Iodine (III)-mediated generation of nitrogen-tethered orthoquinol acetates for the construction of oxygenated indole, quinoline, and phenanthridine alkaloid motifs

Article abstract of DOI:10.1021/jo020010d

Functionalized indole and quinoline derivatives are conveniently prepared from nitrogen-tethered 2-methoxyphenols via phenyliodine(III) diacetate mediated oxidative acetoxylation, followed by a fluoride- or base-induced intramolecular nucleophilic addition reaction. This regioselective Michael-type addition step is further discussed in view of the rearrangement of orthoquinol acetate intermediates into paraquinol acetates that is sometimes observed in situ. Application of this methodology to the synthesis of a functionalized phenanthridine, and its potential for the construction of polyoxygenated lycorine-type alkaloid skeleta are here described.

Full text of DOI:10.1021/jo020010d

J . Org. Chem. 2002, 67, 3425-3436
3425
Iod in e(III)-Med ia ted Gen er a tion of Nitr ogen -Teth er ed
Or th oqu in ol Aceta tes for th e Con str u ction of Oxygen a ted In d ole,
Qu in olin e, a n d P h en a n th r id in e Alk a loid Motifs
Laurent Pouyse´gu, Anne-Virginie Avellan, and Ste´phane Quideau*
Laboratoire de Chimie des Substances Ve´ge´tales, Centre de Recherche en Chimie Mole´culaire,
Universite´ Bordeaux 1, 351 cours de la Libe´ration, 33405 Talence Cedex, France
s.quideau@ipin.u-bordeaux.fr
Received J anuary 3, 2002
Functionalized indole and quinoline derivatives are conveniently prepared from nitrogen-tethered
2-methoxyphenols via phenyliodine(III) diacetate mediated oxidative acetoxylation, followed by a
fluoride- or base-induced intramolecular nucleophilic addition reaction. This regioselective Michael-
type addition step is further discussed in view of the rearrangement of orthoquinol acetate
intermediates into paraquinol acetates that is sometimes observed in situ. Application of this
methodology to the synthesis of a functionalized phenanthridine, and its potential for the
construction of polyoxygenated lycorine-type alkaloid skeleta are here described.
In tr od u ction
The unique polycyclic structures and potentially useful
pharmacological properties of Amaryllidaceae alkaloids
continue to fuel numerous synthetic studies.1-7 The
lycorine-type alkaloids, which are characterized by the
presence of the ABCD tetracyclic R-lycorane core (1),
represent an important subclass of this family of natural
products (Figure 1). Among them, lycorine (2) was the
first Amaryllidaceae alkaloid isolated in 1877 from
Narcissus pseudonarcissus.8 It is the bioactive principle
that is the most frequently isolated from ornamental
plants of the Amaryllidaceae family, and it displays
analgesic,9 antiviral,10 and antineoplastic activities,11-13
as well as insect antifeedant activities.14,15 It is known
to inhibit protein and DNA syntheses and was also found
to inhibit mouse tumor cell apoptosis induced by poly-
morphonuclear leukocyte-derived calprotectin (EC50
)
0.1-0.5 µg/mL).16 The nonchiral benzannulated anhy-
(1) Ghosal, S.; Saini, K. S.; Razdan, S. Phytochemistry 1985, 24,
2141-2156.
(2) Martin, S. F. In The Alkaloids. Chemistry and Pharmacology;
Brossi, A., Ed.; Academic Press: San Diego, 1987; Vol. 30, pp 251-
376.
F igu r e 1.
(3) Lewis, J . R. Nat. Prod. Rep. 1993, 291-299.
(4) Lewis, J . R. Nat. Prod. Rep. 1995, 339-345.
(5) Lewis, J . R. Nat. Prod. Rep. 1998, 15, 107-110.
(6) Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: 1998; Vol. 51, pp 323-433.
(7) Lewis, J . R. Nat. Prod. Rep. 2000, 17, 57-84.
(8) Cook, J . W.; Loudon, J . D. In The Alkaloids; Manske, R. H. F.,
Holmes, H. L., Eds.; Academic Press: New York, 1952; Vol. II, pp 331-
352.
drolycorinium chloride (3a , R ) H) is effective in vivo
against murine P-388 lymphocytic leukemia,17 and un-
geremine (3b, R ) OH) is active against some types of
carcinoma.18 The indolic 3,4-dehydroanhydrolycorine (4a ,
X ) H, H) and hippadine (4b, X ) O) are both biosyn-
thetically derived from 2-epi-lycorine,19 and 4b reversibly
inhibits fertility in male rats.20,21 The structurally related
(9) Tanker, M.; Citoglu, G.; Gumusel, B.; Sener, B. Int. J . Pharma-
cogn. 1996, 34, 194-197.
(10) Gabrielsen, B.; Monath, T. P.; Huggins, J . W.; Kefauver, D. F.;
Pettit, G. R.; Groszek, G. J . Nat. Prod. 1992, 55, 1569-1581.
(11) Ceriotti, G. Nature 1967, 213, 595-596.
(12) J imenez, A.; Santos, A.; Alonso, G.; Vazquez, D. Biochim.
Biophys. Acta 1976, 425, 342-348.
(17) Pettit, G. R.; Gaddamidi, V.; Goswani, A.; Cragg, G. M. J . Nat.
Prod. 1984, 47, 796-801.
(18) Xu, B.; Chen, J .-T.; Yang, J .-L.; Chang, S.-Y.; Yueh, H.-F.;
Wang, T.-W.; Chou, C.-H. In US-China Pharmacology Symposium;
Burns, J . J ., Tsuchitani, P. J ., Eds.; National Academy of Sciences:
Washington, DC, 1980; p 151.
(13) Baez, A.; Vazquez, D. Biochim. Biophys. Acta 1978, 518, 95-
103.
(14) Numata, A.; Takemura, T.; Ohbayashi, H.; Katsuno, T.; Yama-
moto, K.; Sato, K.; Kobayashi, S. Chem. Pharm. Bull. 1983, 31, 2146-
2149.
(15) Singh, R. P.; Pant, N. C. Experientia 1980, 36, 552-553.
(16) Yui, S.; Mikami, M.; Kitahara, M.; Yamazaki, M. Immuno-
pharmacology 1998, 40, 151-162.
(19) Ghosal, S.; Unnikrishnan, S.; Singh, S. K. Phytochemistry 1989,
28, 2535-2537.
(20) Ghosal, S.; Rao, P. H.; J aiswal, D. K.; Kumar, Y.; Frahm, A.
W. Phytochemistry 1981, 20, 2003-2007.
(21) Chattopadhyay, S.; Chattopadhyay, U.; Mathur, P. P.; Saini,
K. S.; Ghosal, S. J . Med. Plant. Res. 1983, 49, 252-254.
10.1021/jo020010d CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/18/2002

3426 J . Org. Chem., Vol. 67, No. 10, 2002
Pouyse´gu et al.
Sch em e 1
Sch em e 2
ABC tricyclic lycoricidine (5) exhibits in vitro antiviral
activity against RNA-containing flaviviruses and bunya-
viruses,10 as well as antitumoral activity against Ehrlich
carcinoma.22
Sch em e 3
This structural diversity in bioactive Amaryllidaceae
alkaloids has provided organic chemists with attractive
targets for the development of various synthetic method-
ologies.23-30 Considerable efforts have been directed
toward the elaboration of the ABCD tetracyclic skeleton
of alkaloids 2-4. In most cases, introduction of the
oxygenated functions on cycle C was carried out after
construction of the R-lycorane core 1.
All of these lycorine-type alkaloids are biosynthetically
derived from a common diphenolic precursor identified
as 4′-O-methylnorbelladine (6), which presumably un-
dergoes a one-electron oxidative para-ortho phenolic
coupling in route to the lycorine-type norpluviine (7)
(Scheme 1).31
The synthetic utility of such radical coupling reactions
is, however, poor because of the lack of regiochemical
control and competing polymerization processes.32-34
A
two-electron oxidative activation of a nitrogen-linked
diphenol such as 6 or an analogue thereof could provide
a solution to this synthetic challenge. Our investigations
on orthoquinone monoketal chemistry for the synthesis
of polyoxygenated benzannulated heterocyclic systems
led us to consider nitrogen heterocyclization as a poten-
tially useful alternative route. In this context, oxidative
acetoxylation of 2-alkoxyarenols allows the transforma-
tion of functionalized arenols (i.e., hydroxylated arenes)
into orthoquinol acetates (i.e., 6-acetoxy-6-alkoxycyclo-
hexa-2,4-dienones). Their conjugated enone system can
be exploited to induce intramolecular nucleophilic addi-
tion reactions in a regiocontrolled manner. We already
applied this strategy for exo-trig35 selective oxygen het-
erocyclization using phenyliodine(III) diacetate (PIDA)36
as a convenient alternative to the use of metal-based
oxidizing reagents such as Pb(OAc)4
and Tl(NO3)3.39
37,38
We discuss here nitrogen versions of these heterocycliza-
tions (Scheme 2). Elaboration of various benzannulated
nitrogen-containing five- and six-membered rings, i.e.,
indolines and tetrahydroquinolines, is described in full
detail. Application of this novel methodology to the
synthesis of a lycoricidine analogue and of lycorine-type
advanced intermediates is also presented.
Resu lts a n d Discu ssion
(22) Okamoto, T.; Torii, Y.; Isogai, Y. Chem. Pharm. Bull. 1968, 16,
1860-1864.
Phenols 8a -e were prepared in good yields from
commercially available 2-methoxyphenols. The N-Tsoc-
protected amino phenol 8a was synthesized in one step
from 3-O-methyldopamine hydrochloride 11 in 78% yield
(Scheme 3).40 The introduction of the tri-iso-propyl-
silyloxycarbonyl protective group C(O)OSi(i-Pr)3 (Tsoc)
does not require preliminary phenol protection,41 and was
chosen by analogy with our work on silylated oxygen-
tethered 2-methoxyphenols used in PIDA-mediated acet-
oxylation.36 The synthesis of phenol 8b began with
(23) Boeckman, R. K., J r.; Goldstein, S. W.; Walters, M. A. J . Am.
Chem. Soc. 1988, 110, 8250-8252.
(24) Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J . Am. Chem.
Soc. 1993, 115, 7904-7905.
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9696.
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1994, 116, 5108-5115.
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(29) Boger, D. L.; Wolkenberg, S. E. J . Org. Chem. 2000, 65, 9120-
9124.
(30) Acena, J . L.; Arjona, O.; Leon, M. L.; Plumet, J . Org. Lett. 2000,
2, 3683-3686.
(31) Eichhorn, J .; Takada, T.; Kita, Y.; Zenk, M. H. Phytochemistry
1998, 49, 1037-1047.
(36) Quideau, S.; Pouyse´gu, L.; Looney, M. A. J . Org. Chem. 1998,
63, 9597-9600.
(37) Wessely, F.; Sinwel, F. Monatsh. Chem. 1950, 81, 1055-1070.
(38) Bubb, W. A.; Sternhell, S. Tetrahedron Lett. 1970, 51, 4499-
4502.
(39) McKillop, A.; Perry, D. H.; Edwards, M.; Antus, S.; Farkas, L.;
No´gra´di, M.; Taylor, E. C. J . Org. Chem. 1976, 41, 282-287.
(40) Quideau, S.; Pouyse´gu, L.; Oxoby, M.; Looney, M. A. Tetra-
hedron 2001, 57, 319-329.
(41) Lipshutz, B. H.; Papa, P.; Keith, J . M. J . Org. Chem. 1999, 64,
3792-3793.
(32) Schwartz, M. A.; Rose, B. F.; Holton, R. A.; Scott, S. W.;
Vishnuvajjala, B. J . Am. Chem. Soc. 1977, 99, 2571-2578.
(33) McDonald, P. D.; Hamilton, G. A. In Oxidation in Organic
Chemistry, Part B; Trahanovsky, W. S., Ed.; Academic Press: New
York, 1973; pp 97-134.
(34) Battersby, A. R. In Oxidative Coupling of Phenols; Taylor, W.
I., Battersby, A. R., Eds.; Marcel Dekker Inc.: New York, 1967; pp
119-165.
(35) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734-736.

Functionalized Indole and Quinoline Derivatives
J . Org. Chem., Vol. 67, No. 10, 2002 3427
Ta ble 1. Nitr ogen Ben za n n u la tion of Or th oqu in ol
Aceta tes in to In d olin e a n d Qu in olin e Der iva tives
Sch em e 4
Sch em e 5
benzylation of vanillin (12). The aldehyde function of the
resulting benzyl ether (13) was reacted with the anion
derived from diethyl cyanomethylphosphonate to furnish
the R,â-unsaturated nitrile 14 in 82% yield from 12
(Scheme 3). Treatment with hydrogen in EtOH-CHCl3
(20:1) in the presence of Adam’s catalyst42 gave the
corresponding phenolic primary amine,43 which was
submitted to Lipshutz’s procedure41 to give the N-
silylated carbamate phenol 8b in 27% yield from 14
(Scheme 3).
Phenol 8c was prepared in order to probe the capacity
of its carbamate nitrogen atom to perform the desired
heterocyclization. Henry condensation between the al-
dehyde group of benzylated vanillin (13) and nitromethane
in the presence of ammonium acetate in refluxing acetic
acid furnished the corresponding nitrostyrene (Scheme
4). Reduction of this compound with LiAlH4 in refluxing
Et2O/THF (1:1) gave rise to the primary amine 15 in 48%
yield from 13. Reaction of this free amine in refluxing
acetone with methyl chloroformate (4 equiv) and anhy-
drous potassium carbonate (6 equiv)44 furnished a car-
bamate derivative, which was submitted to standard
debenzylation in THF to give phenol 8c in 49% yield from
15.
Finally, the two N-benzylated amido phenols 8d and
8e were prepared in good yields by direct condensation
of homovanillic acid (16) or ethyl 3-(4-hydroxy-3-meth-
oxyphenyl)propanoate (17),36 in the presence of 4 Å
molecular sieves45 in neat benzylamine at 140-150 °C46
(Scheme 5).
a
b
PIDA (1.0 equiv), CH2Cl2, -78 °C. Exo-trig cyclization.
ation, in methylene chloride at -78 °C, according to our
previously reported procedure.36 The corresponding ortho-
quinol acetates 9a -e were obtained in excellent yields
(Table 1).40 In contrast to the use of metal-based oxidizing
systems, the iodobenzene and acetic acid byproducts are
conveniently removed by drying under vacuum, and no
spent toxic salts are generated. Of particular note is the
fact that similar PIDA oxidations of free amino-tethered
phenols 11 and debenzylated 15 gave rise to intractable
mixtures. Protection of the appended amino group thus
proved to be crucial to the success of these dearomatizing
acetoxylations. The nature of the amino protective group
influenced the propensity with which annulation could
be promoted, and different condition sets had to be
selected to carry out regioselective cyclizations to indoline
and tetrahydroquinoline compounds 10a -e (Table 1).40
We already reported that oxygen-tethered orthoquinol
acetates can be stored as dry oils for several days at -20
°C without any noticeable degradation.36 A similar be-
havior was observed with the nitrogen versions, but the
orthoquinonoid species 9c-e that bear a methyl carbam-
ate or a benzyl amide were somewhat less stable in
All of the nitrogen-tethered 2-methoxyphenols 8a -e
were submitted to PIDA-mediated oxidative acetoxyl-
(42) Banwell, M. G.; Harvey, J . E.; Hockless, D. C. R. J . Org. Chem.
2000, 65, 4241-4250.
(43) Elorriaga, C.; Cortes Fernandez, M. A.; Fernandez Alvarez, E.;
Nieto Lopez, O.; Piedrafita, F. J . An. Qu´ım., Ser. C 1987, 83, 70-76.
(44) Corey, E. J .; Bock, M. G.; Kozikowski, A. P.; Rama Rao, A. V.;
Floyd, D.; Lipshutz, B. Tetrahedron Lett. 1978, 12, 1051-1054.
(45) Cossy, J .; Pale-Grosdemange, C. Tetrahedron Lett. 1989, 30,
2771-2774.
(46) Braun, N. A.; Ousmer, M.; Bray, J . D.; Bouchu, D.; Peters, K.;
Peters, E.-M.; Ciufolini, M. A. J . Org. Chem. 2000, 65, 4397-4408.

3428 J . Org. Chem., Vol. 67, No. 10, 2002
Pouyse´gu et al.
Sch em e 6
Sch em e 7
solution. For example, proton NMR monitoring of 9e in
a CDCl3 solution (ca. 0.4 M) indicated that this monoketal
intermediate began to evolve over prolonged periods of
time at room temperature. After 3 days at ambient
temperature, 9e was completely and cleanly transformed
into a new compound that was then identified as the
cyclohexa-2,5-dienone 9h (Scheme 6). Despite very simi-
lar spin systems, compounds 9e and 9h could be distin-
guished on the basis of certain carbon chemical shifts.
For example, the carbonyl carbon-1 of the cyclohexa-2,4-
dienone 9e resonates at 191.5 ppm, whereas carbon-1 of
the 2,5-dienone counterpart 9h is expectedly shifted
upfield by about 11 ppm. The ketal carbon-6 of 9e
resonating at 92.9 ppm is converted into the methyl enol
ether carbon-2, which gives a downfield signal at 151.2
ppm. Structure 9h was further confirmed by establishing
proton-proton and proton-carbon connectivities by two-
dimensional NMR experiments (see Experimental Sec-
tion). A [3,3] sigmatropic shift of the acetate group can
be invoked to explain the transformation of the 2,4-
dienone derivative 9e into the apparently more thermo-
dynamically stable 2,5-counterpart 9h (Scheme 6). Simi-
lar rearrangements have been observed for orthoquinol
clization of the benzylated amido orthoquinol acetates
9d /e was base-induced. Potassium tert-butoxide in re-
fluxing THF (ca. 70 °C) was, in this case, identified as
the best system to induce the desired benzannulation.
The 2-oxindole 10d and the 3,4-dehydro-2-oxoquinoline
10e were obtained in unoptimized yields of 17% and 38%,
respectively. These moderate yields of heterocyclizations
and the observation of acetate shifts (vide supra) led us
to wonder about the nature of the cyclohexadienone (2,4-
vs 2,5-) intermediates really involved in the cyclization
process. Nitrogen-tethered cyclohexa-2,5-dienones 19a -
d , also generated by iodine(III)-mediated oxidations of
p-phenols, are indeed known to undergo intramolecular
Michael-type nitrogen additions leading to the formation
of hydroindolenones and hydroquinolenones 20a -d
(Scheme 7).46,50-52
The cyclohexa-2,5-dienone 9h was submitted to the
cyclization conditions set up for the orthoquinol acetate
9e. Refluxing at 70 °C in THF for 1.5 days did not
promote any cyclization, whereas more drastic conditions,
i.e., 150 °C for 3 h, induced the formation of the desired
benzannulated target 10e, which was isolated in 36%
yield. This result demonstrated that the conditions
proposed in our methodology clearly involved cyclohexa-
2,4-dienone entities. The regiochemistry of all cyclized
products was readily determined by the observation of
two aromatic singlets in their 1H NMR spectrum. The
cyclic connectivity at the nitrogen atom of the amide
function was further confirmed on structure 10e by the
detection of a diagnostic three-bond response in its long-
range C-H correlation 2D map. The methylene hydrogen
atoms of the benzyl group were nicely correlated with
the nitrogen-bearing quaternary carbon atom resonating
at 133.7 ppm (Table 1). Assignment of this carbon signal
1
acetates 9c and 9d in the course of their H and 13C NMR
analyses. Reaction equilibria led to mixtures of 2,4- and
2,5-dienone derivatives, which suffered degradation after
3 days.
Orthoquinol acetates were consequently submitted to
the cyclization conditions immediately after preparation.
The silylated amines 9a /b were treated with tetrabutyl-
ammonium fluoride (TBAF) in THF to afford the benz-
annulated indoline 10a and tetrahydroquinoline 10b
(Table 1). The carbamate 9c was instead deprotonated
to induce cyclization. Various bases such as Na2CO3 in
THF, K2CO3 in refluxing CH3CN, NaH in THF, and
tetramethylpiperidine in THF were tried without any
success, but treatment with lithium hexamethyldi-
silazane (LHMDS) in THF gave the indoline 10c in 32%
yield. At this point, it was not clear whether this
moderate cyclization yield was due to the relative insta-
bility of the orthoquinol acetate 9c or to the lower
nucleophilic force of the carbamate nitrogen when com-
pared to that of the transient amino anion in 9a /b. Amide
nitrogen heterocyclization was next investigated with the
aim of preparing functionalized 2-oxindoles and oxo-
quinolines, which constitute potentially useful pharma-
cophores.47-49 As in the case of the carbamate 9c, cy-
(48) Carling, R. W.; Leeson, P. D.; Moseley, A. M.; Smith, J . D.;
Saywell, K.; Tricklebank, M. D.; Kemp, J . A.; Marshall, G. R.; Foster,
A. C.; Grimwood, S. Bioorg. Med. Chem. Lett. 1993, 3, 65-70.
(49) De Kimpe, N.; Keppens, M. Tetrahedron 1996, 52, 3705-3718.
(50) Wipf, P.; Kim, Y. Tetrahedron Lett. 1992, 33, 5477-5480.
(51) Karam, O.; Martin, A.; J ouannetaud, M.-P.; J acquesy, J .-C.
Tetrahedron Lett. 1999, 40, 4183-4186.
(52) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T. J .
Org. Chem. 1991, 56, 435-438.
(47) Hesse, M. In Alkaloid Chemistry; Wiley: New York, 1978.

Functionalized Indole and Quinoline Derivatives
J . Org. Chem., Vol. 67, No. 10, 2002 3429
Sch em e 8
Sch em e 9a
a
Reagents: (a) TES-OTf, Et3N, CH2Cl2; (b) BnBr, K2CO3, EtOH;
was deduced from its two-bond correlation with the
hydrogen atom ortho to the phenol. Similar NMR data
were obtained with indoline 10c and oxindole 10d . These
structural determinations are important since the nu-
cleophilicity of an amide oxygen is known to compete with
that of the nitrogen atom (Scheme 7).46,52 In most cases,
both PIDA- and phenyliodine(III) bis(trifluoroacetate)
PIFA-mediated oxidation of amido p-phenols furnish
O-spirocyclohexa-2,5-dienones (e.g., 21 f 22, Scheme
7).46,53 Only the use of imidate groups results in nitrogen
attack at the para-substituted electrophilic site46 of the
phenoxenium-type intermediate.54 In our work, tempo-
rary introduction of the acetate group allows us to
prepare the arene ring to undergo benzannulation with-
out spiroannulation. Direct PIFA-mediated oxidation of
phenol 8e under Kita’s conditions53 afforded unidentified
complex mixtures. The methoxy group in the 2-position
of the starting phenols acts as an orienting group for the
oxidative acetoxylation.55 Orthoquinol acetates derived
from either N-Tsoc-protected amines, benzylated amides,
or carbamates all furnished exo-trig benzannulation
products.
(c) t-BuLi, Et2O, Bu3SnCl, -78 °C; (d) Pd(PPh3)4, Na2CO3, toluene,
∆; (e) TBAF, THF; (f) Zn(N3)2‚2Pyr, DEAD, PPh3, THF/CH2Cl2 (4:
1); (g) PPh3, H2O, THF; (h) CO2, Et3N, CH2Cl2, -78 °C, then TIPS-
OTf; (i) H2, Pd/C, THF; (j) PIDA, CH2Cl2, -78 °C; (k) TBAF,
THF.
steps from 4-bromo-2-methoxyphenol (26).57 Benzyl-
ation58 of 26 was followed by a treatment with tert-
butyllithium (1.5 M in pentane, 1.05 equiv) and tri-
butyltin chloride in Et2O at -78 °C to afford 28 in 85%
overall yield from 26. The Stille coupling of 27 with 28
was carried out in refluxing toluene for 4 days in the
presence of sodium carbonate (7 equiv) and a catalytic
amount of palladium tetrakis(triphenylphosphine). The
resulting O-silylated biaryl 29 (21% yield, not optimized)
was then submitted to a TBAF-mediated desilylation,
followed by a Mitsunobu reaction with Zn(N3)2‚2Pyr (0.75
equiv) in the presence of diethyl azodicarboxylate (DEAD,
1.5 equiv) and PPh3 (1.5 equiv)59 to give the corresponding
azide. Reduction of this compound under standard condi-
tions (PPh3, H2O, THF, 4 days)60 then afforded amine 30
in 28% overall yield from 29. The primary amine 30 was
protected as its N-Tsoc carbamate and debenzylated prior
to PIDA-mediated oxidative acetoxylation. The ortho-
quinol acetate 31 was thus obtained in 58% yield from
amine 30. Of particular note is the fact that only the
cyclohexa-2,4-dienone was experimentally observed, as
in the case of the other N-Tsoc phenols 8a and 8b (vide
supra). Subsequent TBAF-mediated deprotection-cy-
clization sequence furnished an off-white solid (80% yield)
that was identified as the phenanthridine derivative 32.
The 6-exo-trig heterocylization was readily confirmed by
the observation of two additional aromatic singlets and
the disappearance of the orthoquinol acetate conjugated
ethylenic signals in the 1H NMR spectrum. We attempted
to prevent in situ the oxidizing aromatization of the
dihydrophenanthridine 23 into the phenanthridine 32 by
adding 2,6-di-tert-butyl-4-methoxyphenol (1 equiv) into
the reaction medium, but 32 was again formed in a very
This azacyclization methodology led us to envisage the
synthesis of the benzannulated tetracycle 23 (Scheme 8),
a possible advanced synthetic intermediate of lycoricidine
(5) (Figure 1). The retrosynthetic analysis was based on
the regiocontrolled nitrogen-benzannulation of an ortho-
quinol acetate of type 24. A Stille coupling reaction,
involving two compounds derived from readily available
synthons 2556 and 26,57 was selected for the biaryl
carbon-carbon bond formation (Scheme 8).
The 5-(hydroxymethyl)-6-iodo-1,3-benzodioxole (25)56
was protected with triethylsilyl trifluoromethanesulfonate
(TES-OTf) to furnish the iodocompound 27 in 93% yield
(Scheme 9). The tin derivative 28 was obtained in two
(53) Tamura, Y.; Yakura, T.; Haruta, J .-i.; Kita, Y. J . Org. Chem.
1987, 52, 3927-3930.
(54) Quideau, S.; Pouyse´gu, L. Org. Prep. Proc. Int. 1999, 31, 617-
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A. J . Chem. Soc., Perkin Trans. 1 1999, 379-380.
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1925-1933.
(58) Riegel, B.; Wittcoff, H. J . Am. Chem. Soc. 1946, 68, 1913-1917.
(59) Viaud, M. C.; Rollin, P. Synthesis 1990, 130-132.
(60) Knouzi, N.; Vaultier, M.; Carrie´, R. Bull. Soc. Chim. Fr. 1985,
815-819.
(57) Oberhauser, T. J . Org. Chem. 1997, 62, 4504-4506.

3430 J . Org. Chem., Vol. 67, No. 10, 2002
Pouyse´gu et al.
Sch em e 10
Sch em e 11a
good yield. Further investigation is in progress to identify
conditions that will allow one to stop the reaction at the
dihydrophenanthridine stage. Nevertheless, the meth-
odology described offers a new entry into hydroxylated
analogues of fully aromatized benzo[c]phenanthridine
alkaloids, such as trisphaeridine (not shown).61
Application of this methodology to natural products
synthesis is also being explored for the construction of
the lycorine-type polycyclic alkaloid skeleton. A domino
reaction relying on ionic bond formations is thus here
selected over radical processes. Conceptually, the ABCD
tetracyclic Amaryllidaceae alkaloids such as 33-35 can
be accessed via formation of both nitrogen-carbon (N-
Cx) and carbon-carbon (Cy-Cz) core bonds in a single
operation from an adequately functionalized bis(ortho-
quinone monoketal) such as the N-protected bis(ortho-
quinol acetate) 36 (Scheme 10). Of particular note is the
fact that the starting diphenol 37, which is intended for
a synthetic two-electron oxidative activation, is a struc-
tural analogue of the Amaryllidaceae biosynthetic pre-
cursor 6 (Scheme 1).
a
Reagents: (a) 4 Å MS, MeOH, ∆; (b) NaBH4, MeOH; (c) CO2,
Et3N, CH2Cl2, -78 °C, then TIPS-OTf, or Fmoc-Cl, 10% Na2CO3,
THF; (d) H2, Pd/C, THF; (e) PIDA, CH2Cl2, -78 °C.
Sch em e 12
Various protective groups have been envisaged for the
advanced diphenolic intermediate 37. The synthesis of
two variants 37a and 37b was achieved as depicted in
Scheme 11. The known secondary amine 3862 was pre-
pared in 63% yield by reductive amination of the benzyl-
ated vanillin 13 and the primary amine 15 in methanol
in the presence of sodium borohydride.62 As previously
observed with the model compounds (vide supra), direct
PIDA-mediated oxidative acetoxylation of the nonpro-
tected amino diphenol 37 (P ) H) gave intractable
mixtures. Both amino protective groups Tsoc41 and
Fmoc63,64 were selected to resist oxidation in an acidic
medium and to evaluate two different modes of depro-
tection leading to induction of cyclization. The Tsoc group
can be chemoselectively cleaved by a source of fluoride
ions,41 and the Fmoc group necessitates a base treatment
to unveil the nucleophilic power of its linked nitrogen
atom.65 Both Tsoc- and Fmoc-carbamate derivatives
39a /b were obtained in good yields (68% and 76%,
respectively). Debenzylation by hydrogenolysis afforded
the phenols 37a and 37b, which were submitted to the
oxidative acetoxylation to furnish the desired bis(ortho-
quinol acetates) 36a and 36b in excellent yields.
Desilylation of the N-Tsoc carbamate 36a was per-
formed using a commercial 1.0 M solution of TBAF (1.1
equiv) in THF. The indole 40 was isolated in a yield of
33% (Scheme 12). The deprotection-heterocyclization
sequence was thus successful, but the system failed to
convert itself to the desired tetracycle. Departure of the
acetate group seemingly competed with trapping of the
(61) Harayama, T.; Akamatsu, H.; Okamura, K.; Miyagoe, T.;
Akiyama, T.; Abe, H.; Takeuchi, Y. J . Chem. Soc., Perkin Trans. 1 2001,
523-528.
(62) Kametani, T.; Ohkubo, K.; Takano, S. Yakugaki Zasshi 1967,
87, 563-569.
(63) Carpino, L. A.; Han, G. Y. J . Org. Chem. 1972, 37, 3404-3409.
(64) Nevalainen, M.; Kauppinen, P. M.; Koskinen, A. M. P. J . Org.
Chem. 2001, 66, 2061-2066.
(65) Wang, H.; Ganesan, A. J . Org. Chem. 2000, 65, 1022-1030.

Functionalized Indole and Quinoline Derivatives
J . Org. Chem., Vol. 67, No. 10, 2002 3431
Sch em e 13
Exp er im en ta l Section
Gen er a l. Tetrahydrofuran (THF) and diethyl ether (Et2O)
were purified by distillation from sodium/benzophenone under
N2 immediately before use. CH2Cl2 was distilled from CaH2
prior to use. Moisture- and oxygen-sensitive reactions were
carried out in flame-dried glassware under N2. Evaporations
were conducted under reduced pressure at temperatures less
than 45 °C unless otherwise noted. Column chromatography
was carried out under positive pressure using 40-63 µm silica
gel and the indicated solvents. Melting points are uncorrected.
NMR spectra of samples in the indicated solvent were run at
200, 250, or 400 MHz. Carbon multiplicities were determined
by DEPT135 experiments. Diagnostic correlations were ob-
tained by two-dimensional HMQC and HMBC experiments
run on a 400-DPX spectrometer. Electron impact mass spectra
(EIMS) were obtained at 50-70 eV. Electron impact and liquid
secondary ion mass spectrometry low and high resolution
(EIMS, and LSIMS, HRMS) were obtained from the mass
spectrometry laboratory at the CESAMO, Universite´ Bordeaux
1. Combustion analyses were performed by Laboratoires Wolff,
Clichy, France.
second orthoquinol acetate moiety by the transient enol-
ate. We presumed that an indoline structure is initially
made, as in the conversion of 9a into 10a (Table 1), but
an apparent intramolecular oxido-reductive process, prob-
ably driven by the complete aromatization of the system,
led to the formation of the indole 40.
4-Ben zyloxy-3-m eth oxyben za ld eh yd e (13). To a stirred
solution of vanillin 12 (20 g, 0.131 mol) in absolute EtOH (120
mL) were added K2CO3 (19.9 g, 0.144 mol) and benzyl bromide
(15.7 mL, 0.131 mol), and the mixture was maintained under
a nitrogen atmosphere overnight. The solution was filtered
through Celite, washed with CH2Cl2 (3 × 100 mL), and then
concentrated under vacuum. The oily residue was dissolved
in 200 mL of CH2Cl2, washed with 5% NaOH solution, dried
over K2CO3, concentrated, and crystallized from EtOH to
furnish pure 13 as white fine crystals (26.2 g, 82%): mp 61-
We were somewhat worried about this result evidenc-
ing a certain lack of reactivity between the two y and z
carbon centers. We then turned to our second N-protected
bis(orthoquinol acetate) 36b. Upon treatment with 20%
piperidine in dichloromethane at 0 °C,64 the Fmoc protec-
tive group of 36b was easily cleaved, and further stirring
at room temperature for 20 h afforded compound 41 in
21% yield (Scheme 13). Here again, the nitrogen-carbon
bond formation was effective, but the departure of the
acetate group still did not allow the required carbon-
carbon linkage. An overoxidized indolic five-membered
ring was obtained but aromatizaton of the second ortho-
quinol acetate moiety was this time preceded by the
introduction of a piperidine unit at the targeted z-carbon
center. Although the desired in situ carbon-carbon bond
formation has not yet been achieved, the feasability of
trapping the electrophilic site of this orthoquinonoid
species via a Michael addition has been demonstrated.
In view of these promising synthesis inquiries, we are
now working at identifying adequate reaction conditions
and substrate arrangements that will fully open this
intramolecular Michael addition route to the ABCD
tetracyclic core of lycorine-type alkaloids.
62 °C (lit.66 mp 62-63 °C); IR (KBr) 1677 cm-1 1H NMR
;
(CDCl3, 250 MHz) δ 3.86 (s, 3H), 5.17 (s, 2H), 6.94 (d, J ) 8.2
Hz, 1H), 7.27-7.43 (m, 7H), 9.78 (s, 1H); 13C NMR (CDCl3,
62.9 MHz) δ 190.6, 153.2, 149.7, 135.7, 129.9, 128.4, 127.9,
126.9, 126.3, 112.0, 108.9, 70.4, 55.6; EIMS m/z (rel intensity)
242 (M+, 100), 151 (12), 91 (100).
4-Ben zyloxy-3-m eth oxy-â-cya n ostyr en e (14). A stirred
ice-cold suspension of NaH (1.19 g, 24.8 mmol) in 50 mL of
dry THF, maintained under a nitrogen atmosphere, was
treated with diethyl (cyanomethyl)-phosphonate (4.39 g, 24.8
mmol, Aldrich). When the evolution of hydrogen was over (ca.
20 min), a solution of benzylated vanillin 13 (5.00 g, 20.7 mmol)
in 15 mL of dry THF was added dropwise, and the resulting
mixture was stirred at 0 °C for 1.5 h. The reaction mixture
was then filtered through a pad of TLC-grade silica gel and
washed several times with Et2O. Evaporation of the solvents
afforded 14 as a white solid, which was used without any
further purification (5.47 g, quantitative yield): mp 74-75 °C;
1
IR (KBr) 2208, 1622 cm-1; H NMR (CDCl3, 200 MHz) δ 3.89
(s, 3H), 5.18 (s, 2H), 5.71 (d, J ) 16.5 Hz, 1H), 6.85-6.97 (m,
3H), 7.27 (d, J ) 16.5 Hz, 1H), 7.33-7.47 (m, 5H); 13C NMR
(CDCl3, 50 MHz) δ 150.7, 149.9, 149.6, 136.1, 128.4, 127.9,
127.0, 126.7, 121.6, 118.4, 113.1, 109.2, 93.5, 70.5, 55.8; EIMS
m/z (rel intensity) 266 (MH+, 6), 265 (M+, 21), 174 (2), 91 (100);
HRMS (EI) calcd for C17H15NO2 265.1103, found 265.1098.
N-Tsoc-4-h yd r oxy-3-m eth oxyp h en ylp r op yla m in e (8b).
A stirred suspension of cyanostyrene 14 (2.15 g, 8.11 mmol)
in absolute EtOH (40 mL) and CHCl3 (2 mL) containing PtO2
(215 mg, 10 wt %) was placed under H2 (balloon) at room
temperature and under atmospheric pressure. After 20 h, the
mixture was filtered through Celite and washed with MeOH.
Evaporation of the solvents, followed by filtration through a
pad of silica afforded 4-hydroxy-3-methoxyphenylpropylamine43
as a white solid, which was further dried in vacuo and then
crystallized from CH2Cl2/MeOH (1.10 g, 75%): mp 134-135
°C; IR (KBr) 3520 cm-1; 1H NMR (DMSO-d6, 200 MHz) δ 1.85-
1.92 (m, 2H), 2.48-2.55 (m, 2H), 2.76-2.83 (m, 2H), 3.73 (s,
3H), 6.56 (dd, J ) 1.5, 8.1 Hz, 1H), 6.68-6.76 (m, 2H), 8.85
(bs, 2H); 13C NMR (DMSO-d6, 50.3 MHz) δ 147.7, 144.9, 131.6,
120.5, 115.6, 112.7, 55.8, 46.4, 31.7, 27.5; LSIMS m/z (rel
intensity) 183 (10), 182 (MH+, 11), 181 (M+, 31), 166 (12), 137
Con clu sion s
In summary, the present work has demonstrated the
synthetic utility of nitrogen-tethered orthoquinol acetates
in nitrogen heterocyclization chemistry for the elabora-
tion of various benzannulated nitrogen-containing five-
and six-membered rings. These orthoquinonoid species
are conveniently prepared by PIDA-mediated oxidative
acetoxylation and regioselectively benzannulated by in-
tramolecular Michael-type addition reactions. This two-
step methodology was here applied to the construction
of nitrogen-containing polycyclic skeleta such as poly-
oxygenated phenanthridine derivatives. Bis(orthoquinol
acetate) intermediates were also revealed as potentially
useful electrophiles for the construction of lycorine-type
ABCD tetracycles.
(66) Meyers, A. I.; Guiles, J . Heterocycles 1989, 28, 295-301.

3432 J . Org. Chem., Vol. 67, No. 10, 2002
Pouyse´gu et al.
(100). A stirred suspension of this aminophenol (597 mg, 3.30
mmol) and Et3N (1.38 mL, 9.89 mmol) in dry CH2Cl2 (20 mL)
was cooled at -78 °C. Dry ice (7.26 g, ca. 50 equiv) was added
in one portion. After stirring at -78 °C for 1 h, TIPS-OTf (885
µL, 3.30 mmol) was added dropwise via syringe. After 5 min,
the mixture was allowed to warm to room temperature and
was stirred for 30 min. The mixture was then poured into a
separatory funnel containing H2O (20 mL). After separation,
the aqueous phase was extracted with CH2Cl2 (2 × 20 mL);
the combined organic layers were washed with saturated
NaHCO3 (20 mL) and brine (2 × 15 mL) and dried over MgSO4.
Evaporation of the solvent afforded an orange oil, which was
purified by column chromatography, eluting with hexanes/
Et2O (1:1), to give 8b as a pale yellow oil (452 mg, 36%): IR
NMR (CDCl3, 62.9 MHz) δ 156.8, 149.5, 146.6, 137.1, 131.7,
128.3, 127.6, 127.1, 120.5, 114.0, 112.3, 70.9, 55.8, 51.8, 42.1,
35.5; EIMS m/z (rel intensity) 338 (MNa+, 100), 316 (MH+,
44), 315 (M+, 96), 284 (6); HRMS (LSIMS) calcd for C18H21NO4
315.1470, found 315.1471. Debenzylation of this material (990
mg, 3.14 mmol) in 40 mL of dry THF was carried out under
H2 (balloon) overnight at room temperature in the presence
of 10 wt % Pd/C as a catalyst (100 mg). The reaction mixture
was filtered through Celite, and the solid was washed with
acetone. Evaporation of the combined filtrates and washings
afforded a crude oil, which was purified by column chroma-
tography, eluting with hexanes/Et2O (1:4), to give 8c as a pale
yellow oil (459 mg, 65%): IR (NaCl) 3510, 3382, 1702 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 2.72 (bt, J ) 7.0 Hz, 2H), 3.39
(bq, J ) 7.0 Hz, 2H), 3.65 (s, 3H), 3.84 (s, 3H), 4.91 (bs, 1H),
1
(NaCl) 3551, 3388, 1706 cm-1; H NMR (CDCl3, 200 MHz) δ
5.94 (bs, 1H), 6.63-6.68 (m, 2H), 6.83 (d, J ) 8.3 Hz, 1H); 13
C
1.07 (d, J ) 6.9 Hz, 18H), 1.28 (h, J ) 6.9 Hz, 3H), 1.71-1.85
(m, 2H), 2.51-2.59 (m, 2H), 3.08-3.21 (m, 2H), 3.83 (s, 3H),
4.92 (bs, 1H), 5.94 (bs, 1H), 6.60-6.66 (m, 2H), 6.80 (d, J )
7.9 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 155.0, 146.4, 143.7,
133.3, 120.7, 114.3, 111.0, 55.7, 40.6, 32.6, 31.7, 17.7, 11.9;
EIMS m/z (rel intensity) 382 (MH+, 2), 381 (M+, 6), 338 (100),
137 (20).
NMR (CDCl3, 50 MHz) δ 157.0, 146.6, 144.2, 130.4, 121.2,
114.4, 111.2, 55.7, 51.9, 42.3, 35.6; EIMS m/z (rel intensity)
226 (MH+, 7), 225 (M+, 46), 194 (7), 151 (24), 150 (99), 137
(100); HRMS (LSIMS) calcd for C11H15NO4 225.1001, found
225.0997.
N-Ben zyl-4-h yd r oxy-3-m eth oxyp h en yla ceta m id e (8d ).
A mixture of homovanillic acid 16 (500 mg, 2.75 mmol) and
benzylamine (360 µL, 3.30 mmol) was heated at 140-150 °C
in the presence of 4 Å molecular sieves for 3 h under N2
atmosphere, after which time it was diluted with 30 mL of
CH2Cl2, filtered, and evaporated to afford a brown oil. Puri-
fication by column chromatography, eluting with CH2Cl2/
MeOH (20:1), gave 8d as a pale yellow foam (662 mg, 89%):
2-(4-Ben zyloxy-3-m eth oxyp h en yl)eth yla m in e (15).66
A
mixture of NH4OAc (3.82 g, 49.6 mmol), nitromethane (5.9 mL,
108.5 mmol), and benzylated vanillin 13 (15 g, 62.0 mmol) in
AcOH (150 mL) was refluxed for 4 h. Upon cooling, the reaction
deposited 9.7 g of 4-benzyloxy-3-methoxy-â-nitrostyrene as
yellow crystals; the mother liquor was collected, concentrated,
and crystallized from MeOH, giving another 2.3 g of yellow
powder (12.0 g, 68%): mp 124-125 °C (lit.66 mp 126-128 °C);
IR (KBr) 1629 cm-1; 1H NMR (CDCl3, 250 MHz) δ 3.91 (s, 3H),
5.20 (s, 2H), 6.89-7.09 (m, 3H), 7.32-7.42 (m, 5H), 7.52 (d, J
) 13.4 Hz, 1H), 7.93 (d, J ) 13.4 Hz, 1H); 13C NMR (CDCl3,
62.9 MHz) δ 151.7, 149.8, 139.2, 135.9, 135.0, 128.6, 128.1,
127.1, 124.3, 122.9, 113.2, 110.6, 70.6, 55.9; EIMS m/z (rel
intensity) 285 (M+, 100), 147 (20), 91 (100). To a stirred
solution of this nitrostyrene (2.0 g, 7.02 mmol) in 50 mL of
anhydrous Et2O/THF (1:1) was slowly added LiAlH4 (0.8 g,
21.05 mmol). The solution was refluxed for 2 h and then stirred
overnight at room temperature. To this solution were added
water (2 mL), 15% NaOH (2 mL), and then water (6 mL), and
the solution was stirred 30 min before filtering. The phases
were separated, and the aqueous layer was extracted with
ether (3 × 20 mL); the ether washes were combined and
concentrated. The oily residue was dissolved in 10% HCl (3
mL) and washed with ether (10 mL); the aqueous layer was
made basic and extracted with ether (2 × 20 mL). These two
ether washes were combined and washed with water and brine
before drying over K2CO3. Removal of the solvent produced
the titled compound 1566 as an orange oil (1.28 g, 71%): IR
(NaCl) 3367 cm-1; 1H NMR (CDCl3, 250 MHz) δ 2.32 (bs, 2H),
2.69 (bt, J ) 7.0 Hz, 2H), 2.93 (bt, J ) 7.0 Hz, 2H), 3.87 (s,
3H), 5.12 (s, 2H), 6.64-6.83 (m, 3H), 7.28-7.45 (m, 5H); 13C
NMR (CDCl3, 62.9 MHz) δ 149.6, 146.6, 137.2, 132.7, 128.4,
127.7, 127.2, 120.6, 114.2, 112.6, 71.1, 55.9, 43.3, 39.1; EIMS
m/z (rel intensity) 257 (M+, 42), 137 (100), 91 (100).
Met h yl 4-H yd r oxy-3-m et h oxyp h en ylet h ylca r b a m a t e
(8c). To a stirred solution of the primary amine 15 (1.15 g,
4.47 mmol) in acetone (25 mL) was added powdered K2CO3
(3.70 g, 26.85 mmol) in one portion, followed by dropwise
addition of methyl chloroformate (1.38 mL, 17.90 mmol). The
mixture was heated on reflux for 20 h, after which time the
solvent was evaporated, and the residue was treated with 4%
methanolic sodium hydroxide (25 mL) at room temperature
for 1.5 h. Evaporation of MeOH furnished an aqueous phase,
which was extracted with CH2Cl2 (3 × 20 mL), washed with
brine (2 × 15 mL), dried over Na2SO4, filtered, and evaporated.
The resulting brown oil was submitted to column chromatog-
raphy, eluting with CH2Cl2/AcOH/MeOH (200:6:0.5), to afford
methyl 4-benzyloxy-3-methoxyphenylethylcarbamate as an off-
white solid (1.06 g, 75%): mp 65-68 °C; IR (KBr) 3345, 1681
cm-1; 1H NMR (CDCl3, 250 MHz) δ 2.72 (bt, J ) 7.0 Hz, 2H),
3.39 (bq, J ) 7.0 Hz, 2H), 3.64 (s, 3H), 3.87 (s, 3H), 4.85 (bs,
1H), 5.12 (s, 2H), 6.65 (dd, J ) 1.8, 8.2 Hz, 1H), 6.73 (d, J )
1.8 Hz, 1H), 6.81 (d, J ) 8.2 Hz, 1H), 7.26-7.46 (m, 5H); 13C
mp 83-84 °C; IR (KBr) 3506, 3368, 1655 cm-1 1H NMR
;
(CDCl3, 200 MHz) δ 3.53 (s, 2H), 3.83 (s, 3H), 4.40 (d, J ) 5.9
Hz, 2H), 5.94 (bs, 2H), 6.68-6.76 (m, 2H), 6.86 (d, J ) 7.8 Hz,
1H), 7.15-7.36 (m, 5H); 13C NMR (CDCl3, 50 MHz) δ 171.4,
146.9, 144.9, 138.1, 128.5, 127.4, 127.3, 126.3, 122.2, 114.8,
111.7, 55.8, 43.4, 43.3; EIMS m/z (rel intensity) 273 (2), 272
(MH+, 19), 271 (M+, 67), 137 (100), 91 (58).
N-Ben zyl-4-h yd r oxy-3-m eth oxyp h en yleth yla m id e (8e).
A mixture of ethyl 3-(4-hydroxy-3-methoxyphenyl)propanoate
1736 (1.00 g, 4.46 mmol) and benzylamine (536 µL, 4.91 mmol)
was heated at 140-150 °C for 3 h under N2 atmosphere, after
which time it was diluted with 40 mL of CH2Cl2, filtered, and
evaporated to afford a brown oil. Purification by column
chromatography, eluting with CH2Cl2/MeOH (20:1), gave 8e
as a pale yellow oil (1.10 g, 87%): IR (NaCl) 3546, 3359, 1651
cm-1; 1H NMR (CDCl3, 200 MHz) δ 2.45-2.53 (m, 2H), 2.86-
2.94 (m, 2H), 3.75 (s, 3H), 4.36 (d, J ) 5.6 Hz, 2H), 6.35 (bs,
1H), 6.44 (bt, J ) 5.6 Hz, 1H), 6.62-6.69 (m, 2H), 6.82 (d, J )
8.1 Hz, 1H), 7.10-7.32 (m, 5H); 13C NMR (CDCl3, 50.3 MHz)
δ 172.3, 146.5, 143.9, 137.9, 132.3, 128.3, 127.3, 127.1, 120.5,
114.4, 111.2, 55.6, 43.2, 38.4, 31.2; LSIMS m/z (rel intensity)
308 (MNa+, 43), 287 (20), 286 (MH+, 100), 285 (M+, 72); HRMS
(LSIMS) calcd for C17H20NO3 286.1442, found 286.1443.
P r ep a r a tion of Or th oqu in ol Aceta tes (9a -e). A solution
of the phenols 8a -e (ca. 250 mg, 1.0 equiv) in dry CH2Cl2 (2
mL) was added dropwise to a stirred solution of PIDA (1.0
equiv) in 5 mL of dry CH2Cl2 at -78 °C. The reaction mixture
immediately became bright yellow. After 1 h, TLC monitoring
[CH2Cl2/MeOH (20:1)] indicated complete consumption of the
starting material. The mixture was poured into ice-cold
saturated aqueous NaHCO3 (20 mL), extracted with CH2Cl2
(2 × 20 mL), washed with brine (20 mL), dried over Na2SO4,
filtered, and evaporated at room temperature. The residue was
further dried under high vacuum overnight to give the
corresponding orthoquinol acetate 9a -e as a bright yellow oil,
which was used without further purification.
N-Tsoc-6-acetoxy-4-(2-am in oeth yl)-6-m eth oxycycloh exa-
2,4-d ien on e (9a ).40 Bright yellow oil (98%). IR (NaCl) 3394,
1
1750, 1682, 1672 cm-1; H NMR (CDCl3, 200 MHz) δ 1.03 (d,
J ) 6.7 Hz, 18H), 1.25 (h, J ) 6.7 Hz, 3H), 2.05 (s, 3H), 2.37-
2.43 (m, 2H), 3.03-3.19 (m, 1H), 3.33-3.50 (m, 1H), 3.41 (s,
3H), 4.94-5.00 (m, 1H), 5.93 (bs, 1H), 6.10 (d, J ) 9.9 Hz,
1H), 6.76 (dd, J ) 2.2, 9.9 Hz, 1H); 13C NMR (CDCl3, 50 MHz)
δ 191.5, 169.6, 154.8, 141.9, 135.5, 131.0, 126.3, 92.8, 51.2, 38.9,
35.2, 20.5, 17.7, 11.9; EIMS m/z (rel intensity) 425 (M+, 1),

Functionalized Indole and Quinoline Derivatives
J . Org. Chem., Vol. 67, No. 10, 2002 3433
382 (16), 324 (100), 137 (56); HRMS (EI) calcd for C21H35NO6Si
425.2233, found 425.2229.
mediately became darker. After 30 min, the ice bath was
removed, and the reaction was stirred at room temperature
for 1 h. Progression of the reaction was monitored by the
disappearance of the orthoquinol acetate, as indicated by TLC
[hexanes/Et2O (1:1) and then CH2Cl2/MeOH (20:1)]. The
mixture was diluted with EtOAc (30 mL), poured into ice-cold
water (10 mL), extracted with EtOAc (2 × 15 mL), washed
with brine (2 × 10 mL), dried over Na2SO4, filtered, and
evaporated at room temperature. The resulting dark oily
residue was purified by column chromatography, eluting with
CH2Cl2/MeOH (100:1), to afford 10b as an orange oil (26 mg,
N-Tsoc-6-a cetoxy-4-(3-a m in op r op yl)-6-m eth oxycyclo-
h exa -2,4-d ien on e (9b ). Bright yellow oil (98%). IR (NaCl)
3372, 1750, 1702, 1681 cm-1 1H NMR (CDCl3, 200 MHz) δ
;
1.06 (d, J ) 6.7 Hz, 18H), 1.24 (h, J ) 6.9 Hz, 3H), 1.65-1.79
(m, 2H), 2.09 (s, 3H), 2.28 (bt, J ) 7.6 Hz, 2H), 3.05-3.26 (m,
2H), 3.44 (s, 3H), 4.91 (bs, 1H), 5.93 (d, J ) 2.1 Hz, 1H), 6.11
(d, J ) 10.2 Hz, 1H), 6.77 (dd, J ) 2.1, 10.2 Hz, 1H); 13C NMR
(CDCl3, 62.9 MHz) δ 191.5, 169.5, 155.0, 142.1, 137.7, 129.3,
125.8, 92.9, 51.1, 40.1, 29.6, 22.6, 20.4, 17.7, 11.9; LSIMS m/z
(rel intensity) 462 (MNa+, 29), 438 (14), 396 (13), 380 (19).
6-Acetoxy-6-m eth oxy-4-(2-m eth oxyca r bon yla m in o-eth -
yl)-cycloh exa -2,4-d ien on e (9c). Orange oil (92%). A 3:2
mixture of 9c and 9f was obtained after 1 day, and degradation
58%): IR (NaCl) 3406 cm-1 1H NMR (CDCl3, 200 MHz) δ
;
1.86-1.98 (m, 2H), 2.68 (bt, J ) 6.3 Hz, 2H), 3.21-3.26 (m,
2H), 3.79 (s, 3H), 4.28 (bs, 2H), 6.19 (s, 1H), 6.50 (s, 1H); 13C
NMR (CDCl3, 50 MHz) δ 144.6, 139.3, 138.4, 112.9, 101.9, 56.8,
42.1, 26.4, 22.5; LSIMS m/z (rel intensity) 180 (MH+, 54), 179
(M+, 100), 178 (41), 164 (26); HRMS (LSIMS) calcd for
was further observed. IR (NaCl) 3372, 1750, 1692, 1676 cm-1
;
1H NMR (CDCl3, 250 MHz) δ 1.96 (s, 3H), 2.02 (s, 3H), 2.35
(bt, J ) 6.4 Hz, 4H), 3.05-3.22 (m, 4H), 3.36 (s, 3H), 3.37 (s,
3H), 3.55 (s, 3H), 3.59 (s, 3H), 5.06 (bs, 1H), 5.16 (bs, 1H), 5.73
(d, J ) 2.4 Hz, 1H), 5.89 (s, 1H), 6.05 (d, J ) 10.1 Hz, 1H),
6.20 (d, J ) 10.1 Hz, 1H), 6.72 (dd, J ) 1.8, 10.1 Hz, 1H), 6.83
(dd, J ) 2.4, 10.3 Hz, 1H); 13C NMR (CDCl3, 62.9 MHz) δ 191.4,
180.2, 169.7, 169.1, 156.8, 156.7, 151.1, 148.2, 141.9, 135.4,
130.7, 127.7, 126.0, 113.9, 92.7, 77.3, 54.8, 51.8, 51.2, 39.9, 38.6,
36.1, 35.0, 21.3, 20.3; LSIMS m/z (rel intensity) 306 (MNa+,
100), 284 (MH+, 9), 268 (6), 252 (10), 224 (27).
C
10H13NO2 179.0946, found 179.0945.
N-Met h oxyca r b on yl-6-h yd r oxy-5-m et h oxy-2,3-d ih y-
d r oin d ole (10c). To a stirred solution of 9c (100 mg, 0.35
mmol) in dry THF (5 mL) cooled at -8 °C was added dropwise
a commercial solution of LHMDS (1.0 M in THF, 2.0 equiv).
After stirring for 1 h at -8 °C, the mixture was allowed to
warm to room temperature for 30 min, and was then diluted
with EtOAc (30 mL) and water (10 mL). After separation, the
aqueous phase was extracted with EtOAc (20 mL), and the
organic phase was washed with brine (10 mL), dried over
Na2SO4, filtered, and evaporated to furnish a dark oily residue,
which was purified by column chromatography, eluting with
CH2Cl2/MeOH (40:1), to afford 10c as amber crystals (25.2 mg,
6-Acetoxy-4-ben zylca r ba m oylm eth yl-6-m eth oxycyclo-
h exa -2,4-d ien on e (9d ). Bright yellow oil (95%). IR (NaCl)
3318, 1745, 1671, 1652 cm-1 1H NMR (CDCl3, 200 MHz) δ
;
1.98 (s, 3H), 3.16 (d, J ) 3.7 Hz, 2H), 3.42 (s, 3H), 4.25 (dd, J
) 5.5, 14.6 Hz, 1H), 4.42 (dd, J ) 6.3, 14.6 Hz, 1H), 6.08 (bs,
1H), 6.10 (d, J ) 9.8 Hz, 1H), 6.70 (bs, 1H), 6.77 (dd, J ) 2.2,
9.8 Hz, 1H), 7.16-7.31 (m, 5H); 13C NMR (CDCl3, 50.3 MHz)
δ 191.0, 170.2, 168,4, 141.8, 137.9, 133.0, 132.5, 128.3, 127.6,
127.2, 126.4, 92.7, 51.3, 43.4, 42.3, 20.3. Evolution of ortho-
quinol acetate 9d in the NMR tube (CDCl3 as solvent) at room
1
32%): mp 153-155 °C; IR (KBr) 3322, 1695 cm-1; H NMR
(CDCl3, 200 MHz) δ 3.02 (bt, J ) 8.6 Hz, 2H), 3.83 (s, 6H),
3.88-4.06 (m, 2H), 5.75 (bs, 1H), 6.69 (s, 1H), 7.26 (s, 1H); 13
C
NMR (CDCl3, 50 MHz) δ 144.9, 142.3, 121.3, 114.4, 111.2,
107.9, 102.7, 56.5, 52.5, 47.8, 27.8; EIMS m/z (rel intensity)
225 (8), 224 (MH+, 42), 223 (M+, 100), 208 (17); HRMS (LSIMS)
calcd for C11H13NO4 223.0844, found 223.0845.
1
temperature was monitored by H NMR. A 1:1 mixture of 9d
and 9g was obtained after 3 days, and degradation was further
observed. 1H NMR (CDCl3, 200 MHz) δ 1.87 (s, 3H), 194 (s,
3H), 2.69 (s, 2H), 3.12 (d, J ) 3.3 Hz, 2H), 3.37 (s, 3H), 3.51
(s, 3H), 3.62-3.78 (m, 2H), 4.34 (d, J ) 5.9 Hz, 2H), 5.99 (d, J
) 2.7 Hz, 1H), 6.03-6.08 (m, 1H), 6.14 (d, J ) 10.0 Hz, 1H),
6.73 (dd, J ) 2.1, 10.0 Hz, 1H), 6.86 (bs, 2H), 7.05 (dd, J )
2.7, 10.1 Hz, 1H), 7.16-7.29 (m, 11H); 13C NMR (CDCl3, 50
MHz) δ 191.1, 180.3, 173.9, 170.2, 169.3, 168.7, 166.9, 150.7,
147.6, 141.8, 137.9, 137.7, 132.9, 132.4, 128.4, 128.3, 127.4,
127.3, 127.2, 127.1, 126.2, 113.8, 92.7, 76.2, 54.8, 51.3, 46.2,
43.3, 42.1, 21.2, 20.5, 20.3.
N-Ben zyl-6-h yd r oxy-5-m eth oxy-2-oxin d ole (10d ). To a
stirred solution of 9d (75 mg, 0.23 mmol) in dry THF (10 mL)
was added KOt-Bu (28 mg, 0.25 mmol) in one portion. After
refluxing overnight, the reaction mixture was diluted with
EtOAc (50 mL) and water (15 mL); the aqueous phase was
extracted with EtOAc (2 × 20 mL). The combined extracts were
washed with brine (15 mL), dried over Na2SO4, filtered, and
evaporated to afford 26 mg of crude product. Purification by
column chromatography, eluting with CH2Cl2/MeOH (50:1),
furnished 10d as a dark oil (10.6 mg, 17%): IR (NaCl) 3376,
1664 cm-1; 1H NMR (acetone-d6, 200 MHz) δ 3.49 (s, 2H), 3.83
(s, 3H), 4.41 (d, J ) 6.1 Hz, 2H), 6.78 (s, 1H), 6.79 (s, 1H),
7.25-7.35 (m, 5H), 7.49 (s, 1H); 13C NMR (acetone-d6, 50 MHz)
δ 173.7, 146.9, 144.8, 138.2, 128.6, 127.5, 126.5, 122.3, 114.8,
111.7, 55.9, 43.5, 29.7; LSIMS m/z (rel intensity) 292 (MNa+,
5), 272 (100), 271 (54), 270 (MH+, 9), 269 (M+, 5), 254 (5).
N-Ben zyl-7-h yd r oxy-6-m eth oxy-3,4-d ih yd r o-2-oxoqu i-
n olin e (10e). To a stirred solution of 9e (50 mg, 0.146 mmol)
in dry THF (10 mL) was added KOt-Bu (18 mg, 0.160 mmol)
in one portion. After refluxing overnight, the reaction mixture
was diluted with EtOAc (50 mL) and water (15 mL); the
aqueous phase was extracted with EtOAc (2 × 20 mL). The
combined extracts were washed with brine (15 mL), dried over
Na2SO4, filtered, and evaporated to afford a pale orange oily
crude product. Purification by column chromatography, eluting
with CH2Cl2/MeOH (50:1), furnished 10e as an off-white solid
(16 mg, 38%): mp 134-135 °C; IR (KBr) 3404, 1658 cm-1; 1H
NMR (CDCl3, 250 MHz) δ 2.72-2.79 (m, 2H), 2.86-2.94 (m,
2H), 3.85 (s, 3H), 5.12 (s, 2H), 6.55 (s, 1H), 6.67 (s, 1H), 7.19-
7.35 (m, 5H); 13C NMR (CDCl3, 62.9 MHz) δ 170.3, 144.6, 142.0,
136.9, 133.7, 128.7, 127.0, 126.4, 117.5, 110.8, 103.6, 56.3, 46.2,
32.2, 25.2; LSIMS m/z (rel intensity) 306 (MNa+, 45), 285 (31),
284 (MH+, 75), 283 (M+, 100), 268 (22), 252 (29); HRMS
(LSIMS) calcd for C17H17NO3 283.1208, found 283.1210.
5-(Tr ieth ylsilyloxym eth yl)-6-iodo-1,3-ben zodioxole (27).
To a stirred ice-cold suspension of 5-(hydroxymethyl)-6-iodo-
1,3-benzodioxole 2556 (3.00 g, 10.8 mmol) in dry CH2Cl2 (55
mL) were added dropwise Et3N (1.8 mL, 12.9 mmol) and TES-
6-Ace t oxy-4-(2-b e n zylca r b a m oyl-e t h yl)-6-m e t h oxy-
cycloh exa -2,4-d ien on e (9e). Bright yellow oil (99%). IR
(NaCl) 3338, 1750, 1674, 1651 cm-1 1H NMR (CDCl3, 200
;
MHz) δ 2.00 (s, 3H), 2.29-2.37 (m, 2H), 2.50-2.57 (m, 2H),
3.38 (s, 3H), 4.33 (d, J ) 5.9 Hz, 2H), 5.95 (d, J ) 2.0 Hz, 1H),
6.00 (d, J ) 10.0 Hz, 1H), 6.45 (bs, 1H), 6.70 (d, J ) 2.0, 10.0
Hz, 1H), 7.18-7.32 (m, 5H); 13C NMR (CDCl3, 50.3 MHz) δ
191.5, 171.1, 169.5, 142.3, 138.0, 137.4, 129.6, 128.4, 127.5,
127.2, 125.7, 92.9, 51.2, 43.3, 34.9, 30.6, 20.3. Evolution of
orthoquinol acetate 9e in the NMR tube (CDCl3 as solvent) at
room temperature was monitored by 1H NMR. The conversion
to the 4-acetoxy-4-(2-benzylcarbamoyl-ethyl)-2-methoxycyclo-
hexa-2,5-dienone 9h was complete after 3 days. Evaporation
of the solvent afforded an orange oil: IR (NaCl) 3368, 1758
cm-1 1H NMR (CDCl3, 200 MHz) δ 1.99 (s, 3H), 2.09-2.37
;
(m, 2H), 2.45 (bt, J ) 7.4 Hz, 1H), 2.84 (bt, J ) 7.4 Hz, 1H),
3.54 (s, 3H), 4.31 (bt, J ) 5.9 Hz, 2H), 5.67 (d, J ) 2.6 Hz,
1H), 6.15 (d, J ) 10.2 Hz, 1H), 6.64 (bs, 1H), 6.75 (d, J ) 2.6,
10.2 Hz, 1H), 7.04-7.31 (m, 5H); 13C NMR (CDCl3, 50.3 MHz)
δ 180.6, 171.4, 169.2, 151.2, 137.8, 128.4, 128.3, 127.9, 127.5,
127.3, 127.2, 114.3, 78.2, 54.7, 43.4, 34.2, 29.8, 20.6; EIMS m/z
(rel intensity) 343 (M+, 0.5), 285 (99),283 (8),150 (62), 137 (52),
91 (100).
7-Hydr oxy-6-m eth oxy-1,2,3,4-tetr ah ydr oqu in olin e (10b).
To a stirred ice-cold solution of 9b (110 mg, 0.25 mmol) in dry
THF (5 mL) was added dropwise a commercial solution of
TBAF (1 M in THF, 1.1 equiv). The reaction mixture im-

3434 J . Org. Chem., Vol. 67, No. 10, 2002
Pouyse´gu et al.
OTf (2.68 mL, 11.9 mmol). After 10 min, the ice bath was
removed and the mixture was stirred for 3.5 h at room
temperature. The solution was then washed with 1 M H3PO4
(20 mL), water (20 mL) and brine (2 × 20 mL). The organic
layer was dried over Na2SO4, filtered and evaporated to give
4.26 g of crude product. Purification by column chromatogra-
phy, eluting with pentanes, afforded 27 as a colorless oil (3.95
(MH+, 35), 478 (M+, 100), 449 (5), 387 (10), 347 (23); HRMS
(LSIMS) calcd for C28H34O5Si 478.2175, found 478.2175.
2-(4-Be n zyloxy-3-m e t h oxyp h e n yl)-4,5-m e t h yle n e d i-
oxyben zyla m in e (30). To a stirred ice-cold solution of com-
mercial TBAF (1 M in THF, 2.0 equiv) in dry THF (3 mL) was
added dropwise a solution of 29 (817 mg, 2.03 mmol) in dry
THF (5 mL). After 10 min, the ice bath was removed, and the
reaction mixture was stirred at room temperature overnight.
The mixture was then quenched by adding dropwise 20 mL of
a 1:1 mixture of ice-cold water and 1 M H3PO4, and diluted
with EtOAc (30 mL). After extraction with EtOAc (3 × 15 mL),
the combined organic layers were washed with brine (4 × 15
mL), dried over Na2SO4, filtered, and evaporated to give an
oily beige residue, which was subjected to column chromatog-
raphy, eluting with hexanes/Et2O (4:1) to remove impurities
and then hexanes/Et2O (1:1), to afford 2-(4-benzyloxy-3-meth-
oxyphenyl)-4,5-methylenedioxybenzyl alcohol as an off-white
gum (541 mg, 73%): IR (KBr) 3554, 1484, 1241, 934 cm-1; 1H
NMR (CDCl3, 200 MHz) δ 3.43 (bs, 1H), 3.88 (s, 3H), 4.47 (s,
2H), 5.18 (s, 2H), 5.96 (s, 2H), 6.76 (s, 1H), 6.80 (dd, J ) 2.0,
8.2 Hz, 1H), 6.91 (d, J ) 8.2 Hz, 1H), 6.92 (d, J ) 2.0 Hz, 1H),
7.00 (s, 1H), 7.27-7.51 (m, 5H); 13C NMR (CDCl3, 50 MHz) δ
149.0, 147.3, 146.8, 146.6, 137.0, 134.9, 133.6, 131.7, 128.4,
127.7, 127.2, 121.3, 113.5, 113.2, 109.9, 108.7, 101.0, 71.0, 62.7,
55.9; LSIMS m/z (rel intensity) 387 (MNa+, 13), 365 (MH+,
24), 364 (M+, 100), 347 (47), 273 (34). A stirred solution of this
alcohol (532 mg, 1.46 mmol) and PPh3 (574 mg, 2.19 mmol) in
dry THF (6 mL) and dry CH2Cl2 (1.5 mL) was treated with
ZnN6‚2Pyr59 (337 mg, 1.10 mmol). The reaction mixture was
cooled to 0 °C, and DEAD (345 µL, 2.19 mmol) was added
dropwise. After stirring overnight at room temperature, the
mixture was filtered through Celite, and the filtrate was
evaporated to give an oil, which was purified by column
chromatography, eluting with hexanes/Et2O (9:1), to afford
2-(4-benzyloxy-3-methoxyphenyl)-4,5-methylenedioxybenzyl
azide as a white solid (301 mg, 53%): mp 107-108 °C; IR (KBr)
2092, 1488, 1249, 940 cm-1; 1H NMR (CDCl3, 200 MHz) δ 3.90
(s, 3H), 4.17 (s, 2H), 5.20 (s, 2H), 6.00 (s, 2H), 6.77 (dd, J )
2.0, 8.2 Hz, 1H), 6.79 (s, 1H), 6.87 (d, J ) 2.0 Hz, 1H), 6.89 (s,
1H), 6.93 (d, J ) 8.2 Hz, 1H), 7.32-7.50 (m, 5H); 13C NMR
(CDCl3, 50 MHz) δ 149.2, 147.5, 147.4, 146.9, 137.0, 136.2,
133.2, 128.5, 127.8, 127.2, 126.2, 121.4, 113.6, 113.2, 110.3,
109.4, 101.3, 71.0, 55.9, 52.6; LSIMS m/z (rel intensity) 412
(MNa+, 22), 390 (MH+, 8), 389 (M+, 31), 347 (27), 270 (100).
To a stirred solution of this azide (293 mg, 0.75 mmol) in dry
THF (6 mL) were successively added PPh3 (296 mg, 1.13 mmol)
and distilled water (68 µL, 68 mmol). The resulting solution
was stirred at room temperature for 4 days and then concen-
trated under reduced pressure to afford a residue, which was
dissolved in EtOAc (30 mL). The organic layer was extracted
with 1 M HCl aqueous solution (3 × 10 mL), and the pH of
the aqueous layer was adjusted to 12 with KOH pellets. After
extraction with CH2Cl2 (3 × 20 mL), the combined organic
layers were dried over Na2SO4, filtered, and evaporated to give
the primary amine 30 as a colorless oil (197 mg, 72%): IR
(NaCl) 3380 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.42 (bs, 2H),
3.69 (s, 2H), 3.87 (s, 3H), 5.17 (s, 2H), 5.92 (s, 2H), 6.73-6.94
(m, 5H), 7.27-7.49 (m, 5H); 13C NMR (CDCl3, 50 MHz) δ 148.9,
147.0, 146.6, 145.7, 136.8, 134.2, 133.9, 128.2, 127.5, 127.0,
121.1, 113.4, 112.9, 109.9, 108.1, 100.7, 70.7, 55.7, 43.7; LSIMS
m/z (rel intensity) 386 (MNa+, 16), 365 (10), 364 (MH+, 41),
363 (M+, 82), 347 (85), 272 (38), 256 (100); HRMS (LSIMS)
calcd for C22H21NO4 363.1470, found 363.1464.
1
mg, 93%): IR (NaCl) 1480, 1241, 940 cm-1; H NMR (CDCl3,
200 MHz) δ 0.68 (q, J ) 7.3 Hz, 6H), 1.01 (t, J ) 7.3 Hz, 9H),
4.54 (s, 2H), 5.93 (s, 2H), 7.07 (s, 1H), 7.17 (s, 1H); 13C NMR
(CDCl3, 50 MHz) δ 148.3, 147.1, 136.5, 117.8, 108.0, 101.3,
83.1, 68.8, 6.7, 4.4; EIMS m/z (rel intensity) 393 (MH+, 11),
392 (M+, 40), 363 (77), 236 (100); Anal. Calcd for C14H21IO3Si:
C, 42.86; H, 5.40; I, 32.35; O, 12.23; Si, 7.16. Found: C, 42.49;
H, 5.18; I, 32.80.
3-Meth oxy-4-ben zyloxytr ibu tyltin ben zen e (28). To a
stirred solution of 4-bromo-2-methoxyphenol 2657 (6.00 g, 29.4
mol) in absolute EtOH (150 mL) were added K2CO3 (8.12 g,
58.8 mol) and benzyl bromide (6.99 mL, 58.8 mol), and the
mixture was maintained under a nitrogen atmosphere over-
night. The solution was filtered through Celite, washed with
CH2Cl2 (3 × 30 mL), and then concentrated under vacuum.
The oily residue was dissolved in 100 mL of CH2Cl2 and
washed with 1 M H3PO4 (30 mL) and brine (2 × 30 mL) and
dried over MgSO4. Evaporation of the solvent furnished a
yellow oil, which was submitted to column chromatography,
eluting with hexanes/Et2O (4:1), to give pure 3-methoxy-4-
benzyloxybromobenzene58 as a white solid (8.42 g, 97%): mp
49-51 °C (lit.58 mp 61.0-61.2 °C); IR (KBr) 1578, 1030 cm-1
;
1H NMR (CDCl3, 250 MHz) δ 3.85 (s, 3H), 5.10 (s, 2H), 6.72
(d, J ) 8.5 Hz, 1H), 6.94 (dd, J ) 2.3, 8.5 Hz, 1H), 6.98 (d, J
) 2.3 Hz, 1H), 7.24-7.41 (m, 5H); 13C NMR (CDCl3, 62.9 MHz)
δ 150.5, 147.4, 136.7, 128.6, 127.9, 127.3, 123.3, 115.5, 115.4,
113.4, 71.2, 56.1; EIMS m/z (rel intensity) 294, 292 (M+, 68,
67), 213 (3), 203 (7), 201 (11), 91 (100). A stirred solution of
this material (2.41 g, 8.22 mmol) in dry Et2O (60 mL) was
cooled at -78 °C and treated dropwise with a solution of t-BuLi
(1.5 M in pentane, 1.05 equiv). After stirring for 45 min,
tributyltin chloride (2.45 mL, 9.05 mmol) was added dropwise,
and the mixture was allowed to warm to room temperature.
Stirring at room temperature was maintained overnight. The
mixture was then evaporated and directly submitted to column
chromatography, eluting with pentanes/Et2O (25:1), to afford
28 as a pale yellow oil (3.63 g, 88%): IR (NaCl) 1498, 1256,
1
741 cm-1; H NMR (CDCl3, 200 MHz) δ 0.92 (t, J ) 7.1 Hz,
9H), 1.26-1.43 (m, 12H), 1.58-1.71 (m, 6H), 3.89 (s, 3H), 5.16
(s, 2H), 6.74 (d, J ) 8.5 Hz, 1H), 6.87-6.92 (m, 2H), 7.29-
7.46 (m, 5H); 13C NMR (CDCl3, 50 MHz) δ 149.6, 148.1, 137.2,
128.4, 127.9, 127.7, 127.2, 121.4, 120.7, 114.1, 70.9, 55.9, 27.8,
26.8, 17.5, 13.5; EIMS m/z (rel intensity) 503 (M+, 0.02), 446
(0.75), 91 (90), 57 (100).
O-Tr ieth ylsilyl-2-(4-ben zyloxy-3-m eth oxyp h en yl)-4,5-
m eth ylen ed ioxyben zyl a lcoh ol (29). A stirred solution of
27 (6.68 g, 13.28 mmol) and 28 (5.20 g, 13.28 mmol) in dry
toluene (80 mL) was refluxed for 4 days in the presence of 10
wt % Pd(PPh3)4 as a catalyst (1.53 g) and Na2CO3 (9.85 g, 92.96
mmol), until TLC monitoring [hexanes/Et2O (9:1)] indicated
complete consumption of the starting materials. The resulting
dark mixture was then diluted with EtOAc (50 mL) and an
aqueous KF solution (40 mL), before stirring at room temper-
ature for 30 min. The two layers were then separated, and
the organic phase was extracted with EtOAc (4 × 30 mL),
washed with water until pH 7, dried over Na2SO4, filtered,
and evaporated to furnish a dark brown oil (10.20 g). Purifica-
tion by column chromatography, eluting with hexanes/Et2O
(9:1), gave 29 as a colorless oil (1.35 g, 21%): IR (NaCl) 1482,
1239, 936 cm-1; 1H NMR (CDCl3, 200 MHz) δ 0.62 (q, J ) 7.3
Hz, 6H), 0.97 (t, J ) 7.3 Hz, 9H), 3.92 (s, 3H), 4.54 (s, 2H),
5.22 (s, 2H), 5.98 (s, 2H), 6.76 (s, 1H), 6.81 (dd, J ) 2.0, 8.0
Hz, 1H), 6.93 (d, J ) 2.0 Hz, 1H), 6.94 (d, J ) 8.0 Hz, 1H),
7.10 (s, 1H), 7.27-7.53 (m, 5H); 13C NMR (CDCl3, 50 MHz) δ
149.1, 147.2, 146.8, 146.3, 137.1, 134.1, 133.9, 132.2, 128.4,
127.7, 127.2, 121.4, 113.6, 113.2, 109.7, 108.2, 100.9, 71.0, 62.5,
55.9, 6.7, 4.4; LSIMS m/z (rel intensity) 501 (MNa+, 10), 479
4-(N-Tsoc-2-a m in om eth yl-4,5-m eth ylen ed ioxyp h en yl)-
6-a cetoxy-6-m eth oxycycloh exa -2,4-d ien on e (31). A stirred
solution of amine 30 (190 mg, 0.52 mmol) and Et3N (219 µL,
1.57 mmol) in dry CH2Cl2 (10 mL) was cooled at -78 °C. Dry
ice (1.15 g, ca. 50 equiv) was added in one portion. After
stirring at -78 °C for 1 h, TIPS-OTf (140 µL, 0.52 mmol) was
added dropwise via syringe. After 5 min, the mixture was
allowed to warm to room temperature and was stirred for 30
min. The mixture was then diluted with CH2Cl2 (30 mL) and
poured in a separatory funnel containing H2O (20 mL). After
separation, the aqueous phase was extracted with CH2Cl2 (2
× 20 mL); the combined organic layers were washed with

Functionalized Indole and Quinoline Derivatives
J . Org. Chem., Vol. 67, No. 10, 2002 3435
saturated NaHCO3 (20 mL) and brine (2 × 20 mL) and dried
over Na2SO4. Evaporation of the solvent afforded a pale yellow
oil, which was purified by column chromatography, eluting
with pentanes/Et2O (2:1), to give N-Tsoc-2-(4-benzyloxy-3-
methoxyphenyl)-4,5-methylenedioxybenzylamine as a colorless
oil (212 mg, 72%): IR (NaCl) 3381, 1673 cm-1; 1H NMR (CDCl3,
250 MHz) δ 1.09 (d, J ) 7.3 Hz, 18H), 1.30 (h, J ) 7.3 Hz,
3H), 3.87 (s, 3H), 4.22 (d, J ) 5.8 Hz, 2H), 4.99 (bt, J ) 5.8
Hz, 1H), 5.17 (s, 2H), 5.93 (s, 2H), 6.71-6.94 (m, 5H), 7.27-
7.49 (m, 5H); 13C NMR (CDCl3, 62.9 MHz) δ 154.7, 149.0, 147.2,
146.8, 146.3, 136.9, 134.7, 133.5, 129.5, 128.3, 127.7, 127.1,
121.2, 113.4, 112.8, 109.9, 108.2, 100.9, 70.8, 55.7, 42.7, 17.6,
11.8; LSIMS m/z (rel intensity) 586 (MNa+, 31), 564 (MH+,
37), 563 (M+, 40), 520 (34), 347 (61), 256 (100). Debenzylation
of this material (202 mg, 0.36 mmol) in 15 mL of dry THF
was carried out under H2 (balloon) overnight at room temper-
ature in the presence of 10 wt % Pd/C as a catalyst (20 mg).
The reaction mixture was filtered through Celite, and the solid
was washed with acetone. Evaporation of the combined
filtrates and washings afforded a crude oil, which was purified
by column chromatography, eluting with pentanes/Et2O (4:
1), to give N-Tsoc-2-(4-hydroxy-3-methoxyphenyl)-4,5-methyl-
enedioxybenzylamine as a colorless oil (142 mg, 84%): IR
43), 255 (29), 254 (19); HRMS (LSIMS) calcd for C15H12NO4
270.0766, found 270.0766.
N-(4-Ben zyloxy-3-m eth oxyben zyl)-4-ben zyloxy-3-m eth -
oxyp h en yleth yla m in e (38).62 A solution of benzylated vanil-
lin 13 (3.00 g, 12.4 mmol) and primary amine 15 (3.19 g, 12.4
mmol) in dry MeOH (40 mL) was refluxed for 3 h in the
presence of 4 Å molecular sieves. Filtration, followed by
evaporation, furnished the expected imine as an orange oil
(5.77 g, 97% crude yield). This material was submitted to
NaBH4 reduction (1.09 g, 28.8 mmol) in MeOH (60 mL) at room
temperature. After stirring overnight, evaporation of the
solution gave a solid residue, which was redissolved in CH2Cl2
(80 mL), washed with H2O (3 × 20 mL), and dried over MgSO4.
Evaporation of the solvent afforded an off-white solid, which
was purified by column chromatography, eluting with pure
EtOAc in order to remove impurities, and then with EtOAc/
EtOH (1:1) to obtain 38 as an off-white solid (3.77 g, 65%):
mp 94-95 °C (lit.62 mp 106.5-107.5 °C); IR (KBr) 3366 cm-1
;
1H NMR (CDCl3) δ 1.25 (bs, 1H), 2.72-2.76 (m, 2H), 2.82-
2.87 (m, 2H), 3.70 (s, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 5.10 (s,
2H), 5.11 (s, 2H), 6.63-6.85 (m, 6H), 7.22-7.43 (m, 10H); 13
C
NMR (CDCl3) δ 149.5, 149.4, 146.9, 146.4, 137.2, 137.1, 133.2,
133.0, 128.3, 127.6, 127.1, 120.4, 120.0, 113.9, 113.7, 112.3,
111.6, 70.9, 70.8, 55.8, 53.4, 50.3, 35.6; EIMS m/z (rel intensity)
483 (M+, 2), 227 (57), 91 (100).
1
(NaCl) 3402, 3362, 1684 cm-1; H NMR (CDCl3, 200 MHz) δ
1.06 (d, J ) 7.0 Hz, 18H), 1.26 (h, J ) 7.0 Hz, 3H), 3.85 (s,
3H), 4.21 (d, J ) 5.9 Hz, 2H), 4.91 (bt, J ) 5.9 Hz, 1H), 5.95
(s, 2H), 5.96 (bs, 1H), 6.70-6.92 (m, 5H); 13C NMR (CDCl3, 50
MHz) δ 154.8, 146.9, 146.4, 146.3, 144.9, 135.1, 132.5, 129.6,
121.9, 114.3, 111.9, 110.2, 108.4, 101.1, 55.8, 42.9, 17.7, 11.9;
LSIMS m/z (rel intensity) 496 (MNa+, 12), 474 (MH+, 7), 473
(M+, 7), 430 (19), 272 (5), 257 (21), 225 (100); HRMS (LSIMS)
calcd for C25H36NO6Si 474.2311, found 474.2308. A solution
of this phenol (44 mg, 0.09 mmol) in dry CH2Cl2 (2 mL) was
added dropwise to a stirred solution of PIDA (1.0 equiv) in 2
mL of dry CH2Cl2 at -78 °C. The reaction mixture immediately
became bright yellow. After 1 h, TLC monitoring [hexanes/
Et2O (1:1)] indicated complete consumption of the starting
material. The mixture was diluted with 20 mL of CH2Cl2,
poured into ice-cold saturated aqueous NaHCO3 (10 mL),
extracted with CH2Cl2 (2 × 20 mL), washed with brine (20
mL), dried over Na2SO4, filtered, and evaporated at room
temperature. The residue was further dried under high
vacuum overnight to give the corresponding orthoquinol
acetate 31 as an orange oil (96%), which was used without
N-(4-Hyd r oxy-3-m eth oxyben zyl)-N-(Tsoc)-4-h yd r oxy-
3-m eth oxyp h en yleth yla m in e (37a ). A stirred solution of the
secondary amine 38 (745 mg, 1.54 mmol) and Et3N (215 µL,
1.54 mmol) in dry CH2Cl2 (15 mL) was cooled at -78 °C. Dry
ice (3.4 g, ca. 50 equiv) was added in one portion. After 1 h of
stirring at -78 °C, TIPS-OTf (414 µL, 1.54 mmol) was added
dropwise via syringe. After 5 min, the mixture was allowed to
warm to room temperature and was stirred for 30 min. The
mixture was then poured in a separatory funnel containing
H2O (10 mL). After separation, the aqueous phase was
extracted with CH2Cl2 (2 × 10 mL); the combined organic
layers were washed with saturated NaHCO3 (10 mL) and brine
(2 × 10 mL) and dried over MgSO4. Evaporation of the solvent
afforded an orange oil, which was purified by column chro-
matography, eluting with pentanes/EtOAc (6:1), to give N-
(4-benzyloxy-3-methoxybenzyl)-N-(Tsoc)-4-benzyloxy-3-methoxy-
phenylethylamine 39a (1:1 mixture of two isomers) as a
colorless oil (721 mg, 68%): IR (NaCl) 1674 cm-1 1H NMR
;
(CDCl3, 250 MHz) δ 1.11 (d, J ) 7.3 Hz, 18H), 1.17 (d, J ) 7.3
Hz, 18H), 1.27-1.48 (m, 6H), 2.70-2.82 (m, 4H), 3.35-3.48
(m, 4H), 3.85 (s, 6H), 3.86 (s, 6H), 4.32 (s, 2H), 4.34 (s, 2H),
5.14 (s, 4H), 5.15 (s, 4H), 6.58-6.90 (m, 12H), 7.26-7.46 (m,
20H); 13C NMR (CDCl3, 62.9 MHz) δ 155.3, 154.6, 149.8, 149.5,
149.4, 147.3, 147.2, 146.5, 146.4, 137.2, 137.1, 137.0, 136.9,
132.4, 132.1, 131.3, 131.1, 128.3, 127.6, 127.1, 120.6, 120.5,
119.9, 119.3, 114.2, 114.1, 113.7, 113.4, 112.4, 112.3, 111.2,
110.5, 71.0, 70.9, 70.8, 55.8, 55.7, 55.6, 51.2, 50.4, 48.7, 48.3,
34.5, 33.6, 17.9, 17.8, 12.0; LSIMS m/z (rel intensity) 706
(MNa+, 21), 685 (24), 684 (MH+, 54), 683 (M+, 45), 640 (73),
227 (100); HRMS (LSIMS) calcd for C41H53NO6Si 684.3720,
found 684.3711. Debenzylation of this material (700 mg, 1.02
mmol) in 10 mL of dry THF was carried out under H2 (balloon)
overnight at room temperature in the presence of 10 wt % Pd/C
as a catalyst (70 mg). The reaction mixture was filtered
through Celite, and the solid was washed with acetone.
Evaporation of the combined filtrates and washings afforded
a pale yellow oil, which was purified by column chromatog-
raphy, eluting with pentanes/EtOAc (3:1), to give 37a (1:1
mixture of two isomers) as a colorless oil (408 mg, 79%): IR
(NaCl) 3417, 1679 cm-1; 1H NMR (CDCl3, 250 MHz) δ 1.09 (d,
J ) 7.3 Hz, 18H), 1.14 (d, J ) 7.0 Hz, 18H), 1.26-1.44 (m,
6H), 2.63-2.78 (m, 4H), 3.32-3.42 (m, 4H), 3.82 (s, 6H), 3.83
(s, 6H), 4.32 (s, 4H), 5.68 (s, 1H), 5.70 (s, 1H), 5.78 (s, 1H),
5.79 (s, 1H), 6.57-6.87 (m, 12H); 13C NMR (CDCl3, 62.9 MHz)
δ 155.4, 154.7, 146.8, 146.4, 146.3, 145.0, 144.9, 144.1, 143.9,
131.0, 130.7, 130.1, 129.8, 121.3, 121.2, 120.8, 120.2, 114.4,
114.2, 114.1, 113.9, 111.3, 111.2, 110.4, 109.5, 55.8, 55.7, 51.3,
50.6, 48.8, 48.3, 34.6, 33.6, 17.9, 17.8, 12.1; LSIMS m/z (rel
intensity) 526 (MNa+, 31), 505 (31), 504 (MH+, 89), 503 (M+,
further purification: IR (NaCl) 3412, 1740, 1696, 1681 cm-1
;
1H NMR (CDCl3, 250 MHz) δ 1.03 (d, J ) 7.0 Hz, 18H), 1.24
(h, J ) 7.0 Hz, 3H), 2.13 (s, 3H), 3.49 (s, 3H), 4.14 (bt, J ) 5.8
Hz, 2H), 5.36 (bt, J ) 5.8 Hz, 1H), 5.95 (s, 2H), 6.08 (d, J )
2.1 Hz, 1H), 6.17 (d, J ) 10.1 Hz, 1H), 6.66 (s, 1H), 6.85 (dd,
J ) 2.1, 10.1 Hz, 1H), 6.92 (s, 1H); 13C NMR (CDCl3, 62.9 MHz)
δ 191.1, 170.2, 154.8, 147.7, 146.9, 143.0, 137.9, 132.7, 131.2,
130.6, 125.6, 109.8, 108.4, 101.4, 92.9, 51.5, 42.7, 20.6, 17.7,
12.0.
3-Hyd r oxy-2-m eth oxy-8,9-m eth ylen ed ioxyp h en a n th r i-
d in e (32). To a stirred ice-cold solution of 31 (50 mg, 0.094
mmol) in dry THF (1 mL) was added dropwise a commercial
solution of TBAF (1 M in THF, 1.1 equiv). After 10 min, the
ice bath was removed, and the reaction was stirred at room
temperature for 1 h. Progression of the reaction was monitored
by the disappearance of the orthoquinol acetate, as indicated
by TLC [hexanes/Et2O (1:1) and then CH2Cl2/MeOH (20:1)].
The mixture was diluted with EtOAc (20 mL), poured into ice-
cold water (10 mL), extracted with EtOAc (2 × 15 mL), washed
with brine (2 × 10 mL), dried over Na2SO4, filtered, and
evaporated at room temperature. The resulting brown oily
residue was purified by column chromatography, eluting with
CH2Cl2/MeOH (100:1, followed by 50:1), to afford 32 as an off-
white solid (20.2 mg, 80%): mp 259-260 °C; IR (KBr) 3554,
1
1484, 1241, 934 cm-1; H NMR (DMSO-d6, 250 MHz) δ 4.00
(s, 3H), 6.22 (s, 2H), 7.33 (s, 1H), 7.52 (s, 1H), 7.94 (s, 1H),
8.25 (s, 1H), 8.91 (s, 1H), 9.78 (bs, 1H); 13C NMR (DMSO-d6,
62.9 MHz) δ 151.1, 149.4, 149.0, 148.5, 147.0, 140.2, 129.7,
121.8, 117.9, 112.8, 105.1, 103.1, 102.0, 100.1, 56.3; LSIMS
m/z (rel intensity) 292 (MNa+, 12), 270 (MH+, 100), 269 (M+,

3436 J . Org. Chem., Vol. 67, No. 10, 2002
Pouyse´gu et al.
25), 460 (100); HRMS (LSIMS) calcd for C27H41NO6Si 504.2793,
found 504.2781.
111.76, 110.87, 71.1, 71.0, 67.23, 66.67, 55.9, 50.56, 50.4, 49.0,
47.8, 47.45, 47.3, 34.01, 33.8; LSIMS m/z (rel intensity) 728
(MNa+, 14), 706 (MH+, 6), 705 (M+, 10), 527 (2), 482 (2), 227
(100). Debenzylation of this material (434 mg, 0.61 mmol) in
25 mL of dry THF was carried out under H2 (balloon) overnight
at room temperature in the presence of 10 wt % Pd/C as a
catalyst (50 mg). The reaction mixture was filtered through
Celite, and the solid was washed with acetone. Evaporation
of the combined filtrates and washings afforded a pale yellow
oil, which was purified by column chromatography, eluting
with hexanes/Et2O (2:1), to give 37b as a colorless oil (274 mg,
85%) that was immediately submitted to the PIDA-oxidation/
cyclization sequence.
N -(4-H yd r oxy-5-m e t h oxy-2-p ip e r id in ob e n zyl)-6-h y-
d r oxy-5-m eth oxyin d ole (41). To a stirred ice-cold solution
of orthoquinol acetate 36b (444 mg, 0.69 mmol) in dry CH2Cl2
(7 mL) was added dropwise piperidine (1.4 mL, 20 equiv), over
10 min. After 1 h, the ice bath was removed, and the reaction
was allowed to warm to room temperature and was stirred
overnight. Evaporation of the solvent, followed by column
chromatography, eluting with CH2Cl2/MeOH (100:1), afforded
compound 41 as a dark green oil (54 mg, 21%): IR (NaCl) 3518,
3446, 1594 cm-1; 1H NMR (acetone-d6, 400 MHz) δ 1.58-1.63
(m, 2H), 1.76-1.81 (m, 4H), 2.83-2.88 (m, 4H), 3.61 (s, 3H),
3.87 (s, 3H), 5.29 (s, 2H), 6.33 (d, J ) 3.0 Hz, 1H), 6.55 (s,
1H), 6.77 (s, 1H), 6.93 (s, 1H), 7.07 (s, 1H), 7.11 (s, 1H), 7.18
(d, J ) 3.0 Hz, 1H), 7.55 (s, 1H); 13C NMR (acetone-d6, 100.6
MHz) δ 147.3, 147.2, 144.8, 144.5, 144.2, 132.4, 127.3, 124.9,
121.9, 112.9, 108.7, 102.9, 101.2, 96.8, 56.6, 56.4, 55.5, 45.6,
27.4, 24.9 LSIMS m/z (rel intensity) 405 (MNa+, 5), 383 (MH+,
5), 382 (M+, 9), 381 (7), 220 (100); HRMS (LSIMS) calcd for
N-(4-Hydr oxy-3-m eth oxyben zyl)-6-h ydr oxy-5-m eth oxy-
in d ole (40). To a stirred ice-cold solution of orthoquinol
acetate 36a (150 mg, 0.24 mmol) in dry THF (5 mL) was added
dropwise a commercial solution of TBAF (1 M in THF, 1.1
equiv). The reaction mixture immediately became darker. After
20 min, the ice bath was removed, and the reaction was stirred
at room temperature for another 20 min. Progression of the
reaction was monitored by the disappearance of the ortho-
quinol acetate, as indicated by TLC [hexanes/Et2O (1:4)]. The
mixture was diluted with EtOAc (50 mL), washed with brine
(2 × 10 mL), dried over Na2SO4, filtered, and evaporated at
room temperature. The resulting brown residue was purified
by column chromatography, eluting with hexanes/Et2O (1:1),
to afford the indole derivative 40 as a dark oil (23.9 mg, 33%):
IR (NaCl) 3535, 3456, 1588 cm-1 1H NMR (acetone-d6, 200
;
MHz) δ 3.79 (s, 3H), 3.87 (s, 3H), 5.21 (s, 2H), 6.34 (dd, J )
0.7, 3.2 Hz, 1H), 6.67 (dd, J ) 2.0, 8.1 Hz, 1H), 6.78 (d, J )
8.1 Hz, 1H), 6.89 (d, J ) 0.7 Hz, 1H), 6.92 (d, J ) 2.0 Hz, 1H),
7.09 (s, 1H), 7.16 (d, J ) 3.2 Hz, 1H);13C NMR (acetone-d6,
62.9 MHz) δ 148.3, 146.8, 144.5, 144.2, 132.2, 130.5, 127.3,
122.1, 120.7, 115.7, 111.7, 103.0, 101.4, 96.6, 56.6, 56.1, 50.4;
EIMS m/z (rel intensity) 301 (1), 300 (MH+, 11), 299 (M+, 60),
163 (93), 137 (100); HRMS (EI) calcd for C17H17NO4 299.1157,
found 299.1156.
N-(4-Hyd r oxy-3-m eth oxyben zyl)-N-(F m oc)-4-h yd r oxy-
3-m eth oxyp h en yleth yla m in e (37b). To a stirred ice-cold
suspension of the secondary amine 38 (500 mg, 1.03 mmol) in
dry THF (5 mL) and 10% aqueous Na2CO3 (250 µL) was added
dropwise a solution of 9-fluorenylmethylchloroformate (320.5
mg, 1.24 mmol) in dry THF (5 mL). After stirring at 0 °C for
5 h, the resulting mixture was then diluted with H2O (30 mL)
and extracted with Et2O (4 × 20 mL). The combined organic
layers were washed with H2O (3 × 10 mL), dried over MgSO4,
and evaporated to afford an orange syrup, which was purified
by column chromatography, eluting with hexanes/Et2O (1:2),
to give N-(4-benzyloxy-3-methoxybenzyl)-N-(Fmoc)-4-benzyl-
oxy-3-methoxyphenylethylamine 39b as a 1:1 carbamate rota-
meric mixture (554 mg, 76%, off-white foam): IR (KBr) 1694
cm-1; 1H NMR (CDCl3, 200 MHz) δ 2.49 (bt, J ) 7.1 Hz, 2H),
2.81 (bt, J ) 7.1 Hz, 2H), 3.25 (bt, J ) 7.1 Hz, 2H), 3.50 (bt,
J ) 7.1 Hz, 2H), 3.86 (s, 6H), 3.88 (s, 6H), 4.24-4.32 (m, 6H),
4.54-4.67 (m, 4H), 5.16 (s, 4H), 5.18 (s, 4H), 6.41-6.86 (m,
12H), 7.23-7.79 (m, 36H); 13C NMR (CDCl3, 50 MHz) δ 156.4,
155.9, 149.7, 149.5, 147.4, 146.6, 143.9, 141.3, 137.2, 137.0,
132.2, 130.7, 128.4, 128.3, 127.7, 127.6, 127.5, 127.2, 127.1,
126.9, 124.7, 120.6, 120.1, 119.9, 119.3, 114.3, 113.8, 112.5,
C
22H26N2O4 382.1892, found 382.1892.
Ack n ow led gm en t. We wish to thank the De´le´gation
Re´gionale a` la Recherche et a` la Technologie pour
l’Aquitaine (FEDER Grant Z0131) and the Conseil
Re´gional d’Aquitaine (Grant 990209003) for financially
supporting this research. We also thank Daniel K.
Whelligan for its contribution to this work, and Mr.
Michel Pe´traud for the NMR spectroscopic analyses.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 8a -e, 9a -h , 10a -e, 13-15, 27, 29-
1
32, 37a , 38, 39a -b, 40, and 41 and H-1H COSY (41), HMQC
(41), HMBC 2D maps (10e and 41). This material is available
free of charge via the Internet at http://pubs.acs.org.
J O020010D