Enol ethers and acetals: Acylation with dichloroacetyl, acetyl and benzoyl chloride in ionic liquid medium

Article abstract of DOI:10.1016/j.tetlet.2011.10.163

Synthesis of 4-alkoxy-1,1-dichloro-3-alken-2-ones [CHCl₂C(O) C(R²)C(R¹)-OR, where R, R¹, R² = Et, H, H; Me, Me, H; Et, H, Me; Me, -(CH₂)₂-; Me, -(CH ₂)₃-; Et, Et, H; Et, Bu, H; Et, i-Pr, H; Et, i-Bu, H; Me, Ph, H; Me, thien-2-yl, H] from acylation of enol ethers and acetals with dichloroacetyl chloride, in ionic liquid ([BMIM][BF₄] or [BMIM][PF₆]) is reported. The synthesis of alkenones [R ³-C(O)C(R²)C(R¹)-OR], where R/R ¹/R²/R³ = Et/H/H/Ph, t-Bu/H/H/Ph, Me/-(CH ₂)₄/Ph, Me/-(CH₂)₄/Me] from the reaction of enol ethers with benzoyl chloride or acetyl chloride, in ionic liquid [BMIM][BF₄], is also reported. Last products are described for the first time.

Full text of DOI:10.1016/j.tetlet.2011.10.163

Tetrahedron Letters 53 (2012) 170–172
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enol ethers and acetals: acylation with dichloroacetyl, acetyl and benzoyl
chloride in ionic liquid medium
Emerson A. Guarda a, , Mara R.B. Marzari b, Clarissa P. Frizzo b, Patrícia M. Guarda a,
,
Nilo Zanatta b, Helio G. Bonacorso b, Marcos A.P. Martins b,
⇑
a Foundation Federal University of Tocantins, Master in Bioenergy, Av. NS 15, ALCNO 14, 109 North, Laboratory of Chemistry, Block II, 77001-090 Palmas, TO, Brazil
b Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Synthesis of 4-alkoxy-1,1-dichloro-3-alken-2-ones [CHCl2C(O)C(R2)@C(R1)-OR, where R, R1, R2 = Et, H, H;
Me, Me, H; Et, H, Me; Me, –(CH2)2–; Me, –(CH2)3–; Et, Et, H; Et, Bu, H; Et, i-Pr, H; Et, i-Bu, H; Me, Ph, H; Me,
thien-2-yl, H] from acylation of enol ethers and acetals with dichloroacetyl chloride, in ionic liquid
([BMIM][BF4] or [BMIM][PF6]) is reported. The synthesis of alkenones [R3–C(O)C(R2)@C(R1)-OR], where
R/R1/R2/R3 = Et/H/H/Ph, t-Bu/H/H/Ph, Me/-(CH2)4/Ph, Me/-(CH2)4/Me] from the reaction of enol ethers
with benzoyl chloride or acetyl chloride, in ionic liquid [BMIM][BF4], is also reported. Last products are
described for the first time.
Article history:
Received 26 September 2011
Revised 28 October 2011
Accepted 31 October 2011
Available online 7 November 2011
Keywords:
Enol ethers
Acylation
Ionic liquids
Acetals
Ó 2011 Elsevier Ltd. All rights reserved.
The usefulness of b-alkoxyvinyl ketones (alkenones) in hetero-
cyclic synthesis, for example, isoxazoles, pyrazoles, pyrroles,
pyrimidines, pyridines, thiazines and diazepines, has been exten-
sively described by some research groups.1–5 The acylation reac-
tion of enol ethers, isolated or generated in situ (from acetals), is
the main procedure to obtain alkenones.1 However, taking into ac-
count that enol ethers show low reactivity when compared to en-
amines, it should be noted that direct acylation involves problems
such as: (i) the requirement of strongly activated acylating agents,
for example, carbonyl carbon containing electronegative substitu-
catalysis; the use of metal was required, since the reaction would
not occur without the use of this catalyst.
Our research group has systematically studied the acylation
reaction of enol ether, isolated or from acetals, for about twenty
years and has developed a classical method for the acylation of
enol ethers and acetals with trihalomethylated acylants to obtain
a series of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones in the presence
of pyridine and under anhydrous atmosphere, with dichlorometh-
ane as solvent.1,9 However, this procedure is tedious and the reac-
tion is relatively time-consuming (16–48 h).9 Recently, we
reported a method of acylation for enol ethers13 and acetals14 with
trihalomethylated acylants to obtain a series of 4-alkoxy-1,1,1-tri-
halo-3-alken-2-ones in the presence of pyridine, using ionic liquid
in catalytic conditions. This procedure induces faster reaction
times, easy work up, easier purification of products and better
yields than the classical methods.
Considering the importance of 4-alkoxy-3-alken-2-ones in het-
erocyclic synthesis, there is a scarcity of literature reporting prom-
ising methods to synthesize these compounds from the acylation
of enol ethers. Due to the positive results we achieved using ionic
liquids in the acylation reaction of enol ether and acetal with
strong trihalomethylated acylating agents,13,14 the aim of this work
is to evaluate the ability of the ionic liquid to promote these reac-
tions with moderate or weak acylating agents that require some
kind of activation, such as 1,1-dichloroacetyl, benzoyl and acetyl
chlorides.
ents attached, such as trifluoro- or trichloro-methyl groups6–9
;
and (ii) the use of Friedel–Crafts catalysts, which is naturally lim-
ited to enol ethers with a high polymerization tendency.10 In
1964, Maier11 demonstrated how the course of the reaction de-
pends on the electrophilic potential of the acylant agent: while
acetyl chloride does not react with ethyl vinyl ether and chloroace-
tyl chloride causes polymerization; dichloroacetyl chloride gives
the addition product, and trichloroacetyl chloride gives the substi-
tution product. On the other hand, Youssefyeh10 published a work
showing that bulky enol ether or acetal of the cholestan-3-one eth-
ylene was acylated with acetic anhydride, using boron trifluoride
Friedel–Crafts catalyst. Halberg and Andersson12 described the
reaction of butylvinylether with benzoyl chloride using palladium
⇑
Corresponding author. Tel./fax: +55 55 3220 8756.
E-mail address: mmartins@base.ufsm.br (M.A.P. Martins).
The reaction was very successful for a range of enol ethers and
acetals, as shown in Table 1. Enol ethers (1a–c), dichloroacetyl
Tel.: +55 63 3232 8058; fax: +55 63 3232 8039.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.163

E. A. Guarda et al. / Tetrahedron Letters 53 (2012) 170–172
171
Table 1
Yields of 4-alkoxy-1,1-dichloro-3-alken-2-ones 3 obtained from acylation reaction of enol ethers or acetals
OR
O
OR
R1
MeO OMe
ii
i
R1
R1
Cl2HC
R2
R2
3a-k
R2
1a-e
2f-k
°
i: Cl2CHC(O)Cl, Py, IL, 0-40 C, 3 h.
°
ii: Cl2CHC(O)Cl, Py, IL, 0-50 C, 6-8 h.
Reactant
R
R2
R1
Product
Yielda (%)
IL: [BMIM][BF4]
IL: [BMIM][PF6]
1a
1b
1c
1d
1e
2f
2g
2h
2i
Et
Me
Et
–(CH2)2–
–(CH2)3–
Et
Et
Et
Et
Me
Me
H
H
Me
H
Me
H
H
H
Et
Bu
i-Pr
3a
3b
3c
3d
3e
3f
3g
3h
3i
75
77
52
70
71
48
52
64
48
49
52
68
79
10
69
41
46
53
62
47
50
51
H
H
H
H
H
H
i-Bu
Ph
Thien-2-yl
2j
2k
3j
3k
a
Yield of isolated product.
Table 2
Optimization of acylation reaction of enol ether 1a with benzoyl chloride
OEt
O
OEt
i
H
Ph
H
H
1a
4a
i: PhC(O)Cl, Py, IL: [BMIM][BF4]
Entry
Pyridine:acylant:IL molar ratio
Addition ordera
Addition temp. (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
1.0:1.0:0.1
1.0:1.0:0.1
1.0:1.0:1.0
1.0:1.0:1.0
1.0:1.0:1.0
I
I
II
I
III
25
0
0
0
0
14
14
16
16
16
—
—
Traces
10
12
a
I: Acylant in the glass followed by sluggish addition of other reagents and IL. II: Reagents and IL in the flask by sluggish addition of acylant. III: Acylant and IL in the glass
by sluggish addition of other reagents.
b
Yield of isolated product.
chloride and benzoyl chloride are commercially available. Enol
ethers (1d,e) and the acetals (2f–k) were prepared according to
the procedure described in the literature.15 The reaction of dichlo-
roacetyl chloride with 1,2 was performed by slowly adding a mix-
ture of pyridine and 1,2 to the mixture of acylant and IL in an ice
bath. Two equivalents of the acylating agent per acetal were re-
quired to obtain the 4-alkoxy-1,1-dichloro-3-alken-2-ones (3),
since one molecule of the acylant promotes the formation of the
enol ether in situ by trapping the alkoxide group released by the
acetal, and the second molecule of the acylant promotes
acylation.16–20 The E-isomer was the only product observed.17–20
Products 3 were extracted from the reaction media with diethyl
ether and were obtained without further purification. The IL was
completely recovered by the addition of CH2Cl2, filtration of the
precipitate and evaporation of the solvent. The compound struc-
tures were determined by 1H and 13C NMR spectroscopy and data
of compounds 3a–k are given in the Supplementary data.
present study, an additional Lewis acid was not necessary for the
acylation reaction. However, the 1:1 reactant/IL ratio seems to be
critical for conversion into the desired products. The acetal acyla-
tion in equimolar amounts of ILs allowed the formation of alkenon-
es 3,4,5. The results from the present study in regard to the
reactant/IL ratio differ from those published by us for enol ether
acylation,13 where less than an equimolar proportion of the ionic
liquid was sufficient to obtain optimum results beyond which
there was no further increase of conversion.
Reactions yields were higher in [BMIM][BF4] than in
[BMIM][PF6], probably because of the better solubility of reagents
in [BMIM][BF4]. It is noteworthy that products 3a,b,d and e were
already synthesized using a classical method,23,24 however their
yields and spectral data are not described in literature.
We started the evaluation of reaction of enol ethers 1a,l,m with
weakly acylating agents like benzoyl chloride and acetyl chloride,
by the reaction of ethyl vinyl ether (1a) and benzoyl chloride (Ta-
ble 2) in [BMIM][BF4].
The use of [BMIM][BF4] in 0.1 equiv in relation to the acylant
was not effective in promoting the reaction, with addition at
25 °C (entry 1) or 0 °C (entry 2). The addition of an equimolar
Data from the literature21,22 have demonstrated that in the Fri-
edel–Crafts acylation in ionic liquids in the presence of a Lewis
acid, the acylation rate depends on the Lewis acid/IL molar ratio
and that almost no reaction occurs if this ratio is 60.5.21,22 In the

172
E. A. Guarda et al. / Tetrahedron Letters 53 (2012) 170–172
Table 3
Unless otherwise indicated, all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. 1H and 13C NMR spectra were recorded on a Bruker
DPX-400 (1H at 400.13 MHz and 13C at 100.62 MHz) in 5-mm sam-
ple tubes at 298 K in CDCl3/TMS solutions. The general reproduc-
ibility of chemical shift data was estimated to be better than
0.01 ppm. The 1H and 13C NMR data of the compounds 3a–k,
4a,l,m and 5m are given in the Supplementary data.13,14
Yields of 4-alkoxy-3-alken-2-ones 4,5 obtained from acylation reaction of enol ethers
or acetals
OR
O
OR
R1
O
i
+
R1
R3
R3
Cl
R2
1a,l,m
R2
4a,l,m, 5m
°
i : Py, [BMIM][BF4], 0-40 C, 14-16 h.
Acknowledgments
Acylant R3
Enol ether
R
R2
R1
Product
Yielda (%)
The authors thank Conselho Nacional de Desenvolvimento
Científico e Tecnológico—CNPq (Universal/Proc. 485893/2007-0;
Universal/Proc. 471519/2009-0; MAPA/Proc. 578426/2008-0) and
Fundação de Amparo à Pesquisa do Estado do Rio Grande do
Sul—FAPERGS (PRONEX/Proc. 10/0037-8) for financial support
and fellowships from CNPq (M.A.P.M., N.Z., H.G.B., M.R.B.M.) CAPES
(C.P.F., PRODOC/Proc. 2684-32/2010) and FAPERGS as well.
Ph
Ph
Ph
Me
1a
1l
1m
1m
Et
H
H
H
H
4a
4l
4m
5m
12
16
34
22
t-Bu
Me
Me
–(CH2)4–
–(CH2)4–
a
Yield of isolated product.
amount of [BMIM][BF4] and a slight increase of the reaction time
allowed the observation of traces of product 4a (entry 3). Taking
into account that [BMIM][BF4] could change the coordinate of the
reaction by an interaction with reactants, we tested two reactant
addition orders. Both reactant addition orders provided very
similar results in the yields (entries 4 and 5). Thus we decided to
perform the reaction using the reactant addition order III, which
was shown to be better to handle [BMIM][BF4].
Supplementary data
Supplementary data (general procedures and characterization
data (1H NMR, 13C NMR, GC/MS and melting points) of compounds
3a–l) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.10.163.
References and notes
With these results in hand, we performed the acylation reaction
with enol ethers 1a,l,m (Table 3). The yields of products were low,
but the products were obtained for the first time using this meth-
od. In addition, the bulkiness of the enol ether structure seems to
have led to the better yields. Theoretically, it is expected that these
enol ethers are less reactive to polymerization than those that are
less substituted and, additionally, they remain available for the
acylation reaction.
1. Martins, M. A. P.; Cunico, W.; Pereira, C. M. P.; Sinhorin, A. P.; Flores, A. F. C.;
Bonacorso, H. G.; Zanatta, N. Curr. Org. Chem. 2004, 1, 391.
2. Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G. Tetrahedron 2007, 63, 7753.
3. Bonacorso, H. G.; Bittencourt, S. R. T.; Lourega, R. V.; Flores, A. F. C.; Zanatta, N.;
Martins, M. A. P. Synthesis 2000, 1431.
4. Martins, M. A. P.; Sinhorin, A. P.; Zimmermann, N. E. K.; Zanatta, N.; Bonacorso,
H. G.; Bastos, G. P. Synthesis 2001, 1959.
5. Flores, A. F. C.; Zanatta, N.; Rosa, A.; Brondani, S.; Martins, M. A. P. Tetrahedron
Lett. 2002, 43, 5005.
6. Effenberger, F. Angew. Chem. 1969, 81, 374.
These results are preliminary and we have already extended our
study to C-acylation of enamino compounds using acylating agents
that require strong activation, such as 4-nitrobenzoyl-, 4-chloro-3-
nitrobenzoyl- and 3,5-dinitrobenzoyl chlorides. The initial results
show that this method provides good yields of products. These
data will be communicated hereafter.
The results of this work suggest that the presence of IL in this
medium affords strong stabilization of the reaction intermediates
and activated complexes. Accordingly, the enhanced rate of the
reactions is due to the decreased activation energy of the slow
reaction step.25 This behaviour is in agreement with the general
IL effect that can be expected for reactions involving highly polar
or charged intermediates, such as carbocations or carbanions,
and activated complexes which could become more stable and
long-lived in IL media.25
In summary, the method proposed in this study allows for the
preparation of b-alkoxyvinyl ketones in short times and with mod-
erate yields. In addition, it was demonstrated that the method of
acylation of enol ethers or acetals in ionic liquids was efficient
for the acylation of enol ethers using acylating agents that require
strong activation, like benzoyl and acetyl chloride. Our results
show the promising role of [BMIM][BF4] in promoting an acylation
reaction that does not work with molecular solvents.
7. Hojo, M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo, S. Chem. Lett. 1976, 499.
8. The Chemistry of Functional Groups; Fischer, P., Ed.; Wiley Interscience: New
York, 1980. Supplement E, Part 2.
9. Colla, A.; Martins, M. A. P.; Clar, G.; Krimmer, S.; Fischer, P. Synthesis 1991, 483.
10. Youssefyeh, R. D. J. Am. Chem. Soc. 1963, 85, 3901.
11. Maier, R. Diplomarbeit, Universität Stuttgart, 1964.
12. Halberg, A.; Andersson, C.-M. J. Org. Chem. 1988, 53, 4257.
13. Martins, M. A. P.; Guarda, E. A.; Frizzo, C. P.; Scapin, E.; Beck, P.; Costa, A. C.;
Zanatta, N.; Bonacorso, H. G. J. Mol. Catal. A: Chem. 2007, 266, 100.
14. Martins, M. A. P.; Guarda, E. A.; Frizzo, C. P.; Moreira, D. N.; Marzari, M. R. B.;
Zanatta, N.; Bonacorso, H. G. Catal. Lett. 2009, 130, 93.
15. Wohl, R. A. Synthesis 1974, 38.
16. Frizzo, C. P. Synlett 2009, 1019.
17. Bonacorso, H. G.; Martins, M. A. P.; Bittencourt, S. R. T.; Lourega, R. V.; Zanatta,
N.; Flores, A. F. C. J. Fluorine Chem. 1999, 99, 177.
18. Martins, M. A. P.; Bastos, G. P.; Bonacorso, H. G.; Zanatta, N.; Flores, A. F. C.;
Siqueira, G. M. Tetrahedron Lett. 1999, 40, 430.
19. Fischer, P.; Clar, G.; Colla, A.; Martins, M. A. P. Quim Nova 1988, 11, 348.
20. Flores, A. F. C.; Brondani, S.; Zanatta, N.; Rosa, A.; Martins, M. A. P. Tetrahedron
Lett. 2002, 43, 8701.
21. Borodkin, G. I.; Shubin, V. G. Rus. J. Org. Chem. 2006, 42, 1745.
22. Yeung, K.-S.; Qiu, Z.; Farkas, M. E.; Xue, Q.; Regueiro-Ren, A.; Yang, Z.; Bender, J.
A.; Good, A. C.; Kadow, J. F. Tetrahedron Lett. 2008, 49, 6250.
23. Martins, M. A. P.; Zoch, A. N.; Flores, A. F. C.; Clar, G.; Zanatta, N.; Bonacorso, H.
G. J. Heterocycl. Chem. 1995, 32, 739.
24. Martins, M. A. P.; Peres, R. L.; Frizzo, C. P.; Scapin, E.; Moreira, D. N.; Fiss, G. F.;
Zanatta, N.; Bonacorso, H. G. J. Heterocycl. Chem. 2009, 46, 1247.
25. Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Zanata, N.; Bonacorso, H. G. Chem.
Rev. 2008, 108, 2015.