Synthesis of pyrrolo[4,3,2-de]quinolines from 6,7-dimethoxy-4-methylquinoline. Formal total syntheses of damirones A and B, batzelline C, isobatzelline C, discorhabdin C, and makaluvamines A-D

Article abstract of DOI:10.1021/jo961743z

2-Amino-4-nitrophenol and 2-methoxy-5-nitroaniline were converted into the 5-nitroquinolines 6b and 6d, respectively, and then the latter into nitro-acetal 6f. 6,7-Dimethoxy-4-methylquinoline (6g) was nitrated at C-5 and then the methyl substituent conver

Full text of DOI:10.1021/jo961743z

568
J . Org. Chem. 1997, 62, 568-577
Syn th esis of P yr r olo[4,3,2-d e]qu in olin es fr om
6,7-Dim eth oxy-4-m eth ylqu in olin e. F or m a l Tota l Syn th eses of
Da m ir on es A a n d B, Ba tzellin e C, Isoba tzellin e C, Discor h a bd in C,
a n d Ma k a lu va m in es A-D
David Roberts and J ohn A. J oule*
Chemistry Department, University of Manchester, Manchester M13 9PL, U.K.
M. Antonieta Bros and Mercedes Alvarez*
Laboratori de Quı´mica Orga`nica, Facultat de Farma`cia, Universitat de Barcelona,
08028 Barcelona, Spain
Received September 11, 1996X
2-Amino-4-nitrophenol and 2-methoxy-5-nitroaniline were converted into the 5-nitroquinolines 6b
and 6d , respectively, and then the latter into nitro-acetal 6f. 6,7-Dimethoxy-4-methylquinoline
(6g) was nitrated at C-5 and then the methyl substituent converted into aldehyde 6j and then
protected giving acetal 6l. Various means, notably a large excess of NiCl2/NaBH4, were used to
reduce both nitro group and pyridine ring, forming 1,2,3,4-tetrahydroquinolines such as 7b, 7c,
7d , which under acidic conditions closed to give 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolines 9a ,
9d , 9c, respectively. In some cases it was unnecessary to protect the aldehyde function, for example
quinolinium salt 12c gave 9j and nitro-aldehyde 6j gave 9e (after BOC protection) directly by
reaction with NiCl2/NaBH4. Substitution of the indole and aniline nitrogens in the 1,3,4,5-
tetrahydropyrrolo[4,3,2-de]quinolines was based on a combination of protection, selective depro-
tection, and the exploitation of the greater acidity of the indole N-hydrogen. 8-Chlorination of 6h
and then conversions, as above, gave chloro-diamine-acetal 7e which on acid treatment produced
iminoquinone 11b; formylation of the nitrogens in 7e and then acidic treatment allowed formation
of the chlorine-substituted 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline 9m which was then converted
into 9p . De-O-methylation and then oxidation of 9b and 9c gave o-quinones 10b and 10a ,
respectively.
In tr od u ction
dropyrrolo[4,3,2-de]quinoline nucleus. Many11 possess
potentially valuable biological activitysthe makalu-
vamines and wakayin, for example, exhibit potent in vitro
cytotoxicity against human colon tumor cell line HCT116;
they are topoisomerase II inhibitors.7,11
The 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline ring
system was first recognized as a component of a natural
product when the structure of the toad poison, dehy-
drobufotenine, 1, was elucidated.1 Much more recently,
several marine alkaloids2 such as the tricyclic batzel-
lines,3 isobatzellines,4 and damirones,5 and more complex
structures such as wakayin,6 the makaluvamines,7 the
discorhabdines,8 prianosines,9 and epinardins,10 have
been described which are also based on a 1,3,4,5-tetrahy-
X Abstract published in Advance ACS Abstracts, December 15, 1996.
(1) Ma¨rki, F.; Robertson, A. V.; Witkop, B. J . Am. Chem. Soc. 1961,
83, 3341. Robinson, B.; Smith, G. F.; J ackson, A. H.; Shaw, D.;
Frydman, B.; Deulofeu, V. Proc. Chem. Soc. (London) 1961, 310.
(2) Marine Nitrogen-Containing Heterocyclic Natural Products. 1.
Structures and Syntheses of Compounds Containing Quinoline and/
or Isoquinoline Units. Salas, M.; Alvarez, M; J oule, J . A. Heterocycles
1991, 32, 759. Marine Nitrogen-Containing Heterocyclic Natural
Products. 2. Structures and Syntheses of Compounds Containing Indole
Units. ibid. 1991, 32, 1391.
In most synthetic work relating to these natural
products, so far described, including preparations of the
unsubstituted12,13 and 1-methyl14 tricyclic system, of
O-methylnordehydrobufotenine,15 dehydrobufotenine it-
self,16 and of batzelline C and isobatzelline C,17,18 dis-
(9) Kobayashi, J .; Cheng, J .-F.; Ishibashi, M.; Nakamura, H.;
Ohizumi, Y.; Hirata, Y.; Sasaki, T.; Lu, H.; Clardy, J . Tetrahedron Lett.
1987, 28, 4939. Cheng, J .-F.; Ohizumi, Y.; Wa¨lchli, M. R.; Nakamura,
H.; Hirata, Y.; Sasaki, T.; Kobayashi, J . J . Org. Chem. 1988, 53, 4621.
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hedron 1996, 55, 8899.
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Tetrahedron Lett. 1989, 30, 2517.
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1990, 55, 4964.
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(6) Copp, B. R.; Ireland, C. M.; Barrows, L. R. J . Org. Chem. 1991,
56, 4596.
(7) Radisky, D. C.; Radisky, E. S.; Barrows, L. R.; Copp, B. R.;
Kramer, R. A.; Ireland, C. M. J . Am. Chem. Soc. 1993, 115, 1632.
Barrows, L. R.; Radisky, D. C.; Copp, B. R.; Swaffer, D. S.; Kramer, R.
A.; Warters, R. C.; Ireland, C. M. Anti-Cancer Drug Des. 1993, 8, 333.
Ireland, C. M.; Radisky, D. C.; Barrows, L. R.; Kramer, R. A., US Patent
5,414,001 (Chem. Abstr. 1995, 123, 111835).
(11) Wang, H.; Al-Said, N. H.; Lown, J . W. Tetrahedron Lett. 1994,
35, 4085.
(12) Hester, J . B. J . Org. Chem. 1964, 29, 1158.
(13) Hamabuchi, S.; Hamada, H.; Hironaka, A.; Somei, M. Hetero-
cycles 1991, 32, 443.
(14) J ulia, M.; Huang, Y.; Igolen, J . C. R. Hebd. Seances Acad. Sci.
1967, 265, 110.
(15) Lee, F. G. H.; Daly, J . W.; Manian, A. A. J . Med. Chem. 1969,
12, 321.
(8) Perry, N. B.; Blunt, J . W.; McCombs, J . D.; Munro, M. H. G. J .
Org. Chem. 1986, 51, 5476. Perry, N. B.; Blunt, J . W.; Munro, M. H.
G. Tetrahedron 1988, 44, 1727; Perry, N. B.; Blunt, J . W.; Munro, M.
H. G.; Higa, T.; Sakai, R. J . Org. Chem. 1988, 53, 4127.
(16) Gannon, W. F.; Benigni, J . D.; Suzuki, J .; Daly, J . W. Tetra-
hedron Lett. 1967, 1531.
(17) Tao, X. L.; Nishiyama, S.; Yamamura, S. Chem. Lett. 1991,
1785.
S0022-3263(96)01743-4 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Pyrrolo[4,3,2-de]quinolines
J . Org. Chem., Vol. 62, No. 3, 1997 569
Sch em e 1
corhabdin C,18-20 and damirone A21-23 and B,21,23 makalu-
vamine D,20,24 makaluvamines A-E,25 and the structurally
related mushroom pigment haematopodin,26 the tricyclic
heterocycle has been constructed from an indole, i.e. by
forming the six-membered nitrogen-containing ring as a
late step, by cyclization either of a 4-aminoindole carrying
a two-carbon chain at its C-3, or of a tryptamine quinone.
We have been developing27,28 an alternative strategy,
namely the construction of such molecules starting from
a quinoline; recently two other groups have also described
approaches to these tricycles from quinoline or reduced
quinoline intermediates29,30 and one of these was taken
through to dehydrobufotenine, damirones A and B, and
makaluvamine C.29 Scheme 1 summarizes our strategy,
showing the development of a 4-methylquinoline A into
a 5-amino-1,2,3,4-tetrahydroquinoline-4-aldehyde B in
which closure of the pyrrole ring produces target tricycle
C. We have detailed27 syntheses of 8-methoxy-1,3,4,5-
tetrahydropyrrolo[4,3,2-de]quinoline starting from a simple
quinoline, 6-methoxy-4-methylquinoline. This paper de-
scribes our further work in this area, some of which has
been published in preliminary form,28 which constitutes
formal total syntheses of damirones A, 2a , and B, 2b,
batzelline C, 2c, isobatzelline C, 3a , makaluvamines
A-D, 3b-e, respectively, and discorhabdin C, 4.
5b converted in 24% yield into quinoline 6a by reaction
with methyl vinyl ketone using sodium 3-nitrobenzene-
sulfonate31 as oxidant. Exposure to copper(II) nitrate in
acetic anhydride produced the nitroquinoline 6b. Alter-
natively, 2-methoxy-5-nitroaniline, following N-mesyla-
tion (f 5c), was reduced and the resulting aniline 5d
comparably converted into a quinoline 6c, this time
accompanied by a minor amount of its 1,2,3,4-tetrahydro
derivative 7a .
Resu lts a n d Discu ssion
Noting the presence and location of a nitrogen sub-
stituent on the homocyclic ring in many of these alka-
loids, for example, 3, we planned to extend our earlier
work by starting from a quinoline which carried a
nitrogen substituent already in place at C-7. 2-Amino-
4-nitrophenol was mesylated on both oxygen and nitrogen
(f 5a ) and catalytically reduced and the resulting amine
(18) Tao, X. L.; Cheng, J .-F; Nishiyama, S.; Yamamura, S. Tetra-
hedron 1994, 50, 2017.
(19) Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T. J .
Am. Chem. Soc. 1992, 114, 2175.
(20) Sadanandan, E. V.; Pillai, S. K.; Lakshmikantham, M. V.;
Billimoria, A. D.; Culpepper, J . S.; Cava, M. P. J . Org. Chem. 1995,
60, 1800.
(21) Sadanandan, E. V.; Cava, M. P. Tetrahedron Lett. 1993, 34,
2405.
(22) Yamada, F.; Hamabuchi, S.; Shimizu, A.; Somei, M. Heterocycles
1995, 41, 1905.
(23) Baumann, C.; Bro¨ckelmann, M.; Fugmann, B.; Steffan, B.;
Steglich, W.; Sheldrick, W. S. Angew. Chem., Int. Ed. Engl. 1993, 32,
1087.
(24) White, J . D.; Yager, K. M.; Yakura, T. J . Am. Chem. Soc. 1994,
116, 1831.
(25) Izawa, T.; Nishiyama, S.; Yamamura, S. Tetrahedron 1994, 50,
13593.
(26) Hopmann, C.; Steglich, W. Liebigs Ann. 1996, 1117.
(27) Balczewski, P.; J oule, J . A.; Este´vez, C.; Alvarez, M. J . Org.
Chem. 1994, 59, 4571. Este´vez, C.; Venemalm, L.; Alvarez, M.; J oule,
J . A. Tetrahedron 1994, 50, 7879.
(28) Roberts, D.; Venemalm, L.; Alvarez, M.; J oule, J . A. Tetrahedron
Lett. 1994, 35, 7857; Roberts, D.; Alvarez, M.; J oule, J . A. Tetrahedron
Lett. 1996, 37, 1509.
As before, reaction of 6c with copper(II) nitrate in
acetic anhydride brought about two desired changes,
nitration at C-5, and further protection of the 7-amino
substituent proceeded in 59% yield, giving quinoline 6d .
Earlier experiments with similar quinolines, but without
this double protection of an amino substituent, had
shown that oxidation of the 4-methyl, following the
protocol32 (I2/t-BuI/FeCl2/TFA/DMSO) which had proved
useful27 in other related situations, had been totally
(31) Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 59.
(32) Vismara, E.; Fontana, F.; Minisci, F. Gazz. Chim. Ital. 1987,
117, 135.
(29) Peat, A. J .; Buchwald, S. L. J . Am. Chem. Soc. 1996, 118, 1028.
(30) Makosza, M.; Stalewski, J . Tetrahedron 1995, 51, 7263.

570 J . Org. Chem., Vol. 62, No. 3, 1997
Roberts et al.
Sch em e 2a
Sch em e 3a
a
Reagents: (i) NiCl2, NaBH4, MeOH; (ii) TsCl, Et3N then
NaOMe, MeOH, 50 °C; (iii) aqueous 1 N HCl, THF, 80 °C; (iv)
aqueous 1 N HCl, THF, 40 °C.
borane and then REDAL followed by quenching with
methyl chloroformate33 produced the 1,2-dihydroquino-
line 8a . Catalytic reduction of 8a gave an unstable
amine-acetal 7b, now at the appropriate oxidation level
for ring closure to an indole, which was simply achieved
in dilute hydrochloric acid in THF at 55 °C giving 9a ,
characterized as its N-tosyl derivative 9b, the overall
yield from 6j being 7% for the five steps, summarized in
Scheme 2.
Reduction of both nitro group and heterocyclic ring in
6l, in one pot, to produce 7c was achieved with a large
excess of a combination of sodium borohydride and nickel
chloride. Initially, we were cautious over the handling
of this electron-rich benzene, and the indole which would
be obtained from it, and we took the precaution of
converting it into its bis-N-tosyl derivative 7d before
proceeding. Then, as before, mild dilute acid treatment
of 7d effected acetal hydrolysis and ring closure to give
9c in 19% yield for a four-step sequence, summarized in
Scheme 3.
a
Reagents: (i) fuming HNO3, -30 °C; (ii) I2, DMSO, TFA, t-BuI,
FeCl2, 80 °C; (iii) MeOH, HCl, reflux; (iv) BH3‚THF, -78 °C then
REDAL, -78 °C then ClCO2Me; (v) H2, Pd-C, EtOH; (vi) aqueous
1 N HCl, THF, 55 °C; (vii) Bu4NHSO4, NaOH, TsCl.
unsuccessful; however, oxidation of 6d produced aldehyde
6e, albeit in only 54% yield, accompanied by starting
material from which it was very difficult to separate. A
small quantity was characterized; it was also shown that
it could be protected as its acetal 6f.
In view of the practical problems encountered in
handling quinolines 6a -f and also because at this point
it had become clear11,18-20,25 that nitrogen substituents
could be introduced with displacement of methoxide in
late intermediates for the synthesis of these alkaloids,
we turned to the use of 6,7-dimethoxy-4-methylquinoline
(6g), easily produced from reaction of 4-aminoveratrole
with methyl vinyl ketone and ferric chloride. Nitration
of 6g proceeded regioselectively, at <-40 °C, to give the
5-nitro derivative 6h in 63% yield (reaction at 0 °C caused
5,8-dinitration giving 6i) and this, in turn, could be
oxidized to aldehyde 6j.
Our plans now required reduction of the nitro group
and the heterocyclic ring without reduction of the alde-
hyde group. A second consideration was control over the
substitution of the two nitrogen atoms for the various
target natural products. We devised several variants
whereby these aims could be achieved.
Reaction of the doubly protected tricycles 9b and 9c
with BBr3 and then immediate oxidation with CAN,
without purification, gave us the o-quinones 10a (92%)
and 10b (70%). Methanolysis of 10a in the presence of
K2CO3 gave the iminoquinone 11a , though in very low
yield (see later for an efficient synthesis of 11b).
Subsequently, we found that hydrolysis of 7c without
prior N-protection produced the unprotected indole 9d
in 64% yield and that it could be handled, with care, and
characterized. Even more extraordinary, we discovered
that protection of the aldehyde function was unnecessary,
for exposure of nitro-aldehyde 6j to a large excess of
NiCl2/NaBH4, followed by (BOC)2O gave the monopro-
tected tricyclic indole 9e in 19% yield without isolation
of intermediates. Base-promoted indole N-tosylation of
this (f 9f) and then removal of the BOC gave the
alternatively protected 9g, which has been converted in
other work25 into 11a , while base-promoted indole N-
methylation (f 9h ) and then deprotection gave 9i ef-
ficiently.
The obvious route to the preparation of tricycles with
a methyl group on the other ring nitrogen seemed to be
Treatment of the nitro-aldehyde with sodium borohy-
dride simply gave the alcohol 6k . Protection of the
aldehyde functionality as acetal 6l and exposure to
(33) Minter, D. E.; Stotter, P. L. J . Org. Chem. 1981, 46, 3965.

Synthesis of Pyrrolo[4,3,2-de]quinolines
J . Org. Chem., Vol. 62, No. 3, 1997 571
Sch em e 4a
a quinoline-N-quaternization at an early stage, to be
followed by ring reduction, expected to be easier than for
the neutral molecules. However, reaction of nitro-acetal
6l with iodomethane under normal conditions led to a
zwitterionic product, 12a in which O-demethylation had
occurred, as well as the desired N-methylation. The
structure of this unexpected product was secured by
borohydride reduction to an unstable dihydroquinoline
characterized as its O-tosyl derivative 8b. That it is the
6-methoxyl which had suffered demethylation was de-
duced from an NMR study of 8b in which an NOE effect
was found between the remaining 7-methoxyl hydrogens
and the aromatic proton at C-8. Intrigued by the demeth-
ylation process we carried out two model N-methyla-
tions: both 6g and 6h underwent reaction with iodo-
methane in a normal fashion. It seems that the presence
of both a 5-nitro group and a 4-substituent larger than
methyl are required to promote the demethylation. From
reaction at 30 °C, the normal methiodide 12b could be
obtained. Quaternization of 6j could be achieved with
trimethyloxonium borofluoride producing 12c which was
used without purification.
a
Reagents: (i) Me3OBF4, CH2Cl2; (ii) NiCl2, NaBH4, MeOH; (iii)
TsCl, Bu4NHSO4, NaOH; (iv) BBr3, CH2Cl2, -78 °C; (v) air.
Sch em e 5
Sch em e 6a
Reduction of salt 12b with NaBH4 produced the dihy-
droquinoline 8c, whereas the use of the NiCl2/NaBH4
combination on salt 12c gave tricyclic indole 9j, in 12%
yield, converted into its indole N-tosyl derivative 9k . As
before, de-O-methylation and then ceric ammonium
nitrate (CAN) oxidation produced a tricyclic o-quinone
10c (Scheme 4).
Several of the pyrrolo[4,3,2-de]quinoline-containing
alkaloids have a chlorine substituent at C-6. It seemed
possible that electrophilic chlorination of a suitably
protected 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline
might take place at that position, being an activated
benzene ring position. This was attempted using 9h , but
chlorination occurred instead at C-2, the pyrrole ring
R-position, forming 9l. This meant that it would be
necessary to carry the chlorine through the sequence
from the beginning, so the nitroquinoline 6h was reacted
with N-chlorosuccinimide giving 6m accompanied by
minor amounts of side-chain-chlorinated quinolines 6n
and 6o. The chloronitroquinoline 6m was oxidized in the
usual way giving aldehyde 6p , protected as acetal 6q,
and then reduced to the aminotetrahydroquinoline 7e in
28% overall yield from 6h , the scene now being set, we
assumed, for ring closure to a tricyclic chloroindole.
a
Reagents: (i) NCS, DMF, 60 °C; (ii) I2, DMSO, TFA, t-BuI,
FeCl2, 80 °C; (iii) MeOH, HCl, reflux; (iv) NiCl2, NaBH4, MeOH;
(v) aqueous 1 N HCl, THF, 40 °C; (vi) HCO2H, Ac2O; (vii) aqueous
NaOH, CH2Cl2; (viii) MeI, NaH; (ix) aqueous NaOH, reflux.
target systems had occurred: 9m and 13 were isolated
in 54 and 10% yields, respectively. It was further shown
that the latter could be easily transformed into the former
by refluxing in formic acid.
It was a suprise to find that mild acidic treatment of
7e gave iminoquinone 11b in 64% yield. This serendip-
tiously now provides an excellent six-step route to this
key compound (see below) from the simple, starting
quinoline, 6g. We explain this result by postulating an
electrophilic protonation of the electron-rich benzene ring,
either before or after pyrrole ring formation (Scheme 5
shows a sequence assuming this to take place before
pyrrole formation).
On the basis of this rationalization, we argued that
reducing the nucleophilic character of the benzene ring
might prevent the loss of halogen and this we sought to
do by formylation of both amine groups in 7e. Treatment
with Ac2O/HCO2H produced a mixture of doubly formy-
lated products in which, in addition, ring closure to the
Selective hydrolysis of the indole N-formyl (f 9n ) and
then indole N-methylation produced 9o, stronger alkaline
hydrolysis of which gave 9p ; transformations in the
chloro series are summarized in Scheme 6.
Syn th esis of Ma r in e Alk a loid s. The indole 9i has
been converted by ceric ammonium nitrate (CAN) oxida-
tion to the corresponding iminoquinone (60%) followed
by displacement of the methoxyl with ammonium chlo-

572 J . Org. Chem., Vol. 62, No. 3, 1997
Roberts et al.
eluting with CH2Cl2-MeOH (98:2) to give 6a (0.89 g, 24%).
Mp 117-121 °C (CH2Cl2/i-Pr2O). IR (KBr) 3298, 1308. 1H-
NMR (200 MHz) 2.69 (s, 3H); 3.19 (s, 3H); 3.41 (s, 3H); 7.24
(d, J ) 4.4, 1H); 7.98 (s, 1H); 8.33 (s, 1H); 8.80 (d, J ) 4.4,
1H). 13C-NMR (75 MHz) 18.4 (q); 36.0 (q); 39.8 (q); 117.9 (d);
122.0 (d); 125.2 (s); 132.0 (s); 139.3 (s); 145.2 (s); 146.2 (s); 151.0
(d). MS (EI) 330 (M+, 39); 251 (94); 173 (100); 145 (90) Anal.
Calcd for C12H14N2O5S2: C, 43.63; H, 4.24; N, 8.48. Found:
C, 43.76; H, 4.42; N, 8.10.
ride (98%) giving makaluvamine A, 3b, and this was then
dehydrogenated (41%) with palladium on charcoal giving
makaluvamine B, 3c.26 Comparably, indole 9j was
oxidized with CAN then reacted with ammonia affording
makaluvamine C, 3d (reported26 26% overall yield in-
cluded a reduction of a precursor lactam to generate 9j).
Makaluvamine D, 3e, was produced from indole 9d by
CAN oxidation (51%),19 producing 11b which was then
reacted with tyramine (92%),26 or from 11a , as its
toluenesulfonate salt (91%).25 A precursor which was
used for an electrochemical closure giving discorhabdin
C, 4 (24%), resulted from reaction of 11b, produced again
by CAN oxidation of 9d , and then methoxyl displacement
in this case with 3,5-dibromotyramine26 or from tosyl-
protected iminoquinone 11a directly.21 The tosyl-pro-
tected o-quinone 10c upon sodium hydroxide hydrolysis
gave damirone B, 2b, indole N-methylation of which with
iodomethane and base gave damirone A, 2a .22 Finally,
boron tribromide de-O-methylation (78%) and then air
oxidation (64%) of 9p produced batzelline C, 2c; CAN
oxidation followed by displacement of methoxyl with
ammonia (64%) gave isobatzelline C, 3a .19
7-[(Meth an esu lfon yl)acetylam in o]-6-(m esyloxy)-4-m eth -
yl-5-n itr oqu in olin e (6b). To a solution of 6a (150 mg, 0.4
mmol) in AcOH (3 mL) cooled at -78 °C and under nitrogen,
Cu(NO3)2‚3H2O (0.11 g, 0.59 mmol) in AcOH (6 mL) was added
during 6 min. The reaction mixture was stirred at rt for 30
min and 1 h at 80 °C; during this time the color of the reaction
mixture changed to green. The reaction mixture was poured
over ice and extracted with CH2Cl2, the extract was washed
with aqueous 2 N NaOH and then brine, and then dried and
concentrated to give crude material (158 mg) which was
purified by column chromatography, eluting with C6H14-CH2-
Cl2 (3:7-1:9) to give 6b (77 mg, 40%). Mp 153-158 °C (CH2-
Cl2-iPr2O). IR (KBr) 3428, 1722, 1547, 1363. 1H-NMR (300
MHz) 2.13 (3H, s); 2.79 (3H, s); 3.46 (s, 3H); 3.51 (s, 3H); 7.51
(d, J ) 4.4, 1H); 8.36 (s, 1H); 8.93 (d, J ) 4.4, 1H). 13C-NMR
(75 MHz) 18.9 (q); 23.8 (q); 39.6 (q); 43.0 (q); 118.6 (d); 125.4
(d); 130.1 (s); 137.6 (s); 142.5 (s); 145.2 (s); 153.4 (d); 170.3 (s).
MS (EI) 417 (M+, 0.1); 376 (8); 375 (42); 329 (57); 296 (100);
280 (53); 201 (44); 267 (35). Anal. Calcd for C14H15N3O8S2:
C, 40.28; H, 3.62; N, 10.07; S, 15.38. Found: C, 40.37; H, 3.92;
N, 9.78; S, 15.19.
Exp er im en ta l Section
Gen er a l. Proton and carbon nuclear magnetic resonance
spectra were recorded in CDCl3 unless otherwise specified. For
infrared spectra, only structurally significant peaks are listed.
UV spectra were determined in 95% EtOH unless otherwise
stated. Melting points are uncorrected. Tetrahydrofuran was
dried over sodium/benzophenone and then distilled under an
atmosphere of dry N2, or anhydrous commercial solvent was
used. Dichloromethane was distilled from CaH2. TLC and
column chromatography was carried out using SiO2. Organic
extracts were dried over anhydrous Na2SO4 or MgSO4, and
dried solutions were evaporated under reduced presure with
a rotatory evaporator.
4-(Mesyloxy)-3-(m et h a n esu lfon a m id o)n it r ob en zen e
(5a ). MsCl (7.5 g, 65 mmol) was added slowly to a solution of
2-amino-4-nitrophenol (5 g, 32.5 mmol) in pyridine (65 mL)
at 0 °C. After 30 min the reaction mixture was stirred for 4
h at rt and then poured onto ice and the resulting precipitate
filtered, washed several times with H2O and Et2O, and dried
in vacuo at 50 °C to give 5a (9.15 g, 91%). Mp 179-182 °C
(CH2Cl2-MeOH). IR (KBr): 3267, 1532, 1351, 1337. 1H-NMR
(200 MHz, DMSO-d6) 3.16 (s, 3H); 3.62 (s, 3H); 7.70 (d, J )
9.0, 1H); 8.06 (dd, J ) 9.0 and 2.8, 1H); 8.38 (d, J ) 2.8, 1H);
10.12 (bs, 1H). 13C-NMR (50.3 MHz, DMSO-d6) 37.8 (q); 40.5
(q); 108.7 (d); 110.8 (d); 123.8 (d); 130.8 (s); 131.1 (s); 148.4
(s). MS (EI) 312 (M + 2, 3); 311 (M + 1, 3); 310 (M+, 19); 230
(84); 153 (100).
4-(Mesyloxy)-3-(m eth a n esu lfon a m id o)a n ilin e (5b). 5a
(5 g, 16.1 mmol) was dissolved in DMF (25 mL) and hydroge-
nated at 100 psi over 10% Pt/C (0.5 g) at 20 °C for 3 h. The
mixture was filtered through Celite and concentrated to give
a dark red gum which was crystallized from CH2Cl2-Et2O to
yield 5b (4.2 g, 93%). Mp 139-142 °C. IR (KBr) 3475, 3375,
3295, 1328, 1151. 1H-NMR (300 MHz, DMSO-d6) 3.02 (s, 3H);
3.35 (s, 3H); 5.45 (bs, 2H); 6.35 (dd, J ) 8.8 and 2.6, 1H); 6.71
(d, J ) 2.6, 1H); 7.02 (d, J ) 8.8, 1H); 9.09 (bs, 1H). 13C-NMR
(50.3 MHz, DMSO-d6) 38.8 (q); 40.8 (q); 117.9 (d); 120.4 (d);
123.8 (d); 131.7 (s); 144.3 (s); 146.0 (s). MS (EI) 280 (M+, 5);
201 (100); 123 (74).
6-(Mesyloxy)-7-(m eth a n esu lfon a m id o)-4-m eth ylqu in o-
lin e (6a ). Sodium m-nitrobenzenesulfonate (2.55 g, 11.3
mmol) was added to a solution of 5b (3.17 g, 11.3 mmol) in
AcOH (150 mL) under N2. The mixture was warmed at 85
°C, and methyl vinyl ketone (0.8 g, 11.3 mmol) was added
during 2 min. The reaction mixture was stirred at reflux for
4 h. The solvent was removed in vacuo, and to the solid
residue excess saturated aqueous NaHCO3 was added. The
aqueous layer was extracted with CH2Cl2, and the organic
extract was washed with brine, dried, and concentrated to give
an oil (2.62 g) which was purified by column chromatography,
3-(Meth a n esu lfon a m id o)-4-m eth oxyn itr oben zen e (5c).
MsCl (6.8 g, 59.5 mmol) was added drop by drop to a solution
of 2-methoxy-5-nitroaniline (10 g, 59.5 mmol) in pyridine (30
mL) cooled at 0 °C under N2. After 30 min the reaction
mixture was stirred for 4 h at rt. The white suspension
obtained was poured onto ice and filtered. The solid residue
was washed with H2O and Et2O and dried in vacuo at 50 °C
to yield 5c (14.3 g, 98%). Mp 162-166 °C (CH2Cl2-MeOH)).
IR (KBr) 1596, 1508, 1340. 1H-NMR (200 MHz, DMSO-d6)
3.05 (s, 3H); 3.96 (s, 3H); 7.28 (d, J ) 8.8, 1H); 8.10 (dd, J )
8.8 and 2.8, 1H); 9.45 (d, J ) 2.8, 1H). 13C-NMR (50.3 MHz,
DMSO-d6) 40.1 (q); 57.0 (q); 112.0 (d); 118.5 (d); 122.2 (d); 127.1
(s); 140.7 (s); 157.0 (s). MS (EI) 246 (M+, 19); 167 (100); 121
(37); 79 (24).
3-(Met h a n esu lfon a m id o)-4-m et h oxya n ilin e (5d ). 5c
(7 g, 28.4 mmol) dissolved in DMF (43 mL) was hydrogenated
at 100 psi over 10% Pt/C (0.7 g) at 20 °C for 4 h. The mixture
was filtered through Celite and concentrated to give the crude
material as a solid which was crystallized from CH2Cl2-Et2O
to yield 5d (5.8 g, 95%). Mp 123-126 °C (CH2Cl2-Et2O). IR
(KBr) 1732, 1589, 1416. 1H-NMR (200 MHz) 2.90 (s, 3H); 3.67
(s, 3H); 4.75 (bs, 2H); 6.37 (dd, J ) 8.6 and 2.0, 1H); 6.58 (d,
J ) 2.0, 1H); 6.76 (d, J ) 8.6, 1H) 8.56 (bs, 1H). 13C-NMR
(50.3 MHz, DMSO-d6) 40.0 (q); 56.6 (q); 111.6 (d); 111.7 (s);
113.6 (d); 126.6 (s); 142.9 (d); 143.7 (s). MS (EI) 216 (M+, 100);
201 (72); 123 (48); 110 (63); 92 (45).
1,2,3,4-Tetr ah ydr o-7-(m eth an esu lfon am ido)-6-m eth oxy-
4-m eth ylqu in olin e (7a ) a n d 7-(Meth a n esu lfon a m id o)-6-
m eth oxy-4-m eth ylqu in olin e (6c). Sodium m-nitrobenzen-
sulfonate (14.1 g, 62.5 mmol) was added to a solution of 5d (9
g, 41.7 mmol) in AcOH (560 mL) under N2. The mixture was
warmed to 85 °C, and methyl vinyl ketone (2.9 g, 41.7 mmol)
was added during 5 min. The reaction was refluxed for 5 h.
The solvent was evaporated, excess saturated aqueous NaH-
CO3 added, and then organic material extracted with CH2Cl2.
The organic layer was washed with brine, dried, and evapo-
rated to give a crude product (9.8 g) which was purified by
column chromatography. On elution with CH2Cl2 and CH2-
Cl2-MeOH (99:1), 7a was obtained (1.3 g, 12%). Mp 88-90
°C (Me2CO-iPr2O). IR (KBr) 3407, 3268, 1511, 1326. 1H-NMR
(300 MHz) 1.28 (d, J ) 6.9, 3H); 1.60-1.71 (m, 1H); 1.90-
2.03 (m, 1H); 2.90-2.94 (m, 1H); 2.95 (s, 2H); 3.16-3.33 (m,
2H); 3.80 (s, 3H); 6.65 (s, 1H); 6.74 (s, 1H). 13C-NMR (54 MHz)
22.6 (q); 29.6 (t); 29.9 (d); 38.5 (q); 38.8 (t); 56.1 (q); 107.7 (d);
111.4 (d); 123.8 (s); 124.4 (s); 138.1 (s); 141.9 (s). MS (EI) 270
(M + 1, 65); 269 (M+, 0.3); 255 (100); 256 (14); 164 (42); 149

Synthesis of Pyrrolo[4,3,2-de]quinolines
J . Org. Chem., Vol. 62, No. 3, 1997 573
(39). Anal. Calcd for C14H18N3O3S: C, 53.31; H, 6,71; N, 10,-
36. Found: C, 53.10; H, 6.84; N, 10.18.
vol), dried, and concentrated to give the crude product which
was recrystallized from Et2O to give a brown solid (1.35 g,
66%). Mp 112-112.5 °C. UV 216 (4.16), 220 (4.21), 240 (4.48),
316 (3.90), 330 (4.05); IR (film) 1618, 1590, 1503; 1H-NMR (300
MHz) 2.73 (s, 3H); 4.09 (s, 6H); 7.20 (s, 1H); 7.21 (d, J ) 4.7,
1H); 7.59 (s, 1H); 8.62 (d, J ) 4.7, 1H). 13C-NMR (75 MHz)
18.8 (q); 56.0 (q); 101.5 (d); 108.3 (d); 120.4 (d); 123.5 (s); 142.5
(s); 144.8 (s); 147.7 (d); 149.4 (s); 152.0 (s). MS (CI) 204 (M +
1, 100). Anal. Calcd for C12H13NO2: C, 70.9; H, 6.45; N, 6.9.
Found: C, 71.0; H, 6.45; N, 6.8.
6,7-Dim et h oxy-4-m et h yl-5-n it r oq u in olin e (6h ). 6g
(4.4 g, 21.6 mmol) was added over 1 h, in portions, to fuming
HNO3 (68 mL) and cooled to between -50 °C and -40 °C under
argon. The mixture was left to stir for 25 min, keeping the
temperature below -30 °C. The reaction mixture was then
poured onto ice and the temperature maintained between -20
°C to 0 °C while neutralizing the acid with aqueous NaOH
(50% wt/vol, 160 mL). The mixture was rigorously extracted
with CH2Cl2. The combined organic extracts were washed
with aqueous K2CO3 (10% wt/vol), dried, and concentrated to
give a brown solid (3.43 g, 63%). Mp 128 °C. UV 216 (4.13),
220 (4.18), 224 (4.20), 228 (4.26), 232 (4.33), 236 (4.36), 280
(3.46), 318 (3.50), 330 (3.61). IR (film) 1618, 1582, 1447. 1H-
NMR (300 MHz) 2.63 (s, 3H); 4.07 (s, 3H); 4.13 (s, 3H); 7.29
(d, J ) 4.7, 1H); 7.83 (s, 1H); 8.73 (d, J ) 4.7, 1H). 13C-NMR
(75 MHz) 18.4 (q); 56.4 (q); 62.7 (q); 111.7 (d); 114.9 (s); 123.6
(d); 140.9 (s); 141.1 (s); 142.4 (s); 145.8 (s); 150.1 (d); 153.6 (s).
MS (EI) 248 (M+, 100). HRMS: calcd for C12H12N2O4 248.0797,
found 248.0807. Anal. Calcd for C12H12N2O4: C, 58.1; H, 4.87;
N, 11.29. Found: C, 58.0; H, 4.93; N, 11.29.
6,7-Dim eth oxy-4-m eth yl-5,8-d in itr oqu in olin e (6i). 6g
(500 mg, 2.02 mmol) was dissolved in concd H2SO4 (10 mL)
and cooled to 0 °C, and then concd HNO3 (30 mL) was added
dropwise then the mixture was stirred for 1 h. The mixture
was made basic by the careful addition of aqueous NaOH (50%
wt/vol), filtered through Celite, and extracted with CH2Cl2. The
combined organic extracts were dried and concentrated to give
the title compound as a yellow solid (295 mg, 50%). Mp 151-
153 °C. UV 220 (4.47), 236 (4.58), 282 (4.01), 326 (3.94); IR
(film) 1586, 1534, 1490, 1357. 1H-NMR (300 MHz) 2.63 (s, 3H);
4.12 (s, 3H); 4.17 (s, 3H); 7.39 (d, J ) 4.5, 1H); 8.84 (d, J )
4.5, 1H). MS (EI) 293 (M+, 74), 276 (41), 263 (4), 248 (5), 231
(11), 58 (50), 43 (100). HRMS: calcd for C12H11N3O6 293.0648,
found 293.0651.
4-F or m yl-6,7-d im eth oxy-5-n itr oqu in olin e (6j). To 6h
(6.1 g, 23.3 mmol) in DMSO (102 mL) were added TFA (2.23
mL, 29 mmol), t-BuI (0.61 mL, 5.12 mmol), I2 (5.94 g, 23.4
mmol), and FeCl2 (276 mg, 1.38 mmol), and the reaction
mixture was heated at 80-85 °C for 5 h. The DMSO was
removed in vacuo, and the resulting crude red oil was washed
with aqueous Na2S2O3 (20% wt/vol) and then with aqueous K2-
CO3 (10% wt/vol) and extracted with CH2Cl2 (3 × 50 mL). The
combined organic extracts were then washed again with
thiosulfate and carbonate solutions, dried, and concentrated
to give 6h as a yellow solid (4.71 g, 73%). Mp 120-121°C.
UV 218 (4.38), 236 (4.49), 292 (3.67), 320 (3.81), 336 (3.92). IR
(film) 1706, 1619, 1537. 1H-NMR (300 MHz) 4.14 (s, 3H); 4.16
(s, 3H); 7.77 (m, 2H); 9.09 (d, J ) 4.4, 1H); 10.26 (s, 1H). 13C-
NMR (75 MHz) 56.6 (q); 63.0 (q); 111.5 (s); 112.4 (d); 122.0
(d); 137.5 (s); 139.8 (s); 144.9 (s); 146.3 (s); 150.4 (d); 154.8 (s);
189.4 (d). MS (CI) 280 (M + 18, 100), 263 (M + 1, 52).
HRMS: calcd for C12H10N2O5 262.0590, found 262.0589. Anal.
Calcd for C12H10N2O5: C, 55.0; H, 3.84; N, 10.7. Found: C,
55.1; H, 3.90; N, 10.7.
Further elution (CH2Cl2-MeOH; 98:2-96:4) gave 6c (6.2
g, 56%). Mp 171-173 °C (Me2CO-iPr2O): IR (KBr): 3025,
1503, 1430, 1321. 1H-NMR (200 MHz, DMSO-d6) 2.64 (s, 3H);
3.10 (s, 3H); 4.00 (s, 3H); 7.26 (d, J ) 4.4, 1H); 7.36 (s, 1H);
7.87 (s, 1H); 8.57 (d, J ) 4.4, 1H); 9.27 (bs, 1H). 13C-NMR
(50.3 MHz, DMSO-d6) 18.6 (q); 40.0 (q); 56.4 (q); 102.7 (d);
120.1 (d); 121.6 (d); 125.7 (s); 130.6 (s); 142.7 (s); 143.7 (s);
148.4 (d); 150.1 (s). MS (EI) 266 (M+, 1.5); 187 (20); 157 (2);
81 (52); 69 (100). Anal. Calcd for C12H14N2O3S: C, 54.12; H,
5.30; N, 10.52; S, 12.04. Found: C, 54.32; H, 5.33; N, 10.50;
S, 12.05.
7-[(Meth a n esu lfon yl)a cetyla m in o]-6-m eth oxy-4-m eth -
yl-5-n itr oqu in olin e (6d ). To a solution of 6c (2.8 g, 10.7
mmol) in AcOH (70 mL) at -78 °C and under N2 was added a
suspension of Cu(NO3)2‚3H2O (3.4 g, 14.1 mmol) in AcOH (140
mL). After 5 min the mixture was stirred for 40 min at rt
and 1 h at 80 °C. The solvent was evaporated, excess
saturated aqueous NaHCO3 was added, and then the solution
was extracted with CH2Cl2. The organic layer was washed
with brine, dried, and evaporated to afford crude material (4.7
g) as a solid which was purified by column chromatography.
On elution with C6H14-CH2Cl2 (3:7 to 2:8) 6d (2.2 g, 59%) was
obtained. Mp 225-230 °C (Me2CO-iPr2O). IR (KBr) 1717,
1542, 1360. 1H-NMR (300 MHz) 2.05 (3H, s); 2.76 (s, 3H); 3.49
(s, 3H); 4.14 (s, 3H); 7.43 (d, J ) 4.4, 1H); 7.50 (s, 1H); 8.75 (d,
J ) 4.4, 1H). 13C-NMR (75 MHz) 18.7 (q); 23.4 (q); 42.6 (q);
56.9 (q); 104.6 (d); 120.0 (s); 124.8 (d); 130.7 (s); 134.4 (s); 143.5
(s); 144.5 (s); 150.6 (d); 153.2 (s); 170.7 (s). MS (EI) 353 (M+,
5); 338 (16); 293 (82); 184 (65); 232 (91); 214 (100). Anal. Calcd
for C14H15N3O6S: C, 47.58; H, 4.28; N, 11.89; S, 9.07. Found:
C, 47.15; H, 4.42; N, 12.12; S, 9.16.
7-[(Meth an esu lfon yl)acetylam in o]-4-for m yl-6-m eth oxy-
5-n it r oq u in olin e (6e) a n d 7-[(Met h a n esu lfon yl)a cet yl-
a m in o]-4-(d im et h oxym et h yl)-6-m et h oxy-5-n it r oq u in o-
lin e (6f). A mixture of 6d (1 g, 2.8 mmol), TFA (2.2 g,19.1
mmol), I2 (0.9 g, 3.6 mmol), t-BuI (2.3 g, 12.3 mmol), and
FeCl2‚4H2O (catalytic) in dry DMSO (25 mL) was stirred at
80 °C for 16 h under N2. After this time EtOAc was added,
and the mixture was washed several times with H2O and with
saturated aqueous Na2S2O4. The organic layer was dried and
evaporated to give crude material (1.6 g) which was purified
by column chromatography, eluting with C6H14-CH2Cl2 (3:7
to 2:8) giving 6e (540 mg, 54%). Mp 144-147 °C (MeCO-i-
Pr2O). IR (KBr): 1710, 1550. 1H-NMR (300 MHz) 2.06 (s, 3H);
3.49 (s, 3H); 4.18 (s, 3H); 7.97 (d, J ) 4.2, 1H); 8.85 (s, 1H);
9.20 (d, J ) 4.2, 1H); 10.40 (s, 1H). 13C-NMR (75 MHz, CD3-
OD) 23.6 (q); 43.0 (q); 57.5 (q); 106.0 (d); 124.4 (s); 126.1 (s);
130.3 (d); 135.0 (s); 136.2 (s); 150.8 (d); 151.5 (s); 156.2 (s);
170.1 (s); 192.6 (d). MS (EI) 367 (M+, 4); 228 (53); 307 (100).
Trimethyl orthoformate (25 mg, 234 mmol) was added to a
solution of 6e (540 mg, 1.5 mmol) in absolute MeOH (15 mL)
with p-toluenesulfonic acid (catalytic), and the mixture was
refluxed under N2 for 48 h. The solvent was evaporated, and
the residue was purified by column chromatography. On
elution with CH2Cl2 6f was obtained (480 mg, 41%). Mp 174-
178 °C (Me2CO-iPr2O). IR (KBr): 1719, 1546, 1365, 1167.
1H-NMR (300 MHz) 2.06 (s, 3H); 3.39 (s, 6H); 3.48 (s, 3H); 4.11
(s, 3H); 5.82 (s, 1H); 7.76 (d, J ) 4.4, 1H); 7.87 (s, 1H); 8.90 (d,
J ) 4.4, 1H). 13C-NMR (300 MHz) 23.61 (q); 42.88 (q); 53.06
(q); 53.11 (q); 57.14 (q); 100.31 (d); 104.51 (s); 105.50 (d); 122.71
(d); 124.80 (s); 128.16 (s); 141.34 (s); 150.50 (d); 150.72 (s);
153.43 (s); 170.45 (s). MS (EI) 413 (M+, 7); 353 (100); 292 (64);
244 (56); 214 (55). Anal. Calcd for C6H19N3O8S‚1/4 Me2CO:
C, 47.01; H, 4.82; N, 9.82; S, 7.49. Found: C, 47.17; H, 4.80;
N, 10.10; S, 7.50.
4-(Hydr oxym eth yl)-6,7-dim eth oxy-5-n itr oqu in olin e (6k).
To 6j (100 mg, 0.38 mmol) in MeOH (10 mL) was added NaBH4
(100 mg, 2.64 mmol) in portions at 20 °C. After 1 h the
reaction was quenched with H2O and partitioned between
EtOAc and aqueous K2CO3 (10% wt/vol). The combined
organic extracts were dried and concentrated to yield 6k as a
light brown solid (80 mg, 80%). Mp 120-121 °C. UV 220
(4.42), 236 (4.56), 272 (3.84), 318 (3.86), 330 (3.97); IR (film)
3442, 1583, 1532, 1472. 1H-NMR (300 MHz) 1.84 (bs, 1H);
4.06 (s, 3H); 4.12 (s, 3H); 4.99 (s, 2H); 7.74 (s, 1H); 7.77 (d, J
) 4.5, 1H); 8.73 (d, J ) 4.5, 1H). 13C-NMR (75 MHz) 56.5 (q);
59.3 (t); 62.8 (q); 111.7 (d); 112.64 (s); 118.7 (d); 140.2 (s); 142.8
(s); 144.5 (s); 145.2 (s); 150.3 (d); 153.6 (s). MS (EI) 264 (M+,
6,7-Dim eth oxy-4-m eth ylqu in olin e (6g). FeCl3 (2.71 g,
10.0 mmol) was dissolved in glacial AcOH (30 mL) with
warming to 60 °C. 4-Aminoveratrole (1.55 g, 10.1 mmol) was
added followed, after 5 min, by methyl vinyl ketone (0.87 mL,
10.5 mmol) added dropwise over 5 min. The reaction mixture
was refluxed for 1 h. The solvent was removed in vacuo, and
the residue was made alkaline with aqueous NaOH (50% wt/
vol). The aqueous phase was removed in vacuo, and the
residue was extracted with CH2Cl2 (6 × 50 mL). The combined
organic extracts were washed with aqueous K2CO3 (10% wt/

574 J . Org. Chem., Vol. 62, No. 3, 1997
Roberts et al.
8), 248 (2), 230 (22), 218 (72), 203 (100), 188 (58), 160 (33).
HRMS: calcd for C12H12N2O5 264.0746, found 264.0742.
6,7-Dim e t h oxy-4-(d im e t h oxym e t h yl)-5-n it r oq u in o-
lin e (6l). To 6j (0.90 g, 3.44 mmol) in MeOH (100 mL) was
added HCl in Et2O (5 mL, 1 M, 5 mmol), and the reaction was
refluxed for 65 h. The solvent was removed in vacuo, and the
residue was partitioned between EtOAc and aqueous K2CO3
(10% wt/vol). The organic phases were dried and concentrated
to give 6l as a yellow solid (0.99 g, 93%). Mp 118 °C. UV 220
(4.39), 238 (4.54), 282 (3.72), 336 (3.95). IR (film) 1584, 1538.
1H-NMR (300 MHz) 3.43 (s, 6H); 4.12 (s, 3H); 4.15 (s, 3H); 5.64
(s, 1H); 7.93 (d, J ) 4.9, 1H); 7.99 (s, 1H); 8.91 (d, J ) 4.9,
1H). 13C-NMR (75 MHz) 54.3 (q); 56.8 (q); 63.2 (q); 100.5 (d);
112.9 (d); 113.5 (s); 119.6 (d); 140.9 (s); 141.0 (s); 144.4 (s);
146.7 (s); 150.5 (d); 153.9 (s). MS (EI) 308 (M+, 25), 277 (53),
1H); 3.16 (m, 1H); 3.37 (s, 3H); 3.43 (s, 3H); 3.20-3.50 (m, 2H);
3.77 (s, 3H); 3.80 (s, 3H); 4.48 (d, J ) 8.6, 1H); 5.61 (s, 1H).
MS (EI) 282 (M+, 29), 267 (9), 252 (8), 237 (13), 218 (12), 207
(100), 203 (18), 192 (27), 75 (28). HRMS: calcd for C14H22N2O4
282.1580, found 282.1579.
1,2,3,4-Tetr ah ydr o-6,7-dim eth oxy-4-(dim eth oxym eth yl)-
1-(4-m eth ylben zen esu lfon yl)-5-[bis(4-m eth ylben zen esu lfo-
n yl)a m in o]qu in olin e (7f). A mixture of diamine 7c (311 mg,
1.10 mmol) in triethylamine (6 mL) with p-toluenesulfonyl
chloride (1.56 g, 8.2 mmol) and imidazole (20 mg, 0.3 mmol)
was stirred for 18 h. The reaction was quenched with water
and extracted with CH2Cl2. The dried organic extract was
concentrated to give an oil which was purified by flash column
chromatography (petroleum ether (40-60)-EtOAc (2:1)) to
give the 7f as a white solid (552 mg, 67%). Mp 119-123 °C.
UV 236 (4.67). IR (film) 3063, 2948, 2840, 1598, 1491, 1455.
1H-NMR (300 MHz) 1.72 (m, 1H); 2.14 (m, 1H); 2.44 (s, 6H);
2.51 (s, 3H); 3.11, 3.04 (2 × s, 2 × 3H); 3.26 (q, J ) 7.2, 1H);
3.83, 3.51 (2 × s, 2 × 3H); 4.0-3.5 (2 × m, 2H); 4.39 (d, J )
5.9, 1H); 7.37-7.27 (3 × d, J ) 8.4, 3 × 2H); 7.48 (d, J ) 8.4,
2H); 7.64 (s, 1H); 7.75 (d, J ) 8.4, 2H); 8.31 (d, J ) 8.4, 2H).
FABMS 744 (M+, 25), 714 (37), 684 (7), 589 (62), 558 (100),
527 (42), 515 (87), 434 (19), 403 (68), 247 (76), 217 (60), 205
(80); HRMS: calcd for C35H40N2O10S3 744.1845, found 744.1831.
1,2,3,4-Tetr ah ydr o-6,7-dim eth oxy-4-(dim eth oxym eth yl)-
1-(4-m et h ylb en zen esu lfon yl)-5-(4-m et h ylb en zen esu lfo-
n yla m in o)qu in olin e (7d ). To 7f (552 mg, 0.743 mmol) in
MeOH (30 mL), NaOMe (1.5 g, 27.5 mmol) was added and the
mixture heated at 50 °C for 66 h. After dilution with H2O,
extraction with CH2Cl2, drying and concentration yielded 7d
as a yellow oil (308 mg, 70%): UV (EtOH) 220 (4.48). IR (film)
3251, 1599. 1H-NMR (300 MHz) 1.60 (m, 1H); 1.85 (m, 1H);
2.29 (s, 3H); 2.33 (s, 3H); 2.85 (s, 3H); 3.06 (s, 3H); 3.13 (m,
1H); 3.37 (s, 3H); 3.37-3.80 (m, 2H); 3.80 (s, 3H); 4.38 (d, J )
5.9, 1H); 7.19-7.14 (m, 4H); 7.39 (d, J ) 8.3, 2H); 7.45 (s, 1H);
7.69 (d, J ) 8.3, 2H). FABMS 590 (M+, 31), 559 (21), 436 (16),
404 (100), 361 (35), 249 (36), 217 (22), 205 (31); HRMS: calcd
for C28H34N2O8S2 590.1756, found 590.1775.
1,3,4,5-Tetr a h yd r o-7,8-d im eth oxy-1,5-bis(4-m eth ylben -
zen esu lfon yl)p yr r olo[4,3,2-d e]qu in olin e (9c). A mixture
of 7d (308 mg, 0.522 mmol) and aqueous HCl (1 N, 9 mL) in
THF (9 mL) was heated at 80 °C for 41 h. The reaction was
quenched with aqueous NaOH (3 N, 3.5 mL) and then
extracted with CH2Cl2. The organic extracts were dried
concentrated to give a crude oil which was purified by flash
column chromatography (petroleum ether (40-60)-EtOAc (1:
1)) to yield 9c as a white solid (132 mg, 48%). Mp 70-72 °C:
UV 230 (4.56), 276 (4.06), 286 (4.06). IR (film) 1617, 1597,
1500. 1H-NMR (300 MHz) 2.41 (s, 6H); 2.47 (m, 2H); 3.92,
3.95 (2 × s, 2 × 3H); 3.97 (m, 2H); 7.19 (d, J ) 8.3, 2H); 7.20
(s, 1H); 7.27 (d, J ) 8.3, 2H); 7.34 (s, 1H); 7.53 (d, J ) 8.3,
2H); 7.84 (d, J ) 8.3, 2H). FABMS 526 (M+, 53), 495 (2), 371
(100), 341 (2), 217 (40), 205 (35). HRMS: calcd for C26H26N2O6S2
526.1232, found 526.1224.
1,3,4,5-Tetr ah ydr o-7,8-dim eth oxypyr r olo[4,3,2-de]qu in -
olin e (9d ). The acetal 7c (100 mg) was reacted with 1 N
aqueous HCl (1.5 mL) in THF (1.5 mL) at 40 °C for 1 h. After
evaporation of THF the solution was made basic and extracted
with CH2Cl2 to afford 9d as an oil (50 mg, 64%). UV 232 (4.31),
268 (4.06). IR (film) 3353, 2932, 2835, 1619. 1H-NMR (300
MHz) 2.99 (t, J ) 5.4, 2H); 3.50 (t, J ) 5.4, 2H); 3.88, 3.90 (2
× s, 2 × 3H); 6.03 (s, 1H), 6.66 (bs, 1H); 7.89 (bs, 1H). FABMS
526 (M+, 53), 495 (2), 371 (100), 341 (2), 217 (40), 205 (35).
MS (EI) 218 (M+, 33), 203 (50). HRMS: calcd for C12H14N2O2
218.1055, found 218.1055.
1,3,4,5-Tetr a h yd r o-1,5-bis(4-m eth ylben zen esu lfon yl)-
p yr r olo[4,3,2-d e]qu in olin e-7,8-d ion e (10a ). To a solution
of 9c (130 mg, 0.247 mmol) in CH2Cl2 (2.5 mL) under argon
with 4 Å sieves at -78 °C was added dropwise BBr3 (0.5 mL,
1 M in CH2Cl2), and then the temperature was allowed to rise
to -20 °C over 50 min. The reaction was quenched with
aqueous saturated NaHCO3 and extracted with CH2Cl2. The
combined organic extracts were dried and concentrated to give
a red oil (130 mg) which was not purified further but oxidized
in MeCN (2 mL) with CAN (370 mg, 0.675 mmol) in H2O (2
mL) at rt for 10 min. After dilution with H2O, extraction with
CH2Cl2, drying, and evaporation gave 10a as an orange oil (113
246 (47), 231 (37), 217 (18), 75 (100). HRMS: calcd for C14H16
-
N2O6 308.1008, found 308.1014. Anal. Calcd for C14H16N2O6:
C, 54.5; H, 5.23; N, 9.08. Found C, 54.3; H, 5.20; N, 9.01.
1,2-Dih yd r o-6,7-d im e t h oxy-1-(m e t h oxyca r b on yl)-4-
(d im eth oxym eth yl)-5-n itr oqu in olin e (8a ). To 6l (236 mg,
0.76 mmol) in THF (10 mL) under argon cooled to -78 °C was
added BH3-THF (4 mL, 1 M in THF), and the mixture was
stirred at -78 °C for 30 min. REDAL (70% solution in PhMe,
1.2 mL, 4.08 mmol) was added dropwise. The color of the
reaction changed from a yellow to a deep red. The reaction
was stirred at -78 °C for 40 min before MeOCOCl (4 mL, 52
mmol) was added all at once. The reaction changed from a
deep red solution to yellow. The reaction was then stirred at
rt for 20 h before quenching with H2O and then filtered
through Celite to remove the coarser aluminum salts. The
organic phase was washed with H2O, dried, and concentrated
to give the crude product. The material was purified by flash
column chromatography (petroleum ether (40-60)-EtOAc (1:
1)) to give 8a as a yellow oil (160 mg, 57%, three steps). UV
218 (4.64), 240 (4.90). IR (film) 1713, 1613, 1537. 1H-NMR
(200 MHz) 3.26 (s, 6H); 3.83 (s, 3H); 3.95 (s, 3H); 3.97 (s, 3H);
4.31 (d, J ) 4.0, 2H); 5.07 (s, 1H); 6.48 (t, J ) 4.0, 1H); 7.42
(bs, 1H). MS (CI) 386 (M + 18, 17), 367 (4), 337 (100), 309
(14), 279 (19), 249 (15), 219 (21); HRMS: calcd for C16H20N2O8
368.1220, found 368.1224.
1,3,4,5-Tetr ah ydr o-7,8-dim eth oxy-5-(m eth oxycar bon yl)-
1-(4-m et h ylben zen esu lfon yl)p yr r olo[4,3,2-d e]q u in olin e
(9b). 8a (140 mg, 0.38 mmol) in absolute EtOH (20 mL) was
hydrogenated at 56 psi over 5% Pt/C (100 mg) at 20 °C for 24
h. The reaction mixture was filtered through Celite and
concentrated to give crude 7b. This material was not further
purified but dissolved in THF (5 mL), aqueous HCl (1 N, 5
mL) was added and the reaction was heated (50-55 °C) for
24 h. The reaction was quenched with aqueous NaOH (3 N)
and extracted with EtOAc. The organic extracts were dried
and concentrated to give crude indole 9a . This material,
without further purification, was dissolved in CH2Cl2 (3 mL),
tetrabutylammonium hydrogen sulfate (12 mg, 34 mmol),
powdered NaOH (200 mg, 5 mmol), and TsCl (300 mg, 1.57
mmol) in CH2Cl2 (1 mL) were added, the reaction was stirred
at 20 °C for 3 h, H2O was added, and the mixture was extracted
with CH2Cl2. The organic extract were dried and concentrated
to give the crude material which was purified by flash column
chromatography (petroleum ether (40-60)-EtOAc (1:1)) to
give 9b as an oil (21 mg, 0.049 mmol, 13% (three steps)). UV
216 (4.33), 232 (4.44), 280 (4.11). IR (film) 1709, 1618, 1443.
1H-NMR (200 MHz) 2.39 (s, 3H); 2.80 (t, J ) 5.9, 2H); 3.82 (s,
3H); 3.99 (t, J ) 5.9, 2H), 3.88 (s, 6H); 7.34-7.25 (m, 4H); 7.87
(d, J ) 8.3, 2H). MS (CI) 448 (M + 18, 38), 431 (M + 1, 23),
277 (100). HRMS: calcd for C21H26N3O6S 448.1542, found
448.1663.
5-Am in o-1,2,3,4-t et r a h yd r o-6,7-d im et h oxy-4-(d im et h -
oxym eth yl)qu in olin e (7c). To 6l (184 mg, 0.597 mmol) and
NiCl2 (1.7 g, 7.13 mmol) in MeOH (20 mL) was added NaBH4
(1.6 g, 42.4 mmol) rapidly in portions with no external cooling.
The temperature in the reaction vessel rose to about 50 °C.
After 5 min the reaction was quenched with H2O and extracted
with EtOAc. The combined organic extracts were dried and
concentrated and then redissolved in CHCl3, and the solution
was dried and concentrated to yield 7c as a red oil (145 mg,
86%). UV 220 (4.42), 246 (4.67), 298 (4.22). IR (film) 3403,
3351, 1612, 1505. 1H-NMR (300 MHz) 1.67 (m, 1H); 2.11 (m,

Synthesis of Pyrrolo[4,3,2-de]quinolines
J . Org. Chem., Vol. 62, No. 3, 1997 575
mg, 92%). UV 232 (4.25), 310 (3.70), 362 (3.48). IR (film) 1687,
1651, 1598. 1H-NMR (300 MHz) 2.45 (s, 3H); 2.47 (s, 3H); 2.90
(t, J ) 6.0, 2H); 4.13 (t, J ) 6.0, 2H); 6.34 (s, 1H); 7.42-7.34
(m, 4H); 7.59 (s, 1H); 7.79 (d, J ) 8.4, 2H); 8.10 (d, J ) 8.4,
2H). FABMS 497 (M + 1, 100), 465 (6), 343 (52), 289 (38),
242 (53). HRMS: calcd for C24H21N2O6S2 497.0841, found
497.0852.
2H); 3.91 (s, 6H); 4.00 (t, J ) 5.5, 2H); 7.26 (d, J ) 8.3, 2H);
7.30 (s, 1H); 7.32 (s, 1H); 7.88 (d, J ) 8.3, 2H). 13C-NMR (75
MHz) 21.6 (q); 22.6 (t); 28.5 (q); 44.6 (t); 57.0 (q); 61.0 (q); 81.5
(s); 102.9 (d); 114.7 (s); 119.1 (s); 120.2 (d); 126.4 (s); 127.7 (d);
128.7 (s); 129.6 (d); 132.7 (s); 136.3 (s); 144.2 (s); 151.4 (s); 153.3
(s). MS (CI) 473 (MH+, 17), 417 (36), 373 (65), 319 (44), 263
(56), 219 (100). HRMS: calcd for C24H28N2O6S 472.1668, found
472.1669.
1,3,4,5-Tet r a h yd r o-5-(m et h oxyca r b on yl)-1-(4-m et h yl-
b en zen esu lfon yl)p yr r olo[4,3,2-d e]q u in olin e-7,8-d ion e
(10b). O-Demethylation of 9b (22 mg, 0.052 mmol) was
achieved in dry CH2Cl2 (1 mL) under argon in the presence of
4 Å sieves and at -78 °C by reaction with BBr3 (0.1 mL, 1 M
in CH2Cl2), and then the temperature was allowed to rise to
-25 °C over 1 h. The reaction was quenched with saturated
aqueous NaHCO3 and extracted with CH2Cl2 and the dried
extract evaporated to give a red oil (15 mg) which without
further purification was dissolved in MeCN (1 mL) and
oxidized with CAN (67 mg, 0.122 mmol) in H2O (1 mL) at rt
for 10 min. The mixture was diluted with H2O and extracted
with CH2Cl2 giving 10b as an orange oil which solidified upon
storage to give a red solid (14 mg, 70%). Mp 114-119 °C. UV
238 (4.25), 314 (3.88), 358 (3.67). IR (film) 2956, 1729, 1686,
1649, 1600, 1441, 1376, 1329, 1212, 1193, 1179, 1094. 1H-
NMR (300 MHz) 2.46 (s, 3H); 2.85 (t, J ) 6.0, 2H); 3.90 (s,
3H); 4.13 (t, J ) 6.0, 2H); 6.58 (s, 1H); 7.37 (d, J ) 8.4, 2H);
7.62 (s, 1H); 8.13 (d, J ) 8.4, 2H). FABMS 401 (M + 1, 100),
247 (35). HRMS: calcd for C19H17N2O6S 401.0807, found
401.0794.
1,3,4,5-Tetr ah ydr o-7-m eth oxy-1-(4-m eth ylben zen esu lfo-
n yl)p yr r olo[4,3,2-d e]qu in olin -8-on e (11a ). To 10a (120 mg,
0.24 mmol) in CH2Cl2-MeOH (1:1) (10 mL) was added K2CO3
(30 mg, 0.22 mmol), and then the mixture was stirred for 30
min, the solution decanted, and the solvent evaporated. The
residue was extracted with CHCl3 and the organic extract
concentrated to give a crude oil which was purified by flash
column chromatography (CH2Cl2-MeOH (99:1)) to give 11a
as a red oil (8 mg, 9%). UV (EtOH) 234 (4.38), 320 (3.88), 386
(3.80). IR (film) 1670, 1643, 1589, 1525. 1H-NMR (300 MHz)
2.47 (s, 3H); 2.83 (t, J ) 6.0, 2H); 3.93 (s, 3H); 4.13 (t, J ) 6.0,
2H); 6.25 (s, 1H); 6.68 (s, 1H); 7.38 (d, J ) 8.4, 2H); 7.82 (d, J
) 8.4, 2H). MS (CI) 357 (M + 1, 39), 203 (100). HRMS: calcd
for C18H17N2O4S 357.0909, found 357.0913.
1,3,4,5-T e t r a h y d r o -5-(t er t -b u t y lo x y c a r b o n y l)-7,8-
d im eth oxyp yr r olo[4,3,2-d e]qu in olin e (9e). To nitro-alde-
hyde 6j (115 mg, 0.44 mmol) in methanol (15 mL) was added
NiCl2 (1.35 g, 5.72 mmol). After 5 min, NaBH4 (1.32 g, 35.2
mmol) was added rapidly with no external cooling. The
mixture was allowed to stir for 5 min and was then diluted
with H2O. The reaction was extracted rigorously with EtOAc,
and then the combined organic extracts were dried and
concentrated. The resulting residue was extracted with CHCl3
and the organic extract again dried and concentrated to yield
a red oil which was not purified further but dissolved in CH2-
Cl2 (5 mL) and reacted with (BOC)2O (150 mg, 0.69 mmol) at
rt for 15 h. The solvent was removed and the crude residue
purified by flash column chromatography (C6H14-EtOAc (3:
2)) to yield 9e as an oil (27 mg, 19%). UV 230 (4.27), 286 (3.91).
IR (film) 3347, 1697, 1514. 1H-NMR (300 MHz) 1.61 (s, 9H);
2.95 (t, J ) 5.6, 2H); 3.95 (s, 3H); 3.98 (s, 3H); 4.05 (t, J ) 5.6,
2H); 6.78 (bs, 1H); 7.25 (bs, 1H); 8.38 (bs, 1H). 13C-NMR (75
MHz) 22.9 (t); 28.5 (q); 45.4 (t); 57.8 (q); 61.0 (q); 81.1 (s); 100.3
(d); 110.6 (s); 116.4 (d); 117.3 (s); 128.2 (s); 128.3 (s); 130.7 (s);
147.9 (s); 153.8 (s) MS (EI) 318 (M+, 29), 262 (100), 247 (93),
203 (48). HRMS: calcd for C17H22N2O4 318.1580, found
318.1585.
1,3,4,5-T e t r a h y d r o -5-(t er t -b u t y lo x y c a r b o n y l)-7,8-
dim eth oxy-1-(4-m eth ylben zen esu lfon yl)pyr r olo[4,3,2-de]-
qu in olin e (9f). 9e (180 mg, 0.57 mmol) in THF (1 mL) was
added to a suspension of oil-free NaH (34 mg, 0.85 mmol) at
rt and the mixture stirred for 45 min, refluxed for 15 min,
and cooled. TsCl (150 mg, 0.77 mmol) was added and after
14 h at room temperature the mixture diluted with H2O and
extracted with CH2Cl2. The organic extracts were dried
concentrated to give an oil which was purified by flash column
chromatography (C6H14-EtOAc (2:1)) to yield 9f as an oil (90
mg, 34%). UV 242 (4.35), 282 (4.35). IR (film) 1698, 1502.
1H-NMR (300 MHz) 1.61 (s, 9H); 2.39 (s, 3H); 2.91 (t, J ) 5.5,
1,3,4,5-Tetr a h yd r o-7,8-d im eth oxy-1-(4-m eth ylben zen e-
su lfon yl)p yr r olo[4,3,2-d e]qu in olin e (9g). 9f (17 mg, 0.04
mmol) in CH2Cl2 (1 mL) was treated with TFA (0.1 mL) at rt
for 90 min. The mixture was diluted with CH2Cl2 and made
basic with NaHCO3. The combined organic extracts were dried
over MgSO4 and concentrated to give 9g as an oil (12 mg, 80%).
UV 218 (3.58), 244 (4.48), 278 (4.29). IR (film) 3384, 1621,
1596. 1H-NMR (300 MHz) 2.36 (s, 3H); 2.90 (t, J ) 5.8, 2H);
3.39 (t, J ) 5.8, 2H); 3.84 (s, 3H); 3.87 (s, 3H); 6.14 (s, 1H);
7.21 (s, 1H); 7.23 (d, J ) 8.3, 2H); 7.90 (d, J ) 8.3, 2H). 13C-
NMR (75 MHz) 21.6 (t); 22.6 (t); 42.8 (t); 56.9 (q); 61.2 (q); 93.2
(d); 114.9 (s); 115.3 (s); 118.8 (d); 127.0 (s); 127.8 (d); 129.5 (s);
129.6 (d); 136.4 (s); 136.8 (s); 144.0 (s); 152.6 (s). MS (EI) 372
(M+, 15), 217 (100). HRMS: calcd for C19H20N2O4S 372.1144,
found 372.1144.
1,3,4,5-T e t r a h y d r o -5-(t er t -b u t y lo x y c a r b o n y l)-7,8-
d im eth oxy-1-m eth ylp yr r olo[4,3,2-d e]qu in olin e (9h ). To
9e (180 mg, 0.57 mmol) in THF (1 mL) was added, oil-free
NaH (34 mg, 0.85 mmol) and the whole was stirred at rt for
45 min, refluxed for 15 min, and cooled. MeI (0.5 mL, 8.1
mmol) was added, and the mixture was stirred for 14 h, diluted
carefully with H2O, and extracted with CH2Cl2. The organic
extracts were dried and concentrated to give an oil which was
purified by flash column chromatography (C6H14-EtOAc (3:
1)) to yield 9h as an oil (105 mg, 56%). UV 220 (4.19), 236
(4.41), 294 (4.12). IR (film) 1698, 1511. 1H-NMR (300 MHz)
1.62 (s, 9H); 2.95 (t, J ) 5.6, 2H); 3.95 (s, 9H); 4.00 (t, J ) 5.6,
2H); 6.56 (s, 1H); 7.19 (bs, 1H). 13C-NMR (75 MHz) 22.8 (t);
28.5 (q); 34.7 (q); 45.3 (t); 57.8 (q); 62.0 (q); 81.0 (s); 100.2 (d);
109.3 (s); 118.0 (s); 122.1 (d); 128.0 (s); 128.4 (s); 131.8 (s); 148.5
(s); 153.7 (s). MS (EI) 332 (M+, 14), 276 (58), 261 (92), 217
(48). HRMS: calcd for C18H24N2O4 332.1736, found 332.1736.
1,3,4,5-Tetr ah ydr o-7,8-dim eth oxy-1-m eth ylpyr r olo[4,3,2-
d e]qu in olin e (9i). 9h (30 mg, 0.09 mmol) in CH2Cl2 (1 mL)
was treated with TFA (0.1 mL), and the mixture was stirred
at rt for 90 min, diluted with CH2Cl2, and made basic with
aqueous NaHCO3. The organic layer was dried and evapo-
rated to give 9i as an oil (16 mg, 80%). UV 234 (4.10), 290
(3.74). IR (film) 3364, 1691, 1634. 1H-NMR (300 MHz) 2.94
(t, J ) 5.8, 2H); 3.42 (t, J ) 5.8, 2H); 3.86 (bs, 1H); 3.86 (s,
9H); 5.99 (s, 1H); 6.43 (bs, 1H). MS (EI) 232 (M+, 60), 217
(100), 202 (42). HRMS: calcd for C13H16N2O2 232.1225, found
232.1221.
7-Met h oxy-4-(d im et h oxym et h yl)-1-m et h yl-5-n it r o-6-
oxid oqu in olin iu m (12a ). The nitroquinoline 6l (0.573 g, 1.86
mmol) was heated in MeCN (15 mL) with MeI (6 mL, 96.3
mmol) at 50 °C for 44 h. The reaction mixture was cooled to
0 °C to complete precipitation of an orange solid which was
was filtered, washed with Et2O, and dried to yield 12a (0.35
g, 61%). Mp > 230 °C. UV (H2O) 228 (4.57), 270 (4.31), 376
(4.09). IR (KBr) 1566, 1467, 1453. 1H-NMR (300 MHz,
DMSO-d6) 3.32 (s, 6H); 4.11 (s, 3H); 4.54 (s, 3H); 5.56 (s, 1H);
7.26 (s, 1H); 7.83 (d, J ) 6.3, 1H); 8.64 (d, J ) 6.3, 1H).
FABMS 309 (M + 1, 100), 293 (3), 277 (10), 261 (11), 232 (15).
HRMS: calcd for C14H17N2O6 309.1087, found 309.1086.
1,2-Dih yd r o-7-m eth oxy-4-(d im eth oxym eth yl)-1-m eth -
yl-6-[(4-m eth ylben zen esu lfon yl)oxy]-5-n itr oqu in olin e (8b).
To the zwitterion 12a (155 mg, 0.50 mmol) in cold MeOH/H2O
(1:1) (30 mL) was added NaBH4 (190 mg, 5.0 mmol) all at once
and the reaction stirred for 1 h. The MeOH was removed in
vacuo, saturated aqueous NaHCO3 was added, and then
organic material was extracted with CHCl3. The combined
organic extracts were dried concentrated to give a red solid
which was unstable with respect to reoxidation to starting
material. The crude solid was dissolved in CH2Cl2-Et3N (1:
1) (6 mL), TsCl (287 mg, 1.50 mmol) was added, and the
mixture was stirred for 18 h, quenched with saturated aqueous
NaHCO3, and extracted with CHCl3. The organic extracts
were dried and concentrated, leaving an oil which was purified

576 J . Org. Chem., Vol. 62, No. 3, 1997
Roberts et al.
by flash column chromatography (petroleum ether (40-60)-
EtOAc (1:1)) to give 8b as an orange solid (79 mg, 34%). Mp
127-128.5 °C. UV 236 (4.35), 282 (3.65). IR (film) 1607, 1535,
1370. 1H-NMR (300 MHz) 2.50 (s, 3H); 2.90 (s, 3H); 3.22 (s,
6H); 3.77 (s, 3H); 3.81 (d, J ) 5.0, 2H); 4.96 (s, 1H); 6.26 (s,
1H); 6.27 (t, J ) 5.0, 1H); 7.37 (d, J ) 8.3, 2H); 7.84 (d, J )
8.3, 2H). FABMS 464 (M+, 48), 463 (82), 433 (67), 309 (100).
HRMS: calcd for C21H23N2O8S 463.1175, found 463.1170.
6,7-Dim eth oxy-4-(d im eth oxym eth yl)-1-m eth yl-5-n itr o-
qu in olin iu m Iod id e (12b). 6l (50 mg, 0.16 mmol) in MeCN
(1.3 mL) with MeI in the presence of 4 Å sieves under argon
was kept at 30 °C for 42 h. The solvent was removed in vacuo
and the residue was washed with Et2O to remove unreacted
starting material. The residual solid was dried in vacuo, to
yield 12b as an orange solid (31 mg, 43%). Mp >230 °C. UV
(H2O) 222 (4.51), 246 (4.36), 358 (3.99). IR (KBr) 3415, 3000,
2948, 1618, 1549, 1501. 1H-NMR (300 MHz, Me2CO-d6) 3.52
(s, 6H); 4.26 (s, 3H); 4.56 (s, 3H); 5.11 (s, 3H); 5.75 (s, 1H);
8.38 (s, 1H); 8.47 (d, J ) 6.3, 1H); 9.94 (d, J ) 6.3, 1H).
FABMS 323 (M+, 15), 309 (100), 277 (8), 261 (13), 248 (6), 232
(14), 218 (10). HRMS: calcd for C15H19N2O6 323.1243, found
323.1252.
6,7-Dim eth oxy-1,4-d im eth ylqu in olin iu m Iod id e (12d ).
Quaternization of 6g (200 mg, 0.99 mmol) was achieved in
MeCN (7 mL) with MeI (1.7 mL, 27.2 mmol) at 40 °C for 63 h.
A pale yellow precipitate formed which was filtered, washed
with CH2Cl2, and dried at the pump to yield 12d as a yellow
solid (250 mg, 72%). Mp 211-212 °C. UV (H2O) 220 (4.38),
246 (4.33), 346 (4.05). IR (KBr) 3508, 2978, 1626, 1577, 1513,
1491, 1443, 1285, 1231, 1213, 1039. 1H-NMR (300 MHz,
DMSO-d6) 2.93 (s, 3H); 4.07 (s, 3H); 4.14 (s, 3H); 4.51 (s, 3H);
7.61 (s, 2H); 7.81 (d, J ) 6.2, 1H); 9.04 (d, J ) 6.2, 1H).
FABMS 218 (M+, 100). HRMS: calcd for C13H16NO2 218.1181,
found 218.1186.
6.69 (s, 1H); 7.89 (bs, 1H). FABMS 232 (M+, 61), 217 (100).
HRMS: calcd for C13H16N2O2 232.1212, found 232.1212.
The crude indole 9j in CH2Cl2 (3 mL) was reacted without
further purification, with Bu4NHSO4 (10 mg, 28 mmol),
powdered NaOH (200 mg, 5 mmol), and TsCl (400 mg, 2.01
mmol) at rt for 3 h. H2O was added, and the mixture was
extracted with CH2Cl2. The organic extracts were dried and
concentrated to yield an oil which was purified by flash column
chromatography (CH2Cl2-MeOH) (99:1)) to yield the tosylated
indole 9k as an oil (39 mg, two steps 14%). UV 232 (4.47),
286 (4.02). IR (film) 1617, 1507. 1H-NMR (300 MHz) 2.37 (s,
3H); 2.92 (s, 3H); 2.98 (t, J ) 5.9, 2H); 3.23 (t, J ) 5.9, 2H);
3.86 (s, 3H); 3.91 (s, 3H); 6.12 (s, 1H); 7.21 (s, 1H); 7.25 (d, J
) 8.4, 2H); 7.89 (d, J ) 8.4, 2H). MS (EI) 386 (M+, 3), 232
(58), 217 (100), 124 (65), 91 (53). HRMS: calcd for C20H22N2O4S
386.1300, found 386.1307.
1,3,4,5,7,8-H exa h yd r o-5-m et h yl-1-(4-m et h ylb en zen e-
su lfon yl)p yr r olo[4,3,2-d e]qu in olin e-7,8-d ion e (10c). De-
O-methylation of 9k (15 mg, 0.04 mmol) was achieved in dry
CH2Cl2 (1.5 mL) with 4 Å sieves under argon at -78 °C with
BBr3 (0.2 mL of a 1 M solution in CH2Cl2) added dropwise.
The mixture was allowed to warm up to -30 °C over 1.5 h
and then maintained at -30 to -20 °C for 30 min. The
reaction was quenched with saturated aqueous NaHCO3
solution and extracted with CH2Cl2. The combined organic
extracts were dried and concentrated to give a red oil which
was purified by flash column chromatography (CH2Cl2-MeOH
(95:5)) to yield 10c as a red oil which solidified upon storage
(5 mg, 37%). Mp 174-176 °C dec. UV 238 (4.26), 334 (3.95),
515 (3.11). IR (film) 1681, 1607. 1H-NMR (300 MHz) 2.45 (s,
3H); 2.94 (t, J ) 6.7, 2H); 3.08 (s, 3H); 3.61 (t, J ) 6.7, 2H);
5.34 (s, 1H); 7.35 (d, J ) 8.4, 2H); 7.56 (s, 1H); 8.14 (d, J )
8.4, 2H). MS (CI) 357 (M + 1, 42). HRMS: calcd for
C18H17N2O4S 357.0909, found 357.0927.
6,7-Dim et h oxy-1,4-d im et h yl-5-n it r oq u in olin iu m Io-
d id e (12e). Quaternization of 6h (200 mg, 0.76 mmol) was
effected in MeCN (7 mL) with MeI (1.7 mL, 27.2 mmol) at 40
°C for 63 h. The precipitate which formed was filtered, washed
with CH2Cl2, and dried to yield salt 12e as a brown solid (112
mg, 56%). Mp > 230 °C. UV (H2O) 226 (4.37), 270 (3.92), 350
(3.85). IR (KBr) 3436, 3050, 1620, 1590, 1524, 1504, 1282,
1213. 1H-NMR (300 MHz, DMSO-d6) 2.69 (s, 3H); 4.05 (s, 3H);
4.28 (s, 3H); 4.60 (s, 3H); 7.90 (s, 1H); 8.02 (d, J ) 6.1, 1H);
9.32 (d, J ) 6.1, 1H). FABMS 263 (M+, 100). HRMS: calcd
for C13H15N2O4 263.1032, found 263.1030.
1,2-Dih yd r o-6,7-d im e t h oxy-4-(d im e t h oxym e t h yl)-1-
m eth yl-5-n itr oqu in olin e (8c). Salt 12b (300 mg, 0.67 mmol)
in MeOH (20 mL) at 0 °C was reduced with NaBH4 (0.25 g,
6.7 mmol) added in portions over 1.5 h. The mixture was then
stirred for 1 h, solvent removed in vacuo, and the solid residue
was partitioned between EtOAc and aqueous K2CO3 (10% wt/
vol). The organic extracts were dried and concentrated to give
8c as an unstable red oil (200 mg, 92%). UV 218 (4.38), 222
(4.40), 236 (4.49), 272 (3.92), 332 (3.72). IR (film) 1611, 1534,
1499. 1H-NMR (300 MHz) 2.83 (s, 3H); 3.25 (s, 6H); 3.70 (d,
J ) 7.6, 2H); 3.84 (s, 3H); 3.91 (s, 3H); 4.98 (s, 1H); 6.27 (m,
2H). MS (CI) 325 (M + 1, 12), 309 (19), 293 (7), 254 (40), 237
(52), 208 (100), 154 (50).
1,3,4,5-Tetr ah ydr o-7,8-dim eth oxy-5-m eth ylpyr r olo[4,3,2-
d e]qu in olin e (9j) a n d 1,3,4,5-Tetr a h yd r o-7,8-d im eth oxy-
5-m eth yl-1-(4-m eth ylben zen esu lfon yl)p yr r olo[4,3,2-d e]-
qu in olin e (9k ). To Me3OBF4 (180 mg, 1.20 mmol) suspended
in dry CH2Cl2 (8.5 mL) with 4 Å sieves under argon and cooled
to 0 °C was added 6l (191 mg, 0.73 mmol) in CH2Cl2 (3 mL),
dropwise. The mixture was stirred for 22 h at room temper-
ature, the solvent removed in vacuo, and then the residue
redissolved in MeOH (25 mL). NiCl2 (4.28 g, 18.0 mmol) was
added and after 5 min NaBH4 (4.54 g, 120 mmol) was added
rapidly in portions with no external cooling. After 5 min the
reaction was diluted with H2O and extracted with EtOAc. The
organic extracts were dried, concentrated, redissolved in
CHCl3, redried, and evaporated to yield an oil which could be
purified by flash column chromatography (petroleum ether
(40-60)-EtOAc (1:1)) to yield the indole 9j as an oil (20 mg,
12%). UV 232 (4.56), 290 (4.15). IR (film) 3400, 3368, 1621,
1520. 1H-NMR (300 MHz) 2.97 (s, 3H); 3.07 (t, J ) 5.3, 2H);
3.30 (t, J ) 5.3, 2H); 3.95 (s, 3H); 3.97 (s, 3H); 6.03 (s, 1H);
5-(ter t-Bu tyloxyca r bon yl)-2-ch lor o-1,3,4,5-tetr a h yd r o-
7,8-d im eth oxy-1-m eth ylp yr r olo[4,3,2-d e]qu in olin e (9l).
The BOC-protected pyrroloindole 9h (20 mg, 0.06 mmol) was
reacted with N-chlorosuccinimide (10 mg, 0.07 mmol) in CH2-
Cl2 (1 mL) at 0 °C for 10 min. The mixture was diluted with
CH2Cl2, washed with aqueous KCO3, dried, and evaporated
leaving 9l (17 mg, 77%) as an oil: UV 224 (4.54). IR (film)
3382, 2933, 1702, 1159. 1H-NMR (300 MHz) 1.57 (s, 9H); 2.84
(t, J 5.6, 2H); 3.87 (s, 3H); 3.90 (s, 6H); 3.99 (t, J 5.6, 2H); 7.17
(bs, 1H). MS (CI) 367 (M + 1, 100), 311 (98), 267 (32).
HRMS: calcd for C18H2335ClN2O4 367.1344, found 366.1344.
8-Ch lor o-6,7-dim eth oxy-4-m eth yl-5-n itr oqu in olin e (6m ),
4-(Dich lor om eth yl)-6,7-d im eth oxy-5-n itr oqu in olin e (6n ),
a n d 8-Ch lor o-4-(d ich lor om eth yl)-6,7-d im eth oxy-5-n itr o-
qu in olin e (6o). The nitroquinoline 6h (3.00g, 12.1 mmol) in
DMF (38 mL) was heated at 60 °C while NCS (1.8 g, 13.6
mmol) was added in portions (3 × 0.6 g) at 20 min intervals.
After 2 h a further portion of NCS (0.4 g, 3.17 mmol) was added
and the reaction heated for a further 45 min. After cooling,
the mixture was diluted with CH2Cl2 and washed thoroughly
with H2O. The organic phase was dried and concentrated to
give crude material which was purified by flash column
chromatography (CH2Cl2) to give 6o as an oil (0.2 g, 5%). UV
218 (4.34), 246 (4.47), 320 (3.81). IR (film) 1536, 1404. 1H-
NMR (300 MHz) 4.14 (s, 6H); 7.12 (s, 1H); 8.33 (d, J ) 4.7,
1H); 9.18 (d, J ) 4.7, 1H). MS (EI) 350 (M+, 50). HRMS: calcd
for C12H9N2O435Cl3 349.9628, found 349.9624, and 6n as an
oil (0.4 g, 10%). UV (EtOH) 220 (4.13), 248 (4.37), 304 (3.75),
342 (3.96). IR (film ) 1623, 1535. 1H-NMR (300 MHz) 4.07 (s,
3H); 4.10 (s, 3H); 7.08 (s, 1H); 7.75 (s, 1H); 8.14 (d, J ) 4.9,
1H); 8.96 (d, J ) 4.9, 1H). 13C-NMR (75 MHz) 56.7 (q); 62.9
(q); 64.8 (d); 109.9 (s); 111.9 (d); 121.1 (d); 139.5 (s); 142.8 (s);
144.2 (s); 145.4 (s); 150.0 (d); 154.3 (s). MS (EI) 316 (M+, 60),
281 (32), 245 (38). HRMS: calcd for C12H10N2O435Cl2 316.0018,
found 316.0018, and 6m as a solid (1.88 g, 55%). Mp 81-83
°C. UV 224 (4.38), 240 (4.57), 290 (3.85). IR (Film) 2947, 1606,
1538. 1H-NMR (75 MHz) 2.61 (s, 3H); 4.10 (s, 6H); 7.34 (d, J
) 4.3, 1H); 8.88 (d, J ) 4.3, 1H). 13C-NMR (75 MHz) 18.7 (q);
61.4 (q); 63.1 (q); 112.0 (s); 117.6 (s); 125.5 (d); 129.8 (s); 141.9
(s); 145.7 (s); 150.4 (d); 151 (s). MS (EI) 282 (M+, 100).
HRMS: calcd for C12H11N2O435Cl 282.0407, found 282.0410.
8-Ch lor o-4-for m yl-6,7-dim eth oxy-5-n itr oqu in olin e (6p).
The chloroquinoline 6m (5.0 g, 17.7 mmol) was oxidized in

Synthesis of Pyrrolo[4,3,2-de]quinolines
J . Org. Chem., Vol. 62, No. 3, 1997 577
DMSO (75 mL) with a combination of TFA (1.70 mL, 22 mmol),
tBuI (0.46 mL, 3.90 mmol), I2 (4.52 g, 17.8 mmol), and FeCl2
(210 mg, 1.05 mmol) at 80-85 °C for 5 h. The solvent was
removed in vacuo, and the resulting oil was washed with aque-
ous Na2S2O3 (20% wt/vol) and then with aqueous K2CO3 (10%
wt/vol) and extracted with CH2Cl2. The combined organic
extracts were dried and concentrated to give 6p as a solid (3.98
g, 76%). Mp 131.9-133.9 °C: UV 218 (4.32), 240 (4.49), 300
(3.79), 330 (3.75). IR (film) 2952, 1713, 1535. 1H-NMR (300
MHz) 4.10 (s, 3H); 4.14 (s, 3H); 7.84 (d, J ) 6.3, 1H); 9.19 (d,
J ) 6.3, 1H); 10.20 (s, 1H). 13C-NMR (75 MHz) 61.6 (q); 63.4
(q); 114.5 (s); 123.8 (d); 131.5 (s); 138.5 (s); 142.4 (s); 148.3 (s);
150.8 (d); 152.3 (s); 188.6 (d). MS (EI) 296 (M+, 43), 250 (100).
HRMS: calcd for C12H9N2O535Cl 296.0200, found 296.0208.
8-Ch lor o-6,7-d im eth oxy-4-(d im eth oxym eth yl)-5-n itr o-
qu in olin e (6q). The chloro-aldehyde 6p (3g, 10.1 mmol) was
heated at reflux in methanol (300 mL) with 1 M HCl in Et2O
(14.7 mL, 14.7 mmol) for 48 h. The solvent was removed, and
the residue was partitioned between CH2Cl2 and aqueous K2-
CO3 (10% wt/vol). The organic extracts were dried and evapor-
ated to give 6q as a solid (2.9 g, 84%). Mp 79.5-81 °C. UV
(EtOH) 216 (3.98), 242 (4.41), 302 (3.88), 330 (383). IR (film)
1600, 1105. 1H-NMR (300 MHz) 3.38 (s, 6H); 4.10 (s, 3H); 4.12
(s, 3H); 5.61 (s, 1H); 7.93 (d, J ) 4.5, 1H); 9.06 (d, J ) 4.5,
1H). 13C-NMR (75 MHz) 54.0 (2 × q); 61.4 (q); 63.2 (q); 100.0
(d); 116.2 (s); 121.4 (d); 130.9 (s); 139.6 (s); 141.6 (s); 142.5 (s);
147.4 (s); 150.4 (d); 151.2 (s). MS (CI) 100 (MH+, 100), 311
(18), 296 (10). HRMS: calcd for C14H15N2O635Cl 342.0619,
found 342.0622.
5-Am in o-8-ch lor o-1,2,3,4-tetr a h yd r o-6,7-d im eth oxy-4-
(d im eth oxym eth yl)qu in olin e (7e). The chloro-acetal 6q
(300 mg, 0.88 mmol) was reduced in MeOH (30 mL) by adding
first NiCl2 (1.26 g, 5.28 mmol) and then, after 5 min, NaBH4
(1.06 g, 28.2 mmol) in portions as rapidly as possible. After
20 min the reaction was quenched with H2O and extracted
with CH2Cl2. The organic extracts were dried and concen-
trated to give 7e as an oil (222 mg, 80%). UV 228 (4.45), 308
(3.63). IR (film) 1603, 1102. 1H-NMR (300 MHz) 1.60 (m, 1H);
2.13 (m, 1H); 3.23 (m, 1H); 3.41 (m, 2H); 3.37 (s, 3H); 3.44 (s,
3H); 3.81 (s, 3H); 3.92 (s, 3H); 4.40 (bs, 3H); 4.47 (d, J ) 8.7,
1H). 13C-NMR (75 MHz) 22.2 (t); 34.6 (d); 37.5 (t); 51.2 (q);
56.7 (q); 60.6(q); 60.8 (q); 101.0 (s); 102.6 (s); 107.4 (d); 132.3
(s); 137.0 (s); 139.6 (s); 148.3 (s). MS (EI) 316 (M+, 53), 286
(14), 271 (30), 241 (100). HRMS: calcd for C14H21N2O435Cl
316.1190, found 316.1200.
1,3,4,8-Tetr ah ydr o-7-m eth oxypyr r olo[4,3,2-de]qu in olin -
8-on e (11b). Amine 7e (100 mg, 0.32 mmol) heated in aque-
ous HCl (1 N, 1 mL) and THF (1 mL) at 40 °C for 30 min. The
mixture was cooled, and the solvent was evaporated leaving
a residue which was partitioned between saturated aqueous
NaHCO3 and CH2Cl2. The combined organic extracts were
dried and concentrated to give 11b as an oil (41 mg, 64%). UV
240 (3.69), 306 (4.09), 400 (3.12). IR (KBr disc) 1659, 1567.
1H-NMR (200 MHz) 2.78 (t, J ) 7.9, 2H); 3.84 (s, 3H); 4.19 (t,
J ) 7.9, 2H); 6.14 (s, 1H); 6.92 (s, 1H); 10.40 (bs, 1H). 13C-
NMR (75 MHz) 18.8 (t); 51.4 (t); 56.9 (q); 106.8 (d); 117.5 (s);
121.8 (s); 123.1 (d); 124.3 (s); 156.9 (s); 158.8 (s); 171.5 (s). MS
(EI) 202 (M+, 40), 187 (12). HRMS: calcd for C11H10N2O2
202.0742, found 202.0742.
6-Ch lor o-1,5-d ifor m yl-1,3,4,5-t et r a h yd r o-7,8-d im et h -
oxyp yr r olo[4,3,2-d e]q u in olin e (9m ) a n d 6-Ch lor o-1,5-
d ifor m yl-1,2,2a ,3,4,5-h exa h yd r o-2,7,8-tr im eth oxyp yr r olo-
[4,3,2-d e]qu in olin e (13). Reaction of 7e (500 mg, 1.58 mmol)
with Ac2O (3 mL) and formic acid (1.5 mL) at rt for 48 h
followed by evaporation of excess reactant in vacuo gave a
crude residue which was purified by flash column chromatog-
raphy to give 9m as a solid (262 mg, 54%). Mp 79.5-81 °C.
UV 220 (4.23), 250 (4.38), 278 (4.18), 320 (3.86). IR (film) 1702,
1674. 1H-NMR (200 MHz) 2.93 (t, J ) 5.7, 2H); 3.97 (s, 3H);
4.08 (s, 3H); 4.10 (t, J ) 5.7, 2H); 7.56 (s, 1H); 9.05 (s, 1H);
9.71 (s, 1H). 13C-NMR (75 MHz) 22.5 (t); 40.2 (t); 61.1 (q); 61.6
(q); 114.0 (s); 116.7 (d); 117.3 (s); 121.5 (s); 124.6 (s); 125.6 (s);
10%). UV 246 (4.46). IR (film) 1681, 1603. 1H-NMR (200
MHz) 1.98 (m, 1H); 2.23 (m, 1H); 3.24 (m, 1H); 3.55 (s, 3H);
3.79 (m, 1H); 3.96 (m, 1H); 3.95 (s, 3H); 3.96 (s, 3H); 5.91 (d,
J ) 6.1, 1H); 9.08 (s, 1H); 9.26 (s, 1H); 9.71 (s, 1H). 13C-NMR
(75 MHz) 21.5 (t); 40.0 (d); 41.5 (t); 58.0 (q); 60.9 (q); 61.1 (q);
90.3 (d); 114.5 (s); 122.2 (s); 129.3 (s); 129.8 (s); 139.8 (s); 151.3
(s); 161.8 (d); 162.8 (d). MS (CI) 341 (MH+, 36), 281 (52), 247
(100). HRMS: calcd for C15H17N2O535Cl 340.0826, found
340.0818.
6-Ch lor o-5-for m yl-1,3,4,5-t et r a h yd r o-7,8-d im et h oxy-
p yr r olo[4,3,2-d e]qu in olin e (9n ). 9m (250 mg, 0.81 mmol)
was hydrolyzed in CH2Cl2/MeOH (4 mL, 1:1) with aqueous
NaOH (10% wt/vol) (2 mL) at rt for 1 h. The solvent was re-
moved, and the residue was partitioned between CH2Cl2 and
H2O. The organic extracts were dried and evaporated to give
9n as a solid (180 mg, 82%). Mp 214-216. UV 232 (4.58),
292 (4.11). IR (KBr disc) 3435, 1649. 1H-NMR (200 MHz) 2.97
(t, J ) 5.7, 2H); 3.96 (s, 3H); 4.08 (s, 3H); 4.13 (t, J ) 5.7, 2H);
6.93 (bs, 1H); 8.26 (bs, 1H); 9.12 (s, 1H). 13C-NMR (75 MHz)
22.6 (t); 40.8 (t); 61.2 (q); 61.6 (q); 109.7 (s); 110.5 (s); 118.7
(d); 119.4 (s); 124.4 (s); 126.2 (s); 137.3 (s); 144.8 (s); 162.7 (d).
MS (CI) 280 (MH+, 100). HRMS: calcd for C13H13N2O335Cl
280.0615, found 280.0617.
6-Ch lor o-5-for m yl-1,3,4,5-tetr a h yd r o-7,8-d im eth oxy-1-
m eth ylp yr r olo[4,3,2-d e]qu in olin e (9o). N-Methylation of
9n (150 mg, 0.54 mmol) was achieved in THF (2 mL) by
addition dropwise to a suspension of oil-free NaH (39 mg, 1
mmol) in THF (2 mL), stirring at rt for 30 min, and then
refluxing for 15 min. After cooling, MeI (0.4 mL) was added
and the reaction stirred at rt for 20 h. The solvent was re-
moved and the residue partitioned between CH2Cl2 and H2O.
The organic layer was dried and concentrated to give 9o as a
solid (89 mg, 56%). Mp 138-140 °C. UV 240 (475), 298 (4.34).
IR (film) 2936, 1680. 1H-NMR (200 MHz) 2.92 (t, J ) 5.7, 2H);
3.95 (s, 3H); 3.98 (s, 3H); 4.03 (s, 3H); 4.09 (t, J ) 5.7, 2H);
6.69 (s, 1H); 9.08 (s, 1H). 13C-NMR (75 MHz) 34.8 (q); 22.5
(t); 40.7 (t); 61.5 (q); 62.0 (q); 109.0 (s); 120.1 (s); 124.5 (s); 124.6
(d); 126.4 (s); 138.4 (s); 145.3 (s); 162.7 (d). MS (EI) 294 (M+,
100), 279 (40), 251 (61). HRMS: calcd for C14H15N2O335Cl
294.0771, found 294.0775.
6-Ch lor o-1,3,4,5-tetr ah ydr o-7,8-dim eth oxy-1-m eth ylpyr -
r olo[4,3,2-d e]qu in olin e (9p ). Hydrolysis of 9o (50 mg, 0.17
mmol) at reflux with aqueous NaOH (2.5 N) for 24 h was
followed by removal of solvent, and then the residue was dis-
solved in CH2Cl2 which was dried and evaporated to give 9p
as a foam (45 mg, 100%). UV 238 (4.56), 286 (3.96), 312 (3.97).
IR (film) 3372, 2839. 1H-NMR (200 MHz) 2.98 (t, J ) 5.8, 2H);
3.51 (t, J ) 5.8, 2H); 3.95 (s, 9H); 4.31 (bs, 1H); 6.55 (s, 1H).
13C-NMR (75 MHz) 22.7 (t); 34.6 (q); 43.2 (t); 61.5 (q); 62.3 (q);
99.8 (s); 109.2 (s); 115.8(s); 121.8 (d); 126.4 (s); 132.8 (s); 133.6
(s); 145.4 (s). MS (EI) 266 (M+, 100), 251 (72). HRMS: calcd
for C13H15N2O235Cl 266.0822, found 266.0817.
Ack n ow led gm en t. We thank the Gratrix Fund (The
University of Manchester) for a studentship (D.R.) and
for additional funds for work (D.R.) carried out in
Barcelona, CIRIT, Generalitat de Catalunya (QFN 92-
4315 and 96-4701) for generous support including
additional funds for work (M.A.B.) carried out in
Manchester, and Comissionat per a Universitats i
Recerca (Generalitat de Catalunya) for Grant GRQ94-
1009.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 5a -d , 6a -m ,p ,q, 7a ,c-f, 8a -c, 9b-p , 10a -c,
11a ,b, 12a ,b,d ,e, and 13, 13C NMR spectra for compounds 5a -
d , 6a -h ,j-m ,p ,q, 7a ,f, 9e-h ,m -p , 11b, and 13 (83 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
139.4 (s); 148.0 (s); 158.8 (d); 162.2 (d). MS (CI) 326 (M + 18,
35
51), 309 (MH+, 100), 281 (24). HRMS: calcd for C14H13N2O4
-
J O961743Z
Cl 308.0564, found 308.0569, and then 13 as an oil (54 mg,