Iridium-Catalyzed Intramolecular Methoxy C?H Addition to Carbon–Carbon Triple Bonds: Direct Synthesis of 3-Substituted Benzofurans from o-Methoxyphenylalkynes

Article abstract of DOI:10.1002/chem.201602152

Catalytic hydroalkylation of an alkyne with methyl ether was accomplished. Intramolecular addition of the C?H bond of a methoxy group in 1-methoxy-2-(arylethynyl)benzenes across a carbon–carbon triple bond took place efficiently either in toluene at 110 °C or in p-xylene at 135 °C in the presence of an iridium catalyst. The initial 5-exo cyclization products underwent double-bond migration during the reaction to give 3-(arylmethyl)benzofurans in high yields.

Full text of DOI:10.1002/chem.201602152

DOI: 10.1002/chem.201602152
Communication
&
CÀH Activation
Iridium-Catalyzed Intramolecular Methoxy CÀH Addition to
Carbon–Carbon Triple Bonds: Direct Synthesis of 3-Substituted
Benzofurans from o-Methoxyphenylalkynes
Takeru Torigoe, Toshimichi Ohmura,* and Michinori Suginome*[a]
gold catalysts are known for benzylic and cyclic ethers.[4] In ad-
Abstract: Catalytic hydroalkylation of an alkyne with
methyl ether was accomplished. Intramolecular addition
of the CÀH bond of a methoxy group in 1-methoxy-2-
(arylethynyl)benzenes across a carbon–carbon triple bond
took place efficiently either in toluene at 1108C or in p-
xylene at 1358C in the presence of an iridium catalyst. The
initial 5-exo cyclization products underwent double-bond
migration during the reaction to give 3-(arylmethyl)benzo-
furans in high yields.
dition, transition-metal-catalyzed hydroalkylation with alcohols
and THF, which may involve a radical process[5] or a redox-trig-
gered C–C coupling mechanism[6] instead of direct activation
and insertion of a-CÀH into CÀC unsaturated bonds, has also
been reported. However, to our knowledge, hydroalkylation
with methyl ethers (ROCH3) has not been achieved.[7] Given
that the methyl ether functionality is ubiquitous in organic
compounds, it is synthetically valuable to establish hydroalky-
lation at the a-CÀH bond of methoxy groups by using transi-
tion-metal catalysts. In the course of our study on the catalytic
activation of C(sp3)ÀH bonds of the methyl group on a silicon
atom,[8] we became interested in the activation of methyl
groups bound to an oxygen atom. We herein report the intra-
molecular addition of a CÀH bond of the methoxy group
across the carbon–carbon triple bond of o-methoxyphenylal-
kynes. The initial 5-exo cyclization products underwent double-
bond migration during the reaction to afford 3-substituted
benzofurans selectively.
Transition-metal-catalyzed hydroalkylation, that is, addition of
a C(sp3)ÀH bond to a carbon–carbon unsaturated bond, is an
atom- and step-economical bond-forming reaction. Hydroalky-
lation at the CÀH bond a to a heteroatom such as oxygen, ni-
trogen, and sulfur is particularly attractive because it allows
chemoselective functionalization of heteroatom-containing or-
ganic compounds (Scheme 1).[1] Indeed, catalytic addition of
1-Methoxy-2-(phenylethynyl)benzene (1a) was reacted in
toluene at 1108C in the presence of [IrCl(C2H4)2]2 (2 mol%) as
a catalyst precursor and DTBM-SEGPHOS (L1, 4 mol%) as
a ligand (Table 1, entry 1).[9] The reaction gave 3-benzylbenzo-
furan (2a) and (E)-3-benzylidene-2,3-dihydrobenzofuran ((E)-
3a) in 36 and 20% yield, respectively, after 12 h (entry 1).
When the reaction was carried out with an extended reaction
time (24 h), 2a and (E)-3a were formed in 91 and 2% yield, re-
spectively (entry 2). These results and deuterium-labeling ex-
periments, which are described later, indicate that intramolecu-
lar addition of a CÀH bond of the methoxy group of 1a took
place across the C–C triple bond in a syn fashion to give (E)-
3a, which underwent double-bond migration to afford 2a. The
reaction proceeded efficiently at 1108C, whereas conducting
the reaction at 808C resulted in low conversion (entry 3).
[IrCl(C2H4)2]2 was the most suitable catalyst precursor, whereas
the use of [IrCl(cod)]2 or [Ir(OMe)(cod)]2 (cod=1,5-cycloocta-
diene) resulted in slower or no reaction (entries 4 and 5). Li-
gands L1 and DTBM-MeOBIPHEP (L4) were optimal for both
hydroalkylation and double-bond migration (entries 2 and 9);
an inefficient catalyst was formed with DM-SEGPHOS (L2,
entry 7), and the iridium complex bearing DTBM-BINAP (L3)
demonstrated moderate catalyst activity (entry 8). These results
indicate that the 3,5-tert-butyl-4-methoxyphenyl (DTBM) group
on the phosphorus atoms and the 6,6’-dialkoxy-1,1’-biphenyl
backbone are key ligand structures that are required to accom-
plish high catalyst efficiency. Iridium and ligand were both es-
Scheme 1. Transition-metal-catalyzed hydroalkylation of alkynes and alkenes
by cleavage of the C(sp3)ÀH bond a to heteroatoms.
a CÀH bond a to nitrogen atoms in alkylamines and their de-
rivatives to carbon–carbon unsaturated bonds has been dem-
onstrated by using various transition-metal catalysts
(Scheme 1, X=N).[2,3] The protocol has been extended to intra-
molecular variants, which lead to the formation of nitrogen-
containing heterocyclic compounds.[3d,e,g] In contrast, utilization
of an oxygen-bound CÀH bond in hydroalkylation remains lim-
ited (Scheme 1, X=O).[3d,e,4–6] Lewis acid mediated reactions in-
volving a 1,5-hydride shift and variants using platinum and
[a] T. Torigoe, Dr. T. Ohmura, Prof. M. Suginome
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of Engineering, Kyoto University
Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
E-mail: ohmura@sbchem.kyoto-u.ac.jp
suginome@sbchem.kyoto-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201602152.
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Table 1. Reaction conditions.[a]
Table 2. Iridium-catalyzed intramolecular hydroalkylation double-bond
migration of 1 to give benzofuranes.[a]
Entry Ir precursor
L
Solvent T [8C], t [h] Yield [%]
2a[b] 3a[b] 4[b]
Entry Substrate
T [8C],
Yield [%][b]
1
2
3
4
[IrCl(C2H4)2]2
[IrCl(C2H4)2]2
[IrCl(C2H4)2]2
[IrCl(cod)]2
L1 toluene 110, 12
L1 toluene 110, 24
36
91
1
57
0
20
2
6
18
0
0
0
0
2
0
[IrCl(C2H4)2]2 [mol%]
L1 toluene
80, 24
L1 toluene 110, 24
5
[Ir(OMe)(cod)]2 L1 toluene 110, 24
6
7
8
9
10
11
12
–
L1 toluene 110, 24
L2 toluene 110, 24
L3 toluene 110, 24
L4 toluene 110, 24
0
6
36
89
0
0
3
16
2
0
0
0
0
0
0
40
40
[IrCl(C2H4)2]2
[IrCl(C2H4)2]2
[IrCl(C2H4)2]2
[IrCl(C2H4)2]2
[IrCl(C2H4)2]2
[IrCl(C2H4)2]2
1
2
3
4
5
6
7
8
R=H (1a)
R=CH3 (1b)
R=CF3 (1c)
110, 2
110, 2
110, 4
135, 4
135, 4
110, 4
110, 3
110, 3
135, 3
135, 5[c]
135, 5[c]
85 (2a)
82 (2b)
83 (2c)
74 (2d)
74 (2e)
77 (2 f)
80 (2g)
84 (2h)
78 (2i)
-
toluene 110, 24
L1 THF
L1 octane
110, 24
110, 24
0
11
4
10
R=OCH3 (1d)
R=OCH2Ph (1e)
R=OTBS (1 f)
R=OPh (1g)
R=OCF3 (1h)
R=B(pin) (1i)
R=C(O)CH3 (1j)
R =C(O)CF3 (1k)
[a] 1a (0.10 mmol), an Ir precursor (0.0020 mmol), and L (0.0040 mmol)
were stirred in solvent (0.2 mL) at 80–1108C for 12–24 h. [b] 1H NMR yield.
9
10
11
46 (2j)
66 (2k)
12
13
14
R=CH3 (1l)
R=OCH3 (1m)
R=Br (1n)
110, 3
135, 2
135, 5
81 (2l)
80 (2m)
76 (2n)
sential; no reaction took place in the absence of either of
these components (entries 6 and 10). A possible side reaction
was hydrogenation of the CÀC triple bond to give 1,2-diaryl-
ethane (E)-4, which can occur through iridium-catalyzed hydro-
gen transfer from solvent.[10,11] Indeed, the reaction of 1a in
either THF or octane gave predominantly (E)-4, rather than 2
and (E)-3a (entries 11 and 12). This undesirable reaction was
completely suppressed when the reaction was conducted in
toluene (entry 2).[12]
15
16
135, 5[c]
135, 5[c]
40 (2o)
70 (2p)
17
18
Ar=2-naphthyl (1q)
Ar=1-naphthyl (1r)
110, 2
135, 3
77 (2q)
85 (2r)
A range of 1-methoxy-2-(arylethynyl)benzene derivatives
were subjected to the iridium-catalyzed intramolecular hydro-
alkylation double-bond migration (Table 2).[13] Substrate 1b,
bearing a 4-tolyl group at the terminus of the ethynyl group,
reacted smoothly under the standard conditions to give 2b in
high yield (Table 2, entry 2). Higher catalyst loading (8 mol%)
was required for full conversion in the reaction of trifluorome-
thylphenyl-substituted substrate 1c (entry 3). The relative reac-
tivity decreased in the order 1b>1a>1c,[14] indicating that
the presence of an electron-rich aryl group increases the reac-
tivity. Substrates 1d–h bearing methoxy, benzyloxy, siloxy,
phenoxy, and trifluoromethyloxy groups, respectively, were all
tolerated in the reaction (entries 4–8). Methoxy- and benzy-
loxy-substituted compounds 1d and 1e showed lower reactivi-
ty than 1 f–h and the reaction required both elevated tempera-
ture and higher catalyst loading (entries 4 and 5), indicating
that coordination of the ether functionality may reduce the ac-
tivity of the catalyst.
19
20
110, 2
81 (2s)
33 (2t)
135, 5[c]
[a] 1 (0.20 mmol), [IrCl(C2H4)2]2 (0.0040–0.010 mmol), and L1 (L1/Ir=1)
were stirred for 24 h either in toluene (0.2 mL) at 1108C or in p-xylene
(0.2 mL) at 1358C unless otherwise noted. [b] Isolated yield. [c] L4 was
used as a ligand.
The reaction was applicable to a boronic ester 1i, giving the
synthetically attractive compound 2i in good yield (Table 2,
entry 9). In the reaction of methyl- and trifluoromethyl ketone
derivatives 1j and 1k, ligand L4 was more suitable than L1; by
using L4, the corresponding benzofurans 2j and 2k were ob-
tained in moderate yields (entries 10 and 11). The reaction of
1l–n, bearing ortho-substituted phenyl groups, proceeded effi-
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ciently either by increasing the catalyst amount or upon heat-
ing the system to 1358C (entries 12–14). The 2-bromophenyl
group of 1n was tolerated (entry 14), whereas the reaction
was completely inhibited by the 4-bromophenyl group of 1z
(Scheme 2). Similar effects of neighboring substituents were
observed in the reaction of carbonyl-substituted substrates:
only low conversion was observed in the reaction of methyl
ester 1aa (Scheme 2), whereas the o-methyl-substituted com-
pound 1o gave 2o in moderate yield (entry 15). Ketone 1p,
bearing a methoxy group ortho to the carbonyl group, gave
a higher yield than that obtained for 1j (entries 10 and 16).
The higher catalyst efficiency with these substrates than with
1aa is probably due to steric shielding of the carbonyl group
from interaction with the iridium catalyst. In addition to naph-
thalene derivatives 1q and 1r (entries 17 and 18), the hydroal-
kylation double-bond migration was applicable to 1s and 1t,
which bear 5-indolyl and 2-pyridyl groups, respectively (en-
tries 19 and 20).
than that of 1u, probably for steric reasons (entry 3). Slower re-
action was also observed for 1x (R2 =OCH3), which required
1358C for full conversion (entry 4). In contrast, 1y (R4 =OCH3)
reacted smoothly under the standard conditions to give 2y in
good yield (entry 5).
Substrates that were not suitable for the reaction under the
present conditions are summarized in Scheme 2. In addition to
the reaction of 1z and 1aa described above, no desired cycli-
zation occurred in the reaction of either 1ab or 1ac, bearing
Scheme 2. Unsuitable substrates.
1-Methoxy-2-(phenylethynyl)benzene
derivatives
1u–y,
which bear substituents R1–R4 on the tethering benzene ring,
were then subjected to the hydroalkylation double-bond mi-
gration (Table 3).[13] Compound 1u (R3 =CH3) was slightly more
reactive than 1a, and 2u was formed efficiently under the
standard conditions (entry 1). In contrast, the reaction of 1v
(R3 =CF3) was slower than that of 1a and 1u (entry 2), indicat-
ing that an electron-withdrawing group at the R3-position de-
creases the reactivity. The reaction of 1w (R1 =CH3) was slower
ethoxy or benzyloxy groups, respectively, instead of a methoxy
group. Submitting terminal alkyne 1ad to the reaction condi-
tions resulted in the formation of a complex mixture, whereas
no reaction took place with trimethylsilylethyne 1af. Com-
pound 1ae did not give the desired product, although its con-
version was observed at 1358C.
To obtain insight into the mechanism, the reaction of 1b-D
was carried out (Scheme 3A). Given that the reaction of 1b-D
at 1108C was rather slow compared with that of 1b, the reac-
tion temperature was set to 1358C. A benzofuran 2b-D was
Table 3. Effect of substituents on the tethering benzene ring.[a]
Entry Substrate
1
Conditions[b]
Product
Yield [%][c]
80
110 8C, 2 mol%
2
3
110 8C, 4 mol%
1358C, 2 mol%
78
81
Scheme 3. d-Labeling experiments.
obtained in 79% yield with reasonably high deuterium incor-
poration at both C2 and the benzylic carbon atoms (79 and
90% D, respectively). The observed decrease in the deuterium
content is attributed to partial delivery of the deuterium to the
CÀH bond at C7 of the benzofuran ring.[15] A large kinetic iso-
tope effect (kH/kD =3.4) was observed in the independent reac-
tions of 1b and 1b-D (Scheme 3B). Based on these results, we
propose a possible mechanism for the hydroalkylation double-
bond migration (Scheme 4). Coordination of the CÀC triple
bond of 1 and oxidative addition of the CÀH bond of the me-
thoxy group to IrI give complex A. Insertion of the CÀC triple
bond into either the IrÀH or IrÀC bond proceeds in an intra-
molecular syn fashion to afford alkenyliridium B1 or B2. Subse-
4
5
1358C, 4 mol%
110 8C, 2 mol%
75
76
[a] 1 (0.20 mmol), [IrCl(C2H4)2]2 (0.0040–0.0080 mmol), and L1 (L1/Ir=1)
were stirred for 24 h either in toluene (0.2 mL) at 1108C or in p-xylene
(0.2 mL) at 1358C. [b] Mol% of [IrCl(C2H4)2]2 is given. [c] Isolated yield.
Chem. Eur. J. 2016, 22, 1 – 6
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Acknowledgements
This work was partially supported by a Grants-in-Aid for Scien-
tific Research (B) No. 26288048(T.O.) and JSPS Fellows No.
26·5249 (T.T.).
Keywords: CÀC bond formation
·
CÀH activation
·
hydroalkylation · iridium · oxygen heterocycles
Scheme 4. Possible mechanism.
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quent reductive elimination gives (E)-3 with regeneration of IrI.
Compound (E)-3 then undergoes migration of the double
bond through a 1,3-H shift via p-allyl iridium C, which is
formed through oxidative addition of the allylic CÀH to IrI. The
observed large kinetic isotope effect indicates that cleavage of
the CÀH bond to form A should be the rate-determining step
in the intramolecular hydroalkylation.
2-Alkyl-3-aroylbenzofurans constitute an important structural
motif in certain bioactive compounds such as amiodaron[16]
and benzbromarone.[17] (Scheme 5A). The hydroalkylation
double-bond migration of 1 provides a new route to such
compounds through conversions of 2. Direct conversion of 2a
into 2-bromo-3-benzoylbenzofuran (5) was accomplished by
treatment with KBr/Oxone under visible-light irradiation
(Scheme 5B).[18] It has been reported that the bromo group in
5 can be converted by Negishi coupling into an alkyl group
with retention of the carbonyl group.[19]
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2010, 132, 3543; d) B. Bolte, F. Gagosz, J. Am. Chem. Soc. 2011, 133,
7696.
[5] For hydroalkylation with alcohols and cyclic ethers catalyzed by Fe, Co,
Rh, and Cu, see: a) L. Shi, Y.-Q. Tu, M. Wang, F.-M. Zhang, C.-A. Fan, Y.-M.
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Zhang, Synthesis 2009, 3504; d) L. Chen, J. Yang, L. Li, Z. Weng, Q. Kang,
Tetrahedron Lett. 2014, 55, 6096.
Scheme 5. 2-Substituted 3-aroylbenzofurans as a core structure of biologi-
cally active molecules (A), and synthesis of 3-benzoyl-2-bromobenzofuran
from the hydroalkylation product (B).
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2014, 53, 9142; Angew. Chem. 2014, 126, 9294.
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In conclusion, we have established the first catalytic hydroal-
kylation of CÀC multiple bonds with methyl ethers in the iridi-
um-catalyzed conversion of o-methoxyphenylalkynes. 3-Substi-
tuted benzofurans are formed through intramolecular addition
of a CÀH bond of a methoxy group across a CÀC triple bond
and subsequent migration of the double bond. The insights
obtained in this study are expected to lead to further catalytic
functionalization of C(sp3)ÀH bonds, the development of which
still lags behind that of C(sp2)ÀH bonds. Further exploration of
catalytic addition reactions utilizing C(sp3)ÀH bonds is being
undertaken in this laboratory.
[9] Ir–L1 has been reported as an effective catalyst for the hydroarylation
of alkenes. C. S. Sevov, J. F. Hartwig, J. Am. Chem. Soc. 2013, 135, 2116.
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[10] J. Choi, A. H. R. MacArthur, M. Brookhart, A. S. Goldman, Chem. Rev.
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ortho C(sp2)ÀH (path a). The other is an alternative formation of E via A
(path b).
[11] Probably the reaction took place in a syn fashion to give (Z)-4, which
underwent subsequent iridium-catalyzed isomerization to form (E)-4.
The Z to E isomerization was confirmed by an independent reaction of
(Z)-4 (see the Supporting Information).
[12] Formation of a small amount of 4 in entry 4 (Table 1) is probably due
to hydrogen transfer from cod.
[13] A protocol to find the suitable reaction conditions is as follows: i) The
standard conditions (1108C/24 h with 4 mol% of Ir–L1) were applied;
ii) for the substrates that reacted moderately but did not reach full con-
version, the reaction was re-examined with higher catalyst loading (6–
8 mol%); iii) For the substrates that resulted in low conversion or no re-
action, the reaction was retried at 1358C.
[16] J. Wolff, Pharmacol. Rev. 1998, 50, 89.
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[14] Conversions after 12 h at 1108C in the presence of Ir–L1 (4 mol%): 1a
(56%), 1b (76%), and 1c (35%).
Received: May 6, 2016
[15] There are two possible pathways for partial H/D exchange at C7. One is
reversible formation of iridacycle E from 1 triggered by activation of
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Communication
COMMUNICATION
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CÀH Activation
T. Torigoe, T. Ohmura,* M. Suginome*
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Make it active: Intramolecular addition
of the CÀH bond of a methoxy group in
1-methoxy-2-(arylethynyl)benzenes
across a carbon–carbon triple bond
took place efficiently in the presence of
an iridium catalyst. The initial 5-exo-cy-
clized products underwent double-bond
migration during the reaction to give 3-
(arylmethyl)benzofurans in high yields
(see scheme).
Iridium-Catalyzed Intramolecular
Methoxy CÀH Addition to Carbon–
Carbon Triple Bonds: Direct Synthesis
of 3-Substituted Benzofurans from o-
Methoxyphenylalkynes
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Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!