LETTER
P(MeNCH CH ) N: An Efficient Catalyst
671
2
2 3
1
,8-diazabicyclo[5.3.0]undec-7-ene (DBU), 60%; 4-di- um with 1 equivalent of water in CD CN with the ratio of
3
methylaminopyridine (DMAP), 0%; diazabicyc- 1a:11(OH) being 4:1. This equilibrium was shifted to the
2
6
lo[2.2.2]octane, 0%; 1a, 98%; sodium ethoxide, 0%; di- right by adding excess water. Interestingly, a tetraalkyl-
iso-propylethylamine, 0%. The yield of 7 in a variety of ammonium isopropoxide has been used to alkylate alde-
solvents such as THF, trifluorotoluene and ethanol using hydes directly,27 although the reaction studied by these
0
.4 equivalents of 1a at 70 °C for 3 hours was >98%. It authors was not a condensation per se as in our experi-
should be noted that trifluorotoluene (bp 102 °C) is a sub- ments.
stitute for methylene chloride (suspected carcinogen) and
related solvents, not only because of recent regulations
enforced by OSHA but also because of its compatibility
H
P
H
H
P
Me
Me
Me
Me
Me
Me
2
5
with a wide variety of organic reactions. When 5 was re-
Me
Me
P
+
Me
N
N
N
N
N
N
N
N
N
+
fluxed in dioxane with 3 equivalents of potassium hydrox-
9
ide, only 1% of 10 was obtained. Recently, Patel and
+
coworkers reported that they tried several methods (un-
specified) to synthesize 10 from 5 and that the best meth-
od utilized 1.1 equivalents of DBU as a base in refluxing
N
N
N
11
12
13
6
ethanol to give the product in only 44% yield. By con-
trast, our method gave the product in 80% yield using only
Ethanol, trifluorotoluene, tetrahydrofuran, acetonitrile, dimethyl
formamide, methanol, salicylaldehyde, ethyl bromoacetate, o-van-
illin and 5-bromo salicylaldehyde (Aldrich Chemical Co.) were
0
.4 equivalents of 1a. Whereas compound 9 was prepared
from 4 using 1.1 equivalents of NaOEt in refluxing etha-
nol to give the hydroxy dihydrofuran (which was subse- used as received. 2-Hydroxy-3-methoxy-5-nitrobenzaldehyde
quently dehydrated with concentrated sulfuric acid to give (Lancaster Chemical Co.) was used as received. All reactions were
5
carried out under N . Although the nonionic base 1a is commercial-
the desired product in 55% overall yield ) our method
2
ly available (Strem), we prepared it according to our previously
gave a 98% yield of the product using 40 mol% of 1a at
2
8
published method and stored it under N2.
7
0 °C in 3 hours.
General procedure for the preparation of 3-6
In a round-bottomed flask fitted with a thermometer, a reflux con-
denser and a nitrogen inlet, was added 50 mL of methanol followed
by the addition of 0.3 g (6 mmol) of finely powdered potassium hy-
droxide. To this stirred suspension was added 5 mmol of the alde-
hyde. The reaction mixture was heated to 50 °C for 30 min and then
concentrated to dryness under vacuum. After the addition of DMF
Table Synthesis of Substituted Benzofurans Using 0.4 equivalents
of 1a in Ethanol at 70 °C for 3 h
(
50 mL) to the solid, the reaction mixture was stirred for 5 min and
then it was cooled to 0 °C. To this was added 1.0 mL of ethyl bro-
moacetate followed by allowing the reaction mixture to warm up to
2
5 °C overnight. Removal of the DMF was carried out under vacu-
um at 50 °C. To the solid residue was added 20 mL of water fol-
lowed by the addition of 25 mL of ethyl acetate. After stirring for
a
Hexanes:ethyl acetate.
1
5 min the layers were separated. The aqueous layer was extracted
with 2 25 mL of ethyl acetate. The combined organic layer was
washed with 25 mL of water and then with saturated brine. The or-
ganic layer was dried over magnesium sulfate and concentrated to
give the crude product which was purified by silica gel column
The pathway for the formation of the benzofurans is as-
sumed to proceed via deprotonation of the methylene
group by EtO formed as a result of the deprotonation of
−
EtOH by 1a. The enolate thus produced undergoes C-C chromatography using the gradient elution technique. After the col-
bond formation to form an alkoxide that abstracts a proton umn was loaded with the crude product, the polarity of the solvent
was increased in steps of 5% using 50 mL of eluent in each step,
from the solvent to forma a -hydroxy ester. The -hy-
starting from 50 mL of 100% hexanes and ending with the ratio in-
droxy ester finally undergoes base-assisted thermal dehy-
dicated in the Table. The fractions containing the product were con-
dration. The unusually strong basicity of 1a is associated
centrated under vacuum to give the product that was found to be
with the formation of three stable five-membered rings in
the corresponding conjugate acid after proton abstraction
from a substrate. We have already documented that 1a is
capable of deprotonating primary alcohols. We believe
that the extensive delocalization of the positive charge (as
1
>98% pure by H NMR analysis.
General procedure for the preparation of 7-10
In a test tube containing a magnetic stir bar was placed 1 mL of eth-
anol and 0.4 mmol (86 mg) of 1a under nitrogen. To this homoge-
neous solution was added 1 mmol of the substrate. The reaction
1
7
indicated in structures 11, 12 and the three resonance mixture was stirred under nitrogen at 70 °C for 3 h. The crude prod-
structures implied in 13) in the bulky cation 11 enhances uct was purified by silica gel column chromatography using the gra-
dient elution technique. Thus, after the column was loaded with the
the reactivity of the weakly bound ion pairs compared
crude product, the polarity of the solvent was increased in steps of
with the strongly bound ion pairs formed from ionic bases.
The low charge density on cation 11 probably prevents it
from activating the carbonyl group of the ester (for base
5
% using 50 mL of eluent in each step, starting from 50 mL of 100%
hexanes and ending with the ratio indicated in the Table. The frac-
tions containing the desired compound were concentrated under
hydrolysis) and the aldehyde functionality (for the Can- vacuum to give the product, which was found to be >98% pure by
1
nizarro reaction). It should be noted that 1a is in equilibri-
H NMR analysis.
Synlett 2001, No. 5, 670–672 ISSN 0936-5214 © Thieme Stuttgart · New York