Consecutive β,β′-Selective C(sp3)?H Silylation of Tertiary Amines with Dihydrosilanes Catalyzed by B(C6F5)3

Article abstract of DOI:10.1002/anie.202016664

Tris(pentafluorophenyl)borane has been found to catalyze the two-fold C(sp³)?H silylation of various trialkylamine derivatives with dihydrosilanes, furnishing the corresponding 4-silapiperidines in decent yields. The multi-step reaction cascade involves amine-to-enamine dehydrogenation at two alkyl residues and two electrophilic silylation reactions of those enamines, one inter- and one intramolecular.

Full text of DOI:10.1002/anie.202016664

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Communications
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How to cite: Angew. Chem. Int. Ed. 2021, 60, 8542–8546
International Edition:
German Edition:
doi.org/10.1002/anie.202016664
doi.org/10.1002/ange.202016664
ꢀ
C H Activation
Hot Paper
3
ꢀ
Consecutive b,b’-Selective C(sp ) H Silylation of Tertiary Amines with
Dihydrosilanes Catalyzed by B(C6F5)3
Huaquan Fang, Kaixue Xie, Sebastian Kemper, and Martin Oestreich*
Dedicated to Professor Siegfried Blechert on the occasion of his 75th birthday
Abstract: Tris(pentafluorophenyl)borane has been found to
3
ꢀ
catalyze the two-fold C(sp ) H silylation of various trialkyl-
amine derivatives with dihydrosilanes, furnishing the corre-
sponding 4-silapiperidines in decent yields. The multi-step
reaction cascade involves amine-to-enamine dehydrogenation
at two alkyl residues and two electrophilic silylation reactions
of those enamines, one inter- and one intramolecular.
3
ꢀ
S
elective functionalization of C(sp ) H bonds is an impor-
tant goal in synthetic chemistry.[1] One way to achieve this is
3
[2,3]
ꢀ
by transition-metal-catalyzed C(sp ) H silylation,
and
recently selected boron Lewis acids also emerged as catalysts
for this purpose.[4] For example, B(C6F5)3 has been shown to
3
ꢀ
abstract hydride from a-C(sp ) H bonds of amines to result in
the formation of iminium ions and the borohydride;[5] that
ꢀ
iminium ion is C H acidic and can be deprotonated by
another molecule of the amine, affording the corresponding
enamine along with the ammonium borohydride[6,7]
(Scheme 1, gray box). The net reaction is a dehydrogenation
that enables subsequent bond formation with electrophiles in
the b-position to the nitrogen atom, thereby representing
3
ꢀ
a formal activation of the b-C(sp ) H bond. This process has
3
already been employed for silylation,[8] alkylation,[9] deutera-
ꢀ
Scheme 1. B(C6F5)3-catalyzed b-C(sp ) H functionalization of tertiary
amines. R groups=various aryl and alkyl groups as well as H;
Ar=aryl group.
tion,[10] and olefination[11] of the b-carbon atom of various
(a)cyclic tertiary amines (Scheme 1, top). Of note, Park and
3
ꢀ
Chang merged the C(sp ) H silylation with a B(C6F5)3-
catalyzed intramolecular Friedel–Crafts-type silylation[12] for
the synthesis of bridged silicon-containing nitrogen hetero-
cycles starting from N-arylated piperidines.[8a] However, the
medicinal chemistry,[13] for example, for the dopamine
receptor antagonist sila-haloperidol (Scheme 1, bottom
right).[14] Different from our approach, established syntheses
typically start from divinyl-substituted silanes employing
a sequence of hydrobromination or hydroboration–oxida-
tion–sulfonylation followed by dialkylation of a primary
amine.[15]
undirected silylation of acyclic tertiary amines[3c] as well as
3
ꢀ
their challenging two-fold C(sp ) H silylation are unprece-
3
ꢀ
dented. We disclose here a b,b’-selective C(sp ) H silylation
of acyclic tertiary amines and dihydrosilanes catalyzed by
B(C6F5)3 to directly arrive at sila analogues of piperidines
(Scheme 1, bottom left). These are valuable building blocks in
We began our investigation with optimizing the two-fold
3
ꢀ
C(sp ) H silylation of benzyldiethylamine (1a!3aa;
Table 1). Treatment of 1a and Ph2SiH2 (2a, 2.0 equiv) with
20 mol% of B(C6F5)3 in p-xylene at 1508C afforded 3aa after
15 h in 56% yield (Table 1, entry 1). Previous reports had
indicated that the use of a metal oxide[8a] or a silyl triflate[5c] as
an additive could improve the reactivity.[16] However, sub-
stoichiometric amounts of CaO or SrO decreased the yield
(Table 1, entries 2 and 3). The addition of 40 mol% of a silyl
triflate improved the reactivity (Table 1, entries 4–6), and
a 75% yield of 3aa was obtained with Me3SiOTf as the
additive. That yield was somewhat lower when using less and
more Me3SiOTf, respectively (Table 1, entries 7 and 8). The
reaction was completed within 2 h while a further shortened
[*] Dr. H. Fang, K. Xie, Dr. S. Kemper, Prof. Dr. M. Oestreich
Institut fꢀr Chemie, Technische Universitꢁt Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oestreich@tu-berlin.de
Homepage: http://www.organometallics.tu-berlin.de
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.202016664.
ꢂ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
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Table 1: Selected examples of the optimization of B(C6F5)3-catalyzed two-
3
[a]
ꢀ
fold C(sp ) H silylation.
Entry
Additive (mol%)
Solvent
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
–
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
toluene
benzene
C6H5Cl
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
15
15
15
15
15
15
15
15
2
1
2
2
2
56
48
50
75
66
62
67
60
75 (73)
42
74
62
55
0
49
68
61
60
34
(65)
CaO (50)
SrO (50)
Me3SiOTf (40)
tBuMe2SiOTf (40)
iPr3SiOTf (40)
Me3SiOTf (20)
Me3SiOTf (80)
Me3SiOTf (40)
Me3SiOTf (40)
Me3SiOTf (40)
Me3SiOTf (40)
Me3SiOTf (40)
Me3SiOTf (40)
Me3SiOTf (40)
Me3SiOTf (40)
Me3SiOTf (40)
Me3SiOTf (40)
Me3SiOTf (40)
Me3SiOTf (40)
9
10
11
12
13
14[c]
15[d]
16[e]
17[f]
18[g]
19[h]
20[i,j]
2
2
2
15
2
Scheme 2. Scope I: Variation of the tertiary amine. Reaction conditions
(0.10 mmol scale): B(C6F5)3 (20 mol%), Me3SiOTf (40 mol%), Ph2SiH2
2
12
(2a, 2.0 equiv), and p-xylene (0.80 mL) at 1508C for 2 h. Yields are
isolated yields. [a] See Table 1, entry 20. [b] Starting from N-ethyl-N-(3-
methoxybenzyl)ethanamine (1l). [c] 40 mol% of B(C6F5)3, 80 mol% of
Me3SiOTf, and 4.0 equiv of Ph2SiH2 (2a) used. Bn=benzyl, Cy=cyclo-
hexyl.
[a] All reactions were performed on a 0.050 mmol scale in a 10 mL sealed
tube. [b] Yields determined by 1H NMR spectroscopy using mesitylene
as an internal standard; isolated yields in parentheses. [c] Without
B(C6F5)3. [d] 10 mol% B(C6F5)3 used. [e] 1.5 equiv Ph2SiH2 (2a) used.
[f] Run at 1208C. [g] 5.0 mL sealed tube used. [h] 1.0 mL sealed tube
used. [i] Open system with a continuous flow of nitrogen gas.
[j] 5.0 mmol scale.
amine 1l containing a methyl ether underwent demethyla-
tion/silylation, and the free phenol was isolated in 50% yield
after purification by flash chromatography on silica gel (1l!
3la). A lower yield was obtained for a naphth-2-ylmethyl
reaction time to 1 h resulted in a lower yield (Table 1,
entries 9 and 10). Other arene solvents were tested but none
provided a better outcome (Table 1, entries 11–13). A control
experiment verified that Me3SiOTf is unable to mediate the
reaction in the absence of B(C6F5)3 (Table 1, entry 14). Less
B(C6F5)3 or Ph2SiH2 (2a) as well as lowering the temperature
to 1208C led to a decreased reactivity (Table 1, entries 15–17).
The volume of the reaction vessel was also examined, and the
results indicate that vessels smaller than 10 mL are detrimen-
tal (Table 1, entries 18 and 19). We ascribe this to catalyst
inhibition by dihydrogen at high pressure.[7] A good yield was
instead of the benzyl group (1m!3ma). The bis(4-silapiper-
3
ꢀ
idine) 3na was formed in 47% yield by four-fold C(sp ) H
silylation of 1n. Replacing the benzyl group by an alkyl group
3
ꢀ
was feasible (1o-q!3oa-qa). Notably, the two-fold C(sp ) H
silylation of substrate 1o bearing two ethyl groups and one
cyclohexyl group proceeded chemoselectively at the ethyl
groups to form 3oa. Substituted 4-silapiperidine derivatives
were obtained from tertiary amines with groups other than
ethyl (1r–t!3ra–ta). As expected, 1t gave 3ta with essen-
tially no diastereoselectivity (cis/trans = 58:42). Attempted
but failed cyclizations included tertiary benzylamines as
precursors having two isopropyl, cyclohexyl, isobutyl, or
phenethyl groups as well as 1-benzylazepane (see the
Supporting Information for details).
restored on a 5.0 mmol scale when performing the two-fold
3
ꢀ
C(sp ) H silylation in an open system with a continuous flow
of nitrogen gas (Table 1, entry 20).
We continued exploring the scope under the optimized
reaction setup (Scheme 2; cf. Table 1, entry 9). It must be
3
noted that reductive C(sp ) N bond cleavage[17] is competing
We also tried the silylation of the tertiary aniline
derivative 1u which did not react under Parkꢀs and Changꢀs
catalytic system (Scheme 3).[8a] Bicyclic 4ua and tricyclic 5ua
formed in yields of 50% and 8%, respectively. The propor-
tion of 5ua increased at longer reactions times, for example,
44% yield of 4ua and 25% yield of 5ua after 3 h. As for the
ꢀ
in any of the reactions summarized in Scheme 2, and
secondary amines are the major byproducts (not quantified
because of their volatility). N-Benzylated diethylamine
derivatives bearing various electron-donating or -withdrawing
substituents on the aryl moiety reacted with Ph2SiH2 (2a) to
furnish the corresponding 4-silapiperidines in moderate to
good yields (1b–l!3ba–la; gray box). All halo groups (1g–j)
and a trifluoromethyl group (1k) were compatible. Tertiary
aforementioned method,[8a] intramolecular Friedel–Crafts
2
C(sp ) H silylation[12] is favored over intramolecular
ꢀ
3
ꢀ
C(sp ) H silylation.
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Scheme 4. Elaboration of an N-benzylated 4-silapiperidine. [a] 1) 1-
chloroethyl chloroformate (1.2 equiv), CH2Cl2, 08C to D, 1 h; RT, 20 h;
2) MeOH, D, 1 h; [b] KMnO4 (3.0 equiv), BnNEt3Cl (3.0 equiv), CH2Cl2,
D, 3 h.
3
2
ꢀ
ꢀ
Scheme 3. Consecutive C(sp ) H/C(sp ) H silylation of an aniline
derivative.
We next assessed the dihydrosilane scope in the reaction
of model substrate 1a (Table 2). Diarylsilanes 2b–e exhibited
good reactivity, furnishing the corresponding products in the
same yield range as compared to 2a (1a!3ab–ae; Table 2,
entries 1–4). No reaction was seen with sterically hindered
dimesitylsilane (2 f; Table 2, entry 5). Modest yield was
obtained with MePhSiH2 (2g in 1a!3ag; Table 2, entry 6)
but the synthesis of a spirocyclic derivative with 1-silaindane
(2h) was low yielding (Table 2, entry 7).[18] The dialkylsilane
Et2SiH2 (2i) afforded desired 3ai in moderate yield (Table 2,
entry 8), but again, there was no reaction with bulky tBu2SiH2
(2j; Table 2, entry 9). The reaction of the primary hydrosilane
PhSiH3 yielded only trace amounts of the 4-silapiperidine
(not shown).
The benzyl group in 4-silapiperidines such as 3aa serves as
a linchpin for further manipulations (Scheme 4). Debenzyla-
tion was achieved by treatment with 1-chloroethyl chlorofor-
mate followed by the reaction of the resulting carbamate with
MeOH (3aa!6). The benzyl group can also be converted
into a benzoyl group by oxidation with KMnO4 in the
presence of BnNEt3Cl (3aa!7).
Scheme 5. Deuterium-labeling and stoichiometric experiments. Individ-
ual deuteration grades were estimated by 1H NMR spectroscopy. The
overall deuteration grades of 2.87 D for 3aa-d3 and 2.98 D for 1v-d3
were determined by mass spectrometry.
To gain insight into the reaction mechanism of this two-
3
ꢀ
fold C(sp ) H silylation, deuterium-labeling experiments and
stoichiometric experiments were performed (Scheme 5). The
reaction of 1a with Ph2SiD2 (2a-d2) under standard conditions
gave 3aa-d3 in the expected yield with 41% deuterium
incorporation in the benzylic position as well as at the
a to an amine nitrogen atom.[6] Importantly, 6% deuterium
incorporation was also detected for the b carbon atoms, which
is evidence for hydrogenation of the enamine intermediate. In
the case of diethyl-substituted 1a, silylation is faster than this
backward reaction. Conversely, di-n-butyl-substituted 1v
shows a different outcome (Scheme 5, top). None of the
hypothetical 4-silapiperidine 3va-d3 was found (not shown)
but instead 1v-d3 with the usual deuteration in the a-
positions. However, the deuteration grade in the b-positions
was 24%, demonstrating that enamine hydrogenation is now
a competitive if not the only reaction pathway for more
hindered alkyl chains. To inspect the influence of the
Me3SiOTf additive, we mixed 1a and B(C6F5)3 in an
equimolar ratio (Scheme 5, bottom). This known reaction[6]
led to the formation of the three boron species 8a–10a in
52%, 30%, and 17% yield, respectively, and this product
distribution was not affected by the addition of 1.0 equiv of
Me3SiOTf.
a carbon atoms (Scheme 5, top). This result confirms the
3
ꢀ
known reversible hydride abstraction from C(sp ) H bonds
Table 2: Scope II: Variation of the hydrosilane.[a]
Entry
Hydrosilane
R
R’
Yield [%][b]
1
2
3
4
5
6
7
8
9
2b
2c
2d
2e
2 f
2g
2h
2i
4-MeC6H4
4-tBuC6H4
4-FC6H4
Ph
Mes
Ph
1-silaindan-1,1-diyl
Et
tBu
4-MeC6H4
4-tBuC6H4
4-FC6H4
Naphth-1-yl
Mes
65 (3ab)
65 (3ac)
67 (3ad)
68 (3ae)
no reaction (3af)
40 (3ag)
traces (3ah)
42 (3ai)
Me
On the basis of the above experimental results and the
literature precedent[6,8] as well as DFT calculations by Park
and Dang,[8b] a plausible reaction mechanism is proposed
(Scheme 6). B(C6F5)3 promotes hydride abstraction from the
tertiary amine 1a to generate the iminium borohydrides 11a
Et
tBu
2j
no reaction (3aj)
[a] Reaction conditions (0.10 mmol scale): B(C6F5)3 (20 mol%),
Me3SiOTf (40 mol%), hydrosilane 2 (2.0 equiv), and p-xylene (0.80 mL)
at 1508C for 2 h. [b] Isolated yield. Mes=mesityl.
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Foundation Berlin for an endowed professorship. We also
thank Dr. Maria Schlangen (TU Berlin) for expert advice
with the MS measurements. Open access funding enabled and
organized by Projekt DEAL.
Conflict of interest
The authors declare no conflict of interest.
ꢀ
ꢀ
Keywords: amines · boron · C H activation · Si H activation ·
silicon
[1] C. He, W. G. Whitehurst, M. J. Gaunt, Chem 2019, 5, 1031 – 1058,
and references therein.
[2] For authoritative reviews, see: a) S. C. Richter, M. Oestreich,
Trends Chem. 2020, 2, 13 – 27; b) J. F. Hartwig, E. A. Romero,
Tetrahedron 2019, 75, 4059 – 4070; c) Y. Fukumoto, N. Chatani in
Organosilicon Chemistry: Novel Approaches and Reactions
(Eds.: T. Hiyama, M. Oestreich), Wiley-VCH, Weinheim, 2019,
pp. 171 – 211.
3
ꢀ
[3] For examples of transition-metal-catalyzed C(sp ) H silylation
a or b to an amine nitrogen atom, see: a) T. Mita, K. Michigami,
Y. Sato, Chem. Asian J. 2013, 8, 2970 – 2973 (a, directed, and
intermolecular); b) H. Fang, W. Hou, G. Liu, Z. Huang, J. Am.
Chem. Soc. 2017, 139, 11601 – 11609 (a and intramolecular);
c) B. Su, T. Lee, J. F. Hartwig, J. Am. Chem. Soc. 2018, 140,
18032 – 18038 (b and intramolecular).
Scheme 6. Plausible mechanism for the formation of 3aa from 1a and
2a (Si=HPh2Si). rds=rate-determining step.
[4] For a review, see: a) S. Park, Chin. J. Chem. 2019, 37, 1057 – 1071;
and 11a’ in equilibrium. Their subsequent deprotonation by
unreacted 1a yields enamine 12a and FLP-type dihydrogen
adduct 8a; these can regenerate the free amine 1a and the
catalyst B(C6F5)3 along with release of dihydrogen.[7,19] The
thus-formed enamine 12a then engages in the rate-determin-
ing B(C6F5)3-catalyzed intermolecular hydrosilylation[8b]
through the Piers mechanism[20] with 12a as a carbon
ꢀ
for a review dedicated to transition-metal-free C H silylation,
see: b) D. P. Schuman, W.-B. Liu, N. Nesnas, B. M. Stoltz in
Organosilicon Chemistry: Novel Approaches and Reactions
(Eds.: T. Hiyama, M. Oestreich), Wiley-VCH, Weinheim, 2019,
pp. 213 – 240.
[5] For examples of B(C6F5)3-catalyzed a-functionalization of
tertiary amines, see: a) M. Shang, J. Z. Chan, M. Cao, Y.
Chang, Q. Wang, B. Cook, S. Torker, M. Wasa, J. Am. Chem.
Soc. 2018, 140, 10593 – 10601; b) A. F. G. Maier, S. Tussing, H.
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[7] These ammonium borohydrides are dihydrogen adducts of
amine/borane FLPs (FLP = frustrated Lewis pair). While release
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nucleophile
(B(C6F5)3!13a!15aa).
Alternatively,
B(C6F5)3-activated hydrosilane 13a can also react with the
amine nitrogen nucleophile 1a to equilibrate with silylam-
monium borohydride 14aa, the resting species of the overall
process.[8a,b] Initially formed 15aa stands in equilibrium with
regioisomeric 15aa’ and 15aa’’, and 15aa’’ can undergo
another deprotonation affording enamine 16aa. That enam-
ine again enters the catalytic cycle of the B(C6F5)3-promoted,
now intramolecular hydrosilylation to eventually arrive at the
title compound 3aa.
In summary, we have developed a B(C6F5)3-catalyzed two-
3
ꢀ
fold b,b’-selective (formal) C(sp ) H silylation of acyclic
tertiary amines with dihydrosilanes to construct 4-silapiper-
idines and its derivatives. The reaction involves two amine-to-
enamine dehydrogenation reactions each followed by an
inter- and an intramolecular electrophilic enamine silylation,
respectively.
[8] a) J. Zhang, S. Park, S. Chang, J. Am. Chem. Soc. 2018, 140,
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Acknowledgements
H.F. gratefully acknowledges the Alexander von Humboldt
Foundation for a postdoctoral fellowship (2018–2020), and
K.X. thanks the China Scholarship Council for a predoctoral
fellowship (2019–2023). M.O. is indebted to the Einstein
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[14] The 4-silapiperidine core was prepared in several steps with
a ring-forming dialkylation of a primary amine as the key step
(908C in an autoclave for 16 h): R. Tacke, T. Heinrich, R.
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Yus, Synthesis 1982, 414 – 417.
are thought to enhance hydride release from the borohydride
through the intermediate formation of a pentacoordinate silicon
hydride as a hydride shuttle.[5c]
[17] a) H. Fang, M. Oestreich, Angew. Chem. Int. Ed. 2020, 59,
11394 – 11398; Angew. Chem. 2020, 132, 11491 – 11495; see also:
b) Ref. [8c].
[18] Such spirocyclic systems are also relevant in medicinal chemis-
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Manuscript received: December 15, 2020
Revised manuscript received: February 16, 2021
Accepted manuscript online: February 19, 2021
Version of record online: March 3, 2021
[16] The roles of these additives are not entirely clear. The metal
oxides are believed to facilitate the deprotonation step[8a]
(iminium ion!enamine; Scheme 1, gray box) while silyl triflates
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