Synthesis of spiro- and fused heterocycles by palladium catalysed carbo- and heteroannulation cascades of allenes

Article abstract of DOI:10.1039/b102046n

Two novel palladium catalysed cascade processes involving the generation of a (π-allyl)palladium intermediate from allenes in an intra- or intermolecular fashion, followed by regioselective intramolecular nucleophilic addition of amines, alcohols or malon

Full text of DOI:10.1039/b102046n

Synthesis of spiro- and fused heterocycles by palladium catalysed
carbo- and heteroannulation cascades of allenes
Ronald Grigg,* Ines Köppen, Marcello Rasparini and Visuvanathar Sridharan
Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds
University, Leeds, UK LS2 9JT. E-mail: R.Grigg@chem.leeds.ac.uk
Received (in Cambridge, UK) 5th March 2001, Accepted 23rd April 2001
First published as an Advance Article on the web 10th May 2001
Two novel palladium catalysed cascade processes involving
the generation of a (p-allyl)palladium intermediate from
allenes in an intra- or intermolecular fashion, followed by
regioselective intramolecular nucleophilic addition of
amines, alcohols or malonates provide spiro- or linear fused
heterocycles in good yield.
Substrates 2a–c and 4a–b were then reacted with allene (1.0
bar) or 3-methylbuta-1,2-diene (dimethylallene) in the presence
of a base and Pd(0) to afford the spirocyclic products in good
yield7 (Table 1). When dimethylallene was employed, exclusive
formation of the regioisomer arising from attack at the less
hindered end of the (p-allyl)palladium moiety was observed in
all the cases.
The importance and versatility of palladium catalysed processes
involving allenes for the construction of carbon–carbon and
carbon–heteroatom bonds is amply documented in a recent
review.1
We have demonstrated that allenes are powerful relay
switches in palladium catalysed polycomponent (poly)-cyclisa-
tion anion capture cascades.2 Reaction of aryl/vinyl palla-
dium(II) intermediates with allene leads to the formation of (p-
allyl)palladium species able to undergo a wide range of
transformations including attack by nucleophiles,3 electro-
philes4 or transmetallation.5
We then focused our attention on a fully intramolecular
process: a scaffold precursor 7 was synthesised in 57% overall
yield from 2-bromobenzaldehyde (Scheme 3).
The formyl group was then exploited for the introduction of
the desired nucleophiles (Scheme 4). The N-propargyl amides
were then isomerised to the relatively labile N-allenyl amides
The tactical combination of these transformations in an inter-
and/or intramolecular fashion6 enables expeditious increments
of the molecular complexity of the products that are limited only
by the ingenuity of the chemist.
We now report two novel palladium catalysed cascades
(‘Class 1’ and ‘Class 2’) characterised by intramolecular anion
capture2 as the termination step. Both cascades are initiated by
oxidative addition of Pd(0) into an Ar–I bond. In the ‘Class 1’
process this step is followed by an exo-trig cyclisation,
intermolecular allene insertion and intramolecular capture of
the resultant (p-allyl)palladium complex with a tethered
nucleophile (amine or malonate anion) (Scheme 1a). This
cascade results in the formation of three bonds and a spiro-fused
ring system.
Scheme 2 Reagents and conditions: (1) 2-iodo-N-tosylaniline, NaH,
3-chloro-2-chloromethylpropene, DMF, rt, 48 h, 95% or 2-iodophenol,
3-chloro-2-chloromethylpropene, K2CO3, MeCN, reflux, 2 h, 91%; (2)
primary amine (see Table 1), K2CO3, MeCN, reflux, 18 h (2a, 64%; 2b
54%; 4a, 61%, 4b, 60%) or dimethyl malonate, K2CO3, CH3CN, reflux, 18
h (2c, 80%, 4c, 84%).
Table 1 Class 1 processes
In the ‘Class 2’ process the (p-allyl)palladium complex is
generated by an exo-dig cyclisation of the Ar–Pd species onto a
proximal 1,2-dienamide. Subsequent interception of the result-
ing (p-allyl)palladium(II) species by a nucleophile leads to
bicyclic lactams with formation of two rings and two new bonds
(Scheme 1b).
The substrates for ‘Class 1’ process (Y = NR, C(CO2Me)2)
were prepared in two steps by displacement of the allylic
chlorides 1 or 3 with amines or dimethyl malonate (Scheme
2).
Yield
Entry
X
Y
R
Basea
Product (%)b
1 (2a)
2 (2b)
3 (2b)
4 (2c)
5 (2c)
6 (4a)
7 (4a)
8 (4b)
9 (4b)
NTs N-Cyclopropyl
NTs NBn
NTs NBn
NTs C(CO2Me)2
NTs C(CO2Me)2
O
O
O
O
H
H
Me
H
Me
H
Me
H
Me
K2CO3
K2CO3
K2CO3
Cs2CO3 5d
Cs2CO3 5e
K2CO3
K2CO3
K2CO3
K2CO3
5a
5b
5c
59
54
56
66
72
55
59
65
66
NBn
NBn
N-Cyclopropyl
N-Cyclopropyl
6a
6b
6c
6d
a For experimental, see ref. 7. b Isolated analytically pure products.
Scheme 3 Reagents and conditions: (1) MeOH, CH(OMe)3, Dowex 50W
X8-200, reflux, 18 h, 92%; 2) THF, n-BuLi, 278 °C, 30 min, then DMF,
278 °C to rt, 98%; (3) propargylamine, MgSO4, DCM, 100%; (4) MeOH,
NaBH4, 0 °C, 95%; (5) 2-iodobenzoyl chloride, TEA, DCM, 0 °C to rt,
69%; (6) Montmorillonite K10, DCM, rt 10 min, 97%.
Scheme 1
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Chem. Commun., 2001, 964–965
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102046n

Table 2 Class 2 processes
Entry
Y
Basea
Time (h)
Product
Yield (%)d
1 (8a)
2 (8b)
3 (8c)
4 (8d)
5 (10)
6 (11)
NBn
K2CO3
K2CO3
Ag2CO3
Ag2CO3
Cs2CO3
Cs2CO3
24
24
24
24
48
48
12a
12b
12cb
12dc
12e
63
55
52
54
50
45
N-Cyclopropyl
N-(1-Phenyl)ethyl
N-(1-Naphthalen-1-yl)ethyl
O
C(CO2Me)2
12f
a For experimental, see ref. 8. b 1.2+1 mixture of diasteroisomers (HPLC). c 1.5+1 mixture of diastereoisomers (1H NMR). d Isolated analytically pure
products.
a diastereofacial preference during the nucleophilic attack on
the (p-allyl)palladium complex. When K2CO3 was employed,
in both the cases a 1+1 mixture of diasteroisomers was obtained.
Little improvement was achieved using Ag2CO3 (entry 3) or by
increasing the steric hindrance around the nitrogen (entry 4).
However, the two diasteroisomers were easily separated by
crystallisation from EtOH.
A stronger base (entry 11) and longer reaction times were
required (entry 10) for the less nucleophilic alcohol and
malonate moieties.
In conclusion we have shown that this methodology permits
access to unusual spiro- and fused heterocyclic frameworks.
We thank Leeds University and the EU for support.
Notes and references
Scheme 4 Reagents and conditions: (1) Primary amine, MgSO4, DCM, then
1 R. Zimmar, C. U. Dinesh, E. Nandanan and F. A. Khan, Chem. Rev.,
MeOH, NaBH4 0 °C, 10 min, (8a, 85%, 8b, 76%, 8c, 71%, 8d, 84%); (2)
2000, 100, 3067.
THF, t-BuOK (1.0 eq.), 0 °C, 1 min; (3) MeOH, NaBH4 0 °C, 10 min, 87%;
2 R. Grigg and V. Sridharan, J. Organomet. Chem., 1999, 576, 65.
(4) THF, t-BuOK (2.0 eq.), 0 °C, 1 min; (5) MsCl, TEA, DCM, 0 °C then
3 R. Grigg, V. Sridharan and L.-H. Xu, J. Chem. Soc., Chem. Commun.,
DMF, sodium dimethyl malonate, 0 °C to rt, 60%; (6) THF, t-BuOK (2.0
eq.), 0 °C, 1 min.
1995, 1903.
4 X. Gai, R. Grigg, S. Collard and J. Muir, Chem. Commun., 2000,
1765.
immediately prior to the last Pd(0) catalysed step. The best
conditions employed t-BuOK (1.1 eq. or 2.1 eq. when alcohols
or malonates were used) in THF at 0 °C for 1 min. The
transformation is nearly instantaneous and longer reaction times
result in further isomerisation to N-prop-1-ynyl amides and to
the formation of alcoholysis products.
All the substrates 8a–d and 10–11 cyclised in 24–48 h in
toluene at 50 °C in the presence of Pd(0) and an inorganic base8
(Table 2).
5 U. Anwar, R. Grigg, M. Rasparini, V. Savic and V. Sridharan, Chem.
Comm., 2000, 645.
6 For a recent example of an intramolecular (p-allyl)palladium capture:
L. E. Overman and M. D. Rosen, Angew. Chem., Int. Ed., 2000, 39,
4596.
7 Typical experimental conditions for ‘Class 1’ process: substrate (0.3
mmol), allene (1.0 bar, 100 ml one-neck pressure dram vessel) or
dimethylallene (4.0 eq.), base (2.0 eq.), tri(2-furyl)phosphine (0.2 eq.),
Pd(OAc)2 (0.1 eq.), toluene (5.0 ml), 110 °C, 18 h.
8 Typical experimental conditions for ‘Class 2’ process: substrate (1.0
mmol), base (2.0 eq.), tri(2-furyl)phosphine (0.2 eq.), Pd(OAc)2 (0.1
eq.), toluene (5 ml), 50 °C, 24–48 h.
We employed two chiral amines (8c and 8d) in order to
establish if the stereocenter a- to the nitrogen is able to induce
Chem. Commun., 2001, 964–965
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