Twofold unsymmetrical C-H functionalization of PyrDipSi-substituted arenes: A general method for the synthesis of substituted meta-halophenols

Article abstract of DOI:10.1002/anie.201304884

And the world is your oyster Sequential halogenation/oxygenation reactions of 2-diisopropylsilylpyrimidine-substituted arenes provide a general and efficient synthesis of substituted meta-halophenols from simple aryl iodides (see scheme; Piv=pivaloyl). The products are poised to undergo diverse C-C, C-N, and C-O bond-forming reactions that enable the transformation of their framework and the introduction of valuable functionalities. Copyright

Full text of DOI:10.1002/anie.201304884

Angewandte
Chemie
DOI: 10.1002/anie.201304884
ꢀ
C H Activation
ꢀ
Twofold Unsymmetrical C H Functionalization of PyrDipSi-
Substituted Arenes: A General Method for the Synthesis of Substituted
meta-Halophenols**
Dhruba Sarkar, Ferdinand S. Melkonyan, Anton V. Gulevich, and Vladimir Gevorgyan*
ꢀ
Transition-metal-catalyzed heteroatom-directed C H func-
tionalization of arenes has emerged as a powerful and
environmentally benign tool for carbon–carbon and carbon–
heteroatom bond formation.[1] Moreover, twofold aromatic
would provide straightforward access to a variety of densely
functionalized multisubstituted arenes. Herein, we report an
ꢀ
unprecedented twofold unsymmetrical C H functionalization
of arenes that enables the introduction of two different
functional groups (OR and Hal).[4] This concise synthesis of
substituted meta-halophenols from aryl iodides proceeds by
ꢀ
C H functionalization is synthetically even more appealing as
it allows for the introduction of two substituents in a one-pot
or a two-step procedure. However, twofold C H functional-
ization has been used only for the introduction of the same
(e.g. alkenyl/alkenyl, aryl/aryl, OR/OR, Hal/Hal; Sche-
me 1A, I)[2] or similar functionalities (e.g. alkenyl/alkenyl’,
OAc/OPiv (Piv = pivaloyl), Cl/Br; Scheme 1A, II).[3] To the
sequential C H halogenation/oxygenation reactions[5,6]
ꢀ
ꢀ
directed by
a
removable/functionalizable[7,8] pyrimidine-
based silicon-tethered directing group (Scheme 1B).
Recently, we developed a traceless/modifiable 2-diisopro-
pylsilylpyrimidine (PyrDipSi) directing group for the selective
mono- and bisoxygenation of arenes.[3c] Notably, this oxygen-
ation reaction tolerated an ortho substituent, which makes
this transformation potentially compatible with other ortho
ꢀ
C H functionalization reactions. We therefore considered the
ꢀ
development of a twofold unnsymmetrical C H functional-
ization process with this directing group. A halogenation/
oxygenation sequence was chosen, as it would provide access
to valuable meta-halophenols.[9]
ꢀ
First, we optimized the palladium-catalyzed C H halo-
genation of PyrDipSi-substituted benzene (1a). The bromi-
nation of 1a with N-bromosuccinimide (NBS; 2 equiv)
afforded the desired product 2a in promising 35% yield
(Table 1, entry 1). Upon screening additives, we discovered
that PhI(OAc)2 facilitates the bromination reaction (Table 1,
Table 1: Optimization of the halogenation reactions.
ꢀ
Scheme 1. Twofold C H functionalization adjacent to a directing group
(DG). A) I,II) Previously reported bisfunctionalization with two identi-
cal or similar groups; III) unsymmetrical bisfunctionalization. B) The
approach developed in this study for unsymmetrical bisfunctionaliza-
tion.
Entry Hal Oxidant (equiv) Additive (equiv) T [8C] Yield [%][a,b]
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
I
NBS (2.0)
NBS (2.0)
NBS (2.0)
NBS (2.0)
NBS (2.0)
NBS (1.25)
NBS (1.2)
NBS (1.2)
NCS (2.0)
NCS (2.0)
NCS (5.0)
NIS (1.5)
–
60
60
60
60
60
60
60
50
60
35
trace
43
40
70
75
85
85
– (30)
– (56)
75 (90)
94
ꢀ
best of our knowledge, unsymmetrical C H functionalization
with the introduction of two different functional groups is
unknown (Scheme 1A, III). If developed, this methodology
BQ (1.0)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.0)
PhI(OAc)2 (0.5)
PhI(OAc)2 (0.3)
PhI(OAc)2 (0.1)
PhI(OAc)2 (0.1)
PhI(OAc)2 (0.1)
PhI(OAc)2 (1.0) 100
PhI(OAc)2 (1.3)
–
[*] D. Sarkar, Dr. F. S. Melkonyan, Dr. A. V. Gulevich,
Prof. Dr. V. Gevorgyan
9[c]
10[c]
11[c]
12[d]
Department of Chemistry, University of Illinois at Chicago
845 W. Taylor Street, Rm 4500, Chicago, IL 60607 (USA)
E-mail: vlad@uic.edu
100
60
Homepage: http://www.chem.uic.edu/vggroup
[**] The support of the NIH (GM-64444) is gratefully acknowledged.
[a] Yield of the isolated product. [b] Yields determined by GC are given in
parentheses. [c] The reaction was performed in EtCN (0.05m solution).
[d] The reaction was performed with Pd(OAc)2 (5 mol%). BQ=benzo-
quinone, DCE=1,2-dichloroethane.
PyrDipSi=2-diisopropylsilylpyrimidine.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304884.
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entries 3 and 4). Finally, it was found that the reaction
required only a catalytic amount of PhI(OAc)2 (10 mol%) for
the production of 2a in high yield (Table 1, entry 8).[10] On the
PyrDipSi-substituted arenes 1 bearing electron-neutral (Me,
tBu, Ph) and electron-donating substituents (OMe) were
efficiently converted into ortho-bromo derivatives 2b–e. A
subsequent pivaloyloxylation furnished the corresponding
products 3b–e in good yields (Table 2, entries 3–6). Substrates
possessing electron-withdrawing groups, namely, CO2Me,
ꢀ
other hand, the C H chlorination of 1a required a super-
stoichiometric amount of PhI(OAc)2 (1.3 equiv), as well as
excess N-chlorosuccinimide (NCS) and elevated temper-
atures (EtCN, 1008C; Table 1, entry 11). The iodination of
1a with N-iodosuccinimide (NIS; 1.2 equiv) afforded the
iodination product 2p in 94% yield without any additive
(Table 1, entry 12). Control experiments without Pd(OAc)2
did not provide any products.
ꢀ
COMe, and CONiPr2, smoothly underwent the C H bromi-
nation reaction (to form 2 f–h) as well as a further pivaloyl-
oxylation reaction to produce the desired products 3 f–h
(Table 2, entries 7–9). An electron-deficient CF3-substituted
arene was converted into the brominated product 2i, which
then was oxygenated to form 3i in moderate yield (Table 2,
entry 10). Notably, halo-substituted substrates underwent
efficient bromination (to form 2j–l) as well as a pivaloyl-
oxylation reaction to produce the valuable dihalophenol
derivatives 3j–l (Table 2, entries 11–13). This halogenation/
oxygenation reaction sequence was also successfully utilized
for the synthesis of meta-chloro- and meta-iodophenol
Next, we attempted to use the newly found conditions for
ꢀ
ꢀ
the C H bromination process in combination with the C H
oxygenation reaction[3c] for a two-step synthesis[11] of meta-
bromophenol derivatives (Table 2). We found that compound
1a could be converted efficiently into bromophenol deriva-
tives 3a and 3aa in a two-step sequential bromination/
oxygenation procedure (Table 2, entries 1 and 2). Likewise,
Table 2: Sequential halogenation/oxygenation of PyrDipSi-substituted arenes.[a]
Entry
1
2, yield [%][b]
3, yield [%][b]
Entry
2, yield [%][b]
3, yield [%][b]
2a, 85 (82)[c]
3a, 72 (79)[c] 10
2i, 58
3i, 51
2
3
4
5
6
7
8
2a, 85
2b, 90
2c, 76
2d, 84
2e, 88
2 f, 81
2g, 74
3aa, 71
11
12
13
14
15
16
17
2j, 77
3j, 69
3b, 78
3c, 73
3d, 69
3e, 75
3 f, 72
3g, 59
2k, 78
3k, 72
3l, 68
2l, 74
2m, 75[d]
2n, 64[d]
2o, 59[d]
2p, 94[e]
3m, 65
3n, 84
3o, 61
3p, 55[f]
9
2h, 72
3h, 74
18
2q, 80[e]
3q, 40[f]
[a] The reaction was carried out on a 0.4 mmol scale (see the Supporting Information for experimental details). [b] Yield of the isolated product. [c] The
yield for a reaction carried out on a 5 mmol scale is given in parentheses. [d] The reaction was performed in EtCN (0.05m solution) with NCS (5 equiv)
and PhI(OAc)2 (1.3 equiv) at 1008C. [e] The reaction was performed without PhI(OAc)2, with Pd(OAc)2 (5 mol%) and NIS (1.5 equiv) at 608C. [f] The
reaction was performed with PhI(OPiv)2 (2 equiv).
2
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ꢀ
derivatives. Thus, the C H chlorination reaction afforded 2-
chloro derivatives 2m–o in slightly diminished yields, whereas
block 3 (Scheme 2B). Clearly, the PyrDipSi group can be
selectively removed to provide pivaloyl-protected meta-
bromophenols 4. Similarly, it can be replaced with a deuterium
atom to provide deuterated analogues 5. The directing group
can be readily substituted by iodide to produce valuable
polyhalophenol derivatives 6 containing up to four different
sites for cross-coupling reactions and thus modular function-
alization of the benzene ring. Compound 6a underwent
ꢀ
the C H oxygenation reaction produced meta-chlorophenols
3m–o in good yields (Table 2, entries 14–16). In contrast, C
ꢀ
H iodination proceeded uneventfully to produce the iodoar-
enes 2p,q in excellent yields, whereas the subsequent
pivaloyloxylation reaction was less efficient (Table 2,
entries 17 and 18). The practical usefulness of the method
was shown by scaling up the reaction: When 1a was subjected
to bromination and pivaloyloxylation on a 5 mmol scale, 3a
was formed in good yield. Importantly, both the PyrDipSi and
the pivaloyl group can be cleaved in the obtained products 3
under mild conditions in nearly quantitative yield.[12] Thus,
our newly developed two-step protocol for the synthesis of
meta-halophenol derivatives features broad substrate scope,
high functional-group tolerance, and mild reaction conditions.
Traditional approaches to meta-halophenols[9] are mostly
based on electrophilic aromatic substitution[13] or cycloaddi-
tion reactions.[14] However, these methods require multistep
procedures and harsh conditions and suffer from limited
scope and low selectivity. Substituted meta-halophenols can
also be prepared from 1,3-disubstituted arenes by meta-
selective iridium-catalyzed C H borylation/oxidation or C H
borylation/halogenation protocols.[15] Our method can serve
as a general and efficient alternative to all these methods, as it
enables the synthesis of functionalized meta-halophenols
from a monosubstituted arene (aryl iodide).[16] Furthermore,
our approach utilizes a removable/modifiable[7] directing
group, which offers an additional handle for further function-
alization of the obtained
ꢀ
a selective Sonogashira cross-coupling reaction at the C I
ꢀ
bond rather than at the less sterically hindered C Br site to
produce tolane derivative 7.[20] The pyrimidyl group in 3 was
replaced with fluoride to furnish the polyfunctional fluorosi-
lane derivative 8, which can be used for orthogonal cross-
coupling reactions. For example, compound 8 underwent an
ꢀ
efficient Hiyama–Denmark cross-coupling reaction at the C
Si bond with phenyl iodide to produce the biphenyl-contain-
ꢀ
ing building block 9. On the other hand, the C Br bond of 8
can be utilized in Suzuki–Miyaura as well as Sonogashira
cross-coupling reactions, as demonstrated by the synthesis of
derivatives 10 and 11, respectively.
Finally, we illustrated the use of the 3-halo-2-silaphenol
scaffold in the synthesis of fused systems (Scheme 3). Ready
substitution of the silyl group by iodide to give 12, followed by
oxygen deprotection, furnished the 2,3-dihalophenol 13 in
excellent yield. Compound 13 underwent a cascade Sonoga-
shira coupling/5-endo-dig cyclization reaction with phenyl-
acetylene to produce the 4-bromobenzofuran 14 in 90%
yield.[21] Notably, our newly developed methodology provides
general access to substituted 4-halobenzofurans.[21] Building
ꢀ
ꢀ
meta-halophenols.
The usefulness of the
ꢀ
developed twofold C H
functionalization method is
highlighted by the concise
synthesis polyfunctionalized
arenes. In fact, this method
can be used to transform
readily available aryl iodides
into a unique 3-halo-2-sila-
phenol scaffold 3’ (Sche-
me 2A). This multifunction-
alized arene can potentially
ꢀ
ꢀ
undergo diverse C C, C N,
ꢀ
and C O bond-forming
ꢀ
reactions at the C Br site
through cross-coupling, ipso
substitution or Hiyama–
Denmark
cross-coupling
ꢀ
reactions at the C Si site,
ꢀ
C C
bond
formation
through cross-coupling reac-
tions at the C OPiv site,
[17]
ꢀ
Scheme 2. A) Transformation of a simple aryl iodide into a polyfunctional arene building block 3’. B) Trans-
formations of arenes 3: a) HF, THF, 08C!RT, then AgF (2.5 equiv), H2O in THF, room temperature; b) HF,
THF, 08C!RT, then AgF (2.5 equiv), D2O in THF, room temperature; c) HF, THF, 08C!RT, then AgF (2.5–
3.0 equiv), NIS (3–4 equiv), THF, RT!708C; d) phenylacetylene (1.5 equiv), [PdCl2(PPh3)2] (3 mol%), CuI
(5 mol%), DMF, Et2NH (1.5 equiv), 508C; e) HF, THF, 08C!RT; f) PhI (1.5 equiv), [Pd(PPh3)4] (5 mol%),
Ag2O (1.1 equiv), THF, 608C; g) 4-MeOC6H4B(OH)2 (1.5 equiv), [Pd2(dba)3] (5 mol%), PtBu3 (10 mol%),
K3PO4 (2 equiv), dioxane, 908C; h) phenylacetylene (1.2 equiv), [Pd2(dba)3] (2.5 mol%), PtBu3 (10 mol%),
and OPiv-directed ortho
metalation (DoM)[18] or C
ꢀ
H activation reactions.[19]
Accordingly,
explored selected transfor-
we
mations of this building Et3N, room temperature. dba=dibenzylideneacetone, DMF=N,N-dimethylformamide.
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Mo, Y. Zhu, Z. Shen, Org. Biomol. Chem. 2013, 11, 2756; j) X.
Zhao, C. S. Yeung, V. M. Dong, J. Am. Chem. Soc. 2010, 132,
5837; k) H. Wang, N. Schrçder, F. Glorius, Angew. Chem. 2013,
125, 5495; Angew. Chem. Int. Ed. 2013, 52, 5386.
[3] For examples of unsymmetrical bisfunctionalization with the
introduction of similar functionalities, see: a) N. Umeda, K.
Hirano, T. Satoh, M. Miura, J. Org. Chem. 2009, 74, 7094;
b) K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. 2010, 122,
6305; Angew. Chem. Int. Ed. 2010, 49, 6169; c) A. V. Gulevich,
F. S. Melkonyan, D. Sarkar, V. Gevorgyan, J. Am. Chem. Soc.
2012, 134, 5528; d) C. Cong, J. You, G. Gao, J. Lan, Chem.
Commun. 2013, 49, 662; e) X. Sun, G. Shan, Y. Sun, Y. Rao,
Angew. Chem. 2013, 125, 4536; Angew. Chem. Int. Ed. 2013, 52,
4440.
[4] During the preparation of this manuscript, examples of unsym-
metrical bisfunctionalization with the introduction of two differ-
ent functionalities were reported: a) W. Hengbin, G. Li, K. M.
Engle, J.-Q. Yu, H. M. L. Davies, J. Am. Chem. Soc. 2013, 135,
6774; b) B. R. Rosen, L. R. Simke, P. S. Thuy-Boun, D. D. Dixon,
J.-Q. Yu, P. S. Baran, Angew. Chem. 2013, 125, 7458; Angew.
Chem. Int. Ed. 2013, 52, 7317.
Scheme 3. Synthesis of fused heterocycles: a) HF, THF, 08C!RT, then
AgF (3 equiv), NIS (4 equiv), THF, RT!708C; b) Cs2CO3 (1 equiv),
MeOH, 08C!RT; c) phenylacetylene (1.1 equiv), [PdCl2(PPh3)2]
(5 mol%), CuI (10 mol%), DMF, piperidine (1 equiv), 608C; d) Cs2CO3
(10 mol%), MeOH, 08C!RT, then Tf2O (1.1 equiv), EtNiPr2 (2 equiv),
CH2Cl2, room temperature, then HF, THF, 08C!RT; e) CsF (3 equiv),
CH3CN, then furan (5 equiv), room temperature. Tf=trifluoromethane-
sulfonyl.
ꢀ
[5] For selected examples of the transition-metal-catalyzed C H
ꢀ
ꢀ
block 3aa contains the C Si bond next to the C O bond on
the benzene ring, and this arrangement can be used for the
generation of bromobenzyne 16. Thus, 3aa was readily
converted into the benzyne precursor 15. The treatment of
15 with CsF produced bromobenzyne 16, which was trapped
through a [4+2] cycloaddition reaction with furan to produce
5-bromo-1,4-dihydroepoxynaphthalene (17).[22] Therefore,
this method is also useful for the generation of halo-
substituted benzynes for broad application in synthesis.
In conclusion, we have developed a general and efficient
halogenation of arenes, see Ref. [2a,d] and: a) X. Wan, Z. Ma, B.
Li, K. Zhang, S. Cao, S. Zhang, Z. Shi, J. Am. Chem. Soc. 2006,
128, 7416; b) T.-S. Mei, R. Giri, N. Maugel, J.-Q. Yu, Angew.
Chem. 2008, 120, 5293; Angew. Chem. Int. Ed. 2008, 47, 5215;
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D.-H. Wang, J.-Q. Yu, Org. Lett. 2010, 12, 3140; e) F. Kakiuchi, T.
Kochi, H. Mutsutani, N. Kobayashi, S. Urano, M. Sato, S.
Nishiyama, T. Tanabe, J. Am. Chem. Soc. 2009, 131, 11310; f) Z.
Shen, Y. Lu, R. Wang, X. Qiao, Synlett 2011, 1038; g) R. B.
Bedford, M. F. Haddow, C. J. Mitchell, R. L. Webster, Angew.
Chem. 2011, 123, 5638; Angew. Chem. Int. Ed. 2011, 50, 5524;
h) N. Schrçder, J. Wencel-Delord, F. Glorius, J. Am. Chem. Soc.
2012, 134, 8298; i) X. T. Ma, S.-K. Tian, Adv. Synth. Catal. 2013,
355, 337; j) A. S. Dudnik, N. Chernyak, C. Huang, V. Gevorgyan,
Angew. Chem. 2010, 122, 8911; Angew. Chem. Int. Ed. 2010, 49,
8729; k) C. Huang, N. Chernyak, A. S. Dudnik, V. Gevorgyan,
Adv. Synth. Catal. 2011, 353, 1285.
ꢀ
twofold unsymmetrical C H functionalization of arenes,
namely, a C H halogenation/oxygenation reaction, with
ꢀ
a PyrDipSi directing group. This protocol enables the efficient
preparation of substituted meta-halophenols as well as
polyfunctionalized arenes from simple aryl iodides. The
obtained molecules were shown to undergo a variety of
synthetically useful transformations to produce diversely
functionalized aromatic compounds, such as iodoarenes,
biaryl compounds, tolanes, and fused heterocycles.
ꢀ
[6] For selected examples of the C H oxygenation of arenes, see:
a) A. R. Dick, J. W. Kampf, M. S. Sanford, J. Am. Chem. Soc.
2005, 127, 12790; b) D. Kalyani, M. S. Sanford, Org. Lett. 2005, 7,
4149; c) L. V. Desai, H. A. Malik, M. S. Sanford, Org. Lett. 2006,
8, 1141; d) G.-W. Wang, T.-T. Yuan, X.-L. Wu, J. Org. Chem.
2008, 73, 4717; e) J. M. Racowski, R. Dick, M. S. Sanford, J. Am.
Chem. Soc. 2009, 131, 10974; f) K. J. Stowers, M. S. Sanford, Org.
Lett. 2009, 11, 4584; g) S. Gu, C. Chen, W. Chen, J. Org. Chem.
2009, 74, 7203; h) F.-R. Gou, X.-C. Wang, P.-F. Huo, H.-P. Bi, Z.-
H. Guan, Y.-M. Liang, Org. Lett. 2009, 11, 5726; i) N. Chernyak,
A. S. Dudnik, C. Huang, V. Gevorgyan, J. Am. Chem. Soc. 2010,
132, 8270; j) C. Huang, N. Ghavtadze, B. Chattopadhyay, V.
Gevorgyan, J. Am. Chem. Soc. 2011, 133, 17630; k) C. Huang, N.
Ghavtadze, B. Godoi, V. Gevorgyan, Chem. Eur. J. 2012, 18,
9789; l) P. Sun, W. Li, J. Org. Chem. 2012, 77, 8362; and Ref. [2f].
[7] For recent reviews on removable/modifiable directing groups,
see: a) S. Bracegirdle, E. A. Anderson, Chem. Soc. Rev. 2010, 39,
4114; b) G. Rousseau, B. Breit, Angew. Chem. 2011, 123, 2498;
Angew. Chem. Int. Ed. 2011, 50, 2450; c) Y. Huang, C. Wang,
Synlett 2013, 24, 145.
[8] For the use of pyridine-based silicon-tethered directing groups in
Heck reactions, see: a) K. Itami, K. Mitsudo, T. Nokami, T.
Kamei, T. Koike, J.-i. Yoshida, J. Organomet. Chem. 2002, 653,
105.
[9] For the importance of meta-halophenols, see: a) J. H. P. Tyman,
Synthetic and Natural Phenols, Elsevier, New York, 1996;
b) Ullmannꢀs Encyclopedia of Industrial Chemistry, 5th ed.,
Wiley-VCH, Weinheim, 1998; c) C. G. Hartung, V. Snieckus,
Received: June 6, 2013
Published online: && &&, &&&&
ꢀ
Keywords: C H activation · cross-coupling · halogenation ·
.
oxygenation · palladium
ꢀ
[1] For a review on the transition-metal-catalyzed C H activation of
ꢀ
arenes, see: C H Activation, Topics in Current Chemistry,
Vol. 292 (Eds.: J.-Q. Yu, Z. Shi), Springer, Berlin, 2010.
[2] For selected examples of the transition-metal-catalyzed sym-
metrical bisfunctionalization of arenes, see: a) A. R. Dick, K. L.
Hull, M. S. Sanford, J. Am. Chem. Soc. 2004, 126, 2300; b) O.
Daugulis, Z. G. Zaitsev, Angew. Chem. 2005, 117, 4114; Angew.
Chem. Int. Ed. 2005, 44, 4046; c) L. Ackermann, Org. Lett. 2005,
7, 3123; d) D. Kalyani, A. R. Dick, W. Q. Anani, M. S. Sanford,
Tetrahedron 2006, 62, 11483; e) E. W. Kalberer, S. R. Whitfield,
M. S. Sanford, J. Mol. Catal. A 2006, 251, 108; f) L. V. Desai, K. J.
Stowers, M. S. Sanford, J. Am. Chem. Soc. 2008, 130, 13285; g) P.
Arockiam, V. Poirier, C. Fischmeister, C. Bruneau, P. H.
Dixneuf, Green Chem. 2009, 11, 1871; h) X. Zheng, B. Song, G.
Li, B. Liu, H. Deng, B. Xu, Tetrahedron Lett. 2010, 51, 6641; i) S.
4
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Chemie
Modern Arene Chemistry (Ed.: D. Astruc), Wiley-VCH, Wein-
heim, 2002.
Holmes, M. R. Smith III, J. Am. Chem. Soc. 2003, 125, 7792;
b) J. M. Murphy, X. Liao, J. F. Hartwig, J. Am. Chem. Soc. 2007,
129, 15434; c) B. M. Partridge, J. F. Hartwig, Org. Lett. 2013, 15,
140.
ꢀ
[10] Although the exact role of PhI(OAc)2 in the C H halogenation
is currently unclear, it presumably helps to maintain the reactive
Pd species.
[16] For an example of the meta functionalization of phenol, see: H.-
X. Dai, G. Li, X.-G. Zhang, A. F. Stepan, J.-Q. Yu, J. Am. Chem.
Soc. 2013, 135, 7567.
[17] For examples of cross-coupling reactions of aryl pivalates, see:
a) K. W. Quasdorf, X. Tian, N. K. Garg, J. Am. Chem. Soc. 2008,
130, 14422; b) B.-T. Guan, Y. Wang, B.-J. Li, D.-G. Yu, Z.-J. Shi, J.
Am. Chem. Soc. 2008, 130, 14468; c) B.-J. Li, Y.-J. Li, X.-Y. Lu, J.
Liu, B.-T. Guan, Z.-J. Shi, Angew. Chem. 2008, 120, 10278;
Angew. Chem. Int. Ed. 2008, 47, 10124.
[11] Attempts at
a one-pot bromination/oxygenation reaction
sequence were not successful. We attribute this lack of success
to potential deactivation of the palladium catalyst by succin-
imide formed in the halogenation reaction.
[12] Compound 3a underwent smooth double deprotection to give
meta-bromophenol (3a’):
[18] For a general review on directed ortho metalation for the
synthesis of polysubstituted aromatic compounds, see: V.
Snieckus, Chem. Rev. 1990, 90, 879.
ꢀ
[19] For examples of pivalate-directed C H activation, see: a) B.
Xiao, Y. Fu, J. Xu, T.-J. Gong, J.-J. Dai, J. Yi, L. Liu, J. Am. Chem.
Soc. 2010, 132, 468; b) T. Gensch, M. Rçnnefahrt, R. Czerwonka,
A. Jꢀger, O. Kataeva, I. Bauer, H.-J. Knçlker, Chem. Eur. J. 2012,
18, 770.
[13] For an approach to meta-bromophenols based on electrophilic
substitution, see: C. F. Koelsch, J. Am. Chem. Soc. 1939, 61, 969.
[14] For a nonselective synthesis of substituted meta-halophenols by
cycloaddition chemistry, see: a) J. W. Patterson, J. Org. Chem.
1995, 60, 560; b) S. Choudhury, F. A. Khan, Eur. J. Org. Chem.
2010, 2954.
[20] R. Sanz, V. Guilarte, N. Garcꢁa, Org. Biomol. Chem. 2010, 8,
3860.
[21] R. Sanz, M. P. Castroviejo, Y. Fernꢂndez, F. J. FaÇanꢂs, J. Org.
Chem. 2005, 70, 6548.
[22] Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett. 1983, 1211.
[15] For the synthesis of substituted meta-bromophenols by iridium-
ꢀ
catalyzed C H activation, see: a) R. E. Maleczka, Jr., F. Shi, D.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
ꢀ
C H Activation
D. Sarkar, F. S. Melkonyan, A. V. Gulevich,
V. Gevorgyan*
&&&& — &&&&
ꢀ
Twofold Unsymmetrical C H
Functionalization of PyrDipSi-Substituted
Arenes: A General Method for the
Synthesis of Substituted meta-
Halophenols
And the world is your oyster… Sequential
halogenation/oxygenation reactions of 2-
diisopropylsilylpyrimidine-substituted
arenes provide a general and efficient
synthesis of substituted meta-halophe-
nols from simple aryl iodides (see
scheme; Piv=pivaloyl). The products are
ꢀ
ꢀ
poised to undergo diverse C C, C N, and
ꢀ
C O bond-forming reactions that enable
the transformation of their framework
and the introduction of valuable func-
tionalities.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!