Bronsted acid catalyzed propargylation of 1,3-dicarbonyl derivatives. Synthesis of tetrasubstituted furans

Article abstract of DOI:10.1021/ol0631298

Simple Bronsted acids such as p-toluenesulfonic acid monohydrate (PTS) efficiently catalyze a direct substitution of the hydroxyl group in propargylic alcohols with 1,3-dicarbonyl compounds. Selective propargylation or allenylation is obtained depending o

Full text of DOI:10.1021/ol0631298

ORGANIC
LETTERS
2007
Vol. 9, No. 4
727-730
Brønsted Acid Catalyzed Propargylation
of 1,3-Dicarbonyl Derivatives. Synthesis
of Tetrasubstituted Furans
Roberto Sanz,*,† Delia Miguel,† Alberto Mart´ınez,† Julia M. A
Ä
lvarez-Gutie´rrez,† and
Fe´lix Rodr´ıguez‡
Departamento de Qu´ımica, AÄ rea de Qu´ımica Orga´nica, Facultad de Ciencias,
UniVersidad de Burgos, Pza. Misael Ban˜uelos s/n, 09001-Burgos, Spain, and Instituto
UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”, UniVersidad de OViedo,
C/Julia´n ClaVer´ıa, 8, 33006-OViedo, Spain
rsd@ubu.es
Received December 27, 2006
ABSTRACT
Simple Brønsted acids such as p-toluenesulfonic acid monohydrate (PTS) efficiently catalyze a direct substitution of the hydroxyl group in
propargylic alcohols with 1,3-dicarbonyl compounds. Selective propargylation or allenylation is obtained depending on the nature of the
alkynol. Reactions can be performed in air in undried solvents with water being the only side product of the process. By applying this reaction
as the key step, a range of interesting polysubstituted furans can easily be synthesized in a one-pot procedure.
The alkylation of 1,3-dicarbonyl compounds represents
one of the most useful methodologies for carbon-carbon
bond formation. Usually, this process requires the use of a
stoichiometric amount of base and an organic halide as the
alkylating agent. An alternative approach, via acid-cata-
lyzed addition of active methylenes to alcohols, would
provide a more atom-economical process.1 However, this
strategy still remains a major goal of modern organic
synthesis.2
allylic and benzylic alcohols by using simple Brønsted acids
as catalysts. The efficiency of this environmentally friendly
methodology led us to explore the scope of such a substitu-
tion reaction on propargylic alcohols. Recently, some
catalytic methodologies for the direct substitution of pro-
pargylic alcohols in the presence of ruthenium,5 rhenium,6
gold,7 or bismuth8 catalysts have been reported. Nevertheless,
the use of 1,3-dicarbonyl compounds as nucleophiles has not
been well established in any of these works.9
In this context, we,3 and others,4 have been involved in
the development of “greener” and cheaper methods for the
alkylation of active methylenes, such as 1,3-dicarbonyls, with
(2) An interesting direct substitution of allylic and benzylic alcohols by
nucleophiles catalyzed by indium trichloride has recently appeared. See:
Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2006, 45, 793.
(3) Sanz, R.; Mart´ınez, A.; Miguel, D.; AÄ lvarez-Gutie´rrez, J. M.;
Rodr´ıguez, F. AdV. Synth. Catal. 2006, 348, 1841.
† Universidad de Burgos.
‡ Universidad de Oviedo.
(4) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda,
K. Angew. Chem., Int. Ed. 2006, 45, 2605.
(1) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
10.1021/ol0631298 CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/27/2007

Herein, we wish to report that both secondary and tertiary
propargylic alcohols undergo efficient and highly regio-
selective substitution with â-dicarbonyl compounds under
Brønsted acid catalysis. This method allows the easy
preparation of useful synthetic intermediates for various
applications.
Surprisingly, to the best of our knowledge, no reports
(general methods) have been described in the literature for
the preparation of apparently simple 2-propargylic-1,3-
dicarbonyl compounds further substituted at the propargylic
position. Our studies started with the reaction between 1,3-
diphenyl-2-propyn-1-ol 1a and several â-dicarbonyl com-
pounds (Figure 1) in analytical grade acetonitrile as solvent,
Internal alkynes 1b-e with either an aromatic or hetero-
aromatic group at the propargylic position (R1),11 or with an
aromatic, heteroaromatic, or alkyl group at the terminal
position (R2), gave good results allowing the synthesis of
propargylated derivatives 3 in high to moderate yields (Table
1, entries 7-16). Moreover, the reactions also proceeded with
terminal alkynols such as 1f and 1g, though slightly lower
yields were obtained in some cases (Table 1, entries 17-
20).
We were interested in studying the reactivity of tertiary
alkynols. Propargylic alcohols 1h and 1i were selected as
model compounds and tested as substrates under PTS
catalysis with 1,3-diketones 2a and 2b (Scheme 1). However,
Scheme 1. Reaction of Diketones 2a and 2b with Tertiary
Alkynols 1h and 1i
Figure 1. 1,3-Dicarbonyl compounds examined.
at room temperature under p-toluenesulfonic acid mono-
hydrate (PTS) catalysis (5 mol %).10 As shown in Table 1
(entries 1-6), the process was general with respect to the
nature of the 1,3-dicarbonyl derivative 2 employed, and the
regioselectivity always completely favored the propargylation
reaction of the active methylene or methine compound.
Although in general the reactions were run in acetonitrile, it
was also possible to carry them out in the absence of solvent
using an excess of the 1,3-dicarbonyl compound. In this way,
3aa could be obtained in 82% yield by treatment of alkynol
1a with 2a (5 equiv) and PTS (5 mol %) at room temperature
for 8 h (Table 1, entry 1). The effectiveness of the process
was evaluated by a gram-scale experiment (15 mmol), which
gave 3aa (4.0 g) in 92% yield (Table 1, entry 1).
the conjugated diene-diones 4a and 4b were obtained in
these cases as the only isolable compounds. We believe that
under the catalytic acid conditions the highly activated
tertiary alkynols 1h and 1i undergo an isomerization into
the corresponding R,â-unsaturated ketone 5a or aldehyde 5b,
respectively (Meyer-Schuster rearrangement).12 These car-
bonyl derivatives undergo aldol-type condensation with
diketones 2 to afford the final isolated compounds 4 (Scheme
1).13
Interestingly, we found that the presence of a substituent
at the active methylene position of â-diketones, such as in
2d, 2e, and 2g, gave rise to substitution reactions with tertiary
alkynols 1h and 1i (Table 2) under PTS catalysis. However,
in these cases, a regioselective allenylation reaction took
place affording allene derivatives 6 in moderate to good
yields. These results seem to indicate that all these reactions
We then explored the generality of the reaction by varying
the substituents R1 and R2 of the propargylic alcohols 1
(Table 1, entries 7-20).
(5) Nishibayashi, Y.; Milton, M. D.; Inada, Y.; Yoshikawa, M.; Wakiji,
I.; Hidai, M.; Uemura, S. Chem.-Eur. J. 2005, 11, 1433 and references
therein.
(6) Ohri, R. V.; Radosevich, A. T.; Hrovat, J.; Musich, C.; Huang, D.;
Holman, T. R.; Toste, F. D. Org. Lett. 2005, 7, 2501 and references therein.
(7) Georgy, M.; Boucard, V.; Campagne, J. M. J. Am. Chem. Soc. 2005,
127, 14180.
(8) Zhan, Z.-p.; Yang, W.-z.; Yang, R.-f.; Yu, J.-l.; Li, J.-p.; Liu, H.-j.
Chem. Commun. 2006, 3352.
(9) As known, 1,3-dicarbonyls compounds are good ligands for a broad
range of metals. So, we speculate that the complexation between the metal
center and the dicarbonyl derivative could inhibit the reaction in some cases.
Nevertheless, for the Ru-catalyzed coupling of ketones with terminal
alkynols, see: Nishibayashi, Y.; Wakiji, I.; Ishii, Y.; Uemura, S.; Hidai,
M. J. Am. Chem. Soc. 2001, 123, 3393.
(10) Generally, the reactions are slow at room temperature (1-12 h),
whereas at reflux shorter reaction times (0.5-3 h) were required for
complete conversions. See Supporting Information for details.
(11) The presence of a cation-stabilizing aryl-type substituent at the
propargylic position seems to be necessary for the success of the reaction.
An alkyl-substituted propargylic alcohol, such as 1-cyclohexyl-3-phenyl-
2-propyn-1-ol, failed to react under the standard conditions.
(12) We have previously observed this Meyer-Schuster rearrangement
with these tertiary alkynols and heteroatom-centered nucleophiles: Sanz,
R.; Mart´ınez, A.; AÄ lvarez-Gutie´rrez, J. M.; Rodr´ıguez, F. Eur. J. Org. Chem.
2006, 1383.
(13) Similar tandem isomerization/condensation processes have been
reported under ruthenium catalysis: (a) Onodera, G.; Matsumoto, H.;
Nishibayashi, Y.; Uemura, S. Organometallics 2005, 24, 5799. (b) Cadierno,
V.; D´ıez, J.; Garc´ıa-Garrido, S. E.; Gimeno, J.; Nebra, N. AdV. Synth. Catal.
2006, 348, 2125. As suggested by a referee, an alternative mechanism may
involve allenylation of the diketone followed by isomerization to the
conjugated diene.
728
Org. Lett., Vol. 9, No. 4, 2007

Table 1. Reactions of Propargylation of â-Dicarbonyl Compounds 2 with Alkynols 1a
a
b
Reaction conditions: 2 (1 mmol), 1 (1 mmol), PTS (0.05 mmol) in MeCN (5 mL) at room temperature or reflux (see Supporting Information).
c
1
Isolated yields based on starting alkynols 1. When it is the case, and unless otherwise stated, the ratio of diastereoisomers was ca. 1:1 (determined by H
NMR of the crude). Carried out in the absence of solvent. Carried out in a 15 mmol scale. The two diastereoisomers were separated by column
chromatography (see Supporting Information). 3-Thienyl. Ca. a 2:1 mixture of diastereoisomers. Run at reflux. 2-Naphthyl.
d
e
f
g
h
i
j
proceed through the formation of a cationic species, and the
regioselectivity of nucleophilic trapping depends on the
structure of 1.14 The formation of propargylic products such
as 3 was highly sensitive to the nature of the starting alcohol,
so for tertiary alkynols 1h and 1i, an allenyl-type cation was
trapped by the nucleophile.
Org. Lett., Vol. 9, No. 4, 2007
729

at the propargylic position. So, reaction of alkynols 1 with
â-dicarbonyl derivatives 2 and a catalytic amount of PTS
followed by addition of potassium carbonate allows the
synthesis of functionalized furans 7 in moderate to good
yields (Table 3). Thus, a straightforward one-pot procedure
Table 2. Allenylation of Substituted 1,3-Diketones 2d, 2e, and
2g with Tertiary Propargylic Alcohols 1h and 1ia
Table 3. Application of the Propargylation of 1,3-Dicarbonyls
to the Synthesis of Functionalized Furans 7
entry
alkynol
diketone
product
yield (%)b
1
2
3
4
5
6
1h
1h
1h
1i
1i
1i
2d
2e
2g
2d
2e
2g
6a
6b
6c
6d
6e
6f
68
53
72
61
64
50
entry
1
R1
R2
Ph
Ph
Ph
2
R3
R4 product yield (%)a
a
Reaction conditions: alkynol (1 mmol), diketone (1 mmol), PTS (0.05
mmol) in MeCN (5 mL) at room temperature (4 h for 1h and 24 h for 1i).
Isolated yields based on starting alkynols 1.
1
2
3
4
5
1a Ph
1a Ph
1a Ph
1b Ph
2a Me
2b Ph
2f OEt Me
Me
Ph
7a
7b
7c
7d
7e
70
75
45
52
78
b
n-Bu 2a Me
2a Me
Me
Me
Having successfully developed an efficient propargylation
of â-dicarbonyl compounds, we finally turned our attention
to the application of this methodology to the synthesis of
highly substituted furans.15 It should be remarked that the
development of routes that allow the facile assembly of
substituted furans under mild conditions from simple readily
available starting materials remains an important objective.16
Although there are many reports in the literature about the
cyclization of alkynes with enolizable â-dicarbonyls mainly
under transition metals or base catalysis,17 most of them give
rise to 2,3,5-trisubstituted furans18 due to the difficulty in
accessing 2-propynyl-1,3-dicarbonyl compounds substituted
1c 3-Thb Ph
a
b
Isolated yields based on starting alkynols 1. 3-Thienyl.
for the synthesis of tetrasubstituted furans has been developed
from simple starting materials, using only a catalytic amount
of a Brønsted acid and an inorganic base.
In summary, we have presented the first examples of
Brønsted acid catalyzed nucleophilic substitution of pro-
pargylic alcohols with active methylene and methine 1,3-
dicarbonyl compounds. The protocol is operationally simple
and generates only H2O as a side product. In many cases,
due to the easier availability of alcohols with respect to
halides, the method may favorably compete with the more
classical halide-based methodologies under basic conditions.
Moreover, we have developed a simple strategy for the
synthesis of polysubstituted furans by using the Brønsted
acid catalyzed nucleophilic substitution as the key step.
(14) A similar tendency was observed in the Lewis acid catalyzed
nucleophilic substitution of propargylic silyl ethers: Ishikawa, T.; Aikawa,
T.; Mori, Y.; Satio, S. Org. Lett. 2003, 5, 51 and references therein. As
suggested by a referee, an alternative mechanism for the formation of the
allenyl derivatives may involve initial capture of the propargylic cation by
the enol form of the 1,3-diketone and subsequent Claisen rearrangement of
the propargylic enol ether. However, we have never observed O-alkylated
products in any of the reactions.
(15) These compounds play an important role as structural elements of
many natural and pharmaceutically important substances: Keay, B. A.;
Dibble, P. W. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Eds.; Elsevier: Oxford, 1997; Vol. 2, pp 395-436.
(16) For recent reviews about the synthesis of polysubstituted furans,
see: (a) Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850. (b) Kirsch,
S. F. Org. Biomol. Chem. 2006, 4, 2076.
(17) See, for instance: (a) Marshall, J. A.; Van Devender, E. A. J. Org.
Chem. 2001, 66, 8037. (b) Wipf, P.; Soth, M. J. Org. Lett. 2002, 4, 1787.
(c) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L. M.
Tetrahedron 2003, 59, 4661. (d) Imagawa, H.; Kurisaki, T.; Nishizawa,
M. Org. Lett. 2004, 6, 3679.
(18) For alternative syntheses of tetrasubstituted furans, see, for in-
stance: (a) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton, M. D.;
Hidai, M.; Uemura, S. Angew. Chem., Int. Ed. 2003, 42, 2681. (b) Ma, S.;
Lu, L.; Zhang, J. J. Am. Chem. Soc. 2004, 126, 9645. (c) Sromek, A. W.;
Kel’in, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2004, 43, 2280. (d)
Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925. (e) Liu, Y.;
Song, F.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7, 5409.
Acknowledgment. We gratefully thank Junta de Castilla
y Leo´n (BU012A06) and Ministerio de Educacio´n y Ciencia
(MEC) and FEDER (CTQ2004-08077-C02-02/BQU) for
financial support. D.M. and A.M. thank MEC for FPU
predoctoral fellowships. J.M.A.-G. and F. R. are grateful to
MEC and the Fondo Social Europeo (“Ramo´n y Cajal”
contracts).
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds. Copies of
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0631298
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Org. Lett., Vol. 9, No. 4, 2007