Synthesis of 3-Alkylideneisoindolin-1-ones via Sonogashira Cyclocarbonylative Reactions of 2-Ethynylbenzamides

Article abstract of DOI:10.1021/acs.joc.0c01282

Cyclocarbonylative Sonogashira reactions of ortho-ethynylbenzamides have been investigated. The process is carried out under CO pressure, in the presence of a very small amount of PdCl2(PPh3)2 (0.4 mol %) as a catalytic precursor and without the need for

Full text of DOI:10.1021/acs.joc.0c01282

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Article
Synthesis of 3-alkylideneisoindolin-1-ones via Sonogashira
cyclocarbonylative reactions of 2-ethynylbenzamides
Gianluigi Albano, Stefano Giuntini, and Laura Antonella Aronica
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01282 • Publication Date (Web): 03 Jul 2020
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Synthesis of 3-alkylideneisoindolin-1-ones via Sonogashira
cyclocarbonylative reactions of 2-ethynylbenzamides
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Gianluigi Albano,a,b Stefano Giuntinic,d and Laura Antonella Aronicaa,*
a. Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Giuseppe Moruzzi 13, 56124 Pisa,
Italy.
b. Present address: Dipartimento di Chimica, Università degli Studi di Bari “Aldo Moro”, Via Edoardo
Orabona 4, 70126 Bari, Italy.
c. Dipartimento di Chimica “Ugo Schiff”, Università degli Studi di Firenze, Via della Lastruccia 3, 50019
Sesto Fiorentino, Italy.
d. Centro di Risonanze Magnetiche (CERM), Università degli Studi di Firenze and Consorzio
Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP), Via Luigi Sacconi 6, 50019 Sesto
Fiorentino, Italy
* Corresponding author: laura.antonella.aronica@unipi.it
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ABSTRACT
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Cyclocarbonylative Sonogashira reactions of ortho-ethynylbenzamides have been investigated. The
process is carried out under CO pressure, in the presence of a very small amount of PdCl2(PPh3)2 (0.4
mol %) as a catalytic precursor, and without the need for a Cu salt as co-catalyst. 2-Ethynylbenzamide
reacted successfully with iodoarenes bearing electron-withdrawing and electron-donating groups giving
rise to different classes of compounds depending on the solvent used. On the contrary, N-(4-
chlorophenyl)-2-ethynylbenzamide afforded exclusively polyfunctionalized isoindolinones with high
stereoselectivity towards (E) isomers.
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INTRODUCTION
N-containing heterocycles are structural motifs frequently found in a large number of biologically active
compounds. For instance, isoindolinone is the core structural unit in several natural products such as
chilenine,1 lennoxamine,2 nuevamine,3 chaetosisoindolinone,4 stachybotrisan,5 erinacerin,6
meyeroguilline7 and caputmedusin.8 In particular, 3-methyleneisoindolin-1-ones have been recognized
as nuclei of natural and synthetic compounds such as fumaridine,9 narceine imide,10 stigmalactam,11
magallinesine,12 chartarlactam L,13 aristoyagonine,14 aristolactams15 and AKS-186.16 These
heterocycles have been found to possess antimycobacterial17 and antifungal18 activities, antiplatelet11,19
properties, to act as anti-inflammatory20-22 and neuroprotective23 agents, to inhibit vasoconstriction,24,25
and to show cytotoxic and antitumoral activities.26-30
Owing to their great importance, there has been a continuous interest in developing metal-promoted
cyclization methods for the syntheses of 3-methyleneisoindolin-1-ones.31 Transition-metal-catalysed
cyclocarbonylation reaction is a useful approach to the formation of lactame moiety.32-41 Mancuso and
co-workers developed an interesting synthesis of 3-methyleneisoindolin-1-ones based on a PdI2-
catalyzed cyclization of 2-alkynylbenzamides with secondary amines under oxidative carbonylation
conditions;42,43 Huang44 and Hua45 proposed cyclocarbonylation of ketimines under CO pressure as
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valuable approach to isoindolinones; Wu’s group46 described an elegant procedure based on the
cyclization of arylketimine using Mo(CO)6 as CO source and Jiang and co-workers47 developed a
palladium-catalyzed carbonylation reaction of aromatic oxime for the synthesis of isoindolinones
derivatives.
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In the last years, our research group have acquired a large experience in the synthesis of heterocyclic
compounds via transition metal-promoted cyclocarbonylative coupling.48-53 Due to the large interest of
isoindolinone scaffold, in the present work we explored a new approach for the synthesis of 3-
alkylideneisoindolin-1-ones via copper-free Pd-catalysed Sonogashira cyclocarbonylative reaction54-58
between 2-ethynylbenzamides and various iodoarenes.
RESULTS AND DISCUSSION
We started our study with the synthesis of 2-ethynylbenzamide (1), which was easily obtained from
commercially available 2-bromobenzamide according to a sequence of Sonogashira reaction with
trimethylsilylacetylene and following desilylation process performed with CsF in MeOH (Scheme S1
in Supporting Information). Then, the first cyclocarbonylative Sonogashira reaction was carried out
with equimolar quantities of 2-ethynylbenzamide 1 and iodobenzene 2a, in a stainless steel autoclave
placed under CO pressure (20 atm) using a very low amount of PdCl2(PPh3) (0.4 mol%), a mixture of
CH2Cl2 and triethylamine for 4 h at 100 °C (Table 1, entry 1). Analysis of the 1H-NMR spectrum of the
crude product showed the partial conversion of precursors and the presence of proton signals that
indicated the formation of two different compounds. The first product was the expected 3-(2-oxo-2-
phenylethylidene)isoindolin-1-one 3a, recovered chemically pure with 34% of yield. Its structure was
confirmed by spectroscopic (1H-NMR and 13C-NMR), spectrometric (LC-MS) and elemental analysis
(see Experimental Section). Moreover, NOE (Nuclear Overhauser Effect) experiments (Figure 1, A)
highlighted not only a strong dipolar coupling between the vinyl proton Ha and the aromatic protons Hb
and Hc but also the absence of interactions of the amide proton He with other hydrogens. These
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evidences allowed the attribution of Z configuration to 3a obtained also as a single conformational
isomer, the s-cis, probably due to hydrogen bond between amide proton and carbonyl oxygen (Figure
1, A).
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Figure 1. Chemical structure of the products of cyclocarbonylative Sonogashira reaction between 1 and 2a: A) 3-(2-oxo-2-
phenylethylidene)isoindolin-1-one 3a; B) 3-amino-2-benzoyl-1H-inden-1-one 4a; C) (Z)-2-(1-hydroxy-3-oxo-3-
phenylprop-1-en-1-yl)benzonitrile 5a.
The second product (21% yield), required a more in-depth structural study. First, the analysis of the 1H-
NMR spectrum highlighted the presence of two broad singlet signals at particularly low fields (10.09
and 10.21) which were attributed to amino protons Ha,a' (Figure 1, B). Moreover, 13C-NMR spectrum
indicated the presence of two signals corresponding to two carbonyl carbons (186.73 ppm and 190.22
ppm). Two peaks corresponding to a double bond were also detected: the first at 172.21 ppm was related
to a carbon atom linked to NH2 group and the other at 103.02 ppm was due to ≡C-CO. All these data
confirmed the formation of 3-amino-2-benzoyl-1H-inden-1-one 4a (Table 1, entry 1). Moreover, NOE
experiments conducted on the pure product highlighted a dipolar coupling between the protons Ha, Hb
and Hc and the absence of couplings between Hc' and Hd (Figure 1, B), thus indicating also for product
4a a s-cis conformation.
With the aim to increase the conversion and the selectivity towards desired compound 3a,
cyclocarbonylative Sonogashira tests at different reaction times, temperatures and amounts of catalytic
precursor were performed. As is evident from the results described in Table 1, increasing the reaction
time from 4 to 8 hours (Table 1, entry 2) or the amount of PdCl2(PPh3)2 (Table 1, entry 3, 1 mol%) did
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not affect the conversion significantly. On the contrary, an increase in selectivity towards the amino
product 4a was observed (up to ~ 70%). A similar result was obtained by conducting the reaction at 70
°C for 24 h (Table 1, entry 4).
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Table 1. Optimization study of the cyclocarbonylative Sonogashira reaction between 2-ethynylbenzamide 1 and
iodobenzene 2a.
Selectivityc (%)
Conversionb
Entrya
Solvent
T (°C)
t (h)
(%)
3a
4a
5a
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
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100
70
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69
79
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94
79
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83
100
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43 (21)
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26
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61
72
71
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4
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50
79 (42)
71 (44)
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100
50
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THF
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THF
30
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CH3CN
CH3CN
DMF
100
50
/
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10
11
24
4
/
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100
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a) All reactions were carried with 2-ethynylbenzamide 1 (1.0 mmol), iodobenzene 2a (1.0 mmol), CO (20 atm), PdCl2(PPh3)2
(0.4 mol%), Et3N (1.5 mL) and the solvent (4.0 mL), unless otherwise stated. b) Conversion was determined by 1H-NMR
peak integration on the crude product. c) Selectivity was estimated by 1H-NMR spectroscopy; isolated yields of pure products
are reported in parentheses. d) Reaction performed with 1 mol% of PdCl2(PPh3)2.
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A further reduction in temperature to 50 °C (Table 1, entry 5) gave instead an unexpected result. The
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analysis of the H-NMR spectrum of the crude product showed, in addition to the presence of the
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olefinic proton signal at 6.95 ppm. After purification the new compound was subjected to H-NMR,
13CNMR, LC-MS and elemental analyses in order to determine its exact structure, which resulted to be
(Z)-2-(1-hydroxy-3-oxo-3-phenylprop-1-en-1-yl)benzonitrile 5a (Figure 1, C). In fact, analysis of 1H-
NMR spectrum indicated the presence of a signal that resonates at very low fields (16.44 ppm),
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characteristic of a 1,3-diketonic system in enolic form.59 Furthermore, in the C-NMR spectrum, an
olefinic carbon (96.00 ppm), a signal corresponding to C≡N (118.00 ppm) and two peaks at 183.14 and
186.21 ppm (carbonyl and enolic carbon atoms) were clearly observed, thus confirming the structure
of 5a (42% yield of isolated product). The formation of the three products 3a, 4a and 5a can be
tentatively explained by the mechanism described in Scheme 1. First, expected isoindolin-1-one 3a was
generated via initial formation of the Sonogashira product (I), which is in situ cyclized as previously
observed (Scheme 1, path A).48,49 On the other hand, in the case of 4a a process of addition of carbonyl
oxygen to the triple bond can be hypothesized with formation of an allenyl species (II). After
prototropic exchange and subsequent opening of the cycle, 1,3-diketone 5a in enolic form can be
generated (Scheme 1, path B). Finally, indenone 4a can derive directly from 5a. Indeed, under the
experimental conditions (i.e., high temperature and excess of Et3N), diketone (III) can be deprotonated
and the obtained carbanion can attack the -CN functionality forming the cycle. Finally, after protonation
(for example, by Et3NH+) and subsequent imine-enamine rearrangement of (IV), 4a product is formed.
A confirmation of the above mechanism was given by treating 5a under the cyclocarbonylative
Sonogashira conditions of Table 1, entry 1 (0.4 mol% of PdCl2(PPh3)2, CH2Cl2 and Et3N, 20 atm of
CO, 100 °C, for 4h). Indeed, indenone 4a was exclusively formed (Scheme S2 in Supporting
Information). In order to obtain more information regarding the reactivity of benzamide 1, further
experiments were performed under different experimental conditions.
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Scheme 1. Plausible mechanism for the formation of products 3a, 4a and 5a via Sonogashira cyclocarbonylative reaction
between 2-ethynylbenzamide 1 and iodobenzene 2a.
As reported in Table 1, the nature of the solvents seemed to influence markedly the chemoselectivity
of the reactions. In fact, when CH2Cl2 is used as solvent the chemoselectivity depends on the
experimental conditions (Table 1, entries 1-5). On the contrary, tests carried out in THF (Table 1, entries
6-8) afforded 5a with high selectivity (71-79%), regardless of temperature and duration of the reactions.
The particular behavior of THF can be ascribed to a strong coordination effect (hydrogen bond) between
ketoenol hydrogen and THF oxygen atom as depicted in Figure 2.
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Figure 2. Stabilization of (Z)-2-(1-hydroxy-3-oxo-3-phenylprop-1-en-1-yl)benzonitrile (5a) by coordination with THF.
As for as acetonitrile and DMF are concerned, in the first case the preferential formation of 5a was
observed at high temperature (Table 1, entry 9) while the use of DMF involved the formation of a
mixture of products.
Given the data obtained in the reactions between 2-ethinylbenzamide 1 and iodobenzene 2a, the
extension of Sonogashira cyclocarbonylative reactions to iodoarenes having different steric and
electronic requirements was subsequently investigated. The reactions were carried out under the
reaction conditions which provided the desired isoindolinone 3a with better conversion and
chemoselectivity, i.e. operating in dichloromethane and triethylamine, with 0.4 mol% of PdCl2(PPh3)2,
20 atm of CO, at 100 ° C. Main results are described in Table 2. In all cases a mixture of isoindolinone
3 and indenone 4 was obtained. However the products could be easily separated, and isolated chemically
pure with satisfactory yields. As reported in Table 2, compared to preliminary reactions conducted with
iodobenzene 2a, the use of p-methoxy derivative 2b showed a similar trend in terms of chemoselectivity
and yield. Moreover, increasing the reaction time, an increase in the conversion was observed while the
ratio between 3b and 4b remained substantially the same (Table 2, entries 2-4). Instead, when the
reaction was performed with the more sterically hindered ortho-methoxyiodobenzene 2c, a decrease in
reaction rate was observed even if the reaction was carried out with 1 mol% of PdCl2(PPh3)2 (Table 2,
entry 5, 73% conversion). Finally the reaction could be performed successfully also in the case of
iodoarenes characterized by electron-withdrawing groups such as -Cl and -CN (2d-e) (Table 2, entries
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Table 2. Cyclocarbonylative Sonogashira reactions of 2-ethynylbenzamide 1 with iodoarenes 2 performed in CH2Cl2.
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Selectivityc (%)
Conversionb
Entrya
Ar
2
3,4
t (h)
(%)
3
4
1
2
Ph
a
b
b
b
c
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4
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79
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b
b
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c
57 (34)
43 (21)
4-OMePh
4-OMePh
4-OMePh
2-OMePh
4-ClPh
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56
45 (30)
44
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84
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100
73
58
42
5d
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58 (32)
36 (15)
50 (29)
42 (37)
64 (44)
d
e
90
d
e
7
4-CNPh
4
86
a) All reactions were carried with 2-ethynylbenzamide 1 (1.0 mmol), iodoarene 2 (1.0 mmol), CO (20 atm), PdCl2(PPh3)2
(0.4 mol%), Et3N (1.5 mL) and CH2Cl2 (4.0 mL) at 100 °C, unless otherwise stated. b) Conversion was determined by 1H-
NMR peak integration on the crude product. c) Selectivity was estimated by 1H-NMR spectroscopy; isolated yields of pure
products are reported in parentheses. d) Reaction performed with 1 mol% of PdCl2(PPh3)2.
Considering the interesting synthetic potentialities of compound 5a possessing a diketo group60-66 in
keto-enolic form, a few cyclocarbonylative Sonogashira reactions between 2-ethynylbenzamide 1 and
different iodoarenes 2 were also performed in THF. As reported in Table 3, a high conversion of the
reactants (75-100%) was observed and the formation of a mixture of isoindolinone 3 and ketoenol 5
was obtained. Nevertheless, compounds 5a-e could be easily isolated chemically pure in moderate
yields. The composition of crude products depended on the nature of the functional group on iodoarene
2. Indeed, using 4-iodoanisole 2b we obtained almost the same result of iodobenzene 2a (Table 3,
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entries 1-2), while in the reaction between 1 and 1-chloro-4-iodobenzene 2c (Table 3 entry 3) the
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selectivity changed slightly (40/60).
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Table 3. Cyclocarbonylative Sonogashira reactions of 2-ethynylbenzamide 1 with iodoarenes 2 performed in THF.
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Selectivityc (%)
Conversionb
Entrya
Ar
2
3,5
t (h)
(%)
3
5
1
2
3
4
Ph
a
b
d
e
4
4
4
4
94
75
a
b
d
e
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71 (44)
4-OMePh
4-ClPh
29
40
72
71 (41)
60 (39)
28 (22)
89
4-CNPh
100
a) All reactions were carried with 2-ethynylbenzamide 1 (1.0 mmol), iodoarene 2 (1.0 mmol), CO (20 atm), PdCl2(PPh3)2
(0.4 mol%), Et3N (1.5 mL) and CH2Cl2 (4.0 mL) at 100 °C, unless otherwise stated. b) Conversion was determined by 1H-
NMR peak integration on the crude product. c) Selectivity was estimated by 1H-NMR spectroscopy; isolated yields of pure
products are reported in parentheses.
Finally, using 4-iodobenzonitrile 2e as reactant, there was a clear prevalence of the isoindolinone 3e
(72%) (Table 3, entry 4). These data clearly showed the need for a fine-tuning of the cyclocarbonylation
process in the event that keto-enols 5 possessing strong electron withdrawing groups are desired.
The obtained results described so far indicated that the free -NH2 group is involved in the formation of
different products depending on the experimental conditions used. In order to increase the
chemoselectivity towards isoindolinones compounds, N-(4-chlorophenyl)-2-ethynylbenzamide 6 was
prepared from 2-iodobenzoic acid according to the four-step synthetic procedure depicted in the Scheme
S3 of Supporting Information.
Initially, N-(4-chlorophenyl)-2-ethynylbenzamide
6
was submitted to
a
Sonogashira
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cyclocarbonylation reaction with iodobenzene 2a under experimental conditions which generally
favored isoindolinone formation, i.e. CH2Cl2, 100 °C, 20 atm CO, 0.4 mol % of PdCl2(PPh3)2 (Table 4,
entry 1). To our delight, analysis of crude product indicated the complete conversion of starting
materials and the formation of two isomers which were identified as (Z)- and (E)-2-(4-chlorophenyl)-
3-(2-oxo-2-phenylethylidene)isoindolin-1-one 7a. Moreover the synthesis was highly stereoselective,
i.e. with a (E)-7a/(Z)-7a molar ratio of 89/11, probably due to the lower steric hindrance of the (E)-
isomer. Indeed, when a sample of (Z)-7a in CDCl3 was maintained for 40 h at room temperature, its
complete conversion into (E)-isomer was observed (Scheme 2). As previously observed,48 the presence
of acid traces in chloroform could cause the interconversion to occur.
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Scheme 2. Interconversion of 2-(4-chlorophenyl)-3-(2-oxo-2-phenylethylidene)isoindolin-1-one 7a from the (Z)-isomer to
the (E)-isomer, performed in CDCl3 at room temperature.
When the cyclocarbonylative reaction of amide 6 with iodobenzene 2a was carried out for a longer
reaction time (24 h) but at 50 °C, a reduction of conversion was observed (84%) while stereoselectivity
resulted almost the same (Table 4, entry 2, (E)-7a/(Z)-7a molar ratio 90/10). Therefore all subsequent
reactions were carried out at 100 °C for 4 h (Table 4, entries 3-9). In all cases a quantitative conversion
of reagents was observed and a generally a mixture of two E/Z isomers (ca. 90/10) was obtained. Both
compounds could be easily separated and isolated chemically pure by neutral alumina column
chromatography.
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Table 4. Cyclocarbonylative Sonogashira reactions of N-(4-chlorophenyl)-2-ethynylbenzamide 6 with iodoarenes 2.
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Selectivityc (%)
Conversionb
Entrya
Ar
2
7
t (h)
(%)
(E)-7
(Z)-7
1
2d
3
Ph
a
a
b
c
4
24
4
100
84
a
a
b
c
89 (66)
11 (6)
Ph
90
10
4-OMePh
2-OMePh
4-ClPh
4-ClPh
1-Napht
4-MePh
2-MePh
100
100
100
100
100
100
100
88 (69)
93 (74)
84f (51)
86f
12 (10)
7 (3)
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5
d
d
f
4
d
d
f
10f (7)
10f
6e
7
4
4
89 (69)
90 (67)
88 (60)
11 (5)
10 (7)
12 (5)
8
g
h
4
g
h
9
4
a) All reactions were carried with N-(4-chlorophenyl)-2-ethynylbenzamide 6 (1.0 mmol), iodoarene 2 (1.0 mmol), CO (20
atm), PdCl2(PPh3)2 (0.4 mol%), Et3N (1.5 mL) and CH2Cl2 (4.0 mL) at 100 °C, unless otherwise stated. b) Conversion was
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1
determined by H-NMR peak integration on the crude product. c) Selectivity was estimated by H-NMR spectroscopy;
isolated yields of pure products are reported in parentheses. d) Reaction performed at 50 °C. e) Reaction performed under
40 atm of CO. f) The remainder of the product was (Z)-3-(4-chlorobenzylidene)-2-(4-chlorophenyl)isoindolin-1-one 8.
Reactions performed between amide 6 and iodoarenes possessing electrondonating groups (i.e., 2b-c
and 2f-h) (Table 4, entries 3-4 and 7-9) afforded the (E)-isomers as principle products in good yields
(60-74%). In the case of cross coupling with 1-chloro-4-iodobenzene 2d (Table 4, entry 5), a small
amount of (Z)-3-(4-chlorobenzylidene)-2-(4-chlorophenyl)isoindolin-1-one 8 was obtained. Its
structure has been assigned by comparison with a pure sample prepared via cyclic Sonogashira reaction
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as depicted in Scheme 3. The products composition did not change even performing the
cyclocarbonylative reaction of amide 6 with 1-chloro-4-iodobenzene 2d under 40 atm of carbon
monoxide pressure (Table 4, entry 6).
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Scheme 3. Cyclocarbonylative Sonogashira and cyclic Sonogashira reactions of amide 6 with 1-chloro-4-iodobenzene 2d.
A cyclocarbonylative Sonogashira reaction of N-(4-chlorophenyl)-2-ethynylbenzamide 6 was also
carried out in the presence of the electron-poor 4-iodobenzonitrile 2e: in this case, only small amounts
of (E)-4-(2-(2-(4-chlorophenyl)-3-oxoisoindolin-1-ylidene)acetyl)benzonitrile (E)-7e (yield 18%) and
(Z)-4-(2-(2-(4-chlorophenyl)-3-oxoisoindolin-1-ylidene)acetyl)benzonitrile (Z)-7e (yield 5%), together
with (Z)-4-((2-(4-chlorophenyl)-3-oxoisoindolin-1-ylidene)methyl)benzonitrile 9 (yield 4%) were
isolated (Scheme S4 in Supporting Information).
Finally, considering the general toxicity of iodoarenes, a test between 4-bromonitrobenzene 2i and
ethynylbenzamide 6 was performed under 20 atm of CO, at 100 °C for 4 h (Scheme 4). Unfortunately,
the bromoderivative 2i was recovered unreacted while benzamide 6 was completely consumed. After
purification of the crude mixture, 2-(4-chlorophenyl)-3-methyleneisoindolin-1-one (10)45 was isolated
in 85% yield. The formation of cyclisation product 10 could be explained considering the insertion of
Pd(0) into N-H bond, Pd-hydride addition to the triple bond followed by reductive elimination with
generation of methyleneisoindolinone 10 and Pd(0).
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Scheme 4. Cyclocarbonylative Sonogashira and cyclic Sonogashira reactions of amide 6 with 1-chloro-4-iodobenzene 2d.
CONCLUSIONS
In conclusion, we have developed an atom-efficient approach to alkylidene isoindolin-1-ones through
a Pd-catalysed copper-free cyclocarbonylative Sonogashira reaction between benzamides and aryl
iodides. In particular, when 2-ethynylbenzamide 1 was used in CH2Cl2, the reaction generally afforded
(Z)-isoindolinones in major amount together with indenones derivatives. Changing the solvent to THF
determined the preferential formation of keto-enols compounds. On the other hand, the Sonogashira
cyclocarbonilative reaction of N-(4-chlorophenyl)-2-ethynylbenzamide 6 with iodoarenes generated
almost exclusively the corresponding (E)-isoindolinones in satisfactory yields.
EXPERIMENTAL SECTION
General information. Solvents were purified by conventional methods, distilled and stored over
activated molecular sieves under argon. All the chemicals were purchased from commercial sources
and used as received without purification. All the operations under inert atmosphere were carried out
using standard Schlenk techniques and employing dried nitrogen. Reactions that required heating were
performed in an oil bath. For all reactions, conversion was monitored by thin-layer chromatography
(TLC) analysis on pre-coated silica gel plates (VWR Macherey-Nagel, 0.2 mm thick) or pre-coated
neutral alumina plates (Sigma Aldrich, 0.25 mm thick). Column chromatography was performed with
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Fluka silica gel, pore size 60 Å, 70-230 mesh, 63-200 μm or Sigma Aldrich activated, neutral alumina.
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1H-NMR and C-NMR spectra were recorded at room temperature in CDCl3 or DMSO-d6 solution
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with a Varian INOVA – 600 spectrometer, operating at a frequency of 600 MHz for 1H and 150 MHz
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for C, using the residual solvent peak as internal reference; chemical shifts (δ) values are given in
parts per million (ppm) and coupling constants (J) in Hertz. Mass spectra were obtained with an Applied
Biosystems-MDS Sciex API 4000 triple quadrupole mass spectrometer (Concord, Ont., Canada),
equipped with a Turbo-V ion-spray (TIS) source. Elemental analyses were performed on a Elementar
Vario Micro Cube CHN-analyzer.
Synthesis of ethynylbenzamides. 2-((Trimethylsilyl)ethynyl)benzamide (B).67 2-Bromobenzamide (A)
(7.00 g, 35.0 mmol), PdCl2(PPh3)2 (983 mg, 1.40 mmol), CuI (267 mg, 1.40 mmol), Et3N (160 mL) and
DMF (50 mL) were mixed together, then trimethylsilylacetylene (7.4 mL, 52.5 mmol) was added
dropwise. The resulting mixture was refluxed under stirring for 24 h, then it was cooled to room
temperature, hydrolyzed with saturated ammonium chloride solution (150 mL) and extracted with
CH2Cl2 (3×150 mL). The combined organic phases were washed with brine (150 mL), dried over
anhydrous Na2SO4 and the solvent was removed under vacuum. The crude product was purified by
column chromatography (SiO2, n-hexane/AcOEt 1:1) to give 3.18 g (yield 42%) of 2-
((trimethylsilyl)ethynyl)benzamide (B).67
1H-NMR (600 MHz, CDCl3), δ (ppm): 0.28 (9H, s); 6.04 (1H, bs); 7.43-7.46 (2H, m); 7.55-7.56 (1H,
m); 7.76 (1H, bs); 8.13-8.17 (1H, m). 13C-NMR (150 MHz, CDCl3), δ (ppm): -0.2 (3C); 102.3; 104.4;
120.1; 129.3; 130.6; 131.1; 134.1; 134.7; 168.2. LC-MS (APCI+), m/z: 218.1 [M+H]+.
2-Ethynylbenzamide (1).67 2-((Trimethylsilyl)ethynyl)benzamide (B) (3.18 g, 14.6 mmol), cesium
fluoride (3.33 g, 21.9 mmol) and methanol (100 mL) were mixed together. The resulting mixture was
left under stirring for 3 h at room temperature, then it was hydrolyzed with brine (100 mL) and extracted
with AcOEt (3×50 mL). The combined organic phases were washed with brine (100 mL), dried over
anhydrous Na2SO4 and the solvent was removed under vacuum. The crude product was purified by
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column chromatography (SiO2, n-hexane/AcOEt 1:1) to give 1.51 g (yield 71%) of 2-ethynylbenzamide
(1).67
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1H-NMR (600 MHz, CDCl3), δ (ppm): 3.52 (1H, s); 6.10 (1H, bs); 7.34 (1H, bs); 7.45-7.49 (2H, m);
7.59-7.61 (1H, m); 8.08-8.09 (1H, m). 13C-NMR (150 MHz, CDCl3), δ (ppm): 82.5; 84.2; 119.1; 129.6;
130.3; 131.2; 134.5; 135.5; 168.3. LC-MS (APCI+), m/z: 146.1 [M+H]+.
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2-Iodobenzoyl chloride (D).68 2-Iodobenzoic acid (C) (4.97 g, 20.0 mmol), DMF (46 μL, 0.6 mmol)
and CH2Cl2 (50 mL) were mixed together, then oxalyl chloride (3.5 mL, 40.8 mmol), was added
dropwise to the solution at 0 °C. The mixture was left under stirring for 2 h at room temperature, then
it was evaporated under vacuum to give 2-iodobenzoyl chloride (D)68 (4.66 g, yield 87%) which was
used without further purification.
1H-NMR (600 MHz, CDCl3), δ (ppm): 7.23-7.26 (1H, m); 7.49-7.51 (1H, m); 8.04-8.05 (1H, m); 8.07-
8.08 (1H, m). 13C-NMR (150 MHz, CDCl3), δ (ppm): 94.1; 128.2; 133.9; 134.3; 138.2; 141.7; 166.8.
N-(4-Chlorophenyl)-2-iodobenzamide (E).69 4-Chloroaniline (3.19 g, 25.0 mmol), Et3N (3.5 mL, 25.0
mmol) and CH2Cl2 (25 mL) were mixed together, then a solution of 2-iodobenzoyl chloride (D) (6.67
g, 25.0 mmol) in CH2Cl2 (25 mL) was added dropwise to the solution at 0 °C. The mixture was left
under stirring for 90 min at room temperature, then it was hydrolyzed with water (100 mL) and extracted
with CH2Cl2 (3×50 mL). The combined organic phases were washed, in order, with HCl 1 M solution
(100 mL), water (100 mL), saturated NaHCO3 solution (100 mL) and brine (100 mL), then dried over
anhydrous Na2SO4 and the solvent was removed under vacuum to give N-(4-chlorophenyl)-2-
iodobenzamide (E)69 (7.24 g, yield 81%) which was used without further purification.
1H-NMR (600 MHz, CDCl3), δ (ppm): 7.13-7.15 (1H, m); 7.32 (2H, d, J = 8.7 Hz); 7.39-7.42 (1H, m);
7.46-7.48 (1H, m); 7.57 (2H, d, J = 8.7 Hz); 7.70 (1H, bs); 7.88-7.89 (1H, m). 13C-NMR (150 MHz,
CDCl3), δ (ppm): 92.4; 121.4 (2C); 128.2; 128.4; 129.0 (2C); 129.8; 131.5; 136.1; 139.9; 141.6; 167.4.
LC-MS (APCI+), m/z: 358.0 [M+H]+.
N-(4-Chlorophenyl)-2-((trimethylsilyl)ethynyl)benzamide (F).70 N-(4-Chlorophenyl)-2-iodobenzamide
(E) (6.80 g, 19.0 mmol), PdCl2(PPh3)2 (534 mg, 0.76 mmol), CuI (145 mg, 0.76 mmol), Et3N (5.3 mL,
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38.0 mmol) and THF (120 mL) were mixed together, then trimethylsilylacetylene (4.1 mL, 28.9 mmol)
was added dropwise. The resulting mixture was left under stirring for 24 h at room temperature, then it
was hydrolyzed with saturated ammonium chloride solution (100 mL) and extracted with CH2Cl2
(3×100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous
Na2SO4 and the solvent was removed under vacuum. The crude product was purified by column
chromatography (SiO2, n-hexane/AcOEt 6:1) to give 4.95 g (yield 79%) of N-(4-chlorophenyl)-2-
((trimethylsilyl)ethynyl)benzamide (F).70
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1H-NMR (600 MHz, CDCl3), δ (ppm): 0.25 (9H, s); 7.34 (2H, d, J = 9.0 Hz); 7.44-7.48 (2H, m); 7.58-
7.59 (1H, m); 7.62 (2H, d, J = 9.0 Hz); 8.10-8.12 (1H, m); 9.33 (1H, bs). 13C-NMR (150 MHz, CDCl3),
δ (ppm): -0.2 (3C); 102.9; 103.0; 119.3; 121.3 (2C); 129.0 (2C); 129.4; 129.5; 130.3; 130.9; 134.1;
135.4; 136.5; 164.0. LC-MS (APCI+), m/z: 328.1 [M+H]+.
N-(4-Chlorophenyl)-2-ethynylbenzamide (6). N-(4-Chlorophenyl)-2-((trimethylsilyl)ethynyl)benzamide
(F) (3.94 g, 12.0 mmol) and methanol (100 mL) were mixed together, then a solution of
tetrabutylammonium fluoride trihydrate (4.54 g, 14.4 mmol) in methanol (100 mL) was added dropwise
to the solution. The resulting mixture was left under stirring for 1 h at room temperature, then it was
hydrolyzed with brine (200 mL) and extracted with AcOEt (3×150 mL). The combined organic phases
were washed with brine (100 mL), dried over anhydrous Na2SO4 and the solvent was removed under
vacuum. The crude product was purified by column chromatography (SiO2, n-hexane/AcOEt 4:1) to
give 1.78 g (yield 58%) of N-(4-chlorophenyl)-2-ethynylbenzamide (6).
1H-NMR (600 MHz, CDCl3), δ (ppm): 3.57 (1H, s); 7.27 (2H, d, J = 9.0 Hz); 7.39-7.42 (2H, m); 7.54-
7.56 (1H, m); 7.59 (2H, d, J = 9.0 Hz); 7.91-7.92 (1H, m); 9.10 (1H, bs). 13C-NMR (150 MHz, CDCl3),
δ (ppm): 81.9; 84.4; 118.4; 121.2 (2C); 129.0 (2C); 129.5; 129.6; 129.9; 130.9; 134.2; 136.4; 136.5;
164.3. LC-MS (APCI+), m/z: 256.0 [M+H]+. Anal. calcd for C15H10ClNO: C, 70.46; H, 3.94; N, 5.48;
found: C, 70.39; H, 3.99; N, 5.47.
Cyclocarbonylative Sonogashira reactions of 2-ethynylbenzamide (1). General procedure. A Pyrex
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Schlenk tube under CO atmosphere was charged with 2-ethynylbenzamide (1) (1.0 mmol), iodoarene
(1.0 mmol), Et3N (1.5 mL) and the solvent (4.0 mL). This solution was introduced by a steel siphon
into a 25 mL stainless steel autoclave, fitted with a Teflon inner crucible and a stirring bar, previously
carried with PdCl2(PPh3)2 (0.4-1.0 mol%) and placed under vacuum (0.1 Torr). The reactor was
pressurized with CO (20 atm) and the mixture was stirred for a selected time at a selected temperature.
After removal of excess CO (fume hood), the reaction mixture was diluted with CH2Cl2 (20 mL),
washed with brine (15 mL), dried over anhydrous Na2SO4 and the solvent was removed under vacuum.
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1
The reagent conversion and the product composition were determined by H-NMR spectroscopic
analysis. All crude products were purified through column chromatography on silica gel and
characterized with 1H-NMR, 13C-NMR, LC-MS and elemental analysis techniques.
Cyclocarbonylative Sonogashira of 2-ethynylbenzamide (1) and iodobenzene (2a) in CH2Cl2 at 100 °C
(Table 1, entry 1 & Table 2, entry 1). Following the general procedure, 2.8 mg (0.004 mmol) of
PdCl2(PPh3)2, 145.2 mg (1.0 mmol) of 2- ethynylbenzamide (1), 204.0 mg (1.0 mmol) of iodobenzene
(2a), 1.5 mL of Et3N and 4 mL of CH2Cl2 were put in the autoclave. The resulting mixture was stirred
for 4 h at 100 °C. The crude product was purified through column chromatography (SiO2, n-
hexane/AcOEt 1:1), obtaining 85 mg (yield 34%) of (Z)-3-(2-oxo-2-phenylethylidene) isoindolin-1-one
(3a) and 52 mg (yield 21%) of 3-amino-2-benzoyl-1H-inden-1-one (4a).
3a. 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 7.41 (1H, s); 7.58-7.61 (2H, m); 7.67-7.70 (1H, m); 7.72-
7.74 (1H, m); 7.81-7.83 (1H, m); 7.85-7.86 (1H, m); 8.20-8.21 (2H, m); 8.35-8.37 (1H, m); 10.92 (1H,
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bs). C-NMR (150 MHz, DMSO-d6), δ (ppm): 95.7; 122.6; 123.4; 128.1 (2C); 128.5; 128.8 (2C);
132.1; 133.1; 133.2; 137.2; 137.8; 147.6; 168.8; 189.8. LC-MS (APCI+), m/z: 250.1 [M+H]+. Anal.
calcd for C16H11NO2: C, 77.10; H, 4.45; N, 5.62; found: C, 77.19; H, 4.41; N, 5.63.
4a. 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 7.39-7.42 (2H, m); 7.47-7.51 (2H, m); 7.60-7.62 (2H,
m); 7.63-7.67 (2H, m); 8.06-8.10 (1H, m); 10.09 (1H, bs); 10.21 (1H, bs). 13C-NMR (150 MHz, DMSO-
d6), δ (ppm): 103.0; 121.4; 121.5; 127.2 (2C); 128.5 (2C); 130.5; 132.3; 133.5; 134.9; 135.5; 140.1;
172.2; 186.7; 190.2. LC-MS (APCI+), m/z: 250.1 [M+H]+. Anal. calcd for C16H11NO2: C, 77.10; H,
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Cyclocarbonylative Sonogashira of 2-ethynylbenzamide (1) and iodobenzene (2a) in CH2Cl2 at 50 °C
(Table 1, entry 5). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2, 145.2 mg
(1.0 mmol) of 2- ethynylbenzamide (1), 204.0 mg (1.0 mmol) of iodobenzene (2a), 1.5 mL of Et3N and
4 mL of CH2Cl2 were put in the autoclave. The resulting mixture was stirred for 24 h at 50 °C. The
crude product was purified through column chromatography (SiO2, CH2Cl2), obtaining 105 mg (yield
42%) of (Z)-2-(1-hydroxy-3-oxo-3-phenylprop-1-en-1-yl)benzonitrile (5a).
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5a. 1H-NMR (600 MHz, CDCl3), δ (ppm): 6.95 (1H, s); 7.48-7.51 (2H, m); 7.56-7.59 (1H, m); 7.61-
7.64 (1H, m); 7.71-7.74 (1H, m); 7.82-7.83 (1H, m); 7.97-8.01 (3H, m); 16.44 (1 H, bs). 13C-NMR (150
MHz, CDCl3), δ (ppm): 96.0; 110.6; 118.0; 127.4 (2C); 128.8 (2C); 129.0; 131.5; 132.8; 133.0; 134.7;
134.7; 139.1; 183.1; 186.2. LC-MS (APCI+), m/z: 250.1 [M+H]+. Anal. calcd for C16H11NO2: C, 77.10;
H, 4.45; N, 5.62; found: C, 77.18; H, 4.39; N, 5.61.
Cyclocarbonylative Sonogashira of 2-ethynylbenzamide (1) and iodobenzene (2a) in THF at 100 °C
(Table 1, entry 6 & Table 3, entry 1). Following the general procedure, 2.8 mg (0.004 mmol) of
PdCl2(PPh3)2, 145.2 mg (1.0 mmol) of 2- ethynylbenzamide (1), 204.0 mg (1.0 mmol) of iodobenzene
(2a), 1.5 mL of Et3N and 4 mL of THF were put in the autoclave. The resulting mixture was stirred for
4 h at 100 °C. The crude product was purified through column chromatography (SiO2, CH2Cl2),
obtaining 110 mg (yield 44%) of (Z)-2-(1-hydroxy-3-oxo-3-phenylprop-1-en-1-yl) benzonitrile (5a).
Cyclocarbonylative Sonogashira of 2-ethynylbenzamide (1) and iodobenzene (2a) in acetonitrile at 100
°C (Table 1, entry 9). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2, 145.2
mg (1.0 mmol) of 2- ethynylbenzamide (1), 204.0 mg (1.0 mmol) of iodobenzene (2a), 1.5 mL of Et3N
and 4 mL of acetonitrile were put in the autoclave. The resulting mixture was stirred for 4 h at 100 °C.
The composition of crude product was determined by 1H-NMR analysis, resulting in a mixture of (Z)-
3-(2-oxo-2-phenylethylidene) isoindolin-1-one (3a) and (Z)-2-(1-hydroxy-3-oxo-3-phenylprop-1-en-1-
yl) benzonitrile (5a) in the molar ratio 78/22.
Cyclocarbonylative Sonogashira of 2-ethynylbenzamide (1) and iodobenzene (2a) in DMF at 100 °C
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(Table 1, entry 11). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2, 145.2 mg
(1.0 mmol) of 2- ethynylbenzamide (1), 204.0 mg (1.0 mmol) of iodobenzene (2a), 1.5 mL of Et3N and
4 mL of DMF were put in the autoclave. The resulting mixture was stirred for 4 h at 100 °C. The
composition of crude product was determined by 1H-NMR analysis, resulting in a mixture of (Z)-3-(2-
oxo-2-phenylethylidene) isoindolin-1-one (3a), 3-amino-2- benzoyl-1H-inden-1-one (4a) and (Z)-2-(1-
hydroxy-3-oxo-3-phenylprop-1-en-1-yl) benzonitrile (5a) in the molar ratio 33/32/35.
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Cyclocarbonylative Sonogashira of 2-ethynylbenzamide (1) and 4-iodoanisole (2b) in CH2Cl2 (Table
2, entry 2). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2, 145.2 mg (1.0
mmol) of 2- ethynylbenzamide (1), 234.0 mg (1.0 mmol) of 4-iodoanisole (2b), 1.5 mL of Et3N and 4
mL of CH2Cl2 were put in the autoclave. The resulting mixture was stirred for 4 h at 100 °C. The crude
product was purified through column chromatography (SiO2, n-hexane/AcOEt 1:1), obtaining 106 mg
(yield 38%) of (Z)-3-(2-(4-methoxyphenyl)-2- oxoethylidene)isoindolin-1-one (3b) and 84 mg (yield
30%) of 3-amino-2-(4-methoxybenzoyl)-1H-inden-1-one (4b).
3b. 1H-NMR (600 MHz, CDCl3), δ (ppm): 3.84 (3H, s); 6.79 (1H, s); 6.91-6.93 (2H, m); 7.56-7.58 (1H,
m); 7.61-7.64 (1H, m); 7.77-7.78 (1H, m); 7.82-7.83 (1H, m); 7.96-7.99 (2H, m); 10.57 (1H, bs). 13C-
NMR (150 MHz, CDCl3), δ (ppm): 55.5; 94.75 113.9 (2C); 121.0; 124.0; 129.2; 130.2 (2C); 131.2;
131.7; 132.7; 137.1; 147.6; 163.5; 169.0; 189.4. LC-MS (APCI+), m/z: 280.1 [M+H]+. Anal. calcd for
C17H13NO3: C, 73.11; H, 4.69; N, 5.02; found: C, 73.07; H, 4.78; N, 5.02.
4b. 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 3.82 (3H, s); 6.93-6.95 (2H, m); 7.49-7.51 (1H, m); 7.62-
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7.66 (4H, m); 8.02-8.05 (1H, m); 9.96 (1H, bs); 10.14 (1H, bs). C-NMR (150 MHz, DMSO-d6), δ
(ppm): 55.3; 103.1; 112.5; 121.3; 121.3 (2C); 130.9 (2C); 132.2; 132.4; 133.4; 135.0; 135.5; 161.4;
172.2; 186.8; 189.18. LC-MS (APCI+), m/z: 280.1 [M+H]+. Anal. calcd for C17H13NO3: C, 73.11; H,
4.69; N, 5.02; found: C, 73.05; H, 4.74; N, 5.01.
Cyclocarbonylative Sonogashira of 2-ethynylbenzamide (1) and 2-iodoanisole (2c) in CH2Cl2 (Table 2,
entry 5). Following the general procedure, 7.1 mg (0.01 mmol) of PdCl2(PPh3)2, 145.2 mg (1.0 mmol)
of 2- ethynylbenzamide (1), 234.0 mg (1.0 mmol) of 2-iodoanisole (2c), 1.5 mL of Et3N and 4 mL of
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CH2Cl2 were put in the autoclave. The resulting mixture was stirred for 24 h at 100 °C. The crude
product was purified through column chromatography (SiO2, n-hexane/AcOEt 1:1), obtaining 104 mg
(yield 37%) of (Z)-3-(2-(2-methoxyphenyl)-2- oxoethylidene)isoindolin-1-one (3c) and 81 mg (yield
29%) of 3-amino-2-(2-methoxybenzoyl)-1H-inden-1-one (4c).
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3c. 1H-NMR (600 MHz, CDCl3), δ (ppm): 3.95 (3H, s); 6.94 (1H, s); 7.00-7.01 (1H, m); 7.03-7.06 (1H,
m); 7.47-7.50 (1H, m); 7.58-7.64 (2H, m); 7.73-7.76 (2H, m); 7.87-7.88 (1H, m); 10.48 (1H, bs). 13C-
NMR (150 MHz, CDCl3), δ (ppm): 55.8; 100.2; 111.7; 120.9; 121.1; 123.5; 124.1; 130.6; 131.6; 132.7;
133.5; 135.9; 137.4; 146.5; 158.1; 169.1; 192.3. LC-MS (APCI+), m/z: 280.1 [M+H]+. Anal. calcd for
C17H13NO3: C, 73.11; H, 4.69; N, 5.02; found: C, 73.22; H, 4.63; N, 5.03.
4c. 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 3.64 (3H, s); 6.91-6.93 (1H, m); 7.00-7.01 (1H, m); 7.08-
7.10 (1H, m); 7.34-7.36 (1H, m); 7.40-7.42 (1H, m); 7.60-7.62 (2H, m); 8.03-8.04 (1H, m); 9.98 (1H,
s); 10.06 (1H, s). 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 55.4; 104.5; 111.1; 119.7; 121.2; 121.6;
127.6; 130.0; 131.6; 132.3; 133.4; 135.1; 135.6; 156.4; 170.7; 186.6; 189.2. LC-MS (APCI+), m/z: 280.1
[M+H]+. Anal. calcd for C17H13NO3: C, 73.11; H, 4.69; N, 5.02; found: C, 73.18; H, 4.64; N, 5.02.
Cyclocarbonylative Sonogashira of 2-ethynylbenzamide (1) and 1-chloro-4-iodobenzene (2d) in
CH2Cl2 (Table 2, entry 6). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2,
145.2 mg (1.0 mmol) of 2- ethynylbenzamide (1), 238.5 mg (1.0 mmol) of 1-chloro-4-iodobenzene
(2d), 1.5 mL of Et3N and 4 mL of CH2Cl2 were put in the autoclave. The resulting mixture was stirred
for 4 h at 100 °C. The crude product was purified through column chromatography (SiO2, n-
hexane/AcOEt 1:1), obtaining 91 mg (yield 32%) of (Z)-3-(2-(4-chlorophenyl)-2-
oxoethylidene)isoindolin-1-one (3d) and 105 mg (yield 37%) of 3-amino-2-(4-chlorobenzoyl)-1H-
inden-1-one (4d).
3d. 1H-NMR (600 MHz, CDCl3), δ (ppm): 6.81 (1H, s); 7.49 (2H, d, J = 8.7 Hz); 7.64-7.70 (2H, m);
7.82-7.83 (1H, m); 7.90-7.91 (1H, m); 7.98 (2H, d, J = 8.7 Hz); 10.57 (1H, bs). 13C-NMR (150 MHz,
CDCl3), δ (ppm): 94.2; 121.1; 124.3; 129.0 (2C); 129.3 (2C); 130.6; 132.1; 132.9; 136.7; 137.00; 139.4;
148.9; 169.00; 189.6. LC-MS (APCI+), m/z: 283.9 [M+H]+. Anal. calcd for C16H10ClNO2: C, 67.74; H,
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4d. 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 7.46 (2H, d, J = 8.4 Hz); 7.50-7.51 (1H, m); 7.61 (2H,
d, J = 8.4 Hz); 7.64-7.66 (2H, m); 8.06-8.08 (1H, m); 10.14 (1H, bs); 10.19 (1H, bs). 13C-NMR (150
MHz, DMSO-d6), δ (ppm): 102.9; 121.5; 121.7; 127.3 (2C); 130.4 (2C); 132.5; 133.8; 134.9; 135.2;
135.5; 138.8; 172.2; 186.8; 188.7. LC-MS (APCI+), m/z: 283.9 [M+H]+. Anal. calcd for C16H10ClNO2:
C, 67.74; H, 3.55; N, 4.94; found: C, 67.63; H, 3.59; N, 4.95.
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Cyclocarbonylative Sonogashira of 2-ethynylbenzamide (1) and 4-iodobenzonitrile (2e) in CH2Cl2
(Table 2, entry 7). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2, 145.2 mg
(1.0 mmol) of 2- ethynylbenzamide (1), 229.0 mg (1.0 mmol) of 4-iodobenzonitrile (2e), 1.5 mL of
Et3N and 4 mL of CH2Cl2 were put in the autoclave. The resulting mixture was stirred for 4 h at 100
°C. The crude product was purified through column chromatography (SiO2, n-hexane/AcOEt 1:1),
obtaining 41 mg (yield 15%) of (Z)-4-(2-(3-oxoisoindolin-1-ylidene) acetyl)benzonitrile (3e) and 121
mg (yield 44%) of 4-(3-amino-1-oxo-1H-indene-2-carbonyl)benzonitrile (4e).
3e. 1H-NMR (600 MHz, CDCl3), δ (ppm): 6.81 (1H, s); 7.67-7.73 (2H, m); 7.82-7.85 (3H, m); 7.92-
7.94 (1H, m); 8.12 (2H, d, J = 8.4 Hz); 10.56 (1H, bs). 13C-NMR (150 MHz, CDCl3), δ (ppm): 93.8;
116.1; 117.9; 121.3; 124.4; 128.3 (2C); 132.4; 132.5 (2C); 132.8; 133.1; 136.8; 141.6; 150.0; 168.9;
189.3. LC-MS (APCI+), m/z: 275.1 [M+H]+. Anal. calcd for C17H10N2O2: C, 74.44; H, 3.67; N, 10.21;
found: C, 74.52; H, 3.60; N, 10.22.
4e. 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 7.50-7.52 (1H, m); 7.66-7.68 (2H, m); 7.70 (2H, d, J =
8.7 Hz); 7.87 (2H, d, J = 8.7 Hz); 8.09-8.11 (1H, m); 10.23 (1H, bs); 10.26 (1H, bs). 13C-NMR (150
MHz, DMSO-d6), δ (ppm): 112.4; 118.7; 121.5; 121.9; 128.9 (2C); 131.4 (2C); 132.0; 132.6; 133.8;
134.8; 135.6; 144.3; 172.2; 186.7; 188.3. LC-MS (APCI+), m/z: 275.1 [M+H]+. Anal. calcd for
C17H10N2O2: C, 74.44; H, 3.67; N, 10.21; found: C, 74.51; H, 3.59; N, 10.21.
Cyclocarbonylative Sonogashira of 2-ethynylbenzamide (1) and 4-iodoanisole (2b) in THF (Table 3,
entry 2). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2, 145.2 mg (1.0 mmol)
of 2- ethynylbenzamide (1), 234.0 mg (1.0 mmol) of 4-iodoanisole (2b), 1.5 mL of Et3N and 4 mL of
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THF were put in the autoclave. The resulting mixture was stirred for 4 h at 100 °C. The crude product
was purified through column chromatography (SiO2, CH2Cl2), obtaining 115 mg (yield 41%) of (Z)-2-
(1-hydroxy-3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl) benzonitrile (5b).
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5b. 1H-NMR (600 MHz, CDCl3), δ (ppm): 3.88 (3H, s); 6.91 (1H, s); 6.98 (2H, d, J = 9.0 Hz); 7.60
(1H, t); 7.71 (1H, t); 7.82 (1H, d, J = 7.8 Hz); 7.96-7.99 (3H, m); 16.59 (1H, bs). 13C-NMR (150 MHz,
CDCl3), δ (ppm): 55.5; 95.4; 110.4; 114.1 (2C); 118.1; 127.4; 128.9; 129.7 (2C); 131.2; 132.8; 134.7;
139.2; 163.7; 181.2; 186.5. LC-MS (APCI+), m/z: 280.1 [M+H]+. Anal. calcd for C17H13NO3: C, 73.11;
H, 4.69; N, 5.02; found: C, 73.21; H, 4.62; N, 5.03.
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Cyclocarbonylative Sonogashira of 2-ethynylbenzamide (1) and 1-chloro-4-iodobenzene (2d) in THF
(Table 3, entry 3). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2, 145.2 mg
(1.0 mmol) of 2- ethynylbenzamide (1), 238.5 mg (1.0 mmol) of 1-chloro-4-iodobenzene (2d), 1.5 mL
of Et3N and 4 mL of THF were put in the autoclave. The resulting mixture was stirred for 4 h at 100
°C. The crude product was purified through column chromatography (SiO2, CH2Cl2), obtaining 111 mg
(yield 39%) of (Z)-2-(3-(4-chlorophenyl)-1-hydroxy-3-oxoprop-1-en-1-yl)benzonitrile (5d).
5d. 1H-NMR (600 MHz, CDCl3), δ (ppm): 6.93 (1H, s); 7.47 (2H, d, J = 8.4 Hz); 7.62-7.65 (1H, m);
7.72-7.75 (1H, m); 7.84 (1H, d, J = 7.8 Hz); 7.94 (2H, d, J = 8.4 Hz); 7.98 (1H, d, J = 7.8 Hz); 16.35
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(1H, bs). C-NMR (150 MHz, CDCl3), δ (ppm): 96.0; 110.6; 118.0; 128.8 (2C); 129.1; 129.2 (2C);
131.6; 132.8; 133.2; 134.8; 138.9; 139.4; 183.0; 185.1. LC-MS (APCI+), m/z: 284.1 [M+H]+. Anal.
calcd for C16H10ClNO2: C, 67.74; H, 3.55; N, 4.94; found: C, 67.82; H, 3.49; N, 4.93.
Cyclocarbonylative Sonogashira of 2-ethynylbenzamide (1) and 4-iodobenzonitrile (2e) in THF (Table
3, entry 4). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2, 145.2 mg (1.0
mmol) of 2- ethynylbenzamide (1), 229.0 mg (1.0 mmol) of 4-iodobenzonitrile (2e), 1.5 mL of Et3N
and 4 mL of THF were put in the autoclave. The resulting mixture was stirred for 4 h at 100 °C. The
crude product was purified through column chromatography (SiO2, CH2Cl2), obtaining 61 mg (yield
22%) of (Z)-2-(3-(4-cyanophenyl)-1-hydroxy-3-oxoprop-1-en-1-yl)benzonitrile (5e).
5e. 1H-NMR (600 MHz, CDCl3), δ (ppm): 7.00 (1H, s); 7.66-7.69 (1H, m); 7.75-7.77 (1H, m); 7.81
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(2H, d, J = 8.4 Hz); 7.86-7.87 (1H, m); 8.01 (1H, d, J = 7.8 Hz); 8.09 (2H, d, J = 8.4 Hz); 16.16 (1H,
bs). 13C-NMR (150 MHz, CDCl3), δ (ppm): 96.7; 110.6; 116.0; 117.9; 117.9; 127.8 (2C); 129.2; 132.0;
132.5 (2C); 132.9; 134.8; 138.5; 138.6; 182.9; 184.7. LC-MS (APCI+), m/z: 275.1 [M+H]+. Anal. calcd
for C17H10N2O2: C, 74.44; H, 3.67; N, 10.21; found: C, 74.55; H, 3.61; N, 10.21.
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Cyclocarbonylative Sonogashira reactions of N-(4-chlorophenyl)-2-ethynylbenzamide (6). General
procedure. A Pyrex Schlenk tube under CO atmosphere was charged with N-(4-chlorophenyl)-2-
ethynylbenzamide (6) (1.0 mmol), haloarene (1.0 mmol), Et3N (1.5 mL) and CH2Cl2 (4.0 mL). This
solution was introduced by a steel siphon into a 25 mL stainless steel autoclave, fitted with a Teflon
inner crucible and a stirring bar, previously carried with PdCl2(PPh3)2 (0.4 mol%) and placed under
vacuum (0.1 Torr). The reactor was pressurized with CO (20-40 atm) and the mixture was stirred for a
selected time at a selected temperature. After removal of excess CO (fume hood), the reaction mixture
was diluted with CH2Cl2 (20 mL), washed with brine (15 mL), dried over anhydrous Na2SO4 and the
solvent was removed under vacuum. The reagent conversion and the product composition were
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determined by H-NMR spectroscopic analysis. All crude products were purified through column
chromatography on neutral alumina and characterized with 1H-NMR, 13C-NMR, LC-MS and elemental
analysis techniques.
Cyclocarbonylative Sonogashira of N-(4-chlorophenyl)-2-ethynylbenzamide (6) and iodobenzene (2a)
at 100 °C (Table 4, entry 1). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2,
255.7 mg (1.0 mmol) of N-(4- chlorophenyl)-2-ethynylbenzamide (6), 204.0 mg (1.0 mmol) of
iodobenzene (2a), 1.5 mL of Et3N and 4 mL of CH2Cl2 were put in the autoclave charged with 20 atm
of CO. The resulting mixture was stirred for 4 h at 100 °C. The crude product was purified through
column chromatography (neutral Al2O3, n-hexane/AcOEt 4:1), obtaining 238 mg (yield 66%) of (E)-2-
(4-chlorophenyl)-3-(2-oxo-2-phenylethylidene)isoindolin-1-one ((E)-7a) and 22 mg (yield 6%) of (Z)-
2-(4-chlorophenyl)-3-(2-oxo-2-phenylethylidene)isoindolin-1-one ((Z)-7a).
(E)-7a. 1H-NMR (600 MHz, CDCl3), δ (ppm): 6.53 (1H, s); 7.36 (2H, d, J = 7.6 Hz); 7.46 (2H, t, J =
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7.8 Hz); 7.55-7.59 (3H, m); 7.67-7.69 (1H, m); 7.72-7.75 (1H, m); 7.84 (2H, d, J = 7.6 Hz); 7.97 (1H,
d, J = 7.2 Hz); 8.94 (1H, d, J = 7.8 Hz). 13C-NMR (150 MHz, CDCl3), δ (ppm): 105.3; 123.6; 127.3;
128.1 (2C); 128.6 (2C); 129.4; 130.1 (4C); 131.9; 132.3; 132.9; 133.6; 133.8; 135.0; 138.8; 149.2;
166.8; 189.6. LC-MS (APCI+), m/z: 360.1 [M+H]+. Anal. calcd for C22H14ClNO2: C, 73.44; H, 3.92;
N, 3.89; found: C, 73.41; H, 3.98; N, 3.88.
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(Z)-7a. 1H-NMR (600 MHz, CDCl3), δ (ppm): 6.61 (1H, s); 6.99 (2H, d, J = 8.4 Hz); 7.15 (2H, d, J =
8.4 Hz); 7.36-7.38 (2H, m); 7.49-7.52 (1H, m); 7.63-7.65 (2H, m); 7.68 (1H, d, J = 7.8 Hz); 7.73-7.76
(1H, m); 7.88 (1H, d, J = 7.8 Hz); 7.96 (1H, d, J = 7.8 Hz). 13C-NMR (150 MHz, CDCl3), δ (ppm):
101.6; 105.4; 120.3; 124.3; 128.3 (2C); 128.4 (2C); 128.5 (2C); 128.9 (2C); 130.1; 130.2; 131.2; 133.1;
133.2; 137.2; 138.0; 143.0; 167.5; 191.2. LC-MS (APCI+), m/z: 360.1 [M+H]+. Anal. calcd for
C22H14ClNO2: C, 73.44; H, 3.92; N, 3.89; found: C, 73.40; H, 3.99; N, 3.88.
Cyclocarbonylative Sonogashira of N-(4-chlorophenyl)-2-ethynylbenzamide (6) and iodobenzene (2a)
at 50 °C (Table 4, entry 2). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2,
255.7 mg (1.0 mmol) of N-(4- chlorophenyl)-2-ethynylbenzamide (6), 204.0 mg (1.0 mmol) of
iodobenzene (2a), 1.5 mL of Et3N and 4 mL of CH2Cl2 were put in the autoclave charged with 20 atm
of CO. The resulting mixture was stirred for 24 h at 50 °C. The composition of crude product was
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determined by H-NMR analysis, resulting in a mixture of (E)-2-(4- chlorophenyl)-3-(2-oxo-2-
phenylethylidene)isoindolin-1-one
((E)-7a)
and
(Z)-2-(4-chlorophenyl)-3-(2-oxo-2-phenyl-
ethylidene)isoindolin-1-one ((Z)-7a) in the molar ratio 90/10.
Cyclocarbonylative Sonogashira of N-(4-chlorophenyl)-2-ethynylbenzamide (6) and 4-iodoanisole (2b)
(Table 4, entry 3). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2, 255.7 mg
(1.0 mmol) of N-(4-chlorophenyl)-2-ethynylbenzamide (6), 234.0 mg (1.0 mmol) of 4-iodoanisole (2b),
1.5 mL of Et3N and 4 mL of CH2Cl2 were put in the autoclave charged with 20 atm of CO. The resulting
mixture was stirred for 4 h at 100 °C. The crude product was purified through column chromatography
(neutral Al2O3, n-hexane/AcOEt 3:1), obtaining 269 mg (yield 69%) of (E)-2-(4-chlorophenyl)-3-(2-
(4-methoxyphenyl)-2-oxoethylidene)isoindolin-1-one ((E)-7b) and 39 mg (yield 10%) of (Z)-2-(4-
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(E)-7b. 1H-NMR (600 MHz, CDCl3), δ (ppm): 3.85 (3H, s); 6.49 (1H, s); 6.91 (2H, d, J = 9.0 Hz); 7.36
(2H, d, J = 8.7 Hz); 7.56 (2H, d, J = 8.7 Hz); 7.63-7.65 (1H, m); 7.68-7.71 (1H, m); 7.83 (2H, d, J =
9.0 Hz); 7.94 (1H, d, J = 7.2 Hz); 8.86 (1H, d, J = 7.8 Hz). 13C-NMR (150 MHz, CDCl3), δ (ppm): 55.5;
105.7; 113.8 (2C); 123.6; 127.38; 129.5; 130.1 (2C); 130.1 (2C); 130.6 (2C); 131.7; 131.7; 132.5; 133.6;
133.9; 135.0; 148.4; 163.5; 166.8; 188.3. LC-MS (APCI+), m/z: 390.1 [M+H]+. Anal. calcd for
C23H16ClNO3: C, 70.86; H, 4.14; N, 3.59; found: C, 70.75; H, 4.21; N, 3.59.
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(Z)-7b. 1H-NMR (600 MHz, CDCl3), δ (ppm): 3.86 (3H, s); 6.58 (1H, s); 6.84 (2H, d, J = 9.0 Hz); 7.00
(2H, d, J = 8.7 Hz); 7.15 (2H, d, J = 8.7 Hz); 7.62 (2H, d, J = 9.0 Hz); 7.66 (1H, d, J = 7.2 Hz); 7.72-
7.74 (1H, m); 7.86 (1H, d, J = 7.8 Hz); 7.95 (1H, d, J = 7.8 Hz). 13C-NMR (150 MHz, CDCl3), δ (ppm):
55.5; 102.1; 113.5 (2C); 120.2; 124.2; 127.9; 128.6 (2C); 128.8 (2C); 130.8 (2C); 131.0; 131.1; 133.1;
133.3; 134.3; 137.2; 142.0; 163.6; 167.5; 189.8. LC-MS (APCI+), m/z: 390.1 [M+H]+. Anal. calcd for
C23H16ClNO3: C, 70.86; H, 4.14; N, 3.59; found: C, 70.78; H, 4.22; N, 3.59.
Cyclocarbonylative Sonogashira of N-(4-chlorophenyl)-2-ethynylbenzamide (6) and 2-iodoanisole (2c)
(Table 4, entry 4). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2, 255.7 mg
(1.0 mmol) of N-(4- chlorophenyl)-2-ethynylbenzamide (6), 234.0 mg (1.0 mmol) of 2-iodoanisole (2c),
1.5 mL of Et3N and 4 mL of CH2Cl2 were put in the autoclave charged with 20 atm of CO. The resulting
mixture was stirred for 4 h at 100 °C. The crude product was purified through column chromatography
(neutral Al2O3, n-hexane/AcOEt 3:1), obtaining 289 mg (yield 74%) of (E)-2-(4-chlorophenyl)-3-(2-
(2-methoxyphenyl)-2-oxoethylidene)isoindolin-1-one ((E)-7c) and 12 mg (yield 3%) of (Z)-2-(4-
chlorophenyl)-3-(2-(2-methoxyphenyl)-2-oxoethylidene)isoindolin-1-one ((Z)-7c).
(E)-7c. 1H-NMR (600 MHz, CDCl3), δ (ppm): 3.72 (3H, s); 6.63 (1H, s); 6.91 (1H, d, J = 8.4 Hz); 7.01-
7.04 (1H, m); 7.33 (2H, d, J = 8.7 Hz); 7.44-7.47 (1H, m); 7.53 (2H, d, J = 8.7 Hz); 7.66-7.68 (1H, m);
7.73-7.77 (2H, m); 7.96 (1H, d, J = 7.8 Hz); 9.15 (1H, d, J = 8.4 Hz). 13C-NMR (150 MHz, CDCl3), δ
(ppm): 55.3; 110.5; 111.6; 120.8; 123.6; 127.5; 129.5; 129.6; 129.7 (2C); 130.3 (2C); 130.8; 131.7;
132.7; 133.6; 133.7; 133.9; 134.8; 147.6; 158.1; 167.0; 189.7. LC-MS (APCI+), m/z: 390.1 [M+H]+.
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Anal. calcd for C23H16ClNO3: C, 70.86; H, 4.14; N, 3.59; found: C, 70.77; H, 4.20; N, 3.59.
(Z)-7c. 1H-NMR (600 MHz, CDCl3), δ (ppm): 3.89 (3H, s); 6.77 (1H, s); 6.92 (2H, t, J = 7.8 Hz); 7.13
(2H, d, J = 8.7 Hz); 7.25 (2H, d, J = 8.7 Hz); 7.38-7.40 (2H, m); 7.62-7.65 (1H, m); 7.69-7.72 (1H, m);
7.82 (1H, d, J = 7.8 Hz); 7.94 (1H, d, J = 7.8 Hz).
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Cyclocarbonylative Sonogashira of N-(4-chlorophenyl)-2-ethynylbenzamide (6) and 1-chloro-4-
iodobenzene (2d) with 20 atm of CO (Table 4, entry 5). Following the general procedure, 2.8 mg (0.004
mmol) of PdCl2(PPh3)2, 255.7 mg (1.0 mmol) of N-(4- chlorophenyl)-2-ethynylbenzamide (6), 238.5
mg (1.0 mmol) of 1-chloro-4-iodobenzene (2d), 1.5 mL of Et3N and 4 mL of CH2Cl2 were put in the
autoclave charged with 20 atm of CO. The resulting mixture was stirred for 4 h at 100 °C. The crude
product was purified through column chromatography (neutral Al2O3, n-hexane/AcOEt 3:1), obtaining
201 mg (yield 51%) of (E)-2-(4-chlorophenyl)-3-(2-(4-chlorophenyl)-2-oxoethylidene)isoindolin-1-
one ((E)-7d), 28 mg (yield 7%) of (Z)-2-(4-chlorophenyl)-3-(2-(4-chlorophenyl)-2-
oxoethylidene)isoindolin-1-one ((Z)-7d) and 11 mg (yield 3%) of (Z)-3-(4-chlorobenzylidene)-2-(4-
chlorophenyl)isoindolin-1-one (8).
(E)-7d. 1H-NMR (600 MHz, CDCl3), δ (ppm): 6.45 (1H, s); 7.35 (2H, d, J = 9.0 Hz); 7.42 (2H, d, J =
8.4 Hz); 7.57 (2H, d, J = 8.4 Hz); 7.68 (1H, t, J = 7.8 Hz); 7.72-7.77 (3H, m); 7.96 (1H, d, J = 7.2 Hz);
8.94 (1H, d, J = 7.8 Hz). 13C-NMR (150 MHz, CDCl3), δ (ppm): 104.7; 123.8; 127.5; 128.9 (2C); 129.6
(2C); 130.1 (2C); 130.2 (2C); 132.1; 132.3; 133.7; 133.8; 134.5; 135.2; 137.2; 139.47; 149.9; 166.9;
188.3. LC-MS (APCI+), m/z: 394.1 [M+H]+. Anal. calcd for C22H13Cl2NO2: C, 67.02; H, 3.32; N, 3.55;
found: C, 67.08; H, 3.35; N, 3.55.
(Z)-7d. 1H-NMR (600 MHz, CDCl3), δ (ppm): 6.56 (1H, s); 7.00 (2H, d, J = 8.4 Hz); 7.18 (2H, d, J =
8.4 Hz); 7.34 (2H, d, J = 8.4 Hz); 7.58 (2H, d, J = 8.4 Hz); 7.67 (1H, t, J = 7.2 Hz); 7.75 (1H, t, J = 7.2
Hz); 7.87 (1H, d, J = 7.2 Hz); 7.96 (1H, d, J = 7.8 Hz). 13C-NMR (150 MHz, CDCl3), δ (ppm): 100.8;
120.3; 124.4; 127.8; 128.4 (2C); 128.6; 128.7 (2C); 129.0 (2C); 129.7 (2C); 131.4; 133.3; 133.5; 134.4;
136.3; 137.1; 139.5; 143.5; 189.8. LC-MS (APCI+), m/z: 394.1 [M+H]+. Anal. calcd for C22H13Cl2NO2:
C, 67.02; H, 3.32; N, 3.55; found: C, 67.10; H, 3.37; N, 3.55.
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8. 1H-NMR (600 MHz, CDCl3), δ (ppm): 6.75 (1H, s); 6.80 (2H, d, J = 8.4 Hz); 6.97 (2H, d, J = 8.4
Hz); 7.01 (2H, d, J = 8.7 Hz); 7.11 (2H, d, J = 8.7 Hz); 7.57 (1H, t, J = 7.2 Hz); 7.69 (1H, t, J = 7.2 Hz);
7.84 (1H, d, J = 7.8 Hz); 7.95 (1H, d, J = 7.8 Hz). 13C-NMR (150 MHz, CDCl3), δ (ppm): 106.1; 110.6;
119.4; 124.0; 127.4; 127.5 (2C); 128.3 (2C); 128.4 (2C); 129.5; 129.8; 130.3 (2C); 130.7; 132.7; 134.2;
134.7; 138.3; 167.7. LC-MS (APCI+), m/z: 366.0 [M+H]+. Anal. calcd for C21H13Cl2NO: C, 68.87; H,
3.58; N, 3.82; found: C, 68.81; H, 3.54; N, 3.81.
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Cyclocarbonylative Sonogashira of N-(4-chlorophenyl)-2-ethynylbenzamide (6) and 1-chloro-4-
iodobenzene (2d) with 40 atm of CO (Table 4, entry 6). Following the general procedure, 2.8 mg (0.004
mmol) of PdCl2(PPh3)2, 255.7 mg (1.0 mmol) of N-(4- chlorophenyl)-2-ethynylbenzamide (6), 238.5
mg (1.0 mmol) of 1-chloro-4-iodobenzene (2d), 1.5 mL of Et3N and 4 mL of CH2Cl2 were put in the
autoclave charged with 40 atm of CO. The resulting mixture was stirred for 4 h at 100 °C. The
composition of crude product was determined by 1H-NMR analysis, resulting in a mixture of (E)-2-(4-
chlorophenyl)-3-(2-(4-chlorophenyl)-2-oxoethylidene)isoindolin-1-one
((E)-7d),
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chlorophenyl)-3-(2-(4-chlorophenyl)-2-oxoethylidene)isoindolin-1-one ((Z)-7d) and (Z)-3-(4-
chlorobenzylidene)-2-(4-chlorophenyl) isoindolin-1-one (8) in the molar ratio 86/10/4.
Cyclocarbonylative Sonogashira of N-(4-chlorophenyl)-2-ethynylbenzamide (6) and 1-
iodonaphthalene (2f) (Table 4, entry 7). Following the general procedure, 2.8 mg (0.004 mmol) of
PdCl2(PPh3)2, 255.7 mg (1.0 mmol) of N-(4- chlorophenyl)-2-ethynylbenzamide (6), 254.1 mg (1.0
mmol) of 1-iodonaphthalene (2f), 1.5 mL of Et3N and 4 mL of CH2Cl2 were put in the autoclave charged
with 20 atm of CO. The resulting mixture was stirred for 4 h at 100 °C. The crude product was purified
through column chromatography (neutral Al2O3, n-hexane/AcOEt 6:1), obtaining 283 mg (yield 69%)
of (E)-2-(4-chlorophenyl)-3-(2-(naphthalen-1-yl)-2-oxoethylidene)isoindolin-1-one ((E)-7f) and 21 mg
(yield 5%) of (Z)-2-(4-chlorophenyl)-3-(2-(naphthalen-1-yl)-2-oxoethylidene)isoindolin-1-one ((Z)-
7f).
(E)-7f. 1H-NMR (600 MHz, CDCl3), δ (ppm): 6.41 (1H, s); 7.33 (2H, d, J = 8.7 Hz); 7.46 (1H, t, J =
7.8 Hz); 7.49 (2H, d, J = 8.7 Hz); 7.54 (1H, t, J = 7.2 Hz); 7.59 (1H, t, J = 7.2 Hz); 7.69-7.72 (2H, m);
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7.76 (1H, t, J = 7.8 Hz); 7.89 (1H, d, J = 8.4 Hz); 7.96-8.00 (2H, m); 8.56 (1H, d, J = 8.4 Hz); 9.11 (1H,
d, J = 7.8 Hz). 13C-NMR (150 MHz, CDCl3), δ (ppm): 109.0; 123.7; 124.4; 125.4; 126.5; 127.6; 127.7;
127.7; 128.5; 129.1; 129.5; 130.0 (4C); 130.1; 132.0; 132.2; 132.57; 133.8; 133.8; 135.0; 137.7; 149.1;
166.9; 192.9. LC-MS (APCI+), m/z: 410.0 [M+H]+. Anal. calcd for C26H16ClNO2: C, 76.19; H, 3.93;
N, 3.42; found: C, 76.07; H, 3.99; N, 3.43.
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(Z)-7f. 1H-NMR (600 MHz, CDCl3), δ (ppm): 6.62 (1H, s); 6.84 (2H, d, J = 8.4 Hz); 6.88 (2H, d, J =
8.4 Hz); 7.40 (1H, t, J = 7.8 Hz); 7.49-7.54 (2H, m); 7.68 (1H, t, J = 7.8 Hz); 7.76 (1H, t, J = 7.8 Hz);
7.79-7.82 (2H, m); 7.89 (1H, d, J = 7.2 Hz); 7.95 (2H, t, J = 6.6 Hz); 8.32-8.33 (1H, m). 13C-NMR (150
MHz, CDCl3), δ (ppm): 104.3 120.4; 124.0; 124.3; 125.6; 126.7; 127.5 (2C); 127.7; 127.9; 128.0; 129.1
(2C); 130.1; 130.1; 131.3; 133.0; 133.3; 133.5; 133.9; 135.5; 137.4; 142.8; 167.6; 193.5. LC-MS
(APCI+), m/z: 410.0 [M+H]+. Anal. calcd for C26H16ClNO2: C, 76.19; H, 3.93; N, 3.42; found: C, 76.11;
H, 3.97; N, 3.43.
Cyclocarbonylative Sonogashira of N-(4-chlorophenyl)-2-ethynylbenzamide (6) and 4-iodotoluene
(2g) (Table 4, entry 8). Following the general procedure, 2.8 mg (0.004 mmol) of PdCl2(PPh3)2, 255.7
mg (1.0 mmol) of N-(4- chlorophenyl)-2-ethynylbenzamide (6), 92.1 mg (1.0 mmol) of 4-iodotoluene
(2g), 1.5 mL of Et3N and 4 mL of CH2Cl2 were put in the autoclave charged with 20 atm of CO. The
resulting mixture was stirred for 4 h at 100 °C. The crude product was purified through column
chromatography (neutral Al2O3, n-hexane/AcOEt 3:1), obtaining 251 mg (yield 67%) of (E)-2-(4-
chlorophenyl)-3-(2-oxo-2-(p-tolyl)ethylidene)isoindolin-1-one ((E)-7g) and 26 mg (yield 7%) of (Z)-2-
(4-chlorophenyl)-3-(2-oxo-2-(p-tolyl)ethylidene)isoindolin-1-one ((Z)-7g).
(E)-7g. 1H-NMR (600 MHz, CDCl3), δ (ppm): 2.39 (3H, s); 6.51 (1H, s); 7.24 (2H, d, J = 8.4 Hz); 7.36
(2H, d, J = 8.4 Hz); 7.56 (2H, d, J = 8.4 Hz); 7.65 (1H, t, J = 7.8 Hz); 7.70 (1H, t, J = 7.8 Hz); 7.74 (2H,
d, J = 8.4 Hz); 7.94 (1H, d, J = 7.2 Hz); 8.91 (1H, d, J = 7.8 Hz). 13C-NMR (150 MHz, CDCl3), δ (ppm):
21.6; 105.6; 123.6; 127.4; 128.4 (2C); 129.3 (2C); 129.5; 130.1 (2C); 130.1 (2C); 131.8; 132.5; 133.6;
133.9; 135.0; 136.4; 143.9; 148.8; 166.9; 189.4. LC-MS (APCI+), m/z: 374.1 [M+H]+. Anal. calcd for
C23H16ClNO2: C, 73.90; H, 4.31; N, 3.75; found: C, 74.01; H, 4.25; N, 3.76.
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