Efficient iridium-catalyzed C-H functionalization/silylation of heteroarenes

Article abstract of DOI:10.1002/anie.200802456

CSi investigation: The efficient iridium-catalyzed C-H functionalization/ silylation of a wide variety of N-, S-, and O-heteroarenes, including N-unsubstituted indoles, is promoted by 2-norbornene and features a high level of regioselectivity (see scheme; Ts = p-toluenesulfonyl, cod = cyclooctadiene). (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200802456

Communications
DOI: 10.1002/anie.200802456
Synthetic Methods
ꢀ
Efficient Iridium-Catalyzed C H Functionalization/Silylation of
Heteroarenes**
Biao Lu and John R. Falck*
As a consequence of their unique chemical, physical, and
biological properties, silyl-substituted arenes have attracted
wide interest from the synthetic,[1] material science,[2] and
pharmaceutical sectors.[3] Traditionally, silyl substituents have
been introduced by the addition of aryl lithium or magnesium
reagents to silicon electrophiles, and this method often
necessitates the use of protecting groups.[4] Consequently,
transition-metal-catalyzed cross couplings of aryl halides with
disilanes or hydrosilanes have grown in popularity, especially
Figure 1. Comparison of silyl indole syntheses. PG=protecting group.
if base- or nucleophile-sensitive functional groups are pres-
[6]
ent.[5] More recently, direct C H functionalization has
ꢀ
emerged as a conceptually and economically attractive
alternative for the direct silylation of arenes. However,
challenges remain and the general utility of this strategy is
restricted in many instances by 1) poor regioselectivity,
2) stringent structural requirements, 3) noncommercial/
expensive reagents, 4) harsh reaction conditions (typically
120–2008C), and 5) impractical ratios of arene to the silicon
reagent (10:1–60:1).[7–9] Herein, we report an efficient,
regioselective protocol for the bipyridine-ligated, iridium-
unprotected 1 only gave complex product mixtures when
using the [{Ir(OMe)(cod)}2]/4,4-di-tert-butyl-2,2-bipyridine
(dtbpy) (cod = cycloocta-1,5-diene) catalytic system in
octane; silylated adducts could only be obtained by using
N-substituted indoles at elevated temperatures (1208C) with
a large excess of substrate. It was, thus, not surprising that 1
was unreactive to triethylsilane under comparable reaction
conditions and could be recovered unchanged despite pro-
longed heating (Table 1, entry 1). However, switching to THF
as the solvent and lowering the temperature to 808C
rewarded us with 2-(triethylsilyl)-1H-indole (2),[14] albeit in
4% yield (Table 1, entry 2). This yield was then boosted to
15% upon addition of cyclopentene as a co-reactant (Table 1,
entry 3). Optimization ultimately led using the more hindered
olefin, 2-norbornene,[15] which dramatically improved the
yield of 2 (Table 1, entry 4).[16,17] Notably, 3-(triethylsilyl)-1H-
indole was not detected in the crude reaction mixture by 1H/
13C NMR analyses. Other solvents, including octane (Table 1,
entry 5), DME (DME = 1,2-dimethoxyethane; Table 1,
entry 6), and dioxane (Table 1, entry 7) were less satisfactory.
catalyzed[9] C H functionalization/silyation of a wide variety
ꢀ
of heteroarenes under comparatively mild conditions. Impor-
ꢀ
tantly, the reaction does not require protection of the N H
groups and uses only a small excess (3 equiv) of the
inexpensive triethylsilane [Eq. (1)].
[a]
Indole 1 was selected as the model heteroarene for initial
studies because of its prominence in many natural products
and pharmaceuticals.[10] Whereas several laboratories have
cogently demonstrated arylation[11] and borylation[12] of
ꢀ
Table 1: Reaction parameters for C H functionalization of indole 1 to 2.
ꢀ
indoles by transition-metal-catalyzed C H functionalization,
corresponding silylations are much less efficient (Figure 1). In
Entry
Et3SiH [equiv]
Co-reactant (equiv)
Solvent
Yield [%]
an instructive example, Ishiyama et al. reported[13] that
1
2
5
5
none
none
octane
THF
0[b]
4
3
4
5
6
7
8
9
10
11
5
5
5
5
5
3
1.5
3
1.5
cyclopentene (5)
2-norbornene (5)
2-norbornene (5)
2-norbornene (5)
2-norbornene (5)
2-norbornene (3)
2-norbornene (1.5)
2-norbornene (0.5)
2-norbornene (3)
THF
THF
octane
DME
dioxane
THF
THF
THF
THF
15
85
22
49
59
87
15
7
[*] Dr. B. Lu, Prof. J. R. Falck
Departments of Biochemistry and Pharmacology, University of
Texas Southwestern Medical Center
5323 Harry Hines Blvd., Dallas, TX 75390-9038 (USA)
Fax: (+1)214-648-6455
E-mail: j.falck@utsouthwestern.edu
[**] We thank the NIH (GM31278, DK38226, AI077853) and the
Robert A. Welch Foundation for financial support.
43
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802456.
[a] Reaction conditions: [{Ir(OMe)(cod)}2] (5 mol%) and 4,4-di-tert-
butyl-2,2-bipyridine (10 mol%) at 808C for 24 h. [b] At 1208C for 24 h.
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Reducing the number of equivalents of both Et3SiH and
2-norbornene from 5 equivalents to 3 equivalents had no
5-bromo (15!16, Table 2, entry 7) and 4-cyano groups (17!
18, Table 2, entry 8), which were accompanied by lesser
effect on the yield or the reaction rate (Table 1, entry 8), but amounts of unidentified byproducts; approximately 20% of
additional reductions in the amount of either reagent were
detrimental to the yield (Table 1, entries 9–11).
Having established suitable reaction conditions, we
explored the scope and generality of the methodology starting
the starting material was recovered.
Whereas the mechanistic details have yet to be elucidated,
the observed regioselectivity is most consistent with a
chelation-assisted reaction, that is, coordination between the
with substituted indoles (Table 2). Generally, silylations of iridium catalyst and indole nitrogen atom with subsequent
[12a]
ꢀ
indoles bearing electron-donating substituents proceeded
well; for example, substrates with groups such as 5-methoxy
(3!4, Table 2, entry 1), 4-tert-butyldimethylsilyloxy (5!6,
insertion into the adjacent C H bond.
As anticipated,
N-methylindole (19!20, Table 2, entry 9) behaved similarly,
although the increased steric hindrance around the nitrogen
Table 2, entry 2), and 6-methyl (7!8, Table 2, entry 3). In center somewhat suppressed the yield (see Table 2, entry 4).
contrast, 3-methylindole (9!10, Table 2, entry 4) reacted Notably, tosylation of the ring nitrogen atom redirected the
sluggishly, which we attribute to steric congestion, but the
strict C2 regioselectivity was consistent with that found with
other substrates of the series. Electron-withdrawing substitu-
regioselectivity toward silylation at C3 (21!22, Table 2,
entry 10), suggesting a change in the mechanism or a metal
migration from C2 to C3 as proposed for palladium-mediated
[6b]
ꢀ
ents, including 5-fluoro (11!12, Table 2, entry 5) and indole C H functionalizations.
7-chloro groups (13!14, Table 2, entry 6) were tolerated.
Gratifyingly, S- and O-heteroarenes were also suitable
More modest yields of silylated adducts were obtained with
substrates (Table 3). Thiophene (23) was smoothly function-
alized to the 2,5-disilyl derivative (24) in excellent yield
(Table 3, entry 1) when 4 equivalents each of the triethylsi-
lane and norbornene were used.[18] Not surprisingly, a
2-substituted thiophene underwent monosilylation at C5
in very good yield (25!26, Table 3, entry 2), whereas a
3-substituted thiophene gave rise to a 2:1 mixture of
5-triethylsilyl and 2,5-bis(silylated) adducts (27!28, Table 3,
entry 3). Benzofuran (31) and furan (33) gave analogous
results (Table 3, entries 5 and 6, respectively).
[a]
ꢀ
Table 2: C H functionalization/triethylsilylation of substituted indoles.
Entry
Indole
Adduct
Yield [%]
90
1
2
82
In summary, this report describes an efficient iridium-
ꢀ
catalyzed C H functionalization/silylation of N-, S-, O-
heteroarenes including N-unsubstituted indoles under mild
conditions and a modest excess (3 equiv) of Et3SiH. The
silylation is strongly promoted by 2-norbornene and features
a high level of regioselectivity. Initial results indicate the
general procedure described herein is also applicable to other
3
4
5
86
55[b]
76
ꢀ
Table 3: C H functionalization/triethylsilylation of S- and O-heteroare-
nes.[a]
Entry
1
Heteroarene
Adduct
Yield [%]
98[b]
6
7
8
64
52[b]
41[b]
2
3
91
67[c]
4
5
6
99
83
93
9
49
70
10
[a] Reaction conditions: [{Ir(OMe)(cod)}2] (5 mol% ), dtbpy (10 mol%),
Et3SiH (3 equiv), and norbornene (3 equiv) in THF at 808C for 24 h.
[b] Same as [a], except 10 mol% [{Ir(OMe)(cod)}2]and 20 mol% dtbpy
for 36–48 h. TBS=tert-butyldimethylsilyl; Ts=p-toluenesulfonyl.
[a] Reaction conditions described in Table 2, footnote [a]. [b] Used
triethylsilane (4 equiv) and norbornene (4 equiv). [c] 2,5-bis-triethylsilyl
adduct obtained in 33% yield.
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Communications
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[15] Other unsaturated molecules, e.g., tetramethylethylene, 1-
hexene, 1-heptyne, and diisopropyl azodicarboxylate, had no
effect on the yield of 2.
Experimental Section
General procedure: A flamed-dried Schlenk tube was charged with
heteroarene (0.2 mmol), [{Ir(OMe)(cod)}2] (6.6 mg, 0.01 mmol) and
dtbpy (5.4 mg, 0.02 mmol), and then evacuated and flushed with
argon three times. Under a positive flow of argon, 2-norbornene
(56 mg, 0.6 mmol) and dry THF (1 mL) were added. After stirring for
5 min, triethylsilane (98 mL, 0.6 mmol) was added dropwise and the
reaction mixture was heated at 808C for 24 h or indicated time. The
solvent was concentrated under reduced pressure and the residue
was then purified by flash chromatography on silica gel to give
2-(triethylsilyl)heteroarene.
For 1-tosyl-indole, the 3-silylation product was obtained by using
the above general procedure.
For furan (0.2 mmol) and thiophene (0.2 mmol), 2-norbornene
(75 mg, 0.8 mmol) and triethylsilane (130 mL, 0.8 mmol) were
employed.
Received: May 26, 2008
Revised: July 8, 2008
Published online: August 13, 2008
ꢀ
[16] For prior use of 2-norbornene in catalytic C H activations, see
references [7a and c]. The exact role of 2-norbornene as a
promoter of the iridium-catalyzed reactions reported herein is
unclear. The identification of norbornane, by GC-MS methods,
in the reaction mixture suggests it functions as a sink for the
hydrogen generated during the reaction. Additionally, it may
play a more intimate role as a participant in the catalytic cycle.
We speculate the bicyclic skeleton of norbornene affords greater
steric shielding or stability towards unproductive b-hydride
eliminations than comparable iridium complexes with cyclic or
acyclic olefins. Unfortunately, attempts to detect Ir–norbornene
intermediates by NMR methods were disappointing.
ꢀ
Keywords: C H activation · heterocycles · iridium · silanes
.
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