Polystyrene sulfonyl chloride: A highly orthogonal linker resin for the synthesis of nitrogen-containing heterocycles

Article abstract of DOI:10.1002/anie.200901643

One linker, broad application: A simple sulfonamide linker for primary and secondary amines was used for the construction of small libraries of privileged indole and quinolone structures on a solid phase. After the synthesis, the products can be liberated ion a traceless manner under electron transfer conditions or according to a "safety catch" principle.

Full text of DOI:10.1002/anie.200901643

Angewandte
Chemie
DOI: 10.1002/anie.200901643
Solid-Phase Synthesis
Polystyrene Sulfonyl Chloride: A Highly Orthogonal Linker Resin for
the Synthesis of Nitrogen-Containing Heterocycles**
Matthias Mentel, Axel M. Schmidt, Michael Gorray, Peter Eilbracht, and Rolf Breinbauer*
In memory of Peter Welzel
Solid-phase organic synthesis (SPOS) is probably the most
efficient tool for the synthesis of large and diverse compound
libraries. During the last few years, the focus has shifted
towards libraries of more complex and structurally diverse
substances (diversity-oriented synthesis; DOS)[1] and natural
products (biology-inspired synthesis; BIOS).[2] Concomi-
tantly, the methodological frontiers of SPOS have been
redefined. To achieve the highest possible flexibility in
synthesis a highly orthogonal linker system is needed, which
means that the chemical entity which attaches the substrate to
the polymer should not only be stable against a very diverse
set of reaction conditions, but also be cleaved quantitatively
under very mild conditions at the end of the reaction
sequence.[3] Unfortunately, most linker systems used in
SPOS exhibit only limited orthogonality. Herein, we report
on the use of commercially available polystyrene sulfonyl
chloride[4] as an inexpensive support with built-in linker
functionality, and its application in the synthesis of amine-
based compound libraries of privileged structures.[5] The
superior stability of this linker allows the synthesis of scaffold-
rearranged libraries of nitrogen-containing heterocycles,
which can be cleaved from the resin in a traceless manner
under electron transfer mediated by radical anions or
according to the “safety catch” principle.
The arenesulfonyl moiety can be regarded as one of the
most stable protecting groups for primary and secondary
amines.[6,7] Whilst it is stable against most acidic, basic, and
oxidative reaction conditions and also common reducing
agents, it can be cleaved under electron-transfer conditions,
such as Na/NH3,[8] radical anions,[9] SmI2,[10] or electrolysis,[11]
in a mild fashion. Our interest in the implementation of
electron-transfer conditions in SPOS[12] has motivated us to
take advantage of these opportunities to establish a reduc-
tively cleavable linker system.[13]
Starting from inexpensive polystyrene sulfonyl chloride
(1; loading 1.5 mmolgÀ1, 1% DVB, 100–200 mesh), olefinic
secondary amines 2 were immobilized on the solid support.
The olefinic sulfonamides 3 were transformed on the solid
phase using a domino hydroformylation/Fischer indole syn-
thesis[14–17] (Scheme 1, Table 1). The sulfonamide linker was
[*] Prof. Dr. R. Breinbauer
Institute of Organic Chemistry, Graz University of Technology
Stremayrgasse 16, 8010 Graz (Austria)
Fax: (+43)316-873-8740
E-mail: breinbauer@tugraz.at
Dr. M. Mentel, Dr. A. M. Schmidt, Prof. Dr. P. Eilbracht,
Prof. Dr. R. Breinbauer
Department 3, Organic Chemistry
Technische Universitꢀt Dortmund
Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
Dr. M. Mentel, Dipl.-Chem. M. Gorray, Prof. Dr. R. Breinbauer
Department of Chemical Biology
Max Planck Institute of Molecular Physiology
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
Scheme 1. Immobilization of olefins and domino hydroformylation/
indole synthesis followed by radical-anion-mediated cleavage: a) 2a,
Py/THF 1:1, RT, overnight; b) 20 mol% [Rh(acac)(CO)2], 50 bar CO,
10 bar H2, 4a, PTSA, THF, 808C, 2 d; c) 10 equiv 6 (1m in THF), THF,
08C, 2 h. Py=pyridine, THF=tetrahydrofuran, acac=acetylacetonate,
PTSA=para-toluenesulfonic acid.
Dr. M. Mentel, Prof. Dr. R. Breinbauer
Institute of Organic Chemistry, University of Leipzig
Johannisallee 29, 04103 Leipzig (Germany)
Dr. M. Mentel
European Molecular Biology Laboratory (EMBL)
Meyerhofstrasse 1, 69117 Heidelberg (Germany)
[**] This work was supported by the Max Planck Society, the Fonds der
Chemischen Industrie (Liebig scholarship for R.B.), the Deutsche
Forschungsgemeinschaft (Br2324/1-1), the State of Northrhine–
Westfalia, and the University of Leipzig.
stable under the acidic reaction conditions, whereas the use of
a hydroxymethylbenzoic acid (HMBA) linker[18] resulted in
cleavage. Both benzhydrylidene- (4a,b) and benzylidene-
protected (4c) phenylhydrazines could be successfully
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901643.
Angew. Chem. Int. Ed. 2009, 48, 5841 –5844
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5841

Communications
Table 1: Yields and purities [%] in the synthesis of tryptamine and
homotryptamine derivatives from olefins 2a,b and phenylhydrazones
4a–c.[a]
4a
4b
4c
R=H
R’=Ph
R=o-Me
R’=Ph
R=p-OMe
R’=H
2a
7aa
36
7ab
27
7ac
38
(96/88)
(98/89)
(93/75)
Scheme 2. Immobilization of 4-piperidone and synthesis of a pyrrolo-
[3,2-b]quinolone library: a) BnPPh3Br, nBuLi, THF, 08C to reflux, 7 h;
b) KOH, EtOH, reflux, 19 h, 81% (2 steps); c) 1, Py/THF 1:1, RT, 2 d;
d) O3, CH2Cl2, À788C, 2 h, then PPh3 or Py, RT, overnight, 85%
(2 steps); e) phenylhydrazine 11, ZnCl2, THF, MS 4 ꢁ, 708C, 18 h;
f) O3, CH2Cl2, À788C, 15 min, then Py, to RT, 1 h; g) Et3N/DMF 1:1,
808C, overnight. Bn=benzyl, MS=molecular sieves, DMF=N,N-
dimethylformamide.
2b
7ba
34
(73/85)
7bb
36
(84/88)
7bc
21
(70/83)
[a] Yields after cleavage with lithium biphenyl and aqueous workup. GC-
MS/HPLC-UV purities (280 nm) are given in brackets.
Table 2: Synthesis of pyrrolo[3,2-b]quinolones.
11
R=
15
R=
yield of crude material isolated yield[b]
(purity)[a] [%]
[%]
employed as substrates. The generated tryptamine and
homotryptamine derivatives 5 were cleaved from the solid
phase under electron-transfer conditions by employing lith-
ium biphenyl (6) in high purity and good yields (21–38% over
all steps; Scheme 1, Table 1).[19,20]
Limitations of this cleavage method were found in the use
of bromine-substituted phenylhydrazones, which delivered
the corresponding dehalogenated indoles after cleavage in
similar yields. The use of nitro-substituted phenylhydrazones,
which are known to be notoriously problematic substrates in
Fischer indole synthesis for electronic reasons, was not
successful, and delivered only 1,4-phenylenediamine after
cleavage. This result can be explained by the reductive
cleavage of the corresponding solid-phase-bound nitrophe-
nylhydrazone.
In a further library synthesis of indole-based nitrogen-
containing heterocycles, polymer-bound 4-piperidone 10 was
synthesized starting from 1 and benzylidene-masked piper-
idone 9 (after 9 was immobilized on the resin and the ketone
moiety was then liberated by ozonolysis; Scheme 2). The
success of immobilization was ascertained qualitatively by
FTIR spectroscopy (carbonyl stretching frequency at
1730 cmÀ1) and quantitatively by employing the FmPH
method.[21] By this method, piperidone resin 10 with a loading
of 1.16 mmolgÀ1 was prepared on 20 g scale. The subsequent
conversion of piperidone 10 into indoles under Fischer
conditions proved challenging, which was due in part to the
high hydrolytic instability of the phenylhydrazone intermedi-
ate. Considerable experimentation was required to identify
suitable water- and oxygen-free conditions, which were
achieved by addition of molecular sieves and “degassing” of
the resin by swelling in toluene and evaporation of the
solvent. These precautions then allowed Fischer indolization
with ZnCl2 catalysis (Table 2). The intended cleavage of
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
H
59 (84)
15
14
8
4-Br
4-OMe
4-Me
7-Br
7-OMe
7-Me
67 (97)
30 (90)
26 (84)
8
4-SO2NH2 7-SO2NH2 25 (n.d.)
4-tBu
4-F
5
7-tBu
7-F
7-CN
50 (94)
60 (91)
19 (26)
19
14
2
4-CN
4-triazolyl 7-triazolyl 41 (82)
3-F
–
5
8-F
6-F
4
15
7
13
–
2
38 (27+71)
41 (53+43)
21 (25+31)
3-Me
–
3-NO2
–
2-Et
2-Br
2-F
2,3-Me2
2,4-F2
8-Me
6-Me
8-NO2
6-NO2
5-Et
5-Br
5-F
5,6-Me2
5,7-F2
32 (92)
72 (92)
64 (73)
53 (86)
74 (75)
12
15
20
3
s
t
10[c]
[a] HPLC purity at 254 nm. [b] Yields of isolated product after three steps
based on the loading of piperidone resin 10. [c] Yield determined by
NMR spectroscopy.
indoles 12 under reductive conditions mediated by radical
anions was problematic in this case; highly variable yields and
purities of the cleavage products were obtained.
Our intention to increase the diversity of the library by
implementing the Witkop–Winterfeldt reaction on a solid
phase for the first time was unaffected by these problems, and
resulted in the scaffold-rearranging conversion of indoles into
quinolones.[22] Indoles 12 were converted by ozonolysis into
ketolactam intermediates 13, which were sequentially con-
densed selectively under basic conditions into g-quinolones 14
5842
www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 5841 –5844

Angewandte
Chemie
Table 3: Yields [%] of phenylpyrrolo[3,2-b]quinolones.[a]
and cleaved from the resin as pyrrolo[3,2-b]quinolones 15.
Such a simple detosylation reaction has not yet been reported
for comparable sulfonamides, and benefits from the forma-
tion of an extended aromatic system as the driving force
(Scheme 2, Table 2).
Ar=
18b (7-Ar)
18q (5-Ar)
16a
16b
16c
16d
16e
16 f
3-MeC6H4
4-FC6H4
3-MeOC6H4
4-MeOC6H4
3-NO2C6H4
4-CHOC6H4
10
7
16
13
13
11[b]
9[c]
7
3
The selectivity of the ozonolysis reaction for indoles and
the subsequent selective cleavage of the oxidation products
are instrumental to the success of the synthesis. Upon using 3-
substituted phenylhydrazines 11j, 11l, and 11n in the Fischer
indole synthesis, regioisomers are obtained that can be
isolated by HPLC after cleavage from the resin. A remark-
able result is the successful [3,3]-sigmatropic rearrangement
of the phenylhydrazones generated from electron-deficient
sulfonamido-, nitrilo-, and nitrophenylhydrazines 11e, 11h,
and 11n. In total, we were able to assemble 20 differently
substituted pyrrolo[3,2-b]quinolones, which is a heterocyclic
scaffold that has not been described in the literature to
date.[23] The relatively low yields reflect both the ambitious
and multi-step reaction sequence and the non-quantitative
indole rearrangement for electron-deficient substrates. The
desired pyrrolo[3,2-b]quinolones were obtained mostly in
high purity (> 80% from HPLC) without contamination by
intermediate phenylhydrazone or unreacted piperidone. For
screening purposes, all the compounds were purified by
means of semi-preparative RP-HPLC.
To increase the diversity of the library, the derivatization
of bromo derivatives 12b and 12q by Suzuki coupling was
explored (Scheme 3, Table 3). Double coupling with S-Phos–
palladium catalyst[24] finally enabled the reaction with these
indole derivatives, which are highly unreactive because of
their electron-rich nature, with conversions of 85–100%.
Suzuki reaction with 4-formylphenylboronic acid (16 f)
furnished coupling products 17bf and 17qf, which were
converted on resin with sodium cyanoborohydride into
benzylic alcohols 19. Cleavage and flash chromatographic
purification delivered pyrrolo[3,2-b]quinolones 20.
21
3[d] (20bf)
6[d] (20qf)
[a] Yields of isolated product over four steps based on the loading of
piperidone resin 10. [b] Yield determined by NMR spectroscopy.
[c] Coupling conditions: toluene/THF/H2O 1.45:1.45:0.1, 908C, 40 h
(single coupling). [d] Yields over 5 steps.
In conclusion, polystyrene sulfonyl chloride is an inex-
pensive linker resin for the synthesis of privileged nitrogen-
containing heterocycles, such as indoles and quinolones,
which can be cleaved under electron-transfer conditions.
The extraordinary orthogonality of this linker resin allowed
the synthesis of a small library of novel pyrrolo[3,2-b]quino-
lones in which we could employ acidic (Fischer indole
synthesis), basic and transition-metal-mediated (Suzuki cou-
pling), oxidative (Witkop–Winterfeldt oxidation), and reduc-
tive conditions (borohydride reduction) in a single sequence
on a solid phase. We are convinced that with the development
of further such highly orthogonal linker system, new oppor-
tunities for SPOS will arise.
Received: March 25, 2009
Published online: July 6, 2009
Keywords: domino reactions · quinolones ·
.
solid-phase synthesis · sulfonamide linkers · Witkop–
Winterfeldt oxidation
[1] a) M. D. Burke, S. L. Schreiber, Angew. Chem. 2004, 116, 48 – 60;
Angew. Chem. Int. Ed. 2004, 43, 46 – 58; b) T. E. Nielsen, S. L.
Schreiber, Angew. Chem. 2008, 120, 52 – 61; Angew. Chem. Int.
Ed. 2008, 47, 48 – 56.
[2] A. Nꢀren-Mꢁller, I. Reis-CorrÞa Jr. , H. Prinz, C. Rosenbaum,
K. Saxena, H. J. Schwalbe, D. Vestweber, G. Cagna, S. Schunk,
O. Schwarz, H. Schiewe, H. Waldmann, Proc. Natl. Acad. Sci.
USA 2006, 103, 10606 – 10611. Selected Reviews: a) L. A.
Wessjohann, Curr. Opin. Chem. Biol. 2000, 4, 303 – 309; b) R.
Breinbauer, I. R. Vetter, H. Waldmann, Angew. Chem. 2002,
114, 3002 – 3015; Angew. Chem. Int. Ed. 2002, 41, 2878 – 2890;
c) P. M. Abreu, P. S. Branco, J. Braz. Chem. Soc. 2003, 14, 675 –
712; d) A. Ganesan, Curr. Opin. Biotechnol. 2004, 15, 584 – 590;
e) M. Mentel, R. Breinbauer, Top. Curr. Chem. 2007, 278, 209 –
241.
[3] Reviews: a) S. Brꢂse, S. Dahmen in Handbook of Combinatorial
Chemistry ((Eds.: K. C. Nicolaou, R. Hanko, W. Hartwig),
Wiley-VCH, Weinheim, 2002, pp. 59 – 169; b) F. Guillier, D.
Orain, M. Bradley, Chem. Rev. 2000, 100, 2091 – 2157; c) I. W.
James, Tetrahedron 1999, 55, 4855 – 4946.
Scheme 3. Suzuki cross-coupling of polymer-bound bromoindoles,
aldehyde reduction, and cleavage after Witkop–Winterfeldt oxidation:
a) 0.2 equiv Pd(OAc)2, 0.8 equiv S-Phos, ArB(OH)2 (16), K3PO4, THF,
808C, 24 h, double coupling; b) O3, CH2Cl2, À788C, 15 min, then Py,
warming to RT, 1 h; c) Et3N/DMF 1:1, 808C, overnight; d) 1% AcOH/
THF, NaBH3CN, RT, overnight.
[4] For applications of polystyrene sulfonyl chloride in the immobi-
lization of reagents, see: a) W. R. Roush, D. Feitler, J. Rebek,
Tetrahedron Lett. 1974, 15, 1391 – 1392; b) F. Gaviꢃa, P. Gil, B.
Palazꢄn, Tetrahedron Lett. 1979, 15, 1333 – 1336; c) K. Kama-
hori, S. Tada, K. Ito, S. Itsuno, Tetrahedron: Asymmetry 1995, 6,
2547 – 2555; d) J.-b. Hu, G. Zhao, Z.-d. Ding, Angew. Chem.
Angew. Chem. Int. Ed. 2009, 48, 5841 –5844
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5843

Communications
2001, 113, 1143 – 1145; Angew. Chem. Int. Ed. 2001, 40, 1109 –
2, 89 – 92; e) L. Yang, Tetrahedron Lett. 2000, 41, 6981 – 6984;
f) D. M. Ketcha, L. J. Wilson, D. E. Portlock, Tetrahedron Lett.
2000, 41, 6253 – 6257; g) H.-C. Zhang, H. Ye, K. B. White, B. E.
Maryanoff, Tetrahedron Lett. 2001, 42, 4751 – 4754; h) T. Y. H.
Wu, S. Ding, N. S. Gray, P. G. Schultz, Org. Lett. 2001, 3, 3827 –
3830; i) C. Macleod, R. C. Hartley, D. W. Hamprecht, Org. Lett.
2002, 4, 75 – 78; j) S.-H. Lee, B. Clapham, G. Koch, J. Zimmer-
mann, K. D. Janda, J. Comb. Chem. 2003, 5, 188 – 196; k) H.
Tanaka, H. Ohno, K. Kawamura, A. Ohtake, H. Nagase, T.
Takahashi, Org. Lett. 2003, 5, 1159 – 1162; l) C. Rosenbaum, C.
Katzka, A. Marzinzik, H. Waldmann, Chem. Commun. 2003,
1822 – 1823; m) K. Knepper, S. Brꢂse, Org. Lett. 2003, 5, 2829 –
2832; n) H. Ohno, H. Tanaka, T. Takahashi, Synlett 2004, 508 –
511; o) C. Rosenbaum, P. Baumhof, R. Mazitschek, O. Mꢁller, A.
Giannis, H. Waldmann, Angew. Chem. 2004, 116, 226 – 230;
Angew. Chem. Int. Ed. 2004, 43, 224 – 228; p) H.-S. Mun, W.-H.
Ham, J.-H. Jeong, J. Comb. Chem. 2005, 7, 130 – 135; q) M.
Koppitz, G. Reinhardt, A. van Lingen, Tetrahedron Lett. 2005,
46, 911 – 914; r) T. Yao, D. Yue, R. C. Larock, J. Comb. Chem.
2005, 7, 809 – 812; s) L.-P. Sun, W.-M. Dai, Angew. Chem. 2006,
118, 7413 – 7416; Angew. Chem. Int. Ed. 2006, 45, 7255 – 7258;
reviews: t) S. Brꢂse, C. Gil, K. Knepper, Bioorg. Med. Chem.
2002, 10, 2415 – 2437; u) J. Tois, R. Franzꢅn, A. Koskinen,
Tetrahedron 2003, 59, 5395 – 5405.
1111; e) G. Wang, Y. Liu, G. Zhao, Tetrahedron: Asymmetry
2005, 16, 1873 – 1879; f) S. Itsuno, S. Arima, N. Haraguchi,
Tetrahedron 2005, 61, 12074 – 12080; g) A. Porcheddu, G.
Giacomelli, J. Org. Chem. 2006, 71, 7057 – 7059.
[5] B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo, R. M.
Freidinger, W. L. Whitter, G. F. Lundell, D. F. Veber, P. S.
Anderson, R. S. L. Chang, V. J. Lotti, D. J. Cerino, T. B. Chen,
P. J. Kling, K. A. Kunkel, J. P. Springer, J. Hirshfield, J. Med.
Chem. 1988, 31, 2235 – 2246.
[6] T. W. Greene, P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3rd ed., Wiley, New York, 1999.
[7] For
a thiol-cleavable nitrobenzenesulfonamide linker, see:
a) M. S. Congreve, C. Kay, J. J. Scicinski, S. V. Ley, G. Williams,
P. J. Murray, S. C. McKeown, S. P. Watson, Tetrahedron Lett.
2003, 44, 4153 – 4156; b) C. Kay, P. J. Murray, L. Sandow, A. B.
Holmes, Tetrahedron Lett. 1997, 38, 6941 – 6944.
[8] V. du Vigneaud, O. K. Behrens, J. Biol. Chem. 1937, 117, 27 – 36.
[9] S. Ji, L. B. Gortler, A. Waring, A. Battisti, S. Bank, W. D.
Closson, P. Wriede, J. Am. Chem. Soc. 1967, 89, 5311 – 5312.
[10] E. Vedejs, S. Lin, J. Org. Chem. 1994, 59, 1602 – 1603.
[11] L. Horner, H. Neumann, Chem. Ber. 1965, 98, 3462 – 3469.
[12] a) S. Nad, R. Breinbauer, Synthesis 2005, 3654 – 3665; b) S. Nad,
R. Breinbauer, Angew. Chem. 2004, 116, 2347 – 2349; Angew.
Chem. Int. Ed. 2004, 43, 2297 – 2299; c) For a review of the
application of electron,transfer reagents in SPOS, see: M.
Mentel, R. Breinbauer, Eur. J. Org. Chem. 2007, 4283 – 4292.
[13] For a related approach in which electrodes have been function-
alized with a sulfonamide linker, see: a) J. F. Pilard, G. March-
and, J. Simonet, Tetrahedron 1998, 54, 9401 – 9414; b) G. March-
and, J. F. Pilard, B. Fabre, J. Rault-Berthelot, J. Simonet, New J.
Chem. 1999, 23, 869 – 875; c) G. Marchand, J. F. Pilard, J.
Simonet, Tetrahedron Lett. 2000, 41, 883 – 885; d) J. F. Pilard,
C. Cougnon, J. Rault-Berthelot, A. Berthelot, C. Hubert, K.
Tran, J. Electroanal. Chem. 2004, 568, 195 – 201.
[18] For examples for the SPOS of indoles using an HMBA linker,
see: a) R. M. Kim, M. Manna, S. M. Hutchins, P. R. Griffin, N. A.
Yates, A. M. Bernick, K. T. Chapman, Proc. Natl. Acad. Sci.
USA 1996, 93, 10012 – 10017; b) S. M. Hutchins, K. T. Chapman,
Tetrahedron Lett. 1996, 37, 4869 – 4872; c) Y. Cheng, K. T.
Chapman, Tetrahedron Lett. 1997, 38, 1497 – 1500.
[19] Apart from lithium biphenyl, lithium di-tert-butylbiphenyl and
lithium naphthalene have also been studied as radical anions in
initial experiments that enabled the cleavage of polymer-bound
sulfonamides in similar yields.
[20] For the cleavage from a polymeric support with reductive
desulfonylation, see: a) Y. F. Chang, C.-Y. Liu, C.-W. Guo, Y.-C.
Wang, J.-M. Fang, W.-C. Cheng, Mol. Diversity 2003, 6, 33 – 41;
b) Y. F. Chang, C.-Y. Liu, C.-W. Guo, Y.-C. Wang, J.-M. Fang, W.-
C. Cheng, J. Org. Chem. 2008, 73, 7197 – 7203.
[14] a) P. Kꢀhling, A. M. Schmidt, P. Eilbracht, Org. Lett. 2003, 5,
3213 – 3216; b) A. M. Schmidt, P. Eilbracht, J. Org. Chem. 2005,
70, 5528 – 5535; c) P. Linnepe (nꢅe Kꢀhling), A. M. Schmidt, P.
Eilbracht, Org. Biomol. Chem. 2006, 4, 302 – 313; d) B. P.
´
Bondzic, P. Eilbracht, Org. Lett. 2008, 10, 3433 – 3436; e) B. P.
[21] The quantification was performed by derivatization with FmPH
reagent and subsequent Fmoc determination in a manner similar
to: S. K. Shannon, G. Barany, J. Org. Chem. 2004, 69, 4586 – 4594.
[22] M. Mentel, R. Breinbauer, Curr. Org. Chem. 2007, 11, 159 – 176.
[23] The pyrrolo[3,2-b]quinolones described herein can be found as
substructures in quindolinone alkaloids: a) R. C. Crouch, A. O.
Davis, T. D. Spitzer, G. E. Martin, M. H. M. Sharaf, P. L. Schiff,
C. H. Phoebe, A. N. Tackie, J. Heterocycl. Chem. 1995, 32, 1077 –
1080; for N-isomeric dihydropyrrolo[3,4-b]quinolones, see: b) B.
Willemsens, I. Vervest, D. Ormerod, W. Aeltermann, C. Fannes,
N. Mertens, I. E. Markꢄ, S. Lemaire, Org. Process Res. Dev. 2006,
10, 1275 – 1281; c) X. Li, S. Branum, R. K. Russell, W. Jiang, Z.
Sui, Org. Process Res. Dev. 2005, 9, 640 – 645.
Bondzic, A. Farwick, J. Liebich, P. Eilbracht, Org. Biomol.
Chem. 2008, 6, 3723 – 3731; f) B. P. Bondzic, P. Eilbracht, Org.
Biomol. Chem. 2008, 6, 4059 – 4063.
[15] M. Ahmed, R. Jackstell, A. M. Seayad, H. Klein, M. Beller,
Tetrahedron Lett. 2004, 45, 869 – 873.
[16] For reviews of domino reactions, see: a) L. F. Tietze, Chem. Rev.
1996, 96, 115 – 136; b) L. F. Tietze, G. Brasche, K. M. Gericke,
Domino Reactions in Organic Synthesis, Wiley-VCH, Weinheim,
2006.
[17] For selected examples for the SPOS of indoles, see: a) M. C.
Fagnola, I. Candiani, G. Visentin, W. Cabri, F. Zarini, N.
Mongelli, A. Bedeschi, Tetrahedron Lett. 1997, 38, 2307 – 2310;
b) H.-C. Zhang, K. K. Brumfield, B. E. Maryanoff, Tetrahedron
Lett. 1997, 38, 2439 – 2442; c) H. Stephensen, F. Zaragoza,
Tetrahedron Lett. 1999, 40, 5799 – 5802; d) H.-C. Zhang, H. Ye,
A. F. Moretto, K. K. Brumfield, B. E. Maryanoff, Org. Lett. 2000,
[24] K. L. Billingsley, K. W. Anderson, S. L. Buchwald, Angew.
Chem. 2006, 118, 3564 – 3568; Angew. Chem. Int. Ed. 2006, 45,
3484 – 3488.
5844
www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 5841 –5844