Silver-Catalysed Domino Approach to 1,3-Dicarbo-Substituted Isochromenes

Article abstract of DOI:10.1002/ejoc.201601602

We report herein the first example of the silver triflate catalysed synthesis of 1,3-dicarbo-substituted isochromene derivatives starting from 2-alkynyl(hetero)arylaldehydes and enolizable ketones. The reaction proceeds in a cascade fashion under mild heating with complete regioselectivity and moderate-to-good yields. In some cases, the reaction gives unexpected homodimeric products. Two competitive mechanistic paths for the formation of the desired isochromene derivatives and the homodimeric products are described.

Full text of DOI:10.1002/ejoc.201601602

A Journal of
Accepted Article
Title: Silver Catalyzed Domino Approach to 1,3-Dicarbosubstituted
Isochromenes
Authors: Monica Dell'Acqua, Valentina Pirovano, Stefano Peroni,
Giorgio Tseberlidis, Donatella Nava, Elisabetta Rossi, and
Giorgio Abbiati
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
Silver Catalyzed Domino Approach to
1,3-Dicarbosubstituted Isochromenes
Monica Dell’Acqua,a Valentina Pirovano,a Stefano Peroni,a
Giorgio Tseberlidis,b Donatella Nava,a Elisabetta Rossi,a and Giorgio Abbiati*,a
a Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Generale e Organica “A. Marchesini”,
Università degli Studi di Milano, Via Venezian, 21 – 20133 Milano – Italy
b Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi, 19 – 20133 Milano – Italy
E-mail: giorgio.abbiati@unimi.it
Url: http://users.unimi.it/istchimorg/giorgio.htm
Keywords Isochromenes; Alkynes; Isochromenylium; Domino reaction; Silver
Abstract
In this paper, we report the first example of silver triflate-catalyzed synthesis of 1,3-
dicarbosubstituted isochromene derivatives starting from 2-alkynyl(hetero)arylaldehydes and
enolizable ketones. The reaction proceeds in a cascade fashion under mild heating with complete
regioselectivity. The reaction yields range from moderate to good. In some cases, the reaction gives
unexpected homodimeric products. Two competitive mechanistic paths for the formation of the
desired isochromene derivatives and of the homodimeric products have been described.
1
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
Introduction
One of the most efficient methods for the synthesis of 1-substituted isochromenes (and related
heteroaryl compounds such as pyrano[4,3-b]pyridines) is the metal-catalyzed regioselective domino
cycloisomerization/nucleophilic
addition
reaction
of
a
properly
substituted
2-
alkynyl(hetero)arylaldehyde in the presence of a suitable nucleophile.1 The reactions with oxygen
nucleophiles are the most studied and several metal catalysts, i.e., Pd(II),2 Cu(I),3 Ag(I),4 Au(I)5 and
In(III),6 demonstrated to be effective for the synthesis of 1-alkoxyisochromenes. Conversely, the
reactions with carbon nucleophiles are relatively less investigated. One of the earlier examples has
been reported by Asao and co-workers in 2005: the Japanese group investigated the reactivity of
allyltrimethylsilane and trimethylsilylcyanide in the presence of a Pd(II)-Cu(II) bimetallic system.7
Yao and Li in 20068 reported a gold(I) catalyzed domino approach involving terminal alkynes,
whereas some examples of Rh(I) catalyzed reactions of methylene active compounds have been
reported by Porco Jr. and co-workers in 2007 as part of a more extensive study on multidimensional
reaction screening of ortho-alkynyl benzaldehydes.9 The reactivity of indole as nucleophile has been
explored by Tang and Li by means of Pd(II) catalysis10 and by Peng, Wu and co-workers with Ag(I)
as catalyst.11
A
broader investigation on the Ag(I) catalyzed reaction of 2-
alkynyl(hetero)arylaldehydes in the presence of electron reach (hetero)aromatic compounds has been
recently published by Belmont, Michelet and co-workers.12
Moreover, few different groups have investigated the reactivity of 2-alkynylbenzaldehydes and
enolizable carbonyl compounds and the pattern of products obtained is different depending on the
catalytic system used (Scheme 1). The Au(I)-catalyzed approach reported by Asao and Yamamoto13
resulted in the formation of naphthylketone derivatives (beside the corresponding decarbonylated
naphthalenes as by-products), through a inverse electron demand-type Diels-Alder reaction between
the isochromenylium 4π system and enol 2π system derived from the tautomeric equilibria of the
carbonyl compounds. Ten years later, Snivarsan14 and co-workers increased the selectivity of this
transformation by using a In(III) salt as catalyst, which produces the corresponding naphthylketones
avoiding the formation of decarbonylation by-products. Manojveer and Malaburugan15 have also
obtained similar results in the presence of trimethyl orthoformate and a Brønsted acid such as triflic
acid, but through a very different reaction mechanism: an in situ formed acetal assists the formation
of a chalcone-type intermediate, which, after a trans/cis isomerization, undergoes, a methanol assisted
annulation. Conversely, Cheng and Fan, within a more extensive work, were able to obtain selectively
the 1-carbosubstituted isochromene derivatives, despite in fair yields, through an unprecedented
cycloisomerization/addition path promoted by a simple Pd(II) salt.16
2
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
Scheme 1. Reactivity of 2-alkynylbenzaldehydes and enolizable carbonyl compounds.
In connection with our ongoing interest in silver catalysis,17 and in the development of domino
approaches18 for the synthesis of oxygen containing heterocycles19 starting from alkyne derivatives,20
we report here a AgOTf catalyzed cascade approach for the regioselective synthesis of isochromenes
starting from 2-alkynyl(hetero)arylaldehydes and enolizable carbonyl compounds.
Results and discussion
The reaction between 2-[(4-tolyl)-ethynyl]benzaldehyde 1a and acetone was chosen as model
reaction to screen among different catalytic systems and to optimize the reaction conditions (Table
1). To obtain a reference product, first we performed the reaction under the conditions reported by
Fan.16 The model reaction performed in an excess of acetone as reagent/solvent, at 60 °C in the
presence of 10 mol% of PdCl2 proceeded fast to give the isochromene 2a in good yield (Table 1,
entry 1). Under the same reaction conditions, we replaced the palladium catalyst with silver triflate,
and we were pleased to observe the selective formation of desired isochromene 2a in a promising
45% yield (Table 1, entry 2). We tried to reduce the equivalents of acetone by performing the reaction
in some different non-polar and polar solvents, but the results were rather unsatisfactory (Table 1,
entries 3-5). Therefore, the use of an enolizable ketone as reagent/solvent seemed to be mandatory
3
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
for our purpose. A reduction of the temperature resulted in a sluggish reaction (Table 1, entry 6),
while higher reaction temperature gave 2a in very good yield and in a reduced reaction time (Table
1, entry 7). The use of microwave heating resulted in lower yield and promoted the formation of some
unidentified by-products (Table 1, entry 8). By changing the counter ion of the metal from triflate to
a more bulky and charge delocalized anion as triflimidate,21 the reaction became slower (Table 1,
entry 9), whereas in the presence of AgNO3 we obtained a complex mixture of by-products (Table 1,
entry 10). We also tested the activity of a copper(I) salt, frequently used in domino
cycloisomerization/addition reactions, but surprisingly, CuI hampered the reactivity (Table 1, entry
11). A more traditional Lewis acid such as FeCl3 was unable to catalyze the reaction and a mixture
of 1a and some unidentified by-products was obtained (Table 1, entry 12). To confirm that the
reaction needed a metal catalyst with a well-biased Lewis acidic character, we performed a reaction
in the presence of a palladium complex such as PdCl2(PPh3)2 and, as expected, the reaction failed,
also after a prolonged reaction time, and the starting material was almost quantitatively recovered
(Table 1, entry 13). Finally, to verify if the reaction could proceed under simple Brønsted acid
catalysis, we performed a test in the presence of 1,1′-binaphthyl-2,2′-diyl hydrogenphosphate, but
also in this case the reaction resulted in a tarnish mixture of unidentified by-products (Table 1, entry
14).
Table 1. Optimization of the reaction conditions.
Catalyst
2a
1a rec.
t
(h)
Entry
Solvent
T (°C)
(10 mol-%)
(yield%)a (yield%)a
1
2
PdCl2
Acetone (68 equiv.)
Acetone (68 equiv.)
60
60
4
63
-
-
AgOTf
12 45
25 15b
Toluene:Acetone 9:1
(Acetone ~6 equiv.)
3
4
5
AgOTf
AgOTf
AgOTf
60
60
60
-
DCE:Acetone 9:1
25 10b
25 15b
-
(Acetone ~6 equiv.)
DMF:Acetone 9:1
(Acetone ~6 equiv.)
30b
4
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European Journal of Organic Chemistry
6
AgOTf
AgOTf
AgOTf
AgNTf2
AgNO3
CuI
Acetone (68 equiv.)
Acetone (68 equiv.)
Acetone (68 equiv.)
Acetone (68 equiv.)
Acetone (68 equiv.)
Acetone (68 equiv.)
Acetone (68 equiv.)
r.t.
80
24 33b
-
7
7
74
-
8
100c
80
0.5 35b
5b
9
7
42b
56b
10
11
12
13
80
3
-
-
-
-
-
60
22
29
27
quant.d
30b
FeCl3
60
PdCl2(PPh3)2 Acetone (68 equiv.)
Acetone (68 equiv.)
60
quant.d
14
60
24
-
40b
a Isolated yields. b Yields calculated via 1H NMR using dimethyl terephthalate (DMT) as internal standard. c Under microwave heating.
d Determined by TLC-analysis.
Under the best reaction conditions achieved (Table 1, entry 7), we tested scope and limitations of the
approach. We selected some 2-alkynylbenzaldehydes characterized by the presence on the alkyne
moieties of electron-donating (ED) or electron-withdrawing (EW) groups (1a-l), some 2-
alkynylarylaldehydes with matching or mismatching electronic properties at their ends (1m-p), and
a couple of 2-alkynylnicotinaldehydes bearing an EW or an ED group on the arylalkyne terminus
(1q,r). The 2-alkynyl(hetero)arylaldehydes 1a-q were synthesized by means of a typical Sonogashira
coupling22 in good to excellent yields starting from the proper 2-bromo(hetero)arylaldehydes and
suitable terminal acetylenes (see Supporting Information).
The results of the scope and limitations study are depicted in Scheme 2. The approach gave in general
the desired products in good yields. The reaction well tolerated the presence of electron-donating
(2a,b) as well as electron-withdrawing groups (2c-g) in the para and meta positions of the aryl
terminus of the alkyne moiety: only the presence of a nitro group (2f) adversely affected the reaction,
while the substitution in the ortho position (2h,i) was not tolerated at all and the starting material was
quantitatively recovered. Probably in these cases, the initial silver promoted formation of the
isochromenylium intermediate is hampered for steric reasons, and in fact, we did not observed the
formation of any degradation product (see below). Alkyl alkyne (2j) gave poor results, while the
reaction of the trimethylsilylacetylene derivative (2k) gave a mixture of unidentified products. 2-
Alkynylarylaldehydes with mismatching electronic properties at their ends gave better results with
5
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European Journal of Organic Chemistry
respect to matching ones (compare the reaction yields of 2n,o with respect to 2m). We also tested the
reaction of 1a with a different ketone such as cyclopentanone, and a mixture of the two
diastereoisomeric products in 1 : 2.4 ratio was obtained in 68% overall yield (2s).
Scheme 2. Scope and limitations of the approach (isolated yields).
With the aim to verify the stability of isolated isochromenes 2 under different conditions, we made
an additional experiment. We prepared three samples of the isochromene 2f (20 mg, 0.065 mmol) in
1 mL of ethyl acetate, and in two of them 0.2 equiv of triethylamine and p-TSA, respectively, were
added. Then, we followed the behaviour of the three sample by TLC analyses after 0,5, 1, 3, 24, 48,
72, and 96 hours. The results evidenced that 2f is stable under neutral and basic conditions, whereas
in the presence of p-TSA a number of unidentified breakdown products started to appear on the TLC
plate after only 0.5 h, and approximately half of the isochromene 2f was degraded after 96 h under
these conditions (checked by TLC analysis).
6
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
It is worth to note that this domino approach displays some surprising results when four particular 2-
alkynyl(hetero)arylaldehydes were used. In fact, the reaction of compounds 1l, 1p, 1q and 1r with
acetone under the optimized conditions did not gave the expected products 2, but led to the formation
of the corresponding couples of homodimeric diastereoisomers 3a-d (Table 2). All new compounds
have been fully characterized by 1H and 13C NMR spectroscopies, and MS spectrometry.
Table 2. Formation of homodimeric diastereoisomers 3a-d.
X
C
C
N
N
R1
H
F
R2
t (h)
24
6
Yield (%)a drb
1 rec. (%)
2-pyridinyl
3-CF3-C6H4
4-MeO-C6H4
3-F-C6H4
3a 67
3b 39
3c 90
3d 57
1 : 4.5
-
1l
1.5 : 1
1 : 1.4
1 : 1.9
8
-
1p
1q
1r
H
7
H
2.5
-
a Yields of pure isolated product. b Syn-anti ratio.
As previously observed9,23 the formation of dimers 3 can been ascribed to a silver-catalyzed addition
of water to the triple bond of the 2-alkynyl-(hetero)arylaldehyde 2, or to the respective organosilver
isochromenylium intermediate, thus generating a ketone which in the enol form attacks as a
nucleophile a second electrophilic isochromenylium intermediate. Nevertheless, when we tried to
perform the reaction in strongly anhydrous conditions (under a nitrogen atmosphere and in the
presence of 4 Å molecular sieves), we observed that the reaction was totally hampered, and the
starting material was almost quantitatively recovered. This behaviour confirms the presence of traces
of water in the reaction mixture plays an essential role for the keto-enol tautomeric equilibria.13
Based on our findings and the previous literature, to explain the formation of isochromenes 2 and
homodimers 3 we suggested the mechanism illustrated in Scheme 3. The coordination of the triple
bond to AgOTf enhances the electrophilicity of alkyne, and the subsequent nucleophilic attack of the
aldehyde oxygen to the electron-deficient alkyne would form the isochromenylium cation (I) (ate
complex).24 At the same time, the catalyst could coordinate to the carbonyl group of the enolizable
ketone thus promoting, assisted by traces of water, the formation of the corresponding enol (II).25
Then, following the path A, the enol (II) can attack the activate isochromenylium intermediate (I) to
7
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
give the intermediate (III). A fast protodemetallation, maybe assisted by the acidic proton of the
nucleophile,12 leads to the 1-acylsubstituted-isochromene 2 and regenerates the catalyst.
Alternatively, following path B, the isochromenylium (I) can be hydrated to give the ketoaldehyde
(IV)9,23 which then attacks as a nucleophile a second isochromenylium intermediate (I), yielding the
dimeric compound 3. Thus, in this cascade process the silver catalyst plays a double role: 1. as -
philic activator of the triple bond able to promote the formation of the isochromenylium intermediate
(I) and 2. as -philic activator of the carbonyl oxygen, able to promote a fast keto-enolic equilibria
in the ketone. And worth noting, both of them are equally important for the success of the
transformation.
Scheme 3. Suggested reaction paths.
Regarding the hydration step, a possible formation of intermediate IV by direct silver catalyzed
hydration of the triple bond was ruled out based on the results of the following experiments. When
alkynes 4a or 4b (Scheme 4) were reacted in the presence of silver triflate under the standard reaction
conditions, the corresponding possible hydration products were never observed. Also when the
reaction was performed in the presence of 1.5 equiv. of water, the starting materials 4a,b were
8
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
quantitatively recovered (Scheme 4). Moreover, a path involving hydration of the isochromenylium
intermediate (I) well fits with the total regioselectivity observed in this process.
Scheme 4. Control experiments on direct Ag catalyzed hydration of alkynes.
The hydrolytic path B is competitive with the formation of the isochromenes 2 (path A), and the
former is the preferred one when the substrate 1 has a pyridine moiety (1l,q,r) or when the alkyne is
strongly electron-poor and little polarized (1p). The more pronounced nucleophilic character of
nitrogen with respect to oxygen is well known as well as the complexation abilities of pyridine. Thus
we argued that, probably, the pyridine nitrogen of compounds 1l,q,r is able to coordinate to the silver
atom so reducing its availability to promote the required enolization of acetone. This inevitably
favours path B that implies a cascade addition reaction involving first a small nucleophile like
adventitious water, and second an easily formable and more stable conjugated enol such as
intermediate IV. On the other hand, when the alkyne is extremely electron-poor and little polarized,
as in the case of alkynylaldehyde 1p, the electrophilic properties of the resulting isochromenylium
intermediate I are reduced. As a result, acetone is probably a too weak nucleophile to react with this
isochromenylium intermediate I, and therefore path B results favoured also in this case.
Conclusions
In conclusion, we reported here a useful synthesis of 1,3-dicarbosubstituted isochromene derivatives
starting from 2-alkynyl(hetero)arylaldehydes and enolizable ketones, by means of a silver(I)
catalyzed domino approach. The importance to employ a silver catalyst with well-balanced
oxophilicity and alkynephilicity features26 such as silver triflate has been pointed out. In the majority
of cases, the cascade reaction proceeded under relatively mild reaction condition and with absolute
9
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European Journal of Organic Chemistry
regioselectivity, yielding the desired products in moderate to good yields. In the presence of 2-
alkynyl(hetero)arylaldehydes characterized by the presence of a pyridine moiety or by a particular
electronic distribution, the reaction produces diastereoisomeric couples of homodimeric products.
The divergent formation of the 1-acylisochromenes and the alternative homodimeric products has
been tentatively explained by some experiments and suggesting two conceivable competitive paths.
Experimental section
General experimental details
All the reactions, that involve the use of reagents sensitive to oxygen or hydrolysis, were carried out
under inert atmosphere. The glassware was previously dried in an oven at 110 °C and set with cycles
of vacuum and nitrogen. Also syringes, used to transfer reagents and solvents, were previously set
under nitrogen atmosphere. All chemicals and solvents are commercially available and were used
without further purification. The chromatographic column separations were performed by flash
technique, using silica gel (pore size 60Å, particle size 230-400 mesh, Merck Grade 9385). For thin-
layer chromatography (TLC), Silica on TLC Alu foils with fluorescent indicator (254 nm) was
employed and the detection was performed by irradiation with UV light (λ = 254 nm and/or 366 nm).
1H NMR analysis were performed with 300 MHz spectrometers at room temperature. The coupling
constants (J) are expressed in Hertz (Hz), 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), dt (double triplet), dd (double doublet), td (triple doublet), m (multiplet), br (broad), ps
(pseudo). 13C NMR analysis were performed with the same instruments at 74.45 MHz; 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.
Low resolution MS spectra were recorded with electron impact source and electrospray/ion trap
instruments, using a syringe pump device to directly inject sample solutions. 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 a ICR-FTMS electrospray equipped instrument. The
melting points are uncorrected. For the synthesis of starting materials sees Supporting Information.
General Procedure for the addition/cycloisomerization reactions of alkynylaldehydes 1. The
catalyst AgOTf (10 mol%) was added to a stirred solution of the proper 2-alkynylbenzaldehydes 1a-
r (0.46 mmol) in acetone or cyclopentanone ([1] = 0.20 M), under a nitrogen atmosphere. The reaction
mixture was stirred at 80 °C until no more starting product was detectable by TLC analysis. The
reaction mixture was diluted with H2O (25 mL) and extracted with ethyl acetate (3 × 15 mL). The
10
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
organic layer was dried with Na2SO4 and then evaporated to dryness under reduced pressure. The
crude was purified by flash chromatography over a silica gel column yielding the corresponding
product 2 or 3.
1-(3-(p-tolyl)-1H-isochromen-1-yl)propan-2-one (2a): Eluent for chromatography: hexane–EtOAc
(95 : 5). Yellow solid. Yield: 74% (95 mg); mp 108-110 °C (lit.16 112-113 °C). 1H NMR (300 MHz,
CDCl3): δ = 7.57 (d, J = 8.2 Hz, 2H, Har), 7.14–7.28 (m, 4H, Har), 7.10 (dd, J = 7.4, 1.2 Hz, 1H, Har),
7.06 (ddd, J = 7.4, 1.4, 0.7 Hz, 1H, Har), 6.41 (s, 1H, Csp2-H), 5.85 (dd, J = 8.8, 4.6 Hz, 1H, CH-O),
3.30 (dd, J = 16.1, 8.8 Hz, 1H, CH2), 2.78 (dd, J = 16.1, 4.6 Hz, 1H, CH2), 2.37 (s, 3H, CH3), 2.19 (s,
3H, CH3). These data are in good agreement with literature values.16
1-(3-(4-methoxyphenyl)-1H-isochromen-1-yl)propan-2-one (2b): Eluent for chromatography:
hexane–EtOAc (95 : 5). Yellow-orange solid. Yield: 65% (88 mg); mp 103-105 °C (lit.16 118-119
°C). 1H NMR (300 MHz, CDCl3): δ = 7.61 (d, J = 9.0 Hz, 2H, Har), 7.21–7.27 (m, 1H, Har), 7.15 (td,
J = 7.4, 1.4 Hz, 1H, Har), 7.09 (dd, J = 7.5, 1.0 Hz, 1H, Har), 7.05 (dd, J = 7.4, 0.6 Hz, 1H, Har), 6.90
(d, J = 9.0 Hz, 2H, Har), 6.34 (s, 1H, Csp2-H), 5.83 (dd, J = 8.9, 4.5 Hz, 1H, CH-O), 3.83 (s, 3H, CH3),
3.30 (dd, J = 16.1, 8.9 Hz, 1H, CH2), 2.79 (dd, J = 16.1, 4.5 Hz, 1H, CH2), 2.19 (s, 3H, CH3). 13C
NMR (75.45 MHz, CDCl3): δ = 206.3 (C=O), 160.6 (Cq), 151.5 (Cq), 131.3 (Cq), 130.2 (Cq), 128.5
(CHar), 127.1 (Cq), 126.8 (CHar), 126.6 (CHar), 124.0 (CHar), 123.8 (CHar), 114.0 (CHar), 99.1 (CH),
74.3 (CH), 55.6 (CH3), 47.4 (CH2), 31.4 (CH3). MS ESI(+): m/z (%) = 294.8 (100) [M + 1]+, 317.0
[M + Na]+ (65). These data are in good agreement with literature values.16
1-(3-(3-fluorophenyl)-1H-isochromen-1-yl)propan-2-one (2c): Eluent for chromatography: hexane–
EtOAc (95 : 5). Pale yellow solid. Yield: 64% (83 mg); mp 83-85 °C. 1H NMR (300 MHz, CDCl3):
δ = 7.46 (ddd, J = 7.9, 1.6, 1.0 Hz, 1H, Har), 7.39–7.28 (m, 2H, Har), 7.25 (dd, J = 7.4, 1.4 Hz, 1H,
Har), 7.20 (td, J = 7.4, 1.5 Hz, 1H, Har), 7.12 (dd, J = 7.3, 1.2 Hz, 1H, Har), 7.10–6.98 (m, 2H, Har),
6.46 (s, 1H, Csp2-H), 5.86 (dd, J = 8.6, 4.6 Hz, 1H, CH-O), 3.28 (dd, J = 16.2, 8.7 Hz, 1H, CH2), 2.82
(dd, J = 16.2, 4.7 Hz, 1H, CH2), 2.19 (s, 3H, CH3). 13C NMR (75.45 MHz, CDCl3): δ = 205.8 (C=O),
163.2 (d, 1JC,F = 245.2 Hz, CF), 150.2 (d, 4JC,F = 2.9 Hz, Cq), 136.8 (d, 3JC,F = 7.9 Hz, Cq), 130.6 (Cq),
3
130.5 (Cq), 130.1 (d, JC,F = 8.3 Hz, CHar), 128.6 (CHar), 127.4 (CHar), 124.6 (CHar), 123.9 (CHar),
120.8 (d, 4JC,F = 2.9 Hz, CHar), 115.9 (d, 2JC,F = 21.4 Hz, CHar), 112.1 (d, 2JC,F = 23.3 Hz, CHar), 101.7
(CH), 74.3 (CH), 47.5 (CH2), 31.3 (CH3). MS ESI(+): m/z (%) = 304.9 [M + Na]+ (100), 225.1 (40)
[M – CH2COCH3]+. Anal. Calcd for C18H15FO2: C, 76.58; H, 5.36. Found: C, 76.64; H, 5.32.
1-(3-(3-(trifluoromethyl)phenyl)-1H-isochromen-1-yl)propan-2-one
(2d):
Eluent
for
chromatography: hexane–EtOAc (94 : 6). Pale yellow oil. Yield: 64% (98 mg). 1H NMR (300 MHz,
CDCl3): δ = 7.93 (s, 1H, Har), 7.84 (d, J = 7.8 Hz, 1H, Har), 7.58 (d, J = 7.7 Hz, 1H, Har), 7.49 (t, J =
11
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7.8 Hz, 1H, Har), 7.25–7.30 (m, 1H, Har), 7.21 (td, J = 7.4, 1.6 Hz, 1H, Har), 7.14 (dd, J = 7.2, 1.4 Hz,
1H, Har), 7.08 (d, J = 7.3 Hz, 1H, Har), 6.52 (s, 1H, Csp2-H), 5.88 (dd, J = 8.6, 4.7 Hz, 1H, CH-O),
3.28 (dd, J = 16.2, 8.8 Hz, 1H, CH2), 2.85 (dd, J = 16.2, 4.7 Hz, 1H, CH2), 2.19 (s, 3H, CH3). 13C
NMR (75.45 MHz, CDCl3): δ = 205.8 (C=O), 150.0 (Cq), 135.3 (Cq), 131.1 (q, 2JC,F = 32.3 Hz, C-
4
CF3), 130.5 (Cq), 130.4 (Cq), 129.2 (CHar), 128.7 (CHar), 128.3 (q, JC,F = 1.1 Hz, CHar), 127.9 (q,
1JC,F = 272.5 Hz, CF3), 127.6 (CHar), 125.5 (q, 3JC,F = 3.8 Hz, CHar), 124.7 (CHar), 124.0 (CHar), 121.9
(q, 3JC,F = 3.8 Hz, CHar), 102.1 (CH), 74.4 (CH), 47.6 (CH2), 31.2 (CH3). MS ESI(+): m/z (%) = 387.0
[M + Na + CH3OH]+ (100). Anal. Calcd for C19H15F3O2: C, 68.67; H, 4.55. Found: C, 68.81; H, 4.58.
1-(3-(4-chlorophenyl)-1H-isochromen-1-yl)propan-2-one (2e): Eluent for chromatography: hexane–
EtOAc (98 : 2). Yellowish solid. Yield: 70% (96 mg); mp 77-78 °C (lit.16 89-90 °C). 1H NMR (300
MHz, CDCl3): δ = 7.60 (d, J = 8.9 Hz, 2H, Har), 7.34 (d, J = 8.9 Hz, 2H, Har), 7.26 (td, J = 7.4, 1.5
Hz, 1H, Har), 7.19 (td, J = 7.4, 1.5 Hz, 1H, Har), 7.11 (dd, J = 7.3, 1.4 Hz, 1H, Har), 7.06 (dd, J = 7.4,
0.7 Hz, 1H, Har), 6.43 (s, 1H, Csp2-H), 5.85 (dd, J = 8.8, 4.4 Hz, 1H, CH-O), 3.28 (dd, J = 16.2, 8.8
Hz, 1H, CH2), 2.80 (dd, J = 16.2, 4.4 Hz, 1H, CH2), 2.19 (s, 3H, CH3). 13C NMR (75.45 MHz, CDCl3):
δ = 206.0 (C=O), 150.4 (Cq), 134.9 (Cq), 132.9 (Cq), 130.7 (Cq), 130.4 (Cq), 128.9 (CHar), 128.6
(CHar), 127.3 (CHar), 126.5 (CHar), 124.5 (CHar), 123.9 (CHar), 101.1 (CH), 74.3 (CH), 47.5 (CH2),
31.3 (CH3). MS ESI(+): m/z (%) = 298.9 (100) [M + H]+. These data are in good agreement with
literature values.16
1-(3-(4-nitrophenyl)-1H-isochromen-1-yl)propan-2-one (2f): Eluent for chromatography: hexane–
EtOAc (95 : 5). Yellow solid. Yield: 45% (64 mg); mp 129-132 °C. 1H NMR (300 MHz, CDCl3): δ
= 8.20 (d, J = 8.8 Hz, 2H, Har), 7.79 (d, J = 8.8 Hz, 2H, Har), 7.33–7.20 (m, 2H, Har), 7.16 (d, J = 6.7
Hz, 1H, Har), 7.08 (d, J = 6.9 Hz, 1H, Har), 6.62 (s, 1H, Csp2-H), 5.89 (dd, J = 8.8, 4.4 Hz, 1H, CH-
O), 3.27 (dd, J = 16.5, 8.8 Hz, 1H, CH2), 2.83 (dd, J = 16.5, 4.4 Hz, 1H, CH2), 2.20 (s, 3H, CH3). 13C
NMR (75.45 MHz, CDCl3): δ = 205.6 (C=O), 149.2 (Cq), 147.8 (Cq), 140.5 (Cq), 130.7 (Cq), 130.0
(Cq), 128.8 (CHar), 128.3 (CHar), 125.6 (CHar), 125.2 (CHar), 124.0 (CHar), 104.5 (CH), 74.3 (CH),
47.6 (CH2), 31.2 (CH3) (one CHar overlapped). MS ESI(+): m/z (%) = 252.0 (100) [M – CH2COCH3]+.
Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.81; H, 4.94; N, 4.47.
1-(3-(4-(methylsulfonyl)phenyl)-1H-isochromen-1-yl)propan-2-one
(2g):
Eluent
for
1
chromatography: hexane–EtOAc (70 : 30). Pale yellow wax. Yield: 79% (124 mg). H NMR (300
MHz, CDCl3): δ = 7.92 (d, J = 8.6 Hz, 2H, Har), 7.83 (d, J = 8.6 Hz, 2H, Har), 7.33–7.19 (m, 2H, Har),
7.15 (dd, J = 7.1, 1.5 Hz, 1H, Har), 7.08 (d, J = 7.1 Hz, 1H, Har), 6.60 (s, 1H, Csp2-H), 5.90 (dd, J =
8.8, 4.4 Hz, 1H, CH-O), 3.27 (dd, J = 16.2, 8.8 Hz, 1H, CH2), 3.06 (s, 3H, CH3), 2.83 (dd, J = 16.2,
4.4 Hz, 1H, CH2), 2.20 (s, 3H, CH3). 13C NMR (75.45 MHz, CDCl3): δ = 205.6 (C=O), 149.4 (Cq),
12
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
140.3 (Cq), 139.7 (Cq), 130.7 (Cq), 130.1 (Cq), 128.8 (CHar), 128.1 (CHar), 127.8 (CHar), 125.7 (CHar),
125.0 (CHar), 124.0 (CHar), 103.9 (CH), 74.3 (CH), 47.6 (CH2), 44.7 (CH3), 31.2 (CH3). MS ESI(+):
m/z (%) = 342.9 [M + H]+ (100), 365.2 [M + Na]+ (40). Anal. Calcd for C19H18O4S: C, 66.65; H, 5.30.
Found: C, 66.78; H, 5.39.
1-(3-propyl-1H-isochromen-1-yl)propan-2-one (2j): Eluent for chromatography: hexane–EtOAc (93
: 7). Yellow oil. Yield: 29% (31 mg). 1H NMR (300 MHz, C6D6): δ = 7.01 (td, J = 7.5, 1.3 Hz, 1H,
Har), 6.90 (td, J = 7.5, 1.3 Hz, 1H, Har), 6.79 (d, J = 7.5 Hz, 1H, Har), 6.70 (ddd, J = 6.9, 1.2, 0.6 Hz,
1H, Har), 5.64 (dd, J = 8.4, 4.9 Hz, 1H, CH-O), 5.45 (s, 1H, Csp2-H), 2.79 (dd, J = 16.0, 8.4 Hz, 1H,
CH2), 2.28 (dd, J = 16.0, 4.9 Hz, 1H, CH2), 1.98 (td, J = 7.2, 4.3 Hz, 2H, CH2), 1.62 (s, 3H, CH3),
13
1.45 (ddd, J = 15.0, 7.5, 3.0 Hz, 2H, CH2), 0.80 (t, J = 7.4 Hz, 3H, CH3). C NMR (75.45 MHz,
C6D6): δ = 203.4 (C=O), 156.2 (Cq), 131.3 (Cq), 129.9 (Cq), 126.0 (CHar), 123.9 (CHar), 123.1 (CHar),
100.8 (CH), 73.9 (CH), 47.5 (CH2), 36.0 (CH2), 30.0 (CH3), 20.2 (CH2), 13.6 (CH3) (one CHar
obscured). MS ESI(+): m/z (%) = 252.9 [M + Na]+ (50). Anal. Calcd for C15H18O2: C, 78.23; H, 7.88.
Found: C, 78.36; H, 7.91.
1-(7-methoxy-3-(4-methoxyphenyl)-1H-isochromen-1-yl)propan-2-one
(2m):
Eluent
for
chromatography: hexane–EtOAc (80 : 20). Brownish wax. Yield: 26% (39 mg). 1H NMR (300 MHz,
CDCl3): δ = 7.58 (d, J = 8.3 Hz, 2H, Har), 7.03 (d, J = 8.3 Hz, 1H, Har), 6.89 (d, J = 8.3 Hz, 2H, Har),
6.79 (dd, J = 8.3, 2.2 Hz, 1H, Har), 6.64 (d, J = 2.4 Hz, 1H, Har), 6.31 (s, 1H, Csp2-H), 5.79 (dd, J =
8.8, 4.5 Hz, 1H, CH-O), 3.82 (d, J = 0.8 Hz, 3H, CH3), 3.80 (d, J = 0.8 Hz, 3H, CH3), 3.28 (dd, J =
13
16.1, 8.9 Hz, 1H, CH2), 2.74 (dd, J = 16.1, 4.5 Hz, 1H, CH2), 2.18 (s, 3H, CH3). C NMR (75.45
MHz, CDCl3): δ = 206.4 (C=O), 160.2 (Cq), 158.7 (Cq), 149.3 (Cq), 131.9 (Cq), 127.3 (Cq), 126.4
(CHar), 125.3 (CHar), 124.2 (Cq), 114.0 (CHar), 113.6 (CHar), 110.1 (CHar), 98.9 (CH), 74.2 (CH),
55.7 (CH3), 55.5 (CH3), 47.4 (CH2), 31.4 (CH3). MS ESI(+): m/z (%) = 325.1 [M + H]+ (60). Anal.
Calcd for C20H20O4: C, 74.06; H, 6.21. Found: C, 73.88; H, 6.17.
1-(3-(3-fluorophenyl)-7-methoxy-1H-isochromen-1-yl)propan-2-one
(2n):
Eluent
for
chromatography: hexane–EtOAc (90 : 10). White solid. Yield: 58% (83 mg); mp 97-99 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.42 (dd, J = 8.1, 1.3 Hz, 1H, Har), 7.37–7.27 (m, 2H, Har), 7.06 (d, J = 8.4
Hz, 1H, Har), 6.99 (tdd, J = 8.3, 2.6, 1.0 Hz, 1H, Har), 6.80 (dd, J = 8.3, 2.6 Hz, 1H, Har), 6.65 (d, J =
2.5 Hz, 1H, Har), 6.43 (s, 1H, Csp2-H), 5.81 (dd, J = 8.6, 4.6 Hz, 1H, CH-O), 3.81 (s, 3H, CH3), 3.25
(dd, J = 16.2, 8.6 Hz, 1H, CH2), 2.77 (dd, J = 16.2, 4.7 Hz, 1H, CH2), 2.18 (s, 3H, CH3). 13C NMR
(75.45 MHz, CDCl3): δ = 206.0 (C=O), 163.2 (d, 1JC,F = 245.0 Hz, CF), 159.3 (Cq), 148.1 (d, 4JC,F
=
2.9 Hz, Cq), 137.0 (d, 3JC,F = 8.0 Hz, Cq), 132.3 (Cq), 130.1 (d, 3JC,F = 8.3 Hz, CHar), 125.9 (CHar),
123.4 (Cq), 120.4 (d, 4JC,F = 2.6 Hz, CHar), 115.4 (d, 2JC,F = 21.2 Hz, CHar), 113.7 (CHar), 111.7 (d,
13
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
2JC,F = 23.2 Hz, CHar), 110.2 (CHar), 101.5 (CH), 74.2 (CH), 55.7 (CH3), 47.5 (CH2), 31.4 (CH3). MS
ESI(+): m/z (%) = 335.2 (100) [M + Na]+. Anal. Calcd for C19H17FO3: C, 73.06; H, 5.49. Found: C,
73.17; H, 5.51.
1-(7-fluoro-3-(4-methoxyphenyl)-1H-isochromen-1-yl)propan-2-one
(2o):
Eluent
for
chromatography: hexane–EtOAc (90 : 10). Pale yellow solid. Yield: 69% (99 mg); mp 96-98 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.59 (d, J = 9.0 Hz, 2H, Har), 7.05 (dd, J = 8.4, 5.5 Hz, 1H, Har), 6.95
(dd, J = 8.6, 2.5 Hz, 1H, Har), 6.90 (d, J = 9.0 Hz, 2H, Har), 6.80 (dd, J = 8.7, 2.5 Hz, 1H, Har), 6.31
(s, 1H, Csp2-H), 5.78 (dd, J = 8.6, 4.7 Hz, 1H, CH-O), 3.83 (s, 3H, CH3), 3.27 (dd, J = 16.3, 8.6 Hz,
1H, CH2), 2.79 (dd, J = 16.3, 4.7 Hz, 1H, CH2), 2.19 (s, 3H, CH3). 13C NMR (75.45 MHz, CDCl3): δ
1
= 205.8 (C=O), 161.7 (d, JC,F = 245.0 Hz, CF), 160.6 (Cq), 150.9 (d, 6JC,F = 2.3 Hz, Cq), 132.2 (d,
3JC,F = 6.9 Hz, Cq), 127.5 (d, 4JC,F = 2.9 Hz, Cq), 126.9 (Cq), 126.7 (CHar), 125.4 (d, 3JC,F = 7.7 Hz,
CHar), 115.2 (d, 2JC,F = 21.8 Hz, CHar), 114.1 (CHar), 111.3 (d, 2JC,F = 23.2 Hz, CHar), 98.4 (CH), 73.7
(CH), 55.6 (CH3), 47.1 (CH2), 31.4 (CH3). ESI(+): m/z (%) = 335.3 (100) [M + Na]+. Anal. Calcd for
C19H17FO3: C, 73.06; H, 5.49. Found: C, 73.21; H, 5.45.
2-(3-(p-tolyl)-1H-isochromen-1-yl)cyclopentanone (2s): Eluent for chromatography: hexane–EtOAc
(from 99 : 1 to 90 : 10).
Diast.1: fr.40-45. Yellow oil. Yield: 20% (28 mg). 1H NMR (300 MHz, CDCl3): δ = 7.67 (d, J = 8.2
Hz, 2H, Har), 7.31-7.17 (m, 3H, Har), 7.16-7.08 (m, 2H, Har), 6.96 (d, J = 7.0 Hz, 1H, Har), 6.32 (s,
1H, Csp2-H), 5.87 (d, J = 4.6 Hz, 1H, CH-O), 2.85 (dd, J = 9.2, 4.6 Hz, 1H, CH-CO), 2.40 (s, 3H,
13
CH3), 2.33-2.22 (m, 1H, CH2), 2.11-1.82 (m, 3H, CH2), 1.72-1.61 (m, 2H, CH2). C NMR (75.45
MHz, CDCl3): δ = 217.7 (C=O), 152.1 (Cq), 139.0 (Cq), 131.72 (Cq), 131.66 (Cq), 129.1 (CHar), 128.3
(CHar), 128.0 (Cq), 126.4 (CHar), 125.1 (CHar), 124.9 (CHar), 123.7 (CHar), 99.5 (CH), 76.7 (CH),
55.2 (CH), 38.5 (CH2), 25.4 (CH2), 21.3 (CH3), 20.5 (CH2). ESI(+): m/z (%) = 327.0 (100) [M + Na]+,
304.8 (60) [M + H]+. Anal. Calcd for C21H20O2: C, 82.86; H, 6.62. Found: C, 82.68; H, 6.66.
1
Diast.2: fr.50-55. Yellow wax. Yield: 48% (67 mg). H NMR (300 MHz, CDCl3): δ = 7.53 (d, J =
8.2 Hz, 2H, Har), 7.32-7.14 (m, 4H, Har), 7.12-7.07 (m, 2H, Har), 6.35 (s, 1H, Csp2-H), 5.82 (d, J = 2.9
Hz, 1H, CH-O), 2.85 (dt, J = 9.3, 2.7 Hz, 1H, CH-CO), 2.52-2.17 (m, 4H, CH2), 2.39 (s, 3H, CH3),
2.14-2.00 (m, 1H, CH2), 1.87-1.77 (m, 1H, CH2). 13C NMR (75.45 MHz, CDCl3): δ = 218.7 (C=O),
153.1 (Cq), 139.0 (Cq), 131.3 (Cq), 131.2 (Cq), 129.4 (Cq), 129.1 (CHar), 128.2 (CHar), 126.4 (CHar),
125.0 (CHar), 123.9 (CHar), 123.4 (CHar), 99.6 (CH), 76.9 (CH), 52.3 (CH), 39.4 (CH2), 24.2 (CH2),
21.3 (CH3), 20.5 (CH2). ESI(+): m/z (%) = 327.0 (50) [M + Na]+, 304.9 (100) [M + H]+. Anal. Calcd
for C21H20O2: C, 82.86; H, 6.62. Found: C, 82.75; H, 6.64.
14
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
2-(2-oxo-2-(pyridin-2-yl)-1-(3-(pyridin-2-yl)-1H-isochromen-1-yl)ethyl)benzaldehyde (3a):
Reaction time: 24 h. Eluent for chromatography: hexane–EtOAc (90 : 10 → 80 : 20).
Diast.1: fr.50-54. Pale green solid. Yield: 13% (13 mg); mp 130 °C dec. 1H NMR (300 MHz, CDCl3):
δ = 10.65 (s, 1H, CHO), 8.52 (d, J = 4.7 Hz, 1H, Har), 8.38 (d, J = 4.7 Hz, 1H, Har), 7.93 (d, J = 7.7
Hz, 1H, Har), 7.81 (d, J = 8.4 Hz, 1H, Har), 7.76–7.53 (m, 4H, Har), 7.40–7.06 (m, 8H, Har), 7.03 (d, J
13
= 10.3 Hz, 1H, Har), 6.44 (pst, 2H, CH). C NMR (75.45 MHz, CDCl3): δ = 197.8 (C=O), 190.9
(CHO), 151.9 (Cq), 151.4 (Cq), 150.0 (Cq), 149.3 (CHar), 149.0 (CHar), 138.6 (Cq), 137.1 (CHar), 136.4
(CHar), 135.6 (Cq), 133.6 (CHar), 130.9 (Cq), 130.5 (Cq), 128.93 (CHar), 128.87 (CHar), 128.76 (CHar),
127.7 (CHar), 127.5 (CHar), 127.4 (CHar), 126.2 (CHar), 125.6 (CHar), 123.4 (CHar), 122.7 (CHar),
119.2 (CHar), 104.4 (CH), 78.5 (CH), 48.5 (CH). MS ESI(+): m/z (%) = 433.0 [M + H]+ (100), 455.2
[M + Na]+ (50). HRMS ESI (M + H)+ calculated for C28H21N2O3 433.1546, found 433.1549.
Diast.2: fr.63-73. Green solid. Yield: 54% (54 mg); mp 100 °C dec. 1H NMR (300 MHz, CDCl3): δ
= 10.18 (s, 1H, CHO), 8.50 (d, J = 4.7 Hz, 1H, Har), 8.31 (d, J = 4.7 Hz, 1H, Har), 8.08 (d, J = 7.9 Hz,
1H, Har), 7.76–7.61 (m, 3H, Har), 7.53 (td, J = 7.6, 1.5 Hz, 1H, Har), 7.46 (td, J = 7.7, 1.7 Hz, 1H, Har),
7.37 (d, J = 7.9 Hz, 1H, Har), 7.35–7.09 (m, 6H, Har), 7.07 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H, Har), 6.75
(td, J = 7.3, 1.5 Hz, 1H, Har), 6.25 (d, J = 10.4 Hz, 1H, CH), 6.10 (d, J = 7.5 Hz, 1H, CH). 13C NMR
(75.45 MHz, CDCl3): δ = 198.5 (C=O), 190.6 (CHO), 152.5 (Cq), 152.0 (Cq), 149.5 (Cq), 149.3
(CHar), 137.0 (Cq), 136.9 (CHar), 136.7 (CHar), 135.5 (Cq), 133.6 (CHar), 130.4 (Cq), 129.1 (CHar),
128.9 (CHar), 128.8 (CHar), 128.1 (CHar), 127.9 (Cq), 127.4 (CHar), 126.5 (CHar), 125.7 (CHar), 125.3
(CHar), 123.2 (CHar), 122.4 (CHar), 119.3 (CHar), 103.2 (CH), 79.6 (CH), 45.1 (CH) (one CHar
obscured). MS ESI(+): m/z (%) = 433.0 [M + H]+ (100), 455.2 [M + Na]+ (50). HRMS ESI (M + H)+
calculated for C28H21N2O3 433.1546, found 433.1541.
5-fluoro-2-(1-(7-fluoro-3-(3-(trifluoromethyl)phenyl)-1H-isochromen-1-yl)-2-oxo-2-(3-
(trifluoromethyl)phenyl)ethyl)benzaldehyde (3b): Reaction time: 6 h. Eluent for chromatography:
hexane–EtOAc (70 : 30).
Diast.1: fr.19-24. Yellow solid. Yield: 23% (32 mg); mp 106-108 °C. 1H NMR (300 MHz, CDCl3):
δ = 9.46 (s, 1H, CHO), 8.16 (s, 1H, Har), 8.04 (d, J = 7.9 Hz, 1H, Har), 7.94 (dd, J = 8.7, 5.1 Hz, 1H,
Har), 7.67 (d, J = 7.8 Hz, 1H, Har), 7.56–7.33 (m, 5H, Har), 7.20–7.08 (m, 3H, Har), 7.02–6.86 (m, 3H,
CH + Har), 6.68 (s, 1H, CH), 6.22 (d, J = 10.0 Hz, 1H, CH). 13C NMR (75.45 MHz, CDCl3): δ = 197.2
1
1
(C=O), 192.0 (CHO), 162.5 (d, JC,F = 251.9 Hz, CF), 161.9 (d, JC,F = 247.6 Hz, CF), 148.5 (Cq),
3
3
137.0 (Cq), 136.2 (d, JC,F = 4.7 Hz, Cq), 134.4 (Cq), 132.1 (d, JC,F = 7.4 Hz, CHar), 131.9 (CHar),
131.5 (d, 3JC,F = 7.4 Hz, Cq), 131.5 (Cq), 131.5 (q, 2JC,F = 33.0 Hz, C-CF3), 131.0 (q, 2JC,F = 33.0 Hz,
C-CF3), 130.2 (q, 3JC,F = 3.3 Hz, CHar), 129.5 (CHar), 128.8 (CHar), 127.5 (CHar), 126.7 (d, 3JC,F = 8.0
15
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
Hz, CHar), 126.2 (d, 4JC,F = 3.1 Hz, Cq), 125.9 (q, 3JC,F = 3.9 Hz, CHar), 125.5 (q, 3JC,F = 3.5 Hz, CHar),
2
123.7 (q, 1JC,F = 272.8 Hz, CF3), 122.4 (d, 2JC,F = 21.7 Hz, CHar), 121.6 (d, JC,F = 21.1 Hz, CHar),
121.2 (q, 3JC,F = 3.8 Hz, CHar), 115.9 (d, 2JC,F = 22.0 Hz, CHar), 113.8 (d, 2JC,F = 23.4 Hz, CHar), 102.0
(CH), 79.4 (CH), 48.8 (CH) (one CF3 obscured). MS ESI(+): m/z (%) = 603.3 [M + H]+ (100). HRMS
ESI (M + H)+ calculated for C32H19F8O3 603.1201, found 603.1205.
Diast.2: fr.26-33. Yellow wax. Yield: 16% (22 mg). 1H NMR (300 MHz, CDCl3): δ = 9.54 (s, 1H,
CHO), 8.28 (s, 1H, Har), 8.11 (d, J = 7.8 Hz, 1H, Har), 7.91 (dd, J = 8.6, 5.2 Hz, 1H, Har), 7.62–7.65
(m, 3H, Har), 7.46–7.23 (m, 5H, Har), 7.11 (d, J = 9.9 Hz, 1H, Har), 7.07 (dd, J = 8.2, 5.2 Hz, 1H, Har),
6.87 (td, J = 8.5, 2.6 Hz, 1H, Har), 6.65 (s, 1H, CH), 6.08 (d, J = 9.7 Hz, 1H, CH), 5.79 (dd, J = 8.7,
1
2.5 Hz, 1H, CH). 13C NMR (75.45 MHz, CDCl3): δ = 197.1 (C=O), 191.4 (CHO), 162.6 (d, JC,F
=
252.2 Hz, CF), 161.1 (d, 1JC,F = 247.3 Hz, CF), 148.5 (Cq), 137.2 (Cq), 136.3 (d, 3JC,F = 5.4 Hz, Cq),
134.5 (Cq), 132.0 (d, 3JC,F = 7.4 Hz, CHar), 131.9 (CHar), 131.6 (q, 2JC,F = 32.6 Hz, C-CF3), 131.0 (q,
2JC,F = 32.4 Hz, C-CF3), 130.6 (d, 4JC,F = 3.4 Hz, Cq), 130.2 (q, 3JC,F = 3.1 Hz, CHar), 129.6 (CHar),
129.3 (d, 3JC,F = 7.2 Hz, Cq), 128.9 (CHar), 127.9 (CHar), 127.1 (d, 4JC,F = 3.1 Hz, Cq), 126.0 (d, 3JC,F
= 7.7 Hz, CHar), 125.7 (q, 3JC,F = 4.0 Hz, CHar), 125.5 (q, 3JC,F = 3.4 Hz, CHar), 124.0 (q, 1JC,F = 272.8
Hz, CF3), 123.6 (q, 1JC,F = 272.5 Hz, CF3), 122.3 (d, 2JC,F = 21.8 Hz, CHar), 121.7 (q, 3JC,F = 4.0 Hz,
2
2
2
CHar), 121.3 (d, JC,F = 21.2 Hz, CHar), 115.7 (d, JC,F = 21.8 Hz, CHar), 112.9 (d, JC,F = 23.2 Hz,
CHar), 101.5 (CH), 80.3 (CH), 45.1 (CH). MS ESI(+): m/z (%) = 603.4 [M + H]+ (100). HRMS ESI
(M + H)+ calculated for C32H19F8O3 603.1201, found 603.1206.
2-(2-(4-methoxyphenyl)-1-(7-(4-methoxyphenyl)-5H-pyrano[4,3-b]pyridin-5-yl)-2-oxoethyl)-
nicotinaldehyde (3c): Reaction time: 7 h. Eluent for chromatography: hexane–EtOAc (70 : 30).
Diast.1: fr.16-28. Ochre solid. Yield: 38% (43 mg); mp 130-134 °C. 1H NMR (300 MHz, CDCl3): δ
= 9.79 (s, 1H, CHO), 8.84 (d, J = 4.5 Hz, 1H, Har), 8.37 (d, J = 4.8 Hz, 1H, Har), 7.87 (d, J = 7.9 Hz,
1H, Har), 7.83 (d, J = 8.8 Hz, 2H, Har), 7.70 (d, J = 7.4 Hz, 1H, Har), 7.39 (dd, J = 7.6, 4.8 Hz, 1H,
Har), 7.06 (d, J = 8.5 Hz, 2H, Har), 6.97 (dd, J = 7.2, 5.1 Hz, 1H, Har), 6.82–6.60 (m, 7H, Har + CH),
3.80 (s, 3H, CH3), 3.73 (s, 3H, CH3). 13C NMR (75.45 MHz, CDCl3): δ = 193.9 (C=O), 191.1 (CHO),
163.9 (Cq), 161.0 (Cq), 156.5 (Cq), 155.8 (Cq), 153.8 (CHar), 150.6 (Cq), 149.3 (CHar), 141.1 (CHar),
134.7 (CHar), 131.2 (CHar), 130.8 (Cq), 129.8 (Cq), 126.8 (CHar), 125.6 (Cq), 124.8 (Cq), 122.7 (CHar),
121.0 (CHar), 114.0 (CHar), 113.7 (CHar), 100.6 (Csp2-H), 79.1 (CH), 55.6 (CH3), 55.5 (CH3), 53.0
(CH). MS ESI(+): m/z (%) = 493.1 [M + H]+ (100). HRMS ESI (M + H)+ calculated for C30H25N2O5
493.1758, found 493.1763.
Diast.2: fr.48-91. Dark orange solid. Yield: 52% (59 mg); mp 101-103 °C. 1H NMR (300 MHz,
CDCl3): δ = 9.74 (s, 1H, CHO), 8.75 (dd, J = 4.8, 1.8 Hz, 1H, Har), 8.24 (dd, J = 4.9, 1.3 Hz, 1H, Har),
16
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
7.91 (d, J = 8.9 Hz, 2H, Har), 7.81 (dd, J = 7.8, 1.8 Hz, 1H, Har), 7.54 (d, J = 8.9 Hz, 2H, Har), 7.31
(dd, J = 7.7, 4.8 Hz, 1H, Har), 6.85 (d, J = 9.1 Hz, 1H, Har), 6.77 (d, J = 8.9 Hz, 2H, Har), 6.74 (d, J =
8.9 Hz, 2H, Har), 6.64 (m, 2H, Har), 6.57 (dd, J = 7.5, 4.9 Hz, 1H, CH), 6.39 (d, J = 7.0 Hz, 1H, CH),
3.76 (s, 3H, CH3), 3.72 (s, 3H, CH3). 13C NMR (75.45 MHz, CDCl3): δ = 193.4 (C=O), 190.5 (CHO),
163.8 (Cq), 161.1 (Cq), 156.5 (Cq), 155.6 (Cq), 153.3 (CHar), 151.3 (Cq), 149.1 (CHar), 141.1 (CHar),
132.6 (CHar), 131.2 (CHar), 130.3 (Cq), 130.1 (Cq), 127.7 (CHar), 126.2 (Cq), 123.0 (CHar), 122.9 (Cq),
119.7 (CHar), 114.1 (CHar), 114.0 (CHar), 99.9 (Csp2-H), 78.6 (CH), 55.6 (CH3), 55.5 (CH3), 50.6
(CH). MS ESI(+): m/z (%) = 493.3 [M + H]+ (100). HRMS ESI (M + H)+ calculated for C30H25N2O5
493.1758, found 493.1754.
2-(2-(3-fluorophenyl)-1-(7-(3-fluorophenyl)-5H-pyrano[4,3-b]pyridin-5-yl)-2-
oxoethyl)nicotinaldehyde (3d): Reaction time: 3 h. Eluent for chromatography: hexane–EtOAc (70 :
30).
Diast.1: fr.13-15. Dark orange solid. Yield: 20% (22 mg); mp 90-93 °C. 1H NMR (300 MHz, CDCl3):
δ = 9.67 (s, 1H, CHO), 8.83 (dd, J = 4.8, 1.8 Hz, 1H, Har), 7.88 (dd, J = 7.8, 1.8 Hz, 1H, Har), 7.77 (d,
J = 7.6 Hz, 1H, Har), 7.61 (td, J = 7.7, 1.4 Hz, 1H, Har), 7.56 (ddd, J = 9.7, 2.5, 1.7 Hz, 1H, Har), 7.45
(dd, J = 7.8, 4.8 Hz, 1H, Har), 7.28–7.17 (m, 3H, Har), 7.15–7.04 (m, 3H, Har), 6.99 (td, J = 8.2, 2.6
Hz, 1H, Har), 6.83 (m, 2H, CH + Har), 6.70–6.56 (m, 2H, CH). 13C NMR (75.45 MHz, CDCl3): δ =
1
194.5 (C=O), 191.5 (CHO), 162.9 (d, 1JC,F = 248.5 Hz, CF), 162.8 (d, JC,F = 245.6 Hz, CF), 155.4
(Cq), 154.6 (Cq), 153.8 (CHar), 149.8 (Cq), 149.3 (CHar), 142.3 (CHar), 138.7 (d, 3JC,F = 6.3 Hz, Cq),
135.4 (d, 3JC,F = 8.0 Hz, Cq), 135.1 (CHar), 130.6 (Cq), 130.5 (d, 3JC,F = 7.7 Hz, CHar), 130.0 (d, 3JC,F
= 8.0 Hz, CHar), 125.1 (Cq), 125.4 (d, 4JC,F = 2.9 Hz, CHar), 123.2 (CHar), 121.9 (CHar), 120.9 (d, 4JC,F
= 2.9 Hz, CHar), 120.7 (d, 2JC,F = 21.6 Hz, CHar), 116.7 (d, 2JC,F = 21.3 Hz, CHar), 115.5 (d, 2JC,F
=
22.7 Hz, CHar), 112.0 (d, 2JC,F = 23.7 Hz, CHar), 103.1 (CH), 79.0 (CH), 53.8 (CH). MS ESI(+): m/z
(%) = 469.1 (100) [M + H]+. HRMS ESI (M + H)+ calculated for C28H19N2F2O3 469.1358, found
469.1355.
Diast.2: fr.29-51. Pale orange solid. Yield: 37% (40 mg); mp 108-111 °C. 1H NMR (300 MHz,
CDCl3): δ = 9.67 (s, 1H, CHO), 8.74 (dd, J = 4.8, 1.8 Hz, 1H, Har), 8.28 (dd, J = 4.9, 1.5 Hz, 1H, Har),
7.83 (dd, J = 7.8, 1.8 Hz, 1H, Har), 7.65 (t, J = 8.5 Hz, 2H, Har), 7.43–7.33 (m, 2H, Har), 7.30–7.17
(m, 3H, Har), 7.07 (td, J = 7.5, 1.8 Hz, 1H, Har), 6.98 (td, J = 8.3, 2.1 Hz, 1H, Har), 6.91 (d, J = 9.0
Hz, 1H, Har), 6.76 (s, 1H, CH), 6.63 (d, J = 7.6 Hz, 1H, CH), 6.61 (d, J = 8.9 Hz, 1H, Har), 6.38 (d, J
= 7.6 Hz, 1H, CH). 13C NMR (75.45 MHz, CDCl3): δ = 193.8 (C=O), 190.9 (CHO), 163.00 (d, 1JC,F
= 245.3 Hz, CF), 162.98 (d, 1JC,F = 248.5 Hz, CF), 154.7 (Cq), 153.3 (CHar), 150.7 (Cq), 149.6 (CHar),
142.1 (CHar), 138.9 (d, 3JC,F = 6.3 Hz, Cq), 135.8 (d, 3JC,F = 8.0 Hz, Cq), 132.5 (CHar), 130.5 (d, 3JC,F
17
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10.1002/ejoc.201601602
European Journal of Organic Chemistry
3
4
= 7.6 Hz, CHar), 130.2 (d, JC,F = 8.3 Hz, CHar), 130.2 (Cq), 124.5 (d, JC,F = 2.9 Hz, CHar), 123.3
4
(CHar), 123.0 (Cq), 121.5 (d, JC,F = 2.8 Hz, CHar), 120.5 (d, 2JC,F = 18.6 Hz, CHar), 120.4 (CHar),
2
2
2
116.8 (d, JC,F = 21.3 Hz, CHar), 115.6 (d, JC,F = 22.6 Hz, CHar), 112.7 (d, JC,F = 23.5 Hz, CHar),
102.8 (CH), 78.6 (CH), 51.4 (CH) (one Cq obscured). MS ESI(+): m/z (%) = 469.3 (100) [M + H]+.
HRMS ESI (M + H)+ calculated for C28H19N2F2O3 469.1358, found 469.1353.
Notes and references
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18
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