P(RNCH2CH2)3N: An efficient promoter for the synthesis of 3-substituted coumarins

Article abstract of DOI:10.1081/SCC-120003602

The title compounds wherein R = Me or i-Pr function as efficient promoters for the formation of coumarins in good to excellent yields (80-95%) from salicylaldehydes and di-activated methylene compounds of the type R′CH₂CO₂Et (R′ = CO₂Et, COMe, CN). Although the yields are not generally superior to those reported in the literature, our methodology is more convenient in that milder conditions and shorter reaction times are facilitated by the use of the aforementioned commercially available catalysts.

Full text of DOI:10.1081/SCC-120003602

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P(RNCH CH ) N: AN EFFICIENT PROMOTER FOR THE
2
2 3
SYNTHESIS OF 3-SUBSTITUTED COUMARINS
a
a
a
Philip Kisanga , Xiangshu Fei & John Verkade
a
Department of Chemistry, Iowa State University, Gilman Hall, Ames, IA, 50011-3111, U.S.A.
Version of record first published: 16 Aug 2006.
To cite this article: Philip Kisanga , Xiangshu Fei & John Verkade (2002): P(RNCH CH ) N: AN EFFICIENT PROMOTER FOR THE
2
2 3
SYNTHESIS OF 3-SUBSTITUTED COUMARINS, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 32:8, 1135-1144
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SYNTHETIC COMMUNICATIONS, 32(8), 1135–1144 (2002)
P(RNCH CH ) N: AN EFFICIENT
2
2 3
PROMOTER FOR THE SYNTHESIS OF
-SUBSTITUTED COUMARINS
3
Philip Kisanga, Xiangshu Fei, and John Verkade*
Department of Chemistry, Gilman Hall, Iowa State
University, Ames, IA 50011-3111
ABSTRACT
The title compounds wherein R ¼ Me or i-Pr function as
efficient promoters for the formation of coumarins in good
to excellent yields (80–95%) from salicylaldehydes and
0
di-activated methylene compounds of the type R CH CO Et
2
2
0
(
R ¼ CO Et, COMe, CN). Although the yields are not gen-
2
erally superior to those reported in the literature, our method-
ology is more convenient in that milder conditions and shorter
reaction times are facilitated by the use of the aforementioned
commercially available catalysts.
Recently we reported that bases of type 1 efficiently deprotonate ethyl
acetate to afford enolates that can then be added to aldehydes to produce
1
the corresponding E-a,b-unsaturated esters.
Also described in that paper was promotion by 1b of the direct
condensation of aromatic aldehydes and methyl propionate to form the
trisubstituted E-methyl acrylate as the sole product (Eq. 1). Herein we
*
Corresponding author.
1
135
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1
136
KISANGA, FEI, AND VERKADE
relate the use of 1a and 1b in this methodology in an intramolecular syn-
thesis of coumarins. This class of compounds has recently been prepared by
2
Cartwright et al. by flash vacuum pyrolysis in an attempt to circumvent
the variable yields and inconvenient work-ups encountered in Wittig
3
4
olefination–cyclizations. More recently, a rhodium-catalyzed process has
been introduced that produces a mixture of coumarins and benzofurans in
variable yields.
The required salicylaldehyde 2-carboxylates were prepared according
5
to a published method as shown in step one of Scheme 1. Crude 4a and 4b
were then used in an intramolecular olefination using 1b as a promoter.
ꢀ
When 4a was reacted with 1.2 equiv of 1b at 40 C for 3 h, a 50 : 50 mixture
of 2 and 5a was observed to be present in the reaction mixture. A similar
product mixture was obtained with 4b. Decreasing the amount of 1b to 0.5
or 0.4 equiv gave an identical product mixture. Further reduction in the
amount of 1b to 0.3 equiv resulted in an incomplete reaction. Therefore we
assumed that 0.4 equiv of 1b was an optimum amount of 1b required for the
ꢀ
reaction. When we attempted to increase the reaction temperature to 60 C
Scheme 1.

P(RNCH
2
CH
2
)
3
N
1137
6
or to use magnesium sulfate (a Lewis acid we have found to be compatible
,7
˚
with bases of type 1), over 70% deacylation to 2 was observed. When 4 A
ꢀ
molecular sieves were added in a repetition of the reaction at 40 C for 3 h in
the presence of 0.4 equiv of 1b, 71% and 67% of the coumarins 5a and 5b,
respectively, were isolated, while the remaining starting material in each case
(
to proceed through the pathway shown in Scheme 2. Such reactions have
4a and 4b, respectively) was deacylated to 2. The deacylation of 4 is assumed
8
recently been studied in our laboratories in a different context. Although
the isolated yields of the coumarins synthesized herein are not superior to
2
those reported by Cartwright, the methodology represents a more simple
and convenient alternative to pyrolysis or Wittig olefination–cyclization.
Scheme 2.
The Knoevenagel condensation has often been used to prepare 3-sub-
stituted coumarins. Highly efficient reactions have recently been reported
involving the condensation of salicylaldehydes with malonates in the pres-
9
a
ence of piperidine under microwave conditions,
b
and the use of
montmorillonite/KSF. Both strategies produced this class of compounds
9
4
in yields up to 94 and 92%, respectively. However, the temperature at the
0
ꢀ
9a
end of the 10-minute microwave reaction is 120 C and the montmorillo-
ꢀ
9b
nite process requires a reaction temperature of 100 C for 24 h. When we
attempted the reaction of salicylaldehyde with diethyl malonate in the pres-
ence of 1.0 equiv of 1b in benzene or isobutyronitrile, the isolated yield of 6
was 84% (Scheme 3). Increasing the amount of 1b to 1.5 equiv and the
quantity of diethyl malonate to 1.2 equiv led to the isolation of 94% of
the desired product 6. Although this result is more favorable than that
Scheme 3.

1
138
KISANGA, FEI, AND VERKADE
9
ꢀ
reported in the literature owing to the lower temperature we employ (50 C),
the relatively large amount of 1b (1.5 equiv) required, coupled with the
inability of ethyl cyanoacetate to afford a high conversion to the corre-
1
sponding coumarin (ꢁ20% as determined by H NMR integration) were
disappointing. The latter result may be associated with an intermediate
Knoevenagel product such as 7 in isobutyronitrile, whose conformation is
unfavorable for the formation of the desired coumarin. A solution to this
apparent problem was realized by employing either a neat reaction or by
using ethanol as the solvent. Under these conditions, a catalytic reaction
occurred in the presence of 5 mol% of 1a or 1b to afford the desired cou-
marins as the only products in high yields (Scheme 4 and Table 1).
Scheme 4.
While the yields in Table 1 are not generally superior to those reported
9
in the literature, they are competitive. Moreover, the mild conditions and
the shorter reaction times in our methodology constitute a more practical
alternate route to coumarins. It should be mentioned that the reaction of
either 2 or its substituted analogues 8 with ethyl acetate or methyl propio-
nate under the conditions given in Scheme 4 did not afford detectable
amounts of the desired coumarins 5a or 5b, respectively.
EXPERIMENTAL SECTION
All reactions were carried out under nitrogen. The bases 1a–c were
1
7
prepared according to previously reported methods although both are
commercially available (Aldrich Chemical Co.).

P(RNCH
2
CH
2
)
3
N
1139

1
140
KISANGA, FEI, AND VERKADE

P(RNCH
2
CH
2
)
3
N
1141

1
142
KISANGA, FEI, AND VERKADE
Procedure for the Synthesis of Coumarins 5a and 5b: In a typical experi-
ment, 0.800 mol of 1b (240 mg) was weighed into a small flask followed by
the addition of 2.0 ml of dry isobutyronitrile or benzene. Into another flask
˚
containing activated 4 A molecular sieves under nitrogen was syringed
1.0 ml of the solvent (isobutyronitrile or benzene) followed by 2.00 mmol
of the 2-salicylaldehyde alkyl carboxylate (328 mg of 4a or 356 mg of 4b).
ꢀ
The second flask was warmed to 40 C for 2 min followed by the addition of
the contents of the first flask by means of a syringe. After stirring for 3 h, the
reaction mixture was allowed to cool to room temperature and then it was
flushed through a small silica gel column with 5% methanol in ethyl ether.
Removal of the solvent under reduced pressure afforded the crude coumarin
which was fractionated on a silica gel column with an eluent made up of
ethyl acetate in hexane. The ratio of ethyl acetate was increased in 5%
increments and the coumarins eluted with about 25% ethyl acetate in
hexanes to afford 71% of 5a and 67% of 5b, respectively.
General Procedure for the Preparation of Coumarins in the Presence of
Catalytic Amounts of 1a or 1b Method A: Neat Reaction. 2.00 mmol of the
aldehyde 8, 2.40 mmol of the di-activated methylene compound 9 and
ꢀ
0
7
.1 mmol of 1a or 1b were mixed under nitrogen and heated at 60 C for
h with continuous stirring. The reaction mixture was then allowed to
cool to room temperature. The crude products were purified by eluting on
a silica gel column using a 3 : 1 mixture of ethyl acetate and hexanes. The
coumarins 10d, 10f, and 10j were purified by eluting on a silica gel column
using a 3 : 1 : 1 mixture of hexane, ethylacetate and methylene chloride as
eluent.
Method B: Reaction in ethanol. 2.00 mmol of the aldehyde 8 and
.40 mmol of the di-activated methylene compound 9 were mixed under
2
nitrogen. To this mixture was added 0.1 mmol of 1a or 1b dissolved in
2
6
0 ml of absolute ethanol and then the reaction mixture was heated at
ꢀ
0 C for 3–4 h (Table 1) with continuous stirring. At the end of this time,
the reaction mixture was allowed to cool to room temperature and the
solvent was removed under reduced pressure. The crude products were
purified as stated in Method A.
CONCLUSION
Compounds 1a and 1b are superior promoters for the synthesis of
coumarins. Yields competitive with the literature are achieved in reactions
carried out in the presence or absence of a solvent, at milder temperatures
and in shorter times.

P(RNCH
2
CH
2
)
3
N
1143
SUPPORTING INFORMATION
1
13
H and C NMR data and mass spectral molecular weights.
ACKNOWLEDGMENT
The authors are grateful to the NSF and to the Donors of the PRF
administered by the ACS for grant support.
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Received in the USA March 28, 2001