From domino to multicomponent: Synthesis of dihydroisobenzofurans

Article abstract of DOI:10.1016/j.tet.2010.12.056

A variety of substituted dihydroisobenzofurans can be easily synthesized in high yields by a one-pot three-component approach starting from o-bromoarylaldehydes, methanol, and terminal alkynes. The reaction occurs through an unprecedented cooperative pall

Full text of DOI:10.1016/j.tet.2010.12.056

Tetrahedron 67 (2011) 1552e1556
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
From domino to multicomponent: synthesis of dihydroisobenzofurans
*
Monica Dell’Acqua, Diego Facoetti, Giorgio Abbiati , Elisabetta Rossi
ꢀ
Dipartimento di Scienze Molecolari Applicate ai Biosistemi (DISMAB)dSezione di Chimica Organica ‘A. Marchesini’, Universita degli Studi di Milano, via G. Venezian 21,
20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 October 2010
Received in revised form 29 November 2010
Accepted 20 December 2010
Available online 25 December 2010
A variety of substituted dihydroisobenzofurans can be easily synthesized in high yields by a one-pot
three-component approach starting from o-bromoarylaldehydes, methanol, and terminal alkynes. The
reaction occurs through an unprecedented cooperative palladium/base promoted coupling/addition/
cyclization sequence.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reactions
Heterocycles
Dihydroisobenzofurans
Microwaves
Palladium
1. Introduction
functionalization of the 2-bromobenzaldehyde 1 with a proper
monosubstituted acetylene derivative and (2) the base promoted
Multicomponent reactions (MCRs) are a powerful tool for the
synthesis of complex molecules starting from readily available
building blocks in a ‘well-contrived’ one-pot sequential procedure.1
These approaches allow an overall reduction of the time required to
obtain the desired product with an advantageous economy of sol-
vents and energy and an overall reduction of waste production.
MCRs have been widely used for the preparation of heterocyclic
structures,2 as well as key steps in the total synthesis of natural
products.3 Moreover, the enhancing power of microwaves in MCRs
has been recently highlighted.4
microwave-assisted domino addition/annulation reaction of the 2-
alkynylbenzaldehyde derivative 2 in the presence of methanol, to
give the desired dihydroisobenzofuran 3.
The dihydroisobenzofuran nucleus is the core of some impor-
tant biologically active molecules, such as BcF,5 a compound under
investigation as a more lipophilic analogue of the anti-HIV drug d4T
(Stavudine),6 and two diterpenes from the Antarctic sponge Den-
drilla membranosa called membranolides C and D,7 that showed
antimycotic and antibiotic activity against Candida albicans and
Gram-negative bacteria.
In the literature there are some examples of the base-promoted
domino synthesis of dihydroisobenzofurans and related systems in
the presence of different nucleophiles.8
We also recently reported a selective synthesis of the dihy-
droisobenzofuran skeleton by a microwave-promoted domino ad-
dition/annulation reaction of 2-alkynylbenzaldehydes and methanol
in the presence of a suitable base.9 The overall process involves two
steps (Scheme 1, pathway a): (1) the palladium catalyzed
Scheme 1.
We wanted to simplify and improve this procedure. The two
steps of the domino approach have two common requirements:
base and energy. In the first step, it is assumed that the role of the
base is to promote the Sonogashira coupling by abstracting the
* Corresponding author. E-mail address: giorgio.abbiati@unimi.it (G. Abbiati).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.056

M. Dell’Acqua et al. / Tetrahedron 67 (2011) 1552e1556
1553
acetylenic proton from the terminal alkyne,10 whereas in the sec-
ond step, the role of the base is to activate the nucleophile.8 Fur-
thermore, microwave radiationdthat so effectively can promote
the cyclization step9dcould also assist the Sonogashira reaction.11
Thus a proper choice of base and reaction temperature could be
key factors for the success of the planned strategy. Moreover the
reagents featured in each step do not seemed to hamper the mul-
ticomponent approach; on contrary, the use of methanol as solvent
for the Sonogashira coupling is well known12 and palladium could
also assist the cyclization step enhancing the reactivity of triple
bond, in particular in the presence of less reactive alkyne
derivatives.13
On the basis of these preliminary remarks, we planned a novel
microwave-enhanced three-component synthesis of the dihy-
droisobenzofuran nucleus involving a one-pot coupling/addition/
annulation reaction (Scheme 1, pathway b) promoted by palladium
and base.
a base analogous to that employed in Cassar reaction condition)27
the outcome was satisfactory at 80 ꢀC in 2 h (Table 1, entry 3),
whereas rising the temperature to 110 ꢀC gave poorer results (Table
1, entry 4). These results suggested that the use of a stronger base
allowed the reaction to work at lower temperature. Next we tried to
fine-tune-upthe reaction conditions. The reduction of the amountof
baseto1 equivmade thereaction sluggish, and the alkyne2awas the
main product detected in the crude reaction mixture (Table 1, entry
5). We were pleasured to find that dichloro bis(triphenyl-phos-
phine)palladium(II)dcheaper than tetrakis triphenyl-phosphine
palladiumdgave slightly better results (Table 1, entry 6). A further
lowering of the temperature to 60 ꢀC gave aworse result in a twofold
reaction time (Table 1, entry 7). The studies on copper-free Sono-
gashira coupling (more correctly named CassareHeck coupling) are
widely reported in the literature,28 and we were delighted to ob-
serve that our multicomponent approach also worked well under
these favorable conditions, in spite of a modest reduction of yield
(Table 1, entry 8). Also, half loading of the catalyst/cocatalyst gave
consistent results in the same reaction time (Table 1, entry 9). Finally,
on the basis of recent studies on palladium-free coupling between
terminal alkynes and aryl halides, we tested some alternative metal
promoted routes bymeans of copper iodide,29 silvertriflate30 or gold
iodide31 in the presence of an appropriate phosphine ligand, but
unfortunately all these conditions did not give noteworthy results
(Table 1, entries 10e12).
In the literature there are some example of MCR’s involving
a Sonogashira coupling as key step for the synthesis of different het-
erocycles, such as pyrazoles,14 isoxazoles,14,15 halofurans,16 substituted
and annulated pyridines,17 pyrimidines,18 dihydroisoquinolines,19 in-
doles,20 indolizines,21 furo[2,3-b]pyridones,22 thiochromen-4-ones,23
thiopyran-4-ones,24 tetrahydro- -carbolines,25 and pyrano[4,3-b]
b
quinolines26 but to the best of our knowledge, this is the first example
of a multicomponent synthesis of dihydroisobenzofurans.
With the best conditions in hand, we tested the scope and
limitation of the approach by changing the substitution pattern on
the triple bond, on the benzaldehyde framework and modifying the
nature of the aromatic aldehyde. The reactions proceeded with
complete regiospecificity, leading to the formation of the corre-
sponding 5-exo-dig heterocycles in high yields. The (Z)-configura-
tion of the exocyclic double bond was established by comparison
with literature data8 and our previous findings.9 The results are
depicted in the Table 2.
Electron-poor phenylacetylenes gave excellent yields under
standard conditions (Table 2, entries 1 and 2), whereas in the
presence of an electron-donating group on the aryl moiety (Table 2,
entry 3) the best result was obtained at 130 ꢀC. When the electron
donating substituent on the aryl framework was in a sterically
2. Results and discussion
First, we looked for the optimum reaction conditions. The
screening was performed with 2-bromobenzadehyde 1a, methanol,
and 1-ethynyl-4-methylbenzene as a model system, and the results
are reported in Table 1. The first experiment was performed under
the standard Sonogashira conditions (Pd(PPh3)4, CuI, and K2CO3) but
with methanol as solvent and at a higher temperature by microwave
irradiation. After 1 h at 110 ꢀC the reaction gave the desired product
3a in a promising 75% yield, with traces of the simple coupling
product 2a (Table 1, entry 1). The reduction of reaction temperature
resulted in a worse yield in a twofold time (Table 1, entry 2). In the
presence of 3 equiv of a stronger base, such as t-BuOK (i.e., using
Table 1
Optimization of the reaction conditions
Entry
Base
Catalyst
Co-catalyst/ligand
Time (h)
Temp (ꢀC)
3a (Yield %)a
2a (Yield %)a
1
2
3
4
5
6
7
8
K2CO3 (5 equiv)
K2CO3 (5 equiv)
t-BuOK (3 equiv)
t-BuOK (3 equiv)
t-BuOK (1 equiv)
t-BuOK (3 equiv)
t-BuOK (3 equiv)
t-BuOK (3 equiv)
t-BuOK (3 equiv)
t-BuOK (3 equiv)
t-BuOK (3 equiv)
t-BuOK (3 equiv)
Pd(PPh3)4 (2 mol %)
Pd(PPh3)4 (2 mol %)
Pd(PPh3)4 (2 mol %)
Pd(PPh3)4 (2 mol %)
Pd(PPh3)4 (2 mol %)
PdCl2(PPh3)2 (2 mol %)
PdCl2(PPh3)2 (2 mol %)
PdCl2(PPh3)2 (2 mol %)
PdCl2(PPh3)2 (1 mol %)
CuI (10 mol %)
CuI (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
d
1
2
2
1
2
2
4
2
2
4
2
4
110
80
80
110
80
80
60
80
80
60
80
80
75
63
80
3
17
2
63
1
30b
82c
70
60b
d
3
67
72
d
2
1
d
d
d
9
CuI (1 mol %)
PPh3 (2 mol %)
PPh3 (3 mol %)
dppf (1 mol %)
10
11
12
AgOTf (10 mol %)
AuI (1 mol %)
d
Trace
a
Yields refer to pure isolated product.
Yields calculated from 1H NMR spectroscopy of the reaction crude.
Under conventional heating the reaction was complete in 2 h and gave 3a in 71% yield.
b
c

1554
M. Dell’Acqua et al. / Tetrahedron 67 (2011) 1552e1556
Table 2
Scope and limitation of the three-component approach to dihydroisobenzofuran derivatives
Entry
X
R1
Aldehyde
R2
Time (h)
Temp (ꢀC)
Product
Yielda (%)
1
2
3
4
5
6
7
8
CH
CH
CH
CH
CH
N
N
N
N
CH
CH
eH
eH
eH
eH
eH
eH
eH
eH
eH
eF
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1d
m-CF3ePhe
m-FePhe
2
2
2
4
2
2
2
2
80
80
130
130
80
80
60
60
60
3b
3c
3d
3e
3f
3g
3g
3h
3i
88
92
99
79
89
66
78
85
77
98
88
p-MeOePhe
p-MeOe(o-Me)ePhe
(EtO)2eCHe
p-CH3ePhe
p-CH3ePhe
m-FePhe
(EtO)2CHe
Phe
Phe
9
10
11
1
2
2.5
80
80
3j
3k
eOMe
a
Yields refer to pure isolated product.
demanding ortho-position, a twofold reaction time was required
(Table 2, entry 4). When the triple bond was substituted with an
acetal moiety the reaction gave the corresponding dihy-
droisobenzofuran 3f in very good yield (Table 2, entry 5).32 The
approach was also effective starting from the electron-poor
2-bromonicotinaldehyde 1b (Table 2, entry 6), but for this more
reactive substrate best results were obtained lowering the tem-
perature to 60 ꢀC (Table 2, entries 7e9). Finally, the effect of elec-
tron-withdrawing and electron-donating groups on the
2-bromobenzaldehyde was briefly investigated (Table 2, entries 10
and 11). In the first case the yields are excellent under standard
conditions (Table 2, entry 10), whereas in the presence of EDG the
best result was obtained in a quite longer reaction time (Table 2,
entry 11). Unfortunately, several attempts to react aliphatic alkynes
under the standard MCR conditions completely failed, also in the
presence of catalytic amounts of gold salts.33
According to literature, the reaction mechanism probably in-
volves an earlier Sonogashira coupling (testified by the isolation of
the coupling product if the reaction partners were reacted for an
insufficient reaction time), followed by a sequential base triggered
addition/annulation cascade. The involvement of metal in the ac-
tivation of the triple bond during the cyclization step was not in-
vestigated but at the moment, it cannot be ruled out. This
contribution has been proven on the related cyclization of carbonyl
groups on alkynes, activated with palladium/copper,13,34 gold/sil-
ver35 and also ruthenium or tungsten.36 Moreover it is worth not-
ing that the 5-exo-dig cyclization observed here with palladium is
quite different to the cyclization observed in similar reactions with
different benzylic O-nucleophiles catalyzed by gold, which pro-
ceeds by a 6-endo-dig ring closure.37
3. Conclusions
A different result was observed in the reaction of 1a with trie-
thylsilylacetylene (TES). The main product obtained was 3l along
with a minor amount of the expected desilylated compound 3m.
This is probably due to an early desilylation path occurring after the
Sonogashira coupling, followed by a second coupling of terminal
acetylene 2b with 1a, and a final addition/cyclization step to give 3l
(Scheme 2).
In summary, we have successfully transformed the previously
reported two-step domino approach9 to dihydroisobenzofurans
into an unprecedented high yielding MCR. The strategy demon-
strated tolerance to a variety of substituents on both alkynyl and
aldehyde partners. Moreover the approach was successfully applied
to the preparation of related dihydrofuro[3,4-b]pyridines. With
respect to the domino approach, this MCR allows a slight im-
provement on reaction yields together with a considerable re-
duction in operative steps, reaction times, and consumption of
energy, solvent and reagents.
4. Experimental section
4.1. General
All chemicals and solvents are commercially available and were
used after distillation or treatment with drying agents. Catalysts
were purchased from SigmaeAldrich. Silica gel F254 thin-layer
plates were employed for thin-layer chromatography (TLC). Silica
ꢁ
gel 40e63
m
/60A was employed for flash column chromatography.
Melting points are uncorrected. Infrared spectra were recorded on
a FT-IR spectrophotometer using KBr tablets for solids and NaCl
disks for oils. Proton NMR spectra were recorded at room temper-
ature, at 200 or 500 MHz, with the resonance of solvent as the
Scheme 2.

M. Dell’Acqua et al. / Tetrahedron 67 (2011) 1552e1556
1555
internal reference. 13C NMR spectra were recorded at room tem-
perature at 50.3 or 125.75 MHz, with the resonance of solvent as
the internal reference. The APT sequence was used to distinguish
the methine and methyl carbon signals from those due to methy-
lene and quaternary carbons. 2D-NOESY spectra were acquired at
500 MHz in the phase-sensitive TPPI mode with 2 Kꢁ256 complex
FIDs, spectral width of 5682 Hz, recycling delay of 3 s, 8 scans and
a mixing time of 1.3 s. All spectra were transformed and weighted
with a 90ꢀ shifted sine-bell squared function to 1 ꢁ1 K real data
points. Microwave assisted reactions were performed in multimode
oven, using 12 mL sealed glass vessels. The reaction times specified
in Tables 1 and 2 include ‘ramp times’. The internal temperature
was detected with a fiber optic sensor.
152.2, 154.7 ppm. ESI-MS: m/z (%)¼254 (100) [Mþ1]þ. MSeMS: m/z
(%)¼222 (100) [MꢂOCH3]. HRMS (ESI) calcd for C16H16NO2(þ1),
254.1176. Found: 254.1175.
4.2.4. (Z)-7-(3-Fluorobenzylidene)-5-methoxy-5,7-dihydrofuro[3,4-
b]pyridine (3h). Yield: 220 mg (85%). Rf (40% EtOAc/hexane) 0.26.
Eluent for chromatography: hexane/EtOAc/TEA (85:15:0.6). Orange
solid; mp 89ꢂ93 ꢀC. IR (KBr): nmax¼3069, 2939, 1671, 1613, 1579,
1485,1443,1423,1385,1271,1146,1118,1089, 945, 785, 680 cmꢂ1.1H
NMR (CDCl3, 200 MHz):
d
¼3.60 (s, 3H, CH3), 6.48 (s,1H, CH), 6.56 (s,
1H, CH), 6.87e6.97 (m, 1H, arom.), 7.26e7.37 (m, 2H, arom.), 7.47 (d,
J¼7.7 Hz,1H, arom.), 7.59e7.67 (m,1H, arom.), 7.79 (dd, J¼7.7,1.1 Hz,
1H, arom), 8.68 (dd, J¼4.8, 1.5 Hz, 1H, arom.) ppm. 13C NMR
(50.3 MHz, CDCl3, APT):
d
¼55.3, 99.2(d, 4JC,F¼2.7 Hz),106.3,113.5 (d,
4.2. Representative procedure for the synthesis of
compounds 3
2JC,F¼21.7 Hz), 115.5 (d, 2JC,F¼22.5 Hz), 123.4, 124.9 (d, 4JC,F¼2.7 Hz),
3
3
129.9 (d, JC,F¼8.4 Hz), 130.8, 131.7, 137.7 (d, JC,F¼8.4 Hz), 152.1,
152.4,154.2,160.8,165.6 (d,1JC,F¼244 Hz) ppm. ESI-MS: m/z (%)¼258
(100) [Mþ1]þ. MSeMS: m/z (%)¼226 (100) [MꢂOCH3]. HRMS (ESI)
calcd for C15H12NO2F(þ1), 258.0925. Found: 258.0925.
In a 12 mL MW glass vessel, a mixture of the appropriate 2-
bromoarylaldehyde
1 (1 mmol), alkyne (1.2 mmol), t-BuOK
(337 mg, 3 mmol), and PdCl2(PPh3)2 (14.0 mg, 0.02 mmol) in dry
methanol (4 mL) was stirred at room temperature under a nitrogen
atmosphere for 10 min, then CuI (3.81 mg, 0.02 mmol) was added.
The reactor vessel was sealed and the stirred mixture was heated at
the suitable temperature for the proper time in a multimode mi-
crowave oven (for times and temperatures see Table 2). After
cooling, the reaction mixture was poured into NaHCO3 satd soln
(20 mL) and extracted with ethyl acetate (3ꢁ10 mL). The organic
layer, dried over Na2SO4, was evaporated under reduced pressure.
The reaction crude was purified by flash column chromatography
4.2.5. (Z)-7-(2,2-Diethoxyethylidene)-5-methoxy-5,7-dihydrofuro
[3,4-b]pyridine (3i). Yield: 204 mg (77%). Rf (40% EtOAc/hexane)
0.20. Eluent for chromatography: hexane/EtOAc/TEA (80:20:0.6).
Orange oil. IR (neat, NaCl): nmax¼2975, 2931, 2897, 1695, 1588, 1424,
1376, 1119, 1093, 1055, 993, 948, 792 cmꢂ1 1H NMR (CDCl3,
.
200 MHz):
d
¼1.24 (t, J¼6.9 Hz, 6H, 2CH3), 3.49 (s, 3H, CH3),
3.57e3.79 (m, 4H, 2CH2), 5.62 (d, J¼7.7 Hz, 1H, CH), 5.72 (d,
J¼7.7 Hz, 1H, CH), 6.39 (s, 1H, CH), 7.25e7.31 (m, 1H, arom.), 7.74
(dd, J¼7.7, 1.1 Hz, 1H, arom.), 8.65 (dd, J¼4.8, 1.5 Hz, 1H, arom.) ppm.
on SiO2 (40ꢂ63
m
m). Compounds 3aec, e are known.9
13C NMR (50.3 MHz, CDCl3, APT):
d
¼15.5, 55.0, 61.1, 97.2, 97.8, 105.3,
123.7, 131.4, 131.5, 152.3, 153.1, 153.4 ppm. ESI-MS: m/z (%)¼288
(80) [MþNa]þ, 220 (100) [MꢂOEt]þ. Anal. Calcd for C14H19NO4: C,
63.38; H 7.22; N, 5.28. Found: C, 63.44; H, 7.23; N, 5.26.
4.2.1. (Z)-1-Methoxy-3-(4-methoxybenzylidene)-1,3-dihy-
droisobenzofuran (3d). Yield: 201 mg (75%). Rf (5% EtOAc/hexane)
0.15. Eluent for chromatography: hexane/EtOAc/TEA (99:1:0.6).
Orange solid; mp 97e99 ꢀC. IR (KBr): nmax¼2897, 2838, 1693, 1604,
4.2.6. (Z)-1-Benzylidene-5-fluoro-3-methoxy-1,3-dihy-
droisobenzofuran (3j). Yield: 250 mg (98%). Rf (10% EtOAc/hexane)
0.28. Eluent for chromatography: hexane/EtOAc/TEA (99:1:0.6). Red
oil. IR (neat, NaCl): nmax¼3064, 2935, 1666, 1618, 1595, 1493, 1483,
1508, 1467, 1377, 1115, 1088, 844, 763 cmꢂ1 1H NMR (CDCl3,
.
200 MHz):
d
¼3.49 (s, 3H, CH3), 3.83 (s, 3H, CH3), 5.96 (s, 1H,
C
sp2eH), 6.56 (s, 1H, Csp3eH), 6.91 (d, J¼8.4 Hz, 2H, arom.),
7.35e7.60 (m, 4H, arom.), 7.73 (d, J¼8.4 Hz, 2H, arom.) ppm. 13C
1449, 1370, 1255, 1142, 1119, 1084, 964, 783, 694 cmꢂ1 1H NMR
.
NMR (CDCl3, 50.3 MHz):
d¼54.3, 55.5, 98.1, 107.5, 114.2, 119.7, 123.3,
(CDCl3, 200 MHz):
d
¼3.52 (s, 3H, CH3), 5.93 (s, 1H, CH), 6.52 (s, 1H,
128.8, 128.9, 129.8, 130.1, 136.0, 136.9, 151.8, 158.2 ppm. ESI-MS: m/z
(%)¼291 (95) [MþNa]þ, 237 (100) [MꢂOCH3]þ. HRMS (ESI) calcd for
C17H16O3Na(þ1), 291.0992. Found: 291.0990.
CH), 7.12e7.26 (m, 3H, arom.), 7.32e7.40 (m, 2H, arom.), 7.50e7.57
(m, 1H, arom), 7.74e7.78 (m, 2H, arom.) ppm. 13C NMR (50.3 MHz,
6
4
CDCl3, APT):
d
¼54.6, 98.3 (d, JC,F¼2.3 Hz), 106.9 (d, JC,F¼2.7 Hz),
2
2
110.5 (d, JC,F¼24.0 Hz), 117.9 (d, JC,F¼24.0 Hz), 121.6 (d,
3JC,F¼9.1 Hz), 126.2, 128.5, 128.6, 131.8 (d, 4JC,F¼2.7 Hz), 135.9, 139.2
(d, 3JC,F¼8.8 Hz),152.3,161.1,166.1 (d,1JC,F¼249 Hz) ppm. ESI-MS: m/
z (%)¼257 (100) [Mþ1]þ. MSeMS: m/z (%)¼225 (100) [MꢂOCH3].
Anal. Calcd for C16H13FO2: C, 74.99; H 5.11. Found: C, 75.08; H, 5.07.
4.2.2. (Z)-1-(2,2-Diethoxyethylidene)-3-methoxy-1,3-dihy-
droisobenzofuran (3f). Yield: 235 mg (89%). Rf (20% EtOAc/hexane)
0.34. Eluent for chromatography: hexane/EtOAc/TEA (90:10:0.6).
Pale yellow oil. IR (neat, NaCl): nmax¼2975, 2930, 2881, 1689, 1469,
1373, 1116, 1092, 1054, 994, 954, 758 cmꢂ1 1H NMR (CDCl3,
.
200 MHz):
d
¼1.25 (t, J¼6.8 Hz, 6H, 2CH3), 3.42 (s, 3H, CH3),
4.2.7. (Z)-1-Benzylidene-3,5-dimethoxy-1,3-dihydroisobenzofuran
(3k). Yield: 206 mg (77%). Rf (10% EtOAc/hexane) 0.13. Eluent for
chromatography: hexane/EtOAc/TEA (98:2:0.6). Red solid; mp
64e67 ꢀC. IR (KBr): nmax¼2915, 2838, 1659, 1612, 1492, 1454, 1369,
3.53e3.80 (m, 4H, 2CH2), 5.21 (d, J¼7.6 Hz, 1H, CH), 5.61 (d,
J¼7.6 Hz, 1H, CH), 6.40 (s, 1H, CH), 7.39e7.51 (m, 4H, arom.) ppm.
13C NMR (50.3 MHz, CDCl3, APT):
d¼15.5, 54.3, 61.4, 95.7, 97.7, 106.9,
120.6, 123.2, 129.7, 130.0, 134.3, 138.0, 155.0 ppm. ESI-MS: m/z (%)¼
287 (100) [MþNa]þ, 219 (25) [MꢂOEt]þ. Anal. Calcd for C15H20O4: C,
68.16; H, 7.63. Found: C, 68.09; H, 7.65.
1262, 1035, 964, 820 cmꢂ1
.
1H NMR (CDCl3, 200 MHz):
d¼3.51 (s,
3H, CH3), 3.86 (s, 3H, CH3), 5.86 (s, 1H, CeH), 6.52 (s, 1H, CeH),
6.94e7.03 (m, 2H, arom.), 7.12e7.21 (m, 1H, arom.), 7.31e7.39 (m,
2H, arom.), 7.49 (d, J¼8.4 Hz, 1H, arom.), 7.75 (dd, J¼8.4, 1.1 Hz, 2H,
4.2.3. (Z)-5-Methoxy-7-(4-methylbenzylidene)-5,7-dihydrofuro[3,4-
b]pyridine (3g). Yield: 197 mg (78%). Rf (40% EtOAc/hexane) 0.30.
Eluent for chromatography: hexane/EtOAc/TEA (90:10:0.6). Orange
solid; mp 122e126 ꢀC. IR (KBr): nmax¼2954, 2924, 1667, 1583, 1422,
arom.) ppm. 13C NMR (CDCl3, 50.3 MHz, APT):
107.2 (two signals), 117.8, 121.2, 125.7, 128.3, 128.4, 128.6, 136.4,
138.9, 153.3, 161.2 ppm. ESI-MS: m/z (%)¼269 (100) [Mþ1]þ. Anal.
Calcd for C17H16O3: C, 76.10; H 6.01. Found: C, 76.04; H, 6.08.
d
¼54.3, 55.9, 96.8,
1378, 1117, 1085, 943, 790 cmꢂ1. 1H NMR (CDCl3, 200 MHz):
d¼2.36
(s, 3H, CH3), 3.56 (s, 3H, CH3), 6.49 (s, 1H, CH), 6.56 (s, 1H, CH),
4.2.8. (Z)-2-((3-Methoxyisobenzofuran-1(3H)-ylidene)methyl)benz-
aldehyde (3l). Yield: 71 mg (54%). Rf (5% EtOAc/hexane) 0.10. Eluent
for chromatography: hexane/EtOAc/TEA (95:5:0.6). Dark yellow oil.
IR (KBr): nmax¼2933, 2836, 1692, 1647, 1612, 1594, 1484, 1467, 1375,
7.17e7.29 (m, 3H, arom.), 7.70e7.80 (m, 3H, arom.), 8.66 (dd, J¼5.1,
1.5 Hz, 1H, arom.) ppm. 13C NMR (50.3 MHz, CDCl3, APT):
d¼21.5,
54.9,100.4,105.8,122.9,129.2,129.4,130.4,131.6,132.6,136.6,150.6,

1556
M. Dell’Acqua et al. / Tetrahedron 67 (2011) 1552e1556
1205, 1117, 1089, 946, 762 cmꢂ1. 1H NMR (C6D6, 500 MHz):
d¼3.22
8. (a) Nishiwaki, N.; Minakata, S.; Komatsu, M.; Ohshiro, Y. Synlett 1990, 273; (b)
Godet, T.; Bosson, J.; Belmont, P. Synlett 2005, 2786; (c) Abbiati, G.; Canevari, V.;
Caimi, S.; Rossi, E. Tetrahedron Lett. 2005, 46, 7117; (d) Wang, F.; Wang, Y.; Cai,
L.; Miao, Z.; Chen, R. Adv. Synth. Catal. 2008, 350, 2733; (e) Cikotiene, I.; Mor-
kunas, M.; Motiejaitis, D.; Brukstus, A. Synlett 2008, 1693; (f) Kanazawa, C.; Ito,
A.; Terada, M. Synlett 2009, 638.
(s, 3H, CH3), 6.29 (s, 1H, CeH), 7.04e7.10 (m, 2H, arom.), 7.12e7.21
(m, 1H, arom.), 7.19 (m, 1H, arom.), 7.38 (dt, J¼7.8, 1.5 Hz, 1H, arom.),
7.52 (dd, J¼6.6, 1.4 Hz, 1H, arom.), 7.59 (s, 1H, CeH), 7.63 (dd, J¼7.7,
1.4 Hz, 1H, arom.), 8.57 (dd, J¼8.0, 0.6 Hz, 1H, arom.), 10.2 (s, 1H,
9. Dell’Acqua, M.; Facoetti, D.; Abbiati, G.; Rossi, E. Synthesis 2010, 2367.
CHO) ppm. 13C NMR (C6D6, 125.75 MHz, APT):
d
¼53.0, 92.7, 107.2,
ꢂ
10. Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
11. For an extensive study on microwave-enhanced Sonogashira reaction see:
119.9, 122.3, 125.6, 128.6, 129.2, 129.5, 131.8, 132.2, 132.9, 134.8,
136.8, 134.8, 155.1, 191.8 ppm. ESI-MS: m/z (%)¼267 (100) [Mþ1]þ.
MSeMS: m/z (%)¼235 (100) [MꢂOCH3]. Anal. Calcd for C17H14O3: C,
76.68; H 5.30. Found: C, 76.64; H, 5.31.
ꢂ
Erdelyi, M.; Gogoll, A. J. Org. Chem. 2001, 66, 4165.
12. Wang, L.; Li, P.-H. Chin. J. Chem. 2003, 21, 474.
13. Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002,124, 764.
14. (a) Ahmed, M. S. M.; Kobayashi, K.; Mori, A. Org. Lett. 2005, 7, 4487; (b) Willy, B.;
€
Muller, T. J. J. Eur. J. Org. Chem. 2008, 4157.
€
15. Willy, B.; Rominger, F.; Muller, T. J. J. Synthesis 2008, 293.
4.2.9. 1-Methoxy-3-methylene-1,3-dihydroisobenzofuran
(3m). Yield: 41 mg (25%). Rf (5% EtOAc/hexane) 0.26. Eluent for
chromatography: hexane/EtOAc/TEA (98:2:0.6). Yellow oil. IR
(NaCl): nmax¼3079, 2934, 1668, 1467, 1377, 1210, 1100, 982, 766,
€
16. (a) Karpov, A. S.; Merkul, E.; Oeser, T.; Muller, T. J. J. Chem. Commun. 2005, 2581;
€
(b) Karpov, A. S.; Merkul, E.; Oeser, T.; Muller, T. J. J. Eur. J. Org. Chem. 2006, 2991.
€
17. (a) Yehia, N. A. M.; Polborn, K.; Muller, T. J. J. Tetrahedron Lett. 2002, 43, 6907; (b)
€
Dediu, O. G.; Yehia, N. A. M.; Oeser, T.; Polborn, K.; Muller, T. J. J. Eur. J. Org. Chem.
€
2005, 1834; (c) Schramm, O. G.; Oeser, T.; Muller, T. J. J. J. Org. Chem. 2006, 71,
749 cmꢂ1. 1H NMR (C6D6, 200 MHz):
d
¼3.14 (s, 3H, CH3), 4.54 (d,1H,
3494.
€
€
18. (a) Karpov, A. S.; Muller, T. J. J. Org. Lett. 2003, 5, 3451; (b) Karpov, A. S.; Muller,
J¼2.1 Hz, ]CH2), 4.73 (d, 1H, J¼2.1 Hz, ]CH2), 6.09 (s, 1H, CeH),
€
T. J. J. Synthesis 2003, 2815; (c) Karpov, A. S.; Merkul, E.; Rominger, F.; Muller, T.
6.91e6.96 (m, 2H, arom.), 7.05e7.13 (m, 2H, arom.) ppm. 13C NMR
J. J. Angew. Chem., Int. Ed. 2005, 44, 6951.
19. Zhou, H.; Jin, H.; Ye, S.; He, X.; Wu, J. Tetrahedron Lett. 2009, 50, 4616.
(C6D6, 50.3 MHz, APT):
d
¼54.7, 81.2, 107.4, 121.2, 124.0, 129.9, 130.4,
135.7, 139.6, 160.4 ppm. APCI-MS: m/z (%)¼163 (100) [Mþ1]þ. Anal.
20. Kaspar, L. T.; Ackermann, L. Tetrahedron 2005, 61, 11311.
€
21. Rotaru, A. V.; Druta, I. D.; Oeser, T.; Muller, T. J. J. Helv. Chim. Acta 2005, 88,
Calcd for C10H10O2: C, 74.06; H 6.21. Found: C, 74.12; H, 6.17.
1798.
22. Bossharth, E.; Desbordes, P.; Monteiro, N.; Balme, G. Org. Lett. 2003, 5, 2441.
€
23. Willy, B.; Muller, T. J. J. Synlett 2009, 1255.
Acknowledgements
€
24. Willy, B.; Frank, W.; Muller, T. J. J. Org. Biomol. Chem. 2010, 8, 90.
25. (a) Karpov, A. S.; Oeser, T.; Muller, T. J. J. Chem. Commun. 2004, 1502; (b) Karpov,
A. S.; Rominger, F.; Muller, T. J. J. Org. Biomol. Chem. 2005, 3, 4382.
26. Chandra, A.; Singh, B.; Khanna, R. S.; Singh, R. M. J. Org. Chem. 2009, 74, 5664.
€
This work was supported by Ministero dell’Istruzione, Uni-
€
ꢀ
versita e Ricerca, Roma.
27. Cassar, L. J. Organomet. Chem. 1975, 93, 253.
28. For some representative examples see: (a) Alami, M.; Ferri, F.; Linstrumelle, G.
Tetrahedron Lett. 1993, 34, 6403; (b) Leadbeater, N. E.; Tominack, B. J. Tetrahe-
Supplementary data
ꢂ
ꢂ
dron Lett. 2003, 44, 8653; (c) Gil-Molto, J.; Najera, C. Eur. J. Org. Chem. 2005,
4073; (d) Bakherad, M.; Keivanloo, A.; Bahramian, B.; Mihanparast, S. Tetrahe-
dron Lett. 2009, 50, 6418.
Supplementary data associated with this article (1H, 13C, and
HSQC NMR spectra for compounds 3aem) can be found in online
version at doi:10.1016/j.tet.2010.12.056. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
29. Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58,
4716.
30. Li, P.; Wang, L. Synlett 2006, 2261; For a recent review on silver catalyzed
CspeH bond transformation see: Yamamoto, Y. Chem. Rev. 2008, 108, 3199.
31. Li, P.; Wang, L.; Wang, M.; You, F. Eur. J. Org. Chem. 2008, 5946.
32. It is interesting to note that the previously reported domino addition/annula-
tion of preformed 2-(3,3-diethoxyprop-1-ynyl)benzaldehyde gave directly the
corresponding free aldehyde derivative (see Ref. 9).
References and notes
33. In the domino approach this drawback has been overcome performing the
reaction at room temperature in the presence of a catalytic amount of NaAuCl4
(see Ref. 9).
34. (a) Wei, L.-L.; Wei, L.-M.; Pan, W.-B.; Wu, M.-J. Synlett 2004, 1497; (b) Patil, N. T.;
Yamamoto, Y. J. Org. Chem. 2004, 69, 5139; (c) Mondal, S.; Nogami, T.; Asao, N.;
Yamamoto, Y. J. Org. Chem. 2003, 68, 9496.
ꢂ
1. (a) Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-WCH: Wein-
heim, 2006; (b) Ganem, B. Acc. Chem. Res. 2009, 42, 463.
2. (a) Orru, R. V. A.; de Greef, M. Synthesis 2003,1471; (b) D’Souza, D. M.; Muller, T. J. J.
Chem. Soc. Rev. 2007, 36, 1095; (c) Sunderhaus, J. D.; Martin, S. F. Chem.dEur. J.
2009, 15, 1300.
35. Godet, T.; Vaxelaire, C.; Michel, C.; Milet, A.; Belmont, P. Chem.dEur. J. 2007, 13,
5632.
36. Gulías, M.; Rodríguez, J. R.; Castedo, L.; Mascarenas, J. L. Org. Lett. 2003, 5, 1975.
3. Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439.
4. (a) de Boer, T.; Amore, A.; Orru, R. V. A. In Microwaves in Organic Synthesis, 2nd
ed.; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2006; Vol. 2, p 788; (b) Caddick, S.;
Fitzmaurice, R. Tetrahedron 2009, 65, 3325.
5. Lipka, E.; Vaccher, M.-P.; Vaccher, C.; Len, C. Bioorg. Med. Chem. Lett. 2005, 15,
501 and citation therein.
~
37. (a) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc.
€
€
2002, 124, 12650; (b) Hashmi, A. S. K.; Schafer, S.; Wolfle, M.; Diez Gil, C.;
Fischer, P.; Laguna, A.; Blanco, M. C.; Gimeno, M. C. Angew. Chem., Int. Ed. 2007,
€
ꢂ
46, 6184; (c) Hashmi, A. S. K.; Buhrle, M.; Salathe, R.; Bats, J. W. Adv. Synth. Catal.
6. Lea, A. P.; Faulds, D. Drugs 1996, 51, 846.
2008, 350, 2059.
7. Ankisetty, S.; Amsler, C. D.; Clintock, J. B.; Baker, B. J. J. Nat. Prod. 2004, 67, 1172.