Indium-catalyzed intramolecular hydroarylation of aryl propargyl ethers

Article abstract of DOI:10.1039/c4ob02033b

Indium(iii) halides catalyze efficiently the intramolecular hydroarylation (IMHA) of aryl propargyl ethers. The reaction proceeds regioselectively with terminal and internal alkynes bearing electron-rich and electron-deficient substituents in the benzenes

Full text of DOI:10.1039/c4ob02033b

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Indium-catalyzed intramolecular hydroarylation of
aryl propargyl ethers†
Cite this: DOI: 10.1039/c4ob02033b
Lorena Alonso-Marañón, M. Montserrat Martínez, Luis A. Sarandeses and
José Pérez Sestelo*
Indium(III) halides catalyze efficiently the intramolecular hydroarylation (IMHA) of aryl propargyl ethers.
The reaction proceeds regioselectively with terminal and internal alkynes bearing electron-rich and
electron-deficient substituents in the benzenes and alkynes affording only the 6-endo dig cyclization
product. Additionally, a sequential indium-catalyzed IMHA and palladium-catalyzed Sonogashira coupling
can be performed in one reaction vessel. Experiments with deuterium support a mechanism through
electrophilic aromatic substitution.
Received 24th September 2014,
Accepted 21st October 2014
DOI: 10.1039/c4ob02033b
www.rsc.org/obc
are required.6 On the other hand, IMHA of aryl propargyl
ethers provides a straightforward synthesis of 2H-chromenes, a
Introduction
Metal-catalyzed hydroarylation of alkynes is an efficient and structural unit that is present in a vast number of naturally
atom-economy methodology that enables the insertion of a occurring and pharmaceutically active compounds.13 As a
C–C triple bond into a C–H bond of aromatic compounds.1 result, the development of a general protocol with a non-toxic
This method offers an attractive alternative to Heck and cross- and affordable catalyst is highly desirable.
coupling reactions, and can be performed in an inter- or intra-
In recent decades indium has gained considerable impor-
molecular fashion with variable regio- and stereoselectivity tance in organic synthesis.14 Indium organometallics have
depending on the reaction partners, the metal, and the reac- proven to be useful reagents in metal-catalyzed reactions and
tion conditions. Intramolecular hydroarylation (IMHA) of indium salts are efficient catalysts to promote nucleophilic
alkynes is particularly useful for the synthesis of cyclic frame- addition to carbonyl derivatives and unsaturated carbon–
works as the reaction can be catalyzed by several transition carbon bonds.15 Indium-catalyzed addition to alkynes has
metals such as palladium,2 platinum,3 ruthenium,4 rhodium,5 been described in inter- and intramolecular reactions invol-
gold,6 and silver.7 More recently, non-precious metals such ving 1,3-dicarbonyls,16 and in cycloisomerization reactions of
as iron,8 gallium,9 and indium10 have been suggested as alkynyl anilines.17 Furthermore, indium catalysis has been
promising alternatives in terms of economy and reactivity.
used in intramolecular hydroarylations during the synthesis of
In the context of a research program aimed at developing phenanthrenes and derivatives from alkynylated biphenyl
new metal-catalyzed reactions using indium11 and gold,12 we derivatives.10 Recently, Corey has also found that indium is an
report here the indium-catalyzed intramolecular hydroaryl- excellent catalyst promoting the cascade polycyclization of
ation of aryl propargyl ethers. Although this transformation enynes, and has also proven effective in the hydroarylation of
can be performed with various precious metals, there are some aryl propargyl ethers.18 In addition, indium also offers
still limitations associated with the substrate (i.e., terminal significant advantages in terms of cost and low toxicity.14,15
alkynes), regioselectivity (6-endo vs. 5-exo), side reactions such
as ether cleavage or alkene isomerization and the economy of
the transformation.3a Gold(I) catalysis is probably the best
choice, although silver cocatalysis or highly active complexes
Our research started with the intramolecular hydroarylation of
4-methoxyphenyl 2-propynyl ether (1a) under indium(III) cata-
Results and discussion
lysis. Initially, the addition of InCl3 under different reaction
conditions proved to be ineffective (Table 1, entries 1 and 2).
However, on using InBr3 (5 mol%) the reactivity changed
dramatically and the hydroarylation product (6-methoxy-2H-
chromene, 2a) was obtained in 58% yield after 16 h at room
temperature (entry 3). More encouragingly, we found that the
Departamento de Química Fundamental and Centro de Investigaciones Científicas
Avanzadas (CICA), Universidade da Coruña, E-15071 A Coruña, Spain.
E-mail: sestelo@udc.es
†Electronic supplementary information (ESI) available: Experimental details of
the preparation of aryl propargyl ethers 1a–f and 3a–k, full characterization and
copies of the 1H and 13C NMR for all the compounds used. See DOI: 10.1039/
c4ob02033b
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Table 1 Indium-catalyzed hydroarylation of aryl propargyl ether 1a
Table 2 Indium-catalyzed IMHA with phenyl-substituted propargyl
ethers
Entry
InX3
Solvent
T (°C)
t (h)
Yielda,b (%)
Entry
R
T (°C)
t (h)
2H-Chromene
Yielda (%)
1
2
3
4
5
6
7
8
9
InCl3
InCl3
InBr3
InI3
In(OTf)3
InI3
InI3
InBr3
InI3
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
rt
100
rt
rt
100
rt
80
80
80
48
24
16
4
24
4
24
24
24
— (100)
— (100)
58
85
—
1
2
3
4
5
6
OMe (1a)
Me (1b)
CO2Me (1c)
NO2 (1d)
CN (1e)
rt
rt
100
100
100
100
4
12
24
24
24
24
2a
2b
2c
2d
2e
2f
85
63
90
98
63
70
83
— (100)
15 (85)c
— (100)
Br (1f)
MeOH
MeOH
a Isolated yield.
a Isolated yield. b Recovered starting material in parentheses.
c Conversion determined by 1H NMR.
(I) catalysis,6 indium(III) provides the 6-endo product exclusively
and neither the ether cleavage nor isomerization byproducts
were isolated. These results support a mechanism based on an
electrophilic aromatic substitution process.
use of InI3 (5 mol%) increased the yield to 85% after only 4 h at
rt (entry 4). Interestingly, the reaction proceeded regioselectively
to produce only the 6-endo product and cleavage of the ether
was not observed. The importance of the halide ion led us to
test the reactivity of In(OTf)3 but, despite some precedents with
intermolecular hydroarylation,19 the use of this reagent led to
decomposition of the aryl propargyl ether (entry 5). During our
optimization process we found that the reaction can be per-
formed efficiently using other solvents such as CH2Cl2 but not
with coordinating solvents such as THF or MeOH (entries 6–9).
These promising results led us to survey the scope of the
indium-catalyzed IMHA with functionalized aryl propargyl
ethers (Table 2). The metal-catalyzed hydroarylation reaction is
usually sensitive to electronic effects and limitations can arise
with electron-deficient benzenes. Using InI3 (5 mol%) as the
catalyst and toluene as the solvent, we found that the presence
of a methoxy group on benzene is not essential, since the reac-
tion with p-tolyl propargyl ether 1b gave the 6-endo product 2c
in 63% yield at rt in 12 h (entry 2). This transformation
Given our success in the intramolecular hydroarylation with
terminal alkynes, we turned our attention to internal alkynes
that would allow the synthesis of 4-substituted 2H-chromenes
and, with this aim in mind, a variety of internal alkynes were
prepared (Table 3). Hydroarylation of 4-methoxyphenyl
3-phenyl-2-propynyl ether (3a) proceeded with InBr3 or InI3
(5 mol%) at rt and the corresponding 4-phenyl-2H-chromene
4a was obtained in good yields (65% and 79%, respectively,
entry 1). As with terminal alkynes, the indium-catalyzed IMHA
afforded only the 6-endo product, as evidenced by 1H NMR
spectroscopy. The electronic effects were analyzed with elec-
tron-donating and -withdrawing substituents in the benzene
and alkyne. Aryl propargyl ethers 3b and 3c bearing a methoxy
group in the benzene and p-tolyl or p-acetylphenyl groups in
the alkyne reacted efficiently when using InI3 (85% and 78%,
respectively, entries 2 and 3). Internal alkynes 3d and 3e, both
substituted with a methyl carboxylate in the benzene, reacted
sluggishly and required longer reaction times and a higher
catalyst loading (10 mol%, entries 4 and 5).
1
showed a higher conversion by H NMR, but isolated yield is
usually lower due to decomposition by traces of acids. When
an ester group was incorporated into the benzene (1c), InI3
was ineffective at rt but at 100 °C the hydroarylation took place
in 24 h and the 2H-chromene 2c was isolated in 90% yield
(entry 3). In a similar way, reaction of p-nitrophenyl 2-propynyl
ether (1d) at 100 °C for 24 h gave the desired 6-nitro-2H-
chromene (2d) in 98% yield as a single product (entry 4). The
IMHA reaction with arenes functionalized with other electron-
withdrawing groups such as cyano 1e or bromo 1f proceeded
at 100 °C for 24 h in high yields (entries 5 and 6). Overall, it
has been demonstrated that indium(III) hydroarylation can be
performed efficiently with aryl 2-propynyl ethers (terminal
alkynes) substituted with electron-rich and electron-deficient
functional groups. These results are better than those
obtained using other metals catalysts, such as ruthenium(II),4
platinum(II),3a and gallium(III),9 in terms of efficiency and
regioselectivity. It is interesting to note that, in contrast to gold
To study further the scope of the reaction, methyl alkynes
and alkynoates were also assessed. Interestingly, the IMHA
reaction of methyl alkynes 3f and 3g, which bear either a
methoxy or an ester group in the benzene, proceeded to give
97% and 75% yields, respectively (entries 6 and 7). As observed
previously, the nature of the substituent in the benzene deter-
mines the reactivity, and the presence of a methyl group in the
alkyne did not affect the regioselectivity of the reaction. The
IMHA of alkynoate ester 3h afforded the 6-endo-dig cyclization
product 4h in 98% yield (Table 3, entry 8).
As part of this study we also assessed the reactivity of
haloalkynes, which are alternative substrates when IMHA does
not proceed with terminal alkynes and whose hydroarylation
under gold catalysis takes place with 1,2-halide migration.20
Interestingly, it was found that reaction of 3-bromo-2-propynyl
aryl ether 3i with InI3 (5 mol%) proceeded at rt in 6 h to give
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Table 3 Indium-catalyzed hydroarylation with internal alkynes
Entry
1
Arylpropargyl ether
Conditions
rt, 16 h
2H-Chromene
Yielda (%)
65b
79
2
3
4
5
rt, 16 h
85
100 °C, 36 h
100 °C, 72 h
100 °C, 72 h
78
45 (38)c
38 (45)c
6
7
8
rt, 16 h
97
75
98
100 °C, 24 h
100 °C, 4 h
rt, 6 h
60 °C, 4 h
95
95d
9
95
10
100 °C, 24 h
85d
rt, 16 h
60 °C, 1 h
30
95d
11
a Isolated yields, recovered starting material in parentheses. b Using 5 mol% InBr3. c 10 mol% InI3 was used. d 5 mol% InCl3 was used.
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the 4-bromo-2H-chromene (4i) in 95% yield as a single
Finally, the mechanism of the indium-catalyzed IMHA of
product. On the other hand, the reaction with InCl3 took place at aryl propargyl ethers was investigated. Our results suggest that
60 °C in 4 h (entry 9). As observed previously, when the reaction the reaction takes place through an electrophilic aromatic
was performed with 3j, which contains an ester group, the reac- substitution promoted by π-alkyne activation through coordi-
tivity decreased but the IMHA product 4j was obtained in 95% nation with indium. A Claisen mechanism, based in a coordi-
yield after 24 h at 100 °C (entry 10). Moreover, the indium-cata- nation with the oxygen, can be discarded since it should
lyzed IMHA was extended to iodoalkyne 3k and, in this case, the provide the benzofuran product (not detected). Therefore, an
best results were obtained using InCl3 (entry 11). In general, it alkenylindium compound should be generated during the
has been shown that 4-halo-2H-chromenes can be efficiently pre- electrophilic addition and, after aromatization with concomi-
pared from the corresponding haloalkynes 3i–k and that these tant acid release, the last step should be protonation
compounds are more reactive than aryl alkynyl ethers 3a–e.
(Scheme 2). The catalytic cycle could be initiated either by InX3
+
The synthesis of 4-halo-2H-chromenes (4i–k) prompted us or InX2 as has been reported for InCl3-catalyzed cycloisomeri-
to study the possibility of combining the indium-catalyzed zations of 1,6-enynes.23
hydroarylation with palladium-catalyzed cross-coupling reac-
tions. The development of sequential metal-catalyzed reactions
is an appealing trend in organic synthesis, although the
combination of two metals in one pot may lead to significant
interference through either redox processes, ligand exchange
or incompatible reaction conditions.21 Nevertheless, we
attempted to combine the indium-catalyzed IMHA with a palla-
dium-catalyzed Sonogashira coupling in one vessel. It was
found that the hydroarylation reaction of bromoalkyne 3i with
InCl3 (5 mol%) in toluene at 60 °C, followed by the addition of
phenylethyne (2 equiv.) and Pd(PPh3)2Cl2 (5 mol%) gave, after
12 h, the 4-phenylethynyl-2H-chromene 5a in 85% overall yield
(two steps). Interestingly, and despite their higher reactivity in
the IMHA, the use of InBr3 or InI3 gave lower yields. Under the
same reaction conditions, the sequential indium/palladium-
catalyzed procedure also proved useful with bromoalkyne 3j and
the corresponding 4-phenylethynyl-2H-chromene (5b) was
obtained in 83% overall yield. To the best of our knowledge, this
reaction constitutes the first example of a sequential one-pot
transformation that includes an indium-catalyzed hydroarylation
and a palladium-catalyzed copper-free Sonogashira coupling. It
is remarkable that the Sonogashira coupling proceeds in higher
Scheme 2 Plausible mechanism for the indium-catalyzed intramole-
yield in the sequential procedure than with the isolated alkenyl- cular hydroarylation.
bromide 4i or 4j (80% and 66%, Scheme 1), which suggests that
indium could catalyze both transformations.22
To gain insight into the mechanism, the IMHA reaction
was performed in the presence of a deuterium source. In this
case, we found that hydroarylation of 3i using InI3 (5 mol%) in
toluene and CF3CO2D (2 equiv.) afforded the chromene 4i-d1
in 83% yield with significant incorporation of deuterium at
the C-3 position (55/45, H/D ratio). Under the same conditions,
the IMHA of internal alkyne 3a gave 4a-d1 and deuterium
was also incorporated at the C-3 position with a 40/60 H/D
ratio (Scheme 3). Additionally, hydroarylation of 1a-d1 with
a deuterium label at the terminal alkyne gave 2a-d1 without
any shift in the position of the deuterium. These results
support the mechanism proposed in Scheme 2 and are remi-
niscent of deuterium experiments carried out under silver
catalysis.7
Scheme 1 Sequential indium-catalyzed hydroarylation/palladium-cata-
lyzed Sonogashira coupling.
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ambient temperature, and calibrated to the solvent peak. DEPT
data were used to assign carbon types. The low resolution EIMS
were measured on a Thermo Finnigan Trace MS spectrometer at
70 eV. The HRMS were measured on a Thermo Finnigan MAT
95XP spectrometer or in a QSTAR LC/MS Turbo Spray. IR spectra
were recorded using a Bruker Vector 22 and with ATR (“attenu-
ated total reflectance”). Melting points were measured on a Stuart
Scientific melting point apparatus SMP3 and are uncorrected.
General procedure for the indium-catalyzed IMHA of aryl
propargyl ethers 1a–f
Scheme 3 Indium-catalyzed IMHA using deuterated compounds or
solvents.
In a Schlenk tube with InI3 (18 mg, 0.037 mmol) a solution of
the aryl propargyl ether 1a–1f (100 mg scale) in dry toluene
(5 mL) was added. The reaction was monitored by TLC under the
reaction conditions described in Table 2. The solvent was evapor-
ated and the residue was purified by flash chromatography on
silica gel (EtOAc–hexanes) to afford, after concentration and
high-vacuum drying, the corresponding 2H-chromenes (2a–f).
6-Methoxy-2H-chromene (2a).24 According to the general
procedure, the reaction of 1a (120 mg, 0.742 mmol) with InI3
afforded, after purification by column chromatography (Rf =
0.24, 5% EtOAc–hexanes, 1% Et3N), 2a as a colorless oil
(94 mg, 0.631 mmol, 85%): 1H NMR (300 MHz, CDCl3) δ
6.74–6.66 (m, 2H), 6.56 (d, J = 2.8 Hz, 1H), 6.46 (d, J = 9.8 Hz,
1H), 5.84 (dt, J = 9.8, 3.6 Hz, 2H), 4.77 (dd, J = 3.6, 1.8 Hz, 2H),
3.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.1 (C), 148.0 (C),
124.7 (CH), 123.1 (C), 123.0 (CH), 116.2 (CH), 114.1 (CH), 111.8
(CH), 65.4 (CH2), 55.7 (CH3); IR (ATR) νmax 2997, 2832, 1724,
1490 cm−1; MS (EI) m/z 162 [M]+ (80), 161 [M − H]+ (100);
HRMS (EI) calcd for C10H10O2 [M]+ 162.0675, found 162.0670.
6-Methyl-2H-chromene (2b).24 According to the general pro-
cedure, the reaction of 1b (108 mg, 0.742 mmol) with InI3
afforded, after purification by column chromatography (Rf =
Conclusions
Indium(III) halides are efficient catalysts for the intramolecular
hydroarylation of aryl propargyl ethers. The reaction proceeds
with terminal and internal alkynes bearing electron-rich and
electron-deficient substituents in the benzenes and alkynes
affording the 6-endo cyclization product regioselectively. The
indium-catalyzed IMHA of haloalkynes can also be combined
with palladium-catalyzed Sonogashira coupling in a sequential
one-pot transformation. These results highlight indium as one
of the best metals for IMHA in terms of cost, lack of toxicity,
and intrinsic effectiveness. In addition, mechanistic studies
carried out with deuterium support an electrophilic aromatic
substitution pathway.
Experimental
General methods
All reactions were carried out in flame-dried glassware, under 0.25, 2% EtOAc–hexanes, 1% Et3N), 2b as a colorless oil
1
an argon atmosphere, using standard gastight syringes, (68 mg, 0.467 mmol, 63%): H NMR (300 MHz, CDCl3) δ 6.92
cannula and septa. Toluene and THF were distilled from (dd, J = 8.1, 1.7 Hz, 1H), 6.79 (d, J = 1.7 Hz, 1H), 6.70 (d, J = 8.1
sodium/benzophenone. Dichloromethane was distilled from Hz, 1H), 6.40 (d, J = 9.8 Hz, 1H), 5.77 (dt, J = 9.8, 3.6 Hz, 1H),
calcium hydride. Dry acetone, DMF and MeOH and other com- 4.80 (dd, J = 3.6, 1.8 Hz, 2H), 2.27 (s, 3H); 13C NMR (75 MHz,
mercially available reagents were used as received. Reaction CDCl3) δ 151.9 (C), 130.5 (C), 129.5 (CH), 127.1 (CH), 124.7
temperatures refer to external bath temperatures. Butyllithium (CH), 122.2 (C), 122.0 (CH), 115.4 (CH), 65.5 (CH2), 20.5 (CH3);
was titrated prior to use. Indium(III) iodide (99.998%), indium(III) IR (ATR) νmax 3019, 2922, 2825, 2729, 1491 cm−1; MS (EI) m/z
bromide (99%), indium(III) chloride (99.99%) and indium(III) 146 [M]+ (44), 145 [M − H]+ (100); HRMS (EI) calcd for C10H10O
trifluoromethanesulfonate were purchased from Aldrich and [M]+ 146.0726, found 146.0726.
used as received under argon. NBS was recrystallized from
Methyl 2H-chromene-6-carboxylate (2c). According to the
water. Reactions were monitored by TLC using pre-coated general procedure, the reaction of 1c (141 mg, 0.742 mmol)
silica gel plates (Alugram® Xtra SIL G/UV254, 0.20 mm thick), with InI3 afforded, after purification by column chromato-
UV light as the visualizing agent and ethanolic phosphomolyb- graphy (Rf = 0.24, 10% EtOAc–hexanes, 1% Et3N), 2c as a
dic acid as the developing agent. Organic extracts were dried viscous white oil (127 mg, 0.668 mmol, 90%): 1H NMR
with anhydrous MgSO4, filtered, and concentrated using a (300 MHz, CDCl3) δ 7.79 (dd, J = 8.5, 2.1 Hz, 1H), 7.64 (d, J =
rotary evaporator under reduced pressure. Flash column 2.1 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 6.43 (d, J = 9.9 Hz, 1H),
chromatography was performed with 230–400 mesh silica gel 5.78 (dt, J = 9.9, 3.4 Hz, 1H), 4.92 (dd, J = 3.4, 2.0 Hz, 2H), 3.87
packed in glass columns. 1H and 13C NMR spectra were (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.7 (C), 158.1 (C), 131.2
recorded in CDCl3 or MeOD-d4 at 300 MHz and 75 MHz, (CH), 128.2 (CH), 123.8 (CH), 123.1 (C), 122.2 (CH), 121.5 (C),
respectively, using a Bruker Avance 300 spectrometer at 115.6 (CH), 66.1 (CH3), 51.8 (CH2); IR (ATR) νmax 2951, 2848,
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1713, 1612, 1493 cm−1; MS (EI) m/z 190 [M]+ (53), 189 [M − H]+ white solid (87 mg, 0.365 mmol, 79%): mp 62–64 °C; H NMR
(92), 83 [M − C5H7O2]+ (100); HRMS (EI) calcd for C11H10O3 (300 MHz, CDCl3) δ 7.43–7.36 (m, 5H), 6.87 (d, J = 8.7 Hz, 1H),
[M]+ 190.0624, found 190.0614.
6.74 (dd, J = 8.7, 3.0 Hz, 1H), 6.51 (d, J = 3.0 Hz, 1H), 5.87 (t, J =
6-Nitro-2H-chromene (2d).6d According to the general pro- 4.0 Hz, 1H), 4.81 (d, J = 4.0 Hz, 2H), 3.69 (s, 3H); 13C NMR
cedure, the reaction of 1d (128 mg, 0.742 mmol) with InI3 (75 MHz, CDCl3) δ 150.0 (C), 148.6 (C), 138.1 (C), 137.2 (C),
afforded, after purification by column chromatography (Rf = 128.6 (2 × CH), 128.4 (2 × CH), 127.8 (CH), 124.5 (C), 120.9
0.28, 10% EtOAc–hexanes, 1% Et3N), 2e as a light yellow solid (CH), 116.6 (CH), 114.1 (CH), 111.6 (CH), 65.2 (CH2), 55.7
(129 mg, 0.727 mmol, 98%): mp 134–135 °C; 1H NMR (CH3); IR (ATR) νmax 2997, 2939, 2832, 1736, 1576, 1486 cm−1
;
(300 MHz, CDCl3) δ 8.02 (dd, J = 8.9, 2.7 Hz, 1H), 7.85 (d, J = MS (EI) m/z 238 [M]+ (46), 237 [M − H]+ (52); HRMS (EI) calcd
2.7 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.45 (dt, J = 9.8, 1.7 Hz, for C16H14O2 [M]+ 238.0988, found 238.0984.
1H), 5.88 (dt, J = 10.0, 3.4 Hz, 1H), 5.01 (dd, J = 3.4, 2.0 Hz,
6-Methoxy-4-(p-tolyl)-2H-chromene (4b). According to the
2H); 13C NMR (75 MHz, CDCl3) δ 159.5 (C), 141.8 (C), 125.3 general procedure, the reaction of 3b (117 mg, 0.462 mmol)
(CH), 123.7 (CH), 122.9 (CH), 122.1 (CH), 121.7 (C), 116.0 (CH), with InI3 afforded, after purification by column chromato-
66.7 (CH2); IR (ATR) νmax 2920, 2850, 1505, 1400 cm−1; MS (EI) graphy (Rf = 0.28, 2% EtOAc–hexanes), compound 4b as a light
m/z 176 [M − H]+ (7), 83 [M − C4H4NO2]+ (100); HRMS (EI) yellow solid (99 mg, 0.393 mmol, 85%): mp 82–84 °C; 1H NMR
calcd for C9H7NO3 [M]+ 177.0420, found 177.0415.
(300 MHz, CDCl3) δ 7.26–7.19 (m, 4H), 6.85 (d, J = 8.7 Hz, 1H),
2H-Chromene-6-carbonitrile (2e).6d According to the general 6.72 (dd, J = 8.7, 3.0 Hz, 1H), 6.61 (d, J = 3.0 Hz, 1H), 5.83 (t, J =
procedure, the reaction of 1e (117 mg, 0.742 mmol) with InI3 4.0 Hz, 1H), 4.78 (d, J = 4.0 Hz, 2H), 3.66 (s, 3H), 2.39 (s, 3H);
afforded, after purification by column chromatography (Rf = 13C NMR (75 MHz, CDCl3) δ 153.9 (C), 148.7 (C), 137.6 (C),
0.30, 10% EtOAc–hexanes, 1% Et3N), compound 2e as a white 137.1 (C), 135.2 (C), 129.1 (2 × CH), 128.4 (2 × CH), 124.6 (C),
solid (74 mg, 0.467 mmol, 63%): mp 65–67 °C; 1H NMR 120.4 (CH), 116.6 (CH), 114.1 (CH), 111.6 (CH), 65.1 (CH2),
(300 MHz, CDCl3) δ 7.35 (dd, J = 8.4, 2.1 Hz, 1H), 7.19 (d, J = 55.7 (CH3), 21.2 (CH3); IR (ATR) νmax 2995, 2939, 2832, 1486,
2.0 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.36 (dt, J = 10.0, 1.7 Hz, 1463, 1425 cm−1; MS (EI) m/z 252 [M]+ (100); HRMS (EI) calcd
1H), 5.83 (dt, J = 10.0, 3.4 Hz, 1H), 4.94 (dd, J = 3.4, 2.0 Hz, for C17H16O2 [M]+ 252.1145, found 252.1139.
2H); 13C NMR (75 MHz, CDCl3) δ 157.7 (C), 133.4 (CH), 130.2
1-(4-(6-Methoxy-2H-chromen-4-yl)phenyl)ethanone
(4c).7
(CH), 123.5 (CH), 122.7 (CH), 122.6 (C), 119.0 (C), 116.6 (CH), According to the general procedure, the reaction of 3c
104.4 (C), 66.3 (CH2); IR (ATR) νmax 2922, 2872, 2222, 1647, (129 mg, 0.462 mmol) with InI3 afforded, after purification by
1488 cm−1; HRMS (ESI) calcd for C10H8NO [M + H]+ 158.0600, column chromatography (Rf = 0.26, 20% EtOAc–hexanes), com-
found 158.0601.
pound 4c as a yellow solid (101 mg, 0.360 mmol, 78%): mp
6-Bromo-2H-chromene (2f).25 According to the general pro- 96–98 °C; 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H),
cedure, the reaction of 1f (153 mg, 0.742 mmol) with InI3 7.45 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.8 Hz, 1H), 6.73 (dd, J =
afforded, after purification by column chromatography (Rf = 8.8, 3.0 Hz, 1H), 6.51 (d, J = 3.0 Hz, 1H), 5.90 (t, J = 4.0 Hz, 1H),
0.25, 2% EtOAc–hexanes, 1% Et3N), compound 2f as a color- 4.79 (d, J = 4.0 Hz, 2H), 3.63 (s, 3H), 2.94 (s, 3H); 13C NMR
less oil (110 mg, 0.519 mmol, 70%): 1H NMR (500 MHz, (75 MHz, CDCl3) δ 197.6 (C), 154.0 (C), 148.6 (C), 143.0 (C),
CDCl3) δ 7.17 (dd, J = 8.5, 2.4 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 136.5 (2 × C), 128.8 (2 × CH), 128.5 (2 × CH), 123.8 (C), 122.0
6.64 (d, J = 8.5 Hz, 1H), 6.34 (dt, J = 9.9, 1.6 Hz, 1H), 5.79 (dt, (CH), 116.9 (CH), 114.5 (CH), 111.4 (CH), 65.0 (CH2), 55.7
J = 9.9, 3.5 Hz, 1H), 4.82 (dd, J = 3.5, 1.9 Hz, 2H); 13C NMR (CH3), 26.6 (CH3); IR (ATR) νmax 2959, 2910, 2835, 1679, 1600,
(125 MHz, CDCl3) δ 153.1 (C), 131.6 (CH), 129.0 (CH), 124.1 1505, 1429 cm−1; HRMS (ESI) calcd for C18H17O3 [M + H]+
(C), 123.5 (CH), 123.2 (CH), 117.4 (CH), 113.2 (C), 65.6 (CH2); 281.1172, found 281.1166.
IR (ATR) νmax 2955, 2916, 2848, 2755, 1479, 1421, 1232 cm−1
;
Methyl 4-(p-tolyl)-2H-chromene-6-carboxylate (4d). Accord-
MS (EI) m/z 212 [M, 81Br]+ (55), 210 [M, 79Br]+ (100); HRMS (EI) ing to the general procedure, the reaction of 3d (129 mg,
calcd for C9H7BrO [M]+ 209.9675, found 209.9668.
0.462 mmol) with InI3 afforded, after purification by column
chromatography (Rf = 0.22, 2% EtOAc–hexanes), compound 4d
as a light yellow solid (58 mg, 0.208 mmol, 45%): mp
84–86 °C; 1H NMR (500 MHz, CDCl3) δ 7.87 (dd, J = 8.5, 2.1 Hz,
General procedure for indium-catalyzed IMHA with internal
alkynes 3a–3k
Into a Schlenk tube with InI3 (11 mg, 0.023 mmol), a solution 1H), 7.74 (d, J = 2.1 Hz, 1H), 7.27 (br s, 4H), 6.91 (d, J = 8.5 Hz,
of the alkyne 3a–3k (0.462 mmol) in dry toluene (5 mL) was 1H), 5.80 (t, J = 3.9 Hz, 1H), 4.95 (d, J = 3.9 Hz, 2H), 3.83 (s,
added. The reaction was monitored by TLC under the reaction 3H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.8 (C), 158.8
conditions described in Table 3. The solvent was evaporated (C), 137.9 (C), 136.4 (C), 134.7 (C), 131.1 (CH), 129.3 (2 × CH),
and the residue was purified by flash chromatography on silica 128.3 (2 × CH), 127.5 (CH), 123.1 (C), 123.0 (C), 119.8 (CH),
gel (EtOAc–hexanes) to afford, after concentration and high- 116.2 (CH), 65.8 (CH2), 51.9 (CH3), 21.3 (CH3); IR (ATR) νmax
vacuum drying, the corresponding 2H-chromenes 4a–k.
6-Methoxy-4-phenyl-2H-chromene (4a).25 According to the (ESI) calcd for C18H16O3 [M + H]+ 281.1172, found 281.1169.
general procedure, the reaction of 3a (110 mg, 0.462 mmol) Methyl 4-(4-acetylphenyl)-2H-chromene-6-carboxylate (4e).
2951, 2923, 2850, 2225, 1713, 1605, 1507, 1436 cm−1; HRMS
with InI3 afforded, after purification by column chromato- According to the general procedure, the reaction of 3e
graphy (Rf = 0.33, 5% EtOAc–hexanes), compound 4a as a (142 mg, 0.462 mmol) with InI3 afforded, after purification by
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column chromatography (Rf = 0.21, 20% EtOAc–hexanes), com- CDCl3) δ 6.97 (t, J = 1.7 Hz, 1H), 6.73 (d, J = 1.7 Hz, 2H), 6.18 (t,
pound 4e as a white solid (54 mg, 0.175 mmol, 38%): mp J = 4.0 Hz, 1H), 4.72 (d, J = 4.0 Hz, 2H), 3.79 (s, 3H); 13C NMR
1
119–121 °C; H NMR (300 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, (75 MHz, CDCl3) δ 154.3 (C), 148.3 (C), 124.3 (CH), 122.7 (C),
2H), 7.87 (dd, J = 8.5, 2.1 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.44 118.0 (C), 116.5 (CH), 115.8 (CH), 112.3 (CH), 66.7 (CH2), 55.8
(d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.5 Hz, 1H), 5.86 (t, J = 3.9 Hz, (CH3); IR (ATR) νmax 2954, 2906, 2832, 2722, 1687, 1621, 1574,
1H), 4.96 (d, J = 3.9 Hz, 2H), 3.81 (s, 3H), 2.64 (s, 3H); 13C NMR 1480, 1427 cm−1; MS (EI) m/z 242 [M, 81Br]+ (54), 240 [M, 79Br]+
(75 MHz, CDCl3) δ 197.6 (C), 166.5 (C), 158.7 (C), 142.4 (C), (56); HRMS (EI) calcd for C10H9O2Br [M]+ 239.9780, found
136.7 (C), 135.8 (C), 131.5 (CH), 128.7 (2 × CH), 127.2 (CH), 239.9790.
123.2 (C), 122.4 (C), 121.3 (CH), 116.4 (CH), 65.7 (CH2), 51.9
Methyl 4-bromo-2H-chromene-6-carboxylate (4j). According
(CH3), 26.7 (CH3); IR (ATR) νmax 2955, 2842, 1717, 1679, 1603, to the general procedure, the reaction of 3j (124 mg,
1575 cm−1; HRMS (ESI) calcd for C19H16O4 [M + H]+ 309.1121, 0.462 mmol) with InI3 afforded, after purification by column
found 309.1121.
chromatography (Rf = 0.28, 10% EtOAc–hexanes), compound 4j
6-Methoxy-4-methyl-2H-chromene (4f).25 According to the as a white solid (112 mg, 0.416 mmol, 90%): mp 104–106 °C;
general procedure, the reaction of 3f (81 mg, 0.462 mmol) with 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 2.0 Hz, 1H), 7.85 (dd,
InI3 afforded, after purification by column chromatography J = 8.5, 2.0 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 6.15 (t, J = 3.8 Hz,
(Rf = 0.41, 5% EtOAc–hexanes), compound 4f as a light yellow 1H), 4.87 (d, J = 3.8 Hz, 2H), 3.88 (s, 3H); 13C NMR (75 MHz,
oil (79 mg, 0.448 mmol, 97%): 1H NMR (300 MHz, CDCl3) δ CDCl3) δ 163.3 (C), 158.1 (C), 132.5 (CH), 128.8 (CH), 123.8
6.77–6.66 (m, 3H), 5.62 (dd, J = 3.6, 1.8 Hz, 1H), 4.68 (dd, J = (CH), 123.5 (C), 121.2 (C), 117.2 (C), 115.8 (CH), 66.3 (CH2),
3.5, 1.8 Hz, 2H), 3.77 (s, 3H), 2.02 (dd, J = 3.3, 1.7 Hz, 3H); 52.0 (CH3); IR (ATR) νmax 3070, 2954, 2909, 2860, 1708, 1640,
13C NMR (75 MHz, CDCl3) δ 154.1 (C), 148.1 (C), 130.3 (C), 1327 cm−1; MS (EI) m/z 270 [M, 81Br]+ (39), 268 [M, 79Br]+ (38);
125.2 (C), 119.4 (CH), 116.0 (CH), 113.3 (CH), 109.7 (CH), 65.3 HRMS (EI) calcd for C11H9O3Br [M]+ 267.9730, found 267.9738.
(CH2), 55.8 (CH3), 17.9 (CH3); IR (ATR) νmax 2943, 2919, 2832,
4-Iodo-6-methoxy-2H-chromene (4k). According to the
2733, 1577, 1490, 1425 cm−1; MS (EI) m/z 176 [M]+ (62), 161 general procedure, the reaction of 3k (133 mg, 0.462 mmol)
[M − CH3]+ (87); HRMS (EI) calcd for C11H12O2 [M ]+ 176.0832, with InCl3 (5.1 mg, 0.023 mmol) afforded, after purification by
found 176.0827.
column chromatography (Rf = 0.32, 10% EtOAc–hexanes), com-
1
Methyl 4-methyl-2H-chromene-6-carboxylate (4g). According pound 4k as a yellow oil (126 mg, 0.439 mmol, 95%): H NMR
to the general procedure, the reaction of 3g (94 mg, (300 MHz, CDCl3) δ 6.85 (d, J = 2.6 Hz, 1H), 6.75–6.65 (m, 2H),
0.462 mmol) with InI3 afforded, after purification by column 6.53 (t, J = 4.0 Hz, 1H), 4.68 (d, J = 4.0 Hz, 2H), 3.80 (s, 3H);
chromatography (Rf = 0.25, 5% EtOAc–hexanes), compound 4g 13C NMR (75 MHz, CDCl3) δ 154.4 (C), 147.7 (C), 133.4 (CH),
1
as a yellow oil (71 mg, 0.347 mmol, 75%): H NMR (300 MHz, 124.2 (C), 116.6 (2 × CH), 115.7 (CH), 93.1 (C), 67.5 (CH2), 55.8
CDCl3) δ 7.83–7.79 (m, 2H), 6.78 (d, J = 8.9 Hz, 1H), 5.59 (m, (CH3); IR (ATR) νmax 2932, 2832, 1682, 1608, 1514, 1487,
1H), 4.85 (dd, J = 3.4, 1.7 Hz, 2H), 3.88 (s, 3H), 2.06 (dd, J = 3.4, 1428 cm−1; HRMS (EI) calcd for C10H9O2I [M]+ 287.9642,
1.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.9 (C), 158.3 (C), found 287.9631.
131.0 (CH), 129.5 (CH), 125.3 (CH), 123.5 (C), 122.8 (C),
118.6 (CH), 115.5 (CH), 66.0 (CH2), 51.9 (CH3), 18.0 (CH3); tion of 3i (100 mg, 0.415 mmol, 1.0 equiv.) in dry toluene
IR (ATR) νmax 2951, 2844, 1711, 1607, 1492, 1437 cm−1
(5 mL), InCl3 (4.60 mg, 0.021 mmol, 0.05 equiv.) was added
HRMS (ESI) calcd for C12H12O3 [M + H]+ 205.0859, found and the mixture was stirred at 60 °C for 1 h. Then, a solution
205.0861. of phenyl acetylene (91 μL, 0.830 mmol, 2.0 equiv.), i-Pr2NH
6-Methoxy-4-(phenylethynyl)-2H-chromene (5a). To a solu-
;
Methyl 6-methoxy-2H-chromene-4-carboxylate (4h). Accord- (1.15 mL, 8.30 mmol, 20.0 equiv.) and Pd(PPh3)2Cl2 (14.6 mg,
ing to the general procedure, the reaction of 3h (102 mg, 0.021 mmol, 0.05 equiv.) in dry toluene (5 mL) was added.
0.462 mmol) with InI3 afforded, after purification by column After stirring for 16 h at 80 °C the mixture was cooled to rt and
chromatography (Rf = 0.26, 20% EtOAc–hexanes), compound the solvent was concentrated. Purification by flash chromato-
4h as a yellow oil (100 mg, 0.453 mmol, 98%): 1H NMR graphy (Rf = 0.29, 5% EtOAc–hexanes) gave compound 5a as a
(300 MHz, CDCl3) δ 7.55 (d, J = 2.8 Hz, 1H), 6.89 (t, J = 4.2 Hz, brown oil (99 mg, 0.377 mmol, 85%): 1H NMR (300 MHz,
1H), 6.80–6.72 (m, 2H), 4.77 (d, J = 4.2 Hz, 2H), 3.84 (s, 3H), CDCl3) δ 7.55–7.51 (m, 2H), 7.39–7.34 (m, 3H), 7.13 (d, J = 2.6
3.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.1 (C), 154.2 (C), Hz, 1H), 6.76–6.73 (m, 2H), 6.24 (t, J = 4.1 Hz, 1H), 4.82 (d, J =
148.0 (C), 132.8 (CH), 127.1 (C), 120.2 (C), 116.7 (CH), 115.4 4.1 Hz, 1H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.3
(CH), 111.5 (CH), 64.6 (CH2), 55.7 (CH3), 51.9 (CH3); IR (ATR) (C), 147.6 (C), 131.7 (2 × CH), 128.6 (2 × CH), 128.4 (CH), 122.8
νmax 2996, 2951, 2834, 1717, 1574, 1487, 1434 cm−1; MS (EI) (C), 122.2 (C), 119.5 (C), 116.5 (CH), 114.9 (CH), 111.1 (CH),
m/z 220 [M]+ (93), 205 [M − CH3]+ (83); HRMS (EI) calcd for 92.2 (C), 84.7 (C), 65.3 (CH2), 55.8 (CH3); IR (ATR) νmax 2955,
C12H12O4 [M]+ 220.0730, found 220.0729.
2923, 2855, 1623, 1560, 1492, 1432 cm−1; MS (EI) m/z 262 [M]+
4-Bromo-6-methoxy-2H-chromene (4i).25 According to the (10); HRMS (EI) calcd for C18H14O2 [M ]+ 262.0988, found
general procedure, the reaction of 3i (111 mg, 0.462 mmol) 262.0983.
with InI3 afforded, after purification by column chromato-
Methyl 4-(phenylethynyl)-2H-chromene-6-carboxylate (5b).
graphy (Rf = 0.25, 5% EtOAc–hexanes), compound 4i as a color- To a solution of 3j (100 mg, 0.372 mmol) in dry toluene
less oil (106 mg, 0.439 mmol, 95%): 1H NMR (300 MHz, (5 mL), InCl3 (8.20 mg, 0.037 mmol) was added and the result-
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ing mixture was stirred at 100 °C for 24 h, cooled to 80 °C, and (d, J = 8.7 Hz, 1H), 6.74 (dd, J = 8.7, 3.0 Hz, 1H), 6.51 (d, J =
a solution of phenyl acetylene (82 μL, 0.743 mmol), i-Pr2NH 3.0 Hz, 1H), 5.87 (t, J = 4.0 Hz, 1H), 4.81 (d, J = 4.0 Hz, 2H),
(1.04 mL, 7.43 mmol) and Pd(PPh3)2Cl2 (13 mg, 0.019 mmol) 3.69 (s, 3H).
in toluene (5 mL) was added. The mixture was stirred at 80 °C
for 24 h, cooled to rt and the solvent was concentrated. Purifi-
cation by flash chromatography (Rf = 0.22, 10% EtOAc–
hexanes) afforded 5b as a viscose brown-orange oil (90 mg,
Acknowledgements
0.310 mmol, 83%): 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J = We are grateful to the Ministerio de Ciencia e Innovación
2.1 Hz, 1H), 7.87 (dd, J = 8.5, 2.1 Hz, 1H), 7.60–7.52 (m, 2H), (grant number CTQ2012-31200) and the EDRF funds for
7.42–7.32 (m, 3H), 6.82 (d, J = 8.5 Hz, 1H), 6.19 (t, J = 4.0 Hz, financial support.
1H), 4.98 (d, J = 4.0 Hz, 2H), 3.90 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 166.6 (C), 157.6 (C), 131.8 (2 × CH), 128.7 (CH), 128.4
(2 × CH), 127.5 (CH), 126.9 (CH), 123.4 (C), 122.6 (C), 120.6 (C),
118.8 (C), 115.8 (CH), 92.9 (C), 84.0 (C), 66.0 (CH2), 51.9 (CH3);
Notes and references
IR (ATR) νmax 2951, 2924, 2853, 1715, 1613, 1570, 1492,
1437 cm−1; MS (EI) m/z 290 [M]+ (100); HRMS (EI) calcd for
C19H14O3 [M]+ 290.0937, found 290.0931.
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1-Methoxy-4-((3-d)prop-2-yn-1-yloxy)benzene (1a-d1). n-BuLi
(0.9 mL, 2.03 mmol, 2.25 M in hexanes) was added to a solu-
tion of 1a (316 mg, 1.95 mmol) in dry THF (10 mL) at −78 °C.
After stirring for 1 h, D2O (70 μL, 3.90 mmol, 2 equiv.) was
added and the reaction mixture was warmed to rt. The
crude was diluted with H2O (5 mL) and extracted with EtOAc
(2 × 15 mL). The organic phase was dried, filtered and concen-
trated to afford 1a-d1 as a light yellow oil (Rf = 0.27, 10%
EtOAc–hexanes, 291 mg, 1.78 mmol, 83%, 96% D), which
was used in the next step without further purification:
1H NMR (300 MHz, CDCl3) δ 6.92 (dt, J = 9.3, 3.4 Hz, 2H), 6.85
(dt, J = 9.3, 3.4 Hz, 2H), 4.64 (s, 2H), 3.77 (s, 3H).
6-Methoxy-2H-(4-d)chromene (2a-d1). A solution of 1a-d1
(104 mg, 0.637 mmol, 1.0 equiv.) and InI3 (16 mg, 0.032 mmol,
0.05 equiv.) in dry toluene (5 mL) was stirred at rt for 12 h.
After evaporation of the solvent, the residue was purified by
flash chromatography on silica gel (Rf = 0.32, 5% EtOAc–
hexanes, 1% Et3N) to afford 2a-d1 as a colorless oil (83 mg,
0.509 mmol, 80%): 1H NMR (300 MHz, CDCl3) δ 6.70 (br s,
1H), 6.67 (d, J = 2.7 Hz, 1H), 6.54 (d, J = 2.7 Hz, 1H), 5.83–5.80
(m, 1H), 4.76 (d, J = 3.6 Hz, 2H), 3.76 (s, 3H).
4-Bromo-6-methoxy-2H-(3-d)chromene (4i-d1). A solution of
3i (95 mg, 0.394 mmol, 1.0 equiv.), TFA-d1 (61 μL, 0.788 mmol,
2.0 equiv.) and InI3 (9.7 mg, 0.019 mmol, 0.05 equiv.) in
dry toluene (5 mL) was stirred for 12 h at rt. The solvent was
evaporated and the residue was purified by flash chromato-
graphy on silica gel (Rf = 0.36, 5% EtOAc–hexanes, 1% Et3N)
to afford 4i-d1 as a colorless oil (79 mg, 83%, 3H/3D 55 : 45):
1H NMR (300 MHz, CDCl3) δ 6.97 (t, J = 1.7 Hz, 1H), 6.73 (d, J =
1.7 Hz, 2H), 6.18 (t, J = 4.0 Hz, 1H), 4.71 (d, J = 4.0 Hz, 2H),
3.79 (s, 3H).
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6-Methoxy-4-phenyl-2H-(3-d)chromene (4a-d1).7 A solution
of 3a (75 mg, 0.315 mmol, 1.0 equiv.), TFA-d1 (48 μL,
0.629 mmol, 2.0 equiv.) and InI3 (8.0 mg, 0.016 mmol, 0.05
equiv.) in dry toluene (5 mL) was stirred for 12 h at rt. The
solvent was evaporated and the residue was purified by flash
chromatography on silica gel (Rf = 0.32, 5% EtOAc–hexanes,
1% Et3N) to afford 4a-d1 as a colorless oil (47 mg, 63%, 3H/3D
1
40 : 60): H NMR (300 MHz, CDCl3) δ 7.43–7.36 (m, 5H), 6.87
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