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Synthesis of Multisubstituted Arenes via PyrDipSiDirected Unsymmetrical Iterative C-H Functionalizations Dhruba Sarkar, Anton V. Gulevich, Ferdinand S. Melkonyan, and Vladimir Gevorgyan ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b01724 • Publication Date (Web): 06 Oct 2015 Downloaded from http://pubs.acs.org on October 12, 2015
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ACS Catalysis
Synthesis of Multisubstituted Arenes via PyrDipSi-Directed Unsymmetrical Iterative C-H Functionalizations Dhruba Sarkar, Anton V. Gulevich, Ferdinand S. Melkonyan, and Vladimir Gevorgyan* Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United Stated
ABSTRACT: A modifiable or removable pyrimidyldiisopropylsilyl (PyrDipSi) directing group for double-fold symmetrical and unsymmetrical C-H functionalizations of arenes has been developed. The PyrDipSi directing group can be efficiently installed on arenes via the Rh-catalyzed cross-coupling reaction of an aryl iodide with 2-(diisopropylsilyl)pyrimidine (PyrDipSiH). This directing group allows for a highly efficient Pd-catalyzed C-H oxygenation and halogenation reaction of various arenes to produce a variety of symmetrically and unsymmetrically-substituted arenes, including resorcinols, meta-halophenols, and 1,3-dihaloarenes. Importantly, the PyrDipSi group can easily be removed or efficiently converted into valuable functionalities, which opens an access to densely substituted arene products from aryl iodides. Hence, the generality of this strategy was highlighted by synthesis of up to hexasubstituted arene products from simple iodobenzene via iterative C-H functionalization reactions. KEYWORDS: C-H functionalization, Palladium, C-H oxygenation, C-H halogenation, catalysis, silicon-tether.
Previous work (1)
1. INTRODUCTION Transition metal-catalyzed directing group-assisted C-H functionalization has become one of the most powerful strategies for construction of carbon-carbon and carbon-heteroatom bonds in arenes.1 A variety of directing groups bearing nitrogen and oxygen heteroatom such as amide, oxime, ether, carboxylic acid, alcohol, pyridine, pyrimidine, pyrazole, oxazoline are commonly used for arene C-H functionalizations.2 Along this line, synthetically more appealing double-fold C-H functionalization has also been developed (Scheme 1, a).3 Unsymmetrical double-fold C-H functionalization reactions with similar functionality are also feasible, although less common (Scheme 1, b).4 Moreover, introduction of two different substituents at orthopositions to a directing group has also been recently reported (Scheme 1, c).5
i-Pr i-Pr Si
[Pd]
X
X
a
H
Symmetrical bis-functionalization
H
i-Pr i-Pr Si Cl
i-Pr i-Pr Si R1O
N N I
[Pd]
Y
Unsymmetrical with different functionality
Scheme 1. Double-fold C-H Fuctionalization of Arenes Although most of the directing groups2 are important functionalities on their own, sometimes, removal or further modifications of the directing groups after C-H functionalization reactions is required. Subsequently, a number of transformable directing groups such as boronic amides, carboxylic acid, triazene, pyridyloxy were developed for C-H functionalization of arenes.6 However, a vast majority of them are efficient for either selective mono C-H functionalization or nonselective mono and double C-H functionalization. Thus, development of transformable directing groups, which would allow for selective double-fold C-H functionalization reaction, is beneficial, as it would give access to highly polyfunctionalized aromatic compounds.
MeO
R1O
OR2
R1 = Piv, Ac, R2 = Piv
N N
E = H, D, I, Ph
PyrDipSi-Ar two steps
d
i-Pr i-Pr Si
R1O
N N Hal
b
OH
OMe
E E a'
[Pd]
Iterative C-H oxygenation
MeO
DG X
N OR2
a i-Pr i-Pr Si
c
X2
N
[Pd]
two steps
Unsymmetrical with similar functionality c
FG
This work (2)
I
DG
E
E
∗ mono-functionalization ∗ ortho-substituents not tolerated
b DG
N FG
FG = OPiv, OAc I, Br, Cl
PyDipSi-Ar
DG X1
i-Pr i-Pr Si
N
E E
R1O
Hal
b' Hal = I, Br, Cl R1 = Piv, Ac
Me
∗ double-functionalization ∗ symmetic and unsymmetric ∗ ortho-substituents tolerated
Scheme 2. Silicon-Tethered Directing Group for C-H Fuctionalization of Arenes We have previously developed the removable/modifiable7 silicontethered8,9 pyridyldiisopropylsilyl (PyDipSi)10 directing group for the Pd-catalyzed mono C-H oxygenation11 and halogenation12 reactions of arenes (Scheme 2, eq. 1). Moreover, we have recently communicated pyrimidine-based pyrimidyldiisopropylsilyl (PyrDipSi) directing group for the Pd-catalyzed symmetric and unsymmetrical double C-H oxygenation (Scheme 2, eq. 2a)13a and sequential halogenation/oxygenation (Scheme 2, eq. 2b)13b reactions of arenes. These transformations provided access to resorcinol derivatives and meta-halophenols, which are valuable building blocks for synthetic and medicinal chemistry, and material science.14
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Herein, we provide a full account on symmetrical and unsymmetrical double-fold C-H oxygenation (Scheme 2, eq. 2a) and sequential halogenation/oxygenation reactions (Scheme 2, eq. 2b), as well as new unsymmetrical double-fold C-H halogenation reactions of arenes (Scheme 2, eq. 2c). In addition, we report expanded synthetic transformations of PyrDipSi group toward diversely functionalized aromatic compounds, such as biaryls, tolanes, and fused heterocycles (Scheme 2, eq. 2a’ and 2b’). The synthetic usefulness of this methodology was demonstrated by synthesis of up to hexasubstituted arenes from simple iodobenzene using iterative C-H oxygenation reactions (Scheme 2, eq. 2d). RESULTS AND DISCUSSIONS 2.1 Pd-Catalyzed Double-fold C-H Oxygenation Reaction of PyrDipSi-Arenes. We have previously shown10 that the pyridinebased PyDipSi directing group allows for exclusive mono-acetoxylation reaction to produce 3 (Table 1, entry 1). Aiming at development of a double-fold acetoxylation reaction, we tested different silicon-tethered heterocycle-containing directing groups under our previously
Table 1. Optimization of Silicon-Tethered Directing Groupsa i-Pr Het i-Pr Si
Pd(OAc)2 (10 mol%) PhI(OAc)2 (2 equiv) AgOAc (1 equiv)
i-Pr Het i-Pr Si OAc
i-Pr Het i-Pr Si AcO OAc +
DCE, 80 oC 2
1
Entry 1
Heterocycles
3
Yield 3, 80%
Table 2. Optimization of Double Acyloxylation Reactiona
DCE, 80 oC
3
Decomposition
N
RO
1a
Entry
Catalyst, (mol%)
Oxidant, (equiv)
Additive, (equiv)
Yield, %b,c
1 2 3 4 5 6
10 10 10 10 5 5
PhI(OAc)2, (4.0) PhI(OAc)2, (4.0) PhI(OAc)2, (4.0) PhI(OAc)2, (4.0) PhI(OAc)2, (2.5) PhI(OPiv)2, (2.5)
None Air AgOAc, (1.0) AgOAc/LiCl, 1.0 LiOAc, (0.3) LiOAc, (0.3)
40 34 60 90 97(87)d 99(97)d,e
a
Reaction was performed with 1a(0.1 mmol), catalyst, oxidant, additive and DCE (0.4 M) at 80 oC in a sealed vial under N2-atmosphere. bGC yields are given. cIsolated yields are given in parentheses. d Concentration 1M. e3 mmol scale. PyrDipSi-H 5 (Scheme 3). The latter was prepared in an excellent yield from 2-iodopyrimidine 4 by its conversion to 2-pyrimidylmagnesium compound, followed by a subsequent reaction with commercially available chlorodiisopropylsilane (eq. 1). Subsequently, PyrDipSiarenes 1 were prepared using a modified Rh-catalyzed17 cross coupling reaction of aryl iodides 6 with PyrDipSi-H (eq. 2). Notably, synthesis of PyrDipSi-benzene 1a can easily be scaled up to 20 mmol. This protocol features an excellent functional group compatibility and a broad substrate scope.17 a) i-PrMgCl•LiCl (1.2 equiv), THF, 0 oC
N I
N
N H
b)
i-Pr i-Pr
4
Si
Cl
THF, r.t.
6
N
i-Pr i-Pr Si H
(1)
PyrDipSiH, 5 90%, 40 mmol scale PyrDipSiH 4 (1.2-1.3 equiv)
S N
N
3, Traces
N
5
N
H
N Me
4
R = OAc, 2a R = OPiv, 2b
PyrDipSi
PyrDipSi
Decomposition
N
RO
Pd(OAc)2 PhI(OR)2, addtive
N
2
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I
Rh2(OAc)4 (1.25-2.5 mol%) K3PO4 (2 equiv)
No reaction
i-Pr i-Pr Si
N N (2)
S
3, 60%; 2, 26%
R
dioxane, 80-100 oC
6
N a
Reaction was performed with 1(0.1 mmol), catalyst, oxidant, additive and DCE (0.4 M) at 80 oC in a sealed vial under N2-atmosphere. developed oxygenation reaction conditions.10a It was found that imidazole (entry 2),15 N-methylimidazole (entry 3),15 thiazole (entry 4)15 and benzothiazole (entry 5) were inefficient for this transformations. We were pleased to find that the pyrimidine16containing directing groups produced the desired double-oxygenated product 2 albeit in 26% yield (entry 6). Further optimization of the reaction conditions revealed a significant role of additives for this transformation. Thus, it was found that addition of AgOAc slightly facilitates the double-oxygenation reaction (Table 2, entry 3). A combination of AgOAc with LiCl led to further improvement of the yield (entry 4). Remarkably, the use of LiOAc (0.3 equiv) in combination with 5 mol % of Pd(OAc)2 catalyst, and 2.5 equiv. of PhI(OAc)2 oxidant afforded quantitative GC yield of 2a. However, a diminished isolated yield was obtained due to a poor stability of the bis-acyloxy derivative 2a under column chromatography (entry 5). Thus, switching to PhI(OPiv)2 oxidant furnished the column-stable bis-pivaloxy derivative 2b in nearly quantitative isolated yield (entry 6). Next, we turned our attention for the installation of PyrDipSi group on arenes via a cross coupling reaction of aryl iodides 6 with with
R 1, up to 95% up to 20 mmol scale
Scheme 3. Installation of the PyrDipSi Group After developing an efficient method for synthesis of aryl silanes 1, the scope of the Pd-catalyzed double-fold acyloxylation reaction was examined (Table 3). It was found that this transformation is efficient for a wide range of substrates. Aryl silanes containing substituents such as phenyl, benzyl, methyl, t-butyl and 2-acetate were efficiently converted into resorcinols 2c-g. Para-substituted aryl silanes possessing both electron-donating (methoxy, 2h) or electronwithdrawing (acyl 2i, carbomethoxy 2j, amide 2k, and trifluoromethyl 2l) groups were compatible with these reaction conditions. Expectedly, halogenated aryl silanes were perfectly tolerated, providing the corresponding haloarenes 2m-p possessing an additional handle for further functionalization. Aryl silane bearing meta substituent produced double oxygenation product 2q with slightly diminishing yield due to a disfavorable steric interaction in the second C-H functionalization step. Furthermore, aryl silanes possessing easily oxidizable styryl (2r) and formyl (2s) group afforded bis-pivaloxylated product uneventfully. Naturally, after establishing the scope of the double oxygenation reaction, we investigated possible transformations of the PyrDipSiarenes 2a,b,c,n (Scheme 4). First, the silyl-directing group was efficiently removed to produce the pivaloyl-protected resorsinols14
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Table 3. Pd-Catalyzed Bis-pivaloxylation of PyrDipSi-Arenesa Pd(OAc)2 (5 mol%) PhI(OPiv)2 (2.5 equiv) LiOAc (30 mol%)
PivO PyrDipSi
PyrDipSi DCE (1M), 80 oC 14-120 h
R 1
R
PivO 2
Entry
Product
2
Yield (%)b
Entry
Product
2b
97
10
PyrDipSi
PivO
1
Yield (%)b
CONEt2
2k
69
CF3
2l
80
I
2m
82
Br
2n
95
Cl
2o
83
F
2p
80
2q
41c
2r
86
2s
60
PivO
PyrDipSi
2
2
PivO
PivO
PivO
PivO
2c
Ph
PyrDipSi
74
11
PyrDipSi PivO
PivO PivO
PivO Ph
3
2d
PyrDipSi
75
12
PivO PivO
4
PivO PivO
2e
Me
PyrDipSi
5
95
13
PivO
PivO
PivO
2f
t-Bu
88
14
PivO
PyrDipSi PivO PivO
PivO CO2Et
2g
PyrDipSi
82
15
PivO
PyrDipSi PivO
PivO
7
PyrDipSi
PivO
PyrDipSi
6
PyrDipSi
PivO
PyrDipSi
2h
OMe
90
16
F
PyrDipSi
PivO
PivO
PivO
PivO Ph
8
PyrDipSi
2i
COMe
65
17
PivO
PivO
PivO
9
PivO
PyrDipSi
2j
CO2Me
98
18
PivO a
PyrDipSi
PyrDipSi
CHO
PivO
0.2mmol scale. bisolated yields. c10% of Pd(OAc)2 was used. H PivO
R
PivO a
OPiv
b
i) HF ii) AgF
7a, R = H, 96% 7b, R = Ph, 95%
i-Pr i-Pr Si ' RO
2a,b,c,n
c i)HF ii) [Pd] OR' 8a, R' = Ac, 62% 8b, R' = Piv, 65%
i) HF ii) AgF, D2O
N
R
R'O
7a,b. Likewise, it was substituted by a deuterium-atom to give the deuterated analogues 9a,b. Moreover, compounds 2a,b underwent efficient Hiyama-Denmark cross-coupling reaction to produce biaryl resorcinols 8a,b. Finally, the silyl-group could easily be substituted with an iodide to obtain 2-iodoresorsinols 10a-c, which were then utilized in Suzuki-Miyaura cross-coupling reaction toward biaryls 11a,b.
D
OPiv
N OR'
R
9a, R = H, 93% 9b, R = Ph, 90%
i) HF ii) AgF, NIS d
OMe
I PivO
OPiv e R
10a, R = H, 95% 10b, R = Ph, 95% 10c, R = Br, 90%
[Pd]
PivO
OPiv
11a, R = H, 75% 11b, R = Ph, 73% R
a
Conditions: (a) HF, MeOH, 0 oC to rt then AgF (1.2 equiv). (b) HF, THF, 0 oC to rt then AgF (1.2 equiv), D2O (10 equiv), THF. (c) HF, THF, 0 oC to rt then PhI (1.3 equiv), Pd(PPh3)4 (5 mol %), Ag2O (1.1 equiv), THF, 70 oC. (d) HF, THF, 0 oC to rt then AgF (1.2 equiv), NIS (2 equiv), THF, rt. (e) 4-MeOC6H4B(OH)2 (1.5 equiv), Pd2(dba)3 (5 mol %), PPh3 (10 mol %), K3PO4 (2 equiv), dioxane, 100 °C.
Scheme 4. Further Transformations of the Double Oxygenated producta
Next, we examined unsymmetrical double-oxygenation reaction of PyrDipSi-arenes. We were pleased to find an efficient protocol for a one-pot C-H acetoxylation reaction followed by a pivaloxylation step (Scheme 5). Thus, the reaction of 1a,d,g with Pd(OAc)2 (5 mol%), PhI(OAc)2 (1.05 equiv) followed by a subsequent addition of PhI(OPiv)2 (1.25 equiv) and LiOAc (0.3 equiv) afforded unsymmetrical resorcinols 12a,b,c in good yield (Scheme 5, eq. 1). Naturally, an acetyl group can selectively be deprotected in the presence of a pivaloyl group.18 Accordingly, we explored the synthetic utility of the obtained unsymmetrically substituted resorcinols (Scheme 5, eq. 2). Thus, selective deprotection of the acetyl group from 12a, followed by the triflate protection and a subsequent replacement of the pyrimidine group with fluorine atom, efficiently furnished aryl fluorosilane 13. Obviously, the compound 13, which
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a) Pd(OAc)2 (5-10 mol%) PhI(OAc)2 (1.05 equiv) LiOAc (30 mol%) DCE (1M), 80 oC
R
PyrDipSi b) PhI(OPiv)2 (1.25 equiv) LiOAc (30 mol%) 80 oC
1a,d,g
underwent smooth pivaloxylation reaction. In addition, 2-fluoroaryl silanes underwent oxygenation reaction to produce metafluorophenols 18g-i.24 Furthermore, ortho-pivaloxylation of 1napthalene derivatives occurred uneventfully producing 18j in good yield.
PivO
R
PyrDipSi
AcO
(1)
12a, R = H, 75% 12b, R = Ph, 60% 12c, R = CO2Me, 68%
one-pot
1. Cs2CO3 MeOH, 0 oC - rt PivO 2. Tf2O, Pyridine i-Pr DCM, 0 oC - rt i-Pr Si F 3. HF, THF TfO 3 steps 13, 83%
PivO
PivO
PivO
furan, MeCN CsF
O 14
15, 82%
12a
PyrDipSi
(2)
AcO
PivO
PivO
1. HF, THF AgF, NIS, THF
Phenylacetylene PdCl2(PPh3)2 (5%)
I 2. Cs2CO3 MeOH, 0 oC - rt
CuI (10%), piperidine DMA, 60 oC
HO 16, 71%
2 steps
O
Ph
17, 71%
Scheme 5. Unsymmetrical Double C-H Oxygenation contains triflate adjacent to a silyl group, can be used as an aryne surrogate.19 Thus, treatment of 13 with CsF produced aryne20intermediate 14, which was trapped with furan via a [4+2] cycloaddition reaction to produce 15 in good yield. Next, silyl group in compound 12a was substituted with iodide, followed by a selective deprotection of an acetyl group to afford 2-iodophenol 16 in good yield. The latter was converted to 4-pivaloxybenzofuran21 17 via a cascade Sonogashira coupling/5-endo-dig cyclization reaction with phenyl acetylene.22
2.2 Synthesis of phloroglucinols 23 and 24. Motivated by the successful double-fold oxygenation reaction of PyrDipSi-arenes and oxygenation reaction of ortho-substituted aryl silanes, we next attempted a straightforward synthesis of densely functionalized highly substituted phloroglucinols25 (1,3,5 trihydroxybenzene) derivative 23 and 24 from readily available iodobenzene by using an iterative C-H functionalization reactions (Scheme 7). Installation of the PyrDipSigroup at iodobenzene, followed by a double-fold C-H acetoxylation reaction gave easy access to resorcinol derivative 2a. Deprotection of acyl groups and a subsequent O-methylation provided resorcinol derivative 19. The Hiyama-Denmark cross-coupling reaction of 19 with aryl iodide produced the biaryl 20, which upon electrophilic iodination reaction was converted to aryl iodide 21. The PyrDipSigroup was reinstalled via the Rh-catalyzed cross-coupling reaction to provide 22. Finally, the aryl silane 22 was efficiently converted to phloroglucinol derivative 23 via the Pd-catalyzed C-H pivaloxylation reaction. PyrDipSi OAc
PyrDipSi
I a
AcO
b
[Rh] PyrDipSiH
1a, 93%
[Pd] PhI(OAc)2
2a, 89%
d
e MeO
c i) Cs2CO3 ii) MeI
OMe
OMe
C-H oxygenation reaction of ortho-substituted arenes by employing previously developed pyridyldiisopropylsilyl (PyDipSi) group was appeared to be inefficient.10a,23 We hypothesized that employment of PyrDipSi-group, which is efficient for a double-fold oxygenation reaction may help solving this problem. To this end, monopivaloxylation reaction of ortho-substituted PyrDipSi-arenes was Pd(OAc)2 (5 mol%) PhI(OPiv)2 (1.25 equiv) LiOAc (30 mol%)
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OMe
NaI Oxone
MeO
OMe
MeO
i) HF ii) [Pd] 19, 77%
I
20, 83% 21, 66% OMe
OMe
f [Rh] PyrDipSiH
PivO
g MeO
OMe
[Pd] PhI(OPiv)2
MeO
R
DCE (1M), 20 h
1
PivO
22, 76%
80 oC R
PivO Me
PyrDipSi
PyrDipSi
Me
Me 18a, 80%
PyrDipSi
PivO
I
PivO
PyrDipSi
Br
Cl
18e, 72%
18f, 65%
PyrDipSi F
Br F 18h, 66%
18g, 87% PivO
PivO Me
PyrDipSi
18d, 55%c
18c, 75% PivO
PyrDipSi
a
PyrDipSi
MeO
18b, 79%
PivO
PivO
PyrDipSi
OPiv 23, 73% phloroglucinol
18
PivO
OMe
PyrDipSi
PyrDipSi PyrDipSi
PyrDipSi
PyrDipSi OMe
Conditions: (a) PyrDipSiH (1.3 equiv), Rh2(OAc)4 (1.25 mol%), K3PO4 (2 equiv), dioxane, 80 oC. (b) Pd(OAc)2 (5 mol%), PhI(OAc)2 (2.5 equiv), LiOAc (30 mol%), DCE, 80 oC. (c) Cs2CO3 (2 equiv), MeOH then MeI (2.5 equiv), K2CO3 (3 equiv). (d) HF, THF then 4MeOC6H4I (1.3 equiv), Ag2O (1.2 equiv), Pd(PPh3)4 (5 mol%), THF, 60 oC. (e) NaI (1.5 equiv), Oxone (1.5 equiv), MeOH, rt. (f) PyrDipSiH (1.3 equiv), Rh2(OAc)4 (1.25 mol%), K3PO4 (2 equiv), dioxane, 80 oC. (g) Pd(OAc)2 (5 mol%), PhI(OPiv)2 (1.25 equiv), LiOAc (30 mol%), DCE, 80 oC.
Scheme 7. Synthesis of Phloroglucinol Derivativea
PyrDipSi
F 18i, 85% 18j, 72% a
0.2 mmol scale. b Isolated yields. c Pd(OAc)2 (10%), PhI(OPiv)2 (1.5 equiv)
Scheme 6. Oxygenation of ortho-Substituted PyrDipSiArenesa,b explored (Scheme 6). Indeed, various ortho-substituted aryl silanes were efficiently converted to oxygenated products. Thus, aryl silanes possessing methyl (18a,b), methoxy (18c), and halogens (18d-f),
Next, synthetic utility of the building block 23 was explored (Scheme 8). The PyrDipSi group could be easily replaced with bromide or iodide to produce bromo and iodoarene 24, 25 in excellent yield. Naturally, the silyl group could be easily deprotected to furnish 26 in good yield. The Hiyama-Denmark cross-coupling reaction of aryl silane 23 with aryl iodide provided compound 27 in reasonable yield. A routine deprotection of pivaloyl group of 27 followed by a conventional electrophilic iodination reaction of the formed 28 with NIS provided a fully functionalized hexa-substituted benzene 29.26 2.3 Pd-Catalyzed C-H Halogenation Reaction of PyrDipSiArenes. Polyhalogenated arenes are important building blocks widely
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ACS Catalysis OMe
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MeO
OMe
d i) HF ii) [Pd]
OPiv
Me
OMe
OMe
MeO
a, b, or c MeO
OMe
E PyrDipSi
OPiv
OPiv
27, 52%
OMe
E
24, E = Br, 94% 25, E = I, 74% 26, E = H, 83%
23
OMe
OMe
Next, we tested both symmetrical and unsymmetrical double-fold C-H halogenation reactions of aryl silane. Although, we could not find efficient conditions for a one-step double-fold C-H halogenation reaction, this transformation can be accomplished in a two-steps C-H chlorination/iodination sequence providing unsymmetrical double halogenation products (Scheme 9). Accordingly, C-H chlorination reaction of 1 with NCS produced ortho-chloro aryl silanes 30d,e, which upon a subsequent C-H iodination reaction with NIS afforded the dihalo products 31a,b with reasonable yields. 2 steps
f
e MeO
K2CO3
OMe
MeO
NIS
R
PyrDipSi
OMe
OH 28, 82%
Conditions: (a) NBS (1.2 equiv), DCM, rt, silica gel column. (b) Py2IBF4 (1.2 equiv), HBF4 (0.5 equiv), DCM, rt. (c) AgF (4 equiv), MeOH, rt. (d) HF, THF then 4-MeC6H4I (1.3 equiv), Pd(PPh3)4 (5 mol %), Ag2O (1.1 equiv), THF, 70 oC. (e) K2CO3 (3 equiv), MeOH, rt. (f) NIS (1.2 equiv), DMF, rt.
Scheme 8. Synthesis of Fully Substituted Arenea used in cross-coupling reactions, as well as many other useful synthetic transformations.27 Although, 1,2- and 1,4-dihalogenated arenes are traditionally accessible via electrophilic halogenation reactions, synthesis of 1,3-dihaloarenes via this approach is quite challenging. Thus, approaches to 1,3-dihaloarenes are mostly based on substitution reactions of aryldizonium salts or metalloarenes. However, these methods required harsh reaction conditions and multistep procedures.28 Thus, we turned our attention to the development of a double-fold C-H halogenation reaction of PyrDipSi-arenes enroute to 1,3-dihalogenated arenes. First, a brief optimization of mono halogenation reaction was performed (Table 4). It was found that in the presence of 5 mol% Pd(OAc)2 C-H iodination reaction of aryl silane with N-iodosucsinamide (1.5 equiv), provided the desired product 30a in 94% yield (entry 1). Diminishing yield was obtained for C-H bromination reaction even with 10 mol% Pd(OAc)2 (entry 2). Employment of PhI(OAc)2 as co-oxidant11a,b slightly improved the yield (entry 3). Gratifyingly, lowering the amount of Nbromosuccsinamide (1.2 equiv) and additive (10 mol%) significantly improved the yield (entry 4). C-H chlorination reaction of 1a in EtCN required elevated temperatures, excess of N-chlorosuccsinamide (5 equiv), and PhI(OAc)2 (1.3 equiv), (entry 6).
Table 4. Optimization of C-H Halogenation Reactions Pd(OAc)2 (10 mol%) NXS, addtive
PyrDipSi
Hal
1a
Entry 1b 2 3 4 5e 6e a
Hal I Br Br Br Cl Cl
30a, Hal = I 30b, Hal = Br 30q, Hal = Cl
PyrDipSi
DCE, T oC
a
Oxidant, (equiv)
Additive, (equiv)
T,
(oC)
Yield, %c,d
NIS, (1.5) NBS, (2.0) NBS, (2.0) NBS, (1.2) NCS, (1.2) NCS, (5.0)
PhI(OAc)2, (1.0) PhI(OAc)2, (0.1) PhI(OAc)2, (0.1) PhI(OAc)2, (1.3)
60 60 60 50 60 100
94 35 40 85 -(30) 75(90)
Reactions were performed with 1a (0.1 mmol), catalyst, oxidant, additive and DCE (0.2 M) in a sealed vial under N2-atmosphere. b Reaction was performed with Pd(OAc)2 (5 mol%). cIsolated yields. d GC yields are given in parentheses. eReactions were performed in EtCN (0.05M).
R
PyrDipSi Cl
30p, R = Me, 64% 30s, R = CH2CO2Et, 52%
29, 48%
a
b [Pd] NIS
Cl
OH
Me
I R
PyrDipSi
[Pd] NCS
1
I Me
a
31a, R = Me,45% (NMR) 31b, R = CH2CO2Et, 42%
a
Conditions: (a) Pd(OAc)2 (10 mol %), NCS (5 equiv), PhI(OAc)2 (1.3 equiv), EtCN (0.05 M), 100 oC, 12h. bPd(OAc)2 (5 mol %), NIS (1.5 equiv), DCE (0.2 M), 100 oC, 9h.
Scheme 9. Pd-Catalyzed Chlorination/Iodination of PyrDipSiArenesa Previously reported pyridyldiisopropylsilyl (PyDipSi) group was not efficient for the C-H halogenation reaction of ortho-substituted arenes.10b Since, newly developed PyrDipSi-group proved to be effective for unsymmetrical double C-H halogenation reaction, we thought it would also be able to tolerate ortho-substituents as well. Thus, C-H halogenation reaction of ortho-substituted PyrDipSi arenes was tested (Scheme 10). Indeed, it was found that treatment of 1 with Pd(OAc)2 (10 mol%) and NIS provided the corresponding iodinated products 32a-c efficiently. Notably, the aryl silanes possessing methoxy (32a) and fluoro (32b) groups were also compatible with these reaction conditions. Moreover, 1-napthalene derivative was successfully converted into the corresponding iodinated product 32c. I
Pd(OAc)2 (10 mol%) NIS (1.5-2.5 equiv) PyrDipSi R
MeO 32a, 51%
R
1
I PyrDipSi
PyrDipSi
DCE , 60-80oC 12-18 h
I
PyrDipSi
PyrDipSi
Me
F 32b, 56%
I
I Me
PyrDipSi
32
32c, 61%
32d, traces
Scheme 10. Iodination of ortho-Substituted PyrDipSi-Arenes 2.4 Pd-Catalyzed Unsymmetrical C-H Halogenation/Oxygenation Reaction of PyrDipSi-Arenes. Inspired by the successful double-fold oxygenation and halogenation reaction of PyrDipSi-arenes, and oxygenation and halogenation reaction of orthosubstituted aryl silanes, we envisioned that the development of a sequential C-H halogenation/oxygenation11,12 reaction toward valuable meta-halophenols is also feasible.14 Therefore, an unsymmetrical twofold C-H functionalization reaction of PyrDipSi-arenes by employing a two steps sequence involving a C-H halogenation, followed by C-H oxygenation reaction, has been examined. First, we studied the scope of this two-steps protocol by combining C-H iodination reaction condition (Table 4, entry 1) and C-H oxygenation reaction condition (Table 2, entry 6). Slightly diminishing yields of meta-iodophenols were obtained (Table 5, entry 1,2), possibly due to a disfavorable steric interaction in the C-H oxygenation reaction step. Next, we explored the C-H bromination (Table 2, entry 4) and CH oxygenation (Table 2, entry 5, 6) two-steps sequence for synthesis of meta-bromophenols (Table 5, entry 3-17). It was found that
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bromination reaction of aryl silane 1a, followed by oxygenation reaction provided bromophenols 33b, bb in good yields. Similarly, aryl silanes 1 possessing various substituents such as methyl, methoxy, phenyl, benzyl, 2-acetate, t-butyl were uneventfully converted into ortho-bromo products 30c-h, followed by their efficient pivaloxylation reaction into 33c-h. In addition, two-steps sequential bromination/oxygenation reaction of halogen-containing aryl silanes 1 allowed for efficient synthesis of valuable dihalophenol derivatives 33ik. Moreover, electron-deficient substrates possessing trifluoromethyl,
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carbomethoxy, acetyl and amide groups underwent C-H bromination reaction smoothly furnishing the brominated products 30l-o. A subsequent C-H oxygenation reaction provided bromophenols 33l-o. Furthermore, chlorination/oxygenation reaction sequence toward meta-chlorophenols was examined. It was found that C-H chlorination reaction produced 2-chloro aryl silanes 30p-r with good to moderate yields and a subsequent C-H oxygenation reaction proceeded efficiently to produce meta-chlorophenols 33p-r in good yields. Notably, the bromination/pivaloxylation reaction sequence can be
Table 5. Pd-Catalyzed Halogenation/Oxygenation of PyrDipSi-Arenesa C-H halogenation R
PyrDipSi
2 steps
[Pd], NXS PhI(OAc)2
R
PyrDipSi
DCE, temp. 1
Entry
Halogenationa,b
Oxygenationd
94
PyrDipSi
I
30a
I
80
30aa
f
85 (82)g
30b
Me
40f
12
13
71
5
Br
90
6
76
Ph
PyrDipSi
30e
Br
73
84
Br 30h
Cl
69
20
84
33p
PivO
Cl
PyrDipSi
75 30q
Cl
Br
PyrDipSi
59
30r
Cl o
33q
PivO
33h
a
65 Cl
Br
PyrDipSi t-Bu
Br
Me
PyrDipSi
64
30p
33g
PyrDipSi
74
PivO
Me Cl
19
PivO
t-Bu
NiPr2 Br
PyrDipSi
72 Br
PyrDipSi
72
33f
PyrDipSi
30g
Br
18
CO2Et
PyrDipSi
33n
33o
PivO
78
59
O
PyrDipSi
57 Br
COMe
PivO
33e
PyrDipSi Br
Br
30o
PyrDipSi
33f
72
33m
PyrDipSi
74 30n
NiPr2
17
PivO
CO2Et
10
75
CO2Me
PivO
O
Ph
Br
Br
COMe Br
51
33l
PyrDipSi
81 30m
33d
PyrDipSi
9
16
CF3
PivO
PyrDipSi
88
Ph
8
Br
PivO
Ph Br
73
69
33k
PyrDipSi
58
CO2Me Br
F
PivO
30l
PyrDipSi OMe
Br
Br
33c
PyrDipSi
30d
PyrDipSi
7
15
PivO
OMe Br
78
72
33j
PyrDipSi
77
CF3 Br
Cl
PivO
30k
PyrDipSi Me
Br
Br
33bb
PyrDipSi
30c
PyrDipSi
14
68
33i
PyrDipSi
78
F Br
I
PivO
30j
PyrDipSi
PivO
Me
PyrDipSi
Br
Cl Br
Yield, %e
PivO
33b
PyrDipSi Br
74
PyrDipSi
30i
PyrDipSi
72 (79)g
AcO
4
Oxygenationd
33aa
PyrDipSi Br
Br
33
Yield, %e I
PyrDipSi
PivO
Br
Hal
R' = Piv, Ac
33a
PyrDipSi I
R
PyrDipSi
Halogenationb,c
11
PivO
PyrDipSi
3
30
Entry
PyrDipSi
55 I
Me
PyrDipSi
2
Hal
Yield, %e
PivO
PyrDipSi
1
R'O
[Pd], PhI(OR')2 LiOAc DCE, temp.
X = Hal
Yield, %e
C-H oxygenation
b
61
33r
C-H iodination condition: 1 (0.4 mmol), Pd(OAc)2 (5 mol %), NIS (1.5 equiv), DCE (0.2 M), 60 C, 4-6h. C-H bromination condition: 1 (0.4 mmol), Pd(OAc)2 (10 mol %), NBS (1.2-1.5 equiv), PhI(OAc)2 (10-20 mol %), DCE (0.2 M), 45-55 oC, 12-48h. cC-H chlorination condition: 1 (0.2 mmol), Pd(OAc)2 (10 mol %), NCS (5 equiv), PhI(OAc)2 (1.3 equiv), EtCN (0.05 M), 100 oC, 12h, dC-H oxygenation condition: 30 (0.2 mmol), Pd(OAc)2 (5-10 mol %), PhI(OAc)2/PhI(OPiv)2 (1.25-1.5 equiv), LiOAc (30 mol%), DCE (1 M), 80 oC, 20-168h. eIsolated yields. f 2 equiv of PhI(OPiv)2 was used. gThe yield for a reaction carried out on a 5 mmol scale is given in parentheses.
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scaled up to 5 mmol affording the meta-bromophenols 33b in good yield (Table 5, entry 3). Therefore, this protocol can serve as a practical and general two-steps approach toward meta-halophenols, featuring broad substrate scope and high functional group tolerance.
fluorosilane derivative 44. Notably, compound 44, could be used in a series of orthogonal cross-coupling reactions to produce different building blocks. First, biaryl 45 was made from phenyl iodide in good yield via the Hiyama-Denmark cross-coupling reaction. A subsequent Suzuki-Miyaura cross coupling reaction of 45 with 4-methoxyphenyl iodide afforded 46 uneventfully. In addition, building block 45 underwent a Sonogashira cross-coupling reaction to produce 47. On the other hand, aryl silane 44 was efficiently converted to biaryl 48 by Suzuki-Miyaura cross-coupling reaction. Finally, tolane 49 was prepared from compound 44 by a Sonogashira cross-coupling reaction. Notably, all these obtained molecules possess at least one site for further functionalizations.
Next, we explored synthetic transformations of the ambiphilic building block 33 (Scheme 11). First, the silyl-directing group was removed selectively to produce pivaloyl-protected meta-bromophenol 34a,b. Likewise, the deuterium analogues of bromophenols 35a,b were synthesized by replacing the directing group with a deuterium atom. Replacement of the PyrDipSi-group with iodide occurred uneventfully providing valuable polyhalophenols 36a,b. Notably, trihalophenol 36b contains four sites for cross-coupling reaction and thus, could be used for modular functionalization of a benzene ring. A site selective Sonogashira cross-coupling reaction occurred at the C-I bond of 36a rather than at the less sterically hindered C-Br bond to furnish tolane derivative 37.29 Next, reaction of aryne19,20 intermediate from the scaffold 33bb was explored. Thus, a selective deprotection of acetyl group, a subsequent triflate protection, and a replacement of pyrimidine with fluorine atom provided the aryne precursor 38. The latter, upon treatment with CsF generated aryne 39, which was efficiently trapped by [4+2] cycloaddition reaction with furan to produce 40. Next, we turned our attention to synthesis of halogenated benzofuran, which is an important building block for synthesis of natural products and medicinal targets.30 Thus, substitution of PyrDipSi-group with iodide, a subsequent acetoxy group deprotection, followed by a cascade Sonogashira coupling/5-endo-dig cyclization of compound 42 produced 4-bromobenzofuran in an excellent yield. Next, pyrimidyl group in 33b was replaced by fluoride to produce
2.5 Pd-Catalyzed Halogenation and Oxygenation of bisPyrDipSi-Arenes. We also explored the C-H halogenation and oxygenation reaction of bis-PyrDipSi arenes (Scheme 12). Hence, compound 1z underwent double C-H oxygenation to provide quinol derivative 50 uneventfully. Next, aryl silane 1z was converted into diiodoarene 51 and dibromoarene 52 in reasonable yields via a twofold C-H halogenation reaction. The unsymmetrical two-fold C-H functionalization reactions were also investigated. Thus, a two-step reaction sequence including, pivaloxylation reaction, followed by a bromination reaction produced bromophenol derivative 54 efficiently. Similarly, the bromination/iodination reaction sequence smoothly furnished 2-bromo-5-iodo arene 56. Notably, these multifunctional arenes can potentially undergo cross-coupling reactions and ipsosubstitution reactions toward complex molecules. Accordingly, it was shown that silyl groups could easily be removed from compound 50 to
i-Pr F i-Pr Si Br OTf
e i) Cs2CO3 ii) Tf2O iii) HF
I Br
OPiv
d
Br
OPiv
c
[Pd]
i-Pr i-Pr Si Br
D Br
i) HF ii) AgF, D2O
R 35a, R = H, 88% 35b, R = F, 81%
N OR'
Br
i) HF ii) AgF, NIS
OPiv
Br
OH
Cs2CO3
i
O
Br
[Pd]
41, 87%
R 33b,bb,e,k
h
OAc
42, 95%
43, 90%
j HF
i-Pr F i-Pr Si Br OPiv
i) HF ii) AgF
H
40, 89%
I
I
g
N
a
Br
O Br
39
38, 52%
b
OPiv
[4+2]
i) HF ii) AgF, NIS
R 36a, R = H, 85% 36b, R = Cl, 89%
R 37, R = H, 73%
Br
f Furan CsF
MeO l [Pd]
k 44, R = H, 92%
[Pd]
Br
OPiv 46, 71%
OPiv
R m
[Pd]
R 34a, R = H, 86% 34b, R = Ph, 83%
i-Pr
o
n
45, 92%
[Pd] OPiv
[Pd]
i-Pr
MeO
Si F OPiv
i-Pr
47, 87%
i-Pr Si F OPiv
48, 87%
49, 91% a
Conditions: (a) HF, THF, 0 oC to rt then AgF (2.5 equiv), H2O in THF, rt. (b) HF, THF, 0 oC to rt then AgF (2.5 equiv), D2O in THF, rt. (c) HF, THF, 0 oC to rt then AgF (2.5-3.0 equiv), NIS (3-4 equiv), THF, rt to 70 oC. (d) Phenylacetylene (1.5 equiv), PdCl2(PPh3)2 (3 mol%), CuI (5 mol%), DMF, Et2NH (1.5 equiv), 50 oC. (e) Cs2CO3 (10 mol%), MeOH, 0 oC to rt then Tf2O (1.1 equiv), EtNiPr2 (2 equiv), DCM, rt. (f) furan (5 equiv), CH3CN then CsF (3 equiv), rt. (g) HF, THF, 0 oC to rt then AgF (3 equiv), NIS (4 equiv), THF, rt to 70 oC. (h) Cs2CO3 (1 equiv), MeOH, 0 o C to rt. (i) Phenylacetylene (1.1 equiv), PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), DMF, piperidine (1 equiv), 60 oC. (j) HF, THF, 0 oC to rt. (k) PhI (1.5 equiv), Pd(PPh3)4 (5 mol %), Ag2O (1.1 equiv), THF, 60 oC. (l) 4-MeOC6H4B(OH)2 (1.5 equiv), Pd2(dba)3 (5 mol %), PPh3(10 mol %), K3PO4 (2 equiv), Dioxane, 100 oC. (m) Phenylacetylene (1.2 equiv), Pd2(dba)3 (2.5 mol %), PtBu3 (10 mol%), Et3N, rt. (n) 4-MeOC6H4B(OH)2 (1.5 equiv), Pd2(dba)3 (5 mol %), PtBu3 (10 mol %), K3PO4 (2 equiv), Dioxane, 90 oC. (o) Phenylacetylene (1.2 equiv), Pd2(dba)3 (2.5 mol %), PtBu3 (10 mol%), Et3N, rt.
Scheme 11. Further Transformations of Building Block 33a
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provide quinol 57 in excellent yield. Furthermore, both PyrDipSigroups could easily be substituted with iodide (58), which provides additional handle for further modification. Therefore, these symmetrically substituted 50-52 and unsymmetrically substituted 54, 56 aryl silanes could serve as valuable building blocks for organomaterials31 and supramolecular chemistry. 32 PivO
Br
PyrDipSi
PyrDipSi
PyrDipSi
I
OPiv
PyrDipSi
50, 71% Br
PyrDipSi 52, 52%
a
[Pd]/NBS
PyrDipSi
Br
PyrDipSi
51, 28% [Pd]/NIS [Pd] PhI(OPiv)2
1z
PyrDipSi
f PyrDipSi
b
PyrDipSi
55, 61% g
OPiv
53, 52% [Pd]/NIS I
Br
PyrDipSi Br
PyrDipSi
I
PivO I
OPiv 58, 82%
i AgF NIS
e
PyrDipSi
PyrDipSi
[Pd] NBS
OPiv 54, 64%
56, 80% PivO
PyrDipSi
PyrDipSi
OPiv 50
H
PivO
h HF AgF
H
OPiv 57, 94%
a
Conditions: (a) Pd(OAc)2 (5 mol%), PhI(OPiv)2 (2.5 equiv), LiOAc (30 mol%), 80 oC, DCE. (b) Pd(OAc)2 (10 mol%), NIS (3 equiv), DCE, 60 oC. (c) Pd(OAc)2 (20 mol%), PhI(OAc)2 (20 mol%), NBS (2.5 equiv), DCE, 50 oC. (d) Pd(OAc)2 (5 mol%), PhI(OPiv)2 (1.1 equiv), LiOAc (30 mol%), 80 oC, DCE. (e) Pd(OAc)2 (10 mol%), PhI(OAc)2 (20 mol%), NBS (1.2 equiv), DCE, 50 oC. (f) Pd(OAc)2 (10 mol%), PhI(OAc)2 (20 mol%), NBS (1.1 equiv), DCE, 50 oC. (g) Pd(OAc)2 (10 mol%), NIS (1.3 equiv), DCE, 60 oC. (h) HF/MeOH then AgF (4 equiv), rt. (i) HF/THF then NIS (3 equiv), AgF (4 equiv), THF, rt.
Scheme 12. Pd-Catalyzed C-H Halogenation and Oxygenation of bis-PyrDipSi-Arenesa 3. CONCLUSIONS In summary, we have developed a new, general, efficient and robust removable/functionalizable pyrimidyl-based silicon-tethered directing group for diverse C-H functionalization of arenes. This directing group can easily be installed on aryl iodide by the Rh-catalyzed crosscoupling reaction in the presence of a broad range of functional groups. PyrDipSi directing group allows for efficient and highly functional groups compatible symmetrical and unsymmetrical double C-H oxygenation of arenes producing valuable resorcinol derivatives. A general and efficient synthesis of substituted meta-halophenols was shown via a sequential unsymmetrical C-H halogenation/oxygenation reaction. Moreover, PyrDipSi group allows for a sequential chlorination/iodiniation reaction toward dihaloarenes. Importantly, it was shown that this directing group could easily be removed or transformed into aryl iodides and biphenyls. Further synthetic utility was demonstrated in an efficient formation of 4-substituted benzofurans, clean generation of aryne intermediates, as well as diversely functionalized aromatic compounds, such as iodoarenes, biaryls, tolanes, substituted phenols, and quinols. Furthermore, the utility of PyrDipSi directing group was highlighted by synthesis of up to hexa-substituted benzene in a straightforward reaction sequence.
ASSOCIATED CONTENT
characterization data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author
[email protected] We thank the National Institutes of Health (GM-64444) and National Science Foundation (CHE-1362541) for financial support of this work.
PyrDipSi
d
[Pd] NBS
Supporting Information. Detailed experimental procedures and
ACKNOWLEDGMENT
I
PyrDipSi
[Pd] PhI(OPiv)2
c
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REFERENCES (1) For selected reviews on transition metal-catalyzed directing group assisted C-H activation of arenes, see: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094-5115. (b) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447-2464. (c) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147-1169. (d) Wencel-Delord, J.; Dröge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 740-4761. (e) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788-802. (f) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936-946. (g) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236-10254. (h) Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886. (i) Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (j) Ackermann, L. Acc. Chem. Res. 2014, 47, 886-896. (k) Ryu, J. Kwak, J. Shin, K. Lee, D. Chang, S. J. Am. Chem. Soc. 2013, 135, 1286112868. (l) Rouquet G.; Chatani, N. Angew. Chem., Int. Ed., 2013, 52, 11726-11743. (m) Huang, Z.; Lim, H. N.; Mo, F.; Young, M. C.; Dong, G. Chem. Soc. Rev. 2015, DOI: 10.1039/C5CS00272A. (2) For selected examples of directing groups, see (a) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 12634-12635. (b) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141-1144. (c) Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066-6067. (d) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285-13293. (e) Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008, 47, 5215-5219. (f) Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9982-9983. (g) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.Q. J. Am. Chem. Soc. 2010, 132, 5916-5921. (h) Wang, X.; Lu, Y.; Dai, H.X.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 12203-12205. (i) Jia, X.; Yang, D.; Wang, W.; Luo, F.; Cheng, J. J. Org. Chem. 2009, 74, 9470-9474. (j) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648-3649. (k) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2005, 128, 78-79. (l) Ackermann, L.; Novák, P. Org. Lett. 2009, 11, 4966-4969. (m) Sun, C.-L.; Liu, N.; Li, B.-J.; Yu, D.-G.; Wang, Y.; Shi, Z.-J. Org. Lett. 2010, 12, 184-187. (n) Wang, H. Schroder, N. Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 5386-5389. (3) For selected examples of transition metal-catalyzed symmetrical bisfunctionalization of arenes, see: (a) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046-4068. (b) Ackermann, L. Org. Lett. 2005, 7, 3123-3125. (c) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Tetrahedron 2006, 62, 11483-11498. (d) Kalberer, E. W.; Whitfield, S. R.; Sanford, M. S. J. Mol. Catal. A: Chem. 2006, 251, 108-113. (e) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285-13293. (f) Arockiam, P.; Poirier, V.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Green Chem. 2009, 11, 1871-1875. (g) Zheng, X.; Song, B.; Li, G.; Liu, B.; Deng, H.; Xu, B. Tetrahedron Lett. 2010, 51, 6641-6645. (h) Mo, S.; Zhu, Y.; Shen, Z. Org. Biomol. Chem. 2013, 11, 2756-2760. (i) Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837-5844. (j)Truong, T.; Klimovica, K.; Daugulis, O. J. Am. Chem. Soc. 2013, 135, 9342-9345. (k) Tran, L. D.; Popov, I.; Daugulis, O. J. Am. Chem. Soc. 2012, 134, 1823718240 and 13a. (4) For examples of unsymmetrical bis-functionalization with similar functionality, see: (a) Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 7094-7099. (b) Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
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Angew. Chem., Int. Ed. 2010, 49, 6169-6173. (c) Cong, C.; You, J.; Gao, G.; Lan, J. Chem. Commun. 2013, 49, 662-664. (d) Deb, A.; Bag, S.; Kancherla, R.; Maiti, D. J. Am. Chem. Soc. 2014, 136, 13602-13605 and 13a. (5) For examples of unsymmetrical bis-functionalization with different functionality, see: (a) Wang, H.; Li, G.; Engle, K. M.; Yu, J.-Q.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135, 6774-6777. (b) Rosen, B. R.; Simke, L. R.; Thuy-Boun, P. S.; Dixon, D. D.; Yu, J.-Q.; Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, 7317-7320. (c) Kim, H. J.; Ajitha, M. J.; Lee, Y.; Ryu, J.; Kim, J.; Lee, Y.; Jung, Y.; Chang, S. J. Am. Chem. Soc. 2013, 136, 1132 1140. (d) Zhang, S.-Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2015, 137, 531-539 and 13b. (6) For examples of tranformable directing groups, see: (a) Ihara, H.; Suginome, M. J. Am. Chem. Soc. 2009, 131, 7502 -7503. (b) Ihara, H.; Koyanagi, M.; Suginome, M. Org. Lett. 2011, 13, 2662-2665. (c) Hafner, A.; Bräse, S. Angew. Chem., Int. Ed. 2012, 51, 3713-3715. (d) Wang, C.; Chen, H.; Wang, Z.; Chen, J.; Huang, Y. Angew. Chem., Int. Ed. 2012, 51, 7242-7245. (e) Cornella, J.; Righi, M.; Larrosa, I. Angew. Chem., Int. Ed. 2011, 50, 9429-9432. (f) Sun, X.; Shan, G.; Sun, Y.; Rao, Y. Angew. Chem., Int. Ed. 2013, 52, 4440-4444. (g) Kinuta, H.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2015, 137, 1593-1600. (h) Zhang, Y.; Zhao, H.; Zhang, M.; Su, W. Angew. Chem., Int. Ed. 2015, 54, 3817-3821. (7) For reviews on removable/modifiable directing groups, see: (a) Bracegirdle, S.; Anderson, E. A. Chem. Soc. Rev. 2010, 39, 4114-4129. (b) Huang, Y.; Wang, C. Synlett 2013, 24, 145-149. (c) Zhang, F.; Spring, D. R. Chem. Soc. Rev. 2014, 43, 6906-6919. (8) For examples of silicon-tethered strategy in arene C-H functionalization, see: (a) Shimizu, M.; Mochida, K.; Hiyama, T. Angew. Chem., Int. Ed. 2008, 47, 9760-9764. (b) Furukawa, S.; Kobayashi, J.; Kawashima, T. J. Am. Chem. Soc. 2009, 131, 14192-14193. (c) Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, 10844-10845. (d) Mochida, K.; Shimizu, M.; Hiyama, T. J. Am. Chem. Soc. 2009, 131, 8350-8351. (e) Huang, C.; Gevorgyan, V. Org. Lett. 2010, 12, 2442-2445. (f) Simmons, E. M.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 17092-17095. (g) Ureshino, T.; Yoshida, T.; Kuninobu, Y.; Takai, K. J. Am. Chem. Soc. 2010, 132, 14324-14326. (h) Huang, C.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 12406-12409. (i) Kuznetsov, A.; Onishi, Y.; Inamoto, Y.; Gevorgyan, V. Org. Lett. 2013, 15, 2498-2508. (j) Li, Q.; Driess, M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2014, 53, 8471-8474. (h) Wang, Y.; Gevorgyan, V. Angew. Chem., Int. Ed. 2015, 54, 2255-2259. (9) For review on pyridyldimethylsilyl-group driven reactions, see: (a) Itami, K.; Mitsudo, K.; Nokami, T.; Kamei, T.; Koike, T.; Yoshida, J.-i. J. Organomet. Chem. 2002, 653, 105-113. (b) Itami, K.; Yoshida, J.-i. Synlett 2006, 2006, 157-180. (10) For PyDipSi directed C-H functionalization reactions, see: (a) Chernyak, N.; Dudnik, A. S.; Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2010, 132, 8270-8272. (b) Dudnik, A. S.; Chernyak, N.; Huang, C.; Gevorgyan, V. Angew. Chem. Int. Ed. 2010, 49, 8729-8732. (c) Huang, C.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Adv. Synth. Catal. 2011, 353, 1285-1305. (11) For selected examples of C-H oxygenation of arenes, see: (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300-2301. (b) Racowski, J. M.; Dick, . R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 10974-10983. (c) Gu, S.; Chen, C.; Chen, W. J. Org. Chem. 2009, 74, 7203-7206. (d) Gou, F.-R.; Wang, X.-C.; Huo, P.-F.; Bi, H.-P.; Guan, Z.H.; Liang, Y.-M. Org. Lett. 2009, 11, 5726-5729. (e) Huang, C.; Ghavtadze, N.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 17630-17633. (f) Huang, C.; Ghavtadze, N.; Godoi, B.; Gevorgyan, V. Chem. Eur. J. 2012, 18, 9789-9792. (g) Sun, P; Li, W. J. Org. Chem. 2012, 77, 8362-8366. (h) Banerjee, A.; Bera, A.; Guin, S.; Rout, S. K.; Patel, B. K. Tetrahedron 2013, 69, 2175-2183. (i) Roane, J.; Daugulis, O. Org. Lett. 2013, 15, 5842-5845. (j) Wang, Y.; Gulevich, A. V.; Gevorgyan, V. Chem. Eur. J. 2013, 19, 15836-15840. (k) Rit, R. K.; Yadav, M. R.; Sahoo, A. K. Org. Lett. 2014, 16, 968-971. (g) Yang, X.; Sun, Y.; Chen, Z.; Rao, Y. Adv. Synth. Catal. 2014, 356, 1625-1630. (12) For selected examples of transition metal-catalyzed C-H halogenation of arenes, see: (a) Wan, X.; Ma, Z; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 7416-7417. (b) Mei, T.-S.;
Giri, R. ; Maugel, N.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 5215-5219. (c) Kakiuchi, F.; Kochi, T.; Mutsutani, H.; Kobayashi, N.; Urano, S.; Sato, M.; Nishiyama, S. ; Tanabe, T. J. Am. Chem. Soc. 2009, 131, 11310-11311. (d) Bedford, R. B.; Haddow, M. F.; Mitchell, C. J.; Webster, R. L. Angew. Chem., Int. Ed. 2011, 50, 5524-5527. (e) N. Schröder, J. Wencel-Delord, F. Glorius, J. Am. Chem. Soc. 2012, 134, 8298-8301. (f) Ma, X. -T.; Tian, S.; K. Adv. Synth. Catal. 2013, 355, 337-340. (g) Wang, X.-C.; Hu, Y.; Bonacorsi, S.; Hong, Y.; Burrell, R.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 10326-10329. (h) Lu, C.; Zhang, S.-Y.; He, G.; Nack, W. A.; Chen, G. Tetrahedron 2014, 70, 4197-4203. (i) Wang, L.; Ackermann, L. Chem. Commun. 2014, 50, 1083-1085. (j) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006, 8, 2523-2526. (13) For PyrDipSi directed C-H functionalization reactions, see: (a) Gulevich, A. V.; Melkonyan, F. S.; Sarkar, D.; Gevorgyan, V. J. Am. Chem. Soc. 2012, 134, 5528-5531. (b) Sarkar, D.; Melkonyan, F. S.; Gulevich, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2013, 52, 10800-10804. (14) For applications of resorcinol derivatives, see: (a) Durairaj, R. B. Resorcinol: Chemistry, Technology, And Applications; Springer: Berlin, 2005. (b) Dressler, H. Resorcinol: Its Uses and Derivatives: Plenum Press, New York, 1994. Importance of meta-halophenols, see: (a) Tyman, J. H. P. Synthetic and Natural Phenols; Elsevier: New York, 1996. (b) Ullmann’s Encyclopedia of Industrial Chemistry, 5th ed., Wiley-VCH, Weinheim, 1998. (c) Hartung, C. G.; Snieckus V. Modern Arene Chemistry (Ed.: D. Astruc), Wiley-VCH, Weinheim, 2002. (15) For use of thiazole and N-methylimidazole, as directing groups for C−H trifluoromethylation, see: Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648-3649. (16) For selected examples of pyrimidine as a directing group for C−H activation, see: (a) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904-11905. (b) Gu, S.; Chen, C.; Chen, W. J. Org. Chem. 2009, 74, 7203-7206. (c) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 1027210274. (d) Song, B.; Zheng, X.; Mo, J.; Xu, B. Adv. Synth. Catal. 2010, 352, 329-325. (e) Zheng, X.; Song, B.; Xu, B. Eur. J. Org. Chem. 2010, 43764380. (f) Ackermann, L.; Lygin, A. V. Org. Lett. 2011, 13, 3332-3335. (g) Chen, J.; Pang, Q.; Sun, Y.; Li, X. J. Org. Chem. 2011, 76, 3523-3526. (h) Ackermann, L.; Lygin, A. V. Org. Lett. 2012, 14, 764-767. (i) Feng, C.-G.; Ye, M.; Xiao, K.-J.; Li, S.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 9322-9325. (j) hirunavukkarasu, V. S.; Raghuvanshi, K.; Ackermann, L. Org. Lett. 2013, 15, 3286-3289. (k) Xie, F.; Qi, Z.; Li, X. Angew. Chem., Int. Ed. 2013, 52, 11862-11866. (l) Hong, X.; Wang, H.; Qian, G.; Tan, Q.; Xu, B. J. Org. Chem. 2014, 79, 3228-3237. (m) Lu, M.-Z.; Lu, P.; Xu, Y.-H.; Loh, T.-P. Org. Lett. 2014, 16, 2614-2617. (n) Xu, C.; Shen, Q. Org. Lett. 2014, 16, 2046-2049. (17) For cross-coupling of aryl iodides and silanes, see ref 10c and references therein. For optimization of the arylation reaction and preparation of 1, see Supporting Information. (18) For selective deprotection of acetyl group in presence of pivaloyl group, see Supporting Information. (19) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211-1214. (20) For reviews on aryne chemistry, see: (a) Wenk, H. H.; Winkler, M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502-528. (b) Sanz, R. Org. Prep. and Proced. Int. 2008, 40, 215-291. (21) (a) Hévenin, M.; Thoret, S.; Grellier, P.; Dubois, J. Bioorg. Med. Chem. 2013, 21, 4885-4892. (b) Masubuchi, M.; Ebiike, H.; Kawasaki, K.i.; Sogabe, S.; Morikami, K.; Shiratori, Y.; Tsujii, S.; Fujii, T.; Sakata, K.; Hayase, M.; Shindoh, H.; Aoki, Y.; Ohtsuka, T.; Shimma, N. Bioorg. Med. Chem. 2003, 11, 4463-4478. (c) Ryu, C.-K.; Song, A. L.; Lee, J. Y.; Hong, J. A.; Yoon, J. H.; Kim, A. Bioorg. Med. Chem. Lett. 2010, 20, 6777-6986. (22) Sanz, R.; Castroviejo, M. P.; Fernández, Y.; Fañanás, F. J. J. Org. Chem 2005, 70, 6548-6551. (23) For inefficient oxygenation reaction of o-Br-PyDipSi-Ar, see Supporting Information. (24) For selected reviews, see: (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881-1886. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320-330.
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TOC Graphics OR2
I R1 = Piv, Ac R2 = Piv
PyrDipSi Cl unsymmetrical C-H halogenation
i-Pr i-Pr N Si N
OH
MeO
Iterative C-H oxygenation OMe
Me
OR2 E
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Symmetrical/unsymmetrical C-H oxygenation
PyrDipSi-Ar
I
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E = H, D, I, Ar
Hal PyrDipSi
Hal E
R1O unsymmetrical C-H halogenation/oxygenation Hal = I, Br, Cl R1 = Piv, Ac
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E R1O
