Anomalous substituent effects in the Bischler-Napieralski reaction of 2-aryl aromatic formamides

Article abstract of DOI:10.1021/jo0012849

Treatment of some 1-naphthylformamides (or formanilides) possessing a 2,4,5-trioxygenated phenyl substituent at the 2-position with POCl₃ caused an unprecedented carbon insertion reaction into a benzene ring, producing 7-5 ring (azaazulene) systems as valence isomers of isoquinoline skeletons. Precise examination of this abnormal Bischler-Napieralski reaction (BNR) using various substrates led to the following scope and limitations: (i) the 7-5 ring systems were constructed when either 2-alkoxy-4,5-methylenedioxyphenyl- or 4,5-dialkoxy-2-hydroxyphenyl-substituted formamides were used as a starting substrate; (ii) in the former case the formyl carbon was inserted into the C₁-C₆ bond of the 2-phenyl group, and normal isoquinoline cyclization competed with an abnormal carbon insertion reaction; (iii) the presence of a hydroxy group at the 2′-position as in the latter cases caused exclusive carbon insertion, in which alternative C₁-C₂ insertion products were quantitatively formed; (iv) 3,6-dimethoxy-2-hydroxyphenyl-substituted formanilide electronically equivalent to 4,5-dialkoxy-2-hydroxy derivatives produced an indole-pyrone as an abnormal BNR product. Theoretical approaches using the PM-3 method indicated that these abnormal BNRs could be triggered by ipso attack at the 1′-position yielding spiro intermediates. Ring cleavege of the six-membered ring in the spiro intermediates to a ketene function followed by recyclization was proposed for the 2′-hydroxy-directed abnormal BNRs leading to the C₁-C₂ insertion product or the indole-pyrone derivative.

Full text of DOI:10.1021/jo0012849

J . Org. Chem. 2000, 65, 9143-9151
9143
An om a lou s Su bstitu en t Effects in th e Bisch ler -Na p ier a lsk i
Rea ction of 2-Ar yl Ar om a tic F or m a m id es
Tsutomu Ishikawa,*,† Kazunari Shimooka,† Tomoko Narioka,† Shigeru Noguchi,†
Tatsuru Saito,† Akiko Ishikawa,† Emi Yamazaki,† Takashi Harayama,†,‡ Hiroko Seki,§ and
Kentaro Yamaguchi§
Faculty of Pharmaceutical Sciences and Chemical Analysis Center, Chiba University,
1-33 Yayoi, Inage, Chiba 263-8522 J apan
benti@p.chiba-u.ac.jp
Received August 24, 2000
Treatment of some 1-naphthylformamides (or formanilides) possessing a 2,4,5-trioxygenated phenyl
substituent at the 2-position with POCl3 caused an unprecedented carbon insertion reaction into
a benzene ring, producing 7-5 ring (azaazulene) systems as valence isomers of isoquinoline skeletons.
Precise examination of this abnormal Bischler-Napieralski reaction (BNR) using various substrates
led to the following scope and limitations: (i) the 7-5 ring systems were constructed when either
2-alkoxy-4,5-methylenedioxyphenyl- or 4,5-dialkoxy-2-hydroxyphenyl-substituted formamides were
used as a starting substrate; (ii) in the former case the formyl carbon was inserted into the C1-C6
bond of the 2-phenyl group, and normal isoquinoline cyclization competed with an abnormal carbon
insertion reaction; (iii) the presence of a hydroxy group at the 2′-position as in the latter cases
caused exclusive carbon insertion, in which alternative C1-C2 insertion products were quantitatively
formed; (iv) 3,6-dimethoxy-2-hydroxyphenyl-substituted formanilide electronically equivalent to 4,5-
dialkoxy-2-hydroxy derivatives produced an indole-pyrone as an abnormal BNR product. Theoreti-
cal approaches using the PM-3 method indicated that these abnormal BNRs could be triggered by
ipso attack at the 1′-position yielding spiro intermediates. Ring cleavege of the six-membered ring
in the spiro intermediates to a ketene function followed by recyclization was proposed for the 2′-
hydroxy-directed abnormal BNRs leading to the C1-C2 insertion product or the indole-pyrone
derivative.
In tr od u ction
3. On the other hand, application of BNR to 2-(4,5-
dialkoxy-2-methoxyphenyl)-1-naphthylformamides6 4 has
afforded 7,8-dialkoxy-10-methoxy O5-bases4 5 as ortho-
orientation products because an electronically more
activated 2′-position to be cyclized is blocked by the
presence of an additional methoxy group (Scheme 1).
Traditional Bischler-Napieralski reaction (BNR) is
one of the most important synthetic tools for the con-
struction of isoquinoline skeleton.1 Although many kinds
of dehydrating agents such as phosphoric acid and
sulfonic acid derivatives are available for BNR, we have
applied BNR using phosphorus oxychloride (POCl3) as a
dehydrating agent to the construction of isoquinoline
skeletons from 2-aryl-N-methyl-1-naphthylformamides in
the final step of the synthesis of benzo[c]phenanthridine
alkaloids for the structure-activity relationship of their
antitumor activity.2 In general, direction of the cyclization
in the BNRs of 2-aryl-1-naphthylformamides is strictly
controlled by the substitution pattern of alkoxy functions
on the 2-aryl substituent. Thus, in the case of 2-(3,4-
dialkoxyphenyl)-1-naphthylformamides3 1 exclusive cy-
clization to the para position to the 3′-alkoxy group has
occurred to quantitatively yield 8,9-dialkoxy O4-bases4 2
(para-orientation),5 but not isomeric 7,8-dialkoxy O4-ones4
In the synthetic studies of macarpine7 (7), an O6-base,4
we found that an unexpected 12-azonianaphth[1.2-b]-
azulene (a 7-5 ring system in the rings A and B)8 8, which
was produced by the insertion of a formamide carbon into
the C1-C6 bond of the 2-aryl group in the naphthyl-
formamide 6, was concomitantly produced together with
an expected isoquinoline product (a 6-6 ring system) 7,
(3) (a) Ishii, H.; Chen, I.-S.; Ueki, S.; Akaike, M.; Ishikawa, T. Chem.
Pharm. Bull. 1987, 35, 2717-2725. (b) Ishii, H.; Chen, I.-S.; Ishikawa,
T. J . Chem. Soc., Perkin Trans. 1 1987, 671-676. (c) Green, G. R.;
Mann, I. S.; Mullane, M. V.; McKillop, A. J . Chem. Soc., Perkin Trans.
1 1996, 1647-1648.
(4) See: Ishikawa, T. Hetrocycles 1999, 50, 627-639 and references
therein.
(5) Calculation of electron density of the 2-aryl group in 2-(3,4-
dimethoxyphenyl)-6,7-methylenedioxy-1-(N-methylformamido)naph-
thalene (1: 2R1 ) CH2; R2 ) Me) using the AM-1 method with CAChe
ver. 3.6 showed higher electron density at C6′ (4.0981) than at C2′
(4.0888), supporting the para-orientation in BNR.
(6) Ishii, H.; Ishikawa, T.; Ichikawa, Y.-I.; Sakamoto, M. Chem.
Pharm. Bull. 1977, 25, 3120-3121. (b) Ishii, H.; Watanabe, T.;
Ishikawa, T. Chem. Pharm. Bull. 1978, 26, 3252-3254. (c) Ishii, H.;
Ishikawa, T.; Watanabe, T.; Ichikawa, Y.-I.; Kawanabe, E. J . Chem.
Soc., Perkin Trans. 1 1984, 2283-2289.
(7) Ishikawa, T.; Saito, T.; Ishii, H. Tetrahedron 1995, 51, 8447-
8458.
(8) Ishikawa, T.; Saito, T.; Noguchi, S.; Ishii, H.; Ito, S.; Hata, T.
Tetrahedron Lett. 1995, 36, 2795-2798.
† Faculty of Pharmaceutical Sciences.
‡ Present address: Faculty of Pharmaceutical Sciences, Okayama
University, 1-1-1 Tsushimanaka, Okayama 700-0082, J apan.
§ Chemical Analysis Center.
(1) (a) Whaley, W. M.; Govindachari, T. R. Organic Reactions;
Adams, R., Ed.; J ohn-Wiley and Sons: New York, 1951; Vol 6, pp 74-
150. (b) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279-1300.
(c) Fowler, F. W. Comprehensive Hetrocyclic Chemistry; Katrirzky, A.
R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol 2, pp 410-
416.
(2) Ishii, H.; Ichikawa, Y.-I.; Kawanabe, E.; Ishikawa, M.; Ishikawa,
T.; Kuretani, K.; Inomata, M.; Hoshi, A. Chem. Pharm. Bull. 1985,
33, 4139-4151.
10.1021/jo0012849 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/07/2000

9144 J . Org. Chem., Vol. 65, No. 26, 2000
Ishikawa et al.
Sch em e 1
Sch em e 3
amides; (v) thus, direction of the insertion is strictly
dependent upon the nature of oxygen functions in the
2-aryl substituent; (vi) on the other hand, 3,6-dimethoxy-
2-hydroxyphenyl-substituted formanilide, electronically
equivalent to 4,5-dialkoxy-2-hydroxy derivatives, pro-
duced an indole-pyrone as an abnormal BNR product.
In this paper we present not only the scope and limitation
of these anomalous carbon insertions into a benzene ring
producing 7-5 ring systems, but also the formation of an
indole product under the conditions of BNR.
Sch em e 2
Resu lts a n d Discu ssion
(1) BNRs of 2-Ar yl-1-n a p h th ylfor m a m id es. Pre-
liminary BNR of 4-methoxy-2-(2-methoxy-4,5-methylene-
dioxyphenyl)-1-(N-methylformamido)naphthalene (6) for
macarpine (7) synthesis gave a red brown solid 8 different
from an expected 7 in ca. 40% yield. The same molecular
formula of the product as that of 7 was suggested by its
fast atom bombardment mass spectrum (FABMAS);
however, its 1H NMR spectrum showed that it was a
mixture contaminated with small amounts of 7. There-
fore, we tried to isolate the BNR product(s) after reduc-
tion. Treatment of 6 with POCl3 followed by NaBH4
reduction afforded a benzindole 10 (25%) together with
dihydromacarpine (9) (32%) which was smoothly con-
verted into macarpine7 (7) by dehydrogenation with
DDQ.6 Opimization of the isolation of BNR product(s) by
fractional recrystallization (MeOH-EtOH) successfully
afforded a pure azoniaazulene product 8 in 28% yield.
Reduction of 8 with NaBH4 gave the benzindole 10 in
72% yield (Scheme 2).
and that sodium borohydride (NaBH4) reduction of the
azoniaazulene 8 led to the formation of benz[g]indole 10
fused to a 1-alkoxy-8-oxabicylo[3.2.1]octa-2-ene skeleton8
(see Scheme 2).
Extensive examination of this new carbon insertion
reaction (abnormal BNR) using related aromatic form-
amides such as 2,4,5-trioxygenated phenyl-substituted
naphthylformamides 11 and phenolic 2-arylformanilides
20 led to the following conclusions: (i) 2-alkoxy-4,5-
methylenedioxy or 4,5-dialkoxy-2-hydroxy functions on
the 2-aryl-substituted formamides play crucial roles for
the construction of 7-5 ring systems (azaazulenes) as
valence isomers of isoquinoline skeletons; (ii) in the latter
cases the 7-5 ring systems are given as sole abnormal
BNR products; (iii) carbon insertion occurs beween the
C1-C6 bond of the 2-aryl group when 2-alkoxy-4,5-
methylenedioxyphenyl-substituted formamides are sub-
jected to BNR; (iv) an alternative carbon insertion into
the C1-C2 bond of the 2-aryl group is observed in the
case of 4,5-dialkoxy-2-hydroxyphenyl-substituted form-
The full structures of an azoniaazulene 8 and a
benzindole 10 were determined to be 5,7-dimethoxy-12-
methyl-2,3;9,10-bismethylenedioxy-12-azonianaphth[1,2-
b]azulene chloride and 5-methoxy-2,3-(1-methoxy-8-
oxabicylo[3.2.1]octeno)-1-methyl-7,8-methylenedioxy-
benz[g]indole, respectively, based on structural elucida-
tion of the corresponding isopropoxy derivatives as
mentioned below (see Scheme 3). This abnormal BNR,
producing a 7-5 ring system 8, made us precisely re-
examine BNRs of 1-naphthylformamides 11 with a 2,4,5-
trialkoxyphenyl function at the 2-position like 4, in which
normal benzo[c]phenanthridine alkaloids had been ob-
tained as isolable products.6
On
2-(2,4,5-Tr ia lk oxyp h en yl)-1-n a p h t h ylfor m -
a m id es 11. 2-(4,5-Dialkoxy-2-isopropoxyphenyl)-1-naph-
i
thylformamides 11 (R1 ) Pr; R2 ) Me or R2 ) -CH2-),

Bischler-Napieralski Reaction
Ta ble 1. Rein vestiga tion of BNRs of
J . Org. Chem., Vol. 65, No. 26, 2000 9145
2-(2,4,5-Tr ia lk oxyp h en yl)-1-n a p h th ylfor m a m id es 11
F ollow ed by Na BH4 Red u ction
yield (%)a
time (h)
run
R1
R2
R2
in step 1
12
13
1
2
3
4
Me
iPr
Me
iPr
Me
Me
Me
Me
1.5
3
8
89b
91
-
-
CH2
CH2
30c
44
30 (R1 ) H)d
22 (R1 ) iPr)d
9
a
b
Isolated, nonoptimized yields. Isolated as the quaternary
chloride before the reduction. The starting formamide is known.
The chloride (chelilutine chloride) had been obtained in 56% yield
in the previous experiment.6c c The starting formamide is known.
The corresponding quaternary (chelirubine) chloride had been
F igu r e 1. Selected NOE enhancements of 7-5 ring system
products 14 and 17.
Sch em e 4
d
obtained in 30% yield in the previous experiment.6c Acetal
function (OR1) was dependent upon the conditions used for
workup.
among four naphthylformamides examined, were newly
prepared according to our reported method3 (See Sup-
porting Information).
Treatment of 11 with POCl3 at 70 °C followed by
NaBH4 reduction gave cyclized product(s) 12 and/or 13
(Table 1). Exclusive normal cyclization to isoquinoline
skeletons 12 was observed when dimethoxy-substituted
naphthylformamides 11 (R2 ) Me) were used as sub-
strates (runs 1 and 2), while displacement of the methoxy
groups into a methylenedioxy function in 11 led to the
production of indole systems 13 in moderate yields along
with normal cyclized products 12 (runs 3 and 4). The
structures of indole skeletons were established based on
the X-ray crystallographic analysis8 of a benzindole 13
i
propoxyformamide 11 (R1 ) Pr; R2 ) Me) by treatment
with 10% methanesulfonic acid in chloroform (see Sup-
porting Information). Heating 16 in acetonitrile with
POCl3 at 80 °C afforded a single product 17 quantita-
tively, which was inert to NaBH4 reduction. Its molecular
formula was determined to be C21H17NO5 by elemental
analysis and high resolution (HR) FABMS. Although no
absorption appeared in the typical carbonyl region of the
IR spectrum, appearance of a signal at δ 175.2 in the
13C NMR spectrum indicated the presence of a conjugated
carbonyl carbon in the molecule. Further inspection of
the spectral data (see Experimental Section) allowed us
to deduce the product to be an azaazulenone with a 7-5
ring system, which was temporarily supposed to be a C1-
C6 insertion product 17A based on the structure of the
azoniaazulene 14 produced in the BNR of 2′-isopropoxy-
i
(R1 ) Pr) obtained in run 4 in Table 1.
Carefully fractional recrystallization of the crude BNR
product of the 2′-isopropoxy-4′,5′-methylenedioxy form-
i
amide 11 (R1 ) Pr; R2 ) -CH2-) from MeOH led to
successful isolation of two products, an azoniaazulene
chloride 14 (21%) and an isoquinolinium chloride 15
(35%) as less soluble and more soluble components,
respectively. Independent NaBH4 reduction of each qua-
ternary base afforded the same cyclized products ob-
tained in the above two-step reaction of BNR and
reduction (Scheme 3). The structure of 7-isopropoxy-12-
azoniaazulene skeleton for 14 was determined by precise
inspection of its spectral data, especially the NMR data
including NOE experiments (see Figure 1), as described
in a preliminary communication.8
i
4′,5′-methylenedioxy naphthylformamide 11 (R1 ) Pr;
R2 ) -CH2-) (Scheme 4).
However, NOE experiments of the product indicated
some discrepancies for the supposed structure 17A. The
C1-C6 insertion product 14 showed NOE enhancements
between an N-methyl group (δ 4.34) and both singlets
due to 1-H (δ 7.93) and 11-H (δ 8.24), respectively,
whereas only single NOE enhancement between an
N-methyl group (δ 4.63) and a singlet (δ 8.12) assignable
to 1-H was observed in 17 (Figure 1). Furthermore, no
enhancement was detectable between a doublet due to
6-H and any singlet signals in 14; however, 6% enhance-
ment of the corresponding doublet (δ 8.17) was observed
on irradiation of the singlet at δ 7.55 due to a seven-
membered ring proton of 17. These facts suggested that
the 7-5 ring system produced in the BNR of a phenolic
formamide 16 could be an alternative C1-C2 insertion
product 17B.
Thus, it was clear that the presence of methylenedioxy
function at the 4′ and 5′ positions in 2,4,5-trialkoxy-
phenyl-substituted naphthylformamides was responsible
for the 7-5 ring construction through carbon insertion into
the C1-C6 bond of the 2-aryl group.
2-(4,5-Dim et h oxy-2-h yd r oxyp h en yl)-1-n a p h t h yl-
for m a m id e 16. Next we examined the BNR of 2-(4,5-
dimethoxy-2-hydroxyphenyl)-1-naphthylformamide 16 in-
volving a phenolic function at the 2′-position, which had
been isolated as isoarnottianamide9 from plant sources.
The phenolic formamide 16 was prepared from an iso-
Unfortunately, in this stage no further information on
the correct structure of 17 could be obtained because of
their low solubility to usual organic solvents. Trials for
preparation of a single crystal for X-ray crystallographic
(9) Ishii, H.; Ishikawa, T.; Lu, S.-T.; Chen, I.-S. Tetrahedron Lett.
1976, 1203-1206.

9146 J . Org. Chem., Vol. 65, No. 26, 2000
Ishikawa et al.
Sch em e 5
Sch em e 7
Treatment of 21 with lithium aluminum hydride gave
a tetrahydro derivative 22 in 53% yield. Reduction of a
ketonic function to a methylene unit was indicated by
the appearance of an A2X signal pattern [δ 3.14 (2H, d,
J ) 7.6 Hz) and δ 4.89 (1H, t, J ) 7.6 Hz)] in the 1H
NMR spectrum of 22. Successful preparation of a single
crystal for X-ray crystallographic analysis11 resulted in
unambiguously establishing the structure of 22 to be 9H-
6,7-dimethoxy-10-methylbenz[b]azaazulene (see Sup-
porting Information). This indicated that 21 was 9-aza-
azulenone corresponding to a C1-C2 insertion product
and that a cyclized product derived from 16 must be C1-
C2 insertion product 17B. Thus, NOE enhancements
observed in 17 could be reasonably explained by the
presence of a carbonyl group at the peri position to an
indole nitrogen in C1-C2 insertion products.
Sch em e 6
An alternative cyclized product 23 was additionally
obtained as a minor product (15% yield) in the above BNR
of 20a . The same 23 was produced in 86% yield when
BNR was carried out under heating at 50 °C. Its spectral
data showed that 23 was a chlorine-substituted aza-
azulenone, in which the 7-methoxy group of 21 was
displaced by a chlorine atom.12 Easy dechlorination of 23
to 24 with NaBH4 could support the 7-chloro structure
of 23 corresponding to a vinylogous acid chloride moiety
(see Scheme 6).
Interestingly, it was found that a relatively labile
chlorine-incorporating quaternary azoniaazulene product
25 was quantitatively obtained in the BNR of 20a
without aqueous workup and that aqueous treatment of
25 afforded the chloroazaazulenone 23 in 85% yield.13
Inspection of the spectral data showed that 25 was
9-chloro-6,7-dimethoxy-10-methyl-10-azoniabenz[b]azu-
lene chloride (see Experimental Section). The same type
of 9-chloroazoniaazulene 26 was also obtained in the BNR
(without aqueous workup)14 of 2-hydroxyphenyl form-
anilide 20b carrying a methylenedioxy function in place
of dimethoxy groups in 20a (Scheme 7). These experi-
mental facts indicated that the location of a hydroxy
function at the 2′-position in a 2′,4′,5′-trialkoxy system
was inevitable for the cyclization to 7-5 ring systems
producing C1-C2 insertion products.
analysis also failed. Therefore, we decided to examine
BNRs of phenolic 2-arylformanilides 20 for the scope and
limitations of this abnormal cyclization to 7-5 ring
systems in addition to structural determination of the
azaazulenone product 17.
(2) BNRs of P h en olic 2-Ar ylfor m a n ilid es 20. Phe-
nolic 2-arylformanilides 20 were basically prepared by a
Suzuki-type coupling reaction10 between protected aryl-
boronic acids 18 and 2-bromoformanilide (19) followed
by methylation and deprotection (Scheme 5). Thus, eight
formanilides 20a -h were prepared (see Supporting
Information).
Oth er P h en olic F or m a n ilid es 20c-g. Next, the
other five phenolic formanilides of 2-hydroxyphenyl- 20c,
2-(4,5-Dialkoxy-2-h ydr oxyph en yl)for m an ilides 20a
a n d 20b. At first we examined the BNR of 2-(4,5-
dimethoxy-2-hydroxyphenyl)formanilide 20a having the
same substitution pattern as that in the phenolic naph-
thylformamide 16. Treatment of 20a with POCl3 at room
temperature afforded a cyclized product 21 in 63% yield
(Scheme 6). The expected production of a 7-5 ring system
was reasonably deduced by inspection of its spectral data
(see Experimental Section).
(11) Crystal data for 22: C16H17NO2 ) 255.32, monoclinic, space
group P21 (#4); a ) 8.130(9), b ) 7.780(9) Å, c ) 10.94(2), â ) 99.97
(8)°; V ) 681(1) Å3; Z ) 2; Dcalc ) 1.244 g/cm3; µ(Mo KR) ) 1.24 cm-1
.
A total of 1231 reflections (1229 unique) were recorded on a Rigaku
RAXIS-II diffractometer. Anisotropic full-matrix least squares based
on F2 for non-H atoms and isotropic for H atoms converged to a
standard agreement factor, R ) 0.060, Rw ) 0.069, using 1192
reflections [I > 2σ(I)].
(12) Irradiation of 5-H (δ 7.59) led to 14% and 12% NOE enhance-
ments of 4-H (δ 8.02) and a methoxy signal (δ 4.07), respectively.
(13) Chemical reactivity of azaazulene systems obtained in abnormal
BNRs will be discussed elsewhere.
(14) Aqueous workup of 26 afforded a 9-azaazulenone similar to 21
as a sole isolable product; however, the yield was low (11%).
(10) Suzuki, A. Acc. Chem. Res. 1982, 15, 178-184.

Bischler-Napieralski Reaction
J . Org. Chem., Vol. 65, No. 26, 2000 9147
Ta ble 2. BNRs of Oth er P h en olic 2-P h en ylfor m a n ilid es
Sch em e 9
20c-g
a
b
The starting 20c was recovered in 11%. The starting 20d
was recovered in 37%. c The starting 20d was recovered in 20%.
Isolated before reduction.
d
Sch em e 8
skeleton. Further inspection of the spectral data (see
Experimental Section) allowed us to deduce the new
product to be an indole-pyrone derivative depicted as
29, and the structure was completely confirmed by X-ray
crystallographic analysis16 (see Supporting Information).
Thus, it was clear that 2′,3′,6′-oxygenated system con-
taining a hydroxy group at the 2′-position caused abnor-
mal BNR giving an indole product accompanied by
destruction of a benzene ring.
(3) Mech a n ist ic Con sid er a t ion for Ab n or m a l
BNRs. Anomalous carbon insertion reactions into ben-
zene ring during the BNRs of 2-aryl aromatic formamides
are summerized as follows: (i) abnormal BNRs are
observed in the BNRs of 2′,4′,5′-trioxygenated aromatic
formamides; (ii) in the cases of trialkoxy substituents, a
methylenedioxy group at the 4′,5′ positions causes the
carbon insertion, in which C1-C6 insertion is observed,
and normal isoquinoline cyclization competes with ab-
normal insertion reaction; (iii) in the cases of monohy-
droxy and dialkoxy substituents, the presence of a
hydroxy group at the 2′-position is responsible for the
exclusive carbon insertion reaction, in which alternative
C1-C2 insertion products are produced; (iv) on the other
hand, 3,6-dimethoxy-2-hydroxyphenyl-substituted form-
anilide affords an indole-pyrone as an abnormal BNR
product.
4-hydroxyphenyl- 20d , 2-hydroxy-5-methoxyphenyl- 20e,
2,4-dimethoxy-5-hydroxyphenyl- 20f, and 2,5-dimethoxy-
4-hydroxyphenylformanilides 20g were treated with
POCl3 under the conditions given in Table 2, respectively.
However, only either deformylation or normal isoquino-
line cyclization was observed in all cases, resulting in no
production of azaazulene systems.
2-(3,6-Dim et h oxy-2-h yd r oxyp h en yl)for m a n ilid e
20h . 2-(3,6-Dimethoxy-2-hydroxyphenyl)formanilide15 20h
could be supposed to be a synthon of the 4,5-dimethoxy-
2-hydroxy system 20a in the viewpoint of electronic
contribution of alkoxy groups to the benzene ring. We
finally examined the BNR of 20h , in which carbon
insertion could be the sole expected reaction because of
the presence of substituents at both positions to be
cyclized. Treatment of 20h with POCl3 at 50 °C afforded
a new indole product 29 with a pyrone ring in 19% yield
together with a deformylated product 30 (19%) and a
starting 20h (29%) (Scheme 8).
On the basis of these facts, we supposed a mechanism
for abnormal BNRs as shown in Schemes 9-11. In all
cases, ipso attack17 of the formyl carbon18 to the 1′-
(15) 20h was prepared from 2-(2,6-dimethoxyphenyl)formanilide
obtained by Suzuki-type coupling reaction of 19 and 2,6-dimethoxy-
phenylboronic acid through seven steps (see Supporting Information).
(16) Crystal data for 29: C16H13NO4 ) 283.28, orthorhombic, space
group P212121 (#19); a ) 7.987(10), b ) 22.97(2), c ) 7.255(5) Å; V )
1330(2) Å3; Z ) 4; Dcalc ) 1.414 g/cm3; µ(Mo KR) ) 1.03 cm-1. 1213
independent reflections were recorded on a Rigaku RAXIS-II diffrac-
tometer. Anisotropic full-matrix least squares based on F2 for non-H
atoms and isotropic for H atoms converged to a standard agreement
factor, R ) 0.069, Rw ) 0.083, using 1047 reflections [I > 3σ(I)].
The molecular formula of 29 was determined to be
C16H13NO4 by its HRFABMS. Conjugated lactone and
aldehyde functions in its molecule were observed in the
IR and 13C NMR spectra. Appearance of a 3H singlet at
δ 3.05 and a 1H singlet at δ 7.55 in the 1H NMR spectrum
indicated the presence of 3-substituted N-methylindole

9148 J . Org. Chem., Vol. 65, No. 26, 2000
Ishikawa et al.
Sch em e 10
F igu r e 2. Selected calculated electron density of 2-(2,4,5-
trialkoxyphenyl)formanilides 37 and 38.
2-Alk oxy-4,5-m eth ylen ed ioxyp h en yl For m a m id es:
C1-C6 In ser tion Rea ction . In 2-alkoxy-4,5-methylene-
dioxyphenyl formamides 31 (R2 ) -CH2-) a fused 6-3-6
ring system 34 could be formed by the C-C bond
formation at the 2-position of the indolenium skeleton
of a spiro compound 33 triggered by the 5′-oxygen group
after ipso attack in an activated amide 32.20 Valence
isomerization of 34 into a 7-5 ring system 35 results in
carbon insertion into the C1-C6 bond of the 2-aryl group
(Scheme 9).
In contrast, only normal isoquinoline cyclization was
observed in the BNRs of formamides 31 (R2 ) Me) with
4,5-dimethoxyphenyl function. These facts could be ex-
plained by more effective conjugation of a methoxy group
to a benzene ring rather than a methylenedioxy group.21
Thus, in the 4,5-dimethoxyphenyl-substituted form-
amides the 6′-position would be reactive enough to be
directly attacked by the formyl carbon, exclusively yield-
ing an isoquinoline skeleton 36 (R2 ) Me).
Sch em e 11
To rationalize the reactivities of the BNR mentioned
above, MO calculations on the 2-aryl substituent in
2-(2,4,5-trialkoxyphenyl)formanilides 37 and 38 by the
PM-3 method22 were performed (Figure 2). In these
systems a main reaction course is a normal isoquinoline
cyclization due to direct attack of the formyl carbon at
the more electron-rich 6′-position. However, the 1′- and
6′-positions in 37 carrying a methylenedioxy function
show closer electron density (∆6′-1′ ) 0.0188) than in 38
(17) (a) March, J . Advanced Organic Chemistry, 3rd. ed.; Wiley-
Interscience: New York; 1985; pp 458-459. (b) For BNR, see Doi, S.;
Shirai, N.; Sato, Y. J . Chem. Soc., Perkin Trans. 1 1997, 2217-2221.
(18) In the preliminary communication8 carbene insertion into the
benzene ring had been supposed for the ring expansion. However, a
substituent-dependent direction in carbon insertions required the
proposed mechanism to be revised.
(19) Kusama, H.; Yamashita, Y.; Uchiyama, K.; Narasaka, K. Bull.
Chem. Soc. J pn. 1997, 70, 965-975.
(20) A similar dichlorophosphorate had been supposed as a reactive
intermediate in the BNR of 4-methoxyphenylethylbenzamide, in which
migration of a carbon unit through a spiro compound producing an
isomeric isoquinoline was observed together with an expected iso-
quinoline formation.17b
(21) (a) Buckley, T. F., III; Rapport, H. J . Am. Chem. Soc. 1980,
102, 3056-3062. (b) Sha, C.-K.; Young, J .-J .; Yeh, C.-P.; Cheng, S.-C.;
Wang, S.-L. J . Org. Chem. 1991, 56, 2694-2696. (c) Isono, N.; Mori,
M. J . Org. Chem. 1995, 60, 115-119.
(22) MO calculations were performed by the PM-3 method with
MOPAC ver 6.0. Results were obtained after full optimization of
possible geometries.
position doubly activated by 2′,4′- or 2‘,6′-dioxygen func-
tions should initiate the reaction to give spiro inter-
mediates17b,19 such as 33 in Scheme 9.

Bischler-Napieralski Reaction
J . Org. Chem., Vol. 65, No. 26, 2000 9149
Con clu sion s
In conclusion, it was found that fused azaazulene ring
systems triggered by carbon insertion into a benzene ring
were constructed when 2-alkoxy-4,5-methylenedioxy-
phenyl or 4,5-dialkoxy-2-hydroxyphenyl systems among
aromatic formamides25 with a 2,4,5-trialkoxyphenyl sub-
stituent at the 2-position were subjected to BNR and that
direction of carbon insertion could be controlled by their
substituent patterns. Furthermore, C1-C2 insertion was
suggested to be a normal reaction path in the latter BNR.
In fact we have observed that some modified formanilides
with a 4,5-dimethoxy-2-hydroxyphenyl system afford
9-azaazulenones as sole cyclized products in expected
high yields.26 In addition, an indole-pyrone derivative,
the pyrone unit of which would be derived from a benzene
ring, was obtained as an alternative BNR product in the
case of a 3,6-dialkoxy-2-hydroxy system. Thus, these
abnormal BNRs were found to be strictly dependent upon
the nature of oxygen functions in the 2-aryl substituent.
In the literature azaazulene skeletons including ben-
zene ring-fused ones have been generally prepared by
cyclization of the corresponding troponoids.27 On the
other hand, it has been reported that Wittig reaction of
N-methylanilides of R-keto acids with diazomethane
derivatives yields 1-azaazulenes by expansion of the
benzene ring to a seven-membered ring through alkyl-
idene carbene intermediates.28 Similar carbene-insertion
reactions have been also observed in the rhodium (II)-
catalyzed intramolecular Bucher reaction.29 However, our
new 7-5 ring construction reactions should be classified
into quite a different reaction category from the reported
methods because of SEAr reactions being controlled by
substituents.
F igu r e 3. Selected calculated electron density of 2-(4,5-
dialkoxy-2-hydroxyphenyl)formanilides 20a and 20b.
carrying a dimethoxy function (∆6′-1′ ) 0.0607). Thus, ipso
attack to the 1′-position, resulting in the formation of a
C1-C6 carbon insertion product, could be expected to
compete with normal isoquinoline cyclization in the
former case as shown in the BNRs of the related naph-
thylformamides such as 6 and 11 (R2 ) -CH2-).
4,5-Dia lk oxy-2-h yd r oxyp h en yl F or m a m id es: C1-
C2 In ser tion Rea ction . An alternative reaction route
must be active for exclusive C1-C2 carbon insertion
observed in the 2-hydroxyphenyl formamide 39. A spiro
ketone 41 should be produced by ipso attack because of
the presence of a hydroxy group at 2′-position. Participa-
tion of 4′-alkoxy group could cause ring cleavage to give
a ketene indole 42. Nucleophilic attack of the enamine
function of an indole skeleton to the ketene unit results
in carbon insertion into the C1-C2 bond of 2-aryl group
affording a 7-5 ring system 43.23 Final products 45 or 46
are dependent upon workup conditions24 used (Scheme
10).
On the other hand, azaazulene systems obtained here
could be regarded as seven-membered ring-fused indole
(or benzindole) equivalents. Therefore, these abnormal
BNRs could be replaced by new indole syntheses.30 In
particular they may be useful for the preparation of
ervatamine-type indole alkaloids31 containing a seven-
membered ring.
This speculation is also supported by similar MO
calculations of 2-(4,5-dialkoxy-2-hydroxyphenyl)form-
anilides 20a and 20b by the PM-3 method22 (Figure 3).
Preferential ipso attack at more electron-rich 1′-position
(∆1′-6′ ) 0.1149 in 20a ; ∆1′-6′ ) 0.0991 in 20b) should be
responsible for the exclusive formation of C1-C2 insertion
products.
Exp er im en ta l Section
Gen er a l. See Suporting Information.
BNR of 4-Meth oxy-2-(2-m eth oxy-4,5-m eth ylen ed ioxy-
phenyl)-6,7-methylenedioxy-1-(N-methylformamido)naphtha-
(25) No azaazulene formation was observed in the BNR of 4,5-di-
methoxy-2-hydroxyphenylethyl-N-methylformamide, an aliphatic form-
amide.
3,6-Dim eth oxy-2-h yd r oxyp h en yl F or m a m id e: De-
str u ction of th e Ben zen e Rin g. It could be also
supposed that a spiro ketone 48 and a ketene indole 49
are formed as reactive intermediates in the BNR of 2-(3,6-
dimethoxy-2-hydroxyphenyl)formanilide 20h . The sub-
stitution pattern of alkoxy groups in the hexadienone ring
of 48 leads to a conjugate ketene 49 without a cationic
charge by ring cleavage triggered by the 6′-methoxy
group. A 6π system of the ketene unit in 49 causes to
electrocyclic reaction to give a lactone 50,23 and the
subsequent Vilsmeyer-Haack type formylation with an
activated amide such as 47 produces indole-pyrone 29
(Scheme 11).
(26) Experimental details will be reported elsewhere.
(27) (a) Nishiwaki, T.; Abe, N. Heterocycles 1981, 15, 547-582. (b)
Takayashu, T.; Nitta, M. J . Chem. Soc., Perkin Trans. 1 1999, 687-
692.
(28) (a) Gilbert, J . C.; Blackburn, B. K. J . Org. Chem. 1986, 51,
4087-4089. (b) Shioiri, T.; Aoyama, T. J . Synth. Org. Chem. J pn 1996,
54, 918-928. (c) Horwell, D. C.; McKiernan, M. J .; Osborne, S.
Tetrahedron Lett. 1998, 39, 8729-8732.
(29) (a) Manitto, P.; Monti, D.; Speranza, G. J . Org. Chem. 1995,
60, 484-485. (b) Moody, C. J .; Miah, S.; Slawin, A. M. Z.; Mansfield,
D. J .; Richards, J . C. J . Chem. Soc., Perkin Trans. 1 1998, 4067-4075.
(c) Maguire, A. R.; Buckley, N. R.; O’leary, P.; Ferguson, G. J . Chem.
Soc., Perkin Trans. 1 1998, 4077-4091.
(30) Gribble, G. W. J . Chem. Soc., Perkin Trans. 1 2000, 1045-1075.
(31) (a) J oule, J . A. Indoles, The Monoterpenoid Indole Alkaloids
(Saxton, J . E., Ed.). In The Chemistry of Heterocyclic Compounds;
Weissberger, A.; Taylor, E. C., Eds.; Wiley: New York, 1983; Vol 25,
part 4, pp 232-239. Alvarez, M.; J oule, J . Monoterpenoid Indole
Alkaloids (Saxton, J . E., Ed.). In The Chemistry of Heterocyclic
Compounds; Taylor, E. C., Ed.; Wiley: Chichester, 1994; Vol 25,
Supplement to Part 4, pp 234-236. (b) Clivio. P.; Richard, B.; Nuzillard,
J .-M.; Zeches-Hanrot, M. Phytochemistry 1995, 40, 987-990.
(23) The outline of this mechanism was suggested by one of the
reviewers. We thank him for this valuable suggestion of a more
reasonable mechanism than our original one.
(24) In the BNR of 20a use of P2O5 in hot toluene instead of POCl3
afforded 6,7-dimethoxyazaazulenone 21 in 46% yield as a sole product.

9150 J . Org. Chem., Vol. 65, No. 26, 2000
Ishikawa et al.
len e (6). (i) F ollow ed by Na BH4 Red u ction : Isola tion of
5-Meth oxy-2,3-(1-m eth oxy-8-oxa bicyclo[3.2.1]octen o)-1-
m eth yl-7,8-m eth ylen ed ioxyben z[g]in d ole (10). A solution
of 6 (30 mg, 0.073 mmol) in POCl3 (0.5 mL, 5.36 mmol) was
stirred at 80 °C for 4 h. After evaporation of the POCl3, the
residue was dissolved in MeOH (3.0 mL), and then a large
excess of NaBH4 (50 mg, 1.22 mmol) was added. The whole
was stirred at room temperature for 2 h. After workup
purification of the residue by preparative TLC (hexane:EtOAc
) 3:1) gave dihydromacarpine7 (9) (9 mg, 31%) from a less
polar fraction and an indole 10 (7 mg, 25%) from a more polar
fraction as a light brown solid; 1H NMR (500 MHz) δ 1.64 (1H,
m), 2.18 (1H, m), 2.30 (1H, m), 2.40 (1H, m), 2.44 (1H, d, J )
14.9 Hz), 3.36 (1H, dd, J ) 14.9, 4.6 Hz), 3.58 (3H, s), 4.00
(6H, s), 4.98 (1H, dif. t, J ) 4.6 Hz), 6.05 (2H, fine splitting),
6.99 (1H, s), 7.74 (1H, s), 7.78 (1H, s); HRFABMS m/z 367.1425
afforded 17B (285 mg, quant) as yellow needles, mp 283-285
°C, which were recrystallized from CHCl3-MeOH; 1H NMR
(500 MHz) δ 3.96 (3H, s), 4.04 (3H, s), 4.74 (3H, s), 6.12 (2H,
s), 6.74 (1H, s), 7.32 (1H, s), 7.35 (1H, s), 7.52 (1H, d, J ) 8.8
Hz), 7.83 (1H, d, J ) 8.8 Hz), 8.03 (1H, s); 13C NMR (125 MHz)
δ 37.4, 56.0, 56.4, 100.8, 101.5, 104.1, 106.4, 115.2, 116.3, 118.4,
120.2, 121.5, 122.2, 131.2, 135.7, 136.8, 147.0, 147.5, 149.9,
157.7, 176.5; HRFABMS m/z 364.1183 (M + H+, C21H18NO5
requires 364.1185). Anal. Calcd for C21H17NO5 1/2H2O: C,
67.73; H, 4.87; N, 3.76. Found: C, 67.80; H, 4.85; N, 3.73.
BNR of 2-(4,5-Dim eth oxy-2-h yd r oxyp h en yl)-N-m eth -
ylfor m a n ilid e (20a ) u n d er Va r iou s Con d ition s. (i) At
Room Tem p er a tu r e w ith Aqu eou s Wor k u p : 6,7-Dim eth -
oxy-10-m eth ylben z[b]a za a zu len -9-on e (21) a n d 7-Ch lor o-
6-m eth oxy-10-m eth ylben z[b]a za a zu len -9-on e (23). A solu-
tion of 20a (11 mg, 0.038 mmol) in POCl3 (0.4 mL, 3.97 mmol)
was stirred at room temperature for 3 days. The reaction
mixture was evaporated and extracted with CHCl3. After
workup, purification of the crude product by preparative TLC
(CHCl3:MeOH ) 30:1) afforded 21 (6 mg, 63%) as yellow fine
(M+, C21H21NO5 requires m/z 367.1418). Anal. Calcd for C21H21
-
NO5: C, 68.65; H, 5.76; N, 3.81. Found: C, 68.46; H, 5.69; N,
3.82.
(ii) Isola tion of 5,7-Dim eth oxy-12-m eth yl-2,3;9,10-bis-
m et h ylen ed ioxy-12-a zon ia n a p h t h [1,2-b]a zu len e Ch lo-
r id e (8). A solution of 6 (101 mg, 0.247 mmol) in POCl3 (1.0
mL, 10.8 mmol) was stirred at 80 °C for 8 h. After evaporation
of the POCl3, fractional recrystallization of the residue from
MeOH-EtOH afforded 8 (29 mg, 28%) as dark red needles,
mp >300 °C; 1H NMR (500 MHz, DMSO-d6) δ 4.09 (3H, s),
4.51 (3H, s), 4.52 (3H, s), 6.31 (2H, s), 6.62 (2H, s), 7.69 (1H,
s), 7.82 (1H, s), 7.91 (1H, s), 8.25 (1H, s), 8.68 (1H, s); 13C NMR
(125 MHz, DMSO-d6) δ 36.1, 55.6, 59.3, 97.9, 100.0, 100.7,
100.9, 102.4, 103.7, 106.2, 117.0, 117.1, 119.6, 123.5, 131.3,
143.5, 148.0, 148. 5, 151. 6, 152.9, 161.3, 169.9; HRFABMS
m/z 392.1131 (M+, C22H18NO6 requires m/z 392.1134). Anal.
Calcd for C22H18ClNO6 2H2O: C, 56.95; H, 4.78; N, 3.02.
Found: C, 56.93; H, 4.54; N, 3.02. A mixture of 8 (15 mg, 0.04
mmol) and NaBH4 (10 mg, 0.273 mmol) in MeOH (1.5 mL)
was stirred at room temperature for 1.5 h, and workup yielded
10 (10 mg, 75%).
1
prisms, mp 223-224 °C; IR (Nujol) νmax 1559 cm-1; H NMR
(400 MHz) δ 3.96 (3H, s), 4.02 (3H, s), 4.40 (3H, s), 6.75 (1H,
s), 7.33 (1H, dt, J ) 8.0, 1.2 Hz), 7.39 (1H, s), 7.53 (1H, dif d,
J ) 8.0 Hz), 7.55 (1H, dt, J ) 8.0, 1.0, 1.2 Hz), 8.03 (1H, d, J
) 8.0 Hz); 13C NMR (100 MHz) δ 33.0, 56.0, 56.5, 104.7, 110.5,
115.2, 119.1, 120.0, 120.8, 125.1, 127.2, 135.8, 140.1, 149.4,
158.1, 177.0; HRFABMS m/z 270.1119 (M + H+, C16H16NO3
requires m/z 270.1130). Anal. Calcd for C16H15NO3: C, 71.36;
H, 5.61; N, 5.20. Found: C, 71.27; H, 5.63; N, 4.85 and 23 (2
mg, 15%), which was identical with the sample obtained from
the reaction at 50 °C mentioned below.
(ii) At 50°C w ith Aqu eou s Wor k u p : 7-Ch lor oa za a zu -
len on e 23. A solution of 20a (51 mg, 0.176 mmol) in POCl3
(0.8 mL, 8.6 mmol) was stirred at 50 °C for 3 h. The reaction
mixture was evaporated and extracted with CHCl3 containing
a small amount of MeOH. After workup, the crude product
was recrystallized from MeOH-CHCl3 to afford 23 (41 mg,
85%) as yellow prisms, mp 209-212.5 °C; IR (Nujol) νmax 1654
BNR of 2-(2-Isop r op oxy-4,5-m eth ylen ed ioxyp h en yl)-
6,7-m e t h yle n e d ioxy-1-(N-m e t h ylfor m a m id o)n a p h t h a -
len e (11: R1 ) iP r ; R2 ) -CH2-): 7-Isop r op oxy-12-m eth yl-
2,3;9,10-bism eth ylen ed ioxy-12-a zon ia n a p h th [1.2-b]a zu -
len e Ch lor id e (14) a n d 10-Isop r op oxysa n gu in a r in e Ch lo-
cm-1 1H NMR (400 MHz) δ 4.07 (3H, s), 4.27 (3H, s), 7.37
;
(1H, ddd, J ) 10.0, 10.0, 1.2 Hz), 7.51 (1H, d, J ) 10.0 Hz),
7.58 (1H, ddd, J ) 10.0, 10.0, 1.2 Hz), 7.59 (1H, s), 7.64 (1H,
s), 8.02 (1H, d, J ) 10.0 Hz); 13C NMR (100 MHz) δ 35.0, 56.1,
107.2, 110.6, 119.5, 120.2, 121.6, 125.0, 127.7, 133.6, 134.2,
134.7, 140.8, 157.0, 176.7; HRFABMS m/z 274.0636 (M+,
i
r id e (15). 11 (R1 ) Pr; R2 ) -CH2-) (500 mg, 1.23 mmol)
and POCl3 (2.4 mL, 25.8 mmol) were reacted for 8 h. After
washing with Et2O, fractional recrystallization of the residue
from MeOH afforded 14 (111 mg, 21%) as light orange needles,
C
C
15H13ClNO2 requires m/z 274.0635) and 276.0615 (M+ + 2,
15H13ClNO2 requires m/z 276.0606). Anal. Calcd for C15H12
-
ClNO2: C, 65.82; H, 4.42; N, 5.12. Found: C, 65.66; H, 4.33;
N, 5.08.
1
mp >300 °C; H NMR (500 MHz, CD3OD) δ 1.76 (6H, d, J )
6.0 Hz), 4.34 (3H, s), 5.46 (1H, septet, J ) 6.0 Hz), 6.22 (2H,
s), 6.54 (2H, s), 7.35 (1H, s), 7.69 (1H, d, J ) 8.8 Hz), 7.85
(1H, s), 7.93 (1H, s), 8.24 (1H, s), 8.47 (1H, d, J ) 8.8 Hz);
HRFABMS m/z 390.1345 (M+, C23H20NO5 requires m/z
390.1341). Anal. Calcd for C23H20Cl NO5 3H2O: C, 57.56; H,
5.46; N, 2.92. Found: C, 57.58; H, 5.23; N, 2.97. Treatment of
14 (21 mg, 0.05 mmol) in MeOH (2.0 mL) with NaBH4 (12 mg,
(iii) At 50°C w ith ou t Aqu eou s Wor k u p : 9-Ch lor o-6,7-
d im eth oxy-10-m eth yl-10-a zon ia ben z[b]a zu len e Ch lor id e
(25). A solution of 20a (50 mg, 0.17 mmol) in POCl3 (0.8 mL,
8.6 mmol) was stirred at 50 °C for 2 h. After evaporation
washing the residue with Et2O afforded 25 (58 mg, quant) as
a yellow solid, mp 157-159 °C, which was slowly liquefied;
1H NMR (400 MHz, CDCl3+CD3OD) δ 4.32 (3H, s), 4.38 (3H,
s), 4.54 (3H, s), 7.51 (1H, s), 7.66 (1H, t, J ) 8.0 Hz), 7.87 (1H,
d, J ) 8.0 Hz), 7.99 (1H, t, J ) 8.0 Hz), 8.65 (1H, d, J ) 8.0
Hz), 9.02 (1H, s); HRFABMS m/z 288.0786 (M+, C15H15ClNO2
requires m/z 288.0791) and 290.0736 (M+ + 2, C15H15ClNO2
requires m/z 290.0791).
i
0.329 mmol) for 1.5 h gave 13 (R1 ) Pr) (14 mg, 75%).
On the other hand evaporation of the mother liquor followed
by recrystallization from EtOH-Et2O gave 15 (183 mg, 35%)
as dark red needles, mp 253-259 °C; 1H NMR (500 MHz,
DMSO-d6) δ 1.45 (6H, d, J ) 10.0 Hz), 4.81(3H, s), 5.01 (1H,
septet, J ) 10.0 Hz), 6.31 (2H, s), 6.54 (2H, s), 7.68 (1H, s),
8.00 (1H, s), 8.13 (1H, s), 8.20 (1H, d, J ) 10.0 Hz), 9.48 (1H,
d, J ) 10.0 Hz), 10.00 (1H, s); HRFABMS m/z 390.1368 (M+,
C23H20NO5 requires m/z 390.1341). Treatment of 15 (20 mg,
0.05 mmol) in MeOH (1.5 mL) with NaBH4 (11 mg, 0.283
9H-6,7-Dim eth oxy-10-m eth ylben z[b]a za a zu len e (22). A
mixture of 21 (111 mg, 0.41 mmol) and LiAlH4 (47 mg, 1.22
mmol) in THF (19 mL) was refluxed for 1 h. After addition of
water and 20% NaOH, precipitates were removed by filtration
through Celite and washing with EtOAc and MeOH. The
filtrate was evaporated and purified by SiO2 column chroma-
tography (hexane:EtOAc ) 5:1) to give 22 (56 mg, 53%) as
i
mmol) for 1 h gave 12 (R1 ) Pr; R2 ) -CH2-) (14 mg, 83%).
BNR of 2-(4,5-Dim eth oxy-2-h yd r oxyp h en yl)-6,7-m eth -
ylen ed ioxy-1-(N-m et h ylfor m a m id o)n a p h t h a len e (Iso-
a r n ottia n a m id e) (16): 8,9-Dim eth oxy-12-m eth yl-2,3-m e-
th ylen ed ioxy-12-a za a zu len -11-on e (17B). A mixture of 16
(300 mg, 0.79 mmol) and POCl3 (1.2 mL, 13 mmol) in MeCN
(50 mL) was stirred at 80 °C for 1 h. The reaction mixture
was made alkaline with 5% NH4OH and extracted with CHCl3.
After workup, purification of the crude product by SiO2 column
chromatography (CHCl3) followed by washing with MeOH
1
colorless prisms, mp 163-166 °C; H NMR (400 MHz) δ 3.14
(2H, d, J ) 7.6 Hz), 3.59 (3H, s), 3.74 (3H, s), 3.87 (3H, s),
4.89 (1H, t, J ) 7.6 Hz), 6.55 (1H, s), 7.13 (1H, dt, J ) 7.6, 1.1
Hz), 7.19 (1H, dt, J ) 7.6, 1.1 Hz), 7.28 (1H, d, J ) 7.6 Hz),
7.60 (1H, d, J ) 7.6 Hz); 13C NMR (100 MHz) δ 20.3, 29.5,
55.8, 55.9, 94.7, 100.4, 108.7, 109.4, 117.6, 119.6, 121.0, 126.0,
135.2, 137.3, 149.9, 152.8; HRFABMS m/z 255.1252 (M+,
C
16H17NO2 requires m/z 255.1259).

Bischler-Napieralski Reaction
J . Org. Chem., Vol. 65, No. 26, 2000 9151
6-Meth oxy-10-m eth ylben z[b]a za a zu len -9-on e (24). A
mixture of 23 (50 mg, 0.18 mmol) and NaBH4 (83 mg, 2.2
mmol) in MeOH (13 mL) was stirred at room temperature for
1.5 h and extracted with CHCl3. After workup, purification of
the crude product by preparative TLC (hexane:EtOAc ) 2:1)
afforded 24 (56 mg, 53%) as colorless prisms, mp 159-160 °C;
1H NMR (400 MHz) δ 3.93 (3H, s), 4.39 (3H, s), 7.16 (1H, s),
7.16 (1H, d, J ) 1.0 Hz), 7.32 (1H, dt, J ) 8.3, 1.0 Hz), 7.34
(1H, dif s), 7.51 (1H, d, J ) 8.3 Hz), 7.56 (1H, dt, J ) 8.3, 1.0
Hz), 8.06 (1H, d, J ) 8.3 Hz); 13C NMR (100 MHz) δ 33.6, 55.5,
104.4, 110.4, 120.5, 120.8, 123.1, 125.0, 127.7, 131.8, 136.8,
136.8, 140.4, 155.3, 178.4; HRFABMS m/z 240.1010 (M + H+,
EtOAc ) 1:1) afforded 29 (38 mg, 19%) as yellow prisms, mp
1
205-209 °C; IR (Nujol) νmax 1741, 1664 cm-1; H NMR (400
MHz) δ 3.92 (6H, s), 7.11 (1H, s), 7.31 (1H, dd, J ) 8.0, 1.2
Hz), 7.38 (1H, dd, J ) 8.0, 1.2 Hz), 7.42 (1H, d. J ) 8.0 Hz),
7.49 (1H, s), 7.95 (1H, d, J ) 8.0 Hz), 9.92 (1H, s); 13C NMR
(125 MHz) δ 33.6, 56.4, 105.2, 110.08, 110.13, 114.3, 120.7,
122.4, 123.9, 126.1, 133.2, 137.3, 142.9, 157.6, 160.8, 187.7;
HRFABMS m/z 284.0927 (M + H+, C16H14NO4 requires m/z
284.0923). A deformylated product 30 (34 mg, 19%) was also
obtained with recovery of 20h (59 mg, 29%).
Su p p or tin g In for m a tion Ava ila ble: Preparation method
C
15H14NO2 requires m/z 240.1025). Anal. Calcd for C15H13-
and spectral data of the starting aromatic formamides for BNR
NO2: C, 75.30; H, 5.48; N, 5.86. Found: C, 74.91; H, 5.36; N,
5.71.
i
[11 (R1 ) Pr; R2 ) Me or R2 ) -CH2-) and 16, 20a -g, and
20h ], reaction conditions of BNRs in Table 1 and 20b without
aqueous workup, and the spectral data of products obtained,
1H NMR charts of 13 (R ) H), 15, 22, 25, 26, and 29, and
X-ray data of 22 and 29. This material is available free of
charge via the Internet at http://pubs.acs.org.
BNR of 2-(3,6-Dim eth oxy-2-h yd r oxyp h en yl)-N-m eth yl-
for m a n ilid e (20h ): 5-F or m yl-3-m eth oxy-6-[3-(1-m eth yl-
in d oyl)]-2H-p yr a n -2-on e (29). A solution of 20h (202 mg,
0.702 mmol) in POCl3 (3.2 mL, 34.3 mmol) was stirred at 50
°C for 4 h. The reaction mixture was evaporated, poured into
water, and extracted with CHCl3. After workup, purification
of the crude product by SiO2 column chromatography (hexane:
J O0012849