The efficient one-pot synthesis of tetraalkyl substituted furans from symmetrical acetylenes, EtAlCl2, and carboxylic esters catalyzed by Cp2TiCl2

Article abstract of DOI:10.1016/j.tetlet.2014.01.015

A new one-pot method for the synthesis of tetraalkyl substituted furans in 74-80% yields has been implemented via the reaction between symmetrical acetylenes, ethylaluminum dichloride, and carboxylic esters in the presence of metallic Mg as an acceptor of halide ions, catalyzed by bis(cyclopentadienyl) titanium dichloride. A mechanism for the reaction is proposed and discussed.

Full text of DOI:10.1016/j.tetlet.2014.01.015

Accepted Manuscript
The efficient one-pot synthesis of tetraalkyl substituted furans from symmetrical
acetylenes, EtAlCl2 and carboxylic esters catalyzed by Cp2TiCl2
Mariya G. Shaibakova, Leila O. Khafizova, Nuri M. Chobanov, Rinat R.
Gubaidullin, Natal’ya R. Popod’ko, Usein M. Dzhemilev
PII:
S0040-4039(14)00020-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.015
TETL 44046
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 July 2013
17 December 2013
6 January 2014
Please cite this article as: Shaibakova, M.G., Khafizova, L.O., Chobanov, N.M., Gubaidullin, R.R., Popod’ko, N.R.,
Dzhemilev, U.M., The efficient one-pot synthesis of tetraalkyl substituted furans from symmetrical acetylenes,
EtAlCl2 and carboxylic esters catalyzed by Cp2TiCl2, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/
j.tetlet.2014.01.015
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Graphical Abstract
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The efficient one-pot synthesis of tetraalkyl
substituted furans from symmetrical
acetylenes, EtAlCl2 and carboxylic esters
catalyzed by Cp2TiCl2
R
R
Mariya G. Shaibakova, Leila O. Khafizova,
Nuri M. Chobanov, Rinat R. Gubaidullin,
Natal’ya R. Popod’ko, Usein M. Dzhemilev
Cp2TiCl2 , Mg
R
R
+
EtAlCl2 + R'CO2R"
R'
R'
O
THF, 60 oC, 6 h
R = R' = R" = alkyl
7480%
The efficient one-pot synthesis of tetraalkyl substituted furans from
symmetrical acetylenes, EtAlCl2 and carboxylic esters catalyzed by
Cp2TiCl2
Mariya G. Shaibakova, Leila O. Khafizova, Nuri M. Chobanov, Rinat R.
Gubaidullin, Natal’ya R. Popod’ko, Usein M. Dzhemilev
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences,
141 Prospekt Oktyabrya, Ufa 450075, Russia
Abstract
A new one-pot method for the synthesis of tetraalkyl substituted furans in 74−80% yields has been
implemented via the reaction between symmetrical acetylenes, ethylaluminum dichloride, and
carboxylic esters in the presence of metallic Mg as an acceptor of halide ions, catalyzed by
bis(cyclopentadienyl)titanium dichloride. A mechanism for the reaction is proposed and discussed.
Keywords: Furans; Symmetrical acetylenes; Carboxylic esters; Titanium catalyst; Ethylaluminum
dichloride.
The synthetic chemistry of heterocyclic compounds, in particular, the chemistry of furans
represents an important section of organic chemistry, which is closely related to the problem of
producing biologically active compounds. The furan moiety is present in many natural products and
 Corresponding author. Tel./fax: +7 347 2842750.
E-mail address: khafizovaleila@gmail.com (L.O. Khafizova).

2
important pharmaceuticals.1−4 Substituted furans are the key structural units in many biologically
active compounds, and they are widely used as intermediates in organic synthesis.5,6
Most synthetic methods for preparing substituted furans described in the literature are multi-
step or require expensive reagents.7−12 Therefore, the search for convenient and promising methods
to synthesize furans is of practical interest for chemists.
We have previously shown that the reaction between α-olefins, alkylalanes, and carboxylic
esters in the presence of metallic Mg as an acceptor of halide ions and Cp2ZrCl2 as the catalyst
affords alkoxy(hydroxy)cyclopropanes.13,14 In continuation of our ongoing investigations, we have
studied the reaction between symmetrical acetylenes, ethylaluminum dichloride and different
carboxylic
esters
under
the
action
of
bis(cyclopentadienyl)zirconium
and
bis(cyclopentadienyl)titanium catalysts. Hex-3-yne, oct-4-yne, and dec-5-yne as well as carboxylic
esters, namely, ethyl acetate, ethyl propionate, and isoamyl butyrate were selected as the substrates
for this study.
Our experiments revealed that the model reaction of oct-4-yne with EtAlCl2 and ethyl acetate
mediated by metallic Mg and 10 mol% Cp2ZrCl2 (oct-4-yne:[Al]:ester:Mg:[Zr] = 1:4:2:4:0.1, THF,
20 oC, 48 h), after hydrolysis of the reaction mixture, gave 2,5-dimethyl-3,4-dipropylfuran (1) (40%
yield) together with two by-products, namely, 1,2,3,4-tetrapropylbuta-1,3-diene (2) and
hexapropylbenzene (3) ( 3:3:1 ratio) in 95% total yield (Scheme 1).15 Product 2 can be derived from
1-ethyl-2,3,4,5-tetrapropylaluminacyclopentadiene resulting from the catalytic cycloalumination of
the starting oct-4-yne.16
Scheme 1
Using this approach, we have optimized the reaction parameters by varying the catalyst and
solvent, temperature and duration of the reaction as well as the ratio of reactants.
Thus, we found that the solvent plays a significant role in this reaction, which occurs only in
tetrahydrofuran. The use of other solvents such as hexane, benzene, toluene, diethyl ether, and also
o
methylene dichloride suppressed furan formation. The use of an elevated temperature (60 C)
greatly reduced the reaction time from 48 to 6 hours and the highest yield of furan 1 (48%) was
achieved at a molar ratio of [Zr]/oct-4-yne/[Al]/ethyl acetate/Mg = 0.1:1:4:2:4.
However, the most surprising effect was observed, when Cp2ZrCl2 was replaced by
Cp2TiCl2. With this catalyst, the highest yield of 2,5-dimethyl-3,4-dipropylfuran (1) was achieved
(78%) under optimum reaction conditions (THF, 60 °C, 6 h, [Ti]/oct-4-yne/[Al]/ester/Mg =
0.1:1:4:2:4) .
The developed reaction is of a general nature allowing the formation of furans 4a and 4b,17
from ethyl propionate and isoamyl butyrate.
In an analogous fashion, hex-3-yne and dec-5-yne, reacted with EtAlCl2 and carboxylic
esters in the presence of the Cp2TiCl2 as the catalyst giving rise to the corresponding tetraalkyl
substituted furans 4c and 4d,18 under similar reaction conditions with good yields (Scheme 2).

3
Scheme 2
The structures of the prepared furans 1 and 4 were proved by means of spectroscopic
methods including one-dimensional (1H, 13C) and two-dimensional (HSQC, HMBC) NMR, IR, and
also by using mass spectrometry.
The published literature data and also our own experimental findings allow us to propose a
mechanism for the formation of tetraalkyl substituted furans via the reaction of acetylenes with
EtAlCl2 and carboxylates catalyzed by Cp2TiCl2 as follows.
The first stage of the reaction under the optimized reaction conditions involves generation of
the metallocene “Cp2Ti”, which then undergoes a reaction with the initial acetylene yielding the
titanacyclopropene 5 (Scheme 3).19−24 The reaction between 5 involving both the active Ti−C bonds
and two molecules of the appropriate ester leads to ring expansion and formation of
dioxatitanacycloheptene 6.25 Transmetallation of the latter mediated by EtAlCl2 leads to
oxadialuminum species 7 with simultaneous regeneration of Cp2TiCl2.
Scheme 3
Migration of the alkoxide group to the aluminum atom in 7 followed by elimination of
aluminum alkoxide EtAlCl(OR) leads to 1,4-diketone 8, which under the reaction conditions forms
furan 1 or 4. Similar examples of furan formation have been reported.26−28
In conclusion, we have developed a new and efficient procedure for the synthesis of tetraakyl
substituted furans in 74−80% yields through the reaction between symmetrical acetylenes (hex-3-
yne, oct-4-yne, dec-5-yne), EtAlCl2 and carboxylic esters (ethyl acetate, ethyl propionate, isoamyl
butyrate) under the action of bis(cyclopentadienyl)titanium dichloride as the catalyst. Currently,
systematic investigations on the formation of substituted furans in order to apply this method to
other acetylenes and carboxylates are being carried out.
Acknowledgments
This work was supported financially by the Program of the Presidium of RAS (Program No.8) and
the Russian Foundation of Basic Research (Grant No. 11-03-97008-р_Povolzh’e_a, Grant No.12-
03-31283 Young_a).
References and notes
1.
2.
3.
4.
Marshall, J. A.; Wang, X. J. J. Org. Chem. 1992, 57, 3387.
Marshall, J. A.; Wallace, E. M. J. Org. Chem. 1995, 60, 796.
Mendez-Andino, J.; Paquette, L. A. Org.Lett. 2000, 2, 4095.
Hou, X. L.; Yang, Z.; Wong, H. N. C. In: Progress in Heterocyclic Chemistry, Gribble, G. W.;
Gilchrist, T. L. Eds.; Pergamon, Oxford, 2003, Vol. 115, 167−205.
Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C.
Tetrahedron 1998, 54, 1955.
5.

4
6.
7.
Katritzky, A. R.; Rees, C. W. In Comprehensive Heterocyclic Chemistry, Eds.; Pergamon
Press: Oxford, U.K., 1984, Vol. 4.
Suzuki, D.; Nobe, Y.; Tanaka, R.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005,
127, 7474.
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9.
Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500.
Aponick, A.; Li, C.-Y.; Malinge, J.; Marques, E. F. Org. Lett. 2009, 11, 4624.
10. Blanc, A.; Tenbrink, K.; Weibel, J.-M.; Pale, P. J. Org. Chem. 2009, 74, 4360.
11. Chen, Z.; Huang, G.; Jiang, H.; Huang, H.; Pan, X. J. Org. Chem. 2011, 76, 1134.
12. Kramer, S.; Madsen, J. L. H.; Rottländer, M.; Skrydstrup, T. Org. Lett. 2010, 12, 2758.
13. Dzhemilev, U. M.; Khafizova, L. O.; Gubaidullin, R. R.; Khalilov, L. M; Ibragimov, A. G.
Tetrahedron Lett. 2009, 50, 7086.
14. Khafizova, L. O.; Gubaidullin, R. R.; Dzhemilev, U. M. Tetrahedron 2011, 67, 9142.
15. The reaction of acetylenes with EtAlCl2 and R'CO2R'' catalyzed by Cp2MCl2 (where M is Zr or
Ti). A 50 mL glass reactor equipped with a magnetic stirrer under a dry argon atmosphere at 0
oC, was charged under stirring with THF (15 mL), EtAlCl2 (20 mmol), Mg (20 mg,
powdered), and catalyst (1.0 mmol). After an 1 h, acetylene (hex-3-yne, oct-4-yne, dec-5-yne)
(10 mmol) and the ester (ethyl acetate, n-butyl acetate, allyl acetate, isoamyl propionate, or
o
methyl caproate) (20 mmol) were added. The temperature was raised to 60 C and the mixture
was stirred for an additional 6 h. The mixture was cooled under an argon stream to 0 oC. After
addition of Et2O (10−15 mL) the mixture was quenched with a 5% aqueous solution of HCl.
The organic layer was separated. The aqueous layer was extracted with Et2O (2 x 30 mL). The
combined organics were washed with NaHCO3 (until neutral) and dried over MgSO4. The
final products were isolated by vacuum distillation.
o
2,5-Dimethyl-3,4-dipropylfuran (1): Yield 78%. B.p. 73 C (3 mm Hg). IR (ν, см–1): 3445,
2959, 2930, 2871, 1714, 1459, 1384, 1252, 1223, 1096, 1071. UV (CHCl3), λmax, nm (lg ε):
1
359 and 304. Н NMR (400 MHz, CDCl3): δ 0.93 (t, J = 7.2 Hz, 6Н, СН3), 1.47 (sextet, J =
13
7.6 Hz, 4Н, СН2), 2.17 (s, 6H, CH3), 2.24 (t, J = 7.6 Hz, 4Н, СН2). С NMR (100 MHz,
CHCl3): δ 11.6, 14.0, 23.9, 25.8, 119.2, 144.5. MS, m/z 180 (М+). Anal. Calcd for C12H20O: C
79.94; H 11.18. Found: C 79.66; H 10.87.
16. Dzhemilev, U. M.; Ibragimov, A. G.; Khafizova, L. O.; Yakupova, L.R.; Khalilov, L. M.
Russ. J. Org. Chem. 2005, 41, 667.
o
1
17. 2,5-Diethyl-3,4-dipropylfuran (4a). Yield 74%. B.p. 81 C (1 mm Hg). Н NMR (400 MHz,
CDCl3): δ 0.96 (t, J = 7.2 Hz , 6Н, СН3), 1.19 (t, J = 7.2 Hz, 6Н, СН3), 1.46 (sextet, J = 7.6
13
Hz, 4Н, СН2), 2.25 (t, J = 7.6 Hz, 4Н, СН2), 2.54 (q, J = 7.6 Hz, 4Н, СН2). С NMR (100
MHz, CDCl3): δ 13.4, 14.2, 19.6, 24.2, 25.8, 28.3, 118.2, 149.8. MS, m/z: 208 (М+). Anal.
Calcd for C14H24O: C 80.71; H 11.61. Found: C 80.46; H 11.33. Tetrapropylfuran (4b). Yield
o
1
79%. B.p. 98 C (1 mm Hg). Н NMR (400 MHz, CDCl3): δ 0.90−0.97 (m, 12Н, СН3), 1.46
(sextet, J = 7.6 Hz, 4Н, СН2), 1.62 (sextet, J = 7.6 Hz, 4Н, СН2, СН2), 2.25 (t, J = 7.2 Hz, 4Н,
13
СН2), 2.48 (t, J = 7.2 Hz, 4Н, СН2). С NMR (100 MHz, CDCl3): δ 13.9, 14.2, 22.2, 24.2,
25.9, 28.3, 118.9, 148.7. MS, m/z: 236 (М+). Anal. Calcd for C16H28O: C 81.29; H 11.94.
Found: C 81.13; H 11.66.
o
1
18. 2,5-Dimethyl-3,4-diethylfuran (4с). Yield 74%. B.p. 54 C (10 mm Hg). Н NMR (400 MHz,
CDCl3): δ 1.09 (t, J = 7.6 Hz, 6Н, СН3), 2.18 (s, 6H, CH3), 2.32 (q, J = 7.6 Hz, 4Н, СН2). 13С
NMR (100 MHz, CDCl3): δ 11.4, 15.5, 16.8, 120.8, 144.0. MS, m/z: 152 (М+). Anal. Calcd
for C10H16O: C 78.90; H 10.59. Found: C 78.61; H 10.27. 2,5-Dimethyl-3,4-dibutylfuran (4d).
o
1
Yield 80%. B.p. 77 C (1 mm Hg). Н NMR (400 MHz, CDCl3): δ 0.93 (t, J = 7.2 Hz, 6Н,

5
13
СН3), 1.45–1.50 (m, 8Н, СН2), 2.18 (s, 6H, CH3), 2.26 (t, J = 7.6 Hz, 4Н, СН2). С NMR
(100 MHz, CDCl3): δ 11.6, 14.0, 22.6, 23.4, 32.9, 119.4, 144.3. MS, m/z: 208 (М+). Anal.
Calcd for C14H24O: C 80.71; H 11.61. Found: C 80.40; H 11.45.
19. Sato, F; Urabe, H. In Titanium and Zirconium in Organic Synthesis, Marec, I., Ed.; Wiley-
VCH: Weinheim, Germany, 2002, 319−354.
20. Okamoto, S. Adv. Synth. Catal. 2001, 343, 759.
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22. Sato, F.; Urabe, H.; Okamoto, S. S. Pure Appl. Chem. 1999, 71, 1511.
23. Eisch, J. J. Organomet. Chem. 2001, 617, 148.
24. Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789.
25. The seven-membered intermediate, having an O-Ti-O moiety and some resemblance to
intermediate 6, has been reported before [de Meijere, A.; Stecker, B.; Kourdioukov, A.;
Williams, C. M.; Synthesis; 2000, 929], but the pathway to a seven-membered ring differs and
was derived from titanium dimerization of an alkene.
26. Cai, R.; Huang, M.; Cui, X.; Zhang, J.; Du, C.; Wu, Y.; Wu, Y. RSC Adv. 2013, 3, 13140.
27. Yin, G.; Wang, Z.; Chen, A.; Gao, M.; Wu, A.; Pan, Y. J. Org. Chem. 2008, 73, 3377.
28. Haddadin, M. J.; Agha, B. J.; Tabri, R. F. J. Org. Chem. 1979, 44, 494.

Highlights
 Cp2TiCl2 catalyzes the reaction of symmetrical alkynes with EtAlCl2 and R’CO2R’’.
 Tetraalkyl substituted furans are the final products.
 Good product yields (74−80%) are obtained at 60 oC in tetrahydrofuran.
 Titanacyclopropenes are proposed as key intermediates.

Pr
Pr + EtAlCl2 + MeCO2Et
+
2
Mg
Cp ZrCl
1.
2.
2
THF
H3O+
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
4
3
+
+
2
5
1
Me
Me
O
3
2
1
(1 : 2 : 3 = 3 : 3 : 1)
95% yield
Scheme 1

R
R
Cp2TiCl2 , Mg
THF, 60 oC, 6 h
R
R
+
EtAlCl2 + R'CO2R"
R'
R'
O
4ad
(a) R = Pr, R' = Et, R" = Et
(b) R = Pr, R' = Pr, R" = Ami
(c) R = Et, R' = Me, R" = Et
(d) R = Bu, R' = Me, R" = Et
7480%
Scheme 2.

R
R
R
R
MgCl2
"Cp2Ti"
R
R'
R'
Mg
O
Cp2Ti
1 or 4
R
R
R
Cp2TiCl2
Cp2Ti
5
R
R
R'
R'
2 R'CO2R''
-Cp2TiCl2
R
R
O
O
8
R'
R''O
R'
R
R
O
OR''
O
R'
R''O
O
R'
Ti
Cp2
6
2 EtAlCl(OR'')
OR''
O
2 EtAlCl2
Al
Cl
Al
7
Et
Et
Cl
Scheme 3.