DABCO-induced [2+2+2]-cycloaddition reaction of ethyl propiolate and aryl aldehydes for the synthesis of 4-aryl-4 H -pyrans

Article abstract of DOI:10.1055/s-0029-1218367

The first DABCO-induced [2+2+2]-cycloaddition reaction of ethyl propiolate and aryl aldehydes is reported for selectively constructing 4-aryl-4H-pyrans in moderate to good yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218367

LETTER
3295
DABCO-Induced [2+2+2]-Cycloaddition Reaction of Ethyl Propiolate and
Aryl Aldehydes for the Synthesis of 4-Aryl-4H-pyrans
C
ycloaddition Reaction
e
of Ethyl Pr
i
b
and
A
ryl
A
i
ldehyd
n
e
s
g Liu, Huanfeng Jiang,* Peng Zhou, Shifa Zhu
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. of China
Fax +86(20)87112906; E-mail: jianghf@scut.edu.cn
Received 3 September 2009
obtained in 26% GC yield. The structure of 3a was fully
characterized by NMR spectra and further confirmed by
C–H COSY (HMQC) spectra.7 The DABCO-based cata-
lytic system was further improved by optimizing other
reaction conditions, such as solvent, reaction temperature,
reaction time as well as the amount of the catalyst
(Table 1, entries 8–22). As the results showed, 1,4-diox-
ane was found to be suitable for this cyclization reaction
(Table 1, entries 3, 8–15). The yield of 3a can be im-
proved to 40% when raising the temperature from room
temperature to 90 °C. However, the yield was not very
sensitive to the reaction time (Table 1, entries 16–19).
Abstract: The first DABCO-induced [2+2+2]-cycloaddition reac-
tion of ethyl propiolate and aryl aldehydes is reported for selectively
constructing 4-aryl-4H-pyrans in moderate to good yields.
Key words: DABCO, [2+2+2]-cycloaddition reaction, ethyl propi-
olate, aldehydes, 4-aryl-4H-pyrans
The development of new methods leading to the carbon–
carbon and carbon–heteroatom bonds that would rapidly
transform readily accessible starting materials into func-
tionalized complex molecules is of considerable current
interest in organic synthesis.1 Great progress has been
achieved during the past decades in these methodologies
which have mainly focused on transition-metal-catalyzed
procedures with palladium, rhodium, nickel, ruthenium,
copper, silver, and gold.2 Recently, significant efforts
have been made to develop cascade reactions with orga-
nocatalysts, such as enamine, 1,4-diazabicyclo[2.2.2]oc-
tane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), 4-(dimethylamino)pyridine (DMAP), triphenyl-
phosphine (Ph3P), tributylphosphine (Bu3P), pyridine, and
dimethyl sulfoxide (DMSO) activation modes.3 DABCO
is a commercial available small molecule, which has been
found various applications in catalyzing ring-formation
reactions4 and provides an important platform for the de-
velopment of novel cascade strategies for its reactivity. As
a part of an ongoing program to develop novel protocols
that are capable of building molecular complexity from
simple substrates, herein we wish to describe a new cas-
cade protocol: an unprecedented coupling of ethyl propi-
olate and aryl aldehydes catalyzed by DABCO to afford
diverse and structurally meaningful 4-aryl-4H-pyrans,
which are one of the structural units in many natural prod-
ucts and important synthons to construct other heterocy-
clic compounds,5 and show a broad range of biological
and pharmacological activities.6
As shown in Table 2, the substrate scope of DABCO-cat-
alyzed system was then examined under our optimized re-
action conditions.8 The reaction of a wide range of
aromatic aldehydes with ethyl propiolate proceeded
smoothly to furnish the corresponding 4-aryl-4H-pyrans
in moderate to good isolated yields. The steric hindrance
and electronic properties of the substituents on the aro-
matic aldehydes have significant influence on the reaction
(Table 2, entries 1–7). The aromatic ring with electron-
donating groups, such as methyl and methoxy groups,
failed to produce the products. para-Halogen-substituted
aryl aldehydes afforded the corresponding products in
30%, 55%, and 60% yields accompanied by the increase
of atomic weight of halogen (Table 2, entries 2–4). The al-
dehydes bearing electron-withdrawing groups at para or
meta position could be successfully used to furnish the
products in good yields (Table 2, entries 5–7).
A likely mechanistic scenario for the catalytic ring forma-
tion is outlined in Scheme 1.9 The reaction is initiated by
DABCO nucleophilic attack on the carbon–carbon triple
bond of ethyl propionate 1, resulting in the formation of
1,3-dipole 4. Subsequent carbon anion nucleophilic attack
occurs on the carbonyl carbon of aldehyde leading to in-
termediate 5, which then undergoes intramolecular ring
formation to give the [2+2]-addition product 6, accompa-
nied with the regeneration of DABCO. Finally, driven by
the release of the four-membered ring strain, intermediate
6 then reacts with a second molecule 4, allowing for the
formation of the final product 3.
Initial efforts were focused on the systematic evaluation
of various conditions for the ring formation to synthesize
4H-pyrans starting from ethyl propiolate (1) and benzal-
dehyde (2a). Among the seven common used Lewis bases
as the organocatalysts, only DABCO proved to be effec-
tive for this transformation (Table 1, entries 1–7), and
diethyl 4-phenyl-4H-pyran-3,5-dicarboxylate (3a) was
In summary, a formal [2+2+2]-cycloaddition cascade
reaction for the synthesis of 4-aryl-4H-pyrans via organo-
catalytic reaction was developed. DABCO was found to
provide the best results in this reaction. This practical pro-
tocol will be the choice for chemists to prepare this type
of 4-aryl-4H-pyrans in a highly concise fashion. Current
SYNLETT 2009, No. 20, pp 3295–3298
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x
.x
x
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0
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Advanced online publication: 13.11.2009
DOI: 10.1055/s-0029-1218367; Art ID: W13809ST
© Georg Thieme Verlag Stuttgart · New York

3296
W. Liu et al.
LETTER
efforts directed towards the mechanism studies of this
reaction as well as extension of the substrate scope are
ongoing in our laboratory.
R
O
CO2Et
EtO2C
CO2Et
1
DABCO
3
EtO2C
R
Table 1 Optimization of the Reaction Conditions for the Organo-
catalyzed Cycloaddition Cascade of Ethyl Propiolate (1) with Benz-
aldehyde (2a)a
EtO2C
N
CO2Et
R
H
N
4
7
O
O
R
2
CO2Et
DABCO
N
EtO2C
N
catalyst
O
+
CHO
O
2
solvent
CO2Et
EtO2C
EtO2C
R
CO2Et
1
2a
5
4
6
O
3a
Scheme 1 A possible reaction mechanism
Entry Cat.
Solvent
Temp
Time
Yield
(%)b
Table 2 Synthesis of 4-Aryl-4H-Pyrans via DABCO-Catalyzed
Cycloaddition Reaction of Ethyl Propiolate with Representative Aryl
Aldehydesa
(°C)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
90
(h)
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
6
1
2
pyridine
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
MeOH
trace
trace
26
Ar
Et3N
CO2Et
EtO2C
CO2Et
DABCO (1 mol%)
+
ArCHO
3
DABCO
PBu3
2
1,4-dioxane, 90 °C, 12 h
O
4
none
none
none
none
trace
6
1
2
3
5
DBU
Ph3P
Entry
Aromatic
aldehyde
Product
Yield
(%)b
6
7
urotropine
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCOc
DABCOd
none
8
1
3a
40
30
9
MeCN
EtO2C
CO2Et
CHO
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
DMSO
16
O
DMF
13
Cl
CHCl3
10
2
3
4
3b
3c
3d
THF
20
EtO2C
EtO2C
EtO2C
CO2Et
CO2Et
CO2Et
cyclohexane
toluene
trace
8
CHO
Br
O
Br
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
30
90
10
12
24
12
12
12
37
55
60
90
40
90
40
CHO
I
O
I
90
30
90
10
90
none
a The reaction was carried out using 0.5 mmol of 1, 0.25 mmol of 2a,
and 1 mol% of the catalyst in solvent (6.0 mL).
b GC yield.
CHO
O
c Conditions: 5 mol% of DABCO.
d Conditions:10 mol% of DABCO.
Synlett 2009, No. 20, 3295–3298 © Thieme Stuttgart · New York

LETTER
Cycloaddition Reaction of Ethyl Propiolate and Aryl Aldehydes
3297
Table 2 Synthesis of 4-Aryl-4H-Pyrans via DABCO-Catalyzed
Cycloaddition Reaction of Ethyl Propiolate with Representative Aryl
Aldehydesa (continued)
2008, 41, 1545. (f) Patil, N. T.; Yamamoto, Y. Chem. Rev.
2008, 108, 3395.
(3) (a) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem.
Int. Ed. 2007, 46, 1570. (b) Johnson, A. W.; Tebby, J. C.
J. Chem. Soc. 1961, 2126. (c) Tebby, J. C.; Wilson, I. F.;
Grifiths, D. V. J. Chem. Soc., Perkin Trans. 1 1979, 2133.
(d) Diels, O.; Alder, K. Liebigs Ann. Chem. 1932, 498, 16.
(e) Acheson, R. M. Adv. Heterocycl. Chem. 1963, 1, 125.
(f) Yu, X. Z.; Ren, H. J.; Xiao, Y. J.; Zhang, J. L. Chem. Eur.
J. 2008, 14, 8481.
Ar
CO2Et
EtO2C
CO2Et
DABCO (1 mol%)
+
ArCHO
2
1,4-dioxane, 90 °C, 12 h
O
1
2
3
(4) (a) Zhu, S.; Hudson, T. H.; Kyle, D. E.; Lin, A. J. J. Med.
Chem. 2002, 45, 3491. (b) Chung, Y. M.; Gong, J. H.; Kim,
T. H.; Kim, J. N. Tetrahedron Lett. 2001, 42, 9023.
(c) Ciclosi, M.; Fava, C.; Galeazzi, R.; Orena, M.;
Sepulveda-Arques, J. Tetrahedron Lett. 2002, 43, 2199.
(d) Kim, J. N.; Lee, H. J.; Lee, K. Y.; Gong, J. H. Synlett
2002, 173. (e) Gong, J. H.; Kim, H. R.; Ryu, E. K.; Kim,
J. N. Bull. Korean Chem. Soc. 2002, 23, 789. (f) Lawrence,
N. J.; Crump, J. P.; McGown, A. T.; Hadfield, J. A.
Tetrahedron Lett. 2001, 42, 3939. (g) Yadav, J. S.;
Subba Reddy, B. V.; Geetha, V. Synlett 2002, 513.
(h) Wang, B.; Yu, X.-M.; Lin, G.-Q. Synlett 2001, 904;
special issue. (i) Rose, P. M.; Clifford, A. A.; Rayner, C. M.
Chem. Commun. 2002, 968. (j) Gawronski, J.; Wascinska,
N.; Gajewy, J. Chem. Rev. 2008, 108, 5227. (k) Brandi, A.;
Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988.
(l) Meng, X. T.; Huang, Y.; Chen, R. Y. Org. Lett. 2009, 11,
137.
Entry
Aromatic
aldehyde
Product
Yield
(%)b
NO2
NO2
5
3e
3f
80
78
82
EtO2C
O2N
CO2Et
CHO
O
O2N
6
7
EtO2C
CO2Et
CHO
O
(5) (a) Gonzalez, R.; Martin, N.; Seoane, C. Tetrahedron Lett.
1992, 33, 3809. (b) Shestopalov, A. M.; Niazimbetova,
D. H. Heterocycles 1999, 51, 1101.
CF3
CF3
(6) (a) Mulwad, V. V.; Shirodkar, J. M. Indian J. Heterocycl.
Chem. 2002, 11, 199. (b) Mulwad, V. V.; Pawar, R. B.
Indian J. Heterocycl. Chem. 2001, 10, 241. (c) Lei, Y. J.;
Yang, Y. Z.; Liu, H.; Zhu, C. H. Chin. J. Med. Chem. 2001,
11, 270. (d) Kortenska, V. D.; Velikova, M. P.; Yanishlieva,
N. V.; Totzeva, I. R.; Bankova, V. S.; Marcucci, M. C. Eur.
J. Lipid. Sci. Technol. 2002, 104, 19. (e) Longobardi, M.;
Mariani, E.; Bargagna, A.; Mazzeo, F.; Vitelli, M. R.;
Giordano, L.; Falcone, G. Farmaco 2001, 56, 625.
(f) Horino, H.; Mimura, T.; Kagechika, K.; Ohta, M.; Kubo,
H.; Kitagawa, M. Chem. Pharm. Bull. 1998, 46, 602.
(g) Manolov, L.; Danchev, N. D. Arch. Pharm. 2003, 336,
83. (h) Shafae, A. M.; Ibrahim, M. A. Pharmazie 2003, 58,
143. (i) Wu, J. Y.; Fong, W. F.; Zhang, J. X.; Leung, C. H.;
Kwong, H. L.; Meng, S.; Li, D.; Chenug, H. Y. Eur. J.
Pharm. 2003, 473, 9. (j) Yong, J.; Zhao, Y. F.; Still, C. C.;
Sacalis, J. N. Tsinghua Sci. Technol. 2000, 5, 159.
(k) Ahluwalia, V. K.; Kaila, N.; Bala, S. Indian. J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 1987, 26, 700.
(l) Mail, R. S.; Joshi, P. P.; Sandhu, P. K.; Manekar-Tilve, A.
J. Chem. Soc., Perkin Trans. 1 2002, 371. (m) Magiatis, P.;
Melliou, E.; Skaltsounis, A. L.; Mitaku, S.; Leonce, S.;
Reard, P.; Pierre, A.; Atassi, G. J. Nat. Prod. 1998, 61, 982.
(n) Madkour, H. M. F.; Mahmoud, M. R.; Sakr, A. M.;
Habashy, M. M. Sci. Pharm. 2001, 69, 33. (o) Jolivet, C.;
Rivalle, C.; Bisagni, E. Heterocycles 1996, 43, 995.
(p) Marco, J. L.; Delos, R. C.; Carreiras, M. C.; Banos, J. E.;
Badia, A.; Vivas, N. M. Bioorg. Med. Chem. 2001, 9, 727.
(q) Bloxhem, J.; Dell, C. P.; Smith, C. W. Heterocycles
1994, 38, 399.
3g
EtO2C
CO2Et
CHO
O
a All the reactions were carried out using 1 (1 mmol), 2 (0.5 mmol),
and DABCO (1 mol%) in 1,4-dioxane (6.0 mL) at 90 °C for 12 h.
b Isolated yield.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors thank National Natural Science Foundation of China
(Nos. 20932002, 20772034 and 20625205) and Guangdong Natural
Science Foundation (No. 07118070) for the financial support of this
work.
References and Notes
(1) (a) Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 1477.
(b) Tietze, L. F.; Haunert, F. Stimulating Concepts in
Chemistry; Wiley: New York, 2000. (c) Wender, P. A.;
Miller, B. L. In Organic Synthesis: Theory and
Applications, Vol. 2; Hudlicky, T., Ed.; JAI Press:
Greenwich CT, 1993, 27.
(2) (a) Müller, T. J. J. Metal Catalyzed Cascade Reactions, In
Topics in Organometallic Chemistry, Vol. 19; Springer:
New York, 2006. (b) Hayashi, T.; Yamasaki, K. Chem. Rev.
2003, 103, 2829. (c) Naodovic, M.; Yamamoto, H. Chem.
Rev. 2008, 108, 3132. (d) Paull, D. H.; Abraham, C. J.;
Scerba, M. T.; Alden, D. E.; Lectka, T. Acc. Chem. Res.
2008, 41, 655. (e) Terao, J.; Kambe, N. Acc. Chem. Res.
(7) The HMQC spectrum of diethyl 4-(3-nitrophenyl)-4H-
pyran-3,5-dicarboxylate enabled assignment of the directly
bonded C–H moieties. The results showed that H–C
correlations signals were 1.15–1.22/14.0, 4.01–4.13/60.9,
4.78/35.6, 7.41–7.45/128.9, 7.62/148.7, 7.68–7.70/135.1,
8.03–8.12/122.1 and 8.12/123.6, respectively.
Synlett 2009, No. 20, 3295–3298 © Thieme Stuttgart · New York

3298
W. Liu et al.
LETTER
(8) Typical Procedure for the Cascade Reaction of Ethyl
Propiolate with Benzaldehyde
PTLC (GF254), eluted with a PE–Et2O (10:1) mixture to
afford the desired product diethyl 4-phenyl-4H-pyran-3,5-
To a stirring mixture of ethyl propiolate (98 mg, 1 mmol)
and benzaldehyde (53 mg, 0.5 mmol) in a round-bottom
flask, 1,4-dioxane (6 mL), and DABCO (0.56 mg, 0.005
mmol) were added successively, and then the mixture was
stirred at 90 °C for 12 h. After the reaction accomplished, the
solvent was diluted with H2O and extracted with Et2O. The
ether layer was washed with sat. salt water, and dried with
anhyd MgSO4. The resulting mixture was then analyzed by
GC and GC-MS. Volatiles were removed under reduced
pressure, and the crude product was subjected to isolation by
dicarboxylate(3a). Colorless viscous oil. IR (KBr): nmax =
1713, 1655, 1616, 1475, 1248, 1178, 1077, 894, 695 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.56 (s, 2 H), 7.22 (m, 5
H), 4.65 (s, 1 H), 4.06 (m, 4 H), 1.17 (m, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): d = 165.5, 148.0, 143.7, 128.7, 128.1,
126.9, 112.9, 60.6, 35.7, 14.0 ppm. GC-MS: m/z (%) =
302.07 (27) [M+], 225.00(100). Anal. Calcd for C17H18O5: C,
67.54; H, 6.00. Found: C, 67.52; H, 6.03.
(9) Nair, V.; Sreekanth, A. R.; Vinod, A. U. Org. Lett. 2001, 3,
3495.
Synlett 2009, No. 20, 3295–3298 © Thieme Stuttgart · New York

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