An efficient synthesis of 2-aryl-1,4-diketones via hydroacylation of enones

Article abstract of DOI:10.1016/j.tetlet.2011.12.104

An improved method has been developed for the hydroacylation of enones with aldehydes employing bis-5-(2-hydroxyethyl)-1,3-thiazolium bromide/Et ₃N system to afford the corresponding 1,4-diketones in good yields. This method is effective for the preparation of 1,4-diketones from both aromatic and aliphatic aldehydes.

Full text of DOI:10.1016/j.tetlet.2011.12.104

Tetrahedron Letters 53 (2012) 1546–1549
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Tetrahedron Letters
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An efficient synthesis of 2-aryl-1,4-diketones via hydroacylation of enones
P. Lakshmi Reddy a, K. Praveen Kumar a, S. Satyanarayana a, R. Narender a, B.V. Subba Reddy b,
⇑
a Crop Protection Chemicals, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Natural Product 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
Article history:
An improved method has been developed for the hydroacylation of enones with aldehydes employing
bis-5-(2-hydroxyethyl)-1,3-thiazolium bromide/Et3N system to afford the corresponding 1,4-diketones
in good yields. This method is effective for the preparation of 1,4-diketones from both aromatic and ali-
phatic aldehydes.
Received 19 September 2011
Revised 19 December 2011
Accepted 24 December 2011
Available online 30 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Stetter reaction
Aldehydes
a,b-Unsaturated ketones
1,4-Diketones
Conjugate addition has emerged as a powerful tool for a new C–
C bond and carbon–heteroatom bond formation.1,2 In particular,
hydroacylation of olefins with aldehydes has received considerable
attention because the resultant 1,4-diketones are used widely in
the synthesis of various heterocycles such as furan, pyrrole, thio-
phene, and pyridiazine derivatives.3,4 Indeed, these heterocycles
are versatile pharmacophores with a wide range of biological activ-
ities.5 Besides heterocyclic compounds synthesis, they are also
used in the synthesis of cyclopentenone derivatives.6 Generally,
1,4-diketones are prepared by a conjugate addition of aldehydes
Br
Br
Me
Me
N
N
S
S
HO
N
OH
Br
(I)
Br
Me
Br
N
Me
Me
onto
a,b-unsaturated ketones using thiazolium salts in the pres-
N
ence of a tertiary amine.6–8 Though these methods provide good
yields with aliphatic aldehydes, the reactions with aromatic alde-
hydes require high temperatures and longer reaction times and
also the yields are far from satisfactory. Thus there is a need to de-
velop high yielding protocol for the preparation of 1,4-diketones.
Recently, chiral N-heterocyclic carbenes (NHCs) have also been
developed for the enantioselective version of this reaction.9
Herein, we report a new organocatalyst, that is, bis-thiazolium
bromide, for the synthesis of 1,4-diketones via the hydroacylation
of enones with aldehydes. The catalysts I and II were prepared
by the treatment of 2:1 ratio of 5-(2-hydroxyethyl)-4-methyl-
1,3-thiazole (4.8 g, 38.1 mmol) with bis(bromomethylbenzene)
(5 g, 19.0 mmol) in dry acetonitrile (Fig. 1).10
S
S
S
HO
HO
OH
(II)
(III)
Figure 1. Chemical structures of catalysts I and II and III.
O
O
S
O
Catalyst I
O
+
O
N
S
Et3N, EtOH, reflux
N
O
H
1
2
3a
Scheme 1. Preparation of 1,4-diketone 3a via hydroacylation.
We first attempted hydroacylation of
a,b-unsaturated ketone
(0.199 g, 1 mmol, 1) with thiophene-2-carboxaldehyde (0.11 g,
1.2 mmol, 2) in ethanol (3 mL) using 20 mol % of bis-thiazolium salt
(0.109 g, 0.2 mmol, I) in the presence of triethylamine (0.14 mL,
1 mmol). The reaction proceeded smoothly under reflux to
afford the corresponding 1,4-diketone 3a (0.236 g) in a 76% yield
(Scheme 1).
The effect of the catalyst, base, and solvent was examined in the
formation of 3a and the results are presented in Table 1. The
⇑
Corresponding author. Fax: 91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.104

P. Lakshmi Reddy et al. / Tetrahedron Letters 53 (2012) 1546–1549
1547
Table 1
product 3a was obtained in only a 58% yield when the reaction was
performed with a commercially available mono-functional thiazo-
lium salt III (20 mol %) in the presence of DBU (1 mmol) in ethanol.
The yield of 3a was significantly increased to 81% by performing
the above reaction with a bifunctional catalyst I (20 mol %) under
similar conditions. As seen from Table 1, bifunctional catalyst I
gave the best results. Of various solvents such as DCM, EtOH, and
THF, ethanol appeared to give the best results. Among various
bases, DBU was found to be superior in terms of conversion (Table
1).
Under optimized conditions, the reaction proceeds well in the
presence of 20 mol % of the catalyst I and 1 mmol of Et3N in etha-
nol at 78 °C. Since triethylamine is readily accessible, we per-
formed further reactions with Et3N. Next, we carried out two
parallel experiments using different amount of the catalysts in
the presence of triethylamine so as to show the superiority of the
catalyst I over catalyst III (Scheme 2).
The catalytic efficiency of various thiazolium salts for the preparation of product 3a
Entry
Catalysta
Solvent
Baseb
Time (h)
Yieldc (%)
a
b
c
d
e
f
g
h
i
Thiazolium salt (I)
Thiazolium salt (II)
Thiazolium salt (III)
Thiazolium salt (I)
Thiazolium salt (II)
Thiazolium salt (III)
Thiazolium salt (I)
Thiazolium salt (II)
Thiazolium salt (III)
Thiazolium salt (I)
Thiazolium salt (II)
Thiazolium salt (III)
DCM
DCM
DCM
THF
THF
THF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
DBU
DBU
15
15
15
15
15
15
15
15
15
13
13
13
45
35
25
71
64
49
76
68
53
81
73
58
j
k
l
a
b
c
The reactions were carried out in 1 mmol scale using 20 mol % catalysts.
The ratio of chalcone/aldehyde/base (1:1.2:1).
Yield refers to pure products.
The Scheme 2 shows that 40 mol % of commercially available
mono-functional catalyst III was not as good as 20 mol % of bifunc-
tional catalyst I. Thus, we found that catalysts I and II are more
reactive than catalyst III. The reason may be attributed to the distal
OH group present on the 2nd carbene on catalysts I and II, which
helps intramolecularly to increase the turnover of the catalyst.
Next, the role of alcohol additive was studied by performing the
reaction with a reduced amount of the catalyst I from 20 to
10 mol %. Indeed, the desired product 3a was obtained in similar
yield as that of 20 mol % when the reaction was performed in the
Cat. I (20 mol%)
3a
76%
EtOH (3 mL)
Enone
Aldehyde
+
Et3N(1 mmol)
15 h
1
2
Cat. III (40 mol%)
1 mmol
1.2 mmol
3a
61%
Scheme 2. Comparison of the mono- and bifunctional catalysts (III and I) in the
formation of 3a.
Table 2
Preparation of 1,4-diketones using C2-symmetric NHC via Stetter reactiona,b
Entry
a
,b-Unsaturated ketone
Aldehyde
1,4-Diketone (3)
Time (h)
15
Yieldc (%)
76
O
O
O
CHO
S
S
a
O
N
O
O
O
O
O
O
O
N
N
N
N
N
N
N
CHO
O
O
S
S
S
S
O
O
O
O
O
O
b
c
d
e
f
’’
’’
15
15
15
15
15
15
68
72
74
70
77
CHO
CHO
Me
Me
Me
O
Me
O
S
N
CHO
O
’’
’’
’’
CHO
F
F
CHO
Br
g
Br
71
(continued on next page)

1548
P. Lakshmi Reddy et al. / Tetrahedron Letters 53 (2012) 1546–1549
Table 2 (continued)
Entry
a
,b-Unsaturated ketone
Aldehyde
CHO
1,4-Diketone (3)
Time (h)
15
Yieldc (%)
65
S
O
h
i
’’
O
O
O
O
O
O
O
N
N
N
N
O
N
CHO
CHO
Me
Cl
O
O
O
O
O
O
Me
Cl
15
15
15
15
15
15
72
70
69
78
74
75
j
’’
’’
CHO
k
l
O
CHO
CHO
Me
Cl
Me
Cl
m
n
’’
’’
CHO
O
N
CHO
O
O
o
p
15
10
78
83
N
O
BnO
BnO
CHO
O
O
O
O
OBn
OBn
N
O
O
N
O
CHO
q
12
81
a
The reactions were carried out in 1 mmol scale using 20 mol % catalyst I.
The ratio of chalcone:aldehyde:base (1:1.2:1).
Yield refers to pure products.
b
c
presence of 5 equiv of isopropanol in THF. Among the catalysts I
and II, para-substituted catalyst I gave slightly higher yields than
meta-substituted catalyst II (Table 1). The reactivity of NHC’s
may also be affected by steric and electronic properties which
may be the cause of difference in reactivity between catalysts I
and II.
all cases, the reactions are clean and the desired products were iso-
lated in good yields. The catalysts I and II are effective not only
with aliphatic aldehydes but also with aromatic and heterocyclic
aldehydes (Table 2). The scope of this method is presented in Table
2. This method works well not only with chalcones but also with
enones derived from heterocyclic aldehydes (Table 1).11
The above observations provided the incentive to extend this
In the absence of either thiazolium catalyst I, or a base, the reac-
tion did not proceed even after an extended reaction time (24 h).
The base is essential to generate N-heterocyclic carbene (NHC)
in situ from thiazolium salt.
In summary, we have developed an efficient bifunctional thia-
zolium catalysts (I and II) for the synthesis of 1,4-diketones by
means of hydroacylation of enones with aldehydes. The method
process for various aldehydes and
a,b-unsaturated ketones. Inter-
estingly, several aldehydes such as aromatic, heteroaromatic, and
aliphatic substrates participated well in this reaction. A wide range
of 1,4-diketones, were prepared using the bifunctional catalyst (I).
The end products are very useful building blocks for the prepara-
tion of trisubstituted pyrrole, furan, and thiophene derivatives. In

P. Lakshmi Reddy et al. / Tetrahedron Letters 53 (2012) 1546–1549
1549
7. (a) Stetter, H.; Kuhlmann, H. Angew. Chem., Int. Ed. Engl. 1974, 13, 539; (b)
Amarnath, V.; Anthony, D. C.; Amarnath, K.; Valentine, W. M.; Wetterau, L. A.;
Graham, D. G. J. Org. Chem. 1991, 56, 6924.
8. (a) Barrett, A. G. M.; Love, A. C.; Tedeschi, L. Org. Lett. 2004, 6, 3377; (b) Kerr, M.
S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70, 5725.
works well with aliphatic, aromatic, and heterocyclic aldehydes.
This method is effective for the preparation of -diketones in good
yields especially from aromatic aldehydes, which are known to
c
give low yields under classical conditions.
9. (a) Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J.
J. Am. Chem. Soc. 2001, 123, 9696; (b) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J.
Am. Chem. Soc. 2002, 124, 10298; (c) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K.
A. J. Am. Chem. Soc. 2004, 126, 2314; (d) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc.
2004, 126, 8876; (e) Piel, I.; Steinmetz, M.; Hirano, K.; Frhlich, R.; Grimme, S.;
Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 4983; (f) DiRocco, D. A.; Rovis, T.
Angew. Chem. Int. Ed. 2011, 50, 7982; (g) Nunez, M. G.; Garcıa, P.; Moro, R. F.;
Dıez, D. Tetrahedron 2010, 66, 2089.
Acknowledgments
PLR thanks UGC and KPK & SS thank the CSIR, New Delhi for the
award of fellowships.
10. Preparation of the catalysts (I and II): 3,30-(1,4-Phenylenebis(methylene)bis(5-
(2-hydroxyethyl)-4-methylthiozol-3-ium)bromide (I): 5-(2-Hydroxyethyl)-4-
methyl-1,3-thiazole (4.8 g, 38.1 mmol) and bis(1,4-bromomethylbenzene) (5 g,
19.0 mmol) in dry acetonitrile (100 mL) were mixed together in a 250 mL two-
necked round bottom flask fitted with a stirrer and a reflux condenser and
heated for 24 h under reflux. After completion, the mixture was allowed to cool
to room temperature with constant stirring and the resulting product was
isolated by vacuum filtration. The solid was subjected to drying to give the
pure catalyst (I). Yield: 9.08 g (86.4%); mp 252–254 °C; 1H NMR (300 MHz): d
10.32 (s, 2H), 7.66 (d, 2H, J = 7.4 Hz), 7.48 (t, 1H, J = 7.5 Hz), 7.35 (s, 1H), 5.88 (s,
4H), 3.66 (t, 4H, J = 5.2 Hz), 3.03 (t, 4H, J = 5.2 Hz), 2.39 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 156.6, 141.3, 135.9, 133.3, 128.5, 59.2, 55.0, 29.1, 11.2; IR
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.104.
References and notes
1. (a) Myers, M. C.; Bharadwaj, A. R.; Milgram, B. C.; Scheidt, K. A. J. Am. Chem. Soc.
2005, 127, 14675; (b) Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.;
Grabowski, E. J. J.; Reider1, P. J. J. Am. Chem. Soc. 2001, 123, 9696; (c) Mattson, A.
C.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314.
2. (a) Stetter, H. Angew. Chem. Int. Ed. 1976, 15, 639; (b) Stetter, H.; Kuhlmann, H.
Org. React. 1991, 40, 407; (c) Raghavan, S.; Anuradha, K. Tetrahedron Lett. 2002,
43, 5181; (d) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326.
3. (a) Stetter, H.; Schlenker, W. Tetrahedron Lett. 1980, 21, 3479; (b) Hirano, K.;
Biju, A. T.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 14190; (c) Biju, A. T.;
Glorius, F. Angew. Chem. Int. Ed. 2010, 49, 9761; (d) Biju, A. T.; Wurz, N. E.;
Glorius, F. J. Am. Chem. Soc. 2010, 132, 5970; (e) Bugaut, X.; Liu, F.; Glorius, F. J.
Am. Chem. Soc. 2011, 133, 8130.
4. (a) Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.; Katzenellenbogen, B.
S.; Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 3838; (b) El-Haji, T.; Martin, J.
C.; Descotes, G. J. J. Heterocycl. Chem. 1983, 20, 233; (c) Bharadwaj, A. R.;
Scheidt, K. A. Org. Lett. 2004, 6, 2465; (d) Perrine, D. M.; Kagan, J.; Huang, D. B.;
Zeng, K.; Theo, B. K. J. Org. Chem. 1987, 52, 2213; (e) Jones, T. H.; Franko, J. B.;
Blum, M. S.; Fales, H. M. Tetrahedron Lett. 1980, 21, 789; (f) Raghavan, S.;
Anuradha, K. Synlett 2003, 711; (g) Yadav, J. S.; Reddy, B. V. S.; Eeshwaraiah, B.;
Gupta, M. K. Tetrahedron Lett. 2004, 45, 5873.
5. (a) Jones, R. A.; Bean, G. P. The Chemistry of Pyrroles; Academic: London, 1977;
(b) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4, pp 329–330; (c)
Friedrischsen, W.; Pagel, K. Prog. Heterocycl. Chem. 1995, 7, 130; (d) Saltiel, E.;
Ward, A. Drugs 1987, 34, 222; (e) Sridhar, D. R.; Jogibhukta, M.; Rao, P. S.;
Handa, V. K. Synthesis 1982, 1061.
(KBr):
20H25N2O2S2: 389.1357 [M+H]2- found: 389.1358, C10H13NOS: 195.0717,
[M+H]1ꢀ found: 195.0725.
m ; HRMS (ESI) calcd for
3254, 3001, 1583, 1445, 1081, 605 cmꢀ1
C
3,30-(1,3-Phenylenebis(methylene)bis(5-(2-hydroxyethyl)-4-methylthiozol-3-
ium)bromide (II): 5-(2-Hydroxyethyl)-4-methyl-1,3-thiazole (1.0 g, 7.6 mmol)
and bis(1,3-bromomethylbenzene) (1.0 g, 3.8 mmol) in dry acetonitrile (18 mL)
were mixed thoroughly in a 50 mL two necked round bottom flask fitted with a
stirrer and a reflux condenser. The mixture was heated for 24 h under reflux
and then allowed to cool to room temperature with constant stirring. The
product was isolated by vacuum filtration and then washed with ether to
afford colorless solid which was subjected to preliminary drying to afford the
catalyst (II). Yield: 1.76 g (83.8%); 1H NMR (300 MHz): d 10.31 (s, 2H), 7.66 (d,
2H, J = 7.4 Hz), 7.48 (t, 1H, J = 7.5 Hz), 7.35 (s, 1H), 5.88 (s, 4H), 3.66 (t, 4H,
J = 5.2 Hz), 3.03 (t, 4H, J = 5.2 Hz), 2.39 (s, 6H); 13C NMR (75 MHz, CDCl3): d
157.5, 143.5, 136.6, 133.9, 130.6, 129.6, 126.4, 60.0, 55.7, 29.9, 12.2; IR (KBr):
m
3294, 2965, 1587, 1445, 1057, 697 cmꢀ1; HRMS (ESI) calcd for C20H25N2O2S2,
389.1357 [M+H]2ꢀ found: 389.1356, C10H13NOS, 195.0717, [M+H]1ꢀ found:
195.0716.
11. Experimental procedure: To a stirred solution of the catalyst (I) (0.2 mmol) in
3 mL of ethanol were added 0.14 mL of Et3N (1.0 mmol) and an aldehyde
(1.2 mmol). The mixture was allowed to stir for 10 min at room temperature
and then chalcone (1 mmol) was added. The resulting mixture was kept under
reflux for 15 h at 70 °C. The progress of the reaction was monitored by TLC.
After completion, the mixture was quenched with water and extracted with
ethyl acetate (2 ꢁ 15 mL). Removal of the solvent followed by purification on
silica gel column chromatography gave the pure 1,4-diketone.
6. (a) Stetter, H.; Kuhlmann, H. Synthesis 1975, 379; (b) Stetter, H.; Mohrmann, K.-
H.; Schlenker, W. Chem. Ber. 1981, 114, 581; (c) Yadav, J. S.; Anuradha, K.;
Reddy, B. V. S.; Eeshwaraiah, B. Tetrahedron Lett. 2003, 44, 8959.