Improved preparation and structural investigation of 4-aryl-4-oxo-2- hydroxy-2-butenoic acids and methyl esters

Article abstract of DOI:10.1016/j.tet.2004.06.030

A simple and efficient oxalylation of aryl methyl ketones was accomplished with dimethyl oxalate in the presence of sodium methoxide. The unpreviously reported sodium ketoenolate esters were isolated and gently hydrolyzed into the ketoenol esters in good yields. Alternatively the sodium ketoenolate esters hydrolysis could also be conducted to directly afford the ketoenol acids, which represent one of the most promising class of HIV-1 integrase inhibitors. Advantages over previously reported procedures were better yields and simplicity of the purification protocol.

Full text of DOI:10.1016/j.tet.2004.06.030

Tetrahedron 60 (2004) 6479–6486
Improved preparation and structural investigation of
4-aryl-4-oxo-2-hydroxy-2-butenoic acids and methyl esters
*
´
Cedric Maurin, Fabrice Bailly and Philippe Cotelle
´ ´ ´
Laboratoire de Chimie Organique et Macromoleculaire, UMR CNRS 8009, Universite de Lille 1, cite scientifique,
59655 Villeneuve d’Ascq, France
Received 6 April 2004; revised 1 June 2004; accepted 7 June 2004
Available online 24 June 2004
Abstract—A simple and efficient oxalylation of aryl methyl ketones was accomplished with dimethyl oxalate in the presence of sodium
methoxide. The unpreviously reported sodium ketoenolate esters were isolated and gently hydrolyzed into the ketoenol esters in good yields.
Alternatively the sodium ketoenolate esters hydrolysis could also be conducted to directly afford the ketoenol acids, which represent one of
the most promising class of HIV-1 integrase inhibitors. Advantages over previously reported procedures were better yields and simplicity of
the purification protocol.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Among numerous classes of molecules,2 b-diketoacid
containing inhibitors (their usual name is DKAs but their
structures correspond to 4-aryl-(or 4-styryl-)3 4-oxo-2-
hydroxy-2-butenoic acids, see Scheme 1) have emerged as
the most promising drug candidates,4 which are selective
for integrase. S-13605 from Shionogi Company and L-
708,9066,7 from Merck Company are the best examples of
this family, S-1360 being one of the only two currently
available integrase inhibitors under clinical studies. Starting
with this b-diketoacid structure, novel 8-hydroxynaphthyri-
dine derivatives8 have been designed and L-870,810 is
under clinical evaluation.9
Human immunodeficiency virus type 1 (HIV-1) is the
etiological agent of AIDS. The replicative cycle of this
retrovirus has been intensively studied in order to identify
targets and design specific inhibitors. To date, Food and Drug
Administration approved drugs target reverse transcription
(inhibition of reverse transcriptase), protein synthesis (inhi-
bition of protease) and fusion (interaction with glycoprotein
41).1 Persistence of latent HIV-1 in resting memory CD4þT
cells, emergence of resistant HIV strains, drug toxicity and
expensive medication have led to the development of novel
drugs which interact with other viral replication processes.
Integrase that catalyzes the insertion of the proviral DNA into
the genome of the host cell, has emerged as an attractive target
because it is necessary for stable infection and counterpart
enzymes are lacking in the host.
The synthesis of 4-aryl-4-oxo-2-hydroxy-2-butenoic acids
4 was achieved by the oxalylation of the corresponding
aryl methyl ketones 1 in the presence of base followed by
either alkaline or acidic hydrolysis (Scheme 2).10–16 The
Scheme 1.
Keywords: HIV integrase inhibitors; Tautomerism; Antiviral agents; Diketoacids.
*
Corresponding author. Tel.: þ33-320337231; fax: þ33-320336309; e-mail address: philippe.cotelle@univ-lille1.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.030

6480
C. Maurin et al. / Tetrahedron 60 (2004) 6479–6486
Scheme 2. Reagents and conditions: (i) dimethyl oxalate (1 equiv.) in Et2O, then 2 M MeONa in MeOH, 1 h 30, rt; (ii) H2O, then CH3COOH to reach pH 3–4;
(iii) 1,4-dioxane/1 M HCl, 4 h, reflux.
oxalylation of aryl methyl ketones afforded the ketoenol
esters 3, using diethyl or dimethyl oxalate in the presence of
NaH (in benzene, toluene or DMF) or NaOEt or NaOMe (in
the appropriate alcohol). The reported yields were moderate
to good depending on the structure of the aryl methyl ketone
and the reaction conditions (base, solvent, reaction tem-
perature and time). Recently, in order to improve this key
step, a new procedure using tert-butyl methyl oxalate was
reported.16 The reported procedures suffered from a lack of
reproducibility, the use of commercially unavailable start-
ing oxalate, long time reaction and high reaction tempera-
ture or sometimes tedious extractive work-up.
the cases of 2a and 2h) (Table 2) as a mixture of two species,
namely Z,Z and E,Z configurations according to Raban and
Haritos17 (Scheme 3). Depending on the ring substitution,
the 1H NMR spectra were more or less broadened probably
due to a more or less rapid exchange between the two
isomers. The sodium ketoenolate esters isomers could be
differentiated by the methyl ester signal and the enolic
proton signal. Z,Z Configurations gave a methyl ester signal
at 3.63–3.70 ppm and an enolic proton signal at 6.05–
6.56 ppm whereas for the E,Z forms the same signals were
at 3.56–3.70 ppm and 5.05–5.57 ppm respectively. The
Z,Z/E,Z ratio was estimated to be 4:1 except for 2e (in this
case, the characteristic signals of an E,Z isomer have not
been observed on the 1H and 13C NMR spectra). In order to
clearly establish the existence of ketoenolate anions and the
respective structures of the two configurations, 13C NMR
spectra were recorded for 2a and 2h. The hydrogen attached
to carbon 3 and the carbon 3 of the ketoenolate esters
presented strong upfield shifts for the two configurations of
2 (for example: Z,Z-2a: 6.34 and 92.0 ppm, E,Z-2a: 5.31 and
91.9 ppm) versus the chemical shifts in 3 (3a: 7.12 and
98.1 ppm) whereas the quaternary carbon of the aromatic
ring presented a strong downfield shift (142.2 and
142.4 ppm for Z,Z-2a and E,Z-2a, respectively versus
134.3 ppm for 3a). These differences were in accordance
We herein report a rapid alternative method for the synthesis
of ketoenol esters 3 from aryl methyl ketones 1 based on the
isolation of sodium ketoenolate esters 2. Ketoenol acids 4
may be obtained by hydrolysis of 310–16 or more directly
from 2 (this work).
2. Results and discussion
The causes for the absence of a general procedure, the
differences in yield and the irreproducibility are mainly due
to variable solubility of the starting materials. To overcome
this problem, we decided to solubilize the aryl methyl
ketone 1 and dimethyl oxalate in dry ether. To this ethereal
solution, sodium methoxide in methanol was added.
Depending on the aryl methyl ketone used, a precipitate
appeared immediately or within half an hour. A reaction
time standardized to one night gave satisfactory yields (75–
92%) (Table 1). The sodium ketoenolate esters 2(a–j) were
obtained as white to yellowish powders and characterized
1
with previous H and 13C NMR studies18,19 on enolates.
2(a–j) were converted into the corresponding ketoenol
esters 3(a–j) by acidic hydrolysis in moderate to good
yields (70–90%). 2(a–c;g–i) were exhaustively hydro-
lyzed to give the corresponding ketoenol acids 4(a–c;g–i)
in 45–68% yields by stronger acidic conditions in refluxing
dioxane/water mixture. Overall yields (1!3) ranged from
58 to 81%. These results suffer the comparison with
1
by H NMR spectroscopy (and 13C NMR spectroscopy in
Scheme 3.

C. Maurin et al. / Tetrahedron 60 (2004) 6479–6486
6481
Table 1. Preparation of compounds 2, 3 and 4
1
1!2a (%)
2!3a (%)
1!3
2!4a (%)
1!4
a
92
88
81% (lit. 38%b, 59%c)
68
63% (lit. 9%20
)
b
88
79
79
74
70%
58%
58
50
51%
c
40%
d
e
f
85
86
80
79
90
73
70
87
77% (lit. 100%d,12%e)
63%
56% (lit. 52%d, 30%e)
g
69%
45
65
55
36%
h
75
82
62% (lit. 85%f)
49% (lit. 64%20
)
i
82
86
74
76
61% (lit. 94%g)
45% (lit. 38%11
)
j
65%
a
Yields in isolated pure mixtures of Z,Z and E,Z forms (2) or tautomers (3 and 4).
(CO2Me)2, NaOMe, MeOH, rt, .12 h.13
b
c
d
e
f
NaH, DMF, (CO2Me)2, 50 8C, 30 min.12
t-BuOOCCOOMe, NaOMe, THF–DME (1:1), rt, ,2 h.16
(CO2Me)2, NaOMe, THF–DME (1:1), rt, .12 h.16
NaH, Toluene, (CO2Et)2, reflux, 1 h.20
NaH, MeOH, Benzene, then 1 and (CO2Me)2, 12 h.11
g

Table 2. Spectroscopic data of compounds 2(a–j)
Product
1H NMR (200 MHz, DMSO-d6) d, ppm (J, Hz)
13C NMR (50 MHz, DMSO-d6) d, ppm (J, Hz)
1H NMR (200 MHz, DMSO-d6) d, ppm (J, Hz)
2a
2b
3.68 (s, 3H), 6.34 (s, 1H), 7.40 (m, 3H), 7.79 (br d, 2H)
51.5 (CH3), 92.0 (CH), 126.5 (2CH), 128.0 (2CH), 129.8 (CH),
142.3 (C), 167.7 (C), 170.3 (C), 185.0 (C)
51.5 (CH3), 55.4 (CH3), 97.6 (CH), 111.7 (CH),
120.0 (CH), 128.6 (CH), 129.7 (CH), 133.8 (C),
156.2 (C), 167.8 (C), 169.1 (C), 187.2 (C)
51.6 (CH3), 55.2 (CH3), 91.6 (CH), 113.3 (2CH),
128.4 (2CH), 134.5 (C), 160.9 (C), 167.9 (C), 169.5 (C),
184.8 (C)
3.59 (s, 3H), 5.31 (s, 1H), 7.34 (m, 3H),
7.70 (br d, 2H)a
3.63 (s, 3H), 3.74 (s, 3H), 5.05 (br s, 1H),
6.91–7.00 (m, 2H), 7.28–7.34 (m, 2H)
3.63 (s, 3H), 3.74 (s, 3H), 6.05 (s, 1H),
6.91–7.00 (m, 2H), 7.28–7.34 (m, 2H)
2c
2d
2e
3.66 (s, 3H), 3.78 (s, 3H), 6.33 (s, 1H),
6.92 (d, 2H, 3J¼8.1), 7.77 (d, 2H, 3J¼8.1)
3.56 (s, 3H), 3.78 (s, 3H), 5.28 (s, 1H),
6.88 (d, 2H, J¼7.6), 7.66 (d, 2H, 3J¼7.6)
3
3.67 (s, 3H), 6.29 (s, 1H), 7.19 (br dd, 2H, 3JHH¼8.3,
51.7 (CH3), 91.9 (CH), 114.8 (2CH, JCF¼22.0),
3.58 (s, 3H), 5.28 (s, 1H), 7.14 (m, 2H),
7.77 (m, 2H)
2
3JHF¼9.0), 7.83 (dd, 2H, 3JHH¼8.3, 4JHF¼5.9)
129.0 (2CH, JCF¼9.2), 138.5 (C, JCF¼3.0),
3
4
1
163.3 (C, JCF¼247.8), 167.6 (C), 170.2 (C), 184.2 (C)
3.67 (s, 3H), 6.20 (br s, 1H), 7.68 (br t, 1H, 3J¼7.9),
51.6 (CH3), 92.1 (CH), 121.0 (CH), 124.5 (CH), 129.9 (CH),
132.8 (CH), 143.2 (C), 147.9 (C), 167.3 (C), 172.9 (C),
181.7 (C)
8.19–8.26 (m, 2H), 8.53 (br s, 1H)
3
2f
3.68 (s, 3H), 6.33 (s, 1H), 7.98 (d, 2H, J¼8.3),
51.6 (CH3), 92.5 (CH), 123.4 (2CH), 127.7 (2CH),
148.0 (C), 148.1 (C), 167.1 (C), 171.8 (C), 182.1 (C)
51.5 (CH3), 55.3 (CH3), 55.5 (CH3), 91.6 (CH),
109.9 (CH), 110.7 (CH), 119.7 (CH), 134.7 (C),
148.2 (C), 150.6 (C), 167.8 (C), 169.8 (C), 184.6 (C)
51.4 (CH3), 69.3 (2CH2), 91.9 (CH), 103.4 (CH),
105.6 (2CH), 127.6 (4CH), 127.8 (2CH), 128.40 (4CH),
137.0 (2C), 144.8 (C), 159.2 (2C), 167.6 (C),
3.60 (s, 3H), 5.36 (s, 1H), 7.93 (d, 2H, 3J¼8.3),
8.23 (d, 2H, 3J¼8.3)
8.17 (d, 2H, J¼8.3)
3
2g
3.66 (s, 3H), 3.77 (br s, 6H), 6.36 (br s, 1H),
6.94 (br d, 1H), 7.39 (m, 2H)
3.66 (s, 3H), 3.77 (br s, 6H), 5.30 (br s, 1H),
6.94 (br d, 1H), 7.39 (m, 2H)
2h
3.66 (s, 3H), 5.10 (s, 4H), 6.22 (s, 1H), 6.73 (br s, 1H),
6.98 (br s, 2H), 7.32–7.43 (m, 10H)
3.57 (s, 3H), 5.10 (s, 4H), 5.24 (s, 1H),
6.63 (br s, 1H), 6.95 (br s, 1H), 7.32–7.43
(m, 10H)b
170.8 (C), 184.2 (C)
2i
2j
3.72 (s, 3H), 6.60 (s, 1H), 7.52 (br s, 2H), 7.91 (m, 4H),
8.39 (br s, 1H)
51.8 (CH3), 92.6 (CH), 124.5 (CH), 126.4 (2CH), 127.0 (CH),
127.5 (CH), 127.6 (CH), 129.0 (CH), 132.6 (C), 133.9 (C),
139.6 (C), 167.8 (C), 170.4 (C), 185.4 (C)
51.5 (CH3), 55.4 (CH3), 55.6 (CH3), 92.1 (CH), 106.1 (CH),
107.5 (CH), 122.5 (CH), 124.9 (CH), 125.8 (CH), 128.2 (C), 129.9 (C),
137.7 (C), 149.4 (C), 150.1 (C), 167.9 (C), 170.2 (C), 185.3 (C)
3.72 (s, 3H), 5.57 (br s, 1H), 7.52 (br s, 2H),
7.91 (m, 4H), 8.39 (br s, 1H)
3.69 (s, 3H), 3.88 (br s, 6H), 6.50 (br s, 1H),
7.29 (br s, 1H), 7.45 (br s, 1H),
7.73–7.80 (m, 2H), 8.23 (br s, 1H)
3.60 (s, 3H), 3.88 (br s, 6H), 5.46 (br s, 1H),
7.29 (br s, 1H), 7.45 (br s, 1H),
7.73–7.80 (m, 2H), 8.12 (br s, 1H)
a
13C NMR (50 MHz, DMSO-d6): d¼50.3 (CH3), 91.9 (CH), 126.4 (2CH), 127.6 (2CH), 129.0 (CH), 142.4 (C), 170.4 (C), 180.2 (C), 182.7 (C).
b
13C NMR (50 MHz, DMSO-d6): d¼50.3 (CH3), 69.2 (2CH2), 92.1 (CH), 103.2 (CH), 105.3 (2CH), 127.5 (4CH), 127.7 (2CH), 128.38 (4CH), 137.2 (2C), 145.1 (C), 158.9 (2C), 170.3 (C), 180.4 (C), 182.0 (C).

Table 3. Spectroscopic data of compounds 3(a–j)
Product
Ketoenol/diketo ratioa
Ketoenol-form
1H NMR (200 MHz, DMSO-d6) d, ppm (J, Hz)
Diketo-form
13C NMR (50 MHz, DMSO-d6) d, ppm (J, Hz)
1H NMR (200 MHz, DMSO-d6)
Detectable signals d, ppm (J, Hz)
3a
3b
90:10
84:16
3.86 (s, 3H), 7.12 (s, 1H), 7.57 (br t, 2H, 3J¼7.1),
53.0 (CH3), 98.1 (CH), 127.9 (2CH), 129.1 (2CH), 134.1
(CH), 134.3 (C), 162.0 (C), 168.7 (C), 190.2 (C)
52.9 (CH3), 55.9 (CH3), 102.8 (CH), 112.7 (CH), 120.7
(CH), 123.6 (C), 130.0 (CH), 135.1 (CH), 158.9 (C),
162.3 (C), 168.4 (C), 189.4 (C)
3.78 (s, 3H), 4.62 (s, 2H), 7.99 (br d, 2H)
4.38 (s, 2H), 7.73 (br d, 1H)
3
7.70 (br t, 1H, J¼7.1), 8.06 (br d, 2H, 3J¼7.1)
3.82 (s, 3H), 3.89 (s, 3H), 7.06 (br dd, 1H, 3J¼7.3,
3J¼6.7),
7.15 (s, 1H), 7.17 (br d, 1H, 3J¼8.8),
7.58 (1H, br dd, 3J¼8.8, 3J¼6.7), 7.77 (1H, br d, 3J¼7.3)
3.84 (s, 3H), 3.85 (s, 3H), 7.05 (s, 1H), 7.07 (d, 2H,
3J¼8.9),
3c
3d
3e
96:4
91:9
90:10
52.9 (CH3), 55.7 (CH3), 97.7 (CH), 114.5 (2CH), 127.2
(C), 130.5 (2CH), 162.5 (C), 164.1 (C), 167.2 (C), 189.9
(C)
4.53 (s, 2H)
8.05 (d, 2H, 3J¼8.9)
3.85 (s, 3H), 7.10 (s, 1H), 7.38 (br dd, 2H, 3JHH¼8.6,
3JHF¼9.0),
53.1 (CH3), 98.2 (CH), 116.2 (2CH, 2JCF¼22.0), 131.1
(2CH, 3JCF¼9.8), 131.5 (C), 162.0 (C), 165.6 (C,
1JCF¼253.3), 167.8 (C), 189.4 (C)
3.77 (s, 3H), 4.60 (s, 2H), 7.38 (br dd, 2H, JHH¼8.6,
3
3JHF¼9.0), 8.05 (dd, 2H, 3JHH¼8.6, 4JHF¼5.6)
8.15 (dd, 2H, 3JHH¼8.6, 4JHF¼5.6)
3.86 (s, 3H), 7.14 (s, 1H), 7.82 (m, 1H), 8.44–8.47
(m, 2H), 8.64 (br s, 1H)
53.1 (CH3), 98.6 (CH), 122.1 (CH), 127.9 (CH), 130.8
(CH), 134.0 (CH), 135.9 (C), 148.2 (C), 161.9 (C), 168.7
(C), 187.4 (C)
3.79 (s, 3H), 4.70 (s, 2H)
3f
93:7
93:7
3.86 (s, 3H), 7.12 (s, 1H), 8.27 (d, 2H, 3J¼9.0), 8.34
53.2 (CH3), 98.8 (CH), 124.0 (2CH), 129.2 (2CH), 139.5
(C), 150.2 (C), 161.9 (C), 170.2 (C), 186.5 (C)
53.0 (CH3), 55.6 (CH3), 55.9 (CH3), 98.1 (CH), 110.0
(CH), 111.3 (CH), 123.2 (CH), 127.1 (C), 148.9 (C),
154.2 (C), 162.3 (C), 166.7 (C), 190.5 (C)
52.5 (CH3), 69.6 (2CH2), 96.8 (CH), 106.4 (3CH), 127.7
(4CH), 127.9 (2CH), 128.5 (4CH), 136.7 (2C), 138.8
(C), 159.7 (2C), 163.7 (C), 169.5 (C), 188.3 (C)
53.0 (CH3), 98.3 (CH), 123.0 (CH), 127.1 (CH), 127.7
(CH), 128.7 (CH), 129.1 (CH), 129.8 (CH), 130.1 (CH),
131.8 (C), 132.2 (C), 135.4 (C), 162.2 (C), 168.1 (C),
190.3 (C)
3.78 (s, 3H), 4.68 (s, 2H), 8.20 (d, 2H, 3J¼9.0), 8.34 (d,
(d, 2H, 3J¼9.0)
2H, J¼9.0)
3
3g
3.84 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 7.10 (d, 1H,
4
3.77 (s, 3H), 3.81 (s, 3H), 4.56 (s, 2H), 7.08 (d, 1H,
3
3J¼8.6), 7.11 (s, 1H), 7.52 (d, 1H, J¼2.2), 7.77
3J¼8.7), 7.42 (br s, 1H), 7.63 (br d, 1H, J¼8.7)
(dd, 1H, 3J¼8.6, 4J¼2.2)
3h
3i
Diketo-form undetected
97:3
3.79 (s, 3H), 5.16 (br s, 4H), 6.93 (br s, 2H), 7.20
(br s, 2H), 7.37–7.44 (m, 10H)
3.86 (s, 3H), 7.24 (s, 1H), 7.60–7.66 (m, 2H), 7.95–8.00
(m, 3H), 8.13 (d, 1H, 3J¼7.6), 8.75 (br s, 1H)
4.74 (s, 2H), 8.62 (br s, 1H)
4.66 (s, 2H), 8.51 (br s, 1H)
3j
96:4
3.87 (s, 3H), 3.90 (s, 3H), 3.92 (s, 3H), 7.24 (s, 1H), 7.40
(s, 1H), 7.58 (s, 1H), 7.87 (m, 2H), 8.64 (br s, 1H)
53.0 (CH3), 55.5 (CH3), 55.7 (CH3), 98.1 (CH), 106.4
(CH), 108.1 (CH), 121.5 (CH), 127.0 (CH), 128.1 (C),
128.5 (CH), 129.9 (C), 132.3 (C), 149.9 (C), 151.9 (C),
162.3 (C), 167.6 (C), 190.7 (C)
a
The ratios were calculated from the ethylenic proton signal of the ketoenol isomer and the methylenic protons signal of the diketo isomer in DMSO-d6.

6484
C. Maurin et al. / Tetrahedron 60 (2004) 6479–6486
Table 4. Physical, analytical and mass spectroscopic data for compounds 3(b–c), 3(e–h) and 3ja
Product
State
Mp (8C)
Elemental analyses
MS (EI)
3b
3c
3e
3f
Yellow powder
Yellow powder
Beige powder
White powder
Yellow powder
Yellow powder
Yellow powder
75–76
92–93
Anal. calcd for C12H12O5 (236.22): C, 61.01; H,
5.12. Found: C, 61.28; H, 5.22
Anal. calcd for C12H12O5 (236.22): C, 61.01; H,
5.12. Found: C, 61.35; H, 5.06
Anal. calcd for C11H9NO6 (251.20): C, 52.60; H,
3.61; N, 5.58. Found: C, 52.31; H, 3.72; N, 5.35
Anal. calcd for C11H9NO6 (251.20): C, 52.60; H,
3.61; N, 5.58. Found: C, 52.25; H, 3.68; N, 5.42
Anal. calcd for C13H14O6 (266.25): C, 58.64; H,
5.30. Found: C, 58.96; H, 5.22
m/z (%)¼236 ([Mþ], 1), 177 (56), 135 (100),
77 (19)
m/z (%)¼236 ([Mþ], 16), 178 (12), 177 (100),
135 (33), 109 (38)þ, 94 (14), 77 (12), 69 (21)
m/z (%)¼251 ([M ], 2), 193 (10), 192 (100), 150
(18), 105 (11), 69þ(11)
112–113
161–162
150–151
121–123
170–172
m/z (%)¼251 ([M ], 2), 193 (11), 192 (100),
150 (19), 146 (13)þ, 105 (14), 69 (19)
m/z (%)¼266 ([M ], 56), 208 (12), 207 (100),
165 (24), 139 (87), 124 (69), 69 (14)
m/z (%)¼418 ([Mþ], 29), 359 (9), 327 (16), 227
(10), 181 (48), 180 (34), 91 (100)
3g
3h
3j
Anal. calcd for C25H22O6 (418.45): C, 71.76; H,
5.30. Found: C, 71.95; H, 5.35
Anal. calcd for C17H16O6 (316.31): C, 64.55; H,
5.10. Found: C, 64.24; H, 5.15
m/z (%)¼317 (11), 316 ([Mþ], 64), 258 (19), 257
(98), 230 (12), 215 (46), 190 (14), 189 (100), 174
(78), 172 (11)
a
Known products: 3a, white powder, mp 57–58 8C (lit.13 mp 56–57 8C); 3d, white powder, mp 124–125 8C (lit.13 mp 125 8C); 3i, white powder, mp 104–
105 8C (lit.11 mp 104–106 8C).
previous articles except for the yield of 1d!3d that was
reported to reach 100% after column chromatography
purification.16 L-708,906, 4h was obtained in 64% yield in
a recent patent,20 whereas its unsubstituted parent molecule
4a was obtained in the same report in a poor 9% yield. No
doubt the procedure for the synthesis of L-708,906 was
optimized in comparison with that of 4a. A 94% yield was
also reported for the synthesis of 3i but the yield of its
conversion into 4i dropped to 38%.11 Since our overall
yields in 4i from 1i are similar, we may have some doubt
about the purity of 3i in the cited paper. Physical data of
ketoenol esters 3 are reported in Tables 3 and 4 and physical
data of DKAs 4 in Table 5.
Impact). Elemental analyses were performed by CNRS
laboratories (Vernaison).
3.1. Synthesis of sodium ketoenolate ester 2. General
procedure
Sodium (0.28 g, 12 mmol) was added slowly in methanol
(6 mL) at 25 8C to give a 2 M solution of sodium
methoxide. Arylmethyl ketone 1 (10 mmol) and dimethyl
oxalate (1.18 g, 10 mmol) were dissolved in dried diethyl
ether (10 mL) and the freshly prepared solution of sodium
methoxide was slowly added. The mixture was stirred
overnight, the solid was filtered off, washed with methanol,
diethyl ether and dried. Sodium ketoenolate esters 2 were
obtained in yields ranging from 75 to 92%.
As a conclusion, we reported in this paper, a very simple and
efficient procedure for the synthesis of ketoenol esters 3 and
acids 4 that allows variable substitution on the aromatic
ring. This new protocol involves the isolation of the
unpreviously reported sodium keto enolate esters 2 as a
key step that may be hydrolyzed under soft conditions into 3
or more hardly treated to give 4. The yields in 2 are quite
good and the conversions into 3 or 4 are acceptable. Due to
its remarkable simplicity, this new procedure may be of
great interest for the rapid synthesis of a wide range of new
DKAs.
3.2. Synthesis of ketoenol ester 3. General procedure
Sodium ketoenolate ester 2 (1 g) was dissolved in water
(about 100 mL) at rt for 1 h. Then the solution was acidified
by adding acetic acid to reach pH 3–4 and kept at 0 8C for
1 h. The precipitate was filtered off, washed with water and
dried. Ketoenol esters 3 were obtained in yields ranging
from 70 to 90%.
3.3. Synthesis of ketoenol acid 4. General procedure
Sodium ketoenolate ester 2 (1 g) was partially dissolved in
1,4-dioxane (20–30 mL) and 1 M HCl (100 mL) was added.
The mixture was refluxed during 6 h. Removal of the
solvent under reduced pressure gave a solid, which was
washed with water, CH2Cl2 and dried. The product was
recrystallized from diethyl ether (4a), toluene/ethyl acetate
(4b–c) or ethyl acetate (4g–i). Ketoenol acids 4 were
obtained as yellow solids in yields ranging from 45 to 68%.
3. Experimental
All solvents were of commercial quality used from freshly
opened containers and were dried and purified by conven-
tional methods. Aryl methyl ketones 1 were purchased from
Aldrich-Chimie (St Quentin-Fallavier, France) except for
1j. 1-(6,7-dimethoxynaphthalen-2-yl)-ethanone 1j was pre-
pared in two steps from 2,3-dimethoxynaphthalene accord-
ing to a known procedure.23
Mps were determined on a Reichert Thermopan
apparatus, equipped with a microscope and are uncor-
rected. NMR spectra were obtained on a AC 200 Bruker
spectrometer in DMSO-d6 with TMS as internal
reference. Mass spectra were recorded on a Thermo-
Finnigan PolarisQ mass spectrometer (70 eV, Electronic
Acknowledgements
This work was financially supported by grants from le
Centre National de la Recherche Scientifique (CNRS) and
l’Agence Nationale de la Recherche contre le SIDA
(ANRS).

Table 5. Physical and spectroscopic data of compounds 4(a–c) and 4(g–i)
Product
Mp (8C)
Ketoenol/diketo
ratioa
Ketoenol-form
1H NMR (200 MHz, DMSO-d6) d, ppm (J, Hz)
Diketo-form
13C NMR (50 MHz, DMSO-d6) d, ppm
1H NMR (200 MHz, DMSO-d6), detectable
signals d, ppm (J, Hz)
3
4a
4b
154–157
(lit.15 155–158)
155–157b
91:9
7.09 (s, 1H), 7.55 (br dd, 2H, J¼7.3, 3J¼6.7),
97.8 (CH), 127.8 (2CH), 129.1 (2CH), 134.0
(CH), 134.6 (C), 163.1 (C), 170.1 (C), 190.4 (C)
56.1 (CH3), 102.8 (CH), 112.8 (CH), 120.9 (CH),
124.0 (C), 130.1 (CH), 135.1 (CH), 158.9 (C),
163.4 (C), 169.8 (C), 189.9 (C)
55.7 (CH3), 97.4 (CH), 114.4 (2CH), 127.5 (C),
130.2 (2CH), 162.5 (C), 163.6 (C), 171.1 (C),
188.7 (C)
55.6 (CH3), 55.9 (CH3), 97.8 (CH), 109.9 (CH),
111.3 (CH), 123.0 (CH), 127.3 (C), 148.9 (C),
154.0 (C), 163.4 (C), 168.3 (C), 190.4 (C)
69.7 (2CH2), 98.2 (CH), 106.6 (2CH), 107.6
(CH), 127.8 (4CH), 128.0 (2CH), 128.5 (4CH),
136.6 (2C), 136.8 (C), 159.8 (2C), 163.2 (C),
170.2 (C), 190.0 (C)
4.56 (s, 2H), 7.96 (br d, 2H, 3J¼7.4)
7.68 (br t, 1H, J¼6.7), 8.04 (br d, 2H, 3J¼7.3)
3
3
83:17
3.89 (s, 3H), 7.07 (br dd, 1H, J¼7.3, 3J¼6.6),
3.81 (s, 3H), 4.34 (s, 2H), 7.72 (br d, 1H)
7.17 (s, 1H), 7.19 (br d, 1H, 3J¼8.3), 7.59 (br dd,
1H, J¼8.3, 3J¼6.6), 7.78 (br d, 1H, 3J¼7.3)
3
3
4c
4g
4h
157–158
(lit.21 160–162)
89:11
90:10
90:10
3.84 (s, 3H), 6.90 (s, 1H), 7.06 (d, 2H, J¼8.3),
4.41 (s, 2H), 7.93 (d, 2H, 3J¼8.4)
8.01 (d, 2H, 3J¼8.3)
188–189
(lit.22 179–180 dec.)
3.84 (s, 3H), 3.86 (s, 3H), 7.08 (s, 1H), 7.10 (d,
1H, 3J¼8.6), 7.53 (d, 1H, 4J¼1.5), 7.76 (dd, 1H,
3J¼8.6, 4J¼1.5)
3.81 (s, 3H), 4.50 (s, 2H), 7.43 (br s, 1H), 7.63
3
(br d, 1H, J¼8.8)
171–173
(lit.15 170–172)
5.18 (s, 4H), 6.99 (br s, 1H), 7.09 (s, 1H), 7.26 (br
s, 2H), 7.31–7.47 (m, 10H)
4.54 (s, 2H), 7.20 (br s, 2H)
4i
174–175
(lit.11 173–175)
93:7
7.29 (s, 1H), 7.60–7.70 (m, 2H), 7.98–8.05 (m,
3H), 8.17 (d, 1H, 3J¼8.3), 8.81 (br s, 1H)
98.2 (CH), 123.1 (CH), 127.1 (CH), 127.7 (CH),
128.8 (CH), 129.1 (CH), 129.8 (CH), 130.1
(CH), 132.0 (C), 132.3 (C), 135.4 (C), 163.2 (C),
169.6 (C), 190.6 (C)
4.70 (s, 2H), 8.71 (br s, 1H)
a
The ratios were calculated from the ethylenic proton signal of the ketoenol isomer and the methylenic protons signal of the diketo isomer in DMSO-d6.
Anal. calcd for C11H10O5 (222.20): C, 59.46; H, 4.54. Found: C, 59.24; H, 4.63. MS (EI): m/z (%)¼222 ([Mþ], 2), 192 (11), 177 (70), 149 (10), 135 (100), 79 (12), 77 (27).
b

6486
C. Maurin et al. / Tetrahedron 60 (2004) 6479–6486
N.; Sawada, M.; Takasugi, H.; Tanaka, H. J. Med. Chem.
References and notes
1998, 41, 2390.
13. Drysdale, M. J.; Hind, S. L.; Jansen, M.; Reinhard, J. F., Jr.
J. Med. Chem. 2000, 43, 123.
1. Pomerantz, R. J.; Horn, D. L. Nat. Med. 2003, 9, 867.
2. Maurin, C.; Bailly, F.; Cotelle, P. Curr. Med. Chem. 2003, 10,
1795.
14. Wai, J. S.; Egbertson, M. S.; Payne, L. S.; Fisher, T. E.;
Embrey, M. W.; Tran, L. O.; Melamed, J. Y.; Langford, H. M.;
Guare, J. P., Jr.; Zhuang, L.; Grey, V. E.; Vacca, J. P.;
Holloway, M. K.; Naylor-Olsen, A. M.; Hazuda, D. J.; Felock,
P. J.; Wolfe, A. L.; Stillmock, K. A.; Schleif, W. A.;
Gabryelski, L. J.; Young, S. D. J. Med. Chem. 2000, 43, 4923.
15. Pais, G. C.; Zhang, X.; Marchand, C.; Neamati, N.; Cow-
ansage, K.; Svarovskaia, E. S.; Pathak, V. K.; Tang, Y.;
Nicklaus, M.; Pommier, Y.; Burke, T. R., Jr. J. Med. Chem.
2002, 45, 3184.
3. Costi, R.; Di Santo, R.; Artico, M.; Roux, A.; Ragno, R.;
Massa, S.; Tramontano, E.; La Colla, M.; Loddo, R.;
Marongiu, M. E.; Pani, A.; La Colla, P. Bioorg. Med. Chem.
Lett. 2004, 14, 1745.
4. Neamati, N. Expert. Opin. Ther. Pat. 2002, 12, 709.
5. Billich, A. Curr. Opin. Investig. Drugs 2003, 4, 206.
6. Hazuda, D. J.; Felock, P.; Witmer, M.; Wolfe, A.; Stillmock,
K.; Grobler, J.; Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau,
C.; Miller, M. D. Science 2000, 287, 646.
16. Jiang, X. H.; Song, L. D.; Long, Y. Q. J. Org. Chem. 2003, 68,
7555.
7. Egbertson, M.; Hazuda, D. J.; Clark, D. L.; Medina, J. C.; Wai,
J. S.; Young, S. D.; Guare, J. P. Jr.,; Selnick, H. G. US Pat.
WO9962513, 1999; Chem. Abstr. 1999, 132, 22866.
8. Zhuang, L.; Wai, J. S.; Embrey, M. W.; Fisher, T. E.;
Egbertson, M. S.; Payne, L. S.; Guare, J. P., Jr.; Vacca, J. P.;
Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.; Stillmock, K. A.;
Witmer, M. V.; Moyer, G.; Schleif, W. A.; Gabryelski, L. J.;
Leonard, Y. M.; Lynch, J. J., Jr.; Michelson, S. R.; Young,
S. D. J. Med. Chem. 2003, 46, 453.
17. Raban, M.; Haritos, D. P. J. Am. Chem. Soc. 1979, 101, 5178.
18. Smith, J. A. S.; Wilkins, E. J. J. Chem. Soc. (A) 1966, 1749.
19. Vogt, H. H.; Gompper, R. Chem. Ber. 1981, 114, 2884.
20. Marchand, C.; Zhang, X.; Pais, G. C. G.; Pathak, V. K.;
Pommier, Y.; Burke, T. R.; Svaroskaia, E. US Pat.
WO03049695, 2003; Chem. Abstr. 2003, 139, 36342.
21. Andreichikov, Y. S.; Maslivets, A. N.; Smirnova, L. I.;
Krasnykh, O. P.; Kozlov, A. P.; Perevozchikov, L. A. J. Org.
Chem. USSR (transl. version) 1987, 23, 1378.
9. Pais, G. C. G.; Burke, T. R., Jr. Drugs Future 2002, 27, 1101.
10. Williams, H. W. R.; Eichler, E.; Randall, W. C.; Rooney, C. S.;
Cragoe, E. J.; Streeter, K. B.; Schwam, H.; Michelson, S. R.;
Patchett, A. A.; Taub, D. J. Med. Chem. 1983, 26, 1196.
11. Kees, K. L.; Caggiano, T. J.; Steiner, K. E.; Fitzgerald, J. J.,
Jr.; Kates, M. J.; Christos, T. E.; Kulishoff, J. M., Jr.; Moore,
R. D.; McCaleb, M. L. J. Med. Chem. 1995, 38, 617.
12. Tanaka, A.; Terasawa, T.; Hagihara, H.; Sakuma, Y.; Ishibe,
22. Sof’ina, O. A.; Igidov, N. M.; Koz’minykh, E. N.; Trapezni-
kova, N. N.; Kasatkina, Y. S.; Koz’minykh, V. O. Russ. J. Org.
Chem. (Transl. version) 2001, 37, 1067.
23. Naito, Y.; Sugiura, M.; Yamaura, Y.; Fukaya, C.; Yokoyama,
K.; Nakagawa, Y.; Ikeda, T.; Senda, M.; Fujita, T. Chem.
Pharm. Bull. 1991, 39, 1736.