Catalytic Access to Bridged Sila- N-heterocycles from Piperidines via Cascade sp3 and sp2 C-Si Bond Formation

Article abstract of DOI:10.1021/jacs.8b08733

Described herein is the development of an unprecedented route to bridged sila-N-heterocycles via B(C₆F₅)₃-catalyzed cascade silylation of N-aryl piperidines with hydrosilanes. Mechanistic studies indicated that an outer-sp

Full text of DOI:10.1021/jacs.8b08733

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Communication
Catalytic Access to Bridged Sila-N-Heterocycles from
Piperidines via Cascade sp3 and sp2 C-Si Bond Formation
Jianbo Zhang, Sehoon Park, and Sukbok Chang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 01 Oct 2018
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Catalytic Access to Bridged Sila-N-Heterocycles from Piperidines via
3
2
Cascade sp and sp C−Si Bond Formation
1
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†,‡
,†,‡
,†,‡
Jianbo Zhang, Sehoon Park,* and Sukbok Chang*
†
Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea
‡
Department of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Daejeon 34141, Korea
Supporting Information Placeholder
transformation of N-aryl piperidines to polycyclic bridged
sila-N-heterocycles
ABSTRACT: Described herein is the development of an un-
precedented route to bridged sila-N-heterocycles via
B(C F ) -catalyzed cascade silylation of N-aryl piperidines
Scheme 1
6
5 3
with hydrosilanes. Mechanistic studies indicated that an
outer-sphere ionic path is operative to involve three sequen-
tial catalytic steps having N-silyl piperidinium borohydride
as a resting species: (i) dehydrogenation of the piperidine
ring, (ii) β-selective hydrosilylation of a resultant enamine2
intermediate, and (iii) intramolecular dehydrogenative sp
C−H silylation.
(
A) Examples of bioisosteres containing a silaꢀNꢀheterocyclic unit:
NMe2
Cl
OBn
O
N
F
N
OBn
Si
N Bn
Si
N
H
SiPh2
2
Si
HO
Me Me
sila-haloperidol
B) Previous scope of catalytic C H silylation:
catalyst (TM, TM-free)
sila-dimetracrine (+)-sila-Lentiginosine
spirocyclic sila-
analogue of -receptor
ligand
(
H
[Si]
(i)
Het
or
R
H
+
[Si]H
Het
or
R
[Si]
+
H2
I
n medicinal chemistry, silicon-linked heterocycles are con-
TM-free catalysts: MOR/MOH (M = K, Na) (Stoltz and Grubbs)
+
-
[
R3Si] [BAr4] (in situ) (Oestreich)
sidered to be able to constitute an interesting carbon isostere
B(C6F5)3 (Ingleson, Hou)
of the corresponding bioactive molecules since silicon has
unique physicochemical properties. With the prevalence of
1
[Si]
cat. B(C6F5)3
(
ii)
+
+
[Si]H
[Si]H
N
our previous work
N
N-heterocyclic units in numerous pharmacophores and alka-
loids, the preparation of sila-N-heterocycles (azasilahetero-
cycles) as a potent bioisostere is of growing interest (Scheme
[Si]
[
Si]
cat. B(C6F5)3
1
d,2
(iii)
R
R
+
R
1
A). In this regard, the development of a catalytic system
(Zhang)
B(C6F5)3
N
N
N
Me
Me
Me
enabling the construction of azasilaheterocycles from readily
accessible compounds via a cyclization approach accompa-
nied by new C−Si bond formation would be highly promising,
up to 99%
H2
(
C) Catalytic route to bridged silaꢀNꢀazacycles via a silylation cascade (This Work):
formed via cyclization
3
but still challenging.
R'
R'
cat. B(C6F5)3
Si
Dehydrogenative silylation of organic compounds by the
reaction with hydrosilanes is one of the most straightforward
synthetic strategies to install a silyl group at the targeted
R
+
[Si]H
Ar
R
N
R
R
N
[Si]
Ar
N
N
Distal silylative cyclization
to form bridge (unprecedented)
4
H2
H2
C−H bonds. While a number of transition metal complexes
Ar
Ar
are shown to facilitate the dehydrogenative silylation of (het-
Ar
+
-
N
HB(C6F5)3
5
-6
A detour route for sp3 C H silylation of
piperidines (unprecedented)
R'RHSi
ero)arenes to form C−Si bonds, more convenient “transi-
resting species
tion metal-free” catalytic procedures using alkaline metal
7
8
9
alkoxides, borate salts, and B(C F ) have been document-
Transition metal-free / one-pot / scalable
Catalytic access to sila-N-heterocycles
Cascade of dehydrogenation / hydrosilylation / C H silylation
Mechansitic clarification of the cascade processes
6
5 3
ed [Scheme 1B(i)]. Our group also found that B(C F ) catalyst
6
5 3
enables
a dearomative hydrosilylation cascade of N-
3
heteroarenes to afford reduced N-heterocycles bearing a sp
by inducing cascade processes which are all predicted to be
catalytic in B(C F ) : (i) dehydrogenation of N-aryl piperi-
10-11
C−Si bond beta to nitrogen [Scheme 1B(ii)].
Being related
6
5 3
to this dearomative reduction, B(C F ) has been recently
dines; (ii) β-selective hydrosilylation of the resultant
enamine intermediates; and (iii) a unique remote silylative
cyclization (Scheme 1C). Described herein is the experi-
mental results on our working hypothesis that represent the
first catalytic route to such bridged sila-N-heterocycles. The
scope of substrates is presented along with mechanistic de-
tails.
6
5 3
demonstrated to catalyze dehydrogenation of saturated N-
heterocycles to provide synthetically important N-
1
2
heteroarenes. Similarly, Zhang showed that B(C F ) cata-
6
5 3
lyzes convergent disproportionation reaction of indoles with
hydrosilanes, in which some portion of the in situ generated
indolines are converted back to the parent indoles via dehy-
drogenation to eventually deliver C3-silylated indoles as the
At the outset of this study, we chose 1-tolylpiperidine 1a as
a model substrate and it was subjected to tentative thermal
conditions with a B(C F ) (cat.)/hydrosilane system (Scheme
1
3
final product up to 99% yields [Scheme 1B(iii)]. Being aware
9-13
of the catalytic versatility of B(C F ) , we envisaged a new
6
5
3
6 5 3
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1
4
2
). To our delight, the reaction furnished a tricyclic sila-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
amine product 2a-[Si] in 38% yield (1.7:1 d.r.), while the pre-
To improve the reaction efficiency, the use of metal oxide
additives was considered with an assumption that they could
work as a base to affect the presupposed ionic cascade trans-
formation. Gratifyingly, sub-stoichiometric amounts of
MgO,
supposed β-silylated piperidine intermediate was detected in
1
~5% by H NMR. This result implies that, as we envisioned, a
1
8
Scheme 2. B(C F ) -Catalyzed Silylation Cascade of 1a
6
5 3
a
Table 2. Scope of the Cascade Silylation
i) B(C6F5)3 (5 mol%)
+
CaO (50 mol%)
C6H5Cl, 120 oC, 12 h
N
o
+
MePhSiH2
(5 equiv)
N
R'
m
R' p
ii) B(C6F5)3 (5 mol%)
Si
R
R
20 oC, 12 h
Me
Ph
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
aꢀ1v
2aꢀ2v
N
N
N
iPr
tBu
Me
Si
Si
Si
Me
Ph
Me
Ph
Me
Ph
2a (71%, 6:1 d.r.)
2b (58%, 10:1 d.r.) 2c (58%, 10:1 d.r.)
Xꢀray (2a)
Me
N
newly introduced silyl group undergoes an intramolecular
N
N
Me
Me
N
2
dehydrogenative coupling with the N-tolyl C(sp )−H bond
Si
Ph
Si
PhO
Si
Si
Ph
1
5-16
Me
d (50%, 6:1 d.r.)
Ph
Me
Ph
Me
Ph
Me Me
presumably via a Wheland complex.
2
2e (16%, 6:1 d.r.)
2f (62%, 4:1 d.r.)
2g (52%, 1.4:1 d.r.)
Encouraged by this promising observation, an optimiza-
[25% r.s.m.]
[44% r.s.m.]
[32% r.s.m.]
tion study for this transformation was next conducted (Table
17
N
N
1
). Reactions with PhSiH were performed in various sol-
B
3
N
+
vents: a reaction in C H Cl gave the corresponding tricyclic
Si
Si
Ph
6
5
Me
Ph
o
Me
sila-amine 2a-[Si] in 38% yield at 120 C for 24 h in the pres-
1h
(2.5:1 d.r.)
(4:1 d.r.)
ence of B(C F ) (10 mol %), while reactions in other solvents
2h + 2h' (68%, 1.7:1)
6
5 3
or neat conditions afforded 2a-[Si] in 7~21% yield (entries
1−4). The use of cyclohexene as a hydrogen acceptor did not
improve the catalytic efficiency (entry 5).
F
N
N
B
F
N
+
[34% r.s.m.]
Me
Si
Me
Si
Me
Ph
Me Ph
Me
F
a
1i
2i (27%, 4:1 d.r.)
2i' (32%, 4:1 d.r.)
Table 1. Optimization of Reaction Conditions
Me
2
Me
2
B
N
5
N
5
Ph
[Si]
Me
Si
Me
Me
Me
1
j
2j (43%, 1.1:1 d.r.)
Xꢀray (2i')
b
entry
solvent
Cl
silane
additive
2a-[Si] (d.r.)
R
3
c
[1a]
3
R R = Me, (2k, 63%, 7:1 d.r.)
= Bn, (2l, 71%, 4:1 d.r.)
N
B
1
C
6
H
5
PhSiH
PhSiH
PhSiH
PhSiH
PhSiH
3
-
38(1.7:1) [14]
18(1.1:1) [59]
7(1.2:1) [53]
21(1.7:1) [18]
16(1.2:1) [67]
N
5
i
5
= Pr, (2m, 65%, 4.9:1 d.r.)
Me
Si
2
3
4
5
toluene
1,2-DCE
neat
3
3
3
3
-
[Si]
R
Me
Ph
= nPent, (2n, 60%, 4.6:1 d.r.)
3
1
k~1o
= Ph, (2o, 22%, 1:1 d.r.)
via
-
-
N
[23% r.s.m.]
tolyl
[Si]
4
R
N
C
6
H
5
Cl
cyclo-
hexene
B
d
N
5
4
R
Me
Si
5
Ph
trans
Me
[
Si]
Xꢀray (2l)
6
7
8
C
6
C
6
C
6
C
6
C
6
C
6
C
6
C
6
C
6
C
6
H
5
H
5
H
5
H
5
H
5
H
5
H
5
H
5
H
5
H
5
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
PhSiH
PhSiH
PhSiH
PhSiH
3
3
3
3
MgO
ZnO
CaO
CaO
CaO
CaO
CaO
CaO
CaO
CaO
45(1.8:1) [11]
43(1.5:1) [5]
47(1.2:1) [17]
59(1.4:1) [<5]
68(1.5:1) [<5]
26 [50]
Me
Ref. 10a
N
R = Me, (2p, 28%, 9:1 d.r.)
[38% r.s.m.]
= Bn, (2q, 31%, 1:1 d.r.)
[43% r.s.m.]
1
p~1q
R
via
4
tolyl
[
Si]
e
9
R
R = H, (2r, 82%, 2.3:1 d.r.)
= Me, (2s, 83%, 2.3:1 d.r.)
N
B
e
n
10
BuSiH
Et SiH
Ph SiH
MePhSiH
Me PhSiH
PhSiH
3
N
=
F, (2t, 71%, 2.3:1 d.r.)
= Cl, (2u, 47%, 2.3:1 d.r.)
31% r.s.m.]
R
Me
Si
e
1
Me
Ph
1
2
2
Me
1r~1v
[
e
2
1
2
2
29 [43]
= Br, (2v, 46%, 2.6:1 d.r.)
[32% r.s.m.]
e
3
1
2
71 (2a, 6:1) [<5]
5 mmol scale reaction
N
e
f
14
2
22 [44]
2a
2k
(53%, 0.78 g, 6:1 d.r.)
aꢀ[Si] with PhSiH3
(61%, 0.85 g, 1.3:1 d.r.)
(69%, 1.06 g, 6:1 d.r.)
Me
Si
g
R
Ph
15
3
<1 [95]
2
2r
a
R = H, 2aꢀ[Si]
(88%, 1.52 g, 2.3:1 d.r.)
NaOH,
B(C
6
F
5
)
3
(10 mol%), 1a (0.2 mmol), silane (5 equiv), and solvent
THF/H2O
o
b
c
(0.5 mL) at 120 C for 24 h. Isolated yields of 2a-[Si]. Recovered
1a. 2 Equivalents were added. B(C
2rꢀ[Si] with PhSiH3
= OH
d
e
(
95%, 1.63 g, 2:1 d.r.)
(65%, 1.4:1 d.r.)
6 5 3
F ) was added in two por-
f
a
tions (5+5) mol% over a (12+12) h period. Isolated yield of β-silyl-
piperidine. Ph B (10 mol %) was used instead of B(C F ) .
3 6 5 3
B(C
6
F
5
)
3
(5+5) mol%, substrate (0.2 mmol), MePhSiH
Cl (0.5 mL) at 120 C for (12+12) h in a reaction vial.
2
(5 equiv)
g
o
and C
6
H
5
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Yields and diastereomeric ratio of isolated products. The num-
bers (%) in brackets indicate the recovered starting materials
r.s.m.).
mmol-scale runs. Considering the biological relevance
1
c,1g-h
1
2
3
4
5
6
7
8
9
(Scheme 1A) as well as synthetic utility of silanols,
we
(
oxidized the Si−H bond of product 2a-[Si] (R = H) to its si-
lanol in good yield by treating NaOH in THF/H O.
2
ZnO, or CaO additives (0.5 equiv) led to improved yield of
a-[Si] (entries 6−8 vs. entry 1) (also see the S.I. for details).
Moreover, the addition of B(C F ) catalyst in two portions of
To shed light on the pathway of the present silylative cy-
clization, a series of mechanistic experiments were per-
formed (Scheme 3). Firstly, a reaction progress was moni-
tored by NMR spectroscopy under the developed catalytic
conditions (Scheme 3A). While the conversion of 1a was 40%
2
6
5 3
(
5+5) mol% over a period of (12+12) h was more effective in
giving higher yield (entry 9). With this two-portion addition
protocol, the scope of silanes was further explored: a reaction
(
6 h) and 61% (24 h) in reaction with MePhSiH , product
2
n
with BuSiH3 furnished the desired product in 68% yield
yields of 2a were 33% (6 h) and 43% (24 h), suggesting that
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(1.5:1 d.r.), whereas the use of Et SiH or Ph SiH brought
2 2 2 2
the product-yielding pathway competes with certain side
1
9
about lower yields of 2a-[Si] (entries 10−12). Finally, a reac-
reaction(s). F NMR of the crude reaction mixture exhibited
one set of major signals assignable to N-silyl piperidinium
borohydride, thus leading us to assume that piperidinium
tion with MePhSiH provided the best yield of 2a (71%) with
2
1
9
good diastereoselectivity (6:1) (entry 13). As predicted, a β-
silylated piperidine was obtained albeit in moderate yield
when a tertiary silane was applied (entry 14), again support-
-
ion species having a borohydride (C F ) BH counter anion is
6
5 3
in a resting state. Indeed, a stoichiometric treatment of 1a
ing our mechanistic consideration. Ph B was inactive under
with B(C F ) (1 equiv) and MePhSiH (5 equiv) generated the
3
6
5
3
2
the standard conditions (entry 15).
supposed N-silyl piperidinium borohydride 3 in quantitative
o
13,23
With the optimal conditions in hand (Table 1, entry 13),
substrate scope and scalability of this unprecedented trans-
formation were investigated (Table 2). N-Aryl piperidines
bearing an alkyl or phenyl group at the para-position of the
aryl moiety reacted with MePhSiH2 to provide the corre-
sponding bridged sila-N-heterocycles in 50~71% yields with
high diastereomeric ratios of 6:1~10:1 (2a-2d). The solid struc-
ture of 2a was unambiguously confirmed by X-ray crystallo-
graphic analysis. A phenoxy substituent at the same position,
however, gave inferior yield (2e, 16%, 6:1 d.r.). Substrates
bearing a disubstituted N-aryl ring at the meta- and/or para-
positions smoothly underwent the desired cyclization reac-
tions (2f-2i, 52~68%, 1.4:1~4:1 d.r.). When N-indanyl piperi-
dine (1h) was subjected to the optimal conditions, two regi-
oisomeric tetracyclic products (2h and 2h’) were obtained,
slightly favoring a cyclization path at the sterically less de-
manding position. It needs to be mentioned that the present
procedure readily offers a route to polycyclic products as in
this case.
yield within 10 min at 25 C (Scheme 3B).
A reaction of 1a
with deuterated silane MePhSiD was monitored under the
2
present catalyst system
Scheme 3. Mechanistic Studies
As another probe of substrate scope, variation at the piper-
idine moiety was next examined. When N-tolyl-(2-
methyl)piperidine (1j) was subjected, a cyclized product 2j
3
was obtained bearing a new sp C−Si bond at the sterically
less demanding C-5 position rather than C-3. The same regio-
outcome was observed with substrates having
a C3-
substituted piperidinyl unit. In these cases, a range of sub-
strates were viable (1k−1n), whereas a reaction of 3-
phenylpiperidinyl substrate (1o) was rather inefficient. The
crystal structure of 2l was obtained to exhibit a trans rela-
tionship between the Si−C5 and the prepositioned C3−Bn
bonds, suggesting stereoselective hydrosilylation of a pre-
supposed enamine intermediate. Cyclization of N-tolyl-
piperidines (1p−1q) possessing substituents at the C-4 posi-
tion of a piperidine moiety were found to be less efficient
20
albeit with varied diastereoselectivity. Low product yields
are attributable to steric congestion around the reacting C5
(Scheme 3C). While the cyclized product was not formed at
3
o
position during the sp C−Si bond forming hydrosilylation
80 C, only deuterium incorporation occurred at the
process. A significant structural variation was tested by em-
ploying tetrahydroisoquinoline derivatives instead of piperi-
dines. Pleasingly, they reacted all smoothly to afford the cor-
responding tetracyclic products in moderate to good yields
α carbon of the piperidine ring (21% D in 2 h and 86% D in
2
4 h) along with the H/D exchange of MePhSiD . In contrast,
2
deuterium was not incorporated at the β-carbon (C ). Based
β
on these observations, we propose that B(C F ) catalyzes the
21-22
2r-2v).
6 5 3
(
The present borane catalysis was also operative
α-hydrogen abstraction of substrate 1a to form an iminium
borohydride 4, and this process is reversible in the presence
even in gram scale as demonstrated for the formation of sev-
eral multicyclic products (2a, 2a-[Si], 2k, 2r, 2r-[Si]) in 5
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o
o
of hydrosilane at 80 C. Upon heating at 120 C, 1a smoothly
underwent the cascade silylation to give 2a-d in 36% yield
over 12 h. Notably, the fact that both 2a-d (Cα+α' = 77% D)
cles, potentially a carbon isostere of alkaloids and bioactive
compounds.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
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ASSOCIATED CONTENT
Supporting Information
and recovered 1a-d (C > 90% D) did not incorporate deuter-
α
ium at the β-carbons, corroborates that the β-hydrogen
cleavage of a putative iminium intermediate 4 is likely irre-
versible to give enamine 5.
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental details, characterization data, and copies of
NMR spectra (PDF)
In an effort to observe an enamine 5 as a plausible inter-
mediate, a stoichiometric reaction of 1a with B(C F ) was
6
5 3
attempted in the presence of CaO (0.5 equiv) (Scheme 3D). A
24
Crystallographic data for 2a, 2i′, and 2l (CIF)
zwitterion species 6 consisted of iminium and borate was
0
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found to form in 32% yield in 10 min. Although enamine like
AUTHOR INFORMATION
5
is not detected in this experiment, we assume that the for-
mation of 6 supports our working hypothesis on the cascade
event, wherein B(C F ) first mediates an α-hydrogen abstrac-
Corresponding Authors
6
5
3
*sehoonp@kaist.ac.kr
tion of 1a to lead to iminium 4, and then a relatively acidic
*sbchang@kaist.ac.kr
13
C -H bond is deprotonated presumably by the assistance of
β
1a to afford enamine 5 along with protonated piperidinium
borohydride 7. Enamine 5 is proposed to rapidly interact
Notes
The authors declare no competing financial interests.
24
with B(C F ) to give 6 in the absence of hydrosilanes, while
6
5 3
the presence of silane would induce the B(C F ) -catalyzed
6
5 3
ACKNOWLEDGMENT
hydrosilylation to furnish β-silylated piperidines as seen in
the above experiments (Scheme 2 and Table 1: entry 13).
This research was supported by the Institute for Basic Science
(
IBS-R010-D1) in Korea. We are thankful to Dr. Dongwook
Kim for the X-ray crystallographic analysis.
Scheme 4. Proposed Catalytic Pathway
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3844.
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9c,10a,28
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1
0
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β-silylated piperidine E; and (v) intramolecular sp C−H
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(
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1
2
(
10a
β
the C of a presupposed enamine.
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