The cation exchange resin-promoted coupling of alkynes with aldehydes: one-pot synthesis of α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2008.05.056

Alkynes undergo smooth coupling with aldehydes in the presence of Amberlyst-15 at room temperature to produce the corresponding α,β-unsaturated ketones in high yields with E-geometry. The use of an inexpensive, readily available, and recyclable cation exchange resin makes this method quite simple and convenient.

Full text of DOI:10.1016/j.tetlet.2008.05.056

Tetrahedron Letters 49 (2008) 4498–4500
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Tetrahedron Letters
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The cation exchange resin-promoted coupling of alkynes with aldehydes:
one-pot synthesis of a,b-unsaturated ketones
*
J. S. Yadav , B. V. Subba Reddy, P. Vishnumurthy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Alkynes undergo smooth coupling with aldehydes in the presence of Amberlyst-15Ò at room temperature
Article history:
Received 1 February 2008
Revised 2 May 2008
Accepted 13 May 2008
Available online 15 May 2008
to produce the corresponding
a,b-unsaturated ketones in high yields with E-geometry. The use of an
inexpensive, readily available, and recyclable cation exchange resin makes this method quite simple
and convenient.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Ion-exchange resin
Aldehydes
Alkynes
Conjugated ketones
a
,b-Unsaturated ketones have attracted increasing attention
ity in operation, environmental compatibility, reusability, greater
selectivity, non-corrosiveness, and ready availability of the re-
agents at low cost.11 In particular, ion-exchange resins can make
reaction processes simple, more convenient, economic, and envi-
ronmentally benign which enable them to function as efficient
catalysts for various transformations.12
due to their numerous pharmacological properties such as anti-
cancer activity, cytotoxicity, anti-inflammatory, analgesic, and
antipyretic behavior.1 Some of them are potential antibacterial,
antifungal, and anti-ulcer agents.2 They are also very useful inter-
mediates in organic synthesis, especially for heterocycles.3 These
findings have attracted the attention of chemists, biochemists,
and pharmacologists to this particular group of compounds. The
In continuation of our interest in the use of solid acid cata-
lysts,13 herein, we report an efficient and metal-free method for
stereoselective synthesis of
a,b-unsaturated ketones is generally
the preparation of a,b-unsaturated ketones by means of coupling
accomplished by various methods such as condensation, oxidation,
elimination, acylation, and insertion of carbon monoxide among
others.4 However, in most cases, the stereoselective control of
the carbon–carbon double bond remains unsolved. The coupling
of alkynes to aldehydes is an important transformation in organic
synthesis to generate carbon–carbon multiple bonds.5 Though
the addition of alkynylmetal reagents to aldehydes to produce
propargyl alcohols has been studied extensively,5 the reaction be-
alkynes with aldehydes using a cheap and readily available cation
exchange resin. Initially, we attempted the coupling of phenyl-
acetylene (1) with paraformaldehyde (2) in the presence of
Amberlyst-15Ò. The reaction was complete within 2.0 h and the
product, 1-phenylprop-2-en-1-one 3a was obtained in 86% yield
(Scheme 1).
Other terminal alkynes such as p-methylphenylacetylene and 4-
phenylbut-1-yne were also coupled effectively with paraformalde-
hyde under similar conditions (Table 1, entries b and c). These re-
sults provided the incentive for further study with various alkynes
and aldehydes. Interestingly, several aldehydes such as cyclohex-
anecarboxaldehyde, n-hexanal, n-butyraldehyde, benzaldehyde,
tween alkynes and aldehydes to generate a,b-unsaturated ketones
has received little attention. Only a few methods are known in the
literature for the direct preparation of conjugated enones from
alkynes and aldehydes. Lewis acids such as SbF5, Yb(OTf)3, and In-
(OTf)3 are employed to accomplish this reaction.6–8 Other reagents
such as VO(OSiPh3)3 and InCl3 have been used in the coupling of
allenyl carbinols with aldehydes to generate b-hydroxy enones.9,10
In recent years, the use of heterogeneous catalysts such as ion-
exchange resins, clay, and zeolites has received significant atten-
tion in different areas of organic synthesis because of their simplic-
O
Amberlyst-15
+
HCHO
CH2Cl2, r.t.
1
3a
2
* Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail addresses: yadav@iict.res.in, yadavpub@iict.res.in (J. S. Yadav).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.056

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 4498–4500
4499
Table 1
Amberlyst-15-promoted coupling of alkynes with aldehydes
Entry
Alkyne
Aldehyde
Producta
Time (h)
2.0
Yieldb (%)
86
O
a
HCHO
O
b
c
d
e
f
HCHO
HCHO
2.0
3.0
2.5
2.5
3.0
3.5
4.0
2.0
2.5
3.5
4.5
90
81
85
87
80
78
70
90
85
80
70
H3C
H3C
O
O
CHO
CHO
CHO
O
H3C
H3C
O
O
g
h
i
CHO
O
CHO
CHO
O
O
CHO
j
MeO
OMe
O
CHO
CHO
k
l
O
S
S
O
CH3
O
CH3
O
CH3
m
n
HCHO
2.0
2.5
85c
80c
Ph
Ph
O
O
O
CH3
HCHO
CH3
Ph
CH3
Ph
Ph
O
O
O
O
O
CH3
78c
CH3
o
HCHO
3.0
Ph
CH3
O
The products were characterized by 1H NMR, IR and mass spectrometry.
Yield refers to pure products after chromatography.
Enone and dioxane (3 and 4) were obtained in a ratio of 2:1.
a
b
c
p-methoxy-benzaldehyde and thiophene-2-carboxaldehyde reac-
ted well with alkynes under similar conditions to afford a wide
range of conjugated enones (Table 1, entries d–l). This method
worked equally well with aliphatic, heterocyclic and aromatic
aldehydes (Table 1). Though the reaction proceeded with phenyl-
acetylene and electron-deficient substrate, that is p-nitrobenzalde-

4500
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 4498–4500
Acknowledgment
O
O
R'
O
Amberlyst-15
CH2Cl2, r.t.
R
R'
R'
HCHO
R
PVM thanks CSIR, New Delhi, for the award of fellowship.
References and notes
R
+
+
O
3 major
4 minor
1. Nowakowska, Z. Eur. J. Med. Chem. 2007, 42, 125.
Scheme 2.
2. Dimmock, J. R.; Elias, D. W.; Beazel, M. A.; Kandepu, N. M. Curr. Med. Chem.
1999, 6, 1125.
3. (a) Bhat, B. A.; Dhar, K. L.; Puri, S. C.; Saxena, A. K.; Shanmugavel, M.; Qazi, G. N.
Bioorg. Med. Chem. Lett. 2005, 15, 3177; (b) Wang, S.; Yu, G.; Lu, J.; Xiao, K.; Hu,
Y.; Hu, H. Synthesis 2003, 487; (c) Wei, X.; Fang, J.; Hu, Y.; Hu, H. Synthesis 1992,
1205.
4. (a) Sugawara, Y.; Yamada, W.; Yoshida, S.; Ikeno, T.; Yamada, T. J. Am. Chem.
Soc. 2007, 129, 12902; (b) Petrov, O.; Ivanova, Y.; Gerova, M. Catal. Commun.
2008, 9, 315 and references cited therein.
H
Ph
D
+
H
O
O
Ph
D
H
+
5. (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806; (b)
Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687; (c) Tzalis, D.;
Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 1463.
6. Hayashi, A.; Yamaguchi, M.; Hirama, M. Synlett 1995, 195 and references cited
therein.
Oxete intermediate
+
H
H
O
Ph
D
7. (a) Asano, Y.; Hara, K.; Ito, H.; Sawamura, M. Org. Lett. 2007, 9, 3901; (b) Yang,
F.; Xi, P.; Yang, L.; Lan, J.; Xie, R.; You, J. J. Org. Chem. 2007, 72, 5457; (c)
Yamashita, M.; Yamada, K.; Tomioka, K. Adv. Synth. Catal. 2005, 347, 1649.
8. (a) Viswanathan, G. S.; Li, C.-J. Tetrahedron Lett. 2002, 43, 1613; (b) Curini, M.;
Epifano, F.; Maltese, F.; Rosati, O. Synlett 2003, 552; (c) Xu, B.; Shi, M. Synlett
2003, 1639.
Scheme 3.
hyde, the yield is very low (35%) over a long reaction time (24 h).
However, both aliphatic and aromatic alkynes underwent facile
9. Trost, B. M.; Jonasson, C.; Wuchrer, M. J. Am. Chem. Soc. 2001, 123, 12736.
10. (a) Yu, C.-M.; Kim, Y.-M.; Kim, J. M. Synlett 2003, 1518; (b) Miranda, P. O.;
Ramirez, M. A.; Padron, J. I.; Martin, V. S. Tetrahedron Lett. 2006, 47, 283.
11. (a) Cornelis, A.; Laszlo, P. Synlett 1994, 155; (b) Sen, S. E.; Smith, S. M.; Sullivan,
K. A. Tetrahedron 1999, 55, 12657.
12. (a) Ko, S.; Yao, C. F. Tetrahedron Lett. 2006, 47, 8827; (b) Solladie-Cavallo, A.;
Choucair, E.; Balaz, M.; Lupattelli, P.; Bonini, C.; di Blasio, N. Eur. J. Org. Chem.
2006, 3007; (c) Solladie-Cavallo, A.; Lupattelli, P.; Bonini, C. J. Org. Chem. 2005,
70, 1605; (d) Vuano, B.; Pieroni, O. L. Synthesis 1999, 72; (e) Boudart, M.
Chem. Rev. 1995, 95, 661; (f) Ballini, R.; Baboni, L.; Filippone, P. Chem. Lett.
1997, 475.
coupling with aldehydes to furnish disubstituted (E)-a,b-unsatu-
rated ketones (Table 1). The cross-coupling between terminal
alkynes and paraformaldehyde gave the corresponding vinyl
ketones in good yields (Table 1, entries a–c). Surprisingly, the
cross-coupling of internal alkynes such as 1-phenylprop-1-yne,
1-phenylbut-1-yne and 1-phenylhex-1-yne with paraformalde-
hyde gave a mixture of vinyl ketone and 1,3-dioxane in a 2:1 ratio
(Scheme 2, Table 1 entries m–o).14
Both the enone and 1,3-dioxane could be separated easily by
column chromatography. In all cases, the reactions proceeded effi-
ciently in high yields at room temperature under mild conditions.
As solvent, dichloromethane gave the best results. All the products
were characterized by NMR, IR, and mass spectrometry. In the ab-
sence of acid resin, no reaction was observed between the alde-
hyde and alkyne. Furthermore, the reaction did not proceed with
other solid acids including Montmorillonite KSF and the hetero-
polyacid H3PW12O40. The catalyst could be separated easily by sim-
ple filtration, and the recovered acid resin was reused in
subsequent reactions with only a gradual decrease in activity. For
example, benzaldehyde and paraformaldehyde gave 3a in 86%,
82%, 75%, and 72% yields over four cycles. The scope and generality
of this process was illustrated with respect to various alkynes and
aldehydes, and the results are presented in Table 1.15 The probable
reaction mechanism is depicted in Scheme 3.
13. (a) Yadav, J. S.; Reddy, B. V. S.; Vishnumurthy, P. Tetrahedron Lett. 2005, 46,
1311; (b) Meshram, H. M.; Reddy, P. N.; Sadashiv, K.; Yadav, J. S. Tetrahedron
Lett. 2005, 46, 623; (c) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.; Niranjan, N.
J. Mol. Catal. A 2004, 210, 99; (d) Yadav, J. S.; Reddy, B. V. S.; Sunitha, V.; Reddy,
K. S.; Ramakrishna, K. V. S. Tetrahedron Lett. 2004, 45, 7947.
14. Polshettiwar, V.; Varma, R. S. J. Org. Chem. 2007, 72, 7420.
15. Experimental procedure: A mixture of aldehyde (1 mmol), alkyne (1.2 mmol),
and Amberlyst-15Ò (0.75 g) in dichloromethane (10 L) was stirred at room
temperature for the appropriate time (Table 1). After completion of the
reaction, as indicated by TLC, the reaction mixture was filtered and washed
with dichloromethane (2 Â 10 mL). The combined organic extracts were
concentrated in vacuo and the resulting product was charged on small silica
gel column and eluted with a mixture of ethyl acetate–n-hexane (1:9) to afford
pure enone. Spectral data for selected products: compound 3c: Liquid, IR (KBr):
m
3443, 3019, 2923, 1715, 1455, 1216, 1029, 757 cmÀ1 1H NMR (200 MHz,
;
CDCl3): d 7.34–7.12 (m, 5H), 6.49–6.25 (m, 2H), 5.80 (d, 1H, J = 16.2 Hz), 2.95–
2.85 (m, 4H). EIMS: m/z: 160 (M+) 105, 91, 56, 78; HRMS calcd for C11H12O:
160.2156, found: 160.2142. Compound 3g: Liquid, IR (KBr):
m 3441, 3061,
2930, 2855, 1750, 1621, 1037, 761, 753 cmÀ1 1H NMR (200 MHz, CDCl3): d
;
7.85 (d, 2H, J = 7.5 Hz), 7.55–7.41 (m, 3H), 6.98 (d, 1H, J = 6.9 Hz), 2.30–2.20 (m,
2H), 1.75–1.32 (m, 10H); EIMS:m/z: 202 (M+) 131, 105, 77; HRMS calcd for
To realize the reaction mechanism, we have carried out the
reaction between deuterated phenylacetylene and cyclohexane-
carboxaldehyde. As shown in Scheme 3, no loss of deuterium label
was observed in the product. This clearly indicates that the reac-
tion proceeds via cyclic oxete intermediate as has been reported
by Yamaguchi and co-workers.6
C
14H18O: 202.2963, found: 202.2951. Compound 3j: Liquid, IR (KBr):
m 3423,
3058, 2924, 2850, 1891, 1657, 1597, 1255, 719 cmÀ1 1H NMR (200 MHz,
;
CDCl3): d 8.20 (d, 2H, J = 8.7 Hz), 7.80 (d, 1H, J = 16.3 Hz), 7.60–7.25 (m, 5H),
7.20 (d, 1H, J = 16.3 Hz), 6.95 (d, 2H, J = 8.7 Hz), 3.94 (s, 3H); EIMS: m/z: 238
(M+) 161, 131, 105, 118. 77; HRMS calcd for C16H14O2: 238.2859, found:
238.2839. Compound 3o: Liquid, IR (KBr):
m 3453, 2957, 2868, 1740, 1659,
1076, 753 cmÀ1 1H NMR (200 MHz, CDCl3): d 7.55 (d, 2H, J = 7.9 Hz), 7.55–7.32
;
(m, 3H), 5.72 (s, 1H), 5.25 (s, 1H), 2.45 (t, 2H, J = 7.1 Hz), 1.31–1.55 (m, 4H), 0.95
In summary, we have described a simple, convenient and me-
(t, 3H, J = 6.7 Hz); EIMS: m/z: 188 (M+) 145, 105, 77, 41; HRMS calcd for
tal-free protocol for the preparation of
a,b-unsaturated ketones
C
13H16O: 188.2694, found: 188.2682. Compound 4o: Liquid, IR (KBr):
m 3496,
2934, 2870, 1780, 1696, 1030, 770 cmÀ1 1H NMR (200 MHz, CDCl3): d 7.65 (d,
;
from alkynes and aldehydes using Amberlyst-15Ò as a novel pro-
moter. In addition to its simplicity and mild reaction conditions,
this method provides high yields of products in short reaction
times with high selectivity. The use of an inexpensive and recycl-
able acid resin makes this method simple, convenient, and
economically viable.
2H, J = 7.9 Hz), 7.55–7.35 (m, 3H), 4.75 (s, 2H), 4.21 (d, 2 H, J = 9.5 Hz), 3.85 (d,
2H, J = 10.1 Hz), 1.85 (t, 2H, J = 7.5 Hz), 1.35–1.20 (m, 4H), 0.85 (t, 3H,
J = 7.2 Hz); EIMS: m/z:248 (M+) 192, 105, 79, 77. HRMS calcd for C15H20O3:
248.3221, found: 248.3214.