Sequential one-pot three component rhodium-catalysed isomerisation/1,3- dipolar cycloaddition cascades to fused-ring heterocycles

Article abstract of DOI:10.1039/c3ra45906c

One-pot three component rhodium-catalysed isomerisation/1,3-dipolar cycloaddition cascades to fused ring heterocycles with formation of three new bonds and four stereo centres occurred in good yields.

Full text of DOI:10.1039/c3ra45906c

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Sequential one-pot three component rhodium-
catalysed isomerisation/1,3-dipolar cycloaddition
cascades to fused-ring heterocycles†
Cite this: RSC Adv., 2014, 4, 2624
Received 21st October 2013
Accepted 30th October 2013
Jonathan Windle, Matthew Allison, Helena Shepherd and Visuvanathar Sridharan*
DOI: 10.1039/c3ra45906c
www.rsc.org/advances
One-pot three component rhodium-catalysed isomerisation/
,3-dipolar cycloaddition cascades to fused ring heterocycles with rhodium catalysed isomerisation/1,3-dipolar cycloaddition
formation of three new bonds and four stereo centres occurred in cascades to generate fused-ring heterocycles with formation of
In this communication we report a novel three component
1
good yields.
three new bonds and four stereocentres using either acylic
allylamines e.g. N-methylallylamine (Scheme 1a) or cyclic allyl-
amines e.g. 3-pyroline (Scheme 1b). In the case of using 3-pyr-
roline in addition to the cycloadduct a pyrrole was also formed
The development of facile methods to form heterocyclic scaf-
folds is critical to the drug-discovery process. Cascade or
domino reactions have emerged as a powerful tool for synthetic
(Scheme 1b).
3 3
We have identied Rh(PPh ) Cl as an effective catalyst for
1
chemists. These cascade processes generate a high level of
13
similar transformation.
molecular complexity in one efficient step, minimising solvent
use, reagents, time and energy.
We have been involved in generating azomethine ylides
via catalytic dehydrogenation methods utilising either
palladium or ruthenium black. Functionalisation of sp
C–H bonds adjacent to a nitrogen atom has generally
Initially we carried out the cascade reaction of 2-bromoace-
tophenone 1 (1 mmol) with N-methylallylamine (1 mmol) and
triethylamine (1 mmol) in toluene (20 mL) at room temperature
until the alkylation was completed as shown by TLC, followed
2
3
by addition of N-methylmaleimide (1 mmol) and (PPh
3
)
3
RhCl
ꢀ
(10 mol%) at 110 C for 8 h which afforded cleanly the cyclo-
been achieved utilising transition metal catalysts such as
adduct 3 (Table 1 entry 1) in 73% yield. The relative stereo-
chemistry of the cycloadduct 3 was assigned using n.O.e.
studies and was conrmed with X-ray crystallography (Fig. 1).
Cycloaddition was stereoselective and occurred via an endo
transition state of the anti dipole 2 (with respect to the ethyl
group and maleimide) (Scheme 2).
3
4
5
Ru, Rh, and V with co-oxidants, such as tert-butylhy-
droperoxide (TBHP), H , molecular oxygen and others to
2
O
2
generate iminium ion species, which in turn react
with various nucleophiles. Recently Maycock et al. have
6
reported dehydrogenation of tertiary amines using a copper
7
catalyst.
We also explored the rhodium catalysed cycloaddition of
other symmetrical dipolarophiles such as N-phenylmaleimide,
maleimide with 2-bromoacetophenone and N-methylallylamine
Metal catalysed double bond isomerisation of allylic
amines to enamines have been utilised in organic
8
–10
synthesis.
Nielsen et al. have reported the ruthenium
ꢀ
under essentially same conditions as above in toluene at 110 C
catalysed generation of cyclic N-acyliminium ion followed by
the subsequent synthesis of heterocycles whilst Sorimachi
and Terada have reported the ruthenium/Bronsted acid
catalysed cascade isomerisation/Fridel–Cras type reac-
which resulted in good yield of the cycloadducts (Table 1
1
1,12
tions.
We have recently reported the rhodium catalysed
isomerisation of N-allyl proline methylester to generate
1
3
azomethine ylides.
School of Chemistry, University of Leeds, LS2 9JT, UK. E-mail: v.sridharan@leeds.ac.
uk; Fax: +44 (0)1133436401; Tel: +44-(0)1133436520
†
Electronic supplementary information (ESI) available: Experimental details and
characterisation data. CCDC 948607. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3ra45906c
Scheme 1
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Table 1 Rhodium catalysed three component cycloaddition cascade
reaction using N-methylallylamine
a
Entry
Alkylbromide
Product
1
Fig. 1 Molecular structure of cycloadduct 3.
2
3
Scheme 2
stereochemistry of the cycloadduct 11 and 12 were assigned using
n.O.e. studies. Cycloadduct 12 could arise via the rhodium-cata-
lysed epimerisation of cycloadduct 11 or via the endo transition
state of the syn dipole (Scheme 3). To probe this mechanistic
3 3
rationale further, cycloadduct 11 was subjected to (PPh ) RhCl
4
under the same reaction conditions and afforded a mixture of
cycloadducts 11 and 12 in the ratio of 3.2 : 1. This implies that
the cycloadduct 12 is more likely to arrise via epimerisation or
alternatively that 11 might undergo a slow retero 1,3-dipolarcy-
cloaddition to generate a new syn dipole which then undergoes a
1,3-dipolar cycloaddition with N-methylmalemide via an endo
transition to afford 12. Further studies are clearly required to
delineate the precise order and nature of the steps involved in
this three-component cascade.
5
Similar results were obtained but in shorter reaction time (4 h)
0
with 2,4 -dibromoacetophenone and N-phenyl maleimide resulted
in two stereomeric cycloadduct 13 and 14 ratio of (5 : 1) in 77%
yield. We briey looked at the use of bromomethyl tert-butylke-
tone in the above cycloaddition cascade. Thus rhodium catalysed
cycloaddition of N-phenylmaleimide, N-methylmaleimide with
a
Isolated yields.
entry 1). Once again the cycloaddition was stereoselective and bromomethyl tert-butylketone and N-methylallylamine under
ꢀ
occurred via the endo transition state of the anti dipole 2.
essentially same conditions as above in toluene at 110 C which
Next we explored the effects of substitution on the benzene resulted in moderate yield of the cycloadducts 15 and 16 (Table 1,
ring in 2-bromoacetophenone during the cycloaddition entry 5). Related azomethine ylide cycloadditions are known in the
cascades. Thus electron donating groups on the benzene ring literature and they are generated from either 4-oxazoline or from
14
resulted in good yield of the cycloadducts (Table 1 entries 2 and 2-acylaziridine.
3
). However when using an electron withdrawing group, in the
Next we explored the rhodium catalysed three component
0
benzene ring e.g. 2,4 -dibromoacetophenone with N-methyl- cascade cycloaddition reaction using 3-pyrroline (Scheme 1b).
maleimide resulted in two stereomeric cycloadducts 11 and 12 The initial reaction was carried out using 2-bromoacetophe-
in a ratio of (3.5 : 1) in 66% yield (Table 1 entry 4). The relative none 1 (1 mmol) with 3-pyrroline (1 mmol) and triethylamine
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dipolarophiles such N-methylmalemide, malemide with 2-bro-
moacetophenone and 3-pyrroline were also explored under
essentially the same reaction conditions as above in toluene at
ꢀ
1
10 C which resulted in good yield of cycloadducts together with
N-substituted pyrrole (Table 2 entry 1). Once again cycloaddition
was stereoselective and occurred via the endo transition state of
the anti dipole. Cycloadduct formation versus pyrrole formation
depends on the nature of the dipolarophile i.e. (N-phenyl-
maleimide > maleimide > N-methylmaleimide). The substitution
effects on the benzene ring in 2-bromoacetophenone during
cycloaddition cascades were then explored. Thus both an electron
0
0
donating group (2 ,4 -dimethoxy) and withdrawing group
0
(
4 -bromo) on the benzene ring resulted in good yields of cyclo-
adducts together with pyrroles (Table 2 entry 2) ratio of 1 : 1 and
1 : 1.6 respectively. Substitution on the benzene ring clearly have
an effect on the rate at which oxidation to pyrrole occurs.
Finally we briey explored the pyrrole formation in the
absence of a dipolarophile added. This lead to the formation of
pyrrole in good yield. It was found that an electron withdrawing
Scheme 3
(
1 mmol) in toluene (20 mL) at room temperature until the
alkylation is completed, by TLC, followed by addition of
N-methylmaleimide (1 mmol) and (PPh RhCl (10 mol%) at
10 C for 4 h which afforded cleanly the cycloadduct 17 and
0
group e.g. 3 nitro group on the benzene ring resulted in excel-
lent yield of N-substituted pyrrole 25 (see ESI†).
3 3
)
ꢀ
1
Proposed mechanism for the formation of cycloadduct and
pyrrole is shown in Scheme 4. At this stage, it must be
emphasised that the proposed mechanism (Scheme 4) for the
process is merely tentative and is the subject of ongoing
research. Upon C–H activation at the allylic position, organo-
metallic species A, stabilised through iminium complex B, is
generated. Subsequent hydride migration to the olenic carbon
affords intermediate C which undergoes either decomplexation,
releasing the enamine D or generates the azomethine ylide E
which undergoes the cycloaddition reaction with dipolar-
ophiles. Potentially azomethine ylide could be generated from B
or C where Rh is still bound to the azomethine ylide.
pyrrole 18 with a ratio of 1.8 : 1 in 53% and 26% isolated yields
respectively (Table 2, entry 1). The relative stereochemistry of the
cycloadduct 17 was assigned using n.O.e. studies. In an attempt
to limit the formation of the pyrrole, the reaction was performed
under an atmosphere of nitrogen however the difference in the
ratio of the cycloadduct : pyrrole was found to be marginal. For
the above reaction cycloadduct : pyrrole ratio of 1.8 : 1in the
absence of nitrogen and 2 : 1 in the presence of nitrogen was
observed. Rhodium catalysed cycloadditon of other symmetrical
Table 2 Rhodium catalysed three component cycloaddition cascade
reaction using 3-pyrroline
In summary we have successfully carried out one-pot three
component rhodium catalysed isomerisation/1,3-dipolar cyclo-
addition cascades to fused ring heterocycles in good yield.
Future efforts will focus on Petasis reaction followed by
rhodium catalysed isomerisation/1,3-dipolar cycloaddition
cascades to generate more diversity in the process.
a,b
Entry
Alkylbromide
Product
1
2
a
b
Isolated total yields. Cycloadduct : pyrrole ratio was determined
from the NMR of the crude product.
Scheme 4
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9
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Acknowledgements
We thank Leeds University and Prof. Chris Rayner for support.
1819.
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