The pyridyldiisopropylsilyl group: A masked functionality and directing group for monoselective ortho-Acyloxylation and ortho-Halogenation reactions of arenes

Article abstract of DOI:10.1002/adsc.201000975

A novel, easily removable and modifiable silicon-tethered pyridyldiisopropylsilyl directing group for C-H functionalizations of arenes has been developed. The installation of the pyridyldiisopropylsilyl group can efficiently be achieved via two complementary routes using easily available 2-(diisopropylsilyl)pyridine (5). The first strategy features a nucleophilic hydride substitution at the silicon atom in 5 with aryllithium reagents generated in situ from the corresponding aryl bromides or iodides. The second milder route exploits a highly efficient room-temperature rhodium(I)-catalyzed cross-coupling reaction between 5 and aryl iodides. The latter approach can be applied to the preparation of a wide range of pyridyldiisopropylsilyl- substituted arenes possessing a variety of functional groups, including those incompatible with organometallic reagents. The pyridyldiisopropylsilyl directing group allows for a highly efficient, regioselective palladium(II)-catalyzed mono-ortho-acyloxylation and ortho-halogenation of various aromatic compounds. Most importantly, the silicon-tethered directing group in both acyloxylated and halogenated products can easily be removed or efficiently converted into an array of other valuable functionalities. These transformations include protio-, deuterio-, halo-, boro-, and alkynyldesilylations, as well as a conversion of the directing group into the hydroxy functionality. In addition, the construction of aryl-aryl bonds via the Hiyama-Denmark cross-coupling reaction is feasible for the acetoxylated products. Moreover, the ortho-halogenated pyridyldiisopropylsilylarenes, bearing both nucleophilic pyridyldiisopropylsilyl and electrophilic aryl halide moieties, represent synthetically attractive 1,2-ambiphiles. A unique reactivity of these ambiphiles has been demonstrated in efficient syntheses of arylenediyne and benzosilole derivatives, as well as in a facile generation of benzyne. In addition, preliminary mechanistic studies of the acyloxylation and halogenation reactions have been performed. A trinuclear palladacycle intermediate has been isolated from a stoichiometric reaction between diisopropyl(phenyl)pyrid-2-ylsilane (3a) and palladium acetate. Furthermore, both C-H functionalization reactions exhibited equally high values of the intramolecular primary kinetic isotope effect (k_H/k _D=6.7). Based on these observations, a general mechanism involving the formation of a palladacycle via a C-H activation process as the rate-determining step has been proposed.

Full text of DOI:10.1002/adsc.201000975

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DOI: 10.1002/adsc.201000975
The Pyridyldiisopropylsilyl Group: A Masked Functionality and
Directing Group for Monoselective ortho-Acyloxylation and
ortho-Halogenation Reactions of Arenes
Chunhui Huang,a Natalia Chernyak,a Alexander S. Dudnik,a
and Vladimir Gevorgyana,*
a
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, USA
Fax : (+1)-312-355-0836; phone: (+1)-312-355-3579; e-mail: vlad@uic.edu
Received: December 27, 2010; Published online: May 17, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000975.
Abstract: A novel, easily removable and modifiable group into the hydroxy functionality. In addition, the
silicon-tethered
pyridyldiisopropylsilyl
directing construction of aryl-aryl bonds via the Hiyama–Den-
À
group for C H functionalizations of arenes has been mark cross-coupling reaction is feasible for the ace-
developed. The installation of the pyridyldiisopropyl- toxylated products. Moreover, the ortho-halogenated
silyl group can efficiently be achieved via two com- pyridyldiisopropylsilylarenes, bearing both nucleo-
plementary routes using easily available 2-(diisopro- philic pyridyldiisopropylsilyl and electrophilic aryl
pylsilyl)pyridine (5). The first strategy features a nu- halide moieties, represent synthetically attractive 1,2-
cleophilic hydride substitution at the silicon atom in ambiphiles. A unique reactivity of these ambiphiles
5 with aryllithium reagents generated in situ from has been demonstrated in efficient syntheses of ary-
the corresponding aryl bromides or iodides. The lenediyne and benzosilole derivatives, as well as in a
second milder route exploits a highly efficient room- facile generation of benzyne. In addition, preliminary
temperature rhodium(I)-catalyzed cross-coupling re- mechanistic studies of the acyloxylation and halogen-
action between 5 and aryl iodides. The latter ap- ation reactions have been performed. A trinuclear
proach can be applied to the preparation of a wide palladacycle intermediate has been isolated from a
range of pyridyldiisopropylsilyl-substituted arenes stoichiometric
reaction
between
diisopropyl-
possessing a variety of functional groups, including (phenyl)pyrid-2-ylsilane (3a) and palladium acetate.
AHCTUNGTRENNUNG
À
those incompatible with organometallic reagents. Furthermore, both C H functionalization reactions
The pyridyldiisopropylsilyl directing group allows for exhibited equally high values of the intramolecular
a highly efficient, regioselective palladium(II)-cata- primary kinetic isotope effect (kH/kD =6.7). Based on
lyzed mono-ortho-acyloxylation and ortho-halogena- these observations, a general mechanism involving
À
tion of various aromatic compounds. Most impor- the formation of a palladacycle via a C H activation
tantly, the silicon-tethered directing group in both process as the rate-determining step has been pro-
acyloxylated and halogenated products can easily be posed.
removed or efficiently converted into an array of
other valuable functionalities. These transformations
include protio-, deuterio-, halo-, boro-, and alkynyl- Keywords: acyloxylation; catalysis; C H activation;
desilylations, as well as a conversion of the directing halogenation; palladium; silicon
À
Introduction
spite several advantages achieved in this field, a selec-
tive functionalization of a particular C H bond of in-
À
À
Transition metal-catalyzed direct C H functionaliza- terest remains challenging. One of the possible solu-
tions of arenes have emerged recently as one of the tions involves the employment of directing groups,[3]
most powerful strategies for a rapid and atom-eco- which, by coordination to a metal catalyst, enable a
À
nomical construction of a variety of bioactive mole- selective activation of proximal C H bonds via a cy-
cules, pharmaceutical targets, and materials.[1,2] De- clometalation process. Accordingly, a variety of di-
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Chunhui Huang et al.
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demonstrated further applications of the pyridyldime-
thylsilyl directing group to a variety of highly efficient
and regioselective transformations, including carbo-
magnezation,[8] Pauson–Khand reaction,[9] directed
ortho-metalation,[10] Stille cross-coupling,[11] and car-
bonyl allylation.[12]
Along this line, we have recently communicated a
traceless/modifiable silicon-tethered pyridyldiisopro-
pylsilyl (PyDipSi) directing group for the Pd-catalyzed
ortho-acyloxylation[13] and ortho-halogenation[14] reac-
À
tions of aromatic and heteroaromatic C H bonds
(Scheme 2). These transformations allowed for effi-
cient syntheses of the corresponding PyDipSi-arenes
in a highly regioselective mono-functionalization fash-
ion. Most importantly, in contrast to the directing
groups mentioned above, the PyDipSi group could ef-
ficiently be removed or converted into a variety of
other synthetically valuable functionalities.
À
Scheme 1. Commonly used directing groups for C H activa-
tions.
Herein, we report an expanded scope of the Pd-cat-
recting groups, such as pyridine,[2n,3a–f] pyrimidine,[2- alyzed ortho-acyloxylation and ortho-halogenation re-
pyrazole,[2r,3h] oxazoline,[3i–l] amide,[2j,m,3m–p] oxime actions of arenes and heteroarenes; further applica-
n,3a,g]
ether,[3i,q] carboxylic acid,[2i,3r–t] and hydroxy group,[3u,v] tions of the corresponding functionalized PyDipSi-
have been developed for these transformations arenes for facile syntheses of a variety of synthetically
(Scheme 1). Despite the efficiencies achieved in the valuable building blocks and products, including
À
directed ortho-selective C H functionalizations, the ortho-functionalized boronates, phenols, polyhaloaro-
employment of the above-mentioned directing groups matic compounds, catechols, benzosiloles, benzofuran,
limits these transformations to particular types of sub- diarylenediynes, and the generation of arynes; mecha-
strates. Moreover, a control of reaction selectivities nistic studies; as well as a new, mild, and a highly
toward mono- versus bis-functionalization products functional group-tolerant method for the installation
for most directing groups is still problematic of the PyDipSi directing group.
(Scheme 1, bottom).[2h,3p,w,4] Furthermore, a removal or
conversion of these directing groups into other func-
tionalities often represents a quite challenging syn- Results and Discussion
thetic task, and in many cases cannot be achieved at
all.[5]
Design of a Removable Directing Group
Employment of a silicon-tethered[6] directing group
seems as a viable solution to this problem. Originally, Our design of a removable directing group was based
this concept was applied by Yoshida for the highly on the following criteria: (a) the group should be ca-
regio- and stereoselective Pd-catalyzed Heck reac- pable of coordinating a Pd catalyst; (b) synthesis and
tions of vinylsilanes [Eq. (1)].[7] Later, the same group installation of the directing group onto aromatic rings
should be highly efficient and straightforward; (c) the
group should be sufficiently stable under typical Pd-
À
catalyzed C H activation reaction conditions, involv-
ing the use of oxidants, electrophilic metals and re-
À
Scheme 2. Pd(II)-catalyzed PyDipSi-directed C H functionalizations of arenes.
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The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group
agents at elevated temperatures; yet, (d) it should wise, an attempted acetoxylation of the silacyclopen-
remain labile enough to allow for its easy removal tane 2 led to a complete decomposition of the starting
À
from the products of a C H functionalization. Con- material only (entry 2). Promisingly, the employment
sidering that pyridine is among the best coordinating of the
À
ligands for Pd complexes in the directed C H activa- PyDipSi-benzene 3a under these reaction conditions
tion transformations,[1q,3a] we chose pyridine as the co- provided a 15% NMR yield of the desired product 4a
ordination site of our removable directing group. We (entry 3). Further increase of the reaction tempera-
envisioned that the employment of a temporary sili- ture to 1008C allowed for a slight improvement of the
con linker to connect pyridine with an aromatic sub- reaction outcome (entry 4). At this point, it became
strate would fulfill the above requirements for a gen- apparent that the PyDipSi-directing group is suffi-
À
eral removable directing group. To this end, we aimed ciently stable under oxidative conditions of C H
at establishing a suitable silicon tether for the pyri- functionalizations. Thus, we turned our attention to
dine group by tuning different substituents at silicon. the development of practical and general methods for
Accordingly, substrates 1, 2 and 3a were synthesized the installation of the PyDipSi group onto arenes and
À
and examined under the Pd-catalyzed C H activation heteroarenes.
conditions (Figure 1).
To this end, we decided to test our substrates in the
[2f,3a,c,e,g,i,m,n,15]
À
Pd-catalyzed directed C H acetoxylation
Installation of the PyDipSi-Directing group onto Aryl
reactions first. These transformations are particularly and Heteroaryl Halides
important as they allow for a direct and selective
preparation of oxygenated arenes.[16] Besides, typical Nucleophilic Substitution (Method A)
Pd(II)-catalyzed ortho-acetoxylation reactions involve
the employment of strong oxidants, such as The most common strategy for the installation of a
PhIACHTUNGTRENNUNG(OAc)2, in acidic or neutral media at elevated silyl group onto an aromatic ring involves a nucleo-
temperatures. Unfortunately, arylsilane 1, bearing philic substitution reaction between the corresponding
Yoshidaꢁs pyridyldimethylsilyl directing group, ap- chloro- or hydrosilane and aryl organometallic re-
peared to be unstable under the common acetoxyla- agent. Accordingly, we chose to use a more stable
tion reaction conditions (Table 1, entry 1).[15] Like- PyDipSi hydride (5) for this purpose. Indeed, treat-
ment of PyDipSiH (5) with phenyllithium smoothly
produced the desired product 3a in 92% yield. Next,
installation of the PyDipSi group on halogenated
arenes 6 was accomplished in a one-pot fashion via a
nucleophilic hydride substitution in PyDipSiH with
aryllithium reagents generated in situ from the corre-
sponding aryl bromides or iodides [Eq. (2)]. It was
Figure 1. Substrates for silicon tether screen.
Table 1. Optimization of silicon-tethered directing group
under the ortho-acetoxylation reaction conditions.
shown that an array of PyDipSi-arenes 3 could be ac-
cessed via this route (Table 3, method A). Bromo-sub-
stituted substrates 3f and 3t were obtained via a selec-
tive monolithiation of the corresponding 1,3- and 1,4-
Entry
Substrate
T [8C]
Yield [%][a]
dibomobenzenes. Substrates 3i’ and 3o, bearing ester
and amide functional groups, were synthesized by a
subsequent lithiation/quenching with an electrophilic
reagent sequence from 3f. In addition, a number of
heterocycles, such as benzofuran, indole, benzoxazole,
and carbazole were compatible with the organolithi-
um reagents and afforded PyDipSi-heteroarenes
(3ao–3ar) in good to excellent yields (entries 41–44).
[b]
1
2
3
4
1
2
3a
3a
80
80
80
100
–
–
[b]
15 (4a)
30 (4a)
[a]
NMR yield.
[b]
Decomposition of starting arylsilane was observed, no
desired product was formed.
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Table 2. Optimization of a direct coupling of haloarenes with PyDipSiH.[a]
Entry
Catalyst
(%)
X/R
Solvent
T [8C]
Yield [%][b]
[c]
[g]
1
2
3
4
5
6
7
8
Pd
Pd
Pd
PtO2
[Rh
[Rh
[Rh(OH)
[Rh
Rh
G
1.5
5
4
5
5
5
5
5
5
5
5
5
5
5
5
5
2.5
1
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
I/OMe
Br/H
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMF
THF
MeCN
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
r.t.
100
r.t.
70
dec
dec
dec
dec
13
25
16
19
dec
19
27
55
54
74
70
96
(98)
79
51
40
1
[d]
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
100
100
100
100
100
100
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
T
N
R
N
G
E
E
E
G
G
G
N
G
A
[h,i]
2.5
2.5
2.5
2.5
2.5
2.5
Br/H
Cl/H
Cl/H
OTf/H
OTf/H
0
2
30
[a]
Reaction conditions: PyDipSiH (0.1 mmol), aryl halide (0.2 mmol), catalyst, K3PO4 (0.3 mmol), and solvent (0.5 mL) were
stirred overnight at the indicated temperature.
GC yields, isolated yields are in parenthesis.
[b]
[c]
[d]
[e]
[f]
The reaction was carried out in the presence of 6 mol% of P
KOAc (2 equiv.) was used as a base, 4 h.
ACHTUNGRTEN(UNNG o-tol)3 as a ligand, (i-Pr)2NEt (3 equiv.) as a base, 22 h.
Pyridine (2.5 equiv.) was used as a base and LiCl (4 equiv.) as an additive, 4 h.
NaOAc (2 equiv.) was used as a base, 29 h.
The reaction time was 48 h.
The reaction was run on a 0.2-mmol scale. Amounts of aryl halide or triflate were reduced to 1.1 equiv., 8 h.
[g]
[h]
[i]
72 h.
[j]
TBAI (1.1 equiv.) was used as an additive.
Finally, it is worth mentioning that PyDipSiH was Rh(I)-Catalyzed Cross-Coupling (Method B)
made in an excellent yield from a commercially avail-
Although method A is quite efficient for the prepara-
tion of PyDipSi-arenes, it suffers from low functional
group compatibility owing to a requisite use of strong
organolithium reagents. In contrast to the methods re-
lying on strong organometallic reagents, the transition
metal-catalyzed cross-coupling reaction of aryl halides
with hydrosilanes is a well-precedented functional
able chlorodiisopropylsilane and 2-bromopyridine on
a 170-mmol scale [Eq. (3)].
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The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group
group-compatible strategy for the installation of alkyl, tries 1–4), whereas the use of the Rh(I) catalyst pro-
aryl, or alkoxysilyl groups onto arenes [Eq. (4)].[17] vided the desired product 3b in a very low yield
However, there are no reports on a direct coupling of (entry 5). Further optimization of the Rh(I)-catalyzed
haloarenes with hydrosilanes possessing a heterocyclic
substituent. Thus, we envisioned that the development
of the cross-coupling approach for the introduction of
the PyDipSi group onto aryl and heteroaryl halides 6
would allow for a better functional group tolerance,
thus complying with the requirements for our direct-
ing group design [Eq. (5)].
Accordingly, known Pd-,[17a–i] Pt-,[17j] and Rh-cata-
ACHTUNGTRENNUNG ACHUTNGTREN(NUGN NBD)]2 as a
lyzed[17k,l] methods for the coupling of hydrosilanes reactions (entries 6–12) revealed [RhCl
with aryl halides were tested in the reaction of PyDip- feasible catalyst for this transformation (entry 12).[18]
SiH with 4-iodoanisole (Table 2, entries 1–5). It was Notably, switching the solvent to 1,4-dioxane dramati-
found that employment of Pd- and Pt-based catalytic cally improved the product yield to 96% (entry 16).
systems led to a decomposition of PyDipSiH (en- Finally, decreasing both catalyst loading and amount
Table 3. Installation of the PyDipSi group on haloarenes.[a]
Entry Product
Yield
[%][b]
A
Entry Product
Yield
[%][b]
B
A
B
3ab
1
2
3a (H)
92
>99 28
–
–
99
78
(R1 =R2 =F)
3ac
3b (OMe)
92 98
91 98
29
30
(R1 =R2 =Cl)
3ad (R1 =F,
R2 =Me)
3
3c (Me)
–
69
4
5
3d (F)
3e (Cl)
73 85
87 95
31
32
3ae
31 73
6
7
3f (Br)
3g (CN)
72 84
33 94
3af
–
88
[c]
8
9
3h (COMe)
3i (CO2Me)
3iꢀ (CO2Et)
-
>99
>99
–
-
33
34
3ag
3ah
97 –
53[d]
10
11
3j (CHO)
3k (NO2)
–
–
93
72
–
69
12
13
3l (NH2)
3m (Ph)
–
94
–
35
36
3ai
3aj
30 84[f]
36 99[f]
95
14
15
3n (PIN)[e]
95
–
–
37
38
3ak
3al
–
–
>99
>99
3o [CONACTHNUGRTNEUNG(i-
Pr)2]
71[d]
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Table 3. (Continued)
Entry Product
Yield
[%][b]
A
Entry Product
Yield
[%][b]
B
A
B
16
17
3p (CF3)
67 77
39
3am
3an
–
75f)
3q (CO2Et)
–
92[f] 40
–
93
18
19
3r (NO2)
3s (F)
–
–
70
>99
41
3ao
95 –
20
21
22
3t (Br)
3u (Ph)
3v (Me)
50 90
93
94 96
–
42
43
3ap
3aq
77 –
87 –
23
24
3w (OMe)
3x
91 95
58 96
(R1 =R2 =Me)
3y (R1 =Me,
R2 =F)
25
26
86 75
3z (R1 =F,
R2 =Me)
3aa (R1 =Cl,
R2 =Me)
96
97
–
–
44
3ar
50 –
27
[a]
Reaction conditions: method A: aryl bromide or iodide (1 equiv.), n-BuLi (1 equiv.), THF (0.7M), À788C; then
PyDipSiH (1 equiv.), À78 to À308C; method B: PyDipSiH (1 equiv.), aryl iodide (1.1 equiv.), [RhCl
K3PO4 (3 equiv.), and dioxane (0.2M), room temperature.[18]
Isolated yields.
ACHTUNGTERN(NGNU NBD)]2 (2.5 mol%),
[b]
[c]
[d]
[e]
[f]
The reaction was not performed.
Combined yield for two steps via intermediate 3f.
PIN=4,4,5,5-tetramethyl-1,3-dioxolan-2-yl.
Reaction was performed at 808C.
of aryl iodide to 2.5 mol% and 1.1 equivalents, respec- the method A. Expectedly, the functional group toler-
tively, allowed for the highest isolated yield of 3b ance of the method B was much better compared to
(entry 17). The catalyst loading could further be re- that of the method A, which required the employ-
duced to 1 mol% at the expense of both product yield ment of organolithium reagents. Thus, in addition to
and the reaction time (entry 18). Aryl iodides were F, Cl, Br, CF3, and OMe, a variety of other functional
notably more reactive in this transformation than the groups, such as ketone (3h), ester (3i), nitrile (3g),
corresponding bromides, chlorides, and triflates (en- nitro (3k and 3r), and even aldehyde (3j) and amino
tries 19–24). Addition of stoichiometric amounts of group (3l), were perfectly tolerated under these reac-
tetrabutylammonium iodide (TBAI), known to en- tion conditions, providing PyDipSi-arenes in high to
hance the reactivity of the latter electrophiles,[17k] quantitative yields. Moreover, arylsilane 3i, whose an-
however, showed no improvement of the reaction alogue 3i’ was previously synthesized via a two-step
outcome for phenyl bromide and chloride (entries 20 sequence involving intermediate 3f, could be accessed
and 22), while a slight increase of the product yield directly in one step and in an excellent yield using
was observed for phenyl triflate (entry 24).
method B (Table 3, entry 9). Furthermore, employ-
Next, the generality of this protocol toward the in- ment of the method B allowed for an efficient cou-
stallation of the PyDipSi group on differently substi- pling of PyDipSiH with different heteroaryl iodides,
tuted aryl iodides was examined (Table 3, method B). such as iodopyridine, iodothiophene, iodobenzofuran,
To our delight, it was found that this transformation and iodoindole derivatives, affording the desired
worked equally well for both electron-rich and elec- products 3ai–3an in excellent yields (Table 3, en-
tron-deficient arenes. Notably, in most cases, a direct tries 35–40, method B).
method B appeared to be even more efficient than
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The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group
Table 4. Further optimization of the ortho-acetoxylation re-
action conditions.
Pd-Catalyzed ortho-Acyloxylation of Arylsilanes
With two efficient and general methods for the instal-
lation of the PyDipSi-directing group onto arenes and
heteroarenes in hand, the Pd-catalyzed ortho-acetoxy-
lation reaction of the PyDipSi-arenes 3 was optimized
further (Table 4). Thus, it was found that performing
the reaction in acetic acid resulted in a rapid decom-
position of 3a (Table 4, entry 1). Similarly, the em-
Entry Additive (equiv) Solvent T [8C] Yield [%][a]
[b]
1
2
3
4
5
none
Cu(OAc)2 (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AcOH
PrCN
PrCN
PrCN
DCE
100
100
80
100
80
–
ployment of a stoichiometric amount of CuACHTUNGTRENNUNG(OAc)2
G
trace
70
80
gave only traces of the product (entry 2). Gratifyingly,
the use of 1 equivalent of AgOAc additive afforded
the desired 4a in 70% yield (entry 3). Performing the
reaction at a slightly higher temperature (1008C) pro-
vided a better yield of 4a (80%, entry 4). Finally,
switching the solvent to 1,2-dichloroethane (DCE)
furnished 4a with the highest yield (85%) at lower
(808C) temperature (entry 5).
85
[a]
[b]
NMR yield.
Decomposition of starting arylsilane was observed, no
desired product was formed.
Table 5. Pd-catalyzed ortho-acyloxylation of arylsilanes.
Entry
1
Product
t [h]
Yield [%][a]
80
Entry
14
Product
t [h]
Yield [%][a]
68
4a
2
4n
5
2
3
4b
4c
2
2
84
93
15
16
4o
4p
4
4
67
79
4
5
6
7
4d
4e
4f
4g
7
2
3
3
64
88
90
80
17
18
19
20
4q
4r
4s
4t
5
5
1
5
60
93
79
60
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Table 5. (Continued)
Entry
Product
t [h]
Yield [%][a]
78
Entry
21
Product
t [h]
Yield [%][a]
90
8
4h
4i
7
4u
4v
4w
5
9
5
1
78
81
22
23
8
2
84
72
10
4j
11
12
4k
4l
8
8
74
82
24
25
4x
4y
8
83
80
1.5
13
4m
8
77
26
4z
1.5
70
[a]
Isolated yields.
Next, the scope of the Pd-catalyzed ortho-acetoxy- tion of these C-6 hydroxy derivatives of heterocycles
lation reaction was examined (Table 5). It was found is a quite challenging synthetic task requiring a multi-
À
that this reaction was quite general and allowed for step synthesis. Using the PyDipSi-directed C H acy-
an efficient introduction of an acetoxy group into a loxylation reaction, these derivatives now can easily
variety of PyDipSi-arenes 4a–4f (entries 1–6). Like- be synthesized in high yields from the corresponding
wise, ortho-pivaloxylation reaction was efficiently readily available C-5 haloheterocyclic precursors. Fi-
achieved under similar reaction conditions by switch- nally, it is worth mentioning that the introduction of
ing the oxidant to PhIACHTNUTRGENNG(U OPiv)2. In contrast to the these acylACHTUTGNRENoNUGN xy groups into aromatic substrates is a
known directed ortho-acyloxylation reactions, a re- highly important transformation as they can serve as
À
markable monoselectivity for most of the substrates directing groups in the Pd-catalyzed C H arylation
was observed in both acetoxylation and pivaloxylation reactions,[20] as well as electrophilic partners in the Ni-
reactions.[19] In addition, a variety of functional catalyzed cross-coupling reactions.[21]
groups, including OMe (4b, 4h, 4q), F (4l, 4v), Cl (4d,
4k, 4w), Br (4m, 4t), acetal (4n), ester (4o), and
amide (4p), remained intact under these reaction con- Pd-Catalyzed ortho-Halogenation of Arylsilanes
ditions. Notably, meta-substituted substrates under-
went the acylACHTUNGTRENNUNGoxylation reaction providing the corre- Halogenated arenes are very useful building blocks in
sponding acyl
ACHTUNGTRENNUNG
gioisomers, where acyloxy groups were installed at immense synthetic potential of aryl halides as electro-
the less hindered ortho-position. In addition, the 2- philic reagents, we next aimed at the development of
[1q,2h,23]
À
naphthyl derivative (entires 6 and 24) was acyloxylat- the Pd-catalyzed C H halogenation reaction
of
ed exclusively at the C-3 position. The C-5-substituted PyDipSi-arenes. Accordingly, PyDipSi-benzene 3a
PyDipSi-heterocycles, such as benzofuran and indole was tested under various ortho-halogenation reaction
derivatives (entries 25 and 26), under the standard conditions in the presence of Pd
acyloxylation reaction conditions produced the C-6 (Table 6).
ACHTUNGRTEN(NUNG OAc)2 catalyst
pivaloxy-functionalized heterocycles as sole re-
First, the bromination reaction of 3a using 2 equiva-
gioisomers in high yields. Notably, a selective prepara- lents of N-bromosuccinimide (NBS) in PrCN at 808C
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The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group
functionalization processes,[23a,b] resulted in a signifi-
cant decrease of the reaction yield (entry 3). The em-
ployment of 1 equivalent of Cu(OAc)2 additive pro-
vided only traces of the brominated product (entry 4).
Remarkably, addition of 1.5 equivalents of PhI(OAc)2
Table 6. Optimization of reaction conditions for PyDipSi-di-
rected ortho-halogenation.
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
facilitated the bromination reaction, furnishing prod-
uct 8x in 80% yield (entry 5). However, performing
the reaction at the elevated temperature (1008C) low-
ered the yield of 8x (entry 6). Notably, switching the
solvent to DCE allowed for a higher reaction yield
(85%) at lower temperature (608C; entry 7). Next,
halogenating reagents other than NBS were also
tested. Thus, the employment of N-iodosuccinimide
(NIS) under these reaction conditions furnished the
ortho-iodinated PyDipSi-benzene (8a) in an excellent
95% yield (entry 8; Hal=I). However, the employ-
ment of N-chlorosuccinimide (NCS) afforded the cor-
responding chlorinated product in a moderate yield
only (entry 9; Hal=Cl).
Entry Additive (equiv.) Hal Solvent T [8C] Yield [%][a]
1
2
3
4
5
6
7
8
9
none
none
HOAc (50)
Br PrCN
Br PrCN
Br PrCN
Br PrCN
80
100
80
100
80
100
60
50
65
15
trace
80
65
85
95
42
Cu
N
PhI
PhI
ACHTUNGTRENNUNG
A
PhI
PhI
U
E
E
I
65
65
PhI
A
[a]
NMR yield.
Subsequently, the scope of the Pd-catalyzed ortho-
provided 50% yield of the desired product 8x halogenation reaction of the PyDipSi-arenes was ex-
(Table 6, entry 1, Hal=Br). Increasing the reaction amined under the optimized reaction conditions
temperature to 1008C led to a slight improvement of (Table 7). It was found that the ortho-iodination reac-
the product yield (entry 2). Addition of 50 equivalents tion displayed a high efficiency for a variety of sub-
À
of acetic acid, commonly used in Pd-catalyzed C H strates, which allowed for the preparation of mono-io-
Table 7. Pd-catalyzed ortho-halogenation of arylsilanes.
Entry Product
t [h] Yield [%][a] Entry Product
t [h] Yield [%][a]
1
8a
8b
8c
8d
8e
0.75 91
15
16
17
18
19
8o
8p
8q
8r
2
86
78
78
68
87
2
3
4
5
1
70
88
87
84
2
1.5
2.5
1.2
2
5
8s
1.5
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Table 7. (Continued)
Entry Product
t [h] Yield [%][a] Entry Product
t [h] Yield [%][a]
6
7
8f
8g
1.2
2
75
76
20
21
8t
5
72
77
8u
1.5
8
8h
2
78
22
8v
2
69
9
8i
2
70
93
90
85
88
84
23
24
25
26
8w
8x
8y
8z
1.5
3
74b)
80
10
11
12
13
14
8j
1
8k
8l
1.5
1.2
2
3.5
3
75
91
8m
8n
27
8aa
4
69c)
2
[a]
Isolated yields.
[b]
Reaction was performed without PhIACTHNUTRGNEUNG
(OAc)2 and with 1 equivalent of NIS.[c] Reaction was performed in PrCN at 1008C.
dinated arylsilanes in good to excellent yields. A vari- deficient substrates (entries 24–26). Notably, the
ety of functional groups, such as OMe (8b, 8l), F (8d, chlorination reaction of electron-rich PyDipSi-arene
8n, 8p, 8q), Cl (8e, 8r), Br (8f, 8m, 8v), ketone (8i), 3w was more efficient than that of electron-neutral
ester (8g), and amide (8h), were perfectly tolerated 3a, providing 8aa in 69% yield. Finally, the iodination
under the halogenation reaction conditions. More- reactions of PyDipSi-heterocycles, such as benzoxa-
over, meta-substituted substrates demonstrated excel- zole (8t), benzofuran (8u), carbazole (8v), and indole
lent site selectivity in the halogenation reaction, pro- (8w), occurred exclusively at the C-6 positions. Simi-
viding mono-iodinated compounds as sole regioisom- larly to the C-6 acyloxylated heterocyclic derivatives
ers (entries 10–13). In addition, ortho-iodination of described above, a selective preparation of the C-6
multisubstituted arylsilanes (entries 14–18) and 2- halogenated heterocycles is a challenging task. Now,
naphthyl derivative (entry 19) occurred smoothly fur- these compounds can easily be accessed via the
À
nishing the desired products as single regioisomers in PyDipSi-directed C H halogenation reactions of the
high yields. Likewise, the bromination reaction al- C-5 PyDipSi-derived heterocycles, which are accessed
lowed for an efficient synthesis of ortho-brominated from the corresponding easily available C-5 halogen-
arylsilanes, tolerating both electron-rich and electron- ated heterocyclic precursors.
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The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group
Scheme 3. Intramolecular kinetic isotope effect studies of pivaloxylation and halogenation reactions.
Mechanistic Considerations
To shed light on possible reaction mechanisms of the
Pd-catalyzed ortho-acyloxylation and ortho-halogena-
tion reactions, intramolecular primary kinetic isotope
effect (KIE) measurements have been performed
first. Substantial kH/kD values of 6.7 were found for
À
both C H functionalization reactions (Scheme 3). Ob-
servation of equally high values of KIEs for both
transformations suggested that these reactions pro-
À
ceed via similar C H activation pathways involving
the formation of palladacycle 9 as a reactive inter-
mediate. In addition, relative rate measurements indi-
cated that the electron-rich arene (3v) underwent the
pivaloxylation reaction more rapidly than electron-de-
ficient 3p (kMe/kH =1.37Æ0.04; kH/kCF >100). Only
traces of the pivaloxylation product for3m-CF3-substi-
tuted substrate 3p were observed, even when a full time (Table 8, entries 1 and 2). Recently, Ritter’s
conversion was achieved for its unsubstituted ana- group observed
logue 3a. during a mechanistic study of the Pd-catalyzed acet-
To further support a possible involvement of the oxylation reaction of 2-phenylpyridine. According to
palladacycle intermediate 9, a stoichiometric reaction this phenomenon, addition of 20 equivalents of start-
of 3a with Pd(OAc)2 in DCE solvent was performed ing material, 2-phenylpyridine, to the thermolysis re-
next. A trinuclear palladacycle 10 was isolated in 25% action of the bimetallic Pd
(III) complex[23c,27,28] result-
a
“nitrogenous ligand effect”[27]
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
1
yield [Eq. (6)], which was characterized by H and ed in a significant increase of the acetoxylated prod-
13C NMR as well as HR-MS analyses. It is worth men- uct yield. Similar to the above case, treatment of the
tioning that using different ratios of 3a and PdACTHNUTRGENNUG(OAc)2 trinuclear Pd(II) species 10 with PhIACHTUTGNREN(NUGN OPiv)2 in the
did not provide any other palladium species and pal- presence of 20 equivalents of substrate 3a, provided
ladacycle 10 was isolated as the only complex in all the desired product 4g in 78% yield (entry 3). Fur-
cases. Similar trimetallic palladium species[24] were re- thermore, addition of 1 equivalent of AgOAc im-
ported by Yu in the Pd
rected iodination of unactivated C H bonds in the
presence of IOAc[25] and in the oxygenation reaction genous ligand”, the reaction of the palladacycle 10
of unactivated methyl groups in the presence of car- with PhI(OPiv)2 afforded two pivaloxylated products
boxylic acid anhydrides.[26]
4g and 4r in 35% and 30% GC yield, respectively
Next, the palladacycle 10 was subjected to a stoi- [Eq. (7)]. Expectedly, when the reaction of the palla-
chiometric reaction with PhI(OPiv)2, however, no de- dacycle 10 with PhI(OPiv)2 was carried out in the
(OAc)2-catalyzed oxazoline-di- proved the yield to 87% (entry 4).[29]
ACHTUNGTRENNUNG
À
Moreover, when substrate 3v was used as a “nitro-
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
sired pivaloxylated product 4g was formed under the presence of 20 equivalents of an unreactive ortho-
standard pivaloxylation reaction conditions even at methyl derivative 11, no formation of 12 was ob-
elevated temperature and upon a prolonged reaction served, while 5g was formed in 80% yield as a single
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Table 8. Stoichiometric reactions of palladacycle 10 with PhIACTHNUTRGNEUNG(OPiv)2.
Entry
Oxidant (equiv.)
Co-oxidant (equiv.)
Substrate (equiv.)
Yield [%][a]
1
2
3
4
PhI
PhI
PhI
PhI
N
none
AgOAc (2)
none
none
none
3a (20)
3a (20)
0[b]
0[b]
78
AgOAc (1)
87
[a]
GC yield, pentadecane was used as internal standard.
The reaction mixture was heated up to 1008C for 12 h.
[b]
product [Eq. (8)]. The above results can easily be ex- high values of the primary KIEs. A subsequent oxida-
plained by the release of reactive Pd(II) species upon tion of Pd(II) in trinuclear species 10 with N-halosuc-
the formation of 4g, which can further catalyze the cinimides or hypervalent iodine
ACHTUNGERTN(NUNG III) reagents provides
pivaloxylation reaction of 3v to form 4r. In contrast, Pd
AHCTUNGTRENNUNG
in the case of an unreactive 11, serving solely as a “ni- ductive elimination from 13 or 14 affords the ob-
trogenous ligand”, the pivaloxylation reaction leading served functionalization products and regenerates the
to 12 is suppressed, resulting in the formation of 4g active Pd(II) catalyst.
only. These observations strongly support the involve-
ment of Ritterꢁs “nitrogenous ligand effect” in the
Pd-catalyzed pivaloxylation reaction of PyDipSi- Further Transformations of Functionalized PyDipSi-
arenes.
In light of these observations, a generalized mecha-
Arenes
nism for the PyDipSi-directed ortho-acyloxylation and Next, we examined the synthetic usefulness of both
À
ortho-halogenation reactions of C H bonds is pro- acyloxylated and halogenated products. The cleavage
posed (Scheme 4). According to it, palladium acetate of the PyDipSi directing group of the acyloxylated
first reacts with arylsilane 3 affording the trinuclear PyDipSi-arene 4r was tested first (Scheme 5). Thus,
palladium(II) complex via a cyclopalladation process, the reaction of 4r with AgF[11b,31] in methanol resulted
which is a rate-limiting step based on the observed in efficient removal of the PyDipSi directing group,
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The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group
Scheme 4. Generalized mechanism for the Pd-catalyzed acyloxylation and halogenation reactions.
Scheme 5. Further transformations of the PyDipSi group in acyloxylated products.
producing tolyl pivalate 15 in 92% yield. In a similar product 16, quantitatively. Of note, the overall three-
manner, switching solvent to THF/D2O, a deuterated step transformation of m-iodotoluene into pivaloxy-
tolyl pivalate 15-d1 was produced in 95% yield. Re- lated arene 16 constitutes a formal ortho-oxygenation
markably, the reaction of 4r in the presence of AgF of m-iodotoluene.[32] Moreover, borodesilylation of
and NIS in anhydrous THF led to iododesilylation the PyDipSi group in 4r with BCl3, followed by the
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Scheme 6. Synthesis of unsymmetrically substituted 2,6-diarylphenol derivatives.
protection of the generated aryldichloroborane with easy entry into not so readily accessible unsymmetri-
pinacol under basic conditions,[7d,33] furnished a syn- cally
substituted
2,6-diarylphenol
derivatives
thetically valuable arylboronate 17[34] in an excellent (Scheme 6). Next, the pivaloxy-directed arylation re-
yield. Likewise, a one-pot sequence involving the bor- action was examined for substrate 4r, however, no for-
odesilylation of 4r, followed by the oxidation step in mation of the desired arylated product was observed
the presence of H2O2/NaOH, led to 4-methylcatechol (Scheme 7, route A). We reasoned that the relatively
(18) in 89% yield.
strong coordinating pyridyl moiety in the PyDipSi
Furthermore, the Hiyama–Denmark cross-cou- group might deactivate the Pd catalyst. To test this
pling[35] of the acetoxylated product 4a proceeded hypothesis, the pyridyl group was replaced with fluo-
smoothly with a concomitant acetoxy group hydroly- ride in almost quantitative yield by treatment of 4r
sis, affording the ortho-arylated phenols 19 in excel- with aqueous HF in THF. Indeed, a subsequent piva-
lent yields (Scheme 6). However, ortho-pivaloxylated loxy-directed ortho-arylation reaction of pyridyl-free
PyDipSi-analogue 4g remained intact under the same 22 occurred smoothly with a concomitant desilylation
cross-coupling reaction conditions, suggesting that the process, producing the arylated product 23 in 84%
hydrolysis of acetoxy group in 4a into the correspond- yield (Scheme 7, route B). Next, employment of the
ing phenoxide is required prior to the coupling step. PyDipSi-arenes as nucleophilic aryl group donors for
As mentioned above, the pivaloxy group can serve as the functionalization of terminal acetylenes was ex-
a directing group in the Pd-catalyzed ortho-arylation amined. Thus, the reaction of PyDipSi-arene 4c with
of arenes.[20] To test this reaction, 2-(4-tolyl)phenol phenylacetylene using the PdCl
2ACTHNUTRGNEUNG(dppf)/AgF catalytic
19b was converted into the corresponding pivalate 20 system, previously developed for the alkynylation of
quantitatively. The latter was subjected to the piva- aryltrimethoxysilanes,[36] allowed for the formation of
loxy-directed ortho-arylation reaction conditions[20] the alkynylated cross-coupling product 24 in 91%
furnishing the arylated product 21 in 68% (98% yield. A subsequent saponification/cyclization cas-
BORSM) yield (Scheme 6). The overall five-step cade[37] afforded benzofuran derivative 25 in 72%
transformation of haloarenes 6a into 21 provides an yield (Scheme 8). The overall four-step sequence, in-
Scheme 7. Pd-catalyzed pivaloxy-directed ortho-arylation of PyDipSi-arene.
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The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group
Scheme 8. Synthesis of benzofuran.
upon the borodesilylation with BCl3, was efficiently
converted into o-iodoarylboronate 28,[40] another syn-
thetically valuable ambiphile. Likewise, o-iodophenol
29 could be accessed via a similar one-pot sequence
involving the borodesilylation reaction followed by
the oxidation step with hydrogen peroxide
(Scheme 10).
Next, coupling of the electrophilic aryl iodide func-
tionality in PyDipSi-iodoarenes 8, introduced by the
À
C H halogenation reaction, was examined. Thus,
double alkynylation of the iodinated PyDipSi-ben-
zene 8a via a sequence involving Sonogashira reaction
Scheme 9. Desilylation of iodinated PyDipSi-arene.
cluding the installation of the PyDipSi group and the
Pd-catalyzed ortho-acetoxylation reaction, constitutes
a powerful strategy for the synthesis of the polysubsti-
tuted benzofuran core from simple haloarenes.
As it was demonstrated above, the PyDipSi direct-
ing group could efficiently participate in a variety of
reactions as a nucleophilic entity. Considering the
electrophilic nature of haloarenes, ortho-halogenated of the aryl iodide and a subsequent cross-coupling re-
PyDipSi-arene derivatives 8, possessing both nucleo- action of the PyDipSi group with phenylacetylene af-
philic and electrophilic reactive sites, represent pow- forded diaryl enediyne 31 in good overall yield
erful 1,2-ambiphilic synthons,[38] which are traditional- (Scheme 11). The latter is a common precursor for
ly accessed through a multistep synthesis.[39]
the construction of a variety of building blocks, for in-
To this end, we decided to test possible reactions of stance, benzofulvenes via a 5-exo-dig radical cycliza-
the ortho-halogenated PyDipSi-arenes 8 as nucleo- tion[41] or naphthalene derivatives via the Bergman
philic coupling partners first. Similarly to the reac- cyclization.[42]
tions of ortho-acyloxylated PyDipSi-arenes, the same
Recently, silole derivatives have received much at-
efficient removal or modification of the PyDipSi tention as highly versatile organic optoelectronic ma-
group was achieved. It was found that the removal of terials.[43] We envisioned that a selective removal of
the silicon-tethered directing group in 8c occurred the pyridyl moiety from the PyDipSi group and subse-
smoothly in the presence of AgF in THF/H2O afford- quent modifications of silicon and halogen handles
ing m-iodobiphenyl 26 in 97% yield (Scheme 9). Inter- could provide an easy access to silole derivatives from
estingly, this transformation, taken together with the in- PyDipSi-haloarenes 8. Thus, 8j was subjected to a So-
stallation of the PyDipSi group and the Pd-catalyzed nogashira reaction with phenylacetylene to produce
ortho-iodination steps, represents an example of a alkynylated PyDipSi-arene 32 in 69% yield. A subse-
formal “Finkelstein/1,2-halogen dance” reaction! Next, quent selective substitution of the pyridyl moiety in
use of a combination of AgF and NIS in anhydrous the PyDipSi group with fluoride provided fluorosilane
THF allowed for an efficient iododesilylation of 33 in 90% yield.[44] Alternatively, fluorosilane 33
chloroACHTUNGTRENNUNGbromoarylsilane 8y, producing 1-chloro-3- could be prepared with a similar efficiency via a se-
bromo-4-iodobenzene 27 in 95% yield [Eq. (9)], a quence involving exchange of the pyridyl group to
useful building block for a modular functionalization fluoride and Suzuki cross-coupling reaction[45] of the
of the benzene ring. Moreover, o-iodoarylsilane 8j, formed iodoarene 34 with potassium phenylethynyltri-
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Scheme 10. Conversion of the PyDipSi group into boronate and phenol.
fluoroborate. A subsequent reduction of fluorosilane utilize this approach, biphenylsilane 37 was prepared
33 with LiAlH4 resulted in hydrosilane 35 in an excel- in 89% yield by treating o-iodoarylsilane 8j with 4-
lent yield. Finally, unsymmetrically substituted ben- methoxyphenylboronic acid under the Suzuki cross-
zo[b]silole 36 was obtained in 72% yield via a 5-endo- coupling reactions conditions. Synthesis of the key hy-
dig cyclization of hydrosilane 31 in the presence of dride 38 was achieved in 79% yield using a standard
KH in DME (Scheme 12).[46] Dibenzosilole frame- pyridyl/fluoride exchange followed by reduction with
works, as reported by Kawashima and Kobayashi, LiAlH4. A subsequent treatment of biphenylhydrosi-
could efficiently be accessed from biphenylhydrosi- lane 38 with Ph3CBACHTUNGTRNEUNG(C6F5)4 under the sila-Friedel–
lanes via a sila-Friedel–Crafts reaction.[47a] In order to Crafts reaction conditions provided unsymmetrically
substituted dibenzosilole 39 in 71% yield
(Scheme 13).[47]
Benzynes represent a highly important class of re-
active intermediates widely used in organic synthe-
sis.[48] Although a number of benzyne precursors have
been disclosed,[49] structures of the most efficient and
mild benzyne surrogates incorporate arylsilane moiet-
ies having a good leaving group adjacent to the silicon
atom, such as in o-silylphenyl triflates and o-silylphe-
nyliodonium salts. We thought that if the iodide func-
tionality in the ortho-iodinated PyDipSi-arenes could
serve as a good leaving group, benzynes could easily
be generated from this precursor in one step. Howev-
er, treatment of 8e and furan with TBAF resulted
only in desilylation product. Accordingly, the iodide
functionality in iodoarene 8e was converted into a
Scheme 11. Double alkynylation towards bis
G
better leaving iodonium group.[50] In order to prevent
Scheme 12. Synthesis of benzosilole from ortho-iodinated PyDipSi-arene.
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The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group
Scheme 13. Synthesis of unsymmetrically substituted dibenzosilole from iodinated PyDipSi-arene.
Scheme 14. Generation and trapping of benzyne.
À
oxidation of the pyridine core in the PyDipSi group, group for C H functionalization of arenes. Two com-
the pyridyl group was replaced with fluoride under plementary methods for the installation of the
standard reaction conditions to give 40 in an excellent PyDipSi group onto haloarenes have been demon-
yield. The latter silyl fluoride 40 was treated with m- strated. The first strategy involves a nucleophilic hy-
CPBA and boron trifluoride-etherate complex fol- dride substitution at silicon with organolithium re-
lowed by the addition of phenylboronic acid to pro- agents. The other approach features a very mild and
duce the corresponding diaryliodonium tetrafluorobo- highly functional group-compatible room temperature
rate 41 (Scheme 14).[51] Treatment of 41 with excess Rh(I)-catalyzed cross-coupling reaction. The PyDipSi
amounts of furan in the presence of TBAF at room directing group allows for a highly efficient mono-
temperature afforded 1,4-epoxydihydronaphthalene and regioselective Pd(II)-catalyzed ortho-acyloxyla-
43 in 89% yield, suggesting a very efficient generation tion and ortho-halogenation of arenes. Most impor-
À
of benzyne 42 during the reaction course. Remarka- tantly, the synthetic utility of the PyDipSi-directed C
bly, the above sequence involving the ortho-iodination H functionalization products was demonstrated in di-
of PyDipSi-arenes, represents an unprecedented ben- verse transformations, involving protio-, deuterio-,
À
zyne generation approach featuring a C H activation halo-, boro-, alkynyldesilylations, and conversion of
strategy.
the
PyDipSi group into the OH functionality, as well as
the formation of aryl-aryl bonds via Hiyama–Den-
mark cross-coupling reaction. Moreover, the ortho-
halogenated PyDipSi-arenes represent synthetically
Conclusions
In summary, we have developed an easily removable attractive 1,2-ambiphiles. The unique reactivity of
and modifiable silicon-tethered PyDipSi-directing these ambiphiles was illustrated in efficient formation
Adv. Synth. Catal. 2011, 353, 1285 – 1305
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asc.wiley-vch.de
1301

Chunhui Huang et al.
FULL PAPERS
down to room temperature and filtered through a layer of
silica gel with the aid of EtOAc. The filtrate was concentrat-
ed under reduced pressure and the residue was purified by
column chromatography on a silica gel (eluent: hexanes/
EtOAc=1/10–1/2) affording the corresponding halogenated
product.
of aryl enediyne, benzosilole derivatives, as well as in
the efficient generation of benzyne. A general reac-
tion mechanism involving a cyclopalladation process
À
via a C H activation at the rate-determining step for
both acyloxylation and halogenation reactions has
been proposed. Further studies on the application of
temporary silicon tethers in directed transition metal-
catalyzed transformations are underway in our labora-
tory.
Acknowledgements
The support of the National Institutes of Health (GM-64444)
and of the National Science Foundation (CHE-0710749) is
gratefully acknowledged.
Experimental Section
General Procedure for Rh(I)-Catalyzed Installation
of PyDipSi Group on Arenes
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An oven-dried 10-mL Wheaton V-vial, containing a stirring
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N
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1302
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Adv. Synth. Catal. 2011, 353, 1285 – 1305

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À
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