Palladium-Catalyzed Silacyclization of (Hetero)Arenes with a Tetrasilane Reagent through Twofold C?H Activation

Article abstract of DOI:10.1002/anie.202015117

The use of an operationally convenient and stable silicon reagent (octamethyl-1,4-dioxacyclohexasilane, ODCS) for the selective silacyclization of (hetero)arenes via twofold C?H activation is reported. This method is compatible with N-containing heteroarenes such as indoles and carbazoles of varying complexity. The ODCS reagent can also be utilized for silacyclization of other types of substrates, including tertiary phosphines and aryl halides. A series of mechanistic experiments and density functional theory (DFT) calculations were used to investigate the preferred pathway for this twofold C?H activation process.

Full text of DOI:10.1002/anie.202015117

Angewandte
Communications
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 7066–7071
CÀH Activation
International Edition:
German Edition:
doi.org/10.1002/anie.202015117
doi.org/10.1002/ange.202015117
Palladium-Catalyzed Silacyclization of (Hetero)Arenes with
À
a Tetrasilane Reagent through Twofold C H Activation
Dingyi Wang, Mingjie Li, Xiangyang Chen, Minyan Wang,* Yong Liang, Yue Zhao,
Kendall N. Houk, and Zhuangzhi Shi*
Dedicated to the 100th anniversary of the College of Chemistry, Nankai University
Abstract: The use of an operationally convenient and stable
silicon reagent (octamethyl-1,4-dioxacyclohexasilane, ODCS)
for the selective silacyclization of (hetero)arenes via twofold
CÀH activation is reported. This method is compatible with N-
containing heteroarenes such as indoles and carbazoles of
varying complexity. The ODCS reagent can also be utilized for
silacyclization of other types of substrates, including tertiary
phosphines and aryl halides. A series of mechanistic experi-
ments and density functional theory (DFT) calculations were
used to investigate the preferred pathway for this twofold CÀH
activation process.
I
n the fields of complex molecule synthesis, advanced
materials, and biomedical applications, (hetero)arenes con-
[
1]
taining CÀSi bonds are of considerable interest. Many
[
2]
methods are available to construct CÀSi bonds, among
[
3]
which CÀH silylation is particularly attractive. Significant
progress has been made since the first appearance of seminal
[
4]
Figure 1. Pd-catalyzed silacyclization using ODCS reagent through
twofold CÀH activation.
reports on aromatic CÀH silylation in 1982, and a variety of
[5]
directing groups have recently been identified that lead to
[6]
[7]
excellent ortho and remote meta selectivity with common
hydrosilanes or disilanes (Figure 1a). Octamethyl-1,4-dioxa-
cyclohexasilane (ODCS) has been employed for ring-opening
from the commercially available and inexpensive disilane I on
the gram scale as an air-stable and colorless solid (Scheme 1).
[
8]
[10]
polymerization. However, this compound has never been
used as a silicon reagent to build CÀSi bonds. Here, the
application of the ODCS reagent to CÀH silylation is
The indole moiety is an intriguing structural motif, and
the CÀH silylation of indoles has been explored over the
[11]
years. It is typically extremely challenging to circumvent
the inherent C3/C2 selectivity of indoles to access the benzene
reported for the first time (Figure 1b). A significant obser-
[
12]
III
[13]
vation on the reactivity of this reagent is that two CÀH bonds
core. Our group recently found that P -directing groups
in (hetero)arenes can be silylated to form benzoxadisilole
can enable the preferential regioselective CÀH functionaliza-
[9]
[14]
compounds in the presence of a palladium catalyst, whereas
conventional silicon reagents cannot deliver the related
products directly. Notably, ODCS reagent is easily prepared
tion of indoles at the C7 position. However, the simulta-
neous functionalization of two CÀH bonds at the benzene
core of indoles remains a largely elusive and unmet goal for
chemical synthesis. We tested the applicability of the ODCS
reagent to CÀH silylation by investigating the reactions of
t
t
a model substrate, N-P Bu ( Bu = tert-butyl) indole 1a
2
[*] D. Wang, M. Li, Prof. Dr. M. Wang, Prof. Dr. Y. Liang, Dr. Y. Zhao,
(
Table 1). A series of experiments showed that the silacycli-
Prof. Dr. Z. Shi
State Key Laboratory of Coordination Chemistry, Chemistry and
Biomedicine Innovation Center (ChemBIC), School of Chemistry and
Chemical Engineering, Nanjing University
Nanjing 210093 (China)
zation product 2a was obtained in an 86% GC yield using
Pd(OAc) as a catalyst and DMBQ as the oxidant in a toluene
2
solvent at 1208C (entry 1). The structure of 2a with two CÀSi
E-mail: wangmy@nju.edu.cn
shiz@nju.edu.cn
Dr. X. Chen, Prof. Dr. K. N. Houk
Department of Chemistry and Biochemistry, University of California
Los Angeles, CA 90095 (USA)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202015117.
Scheme 1. Large-scale synthesis of ODCS reagent.
Angew. Chem. Int. Ed. 2021, 60, 7066 –7071
7066
ꢀ 2020 Wiley-VCH GmbH

Angewandte
Communications
Chemie
[
a]
[a]
Table 1: Reaction development.
Table 2: Substrate scope of silacyclization.
[
b]
Entry
Variation from “standard conditions”
Yield of 2a [%]
[
c]
1
2
3
4
5
6
7
8
none
86 (77)
Use of Ag CO instead of DMBQ
Use of CuCl instead of DMBQ
Use of BQ instead of DMBQ
Use of Pd(TFA) instead of Pd(OAc)2
At 1008C
Without DMBQ
Without Pd(OAc)2
5
2
3
19
28
47
76
14
0
2
2
[a] Reaction conditions: 1a (0.20 mmol), ODCS (0.5 mmol), catalyst
(
10 mol%), oxidant (0.5 mmol) in toluene (0.5 mL), 48 h, 1208C, under
Ar; [b] GC yield; [c] isolated yield; 2,5-dimethyl-1,4-benzoquinone
DMBQ), 1,4-benzoquinone (BQ).
(
bonds at the indole C6 and C7 positions was unambiguously
confirmed by X-ray crystallographic analysis. The use of
DMBQ in the system appeared to be crucial for suppressing
t
oxidation of the N-P Bu motif and maintaining the catalytic
cycle,
2
[
15]
whereas other conventional oxidants, such as
Ag CO , CuCl , and BQ, reacted to produce lower yields
2
3
2
(
entries 2–4). Reactions with palladium catalysts lacking OAc
produced considerably lower yields than those catalyzed by
Pd(OAc) (entry 5). Good reactivity (in terms of the reaction
2
outcome) was maintained upon lowering the reaction temper-
ature to 1008C (entry 6). Finally, control experiments showed
poor conversion without the use of the DMBQ oxidant
(
entry 7), and silylation did not proceed in the absence of the
palladium catalyst (entry 8).
We next evaluated the scope and generality of this method
under optimized reaction conditions (Table 2). Indoles bear-
ing electron-neutral and electron-donating substituents, such
as methyl (1b–1d), phenyl (1e), thioether (1 f), ether (1g) and
alkenyl (1g) groups at C3-C5 positions, were well tolerated,
affording the corresponding silacycles 2b–2g in 41–75%
yields. These reactions proceed without any interference from
halides, such as the F (2i and 2j) and Cl (2k) units. Indoles
containing electron-withdrawing groups, such as ester (1l)
[
a] Reaction conditions: 1 (0.20 mmol), ODCS (0.5 mmol), Pd(OAc)2
(10 mol%), DMBQ (0.5 mmol) in toluene (0.5 mL), 48 h, 1208C, under
Ar; isolated yield; [b] at 1408C.
III
and acetyl (1m), were also suitable for P -directed silacyc-
lization with ODCS, providing products 2l and 2m in 74%
and 55% yields, respectively. The reaction of indole 1n with
a methyl group at the C2 position did not inhibit the process,
including 5H-benzo[b]carbazole 1w, 7H-dibenzo[c,g]-
carbazole 1x and 5,11-dihydroindeno[1,2-b]carbazole 1y,
were also examined, and the silacyclization products (2w–
2y) were obtained in 46–64% yields.
but the smaller N-PCy2 (Cy = cyclohexyl) directing group
t
exhibited higher reactivity than the N-P Bu motif, affording
2
the desired product 2n in a 63% yield. The 2,3-disubstituted
indole skeletons 1o–1q also underwent cyclization to form
Further investigations were conducted to demonstrate the
practicability of the ODCS reagent (Scheme 2). First, the
ODCS reagent could also be used for the late-stage CÀH
2
o, 2p, and 2q in 46–71% yields. In addition to indoles, the
silacyclization of carbazoles 1r–1s occurred with excellent
site selectivity for ortho and meta positions to the N-PCy2
group. The regioselectivity of the silylation of unsymmetrical
carbazoles with methyl (1t), methoxy (1u) and Cl (1v) groups
at the less hindered benzene core led to a high level of steric
control by substituents ortho to the reacting CÀH bond. In
modification of complex molecules (Scheme 2a). When
complex indole molecules 3a and 3b were subjected to the
developed system, high levels of selectivity were observed for
CÀH silylation in products 4a and 4b, despite multiple
potentially reactive positions. Second, silacyclization with the
ODCS reagent could be used for rapidly modification of
addition, several highly p-extended heterocyclic skeletons,
Angew. Chem. Int. Ed. 2021, 60, 7066 –7071
ꢀ 2020 Wiley-VCH GmbH
www.angewandte.org 7067

Angewandte
Communications
Chemie
Scheme 2. Additional silacyclization studies.
tertiary phosphines (Scheme 2b). For example, twofold CÀH
silylation of tri-1-naphthylphosphine (5) produced a new
ligand 6 in one step. Third, the ODCS reagent has the
potential to conduct other types of silacyclization reactions
iodo-substituted indole 13. Interestingly, Tamao-Fleming
[
18]
oxidation of indole 2a with or without MeLi reagent was
found to selectively produce C7- and C6-hydroxy indoles 14
and 16, which further underwent one-pot deprotection with
TBAF to generate N-free indoles 15 and 17, respectively.
Several experiments were carried out to elucidate the
CÀH activation process (Scheme 3). First, a stoichiometric
(
Scheme 2c). Disiloxane-bridged biphenyl 9 is a widely
[
16]
studied OLED material that was previously synthesized
from iodoarene 7 by palladium-catalyzed disilylation (8),
[
17]
followed by cyclization with a BBr reagent.
Using the
reaction of indole 1a with Pd(OAc) was found to produce
3
2
II
t
ODCS reagent for the direct silacyclization of substrate 7
could afford product 9 in a good yield in the presence of
a palladium salt, shortening the reaction path. Moreover, aryl
halide 10 could undergo silacyclization to form product 11
through activation of an aliphatic CÀH bond. Finally,
a bimetallic Pd complex 18 chelation by N-P Bu group, as
[
19]
characterized by X-ray analysis (Scheme 3a). The use of
either complex 18 as a catalyst or the starting material with
the ODCS reagent was found to yield the desired product 2a,
indicating the CÀH metalation complex 18 as a possible
molecular scaffolds bearing disiloxane are known to undergo
a variety of downstream transformations (Scheme 2d). For
instance, treatment of compound 2a with a MeLi reagent
furnishes C6-silylated indole 12, which could further form
intermediate in the reaction. Similarly, the reaction of
carbazole 1r with stoichiometric Pd(OAc)2 afforded the
dimer complex 19, as confirmed by X-ray analysis (Sche-
me 3b). In addition, a KIE of 1.45 between indoles 1a and
7068 www.angewandte.org
ꢀ 2020 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 7066 –7071

Angewandte
Communications
Chemie
group, forming
a 14-membered intermediate
INT5A to release ring strain and tension. In the
presence of DMBQ and the in situ-formed AcOH,
the palladium center is oxidized to regenerate the
Pd catalyst and form the intermediate INT6A,
whereas the alternative pathway involving the
insertion of the catalyst into the SiÀSi bond is less
favorable. The insertion of the Pd catalyst into the
SiÀSi bond of INT6A requires a free energy of
À1
3
3.8 kcalmol to form the intermediate INT7A.
The calculated energy profile shows that the
II
oxidative addition of the Pd species to the SiÀSi
bond of INT6A is the rate-determining step in the
overall reaction pathway. The second CÀH metal-
ation proceeds with an activation barrier of
À1
3
0.2 kcalmol via a CMD process to form the
intermediate INT8A. The second reductive elim-
ination results in the formation of the desired
product 3aa and the Pd species INT9A. Finally, the
active palladium catalyst can be regenerated in the
presence of DMBQ and the in situ-generated
AcOH. Detected by high-resolution electrospray
ionization mass spectrometry (ESI-HRMS), the
reaction mixture showed a clearly signal for the
+
byproduct 20 (ESI-HRMS [M+K] calculated for
C H KO Si : 445.1263, found: 445.1262.).
2
0
30
5
2
In summary, a silicon reagent (ODCS) has
been developed for the silacyclization of (hetero)-
arenes through twofold CÀH silylation. ODCS is
a credible reagent for the direct transfer of
a disiloxane-bridged unit to diverse substrates,
including indoles, carbazoles, tertiary phosphines
and aryl halides, by Pd catalysis. The mechanistic
features of this silacyclization process have been
investigated. An investigation of the general use of
the ODCS reagent for other organic substrates is
ongoing and will be reported in due course.
Scheme 3. Mechanistic experiments.
d-1a with the ODCS reagent showed that the CÀH cleavage
step was fast and did not function as a rate-determining
Acknowledgements
[20]
step.
Density functional theory (DFT) calculations were con-
ducted to elaborate the detailed reaction mechanism
We would like to thank the National Natural Science
Foundation of China (Grants 22025104, 21972064, and
21672097), the National Natural Science Foundation of
Jiangsu Province (Grant BK20170632), the Excellent Youth
Foundation of Jiangsu Scientific Committee (Grant
BK20180007), the “Innovation & Entrepreneurship Talents
Plan” of Jiangsu Province and the Fundamental Research
Funds for the Central Universities for their financial support.
We are also grateful to the High Performance Computing
Center of Nanjing University for doing the numerical
calculations in this paper on its blade cluster system.
[
21]
(
Figure 2). Initially, an active Pd catalyst associates with
indole 1a to generate INT1, which preferentially deproto-
nates the C7 position of 1a to form the CÀH metalated
palladacycle INT2A through a concerted metalation depro-
[
22]
À1
tonation (CMD) pathway
with a 12.7 kcalmol energy
barrier. Dimerization of INT2A to form the intermediate 18 is
À1
exothermic by 10.2 kcalmol , suggesting that the active
catalyst is in a rest state. Oxidative addition of INT2A with
the ODCS reagent forms the 7-membered palladacycle
INT3A through the transition state TS3A with an energy
À1
barrier of 18.7 kcalmol . Subsequent reductive elimination
results in the formation of the first CÀSi bond at the indole C7 Conflict of interest
À1
position with an energy demand of 10.7 kcalmol , leading to
the formation of INT4A. The intermediate INT4A easily
undergoes further reductive elimination to transfer the silicon
connected with the palladium atom to the O of the acetoxy
The authors declare no conflict of interest.
Angew. Chem. Int. Ed. 2021, 60, 7066 –7071
ꢀ 2020 Wiley-VCH GmbH
www.angewandte.org 7069

Angewandte
Communications
Chemie
Figure 2. Plausible reaction mechanism and free energy profiles for silacyclization of indole 1a with ODCS reagent; bond lengths are in ꢀ.
Keywords: heteroarenes · ODCS · palladium · silacyclization ·
silylation
1258 – 1269; b) J. F. Hartwig, Acc. Chem. Res. 2012, 45, 864 – 873;
c) C. Cheng, J. F. Hartwig, Chem. Rev. 2015, 115, 8946 – 8975.
4] W. A. Gustavson, P. S. Epstein, M. D. Curtis, Organometallics
[
[
1982, 1, 884 – 885.
5] a) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 2375 – 2378;
b) F. Zhang, D. R. Spring, Chem. Soc. Rev. 2014, 43, 6906 – 6919;
c) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu, Y. Zhang, Org.
Chem. Front. 2015, 2, 1107 – 1295; d) C. Sambiagio, D. Schçn-
bauer, R. Blieck, T. Dao-Huy, G. Pototschnig, P. Schaaf, T.
Wiesinger, M. F. Zia, J. Wencel-Delord, T. Besset, B. U. W. Maes,
M. Schnꢀrch, Chem. Soc. Rev. 2018, 47, 6603 – 6743.
[
1] a) A. Showell, J. S. Mills, Drug Discovery Today 2003, 8, 551 –
5
4
2
56; b) A. K. Franz, S. O. Wilson, J. Med. Chem. 2013, 56, 388 –
05; c) D. Sun, Z. Ren, M. R. Bryce, S. Yan, J. Mater. Chem.
015, 3, 9496 – 9508.
[
2] M. Mortensen, R. Husmann, E. Veri, C. Bolm, Chem. Soc. Rev.
2009, 38, 1002 – 1010.
[
3] For reviews on CÀH silylation, see: a) L. Omann, C. D. F.
[6] a) H. Ihara, M. Suginome, J. Am. Chem. Soc. 2009, 131, 7502 –
7503; b) E. M. Simmons, J. F. Hartwig, J. Am. Chem. Soc. 2010,
Kçnigs, H. F. T. Klare, M. Oestreich, Acc. Chem. Res. 2017, 50,
7070 www.angewandte.org
ꢀ 2020 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 7066 –7071

Angewandte
Communications
Chemie
132, 17092 – 17095; c) Y. Hua, P. Asgari, T. Avullala, J. Jeon, J.
Miura, Angew. Chem. Int. Ed. 2019, 58, 9856 – 9860; Angew.
Am. Chem. Soc. 2016, 138, 7982 – 7991; d) J. Wen, B. Dong, J.
Zhu, Y. Zhao, Z. Shi, Angew. Chem. Int. Ed. 2020, 59, 10909 –
Chem. 2019, 131, 9961 – 9965; e) I. Choi, A. M. Messinis, L.
Ackermann, Angew. Chem. Int. Ed. 2020, 59, 12534 – 12540;
Angew. Chem. 2020, 132, 12635 – 12641.
10912; Angew. Chem. 2020, 132, 11001 – 11004.
[
7] a) A. Maji, S. Guin, S. Feng, A. Dahiya, V. K. Singh, P. Liu, D.
Maiti, Angew. Chem. Int. Ed. 2017, 56, 14903 – 14907; Angew.
Chem. 2017, 129, 15099 – 15103; b) A. Modak, T. Patra, R.
Chowdhury, S. Raul, D. Maiti, Organometallics 2017, 36, 2418 –
[13] For some recent examples, see: a) X. Qiu, P. Wang, D. Wang, M.
Wang, Y. Yuan, Z. Shi, Angew. Chem. Int. Ed. 2019, 58, 1504 –
1508; Angew. Chem. 2019, 131, 1518 – 1522; b) J. Wen, D. Wang,
J. Qian, D. Wang, C. Zhu, Y. Zhao, Z. Shi, Angew. Chem. Int. Ed.
2019, 58, 2078 – 2082; Angew. Chem. 2019, 131, 2100 – 2104; c) K.
Fukuda, N. Iwasawa, J. Takaya, Angew. Chem. Int. Ed. 2019, 58,
2850 – 2853; Angew. Chem. 2019, 131, 2876 – 2879; d) Z. Zhang,
T. Roisnel, P. H. Dixneuf, J.-F. Soulꢁ, Angew. Chem. Int. Ed.
2019, 58, 14110 – 14114; Angew. Chem. 2019, 131, 14248 – 14252.
[14] a) A. J. Borah, Z. Shi, J. Am. Chem. Soc. 2018, 140, 6062 – 6066;
b) X. Qiu, H. Deng, Y. Zhao, Z. Shi, Sci. Adv. 2018, 4, eaau6468.
[15] C. A. Salazar, K. N. Flesch, B. E. Haines, P. S. Zhou, D. G.
Musaev, S. S. Stahl, Science 2020, 370, 1454 – 1460.
[16] H. Kai, J. Ohshita, S. Ohara, N. Nakayama, A. Kunai, I.-S. Lee,
Y.-W. Kwak, J. Organomet. Chem. 2008, 693, 3490 – 3494.
[17] A. Lu, X. Ji, B. Zhou, Z. Wu, Y. Zhang, Angew. Chem. Int. Ed.
2018, 57, 3233 – 3237; Angew. Chem. 2018, 130, 3287 – 3291.
[18] I. Fleming, R. Henning, D. C. Parker, H. E. Plaut, P. E. J.
Sanderson, J. Chem. Soc. Perkin Trans. 1 1995, 317 – 337.
[19] T. W. Lyons, K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2011,
133, 4455 – 4464.
2
423; c) A. Dey, S. K. Sinha, T. K. Achar, D. Maiti, Angew.
Chem. Int. Ed. 2019, 58, 10820 – 10843; Angew. Chem. 2019, 131,
0934 – 10958; d) G. Meng, N. Y. S. Lam, E. L. Lucas, T. G. Saint-
Denis, P. Verma, N. Chekshin, J.-Q. Yu, J. Am. Chem. Soc. 2020,
42, 10571 – 10591.
1
1
[
8] M. Cypryk, J. Chojnowski, J. Kurjata in The Science and
Technology of Silicones and Silicone-Modified Materials (Eds.:
S. J. Clarson, J. J. Fitzgerald, M. J. Owen, S. S. Smith, M. E.
Van Dyke), American Chemical Society, Washington, 2007,
pp. 10 – 26.
9] a) R. J. P. Corriu, J. J. E. Moreau, M. Pataud-Sat, Organometal-
lics 1985, 4, 623 – 629; b) W. Setaka, K. Ebata, H. Sakurai, M.
Kira, J. Am. Chem. Soc. 2000, 122, 7781 – 7786; c) B.-J. Pei, W.-H.
Chan, A. W. M. Lee, Org. Lett. 2011, 13, 1774 – 1777; d) Y. Lin,
K.-Z. Jiang, J. Cao, Z.-J. Zheng, Z. Xu, Y.-M. Cui, L.-W. Xu, Adv.
Synth. Catal. 2017, 359, 2247 – 2252.
[
[
[
10] L. Joucla, L. Djakovitch, Adv. Synth. Catal. 2009, 351, 673 – 714.
11] a) B. Lu, J. R. Falck, Angew. Chem. Int. Ed. 2008, 47, 7508 – 7510;
Angew. Chem. 2008, 120, 7618 – 7620; b) A. A. Toutov, W.-B.
Liu, K. N. Betz, A. Fedorov, B. M. Stoltz, R. H. Grubbs, Nature
[20] E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51,
3066 – 3072; Angew. Chem. 2012, 124, 3120 – 3126.
[21] Y. Kim, Y. Park, S. Chang, ACS Cent. Sci. 2018, 4, 768 – 775.
[22] L. Ackermann, Chem. Rev. 2011, 111, 1315 – 1345.
2015, 518, 80 – 84; c) Q.-A. Chen, H. F. T. Klare, M. Oestreich, J.
Am. Chem. Soc. 2016, 138, 7868 – 7871; d) Y. Han, S. Zhang, J.
He, Y. B. Zhang, J. Am. Chem. Soc. 2017, 139, 7399 – 7407.
[
12] a) L. Ping, D. S. Chung, J. Bouffard, S.-g. Lee, Chem. Soc. Rev.
Manuscript received: November 11, 2020
2
017, 46, 4299 – 4328; b) J. A. Leitch, Y. Bhonoah, C. G. Frost,
Revised manuscript received: December 12, 2020
Accepted manuscript online: December 29, 2020
Version of record online: February 24, 2021
ACS Catal. 2017, 7, 5618 – 5627; c) Y. Yang, Z. Shi, Chem.
Commun. 2018, 54, 1676 – 1685; d) C. N. Kona, Y. Nishii, M.
Angew. Chem. Int. Ed. 2021, 60, 7066 –7071
ꢀ 2020 Wiley-VCH GmbH
www.angewandte.org
7071