Hafnium chloride tetrahydrofuran complex-catalyzed Diels-Alder cycloadditions of 3-ethoxycarbonylcoumarins with 1,3-dienes under solvent-free conditions

Article abstract of DOI:10.1002/adsc.200505297

Hafnium chloride tetrahydrofuran complex (HfCl₄·2 THF) is an efficient catalyst for the Diels-Alder cycloadditions of 3-ethoxycarbonylcoumarins 1a-c and 1,3-butadienes 2x-z under solvent-free conditions furnishing the corresponding cycloadducts in excellent yields. This salt is an air stable Lewis acid and therefore the reactions can be performed in air atmosphere making the procedure simple to be carried out.

Full text of DOI:10.1002/adsc.200505297

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DOI: 10.1002/adsc.200505297
Hafnium Chloride Tetrahydrofuran Complex-Catalyzed
Diels–Alder Cycloadditions of 3-Ethoxycarbonylcoumarins with
1,3-Dienes under Solvent-Free Conditions
Francesco Fringuelli*, Rugiada Girotti, Ferdinando Pizzo*, Ennio Zunino,
Luigi Vaccaro
`
CEMIN – Centro di Eccellenza Materiali Innovativi Nanostrutturati, Dipartimento di Chimica, Universita di Perugia,
Via Elce di Sotto 8, 06123 Perugia, Italy
Fax: (þ39)-075-585-5560, e-mail: frifra@unipg.it, pizzo@unipg.it
Received: July 26, 2005; Accepted: December 15, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Hafnium chloride tetrahydrofuran com-
plex (HfCl4 ·2 THF) is an efficient catalyst for the
Diels–Alder cycloadditions of 3-ethoxycarbonylcou-
marins 1a–c and 1,3-butadienes 2x–z under sol-
vent-free conditions furnishing the corresponding cy-
cloadducts in excellent yields. This salt is an air sta-
ble Lewis acid and therefore the reactions can be
performed in air atmosphere making the procedure
simple to be carried out.
We have shown that 3-nitrocoumarins have satisfacto-
ry reactivity[5] and they were used as 4p components for
the preparation of chromene derivatives[5b] and as 2p
components for the synthesis of tetrahydrobenzo[c]-
chromenones and dihydrobenzo[b, d]furans[5a] in water
and under solvent-free conditions (SFC). Limitations
were encountered in the case of deactivated 6- and 7-hy-
droxy-substituted 3-nitrocoumarins.[5a]
Our research is mainly devoted to the definition of
new chemically efficient and environmentally responsi-
ble synthetic procedures by using water as reaction me-
dium[6] or SFC.[7] We have recently disclosed the
Cu(NO3)2-catalyzed one-pot synthesis of optically ac-
tive norstatines in water[6b] and the one-pot preparation
of benzo[e][1,4]-oxathiepin-5-ones[7b] and of pyrido[1,2-
a]quinoxalin-11-ium ions under SFC.[7a]
Keywords: cycloaddition; Diels–Alder reaction; haf-
nium chloride tetrahydrofuran complex; Lewis acid
catalysis; solvent-free conditions;
Our current project deals with the preparation of the
Coumarins are potentially versatile building blocks al- tetrahydrobenzo[c]chromenone unit 3 under SFC. This
though, owing to their generally low reactivity, they moiety has a high incidence in natural products and
have been scarcely investigated. The olefin of the cou- therefore is included in the set of “privileged struc-
marin ring is a very poor dienophile giving [4þ2] cyclo- tures”.[8] Among all the biologically active compounds
addition with 2,3-dimethyl-1,3-butadiene only under se- possessing the benzopyran template,[8] we are interested
vere reaction conditions and with an unsatisfactory in the synthesis of cannabinoids 4 through a new syn-
yield.[1]
thetic approach based on the Diels–Alder cycloaddi-
Examples of the reactivity of 3-substituted coumarins tion of 3-ethoxycarbonylcoumarins 1 with 1,3-buta-
as dienophiles are rare.[2] The introduction of an alkoxy- dienes 2, under SFC, and subsequent manipulation of
carbonyl at the C-3 position[2a–c, e] or a sulfinyl groupat
the corresponding tetrahydrobenzo[c]chromenone 3
the C-4 position[3] slightly increases the reactivity of (Scheme 1).
the 2p coumarinic system. 3-Ethoxycarbonylcoumarins
Considering that 3-ethoxycarbonylcoumarins 1 re-
underwent an ionic Diels–Alder[4] cycloaddition with quire a significant activation to react as dienophiles
1,3-dienes in satisfactory yields upon treatment with t- with electron-rich 1,3-dienes, we have planned to reach
butyldimethylsilyl triflate to form the corresponding 2- this goal by combining the use of a Lewis acid and SFC.
(t-butyldimethylsilyloxy)pyrylium salt.[2e] Activation of In fact in the absence of reaction medium the reactions
3-alkoxycarbonylcoumarins by a Lewis acid was report- are generally faster and give higher selectivities and
ed by using 1.2 molar equivs. of ZnCl2 and a very large yields; in addition, they require simpler equipments
excess of 1,3-dienes (44 equivs.).[2c]
and work-upprocedures are usually easier. [7,9,10] In this
paper we report the results obtained in the reactions of
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297

Francesco Fringuelli et al.
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Diels–Alder cycloaddition in organic solvents.[14] Al-
though their catalytic efficiency has been scarcely inves-
tigated, HfCl4 and Hf(OTf)4 have recently proved to be
very efficient oxophilic Lewis acids promoting a number
of useful transformations[12] including Diels–Alder cy-
cloadditions.[12a, b] To our knowledge HfCl4 ·2 THF has
never been used as catalyst for this transformation.
Although in the absence of the catalyst the conversion
of 1a to adduct 3ax was low also at 1408C, it can be con-
cluded that SFC promoted the cycloaddition if com-
pared to the results obtained in toluene (Table 1, entry
1 vs. 2). Zn(OTf)2, Cu(OTf)2, Yb(OTf)3, In(OTf)3,
Hf(OTf)4 and HfCl4 gave at 308C after 6 h only traces
or very low conversions to 3ax (Table 1, entries 3–7,
and 11). TiCl4 did not work at all while 25 mol % of
Scheme 1.
3-ethoxycarbonylcoumarins 1a–c with 1,3-dienes 2x–z TiCl4 ·2 THF allowed a complete conversion to be
in the presence of a variety of Lewis acid catalysts under reached after 24 h (Table 1, entries 9 and 10, see foot-
SFC and in comparison with different reaction media.
Considering that metal triflates are proving to be very
note [e]).
Excellent conversions were obtained by using
efficient Lewis acid catalysts for fundamental organic Al(OTf)3 and HfCl4 ·2 THF (Table 1, entry 8 and 12)
processes[11,12] and that, in our hands, under SFC with a slightly better result for the latter which gave a
In(OTf)3 was a more efficient catalyst for the thiolysis very clean reaction mixture and allowed the adduct
of 1,2-epoxides than other In(III) salts,[13] we have ini- 3ax to be isolated in 95% yield.
tially studied the cycloaddition reaction of the represen-
The higher catalytic efficiency of Al(OTf)3 and HfCl4 ·
tative 3-ethoxycarbonylcoumarin (1a) and isoprene (2x) 2 THF can be ascribed to their higher ability to coordi-
under SFC at 308C in the presence and absence of vari- nate both the carbonyl oxygens of the ester and lactone
ous triflate catalysts [Zn(II), Cu(II), Yb(III), In(III), functionalities of 1 with the formation of the corre-
Hf(IV), and Al(III)]. To compare the efficiency of this sponding pyrylium cation (A, Figure 1) which is strongly
pool of catalysts, we have also included in our study activated towards the normal electron demand cationic
two chloride salts such as TiCl4 and HfCl4 and their Diels–Alder reaction.[4a] To the best of our knowledge
THF complexes, TiCl4 ·2 THF and HfCl4 ·2 THF. All the significantly better catalytic properties of HfCl4 ·
the results are illustrated in Table 1.
2 THF vs. HfCl4 in the carbo-Diels–Alder reaction
With the exception of Al(OTf)3 all the triflates consid- have never been noticed.
ered in this study have been already used to catalyze the
We have chosen HfCl4 ·2 THF to continue our investi-
gations considering that this THF-complex salt is a very
convenient and easy to handle Hf(IV) source, in fact it is
an air-stable solid which melts at 1878C.
Table 1. Lewis acid-catalyzed cycloaddition of 1a with iso-
prene (2x).[a]
In addition, we compared the catalytic efficiency of
HfCl4 ·2 THF the use of various reaction media was
Entry
Lewis acid (5 mol %)
Conversion[b]
1
2
3
4
5
6
7
8
9
None
None
32[c]
12[c, d]
Traces
Traces
Traces
12
Zn(OTf)2
Cu(OTf)2
Yb(OTf)3
In(OTf)3
Hf(OTf)4
Al(OTf)3
TiCl4 ·2 THF
TiCl4
25
95
traces[e]
–
10
11
12
HfCl4
HfCl4 ·2 THF
24
98[f]
[a]
4 molar equivs., 308C, 6 h.
Conversion to adduct 3ax determined by GLC analyses.
Reaction performed at 1408C.
Reaction performed in toluene.
Complete conversion was reached after 24 h by using
25 mol % of TiCl4 ·2 THF.
[b]
[c]
[d]
[e]
[f]
Adduct 3ax was isolated in 95% yield.
Figure 1.
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Diels–Alder Cycloadditions of 3-Ethoxycarbonylcoumarins with 1,3-Dienes
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Table 2. HfCl4 ·2 THF-catalyzed cycloaddition of 1a with 2x
in various reaction media at 308C.[a]
the same reaction in nitromethane the yield was lower
but the composition of the reaction mixture was identi-
cal (Table 3, entry 3). The diasteroselectivity of the reac-
tion reflects a balance between steric interactions and
electronic effects.
The coumarin 1b is poorly reactive due to the presence
of a hydroxy group,[5a] nevertheless, by using 0.25 molar
equivs. of HfCl4 ·2 THF, adducts 3bx and 3by were ob-
tained in good yields (Table 3, entries 4 and 5). 6-
Chloro-3-ethoxycarbonylcoumarin (1c) reacted rapidly
at 308C with both 2x and 2y giving the corresponding ad-
ducts 3cx and 3cy in almost quantitative yields (Table 3,
entries 6 and 7).
Entry
Reaction Medium
Conversion[b]
1
2
3
4
5
6
7
8
SFC
CH3NO2
CH2Cl2
CH3CN
MeOH
THF
98
50
40
10
5c
2
H2O (pH 1.6)
[bmim]PF6
–
35
[a]
0.05 molar equivs. of HfCl4 ·2 THF, 4 equivs. of 2x.
Conversion to adduct 3ax determined by GCL analyses
after 6 h reaction time.
[b]
[c]
In conclusion, we have found that under SFC, HfCl4 ·
2 THF is a very efficient Lewis acid for Diels–Alder cy-
cloadditions of 3-ethoxycarbonylcoumarins 1a–c with
1,3-butadienes 2x–z,[15] allowing the corresponding cy-
43% of the corresponding methyl ester of 1a.
also considered and compared with SFC, the results are cloadducts to be prepared in excellent yields. This result
illustrated in Table 2. Among the organic media nitrome- opens, for the first time, a chemically efficient and envi-
thane, as expected, was the best organic solvent giving af- ronmentally safe general route to access tetrahydroben-
ter 6 h at 308C 50% conversion of 1a to 3ax (Table 2, entry zo[c]chromene derivatives.
2). Slightly lower conversions were obtained in CH2Cl2
and in the ionic liquid [bmim]PF6 (Table 2, entries 3 and
8), while very low conversions to adduct 3ax were reached
in strongly complexing media such as CH3CN, MeOH,
THF, and water (Table 2, entries 4–7). In conclusion the
Experimental Section
Diels–Alder reaction of 1a with 2x gave the best result
when it was carried out under SFC and in the presence
of 0.05 equivs. of HfCl4 ·2 THF at 308C for 6 h.
Typical Procedure for the HfCl4 ·2 THF-Catalyzed
Diels–Alder Cycloaddition
The protocol was then extended to the cycloadditions
of 1a with 2,3-dimethyl-1,3-butadiene (2y) and (E)-pi-
A screw-capped vial equipped with a magnetic stirrer was
charged with HfCl4 ·2 THF, (0.05 mmol, 0.023 g) and 3-ethoxy-
perylene (2z) and to those of 7-hydroxy-3-ethoxycarbo- carbonylcoumarin (1a; 1.0 mmol, 0.218 g), then isoprene (2x;
4.0 mmol, 0.272 g) was added The resulting mixture was left
under magnetic stirring at 308C for 6 h. After silica-gel column
chromatography of the final mixture (EtOAc/petroleum ether,
2/8 gradient) cycloadduct 3ax was isolated; yield: 0.272 g
(95%).
nylcoumarin (1b) and 6-chloro-3-ethoxycarbonylcou-
marin (1c) with 2x and 2y. The Diels–Alder reaction of
1a and 2y is very fast and gave a quantitative conversion
at 308C in 4 h (Table 3, entry 1) . To complete the reac-
tion of 1a with the poorly reactive 2z 0.25 equivs. of cat-
alyst were necessary at 508C and a mixture of ortho ad-
ducts 3az (endo):4az (exo):5az in a 17:26:57 ratio was
obtained in 92% overall yield (Table 3, entry 2). Com-
pound 5az is formed upon double bond migration
Helped by our previous experience with similar com-
pounds,[5a] all the structures of the cycloadducts have been con-
firmed by the spectroscopic data. In the case of 4az, which has
been isolated as a pure compound, NOESY correlations be-
tween Me and H-10a and between Me and H-1 confirmed
from 3az and 4az as already observed.[5a] By performing the exo structure.
Table 3. HfCl4 ·2 THF-catalyzed cycloaddition of 1a–c with 2x–z under SFC at 308C.
Entry
Coumarin
1,3-Diene (equivs.)
HfCl4 ·2 THF (equivs.)
t (h)
Products
Yield[a]
1
2
3
4
5
6
7
1a
1a
1a
1b
1b
1c
1c
2y (4)
2z (7)
2z (7)
2x (7)
2y (7)
2x (4)
2y (4)
0.05
0.25
0.25
0.25
0.25
0.05
0.05
4
15
15
30
30
6
3ay
3az : 4az : 5az
3az : 4az : 5az
3bx
3by
3cx
3cy
95
92[b, c]
60[b, d]
75[b]
82
90
92
4
[a]
Yield of isolated products after purification on silica gel column chromatography.
Reaction performed at 508C.
Adducts ratio 17: 26: 57, respectively.
[b]
[c]
[d]
Nitromethane as reaction medium, adducts ratio 21: 24: 55.
Adv. Synth. Catal. 2006, 348, 297 – 300
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asc.wiley-vch.de
299

Francesco Fringuelli et al.
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Full characterization charts (1H NMR, 13C NMR, IR, GC-
MS, Rf) for compounds 1b, 1c, 3ax–z, 3bx–y, 4az, 5az are avail-
able in the Supporting Information.
Fringuelli, F. Pizzo, S. Tortoioli, L. Vaccaro, Tetrahedron
Lett. 2003, 44, 6785–6787; e) D. Amantini, F. Fringuelli,
F., Pizzo, L. Vaccaro, J. Org. Chem. 2001, 66, 6734–6737.
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Cao, S. Barluenga, H. J. Mitchell, J. Am. Chem. Soc.
2000, 122, 9939–9953.
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`
The Ministero dellꢀIstruzione dellꢀUniversita e della Ricerca
`
(MIUR) and the Universita degli studi di Perugia [within the
funding projects: COFIN, COFINLAB (CEMIN) and FIRB
2001] are thanked for financial support.
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[15] HfCl4 ·2 THF proved to be a very efficient catalyst for
the Diels–Alder reaction of various a,b-unsaturated car-
bonyl compounds. For example, by using the protocol re-
ported in this paper, ethyl acrylate, 3-hepten-2-one, and
3-acryloyl-1,3-oxazolidin-2-one reacted with 2,3-dimeth-
yl-1,3-butadiene at 508C in 15, 12, and 0.5 h, respectively,
giving almost complete conversions to the corresponding
cycloadducts.
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