Enantioselective Si-H Insertion Reactions of Diarylcarbenes for the Synthesis of Silicon-Stereogenic Silanes

Article abstract of DOI:10.1021/jacs.0c04533

We report the first example of enantioselective, intermolecular diarylcarbene insertion into Si-H bonds for the synthesis of silicon-stereogenic silanes. Dirhodium(II) carboxylates catalyze an Si-H insertion using carbenes derived from diazo compounds where selective formation of an enantioenriched silicon center is achieved using prochiral silanes. Fourteen prochiral silanes were evaluated with symmetrical and prochiral diazo reactants to produce a total of 25 novel silanes. Adding an ortho substituent on one phenyl ring of a prochiral diazo enhances enantioselectivity up to 95:5 er with yields up to 98percent. Using in situ IR spectroscopy, the impact of the off-cycle azine formation is supported based on the structural dependence for relative rates of diazo decomposition. A catalytic cycle is proposed with Si-H insertion as the rate-determining step, supported by kinetic isotope experiments. Transformations of an enantioenriched silane derived from this method, including selective synthesis of a novel sila-indane, are demonstrated.

Full text of DOI:10.1021/jacs.0c04533

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Communication
Enantioselective Si–H Insertion Reactions of Diarylcarbenes
for the Synthesis of Silicon-Stereogenic Silanes
Jake R. Jagannathan, James C. Fettinger, Jared T. Shaw, and Annaliese K. Franz
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04533 • Publication Date (Web): 16 Jun 2020
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Enantioselective Si–H Insertion Reactions of Diarylcarbenes for the
Synthesis of Silicon-Stereogenic Silanes
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Jake R. Jagannathan, James C. Fettinger, Jared T. Shaw*, and Annaliese K. Franz*
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
Supporting Information Placeholder
ABSTRACT: We report the first example of enantioselective, intermolecular diarylcarbene insertion into Si–H bonds for synthesis
of silicon-stereogenic silanes. Dirhodium(II) carboxylates catalyze an Si–H insertion using carbenes derived from diazo compounds
where selective formation of an enantioenriched silicon center is achieved using prochiral silanes. Fourteen prochiral silanes were
evaluated with symmetrical and prochiral diazo reactants to produce a total of 25 novel silanes. Adding an ortho substituent on one
phenyl ring of a prochiral diazo enhances enantioselectivity up to 95:5 er with yields up to 98 %. Using in situ IR spectroscopy, the
impact of the off-cycle azine formation is supported based on the structural dependence for relative rates of diazo decomposition. A
catalytic cycle is proposed with Si–H insertion as the rate-determining step, supported by kinetic isotope experiments. Transfor-
mations of an enantioenriched silane derived from this method, including selective synthesis of a novel sila-indane, are demonstrated.
A. Enantioselective Si–H insertion of donor/acceptor carbenes:
The potential utility of chiral-at-silicon compounds incorpo-
rated into more complex structures has not been fully under-
chiral Rh, Cu, Fe,
Ru, Pd, Ir
SiR3
N2
stood due to a shortage of synthetic methods. Silicon-stereo-
genic molecules are rare in number and diversity of structures
as compared to carbon. Selected examples to generate silicon-
stereogenic silanes include dehydrocouplings,1–3 arylation,4,5
hydrosilylation,6–9 Si–C activation,10,11 and reactions controlled
by chiral auxillaries.12–14 Brief explorations of the effect of sili-
con chirality on reaction outcome to produce more complex
molecules have occurred,15–17 yet remain limited.
OCH3
OMe
OR’
R3Si–H
Ph
*
Ph
up to 98% yield
up to 99:1 er
O
O
chiral Ir or Ru catalyst
H
Ar
N2
R
H
Ar
H
up to 93% yield
up to 99.5:0.5 dr
up to 99.5:0.5 er
Si
*
H3C
CO2R’
Si
*
H3C
R
H
O
B. Intermolecular Si–H insertion of donor/donor carbenes:
M = Ag, Fe, Pd,
or chiral Rh
SiR3
M
The catalytic insertion of carbenes into Si–H bonds to gen-
erate organosilicon compounds has been intermittently ex-
plored since Doyle’s original work in 1988.18,19 Methods to date
have focused on generation of stereogenic carbon centers using
donor/acceptor carbenes (Figure 1A).20–23 Si–H insertion to
generate stereogenic silicon centers has been demonstrated by
Katsuki24 and Iwasa25 using donor/acceptor carbenes (Figure
1A). Diarylcarbenes are commonly referred to as donor/donor
carbenes because they are typically less reactive, with few re-
ports of intermolecular Si–H insertion, and one report of an en-
antioselective variant using functionalized alkynes as precur-
sors (Figure 1B). 26–29
R3Si–H
Ph
Ar
Ph
• 1 enantioselective report
• No stereogenic silicon variant
Ar
up to 98% yield
up to 99:1 er
Ar = Ph, 2-furanyl
C. This work: enantioselective Si–H insertion of donor/donor carbenes
for silicon-stereogenic silanes
Ar
Rh2(S-TCPTTL)4 (1 mol %)
H
*
N2
R
H
Ar
H
R
Si
PhMe, 23 ˚C, 1.5 h
up to 98% yield
up to 98:2 dr
Si
Ar’
Ar’
*
up to 95:5 er
Figure 1. Insertion of carbenes into Si–H bonds.
Donor/donor carbenes have recently emerged as useful sub-
strates for highly selective C–H insertion reactions.30–34 Rho-
dium carbene complexes demonstrate sufficient reactivity at the
insertion carbon despite the presence of two aryl rings for po-
tential stabilization.35,36 The Franz group has a long-standing in-
terest in organosilicon chemistry and expertise synthesizing
prochiral dihydridosilanes with variation of steric and elec-
tronic factors.37–39 We envisioned that the additional aryl ring
could accomplish an enantioselective intermolecular Si-H in-
sertion process with prochiral silanes (Figure 1C). Herein, we
communicate the first enantioselective diarylcarbene Si–H in-
sertion to produce silicon-stereogenic organosilanes.
We began our studies screening metal catalysts [Ru(II), Ir(I),
Fe(II), Rh(II) and Cu(II)] with diphenyldiazomethane (2a) and
prochiral methylphenylsilane (1a). Inverse addition of 2a using
a syringe pump (over 1 hour) increased yield of 4a by prevent-
ing azine formation, as seen in previous studies with Si–H in-
sertion methodologies.21,40,41 Insertion product 4a was only ob-
served using dirhodium tetraacetate (Table 1, entry 1).42 Based
on this lead result, we proceeded to screen chiral dirhodium(II)-
based catalysts to identify an enantioselective variant.
A screen of well-studied chiral dirhodium compounds high-
lighted the reactivity of dirhodium tetracarboxylates (Table 1).
Carboxylate ligands afforded higher yields compared to amido-
containing ligands due to the increased electrophilicity of the
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Page 2 of 7
metal center and resulting carbene (entry 2 vs. entries 4-9).43 Of
below 23 ˚C did not increase selectivity and no insertion was
observed below –30 ˚C. With optimized conditions in hand, we
investigated the effect of substituents with both symmetrical
and prochiral diazo compounds.
1
2
3
4
5
6
7
8
the catalysts studied, Rh2(S-TCPTTL)4 provided the highest
levels of enantioselectivity when compared to others (entries 5-
8 vs 9), which improved further using toluene (entry 10). When
an insertion was tested using prochiral diazo carbene 3a, the en-
antioselectivity of silane product 5a increased from 82:18 to
93:7 er, with a notable increase in yield (76% to 91% yield,
entry 10 vs. 14).
A series of sterically and electronically varied silanes and
symmetrical diazo compounds were evaluated to study the ef-
fects on enantioselectivity (Scheme 1, 4a-o). Electron-rich di-
azo 2b was less reactive than 2a and provides lower yield for
4b (45%, 81:19 er). Yield improved using diazo 2c (91%) and
lower enantioselectivity was observed for silane 4c (76:24 er).
Electron-withdrawing groups do not strongly affect selectivity
(4d, 80:20 er) while electron-donating groups on the silane
proved deleterious to enantioselectivity (4e and 4f, 50:50 er and
74:26 er respectively). Additional steric bulk on the aryl ring of
the silane generally eroded enantioselectivity (4g-j) but main-
tained fair to good yields (55-69%). Selectivity similar to 4a
(82:18) was also observed using 2-naphthyl silane 1g, with the
yield also higher compared to 4h (69 vs 60%). A slight recovery
of enantioselectivity was also observed with 4k (52%, 82:18 er)
compared to 4h (79:21 er), and comparable to 4a. Studies with
varied alkyl substitution on the silicon center were conducted
with diazo 2a.
Table 1. Optimization of donor/donor Si–H insertion
9
Ph
N2
R
H
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12
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H3C Si
CH3
H
Ph
H
1 mol % Rh2L4
Ph
Si
Ph
DCM (0.05 M), 4Å MS
2a; R = H
3a; R = CH3
1a
23 ˚C, 1.5 h
R
5 equiv
5a; R = CH3
4a; R = H
Inverse addition
R’
R’
R’
R’
Rh2(S-BPTTL)4
RhII
O
N
O
RhII
RhII
O
O
N
4
O
RhII
O
N
CO2CH3
RhII
O
O
R
RhII
O
Rh2(5R-MEPY)4
4
t-Bu
Scheme 1. Scope of enantioselective Si–H insertion with sym-
4
R = t-Bu, R’ = Cl
Rh2(S-TCPTTL)4
metrical diazo compoundsa
R
O
S
inverse addition
N2
R = t-Bu, R’ = H
Rh2(S-PTTL)4
Ph
O
O
RhII
O
RhII
N
Ar
R
H
1 mol %
Rh2(S-TCPTTL)4
Ar
H
Ph
H
R
Si
Si
RhII
R
RhII
Ar
Ar
2a-c
O
O
H
R = 1-Ad, R’ = H
PhMe (0.05 M), 4Å MS
Ar
Ar
4
Rh2(S-PTAD)4
4
1a-f, h-n 2b, Ar = PMP
23 ˚C, 1.5 h
5 equiv
2c, Ar = 4-ClC6H4
4a-4o
R = 4-BrC6H4
Rh2(S-BTPCP)4
R = 4-(C12H25)C6H4
Rh2(S-DOSP)4
R = i-Pr, R’ = H
Rh2(S-PTV)4
R
% yield
er
82:18
78b
45
91
66
72
76
4a, R = R’ = H
4b, R = H, R’ = OCH3
4c, R = H, R’ = Cl
4d, R = F, R’ = H
4e, R = OCH3, R’ = H
4f, R = CH3, R’ = H
81:19
76:24
80:20
50:50
74:26
entry
R
H
Rh2L4
% yielda
drb
erc
H
H3C Si
1
2
Rh2(OAc)4
34
<5
<5
65
67
62
62
67
76
78
45
72
75
91
81
-
50:50
ND
H
Rh2(5R-MEPY)4
Rh2(S-BTPCP)4
Rh2(S-DOSP)4
Rh2(R-PTAD)
Rh2(S-PTTL)4
Rh2(S-BPTTL)4
Rh2(S-PTV)4
-
R’
R’
Mes = 2,4,6-
(CH3)3C6H2
3
H
-
ND
Ar
4
H
-
55:45
61:39
64:36
64:36
59:41
76:24
82:18
50:50
ND
CH3
H
H
Mes
H3C Si
H
5
H
-
H
Si
H3C Si
H3C Si
Ph
Ph
i-Pr
6
H
-
-
Ph
Ph
Ph
4j
64%
Ph
4g (Ar = 2-naphthyl)
69%, 82:18 er
4h (Ar = 1-naphthyl)
60%, 79:21 er
Ph
Ph
4k
60%
7
H
4i
55%
69:31 er
82:18 er
8
H
-
60:40 er
Ph
H
Ph
Ph
Ph
9
H
Rh2(S-TCPTTL)4
Rh2(S-TCPTTL)4
Rh2(OAc)4
-
H
H
H
Si
Si
Si
Et3SiO Si
d
d
10
11
12
13
14
15e
H
-
i-Pr
t-Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3
CH3
CH3
55:45
60:40
61:39
93:7
93:7
4l
45%
86:14 er
4m
60%
50:50 er
4n
77%
71:29 er
4o
60%
61:39 er
Rh2(R-PTAD)4
Rh2(S-DOSP)4
ND
a isolated yields; er determined using CSP-HPLC analysis of silanol
obtained from Pd/C hydrolysis. b Reaction performed using 1 mmol
of 2a.
CH3 Rh2(S-TCPTTL)4
93:7
93:7
d
CH3 Rh2(S-TCPTTL)4
a NMR yield using Ph-TMS as an internal standard. b Determined
using 1H NMR Spectroscopy. c Determined using CSP-HPLC anal-
ysis of silanol obtained from Pd/C hydrolysis; major diastereomer
if relevant. d Toluene used as a solvent. e Diazo added via syringe
over five minutes (without syringe pump).
Isobutyl-containing 4l provided the highest enantioselectivity
observed using 2a (86:14 er). However, neopentyl substitution
led to loss of enantioselectivity (4m, 50:50 er), and cyclohexyl
substitution reduced enantioselectivity as well (4n, 70:30 er).
Lastly, switching to a siloxane also deleteriously affected enan-
tioselectivity while maintaining fair yield (4o, 60%, 61:39 er).
We next turned our focus to insertion of prochiral diazo reac-
tants.
Under optimized conditions, slow addition of 3a over 5 minutes
without a syringe pump forms 5a in comparable yield and se-
lectivity (entry 14 vs. 15). Reducing the reaction temperature
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The ability of the ortho substituent on one phenyl ring of the
diazo compounds to control enantioselectivity was explored
(Scheme 2). Electron-donating substituents lower diastereose-
lectivity (5b, 90:10 dr vs 93:7 dr), but slightly improve enanti-
oselectivity (95:5 vs 93:7 er). With an electron-withdrawing
group (5c), excellent yield and enantioselectivity is observed
(93%, 93:7 er) and diastereoselectivity increased (98:2 vs 93:7
dr). Recent work has noted potential synergistic effects of elec-
tronics and ortho substitution on the selectivity of donor/donor
effects are present. We sought to explore varied substitution of
silanes with prochiral diazo 3a, given the increase in yield and
enantioselectivity compared to using 2a. Prochiral silanes were
tested with diazo 3a and all demonstrated above 90:10 er for
the major diastereomer (Scheme 2, 5f-5j). Additionally, the re-
action performed with 1 gram of 3a using <1 mol% catalyst af-
fords excellent yield, diastereoselectivity and enantioselectivity
(Scheme 2, 5a). Overall, the data shows that diastereoselectivity
is substrate controlled, while enantioselectivity is controlled by
the rhodium catalyst.. Notably, using a diastereoselective reac-
tion with silane 1c promotes enantioselectivity with 5f (94:6 er)
compared to 4e (50:50 er). This result highlights the benefit of
using prochiral 3a to improve enantioselectivity.
1
2
3
4
5
6
7
8
Scheme 2. Scope of enantioselective Si–H insertion with
9
prochiral diazo reagentsa
10
11
12
13
14
15
16
17
18
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inverse addition
Ar
CH3
H
Ar
H
N2
H
1 mol %
Rh2(S-TCPTTL)4
A catalytic cycle for the enantioselective Si–H insertion of
diarylcarbenes is proposed (Figure 2A).36 The Rh(II) carbox-
ylate catalyst (I) reacts with the diazo compound (2a or 3a) to
form complex II, which is approached by prochiral silane 1a to
produce the silicon-stereogenic silane and regenerate catalyst.
Kinetic isotope experiments support the rate-determining inser-
tion step (kH/kD = 1.6), fitting closely with previous experiments
Si
H3C Si
Ar
Ar’
PhMe (0.05 M), 4Å MS
Ar
5a-5j
Ar’
1a-c; e-g
5 equiv
3a-3e
23 ˚C, 1.5 h
Ph
Ph
Ph
Ph
H
H
H
H
H3C Si
H3C Si
Ph
H3C Si
Ph
H3C Si
Ph
Ar
Cl
H3C
H3CO
F3C
Ar = PMP
Ar
A. Catalytic Cycle
5a, 89%b
93:7 dr
93:7 er
5b, 91%b
90:10 dr
95:5 er
5c, 93%b
98:2 drc
93:7 er
5d, 98%b
90:10 dr
89:11 er
Ph
Ar
N
Ph
Ar
k (s-1)
N2
Ph
N
Ph
H3CO
F
N2
N2
k2a
6; Ar = Ph
7; Ar = (2-CH3)-C6H4
> 120
Ar
Ph
k3a
H
2a or 3a
H3C Si
Ph
H
H
H
Ar
H3C Si
Ph
H3C
H3C Si
Ph
H3C Si
Ph
H3C
Ph
N
2a or 3a
favored for 2a
disfavored for 3a
Ph
Ar
Rh2L4*
Rh2(S-TCPTTL)4
Ph
N
Ar
II
I
H3C
kH
kD
6 or 7
= 1.6
5e, 78%b
85:15 dr
61:39 er
5f, 85%b
94:6 dr
94:6 er
5g, 90%b
5h, 95%b
91:9 dr
93:7 er
91:9 dr
93:7 er
RDS
Ph
H
CH3
Ph
Ph
H3C Si
H
CH3
H
Ph
H
Rh2(S-TCPTTL)4
H3C Si
O
F
Si
Si
H2O
Ph Ar
4a or 5a
H
1a
8
H
H
H3C Si
Ph
H3C Si
Ph
B. Stereochemical Model
R
Rh2L*4
Cl
Cl
Cl
H3C
5id, 55%
82:18 dr
92:8 er
H3C
O
Cl
5j, 66% b
84:16 dr
93:7 er
t-Bu
N
out-of-plane tilt
O
(±) 5i hydrolysis
product
H
H
Ph
Si CH3
H
O
a
1
Isolated yields; dr determined using H NMR spectroscopy; er
O
O
O
O
H
Determined using CSP-HPLC analysis of silanol obtained from
=
II
Rh Rh
Pd/C hydrolysis. b Reaction performed using 1.00 g of 3a and 0.05
O
H
O
H
O
mol % catalyst, at 0.1 M in toluene. c dr was determined using 19
F
Approach
blocked by R
R
X
d
NMR spectroscopy. Relative configuration assigned by X-ray
analysis.
carbene chemistry.44 Substitution on both phenyl rings was able
to achieve excellent yield and good selectivity in 5d (98% yield,
90:10 dr . 89:11 er), although slightly lower compared to other
substitution patterns. The combined steric and push-pull elec-
tronic effects improve enantioselectivity compared to symmet-
rical diazo compounds. These substrates demonstrate that the
presence of ortho-substitution iso-steric to a methyl may induce
enantioselectivity. Replacing phenyl with a 1-naphthyl group
led to decreased diastereoselectivity (5e, 85:15 dr) and low en-
antioselectivity (61:39 er), suggesting other competitive steric
Figure 2. A. Proposed catalytic cycle with kinetic isotope effect; B.
Diagram of proposed selectivity rationale of donor/donor inser-
tions.
of Si–H insertion with donor-acceptor20,41,45 and donor/donor
carbenes.29 Off-cycle formation of azine (6 or 7) can occur
when metal carbene II reacts with another diazo reactant. Using
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Journal of the American Chemical Society
in situ IR spectroscopy, we determined that the ortho-substi-
Page 4 of 7
Rh2(S-TCPTTL)4, yielding silicon-stereogenic benzhydryl
silanes. While symmetrical diazo compounds demonstrated in-
itial enantioselectivity, using a prochiral diazo reactant dramat-
ically improved the reaction, providing yields up to 98% with
98:2 dr and 95:5 er. A catalytic cycle is proposed and the impact
of the off-cycle azine formation is supported based on the struc-
tural dependence for relative rates of diazo decomposition.
Transformation of the enantioenriched silane affords access to
silicon-stereogenic silanol, dehydrocoupling and intramolecu-
lar C–H silylation products.
1
2
3
4
5
6
7
8
tuted prochiral diazo 3a has a significantly reduced rate of azine
formation (vs 2a), which accounts for higher yields of the Si–H
insertion products. Relative rates of azine formation (krel > 120)
was observed for decomposition of diazo 2a vs 3a with Rh2(S-
TCPTTL)4 (in toluene) in the absence of silane (Figure 2A).46
Increased yields of Si–H insertion products with ortho-substitu-
tion (5a-i) are attributed to steric interactions blocking the ap-
proach of diazo 3a to II, which reduces off-cycle azine for-
mation. The addition of 4Å mol sieves reduces off-cycle pro-
cesses leading to formation of siloxane 8.42 The increase in en-
antioselectivity observed with prochiral donor/donor diazo 3 is
attributed to a twisting of the ortho-substituted aryl ring, which
blocks one face of the carbene in II to promote selective ap-
proach of the silane (Figure 2B).44,47,48 Davies recently reported
that the twisting effect has electronic contributions similar to
that of a donor/acceptor carbene;44 however, our data supports
that the steric effect of an out-of-plane phenyl twist is signifi-
cant.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures, spectra for all new compounds, HPLC
data, procedures for in situ IR experiments, and X-ray structure in-
formation for hydrolysis product of 5i (CCDC 2009546) (PDF).
To demonstrate the utility of enantioenriched silanes,
silane 5a was transformed to silanol, dehydrocoupling, and in-
tramolecular C–H silylation products. Silanes are useful inter-
mediates in stereoselective synthesis, and have versatile reac-
tivity with the remaining Si–H bond.49 It is well know that tran-
AUTHOR INFORMATION
Corresponding Authors
* email: akfranz@ucdavis.edu or jtshaw@ucdavis.edu
sition metals are capable of oxidative insertion into Si–H bonds
Funding Sources
50,51
with retention of configuration.
Pd/C-catalyzed silane hy-
We acknowledge the National Science Foundation for support of
this research (CHE-1900300, CHE-1363375; AKF) and the dual
source diffractometer (CHE-1531193) used in this study. The Na-
tional Institutes of Health (R01 GM124234; JTS) is also acknowl-
edged for support of this research.
drolysis affords silanol 9 in 90% yield with 90:10 dr and 93:7
er.38,51,52 Under attempted hydrosilylation conditions, an unex-
pected dehydrocoupling product 10 was isolated in good yield
(62%) and 93:7 dr.53–55 Exploiting the presence of the ortho-me-
thyl group, diasteroenriched sila-indane 11 was accessed in
90% yield with 90:10 dr using Ir-catalyzed C–H silylation
methodology developed by the Hartwig group.56,57
Author Contributions
All authors have given approval to the final version of the manu-
script.
Notes
H3C
OH
9
The authors declare no competing financial interest.
Pd/C (10 wt%)
Ph Si
90% yield
90:10 dr
93:7 er
THF/H2O (0.1 M)
rt, 10 min
ACKNOWLEDGMENT
5a
H3C
Will Jewell is acknowledged for assistance with acquiring mass
spectrometry data. Benjamin Bergstrom, Sarah Dishman and Lucas
Souza are acknowledged for helpful discussion.
93:7 dr
93:7 er
F
4-fluorostyrne (3.0 equiv)
[Rh(COD)Cl]2 (2.5 mol%)
Ph
H3C Si
10
62% yieldb
93:7 drc
DCM (0.1 M), 40 ˚C, 16 h
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Isolated yields; dr determined using H NMR spectroscopy; er
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• 24 examples
• Up to 98:2 dr
• Up to 95:5 er
Si
Si
1
2
3
4
5
6
7
8
H
H
N2
Rh(II)
ACS Paragon Plus Environment
Ar’
Si
H
H