The synthesis of indoline and benzofuran scaffolds using a Suzuki-Miyaura coupling/oxidative cyclization strategy

Article abstract of DOI:10.1021/ol401974v

The generation of indolines and benzofurans from the combination of Suzuki-Miyaura coupling reactions with oxidative cyclizations is described.

Full text of DOI:10.1021/ol401974v

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
The Synthesis of Indoline and Benzofuran
Scaffolds Using a SuzukiÀMiyaura
Coupling/Oxidative Cyclization Strategy
Somnath Jana and Jon D. Rainier*
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112,
United States
rainier@chem.utah.edu
Received July 12, 2013
ABSTRACT
The generation of indolines and benzofurans from the combination of SuzukiÀMiyaura coupling reactions with oxidative cyclizations is
described.
Over the past several years we have become intrigued
with the synthesis and study of indoline containing natural
products including those that have a pyrido[2,3-b]indoline
(tetrahydro-R-carboline) skeleton as part of their archi-
tecture.1 Tetrahydro-R-carbolines that are of interest
to us include cytotoxic metabolites from both marine
(kapakahine E) and terrestrial organisms (chaetominine
and oxaline) (Figure 1).2À4
into tetrahydro-R-carboline 2 (Scheme 1).7 While impres-
sive, this latter transformation required a large excess of
AlMe3 making it not too surprising that the reaction also
Previously, all synthetic work to these substrates had
relied on the use of indolines or indoles asprecursors.5,6 An
example from our laboratory is illustrated in Scheme 1.
During our total synthesis of kapakahine E we generated
pyrroloindoline 1 from tryptophan and in turn converted 1
(1) (a) Espejo, V. R.; Rainier, J. D. Org. Lett. 2010, 12, 2154. (b)
Sabahi, A.; Novikov, A.; Rainier, J. D. Angew. Chem., Int. Ed. 2006, 45,
4317.
(2) (a) Nakao, Y.; Yeung, B. K. S.; Yoshida, W. Y.; Scheuer, P. J.;
Kelly-Borges, M. J. Am. Chem. Soc. 1995, 117, 8271. (b) Yeung, B. K. S.;
Nakao, Y.; Kinnel, R. B.; Carney, J. R.; Yoshida, W. Y.; Scheuer, P. J.;
Kelly-Borges, M. J. Org. Chem. 1996, 61, 7168. (c) Nakao, Y.; Kuo, J.;
Yoshida, W. Y.; Kelly-Borges, M.; Scheuer, P. J. Org. Lett. 2003, 5,
1387.
(3) Jiao, R.; Xu, S.; Liu, J.; Ge, H.; Ding, H.; Xu, C.; Zhu, H.; Tan, R.
Org. Lett. 2006, 8, 5709.
~
(4) (a) Konda, Y.; Onda, M.; Hirano, A.; Omura, S. Chem. Pharm.
~
Bull. 1980, 28, 2987. (b) Koizumi, Y.; Arai, M.; Tomoda, H.; Omura, S.
Biochim. Biophys. Acta 2004, 1693, 47.
(5) (a) Kennedy, A. R.; Taday, M. H.; Rainier, J. D. Org. Lett. 2001,
3, 2407. (b) Boyarskikh, V.; Nyong, A.; Rainier, J. D. Angew. Chem., Int.
Ed. 2008, 47, 5374. (c) Espejo, V. R.; Rainier, J. D. J. Am. Chem. Soc.
2008, 130, 12894. (d) Espejo, V. R.; Li, X.-B.; Rainier, J. D. J. Am. Chem.
Soc. 2010, 132, 8282.
Figure 1. Tetrahydro-R-carboline containing natural products.
r
10.1021/ol401974v
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resulted in the generation of significant quantities of
methyl ketone 3.
Although, as mentioned above, our inspiration for
these studies was the tetrahydro-R-carboline skeleton,
we chose to initially examine the proposed sequence
using D-glucal 9 (Scheme 3). This was largely a conse-
quence of reports from Boutrueira, Davis and co-workers
that described the generation and conversion of 3-iododi-
hydropyrans into 3-arylglycosides using SuzukiÀMiyaura
coupling reactions.11,12 Pleasingly, we were able to follow
the Boutrueira protocol and both convert glucal 9 into
2-iodoglucal 10 and generate 2-arylglycal 12 by subjecting
10 to 2-aminophenylpinacolborane 11 and Pd(0). Sulfo-
namide formation gave cyclization precursor 13. It was
interesting to us that the sulfonamide analog of 11 under-
went exclusive protodeborylation when exposed to the
SuzukiÀMiyaura reaction conditions.13
Scheme 1. R-Carbolines from Pyrroloindolines
Scheme 3. SuzukiÀMiyaura Coupling to Aryl Glycal 13
Our struggles with the generation of 3 from 1 along with
the lack of a general synthetic approach to tetrahydro-R-
carbolinesled us to consider whether a route that started
with the piperidine subunit intact might be feasible.
This idea ultimately led us to explore the coupling,
oxidative cyclization route that is the focus of this letter
(Scheme 2).8À10 In addition to leading to the synthesis
of tetrahydro-R-carbolines, a bonus to our approach is
that it has enabled us to extend the targets that are
accessible to us to include aminals and benzofurans.
Scheme 2. Proposed CouplingÀOxidative Cyclization Strategy
to Tetrahydro-R-carbolines
With 13 in hand, we explored its conversion into the
desired indolines (Schemes 4 and 5). To this end we were
pleased to find that 13 was transformed into hydroxyindo-
line 14 after being exposed to m-CPBA. This transforma-
tion could also be carried out with dimethyldioxirane but
only if the oxidation was followed by the treatment of the
presumed epoxide intermediate with SiO2.14 That 14 was
cis-fused was verified by the 3J value between H-4 and H-5
(9.5 Hz), by the NOE that was observed between H-2 and
H-6, and by comparison of the spectral data for 14 with
those for trans-fused 16 (vide infra).
As alluded to above, the stereochemistry at the new ring
junction was dependent on the reagent used to activate the
dihydropyran. In contrast to the epoxide initiated cycliza-
tion, the use of NBS as the oxidant resulted in the generation
of trans-fused indoline 16 in 62% yield (Scheme 5). As with
(6) For other syntheses of R-carbolines, see: (a) Newhouse, T.; Lewis,
C. A.; Baran, P. S. J. Am. Chem. Soc. 2009, 131, 6360. (b) Snider, B. B.;
Wu, X. Org. Lett. 2007, 9, 4913. (c) Toumi, M.; Couty, F.; Marrot, J.;
Evano, G. Org. Lett. 2008, 10, 5027. (d) Malgesini, B.; Forte, B.; Borghi,
D.; Quartieri, F.; Gennari, C.; Papeo, G. Chem.;Eur. J. 2009, 15, 7922.
(e) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Synthesis 2009,
2927. (f) Newhouse, T.; Lewis, C. A.; Eastman, K. J.; Baran, P. S. J. Am.
Chem. Soc. 2010, 132, 7119.
(7) See ref 1a and Espejo, V. R.; Rainier, J. D. Isr. J. Chem. 2011, 51,
473.
(8) For a recent review, see: de Vries, J. G. Top. Organomet. Chem.
2012, 42, 1.
ꢀ
(11) Rodrıguez, M.; Boutureira, O.; Matheu, M.; Dıaz, Y.; Castillon,
S.; Seeberger, P. J. Org. Chem. 2007, 72, 8998.
ꢀ
(12) Cobo, I.; Matheu, M.; Castillon, S.; Boutureira, O.; Davis, B.
Org. Lett. 2012, 14, 1728.
(13) Fier, P. S.; Luo, J.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135,
2552.
(14) For seminal work on glycal epoxides and their reactivity, see:
Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6661.
(9) For a related NBS induced oxidative cyclization, see: Chang,
M.-Y.; Tai, H.-Y.; Chen, Y.-L. Tetrahedron 2011, 67, 7673.
(10) For examples of related oxidative spirocyclizations, see: (a) Liu,
G.; Wurst, J. M.; Tan, D. S. Org. Lett. 2009, 11, 3670. (b) Robertson, J.;
Chovatia, P. T.; Fowler, T. G.; Withey, J. M.; Woollaston, D. J. Org.
Biomol. Chem. 2010, 8, 226. (c) Potuzak, J. S.; Moilanen, S. B.; Tan, D. S.
J. Am. Chem. Soc. 2005, 127, 13796.
B
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Scheme 4. Glycal Epoxide Cyclization to Indoline 14
Scheme 6. SuzukiÀMiyaura Coupling to Piperidine 21
14, the relative stereochemistry of 16 was determined using a
series of 1H NMR experiments (lack of NOE between H-2
and H-6, the H-4, H-5 3J value (3.3 Hz), and a comparison
with the spectral data for 14).15 We speculate that 16 comes
from axial attack of the sulfonamide onto oxocarbenium
ion intermediate 17 while the cis-fused ring in 14 results from
the direct addition of the sulfonamide onto the activated
epoxide intermediate 15.16
In a related fashion to the reaction of 13, 22 underwent a
smooth oxidative cyclization reaction when treated with
m-CPBA to give cis-fused indoline 23 (Scheme 7).19
Scheme 7. Oxidative Cyclization to R-Carboline 22
Scheme 5. NBS Initiated Cyclization to Indoline 15
In contrast to the reaction of dihydropyran 13, the reac-
tion of 22 with NBS gave cis-fused bromide 24 (Scheme 8).
The ring junction stereochemistry in 24 was determined
by subjecting 24 to LiHMDS to generate cyclopropane 25
whose relative stereochemistry was confirmed through NOE
correlations.20 While additional experiments are required
to fully explain these results, we speculate that the active
intermediate from enamide 22 reacts as a bromonium ion
rather than as an iminium ion.
Having generated pyrano[2,3-b]indolines 14 and 16, we
targeted tetrahydro-R-carbolines next and used glutari-
mide (18) as the starting material (Scheme 6). The conver-
sionof 18into enamide 19was relativelystraightforward.17
The generation of iodide 20 did not require a separate
dehydration as was required for 10 but instead occurred
directly from 19 by treating it with NIS.18 The SuzukiÀ
Miyaura coupling of 20 with aniline 11 was equally
uneventful providing cyclization precursor 22 after sulfo-
namide formation.
Scheme 8. Oxidative Cyclization to R-Carboline 24 and Its
Conversion into Cyclopropane 25
(15) The 3J coupling constants in 16 are consistent with the pyran ring
adopting a boat conformation.
(16) For a related argument in the stereoselective generation of
C-glycosides, see: (a) Rainier, J. D.; Cox, J. M. Org. Lett. 2000, 2,
2707. (b) Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, H. W. B.;
Rainier, J. D. Tetrahedron 2002, 58, 1997. (c) Roberts, S. W.; Rainier,
J. D. Org. Lett. 2005, 7, 1141.
(17) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N. Tetra-
hedron 1975, 31, 1437.
(18) Related reactions are known. See: van den Broek, S. A. M. W.;
Rensen, P. G. W.; van Delft, F. L.; Rutjes, F. P. J. T. Eur. J. Org. Chem.
2010, 5906.
Having demonstrated the synthesis of tetrahydro-R-
carbolines, we decided to determine whether the oxidative
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Scheme 9. Oxidative Cyclizations to Benzofurans
Scheme 10. Oxidative Cyclization to Benzofuran 29
31 when exposed to m-CPBA (Scheme 10). Presumably,
the difference in reactivity between 28 and 29 is due to the
enhanced ability of the benzyl amide to donate electron
density to the epoxide intermediate when compared to the
corresponding Boc amide.22
In conclusion, we have uncovered a simple and general
means of synthesizing pyrido[2,3-b]indolines (tetrahydro-
R-carbolines), pyrano[2,3-b]indolines, and corresponding
benzofurans that is centered around SuzukiÀMiyaura
coupling reactions of electron-rich olefins with a subse-
quent oxidative cyclization.
cyclization strategy could be employed in the synthesis of
benzofurans. To this goal, we examined both Boc pro-
tected enamide 20 and Bn protected substrate 26.21 Both
reacted with ortho-substituted boronic acid 27 in the
presence of Pd(0) to give 28 and 29 in 55% and 63%
yields, respectively (Scheme 9). As with the corresponding
aniline, the treatment of 28 with NBS and PPTS resulted in
the generation of benzofuran 30.
Acknowledgment. We are grateful to the National
Science Foundation (CHE 0650405) and to Cephalon for
support of this work. We would like to thank the support
staff at the University of Utah and especially Dr. Peter
Flynn (NMR) and Dr. Jim Muller (mass spectrometry) for
help in obtaining data.
Interestingly, the epoxidation and cyclization of 28
resulted in an intractable mixture of products. In contrast,
N-benzyl analog 29 successfully underwent cyclization to
(19) The ring junction stereochemistry for 23 has been assigned based
on an assessment of NOE correlations in the corresponding N-benzyl
isopropyl ester. See Supporting Information.
(20) We believe that 25 comes from an intramolecular SN2 displace-
ment. See ref 5d.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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(21) de Villar, I. S.; Gradillas, A.; Perez-Castells, J. Eur. J. Org.
Chem. 2010, 5850 and the Supporting Information for the synthesis of
26.
(22) We speculate that competitive quinone methide generation leads
to the observed decomposition of the epoxide from 28.
The authors declare no competing financial interest.
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