3
find broad application in the synthesis of novel bioactive
carbazole and β-carboline derivatives.
1. Et3N, acetonitrile
2. DBU
(see Scheme 1)
2a-c
+
R
NH4OAc, AcOH
60 °C, 12 h
O
N
N
H
3a/3c/3d
Br
R'
Supplementary Material
R'
5 a:
c:
d:
R = phenyl, R' = methyl (69%)
R = R' = methyl (56%)
R = methyl, R' = phenyl (57%)
R = phenyl/
ethyl/methyl
Experimental section and copies of NMR spectra are available as
supplementary data.
1. Et3N, 60 °C, 30 min
2. DBU, 60 °C, 30 min
3. NH4OAc, 60, °C, 12 h
b:
e:
R = ethyl, R' = phenyl (41%)
R = methyl, R' = ethyl (58%)
References and notes
1.
Dai, J.; Dan, W.; Schneider, U.; Wang, J. Eur. J. Med.
Chem. 2018, 157, 622-656.
Scheme 2: Three-step cascade synthesis of β-carbolines starting
from sulfonamides 2a-c.
2.
3.
4.
Knölker, R. Chem. Rev. 2002, 102, 4303-4428.
Love, B. E. Org. Prep. Proc. Int. 1996, 28, 1-64.
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1315-1319; (b) Bracher, F.; Hildebrand, D. Liebigs Ann.
Chem. 1993, 1335-1337.
Bracher, F.; Hildebrand, D. Tetrahedron 1994, 50, 12329-
12336.
Ábrányi-Balogh, P.; Volk, B.; Milen, M. Tetrahedron Lett.
2018, 59, 617-619.
Letessier, J.; Detert, H.; Götz, K.; Opatz, T. Synthesis
2012, 44, 747-754.
Abbiati, G.; Beccalli, E. M.; Marchesini, A.; Rossi, E.
Synthesis 2001, 2477-2483.
(a) Milen, M.; Ábrányi-Balogh, P. Chem. Heterocycl.
Comp. 2016, 52, 996-998; (b) Dhiman, S.; Mishra, U. K.;
Ramasastry, S. S. V. Angew. Chem., Int. Ed. 2016, 55,
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1967-1976.
(a) Knölker, H.-J. Chem. Lett. 2009, 38, 8-13; (b) Sadig, J.
E. R.; Willis, M. C. Synthesis 2011, 1-22.
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253.
(a) Poudel, T. N.; Lee, Y. R. Chem. Sci. 2015, 6, 7028-
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Gehring, A. P.; Strödke, B.; Wirth, C. C.; Brügl, T.;
Abodo, L. O.; Dandekar, T.; Doerig, C.; Fischer, R.;
Tobin, A. B.; Alam, M. M.; Bracher, F.; Pradel, G. PLOS
one 2014, 9, 1-15; (c) Karlas, A.; Berre, S.; Couderc, T.;
Varjak, M.; Braun, P.; Meyer, M.; Gangneux, N.; Karo-
Astover, L.; Weege, F.; Raftery, M.; Schonrich, G.;
Klemm, U.; Wurzlbauer, A.; Bracher, F.; Merits, A.;
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A.; Huber, K.; Bracher, F.; Hartmann, R. K.; Aigner, A.
Neoplasia 2013, 15, 783-794.
This cascade reaction was further applied to the synthesis of a 3-
alkoxycarbonyl β-carboline. Preparation of the required
intermediate 6 could not be accomplished with the standard aldol
condensation of aldehyde 1 and ethyl pyruvate, and Lewis acid–
mediated condensation using BF3/acetic anhydride26 was also not
successful. Hence, the required enone moiety was built up by
Wittig olefination of aldehyde 1 with a pyruvate-derived
phosphorane. Upon conversion of the obtained α-ketoester
intermediate 6 with bromoacetophenone under the conditions
described above for diketoindole synthesis, the desired indole
was accompanied by poorly separable side-products. It was
again found that a one-pot procedure involving addition of
excess ammonium acetate immediately after DBU-mediated
generation of the diketoindole was most convenient, and 1-
phenylindole-3-carboxylate 7 was obtained in 63% yield
(Scheme 3).
5.
6.
7.
8.
9.
10.
11.
12.
13.
O
O
Ph3P
CHO
COOEt
COOEt
COOEt
acetonitrile, 50 °C, 16 h
NH
NH
32%
SO2
SO2
Ph
Ph
1
6
14.
1. bromoacetophenone (1.5 equiv.),
Et3N (1.5 equiv.), acetonitrile
2. DBU (3.5 equiv.), 60 °C, 30 min
3. NH4OAc (20 equiv.), 60 °C, 12 h
N
N
H
one-pot procedure
(63% overall yield)
7
Scheme 3: Wittig olefination to give vinylogous ketoester 6,
followed by one-pot conversion into β-carboline-3-carboxylate
7.
15.
(a) Honarnejad, K.; Daschner, A.; Gehring, A. P.;
Szybinska, A.; Giese, A.; Kuznicki, J.; Bracher, F.; Herms,
J. Transl. Psychiatry 2014, 4, e489; (b) Gehring, A. P.;
Tremmel, T.; Bracher, F. Synthesis 2014, 893-898; (c)
Strödke, B.; Gehring, A. P.; Bracher, F. Archiv Pharm.
2015, 348, 125-131; (d) Schuller, M.; Riedel, K.; Gibbs-
Seymour, I.; Uth, K.; Sieg, C.; Gehring, A. P.; Ahel, I.;
Bracher, F.; Kessler, B. M.; Elkins, J. M.; Knapp, S. ACS
Chem. Biol. 2017, 12, 2866-2874; (e) Moustakim, M.;
Riedel, K.; Schuller, M.; Gehring, A. P.; Monteiro, O. P.;
Martin, S. P.; Fedorov, O.; Heer, J.; Dixon, D. J.; Elkins, J.
M.; Knapp, S.; Bracher, F.; Brennan, P. E. Bioorg. Med.
Chem. 2018, 26, 2965-2972.
3. Conclusion
In conclusion, we have, based on valuable previous work on
both the preparation of diketoindole intermediates17 and their
further conversion into tricyclic heterocycles,16 developed novel
short cascade reactions leading to either highly substituted 1-
hydroxycarbazoles, 3-hydroxycarbazoles or β-carbolines starting
from readily accessible ortho-arylsulfonylaminobenzaldehydes.
Olefination of the aldehyde functionality by aldol condensation
or Wittig olefination gave reactive enone intermediates, which
underwent cascade reactions, either in two steps or in one-pot
conversions giving either hydroxycarbazoles or complex β-
carbolines. This divergent and straightforward approach should