Conjugate addition of nitroalkanes to dimethyl maleate. Regioselective formation of both monoesters of 2-alkylsuccinic acids

Article abstract of DOI:10.1016/S0040-4020(03)01175-X

Diesters of (E)-2-alkylidenesuccinic acids obtained by conjugate addition of nitroalkanes to dimethyl maleate can be selectively monohydrolyzed at the more reactive carboxyl group to the corresponding half-ester. Alternatively, total hydrolysis to the dia

Full text of DOI:10.1016/S0040-4020(03)01175-X

Tetrahedron 59 (2003) 7283–7289
Conjugate addition of nitroalkanes to dimethyl maleate.
Regioselective formation of both monoesters
of 2-alkylsuccinic acids
*
Roberto Ballini, Giovanna Bosica, Alessandro Palmieri, Marino Petrini
and Claudio Pierantozzi
*
`
Dipartimento di Scienze Chimiche, Universita di Camerino, via S. Agostino, 1. I-62032 Camerino, Italy
Received 28 April 2003; revised 3 July 2003; accepted 25 July 2003
Abstract—Diesters of (E)-2-alkylidenesuccinic acids obtained by conjugate addition of nitroalkanes to dimethyl maleate can be selectively
monohydrolyzed at the more reactive carboxyl group to the corresponding half-ester. Alternatively, total hydrolysis to the diacid allows a
subsequent selective methyl esterification of the alkanoic carboxyl group to give the other regioisomeric half-ester. 2-Alkylsuccinic
monoesters can be finally obtained by catalytic hydrogenation of the unsaturated derivatives.
q 2003 Published by Elsevier Ltd.
1. Introduction
the corresponding monoesters only by means of a
regioselective hydrolysis that is particularly difficult to
carry out by conventional methods because of the close
reactivity of the two ester functions. This problem can
be partially worked out by enzymatic hydrolysis that
however, is particularly suitable for the resolution of
racemic mixtures since only one stereoisomer is actually
hydrolyzed.8
Monoesters of 2-substituted succinic acids are involved in a
large number of synthetic processes leading to the
preparation of biologically active substances.1 Deprotona-
tion at the a position of succinic acid esters provides the
corresponding carbanions that are associated to the classical
Stobbe condensation with aromatic aldehydes.2 This
condensation leads to the synthesis of 2-arylidenesuccinic
acid monoesters but it works efficiently only with non-
enolisable aldehydes. A Stobbe-like procedure using less
basic phosphonate carbanions of t-butyl/ethyl succinates
greatly improves the process effectiveness especially in the
reaction with aliphatic aldehydes.3 The obtained adducts
can be regioselectively hydrolyzed since t-butyl esters are
easily cleaved in acidic conditions.4 t-Butyl monoesters of
succinic acids can also be transformed into the correspond-
ing dianions with LDA and directly alkylated at low
temperature giving 2-alkyl derivatives.5 A complementary
approach concerns a conjugate addition of nucleophilic
reagents to ester derivatives of maleic acid 1 (Scheme 1).6
In this paper, a new synthetic approach to the regioselective
preparation of monoesters of 2-alkylsuccinic acids is
presented. Our procedure is based on the lesser reactivity
displayed by 2-alkenoic esters compared to their saturated
homologs toward hydrolysis.
2. Results and discussion
Some years ago, we reported that methyl maleate 3 reacts
with nitroalkanes 4 in the presence of DBU to give Michael
adducts 5 that suffer elimination of nitrous acid affording
unsaturated derivatives 6 as single E stereoisomers in good
yield (Scheme 2).9
The presence of two ester groups linked to each side of the
double bond increases the reactivity toward conjugate
addition but inevitably dictates the utilization of symmetric
maleic esters in order to avoid regiochemical problems.7 2-
Alkylsuccinates 2 obtained in this way can be converted into
Keywords: addition reactions; esters; hydrolysis; nitro compounds;
reduction.
*
Corresponding authors. Tel.: þ39-737-402270/402253; fax: þ39-737-
402297; e-mail: roberto.ballini@unicam.it; marino.petrini@unicam.it
Scheme 1.
0040–4020/$ - see front matter q 2003 Published by Elsevier Ltd.
doi:10.1016/S0040-4020(03)01175-X

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R. Ballini et al. / Tetrahedron 59 (2003) 7283–7289
a,b-unsaturated ester. This goal is usually attained through
a regioselective esterification of the corresponding cyclic
anhydrides that privileges the formation of the ester at the
more reactive alkanoic side of the molecule.12 A similar
selective esterification can be also conducted on the
corresponding diacid 8 that is obtained by total hydrolysis
of diester 6 using 0.5N NaOH in EtOH/water at reflux
(Scheme 4).13
Scheme 2.
This reactivity is peculiar of enedione systems and has been
exploited for the synthesis of important intermediates.10 The
ester groups in compounds 6 are well differentiated since
one of them is part of an a,b-unsaturated moiety while the
other can be considered as a simple alkanoic ester. It is
conceivable that using carefully controlled conditions the
alkanoic ester group would be hydrolyzed faster than the
less reactive unsaturated ester. According to the procedure
of Niwayama11 diesters 6 have been selectively mono-
hydrolyzed using 0.25N NaOH in THF–water (1:10) at 08C
(Scheme 3, Table 1).
Scheme 4.
Crude diacid 8 is regioselectively monomethylated at
the alkanoic group using the acidic macroreticular
resin Amberlyst 15 in methanol at reflux (Scheme 4,
Table 2).14
Table 2. Regioselective methyl esterification of diacid 8 obtained from
complete hydrolysis of diester 6
Entry
Diester 6
Diacid 8
(yield %)a
Monoester 9
Time
(h)
Yieldb
(%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
8a (95)
8b (92)
8c (98)
8d (90)
8e (95)
8f (89)
8g (91)
8h (97)
8i (90)
8j (96)
9a
9b
9c
9d
9e
9f
9g
9h
9i
15
7
7
16
4
16
17
15
6.5
7.5
82
80
86
85
78
76
71
75
86
84
Scheme 3.
Table 1. Regioselective hydrolysis of diester 6
Entry
Diester 6
Mono ester 7 Time (h) Yielda (%)
9
10
R
R1
6j
9j
a
Yields of crude diacid, after complete hydrolysis.
Overall yields of pure, isolated products from diester 6.
1
2
3
4
5
6
7
8
9
10
6a CH3(CH2)3
6b –(CH2)5–
6c CH3CH2
6d CH3(CH2)4
6e CH3
6f HO(CH2)4CH2
6g CH3OCCH2CH2
6h (CH3)2CH
6i (CH3)2CHCH2
6j –(CH2)4–
H
7a
7b
7c
7d
16
7.5
7.5
17
7
6
5
5
6.5
7
68
85
95
63
80
74
73
68
76
80
b
H
H
Monoesters 7,9 are obtained together with a slight amount
of diesters 6 (5–6%) from which can be easily separated by
column chromatography. Compounds 7,9 can be finally
reduced to 2-alkylsuccinic monoesters 10,11 by a classical
catalytic hydrogenation in the presence of Pd/C (Scheme 5,
Table 3).13
CH3 7e
H
H
H
H
7f
7g
7h
7i
7j
a
Yields of pure, isolated products.
Temperature control is mandatory for the regioselectivity of
the process since at room temperature variable amounts of
the corresponding diacid are also formed. However, when
the hydrolysis is carried out at 08C, a good regioselectivity is
usually observed since the yield of diacid derivatives never
exceeds 4–5%.The major propensity of the alkanoic portion
of diester 6 to undergo a selective hydrolysis makes rather
troublesome the reverse process, i.e. monohydrolysis of the
Scheme 5.

R. Ballini et al. / Tetrahedron 59 (2003) 7283–7289
7285
Table 3. Reduction of unsaturated monoesters 7,9
and then was acidified with 1N HCl. The aqueous solution
was extracted with ethyl acetate (5£30 mL), washed with
brine and dried over MgSO4. After filtration and evapor-
ation of the solvent, crude monoester 7 was purified by
column chromatography (1:9 methanol–chloroform)
Entry
Alkenyl monoester 7,9
Alkyl monoester 10,11
Yielda (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
10a
10b
10c
10d
10e
10f
10g
10h
10i
95
93
96
97
94
97
93
98
91
95
89
98
97
99
96
94
94
96
96
97
4.2.1. (E)-3-(Methoxycarbonyl)oct-3-enoic acid, 7a.
Yield 68%; clear oil; IR (cm21, neat) 1654, 1717, 3250;
1H NMR d (ppm) 0.93 (t, 3H, J¼6.9 Hz), 1.27–1.50 (m,
4H), 2.17–2.31 (m, 2H), 3.41 (s, 2H), 3.78 (s, 3H), 7.01 (t,
1H, J¼7.7 Hz). 13C NMR d (ppm) 13.8, 22.4, 28.7, 30.5,
32.2, 52.1, 124.7, 146.7, 167.6, 176.2. Anal. calcd for
C10H16O4 (200.23) C, 59.99; H, 8.05. Found C, 60.05; H,
8.09.
9
10
11
12
13
14
15
16
17
18
19
20
7j
10j
11a
11b
11c
11d
11e
11f
11g
11h
11i
9a
9b
9c
9d
9e
9f
9g
9h
9i
4.2.2. 3-Cyclohexylidene-4-methoxy-4-oxobutanoic acid,
7b. Yield 85%; waxy solid; IR (cm21, neat) 1633, 1713,
1
1748, 3300; H NMR d (ppm) 1.60–1.72 (m, 6H), 2.23–
2.30 (m, 2H), 2.62–2.70 (m, 2H), 3.44 (s, 2H), 3.77 (s, 3H).
13C NMR d (ppm) 26.3, 27.9, 28.2, 32.5, 32.6, 34.9, 51.7,
116.7, 156.4, 169.2, 176.9. Anal. calcd for C11H16O4
(212.24) C, 62.25; H, 7.60. Found C, 62.21; H, 7.63.
9j
11j
a
Yields of pure, isolated products.
3. Conclusions
4.2.3. (E)-3-(Methoxycarbonyl)hex-3-enoic acid, 7c.
Yield 95%; waxy solid; IR (cm21, neat) 1648, 1654,
1718, 3280; 1H NMR d (ppm) 1.06 (t, 3H, J¼7.5 Hz), 2.14–
2.28 (m, 2H), 3.34 (s, 2H), 3.74 (s, 3H), 7.11 (t, 1H,
J¼7.5 Hz). 13C NMR d (ppm) 12.9, 22.3, 32.1, 51.9, 125.0,
147.3, 167.7, 173.4. Anal. calcd for C8H12O4 (172.18) C,
55.81; H, 7.02. Found C, 55.86; H, 7.03.
In summary, diesters of (E)-2-alkylidenesuccinic acids 6
can be selectively transformed into both regioisomeric
monoesters 7,9 by operationally simple and straightforward
procedures. Monohydrolysis of the more reactive alkanoic
ester function in 6 provides the corresponding half-ester 7.
Regioisomeric half-ester 9 is obtained from diester 6 by a
total hydrolysis to diacid 8 followed by a selective
esterification of the alkanoic acid portion of the molecule.
Catalytic hydrogenation of the double bond in compounds
7,9 gives the corresponding 2-alkylsuccinic monoesters
10,11 in good overall yields.
4.2.4. (E)-3-(Methoxycarbonyl)non-3-enoic acid, 7d.
Yield 63%; yellow oil; IR (cm21, neat) 1654, 1718, 3350;
1H NMR d (ppm) 0.90 (t, 3H, J¼6.8 Hz), 1.26–1.38 (m,
4H), 1.40–1.56 (m, 2H), 2.17–2.31 (m, 2H), 3.42 (s, 2H),
3.77 (s, 3H), 7.00 (t, 1H, J¼7.7 Hz). 13C NMR d (ppm) 13.9,
22.4, 28.1, 28.9, 31.4, 32.2, 52.1, 124.6, 146.8, 167.7, 175.4.
Anal. calcd for C11H18O4 (214.26) C, 61.66; H, 8.47. Found
C, 61.70; H, 8.44.
4. Experimental
4.1. General
4.2.5. (E)-3-(Methoxycarbonyl)-4-methylpent-3-enoic
acid, 7e.15 Yield 80%; white solid, mp 588C; IR (cm21
,
1H NMR were recorded at 300 MHz on a Varian VXR300 in
CDCl3 as solvent. 13C NMR were recorded at 75 MHz in
CDCl3 as solvent. Microanalyses were performed with a
CHNS-O analyzer Model EA 1108 from Fisons Instru-
ments. IR spectra were recorded with a Perkin–Elmer
Paragon 500 FT-IR. GLC analyses were performed on a
Hewlett–Packard 5890 equipped with a capillary column of
fused silica (0.32 mm£25 m), stationary phase SE54. Mass
spectra were performed on a Hewlett–Packard GC/MS
5970 by means of the EI technique (70 eV). THF was dried
by refluxing it over sodium wire then distilled. All
chemicals used are available commercially. Diesters 6 as
pure E stereoisomers were prepared as previously
described.9,10
KBr) 1633, 1715, 3300; 1H NMR d (ppm) 1.91 (s, 3H), 2.17
(s, 3H), 3.43 (s, 2H), 3.76 (s, 3H). 13C NMR d (ppm) 23.3,
23.4, 35.3, 51.7, 119.7, 144.7, 170.0, 175.6. Anal. calcd for
C8H12O4 (172.18) C, 55.81; H, 7.02. Found C, 55.77; H,
6.99.
4.2.6. (E)-9-Hydroxy-3-(methoxycarbonyl)non-3-enoic
acid, 7f. Yield 74%; yellow oil; IR (cm21, neat) 1651,
1
1714, 3400; H NMR d (ppm) 1.28–1.60 (m, 6H), 2.17–
2.31 (m, 2H), 3.37 (s, 2H), 3.61 (t, 2H, J¼6.4 Hz), 3.74 (s,
3H), 5.90 (br s, 2H), 6.97 (t, 1H, J¼7.7 Hz). 13C NMR d
(ppm) 25.4, 28.2, 28.9, 32.2, 32.3, 52.2, 62.6, 125.3, 146.5,
167.8, 175.5. Anal. calcd for C11H18O5 (230.26) C, 57.38;
H, 7.88. Found C, 57.41; H, 7.85.
4.2. General procedure for the preparation of
mono-esters 7
4.2.7. (E)-3-(Methoxycarbonyl)-7-oxooct-3-enoic acid,
7g. Yield 73%; yellow oil; IR (cm21, neat) 1648, 1654,
1718, 3350; H NMR d (ppm) 2.17 (s, 3H), 2.40–2.53 (m,
2H), 2.60–2.71 (m, 2H), 3.46 (s, 2H), 3.76 (s, 3H), 6.90 (t,
1H, J¼7.5 Hz). 13C NMR d (ppm) 17.7, 24.7, 26.9, 36.4,
46.9, 120.5, 139.1, 162.0, 165.8, 201.7. Anal. calcd for
1
Sodium hydroxide 0.25N (32 mL) was added dropwise at
08C to a solution of diester 6 (5 mmol) dissolved in THF–
H2O (1:10, 90 mL). The mixture was stirred at 08C until
TLC indicates that no starting material remains, (Table 1)

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R. Ballini et al. / Tetrahedron 59 (2003) 7283–7289
C10H14O5 (214.22) C, 56.07; H, 6.59. Found C, 56.02; H,
6.63.
13C NMR d (ppm) 26.3, 28.1, 28.4, 32.6, 33.2, 34.6, 52.1,
116.7, 159.1, 172.2, 173.0. Anal. calcd for C11H16O4
(212.24) C, 62.25; H, 7.60. Found C, 62.29; H, 7.57.
4.2.8. (E)-3-(Methoxycarbonyl)-5-methylhex-3-enoic
acid, 7h. Yield 68%; white solid, mp 758C; IR (cm21
,
4.3.3. (E)-2-(2-Methoxy-2-oxoethyl)pent-2-enoic acid, 9c.
Yield 86%; white solid, mp 688C; IR (cm21, KBr) 1644,
1693, 1727, 3285; 1H NMR d (ppm) 1.10 (t, 3H, J¼7.5 Hz),
2.19–2.32 (m, 2H), 3.37 (s, 2H), 3.70 (s, 3H), 7.12 (t, 1H,
J¼7.5 Hz). 13C NMR d (ppm) 13.0, 22.7, 31.9, 52.3, 124.5,
150.2, 171.4, 172.3. Anal. calcd for C8H12O4 (172.18) C,
55.81; H, 7.02. Found C, 55.80; H, 7.05.
KBr) 1708, 3250; 1H NMR d (ppm) 1.03 (d, 6H, J¼6.6 Hz),
2.54–2.66 (m, 1H), 3.33 (s, 2H), 3.73 (s, 3H), 6.78 (d, 1H,
J¼10.0 Hz). 13C NMR d (ppm) 21.9, 28.4, 32.2, 51.9, 123.3,
152.0, 168.2, 173.3. Anal. calcd for C9H14O4 (186.21) C,
58.05; H, 7.58. Found C, 58.09; H, 7.61.
4.2.9. (E)-3-(Methoxycarbonyl)-6-methylhept-3-enoic
acid, 7i.16 Yield 76%; clear oil; IR (cm21, neat) 1645,
1690, 1747, 3300; 1H NMR d (ppm) 0.96 (d, 6H, J¼6.6 Hz),
1.71–1.91 (m, 1H), 2.12 (t, 2H, J¼7.4 Hz), 3.41 (s, 2H),
3.79 (s, 3H), 7.03 (t, 1H, J¼7.4 Hz). 13C NMR d (ppm) 22.4,
28.2, 32.3, 38.0, 52.1, 125.3, 145.6, 167.6, 175.9. Anal.
calcd for C10H16O4 (200.23) C, 59.99; H, 7.58. Found C,
59.95; H, 7.62.
4.3.4. (E)-2-(2-Methoxy-2-oxoethyl)oct-2-enoic acid, 9d.
Yield 85%; white solid, mp 508C; IR (cm21, KBr) 1732,
1749, 3300; 1H NMR d (ppm) 0.91 (t, 3H, J¼6.6 Hz), 1.24–
1.39 (m, 4H), 1.41–1.57 (m, 2H), 2.18–2.33 (m, 2H), 3.36
(s, 2H), 3.70 (s, 3H), 7.12 (t, 1H, J¼7.6 Hz). 13C NMR d
(ppm) 13.9, 22.4, 28.0, 29.1, 31.5, 31.8, 52.1, 124.7, 148.8,
171.1, 172.0. Anal. calcd for C11H18O4 (214.26) C, 61.66;
H, 8.47. Found C, 61.71; H, 8.45.
4.2.10. 3-Cyclopentylidene-4-methoxy-4-oxobutanoic
acid, 7j. Yield 80%; white solid, mp 1078C; IR (cm21
,
4.3.5. (E)-2-(2-Methoxy-2-oxoethyl)-3-methyl but-2-
enoic acid, 9e.12b Yield 78%; white solid, mp 978C; IR
(cm21, KBr) 1659, 1694, 1747, 3300; 1H NMR d (ppm) 1.92
(s, 3H), 2.24 (s, 3H), 3.42 (s, 2H), 3.70 (s, 3H), 10.74 (br s,
1H). 13C NMR d (ppm) 23.7, 24.1, 35.0, 52.0, 119.8, 153.9,
171.9, 173.2. Anal. calcd for C8H12O4 (172.18) C, 55.81; H,
7.02. Found C, 55.83; H, 7.06.
1
KBr) 1693, 1710, 3250; H NMR d (ppm) 1.61–1.79 (m,
4H), 2.40 (t, 2H, J¼6.4 Hz), 2.79 (t, 2H, J¼6.4 Hz), 3.36 (s,
2H), 3.72 (s, 3H), 10.53 (bs, 1H). 13C NMR d (ppm) 25.7,
27.2, 34.5, 34.8, 36.2, 51.8, 116.3, 166.2, 167.9, 177.7.
Anal. calcd for C10H14O4 (198.21) C, 60.59; H, 7.12. Found
C, 60.64; H, 7.09.
4.3. General procedure for the preparation of
mono-esters 9
4.3.6. (E)-8-Hydroxy-2-(2-methoxy-2-oxoethyl)oct-2-
enoic acid, 9f. Yield 76%; white solid, mp 718C; IR
1
(cm21, KBr) 1643, 1681, 1731, 3380 H NMR d (ppm)
Diester 6 (2.6 mmol) was dissolved in EtOH (10 mL) and
0.5N NaOH (50 mL) was added at room temperature. The
solution was refluxed for 6 h then concentrated to 1/3 of the
volume. Water (100 mL) was added and the solution was
washed with EtOAc (3£10 mL). The aqueous phase was
acidified to pH 1 with 2N HCl, extracted with EtOAc
(5£20 mL), washed with brine (20 mL) and dried over
MgSO4. After filtration and evaporation of the solvent at
reduced pressure diacid 8 was obtained enough pure to be
used in the next step. To a solution of diacid 8 (2.0 mmol) in
MeOH (10 mL), Amberlyst 15 (0.35 g) was added at room
temperature and the obtained suspension was refluxed for
the appropriate time (Table 2). After cooling at room
temperature the resin was filtered off and washed with
methanol, the solvent was then evaporated to give product 9
which was purified by column chromatography (1:9
methanol–chloroform).
1.30–1.63 (m, 6H), 2.18–2.33 (m, 2H), 3.35 (s, 2H), 3.64 (t,
2H, J¼6.3 Hz), 3.69 (s, 3H), 5.48 (br s, 2H), 7.09 (t, 1H,
J¼7.7 Hz). 13C NMR d (ppm) 25.4, 28.1, 29.0, 31.8, 32.2,
52.1, 62.4, 125.0, 147.9, 170.9, 171.4. Anal. calcd for
C11H18O5 (230.26)C, 57.38;H, 7.88. FoundC, 57.43; H, 7.85.
4.3.7. (E)-2-(2-Methoxy-2-oxoethyl)-6-oxohept-2-enoic
acid, 9g. Yield 71%; yellow oil; IR (cm21, neat) 1715,
1
3380; H NMR d (ppm) 2.20 (s, 3H), 2.41–2.53 (m, 2H),
2.62–2.71 (m, 2H), 3.42 (s, 2H), 3.71 (s, 3H), 7.03 (t, 1H,
J¼7.5 Hz). 13C NMR d (ppm) 23.3, 30.1, 31.9, 41.8, 52.3,
125.9, 146.6, 171.3, 172.6, 207.0. Anal. calcd for C10H14O5
(214.22) C, 56.07; H, 6.59. Found C, 56.01; H, 6.63.
4.3.8. (E)-2-(2-Methoxy-2-oxoethyl)-3-methylbut-2-
enoic acid, 9h.17 Yield 75%; white solid, mp:618C; IR
(cm21, KBr) 1643, 1697, 1732, 3250; 1H NMR d (ppm) 1.06
(d, 6H, J¼6.6 Hz), 2.57–2.70 (m, 1H), 3.37 (s, 2H), 3.70 (s,
3H), 6.90 (d, 1H, J¼9.9 Hz). 13C NMR d (ppm) 22.0, 28.9,
32.1, 52.3, 122.8, 154.7, 171.5, 172.2. Anal. calcd for
C9H14O4 (186.21) C, 58.05; H, 7.58. Found C, 58.01; H,
7.63.
4.3.1. (E)-2-(2-Methoxy-2-oxoethyl)hept-2-enoic acid,
9a. Yield 82%; white solid, mp 488C; IR (cm21, KBr)
1
1644, 1694, 1749, 3300; H NMR d (ppm) 0.93 (t, 3H,
J¼6.9 Hz), 1.20–1.60 (m, 4H), 2.16–2.30 (m, 2H), 3.37 (s,
2H), 3.70 (s, 3H), 7.13 (t, 1H, J¼7.6 Hz). 13C NMR d (ppm)
13.8, 22.4, 28.9, 30.4, 31.8, 52.0, 124.7, 148.8, 171.2, 172.0.
Anal. calcd for C10H16O4 (200.23) C, 59.99; H, 8.05. Found
C, 59.95; H, 8.01.
4.3.9. (E)-2-(2-Methoxy-2-oxoethyl)-4-methyl pent-2-
enoic acid, 9i.16 Yield 86%; waxy solid; IR (cm21, neat)
1
1644, 1687, 1742, 3320; H NMR d (ppm) 0.96 (d, 6H,
J¼6.6 Hz), 1.70–1.90 (m, 1H), 2.13 (t, 2H, J¼7.4 Hz), 3.39
(s, 2H), 3.70 (s, 3H), 7.15 (t, 1H, J¼7.4 Hz), 8.17 (bs, 1H).
13C NMR d (ppm) 22.4, 28.2, 31.9, 38.1, 52.1, 125.4, 147.7,
171.2, 172.2. Anal. calcd for C10H16O4 (200.23) C, 59.99;
H, 7.58. Found C, 60.05; H, 7.60.
4.3.2. 2-Cyclohexylidene-4-methoxy-4-oxobutanoic acid,
9b. Yield 80%; waxy solid; IR (cm21, neat) 1654, 1687,
1740, 3280; H NMR d (ppm) 1.54–1.70 (m, 6H), 2.21–
2.29 (m, 2H), 2.71–2.78 (m, 2H), 3.40 (s, 2H), 3.67 (s, 3H).
1

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7287
4.3.10. 2-Cyclopentylidene-4-methoxy-4-oxobutanoic
acid, 9j. Yield 84%; white solid, mp 1038C; IR (cm21
4.4.6. (E)-9-Hydroxy-3-(methoxycarbonyl)nonanoic
acid, 10f. Yield 97%; yellow oil; IR (cm21, neat) 1735,
3400; 1H NMR d (ppm) 1.20–1.40 (m, 6H), 1.41–1.69 (m,
4H), 2.40 (dd, 1H, J¼15.4, 4.4 Hz), 2.63–2.85 (m, 2H),
3.54 (t, 2H, J¼6.6 Hz), 3.64 (s, 3H), 6.21 (bs, 2H). 13C
NMR d (ppm) 25.5, 26.9, 29.2, 31.7, 32.5, 36.2, 41.1, 51.9,
62.6, 175.2, 175.8. Anal. calcd for C11H20O5 (232.27) C,
56.88; H, 8.68. Found C, 56.83; H, 8.70.
,
KBr) 1690, 1711, 1738, 3250; 1H NMR d (ppm) 1.62–1.83
(m, 4H), 2.42 (t, 2H, J¼6.2 Hz), 2.85 (t, 2H, J¼6.2 Hz),
3.34 (s, 2H), 3.68 (s, 3H), 11.81 (s, 1H). 13C NMR d (ppm)
25.6, 27.1, 34.9, 35.1, 35.8, 52.1, 116.6, 168.9, 172.1, 173.0.
Anal. calcd for C10H14O4 (198.21) C, 60.59; H, 7.12. Found
C, 60.55; H, 7.10.
4.4. General procedure for catalytic hydrogenation of
monoesters 7,9
4.4.7. (E)-3-(Methoxycarbonyl)-7-oxooctanoic acid, 10g.
Yield 93%; clear oil; IR (cm21, neat) 1710, 1735, 3320; 1H
NMR d (ppm) 1.42–1.78 (m, 4H), 2.12 (s, 3H), 2.41–2.54
(m, 3H), 2.73–2.84 (m, 2H), 3.68 (s, 3H), 9.25 (bs, 1H). 13C
NMR d (ppm) 21.1, 30.1, 31.2, 35.8, 40.8, 43.2, 52.2, 175.2,
177.6, 208.8. Anal. calcd for C10H16O5 (216.23) C, 55.55;
H, 7.46. Found C, 55.50; H, 7.49.
Monoester 7,9 (2 mmol) was dissolved in EtOAc (20 mL)
and 10% Pd/C (0.1 g) was added. The suspension was
hydrogenated (3 atm) at room temperature for 16 h. The
catalyst was removed by filtration through celite pad and
washed with EtOAc (3£5 mL). After evaporation of the
solvent the crude product 10,11 was purified by flash
chromatography (5:95 methanol–chloroform).
4.4.8. (E)-3-(Methoxycarbonyl)-5-methylhexanoic acid,
10h. Yield 98%; clear oil; IR (cm21, neat) 1712, 1740,
3280; 1H NMR d (ppm) 0.86–0.94 (m, 6H), 1.22–1.37 (m,
1H), 1.48–1.67 (m, 2H), 2.43 (dd, 1H, J¼16.8, 4.9 Hz),
2.62–2.79 (m, 1H), 2.82–2.98 (m, 1H), 3.67 (s, 3H), 11.17
(br s, 1H). 13C NMR d (ppm) 22.4, 22.7, 25.9, 36.2, 39.4,
41.3, 52.1, 176.0, 178.2. Anal. calcd for C9H16O4 (188.22)
C, 57.43; H, 8.57. Found C, 57.38; H, 8.61.
4.4.1. (E)-3-(Methoxycarbonyl)octanoic acid, 10a. Yield
1
95%; yellow oil; IR (cm21, neat) 1709, 1733, 3300; H
NMR d (ppm) 0.87 (t, 3H, J¼7.0 Hz), 1.21–1.38 (m, 6H),
1.40–1.63 (m, 2H), 2.43–2.50 (m, 1H), 2.69–2.85 (m, 2H),
3.69 (s, 3H), 11.21 (bs, 1H). 13C NMR d (ppm) 14.1, 22.6,
26.7, 31.7, 32.0, 35.9, 41.0, 52.1, 175.6, 178.4. Anal. calcd
for C10H18O4 (202.25) C, 59.39; H, 8.97. Found C, 59.34; H,
9.01.
4.4.9. (E)-3-(Methoxycarbonyl)-6-methylheptanoic acid,
10i. Yield 91%; clear oil; IR (cm21, neat) 1712, 1739, 3308;
1H NMR d (ppm) 0.84 (d, 6H, J¼6.6 Hz), 1.08–1.34 (m,
2H), 1.40–1.78 (m, 3H), 2.38–2.58 (m, 1H), 2.62–2.91 (m,
2H), 3.68 (s, 3H), 11.03 (bs, 1H). 13C NMR d (ppm) 22.6,
28.1, 29.9, 35.9, 36.1, 41.2, 52.1, 175.7, 178.3. Anal. calcd
for C10H18O4 (202.25) C, 59.39; H, 8.97. Found C, 59.37; H,
9.00.
4.4.2. 3-Cyclohexyl-4-methoxy-4-oxobutanoic acid, 10b.
Yield 93%; clear oil; IR (cm21, neat) 1761, 1790, 3300; 1H
NMR d (ppm) 0.98–1.36 (m, 5H), 1.54–1.82 (m, 6H),
2.38–2.60 (m, 1H), 2.63–2.83 (m, 2H), 3.71 (s, 3H). 13C
NMR d (ppm) 25.8, 26.1, 29.9, 30.3, 32.8, 39.6, 46.5, 51.4,
174.7, 177.2. Anal. calcd for C11H18O4 (214.26) C, 61.66;
H, 8.47. Found C, 61.61; H, 8.51.
4.4.10. 3-Cyclopentyl-4-methoxy-4-oxobutanoic acid,
10j. Yield 95%; yellow oil; IR (cm21, neat) 1711, 1734,
3270; 1H NMR d (ppm) 1.10–1.30 (m, 2H), 1.41–1.85 (m,
6H), 1.88–2.05 (m, 1H), 2.38–2.60 (m, 1H), 2.61–2.83 (m,
2H), 3.71 (s, 3H), 10.1 (bs, 1H). 13C NMR d (ppm) 25.0,
25.1, 30.6, 30.7, 35.6, 42.5, 46.1, 51.9, 175.6, 178.2. Anal.
calcd for C10H16O4 (200.23) C, 59.99; H, 7.58. Found C,
59.94; H, 7.60.
4.4.3. (E)-3-(Methoxycarbonyl)hexanoic acid, 10c. Yield
1
96%; yellow oil; IR (cm21, neat) 1707, 1742, 3290; H
NMR d (ppm) 0.89 (t, 3H, J¼7.0 Hz), 1.24–1.42 (m, 2H),
1.44–1.67 (m, 2H), 2.44 (dd, 1H, J¼16.1, 4.3 Hz), 2.68–
2.86 (m, 2H), 3.68 (s, 3H), 10.57 (bs, 1H). 13C NMR d
(ppm) 14.0, 20.3, 34.2, 35.9, 40.9, 52.1, 175.7, 178.2. Anal.
calcd for C8H14O4 (174.19) C, 55.16; H, 8.10. Found C,
55.18; H, 8.07.
4.4.11. (E)-2-(2-Methoxy-2-oxoethyl)heptanoic acid, 11a.
Yield 89%; yellow oil; IR (cm21, neat) 1701, 1742, 3300;
1H NMR d (ppm) 0.89 (t, 3H, J¼7.1 Hz), 1.20–1.67 (m,
8H), 2.44 (dd, 1H, J¼16.6, 5.1 Hz), 2.66–2.85 (m, 2H),
3.67 (s, 3H), 10.62 (bs, 1H). 13C NMR d (ppm) 14.2, 22.6,
26.7, 30.6, 31.7, 35.6, 41.3, 52.1, 172.6, 181.4. Anal. calcd
for C10H18O4 (202.25) C, 59.39; H, 8.97. Found C, 59.44; H,
8.93.
4.4.4. (E)-3-(Methoxycarbonyl)nonanoic acid, 10d. Yield
97%; clear oil; IR (cm21, neat) 1712, 1741, 3300; 1H NMR
d (ppm) 0.89 (t, 3H, J¼6.6 Hz), 1.24–1.38 (m, 8H), 1.48–
1.72 (m, 2H), 2.49 (dd, 1H, J¼15.4, 1.8 Hz), 2.78–2.92 (m,
2H), 3.72 (s, 3H). 13C NMR d (ppm) 14.0, 22.5, 26.8, 29.0,
31.6, 31.9, 35.5, 40.9, 51.9, 175.4, 176.7. Anal. calcd for
C11H20O4 (216.27) C, 61.09; H, 9.32. Found C, 61.015; H,
9.28.
4.4.12. 2-Cyclohexyl-4-methoxy-4-oxobutanoic acid,
11b. Yield 98%; yellow oil; IR (cm21, neat) 1705, 1756,
3270; 1H NMR d (ppm) 1.01–1.35 (m, 5H), 1.60–1.84 (m,
6H), 2.42–2.58 (m, 1H), 2.70–2.83 (m, 2H), 3.69 (s, 3H).
13C NMR d (ppm) 26.3, 26.5, 30.0, 30.8, 33.0, 39.9, 46.9,
52.0, 173.2, 178.9.0. Anal. calcd for C11H18O4 (214.26) C,
61.66; H, 8.47. Found C, 61.72; H, 8.50.
4.4.5. (E)-3-(Methoxycarbonyl)-4-methylpentanoic acid,
10e. Yield 94%; yellow oil; IR (cm21, neat) 1710, 1736,
3300; 1H NMR d (ppm) 0.94 (d, 3H, J¼6.7 Hz), 0.97 (d, 3H,
J¼6.7 Hz), 1.92–2.10 (m, 1H), 2.50 (dd, 1H, J¼15.7,
2.9 Hz), 2.64–2.81 (m, 2H), 3.65 (s, 3H), 10.61 (bs, 1H).
13C NMR d (ppm) 19.7, 20.2, 30.3, 32.9, 47.4, 51.9, 175.0,
178.0. Anal. calcd for C8H14O4 (174.19) C, 55.16; H, 8.10.
Found C, 55.22; H, 8.13.
4.4.13. (E)-2-(2-Methoxy-2-oxoethyl)-3-methylbutanoic
acid, 11c. Yield 97%; yellow oil; IR (cm21, neat) 1705,

7288
R. Ballini et al. / Tetrahedron 59 (2003) 7283–7289
1746, 3290; 1H NMR d (ppm) 0.90 (t, 3H, J¼7.0 Hz), 1.30–
1.42 (m, 2H), 1.45–1.69 (m, 2H), 2.42 (dd, 1H, J¼16.6,
5.0 Hz), 2.66–2.91 (m, 2H), 3.67 (s, 3H). 13C NMR d (ppm)
13.8, 20.0, 33.8, 35.4, 40.8, 51.8, 172.4, 180.6. Anal. calcd
for C8H14O4 (174.19) C, 55.16; H, 8.10. Found C, 55.20; H,
8.06.
3280; 1H NMR d (ppm) 1.10–1.39 (m, 2H), 1.41–1.90 (m,
6H), 1.93–2.05 (m, 1H), 2.35–2.53 (m, 1H), 2.63–2.78 (m,
2H), 3.64 (s, 3H), 10.72 (bs, 1H). 13C NMR d (ppm) 25.1,
25.2, 30.6, 30.7, 35.3, 42.3, 46.3, 52.0, 172.9, 180.3. Anal.
calcd for C10H16O4 (200.23) C, 59.99; H, 7.58. Found C,
59.94; H, 7.60.
4.4.14. (E)-2-(2-Methoxy-2-oxoethyl)octanoic acid, 11d.
Yield 99%; yellow oil; IR (cm21, neat) 1740, 1763, 3300;
1H NMR d (ppm) 0.89 (t, 3H, J¼6.6 Hz), 1.22–1.42 (m,
8H), 1.50–1.75 (m, 2H), 2.46 (dd, 1H, J¼16.3, 5.0 Hz),
2.53–2.98 (m, 2H), 3.70 (s, 3H). 13C NMR d (ppm) 17.2,
22.7, 27.0, 29.2, 31.8, 31.9, 35.6, 41.2, 52.0, 172.6, 180.6.
Anal. calcd for C11H20O4 (216.27) C, 61.09; H, 9.32. Found
C, 61.13; H, 9.33.
Acknowledgements
Financial support from University of Camerino and MIUR
`
`
(National Project ‘Sintesi e Reattivita-attivita di Sistemi
Insaturi Funzionalizzati’) is gratefully acknowledged.
4.4.15. (E)-2-(2-Methoxy-2-oxoethyl)-3-methylbutanoic
acid, 11e.12b Yield 96%; clear oil; IR (cm21, neat) 1709,
1740, 3300; 1H NMR d (ppm) 0.94 (d, 3H, J¼7.0 Hz), 0.96
(d, 3H, J¼7.0 Hz), 1.92–2.10 (m, 1H), 2.42–2.58 (m, 1H),
2.70–2.90 (m, 2H), 3.71 (s, 3H). 13C NMR d (ppm) 19.5,
20.3, 30.1, 32.5, 47.4, 52.1, 173.2, 180.6. Anal. calcd for
C8H14O4 (174.19) C, 55.16; H, 8.10. Found C, 55.11; H,
8.07.
References
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3307; 1H NMR d (ppm) 1.11–1.20 (m, 6H), 1.22–1.78 (m,
4H), 2.43 (dd, 1H, J¼16.3, 5.0 Hz), 2.63–2.95 (m, 2H),
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1
1736, 3300; H NMR d (ppm) 1.45–1.77 (m, 4H), 2.13 (s,
3H), 2.38–2.57 (m, 3H), 2.61–2.91 (m, 2H), 3.67 (s, 3H),
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1741, 3300; H NMR d (ppm) 0.85–0.99 (m, 6H), 1.21–
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4.9 Hz), 2.61–2.72 (m, 1H), 2.83–2.97 (m, 1H), 3.64 (s,
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3320; 1H NMR d (ppm) 0.86 (d, 6H, J¼6.6 Hz), 1.14–1.28
(m, 2H), 1.41–1.80 (m, 3H), 2.42 (dd, 1H, J¼15.9, 4.6 Hz),
2.62–2.91 (m, 2H), 3.66 (s, 3H), 7.72 (bs, 1H). 13C NMR d
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R. Ballini et al. / Tetrahedron 59 (2003) 7283–7289
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