Copper-catalyzed tandem annulation/arylation for the synthesis of diindolylmethanes from propargylic alcohols

Article abstract of DOI:10.1039/c4cc05901h

Various highly substituted 2,3′-diindolylmethane heterocycles were prepared from propargylic alcohols and indole nucleophiles via a transition metal-catalyzed tandem indole annulation/arylation reaction for the first time. Among the metal catalysts we exa

Full text of DOI:10.1039/c4cc05901h

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Copper-catalyzed tandem annulation/arylation
for the synthesis of diindolylmethanes from
propargylic alcohols†
Cite this: Chem. Commun., 2014,
50, 12293
Received 29th July 2014,
Accepted 25th August 2014
Hui Li,ab Xiaoxun Li,a Hao-Yuan Wang,a Gabrielle N. Winston-McPherson,a
Hao-miao Julie Geng,a Ilia A. Guzeic and Weiping Tang*ac
DOI: 10.1039/c4cc05901h
www.rsc.org/chemcomm
Various highly substituted 2,30-diindolylmethane heterocycles were
prepared from propargylic alcohols and indole nucleophiles via a
transition metal-catalyzed tandem indole annulation/arylation
reaction for the first time. Among the metal catalysts we examined,
the most economical copper(I) catalyst provided the highest efficiency.
The indole nucleophiles could also be replaced by other electron-rich
arenes or alcohols.
As one of the most abundant heterocycles in natural products and
pharmaceutical agents, indole continuously attracts significant
attention of the synthetic community and many efficient indole
annulation methods have been developed to date.1 To increase the
synthetic efficiency of indole derivatives, it is ideal to combine the
indole annulation with other transformations in a cascade process. We
have recently coupled indole annulation with [4+3] cycloaddition for
the synthesis of cyclohepta[b]indoles2 and arylation for the synthesis
of 2,30-diindolylmethanes using platinum or rhodium catalysts.3
2,30-Diindolylmethanes are not only present in bioactive compounds4
but also important precursors for other heterocycles.5 We recently
Fig. 1 Two complementary approaches for 2,30-diindolylmethanes via
tandem indole annulation and arylation.
evaluated various 2,30-diindolylmethanes as selective agonists of the heterocycles with diverse substituents under mild conditions would
arylhydrocarbon receptor,6 which are potential therapeutics for benign help us to further study their biological activities.6 Inspired by
prostate hyperplasia,7 inflammation disorders,8 and cancers.9
Chan’s pioneering work on preparing indole derivatives from
Our previously developed Pt- or Rh-catalyzed indole annulation/ propargylic alcohol 5,11 we proposed the synthesis of 2,30-diindolyl-
arylation cascade is shown in Fig. 1a. Metal carbene intermediate 4 methane 6 from the same type of propargylic alcohol to overcome
was generated by the annulation of propargylic ether 1 via inter- the limitation of our previous method (Fig. 1b). In addition to
mediate 3.10 An indole nucleophile could then react with this expensive platinum, gold, and palladium catalysts, we found that
carbene to afford 2,30-diindolylmethane 2.3 Substituent on the the much cheaper copper catalysts were also very effective for the
20-position can be introduced by starting with the corresponding synthesis of heterocycle 6 with an additional R2-substituent from
substituted indoles. However, substituent on the 3-position of 2 alcohol 5. Preliminary mechanistic investigations suggest that the
cannot be introduced by this method. Being able to access these mechanism for the formation of 6 involves an allyl cation inter-
mediate instead of a metal carbene intermediate in the synthesis of
a School of Pharmacy, University of Wisconsin, Madison, WI, 53705, USA.
product 2 from ether 1. The starting material, mechanism and
products of the new method described here are thus all different
from our previous approach. The current method has the
advantages of being able to access more substituted indoles
and use cheaper copper catalyst.
E-mail: wtang@pharmacy.wisc.edu
b School of Pharmaceutical Science and Technology, Tianjin University, Tianjin,
300072, P. R. China
c Department of Chemistry, University of Wisconsin, Madison, WI, 53706, USA
† Electronic supplementary information (ESI) available: 1H NMR, 13C NMR, IR, and
HRMS of new compounds. CCDC 1016687 and 1016688. For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c4cc05901h
Propargylic alcohol 7 was prepared according to literature
procedures12 and treated with various catalysts in the presence
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 12293--12296 | 12293

View Article Online
Communication
ChemComm
Table 1 Screening conditionsa
Table 2 Scope of indoles 8a
Entry
Conditions
Yield (%) Entry
Substrate
Product
Yieldb (%)
73
1
2
3
4
5
6
7
8
9
PtCl2 (10 mol%)
71
55
0
50
48
0
58
Trace
72
75
Pd(OAc)2 (10 mol%)
Au(PPh3)Cl (10 mol%)
Au(PPh3)Cl (10 mol%), AgOTf (10 mol%)
AgO2CCF3 (10 mol%)
CuI
CuCl2 (10 mol%)
CuBr2 (10 mol%)
1
2
75
77
CuOTf (10 mol%)
Cu(CH3CN)4PF6 (10 mol%)
10
a
The yield of 9a was determined by 1H NMR of the crude product.
3
of N-methylindole 8a (eqn (1), Table 1). A 71% yield of product
9a was obtained when a previously used PtCl2 catalyst3 was
employed (entry 1). Lower yields were observed for most other
catalysts (entries 2–8). Cationic copper(I) catalysts afforded the
highest yield of 9a (entries 9 and 10). We also examined other
solvents including toluene, acetonitrile, THF, dioxane, methylene
chloride, methanol, and DMF. No desired product was observed in
DMF. The yields ranged from 27% to 60% in other solvents.
Conditions in entry 10 using an economically affordable copper
catalyst were then selected for further study.
4
5
6
7
8d, R = OMe
8e, R = Me
8f, R = Cl
9d
9e
9f
95
68
63
70
8g, R = F
9g
Under the conditions in entry 10 of Table 1, we also tried to
replace the tosyl group in 7 by Boc or hydrogen (free aniline).
No desired product was observed.
8
9
8h, R = Me
8i, R = F
9h
9i
70
70
(1)
10
11
12
8j, R = Me
8k, R = Cl
8l, R = F
9j
9k
9l
67
65
81
We next examined the scope of indole nucleophiles using
propargylic alcohol 7 as the electrophile (eqn (2), Table 2). A similar
yield was obtained for the parent indole 8b without the N-methyl
group. The structure of 9b was unambiguously established by X-ray
analysis (CCDC 1016687). We also tried a cationic gold catalyst
(entry 4 in Table 1) for the reaction between propargylic alcohol 7
and indole 8b. No desired product was observed in this case.
We next examined different substituents on the benzene
part of indole (C4–C7 positions). Most indoles could participate
in the tandem reaction. The reaction was not very sensitive to
steric hindrance since 4-methyl substituted indoles 8c worked
fine. The highest yield was obtained using electron-rich indole 8d.
Other substituents such as methyl, chloro, and fluoro groups
could be tolerated on 5-, 6-, and 7-positions of indoles 8e to 8l.
A phenyl group could be tolerated on the 2-position of indole 8m.
For 3-substituted indole 8n, the alkylation occurred on the
2-position to yield 2,20-diindolylmethane 10. Surprisingly,
complex mixtures were observed for 2-, or 3-methyl substituted
indoles 8o and 8p. No desired product was obtained for indole
8q, which may be due to the combination of unfavorable steric
and electronic factors.
13
71
14
78
15
16
A complex mixture
A complex mixture
17
No reaction
a
Conditions: 7 (1 equiv.), indole 8 (2 equiv.), Cu(CH3CN)4PF6 (10 mol%),
b
60 1C, ClCH2CH2Cl. Isolated yield.
The scope of the propargylic alcohols was also examined by groups (11c and 11d), though the yields were lower for the latter.
varying R1 and R2 substituents in structure 11 (eqn (3), Table 3).11,13 Surprisingly, product 13 was observed when R2 was a phenyl group
The R1 of 11 could be various alkyl groups (11a and 11b) or aryl in substrate 11e. The structure of compound 13 was unambiguously
12294 | Chem. Commun., 2014, 50, 12293--12296
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
Table 3 Scope of propargylic alcohols 9a
Entry
Substrate
Product
Yieldb (%)
1
2
3
11a, R = nBu
11b, R = iPr
11c, R = Ph
12a
12b
12c
72
83
42
4
60
Fig. 2 Coupling with other nucleophiles.
5
63c
a
Conditions: 9 (1 equiv.), indole 8a (2 equiv.), Cu(CH3CN)4PF6 (10 mol%),
b
c
60 1C, ClCH2CH2Cl. Isolated yield. Indole 8b was employed.
determined by X-ray analysis (CCDC 1016688). No reaction
occurred when both R1 and R2 were methyl groups. When both
R1 and R2 were hydrogen, no desired product was observed,
suggesting that the two methods outined in Fig. 1 are completely
complementary to each other.
Fig. 3 Preliminary investigation of the mechanism.
(2)
with indole 8a under our standard conditions, product 9a was
obtained. No reaction occurred between 17 and 8a in the absence
of any catalyst. Brønsted acid could promote the arylation of 17 but
not the cyclization of 7.
The mechanism for the copper-catalyzed indole annulation/
arylation is proposed in Fig. 4. Copper-catalyzed intramolecular
hydroamination will afford intermediate 17, which can be trapped
by indole nucleophile 8a. The alkylation of indole 8a occurs at the
30-position only. In the presence of acid, an allyl cation intermediate
19 may be formed. Indole nucleophile 8a attacks the 2a-position of
the allyl cation to afford the final product 9a.
We also examined nucleophiles besides indoles. We were
pleased to find that 1,3-dimethoxybenzene also participated in
the tandem indole annulation/arylation cascade reaction
(Fig. 2). Alcohols could also serve as nucleophiles to yield
adducts 15 and 16. Product 16 has been previously prepared
from substrate 11c using a cationic gold catalyst.11 We demon-
strated that a much more economically affordable copper
catalyst was also effective for this transformation.
(3)
Chan’s group reported that 7 could undergo intramolecular
hydroamination to yield product 17 in the presence of a silver
catalyst (Fig. 3).14 This intermediate can undergo further cyclo-
isomerization and addition reactions to afford various indole
derivatives in the presence of a gold catalyst.11,12,14,15 When we
treated compound 17 derived from silver-catalyzed hydroamination
Fig. 4 Proposed mechanism.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 12293--12296 | 12295

View Article Online
Communication
ChemComm
Med. Chem., 2001, 9, 955; (b) H. J. Kramer, M. Podobinska,
A. Bartsch, A. Battmann, W. Thoma, A. Bernd, W. Kummer,
B. Irlinger, W. Steglich and P. Mayser, ChemBioChem, 2005, 6, 860.
5 (a) N. Wahlstrom, I. Romero and J. Bergman, Eur. J. Org. Chem.,
In summary, we have developed an efficient method for the
synthesis of diverse substituted 2,30-diindolylmethanes from
propargylic alcohols and indoles. The indole nucleophiles can be
replaced by other carbon or oxygen nucleophiles. Being able to use
economical copper catalyst to promote the hydroamination and
arylation cascade reaction makes this method and the syntheses
of related indole derivatives ideal for both medicinal and process
chemistry.
We thank the University of Wisconsin and NIH (R01GM088285)
for financial support. H.L. thanks Chinese Scholarship Council for
a fellowship and Dr Yu Tang (Tianjin University) for his mentoring.
H.-m.J.G. is a high school student from St. Mark’s School.
¨
2004, 2593; (b) H.-J. Knolker and K. R. Reddy, Chem. Rev., 2002,
¨
102, 4303; (c) A. W. Schmidt, K. R. Reddy and H.-J. Knolker, Chem.
Rev., 2012, 112, 3193.
6 G. N. Winston-McPherson, D. Shu and W. Tang, Bioorg. Med. Chem.
Lett., 2014, 24, 4023.
7 V. Mehta and C. M. Vezina, Differentiation, 2011, 82, 211.
8 (a) C. A. Beamer and D. M. Shepherd, Semin. Immunopathol., 2013,
35, 693; (b) P. B. Busbee, M. Rouse, M. Nagarkatti and
P. S. Nagarkatti, Nutr. Rev., 2013, 71, 353.
9 (a) S. Safe, S.-O. Lee and U.-H. Jin, Toxicol. Sci., 2013, 135, 1;
(b) W. A. Fritz, T.-M. Lin, S. Safe, R. W. Moore and R. E. Peterson,
Biochem. Pharmacol., 2009, 77, 1151; (c) A. McDougal, M. S. Gupta,
D. Morrow, K. Ramamoorthy, J. E. Lee and S. H. Safe, Breast Cancer
Res. Treat., 2001, 66, 147.
10 (a) K. Saito, H. Sogou, T. Suga, H. Kusama and N. Iwasawa, J. Am.
Chem. Soc., 2011, 133, 689; (b) P. A. Allegretti and E. M. Ferreira, Org.
Lett., 2011, 13, 5924; (c) P. A. Allegretti and E. M. Ferreira, Chem. Sci.,
2013, 4, 1053.
11 P. Kothandaraman, W. Rao, S. J. Foo and P. W. H. Chan, Angew.
Chem., Int. Ed., 2010, 49, 4619.
12 (a) P. Kothandaraman, S. R. Mothe, S. S. M. Toh and P. W. H. Chan,
J. Org. Chem., 2011, 76, 7633; (b) P. Kothandaraman, S. J. L. Lauw
and P. W. H. Chan, Tetrahedron, 2013, 69, 7471.
13 S. Ali, H.-T. Zhu, X.-F. Xia, K.-G. Ji, Y.-F. Yang, X.-R. Song and Y.-M.
Liang, Org. Lett., 2011, 13, 2598.
Notes and references
1 For recent reviews on indole synthesis, see: (a) J. Barluenga, F. Rodriguez
and F. J. Fananas, Chem. – Asian J., 2009, 4, 1036; (b) D. F. Taber and
P. K. Tirunahari, Tetrahedron, 2011, 67, 7195; (c) R. Vicente, Org. Biomol.
Chem., 2011, 9, 6469; (d) M. Platon, R. Amardeil, L. Djakovitch and
J.-C. Hierso, Chem. Soc. Rev., 2012, 41, 3929.
2 (a) D. Shu, W. Song, X. Li and W. Tang, Angew. Chem., Int. Ed., 2013,
52, 3237; for related [4+3] cycloadditions, see: (b) H. Kusama, H. Sogo,
K. Saito, T. Suga and N. Iwasawa, Synlett, 2013, 1364; (c) X. Han, H. Li,
R. P. Hughes and J. Wu, Angew. Chem., Int. Ed., 2012, 51, 10390.
3 D. Shu, G. N. Winston-McPherson, W. Song and W. Tang, Org. Lett.,
2013, 15, 4162.
14 D. Susanti, F. Koh, J. A. Kusuma, P. Kothandaraman and
P. W. H. Chan, J. Org. Chem., 2012, 77, 7166.
4 (a) G. Wille, P. Mayser, W. Thoma, T. Monsees, A. Baumgart,
H. J. Schmitz, D. Schrenk, K. Polborn and W. Steglich, Bioorg.
15 C. Chowdhury, B. Das, S. Mukherjee and B. Achari, J. Org. Chem.,
2012, 77, 5108.
12296 | Chem. Commun., 2014, 50, 12293--12296
This journal is ©The Royal Society of Chemistry 2014