Benzannulation reactions of Fischer carbene complexes for the synthesis of indolocarbazoles

Article abstract of DOI:10.1016/S0040-4020(01)00360-X

The synthesis of indolocarbazoles was achieved via photochemical and thermal annulation reactions of chromium Fischer carbene complexes. This methodology allows for facile incorporation of hydrogen bonding functionality which complements the pharmacophore contained within bioactive indolocarbazole natural products.

Full text of DOI:10.1016/S0040-4020(01)00360-X

TETRAHEDRON
Pergamon
Tetrahedron 57 42001) 5199±5212
Benzannulation reactions of Fischer carbene complexes for the
synthesis of indolocarbazoles
Craig A. Merlic,p Ying You, Daniel M. McInnes, Andrea L. Zechman,
Michael M. Miller and Qiaolin Deng
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, USA
Dedicated to Professor Barry M. Trost on the occasion of his 60th birthday
Received 9 February 2001; accepted 26March 2001
AbstractÐThe synthesis of indolocarbazoles was achieved via photochemical and thermal annulation reactions of chromium Fischer
carbene complexes. This methodology allows for facile incorporation of hydrogen bonding functionality which complements the pharma-
cophore contained within bioactive indolocarbazole natural products. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
bond, i.e. rebeccamycin, inhibit DNA topoisomerase I,12
while those with two N-glycosidic bonds present, i.e.
staurosporin, exhibit high levels of protein kinase C
4PKC) inhibition.10,13 A key structural feature of the hetero-
chromatic aglycone is the presence of hydrogen bonding
moieties at its top and bottom. Synthetic analogues containing
labile hydrogen functionalities 4i.e. ±OH, ±CH2OH, ±NH2)
on the imide nitrogen have been shown to possess enhanced
inhibition of PKC and other biological activities.14 Additional
structure±activity relationship studies have revealed that
the high potency of 1 is signi®cantly reduced in the
aglycon system 44).15,16 Presently, several indolocarbazole
alkaloids are in clinical trials for potential use in cancer
therapy.1d
The indolocarbazoles are natural products of medicinal and
biochemical importance.1 Their history dates back to 1977
with the isolation of staurosporine 41), initially named AM-
2282, from Streptomyces staurosporeus by Omura and
co-workers while searching for new microbial alkaloids
present in actinomycetes.2 The following year, the structure
of 1 was established by X-ray crystallographic analysis to be
comprised of a central indolocarbazole ring system linked
by two N-glycosidic bonds to a lower carbohydrate moiety
and an upper lactam ring 4Fig. 1).3 In addition to 1, other
indolocarbazoles were isolated soon thereafter including
the arcyria¯avins 43) from the slime mold Arcyria
denudata,4 K-252a 46a) and K-252c 44) from Nocardiopsis
strains K-252 and K-290, respectively,5 and rebeccamycin
48a) from Nocardia aerocoligenes.6 As indicated by the
distinctive UV chromophore of these alkaloids, all
possess the indolocarbazole backbone. In the subsequent
years, many additional indolocarbazoles have been
discovered.7,8
The novel structural features of these compounds and their
signi®cant biological relevance has prompted a ¯ourish of
activity from the synthetic community resulting in numer-
ous studies directed towards the synthesis, as well as several
disclosed total syntheses, of these natural products and their
structural analogs 4Fig. 2).4,17±46 A number of interesting
synthetic strategies were employed to prepare the indo-
locarbazole core in these syntheses. Most targeted construc-
tion of the central benzene ring, half used preformed
indole units, and several utilized Diels±Alder reactions as
the key step. Of particular note are the total syntheses of
rebeccamycin and staurosporin, revealed by Clardy22 and
Danishefsky,26 employing the reaction of 3,4-dibromo-N-
methylmaleimide with indolylmagnesium halide, developed
by Steglich,4 to construct the main carbon skeleton. Through
the use of a novel rhodium catalyzed carbenoid coupling to
indole, Wood and co-workers37 disclosed a common inter-
mediate that led to the ef®cient synthesis of staurosporine
and a number of its congeners. Van Vranken and coworkers38
The indolocarbazole alkaloids are extremely interesting
owing to the wide range of biological activities that they
possess, including antimicrobial,2 hypotensive,9 and cell
cytotoxic10 activities, as well as inhibition of platelet aggre-
gation.11 The greatest interest in these compounds, however,
has been due to their potent antitumor activity. Compounds
containing the indolocarbazole core with one N-glycosidic
Keywords: benzannulation; carbene complex; indolocarbazoles; palladium
catalyzed cross-coupling.
Corresponding author. Tel.: 11-310-825-5466; fax: 11-310-206-3722;
e-mail: merlic@chem.ucla.edu
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020401)00360-X

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C. A. Merlic et al. / Tetrahedron 57 *2001) 5199±5212
Figure 1. Representative indolocarbazoles.
elegantly demonstrated highly regioselective halogenation
and glucosylation of Mannich cyclization products,23c
allowing for the dissymmetric synthesis of several unsym-
metrical rebeccamycin type indolocarbazoles. Other than
Wood's route, the only other transition metal mediated
procedure shown is that of Saulnier employing a novel
double palladium catalyzed cyclization.35
ꢀ2†
We recently disclosed two alternative approaches to the
indolocarbazole ring system through: 41) palladium cata-
lyzed benzannulation reactions of biindolyl iodides and
alkynes 4Eq. 41)),47 and 42) annulations of Fischer carbene
intermediates 4Eq. 42)).48 Herein, we report a full account of
our efforts in this arena expanding upon the latter strategy.
This route provides access to a number of indolocarbazole
cores containing new patterns of hydrogen bonding func-
tionality on the central aryl ring which mimic or comp-
lement the pharmacophore contained within the bioactive
indolocarbazole natural products.
2. Results and discussion
Our goal was to provide a short synthesis of the indolo-
carbazole core containing two orthogonal protecting groups
to differentiate the indole nitrogens, as well as dissymmetric
hydrogen bonding groups on the central benzene ring. The
protecting groups could thus be removed and the indole
nitrogens could consequently be selectively functionalized
late in a synthesis installing the sugar moiety necessary in a
total synthesis of the indolocarbazole natural products.
Our strategy to form such differentially substituted indolo-
carbazoles centered on 2,20-biindolyl intermediates, their
conversion to Fischer chromium carbene complexes, and
subsequent benzannulation reactions of these key com-
plexes to establish the ABCEF ring system 4Scheme 1),
and thus the central core of the indolocarbazole alkaloids.
The requisite 2,20-biindolyl intermediates could arise by a
variety of routes, but we eventually developed palladium
ꢀ1†

C. A. Merlic et al. / Tetrahedron 57 *2001) 5199±5212
5201
Figure 2. Approaches to indolocarbazole alkaloids.
catalyzed cross-coupling of two indole substructures. This
overall synthetic route demonstrates the utility of our
previously reported Fischer carbene methodology, in which
carbene complexes are converted into aromatic alcohols and
amines.49,50
bis4o-tolyl)oxamide.27 Oxalyl chloride was condensed with
ortho-toluidene 415) according to the procedure of Wallace
and co-workers to form N,N0-bis4o-tolyl)oxamide 416), in
quantitative yields. The Madelung cyclization was then
accomplished by heating 16 with freshly prepared potas-
sium tert-butoxide to 2508C and then to 3208C 4Scheme
2). Much decomposition occurred under these extreme
conditions and yields of 2,20-biindolyl 417) were typically
on the order of 20%, though reactions at lower temperatures
resulted in little or no product.51
2.1. Approaches toward symmetrical 2,20-biindolyls
The ®rst method for preparation of 2,20-biindolyls explored
involved a double Madelung cyclization reaction of N,N0-
Scheme 1. Synthetic design.
Scheme 2.

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C. A. Merlic et al. / Tetrahedron 57 *2001) 5199±5212
mono-protected 2,20-biindolyl in modest yield 4Scheme 4).
N-alkylation or sulfonylation of indole took place in high
yields using the procedure of Kikugawa.56 Using the pro-
cedure of Hoffmann and co-workers,57 formylation of the 2
position of N-methylindole 422a) was accomplished in 81%
yield. Lower yields were obtained, however, when N-tosyl
or N-benzyl indoles, 22b and 22c, were used and efforts to
optimize the reaction using other formylation conditions
were unsuccessful. Applying the methodology of Watanabe
and coworkers,58 condensation of N-methylindole-2-
carboxaldehyde 423a) with 2-nitrotoluene resulted in indole
substituted alkene 25a in modest yield. A similar yield was
observed for condensation with N-benzylindole-2-carboxal-
dehyde. Varying conditions such as solvent 4DMF, THF)
and base 4KOMe, NaH) led to minimal product formation.
A higher yielding route to the indole substituted alkene was
achieved using a Wittig reaction.59 Addition of N-methylin-
dole-2-carboxaldehyde to a cold solution of ylide 24
resulted in 59% and 25% yields of trans and cis indole
substituted alkenes 25, respectively. Unfortunately, modest
yields of the subsequent nitrene cyclization were achieved.
Employing Cadogan's protocol,55 cyclization of trans-
alkene 25a with triethylphosphite resulted in a 50% yield
of 26a. Due to the limitations in this strategy of modest
yields, limits on structural diversity, and the number of
steps, a more ef®cient and versatile synthetic route toward
unsymmetrical 2,20-biindolyls was devised.
Scheme 3.
Due to the inef®cient Madelung cyclization of 16 our next
approach involved a palladium mediated coupling of the 2
and 20 positions of 1,10-carbonyldiindole 419) to form 1,10-
carbonyl-2,20-biindolyl 420). Two major advantages of this
route were foreseen: 41) the 2,20-biindolyl core would be
assembled without employing the problematic Madelung
cyclization; and 42) ring opening with a nucleophilic organo-
metallic reagent would lead directly to an unsymmetrical
mono-protected 2,20-biindolyl. As shown in Scheme 3,
1,10-carbonyldiimidazole52 was converted to N,N0-carbonyl-
diindole 419) in 41% yield using the procedure developed by
Bergman.53 The key coupling step provided the desired
product in low yield and required stoichiometric amounts
of palladium acetate, so it was deemed prohibitively expen-
sive.54 Addition of various co-oxidants 4Ac2O, MnO2, and
Cu4OAc)2) in attempts to make the reaction catalytic in
palladium resulted in no marked improvement in yield.
2.3. Palladium catalyzed cross-coupling approach to
unsymmetrical 2,20-biindolyls
Cross-coupling of two indole units under palladium cataly-
sis turned out to be ideal for the preparation of unsym-
metrical 2,20-biindolyls as illustrated in Scheme 5.60
Formation of 2-iodoindole 427) from indole using the
method reported by Bergman proceeded in 91% yield.61
N-Protection of 2-iodoindole with alkyl and sulfonyl groups
proceeded in excellent yields. 2-Iodo-1-methoxymethylin-
dole 428c) was initially prepared by a standard method for
the synthesis of N-substituted 2-iodoindoles 4KOH, DMF,
08C; CH3OCH2Br), but this procedure requires a large
excess of expensive methoxymethyl bromide with only
modest product yields. In addition, dif®culty arises in
separating the product from excess starting material in
large scale protocols due to similar Rf values of the two
compounds. These obstacles were overcome by optimi-
zation of the reaction conditions using NaH and a mixed
solvent system of 2:1 THF/DMF leading to excellent yields
of the desired product 4Eq. 43)).
2.2. Nitrene cyclization approach to unsymmetrical 2,20-
biindolyls
The next strategy employed the nitrene cyclization reaction
of Cadogan55 to build one indole ring, and resulted in a
ꢀ3†
In the ®rst palladium catalyzed cross-coupling reaction, N-
methyl-2-iodoindole 428a) was converted into the boronic
ester 29a. Using modi®ed Suzuki conditions, the in situ
prepared 29a was coupled with 2-iodoindole to afforded
Scheme 4.

C. A. Merlic et al. / Tetrahedron 57 *2001) 5199±5212
5203
Scheme 5. Palladium catalyzed biindolyl synthesis.
unsymmetrical 2,20-biindolyl 26a in 51% overall yield from
28a 4Scheme 5).62 Side products included the homocoupling
of 27, as well as of 29a. Several other palladium-catalyzed
cross-coupling reactions were investigated in attempts to
further improve the biindolyl preparation. Employing
Hudkins' procedure,63 the Stille cross-coupling reaction of
organotin 30 and iodoindole 28a produced biindolyl 26a in
41% yield 4Eq. 44)). In contrast, the Negishi method64 led to
the protonated product, 1-methylindole, which most likely
arose from protonation of the zinc reagent by the unprotected
2-iodoindole coupling partner 4Eq. 45)). Based on these results,
the Suzuki method was utilized for the other biindolyls.
iodoindole 428c) were successfully converted to the corre-
sponding biindolyls 26b and 26c in 62% and 61% yields,
respectively. N-allyl 2-iodoindole 428d) was coupled with
2-iodoindole to form 1-allyl-2-4indol-20-yl)indole 426d) in
low yield, with many side products being formed, possibly
due to intra- or intermolecular Heck type reactions. Due to
the problematic nature of the synthesis of 26d, the reactivity
of this compound was not investigated further. Attempts to
couple either N-benzenesulfonylindol-2-yl boronic acid or
the corresponding zinc chloride resulted in recovery of
the protonated product, N-benzenesulfonylindole 422e)
4Eq. 47)). In general, biindolyls 26 are easily visualized
on TLC under UV light due to their very intense
¯uorescence.
ꢀ6†
ꢀ4†
ꢀ5†
ꢀ7†
Due to the known dif®culty in unmasking protected indoles,
efforts were made to synthesize 2,20-biindolyl systems with
several different removable protecting groups 4Scheme 5).
N-Benzyl-2-iodoindole 428b) and N-methoxymethyl-2-

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C. A. Merlic et al. / Tetrahedron 57 *2001) 5199±5212
complexes were diastereotopic due to hindered rotation
about the biaryl axis. In fact, spectral analysis of complex
12f was quite complex due to additional hindered rotations,
most likely about the C3 to carbene carbon bond as we have
seen in previous systems.49b
ꢀ8†
Figure 3. Most stable conformer of 34.
2.4. Preparation of key chromium carbene complexes
and subsequent benzannulation reactions
Chromium carbene precursors were prepared via iodination
at the 3 position of biindolyls 26 using the procedure of
Bocchi and Palla,65 followed by N-protection 4Eq. 47)).
The resultant iodides 33 were formed in good to excellent
yields. Hindered rotation about the 2±20 bond was evident
from the diastereotopic AB patterns in the 1H NMR spectra
for the protons in the methylene groups of 33b, 33c, 33d,
33e, and 33f. Due to the presence of a heavy atom, iodides
33 do not ¯uoresce.66
To better understand the steric effects involved in these
systems, a Monte Carlo conformational search was carried
out with the AMBER force ®eld in Macromodel on a series
of substituted 2,20-biindolyls.68 Calculations indeed supported
the claim that the dif®culty encountered in generating the
desired carbene intermediates was due to the sterically
encumbering protecting groups. For example, with two
large protecting groups, the preferred conformation of N-
benzenesulfonyl-N0-benzyl-2,20-biindolyl 434) has an N1±
C2±C20 ±N10 dihedral angle of 72.88 4Fig. 3). The two in-
dole planes are nearly perpendicular to one other and the
aryl rings of the benzyl and benzenesulfonyl protecting
groups p-stack with the opposite indole moieties with the
distances between the benzene rings and indole moieties
Preparations of carbene complexes 12a and 12b were
accomplished under the standard conditions of metal halo-
gen exchange with n-butyllithium, addition to chromium
hexacarbonyl and methylation with methyl tri¯ate 4Eq.
48)).67 Both complexes were isolated as deep red solids
with spectral signals typical of carbene complexes.
However, differentially protected biindolyls 33c and 33d
failed to yield the corresponding carbene complexes under
such conditions and only methylated products were
observed. Initially, we proposed that the electron withdraw-
ing benzenesulfonyl protecting group in 33c inductively
stabilized an anion at the 3 position making it less nucleo-
philic and unable to add to the weakly electrophilic chro-
mium hexacarbonyl. However, the failure using biindolyl
33d, which possesses an allyl protecting group instead of a
benzenesulfonyl protecting group rules out that possibility.
These results then pointed to the possible role of sterics in
limiting formation of carbene complexes. Nucleophilic
addition to a carbonyl ligand in chromium hexacarbonyl is
hindered by the presence of the four cis CO ligands which
effectively create a `wall' of steric hindrance, so smaller
nucleophiles should be less problematic. Indeed, iodide
33e, with small allyl and methoxymethyl nitrogen protect-
ing groups, led smoothly to carbene complex 12e. Surpris-
ingly, iodide 33f, with a large BOC protecting group, also
successfully led to a carbene complex 412f). As with the
starting iodides 33e and 33f, the methylene protons in the
Ê
less than 4 A. Because the protecting groups reach across
to block the 3 position of the adjacent indole nucleus, bulky
chromium hexacarbonyl may not be able to access either the
C3 or C30 positions in such a system, while small electro-
philes such as methyl tri¯ate may still react.
By substituting the benzenesulfonyl group of 34 with the
smaller methoxymethyl protecting group, the N1±C2±C20 ±
N10 dihedral angle in the preferred conformation of N-benzyl-
N0-methoxymethyl-2,20-biindolyl 435) increases to 2103.18
4Fig. 4). p-Stacking interactions that block the C30 position
were again observed between the aryl ring of the benzyl
group and the opposite indole moiety, thus providing a
reasonable explanation why N0-benzyl-3-iodo-N-allyl-2,20-
biindolyl 433d) failed to produce the desired Fischer carbene
complex. However, the C3 position is not predicted to
be blocked by the MOM protecting group. Therefore, 3-
iodo-2,20-biindolyls with small protecting groups at the N0
position are predicted to be convertible to the corresponding

C. A. Merlic et al. / Tetrahedron 57 *2001) 5199±5212
5205
protecting groups 4Scheme 6). In analogy to complexes 12a
and 12b, both photochemical and isonitrile-initiated thermal
annulation reactions were successful, generating products
13e 463%) and 14e 474%) from 12e and 13f 471%) and
14f 468%) from 12f. In fact, it seemed that the nature of
the protecting groups did not exert a strong in¯uence on the
outcome of the benzannulation reactions. However, choice
of solvent did play a signi®cant role in some of the photo-
chemical reactions. When toluene was used as the solvent,
the cyclization product of 12e was isolated in a substantially
lower yield 414%) as compared to the reaction in THF
463%). Surprisingly, cyclization of 12f in toluene proceeded
in a 71% yield. In contrast to the corresponding precursor
iodides and carbenes, diastereotopic AB patterns for the
methylene protons were not observed in the 1H NMR spec-
tra for the benzannulation products.
In summary, we have demonstrated that complex and steri-
cally encumbered 2,20-biindolyl chromium carbene com-
plexes containing removable protecting groups can be
prepared and subsequently employed in both thermal and
photochemical annulation reactions. The differentially
protected indolocarbazole nitrogens will allow for concise
and selective glycoside formation in route to analogues of
indolocarbazoles containing hydrogen bonding functional-
ity complementing important protein kinase C inhibiting
indolocarbazole natural products.
Figure 4. Most stable conformer of 35.
Fischer carbene complex. Indeed, iodides 33e and 33f 4with
a large BOC group on the same ring) were successfully
converted into carbene complexes 12e and 12f, respectively.
Benzannulation reactions of chromium carbene complexes
12a, 12b, 12e and 12f were employed to construct the
central ring of the indolocarbazoles with concomitant
formation of hydrogen bonding moieties 4Scheme 6).
Photolysis of 12a generated the benzannulation product
13a in 51% yield via the intermediacy of a photogenerated
ketene, as previously reported from our group.49a,b Product
formation was con®rmed by the presence of two doublets at
8.22 and 8.37 ppm for the bay region protons in the 1H NMR
spectrum and the phenolic proton at 9.37 ppm. Complex
12a also underwent an aminobenzannulation reaction49c,d
via a thermal reaction with tert-butyl isonitrile to produce
amine 14a in 89% yield. Addition of tert-butyl isonitrile to
the carbene complex generates an intermediate ketenimine
complex that undergoes a thermal 6p electrocyclization
reaction followed by tautomerization to yield the product
amine. Again, the desired product was obvious from the bay
3. Experimental
3.1. General experimental procedures
All reactions were carried out in ¯ame-dried glassware
under a static argon or nitrogen atmosphere unless otherwise
stated. Tetrahydrofuran 4THF), dioxane, and diethyl ether
were distilled from sodium-benzophenone ketyl; dichloro-
methane, acetonitrile, pyridine, and hexanes were distilled
from calcium hydride. Reagents were obtained commer-
cially and puri®ed before use unless otherwise indicated.
Flash column chromatography was performed employing
the Still protocol.69
1
region protons at 8.35 and 8.77 ppm in the H NMR spec-
Infrared 4IR) spectra were recorded on a Nicolet 510P FT-IR
spectrophotometer and selected absorption maxima are
trum. Indolocarbazoles 13b and 14b were also obtained in
good yields from the photochemical and thermal benzannu-
lation reactions of carbene complex 12b.
1
reported in cm21. H and 13C nuclear magnetic resonance
4NMR) spectra were obtained with a Bruker AM 200 or AM
360 or ARX 400 or 500 spectrometer in deuteriochloroform
4CDCl3: d 7.26ppm for 1H, d 77.0 ppm for 13C); benzene
4C6D6: d 7.16ppm for 1H, d 128.39 ppm for 13C); acetone
Finally, our focus turned to the cyclization reactions of
carbene complexes 12e and 12f, which contain removable
Scheme 6. Benzannulation reactions of Fischer carbene complexes.

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C. A. Merlic et al. / Tetrahedron 57 *2001) 5199±5212
1
44CD3)2CO: d 2.05 ppm for H, d 29.92 ppm for 13C); or
dimethylsulfoxide 44CD3)2SO: d 2.50 ppm for 1H, d
39.52 ppm for 13C) solution. Chemical shifts are given
in ppm 4d); multiplicities are indicated by s 4singlet), d
4doublet), t 4triplet), q 4quartet), m 4multiplet), or br
4broadened). Coupling constants, J, are reported in Hertz.
Mass spectra were obtained on either an AEI MS902 spec-
trometer with an ionization voltage of 70 eV or a VG ZAB-
SE spectrometer.
1.96mmol) was added dropwise and the reaction mixture
was warmed to 08C and stirred 1.5 h. The solvent was removed
in vacuo and 10 mL of toluene was added to the yellow oil. 2 M
Na2CO3 41.5 mL, purged with Ar) aqueous solution and
powdered 2-iodoindole 4300 mg, 1.24 mmol) in 3 mL of tolu-
ene were added to the reaction mixture. Pd4PPh3)4 was prepared
by stirring PPh3 4197 mg, 0.75 mmol) with Pd4OAc)2 434 mg,
0.15 mmol) in 3 mL of THF under Ar at rt for 15 min followed
by the dropwise addition of n-BuLi 40.13 mL, 0.30 mmol). The
catalyst reaction mixture was stirred for an additional 15 min at
rt and the freshly made Pd4PPh3)4 was added to the reaction
mixture. After re¯uxing for 18 h, the reaction mixture was
cooled to rt and extracted into ether, washed with H2O, dried
4MgSO4) and the solvent was removed in vacuo. Puri®cation by
¯ash chromatography 490:10 hexane/EtOAc) yielded 157 mg
451%) of 1-methyl-2-4indol-20-yl)indole 426a) as a yellow
solid.
3.1.1. 1-Benzyl-2-iodoindole 028b). 2-Iodoindole 4800 mg,
3.29 mmol) was dissolved in DMF 410 mL) and the solution
was cooled to 08C. Powdered KOH 4277 mg, 4.94 mmol)
was added and the mixture stirred for 5 min at 08C. Benzyl
bromide 4619 mg, 362 mmol) was added dropwise to the
reaction mixture. After 5 min, the reaction mixture was
diluted with Et2O and washed with saturated NaCl solution.
The organic layer was dried 4MgSO4) and the solvent was
removed in vacuo to yield 1.10 g 496%) of 1-benzyl-2-
iodoindole 428b) as a white solid after chromatography
495:5 hexane/EtOAc).
1H NMR 4360 MHz, CDCl3) d: 3.95 43H, s), 6.72 41H, s),
6.75 41H, s), 7.19 42H, t, Jˆ7.50 Hz), 7.25±7.33 42H, m),
7.42 42H, t, Jˆ8.15 Hz), 7.69 42H, t, Jˆ8.16Hz), 8.2641H,
s 4broad)). 13C NMR 490 MHz, CDCl3) d: 31.3, 100.8,
102.4, 109.5, 110.8, 120.1, 120.3, 120.5, 120.6, 122.2,
122.7, 127.6, 128.8, 129.5, 133.0, 136.1, 138.5. IR
1H NMR 4360 MHz, CDCl3) d: 5.42 42H, s), 6.88 41H, s),
7.04±7.11 44H, m), 7.23±7.30 44H, m), 7.55±7.58 41H, m).
13C NMR 490 MHz, CDCl3) d: 50.4, 83.8, 110.1, 112.6,
119.5, 120.0, 122.0, 126.3 42C), 127.4, 128.7 42C), 129.9,
137.1, 137.7. IR 4thin ®lm): 3061, 3000, 1495, 1448, 1455,
1348, 1331, 1307, 777, 744, 725 cm21. MS 4EI): 333 4M1,
100), 206443), 115 47). Mass calcd for C 15H12NI: 333.0015;
found: 333.0012.
4CDCl3): 3411, 3010, 1470, 1451, 1428, 1391, 909, 802,
779, 735, 650 cm21. MS 4EI): 247 4M111, 19), 2464M
1
,
100), 245 430), 231 46), 123 48). Mass calcd for C17H14N2:
246.1157; found: 246.1158.
3.2.2. 1-Benzyl-2-0indol-20-yl)indole 026b). Following the
general procedure for the synthesis of biindolyls, 1-benzyl-2-
iodoindole 41.31 g, 3.95 mmol) was used to yield 790 mg
462%) of 1-benzyl-2-4indol-20-yl)indole 426b) as a yellow
solid after chromatography 490:10 hexane/EtOAc).
3.1.2. 2-Iodo-1-methoxymethylindole 028c). A solution of
2-iodoindole 41.21 g, 5.00 mmol) in THF 410 mL) was
added dropwise to a slurry of NaH 4300 mg, 7.50 mmol,
washed with 3 mL of hexanes) in THF 45 mL) and DMF
42.5 mL) at 08C. After stirring for 1 h, neat methoxymethyl
bromide 40.55 mL, 6.06 mmol) was added dropwise to
the reaction mixture. Upon disappearance of the starting
material as indicated by TLC 41 h), the reaction mixture
was diluted with Et2O and washed with sat. NaCl. The
organic layer was dried 4MgSO4) and the solvent was
removed in vacuo. The crude material was puri®ed by
¯ash chromatography 490:10 hexane/EtOAc) to yield
1.29 g 490%) of 2-iodo-1-methoxymethylindole 428c), as a
colorless oil.
1H NMR 4360 MHz, CDCl3) d: 5.59 42H, s), 6.54 41H, s),
6.83 41H, s), 7.11±7.13 43H, m), 7.13±7.37 48H, m), 7.58
41H, d, Jˆ7.87 Hz), 7.72 41H, d, Jˆ7.35 Hz), 8.21 41H, s).
13C NMR 490 MHz, CDCl3) d: 47.8, 101.7, 102.3, 110.2,
110.8, 120.3, 120.5, 120.7, 120.7, 122.6, 122.8, 125.9 42C),
127.4, 128.0, 128.7, 129.0 42C), 129.2, 133.2, 136.3, 138.0,
138.3. IR 4thin ®lm): 3410, 3100, 1495, 1452, 1437, 1394,
1338, 1323, 908, 783, 748, 727, 694 cm21. MS 4EI): 322
4M1, 100), 267 421), 245 416), 231 460), 217 417), 186 416),
162 442), 113 424). Mass calcd for C23H18N2: 322.1470;
found: 322.1464.
1H NMR 4400 MHz, C6D6) d: 2.91 43H, s), 5.04 42H, s),
6.75 41H, d, Jˆ0.6Hz), 7.12±7.15 42H, m), 7.33 41H, m),
7.47 41H, m). 13C NMR 4100 MHz, C6D6) d: 55.1, 76.8,
82.7, 110.2, 114.0, 119.7, 120.8, 122.4, 130.4, 138.4. IR
4thin ®lm): 2934, 1458, 1441, 1393, 1339, 1304, 1281,
1225, 1190, 1161, 1125, 1098, 1078, 912, 783, 743,
590 cm21. MS 4EI): 287 4M1, 100), 256420), 205.1 45),
130.1 420), 129 412), 115 45). Mass calcd for C10H10NIO:
286.9807; found: 286.9811.
3.2.3. 1-Methoxymethyl-2-0indol-20-yl)indole 026c). Follow-
ing the general procedure for the synthesis of biindolyls, 1-
methoxymethyl-2-iodoindole 4830 mg, 2.90 mmol) was used
to yield 488 mg 461%) of 1-methoxymethyl-2-4indol-20-yl)
indole 426c) as a yellow solid after chromatography 485:15
hexane/EtOAc).
3.2. General procedure for the preparation of biindolyls
026)
1H NMR 4400 MHz, C6D6) d: 2.90 43H, s), 4.99 42H, s),
6.80 41H, s), 7.08 41H, s), 7.17±7.20 41H, m), 7.23±7.30
45H, m), 7.71 41H, d, Jˆ5.6Hz), 7.80 41H, d, Jˆ8.1 Hz),
9.04 41H, s 4broad)). 13C NMR 4100 MHz, C6D6) d: 55.4,
74.1, 103.3, 103.8, 109.4, 111.2, 120.5, 120.9, 120.9, 121.0,
122.6, 122.7, 128.6, 129.2, 129.6, 133.6, 137.1, 139.0. IR
4KBr plate): 3412, 3373, 1460, 1441, 1387, 1348, 1331,
3.2.1. 1-Methyl-2-0indol-20-yl)indole 026a). n-BuLi 40.72 mL,
1.66 mmol, 2.3 M in hexane) was added to a solution of 2-iodo-
1-methylindole 4389 mg, 1.51 mmol) in THF 410 mL) at
2788C. After stirring 20 min, trimethyl borate 4204 mg,

C. A. Merlic et al. / Tetrahedron 57 *2001) 5199±5212
5207
1314, 1292, 1159, 1101, 1071, 910, 793, 746, 727 cm21. MS
4EI): 277.1 4M111, 26), 276.1 4M1, 100), 245.1 433), 244.1
496), 243.1 455), 231.1 416), 204.1 47). Mass calcd for
C18H16N2O: 276.1263; found: 276.1270.
137.1, 137.8. IR 4KBr plate): 3056, 2936, 1456, 1424,
1383, 1352, 1338, 1310, 1209, 1013, 934, 799, 743 cm21
.
MS 4EI): 412.0 4M1, 100), 285.1 455), 270.1 424), 243.1
443). Mass calcd for C20H17IN2: 412.0437; Found:
412.0437.
3.3. General procedure for iodination and subsequent
protection 033)
3.3.3. 3-Iodo-1-benzenesulfonyl-2-010-benzylindol-20-yl)
indole 033c). Following the general procedure for iodination
and subsequent protection, 1-benzyl-2-4indol-20-yl)indole
4283 mg, 0.88 mmol) was used to yield 330 mg 464%, two
steps) of 3-iodo-1-benzenesulfonyl-2-410-benzylindol-20-
yl)indole 433c) as a white solid after chromatography
475:25 hexane/EtOAc).
3.3.1. 3-Iodo-1-methyl-2-010-methylindol-20-yl)indole 033a).
1-Methyl-2-4indol-20-yl)indole 4256mg, 1.04 mmol) was
dissolved in DMF 45 mL) and the solution cooled to 08C.
Powdered KOH 4116mg, 2.08 mmol) was added and the
mixture stirred 5 min at 08C. Iodine 4289 mg, 1.14 mmol)
in DMF 41 mL) was added dropwise resulting in a brown
reaction mixture. After 5 min, the reaction mixture was
diluted with Et2O and washed with 15% Na2S2O3. The
organic layer was dried 4MgSO4) and the solvent was
removed in vacuo to yield 3-iodo- 2-410-methylindol-20-yl)
indole, which was immediately carried forward to the next
step.
1H NMR 4360 MHz, CDCl3) d: 5.53 42H, s), 6.66 41H, s),
7.11±7.21 43H, m), 7.28±7.58 412H, m), 7.70 41H, d,
Jˆ7.66 Hz), 7.85 41H, d, Jˆ7.36Hz), 8.45 41H, d,
Jˆ8.38 Hz). 13C NMR 490 MHz, CDCl3) d: 48.8, 80.9,
107.4, 110.8, 115.5, 119.9, 121.1, 122.7, 122.9, 124.7,
126.8, 126.9 42C), 127.0 42C), 127.1, 127.1, 128.3 42C),
128.8 42C), 129.3, 129.6, 132.1, 132.3, 134.1, 136.7,
137.2, 137.4. IR 4thin ®lm): 3080, 3000, 1458, 1446,
1377, 1346, 1316, 1190, 1174, 1089, 908, 750, 729,
684 cm21. MS 4EI): 588 4M1, 70), 448 48), 397 47), 320
4100), 243 412). Mass calcd for C29H21N2SO2I: 588.0369;
found: 588.0370.
NaH 460 mg, 1.5 mmol, washed with 2 mL of hexane) was
suspended in DMF 43 mL) and brought to 08C. Freshly
prepared 3-iodo-2-410-methylindol-20-yl)indole was dissolved
in dry DMF 42 mL) and added dropwise to the NaH mixture.
After 1 h at 08C, MeI 4213 mg, 1.5 mmol) was added drop-
wise to the green reaction mixture. After disappearance of
the starting material as indicated by TLC, the reaction
mixture was diluted with Et2O and washed with H2O. The
organic layer was dried 4MgSO4) and the solvent was
removed in vacuo. Puri®cation by ¯ash chromatography
475:25 hexane/EtOAc) yielded 387 mg 497%, two steps)
of 3-iodo-1-methyl-2-410-methylindol-20-yl)indole 433a) as
a white solid.
3.3.4. 1-Allyl-3-iodo-2-010-benzylindol-20-yl)indole 033d).
Following the general procedure for iodination and subse-
quent protection, 1-benzyl-2-4indol-20-yl)indole 4332 mg,
1.03 mmol) was used to yield 339 mg 468%, two steps) of
1-allyl-3-iodo-2-410-benzylindol-20-yl)indole 433d) as a
white solid after chromatography 498:2 hexane/EtOAc).
1H NMR 4400 MHz, CDCl3) d: 4.31 41H, dd, Jˆ16.6,
4.7 Hz), 4.41 41H, dd, Jˆ16.6, 4.7 Hz), 4.99 41H, dd,
Jˆ17.1, 1.0 Hz), 5.18 41H, dd, Jˆ10.3, 1.0 Hz), 5.32 41H,
d, Jˆ16.1 Hz), 5.47 41H, d, Jˆ16.1 Hz), 5.78 41H, ddt,
Jˆ17.1, 10.3, 4.7 Hz), 6.91 41H, s), 6.92 41H, d,
Jˆ8.2 Hz), 6.93 41H, d, Jˆ7.0 Hz), 7.20±7.2643H, m),
7.33±7.45 45H, m), 7.53 41H, d, Jˆ8.2 Hz), 7.70 41H, dd,
1H NMR 4360 MHz, CDCl3) d: 3.65 43H, s), 3.68 43H, s),
6.74 41H, s), 7.25 41H, t, Jˆ7.12 Hz), 7.30±7.48 45H, m),
7.58 41H, d, Jˆ8.04 Hz), 7.7641H, d, Jˆ7.88 Hz). 13C
NMR 490 MHz, CDCl3) d: 30.8, 31.6, 105.6, 109.8, 109.9,
110.1, 120.0, 120.8, 121.1, 121.5, 121.7, 122.4, 123.5,
123.7, 127.5, 129.9, 133.7, 137.7. IR 4CDCl3): 3154,
3061, 2942, 1611, 1462, 1325, 1233, 1101, 909, 735,
650 cm21. MS 4EI): 3864M 1, 100), 259 467), 244 421),
217 47), 130 412). Mass calcd for C18H15N2I: 386.0280;
found: 386.0278.
Jˆ7.0, 1.0 Hz), 7.8641H, d,
Jˆ7.8 Hz). 13C NMR
4100 MHz, CDCl3) d: 47.4, 48.4, 64.1, 107.0, 110.8,
111.0, 116.9, 120.4, 121.1, 121.4, 121.8, 123.0, 123.7,
127.1, 127.1, 127.5, 127.9, 128.6, 128.6, 129.7, 130.4,
133.3, 133.5, 137.1, 137.6, 137.7. IR 4thin ®lm): 3059,
1495, 1452, 1418, 1387, 1344, 1329, 1310, 1252, 1194,
1161, 1111, 1013, 908, 800, 739, 696 cm21. MS 4FAB):
489 4M111, 100), 488 4M1, 96), 361 478). Mass calcd for
C26H21IN2: 488.07495; found: 488.0751.
3.3.2. 1-Allyl-3-iodo-2-010-methylindol-20-yl)indole 033b).
Following the general procedure for iodination and subse-
quent protection, 1-methyl-2-4indol-20-yl)indole 4338 mg,
1.46mmol) was used to yield 426mg 475%, two steps) of
1-allyl-3-iodo-2-410-methylindol-20-yl)indole 433b) as a
white solid after chromatography 490:10 hexane/EtOAc).
3.3.5.
1-Allyl-3-iodo-2-010-methoxymethylindol-20-yl)
indole 033e). Following the general procedure for iodination
and subsequent protection, 1-methoxymethyl-2-4indol-20-
yl)indole 4772 mg, 2.80 mmol) was used to yield 885 mg
472%, two steps) of 1-allyl-3-iodo-2-410-methoxymethylin-
dol-20-yl)indole 433e) as a white solid after chromatography
490:10 hexane/EtOAc).
1H NMR 4400 MHz, CD2Cl2) d: 3.66 43H, s), 4.63 41H, ddt,
Jˆ16.9, 4.6, 1.8 Hz), 4.78 41H, ddt, Jˆ16.9, 5.3, 1.6 Hz),
4.83 41H, dtd, Jˆ17.1, 1.8, 1.3 Hz), 5.11 41H, dtd, Jˆ10.3,
1.6, 1.2 Hz), 5.84 41H, dddd, Jˆ17.1, 10.3, 5.3, 4.6Hz),
6.71 41H, d, Jˆ0.8 Hz), 7.18±7.38 45H, m), 7.45 41H, dd,
Jˆ8.3, 0.8 Hz), 7.55 41H, d, Jˆ7.8 Hz), 7.71 41H, d,
Jˆ7.9 Hz). 13C NMR 4100 MHz, CD2Cl2) d: 30.9, 47.4,
63.8, 105.3, 109.9, 110.8, 116.5, 120.0, 120.9, 120.9,
121.4, 122.5, 123.5, 127.5, 130.0, 130.1, 133.2, 133.5,
1H NMR 4400 MHz, C6D6) d: 2.7643H, s), 4.20 41H, dd,
Jˆ17.0, 4.9 Hz), 4.2641H, dd, Jˆ17.0, 4.9 Hz), 4.64 41H, d,
Jˆ17.9 Hz), 4.82 41H, d, Jˆ10.3 Hz), 5.08 41H, d,
Jˆ10.8 Hz), 5.18 41H, d, Jˆ10.8 Hz), 5.4641H, ddt,

5208
C. A. Merlic et al. / Tetrahedron 57 *2001) 5199±5212
Jˆ17.9, 10.3, 4.9 Hz), 6.74 41H, s), 7.16 41H, d, Jˆ6.9 Hz),
7.24±7.30 43H, m), 7.33 41H, m), 7.5641H, d, Jˆ8.1 Hz),
7.70 41H, d, Jˆ7.8 Hz), 7.78 41H, dd, Jˆ6.8, 1.8 Hz). 13C
NMR 4100 MHz, C6D6) d: 47.4, 55.6, 64.5, 75.3, 107.9,
111.0, 111.1, 116.2, 121.1, 121.3, 121.4, 121.9, 123.4,
123.7, 127.6, 128.3, 129.7, 130.6, 133.2, 137.4, 137.9. IR
4KBr plate): 2942, 1456, 1437, 1381, 1368, 1346, 1305,
1285, 1013, 939, 908, 806, 741 cm21. MS 4FAB): 442.1
4M1, 100), 411.0 426). Mass calcd for C21H19IN2O:
442.0542; Found: 442.0531.
1217, 839, 748 cm21. MS 4FAB): 494 4M1, 20), 466 425),
440 420), 410 445), 382 443). Mass calcd for C25H18N2O6Cr:
494.0570; found: 494.0575.
3.4.2. [01-Allyl-2-010-methylindol-20-yl)indol-3-yl)methoxy-
methylene]pentacarbonylchromium 012b). Following the
general procedure for Fischer carbene preparation,1-allyl-3-
iodo-2-410-methylindol-20-yl)indole 4158 mg, 0.38 mmol)
was used to yield 128 mg 466%) of [41-allyl-2-410-methy-
lindol-20-yl)indol-3-yl)methoxymethylene]pentacarbonyl-
chromium 412b) as a red solid together with a ¯uorescent
impurity after chromatography 480:20 hexane/EtOAc).
Chromium carbene 12b was the major product as evidenced
by 1H and 13C NMR.
3.3.6. 1-tert-Butoxycarbonyl-2-iodo-3-010-methoxymethyl-
indol-20-yl)indole 033f). Following the general procedure
for iodination and subsequent protection, 1-methoxy-
methyl-2-4indol-20-yl)indole 4232 mg, 0.84 mol) was used
to yield 230 mg 453%) 1-tert-butoxycarbonyl-2-iodo-3-410-
methoxymethylindol-20-yl)indole 433f) as a yellow solid
after chromatography 490:10 hexane/EtOAc).
1H NMR 4200 MHz, C6D6) d: 3.0643H, s), 3.71 43H, s),
3.94±3.98 42H, m), 4.54 41H, d, Jˆ16.1 Hz), 4.77 41H, d,
Jˆ10.2 Hz), 5.29±5.43 41H, m), 6.69 41H, s), 7.00±7.28
46H, m), 7.67 41H, d, Jˆ7.1 Hz), 7.8641H, d, Jˆ6.3 Hz).
13C NMR 4100 MHz, acetone-d6) d: 33.1, 46.4, 66.6, 106.6,
110.0, 111.6, 116.1, 120.0, 120.4, 120.9, 122.3, 122.7,
123.8, 127.6, 128.6, 129.3, 131.6, 133.1, 134.4, 136.5,
138.8, 216.0, 224.9, 343.5.
1H NMR 4500 MHz, CDCl3) d: 1.23 49H, s), 3.21 43H, s),
5.15 41H, d, Jˆ11.0 Hz), 5.47 41H, d, Jˆ11.0 Hz), 6.72 41H,
s), 7.24±7.60 46H, m), 7.73 41H, d, Jˆ7.8 Hz), 8.32 41H, d,
Jˆ8.2 Hz). 13C NMR 4125 MHz, CDCl3) d: 27.5, 56.3,
75.5, 77.9, 84.1, 106.5, 110.1, 115.8, 120.4, 121.0, 122.2,
122.8, 123.7, 126.3, 127.9, 131.0, 131.3, 131.9, 136.6, 137.1,
148.2. IR 4thin ®lm): 3054, 2980, 2932, 1732, 1447, 1325,
1256, 1156, 1098, 1018, 916, 833, 754, 714 cm21. MS 4EI):
502 4M1, 100), 496420), 415 437), 402 455), 370 499), 259
440), 243 470), 232 453), 229 428), 204 417). Mass calcd for
C23H23IN2O3: 502.0753; found: 502.0750.
3.4.3. [01-Allyl-2-010-methoxymethylindol-20-yl)indol-3-yl)
methoxymethylene]-pentacarbonylchromium 012e).
Following the general procedure for Fischer carbene
preparation, 1-allyl-3-iodo-2-410-methoxymethylindol-20-
yl)indole 4221 mg, 0.50 mmol) was used to yield 157 mg
459%) of [41-allyl-2-410-methoxymethylindol-20-yl)indol-
3-yl) methoxymethylene]pentacarbonylchromium 412e) as
a red solid, together with a ¯uorescent impurity after
chromatography 485:15 hexane/EtOAc).
3.4. General procedure for Fischer carbene synthesis
012)
1H NMR 4200 Hz, CDCl3) d: 3.23 43H, s), 4.45 43H, s),
4.58±4.65 42H, m), 4.80±4.95 42H, m), 5.17 41H, d,
Jˆ9.9 Hz), 5.24 41H, d, Jˆ9.9 Hz), 5.82±5.84 41H, m),
6.86 41H, s), 7.25±7.35 46H, m), 7.50 41H, d, Jˆ7.8 Hz),
7.71 41H, d, Jˆ8.3 Hz). 13C NMR 4100 Hz, acetone-d6) d:
46.4, 55.6, 66.9, 74.6, 106.3, 108.4, 110.3, 111.4, 116.4,
120.5, 121.0, 121.9, 122.3, 123.3, 123.7, 127.7, 127.8,
129.1, 133.5, 136.1, 138.9, 216.2, 225.0, 4carbene carbon
not observed).
3.4.1. [01-Methyl-2-010-methylindol-20-yl)indol-3-yl)meth-
oxymethylene]pentacarbonylchromium 012a). n-BuLi
41.78 mL, 4.00 mmol, 2.25 M in hexane) was added drop-
wise to a solution of 3-iodo-1-methyl-2-410-methylindol-20-
yl)indole 41.286g, 3.33 mmol) in a 50:50 mixture of
THF:Et2O 420 mL) at 2788C. After 1 h at 2788C, the reac-
tion mixture was cannulated into a mixture of Cr4CO)6
4733 mg, 3.33 mmol) in Et2O 410 mL) at 08C resulting in
a red±orange reaction mixture. After 15 min, no solid was
present in the reaction mixture and it was quenched with
0.25 mL of sat. aqueous Na2CO3 solution followed by
MeOTf 41.09 g, 6.66 mmol), resulting in a bright red reac-
tion mixture. When the reaction was complete, as evidenced
by disappearance of the low Rf acylate on the TLC, the
reaction mixture was diluted with CH2Cl2 and washed
with sat. Na2CO3 solution. The organic layer was dried
4MgSO4) and plated onto diatomaceous earth. Flash chro-
matography 490:10 hexane/EtOAc) yielded 912 mg 455%)
of [41-methyl-2-410-methylindol-20-yl)indol-3-yl)methoxy-
methylene]pentacarbonylchromium 412a) as a red solid.
3.4.4.
[01-tert-Butoxycarbonyl-2-010-methoxymethyl-
indol-2'-yl)indol-3-yl)methoxymethylene]-pentacarbonyl-
chromium 012f). Following the general procedure for
Fischer carbene preparation, 1-tert-butoxycarbonyl-2-iodo-
3-410-methoxymethylindol-20-yl)indole 40.170 g, 0.339 mmol)
was used to yield 85 mg 442%) of [41-tert-butoxycarbonyl-
2-410-methoxymethylindol-20-yl)indol-3-yl)-methoxymethyl-
ene]pentacarbonylchromium 412f) as a red solid after
chromatography 495:5 hexane/EtOAc).
Note: Due to restricted rotation about more than one bond,
the NMR spectra were unusually complex due to the
presence of several rotomers. H NMR 4500 Hz, CDCl3)
d: 1.1649H, s), 1.21 49H, s), 1.25 49H, s), 3.13 43H, s),
3.21 43H, s), 3.39 43H, s), 3.61 43H, s), 3.70 43H, s),
5.19±5.41 42H, m), 6.57 41H, s), 7.16±7.68 46H, m),
8.20±8.37 42H, m). 13C NMR 4125 Hz, acetone-d6) d:
22.5, 27.3, 27.4, 28.0, 28.1, 31.5, 34.6, 51.4, 62.2, 75.2,
75.7, 79.7, 84.5, 84.9, 105.4, 107.2, 109.7, 110.0, 110.7,
1H NMR 4360 MHz, C6D6) d: 2.72 43H, s), 3.03 43H, s),
3.62 43H, s), 6.50 41H, s), 6.89 41H, d, Jˆ7.74 Hz),
7.15±7.32 45H, m), 7.69 41H, d, Jˆ7.82 Hz), 7.84 41H, d,
Jˆ7.41 Hz). 13C NMR 490 MHz, C6D6) d: 30.2, 30.6, 65.2,
107.3, 109.9, 110.5, 120.9, 121.1, 121.5, 122.6, 123.0,
123.3, 123.9, 127.1, 127.2, 129.1, 134.8, 137.3, 138.8,
216.7, 224.7, 4carbene carbon not observed). IR 4thin
®lm): 3100, 3010, 2058, 1930, 1849, 1462, 1387, 1329,
1

C. A. Merlic et al. / Tetrahedron 57 *2001) 5199±5212
5209
115.2, 115.9, 119.6, 120.3, 120.5, 120.6, 120.8, 120.9,
121.3, 121.9, 122.1, 122.5, 122.6, 123.2, 123.4, 123.9,
124.0, 124.1, 125.7, 126.0, 126.8, 127.89, 128.0, 129.8,
132.4, 134.2, 136.3, 136.9, 137.4, 137.6, 149.0, 149.5,
163.3, 164.2, 215.3, 224.2, 351.6. IR4thin ®lm): 3056,
2976, 2930, 2062, 1935, 1738, 1698, 1451, 1346, 1254,
1148, 1082, 1017, 916, 841, 748, 646 cm21. MS 4FAB):
610.2 4M1, 4), 526.1 447), 470.1 477), 418.1 451). Mass
calcd for C27H26N2O6Cr 4loss of 3 COs): 526.1207; found:
526.1196.
3393, 3054, 2930, 2855, 1499, 1468, 1454, 1239, 1429,
1344, 1321, 1248, 1146, 908, 735 cm21. MS 4EI): 356.2
4M1, 100), 341.1 425), 315.1 478), 300.1 458), 271.1 422),
244.1 422). Mass calcd for C23H20N2O2: 356.1525; found:
356.1532.
3.5.3. 12-Allyl-6-hydroxy-5-methoxy-11-methoxymethyl-
11,12-dihydroindolo[2,3-a]carbazole 013e). Following
the general procedure for benzannulation via photolysis,
[41-allyl-2-410-methoxymethyl-indol-20-yl)indol-3-yl)methoxy
methylene]pentacarbonylchromium 482 mg, 0.152 mmol,
impure) was used to yield 59.6 mg 463%) of 12-allyl-6-
hydroxy-5-methoxy-11-methoxymethyl-11,12-dihydroin-
dolo-[2,3-a]carbazole 413e) as a pale yellow solid after
chromatography 480:20 hexane/EtOAc).
3.5. General procedure for benzannulation via
photolysis 013)
3.5.1. 6-Hydroxyl-5-methoxy-11,12-dimethyl-11,12-dihy-
droindolo[2,3-a]carbazole 013a). [41-Methyl-2-410-methyl-
indol-20-yl)indol-3-yl)methoxymethylene]pentacarbonylchro-
mium 438 mg, 0.077 mmol) was dissolved in toluene 43 mL)
and placed in a pyrex pressure tube. The pressure tube was
purged with Ar by evacuating it and then ®lling it with Ar
42£). The pressure tube was then evacuated and ®lled with
20 psi of CO 42£). Photolysis proceeded using a medium
pressure mercury lamp, UV 450W immersion type from
Ace Glass, which was surrounded by a quartz cooling tube.
After 3 h, the reaction was complete as evidenced by disap-
pearance of the bright-red color of the carbene. The crude
product was plated onto diatomaceous earth and was puri®ed
by ¯ash chromatography 475:25 hexane/EtOAc) to yield
13 mg 451%) of 6-hydroxyl-5-methoxy-11,12-dimethyl-
11,12-dihydroindolo[2,3-a]carbazole 413a) as a white solid.
1H NMR 4400 MHz, DMSO-d6) d: 3.38 43H, s), 3.9643H,
s), 5.13 42H, s 4broad)), 5.1641H, d, Jˆ16.4 Hz), 5.25 41H,
d, Jˆ10.3 Hz), 5.63 42H, s 4broad)), 6.01 41H, s), 6.12 41H,
m), 7.24±7.31 42H, m), 7.39±7.7.47 43H, m), 7.62 41H, d,
Jˆ7.8 Hz), 8.2641H, d, Jˆ7.6Hz), 8.42 41H, d, Jˆ7.6Hz).
13C NMR 4100 MHz, DMSO-d6) d: 48.4, 55.4, 60.4, 77.4,
110.7, 111.2, 114.2, 116.1, 117.4, 120.0, 120.6, 121.7,
122.4, 122.6, 122.9, 124.4, 124.5, 125.0, 125.2, 134.7,
135.8, 139.0, 142.3, 143.2. IR 4KBr plate): 3409, 3056,
2994, 2926, 1499, 1453, 1431, 1391, 1323, 1250, 1215,
1180, 1144, 1103, 1061, 1026, 1001, 988, 945, 928,
743 cm21. MS 4EI): 386.2 4M1, 100), 341.1 428), 326.1
416), 311.1 419). Mass calcd for C24H22N2O3: 386.1630;
found: 386.1637.
1H NMR 4360 MHz, DMSO-d6) d: 3.93 43H, s), 4.14 43H,
s), 4.1643H, s), 7.21±7.27 42H, m), 7.42±7.48 42H, m),
7.59±7.63 42H, m), 8.22 41H, d, Jˆ7.74 Hz), 8.37 41H, d,
Jˆ7.68 Hz), 9.37 41H, s). 13C NMR 490 MHz, DMSO-d6) d:
36.5, 36.8, 60.9, 110.3, 110.8, 113.8, 116.8, 119.8, 119.9,
121.97, 122.6, 122.7, 123.3, 124.0, 125.0, 125.4, 126.3,
135.2, 139.1, 143.0, 143.5. IR 4KBr): 3500±3100 4br),
3050, 3020, 2980, 2940, 1600, 1504, 1458, 1421, 1363,
3.5.4. 12-tert-Butoxycarbonyl-6-hydroxy-5-methoxy-11-
methoxymethyl-11,12-dihydroindolo [2,3-a]carbazole 013f).
Following the general procedure for benzannulation via
photolysis, [41-tert-butoxycarbonyl-2-410-methoxymethyl-
indol-20-yl)indol-3-yl)methoxymethylene]pentacarbonyl-
chromium 40.042 g, 0.0702 mmol) was used to yield 22 mg
471%) of 12-tert-butoxycarbonyl-6-hydroxy-5-methoxy-11-
methoxymethyl-11,12-dihydroindolo[2,3-a]carbazole 413f)
as a yellow oil after chromatography 490:10 hexane/
EtOAc).
1321, 1261, 1155, 1095, 989, 922, 790, 741, 640 cm21
.
MS 4EI): 330.1 4M1, 85), 315.1 4100), 287.1 46), 244.1
45), 165.1 47), 143.6 46). Mass calcd for C21H18N2O2:
330.1368; found: 330.1371.
1H NMR 4400 MHz, DMSO-d6) d: 1.62 49H, s), 2.68 43H,
s), 3.94 43H, s), 5.75 42H, s), 7.25±7.32 41H, m), 7.42±7.55
43H, m), 7.75 41H, d, Jˆ8.09 Hz), 8.10 41H, d,Jˆ8.24 Hz),
8.21 41H, d, Jˆ7.69 Hz), 8.34 41H, d, Jˆ7.61 Hz), 9.91 41H,
s). 13C NMR 4100 MHz, DMSO-d6) d: 25.4, 27.9, 56.0,
61.1, 84.7, 111.5, 115.2, 116.3, 118.2, 120.0, 120.8, 122.2,
122.8, 124.4, 125.6, 126.1, 127.0, 128.5, 129.2, 135.7,
140.1, 141.9, 142.9, 152.0. IR 4thin ®lm): 3357, 2926,
1732, 1651, 1504, 1454, 1372, 1260, 1150, 1022, 909,
750 cm21. MS 4FAB): 446.2 4M1, 86), 415.2 419), 359.0
4100), 345.1 448). Mass calcd for C26H26N2O5: 446.1835;
found: 446.1841.
3.5.2. 12-Allyl-6-hydroxy-5-methoxy-11-methyl-11,12-
dihydroindolo-[2,3-a]carbazole 013b). Following the
general procedure for benzannulation via photolysis, [41-
allyl-2-410-methylindol-20-yl)indol-3-yl)methoxymethylene]-
pentacarbonylchromium 486.6 mg, 0.170 mmol, impure,)
was used to yield 35.2 mg 458%) of 12-allyl-6-hydroxy-5-
methoxy-11-methyl-11,12-dihydroindolo-[2,3-a]carbazole
413b) as a yellow solid after chromatography 485:15 hexane/
EtOAc).
1H NMR 4360 MHz, CDCl3) d: 4.03 43H, s), 4.12 43H, s),
4.99 42H, m), 5.44 41H, dd, Jˆ10.6, 1.3 Hz), 5.49 41H, dd,
Jˆ17.2, 1.3 Hz), 6.15 41H, s), 6.20 41H, ddt, Jˆ17.2, 10.6,
3.8 Hz), 7.33±7.38 42H, m), 7.42 41H, d, Jˆ8.0 Hz), 7.48±
7.7.52 43H, m), 8.33 41H, d, Jˆ7.8 Hz), 8.50 41H, d,
Jˆ7.8 Hz). 13C NMR 4100 MHz, CDCl3) d: 34.8, 50.3,
60.1, 108.4, 110.2, 111.8, 115.7, 116.1, 118.9, 119.3,
120.9, 121.6, 122.5, 122.8, 122.9, 123.8, 124.1, 125.9,
132.8, 133.2, 137.4, 142.5, 143.0. IR 4thin ®lm): 3532,
3.6. General procedure for thermal benzannulation 014)
3.6.1. 6-tert-Butylamino-5-methoxy-11,12-dimethyl-11,12-
dihydroindolo[2,3-a]carbazole 014a). t-Butyl isonitrile
40.021 mL, 0.186mmol) was added to a solution of [41-
methyl-2-410-methylindol-20-yl)indol-3-yl)methoxymethyl-
ene]pentacarbonylchromium 446mg, 0.093 mmol) in
toluene 43 mL) at 08C. After 1 h at 08C, the carbene was

5210
C. A. Merlic et al. / Tetrahedron 57 *2001) 5199±5212
completely reacted as evidenced by TLC. The reaction
mixture was then re¯uxed 5 h. The crude reaction mixture
was then plated onto diatomaceous earth and puri®ed by
¯ash chromatography 490:10 hexane/EtOAc) yielding
32 mg 489%) of 6-tert-butylamino-5-methoxy-11,12-
dimethyl-11,12-dihydroindolo[2,3-a]carbazole 414a) as a
yellow solid.
127.3, 127.4, 128.4, 129.3, 129.4, 136.6, 145.9, 146.0,
148.7. IR 4KBr plate): 3600±3200 4broad), 2963, 1491,
1449, 1420, 1389, 1364, 1342, 1325, 1271, 1198, 1146,
1105, 1074, 1005, 745 cm21. MS 4FAB): 441.2 4M1,
100), 384 411). Mass calcd for C28H31N3O2: 441.2416;
found: 441.2417.
3.6.4. 12-tert-Butoxycarbonyl-6-tert-butylamino-5-meth-
oxy-11-methoxymethyl-11,12-dihydroindole[2,3-a]car-
bazole 014f). Following the general procedure for thermal
benzannulation, [41-tert-butoxycarbonyl-2-410-methoxy-
methylindol-20-yl)indol-3-yl)methoxymethylene]pentacar-
bonylchromium 40.042 g, 0.070 mmol) was used to yield
24 mg 468%) of 12-tert-butoxycarbonyl-6-tert-butylamino-
5-methoxy-11-methoxymethyl-11,12-dihydroindole[2,3-a]
carbazole 414f) as a white solid after chromatography 495:5
hexane/EtOAc).
1H NMR 4360 MHz, CDCl3) d: 1.32 49H, s), 4.01 43H, s),
4.13 43H, s), 4.1643H, s), 7.26±7.3643H, m), 7.46±7.54 44H,
m), 8.35 41H, d, Jˆ7.80 Hz), 8.77 41H, d, Jˆ7.87 Hz). 13C
NMR 490 MHz, CDCl3) d: 29.9 43C), 30.7, 36.3, 36.5, 60.5,
109.7, 109.8 42C), 116.8, 119.2, 120.1, 122.3 42C), 123.1
42C), 123.3, 124.7, 124.9 42C), 126.9, 143.9, 144.2, 145.5.
IR 4thin ®lm): 2960 4broad), 1453, 1318, 1153, 1091,
744 cm21. MS: 385.2 4M1, 100), 370.2 48), 328.1 462),
314.1 470), 300.1 420), 384.1 417), 270.1 47). Mass calcd
for C25H27N3O: 385.2151; found: 385.2150.
1H NMR 4500 MHz, CDCl3) d: 1.38 49H, s), 1.74 49H, s),
2.72 43H, s), 3.50 41H, s 4broad)), 4.02 43H, s), 5.83 42H, s),
7.42±7.53 44H, m), 7.62 41H, d, Jˆ8.1 Hz), 8.19 41H, d,
Jˆ8.0 Hz), 8.35 41H, d, Jˆ7.5 Hz), 8.71 41H, d, Jˆ7.8 Hz).
13C NMR 4125 MHz, CDCl3) d: 28.1, 30.0, 30.7, 55.8, 56.6,
60.2, 84.2, 111.3, 116.2, 119.8, 120.2, 122.2, 122.4, 122.9,
123.4, 123.8, 125.0, 125.6, 126.0, 126.6, 128.7, 131.5,
140.2, 141.7, 145.2, 151.9. IR 4thin ®lm): 3054, 2978,
2824, 1728, 1450, 1369, 1294, 1246, 1152, 1084, 910,
733, 655 cm21. MS 4FAB): 501.2 4M1, 95), 414.1 455),
356.1 484), 329.9 4100). Mass calcd for C30H35N3O4:
501.2633; found: 501.2628.
3.6.2. 12-Allyl-6-tert-butylamino-5-methoxy-11-methyl-
11,12-dihydro-indolo[2,3-a]carbazole 014b). Following
the general procedure for thermal benzannulation, [41-
allyl-2-410-methylindol-20-yl)indol-3-yl)methoxymethylene]
pentacarbonylchromium 4128 mg, 0.246mmol, impure)
was used to yield 60 mg 458%) of 12-allyl-6-tert-butyl-
amino-5-methoxy-11-methyl-11,12-dihydro-indolo[2,3-a]-
carbazole 414b) as a white solid after chromatography
490:10 hexane/EtOAc).
1H NMR 4400 MHz, C6D6) d: 1.50 49H, s), 3.44 43H, s),
3.52 41H, s 4broad)), 3.85 43H, s), 4.44 42H, m), 5.12 41H,
dd, Jˆ10.6, 1.4 Hz), 5.27 41H, dd, Jˆ17.3, 1.4 Hz), 5.70
41H, ddt, Jˆ17.3, 10.6, 4.5 Hz), 7.28 41H, d, Jˆ8.1 Hz),
7.43±7.5645H, m), 8.69 41H, d, Jˆ7.6Hz), 9.2641H, d,
Jˆ7.8 Hz). 13C NMR 4100 MHz, CD2Cl2) d: 29.9, 36.1,
51.6, 56.4, 60.4, 110.0, 111.3, 117.0, 117.4, 119.1, 120.5,
122.3, 122.5, 123.2, 124.1, 124.8, 125.0, 125.5, 127.0,
127.3, 127.3, 134.1, 144.1, 144.3, 145.7. IR 4KBr plate):
3081, 3059, 2977, 1474, 1451, 1418, 1364, 1323, 1273,
1223, 1148, 1098, 1009, 999, 932, 823, 747 cm21. MS
4FAB): 411.2 4M1, 100), 370.2 411), 354.2 451), 340.1
425), 314.1 482), 299.1 429), 284.1 427), 270.1 415). Mass
calcd for C27H29N3O: 411.2304; found: 411.2311.
Acknowledgements
We thank the National Institutes of Health 4GM46509)
for ®nancial support. M. M. M. is a recipient of a Novartis
Pharmaceutical Fellowship 42000).
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