Palladium-catalyzed cycloaddition of alkynyl aryl ethers with internal alkynes via selective ortho C-H activation

Article abstract of DOI:10.1021/ja301588z

Alkynyl aryl ethers react with internal alkynes through selective ortho C-H activation by a palladium(0) catalyst to give substituted 2-methylidene-2H- chromenes. The alkynoxy group acts as a directing group to promote ortho C-H functionalization. Deuterium-labeling experiments indicated that the arylpalladium hydride complex is a key intermediate via oxidative addition. Various functional groups tolerate the present transformation to give the corresponding products.

Full text of DOI:10.1021/ja301588z

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Cycloaddition of Alkynyl Aryl Ethers with
Internal Alkynes via Selective Ortho C−H Activation
Yasunori Minami,* Yuki Shiraishi, Kotomi Yamada, and Tamejiro Hiyama*
Research and Development Initiative, Chuo University, Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
S
* Supporting Information
and 39% with 21 and 35% yields of homocycloadduct 6 (the
dimer of 1a) as regio- and stereoisomers, respectively.9 These
results indicate that the bulkiness of the ligand leads to the
formation of 3a in preference to 6. The Zn reduces
palladium(II) to palladium(0), as shown in entry 1. In the
absence of Zn, no desired product 3a was formed (entry 2).
Use of Pd(PCy3)2 instead of Pd(OAc)2/PCy3/Zn was equally
effective (entry 3). Further co-use of Zn(OAc)2 led to no
improvement (entry 4). A reduced catalyst loading [0.5 mol %
Pd(PCy3)2] was found to give 3a in 85% yield (entry 5).
The cycloadditions of 1a with various alkynes were
examined, and the results are shown in Table 2. The reactions
using diphenylacetylene (2b) and bis(trimethylsilyl)acetylene
(2c) gave the corresponding adducts 3b and 3c in 92 and 23%
yield, respectively (entries 1 and 2). In the case of 2c, the main
product generated was 6, probably as a result of steric
hindrance during the alkyne insertion event. When 1,4-
bis(trimethylsilyl)-2-butyne (2d) was used, the corresponding
adduct (3d) was obtained in 73% NMR yield (entry 3).
However, attempted HPLC purification caused protodesilyla-
tion of the 4-methyl to give 3d′. The reaction of 1a with 1-
phenyl-1-propyne (2e) occurred regioselectively to give 3e in
70% yield with the phenyl group at the C4 position (entry 4).
Annulation with sterically biased alkyne 2f occurred highly
regioselectively to give cyclic product 3f with a bulkier
substituent at the C3 position (entry 5). Unfortunately, the
reaction with 1-octyne provided only the simple alkynyl−H
adduct (E)-(4-MeOC6H4O)(HexCC)CC(TIPS)(H) in
37% yield without any formation of the expected cycloadduct.11
Variously substituted alkynyl aryl ethers 1 were next applied
to this reaction (Table 3). The substrate containing the tert-
butyldimethylsilyl (TBDMS) group for R4 underwent annula-
tion with 2a and 2b (5 equiv) to form 2H-chromenes 3g and
3h in 44 and 67% yield, respectively (entries 1 and 2). The
triethylsilyl (TES)- and tert-butyldiphenylsilyl (TBDPS)-
protected alkynes 1c and 1d upon reaction with 2b gave 3i
and 3j in 56 and 85% yield, respectively (entries 3 and 4). The
structure of 3j was unambiguously determined by X-ray
crystallographic analysis (Figure 1).12 In contrast, the
trimethylsilyl (TMS)-substituted alkynyl ether did not provide
the desired product, indicating that a bulky silyl substituent at
R4 is key for achieving the present cycloaddition. Variously
substituted phenyl groups bound to the alkynoxy group did not
hamper the reaction with 2a (entries 5−8). The reaction of m-
methyl-substituted substrate 1g provided product 3m in 73%
ABSTRACT: Alkynyl aryl ethers react with internal
alkynes through selective ortho C−H activation by a
palladium(0) catalyst to give substituted 2-methylidene-
2H-chromenes. The alkynoxy group acts as a directing
group to promote ortho C−H functionalization. Deute-
rium-labeling experiments indicated that the arylpalladium
hydride complex is a key intermediate via oxidative
addition. Various functional groups tolerate the present
transformation to give the corresponding products.
elective C−H bond functionalization by transition-metal
S
complexes is recognized as an important process in
synthetic organic chemistry.1 To achieve this transformation,
the use of a coordinating group (a so-called directing group) in
the substrate is a promising approach for site-selective C−H
bond functionalization. A variety of functional groups, such as
carbonyl, imine, carboxyl, and pyridyl groups, are appropriate
for this process. Since unsaturated C−C bonds can interact
with metals through their π bonds to give η2-metal complexes
that undergo intramolecular hydroarylation with electron-rich
aryl rings,2 these unsaturated bonds have high synthetic
potential. However, except for nitriles, they are seldom used
as directing groups.3 Other examples include rhodium-catalyzed
intermolecular cyclization of 4-alkynals with alkynes, rhodium-
catalyzed dimerization of styrene, and palladium-catalyzed
intramolecular cyclization of o-alkynyl biaryls and alkynyl
ketones.4−7 Herein we report that palladium-catalyzed
activation of an ortho C−H bond followed by cycloaddition
of alkynoxyarenes (1) with internal alkynes (2) produces 2-
methylidene-2 H-chromenes (2-methylidene-2H-1-benzopyr-
ans, 3). The presence of both oxygen and alkynyl moieties in
1 is essential for the success of the annulation. Chromenes are
an important structural motif in medicinal and material
chemistry.8
When the reaction of 4-MeOC6H4OCCTIPS (1a; TIPS =
triisopropylsilyl) with 4-octyne (2a) was performed in the
presence of catalytic amounts of Pd(OAc)2 (5 mol %),
tricyclohexylphosphine (5 mol %), and Zn (5 mol %) in
toluene at 90 °C for 6 h, it produced cyclic adduct 3a in 86%
yield after isolation by neutral silica-gel column chromatog-
raphy and high-pressure liquid chromatography (HPLC)
(Table 1, entry 1). The structure of 3a was unambiguously
determined by NMR spectroscopy.9 No trace of the simple
alkyne adduct 4, benzoxepin 5, or the [2 + 2 + 2] trimer of 1a
or 2a10 was observed. When the less bulky ligands PPh3 and
PBu3 were used in the reaction, 3a was produced in yields of 79
Received: February 17, 2012
Published: March 28, 2012
© 2012 American Chemical Society
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Table 1. Palladium-Catalyzed Cycloaddition of 1a with 4-Octyne (2a)
a
entry
Pd
ligand
additive
Zn
yield (%)
b
c
1
Pd(OAc)2
Pd(OAc)2
Pd(PCy3)2
Pd(PCy3)2
PCy3
PCy3
−
−
−
94 (86 )
2
3
4
5
−
−
0
93
94
85
Zn(OAc)2
d
Pd(PCy3)2
−
a
b
c
d
TIPS = triisopropylsilyl. NMR yields. 6 h. isolated yield. 0.5 mol %.
a
Table 2. Palladium-Catalyzed Cycloaddition of 1a with 2
b
entry
2
x
time (h)
product
yield (%)
1
2
3
4
5
2b
2c
2d
2e
2f
1.1
5
6
13
6
3b (R1 = R2 = Ph)
92
23
3c (R1 = R2 = TMS)
3d (R1 = R2 = CH2TMS)
3e (R1 = Ph, R2 = Me)
3f (R1 = Ph, R2 = TMS)
c
5
(73 )
1.1
1.1
6
70
60
6
a
Unless otherwise noted, a mixture of 1a (0.5 mmol), 2, Pd(OAc)2 (0.025 mmol), PCy3 (0.05 mmol), Zn (0.025 mmol), and toluene (0.5 mL) was
b
c
heated at 90 °C. TMS = trimethylsilyl. Isolated yields. NMR yield.
yield as a single isomer, indicating that annulation was
completed at the less hindered ortho position (entry 7).
To gain insight into the mechanism, the following experi-
ments were conducted. In contrast to the rhodium-catalyzed
ortho-selective alkenylation of anisole with internal alkynes,13
the reaction of 1,4-dimethoxybenzene with 2a did not occur
under the optimized conditions. In addition, 4-
MeOC6H4CH2CCTIPS remained totally intact under similar
conditions. These results indicated that sole ligation by the
oxygen atom or by the CC bond to palladium(0) does not
induce C−H cleavage. 4-MeOC6H4C(O)CCTIPS gave no
adduct, demonstrating that the carbonyl group is not
appropriate for the cyclization. These results demonstrate
that the presence of a highly polarized alkynyl ether group is
crucial for successful annulation.
shows that the sequential bimolecular insertion of two CC
bonds into the ortho C−H bond is actually what occurs. This
result and the fact that the palladium(0) complex is the active
catalyst strongly indicate that the C−H bond functionalization
proceeds via oxidative addition to a palladium(0) complex to
give the arylpalladium hydride complex. The kinetic isotope
effect (KIE) was investigated by a competitive experiment
between 1e and 1e-d5 in C6D6 (eq 2), which revealed a high
intermolecular KIE of 4.7. Accordingly, the C−H bond cleavage
step is concluded to be turnover-limiting.
The reaction of 1e-d5 with 2a in C6D6 resulted in the
formation of 3k-d5, as shown by 1H NMR analysis,
demonstrating that the original o-deuterium was selectively
shifted to the 2-methylidene position (eq 1). This result clearly
The triple bond of the O-alkynyl group may have a ketene-
like polarized resonance structure (i) (Scheme 1).14,15 The α-
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Journal of the American Chemical Society
Communication
a
Table 3. Palladium-Catalyzed Cycloaddition of 1 with 2
Scheme 1. Resonance Structure of Alkynyl Ether and Its
Reaction with a Low-Valent Transition Metal
Scheme 2. Plausible Catalytic Cycle
a
Unless otherwise noted, a mixture of 1 (0.5 mmol), 2, Pd(OAc)2
(0.025 mmol), PCy3 (0.05 mmol), Zn (0.025 mmol), and toluene (0.5
mL) was heated at 90 °C. TBDMS = tert-butyldimethylsilyl, TES =
explained as follows: the formation of 8 is promoted by
stabilization of the negative charge by silicon, which may push
the η2-palladium(0) complex to the electrophilic α-carbon
because of steric repulsion. Subsequent formation of pallada-
cycle 9 from 8 and a 1,2-hydrogen shift induce the oxidative
addition to give palladium hydride complex 10.16,17 Insertion of
alkyne 2 into the aryl−palladium bond of 10 gives
alkynylpalladium 11, which undergoes addition to the CC
bond to give the intermediate alkenylpalladium hydride 13 or
palladacycle 14.17 Subsequent reductive elimination of 3 from
either 13 or 14 regenerates 7 and completes the catalytic cycle.
An alternative insertion pathway could be also assumed:
intramolecular insertion of the CC bond into the Pd−H
bond in 10 could give five-membered palladacycle 12, which
could react with alkyne 2 to give 14. The regioselectivity of 3e
with a phenyl group at R1 is derived from a plausible π-stacking
interaction between the two aryl rings in the coordination of 2e
to 10 or 12 followed by the arylpalladation. For sterically biased
alkynes such as 2f, the coordination takes place in the direction
that avoids steric repulsion between the bulky R2 group and the
aryl group in 10 and 12.
b
c
triethylsilyl, TBDPS = tert-butyldiphenylsilyl. Isolated yields. 3 h.
d
Toluene (2.0 mL).
Figure 1. ORTEP diagram of 3j.
carbon in this structure may be effectively attacked by a
nucleophilic low-valent transition-metal complex to give a
cationic metal (ii). On the basis of this working hypothesis, a
plausible mechanism is briefly described in Scheme 2. Initially,
ligation of the CC bond in 1 to the palladium(0) complex
forms η2-complex 7, which is converted into zwitterionic
palladium complex 8. The effect of bulky silyl groups can be
Synthetic transformations of the products are depicted in
Scheme 3. Cross-coupling of the aryl−OMe bond in 3a with
(p-tolyl)MgBr under Dankwardt’s conditions gave 15 in 57%
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Journal of the American Chemical Society
Communication
yield without cleavage of the cyclic aryl−O bond (eq 3).18
Treatment of 3b with hydrogen bromide in acetic acid
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a
Scheme 3. Synthetic Transformations
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a
Reagents and conditions; (a) 3a (1.0 equiv), (p-tolyl)MgBr (6.0
i
equiv), NiCl2(PCy3)2 (5 mol %), PCy3 (10 mol %), Pr2O, 60 °C, 16
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produced benzopyrylium salt 16 in 89% yield via hydro-
desilylation, hydrobromination of the resultant carbon−carbon
double bond, and elimination of bromide ion (eq 4).19
In conclusion, the present study has demonstrated that the
palladium-catalyzed cycloaddition of alkynyl aryl ethers with
internal alkynes gives 2-methylidene-2H-chromenes via ortho
C−H activation. The alkynoxy moiety as a directing group
plays a key role in the present transformation. Synthetic
applications of these reaction products have been accom-
plished. Current efforts are directed toward understanding the
detailed reaction mechanism and developing similar cyclo-
additions.
(11) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ruhter, G.
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Å, b = 9.338(3) Å, c = 19.236(5) Å, β = 116.261(3)°; Z = 4; ρ = 1.231
g/cm3; R = 0.0557, Rw = 0.1178.
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ASSOCIATED CONTENT
48, 5848.
■
(16) Oxidative addition of the ortho C−H bond of anisole to a
pincer-ligated iridium complex has been reported. See: Ben-Ari, E.;
Cohen, R.; Gandelman, M.; Shimon, L. J. W.; Martin, J. M. L.;
Milstein, D. Organometallics 2006, 25, 3190.
(17) For stoichiometric reactions involving ortho C−H activation of
anisole by transition-metal complexes, see: (a) Slugovc, S.; Mereiter,
K.; Trofimenko, S.; Carmona, E. Angew. Chem., Int. Ed. 2000, 39, 2158.
(b) Santos, L. L.; Mereiter, K.; Paneque, M.; Slugovc, C.; Carmona, E.
New J. Chem. 2003, 27, 107. (c) Tsang, J. Y. K.; Buschhaus, M. S. A.;
Legzdins, P.; Patrick, B. O. Organometallics 2006, 25, 4215.
(d) Conejero, S.; Paneque, M.; Poveda, M. L.; Santos, L. L.;
Carmona, E. Acc. Chem. Res. 2010, 43, 572. (e) Lara, P.; Paneque, M.;
S
* Supporting Information
Detailed experimental procedures, characterization data for new
compounds, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
yminami@kc.chuo-u.ac.jp; thiyama@kc.chuo-u.ac.jp
Notes
The authors declare no competing financial interest.
Poveda, M. L.; Santos, L. L.; Valpuesta, J. E. V.; Carmona, E.; Moncho,
ACKNOWLEDGMENTS
́
■
S.; Ujaque, G.; Agusti Lledos
J. 2009, 15, 9034.
́
, A.; Alvarez, E.; Mereiter, K. Chem.Eur.
This work was financially supported by a Grant-in-Aid for
Scientific Research (S) (21225005 to T.H.) from JSPS. Y.M.
acknowledges the JSPS for a postdoctoral fellowship.
(18) Dankwardt, J. W. Angew. Chem., Int. Ed. 2004, 43, 2428.
(19) Donets, P. A.; Goeman, J. L.; Eycken, J. V. D.; Robeyns, K.;
Meervelt, L. V.; Van der Eycken, E. V. Eur. J. Org. Chem. 2009, 793.
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