Preparation of novel unsymmetrical bisindoles under solvent-free conditions: Synthesis, crystal structures, and mechanistic aspects

Article abstract of DOI:10.1021/jo7016026

(Chemical Equation Presented) Indole aziridines and their hydroxyl derivatives have been used for the preparation of a small library of novel functionalized bisindoles. Diversification of these building blocks by solvent-free C-C-bond formation on solid s

Full text of DOI:10.1021/jo7016026

Preparation of Novel Unsymmetrical Bisindoles under Solvent-Free
Conditions: Synthesis, Crystal Structures, and Mechanistic Aspects
Hanns Martin Kaiser,†,‡ Ivo Zenz,† Wei Fun Lo,† Anke Spannenberg,† Kristin Schro¨der,†
Haijun Jiao,† Dirk Go¨rdes,‡ Matthias Beller,†,‡ and Man Kin Tse*,†,‡
Leibniz-Institut fu¨r Katalyse e.V. an der UniVersita¨t Rostock, Albert-Einstein-Strsse 29a, D-18059 Rostock,
Germany, and UniVersita¨t Rostock, Center for Life Science Automation (CELISCA),
Friedrich-Barnewitz-Strasse 8, D-18119 Rostock-Warnemu¨nde, Germany
man-kin.tse@catalysis.de
ReceiVed July 27, 2007
Indole aziridines and their hydroxyl derivatives have been used for the preparation of a small library of
novel functionalized bisindoles. Diversification of these building blocks by solvent-free C-C-bond
formation on solid support yielded annulated Hymenialdisine analogues under mild reaction conditions.
Indoles as C-nucleophiles form potentially pharmacologically active bisindoles through an electrophilic
aromatic substitution pathway in good to excellent yields. Further transformations of the indole aziridines
with H-, N-, and O-nucleophiles demonstrate their versatility as key intermediates in diversity oriented
synthesis. The hydroxyl precursor leads also to unsymmetrical bisindoles under similar reaction conditions.
Important intermediates and final library compounds were confirmed by X-ray analysis. Theoretical studies
on these systems show the possible cationic intermediate in the substitution pathway.
Introduction
preparation of diversified compound libraries. Thus, during the
last decades significant attention has been paid to the racemic
and stereoselective preparation of these nitrogen-containing
three-membered-ring systems.5 N-Arylsulfonylaziridines are
especially important since they react smoothly with C-,6 O-,7
S-,8 N-,9 halogen-,10 and hydrogen-nucleophiles11 in the presence
of Brønstedt bases, Brønstedt acids, or Lewis acids.12
Aziridines are versatile and highly valuable intermediates in
organic synthesis.1 In addition, natural products containing an
aziridine moiety are known; some of them like Mitomycin A
and B exhibit interesting biological activity.2 Probably most
importantly, aziridines serve as building blocks in drug research,
such as in the development of neuramidase inhibitors3 and
calcium sensing receptor ligands,4 and allow a straightforward
(4) Kessler, A.; Faure, H.; Petrel, C.; Rognan, D.; Ce´sario, M.; Ruat,
M.; Dauban, P.; Dodd, R. H. J. Med. Chem. 2006, 49, 5119-5128.
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Tanner, D. Angew. Chem., Int. Ed. 1994, 33, 599-619. (c) Osborn, H. M.
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Church, N. J.; Young, D. W. Org. Biomol. Chem. 2006, 4, 2888-2897. (b)
Pineschi, M.; Bertolini, F.; Crotti, P.; Macchia, F. Org. Lett. 2006, 8, 2627-
2630. (c) Pattenden, L. C.; Wybrow, R. A. J.; Smith, S. A.; Harrity, J. P.
A. Org. Lett. 2006, 8, 3089-3091. (d) Minakata, S.; Hotta, T.; Oderaotoshi,
Y.; Komatsu, M. J. Org. Chem. 2006, 71, 7471-7472.
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Eur. J. Org. Chem. 2006, 4787-4790. (b) Das, B.; Reddy, V. S.; Tehseen,
F. Tetrahedron Lett. 2006, 47, 6865-6868. (c) Xichun, F.; Guofu, Q.;
Shucai, L.; Hanbing, T.; Lamei, W.; Xianming, H. Tetrahedron: Asymmetry
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† Leibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock.
‡ Universita¨t Rostock, Center for Life Science Automation (CELISCA).
(1) Aziridines and Epoxides in Organic Synthesis; Yudin, A., Ed.; Wiley-
VCH: Weinheim, Germany, 2006.
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Discovery, Biological Acitvity and Biosynthesis. In Aziridines and Epoxides
in Organic Synthesis; Yudin, A., Ed.; Wiley-VCH: Weinheim, Germany,
2006; pp 399-442.
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Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C.
Y.; Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681-690.
(b) Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H.; Zhang, L.; Chen, X.;
Escarpe, P. A.; Mendel, D. B.; Laver, W. G.; Stevens, R. C. J. Med. Chem.
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10.1021/jo7016026 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/10/2007
J. Org. Chem. 2007, 72, 8847-8858
8847

Kaiser et al.
In general, aziridines are prepared either via traditional
cyclization reactions of 1,2-aminoalcohols, 1,2-aminohalides,
or 1,2-azidoalcohols or via catalytic carbene- or nitrene-transfer
methods to double bonds (CdN or CdC). Unfortunately, most
catalytic aziridinations of olefins require a large excess of olefin,
and need metal catalysts based on copper, rhodium, ruthenium,
iron, cobalt, manganese, silver, or gold.13 Also, electrochemical
nitrene transfer methods were introduced.14 Notably, these
protocols were transferred to easily manageable protocols with
phenyliodo(III) diacetate as an oxidant later on.15 In addition,
Sharpless and co-workers introduced the bromine-catalyzed
aziridination procedure that does not necessarily require an
excess of alkene.16
FIGURE 1. Structures of Staurosporine (1), Hymenialdisine (HMD)
(2), and HMD analogues 3.
On the basis of our experience with the application of catalytic
reactions for the synthesis of new pharmacologically interesting
compounds22 and our background in catalytic oxidation meth-
ods,23 we have been interested in the synthesis of potentially
bioactive bisindoles as kinase inhibitors employing catalytic
aziridination and epoxidation for diversity oriented synthesis24
on complex organic natural product analogues. The prior work
of Gray and co-workers20c showed that the kinase inhibiting
activities of annulated HMDs (3) vary a great deal, if other
heterocycles instead of imidazole are introduced. Therefore we
focused on the introduction of different indoles onto the structure
of annulated HMDs (3) to form new unsymmetrical bisindoles.
Here, we report the detailed studies of a solvent-free, efficient,
and easy to handle diversification strategy for annulated HMD-
type bisindoles via C-C bond formation reaction on activated
silica under mild reaction conditions, in which aziridines and
hydroxyl compounds were used as the starting materials.
Kinase inhibitors are involved in fundamental regulatory
cellular functions such as gene expression, cellular proliferation,
differentiation, membrane transport, and apoptosis.17 As one of
the first kinase inhibitors, the bisindole Staurosporine (1) was
found to be active in nanomolar concentration in the 1980s.18
Besides, some other small molecules also act as kinase inhibitors
as well.19 Among them natural products like Hymenialdisine
(HMD) (2) and its annulated derivatives 3 showed very
promising kinase inhibiting properties20 and prevent the produc-
tion of cytokines (Figure 1).21
(8) For recent publications in this area see: (a) Krishnaveni, N. S.;
Surendra, K.; Rao, K. R. AdV. Synth. Catal. 2006, 348, 696-700. (b) Wu,
J.; Sun, X.; Sun, W. Org. Biomol. Chem. 2006, 4, 4231-4235. (c) Kamal,
A.; Reddy, D. R.; Rajendar Tetrahedron Lett. 2006, 47, 2261-2264. (d)
Wu, J.; Sun, X.; Li, Y. Eur. J. Org. Chem. 2005, 4271-4275.
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Petrel, C.; Rognan, D.; Ce´sario, M.; Ruat, M.; Dauban, P.; Dodd, R. H. J.
Med. Chem. 2006, 49, 5119-5128. (b) Markov, V. I.; Polyakov, E. V.
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Crousse, B.; Bonnet-Delpon, D. Tetrahedron Lett. 2006, 47, 2065-2068.
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X.; Hou, X.-L. Synlett 2004, 2218-2220. (b) Ghorai, M. K.; Das, K.;
Kumar, A.; Ghosh, K. Tetrahedron Lett. 2005, 46, 4103-4106. (c) Das,
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4460. (d) Hanessian, S.; Del Valle, J. R.; Xue, Y.; Blomberg, N. J. Am.
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Results and Discussion
Several strategies for the synthesis of the pyrrolo[2,3-c]-
azepine motif of HMD and the annulated derivatives have been
published. The first total synthesis of HMD (2) was developed
by Annoura.25 Later Horne introduced another synthetic path-
way26 and Papeo developed a new total synthesis recently.27
(22) (a) Kaiser, H. M.; Lo, W. F.; Riahi, A. M.; Spannenberg, A.; Beller,
M.; Tse, M. K. Org. Lett. 2006, 8, 5761-5764. (b) Kumar, K.; Michalik,
D.; Castro, I. G.; Tillack, A.; Zapf, A.; Arlt, M.; Heinrich, T.; Bo¨ttcher,
H.; Beller, M. Chem. Eur. J. 2004, 10, 746-757. (c) Michalik, D.; Kumar,
K.; Zapf, A.; Tillack, A.; Arlt, M.; Heinrich, T.; Beller, M. Tetrahedron
Lett. 2004, 45, 2057-2061. (d) Tewari, A.; Hein, M.; Zapf, A.; Beller, M.
Tetrahedron Lett. 2004, 45, 7703-7707. (e) Khedkar, V.; Tillack, A.;
Michalik, M.; Beller, M. Tetrahedron 2005, 61, 7622-7631. (f) Neumann,
H.; Stru¨bing, D.; Lalk, M.; Klaus, S.; Hu¨bner, S.; Spannenberg, A.;
Lindequist, U.; Beller, M. Org. Biomol. Chem. 2006, 4, 1365-1375. (g)
Schwarz, N.; Tillack, A.; Alex, K.; Sayyed, I. A.; Jackstell, R.; Beller, M.
Tetrahedron Lett. 2007, 48, 2897-2900.
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Beller, M., Bolm, C., Eds.; Wiley-VCW: Weinheim, Germany, 2004; Vol.
2, pp 389-402. (b) For recent developments with Au and Ag, see: Li, Z.;
Ding, X.; He, C. J. Org. Chem. 2006, 71, 5876-5880. Cui, Y.; He, C. J.
Am. Chem. Soc. 2003, 125, 16202-16203.
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Bitterlich, B.; Anilkumar, G.; Tse, M. K.; Beller, M. Angew. Chem., Int.
Ed. 2007, 46, 7293-7296. (b) Bitterlich, B.; Anilkumar, G.; Gelalcha, F.
G.; Spilker, B.; Grotevendt, A.; Jackstell, R.; Tse, M. K.; Beller, M. Chem.
Asian J. 2007, 2, 521-529. (c) Anilkumar, G.; Bitterlich, B.; Gelalcha, F.
G.; Tse, M. K.; Beller, M. Chem. Commun. 2007, 289-291. (d) Tse, M.
K.; Bhor, S.; Klawonn, M.; Anilkumar, G.; Jiao, H.; Do¨bler, C.; Spannen-
berg, A.; Ma¨gerlein, W.; Hugl, H.; Beller, M. Chem. Eur. J. 2006, 12, 1855-
1874. (e) Tse, M. K.; Bhor, S.; Klawonn, M.; Anilkumar, G.; Jiao, H.;
Spannenberg, A.; Do¨bler, C.; Ma¨gerlein, W.; Hugl, H.; Beller, M. Chem.
Eur. J. 2006, 12, 1875-1888. (f) Tse, M. K.; Klawonn, M.; Bhor, S.; Do¨bler,
C.; Anilkumar, G.; Hugl, H.; Ma¨gerlein, W.; Beller, M. Org. Lett. 2005, 7,
987-990. (g) Tse, M. K.; Do¨bler, C.; Bhor, S.; Klawonn, M.; Ma¨gerlein,
W.; Hugl, H.; Beller, M. Angew. Chem., Int. Ed. 2004, 43, 5255-5260.
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K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell,
H. J. J. Am. Chem. Soc. 2000, 122, 9939-9953.
(15) Krasnova, L. B.; Hili, R. M.; Chernoloz, O. V.; Yudin, A. K.
ARKIVOC 2005, 4, 26-38.
(16) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1998, 120, 6844-6845.
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8848 J. Org. Chem., Vol. 72, No. 23, 2007

Preparation of NoVel Unsymmetrical Bisindoles
TABLE 1. Copper-Catalyzed Aziridination of 7 to Aziridine
SCHEME 1. Synthesis of Alcohol (()-6 and Olefin 7
(()-8ca
molar ratio
of 7:9:10
conv
[%]
yieldb
[%]
entry
catalyst
1
2
3
4
5
1:0.8:0.8
1:0.8:0.8
1:0.8:0.8
1:1.5:1.5
1:0.8:0.8
5 mol % of Cu(OTf)2
5 mol % of Fe(acac)3
5 mol % of Cu(tfac)2
5 mol % of Cu(tfac)2
10 mol % of Cu(tfac)2
45
23
55
50
51
27
0
70
62
69
a Reaction conditions: olefin 7 (100 mg, 0.25 mmol), appropriate
amounts of 9, 10, catalyst, 4 Å MS (500 mg), anhydrous CH3CN (2 mL),
Ar, 13 h. b Isolated yield based on recycled precursor 7.
Annulated HMD derivatives (3) were usually prepared via the
ketone 5 intermediate or the corresponding alcohol (()-6 and
subsequent attachment of the imidazole heterocycle.20c Azepino-
indole 5 is usually synthesized via intramolecular cyclization
reactions with MsOH/P2O5.28 In addition, protocols employing
ring-closure metathesis29 and polyphosphoric acid30 were in-
troduced.
Starting from indole-2-carboxylic acid (4) amide-bound
formation with â-alanin ethyl ester in the presence of dicyclo-
hexylcarbodiimine (DCC), triethylamine, and 4-hydroxybenzo-
triazole (BTA), subsequent ester cleavage and cyclization with
phosphorus(V) oxide in methansulfonic acid yielded azepino-
indole 5 (60%). Subsequent reduction of the keto-group with
sodium borohydride in ethanol gave (()-6 in excellent yield
(99%). The ease of isolation of (()-6 is strongly dependent on
the purity of the azepino-indole 5. Compound 5 has very low
solubility in common organic solvents and can be purified by
treatment with activated charcoal in hot acetone and subsequent
recrystallization from a concentrated acetone solution. Olefin
7 was obtained by a one-pot elimination-protection procedure
from (()-6 (Scheme 1).20c Introduction of two boc-protecting
groups was crucial to provide a more stable and storable alkene
from these acidic reaction conditions.
Next, we focused on the oxidation of olefin 7 to aziridines
(()-8a-c. As stated above, most catalytic aziridination meth-
odologies generally require an excess of olefin. As a key
building block for subsequent chemical diversification, it was
crucial to introduce applicable and high-yielding aziridination
methods. In this respect, we utilized the bromine-catalyzed
aziridination protocol developed by Sharpless and co-workers,16
because this method, in principle, does not require an excess
of olefin. In contrast to conditions reported in the literature,
we obtained our best results ((()-8a: 78%) with an under-
stoichiometric amount of the nitrogen source (chloramine-T)
in the presence of only 5 mol % of phenyltrimethylammonium
tribromide (PTAB) and 2 equiv of alkene 7 (eq 1).
Employing these reaction conditions, we were able to reduce
the degree of reaction side products such as the brominated
olefin and the ring-opening product of the product aziridine with
the amide salt.31 Applying the same procedure to compound 7
with chloramine-B, aziridine (()-8b was obtained in a reason-
able (54%) yield.
Next, we planned to introduce a heterocyclic sulfonyl group
to the aziridine motif. Once again the major drawback of most
of the synthetic methods was the large excess of olefin
required.32 Optimization of the reaction conditions of the copper-
catalyzed aziridination method introduced by Chang and co-
workers33 showed that a large excess of olefin 7 was not neces-
sary to obtain the desired product (()-8c in high yield (70%)
(Table 1). The best result with respect to conversion and yield
was obtained employing 5-10 mol % of copper(II) trifluoro-
acetylacetonate [Cu(tfac)2] with a slight excess of olefin 7 (Table
1, entries 3 and 5). Unfortunately further attempts to introduce
the 2-nitrobenezenesulfonyl group onto the aziridine via a gold-
catalyzed procedure gave only a trace amount of the product.13b
We were delighted to be able to apply all of these methods
for the preparation of aziridines (()-8a-c in multigram-scale.
With three different aziridines in hand, we looked for suitable
conditions to affect the nucleophilic ring-opening reaction of
(26) (a) Xu, Y.-Z.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1997,
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Chem. 2000, 65, 610-611.
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Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328-5329. (b) Evans, D.
A.; Faul, M. M.; Bilodeau, M. T. J. Org. Chem. 1991, 56, 6744-6746. (c)
Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116,
2742-2753.
(28) Cho, H.; Matsuki, S. Heterocycles 1996, 43, 127-131.
(29) Chacun-Lefe`vre, L.; Be´ne´teau, V.; Joseph, B.; Me´rour, J.-Y.
Tetrahedron 2002, 58, 10181-10188.
(30) Suzuki, H.; Shinpo, K.; Yamazaki, T.; Niwa, S.; Yokoyama, Y.;
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2004, 6, 4109-4112.
J. Org. Chem, Vol. 72, No. 23, 2007 8849

Kaiser et al.
TABLE 2. Variation of Solid Support, Temperature, and Amount
of C-Nucleophile in the Ring-Opening Reaction of Aziridine (()-8a
with Indolea
TABLE 3. Ring-Opening Reactions of (()-8a with Various
Indolesa
temp
[°C]
ratio of
indole:(()-8a
yieldb
[%]
entry
solid support
1
2
3
4
5
6
7
activated silica
activated silica
activated silica
activated silica
activated silica
montmorillonite K-10
alumina (neutral)
rt
10:1
10:1
10:1
3:1
1:1
10:1
10:1
0 (34)c
75
93
81
40
40
70
70
70
70
70
70
21
a Reaction conditions: aziridine (()-8a (113 mg, 0.2 mmol), indole (234
mg, 2.00 mmol), 429 mg of solid support, Ar, 16 h. b Isolated yield of
product (()-11a. c Isolated yield of product (()-12.
these aziridines. Therefore, key intermediate (()-8a was allowed
to react with indole as C-nucleophile in the presence of different
acidic solid supports such as silica,34,6d alumina, and clay
(Montmorillonite K-10).35 Moreover, the reaction temperature
and the ratio of indole to (()-8a were varied (Table 2).
The results demonstrate that a high molar ratio of indole at
a moderate temperature of 70 °C (Table 2, entry 3) gave the
desired bisindole (()-11a in excellent yield (93%). In principle,
only a slight excess of indole is consumed and it can be recycled.
Since indole sublimes during the reaction, 10 equiv of indole
is used to ensure efficient conversion of the aziridine to our
product. All arylations proceeded with excellent regioselectivity
at the benzylic position of (()-8a and at the 3-position of the
attached indole. The best conditions were then tested with other
solid supports such as clay (Montmorillonite K-10) (Table 2,
entry 6) and alumina (Table 2, entry 7). These solid supports
exhibit significant disadvantages such as side product formation
or lower yields. For example, employing clay as the solid
support we observed both possible ring-opening products of the
aziridine by 1H NMR. In the case of neutral alumina the desired
1
product (()-11a was formed in lower yield. The H NMR
spectrum of the reaction mixture indicated also that deprotection
of both boc-groups under the employed reaction conditions on
clay or alumina was not complete. In contrast, the protecting
boc-groups could be easily removed under the reaction condi-
tions on activated silica. The isolation of the N,N-di-boc-
protected ring-opening product (()-12 in low yields at room
temperature (Table 2, entry 1) provides direct evidence that the
ring-opening reaction proceeds significantly faster than the
deprotection of the boc-protecting groups under mild conditions.
Moreover, the deprotection of the nitrogen atoms does not seem
to be required for the activation of the indole for the ring-
opening reaction. In a few attempts (Table 2, entries 1, 2, and
a Reaction conditions: aziridine (()-8a (113 mg, 0.20 mmol), indole
derivative (2.00 mmol), activated silica (0.040-0.063 mm, 429 mg),
70 °C, Ar, overnight. b Isolated yield.
(34) Hudlicky, T.; Rinner, U.; Finn, K. J.; Ghiviriga, I. J. Org. Chem.
2005, 70, 3490-3499.
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7), the ring-opening products with only one protecting group
were also observed (1H NMR) on the lactam moiety.
8850 J. Org. Chem., Vol. 72, No. 23, 2007

Preparation of NoVel Unsymmetrical Bisindoles
TABLE 4. Ring-Opening Reactions of (()-8b with Various
TABLE 5. Ring-Opening Reactions of (()-8c with Various
Indolesa
Indolesa
a Reaction conditions: aziridine (()-8b (111 mg, 0.20 mmol), indole
derivative (2.00 mmol), activated silica (0.040-0.063 mm, 429 mg),
70 °C, Ar, overnight. b Isolated yield.
a Reaction conditions: aziridine (()-8b (114 mg, 0.20 mmol), indole
derivative (2.00 mmol), activated silica (0.040-0.063 mm, 429 mg),
70 °C, Ar, overnight. b Isolated yield.
Next, we adopted the optimized protocol to the prepara-
tion of unsymmetrical bisindoles starting from aziridines (()-
8a-c. All reactions ran overnight at 70 °C and yielded the trans-
ring-opening product (see the crystal structure of (()-11f) in
good to excellent yields (Table 3).
the same reaction conditions, compounds (()-13a-h (36-83%)
and (()-14a-i (47-92%) were obtained in moderate to good
yield.
Functional groups on the indole ring such as halides and
alkoxy and ester groups were tolerated under these mild reaction
conditions. However, under similar conditions the ring-opening
product with 5-nitro-indole was only obtained in poor (<20%)
yields. Using 5,6-dimethylindole we obtained an inseparable
70:30 mixture of two different regioisomers likely caused by
the electron-rich aromatic system of the substrate. The reaction
of (()-8a with indole (Table 3, entry 1) also can be performed
on gram-scale and provided the desired product in excellent
yield (95%). Employing the precursors (()-8b and (()-8c under
To determine the structural influence of the aryl-sulfonamide
side chain in biological screenings, we also decided to prepare
the analogues (()-15a-l. For this purpose we tested the
hydroxyl-precursor (()-6 under similar reaction conditions.
Fortunately the desired bisindoles (()-15a-l were obtained in
moderate to good yields (Table 6). Direct benzylations with
alcoholic precursors were of significant interest for the prepara-
tion of diarylmethanes.36 Usually Lewis acid catalyst in
homogeneous solution is required for this reaction.37 To the best
of our knowledge this is the first direct benzylation of indoles
J. Org. Chem, Vol. 72, No. 23, 2007 8851

Kaiser et al.
TABLE 6. Formation of Bisindoles (()-15a-l from Alcohol (()-6a
To demonstrate the versatility of the aziridines for further
diversification reactions, we examined aziridine (()-8a in
ring-opening reactions with H-, O-, and N-nucleophiles. First
(()-16a was prepared by reductive ring-opening reaction with
ammonium formate in the presence of palladium on charcoal.38
After deprotection with TFA, (()-16b was obtained in excel-
lent yield (73%, over two steps). This product can give
direct comparison information for the structural influence of
the indole group in products (()-11a-n. Direct deprotection
of crude (()-16a with TFA in CH2Cl2 gave (()-16b in sim-
ilar yield (68%) (Scheme 2).39 It should be noted that this
two-step aziridination-hydrogenation sequence offers a straight-
forward approach to novel sulfonylated tryptamine deriva-
tives, which may be of interest in various pharmaceutical
applications.
Next, we turned our interests to other nucleophiles such as
alcohols or amines. Initial experiments designed to react
aziridine (()-8a with n-octanol similar to the indole-ring-
opening reactions on silica led only to the decomposition of
the starting material. However, the reaction of alcohol (()-6
with n-octanol proceeded overnight with low conversion of
(()-6 on silica. After 15 h the desired substitution product
(()-17 was isolated in 15% yield (eq 2). Further we tried to
convert alcohol (()-6 on silica with tosylamide and various
amines. Unfortunately these reactions failed to produce any
conversion.
Next, aziridine (()-8a was successfully converted with
MeOH as an O-nucleophile by reaction with ceric ammonium
nitrate (CAN) (Scheme 3).40 Hence, (()-18a was synthesized
from (()-8a in MeOH with 10 mol % of CAN at room
temperature for 9 h in excellent yield (99%) based on recycled
aziridine (()-8a (52%). Further, the catalyst loading up to 40
mol % gave full conversion of (()-8a (TLC) and the subsequent
deprotection of (()-18a on silica at 70 °C yielded (()-18b in
good yield (74%).
In addition, we also explored the ring-opening reaction of
aziridine (()-8a in the presence of pyrazoles on activated silica.
To our delight, reactions employing our standard reaction
conditions (Table 2) yielded compounds (()-19a and (()-19b
in moderate yields (37% and 59%, eq 3).
a Reaction conditions: alcohol (()-6 (100 mg, 0.462 mmol), indole
derivative (4.62 mmol), activated silica (0.040-0.063 mm, 800 mg),
70 °C, overnight. b Isolated yield.
with an alcohol precursor on solid support.22a The reaction of
alcohol (()-6 with C-nucleophiles on silica enables a convenient
access to this class of compounds. Compared with the method
employing olefin 7a and other heterocyclic C-nucleophiles under
strong acidic conditions (MsOH as solvent), our method is more
managable.20c
8852 J. Org. Chem., Vol. 72, No. 23, 2007

Preparation of NoVel Unsymmetrical Bisindoles
SCHEME 2. Formation of Protected Sulfonamides (()-16a from (()-8a and Subsequent Deprotection to (()-16b
SCHEME 3. Synthesis of (()-18a and Subsequent Deprotection to (()-18b
Aziridine (()-8a could be opened smoothly with more
volatile secondary amines.41 To our surprise, (()-8a underwent
the direct amination reaction smoothly at 80 °C in homogeneous
solution without any catalyst or further activating reagent (e.g.,
organic base, etc.) to give also the in situ deprotected compounds
(()-20a-c (eq 4). Depending on the solubility of the products
during the recrystallization step, we obtained good to very good
yields (74-84).
of methanol, ethyl acetate, diethyl ether, or dichlormethane
solutions. The molecular structures of 7, (()-8a, (()-8b, (()-
8c, (()-11f, and (()-15d confirmed our assignments (see the
Supporting Information). Among them, the crystal structure of
bisindole (()-11f has been reported by us previously.22a The
CdC double bond in olefin 7 exhibits a length of 1.323(2) Å.
Possibly with respect to the nonplanarity of the seven-membered
ring, the olefinic CdC bond puckered from the plane of the
indole moiety [torsion angle: 156.0(2)°]. The molecular struc-
tures of aziridines (()-8a-c showed that the angles between
the three-atom-ring plane of the aziridines and the indole plane
are almost in the same range for all aziridines [(()-8a: 57.7-
(2)°; (()-8b: 60.3(1)°; (()-8c: 61.4(1)°]. Also, the bond lengths
of the aziridine moieties of (()-8a-c showed the structural
similarities of these compounds: (a) C-C: (()-8a 1.471(4)
Å, (()-8b 1.473(2) Å, (()-8c 1.472(2) Å; (b) N-C: (()-8a
1.502(4) Å, (()-8b 1.501(2) Å, (()-8c 1.512(2) Å; (b) C-N:
(()-8a 1.490(4) Å, (()-8b 1.488(2) Å, (()-8c 1.493(2) Å. The
X-ray analysis of bisindole (()-11f gives direct evidence for
the trans configuration of the ring-opening product. The
comparison of bisindole (()-11f and its analogue (()-15d
without the tosyl-amide side chain showed significant differ-
ences in the angle between the two planes of the indole ring
systems [(()-11f: 83.37(6)°; (()-15d: 73.87(5)°] in the
crystal structures. However, in both cases the planes of the
indole systems are clearly out of the same plane from each
other.
X-ray Crystallographic Studies. Single crystals suitable for
X-ray diffraction analysis were obtained by slow evaporation
(36) (a) Iovel, I.; Mertins, K.; Kischel, J.; Zapf, A.; Beller, M. Angew.
Chem., Int. Ed. 2005, 44, 3913-3917. (b) Mertins, K.; Iovel, I.; Kischel,
J.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 238-242.
(37) (a) Brandt, S. D.; Freemanb, S.; McGagha, P.; Abdul-Halima, N.;
Alder, J. F. J. Pharm. Biomed. Anal. 2004, 36, 675-691. (b) Magesh, C.
J.; Nagarajan, R.; Karthik, M.; Perumal, P. T. Appl. Catal. A 2004, 266,
1-10. (c) El Gihani, M. T.; Heaney, H.; Shuhaibar, K. F. Synlett 1996,
871-872. (d) Crookes, D. L.; Parry, K. P.; Smith, G. F., Pol. J. Chem.
1979, 53, 73-78.
Mechanistic Aspects. Inspired by the previous reports about
the concept of an aza-fulvenium ion as the intermediate in the
reaction mechanism,26a we became interested in the process of
the charge-stabilization of the cationic intermediate during the
bisindole formation from alcohol (()-6 and aziridines (()-
8a-c. It is well-known that the elimination of benzylic OH-
groups proceeds smoothly to afford olefins in the presence of
acids. Thus a carbocationic intermediate is formed in situ and
subsequent elimination of proton yields the corresponding olefin.
(38) Sayyed, I. A. Ph.D. Thesis, University of Pune, India, 2003.
(39) Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J. Org.
Chem. 2003, 68, 2410-2419.
(40) Chandrasekhar, S.; Narsihmulu, Ch; Sultana, S. S. Tetrahedron Lett.
2002, 43, 7361-7363.
(41) Mao, J.; Wan, B.; Wang, R.; Wu, F.; Lu, S. J. Org. Chem. 2004,
69, 9123-9127.
J. Org. Chem, Vol. 72, No. 23, 2007 8853

Kaiser et al.
SCHEME 4. Proposed Mechanism for the Synthesis of
Unsymmetrical Bisindoles from Alcohol (()-6
stands in contrast to the known literature and established aza-
fulvenium ion.26a
On the basis of the DFT calculations and our observations
of the reactions of alcohol (()-6 with indoles on silica, we
believe the reaction proceeds through the attack of the indole
to the LUMO of the cationic diene species, which is stabilized
by delocalization of the positive charge on the N1-C1-C2-
C5 moiety (Scheme 4). It is also possible for the same charge
stabilization mechanism to proceed during the ring-opening and
subsequent aromatic substitution reactions of aziridines (()-
8a-c with indoles.
FIGURE 2. Calculated molecular structures of alcohol (()-6 (A) and
the cationic intermediate (B).
Conclusion
In summary, a practical and easy to handle protocol for the
synthesis of unsymmetrical bisindoles was developed. The
arylation reactions proceed in a highly regio- and stereoselctive
manner at the benzylic position of the azepino[3,4-b]indol-
1(10H)-one moiety and at the 3-position of the attached indole
on a solid support. The solvent-free synthetic protocol is easily
manageable and yields the desired bisindoles from the aziridines
or alcohols. In addition, boc-protecting groups can be removed
in situ smoothly. The versatility of these aziridines was
demonstrated with H-, O-, and N-nucleophiles in a diversity
oriented synthesis to build up a small compound library. X-ray
analysis confirmed the molecular structures of important key
intermediates and library compounds. Specifically, the molecular
structure of (()-11f gives direct evidence for the trans-ring-
opening reaction. In addition, DFT calculations indicate that
the mechanism might proceed via a charge stabilized azabuta-
diene motif, which reacts further exclusively at the benzylic
position to rebuild the aromatic ring system.
1
During initial H NMR experiments of alcohol (()-6 with
MsOH in CD2Cl2, only olefin 7a was observed immediately
after addition of a catalytic amount of MsOH to alcohol (()-6.
Further, the boc-protected olefin 7 did not react with indole on
silica to form the desired product (()-15a. Here, only olefin
7a was observed on TLC. In fact, olefin 7 can be deprotected
on activated silica at 70 °C overnight to yield the N,N-
deprotected olefin 7a in 98% yield. Attempts to produce
bisindole from 7a on silica or in MsOH with indole were
performed. However, no reaction was observed on silica and
no well-defined product could be isolated from the MsOH-
reaction system. This indicates that the generation of the active
cationic intermediate from 7a is significantly slower than that
from the hydroxyl precursor (()-6.
To understand the structure of the cationic intermediate (B),
we have carried out B3LYP/6-311G(d) density functional theory
calculations along with the alcohol (A) by using the Spartan
04 program package.42 As shown in Figure 2, the five-membered
ring in A has a pyrrole moiety and the exocyclic C2-C5 bond
length is 1.501 Å. In the cationic intermediate (B), however,
the C2-C5 and C1-N1 bond lengths become shorter (1.357
and 1.316 Å, respectively) and the C1-C2 bond length becomes
longer (1.453 Å). This change is due to the delocalization effect
with the formation of the butadiene moiety of N1-C1-C2-
C5. In addition to the changes of the bond lengths, it is also
interesting to compare the Mulliken charges between A and B.
Therefore it seems to be clear that the positive charge from a
theoretical perspective point of view has to be delocalized over
C1, C2, and C5 (the computed Mulliken chargessfor A: N1
) -0.701; C1 ) 0.156; C2 ) -0.021; C5 ) -0.030; for B:
N1 ) -0.632; C1 ) 0.242; C2 ) -0.018; C5 ) -0.094). This
Experimental Section
5-Hydroxy-2,3,4,5-tetrahydroazepino[3,4-b]indol-1(10H)-
one ((()-6). Ketone 5 (3.31 g, 15.5 mmol) was suspended in
degassed absolute ethanol (250 mL) under argon.43 Then freshly
ground NaBH4 (2.92 g, 77.3 mmol) was added and the reaction
mixture was stirred at ambient temperature overnight (∼14 h). The
mixture was filtered over celite and washed with acetone. After
removal of the solvent under reduced pressure, purification by
column chromatography (silica gel 70-230 mesh, CH2Cl2 to
CH2Cl2:MeOH 100:7 as a gradient eluent) yielded an off-white solid
(3.30 g, 99%). Rf 0.40 (CH2Cl2:MeOH:NEt3 100:10:1). Mp 167-
1
169 °C (ethyl acetate). H NMR (300 MHz, DMSO-d6) δ (ppm)
11.29 (1H, br s), 8.15 (1H, dd, J ) 6.0, 3.2 Hz), 7.78 (1H, d, J )
7.9 Hz), 7.41 (1H, d, J ) 8.1 Hz), 7.19 (1H, ddd, J ) 8.1, 7.0, 1.1
(42) SPARTAN’04: Copyright 1991-2005 by Wavefunction Inc.; ww-
w.wavefun.com.
(43) For the synthesis of the precursors, please see the Supporting
Information.
8854 J. Org. Chem., Vol. 72, No. 23, 2007

Preparation of NoVel Unsymmetrical Bisindoles
Hz), 7.04 (1H, ddd, J ) 8.1, 7.0, 1.0 Hz), 5.23 (1H, d, J ) 6.6
Hz), 5.18-5.10 (1H, m), 3.59-3.45 (1H, m), 3.22-3.08 (1H, m),
2.22-2.10 (1H, m), 2.07-1.93 (1H, m). 13C NMR (75 MHz,
DMSO-d6) δ (ppm) 163.7, 135.8, 127.7, 126.8, 123.9, 121.5, 119.5,
119.1, 112.1, 63.5, 36.5, 35.5. IR (KBr) ν (cm-1) 3520 m, 3281 s,
3211 sh, 3051 m, 2952 m, 2917 m, 2861 sh, 1647 s, 1550 s, 1478
s, 1456 m, 1412 m, 1362 m, 1334 s, 1297 m, 1239 w, 1185 w,
1160 w, 1144 w, 1063 w, 1047 m, 1003 m, 958 m, 924 w, 881 m,
792 m, 740 s, 680 m, 606 w, 539 w, 465 w, 435 w. MS (EI) m/z
(rel. intensity) 217 (13), 216 (72), 200 (13), 199 (36), 198 (100),
197 (50), 189 (13), 186 (11), 172 (10), 171 (25), 170 (37), 169
(50), 168 (13), 159 (35), 158 (17), 155 (14), 154 (15), 149 (14),
145 (16), 144 (30), 143 (29), 142 (12), 141 (11), 140 (15), 130
(12), 129 (12), 128 (10), 117 (13), 116 (17), 114 (11), 89 (17), 83
(11), 78 (13), 77 (18), 71 (14), 69 (12), 63 (19), 57 (22), 55 (16),
44 (46), 43 (14), 41 (17). HRMS (ESI) calcd for C12H12N2O2Na
(20), 198 (100), 170 (20), 169 (77), 168 (12), 155 (16), 154 (16),
140 (11), 115 (24), 86 (30), 84 (50), 83 (13), 71(12), 70 (11), 69
(14), 63 (11), 57 (21), 55 (18), 51 (18), 49 (62), 43 (19), 41 (18).
HRMS (EI) calcd for C12H10N2O (M+) 198.0788, found 198.0782.
Aziridiniation of (Z)-Di-tert-butyl 1-Oxoazepino[3,4-b]indole-
2,10(1H,3H)-dicarboxylate (7) with Chloramine-T, Synthesis of
(()-8a. Olefin 7 (3.10 g, 7.78 mmol) was dissolved under argon
in anhydrous acetonitrile (200 mL), then PhNMe3Br3 (146 mg,
0.390 mmol) and chloramine-T × 3H2O (1.10 g, 3.89 mmol) were
added. The mixture was stirred for 13 h and was quenched with
saturated Na2SO3(aq) (200 mL). After extraction with ethyl acetate
(3 × 200 mL), the combined organic layers were dried over MgSO4
and filtered, and the solvent was removed under reduced pressure.
The crude orange solid product was purified by column chroma-
tography (silica gel 70-230 mesh, n-hexane to n-hexane:ethyl
acetate 5:1 as the gradient eluent) to yield a white solid product
(1.74 g, 78%) and a pure fraction of starting material 7 (1.19 g,
38%). The product was recrystallized from ethyl acetate:n-heptane
(1:4) at 4 °C. Crystals suitable for X-ray diffraction analysis were
obtained by slow evaporation of a solution of ethyl acetate at room
temperature. Mp 169-170 °C (ethyl acetate). Rf 0.24 (n-hexane:
ethyl acetate 4:1). 1H NMR (300 MHz, CDCl3) δ (ppm) 8.03 (1H,
d, J ) 8.5 Hz), 7.89 (2H, d, J ) 8.3 Hz), 7.44-7.34 (3H, m),
7.17-6.95 (2H, m), 4.60 (1H, br s), 3.92 (1H, d, J ) 6.9 Hz),
3.81-3.72 (1H, m), 3.60 (1H, br s), 2.49 (3H, s), 1.59 (9H, s),
1.56 (9H, s). 13C NMR (75 MHz, CDCl3) δ (ppm) 159.9, 151.8,
148.9, 145.4, 137.9, 134.6, 130.3, 130.1, 128.5, 127.8, 126.9, 123.7,
(M
+
Na+) 239.0791, found 239.0803. Anal. Calcd for
C12H12N2O2: C, 66.65; H, 5.59; N, 12.96. Found: C, 66.59; H,
5.33; N, 12.90.
(Z)-Di-tert-butyl 1-Oxoazepino[3,4-b]indole-2,10(1H,3H)-di-
carboxylate (7). To a solution of alcohol (()-6 (3.30 g, 15.3 mmol)
in CH2Cl2 (500 mL) was added methanesulfonic acid (0.730 g, 7.63
mmol) dropwise. The solution was stirred at room temperature for
∼40 min. After the full conversion of (()-6 as indicated by TLC
analysis, 4-dimethylaminopyridine (4.47 g, 36.6 mmol) and di-tert-
butyl dicarbonate (6.97 g, 30.5 mmol) were added. The reaction
was monitored by TLC (CH2Cl2:MeOH:NEt3 100:10:1) and portions
of di-tert-butyl dicarbonate (3 × 2.30 g, 3 × 10.2 mmol) were
added further to complete the reaction. The solvent was removed
in vacuo and the residual brown reaction mixture was purified via
column chromatography (silica gel 70-230 mesh, n-hexane:ethyl
acetate 6:1, packed with 1% NEt3) to yield a white solid (5.19 g,
85%). Crystals suitable for X-ray diffraction analysis were obtained
by slow evaporation of a solution of diethyl ether at room
temperature. Rf 0.23 (n-hexane:ethyl acetate 6:1). Mp 127-128 °C
(Et2O). 1H NMR (300 MHz, CDCl3) δ (ppm) 8.11 (1H, d, J ) 8.5
Hz), 7.67 (1H, d, J ) 7.9 Hz), 7.48 (1H, ddd, J ) 8.4, 7.2, 1.3
Hz), 7.31 (1H, ddd, J ) 8.1, 7.2, 0.9 Hz), 7.19 (1H, d, J ) 9.6
Hz), 6.57 (1H, dt, J ) 9.7, 6.5 Hz), 4.29 (2H, br s), 1.64 (9H, s),
1.55 (9H, s). 13C NMR (75 MHz, CDCl3) δ (ppm) 159.3, 151.4,
149.5, 138.3, 132.1, 131.2, 128.0, 125.9, 125.5, 123.8, 123.4, 120.4,
114.8, 84.8, 83.5, 43.6, 28.2, 27.9. IR (KBr) ν (cm-1) 3438 w,
3053 w, 2983 m, 2940 w, 1764 s, 1730 s, 1691 sh, 1670 w, 1532
w, 1448 m, 1418 m, 1373 s, 1339 s, 1326 s, 1278 m, 1264 m,
1229 s, 1141 s, 1118 s, 1027 m, 1016 m, 1011 m, 976 m, 951 w,
895 w, 862 m, 834 m, 805 m, 780 m, 767 m, 747 s, 695 w, 674 w,
607 w, 588 w, 511 w, 470 w, 442 w. MS (EI) m/z (rel. intensity)
398 (2), 242 (7), 199 (11), 198 (100), 197 (33), 170 (6), 169 (20),
157 (6), 56 (7), 44 (21), 41 (13). HRMS (ESI+) calcd for
C22H26N2O5Na (M + Na+) 421.1734, found 421.1735.
(Z)-2,3-Dihydroazepino[3,4-b]indol-1(10H)-one (7a). Olefin 7
(600 mg, 1.51 mmol) was dissolved in CH2Cl2 and activated silica
(1.0 g, 0.040-0.063 mm) was added. After removal of the solvent
the mixture was heated at 70 °C for 16 h. Purification by column
chromatography (silica gel 70-230 mesh, n-hexane:ethyl acetate
1:1 to ethyl acetate as the gradient eluent) yielded a white solid
(293 mg, yield: 98%). Rf 0.44 (ethyl acetate). Mp 198 °C (n-hexane:
ethyl acetate). 1H NMR (300 MHz, DMSO-d6) δ (ppm) 11.86 (1H,
br s), 7.91 (1H, unresolved dd), 7.76 (1H, d, J ) 8.1 Hz), 7.45
(1H, unresolved ddd), 7.28 (1H, ddd, J ) 8.1, 7.0, 1.1 Hz), 7.15
(1H, d, J ) 10.0 Hz), 7.12 (1H, ddd, J ) 7.9, 7.0, 0.9 Hz), 6.04
(1H, dt, J ) 9.9, 6.5 Hz), 3.53 (2H, unresolved dd). 13C NMR (75
MHz, DMSO-d6) δ (ppm) 163.9, 136.1, 130.6, 125.3, 125.2, 124.5,
124.0, 120.0, 119.9, 116.0, 112.3, 38.4. IR (KBr) ν (cm-1) 3209 s,
3060 sh, 2984 sh, 2924 sh, 1911 w, 1627 s, 1574 sh, 1525 s, 1500
m, 1478 s, 1438 m, 1419 m, 1394 m, 1333 s, 1301 m, 1271 m,
1246 w, 1233 w, 1156 m, 1114 w, 1071 w, 1021 w, 1007 w, 932
w, 904 m, 854 w, 810 m, 775 m, 758 s, 675 m, 620 w, 596 m, 586
w, 564 w, 515 m, 436 m, 423 m. MS (EI) m/z (rel. intensity) 199
1
120.2, 117.1, 114.8, 85.3, 84.5, 35.6, 28.2, 27.7, 21.9. H NMR
(300 MHz, 323 K, CDCl3) δ (ppm) 8.04 (1H, ddd, J ) 8.6, 1.0,
0.7 Hz), 7.89 (2H, unresolved ddd), 7.37 (1H, ddd, J ) 8.5, 6.7,
1.8 Hz), 7.21-7.12 (2H, m), 4.60-4.47 (1H, m), 3.95 (1H, d, J )
6.8 Hz), 3.76 (1H, ddd, J ) 9.0, 7.0, 4.5 Hz), 3.72-3.58 (1H, m),
2.48 (3H, s), 1.59 (9H, s), 1.57 (9H, s). 13C NMR (75 MHz, 323
K, CDCl3) δ (ppm) 159.8, 152.1, 149.0, 145.3, 138.1, 135.2, 130.5,
130.1, 128.5, 127.8, 127.1, 123.7, 120.4, 117.2, 114.8, 85.3, 84.5,
45.7 (br s), 41.9 (br s), 35.8, 28.3, 27.8, 21.8. IR (KBr) ν (cm-1
)
3428 w, 2977 w, 2934 w, 1745 s, 1723 s, 1701 s, 1596 w, 1556 w,
1477 w, 1447 m, 1396 m, 1369 s, 1323 s, 1289 s, 1260 m, 1225
m, 1207 m, 1160 s, 1124 m, 1111 m, 1091 m, 1018 w, 999 w, 974
w, 951 w, 876 w, 864 w, 829 w, 811 w, 768 w, 741 m, 706 w, 679
m, 659 w, 590 w, 567 m, 548 m, 509 w. MS (EI) m/z (rel. intensity)
567 (3), 511 (2), 367 (4), 356 (7), 300 (21), 256 (24), 212 (53),
181 (26), 155 (11), 131 (31), 91 (18), 59 (56), 57 (47), 56 (100),
55 (36), 53 (12), 51 (13), 49 (13). HRMS (ESI) calcd for
C29H33N3O7SNa (M + Na+) 590.1931, found 590.1937. HPLC
(column: Reprosil 100 Chiral-NR 8 µm, solvent: n-hexane:ethanol
97:7, flow ) 0.8 mL/min) tR ) 63.37, 70.22 min. Anal. Calcd for
C29H33N3O7S: C, 61.36; H, 5.86; N, 7.40; S, 5.65. Found: C, 61.16;
H, 5.57; N, 7.16; S, 5.68.
Aziridiniation of (Z)-Di-tert-butyl 1-Oxoazepino[3,4-b]indole-
2,10(1H,3H)-dicarboxylate (7) with Chloramine-B, Synthesis of
(()-8b. Olefin 7 (1.51 g, 3.78 mmol) was dissolved under argon
in anhydrous acetonitrile (200 mL), then PhNMe3Br3 (71 mg, 0.189
mmol) and chloramine-B × 3 H2O (405 mg, 1.89 mmol) were
added. The mixture was stirred for 13 h and was quenched with
saturated Na2SO3(aq) (200 mL). After extraction with ethyl acetate
(3 × 200 mL), the combined organic layers were dried over MgSO4
and filtered, and the solvent was removed under reduced pressure.
The crude orange product was purified by column chromatography
(silica gel 70-230 mesh, n-hexane to n-hexane:ethyl acetate (8:1)
as the gradient eluent) to yield a white solid product and the starting
material (0.81 g). The product was recrystallized from CH2Cl2:n-
hexane to yield a white solid product (0.57 g, 54%). Crystals
suitable for X-ray diffraction analysis were obtained by slow
evaporation of a solution of ethyl acetate at room temperature. Rf
0.24 (n-hexane:ethyl acetate 6:1). Mp 203 °C (CH2Cl2:ethyl acetate).
1H NMR (400 MHz, CDCl3) δ (ppm) 8.05-7.99 (3H, m), 7.71
(1H, unresolved dd), 7.59 (2H, unresolved dd), 7.40 (1H, unresolved
ddd), 7.13 (1H, unresolved dd), 7.06 (1H, s), 4.60 (1H, s), 3.96
J. Org. Chem, Vol. 72, No. 23, 2007 8855

Kaiser et al.
(1H, d, J ) 6.6 Hz), 3.85-3.74 (1H, m), 3.61 (1H, s), 1.59 (9H,
s), 1.56 (9H, s). 13C NMR (100 MHz, CDCl3) δ (ppm) 159.8, 151.8,
148.9, 137.9, 137.7, 134.2, 130.3, 129.5, 128.4, 127.8, 126.9, 123.8,
heated under argon at 70 °C overnight (∼12-16 h). Purification
by column chromatography (silica gel 70-230 mesh, CH2Cl2 to
CH2Cl2:MeOH 10:1 as the gradient eluent) yielded the crude
product. It was then washed or recrystallized as described below
and in the Supporting Information.
1
120.1, 116.9, 114.8, 85.3, 84.5, 35.8, 28.2, 27.8. H NMR (400
MHz, 323 K, CDCl3) δ (ppm) 8.03 (3H, m), 7.69 (1H, unresolved
dddd), 7.57 (1H, unresolved dddd), 7.40 (1H, ddd, J ) 8.4, 6.7,
1.7 Hz), 7.21-7.12 (2H, m), 4.54 (1H, d, J ) 12.5 Hz), 3.90 (1H,
d, J ) 6.8 Hz), 3.83-3.76 (1H, m), 3.74-3.57 (1H, m), 1.59 (9H,
s), 1.57 (9H, s). 13C NMR (100 MHz, 323 K, CDCl3) δ (ppm)
159.8, 152.1, 149.0, 138.3, 138.1, 134.1, 130.5, 129.5, 128.4, 127.8,
127.1, 123.8, 120.3, 117.0, 114.9, 85.3, 84.5, 45.6, 42.0, 36.0, 28.3,
27.8. IR (KBr) ν (cm-1) 3423 w, 3119 w, 3070 w, 2981 m, 2932
w, 1751 s, 1720 s, 1696 s, 1607 w, 1556 w, 1474 sh, 1448 m,
1428 sh, 1395 m, 1369 s, 1338 s, 1322 s, 1290 s, 1261 s, 1222 s,
1208 s, 1170 s, 1150 s, 1125 m, 1091 s, 1020 m, 1002 m, 976 m,
954 m, 895 w, 879 m, 857 m, 811 m, 773 m, 754 m, 744 s, 726 m,
692 w, 670 w, 639 w, 594 m, 555 m, 504 w, 486 w, 442 w. MS
(EI) m/z (rel. intensity) 553 (1), 353 (18), 356 (36), 213 (81), 212
(100), 199 (10), 198 (75), 197 (25), 185 (63), 184 (60), 183 (60),
169 (31), 168 (13), 167 (17), 157 (16), 156 (26), 155 (43), 142
(11), 130 (13), 129 (22), 128 (25), 127 (15), 126 (10), 101 (14), 78
(42), 77 (63), 64 (11), 57 (68), 56 (87), 55 (43), 53 (11), 51 (29),
50 (18), 44 (69), 41 (85), 40 (16), 39 (76). HRMS (EI) calcd for
C28H31N3O7S (M+) 553.1877, found 553.1877. Anal. Calcd for
C28H31N3O7S: C, 60.74; H, 5.64; N, 7.59; S, 5.79. Found: C, 60.53;
H, 5.93; N, 7.56; S, 6.02.
N-(5-(1H-Indol-3-yl)-1-oxo-1,2,3,4,5,10-hexahydroazepino[3,4-
b]indol-4-yl)tosylamide ((()-11a). A crude product was obtained
following general procedure A. It was dissolved in CH2Cl2;
n-hexane was added dropwise until some precipitate was formed.
Then the solution was cooled to 4 °C and finally filtered to yield
a white solid product (90 mg, 93%). Rf 0.12 (CH2Cl2:MeOH 20:
1). Mp 145-146 °C (CH2Cl2:n-hexane, dec). 1H NMR (300 MHz,
DMSO-d6) δ (ppm) 11.34 (1H, br s), 10.73 (1H, br s), 8.06-7.96
(2H, m), 7.61 (2H, d, J ) 8.1 Hz), 7.38 (1H, d, J ) 8.1 Hz), 7.27-
7.20 (3H, m), 7.08 (1H, unresolved ddd), 7.04-6.96 (1H, m), 6.92
(1H, d, J ) 8.1 Hz), 6.80-6.71 (3H, m), 4.69 (1H, d, J ) 4.3 Hz),
3.64-3.56 (1H, m), 3.51-3.47 (1H, m), 3.19-3.06 (1H, m), 2.37
(3H, s). 13C NMR (75 MHz, DMSO-d6) δ (ppm) 164.0, 142.4,
137.6, 136.3, 136.2, 129.4, 127.5, 126.6, 125.1, 124.7, 123.7, 120.9,
120.6, 118.7, 118.4, 117.5, 117.4, 116.8, 115.4, 112.1, 111.7, 54.6,
41.6, 25.0, 21.1. IR (KBr) ν (cm-1) 3361 s, 3057 m, 2923 m, 2863
m, 1926 w, 1644 s, 1547 m, 1481 s, 1455 s, 1338 s, 1291 m, 1244
w, 1222 w, 1185 w, 1158 s, 1088 s, 1006 w, 989 w, 943 w, 883 w,
814 m, 744 s, 661 m, 578 m, 552 m, 531 m, 428 w. MS (CI) m/z
(rel. intensity) 485 (12), 484 (39), 329 (35), 314 (19), 313 (100),
312 (21), 301 (15), 300 (82), 272 (19), 271 (29), 270 (11), 243
(24), 242 (15), 216 (12), 212 (20), 185 (20), 145 (86), 91 (15).
HRMS (ESI) calcd for C27H25N4O3S (M + H+) 485.1642, found
485.1639.
Copper-Catalyzed Aziridiniation of (Z)-Di-tert-butyl 1-Oxoaze-
pino[3,4-b]indole-2,10(1H,3H)-dicarboxylate, Synthesis of (()-
8c.33 Olefin 7 (4.00 g, 10.0 mmol), PhI(OAc)2 (2.58 g, 8 mmol),
5-methylpyridine-2-sulfonamide (1.38 g, 8.00 mmol), copper(II)
trifluoroacetylacetonate [Cu(tfac)2] (148 mg, 0.40 mmol), and
activated 4 Å molecular sieve (20 g) were suspended under argon
in anhydrous acetonitrile (80 mL). The mixture was stirred for 13
h. It was then diluted with ethyl acetate (400 mL) and washed with
water (400 mL). The aqueous layer was further extracted with ethyl
acetate (3 × 10 mL). The combined organic layers were dried over
MgSO4 and filtered, and the solvent was removed under reduced
pressure. The crude solid product was purified by column chro-
matography (silica gel 70-230 mesh, n-hexane to n-hexane:ethyl
acetate 4:1 as the gradient eluent) to yield a white solid product
(2.44 g, 76%) and a pure fraction of starting material 7 (1.74 g,
43%). The product was recrystallized from diethyl ether:n-hexane.
Crystals suitable for X-ray diffraction analysis were obtained by
slow evaporation of a solution of CH2Cl2 at ambient temperature.
Rf 0.06 (n-hexane:ethyl acetate 4:1). Mp 149-150 °C (Et2O:n-
N-(5-(1H-Indol-3-yl)-1-oxo-1,2,3,4,5,10-hexahydroazepino[3,4-
b]indol-4-yl)benzenesulfonamide ((()-13a). A crude product was
obtained following general procedure A. It was recrystallized from
CH2Cl2 to yield a white solid product (61 mg, 66%). Rf 0.37
1
(CH2Cl2:MeOH 10:1) mp 189 °C (CH2Cl2). H NMR (300 MHz,
DMSO-d6) δ (ppm) 11.33 (1H, br s), 10.73 (1H, d, J ) 2.2 Hz),
8.10 (1H, d, J ) 5.9 Hz), 7.98 (1H, dd, J ) 6.3, 3.2 Hz), 7.80-
7.74 (2H, m), 7.60 (1H, unresolved dddd), 7.52-7.42 (2H, m), 7.39
(1H, d, J ) 8.3 Hz), 7.25 (1H, d, J ) 8.1 Hz), 7.09 (1H, unresolved
ddd), 7.04-6.97 (1H, m), 6.91 (1H, d, J ) 8.1 Hz), 6.83-6.78
(2H, m), 6.75 (1H, unresolved ddd), 6.62 (1H, d, J ) 2.2 Hz),
4.71 (1H, d, J ) 4.2 Hz), 3.65 (1H, dd, J ) 10.8, 6.1 Hz). 13C
NMR (75 MHz, DMSO-d6) δ (ppm) 164.0, 140.7, 136.3, 126.2,
132.3, 129.0, 127.6, 127.5, 126.5, 125.1, 124.7, 123.7, 121.0, 120.6,
118.7, 118.5, 117.4, 117.0, 115.3, 112.1, 111.7, 54.9, 54.4, 41.3.
IR (KBr) ν (cm-1) 3411 s, 3313 s, 3063 m, 2874 m, 1640 s, 1550
m, 1480 s, 1454 m, 1419 m, 1338 s, 1294 sh, 1265 sh, 1245 m,
1220 m, 1161 s, 1088 s, 1011 w, 989 w, 950 m, 879 w, 812 w,
739 s, 688 s, 585 s, 528 m, 488 m, 451 m, 426 m. MS (EI) m/z
(rel. intensity) 470 (22), 329 (23), 314 (11), 313 (49), 312 (13),
301 (11), 300 (51), 272 (14), 271 (24), 270 (11), 243 (28), 242
(17), 216 (18), 212 (17), 207 (13), 185 (19), 145 (91), 77 (22), 69
(12), 45 (11), 44 (100), 43 (21), 41 (10). HRMS (EI) calcd for
C26H22N4O3S (M+) 470.1407, found 470.1407.
N-(5-(1H-Indol-3-yl)-1-oxo-1,2,3,4,5,10-hexahydroazepino[3,4-
b]indol-4-yl)-5-methylpyridine-2-sulfonamide ((()-14a). A crude
product was obtained following general procedure A. It was washed
with diethyl ether and finally filtered to yield a white solid product
(89 mg, 92%). Rf 0.17 (CH2Cl2:MeOH 100:5). mp >300 °C (Et2O).
1H NMR (300 MHz, DMSO-d6) δ (ppm) 11.28 (1H, s), 10.67 (1H,
d, J ) 2.0 Hz), 8.25 (1H, br s), 8.02-8.06 (2H, m), 7.61 (2H, m),
7.34 (1H, d, J ) 8.2 Hz), 7.22 (1H, d, J ) 8.1 Hz), 7.17 (1H, d,
J ) 7.9 Hz), 6.96-7.08 (3H, m), 6.81-6.85 (1H, m), 6.71-6.76
(2H, m), 4.82 (1H, d, J ) 5.3 Hz), 4.03 (1H, dd, J ) 12.9, 6.6
Hz), 3.49 (1H, dd, J ) 14.0, 3.9 Hz), 3.17-3.26 (1H, m), 2.30
(3H, s). 13C NMR (75 MHz, DMSO-d6) δ (ppm) 164.3, 155.3,
149.9, 138.1, 136.8, 136.5, 136.4, 127.7, 127.5, 125.4, 124.8, 123.8,
121.0, 120.9, 120.8, 118.8, 118.5, 118.1, 116.9, 115.8, 112.2, 111.8,
55.8, 42.9, 40.1, 18.2. IR (KBr) ν (cm-1) 3411 s, 3359 s, 3191 sh,
3083 sh, 2871 m, 1930 w, 1648 s, 1556 m 1485 s, 1456 s, 1340 s,
1
hexane). H NMR (300 MHz, CDCl3) δ (ppm) 8.57 (1H, s), 8.01
(1H, d, J ) 8.5 Hz), 7.99 (1H, d, J ) 8.0 Hz), 7.71 (1H, dd, J )
8.0, 1.7 Hz), 7.67 (1H, d, J ) 8.0 Hz), 7.39-7.44 (1H, m), 7.22-
7.27 (1H, m), 4.60 (1H, br s), 4.21 (1H, d, J ) 7.0 Hz), 3.93 (1H,
ddd, J ) 8.9, 7.0, 4.7 Hz), 3.63 (1H, br s), 2.44 (3H, s), 1.57 (9H,
s), 1.53 (9H, s). 13C NMR (75 MHz, CDCl3, 323 K) δ (ppm) 159.7,
153.4, 151.8, 150.8, 148.8, 138.5, 138.2, 138.0, 130.4, 127.7, 127.0,
123.6, 122.8, 120.7 117.2, 114.6, 85.1, 84.2, 45.4, 42.2, 35.8, 28.1,
27.7, 18.5. IR (KBr) ν (cm-1) 3443 s, 2981 s, 2934 m, 1770 sh,
1749 s, 1721 s, 1635 w, 1558 w, 1447 s, 1394 m, 1370 s, 1315 s,
1292 sh, 1259 s, 1227 s, 1156 s, 1104 s, 1083 s, 1024 m, 1000 m,
975 m, 952 m, 850 m, 832 m, 810 w, 767 m, 751 m, 744 m, 693
m, 679 w, 659 w, 638 w, 589 w, 569 m, 562 m, 549 m, 524 w,
495 w, 469 w, 425 w. HRMS (ESI) calcd for C28H33N4O7S+ (M +
H+) m/z 569.2064, found 569.2072 and calcd for C28H32N4O7SNa
(M+Na+) m/z 591.1884, found 591.1897. Anal. Calcd for
C28H32N4O7S: C, 59.14; H, 5.67; N, 9.85; S, 5.64. Found: C, 58.93;
H, 5.46; N, 9.54; S, 5.80.
General Procedure for the Ring-Opening Reaction of Aziri-
dines with Indoles (General Procedure A). Aziridine (()-8a-c
(0.2 mmol) and an indole derivative (2 mmol) were dissolved in
an appropriate solvent (e.g., CH2Cl2, acetone or ethyl acetate) and
activated silica (429 mg, 0.040-0.063 mm) was added. The solvent
was removed under reduced pressure and the solid mixture was
8856 J. Org. Chem., Vol. 72, No. 23, 2007

Preparation of NoVel Unsymmetrical Bisindoles
1307 s, 1247 w, 1223 m, 1202 w, 1163 s, 1131 w, 1109 m, 1094
s, 1051 w, 1028 w, 1003 m, 993 m, 960 m, 881 w, 835 w, 807 w,
747 s, 663 s, 636 m, 612 m, 575 m, 554 s, 530 m, 501 w, 427 w.
HRMS (CI) calcd for C26H22N5O3S (M-) 484.1449, found 484.1437.
General Procedure for the Reaction of 5-Hydroxy-2,3,4,5-
tetrahydroazepino[3,4-b]indol-1(10H)-one ((()-6) with Indoles
(General Procedure B). Alcohol (()-6 (100 mg, 0.462 mmol) and
an indole derivative (4.62 mmol) were dissolved in the heat with
an appropriate solvent (acetone or dichloromethane and ethyl
acetate) and activated silica (800 mg, 0.040-0.063 mm) was added.
The solvent was removed under reduced pressure and the mixture
was heated to 70 °C overnight (∼12-16 h). Purification by column
chromatography (silica gel 70-230 mesh, CH2Cl2 to CH2Cl2:MeOH
20:1 as the gradient eluent) yielded the crude product. It was then
washed or recrystallized as described below and in the Supporting
Information.
0.158 mmol) was dissolved in 7:1 CH2Cl2:TFA and the mixture
was stirred for 2 h at room temperature. Then saturated NaHCO3-
(aq) (30 mL) was added slowly and the mixture was extracted with
CH2Cl2 (4 × 30 mL). The combined organic layers were dried over
MgSO4. After filtration the solvent was removed under reduced
pressure to yield a green oil. Purification by column chromatography
(silica gel 70-230 mesh, ethyl acetate) yielded a white solid (56
mg, 96%). Rf 0.46 (n-hexane:ethyl acetate 1:1). Mp 206 °C (ethyl
1
acetate). H NMR (400 MHz, DMSO-d6) δ (ppm) 11.27 (1H, s),
8.00 (1H, d, J ) 6.2 Hz), 7.97 (1H, unresolved dd), 7.76 (2H, d,
J ) 8.3 Hz), 7.43-7.32 (4H, m), 7.19 (1H, ddd, J ) 8.2, 7.0, 1.0
Hz), 7.00 (1H, unresolved ddd), 3.58-3.46 (1H, m), 3.32-3.27
(2H, m), 3.00 (1H, dd, J ) 17.1, 5.4 Hz), 2.91 (1H, dd, J ) 16.9,
8.7 Hz), 2.38 (3H, s). 13C NMR (100 MHz, DMSO-d6) δ (ppm)
163.9, 142.7, 138.2, 136.0, 129.7, 127.1, 126.9, 126.5, 124.1, 119.5,
119.2, 112.8, 112.1, 51.9, 46.7, 31.4, 21.0. IR (KBr) ν (cm-1) 3297
s, 3247 s, 3061 sh, 2918 m, 1615 s, 1550 m, 1478 s, 1452 s, 1414
m, 1325 s, 1284 s, 1269 m, 1228 w, 1185 w, 1154 s, 1117 w, 1092
m, 1061 w, 1005 w, 957 w, 916 w, 889 m, 943 w, 832 w, 812 m,
787 w, 761 m, 741 m, 662 m, 590 w, 570 w, 550 m, 522 m, 431
w. MS (EI) m/z (rel. intensity) 369 (11), 199 (29), 198 (100), 185
(31), 169 (17), 167 (13), 158 (11), 157 (12), 155 (10), 130 (19),
129 (19), 128 (13), 91 (19), 44 (11). HRMS (EI) calcd for
C19H20N3O3S (M + H+) 370.1220, found 370.1228.
5-(1H-Indol-3-yl)-2,3,4,5-tetrahydroazepino[3,4-b]indol-1(10H)-
one ((()-15a). A crude product was obtained following general
procedure B. After recrystallization from hot MeOH a white solid
(133 mg, yield: 91%) was obtained at 4 °C. Rf 0.23 (CH2Cl2:MeOH
1
20:1). Mp 271 °C (MeOH, dec). H NMR (300 MHz, DMSO-d6)
δ (ppm) 11.24 (1H, br s), 10.76 (1H, d, J ) 1.9 Hz), 8.11 (1H, dd,
J ) 5.7, 4.0 Hz), 7.52 (1H, d, J ) 7.7 Hz), 7.38 (1H, d, J ) 8.1
Hz), 7.32 (1H, d, J ) 8.1 Hz), 7.12-7.01 (3H, m), 6.94 (1H,
unresolved ddd), 6.79-6.70 (2H, m), 4.95 (1H, dd, J ) 5.3, 5.1
Hz), 3.36-3.25 (1H, m), 3.22-3.08 (1H, m), 2.34-2.23 (2H, m).
13C NMR (75 MHz, DMSO-d6) δ (ppm) 164.1, 136.4, 136.0, 127.8,
127.4, 125.8, 123.8, 123.6, 121.0, 120.9, 119.3, 119.0, 118.6, 118.3,
118.3, 112.1, 111.6, 37.7, 34.8, 33.4. IR (KBr) ν (cm-1) 3351 s,
3306 s, 3055 m, 2951 m, 2930 m, 2865 m, 1895 w, 1780 w, 1623
s, 1575 m, 1542 s, 1482 s, 1455 m, 1447 m, 1420 m, 1402 m,
1369 m, 1335 s, 1310 m, 1293 m, 1246 m, 1223 m, 1190 w, 1158
m, 1112 w, 1095 m, 1054 m, 1039 w, 1010 m, 991 w, 973 w, 946
w, 913 w, 880 w, 819 w, 776 m, 765 sh, 752 s, 745 s, 713 m, 678
m, 653 m, 631 w, 605 m, 585 m, 528 w, 505 m, 473 w, 446 w,
424 w, 408 w. MS (EI) m/z (rel. intensity) 316 (21), 315 (100),
298 (39), 297 (12), 286 (22), 285 (30), 272 (15), 271 (20), 269
(13), 258 (23), 257 (35), 256 (15), 243 (12), 198 (45), 128 (10), 44
(13). HRMS (EI) calcd for C20H17N3O (M+) 315.1366, found
315.1366.
5-(Octyloxy)-2,3,4,5-tetrahydroazepino[3,4-b]indol-1(10H)-
one ((()-17). Alcohol (()-6 (100 mg, 0.462 mmol) and n-octanol
(602 mg, 4.62 mmol) were dissolved in acetone and activated silica
(800 mg, 0.040-0.063 mm) was added. The solvent was removed
under reduced pressure and the mixture was heated to 70 °C for
15 h. Purification by column chromatography (silica gel 70-230
mesh, ethyl acetate) yielded 23 mg (15%) of a colorless solid. Rf
0.31 (ethyl acetate). 1H NMR (300 MHz, DMSO-d6) δ (ppm) 11.38
(1H, br s), 8.18 (1H, dd, J ) 6.2, 3.0 Hz), 7.63 (1H, d, J ) 8.1
Hz), 7.42 (1H, d, J ) 8.3 Hz), 7.20 (1H, ddd, J ) 8.3, 7.0, 1.1
Hz), 7.04 (1H, ddd, J ) 7.9, 7.0, 0.9 Hz), 4.88 (1H, unresolved
dd), 3.68-3.50 (2H, m), 3.49-3.37 (1H, m), 3.22-3.09 (1H, m),
2.46-2.32 (1H, m), 1.98-1.84 (1H, m), 1.57-1.43 (2H, m), 1.39-
1.14 (10H, m), 0.84 (3H, t, J ) 6.9 Hz). 13C NMR (75 MHz,
DMSO-d6) δ (ppm) 163.4, 135.7, 127.7, 127.6, 123.9, 120.8, 119.4,
117.1, 112.2, 71.7, 67.4, 35.5, 31.2, 30.8, 29.8, 28.8, 28.7, 25.9,
22.1, 14.0. HRMS (ESI) calcd for C20H28N2NaO2 (M + Na+)
351.2043, found 351.2046.
Di-tert-butyl 4-(4-Methylphenylsulfonamido)-1-oxo-4,5-dihy-
droazepino[3,4-b]indole-2,10(1H, 3H)-dicarboxylate ((()-16a).
Aziridine (()-8a (200 mg, 0.352 mmol) and ammonium formate
(33 mg, 0.528 mmol) were dissolved in absolute MeOH (10 mL).
After addition of Pd/C (10 mg, 5%(w/w)) the reaction was heated
to reflux for 1.5 h. After cooling to room temperature the reaction
mixture was filtered and the solvent was removed in vacuo.
Purification by column chromatography (silica gel 70-230 mesh,
n-hexane:ethyl acetate 6:1) yielded an off-white solid (155 mg,
76%). Rf 0.58 (n-hexane:ethyl acetate 1:1). mp 71 °C (ethyl acetate:
Di-tert-butyl 5-Methoxy-4-(4-methylphenylsulfonamido)-1-
oxo-4,5-dihydroazepino[3,4-b]indole-2,10(1H,3H)-dicarboxy-
late ((()-18a). Aziridine (()-8a (284 mg, 0.50 mmol) was
suspended in absolute MeOH (5 mL) and ceric ammonium nitrate
(CAN) (27 mg, 0.05 mmol) was added. The reaction was stirred at
room temperature for 9 h until no further changes were observed
by TLC. The solvent was removed in vacuo. Purification by column
chromatography (silica gel 70-230 mesh, n-hexane:ethyl acetate
3:1) yielded the starting material (150 mg) and a white solid product
(141 mg, 47%, 99% based on recycled starting material). Rf 0.21
(n-hexane:ethyl acetate 3:1). Mp 79-80 °C (n-hexane:ethyl acetate).
1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.00 (1H, d, J ) 8.6 Hz),
7.82 (1H, d, J ) 8.3 Hz), 7.73 (2H, d, J ) 8.1 Hz), 7.60 (1H, d,
J ) 7.8 Hz), 7.55 (1H, ddd, J ) 8.4, 7.2, 1.2 Hz), 7.47 (2H, d, J
) 7.8 Hz), 7.39 (1H, unresolved ddd), 4.70 (1H, br s), 4.07-3.96
(1H, m), 3.83 (1H, dd, J ) 14.9, 5.6 Hz), 3.43 (1H, dd, J ) 14.8,
1
n-hexane). H NMR (400 MHz, DMSO-d6) δ (ppm) 7.97 (1H, d,
J ) 8.6 Hz), 7.84 (1H, d, J ) 7.1 Hz), 7.73 (1H, d, J ) 8.3 Hz),
7.51 (1H, unresolved ddd), 7.50-7.44 (3H, m), 7.33 (1H, unre-
solved ddd), 4.00-3.84 (2H, m), 3.54 (1H, dd, J ) 14.7, 8.3 Hz),
2.99 (1H, dd, J ) 15.7, 3.2 Hz), 2.88 (1H, dd, J ) 15.7, 6.6 Hz),
2.44 (3H, s), 1.53 (9H, s), 1.45 (9H, s). 13C NMR (100 MHz,
DMSO-d6) δ (ppm) 161.1, 150.6, 148.5, 143.0, 138.4, 137.4, 130.2,
129.8, 127.8, 127.4, 126.5, 123.3, 123.1, 120.8, 114.0, 84.4, 82.6,
52.3, 47.8, 27.5, 27.2, 26.0, 21.0. IR (KBr) ν (cm-1) 3439 m, 3267
sh, 2978 m, 2927 m, 2856 sh, 1742 s, 1599 w, 1553 w, 1450 m,
1415 m, 1395 m, 1370 s, 1326 m, 1236 m, 1158 s, 1122 sh, 1092
m, 1064 m, 1022 w, 992 m, 956 w, 893 w, 852 w, 816 w, 764 m,
750 m, 707 w, 664 m, 590 w, 552 w, 524 w. MS (EI) m/z (rel.
intensity) 569 (1), 383 (9), 369 (7)339 (12), 275 (6), 199 (14), 198
(100), 197 (19), 185 (33), 184 (18), 91 (8), 56 (42), 55 (14). HRMS
(ESI) calcd for C29H35N3NaO7S (M + Na+) 592.2088, found
592.2091.
10.4 Hz), 2.99 (3H, s), 2.44 (3H, s), 1.54 (9H, s), 1.38 (9H, s). 13
C
NMR (75 MHz, DMSO-d6) δ (ppm) 160.4, 150.1, 148.4, 143.2,
138.3, 136.7, 130.7, 130.0, 127.8, 127.7, 126.5, 123.8, 122.4, 120.1,
114.1, 85.0, 82.2, 76.1, 56.5, 55.0, 46.7, 27.5, 27.2, 21.0. IR (KBr)
ν (cm-1) 3438 m, 3278 m, 2981 m, 2933 m, 2821 w, 1753 s, 1679
w, 1665 w, 1649 w, 1599, 1548 w, 1477 sh, 1449 s, 1416 m, 1394
sh, 1372 s, 1350 s, 1325 s, 1288 s, 1261 m, 1228 m, 1213 m, 1160
s, 1093 s, 1078 sh, 1043 w, 1025 m, 994 s, 958 w, 892 m, 862 m,
833 m, 815 w, 785 m, 772 m, 753 m, 707 w, 664 m, 596 w, 553
s, 538 sh, 472 w. MS (EI) m/z (rel. intensity) 599 (1), 499 (4), 399
(13), 339 (11), 338 (15), 288 (33), 274 (17), 244 (29), 228 (11),
4-Methyl-N-(1-oxo-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-
4-yl)benzenesulfonamide ((()-16b). Compound (()-16a (90 mg,
J. Org. Chem, Vol. 72, No. 23, 2007 8857

Kaiser et al.
215 (15), 214 (13), 213 (26), 212 (100), 198 (12), 187 (14), 186
(28), 185 (92), 184 (31), 183 (19), 169 (12), 156 (17), 155 (20),
130 (24), 129 (16), 128 (14), 92 (13), 91 (36), 60 (15), 57 (12), 56
(51), 55 (14), 44 (72), 41 (79). HRMS (EI) calcd for C30H37N3O8S
(M+) 599.2296, found 599.2296.
156 (16), 155 (19), 97 (10), 91 (30), 83 (12), 71 (15), 68 (33), 57
(24), 55 (17). HRMS (EI) calcd for C22H21N5O3S (M+) 435.1360,
found 435.1360.
General Procedure for Ring-Opening Reactions of Aziridines
with Secondary Amines (Procedure C). Aziridine (()-8a (142
mg, 0.25 mmol) was dissolved in absolute 1,4-dioxane (5 mL) under
argon in a Schlenk tube with a Teflon screwed stopper. After
addition of the appropriate amine (1.25 mmol) the sealed reaction
vessel was heated to 80 °C for 5 d. Then it was cooled to room
temperature and the solvent was removed in vacuo. Purification
by column chromatography (silicagel 70-230 mesh, CH2Cl2 to
CH2Cl2:MeOH 30:1 as a gradient eluent) yielded an oily, pale-
yellow product. This was washed or recrystallized from hot diethyl
ether as described below and in the Supporting Information.
4-Methyl-N-(1-oxo-5-(pyrrolidin-1-yl)-1,2,3,4,5,10-hexahy-
droazepino[3,4-b]indol-4-yl)benzenesulfonamide ((()-20a). A
crude product was obtained following general procedure C.
Recrystallization from boiling diethyl ether yielded a white solid
(86 mg, 78%). Rf 0.37 (CH2Cl2:MeOH 10:1). Mp 185 °C (Et2O).
1H NMR (300 MHz, DMSO-d6) δ (ppm) 11.49 (1H, br s), 7.89-
7.76 (2H, m), 7.72 (2H, d, J ) 8.3 Hz), 7.44-7.33 (4H, m), 7.18
(1H, unresolved ddd), 7.01 (1H, unresolved ddd), 3.94 (1H, d, J )
3.4 Hz), 3.81-3.69 (1H, m), 3.52-3.40 (1H, m), 3.11-2.97 (1H,
m), 2.40 (3H, s), 2.38-2.26 (2H, m), 2.16-2.01 (2H, m), 1.54-
1.35 (4H, br s). 13C NMR (75 MHz, DMSO-d6) δ (ppm) 164.1,
142.5, 138.9, 135.7, 129.5, 128.6, 128.5, 126.6, 123.5, 120.5, 119.1,
N-(5-Methoxy-1-oxo-1,2,3,4,5,10-hexahydroazepino[3,4-b]in-
dol-4-yl)-4-methylbenzenesulfonamide ((()-18b). Sulfonamide
(()-18a (128 mg, 0.213 mmol) was dissolved in CH2Cl2 and
activated silica (600 mg, 0.040-0.063 mm) was added. The solvent
was removed in vacuo and the residue was heated to 70 °C for 13
h. Purification by column chromatography (silica gel 70-230 mesh,
n-hexane:ethyl acetate 1:2) yielded a white solid (63 mg, 74%). Rf
0.31 (n-hexane:ethyl acetate). Mp 170 °C (n-hexane:ethyl acetate).
1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.54 (1H, br s), 8.01-
7.92 (2H, m), 7.77 (2H, unresolved ddd), 7.46-7.37 (4H, m), 7.21
(1H, ddd, J ) 8.3, 6.9, 1.0 Hz), 7.04 (1H, ddd, J ) 8.3, 6.9, 1.0
Hz), 4.42 (1H, d, J ) 3.9 Hz), 3.76-3.69 (1H, m), 3.46-3.38 (1H,
m), 3.19-3.10 (1H, m), 3.06 (3H, s), 2.40 (3H, s). 13C NMR (75
MHz, DMSO-d6) δ (ppm) 163.4, 142.7, 138.5, 135.8, 129.6, 128.0,
127.9, 126.6, 124.0, 120.2, 119.7, 112.8, 112.3, 76.5, 55.3, 51.6,
40.9, 21.0. IR (KBr) ν (cm-1) 3349 s, 3284 m, 3199 m, 2927 m,
2823 sh, 1733 w, 1651 s, 1597 w, 1578 w, 1549 m, 1480 s, 1445
m, 1341 s, 1291 m, 1248 w, 1211 w, 1185 sh, 1158 s, 1116 m,
1091 s, 1020 m, 996 m, 960 m, 884 m, 839 w, 815 m, 781 w,
740 m, 663 m, 615 w, 538 m, 430 w. HRMS (EI) calcd for
C20H21N3NaO4S (M + Na+) 422.1145, found 422.1145.
2,3,4,5-Tetrahydro-5-(1H-pyrazol-1-yl)-4-(tosylamino)azepino-
[3,4-b]indol-1(10H)-one ((()-19a). Aziridine (()-8a (113 mg, 0.2
mmol) and 1H-pyrazole (136 mg, 2.0 mmol) were dissolved in an
CH2Cl2 and activated silica (429 mg, 0.040-0.063 mm) was added.
The solvent was removed under reduced pressure and the solid
mixture was heated under argon at 70 °C for 16 h. Purification by
column chromatography (silica gel 70-230 mesh, CH2Cl2 to CH2-
Cl2:MeOH 50:1 as the gradient eluent) yielded the crude product.
This was dissolved in CH2Cl2 and n-hexane was added dropwise.
After cooling to 4 °C a white solid (51 mg, 59%) was collected by
filtration. Rf 0.34 (CH2Cl2:MeOH 10:1). Mp 206 °C (CH2Cl2:n-
113.1, 112.1, 61.0, 54.0, 50.0, 42.8, 22.8, 21.0. IR (KBr) ν (cm-1
)
3337 s, 3204 s, 3061 sh, 2964 m, 2873 m, 2803 m, 1918 w, 1739
w, 1645 s, 1577 w, 1547 s, 1484 s, 1444 s, 1337 s, 1305 m, 1289
m, 1246 m, 1214 m, 1186 w, 1156 s, 1092 s, 1042 w, 1007 w, 991
m, 948 m, 877 w, 835 w, 814 m, 776 m, 741 s, 660 s, 579 m, 550
s, 536 s, 436 m. MS (EI) m/z (rel. intensity) 438 (5), 367 (44), 283
(13), 213 (60), 212 (100), 199 (10), 198 (72), 197 (17), 185 (67),
169 (12), 167 (14), 156 (19), 155 (24), 129 (11), 128 (16), 92 (12),
91 (29), 71 (51), 70 (68). HRMS (EI) calcd for C23H26N4O3S (M+)
438.1720, found 438.1721.
Acknowledgment. The authors thank the Federal Ministry
of Education and Research (BMBF) and the German Research
Foundation (DFG) for financial support of this work. Dr. C.
Fischer, Mrs. M. Heyken, Mrs. C. Mewe s, Mrs. A. Lehmann,
Mrs. S. Buchholz (all Leibniz Institut fu¨r Katalyse e.V. an der
Universita¨t Rostock), and Mr. E. Schmidt (CELISCA) are
acknowledged for their technical and analytical support.
1
hexane). H NMR (400 MHz, DMSO-d6) δ (ppm) 11.67 (1H, s),
8.23 (1H, d, J ) 5.1 Hz), 8.20 (1H, d, J ) 3.9 Hz), 7.53 (2H,
unresolved ddd), 7.46 (1H, d, J ) 2.2 Hz), 7.41 (1H, unresolved
ddd), 7.31-7.26 (3H, m), 7.18-7.12 (1H, m), 6.89-6.84 (2H, m),
6.05 (1H, unresolved dd), 5.79 (1H, d, J ) 6.1 Hz), 3.96 (1H,
unresolved ddd), 3.31-3.26 (1H, m), 2.37 (3H, s) 13C NMR (100
MHz, DMSO-d6) δ (ppm) 163.2, 142.5, 139.0, 138.0, 135.9, 129.7,
129.6, 128.3, 126.9, 126.3, 124.1, 119.8, 119.4, 112.4, 110.4, 105.0,
61.6, 56.4, 42.4, 21.0. IR (KBr) ν (cm-1) 3321 w, 3060 m, 2921
m, 1645 s, 1599 m, 1580 w, 1554 m, 1479 s, 1454 m, 1397 m,
1338 s, 1288 s, 1248 w, 1221 w, 1185 m, 1160 s, 1091 s, 1046 m,
1020 w, 1007 w, 992 w, 944 w, 882 w, 837 w, 814 m, 747 s, 705
m, 662 m, 579 m, 552 m, 534 m, 433 w. MS (EI) m/z (rel. intensity)
435 (4), 265 (12), 264 (71), 222 (13), 213 (23), 212 (100), 198
(19), 197 (19), 196 (12), 185 (74), 184 (23), 183 (11), 169 (18),
Supporting Information Available: All experimental proce-
dures, characterization of all other compounds, molecular structures,
and crystallographic data of 7, (()-8a-c, (()-11f, and (()-15d
and atom coordinates of calculated (()-6 (A) and cationic
intermediate (B). This material is available free of charge via the
Internet at http://pubs.acs.org.
JO7016026
8858 J. Org. Chem., Vol. 72, No. 23, 2007