One-step conversion of ketones to conjugated acids using bromoform

Article abstract of DOI:10.1080/00397910802531955

Phase-transfer-catalyzed (PTC) reactions of ketones with bromoform and aqueous lithium hydroxide in alcoholic solvent result in the formation of ,-unsaturated carboxylic acids. The reaction was performed at room temperature for 24h. The corresponding conj

Full text of DOI:10.1080/00397910802531955

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One-Step Conversion of
Ketones to Conjugated Acids
Using Bromoform
b
V. D. Vitnik a , M. D. Ivanović , Ž. J. Vitnik b , J.
c
d
B. Đorđević , Ž. S. Žižak d , Z. D. Juranić & I. O.
b
Juranić
a ICTM Centre for Chemistry, Belgrade, Serbia
b Faculty of Chemistry, University of Belgrade,
Belgrade, Serbia
c Faculty of Agriculture, University of Belgrade,
Zemun, Serbia
d Institute for Oncology and Radiology of Serbia,
Belgrade, Serbia
Version of record first published: 19 Mar 2009.
To cite this article: V. D. Vitnik, M. D. Ivanović, Ž. J. Vitnik, J. B. Đorđević, Ž.
S. Žižak, Z. D. Juranić & I. O. Juranić (2009): One-Step Conversion of Ketones to
Conjugated Acids Using Bromoform, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 39:8, 1457-1471
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Synthetic Communications1, 39: 1457–1471, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802531955
One-Step Conversion of Ketones to Conjugated
Acids Using Bromoform
1
V. D. Vitnik, M. D. Ivanovic, Z. J. Vitnik, J. B. Ðordevic,
2
2
3
ˇ
´
Z. S. Zizak, Z. D. Juranic, and I. O. Juranic
´
4
4
2
ˇ
ˇ
ˇ
´
´
1ICTM Centre for Chemistry, Belgrade, Serbia
2Faculty of Chemistry, University of Belgrade, Belgrade, Serbia
3Faculty of Agriculture, University of Belgrade, Zemun, Serbia
4Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
Abstract: Phase-transfer-catalyzed (PTC) reactions of ketones with bromoform
and aqueous lithium hydroxide in alcoholic solvent result in the formation of
a,b-unsaturated carboxylic acids. The reaction was performed at room temperature
for 24 h. The corresponding conjugated acids were obtained from cyclic or aromatic
ketones, whereas bromo acids were obtained from 4-oxo-piperidine-1-carboxylic
acid ethyl ester (13) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (14).
Keywords: Bromoform, phase-transfer-catalyzed reaction, a,b-unsaturated
carboxylic acids
INTRODUCTION
The synthesis of a,b-unsaturated carboxylic acids has gained considerable
attention[1] because of the biologically important properties of these
acids, their occurrence in natural products, and their use as precursors
for the preparation of biologically active compounds.[2]
Many cyclic and acyclic conjugated acids were prepared from ketone
or aldehyde cyanohydrines by sequential dehydration using phosphorous
oxychloride=pyridine[3] or thionyl chloride[4] followed by acidic[5] or
alkaline[6] hydrolysis of the resulting conjugated nitriles. Base-mediated
Received June 28, 2008.
Address correspondence to V. D. Vitnik, ICTM Centre for Chemistry,
Studentski Trg 12-16, 11000 Belgrade, Serbia. E-mail: vesnak@chem.bg.ac.yu
1457

1458
V. D. Vitnik et al.
dehydrohalogenation of a-halocarboxylic esters produced conjugated
systems in variable yields.[7] Both acyclic and cyclic b-keto esters were
converted to (E) and (Z) conjugated acids via 4-halo-2-pyrazolin-5-on
derivatives.[8] Vinyl triflates,[9] prepared from ketones, were reacted with
CO in the presence of palladium catalysts to obtain conjugated acids.
Variations of the Morita–Baylis–Hillman reaction were also used
recently.[10] Cyclopentene carboxylates were obtained via novel catalytic
asymmetric [3 þ 2] cycloaddition.[11]
Conjugated esters and amides are versatile intermediates in organic
synthesis. Of particular importance are their 1,4-additions of various
carbon, oxygen, sulfur, and nitrogen nucleophiles. For example, enantiose-
lective 1,4-addition of thiophenols to methyl cyclopentene carboxylate and
methyl cyclohexenecarboxylate was achieved in the presence of chiral cata-
lysts.[12] Thiols were added in the presence of a base.[13] Numerous enantio-
selective additions of chiral secondary amines were achieved, yielding the
corresponding b-amino esters.[14] Enantioselective addition of achiral
amines was achieved in the presence of chiral ligands.[15] Alkyl and aryl orga-
nocuprates react chemo- and stereoselectively to produce the corresponding
4-substituted saturated esters,[16] whereas enantioselective 1,4-addition of
organolithium reagents was done in the presence of chiral ligands.[17] The
addition of amide enolates was employed in alkaloid synthesis.[18]
Carbanions derived from fluoroform,[19] chloroform,[20] or
bromoform,[21] readily react with aldehydes and ketones to form stable
and isolable a-(trihalomethyl)carbinols. Those derived from fluoroform
are significant precursors of diverse, pharmacologically active com-
pounds possessing aliphatic CF3 groups.[19] a-Trichloromethyl carbinols
undergo a variety of transformations and are precursors to functionalized
thiazolidinone,[22] a-amino acids via the Corey–Link reaction,[23] hetero-
cycles,[24] chiral epoxides,[25] chiral 1-fluoro carboxylic acids,[26] chiral
hydroxy acids,[27] and conjugated acids.[28]
RESULTS AND DISCUSSION
Initially, we attempted to prepare 1-chlorocyclohexane carboxylic acid
from cyclohexanone and chloroform in the presence of 50% aqueous
NaOH and quaternary ammonium chloride according to the published
procedure.[29] However, it was found that under these conditions a
considerable amount of cyclohexene carboxylic acid (1a) was obtained,
too. Typically, the acid fraction of the product (Scheme 1a) contains
cyclohexenecarboxylic acid (1a), 1-chlorocyclohexane carboxylic acid
(3a), and 1-hydroxycyclohexane carboxylic acid (2) [according to gas
chromatography (GC) and thin-layer chromatography (TLC)] in a
variable ratio, depending on the reaction conditions.

Conversion of Ketones to Conjugated Acids
1459
Scheme 1. Reaction of cyclohexane with haloform under different conditions.
When bromoform was used instead of chloroform, cyclohexene-
carboxylic acid (1a) was obtained as the main or sole acid product (Scheme
1b). To elucidate this effect, the reaction was systematically examined by
varying the molar ratios of base, reactants, and phase-transfer catalyst
(PTC). The effect of variation of temperature, reaction time, and cosolvent
was studied, too. The obtained reaction mixtures (acid components) were
examined by GC, TLC, and mass spectrometry (MS). Major variations
included (a) alkaline hydroxyde [lithium hydroxide (LiOH Â H2O=H2O,
40–60% sodium hydroxide (NaOH), 40–60% potassium hydroxide
(KOH)], 10–50 eq. to cyclohexanone; (b) haloform (CHCl3, CHBr3,
CHI3), 2–50 eq. to cyclohexanone; (c) phase catalyst [benzyltriethylammo-
nium chloride (TEBA), tetrabutylammonium bromide TBAB), methyl tri-
octylammonium chloride (aliquat 336)] as well as 18-crown-6=KOH; (d)
solvent [PhMe=H2O, dimethyl sulfoxide (DMSO), CH2Cl2=H2O, tetrahy-
drofuran (THF)=H2O, i-PrOH=H2O t-BuOH=H2O, t-PentOH=H2O and
others]; (e) temperature (0–120ꢀC) and reaction time (4–48 h).
The results are summarized in Table 1.
As can be seen from Table 1, when we used CHBr3 instead CHCl3 and
LiOH instead KOH as the base in alcoholic solvent, the cyclohexenecarbo-
xylic acid (1a) was obtained in the highest yield (entry 14). With chloroform,
in the presence of 50% aqueous NaOH or KOH, cyclohexenecarboxylic acid
and 1-hydroxycyclohexane carboxylic acid (2) were obtained (entries 1, 3,
and 4, Table 1). When we used CHI3 instead CHCl3, 1-lodo-cyclohexane-
carboxylic acid (3c) was also obtained (entry 6) as a product.

1460

1461

1462
V. D. Vitnik et al.
However, a 95% yield of 1a was obtained with lithium hydroxide as
the base in t-Bu-OH=H2O (entry 14). Use of KOH gives consistently
higher yields than those obtained with sodium hydroxide (entries 4, 5,
6, and 8, Table 1) but lower than those obtained with LiOH. Using a lar-
ger excess of base (entries 1 and 12, Table 1) or haloform (entry 3, Table
1) resulted in lower yields of cyclohexenecarboxylic acid (1a) but
increased yield of 1-hydroxycyclohexane carboxylic acid (2).
The reaction was carried out at room temperature for 24 h. Gener-
ally, higher temperatures, 80–120ꢀC, favor higher yields of 1-hydroxycy
clohexane carboxylic acid (2) (entries 2 and 12, Table 1).
The amount of catalyst is one of the critical factors affecting the reac-
tion efficiency. The reduced amount of catalyst gave diminished yield of
1a. The optimal amount of catalyst is 0.1 eq. (TEBA=LiOH) or (18C-6=
KOH) in relation to ketone. For comparison, the reaction with 2 eq. TEBA
gave 1-chloro-cyclohexanecarboxylic acid (3a) and cyclohexenecarboxylic
acid (1a) in 1:1 ratio (entry 11, Table 1). In the absence of catalyst, either no
reaction occured or the yields of conjugated acids were lower.
Higher yields are obtained in polar protic solvents. In polar aprotic sol-
vents, 1-bromo-cyclohexane carboxylic acid (3b) was obtained as a minor or
as a sole product using stoichiometric amounts of 1.8-diazabicyclo[5.4.0]
undec-7-en (DBU) (entry 10). The use of less polar solvents resulted in lower
yields of the desired conjugated acid (entries 1, 2, 9, 15, and 16, Table 1). In
chloroform as a solvent, 1-chlorocyclohexane carboxylic acid (3a) was
obtained in an amount equal to conjugated acids. Increased amount of co
solvent H2O resulted in lower yields of the desired conjugated acid but
increased yield of the corresponding hydroxy acid (entry 7, Table 1).
Scheme 2 presents the optimized reaction of different ketones with
bromoform. Table 2 lists all acids and their corresponding starting
ketones used in this new one-pot reaction, shown in Scheme 2.
Corresponding bromo acids were obtained as main products from
4-oxo-piperidine-1-carboxylic acid ethyl ester (13) and 4-oxo-piperidine-
1-carboxylic acid tert-butyl ester (14), (entries 11 and 12, Table 2). In the
crude reaction mixtures, corresponding conjugated acids were detected
too (5–10%).
Scheme 2. Optimized reaction of different ketones with bromoform.

1463

1464
V. D. Vitnik et al.
It is interesting to note that the reaction of 1,5-diphenyl-pentan-3-one
(15), in all reaction conditions, gives 2-hydroxy-2-phenethyl-4-phenyl-
butyric acid (15a) as the sole product (entry 13, Table 2).
ANTIPROLIFERATIVE ACTIVITY
The antiproliferative activity of obtained acids toward malignant cell
lines was evaluated in this work, too. With the aim to determine the unde-
sirable cytotoxic effect of investigated compounds on immune-competent
cells, the normal peripheral blood mononuclear cells were used as target
cells, too. The majority of synthesized conjugated acids exert antiproli-
ferative activity in vitro toward HeLa, having IC50 values from 122.20
to 192 mM. The most active compound is cyclododec-1-enecarboxylic
acid (IC50 ¼ 122 mM toward HeLa cells). All examined compounds did
not affect proliferation of healthy human blood peripheral mononuclear
cells (PBMC and PBMC þ PHA), IC50 > 200 mM, but all the studied
compounds affected the survival of HeLa (cervical cancer cells line).
EXPERIMENTAL
General Procedure
All used chemicals were of analytical-reagent grade, purchased from
Aldrich, Fluka, or Merck, and used without further purification. The
NMR spectra were recorded on a Varian Gemini 2000 (1H NMR at
200 MHz, 13C NMR at 50 MHz) and on a Bruker Avance 500 spectro-
meter (1H NMR at 500 MHz and 13C NMR at 125 MHz) for samples in
deuterated chloroform. Chemical shifts are expressed in parts per million
(ppm) using tetramethylsilane (TMS) as the internal standard. The infra-
red (IR) spectra were recorded on a Fourier-transform (FT) Perkin-Elmer
1725X spectrometer and Nicolet 6700 FT instrument and are expressed in
centimetersꢁ1. The mass spectra were obtained on an Agilent Technolo-
gies 6210 TOF liquid chromatography=mass spectrometer (LC=MS)
instrument (LC, series 1200). High-resolution mass spectra (HRMS) were
obtained by the electron spray ionization (ESI) method. Melting points
were determined on a Boetius PMHK apparatus and were not corrected.
The elemental analyses were done on Elemetar-Vario EL III equipment.
Cyclohexene-1-carboxylic Acid (1a)
The flask was charged with LiOH solution (1.02 mol, 43.2 g, in 40 mL
H2O), t-BuOH (200 mL), cyclohexanone (0.05 mol, 5 g), and TEBA

Conversion of Ketones to Conjugated Acids
1465
(0.005 mol, 1.14 g). The mixture was stirred vigorously (large egg-shaped
stirring bar) at 20–25ꢀC, while bromoform (0.2 mol, 51.5 g) was added
dropwise from the dropping funnel (ꢂ30 min). The reaction is exother-
mal, and the internal temperature was maintained at less than 50ꢀC by
external cooling (water bath). The stirring continued for 24 h, H2O
(300 mL) was added, and the organic layer was discarded. The aqueous
layer was extracted with toluene (2 ꢃ 50 mL) and then acidified with
HCl (20%) to pH ꢂ1. The separated brown oil was extracted with toluene
(3 ꢃ 50 mL), dried (anh. MgSO4), concentrated, and fractionally distilled
(short Vigreux column) under the reduced pressure. Cyclohexene-1-
carboxylic acid was obtained as a colorless liquid, which solidified in
the receiver. Yield: 6.33 g, 98%; bp: 145–146ꢀC; mp: 36–38ꢀC (lit.
38ꢀC)[30] 1H NMR (CDCl3, 200 MHz; d ppm, J Hz): 11.65 (s, 1H),
;
7.14 (t, J ¼ 2 Hz, 1H), 2.3 (m, 4H), 1.63 (m, 4H), 1.27 (m, 1H), 0.88
(m, 1H); 13C NMR (CDCl3, 50 MHz, d ppm): 173.2 (CO), 142.4 (C),
129.6 (CH), 25.8 (CH2), 23.5 (CH2), 21.8 (CH2), 21.1 (CH2); IR (KBr):
3056, 2936, 2645, 1691, 1424, 1282, 1085 cmꢁ1; HRMS-ESI: calcd. for
C7H10O2 126.0681; calcd. for [M þ H]þ 127.0753, found 127.0751.
tert-Butyl-cyclohex-1-enecarboxylic Acid (4a)
Mp: 182ꢀC (lit. 182–183ꢀC)[31] 1H NMR (CDCl3, 500 MHz) d: 11.6
;
(s, 1H), 7.12 (t, J ¼ 3 Hz, 1H), 2.5 (m, 1H), 2.28 (m, 1H), 2.13 (m, 1H),
1.94 (m, 2H), 1.3 (m, 1H), 1.12 (m, 1H); 13C NMR (CDCl3, 125 MHz)
d: 172.1 (CO), 142.9 (C), 129.5 (CH), 43.1 (CH2), 32.12 (CH2), 27.7
(CH2), 27.1 (CH2), 25.2 (CH2), 23.47 (CH3); IR (KBr): 3297, 3415,
2958, 1681, 1644, 1276, 1177, 1085 cmꢁ1; HRMS-ESI: calcd. for
C11H18O2 182.1306; calcd. for [M þ H]þ 183.1379, found 183.1385.
3-Methyl-cyclohex-1-enecarboxylic Acid (5a)
1
Mp: 26ꢀC (lit. 26–27ꢀC)[32]; H NMR (CDCl3, 500 MHz) d: 11 (s, 1H),
7.16 (t, J ¼ 10 Hz, 1H), 7.26 (t, J ¼ 10 Hz, 1H), 7.12 (s, 1H), 6.98
(s, 1H), 2.5 (m, 1H), 2.4 (m, 1H), 2.3 (m, 1H), 1.8 (m, 4H), 1.2 (m, 1H),
1.17 (d, J ¼ 7 Hz, 1H), 1.02 (d, J ¼ 7 Hz, 1H); 13C NMR (CDCl3,
125 MHz) d: 173.5 (CO), 173.3 (CO), 148.9 (CH), 142.5 (CH), 129.6
(C), 128.4 (C), 125.5 (C), 32.2 (CH2), 31.3 (CH2), 30.2 (CH2), 29.7
(CH2), 28.3 (CH2), 26.3 (CH2), 24 (CH2), 21.7 (CH2), 21.1 (CH3),
20.7 (CH3); IR (KBr): 3409, 2927, 1709, 1459, 1236 cmꢁ1; HRMS-ESI:
calcd. for C8H12O2 140.0837; calcd for [M ꢁ H]ꢁ 139.0764, found
139.0762.

1466
V. D. Vitnik et al.
4-Phenyl-cyclohex-1-enecarboxylic Acid (6a)
Mp: 196–199ꢀC; 1H NMR (CDCl3, 500 MHz) d: 11 (s, 1H), 7.32 (t,
J ¼ 7.5 Hz, 1H), 7.22 (m, 5H), 2.82 (m, 1H), 2.55 (m, 2H), 2.35 (m,
2H), 2.16 (m, 1H), 1.78 (m, 1H); 13C NMR (CDCl3, 125 MHz) d: 171.5
(CO), 146.03 (CH), 141.2 (C), 129.7 (C), 128.77 (CH), 127.01 (CH),
126.6 (CH), 39.24 (C), 34.12 (CH2), 29.5 (CH2), 24.73 (CH2); IR
(KBr): 3409, 2927, 1709, 1459, 1236 cmꢁ1; HRMS-ESI: calcd. for
C13H14O2 202.0993; calcd for [M þ H]þ 203.1066, found 203.1057.
4-Ethyl-cyclohex-1-enecarboxylic Acid (7a)
1
Mp: 81–82ꢀC; H NMR (CDCl3, 500MHz) d: 11 (s, 1H), 7.1 (t, J ¼ 4 Hz,
1H), 2.42 (m, 2H), 2.36 (m, 1H), 2.2 (m, 1H), 1.86 (m, 2H), 1.44 (m, 1H),
1.32 (m, 2H), 1.2 (m, 2H), 0.94 (t, J ¼ 7.5Hz, 1H); 13C NMR (CDCl3,
125 MHz) d: 172.23 (CO), 142.17 (CH), 129.53 (C), 34.22 (CH), 32.3 (CH);
IR (KBr): 3411, 2961, 1708, 1446, 1298, 1227cmꢁ1; HRMS-ESI: calcd. for
C9H14O2 ¼ 154.0993; calcd. for [M þ H]þ 155.1067, found 155.1066.
2-Phenyl-but-2-enoic Acid (8a)
1
Mp: 138–139ꢀC (lit. 132–137ꢀC)[33]; H NMR (CDCl3, 500 MHz) d: 7.33
(m, 6H), 6.44 (q, J ¼ 7.5 Hz, 1H), 2.16 (d, J ¼ 7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) d: 171.18 (CO), 140.27 (CH), 138.2 (C), 134.13 (C),
128.34 (CH), 127.88 (CH), 127.63 (CH), 16.41 (CH3); IR (KBr): 3520,
2977, 2940, 1694, 1602, 1113 cmꢁ1; HRMS-ESI: calcd. for C10H10O2
162.0681; calcd. for [M þ H]þ 163.0754, found 163.0748.
2-Phenyl-acrylic Acid (9a)
1
Mp: 101–102ꢀC (lit. 139–140ꢀC)[34]; H NMR (CDCl3, 500 MHz) d: 7.44
(m, 2H), 7.36 (m, 3H), 6.53 (s, 1H), 6.02 (s, 1H); 13C NMR (CDCl3,
125 MHz) d: 171.18 (CO), 140.5 (CH2), 136.11 (C), 129.36 (C), 128.43
(CH), 128.37 (CH), 128.15 (CH); IR (KBr) 3060, 1691, 1493, 1431,
1223, 1073 cmꢁ1; HRMS-ESI: calcd. for C9H8O2 148.0524; calcd. for
[M þ H]þ 149.0597, found 149.0589.
Cyclopent-1-enecarboxylic Acid (10a)
1
Mp: 120–121ꢀC (lit. 121ꢀC)[30]; H NMR (CDCl3, 500 MHz) d: 6.92 (t,
J ¼ 2 Hz, 1H), 2.56 (m, 4H), 1.98 (m, 2H); 13C NMR (CDCl3,

Conversion of Ketones to Conjugated Acids
1467
125 MHz) d: 169.16 (CO), 146.66 (CH), 135.77 (C), 33.61 (CH2), 31.05
(CH2), 23.14 (CH2); IR (KBr) 2971, 2627, 1674, 1430, 1291 cmꢁ1
;
HRMS-ESI: calcd. for C6H8O2 112.0524; calcd. for [M þ H]þ 113.0597,
found 113.0597.
Cyclohept-1-enecarboxylic Acid (11a)
1
Mp: 51ꢀC (lit. 51ꢀC)[30]; H NMR (CDCl3, 500 MHz) d: 11 (s, 1H), 7.34
(t, J ¼ 7 Hz, 1H), 2.7 (m, 2H), 2.5 (m, 2H), 1.55 (m, 2H), 1.52 (m, 4H); 13
C
NMR (CDCl3, 125 MHz) d: 173.33 (CO), 147.39 (CH), 135.78 (C), 31.97
(CH2), 29 (CH2), 26.95 (CH2), 26.12 (CH2), 25.6 (CH2); IR (KBr): 2926,
2854, 1680, 1468, 1290 cmꢁ1; HRMS-ESI: calcd. for C8H12O2 ¼ 140.0837;
calcd for [M ꢁ H]ꢁ 139.0764, found 139.0760.
Cyclododec-1-enecarboxylic Acid (12a)
1
Mp: 120–122ꢀC (lit. 120–123ꢀC)[8]; H NMR (CDCl3, 200 MHz) d: 9.76
(s, 1H), 6.93 (t, J ¼ 8 Hz, 1H), 6.28 (t, J ¼ 8 Hz, 1H), 2.6 (m, 2H), 2.3
(m, 5H), 1.29 (m, 33H); 13C NMR (CDCl3, 50 MHz) d: 173.86 (CO),
148.64 (CH), 146.1 (CH), 131.4 (C), 129.4 (C), 42.62 (CH2), 34 (CH2),
33.65 (CH2), 32.6 (CH2), 29.74 (CH2), 28.72 (CH2), 27.2 (CH2), 26.55
(CH2), 26.3 (CH2), 26.2 (CH2), 26 (CH2), 25.95 (CH2), 25.894 (CH2),
25.84 (CH2), 25.78 (CH2), 25.6 (CH2), 25.1 (CH2), 24.65 (CH2), 24.56
(CH2), 24.3 (CH2), 24.1 (CH2), 23.5 (CH2), 23.38 (CH2), 23.2 (CH2),
22.89 (CH2), 22.56 (CH2), 22.14 (CH2), 21.9 (CH2), 19.2 (CH2); IR
(KBr): 2927, 2855, 1682, 1468,1289 cmꢁ1; HRMS-ESI: calcd. for
C13H22O2 210.1620; calcd. for [M þ H]þ 211.1693, found 211.1683.
4-Bromo-piperidine-1,4-dicarboxylic Acid Monoethyl Ester (13a)
In a typical procedure, the flask was charged with LiOH ꢃ H2O
(0.23 mol, 9.8 g), t-BuOH (50 mL), H2O (10 mL), 4-oxo-piperidine-1-
carboxylic acid ethyl ester (commercially available from Aldrich, cat.
no. 15,373-7) (0.011 mol, 2.0 g), TEBA (0.001 mol, 0.23 g), and bromo-
form (0.044 mol, 11.3 g). The mixture was stirred vigorously (egg-shaped
stirring bar) at 20ꢀC, for 48 h and then poured into H2O (150 mL). It was
extracted with ether (2 ꢃ 50 mL), and the organic extracts were discarded.
The aqueous layer was acidified to pH ꢂ1 at 0ꢀC (20% HCl), the sepa-
rated solid was extracted with ether (3 ꢃ 20 mL), and the combined
extracts were washed with brine, dried (anh. MgSO4), and concentrated

1468
V. D. Vitnik et al.
at 20ꢀC. Recrystallization of the crude product from hexane gave white
crystals of 4-bromo-piperidine-1,4-dicarboxylic acid monoethyl ester.
1
Yield: 2.5 g, 77%; mp: 108ꢀC; H NMR (CDCl3, 500 MHz) d: 8.7 (s,
1H), 4.16 (q, J ¼ 7 Hz, 2H), 3.83 (m, 2H), 3.44 (m, 2H), 2.22 (m, 2H),
2.12 (m, 2H), 1.27 (t, J ¼ 7 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d: 174.65 (CO), 155.76 (CO), 62.1 (CH2), 59.88 (C), 41 (CH2), 36.3
(CH2), 14.8 (CH3); IR (KBr): 2983, 1732, 1647, 1446, 1280, 1245,
1132 cmꢁ1; HRMS-ESI: calcd. for C9H14BrNO4 279.0106; calcd. for
[MꢁH]ꢁ 280.0179, found 280.0169. Anal. calcd. for C9H14BrNO4: C,
38.59%; H, 5.04%; N, 5.00%. Found: C, 38.57%; H, 4.99%; N, 5.03%.
4-Oxo-piperidine-1-carboxilic Acid–tert-butyl Ester (14)
A solution of 1-benzyl-piperidin-4-one (6 g, 0.032 mol) in MeOH (30 mL)
was stirred at 5 atm. with Pd=C (10%, 1.5 g) in a Parr apparatus at 25ꢀC.
After 20 h, the reaction mixture was filtered through Celite, and the sol-
vent was evaporated. The residual oil was dissolved in NH3=H2O (25 mL)
and extracted with toluene. Evaporation of the dried organic extracts and
purification of the oily residue by crystallization in hexane afforded the
1
title compound 14 as white crystals. Yield: 4.9 g, 78%; mp: 72ꢀC; H
NMR (CDCl3, 200 MHz) d: 3.72 (t, J ¼ 7 Hz, 2H), 2.44 (t, J ¼ 7 Hz,
2H), 1.49 (s, 9H); 13C NMR (CDCl3, 50 MHz) d: 207.9 (CO), 80.44
(C), 42.93 (CH2), 41.15 (CH2), 28.33 (CH3); IR (KBr): 3421, 2974,
1717, 1687, 1432, 1173 cmꢁ1
.
4-Bromo-piperidine-1,4-dicarboxylic Acid Mono-tert-butyl Ester (14a)
The flask was charged with LiOH ꢃ H2O (0.2 mol, 8.4 g), t-BuOH
(50 mL), H2O (10 mL), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester
(0.010 mol, 2.0 g), TEBA (0.001 mol, 0.23 g), and bromoform (0.04 mol,
10.2 g). The mixture was stirred vigorously (egg-shaped stirring bar) at
20ꢀC, for 48 h, poured into H2O (150 mL), and extracted with ether
(2 ꢃ 50 mL). The organic extracts were discarded. The aqueous layer
was acidified to pH ꢂ1 at 0ꢀC, (20% HCl), the separated solid was
extracted with ether (3 ꢃ 20 mL), and the combined extracts were washed
with brine, dried (anh. MgSO4), and concentrated at 20ꢀC. The crude
product, 4-bromo-1-(tert-butoxycarbonyl) piperidine-4-carboxylic acid,
was recrystallized from hexane. Yield: 1.74 g, 65%; mp: 146ꢀC; 1H
NMR (CDCl3, 500 MHz) d: 9.45 (s, 1H), 3.76 (m, 2H), 3.4 (m, 2H), 2.2
(m, 2H), 2.11 (m, 2H), 1.46 (s, 9H); 13C NMR (CDCl3, 125 MHz) d:
174.71 (CO), 154.9 (CO), 80.68 (C), 60.2 (C), 41 (CH2), 36.4 (CH2),

Conversion of Ketones to Conjugated Acids
1469
28.6 (CH3); IR (KBr): 2978, 1737, 1648, 1441, 1243, 1166, 1076, 1050 cmꢁ
1; HRMS-ESI: calcd. for C11H18BrNO4 ¼ 307.0419; calcd. for [M ꢁ H]ꢁ
306.0346, found 306.0280. Anal. calcd. for C11H18BrNO4: C, 42.99%;
H, 5.9%; N, 4.56%. Found: C, 43.25%; H, 5.70%; N, 4.59%.
2-Hydroxy-2-phenethyl-4-phenyl-butyric Acid (15a)
1
Mp: 161–162ꢀC; H NMR (CDCl3, 200 MHz) d: 7.35 (m, 6H), 2.84 (m,
1H), 2.52 (m, 1H), 2.1 (m, 2H); 13C NMR (CDCl3, 50 MHz) d: 181.5
(CO), 141.1 (C), 128.47 (CH), 128.43 (CH), 126.1 (CH), 77.63 (C),
40.95 (CH2), 29.9 (CH2); IR (KBr): 3445, 2959, 1723, 1455, 1273,
1112 cmꢁ1; HRMS-ESI: calcd for C18H20O3 284.1412; calcd. for
[M-H]ꢁ 283.1340, found for [M ꢁ H]ꢁ 283.1338. Anal. calcd. for
C18H20O3: C, 76.01%; H, 7.09%. Found: C, 75.86%; H, 7.08%.
CONCLUSION
This method permits the one-pot preparation of a variety of conjugated
acids in high yield by using the convenient LiOH base in alcohol=H2O
with PTC catalyst at room temperature.
ACKNOWLEDGMENT
This research was part of Project Nos. 142074 and 142010, supported by
the Ministry of Science of the Republic of Serbia.
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