Synthesis of N-substituted 4-methylene-3,4-dihydro-1(2H)-isoquinolin-1-ones via a palladium-catalysed three-component process

Article abstract of DOI:10.1016/S0040-4039(02)00329-5

A novel palladium-catalysed three-component cascade process involving 2-iodobenzoyl chloride or methyl 2-iodobenzoate, allene and primary aliphatic or aromatic amines furnishes N-substituted 4-methylene-3,4-dihydro-1(2H)-isoquinolin-1-ones in good yield.

Full text of DOI:10.1016/S0040-4039(02)00329-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2601–2603
Synthesis of N-substituted
4-methylene-3,4-dihydro-1(2H)-isoquinolin-1-ones via a
palladium-catalysed three-component process
Ronald Grigg,a,* Tossapol Khamnaen,b Shuleewan Rajviroongitb and Visuvanathar Sridharana
aMolecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University,
Leeds LS2 9JT, UK
bDepartment of Chemistry, Faculty of Science, Mahidol University, Rama 6 Rd, Rajthevee, Bangkok 10400, Thailand
Received 25 September 2001; revised 4 February 2002; accepted 12 February 2002
Abstract—A novel palladium-catalysed three-component cascade process involving 2-iodobenzoyl chloride or methyl 2-iodoben-
zoate, allene and primary aliphatic or aromatic amines furnishes N-substituted 4-methylene-3,4-dihydro-1(2H)-isoquinolin-1-ones
in good yield. © 2002 Elsevier Science Ltd. All rights reserved.
Allenes are versatile building blocks in palladium-
catalysed processes but are still under utilised in organic
synthesis.1 They function as powerful relay-switches in
palladium-catalysed cyclisation-anion capture cas-
cades.2 Reactions of aryl/vinyl palladium(II) intermedi-
ates with allene lead to the formation of
(p-allyl)palladium species able to undergo a wide range
of transformations, including attack by nucleophiles,3
electrophiles4 or transmetallation.5 In the context of
heterocycle synthesis allenes offer expeditious routes to
a wide range of oxygen and nitrogen heterocycles.1 A
further feature of incorporation of allenes into hetero-
cycle synthesis is their ability to provide unusual sub-
stituents and substitution patterns. Particularly useful is
the ability to engineer exo-methylene and 1,1-disubsti-
tuted exo-methylene moieties from allenes.6 Recently,
we have developed several three-component syntheses
of chroman-4-ones and quinolin-4-ones.7–9 As part of
our ongoing interest in designing heterocyclic syntheses
involving palladium-catalysed multicomponent pro-
cesses utilising allenes,7 we explored the following pro-
cess (Scheme 1), with both esters (1, Y=OMe) and acyl
chlorides (1, Y=Cl).
2-Iodoesters (1, X=I, Y=OMe) would be expected to
react with allene and a primary amine via path a to
afford 2, whereas 2-iodo acyl chlorides (1, X=I, Y=
Cl) would be expected to react with allene and a
primary amine via path b to give 2. In this communica-
tion we report examples of both path a and path b
processes. We selected methyl 2-iodobenzoate as the
prototypical ester component. Methyl 2-iodobenzoate
(1 mmol) reacted with allene (1 bar), Pd(OAc)2 (10
mol%), PPh3 (20 mol%), K2CO3 or Cs2CO3 (2 mol
equiv.) and an aliphatic primary amine (1.2 mol equiv.)
in toluene (10 ml) at 100°C for 24 h to afford 3–6 in
good yield (Table 1).
Next, we briefly studied the use of chiral primary
amines in the cascades (Table 1, entries 5–8). Thus,
using (R)-(+)-a-methylbenzylamine, (S)-(−)-2-amino-1-
methoxypropane, S-alanine methyl ester and S-phenyl-
alanine methyl ester, afforded 7–10 in good yields
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00329-5

2602
R. Grigg et al. / Tetrahedron Letters 43 (2002) 2601–2603
Table 1. Three-component allenylation–amination
ene-3,4-dihydro-1(2H)-isoquinolinones. We therefore
explored the path b process for these amines with
2-iodobenzoyl chloride. Thus, 2-iodobenzoyl chloride
(1.4 mmol) reacted with allene (1 bar), catalyst 11 (5
mol%),10 an aromatic or heteroaromatic amine (1
mmol), Cs2CO3 (2 mol equiv.) and 4 A molecular sieves
(3 g) in toluene (10 ml) at 100°C for 24 h to afford
12–15 in 53–70% yield (Table 2).
cascadesa
,
We also confirmed that the mechanism of the above
reaction employing methyl 2-iodobenzoate follows path
a, whereas 2-iodobenzoyl chloride follows path b. Thus,
when the reaction of 2-iodobenzoyl chloride with 2-
aminothiazole (Table 2, entry 2) was left for 24 h, a 1:1
mixture of 13 and 16 was obtained. Increasing the
reaction time to 48 h resulted in the sole formation of
13.
Table 2. Three-component allenylation–amination
cascadesa
a
All reactions were carried out in toluene at 100°C for 24 h and
employed 1 mmol methyl 2-iodobenzoate, 10 mol% Pd(OAc)2, 20
mol% PPh3, 2 mol equiv. K2CO3 or Cs2CO3 and 1.2 or 2 mol equiv.
amine.
b Isolated yields.
c Cs2CO3 as base.
d K2CO3 as base.
e 1.2 mol equiv. amine.
f 2 mol equiv. amine.
(Table 1, entries 5–8). In no cases was any racemisation
detected.
a
All reactions were carried out in toluene at 100°C for 24 h and
employed 1.4 mmol 2-iodobenzoyl chloride, 5 mol% catalyst 11, 2
mol equiv. Cs2CO3 and 1.2 mol equiv. amine.
b Isolated yields.
The use of aromatic and heteroaromatic amines in the
above cascades afforded lower yields of N-aryl 4-methyl-
c Reaction time 48 h.

R. Grigg et al. / Tetrahedron Letters 43 (2002) 2601–2603
Chem. Rev. 2000, 100, 3067–3126.
2603
2. Grigg, R.; Sridharan, V. J. Organomet. Chem. 1999, 576,
65–87.
3. Grigg, R.; Ko¨ppen, I.; Rasparini, M.; Sridharan, V. Chem.
Commun. 2001, 964–965.
4. Gai, X.; Grigg, R.; Collard, S.; Muir, J. E. Chem. Commun.
2000, 1765–1766.
5. Anwar, U.; Grigg, R.; Rasparini, M.; Savic, V.; Sridharan,
V. Chem. Commun. 2000, 645–646.
6. For recent examples see: (a) Larock, R. C.; He, Y.; Leong,
W. W.; Han, X.; Refvik, M. D.; Zenner, J. M. J. Org. Chem.
1998, 63, 2154–6160; (b) Zenner, J. M.; Larock, R. C. J.
Org. Chem. 1999, 64, 7312–7322; (c) Larock, R. C.; Tu, C.;
Pace, P. J. Org. Chem. 1998, 63, 6859–6866; (d) Mura-
kami, M.; Minamida, R.; Itami, K., Sawamura, M.; Ito,
Y. Chem. Commun. 2000, 2293–2294; (e) Murakami, M.;
Itami, K.; Ito, Y. Synlett 1999, 951–953; (f) Murakami, M.;
Evidence for the reaction of methyl 2-iodobenzoate
proceeding via path a, rather than path b, was gained
from the reaction of 2-iodobenzamide 17 in the presence
of allene (1 bar), Pd2(dba)3 (5 mol%), tri-2-furylphos-
phine (TFP) (10 mol%) and K2CO3 (2 mol equiv.) in
DMF at 100°C for 24 h, which afforded a 1:1 mixture of
18 and 3.11
In our cascade (Table 1, entry 1) we did not observe 18.
Moreover, a control experiment reacting methyl 2-
iodobenzoate (1 mmol) and benzylamine (1 mmol) in
toluene (10 ml) at 100°C for 24 h failed to give amide 17.
In conclusion, we have developed two complementary
three-component cascades for the synthesis of N-substi-
tuted 4-methylene-3,4-dihydro-1(2H)-isoquinolinones.
Further work is in hand incorporating substituted
allenes into this cascade.
Itami, K.; Ito, Y. Angew. Chem., Int. Ed. 1998, 37,
3418–3420.
7. Grigg, R.; Liu, A.; Shaw, D.; Suganthan, S.; Woodall, D.;
Yoganathan, G. Tetrahedron Lett. 2000, 41, 7125–7128.
8. Grigg, R.; Liu, A.; Shaw, D.; Suganthan, S.; Washington,
M.; Woodall, D.; Yoganathan, G. Tetrahedron Lett. 2000,
41, 7129–7133.
Acknowledgements
9. For a high pressure (20 atm) version of Ref. 6, see: (a)
Okuro, K.; Alper, H. J. Org. Chem. 1997, 62, 1566–1567;
(b) Xiao, X. J.; Alper, H. J. Org. Chem. 1999, 64, 9646–9652.
10. Gai, X.; Grigg, R.; Ramzan, M. I.; Sridharan, V.; Collard,
S.; Muir, J. E. J. Chem. Soc., Chem. Commun. 2000,
2053–2054.
We thank Leeds University and the Thailand Research
Fund (TRF) of the Royal Golden Jubilee project for
support.
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