Efficient one-pot synthesis of 2-substituted furans from 3,3-diethoxypropyne and aldehydes using a Ti(O-i-Pr)4/2i-PrMgCl reagent

Article abstract of DOI:10.3987/com-07-11017

A new, efficient and direct synthetic method for synthesizing 2-substituted furans using titanium-alkyne complex from easily preparable lithium propargyl alcohol derivatives derived from commercially available 3,3-diethoxypropyne, n-butyllithium and aldehydes by a Ti(O-i-Pr)₄/2 i-PrMgCl reagent in 68-85percent yields.

Full text of DOI:10.3987/com-07-11017

HETEROCYCLES, Vol. 71, No. 5, 2007
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HETEROCYCLES, Vol. 71, No. 5, 2007, pp. 1141 - 1146. © The Japan Institute of Heterocyclic Chemistry
Received, 1st February, 2007, Accepted, 5th March, 2007, Published online, 6th March, 2007. COM-07-11017
EFFICIENT ONE-POT SYNTHESIS OF 2-SUBSTITUTED FURANS
FROM 3,3-DIETHOXYPROPYNE AND ALDEHYDES USING A
Ti(O-i-Pr)4 / 2 i-PrMgCl REAGENT
Deok Ki Eom, Seong Jib Choi, and Duk Keun An*
Department of Chemistry, Kangwon National University, Chunchon 200-701,
Korea. E-mail address : dkan@kangwon.ac.kr
Abstract – A new, efficient and direct synthetic method for synthesizing
2-substituted furans using titanium-alkyne complex from easily preparable
lithium propargyl alcohol derivatives derived from commercially available
3,3-diethoxypropyne, n-butyllithium and aldehydes by a Ti(O-i-Pr)4 / 2 i-PrMgCl
reagent in 68-85% yields.
INTRODUCTION
Furans are important heterocyclic compounds broadly used in material science and found in naturally
occurring and biologically important molecules.1 And, one-pot process has recently gained a considerable
and steadily increasing academic, economic, and ecological interest because they address very
fundamental principles of organic synthetic efficiency and reaction design. Most known methods for the
construction of the furan ring proceed via various types of cycloaddition or cycloisomerization of acyclic
precursors.2 Additionally, Sato and co-workers have reported on the synthesis of 2-substituted and
2,3-disubstituted furans from 2-alkynal tetramethylethylene acetals using a Ti(O-i-Pr)4 / 2 i-PrMgCl
reagent.3 The reaction of the titanium-acetylenic complex generated in situ from acetylenic acetals with
Ti(O-i-Pr)4 / 2 i-PrMgCl reagent furnished propargyltitaniums which, in turn, reacted with aldehydes to
yield furans. This work is a convenient way to synthesize 2,3-disubstituted furans from cyclic acetals and
aldehydes in a one-flask operation. However, such a reaction was requires cyclic acetals derived from
2-alkynal to accomplish the reaction.
Reported here is a new, efficient and direct synthetic method for synthesizing 2-substituted furans using
titanium-alkyne complex from easily preparable lithium propargyl alcohol derivatives derived from
commercially available 3,3-diethoxypropyne, n-butyllithium and aldehydes by a Ti(O-i-Pr)4 / 2 i-PrMgCl
reagent (Scheme 1).

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HETEROCYCLES, Vol. 71, No. 5, 2007
i-Pr-O O-i-Pr
O
H+
Ti
Ti(O-i-Pr)4
2 i-PrMgCl
1) n-BuLi
2) RCHO
R
OEt
OEt
R
OEt
OLi OEt
(68-85%)
2-substituted furan
Scheme 1.
RESULTS AND DISCUSSION
Recently, we carried out the synthesis of a titanium-alkynyl complex (3) without an allenyltitanium
moiety (2) from lithium propargyl alcohol derivatives including the acetal group (1) by its reaction with a
o
divalent titanium reagent Ti(O-i-Pr)4 / 2 i-PrMgCl at -35 to -40 C. Fortunately, we gave the
corresponding of cis-allyl alcohols (4) in good yield (89%) after hydrolysis. Subsequent hydrolysis under
acid condition (0.5N HCl) then provided the desired 2-substituted furan (5) in 84% yield.4 The result
o
suggests the titanium-alkynyl complex (3) was stabilized at low reaction temperature (-35 to -40 C)
(Scheme 2).
OLi
R
OEt
H
X
(i-Pr-O)2Ti
OLi
OEt
Ti(O-i-Pr)4
1) n-BuLi
OEt
OEt
Ph
2
OEt
OEt
2 i-PrMgCl
-35 to -40 oC
2) PhCHO
i-Pr-O O-i-Pr
Ti
NaHCO3 (sat)
Ph
OEt
OH OEt
1
Ph
OEt
OLi OEt
4 (89%)
3
H+
O
Ph
5 (84%)
Scheme 2.
With these results in hand, we anticipated that treatment of the reaction product of 3,3-diethoxypropyne
and a Ti(O-i-Pr)4 / 2 i-PrMgCl reagent with various aldehydes might afford one-pot access to
2-substituted furans. Table 1 summarizes the results of successive treatment of various aldehydes with the
Ti(O-i-Pr)4 / 2 i-PrMgCl reagent.

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Table 1. One-pot synthesis of 2-substituted furans from 3,3-diethoxypropyne and aldehydes using
Ti(O-i-Pr)4 / 2 i-PrMgCl reagent.a
Ti(O-i-Pr)4
2 i-PrMgCl
1) n-BuLi
HCl (aq.)
OEt
OEt
product
2) aldehyde
Yield, %b
Product
Aldehyde
Entry
O
84
77
CHO
1
2
O
H3C
CHO
H3C
O
H3CO
H3CO
CHO
3
4
68
72
O
Br
CHO
Br
CHO
O
85
78
5
6
7
8
O
O
O
CHO
O
CHO
75
77
82
68
O
CHO
CHO
O
9
CHO
O
10
a3,3-Diethoxypropyne : n-BuLi : aldehyde : Ti(O-i-Pr)4 : i-PrMgCl = 1 : 1 : 0.8 : 3 : 6. bIsolated yield
after silica column chromatography.

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As shown in Table 1, benzaldehyde was smoothly reacted to produce 2-phenylfuran in an 84% yield
(entry 1). Similarly, aldehydes of electron donating substituents such as 4-methylbenzaldehyde and
4-methoxybenzaldehyde, and electron withdrawing substituents such as 4-bromobenzaldehyde were
readily reacted with the corresponding 2-substituted furans in 77%, 68% and 72% yields, respectively
(entries 2-4). Also, 1-naphthylaldehdye, poly-aromatic aldehyde and 2-furanal, heterocyclic aldehyde
gave the corresponding 2-substituted furans in 85% and 78% yields, respectively (entries 5-6). The case
of alphatic aldehydes, namely caproaldehyde, cyclohexanecarboxaldehyde, hydrocinnamaldehyde, and an
α,β-unsaturated aldehyde, cinnamaldehyde, provided product 2-substituted furan in 68-82 yields (entries
7-10).
In summary, the present one-pot reaction opens presented here affords easy access to a variety of
2-substituted furans, that will find widespread use in organic syntheses such as in preparation of
furan-containing natural products and poly-aromatic macromolecules.1 This reaction method was proved
to be an effective synthetic method for preparation of 2-substituted furans.
EXPERIMENTAL
1
13
General. All reported yields are isolated yields after column chromatography. H-NMR and C-NMR
spectra were recorded on a Bruker DPX FT (400MHz) or Bruker Avance (300MHz) spectrometer. The
chemical shifts are expressed as units with Me4Si as the internal standard in CDCl3.
Typical procedure. To a solution of 3,3-diethoxypropyne (0.144 mL, 1.0 mmol) in Et2O (10 mL) was
o
added n-BuLi (0.4 mL, 2.5M in hexane, 1.0 mmol) at 0 C. After being stirred for 1h at rt, to this was
o
added benzaldehyde (0.08 mL, 0.8 mmol) at 0 C and the mixture was stirred for 1h at rt. To this were
added dropwise i-PrMgCl (4.69 mL, 1.28 M in Et2O, 6.0 mmol) and Ti(O-i-Pr)4 (0.88 mL, 3.0 mmol) at
o
o
-40 C. The resulting clear yellow solution was stirred for 2.5h at -35 to -40 C. During this period the
solution was colored orange to red-brown. The reaction mixture was quenched with saturated aqueous
NaHCO3 (1 mL) and filtered. After addition 0.5N HCl (20 mL), the mixture stirred for 1-2h and extracted
with Et2O (2 X 10 mL). After the mixture dried over MgSO4, and concentrated in vacuum. The residue
1
13
was purified by column chromatography on silica gel. All products were characterized by H and C
NMR spectra.
1
2-Phenylfuran (Entry 1 in Table 1) H-NMR (CDCl3) δ 6.47 (dd, J=1.80, 3.31Hz, 1H), 6.65 (d,
J=3.62Hz, 1H), 7.26 (t, J=7.48Hz, 1H), 7.38 (t, J=7.71Hz, 2H), 7.46 (d, J=1.21Hz, 1H), 7.66-7.68 (m,
2H). 13C NMR (CDCl3) 104.94, 111.63, 123.78, 127.31, 128.66, 130.89, 142.05, 154.03.

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2-(4-Methylphenyl)furan (Entry 2 in Table 1) 1H-NMR (CDCl3) δ 2.36 (s, 3H), 6.45 (dd, J=1.76, 3.64Hz,
1H), 6.58 (d, J=3.2Hz, 1H), 7.18 (d, J=7.93Hz, 2H), 7.44 (d, J=1.27Hz, 1H) 7.56 (d, J=8.19Hz, 2H), 13C
NMR (CDCl3) 21.25, 104.20, 111.53, 123.75, 128.26, 129.34, 137.14, 141.65, 154.20.
1
2-(4-Methoxyphenyl)furan (Entry 3 in Table 1) H-NMR (CDCl3) δ 3.83 (s, 3H), 6.44 (dd J=1.81,
3.30Hz, 1H), 6.51 (d, J=3.5Hz, 1H), 6.92 (d, J=8.88Hz, 2H), 7.42 (d, J=1.21Hz, 1H), 7.60 (d, J=8.78Hz,
2H). 13C NMR (CDCl3) 55.32, 103.34, 111.52, 114.10, 124.03, 125.23, 141.37, 154.03, 159.00.
2-(4-Bromophenyl)furan (Entry 4 in Table 1) 1H-NMR (CDCl3) δ 6.47 (dd, J=1.75, 3.32Hz, 1H), 6.65
(d, J=3.36Hz, 1H), 7.47-7.55 (m, 5H). 13C NMR (CDCl3) 105.53, 111.80, 121.05, 125.28, 129.78, 131.79,
142.38, 152.94.
2-Naphthalen-1-ylfuran (Entry 5 in Table 1) 1H-NMR (CDCl3) δ 6.59 (dd, J=1.84, 3.30Hz, 1H), 6.73 (d,
J=3.23Hz, 1H), 7.48-7.57 (m, 3H), 7.62 (d, J=1.13Hz, 1H), 7.73 (dd, J=1.12, 8.73Hz, 1H), 7.83-7.90 (m,
2H), 8.40 (d, J=6.29Hz, 1H). 13C NMR (CDCl3) 109.19, 111.35, 125.30, 125.54, 125.90, 126.15, 126.52,
128.49, 128.54, 128.59, 130.30, 133.93, 142.40, 153.46.
2,2'-Bifuran (Entry 6 in Table 1) 1H-NMR (CDCl3) δ 6.45 (dd, J=1.81, 3.39Hz), 6.55 (d, J=3.32Hz, 2H),
7.41 (d, J=1.30Hz, 2H). 13C NMR (CDCl3) 105.07, 111.35, 141.74, 146.62.
1
2-Pentylfuran (Entry 7 in Table 1) H-NMR (CDCl3) δ0.81-0.84 (m, 3H), 1.24-1.32 (m, 4H), 1.53-1.59
(m, 2H), 2.54 (t, J=7.62Hz, 2H), 5.90 (dd, J=0.83, 3.1Hz, 1H), 6.21 (dd, J=1.91, 3.07Hz, 1H), 7.23 (dd,
J=0.72, 1.8Hz, 1H) . 13C NMR (CDCl3) 14.40, 22.81, 28.13, 28.35, 31.78, 104.89, 110.41, 141.01,
157.04.
1
2-Cyclohexylfuran (Entry 8 in Table 1) H-NMR (CDCl3) δ 1.12-1.23 (m, 2H), 1.27-1.36 (m, 3H),
1.61-1.66 (m, 2H), 1.69-1.74 (m, 2H), 1.93-1.97 (m, 2H), 2.51-2.57 (m, 1H), 5.87 (dd, J=1.83, 3.16Hz,
1H), 6.21 (dd, J=1.83, 3.16Hz, 1H), 7.21 (t, J=0.96Hz, 1H). 13C NMR (CDCl3) 24.92, 25.10, 30.51, 36.18,
101.50, 108.78, 139.36, 160.02.
1
2-Phenethylfuran (Entry 9 in Table 1) H-NMR (CDCl3) δ 2.88 (t, J=4.90Hz, 4H), 5.90 (d, J=2.98Hz,
13
1H), 6.20 (dd, J=1.86, 3.12Hz, 1H), 7.10-7.12 (m, 4H), 7.19-7.26 (m, 2H). C NMR (CDCl3) 28.90,
33.35, 104.13, 109.09, 125.03, 127.33, 127.34, 139.84, 140.20, 154.35.
1
2-Styrylfuran (Entry 10 in Table 1) H-NMR (CDCl3) δ 6.27 (d, J=3.33Hz, 1H), 6.34 (dd, J=1.82,
3.25Hz, 1H), 6.81 (d, J=16.26Hz, 1H), 6.96 (d, J=16.26Hz, 1H), 7.17 (t, J=7.23Hz, 1H), 7.26 (t,
13
J=7.62Hz, 2H), 7.32 (d, J=1.45Hz, 1H), 7.38 (d, J=7.38Hz, 2H), 7.21-7.48 (m, 5H). C NMR (CDCl3)
107.53, 110.60, 115.44, 125.28, 126.09, 126.53, 127.65, 136.00, 141.09, 152.22.

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ACKNOWLEDGEMENTS
This work was supported by the Research Institute for Basic Science, Kangwon National University,
Korea.
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