Preparation and Reactions of Indoleninyl Halides: Scaffolds for the Synthesis of Spirocyclic Indole Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b03221

The dearomatization of 2-haloindole precursors allows access to indoleninyl halides, a hitherto underexploited functional handle with broad synthetic utility. Indoleninyl iodides have been shown to react via three distinct modes: hydrolysis, nucleophilic substitution, and cross-coupling. This allows a broad array of functionalized spirocyclic indole derivatives to be generated from a common starting material. They are also useful precursors to functionalized quinolines following migratory rearrangement and subsequent derivatization reactions.

Full text of DOI:10.1021/acs.orglett.6b03221

Letter
pubs.acs.org/OrgLett
Preparation and Reactions of Indoleninyl Halides: Scaffolds for the
Synthesis of Spirocyclic Indole Derivatives
John T. R. Liddon, Aimee K. Clarke, Richard J. K. Taylor,* and William P. Unsworth*
Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K.
S
* Supporting Information
ABSTRACT: The dearomatization of 2-haloindole precursors allows access to indoleninyl halides, a hitherto underexploited
functional handle with broad synthetic utility. Indoleninyl iodides have been shown to react via three distinct modes: hydrolysis,
nucleophilic substitution, and cross-coupling. This allows a broad array of functionalized spirocyclic indole derivatives to be
generated from a common starting material. They are also useful precursors to functionalized quinolines following migratory
rearrangement and subsequent derivatization reactions.
indoleninyl chlorides and bromides have each been proposed as
short-lived3 or putative intermediates4 in previous synthetic
protocols and were found to hydrolyze readily in situ,
generating oxindoles.5 It was this precedent that prompted us
to initiate the research program described herein, in which it
was planned to react readily available 2-haloindole precursors of
the form 6 with π-acidic catalysts in the expectation of
promoting dearomatizing spirocyclization6,7 and in situ
hydrolysis to generate spirocyclic oxindoles (e.g., 6 → 7 →
8; Scheme 1). However, when ynone 6a (R = Ph) was reacted
with 10 mol % Cu(OTf)2 in DCM at rt, the only product
isolated after workup and column chromatography was
spirocyclic indolenine 7a in quantitative yield. None of the
expected oxindole 8 was isolated, and spirocycle 7a proved to
be surprisingly stable; it appears to be insensitive to air and
tructural motifs that pair high stability with versatile
Sreactivity are of great value in organic synthesis. Moreover,
such motifs are particularly useful if they are easy to prepare
and can be incorporated into biologically significant frame-
works, rendering them important in pharmaceutical and
agrochemical research programs. Herein we detail the synthesis
and subsequent reactions of indoleninyl halides 2, a vastly
underexploited functional handle for the synthesis of a broad
array of spirocyclic indole derivatives. Simple dearomative
methods1 for their generation (1 → 2) and a series of
procedures for their subsequent reaction (via three distinct
reaction modes, 1 → 3, 4, or 5) are outlined (Figure 1). In view
of their ease of formation, high stability, and diverse reactivity,
indoleninyl halides are expected to be of broad utility in
synthesis.
Indoleninyl halides are surprisingly rare in the chemical
literature, with very little reported about their stability and
reactivity.2 Initially, we postulated that indoleninyl halides 2
would behave similarly to acid chlorides and react readily with
nucleophiles. This notion is supported by literature precedent;
Scheme 1. Indoleninyl Halide Substrate Synthesis
Received: October 27, 2016
Figure 1. Preparation and reactions of indoleninyl halides.
© XXXX American Chemical Society
A
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moisture and can be stored in a freezer for several months with
no evidence of decomposition.
Scheme 2. Indoleninyl Iodide 7a Diversification
While this Cu(II)-mediated spirocyclization worked well, a
brief examination of other catalysts revealed that AgNO3·SiO2
was an even more convenient catalyst system for this
transformation, enabling spirocycle 7a to be isolated in
quantitative yield at just 1 mol % catalyst loading.8 Indoleninyl
iodides 7b−d, as well as indoleninyl bromide 7e and chloride
7f, were also prepared in quantitative yield using the same
procedure and were found to have comparable stability.
With a simple method to generate spirocyclic indoleninyl
halides established, it was next decided to examine their
reactivity. Indoleninyl iodide 7a, an easy-to-handle solid
product that could be readily prepared on a gram scale, was
chosen as the main test substrate. Its reactivity with a range of
nucleophilic reagents was investigated, with three distinct
reaction modes [hydrolysis (8), nucleophilic substitution (9−
13), and transition-metal-catalyzed cross-coupling (14−21)] all
being demonstrated. These results are summarized in Scheme
2.
To begin, indoleninyl iodide 7a was hydrolyzed using
aqueous HCl in THF, affording spirocyclic oxindole 8 in
quantitative yield (Scheme 2A). Next, a selection of
nucleophilic substitution reactions were performed with sulfur
and nitrogen nucleophiles, leading to the formation of
indolenine derivatives 9−13 in high yields (Scheme 2B).
With spirocycle 7a acting as a vinyl halide surrogate, cross-
coupling reactions were performed (Scheme 2C). Suzuki
reactions using arylboronic acids afforded phenyl and 2-
naphthyl derivatives 14 and 15 in good yields. Likewise,
Sonogashira cross-couplings yielded alkyne derivatives 16 and
17, and Stille coupling reactions allowed furan (18), pyridine
(19), thiophene (20), and olefin groups (21) to be added at the
indolenine 2-position, all in good yields. Finally, alcohol
derivative 22 was prepared in quantitative yield with 85:15 dr
following a chemo- and diastereoselective Luche reduction of
the enone moiety of 7a, leaving the indoleninyl halide moiety
intact (Scheme 2D). In terms of the reduction step, hydride
attack presumably occurs predominantly via the most accessible
face of the molecule, i.e., anti to the indole unit.
Having successfully demonstrated the synthesis and utility of
indoleninyl halides derived from ynone precursors, it was then
decided to examine whether the same functional handle could
be installed and used in a much broader range of indole
systems. This was done by applying established indole
dearomatization procedures to previously untested 2-halogen-
ated starting materials, beginning with an enantioselective
iridium-catalyzed allylic dearomatization procedure10a devel-
oped by You and co-workers.10 Thus, 2-iodoindole precursor
23 was prepared and reacted with bis(1,5-cyclooctadiene)-
diiridium(I) dichloride and commercially available chiral
phosphoramidite ligand 27.10a Pleasingly, indoleninyl iodide
24 was produced in near-quantitative yield with >9:1 dr and
86:14 er based on NMR and chiral HPLC data respectively,
with its absolute stereochemistry assigned on the basis of
comparison to literature precedent.10a Its subsequent derivati-
zation was also achieved successfully, with both cross-coupling
and nucleophilic substitution reactions being performed to
produce spirocycles 25 and 26 in good yields (Scheme 3).
In another application, indoleninyl iodide 30 was prepared
from imine 29 and indole 28. These were treated with the
peptide coupling agent T3P and iPr2NEt at rt, using the direct
imine acylation (DIA) method developed by our group,11
a
b
10% HCl(aq), THF, rt, 4 h. Thiol, Cs2CO3, MeCN, rt, 2−4 h.
c
d
NaN3, DMF, 60 °C, 1.5 h. 2-Mercaptoethanol, Et3N, MeCN, rt, 22
e
h. Arylboronic acid, Pd(PPh3)4, K2CO3, toluene/H2O, 80 °C, 16−20
f
g
h. RCCH, iPr2NH, PdCl2(PPh3)2, CuI, THF, rt, 1.5 h. 2-
h
(Tributylstannyl)furan, Pd(PPh3)4, dioxane, 100 °C, 21 h. Stannane,
trans-PdBr(N-Succ)(PPh3)2,9 toluene or dioxane, 100−130 °C, 17−48
i
h. CeCl3·7H2O, NaBH4, MeOH, rt, 90 min.
Scheme 3. Indoleninyl Iodide via Allylic Dearomatization
a
b
24, phenylacetylene, iPr2NH, PdCl2(PPh3), CuI, THF, rt, 1.5 h. 24,
benzyl mercaptan, Cs2CO3, MeCN, 1.5 h.
B
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furnishing spirocycle 30 with 83:17 dr. The relative stereo-
chemistry of 30 was assigned on the basis of analogy to related
compounds.11a This scaffold was again amenable to additional
functionalization either by nucleophilic substitution with benzyl
mercaptan or by hydrolysis, forming products 31 and 32,
respectively (Scheme 4).
Scheme 6. 2-Iodoquinoline 37 Diversification
Scheme 4. Indoleninyl Iodide via Direct Imine Acylation
a
b
30, benzyl mercaptan, Cs2CO3, MeCN, 3.5 h. 30, 10% HCl(aq),
THF, rt, 3 h.
In addition, cyclopropyl substrate 34 was prepared in high
yield by a Mitsunobu-type reaction of indole-tethered alcohol
33. Functionalization by nucleophilic displacement (35) and
cross-coupling (36) again demonstrated the synthetic utility of
the indoleninyl iodide substructure (Scheme 5).
Scheme 5. Indoleninyl Iodide via a Mitsunobu Reaction
a
b
c
10% HCl(aq), 100 °C, 16 h. NaBH4, MeOH, rt, 3.5 h. Thiol,
d
e
Cs2CO3, MeCN, rt, 3−6 h. Benzylamine, rt, 15 h. 2-Aminoethanol,
rt, 5 h. Phenol, trans-PdBr(N-Succ)(PPh3)2,9 Cs2CO3, toluene, 100
f
g
h
°C, 2 h. RCCH, Et3N, PdCl2(PPh3), CuI, DMF, rt, 2−3 h. 2-
Naphthylboronic acid, Pd(PPh3)4, LiCl, Na2CO3, toluene/ethanol/
i
H2O, 80 °C, 16 h. 3-Pyridinylboronic acid, trans-PdBr(N-Succ)-
(PPh3)2,9 LiCl, Na2CO3, toluene/ethanol/H2O, 100 °C, 24 h. 2-
j
(Tributylstannyl)furan, Pd(PPh3)4, LiCl, THF, 85 °C, 16 h.
yield, with reduction presumably occurring anti to the adjacent
phenyl substituent (Scheme 6B).12 A selection of SNAr
derivatizations with sulfur (40−41) and amine nucleophiles
(42−43) were also demonstrated (Scheme 6C). Finally, various
cross-coupling protocols were also tested, with Buchwald−
Hartwig (44), Sonogashira (45−46), Suzuki (47−48), and
Stille (49) cross-coupling reactions all proceeding well in good
yields (Scheme 6D).
In summary, we have demonstrated that indoleninyl iodides
are readily accessible via the dearomatization of 2-iodoindole
derivatives and that they can be used to synthesize a range of
diverse spirocyclic indole derivatives. In view of their ability to
react via three distinct reaction modes (hydrolysis, nucleophilic
substitution, and cross-coupling), we expect indoleninyl iodides
to quickly become established as valuable intermediates and
reagents. Their utility as precursors to easily functionalized 2-
iodoquinolines has also been demonstrated, further expanding
their synthetic utility. Finally, while this work has focused
largely on indoleninyl iodides, we have also demonstrated that
indoleninyl bromide and chloride analogues can also be
prepared using similar methods, and in future work the
reactivity of these systems will also be examined.
a
b
34, benzyl mercaptan, Cs2CO3, MeCN, 3.5 h. 34, phenylacetylene,
Cs2CO3, PdCl2(PPh3), CuI, THF, rt, 5 h.
Finally, it was found that indoleninyl halide 7a rearranges to
form quinoline 37 under basic conditions. A related rearrange-
ment reaction was reported by our group in a 2016 study, in
which non-halogenated spirocyclic indolenines were shown to
rearrange to form quinoline derivatives upon treatment with
either strong base or Lewis acid.6c It was found that treating
spirocyclic indolenine 7a with LHMDS in THF at 0 °C
promoted its conversion into 2-iodoquinoline 37 in 78% yield
via a similar process (Scheme 6; for mechanistic speculation,
see our earlier publication6c). Of course, 2-iodoquinolines are
valuable, versatile building blocks in their own right, and to
demonstrate this, derivatization reactions similar to those
performed on indoleninyl iodide 7a were also explored. These
results are summarized in Scheme 6.
First, it was found that quinoline 37 could be hydrolyzed
with aqueous HCl, affording 2-quinolone 38 in quantitative
yield (Scheme 6A). A chemo- and diastereoselective reduction
was also performed using NaBH4 to yield alcohol 39 in good
C
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J.; Clubley, R. E.; Palate, K. Y.; Procter, T. J.; Wyton, A. C.; O’Brien,
P.; Taylor, R. J. K.; Unsworth, W. P. Org. Lett. 2015, 17, 4372.
(c) Liddon, J. T. R.; James, M. J.; Clarke, A. K.; O’Brien, P.; Taylor, R.
J. K.; Unsworth, W. P. Chem. - Eur. J. 2016, 22, 8777.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03221.
■
S
(7) For related research featuring the dearomatization of indoles via
alkyne activation, see: (a) Loh, C. C. J.; Badorrek, J.; Raabe, G.;
Enders, D. Chem. - Eur. J. 2011, 17, 13409. (b) Peshkov, V. A.;
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2841. (c) Heffernan, S. J.; Tellam, J. P.; Queru, M. E.; Silvanus, A. C.;
Benito, D.; Mahon, M. F.; Hennessy, A. J.; Andrews, B. I.; Carbery, D.
R. Adv. Synth. Catal. 2013, 355, 1149. (d) Corkey, B. K.; Heller, S. T.;
Wang, Y.-M.; Toste, F. D. Tetrahedron 2013, 69, 5640. (e) Xu, W.;
Wang, W.; Wang, X. Angew. Chem., Int. Ed. 2015, 54, 9546.
(f) Schroder, F.; Ojeda, M.; Erdmann, N.; Jacobs, J.; Luque, R.;
Noel, T.; Van Meervelt, L.; Van der Eycken, J.; Van der Eycken, E.
Green Chem. 2015, 17, 3314.
Experimental procedures, spectroscopic data, NMR
spectra, and further discussion of stereochemical assign-
ments (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: richard.taylor@york.ac.uk.
*E-mail: william.unsworth@york.ac.uk.
(8) For a discussion of the practical benefits of AgNO3·SiO2 in
related spirocyclization reactions, see: Clarke, A. K.; James, M. J.;
O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Angew. Chem., Int. Ed.
2016, 55, 13798.
ORCID
William P. Unsworth: 0000-0002-9169-5156
Notes
(9) For more information on trans-PdBr(N-Succ)(PPh3)2, see:
(a) Burns, M. J.; Fairlamb, I. J. S.; Kapdi, A. R.; Sehnal, P.; Taylor,
R. J. K. Org. Lett. 2007, 9, 5397. (b) Crawforth, C. M.; Burling, S.;
Whit-wood, A. C.; Fairlamb, I. J. S.; Taylor, R. J. K. Chem. Commun.
2003, 2194.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the EPSRC (EP/M018601/01, J.T.R.L.),
the University of York (A.K.C.), and the Leverhulme Trust (for
an Early Career Fellowship, ECF-2015-13, W.P.U.) for financial
support.
(10) (a) Wu, Q. F.; He, H.; Liu, W. B.; You, S. L. J. Am. Chem. Soc.
2010, 132, 11418. For related examples of catalytic asymmetric
dearomatization reactions from the same group, see: (b) Zhuo, C. X.;
Zhou, Y.; Cheng, Q.; Huang, L.; You, S. L. Angew. Chem., Int. Ed.
2015, 54, 14146. (c) Zhang, X.; Liu, W. B.; Tu, H. F.; You, S. L. Chem.
Sci. 2015, 6, 4525. (d) Gao, R. D.; Liu, C.; Dai, L. X.; Zhang, W.; You,
S. L. Org. Lett. 2014, 16, 3919. (e) Zhang, X.; Liu, W. B.; Wu, Q. F.;
You, S. L. Org. Lett. 2013, 15, 3746. (f) Zhuo, C. X.; Wu, Q. F.; Zhao,
Q.; Xu, Q. L.; You, S. L. J. Am. Chem. Soc. 2013, 135, 8169. (g) Wu, Q.
F.; Zheng, C.; You, S. L. Angew. Chem., Int. Ed. 2012, 51, 1680.
(11) (a) Chambers, S. J.; Coulthard, G.; Unsworth, W. P.; O’Brien,
P.; Taylor, R. J. K. Chem. - Eur. J. 2016, 22, 6496. (b) Unsworth, W. P.;
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