Divergent palladium iodide catalyzed multicomponent carbonylative approaches to functionalized isoindolinone and isobenzofuranimine derivatives

Article abstract of DOI:10.1021/jo500281h

2-Alkynylbenzamides underwent different reaction pathways when allowed to react under PdI₂-catalyzed oxidative carbonylation conditions, depending on the nature of the external nucleophile and reaction conditions. Thus, oxidative carbonylation of 2-ethynylbenzamides, bearing a terminal triple bond, carried out in the presence of a secondary amine as external nucleophile, selectively led to the formation of 3-[(dialkylcarbamoyl)methylene]isoindolin-1- ones through the intermediate formation of the corresponding 2-ynamide derivatives followed by intramolecular nucleophilic attack by the nitrogen of the benzamide moiety on the conjugated triple bond. On the other hand, 3-[(alkoxycarbonyl)methylene]isobenzofuran-1(3H)imines were selectively obtained when the oxidative carbonylation of 2-alkynylbenzamides, bearing a terminal or an internal triple bond, was carried out in the presence of an alcohol R′OH (such as methanol or ethanol) as the external nucleophile and HC(OR′)₃ as a dehydrating agent, necessary to avoid substrate hydrolysis. In this latter case, the reaction pathway leading to the isobenzofuranimine corresponded to the 5-exo-dig intramolecular nucleophilic attack of the oxygen of the benzamide moiety on the triple bond coordinated to the metal center followed by alkoxycarbonylation. The structures of representative products have been confirmed by X-ray crystallographic analysis.

Full text of DOI:10.1021/jo500281h

Article
pubs.acs.org/joc
Divergent Palladium Iodide Catalyzed Multicomponent
Carbonylative Approaches to Functionalized Isoindolinone and
Isobenzofuranimine Derivatives
Raffaella Mancuso,*,† Ida Ziccarelli,† Donatella Armentano,‡ Nadia Marino,‡ Salvatore V. Giofre,§
̀
and Bartolo Gabriele*,†
†Dipartimento di Chimica e Tecnologie Chimiche, Universita
Italy
̀
̀
della Calabria, Via P. Bucci, 12/C, 87036 Arcavacata di Rende (CS),
della Calabria, Via P. Bucci, 14/C, 87036 Arcavacata di Rende (CS),
‡Dipartimento di Chimica e Tecnologie Chimiche, Universita
Italy
§Dipartimento di Scienze del farmaco e dei prodotti per la salute, Via SS Annunziata, 98168 Messina, Italy
S
* Supporting Information
ABSTRACT: 2-Alkynylbenzamides underwent different reaction pathways when allowed to react under PdI2-catalyzed oxidative
carbonylation conditions, depending on the nature of the external nucleophile and reaction conditions. Thus, oxidative
carbonylation of 2-ethynylbenzamides, bearing a terminal triple bond, carried out in the presence of a secondary amine as
external nucleophile, selectively led to the formation of 3-[(dialkylcarbamoyl)methylene]isoindolin-1-ones through the
intermediate formation of the corresponding 2-ynamide derivatives followed by intramolecular nucleophilic attack by the
nitrogen of the benzamide moiety on the conjugated triple bond. On the other hand, 3-[(alkoxycarbonyl)methylene]-
isobenzofuran-1(3H)imines were selectively obtained when the oxidative carbonylation of 2-alkynylbenzamides, bearing a
terminal or an internal triple bond, was carried out in the presence of an alcohol R′OH (such as methanol or ethanol) as the
external nucleophile and HC(OR′)3 as a dehydrating agent, necessary to avoid substrate hydrolysis. In this latter case, the
reaction pathway leading to the isobenzofuranimine corresponded to the 5-exo-dig intramolecular nucleophilic attack of the
oxygen of the benzamide moiety on the triple bond coordinated to the metal center followed by alkoxycarbonylation. The
structures of representative products have been confirmed by X-ray crystallographic analysis.
Scheme 1. Divergent Syntheses of Carbonylated
Isoindolinone and Isobenzofuranimine Derivatives (3 and 4,
Respectively) Starting from 2-Alkynylbenzamides 1 under
Different Conditions
INTRODUCTION
■
Isoindolinones are very important heterocyclic derivatives with
many important applications.1,2 In fact, many molecules
containing the isoindolinone nucleus have shown important
biological activities, including antimicriobial, antiproliferative
and inhibitor of the MDM2-p53 protein−protein interaction
effect.1 We have recently communicated a novel carbonylation
method for the synthesis of functionalized 3-methyleneisoindo-
lin-1-ones3,4 starting from readily available 2-ethynylbenza-
mides 1 (R2 = H).5 In this paper, a full account of this reactivity
is reported that allows the direct synthesis of [3-
[(dialkylcarbamoyl)methylene]isoindolin-1-ones 3 by PdI2-
catalyzed oxidative aminocarbonylation−N-heterocyclization
of 2-ethynylbenzamides 1 (R2 = H) with secondary amines 2,
according to Scheme 1a.
Very interestingly, it has also been found that 2-
alkynylbenzamides 1, bearing a terminal or an internal triple
bond (R2 = H, alkyl, alkenyl, phenyl), selectively lead to 3-
Received: February 5, 2014
Published: March 11, 2014
© 2014 American Chemical Society
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[(alkoxycarbonyl)methylene]isobenzofuran-1(3H)imines 4,
corresponding to O-heterocyclization, when the oxidative
carbonylation reaction was carried out in the presence of an
alcohol R′OH (such as methanol or ethanol) as the external
nucleophile and HC(OR′)3 as a dehydrating agent (Scheme
1b). The possibility to obtain carbonylated isobenzofurani-
mines in one step by a multicomponent carbonylative approach
is also very attractive, in view of the importance of this class of
heterocycles.6−8 Isobenzofuranimines have, in fact, been
obtained in one step from very simple building blocks.9
minimize the steric repulsion between the bulky substituent
and the morpholine ring.
The structure of 3da-E was confirmed by X-ray diffraction
analysis, as shown in Figure S1 (Supporting Information). In
1
the H NMR spectrum of 3da-E, the olefinic proton absorbed
at 6.1 ppm, so a chemical shift around 6 ppm could be
considered diagnostic for an E configuration around the
exocyclic double bond of diastereoisomers 3aa-E and 3ba-E,
while the olefinic proton for diastereoisomers 3aa-Z, 3ba-Z,
and 3ca-Z absorbed in the range 5.6−5.8 ppm (see the
Experimental Section).
On the other hand, complete diastereoselectivity toward the
isomer Z was observed when R1 = H (3ea-Z, Table 1, entry 5),
due to the stabilization by intramolecular hydrogen bonding
between the NH group and the carbonyl of the exocyclic amido
group, as confirmed by the X-ray crystallographic analysis for
3ea-Z (Figure S2, Supporting Information).
The nature of the secondary amine was also changed, with
substrates 1a (R1 = Bu) and 1d (R1 = tert-butyl). As can be
seen from the results reported in Table 1, entries 6−10, high to
excellent yields of the corresponding isoindolinones (76−96%)
were also observed working with other secondary nucleophilic
cyclic or acyclic amines such as piperidine 2b (Table 1, entries
6 and 7), pyrrolidine 2c (Table 1, entries 8 and 9), or
dibutylamine 2d (Table 1, entry 10). With substrate 1d (R1 =
tert-butyl), again complete E diastereoselectivity was observed
in the final products 3db-E and 3dc-E (Table 1, entries 7 and
9).
RESULTS AND DISCUSSION
■
Synthesis of Carbonylated Isoindolinone Derivatives
3 by PdI2-Catalyzed Aminocarbonylation−N-Heterocyc-
lization of 2-Ethynylbenzamides 1 with Secondary
Amines 2. The first substrate tested under PdI2-catalyzed
oxidative carbonylation conditions was N-butyl-2-ethynylben-
zamide 1a (R1 = Bu, R2 = H), readily available by ethynylation
of N-butyl-2-iodobenzamide (see the Experimental Section for
details). This substrate was initially allowed to react with CO,
O2, and morpholine (2a) at 100 °C for 15 h in a 1:1 (v/v)
mixture of MeCN−morpholine as the solvent under a 4:1
mixture of CO−air (20 atm),10 in the presence of catalytic
amounts of PdI2 (2 mol %) in conjunction with KI (KI/PdI2
molar ratio = 10). Under these conditions, 1a was converted
into a ca. 2:1 Z/E mixture of 2-butyl-3-(2-morpholino-2-
oxoethylidene)isoindolin-1-one 3aa, which was isolated in 48%
yield (eq 1 and entry 1, Table S1, Supporting Information). A
On the basis of what is already known on the PdI2-catalyzed
oxidative aminocarbonylation of terminal alkynes,9,11 the
reaction course leading to the isoindolinone derivatives 3 can
be interpreted as occurring as shown in Scheme 2 (anionic
iodide ligands are omitted for clarity). Thus, formation of an
alkynylpalladium intermediate I takes place by the reaction
between substrate 1a−e, PdI2, and the base, followed by CO
insertion to give an alkynoylpalladium species II. Nucleophilic
displacement by the amine then leads to the 2-ynamide
intermediate III and Pd(0). The latter is reoxidized by the
action of I2 (formed in its turn by oxidation of HI, ensuing from
the carbonylation process, and O2),12 while intermediate III
undergoes 5-exo-dig N-cyclization by intramolecular conjugate
addition to give the final product 3. Clearly, the formation of
alkynylpalladium complex I (and therefore of II and III) is
possible because the starting substrate 1a−e bears a terminal
triple bond. Accordingly, no reaction occurred with 2-
alkynylbenzamides bearing an internal triple bond.
brief optimization study was then carried out in which the gas
total pressure, substrate concentration, temperature, the
amount of KI and morpholine, and the nature of the solvent
were changed. The results, shown in Table S1 (Supporting
Information), allowed the identification of the optimal
conditions for this process, which corresponded to 100 °C
under 40 atm of a 4:1 mixture of CO−air, in a 2:1 mixture of
MeCN−morpholine as the solvent (substrate concentration =
0.05 mmol per mL of solvent). Under these conditions,
isoindolinone 3aa was obtained in 81% yield after 5 h (Z/E =
2.0, Table 1, entry 1).
Synthesis of Carbonylated Isobenzofuranimine De-
rivatives 4 by PdI2-Catalyzed O-Heterocyclization−
Alkoxycarbonylation of 2-Alkynylbenzamides 1. As
already noted, 2-alkynylbenzamides, bearing an internal triple
bond, cannot undergo aminocarbonylation. These substrates,
however, did react under alkoxycarbonylation conditions since,
in this case, the reaction mechanism may start with the
coordination of the triple bond to PdI2 followed by
intramolecular nucleophilic attack (either exo or endo) and
alkoxycarbonylation (Scheme 3).9,11,13
Very interestingly, under alkoxycarbonylation conditions (in
MeOH as the solvent, with a substrate concentration of 0.02
mmol/mL of MeOH, in the presence of 2 mol % PdI2 and 20
mol % of KI, under 40 atm of a 4:1 mixture of CO−air at 100
°C for 5 h), 2-(hex-1-ynyl)-N-phenylbenzamide 1f underwent
O-cyclization rather than N-cyclization, followed by alkox-
ycarbonylation, to give a mixture of methyl 2-[3-
The reactivity of other substrates 1b−e, bearing different
substituents on nitrogen, was then tested, with morpholine as
the base and nucleophile (Table 1, entries 2−5). As can be seen
from these data, the reaction also worked nicely with a benzyl
(R1 = Bn, Table 1, entry 2) and a phenyl (R1 = Ph, Table 1,
entry 3) substituent on nitrogen, with results similar to those
obtained with R1 = Bu (Table 1, entry 1). In both cases, the Z
isomer was obtained as the major stereoisomer or sole
diastereoisomer; the diastereoselectivity was higher with R1 =
Ph (3ca-Z, only Z, Table 1, entry 3) with respect to R1 = Bn
(3ba, Z/E = 2.2, Table 1, entry 2). Quite predictably, the
reaction was slower when the nitrogen was substituted with a
bulky group, such as in substrate 1d (R1 = t-Bu, Table 1, entry
4); in any case, an excellent yield of the corresponding
carbonylated isoindolinone 3da-E was still obtained (93%).
Moreover, in this case, complete diastereoselectivity toward the
E isomer was observed, probably due to the necessity to
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Table 1. Synthesis of [3-[(Dialkylcarbamoyl)methylene]isoindolin-1-ones 3 by PdI2-Catalyzed Aminocarbonylation−N-
a
Heterocyclization of 2-Ethynylbenzamides 1a−e
a
All reactions were carried out in a MeCN−R2NH mixture (2:1, v/v) as the solvent (concentration of 1 = 0.05 mmol per mL of solvent) at 100 °C
and under 40 atm (at 25 °C) of a 4:1 mixture of CO−air, in the presence of 2 mol % of PdI2 in conjunction with an excess of KI (KI/PdI2 molar
b
c
d
ratio = 10). Conversion of 1 was quantitative in all cases. Isolated yield based on starting 1. Z/E ratio = 2.0 (determined by 1H NMR). Z/E ratio
e
f
= 2.2 (determined by 1H NMR). The reaction was selective toward the formation of the Z isomer. The reaction was selective toward the formation
g
of the E isomer. The structure of 3da-E was confirmed by X-ray diffraction analysis. The reaction was selective toward the formation of the Z
h
i
isomer. The structure of 3ea-Z was confirmed by X-ray diffraction analysis. Z/E ratio = 1.0 (determined by 1H NMR). The reaction was selective
j
k
toward the formation of the E isomer. Z/E ratio = 1.8 (determined by 1H NMR). Z/E ratio = 1.0 (determined by isolation of the diastereoisomers
after column chromatography).
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elimination of aniline is necessary to justify the formation of 5f.
It is conceivable that 6-endo-dig nucleophilic attack of the amido
oxygen to the coordinated triple bond gives the vinylpalladium
complex V. Hydrolysis of the exocyclic imino group of V would
then lead to the corresponding lactone-vinylpalladium inter-
mediate VI, whose alkoxycarbonylation would eventually afford
5f (Scheme 4, path b). However, the possibility of an HI-
promoted nucleophilic attack by water to the amidic carbonyl
of 1f, with formation of tetrahedral intermediate VII, cannot be
ruled out. The latter would then undergo 6-endo-dig O-
cyclization to give complex VIII, followed by elimination of
aniline from the HO(C)NHPh moiety to afford the same
lactone-vinylpalladium intermediate VI seen before (Scheme 4,
path c).
Scheme 2. Plausible Reaction Mechanism for the PdI2/KI-
Catalyzed Carbonylative N-Cyclization of 2-
Ethynylbenzamides 1a−e Leading to Carbonylated
a
Isoindolinones 3
In order to minimize the formation of byproduct 5f, the next
experiments were carried out in the presence of a dehydrating
agent, such as trimethyl orthoformate.15 Indeed, when
HC(OMe)3 was used as a cosolvent together with MeOH
(2:1 v/v, R = Me), 4f was selectively obtained in 80% yield,
without any formation of 5f (Table 2, entry 1). The reaction
with a higher alcohol, such as ethanol (R = Et), also afforded a
high yield of the corresponding isobenzofuranimine derivative
4f′ (83%, Table 2, entry 2). The protocol was then extended to
other 2-alkynylbenzamides bearing different substituents on
nitrogen and on the triple bond. As shown in Table 2, the
nitrogen could be successfully substituted with an alkyl or a
benzyl group, while the triple bond could also bear a phenyl or
a 1-cyclohexenyl group. The reaction also worked nicely with a
terminal triple bond, as shown by entries 8−12. In this latter
case, the process was consistently selective toward the
formation of the E stereoisomer. The structure of representa-
tive products, in particular (E)-methyl 2-[3-(tert-butylimino)-
isobenzofuran-1(3H)-ylidene]acetate 4d-E and (E)-methyl 2-
[3-(phenylimino)isobenzofuran-1(3H)-ylidene]-2-phenylace-
tate 4i-E, was confirmed by X-ray diffractometric analysis, as
shown in Figures S3 and S4, respectively (Supporting
Information). A chemical shift for the olefinic proton around
6.0 ppm was diagnostic of E stereochemistry for products 4a-E,
4a′-E, 4b-E, 4c-E, and 4d-E. On the other hand, for products
4f−k, the chemical shift of aromatic proton at ca. 8.2−8.4 ppm
was diagnostic for the E diastereoisomer, while the aromatic
absorptions at ca. 8.5 ppm and 7.9−8.0 ppm were characteristic
of the Z distereoisomer (see the Experimental Section).
a
Anionic iodide ligands are omitted for clarity.
Scheme 3. General Mechanism for the PdI2-Catalyzed
Heterocyclization−Alkoxycarbonylation of Acetylenic
Substrates Bearing a Suitably Placed Nucleophilic Group (Y
= O or NR″)
CONCLUSIONS
■
In conclusion, we have developed divergent, multicomponent
carbonylative approaches to functionalized isoindolinone and
isobenzofuranimine derivatives (3 and 4, respectively) starting
from readily available 2-alkynylbenzamides 1. In particular, by
reacting 2-ethynylbenzamides (bearing a terminal triple bond)
with CO, a nucleophilic secondary amine (2), and O2 in the
presence of the PdI2 /KI catalytic system, [3-
[(dialkylcarbamoyl)methylene]isoindolin-1-ones 3 were selec-
tively obtained by oxidative monoaminocarbonylation of the
triple bond followed by N-cyclization, occurring through
intramolecular conjugate addition to the 2-ynamide intermedi-
ate. On the other hand, 3-[(alkoxycarbonyl)methylene]-
isobenzofuran-1(3H)imines 4 were selectively formed from 2-
alkynylbenzamides 1 bearing a terminal as well as an internal
triple bond, through 5-exo-dig O-cyclyzation−alkoxycarbonyla-
tion, taking place in a ROH/HC(OR)3 mixture (R = Me, Et) as
the solvent in the presence of catalytic amounts of PdI2/KI,
CO, and O2. In this latter case, the use of an excess of
(phenylimino)isobenzofuran-1(3H)-ylidene]hexanoate 4f (Z/E
ca. 1.4) and methyl 3-butyl-1-oxo-1H-isochromene-4-carbox-
ylate 5f (eq 2).
Formation of 4f clearly corresponded to the 5-exo-dig
nucleophilic attack of the amido oxygen to the coordinated
triple bond to give the vinylpalladium complex IV followed by
alkoxycarbonylation (Scheme 4, path a. Partial isomerization of
intermediate IV14 accounted for the formation of the E/Z
mixture). On the other hand, the involvement of water with
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Scheme 4. Proposed Reaction Pathways for the Formation of Methyl 2-[3-(Phenylimino)isobenzofuran-1(3H)-
ylidene]hexanoate 4f and Methyl 3-Butyl-1-oxo-1H-isochromene-4-carboxylate 5f from 2-(Hex-1-ynyl)-N-phenylbenzamide 1f
corresponding to 16.5 mmol), (Ph3P)2PdCl2 (405 mg, 0.58 mmol),
CuI (251 mg, 1.32 mmol), and Et3N (6.7 g, 66 mmol) in anhydrous
DMF (82 mL) was stirred under nitrogen for 1 h. The 1-alkyne (19.8
mmol; trimethylsilylacetylene, 1.95 g; 1-hexyne, 1.63 g; phenyl-
acetylene, 2.02 g; 1-ethynylcyclohex-1-ene, 2.10 g) was added under
nitrogen, and the resulting mixture allowed to stir at 80−85 °C for 15
h. After cooling, CH2Cl2 was added (100 mL) followed by water (70
mL). The phases were separated, and the organic layer was washed
with water (2 × 70 mL). After drying over Na2SO4, the product was
purified by column chromatography on silica gel using as eluent 9:1
hexane−AcOEt (N-phenyl-2-[2-(trimethylsilyl)ethynyl]benzamide, N-
benzyl-2-[2-(trimethylsilyl)ethynyl]benzamide, 1f, 1g, 1h, 1i, 1j, 1k),
or 8:2 hexane−AcOEt (N-butyl-2-[2-(trimethylsilyl)ethynyl]-
benzamide, N-tert-butyl-2-[2-(trimethylsilyl)ethynyl]benzamide).
N-Butyl-2-[2-(trimethylsilyl)ethynyl]benzamide:3k yield 2.66 g,
starting from crude N-butyl-2-iodobenzamide and trimethylsilylacety-
lene (59%); yellow oil; IR (film) ν = 3391 (w, br), 3304 (m, br), 2959
(m), 2157 (m), 1648 (m), 1536 (m), 1475 (w), 1304 (m), 1250 (m),
HC(OR)3 as a dehydrating agent was essential for the success
of the reaction, its function being to avoid the nucleophilic
attack of water to the amide carbonyl of the substrate, which
would favor the formation of 1-oxo-1H-isochromene-4-
carboxylate esters 5 as side products.
EXPERIMENTAL SECTION
■
General Experimental Methods. Melting points are uncorrected.
1H NMR and 13C NMR spectra were recorded at 25 °C in CDCl3 or
DMSO-d6 solutions at 300 or 500 MHz and 75 or 126 MHz,
respectively, with Me4Si as internal standard. Chemical shifts (δ) and
coupling constants (J) are given in ppm and hertz, respectively. IR
spectra were taken with an FT-IR spectrometer. Mass spectra were
obtained using a GC−MS apparatus at 70 eV ionization voltage.
Microanalyses were carried out at our analytical laboratory. All
reactions were analyzed by TLC on silica gel 60 F254 or on neutral
alumina and by GLC using a gas chromatograph and capillary columns
with polymethylsilicone + 5% phenylsilicone as the stationary phase.
Column chromatography was performed on silica gel 60 (70−230
mesh). Evaporation refers to the removal of solvent under reduced
pressure.
Preparation of Substrates. 2-Alkynylbenzamides 1a−d,f−k were
prepared by coupling between the corresponding 2-iodobenzamide
and the suitable terminal alkyne, followed (in the case of
trimethylsilylacetylene) by deprotection, as described below. 2-
Ethynylbenzamide 1e was prepared in a similar manner from 2-
bromobenzamide according to a literature procedure.16 All other
materials were commercially available and were used without further
purification.
General Procedure for the Preparation of N-Substituted 2-
Alkynylbenzamides 1a−d,f−k. First Step: Preparation of 2-
Iodobenzamides. The method of Kundu and Khan17 was employed.
To a stirred solution of 2-iodobenzoyl chloride18 (4.4 g, 16.5 mmol) in
anhydrous benzene (43 mL) was slowly added, under nitrogen and
dropwise, a solution of RNH2 (33.3 mmol; R = Bu, 2.44 g; R = Bn,
3.57 g; R = Ph, 3.10 g; R = t-Bu, 2.44 g) in anhydrous benzene (15
mL). The resulting mixture was taken up with Et2O (100 mL) and
transferred in a separatory funnel. Aqueous HCl (1 M, 70 mL) was
added, and the organic layer was separated and washed again with 1 M
HCl (2 × 70 mL), satd Na2CO3 (3 × 70 mL), and water (3 × 70 mL).
After drying over Na2SO4, the solvent was evaporated, and the crude
2-iodobenzamide thus obtained used as such for the next step.
Second Step: Sonogashira Coupling To Give N-Substituted 2-[(2-
Trimethylsilyl)ethynyl)]benzamides and 2-Alkynylbenzamides 1f−k.
The method of Kundu and Khan17 was employed. A mixture of the
crude 2-iodobenzamide (obtained as described above, formally
1
872 (m), 844 (s), 758 (m) cm−1; H NMR (500 MHz, CDCl3) δ =
8.12−8.08 (m, 1 H), 7.68 (s, br, 1 H), 7.53 (dd, J = 7.3, 1.2, 1 H),
7.47−7.36 (m, 2 H), 3.53−3.45 (m, 2 H), 1.63 (quintuplet, J = 7.3, 2
H), 1.44 (sextuplet, J = 7.3, 2 H), 0.97 (t, J = 7.3, 3 H), 0.29 (s, 9 H);
13C NMR (126 MHz, CDCl3) δ = 166.0, 135.7, 134.2, 130.5, 130.4,
129.3, 119.4, 103.9, 101.7, 40.1, 31.9, 20.6, 14.0, 0.00; GC−MS m/z =
273 (4) [M+], 272 (5), 258 (22), 244 (7), 230 (15), 217 (31), 202
(73), 201 (80), 187 (100), 172 (7), 161 (13), 145 (17), 143 (26), 128
(12), 115 (8), 93 (23), 75 (22). Anal. Calcd for C16H23NOSi
(273.45): C, 70.28; H, 8.48; N, 5.12; Si, 10.27. Found: C, 70.32; H,
8.45; N, 5.14; Si, 10.31.
N-Benzyl-2-[2-(trimethylsilyl]ethynyl]benzamide:19 yield 2.98 g,
starting from crude N-benzyl-2-iodobenzamide and trimethylsilylace-
tylene (59%); yellow solid; mp 80−82 °C; IR (KBr) ν = 3383 (m),
3299 (w), 2154 (m), 1652 (s), 1533 (m), 1296 (m), 1250 (m), 866
(s), 844 (s), cm−1; 1H NMR (500 MHz, CDCl3) δ = 8.23−8.10 (m, 2
H, 1 H), 7.60−7.49 (m, 1 H), 7.48−7.23 (m, 7 H), 4.67 (d, J = 5.5, 2
H), 0.11 (s, 9 H); 13C NMR (126 MHz, CDCl3) δ = 165.7, 138.0,
134.8, 134.1, 130.6, 130.4, 129.2, 128.7, 127.8, 127.5, 119.4, 103.6,
102.1, 44.1, −0.5; GC−MS m/z = 307 (32) [M+], 306 (47), 292 (19),
290 (22), 276 (5), 234 (20), 216 (22), 201 (27), 187 (91), 159 (14),
143 (17), 129 (11), 106 (11), 91 (100), 75 (27), 73 (42). Anal. Calcd
for C19H21NOSi (307.46): C, 74.22; H, 6.88; N, 4.56; Si, 9.13. Found:
C, 74.19; H, 6.85; N, 4.59; Si, 9.12.
N-Phenyl-2-[2-(trimethylsilyl)ethynyl]benzamide: yield 3.20 g,
starting from crude 2-iodo-N-phenylbenzamide and trimethylsilylace-
tylene (66%); yellow solid; mp 97−98 °C (lit.17 mp 95−96 °C, lit.20
mp 96−97 °C); IR (KBr) ν = 3303 (m, br), 2959 (w), 2157 (m), 1660
(s), 1601 (m), 1541 (s), 1500 (m), 1447 (m), 1323 (m), 1250 (m),
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Table 2. Synthesis of 3-[(Alkoxycarbonyl)methylene]isobenzofuran-1(3H)-imines 4 by PdI2-Catalyzed O-Heterocyclization−
a
Alkoxycarbonylation of 2-Alkynylbenzamides 1
a
All reactions were carried out in a HC(OR)3−ROH mixture (2:1, v/v) as the solvent (concentration of 1 = 0.02 mmol per mL of solvent) at 100
°C and under 40 atm (at 25 °C) of a 4:1 mixture of CO−air, in the presence of 2 mol % of PdI2 in conjunction with an excess of KI (KI/PdI2 molar
b
c
d
ratio = 10). Conversion of 1 was quantitative in all cases. Isolated yield based on starting 1. Z/E ratio = 1.4 (determined by 1H NMR). Z/E ratio
e
f
g
1
1
1
ca. 1:1 (determined by H NMR). E/Z ratio = 6.2 (determined by H NMR). E/Z ratio = 4.9 (determined by H NMR). The reaction was
selective toward the formation of the E isomer. The structure of 4i-E was confirmed by X-ray diffraction analysis. The reaction was selective toward
the formation of the E isomer. The reaction was selective toward the formation of the E isomer. The structure of 4d-E was confirmed by X-ray
h
i
diffraction analysis.
3511
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1
868 (s), 844 (s), 756 (m) cm−1; H NMR (500 MHz, CDCl3) δ =
3277 (s), 3056 (w), 2217 (vw), 1654 (s), 1594 (m), 1524 (s), 1440
1
9.29 (s, br, 1 H), 8.13−8.09 (m, 1 H), 7.68 (d, J = 7.9, 2 H), 7.60−7.55
(m, 1 H), 7.48−7.40 (m, 2 H), 7.37 (t, J = 7.9, 2 H), 7.18−7.12 (t, J =
7.3, 1 H), 0.23 (s, 9 H); 13C NMR (126 MHz, CDCl3) δ = 164.1,
138.0, 136.0, 134.0, 130.8, 130.3, 129.3, 129.0, 124.5, 120.3, 119.5,
103.1, 102.8, −0.18; GC−MS m/z = 293 (11) [M+], 278 (5), 219 (6),
201 (100), 161 (7), 145 (12), 143 (9), 117 (5). Anal. Calcd for
C18H19NOSi (293.44): C, 73.68; H, 6.53; N, 4.77; Si, 9.57. Found: C,
73.62; H, 6.50; N, 4.78; Si, 9.62.
N-tert-Butyl-2-[2-(trimethylsilyl)ethynyl]benzamide: yield 2.25 g,
starting from crude N-tert-butyl-2-iodobenzamide (50%) and
trimethylsilylacetylene; yellow solid mp 58−59 °C; IR (KBr) ν =
3293 (m, br), 2962 (m), 2161 (m), 1643 (s), 1598 (w), 1539 (s),
1478 (w), 1447 (w), 1362 (w), 1324 (m), 1249 (m), 1222 (m), 842
(s), 753 (m) cm−1; 1H NMR (500 MHz, CDCl3) δ = 7.96 (d, J = 7.3,
1 H), 7.50 (d, J = 7.3, 1 H), 7.43−7.31 (m, 2 H), 7.22 (s, br, 1 H), 1.49
(s, 9 H), 0.28 (s, 9 H); 13C NMR (126 MHz, CDCl3) δ = 165.5, 137.1,
134.3, 130.0, 129.7, 129.1, 119.3, 103.6, 101.3, 52.1, 28.9, 0.0; GC−MS
m/z = 273 (3) [M+], 258 (4), 217 (67), 202 (100), 184 (24), 161 (5),
145 (12), 143 (24), 121 (15), 75 (20). Anal. Calcd for C16H23NOSi
(273.45): C, 70.28; H, 8.48; N, 5.12; Si, 10.27. Found: C, 70.30; H,
8.44; N, 5.16; Si, 10.24.
2-(Hex-1-ynyl)-N-phenylbenzamide (1f): yield 3.20 g, starting from
crude 2-iodo-N-phenylbenzamide and 1-hexyne (70%); yellow solid;
mp 56−57 °C; IR (KBr) ν = 3467 (m, br), 3315 (s), 2959 (w), 2927
(m), 2858 (w), 2225 (vw), 1664 (s), 1597 (m), 1524 (m), 1436 (m),
1322 (m), 892 (w), 756 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ =
9.40 (s, br, 1 H), 8.13−8.00 (m, 1 H), 7.66 (d, J = 7.9, 1 H), 7.53−7.43
(m, 1 H), 7.43−7.27 (m, 5 H), 7.12 (t, J = 7.3, 1 H), 2.49 (t, J = 7.0, 2
H), 1.64−1.50 (m, 2 H), 1.50−1.34 (m, 2 H), 0.87 (t, J = 7.0, 3 H);
13C NMR (75 MHz, CDCl3) δ = 164.5, 138.1, 135.6, 133.7, 130.7,
130.1, 129.0, 128.3, 124.4, 120.3, 120.1, 98.4, 79.2, 30.6, 22.1, 19.4,
13.5; GC−MS m/z = 277 (100) [M+], 262 (4), 248 (38), 235 (86),
185 (89), 167 (11), 143 (39), 128 (18), 115 (51). Anal. Calcd for
C19H19NO (277.36): C, 82.28; H, 6.90; N, 5.05. Found: C, 82.30; H,
6.88; N, 5.07 .
(m), 1323 (m), 921 (w), 889 (w), 759 (s), 687 (s) cm−1; H NMR
(300 MHz, CDCl3) δ = 9.20 (s, br, 1 H), 8.20−8.12 (m, 1 H), 7.72−
7.60 (m, 3 H), 7.54−7.46 (m, 4 H), 7.44−7.30 (m, 5 H), 7.20−7.10
(m, 1 H); 13C NMR (75 MHz, CDCl3) δ = 164.4, 138.1, 136.1, 133.5,
131.7, 130.8, 130.3, 129.5, 129.3, 129.1, 128.6, 124.5, 122.0, 120.1,
119.7, 96.6, 87.3; GC−MS m/z = 297 (26) [M+], 269 (9), 268 (11),
205 (100), 177 (21), 176 (45), 151 (17). Anal. Calcd for C21H15NO
(297.35): C, 84.82; H, 5.08; N, 4.71. Found: C, 84.80; H, 5.05; N,
4.70.
2-(2-Cyclohexenylethynyl)-N-phenylbenzamide (1j): yield 3.28 g,
starting from crude 2-iodo-N-phenylbenzamide and 1-ethynylcyclohex-
1-ene (66%); yellow solid; mp 97−98 °C (lit.8e mp 99−100 °C); IR
(KBr) ν = 3450 (m, br), 3299 (m), 2929 (s), 2858 (m), 2200 (vw),
1667 (vs), 1601 (w), 1539 (m), 1496 (m), 1440 (m), 1386 (m), 1323
(m), 1255 (m), 1094 (m), 759 (m) cm−1; 1H NMR (300 MHz,
CDCl3) δ = 9.33 (s, br, 1 H), 8.17−8.09 (m, 1 H), 7.69 (d, J = 7.7, 2
H), 7.55−7.48 (m, 1 H), 7.46−7.32 (m, 4 H), 7.19−7.10 (m, 1 H),
6.31−6.22 (m, 1 H), 2.27−2.07 (m, 4 H), 1.72−1.52 (m, 4 H); 13C
NMR (75 MHz, CDCl3) δ = 164.3, 138.1, 137.5, 135.4, 133.5, 130.8,
130.4, 129.0, 128.6, 124.4, 119.9, 98.9, 84.9, 29.0, 25.9, 22.2, 21.4;
GC−MS m/z = 301 (54) [M+], 272 (5), 209 (100), 194 (8), 178 (9),
165 (34), 152 (17), 143 (12), 139 (7), 115 (10). Anal. Calcd for
C21H19NO (301.38): C, 83.69; H, 6.35; N, 4.65. Found: C, 83.70; H,
6.36; N, 4.62.
N-Butyl-2-(2-cyclohexenylethynyl)benzamide (1k): yield 2.69 g,
starting from crude N-butyl-2-iodo-benzamide and 1-ethynylcyclohex-
1-ene (58%); yellow solid; mp 89−90 °C; IR (KBr) ν = 3446 (m, br),
3286 (m), 2928 (m), 2858 (w), 2205 (vw), 1636 (s), 1566 (m), 1434
1
(m), 1311 (m), 1143 (w), 765 (m), 711 (w) cm−1; H NMR (300
MHz, CDCl3) δ = 8.09−8.02 (m, 1 H), 7.47 (s, br, 1 H), 7.50−7.43
(m, 1 H), 7.41−7.33 (m, 2 H), 6.30−6.15 (m, 1 H), 3.53−3.44 (m, 2
H), 2.28−2.12 (m, 4 H), 1.78−1.54 (m, 6 H), 1.53−1.38 (m, 2 H),
0.95 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ = 166.2, 136.7,
135.3, 133.4, 130.2, 130.1, 128.3, 120.2, 120.0, 97.6, 85.3, 39.9, 31.7,
29.0, 25.9, 22.2, 21.4, 20.3, 13.8; GC−MS m/z = 281 (98) [M+], 264
(15), 252 (22), 238 (46), 225 (54), 224 (50), 209 (86), 197 (86), 181
(49), 165 (100), 152 (56), 139 (22), 130 (29), 115 (33), 102 (15), 97
(12), 77 (20). Anal. Calcd for C19H23NO (281.39): C, 81.10; H, 8.24;
N, 4.98. Found: C, 81.08; H, 8.26; N, 4.97 .
Deprotection Step To Give N-Substituted 2-Ethynylbenzamides
1a−d. To a solution of 2-[2-(trimethylsilyl)ethynyl]benzamide
obtained as described above (5.14 mmol; N-butyl-2-[2-
(trimethylsilyl)ethynyl]benzamide, 1.4 g; N-tert-butyl-2-[2-
(trimethylsilyl)ethynyl]benzamide, 1.4 g; N-phenyl-2-[2-
(trimethylsilyl)ethynyl]benzamide, 1.5 g; N-benzyl-2-[2-
(trimethylsilyl)ethynyl]benzamide, 1.6 g) in MeOH (25 mL) was
added KF (1.06 g, 18.2 mmol), and the resulting mixture was allowed
to stir at room temperature for 2 h. The solvent was evaporated, and
the residue was taken up with Et2O (40 mL) and washed with water
(40 mL). The aqueous layer was extracted with Et2O (3 × 40 mL),
and the collected organic phases were dried over MgSO4. After
filtration, the solvent was evaporated to give the N-substituted 2-
ethynylbenzamide, which was sufficiently pure for the carbonylation
reactions.
N-Butyl-2-(hex-1-ynyl)benzamide (1g): yield 2.84 g, starting from
crude N-butyl-2-iodo-benzamide and 1-hexyne (67%); yellow solid;
mp 52−54 °C (lit.21 mp 57−60 °C); IR (KBr) ν = 3278 (m, br), 2953
(m), 2935 (m), 2861 (w), 2225 (vw), 1649 (s), 1548 (m), 1469 (w),
1435 (m), 1313 (m), 763 (s) cm−1; 1H NMR (300 MHz, CDCl3) δ =
8.14−8.04 (m, 1 H), 7.63 (s, br, 1 H), 7.54−7.46 (m, 1 H), 7.45−7.36
(m, 2 H), 3.52 (q, J = 6.7, 2 H), 2.51 (t, J = 6.7, 2 H), 1.78−1.60 (m, 4
H), 1.59−1.45 (m, 4 H), 1.00 (t, J = 7.3, 6 H); 13C NMR (75 MHz,
CDCl3) δ = 166.3, 135.4, 133.7, 130.2, 130.0, 128.1, 120.2, 97.2, 79.6,
39.8, 31.7, 30.6, 22.1, 20.3, 19.4, 13.8, 13.6; GC−MS m/z = 257 (99)
[M+], 242 (10), 228 (77), 215 (100), 200 (18), 185 (33), 172 (54),
158 (52), 143 (25), 128 (21), 115 (51), 103 (8), 77 (8). Anal. Calcd
for C17H23NO (257.37): C, 79.33; H, 9.01; N, 5.44. Found: C, 79.30;
H, 9.02; N, 5.41.
N-Benzyl-2-(hex-1-ynyl)benzamide (1h):19 yield 3.27 g, starting
from crude N-benzyl-2-iodobenzamide and 1-hexyne (68%); yellow
solid; mp 40−41 °C; IR (KBr) ν = 3378 (m, br), 3311 (m, br), 2956
(m), 2935 (m), 2871 (w), 2227 (vw), 1651 (s), 1595 (w), 1531 (s),
1455 (w), 1298 (m), 1154 (w), 757 (m), 699 (m) cm−1; H NMR
1
N-Butyl-2-ethynylbenzamide (1a): yield 0.941 g, starting from 1.40
g of N-butyl-2-[2-(trimethylsilyl)ethynyl]benzamide (91%); yellow
solid; mp 53−54 °C (lit.16 mp 58−60 °C); IR (KBr) ν = 3296 (s, br),
3253 (s, br), 2950 (m), 2869 (m), 2106 (vw), 1655 (s), 1547 (s),
1468 (m), 1351 (m), 1258 (m), 1151 (m), 1099 (w), 942 (w), 856
(w), 761 (m), 694 (s) cm−1; 1H NMR (300 MHz, CDCl3) δ = 7.97−
7.90 (m, 1 H), 7.57−7.52 (m, 1 H), 7.47−7.35 (m, 2 H), 6.88 (s, br, 1
H), 3.48 (s, 1 H), 3.47 (q, J = 6.6, 2 H), 1.68−1.55 (m, 2 H), 1.51−
1.36 (m, 2 H), 0.95 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ =
166.2, 137.1, 134.0, 130.2, 129.7, 129.3, 118.4, 83.3, 82.3, 39.9, 31.4,
20.3, 13.7; GC−MS m/z = 201 (absent) [M+], 200 (2), 186 (7), 172
(9), 159 (26), 158 (26), 146 (12), 145 (60), 130 (21), 129 (100), 102
(300 MHz, CDCl3) δ = 8.16−8.08 (m, 1 H), 8.04 (s, br, 1 H), 7.48−
7.22 (m, 8 H), 4.66 (d, J = 5.4, 2 H), 2.14 (t, J = 6.8, 2 H), 1.45−1.23
(m, 4 H), 0.86 (t, J = 7.0, 3 H); 13C NMR (75 MHz, CDCl3) δ =
166.0, 138.1, 134.7, 133.6, 130.5, 130.2, 128.7, 128.1, 128.0, 127.5,
120.3, 97.8, 79.5, 44.3, 30.3, 22.1, 19.1, 13.5; GC−MS m/z = 291 (9)
[M+], 262 (5), 249 (42), 231 (8), 200 (92), 182 (9), 172 (11), 158
(65), 143 (11), 132 (18), 115 (38), 91 (100). Anal. Calcd for
C20H21NO (291.39): C, 82.44; H, 7.26; N, 4.81. Found: C, 82.47; H,
7.23; N, 4.84.
N-Phenyl-2-(2-phenylethynyl)benzamide (1i): yield 2.83 g, starting
from crude N-phenyl-2-iodobenzamide and phenylacetylene (58%);
white solid; mp 153−154 °C (lit.22 mp 151−153 °C); IR (KBr) ν =
3512
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(11), 101 (45), 75 (18). Anal. Calcd for C13H15NO (201.26): C,
77.58; H, 7.51; N, 6.96. Found: C, 77.61; H, 7.54; N, 6.97.
(t, J = 7.5, 2 H)], 3.88−3.55 [Z (m, 10 H) + E (m, 8 H)], 1.73−1.58
[Z (m, 2 H)], 1.58−1.23 [E (m, 4 H) + Z (m, 2 H)], 1.01−0.88 [Z
(m, 3 H) + E (m, 3 H)]; 13C NMR (75 MHz, CDCl3) δ = 168.1,
166.7, 165.3, 164.8, 142.2, 139.9, 137.2, 134.0, 132.5, 132.2, 130.4,
130.14, 130.07, 128.4, 124.7, 123.4, 123.1, 119.5, 99.5, 96.4, 66.8, 66.7,
66.6, 47.2, 47.1, 42.1, 41.9, 40.7, 39.2, 30.7, 30.3, 20.2, 20.0, 13.9, 13.8;
GC−MS m/z = 314 (12) [M+], 271 (5), 228 (100), 210 (11), 200
(48), 186 (11), 172 (32), 159 (12), 158 (12), 146 (6), 130 (34), 114
(4), 102 (8), 89 (7). Anal. Calcd for C18H22N2O3 (314.38): C, 68.77;
H, 7.05; N, 8.91. Found: C, 68.80; H, 7.04; N, 8.89.
N-Benzyl-2-ethynylbenzamide (1b): yield 1.16 g, starting from 1.60
g of N-benzyl-2-[2-(trimethylsilyl]ethynyl]benzamide (96%); colorless
solid; mp 87−88 °C; IR (KBr) ν = 3286 (s, br), 3062 (w), 2112 (vw),
1643 (s), 1543 (m), 1428 (w), 1310 (m), 1239 (w), 764 (m), 701
(m), 669 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 7.98−7.91 (m,
1 H), 7.55−7.20 (m, 9 H), 4.65 (d, J = 5.6, 2 H), 3.32 (s, 1 H); 13C
NMR (75 MHz, CDCl3) δ = 166.2, 137.9, 136.6, 134.0, 130.4, 129.7,
129.3, 128.6, 127.9, 127.5, 118.6, 83.6, 82.1, 44.3 ; GC−MS m/z = 235
(61) [M+], 234 (79), 218 (67), 216 (27), 189 (30), 130 (25), 129
(69), 102 (54), 101 (100), 91 (72), 77 (24), 75 (47), 65 (24), 51 (33).
Anal. Calcd for C16H13NO (235.28): C, 81.68; H, 5.57; N, 5.95.
Found: C, 81.65; H, 5.56; N, 5.98.
2-Benzyl-3-(2-morpholino-2-oxoethylidene)isoindolin-1-one
(3ba): yield 202.7 mg, starting from 165.0 mg of N-benzyl-2-
ethynylbenzamide (83%) (mixture of diastereoisomers Z/E, Z/E ratio
1
ca. 2.2, determined by H NMR); colorless solid; mp 95−96 °C; IR
(KBr) ν = 3441 (m, br), 2964 (w), 2922 (m), 2856 (w), 1714 (s),
2-Ethynyl-N-phenylbenzamide (1c): yield 1.00 g, starting from
1.50 g of N-phenyl-2-[2-(trimethylsilyl)ethynyl]benzamide (88%);
yellow solid; mp 94−97 °C (lit.20 mp 95−98 °C); IR (KBr) ν = 3282
(s, br), 3130 (w), 2107 (vw), 1647 (s), 1596 (m), 1538 (m), 1491
(w), 1446 (m), 1326 (m), 1256 (w), 754 (m), 675 (m), 633 (m)
1647 (s), 1433 (m), 1272 (w), 1233 (w), 1115 (m), 968 (w), 696 (m)
1
cm−1; H NMR (300 MHz, CDCl3) δ = 8.19−8.11 [Z (m, 1 H) + E
(m, 1 H)], 7.97−7.88 [Z (m, 1 H) + E (m, 1 H)], 7.70−7.51 [Z (m, 2
H) + E (m, 2 H)], 7.38−7.18 [Z (m, 4 H) + E (m, 4 H)], 7.09−7.00
[Z (m, 1 H) + E (m, 1 H)], 5.94 [E (s, 1 H)], 5.63 [Z (s, 1 H)], 5.35
[E (s, 2 H)], 5.04 [Z (s, 2 H)], 3.79−3.53 [Z (m, 6 H) + E (m, 6 H)],
3.53−3.32 [Z (m, 2 H) + E (m, 2 H)]; 13C NMR (75 MHz, CDCl3) δ
= 168.3, 166.9, 164.8, 164.3, 160.9, 141.6, 139.7, 137.32, 137.28, 136.4,
134.0, 132.8, 132.5, 130.6, 130.3, 129.8, 128.9, 128.6, 128.5, 127.7,
127.6, 127.2, 126.9, 126.7, 126.4, 125.2, 123.9, 123.5, 119.6, 66.7, 66.6,
66.2, 65.9, 47.2, 46.7, 43.8, 43.3; GC−MS m/z = 348 (17) [M+], 262
(100), 234 (35), 172 (3), 91 (98), 65 (10). Anal. Calcd for
C21H20N2O3 (348.40): C, 72.40; H, 5.79; N, 8.04. Found: C, 72.38; H,
5.81; N, 8.07.
1
cm−1; H NMR (500 MHz, CDCl3) δ = 9.00 (s, br, 1 H), 8.07−8.02
(m, 1 H), 7.67 (d, J = 7.9, 2 H), 7.63−7.58 (m, 1 H), 7.51−7.43 (m, 2
H), 7.37 (t, J = 7.9, 2 H), 7.19−7.13 (m, 1 H), 3.59 (s, 1 H); 13C
NMR (126 MHz, CDCl3) δ = 164.2, 138.0, 136.9, 134.2, 130.8, 130.1,
129.6, 129.1, 124.6, 120.1, 118.4, 84.3, 82.0; GC−MS m/z = 221 (99)
[M+], 220 (100), 193 (16), 178 (5), 165 (34), 152 (5), 130 (4), 102
(6), 95 (10), 77 (18), 51 (15). Anal. Calcd for C15H11NO (221.25): C,
81.43; H, 5.01; N, 6.33. Found: C, 81.40; H, 5.02; N, 6.31.
N-tert-Butyl-2-ethynylbenzamide (1d): yield 0.88 g, starting from
1.40 g of N-tert-butyl-2-[2-(trimethylsilyl)ethynyl]benzamide (85%);
yellow solid; mp 62.5−63.5 °C; IR (KBr) ν = 3260 (s, br), 3069 (m),
2966 (m), 2106 (vw), 1634 (s), 1550 (s), 1448 (m), 1391 (w), 1364
(Z)-3-(2-Morpholino-2-oxoethylidene)-2-phenylisoindolin-1-one
(3ca-Z): yield 201.6 mg, starting from 155.0 mg of 2-ethynyl-N-
phenylbenzamide (86%); yellow solid; mp 133−134 °C; IR (KBr) ν =
3010 (w), 2969 (m), 2923 (m), 2856 (w), 1716 (s), 1652 (m), 1500
(w), 1472 (w), 1392 (m), 1237 (m), 1117 (m), 1043 (m), 979 (w),
1
(m), 1227 (s), 953 (w), 877 (m), 754 (s), 654 (m) cm−1; H NMR
(300 MHz, CDCl3) δ = 7.95−7.89 (m, 1 H), 7.56−7.50 (m, 1 H),
7.46−7.33 (s, 2 H), 7.03 (s, br, 1 H), 3.49 (s, 1 H), 1.47 (s, 9 H); 13C
NMR (75 MHz, CDCl3) δ = 165.4, 138.1, 133.9, 130.0, 129.4, 129.3,
118.3, 83.4, 82.3, 52.1, 28.7; GC−MS m/z = 201 (2) [M+], 186 (10),
158 (2), 145 (95), 129 (100), 117 (5), 101 (45), 75 (19). Anal. Calcd
for C13H15NO (201.26): C, 77.58; H, 7.51; N, 6.96. Found: C, 77.61;
H, 7.54; N, 6.95.
1
753 (s), 699 (m) cm−1; H NMR (300 MHz, CDCl3) δ = 8.24−8.18
(m, 1 H), 7.98−7.92 (m, 1 H), 7.70−7.41 (m, 5 H), 7.39−7.32 (m, 2
H), 5.64 (s, 1 H), 3.81−3.69 (m, 4 H), 3.64−3.56 (m, 2 H), 3.47−3.38
(m, 2 H); 13C NMR (75 MHz, CDCl3) δ = 166.4, 165.2, 144.2, 134.0,
133.9, 133.0, 130.9, 129.8, 128.9, 128.7, 125.1, 123.7, 101.4, 66.8, 47.0,
42.1; GC−MS m/z = 334 (7) [M+], 248 (100), 221 (11), 202 (3), 191
(7), 165 (23), 101 (3), 89 (3), 77 (10). Anal. Calcd for C20H18N2O3
(334.37): C, 71.84; H, 5.43; N, 8.38. Found: C, 71.86; H, 5.43; N,
8.36.
General Procedure for the PdI2-Catalyzed Aminocarbonyla-
tion−N-Heterocyclization of 2-Ethynylbenzamides 1a−e To
Give Carbonylated Isoindolinone Derivatives 3 (Table 1). A 250
mL stainless steel autoclave was charged in the presence of air with
PdI2 (5.0 mg, 1.39 × 10−2 mmol), KI (23.0 mg, 1.39 × 10−1 mmol),
and a solution of 1 [1a (141 mg), 1b (165 mg), 1c (155 mg), 1d (141
mg), 1e (102 mg); 0.70 mmol] in a 2:1 mixture MeCN−amine
(MeCN: 9.4 mL; amine 2: 4.6 mL). The autoclave was sealed, and
while the mixture was stirred, the autoclave was pressurized with CO
(32 atm) and air (up to 40 atm). After being stirred at 100 °C for the
required time (see Table 1), the autoclave was cooled, degassed, and
opened. When necessary, the mixture was filtered (to remove the solid
oxamide byproduct deriving from double carbonylation of 2) and the
solid washed with cold Et2O. The solvent was evaporated, and the
products were purified by column chromatography on silica gel to give
pure carbonylated isoindolinones 3 (eluent: chloroform for 3aa; 7:3
hexane−AcOEt for 3ca-Z and 3da-E; 8:2 hexane−AcOEt for 3ea-Z;
9:1 hexane−AcOEt for 3db-E) or neutral alumina (eluent: 8:2
hexane−AcOEt for 3ba; 7:3 hexane−AcOEt for 3ab and 3ad; 9:1
hexane−AcOEt for 3ac; 99:1 hexane−AcOEt for 3dc-E). In the case of
3aa, 3ba, 3ab, and 3ac an inseparable mixture of the Z and E
diastereoisomers was obtained. In the case of 3ad, it was possible to
separate the Z and E isomers (order of elution: E, Z).
(E)-2-tert-Butyl-3-(2-morpholino-2-oxoethylidene)isoindolin-1-
one (3da-E): yield 205.0 mg, starting from 141.0 mg of N-tert-butyl-2-
ethynylbenzamide (93%); colorless solid; mp 145−146 °C; IR (KBr)
ν = 2979 (w), 2954 (w), 2855 (w), 1708 (s), 1637 (vs), 1433 (m),
1374 (w), 1301 (w), 1232 (m), 1115 (m), 1020 (w), 772 (m), 699
1
(w) cm−1; H NMR (300 MHz, CDCl3) δ = 7.79−7.71 (m, 2 H),
7.56−7.43 (m, 2 H), 6.14 (s, 1 H), 3.86−3.52 (m, 8 H), 1.78 (s, 9 H);
13C NMR (75 MHz, CDCl3) δ = 166.1, 160.9, 141.0, 134.4, 132.3,
130.0, 128.1, 122.99, 122.97, 104.5, 67.3, 66.5, 57.8, 42.1, 40.7, 30.3;
GC−MS m/z = 314 (6) [M+], 258 (3), 228 (2), 200 (10), 172 (100),
145 (13), 130 (28), 114 (8), 102 (6), 86 (22). Anal. Calcd for
C18H22N2O3 (314.38): C, 68.77; H, 7.05; N, 8.91. Found: C, 68.80; H,
7.03; N, 8.90.
(Z)-3-(2-Morpholino-2-oxoethylidene)isoindolin-1-one (3ea-Z):
yield 117.7 mg, starting from 102.0 mg of 2-ethynylbenzamide
(65%); colorless solid; mp 186−187 °C; IR (KBr) ν = 3412 (s, br),
1711 (s), 1647 (s), 1583 (w), 1399 (m), 1238 (m), 1120 (m), 758 (w)
cm−1; 1H NMR (300 MHz, CDCl3) δ = 10.34 (s, br, 1 H), 7.90−7.83
(s, 1 H), 7.73−7.65 (m, 1 H), 7.64−7.54 (m, 2 H), 6.06 (s, 1 H),
3.83−3.55 (m, 8 H); 13C NMR (75 MHz, CDCl3) δ = 168.2, 166.0,
146.7, 137.0, 132.5, 131.2, 131.0, 129.7, 124.0, 120.5, 89.0, 66.9, 46.9,
45.8; GC−MS m/z = 258 (22) [M+], 172 (100), 145 (16), 130 (45),
102 (15), 89 (28), 86 (41). Anal. Calcd for C14H14N2O3 (258.27): C,
65.11; H, 5.46; N, 10.85. Found: C, 65.10; H, 5.45; N, 10.87.
2-Butyl-3-[2-oxo-2-(piperidin-1-yl)ethylidene]isoindolin-1-one
(3ab): yield 197.1 mg, starting from 141.0 mg of N-butyl-2-
ethynylbenzamide (90%) (mixture of diastereoisomers Z/E, Z/E
2-Butyl-3-(2-morpholino-2-oxoethylidene)isoindolin-1-one (3aa):
yield 178.4 mg, starting from 141.0 mg of N-butyl-2-ethynylbenzamide
(81%) (mixture of diastereoisomers Z/E, Z/E ratio ca. 2.0, determined
by 1H NMR); pale yellow oil; IR (film) ν = 2960 (m), 2928 (m), 1712
(s), 1684 (vs), 1435 (m), 1400 (w), 1231 (m), 1115 (m), 1040 (w),
769 (m), 699 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 8.12−8.01
[Z (m, 1 H)], 7.88−7.76 [Z (m, 1 H) + E (m, 1 H)], 7.70−7.46 [Z
(m, 2 H) + E (m, 3 H)], 6.01 [E (s, 1 H)], 5.81 [Z (s, 1 H)], 4.02 [E
3513
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1
ratio ca. 1.0, determined by H NMR); pale yellow oil; IR (film) ν =
1.73−1.12 (m, 12 H), 1.05−0.62 (m, 9 H); 13C NMR (75 MHz,
CDCl3) δ = 166.0, 157.8, 141.7, 138.7, 132.4, 130.2, 129.9, 125.3,
123.0, 101.1, 47.2, 40.6, 39.3, 32.6, 30.9, 20.3, 20.2, 20.1, 13.9, 13.85,
13.76; GC−MS m/z = 356 (20) [M+], 327 (5), 313 (5), 299 (3), 228
(100), 210 (11), 201 (49), 186 (20), 172 (37), 159 (44), 146 (10),
130 (42), 102 (9). Anal. Calcd for C22H32N2O2 (356.50): C, 74.12; H,
9.05; N, 7.86. Found: C, 74.11; H, 9.07; N, 7.85.
(E)-N,N-Dibutyl-2-(2-butyl-3-oxoisoindolin-1-ylidene)acetamide
(3ad-E): yield 119.7 mg, starting from 141.0 mg of N-butyl-2-
ethynylbenzamide (48%); yellow oil; IR (film) ν = 2958 (m), 2931
(m), 2873 (m), 1716 (m), 1628 (s), 1533 (m), 1467 (m), 1376 (w),
1295 (w), 1219 (w), 1095 (w) cm−1; 1H NMR (300 MHz, CDCl3) δ
= 7.81−7.75 (m, 1 H), 7.72−7.40 (m, 3 H), 6.04 (s, 1 H), 3.52−3.01
(m, 6 H), 2.72−1.15 (m, 12 H), 1.10−0.52 (m, 9 H); 13C NMR (75
MHz, CDCl3) δ = 165.6, 157.8, 139.0, 137.7, 132.1, 129.9, 125.5,
123.4, 119.3, 97.8, 47.1, 40.6, 32.6, 30.9, 20.4, 20.3, 13.88. 13.83; GC−
MS m/z = 356 (19) [M+], 327 (5), 313 (5), 228 (100), 210 (11), 201
(51), 186 (21), 172 (37), 159 (44), 146 (10), 130 (42), 102 (8). Anal.
Calcd for C22H32N2O2 (356.50): C, 74.12; H, 9.05; N, 7.86. Found: C,
74.10; H, 9.06; N, 7.83.
General Procedure for the Synthesis of 3-[(Alkoxycarbonyl)-
methylene]isobenzofuran-1(3H)imines 4 by PdI2-Catalyzed O-
Heterocyclization−Alkoxycarbonylation of 2-Alkynylbenza-
mides 1a−d and 1f−k (Table 2). A 250 mL stainless steel autoclave
was charged in the presence of air with PdI2 (5.0 mg, 1.39 × 10−2
mmol), KI (23.0 mg, 1.39 × 10−1 mmol), and a solution of 1 [1a (141
mg), 1b (165 mg), 1c (155 mg), 1d (141 mg), 1f (194 mg), 1g (180
mg), 1h (204 mg), 1i (208 mg), 1j (211 mg), 1k (197 mg); 0.70
mmol] in a ROH/HC(OR)3 mixture [R = Me, Et; ROH: 11.6 mL;
HC(OR)3: 23.1 mL]. The autoclave was sealed, and while the mixture
was stirred, the autoclave was pressurized with CO (32 atm) and air
(up to 40 atm). After being stirred at 100 °C for the required time (see
Table 2), the autoclave was cooled, degassed, and opened. The solvent
was evaporated, and the products were purified by column
chromatography on neutral alumina to give pure 3-[(alkoxycarbonyl)-
methylene]isobenzofuran-1(3H)imines 4 (eluent: 95:5 hexane−
AcOEt for 4a-E, 4c-E, 4d-E, 4f, 4f′, 4g, 4h, 4i-E, 4j-E, and 4k-E; 9:1
hexane−AcOEt for 4a′-E and 4b-E).
2934 (m), 2956 (m), 1713 (s), 1652 (vs), 1470 (m), 1252 (m), 1023
(m), 953 (w), 770 (m), 698 (w) cm−1; 1H NMR (300 MHz, CDCl3) δ
= 8.03−7.96 [Z (m, 1 H)], 7.86−7.77 [Z (m, 1 H) + E (m, 1 H)],
7.69−7.62 [E (m, 1 H)], 7.61−7.46 [Z (m, 2 H) + E (m, 2 H)], 6.04
[E (s, 1 H)], 5.83 [Z (s, 1 H)], 3.99 [E (t, J = 7.6, 2 H)], 3.83−3.49 [Z
(m, 6 H) + E (m, 4 H)], 1.75−1.24 [E (m, 10 H) + Z (m, 10 H)],
0.96 [Z or E (t, J = 7.3, 3 H)], 0.92 [Z or E (t, J = 7.3, 3 H)]; 13C
NMR (75 MHz, CDCl3) δ = 168.1, 166.8, 165.0, 164.5, 140.9, 138.7,
137.4, 134.3, 132.3, 132.0, 130.1, 129.9, 124.5, 123.3, 123.1, 119.4,
111.7, 109.4, 101.0, 97.9, 48.0, 47.9, 42.8, 42.5, 40.7, 39.2, 30.7, 30.4,
26.7, 26.4, 25.8, 25.5, 24.58, 24.53, 20.2, 20.1, 13.82, 13.78; GC−MS
m/z = 312 (35) [M+], 283 (3), 269 (13), 239 (8), 228 (100), 210
(17), 201 (59), 200 (69), 186 (30), 172 (56), 159 (67), 146 (13), 130
(69), 112 (11), 102 (18), 84 (72). Anal. Calcd for C19H24N2O2
(312.41): C, 73.05; H, 7.74; N, 8.97. Found: C, 73.07; H, 7.71; N,
8.94.
(E)-2-tert-Butyl-3-[2-oxo-2-(piperidin-1-yl)ethylidene]isoindolin-
1-one (3db-E): yield 166.2 mg, starting from 141.0 mg of N-tert-butyl-
2-ethynylbenzamide (76%); colorless solid; mp 135−136 °C; IR
(KBr) ν = 3446 (m, br), 2987 (m), 2938 (m), 2857 (w), 2257 (m),
1713 (m), 1634 (s), 1443 (m), 1373 (m), 1232 (m), 1110 (m), 1023
(m), 756 (m), 696 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ = 7.80−
7.70 (m, 2 H), 7.55−7.40 (m, 2 H), 6.19 (s, 1 H), 3.85−3.70 (m, 2 H),
3.57−3.42 (m, 2 H), 1.78 (s, 9 H), 1.74−1.60 (m, 4 H), 1.60−1.40
(m, 2 H)]; 13C NMR (75 MHz, CDCl3) δ = 167.8, 165.6, 139.9,
134.6, 132.1, 130.6, 129.6, 123.1, 122.8, 106.0, 57.7, 48.0, 42.6, 30.4,
26.7, 25.5, 24.6; GC−MS m/z = 312 (17) [M+], 256 (10), 255 (10),
200 (55), 172 (100), 145 (22), 130 (30), 112 (11), 84 (80). Anal.
Calcd for C19H24N2O2 (312.41): C, 73.05; H, 7.74; N, 8.97. Found: C,
73.04; H, 7.72; N, 8.99.
2-Butyl-3-[2-oxo-2-(pyrrolidin-1-yl)ethylidene]isoindolin-1-one
(3ac): yield 180.0 mg, starting from 141.0 mg of N-butyl-2-
ethynylbenzamide (86%) (mixture of diastereoisomers Z/E, Z/E
ratio ca. 1.8, determined by 1H NMR); yellow oil; IR (film) ν = 2952
(m), 2915 (w), 2871 (m), 1712 (s), 1652 (s), 1616 (s), 1432 (m),
1398 (m), 1346 (m), 1190 (w), 1092 (w), 943 (w), 768 (m), 696 (m)
cm−1; H NMR (300 MHz, CDCl3) δ = 8.61−8.53 [Z (m, 1 H) + E
1
(E)-Methyl 2-[3-(butylimino)isobenzofuran-1(3H)-ylidene]acetate
(4a-E): yield 127.3 mg, starting from 141.0 mg of N-butyl-2-
ethynylbenzamide (70%); colorless solid; mp 106−107 °C; IR
(KBr) ν = 2957 (m), 2932 (m), 2873 (w), 1687 (m), 1646 (s),
1582 (s), 1459 (m), 1402 (m), 1316 (w), 1221 (m), 1142 (m), 768
(m, 1 H)], 7.89−7.78 [Z (m, 1 H) + E (m, 1 H)], 7.64−7.48 [Z (m, 2
H) + E (m, 2 H)], 6.01 [E (s, 1 H)], 5.83 [Z (s, 1 H)], 4.15−4.01 [E
(m, 2 H)], 3.81−3.71 [Z (m, 2 H)], 3.60−3.35 [Z (m, 4 H) + E (m, 4
H)], 2.10−1.62 [Z (m, 4 H) + E (m, 4 H)], 1.50−1.11 [Z (m, 4 H) +
E (m, 4 H)], 1.10−0.80 [Z (m, 3 H) + E (m, 3 H)]; 13C NMR (75
MHz, CDCl3) δ = 168.3, 167.1, 164.5, 164.4, 142.8, 138.9, 137.6,
134.2, 132.6, 132.1, 130.4, 130.1, 130.0, 128.6, 126.2, 123.4, 122.9,
119.4, 101.2, 98.3, 47.8, 47.6, 46.0, 45.8, 40.9, 39.2, 30.1, 29.7, 26.2,
26.1, 24.6, 24.5, 20.2, 20.0, 13.9, 13.8.; GC−MS m/z = 298 (23) [M+],
255 (24), 228 (100), 200 (50), 186 (10), 172 (33), 158 (12), 130
(32), 102 (11), 70 (16), 55 (11). Anal. Calcd for C18H22N2O2
(298.38): C, 72.46; H, 7.43; N, 9.39. Found: C, 72.49; H, 7.42; N,
9.38 .
(E)-2-tert-Butyl-3-[2-oxo-2-(pyrrolidin-1-yl)ethylidene]isoindolin-
1-one (3dc-E): yield 171.6 mg, starting from 141.0 mg of N-tert-butyl-
2-ethynylbenzamide (82%); yellow oil; IR (film) ν = 2970 (w), 2875
(w), 1709 (s), 1631 (s), 1614 (s), 1434 (m), 1367 (m), 1298 (w),
1266 (w), 1112 (w), 1023 (w), 1006 (w), 797 (m), 693 (w) cm−1; 1H
NMR (300 MHz, CDCl3) δ = 8.05−7.91 (m, 1 H), 7.81−7.65 (m, 1
H), 7.60−7.45 (m, 2 H), 6.23 (s, 1 H), 3.70−3.52 (m, 2 H), 3.51−3.40
(m, 2 H), 2.05−1.85 (m, 4 H), 1.79 (s, 9 H); 13C NMR (75 MHz,
CDCl3) δ = 165.3, 163.2, 141.0, 132.3, 129.8, 128.9, 125.8, 123.6,
122.7, 106.5, 47.6, 45.8, 30.4, 28.7, 26.1, 24.5; GC−MS m/z = 298
(17) [M+], 242 (7), 200 (46), 172 (100), 145 (14), 130 (27), 98 (12),
89 (10), 70 (51). Anal. Calcd for C18H22N2O2 (298.38): C, 72.46; H,
7.43; N, 9.39. Found: C, 72.48; H, 7.44; N, 9.37.
1
(m) cm−1; H NMR (300 MHz, CDCl3) δ = 9.09−9.00 (m, 1 H),
7.92−7.84 (m, 1 H), 7.68−7.56 (m, 2 H), 5.94 (s, 1 H), 3.80 (s, 3 H),
3.66 (t, J = 7.2, 2 H), 1.78−1.61 (m, 2 H), 1.52−1.37 (m, 2 H), 0.97
(t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ = 167.0, 161.8, 152.8,
133.7, 132.6, 132.1, 132.0, 127.7, 122.6, 96.6, 51.5, 47.9, 32.9, 20.6,
13.9; GC−MS m/z = 259 (35) [M+], 228 (13), 200 (100), 186 (29),
184 (26), 172 (29), 159 (44), 158 (83), 130 (41), 102 (16), 89 (18).
Anal. Calcd for C15H17NO3 (259.30): C, 69.48; H, 6.61; N, 5.40.
Found: C, 69.50; H, 6.58; N, 5.39 .
(E)-Ethyl 2-[3-(butylimino)isobenzofuran-1(3H)-ylidene]acetate
(4a′-E): yield 134.2 mg, starting from 141.0 mg of N-butyl-2-
ethynylbenzamide (70%); yellow solid; mp 57−58 °C; IR (KBr) ν =
2959 (w), 2929 (w), 1714 (m), 1640 (s), 1475 (w), 1398 (w), 1378
(w), 1249 (m), 1208 (m), 1144 (m), 1102 (m), 1051 (m), 851 (w),
781 (w), 669 (w) cm−1; 1H NMR (300 MHz, CDCl3) δ = 9.09−9.01
(m, 1 H), 7.92−7.85 (m, 1 H), 7.67−7.55 (m, 2 H), 5.95 (s, 1 H), 4.27
(q, J = 7.1, 2 H), 3.66 (t, J = 7.1, 2 H), 1.75−1.62 (m, 2 H), 1.51−1.37
(m, 2 H), 1.35 (t, J = 7.1, 3 H), 0.96 (t, J = 7.3, 3 H); 13C NMR (75
MHz, CDCl3) δ = 166.6, 161.6, 152.8, 133.8, 132.6, 132.04, 131.96,
127.7, 122.6, 97.2, 60.3, 47.9, 32.9, 20.6, 14.4, 13.9; GC−MS m/z =
273 (12) [M+], 244 (11), 230 (19), 200 (89), 186 (44), 172 (100),
159 (65), 145 (20), 130 (76), 102 (21), 89 (11). Anal. Calcd for
C16H19NO3 (273.33): C, 70.31; H, 7.01; N, 5.12. Found: C, 70.33; H,
7.02; N, 5.11.
(Z)-N,N-Dibutyl-2-(2-butyl-3-oxoisoindolin-1-ylidene)acetamide
(3ad-Z): yield 120.0 mg, starting from 141.0 mg of N-butyl-2-
ethynylbenzamide (48%); yellow oil; IR (film) ν = 2958 (m), 2931
(s), 2873 (m), 1714 (m), 1634 (s), 1532 (m), 1467 (m), 1091 (w)
(E)-Methyl 2-[3-(benzylimino)isobenzofuran-1(3H)-ylidene]-
acetate (4b-E): yield 123.4 mg, starting from 165.0 mg of N-benzyl-
2-ethynylbenzamide (60%); yellow solid mp 53−54 °C; IR (KBr) ν =
1
cm−1 ; H NMR (300 MHz, CDCl3) δ = 8.21−8.15 (m, 1 H), 7.85−
7.78 (m, 1 H), 7.61−7.46 (m, 2 H), 5.86 (s, 1 H), 3.61−3.05 (m, 6 H),
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2927 (m), 2854 (w), 1710 (s), 1648 (s), 1470 (m), 1385 (w), 1261
(m), 1208 (m), 1146 (m), 1109 (w), 1053 (m), 979 (m), 861 (m),
134.1, 132.45, 132.35, 130.8, 128.7, 128.6, 128.0, 127.5, 126.1, 125.1,
124.2, 123.7, 123.6, 123.4, 122.5, 113.9, 109.3, 61.4, 60.9, 31.8, 31.3,
29.4, 28.7, 22.6, 22.1, 14.3, 13.8, 13.7; GC−MS m/z = 349 (100)
[M+], 320 (9), 292 (18), 264 (25), 248 (10), 234 (23), 220 (13), 208
(16), 190 (12), 165 (15), 89 (13), 77 (30). Anal. Calcd for
C22H23NO3 (349.42): C, 75.62; H, 6.63; N, 4.01. Found: C, 75.64; H,
6.66; N, 3.99 .
1
775 (m), 735 (m), 705 (m), 669 (m), 626 (w) cm−1; H NMR (300
MHz, CDCl3) δ = 9.08−9.00 (m, 1 H), 7.97−7.89 (m, 1 H), 7.67−
7.54 (m, 2 H), 7.49−7.22 (m, 5 H), 5.99 (s, 1 H), 4.87 (s, 2 H), 3.80
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ = 166.8, 161.7, 153.6, 139.6,
133.8, 132.23, 132.16, 128.5, 127.9, 127.7, 126.9, 122.9, 97.2, 51.9,
51.5; GC−MS m/z = 293 (22) [M+], 262 (4), 234 (19), 232 (26), 130
(6), 102 (5), 91 (100), 65 (13). Anal. Calcd for C18H15NO3 (293.32):
C, 73.71; H, 5.15; N, 4.78. Found: C, 73.70; H, 5.12; N, 4.80.
(E)-Methyl 2-[3-(phenylimino)isobenzofuran-1(3H)-ylidene]-
acetate (4c-E): yield 113.6 mg, starting from 155.0 mg of 2-ethynyl-
N-phenylbenzamide (58%); yellow solid; mp 97−98 °C; IR (KBr) ν =
2939 (m), 1705 (s), 1647 (m), 1491 (w), 1379 (m), 1193 (w), 1138
(m), 847 (m), 762 (m), 692 (m) cm−1; 1H NMR (300 MHz, CDCl3)
δ = 9.10−9.03 (m, 1 H), 8.07−8.01 (m, 1 H), 7.73−7.62 (m, 2 H),
7.45−7.32 (m, 4 H), 7.24−7.16 (m, 1 H), 5.99 (s, 1 H), 3.80 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ = 166.6, 161.7, 151.8, 144.9, 133.4,
Methyl 2-[3-(butylimino)isobenzofuran-1(3H)-ylidene]hexanoate
(4g): yield 165.9 mg, starting from 180.0 mg of N-butyl-2-(hex-1-
ynyl)benzamide (75%) (mixture of diastereoisomers E/Z, E/Z ratio
1
ca. 6.2, determined by H NMR); colorless solid; mp 57−58 °C; IR
(KBr) ν = 2956 (m), 2929 (m), 2863 (m), 1723 (s), 1671 (s), 1629
(m), 1456 (m), 1429 (m), 1348 (m), 1312 (m), 1261 (w), 1207 (m),
1
1105 (m), 1059 (s), 768 (m), 667 (w) cm−1; H NMR (300 MHz,
CDCl3) δ = 8.51−8.45 [Z (m, 1 H)], 8.19−8.13 [E (m, 1 H)], 7.90−
7.84 [Z (m, 1 H)], 7.60−7.26 [E (m, 3 H), + Z (m, 2 H)], 3.92 [E (s,
3 H)], 3.87 [Z (s, 3 H)], 3.71−3.62 [Z (t, J = 7.3, 2 H)], 3.50 [E (t, J =
7.1, 2 H)], 2.71−2.61 [Z (m, 2 H)], 2.60 [E (t, J = 7.5, 2 H)], 1.77−
1.33 [E (m, 8 H) + Z (m, 8 H)], 1.01−0.91 [E (m, 6 H) + Z (m, 6
H)]; 13C NMR (75 MHz, CDCl3) δ = 167.2, 159.6, 148.5, 132.2,
131.7, 131.5, 130.7, 130.2, 129.6, 128.9, 127.7, 126.7, 126.1, 125.0,
123.5, 123.3, 122.7, 111.9, 108.3, 52.0, 46.0, 32.9, 32.2, 29.5, 22.3, 20.8,
14.0, 13.9, 13.8; GC−MS m/z = 315 (19) [M+], 286 (33), 284 (19),
272 (84), 259 (80), 226 (100), 217 (31), 214 (24), 198 (33), 185
(72), 184 (66), 170 (50), 158 (14), 143 (24), 130 (83), 115 (26), 102
(20), 85 (11). Anal. Calcd for C19H25NO3 (315.41): C, 72.35; H, 7.99;
N, 4.44. Found: C, 72.33; H, 8.00; N, 4.45 .
Methyl 2-[3-(benzylimino)isobenzofuran-1(3H)-ylidene]-
hexanoate (4h): yield 110.2 mg, starting from 204.0 mg of N-
benzyl-2-(hex-1-ynyl)benzamide (45%) (mixture of diastereoisomers
E/Z, E/Z ratio ca. 4.9, determined by 1H NMR) yellow oil; IR (film) ν
= 2956 (s), 2931 (m), 2871 (m), 1723 (s), 1666 (s), 1486 (m), 1435
(m), 1345 (m), 1309 (m), 1259 (m), 1206 (m), 1106 (m), 1049 (m),
734 (m), 698 (w) cm−1; 1H NMR (300 MHz, CDCl3) δ = 8.46 [Z (d,
J = 7.8, 1 H)], 8.30 [E (d, J = 7.7, 1 H)], 7.91 [Z (d, J = 7.3, 1 H)],
7.61−7.20 [E (m, 8 H), + Z (m, 7 H)], 4.87 [Z (s, 2 H)], 4.73 [E (s, 2
H)], 3.92 [E (s, 3 H)], 3.88 [Z (s, 3 H)], 2.69 [Z (t, J = 7.6, 2 H)],
2.61 [E (t, J = 7.6, 2 H)], 1.73−1.31 [E (m, 4 H) + Z (m, 4 H)], 1.00−
0.87 [E (m, 3 H) + Z (m, 3 H)]; 13C NMR (75 MHz, CDCl3) δ =
167.1, 159.4, 149.5, 140.7, 134.7, 134.4, 131.94, 131.86, 130.7, 130.2,
129.6, 128.5, 128.3, 127.9, 127.6, 126.9, 126.8, 126.5, 126.0, 125.0,
123.6, 122.9, 112.5, 108.7, 102.8, 52.1, 51.9, 50.8, 50.0, 32.2, 31.2, 29.5,
28.5, 22.6, 22.3, 13.9, 13.8; GC−MS Z: m/z = 349 (6) [M+] 318 (3),
293 (27), 261 (52), 232 (6), 130 (7), 91 (100); E: m/z = 349 (5), 318
(4), 293 (32), 261 (55), 207 (11), 193 (5), 130 (9), 117 (11), 91
(100). Anal. Calcd for C22H23NO3 (349.42): C, 75.62; H, 6.63; N,
4.01. Found: C, 75.61; H, 6.65; N, 4.02.
(E)-Methyl 2-phenyl-2-[3-(phenylimino)isobenzofuran-1(3H)-
ylidene]acetate (4i-E): yield 136.8 mg, starting from 208.0 mg of N-
phenyl-2-(2-phenylethynyl)benzamide (55%); yellow solid; mp 56−57
°C; IR (KBr) ν = 3019 (w), 1712 (s), 1691(s), 1613 (m), 1590 (m),
1489 (w), 1300 (w), 1268 (w), 1216 (m), 1053 (s), 1006 (m), 757
(s), 692 (w) cm−1; 1H NMR (300 MHz, CDCl3) δ = 8.29 (d, J = 7.1, 1
H), 8.07−8.02 (m, 1 H), 7.68−7.57 (m, 2 H), 7.50−7.43 (m, 2 H),
7.43−7.28 (m, 5 H), 7.26−7.19 (m, 2 H), 7.15−7.07 (m, 1 H), 3.89
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ = 167.8, 153.3, 151.8, 144.5,
134.1, 134.0, 132.4, 132.2, 131.2, 129.5, 128.6, 128.2, 127.9, 125.5,
125.2, 124.9, 123.7, 112.7, 52.5; GC−MS m/z = 355 (36) [M+], 324
(16), 296 (100), 295 (46), 267 (21), 246 (5), 219 (5), 190 (7), 165
(7), 77 (16). Anal. Calcd for C23H17NO3 (355.39): C, 77.73; H, 4.82;
N, 3.94. Found: C, 77.71; H, 4.85; N, 3.90.
132.9, 132.6, 132.2, 128.7, 127.6, 125.2, 123.9, 123.3, 98.1, 51.5; GC−
MS m/z = 279 (56) [M+], 248 (37), 236 (8), 220 (100), 191 (8), 165
(29), 96 (5), 77 (13). Anal. Calcd for C17H13NO3 (279.29): C, 73.11;
H, 4.69; N, 5.02. Found: C, 73.10; H, 4.69; N, 5.05.
(E)-Methyl 2-[3-(tert-butylimino)isobenzofuran-1(3H)-ylidene]-
acetate (4d-E): yield 127.2 mg, starting from 141.0 mg of N-tert-
butyl-2-ethynylbenzamide (70%); yellow solid; mp 68−69; IR (KBr) ν
= 2967 (m), 2870 (w), 1711 (s), 1644 (s), 1474 (m), 1364 (w), 1261
(m), 1206 (m), 1146 (s), 1046 (s), 976 (m), 860 (w), 778 (m), 678
1
(m) cm−1; H NMR (300 MHz, CDCl3) δ = 9.08−8.97 (m, 1 H),
7.91−7.81 (m, 1 H), 7.67−7.53 (m, 2 H), 5.94 (s, 1 H), 3.80 (s, 3 H),
1.44 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ = 167.0, 162.1, 149.4,
133.9, 132.9, 132.0, 131.8, 127.5, 123.0, 96.3, 55.1, 51.4, 30.5; GC−MS
m/z = 259 (9) [M+], 244 (35), 203 (23), 172 (100), 145 (37), 130
(35), 106 (11), 101 (10), 57 (35). Anal. Calcd for C15H17NO3
(259.30): C, 69.48; H, 6.61; N, 5.40. Found: C, 69.45; H, 6.60; N,
5.43 .
Methyl 2-[3-(phenylimino)isobenzofuran-1(3H)-ylidene]-
hexanoate (4f): yield 188.2 mg, starting from 194.0 mg of 2-(hex-1-
ynyl)-N-phenylbenzamide (80%) (mixture of diastereoisomers Z/E,
1
Z/E ratio ca. 1.4, determined by H NMR); yellow oil; IR (film) ν =
2955 (m), 2926 (s), 2857 (m), 1715 (s), 1660 (s), 1624 (m), 1593
(m), 1530 (w), 1489 (m), 1455 (m), 1347 (w), 1314 (w), 1262 (m),
1
1212 (s), 1119 (w), 1064 (m), 1041 (m), 762 (m), cm−1; H NMR
(300 MHz, CDCl3) δ = 8.56−8.48 [Z (m, 1 H)], 8.38 [E (d, J = 7.9, 1
H)], 8.07−8.01 [Z (m, 1 H)], 7.64−7.48 [Z (m, 2 H) + E (m, 2 H)],
7.43−7.30 [Z (m, 4 H), + E (m, 4 H)], 7.21−7.08 [Z (m, 1 H) + E
(m, 2 H)], 3.92 [E (s, 3 H)], 3.88 [Z (s, 3 H)], 2.60 [Z (t, J = 7.9, 2
H)], 2.51 [E (t, J = 7.3, 2 H)], 1.60−1.46 [Z (m, 2 H) + E (m, 2 H)],
1.45−1.24 [Z (m, 2 H) + E (m, 2 H)], 0.90 [Z (t, J = 7.3, 3 H)], 0.85
[E (t, J = 7.3, 3 H)]; 13C NMR (75 MHz, CDCl3) δ = 168.1, 166.8,
159.4, 155.5, 152.4, 148.6, 146.1, 145.2, 134.0, 132.5, 132.4, 131.0,
130.9, 128.71, 128.65, 128.1, 127.6, 126.2, 125.1, 124.2, 123.8, 123.7,
123.4, 122.5, 113.6, 109.1, 52.2, 52.0, 31.8, 31.4, 29.3, 28.8, 22.7, 22.1,
13.8, 13.7; GC−MS m/z = 335 (100) [M+], 320 (5), 304 (9), 293
(12), 278 (31), 261 (12), 233 (20), 208 (28), 190 (11), 165 (6), 114
(4), 77 (19). Anal. Calcd for C21H21NO3 (335.40): C, 75.20; H, 6.31;
N, 4.18. Found: C, 75.19; H, 6.33; N, 4.20 .
Ethyl 2-[3-(phenylimino)isobenzofuran-1(3H)-ylidene]hexanoate
(4f′): yield 203.2 mg, starting from 194.0 mg of 2-(hex-1-ynyl)-N-
phenylbenzamide (83%) (mixture of diastereoisomers Z/E, Z/E ratio
ca. 1.0, determined by 1H NMR); yellow oil. IR (film) ν = 2958 (m),
2925 (m), 1710 (s), 1664 (s), 1592 (s), 1489 (w), 1313 (w), 1262
(w), 1210 (m), 1064 (s), 764 (m) cm−1; 1H NMR (300 MHz, CDCl3)
δ = 8.57−8.50 [Z (m, 1 H)], 8.37 [E (d, J = 8.0, 1 H)], 8.06−8.00 [Z
(m, 1 H)], 7.65−7.50 [Z (m, 2 H) + E (m, 2 H)], 7.47−7.30 [Z (m, 4
H), + E (m, 4 H)], 7.23−7.16 [Z (m, 1 H) + E (m, 2 H)], 4.40 [Z or
E (q, J = 7.1, 2 H)], 4.35 [E or Z (q, J = 7.1, 2 H)], 2.66−2.56 [Z or E
(m, 2 H)], 2.51 [E or Z (d, J = 7.3, 2 H)], 1.62−1.47 [Z (m, 2 H) + E
(m, 2 H)], 1.45−1.22 [Z (m, 5 H) + E (m, 5 H)] 0.90 [Z or E (t, J =
7.3, 3 H)], 0.88 [E or Z (t, J = 7.3, 3 H)]; 13C NMR (75 MHz,
CDCl3) δ = 167.7, 166.4, 159.0, 155.2, 152.4, 148.5, 146.3, 145.3,
(E)-Methyl 2-cyclohexenyl-2-[3-(phenylimino)isobenzofuran-
1(3H)-ylidene]acetate (4j-E): yield 196.4 mg, starting from 211.0
mg of 2-(2-cyclohexenylethynyl)-N-phenylbenzamide (78%); yellow
solid; mp 189−190 °C; IR (KBr) ν = 2930 (s), 2958 (w), 1724 (s),
1660 (s), 1592 (m), 1489 (m), 1434 (m), 1347 (m), 1312 (m), 1221
1
(m), 1090 (m), 1057 (m), 771 (m), 694 (w) cm−1; H NMR (300
MHz, CDCl3) δ = 8.42−8.33 (m, 1 H), 7.60−7.51 (m, 1 H), 7.48−
7.29 (m, 4 H), 7.21−7.06 (m, 3 H), 6.10 (s, br, 1 H), 3.84 (s, 3 H),
2.19−2.03 (m, 4 H), 1.72−1.53 (m, 4 H); 13C NMR (75 MHz,
3515
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Article
CDCl3) δ = 167.6, 156.2, 148.4, 146.2, 132.5, 131.8, 131.3, 128.6,
128.3, 127.6, 124.6, 123.7, 123.4, 122.7, 108.3, 52.3, 25.63, 25.59, 22.2,
21.5; GC−MS m/z = 359 (100) [M+], 344 (10), 316 (14), 300 (10),
272 (8), 208 (7), 190 (10), 179 (9), 165 (8), 114 (3), 77 (24). Anal.
Calcd for C23H21NO3 (359.42): C, 76.86; H, 5.89; N, 3.90. Found: C,
76.86; H, 5.91; N, 3.92.
ACKNOWLEDGMENTS
■
Thanks are due to the European Commission, FSE (Fondo
Sociale Europeo), and Calabria Region for fellowship grants to
R.M. and N.M.
(E)-Methyl 2-[3-(butylimino)isobenzofuran-1(3H)-ylidene]-2-cy-
clohexenylacetate (4k-E): yield 161.8 mg, starting from 197.0 mg of
N-butyl-2-(2-cyclohexenylethynyl)benzamide (68%); colorless oil; IR
(film) ν = 2933 (m), 2863 (w), 1723 (s), 1668 (s), 1435 (w), 1338
(m), 1307 (w), 1220 (m), 1089 (m), 1051 (w), 756 (s) (w) cm−1; 1H
NMR (300 MHz, CDCl3) δ = 8.15 (d, J = 8.4, 1 H), 7.50−7.24 (m, 3
H), 6.21−6.13 (m, 1 H), 3.82 (s, 3 H), 3.52−3.43 (m, 2 H), 2.38−2.28
(m, 2 H), 2.23−2.12 (m, 2 H), 1.79−1.60 (m, 6 H), 1.53−1.38 (m, 2
H), 0.96 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3) δ = 167.8,
156.5, 148.3, 132.4, 131.7, 131.5, 127.8, 126.6, 125.0, 123.1, 122.6,
107.7, 52.0, 45.9, 32.8, 25.7, 25.6, 22.3, 21.6, 20.7, 13.9; GC−MS m/z
= 339 (17) [M+], 322 (25), 310 (25), 296 (89), 280 (100), 264 (18),
258 (31), 226 (66), 170 (29), 142 (9) 114 (14), 109 (78), 81 (39).
Anal. Calcd for C21H25NO3 (339.43): C, 74.31; H, 7.42; N, 4.13.
Found: C, 74.30; H, 7.41; N, 4.11.
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Formation of a Mixture of Methyl 2-[3-(Phenylimino)-
isobenzofuran-1(3H)-ylidene]hexanoate 4f and Methyl 3-
Butyl-1-oxo-1H-isochromene-4-carboxylate 5f by PdI2-Cata-
lyzed Heterocyclization−Alkoxycarbonylation of 2-(Hex-1-
ynyl)-N-phenylbenzamide 1f (eq 2). A 250 mL stainless steel
autoclave was charged in the presence of air with PdI2 (3.6 mg, 1.0 ×
10−2 mmol), KI (16.8 mg, 0.1 mmol), and a solution of 1f (140 mg,
0.5 mmol) in MeOH (25 mL). The autoclave was sealed, and while
the mixture was stirred, the autoclave was pressurized with CO (32
atm) and air (up to 40 atm). After being stirred at 100 °C for 5 h, the
autoclave was cooled, degassed, and opened. The solvent was
evaporated, and the products were separated by column chromatog-
raphy on neutral alumina (eluent: hexane−AcOEt from 99:1 to 95:5)
to give methyl 3-butyl-1-oxo-1H-isochromene-4-carboxylate 5f and
methyl 2-[3-(phenylimino)isobenzofuran-1(3H)-ylidene]hexanoate 4f
1
(Z/E ca. 1.4, by H NMR) in that order.
Methyl 3-Butyl-1-oxo-1H-isochromene-4-carboxylate (5f): pale
yellow oil; IR (film) ν = 2958 (m), 2938 (m), 1728 (vs), 1631 (m),
1488 (w), 1457 (m), 1355 (m), 1319 (m), 1258 (m), 1215 (m), 1058
1
(m), 1024 (w), 758 (s) cm−1; H NMR (300 MHz, CDCl3) δ = 8.29
(d, J = 7.9, 1 H), 7.79−7.63 (m, 2 H), 7.56−7.45 (m, 1 H), 3.97 (s, 3
H), 2.69 (t, J = 7.6, 2 H), 1.83−1.63 (m, 2 H), 1.50−1.32 (m, 2 H),
0.95 (t, J = 6.7, 3 H); 13C NMR (75 MHz, CDCl3) δ = 166.4, 161.3,
161.0, 135.0, 134.7, 129.7, 128.2, 124.2, 119.6, 110.0, 52.4, 32.5, 29.8,
22.4, 13.7; GC−MS m/z = 260 (99) [M+], 229 (48), 218 (9), 203
(100), 199 (36), 190 (37), 186 (78), 176 (71), 161 (7), 148 (53), 133
(33), 115 (10), 104 (26), 88 (28), 57 (39). Anal. Calcd for C15H16O4
(260.29): C, 69.22; H, 6.20. Found: C, 69.23; H, 6.23.
ASSOCIATED CONTENT
■
S
* Supporting Information
Table S1, Figures S1−S4, summary of X-ray data for
compounds 3da-E, 3ea-Z, 4d-E, and 4i-E (Tables S2−S13
and Figures S5−S8), X-ray crystallographic files (CIF) for
compounds 3da-E, 3ea-Z, 4d-E, and 4i-E (CCDC 975358−
975361), and copies of 1H and 13C NMR spectra for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: raffaella.mancuso@unical.it.
*E-mail: bartolo.gabriele@unical.it.
Notes
The authors declare no competing financial interest.
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Article
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