Ir-catalyzed functionalization of 2-substituted indoles at the 7-position: Nitrogen-directed aromatic borylation

Article abstract of DOI:10.1021/ja0631652

Ir-catalyzed borylation of 2-substituted indoles selectively yields 7-borylated products in good yields. N-Protection, required for previous functionalizations of 2-substituted indoles, is unnecessary. Copyright

Full text of DOI:10.1021/ja0631652

Published on Web 11/15/2006
Ir-Catalyzed Functionalization of 2-Substituted Indoles at the 7-Position:
Nitrogen-Directed Aromatic Borylation
Sulagna Paul, Ghayoor A. Chotana, Daniel Holmes, Rebecca C. Reichle,
Robert E. Maleczka, Jr.,* and Milton R. Smith, III*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824-1322
Received May 5, 2006; E-mail: smithmil@msu.edu
Scheme 1. Approaches to C7-Arylated Indole Natural Products
Indoles have important biological functions. Traditionally,
substituted indole syntheses fall into two classes:1 (i) construction
of the indole ring system from other substrates,1a and (ii) direct
functionalizations of an existing indole.1b The Fischer indole
synthesis is an example of the former class, while electrophilic
addition is an example of the latter. In this regard, metal-mediated
C-H functionalizations of indoles are particularly attractive because
elaborations of unprotected indoles are possible.2
Table 1. Ir-Catalyzed Synthesis of 7-Borylated Indolesa
7-Functionalized indoles exist in some intriguing natural prod-
ucts,3 such as asperazine,3a chloropeptin I,3b diazonamide A,3c drag-
macidin D,3d and TMC-95A and B.3e Because most of these have
aryl or alkyl substituents at C7, cross-coupling reactions have been
linchpins in synthetic approaches, as indicated in Scheme 1. Since
C7 of indole is difficult to functionalize selectively, construction of
the requisite coupling partners can be a nontrivial synthetic bottleneck.
For N-unprotected, 2-substituted indoles, reactions that selectively
functionalize C7 are extremely rare.4,5 Snieckus and co-workers
have developed the most general method for functionalizing
2-substituted indoles. Theirs is a directed metalation approach that
requires N-protection/deprotection.6 Certainly, direct functional-
ization of unprotected 2-substituted indoles at C7 would have
appeal. In this communication, we offer Ir-catalyzed borylation as
one means toward this end.
In our studies on borylations of heterocycles,7 we noted that small
quantities of a single diborylated product arose when indole
borylation was carried out with pinacolborane (HBPin) at elevated
temperatures. This product could be obtained in good yield by
adjusting the HBPin stoichiometry. A series of NMR experiments
conclusively identified C7 as the site of the second borylation.
To assess the reaction scope, various substrates and conditions
were examined. Bipyridine-ligated catalysts disclosed by Ishiyama,
Miyaura, and Hartwig performed best.8 The conversion of reactants
to products was clean, as judged by 1H and 11B NMR, and
intermediates were not detected. Of note, moderately elevated
temperatures shortened reaction times and improved isolated yields.
As shown in Table 1, borylation yields and functional group
tolerance are good. Because substrates unsubstituted at C2 gave
diborylated products (entries 13 and 14), most of the indoles in
Table 1 are 2-substituted. Entry 11 is noteworthy as selective
removal of the SiMe3 allows access to the 7-borylated indole.9 Entry
12 indicates that, for 2-phenylindole, borylation is favored at the
indole 7-position over the phenyl sites. Significant N-borylation
likely accounts for the low yield in entry 10.
a Typically, a solution containing the indole, 1.5 equiv of HBPin, and 3
mol % of pregenerated Ir catalyst8b was heated at 60 °C until the indole
was consumed. Yields are for isolated products. See Supporting Information
for details. b Reaction at room temperature. c 2.0 equiv of HBPin used.
d B2Pin2 (1.0 equiv) was the borylating reagent. e 2.2 equiv of HBPin used.
f 2.5 equiv of HBPin used.
gen and a pinacolate oxygen directs C-H insertion. In the third
mechanism, coordination of the indole N to Ir directs C-H insertion.10
To test the first mechanism in Scheme 2, catalytic borylation of
N-d1-5-chloro-2-methylindole using HBPin was examined. At 50%
conversion, deuterium incorporation in HBPin or H2 could not be
detected by 1H and 11B NMR. Hence, the N-H activation
mechanism can be excluded.
Borylations at positions flanking the indole N hint at its partici-
pation in the reaction. Three possibilities that we envision are de-
picted in Scheme 2. In the first pathway, initial N-H scission affords
an Ir-N intermediate. Subsequent Ir insertion into the C-H bond at
C7 (not shown) would precede product formation. In the second path-
way, hydrogen bonding between the hydrogen on the indole nitro-
Diborylation of N-methyl indole was initially examined to
exclude the second mechanism in Scheme 2. Like indole, initial
borylation at C2 predominated, but 58 and 22% of the second
borylation occurred at C6 and C5, respectively.11 This outcome
could be construed as support for H bonding, but a N coordination
pathway could also be sterically sensitive to methylation.
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10.1021/ja0631652 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Potential N-Directed Mechanisms for Indole Borylation. Positions Affected by N-Deuteration are Indicated in Red
Chart 1. Regiochemistry for Diborylation of Benzofuran and
References
Indole
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(4) Aluminum anilide has been reported to mediate ethylene insertion into
the C7 C-H bond of 2-methylindole at 280-300 °C: (a) Stroh, R.; Hahn,
W. Justus Liebigs Ann. Chem. 1959, 623, 176-183. Low-yielding Rh-
catalyzed carbene insertion into the C7 C-H of a 3-substituted indole
has been claimed: (b) Kennedy, A. R.; Taday, M. H.; Rainier, J. D. Org.
Lett. 2001, 3, 2407-2409.
(5) While indole itself has not been selectively functionalized at C7, enzymatic
chlorinations at C7 in indole5a and tryptophan5b are known: (a) Wiesner,
W.; Vanpee, K. H.; Lingens, F. FEBS Lett. 1986, 209, 321-324. (b) Dong,
C. J.; Flecks, S.; Unversucht, S.; Haupt, C.; van Pee, K. H.; Naismith, J.
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(6) (a) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org. Lett. 2003,
5, 1899-1902. (b) Regioselectivity of this type, previously ascribed to
directed ortho metalation, is now attributed to a complex-induced proximity
effect (CIPE). See: Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P.
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Scheme 3. One-Pot, 7-Arylation of 2-Substituted Indoles
Because benzofuran is an isosteric analogue of indole absent the
heteroatom-attached proton, its reactivity can address whether
hydrogen bonding is a prerequisite for borylation at C7. As shown
in Chart 1, the 2,7- and 2,6-isomers comprise 65 and 17% of the
diborylated isomers of benzofuran. Even though the respective meta
and para directing effects of OMe and BPin suggest that the second
borylation should be favored at C6,12 the 7-borylated isomer
dominates, as was the case for indole.13 Thus, hydrogen bonding
to an acidic substrate proton is not absolutely required for the
observed regioselectivity. On the basis of these observations, we
presently favor the last mechanism in Scheme 2, where N-chelation
to Ir (or B) directs borylation.14
A recent study raises concerns that the products in Table 1 might
perform poorly in Suzuki-Miyaura cross-couplings.15 Thus, two
one-pot transformations were attempted, where the crude product
from Ir-catalyzed borylation was subjected to Pd-catalyzed cross-
coupling with two aryl bromides (Scheme 3). On the basis of the
starting indoles, the arylated products were isolated in 87 and 82%
yield, bolstering the prospects for synthetic utility.
(8) (a) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390-391. (b) Boller, T. M.;
Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.; Hartwig, J. F. J.
Am. Chem. Soc. 2005, 127, 14263-14278.
(9) TBAF cleaves the SiMe3 group, affording the 7-borylated indole in 88%
yield. See Supporting Information for details.
(10) An intriguing alternative to this latter mechanism, involving coordination
of the indole N to B in one of the boryl ligands, is not shown.
(11) GC-MS indicates 20% of a third isomer. It was not obtained sufficiently
pure for assignment of regiochemistry to be made.
(12) Chotana, G. A.; Rak, M. A.; Smith, M. R., III. J. Am. Chem. Soc. 2005,
127, 10539-10544.
(13) A decrease in selectivity for benzofuran versus indole is consistent with
replacing the indole NH with a less basic O in a heteroatom chelation
mechanism.
In conclusion, Ir-catalyzed borylation provides the first general
approach to functionalizing unprotected indoles at C7. Efforts
toward further validating the mechanism, expanding the substrate
scope, and elaborating the resulting boronate esters are ongoing.
Acknowledgment. We thank Professors Aaron Odom and
Babak Borhan for helpful discussions, BASF, Inc. and Frontier
Scientific, Inc. for generous gifts of HBPin and B2Pin2, and the
Michigan Economic Development Corp., NSF REU (R.C.R.), NIH
(GM63188 to M.R.S.), and the Astellas USA Foundation for
generous financial support.
(14) Though C3 is the thermodynamic site of protonation in indole,14a kinetic
accessibility of the N lone pair is reflected by the fact that acid-catalyzed
deuterium exchange at N is ca. 100 times faster than at C3.14b For both
sites, experimental data strongly support exchange via an SE2 mechanism:
14b (a) Hinman, R. L.; Whipple, E. B. J. Am. Chem. Soc. 1962, 84, 2534-
2539. (b) Muir, D. M.; Whiting, M. C. J. Chem. Soc., Perkin Trans. 2
1976, 388-392.
(15) Prieto, M.; Zurita, E.; Rosa, E.; Munoz, L.; Lloyd-Williams, P.; Giralt,
E. J. Org. Chem. 2004, 69, 6812-6820.
Supporting Information Available: Spectral data for all new
compounds, as well as general experimental procedures. This material
is available free of charge via the Internet at http://pubs.acs.org.
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