One-pot preparation of 2-substituted and 2,3-disubstituted furans from 2-alkynal tetramethylethylene acetals and aldehydes using a divalent titanium reagent Ti(O-i-Pr)4/2 i-PrMgX

Article abstract of DOI:10.1016/S0040-4039(01)01068-1

Sequential treatment of 2-alkynal tetramethylethylene acetals with a divalent titanium reagent Ti(O-i-Pr)₄/2 i-PrMgX and aldehydes gave, after acidic work-up, furans in good to excellent yields, thus providing a new efficient one-pot access to a variety of 2-substituted and 2,3-disubstituted furans including those having a functionalized substituent(s).

Full text of DOI:10.1016/S0040-4039(01)01068-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5501–5503
One-pot preparation of 2-substituted and 2,3-disubstituted furans
from 2-alkynal tetramethylethylene acetals and aldehydes using a
divalent titanium reagent Ti(O-i-Pr)4/2 i-PrMgX
Xin Teng, Takeshi Wada, Sentaro Okamoto and Fumie Sato*
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama,
Kanagawa 226-8501, Japan
Received 28 May 2001; accepted 6 June 2001
Abstract—Sequential treatment of 2-alkynal tetramethylethylene acetals with a divalent titanium reagent Ti(O-i-Pr)4/2 i-PrMgX
and aldehydes gave, after acidic work-up, furans in good to excellent yields, thus providing a new efficient one-pot access to a
variety of 2-substituted and 2,3-disubstituted furans including those having a functionalized substituent(s). © 2001 Elsevier
Science Ltd. All rights reserved.
The synthetic utility of propargylic/allenylic metal
reagents of the type 1 has been investigated, and it has
been revealed that 1 where M is Li, Mg, Zn or Ti
affords b-acetylenic alcohols 2 as the major products by
its reaction with aldehydes,1 while the corresponding
aluminum reagent provides the a-allenylic alcohols 3
exclusively, that are converted to furans 4 by treatment
under acidic conditions (Scheme 1).2 These
organometallic reagents were synthesized from prop-
argyl ethers through deprotonation with t-BuLi for the
Li-reagent and the following transmetallation for the
Mg, Zn, Ti or Al-reagent.
Recently, we reported that propargylic/allenylic tita-
nium compounds can be directly prepared from prop-
argylic alcohol derivatives such as acetates, carbonates
and ethers, by the reaction with a divalent titanium
reagent Ti(O-i-Pr)4/2 i-PrMgX (5) that proceeds via an
oxidative addition pathway.3,4 As expected, the prop-
argylic/allenylic titanium reagent 1 (M=Ti) was readily
generated from 2-alkynal dialkyl acetal and 5, and that,
in turn, reacted with an aldehyde to afford the corre-
sponding 2 predominantly as shown in Scheme 2. We
t-BuLi
or
OR"
MXn
R
t-BuLi then
transmetallation
OR"
R
R
OR"
OR"
XnM
Ti(O-i-Pr)4
2 i-PrMgBr
1
OEt
OEt
R
(5)
OEt
OR"
R'
R
R
R'CHO
(i-PrO)2Ti
OEt
R'
and/or
OH
R
OH
2
3
PhCHO
H+
R
R
OEt
Ph
Ph
R'
O
+
OEt
OH
R
OH
4
2
3
Scheme 1.
R
2 : 3 Yield, %
SiMe3
n-Bu
76 : 24
69 : 31
99
98
Keywords: furan; allenyl; propargyl; titanium.
* Corresponding author. Tel.: +81-45-924-5787; fax: +81-45-924-5826;
e-mail: fsato@bio.titech.ac.jp
Scheme 2.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01068-1

5502
X. Teng et al. / Tetrahedron Letters 42 (2001) 5501–5503
Table 2.a
then carried out the synthesis of a titanium reagent of
the type 1 from 2-alkynal cyclic acetal and its reaction
with an aldehyde in expectation of synthesizing the
corresponding furan via 3. This anticipation was based
on our recent finding that, while the allylic titanium
reagent derived from 5 and acrolein diethyl acetal
reacts with an aldehyde at the g-position exclusively,
the titanium complex obtained from acrolein cyclic
acetal reacts at both the a- and g-positions.5
R
O
O
R'CHO
aq. HCl
5
R
R'
O
4
Isolated
Yield, %
R'CHO
R
4
Entry
n-Bu
O
O
CHO
1
2
n-Bu
74
71
68
76
O
n-Bu
Table 1 summarizes the results of the reaction of the
titanium reagent derived from several different cyclic
acetals of 2-heptynal with benzaldehyde. As antici-
pated, the reaction provided the corresponding furan 4
(through 3), after acidic work-up, as the major
product in a variable ratio depending on the acetal,
and to our satisfaction, the pinacol derivative (2-hep-
tynal tetramethylethylene acetal) afforded 4 exclusively
and in excellent yield (entry 3 in Table 1).
NC
Br
NC
Br
CHO
CHO
O
n-Bu
3
4
O
n-Bu
n-C7H15CHO
n-C7H15
n-Bu
O
CHO
With this finding, we carried out the reaction using
various combinations of 2-alkynal tetramethylethylene
acetals6 and aldehydes, and the results are summarized
in Table 2. As can be seen from Table 2, furans
having various kinds of substituents at the C-2 and
C-3 positions can be readily prepared. Noteworthy is
the fact that, when trimethylsilylpropynal tetra-
methylethylene acetal was used as the starting acetal,
the trimethylsilyl group present at the C-3 position in
the initially formed furan was desilylated during acidic
work-up, and thus, eventually, the reaction allows an
access to monosubstituted furans at the C-2 position
(entries 9 and 10). Several characteristic features of the
5
99
O
MeO2CO
Cl
MeO2CO-
(CH2)4
6
7
8
PhCHO
PhCHO
75
82
Ph
O
Cl-(CH2)4
Ph
Ph
Ph
O
t-BuCHO
83
80
O
O
TMS
9
CHO
R
O
OHC
CHO
Table 1.a
O
R
10b TMS
R = H
75
55
Bu
O
O
5
11b n-Bu
R = n-Bu
1N HCl
2 + 3
2 +
Ph
Bu
aUnless otherwise indicated, all reactions were carried
out using acetal (1.6 eq.), Ti(O-i-Pr)4 (1.4 eq.),
i-PrMgBr (2.8 eq.), and aldehyde (1 eq.). b0.5 equiv of
the aldehyde was added.
then
PhCHO
O
4
Regioselectivity
O
O
Combined
Yield, %
Entry Acetal:
2b
:
4
O
39 : 61
11c : 89
0 : 100
19 : 81
98
1
2
O
O
reaction can be seen from the table. Since an organo-
titanium reagent shows high chemoselectivity, it is pos-
sible to carry out the reaction with aldehydes having a
functional group (entries 2, 3 and 5). Preparation of
furans with a functionalized substituent at the C-3
position is also feasible starting from the acetals con-
taining a functional group (entries 6 and 7). Thus,
furans having a variety of functionalized substituents
at the C-2 and/or C-3 position can be readily synthe-
sized by a one-pot reaction. The preparation of p-
difurylbenzenes starting with terephtalaldehyde (entries
10 and 11) is also noteworthy, because the compounds
having such structure have attracted interest as a start-
ing material for the preparation of conjugated poly-
mers.7
78
O
O
84 (84)d
3
4
O
O
82
O
aReactions were carried out using the acetal (1.6 eq.),
Ti(O-i-Pr)4 (1.4 eq.), i-PrMgBr (2.8 eq.), and PhCHO (1
eq.). bRatio of diastereomers of 2 was 54 : 46 for
entry1 and 54 : 46 for entry 4. cDiastereomeric ratio
was not determined. di-PrMgCl was used instead of
i-PrMgBr.

X. Teng et al. / Tetrahedron Letters 42 (2001) 5501–5503
5503
R
2. Ishiguro, M.; Ikeda, N.; Yamamoto, H. Chem. Lett.
1982, 1029–1030.
O
Ti
3
3. (a) Nakagawa, T.; Kasatkin, A.; Sato, F. Tetrahedron
Lett. 1995, 36, 3207–3210; (b) Yoshida, Y.; Nakagawa,
T.; Sato, F. Synlett 1996, 437–438; (c) Okamoto, S.; An,
D. K.; Sato, F. Tetrahedron Lett. 1998, 39, 4551–4554;
(d) An, D. K.; Okamoto, S.; Sato, F. Tetrahedon Lett.
1998, 39, 4555–4558; (e) An, D. K.; Okamoto, S.; Sato,
F. Tetrahedron Lett. 1998, 39, 4861–4864; (f) An, D. K.;
Hirakawa, K.; Okamoto, S.; Sato, F. Tetrahedron Lett.
1999, 40, 3737–3740; (g) Hanazawa, T.; Okamoto, S.;
Sato, F. Org. Lett. 2000, 2, 2369–2371.
-O
R
O
O
R
O
O
R'CHO
Ti
Ti
O
R'
Scheme 3.
4. Reviews for the synthetic utility of 5: (a) Sato, F.; Urabe,
H.; Okamoto, S. Pure Appl. Chem. 1999, 71, 1511–1519;
(b) Sato, F.; Urabe, H.; Okamoto, S. J. Synth. Org.
Chem. Jpn. 1998, 56, 424–432; (c) Sato, F.; Urabe, H.;
Okamoto, S. Synlett 2000, 753–775; (d) Sato, F.; Urabe,
H.; Okamoto, S. Chem. Rev. 2000, 100, 2835–2886.
5. (a) Teng, X.; Okamoto, S.; Takayama, Y.; Sato, F. J.
Am. Chem. Soc. 1999, 121, 11916–11917; (b) Okamoto,
S.; Teng, X.; Fujii, S.; Takayama, Y.; Sato, F. J. Am.
Chem. Soc. 2001, 123, 3462–3471.
6. 2-Alkynaltetramethylethylene acetals could be readily
prepared from the corresponding diethyl acetals by treat-
ment with pinacol in the presence of a catalytic amount
of p-TsOH in CH2Cl2.
7. (a) Reynolds, J. R.; Child, A. D.; Ruiz, J. P.; Hong, S.
Y.; Marynick, D. S. Macromolecules 1993, 26, 2095–2103;
(b) Child, A. D.; Sankaran, B.; Larmat, F.; Reynolds, J.
R. Macromolecules 1995, 28, 6571–6578.
The predominant production of a-allenyl alcohols 3, i.e.
furans 4, may be explained by assuming that the tita-
nium complex derived from a cyclic acetal of 2-alkynal
would exist mainly as a propargyltitanium, that can be
stabilized by chelation,8 rather than an allenyl deriva-
tive, and the reaction with aldehydes proceeds preferen-
tially via the six-membered transition structure depicted
in Scheme 3. Although an explanation of the result that
2-alkynal tetramethylethylene acetal afforded the
highest selectivity compared with other cyclic acetals
must await further study, it was fortunate that the
acetal prepared from inexpensive pinacol shows the
highest selectivity.
In conclusion, the present one-pot reaction9 opens up
an easy access to a variety of 2-substituted and 2,3-disub-
stituted furans including those having functionalized
substituent(s), that will find widespread use in organic
synthesis such as preparation of furan-containing natu-
ral products10 and poly-aromatic macromolecules.7
8. A similar stabilization of allenyl/propargyltitaniums by
intramolecular chelation or coordination has been
reported: (a) Hoppe, D.; Gonschorrek, C.; Schmidt, D.;
Egert, E. Tetrahedron 1987, 43, 2457–2466; (b) Hamada,
T.; Mizojiri, R.; Urabe, H.; Sato, F. J. Am. Chem. Soc.
2000, 122, 7138–7139.
9. Typical procedure: to a solution of 2-heptynal tetra-
methylethylene acetal (168 mg, 0.8 mmol) and Ti(O-i-Pr)4
(207 mL, 0.7 mmol) in Et2O (6 mL) was added i-PrMgBr
(1.18 mL, 1.19 M in Et2O, 1.4 mmol) at −50°C. After
being stirred for 1.5 h at this temperature, the mixture
was allowed to warm to 0°C and stirred for an additional
30 min. After addition of benzaldehyde (55.6 mL, 0.5
mmol), the mixture was stirred for 30 min at rt. To this
were added aqueous 1N HCl (5 mL), THF (5 mL), and
EtOH (5 mL). The resulting mixture was stirred for 3 h
and then extracted with Et2O (2×5 mL). The combined
organic layers were washed with saturated aqueous
NaHCO3 (10 mL), dried over MgSO4, concentrated in
vacuo, and chromatographed on silica gel to give 2-
phenyl-3-butylfuran (84 mg) in 84% yield.
Acknowledgements
We thank the Ministry of Education, Culture, Sports,
Science and Technology (Japan) for financial support.
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