A green synthesis of highly substituted 1,5-diketones

Article abstract of DOI:10.1039/c5ra08682e

Highly substituted 1,5-diketones have been synthesized in water via the reactions between aryl methyl ketones and aldehydes and the subsequent dimerizations. The reaction was catalyzed by aqueous KOH. The advantages of these aqueous reactions over organic-solvent mediated reactions are better yields, better diastereoselectivities, faster reaction rates, simpler workups, and being more energy efficient. The reaction can be scaled up to 13.9 gram scale and the aqueous KOH can be reused for five cycles. A possible mechanism is proposed to explain the high diastereoselectivities.

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DOI: 10.1039/C5RA08682E
A Green Synthesis of Highly Substituted
1,5-Diketones
Lei Liu,† Suliu Feng† and Chunbao Li*
Department of Chemistry, School of Science, Tianjin University, Tianjin, 300072, P. R. of China.
E-mail: lichunbao@tju.edu.cn; Tel: +86-022-27892351; Fax: +862227403475.
Graphical Abstracts
The advantages of the aqueous reactions over the conventional ones were demonstrated in the
synthesis of highly substituted 1,5-diketones.

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Cite this: DOI: 10.1039/c0xx00000x
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ARTICLE TYPE
A Green Synthesis of Highly Substituted 1,5-Diketones†
Lei Liu,† Suliu Feng† and Chunbao Li*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
Highly substituted 1,5-diketones have been synthesized in water via the reactions between aryl methyl
ketones and aldehydes and the subsequent dimerizations. The reaction was catalyzed by aqueous KOH.
The advantages of these aqueous reactions over organic-solvent mediated reactions are better yields,
better diastereoselectivities, faster reaction rates, simpler workups, and more energy efficient. The
reaction can be scaled up to 13.9-gram scale and the aqueous KOH can be reused for five cycles. A
10 possible mechanism is proposed to explain the high diastereoselectivities.
1.5 equiv or higher, the yields of 3a were above 90% (Table 1,
entries 7-9) and with 2 equiv of KOH or more, the reaction times
decreased from 12 h to 2 h (Table 1, entries 8 and 9). The
reaction did not take place without TBAB or with sodium
Introduction
It is known that 1,5-diketones exhibit various bioactivities
including antitumor,1,2 antidiabetic,3,4 anti-inflammatation,5,6 and
anti-infection7,8 properties and so on.9-11 They are also key
15 intermediates for the construction of substituted pyridines,12-14
quinolines,15 pyrylium16 and thiapyrylium.17 Most commonly 1,5-
diketones are synthesized via condensations between ketones18,19
or silyl enolethers20 with α,β-unsaturated ketones. Dimerization
of the condensation products between aryl methyl ketones and
20 aldehydes under basic conditions can also produce 1,5-
diketones.21-24 However, all the current methods employ volatile
and toxic organic solvents such as methanol, which violates the
principles of “green chemistry”.25-27 Several groups including
ours have reported the successful replacement of volatile organic
25 solvents with water for various organic synthetic reactions.28-34
Herein, an aqueous reaction between aryl methyl ketones and
aldehydes leading to 1,5-diketones is reported. The reaction
produces better yields and diastereoselectivities, has a simpler
workup and is more energy efficient than previously reported
30 organic-solvent mediated reactions.21-24
45 dodecyl sulfate (SDS) (Table 1, entries 10 and 11). However,
when TBAB was replaced by Aliquat 336, a similar yield (95%)
with a shorter reaction time (1 h) was achieved (Table 1, entries
12 and 13). When the amount of 2 was reduced to 1.0 equiv and
that of TBAB to 0.06 equiv, the yield of 3a remained high (Table
50 1, entry 17). Further reducing the amount of TBAB to 0.03 or
0.01 equiv resulted in lower yields of 3a (Table 1, entries 18 and
19). Based on these results, the optimized conditions are:
acetophenone (1, 1.0 equiv), isobutyraldehyde (2, 1.0 equiv),
KOH (2 equiv) and TBAB (0.06 equiv) or Aliquat 336 (0.1 equiv)
55 in water at rt (Table 1, entries 13 and 17).
Next thirteen aryl methyl ketones were chosen for the
condensation reactions with isobutyraldehyde (Scheme 1, 3a-3m).
The reaction times ranged from 2.5-8 h and the yields from 76-
96%. From Scheme 1, it can be seen that both the yields and
60 reaction rates increased with the acidities of the aryl methyl
ketones (3b vs 3c vs 3d vs 3e). The slowest reaction rate was
observed for the formation of 3j, because MeO- is a strong
electron donating group (3j vs 3h, 3i). In the case of the
heterocyclic aryl compounds, the yield of 3l is slightly higher
65 than that of 3m, which is because furanyl group is a poorer
electron-donor than thiofuranyl group. Very similar results
occurred for the reactions of cyclopentyl aldehyde, an analog to
isobutyraldehyde with one hydrogen atom at C-2, with nine aryl
methyl ketones (Scheme 1, 3n-3v), and cyclohexyl aldehyde with
70 two aryl methyl ketones (Scheme 1, 3w-3x). There was a
difference in the reaction rates and yields between
isobutyraldehyde and the two cyclic aldehydes. Better yields and
faster reaction rates were observed in the former cases.
Results and discussion
Initially,
a
mixture of acetophenone (1, 200 mg),
isobutyraldehyde (2, 1.5 equiv) and tetrabutylammonium bromide
(TBAB, 0.1 equiv) in water (1 mL) was stirred at room
35 temperature (rt) and treated with a series of bases for 12 h. No
reaction took place with Na2CO3 (Table 1, entry 1) or K2CO3
(Table 1, entry 2). Product 3a was obtained in 23% yield with 1
equiv of LiOH (Table 1, entry 3), 57% yield with 1 equiv of
NaOH (Table 1, entry 4), and 76% yield with 1 equiv of KOH
40 (Table 1, entry 5). When the amount of KOH was increased to
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Table 1 Optimization of the condensation conditions between acetophenone with isobutyraldehydea
O
O
O
base, PTC
+
O
H2O, rt
1
2
3a
Entry
1
1 (equiv)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2 (equiv)
Base (equiv)
Na2CO3 (1.0)
K2CO3 (1.0)
LiOH (1.0)
NaOH (1.0)
KOH (1.0)
KOH (0.5)
KOH (1.5)
KOH (2.0)
KOH (3.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
PTC (equiv)
TBAB (0.1)
TBAB (0.1)
TBAB (0.1)
TBAB (0.1)
TBAB (0.1)
TBAB (0.1)
TBAB (0.1)
TBAB (0.1)
TBAB (0.1)
-
t (h)
12
12
12
12
12
12
8
3a Yield (%)b
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.2
1.0
1.0
1.0
1.0
1.0
NRc
NRc
23
2
3
4
57
5
76
6
39
7
91
8
2
96
9
2
96
10
11
12
13
14
15
16
17
18
19
12
12
1
NRc
NRc
95
SDS (0.1)
Aliquat 336 (0.1)
Aliquat 336 (0.1)
TBAB (0.1)
1
95
2
96
TBAB (0.1)
2
96
TBAB (0.08)
TBAB (0.06)
TBAB (0.03)
TBAB (0.01)
2
96
2.5
12
12
96
82
53
a Reaction conditions: acetophenone (200 mg), isobutyraldehyde, base, phase transfer catalyst (PTC), H2O (1 mL) at rt. b All yields are isolated yields. c NR:
No reaction.
5
The replacement of TBAB with Aliquat 336 also led to a high-
yielding synthesis of a series of 1,5-diketones (Scheme 1). In
most cases, the yields were similar to those with TBAB, but the
reaction rates were faster with Aliquat 336. The reason is that
Aliquat 336 is a lipophilic syrup at rt, which functions as both a
numbering
diastereoselectivities of the reactions.
see
Scheme
1,
3a),
indicating
anti-
10 PTC and a solvent.30-34 The latter function facilitates the
dissolving of both the high melting-point reaction intermediates
and the final product which may include the reaction
intermediates that are formed during the course of the reaction. In
this system, TBAB is a better choice than Aliquat 336 because
15 less TBAB is needed (by weight) and TBAB is water-soluble.
The reaction using TBAB was scaled up to produce 13.9 g of 3a
with the same yield and reaction rate. An X-ray crystal analysis
of 3m confirmed its anti-stereochemical structure (Fig. 1). The
typical NMR data for all the products are signals at ca. 4.3 ppm (t,
20 J = ca. 10 Hz, 1H, H-2) and at ca. 3.1 ppm (m, 1H, H-3) (for the
25
Fig. 1 ORTEP diagram of compound 3m
2
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Scheme 1 Condensation of aryl methyl ketones with aldehydesa
R
R
R
O
O
O
KOH, TBAB or Aliquat 336
H2O, rt
+
R2CHO
Ar
Ar
Ar
R
-
3a 3x
O
O
O
O
O
O
O
1
O
5
2
4
3
F
F
Br
Br
Cl
Cl
: 90% t: 3 h or 88% t: 2 h
3b
: 87% t: 3 h or 85% t: 2 h
3d
: 88% t: 3 h or 85% t: 2 h
3c
: 96% t: 2.5 h or 95% t: 1 h
3a
O
O
O
O
F
O
O
F
O
O
I
I
: 81% t: 5 h
3h
: 82% t: 3 h
: 87% t: 4 h
3f
3g
: 82% t: 3 h
3e
O
O
O
O
O
O
O
O
N
N
O
O
O
O
: 93% t: 2.5 h or 87% t: 1.5 h
3l
: 87% t: 2.5 h or 90% t: 2 h
3k
: 77% t: 8 h
3j
: 76% t: 5 h or 83% t: 3 h
3i
O
O
O
O
O
O
O
O
S
S
Cl
Cl
F
F
: 83% t: 4.5 h
3p
: 89% t: 2.5 h or 84% t:1.5 h
3m
: 83% t: 4 h or 88% t: 3 h
3n
: 81% t: 4.5 h
3o
O
O
O
O
O
O
O
O
F
F
O
O
: 72% t: 6 h
3s
: 72% t: 4.5 h
3q
: 78% t: 6 h
: 74% t: 8 h
3t
3r
O
O
O
O
O
O
O
O
S
S
O
O
: 74% t: 6 h
3x
: 85% t: 4 h or 86% 2.5 h
3u
: 77% t: 6 h
3w
: 81% t: 4 h or 89% t: 2.5 h
3v
a Reaction conditions: aryl methyl ketones (200 mg), aldehyde (1 equiv), KOH (2 equiv), TBAB (0.06 equiv) or Aliquat 336 (0.1 equiv) and H2O (1 mL)
at rt. All yields are isolated yields.
5
The following mechanism is proposed for the reaction
(Table 1, entry 3) leads to much more complicated products than
(Scheme 2). Deprotonation of I formed from the aldol reaction 15 KOH-catalyzed reaction (Table 1, entry 17). The possible reason
between aryl methyl ketone and aldehyde leads to enolates II and
IIa, which are in equilibrium with I. The Micheal addition of II
to I via III produces IV, which is protonated to yield V. The anti-
is that K+ is such a weak Lewis acid that transition states IIIa and
IIIb are not possible. In contrast, Lewis acid Li+ is capable to
form IIIa, which leads to the desired anti-products. The
conformation of IIIa (M=Li) is eclipsed (syn-periplanar). One
10 diastereoselectivity in the formation of V is determined by
transition state III, which has two polar groups (carbonyl and 20 way of avoiding the eclipsed conformation is through IIIb (anti-
enolate) in the opposite directions in a staggered conformation.
This is further supported by the fact that LiOH-catalyzed reaction
clinal) (M=Li) formed from I and destabilized IIa. Compared to
III, IIIa and IIIb are both destabilized and are roughly in the
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same energy level, the former leading to the anti-product and the 25 was very simple. As the solid product formed during the reaction,
latter to the undesired syn-product. Therefore, KOH is preferred
for this reaction rather than other bases (LiOH, NaOH, Table 1,
entries 3 and 4).
it all adhered together as one large clump of material (SI, S2,
Picture 2). Thus the products were collected by simply decanting
the aqueous KOH from the product. In contrast, the literature
procedures required extractions of the products with organic
30 solvents. 5). This procedure was carried out at rt. All the
literature procedures required that the reaction media be heated
above 50 oC.21-24 Therefore our procedure is more energy-
efficient.
5 Scheme 2 A possible pathway for the highly stereoselective synthesis of
anti-1,5-diketone
Since 1,5-diketones are intermediates for some classes of
35 compounds, 3a, 3d and 3l were used to synthesize highly
substituted pyridines 4a, 4b and 4c (Scheme 3). The pyridines
were obtained in good yields with moderate reaction rates.12-14
Scheme 3 The synthesis of substituted pyridines from 1,5-diketonesa
Table 2 summarizes the results of recycling the aqueous KOH
10 media. After five cycles, the yield was still above 80%. The
reaction rate was slow for the fifth cycle, acceptable for the
fourth cycle and excellent for the first three cycles.
Table 2 Recyclability studies of the aqueous KOH for the condensation
of acetophenone with isobutyraldehydea
40 a Reaction conditions: 1,5-diketones (300 mg), NH4OAc (6 equiv) and
HOAc (5 mL) at 110 0C. All yields are isolated yields.
Cycle
t ( h )
1
Yield %b
Experimental
1
2
3
4
5
95
92
86
84
84
General Experimental Information
All of the chemicals were obtained from commercial sources
45 or prepared according to standard methods. NMR spectra were
1.5
3
1
recorded with a 400 or 600 MHz spectrometer for H NMR, a
100 or 151 MHz spectrometer for 13C NMR and a 377 MHz
spectrometer for 19F NMR. TMS was used as an internal standard.
Chemical shifts () were reported relative to TMS (1H) or CDCl3
50 (13C). Multiplicities were reported as follows: singlet (s), doublet
(d), triplet (t), quartet (q), multiplet (m), dd (doublet of doublets)
and dt (doublet of triplets). Coupling constants were reported in
Hertz (Hz). Melting points were recorded with a micro melting
point apparatus. Infrared analyses (KBr pellet) were performed
55 by FT-IR. X-ray structural analyses were conducted on the
XtaLAB mini diffractometer (600 W, SHINE, CCD, 75 mn, 0.1
electorns/pixel/sec). High resolution mass spectra (HRMS) were
recorded on a QTOF mass analyzer with electrospray ionization
(ESI).
7
17
15 a Reaction conditions: acetophenone (2000 mg), isobutyraldehyde (1
equiv), Aliquat 336 (0.1 equiv), KOH (2 equiv) and H2O (10 mL) at rt.
bAll yields are isolated yields.
Compared with other methods reported in the literature, this
procedure offers the following advantages. 1). Water was used as
20 reaction media instead of MeOH.21-24 2). The aqueous KOH was
recyclable. 3). Better yields and diastereoselectivities were
obtained than those for most reported procedures.21-23 Only
Novikov and Tishchenko reported a yield higher than 90%.24 All
other reports had yields around 60%.21-23 4). The product workup
60 Typical 200 mg-scale condensation procedure using the
synthesis of 3a as an example
4
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Page 6 of 6
†L.L. and S.F. contributed equally to this work.
Acetophenone (200 mg), isobutylaldehyde (1 equiv), KOH (2
equiv), TBAB (0.06 equiv) and water (1 mL) were added to a 10
mL test tube. After the mixture was stirred at rt for 2.5 h and TLC
indicated the completion of the reaction, the crude product
aggregated into a hard clump (SI, S2, Picture 1). The reaction
was then stopped and the aqueous KOH was decanted. The crude
product in the test tube was washed with distilled water (3 x 2
mL), and then crystallized with methanol (1 mL) to give a white
product 3a (279 mg, 96%, mp: 142.1-143.5 oC ).
55 † Electronic Supplementary Information (ESI) available: Pictures of the
synthesis of 3a, General experimental information, General procedure for
all products, Analytical data for all products, References for known
compounds, NMR spectra of the products, X-Ray crystallographic
analysis for product 3m, See DOI: 10.1039/b000000x/
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10
The same procedure was used in preparing 3a using Aliquat
336 as PTC (SI, S3, Picture 3).
Synthesis of 3a in 13.9 g scale
The synthesis of 3a starting from 10 g of acetophenone was
performed in a 100 mL round-bottom flask using the same
70 5. M. Cheng, M. Wu, Y. Su, I. Chen and G. Yuan, Phytochem. Lett.,
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15 procedure as above to yield 3a (13.9 g, 96%, t: 2.5 h).
Recycling procedure in the synthesis of 3a
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(2000 mg), isobutylaldehyde (1 equiv), Aliquat 336 (0.1 equiv),
KOH (2 equiv) and H2O (10 mL) was stirred at rt. After TLC
20 indicated the completion of the reaction, the crude product
aggregated into a hard clump (SI, S3, Picture 4). The reaction
was then stopped and the aqueous KOH was decanted. The crude
product was washed with distilled water (3 x 5 mL), and
crystallized with methanol (10 mL) to yield 3a (2.75 g, 95%). In
25 the second cycle, a new mixture of acetophenone (2000 mg),
isobutylaldehyde (1 equiv), Aliquat 336 (0.1 equiv) and the
aqueous KOH used in the first reaction was subject to the as
above conditions to yield 3a (2.68 g, 92%). The reaction was
repeated in this manner five times. The reaction times ranged
30 from 1-17 h and the yields from 95-84%.
Typical 300 mg-scale synthesis procedure using the synthesis
of 4a as an example
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in ethyl acetate (5 mL), washed with water (2 x 5 mL), and dried
over Na2SO4. The ethyl acetate was then evaporated and the
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(petroleum ether/ethyl acetate=10:1) to give 4a (203 mg, 72%,
40 mp: 62.6-63.5 oC).
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Conclusions
In conclusion, we have successfully replaced volatile and toxic
organic solvent methanol with water in the dimerizations of the
condensation products from aldehydes and aryl methyl ketones.
45 In comparison to the organic-mediated reaction, the aqueous
reaction offered several advantages, including simpler workups,
higher energy efficiency, better yields, diastereoselectivities and
recyclable reaction media. This procedure should be applicable to
the greener manufacture of these types of 1,5-diketones.
50 Notes and references
120 32. T. Li, X. Cui, L. Sun and C. Li, RSC Adv., 2014, 4, 33599.
33. B. Li and C. Li, J. Org. Chem., 2014, 79, 8271-8277.
Department of Chemistry, School of Science, Tianjin University, Tianjin,
300072, P. R. of China. E-mail: lichunbao@tju.edu.cn; Tel: +86-022-
27892351; Fax: +862227403475.
34. X. Cui, B. Li, T. Liu and C. Li, Green Chem., 2012, 14, 668-672.
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