Mild regiospecific synthesis of 1-alkoxy-isochromenes catalyzed by well-defined [silver(I)(pyridine-containing ligand)] complexes

Article abstract of DOI:10.1021/jo5002559

The synthesis of 3-substituted-1-alkoxyisochromenes starting from 2-alkynylbenzaldehydes and different alcohols is reported. The reaction is catalyzed by a silver(I) complex with an original macrocyclic pyridine-containing ligand. The approach is characterized by absolute regioselectivity, mild reaction conditions, good to excellent reaction yields, cleanness of the reaction, and reduced purification steps. The reaction mechanism was investigated by in-depth ¹H NMR experiments and an aimed trapping experiment.

Full text of DOI:10.1021/jo5002559

Article
pubs.acs.org/joc
Mild Regiospecific Synthesis of 1‑Alkoxy-isochromenes Catalyzed
by Well-Defined [Silver(I)(Pyridine-Containing Ligand)] Complexes
Monica Dell’Acqua,† Brunilde Castano,‡ Clara Cecchini,† Tommaso Pedrazzini,‡ Valentina Pirovano,†
Elisabetta Rossi,† Alessandro Caselli,*,‡ and Giorgio Abbiati*,†
†Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Generale e Organica “A. Marchesini”, Universita
̀
degli Studi di Milano,
Via Venezian, 21, 20133 Milano, Italy
‡Dipartimento di Chimica, Universita
̀
degli Studi di Milano, Via Golgi, 19, 20133 Milano, Italy
S
* Supporting Information
ABSTRACT: The synthesis of 3-substituted-1-alkoxyisochro-
menes starting from 2-alkynylbenzaldehydes and different
alcohols is reported. The reaction is catalyzed by a silver(I)
complex with an original macrocyclic pyridine-containing ligand.
The approach is characterized by absolute regioselectivity, mild
reaction conditions, good to excellent reaction yields, cleanness
of the reaction, and reduced purification steps. The reaction
1
mechanism was investigated by in-depth H NMR experiments
and an aimed “trapping” experiment.
usually catalyzed by a metal salt or promoted by a base, but the
regioselectivity of the cycloisomerization step (i.e., 5-exo-dig vs
6-endo dig cyclization) is not always easy to rationalize5
(Scheme 1). In general, the reactions promoted by bases lead
preferentially to the 5-exo-dig cyclization products (i.e.,
dihydroisobenzofurans, dihydrofuroquinolines, or dihydrofuro-
pyrimidines) via an addition/annulation sequence that pro-
bably involves the formation of a hemiacetal anion (Scheme 1,
path B).6 Conversely, the metal-catalyzed approaches can lead
to both products depending on several factors, including the
nature of the aromatic aldehyde (i.e., the presence of one or
more nitrogens in the aromatic ring) and the substitution on
the triple bond. Usually 6-endo-dig cyclization products pre-
dominate (i.e., isochromenes or dihydropyranoquinoline),
whose formation is believed to occur through a highly reactive
benzopyrylium intermediate (metal ate complex) followed by
the nucleophilic attack from the alcohol as a mild nucleophile
(Scheme 1, path A).
INTRODUCTION
■
Isochromene and isochromane nuclei are the core of some in-
teresting bioactive molecules and natural products. For example,
the methyl 1,5,8-trimethoxy-1H-isochromene-3-carboxylate
was patented as a potential antitumor agent against breast
cancer,1 and the related carboxamide derivative BCH2051 dis-
played an interesting activity against the human ovarian cancer
cell line SKOV3 and the human colon carcinoma cell line
HT-29.2 Moreover, the structure of isochromane is the skeleton
of a diterpene from the Antarctic sponge Dendrilla Membranosa
called membranolide B3 (Figure 1). All of these compounds are
characterized by a cyclic-acetal framework due to the presence
of a methoxy group on C1.
Several metal ions, such as Pd(II),7 Cu(I),8 Ag(I),9 Au(I),10
and In(III)11 salts, have been used as catalysts for the synthesis
of isochromenes and analogues following this approach. An
enantioselective version of this reaction, catalyzed by chiral gold
acyclic diaminocarbene (ADC) complexes has also been
reported.12 Aside from the above-mentioned metal-catalyzed
approaches, the research groups of Barluenga13 and Larock14
developed two outstanding synthetic strategies for the syn-
thesis of 4-functionalized-isochromenes by using different
Figure 1. Examples of 1-alkoxy-isochromene/ane-containing bioactive
molecules.
An efficient method to build up 4-unsubstituted-1-alkoxy-
isochromenes and related heteroaryl compounds (e.g., dihy-
dropyranoquinolines) is the regioselective domino addition/
cycloisomerization reaction of a properly substituted 2-alkynyl-
(hetero)arylaldehyde with an alcohol.4 These reactions are
Received: February 2, 2014
Published: March 18, 2014
© 2014 American Chemical Society
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Scheme 1. 5-Exo-dig vs 6-Endo-dig Cyclization Mode of 2-Alkynyl(hetero)arylaldehydes and Alcohols
Scheme 2. Synthesis of Pc-L 1 and Its Silver Complexes 2a−c
electrophiles, i.e., IPy2BF4 or else X2, ICl, NXS, p-O2NC6H4SCl,
and PhSeBr, respectively.
unknown [Ag(I)(Pc-L)] complexes are presented. To the best
of our knowledge, this work represents the first example of
application of [Ag(I)(Pc-L)] complexes in catalysis.
For many years, we have been interested in the development
of domino synthetic strategies15 for the construction of nitro-
gen and/or oxygen containing heterocycles16 starting from alkyne
derivatives.17 In 2010 we reported on a regioselective synthesis
of substituted 1-methoxy-3-methylen-1,3-dihydroisobenzofurans
by a microwave−enhanced domino addition/cycloisomerization
reaction of 2-alkynylbenzaldehydes and methanol in the
presence of a suitable base.5b This approach was successfully
transformed in an advantageous multicomponent process.18
As a followup to these studies, in this work we focused our atten-
tion to the selective synthesis of regioisomeric 1-alkoxyisochromenes
starting from the same substrates (i.e., 2-alkynylbenzaldehydes).
To do this, we used an original, stable, and versatile silver(I)
complex as a catalyst that was characterized by the presence of a
macrocyclic pyridine-containing ligand (Pc-L). This approach
is characterized by absolute regioselectivity, mild reaction
conditions, good to excellent reaction yields, cleanness of the
reaction, and reduced purification steps.
The synthesis of pyridine-containing macrocycles was first
reported by Stetter and co-workers.19 These macrocycles were
originally engaged as ligands for the coordination of lanthanide
ions in MRI contrasting agents.20 Their transition metal
complexes have also been successfully used in catalysis. For
example, [Cu(I)(Pc-L)] complexes have been demonstrated to
be efficient catalysts in the cyclopropanation reaction of
alkenes21 and in the Henry reaction.22 In this work, some
RESULTS AND DISCUSSION
■
Preparation of the Catalysts. The selected pyridine-based
12-membered tetraaza macrocyclic Pc-L 1 was obtained in good
overall yield from commercially available starting materials
according to Scheme 2.22 The synthesis involved the
nucleophilic ring-opening of 1-tosylaziridine by benzylamine
to give the 1,7-ditosyl-4-benzyl-1,4,7-triazaheptane in quantita-
tive yield. Thus, by reacting the bis-protected triamine with 2,6-
pyridinedimethanol 2,6-dimesylate in refluxing anhydrous ace-
tonitrile in the presence of anhydrous K2CO3, the macrocycle
1 was obtained in 88% yield. 2,6-Pyridinedimethanol 2,6-
dimesylate was obtained in 91% yield by the reaction of 2,6-
pyridinedimethanol and an excess of methanesulfonylchloride
in ethyl acetate in the presence of triethylamine. With respect
to the method previously reported,22 we improved the
approach by using dielectric heating, which allowed for an
overall increase in yield and a reduction of the time necessary
to obtain the 1,7-Ditosyl-4-benzyl-1,4,7-triazaheptane. More-
over, the product obtained by this method was sufficiently
pure and could be used for the macrocyclization step with-
out the need for further purification. Macrocyclic ligand 1
was converted in three different “well-defined” Ag(I) complexes
2a−c by reacting with three different silver salts, silver
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Table 1. Optimization of the Reaction Conditions
entry
solvent
equiv MeOH
[3a] M
t (h)
catalyst
catalyst loading (mol %)
4a (yield %)
a
1
MeOH
dioxane
DCE
0.25
0.25
0.25
0.25
0.125
0.50
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
5
5
2a
5
5
83
2
3
2a
88
b
3
3
1
2a
5
94
4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
3
2.5
4
2a
5
99
98
98
92
93
99
99
82
70
5
3
2a
5
6
3
2.5
22
24
2.5
2
2a
5
7
3
2b
5
8
3
2c
5
9
1.5
1.05
1.05
1.05
3
2a
5
10
11
12
13
14
2a
5
8
2a
2.5
1
36
4
2a
c
AgOTf
5
64
c
1.05
3
AgBF4
5
60
a
b
c
Beside dimethyl acetal 5a in 15% yield. Beside traces of acetal 5a. Yields calculated via 1H NMR using dimethyl terephthalate (DMT) as internal
standard.
1
tetrafluoroborate, silver triflate, and silver bis-triflimidate,
respectively.
1,2-dichloroethane, as revealed by the accurate analysis of H
NMR spectra. The same pattern of signals are present in the 1H
NMR spectra of all complexes 2a−c, independently from the
type of counterion: an apparent Cs symmetry of the structure is
observed in solution, with two signals for each couple of
We kept the silver salts and all silver containing solutions
in the dark until we isolated the final products. The three
complexes 2a−c were readily formed by adding the silver salt
to a 1,2-dichloroethane solution of ligand 1 under a nitrogen
protecting atmosphere, yielding a yellowish solution that was
stirred at room temperature (rt) for 1 h. If traces of unreacted
solid were present, the solution was filtered. The reaction mixture
was concentrated to half volume, and the addition of toluene or
n-hexane to these solutions caused the precipitation of complexes
2a−c as a white powder in yields ranging from 57 to 91%
(Scheme 2). All silver complexes were fully characterized by
NMR, electrospray ionization mass spectrometry (ESI-MS), IR,
and UV−vis spectroscopy. The metal atom was placed in the large
macrocyclic cavity of the ligand, which has four potential co-
ordination sites that, upon addition of a fifth external ligand, pro-
vide a strongly distorted trigonal bipyramidal coordination geo-
metry. In sharp contrast to the analogous complexes of copper(I),
these silver complexes do not suffer from oxidation when in con-
tact with air. On the other hand, they have a tendency to absorb
atmospheric moisture to form monoaquo species (Scheme 2).
We also tried to prepare complexes with a coordinating
anion such as a chloride ion. Neither the direct reaction of the
ligand 1 with silver chloride, nor the anion-exchange reaction of
complex 2a with tetrabutylammonium chloride led to the
desired product. In the first case, no reaction occurred, whereas
in the second, immediate expulsion of the metal from the ligand
as silver chloride precipitate was observed. These reactions
demonstrated that silver complexes 2a−c are sensitive to any
chloride anion that may be present in solution.
equivalent methylene groups. A H−19F heteronuclear Over-
1
hauser effect spectroscopy (HOESY) spectrum shows that the
tetrafluoroborate anion in complex 2a has weak proximity
interactions with only the pyridine ring of the ligand. The UV−
vis spectra of complexes 2a and 2b show the absence of
absorption bands at wavelengths higher than 290 nm, which is
consistent with the observed absence of color and the d10 elec-
tronic configuration of the metal (no d−d transitions allowed).
The shape of the UV−vis spectrum of the ligand 1 does not
vary owing to complexation, while the intensities of the absorp-
tions are quite different; therefore, the bands recorded in the
near UV region can be related to ligand-centered transitions.
Addition/Cycloisomerization Reactions. The first ex-
periment was performed on a model reaction with 2-[(4-
methoxyphenyl)-ethynyl]benzaldehyde 3a and methanol as
the reagent/solvent under unoptimized conditions (Table 1,
entry 1). This preliminary test revealed that the silver complex
2a (5 mol %) was able to promote the addition/cycloisomer-
ization of 3a with methanol regioselectively yielding the corre-
sponding isochromene 4a in very good yield (83%) after 5 h.
The thin layer chromatography (TLC) analysis of the reaction
crude was particularly clean and showed only two spots. Thus,
the small amount of dimethyl acetal 5a was the sole byproduct
1
detected by H NMR of the reaction crude and accounted for
the mass balance of the reaction (Table 1, entry 1).23 To
optimize the reaction conditions, we performed a series of new
experiments. Aiming to find a proper medium to be used with
different alcohols and to suppress the formation of the acetal
In the absence of coordinating ligands, the silver complexes
2a−c have a tendency to cocrystallize with a molecule of
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Table 2. Scope and Limitations of the Approach
a
entry
substrate
catalyst
R1
R2
t (h)
4 (yield %)
4a 99
1
3a
3b
3b
3c
3d
3d
3e
3e
3e
3a
3b
3b
3c
3d
3d
3a
3b
3c
3d
3d
3a
2a
2a
2c
2a
2a
2b
2a
2a
2a
2a
2a
2c
2a
2a
2c
2a
2a
2a
2a
2b
2a
2a
p-MeO-Ph-
p-Me-Ph-
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Cy
2
22
24
24
2
2
4b 97
3
p-Me-Ph-
4b 94
4
m-F-Ph-
4c 98
b
5
CH3−CH2−CH2-
CH3−CH2−CH2-
(CH3)3Si-
4d 96 (76)
4d 95
6
2
7
24
- (96% 3e rec.)
- (95% 3e rec.)
- (95% 3e rec.)
4e 99
d
8
(CH3)3Si-
4
c
9
(CH3)3Si-
18
10
11
12
13
14
15
16
17
18
19
20
21
22
p-MeO-Ph-
p-Me-Ph-
6
26
22
24
2
4f 97
p-Me-Ph-
4f 93
m-F-Ph-
4g 97
b
CH3−CH2−CH2-
CH3−CH2−CH2-
p-MeO-Ph-
p-Me-Ph-
4h 89 (62)
4
4h 88
b
24
24
48
2
4i 92 (67)
Cy
4j 94
4k 96
4l 94
4l 86
m-F-Ph-
Cy
CH3−CH2−CH2-
CH3−CH2−CH2-
p-MeO-Ph-
p-MeO-Ph-
Cy
Cy
2
t-Bu
27
d
3a
t-Bu
72
a
b
c
d
After simple workup. After column chromatography. Reaction was performed at 110 °C. Reaction was performed at 80 °C.
5a, we tried some different solvents with decreasing relative
polarity24 (Table 1, entries 2−4) in the presence of 3 equiv of
methanol. All of the solvent tested gave excellent results, and
the formation of dimethyl acetal 5a was strongly reduced
(Table 1, entry 3) or completely avoided (Table 1, entries 2, 4).
Even though the reaction in 1,2-dichloroethane (DCE) ap-
peared to be slightly faster (Table 1, entry 3), the best yield and
cleanness of the reaction were obtained in toluene (Table 1,
entry 4). The concentration of the substrate seemed to have
little effect on the course of the reaction (Table 1, entries 5
and 6), whereas the reaction with Ag(I) complexes 2b and 2c,
characterized by the presence of a slightly more coordinating
counterion such as triflate25 or a more bulky and charge delo-
calized anion as triflimidate,26 respectively, gave lower yields in
prolonged reaction times (Table 1, entries 7, 8). We were
pleased to find that the amount of the alcohol could be reduced
without a loss of yield or an increase in reaction times (Table 1,
entries 9, 10). Conversely, the catalyst loading seemed to be
a critical factor and amounts of catalysts less than 5 mol %
resulted in extended reaction times and lower reaction yields
(Table 1, entries 11, 12). Finally, two control experiments in
the presence of simple silver salts such as AgOTf (5 mol %)
and AgBF4 (5 mol %) as catalysts demonstrated the superiority
of our Ag complexes (Table 1, entries 13 and 14), because in
both cases the reactions appeared to have lower yield and in
particular, were less clean.
saturated solution (sat. sol.) and extraction with dichloro-
methane. The simplicity of the purification step represents an
outstanding peculiarity of our approach, because it is well-
known that the purification of 1-alkoxyisochromenes and
related compounds can be quite troublesome.6,12
With the best reaction conditions in hand, we tested the
scope and limitations of the approach. We selected some al-
kynylaldehydes substituted on alkynyl moiety with an alkyl- or
an aryl-group and characterized by the presence on the aryl
moiety of electron-donating or electron-withdrawing groups.
The 2-alkynylbenzaldehydes 3a−d were synthesized as
previously reported5,17d starting from commercially available
2-bromobenzaldheyde and a selection of terminal acetylenes by
means of a typical Sonogashira coupling,27 offering good to
excellent yields. Their reactivity was tested with four alcohols
with increasing steric hindrance. The results are reported in
Table 2.
All alkynylbenzaldehydes bearing aryl or alkyl substitution on
alkynyl moiety 3a−d reacted with methanol to give the
corresponding isochromenes 4a−d in excellent yields, and the
presence of an electron withdrawing group (EWG) or an elec-
tron donating group (EDG) on the phenyl substituent was well
tolerated (Table 2, entries 1−6). Surprisingly, in the presence
of the trimethylsilyl group on alkynyl moiety the reaction com-
pletely failed: the starting material 3e was recovered unreacted
after a prolonged reaction time (Table 2, entry 7) and under
higher reaction temperatures (Table 2, entries 8, 9).
It is important to emphasize that one of the additional
features of our method is the neatness of the reactions, which
allows, in most cases, the isolation of the pure product through
a simple workup, i.e., washing the crude with NaHCO3
More hindered secondary alcohols, such as isopropyl
alcohol and cyclohexanol reacted smoothly with alkynylbenz-
aldehydes 3a−d to give the desired isochromenes 4e−l in very
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Scheme 3. Plausible Reaction Mechanisms
high yields (Table 2, entries 8−20). Unfortunately, all attempts
to react 3a with highly sterically demanding tertiary alcohols
such as tert-butanol failed, giving rise to unidentified breakdown
products (Table 2, entries 21, 22).
Catalysts 2b and 2c gave only slightly poorer results than 2a
(Table 2, compare entries 2/3, 5/6, 11/12, 14/15, and 19/20).
Aldehyde 3d substituted on alkynyl moiety with a n-propyl
group reacted faster than other aldehydes with all alcohols and
catalysts tested.
catalyst. Nevertheless, the ambivalence of silver salts and complexes,
(i.e., σ-philic vs π-philic character31), has been repeatedly estab-
lished,5a,17b so a plausible alternative path could involve the direct
nucleophilic attack of the alcohol to the metal activated aldehyde to
give a hemiacetal intermediate (III), which itself is able to react with
the metal activated triple bond (Scheme 3, path B). Also in this case,
the following proto-demetalation is the last step that leads to the
formation of the isochromene and restores the catalyst.
To gain insight into the mechanism, kinetic 1H NMR experi-
ments were performed. In the first experiment, the preliminary
reaction conditions were repurposed (see Table 1, entry 1) by
reacting 3a at 30 °C in deuterated methanol in a NMR test
tube (Figure 2).
In some cases, the products obtained after the standard
workup were not sufficiently pure and needed to be purified by
flash column chromatography (Table 2, entries 5, 14, and 16).
In these cases, the resulting yields were lower than usual
because 1-alkoxyisochromenes are not very stable and during
the chromatographic purification partial decomposition of the
product was observed. In particular, we think that the acidic
character of silica is mainly responsible for the degradation of
1-alkoxyisochromenes due to their acetal nature. To confirm
this hypothesis we made two experiments to test the stability of
1-alkoxyisochromenes. A 0.25 M solution of 4a in ethyl acetate
was treated under alkaline or acidic conditions. We observed
that in the presence of a base, such as triethylamine (TEA,
0.2 equiv), the product remained unmodified even after stirring
for 3.5 days, whereas in the presence of an acid, such as
p-toluenesulfonic acid (p-TSA, 0.2 equiv), the isochromene
rapidly decomposed to give a complex mixture of unidentified
In the absence of the catalyst (Figure 2, “no cat” spectrum),
we observed the formation of only a small amount (≈18%) of
the deuteromethyl-hemiacetal 6a-d4 (signal at 5.99 ppm). The
amount of 6a-d4 was roughly calculated based on relative
integration of the hemiacetal proton signal at 5.99 ppm and
the aldehydic signal at 10.59 ppm. The spectrum shape and the
ratio between aldehyde 3a and hemiacetal 6a-d4 do not change
in time (20 h), thus indicating an equilibrium between the
two compounds. Then, 2a (5 mol %) was added (Figure 2,
t0 spectrum). After 20 min (Figure 2, t1 spectrum), two new
signals at 5.75 ppm and 6.16 ppm were detected relative to the
deuterodimethyl-acetal 5a-d6 and the isochromene 4a-d4,
respectively. The spectra appeared very clean, and the reaction
proceeded with complete disappearance of the signals relative
to aldehyde 3a (10.59 ppm) and methyl-hemiacetal 6a-d4
(5.99 ppm). The reaction was complete in 20 h (Figure 2,
t9 spectrum) when only the signals relative to isochromene
4a-d4 and the acetal 5a-d6 were detectable. It should be noted
that, although the reagent concentration in this case was slightly
different, and despite the use of deuteron methanol instead of
methanol, the relative ratio of the integrals of these signals at
the end of the reaction was consistent with the yields of 4a and
5a obtained in the catalytic run (see Table 1, entry 1). The
signal relative to acetal 5a-d6 at 5.75 ppm was attributed by the
comparison with those observed in the spectrum of a pure
sample of the dimethyl-acetal 5a. It is interesting to note that in
all spectra no signal around 10.1 ppm, attributable to a possible
isochromenilium intermediate,32 was ever detected (Figure 2).
Moreover, the analysis of the integrals at different times of the
signals relative to deuterodimethyl-acetal 5a-d6 (5.75 ppm) with
respect to those relative to CH3 of 4-methoxyphenyl moieties
1
byproducts. The H NMR spectrum of the reaction crude
roughly filtered on a silica gel-plug displayed the preponderance
of 2-[2-(4-methoxyphenyl)-2-oxoethyl] benzaldehyde28 (maybe
in equilibrium with its cis/trans enol forms) resulting from the
hydrolysis of 4a.29
We also performed the chromatographic purification of the
new synthesized isochromenes 4 with a basified eluent mixture,
but all the same, a slight reduction of yields was observed due
to partial decomposition of the product.
Mechanistic Studies. As mentioned above, the most
accepted mechanism to explain the silver catalyzed synthesis of
isochromenes invokes the formation of an isochromenilium
intermediate (I) (metal ate complex) stabilized by resonance,
resulting from the direct nucleophilic attack of the aldehyde
oxygen to the metal activated triple bond (Scheme 3,
path A).30 Then, the alcohol can attack the activated isochro-
menilium intermediate (I) to give the intermediate (II). A fast
proto-demetalation leads to the isochromene and restores the
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1
Figure 2. Kinetic H NMR experiment of 3a in CD3OD in the presence of 2a (5 mol %), T = 30 °C.
1
Table 3. Integrals of Selected Signals of Kinetic H NMR Experiment
ref.(3a+4a+5a+6a)
(3.84−3.85 ppm)
CH3O-Ph-
aldehyde 3a
(10.59 ppm)
-CHO
hemiacetal 6a
(5.99 ppm)
-CH(OD)OCH3
acetal 5a
(5.75 ppm)
-CH(OCH3)2
isochromene 4a
(6.16 ppm)
-CH(OCH3)O-
time
0
3
3
3
3
3
3
3
3
3
3
0.57
0.48
0.43
0.33
0.27
0.20
0.12
0.06
0.02
0
0.12
0.10
0.09
0.07
0.06
0.04
0.03
0.01
0
0
0
20 min
40 min
1 h 40 min
2 h 40 min
5 h
0.08
0.12
0.19
0.22
0.23
0.24
0.23
0.23
0.23
0.03
0.05
0.11
0.15
0.23
0.34
0.42
0.48
0.50
9 h
13 h
18 h
20 h
0
chosen as reference (all these signals fall around 3.84−
3.85 ppm and their overall integral is invariable), revealed that
under these reaction conditions, the hydrolysis of deuterodi-
methyl-acetal 5a-d6 to give the methyl-hemiacetal 6a-d4 is a very
slow process (Table 3).
Scheme 4. Reactivity of Acetal 5a
The above statement was confirmed by an additional
experiment: the reaction of a pure sample of the dimethyl-
acetal 5a in CH2Cl2 in the presence of 2a (5 mol %) and 10
equiv of water gave a mixture of isochromene 4a, aldehyde 3a,
and unreacted starting material 5a in a 20:20:60 ratio (roughly
calculated on the H NMR of the reaction crude), after a
prolonged reaction time (72 h at 30 °C) (Scheme 4).
On the basis of these results, we could make some prelimi-
nary considerations: (1) the formation of dimethyl-acetal 5a-d6
in the reaction performed in deutero-methanol in the presence
of complex 2a confirmed its oxo-philic character (as yet pre-
viously observed for Ag(I) salts),5a,17b and its ability to promote
1
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1
Figure 3. Kinetic H NMR experiment of 3a in CDCl3 in the presence of 2 equiv of methanol and 2a (5 mol %), T = 30 °C.
the acetalization of methyl-hemiacetal 6a-d4; (2) such acetali-
zation was probably a competitive side reaction; (3) when the
reaction was performed in deutero-methanol, the methyl-
hemiacetal 6a-d4 was surely an intermediate in the acetalization,
but it could also have been an intermediate in the formation of
isochromene 4a (Scheme 3, path B). Conversely, the absence of
Scheme 5. Intramolecular Addition/Cycloisomerization of
Alkyne 3f
1
any signal in H NMR spectra referable to an isochromenilium
intermediate (Scheme 3, I) does not seem to be sufficient
evidence to rule out its involvement in the process, probably
with very fast kinetics.
The latter concept seemed to be confirmed by a new kinetic
1H NMR experiment. When the reaction was performed in a
NMR tube at 30 °C, using CDCl3 as a solvent and in the
presence of complex 2a (5 mol %), and only 2 equiv of
methanol, no traces of hemiacetal 6a, acetal 5a, or
isochromenilium intermediates were observed. Only a slow
direct conversion of aldehyde 3a into the desired product 4a
was detected (Figure 3).
Thus, to point out the possible involvement of a isochro-
menilium intermediate in the reaction mechanism, a conclusive
intramolecular trapping experiment was performed by reacting
the new synthesized alkyne 3f, characterized by the presence of
a hydroxyethyl pendant at alkyne terminus, under standard
conditions in the absence of any other alcohol (Scheme 5).
Because of geometric requirements, the hypothetical formation
of the corresponding tricyclic isochromene derivative 4m can
only occur by formation of an isochromenilium intermediate,
because an alternative oxa-benzocyclooctyne hemiacetal (I) is
a strongly improbable intermediate and such oxa-benzocyclo-
octyne bicyclic structures were never observed in the
literature.33 Moreover, the feasibility of the synthesis of 4m
was verified independently by the group of Wu and Hammond
by AgOTf34 and triazole-Au35 catalyzed processes, respectively.
We were pleased to find that the reaction in the presence
of Ag(I) complex 2b yielded the attained product 4m in 5 h
(50% yield), thus confirming that an isochromenilium ion is
presumably the main intermediate involved in the reaction
mechanism.
CONCLUSION
■
The [Ag(I)(Pc-L)] complexes 2a−c demonstrated to be
suitable catalysts for the synthesis of 1-alkoxyisocromenes
starting from various 2-alkynylbenzaldehydes and different
primary and secondary alcohols. The best results were obtained
−
with BF4 complex 2a. The approach is characterized by
absolute regioselectivity, mild reaction conditions, good to
excellent reaction yields, cleanness of the reaction, and reduced
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The yellow crude was filtered, washed with ethanol, and recrystallized
purification steps. The [Ag(I)(Pc-L)] complexes 2a−c are quite
stable, versatile, and can be used under open-air atmosphere.
The reaction mechanism was investigated by in depth NMR
studies and an aimed intramolecular trapping experiment. Our
efforts are now devoted to the development of an enantio-
selective version of this transformation. Some preliminary
results with Ag(I) complexes of previously synthesized chiral
pyridine-containing ligands21b are encouraging. We are working
on a synthesis of some new chiral [Pc-L]* ligands characterized
by a well-planned chiral profile.
three times from ethanol, until pyridine was completely removed. The
1
product was obtained as a white powder (18.05 g, 49% yield). H
NMR (400 MHz, CDCl3, δ): 7.76 (d, J = 8.2 Hz, 2H, Har), 7.72 (d, J =
8.2 Hz, 2H, Har), 7.37 (d, J = 8.0 Hz, 2H, Har), 7.32 (d, J = 8.0 Hz, 2H,
Har), 4.83 (t, J = 6.1 Hz, 1H, NH), 4.07 (t, J = 5.1 Hz, 2H, CH2O),
3.25 (pq, J = 5.5 Hz, 2H, CH2NH), 2.48 (s, 3H, CH3), 2.45
(s, 3H, CH3).
Synthesis of 1-Tosylaziridine.20b A solution KOH (3.86 g,
68.8 mmol) in water (20 mL) was added dropwise to a suspension
of 2-(tosylamino)ethyl tosylate (7.48 g, 20.2 mmol) in toluene
(80 mL). After being stirred for 2 h, water (80 mL) and toluene
(20 mL) were added, the organic layer separated, washed with water,
and dried over Mg2SO4. The solvent was evaporated under reduced
pressure. The product was obtained as a white powder (3.69 g,
EXPERIMENTAL SECTION
■
General Experimental Details. All of the reactions that involved
the use of reagents sensitive to oxygen or hydrolysis were carried out
under an inert atmosphere. The glassware was previously dried in an
oven at 110 °C and was set with cycles of vacuum and nitrogen. Also
syringes, used to transfer reagents and solvents, were previously set
under a nitrogen atmosphere. All chemicals and solvents were
commercially available and were used after distillation or treatment
with drying agents. The chromatographic column separations were
conducted by a flash technique, using silica gel (pore size 60 Å, particle
size 230−400 mesh, Merck grade 9385) or neutral aluminum oxide
(Brockman grade I, 0.05−0.15 mm, pH 7 0.5). For TLC, silica was
used on TLC Alu foils with fluorescent indicator (254 nm) and the
detection was performed by irradiation with UV light (λ = 254 nm
1
93% yield). H NMR (400 MHz, CDCl3, δ): 7.85 (d, J = 8.2 Hz,
2H, Har), 7.37 (d, J = 8.2 Hz, 2H, Har), 2.47 (s, 4H, CH2), 2.39
(s, 3H, CH3).
Synthesis of 1,7-Ditosyl-4-benzyl-1,4,7-triazaheptane.22 A sol-
ution of tosyl aziridine (1.60 g, 8.13 mmol) and benzylamine (0.396 g,
0.40 mL, 3.69 mmol) in toluene (15 mL) was stirred and heated by
microwave irradiation for 1 h at 120 °C. The mixture was dried and
used without any further purification. Yield quantitative (1.85 g,
3.69 mmol). 1H NMR (400 MHz, CDCl3, δ): 7.73 (d, J = 8.0 Hz, 4H,
Har), 7.29 (d, J = 8.0 Hz, 4H, Har), 7.27−7.25 (m, 3H, Har), 7.13 (m,
2H, Har), 5.17 (br, 2H, NH), 3.44 (s, 2H, CH2), 2.93 (m, 4H, CH2),
2.52 (m, 4H, CH2), 2.43 (m, 6H, CH3). 13C NMR (100 MHz, CDCl3,
δ): 143.5 (Cq), 137.9 (Cq), 136.8 (Cq), 129.9 (CHAr), 129.0 (CHAr),
128.7 (CHAr), 127.6 (CHAr), 127.3 (CHAr), 58.6 (CH2), 53.3 (CH2),
40.8 (CH2), 21.7 (CH3). MS (EI): m/z (%) = 501 (100) [M]+.
Synthesis of 2,6-bis(Methanesulfonyloxymethyl)pyridine.36 2,6-
Pyridinedimethanol (0.50 g, 3.57 mmol) was suspended in ethyl
acetate (10 mL). Triethylamine (1.82 g, 2.50 mL, 17.90 mmol) was
added and the mixture was cooled to 0 °C. Methanesulfonylchloride
(1.27 g, 0.86 mL, 11.10 mmol) was slowly added and the mixture was
stirred for 15 min, after which the reaction was quenched by the
addition of sat. aq NaHCO3 (10 mL). The mixture was extracted with
ethyl acetate (3 × 15 mL), and the organic layers were washed with
brine and dried over Na2SO4. The solvent was evaporated under
1
or 366 nm). H NMR analyses were performed with 200, 300, or
400 MHz spectrometers at room temperature. The coupling constants
(J) are expressed in hertz (Hz), and the chemical shifts (δ) in ppm.
The multiplicity of the proton spectra were described by the following
abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), hex
(sestet), hept (septet), dt (double triplet), dd (double doublet), td
(triple doublet), m (multiplet), and br (broad). 13C NMR ana-
lyses were performed with the same instruments at 50.3, 75.5, and
100 MHz, and attached proton test (APT) sequence was used to
distinguish the methine and methyl carbon signals from those arising
from methylene and quaternary carbon atoms. All 13C NMR spectra
were recorded with complete proton decoupling. The 1H NMR signals
of the ligand described in the following have been attributed by
correlation spectroscopy (COSY) and nuclear Overhauser effect
spectroscopy (NOESY) techniques. Assignments of the resonance in
13C NMR were made using the APT pulse sequence and heteronuclear
single quantum correlation (HSQC) and heteronuclear multiple bond
correlation (HMBC) techniques. The 15N NMR signals of the
compound described have been attributed by HMBC technique. Low
resolution MS spectra were recorded with instruments equipped with
electron ionization (EI), ESI/ion trap (using a syringe pump device to
directly inject sample solutions), or fast atom bombardment (FAB)
(for Pc-L and metal complexes) sources. The values are expressed as
mass−charge ratio and the relative intensities of the most significant
peaks are shown in brackets. High resolution MS spectra were
recorded with an instrument equipped with an electrospray source and
a ion cyclotron resonance-Fourier transform mass spectroscopy
(ICR-FTMS) analyzer. UV−vis spectra of the ligand and its silver
complexes were recorded in CHCl3. The melting points of the solid
products are uncorrected. The syntheses of the silver complexes
were carried out in a nitrogen atmosphere by employing standard
Schlenk techniques. 1,2-Dichloroethane and n-hexane were distilled
prior to use by standard procedures and stored under nitrogen.
Microwave promoted reactions were performed with a single-mode
Personal Chemistry microwave synthesizer “Emrys Creator,” using
sealed glass vessels. The temperature was detected with a infrared
sensor.
1
reduced pressure. A white solid was obtained (0.96 g, 91% yield). H
NMR (400 MHz, CDCl3, δ): 7.88 (t, J = 7.8 Hz, 1H, Har), 7.52 (d, J =
7.8 Hz, 2H, Har), 5.36 (s, 4H, CH2), 3.13 (s, 6H, CH3).
Synthesis of 6-Benzyl-3,9-ditosyl-3,6,9,15-tetraazabicyclo[9,3,1]-
pentadeca-1(15),11,13-triene 1.22
A solution of 1,7-ditosyl-4-benzyl-1,4,7-triazaheptane (1.85 g, 3.69 mmol),
2,6-bis(methanesulfonyloxymethyl)pyridine (1.09 g, 3.70 mmol), and
micronized anhydrous potassium carbonate (1.53 g, 11.08 mmol)
in freshly distilled acetonitrile (85 mL) was stirred and heated under
reflux for 9 h. The mixture was washed with water (150 mL) and
extracted with ethyl acetate (3 × 100 mL). The organic layers were
dried over Na2SO4. The solvent was evaporated under reduced
pressure. The crude product was then crystallized in ethyl acetate,
1
yielding a white solid. Yield = 1.97 g, 88%. H NMR (400 MHz,
CDCl3, δ): 7.73 (t, J = 7.7 Hz, 1H, Hi), 7.59 (d, J = 8.0 Hz, 4H, Hf),
7.33 (d, J = 7.7 Hz, 2H, Hl), 7.32−7.30 (m, 3H, Har), 7.24 (d, J =
Synthesis of 2-(Tosylamino)ethyl Tosylate.20b Tosyl chloride
(41.88 g, 220 mmol) was suspended in pyridine (25 mL) and the
mixture was cooled to −40 °C. A solution of 2-aminoethanol (6.22 g,
102 mmol) in pyridine (10 mL) was added dropwise over 15 min
under vigorous stirring, resulting in a dark orange mixture. The
reaction temperature was adjusted to −10 °C for 2 h and then to rt.
2
8.0 Hz, 4H, Hg), 7.18 (m, 2H, Har), 4.34 (m, 4H, CH210, CH2 ), 3.48
4
8
(s, 2H, H13), 3.10 (m, 4H, CH2 , CH2 ), 2.40 (s, 6H, CH314), 2.31 (m,
5
7
4H, CH2 , CH2 ). 13C NMR (100 MHz, CDCl3, δ): 155.0 (C1), 143.3
(Ch), 139.2 (Ce), 138.8 (CiH), 136.0 (Ca), 129.8 (CgH), 128.6
(CPhH), 128.3 (CPhH), 128.2 (CPhH), 127.1 (CfH), 124.0 (ClH), 59.4
(C13H2), 54.3 (C5H2), 50.0 (C2H2), 44.2 (C4H2), 21.5 (C14H3).
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15N NMR (40 MHz, CDCl3, δ): 312 (N12), 94 (N-Ts), 32 (N6). MS
(FAB): m/z (%) = 605 (80) [MH]+, 449 (100) [M − Ts]+. UV (5.2 ×
10−5 mol L−1, CHCl3 in 1-cm cuvettes) λmax (log ε) 241 (4.19),
263 nm (3.93).
General Procedure for the Synthesis of Silver Complexes 2a−c.
The silver salt and all silver-containing solutions were kept in the dark
until the final isolation of the product. The ligand 1 was dissolved in
1,2-dichloroethane, the silver salt (weighed under a nitrogen atmo-
sphere) was added, and the mixture was stirred for 1 h. The mixture
was then filtered to remove any unreacted solid. The solvent was
evaporated to dryness, n-hexane was added, and the product was
recovered by filtration.
by TLC analysis (eluent: hexane/ethyl acetate = 6:4). The reaction
mixture was poured into water (200 mL) and was extracted with ethyl
acetate (3 × 50 mL). The organic layer was dried with Na2SO4 and
then evaporated to dryness under reduced pressure. The crude was
purified by flash column chromatography on silica gel (eluent: hexane/
ethyl acetate = 8:2) yielding corresponding 2-(4-hydroxybut-1-
1
ynyl)benzaldehyde (1.12 g, 99%) as a viscous yellow oil. H NMR
(200 MHz, CDCl3, δ): 10.44 (s, 1H, CHO), 7.86 (d, J = 7.7 Hz, 1H,
Har), 7.54−7.39 (m, 3H, Har), 3.87 (t, J = 6.2 Hz, 2H, CH2−O), 2.76
(t, J = 6.2 Hz, 2H, Csp−CH2). Spectral data are in good agreement
with literature values.
General Procedure for the Synthesis of 1-Alkoxyisochromenes 4
a-l. The catalyst 2a (5 mol %) and the alcohol (1.05 equiv) were
added to a stirred solution of the appropriate o-alkynylbenzaldehyde 3a−e
(60 mg) in dry toluene ([3] = 0.25 M). The reaction mixture was
stirred at 30 °C until no more starting product was detectable by TLC
analysis (eluent: toluene/ethyl acetate = 100:1). The reaction mixture
was diluted with sat. aq NaHCO3 (20 mL) and extracted with ethyl
acetate (3 × 10 mL). The organic layer was dried with Na2SO4 and
then evaporated to dryness under reduced pressure. Unless otherwise
stated, after this workup the products 4 were sufficiently pure and did
not require further purification.
2a: 1 (MW = 604.78; 0.5135 g; 0.849 mmol), AgBF4 (MW =
194.67; 0.1653 g; 0.849 mmol), C2H4Cl2 (42 mL), n-hexane (40 mL).
1
Yield 0.66 g (MW = 799.46) 91%. H NMR (300 MHz, CDCl3, δ):
7.77 (t, J = 7.7 Hz, 1H) overlapping with 7.74 (d, J = 8.0 Hz, 4H), 7.60
(d, J = 6.9 Hz, 2H), 7.45 (d, J = 8.0 Hz, 4H) overlapping with 7.42
(m, 3H), 7.28 (d, J = 7.7 Hz, 2H), 5.04 (d, J = 15.2 Hz, 2H), 3.97
(s, 2H), 3.70 (d, J = 15.2 Hz, 2H), 3.51 (m, 2H), 2.94 (m, 2H), 2.65
(m, 2H), 2.49 (s, 6H), 2.06 (m, 2H). 13C NMR (75 MHz, CDCl3, δ):
153.4, 145.9, 140.5, 135.6, 130.9, 130.7, 130.6, 128.8, 128.6, 128.4,
125.0, 58.4, 56.3, 52.9, 47.5, 21.9. 19F NMR (282 MHz, CDCl3, δ):
−152.8. MS (FAB): m/z (%) = 711 m/z (100) [M+ − BF4], 605 (94)
[MH − AgBF4]+. UV (5.2 × 10−5 mol L−1, CHCl3 in 1-cm cuvettes)
λmax (log ε) 243 (4.26), 263 nm (3.89).
1-Methoxy-3-(4-methoxyphenyl)-1H-isochromene 4a. Reaction
1
time: 2 h. White solid. Yield: 99% (67 mg); mp 124−126 °C. H
NMR (200 MHz, CDCl3, δ): 7.76 (d, J = 8.8 Hz, 2H, Har), 7.40−7.16
(m, 4H, Har), 6.94 (d, J = 8.8 Hz, 2H, Har), 6.49 (s, 1H, Csp2−H), 6.13
(s, 1H, Csp3−H), 3.85 (s, 3H, OCH3), 3.60 (s, 3H, OCH3).13C NMR
(50.3 MHz, CDCl3, δ): 160.4 (Cq), 149.7 (Cq), 130.8 (Cq), 129.6
(CHar), 127.4 (Cq), 127.0 (Cq), 126.6 (CHar), 126.5 (CHar), 126.0
(CHar), 124.5 (CHar), 114.1 (CHar), 100.0 (C−H), 99.0 (C−H), 55.6
(CH3), 55.3 (CH3). MS ESI(+): m/z (%) = 291.0 (45) [M + Na]+,
269.3 (4) [M + H]+, 237.2 (100) [M − OCH3]+. HRMS ESI
(M + H)+ calcd for C17H17O3, 269.1172; found, 269.1170.
2b: 1 (MW = 604.78; 0.2088 g; 0.345 mmol), AgOTf (MW =
256.94; 0.0887 g; 0.345 mmol), C2H4Cl2 (17 mL); n-hexane (15 mL),
1
Yield 0.22 g (MW = 861.72) 73%. H NMR (300 MHz, CDCl3, δ):
7.83 (t, J = 7.7 Hz, 1H), 7.72 (d, J = 8.0 Hz, 4H), 7.65 (d, J = 7.1 Hz,
2H), 7.50 (m, 3H) overlapping with 7.45 (d, J = 8.0 Hz, 4H), 7.33 (d,
J = 7.7 Hz, 2H), 5.01 (d, J = 14.9 Hz, 2H), 3.89 (s, 2H) overlapping
with 3.85 (m, 2H), 3.53 (m, 2H), 3.04 (m, 2H), 2.87 (m, 2H), 2.51 (s,
6H), 2.22 (m, 2H). 13C NMR (75 MHz, CDCl3, δ): 153.7, 145.9,
140.5, 136.0, 130.9, 130.7, 130.6, 129.1, 128.7, 128.2, 125.0, 120.7 (q,
CF3, J = 320.4 Hz), 58.9, 56.4, 53.5, 47.7, 21.8. 19F NMR (282 MHz,
1-Methoxy-3-(p-tolyl)-1H-isochromene 4b.12 Reaction time: 24 h.
White solid. Yield: 97% (67 mg); mp 100−102 °C. 1H NMR
(200 MHz, CDCl3, δ): 7.74 (d, J = 8.3 Hz, 2H, Har), 7.29 − 7.22 (m,
6H, Har), 6.59 (s, 1H, Csp2−H), 6.16 (s, 1H, Csp3−H), 3.62 (s, 3H,
OCH3), 2.41 (s, 1H, CH3). 13C NMR (50.3 MHz, CDCl3, δ): 149.9
(Cq), 139.0 (Cq), 132.0 (Cq), 130.7 (Cq), 129.7 (CHar), 129.4 (CHar),
127.2 (Cq), 126.7 (CHar), 126.0 (CHar), 125.1 (CHar), 124.6 (CHar),
100.0 (C−H), 99.9 (C−H), 55.3 (CH3), 21.5 (CH3). MS ESI(+): m/z
(%) = 253.1 (20) [M + H]+, 221.2 (100) [M+ − OCH3]+. Spectral
data are in good agreement with literature values.
CDCl3, δ): −78.7. MS (FAB): m/z (%) = 711 m/z (100) [M+
−
CF3SO3], 605 (90) [MH − AgCF3SO3]+. UV (5.1 × 10−5 mol L−1,
CHCl3 in 1-cm cuvettes) λmax (log ε) 242 (4.32), 263 nm (3.94).
2c: 1 (MW = 604.78; 0.1812 g; 0.300 mmol), AgNTf2 (MW =
388.09; 0.1163 g; 0.300 mmol), C2H4Cl2 (13 mL); n-hexane (15 mL),
1
Yield 0.17 g (MW = 992.80) 57%. H NMR (300 MHz, CDCl3, δ):
7.84 (t, J = 7.7 Hz, 1H), 7.73 (d, J = 8.0 Hz, 4H), 7.65 (d, J = 7.1 Hz,
2H), 7.48 (m, 3H) overlapping with 7.47 (d, J = 8.0 Hz, 4H), 7.29 (d,
J = 7.7 Hz, 2H), 5.07 (d, J = 14.9 Hz, 2H), 3.93 (s, 2H), 3.70 (m, 2H),
3.54 (m, 2H), 3.02 (m, 2H), 2.70 (m, 2H), 2.52 (s, 6H), 2.17 (m, 2H).
13C NMR (75 MHz, CDCl3, δ): 153.7, 146.3, 140.9, 136.2,
131.04, 130.97, 130.85, 129.4, 129.0, 128.5, 125.2, 120.1 (q, CF3,
J = 321.9 Hz), 58.9, 56.6, 53.4, 47.8, 22.1. 19F NMR (282 MHz,
CDCl3, δ): −78.9.
General Procedure for the Synthesis of 2-Alkynylbenzaldehydes
3a−e. The appropriate alkyne (3.89 mmol) and trans-dichlorobis-
(triphenylphosphine)palladium(II) (2 mol %) were added to a
solution of o-bromobenzaldehyde (600 mg, 3.24 mmol) in dry TEA
(30 equiv), under a nitrogen atmosphere. The reaction was stirred at rt
for 10 min, and then CuI (1 mol %) was added. The reaction mixture
was stirred at 50 °C until no more starting product was detectable by
TLC analysis (eluent: hexane/ethyl acetate). The solvent was then
evaporated under reduced pressure and the crude material was purified
by flash chromatography over a silica gel column. Alkynylbenzalde-
hydes 3a,37 3b,17d 3c,17d 3d,38 and 3e17d are known compounds.
They were characterized by 1H NMR and spectral data were in
agreement with literature values.
3-(3-Fluorophenyl)-1-methoxy-1H-isochromene 4c. Reaction
1
time: 24 h. White solid. Yield: 98% (68 mg); mp 93−95 °C. H
NMR (200 MHz, CDCl3, δ): 7.59 (m, 1H, Har), 7.51 (m, 1H, Har),
7.42−7.15 (m, 5H, Har), 7.04 (ddt, J = 8.3, 2.6, 0.9 Hz, 1H, Har), 6.62
(s, 1H, Csp2−H), 6.15 (s, 1H, Csp3−H), 3.61 (s, 3H, OCH3). 13C
1
NMR (50.3 MHz, CDCl3, δ): 163.3 (d, JC−F = 245 Hz, Cq-F), 148.4
(d, 4JC−F = 3.0 Hz, Cq), 137.1 (d, 3JC−F = 8.0 Hz, Cq), 130.2 (d, 3JC−F
=
8.4 Hz, CHar), 130.1 (Cq), 129.8 (CHar), 127.4 (Cq), 127.3 (CHar),
126.1 (CHar), 125.0 (CHar), 120.6 (d, 4JC−F = 2.7 Hz, CHar), 115.7 (d,
2JC−F = 21.4 Hz), 112.0 (d, 2JC−F = 23.4 Hz), 101.6 (CH), 100.1 (CH),
55.5 (CH3). MS ESI(+): m/z (%) = 225.3 (30) [M+ − OCH3]+.
HRMS ESI (m/z): [M + H]+ calcd for C16H14FO2, 257.0972; found,
257.0967.
1-Methoxy-3-propyl-1H-isochromene 4d.8, Reaction time: 2 h.
Yellow oil. Yield (simple workup): 98% (69 mg). Flash column
chromatography: Celite plug/neutral alumina 50%/silica 50%. eluent:
hexane/CH2Cl2 = 8:2 + 5% TEA. Yield (after column): 76% (53 mg).
1H NMR (200 MHz, CDCl3, δ): 7.32−7.18 (m, 4H, Har), 7.05 (d, J =
7.4 Hz, 2H, Har), 5.95 (s, 1H, C−H), 5.79 (s, 1H, C−H), 3.53 (s, 3H,
OCH3), 2.29 (dt, J = 7.2, 4.4 Hz, 2H, CH2), 1.67 (hex, J = 7.3 Hz, 2H,
CH2), 0.98 (t, J = 7.3 Hz, 3H, CH3). 13C NMR (50.3 MHz, CDCl3, δ):
154.3 (Cq), 130.6 (Cq), 129.5 (CHar), 126.5 (Cq), 126.1 (CHar), 126.0
(CHar), 123.6 (CHar), 100.5 (C−H), 99.9 (C−H), 55.2 (CH3), 36.2
(CH2), 20.6 (CH2), 13.8 (CH3). MS ESI(+): m/z (%) = 205.1 (32)
[M + H]+, 173.2 (78) [M+ − OCH3]+. Spectral data are in good
agreement with literature values.
Synthesis of 2-(4-Hydroxybut-1-ynyl)benzaldehyde 3f.39 But-3-
yn-1-ol (0.5 g, 0.539 mL, 7.13 mmol) and trans-dichlorobis-
(triphenylphosphine)palladium(II) (90.9 mg, 0.13 mmol) were
added to a solution of o-bromobenzaldehyde (1.20 g, 6.48 mmol)
and TEA (1.18 g, 1.62 mL, 11.67 mmol) in dry DMF (10 mL) under a
nitrogen atmosphere. The reaction was stirred at rt for 10 min, and
then CuI (24.7 mg, 0.13 mmol) was added. The reaction mixture was
stirred at rt overnight, until no more starting product was detectable
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1-Isopropoxy-3-(4-methoxyphenyl)-1H-isochromene 4e. Reaction
time: 6 h. Yellow solid. Yield (simple workup): 99% (74 mg); mp
120−122 °C. 1H NMR (200 MHz, CDCl3, δ): 7.75 (d, J = 9.0 Hz, 2H,
Har), 7.38−7.17 (m, 4H, Har), 6.94 (d, J = 9.0 Hz, 2H, Har), 6.50 (s,
1H, Csp2−H), 6.30 (s, 1H, Csp3−H), 4.38 (hept, J = 6.2 Hz, 1H, CH
i-Pr), 3.85 (s, 3H, OCH3), 1.32 (d, J = 6.2 Hz, 3H, CH3 i-Pr), 1.19 (d,
J = 6.2 Hz, 3H, CH3 i-Pr). 13C NMR (50.3 MHz, CDCl3, δ): 160.3
(Cq), 149.7 (Cq), 130.9 (Cq), 129.3 (CHar), 127.7 (Cq), 127.6 (Cq),
126.5 (CHar), 126.4 (CHar), 125.7 (CHar), 124.5 (CHar), 114.1
(CHar), 99.0 (Csp2−H), 97.2 (Csp3−H), 70.0 (CH i-Pr), 55.5 (CH3),
23.8 (CH3), 22.2 (CH3). MS ESI(+): m/z (%) = 319.1 (10) [M +
Na]+, 297.2 (5) [M + H]+, 237.3 (100) [M − OCH(CH3)2]+. HRMS
ESI (M + H)+ calcd for C19H21O3, 297.1485; found, 297.1479.
1-Isopropoxy-3-(p-tolyl)-1H-isochromene 4f. Reaction time: 24 h.
Yellow solid. Yield: 97% (77 mg); mp 76− 78 °C. 1H NMR
(200 MHz, CDCl3, δ): 7.69 (d, J = 8.3 Hz, 2H, Har), 7.42 − 7.14 (m,
6H, Har), 6.55 (s, 1H, Csp2−H), 6.29 (s, 1H, Csp3−H), 4.37 (hept, J =
6.1 Hz, 1H, CH i-Pr), 2.38 (s, 3H, CH3), 1.31 (d, J = 6.1, 3H, CH3
i-Pr), 1.17 (d, J = 6.1 Hz, 3H, CH3 i-Pr). 13C NMR (50.3 MHz,
CDCl3, δ): 149.9 (Cq), 138.8 (Cq), 132.3 (Cq), 130.8 (Cq), 129.3
(CHar), 127.8 (Cq), 126.6 (CHar), 125.7 (CHar), 125.0 (CHar), 124.6
(CHar), 99.8 (Csp2−H), 97.2 (Csp3−H), 70.0 (CH i-Pr), 23.8 (CH3),
22.2 (CH3), 21.5 (CH3), (one CHar signal is obscured). MS ESI(+):
m/z (%) = 303.1 (100) [M + Na]+, 221.2 (10) [M − OCH(CH3)2]+.
HRMS ESI (M + H)+ calcd for C19H21O2, 281.1536; found, 281.1531.
3-(3-Fluorophenyl)-1-isopropoxy-1H-isochromene 4g. Reaction
1-(Cyclohexyloxy)-3-(p-tolyl)-1H-isochromene 4j.12 Reaction time:
24 h. Yellow solid; mp 68−70 °C. Yield: 94% (83 mg). H NMR
1
(200 MHz, CDCl3, δ): 7.68 (d, J = 8.2 Hz, 2H, Har), 7.32−7.17 (m,
6H, Har), 6.55 (s, 1H, Csp2−H), 6.34 (s, 1H, Csp3−H), 4.02 (m, 1H, H
Cy), 2.39 (m, 3H, CH3), 2.08 (m, 1H, CH2 Cy), 1.81−1.13 (m, 9H,
CH2). 13C NMR (50.3 MHz, CDCl3, δ): 150.0 (Cq), 138.8 (Cq), 132.4
(Cq), 130.9 (Cq), 129.3 (CHar), 129.2 (CHar), 127.9 (Cq), 126.6
(CHar), 125.8 (CHar), 125.1 (CHar), 124.6 (CHar), 99.8 (Csp2−H),
97.1 (Csp3−H), 76.0 (CH Cy), 33.9 (CH2), 32.3 (CH2), 25.9 (CH2),
24.6 (CH2), 24.5 (CH2), 21.5 (CH3). MS ESI(+): m/z (%) = 343.5
(15) [M + Na]+, 221.4 (10) [M − OC6H11]+. Spectral data are in
good agreement with literature values.
1-(Cyclohexyloxy)-3-(3-fluorophenyl)-1H-isochromene 4k. Reac-
tion time: 48 h. Yellow oil. Yield: 96% (84 mg). 1H NMR (200 MHz,
CDCl3, δ): 7.65−7.20 (m, 7H, Har), 7.05 (tdd, J = 8.3, 2.5, 0.9 Hz, 1H,
Har), 6.62 (s, 1H, Csp2−H), 6.36 (s, 1H, Csp3−H), 4.03 (m, 1H, H Cy),
2.11 (m, 1H, CH2 Cy), 1.82−1.15 (m, 9H, CH2 Cy). 13C NMR
1
(50.3 MHz, CDCl3, δ): 163.3 (d, JC−F = 245 Hz, Cq), 148.6 (d,
3
4JC−F = 2.9 Hz, Cq), 137.5 (d, JC−F = 7.9 Hz, Cq), 130.3 (Cq), 130.1
3
(d, JC−F = 8.3 Hz, CHar), 129.4 (CHar), 128.2 (Cq), 127.2 (CHar),
125.8 (CHar), 124.9 (CHar), 120.6 (d,4JC−F = 2.4 Hz, CHar), 115.5
2
2
(d, JC−F = 21.4 Hz, CHar), 112.0 (d, JC−F = 23.4 Hz, CHar), 101.6
(Csp2−H), 97.2 (Csp3−H), 76.3 (CH Cy), 33.9 (CH2), 32.3 CH2),
25.8 (CH2), 24.5 (CH2), 24.4 (CH2). MS ESI(+): m/z (%) = 347.3
(15) [M + Na]+, 363.3 (25) [M + K]+, 225.3 (85) [M − OC6H11]+.
HRMS ESI (M + H)+ calcd for C21H22FO2 325.1598; found,
325.1602.
1
time: 24 h. Yellow solid. Yield: 97% (77 mg); mp 73 −75 °C. H
1-(Cyclohexyloxy)-3-propyl-1H-isochromene 4l. Reaction time:
NMR (200 MHz, CDCl3, δ): 7.69−7.20 (m, 7H, Har), 7.03 (td, J =
8.3, 2.3 Hz, 1H, Har), 6.61 (s, 1H, Csp2−H), 6.30 (s, 1H, Csp3−H), 4.35
(hept, J = 6.1 Hz, 1H, CH i-Pr), 1.31 (d, J = 6.1 Hz, 3H, CH3 i-Pr),
1.17 (d, J = 6.1 Hz, CH3 i-Pr). 13C NMR (50.3 MHz, CDCl3, δ):
163.3 (d, 1JC−F = 245 Hz, Cq), 148.5 (d, 4JC−F = 2.9 Hz, Cq), 137.4 (d,
3JC−F = 7.9 Hz, Cq), 130.2 (Cq), 130.1 (d, 3JC−F = 8.4 Hz, CHar), 129.4
(CHar), 128.0 (Cq), 127.2 (CHar), 125.8 (CHar), 125.0 (CHar), 120.6
(d, 4JC−F = 2.9 Hz, CHar), 115.6 (d, 2JC−F = 21.4 Hz, CHar), 111.9 (d,
2JC−F = 23.4 Hz, CHar), 101.6 (Csp2−H), 97.3 (Csp3−H), 70.3 (CH3),
23.8 (CH3 i-Pr), 22.2 (CH3 i-Pr). MS ESI(+): m/z (%) = 307.2 (65)
[M + Na]+, 225.4 (42) [M − OCH(CH3)2]+. HRMS ESI (M + H)+
calcd for C18H18FO2 285.1285; found, 285.1291.
1
2 h. Yellow oil. Yield: 94% (89 mg). H NMR (200 MHz, CDCl3,
δ): 7.30−7.13 (m, 3H, Har), 7.02 (m, 1H, Har), 6.16 (s, 1H, C−H),
5.76 (s, 1H, C−H), 3.89 (m, 1H, H Cy), 2.25 (dt, J = 7.0, 3.1 Hz, 2H),
2.07 (m, 1H, CH2), 1.95−1.48 (m, 6H, CH2), 1.40−1.15 (m, 5H,
CH2), 0.98 (t, J = 7.3 Hz, 3H, CH3). 13C NMR (50.3 MHz, CDCl3, δ):
154.3 (Cq), 130.8 (Cq), 129.1 (CHar), 127.2 (Cq), 125.9 (CHar), 125.9
(CHar), 123.6 (CHar), 100.3 (Csp2−H), 96.8 (Csp3−H), 75.8 (CH Cy),
36.4 (CH2), 34.0 (CH2), 32.2 (CH2), 25.9 (CH2), 24.6 (CH2), 24.5
(CH2), 20.4 (CH2), 13.9 (CH3). MS ESI(+): m/z (%) = 295.2 (100)
[M + Na]+. HRMS ESI (M + H)+ calcd for C18H25O2 273.1849;
found, 273.1854.
Synthesis of 1-(Dimethoxymethyl)-2-((4-methoxyphenyl)-
ethynyl)-benzene 5a. To a solution of 2a (60 mg, 0.254 mmol) in
dry MeOH (3 mL), p-TSA (4.4 mg, 0.026 mmol) and 60 mg of
molecular sieves (3 Å) were added. The mixture was stirred at
30 °C, and the progress of the reaction was followed by TLC (eluent:
toluene/ethyl acetate = 99:1). After 1.5 h, the yellow solution was
poured into sat. aq NaHCO3 (20 mL) and extracted with ethyl acetate
(3 × 10 mL). The organic layer was dried with Na2SO4 and then
evaporated to dryness under reduced pressure to give 5a as a yellow oil
(72 mg, quantitative). The crude was sufficiently pure and was used
1-Isopropoxy-3-propyl-1H-isochromene 4h.8 Reaction time: 1 h.
Yellow oil. Yield (simple workup): 89% (72 mg). Flash column chro-
matography: Celite plug/neutral alumina 50%/silica 50%. eluent:
hexane/CH2Cl2 = 8:2 + 5% TEA. Yield (after column): 62% (50 mg).
1H NMR (200 MHz, CDCl3, δ): 7.30−7.14 (m, 3H, Har), 7.03 (m,
1H, Har), 6.11 (s, 1H, C−H), 5.77 (s, 1H, C−H), 4.24 (hept, J =
6.2 Hz, 1H, CH i-Pr), 2.25 (dt, J = 7.0, 3.0 Hz, 2H, CH2), 1.64 (hex,
J = 7.4 Hz, 2H, CH2), 1.27 (d, J = 6.1 Hz, 3H, CH3 i-Pr), 1.21 (d, J =
6.1 Hz, CH3 i-Pr), 0.98 (t, J = 7.3 Hz, 3H, CH3). 13C NMR
(50.3 MHz, CDCl3, δ): 154.2 (Cq), 130.8 (Cq), 129.1 (CHar), 126.8
(Cq), 126.0 (CHar), 125.8 (CHar), 123.7 (CHar), 100.3 (Csp2−H), 96.9
(Csp3−H), 69.7 (CH i-Pr), 36.3 (CH2), 23.8 (CH3), 22.1 (CH3), 20.4
(CH2), 13.9 (CH3). MS ESI(+): m/z (%) = 255 (70) [M + Na]+,
173.3 (50) [M − OCH(CH3)2]+. Spectral data are in good agreement
with literature values.
1
without further purification. H NMR (200 MHz, CDCl3, δ): 7.65−
7.60 (m, 1H, Har), 7.56−7.48 (m, 3H, Har), 7.40−7.26 (m, 2H, Har),
6.89 (d, J = 8.9 Hz, 1H, Har), 5.77 (s, 1H, C−H), 3.83 (s, 3H, CH3),
3.46 (s, 6H, CH3). 13C NMR (50.3 MHz, CDCl3, δ): 160.0 (Cq),
139.7 (Cq), 133.2 (CHar), 132.4 (CHar), 128.6 (CHar), 128.2 (CHar),
126.3 (CHar), 122.8 (Cq), 115.6 (Cq), 114.3 (CHar), 103.1 (Csp3‑H),
94.2 (Csp), 85.9 (Csp), 55.5 (CH3), 54.6 (2 × CH3). HRMS ESI
(M + H)+ calcd for C18H19O3 283.1329; found, 283.1331.
1-(Cyclohexyloxy)-3-(4-methoxyphenyl)-1H-isochromene 4i. Re-
action time: 24 h. White solid; mp 57−59 °C. Yield (simple workup):
92% (79 mg). Flash column chromatography: Celite plug/neutral
alumina 50%/silica 50%. eluent: hexane/CH2Cl2 = 7:3 + 5% TEA.
Reaction of Acetal 5a with the Catalyst 2a. Catalyst 2a (4 mg,
0.0048 mmol) and distilled water (17 mg, 17 μL, 0.95 mmol) were
added to a solution of dimethyl-acetal 5a (27 mg, 0.095 mmol) in
CH2Cl2 (2 mL). The pale yellow mixture was vigorously stirred at
30 °C for 72 h. The organic phase was separated by the water drop,
dried with Na2SO4, and then evaporated to dryness under reduced
1
Yield (after column): 67% (57 mg). H NMR (200 MHz, CDCl3, δ):
7.73 (d, J = 9.0 Hz, 1H, Har), 7.37−7.16 (m, 4H, Har), 6.94 (d, J =
9.0 Hz, 1H, Har), 6.48 (s, 1H, Csp2−H), 6.33 (s, 1H, Csp3−H), 4.02 (m,
1H, H Cy), 3.85 (s, 3H, CH3), 2.10 (m, 1H, CH2 Cy), 1.82−1.13 (m,
9H, CH2). 13C NMR (50.3 MHz, CDCl3, δ): 160.3 (Cq), 149.8 (Cq),
131.0 (Cq), 129.2 (CHar), 127.8 (Cq), 127.7 (Cq), 126.5 (CHar), 126.4
(CHar), 125.7 (CHar), 124.4 (CHar), 114.1 (CHar), 99.0 (Csp2−H),
97.1 (Csp3−H), 76.0 (CH Cy), 55.5 (CH3), 33.9 (CH2), 32.3 (CH2),
25.8 (CH2), 24.6 (CH2), 24.5 (CH2). MS ESI(+): m/z (%) = 359.2
(70) [M + Na]+, 336.2 (15) [M + H]+, 237.2 (100) [M − OC6H11]+.
HRMS ESI (M + H)+ calcd for C22H25O3 337.1798; found, 337.1795.
1
pressure. The H NMR analysis of the reaction crude displayed the
presence of a mixture of isochromene 4a, aldehyde 3a, and unreacted
starting material 5a in a 20:20:60 ratio.
Stability Experiments of Isochromene 4a. Under Acidic
Conditions. Isochromene 4a (80 mg, 0.298 mmol) was dissolved
in ethyl acetate (1.20 mL) and p-toluenesulfonic acid (11.3 mg,
0.06 mmol) was added. The yellow solution was stirred at rt and the
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Article
progress of the reaction was followed by TLC (eluent: toluene/ethyl
acetate = 99:1). After 2 h, the starting material had almost completely
disappeared on TLC (one main new spot with lower retention factor
(rf) became visible) and the solution turned orange. After 24 h, the
mixture was poured into water (30 mL) and was extracted with ethyl
acetate (3 × 10 mL). The organic layer was dried with Na2SO4 and
then evaporated to dryness under reduced pressure to give an orange
oil. The crude was roughly purified by filtration on a silica gel-plug
(eluent: hexane/ethyl acetate = 1:1) to give a yellow oil (60 mg) which
104, 2285−2310. (c) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev.
2004, 104, 3079−3160.
(5) Much work in this field has been done by the group of research of
Belmont. For a discussion on regioselectivity issues see: (a) Godet, T.;
Vaxelaire, C.; Michel, C.; Milet, A.; Belmont, P. Chem.Eur. J. 2007,
13, 5632−5641. (b) Dell’Acqua, M.; Facoetti, D.; Abbiati, G.; Rossi, E.
Synthesis 2010, 2367−2378 and references cited therein.
(6) (a) Godet, T.; Bosson, J.; Belmont, P. Synlett 2005, 2786−2790.
(b) Cikotiene, I.; Morkunas, M.; Motiejaitis, D.; Brukstus, A. Synlett
2008, 1693−1967. (c) Kanazawa, C.; Ito, A.; Terada, M. Synlett 2009,
638−642.
1
was analyzed by H NMR spectroscopy.
Under Alkaline Conditions. Isochromene 4a (80 mg, 0.298 mmol)
was dissolved in ethyl acetate (1.20 mL) and triethylamine (6.03 mg,
8.3 μL, 0.06 mmol) was added. The pale yellow cloudy solution was
stirred at rt and the progress of the reaction was followed by TLC
(eluent: toluene/ethyl acetate = 99:1). After 84 h, the TLC analysis
showed the starting material practically unmodified. The mixture was
poured into water (30 mL) and was extracted with ethyl acetate (3 ×
10 mL). The organic layer was dried with Na2SO4 and then evaporated
to dryness under reduced pressure to give a white solid (77 mg). The
1H NMR analysis confirmed that the product was 4a, unmodified.
Trapping Experiment: Synthesis of Isochromene 4m:35 The
catalyst 2b (16.6 mg, 0.172 mmol) was added to a stirred solution of
2-(4-hydroxybut-1-ynyl)benzaldehyde 3f (60 mg, 0.344 mmol) in dry
toluene (1.4 mL). The reaction mixture was stirred at 30 °C for 4.5 h,
until no more starting product was detectable by TLC analysis (eluent:
hexane/ethyl acetate = 7:3). The reaction mixture was diluted with sat.
aq NaHCO3 (20 mL) and was extracted with ethyl acetate (3 ×
10 mL). The organic layer was dried with Na2SO4 and then evaporated
to dryness under reduced pressure. The crude was purified by flash
column chromatography on a short silica gel column (eluent: hexane/
ethyl acetate = 100:1, + 3% triethylamine) to give corresponding
isochromene 4m (30 mg, 50% yield) as a white solid. 1H NMR
(200 MHz, CDCl3, δ): 7.31−7.17 (m, 3H, Har), 6.97 (d, J = 7.2 Hz,
1H, Har), 6.00 (s, 1H, C−H), 5.77 (s, 1H, C−H), 4.62 (ddd, J = 10.4,
8.7, 4.3 Hz, 1H, CH2), 3.75 (dt, J = 8.7, 3.3 Hz, 1H, CH2), 2.53 (m,
2H, CH2). Spectral data are in good agreement with literature values.
(7) (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am.
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Chem., Int. Ed. 1993, 32, 131−163.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR, spectra of 1,7-ditosyl-4-benzyl-
(16) For reviews on domino approaches to heterocycles, see:
(a) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341−5378. (b) Tietze,
L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967−1983.
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(17) For some recent examples see: (a) Abbiati, G.; Arcadi, A.;
Chiarini, M.; Marinelli, F.; Pietropaolo, E.; Rossi, E. Org. Biomol. Chem.
2012, 7801−7808. (b) Dell’Acqua, M.; Abbiati, G.; Arcadi, A.; Rossi,
E. Org. Biomol. Chem. 2011, 7836−7848. (c) Dell’Acqua, M.; Facoetti,
D.; Arcadi, A.; Abbiati, G.; Rossi, E. Synlett 2010, 2672−2676.
(d) Alfonsi, M.; Dell’Acqua, M.; Facoetti, D.; Arcadi, A.; Abbiati, G.;
Rossi, E. Eur. J. Org. Chem. 2009, 2852−2862. (e) Facoetti, D.;
Abbiati, G.; d’Avolio, L.; Ackermann, L.; Rossi, E. Synlett 2009, 2273−
2276. (f) Facoetti, D.; Abbiati, G.; Rossi, E. Eur. J. Org. Chem. 2009,
2872−2882.
(18) Dell’Acqua, M.; Facoetti, D.; Abbiati, G.; Rossi, E. Tetrahedron
2011, 67, 1552−1556.
(19) Stetter, H.; Frank, W.; Mertens, R. Tetrahedron 1981, 37, 767−
772.
(20) (a) Aime, S.; Botta, M.; Crich, S. G.; Giovenzana, G. B.; Jommi,
G.; Pagliarin, R.; Sisti, M. Inorg. Chem. 1997, 36, 2992−3000.
(b) Aime, S.; Gianolio, E.; Corpillo, D.; Cavallotti, C.; Palmisano, G.;
Sisti, M.; Giovenzana, G. B.; Pagliarin, R. Helv. Chim. Acta 2003, 86,
615−632.
1,4,7-triazaheptane, ligand 1, Ag complexes 2a−c, isochro-
1
menes 4a-l, and acetal 5a. H NMR spectra of aldehydes 3a−f
and isochromene 4m. HOESY spectrum for complex 2a.
Superimposed UV spectra of ligand 1 and Ag complexes 2a and
2b. 1H NMR spectrum of reaction crude of 3a in methanol. 1H
NMR spectra of stability experiments on 4a and reactivity of 5a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: giorgio.abbiati@unimi.it.
*E-mail: alessandro.caselli@unimi.it.
Notes
The authors declare no competing financial interest.
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NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was published ASAP on March 31, 2014. The paper
was corrected for chemical abbreviations in Scheme 2 and a
nomenclature error in the text. The corrected version was
reposted on April 3, 2014.
3505
dx.doi.org/10.1021/jo5002559 | J. Org. Chem. 2014, 79, 3494−3505