Application of 6,7-indole aryne cycloaddition and Pd(0)-catalyzed Suzuki-Miyaura and Buchwald-Hartwig cross-coupling reactions for the preparation of annulated indole libraries

Article abstract of DOI:10.1021/co2000289

The construction of an unprecedented class of an indole-based library, namely, a 6,7-annulated-4-substituted 93-member indole library, using a strategic combination of 6,7-indolyne cycloaddition and cross-coupling reactions under both Suzuki-Miyaura and Buchwald-Hartwig conditions is described. This work represents the first example of library development that employs the indole aryne methodology. Annulated indoles, with the exception of only a few biologically active natural products (i.e., the trikentrins, herbindoles, teleocidins, and nodulisporic acids), have no representation in the PubChem or MLSMR databases. These structural entities are therefore predicted to have unique chemical property space characteristics and a high probability of exhibiting interesting biological activity.

Full text of DOI:10.1021/co2000289

LETTER
pubs.acs.org/acscombsci
Application of 6,7-Indole Aryne Cycloaddition and Pd(0)-Catalyzed
SuzukiÀMiyaura and BuchwaldÀHartwig Cross-Coupling Reactions
for the Preparation of Annulated Indole Libraries
Paul D. Thornton,‡ Neil Brown,†,‡ David Hill,‡ Ben Neuenswander,‡ Gerald H. Lushington,‡
Conrad Santini,‡ and Keith R. Buszek*,†,‡
†Department of Chemistry, University of Missouri, 5100 Rockhill Road, Kansas City, Missouri 64110, United States
‡Center of Excellence in Chemical Methodologies and Library Development, University of Kansas, 2034 Becker Drive, Lawrence,
Kansas 66047, United States
S Supporting Information
b
ABSTRACT: The construction of an unprecedented class of an
indole-based library, namely, a 6,7-annulated-4-substituted 93-
member indole library, using a strategic combination of 6,7-
indolyne cycloaddition and cross-coupling reactions under both
SuzukiÀMiyaura and BuchwaldÀHartwig conditions is de-
scribed. This work represents the first example of library
development that employs the indole aryne methodology. Annulated indoles, with the exception of only a few biologically active
natural products (i.e., the trikentrins, herbindoles, teleocidins, and nodulisporic acids), have no representation in the PubChem or
MLSMR databases. These structural entities are therefore predicted to have unique chemical property space characteristics and a
high probability of exhibiting interesting biological activity.
KEYWORDS: indole, aryne, indolyne, cycloaddition, SuzukiÀMiyaura, BuchwaldÀHartwig, libraries
ndole arynes or indolynes are a completely new class of
reactive aryne intermediate that we discovered and reported
annulated indoles, with the exception of only a few biologically
active natural products such as the trikentrins,15 herbindoles,16
teleocidins,17 and nodulisporic acids,18 (Figure 1) have no repre-
sentation in the PubChem or MLSMR databases.
These structural entities are therefore predicted to have
unique chemical property space characteristics. The indole aryne
methodology offers the most efficient access to these useful and
potentially valuable compounds. Without this methodology, the
construction of annulated indole scaffolds would be rendered
much more difficult, and as a consequence, the therapeutic
potential of their libraries would likely be overlooked. We now
report the first 93-member annulated indole library using a
combination of indole cycloaddition and cross-coupling
chemistry.
The 4,6,7-tribromoindole scaffold was synthesized using the
Bartoli reaction,19 and follows our previously published route
(Scheme 2).4 Thus, o-nitroaniline 11 was first brominated at C2
and C4 (Br2, MeOH/CH2Cl2 (1:1), 95%), followed by diazoti-
zation to afford the 2,3,5-tribromonitrobenzene 12. Application
of the Bartoli reaction conditions (vinylmagnesium bromide, 3.0
equiv, tetrahydrofuran (THF), À45 °C) consistently gave the
desired indole in 45% yield on a 5À10 g scale. The indole
nitrogen was then alkylated with methyl iodide (88%) to afford
the desired N-methyl indole scaffold 13.
I
beginning in 2007.1À5 As their unusual and fascinating chemistry
is revealed, they are becoming versatile and powerful tools for use
in organic synthesis, including natural products total synthesis.
Indeed, indolyne cycloaddition methodologies have already
proven their value, as we recently demonstrated in the total
synthesis of the trikentrins and the herbindoles. Subsequent
work from the Garg6À11 and Lautens12 laboratories using
indolyne chemistry helped to validate this point of view.
During the course of a second-generation formal total synthe-
sis of cis-trikentrin A,4 we found that the 4,6,7-tribromoindole 1
underwent highly selective metalÀhalogen exchange at the C7
bromo position, followed by 6,7-indole aryne formation and
subsequent cycloaddition with cyclopentadiene (Scheme 1) to
give the cycloadduct 3.
The C4 bromine was completely unaffected by these condi-
tions, but readily participated in transition metal-catalyzed cross-
coupling such as the Negishi reaction to afford the common
late stage intermediate 4. This reaction orthogonality appears
to be general in these systems, and has also been observed with 3
in the SuzukiÀMiyaura and BuchwaldÀHartwig cross-coupling
manifolds.4
Encouraged by these results, and in connection with our
ongoing efforts to identify interesting chemotypes for library
development,13,14 we decided to apply the indole aryne metho-
dology to the synthesis of novel, polycyclic annulated indoles.
Our strategy makes use of the unique advantages and properties
of indole aryne chemistry. This goal is significant because
Received: February 10, 2011
Revised:
May 27, 2011
Published: June 14, 2011
r
2011 American Chemical Society
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Scheme 1. Reaction Orthogonality in the 4,6,7-Tribromoindole System
Figure 1. Annulated indole alkaloid natural products.
Scheme 2. Synthesis of the 4-Bromo-6,7-annulated Indole Scaffolds
Scheme 3. Validation for the SuzukiÀMiyaura and BuchwaldÀHartwig Cross-Coupling Chemistry
Indole aryne formation(n-BuLi, 1.2equiv, toluene,À78 °Ctort)
followed by cycloaddition with either cyclopentadiene or furan
gave the corresponding cycloadducts 15 and 16 in 72% and 84%
yields, respectively. We elected to reduce the olefin with diimide
(generated in situ from o-nitrobenzosulfonhydrazide 17 and
triethylamine)20 as the presence of the alkene resulted in sharply
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Scheme 4. Synthesis of the Cyclopentadiene-Annulated SuzukiÀMiyaura Cross-Coupled Library
Scheme 5. Synthesis of the Furan-Annulated SuzukiÀMiyaura Cross-Coupled Library
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Scheme 6. Synthesis of the Cyclopentadiene-Annulated BuchwaldÀHartwig Cross-Coupled Library
Scheme 7. Synthesis of the Furan-Annulated BuchwaldÀHartwig Cross-Coupled Library
diminished yields in the subsequent cross-coupling reactions. In
this manner the final scaffolds 18 and 19 were each produced in
94% yield. The bridged bicyclic system is an uncommon structural
motif in library design. A recent report21 suggests that the presence
of additional sp3-hybridized content in complex library structures
correlates with an increased number of hits for activity in certain
cell-based assays, particularly in the area of CNS (e.g., histone
deacetylase, or HDAC, inhibition).
and BuchwaldÀHartwig reactions based on our successful pre-
vious experience and the fact that a diverse collection of boronic
acid and amine cross-coupling partners for these reactions are
readily available. During the development and validation studies,
we found that microwave heating gave superior results in terms of
yield and the minimization of side-products. Optimization for the
SuzukiÀMiyaura and BuchwaldÀHartwig reactions was carried
out with the furan-based scaffold (Scheme 3). The production
library targeted 128 compounds (2 scaffolds  32 boronic acids;
2 scaffolds  32 amines) on a reaction scale of 105 mg per scaffold.
With the key scaffolds in hand, our attention turned to the
cross-coupling reactions. We elected to use the SuzukiÀMiyaura
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Figure 2. SuzukiÀMiyaura and BuchwaldÀHartwig product distribution.
Of the 128 compounds targeted, 93 were produced and
purified to a threshold of approximately 90% or better via mass-
directed fractionation (MDF), which represents a 73% pass rate.
There were 51 SuzukiÀMiyaura reaction products (Schemes 4
and 5) and 42 BuchwaldÀHartwig coupled products (Schemes 6
and 7). Both the SuzukiÀMiyaura and BuchwaldÀHartwig
library sets showed a broad range of aromatic and heteroaromatic
moieties that support a diverse array of substitution and func-
tional groups (aldehydes, alcohols, alkenes, amides, ethers,
thioethers, halides). The majority of library members in the
SuzukiÀMiyaura series were obtained with a yield of 4À76%,
while those in the BuchwaldÀHartwig manifold were realized
in 5À83%. All library members were produced in quantities
between 20 and 50 mg, with 12 in excess of 50 mg, and six in the
range of 5À20 mg (Figure 2).
(25{13}, 25{18}, and 23{13}) occupied cells with zero existing
MLPCN compounds.
In conclusion, we have prepared the first annulated and
polycyclic 93-member indole library using 6,7-indole aryne
cycloaddition chemistry combined with versatile cross-coupling
reactions to afford a diverse suite of novel structures. All of the
compounds thus produced have been submitted to the NIH
Molecular Libraries Screening Centers Network (MLSCN) for
biological evaluation with a broad range of biochemical and cell-
based assays. Other drug-like designs based on the annulated indole
platform are in progress and will be disclosed in due course.
’ ASSOCIATED CONTENT
S
In silico profiling22À26 of physicochemical and ADME proper-
ties, which is reported in detail in Supporting Information, Table
1, suggests that the 6,7-indole aryne products generated from
both the SuzukiÀMiyaura and BuchwaldÀHartwig libraries
should be reasonably amenable to both biochemical and cell-
based assays. In general, the libraries are fully compliant with the
Lipinski Rule of Five23 in that none of the constituent com-
pounds have more than one violation, and nearly two-thirds of
the species have no violations. The observed violations entail
marginally high cLogP values, which range up to 7.75 among
violators. Predicted solubility in aqueous and 2% DMSO solu-
tions is correspondingly marginal for these violators, but the vast
majority had solubilities adequate for our analytical and pre-
parative processing and thus should be viable for screening. The
library products are generally predicted to yield good cell
permeability profiles, volume distribution, and albumin binding.
Our models suggest that the compounds are not generally very
likely to display hERG blocking tendencies. Many of them are
predicted to exhibit blood-brain-barrier permeability, which
might prove useful for probing central nervous system targets.
As a whole, compounds in this study are exceptionally unique
relative to the current MLPCN screening set that forms our
reference for comparison. The full product manifold spans 46
distinct cells in chemical space, which bespeaks a significant
amount of chemical diversity in these library elaborations. Only
six compounds (24{7}, 24{15}, 24{18}, 21{6}, 21{15} and
21{18}) were found to occupy regions of chemical space whose
compound density was above the mean, while 75 products
occupied areas with less than half the mean density, 23 were in areas
with less than 10% of the mean density, and three compounds
Supporting Information. Detailed experimental proce-
b
dures, H and 13C NMR data for a representative number of
1
compounds reported, computed in silico parameters, and meth-
ods for the in silico analysis. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: buszekk@umkc.edu.
Funding Sources
We acknowledge support of this work by the National Institutes
of Health (The University of Kansas Chemical Methodology and
Library Development Center of Excellence, KU-CMLD),
NIGMS, Grant P50 GM069663. We also acknowledge support
from the National Institutes of Health, NIGMS, Grant R01
GM069711 (KRB).
’ ACKNOWLEDGMENT
We thank Mr. Jonathan Bunn (KU-CMLD) for his technical
assistance in the Bartoli reaction. We also thank Ms. Kathy
Garrison (Department of Chemistry, UMKC) for her help in the
preparation of this manuscript.
’ REFERENCES
(1) Buszek, K. R.; Luo, D.; Kondrashov, M.; Brown, N.;
Vander Velde, D. Indole-Derived Arynes and Their Diels-Alder Reac-
tivity with Furans. Org. Lett. 2007, 9, 4135–4137.
447
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(2) Buszek, K. R.; Brown, N.; Luo, D. Concise Total Synthesis of
(()-cis-Trikentrin A and (()-Herbindole A via Intermolecular Indole
Aryne Cycloaddition. Org. Lett. 2009, 11, 201–204.
Nucleus. Tetrahedron Lett. 1986, 27, 6245–6248. (d) Nakatsuka, S.;
Masuda, T.; Goto, T. Total Synthesis of (()-Teleocidin B-3 and B-4.
Tetrahedron Lett. 1987, 28, 3671–3674.
(3) Brown, N.; Luo, D.; VanderVelde, D.; Yang, S.; Brassfield, A.;
Buszek, K. R. Regioselective Diels-Alder Cycloadditions and Other
Reactions of 4,5-, 5,6-, and 6,7-Indole Arynes. Tetrahedron Lett. 2009,
50, 63–65.
(4) Brown, N.; Luo, D.; Decapo, J. A.; Buszek, K. R. New Synthesis
of (()-cis-Trikentrin A via Tandem Indole Aryne Cycloaddition/
Negishi Reaction. Applications to Library Development. Tetrahedron
Lett. 2009, 50, 7113–7115.
(18) (a) Singh, S. B.; Ondeyka, J. G.; Jayasuriya, H.; Zink, D. L.; Ha,
S. N.; Dahl-Roshak, A.; Greene, J.; Kim, J. A.; Smith, M. M.; Shoop, W.;
Tkacz, J. S. Nodulisporic Acids D-F: Structure, Biological Activities, and
Biogenetic Relationships. J. Nat. Prod. 2004, 67, 1496–1506. For recent
synthetic studies, see:(b) Smith, A. B., III; Kuerti, L.; Davulcu, A. H.;
Cho, Y. S.; Ohmoto, K. Indole Diterpene Synthetic Studies: Develop-
ment of a Second-Generation Synthetic Strategy for (+)-Nodulisporic
Acids A and B. J. Org. Chem. 2007, 72, 4611–4620.
(5) Garr, A. N.; Luo, D.; Brown, N.; Cramer, C. J.; Buszek, K. R.;
VanderVelde, D. Experimental and Theoretical Investigations into the
Unusual Regioselectivity of 4,5-, 5,6-, and6,7-Indole Aryne Cycloadditions.
Org. Lett. 2010, 12, 96–99.
(6) Bronner, S. M.; Bahnck, K. B.; Garg, N. K. Indolynes as
Electrophilic Surrogates: Fundamental Reactivity and Synthetic Appli-
cations. Org. Lett. 2009, 11, 1007–1010.
(7) Tian, X.; Huters, A. D.; Douglas, C. J.; Garg, N. K. Concise
Synthesis of the Bicyclic Scaffold of N-Methylwelwitindolinone
C Isothiocyanate via an Indolyne Cyclization. Org. Lett. 2009, 11,
2349–2351.
(19) (a) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. The
Reaction of Vinyl Grignard Reagents with 2-Substituted Nitroarenes: A
New Approach to the Synthesis of 7-Substituted Indoles. Tetrahedron
Lett. 1989, 30, 2129–2132. (b) Bartoli, G.; Bosco, M.; Dalpozzo, R.;
Palmieri, G.; Marcantoni, E. Reactivity of Nitro- and Nitroso-Arenes
with Vinyl Grignard Reagents: Synthesis of 2-(Trimethylsilyl)indoles.
J. Chem. Soc. PT1 1991, 2757–2761. (c) Bosco, M.; Dalpozzo, R.; Bartoli,
G.; Palmieri, G.; Petrini, M. Mechanistic Studies on the Reaction of
Nitro- and Nitrosoarenes with Vinyl Grignard Reagents. J. Chem. Soc.
PT2 1991, 657–663. (d) Dalpozzo, R.; Bartoli, G. Bartoli Indole
Synthesis. Curr. Org. Chem. 2005, 9, 163–178.
(8) Bronner, S. M.; Garg, N. K. Efficient Synthesis of 2-(Trimethylsilyl)-
phenyl Trifluoromethanesulfonate: A Versatile Precursor to o-Benzyne.
J. Org. Chem. 2009, 74, 8842–8843.
(20) Buszek, K. R.; Brown, N. Improved Method for the Diimide
Reduction of Multiple Bonds on Solid-Supported Substrates. J. Org.
Chem. 2007, 72, 3125–3128.
(9) Cheong, P. H.-Y.; Paton, R. S.; Bronner, S. M.; Im, G.-T. J.; Garg,
N. K.; Houk, K. N. Indolyne and Aryne Distortions and Nucleophilic
Regioselectivities. J. Am. Chem. Soc. 2010, 132, 1267–1269.
(10) Im, G-Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong,
P. H.-Y.; Houk, K. N.; Garg, N. K. Indolyne Experimental
and Computational Studies: Synthetic Applications and Origins of
Selectivities of Nucleophilic Additions. J. Am. Chem. Soc. 2010, 132,
17933–17944.
(21) Marcaurelle, L. A.; Comer, E.; Dandapani, S.; Duvall, J. R.;
Gerard, B.; Kesavan, S.; Lee, M. D.; Liu, H.; Lowe, J. T.; Marie, J.-C.;
Mulrooney, C. A.; Pandya, B. A.; Rowley, A.; Ryba, T. D.; Suh, B.-C.; Wei,
J.; Young, D. W.; Akella, L. B.; Ross, N. T.; Zhang, Y.-L.; Fass, D. M.; Reis,
S. A.; Zhao, W.-N.; Haggarty, S. J.; Palmer, M.; Foley, M. A. An Aldol-
Based Build/Couple/Pair Strategy for the Synthesis of Medium- and
Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase In-
hibitors. J. Am. Chem. Soc. 2010, 132, 16962–16976.
(11) Bronner, S. M.; Goetz, A. E.; Garg, N. K. Overturning Indolyne
Regioselectivities and Synthesis of Indolactam V. J. Am. Chem. Soc. 2011,
133, 3832–3835.
(12) Nguyen, T. D.; Webster, R.; Lautens, M. Rh(I)-Catalyzed Ring-
Opening of Hetaryne-Furan Diels-Alder Adducts: Rapid Access to
Stereochemically Defined Heterocyclic Scaffolds. Org. Lett. 2011,
13, 1370–1373.
(13) Brown,N.;Xie,B.;Markina,N.;VanderVelde,D.;Perchellet,J.-P.H.;
Perchellet, E. M.; Crow, K. R.; Buszek, K. R. Synthesis of a Natural Product-
Inspired Eight-Membered Ring Lactam Library via Ring-Closing Metathesis.
Bioorg. Med. Chem. Lett. 2008, 18, 4876–4879.
(22) SYBYL 8.0; The Tripos Associates: St. Louis, MO, 2008.
(23) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
Experimental and Computational Approaches to Estimate Solubility and
Permeability in Drug Discovery and Development. Adv. Drug Delivery
Rev. 1997, 23, 3–25.
(24) Concord 8.0; The Tripos Associates: St. Louis, MO, 2008.
(25) Cruciani, G., Meniconi, M., Carosati, E., Zamora, I., Mannhold,
R. VOLSURF: A Tool for Drug ADME-Properties Prediction. In
Methods and Principles in Medicinal Chemistry; van de Waterbeemd,
H., Lennern€as, H., Artursson, P., Eds.; Wiley-VCH Verlag GmbH & Co.:
Weinheim, Germany, 2003.
(14) Brown, N.; Gao, G.; Minatoya, M.; Xie, B.; VanderVelde, D.;
Lushington, G. H.; Perchellet, J-P. H.; Perchellet, E. M.; Crow, K. R.;
Buszek, K. R. Design and Synthesis of Medium-Ring Libraries Inspired
by Octalactin A. A Convergent-Divergent Approach. J. Comb. Chem.
2008, 10, 628–631.
(26) Pearlman, R. S.; Smith, K. M. Metric Validation and the
Receptor-Relevant Subspace Concept. J. Chem. Inf. Comput. Sci. 1999,
39, 28–35.
(15) (a) Jackson, S, K.; Kerr, M. A. Total Synthesis of (()-
Herbindole A, (()-Herbindole B, and (()-cis-Trikentrin A. J. Org.
Chem. 2007, 72, 1405–1411. (b) Huntley, R. J.; Funk, R. L. Total
Synthesis of (()-cis-Trikentrin A and (()-cis-Trikentrin B via Electro-
cyclic Ring Closures of 2,3-Divinylpyrrolines. Org. Lett. 2006, 8,
3403–3406. (c) MacLeod, J. K.; Monahan, L. C. The Synthesis of
(()-cis-Trikentrin A. Tetrahedron Lett. 1988, 29, 391–392.
(16) Jackson, S. K.; Banfield, S. C.; Kerr, M. A. Total Synthesis
of (()-Herbindole B and (()-cis-Trikentrin B. Org. Lett. 2005, 7,
1215–1218, and references cited therein.
(17) (a) Hitotsuyanagi, Y.; Fujiki, H.; Suganuma, M.; Aimi, N.;
Sakai, S.-I.; Endo, Y.; Shudo, K.; Sugimura, T. Isolation and Structure
Elucidation of Teleocidin B-1, B-2, and B-4. Chem. Pharm. Bull. 1984,
32, 4233–4236. (b) Nakatsuka, S.; Matsuda, T.; Asano, O.; Terame, T.;
Goto, T. Synthetic Studies on Teleocidin. I. Regioselective Introduction
of 4-Amino and 7-Acyl Groups on Indole Derivative. Tetrahedron Lett.
1986, 27, 4327–4330. (c) Nakatsuka, S.; Masuda, T.; Goto, T. Synthetic
Studies on Teleocidin. II. Synthesis of Indole Derivatives Containing the
Same Substituent to Teleocidin B at 6- and 7-Positions of Indole
448
dx.doi.org/10.1021/co2000289 |ACS Comb. Sci. 2011, 13, 443–448