Isoindolinones via a room temperature palladium nanoparticle-catalysed 3-component cyclative carbonylation-amination cascade

Article abstract of DOI:10.1016/S0040-4039(03)01805-7

A room temperature 3-component cascade process involving nucleophilic substitution/carbonylation/amination, catalysed by palladium nanoparticles generated in situ from palladacycle 5, affords isoindolinones in good yields. The conversions correlate with the pK_a values of the amines.

Full text of DOI:10.1016/S0040-4039(03)01805-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6979–6982
Isoindolinones via a room temperature palladium
nanoparticle-catalysed 3-component cyclative
carbonylation–amination cascade
a,
a
b
b
Ronald Grigg, * Lixin Zhang, Simon Collard and Ann Keep
a
Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University,
Leeds LS2 9JT, UK
b
Johnson Matthey, Orchard Road, Royston, Herts SG8 5HE, UK
Received 19 June 2003; revised 15 July 2003; accepted 24 July 2003
Abstract—A room temperature 3-component cascade process involving nucleophilic substitution/carbonylation/amination,
catalysed by palladium nanoparticles generated in situ from palladacycle 5, affords isoindolinones in good yields. The conversions
correlate with the pK values of the amines.
a
©
2003 Published by Elsevier Ltd.
Palladacycles (PdCy), as a new class of catalyst precur-
sors, have been researched intensively in the last few
(to ca. 100–140°C) to ‘switch on’, the temperature used
depending on the PdCy stability.
1
2–5
years. They have been applied to the Heck reaction,
6
–8
9,10
Suzuki reaction, Stille reaction,
Sonogashira reac-
Recently we established a new route to generating
palladium nanoparticles by treating PdCys or palla-
dium salts with carbon monoxide (1 atm) in DMF or
toluene at room temperature. Transmission electron
microscopy (TEM) studies demonstrated the formation
1
1–13
14,15
tion,
amination
and hetero and carbo-annula-
However, to our knowledge, they
1
6,17
tion processes.
have not been applied to carbonylation reactions.
Moreover, Herrmann’s phosphine palladacycle was
18
19
reported to be unsuitable for carbonylation reactions.
Unlike the traditional Pd(OAc) /PPh catalyst system,
of nanoparticles. This method provides a quick and
mild way to generate palladium nanoparticles. We now
report its application to a carbonylation cascade reac-
2
3
palladacycle catalyst precursors usually require heating
Scheme 1.
*
0
Corresponding author. Tel.: +44-113-343-6501; e-mail: r.grigg@chem.leeds.ac.uk
040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/S0040-4039(03)01805-7

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980
R. Grigg et al. / Tetrahedron Letters 44 (2003) 6979–6982
a
Table 1. Correlation of conversion to isoindolinone with amine pKa
Entry
Primary amine
Conv.b (%)
pK d of amines
pK d of intermediate 2
a
a
c
22
1
2
3
4
5
6
R-a-Methyl benzylamine
Benzylamine
Propargyl amine
98 (81 , 4a)
9.75
9.40
7.89
7.13
5.2
8.27
8.25
7.09
5.56
4.15
3.9
c
84 (72 , 4b)
c
68 (51 , 4c)
c
L
-Phenylalanine methyl ester
49 (33 , 4d)
p-Anisidine
p-Toluidine
13 (4e)
10 (4f)
5.0
a
All reactions carried out in DMF at rt for 48 h in the presence of 1 mol% 5, carbon monoxide (1 atm) and K CO (2 mol equiv.).
Conversion determined by NMR based on intermediate 2.
Isolated yield.
2
3
b
c
d
pKa calculated using ACD/pKa software.
Figure 1.
tion at room temperature. To our knowledge there have
not been any reports of room temperature catalytic
processes employing PdCys.
When the Scheme 1 reactions were repeated at 80°C for
12 h complete conversion of aliphatic amines and aro-
matic amines to products was observed in all cases
(
Table 2).
We selected a 3-component carbonylation–amine cap-
ture cascade process which affords the biologically
2
0
interesting isoindolinones (Scheme 1).
21
When the reaction was carried out at room tempera-
ture (DMF, 48 h) using 1 mol% of precatalyst 5 and
CO (1 atm) the conversions to product correlated with
the pK ’s of the amines and those of the intermediate
a
amines 2 (Table 1).
The formation of isoindolinone 4 from 1, carbon
monoxide (1 atm) and an amine in the presence of
palladium nanoparticles could occur via path a or path
b (Scheme 1). In path b, carbon monoxide insertion is
followed by amination to give the amide 3, which
undergoes intramolecular 5-exo tet nucleophilic substi-
tution to afford 4. In path a, the nucleophilic substitu-
tion affording 2 occurs first. In all cases, after 2 h at
room temperature 90–95% conversion of 1 to interme-
diate 2 was observed thus providing evidence that the
reaction proceeds via path a. Thus, the rate of nucle-
ophilic substitution of the benzyl bromide moiety is
much faster than carbonylation/amination. This
accords with the linear correlation of conversion with
the pK of the primary amines (Fig. 1a) and the pK of
a
Table 2. 3-Component cascade reaction at 80°C/12 h
Yieldb (%)
Entry
Primary amine
1
2
3
4
5
1,2-Diphenylethylamine
Benzylamine
Allylamine
p-Toluidine
S-1-Cyclohexylethylamine
85 (4g)
83 (4b)
77 (4h)
72 (4f)
73 (4i)
a
a
a
Reaction performed as for Table 1 but at 80°C for 12 h.
Isolated yield.
b
intermediate 2 (Fig. 1b).

R. Grigg et al. / Tetrahedron Letters 44 (2003) 6979–6982
6981
Scheme 2.
2
3
Di-isoindolinone analogues 9–11 can be analogously
80°C/48 h) made from diamines 6–8.
4. Iyer, S; Ramesh, C. Tetrahedron Lett. 2000, 41, 8981–
(
8984.
5
. Beletskaya, I.; Kashin, A. N.; Karlstedt, N. B.; Mitin, A.
V.; Cheprakow, A. V.; Kazankow, G. M. J. Organomet.
Chem. 2001, 622, 89–96.
Our proposed catalytic cycle (Scheme 2) involves reduc-
tive degradation of PdCy 5 to palladium nanoparticles
by CO. Nucleophilic substitution of the iodobenzyl
bromide by the primary amine gives intermediate 2.
Oxidative addition of Pd(0) to the ArꢀI bond followed
by CO insertion and subsequent cyclisation affords the
product and regenerates palladium(0).
6. Beller, M.; Fischer, H.; Herrmann, W. A.; Ofele, K.;
8
Brossmer, C. Angew. Chem., Int. Ed. Engl. 1995, 34,
1848–1849.
7. Zim, D.; Gruber, A. S.; Ebiling, G.; Dupont, J.; Mon-
teiro, A. L. Org. Lett. 2000, 2, 2881–2884.
8
. Botella, L.; Najera, C. Angew. Chem., Int. Ed. 2002, 41,
179–181.
In conclusion, we have successfully applied palladacycle
catalysis to a 3-component cascade process which
involves nucleophilic substitution/carbonylation/amina-
tion via palladium nanoparticles generated in situ at
room temperature. At room temperature, the conver-
9. Alonso, D. A.; Najera, C.; Pacheco, M. C. Org. Lett.
2000, 2, 1823–1826.
10. Munoz, M. P.; Martin-Matute, B.; Fernandez-Rivas, C.;
Cardenas, D. J.; Echavarren, A. M. Adv. Synth. Catal.
2001, 343, 338–342.
sions correlate with the pK of the amines.
a
1
1. Herrmann, W. A.; Reisinger, C.-P.; Ofele, K.; Brossmer,
C.; Beller, M.; Fisher, H. J. Mol. Catal. A. 1996, 108,
51–56.
Acknowledgements
12. Alonso, D. A.; Najera, C.; Pacheco, M. C. Tetrahedron
Lett. 2002, 43, 9365–9368.
We thank Tetley and Lupton and Johnson Matthey for
scholarships (to L.Z.) and Leeds University for
support.
13. Eberhard, M. R.; Wang, Z.; Jensen, C. M. Chem. Com-
mun. 2002, 818–819.
14. Beller, M.; Riermeier, T. H.; Reisinger, C.-P.; Herrmann,
W. A. Tetrahedron Lett. 1997, 38, 2073–2074.
1
5. Schnyder, A.; Indolese, A. F.; Studer, M.; Blaser, H.-U.
Angew. Chem., Int. Ed. 2002, 41, 3668–3671.
6. Gies, A. E.; Pfeffer, M.; Sirlin, C.; Spencer, J. Eur. J.
Org. Chem. 1999, 1957–1961.
References
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1
. Dupont, J.; Pfeffer, M.; Spencer, J. Eur. J. Inorg. Chem.
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C.-P.; Beller, M.; Fisher, H. Angew. Chem., Int. Ed. Engl.
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2
17. Gai, X.; Grigg, R.; Collard, S.; Muir, J. E. Chem. Com-
2
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fele, K.; Reisinger,
mun. 2000, 1765–1766.
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Organomet. Chem. 1999, 576, 23–41.
1
3. Ohff, M.; Ohff, A.; Boom, E.; Milstein, D. J. Am. Chem.
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Soc. 1997, 119, 11687–11688.
Organomet. Chem., submitted.

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R. Grigg et al. / Tetrahedron Letters 44 (2003) 6979–6982
1
3
2
2
0. Noda, K.; Nakagawa, A.; Motomura, T.; Ide, H. EP
7674.
(m, 8H, ArH), 7.89 (m, 1H, ArH); C NMR: 168.5
(CꢁO), 141.7 (ArC), 141.1 (ArC), 133.3 (ArCH), 131.6
(ArC), 129.1 (ArCH), 128.4 (ArCH), 127.9 (ArCH), 127.6
4
1. General procedure: 2-iodobenzyl bromide (1 mol equiv.),
aromatic or aliphatic primary amine (1–1.2 mol equiv.),
cyclopalladated complex 5 (1 mol%) and potassium car-
bonate (2 mol equiv.) were mixed in dry DMF. A balloon
containing CO (1 atm) was attached to the flask and the
mixture was stirred at rt or heated. The resulting mixture
was then quenched by addition of water and extracted
with diethyl ether (3×). The combined organic layers were
(ArCH), 124.2 (ArCH), 123.2 (ArCH), 49.5 (CH ), 45.9
(CH), 17.7 (CH ); m/z (EI) (%): 237 (M , 53), 222 (100),
2
+
3
119 (33), 105 (30), 91 (41), 77 (52); w
(film): 1672, 1468,
max
−
1
1452, 1408 and 1216 cm .
23. Compound 11: colourless prisms, mp 224–6°C; [h]
(c 0.5, CHCl ); (found: C, 80.9; H, 5.40; N, 6.20;
requires: C, 81.05; H, 5.40; N, 6.30%); l
4.05 and 4.83 (2×d, 2×2H, J 16.8 Hz, NCH ) 6.62 (s, 2H,
CHN), 7.14–7.51 (m, 16H, ArH), 7.65 (m, 2H, ArH);
+439
D
3
C
30
H
N
O
2
:
H
24
2
washed with water, brine, dried (MgSO ), filtered and the
2
4
13
filtrate evaporated under reduced pressure. The residue
was purified by flash column chromatography.
C
NMR: 169.1 (CꢁO), 142.2 (ArC), 137.0 (ArC), 132.1
(ArC), 131.8 (ArCH), 128.3 (ArCH), 129.1 (ArCH), 128.5
(ArH), 128.1 (ArH), 124.1 (ArH), 123.5 (ArCH), 54.28
2
2. Compound 4a: colourless needles, mp 142–4°C; [h]D +144
(
c 1.33, CHCl ); (found: C, 80.9; H, 6.6; N, 6.0;
3
+
C H NO requires: C, 81.0; H, 6.3; N, 5.9%); l : 1.69
(CH), 46.79 (CH
2
); m/z (ES) (%): 467.0 (M+Na , 100),
16
15
H
(
d, 3H, J 7.1 Hz, CH ), 3.99 and 4.33 (2×d, 2×1H, J 17.0
445.1 (M+H, 18); wmax (film): 1682, 1469, 1452, 1407,
1302 and 1216 cm .
3
−
1
Hz, NCH ), 5.82 (q, 1H, J 7.1 Hz, CH
6
CH ), 7.27–7.65
2
3