Sequential alkylation/transition metal catalysed annulation reactions of 1,3-dicarbonyl compounds with propargyl bromide

Article abstract of DOI:10.1016/S0040-4039(00)01666-X

β-Diketones, β-ketoesters and βketonitriles in the presence of propargyl bromide, DBU and a catalytic amount of CuI in toluene give 2,3,5-trisubstituted furans through sequential alkylation/cyclisation/isomerisation reactions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01666-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9195–9198
Sequential alkylation/transition metal catalysed annulation
reactions of 1,3-dicarbonyl compounds with propargyl
bromide
Antonio Arcadi,* Giorgio Cerichelli, Marco Chiarini, Sabrina Di Giuseppe and
Fabio Marinelli
Dipartimento di Chimica Ingegneria Chimica e Materiali della Facolta` di Scienze, Universita` di L’Aquila,
Via Vetoio, Coppito Due, I-67100 L’Aquila, Italy
Received 24 August 2000; accepted 26 September 2000
Abstract
b-Diketones, b-ketoesters and b-ketonitriles in the presence of propargyl bromide, DBU and a catalytic
amount of CuI in toluene give 2,3,5-trisubstituted furans through sequential alkylation/cyclisation/
isomerisation reactions. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: 1,3-dicarbonyls; propargylation; cyclisation.
The development of environmentally friendly procedures for the synthesis of organic com-
pounds is becoming an area of growing importance.1 Traditional stepwise formation of target
molecules tends to be replaced by domino reactions.2 Indeed, it would be much more efficient
if one could form several bonds in one sequence without isolating the intermediates, changing
the reaction conditions, or adding reagents. It is obvious that this type of reaction would allow
the minimisation of waste since compared to stepwise reactions the amount of solvents, reagents
and energy would be dramatically decreased.
In connection with our ongoing interest in developing new synthetic strategies for the
construction of five-membered heterocyclic rings involving transition metal catalysed domino
reactions,3 we planned to prepare functionalised furans using a simpler, and more efficient
one-pot procedure compared to the classical stepwise methodology (Scheme 1a). The derivatives
2, easily obtained by means of the reaction of sodium salts of b-dicarbonyl compounds with
propargyl halides4 afford the furans 4 through ZnCO3-catalysed enolate cyclisation.5 Examples
of oxygen–carbon ring closures of enolisable pentynones and hexynones with acid, base and
transition metal catalysis have also been described.6
* Corresponding author. Fax: +93 0862 433753; e-mail: arcadi@univaq.it
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01666-X

9196
Scheme 1.
Based on the results of the monoalkylation of acetylacetone using 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU)7 in a non-polar solvent, we report that b-diketones, b-ketoesters and
b-ketonitriles in the presence of propargyl bromide, DBU and a catalytic amount of CuI in
toluene give the expected furans through sequential monoalkylation/cyclisation/isomerisation8
(Scheme 1b) (Table 2). To our knowledge this is the first synthesis of furans directly from
1,3-dicarbonyl compounds and propargyl bromide. Previously the synthesis of 2,3-disubstituted-
5-methylene-4,5-dihydrofurans 3 by reacting alkyl 3-oxoalkanoates with sodium ethoxide in
ethanol/DMF and treating the metallation product thus obtained with propargyl bromide in the
presence of copper (I) bromide was reported. Then the derivatives 3 were isomerised to furans
4 in anhydrous ether in the presence of catalytic amounts of sulfuric acid.9 In all the cases
examined the domino reaction presents the advantage of elimination of the dialkylation reaction
of 1.
In the presence of ZnCl2 and RuCl310 as catalysts, yields of 4 are lower with respect to the CuI
catalyst (compare entry 1 with entries 2, 3 of Table 1 and entries 4, 5, 6 of Table 2). We failed
to synthesise 4a in the presence of ZnCO3 in refluxing ethanol (Table 1, entry 5). Disappointing
results from a synthetic point of view are obtained in water or without any solvent (Table 1,
entries 4 and 6; Table 2 entries 3 and 7).
Table 1
Synthesis of 4a from 1aa
Entry
Solvent/catalyst
4a (% yield)b
1
2
3
4
5
6
PhCH3/CuI
91
60
60
18
–
PhCH3/ZnCl2
EtOH/ZnCl2
H2O,CH3CN/ZnCl2
EtOH/ZnCO3
–/CuI
31
a 1a:propargyl bromide: DBU: catalyst=1:1:2:0.1.
b Isolated yields.

9197
Table 2
Synthesis of 2,3,5-trisubstituted furans 4 from 1
Entry
Substrate 1 R%=; Y=
Solvent/Catalyst
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
1a Ph; COOEt
1b Ph; COPh
1b
1c Ph; CN
1c
1c
1c
1d CH3; COCH3
1e CH3; COOCH3
1f Ph; COCH3
PhCH3/CuI
PhCH3/CuI
4a
4b
4b
4c
4c
4c
4c
4d
91
55
15
55
40
40
20
65
70
60
EtOH, H2O/CuI
PhCH3/CuI
PhCH3/RuCl3
EtOH/ZnCl2
EtOH, H2O/ZnCl2
PhCH3/CuI
PhCH3/CuI
PhCH3/CuI
4e
4f+4f%
10
a Isolated yields.
The reaction of 1b with propargyl bromide/DBU in THF–H2O in the presence of a catalytic
amount of NaAuCl4·2H2O (1b:NaAuCl4·2H2O=1:0.02) gave the tricarbonyl derivative 5 (40%
yield) (Scheme 2). It is very likely that 5 may derive from 2b generated in situ, which undergoes
a regioselective hydration11 by Au(III) catalysis.
Scheme 2.
When the 1-phenyl-1,3-butanedione 1f, which can give two isomeric enolate anions, was
treated with propargyl bromide/DBU/CuI in toluene the exo–dig annulation reaction of the less
stable enolate anion occurs preferentially to give 4f (Scheme 3) (Table 2, entry 10) as the main
reaction product (4f:4f%=2).
Scheme 3.
Very surprisingly, 6 is obtained through regioselective g-propargylation12 of 1f (Scheme 4)
(41% yield) using the EtOH/DBU/ZnCl2 system. Better results are obtained without the catalyst
(74% yield). The product of a-propargylation 2f is ready available in benzene/DBU at rt.

9198
Scheme 4.
In conclusion, b-diketones, b-ketoesters and b-ketonitriles in the presence of propargyl
bromide, DBU and a catalytic amount of CuI in refluxing toluene can give directly 2,3,5-trisub-
stituted furans. A sequential propargylation/Au(III) catalysed hydration of 1b to give a
tricarbonyl derivative may occur. DBU/EtOH promoted g-propargylation of 1,3-dicarbonyl-
compounds is under further investigation because it is promising to overcome some of the
drawbacks of the functionalisation of the terminal carbon atom of 1,3-dicarbonyl compounds.
Acknowledgements
Financial support from MURST (Roma) in the framework of the National Project ‘‘Processi
Puliti per la Chimica Fine’’ is gratefully acknowledged.
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