Rhodium catalyzed, one-pot, three component redox-neutral process towards fused ring heterocycles

Article abstract of DOI:10.1016/j.tetlet.2017.05.077

A three component, rhodium-catalyzed isomerisation/1,3-dipolar cycloaddition reaction is described for the synthesis of fused ring heterocycles as endo/exo isomers, with the formation of three new bonds and four stereocenters.

Full text of DOI:10.1016/j.tetlet.2017.05.077

Accepted Manuscript
Rhodium catalyzed, one-pot, three component redox-neutral process towards
fused ring heterocycles
Robert Lowe, Shereen Fathy, Visuvanathar Sridharan
PII:
S0040-4039(17)30669-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.077
TETL 48970
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 April 2017
9 May 2017
22 May 2017
Please cite this article as: Lowe, R., Fathy, S., Sridharan, V., Rhodium catalyzed, one-pot, three component redox-
neutral process towards fused ring heterocycles, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.05.077
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Rhodium catalysed, one-pot, three component redox-neutral process to
fused ring heterocycles
Robert Lowe, Shereen Fathy and Visuvanathar Sridharan*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Rhodium catalyzed, one-pot, three component redox-neutral process towards fused
ring heterocycles
Robert Lowe, Shereen Fathy and Visuvanathar Sridharan*
School of Chemistry, University of Leeds, LS2 9JT, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
A
three component, rhodium-catalyzed isomerisation/1,3-dipolar cycloaddition reaction is
described for the synthesis of fused ring heterocycles as endo/exo isomers, with the formation of
Received in revised form
Accepted
three new bonds and four stereocenters.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Rhodium
Dehydrogenation
1,3-Dipolar Cycloaddition
Azomethine Ylide
Multicomponent Reaction
Bicyclic pyrrolidine scaffolds are found in various bioactive
molecules, possessing medicinal properties such as potent protein
phosphatase 1 and 2A inhibition, high levels of anticancer
activity against a broad range of tumour cells lines,1 anti-tumour
Pin1 inhibition,2 and antimicrobial activity3 (Fig. 1).
Metals such as Rh, Ru, Ir, Co, Mo, Fe and Cr have been
reported to catalyze the double bond isomerization of allylic
amines to enamines.5 Nielsen and co-workers have reported a
ruthenium/Brønsted acid catalyzed tandem isomerization/N-
acyliminium ion cyclisation sequence for the synthesis of
tetrahydro-β-carbolines whilst Sorimachi and Terada have
reported ruthenium/Brønsted acid catalyzed cascade
isomerization/Friedel-Crafts type reactions.6-7 We have been
involved in generating azomethine ylides via a rhodium catalyzed
isomerization process using either two or three component
processes.8
Herein, we report a novel three component rhodium catalyzed
isomerization/1,3-dipolar cycloaddition cascade for the synthesis
of fused-ring cycloadducts as endo/exo isomers, with the
formation of three new bonds and four stereocenters using either
acyclic allylamines (Scheme 1a) or cyclic allylamines (Scheme
1b, c).
Figure 1. Selected bioactive bicyclic pyrrolidines
Recently, there has been strong interest in cascade reactions4
(multiple consecutive, one-pot reactions - also named domino
reactions) because of their operational simplicity, the
minimization of chemical waste, energy conservation and high
atom economy, which make this approach attractive for the fine
chemical and pharmaceutical industry.
This rhodium catalyzed process has significant advantages
over traditional methods to generate azomethine ylides from
aliphatic aldehydes and sarcosine alkylesters since aliphatic
aldehydes with enolisable hydrogens undergo aldol
condensation/enamine formation which subsequently results in
lower yields of the corresponding cycloadducts.9
The large number of possible transformations, wide
functional group tolerance and the catalytic nature of these
processes make rhodium chemistry an ideal basis for the
development of new cascade reactions, enabling rapid entry to
highly complex molecules.
The initial reaction was carried out using ethylbromoacetate
(1 mmol), N-allylmethylamine (1 mmol) and triethylamine (1
mmol) in toluene (15 mL), stirring at room temperature until the
alkylation was complete as shown by TLC. Subsequent addition
of N-methylmaleimide (1 mmol) and (PPh3)3RhCl (10 mol%),
and heating at 110 °C for 16 h afforded the endo and exo
* Corresponding Author: V.Sridharan@leeds.ac.uk; Tel +44-1133436520

2
Tetrahedron
cycloadducts 2 and 3 in 63% yield with a 1.7:1 ratio,
Table 1. Rhodium catalyzed three component cycloaddition
cascade reaction using N-allylmethylaminea
proceeding via the anti-dipole 1 (Scheme 2, Table 1, entry 1).
Entry Alkylbromide Product
Yield (%)b
1
63
85
57
46
48
77
2
3
4
5
6
Scheme 1. Rhodium catalysed, three component cycloaddition
cascades
7
8
9
43
58
37
Scheme 2. Three component, 1,3-dipolar cycloaddition reaction
The relative stereochemistry of cycloadducts 2 and 3 were
assigned by n.O.e (ESI). The rhodium catalyzed cycloaddition
reaction of symmetrical dipolarophiles such as N-
phenylmaleimide and maleimide with a range of alkyl
bromoacetates and N-methylallylamine was also explored and
gave mixtures of endo and exo cycloadducts in good to high
yields (Table 1 entries 2-8). Cycloadduct 2 was not converted
into cycloadduct 3 under the reaction conditions.
a Reagents and conditions: alkyl bromide (1 mmol), N-allylmethylamine (1
mmol), triethylamine (1 mmol), toluene, room temperature, 16 h, then
dipolarophile (1 mmol), (PPh3)3RhCl (10 mol%), 110 °C, 17-24 h. b Isolated
yield.

3
Next, we briefly examined unsymmetrical dipolarophiles in
the described cascade reaction. Thus benzyl bromoacetate (1
mmol), N-allylmethylamine (1 mmol) and triethylamine (1
mmol) in toluene (15 mL) were stirred at room temperature until
alkylation completion, followed by the addition of
In summary we have successfully carried out a one-pot,
three component, rhodium-catalyzed isomerization/1,3-dipolar
cycloaddition cascade to give fused ring heterocycles as endo/exo
isomers in good yields, with the formation of three new bonds
and four stereocenters.
phenylvinylsulphone (1 mmol) and heating at 110 °C for 24 h to
afford endo-cycloadduct 18 (30%) together with the Michael
adduct 19 (7%). In this case the cycloaddition was both stereo-
and regioselective (Entry 9).
Acknowledgments
We thank Leeds University for support.
The two component cycloaddition reaction of N-allyl-1,2,3,4-
tetrahydroisoquinoline (1 mmol) and N-methylmaleimide (1
mmol), using benzoic acid (20 mol%) and (PPh3)3RhCl (10
mol%) in toluene (15 mL) at 110 °C, afforded the endo 21 (with
respect to the ethyl group and maleimide) and exo 22
Notes and references
1. Thaqi, A.; Scott, J. L.; Gilbert, J.; Sakoff, A.; McCluskey, A., Eur.
J. Med. Chem. 2010, 45, 1717-1723
2. Darwish, S. E. Molecules 2008, 13, 1066–1078.
3. Siegrist, R.; Zurcher, M.; Baumgartner, C.; Seiler, P.; Diederich,
F.; Daum, S.; Fisher, G.; Klein, C.; Dangal M.; Schwaiger, M. A.
Helv. Chem. Acta. 2007, 90, 217-259.
cycloadducts in 40% yield (Scheme 3). In this case benzoic acid
was required as an additive to aid the formation of anti-dipole 20;
the reaction was unsuccessful in its absence. Seidel and
4. Tietze, L. F. Chem. Rev. 1996, 96, 115-136.
5. (a) Escoubt, S.; Gastaldi, S.; Bertrand, M. Eur. J. Org. Chem.
2005, 3855-3873; (b) Krompiec, S.; Krompiec, M.; Penczek, H.;
Ignasiah, H. Coor. Chem. Rev. 2008, 252, 1819-1841.
6. Hansen, C. L.; Clausen, J. W.; Ohm, R. G.; Ascic, E.; Le Qument,
S. T.; Tanner, D.; Nielsen, T. E. J. Org. Chem. 2013, 78, 12545-
12565.
co-workers previously reported that benzoic acid facilitates
amine α-functionalization via an intermediate azomethine ylide.10
7.
Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2008, 130, 14452-
14453.
8. (a) Gorman, R. M.; Little, M. A.; Morris, J. A.; Sridharan, V.
Chem. Commun. 2012, 48, 9537-9539; (b) Windle, J.; Allison, M.;
Sheperd, H.; Sridharan, V. RSC Adv. 2014, 4, 2624-2627.
9. (a) Confalone, P. N.; Earl, R. A.; Tetrahedron Lett. 2003, 44,
8417- 8420; (b) Coldham,I.; Crapnell, K. M.; Moseley, J. D.;
Rabot, R. J. Chem. Soc. Perkin Trans. 1. 2001, 1758-1763.
10. (a) Deb, I.; Das, D.; Seidel, D. Org. Lett. 2011, 13, 812-815; (b)
Mantelingu, K.; Lin, Y.; Seidel, D. Org. Lett. 2014, 16, 5910-
5913.
Scheme 3. Two component, 1,3-dipolar cycloaddition reaction
Finally, we briefly explored the cycloaddition reaction of
1,2,3,6-tetrahydropyridine (1 mmol) and 2-bromo-4’-
methoxyacetophenone (1 mmol) with triethylamine (1 mmol) in
toluene (15 mL) for 16 h, followed by the addition of N-
phenylmaleimide and (PPh3)3RhCl (10 mol%) and heating at 110
°C for 16 h to afford two endo (with respect to the piperidine ring
and maleimide) cycloadducts 25 and 26 in 40% yield with a 0.5:1
ratio, proceeding via the anti-dipoles 23 and 24 (Scheme 4).
O
H
H
N
O
Ph
N
H
O
O
(PPh3)3RhCl
(10 mol%)
25
H
Br
+
+
MeO
N
O
O
+
O
N
H
H
Et3N
toluene, 110 °C
Ph
MeO
N
Ph
N
H
O
O
26
MeO
+
N
N
40%
OMe
OMe
O
O
23
24
Scheme 4. Tetrahydropyridine cycloaddition cascade.
The relative stereochemistry of cycloadducts 25 and 26 were
assigned by n.O.e (ESI). Regiospecific dehydrogenation occurred
during the above cycloaddition reaction.

4
Tetrahedron
Highlights
• Readily available starting materials
were used to increase the molecular
complexity of the scaffolds in one-step
• Atom economical process
• Synthesis of biologically important
motifs