Sequential one-pot bimetallic Ir(III)/Pd(0) catalysed mono-/bis-alkylation and spirocyclisation processes of 1,3-dimethylbarbituric acid and allenes

Article abstract of DOI:10.1039/b614098j

Microwave assisted indirect functionalization of alcohols with 1,3-dimethylbarbituric acid followed by spirocyclisation employing a sequential one-pot Ir(iii)/Pd(0) catalysed process, involving the formation of three new C-C bonds, one spirocyclic ring and one di- or tri-substituted exocyclic alkene, is described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b614098j

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COMMUNICATION
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Sequential one-pot bimetallic Ir(III)/Pd(0) catalysed mono-/bis-
alkylation and spirocyclisation processes of 1,3-dimethylbarbituric acid
and allenes{
Christian Lo¨fberg,a Ronald Grigg,*a Ann Keep,b Andrew Derrick,c Visuvanathar Sridharana and Colin Kilnera
Received (in Cambridge, UK) 28th September 2006, Accepted 27th October 2006
First published as an Advance Article on the web 15th November 2006
DOI: 10.1039/b614098j
barbiturates 6 or unsymmetrical C5-bis-benzylated/29-arylallylated
barbiturates 8. In an initial series of experiments we demonstrated
that our solvent-free microwave protocol developed for a-alkyla-
tion of arylacetonitriles with alcohols6f was equally effective with
Microwave assisted indirect functionalization of alcohols with
1,3-dimethylbarbituric acid followed by spirocyclisation
employing a sequential one-pot Ir(III)/Pd(0) catalysed process,
involving the formation of three new C–C bonds, one
spirocyclic ring and one di- or tri-substituted exocyclic alkene,
is described.
Table 1 Catalytic alkylation of 1,3-dimethylbarbituric acid 1 with
various alcohols 2 under solvent-free microwave irradiation (MWI)
conditionsa
5-Alkylated or benzylated barbituric acids have proven useful both
as pharmaceuticals and as important intermediates in the synthesis
of new drugs.1 Barbiturates produce changes in mental activity
ranging from mild sedation and sleep, to deep coma and are
commonly used in the treatment of anxiety, insomnia, seizure
disorders, migraine headaches, and in surgery as general
anaesthetics.2
Entry
1
Alcohol
Product
Yield (%)b
84
2
3
79
83
More recently, derivatives of barbituric acids have been reported
to exhibit anti-cancer, analeptic, immunomodulating and anti-
AIDS activity3 whilst others are reported to be selective matrix
metalloproteinase (MMP) inhibitors.4 It is therefore clear that the
barbituric acid skeleton is an intriguing and reemerging member of
the privileged structure class.
There was no simple general synthetic procedure for the
preparation of 5-monoalkylated barbituric acid derivatives until,
quite recently, Jursic et al. described an effective reductive
alkylation protocol.5 Direct catalytic alkylation with alcohols is
an alternative and attractive green chemistry solution6,7 which
generates only water as a byproduct. In this communication we
report microwave assisted redox neutral processes (Scheme 1) for
the selective monoalkylation of 1,3-dimethylbarbituric acid
by alcohols and their extension to sequential one-pot bimetallic
Ir(III)/Pd(0) catalytic processes that afford either spirocyclic
4
82
5
6
76c
74
7
8
84d
85d
91
9
Scheme 1
aMolecular Innovation, Diversity and Automated Synthesis (MIDAS)
Centre, School of Chemistry, University of Leeds, Leeds, UK LS2 9JT.
E-mail: r.grigg@leeds.ac.uk; Fax: 0113 343 6530; Tel: 0113 343 6501
bJohnson Matthey, Orchard Road, Royston, Herts, UK SG8 5HE
cPfizer, Ramsgate Road, Sandwich, Kent, UK CT13 9NJ
{ Electronic supplementary information (ESI) available: Experimental
data. See DOI: 10.1039/b614098j
a
The reaction was carried out in a microwave reactor with 1
(1 mmol), alcohol (1.5 mmol), [Cp*IrCl2]2 (2.5 mol%) and KOH
b
c
(15 mol%) at 110 uC for 10 min. Isolated yield. Alcohol
(1.5 mmol) was used in toluene (0.5 mL) for 10 min. Reaction was
performed using traditional heating with alcohol (1.0 mL) at 100 uC
for 14 h.
d
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Investigation of this sequential one-pot Ir(III)/Pd(0) catalysed
process clearly demonstrated that iridium and palladium were
compatible. A series of microwave activated sequential one-pot
Ir(III)/Pd(0) cascades were performed utilising both allene gas and
substituted allenes (Table 2). This bimetallic cascade reaction
involves a number of fundamental organic transformations:
oxidation of an alcohol to the corresponding aldehyde,
Knoevenagel condensation of the in situ formed aldehyde and
the barbituric acid, reduction of the Knoevenagel product,
oxidative addition of Pd(0) to the aryl iodide followed by allene
insertion generating a p-allyl Pd(II) complex. Finally, this species is
captured in a regio- and stereoselective intra-molecular nucleo-
philic attack of the barbiturate C5-carbanion at the least hindered
sp2-carbon atom of the p-allyl species affording the E-alkene. This
highly atom-economic cascade involves the formation of three new
C–C bonds, one tetrasubstituted carbon centre, one spirocyclic
ring and one di- or tri-substituted exocyclic alkene. Alkene
stereochemistry was assigned from n.O.e. data and confirmed, in
the case of 6b, by X-ray crystallography (Fig. 1).§ There are two
independent molecules in the asymmetric unit of which only one is
shown in Fig. 1.
Scheme 2
N,N9-dimethylbarbituric acid 1 (Scheme 1, Table 1). A variety of
benzylic alcohols were successfully utilised to afford C5-mono-
alkylated products 3a–f in high yields (Table 1, entries 1–6).
Aliphatic alcohols such as ethanol 2g and 2-methyl propanol 2h
failed to undergo any reaction using our standard microwave
conditions but conventional thermal heating (100 uC, 14 h)
resulted in full conversion to products 3g and 3h which were
isolated in 84 and 85% yield, respectively (Table 1, entries 7 and 8).
The bis-alcohol 2i proved to be an excellent cascade substrate for
the microwave protocol, affording 3i in 91% yield.{
Formation of 3f opens up further C–C bond formation with
allene/substituted allenes 4a–f under palladium(0) catalysis to form
6-membered spirocyclic barbiturates 6. The reaction takes place via
allene insertion to the arylpalladium(II) iodide species to generate a
p-allyl intermediate 5 followed by cyclisation to afford spirocyclic
barbituric acid derivatives 6 (Scheme 2).
We believe this stereoselectivity arises from steric destabilization
of the syn-p-allyl palladium complex syn-9 favouring initial forma-
tion of anti-9 (Scheme 3) and suppressing p–s–p isomerization.
Inter–inter-molecular versions of this sequential inter–intra one-
pot bimetallic Ir(III)/Pd(0) cascade were also performed using
Table 2 Inter–intra-molecular sequential one-pot Ir(III)/Pd(0) cata-
lysed cascadesa
Entry Allene
1b
Product
Yield (%)c
42
2
3
52
53
Fig. 1 X-Ray crystal structure of 6b.
4
59 E : Z, 87 : 13
Scheme 3
5
50 E : Z, 95 : 5
a
The reaction was carried out in a microwave reactor with 1
(1 mol equiv.), alcohol (1.2 mol equiv.), [Cp*IrCl2]2 (2.5 mol%) and
KOH (15 mol%) at 110 uC for 10 min followed by addition of 4
(1.2 mol equiv.), Pd2dba3 (5 mol%), TFP (20 mol%), K2CO3
(2 mol equiv.), CH3CN (2 mL) and the reaction was continued
b
under microwave irradiation at 110 uC for 20 min. Allene gas
(0.5 bar) was used. Isolated yield.
c
Scheme 4
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Table 3 Inter–inter-molecular sequential one-pot Ir(III)/Pd(0) cata-
lysed cascadesa
Entry Alcohol Ar–I
Product
Yield (%)b
45
1
2b
2
2b
51
Fig. 2 X-Ray crystal structure of 8b.
supported by JM. Colin Kilner is gratefully acknowledged for
providing X-ray crystal structures. The Green Chemistry Centre
for Industrial Collaboration and Yorkshire Forward are acknowl-
edged for funding the CEM microwave reactor.
3
4
5
2d
2d
2d
65
48
53
Notes and references
{ During the purification of the C5-monoalkylated barbiturates 3a–i and
when left in chloroform for slow evaporation at ambient temperature an
autoxidation at the C5-position was observed.
§ Crystallographic data: 6b; CCDC 622415. 8b; CCDC 622416. For
crystallographic data in CIF or other electronic format see DOI: 10.1039/
b614098j
1 For instance, see: C. M. Smith and A. M. Reynard, Essentials of
Pharmacology, W. B. Sanders, Philadelphia, 1995.
2 For general information see: Central Nervous System Drugs, Sedatives
and Hypnotics, Barbiturates, ed. B. R. Olin, in Facts and Comparisons
Drug Information, Facts and Comparisons, St. Louis, MO, p. 1398.
3 (a) F. N. M. Naguib, D. L. Levesque, E.-C. Wang, P. P. Panzica and
M. H. El Kouni, Biochem. Pharmacol., 1993, 46, 1273; (b) D. L. Levesque,
E.-C. Wang, D.-C. Wei, M. H. El Kouni and F. N. M. Naguib,
J. Heterocycl. Chem., 1993, 30, 1399; (c) A. Oliva, G. De-Cillis, F. Grams,
V. Livi, G. Zimmerman, E. Menta and H. W. Krell, US Pat., 6,335,332,
B1, 2002; (d) R. I. Ashkinazi, Int. Pat., WO 99/25699, 1999; (e)
D. M. Neumann, B. S. Jursic and L.-R. Morgan, Abstracts of Papers,
225th ACS National Meeting, New Orleans, LA, United States, March
23–27, 2003.
6
2e
56
4 (a) D. T. Puerta and S. M. Cohen, Curr. Top. Med. Chem., 2004, 4, 1551;
(b) J. W. Skiles, N. C. Gonnella and A. Y. Jeng, Curr. Med. Chem., 2004,
11, 2911.
a
The reaction was carried out in a microwave reactor with 1
(1 mmol), alcohol (1.5 mmol), [Cp*IrCl2]2 (2.5 mol%) and KOH
(15 mol%) at 110 uC for 10 min followed by addition of Pd2dba3
(5 mol%), TFP (20 mol%), aryl iodide (1.5 mmol), K2CO3 (2 mmol),
CH3CN (2 mL) and allene (0.5 bar). The reaction was continued
5 (a) B. S. Jursic and D. M. Neumann, Tetrahedron Lett., 2001, 42, 4103;
(b) B. S. Jursic and E. D. Stevens, Tetrahedron Lett., 2003, 44, 2203.
6 (a) C. E. Bibby, R. Grigg and R. Price, J. Chem. Soc., Dalton Trans.,
1977, 872; (b) R. Grigg, T. R. B. Mitchell and S. Sutthivaiyakit,
Tetrahedron Lett., 1979, 35, 1067; (c) R. Grigg, T. R. B. Mitchell,
S. Sutthivaiyakit and N. Tongpenyai, J. Chem. Soc., Chem. Commun.,
1981, 611; (d) R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit and
N. Tongpenyai, Tetrahedron Lett., 1981, 22, 4107; (e) R. Grigg,
T. R. B. Mitchell and S. Sutthivaiyakit, Tetrahedron, 1981, 37, 4313; (f)
C. Lo¨fberg, R. Grigg, M. A. Whittaker, A. Keep and A. Derrick, J. Org.
Chem., 2006, 71, 8023.
7 For recent examples of similar transfer hydrogenation processes see: (a)
P. J. Black, G. Cami-Kobeci, M. G. Edwards, P. A. Slatford,
M. K. Whittlesey and J. M. J. Williams, Org. Biomol. Chem., 2006, 4,
116; (b) R. Martinez, D. J. Ramon and M. Yus, Tetrahedron, 2006, 62,
8982; (c) R. Martinez, D. J. Ramon and M. Yus, Tetrahedron, 2006, 62,
8988; (d) K. Motokura, D. Nishimura, K. Mori, T. Mizugaki, K. Ebitani
and K. Kaneda, J. Am. Chem. Soc., 2004, 126, 5662; (e) K. Taguchi,
H. Nakagawa, T. Hirabayashi, S. Sakaguchi and Y. Ishii, J. Am. Chem.
Soc., 2004, 126, 72.
b
under microwave irradiation at 110 uC for 20 min. Isolated yield.
substituted benzyl alcohols together with an aryl iodide and allene
gas, as the three carbon component, to afford unsymmetrical C5-
bis-benzylated/29-arylallylated products 8a–f (Scheme 4, Table 3).
The X-ray crystal structure§ of 8b (Fig. 2) suggests there may be
some carbonyl p-stacking interaction with the dichloroaryl ring.
˚
Thus, the centroid of the dichloroaryl ring is 3.7 A from the C6
˚
and 4.1 A from the C2 carbonyl C-atoms.
Further work on these and related Ir(III)/Pd(0) catalysed
processes is currently underway.
This work was a collaboration between the MIDAS Centre,
Johnson Matthey and Pfizer (Process R&D). C. L. was financially
5002 | Chem. Commun., 2006, 5000–5002
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