Preparation of 5-Cyano-4,6-dimethyl-2H-pyran-2-one and 3-Cyano-5-methoxy-4- methyl-5H-furan-2-one via a one-pot, domino-knoevenagel process

Article abstract of DOI:10.1080/00397910903277904

5-Cyano-4,6-dimethyl-2H-pyran-2-one (1) has been prepared via a simple one-pot domino-Knoevenagel reaction starting from ethyl acetoacetate (2) and cyanoacetone (3). Similarly, a new racemic 3-cyano-5-methoxy-4-methyl-5H-furan- 2-one (7) has been prepared from 1,1-dimethoxyacetone (6) and cyanoacetic acid (4). The new alkylidene derivatives (Z/E)-ethyl-4-cyano-3-methylbut-3-enoate (5), (Z/E)-ethyl 5-amino-4-cyano-3-methyl-5-oxopent-3-enoate (9), and (2,2-dimethoxy-1-methylethylidene)malononitrile (11) have been prepared via the Knoevenagel reactions. The easy access to these new compounds in good yields shows that ammonium acetate/acetic acid-catalyzed Knoevenagel reactions and domino-Knoevenagel reactions have a broad scope of application. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903277904

This article was downloaded by: [North Dakota State University]
On: 12 November 2014, At: 11:31
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Preparation of 5-Cyano-4,6-dimethyl-2H-
pyran-2-one and 3-Cyano-5-methoxy-4-
methyl-5H-furan-2-one via a One-Pot,
Domino-Knoevenagel Process
a
a
Prativa B. S. Dawadi & Johan Lugtenburg
a
Leiden Institute of Chemistry, Leiden University , Leiden, The
Netherlands
Published online: 05 Aug 2010.
To cite this article: Prativa B. S. Dawadi & Johan Lugtenburg (2010) Preparation of 5-Cyano-4,6-
dimethyl-2H-pyran-2-one and 3-Cyano-5-methoxy-4-methyl-5H-furan-2-one via a One-Pot, Domino-
Knoevenagel Process, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 40:17, 2539-2546, DOI: 10.1080/00397910903277904
To link to this article: http://dx.doi.org/10.1080/00397910903277904
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“
Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

1
Synthetic Communications , 40: 2539–2546, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903277904
PREPARATION OF 5-CYANO-4,6-DIMETHYL-2H-
PYRAN-2-ONE AND 3-CYANO-5-METHOXY-
-METHYL-5H-FURAN-2-ONE VIA A ONE-POT,
4
DOMINO-KNOEVENAGEL PROCESS
Prativa B. S. Dawadi and Johan Lugtenburg
Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
5
-Cyano-4,6-dimethyl-2H-pyran-2-one (1) has been prepared via a simple one-pot
domino-Knoevenagel reaction starting from ethyl acetoacetate (2) and cyanoacetone
3). Similarly, a new racemic 3-cyano-5-methoxy-4-methyl-5H-furan-2-one (7) has been
(
prepared from 1,1-dimethoxyacetone (6) and cyanoacetic acid (4). The new alkylidene
derivatives (Z=E)-ethyl-4-cyano-3-methylbut-3-enoate (5), (Z=E)-ethyl 5-amino-4-
cyano-3-methyl-5-oxopent-3-enoate (9), and (2,2-dimethoxy-1-methylethylidene)malono-
nitrile (11) have been prepared via the Knoevenagel reactions. The easy access to these
new compounds in good yields shows that ammonium acetate=acetic acid–catalyzed
Knoevenagel reactions and domino-Knoevenagel reactions have
application.
a broad scope of
Keywords: (2,2-Dimethoxy-1-methylethylidene)malononitrile; (Z=E)-ethyl 5-amino-4-cyano-3-methyl-5-
oxopent-3-enoate; (Z=E)-ethyl 4-cyano-3-methylbut-3-enoate; NMR spectroscopy
INTRODUCTION
The 2H-pyran-2-ones (a-pyrones) and 5H-furan-2-ones (but-2-en-4-olides) are
unsaturated lactones. They are components of several classes of bioactive natural
compounds and exhibit a wide range of biological activity such as potent non-
peptidic HIV protease inhibitory, antimicrobial, antifungal, androgen-like, and
[1,2]
pheromonal effects.
2H-Pyran-2-ones (a-pyrones) are also important synthetic
intermediates for the preparations of various aromatic and heteroaromatic com-
pounds. 2H-Pyran-2-ones undergo Diels–Alder reactions with acetylenes and olefin
dienophiles to give addition products. These products give easy access to a whole
range of substituted benzenes and cyclohexadiene derivatives under thermal
[3–6]
expulsion of CO2.
a-Pyrones have been prepared by acid-catalyzed intermolecular condensation
[7]
of two molecules of b-keto esters. However, the 2H-pyran-2-one with a cyano
Received July 27, 2009.
Address correspondence to Prativa B. S. Dawadi, Leiden Institute of Chemistry, Leiden University,
P.O. Box 9502, 2300 RA, Leiden, The Netherlands. E-mail: p.dawadi@chem.leidenuniv.nl
2
539

2540
P. B. S. DAWADI AND J. LUGTENBURG
Scheme 1. Preparation of 5-cyano-4,6-dimethyl-2H-pyran-2-one (1) from ethyl acetoacetate (2) and
-cyanoacetone (3); preparation of (Z=E)-ethyl 4-cyano-3-methylbut-3-enoate (5) from ethyl acetoacetate
1
(
(
2) and cyanoacetic acid (4); and preparation of (R=S)-3-cyano-5-methoxy-4-methyl-5H-furan-2-one
7) from 1,1-dimethoxyacetone (6) and cyanoacetic acid (4) via one-pot domino reactions under the
Knoevenagel conditions.
Scheme 2. Preparation of alkylidene derivatives (Z=E) ethyl 5-amino-4-cyano-3-methyl-5-oxopent-3-
enoate (9) and (2,2-dimethoxy-1-methylethylidene)malononitrile (11).
substituent at position 5 was not known until the preparation of 5-cyano-4,6-
dimethyl-2H-pyran-2-one via a complicated nickel-catalyzed conversion of propar-
[
8]
gyl halide and propargyl alcohol was reported.
We have recently reported an efficient method to convert two bifunctional
reagents into a single multifunctional system via the Knoevenagel condensation in
which the total number of carbon atoms remains the same and which can be converted
[
9]
into a valuable heterocyclic compound in subsequent steps in a simple process.
We now report ammonium acetate=acetic acid–catalyzed domino-Knoevenagel
reactions and Knoevenagel reactions for the preparation of 5-cyano-4,6-dimethyl-2-
H-pyran-2-one (1), (Z=E)-ethyl-4-cyano-3-methylbut-3-enoate (5), 3-cyano-5-
methoxy-4-methyl-5H-furan-2-one (7), (Z=E)-ethyl 5-amino-4-cyano-3-methyl-5-
oxopent-3-enoate (9), and (2,2-dimethoxy-1-methylethylidene)malononitrile (11) in
Schemes 1 and 2. Furthermore, the methodology employs an efficient and diverse
synthesis of new compounds in simple and mild conditions.
RESULTS AND DISCUSSION
Ethyl acetoacetate (2; 6.50 g, 50 mmol) and 1-cyanoacetone (3; 4.14 g, 50 mmol)
ꢀ
were condensed together in toluene (250 mL) for 5 h at 100–110 C in the presence of

ONE-POT, DOMINO-KNOEVENAGEL PROCESS
2541
ammonium acetate (1.00 g) and acetic acid (5 mL) using the Dean–Stark trap.
1
nonitrile by a known procedure.
-Cyanoacetone can easily be prepared from commercially available 3-aminocroto-
This condensation afforded product 1 as a
[10]
colorless powder (5.15 g, 69%) (Scheme 1). The mass spectrometry and other
spectroscopic data are in agreement within experimental error for 5-cyano-4,6-
[8]
dimethyl-2H-pyran-2-one (1).
Previously, we reported the Knoevenagel reactions of 1,1-dimethoxyacetone
[
9]
6) with 1-cyanoacetone (3) and 2-cyanoacetamide (8). We anticipated that the
(
Knoevenagel condensation of ethyl acetoacetate (2) with 1-cyanoacetone (3) should
provide a general synthetic route to the intermediate a,b-unsaturated ketone (A),
which is expected to be converted easily into 5-cyano-4,6-dimethyl-2H-pyran-2-one
(
1) by intramolecular cyclization.
It is interesting that both ethyl acetoacetate (2) and 1-cyanoacetone (3) have
active methylene functions and both are possible keto donors. 5-Cyano-4,6-dimethyl-
H-pyran-2-one (1) is obtained in a very simple one-pot domino-Knoevenagel process
in 69% yield. This result indicates that ethyl acetoacetate (2) reacts as a keto donor and
-cyanoacetone (3) reacts as an active methylene compound. The reaction has occurred
via the intermediacy of an E=Z mixture of ethyl 4-cyano-3-methyl-5-oxohex-3-enoate
A). The Z isomer of intermediate (A) has two functional groups, namely ethyl ester
2
1
(
and carbonyl oxygen in close proximity, and leads to the cyclization (enol-
lactonization) with the elimination of one molecule of ethanol to form an a-pyrone
ring. The carbon–carbon double bond formed between two reactants in the intermedi-
ate (A) becomes the 4–5 bond in the final heterocycle. The E isomer can undergo an
acid-catalyzed E=Z isomerization, leading to the thermodynamically stable product
1. It is to be expected that this domino-Knoevenagel process has a broad scope to pre-
pare a 5-cyano-2H-pyran-2-one system with different substituents at positions 3, 4, and
6
using various b-keto esters and cyanomethyl ketones.
The Knoevenagel reaction of ethyl acetoacetate (2; 6.50 g, 50 mmol) and
cyanoacetic acid (4; 4.25 g, 50 mmol) afforded a Z=E (1:1) mixture of ethyl
1
-cyano-3-methylbut-3-enoate (5) as a light yellow oil in 61% yield. The H NMR
4
of product 5 is in agreement with the proposed structure, which showed two signals
for the CH group corresponding to Z=E isomers at 3.17 and 3.43 ppm and CH sig-
2
1
3
nal at 5.29 ppm. Similarly, in C NMR the CN and the C=O signals of product 5
are noticed at 115.9 and 168.3 ppm, respectively.
We conclude that (Z=E)-ethyl 4-cyano-3-methylbut-3-enoate (5) is obtained via
the intermediate (Z=E)-2-cyano-5-ethoxy-3-methyl-5-oxopent-2-enoic acid, which
undergoes decarboxylation faster than possible intramolecular cyclization. It has
been mentioned that in the Knoevenagel condensation of carbonyl compounds
[
11]
and carboxylic acids, a decarboxylation may take place.
The condensation of commercially available 1,1-dimethoxyacetone (6; 5.90 g,
0 mmol) and cyanoacetic acid (4; 4.25 g, 50 mmol) in toluene (250 mL) for 2 h at
5
1
ꢀ
20–130 C in the presence of ammonium acetate (1.00 g) and acetic acid (5 mL)
afforded a product 7 as a light yellow oil in 86% yield. Based on the spectral data,
the structure of product 7 is assigned to 3-cyano-5-methoxy-4-methyl-5H-furan-2--
one (7) (Scheme 1).
The m=z value of the parent peak of product 7 is 153.1350, which in agreement
1
with the calculated value of 153.13538 for the formula C H NO . The C NMR of
3
7
7
3

2542
P. B. S. DAWADI AND J. LUGTENBURG
product 7 showed seven signals corresponding to 14.09 (CH ), 57.95 (OCH ), 103.8
3
3
(
CH), 107.7 (NCꢁC=), 109.7 (CN), 164.1 (C=O), and 174.2 (CH ꢁC=) ppm. The
3
greater downfield shift (d ¼ 174 ppm) of C-4 relative to the carbonyl carbon at
d ¼ 164 ppm is due to the extended conjugation with the two electron-withdrawing
1
groups at the double bond in the product 7. The H NMR of product 7 is in com-
pliance with the proposed structure, showing peaks at 2.31 ppm for CH at position
3
1
and at 3.65 and 5.81 ppm for OCH and CH at position 5. Also, H NMR assign-
ments were checked by H– C correlation and H correlation spectroscopy (COSY)
spectra.
4
3
1
13
1
To our knowledge, the product 7 with a stereogenic center at position 5 has not
been described previously in the literature. The reaction occurred via the intermedi-
acy of the E=Z mixture of 2-cyano-3,3-dimethoxy-but-2-enoic acid. This is the
expected intermediate in which an acid-catalyzed E=Z isomerization takes place.
The intermediate Z isomer, with the dimethoxy acetal function and carboxylic acid
function in close proximity, leads to the cyclization to form a butenolide ring with
the elimination of one molecule of methanol. The excellent yield (86%) of the pro-
duct 7 shows that the acid-catalyzed condensation of 1,1-dimethoxyacetone (6)
and cyanoacetic acid (4) to obtain 3-cyano-5-methoxy-4-methyl-5H-furan-2-one
(
7) competes very well with the loss of CO in the intermediate.
2
The number of known 5-methoxy substituted (5H)-furan-2-ones is very limited.
5H)-Furan-2-one derivatives often serve as useful synthetic intermediates in the
(
stereoselective construction of substituted c-butyrolactones via conjugated addition
or catalytic hydrogenation of double bond.
[
12]
To test if other functional groups of active methylene compounds besides the
carbonyl group will lead to a domino reaction during the Knoevenagel condensa-
tion, we treated ethyl acetoacetate (2) with 2-cyanoacetamide (8) and 1,1-dimethoxy-
acetone (6) with malononitrile (10) in Scheme 2. In all these cases, only the expected
Knoevenagel alkylidene products (Z=E) ethyl 5-amino-4-cyano-3-methyl-5-oxopent-
3
-enoate (9) and (2,2-dimethoxy-1-methylethylidene)malononitrile (11) were isolated
and characterized. This result shows that under the normal Knoevenagel conditions
the nitrile function and the amide function do not undergo further domino reactions.
Alkylidene derivatives 9 and 11 have not been reported previously in the literature.
CONCLUSIONS
In this article, the preparation of 5-cyano-4,6-dimethyl-2H-pyran-2-one (1)
from simple starting materials ethyl acetoacetate (2) and 1-cyanoacetone (3) cata-
lyzed by ammonium acetate=acetic acid via a one-pot domino-Knoevenagel process
has been described. It is to be expected that a whole range of 3, 4, and 6 trisubstituted
5
-cyano-2H-pyran-2-ones can similarly be prepared via the domino reactions under
Knoevenagel conditions using various substituted b-keto esters and cyanomethyl
ketones. 2H-Pyran-2-one derivatives often used as building blocks in synthetic
organic chemistry and their fruitful application in a variety of transformations has
[13]
been mentioned in the literature.
Similarly, a one-pot domino reaction for the preparation of a new racemic
3-cyano-5-methoxy-4-methyl-5H-furan-2-one (7) from 1,1-dimethoxyacetone (6)
and cyanoacetic acid (4) has been described. The scope of the domino-Knoevenagel

ONE-POT, DOMINO-KNOEVENAGEL PROCESS
2543
condensation is very broad, because many different a,a-dimethoxy ketones and
acetic acids with different electron-withdrawing groups are available that will lead
to a 5-methoxy-5H-furan-2-one system with different substitutions at positions 3
and 4. There is also precedent for the reductive elimination of the substituent at
position 5 in these systems that will allow easy access to prepare biologically active
[
14,15]
3
,4-disubstituted 5H-furan-2-ones.
Moreover, a comparison of the reactions with 2-cyanoacetamide (8) and
malononitrile (10) is presented in Scheme 2 that is informative in determining the
relative importance of the a-carbonyl group in the active methylene compounds 3
and 4 for the cyclization under a domino process. As a result, new alkylidene
derivatives (Z=E)-ethyl-4-cyano-3-methylbut-3-enoate (5), (Z=E)-ethyl 5-amino-4-
cyano-3-methyl-5-oxopent-3-enoate (9), and (2,2-dimethoxy-1-methylethylidene)-
malononitrile (11) are obtained.
EXPERIMENTAL
General
Reactions were monitored by using thin-layer chromatography (TLC, on
Merck F254 silica-gel 60 aluminium sheets, 0.2 mm): spots were visualized by treat-
ment with an oxidizing spray (2 g of KMnO and 4 g of NaHCO in 100 ml of water).
4
3
1
Column chromatography was performed on Merck silica gel 60. H NMR spectra
were recorded on Bruker WM-300 with tetramethylsilane (TMS: d ¼ 0.00 ppm) as
1
13
internal standard. H noise-decoupled C spectra were recorded on a Bruker
WM-300 instrument at 75 MHz. Electron-impact (EI) mass spectrometry was carried
out using a Jeol JMSSX=SX102A four-sector mass spectrometer, coupled to a Jeol
MS-MP9021D=UPD system program. The sample was introduced via a direct inser-
tion probe into the ion source. Perkin-Elmer Paragon 1000 Fourier transform (FT)–
IR spectrophotometer was used for IR measurement. All other chemicals were
purchased from Aldrich Fluka or Acros Chimica.
5-Cyano-4,6-dimethyl-2H-pyran-2-one (1)
A solution of ethyl acetoacetate (2) (6.50 g, 50 mmol), 1-cyanoacetone (3)
4.14 g, 50 mmol), ammonium acetate (1.00 g), and acetic acid (5 mL) in toluene
250 mL) was refluxed for 5 h at 100–110 C using a Dean–Stark trap. The toluene
(
(
ꢀ
layer was separated after washing with half-saturated NaCl, dried with MgSO ,
4
1
and evaporated in vaccuo to yield a colorless solid of 1 (5.15 g, 69%). H NMR
1
3
(
(
1
1
300 MHz, DMSO-d ): d ¼ 2.17 (s, CH ), 2.39 (s, CH ), 6.14 (CH) ppm. C NMR
6
3
3
75 MHz, DMSO-d ): d ¼ 18.26 (CH ), 20.04 (CH ), 110.2 (=CꢁCN), 116.2 (CH),
6 3 3
16.4 (CN), 150.5 (C=C), 154.9 (C=C), 161.7 (C=O). FT-IR (neat): 2216, 1749,
ꢁ
1
þ
652, 1632, 1615 cm . Ms (EI ): m=z (%) ¼ 148 (92), 119 (100), 105 (25), 93 (10).
Mixture of (3Z)- and (3E)-Ethyl-4-cyano-3-methylbut-3-enoate (5)
A solution of ethyl acetoacetate (2) (6.50 g, 50 mmol), cyanoacetic acid (4)
4.25 g, 50 mmol), ammonium acetate (1.00 g), and acetic acid (5 mL) in toluene
(

2544
P. B. S. DAWADI AND J. LUGTENBURG
ꢀ
(250 mL) was refluxed for 7 h at 120–130 C using the Dean–Stark trap. The toluene
layer was separated after washing with half-saturated NaCl, dried with MgSO , and
4
1
evaporated in vacuo to yield a light yellow oil of 5 (4.65 g, 61%) H NMR (300 MHz,
CDCl =TMS) (Z=E, 1:1): d ¼ 1.27 (m, 2 ꢂ CH ), 2.06, 2.34 (s, CH ), 3.17, 3.43 (s,
3
3
3
1
3
CH ), 4.26 (m, 2 ꢂ CH ), 5.30 (br, s, CH) ppm. C NMR (75 MHz, CDCl =TMS)
2
2
3
(
(
Z=E, 1:1): d ¼ 13.87 (2 ꢂ CH ), 21.09, 23.04 (CH ), 40.92, 43.14 (CH ), 61.07
2 3
3
3
2
2 ꢂ CH ), 99.10 (=CꢁCN), 115.9 (CN), 156.4 (=CꢁCH ), 168.3 (C=O) ppm.
HRMS calcd. for C H NO : 153.17838; found: 153.1759.
11
8
2
3-Cyano-5-methoxy-4-methyl-5H-furan-2-one (7)
Ammonium acetate (1.00 g) and acetic acid (5 mL) were added to a mixture of
,1-dimethoxyacetone (6) (5.90 g, 50 mmol) and cyanoacetic acid (4) (4.25 g,
0 mmol) in toluene (250 mL). The mixture was refluxed for 2 h at 120–130 C using
1
5
ꢀ
a Dean–Stark trap. The organic solution was washed with half-saturated NaCl sol-
ution. The aqueous phase was again extracted with CH Cl (3 ꢂ 100 mL). The
2
2
extracted organic solvents were combined together and dried with MgSO The sol-
.
4
vent was removed under reduced pressure to yield a yellow oil (6.57 g, 86%). The
product was purified by column chromatography (silica gel 60, ethyl acetate=hexane,
1
:3) to yield a light yellow oil of 7 (5.89 g, 77%). H NMR (300 MHz, CDCl =TMS):
1
3
1
3
d ¼ 2.31 (s, CH ), 3.65 (s, OCH ), 5.81 (s, CH) ppm. C NMR (75 MHz, CDCl3=
3
3
TMS): d ¼ 14.09 (CH ), 57.95 (OCH ), 103.8 (CH), 107.7 (NCꢁC=), 109.7 (CN),
3
3
1
1
64.1 (C=O), 174.2 (CH -C=) ppm. FT-IR: (neat) n ¼ 2226, 1776, 1667, 1443,
3
ꢁ
1
390 cm . HRMS: calcd. for C H NO : 153.13538; found: 153.1350.
7
7
3
Mixture of (3Z)- and (3E)-Ethyl 5-amino-4-cyano-3-methyl-5-
oxopent-3-enoate (9)
A solution of ethyl acetoacetate (2) (6.50 g, 50 mmol), 2-cyanoacetamide (8)
4.04 g, 50 mmol), ammonium acetate (1.00 g), and acetic acid (5 mL) in toluene
250 mL) was refluxed for 7 h at 160–170 C using a Dean–Stark trap. The
(
(
ꢀ
toluene layer was separated after washing with half-saturated NaCl, dried with
MgSO , and evaporated in vacuo to yield a light yellow powder of 9 (7.45 g,
4
1
3
7
(
6%). H NMR (300 MHz, CDCl =TMS): d ¼ 1.29 (t, J
¼ 7.12 Hz, CH ), 2.32
3
H-H
3
3
s, CH ), 3.86 (s, CH ), 4.16 (q, J
13
¼ 7.12 Hz, CH ), 6.51 (br, NH ) ppm.
C
3
2
H-H
2
2
NMR (75 MHz, CDCl =TMS): d ¼ 13.95 (CH ), 25.96 (CH ), 40.02 (CH ), 61.35
3
3
3
2
(
CH ), 108.4 (=CꢁCN), 116.2 (CN), 162.7 (C=O), 164.0 (C=O), 168.7 (=CꢁCH ).
2
3
FT-IR (neat) n ¼ 3387, 3170 (NH ), 2222 (CN), 1728 (CO Et), 1695 (C=O), 1609
2 2
ꢁ
1
(
C=C) cm
.
(2,2-Dimethoxy-1-methylethylidene)malononitrile (11)
A solution of 1,1-dimethoxyacetone (6) (5.90 g, 50 mmol), malononitrile (10)
3.34 g, 50 mmol), ammonium acetate (1.00 g), and acetic acid (5 mL) in toluene
200 mL) was refluxed for 2 h at 100–110 C. The toluene layer was separated
(
(
ꢀ
after washing with half-saturated NaCl, dried with MgSO , and evaporated
4
1
in vacuo to yield a light brown oil of 11 (7.74 g, 93%). H NMR (300 MHz,

ONE-POT, DOMINO-KNOEVENAGEL PROCESS
2545
1
3
CDCl =TMS): d ¼ 2.23 (CH ), 3.46 (2 ꢂ OCH ), 5.09 (CH) ppm. C NMR
3
3
3
(
75 MHz, CDCl =TMS): d ¼ 17.00 (CH ), 55.58 (2 ꢂ OCH ), 87.19 (=CꢁCN),
3
3
3
1
cm . HRMS calcd. for C H N O : 166.07428; found: 166.0752.
02.4 (CH), 110.4, 110.9 (CN), 174.7 (=CꢁCH ). FT-IR (neat) n ¼ 2230 (CN)
3
ꢁ
1
8
10
2
2
ACKNOWLEDGMENTS
This work was supported by grants from Volkswagen Stiftung (I=79979). We
are very thankful to Dr. W. Gaertner (Max Planck-Institute for Bioinorganic
Chemistry, Muelheim, Germany) for his valuable suggestion. The authors thank
C. Erkelens and F. Lefeber for recording the NMR spectra and H. Peeters (Free
University of Amsterdam, The Netherlands) for recording the mass spectra.
REFERENCES
1
. (a) Vara Prasad, J. V. N.; Para, K. S.; Lunney, E. A.; Ortwine, D. F.; Dunbar, J. B.;
Ferguson, D.; Tummino, P. J.; Hupe, D.; Tait, B. D.; Domagala, J. M.; Humblet, C.;
Bhat, T. N.; Liu, B.; Guerin, D. A. M.; Baldwin, E. T.; Erickson, J. W.; Sawyer, T. K.
Novel series of achiral, low molecular weight, and potent HIV-1 protease inhibitors.
J. Am. Chem. Soc. 1994, 116, 6989–6990; (b) Barrero, A. F.; Oltra, J. E.; Herrador, M.
M.; Cabrera, E.; Sanchez, J. F.; Quilez, J. F.; Rojas, F. J.; Reyes, J. F. Gibepyrones:
a-Pyrones from Gibberella fujikuroi. Tetrahedron 1993, 49, 141–150; (c) Evidente, A.;
Cabras, A.; Maddau, L.; Serra, S.; Andolfi, A.; Motta, A. Viridepyronone, a new antifun-
gal 6-substituted 2H-pyran-2-one produced by Trichoderma viride. J. Agric. Food Chem.
2003, 51, 6957–6960; (d) Schlingmann, G.; Milne, L.; Carter, G. T. New a-pyrones
produced by fungal culture LL-11G219 function as androgen receptor ligands. Tetra-
hedron 1998, 54, 13013–13022; (e) Shi, X.; Leal, W. S.; Liu, Z.; Schrader, E.; Meinwald,
J. A new synthesis of alkylated 2H-pyran-2-ones and its application to the determination
of the relative and absolute configuration of supellapyrone, sex pheromone of the brown-
banded cockroach. Supella longipalpa. Tetrahedron Lett. 1995, 36, 71–74.
2. (a) Rao, Y. S. Chemistry of butenolides. Chem. Rev. 1964, 64, 353–388; (b) Rao, Y. S.
Recent advances in the chemistry of unsaturated lactones. Chem. Rev. 1976, 76, 625–
6
94; (c) Triozze, P. L.; Ailabouni, J.; Rinehart, J. J.; Witiak, D. T. Aci-reductones enhance
interleukin-2-induced lymphocyte cytotoxicity. Int. J. Immunopharmacol. 1993, 15, 47–54;
d) Tanabe, Y.; Ohno, N. Novel and efficient synthesis of 2(5H)-furanone derivatives.
(
J. Org. Chem. 1988, 53, 1560–1563; (e) Fang, X. P.; Anderson, J. E.; Chang, C. J.;
McLaughlin, J. L. Three new bioactive styryl lactones from Goniothalamus giganteus
(
Annonaceae). Tetrahedron 1991, 47, 9751–9758; (f) Roggo, B. E.; Petersen, F.;
Delmendo, R.; Jenny, H. B.; Peter, H. H.; Roesel, J. 3-Alkanoyl-5-hydroxymethyl tetronic
acid homologues and resistomycin: New inhibitors of HIV-1 protease, I: Fermentation,
isolation, and biological activity. J. Antibiot. (Tokyo) 1994, 47, 136–142; (g) Lattmann,
E.; Billington, D. C.; Langley, C. A. Synthesis of combinatorial libraries of 3,4,5-trisub-
stituted 2(5H)-furanones, part two: Construction of a library of 4-amino-5-alkoxy-
2
2(5H)-furanones. Drug Des. Discov. 1999, 16, 243–250; (h) Ma, S.; Wu, S. CuX -Mediated
cyclization reaction of 2,3-allenoic acids: An efficient route to b-halobutenolides. J. Org.
Chem. 1999, 64, 9314–9317.
. (a) Reed, J. A.; Schilling, C. L.; Tarvin, R. F.; Rettig, T. A.; Stille, J. K. Diels–Alder reac-
3
tions of 2-pyrones: Direction of the addition reaction with acetylenes. J. Org. Chem. 1969,
34, 2188–2192; (b) Kim, E. S.; Kim, K. H.; Kim, S. H.; Kim, J. N. Expedient synthesis of

2546
P. B. S. DAWADI AND J. LUGTENBURG
highly substituted a-pyrones from Baylis–Hillman adducts and their conversion to
poly-substituted aromatics. Tetrahedron Lett. 2009, 50, 5098–5101.
4
. Posner, G. H.; Nelson, T. D.; Kinter, C. M.; Johnson, N. Diels–Alder cycloadditions
using nucleophilic 3-(p-tolylthio)-2-pyrone: Regiocontrolled and stereocontrolled syn-
thesis of unsaturated, bridged, bicyclic lactones. J. Org. Chem. 1992, 57, 4083–4088.
. (a) Majumdar, K. C.; Taher, A.; Ray, K. Domino-Knoevenagel–hetero-Diels–Alder
reactions: an efficient one-step synthesis of indole-annulated thiopyranobenzopyran deri-
vatives. Tetrahedron Lett. 2009, 50, 3889–3891; (b) Singh, F. V.; Dixit, M.; Chaurasia, S.;
Raghunandan, R.; Maulik, P. R.; Goel, A. A substituent-controlled general approach to
access arylated pyran-2-ones and pyrano[3,4-c]pyran-1,8-diones. Tetrahedron Lett. 2007,
5
48, 8898–9002.
6
7
. Tietze, L. F.; Rackelmann, N. Domino reactions in the synthesis of heterocyclic natural
products and analogs. Pure Appl. Chem. 2004, 76, 1967–1983.
. (a) Wiley, R. H.; Smith, N. R. The condensation of ethyl acetoacetate to isodehydroacetic
acid and ethyl ester. J. Am. Chem. Soc. 1951, 73, 3531–3533; (b) Shuserina, N. P.;
Dimitrieva, N. D.; Luk’yanets, E. A.; Levina, R. Y. Progress in the chemistry of
2-pyrones. Russ. Chem. Rev. 1967, 36, 175–192.
8
. Rosas, N.; Salmon, M.; Sharma, P.; Alvarez, C.; Ramirez, R.; Garcia, J. L.;
Arzoumanian, H. Nickel-catalyzed cascade conversion of propargyl halide and propargyl
alcohol into 4,6-dimethyl-5-cyano-2-pyrone in water. J. Chem. Soc., Perkin Trans. 2000, 1,
1
493–1494.
1
3
13
. Dawadi, P. B. S.; Lugtenburg, J. Efficient preparation of [2- C]- and [3- C]-3-cyano-4-
9
methyl-3-pyrrolin-2-one. Eur. J. Org. Chem. 2007, 1294–1300.
1
1
0. Cernuchova, P.; Vo-Thanh, G.; Milata, V.; Loupy, A.; Jantova, S.; Theiszova, M. Utiliza-
tion of 2-ethoxymethylene-3-oxobutanenitrile in the synthesis of heterocycles possessing
biological activity. Tetrahedron 2005, 61, 5379–5387.
1. (a) Becker, G. O. H.; Berger, W.; Domschke, G.; Fanghaenel, E.; Faust, J.; Fisher, M.;
Gentz, F.; Gewald, K.; Gluch, R.; Mayer, R.; Mueller, K.; Pavel, D.; Schmidt, H.;
Schollberg, K.; Schwetlich, K.; Seiler, E. In Organikum, 19th ed.; Johann Ambrosius
Barth Leipzig: Berlin; Heidelberg Edition, Deutscher Verlag der Wissenschaften, 1993;
(
b) Cope, A. C. Condensation reactions, I: The condensation of ketones with cyanoacetic
esters and the mechanism of the Knoevenagel reaction. J. Am. Chem. Soc. 1937, 59, 2327–
330; (c) Mundy, B. P.; Ellerd, M. G.; Favaloro, F. J. Name Reactions and Reagents in
2
Organic Synthesis, 2nd ed.; John Wiley & Sons: Hoboken, NJ, 2005.
2. Grieco, P. A.; Pogonowski, C. S.; Burke, S. Organoselenium chemistry: General furan
synthesis. J. Org. Chem. 1975, 40, 542–543.
3. (a) Staunton, J. In Comprehensive Organic Chemistry: The Synthesis and Reactions of
Organic Compounds; P. G. Sammes (Ed.); Pergamon Press: Oxford, England, 1979; vol.
1
1
4
, pp. 629–646; (b) McGlacken, G. P.; Fairlamb, I. J. S. 2-Pyrone natural products and
mimetics: Isolation, characterization, and biological activity. Nat. Prod. Rep. 2005, 22,
69–385; (c) Brogden, P. J.; Gabbutt, C. D.; Hepworth, J. D. In Comprehensive Hetero-
cyclic Chemistry; A. R. Katritzky, C. W. Rees (Eds.); Pergamon Press: New York,
984; vol. 3, part 2B, chapter 2.22, pp. 573–646.
3
1
1
1
4. Bellina, F.; Rossi, R. An efficient and inexpensive multigram synthesis of 3,4-dibromo-
and 3,4-dichlorofuran-2(5H)-one. Synthesis 2007, 1887–1889.
5. Hughes, G.; Kimura, M.; Buchwald, S. L. Catalytic enantioselective conjugate reduction
of lactones and lactams. J. Am. Chem. Soc. 2003, 125, 11253–11258.