Platinum-catalyzed tandem indole annulation/arylation for the synthesis of diindolylmethanes and indolo[3,2-b ]carbazoles

Article abstract of DOI:10.1021/ol4018408

Various diindolylmethanes were prepared from propargylic ethers and substituted indoles via a platinum-catalyzed tandem indole annulation/arylation cascade. The resulting diindolylmethanes could be converted to natural product malassezin by formylation or indolo[3,2-b]carbazoles by cyclization.

Full text of DOI:10.1021/ol4018408

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Platinum-Catalyzed Tandem Indole
Annulation/Arylation for the Synthesis
of Diindolylmethanes and
Indolo[3,2‑b]carbazoles
Dongxu Shu,†,‡ Gabrielle N. Winston-McPherson,† Wangze Song,† and
Weiping Tang*,†,‡
School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705,
United States, and Department of Chemistry, University of Wisconsin, Madison,
Wisconsin 53706, United States
wtang@pharmacy.wisc.edu
Received July 1, 2013
ABSTRACT
Various diindolylmethanes were prepared from propargylic ethers and substituted indoles via a platinum-catalyzed tandem indole annulation/
arylation cascade. The resulting diindolylmethanes could be converted to natural product malassezin by formylation or indolo[3,2-b]carbazoles by
cyclization.
Indole is one of the most abundant heterocycles in
bioactive natural products and pharmaceutical agents.
Not surprisingly, numerous efforts have been devoted to
the preparation of indoles from a diverse range of starting
materials.1,2 Most previous efforts, however, have focused
on indole annulation alone.1 The efficiency of the synthesis
can be increased significantly if the event of indole annula-
tion is coupled with other transformations in a cas-
cade manner. We recently developed a tandem indole
annulation/(4 þ 3) cycloaddition for the construction of
both indole and a seven-membered ring simultaneously in
the synthesis of cyclohepta[b]indoles.3 We herein report a
synthesis of diindolylmethanes via a platinum-catalyzed
indole annulation/arylation cascade as a continuation of
efforts in this area.
† School of Pharmacy.
‡ Department of Chemistry.
(1) For recent reviews on indole synthesis, see: (a) Barluenga, J.;
Rodriguez, F.; Fananas, F. J. Chem.;Asian J. 2009, 4, 1036. (b) Taber,
D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195. (c) Vicente, R. Org.
Biomol. Chem. 2011, 9, 6469. (d) Platon, M.; Amardeil, R.; Djakovitch,
L.; Hierso, J.-C. Chem. Soc. Rev. 2012, 41, 3929.
(2) For recent examples of indole annulations, see: (a) Cui, X.; Li, J.;
Fu, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2008, 49, 3458. (b) Oda, Y.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2012, 14, 664. (c) Ackermann,
L.; Lygin, A. V. Org. Lett. 2012, 14, 764. (d) Inamoto, K.; Asano, N.;
Nakamura, Y.; Yonemoto, M.; Kondo, Y. Org. Lett. 2012, 14, 2622. (e)
Xia, X.-F.; Wang, N.; Zhang, L.-L.; Song, X.-R.; Liu, X.-Y.; Liang,
Y.-M. J. Org. Chem. 2012, 77, 9163. (f) Song, W.; Ackermann, L. Chem.
Commun. 2013, 49, 6638.
(3) (a) Shu, D.; Song, W.; Li, X.; Tang, W. Angew. Chem., Int. Ed.
2013, 52, 3237. For a synthesis of cyclohepta[b]indoles by a different
type of (4 þ 3) cycloaddition, see: (b) Han, X.; Li, H.; Hughes, R. P.; Wu,
J. Angew. Chem., Int. Ed. 2012, 51, 10390.
(4) (a) Wille, G.; Mayser, P.; Thoma, W.; Monsees, T.; Baumgart, A.;
Schmitz, H. J.; Schrenk, D.; Polborn, K.; Steglich, W. Bioorg. Med.
Chem. 2001, 9, 955. (b) Kramer, H. J.; Podobinska, M.; Bartsch, A.;
Battmann, A.; Thoma, W.; Bernd, A.; Kummer, W.; Irlinger, B.;
Steglich, W.; Mayser, P. ChemBioChem 2005, 6, 860.
(5) Wahlstrom, N.; Romero, I.; Bergman, J. Eur. J. Org. Chem. 2004,
2593.
r
10.1021/ol4018408
XXXX American Chemical Society

Diindolylmethanes are present in not only natural pro-
ducts such as malassezin4 but also important precursors
for other naturally occurring heterocycles such as indolo-
carbazoles 2 and 3aꢀ3f5 shown in Figure 1.6 Malassezin,
ICZ, and FICZ are potent agonists of aryl hydrocarbon
receptor (AhR), which is best known for mediating the
toxicity of dioxin and related environmental toxins.7 Re-
cent studies showed that AhR also played a critical role in
immune cell differentiation,8 promoting intestinal immune
function,9 and the development of prostate.10 It has been
demonstrated that selective AhR modulators inhibit pros-
tate tumor metastasis11 and have antiasthmatic effects12 in
animal models. Indolo[3,2-b]carbazoles are also an impor-
tant class of organic electroluminescent compounds.6,13
Rearrangement of the symmetrical 3,30-diindolyl-
methanes to 2,3-diindolylmethanes could be realized using
iodine as the catalyst.14 Low yields, however, were ob-
served when substituted indoles were employed as the
substrates. Synthesis of nonsymmetric 2,3-diindolyl-
methanes requires the joining of two different indoles in
multiple steps.15
A metal carbene intermediate was generated from an-
nulation of propargylic ether 4 and trapped previously by a
diene in a (4 þ 3) cycloaddition.3a We envisioned that this
metal carbene intermediate could also be trapped by other
nucleophiles. In the presence of another indole, diindolyl-
methanes could then be prepared conveniently. We first
examined the conditions that were employed previously
(entries 1 and 2, Table 1). Wewere pleased tofind that both
Pt- and Rh-complexes promoted the formation of 2,30-
diindolylmethane product 6a, though the former provided
a higher yield. A slightly lower yield was obtained with a
lower catalyst loading (entry 3). The electron-poor phos-
phine ligand was proven to becriticalin the previous indole
annulation/(4 þ 3) cycloaddition cascade. In the case of
indole annulation/arylation to form diindolylmethanes,
using PtCl2 alone as the catalyst appeared to be sufficient
(entry 4). The yield again became slightly lower if the
amount of catalyst was lowered to 5 mol % (entry 5).
Other metal complexes did not produce any desired pro-
duct (entries 6ꢀ10).
Table 1. Screening of Catalysts and Conditionsa
entry
conditions
yield (%)
1
2
PtCl2 (10 mol %), P(C6F5)3 (20 mol %)
[Rh(CO)2Cl]2 (10 mol %), P[OCH(CF3)2]3
(20 mol %)
84
56
3
PtCl2 (5 mol %), P(C6F5)3 (10 mol %)
PtCl2 (10 mol %)
77
83b
76
0
4
5
PtCl2 (5 mol %)
6
AgBF4 (10 mol %)
7
AgOTf (10 mol %)
0
8
CuOTf (10 mol %)
0
9
AgOTf (10 mol %), P(C6F5)3 (20 mol %)
CuOTf (10 mol %), P(C6F5)3 (20 mol %)
0
10
0
a Unless noted otherwise, the yield of 6a was determined by 1H NMR
of crude product. b Isolated yield.
The scope of different indoles was examined for this
tandem indole annulation/arylation cascade using pro-
pargylic ether 4 as the starting material (Table 2).
Figure 1. Diindolylmethanes and indolo[3,2-b]carbazoles.
(6) (a) Knolker, H. J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303. (b)
Schmidt, A. W.; Reddy, K. R.; Knoelker, H.-J. Chem. Rev. 2012, 112,
3193.
(7) Denison, M. S.; Soshilov, A. A.; He, G.; Degroot, D. E.; Zhao, B.
Toxicol. Sci. 2011, 124, 1.
(11) Fritz, W. A.; Lin, T.-M.; Safe, S.; Moore, R. W.; Peterson, R. E.
Biochem. Pharmacol. 2009, 77, 1151.
(12) Jeong, K.-T.; Hwang, S.-J.; Oh, G.-S.; Park, J.-H. Int. Immuno-
pharmacol. 2012, 13, 377.
(8) (a) Quintana, F. J.; Basso, A. S.; Iglesias, A. H.; Korn, T.; Farez,
M. F.; Bettelli, E.; Caccamo, M.; Oukka, M.; Weiner, H. L. Nature 2008,
453, 65. (b) Stevens, E. A.; Mezrich, J. D.; Bradfield, C. A. Immunology
2009, 127, 299.
(13) (a) Gu, R.; Robeyns, K.; Van Meervelt, L.; Toppet, S.; Dehaen,
W. Org. Biomol. Chem. 2008, 6, 2484. (b) Boudreault, P. L. T.; Wakim,
S.; Tang, M. L.; Tao, Y.; Bao, Z. A.; Leclerc, M. J. Mater. Chem. 2009,
19, 2921.
(9) (a) Li, Y.; Innocentin, S.; Withers, D. R.; Roberts, N. A.;
Gallagher, A. R.; Grigorieva, E. F.; Wilhelm, C.; Veldhoen, M. Cell
2011, 147, 629. (b) Kiss, E. A.; Vonarbourg, C.; Kopfmann, S.; Hobeika,
E.; Finke, D.; Esser, C.; Diefenbach, A. Science 2011, 334, 1561.
(10) Mehta, V.; Vezina, C. M. Differentiation 2011, 82, 211.
(14) (a) Gu, R.; Hameurlaine, A.; Dehaen, W. Synlett 2006, 1535. (b)
Gu, R.; Hameurlaine, A.; Dehaen, W. J. Org. Chem. 2007, 72, 7207.
(15) (a) Tholander, J.; Bergman, J. Tetrahedron Lett. 1998, 39, 1619.
(b) Tholander, J.; Bergman, J. Tetrahedron 1999, 55, 6243. (c) Wahlstrom,
N.; Stensland, B.; Bergman, J. Synthesis 2004, 1187.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Scope of Indoles for Pt-Catalyzed Tandem Indole
Annulation/Arylation of Propargylic Ether 4a
Table 3. Scope of Aniline and Propargylic Ether for Pt-Cata-
lyzed Tandem Indole Annulation/Arylationa
a See Table 1 for conditions. b Isolated yield.
blocked in substrate 5j, 2,20-diindolylmethane was ob-
tained in 60% yield.
The scope of aniline and propargylic ether was also investi-
gated with different substituents (Table 3). We focused on
the para-position of the aniline to examine how the change
of pKa of the aniline influenced the efficiency of the
reaction. To our delight, anilines with either an electron-
donating methoxy group or an electron-withdrawing ester
group on the para-position participated in the tandem
reaction. Aniline 7a with an electron-donating para meth-
oxy group provided a higher yield of the desired product
than the one with a para electron-withdrawing group (7b).
A moderate 55% yield was observed when aniline 7c with a
free hydroxyl group was employed as the substrate. Sec-
ondary propargylic ether 7d could also participate in the
tandem reaction and afford diindolylethane 8d.
Wenextexaminednucleophiles besides indoles. Wewere
pleased tofindthatN-methylpyrrole could alsoserve asthe
nucleophile and product 9 was isolated in 68% yield (eq 1).
We previously reported that various substituted furans
underwent tandem indole annulation/(4 þ 3) cycloaddi-
tion with substrate 4.3 When 1,3-dimethoxybenzene or thio-
phene was employed, a complex mixture was obtained.
a Conditions: 4 (1 equiv), indole 5 (2 equiv), PtCl2 (10 mol %),
Na2CO3 (1.5 equiv), 100 °C, dioxane. b Isolated yield.
N-Methyl indole 5b afforded a high yield of the 2,30-
diindolyl methane product 6b. The yield became 20%
lower for 4-Br substituted N-methylindole 5c. Interest-
ingly, the 4-cyano substituted indole 5d did not interfere
with the efficiency of the tandem reaction. The indole
annulation/arylation reaction could also tolerate elec-
tron-donating methoxy or halogen substituents on the 5-
or 6-position of the indole (e.g., 5e, 5f, 5g, and 5h).
We then studied the effect of the substituent on the
2- and 3-position of indole 5. With a 2-phenyl substituent
on indole 5i, the yield of product 6i is comparable to 6a.
When the intrinsic more reactive 3-position of the indole is
To demonstrate the utility of the Pt-catalyzed indole
annulation/arylation method, we finished the synthesis
of natural product malassezin and a formal synthesis of
natural product FICZ as shown in Scheme 1. Removal of
the Boc-protecting group in product 6a under thermal
conditions yielded diindolylmethane 10, which could
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 1. Synthesis of Malassezin and FICZ
Scheme 2. Proposed Mechamism
can then lead to final diindolylmethane product 6a.
A (3 þ 2) cycloaddition between metal carbene 14 and
vinyl ethers has been reported.16a In our case, we did not
observe any (3 þ 2) cycloaddition product between metal
carbene 14 and indole.
In summary, we have developed an efficient method for
the synthesis of various highly substituted 2,30-diindolyl-
methanes. The indole annulation event is accompanied by
the coupling of two indole units. An electrophilic platinum
carbene intermediate was proposed to be involved in this
cascade reaction. We also demonstrated that the method
could be applied to the synthesis of natural products
malassezin and indolo[3,2-b]carbazoles.
undergo formylation to afford natural product malassezin
1.4a Acylation of diindolylmethane 10 followed by acid-
mediated cyclization produced indolo[3,2-b]carbazole 11,
which has been converted to natural product FICZ 3a
through a known sequence of reduction and oxidation.5
The spectroscopic data of compounds 1, 10, and 11 are all
in accordance with literature.17 The structure of 2,30-
diindolylmethane 6a is then further confirmed.
The proposed mechanism for the indole annulation/
arylation is shown in Scheme 2. After the coordination
of the metal catalyst to propargylic ether 4, 5-endo-cycliza-
tion of metal complex 12 will lead to the formation of
indole intermediate 13. Elimination of a methanol can then
produce metal carbene intermediate 14, which has been
proposed previously by us and others.3a,16 This electro-
philic metal carbene is then captured by an indole nucleo-
phile to form adduct 15. Protonation and rearomatization
Acknowledgment. We thank the NIH (R01GM088285)
and the University of Wisconsin for financial support.
1
Supporting Information Available. HNMR, 13CNMR,
IR, HRMS for starting materials and products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) (a) Saito, K.; Sogou, H.; Suga, T.; Kusama, H.; Iwasawa, N.
J. Am. Chem. Soc. 2011, 133, 689. (b) Allegretti, P. A.; Ferreira, E. M.
Org. Lett. 2011, 13, 5924. (c) Allegretti, P. A.; Ferreira, E. M. Chem. Sci
2013, 4, 1053.
(17) See Supporting Information for details.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX