Lewis Acid-Directed Cyclocondensation of Piperidone Enol Ethers with 2-Methoxy-4-(N-phenylsulfonyl)-1,4-benzoquinoneimine: A New Regioselective Synthesis of Oxygenated Carbolines

Article abstract of DOI:10.1021/jo9916176

Lewis acid-directed cyclocondensations of piperidone enol ethers with 2-methoxy-4-(N-phenylsulfonyl)-1,4-henzoquinoneimine are reported. Benzofurans are obtained with BF₃·OEt₂ as a promoter, whereas use of excess amounts of TiCl₄:Ti(OiPr)₄ leads to tetrahydrocarbolines. The latter reactions provide expedient routes to oxygen-substituted tetrahydrocarbolines and carbolines. As applications of this new methodology, the preparations of 1-[3-(dimethylamino)propyl]amino-7-methoxy- and 1-[3-(dimethylamino)propyl]amino-7,8-dimethoxy-5H-pyrido[4,3-b]indoles are described.

Full text of DOI:10.1021/jo9916176

2444
J . Org. Chem. 2000, 65, 2444-2457
Lew is Acid -Dir ected Cyclocon d en sa tion of P ip er id on e En ol Eth er s
w ith 2-Meth oxy-4-(N-p h en ylsu lfon yl)-1,4-ben zoqu in on eim in e: A
New Regioselective Syn th esis of Oxygen a ted Ca r bolin es
Thomas A. Engler*,† and J utta Wanner
Department of Chemistry, University of Kansas, Lawrence, Kansas 66045
Received October 15, 1999
Lewis acid-directed cyclocondensations of piperidone enol ethers with 2-methoxy-4-(N-phenylsul-
fonyl)-1,4-benzoquinoneimine are reported. Benzofurans are obtained with BF3‚OEt2 as a promoter,
whereas use of excess amounts of TiCl4:Ti(OiPr)4 leads to tetrahydrocarbolines. The latter reactions
provide expedient routes to oxygen-substituted tetrahydrocarbolines and carbolines. As applications
of this new methodology, the preparations of 1-[3-(dimethylamino)propyl]amino-7-methoxy- and
1-[3-(dimethylamino)propyl]amino-7,8-dimethoxy-5H-pyrido[4,3-b]indoles are described.
Lewis acid-directed reactions of substituted quinones1
and imine derivatives2 with styrenyl systems produce
regioisomeric products depending upon the nature of the
Lewis acid. For example, BF3‚OEt2-promoted reactions
of various styrenes with quinone monoimines 1 afford
dihydrobenzofurans (eq 1), whereas use of excess Ti(IV)
as a promoter produces mainly dihydroindoles (eq 2).2b
Sch em e 1
N-sulfonyl-3- and -4-piperidones.6 The choice to use these
alkenyl systems was prompted by two considerations.
The first was to address the question of whether Lewis
acid activation of the quinone imine could be effected in
the presence of other entities with mildly basic function-
alities and thus significantly extend the synthetic scope
of these processes. The second was the expectation that
the products would be valuable intermediates to a variety
of biologically important alkaloids. For example, numer-
ous â-carbolines 2 possess potent and varied CNS and
anticancer activity,7 and γ-carbolines 3 and 4 have been
studied extensively as antitumor agents.8 The latter are
condensed analogues of the ellipticine/olivacine antican-
cer agents (5), and some do indeed display potent activity.
In both carboline systems, oxygenation in the A ring often
results in more biologically active derivatives.
In an effort to extend the lessons learned from these
studies to reactions of the quinone imines with alkenyl
systems other than styrenes, and to further demonstrate
the concept of selective Lewis acid activation of substi-
tuted quinones3,4 and imine derivatives,5 we have ex-
plored reactions of 1 with enol ethers derived from
† Current address: Lilly Corporate Center, Mail Drop 1523, Eli Lilly
and Company, Indianapolis, IN 46285. Phone: (317)433-2885. Fax:
(317)277-2035. E-mail: ENGLER_THOMAS@Lilly.com.
(1) (a) Engler, T. A.; Combrink, K. D.; Letavic, M. A.; Lynch, K. O.,
J r.; Ray, J . E. J . Org. Chem. 1994, 59, 6567-6587. (b) Engler, T. A.;
Wei, D.; Letavic, M. A.; Combrink, K. D.; Reddy, J . P. J . Org. Chem.
1994, 59, 6588-6599. (c) Engler, T. A.; Iyengar, R. J . Org. Chem. 1998,
63, 1929-1934.
(2) (a) Engler, T. A.; Meduna, S. P.; LaTessa, K. O.; Chai, W. J . Org.
Chem. 1996, 61, 8598-8603. (b) Engler, T. A.; Chai, W.; LaTessa, K.
O. J . Org. Chem. 1996, 61, 9297-9308. (c) Engler, T. A.; Chai, W.
Tetrahedron Lett. 1996 37, 6969-6970.
(3) For early studies of Lewis acid-directed Diels-Alder reactions,
see: (a) Dickinson, R. A.; Kubela, R.; MacAlpine, G. A.; Stojanac, Z.;
Valenta, Z. Can. J . Chem. 1972, 50, 2377-2380. (b) Stojanac, Z.;
Dickinson, R. A.; Stojanac, N.; Woznow, R. J .; Valenta, Z. Can. J . Chem.
1975, 53, 616-618. (c) Das, J .; Kubela, R.; MacAlpine, G. A.; Stojanac,
Z.; Valenta, Z. Can J . Chem. 1979, 57, 3308-3319. (d) Tou, J . S.;
Reusch, W. J . Org. Chem. 1980, 45, 5012-5014. (e) Hendrickson, J .
B.; Singh, V. J . Chem. Soc., Chem. Commun. 1983, 837-838. (f)
Hendrickson, J . B.; Haestier, A. M.; Stieglitz, S. G.; Foxman, B. M.
New. J . Chem. 1990, 14, 689-693. (g) Engler, T. A.; Letavic, M. A.;
Lynch, K. O., J r.; Takusagawa, F. J . Org. Chem. 1994, 59, 1179-1183.
For a theoretical discussion of the regioselectivity of these reactions,
see: Rozeboom, M. D.; Tegmo-Larson, I.-M.; Houk, K. N. J . Org. Chem.
1981, 46, 2338-2345.
Piperidone enol ethers 7 and 9 were prepared as shown
in Scheme 1.9 In these syntheses, 9 were formed as the
10.1021/jo9916176 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/23/2000

Synthesis of Oxygenated Carbolines
J . Org. Chem., Vol. 65, No. 8, 2000 2445
Ta ble 1. BF 3-P r om oted Cyclocon d en sa tion s of Qu in on e
Mon oim in e 1 w ith P ip er id on e En ol Eth er s 7/9
Sch em e 2
a
entry quinone imine enol ether equiv of BF3 products (% yield)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1a
1a
1a
1a
1a
1b
1b
7a
7a
7b
7c
7a
9a
9b
9b
9c
9c
9a
9a
1
2
1
1
1
1
1
1
1
1
1
2
10a (85)
10a (77)
10b (65)
10c (71)
11a (66)
13a (68)
18 (48)b
13b (84)c
13c (33) 19 (35)b
13c (80)c
10
11
12
14a (29) 20 (31)b
14a (78)c
a
b
With respect to imine 1. These reactions were quenched with
saturated aqueous NH4Cl and worked up within 30-60 min.
c These reactions were quenched with NH4Cl, and the mixtures
were stirred until no dihydrobenzofurans were apparent by TLC,
see Experimental Section.
major components of mixtures with their C2-C3 alkenyl
isomers (∼4-12:1). These mixtures were used directly
in the following reactions, and the minor components did
not interfere.
BF3‚OEt2-promoted reactions of imines 12b with enol
ethers 7 or 9 cleanly afforded benzofurans 10/11 and 13/
14, respectively (eqs 3 and 5, and Table 1). Distinguishing
we note that reactions of 1a with 7a and of 1b with 9a
were also studied with 2 equiv of BF3‚OEt2 as the
promoter, and again benzofurans 10a and 14a , respec-
tively, were found in good yields (Table 1, entries 2 and
12).
Focus then shifted to Ti(IV)-promoted reactions of
4-piperidone enol ethers 7 with quinone imine 1a . Guided
by our earlier studies involving styrenes,1,2 we anticipated
that reactions employing 1 equiv of Ti(IV) would give
mixtures of products. Indeed, initial reactions of 7a
spectral characteristics of these benzofurans included
N-H absorbancies at ∼3350 cm-1 in their IR spectra and
coupled doublets (J ∼ 2 Hz) at ∼6.5-6.6 and ∼6.6-6.8
ppm (H-7/-9 in 10/11 and H-5/-7 in 13/14) in their 1H
(4) For other examples of Lewis acid-promoted reactions of quinones
with alkenyl systems, see: (a) Engler, T. A.; Agrios, K.; Reddy, J . P.;
Iyengar, R. Tetrahedron Lett. 1996, 37, 327-330. (b) Murphy, W. S.;
Neville, D. Tetrahedron Lett. 1997, 38, 7933-7936. (c) Hosomi, A.;
Sakurai, H. Tetrahedron Lett. 1977, 4041-4044. (d) Hosomi, A.;
Sakurai, H. Tetrahedron Lett. 1978, 2589-2592. (e) Ipaktschi, J .;
Heydari, A. Angew. Chem., Int. Ed. Engl. 1992, 31, 313-314. (f)
Ipaktschi, J .; Heydari, A. Chem. Ber. 1992, 125, 1513-1515. (g) Naruta,
Y. J . Am. Chem. Soc. 1980, 102, 3774-3783. For reviews, see: (h)
Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Tetrahedron Organic Chemistry Series Vol. 9; Pergamon: Oxford,
1992; pp 322-330. (i) Finley, K. T. In The Chemistry of the Quinonoid
Compounds, Vol. 2; Patai, S., Rappaport, Z., Eds.; Wiley: Chichester,
1988; p 537. (j) Nishigaichi, Y.; Takuwa, A.; Naruta, Y. Maruyama, K.
Tetrahedron 1993, 49, 7395-7426. (k) Cintas, P. Synlett 1995, 1087-
1109. (l) Fleming, I, Dunogue´s, J .; Smithers, R. Org. React. 1989 37,
57-575. (m) Naruta, Y.; Nishigaichi, Y.; Maruyama, K. Org. Synth.
1992 71, 125-131. (n) Naruta, Y.; Maruyama, K. In The Chemistry of
Quinonoid Compounds, Vol. 2; Patai, S., Rappoport, Z., Eds.; Wiley-
Interscience: Chichester; 1988, Chapter 8. (o) Mukaiyama, T.; Iwasa-
wa, N.; Yura, T.; Clark, R. S. J . Tetrahedron 1987, 43, 5003-5017. (p)
Nucleophilic additions to quinones bearing electron-withdrawing
groups are common and are not detailed here; see references cited in
the reviews.
NMR spectra. We rationalized that these reactions oc-
curred via intermediates similar to 16-20 (Scheme 2).
Support for this mechanism was found in some of the
reactions of enol ethers 9 in which 2-methoxydihydroben-
zofurans 18-20 were isolated. Treatment of the latter
with protic acid effected elimination to benzofurans 13/
14. These reactions imply that the BF3 activates 1
through binding to the imine moiety, suggesting that it
is the most basic site. For the discussion that follows,

2446 J . Org. Chem., Vol. 65, No. 8, 2000
Engler and Wanner
Ta ble 2. Ti(IV)-P r om oted Cyclocon d en sa tion s of
Qu in on e Mon oim in e 1 w ith P ip er id on e En ol Eth er s 7/9
equiv of
TiCl4:Ti(OiPr)4
products
(% yield)
a
entry
quinone imine
enol ether
1
2
3
4
5
6
1a
1a
1a
1a
1a
1a
7a
7b
7c
9a
9b
9c
2.5:2.5
2.5:2.5
2.5:2.5
2.5:2.5
2.5:2.5
2.5:2.5
12a (82)
12b (85)
12c (78)
15a (71)
15b (32)
15c (80)
F igu r e 1. Possible examples of 2:1 and 1:1 complexes of 1
with Ti(IV).10r The Ti(IV) is likely octahedral in both, and the
other ligands (Cl and OiPr) are not shown for clarity.
a
Equiv of each TiCl4 and Ti(OiPr)4 with respect to imine 1.
reinforced this bias;6 however, in subsequent studies we
found that these reactions promoted by 1 equiv of Ti-
(IV), as either TiCl4 or a 1:1 mixture of TiCl4:Ti(OiPr)4,
were capricious and inefficient. It was difficult to force
them to completion, and mixtures of benzofurans and
indoles were usually produced in low yield accompanied
by large quantities of the piperidone 6a . That both
benzofuran and indole products were often observed,
albeit inconsistently, suggested a competition between
activation of the quinone imine 1 via Ti(IV) binding to
the C-4 imine moiety and activation via bidentate binding
to the C-1/C-2 oxygens (Scheme 2). Inferring that the
BF3‚OEt2-promoted reactions further suggested that the
imine moiety is the more basic site in 1, we postulated
that if more than 1 equiv of Ti(IV) was employed, then
the first might bind to the imine, leaving the second to
bind to the C-1 and C-2 oxygens in a bidentate man-
ner.10a-j If so, binding of the second equivalent perhaps
would lead to a more reactive complex10k such as 21,10r
with the second Lewis acid directing the reaction. An
alternative hypothesis was that in reactions with 1 equiv
of Ti(IV), perhaps considerable amounts of both [imine]2-
Ti(IV)10l-q and 1:1 complexes (Figure 1)10r were present,
leading to the product mixtures observed. Use of excess
Ti(IV) might then drive the reaction to a 1:1 complex in
which the titanium might prefer bidentate binding
through the C-1 and C-2 oxygens in order for the metal
to attain an octahedral coordination sphere.10r Whether
either of these postulates are valid remains to be estab-
lished; however, reactions of 1a with enol ethers 7 using
5 equiv (with respect to 1) of Ti(IV), as a 1:1 mixture of
TiCl4:Ti(OiPr)4, indeed cleanly produced tetrahydrocar-
bolines 12, generally in good yields (eq 4 and Table 2).11
Similar reactions of enol ethers 9 afforded tetrahydro-
carbolines 15 (eq 6). The distinctive spectral features of
the tetrahydrocarbolines included IR OH absorbancies
at ∼3500 cm-1 and singlets at ∼ 6.8 and 7.7 ppm for
1
H-6/-9 in 12 and H-5/-8 in 15 in their H NMR spectra.
Attempts to develop similar Lewis acid-directed reac-
tions of bisimines 24,2a using either 1 equiv of BF3‚OEt2
or 5 equiv of Ti(IV), gave only tetrahydrocarboline
products 25 and 26 (eq 7).6 Carboxamide N-H absor-
bancies at ∼3425 cm-1 in their IR spectra and singlets
at ∼7.7 and 8.5 ppm in their 1H NMR spectra were
indicative of the structures assigned. These results are
consistent with Boger’s findings that BF3‚OEt2-promoted
allylations of 24 with allyltributylstannane take place
selectively at C-5.5a
(5) Boger has contrasted the regiochemical course of thermal versus
BF3-promoted nucleophilic additions to quinone diimines, and Mu-
kaiyama has reported a limited number of trityl perchlorate-promoted
additions of enol ethers to quinone mono- and diimines. See: (a) Boger,
D. L.; Zarrinmayeh, H. J . Org. Chem. 1990, 55, 1379-1390. (b)
Mukaiyama, T.; Sagawa, Y.; Kobayashi, S. Chem. Lett. 1987, 2169-
2172. For an early extensive review of reactions of quinone mono- and
diimines, see: (c) Adams, R.; Reifschneider, W. Bull. Chim. Soc. Fr.
1958, 23-65.
(6) A preliminary communication has appeared: Engler, T. A.;
Wanner, J . Tetrahedron Lett. 1997, 38, 6135-6138.
(7) For reviews, see: (a) Love, B. Org. Prep Proceed. Int. 1996 28,
1-64. (b) Cox, E. D.; Cook, J . M. Chem. Rev. 1995, 95, 1797-1842. (c)
Baker, B. J . In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Pergamon: New York, 1996; Vol. 10. (d) Ohmoto,
T.; Koike, K. In The Alkaloids; Brossi, A., Ed.; Academic: San Diego,
1989; Vol. 36, pp 135-170. For selected examples, see: (e) Braestrup,
C.; Nielson, M.; Olsen, C. E. Proc. Natl. Acad. Sci. U.S.A. 1980, 77,
2288-2292. (f) Abou-Gharbia, M.; Patel, R. U.; Moyer, J . A.; Muth, T.
A. J . Med. Chem. 1987, 30, 1100-1105. (g) Abou-Gharbia, M.; Patel,
R. U.; Webb, M. B.; Moyer, J . A.; Andree, T. H.; Muth, T. A. J . Med.
Chem. 1987, 30, 1818-1823. (h) Diaz-Arauzo, H.; Evoniuk, G. E.;
Skolnick, P.; Cook, J . M. J . Med. Chem. 1991, 34, 1754-1756. (i) Audia,
J . E.; Evrard, D. A.; Murdoch, G. R.; Droste, J . J .; Nissen, J . S.; Schenk,
K. W.; Fludzinski, P.; Lucaites, V. L.; Nelson, D. L.; Cohen, M. L. J .
Med. Chem. 1996, 39, 2773-2780. (j) Tsuchiya, H.; Shimizu, H.;
Iinuma, M. Chem. Pharm. Bull. 1999, 47, 440-443. (k) Ishida, J .;
Wang, H.-K.; Bastow, K. F.; Hu, C.-Q.; Lee, K.-H. Bioorg. Med. Chem.
Lett. 1999, 9, 3319-3324.
Reactions of quinone imine 1a with enol ethers 7/9
provide an expedient route to oxygenated carboline
platforms, substructures found in a number of biologically
active natural products.7,8 In addition, the adducts in-
corporate diverse functionality which can be selectively
manipulated. For example, the phenolic groups in 12 and
15 are methylated under standard conditions, affording
27 and 30, respectively, or reductively removed to give
29 via the derived triflates 28 (Scheme 3). These steps
remove or alleviate concerns about incompatible func-
tionality in the design of subsequent reactions on tet-
rahydrocarbolines 12 or 15 and establish the potential
utility of the triflates for further transformations. Fur-
thermore, the indole phenylsulfonyl group in 27a is
selectively removed by treatment with either K2CO3/
MeOH or RedAl to give 31 (Scheme 4). On the other
hand, the 2-nitrophenylsulfonyl groups in 27c and 30c
are selectively cleaved with HSCH2CO2H/LiOH, affording
32 and 38, respectively (Schemes 4 and 5).12 Although
(8) For reviews, see: (a) Gribble, G. W. In The Alkaloids; Brossi,
A., Ed.; Academic: San Diego, 1990; Vol. 39, Chapter 7. (b) Tan, G.
T.; Pezzuto, J . M. In Chemistry and Toxicology of Diverse Classes of
Alkaloids; Blum, M. S., Ed.; Alaken, Inc.: 1996; pp 1-119. For recent
reports, see: (c) Nguyen, C. H.; Lavelle, F.; Riou, J .-F.; Bissery, M.-
C.; Huel, C.; Bisagni, E. Anti-Cancer Drug Design 1992, 7, 235-251.
(d) Guillonneau, C.; Pierre´, A.; Charton, Y.; Guilbaud, N.; Kraus-
Berthier, L.; Le´once, S.; Michel, A.; Bisagni, E.; Atassi, G. J . Med.
Chem. 1999, 42, 2191-2203, and references therein.
(9) Barbot, F.; Miginiac, P. Helv. Chim. Acta 1979, 62, 1451-1457.

Synthesis of Oxygenated Carbolines
J . Org. Chem., Vol. 65, No. 8, 2000 2447
Sch em e 3a
Sch em e 5a
a
Reagents and conditions: a, HSCH2CO2H, LiOH, DMF, rt; b,
Na, NH3; c, SeO2, dioxane, reflux; d, KOtBu (10 equiv), THF, rt;
e, K2CO3, MeOH/THF.
a direct oxidation/desulfonylation of the tetrahydrocar-
bolines 27a /29a and 30a with SeO2 to produce the
carbolines 34/35 and 40 in good yields.14 These reactions
are a convenient way to access aromatized carbolines
directly from the sulfonylated tetrahydrocarbolines. Des-
ulfonylations of the indole nitrogens in the aromatized
products also occur under mild conditions with K2CO3/
MeOH and afford 36/37 and 41. A double sulfonyl
elimination of 30a to 41 can be effected with excess
KOtBu, and dehydrogenation of 33 to 36 also occurs upon
heating with Pd/C.
a
Reagents and conditions: a, MeI, K2CO3, acetone, reflux; b,
Tf2O, py, -78 °C f warm (see Experimental Section), c, [Pd(OAc)2]3,
1,1′-bis(diphenylphosphino)ferrocene, Et3N/HO2CH, DMF, 90 °C.
Sch em e 4a
To demonstrate the utility of this new carboline
synthesis, we focused on the preparation of compounds
(10) For a general review of Lewis acid complexes with organic
substrates, see: (a) Shambayati, S.; Schreiber, S. In Comprehensive
Organic Synthesis, Vol. 1; Trost, B. M., Fleming, I., Eds.; Pergamon:
New York, 1991; p 283. For suggestions of carbonyl-(Lewis acid)2
complexes as potential intermediates, see ref 2b and (b) Poll, T.; Metter,
J . O.; Helmchen, G. Angew. Chem., Int. Ed. Engl. 1985, 24, 112. (c)
Schultz, A. G.; Lee, H. Tetrahedron Lett. 1992, 33, 4397-4400. (d)
Majetich, G.; Hull, K.; Casares, A. M.; Khetani, V. J . Org. Chem. 1991,
56, 3958-3973. (e) Snider, B. B.; Rodini, D. J .; van Straten, J . J . Am.
Chem. Soc. 1980, 102, 5872. (f) Simard, M.; Vaugeois, J .; Wuest, J . D.
J . Am. Chem. Soc. 1993, 115, 370-372. (g) Sharma, V.; Simard, M.;
Wuest, J . D. J . Am. Chem. Soc. 1992, 114, 7931-7933. (h) Bachand,
B.; Wuest, J . D.; Organometallics 1991, 10, 2015-2025 (and references
cited in 10f-h). (i) Springer, J . B.; DeBoard, J .; Corcoran, R. C.
Tetrahedron Lett. 1995, 36, 8733-8736. (j) Sato, M.; Aoyagi, S.; Yago,
S.; Kibayashi, C. Tetrahedron Lett. 1996, 37, 9063-9066. (k) For
examples, see 10e and references cited in 10f-h. (l) For selected
discussions of [CdO]2Lewis acid complexes, see: Turin, E.; Nielson,
R. M.; Merbach, A. E. Inorg. Chim. Acta 1987, 134, 79-85, 67-78.
(m) Kiyooka, S.-i.; Nakano, M.; Shiota, F.; Fujiyama, R. J . Org. Chem.
1989, 54, 5409-5411. (n) Denmark, S. E.; Almstead, N. G. Tetrahedron
1992, 48, 5565-5578. (o) Denmark, S. E.; Almstead, N. G. J . Am.
Chem. Soc. 1993, 115, 3133-3139. (p) Walker, M. A.; Heathcock, C.
H. J . Org. Chem. 1991, 56, 5747-5750. (q) Pellissier, H.; Toupet, L.;
Santelli, M. J . Org. Chem. 1994, 59, 1709-1713 and references cited
in 10a and 10i. (r) The complete structures of such complexes are
unkown, and they may be mono- or oligomeric.
(11) Ti(IV)-promoted reactions of 1b were not successful; we suspect
that debenzylation is a complicating factor leading to degradation.
(12) (a) Fukuyama, T.; J ow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373-6374. (b) Fukuyama, T.; Cheung, M.; J ow, C.-K.; Hidai,
Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831-5834.
(13) For example, benzylsulfonamides have been reported to cleave
under mild conditions, see: Larghi, E. L.; Kaufman, T. S. Tetrahedron
Lett. 1997, 38, 3159-3162.
(14) Examples of SeO2 oxidations of tetrahydrocarbolines to carbo-
lines are known (see references that follow); however, to our knowledge
this reaction has not been applied to N-sulfonyltetrahydrocarbolines.
(a) Gatta, F.; Misiti, D. J . Heterocycl. Chem. 1987, 24, 1183-1187. (b)
Lopez-Rodriguez, M. L.; Morcillo, J .; Gil, P. J .; Rosado, L.; Ventura, P.
Heterocycles 1994, 37, 1053-1068. (c) Maki, Y.; Kimoto, H.; Fujii, S.
J . Fluorine Chem. 1987, 35, 685-688.
a
Reagents and conditions: a, K2CO3, MeOH/THF, reflux, or
RedAl, THF, rt; b, HSCH2CO2H, LiOH, DMF, rt; c, Na, NH3; d,
SeO2, dioxane, reflux; e, Pd/C, mesitylene, reflux.
only a few of the possible permutations of these selective
desulfonylations have been explored with the various
adducts,13 the reactions presently described do demon-
strate the potential for selective manipulation of the
different N-sulfonyl groups and thus expand the versatil-
ity of 27-30 as intermediates for specific applications.
As expected, removal of both N-sulfonyl moieties from
27b and 30a occurs with Na/NH3, producing 33 and 39,
respectively.
A particularly noteworthy transformation found was

2448 J . Org. Chem., Vol. 65, No. 8, 2000
Engler and Wanner
Sch em e 6
cleanly (Scheme 6), and efforts to convert these N-oxides
to lactams were explored.
Rearrangement of N-oxides 42/43 in refluxing acetic
anhydride at 130 °C led to the formation of complex
mixtures of 44/45 which were difficult to separate. In an
effort to obtain cleaner reactions, the phenylsulfonyl
groups were removed from 42/43 with K2CO3 in THF/
H2O, affording N-oxides 46 as white solids, which rapidly
colorized when open to air. Thus, these oxides were
prepared and used immediately in subsequent experi-
ments. Reactions with acetic anhydride carried out at
30-80 °C yielded acetylated N-oxides 47/48 as the sole
products. Rearrangement reactions carried out in reflux-
ing acetic anhydride afforded again mixtures of the
desired lactams 49/50 and their acetylated derivatives
45. Eventually a reaction protocol was developed that
effected deacetylation and desulfonylation of the product-
(s) as part of the workup. Thus, the crude reaction
mixtures from the acetic anhydride rearrangements of
42 and 43 were treated with potassium carbonate/MeOH
to remove any remaining N-phenylsulfonyl groups, and
18
LiOH/H2O2 was then employed to remove any remain-
ing acetyl groups. Lactams 49/50 were obtained in 54%
and 48% overall yields, respectively.
Lactams 49/50 could be converted to the chlorocarbo-
lines 51/52 by treatment with hot POCl3, and 51 did
undergo displacement with N,N-dimethyl-1,3-diamino-
propane to afford the desired aminocarboline in 46%
yield; however, we sought an overall more efficient
route.19 We found that reactions of the sulfonylated
N-oxides 42/43 with POCl3 produced chlorocarbolines 53/
54 directly and regioselectively in good yield (Scheme 7).20
This result suggested a direct synthesis of the desired
products 55/56 via concomitant chloride displacement
and desulfonylation. Thus, treatment of 53/54 with N,N-
(16) Among the oxidants examined for 27a were (py)2CrO3, PCC,
TPAP/NMO, Hg(OAc)2, Cr(CO)6/tBuOOH,16a and KMnO4/18-crown-616b
or Et3NBnCl.16c Reaction with aqueous RuO2/NaIO416d produced small
amounts of A (by TLC). Attempts to oxidize 33 were made with
MnO2,16e (COCl)2/DMSO,16f and NaOCl/NaOMe.16g One attempt to
oxidize 31 with aqueous DDQ16h was made without success. For
examples of similar oxidations, see: (a) Pearson, A. J .; Chen, Y.-S.;
Han, G. R.; Hsu, S.-Y.; Ray, T. J . Chem. Soc., Perkin Trans. 1 1985,
267-273. Pearson, A. J .; Han, G. R. J . Org. Chem. 1985, 50, 2791-
2792. (b) Venkov, A. P.; Statkova-Abeghe, S. M. Tetrahedron 1996,
52, 1451-1460. (c) Markgraf, J . H.; Sangani, P. K.; Finkelstein, M.
Synth. Commun. 1997, 27, 1285-1290. (d) Perrone, R.; Bettoni, G.;
Tortella, V. Synthesis 1976, 598-600. (e) Sanmartin, R.; Martinez de
Marigorta, E.; Moreno, I.; Dominguez, E. Heterocycles 1997, 45, 757-
763. (f) Keirs, D.; Overton, K. J . Chem. Soc., Chem. Commun. 1987,
1660-1661. (g) Hanquet, G.; Lusinchi, X.; Milliet, P. Tetrahedron 1993,
49, 423-438. (h) Oikawa, Y.; Yonemitsu, O. J . Org. Chem. 1977, 42,
1213-1216.
related to the antitumor agents 4 and 5. SAR studies on
the γ-carboline system 4 and the ellipticines/olivacines
(5) and have been extensive.8 These studies have estab-
lished the importance of ring A oxygenation, particularly
at C-8 and C-9, respectively, and also revealed that
alkylamino groups at C-1 in both series led to improved
DNA binding and antitumor properties. Initially a route
to ring A oxygenated/C-1-amino carbolines via pyridones
49/50 and chlorocarbolines 51/52 was envisioned (Scheme
6). Bisagni has shown that pyridone moieties in similar
systems can be converted in this way to the alkylami-
nopyridine unit found in 4.8c,15 Using the successful
oxidation of the tetrahydrocarbolines 27a /29a to fully the
aromatized carbolines 34/35 as a guide, a number of
attempts were made to oxidize 27a , 31, or 33 under
conditions where one of the presumed intermediates
might be trapped by water or the oxidant to form the
pyridones directly.16 Unfortunately, either little or no
reaction was observed or complex mixtures were obtained
with much apparent degradation.17 However, oxidations
of 34 and 35 with MCPBA provided N-oxides 42 and 43
(17) Reactions with CrO3 (3 equiv)/HOAc in EtOAc17a and NBS (1-5
equiv)/AIBN/hυ17b produced modest quantities of A17c and B (10-20%
and 28-36%, respectively). (a) Burnham, J . W.; Duncan, W. P.;
Eisenbraun, E. J .; Keen, G. W.; Hamming, M. C. J . Org. Chem. 1974,
39, 1416-1420. (b) Stanley, A. L.; Stanforth, S. P. J . Heterocycl. Chem.
1995, 32, 569-571. (c) Similar ring-opening oxidations of indoles are
known, see: Witkop, B.; Patrick, J . B. J . Am. Chem. Soc. 1950, 72,
633-634. Witkop, B.; Patrick, J . B. J . Am. Chem. Soc. 1951, 73, 2196-
2200. Experimental procedures and spectral data for A/B are included
in the Supporting Information.
(15) (a) Bisagni, E.; Nguyen, C. H.; Pierre´, A.; Pe´pin, O.; Cointet
de, P.; Gros, P. J . Med. Chem. 1988, 31, 398-405. (b) Nguyen, C. H.;
Bisagni, E. Tetrahedron 1986, 42, 2303-2309. (c) Nguyen, C. H.;
Bisagni, E. Tetrahedron 1986, 42, 2311-2318. (d) Nguyen, C. H.;
Bisagni, E. Tetrahedron 1987, 43, 527-535. See also: (e) Harada, K.;
Someya, H.; Zen, S. Heterocycles 1994, 38, 1867-1880.
(18) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141-6144.

Synthesis of Oxygenated Carbolines
J . Org. Chem., Vol. 65, No. 8, 2000 2449
Sch em e 7
2-m et h oxy-4-(N-ph en ylsu lfon yl)-1,4-ben zoqu in on e-
imine. These reactions demonstrate the versatility of this
new indole synthesis and further extend the synthetic
scope of Lewis acid-directed reactions of benzoquinones
and imine derivatives. In addition, a number of trans-
formations of the cycloadducts are described that lay the
groundwork for other specific applications.
Exp er im en ta l Section
Gen er a l. All reactions were done in flame-dried glassware
under an atmosphere of argon or nitrogen with magnetic
stirring. Thin-layer chromatography (TLC) was done on pre-
coated silica plates (Art. 5715, Merck) containing a 254 nm
fluorescent indicator and developed in the indicated solvent
systems. Visualization was effected with a UV lamp and/or
by staining with either p-anisaldehyde/H2SO4 or phosphomo-
lybdic acid solutions. Chromatography refers to flash chroma-
tography on silica gel, unless stated otherwise. NMR spectra
were recorded at room temperature in deuteriochloroform and
referenced to tetramethylsilane (TMS) or residual CHCl3
unless specified otherwise.
Su lfon yl-4-p ip er id on es 6a -c. Benzenesulfonyl chloride
(5 mL, 39 mmol) was added to a slurry of K2CO3 (8.9 g, 64
mmol) and 4-piperidone monohydrate hydrochloride (3.8 g, 25
mmol) in H2O (30 mL)/CHCl3 (30 mL). The reaction mixture
was stirred at room temperature for 10 h, and then the
reaction was quenched by the addition of saturated aqueous
NaHCO3. The aqueous layer was separated and extracted with
CH2Cl2 (3×), and the combined organic extracts were dried
(Na2SO4) and concentrated. Chromatography (EtOAc/hexanes
3/2) afforded 6a (5.6 g, 95%) as a white solid, mp 117.5-118.5
°C (CH2Cl2/hexanes): TLC Rf 0.26 (EtOAc/hexanes 2/3); 1H
NMR (400 MHz) 7.82 (br d, 2H, J ) 8, <2), 7.65 (br t, 1 H, J
) 8, <2), 7.57 (br t, 2H, J ) 8, <2), 3.42 (t, 4H, J ) 6), 2.55 (t,
4H, J ) 6); 13C NMR (100 MHz) 205.2, 136.4, 133.2, 129.3,
127.4, 45.8, 40.6; FABMS m/z 240 (M + H+); HRMS m/z
240.0704 (M + H+) (calcd for C11H14O3NS, 240.0694).
dimethyl-1,3-propanediamine at 160-170 °C afforded the
1
diamines 55/56 of about 70% purity by H NMR. Chro-
matography of these products was difficult, so they were
converted to their BOC derivatives 57/58, which were
easily chromatographed, and the BOC groups were then
removed under mild conditions. Pure 55/56 were obtained
in 31% and 53% overall yields from 53 and 54, respec-
tively. Finally it is noted that reactions of the chlorocar-
bolines 53/54 at lower temperatures (130 °C) produced
mixtures of 55/56, accompanied by sulfonylated products
59/60.
In summary, a new route to oxygenated carboline
platforms is detailed. The process involves a Lewis acid-
directed cyclocondensation of piperidone enol ethers with
Similarly prepared were 6b and 6c; 6b (95%) was isolated
by recrystallization of the crude reaction mixture after workup,
and 6c (88%) was obtained by chromatography.
(19) Conversion of lactam 49 to triflate C was explored in anticipa-
tion that displacement of the triflate with amines could be effected
under conditions milder than those required for chloride displacement.
Triflate C was formed upon treatment of 49 with Tf2O/py; however, it
was quite a sensitive species. Upon standing at room temperature, C
rearranged to a new compound whose spectral data were consistent
with those of structure E. Treatment of C with N,N-1,3-propanedi-
amine at room temperature produced only original lactam 49; a result
also found with the tosyl derivative D. At higher temperatures, reaction
of C with N,N-dimethyl-1,3-propanediamine unexpectedly produced
a product possessing the molecular formula C18H23O3N3 rather than
the expected C18H23O2N4. Spectral data for this compound are consis-
tent with either lactam F or imino-pyran G. We rationalize that the
mechanism by which F /G arises first involves rearrangement of C to
E followed by attack of the diamine on the carbonyl group and collapse
of the tetrahedral intermediate to a ring-opened intermediate. Tau-
tomerization followed by ring closure completes the process. Further
experiments along these lines were abandoned in favor of the shorter,
less laborious route shown in Scheme 7. Experimental details for the
preparation of C-F /G and spectral data are included in the Supporting
Information.
Physical and spectral data for 6b: a white solid, mp 172-
173 °C (CH2Cl2/hexanes); TLC Rf 0.21 (EtOAc/hexanes 2/3);
1H NMR (400 MHz) 7.41 (s, 5H), 4.32 (s, 2H), 3.39 (t, 4H, J )
6), 2.42 (t, 4H, J ) 6); 13C NMR (100 MHz) 206.3, 130.9, 129.5,
129.4, 129.1, 58.9, 46.1, 42.2; FABMS m/z 254 (M + H+);
HRMS m/z 254.0878 (M + H+) (calcd for C12H16O3NS, 254.0851).
Physical and spectral data for 6c: a white solid, mp 121-
122 °C (CH2Cl2/hexanes); TLC Rf 0.34 (EtOAc/hexanes 3/2);
1H NMR (400 MHz) 8.11-8.08 (m, 1H), 7.78-7.69 (m, 3H),
3.69 (t, 4H, J ) 6), 2.60 (t, 4H, J ) 6); 13C NMR (100 MHz)
205.8, 148.5, 134.5, 132.5, 132.3, 131.4, 124.8, 45.9, 41.6;
FABMS m/z 285 (M + H+); HRMS m/z 285.0544 (M + H+)
(calcd for C11H13O5N2S, 285.0545).
Su lfon yl-3-piper idon es 8a-c. 2-Nitrobenzenesulfonyl chlo-
ride (10.0 g, 45 mmol) was added to a slurry of K2CO3 (14.7 g,
0.1 mol) and 3-hydroxypiperidine hydrochloride (5.6 g, 41
mmol) in H2O (50 mL)/CHCl3 (50 mL). The reaction mixture
was stirred at room temperature for 10 h, and then the
reaction was quenched by the addition of saturated aqueous
sodium NaHCO3. The aqueous layer was separated and
extracted with CH2Cl2 (3×), and the combined organic extracts
were dried (Na2SO4) and concentrated. The resultant alcohol
was dissolved in acetone, and J ones reagent was added until
the reaction mixture stayed orange and no alcohol was
detectable by TLC analysis. Water was added, and the reaction
mixture was extracted with Et2O (5×). The combined organic
extracts were washed with saturated aqueous NaHCO3, dried
(Na2SO4), and concentrated. Chromatography (EtOAc/hexanes
1/9 to 3/7) afforded 8c (10.2 g, 88%) as a white solid, mp 86-
87.5 °C (CH2Cl2/hexanes): TLC Rf 0.25 (EtOAc/hexanes 3/2);
1H NMR (400 MHz) 8.05-8.02 (m, 1H), 7.78-7.66 (m, 3H),
3.89 (s, 2H), 3.60 (t, 2H, J ) 6), 2.50 (t, 2H, J ) 6), 2.08
(apparent quintet, 2H, J ) 6); 13C NMR (100 MHz) 202.2,
(20) Lee, C.-S.; Ohta, T.; Shudo, K.; Okamoto, T. Heterocylces 1981,
16, 1081-1084.

2450 J . Org. Chem., Vol. 65, No. 8, 2000
Engler and Wanner
147.9, 133.8, 131.5, 131.0, 130.9, 124.1, 54.6, 43.9, 37.6, 22.6;
FABMS m/z 285 (M + H+); HRMS m/z 285.0551 (M + H+)
(calcd for C11H13O5N2S, 285.0545).
Similarly prepared were 8a (74%) and 8b (83%); both were
isolated by chromatography (EtOAc/hexanes 3/7).
9b, as a 12:1 mixture with its 2,3 double bond isomer: TLC
Rf 0.40 (EtOAc/hexanes 2/3); H NMR (400 MHz) 7.43-7.38
1
(m, 5H), 4.70 (t, 1H, J ) 4), 4.28 (s, 2H), 3.60 (m, 2H), 3.53 (s,
3H), 3.18 (t, 2H, J ) 6), 2.16-2.10 (m, 2H); 13C NMR (125
MHz, 1 aromatic carbon is not apparent) 151.6, 131.1, 129.14,
129.11, 92.0, 57.8, 54.7, 45.8, 43.7, 24.0; FABMS m/z 268 (M
+ H+); HRMS m/z 268.0983 (M + H+) (calcd for C13H18O3NS,
268.1007).
Physical and spectral data for 8a : a white solid, mp 85-86
°C (CH2Cl2/hexanes); TLC Rf 0.40 (EtOAc/hexanes 2/3); 1H
NMR (400 MHz) 7.80 (d, 2H, J ) 7), 7.65 (t, 1H, J ) 7), 7.59
(t, 2H, J ) 7), 3.64 (s, 2H), 3.33 (t, 2H, J ) 6), 2.40 (t, 2H, J
) 6), 2.04 (apparent quintet, 2H, J ) 6); 13C NMR (100 MHz)
202.9, 136.2, 133.7, 129.8, 128.1, 56.1, 44.9, 38.4, 23.1; FABMS
m/z 240 (M + H+); HRMS m/z 240.0694 (M + H+) (calcd for
9c, as a 4:1 mixture with its 2,3 double bond isomer: TLC
1
Rf 0.48 (EtOAc/hexanes 2/3); H NMR (400 MHz) 8.02-8.00
(m, 1H), 7.74-7.58 (m, 3H), 4.74 (t, 1H, J ) 4), 3.76 (m, 2H),
3.54 (s, 3H), 3.43 (t, 2H, J ) 6), 2.29-2.24 (m, 2H); 13C NMR
(125 MHz, 1 aromatic carbon is not apparent) 150.7, 147.3,
133.6, 131.5, 130.8, 124.1, 91.5, 54.4, 45.2, 43.2, 23.2; FABMS
m/z 298 (M+); HRMS m/z 299.0712 (M + H+) (calcd for
C
11H14O3NS, 240.0694).
Physical and spectral data for 8b: a white solid, mp 128-
129 °C (CH2Cl2/hexanes); TLC Rf 0.19 (EtOAc/hexanes 2/3);
1H NMR (400 MHz) 7.41 (s, 5H), 4.29 (s, 2H), 3.62 (s, 2H),
3.33 (t, 2H, J ) 6), 2.42 (t, 2H, J ) 6), 1.90 (apparent quintet,
2H, J ) 6); 13C NMR (100 MHz) 203.3, 131.0, 129.5, 129.4,
129.0, 58.2, 55.9, 44.9, 38.4, 23.8; FABMS m/z 254 (M + H+);
HRMS m/z 254.0836 (M + H+) (calcd for C12H16O3NS, 254.0851).
P ip er id on e Meth yl En ol Eth er s 7a -c a n d 9a -c. A
solution of ketone 6a (2.87 g, 12 mmol) was dissolved in
trimethyl orthoformate (30 mL), and a small amount of
p-TsOH‚H2O was added. The reaction mixture was stirred
until no starting material was detectable by TLC analysis (∼5
h), and then the reaction was quenched by the addition of
saturated aqueous NaHCO3. The aqueous layer was separated
and extracted with Et2O (4×), and the combined organic
extracts were dried (Na2SO4) and concentrated to yield the
crude dimethyl ketal (2.97 g, 87%). This product (2.65 g, 9.5
mmol) was dissolved in Et2O (80 mL) and added to a slurry of
AlCl3 (2.45 g, 18.8 mmol) and Et3N (5.5 mL, 40 mmol) in Et2O
(20 mL). The reaction mixture was again stirred at room
temperature until no dimethyl ketal was detectable by TLC
analysis (∼72 h) and then decanted onto 5 N NaOH (100-
200 mL). The aqueous layer was separated and extracted with
Et2O (3×), and the combined extracts were dried (Na2SO4) and
concentrated to give 7a (1.68 g, 71%) as a white solid, mp
67.5-68 °C (CH2Cl2/hexanes): TLC Rf 0.37 (EtOAc/hexanes
2/3); 1H NMR (400 MHz) 7.82 (br d, 2H, J ) 8, <2), 7.61 (br t,
1 H, J ) 8, <2), 7.55 (br t, 2H, J ) 8, <2), 4.53 (t, 1H, J ) 3),
3.68 (m, 2H), 3.50 (s, 3H), 3.28 (t, 2H, J ) 6), 2.26 (br t, 2H,
J ) 6); 13C NMR (100 MHz) 154.0, 137.1, 133.1, 129.4, 128.0,
89.7, 54.7, 44.1, 43.4, 28.3; FABMS m/z 254 (M + H+); HRMS
m/z 254.0843 (M + H+) (calcd for C12H16O3NS, 254.0851). This
material was used in subsequent reactions without further
purification.
C
12H15O5N2S, 299.0702).
Gen er a l P r oced u r e A: BF 3‚Et2O-P r om oted Rea ction s
of En ol Eth er s 7 a n d 9 w ith Mon o- a n d Diim in es 1 a n d
24. BF3‚Et2O was added to a solution of the imine in CH2Cl2
maintained at -78 °C, followed, after 5-10 min, by the enol
ether as a solution in CH2Cl2. The reaction mixture was
allowed to warm to room temperature and stirred until no
starting material was detected by TLC (∼10 h), unless speci-
fied otherwise, and then the reaction was quenched with
saturated aqueous NH4Cl. In reactions of 7, the resulting
mixture was stirred for 15-30 min, and the aqueous layer was
then separated and extracted with CH2Cl2 (3×). The combined
organic extracts were washed with brine, dried (Na2SO4), and
concentrated, and the residue was purified by chromatography
to give benzofurans as the only products. In reactions with 9,
the elimination of MeOH was slow in some cases, and
2-methoxydihydrobenzofurans could be isolated. To obtain the
benzofurans as the sole products, the reaction mixtures after
quenching were stirred until no 2-methoxydihydrobenzofuran
was detectable by TLC analysis; the aqueous layers were then
separated and extracted with CH2Cl2 (3×). The combined
organic extracts were washed with brine, dried (Na2SO4), and
concentrated, and the residues were purified by chromatog-
raphy.
Gen er a l P r oced u r e B: Ti(IV)-P r om oted Rea ction s of
En ol Eth er s 7 a n d 9 w ith Mon o- a n d Diim in es 1 a n d 24.
TiCl4 was added to a solution of Ti(OiPr)4 in CH2Cl2 at 0 °C.
The resultant solution was stirred for 10-15 min, allowed to
warm to room temperature, and then transferred via syringe
to a solution of the imine in CH2Cl2 maintained at -78 °C.
After 5-10 min, the enol ether was added as a solution in CH2-
Cl2. The reaction mixture was allowed to warm to room
temperature over ∼10 h, unless specified otherwise, and then
the reaction was quenched with saturated aqueous NH4Cl. The
resulting mixture was stirred for 30 min and filtered through
Celite. The aqueous layer was separated and extracted with
CH2Cl2 (3×). The combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated. The residue was
purified by chromatography and/or recrystallization.
Similarly prepared were 7b (62%), 7c, (64%), 9a (78%), 9b
(59%), and 9c (62%); in these reactions, the formation of the
ketals required ∼10 h, and the elimination reactions took 12-
48 h. Physical and spectral properties for these compounds
follow.
7b: a white solid, mp 117-118 °C (CH2Cl2/hexanes); TLC
1
Rf 0.45 (EtOAc/hexanes 2/3); H NMR (400 MHz) 7.41-7.37
N -(2-B e n ze n e s u lfo n y l-6-m e t h o x y -1,2,3,4-t e t r a h y -
d r ob en zo[4,5]fu r o[3,2-c]p yr id in -8-yl)b en zen esu lfon a -
m id e (10a ). According to general procedure A, BF3‚Et2O (54
µL, 0.44 mmol) was added to a solution of monoimine 1a (121
mg, 0.44 mmol) in CH2Cl2 (2 mL) at -78 °C, followed by a
solution of enol ether 7a (121 mg, 0.44 mmol) in CH2Cl2 (2
mL). Workup and chromatography (CH2Cl2/Et2O/hexanes 1/1/
3) afforded 10a (141 mg, 65%) as a colorless solid, mp 192-
192.5 °C (CH2Cl2/hexanes): TLC Rf 0.15 (CH2Cl2/Et2O/hexanes
(m, 5H), 4.52 (t, 1H, J ) 3), 4.25 (s, 2H), 3.75 (m, 2H), 3.52 (s,
3H), 3.26 (t, 2H, J ) 6), 2.09 (br t, 2H, J ) 6); 13C NMR (100
MHz) 154.3, 131.1, 129.4, 129.13, 129.11, 90.4, 57.7, 54.7, 43.9,
43.2, 28.6; FABMS m/z 267 (M+); HRMS m/z 268.1003 (M +
H+) (calcd for C13H18O3NS, 268.1007).
7c: a white solid, mp 145.5-146.5 °C (CH2Cl2/hexanes);
1
TLC Rf 0.36 (EtOAc/hexanes 3/2); H NMR (400 MHz) 8.02-
8.00 (m, 1H), 7.73-7.62 (m, 3H), 4.59 (br t, 1H), 3.90 (m, 2H),
3.53 (s, 3H) overlapping with 3.53 (t, 2H, J ) 6), 2.29 (br t,
2H, J ) 6); 13C NMR (100 MHz) 154.2, 148.7, 134.0, 132.4,
132.0, 131.2, 124.5, 89.9, 54.8, 43.9, 43.3, 28.4; HRMS m/z
298.0626 (M+) (calcd for C12H14O5N2S, 298.0623).
1
3/3/4); H NMR (400 MHz) 7.88-7.86 (m, 2H), 7.77-7.75 (m,
2H), 7.65-7.42 (m, 6H), 6.82 (br s, 1H), 6.71 (d, 1H, J ) 2),
6.53 (d, 1H, J ) 2), 4.22 (br s, 2H), 3.87 (s, 3H), 3.55 (t, 2H, J
) 6), 2.90 (br t, 2H, J ) 6); 13C NMR (125 MHz) 152.0, 145.0,
141.8, 138.7, 136.8, 133.03, 133.01, 132.1, 129.3, 129.0, 127.6,
127.4, 127.3, 110.1, 105.5, 103.1, 56.2, 43.3, 42.3, 24.1. Anal.
Calcd for C24H22O6S2N2: C, 57.81; H, 4.45; N, 5.62. Found: C,
57.42; H, 4.80; N, 5.28.
9a , as a 4:1 mixture with its 2,3 double bond isomer: TLC
1
Rf 0.51 (EtOAc/hexanes 2/3); H NMR (400 MHz) 7.81-7.75
(m, 2H), 7.65-7.50 (m, 3H), 4.64 (t, 1H, J ) 4), 3.52 (m, 2H),
3.49 (s, 3H), 3.14 (t, 2H, J ) 6), 2.24-2.19 (m, 2H); 13C NMR
(125 MHz, 1 aromatic carbon is not apparent) 150.7, 132.8,
129.0, 127.6, 91.2, 54.3, 45.6, 43.2, 23.0; FABMS m/z 254 (M
+ H+); HRMS m/z 254.0840 (M + H+) (calcd for C12H16O3NS,
254.0851).
In another experiment according to general procedure A,
BF3‚Et2O (73 µL, 0.59 mmol) was added to a solution of
monoimine 1a (83 mg, 0.30 mmol) in CH2Cl2 (2 mL) at -78
°C, followed by a solution of enol ether 7a (78 mg, 0.31 mmol)

Synthesis of Oxygenated Carbolines
J . Org. Chem., Vol. 65, No. 8, 2000 2451
in CH2Cl2 (2 mL). After warming to room temperature over
10 h, workup and chromatography (CH2Cl2/Et2O/hexanes 3/3/
4) afforded 10a (115 mg, 77%) as a colorless solid.
(1.35 g, 4.87 mmol) in CH2Cl2 (10 mL) at -78 °C, followed by
a solution of enol ether 7b (1.30 g, 4.87 mmol) in CH2Cl2 (5
mL). Workup and chromatography (EtOAc/hexanes 1/9 to 3/7)
afforded 12b (2.13 g, 85%) as a colorless solid: mp 170-171.5
°C (CH2Cl2/hexanes); TLC Rf 0.54 (EtOAc/hexanes 3/2); 1H
NMR (400 MHz) 7.71 (s, 1H) 7.69 (d, 2H, J ) 8), 7.53 (t, 1H,
J ) 8), 7.42 (t, 2H, J ) 8), 7.34-7.26 (m, 5 H), 6.68 (s, 1H),
5.64 (br s, 1H), 4.24 (s, 2H), 4.15 (br s, 2H), 3.99 (s, 3H), 3.42
(t, 2H, J ) 6), 2.97 (br t, 2H, J ) 6); 13C NMR (125 MHz) 145.4,
143.6, 138.5, 133.9, 131.2, 130.5, 130.0, 129.4, 128.8, 128.77,
128.6, 126.1, 121.1, 115.3, 102.3, 98.0, 57.8, 56.5, 43.4, 42.5,
25.7; HRMS m/z 512.1063 (M+) (calcd for C25H24N2O6S2,
512.1076).
N -(2-B e n z e n e s u lfo n y lm e t h y l-6-m e t h o x y -1,2,3,4-
t et r a h yd r ob en zo[4,5]fu r o[3,2-c]p yr id in -8-yl)b en zen e-
su lfon a m id e (10b). According to general procedure A, BF3‚
Et2O (65 µL, 0.53 mmol) was added to a solution of monoimine
1a (139 mg, 0.50 mmol) in CH2Cl2 (2 mL) at -78 °C, followed
by a solution of enol ether 7b (136 mg, 0.51 mmol) in CH2Cl2
(2 mL). Workup and chromatography (EtOAc/hexanes 3/7)
afforded 10b (218 mg, 85%) as a white solid, mp 177-178 °C
(CH2Cl2/hexanes): TLC Rf 0.37 (EtOAc/hexanes 1/1); 1H NMR
(400 MHz) 7.77 (d, 2H, J ) 7), 7.57 (t, 1H, J ) 7), 7.46 (t, 2H,
J ) 7), 7.38-7.32 (m, 5H), 6.76 (br s, 1H), 6.60 (d, 1H, J ) 2),
6.56 (d, 1H, J ) 2), 4.32 (s, 2H), 4.23 (br s, 2H), 3.90 (s, 3H),
3.48 (t, 2H, J ) 6), 2.69 (br t, 2H, J ) 6); 13C NMR (125 MHz)
152.3, 145.0, 141.7, 138.8, 133.0, 132.1, 130.5, 129.0, 128.9,
128.8, 128.7, 127.4, 127.3, 110.5, 105.5, 103.1, 58.1, 56.2, 43.2,
42.1, 24.6; HRMS m/z 512.1081 (M+) (calcd for C25H24O6S2N2,
512.1076).
N -[6-M e t h o x y -2-(2-n i t r o b e n z e n e s u lfo n y l-1,2,3,4-
t et r a h yd r ob en zo[4,5]fu r o[3,2-c]p yr id in -8-yl)b en zen e-
su lfon a m id e (10c). According to general procedure A, BF3‚
Et2O (40 µL, 0.33 mmol) was added to a solution of monoimine
1a (86 mg, 0.31 mmol) in CH2Cl2 (2 mL) at -78 °C, followed
by a solution of enol ether 7c (93 mg, 0.31 mmol) in CH2Cl2 (2
mL). Workup and chromatography (EtOAc/hexanes 3/7 to 1/1)
afforded 10c (120 mg, 71%) as a white solid: mp 186-188 °C
(CH2Cl2/hexanes); TLC Rf 0.19 (EtOAc/hexanes 1/1); 1H NMR
(400 MHz) 8.10-8.07 (m, 1H), 7.77 (d, 2H, J ) 7), 7.76-7.71
(m, 2H), 7.66-763 (m, 1H), 7.53 (t, 1H, J ) 7), 7.42 (t, 2H, J
) 7), 7.32 (s, 1H), 6.75 (d, 1H, J ) 2), 6.56 (d, 1H, J ) 2), 4.43
(br s, 2H), 3.84 (s, 3H), 3.77 (t, 2H, J ) 6), 2.90 (br t, 2H, J )
6); 13C NMR (125 MHz) 152.0, 147.9, 144.9, 141.6, 138.5, 133.9,
133.0, 132.3, 132.0, 131.9, 130.8, 129.0, 127.4, 127.2, 124.3,
110.2, 105.3, 102.9, 56.1, 43.2, 42.1, 24.2; HRMS m/z 543.0774
(M+) (calcd for C24H21O8S2N3, 543.0770).
N -(2-Be n ze n e su lfon yl-6-b e n zyloxy-1,2,3,4-t e t r a h y-
d r ob en zo[4,5]fu r o[3,2-c]p yr id in -8-yl)b en zen esu lfon a -
m id e (11a ). According to general procedure A, BF3‚Et2O (32
µL, 0.26 mmol) was added to a solution of monoimine 1b (92
mg, 0.26 mmol) in CH2Cl2 (2 mL) at -78 °C, followed by a
solution of enol ether 7a (67 mg, 0.26 mmol) in CH2Cl2 (1 mL).
Workup and chromatography (CH2Cl2/Et2O/hexanes 1/1/3)
afforded 11a (99 mg, 66%) as a white solid: mp 113-114 °C
(CH2Cl2/hexanes); TLC Rf 0.50 (EtOAc/hexanes 3/2); 1H NMR
(400 MHz) 7.86-7.84 (m, 2H), 7.64-7.32 (m, 13H), 6.64 (d,
1H, J ) 2), 6.60 (d, 1H, J ) 2), 6.50 (br s, 1H), 5.14 (s, 2H),
4.19 (br s, 2H), 3.53 (t, 2H, J ) 6), 2.89 (br t, 2H, J ) 6); 13C
NMR (125 MHz) 152.1, 144.0, 142.1, 138.6, 136.9, 136.1, 133.1,
133.0, 132.1, 129.3, 129.0, 128.7, 128.3, 127.9, 127.6, 127.5,
127.2, 110.1, 105.5, 104.7, 71.0, 43.3, 42.3, 24.3. Anal. Calcd
for C30H26O6S2N2: C, 62.70; H, 4.56; N, 4.88. Found: C, 62.50;
H, 4.80; N, 4.70.
2,5-Bis-ben zen esu lfon yl-8-h yd r oxy-7-m eth oxy-2,3,4,5-
tetr a h yd r o-1H-p yr id o[4,3-b]in d ole (12a ). According to gen-
eral procedure B, a mixture of TiCl4 (1.19 mL, 10.8 mmol) and
Ti(OiPr)4 (3.24 mL, 10.9 mmol) in CH2Cl2 (3.5 mL) was added
to a solution of monoimine 1a (1.41 g, 5.1 mmol) in CH2Cl2 (5
mL) at -78 °C, followed by a solution of enol ether 7a (1.28 g,
5.1 mmol) in CH2Cl2 (5 mL). Workup and chromatography
(EtOAc/hexanes 1/9 to 3/7) afforded 12a (1.89 g, 82%) as a
white solid: mp 187.5-188 °C (CH2Cl2/hexanes); TLC Rf 0.19
(EtOAc/hexanes 2/3); 1H NMR (400 MHz) 7.87-7.85 (m, 2H),
7.70 (s, 1H), 7.69-7.41 (m, 8H), 6.79 (s, 1H), 5.62 (s, 1H), 4.16
(br s, 2H), 4.00 (s, 3H), 3.44 (t, 2H, J ) 6), 3.15 (br t, 2H, J )
6); 13C NMR (100 MHz) 145.2, 143.4, 138.3, 136.3, 133.7, 132.8,
130.8, 129.9, 129.2, 129.0, 127.4, 125.9, 121.0, 114.7, 102.1,
97.8, 56.3, 43.4, 42.4, 25.1. Anal. Calcd for C24H22O6S2N2: C,
57.81; H, 4.45; N, 5.62. Found: C, 57.53; H, 4.40; N, 5.38.
5-Be n ze n e su lfon yl-8-h yd r oxy-7-m e t h oxy-2-p h e n yl-
m eth a n esu lfon yl-2,3,4,5-tetr a h yd r o-1H-p yr id o[4,3-b]in -
d ole (12b). According to general procedure B, a mixture of
TiCl4 (1.33 mL, 12.2 mmol) and Ti(OiPr)4 (3.62 mL, 12.2 mmol)
in CH2Cl2 (10 mL) was added to a solution of monoimine 1a
5-Ben zen esu lfon yl-8-h ydr oxy-7-m eth oxy-2-(2-n itr oben -
zen su lfon yl)-2,3,4,5-t et r a h yd r o-1H -p yr id o[4,3-b]in d ole
(12c). According to general procedure B, a mixture of TiCl4
(0.28 mL, 2.5 mmol) and Ti(OiPr)4 (0.77 mL, 2.6 mmol) in CH2-
Cl2 (2 mL) was added to a solution of monoimine 1a (286 mg,
1.0 mmol) in CH2Cl2 (2 mL) at -78 °C, followed by a solution
of enol ether 7c (309 mg, 1.0 mmol) in CH2Cl2 (2 mL). Workup
and chromatography (EtOAc/hexanes 3/7) gave 12c (436 mg,
78%) as a yellow solid: mp 183-184 °C (CH2Cl2/hexanes); TLC
1
Rf 0.22 (EtOAc/hexanes 1/1); H NMR (400 MHz) 8.08-8.06
(m, 1H), 7.76-7.64 (m, 5H) overlapping with 7.71 (s, 1H), 7.56
(t, 1H, J ) 8), 7.44 (t, 2H, J ) 8), 6.83 (s, 1H), 5.65 (br s, 1H),
4.41 (br s, 2H), 4.01 (s, 3H), 3.69 (t, 2H, J ) 6), 3.19 (br t, 2H,
J ) 6); 13C NMR (125 MHz) 148.2, 145.4, 143.6, 138.4, 133.8,
133.78, 131.9, 131.7, 131.0, 130.9, 130.0, 129.3, 126.1, 124.2,
121.0, 114.9, 102.3, 98.0, 56.4, 43.4, 42.4, 25.3. Anal. Calcd
for C24H21O8S2N3: C, 53.03; H, 3.89; N, 7.73. Found: C, 52.83;
H, 4.21; N, 7.77.
N -(2-B e n ze n e s u lfo n y l-8-m e t h o x y -1,2,3,4-t e t r a h y -
d r ob en zo[4,5]fu r o[2,3-c]p yr id in -6-yl)b en zen esu lfon a -
m id e (13a ). According to general procedure A, BF3‚Et2O (35
µL, 0.28 mmol) was added to a solution of monoimine 1a (79
mg, 0.28 mmol) in CH2Cl2 (2 mL) at -78 °C, followed by a
solution of enol ether 9a (92 mg, as a 4:1 mixture with its 2,3
double bond isomer, 0.36 mmol) in CH2Cl2 (2 mL). The reaction
mixture was quenched and stirred for 30 min. Workup and
chromatography (CH2Cl2/Et2O/hexanes 1/1/3) afforded 13a (97
mg, 68%) as a colorless solid: mp 178-179 °C (CH2Cl2/
hexanes); TLC Rf 0.78 (EtOAc/hexanes 3/2); 1H NMR (400
MHz) 7.84-7.82 (m, 2H), 7.71-7.68 (m, 2H), 7.58-7.40 (m,
6H), 6.65 (d, 1H, J ) 2), 6.48 (d, 1H, J ) 2), 6.34 (br s, 1H)
4.33 (br s, 2H), 3.86 (s, 3H), 3.47 (t, 2H, J ) 6), 2.65 (br t, 2H,
J ) 6); 13C NMR (100 MHz) 149.1, 145.1, 142.1, 138.8, 136.9,
133.1, 133.0, 132.0, 129.2, 128.94, 128.89, 127.4, 127.3, 112.1,
106.5, 103.6, 56.2, 43.51, 43.48, 21.0; HRMS m/z 498.0926 (M+)
(calcd for C24H22O6S2N2, 498.0919).
N -(2-B e n z e n e s u lfo n y lm e t h y l-8-m e t h o x y -1,2,3,4-
t et r a h yd r ob en zo[4,5]fu r o[2,3-c]p yr id in -6-yl)b en zen e-
su lfon a m id e (13b). According to general procedure A, BF3‚
Et2O (20 µL, 0.16 mmol) was added to a solution of monoimine
1a (45 mg, 0.16 mmol) in CH2Cl2 (2 mL) at -78 °C, followed
by a solution of enol ether 9b (44 mg, as a 12.3:1 mixture with
its 2,3 double bond isomer, 0.16 mmol) in CH2Cl2 (2 mL). The
reaction mixture was quenched and stirred for 5-6 h. Workup,
chromatography (EtOAc/hexanes 3/7), and recrystallization
(CH2Cl2/hexanes) afforded 13b (70 mg, 84%) as a white solid,
mp 139.5-140.5 °C (CH2Cl2/hexanes): TLC Rf 0.29 (EtOAc/
hexanes 1/1); 1H NMR (400 MHz) 7.76 (d, 2H, J ) 7), 7.55 (t,
1H, J ) 7), 7.44 (t, 2H, J ) 7), 7.38-7.30 (m, 5H), 6.93 (br s,
1H), 6.71 (d, 1H, J ) 2), 6.55 (d, 1H, J ) 2), 4.31 (s, 2H), 4.22
(br s, 2H), 3.87 (s, 3H), 3.45 (t, 2H, J ) 6), 2.50 (br t, 2H, J )
6); 13C NMR (125 MHz) 149.2, 145.1, 141.8, 138.7, 133.0, 132.1,
130.6, 129.0, 128.97, 128.94, 128.8, 128.6, 127.3, 112.4, 106.1,
103.4, 58.4, 56.2, 43.5, 43.47, 21.6; HRMS m/z 512.1079 (M+)
(calcd for C25H24O6S2N2, 512.1076).
In another experiment according to general procedure A,
BF3‚Et2O (31 µL, 0.25 mmol) was added to a solution of
monoimine 1a (69 mg, 0.25 mmol) in CH2Cl2 (2 mL) at -78
°C, followed by a solution of methyl enol ether 9b (74 mg, as
a 12.3:1 mixture with its 2,3 double bond isomer, 0.27 mmol)
in CH2Cl2 (2 mL). The reaction mixture was quenched and
stirred for 0.5-1 h. Workup and chromatography (EtOAc/

2452 J . Org. Chem., Vol. 65, No. 8, 2000
Engler and Wanner
hexanes 3/7) afforded 18 (65 mg, 48%) as a white solid: mp
126-127 °C (CH2Cl2/hexanes); TLC Rf 0.22 (EtOAc/hexanes
21.0. Anal. Calcd for C30H26O6S2N2: C, 62.70; H, 4.56; N, 4.88.
Found: C, 62.40; H, 4.40; N, 4.80.
1
1/1); H NMR (400 MHz) 7.72 (d, 2H, J ) 7), 7.57 (t, 1H, J )
Physical and spectral properties of 20: TLC Rf 0.10 (CH2-
Cl2/Et2O/hexanes 3/3/4); 1H NMR (400 MHz) 7.79-7.77 (m,
2H), 7.60-7.31 (m, 13H), 6.75 (br s, 1H), 6.57 (d, 1H, J ) 2),
6.38 (d, 1H, J ) 2), 5.05 (s, 2H), 3.65 (d, 1H, J ) 13), 3.52 (d,
1H, J ) 13), 3.35 (s, 3H), 3.22 (t, 1H, J ) 6) overlapping with
3.24-3.15 (m, 1H), 2.95-2.89 (m, 1H), 2.08-2.03 (m, 1H),
1.69-1.58 (m, 1H); 13C NMR (125 MHz) 145.0, 143.0, 138.5,
137.5, 136.5, 132.8, 132.7, 130.3, 130.1, 129.0, 128.8, 128.5,
128.0, 127.4, 127.3, 127.2, 112.2, 111.5, 111.2, 71.2, 50.1, 46.4,
7), 7.46-7.30 (m, 7H), 6.58 (d, 1H, J ) 2), 6.53 (br s, 1H), 6.39
(d, 1H, J ) 2), 4.25 (d, 1H, J ) 14), 4.10 (d, 1H, J ) 14), 3.78
(s, 3H), 3.71 (d, 1H, J ) 14), 3.50 (d, 1H, J ) 14), 3.38 (s, 3H),
3.28 (t, 1H, J ) 6), 3.22-3.17 (m, 1H), 2.85-2.78 (m, 1H),
2.08-2.02 (m, 1H), 1.61-1.51 (m, 1H); 13C NMR (125 MHz)
144.7, 144.2, 138.6, 133.0, 130.7, 130.3, 129.7, 128.9, 128.89,
128.62, 128.6, 127.3, 112.3, 111.5, 109.1, 56.9, 56.2, 49.9, 46.0,
44.2, 41.1, 26.3; HRMS m/z 544.1339 (M+) (calcd for C26H28O7-
S2N2, 544.1338).
43.9, 41.1, 26.0; HRMS m/z 606.1522 (M+) (calcd for C31H30
-
In a related experiment, treatment of a CH2Cl2 solution of
18 with p-TsOH‚H2O resulted in the formation of 13b as
observed by TLC.
O7S2N2, 606.1494).
The stereochemistry in 20 was assigned by analogy to 18.
A similar experiment conducted in the same manner using
2 equiv of BF3‚OEt2 as promoter gave only 14a in 78% yield.
2,9-Bis-ben zen esu lfon yl-7-m eth oxy-2,3,4,9-tetr a h yd r o-
1H-â-ca r bolin -6-ol (15a ). According to general procedure B,
a mixture of TiCl4 (1.60 mL, 14.6 mmol) and Ti(OiPr)4 (4.35
mL, 14.6 mmol) in CH2Cl2 (5 mL) was added to a solution of
monoimine 1a (1.62 g, 5.8 mmol) in CH2Cl2 (10 mL) at -78
°C, followed by a solution of enol ether 9a (1.89 g, as a 3.5:1
mixture with its 2,3 double bond isomer, 7.5 mmol) in CH2Cl2
(10 mL). Workup, chromatography (CH2Cl2/Et2O/hexanes 1/1/
3), and recrystallization afforded 15a (2.06 g, 71%) as a white
solid: mp 221.5-222 °C (CH2Cl2/hexanes); TLC Rf 0.22 (CH2-
Cl2/Et2O/hexanes 3/3/4); 1H NMR (400 MHz) 7.83-7.73 (m,
4H), 7.68 (s, 1H), 7.59-7.44 (m, 6H), 6.80 (s, 1H), 5.62 (s, 1H),
4.64 (br s, 2H), 4.00 (s, 3H), 3.48 (t, 2H, J ) 6), 2.63 (br t, 2H,
J ) 6); 13C NMR (125 MHz) 145.5, 143.6, 138.1, 137.6, 133.9,
132.8, 129.8, 129.4, 129.1, 128.3, 127.3, 126.2, 122.9, 117.4,
102.8, 97.7, 56.5, 44.8, 42.8, 21.3. Anal. Calcd for
The stereochemistry of the dihydrobenzofuran moiety was
1
assigned by H-1H NOE experiments.
N -[8-Me t h o x y -2-(2-n it r o b e n ze n e s u lfo n y l)-1,2,3,4-
t et r a h yd r ob en zo[4,5]fu r o[2,3-c]p yr id in -6-yl]b en zen e-
su lfon a m id e (13c). According to general procedure A, BF3‚
Et2O (13 µL, 0.11 mmol) was added to a solution of monoimine
1a (28 mg, 0.10 mmol) in CH2Cl2 (2 mL) at -78 °C, followed
by a solution of enol ether 9c (40 mg, as a 3.6:1 mixture with
its 2,3 double bond isomer, 0.13 mmol) in CH2Cl2 (2 mL). The
reaction mixture was quenched and stirred for 5-6 h. Workup
and chromatography (EtOAc/hexanes 3/7 to 1/1) afforded 13c
(44 mg, 80%) as a white solid, mp 192-194 °C (CH2Cl2/
hexanes): TLC Rf 0.21 (EtOAc/hexanes 1/1); 1H NMR (400
MHz) 8.10-8.08 (m, 1H), 7.75-7.67 (m, 5H), 7.56 (t, 1H, J )
7), 7.45 (t, 2H, J ) 7), 6.72 (d, 1H, J ) 2), 6.53 (d, 1H, J ) 2)
overlapping with 6.53 (s, 1H), 4.57 (br s, 2H), 3.89 (s, 3H), 3.71
(t, 2H, J ) 6), 2.74 (br t, 2H, J ) 6); 13C NMR (125 MHz, 1
aromatic carbon is not observed) 149.0, 148.1, 145.2, 142.1,
138.8, 133.9, 133.0, 132.3, 132.0, 131.8, 130.9, 129.0, 127.3,
124.4, 112.4, 106.5, 103.7, 56.2, 43.6, 43.4, 21.3; HRMS m/z
543.0767 (M+) (calcd for C24H21O8S2N3, 543.0770).
C
24H22O6S2N2: C, 57.81; H, 4.45; N, 5.62. Found: C, 57.53; H,
4.18; N, 5.60.
9-Ben zen esu lfon yl-7-m eth oxy-2-p h en ylm eth a n esu lfo-
n yl-2,3,4,9-tetr a h yd r o-1H-â-ca r bolin -6-ol (15b). According
to general procedure B, a mixture of TiCl4 (107 µL, 0.97 mmol)
and Ti(OiPr)4 (290 µL, 0.97 mmol) in CH2Cl2 (1.5 mL) was
added to a solution of monoimine 1a (108 mg, 0.39 mmol) in
CH2Cl2 (2 mL) at -78 °C, followed by a solution of enol ether
9b (128 mg, as a 4.5:1 mixture with its 2,3 double bond isomer,
0.48 mmol) in CH2Cl2 (2 mL). Workup and chromatography
(EtOAc/hexanes 2/3) afforded 15b (63 mg, 32%) as a colorless
In another experiment according to general procedure A,
BF3‚Et2O (25 µL, 0.20 mmol) was added to a solution of
monoimine 1a (50 mg, 0.18 mmol) in CH2Cl2 (2 mL) at -78
°C, followed by a solution of enol ether 9c (70 mg, as a 3.6:1
mixture with its 2,3 double bond isomer, 0.23 mmol) in CH2-
Cl2 (2 mL). The reaction mixture was quenched and stirred
for 3 h. Workup and chromatography (EtOAc/hexanes 3/7 to
1/1) afforded 13c (32 mg, 33%) and 19 (36 mg, 35%) as white
solids. Physical and spectral properties of 19: TLC Rf 0.15
(EtOAc/hexanes 1/1); 1H NMR (400 MHz) 7.98-7.96 (m, 1H),
7.73-7.60 (m, 5H), 7.56 (t, 1H, J ) 7), 7.45 (t, 2H, J ) 7), 6.83
(br s, 1H), 6.51 (d, 1H, J ) 2), 6.43 (d, 1H, J ) 2), 3.80 (d, 1H,
J ) 14), 3.72 (s, 3H), 3.69 (d, 1H, J ) 14), 3.42-3.34 (m, 2H),
3.38 (s, 3H), 3.10-3.04 (m, 1H), 2.20-2.14 (m, 1H), 1.76-1.71
(m, 1H); 13C NMR (125 MHz) 148.1, 144.6, 144.1, 138.5, 133.5,
133.0, 131.9, 131.6, 130.9, 130.3, 129.3, 128.9, 127.3, 124.0,
112.1, 111.4, 109.2, 56.1, 50.0, 45.9, 44.0, 40.9, 25.8; HRMS
m/z 575.1055 (M+) (calcd for C25H25O9S2N3, 575.1032).
The stereochemistry in 19 was assigned by analogy to 18.
N-(2-Ben zen esu lfon yl-8-ben zyloxy-9a -m eth oxy-1,2,3,4,-
4a ,9a -h exa h yd r oben zo[4,5]fu r o[2,3-c]p yr id in -6-yl)ben ze-
n esu lfon a m id e (20) a n d N-(2-Ben zen esu lfon yl-8-ben zyl-
oxy-1,2,3,4-t e t r a h yd r ob e n zo[4,5]fu r o[2,3-c]p yr id in -6-
yl)ben zen esu lfon am ide (14a). According to general procedure
A, BF3‚Et2O (21 µL, 0.17 mmol) was added to a solution of
monoimine 1b (59 mg, 0.17 mmol) in CH2Cl2 (2 mL) at -78
°C, followed by a solution of methyl enol ether 9a (51 mg, as
a 4.7:1 mixture with its 2,3 double bond isomer, 0.20 mmol)
in CH2Cl2 (2 mL). The reaction mixture was quenched and
stirred for 2 h. Workup and chromatography (CH2Cl2/Et2O/
hexanes 1/1/3) afforded 14a (28 mg, 29%) and 20 (31 mg, 31%)
as white solids. Physical and spectral properties of 14a : mp
135-136 °C (CH2Cl2/hexanes); TLC Rf 0.17 (CH2Cl2/Et2O/
hexanes 3/3/4); 1H NMR (400 MHz) 7.89-7.87 (m, 2H), 7.67-
7.38 (m, 13H), 6.68 (d, 1H, J ) 2), 6.64 (d, 1H, J ) 2), 6.44 (br
s, 1H), 5.19 (s, 2H), 4.38 (s, 2H), 3.51 (t, 2H, J ) 6), 2.70 (br t,
2H, J ) 6); 13C NMR (125 MHz) 149.2, 144.1, 142.3, 138.7,
136.9, 136.1, 133.1, 132.9, 132.0, 129.2, 129.1, 128.9, 128.7,
128.3, 127.5, 127.46, 127.2, 112.1, 106.3, 105.1, 71.1, 43.6, 43.5,
1
solid: TLC Rf 0.31 (EtOAc/hexanes 1/1); H NMR (400 MHz)
7.75-7.73 (m, 2H), 7.68 (s, 1H), 7.56-7.52 (m, 1H), 7.46-7.31
(m, 7H), 6.79 (s, 1H), 5.73 (br s, 1H), 4.63 (br s, 2H), 4.26 (s,
2H), 4.00 (s, 3H), 3.34 (t, 2H, J ) 6), 2.43 (br t, 2H, J ) 6); 13
C
NMR (125 MHz) 145.6, 143.6, 138.0, 134.0, 130.6, 129.7, 129.4,
128.8, 128.77, 128.7, 128.5, 126.2, 123.1, 117.9, 102.9, 97.8,
58.2, 56.5, 44.6, 43.1, 22.0; HRMS m/z 512.1057 (M+) (calcd
for C25H24N2O6S2, 512.1076).
9-Ben zen esu lfon yl-7-m eth oxy-2-(2-n itr oben zen esu lfo-
n yl)-2,3,4,9-tetr a h yd r o-1H-â-ca r bolin -6-ol (15c). According
to general procedure B, a mixture of TiCl4 (0.20 mL, 1.8 mmol)
and Ti(OiPr)4 (0.54 mL, 1.8 mmol) in CH2Cl2 (2 mL) was added
to a solution of monoimine 1a (198 mg, 0.7 mmol) in CH2Cl2
(2 mL) at -78 °C, followed by a solution of enol ether 9c (273
mg, as a 3.6:1 mixture with its 2,3 double bond isomer, 0.9
mmol) in CH2Cl2 (2 mL). Workup and chromatography (CH2-
Cl2/Et2O/hexanes 3/3/4) gave 15c (310 mg, 80%) as a colorless
solid: mp 206.5-207 °C (CH2Cl2/hexanes); TLC Rf 0.42 (CH2-
Cl2/Et2O/hexanes 2/2/1); 1H NMR (400 MHz) 8.07-8.05 (m,
1H), 7.79 (d, 2H, J ) 7), 7.74-7.69 (m, 3H), 7.68 (s, 1H), 7.57
(t, 1H, J ) 7), 7.46 (t, 2H, J ) 7), 6.85 (s, 1H), 5.63 (s, 1H),
4.82 (br s, 2H), 4.01 (s, 3H), 3.71 (t, 2H, J ) 6), 2.74 (br t, 2H,
J ) 6); 13C NMR (125 MHz) 148.1, 145.6, 143.7, 137.9, 134.0,
133.7, 132.6, 131.8, 130.8, 129.8, 129.4, 128.2, 126.3, 124.3,
123.0, 117.8, 102.9, 97.7, 56.5, 44.7, 43.1, 21.8; HRMS m/z
543.0753 (M+) (calcd for C24H21O8S2N3, 543.0769).
N-(2,5-Bis-ben zen esu lfon yl-7-m eth oxy-2,3,4,5-tetr a h y-
d r o-1H-p yr id o[4,3-b]in d ol-8-yl)ben za m id e (25a ). Accord-
ing to general procedure B, a mixture of TiCl4 (85 µL, 0.77
mmol) and Ti(OiPr)4 (0.23 mL, 0.77 mmol) in CH2Cl2 (0.75 mL)
was added to a solution of diimine 24a (117 mg, 0.31 mmol)
in CH2Cl2 (2 mL) at -78 °C, followed by a solution of enol ether

Synthesis of Oxygenated Carbolines
J . Org. Chem., Vol. 65, No. 8, 2000 2453
7a (77 mg, 0.30 mmol) in CH2Cl2 (2 mL). Workup and
chromatography (CH2Cl2/Et2O/hexanes 3/3/4) gave 25a (152
mg, 82%) as a colorless solid: mp 216-217 °C (CH2Cl2/
hexanes); TLC Rf 0.34 (EtOAc/hexanes 2/3); 1H NMR (400
MHz) 8.64 (br s, 1H), 8.51 (s, 1H), 7.91-7.86 (m, 3H), 7.75 (s,
1H), 7.69-7.41 (m, 12H), 4.19 (br s, 2H), 4.03 (s, 3H), 3.43 (t,
2H, J ) 6), 3.17 (br t, 2H, J ) 6); 13C NMR (125 MHz) 165.2,
147.0, 138.4, 136.1, 134.9, 134.0, 133.0, 132.4, 131.8, 131.2,
129.4, 129.2, 128.8, 127.6, 126.9, 126.1, 125.3, 121.0, 115.4,
108.6, 97.2, 56.4, 43.6, 42.8, 25.4. Anal. Calcd for
Cl2/Et2O/hexanes 1/1/3) afforded 27a (2.89 g, 94%) as a white
solid: mp 201-202 °C (CH2Cl2/Et2O/hexanes); TLC Rf 0.27
1
(CH2Cl2/Et2O/hexanes 3/3/4); H NMR (400 MHz) 7.88-7.86
(m, 2H), 7.72 (s, 1H), 7.70-7.54 (m, 6H), 7.43 (t, 2H, J ) 8),
6.71 (s, 1H), 4.22 (br s, 2H), 3.98 (s, 3H), 3.91 (s, 3H), 3.45 (t,
2H, J ) 6), 3.18 (br t, 2H, J ) 6); 13C NMR (125 MHz) 147.9,
147.2, 138.4, 136.4, 133.8, 133.0, 130.6, 130.3, 129.3, 129.2,
127.5, 126.1, 120.4, 114.7, 99.4, 98.6, 56.3, 56.1, 43.5, 42.6, 25.2.
Anal. Calcd for C25H24O6S2N2: C, 58.58; H, 4.72; N, 5.47.
Found: C, 58.37; H, 4.95 N, 5.26.
C
31H27O6S2N3: C, 61.88; H, 4.52; N, 6.99. Found: C, 61.75; H,
5-Ben zen esu lfon yl-7,8-d im et h oxy-2-p h en ylm et h a n e-
su lfon yl-2,3,4,5-tetr a h yd r o-1H-p yr id o[4,3-b]in d ole (27b).
According to the general procedure, a slurry of phenol 12b
(1.00 g, 1.95 mmol) and K2CO3 (3.10 mg, 22.4 mmol) in acetone
(30 mL) was treated with CH3I (0.18 mL, 2.89 mmol). Workup
and chromatography (CH2Cl2/Et2O/hexanes 1/1/6) afforded 27b
(922 mg, 90%) as a white solid: mp 191-192 °C (CH2Cl2/
4.90; N, 7.11.
In an experiment run according to general procedure A, BF3‚
Et2O (41 µL, 0.33 mmol) was added to a solution of diimine
24a (127 mg, 0.33 mmol) in CH2Cl2 (2 mL) at -78 °C, followed
by a solution of enol ether 7a (88 mg, 0.35 mmol) in CH2Cl2 (2
mL). Workup and chromatography (CH2Cl2/Et2O/hexanes 1/1/
3) afforded 25a (154 mg, 77%) as a white solid.
1
hexanes); TLC Rf 0.29 (CH2Cl2/Et2O/hexanes 3/3/4); H NMR
N-(2,5-Bis-ben zen esu lfon yl-7-ben zyloxy-2,3,4,5-tetr ah y-
d r o-1H-p yr id o[4,3-b]in d ol-8-yl)ben za m id e (25b). Accord-
ing to general procedure A, BF3‚Et2O (40 µL, 0.33 mmol) was
added to a solution of diimine 24b (73 mg, 0.16 mmol) in CH2-
Cl2 (2 mL) at -78 °C, followed by a solution of enol ether 7a
(41 mg, 0.16 mmol) in CH2Cl2 (2 mL). The reaction mixture
was stirred for 40 min at -78 °C, and then the reaction was
quenched by the addition of saturated aqueous NaHCO3.
Workup and chromatography (EtOAc/hexanes 1/9 to 25/75)
afforded 25b (67 mg, 62%) as a white solid: mp 203-204 °C
(CH2Cl2/hexanes); TLC Rf 0.43 (EtOAc/hexanes 2/4); 1H NMR
(400 MHz) 8.77 (br s, 1H), 8.53 (s, 1H), 7.90-7.84 (m, 5H),
7.60-7.34 (m, 15 H), 5.34 (s, 2H), 4.20 (br s, 2H), 3.45 (t, 2H,
J ) 6), 3.21 (br t, 2H, J ) 6); 13C (100 MHz) 165.5, 146.2, 138.6,
136.6, 136.5, 135.3, 134.3, 133.4, 132.6, 132.3, 131.8, 129.8,
129.7, 129.3, 129.25, 128.9, 128.1, 127.9, 127.3, 126.5, 126.1,
121.8, 115.9, 109.0, 99.8, 72.0, 44.0, 43.2, 25.9. Anal. Calcd
for C37H31O6S2N3: C, 65.56; H, 4.61; N, 6.20. Found: C, 65.50;
H, 4.50; N, 5.81.
N-(2,9-Bis-ben zen esu lfon yl-7-m eth oxy-2,3,4,9-tetr a h y-
d r o-1H-â-ca r bolin -6-yl)ben za m id e (26). According to gen-
eral procedure B, a mixture of TiCl4 (0.11 mL, 1.0 mmol) and
Ti(OiPr)4 (0.29 mL, 1.0 mmol) in CH2Cl2 (0.97 mL) was added
to a solution of diimine 24a (150 mg, 0.39 mmol) in CH2Cl2 (2
mL) at -78 °C, followed by a solution of enol ether 9a (100
mg, as a 4:1 mixture with its 2,3 double bond isomer, 0.39
mmol) in CH2Cl2 (1 mL). Workup and chromatography (CH2-
Cl2/Et2O/hexanes 1/1/3) gave 26 (152 mg, 80%) as a white
solid: mp 184.5-185.5 °C (CH2Cl2/hexanes); TLC Rf 0.53
(EtOAc/hexanes 3/2); 1H NMR (400 MHz) 8.62 (br s, 1H), 8.50
(s, 1H), 7.89 (d, 2H, J ) 7), 7.79 (d, 2H, J ) 7), 7.73 (d, 2H, J
) 7) overlapping with 7.72 (s, 1H), 7.59-7.43 (m, 9H), 4.64
(br s, 2H), 4.03 (s, 3H), 3.47 (t, 2H, J ) 6), 2.69 (br t, 2H, J )
6); 13C NMR (100 MHz) 165.9, 147.9, 138.6, 137.9, 135.4, 134.5,
133.3, 133.0, 132.3, 129.9, 129.6, 129.2, 128.9, 127.7, 127.4,
126.6, 125.8, 123.1, 118.2, 109.7, 97.5, 56.9, 45.2, 43.3, 21.8.
Anal. Calcd for C31H27O6S2N3: C, 61.88; H, 4.52; N, 6.99.
Found: C, 61.56; H, 4.40; N, 6.90.
(400 MHz) 7.77 (s, 1H), 7.73 (d, 2H, J ) 8), 7.56 (t, 1H, J ) 8),
7.44 (t, 2H, J ) 8), 7.35-7.25 (m, 5H), 6.62 (s, 1H), 4.26 (s,
2H), 4.24 (br s, 2H), 4.01 (s, 3H), 3.89 (s, 3H), 3.46 (t, 2H, J )
6), 3.02 (br t, 2H, J ) 6); 13C NMR (125 MHz) 147.9, 147.3,
138.5, 133.9, 130.9, 130.5, 130.3, 129.4, 128.8, 128.76, 128.6,
126.1, 120.3, 115.3, 99.5, 98.6, 57.9, 56.4, 56.1, 43.4, 42.5, 25.6.
Anal. Calcd for C26H26O6S2N2: C, 59.30; H, 4.98; N, 5.32.
Found: C, 58.97; H, 5.10; N, 5.05.
2-Ben zen esu lfon yl-7,8-d im et h oxy-2-(2-n it r ob en zen e-
su lfon yl)-2,3,4,5-tetr a h yd r o-1H-p yr id o[4,3-b]in d ole (27c).
According to the general procedure, a slurry of phenol 12c (100
mg, 0.18 mmol) and K2CO3 (327 mg, 2.4 mmol) in acetone (10
mL) was treated with CH3I (17 µL, 0.27 mmol) and Bu4NI (7
mg, 0.019 mmol). Workup and chromatography (CH2Cl2/Et2O/
hexanes 1/1/8) afforded 27c (84 mg, 82%) as a white solid: mp
225-226.5 °C (CH2Cl2/hexanes); TLC Rf 0.16 (CH2Cl2/Et2O/
1
hexanes 3/3/4); H NMR (400 MHz) 8.08-8.06 (m, 1H), 7.72
(s, 1H), 7.71-7.63 (m, 5H), 7.54 (t, 1H, J ) 7), 7.42 (t, 2H, J
) 7), 6.74 (s, 1H), 4.47 (br s, 2H), 3.98 (s, 3H), 3.90 (s, 3H),
3.67 (t, 2H, J ) 6), 3.18 (br t, 2H, J ) 6); 13C NMR (125 MHz)
148.0, 147.9, 147.2, 138.2, 133.79, 133.77, 131.9, 131.7, 130.7,
130.6, 130.2, 129.3, 126.0, 124.2, 120.2, 114.9, 99.5, 98.5, 56.3,
56.1, 43.3, 42.4, 25.2; HRMS m/z 557.0909 (M+) (calcd for
C
25H23O8S2N3, 557.0927).
2,9-Bis-ben zen esu lfon yl-6,7-d im eth oxy-2,3,4,9-tetr a h y-
d r o-1H-â-ca r bolin e (30a ). According to the general proce-
dure, a slurry of phenol 15a (391 mg, 0.78 mmol) and K2CO3
(200 mg, 1.4 mmol) in acetone (10 mL) was treated with CH3I
(75 µL, 1.2 mmol). Workup and chromatography (CH2Cl2/Et2O/
hexanes 1/1/3) gave 30a (313 mg, 78%) as a white solid: mp
172-173.5 °C (CH2Cl2/hexanes); TLC Rf 0.37 (CH2Cl2/Et2O/
1
hexanes 3/3/4); H NMR (400 MHz) 7.84 (d, 2H, J ) 7), 7.76
(d, 2H, J ) 7), 7.70 (s, 1H), 7.61-7.44 (m, 6H), 6.72 (s, 1H),
4.65 (br s, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 3.49 (t, 2H, J ) 6),
2.69 (br t, 2H, J ) 6); 13C NMR (100 MHz) 148.0, 147.3, 138.1,
137.5, 134.0, 132.9, 130.2, 129.5, 129.2, 128.1, 127.4, 126.2,
122.1, 117.3, 100.0, 98.4, 56.4, 56.1, 44.8, 42.9, 21.5. Anal.
Calcd for C25H24O6S2N2: C, 58.58; H, 4.72; N, 5.47. Found: C,
58.26; H, 4.94; N, 5.29.
In an experiment run according to general procedure A, BF3‚
Et2O (13 µL, 0.11 mmol) was added to a solution of diimine
24a (41 mg, 0.11 mmol) in CH2Cl2 (2 mL) at -78 °C, followed
by a solution of enol ether 9a (48 mg, as a 4:1 mixture with
its 2,3 double bond isomer, 0.19 mmol) in CH2Cl2 (0.8 mL).
Workup and chromatography (CH2Cl2/Et2O/hexanes 1/1/3)
afforded 26 (25 mg, 39%) as a white solid.
Gen er a l P r oced u r e for Meth yla tion of 12a -c a n d 15a /
c. A slurry of the phenol and K2CO3 in acetone was treated
with CH3I, and in some cases with Bu4NI. The reaction
mixture was refluxed 24 h, cooled to room temperature, poured
into H2O, and extracted with CH2Cl2 (3×). The combined
organic extracts were washed with brine, dried (Na2SO4), and
concentrated.
9-Ben zen esu lfon yl-6,7-d im et h oxy2-(2-n it r ob en zen e-
su lfon yl)-2,3,4,9-tetr a h yd r o-1H-â-ca r bolin e (30c). Accord-
ing to the general procedure, a slurry of phenol 15c (109 mg,
0.20 mmol) and K2CO3 (200 mg, 1.4 mmol) in acetone (10 mL)
was treated with CH3I (18 µL, 0.29 mmol) and Bu4NI (10 mg,
0.027 mmol). Workup and chromatography (CH2Cl2/Et2O/
hexanes 1/1/6 to 3/3/4) afforded 30c (85 mg, 76%) as a white
solid: mp 193-194 °C (CH2Cl2/hexanes); TLC Rf 0.18 (CH2-
Cl2/Et2O/hexanes 3/3/4); 1H NMR (400 MHz) 8.08-8.06 (m,
1H), 7.80-7.67 (m, 5H) overlapping with 7.70 (s, 1H), 7.55 (t,
1H, J ) 7), 7.45 (t, 2H, J ) 7), 6.77 (s, 1H), 4.83 (br s, 2H),
4.00 (s, 3H), 3.91 (s, 3H), 3.73 (t, 2H, J ) 6), 2.79 (br t, 2H, J
) 6); 13C NMR (125 MHz) 148.1, 148.05, 147.4, 137.9, 134.0,
133.7, 132.6, 131.8, 130.8, 130.1, 129.4, 127.9, 126.3, 124.3,
122.2, 117.8, 100.1, 98.4, 56.4, 56.1, 44.7, 43.1, 21.9; HRMS
m/z 557.0914 (M+) (calcd for C25H23O8S2N3, 557.0927).
Gen er a l P r oced u r e for Tr ifla t ion of 12a -c. Pyridine
was added to a solution of the phenol in CH2Cl2 at -78 °C,
2,5-Bis-ben zen esu lfon yl-7,8-d im eth oxy-2,3,4,5-tetr a h y-
d r o-1H-p yr id o[4,3-b]in d ole (27a ). According to the general
procedure, a slurry of phenol 12a (2.98 g, 6.0 mmol) and K2-
CO3 (1.43 g, 10.3 mmol) in acetone (50 mL) was treated with
CH3I (0.6 mL, 9.6 mmol). Workup and chromatography (CH2-

2454 J . Org. Chem., Vol. 65, No. 8, 2000
Engler and Wanner
followed after 5 min by trifluoromethanesulfonic anhydride
(Tf2O). The reaction mixture was allowed to warm until no
phenol was detectable by TLC analysis, and then the reaction
was quenched with water and the solution extracted with CH2-
Cl2. The combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated.
1H, J ) 9), 6.88 (dd, 1H, J ) 9, 2), 4.22 (br s, 2H), 3.89 (s,
3H), 3.46 (t, 2H, J ) 6), 3.19 (br t, 2H, J ) 6); 13C NMR (100
MHz) 158.4, 138.9, 137.7, 136.9, 134.3, 133.4, 131.3, 129.8,
129.6, 127.9, 126.7, 121.7, 118.7, 114.9, 112.8, 99.8, 56.2, 44.0,
43.0, 25.6. Anal. Calcd for C24H22O5S2N2: C, 59.73; H, 4.60;
N, 5.81. Found: C, 59.49; H, 4.52; N, 5.69.
Tr iflu or om eth a n esu lfon ic a cid 2,5-Bis-ben zen esu lfo-
n yl-7-m eth oxy-2,3,4,5-tetr a h yd r o-1H-p yr id o[4,3-b]in d ol-
8-yl Ester (28a ). According to the general procedure, pyridine
(0.56 mL, 6.9 mmol) was added to a solution of phenol 12a
(1.39 g, 2.8 mmol) in CH2Cl2 (10 mL) at -78 °C, followed by
Tf2O (0.61 mL, 3.6 mmol). The reaction mixture was allowed
to warm to -45 °C over 2 h. Workup and chromatography
(CH2Cl2/Et2O/hexanes 1/1/3) gave 28a (1.7 g, 97%) as a white
solid: mp 222-223 °C (CH2Cl2/Et2O/hexanes); TLC Rf 0.42
Similarly prepared were 29b (72%) and 29c (88%).
Physical and spectral properties of 29b: a white solid, mp
160.5-161.5 °C (CH2Cl2/hexanes); TLC Rf 0.56 (CH2Cl2/Et2O/
1
hexanes 3/3/4); H NMR (400 MHz) 7.78-7.76 (m, 2H), 7.74
(d, 1H, J ) 2), 7.57 (t, 1H, J ) 8), 7.46 (t, 2H, J ) 8), 7.35-
7.26 (m, 5H), 7.08 (d, 1H, J ) 9), 6.88 (dd, 1H, J ) 9, 2), 4.27
(s, 2H), 4.23 (br s, 2H), 3.91 (s, 3H), 3.46 (t, 2H, J ) 6), 3.02
(br t, 2H, J ) 6); 13C NMR (125 MHz) 158.0, 138.6, 137.3,
134.0, 131.1, 130.5, 129.4, 128.8, 128.76, 128.6, 126.3, 121.2,
118.3, 114.9, 112.3, 99.4, 57.9, 55.8, 43.4, 42.5, 25.6. Anal.
Calcd for C25H24O5S2N2: C, 60.46; H, 4.87; N, 5.64. Found: C,
60.07; H, 4.82; N, 5.60.
1
(CH2Cl2/Et2O/hexanes 3/3/4); H NMR (400 MHz) 7.89-7.86
(m, 2H) overlapping with 7.87 (s, 1H), 7.76-7.73 (m, 2H),
7.65-7.49 (m, 6H), 7.16 (s, 1H), 4.20 (br s, 2H), 4.01 (s, 3H),
3.46 (t, 2H, J ) 6), 3.18 (br t, 2H, J ) 6); 13C NMR (100 MHz)
149.8, 138.6, 136.8, 136.6, 135.9, 134.9, 133.6, 133.2, 130.1,
129.7, 128.0, 126.7, 120.6, 119.1 (q, J C-F ) 319), 114.5, 111.9,
99.9, 57.1, 43.8, 42.7, 25.6. Anal. Calcd for C25H21O8S3N2F3:
C, 47.61; H, 3.36; N, 4.44. Found: C, 47.67; H, 3.46; N, 4.17.
Tr iflu or om eth a n esu lfon ic Acid 5-Ben zen esu lfon yl-7-
m et h oxy-2-p h en ylm et h a n esu lfon yl-2,3,4,5-t et r a h yd r o-
1H-p yr id o[4,3-b]in d ol-8-yl Ester (28b). According to the
general procedure, pyridine (0.31 mL, 3.83 mmol) was added
to a solution of phenol 12b (787 mg, 1.54 mmol) in CH2Cl2 (5
mL) at -78 °C, followed by Tf2O (0.39 mL, 2.31 mmol). The
reaction mixture was allowed to warm to room temperature
over 12 h. Workup and chromatography (CH2Cl2/Et2O/hexanes
1/1/3) gave 28b (842 mg, 85%) as a white solid: mp 177-178
°C (CH2Cl2/hexanes); TLC Rf 0.53 (CH2Cl2/Et2O/hexanes 3/3/
Physical and spectral characteristics of 29c: a white solid,
mp 171-172 °C (CH2Cl2/hexanes); TLC Rf 0.50 (EtOAc/
hexanes 1/1); 1H NMR (400 MHz) 7.74 (d, 2H, J ) 8), 7.70 (d,
1H, J ) 2), 7.65 (d, 1H, J ) 8), 7.56 (t, 1H, J ) 8), 7.44 (t, 2H,
J ) 8), 7.31-7.28 (m, 1H), 7.18 (d, 1H, J ) 9), 6.87 (dd, 1H, J
) 9, 2), 6.79-6.72 (m, 2H), 5.12 (br s, 2H), 4.30 (br s, 2H),
3.89 (s, 3H), 3.53 (t, 2H, J ) 6), 3.19 (br t, 2H, J ) 6); 13C
NMR (125 MHz) 157.9, 146.3, 138.5, 137.3, 134.4, 133.8, 131.0,
130.1, 129.4, 126.2, 121.4, 118.3, 118.0, 117.8, 117.4, 114.7,
112.2, 99.4, 55.8, 43.5, 42.4, 25.2; FABMS m/z 498 (M + H+).
HRMS m/z 498.1151 (M + H+) (calcd for C24H24O5S2N3,
498.1157).
Gen er a l P r oced u r e C: Desu lfon yla tion of In d ole Ni-
tr ogen s. K2CO3 was added to a THF/MeOH/H2O (10/10/1)
solution of the starting material. The reaction mixture was
either stirred at room temperature or heated to reflux until
no starting material was detectable by TLC and then concen-
trated to dryness. The residue was dissolved in CH2Cl2, washed
with saturated aqueous NaHCO3, dried (Na2SO4), and con-
centrated.
1
4); H NMR (400 MHz) 7.91 (s, 1H), 7.77 (d, 2H, J ) 8), 7.63
(t, 1H, J ) 8), 7.52 (t, 2H, J ) 8), 7.33-7.24 (m, 5H), 7.03 (s,
1H), 4.29 (s, 2H), 4.19 (br s, 2H), 4.03 (s, 3H), 3.45 (t, 2H, J )
6), 3.02 (br t, 2H, J ) 6); 13C NMR (125 MHz) 149.4, 138.3,
136.4, 135.4, 134.5, 132.9, 130.4, 129.7, 128.9, 128.8, 128.4,
126.2, 120.1, 118.7 (q, J C-F ) 319), 114.5, 111.5, 99.4, 58.1,
56.7, 43.2, 42.2, 25.5. Anal. Calcd for C26H23O8S3N2F3: C, 48.44;
H, 3.60; N, 4.35. Found: C, 48.69; H, 3.39; N, 4.25.
2-Ben zen esu lfon yl-7,8-d im et h oxy-2,3,4,5-t et r a h yd r o-
1H-p yr id o[4,3-b]in d ole (31). According to general procedure
C, K2CO3 (406 mg, 2.9 mmol) was added to a solution of 27a
(226 mg, 0.44 mmol) in THF/MeOH/H2O (10.5 mL), and the
reaction mixture was refluxed for 3 d. Workup and chroma-
tography (CH2Cl2/Et2O/hexanes 3/3/4) afforded 31 (98 mg, 60%)
as a white solid: mp 212-213 °C (CH2Cl2/hexanes); TLC Rf
Tr iflu or om eth a n esu lfon ic Acid 5-Ben zen esu lfon yl-7-
m eth oxy-2-(2-n itr oben zen esu lfon yl)-2,3,4,5-tetr a h yd r o-
1H-p yr id o[4,3-b]in d ol-8-yl Ester (28c). According to the
general procedure, pyridine (32 µL, 40 mmol) was added to a
solution of phenol 12c (86 mg, 0.16 mmol) in CH2Cl2 (2 mL)
at -78 °C, followed by Tf2O (0.40 µL, 0.24 mmol). The reaction
mixture was allowed to warm to -10 °C over 3 h. Workup and
chromatography (CH2Cl2/Et2O/hexanes 3/3/4) gave 28c (97 mg,
91%) as a white solid: mp 189-190.5 °C (CH2Cl2/hexanes);
TLC Rf 0.45 (CH2Cl2/Et2O/hexanes 3/3/4); 1H NMR (400 MHz)
8.12-8.10 (m, 1H), 7.88 (s, 1H), 7.77-7-68 (m, 5H), 7.63 (t,
1H, J ) 7), 7.51 (t, 2H, J ) 7), 7.18 (s, 1H), 4.44 (br s, 2H),
4.02 (s, 3H), 3.71 (t, 2H, J ) 6), 3.21 (br t, 2H, J ) 6); 13C
NMR (125 MHz) 149.5, 148.1, 138.2, 136.5, 135.5, 134.4, 134.0,
132.9, 131.9, 131.88, 131.0, 129.7, 126.3, 124.4, 120.1, 118.7
(q, J C-F ) 319), 114.1, 111.6, 99.5, 56.7, 43.2, 42.1, 25.3; HRMS
m/z 675.0253 (M+) (calcd for C25H20O10S3N3F3, 675.0263).
2,5-Bis-ben zen esu lfon yl-7-m eth oxy-2,3,4,5-tetr a h yd r o-
1H-p yr id o[4,3-b]in d ole (29a ). To a solution of triflate 28a
(1.72 g, 2.7 mmol) in DMF (10 mL) were added palladium(II)
acetate trimer (56 mg, 0.083 mmol), 1,1′-bis(diphenylphosphi-
no)ferrocene (79 mg, 0.14 mmol), triethylamine (8 mL, 57
mmol), and a 90% aqueous formic acid solution (2.2 mL, 53
mmol) in sequence. The mixture was heated to 90 °C for 24 h
and then cooled to room temperature. Water was added, and
the mixture was poured into EtOAc. The aqueous layer was
separated and extracted with EtOAc. The combined organic
extracts were washed with saturated aqueous NH4Cl, satu-
rated aqueous NaHCO3 and H2O, and the solution was dried
(Na2SO4) and concentrated. Chromatography (CH2Cl2/Et2O/
hexanes 1/1/3) afforded 29a (1.09 g, 83%) as a white solid: mp
144-145 °C (CH2Cl2/Et2O/hexanes); TLC Rf 0.43 (CH2Cl2/Et2O/
hexanes 3/3/4); 1H NMR (400 MHz) 7.88-7.85 (m, 2H), 7.74-
7.72 (m, 2H), 7.70 (d, 1H, J ) 2), 7.62-7.43 (m, 6H), 7.17 (d,
1
0.35 (CH2Cl2/Et2O/hexanes 2/2/1); H NMR (400 MHz) 7.90-
7.88 (m, 2H), 7.76 (br s, 1H), 7.61-7.53 (m, 3H), 6.84 (s, 1H),
6.83 (s, 1H), 4.38 (br s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.53 (t,
2H, J ) 6), 2.85 (br t, 2H, J ) 6); 13C NMR (100 MHz) 147.1,
145.3, 137.6, 133.2, 130.5, 129.6, 129.5, 127.9, 118.5, 106.2,
100.0, 95.2, 56.7, 56.6, 44.0, 43.6, 24.1; HRMS m/z 372.1146
(M+) (calcd for C19H20O4SN2, 372.1144).
Alter n a tive Meth od . Red-Al (65+ wt % in toluene, 0.22
mL, 0.73 mmol) was added to a solution of 27a (142 mg, 0.28
mmol) in THF (5 mL), and the reaction mixture was stirred
at room temperature for 4 d. The mixture was quenched by
the addition of H2O with ice cooling. The aqueous layer was
extracted with EtOAc (3×), and the combined organic extracts
were dried (Na2SO4) and concentrated. Chromatography (CH2-
Cl2/Et2O/hexanes2/2/1) gave 31 (71 mg, 69%) as a white solid.
5-Ben zen esu lfon yl-7,8-d im et h oxy-2,3,4,5-t et r a h yd r o-
1H-p yr id o[4,3-b]in d ole (32). Compound 27c (49 mg, 0.088
mmol) was dissolved in DMF (2 mL), and LiOH (17 mg, 0.74
mmol) and HSCH2COOH (12.1 µL, 0.18 mmol) were added.
The reaction mixture was stirred at room temperature until
no starting material was detectable by TLC (∼10 h), and then
the reaction was quenched by the addition of saturated
aqueous NaHCO3. The aqueous layer was extracted with Et2O
(3×), and the combined organic extracts were dried (Na2SO4)
and concentrated. Chromatography (MeOH/EtOAc 3/7) gave
32 (15 mg, 46%) as a white solid: mp 176-177 °C (CH2Cl2/
hexanes); TLC Rf 0.14 (MeOH/EtOAc 3/7); 1H NMR (400 MHz)
7.79 (s, 1H), 7.76-7.74 (m, 2H), 7.55 (t, 1H, J ) 8), 7.43 (t,
2H, J ) 8), 6.73 (s, 1H), 4.00 (s, 3H), 3.91 (s, 3H) overlapping
with 3.91 (br s, 2H), 3.17 (t, 2H, J ) 6), 3.02 (br t, 2H, J ) 6),

Synthesis of Oxygenated Carbolines
J . Org. Chem., Vol. 65, No. 8, 2000 2455
(the N-H is not visible); 13C NMR (125 MHz) 147.5, 147.1,
138.9, 133.6, 132.3, 130.1, 129.2, 126.2, 121.5, 118.3, 99.8, 98.8,
56.4, 56.1, 43.6, 42.1, 26.2; HRMS m/z 373.1229 (M + H+)
(calcd for C19H21O4SN2, 373.1222).
Similarly prepared were 34 (84%) and 40 (75%).
Physical and spectral properties of 34: a white solid, mp
233.5-234.5 °C (dec) (CH2Cl2/hexanes); TLC Rf 0.17 (EtOAc/
1
hexanes 4/1); H NMR (400 MHz) 9.13 (s, 1H), 8.60 (d, 1H, J
Compound 30c was converted into 38 in a similar manner.
Thus, a solution of 30c (21 mg, 0.038 mmol) in DMF (1 mL)
was treated with LiOH (9 mg, 0.39 mmol) and HSCH2COOH
(5.3 µL, 0.076 mmol) and stirred for 3 h. Workup and
chromatography (MeOH/EtOAc 3/7) gave 38 (8.5 mg, 60%) as
a white solid: mp 188.5-190 °C (CH2Cl2/hexanes); TLC Rf 0.25
(MeOH/EtOAc 3/7); 1H NMR (400 MHz) 7.76-7.74 (m, 2H)
overlapping with 7.75 (s, 1H), 7.55 (t, 1H, J ) 8), 7.43 (t, 2H,
J ) 8), 6.80 (s, 1H), 4.25 (br s, 2H), 4.00 (s, 3H), 3.92 (s, 3H),
3.12 (t, 2H, J ) 6), 2.62 (br t, 2H, J ) 6), (the N-H is not
visible); 13C NMR (125 MHz) 147.6, 147.1, 138.6, 133.6, 132.3,
129.9, 129.2, 126.1, 123.1, 117.7, 100.0, 98.5, 56.4, 56.1, 44.5,
42.6, 22.6; HRMS m/z 373.1248 (M + H+) (calcd for C19H21O4-
SN2, 373.1222).
7,8-Dim et h oxy-2,3,4,5-t et r a h yd r o-1H -p yr id o[4,3-b]in -
d ole (33). A solution of 27b (532 mg, 1.0 mmol) in THF (30
mL) was added to liquid NH3 (30 mL), followed by Na until a
blue color persisted for 5 min (105 mg, 4.6 mmol). The reaction
was then quenched by the addition of solid NH4Cl. The NH3
was allowed to evaporate, H2O was added to the residue, and
the pH was adjusted to 9-10 by the addition of solid NaOH.
The aqueous layer was extracted with CH2Cl2 (3×), and the
combined organic extracts were dried (Na2SO4) and concen-
trated to give crude 33 (234 mg, 100%) as a yellowish solid
which was ∼90% pure by NMR: 1H NMR (400 MHz) 7.88 (br
s, 1H), 6.88 (s, 1H), 6.84 (s, 1H), 4.05 (br s, 2H), 3.93 (s, 3H),
3.89 (s, 3H), 3.23 (t, 2H, J ) 6), 2.75 (br t, 2H, J ) 6); 13C
NMR (100 MHz) 146.7, 145.1, 131.1, 130.1, 119.1, 109.4, 100.5,
95.3, 56.8, 56.7, 43.7, 42.7, 24.7; HRMS m/z 233.1294 (M +
H+) (calcd for C13H17O2N2, 233.1290).
This material was further purified by formation of its BOC
derivative. Thus, EtN(iPr)2 (18 µL) was added to a solution of
crude 33 (21 mg, 0.091 mmol) in THF (2 mL), followed by
(BOC)2O (22 µL, 0.096 mmol). The reaction mixture was stirred
for 4 h at room temperature, and then the reaction was
quenched by the addition of saturated aqueous NaHCO3. The
aqueous layer was extracted with CH2Cl2, and the combined
organic extracts were dried (Na2SO4) and concentrated. Chro-
matography (CH2Cl2/Et2O/hexanes 1/1/3 to 3/3/4) afforded the
BOC derivative of 33 (15 mg, 50%) as a white solid: mp 189.5-
191.5 °C (CH2Cl2/hexanes); TLC Rf 0.21 (CH2Cl2/Et2O/hexanes
3/3/4); 1H NMR (500 MHz, T ) 323 K) 7.73 (br s, 1H), 6.92 (s,
1H), 6.87 (s, 1H), 4.61 (br s, 2H), 3.93 (s, 3H), 3.91 (s, 3H),
3.82 (t, 2H, J ) 6), 2.80 (t, 2H, J ) 6), 1.54 (s, 9H); 13C NMR
(125 MHz, T ) 323 K, 1 aromatic carbon is not observed) 155.3,
146.9, 145.3, 130.4, 118.8, 107.7, 100.7, 95.5, 79.8, 56.7, 56.6,
41.3 (2 carbons), 28.6, 23.7; EIMS (relative intensity) m/z 332
(M+, 6), 275 (24), 203 (16), 86 (31), 84 (48), 57 (12), 51 (32), 49
(100), 44 (17): HRMS m/z 332.1748 (M+) (calcd for C18H24O4N2,
332.1736).
SeO2 Oxid a tion s of 27a , 29a , a n d 30a . 5-Ben zen esu lfo-
n yl-7-m eth oxy-5H-p yr id o[4,3-b]in d ole (35). A solution of
29a (1.09 g, 2.26 mmol) and SeO2 (1.28 g, 11.5 mmol) in
dioxane (20 mL) was refluxed for 24-48 h (until no starting
material was detectable by TLC). The reaction mixture was
cooled to room temperature and stirred with anhydrous
NaHCO3 powder and anhydrous MgSO4.21 The slurry was
filtered through a thin pad of a 1:1 mixture of Florisil and
Celite, rinsed with CHCl3, dried (Na2SO4), and concentrated.
Chromatography (EtOAc/hexanes 3/7 to 1/1 to 4/1) gave 35
(685 mg, 90%) as a white solid: mp 191-192 °C (EtOAc/
hexanes); TLC Rf 0.44 (EtOAc/hexanes 4/1); 1H NMR (400
MHz) 9.17 (s, 1H), 8.62 (d, 1H, J ) 6), 8.31 (d, 1H, J ) 6),
7.94-7.90 (m, 3H), 7.88 (d, 1H, J ) 2), 7.60 (t, 1H, J ) 8),
7.46 (t, 2H, J ) 8), 7.09 (dd, 1H, J ) 9, 2), 4.00 (s, 3H); 13C
NMR (125 MHz) 160.5, 146.2, 143.4, 141.9, 139.4, 137.6, 134.4,
129.4, 126.5, 122.4, 121.1, 117.1, 112.7, 109.5, 99.6, 55.9;
HRMS m/z 339.0795 (M + H+) (calcd for C18H15O3SN2,
339.0803).
) 6), 8.17 (d, 1H, J ) 6), 7.89 (s, 1H), 7.82 (d, 2H, J ) 8), 7.54
(t, 1H, J ) 8), 7.40 (t, 2H, J ) 8) overlapping with 7.40 (s,
1H), 4.08 (s, 3H), 4.01 (s, 3H); 13C NMR (125 MHz) 150.6,
147.8, 145.2, 143.3, 141.3, 137.4, 134.4, 132.5, 129.3, 126.4,
122.9, 116.1, 109.8, 101.8, 98.4, 56.4, 56.3. Anal. Calcd for
C
19H16O4SN2, C, 61.94; H, 4.38; N, 7.61. Found: C, 61.68; H,
4.35; N, 7.37.
Physical and spectral properties of 40: a white solid, mp
241-242 °C (dec) (EtOAc/hexanes); TLC Rf 0.36 (EtOAc/
1
hexanes 4/1); H NMR (400 MHz) 9.55 (s, 1H), 8.55 (d, 1H, J
) 5), 7.92 (s, 1H), 7.81-7.79 (m, 2H), 7.68 (d, 1H, J ) 5), 7.50
(t, 1H, J ) 8), 7.35 (t, 2H, J ) 8) overlapping with 7.33 (s,
1H), 4.11 (s, 3H), 4.00 (s, 3H); 13C NMR (125 MHz) 151.9,
147.7, 143.8, 137.14, 137.1, 134.7, 134.1, 133.8, 133.1, 129.2,
126.4, 116.7, 113.4, 102.3, 98.4, 56.5, 56.3; HRMS m/z 369.0909
(M + H+) (calcd for C19H17O4SN2, 369.0909).
7,8-Dim eth oxy-5H-p yr id o[4,3-b]in d ole (36). According to
general procedure C, K2CO3 (100 mg, 0.72 mmol) was added
to a solution of 34 (71 mg, 0.19 mmol) in THF/MeOH/H2O (4.2
mL), and the reaction mixture was refluxed overnight. Workup
and chromatography (EtOAc/MeOH 19/1 to 7/3) afforded 36
(27 mg, 61%) as a white solid: mp 206-207 °C (EtOAc/MeOH);
1
TLC Rf 0.26 (EtOAc/MeOH 7/3); H NMR (400 MHz) 9.24 (s,
1H), 8.83 (bs, 1H), 8.46 (d, 1H, J ) 6), 7.58 (s, 1H), 7.34 (d,
1H, J ) 6), 7.02 (s, 1H), 4.04 (s, 3H), 4.00 (s, 3H); 13C NMR
(125 MHz) 150.2, 145.4, 143.5, 143.0, 141.5, 134.0, 120.7, 113.3,
106.0, 102.6, 94.5, 56.5, 56.2; HRMS m/z 229.0979 (M + H+)
(calcd for C13H13O2N2, 229.0977).
Alter n a tive Meth od . Red-Al (65+ wt % in toluene, 0.72
mL, 2.40 mmol) was added to a solution of 34 (289 mg, 0.79
mmol) in THF (15 mL). The reaction mixture was stirred at
room temperature for 2 d, and then the reaction was quenched
by the addition of water with ice cooling. The aqueous layer
was extracted with EtOAc (3×), and the combined organic
extracts were dried (Na2SO4) and concentrated. Chromatog-
raphy (EtOAc/MeOH 19/1) gave 36 (106 mg, 59%) as a white
solid.
Alter n a tive Meth od . 10% Pd/C (10 mg) was added to a
solution of crude 33 (27 mg, 0.12 mmol) in mesitylene, and
the reaction mixture was heated to 150-160 °C overnight.
After cooling to room temperature, the reaction mixture was
filtered through Celite, the Celite rinsed with CH2Cl2, and the
filtrate was washed with 10% aqueous HCl. The aqueous layer
was treated with solid NaOH until pH 8 was reached, the
solution was extracted with CH2Cl2 (3×), and the combined
organic extracts were dried (Na2SO4) and concentrated. Chro-
matography (EtOAc/MeOH 7/3) gave 36 (23 mg, 87%) as a
white solid.
7-Meth oxy-5H-p yr id o[4,3-b]in d ole (37). According to
general procedure C, K2CO3 (104 mg, 0.75 mmol) was added
to a solution of 35 (98 mg, 0.29 mmol) in THF/MeOH/H2O (5.3
mL), and the reaction mixture was refluxed overnight. Workup
and chromatography (EtOAc/MeOH 9/1) afforded 37 (29 mg,
51%) as a white solid: mp 172-173 °C (CH2Cl2/hexanes); TLC
1
Rf 0.43 (EtOAc/MeOH 7/3); H NMR (400 MHz) 9.24 (s, 1H),
8.94 (br s, 1H), 8.48 (d, 1H, J ) 6), 8.02 (d, 1H, J ) 9), 7.34 (d,
1H, J ) 6), 6.99 (d, 1H, J ) 2), 6.96 (dd, 1H, J ) 9, 2), 3.93 (s,
3H); 13C NMR (125 MHz) 159.8, 143.9, 143.8, 141.7, 140.7,
121.4, 120.4, 115.1, 109.5, 105.8, 95.2, 55.7; HRMS m/z
199.0872 (M + H+) (calcd for C12H11ON2, 199.0871).
Alter n a tive Meth od . Red-Al (65+ wt % in toluene, 0.11
mL, 0.37 mmol) was added to a solution of 35 (34 mg, 0.10
mmol) in THF (4 mL). The reaction mixture was stirred at
room temperature for 1 d, and then the reaction was quenched
by the addition of water with ice cooling. The aqueous layer
was extracted with EtOAc (3×), and the combined organic
extracts were dried (Na2SO4) and concentrated. Chromatog-
raphy (EtOAc/MeOH 9/1) gave 37 (14 mg, 70%) as a white
solid.
6,7-Dim eth oxy-2,3,4,9-tetr a h yd r o-1H-â-ca r bolin e (39).
A solution of 30a (228 mg, 0.45 mmol) in THF (20 mL) was
(21) Ren, R. X.-F.; Nakanishi, K. Aldrichimica Acta 1997, 30, 106.

2456 J . Org. Chem., Vol. 65, No. 8, 2000
Engler and Wanner
added to liquid NH3 (30 mL), followed by Na (46 mg, 2.0 mmol),
until a blue color persisted for 5 min. The reaction was then
quenched by the addition of solid NH4Cl. The ammonia was
allowed to evaporate, H2O was added to the residue, and the
pH was adjusted to 9-10 by the addition of solid NaOH. The
aqueous layer was extracted with CH2Cl2 (3×), and the
combined organic extracts were dried (Na2SO4) and concen-
trated to give crude 39 (93 mg, 90%) as a yellowish solid which
was ∼90% pure by NMR: 1H NMR (400 MHz) 7.80 (br s, 1H),
6.94 (s, 1H), 6.85 (s, 1H), 4.00 (br s, 2H), 3.94 (s, 3H), 3.90 (s,
3H), 3.19 (t, 2H, J ) 6), 2.73 (br t, 2H, J ) 6); 13C NMR (100
MHz) 146.8, 145.1, 131.7, 130.1, 120.7, 108.8, 100.5, 95.2, 56.8,
56.7, 44.3, 43.7, 23.0; HRMS m/z 233.1277 (M + H+) (calcd
for C13H17O2N2, 233.1290).
This material was further purified by conversion to its BOC
derivative. Thus, EtN(iPr)2 (15 µL) was added to a solution of
crude 39 (18 mg, 0.078 mmol) in THF (2 mL), followed by
(BOC)2O (20 µL, 0.087 mmol). The reaction mixture was stirred
for 4 h at room temperature, and then the reaction was
quenched by the addition of saturated aqueous NaHCO3. The
aqueous layer was extracted with CH2Cl2, and the combined
organic extracts were dried (Na2SO4) and concentrated. Chro-
matography (CH2Cl2/Et2O/hexanes 1/1/3 to 3/3/4) afforded the
BOC derivative of 39 (14 mg, 54%) as a white solid: mp 166-
167 °C (CH2Cl2/hexanes); TLC Rf 0.20 (CH2Cl2/Et2O/hexanes
3/3/4); 1H NMR (500 MHz, T ) 323 K) 7.77 (br s, 1H), 6.95 (s,
1H), 6.88 (s, 1H), 4.62 (br s, 2H), 3.95 (s, 3H), 3.91 (s, 3H),
3.78 (t, 2H, J ) 6), 2.77 (t, 2H, J ) 6), 1.52 (s, 9H); 13C NMR
(125 MHz, T ) 323 K, 1 aromatic carbon is not observed) 155.2,
147.1, 145.3, 130.7, 129.3, 120.2, 101.0, 95.5, 80.0, 56.7, 56.6,
42.0 (2 carbons), 28.5, 21.5; HRMS m/z 332.1715 (M+) (calcd
for C18H24O4N2, 332.1736).
6,7-Dim eth oxy-9H-â-ca r bolin e (41). According to general
procedure C, K2CO3 (25 mg, 0.18 mmol) was added to a
solution of 40 (23 mg, 0.063 mmol) in THF/MeOH/H2O (2.1
mL), and the reaction mixture was stirred at room tempera-
ture for 5 d. Workup and chromatography (EtOAc/MeOH 9/1)
afforded 41 (10 mg, 70%) as a yellowish solid: mp 216.5-218
°C (CH2Cl2/hexanes); TLC Rf 0.33 (EtOAc/MeOH 7/3); 1H NMR
(400 MHz) 9.44 (br s, 1H), 8.88 (d, 1H, J ) 1), 8.44 (d, 1H, J
) 5), 7.88 (dd, 1H, J ) 5, 1), 7.54 (s, 1H), 7.01 (s, 1H), 4.03 (s,
3H), 4.00 (s, 3H); 13C NMR (125 MHz) 151.7, 145.0, 138.5,
136.1, 136.0, 133.1, 129.2, 113.8, 113.3, 102.9, 94.3, 56.5, 56.1;
HRMS m/z 229.0996 (M + H+) (calcd for C13H13O2N2, 229.0977).
Alter n a tive Meth od . KOtBu (83 mg, 0.74 mmol) was
added to a solution of 30a (38 mg, 0.074 mmol) in THF (5 mL).
The reaction mixture was stirred at room temperature for 4
h, and then the reaction was quenched by the addition of H2O.
The aqueous layer was extracted with CH2Cl2 (3×), and the
combined organic extracts were dried (Na2SO4) and concen-
trated. Chromatography (EtOAc/MeOH 9/1) afforded 41 (12
mg, 71%).
5-Ben zen esu lfon yl-7,8-d im eth oxy-5H-p yr id o[4,3-b]in -
d ole 2-Oxid e (42). Carboline 34 (238 mg, 0.65 mmol) was
dissolved in CH2Cl2 (10 mL), and m-CPBA (250 mg, 1.45 mmol)
was added. The reaction mixture was allowed to warm to room
temperature, stirred for 15 h, and then transferred directly
to a silica gel column. Chromatography (EtOAc/hexanes 4/1,
to remove excess m-CPBA, and then MeOH/EtOAc 1/9 to 3/7)
gave 42 (227 mg, 91%) as a white solid: mp 218.5-220 °C
(dec) (EtOAc/MeOH/hexanes); TLC Rf 0.45 (MeOH/EtOAc 3/7);
1H NMR (400 MHz) 8.78 (d, 1H, J ) 1), 8.24 (dd, 1H, J ) 7,
1), 8.12 (d, 1H, J ) 7), 7.79 (s, 1H), 7.76 (d, 2H, J ) 8), 7.57 (t,
1H, J ) 8), 7.41 (t, 2H, J ) 8), 7.24 (s, 1H), 4.08 (s, 3H), 3.99
(s, 3H); 13C NMR (100 MHz) 152.2, 148.6, 137.2, 136.6, 135.4,
135.2, 134.7, 131.3, 129.9, 126.8, 125.8, 114.8, 112.2, 102.3,
98.7, 56.9, 56.8. Anal. Calcd for C19H16O5SN2: C, 59.36; H, 4.20;
N, 7.29. Found: C, 59.15; H, 4.52; N, 7.11.
141.1, 137.0, 136.5, 135.0, 134.8, 130.9, 129.6, 126.5, 125.1,
121.8, 115.2, 113.5, 111.6, 99.7, 56.0; HRMS m/z 355.0735 (M
+ H+) (calcd for C18H15O4SN2, 355.0753).
1-(7-Met h oxy-2-oxyp yr id o[4,3-b]in d ol-5-yl)et h a n on e
(48). A mixture of K2CO3 (25 mg, 0.18 mmol) and 43 (24 mg,
0.068 mmol) in THF (5 mL)/H2O (1 mL) was refluxed for 4 d.
The reaction mixture was allowed to cool to room temperature
and concentrated to dryness. The residue was dissolved in CH2-
Cl2 and transferred to a short plug of silica gel and eluted with
MeOH/EtOAc 3/7. Concentration of the eluent afforded the
deprotected N-oxide (15 mg, 100%). This material was dis-
solved in Ac2O (5 mL)/THF (0.5), sodium acetate (13 mg, 0.16
mmol) was added, and the reaction mixture was stirred at
room temperature for 10 h. The excess Ac2O was coevaporated
with toluene, and the residue was dissolved in CH2Cl2, washed
with saturated aqueous NaHCO3, dried (Na2SO4), and con-
centrated. Chromatography (MeOH/EtOAc 3/7) gave 48 (13
mg, 83%) as a white solid: TLC Rf 0.19 (MeOH/EtOAc 3/7);
1H NMR (400 MHz) 8.78 (d, 1H, J ) 2), 8.25 (dd, 1H, J ) 7,
2), 8.15 (d, 1H, J ) 7), 7.84 (d, 1H, J ) 9), 7.63 (d, 1H, J ) 2),
7.07 (dd, 1H, J ) 9, 2), 3.96 (s, 3H), 2.89 (s, 3H); 13C NMR
(125 MHz) 169.3, 161.4, 140.9, 136.3, 135.3, 130.4, 124.8, 121.6,
115.4, 113.1, 111.9, 101.7, 55.9, 27.3; HRMS m/z 257.0948 (M
+ H+) (calcd for C14H13O3N2, 257.0926).
A similar procedure was followed for N-oxide 42 (16 mg),
except that the rearrangement reaction with Ac2O was carried
out at 80 °C for 4 h, and gave 47 (10 mg, 85%) as a white
solid: mp 225-226 °C (dec) (MeOH/EtOAc); TLC Rf 0.15
1
(MeOH/EtOAc 3/7); H NMR (400 MHz) 8.77 (d, 1H, J ) 2),
8.25 (dd, 1H, J ) 7, 2), 7.98 (d, 1H, J ) 7), 7.82 (s, 1H), 7.29
(s, 1H), 4.04 (s, 3H), 4.036 (s, 3H), 2.90 (s, 3H); 13C NMR (125
MHz) 168.9, 151.4, 147.7, 135.9, 134.63, 134.61, 130.4, 125.2,
114.3, 112.5, 101.6, 100.2, 56.4, 56.38, 27.2; EIMS (relative
intensity) m/z 286 (M+, 2), 270 (57), 228 (100), 213 (65), 185
(42), 170 (18), 155 (11), 84 (35), 75 (12).
7,8-Dim eth oxy-2,5-dih ydr opyr ido[4,3-b]in dol-1-on e (49).
A mixture of N-oxide 42 (240 mg, 0.63 mmol) and NaOAc (164
mg, 2.0 mmol) was refluxed in Ac2O (10 mL) for 24 h. The
mixture was allowed to cool to room temperature, and the
excess Ac2O was coevaporated with toluene. The residue was
dissolved in CH2Cl2, washed with saturated aqueous NaHCO3,
dried (Na2SO4), and concentrated to afford a brown residue
which was dissolved in MeOH (10 mL), and K2CO3 (190 mg,
1.4 mmol) was added. The reaction mixture was stirred for
1-2 h and then concentrated to dryness. The residue was
dissolved in dioxane/H2O (10 mL/0.7 mL) and cooled to 0 °C,
and aqueous H2O2 (30%, 0.26 mL) was added, followed by
aqueous LiOH (0.8 M, 1.2 mL). The reaction mixture was
allowed to warm to room temperature over 4 h, and then the
reaction was quenched by the addition of saturated aqueous
NaHSO3. The solvent was evaporated, and chromatography
of the residue (EtOAc/hexanes 2/3 to 4/1 then MeOH/EtOAc
1/9) afforded 49 (83 mg, 54%) as a white solid: mp 270-272.5
°C (dec) (H2O); TLC Rf 0.33 (MeOH/EtOAc 1/9); 1H NMR (400
MHz, DMSO-d6) 11.44 (br s, 1H), 11.00 (br s, 1H), 7.57 (s, 1H),
7.17 (d, 1H, J ) 7), 7.04 (s, 1H), 6.47 (d, 1H, J ) 7), 3.83 (s,
3H), 3.82 (s, 3H); 13C NMR (125 MHz, DMSO-d6) 159.8, 147.5,
145.0, 143.7, 131.7, 130.2, 116.5, 107.4, 102.7, 95.2, 94.6, 55.8,
55.7; HRMS m/z 245.0939 (M + H+) (calcd for C13H13O3N2,
245.0926).
A similar procedure starting with N-oxide 43 (148 mg) gave
50 (43 mg, 48%) as a white solid: mp 286-287.5 °C (dec)
(H2O); TLC Rf 0.43 (MeOH/EtOAc 1/9); 1H NMR (500 MHz,
DMSO-d6) 11.55 (br s, 1H), 11.04 (br s, 1H), 7.93 (d, 1H, J )
9), 7.21 (d, 1H, J ) 7), 6.97 (d, 1H, J ) 1), 6.81 (dd, 1H, J )
9, 1), 6.46 (d, 1H, J ) 7), 3.80 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) 159.6, 157.0, 144.5, 138.5, 130.9, 121.0, 117.8, 109.6,
107.2, 95.0, 94.4, 55.3; HRMS m/z 214.0721 (M+) (calcd for
A similar procedure starting with carboline 35 (125 mg)
afforded 43 (120 mg, 92%), a white solid: mp 209.5-210.5 °C
(dec) (MeOH/EtOAc); TLC Rf 0.29 (MeOH/EtOAc 3/7); 1H NMR
(400 MHz) 8.71 (s, 1H), 8.26 (dd, 1H, J ) 7, 1), 8.15 (d, 1H, J
) 7), 7.85-7.83 (m, 2H) overlapping with 7.82 (d, 1H, J ) 2),
7.74 (d, 1H, J ) 9), 7.60 (t, 1H, J ) 8), 7.45 (t, 2H, J ) 8), 7.05
(dd, 1H, J ) 9, 2), 3.99 (s, 3H); 13C NMR (125 MHz) 161.6,
C
12H10O2N2, 214.0747).
Gen er a l P r oced u r e D: F or m a tion of Ch lor oca r bolin es
51-54. The starting material was refluxed in POCl3 for 40-
41 h. The mixture was cooled to room temperature, the excess
POCl3 was removed under vacuum, and 10% aqueous HCl was
added to the residue with ice cooling. The resultant slurry was
refluxed for 2 h in the case of 51/52 and for 30 min in the case

Synthesis of Oxygenated Carbolines
J . Org. Chem., Vol. 65, No. 8, 2000 2457
of 53/54. After cooling, the mixture was transferred to a
beaker, and solid NaHCO3 was added until a pH of 7-8 was
reached. The aqueous layer was extracted with CH2Cl2 (3×),
and the combined organic extracts were dried (Na2SO4) and
concentrated.
dried (Na2SO4) and concentrated. Chromatography (MeOH/
EtOAc/Et3N 4.5/85.5/10) afforded BOC derivative 57 (19 mg,
37%) as a white solid: TLC Rf 0.23 (MeOH/EtOAc/Et3N 4.5/
85.5/10); 1H NMR (400 MHz) 8.12 (d, 1H, J ) 6), 8.08 (s, 1H),
7.48 (d, 1H, J ) 6) overlapping with 7.48 (s, 1H), 6.43 (br s,
1H), 4.03 (s, 3H), 4.02 (s, 3H), 3.80 (br t, 2H, J ) 6), 2.56 (t,
2H, J ) 6), 2.32 (s, 6H), 1.93 (apparent quintet, 2H, J ) 6),
1.77 (s, 9H); 13C NMR (125 MHz) 153.7, 150.7, 149.0, 146.3,
144.4, 144.1, 132.7, 116.7, 106.4, 105.7, 102.0, 100.3, 84.4, 59.7,
58.2, 56.1, 45.8, 42.3, 28.3, 26.1; FABMS m/z 429 (M + H+);
HRMS m/z 429.2481 (M + H+) (calcd for C23H33O4N4, 429.2502).
The BOC derivative 57 (14 mg, 0.033 mmol) was dissolved
in EtOAc (4 mL), and concentrated aqueous HCl (1 mL) was
added. The reaction mixture was stirred for 48 h and then
concentrated to dryness. The residue was dissolved in water,
and the pH of the solution was adjusted to 7-8 by the addition
of solid KHCO3. The free diamine was extracted with CH2Cl2
(3×), and the combined organic extracts were dried (Na2SO4)
and concentrated. Chromatography (MeOH/EtOAc/Et3N 4.5/
85.5/10) afforded 55 (9 mg, 84%) as a white solid: mp 170-
171.5 °C (CH2Cl2/hexanes); TLC Rf 0.18 (MeOH/EtOAc/Et3N
1-Ch lor o-7,8-dim eth oxy-5H-pyr ido[4,3-b]in dole (51). Ac-
cording to general procedure D, lactam 49 (50 mg, 0.20 mmol)
gave, after workup and chromatography (MeOH/EtOAc 1/19
to 1/9), 51 (23 mg, 43%) as a white solid: mp 257-258 °C (CH2-
1
Cl2/hexanes); TLC Rf 0.64 (MeOH/EtOAc 1/9); H NMR (400
MHz, DMSO-d6) 11.96 (br s, 1H), 8.11 (d, 1H, J ) 6), 7.79 (s,
1H), 7.47 (d, 1H, J ) 6), 7.17 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H);
13C NMR (125 MHz, DMSO-d6) 150.3, 144.9, 144.8, 142.3,
141.9, 134.7, 116.6, 111.2, 106.3, 104.1, 95.0, 56.1, 55.7; HRMS
m/z 263.0596 (M + H+) (calcd for C13H12O2N235Cl, 263.0587).
1-Ch lor o-7-m eth oxy-5H-p yr id o[4,3-b]in d ole (52). Ac-
cording to general procedure D, lactam 50 (21 mg, 0.098 mmol)
gave, after workup and chromatography (CH2Cl2/Et2O/hexanes
3/3/4), 52 (14 mg, 61%) as a white solid: mp 256-266 °C (CH2-
Cl2/hexanes); TLC Rf 0.11 (CH2Cl2/Et2O/hexanes 3/3/4); 1H
NMR (400 MHz, DMSO-d6) 12.04 (br s, 1H), 8.21 (d, 1H, J )
9), 8.16 (d, 1H, J ) 5), 7.49 (d, 1H, J ) 5), 7.12 (d, 1H, J ) 2),
6.97 (dd, 1H, J ) 9, 2), 3.88 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) 159.5, 145.6, 142.7, 142.4, 141.3, 122.7, 116.5, 113.0,
110.0, 106.2, 95.2, 55.4; HRMS m/z 233.0467 (M + H+) (calcd
for C12H10ON235Cl, 233.0482).
5-Ben zen esu lfon yl-1-ch lor o-7,8-d im eth oxy-5H-p yr id o-
[4,3-b]in d ole (53). According to general procedure D, N-oxide
42 (78 mg, 0.20 mmol) gave, after workup and chromatography
(EtOAc/hexanes 2/3) 53 (67 mg, 82%) as a white solid: mp
254.5-255.5 °C (CH2Cl2/hexanes); TLC Rf 0.30 (EtOAc/hexanes
2/3); 1H NMR (400 MHz) 8.35 (d, 1H, J ) 6), 8.15 (d, 1H, J )
6), 7.92 (s, 1H), 7.88 (s, 1H), 7.82 (d, 2H, J ) 8), 7.56 (t, 1H, J
) 8), 7.41 (t, 2H, J ) 8), 4.10 (s, 3H), 4.02 (s, 3H); 13C NMR
(125 MHz) 150.8, 147.6, 144.7, 144.68, 144.0, 137.3, 134.6,
132.7, 129.4, 126.4, 120.5, 115.4, 109.0, 104.2, 97.9, 56.4, 56.3;
FABMS m/z 403 (M + H+); HRMS m/z 403.0530 (M + H+)
(calcd for C19H16O4SN235Cl, 403.0519).
5-Ben zen esu lfon yl-1-ch lor o-7-m eth oxy-5H-p yr id o[4,3-
b]in d ole (54). According to general procedure D, N-oxide 43
(106 mg, 0.30 mmol) gave, after workup and chromatography
(EtOAc/hexanes 1/1), 54 (92 mg, 83%) and 52 (2 mg, 3%) as
white solids. Physical and spectral properties of 54: mp 208-
209 °C (CH2Cl2/hexanes); TLC Rf 0.51 (EtOAc/hexanes 1/1);
1H NMR (400 MHz) 8.37 (d, 1H, J ) 6), 8.32 (d, 1H, J ) 9),
8.17 (d, 1H, J ) 6), 7.87 (d, 2H, J ) 8) overlapping with 7.88
(d, 1H, J ) 2), 7.57 (t, 1H, J ) 8), 7.43 (t, 2H, J ) 8), 7.07 (dd,
1H, J ) 9, 2), 3.98 (s, 3H); 13C NMR (100 MHz) 160.8, 144.96,
144.95, 144.2, 139.6, 137.4, 134.7, 129.5, 126.6, 123.8, 120.2,
116.1, 112.8, 108.8, 99.2, 55.9; FABMS m/z 373 (M + H+);
HRMS m/z 373.0396 (M + H+) (calcd for C18H14O3SN235Cl,
373.0414).
N-(7,8-Dim eth oxy-5H-pyr ido[4,3-b]in dol-1-yl)-N′,N′-dim -
eth ylp r op a n e-1,3-d ia m in e (55) a n d (7,8-Dim eth oxy-5H-
p yr id o[4,3-b]in d ol-1-yl)-1,3-(d im eth yla m in o)p r op yl)ca r -
ba m ic Acid ter t-Bu tyl Ester (57). A solution of 53 (50 mg,
0.12 mmol) in N,N-dimethyl-1,3-propanediamine (5 mL) was
heated to 170 °C for 12 d. The reaction mixture was allowed
to cool to room temperature, and the excess amine was
removed under reduced pressure. The residue was dissolved
in 10% aqueous NaOH and extracted with CH2Cl2 (3×), and
the combined organic extracts were dried (Na2SO4) and
concentrated. Chromatography (MeOH/EtOAc/Et3N 4.5/85.5/
10) gave 55 as a yellowish solid which was ∼70% pure by
NMR. The compound was dissolved in CH2Cl2 (3 mL), and
DMAP (9 mg, 0.07 mmol) was added followed by (BOC)2O (37
µL, 0.16 mmol). The reaction mixture was stirred for 30 min,
and then the reaction was quenched by the addition of
saturated aqueous NaHCO3. The aqueous layer was extracted
with CH2Cl2 (3×), and the combined organic extracts were
1
4.5/85.5/10); H NMR (400 MHz) 9.17 (br s, 1H), 7.96 (d, 1H,
J ) 6), 7.54 (s, 1H), 6.96 (s, 1H), 6.73 (d, 1H, J ) 6), 6.53 (br
s, 1H), 4.02 (s, 3H), 3.93 (s, 3H), 3.83 (t, 2H, J ) 6), 2.55 (t,
2H, J ) 6), 2.34 (s, 6H), 1.93 (apparent quintet, 2H, J ) 6);
13C NMR (125 MHz) 153.6, 149.0, 144.8, 144.4, 141.7, 133.5,
114.1, 106.0, 104.5, 98.0, 94.6, 59.4, 58.4, 56.1, 45.7, 42.1, 26.2;
FABMS m/z 329 (M + H+); HRMS m/z 329.1988 (M + H+)
(calcd for C18H25O2N4, 329.1977).
In a similar manner, chlorocarboline 54 (60 mg, 0.16 mmol)
gave, after workup and chromatography (MeOH/EtOAc/Et3N
4.5/85.5/10), 56 as a yellowish solid which was ∼70% pure by
NMR. This compound was converted as described above to
BOC derivative 58 (37 mg, 58%), a white solid: TLC Rf 0.28
(MeOH/EtOAc/Et3N 4.5/85.5/10); 1H NMR (400 MHz) 8.12 (d,
1H, J ) 6), 7.99 (d, 1H, J ) 2), 7.87 (d, 1H, J ) 9), 7.48 (d, 1H,
J ) 6), 7.06 (br s, 1H), 6.99 (dd, 1H, J ) 9, 2), 3.94 (s, 3H),
3.79 (br t, 2H, J ) 6), 2.62 (t, 2H, J ) 6), 2.38 (s, 6H), 1.94
(apparent quintet, 2H, J ) 6), 1.77 (s, 9H); 13C NMR (125 MHz)
158.3, 153.6, 150.7, 144.5, 144.3, 138.7, 119.9, 117.8, 111.3,
106.0, 101.6, 100.9, 84.4, 59.8, 55.6, 45.7, 42.7, 28.3, 25.4;
FABMS m/z 399 (M + H+); HRMS m/z 399.2411 (M + H+)
(calcd for C22H31O3N4, 399.2396).
The BOC derivative 58 (16 mg, 0.040 mmol) was deprotected
as described above, and chromatography (MeOH/EtOAc/Et3N
4.5/85.5/10) afforded 56 (11 mg, 92%) as a white solid: mp
169.5-170.0 °C (CH2Cl2/hexanes); TLC Rf 0.19 (MeOH/EtOAc/
Et3N 4.5/85.5/10); 1H NMR (400 MHz) 9.01 (br s, 1H), 8.00 (d,
1H, J ) 6), 7.88 (d, 1H, J ) 9), 7.09 (br s, 1H), 6.97 (d, 1H, J
) 2), 6.91 (dd, 1H, J ) 9, 2), 6.72 (d, 1H, J ) 6), 3.89 (s, 3H),
3.83 (t, 2H, J ) 6), 2.60 (t, 2H, J ) 6), 2.38 (s, 6H), 1.93
(apparent quintet, 2H, J ) 6); 13C NMR (125 MHz) 157.8,
153.5, 144.7, 142.2, 139.4, 120.4, 115.8, 108.8, 104.0, 97.6, 95.2,
59.7, 55.6, 45.7, 42.7, 25.6; FABMS m/z 299 (M + H+); HRMS
m/z 299.1890 (M + H+) (calcd for C18H25O2N4, 299.1872).
Ack n ow led gm en ts. Financial support from the De-
partment of Chemistry at the University of Kansas and
the National Science Foundation is gratefully acknowl-
edged. We thank Professors Paul Hanson and Robert
Carlson for helpful discussions and guidance during the
later stages of this work.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for A-F /G and 59/60 and IR and
mass spectral data and NMR spectra for all compounds lacking
CHN analyses. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O9916176