A general strategy toward aromatic 1,2-ambiphilic synthons: Palladium-catalyzed ortho-halogenation of PyDipSi-arenes

Article abstract of DOI:10.1002/anie.201004426

A general and efficient strategy to synthesize 1,2-ambiphilic aromatic and heteroaromatic synthons from haloarenes has been developed. The method involves installation of the PyDipSi directing group, and subsequent palladium-catalyzed directed ortho-halogenation of aryl silanes (see scheme; Py=2-pyridyl). The usefulness of these 1,2-ambiphilic building blocks was shown in their participation as both nucleophilic aryl silane and electrophilic aryl iodide moieties.

Full text of DOI:10.1002/anie.201004426

Angewandte
Chemie
DOI: 10.1002/anie.201004426
À
C H Activation
A General Strategy Toward Aromatic 1,2-Ambiphilic Synthons:
Palladium-Catalyzed ortho-Halogenation of PyDipSi-Arenes**
Alexander S. Dudnik, Natalia Chernyak, Chunhui Huang, and Vladimir Gevorgyan*
Table 1: Optimization of ortho-halogenation reaction. X=halide.
Ambiphilic aromatic synthons—compounds possessing both
electrophilic and nucleophilic centers in the same molecule—
are important building blocks that are widely used for a
modular construction of complex molecules in organic syn-
thesis, medicinal chemistry, and materials science.[1] Tradi-
tionally, they are accessed through multistep syntheses. One
of the most efficient strategies toward 1,2-ambiphilic struc-
tures involves directed ortho-metalation (DOM) approach.[2]
Our research group has recently developed the palladium-
catalyzed directed ortho-acyloxylation of pyridyldiisopropyl-
Entry
Additive (equiv)
Hal
Solvent
T [8C]
Yield [%][a]
1
2
3
4
5
6
7
8
9
none
none
AcOH (50)
Cu(OAc)2 (1)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
Br
Br
Br
Br
Br
Br
Br
I
PrCN
PrCN
PrCN
PrCN
PrCN
PrCN
C2H4Cl2
C2H4Cl2
C2H4Cl2
80
100
80
100
80
100
60
65
50
65
15
trace
80
65
85
95
42
silyl (PyDipSi) arenes B[3] [Eq. (1)] based on a C H activation
À
process.[4] Most importantly, we have shown that the PyDipSi
directing group[5] could efficiently participate in a variety of
reactions as a nucleophilic entity. Because the acyloxy group
is known to serve as an electrophilic coupling partner,[6] the
o-acyloxylated PyDipSi-arenes can be formally considered as
1,2-ambiphiles. Taking into account the immense synthetic
potential of aryl halides as electrophilic reagents, we aimed at
the development of a general strategy for the synthesis of
ortho-halogenated aryl silanes C, which are much more
powerful 1,2-ambiphiles. Herein, we report the palladium-
catalyzed ortho-halogenation reaction of easily accessible
PyDipSi-arenes B into 1,2-ambiphiles C and their further
transformations to a variety of valuable building blocks.
Cl
65
[a] Yield determined by NMR spectroscopy.
mide) in PrCN at 808C afforded 50% of the desired product 2
(Table 1, entry 1; Hal = Br). Further increase of temperature
to 1008C led to a slight improvement of the reaction outcome
(Table 1, entry 2). Addition of 50 equivalents of acetic
acid[7a,b] resulted in significant decrease of the reaction yield
(Table 1, entry 3). The employment of a stoichiometric
amount of Cu(OAc)2 additive gave only traces of brominated
product (Table 1, entry 4). Remarkably, addition of 1.5 equiv-
alents of PhI(OAc)2 dramatically improved the reaction, and
provided the bromination product in 80% yield (Table 1,
entry 5). Performing the reaction at the elevated temperature
(1008C), however, gave a lower yield of 2 (Table 1, entry 6).
Gratifyingly, switching solvent to 1,2-dichloroethane allowed
for a better reaction yield (85%) at lower temperature (608C;
Table 1, entry 7). Employment of NIS (N-iodosuccinimide) as
a halogen source under these reaction conditions produced
iodinated aryl silane 2 in 95% yield (Table 1, entry 8;
Hal = I). On the other hand, employment of NCS
(N-chlorosuccinimide) gave the chlorinated product in a
moderate yield only (Table 1, entry 9; Hal = Cl).
First, we tested PyDipSi-arene 1a under a variety of
halogenation reaction conditions in the presence of 10 mol%
of Pd(OAc)2 (Table 1).[4a,7] Initially, the palladium-catalyzed
bromination with 2 equivalents of NBS (N-bromosuccini-
Next, the generality of the palladium-catalyzed
ortho-halogenation of PyDipSi-arenes 1 was examined. The
iodination reaction with NIS in the presence of 1.5 equiv-
alents of PhI(OAc)2 was studied first. We found this trans-
formation to be efficient for a wide range of substrates, which
allowed for the synthesis of monoiodinated aryl silanes
2a–w in good to excellent yields (Scheme 1). It was found
that a variety of groups, including OMe (2b, 2k), F (2d, 2n),
Cl (2e), Br (2 f, 2l), ester (2g), and amide (2h) were perfectly
tolerated under the halogenation reaction conditions.
Iodination of para-substituted aryl silanes possessing both
[*] A. S. Dudnik, N. Chernyak, C. Huang, Prof. V. Gevorgyan
Department of Chemistry
University of Illinois at Chicago
845 W Taylor St, Rm 4500, Chicago, IL 60607 (USA)
Fax: (+1)312-355-0836
E-mail: vlad@uic.edu
Homepage: http://www.chem.uic.edu/vggroup
[**] The support of the NIH (GM-64444) and of the NSF (CHE-0710749)
is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004426.
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Scheme 1. Palladium-catalyzed ortho-halogenation of aryl silanes. [a] Yield of isolated product. [b] See Supporting Information for experimental
details. [c] Reaction was performed in PrCN at 1008C. [d] Reaction was performed without PhI(OAc)2 and with 1 equivalent of NIS. Boc=tert-
butoxycarbonyl.
electron-donating (2b) and electron-withdrawing (2d–h)
substituents proceeded with equal efficiency. meta-Substi-
tuted substrates displayed excellent site selectivity in the
iodination reaction, and provided monoiodinated compounds
as single regioisomers (2i–l). In addition, ortho-iodination of
m-, p-disubstituted aryl silanes (2m,n), and 2-naphthyl
derivative (2o) occurred uneventfully and furnished the
desired products as sole regioisomers in high yields. Next,
the bromination reaction of 1 allowed for efficient synthesis of
o-bromo aryl silanes 2p–r. Notably, chlorination of electron-
rich aryl silane, possessing an OMe group para to the
Scheme 2. Transformations of the PyDipSi group in haloarene deriva-
tives. Reagents and conditions: a) AgF (4 equiv), H2O (6 equiv), THF,
functionalization site, was found to be more efficient than
that of electron-neutral 1a (Table 1, entry 9), thus producing
chloro-derivative 2s in 69% yield. Finally, PyDipSi deriva-
tives of various heterocycles, such as benzofuran (2t),
RT, 12 h; b) AgF (4 equiv), NIS (4 equiv), THF, RT, 12 h; c) 1. BCl3
o
(4.4 equiv), DCM, 0 C, RT, 6 h; 2. 30 wt% H2O2/3 wt% NaOH
o
(excess), H2O, RT, 12 h; d) 1. BCl3 (4.4 equiv), DCM, 0 C, RT, 6 h;
carbazole (2u), indole (2v), and benzoxazole (2w), were
monoiodinated in good yields. We find these results remark-
able, as 6-halo derivatives of most of these heterocycles are
not readily available and require multistep preparation. These
derivatives now can be accessed from the 5-haloprecursors of
the corresponding PyDipSi-heterocycles, which are either
commercially available or can be easily synthesized in one
step.
Naturally, after the development of efficient palladium-
catalyzed halogenation of aryl silanes, we investigated
possible transformations of the PyDipSi directing group
(Scheme 2).[8] First, the reaction of 2c with AgF/H2O (2:3)
in THF resulted in efficient removal of the directing group,
thus affording m-iodobiphenyl (6) in 97% yield.[9] Interest-
2. pinacol (excess), Et3N/DCM (1:1), RT, 12 h. THF=tetrahydrofuran.
ingly, the overall three-step transformation of p-bromobi-
phenyl into m-iodobiphenyl constitutes an example of a
formal Finkelstein/“1,2-halogen dance” reaction. Next, the
iododesilylation reaction of chlorobromoaryl silane 2e with
NIS in the presence of AgF in THF allowed for efficient
preparation of 1-cloro-3-bromo-4-iodobenzene (3), which is a
synthetically useful and versatile building block for modular
functionalization of the benzene ring. Furthermore, iodoaryl
silane 2i was efficiently converted into o-iodoaryl boronate
4,[10] which is another powerful 1,2-ambiphile, in 87% yield by
a one-pot sequence involving borodesilylation with BCl3, and
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subsequent protection with pinacol.[11,12] Furthermore, boro-
desilylation of 2i and subsequent oxidation with H2O2/NaOH
afforded o-iodophenol 5 in 80% yield.
triflates are known to efficiently generate benzynes in the
presence of TBAF,[20,21] we decided to convert the iodide
functionality in PyDipSi-arenes 2 into a better leaving
iodonium group. Accordingly, substrate 2e, after exchange
of the pyridine group to fluoride, was smoothly converted into
Further utility of o-halogenated PyDipSi-arene deriva-
tives was demonstrated by a convergent synthesis of unsym-
metrically substituted benzo[b]silole 10 and dibenzosilole 15
(Scheme 3). First, treatment of 2i with HF at room temper-
ature led to selective substitution of the pyridine group with
fluoride,[13] thus providing fluorosilane 7 in excellent yield.
Next, o-iodoaryl fluorosilane 7 was alkynylated with potas-
sium phenylethynyltrifluoroborate under Suzuki reaction
conditions[14] and produced 8 in 66% yield. Alternatively,
alkynylated aryl silane 8 can be accessed from 2i through a
sequence involving Sonogashira reaction[15] with phenylace-
tylene and subsequent substitution of the pyridine group with
fluoride. A subsequent reduction of silylfluoride 8 with
LiAlH4 furnished silylhydride 9. 5-Endo-dig cyclization of
the latter in the presence of KH in DME[16] provided 10 in
72% yield. En route to dibenzosilole derivative 15, o-iodoaryl
the
corresponding
iodonium
tetrafluoroborate
16
(Scheme 4).[22] Treatment of the latter with TBAF in CH2Cl2
allowed for the efficient generation of benzyne 17, trapping of
which with furan provided
Scheme 4. Conversion of PyDipSi-iodoarenes into benzyne. Reagents
and conditions: a) 1. 48 wt% HF (excess), THF, RT, 1 h; 2. m-CPBA
(1.2 equiv), DCM, then BF3·Et2O (2.5 equiv), RT, 1 h; 3. PhB(OH)2
(1.1 equiv), 0oC, RT, 30 min ; b) TBAF (1.2 equiv), furan (5 equiv),
DCM, RT, 1 h. m-CPBA=meta-chloroperbenzoic acid,
TBAF=tetra-n-butylammonium fluoride.
1,4-epoxydihydronaphthalene 18 in 89% yield. To the
best of our knowledge, the above sequence, taken
together with the o-iodination of PyDipSi-arenes,
represents the first example of benzyne synthesis
À
featuring C H activation strategy.
In conclusion, we have developed a general and
efficient strategy for the synthesis of 1,2-ambiphilic
aromatic and heteroannulated aromatic synthons.
This method features installation of the removable/
modifiable PyDipSi directing group on haloarenes
and subsequent palladium-catalyzed directed
ortho-halogenation reaction to give the o-halogenated
PyDipSi-arene derivatives. Synthetic usefulness of
these 1,2-ambiphilic building blocks was demon-
strated in a variety of transformations, involving
participation of both nucleophilic aryl silane and
electrophilic aryl iodide moieties. These transforma-
tions include protio-, halo-, borodesilylations, and
conversion of the PyDipSi group into the OH
functionality, as well as Suzuki and Sonogashira
cross-coupling reactions of the aryl iodide unit.
Finally, the unique reactivity of these 1,2-ambiphiles
was illustrated in convergent syntheses of benzannu-
lated silole derivatives, as well as in the efficient
generation of o-benzyne.
Scheme 3. Synthesis of benzannulated siloles 10 and 15. Reagents and con-
ditions: a) HF, THF, RT, 1 h; b) PhCCH, [{Pd(CH3CN)2}Cl2] (3 mol%), tBu3P
(6 mol%), CuI (2 mol%), iPr2NH, 1,2-dioxane, 608C, 12 h; c) PhCCBF3K,
[{Pd(dppf)}Cl2]·DCM (10 mol%), Cs2CO3, THF, reflux, 48 h; d) LiAlH4
(2.5 equiv), THF, reflux, 12 h; e) KH (1.4 equiv), DME, 5 h; f) 4-MeO-
C6H4B(OH)2 (1.2 equiv), [Pd2(dba)3] (5 mol%), tBu3P (10 mol%), K3PO4,
1,2-dioxane, 708C, 12 h; g) Ph3CB(C6F5)4, 1,6-lutidine, CH2Cl2, RT, 1 h.
dba=trans,trans-dibenzylideneacetone, DME=1,2-dimethoxyethane,
dppf=1,1’-bis(diphenylphosphanyl)ferrocene, Py=pyridine.
Received: July 20, 2010
Published online: September 30, 2010
silane 2i was subjected to Suzuki coupling[17] with 4-methox-
yphenylboronic acid and gave biphenylsilane 12 in 89% yield.
Next, substitution of the pyridine group in 12 with fluoride
produced silylfluoride 13 quantitatively. Smooth reduction of
13 into hydride 14 and its subsequent electrophilic cyclization
reaction with trityl tetrakis(pentafluorophenyl)borate[18]
resulted in formation of dibenzosilole 15 in 71% yield
(Scheme 3).
À
Keywords: benzynes · C H activation · halogenation ·
palladium · siloles
.
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Communications
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