Transition-Metal-Free Ring-Opening Silylation of Indoles and Benzofurans with (Diphenyl-tert-butylsilyl)lithium

Article abstract of DOI:10.1002/anie.201707309

A practical method is presented for ring opening various indoles and benzofurans with concomitant stereoselective silylation using readily generated (diphenyl-tert-butylsilyl)lithium to afford ortho-β-silylvinylanilines or -phenols. Dearomatization of the heteroarene core proceeds in the absence of any transition-metal catalyst through addition of a silyl anion and a subsequent stereoselective β-elimination. DFT calculations provide insight into the mechanism. Functionalizing C?X bond cleavage of heteroarenes is rare and generally requires transition-metal catalysts.

Full text of DOI:10.1002/anie.201707309

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Accepted Article
Title: Transition-Metal-Free Ring Opening Silylation of Indoles and
Benzofurans with (Diphenyl-tert-butylsilyl)lithium
Authors: Pan Xu, Ernst-Ulrich Würthwein, Constantin Gabriel Daniliuc,
and Armido Studer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707309
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Transition-Metal-Free Ring Opening Silylation of Indoles and
Benzofurans with (Diphenyl-tert-butylsilyl)lithium
Pan Xu, Ernst-Ulrich Würthwein, Constantin G. Daniliuc and Armido Studer*
Abstract: A practical method for ring opening of various indoles and
benzofurans with concomitant stereoselective silylation using readily
generated (diphenyl-tert-butylsilyl)lithium to provide ortho-β-silylvinyl
anilines or phenols is presented. Dearomatization of the heteroarene
core proceeds in the absence of any transition metal catalyst via silyl
anion addition and subsequent stereoselective β-elimination. DFT
calculations provide insights into the mechanism. Functionalizing C-X
bond cleavage in heteroarenes is rare and generally requires
transition metal catalysis.
Due to the importance of Si-based compounds in materials
science,
for
biomedical
applications
and
as
intermediates/reagents in synthesis, organosilane chemistry has
attracted considerable attention.[1] Heteroarylsilanes occupy a
prominent role and the direct introduction of silyl groups into
heteroarenes such as indoles and benzofurans has been
intensively investigated. Recent reports focus on the direct C-H
bond silylation that complement conventional silylation of a
preformed metalated heteroarene. Friedel-Crafts type,[
Scheme 1. C-H bond silylation and ring opening functionalization of indoles and
benzofurans
2]
[
3]
transition-metal (Rh, Ir, Ru) catalyzed and KOtBu catalyzed C–
H silylation[4] have to be mentioned along these lines (Scheme 1a).
Arenes express high stability due to their resonance
stabilization. The typical transformation at an arene being radical
or ionic in nature proceeds via temporary disruption of the arene
resonance with subsequent rearomatization. Compared to such
widely studied arene functionalizations, much less attention has
been devoted to the ring opening functionalization of aromatic
compounds.[5] Whereas C-H functionalization of indoles has been
widely explored,[6] indole C-N bond ring opening functionalization
is unknown (Scheme 1b). However, benzofurans are known to
undergo C(2)-O bond cleavage/functionalization using Ni- or Rh-
catalysis (Scheme 1b).[7] Yorimitsu reported a Ni-catalyzed ring-
opening/insertion borylation of benzofurans,[7e] where the arene
core is destructed via oxidative addition of a Ni-complex into the
C(2)-O bond. However, such a mechanistic option is not offered
in transition metal free approaches and the development of arene
ring opening functionalization in the absence of any transition
metal remains challenging. We disclose herein transition metal
free ring opening silylation of indoles and benzofurans through
C(2)-N/O bond cleavage by a silyl anion (Scheme 1c). Product
vinyl silanes, that are versatile synthetic intermediates, are
obtained with moderate to excellent stereoselectivity.
Silyllithium compounds react efficiently with various organic
electrophiles,[8] but their reactivity towards arenes and
heteroarenes has not been well explored. Rossi investigated the
nucleophilic aromatic silylation using the highly reactive
(
trimethylsilyl)lithium.[9] Likely due to the fact that Me
3
SiLi is too
reactive and not readily generated, this area has remained
unexplored. We decided to study the reaction of various
arylsilyllithium reagents with N-phenylindole 1a as a model
substrate. The silyllithium reagents were readily generated from
the corresponding silyl chlorides by reductive lithiation with
elemental lithium in THF. Reactions were generally conducted at
room temperature for 24
systematically varied. With Me
corresponding ring opening silylation products were not formed
Table 1, entries 1-3) and traces of C(2)-H bond silylation were
identified by GC mass spectrometry. Pleasingly, the targeted 2a
was isolated in 57% yield with high E-selectivity using tBuPh SiLi
Table 1, entry 4). Yield further increased to 80% upon raising
temperature to 50 oC but E/Z selectivity slightly decreased.
Attempted generation of tBuPh SiNa failed and large amounts of
tBuPh SiSiPh tBu were observed. Reaction with tBuPh SiK
resulted in a complex mixture and the target 2a was not identified
h
and the silyl-Li reagent was
2
PhSiLi, MePh SiLi and Ph SiLi the
2
3
(
2
(
2
2
2
2
(
(
2 2
Table 1, entry 6). (tBuPh Si) Zn did also not react with 1a to 2a
Table 1, entries 7, 8).
[*]
P. Xu, Prof. Dr. E. U. Würthwein, Dr. C. G. Daniliuc, Prof. Dr. A.
Studer
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Corrensstraße 40, 48149 Munster (Germany)
̈
E-mail: studer@uni-muenster.de
Supporting information for this article is given via a link at the end of
the document.
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Angewandte Chemie International Edition
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COMMUNICATION
Table 1. Reaction optimization.
With optimized conditions in hand, we next investigated
scope and limitations of this novel indole ring opening (Table 2).
Effects exerted by indole substituents were investigated first. The
5
1
8
3
-F, 6-F, 5-Ph, 5-Me Si, and 4-OPh substituted N-phenyl indoles
b-1f worked well and the vinyl silanes 2b-2f were isolated in 71-
6% yield. E/Z-selectivity varied from 7:1 to >20:1. The N-phenyl
entrya
Si-reagent (2 equiv)
Me PhSiLi
MePh SiLi
Ph SiLi
tBuPh SiLi
tBuPh
temp
rt
ratio (E/Z)b
yield (%)c
group could be replaced by substituted phenyl groups (see 2g-2j)
and also the N-naphthyl indole 1k underwent ring opening to
provide 2k in 76% yield. Selectivity varied in this series without
identifying any trend. Unfortunately, N-methylindole did not
provide the corresponding vinylsilane (not shown). We assume
that the anion stabilizing effect of the aryl group at the nitrogen
atom to be of key importance. Reaction did also not work for N-
phenyl pyrrole as an acceptor and n-BuLi or t-BuLi did not ring-
open 1a under the same conditions.
1d
2d
3
-
0
2
2
rt
-
0
3
rt
-
0
4
2
rt
>20:1
57
80
0
5
2
SiLi
50 °C
8:1
6
tBuPh
(tBuPh
(tBuPh
2
SiK
rt
rt
rt
-
-
-
7
8e
2
Si)
2
Zn
0
Zne
0
2
Si)
2
If reaction is quenched with methyl iodide or allyl bromide in
place of water, the N-atom could be directly methylated or
allylated. The corresponding products 2l and 2m were isolated in
good yields but moderate E/Z-selectivity. Successful gram scale
synthesis of 2l without any loss in yield demonstrated the
robustness and practicability of the transformation.
a
Reaction condition: 1a (0.2 mmol, 1.0 equiv), Si-reagent (0.4 mmol, 2.0 equiv),
THF (1 mL). E/Z isomer ratio determined by 1H NMR. cIsolated yield. dTraces
of the C(2)-H bond silylation product were identified by GC mass spectrometry.
b
e
CuI (0.01 mmol, 0.05 equiv) was added.
Table 2. Ring opening silylation of various indoles.a,b
Table 3. Ring opening silylation of various benzofurans.a,b
a
2
Reaction conditions: 3 (0.2 mmol, 1.0 equiv), tBuPh SiLi (0.4 mmol, 2.0 equiv),
THF (1 mL), 25 oC, 24 h. bYield corresponds to isolated yield.
We then turned our attention to the ring opening of
benzofurans and found that the parent 3a reacted efficiently at
room temperature with tBuPh
selectivity to vinyl silane 4a (Table 3). Me
also worked, but lower yields were obtained in these cases. The
-F, 5-tBu, 5-PhO, 5-Ph N, 5-Ph, and 7-Ph substituted
benzofurans 3b-3g reacted with tBuPh SiLi to 4b-4g in excellent
2
SiLi in 90% yield and complete E-
2
PhSiLi and MePh SiLi
2
5
2
2
yields (90-96%) and excellent selectivity (E/Z > 20:1). The
phenolate could be directly alkylated with MeI to give the methyl
ether 4h. The structure of 4h was confirmed by X-ray
crystallographic analysis.[10]
The suggested mechanism for the indole ring opening
silylation based on DFT calculations (TPSS/def2-TZVP-
PCM(THF)), for details see the Supporting Information) is
depicted in Scheme 2. The silyl lithium compound first interacts
with the five-membered ring of indole via Lewis acid/base
interaction to give complex A. The Si-anion then adds at the 2-
position via TS(AB) to give a benzylic anion B. The Li-ion is
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), tBuPh
2
SiLi (0.4 mmol, 2.0 equiv),
o
b
c
THF (1 mL), 50 C, 24 h. Yield corresponds to isolated yield. Conducted at rt.
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Angewandte Chemie International Edition
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COMMUNICATION
located syn to the bulky Si group and interacts also with the
dihydroindole N-atom. We found a low barrier (TS(BC)) for β-
elimination to give the major E-complex C.[11] Formation of the Z-
isomer D via TS(BD) is less favored but feasible, as observed in
the experiments. Interestingly, isomers C and D are very close in
energy. N-protonation or N-alkylation eventually provides 2 (not
shown).
2
introduced herein uses readily generated tBuPh SiLi and does not
require any transition metal catalyst. Transformations proceed
under mild conditions and indole derived products are obtained in
moderate to excellent yields with generally very high E-selectivity.
For benzofurans, all transformations occurred with excellent
yields and complete E-selectivity. Importantly, vinyl silanes
obtained as products are valuable building blocks in synthesis.
For benzofuran 3a, a similar addition-elimination mechanism
is suggested (see SI). To exclude that reaction proceeds via -
lithiation of benzofuran,[11a,b] 2-deuterated benzofuran 3a-D was
2
reacted with tBuPh SiLi and the deuterated vinylsilane 4a-D was
obtained without any loss in deuterium content (see SI), clearly
showing that deprotonation is not occurring. In addition, DFT
calculations (TPSS/def2-TZVP-PCM(THF)) were also conducted
on 3a (see SI). We found the barrier for tBuPh
to lie at 21.53 kcal/mol (298 K) and addition to be exothermic by
.02 kcal/mol. The TS for -elimination to the E-isomer lies at 6.25
2
SiLi-addition to 3a
2
kcal/mol and for the Z-isomer at 8.40 kcal/mol. -Elimination is
highly exothermic for both isomers (E-isomer: -42.93 kcal/mol; Z-
isomer: -43.20 kcal/mol). We also repeated the calculations of 3a
2
with tBuPh SiLi including two THF molecules complexed at the Li-
atom and found similar energies (see SI).
Scheme 3. Follow-up chemistry
Acknowledgements
This work was supported by the China Scholarship Council
(
stipend to Pan Xu) and the Westfälische Wilhelms-University
Münster.
Keywords: dearomatization • benzofuran • indole • transition-
metal-free • silylation
[
1]
(a) M. G. Steinmetz, Chem. Rev. 1995, 95, 1527–1588; (b) M.
Weidenbruch, Chem. Rev. 1995, 95, 1479–1493; (c) A. Hosomi, K. Miura,
Bull. Chem. Soc. Jpn. 2004, 77, 835-851; (d) L. Nicole, C. Boissier, D.
Grosso, A. Quach. C. Sanchez. J. Mater. Chem. 2005, 15, 2590-2598.
(a) L. D. Curless, E. R. Clark, J. J. Dunsford, M. J. Ingleson, Chem.
Commun. 2014, 50, 5270−5272; (b) T. Stahl, P. Hrobárik, C. D. F. Königs,
Y. Ohki, K. Tatsumi, S. Kemper, M. Kaupp, H. F. T. Klare, M. Oestreich,
Chem. Sci. 2015, 6, 4324-4334; (c) Y. H. Ma, B. L. Wang, L. Zhang, Z.
M. Hou, J. Am. Chem. Soc. 2016, 138, 3663−3666; (d) Q.−A. Chen, H.
F. T. Klare, M. Oestreich, J. Am. Chem. Soc. 2016, 138, 7868−7871; (e)
Y. X. Han, S. T. Zhang, J. H. He, Y. T. Zhang, J. Am. Chem.
Soc. 2017, 139, 7399–7407.
[
2]
2
Scheme 2. Structures of intermediates for reaction of 1a with tBuPh SiLi and
calculated free energies (kcal/mol at 298 K) for intermediates and transitions
states.
[
3]
(a) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173−1193;
(b) B. Lu, J. R. Falck, Angew. Chem., Int. Ed. 2008, 47, 7508−7510;
To demonstrate the synthetic value of the method, we
investigated follow-up chemistry on vinylsilanes 2l and 4h
Angew. Chem. 2008, 120, 7618-7620; (c) H. F. T. Klare, M. Oestreich, J.
Ito, H. Nishiyama, Y. Ohki, K. Tatsumi, J. Am. Chem. Soc. 2011, 133,
3312−3315; (d) C. Cheng, J. F. Hartwig, Science 2014, 343, 853−857;
(e) K. Devaraj, C. Sollert, C. Juds, P. J. Gates, L. T. Pilarski, Chem.
Commun. 2016, 52, 5868−5871; (f) H. Fang, L. Guo, Y. Zhang, W. Yao,
Z. Huang, Org. Lett. 2016, 18, 5624–5627.
(
Scheme 3). Reaction of 2l with TBAF at 80 °C provided the ortho-
vinylaniline 5 in 90% yield.[12] Vinylsilane 2l was easily converted
to silanol 6 with tBuOK and 18-crown-6 in wet THF.[13] Epoxidation
of the E-vinylsilane 4h with meta-chloroperbenzoic acid (MCPBA)
and subsequent acid-catalyzed rearrangement gave the α-silyl
aldehyde 7.[14d] α-Silylaldehydes are valuable intermediates in
organic synthesis.[14] Stereospecific iodinolysis of the C−Si bond
in 4h with ICl provided vinyl iodide 8.[15]
In summary, we have demonstrated a practical method for ring
opening silylation of various indoles and benzofurans. Whereas
the benzofuran C(2)-O bond cleavage functionalization has
previously been achieved using transition metal catalysis the
analogous process on indoles is unprecedented. The method
[
4]
(a) A. A. Toutov, W. B. Liu, K. N. Betz, A. Fedorov, B. M. Stoltz, R. H.
Grubbs, Nature 2015, 518, 80−84; (b) A. A. Toutov, W.−B. Liu, K. N. Betz,
B. M. Stoltz, R. H. Grubbs, Nat. Protoc. 2015, 10, 1897−1903; (c) S.
Banerjee, Y. F. Yang, L. D. Jenkins, Y. Liang, A. A.Toutov, W. -B. Liu, D.
P. Schuman, R. H. Grubbs, B. M. Stoltz, E. H. Krenske, K. N. Houk, R.
N. Zare, J. Am. Chem. Soc. 2017, 139, 6880–6887; (d) W.-B. Liu, D. P.
Schuman, Y.-F. Yang, A. A. Toutov, Y. Liang, H. F. T. Klare, N. Nesnas,
M. Osetreich, D. G. Blackmond, S. C. Virgil, S. Banerjee, R. N. Zare, R.
H. Grubbs, K. N. Houk, B. M. Stoltz, J. Am. Chem. Soc. 2017, 139, 6867–
6879.
[5]
K. Nogi, H. Yorimitsu, Chem. Commun. 2017, 53, 4055-4065.
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COMMUNICATION
[
[
6]
7]
For a review: A. H. Sandtorv, Adv. Synth. Catal. 2015, 357, 2403-2435.
For Ni catalysts, see: (a) E. Wenkert, L. E. Michelotti, C. S. Swindell, J.
Am. Chem. Soc. 1979, 101, 2246-2247; (b) J. Cornella, R. Martin, Org.
Lett. 2013, 15, 6298-6301; (c) M. Tobisu, T. Takahira, T. Morioka, N.
Chatani, J. Am. Chem. Soc. 2016, 138, 6711-6714; (d) L. Guo, M.
Leiendecker, C.-C. Hsiao, C. Baumann, M. Rueping, Chem. Commun.
2015, 51, 1937-1940; (e) H. Saito, S. Otsuka, K. Nogi, H. Yorimitsu, J.
Am. Chem. Soc. 2016, 138, 15315−15318; For Rh catalyst, see: (f) K.
Itami, S. Tanaka, K. Sunahara, G. Tatsuta, A. Mori, Asian J. Org. Chem.
2015, 4, 477-481.
[
8]
(a) A. G. Brook, S. Wolfe. J. Am. Chem. Soc. 1957, 79, 1431–1437; (b)
H. Gilman, G. D. Lichtenwalter, J. Am. Chem. Soc. 1958, 80, 608-611;
(c) D. P. Dervan, M. A. Shippey, J. Am. Chem. Soc. 1976, 98, 1265-
1267; (d) S. Saito, K. Shimada, H. Yamamoto, E. M. D. Marigorta, I.
Fleming, Chem. Commun. 1997, 1299-1300.
[
[
9]
(a) A. Postigo, R. A. Rossi, Org. Lett. 2001, 3, 1197-1200; (b) A. Postigo,
S. E. Vaillard, R. A. Rossi, J. Phys. Org. Chem. 2002, 15, 889–893.
10] CCDC 1562830 contains the supplementary crystallographic data for
compound 4h of this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre.
[
11] Formal addition elimination of alkyl Li-compounds in enol ethers, see: (a)
P. Kocienski, S. Wadman, K. Cooper, J. Am. Chem. Soc. 1989, 111,
2363-2565; (b) T. Nguyen, E.-i. Negishi, Tetrahedron Lett. 1991, 32,
5903-5906. Cyclization of alkyl-Li onto activated pyrroles and thiophenes,
see: (c) J. Clayden, R. Turnbull, M. Helliwell, I. Pinto, Chem. Commun.
2004, 2430-2431; (d) J. Clayden, R. Turnbull, I. Pinto, Org. Lett. 2004, 6,
609-611; (e) J. Clayden, R. Turnbull, I. Pinto, Tetrahedron: Asymmetry
2005, 16, 2235-2241.
[
[
[
12] A. Giraud, O. Provot, A. Hamzé, J. D. Brion, M. Alami, Tetrahedron Lett.
008, 49, 1107-1110.
13] J. C. Anderson, S. Anguille, R. Bailey, Chem. Commun. 2002, 2018-
019.
14] (a) D. Enders, V. Bhushan, B. B. Lohray, Tetrahedron Lett. 1993, 34,
067–5070; (b) L. F. Tietze, T. Neumman, M. Kajino, M. Pretor,
2
2
5
Synthesis 1995, 1003–1006; (c) A. Barbero, Y. Blanco, C. García, F. J.
Pulido, Synthesis 2000, 1223–1228; (d) F. J. Pulido, A. Barbero, Nat.
Protoc. 2006, 1, 2068-2074.
[
.
15] S. P. Chou, H. L. Kuo, C. J. Wang, C. Y. Tsai, C. M. Sun, J. Org.
Chem. 1989, 54, 868-872.
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COMMUNICATION
COMMUNICATION
Pan
Xu,
Ernst-Ulrich
Würthwein,
Constantin G. Daniliuc and Armido
Studer*
Page No. – Page No.
Transition-Metal-Free Ring Opening
Silylation of Indoles and Benzofurans
with (Diphenyl-tert-butylsilyl)lithium
Ring opening silylation of various indoles and benzofurans using diphenyl-tert-
butylsilyllithium to provide ortho-β-silylvinyl anilines or phenols is presented.
Dearomatization of the heteroarene core proceeds in the absence of any transition
metal catalyst via silyl anion addition and subsequent stereoselective β-elimination.
This article is protected by copyright. All rights reserved.