Catalytic Reductive ortho-C-H Silylation of Phenols with Traceless, Versatile Acetal Directing Groups and Synthetic Applications of Dioxasilines

Article abstract of DOI:10.1021/jacs.6b04018

A new, highly selective, bond functionalization strategy, achieved via relay of two transition metal catalysts and the use of traceless acetal directing groups, has been employed to provide facile formation of C-Si bonds and concomitant functionalization of a silicon group in a single vessel. Specifically, this approach involves the relay of Ir-catalyzed hydrosilylation of inexpensive and readily available phenyl acetates, exploiting disubstituted silyl synthons to afford silyl acetals and Rh-catalyzed ortho-C-H silylation to provide dioxasilines. A subsequent nucleophilic addition to silicon removes the acetal directing groups and directly provides unmasked phenol products and, thus, useful functional groups at silicon achieved in a single vessel. This traceless acetal directing group strategy for catalytic ortho-C-H silylation of phenols was also successfully applied to preparation of multisubstituted arenes. Remarkably, a new formal α-chloroacetyl directing group has been developed that allows catalytic reductive C-H silylation of sterically hindered phenols. In particular, this new method permits access to highly versatile and nicely differentiated 1,2,3-trisubstituted arenes that are difficult to access by other catalytic routes. In addition, the resulting dioxasilines can serve as chromatographically stable halosilane equivalents, which allow not only removal of acetal directing groups but also introduce useful functional groups leading to silicon-bridged biaryls. We demonstrated that this catalytic C-H bond silylation strategy has powerful synthetic potential by creating direct applications of dioxasilines to other important transformations, examples of which include aryne chemistry, Au-catalyzed direct arylation, sequential orthogonal cross-couplings, and late-stage silylation of phenolic bioactive molecules and BINOL scaffolds.

Full text of DOI:10.1021/jacs.6b04018

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Article
Catalytic Reductive ortho-C–H Silylation of Phenols with Traceless,
Versatile Acetal Directing Groups and Synthetic Applications of Dioxasilines
Yuanda Hua, Parham Asgari, Thirupataiah Avullala, and Junha Jeon
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04018 • Publication Date (Web): 06 Jun 2016
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Journal of the American Chemical Society
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Catalytic Reductive ortho-C–H Silylation of Phenols with
Traceless, Versatile Acetal Directing Groups and Synthetic
Applications of Dioxasilines
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Yuanda Hua,§ Parham Asgari,§ Thirupataiah Avullala, and Junha Jeon*
Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas 76019, United States
ABSTRACT: A new, highly selective, bond functionalization strategy, achieved via relay of two transition metal catalysts and use of
traceless acetal directing groups, has been employed to provide facile formation of C–Si bonds, and concomitant functionalization
of a silicon group, in a single vessel. Specifically, this approach involves the relay of Ir-catalyzed hydrosilylation of inexpensive and
readily available phenyl acetates, exploiting disubstituted silyl synthons, to afford silyl acetals and Rh-catalyzed ortho-C–H silylation
to provide dioxasilines. A subsequent nucleophilic addition to silicon removes the acetal directing groups and directly provides
unmasked phenol products and, thus, useful functional groups at silicon achieved in a single vessel. This traceless acetal directing
group strategy for catalytic ortho-C–H silylation of phenols was also successfully applied to preparation of multi-substituted arenes.
Remarkably, a new, formal α-chloroacetyl directing group has been developed which allows catalytic reductive C–H silylation of
sterically hindered phenols. In particular, this new method permits to access to highly versatile and nicely differentiated 1,2,3-
trisubstiuted arenes that are difficult to access by other catalytic routes. In addition, the resulting dioxasilines can serve as chroma-
tographically stable halosilane equivalents which allow not only removal of acetal directing groups, but also introduce useful func-
tional groups leading to silicon-bridged biaryls. We demonstrated that this catalytic C–H bond silylation strategy has powerful syn-
thetic potential by creating direct applications of dioxasilines to other important transformations, examples of which include aryne
chemistry, Au-catalyzed direct arylation, sequential orthogonal cross-couplings, and late-stage silylation of phenolic bioactive mole-
cules and BINOL scaffolds.
KEYWORDS: phenol, C–H activation, silylation, silyl acetal, traceless directing group
INTRODUCTION
they generally require a (sub-)stoichiometric amount of basic
reagents, thereby displaying modest functional group compat-
ibility, or involve a limited substrate scope and/or moderate
yields.
Interest in organosilane chemistry has increased rapidly in
recent years,1 including development of silicon-based materi-
als2 and many biomedically relevant agents.1a, 3 The recent ex-
panding use of these compounds has included their participa-
tion in a wide variety of chemical transformations. Such syn-
thetic activities include silicon-based cross-coupling reac-
tions,4 oxidations,5 silanol hydrogen bond donor catalysts,6 and
as directing groups for C–H functionalization.7 In particular,
selective silylative functionalization of phenols is important
because many bioactive natural products and unnatural con-
geners, including medicinally important molecules, contain
phenolic moieties that contribute to their biological activities.8
In light of this fact, there is a fundamental need for develop-
ment of more efficient catalytic strategies that provide site-
selective access to this motif from readily available precursors.
Thus far, several very useful phenol silylation methods have
been developed: 1) a sequence of (non-)selective bromination,
O-silylation, and lithium-halogen exchange followed by retro-
Brook reactions,9 2) metal-catalyzed silylation of prefunction-
alized, protected halopheonls,10 3) directed ortho-metalation
(DoM)/silylation of phenols,11 and 4) KOt-Bu-catalyzed silyla-
tion of aromatic heterocycles.12 These methods offer excellent
site-selectivity. However, limitations in these systems exist as
Significant advances to transition metal-catalyzed selective
C–H bond functionalizations for preparing structurally di-
verse, bioactive molecules.13 have been made through directing
group-assisted13a, 13g, 13h, 13j, 13k, 13p, 14 or direct13d, 13f C–H bond acti-
vation strategies. Although directing group-assisted C–H bond
functionalization strategies can achieve the desired transfor-
mation with high reactivity and selectivity, directing groups
are often difficult to install and manipulate after processes are
completed. Additional functional group interconversions,
typically involving redox adjustment, are usually carried out
under harsh reaction conditions, if indeed removal of the di-
recting group is at all possible. To resolve these limitations,
strategies for traceless directing group-assisted C–H function-
alization have been developed.7a-d, 15 For instance, Gevorgyan7a,
7b, 16
and Ge7c reported remarkable C–H ortho-alkenylation,
oxygenation, and carboxylation of phenols with silanol trace-
less directing groups. However, a traceless directing group
approach for ortho-C–H silylation has not been reported to
date.
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Scheme 1. Catalytic, Site-Selective C–H Silylation of Phenols and Phenol Derivatives
1
a. Prior approaches for transition metal-catalyzed C–H silylation
2
3
4
b. This work: Strategy for use of a disubstituted silyl synthon (7) and phenyl
of protected phenols (ortho and meta/para)
acetate (8) for catalytic reductive ortho-C–H silylation of phenols using
a traceless acetal directing group (DG)
a1. Directing control: Catalytic method limited efficiency
5
6
7
8
electrophilc
site
R
R
R
OR
O
[M]
H
[Si]–H
Si
R = alkyl
H
H
[Si]
ester
hydrosilylation
C–H
activation
7
[M] = Sc
9
1
2
R
1)
10
11
12
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60
Hou (Sc cat.)
e.g.,
FG
Ir
Rh
H
R
R
O
■
OR
OR
O
O
limited directing
diverse
synthetic
H2SiR2
Si
groups (R = alkyl)
FG
[Si]
Sc cat.
■
10-fold excess of 1
Nu
applications
■
limited substrate scope
2)
Nu
(e.g., inaccessible to
8
9
3
4
1,2,3-trisubstituted arenes 4)
inexpensive and easily
diversely functionalized
installable acetyl DG
ortho-silyl phenols without DG
a2. Steric Control: Catalytic method well developed
■
Proposed reaction mechanism
OR
OR
[Si]–H or [Si]–[Si]
[Si]
[M]
R
R = Me, TIPS, alkyl
R
R
H/[Si]
H
H
H
H
O
O
O
O
O
O
[M] = Ir or Rh
[Si]
Ir
Rh
Nu
5
6
[Si]H
[Si]
[M]
8
9
Hartwig (Rh cat.)
Miyaura (Ir cat.)
– H2
[Si]H2
■
■
broad scope
60-fold excess of substrate 1
use of [Si]–[Si] (t-BuF2Si-SiF2t-Bu)
10
11
12
■
■
high site-selectivity
Although diverse catalytic arene dehydrogenative silylations
have been developed to prepare valuable organosilanes,17 sur-
prisingly, only one example of catalytic ortho-C–H silylation of
phenol derivatives has been developed (Hou group, 2011)17h as
depicted in Scheme 1.a1. While this Hou’s pioneering work
associated with scandium metallocene-catalyzed directed or-
tho-silylation of anisoles exhibited excellent site-selectivity,
despite requiring a highly strained, four-membered metallacy-
cle 2, it requires excess anisole substrates (10-fold) and has
somewhat limited substrate scope (inaccessible to 1,2,3-
trisubstituted arenes, 3 to 4). Furthermore, the removal of
alkyl masking groups in the presence of silanes is not trivial.
Miyaura18 and Hartwig19 have reported Rh and Ir-catalyzed
steric-controlled meta- or para-silylation of anisoles, respec-
tively (Scheme 1.a2). While Miyaura’s Ir-catalyzed silylation
required 60-fold excess of anisole substrates 5, the method
developed by Hartwig showed broad substrate scope and high
site-selectivity, yet the removal of a hydroxyl masking group in
the presence of silanes is again questionable.
We recently demonstrated the design and application of a
single-pot, catalytic (exhaustive) reductive Csp2–H and Csp3–H
silylation and silanolization of aromatic carboxylic acid deriva-
tives.20 In these studies, we established the mechanism for the
hydridosilyl O,O-silyl acetal–directed catalytic C–H silylation,
where the turnover-determining step is an irreversible sub-
strate-metal coordination that proceeds to C–H bond cleav-
age.1a, 21 To develop a more general, catalytic method to im-
prove arene ortho-C–H silylation of phenols, we have designed
a novel approach to sequential catalytic reductive C–H silyla-
tion. This process centers on post-installation of other useful
moieties on a silicon center that includes spontaneous removal
of directing groups by employing versatile silyl acetal directing
groups. Hence, we specifically address the aforementioned
challenges and limitations in synthesis of diversely functional-
ized silyl phenols and significantly expand the versatility of C–
H functionalization (Scheme 1.b). Herein, we report a single-
pot sequential metal-catalyzed reductive ortho-C–H silylation
of phenols, with traceless mixed acetal directing groups, utiliz-
ing inexpensive and easily installable acetyl formal directing
group and readily available catalyst and silane. This strategy
involves the relay of Ir-catalyzed hydrosilylation of phenyl
acetates 822 exploiting disubstituted silyl synthons 7 to afford
silyl acetals 10 and Rh-catalyzed C–H silylation17b, 17c, 17e, 17n, 17q, 17r
to provide dioxasilines 12. A subsequent nucleophilic addition
to silicon removes the acetal directing groups and provides
unmasked phenol products 9 in a single vessel. Importantly,
the resulting ortho-silyl phenols 9 are useful synthetic vehicles
for direct applications to many other important transfor-
mations, examples of which include: harnessing aryne chemis-
try;23 Au-catalyzed oxidative cross-coupling;4d, synthesis of
4e
dibenzosiloles;24 and catalytic synthesis of a chiral BINOL25
scaffold.
RESULTS AND DISCUSSION
A Single-Pot Catalytic Reductive ortho-C–H Silylation of
Phenols with Traceless Mixed O,O-Acetal Directing group.
Prevalent directed C–H bond functionalizations proceed
through
five-
or
six-membered
cyclometallated
intermediates.4a However, our initial concern was that our
proposed process conceivably requires a rather unfavorable
rhodacycloheptane intermediate 11 (Scheme 1.b). To address
this concern, we demonstrated the strategy for traceless, for-
mal acetate directing group-assisted ortho-silylation of phenols
(Table 1). Gratifyingly, the single-pot, two-step strategy in-
volving Ir-catalyzed ester hydrosilylation (0.1 mol % of
[Ir(coe)Cl]2]) and Rh-catalyzed C–H bond silylation using
[Rh(nbd)Cl]2 (0.4 mol %) and monodentate phosphine P(4-
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MeOPh)3)17e (2.4 mol %) directly produced benzodioxasiline
12a in excellent yield (95%). A distinctive feature of this mixed
O,O-acetal directed Rh-catalyzed C–H silylation was essential-
ly complete reaction within 15 min, despite the fact that a pu-
tative cyclometallated rhodacycloheptane intermediate might
be involved.
1
2
3
4
5
6
We then investigated the scope of the single-pot sequential
catalytic reductive ortho-C–H silylation of phenyl acetates
(Table 1). Phenyl acetates bearing a substituent at the ortho
position (i.e., methyl, methoxy, fluoro) underwent the C–H
silylation to provide benzodioxasilines (12b-12d) in good
yields. The reaction of phenyl acetates possessing a meta sub-
stituent (12e-12i) exhibited high site selectivity favoring silyla-
tion at less congested C–H bonds (>20:1 regioselectivity). pa-
ra-Substituted phenyl acetates holding methyl, t-butyl, meth-
oxy, halogens (F and Cl), trifluoromethyl, silyl blocking group
(TBS), and trisubstituted alkene groups were tolerated by the
reaction conditions to afford benzodioxasilines (12j-12q).
Interestingly, 4-hydroxyphenyl acetate initially afforded C–H
silylation product 12r, wherein unprotected hydroxy group
efficiently underwent dehydrogenative silylation with excess
diethylsilane, followed by hydrosilylation with norbornene
(hydrogen acceptor). Reductive C–H silylation of both 1- and
2-naphthyl acetates provided single regioisomers (12s and 12t,
respectively) with excellent yields. Disubstituted 2,4-
dimethylphenyl acetate also generated product 12u via selec-
tive activation of C(sp2)–H bond over C(sp3)–H bond, with
good yield (84%). C–H silylation of sesamol acetate afforded
the major product 12v (4-Si:6-Si = 3:1) at the more sterically
hindered position. The subsequent nucleophilic ring-opening
reactions of the resulting 12 with MeLi in the same vessel af-
forded ortho-silyl phenols, which allow concomitant removal
of acetal directing group, thereby revealing hydroxy groups.
These results clearly establish that the sequence of Ir and Rh-
catalyzed reactions, followed by the ring-opening process,
provides a viable catalytic synthesis of ortho-silyl phenols.
7
8
9
10
11
12
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Table 1. Catalytic Reductive ortho-C–H Silylation of Phenyl Acetates with a Traceless Acetal Directing Groupa
1
2
3
4
5
6
7
8
[Ir(coe)2Cl]2 (0.1 mol %)
H2SiEt2 (2 equiv)
i)
Me
H
O
OAc
HO
Et2
Si
MeLi
THF, rt to 60 °C;
O
Me
R1
R1
SiEt2
THF, –78 °C-rt
R1
[Rh(nbd)Cl]2 (0.4 mol %)
P(4-OMePh)3 (2.4 mol %)
nbe (2 eqiuv), THF, 120 °C
ii)
9
8
12
9
cyclization
addition
cyclization
addition
cyclization
addition
cyclization
addition
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
Me
Me
Me
O
O
OH
O
O
OH
O
O
OH
O
O
OH
Et2
Si
Et2
Si
Et2
Si
Et2
Si
SiEt2
Me
SiEt2Me
MeO
SiEt2 MeO
F
SiEt2
F
Me
Me
Me
Me
12a 95%
9a 83%
12b 92%b
9b 83%
12c 81%
9c 66%
12d 61%
9d 48%
Me
Me
Me
Me
O
O
OH
O
O
OH
O
O
OH
O
O
OH
Et2
Et2
Si
Et2
Et2
SiEt2
Si
SiEt2
SiEt2
Si
SiEt2
Si
Me
Me
Me
Me
Me2N
Me2N
Me
Me
F
F
Cl
Cl
12e 82%b
9e 72%
12g 79%b
9g 64%
12h 62%b
9h 46%
12f 48%b, c
Me
9f 34%
Me
Me
Me
O
O
OH
Et2
Si
O
O
OH
Et2
O
O
OH
Et2
O
O
OH
Et2
Si
SiEt2
SiEt2
Si
SiEt2
Si
SiEt2
Me
Me
Me
Me
F3C
F3C
Me
Me
t-Bu
t-Bu
OMe
OMe
12i 94%b
9i 83%
12j 91%
9j 84%
12k 96%
9k 90%
12l 91%
9l 81%
Me
Me
Me
Me
O
O
OH
Et2
Si
O
O
OH
Et2
O
O
OH
O
O
OH
Et2
Si
Et2
Si
SiEt2
SiEt2
Si
SiEt2
SiEt2
Me
Me
Me
Me
CF3
CF3
F
F
Cl
Cl
TBSO
TBSO
12m 93%
Me
9m 70%
12n 89%b
9n 70%
12o 93%b
9o 74%
12p 87%
9p 74%
Me
Me
OH
Et2
Si
OH Me
SiEt2
Me
OH
Et2
O
O
O
O
O
O
OH
Et2
Si
Me
Si
SiEt2
SiEt2
O
O
Me
SiEt2
Me
SiEt2
Me
O
OH
Me
Me
O
O
Si
Et2
Me
12q 62%b
9q 36%
12r 81%b, c
9r 67%
12s 92%b
9s 84%
12t 89%
9t 76%
Me
Me
OH
Et2
OH
Et2
Si
O
O
O
O
Si
Me
SiEt2
Me
Me
Me
SiEt2
O
O
O
Me
Me
O
12u 84%
9u 62%
12v 80%d
9v 42%
aConditions: phenol acetates 8 (1 mmol), [Ir(coe)2Cl]2 (0.1 mol %), THF (3.3 M); [Rh(nbd)Cl]2 (0.4 mol %), P(4-OMePh)3 (2.4 mol %),
norbornene (2 equiv), THF (1M), 120 °C, 15 min; MeLi (3 equiv), THF (0.5 M), –78 °C. bDetermined by 1H NMR spectroscopy utilizing an
internal standard (CH2Br2). c[Ir(coe)2Cl]2 (0.5 mol %), H2SiEt2 (4 equiv); [Rh(nbd)Cl]2 (1 mol %), P(4-OMePh)3 (6 mol %), 120 °C. 60
min; MeLi (6 equiv). d3:1 regioisomeric ratio of 12v.
Synthesis of Multi-Substituted Arenes. Catalytic transfor-
mation of diacetates or N-acetyl acetates into multi-substituted
arenes, were examined with this C–H bond silylation strategy
using traceless mixed O,O- and N,O-acetal directing groups
(Scheme 2). Dual catalytic reductive C–H silylation of 1,4-
phenylene diacetate 8x, followed by the double-fold ring-
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opening with MeLi furnished tetra-substituted arene (9x) in the reaction conditions to provide dual C–H silylation product
1
2
3
4
5
6
7
8
excellent yield (88%). Furthermore, highly chemoselective
reductive C–H silylation/ring-opening of 4-acetoxyphenyl
pivolate 8y to afford tri-substituted arene (9y) in 72% yield was
observed, as achieved by selective hydrosilylation of acetate
Scheme 2. Synthesis of Multi-Substituted Arenes via Dual
Catalytic Reductive ortho-C–H Silylation of Aromatic Ace-
tates with Traceless Acetal Directing Groupsa
12aa, via formation of the intermediate containing mixed
O,O- and N,O-silyl acetals (not shown). Upon treatment with
MeLi, 9aa was generated in 38% yield over three steps. Several
conditions were employed in attempts to remove the hemi-
aminal group; however protodesilylation (at C-5) was ob-
served under most reaction conditions studied. Notably, when
para-acetamide substituted phenyl acetate (i.e., O-acetyl acet-
aminophen) was subjected to the hydrosilylation conditions
mixed O,O-silyl acetal, with concomitant reduction of amide
to secondary silyl amine, initially formed which subsequently
underwent C–H silylation to provide 12ab, after pivalation of
the amine. Subsequent treatment with MeLi afforded trisubsti-
tuted arene 9ab.
9
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
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OAc
O
O
OH
OH
Et2
Si
SiEt2
a,b
c
Me
Me
Et2Si
Si
Et2
OAc
O
O
Dioxasilines as Halosilane Equivalents for Synthesis of
Functionalized Silanes. Organosilanes and organosilanols
have been utilized for their unique biological functions and
biomedically relevant agents.3, 26 Although advances have been
achieved, syntheses of diverse silanes by catalytic means re-
main significantly limited. For example, Brookhart reported
only two synthetically useful silanes (Et2SiH2 and PhMeSiH2)
for Ir-catalyzed ester hydrosilylation.22f Furthermore, a stoi-
chiometric method for synthesis of functionalized phenolic
silanes 15, involving (non-)selective bromination/retro-Brook
reactions, requires substantial effort (i.e., preparation of chlo-
roarylsilanes 14 bearing various aryl moieties) and the overall
yield is unknown (Scheme 3.a).9b Alternatively, directed ortho-
metalation (DoM)/silylation of phenols11 also has limitations
imposed by generation of chromatographically unstable
chlorosilanes 17 and a difficult directing group removal step,
associated with facile protodesilylation (Scheme 3.b). To im-
prove this limited silane scope, and thereby prepare diversely
functionalized silanes, we investigated sequential catalytic C–
H silylation, coupled with nucleophilic ring-opening reactions
of “dioxasilines as stable halosilane equivalents” that readily
incorporate a variety of motifs (Scheme 3.c). Advantages of
this method would be two-fold; first, it provides a post-
introduction of silyl substituents containing useful functional
groups, which may be not compatible with an Ir/Rh-catalytic
cascade; second, it eliminates the need to prepare a variety of
the not readily available dihydrosilanes for hydrosilylation.
Therefore, we explored an array of nucleophiles; hydride (lith-
ium aluminum hydride) (to 9ac), carbon nucleophiles [MeLi
(or MeMgBr) (to 9a), n-BuLi (to 9ad), PhLi (or PhMgBr) (to
9ae), vinyl magnesium chloride (to 9af), allyl magnesium
chloride (to 9ag), lithium trimethylsilyl acetylide (to 9ah),
heteroaryl lithium reagents (to 2-silyl furan 9ai, 2-silyl benzo-
furan 9aj, 2-thiofuran 9ak, 2-silyl benzothiofuran 9al, and 2-
silyl indole 9am], and oxygen nucleophiles (lithium mentho-
late) (to 9an). All these nucleophiles afforded excellent to
good yields of corresponding silyl phenols.
Me
8x
12x 91%
9x 88%
Me
Me
O
O
O
O
OH
Et2
Si
d,b
SiEt2
e
Me
O
t-Bu
O
O
O
O
O
t-Bu
t-Bu
8y
12y 72%
9y 63%
Me
O
O
OH
Et2
Si
SiEt2
a,b
e
Me
Et2Si
Et2Si
O
O
O
O
t-Bu
t-Bu
12z 83%b
9z 57%
Me
O
OH
Et2
Si
OAc
O
Me
Me
a,b
c
Et2Si
Si
Et2
N
SiEt2
O
N
Ac
N
OH
Me
Me
8aa
12aa 71%b
9aa 38%
Me
Me
O
N
O
OH Me
O
O
SiEt2
SiEt2
a,b,f
e
N
O
NH
Me
Piv
Piv
Me
12ab 64%
Me
9ab 68%
8ab
aConditions: (a) [Ir(coe)Cl]2 (0.5 mol %), H2SiEt2 (4 equiv), THF
(2 M), 60 °C, 10 h. (b) [Rh(nbd)Cl]2 (1 mol %), P(4-OMePh)3 (6
mol %), nbe (4 equiv), THF (1 M), 120 °C, 30 min. (c) MeLi (6
equiv), THF, –78 °C. (d) [Ir(coe)Cl]2 (0.5 mol %), H2SiEt2 (2
equiv), THF (2 M), rt, 10 h. (e) MeLi (3 equiv), THF, –78 °C. (f)
PivCl (1.5 equiv), Et3N (2 equiv), CH2Cl2, rt.
over pivolate (2 equiv of H2SiEt2 at rt). However, under dual
hydrosilylation conditions (4 equiv of H2SiEt2 at 60 °C) dual
C–H silylation of 8y provided tetra-substituted arene (12z)
(83% yield), which underwent ring-opening reaction with
MeLi to give 9z. N-Acetyl-4-indolyl acetate 8aa also tolerated
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 13
Scheme 3. Dioxasilines as Halosilane Equivalents for Syn-
similar reactivity, in fact even more sensitive to the sterics,
thesis of Functionalized Silanesa
with Sc-catalyzed arene ortho-silylation, where even ortho-
methyl anisole did not react (see 3 to 4 in Scheme 1.a1).17h Of
note, efficient catalytic synthesis of 1,2,3-trisubtituted arenes
are not trivial owing to the necessity of high reactivity over
1
2
3
4
5
6
7
8
a. Bromination/retro-Brook rearrangement approach
R
R
HO
OH
1. bromination
Si
(mixture of products)
X
X
Ar
2.
Ar
ClR2Si
Scheme 4. Synthesis of 1,2,3-Trisubstituted Arenes via Cata-
lytic Reductive C–H Silylation of Sterically Hindered Phenyl
Acetates: Dual Activation of Iridium Silyl Hydride by α-
chloroacetyl directing groupa
13
15
14
overall yield
unknown
(arylchlorosilanes 14 needed
9
to be repared)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. t-BuLi
a. Sterically hindered substrates: Reported challenge similarly to Hou's
Sc-catalyzed ortho-silylation
b. DoM chlorosilylation/nucleophilic addition approach
DG
DG
Me
Me
Me
R
1. chlorosilylation
R
HO
O
O
Nu
via DoM
SiR2Cl
Si
O
O
O
O
O
O
i) [Ir]
H2SiEt2
ii) [Rh]
Nu
X
X
X
R
R
SiEt2H
R
SiEt2
R2SiCl2
DG removal
if possible
17
16
9
yield (%)a
yield (%)b
chromatographically unstable
c. Catalytic reductive ortho-C–H silylation with a traceless acetal DG
Me
R
8-Me Me
8-Et Et
10-Me
10-Et
97
5
12-Me
12-Et
92
N/A
Me
1)
2)
Ir
Rh
b. Proposed dual activation of iridium silyl hydride by a-heteroatom-
Et
Et
O
O
O
O
HO
Nu
containing acetyl group
H2SiEt2
Si
SiEt2
X
X
Nu
Ar
Ar
Ar
[Si]–H
[Ir]–H
[Ir]
H
8
12
halosilane equivalents:
O
O
O
O
9
i) recruiting
R
R
[Si]H
18
(turn-over limiting step)
chromatographically stable
[Si] = SiR2
19
X
X
OH
OH
OH
OH
Et2
Si
Et2
Si
Et2
Si
Et2
Si
[Ir]–H
H
H
[Rh]
O
O
O
O
H
Me
nBu
Ph
R
R
[Si]H
[Si]
ii) electronic activation
C–H silylation
of carbonyl by "X (EWG)"
9ac 94% (LAH)
9a 95%
9ad 98%
9ae 90%
20
21
OH
Et2
OH
OH
OH
Et2
Si
Et2
Si
Et2
Si
c. a-Heteroatom-containing phenyl acetates as formal directing groups
Si
X
X
X
O
H
O
TMS
i) [Ir]
H2SiEt2
O
O
O
O
O
9af 97%
9ag 70%
9ah 70%
9ai 73%
ii) [Rh]
Et
Et
[Si]H
Et
SiEt2
OH
Et2
OH
OH
Et2
Si
Et2
Si
Si
yield (%)a
yield (%)b
X
O
S
S
8a-Et
8b-Et
8c-Et
F
20a
20b
20c
20d
92
99
89
95
21a
21b
21c
21d
76
85
0
9aj 80%
9ak 73%
9al 94%
Cl
Br
Me
8d-Et OMe
77
OH
Et2
OH
Et2
Si
Si
d. Evaluation of other sterically demanding phenyl acetates
O
MeN
Cl
Cl
Me
Me
i) [Ir]
H2SiEt2
9am 83%
9an 72%
O
O
O
O
R
R
SiEt2
aIsolation yield from either 12 or 18.
ii) [Rh]
Synthesis of 1,2,3-Trisubstituted Arenes via Catalytic Re-
ductive C–H Silylation. Based on the wide substrate scope
presented in Table 1, we investigated the potential of catalytic
reductive ortho-C–H silylation of phenols directed by silyl
acetal. However, we encountered a problem during our inves-
tigation of the substrate scope of ortho-C–H silylation of steri-
cally hindered phenols. Surprisingly, minor steric variation on
a substrate, such as 8-Et (cf., 8-Me), drastically hindered the
hydrosilylation (Scheme 4.a). The Hou group also observed
yield (%)b
R
8e-iPr iPr
8f-tBu tBu
8g-Ph Ph
21e
21f
21g
89
77
96
aDetermined by 1H NMR spectroscopy utilizing an internal stand-
b
ard (CH2Br2). Isolation yield (two steps from the corresponding
phenyl acetate).
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Journal of the American Chemical Society
steric hindrance and high regioselectivity. Although A-values
of methyl and ethyl are fairly similar (1.7 vs. 1.75 kcal/mol,
Scheme 5. Synthetic applications of Benzodioxasilines
1
2
3
4
5
6
7
8
respectively),27 it is speculated that the population of reactive
conformers by rotation perhaps dictates this unusual reactivity
difference. To overcome this obstacle, we explored a devel-
opment of other efficient traceless directing groups (Scheme
4.b). Brookhart proposed that the turnover-limiting step of Ir-
catalyzed hydrosilylation would be transfer of silylium ions
(R2HSi+) to the carbonyl oxygen of esters.22f, 28 We speculated
that effective recruiting of iridium silyl hydride species to es-
ters could be a crucial factor for hindered esters (18 to 19). In
addition, the electron withdrawing X atom (group) could facil-
itate Ir-mediated hydride transfer to carbonyl (19 to 20).
Therefore, to transfer the silylium ions to carbonyl and suc-
ceeding iridium hydride more easily, we designed and exam-
ined an α-heteroatom-containing acetyl formal directing
group as a bidentate chelating moiety (e.g., an α-fluoro, chlo-
ro, bromo, methoxy acetyl) to metal (Scheme 4.c). We found
that α-chloroacetate was among the most effective formal di-
recting groups. This method was expanded to more sterically
demanding ortho-substituted substrates. Remarkably, the phe-
nyl α-chloroacetate smoothly underwent sequential hydrosi-
lylation/C–H silylation of substrates bearing ortho-isopropyl,
tert-butyl, and phenyl moieties (Scheme 4.d). These are sur-
prising results because only a few successful chelation-
controlled nucleophilic addition to α-halo carbonyl or imino
electrophiles have been reported, owing to the relatively low
basicity of halogens and all these prior examples utilized α-
fluoro carbonyl derivatives.29 Although the Walsh group
demonstrated diastereoselective chelation-controlled addition
of carbon nucleophiles to α-chloro aldimines, transition met-
al-catalyzed chelation-controlled hydrosilylation of α-
chloroesters has not previously been described.30
HO
Et
Et
OTf
Et2
Si
furan, TBAF
rt
O
Si
Me
Nu
R
R
R
22a R = H
22b R = F
22c R = Cl
23a 81%
23b 71%
23c 82%
9 R = H
(Scheme 3)
1. MeLi, –78 °C
2. Tf2O, pyr
9
Nu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1. BCl3
Me
CH2Cl2
80 °C
OH
O
O
OH
ICl
CH2Cl2, rt
I
Bpin
SiEt2
2. Pinacol
Et3N, rt
R
R
R
12
25 (84%)
24 (81%)
R = H
R = H
Hiyama-Denmark
cross-couplings
Au-catalyzed oxidative
direct cross-couplings
Ar
Ar
I
H
HO
OPG
Ar
Ar
R
R
26 R = H
27 PG = Tf, Ms
(Table 2)
(Scheme 7)
Aryne Cycloaddition of ortho-Silyl triflates and Halo and
Boro ipso-desilylations. 1,2-Silyl triflates are versatile motifs
for a variety of areas in organic synthesis. Our catalytic ortho-
silylation method permits access to 1,2-diethylmethylsilyl tri-
flates 22 containing a variety of substituents in an extremely
straightforward fashion. Some of such substrates were previ-
ously difficult to prepare owing to functional group incompat-
ibility or electronic bias. We demonstrated aryne–furan cy-
cloaddition which produced 23a-c in good yields (Scheme 5).23
In addition, benzodioxasiline 12 could easily undergo iodo
and boro-induced ipso-desilylations to generate 24 and 25 in
good yields, respectively (Scheme 5).
Pd-Catalyzed Hiyama-Denmark Cross-Coupling. The
biaryl scaffold is prevalent in biologically active molecules and
is an ubiquitous functional motif in medicines.31 The Hiyama-
Denmark cross-coupling, using non-toxic aryl silanes, is
among the most versatile catalytic method for biaryl
synthesis.4a-c Nonetheless, this strategy suffers from the re-
quirements for aryl halide sources in the C–C bond-forming
reaction and basic conditions for activating silanes. When
attempting Pd-catalyzed Hiyama-Denmark cross-coupling of
benzodisiloxane 12a, we observed product 26a in low to mod-
erate yields (3-50%), along with significant protodesilylation
byproduct 28a (Table 2). Based upon our literature survey the
efficiency of silicon-based cross-coupling of sterically encum-
bered ortho-substituted silanes (or siloxanes) with correspond-
ing haloarene cross-coupling partners has been generally
poor.32
Synthetic Applications of Benzodioxasilines: A major as-
pect of this work is to introduce a novel strategy to catalytic
ortho-C–H silylation via sequential C–H silylation post-
installation of other useful moieties on a silicon center. This
approach permits spontaneous removal of a directing group
and simultaneously addresses the challenges of synthesis of
diversely functionalized unmasked ortho-silyl phenols 9
(Scheme 3). We further explored the powerful synthetic utili-
ties of catalytically generated ortho-silyl phenols to other im-
portant transformations (Scheme 5).
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Journal of the American Chemical Society
Page 8 of 13
Table 2. Pd-Catalyzed Hiyama-Denmark Cross-Couplings
Scheme 6. Au-Catalyzed Oxidative Direct Cross-Coupling of
ortho-Silyl Phenols with Arenes
of Benzodioxasilinea
1
2
3
4
5
Me
Ar
[Pd], ligand
NaOH (aq)
TfO
OPG
H
O
O
OH
OH
Ar
SiEt2Me
Ph3PAuOTs (2 mol %)
SiEt2
+
+
6
7
8
9
I
THF, 80 °C
R
R
PhI(OAc)2, CSA
CHCl3/MeOH, 70 °C
22a R = H; PG=Tf
22b R = F; PG=Tf
22d R = H; PG=Ms
27
12a
26a
28a
entry
PdLn
ligand
yield of 26a (%)c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OMe
OMe
RO
OMe
TfO
TfO
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
PCy3
P(t-Bu)3
RuPhos
XPhos
SPhos
P(4-MeOPh)3
dcpe
dppe
dppp
dppb
dppf
XantPhos
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
20
50
5
5
11
6
3
12
9
10
12
21
5
15
11
5
CO2Me
Br
Cl
27d (71%)
27a R = Tf (93%)
27b R = Ms (89%)
27c (76%)
CO2Me
CO2Me
OMe
TfO
TfO
S
TfO
O
CO2Me
F
27e (92%)
27f (43%)
27g (71%)
CO2Me
OMe
Br
OMe
Cl
TfO
TfO
TfO
S
F
F
F
Pd(PPh3)2Cl2
[allylPdCl]2
PdCl2
27h (81%)
27i (72%)
27j (83%)
functional groups and moieties (e.g., triflate, mesylate, ester,
bromide, chloride, fluoride, furan, and thiopene). These func-
tional groups are useful for subsequent downstream reactions
such as other metal-catalyzed cross-couplings.
Orthogonal Cross-Coupling. The Au-catalyzed oxidative
cross-coupling of biaryls 27a, 27c to 27j, bearing triflate
groups, can be used for subsequent cross-coupling reactions.
Examples include Suzuki cross-coupling of 27e with phenyl
boronic acid to generate 1,2-diaryl benzene 29 (94%) (Scheme
7a) and Heck reaction of 27c with 2-methylstyrene to furnish
1,1-disubstituted alkene 30 (61%) (Scheme 7b).
Pd(CF3CO2)2
23
aConditions: silane 12a (0.1 mmol), solvent (0.2 M) (details in
Supporting Information). bDetermined by GC/MS analysis.
cDetermined by 1H NMR spectroscopy utilizing an internal stand-
ard (CH2Br2). RuPhos
diisopropoxybiphenyl, XPhos = 2-dicyclohexylphosphino-2′,4′,6′-
= 2-dicyclohexylphosphino-2 ′ ,6 ′ -
triisopropylbiphenyl, SPhos
dimethoxybiphenyl,
= 2-dicyclohexylphosphino-2',6'-
dcpe
=
1,2-
1,2-
1,3-
1,4-
1,1'-
4,5-
bis(dicyclohexylphosphino)ethane,
bis(diphenylphosphino)ethane,
bis(diphenylphosphino)propane,
bis(diphenylphosphino)butane,
bis(diphenylphosphino)ferrocene,
dppe
=
dppp
=
dppb
dppf
=
=
Xantphos
=
bis(diphenylphosphino)-9,9-dimethylxanthene.
Au-Catalyzed Oxidative Direct Arylation of Aryl Silanes.
A direct alternative to the Hiyama-Denmark cross-coupling
would be the oxidative direct cross-coupling of aryl silanes,
with simple arenes as a partner,13c, 13f, 13j, 33 as recently reported
by Lloyd-Jones and Russel.4d, 4e This strategy is, however, un-
derexploited in 2-silyl triflates derived from dioxasilines as
oxidative direct coupling partners (Scheme 6). Our developed
reductive C–H silylation strategy would enable the rapid prep-
aration of such triflate-containing partners for the silane-based
oxidative direct coupling. Gratifyingly, gold(I)-catalyzed oxi-
dative cross-coupling of 1,2-silyl triflates 22 with non-
prefunctionalized arenes afforded biaryls 27 in moderate to
excellent yields (Scheme 6). With brief optimization, the Au-
catalyzed silane-based oxidative cross-coupling directly pro-
vided biaryls 27a to 27j, holding useful
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Journal of the American Chemical Society
Scheme 7. Sequential Orthogonal Cross-Couplings of Ben-
zodioxasilines
Scheme 8. Selective C–H Silylation and Ring-Opening Reac-
tions of Estrone and Estradiol
1
2
a. C2-Silylation of estrone
a. A sequential desilylative oxidative and Suzuki-Miyaura cross-coupling
3
4
5
6
7
8
9
Me
S
O
H
CO2Me
1. MeLi
Et2O
1. protection
2. acylation
O
Me
Me
O
O
O
TfO
Et2
Si
Et2
Si
H
H
SiEt2
Me
O
3. i) [Ir]
Et2SiH2
ii) [Rh]
2. Tf2O, pyr
CH2Cl2
Ph3PAuOTs (1 mol %)
PhI(OAc)2 (1.5 equiv)
CSA (1.3 equiv)
H
H
H
H
X
HO
O
X
12a
22a
31
yield C2:C4
30% only C2
CH3Cl/MeOH, 70 °C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
32a
H
32b Cl 88% only C2
CO2Me
S
CO2Me
B(OH)2
TfO
S
O
O
Me
Me
O
MgCl
THF
Pd(OAc)2 (5 mol %)
RuPhos (10 mol %)
K2CO3, PhMe/H2O
80 °C, 12 h
Et2
Si
Et2
Si
H
H
H
H
H
H
29 (94%)
27e (92%)
HO
HO
33 (82%)
34
b. A sequential desilylative oxidative and Heck cross-coupling
OMe
b. C2-Silylation of estradiol
OMe
Cl
OSiEt2H
TfO
H
Cl
TfO
Et2
Si
OH
Me
O
Me
H
Cl
Me
1. bisacylation
Et2
Si
H
Ph3PAuOTs (1 mol %)
PhI(OAc)2 (1.5 equiv)
CSA (1.3 equiv)
H
O
2. i) [Ir]
Et2SiH2
ii) [Rh]
H
H
27c (76%)
22a
H
HO
O
CH3Cl/MeOH, 70 °C
Cl
35
36
Me
[only C2, 78% (NMR yield)]
Me
OMe
Cl
OH
Me
H
MgCl
THF
Et2
Si
Pd(OAc)2 (5 mol %)
dppf (10 mol %)
iPr2NEt, THF
H
H
HO
30 (61%, α:β = 5:1)
80 °C, 12 h
37 (80%)
Late-Stage Functionalization of Phenol-Containing Bio-
active Molecules Estrone and Estradiol. We explored the
synthetic utility of the catalytic reductive acetal directing
group-assisted ortho-C–H silylation of phenols in known bio-
active molecules (Scheme 8). We again exhibited that α-
chloroacetyl-derived silyl acetal was crucial to afford ester hy-
drosilylation/C–H bond silylation (only C2 position) of es-
trone to provide 32b (88% yield) (cf., the parent acetyl direct-
ing group only afforded 32a in 30% yield), presumably due to
remote steric influence (Scheme 8a). Ring-opening of 32b by
vinyl lithium furnished 33 (80% yield).7a, 16, 34 Unfortunately, we
were unable to remove the ketal protecting group within 33
under a variety of reaction conditions, due to concomitant
protodesilylation of C2-silane.34 We then studied a more direct
method involving late-stage functionalization of estradiol 35
Catalytic Synthesis of 3,3’-Bissilyl BINOL Using a Trace-
less Acetal Directing Group. Lastly, we examined whether
this catalytic silylation method is applicable to preparation of a
3,3’-bis-silylation of binaphthol (BINOL), which has been ex-
tensively utilized for asymmetric catalysis. 3,3’-Bis-silyl BINOL
40 was synthesized from rac-BINOL, in high yield, in a four
steps operation–of note, only one enantiomer of the BINOL
racemic mixture is presented in Scheme 9. Overall, our devel-
opment of a strategy for late-stage modification enables syn-
thesis of structurally unique bioactive molecules and chiral
scaffolds in a rapid and highly site-selective manner and obvi-
ates a stepwise, multi-step synthesis, which would be difficult
through the existing catalytic ortho-C–H silylation.17h
(Scheme 8b).
A
four-step sequence, involving bis-
chloroacetylation, reductive C–H silylation, and vinyl addi-
tion, directly permits C2-silyl estradiol 37 (via 36) without
protecting group manipulation.
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Journal of the American Chemical Society
Page 10 of 13
gram. Infrared (IR) spectra were recorded using neat (for liquid
Scheme 9. 3,3’-Bis-Silylation of BINOL
1
2
3
4
5
6
7
8
compound) or a thin film from a concentrated DCM solution.
Absorptions are reported in cm-1. Only the most intense and/or
diagnostic peaks are reported. MPLC refers to medium pressure
liquid chromatography (25-200 psi) using hand-packed columns
of silica gel (20-45 µm, spherical, 70 Å pore size), an HPLC
pump, and a differential refractive index detector. High-resolution
mass spectra (HRMS) were recorded in Electrospray ionization
time-of-flight (ESI-TOF) mode. Samples were introduced as
mixed solutions of methanol and methylene chloride (DCM).
GC-MS experiments using electron impact ionization (EI) were
performed at 70 eV using a mass-selective detector. Analytical
TLC experiments were performed on F254 plate, 250 µm thick-
ness. Detection was performed by UV light or potassium phos-
phomolybdic acid, permanganate, p-anisaldehyde staining.
General Procedure for Ir-catalyzed Reductive Ester Silyla-
tion–Preparation of Silyl Acetals (10): [Ir(coe)2Cl]2 (0.9 mg,
0.1 mol %) and aryl acetates 8 (1 mmol) were added to a flame-
dried, nitrogen-purged septum-capped vial. The mixture was dis-
solved with THF (0.3 mL, 3.3 M), and diethylsilane (0.26 mL, 2
mmol) was added to the mixture. The septum on the vial was
replaced by a screw cap with a Teflon liner under a N2 atmos-
phere [note: diethylsilane (bp 56 °C and density 0.686 g/mL) is
volatile]. The reaction mixture was stirred for 3-12 h at 60 °C.
Volatiles were removed in vacuo to afford silyl acetals 10, which
were directly used for subsequent reactions without further purifi-
cation.
General Procedure for Rh-catalyzed Arene ortho-C–H Si-
lylation of Hydridodiethylsilyl Acetals –Preparation of Benzo-
dioxasilines (12): [Rh(nbd)Cl]2 (1.84 mg, 0.4 mol %), tris(4-
methoxyphenyl)phosphine (8.45 mg, 2.4 mol %), norbornene (188
mg, 2 mmol), and THF (1 mL, 1 M) were added to the crude silyl
acetals 10 (1 mmol). The septum on the vial was replaced by a
screw cap with a Teflon liner, and the mixture was stirred at 120
°C for 15 min (unless otherwise mentioned in Table 1). Reaction
progress was monitored by GC/MS spectrometry. The resulting
benzodioxasilines 12 were directly used for a subsequent reaction
without further purification. For an analytical purpose, volatiles
were removed in vacuo, and the resulting mixture was dissolved
with pentane, filtered through a pad of Celite®, and concentrated
in vacuo. The crude product was purified by MPLC (hex-
anes/EtOAc = 80:1, 5 mL/min, retention time 5-15 min).
Et2
Si
O
1. bis-acylation
OH
MgCl
THF
O
O
Me
Me
OH
2. i) Ir, Et2SiH2
ii) Rh
O
Si
Et2
(±)-39 (92%)
(±)-38
9
Et2
Si
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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40
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47
48
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60
OH
OH
Si
Et2
(±)-40 (85%)
(±)-40 (X-ray)
CONCLUSION
A new strategy, employing disubstituted silyl synthons and
phenyl acetates, for a single-pot sequential metal-mediated,
catalytic reductive C–H silylation of phenols with traceless
acetal directing groups, has been successfully achieved. The
relay of Ir-catalyzed hydrosilylation of phenyl acetates and Rh-
catalyzed C–H silylation provides dioxasilines. A subsequent
nucleophilic addition of diverse nucleophiles to dioxasilines
serving halosilane equivalents not only readily incorporates a
variety of functional moieties, but also concomitantly removes
the acetal directing groups in a single vessel. To resolve syn-
thetic challenges of 1,2,3-trisubstited, hindered arenes, we
developed a new α-chloroacetyl formal directing group which
allows catalytic reductive ortho-C–H silylation of sterically
hindered phenols. We also demonstrated several important
downstream reactions of the resulting 1,2-silyl phenols, in-
cluding Au-catalyzed oxidative direct cross-coupling, aryne
cycloaddition chemistry, and late-stage silylation of phenolic
bioactive molecules and BINOL scaffold, exploiting the trace-
less acetal directing group strategy to afford C2-silyl estrone,
C2-silyl estradiol, and 3,3’-bissilyl BINOL.
General Procedure for Nucleophile Opening of Benzodiox-
asiline–Preparation of 2-Silylphenol (9): The crude benzodiox-
asilines 12 (1 mmol in THF, 1 M) were diluted with THF (1 mL,
0.5 M) and cooled to –78 °C, then nucleophiles (3 equiv) were
added into the reaction mixture and stirred at –78 °C for 30 min.
The reaction was quenched at –78 °C by adding saturated aqueous
ammonium chloride solution, then the mixture was acidified to ca.
pH 4-5 with aqueous HCl (1 M). The mixture was extracted with
diethyl ether. The combined organic layer was washed with water
and brine, and dried over anhydrous sodium sulfate. Volatiles
were removed in vacuo, and the crude mixture was purified by
MPLC to afford 2-silyl phenols 9 (hexanes/EtOAc = 20:1, 5
mL/min, retention time 6-20 min).
EXPERIMENTAL SECTION
General Experimental Information. Reactions requiring anhy-
drous conditions were performed under an atmosphere of nitrogen
or argon in flame- or oven-dried glassware. Anhydrous toluene
and dichloromethane (DCM) were distilled from CaH2. Anhy-
drous tetrahydrofuran (THF) and diethyl ether (Et2O) were dis-
tilled from sodium and benzophenone. Triethylamine and pyri-
dine were distilled from KOH. DMF and DMSO were stored
over 4Å molecular sieves. All other solvents and reagents from
the commercial sources were used as received. NMR spectra
were recorded on a 500 or 300 MHz NMR spectrometer. 1H
NMR chemical shifts are referenced to chloroform (7.26 ppm)and
DMSO-d6 (2.50 ppm). 13C NMR chemical shifts are referenced to
13CDCl3 (77.23 ppm), and DMSO-d6 (39.52 ppm). The following
abbreviations are used to describe multiplets: s (singlet), d (dou-
blet), t (triplet), q (quartet), pent (pentet), m (multiplet), nfom
(non-first-order multiplet), and br (broad). The following format
was used to report peaks: chemical shift in ppm [multiplicity,
coupling constant(s) in Hz, integral, and assignment]. 1H NMR
assignments are indicated by structure environment, e.g., CHaHb.
1H NMR and 13C NMR were processed with iNMR software pro-
ASSOCIATED CONTENT
The following file is available free of charge on the ACS Publica-
tions website at http://pubs.acs.org.
Experimental details and spectroscopic characterization data for
all compounds.
AUTHOR INFORMATION
Corresponding Author
jjeon@uta.edu
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(12) Toutov, A. A.; Liu, W.-B.; Betz, K. N.; Fedorov, A.; Stoltz, B. M.;
Author Contributions
Grubbs, R. H. Nature 2015, 518, 80-84.
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§Y.H and P.A. contributed equally to this work.
(13) (a) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439-2463; (b)
Godula, K.; Sames, D. Science 2006, 312, 67-72; (c) Alberico, D.; Scott, M.
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Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173-1193; (e) Davies, H. M.;
Manning, J. R. Nature 2008, 451, 417-424; (f) Ackermann, L.; Vicente, R.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work is also supported by the ACS Petroleum Research Fund
(PRF# 54831-DNI1), National Institutes of Health (NIH)
(GM116031), and start-up funds provided by the University of
Texas Arlington. The NSF (CHE-0234811 and CHE-0840509) is
acknowledged for partial funding of the purchases of the NMR
spectrometers used in this work.
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X
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Ir
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inexpensive and
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diversely
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ortho-silyl phenols
without DG
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