A new approach to isoindolinone derivatives by sequential palladium iodide-catalyzed oxidative aminocarbonylation-heterocyclization of 2-ethynylbenzamides

Article abstract of DOI:10.1016/j.tetlet.2012.09.109

A novel approach to functionalized isoindolinone derivatives 3 is presented. It is based on a cascade process, consisting of PdI ₂/KI-catalyzed oxidative monoaminocarbonylation of secondary 2-ethynylbenzamides 1 with nucleophilic secondary amin

Full text of DOI:10.1016/j.tetlet.2012.09.109

Tetrahedron Letters 53 (2012) 6694–6696
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new approach to isoindolinone derivatives by sequential palladium
iodide-catalyzed oxidative aminocarbonylation–heterocyclization of
2-ethynylbenzamides
Bartolo Gabriele a, , Raffaella Mancuso b, , Ida Ziccarelli b, Giuseppe Salerno b
⇑
⇑
a Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy
b Dipartimento di Chimica, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to functionalized isoindolinone derivatives 3 is presented. It is based on a cascade pro-
cess, consisting of PdI2/KI-catalyzed oxidative monoaminocarbonylation of secondary 2-ethynylbenza-
mides 1 with nucleophilic secondary amines 2, followed by intramolecular conjugate addition of the
arylamido group to the alkynylamido group of the intermediate alkynylamides. Products have been
obtained in high to excellent yields starting from different N-alkyl 2-ethynylbenzamides and amines,
under relatively mild conditions (100 °C under 40 atm of a 4:1 mixture of CO–air), working in a
MeCN–amine mixture (2:1, v/v) for 5–15 h.
Received 30 August 2012
Accepted 24 September 2012
Available online 29 September 2012
Keywords:
Carbonylation
Cyclization
Heterocycles
Isoindolinones
Palladium
Ó 2012 Elsevier Ltd. All rights reserved.
PdI2/KI-catalyzed oxidative monoaminocarbonylation of
1-alkynes with nucleophilic secondary amines is a powerful meth-
od for the direct synthesis of 2-ynamides starting from simple
building blocks (Eq. 1).1 When applied to suitably functionalized
substrates, it can allow the direct synthesis of carbonylated hetero-
cycles through a sequential process involving oxidative aminocarb-
onylation of the terminal triple bond followed by intramolecular
conjugate addition (Scheme 1).2
acrylamides or alkyl acrylate, has been recently developed.5
3-[(Alkoxycarbonyl)methylene]isoindolin-1-one derivatives were
also obtained in low to moderate yields (25–55%) by Pd-catalyzed
oxidative alkoxycarbonylation of 2-alkynylbenzamides bearing an
internal triple bond, through a completely different reaction course
(nucleophilic attack by the amido group to the coordinated triple
bond followed by alkoxycarbonylation).6
O
O
PdI2 cat
O
ð1Þ
CHCNR2
RC CH + CO + R'2NH + (1/2) O2
NR'2
PdI2 cat
H2O
R
NR2
YH CO, R2NH, O2
(Y = O, NR')
YH
Y
In this Letter, we report a novel application of this kind of reactiv-
ity to the direct synthesis of functionalized isoindolinone deriva-
tives,3 that are, 3-[(dialkylcarbamoyl)methylene]isoindolin-1-ones
3, starting from N-substituted 2-ethynylbenzamides 1 (available
in four steps from 2-iodobenzoic acid)4 and nucleophilic secondary
amines 2, according to Scheme 2. To our knowledge, this is the first
example of synthesis of this class of compounds by direct
carbonylation of acyclic precursors. A non-carbonylative route to
3-[(carbamoyl)methylene]isoindolin-1-ones and 3-[(alkoxycarbon-
yl)methylene]isoindolin-1-ones, involving an oxidative Pd-
catalyzed reaction between N-methoxybenzamides and
Scheme 1. Formation of carbonylated heterocycles through sequential PdI2-cata-
lyzed oxidative monoaminocarbonylation of the triple bond—intramolecular con-
jugate addition.
O
O
CHCNR'2
NR'2
PdI2 cat
N R
O
NHR
NHR
CO, R'2NH, O2
O
2
O
3
1
⇑
Corresponding authors. Tel.: +39 0984 49 2813; fax: +39 0984 49 2044 (B.G.);
Scheme 2. Synthesis of 3-[(dialkylcarbamoyl)methylene]isoindolin-1-ones 3 from
secondary 2-ethynylbenzamides 1 and nucleophilic secondary amines 2 through
sequential PdI2-catalyzed oxidative monoaminocarbonylation of the triple bond—
intramolecular conjugate addition.
tel.: +39 0984 49 2816; fax: +39 0984 49 2044 (R.M.).
E-mail addresses: b.gabriele@unical.it (B. Gabriele), raffaella.mancuso@unical.it
(R. Mancuso).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.109

B. Gabriele et al. / Tetrahedron Letters 53 (2012) 6694–6696
6695
Table 1
Synthesis of 3-[(dialkylcarbamoyl)methylene]isoindolin-1-ones 3 by PdI2/KI-catalyzed oxidative carbonylation of secondary 2-ethynylbenzamides 1 with nucleophilic secondary
amines 2a
O
CHCNR'2
PdI2 cat
+ CO + R'2NH + (1/2) O2
NHR
N R
H2O
2
O
O
1
3
Entry
1
1
2
Time (h)
15
3
Yield of 3b (%)
Z/E ratio
O
CHC N
O
O
NHBu
NHBn
NHtBu
NHPh
O
NH
2a
83
2.0
O
N Bu
O
1a
3aa
O
CHC N
2
3
4
5
6
7
2a
2a
2a
5
83
94
35
81
80
91
2.2
O
N Bn
O
1b
3ba
O
O
N
15
Only E
O
N tBu
1c
O
3ca
O
CHC N
O
8
9.7
O
N Ph
O
1d
3da
3ab
3ac
3ad
O
CHC NBu2
1a
1a
1a
Bu2NH 2b
15
1.0
N Bu
O
O
CHC N
NH
5
1.0
N Bu
O
2c
O
CHC N
NH
15
1.0
N Bu
O
2d
a
All reactions were carried out in a 2:1 MeCN–amine mixture as the solvent (substrate concentration = 0.05 mmol of 1 per mL of solvent, 0.7 mmol scale based on 1) at
100 °C under 40 atm (at 25 °C) of a 4:1 mixture of CO-air, in the presence of PdI2 (2 mol %) in conjunction with KI (KI/PdI2 molar ratio = 10). Substrate conversion was
quantitative in all cases.
b
Isolated yield based on starting 1.
The first substrate we tested was N-butyl-2-ethynylbenzamide
1a, which was allowed to react with morpholine 2a, CO, and O2
using a 2:1 MeCN–morpholine mixture as the solvent under
40 atm of a 4:1 mixture of CO–air,7 in the presence of PdI2
(2 mol%) in conjunction with KI (KI:PdI2 molar ratio = 10). Under
these conditions, after 15 h a 2.0 Z/E mixture of 2-butyl-3-(2-mor-
pholino-2-oxoethylidene)isoindolin-1-one 3aa was obtained, with
a total isolated yield of 83% (Table 1, entry 1).
The aminocarbonylation reaction was then extended to other
differently substituted substrates 1b–d with morpholine 2a as
the nucleophile. Thus, under the same conditions reported above,
N-benzyl-2-ethynylbenzamide 1b led to the formation of the cor-
responding 2-benzyl-3-(2-morpholino-2-oxoethylidene)isoindo-
lin-1-one 3ba in 83% yield after 5 h reaction time (Z/E ratio = 2.2,
entry 2). Interestingly, only the E isomer of 2-tert-butyl-3-(2-mor-
pholino-2-oxoethylidene)isoindolin-1-one 3ca was obtained in
excellent yield (94%) starting from N-tert-butyl-2-ethynylbenza-
mide 1c, bearing a bulky substituent on the triple bond (Table 1,
entry 3). This high stereoselectivity is probably due to the steric
effect exerted by the tert-butyl group, which directs the
dialkylaminocarbamoyl group on the opposite site with respect
to the tert-butyl substituent. As expected in view of the signifi-
cantly lower nucleophilicity of a phenyl-substituted amido group,
the reaction led to less satisfactory results in the case of

6696
B. Gabriele et al. / Tetrahedron Letters 53 (2012) 6694–6696
Drissel, G. M. In Kirk-Othmer Encyclopedia of Chemical Technology; Grayson, M.,
Eckroth, D., Bushey, G. J., Campbell, L., Klingsberg, A., van Nes, L., Eds.; Wiley-
Interscience: New York, 1978; Vol. 4, p 775. 3rd ed.
N-phenyl-2-ethynylbenzamide 1d, which was converted into 2-
phenyl-3-(2-morpholino-2-oxoethylidene)isoindolin-1-one 3da in
only 35% yield (Z/E ratio = 9.7, Table 1, entry 4). On the other hand,
the use of 1a with other nucleophilic secondary amines, such as
dibutylamine 2b, pyrrolidine 2c, and piperidine 2d, led to high to
excellent yields (80–91%) of the corresponding 3-[(dialkylcarba-
moyl)methylene]isoindolin-1-ones 3ab, 3ac, and 3ad, as shown
in Table 1, entries 5–7.8–11
In conclusion, we have reported a convenient and direct
approach to the synthesis of 3-[(dialkylcarbamoyl)methylene]iso-
indolin-1-ones 3 by a novel cascade process, involving PdI2-cata-
lyzed oxidative monoaminocarbonylation of the triple bond of
N-alkyl-2-ethynylbenzamides 1 followed by 5-endo-dig intramo-
lecular conjugate addition. Our method represents an interesting
example of direct synthesis of functionalized heterocyclic deriva-
tives through the sequential multicomponent assembling of simple
building blocks.
8. Typical procedure for the oxidative carbonylative annulation of N-substituted
2-ethynylbenzamides 1 to 3-(dialkylcarbamoylmethylene)isoindolin-1-ones 3:
A 250 mL stainless steel autoclave was charged in the presence of air with PdI2
(5.0 mg, 1.39 ꢀ 10ꢁ2 mmol), KI (23.0 mg, 1.39 ꢀ 10ꢁ1 mmol), and a solution of
1 (0.70 mmol) in a mixture MeCN–amine (MeCN: 9.6 mL; amine 2: 4.8 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 by-product 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 (eluent: chloroform for 3aa;
7:3 hexane–AcOEt for 3ca and 3da) or neutral alumina (eluent: 8:2 hexane–
AcOEt for 3ba; 7:3 hexane–AcOEt for 3ab and 3ad; 9:1 hexane–AcOEt for 3ac)
to give pure isoindolinones 3, which were fully characterized by spectroscopic
techniques and elemental analysis.7 The molecular structure of (Z)-2-tert-
butyl-3-(2-morpholino-2-oxoethylidene)isoindolin-1-one was confirmed by X-
ray diffraction analysis, which will be reported in due course.
9. Characterization data for selected products: For 3aa (mixture of diastereomers
Z/E, Z/E ratio ca. 2.0, determined by 1H NMR): Pale yellow oil. IR (film):
m
= 2960
(m), 2928 (m), 1712 (s), 1684 (vs), 1435 (m), 1400 (w), 1231 (m), 1115 (m),
1040 (w), 769 (m), 699 (w) cmꢁ1 1H NMR (300 MHz, CDCl3): d = 8.12–8.01 [Z
Acknowledgments
;
(m, 1 H, aromatic)], 7.88-7.76 [Z (m, 1 H, aromatic) + E (m, 1 H, aromatic)], 7.70-
7.46 [Z (m, 2 H, aromatic) + E (m, 3 H, aromatic)], 6.01 [E (s, 1 H, = CH)], 5.81 [Z
(s, 1 H, = CH)], 4.02 [E (t, J = 7.5, 2 H, NCH2)], 3.88-3.55 [Z (m, 2 H, NCH2) + Z (m,
8 H, morpholine ring) + E (m, 8 H, morpholine ring)], 1.73-1.58 [Z (m, 2 H,
NCH2CH2)], 1.58-1.23 [E (m, 2 H, NCH2CH2) + Z (m, 2 H, CH2CH3) + E (m, 2 H,
CH2CH3)], 1.01-0.88 [Z (m, 3 H, Me) + E (m, 3 H, Me)]; 13C NMR (75 MHz,
CDCl3): d = 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
(EI, 70 eV): m/z = 314 (M + , 12), 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, 68.84; H,
7.04; N, 8.89. For 3ca (E isomer): Colorless solid. Mp = 145–146 °C IR (KBr):
Thanks are due to the European Commission, FSE (Fondo Sociale
Europeo) and Calabria Region for a fellowship grant to R.M.
References and notes
1. Gabriele, B.; Salerno, G.; Veltri, L.; Costa, M. J. Organomet. Chem. 2011, 622, 84–
88.
2. (a) Gabriele, B.; Salerno, G.; Plastina, P.; Costa, M.; Crispini, A. Adv. Synth. Catal.
2004, 346, 351–358; (b) Gabriele, B.; Salerno, G.; Plastina, P. Lett. Org. Chem.
2004, 1, 134–136; (c) Gabriele, B.; Plastina, P.; Salerno, G.; Costa, M. Synlett
2005, 935–938; (d) Gabriele, B.; Salerno, G.; Veltri, L.; Mancuso, R.; Li, Z.;
Crispini, A.; Bellusci, A. J. Org. Chem. 2006, 71, 7895–7898; (e) Gabriele, B.;
Plastina, P.; Salerno, G.; Mancuso, R. Synthesis 2006, 4247–4251; (f) Gabriele,
B.; Plastina, P.; Salerno, G.; Mancuso, R.; Costa, M. Org. Lett. 2007, 9, 3319–
3322; (g) Plastina, P.; Gabriele, B.; Salerno, G. Synthesis 2007, 3083–3087.
3. 3-Methyleneisoindolin-1-one derivatives are an important class of
heterocycles. In fact, several molecules incorporating the 3-
methyleneisoindolin-1-one core have shown interesting pharmacological
activities; for recent examples, see: (a) Abdou, W. M.; Khidre, R. E.; Barghash,
R. F. Synth. Commun. 2012, 42, 1967–1978; (b) Del Olmo, E.; Barboza, B.; Lopez-
Perez, J. L.; San Feliciano, A.; Chiaradia, L. D.; Moreno, A.; Benito, A.; Carrero-
Lerida, J.; Gonzalez-Pacanowska, D.; Ruiz-Perez, L. M.; Munoz, V.; Gimenez, A.;
Martinez, A. R. Eur. J. Med. Chem. 2011, 46, 5379–5386; (c) Zhu, X.; Greig, N. H.;
Yu, Q.-s.; Utsuki, T.; Holloway, H. W.; Lahiri, D. K.; Brossi, A. Heterocycles 2004,
64, 93–100; (d) Del Olmo, E.; Armas, M. G.; Lopez-Perez, J. L.; Munoz, V.;
Deharo, E.; San Feliciano, A. Bioorg. Med. Chem. Lett. 2001, 11, 2123–2126; (e)
Cid, H. M. B.; Traenkle, C.; Baumann, K.; Pick, R.; Mies-Klomfass, E.; Kostenis, E.;
Mohr, K.; Holzgrabe, U. J. Med. Chem. 2000, 43, 2155–2164.
4. N-substituted 2-ethynylbenzamides 1 were easily prepared from commercially
available 2-iodobenzoic acid through conversion into the corresponding acyl
chloride followed by amidation with the suitable amine, Sonogashira coupling
with trimethylsilylacetylene and deprotection, as reported in the literature:
Varela-Fernández, A.; Varela, J. A.; Saá, C. Adv. Synth. Catal. 2011, 353, 1933–
1937.
5. (a) Li, D.-D.; Yuan, T.-T.; Wang, G.-W. Chem. Commun. 2011, 47, 12789–12791;
(b) Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Org.
Lett. 2011, 13, 5326–5329.
m
= 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 (w) cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d = 7.79-7.71 (m, 2 H, aromatic), 7.56-7.43 (m, 2 H, aromatic), 6.14 (s, 1
H, = CH), 3.86-3.52 (m, 8 H, morpholine ring), 1.78 (s, 9 H, t-Bu); 13C NMR
(75 MHz, CDCl3): d = 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 (EI, 70 eV): m/z = 314
(M+, 6), 258 (3), 228 (2), 200 (41), 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,
68.82; H, 7.03; N, 8.90. For 3ad (mixture of diastereomers Z/E, Z/E ratio ca. 1.0,
determined by 1H NMR): Pale yellow oil. IR (film):
m = 2934 (m), 2956 (m), 1713
(s), 1652 (vs), 1470 (m), 1252 (m), 1023 (m), 953 (w), 770 (m), 698 (w) cmꢁ1
;
1H NMR (300 MHz, CDCl3): d = 8.03-7.96 [Z (m, 1 H, aromatic)], 7.86-7.77 [Z (m,
1 H, aromatic) + E (m, 1 H, aromatic)], 7.69-7.62 [E (m, 1 H, aromatic)], 7.61-
7.46 [Z (m, 2 H, aromatic) + E (m, 2 H, aromatic)], 6.04 [E (s, 1 H, = CH)], 5.83 [Z
(s,
1 H, = CH)], 3.99 [E (t, J = 7.6, 2 H, NCH2CH2)], 3.83-3.49 [Z (m, 2 H,
NCH2CH2) + Z (m, 4 H, CH2NCH2) + E (m, 4 H, CH2NCH2)], 1.75-1.24 [E (m, 10 H,
CH2CH2CH3 + CH2CH2NCH2CH2CH2) + Z (m, 10 H, CH2CH2CH3 + CH2CH2NCH2-
CH2CH2)], 0.96 [Z or E (t, J = 7.3, 3 H, Me)], 0.92 [E or Z (t, J = 7.3, 3 H, Me)]; 13C
NMR (75 MHz, CDCl3): d = 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 (EI, 70 eV): m/z = 312 (M+, 35), 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, 73.12; H, 7.72; N, 8.99.
10. The reaction worked to only
a very little extent with non-nucleophilic
secondary amines, such as hindered amines like diisopropylamine, while
primary amines could not be used owing to their transformation into ureas
according to a known reactivity.11
6. Kondo, Y.; Shiga, F.; Murata, N.; Sakamoto, T.; Yamanaka, H. Tetrahedron 1994,
50, 11803–11812.
7. These conditions (32 atm of CO together with 9 total atm of air, considering
that the autoclave was loaded under 1 atm of air) corresponded to 78.0% of CO
in air and were outside the explosion limits for CO in air (ca. 16–70% at 18–
20 °C and atmospheric pressure, 14.8–71.4% at 100 °C and atmospheric
pressure. At higher total pressure, the range of flammability decreases: for
example, at 20 atm and 20 °C the limits are ca. 19 and 60%. See: Bartish, C. M.;
11. (a) Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. Chem. Commun. 2003, 486–
487; (b) Gabriele, B.; Salerno, G.; Mancuso, R.; Costa, M. J. Org. Chem. 2004, 69,
4741–4750; (c) Della Ca’, N.; Bottarelli, P.; Dibenedetto, A.; Aresta, M.; Gabriele,
B.; Salerno, G.; Costa, M. J. Catal. 2011, 282, 120–127.