room temperature,
afforded 3a in high yield. As expected, conversion 1a to
3a involves the initial formation of an alkoxide derivative,
via addition of the organolithium reagent to the imidic
carbonyl group, followed by protonation and subsequent
dehydration to produce the corresponding N-acyliminium
salt. The former salt readily cyclized to the 8,9-disub-
stituted pyrroloisoquinolone 3a by electrophilic attack of
the aromatic ring. In fact, the intermediate addition
products could be isolated as tautomeric mixtures of
hydroxy lactams 5 and oxo amides 6 when the reaction
was quenched with water (Scheme 3). The structure of
the acidic catalyst is of great influence on the outcome
of the cyclization reaction, as it has been observed in
other amidoalkylation reactions.7 In this case, the fact
that TFA affords the pyrroloisoquinolone 3a in better
yield than HCl could indicate that TFA favors the
Both yield and product distribution are affected by the
steric and electronic nature of the carbon atom directly
attached to the metal in the alkyllithium used as nu-
cleophile (Table 2). The ratio of oxo amides 6 increases
(10) Seyferth, D.; Weiner, M. A. J . Org. Chem. 1961, 26, 4797.

2082 J . Org. Chem., Vol. 62, No. 7, 1997
Collado et al.
Ta ble 3. P r od u cts fr om th e Cycliza tion Step of 5 + 6
Sch em e 4
conditions
entry substrate [time (h), T]
yield
(%)
R
product
1
2
3
4
5
6
7
5a + 6a
5b
6c
6d
5e + 6e
6f
18, refluxa
4, rta
n-Bu
Me
3a
3b
3c
95
98
93
c
120, refluxb s-Bu
-
t-Bu
Ph
PhCtC
CH2dCHCH2
36, refluxa
-
3e
3f
3g
98
c
5g+ 6g
6, refluxa
97d
a
b
CH2Cl2 was used as solvent. CHCl3 was used as solvent.
c Starting material was recovered under various reaction condi-
tions. Based on GC-MS analysis.
d
with the substitution (entries 1-4). Thus, only the cyclic
tautomer was isolated when the reaction was carried out
with MeLi (entry 2), and it is the major tautomer in the
reaction with n-BuLi. J ust in one experiment, formation
of the 4-oxopentanamide 6b (R ) CH3) could be detected
by 1H NMR of the crude reaction mixture, in a 4.8/1 ratio
favoring the hydroxy lactam 5b. The ratio is inverted
in the case of s-BuLi and t-BuLi (entries 3 and 4), where
oxo amides 6c and 6d were the only products isolated.
However, in the case of R ) s-Bu, the presence of a minor
(entry 5). The fact that no cyclization products were
observed in the case of 6d (R ) t-Bu, entry 4) and in 6f
(R ) PhCtC, entry 6) could be explained by the above
mentioned steric and electronic effects, respectively. In
the other cases, yields were quantitative, and pure
products were obtained from the crude reaction mixtures
(GC analysis).
A rational extension of this methodology into other
synthetically useful fields consists in the variation of the
imide skeleton, thus providing a rapid, mild, and re-
giospecific entry to several heterocyclic systems, such as
benzo[a]quinolizidones and their 2-oxa analogs, isoindo-
loisoquinolones, dibenzo[a,h]quinolizidones, and thiazolo-
and oxazolo[4,3-a]isoquinolones. Thus, a series of imides
1i-p were prepared as depicted in Scheme 5. Condensa-
tion of 3,4-dimethoxyphenethylamine 7 with cyclic an-
hydrides 8 under classical conditions afforded imides 1i-
l, while imides 1n and 1p were prepared by Mitsunobu
reaction of 3,4-dimethoxyphenethyl alcohol 9 and imides
10. Reaction of imides 1l and 1n with LDA/MeI yielded
the corresponding dimethylated derivatives 1m and 1o
(Scheme 5).
1
amount of hydroxy lactam could be detected by H NMR
of the crude reaction mixture, whose ratio could not be
determined due to overlapping of representative signals,
and could not be isolated. A GC-MS analysis showed the
presence of a peak of mass 303 (M+ - 18) that could
correspond to hydroxy lactam 5c in a 19/1 6c/5c ratio.
The use of Me3SiCH2Li (entry 5) afforded a mixture of
5b and 6b (R ) Me) in a 4.8/1 ratio favoring the hydroxy
lactam. This result can be rationalized assuming that a
carbon to oxygen migration of the trimethylsilyl group11-13
had occurred, followed by hydrolysis of the O-Si bond
during workup. Both tautomers could be separated by
column chromatography and identified.
The sequence of carbophilic addition-N-acyliminium
ion cyclization was applied on these substrates under the
usual conditions affording the heterocyclic systems in
high overall yields. As in the previous cases described,
when imides 1i-k were subjected to reaction with n-BuLi
(2 equiv), a smooth nucleophilic addition of the organo-
lithium reagent was observed. A simple aqueous workup
yielded the oxo amides 6i-j or the cyclic tautomer,
hydroxy lactam 5k , in excellent yields. Subsequent
treatment of these addition products with TFA in dichlo-
romethane at room temperature resulted in the quanti-
tative formation of the corresponding isoquinoline der-
ivatives: benzo[a]quinolizidone 3i, its 2-oxa analogue 3j,
and nuevamine-type isoindoloisoquinolone 3k (Scheme
6). Comparable yields of isoquinoline derivatives 3i-k
were obtained by quenching the n-BuLi addition reac-
tions with TFA, though in some cases, conversions were
lower. NMR data, including 1H-1H homodecoupling and
DEPT experiments, proved to be useful for structure
determinations here. In the case of benzo[a]quinolizidone
3i, owing to the complex NMR spectra, 1H and 13C
resonances were assigned by analysis of 2D 1H-1H COSY
and HMQC spectra. The latter spectrum was particu-
larly helpful to distinguish between vicinal and geminal
proton signals in the CH2CH2 and CH2CH2CH2 parts of
quinolizidone ring.
As one can see from Table 2, hybridization change on
the nucleophilic carbon atom of the organolithium re-
agent also exerts a strong effect, inverting the 5/6 ratio.
In fact, the hydroxy lactams 5e and 5f (entries 6 and 7)
are more unstable due to inductive effects on C-4, which
favor the equilibrium toward the open chain isomer 6.14
Yield of the tautomeric mixture of 5/6g could not be
accurately calculated due to contamination with the
stannane derivative formed in the transmetalation, even
after chromatography, but conversion was complete and
NMR spectra of the crude reaction mixtures only showed
signals due to both tautomers and the organotin com-
pound. However, hydroxy lactam 5g decomposed during
chromatography, and only the corresponding oxo amide
6g could be isolated and identified.
Cyclization of the tautomeric mixture of 5 and 6 was
accomplished with TFA in CH2Cl2 or CHCl3 to afford the
desired 10b-substituted tetrahydropyrroloisoquinolones
3 (Scheme 4). As shown on Table 3, high cyclization
yields were generally obtained, though the rate was
strongly influenced by the nature of the R group at C-10b.
Higher temperatures and longer reaction times are
required as the steric bulk increases (entry 2 vs 1 and 3)
or as the R group diminishes the electrophility of the
intermediate N-acyliminium ion by resonance effect
The homophthalimide 1l underwent rapid deprotona-
tion at the benzylic position using the n-BuLi addition
conditions (D2O quench). Therefore, 1l was converted in
its silyl enol derivative by deprotonation with n-BuLi (1.1
equiv) in THF at -78 °C, followed by addition of TMSCl,
and then treated with n-BuLi in one pot. By this
(11) Brook, A. G. Acc. Chem. Res. 1974, 7, 77.
(12) Hudrlick, P. F.; Peterson, D.; Rona, R. J . J . Org. Chem. 1975,
40, 2263.
(13) Tietze, L. F.; Geisler, H.; Gewert, J . A.; J acobi, U. Synlett 1994,
511.
(14) Maryanoff, D. F.; McComsey, D. F.; Dhul-Emswiler, B. A. J .
Org. Chem. 1983, 48, 5062.

Reactions of N-Phenethylimides with Organolithium Reagents
Sch em e 5a
J . Org. Chem., Vol. 62, No. 7, 1997 2083
Sch em e 6a
Sch em e 7a
Sch em e 8a
procedure, both the benzylic position and the adjacent
carbonyl group were protected against deprotonation and
addition, respectively, and hydroxy lactam 5l and oxo
amide 6l were obtained with complete regioselectivity in
a 1/1.5 ratio and were chromatographically separated.
However, when these n-BuLi addition products were
submitted to cyclization with TFA, separately or directly
from the crude reaction mixture, the 1-n-butyl-N-(3,4-
dimethoxyphenethyl)-3-hydroxy isoquinolinium salt 11
was obtained as the major product (Scheme 7). In this
case, the facile aromatization of the initially formed
N-acyliminium salt prevented the cyclization.
This problem could be circumvented using the di-
methylated homophthalimide 1m . Two potential reac-
tion pathways are possible. Addition to the carbonyl
group in conjugation with the aromatic ring would result
in the formation of a dibenzo[a,h]quinolizidinone, while
attack to the carbonyl group at C-3 would lead to
protoberberine system. Thus, when homophthalimide
1m was subjected to the RLi addition-cyclization condi-
tions, treatment with n-BuLi and TFA in the one-pot
sequence afforded quantitatively a 1:1.7 mixture of the
corresponding protoberberinone 3m and dibenzo[a,h]-
quinolizidinone 3m ′. In a separate experiment, hydroxy
lactams 5m and 5m ′ were chromatographically sepa-
rated, identified, and cyclized to the protoberberinone 3m
(75% yield) and dibenzo[a,h]quinolizidinone 3m ′ (95%
yield), respectively (Scheme 8). The organolithium ad-
dition to this unsymmetrical imide was attended with
modest regioselectivity, with preferential addition to the
less hindered carbonyl group.
The relative regiochemistry of the products was deter-
mined by a combination of NOE measurements and

2084 J . Org. Chem., Vol. 62, No. 7, 1997
Collado et al.
Sch em e 9a
F igu r e 1.
the ester or thio ester carbonyl groups toward nucleo-
philic attack of the amide nitrogen. On the contrary,
treatment of the hydroxy lactams 5o and 5p with TFA
provided in high yields the corresponding heterocycle-
fused isoquinolines 3o and 3p , respectively.
In addition to high field 1H and 13C NMR spectra,
COSY, NOESY, and HMQC spectra were necessary to
confirm the regiochemistry, due to the complexity of the
spectra. These 2D NMR techniques have also allowed
us to unequivocally assign the chemical shifts of all
protons and carbons. The diagnostic carbonyl carbon and
n-Bu-C-N quaternary carbon resonances, together with
the presence or absence of NOE among the methyl
protons at C-13 and the methylene protons of the n-butyl
group (those directly bonded to the heterocyclic ring), are
the most significant facts. Besides, the NOE observed
between the methyl group at C-13 and the aromatic H-10
proton in the isoquinoline derivatives also supported the
assignments.
P a r h a m Cycliza tion s. Our next concern was the
synthesis of isoquinolones 4 by Parham cyclization of the
halogenated imides 2. A preliminary study of the reac-
tion conditions for the Parham cyclization reaction was
carried out using brominated succinimide 2a (Scheme 1,
X ) Br) as substrate, prepared by treatment of 1a with
bromine in acetic acid.17 Although a variety of experi-
mental conditions were tested, the desired pyrroloiso-
quinolines 4 could not be detected in the crude product
mixture from 2a . When 2a was treated with n-BuLi (1
equiv) at -78 °C for 2.5 h and the reaction quenched by
the addition of HCl, 3a was isolated as the major product
(34%). Metalation of 2a took place partially because
debromination was observed, but lithium-bromine ex-
change is not fast enough to compete effectively with
n-BuLi addition to the imide carbonyl group. In fact,
when 2a was treated under the same conditions previ-
ously used for 1a , the 10b-substituted pyrroloisoqui-
nolone 3a was isolated in a similar yield (52%). When
the reaction was quenched by the addition of water it
afforded the hydroxy lactam 5a (45%), while using more
diluted acid (6 M HCl) enamide 12 was obtained as the
major product (26%) (Figure 1). This compound also
cyclized to 3a when stronger acidic medium (TFA or 12
M HCl) and/or prolonged stirring times were used.
The use of t-BuLi gave also addition to the carbonyl
group, together with bromine-lithium exchange. Thus,
when 2a was treated with t-BuLi (2.1 equiv) at -78 °C,
only the oxo amide 6d was isolated (40%). In addition,
when a larger excess of t-BuLi (4 equiv) was used and
the reaction mixture stirred for 4 h at -78 °C before
quenching, a dimeric byproduct (mass spectroscopy,
elemental analysis) was also isolated (15-18%) (Figure
comparison of trends in the NMR data. When one
examines H NMR resonances, a downfield shift of one
1
aromatic proton for protoberberine 3m can be observed,
relative to the other regioisomer (δ 8.14 for 3m vs δ 7.64
for 3m ′). These values are consistent with the proposed
structure, and the downfield shift observed may be
attributed to the anisotropy of the carbonyl group.
Besides, the conjugation of one of the carbonyl groups
with the aromatic ring is also reflected in the difference
of chemical shifts of the two carbonyl carbons in their
13C NMR spectra (δ 163.6 for 3m vs δ 175.7 for 3m ′).
Although these data are in accordance with those re-
ported for similar systems,15 one should ideally have both
isomers in order to compare values for unambiguous use
of these spectroscopic data as diagnosis. Nevertheless,
nuclear Overhauser effect difference spectroscopy can be
used to confirm the regiochemistry and solve the problem.
Thus, protoberberinone 3m demonstrated an enhance-
ment of the signal of the methyl protons at C-13 upon
irradiation of the methylene protons of the n-butyl group
(those directly bonded to the heterocyclic ring), and vice
versa. On the other hand, dibenzoquinolizidinone 3m ′
showed no NOE between the above-mentioned methyl
and methylene protons. Similar criteria were used to
distinguish the hydroxy lactams 5m and 5m ′ and to
assign the structure of their analogue 5l.
The extension of this methodology to other heteroatom-
inserted imide derivatives was anticipated. It should be
noted that heterocycle-fused isoquinolines, such as thia-
zolo- and oxazolo[4,3-a]isoquinolines, would be attractive
for their potentially biological activities.16 Addition of
n-BuLi to heteroatom-inserted imides 1o and 1p occurred
with high regioselectivity at the more electrophilic amide
carbonyl group (Scheme 9), affording the hydroxy lactams
5o and 5p as the major products (75% and 58%, respec-
tively). Addition to the carbamate or thiocarbamate
carbonyl groups also occurred, and the oxo amides 6o and
6p could be isolated in minor amounts (8% and 16%,
respectively). In this case, the open chain oxo amide is
favored versus the cyclic hydroxy lactam, due to the
inductive effect of the oxygen or sulfur atom, as previ-
ously discussed. In fact, cyclization attempts of oxo
amides 6o and 6p failed, due to the lower reactivity of
(15) Vicente, T.; Mart´ınez de Marigorta, E.; Domı´nguez, E.; Carrillo,
L.; Bad´ıa, M. D. Heterocycles 1993, 36, 2067.
(16) Kano, S.; Yuasa, Y.; Shibuya, S. Synth. Commun. 1985, 15, 883.
(17) Dom´ınguez, E.; Lete, E.; Iriondo, C.; Villa, M. J . Bull. Soc. Chim.
Belg. 1984, 93, 1099.

Reactions of N-Phenethylimides with Organolithium Reagents
J . Org. Chem., Vol. 62, No. 7, 1997 2085
Sch em e 10a
Sch em e 11a
1). The H and 13C NMR indicated the presence of four
1
Sch em e 12a
methoxyl groups, six aromatic protons, and seven meth-
ylene groups. Further spectroscopic analysis, which
included 1H-1H decoupling experiments and 2D C-H
correlation, led us to propose the structure of N-(3,4-
dimethoxyphenethyl)-5-[N-(3,4-dimethoxyphenethyl)suc-
cinimid-3-ylidene]-2-pyrrolidinone (13) for this dimeric
product. Its formation could be explained by aldol-type
condensation of the succinimide. Analogous succinimide
enolate formation have been reported.18
In view of these results the iodinated succinimide 2b,
prepared by treatment of 1a with ICl, was tested as a
substrate for the Parham cyclization. As expected,
iodine-lithium exchange was faster than addition to the
carbonyl group of the imide, and the initially formed
anion was trapped intramolecularly by the imide carbo-
nyl to afford an intermediate 10b-hydroxypyrroloisoqui-
nolone, that dehydrated during workup to afford 4a (75%)
(Scheme 10).
These conditions were applied to the synthesis of more
complex isoquinoline alkaloids. Thus, the iodinated
imides 2c and 2d were prepared by treatment of 1i and
1j with ICl in glacial acetic acid. When 2c and 2d were
treated under the previously tested conditions, the 11b-
hydroxylated benzo[a]quinolizidone 14b and its 2-oxa
analogue 14c were obtained in high yields. These
products spontaneously dehydrated to the corresponding
1,11b-didehydrobenzo[a]quinolizidones 4b and 4c in
chloroform solution (Scheme 11). Similarly, the hydroxy-
substituted isoindoloisoquinolone 14d and dibenzo[a,h]-
quinolizidone 14e were obtained from the iodinated
imides 2e and 2f (Scheme 12). In the latter case,
cyclization took place regioselectively at the less hindered
carbonyl group. The structures were also established by
NMR analysis through the observation of coupling con-
stants, anisotropic shielding, C-H correlations, and
NOEs, following the criteria previously explained (vide
supra).
used in the first step. It has also been shown that the
tautomeric oxo amide-hydroxy lactam equilibrium and
the N-acyliminium ion cyclization are strongly influenced
by the stereoelectronic effects of the substituent R.
Alternatively, bromine-lithium exchange in 2a is not fast
enough to compete effectively with organolithium addi-
tion to the imide carbonyl group. However, iodinated
imides 2b-f tolerate fast iodine-lithium exchange, giv-
ing rise to the isoquinoline nucleus via a Parham-type
cyclization. Thus, convenient alternative routes for the
synthesis of benzo[a]quinolizidones and their 2-oxa ana-
logs, isoindoloisoquinolones, dibenzo[a,h]quinolizidones,
and thiazolo- and oxazolo [4,3-a]isoquinolones19 have
been developed.
Exp er im en ta l Section
Gen er a l. Melting points were determined in unsealed
capillary tubes and are uncorrected. IR spectra were obtained
on KBr pellets (solids) or CHCl3 solution (oils). NMR spectra
Con clu sion s
(19) For a few representative examples, see: (a) Benzo[a]quin-
olizidines: ref 14; Orito, L.; Matsuzaki, T.; Suginome, H. Heterocycles
1988, 27, 2403. (b) Isoindoloisoquinolines: Alonso, R.; Castedo, L.;
Dom´ınguez, D. Tetrahedron Lett. 1985, 26, 2925. Heaney, H.; Shu-
haibar, K. F. Tetrahedron Lett. 1994, 35, 2751; ref 8a. (c) Dibenzo-
[a,h]quinolizidines: Kametani, T.; Fukumoto, K. In Heterocyclic
Compounds. Isoquinolines. Part 1; Grethe, G., Ed.; J ohn Wiley &
Sons: New York, 1981; vol. 38, p 183. (d) Heterocycle-fused isoquino-
lines: Hamersma, J . A. M.; Speckamp, W. N. Tetrahedron 1982, 38,
3255. Kohn, H.; Liao, Z.-K. J . Org. Chem. 1982, 47, 2787. Kano, S.;
Yuasa, Y.; Yokomatsu, T.; Shibuya, S. J . Org. Chem. 1983, 48, 3835-
3837. Kano, S., Yuasa, Y.; Shibuya, S. Heterocycles 1985, 23, 395.
In summary, the application of the carbophilic addi-
tion-N-acyliminium ion cyclization sequence on imides
1a , i-p constitutes an effective route to several types of
isoquinoline alkaloids, with the ability to introduce a
variety of substituents R at the C-1 position of the
isoquinoline unit by changing the organolithium reagent
(18) Speckamp, W. N. Heterocycles 1984, 21, 211.

2086 J . Org. Chem., Vol. 62, No. 7, 1997
Collado et al.
were recorded at 20-25 °C, running at 250 MHz for 1H and
62.8 MHz for 13C in CDCl3 solutions, unless otherwise stated.
Assignment of individual 13C resonances are supported by
DEPT experiments. 1H-{1H} NOE experiments were carried
out in the difference mode by irradiation of all the lines of a
multiplet.20 1H-{1H} COSY, NOESY, and HMQC spectra
were recorded at 300 MHz for 1H and 75.5 MHz for 13C in
CDCl3 solutions. Mass spectra were recorded under electron
impact at 70 eV. GC-MS analyses were performed using a
HP-5 column (5% phenyl methyl polysiloxane, 30 m × 0.25
mm × 0.25 µm). TLC was carried out with 0.2 mm thick silica
gel plates (Merck Kiesegel GF254). Visualization was ac-
complished by UV light or by spraying with Dragendorff’s
reagent.21 Flash column chromatography22 on silica gel was
performed with Merck Kiesegel 60 (230-400 mesh). HPLC
was performed using a LiChrosorb Si60 (7 µm) column with a
refraction index detector. All solvents used in reactions were
anhydrous and purified according to standard procedures.23
Organolithium reagents were titrated with diphenylacetic acid
periodically prior to use. All air- or moisture-sensitive reac-
tions were performed under argon; the glassware was dried
(130 °C) and purged with argon.
N-[2-(3,4-Dim eth oxyp h en yl)eth yl]su ccin im id e (1a ). A
solution of homoveratrylamine 7 (3 g, 16.5 mmol) and succinic
anhydride (2.97 g, 29.7 mmol) in glacial acetic acid (35 mL)
was heated at reflux overnight. The mixture was cooled, and
the acetic acid was evaporated under reduced pressure. Pure
imide 1a was obtained by recrystallization from MeOH (3.46
g, 79%): mp 124-125 °C; IR (KBr) 1700, 1770 cm-1; 1H NMR
(CDCl3) 2.5 (s, 4H), 2.68 (t, J ) 7.7 Hz, 2H), 3.57 (t, J ) 7.7
Hz, 2H), 3.71 (s, 3H), 3.73 (s, 3H), 6.58-6.67 (m, 3H); 13C NMR
(CDCl3) 27.5, 32.5, 39.3, 55.3, 110.7, 110.8, 120.3, 129.7, 147.4,
148.3, 176.5; MS (EI) m/ z (rel intensity) 263 (M+, 23), 164
(100), 151 (52), 107 (9), 91 (8), 77 (9), 65 (6), 55 (13). Anal.
Calcd for C14H17NO4: C, 63.87, H, 6.51, N, 5.32. Found: C,
63.96, H, 6.47, N, 5.37.
10b-Bu tyl-8,9-d im eth oxy-1,5,6,10b-tetr a h yd r op yr r olo-
[2,1-a ]isoqu in olin -3(2H)-on e (3a ). On e-P ot P r oced u r e.
To a solution of the succinimide 1a (263 mg, 1 mmol) in dry
THF (20 mL), was added n-BuLi (1.45 mL of a 1.5 M solution
in hexane, 2.2 mmol) at -78 °C. The resulting mixture was
stirred at this temperature for 6 h, allowed to warm to 20 °C,
and then quenched by addition of TFA (0.5 mL). Et2O (5 mL)
and H2O (10 mL) were added, the organic layer was separated,
and the aqueous phase was extracted with CH2Cl2 (3 × 10 mL).
The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. Flash column chromatography (silica
gel, 20% CH2Cl2/AcOEt) afforded the pyrroloisoquinolone 3a
(288 mg, 92%): IR (CHCl3) 1680, 1515 cm-1; 1H NMR (CDCl3)
0.89 (t, J ) 7.0 Hz, 3H), 1.26-1.35 (m, 4H), 1.88 (t, J ) 7.8
Hz, 2H), 2.35-2.45 (m, 1H), 2.61-2.70 (m, 1H), 2.76-3.04 (m,
4H), 3.34 (ddd, J ) 13.2, 10.2, 5.5 Hz, 1H), 3.87 (s, 3H), 3.89
(s, 3H), 4.27 (ddd, J ) 13.2, 6.2, 2.3 Hz, 1H), 6.57 (s, 1H), 6.65
(s, 1H); 13C NMR (CDCl3) 13.5, 22.6, 26.0, 27.2, 30.6, 31.6, 36.6,
41.4, 56.0, 56.2, 68.0, 108.3, 112.0, 124.5, 133.5, 147.6, 147.6,
173.1; MS (EI) m/ z (rel intensity) 303 (M+, 1), 246 (100), 230
(2), 202 (8), 185 (4), 123 (8), 109 (4), 87 (3), 77 (4).
Ad d it ion of R Li t o Su ccin im id e 1a . P r ep a r a t ion of
Hyd r oxy La cta m s 5 a n d Oxo Am id es 6. Gen er a l P r oce-
d u r e. To a solution of the succinimide 1a (263 mg, 1 mmol)
in dry THF (20 mL) was added RLi (2.2 mmol) at -78 °C. The
resulting mixture was stirred at this temperature for 6 h,
quenched by the addition of H2O (5 mL), and allowed to warm
to 20 °C. Et2O (5 mL) was added, the organic layer was
separated, and the aqueous phase was extracted with CH2Cl2
(3 × 10 mL). The combined organic extracts were dried (Na2-
SO4) and concentrated in vacuo to afford mixtures of hydroxy
lactams 5 and oxo amides 6.
oxyph en yl)eth yl]-4-oxooctan am ide (6a). According to Gen-
eral Procedure, imide 1a (526 mg, 2 mmol) was treated with
n-BuLi (4.90 mL of a 0.9 M solution in hexanes, 4.4 mmol) to
afford hydroxy lactam 5a and oxo amide 6a (370 mg, 61%
overall) in a 5a /6a 4.2/1 ratio. Both tautomers were separated
by column chromatography (silica gel, 5% CH2Cl2/MeOH).
1
Hyd r oxy la cta m 5a : IR (CHCl3) 3380, 1740, 1520 cm-1; H
NMR (CDCl3) 0.86 (t, J ) 7.8 Hz, 3H), 1.15-1.33 (m, 4H), 1.52
(t, J ) 7.3 Hz, 2H), 1.68-1.93 (m, 2H), 2.10-2.95 (m, 4H),
3.10-3.35 (m, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 6.60-6.80 (m,
3H); 13C NMR (CDCl3) 13.6, 22.6, 25.4, 29.1, 34.5, 37.4, 40.6,
41.0, 55.7, 92.2, 114.1, 114.6, 120.7, 137.0, 147.4, 148.7, 171.9;
MS (EI) m/ z (rel intensity) 303 (M+ - 18, 2), 274 (1), 164 (100),
151 (9), 124 (3), 105 (2), 91 (3), 77(3). Anal. Calcd for C18H27
-
NO4: C, 67.26, H, 8.47, N, 4.36. Found: C, 67.20, H, 9.17, N,
4.22. Oxo a m id e 6a : IR (CHCl3) 3380, 1720, 1660, 1520, 1265
cm-1; 1H NMR (CDCl3) 0.89 (t, J ) 7.3 Hz, 3H), 1.31-1.49 (m,
2H), 1.52-1.60 (m, 2H), 2.38 (t, J ) 6.7 Hz, 2H), 2.41 (t, J )
7.3 Hz, 2H), 2.72 (t, J ) 6.7 Hz, 2H), 2.75 (t, J ) 7.0 Hz, 2H),
3.46 (dt, J ) 7.0, 6.2 Hz, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 5.67
(broad s, 1H), 6.60-6.80 (m, 3H); 13C NMR (CDCl3) 13.8, 22.3,
25.9, 29.9, 32.2, 35.2, 37.6, 42.5, 55.8, 111.3, 111.9, 120.6, 131.4,
147.6, 149.0, 171.9, 210.1; MS (EI) m/ z (rel intensity) 321 (M+,
2), 264 (1), 164 (100), 151 (13), 121 (3), 107 (4), 85 (6), 77(4),
57 (10).
Ad d ition of MeLi. N-[2-(3,4-d im eth oxyp h en yl)eth yl]-
4-h yd r oxy-4-m eth yl-γ-la cta m (5b). According to General
Procedure, imide 1a (526 mg, 2 mmol) was treated with MeLi
(2.75 mL of a 1.6 M solution in Et2O, 4.4 mmol) to afford
hydroxy lactam 5b (460 mg, 87%) that was purified by column
chromatography (silica gel, 5% CH2Cl2/MeOH): mp (CH2Cl2/
MeOH) 81-83 °C; IR (CHCl3) 3360, 1740, 1520; 1H NMR
(CDCl3) 1.39 (s, 3H), 1.95-2.13 (m, 2H), 2.38-2.2 (m, 1H),
2.56-2.40 (m, 1H), 2.95-2.67 (m, 3H), 3.50-3.29 (m, 2H), 3.81
(s, 3H), 3.83 (s, 3H), 6.68-6.80 (m, 3H); 13C NMR (CDCl3) 26.1,
29.1, 34.5, 34.7, 40.7, 55.5, 89.7, 111.1, 111.9, 120.5, 131.6,
147.2, 148.6, 174.5; MS (EI) m/ z (rel intensity) 261 (M+ - 18,
8), 164 (100), 151 (30), 110 (10), 91 (11), 82 (29). Anal. Calcd
for C15H21NO4: C, 64.50, H, 7.58, N, 5.01. Found: C, 64.23,
H, 7.71, N, 4.96.
Ad d ition of s-Bu Li. N-[2-(3,4-Dim eth oxyp h en yl)eth yl]-
5-m eth yl-4-oxoh ep ta n a m id e (6c). According to General
Procedure, imide 1a (526 mg, 2 mmol) was treated with s-BuLi
(5.50 mL of a 0.8 M solution in pentane, 4.4 mmol) to afford
oxo amide 6c that was purified by column chromatography
(silica gel, 60% hexane/AcOEt) (315 mg, 52% overall): IR
(CHCl3) 1715, 1660 cm-1 1H NMR (CDCl3) 0.84 (t, J ) 7.5
;
Hz, 3H), 1.04 (d, J ) 6.9 Hz, 3H), 1.31-1.42 (m, 1H), 1.60-
1.68 (m, 1H), 2.35 (t, J ) 6.5 Hz, 2H), 2.45 (q, J ) 6.9 Hz,
1H), 2.68-2.78 (m, 4H), 3.43 (m, 2H), 3.82 (s, 3H), 3.84 (s, 3H),
5.70 (broad s, 1H), 6.68-6.79 (m, 3H); 13C NMR (CDCl3) 11.5,
15.7, 25.8, 29.8, 35.2, 36.1, 40.7, 47.6, 55.7, 111.2, 111.8, 120.5,
131.4, 147.5, 148.9, 171.8, 213.7; MS (EI) m/ z (rel intensity)
321 (M+, 2), 264 (2), 165 (16), 164 (100), 151 (11), 149 (9), 141
(3), 121 (2), 85 (5), 57 (8).
Ad d ition of t-Bu Li. N-[2-(3,4-Dim eth oxyp h en yl)eth yl]-
5,5-d im eth yl-4-oxoh exa n a m id e (6d ). According to General
Procedure, imide 1a (526 mg, 2 mmol) was treated with t-BuLi
(3.85 mL of a 1.3 M solution in pentane, 4.4 mmol). After
workup, the residue was purified by flash column chromatog-
raphy (silica gel, 20% CH2Cl2/AcOEt) to afford oxo amide 6d
(340 mg, 53%): mp (Et2O) 134-136 °C, IR (CHCl3) 1710, 1660
1
cm-1; H NMR (CDCl3) 1.07 (s, 9H), 2.29 (t, J ) 6.5 Hz, 2H),
2.66 (t, J ) 6.5 Hz, 2H), 2.77 (t, J ) 6.7 Hz, 2H), 3.38 (q, J )
6.7 Hz, 2H), 3.78 (s, 3H), 3.80 (s, 3H), 5.78 (broad s, 1H), 6.63-
6.74 (m, 3H); 13C NMR (CDCl3) 26.3, 30.0, 32.0, 35.1, 40.7, 43.8,
55.7, 55.8, 111.2, 111.8, 120.5, 131.3, 147.4, 148.8, 172.0, 215.0;
MS (EI) m/ z (rel intensity) 321 (M+, 2), 264 (4), 165 (21), 164
(100), 151 (11), 149 (10), 113 (7), 77 (3), 57 (8).
Ad d ition of n -Bu Li. 4-Bu tyl-N-[2-(3,4-d im eth oxyp h e-
n yl)eth yl]-4-h yd r oxy-γ-la cta m (5a ) a n d N-[2-(3,4-Dim eth -
Ad d ition of TMS-CH2Li. N-[2-(3,4-Dim eth oxyp h en yl)-
eth yl]-4-h yd r oxy-4-m eth yl-γ-la cta m (5b) a n d N-[2-(3,4-
Dim et h oxyp h en yl)et h yl]-4-oxop en t a n a m id e (6b ). Ac-
cording to General Procedure, imide 1a (526 mg, 2 mmol) was
treated with TMS-CH2Li (5.5 mL of a 0.8 M solution in
pentane, 4.4 mmol) to afford hydroxy lactam 5b and oxo amide
6b (335 mg, 60% overall) in a 5b /6b 4.8/1 ratio, that were
(20) Kinss, M.; Sanders, J . K. M. J . Magn. Reson. 1984, 56, 518.
(21) Stahl, E. Thin-Layer Chromatography; 2nd ed.; Springer Ver-
lag: Berlin, 1969.
(22) Still, W. C.; Kann, H.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(23) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Berlin, 1988.

Reactions of N-Phenethylimides with Organolithium Reagents
J . Org. Chem., Vol. 62, No. 7, 1997 2087
separated by flash column chromatography (silica gel, 5% CH2-
Cl2/MeOH). Data for 5b were identical to those previously
reported (vide supra). Data for 6b: IR (CHCl3) 3370, 1725,
complete evolution of the starting material was observed (1H
NMR monitoring). The reaction mixture was treated with
saturated aqueous Na2CO3, the organic layer was decanted,
and the aqueous phase was extracted with CH2Cl2 (3 × 10 mL).
The combined organic extracts were washed with brine (2 ×
10 mL), dried (Na2SO4), and concentrated in vacuo.
10b-Bu tyl-8,9-d im eth oxy-1,5,6,10b-tetr a h yd r op yr r olo-
[2,1-a ]isoqu in olin -3(2H)-on e (3a ). According to General
Procedure, the mixture of hydroxy lactam 5a and oxo amide
6a (320 mg, 1 mmol) was treated with TFA in CH2Cl2 at reflux
for 18 h. After workup, pure pyrroloisoquinolone 3a was
obtained (287 mg, 95%) as a reddish oil. Data for 3a were
identical to those previously reported (vide supra).
8,9-Dim eth oxy-10b-m eth yl-1,5,6,10b-tetr ah ydr opyr r olo-
[2,1-a ]isoqu in olin -3(2H)-on e (3b). According to General
Procedure, hydroxy lactam 5b (280 mg, 1 mmol) was treated
with TFA in CH2Cl2 at 20 °C for 4 h. After workup, pure
pyrroloisoquinolone 3b was obtained (255 mg, 98%) as a
reddish oil: IR (CHCl3) 1685, 1520 cm-1; 1H NMR (CDCl3) 1.62
(s, 3H), 2.25-2.35 (m, 1H), 2.52-2.63 (m, 1H), 2.75-3.09 (m,
4H), 3.29 (td, J ) 12.2, 5.1 Hz, 1H), 3.88 (s, 3H), 3.89 (s, 3H),
4.27 (ddd, J ) 12.2, 6.2, 1.8 Hz, 1H), 6.58 (s, 1H), 6.63 (s, 1H);
13C NMR (CDCl3) 27.0, 27.6, 30.0, 34.4, 36.0, 55.2, 55.9, 64.6,
107.9, 116.8, 125.5, 133.3, 147.7, 147.9, 175.7; MS (EI) m/ z
(rel intensity) 261 (M+, 8), 246 (100), 230 (14), 202 (9), 185
(4), 172 (4), 123 (6), 117 (4), 91 (5), 77 (8).
1
1660, 1530 cm-1; H NMR (CDCl3) 2.18 (s, 3H), 2.35 (t, J )
6.4 Hz, 2H), 2.72 (t, J ) 7.0 Hz, 2H), 2.75 (t, J ) 6.4 Hz, 2H),
3.40 (dt, J ) 7.0, 5.8 Hz, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 5.7
(broad s, 1H), 6.69-6.78 (m, 3H); 13C NMR (CDCl3) 29.6, 35.0,
38.3, 40.6, 55.6, 111.1, 111.8, 120.4, 131.3, 147.4, 148.7, 171.6,
209.8.
Ad d ition of P h Li. N-[2-(3,4-Dim eth oxyp h en yl)eth yl]-
4-p h en yl-4-h yd r oxy-γ-la cta m (5e) a n d 3-Ben zoyl-N-[2-
(3,4-d im eth oxyp h en yl)eth yl]p r op ion a m id e (6e). Accord-
ing to General Procedure, imide 1a (526 mg, 2 mmol) was
treated with PhLi (2.2 mL of a 2 M solution in benzene/Et2O,
4.4 mmol) to afford hydroxy lactam 5e and oxo amide 6e in a
5e/6e 1/3 ratio (650 mg, 95% overall). Tautomers could not
be separated due to decomposition on elution through silica
1
gel: IR (CHCl3) 3350, 3340, 1700, 1690, 1620, 1520 cm-1; H
NMR (CDCl3) 2.35-2.45 (m, 2H, 5e), 2.56 (t, J ) 6.5 Hz, 2H,
6e) 2.48-2.95 (m, 4H, 5e), 3.00-3.18 (m, 2H, 5e), 3.27 (t, J )
6.5 Hz, 2H, 6e), 3.44 (dt, J ) 7.1, 6.2 Hz, 2H, 6e), 3.70 (s, 3H,
5e), 3.74 (s, 3H, 5e), 3.78 (s, 3H, 6e), 3.82 (s, 3H, 6e), 5.08 (s,
1H, 5e), 6.29 (distorted t, 1H, 6e), 6.53-6.72 (m, 3H, both
tautomers), 7.24-7.57 (m, 3H, both tautomers), 7.92 (dd, J )
7.7, 1.4 Hz, 2H, both tautomers); 13C NMR (CDCl3) 29.6 (5e),
30.1 (6e), 34.0 (6e), 34.4 (5e), 35.2 (5e), 37.7 (6e), 40.9 (5e),
42.0 (6e), 55.7 (both tautomers), 55.8 (both tautomers), 93.0
(5e), 111.2 (5e), 111.4 (5e), 112.0 (6e), 112.1 (6e), 120.7 (both
tautomers), 127.1 (6e), 127.3, 128.0, 128.4, 128.6, 128.8 (both
tautomers), 131.5 (both tautomers), 136.5 (6e), 141.12 (5e),
147.6 (6e), 148.9 (6e), 172.2 (6e), 175.4 (5e), 199.0 (6e); MS
(EI) m/ z (rel intensity) 341 (M+, 2), 164 (100), 133 (5), 105
(17), 91 (5), 77 (19).
10b-sec-Bu tyl-8,9-d im eth oxy-1,5,6,10b-tetr a h yd r op yr -
r olo[2,1-a ]isoqu in olin -3(2H)-on e (3c). According to Gen-
eral Procedure, oxo amide 6c (320 mg, 1 mmol) was treated
with TFA in CHCl3 under reflux for 5 days. After workup,
the residue was purified by column chromatography (silica gel,
20% AcOEt/hexane) to afford pure pyrroloisoquinolone 3c (242
mg, 93%) as a reddish oil: IR (CHCl3) 1685, 1520 cm-1 1H
;
Ad d ition of P h CtCLi. N-[2-(3,4-Dim eth oxyp h en yl)-
eth yl]-6-p h en yl-4-oxoh ex-5-yn a m id e (6f). According to
General Procedure, imide 1a (526 mg, 2 mmol) was treated
with PhCtCLi (4.4 mL of a 1.0 M solution in THF, 4.4 mmol).
After workup, the residue was purified by flash column
chromatography (silica gel, 5% CH2Cl2/MeOH) to afford oxo
amide 6f (445 mg, 61%): IR (CHCl3) 3340, 2200, 1700, 1670,
NMR (CDCl3) 0.81-0.90 (m, 3H), 0.97 (d, J ) 6.7 Hz, 3H),
1.06-1.43 (m, 1H), 1.60-1.85 (m, 2H), 2.10-2.28 (m, 1H),
2.31-2.47 (m, 2H), 2.53-2.60 (m, 1H), 2.65-2.79 (m, 1H),
2.83-2.98 (m, 1H), 3.09-3.27 (m, 1H), 3.84 (s, 3H), 3.85 (s,
3H), 4.19-4.23 (m, 1H), 6.56 (s, 1H), 6.59 (s, 1H); 13C NMR
(CDCl3) 13.3, 14.3, 23.5, 25.0, 26.8, 31.4, 35.3, 44.8, 55.8, 67.2,
109.2, 111.5, 125.5, 134.2, 147.2, 147.7, 175.7; MS (EI) m/ z
(rel intensity) 303 (M+, <1), 247 (17), 246 (100), 230 (10), 202
(6), 185 (3), 172 (3), 146 (1), 132 (1), 117 (2), 91 (1).
8,9-Dim eth oxy-10b-ph en yl-1,5,6,10b-tetr ah ydr opyr r olo-
[2,1-a ]isoqu in olin -3(2H)-on e (3e). According to General
Procedure, the mixture of hydroxy lactam 5e and oxo amide
6e (341 mg, 1 mmol) was treated with TFA in CH2Cl2 at reflux
for 36 h. After workup, pure pyrroloisoquinolone 3e was
obtained (314 mg, 98%) as a reddish oil: IR (CHCl3) 1685, 1520
cm-1; 1H NMR (CDCl3) 2.43-2.70 (m, 4H), 2.81-2.95 (m, 2H),
3.12-3.20 (m, 1H), 3.78-4.0 (m, 1H)*, 3.85 (s, 3H)*, 3.90 (s,
3H)*, 6.62 (s, 1H), 6.80 (s, 1H), 7.1-7.32 (m, 5H) (* designates
partially overlapped signals); 13C NMR (CDCl3) 26.9, 30.7, 35.5,
36.2, 55.9, 56.2, 67.2, 109.2, 111.4, 126.1, 126.7, 127.3, 128.4,
132.6, 144.8, 147.5, 148.2, 176.4; MS (EI) m/ z (rel intensity)
323 (M+, 8), 246 (100), 230 (8), 202 (5), 185 (2), 117 (2), 91 (2),
77 (6). Anal. Calcd for C20H21NO3: C, 74.28, H, 6.55, N, 4.33.
Found: C, 73.72, H, 6.79, N, 3.96.
1
1520 cm-1; H NMR (CDCl3) 2.49 (t, J ) 6.4 Hz, 2H), 2.76 (t,
J ) 6.9 Hz, 2H), 3.07 (t, J ) 6.4 Hz, 2H), 3.49 (dt, J ) 6.9, 5.8
Hz, 2H), 3.85 (s, 3H), 3.88 (s, 3H), 5.67 (broad s, 1H), 6.69-
6.83 (m, 3H), 7.33-7.61 (m, 5H); 13C NMR (CDCl3) 29.9, 35.2,
40.7, 40.8, 55.9, 87.5, 91.4, 111.4, 111.9, 119.7, 120.6, 128.6,
130.8, 131.3, 133.0, 147.7, 149.0, 171.1, 186.2; MS (EI) m/ z
(rel intensity) 365 (M+, 6), 207 (2), 165 (13), 164 (100), 151
(24), 149 (15), 129 (8), 107 (6), 91 (10), 77 (10).
Ad d ition of Allyllith iu m . N-[2-(3,4-Dim eth oxyp h en yl)-
eth yl]-4-oxoh ep t-6-en a m id e (6g). PhLi (15 mL of a 1.2 M
solution in benzene/ether, 18 mmol) was added over a suspen-
sion of allyltriphenyltin (6.39 g, 16 mmol) in Et2O (32 mL),
under argon, and the reaction mixture was stirred for 30 min.
The so obtained yellow allyllithium solution was titrated with
diphenylacetic acid, resulting in a 0.1 M solution. Allyllithium
(22 mL, 2.2 mmol of the freshly prepared 0.1 M solution) was
then added over a solution of imide 1a (263 mg, 1 mmol) at
-78 °C, according to General Procedure. After workup, 1H
NMR of the crude reaction mixture showed the quantitative
formation of hydroxy lactam 5g and oxo amide 6g in a 1.9/1
ratio. Purification by column chromatography (silica gel, 5%
CH2Cl2/MeOH) gave only oxo amide 6g, though contaminated
with Ph4Sn: IR (CHCl3) 3350, 1660, 1640, 1515 cm-1; 1H NMR
(CDCl3) 1.87-2.05 (m, 2H) 2.12-2.22 (m, 2H), 2.49-2.68 (m,
2H), 2.7 (t, J ) 6.9 Hz, 2H), 3.41 (dt, J ) 6.9, 5.1 Hz, 2H),
3.84 (s, 3H), 3.85 (s, 3H), 4.95-5.10 (m, 2H), 5.45 (broad s,
1H), 5.63 (ddt, J ) 11.0, 7.3, 5.3 Hz, 1H), 6.69-6.78 (m, 3H);
13C NMR (CDCl3) 31.1, 35.0, 37.0, 40.7, 48.4, 55.8, 55.9, 111.3,
111.8, 119.0, 120.6, 131.2, 133.6, 145.5, 147.7, 173.8, 209.7;
MS (EI) m/ z (rel intensity) 305 (M+, <1), 161 (100), 133 (17),
105 (35), 77 (24).
10b-Allyl-8,9-d im eth oxy-1,5,6,10b-tetr a h yd r op yr r olo-
[2,1-a ]isoqu in olin -3(2H)-on e (3g). According to General
Procedure, the mixture of hydroxy lactam 5g and oxo amide
6g (1 mmol), taken from the crude reaction mixture of the
addition reaction (vide supra) without further purification, was
treated with TFA in CH2Cl2 at reflux for 6 h. After workup,
the residue was purified by column chromatography (silica gel,
60% hexane/AcOEt) to afford pyrroloisoquinolone 3g, though
contaminated with residual stannane (290 mg), as a reddish
oil. An injection of the crude reaction mixture on GC showed
quantitative formation of the desired pyrroloisoquinoline
1
(97%): IR (CHCl3) 1685, 1510 cm-1; H NMR (CDCl3) 2.67 (t,
J ) 7.9 Hz, 2H), 2.76 (d, J ) 6.9 Hz, 2H), 2.96 (t, J ) 6.9 Hz,
2H), 3.1 (dd, J ) 19.0, 7.9 Hz, 1H), 3.27 (dd, J ) 19.0, 7.9 Hz,
1H), 3.83 (s, 3H)*, 3.83 (s, 3H)*, 3.84-3.88 (m, 2H)*, 5.10-
5.25 (m, 2H), 5.35-5.48 (m, 1H), 6.76 (s, 1H), 6.83 (s, 1H) (*
designates partially overlapped signals); 13C NMR (CDCl3)
29.8, 30.8, 32.3, 45.7, 46.4, 55.9, 55.9, 77.0 (overlapped with
CDCl3), 107.7, 112.3, 121.8, 129.8, 138.5, 147.7, 148.6, 180.2;
Cycliza tion Rea ction s. Syn th esis of P yr r oloisoqu i-
n olon es. Gen er a l P r oced u r e. To a solution of the mixture
of hydroxy lactams 5 and oxo amides 6 (1 mmol) in CH2Cl2 or
CHCl3 (10 mL) was added TFA (0.80 mL, 10.5 mmol), and the
resulting solution was stirred at 20 °C or heated at reflux until

2088 J . Org. Chem., Vol. 62, No. 7, 1997
Collado et al.
MS (EI) m/ z (rel intensity) 287 (M+, 19), 272 (7), 246 (100),
230 (10), 202 (7), 185 (3), 123 (3).
6.72-6.81 (m, 3H), 7.39-7.43 (m, 2H), 7.59 (t, J ) 8.0 Hz, 1H),
8.19 (d, J ) 7.8 Hz, 1H); 13C NMR (CDCl3) 29.1, 33.4, 41.5,
43.3, 55.6, 55.7, 111.1, 112.0, 120.9, 123.6, 125.0, 127.1, 128.7,
130.9, 133.8, 144.9, 147.4, 148.6, 163.9, 176.7; MS (EI) m/ z
(rel intensity) 353 (M+, 7), 164 (100), 149 (14), 91 (5), 77 (5).
Anal. Calcd for C21H23NO4: C, 71.37, H, 6.56, N, 3.96.
Found: C, 71.56, H, 6.85, N, 3.79.
P r ep a r a tion of Im id es. Gen er a l P r oced u r e A.
A
solution of homoveratrylamine 7 (181 mg, 1 mmol) and the
corresponding anhydride 8 (1.8 mmol) in glacial acetic acid (2
mL) was heated at reflux overnight. The mixture was cooled,
and the acetic acid was evaporated under reduced pressure.
Pure imides 1 were obtained by recrystallization from MeOH.
N-[2-(3,4-Dim eth oxyp h en yl)eth yl]glu ta r im id e (1i). Ac-
cording to General Procedure A, amine 7 (3 g, 16.5 mmol) was
treated with glutaric anhydride (3.38 g, 29.7 mmol), affording
glutarimide 1i, which was crystallized from MeOH (3.1 g,
P r ep a r a tion of Im id es. Typ ica l P r oced u r e C. 3-[2-
(3,4-Dim eth oxyp h en yl)eth yl]th ia zolid in e-2,4-d ion e (1n ).
To a solution of thiazolidine-2,4-dione (937 mg, 8 mmol), 2-(3,4-
dimethoxyphenyl)ethanol (9) (1.34 g, 8 mmol), and triph-
enylphosphine (2.1 g, 8 mmol) in THF (16 mL) at 0 °C was
added dropwise DEAD (1.2 mL, 8 mmol), and the mixture was
stirred at 20 °C overnight. The solvent was removed in vacuo,
and the residue was partioned between CH2Cl2 (15 mL) and
5% aqueous KOH (5 mL). The organic layer was then washed
sequentially with 2 M HCl (1 × 2 mL), saturated Na2CO3 (2
mL), and brine (2 × 2 mL). The organic extracts were dried
(Na2SO4), and the solvent was evaporated. The residue was
crystallized from MeOH, to afford imide 1n (1.77 g, 79%): mp
124-126 °C; IR (KBr) 1685, 1745 cm-1; 1H NMR (CDCl3) 2.82-
2.88 (m, 2H), 3.83-3.87 (m, 2H)*, 3.85 (s, 2H)*, 3.88 (s, 3H),
3.89 (s, 3H), 6.72-6.82 (m, 3H) (* designates partially over-
lapped signals); 13C NMR (CDCl3) 32.9, 33.6, 43.1, 55.8, 111.3,
111.9, 120.9, 129.7, 147.8, 148.9, 171.3, 171.7; MS (EI) m/ z
(rel intensity) 281 (M+, 1), 217 (3), 205 (11), 177 (100), 167
1
68%): mp 111-113 °C; IR (KBr) 1690, 1725 cm-1; H NMR
(CDCl3) 1.84 (quin, J ) 6.5 Hz, 2H), 2.57 (t, J ) 6.5 Hz, 4H),
2.68-2.74 (m, 2H), 3.80 (s, 3H), 3.83 (s, 3H), 3.90-3.96 (m,
2H), 6.73 (broad s, 3H); 13C NMR (CDCl3) 16.9, 32.5, 33.4, 40.5,
55.6, 110.9, 111.9, 120.7, 130.9, 147.3, 148.5, 172.1; MS (EI)
m/ z (rel intensity) 277 (M+, 8), 164 (100), 151 (25), 121 (4),
107 (6), 91 (6), 77 (7), 55 (20), 42 (8). Anal. Calcd for C15H19
-
NO4: C, 64.97, H, 6.91, N, 5.05. Found: C, 64.88, H, 6.85, N,
5.12.
N-[2-(3,4-Dim et h oxyp h en yl)et h yl]d iglycolim id e (1j).
According to General Procedure A, amine 7 (544 mg, 3 mmol)
was treated with diglycolic anhydride (626 g, 5.4 mmol),
affording imide 1j, that was crystallized from MeOH (397 mg,
1
47%): mp 137-138 °C; IR (KBr) 1700, 1750 cm-1; H NMR
(6), 131 (19), 105 (71), 77 (10), 59 (2). Anal. Calcd for C13H15
-
(CDCl3) 2.76-2.83 (m, 2H), 3.85 (s, 3H), 3.88 (s, 3H), 3.95-
4.01 (m, 2H), 4.32 (s, 4H), 6.74-6.82 (m, 3H); 13C NMR (CDCl3)
33.0, 39.4, 55.4, 67.2, 110.9, 111.7, 120.5, 130.1, 147.3, 148.5,
168.6; MS (EI) m/ z (rel intensity) 279 (M+, 16), 164 (100), 151
(62), 121 (5), 107 (11), 91 (10), 77 (10), 65 (8), 42 (27). Anal.
Calcd for C14H17NO5: C, 60.21, H, 6.14, N, 5.02. Found: C,
60.18, H, 6.07, N, 5.06.
NO4S: C, 55.50, H, 5.37, N, 4.98. Found: C, 55.74, H, 5.20,
N, 4.90.
3-[2-(3,4-Dim eth oxyp h en yl)eth yl]-5,5-d im eth ylth ia zo-
lid in e-2,4-d ion e (1o). According to the Typical Procedure B
described for the synthesis of 1m , 1n (843 mg, 3 mmol) was
treated with LDA [6 mmol, prepared from diisopropylamine
(0.85 mL, 6 mmol) and n-BuLi (7.8 mL of a 1.3 M solution, 6
mmol)], HMPA (1.1 mL, 6 mmol), and methyl iodide (0.75 mL,
12 mmol). After column chromatography (silica gel, 60%
hexane/AcOEt), 1o was obtained as a white solid (834 mg,
92%): mp (Et2O) 83-85 °C; IR (KBr) 1740, 1670 cm-1; 1H NMR
(CDCl3) 1.48 (s, 6H), 2.77-2.83 (m, 2H), 3.73-3.76 (m, 2H)*,
3.75 (s, 3H)*, 3.78 (s, 3H), 6.62-6.71 (m, 3H) (* designates
partially overlapped signals); 13C NMR (CDCl3) 27.5, 32.5, 42.3,
53.5, 55.5, 55.6, 111.0, 111.9, 120.8, 129.4, 147.6, 148.6, 169.9,
177.8; MS (EI) m/ z (rel intensity) 309 (M+, 27), 164 (100), 151
(42), 107 (7), 91 (6), 77 (5). Anal. Calcd for C15H19NO4S: C,
58.23, H, 6.19, N, 4.53. Found: C, 58.37, H, 6.29, N, 4.51.
3-[2-(3,4-Dim eth oxyp h en yl)eth yl]-5,5-d im eth yloxa zo-
lid in e-2,4-d ion e (1p ). According to the Typical Procedure C
described for the synthesis of 1n , 5,5-dimethyloxazolidine-2,4-
dione (774 mg, 6 mmol) was treated with 2-(3,4-dimethoxy-
phenyl)ethanol (9) (1 g, 6 mmol), triphenylphosphine (1.6 g, 6
mmol), and DEAD (0.9 mL, 6 mmol). After workup, the
residue was column chromatographed (silica gel, 60% hexane/
AcOEt) to afford imide 1p (1.74 g, 99%): mp (CH3OH) 90-91
N-[2-(3,4-Dim eth oxyph en yl)eth yl]ph th alim ide (1k). Ac-
cording to General Procedure A, amine 7 (1 g, 5.5 mmol) was
treated with phthalic anhydride (1.5 g, 10 mmol), affording
imide 1k , that was crystallized from MeOH (1.05 g, 61%): mp
168-170 °C; IR (KBr) 1715, 1770 cm-1; 1H NMR (CDCl3) 2.89
(t, J ) 7.6 Hz, 2H), 3.76 (s, 3H), 3.79 (s, 3H), 3.86 (t, J ) 7.6
Hz, 2H), 6.70-6.73 (m, 3H), 7.63-7.68 (m, 2H), 7.73-7.78 (m,
2H); 13C NMR (CDCl3) 33.9, 39.2, 55.7, 111.2, 111.8, 120.7,
123.0, 130.3, 131.9, 133.7, 147.6, 148.7, 168.7; MS (EI) m/ z
(rel intensity) 311 (M+, 23), 164 (100), 151 (99), 133 (4), 107
(12), 91 (8), 77 (22), 65 (7), 51 (8).
N-[2-(3,4-Dim eth oxyph en yl)eth yl]h om oph th alim ide (1l).
According to General Procedure A, amine 7 (860 mg, 4.7 mmol)
was treated with homophthalic anhydride (1 g, 6.2 mmol),
affording imide 1l, that was crystallized from MeOH (1.11 g,
1
72%): mp 142-143 °C; IR (KBr) 1665, 1710 cm-1; H NMR
(CDCl3) 2.84-2.90 (m, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 4.02 (s,
2H), 4.17-4.23 (m, 2H), 6.78-6.86 (m, 3H), 7.26-7.29 (m, 1H),
7.42-7.48 (m, 1H), 7.56-7.62 (m, 1H), 8.21-8.23 (m, 1H); 13
C
NMR (CDCl3) 33.6, 36.3, 41.5, 55.8, 111.1, 112.0, 120.8, 125.3,
127.0, 127.6, 129.0, 131.0, 134.0, 133.5, 147.5, 148.7, 164.6,
169.7; MS (EI) m/ z (rel intensity) 325 (M+, 6), 164 (100), 149
(18), 107 (6), 91 (11), 77 (7), 65 (5), 51 (3). Anal. Calcd for
C19H19NO4: C, 70.14, H, 5.89, N, 4.30. Found: C, 69.87, H,
5.77, N, 4.39.
1
°C; IR (KBr) 1730, 1810 cm-1; H NMR (CDCl3) 1.34 (s, 6H),
2.87 (t, J ) 7.3 Hz, 2H), 3.69 (t, J ) 7.3 Hz, 2H), 3.76 (s, 3H),
3.78 (s, 3H), 6.63-6.67 (m, 3H); 13C NMR (CDCl3) 23.1, 32.3,
40.3, 55.6, 83.2, 111.0, 111.7, 120.8, 129.0, 147.7, 148.7, 154.2,
175.6; MS (EI) m/ z (rel intensity) 293 (M+, 22), 164 (100), 151
(55), 121 (3), 107 (6), 91 (5),77 (5).
Ad d ition of n -Bu Li to Im id es 1i-p . P r ep a r a tion of
Hyd r oxy La cta m s 5 a n d Oxo Am id es 6. Gen er a l P r oce-
d u r e. To a solution of the imide 1 (1 mmol) in dry THF (20
mL) was added n-BuLi (2 mmol) at -78 °C. The resulting
mixture was stirred at this temperature for 6 h, quenched by
the addition of H2O (5 mL), and allowed to warm to 20 °C.
Et2O (5 mL) was added, the organic layer was separated, and
the aqueous phase was extracted with CH2Cl2 (3 × 10 mL).
The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to afford mixtures of hydroxy lactams
5 and oxo amides 6.
P r ep a r a tion of Im id es. Typ ica l P r oced u r e B. N-[2-
(3,4-Dim eth oxyp h en yl)eth yl]-4,4-d im eth ylh om op h th a l-
im id e (1m ). A solution of homophthalimide 1l (162 mg, 0.5
mmol) in THF (5 mL) was added dropwise over a solution of
LDA [1 mmol, prepared from diisopropylamine (0.14 mL, 1
mmol) and n-BuLi (1.3 mL of a 1.3 M solution, 1 mmol)] in
THF (5 mL) at -78 °C. After 2 h, HMPA (0.18 mL, 1 mmol)
and methyl iodide (0.12 mL, 2 mmol) were added, and the
resulting solution was stirred 2 h at -78 °C. The reaction
mixture was allowed to warm up to 20 °C, saturated NH4Cl
(5 mL) was added, and the aqueous layer was extracted with
Et2O (5 mL) and CH2Cl2 (3 × 5 mL). The combined organic
extracts were washed with brine (2 × 5 mL) and dried (Na2-
SO4), and the solvent was evaporated in vacuo. The residue
was purified by column chromatography (silica gel, 60%
hexane/AcOEt) to afford 1m as a colorless oil (173 mg, 98%):
IR (KBr) 1660, 1705 cm-1; 1H NMR (CDCl3) 1.54 (s, 6H), 2.82-
2.88 (m, 2H), 3.80 (s, 3H), 3.81 (s, 3H), 4.16-4.22 (m, 2H),
N-[2-(3,4-Dim et h oxyp h en yl)et h yl]-5-oxon on a n a m id e
(6i). According to General Procedure, glutarimide 1i (1.11 g,
4 mmol) was treated with n-BuLi (5.3 mL of a 1.5 M solution
in hexanes, 8 mmol) to afford oxo amide 6i (1.32 g, 99%). An
analytical sample was obtained by crystallization from Et2O /
pentane: mp 72-74 °C; IR (CHCl3) 3300, 1710, 1640, 1520

Reactions of N-Phenethylimides with Organolithium Reagents
J . Org. Chem., Vol. 62, No. 7, 1997 2089
1
cm-1; H NMR (CDCl3) 0.88 (t, J ) 7.3 Hz, 3H), 1.28 (sext, J
1H); 13C NMR (CDCl3) 13.8, 22.3, 26.5, 35.0, 40.7, 41.0, 41.7,
55.7, 55.8, 111.1, 111.8, 120.5, 126.9, 128.8, 131.4, 131.9, 132.1,
135.3, 137.5, 147.3, 148.7, 171.0, 205.6; MS (EI) m/ z (rel
intensity) 383 (M+, 1), 202 (3), 175 (5), 164 (100), 151 (9), 119
(6), 91 (7), 77 (3). Anal. Calcd for C23H29NO4: C, 72.04, H,
7.62, N, 3.65. Found: C, 71.84, H, 7.73, N, 3.63.
) 7.3 Hz, 2H), 1.50 (quin, J ) 7.3 Hz, 2H), 1.90 (quin, J ) 7.1
Hz, 2H), 2.13 (t, J ) 7.1 Hz, 2H), 2.37 (t, J ) 7.3 Hz, 2H), 2.44
(t, J ) 7.1 Hz, 2H), 2.75 (t, J ) 7.0 Hz, 2H), 3.44-3.52 (m,
2H), 3.85 (s, 3H), 3.86 (s, 3H), 5.54 (distorted t, 1H), 6.70-
6.82 (m, 3H); 13C NMR (CDCl3) 13.7, 19.6, 22.1, 25.7, 35.1, 35.3,
40.5, 41.3, 42.3, 55.7, 55.7, 111.2, 111.8 120.5, 131.2, 147.5,
148.9, 172.2, 210.8; MS (EI) m/ z (rel intensity) 335 (M+, 1),
164 (100), 151 (10), 85 (3), 57 (5). Anal. Calcd for C19H29NO4:
C, 68.03, H, 8.71, N, 4.18. Found: C, 67.98, H, 9.04, N, 4.08.
N-[2-(3,4-Dim eth oxyp h en yl)eth yl]-2-(2-oxoh exoxy)a c-
eta m id e (6j). According to General Procedure, diglycolimide
1j (279 mg, 1 mmol) was treated with n-BuLi (1.3 mL of a 1.5
M solution in hexanes, 2 mmol) to afford oxo amide 6j (296
mg, 88%). An analytical sample was obtained by crystalliza-
tion from MeOH: mp 105-106 °C; IR (CHCl3) 3340, 1730, 1670,
1525 cm-1; 1H NMR (CDCl3) 0.88 (t, J ) 7.2 Hz, 3H), 1.28 (sext,
J ) 7.2 Hz, 2H), 1.54 (quin, J ) 7.2 Hz, 2H), 2.30 (t, J ) 7.2
Hz, 2H), 2.78 (t, J ) 7.2 Hz, 2H), 3.48-3.57 (m, 2H), 3.83 (s,
3H), 3.85 (s, 3H), 3.97 (s, 2H), 4.11 (s, 2H), 6.71-6.80 (m, 3H),
7.01 (broad s, 1H); 13C NMR (CDCl3) 13.7, 22.2, 25.3, 35.1, 38.3,
40.1, 55.8, 71.2, 76.0, 111.2, 111.8, 120.5, 131.1, 147.6, 148.9,
168.8, 207.0; MS (EI) m/ z (rel intensity) 337 (M+, 1), 207 (4),
164 (100), 151 (30), 107 (5), 85 (7), 57 (17).
3-n -Bu tyl-N-[2-(3,4-dim eth oxyph en yl)eth yl]-3-h ydr oxy-
1,3-d ih yd r oisoin d ol-1(2H)-on e (5k ). According to General
Procedure, phthalimide 1k (311 mg, 1 mmol) was treated with
n-BuLi (1.3 mL of a 1.5 M solution in hexanes, 2 mmol) to
afford hydroxy lactam 5k (339 mg, 92%). An analytical sample
was obtained by crystallization from MeOH: mp 105-106 °C;
IR (KBr) 3440, 1690 cm-1; 1H NMR (CDCl3) 0.47-0.67 (m, 1H),
0.72 (t, J )7.3 Hz, 3H)*, 0.74-0.96 (m, 1H)*, 1.07-1.23 (m,
2H), 1.91-2.13 (m, 2H), 2.72-2.86 (m, 1H), 2.90-3.02 (m, 1H),
3.14-3.26 (m, 1H), 3.59-3.71 (m, 1H), 3.77 (s, 3H)#, 3.79 (s,
3H)#, 3.76-3.79 (m, 1H)#, 6.70-6.72 (m, 3H), 7.28-7.34 (m,
1H), 7.39-7.45 (m, 2H), 7.48-7.52 (m, 1H) (* designates
partially overlapped signals); 13C NMR (CDCl3) 13.7, 22.3, 25.3,
34.3, 35.8, 40.5, 55.7, 91.2, 111.2, 112.0, 120.6, 121.5, 122.8,
129.1, 131.1, 131.7, 132.0, 146.8, 147.4, 148.7, 167.4. Anal.
Calcd for C22H27NO4: C, 71.52, H, 7.37, N, 3.79. Found: C,
71.11, H, 7.37, N, 3.79.
3-n -Bu tyl-N-[2-(3,4-dim eth oxyph en yl)eth yl]-3-h ydr oxy-
4,4-d im eth yl-3,4-d ih yd r oisoqu in olin -1(2H)-on e (5m ) a n d
1-Bu tyl-N-[2-(3,4-d im eth oxyp h en yl)eth yl]-1-h yd r oxy-4,4-
d im et h yl-1,4-d ih yd r oisoq u in olin -3(2H )-on e (5m ′). Ac-
cording to General Procedure, homophthalimide 1m (65 mg,
0.18 mmol) was treated with n-BuLi (0.24 mL of a 1.5 M
solution in hexanes, 0.36 mmol) to afford a mixture of
isoquinolones 5m and 5m ′, which were separated by HPLC
(50% AcOEt/hexane, 6 mL/min). Isoqu in olon e 5m (20 mg,
1
26%): IR (neat) 3340, 1625 cm-1; H NMR (CDCl3) 0.74 (t, J
) 7.0 Hz, 3H), 0.85-1.21 (m, 3H)*, 1.07 (s, 3H)*, 1.43 (s, 3H),
1.56-1.63 (m, 3H), 2.14 (s, 1H), 2.88-2.97 (m, 1H), 3.00-3.10
(m, 1H), 3.55-3.66 (m, 1H), 3.86 (s, 3H), 3.87 (s, 3H), 4.10-
4.22 (m, 1H), 6.83-6.85 (m, 3H), 7.30-7.36 (m, 2H), 7.43-
7.49 (m, 1H), 8.07 (dd, J ) 7.6, 1.2 Hz, 1H) (* designates
partially overlapped signals); 13C NMR (CDCl3) 13.8, 20.8, 23.0,
26.1, 26.3, 35.2, 36.7, 43.2, 44.1, 55.9, 55.9, 91.1, 111.3, 112.5,
121.0, 123.3, 126.8, 127.7, 128.0, 132.4, 145.3, 147.6, 149.0,
164.2; MS (EI) m/ z (rel intensity) 394 (M+ - 17, 1), 378 (2),
242 (9), 229 (23), 214 (48), 200 (19), 164 (100), 129 (3), 115 (3),
103 (4), 91 (5), 77 (4), 56 (3). Anal. Calcd for C25H33NO4: C,
72.96, H, 8.08, N, 3.40. Found: C, 72.93, H, 7.82, N, 3.01.
Isoqu in olon e 5m ′ (33 mg, 44%): IR (neat) 3340, 1725 cm-1
;
1H NMR (CDCl3) 0.71-0.77 (m, 4H), 0.85-0.98 (m, 1H), 1.08-
1.19 (m, 2H), 1.54 (s, 3H), 1.61 (s, 3H), 1.89 (td, J ) 12.9, 4.6
Hz, 1H), 1.99-2.11 (m, 1H), 2.29 (s, 1H), 2.88-2.98 (m, 2H),
3.52-3.64 (m, 1H), 3.77 (s, 3H), 3.83 (s, 3H)*, 3.83-3.97 (m,
1H)*, 6.75-6.77 (m, 3H), 7.23-7.38 (m, 3H), 7.46 (d, J ) 7.5
Hz, 1H) (* designates partially overlapped signals); 13C NMR
(CDCl3) 13.7, 22.2, 26.4, 30.0, 30.8, 34.5, 40.7, 41.6, 43.8, 55.7,
55.8, 88.1, 111.2, 112.3, 121.0, 125.6, 125.9, 126.8, 128.8, 132.6,
134.8, 140.2, 147.4, 148.8, 174.3; MS (EI) m/ z (rel intensity)
393 (M+ - 18, 2), 378 (3), 242 (6), 229 (7), 214 (30), 200 (14),
184 (4), 164 (100), 149 (7), 128 (4), 103 (2), 91 (3), 77 (2). Anal.
Calcd for C25H33NO4: C, 72.96, H, 8.08, N, 3.40. Found: C,
72.81, H, 7.81, N, 3.11
1-n -Bu tyl-N-[(3,4-d im eth oxyp h en yl)eth yl]-1-h yd r oxy-
3(2H)-isoqu in olon e (5l) a n d N-[2-(3,4-Dim eth oxyp h en yl)-
eth yl]-2-(2-p en ta n oylp h en yl)a ceta m id e (6l). To a solution
of homophthalimide 1l (162 mg, 0.5 mmol) in THF (10 mL) at
-78 °C was added n-BuLi (0.47 mL of a 1.18 M solution in
hexanes, 0.55 mmol), and the resulting solution was stirred
for 75 min. Then, TMSCl (0.14 mL, 0.55 mmol) was added,
and the reaction mixture was allowed to warm up to 20 °C.
After 70 min, the resulting solution was cooled to -78 °C,
n-BuLi (0.85 mL of a 1.18 M solution in hexanes, 1 mmol) was
added, and the reaction mixture was stirred for 6 h. The
reaction was quenched by the addition of H2O (5 mL) and
allowed to warm to rt. Et2O (10 mL) was added, the organic
layer was separated, and the aqueous phase was extracted
with CH2Cl2 (3 × 10 mL). The combined organic extracts were
dried (Na2SO4) and concentrated in vacuo to afford a mixture
of hydroxy lactam 5l and oxo amide 6l, that were separated
by HPLC (20% AcOEt/hexane, 6 mL/min). Hyd r oxy la cta m
5l (73 mg, 38%): IR (CHCl3) 3200, 1670 cm-1; 1H NMR (CDCl3)
0.76 (t, J ) 7.2 Hz, 3H), 0.94-1.05 (m, 2H), 1.11-1.16 (m, 2H),
1.77-1.86 (m, 2H), 1.90 (s, 1H), 2.70-3.00 (m, 2H), 3.55 (s,
3H)*, 3.52-3.63 (m, 1H)*, 3.68 (s, 2H), 3.82 (s, 3H), 3.97-
4.07 (m, 1H), 6.54 (d, J ) 1.5 Hz, 1H), 6.68-6.76 (m, 2H),
7.26-7.31 (m, 1H), 7.34-7.38 (m, 3H) (* designates partially
overlapped signals); 13C NMR (CDCl3) 13.8, 22.4, 25.6, 34.7,
36.8, 41.2, 43.5, 55.4, 55.9, 88.4, 111.3, 112.0, 120.9, 125.0,
126.9, 127.1, 128.6, 129.8, 132.6, 138.1, 147.4, 148.7, 168.2;
MS (EI) m/ z (rel intensity) 383 (M+, 1), 214 (2), 202 (6), 173
(14), 164 (100), 152 (16), 119 (8), 91 (10), 77 (6). Oxo a m id e
4-n -Bu tyl-3-[2-(3,4-d im eth oxyp h en yl)eth yl]-4-h yd r oxy-
5,5-d im eth ylth ia zolid in -2-on e (5o) a n d S-[1-[N-[2-(3,4-
Dim eth oxyp h en yl)eth yl]ca r ba m oyl]-1-m eth yleth yl] P en -
ta n eth ioa te (6o). According to General Procedure, imide 1o
(322 mg, 1.04 mmol) was treated with n-BuLi (1.39 mL of a
1.5 M solution in hexanes, 2.08 mmol) to afford a mixture of
hydroxy lactam 5o and thio ester 6o, which were separated
by flash column chromatography (silica gel, 50% AcOEt/
hexane). Hyd r oxy la cta m 5o (275 mg, 75%): white solid,
1
mp (Et2O/pentane) 96-98 °C; IR (KBr) 3240, 1630 cm-1; H
NMR (CDCl3) 0.88-0.95 (m, 3H), 1.21-1.90 (m, 6H)*, 1.36 (s,
3H)*, 1.45 (s, 3H)*, 2.37 (s, 1H), 2.69-3.00 (m, 2H), 3.33-
3.45 (m, 1H), 3.58-3.69 (m, 1H), 3.86 (s, 3H), 3.87 (s, 3H),
6.69-6.79 (m, 3H) (* designates partially overlapped signals);
13C NMR (CDCl3) 13.8, 23.4, 24.8, 25.7, 26.2, 34.7, 34.9, 44.0,
55.8, 55.9, 56.3, 94.6, 111.3, 112.2, 120.8, 131.5, 147.7, 148.9,
169.8; MS (EI) m/ z (rel intensity) 349 (M+ - 18, 1), 185 (2),
164 (100), 151 (9), 138 (6), 107 (3), 91 (3), 79 (3), 55 (3).
1
Th ioester 6o (29 mg, 8%): IR (CHCl3) 3420, 1670 cm-1; H
NMR (CDCl3) 0.88 (t, J ) 7.2 Hz, 3H), 1.23-1.37 (m, 2H),
1.44-1.62 (m, 2H)*, 1.53 (s, 6H)*, 2.42 (t, J ) 7.5 Hz, 2H),
2.73 (t, J ) 7.1 Hz, 2H), 3.42-3.50 (m, 2H), 3.84 (s, 3H), 3.86
(s, 3H), 6.66-6.85 (m, 4H) (* designates partially overlapped
signals); 13C NMR (CDCl3) 13.6, 22.0, 25.9, 27.4, 34.9, 41.2,
44.0, 52.2, 55.8, 55.8, 111.2, 112.0, 120.6, 131.4, 147.5, 148.9,
173.2, 199.4; MS (EI) m/ z (rel intensity) 367 (M+, 1), 249 (1),
164 (100), 151 (15), 85 (12), 77 (4), 57 (12). Anal. Calcd for
C19H29NO4S: C, 62.10, H, 7.95, N, 3.81. Found: C, 61.78, H,
8.05, N, 3.54.
4-n -Bu tyl-3-[2-(3,4-d im eth oxyp h en yl)eth yl]-4-h yd r oxy-
5,5-d im et h yloxa zolid in -2-on e (5p ) a n d 1-[N-[2-(3,4-Di-
m et h oxyp h en yl)et h yl]ca r b a m oyl]-1-m et h ylet h yl P en -
ta n oa te (6p ). According to General Procedure, imide 1p (117
mg, 0.4 mmol) was treated with n-BuLi (0.53 mL of a 1.5 M
(6l) (111 mg, 58%): IR (CHCl3) 3320, 1680, 1590, 1520 cm-1
,
1H NMR (CDCl3) 0.93 (t, J ) 7.4 Hz, 3H), 1.36 (sext, J ) 7.4
Hz, 2H), 1.64 (quin, J ) 7.4 Hz, 2H), 2.68 (t, J ) 7.1 Hz, 2H),
2.91 (t, J ) 7.4 Hz, 2H), 3.37-3.45 (m, 2H), 3.59 (s, 2H), 3.79
(s, 3H), 3.82 (s, 3H), 6.54-6.69 (m, 3H), 6.98 (distorted t, 1H),
7.29-7.35 (m, 1H), 7.43-7.45 (m, 2H), 7.66 (d, J ) 8.0 Hz,

2090 J . Org. Chem., Vol. 62, No. 7, 1997
Collado et al.
solution in hexanes, 0.8 mmol) to afford a mixture of hydroxy
lactam 5p and ester 6p , that were separated by fractional
recrystallisation from hexane/AcOEt. Hyd r oxy la cta m 5p
°C for 16 h to afford isoquinolinium salt 11 (128 mg, 90%):
1H NMR (CDCl3) 0.97 (t, J ) 7.2 Hz, 3H), 1.48 (hept, J ) 7.1
Hz, 2H), 1.56-1.66 (m, 2H), 2.88-2.95 (m, 2H), 3.06 (t, J )
7.5 Hz, 2H), 3.72 (s, 3H), 3.85 (s, 3H), 4.53 (distorted t, 2H),
6.65-6.69 (m, 2H), 6.73-6.86 (m, 2H), 6.87-6.93 (m, 1H),
7.22-7.29 (m, 2H), 7.51 (d, J ) 9.0 Hz, 1H); 13C NMR (CDCl3)
13.6, 22.9, 29.0, 31.6, 34.5, 47.6, 55.6. 55.9, 107.6, 111.3.
111.9, 115.5, 120.7, 122.0, 125.6, 130.7, 131.0, 142.4, 147.9,
149.0, 152.9, 160.5; MS (EI) m/ z (rel intensity) 365 (M+ - 1),
164 (73), 149 (26), 105 (56), 91 (21), 85 (44), 71 (59), 57 (100).
14-n -Bu t yl-13,13-d im et h yl-2,3-d im et h oxy-13,14-d ih i-
d r op r otober ber in -8(2H)-on e (3m ). According to the gen-
eral procedure described for the cyclization reactions, hydroxy
lactam 5m (20 mg, 0.047 mmol) was treated with TFA (0.05
mL, 0.49 mmol) at reflux for 6 days to afford protoberberinone
3m , as an oil that was purified by HPLC (50% hexane/AcOEt,
(82 mg, 58%): IR (KBr) 3320, 1730 cm-1 1H NMR (CDCl3)
;
0.87 (t, J ) 6.9 Hz, 3H), 1.23-1.28 (m, 4H)*, 1.28 (s, 3H)*,
1.41 (s, 3H), 1.47-1.58 (m, 2H), 2.86 (t, J ) 7.3 Hz, 2H), 3.26-
3.38 (m, 1H), 3.41-3.55 (m, 1H), 3.84 (broad s, 7H), 6.71-
6.80 (m, 3H) (* designates partially overlapped signals); 13C
NMR (CDCl3) 13.8, 22.1, 23.2, 24.3, 25.5, 34.0, 35.0, 42.0, 55.8,
55.9, 85.5, 91.7, 111.2, 112.3, 121.0, 131.7, 147.7, 148.9, 157.7;
MS (EI) m/ z (rel intensity) 351 (M+, 3), 208 (27), 164 (65),
151 (100), 135 (4), 107 (12), 91 (8), 77 (6), 59 (85). Ester 6p
(21 mg, 16%): IR (KBr) 3300, 1740, 1660 cm-1 1H NMR
;
(CDCl3) 0.88 (t, J ) 7.2 Hz, 3H), 1.23-1.37 (m, 3H), 1.46-
1.55 (m, 1H)*, 1.58 (s, 6H)*, 2.21 (t, J ) 7.5 Hz, 2H), 2.76 (t,
J ) 6.8 Hz, 2H), 3.46-3.54 (m, 2H), 3.84 (s, 3H), 3.86 (s, 3H),
6.06 (distorted t, 1H), 6.71-6.81 (m, 3H) (* designates partially
overlapped signals); 13C NMR (CDCl3) 13.6, 22.1, 24.3, 26.9,
34.6, 35.1, 40.5, 55.8, 81.2, 111.2, 111.9, 120.6, 131.2, 147.7,
149.0, 171.9, 173.0; MS (EI) m/ z (rel intensity) 351 (M+, 4),
164 (100), 151 (11), 121 (2), 107 (3), 85 (12), 57 (12).
6 mL/min) (14 mg, 75%): IR (CHCl3) 1640 cm-1 1H NMR
;
(CDCl3) 0.71 (t, J ) 6.9 Hz, 3H), 0.89 (s, 3H), 1.01-1.15 (m,
2H), 1.20-1.29 (m, 2H), 1.48 (s, 3H), 1.74 (td, J ) 12.6, 3.9
Hz, 1H), 1.99 (t, J ) 12.6 Hz, 1H), 2.68 (m, 1H), 2.78-2.95
(m, 2H), 3.89 (s, 3H), 3.91 (s, 3H), 5.23-5.31 (m, 1H), 6.69 (s,
1H), 6.82 (s, 1H), 7.33-7.39 (m, 2H), 7.48 (t, J ) 7.2 Hz, 1H),
8.14 (d, J ) 7.5 Hz, 1H); 13C NMR (CDCl3) 13.8, 21.8, 23.0,
27.0, 30.4, 35.8, 40.2, 44.6, 55.8, 56.3, 68.9, 111.2, 112.4, 123.9,
126.4, 126.6, 128.3, 128.7, 132.2, 132.7, 146.3, 146.5, 147.8,
163.6; MS (EI) m/ z (rel intensity) 393 (M+, 19), 336 (100), 321
(8), 306 (14), 248 (12), 146 (82), 131 (97), 117 (29), 103 (11), 91
(7), 78 (8).
13b-n -Bu tyl-9,9-d im eth yl-2,3-d im eth oxyd iben zo[a ,h ]-
qu in olizid in -8-on e (3m ′). According to the general proce-
dure described for the cyclization reactions, hydroxy lactam
5m ′ (52 mg, 0.13 mmol) was treated with TFA (0.10 mL, 1.36
mmol) at 20 °C for 48 h to afford dibenzoquinolizidinone 3m ′
(47 mg, 95%): 1H NMR (CDCl3) 0.83 (t, J )7.1 Hz, 3H), 0.9-
1.32 (m, 4H)*, 1.01 (s, 3H)*, 1.68 (s, 3H), 2.35 (t, J ) 8.0 Hz,
2H), 2.81 (dd, J ) 16.6, 5.5 Hz, 1H), 3.12-3.26 (m, 1H), 3.39-
3.51 (m, 1H), 3.63 (s, 3H), 3.81 (s, 3H), 4.99-5.08 (m, 1H), 6.57
(s, 1H), 6.58 (s, 1H), 7.36-7.46 (m, 3H), 7.62-7.66 (m, 1H) (*
designates partially overlapped signals); 13C NMR (CDCl3)
13.9, 22.4, 26.1, 26.3, 26.4, 31.1, 36.2, 41.3, 55.8, 55.8, 64.5,
108.8, 112.3, 125.4, 125.7, 126.4, 127.0, 128.1, 132.4, 134.9,
142.6, 146.5, 147.8, 175.7; MS (EI) m/ z (rel intensity) 393 (M+,
<1), 336 (100), 321 (12), 306 (4), 293 (4), 278 (8), 249 (3), 191
(1), 178 (1), 168 (2), 146 (16), 102 (1), 77 (1).
11b -n -Bu t yl-9,10-d im et h oxyb en zo[a ]q u in olizid in -4-
on e (3i). According to the general procedure described for the
cyclization reactions, oxo amide 6i (60 mg, 0.18 mmol) was
treated with TFA (0.14 mL, 1.9 mmol) at 20 °C for 16 h to
afford benzo[a]quinolizidinone 3j (54 mg, 94%). An analytical
sample was obtained by crystallization from MeOH: IR
(CHCl3) 1650 cm-1; 1H NMR (CDCl3) 0.85 (t, J ) 6.9 Hz, 3H),
1.19-1.38 (m, 4H), 1.59-1.68 (m, 1H), 1.82-2.03 (m, 4H),
2.24-2.33 (m, 1H), 2.39-2.47 (m, 2H), 2.52-2.62 (m, 1H),
2.84-3.05 (m, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 4.83-4.90 (m,
1H), 6.57 (s, 1H), 6.64 (s, 1H); 13C NMR (CDCl3) 13.9, 17.0,
23.1, 27.0, 28.4, 32.1, 34.8, 36.2, 41.9, 55.7, 56.2, 61.4, 108.4,
111.7, 126.8, 134.0, 147.2, 147.6, 170.1; MS (EI) m/ z (rel
intensity) 317 (M+, <1), 263 (25), 164 (100), 151 (52), 121 (4),
107 (7), 91 (6), 77 (7), 65 (6), 55 (11). Anal. Calcd for C19H27
-
NO3: C, 71.89, H, 8.57, N, 4.41. Found: C, 71.99, H, 8.86, N,
4.12.
11b-n -Bu tyl-9,10-dim eth oxy-2-oxaben zo[a ]qu in olizidin -
4-on e (3j). According to the general procedure described for
the cyclization reactions, oxo amide 6j (200 mg, 0.59 mmol)
was treated with TFA (0.47 mL, 6.2 mmol) at 20 °C for 16 h
to afford oxabenzo[a]quinolizidinone 3j (175 mg, 93%): IR
(CHCl3) 1650 cm-1; 1H NMR (CDCl3) 0.88 (t, J ) 7.1 Hz, 3H),
1.21-1.37 (m, 3H), 1.60-1.64 (m, 1H), 2.01-2.15 (m, 2H),
2.31-2.69 (m, 1H), 2.82-2.91 (m, 1H), 2.92-2.95 (m, 1H), 3.53
(d, J ) 11.6 Hz, 1H), 3.85 (s, 3H), 3.86 (s, 3H), 4.14 (d, J )
16.7 Hz, 1H), 4.22 (d, J ) 11.6 Hz, 1H), 4.33 (d, J ) 16.7 Hz),
4.82-4.92 (m, 1H), 6.51 (s, 1H), 6.63 (s, 1H); 13C NMR (CDCl3)
13.9, 23.3, 27.1, 28.6, 35.5, 40.4, 55.8, 56.2, 59.9, 67.4, 74.2,
108.0, 111.9, 126.8, 128.5, 147.7, 148.1, 166.5; MS (EI) m/ z
(rel intensity) 319 (M+, 1), 262 (100), 234 (10), 206 (6), 117
(4), 102 (4), 91 (2), 71 (1).
12b -n -Bu t yl-2,3-d im et h oxy-5,6-d ih yd r oisoin d oloiso-
qu in olin -8(12bH)-on e (3k ). According to the general pro-
cedure described for the cyclization reactions, hydroxy lactam
5k (160 mg, 0.43 mmol) was treated with TFA (0.35 mL, 4.5
mmol) at 20 °C for 16 h to afford isoindoloisoquinolone 3k , as
a white solid that was crystallized from MeOH (143 mg,
95%): mp 130-133 °C; IR (CHCl3) 1690 cm-1; 1H NMR (CDCl3)
0.76 (t, J ) 7.2 Hz, 3H), 0.90-0.97 (m, 2H), 1.14-1.23 (m, 2H),
2.10-2.42 (m, 2H), 2.72 (dd, J ) 16.0, 4.3 Hz, 1H), 3.05 (m,
1H), 3.28 (td, J ) 12.8, 4.5 Hz, 1H), 3.82 (s, 3H), 3.93 (s, 3H),
4.62 (dd, J ) 13.2, 6.6 Hz, 1H), 6.58 (s, 1H), 7.15 (s, 1H), 7.46
(t, J ) 7.5 Hz, 1H), 7.60 (t, J ) 7.5 Hz, 1H), 7.78 (d, J ) 7.7
Hz, 1H), 7.85 (d, J ) 7.6 Hz, 1H); 13C NMR (CDCl3) 13.8, 22.4,
25.3, 29.1, 34.9, 40.3, 55.8, 56.3, 109.4, 112.0, 122.1, 123.8,
125.7, 128.2, 131.4, 131.7, 132.3 , 147.6, 148.1, 148.7, 167.9;
MS (EI) m/ z (rel intensity) 351 (M+, 4), 200 (15), 164 (100),
149 (8), 115 (3), 91 (3), 77 (3). Anal. Calcd for C22H25NO3: C,
75.19, H, 7.17, N, 3.98. Found: C, 75.11, H, 7.12, N, 4.20.
1-n -B u t y l-N -[2-(3,4-d im e t h o x y p h e n y l)e t h y l]-3-h y -
d r oxyisoqu in olin iu m Tr iflu or a ceta te (11). According to
the general procedure described for the cyclization reactions,
the mixture of hydroxy lactam 5l and oxo amide 6l (150 mg,
0.39 mmol) was treated with TFA (0.31 mL, 4.1 mmol) at 20
10b-n -Bu tyl-1,1-d im eth yl-8,9-d im eth oxy-1,5,6,10b-tet-
r a h yd r oth ia zolo[4,3-a ]isoqu in olin -3(2H)-on e (3o). Ac-
cording to the general procedure described for the cyclization
reactions, hydroxy lactam 5o (100 mg, 0.27 mmol) was treated
with TFA (0.20 mL, 2.86 mmol) at reflux for 24 h to afford
thiazoloisoquinolone 3o (87 mg, 95%): IR (KBr) 1670 cm-1
;
1H NMR (CDCl3) 0.82 (t, J ) 7.1 Hz, 3H), 0.97-1.16 (m, 1H)*,
1.01 (s, 3H)*, 1.18-1.38 (m, 3H), 1.60 (s, 3H), 1.92-2.03 (m,
1H) 2.53-2.60 (dd, J ) 12.8, 4.8 Hz, 1H), 2.64-2.70 (m, 1H),
2.84 (td, J ) 15.3, 5.2 Hz, 1H), 3.06 (td, J ) 12.4, 3.4 Hz, 1H),
3.87 (s, 3H), 3.90 (s, 3.90), 4.49 (dd, J ) 12.7, 4.8 Hz, 1H),
6.63 (s, 1H), 6.68 (s, 1H) (* designates partially overlapped
signals); 13C NMR (CDCl3) 13.9, 22.1, 23.3, 27.3, 28.7, 30.0,
36.5, 40.4, 55.7, 56.1, 59.1, 71.0, 108.2, 111.8, 126.9, 128.5,
147.8, 148.0, 169.5; MS (EI) m/ z (rel intensity) 349 (M+, <1),
149 (4), 136 (9), 121 (8), 109 (7), 95 (13), 69 (100), 55 (13). Anal.
Calcd for C19H27NO3S: C, 65.30, H, 7.79, N, 4.01. Found: C,
65.40, H, 7.85, N, 3.92.
10b -n -Bu t yl-1,1-d im et h yl-8,9-d im et h oxy-1,5,6,10b -t e-
t r a h yd r ooxa zolo[4,3a ]isoq u in olin -3(2H)-on e (3p ). Ac-
cording to the general procedure described for the cyclization
reactions, hydroxy lactam 5p (88 mg, 0.25 mmol) was treated
with TFA (0.19 mL, 2.62 mmol) at reflux for 24 h to afford
oxazoloisoquinolone 3p , as an oil (83 mg, 94%): IR (KBr) 1740
cm-1; 1H NMR (CDCl3) 0.86 (t, J ) 7.1 Hz, 3H), 0.93 (s, 3H)*,
0.92-1.11 (m, 1H)*, 1.13-1.39 (m, 3H), 1.68 (s, 3H), 1.82-
1.95 (m, 1H), 2.03-2.15 (m, 1H), 2.79 (dd, J ) 15.6, 3.8 Hz,
1H), 2.94 (td, J ) 15.6, 6.0 Hz, 1H), 3.26 (td, J ) 13.1, 3.8 Hz,
1H), 3.87 (s, 3H), 3.90 (s, 3H), 4.12 (dd, J ) 13.1, 6.0 Hz, 1H),
6.53 (s, 1H), 6.72 (s, 1H) (* designates partially overlapped
signals); 13C NMR (CDCl3) 13.8, 21.8, 23.2, 25.3, 26.6, 29.6,
37.9, 38.0, 55.8, 56.2, 65.8, 86.4, 107.6, 111.9, 126.9, 127.1,

Reactions of N-Phenethylimides with Organolithium Reagents
J . Org. Chem., Vol. 62, No. 7, 1997 2091
148.1, 156.1; MS (EI) m/ z (rel intensity) 333 (M+, <1), 276
(100), 232 (50), 216 (6), 205 (10), 201 (7), 186 (5), 172 (2), 159
(2), 146 (2), 131 (2), 116 (3), 109 (3), 100 (4), 91 (2),77 (2).
N-[2-(2-Br om o-4,5-d im et h oxyp h en yl)et h yl]su ccin im -
id e (2a ). A solution of bromine (40 mmol, 6.4 g) in glacial
acetic acid (26 mL) was added dropwise to a solution of
succinimide 1a (40 mmol, 10.5 g) in glacial acetic acid (200
mL), and the resulting mixture was stirred at 20 °C for 5 h.
The acetic acid was eliminated under vacuum, and H2O was
added. The resulting precipitate was filtered and crystallized
from MeOH to obtain pure succinimide 2a as a white solid
MeOH to afford pure imide 2b (2.53 g, 65%): mp 152-153
1
°C; IR (KBr) 1700, 1770 cm-1; H NMR (CDCl3) 2.65 (s, 4H),
2.93 (t, J ) 7.1 Hz, 2H), 3.72 (t, J ) 7.1 Hz, 2H), 3.81 (s, 3H),
3.83 (s, 3H), 6.72 (s, 1H), 7.16 (s, 1H); 13C NMR (CDCl3) 28.1,
37.8, 38.7, 55.9, 56.0, 87.9, 112.4, 121.6, 133.1, 148.3, 149.3,
176.8; MS (EI) m/ z (rel intensity) 389 (M+, 28), 290 (100), 277
(46), 262 (26), 150 (12), 120 (12), 107 (7), 92 (7), 77 (14), 55
(10).
N-2-(4,5-Dim eth oxy-2-iodoph en yl)eth ylglu tar im ide (2c).
According to the general procedure for iodination, glutarimide
1i (1 g, 3.6 mmol) was treated with ICl (700 mg, 4.3 mmol).
After workup, the residue was crystallized from MeOH to
afford pure imide 2c (1.19 g, 82%): mp 148-149 °C; IR (KBr)
1725, 1670 cm-1; 1H NMR (CDCl3) 1.91 (quin, J ) 6.5 Hz, 2H),
2.62 (t, J ) 6.5 Hz, 4H), 2.89 (t, J ) 7.5 Hz, 2H), 3.83 (s, 3H),
3.85 (s, 3H), 3.99 (t, J ) 7.5 Hz, 2H), 6.75 (s, 1H), 7.18 (s, 1H);
13C NMR (CDCl3) 17.1, 32.8, 38.2, 39.4, 55.9, 56.0, 88.0, 112.6,
121.5, 134.0, 148.1, 149.2, 172.3; MS (EI) m/ z (rel intensity)
403 (M+, 14), 290 (100), 277 (20), 150 (7), 120 (11), 107 (5), 77
(10), 55 (34). Anal. Calcd for C15H18INO4: C, 44.68, H, 4.50,
N, 3.47. Found: C, 44.85, H, 4.47, N, 3.47.
N-[2-(4,5-Dim et h oxy-2-iod op h en yl)et h yl]d iglycolim -
id e (2d ). According to the general procedure for iodination,
diglycolimide 1j (558 mg, 2 mmol) was treated with ICl (390
mg, 2.4 mmol). After workup, the residue was crystallized
from MeOH to afford pure imide 2d (688 mg, 85%): mp 135-
136 °C; IR (KBr) 1735, 1690 cm-1; 1H NMR (CDCl3) 2.95 (t, J
) 7.3 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 4.02 (t, J ) 7.3 Hz,
2H), 4.32 (s, 4H), 6.73 (s, 1H), 7.20 (s, 1H); 13C NMR (CDCl3)
38.1, 38.5, 56.0, 56.1, 67.7, 88.1, 112.6, 121.7, 133.3, 148.3,
149.37, 168.9; MS (EI) m/z (rel intensity) 405 (M+, 28), 290
(100), 277 (50), 150 (14), 120 (11), 107 (7), 77 (15). Anal. Calcd
for C14H16INO5: C, 41.50, H, 3.98, N, 3.46. Found: C, 41.55,
H, 3.94, N, 3.45.
N-[2-(4,5-Dim e t h oxy-2-iod op h e n yl)e t h yl]p h t h a lim -
id e (2e). According to the general procedure for iodination,
phthalimide 1k (311 mg, 1 mmol) was treated with ICl (195
mg, 1.2 mmol). After workup, the residue was crystallized
from MeOH to afford pure imide 2e (417 mg, 95%): mp 164-
166 °C; IR (KBr) 1715, 1770 cm-1; 1H NMR (CDCl3) 3.03 (t, J
) 7.3 Hz, 2H), 3.67 (s, 3H), 3.79 (s, 3H), 3.89 (t, J ) 7.3 Hz,
2H), 6.66 (s, 1H), 7.16 (s, 1H), 7.65-7.68 (m, 2H), 7.77-7.80
(m, 2H); 13C NMR (CDCl3) 37.7, 38.6, 55.7, 55.9, 88.0, 112.4,
121.6, 123.1, 131.9, 133.1, 133.8, 148.1, 149.2, 168.0; MS (EI)
m/z (rel intensity) 437 (M+, 38), 310 (55), 290 (91), 277 (100),
160 (34), 150 (22), 133 (16), 120 (13), 105 (24), 92 (13), 77 (56),
64 (12), 51 (18). Anal. Calcd for C18H16INO4: C, 49.45, H,
3.69, N, 3.20. Found: C, 49.89, H, 3.47, N, 3.25.
N-[2-(4,5-Dim eth oxy-2-iod op h en yl)eth yl]-5,5-d im eth yl-
h om op h th a lim id e (2f). According to the general procedure
for iodination, homophthalimide 1m (360 mg, 1 mmol) was
treated with ICl (195 mg, 1.2 mmol). After workup, the residue
was crystallized from MeOH to afford pure imide 2e (392 mg,
82%): IR (KBr) 1667, 1712 cm-1; 1H NMR (CDCl3) 1.57 (s, 6H),
3.02 (t, J ) 7.5 Hz, 2H), 3.75 (s, 3H), 3.83 (s, 3H), 4.23 (t, J )
7.5 Hz, 2H), 6.76 (s, 1H), 7.20 (s, 1H), 7.43-7.46 (m, 2H), 7.60-
7.66 (m, 1H), 8.22-8.25 (m, 1H); 13C NMR (CDCl3) 29.2, 38.2,
40.2, 43.4, 55.8, 56.0, 88.1, 112.6, 121.6, 123.8, 125.1, 127.3,
128.9, 133.8, 133.9, 145.01, 148.1, 149.2, 164.1, 176.1; MS (EI)
m/z (rel intensity) 479 (M+, 5), 352 (5), 290 (100), 275 (8), 164
(7), 145 (7), 120 (6), 117 (7), 91 (5), 77 (6), 51 (2). Anal. Calcd
for C21H22INO4: C, 52.62, H, 4.63, N, 2.92. Found: C, 52.65,
H, 4.57, N, 2.98.
P a r h a m Cycliza tion s. Gen er a l P r oced u r e. To a solu-
tion of the iodinated imide 2b-f (1mmol) in dry THF (20 mL),
n-BuLi (2 mmol) was added at -78 °C. The resulting mixture
was stirred at this temperature for 4 h, quenched by the
addition of H2O (5 mL), and allowed to warm to 20 °C. Et2O
(15 mL) was added, the organic layer was separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 15 mL). The
combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo to afford hydroxy lactams 14, which dehy-
drated to give enamides 4.
1
(13 g, 94%): mp 154-155 °C, IR (KBr) 1760, 1700 cm-1; H
NMR (CDCl3) 2.63 (s, 4H), 2.93 (t, J ) 7.0 Hz, 2H), 3.76 (t, J
) 7.0 Hz, 2H), 3.80 (s, 3H), 3.81 (s, 3H), 6.68 (s, 1H), 6.94 (s,
1H); 13C NMR (CDCl3) 28.1, 33.4, 38.5, 56.0, 113.2, 114.3,
115.5, 129.2, 148.4, 176.9. Anal. Calcd for C14H16BrNO4: C,
49.14, H, 4.71, N, 4.09. Found: C, 49.23, H, 4.85, N, 3.91.
N-[2-(3,4-Dim eth oxyp h en yl)eth yl]-5-bu tylid en ep yr r o-
lid in -2-on e (12). To a solution of the succinimide 2a (342
mg, 1 mmol) in dry THF (20 mL) was added n-BuLi (1.55 mL
of a 1.42 M solution in hexanes, 2.2 mmol) at -78 °C. The
resulting mixture was stirred at this temperature for 6 h,
allowed to warm to rt, and then quenched by the addition of
6 M HCl (0.5 mL). Et2O (5 mL) was added, the organic layer
was separated, and the aqueous phase was extracted with CH2-
Cl2 (3 × 10 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo to afford a mixture of
products. Flash column chromatography (silica gel, 25%
AcOEt/hexane) afforded enamide 12 (82 mg, 27%): 1H NMR
(CDCl3) 0.92 (t, J ) 7.9 Hz, 3H), 1.39 (sext, J ) 7.9 Hz, 2H),
1.98 (q, J ) 7.9 Hz, 2H), 2.40-2.47 (m, 2H), 2.56-2.63 (m,
2H), 2.73-2.79 (m, 2H), 3.61-3.67 (m, 2H), 3.84 (s, 3H), 3.86
(s, 3H), 4.68 (t, J ) 7.9 Hz, 1H), 6.73-6.81 (m, 3H); 13C NMR
(CDCl3) 13.6, 21.3, 23.3, 28.7, 28.8, 32.2, 41.2, 55.8, 100.5,
111.2, 111.9, 120.6, 131.1, 138.9, 147.6, 148.8, 175.2. Anal.
Calcd for C18H25NO3: C, 71.26, H, 8.31, N, 4.62. Found: C,
71.44, H, 8.40, N, 4.56.
N-[2-(3,4-Dim eth oxyp h en yl)eth yl]-5-[N-[2-(3,4-d im eth -
oxyp h e n yl)e t h yl]su ccin im id -3-ylid e n e ]p yr r olid in -2-
on e (13). To a solution of the succinimide 2a (342 mg, 1 mmol)
in dry THF (20 mL) was added t-BuLi (2.35 mL of a 1.7 M
solution in hexanes, 4 mmol) at -78 °C. The resulting mixture
was stirred at this temperature for 4 h, allowed to warm to
20 °C, and then quenched by addition of 6 M HCl (0.5 mL).
Et2O (5 mL) and H2O (10 mL) were added, the organic layer
was separated, and the aqueous phase was extracted with CH2-
Cl2 (3 × 10 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo. Flash column chroma-
tography (silica gel, 30% AcOEt/hexane) afforded the pyrro-
lidinone 13 (91 mg, 18%): IR (CHCl3) 1740, 1695 cm-1 1H
;
NMR (CDCl3) 2.52-2.59 (m, 2H), 2.74-2.83 (m, 2H), 2.85-
2.89 (m, 2H), 3.31-3.38 (m, 2H), 3.48 (broad s, 2H), 3.74-
3.81 (m, 2H), 3.86-3.91(m, 2H)*, 3.85 (s, 3H)*, 3.86 (s, 3H)*,
3.88 (s, 6H)*, 6.70-6.83 (m, 6H) (* designates partially
overlapped signals); 13C NMR (CDCl3) 25.7, 27.6, 33.2, 33.5,
34.98, 39.8, 42.8, 55.9, 56.0, 56.1, 95.1, 111.3, 111.5, 111.9,
112.0, 120.7, 120.8, 129.3, 130.5, 147.8, 148.2, 148.9, 149.2,
152.5, 170.8, 173.3, 177.6; MS (EI) m/ z (rel intensity) 508 (M+,
14), 344 (14), 165 (21), 164 (100), 151 (21), 149 (8), 95 (5), 81
(6), 69 (8), 68 (6), 58 (6), 57 (10), 55 (16), 53 (7). Anal. Calcd
for C28H32N2O7: C, 66.13, H, 6.34, N, 5.51. Found: C, 66.02,
H, 6.18, N, 5.42.
Iod in a tion Rea ction s. Gen er a l P r oced u r e. A solution
of ICl (325 mg, 2 mmol) in glacial acetic acid (2.5 mL) was
added dropwise to a solution of the imide 1 (1 mmol) in glacial
acetic acid (5 mL), and the resulting mixture was stirred at
20 °C for 2 h. The acetic acid was evaporated under vacuum,
CH2Cl2 (5 mL) was added, and the resulting solution was
treated with sodium thiosulfate (2 mL of a 10% aqueous
solution). The aqueous phase was extracted with CH2Cl2 (3
× 5 mL), dried (Na2SO4), filtered, and evaporated. The residue
was crystallized from MeOH to afford pure imides 2.
N-[2-(2-Iod o-4,5-d im et h oxyp h en yl)et h yl]su ccin im id e
(2b). According to the general procedure for iodination,
succinimide 1a (2.63 g, 10 mmol) was treated with ICl (3.25
g, 20 mmol). After workup, the residue was crystallized from
10b -Hyd r oxy-8,9-d im et h oxy-1,5,6,10b-t et r a h yd r op yr -
r olo[2,1-a ]isoqu in olin -3(2H)-on e (14a ). According to the
general procedure for Parham cyclizations, iodinated succin-

2092 J . Org. Chem., Vol. 62, No. 7, 1997
Collado et al.
imide 2b (389 mg, 1 mmol) was treated with n-BuLi (1.3 mL
of a 1.5 M solution in hexanes, 2 mmol). After workup, the
residue was identified without further purification as hydroxy
lactam 14a (200 mg, 75%): 1H NMR (CDCl3) 1.96-2.24 (m,
2H), 2.44-2.85 (m, 4H), 3.02-3.14 (m, 1H), 3.72 (s, 3H), 3.76
(s, 3H), 4.05-4.10 (m, 1H), 4.72-5.18 (broad s, 1H), 6.45 (s,
1H), 6.78 (s, 1H). Due to spontaneous dehydration, this
product could not be fully characterized.
8,9-Dim et h oxy-5,6-d ih yd r op yr r olo[2,1-a ]isoq u in olin -
3(2H)-on e (4a ). Spontaneous dehydration of 14a (200 mg)
in CHCl3 solution (1 mL) at 20 °C gave pyrroloisoquinolone
4a (180 mg, quantitative): IR (neat) 1700, 1610 cm-1; 1H NMR
(CDCl3) 2.87 (t, J ) 6.2 Hz, 2H), 3.21 (d, J ) 2.8 Hz, 2H), 3.70
(t, J ) 6.2 Hz, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 5.42 (t, J ) 2.8
Hz, 1H), 6.66 (s, 1H), 7.00 (s, 1H); 13C NMR (CDCl3) 28.3, 36.8,
38.0, 55.9, 56.0, 94.5, 106.5, 110.8, 119.4, 126.7, 139.4, 148.2,
149.8, 176.5.
11b -H yd r oxy-9,10-d im et h oxyb en zo[a ]q u in olizid in -4-
on e (14b). According to the general procedure for Parham
cyclizations, iodinated glutarimide 2c (403 mg, 1 mmol) was
treated with n-BuLi (1.3 mL of a 1.5 M solution in hexanes, 2
mmol). After workup, the residue was identified without
further purification as hydroxy lactam 14b (230 mg, 83%): 1H
NMR (CDCl3) 1.64-1.74 (m, 2H), 2.11-2.40 (m, 2H), 2.30-
2.45 (m, 2H), 2.45-2.55 (m, 1H), 2.72 (td, J ) 14.3, 4.6 Hz,
1H), 2.97 (td, J ) 12.5, 3.3 Hz, 1H), 3.79 (s, 3H), 3.80 (s, 3H),
4.59 (broad s, 1H), 4.65-4.71 (m, 1H), 6.52 (s, 1H), 6.90 (s,
1H); 13C NMR (CDCl3) 15.8, 28.7, 31.9, 35.2, 37.2, 55.8, 56.0,
82.7, 108.9, 110.7, 127.2, 131.4, 147.8, 148.7, 170.0; MS (EI)
m/ z (rel intensity) 259 (M+ - 18, 95), 244 (100), 230 (42), 216
(28), 200 (17), 185 (6), 172 (6), 130 (7), 115 (10), 77 (10), 63
(6), 51 (6). Anal. Calcd for C15H19NO4: C, 64.97, H, 6.90, N,
5.05. Found: C, 65.22, H, 6.76, N, 4.95.
9,10-Dim eth oxy-2,3,6,7-tetr a h yd r oben zo[a ]qu in olizin -
4(4H)-on e (4b). Spontaneous dehydration of 14b (230 mg)
in CHCl3 solution (1 mL) at 20 °C gave pyrroloisoquinolone
4a (210 mg, quantitative), whose data are identical to those
reported in literature:24 1H NMR (CDCl3) 2.34-2.42 (m, 2H),
2.48-2.51 (m, 2H), 2.73 (t, J ) 5.7 Hz, 2H), 3.81-3.86 (m,
2H)*, 3.84 (s, 3H)*, 3.86 (s, 3H)*, 5.65 (t, J ) 4.8 Hz, 1H),
6.58 (s, 1H), 6.99 (s, 1H) (* designates partially overlapped
signals); 13C NMR (CDCl3) 19.4, 28.6, 31.1, 38.3, 55.8, 55.9,
100.5, 106.8, 110.5, 122.3, 127.1, 135.5, 147.9, 146.1, 169.9.
279 (21, M+), 207 (79), 192 (4), 178 (50), 164 (100), 151 (57),
135 (14), 121 (6), 107 (11), 91 (9), 77 (11), 65 (5), 51 (4).
9,10-Dim eth oxy-2-oxa -2,3,6,7-tetr a h yd r oben zo[a ]qu in -
olizin -4(4H)-on e (4c). Spontaneous dehydration of 14c (245
mg) in CHCl3 solution (1 mL) at 20 °C gave pyrroloisoquinolone
4a (225 mg, quantitative): IR (neat) 1685, 1610 cm-1; 1H NMR
(CDCl3) 2.81 (t, J ) 5.9 Hz, 2H), 3.86 (s, 6H)*, 3.83-3.86 (m,
2H)*, 4.46 (s, 2H), 6.62 (s, 1H), 6.71 (s, 1H), 6.78 (s, 1H) (*
designates partially overlapped signals); 13C NMR (CDCl3)
28.2, 37.7, 55.9, 56.0, 67.2, 105.0, 111.1, 119.4, 125.6, 126.1,
148.4, 148.7, 162.6.
12b-Hyd r oxy-2,3-d im eth oxy-5,6-d ih yd r oisoin d oloiso-
qu in olin -8(12bH)-on e (14d ). According to the general pro-
cedure for Parham cyclizations, iodinated phthalimide 2e (437
mg, 1 mmol) was treated with n-BuLi (1.3 mL of a 1.5 M
solution in hexanes, 2 mmol). After workup, the resulting oil
was crystallized from MeOH to afford hydroxy lactam 14d (300
mg, 96%): mp 157-159 °C dec; IR (KBr) 3340, 1670, 1610 cm-1
;
1H NMR (CDCl3) 2.64-2.72 (m, 1H), 2.86-3.00 (m, 1H), 3.41
(td, J ) 12.5, 4.3 Hz, 1H), 3.74 (broad s, 1H), 3.83 (s, 3H),
3.95 (s, 3H), 4.18-4.25 (m, 1H), 6.57 (s, 1H), 7.42 (s, 1H), 7.48
(t, J ) 7.5 Hz, 1H), 7.64 (td, J ) 7.6, 1.2 Hz, 1H), 7.70 (d, J )
7.4 Hz, 1H), 7.99 (d, J ) 7.6 Hz, 1H); 13C NMR (CDCl3) 29.0,
34.7, 55.8, 56.1, 86.2, 110.3, 111.3, 122.9, 123.4, 127.4, 127.7,
129.2, 130.3, 132.4, 147.8, 148.1, 149.1, 167.3; MS (EI) m/ z
(rel intensity) 311 (M+, 14), 294 (100), 278 (12), 264 (8), 250
(14), 220 (6), 151 (4), 130 (4), 105 (35), 91 (10), 77 (15), 71 (7),
57 (11). Anal. Calcd for C18H17NO4: C, 69.44, H, 5.50, N, 4.50.
Found: C, 69.00, H, 5.43, N.4.60.
13b-Hyd r oxy-9,9-d im eth yl-2,3-d im eth oxyd iben zo[a ,h ]-
qu in olizid in -8-on e (14e). According to the general procedure
for Parham cyclizations, iodinated homophthalimide 2f (479
mg, 1 mmol) was treated with n-BuLi (1.3 mL of a 1.5 M
solution in hexanes, 2 mmol). After workup, the resulting oil
was crystallized from Et2O to afford hydroxy lactam 14e (230
mg, 66%): 1H NMR (CDCl3) 1.01 (s, 3H), 1.62 (s, 3H), 2.80
(ddd, J ) 16.5, 5.4, 2.1 Hz, 1H), 3.09 (ddd, J ) 16.5, 6.8, 4.0
Hz, 1H), 3.28 (broad s, 1H), 3.67 (s, 3H), 3.83 (s, 3H), 3.84-
3.98 (m, 1H), 4.64 (ddd, J ) 12.9, 6.8, 2.1 Hz, 1H), 6.63 (s,
1H), 6.74 (s, 1H), 7.43-7.44 (m, 3H), 7.91-7.95 (m, 1H); 13C
NMR (CDCl3) 25.1, 27.0, 29.9, 36.8, 42.0, 55.8, 83.4, 110.0,
111.8, 125.2, 126.0, 127.1, 127.5, 129.3, 130.1, 134.8, 140.6,
146.6, 148.9, 174.7.
11b-Hyd r oxy-9,10-d im eth oxy-2-oxa ben zo[a ]qu in olizi-
d in -4-on e (14c). According to the general procedure for
Parham cyclizations, iodinated diglycolimide 2d (405 mg, 1
mmol) was treated with n-BuLi (1.3 mL of a 1.5 M solution in
hexanes, 2 mmol). After workup, the residue was identified
without further purification as hydroxy lactam 14c (245 mg,
88%): 1H NMR (CDCl3) 2.58-2.65 (m, 1H), 2.80 (td, J ) 16.1,
4.5 Hz, 1H), 3.04 (td, J ) 12.3, 3.3 Hz, 1H), 3.51 (d, J ) 11.0
Hz, 1H), 3.7 (broad s, 1H), 3.81 (s, 6H), 4.10 (d, J ) 16.2 Hz,
1H), 4.26 (d, J ) 11.0 Hz, 1H), 4.31 (d, J ) 16.2 Hz, 1H), 4.68
(dd, J ) 12.3, 4.5 Hz, 1H), 6.60 (s, 1H), 6.76 (s, 1H); 13C NMR
(CDCl3) 28.5, 34.3, 55.8, 55.9, 67.9, 73.9, 80.2, 108.8, 111.2,
125.2, 127.9, 147.9, 149.3, 165.9; MS (EI) m/ z (rel intensity)
Ack n ow led gm en t . Financial support from the
Basque Government (Project PI95/48) and the Univer-
sity of the Basque Country (Project 170.310-EA141/95)
is gratefully acknowledged. We also thank the Depar-
tamento de Educacio´n, Universidades e Investigacio´n
(Gobierno Vasco), for grants to M.I.C. and I.M.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for new compounds described (57 pages). This material
is contained in libraries on microfiche, immediately follows this
article in microfilm version of the journal, and can be ordered
from the ACS; see any current masthead page for ordering
information.
(24) Pecherer, B.; Humiec, F.; Brossi, A. Synth. Commun. 1972, 2,
315.
J O962155O