Recyclable L-proline organocatalyst for Wieland-Miescher ketone synthesis

Article abstract of DOI:10.1007/s12039-013-0527-2

Wieland-Miescher ketone 4 was synthesised using L-proline catalyst in the ionic liquid medium via non-selective conjugated addition reaction followed by an enantioselective intermolecular Aldol condensation reaction of triketone 3 intermediate. Short reaction time, recycling of the catalyst, good yield and selectivity are major outcomes of this proposed protocol. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-013-0527-2

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J. Chem. Sci. Vol. 125, No. 6, November 2013, pp. 1523–1527. ꢀ Indian Academy of Sciences.
Recyclable L-proline organocatalyst for Wieland–Miescher
ketone synthesis
VIVEK SRIVASTAVA
Applied Science, NIIT University, NH-8 Delhi-Jaipur Highway, Neemrana, Distt., Alwar 301 705, India
e-mail: vivek.srivastava.chem@gmail.com
MS received 23 April 2013; revised 3 September 2013; accepted 5 September 2013
Abstract. Wieland–Miescher ketone 4 was synthesised using L-proline catalyst in the ionic liquid medium
via non-selective conjugated addition reaction followed by an enantioselective intermolecular Aldol condensa-
tion reaction of triketone 3 intermediate. Short reaction time, recycling of the catalyst, good yield and selectivity
are major outcomes of this proposed protocol.
Keywords. L-proline; ionic liquid; Wieland–Miescher ketone.
1. Introduction
(only 2%).4a Various proline derivatives such as
D-proline (6 days, 82% yield), L-proline (5 days, 56%
yield) etc. were also tested with or without sol-
vent system to catalyse the Wieland–Miescher ketone
synthesis.4b−h Despite these numerous investigations,
L-proline remains the most interesting catalyst known
for this reaction4b−h,5 (scheme 1), but along with
L-proline and other alternative organocatalysts for
Wieland–Miescher ketone analogues synthesis suffers
from several drawbacks such as long reaction time,
high catalyst loading, low catalyst solubility, require-
ment of polar solvents (Dimethyl sulfoxide (DMSO)
and Dimethylformamide (DMF)), costly starting mate-
rials for catalyst synthesis, tedious work-up proce-
dure at product isolation step, etc. Various protocols
along with ionic liquids, have been reported by dif-
ferent groups time to time in order to overcome the
above mentioned demerits of organocatalysed reac-
tions.6,7 Kodo et al. studied polymer bound (S)-proline
as catalyst8 while Agami et al. described proline
catalysed aldol-cyclodehydrations of acyclic dike-
tones.9 D-phenylanaline and D-camphorsulfonic acid
was tested in [hmim] PF6 along with dimethylimidazo-
lidinone was tested for Wieland–Miescher ketone ana-
logues synthesis.10 Although, 81% yield and 74% ee
Wieland–Miescher ketone analogues are very useful
building blocks to synthesise various biologically active
compounds such as steroids, terpenoids and taxol.1
Wieland–Miescher ketone analogues can be synthe-
sized via two different methods (Hajos–Parrish–Eder–
Sauer–Wiechert reaction and Robinson annulation reac-
tion).1 Various catalysts such as antibody 38 C2 (96%
ee),2a β-amino acid (1R,2S)-cispentacin (86% ee),2b
prolinethiomides (86% ee),2c etc. were tested to
improve the yield and stereoselectivity of the Wieland–
Miescher ketone analogue synthesis.1b Hanessian et al
documented that cis-(2S, 4S, 5S)-4, 5-methanoproline
as an alternative catalyst of L-proline, offers the
Wieland–Miescher ketone analogues with 93% enan-
tiomeric excess along with good yield, whereas
catalysis with trans-(2S, 4S, 5S)-4,5-methanoproline
proceeded at much slower rate than L-proline and offers
enone with lower selectivity (83% ee).3 There are
relatively few examples where primary amino acids
were used as enantioselective catalyst for this reac-
tion such as L-phenylalanine gave (S) enone 85% yield
with 25% e.e., while L-tert-leucine offers (S)-ketone
with higher yield (95%) but lesser enantiomeric excess
O
O
O
HOAc, hydroxyquinone
catalyst
r.t
O
4
water, 72−75°C, 1h
O
O
O
O
1
2
3
Scheme 1. Two-step synthesis of Wieland−Miescher ketone 4.
1523

1524
Vivek Srivastava
along with five times recycling of the catalytic sys- (2 mL each time). The combined extracts were further
tem were the major outcomes of this process, the pro- washed with two 20 mL portions of saturated brine,
posed protocol suffers high catalyst loading, require- dried over anhydrous magnesium sulphate, filtered,
ment of polar solvent (as co-solvent), longer reaction and concentrated. The residue was further purified via
time and continuous drop in yield and selectivity during column chromatography using ethyl acetate and the
recycling of the catalytic system, etc.
hexane mixture (1:2) which offers the titled product 3
In this report, we optimized the reaction conditions as pale-yellow oil in good yield (1.78 g, 97% yield).
of the L-proline-catalysed Wieland–Miescher ketone 1H NMR (300 MHz, CDCl3) 2.53–2.78 (m, 4H), 2.23–
4 synthesis. During the reaction, L-proline was found 2.38 (m, 2H), 2.09 (s, 3H), 1.81–2.07 (m, 4H), 1.22
active, recoverable and relatively inexpensive in [pyC4] (s, 3H). 13C NMR (75 MHz, CDCl3) 17.8, 20.2, 29.7,
NTf2 with respect to conventional solvents. High pola- 30.1, 37.9, 38.5, 64.5, 207.7, 210.2.
rity of ionic liquid is expected to work as an activat-
ing and stabilizing solvent for the L-proline to catalyse
2.1b (S)-8a-Methyl-3, 4, 8, 8-tetrahydro-1, 6 (2H,
Wieland–Miescher ketone 4.
7H)-naphthalen edione (3-S) (4): 50 mL, one-necked,
round-bottomed flask, was charged with L-proline
(0.5–1.5 mol%) or other catalyst and a solution
of 2-methyl-2-(3-oxobutyl)-1,3-cyclohexanedione 3
2. Experimental
(1 mmol) in ionic liquid (1–3 mL) or organic solvent
All the chemicals were purchased from Sigma Aldrich
(2 mL) or water (2 mL). The mixture was allowed
and SD fine chemicals. Commercially supplied reagents
to stir at room temperature for 2 h. Further, volatile
were used as provided. Organic solvents were dried
organic materials was evaporated from the reaction
up as per their specifications. The work-up and purifi-
slurry under vacuum. The reaction product was further
cation procedure were carried out with reagent-grade
solvents. Nuclear magnetic resonance (NMR) spectra
extracted with diethyl ether (5 × 2 mL) by vigorous
stirring followed by decantation of the upper diethyl
were recorded on standard Bruker 300WB spectrom-
ether layer. Evaporation of the combined organic
eter with an Avance console at 300 and 75 MHz for
layer and the subsequent medium pressure-filtration
1H and 13C NMR, respectively. Enantiomeric excesses
chromatography (FC) purification of residue (elu-
were determined by chiral-phase HPLC: Waters 600E
ent: AcOEt: n-hexane=1: 3) offered the titled pro-
System Controller and a Waters 996 Photodiode Array
duct 4. A new portion of reactants was added to recy-
Detector Column with Chiralcel OD-H column from
1
cle the catalytic system. H NMR (300 MHz, CDCl3)
Daicel Chemical Industries Ltd., eluting with n-hexane
1.43 (s, 3H), 1.60–1.77 (m, 2H), 2.06–2.19 (m, 3H),
and ethyl acetate. Ionic liquids were synthesised as per
2.40–2.53 (m, 4H), 2.63–2.77 (m, 2H), 5.83 (d, J =
1
their standard reported procedure.11 The detailed H
1.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) 23.5, 23.9,
NMR and 13C NMR were found similar as per reported
30.2, 32.4, 34.2, 38.3, 51.2, 126.4, 166.5, 199, 211.7.
data.7
[α]2D0 + 1.8 (c = 1.2, CHCl3), HPLC Chiral OD-H,
Hexanes/IPrOH 90/10, 0.5 mL.min−1, minor t =
40.7 min, major t = 31.0 min.
2.1 General experimental procedure
2.1a 2-Methyl-2-(3-oxobutyl)-1,3-cyclohexanedione
or triketone 3: A 100 mL, round-bottomed flask
3. Result and discussion
equipped with a thermometer and a reflux condenser
capped with an argon-inlet tube was charged with
1.26 g (10 mmol) of 2-methylcyclohexane-1, 3-dione 1
and 10 mL of distilled water. To the well-stirred sus-
pension were added 0.023 mL of acetic acid, 0.008 g
of hydroquinone and 1.42 g (20 mmol) of freshly dis-
tilled methyl vinyl ketone 2. The reaction mixture was
stirred under argon at 72–75◦C for 1 h, cooled to room
temperature, treated with sodium chloride (1.03 g), and
poured into a separatory funnel containing ethyl acetate
(4 × 5 mL). The organic phase was collected and
aqueous phase was extracted twice with ethyl acetate
Synthesis of Wieland–Miescher ketone 4 proceeds via
non-selective conjugated addition reaction followed
by an enantioselective intermolecular Aldol conden-
sation reaction of triketone 3 intermediate. The inter-
mediate, triketone 3 was synthesised as per reported
procedure by the reaction between methyl vinyl ketone
2 and 2-methylcyclohexane-1, 3-dione 1.1,2 The iso-
lated yield of triketone 3 was 97%. The identity of the
1
intermediate triketone 3 was confirmed by H NMR
and 13C NMR (scheme 2). Later structurally confirmed,
triketone 3 was used for the synthesis of Wieland–
Miescher ketone 4 under different reaction conditions,

Recyclable L-proline for Wieland–Miescher ketone synthesis
1525
O
O
O
Organocatalysts
O
O
COOH
N
Solvent , 2 h, −5 to 100oC
(1 mol%)
O
H
O
O
3
4
Yield= 15−88%, ee=10−93%
Ionic Liquid (2 mL), r.t, 2 h
O
O
O
3
4
Scheme 2. Organocatalysts/ionic liquid catalytic system
for Wieland–Miescher ketone 4 synthesis under different
parameters.
Scheme 3. L-proline/ionic liquid catalytic system for
Wieland–Miescher ketone 4 synthesis.
also optimised (from −5◦C to 100◦C) (table 2, entries
4–7) for Wieland–Miescher ketone 4 synthesis and it
was concluded that at higher temperature L-proline
gets decomposed and offers lower yield and selectiv-
ity. Lowering the reaction temperature from 0◦ to −5◦C
was also not found suitable in terms of yield and selec-
tivity for Wieland–Miescher ketone 4 synthesis (table 2,
entries 8–9). No reaction was found at −5◦C as the
reaction mass gets solidified. Screening conventional
organic solvents such as DMF, DMSO, NMP, THF,
DCM and water for Wieland–Miescher ketone 4, was
the other major goal of our study in order to under-
stand the behaviour of L-proline catalysts for Wieland–
Miescher ketone 4 synthesis (table 2, entries 10–15).
While decreasing the polarity of the solvent, the cor-
responding yield of the Wieland–Miescher ketone 4
also decreased from 35% to 67% and selectivity was
found to be between 45% and 69%. In DMSO sol-
vent system with L-proline, Wieland–Miescher ketone
responded with 67% yield and 65% ee (table 2, entry
11). Under solventless condition, L-proline also offered
the Wieland–Miescher ketone 4 in acceptable yield
and selectivity (48% yield, 67% ee) (table 2, entry 16).
Apart from L-proline, we also tested other alterna-
tive catalysts for Wieland–Miescher ketone 4 synthe-
sis with [pyC4]NTf2 (table 2, entries 17–21) but no
such significant increase in yield and selectivity was
observed.
in order to achieve the best results with respect to yield
and sterioselectivity.
We tested a series of ionic liquids with L-proline
(1 mol%) as per scheme 3 and the corresponding results
are summarised in table 1, entries 1–6.
Surprisingly, Wieland–Miescher ketone 4 was
obtained in good yield (42–88%) and selectivity (61–
93%) with L-proline (table 1, scheme 2) in different
ionic liquids. Higher yield (88%) and selectivity (93%
ee) was found only with [pyC4]NTf2 reaction medium.
After obtaining good catalytic activity of L-proline in
[PyC4]NTf2 with respect to yield and selectivity, we
further studied various other reaction parameters such
as time, temperature, catalyst loading, solvents such as
N, N-dimethylformamide (DMF), dimethyl sulphoxide
(DMSO), N-methylpyrrolidine (NMP), tetrahydrofu-
ran (THF), dichloromethane (DCM) and water. All the
results were summarised in table 2, entries 1–21.
Lower yield and selectivity (table 2, scheme 2, entry
2) was obtained with smaller quantity (0.50 mol%) of
L-proline, while the higher quantity of the L-proline
(1.5 mol%, table 2, entry 3) gave almost similar results
as we obtained from 1 mol% of L-proline (table 2,
entry 1) in [pyC4]NTf2. Temperature parameters were
To evaluate the possibility of recycling the ionic
liquid mediated L-proline catalytic system for
Wieland–Miescher ketone 4 synthesis, triketone 3
was allowed to react with [pyC4]NTf2 immobilised L-
proline catalyst and the corresponding product was then
extracted with diethyl ether (5 × 2 mL) (scheme 4). A
second amount of triketone 3 was added to the previ-
ously used [pyC4]NTf2 immobilised L-proline catalytic
system and the process was repeated up to eight times.
Surprisingly, there was no significant loss in yield (85–
88%) and selectivity (90–93% ee) was observed during
the eight recycling runs of L-proline/[pyC4]NTf2 cata-
lytic system during the Wieland–Miescher ketone 4
synthesis (figure 1).
Table 1. Screening of L-proline with different ionic
liquids for Wieland–Miescher ketone 4 synthesis.
Results
Yield (%)1
Entry
Ionic liquid (2mL)
ee (%)2
1
2
3
4
5
6
[bmim][PF6]
[pyC4][PF6]
[tmba][PF6]
[bmim][NTf2]
[pyC4][NTf2]
[tmba][NTf2]
68
42
28
76
88
74
65
73
61
78
93
74
1Isolated yields after column chromatography
2Determined by HPLC

1526
Vivek Srivastava
Table 2. Screening reaction parameters for Wieland–Miescher ketone 4 synthesis.
Entry
Solvent (2mL)
Catalyst
T/◦C Yield (%)1 ee (%)2
1
2
3
4
5
6
7
8
[pyC4][NTf2]
[pyC4][NTf2]
[pyC4][NTf2]
[pyC4][NTf2] (1 mL)
[pyC4][NTf2] (3 mL)
[pyC4][NTf2]
[tmba][NTf2]
[tmba][NTf2]
[tmba][NTf2]
DMF
L-proline (1 mol %)
L-proline (0.5 mol %)
L-proline (1.5 mol %)
L-proline (1 mol %)
L-proline (1 mol %)
L-proline (1 mol %)
L-proline (1 mol %)
L-proline (1 mol %)
L-proline (1 mol %)
L-proline (1 mol %)
L-proline (1 mol %)
L-proline (1 mol %)
L-proline (1 mol %)
L-proline (1 mol %)
L-proline (1 mol %)
L-proline (1 mol %)
rt
rt
rt
rt
rt
100
50
−5
0
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
88
67
75
72
78
15
38
nd
25
63
67
55
40
35
37
48
65
48
15
25
68
93
66
79
79
81
75
78
–
54
69
65
67
69
49
45
67
74
68
58
10
72
9
10
11
12
13
14
15
16
17
18
19
20
21
DMSO
NMP
THF
DCM
Water
Neat
[pyC4][NTf2]
[pyC4][NTf2]
[pyC4][NTf2]
[pyC4][NTf2]
[pyC4][NTf2]
L-hydroxyproline (1 mol %)
(S)-phenylanaline (1 mol %)
2-(S)-trans-4-hydroxyproline (1 mol %)
(S)-proline ethyl ester (1 mol %)
rt
(S)-azetidine-2-carboxylic acid (1 mol %) rt
1Isolated yields after column chromatography
2Determined by HPLC
rt, Room temperature
O
4. Conclusion
O
COOH
O
We explored the application of L-proline for the syn-
thesis of Wieland–Miescher ketone 4. In this report, we
optimised reaction parameters such as time, tempera-
ture as well as quantity of catalyst for the synthesis of
Wieland–Miescher ketone 4. As a result of our compre-
hensive study, L-proline (1 mol%) was found suitable
for the synthesis of Wieland–Miescher ketone 4 with
good yield (88%) and selectivity (93% ee) at room tem-
perature. Eight times recycling of the [pyC4] NTf2/L-
proline catalytic system for the synthesis of Wieland–
Miescher ketone 4 is the major outcome of the proposed
protocol.
N
(1 mol%)
H
[pyC4]NTf2 (2 mL), r.t, 2 h
O
O
O
8 times recycling
of Catalytic system
Scheme 4. Recycling parameters for Wieland–Miescher
ketone 4 synthesis.
Supplementary information
The electronic supporting information can be seen in
www.ias.ac.in/chemsci.
Acknowledgement
The author is thankful to Sophisticated Analytical
Figure 1. Recycling of [pyC4]NTf2/L-proline catalytic Instrument Facility, Panjab University, Chandigarh for
system for Wieland–Miescher ketone 4.
NMR and HPLC characterization.

Recyclable L-proline for Wieland–Miescher ketone synthesis
1527
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