Pd-catalyzed modifiable silanol-directed aromatic C-H oxygenation

Article abstract of DOI:10.1002/chem.201201616

Directing group: A Pd-catalyzed aromatic C-H oxygenation has been developed, featuring a modifiable silanol-directing group. The resulting oxasilacycles can be efficiently modified into a variety of valuable building blocks (see scheme). Copyright

Full text of DOI:10.1002/chem.201201616

COMMUNICATION
DOI: 10.1002/chem.201201616
À
Pd-Catalyzed Modifiable Silanol-Directed Aromatic C H Oxygenation
Chunhui Huang, Nugzar Ghavtadze, Benhur Godoi, and Vladimir Gevorgyan*[a]
À
Table 1. Optimization of reaction conditions.
Transition-metal-catalyzed C H functionalizations have
emerged as a powerful tool for the synthetic community.[1]
One common strategy involves the use of directing groups
to achieve high reactivity and selectivity.[1d–g] As a broad
À
spectrum of C H functionalizations becomes a toolkit of
choice, the expansion of substrate scope is therefore in
a high demand. Recently, the employment of removable
Substrate
Pd [mol%]
Additive
Solvent
Yield [%][a]
1
2
3
4
5
6
7
1a (R=Me)
1b (R=Ph)
1c (R=iPr)
1c
1c
1c
1c
1c
1c
1c
10
10
10
10
10
10
10
10
5
Li2CO3
Li2CO3
Li2CO3
none
Li2CO3
none
none
none
none
none
DCE
DCE
DCE
DCE
PhMe
PhMe
PhCF3
PhMe
PhCF3
PhCF3
trace
0
and/or modifiable directing groups has allowed an orthogo-
nal diversification of C H functionalized products. This
strategy illuminates an avenue for a quick functionalization
of products obtained by C H functionalization. Along the
line of our development on silicon-tethered removable/mod-
ifiable directing groups,[3] we have shown that silanol[4] acts
as a traceless directing group for the synthesis of catechols
from phenols.[4a] Herein, we report the Pd-catalyzed, modifi-
able benzylsilanol-directed aromatic C H oxygenation to-
wards oxasilacycles—versatile intermediates for organic syn-
thesis (vide infra).
[2]
35
46
42
54
73
49
73
60
À
À
8[b]
9
10[c]
5
[a] GC yields. [b] The reaction concentration was 0.05m. [c] [PdACHTUNGTRENNUNG(OPiv)2]
(5 mol%) was used as the catalyst.
À
Carbon-based silicon tethers have been shown to exhibit
a high degree of diversification.[3,5] Thus, we started by
searching a suitable carbon-based organosilanol for our
method design. Given the similarity between silanol and al-
yields of 2c (Table 1, entries 3–6). Performing the reaction
in PhCF3 resulted in an increased yield (Table 1, entry 7).
The catalyst loading was reduced to 5 mol% without loss of
efficiency (Table 1, entry 9). Employment of [PdACHTUNGTRENNUNG(OPiv)2],
À
cohol and the generality of hydroxyl-directed C H oxygena-
which was previously found superior for phenoxysilanol-di-
rected catechol synthesis,[4a] resulted in a reduced yield
(Table 1, entry 10).[11]
Next, the generality of this transformation was examined
(Table 2). It was found that both alkyl and aryl groups can
be tolerated at ortho-, meta-, and para-positions of aromatic
rings (Table 2, entries 1–7). For meta-substituted substrates
1i–j, the oxygenation selectively goes to the less hindered
tion[6] reaction developed by Yu and co-workers,[7] three
benzyl-bound silanols[8] were tested under Yuꢀs oxidative C
O cyclization conditions (Table 1). Dimethylsilanol 1a, an
established nucleophilic component in Hiyama–Denmark
cross-coupling reaction,[9] was tested first. However, the re-
ACHTUNGTRENNUNG(OAc)2 and Li2CO3 in the presence of
10 mol% [Pd(OAc)2] in dichloroethane (DCE) at 1008C led
À
action with PhI
ACHTUNGTRENNUNG
À
to decomposition of starting material, providing only trace
amounts of cyclized product 2a (Table 1, entry 1). Likewise,
diphenylsilanol 1b[10] also decomposed under these condi-
tions (Table 1, entry 2). However, bulkier diisopropyl ben-
zylsilanol 1c, which was previously reported in an oxidative
Heck reaction,[4c] was stable yet reactive enough under the
C H site. Besides, silanols 1m and 1n substituted at the
benzylic position were also competent reactants in this
transformation (Table 2, entries 8–9). Moreover, naphtha-
lene-based silanol 1o smoothly underwent oxidative cycliza-
tion to produce tricyclic product in 70% yield. Remarkably,
tetralin- (1p), chroman- (1q), and benzosuberan (1r)-de-
rived silanols were efficiently transformed into their corre-
sponding tricyclic products in good-to-high yields (Table 2,
entries 11–13). It deserves mentioning that the reaction can
be easily scaled up to gram scale with comparable yields
(Table 2, entry 7).
À
C O cyclization conditions to produce five-membered oxa-
silacycle 2c in 35% GC yield (Table 1, entry 3). The reac-
tions under base-free conditions usually afforded higher
[a] C. Huang, Dr. N. Ghavtadze, B. Godoi, Prof. V. Gevorgyan
Department of Chemistry
To verify whether this transformation, similarly to the pre-
viously developed silanol-directed oxygenation reaction
[Eq. (1)],[4a] proceeds via an acetoxylated intermediate of
type B, a GC monitoring of the oxygenation reaction of 1c
was performed. Surprisingly, the reaction profile showed no
formation of substantial amounts of acetoxylated intermedi-
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
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201616.
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Table 2. Reaction scope of silanol-directed C H oxygenation.
Substrate
Product
Yield [%][a]
72
1
2
3
87
74
4
5
6
50[b,c] (72)
(71)[c]
Figure 1. Reaction profile.[12] The reaction was monitored by GC/MS with
~
^
*
tetradecane as the internal standard. =1c; =2c; =3c.
(66)
68 (85)
83[b,d]
wise, prolong (overnight) heating of the completed reaction
did not change 18O-label incorporation in the cyclized prod-
ucts. We envisioned that the in situ generation and accumu-
lation of HOAc[13] during the reaction could be responsible
for the observed downhill trend of 18O-label incorporation
in the products. To verify the role of HOAc, additional ex-
periments with exogenous HOAc were performed in the
presence of base (Li2CO3). As expected, the abundance of
18O label in the products was substantially lower under
acidic conditions, but higher under the basic media com-
pared to that under the additive-free reaction conditions
(Figure 2).
7
8
9
69[b] (80)
58 (76)
10
11
12
13
70
77
58
90
[a] Isolated by column chromatography on Florisilꢂ. 1H NMR yields are
provided in the parentheses. [b] Isolated by Kugelrohr distillation. [c] Re-
gioselectivity is >20:1. [d] Gram scale (5 mmol), isolated with 92%
purity.
Although the mechanistic details of this transformation
are still unclear, the above observations indicate on two pos-
sible general pathways (Scheme 1). According to the first
path, the partial loss of 18O label in the products suggests
the possibility of the previously proposed reaction route,
featuring an acetoxylation/cyclization sequence (path A).[4a]
ate 3c (<3%) during the reaction course (Figure 1). Next,
18O-labeled silanol 4 was subjected to the reaction under the
standard conditions. It was found that, accompanied by the
formation of 2g, cyclized product 5 with 18O label was
indeed formed. Moreover, the amount of 18O label in the cy-
clized products was lower than that of 4 and gradually de-
creased as the reaction proceeded. The test experiments in-
dicated no 16O/18O scrambling in the starting silanol 4
throughout the reaction course occurred (Figure 2). Like-
Alternatively, the formation of 18O-enriched product 5 im-
[7a]
À
plies the possibility of a direct reductive C O cyclization
(path B).[14]
To test the feasibility of this oxygenation reaction on sp3
À
C H systems, silanols D and E were subjected to the stan-
dard oxygenation reaction conditions. However, instead of
À
benzylic C H activation reaction toward silacycles D’ and
E’, an ipso-acetoxydesilylation occurred, producing acyloxy
benzenes D’’ and E’’ in 83 and 67% yield, respectively
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Pd-Catalyzed Silanol-Directed C H Oxygenation
COMMUNICATION
be efficiently opened up
with Meerwein salt in
a single step [Eq. (3)]. In
this hitherto unknown trans-
formation, which we pro-
posed to proceed through
a cationic concerted asyn-
chronous mechanism (sup-
ported by DFT calcula-
tions),[12] trimethyloxonium
tetrafluoroborate
plays
a double duty: it delivers
the methyl cation to the
oxygen atom and the fluo-
ride anion to the silicon
atom. The oxygenation and
ring opening steps could
also be performed in
a semi-one-pot manner, af-
fording compound 9 from
silanol 1i in 51% overall
yield [Eq. (4)].
Figure 2. The abundance of 18O incorporation in the starting silanol 4 shown with solid circles, the abundance of
18O incorporation in the cyclized products (additive-free conditions with solid squares; acidic conditions with
solid triangles; basic conditions with hollow triangles).
The resulted fluorosilane 9 opened up broader opportuni-
ties for the subsequent modifications. As illustrated in
Scheme 2, Kumada oxidation[17] of 9 gave benzyl alcohol 10
in 76% yield. Fluoride-free Hiyama–Denmark cross-cou-
pling of 9 with phenyl iodide, under conditions reported by
Yoshida and co-workers,[18] afforded diarylmethane deriva-
tive 11 in 65% yield. Moreover, fluorosilane 9 in the pres-
ence of CsF can be employed as an equivalent of Grignard
reagent in the reaction with aldehydes.[19] Finally, an unpre-
cedented transformation en route to nitrone derivative 13
was discovered upon treatment of benzylsilane 9 with nitro-
sobenzene in the presence of CsF.[12]
Scheme 1. Possible reaction pathways.
[Eq. (2)]. These results suggest that this method is effective
[15]
À
for aromatic C H oxygenation reaction only.
We envisioned that the synthesized cyclic molecules, con-
À
taining an easily cleavable Si O bond and a potentially
À
modifiable C Si bond, could serve as a precursor for a varie-
À
ty of valuable products. Indeed, Tamao and co-workers have
showed in a single example that this type of oxasilacycles is
useful to achieve functional-group-compatible Kumada
cross-coupling reactions.[16] However, their synthetic useful-
ness has not yet been extensively exploited. Encouraged by
our previous success on the modification of silicon-tethered
directing groups,[3] we were interested to investigate the syn-
thetic potential of oxasilacycles as useful building blocks in
organic synthesis. As expected, desilylation of cyclic product
2h with CsF in DMF gave phenol 8 in good yield [Eq. (3)].
In addition, thermodynamically stable cyclic structure 2 can
In summary, Pd-catalyzed benzylsilanol-directed ortho C
H oxygenation of aromatic rings was developed. This
method allows efficient synthesis of oxasilacycles, which are
valuable synthetic intermediates. The synthetic usefulness
was highlighted by an efficient removal of the silanol-direct-
ing group and by its conversion into a variety of valuable
functionalities. These transformations include known Tamao
oxidation, Hiyama–Denmark cross-coupling, and nucleo-
philic addition, as well as unprecedented Meerwein salt-
mediated ring-opening of oxasilacycles and nitrone forma-
tion from a benzylsilane and a nitroso compound.
Chem. Eur. J. 2012, 00, 0 – 0
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V. Gevorgyan et al.
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Scheme 2. Further transformations.
Experimental Section
General procedure: An oven-dried Wheaton V-vial (10 mL), containing
a stirring bar, was charged with benzylsilanols 1 (0.5 mmol), [Pd(OAc)2]
(5.6 mg, 0.025 mmol) and PhI(OAc)2 (0.6–0.75 mmol) under N2 atmos-
AHCTUNGTRENNUNG
[5] S. Bracegirdle, E. A. Anderson, Chem. Soc. Rev. 2010, 39, 4114.
AHCTUNGTRENNUNG
À
[6] For reviews on transition metal-catalyzed C H oxygenation of
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reaction vessel was capped with pressure screw cap. The reaction mixture
was heated at 1008C for 7 h. The resulting mixture was cooled to RT and
filtered through a short layer of Celite plug with the aid of EtOAc. The
filtrate was concentrated under a reduced pressure. The residue was puri-
fied by column chromatography on Florisilꢂ (eluent: hexanes/EtOAc)
giving the corresponding cyclized products 2.
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Acknowledgements
The support of the National Institutes of Health (GM-64444) is gratefully
acknowledged. C.H. thanks the financial support from the Moriarty
Graduate Fellowship.
À
Keywords: C H activation · oxygenation · palladium ·
[11] Attempts on oxygenative cyclization of homologous silanols 1d–f
silanol · synthetic methods
failed;
(CH2)3SiiPr2OH.
[12] See the Supporting Information for details.
1d=PhSiiPr2OH,
1e=Ph
(CH2)2SiiPr2OH,
1 f=Ph-
AHCTUNGTRENNUNG
[13] It has been shown that HOAc could influence the reductive elimina-
tion pathways from PdIV centers. For a recent example, see: G. He,
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À
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Received: May 8, 2012
Published online: && &&, 0000
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Pd-Catalyzed Silanol-Directed C H Oxygenation
COMMUNICATION
Synthetic Methods
C. Huang, N. Ghavtadze, B. Godoi,
V. Gevorgyan* ................ &&&& — &&&&
Pd-Catalyzed Modifiable Silanol-
À
Directed Aromatic C H Oxygenation
Directing group: A Pd-catalyzed aro-
silacycles can be efficiently modified
À
matic C H oxygenation has been
developed, featuring a modifiable sila-
nol-directing group. The resulted oxa-
into a variety of valuable building
blocks (see scheme).
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!