A new synthetic method to 2-pyridones

Article abstract of DOI:10.1055/s-2000-6254

We report here a simple procedure for the preparation of 4,6- disubstituted- and 3,4,6-trisubstituted-2-pyridones and 3-substituted- isoquinol-1-ones, in good yields, from lithium diene-diolates and nitriles.

Full text of DOI:10.1055/s-2000-6254

PAPER
273
A New Synthetic Method to 2-Pyridones
Eva M. Brun, Salvador Gil, Ramón Mestres, Margarita Parra*
Departament de Química Orgánica, Universitat de València, Burjassot, València, Spain
E-mail: margarita.parra@uv.es
Received 27 July 1999; revised 30 September 1999
reaction mixture. As a special case, double deprotonation
of the 2-pyrone (6) leads, under similar reaction condi-
tions, to the 2-pyridone 12 (Scheme 1).
Abstract: We report here a simple procedure for the preparation of
4,6-disubstituted- and 3,4,6-trisubstituted-2-pyridones and 3-sub-
stituted-isoquinol-1-ones, in good yields, from lithium diene-
diolates and nitriles.
Keywords: pyridones, isoquinolones, nitriles, lithium diene-
diolates, carboxylic acids
O
O
R1
R1
R2
H
R
OH
CH3
1) Base
N
R2
2) R-CN
The synthesis of a substituted 2-pyridone ring is a topical
area of continuing interest due to the number of biologi-
cally active molecules containing this moiety. Over the
last decade, natural compounds with this structure have
emerged as potent antitumor,1,2 antiviral3 and
psychotherapeutic4 agents along with a new antibiotic.5
Besides, pyridones are key intermediates in the synthesis
of the corresponding pyridines.6 Thus, despite the large
number of methods known for their synthesis,7 new pro-
cedures are continuously being developed. 8
7) R1 = R2 = H
8) R1 = CH3 ; R2 = H
9) R1 = H; R2= CH3
1) R1=R2=H (E)
2) R1=CH3; R2=H (E)
3) R1=H; R2=CH3
a) R = CH3
b) R=CH2CH3
c) R=CH(CH3)2
10) R1=-CH2CH2CH2-=R2
4) R1=-CH2CH2CH2-=R2 d) R=
Cl
e) R=
H3C
O
CO2H
1) Base
NH
2) R-CN
5
6
R
11
O
O
1) Base
2)
Our studies on the reactivity of dienediolates of unsaturat-
ed carboxylic acids has led us to a new convenient synthe-
sis of 4,6-disubstituted- and 3,4,6,-trisubstituted-2-
pyridones from lithium dienediolates and nitriles. Synthe-
sis of 1-isoquinolones from nitriles was previously
reported2 by addition of anions derived from o-tolua-
mides. The direct use of unsaturated carboxylic acids,
however, had remained unexplored until our preliminary
communication9 and we wish to report here a more com-
plete study on the scope of the method.
O
NH
O
CN
c
12
O
OH
NH2
CN
13
14
15
Scheme 1
It is well known that unsaturated carboxylic acids are syn-
thetically useful building blocks. Double deprotonation
by lithium amides generate their lithium dienediolates that
behave as ambident nucleophiles, through their a or g car-
bon atoms, leading to single or clearly predominant com-
pounds when allowed to react with electrophiles under
adequate conditions.10 Thus, a attack predominates for ir-
reversible reactions,11,12 whereas, highly stereoselective
g-adducts are obtained when reversible additions to car-
bonyl compounds are carried out under equilibrium con-
ditions.13,14 Therefore, it seemed reasonable, that g-
adducts resulting from the nucleophilic attack of these di-
enediolates to nitriles would afford pyridone rings after
intramolecular cyclization (Scheme 1).
The best results obtained are summarized in Table 1. Al-
though reaction conditions are not critical in order to ob-
tain the corresponding pyridones, for each acid and nitrile,
an optimization of time, temperature, proportions of re-
agents and nature of the base, was performed in order to
attain a better yield. Room temperature (25∞C) is always
the best choice. Lower temperatures led to higher amounts
of unreacted material, while higher temperatures promot-
ed the formation of byproducts. At this temperature, a 24-
hour reaction time is needed in most cases and a longer re-
action time did not improve the yield. Usually, a 1:1 ratio
of nitrile and acid were used, as an increase in the amount
of nitrile did not improve the results.
Both the amine and its amount are expected to control the
aggregation states of dienediolates and were therefore op-
timized. Use of lithium diisopropylamide (LDA) instead
of lithium diethylamide (LDE) as a base led to lower
yields in other additions15 but, in this case, it does not
make a great difference and can even be an advantage for
the ionization of o-toluic acid (Table 1, entries 13 and 15).
The results obtained for this tandem reaction show the
wide applicability of the method. Several a,b-unsaturated
carboxylic acids (1-5), and both alkyl (a-c) or aryl (d, e)
nitriles have been used to obtain substituted 2-pyridones
(7-10) and isoquinol-1-ones (11), easily isolated in most
cases as pure compounds by crystallization from the crude
Synthesis 2000, No. 2, 273–280 ISSN 0039-7881 © Thieme Stuttgart · New York

274
E. M. Brun et al.
PAPER
In most cases dienediolates can be generated, without
Barbier’s reduction or Michael adduct formation, by
deprotonation of the corresponding acids with butyllitium
and a catalytic amount of an amine.16 In this case, a small-
er amount of amine usually led to pyridones in better
yields, but it cannot be considered as a general rule.
Lower yields were obtained for nitriles with acidic pro-
tons at primary carbon atoms due to the formation of self-
condensation products. Thus, when acetonitrile (a) was
used, a polymeric material becomes the main product in
most cases, whereas use of o-tolunitrile (e) led to byprod-
uct 13.
According to our experience on additions of these diene-
diolates to carbonyl compounds,14,15 a mechanistic picture
of the pyridone forming process can be outlined (Scheme
2). Probably, small amounts of a- and g-adducts are in
equilibrium with starting material and only cis g-adducts
can evolve to a stable product that pushes forward the
equilibrium. The g-attack of electrophiles to the diene-
diolates of unsaturated acids is highly stereoselective
leading almost always to a single cis- or trans-g-adduct
according to the substituents at C-3. Thus, butenoic acids
1 and 2, which bear no further alkyl substituent at C-3 af-
ford trans-g-adducts, whereas acids 3 to 5, which bear a
methyl group at C-3 lead mainly to cis-g-adducts. Al-
though it may be expected that s-cis and s-trans confor-
mations of these dianions (Scheme 3) equilibrate in
solution,17 the highly stereoselective trans-g-addition for
crotonic acid (1) and, especially, tiglic acid (2) prevent
further intramolecular cyclization. Accordingly, no py-
rone 8 could be detected (entries 3 and 4). We tried to
force an s-cis conformation for these diendiolates by add-
ing coordinative species such as Fe(CO)5, ferrocene or
CoI2 but only starting material was recovered.
Scheme 2
OLi
OLi
OLi
OLi
s-trans
s-cis
Scheme 3
In order to determine if protonation to the final pyridone
was produced in the reaction mixture or in the work-up
(Scheme 2), iodomethane was added to the reaction mix-
ture. Methylation of the intermediate was expected, but
since no 2-methoxypyridine could be observed, we were
led to think that pyridone was already formed before the
workup.
On the other hand, we expected the addition of diene-
diolates to nitriles to be a slow process as cyano-hydroxy-
acids can be prepared, in good yield, by addition of these
Table 1 Nucleophilic Addition of Dienediolates to Nitriles
Base
Yield (%)
Entry
Acid
Nitrile
BuLi (2 equiv)
Time (h)
Recovered acid
Pyridone
Other
+ Et2NH (n equiv)
Products
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1
1
2
2
3
3
3
3
3
4
4
4
5
5
5
6
6
6
c
d
c
d
a
b
c
d
e
b
c
d
b
c
d
c
c
(2)
(2)
(2)
24
2
5
75
37
80
56
13 (7c)
–
3
(2)
(0.4)
(0)
(0.4)
(2)
24
24
24
24
7
24
24
24
24
21
24
24
24
38 (9a)
65 (9b)
78 (9c)
85 (9d)
33 (9e)
60 (10b)
72 (10c)
82 (10d)
40 (11b)
84 (11c)
62 (11d)
–
Polym.
47 (13)
3 (14)
(0.4)
(0.4)
(0.4)
(0.4)a
(2)
(0.4)a
(0.4)
(1)
3 (14)
27 (15)
5 (15)
40
33
11 (12)
32 (12)
c
(2)
a (i-Pr)2NH
Synthesis 2000, No. 2, 273–280 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A New Synthetic Method to 2-Pyridones
275
dienediolates to cyanoaldehydes.14 However, additions to
cyano and aldehyde groups are reversible processes and
the preferred attack could be due to thermodynamic con-
trol. We expected to establish the rate-determining step in
the pyridone forming process, by means of a competition
reaction (Scheme 4) with 2-cyanobenzyl bromide (Table
2). Only 2-cyanoalkylation products (16-21) were ob-
tained, indicating that the irreversible alkylation is much
faster than addition to the nitrile.11 Otherwise, at least trac-
es of the corresponding isoindole was expected. As no
isoindole could be detected we deduced that addition of
the dienediolate to nitriles should be the rate determining
reversible step. On the other hand, the a:g regioselectivity
ratio found was in the normal trend for these kinds of sub-
strates.12
O-
O
Bu
O-
Bu
Bu
O
O
α
O
BuLi
O-
γ`
O
γ
ε
6
Et2NLi
O-
OH
O
O
Bu
Et2N
Et2NLi
O-
NEt2
O-
O-
R
C
N
Aromatization
O
Bu
Et2N
N-
HN
O
O-
H2O
R
R
OH
12
15
Scheme 5
R2
R2
O
R1
CO2H
CO2H
R1
R2
OH
CH3
1) Base
R1
+
2-pyridones from the addition of lithium dienediolates,
derived from a,b-unsaturated carboxylic acids, to nitriles,
which are either commercially available or conveniently
prepared by conventional or well stabilised procedures.
Besides, the method can be extended to 2-alkylbenzoic
acids leading to the 1-isoquinolone moiety. In addition,
most 2-pyridones and isoquinol-1-ones are easily isolated
from the reaction mixture, as they precipitate on workup
with water and can be easily purified by a simple crystal-
lisation.
CN
Br
2)
NC
f
NC
16) R1=R2= H
17) R1=CH3; R2=H
18) R1=H; R2=CH3
1) R1=R2= H (E)
19) R1=R2= H
2) R1=CH3; R2= H (E)
3) R1= H; R2= CH3
20) R1=CH3; R2=H
21) R1=H; R2=CH3
Scheme 4
The conversion of pyrone (6) to pyridone (12) deserves a
special comment. Following the mechanism outlined in
Scheme 2, a 5-acyl-6-isopropyl-4-methyl-2-pyridone was Mps were determined with a Reichert apparatus and are uncorrect-
ed. IR spectral data were obtained for liquid film or KBr discs, with
a Perkin-Elmer 281 spectrophotometer. NMR spectra were record-
expected from g-attack of the nitrile to the trienolate, gen-
erated from pyrone 6 and one equivalent of base. Howev-
ed for CDCl3 solutions, with a Varian Unity 300 or Unity 400 spec-
er, this product was not observed in any case and phenol
trometers. Elemental analyses were determined by “Servicio de
15 and pyridone 12 were obtained instead (Table 1, entry
Semimicroanálisis del Centro de Investigación y Desarrollo (CSIC)
17). Lower amounts of amine led mainly to 15, whereas
use of two equivalents of base and amine led to 12 as the
main product for this reaction. These results can be ex-
plained (Scheme 5) by considering an addition of the base
to the pyrone carboxyl instead of deprotonation. When
butyllithium is present in the reaction mixture, this is an
irreversible process that leads to the phenol 15. With lith-
ium amides this addition leads to an intermediate which,
on g¢ deprotonation and addition to the nitrile, as proposed
by Kelly,2 leads mainly to pyridone 12 which can be iso-
lated as a yellow oil in moderate yield (Table 1, entry 18).
de Barcelona”. High resolution mass spectra were determined with
a UG Autoespec spectrometer. Silica gel Merck 60 (230-400 mesh)
was used for flash column chromatography, with hexane/Et2O/
MeOH mixtures for elution.
All reactions were carried out under Ar atm, using standard condi-
tions for exclusion of moisture, in oven dried glassware, in THF
freshly distilled from blue benzophenone ketyl and with diethyl-
amine and diisopropylamine distilled from CaH2. The reaction tem-
perature (-78 °C) was achieved by cooling with a CO2/acetone bath.
Organic extracts were dried over anhyd MgSO4, and solutions were
evaporated under reduced pressure with a rotary evaporator and a
bath at 40 °C.
In conclusion, we have found a simple procedure for the
preparation of 4,6-disubstituted and 3,4,6-trisubstituted-
2-Methylcyclopent-1-ene carboxylic acid 4 was prepared by the
method described by Harding and Clement.18 The mp and spectro-
scopic data were in agreement with those already described. Other
starting compounds were purchased and used without purification.
Table 2 Competition Reaction: Addition to Nitrile vs Alkylation
2-Pyridones; General Procedure
Entry
Acid
Yield (%)
Rate (a:g)
Carboxylic acid (2.25 mmol) in THF (2 mL) was slowly added to
stirred LDE (between 0.2-4.8 mmol, see Table 1) in THF (2 mL) at
-78 ºC, according to the method already described.16 The solution
was stirred for 30 min at 0 ºC for unsaturated acids 1-4 and for 4,6-
dimethyl-2H-pyran-2-one (6), and 1 h at r.t. for o-toluic acid 5, and
1
2
3
1
2
3
70
68
85
16:19 (67:33)
17:20 (56:44)
18:21 (74:26)
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276
E. M. Brun et al.
PAPER
then cooled again to -78 ºC. Nitrile (2.25 mmol) in THF (2 mL) was
added dropwise, and the solution stirred at r.t. for the time stated in
each case (Table 1). H2O (20 mL) was added and the product isolat-
ed by crystallization from crude in most cases, leading to pure prod-
ucts. In other cases, H2O was added, extracted with CH2Cl2
(3 x 15mL) and the combined organic layers were washed with
brine to neutral pH, and dried. Evaporation of the solvent gave
crude reaction mixture.
Anal: C8H11NO (137.2): calc C, 70.04; H, 8.08; N, 10.21. Found C,
69.93; H, 8.13; N, 10.23.
6-Isopropyl-4-methylpyridin-2(1H)-one (9c)
From 3-methylbut-2-enoic acid (3) (225 mg, 2.25 mmol) and isobu-
tyronitrile c (0.2 mL, 2.25 mmol), the mixture was stirred at r.t. for
24 h. Yield: 263 mg (78%), white solid; mp 145-146 °C (acetone).
IR (KBr): nmax = 3280, 2961, 2900, 1650, 1623, 1548, 1472, 1366,
1317, 1219, 1102, 984, 945, 851, 815, 741, 620 cm-1.
6-Isopropylpyridin-2(1H)-one (7c)
1H NMR (CDCl3, 400 MHz): d = 1.27 [d, 6H, J = 6.9 Hz,
(CH3)2CH), 2.17 (s, 3H, CH3), 2.84 [m, 1H, CH(CH3)2], 5.89 (s, 1H,
CH-C-NH), 6.21 (s, 1H, CH-CO).
From trans-but-2-enoic acid (1) (194 mg, 2.25 mmol) and isobut-
yronitrile c (0.2 mL, 2.25 mmol), the reaction mixture was stirred at
r.t. for 24 h. Yield: 40 mg (13%), yellow waxy material.
13C NMR (CDCl3, 400 MHz): d = 21.6 (3 CH3), 31.8 [CH(CH3)2],
104.6 (CH-C-N), 115.5 (CH-CO), 153.4 [C-CH(CH3)2], 154.7 (C-
CH3), 165.9 (CO).
EIMS: m/z (%) = 151 (M+, 52), 136 (M-CH3, 100), 123 (M-CO,
11), 108 [M-CH(CH3)2, 17], 91(9), 53 (16).
IR (film): nmax = 3200, 2964, 2933, 1651, 1618, 1552, 1461, 1157,
998, 932, 804, 736, 558 cm-1.
1H NMR (CDCl3, 400 MHz): d = 1.28 [d, 6H, J = 6.9 Hz,
(CH3)2CH], 2.88 [m, 1H, CH(CH3)2], 6.06 (d, 1H, J = 7.0 Hz, CH-
C-NH), 6.40 (d, 1H, J = 9.0 Hz. CH-CO), 7.38 (dd, 1H, J = 9.0, 7.0
Hz, CHCHCHN).
HRMS: m/z calc for C9H13NO (M+) 151.099714. Found:
13C NMR (CDCl3, 400 MHz): d = 19.5 (2 CH3), 29.7 [CH(CH3)2],
102.3 (CH-C-N), 117.0 (CH-CO), 141.8 (CHCHCHN), 155.5 [C-
CH(CH3)2], 165.5 (CO).
151.099545.
Anal: C9H13NO (151.1): calc C, 71.49; H, 8.67; N, 9.26. Found C,
71.38; H, 8.74; N, 9.26.
EIMS: m/z (%) = 137 (M+, 60), 122 (M+-CH3, 100), 109 (M+-CO,
13), 104 (29), 94 [M+-CH(CH3)2, 22].
6-(p-Chlorophenyl)-4-methylpyridin-2(1H)-one (9d)
From 3-methylbut-2-enoic acid (3) (225 mg, 2.25 mmol) and p-
chlorobenzonitrile d (309.5 mg, 2.25 mmol), the mixture was stirred
at r.t. for 24 h. Yield: 420 mg (85%), white solid; mp 234-235 °C
(EtOAc/hexane).
HRMS: m/z calc for C8H11NO (M+) 137.084064. Found:
137.083931.
4,6-Dimethylpyridin-2(1H)-one (9a)
IR (KBr): nmax = 3260, 3070, 2900, 1645, 1615, 1384, 1094, 846,
From 3-methylbut-2-enoic acid (3) (225 mg, 2.25 mmol) and aceto-
nitrile a (0.12 mL, 2.25 mmol), the mixture was stirred at r.t. for 24
h. Yield: 105 mg (38%), yellow solid; mp 166-167 °C.
818 712 cm-1.
1H NMR (CDCl3, 400 MHz): d = 2.25 (s, 3H, CH3), 6.30 (s, 1H,
CH-C-NH), 6.35 (s, 1H, CH-CO), 7.45 (d, 2H, J = 8.4 Hz, 2
CHarom.), 7.65 (d, 2H, J = 8.4 Hz, 2 CHarom.).
IR (KBr): nmax = 3487, 3265, 3060, 1221, 1560, 1498, 1437, 1369,
928, 834, 765, 739, 726, 591 cm-1.
13C NMR (CDCl3, 400 MHz): d = 21.7 (CH3), 107.6 (CH-C-N),
117.6 (CH-CO), 128.0, 129.3, 132.0, 136.0 (6 Carom.), 144.7 (C-Car-
om.), 152.7 (C-CH3), 165.2 (CO).
1H NMR (CDCl3, 400 MHz): d = 2.16 (s, 3H, CH3), 2.29 (s, 3H,
CH3CHN), 5.90 (s, 1H, CH-C-NH), 6.19 (s, 1H, CH-CO).
13C NMR (CDCl3, 400 MHz): d = 18.8 (CH3), 21.5 (CH3CHN),
108.6 (CH-C-N), 115.0 (CH-CO), 149.2 (NCCH3), 153.7 (C-CH3),
165.9 (CO).
EIMS: m/z (%) = 222 (37ClM+1, 6), 221 (37ClM+, 48), 220
(35ClM+1, 17), 219 (35ClM+, 100), 191 (M-CO, 52), 190 (51).
HRMS: m/z calc for C12H1137ClNO (M+) 222.049967. Found:
222.049277. m/z calc for C12H1135ClNO (M+) 220.052917. Found:
220.053013.
EIMS: m/z (%) = 123 (M+, 85), 108 (M-CH3, 2), 95 (M-CO, 34),
94 (M-1-CO, 100), 80 (M-CH3-CO, 22).
HRMS: m/z calc for C7H9NO (M+) 123.068414. Found:
Anal: C12H10ClNO (219.7):Calc C, 65.61; H, 4.59; N, 6.38. Found
C, 65.61; H, 4.57; N, 6.30.
123.068038.
6-Ethyl-4-methylpyridin-2(1H)-one (9b)
4-Methyl-6-(o-methylphenyl)pyridin-2(1H)-one (9e)
From 3-methylbut-2-enoic acid (3) (225 mg, 2.25 mmol) and o-me-
thylbenzonitrile e (263 mg, 2.25 mmol), the mixture was stirred at
r.t. for 7 h. Yield: 148 mg (33%), white solid; mp 204-5 °C (puri-
fied by column chromatography).
From 3-methylbut-2-enoic acid (3) (225 mg, 2.25 mmol) and propi-
onitrile b (0.16 mL, 2.25 mmol), the mixture was stirred at r.t. for
24 h. Yield: 200 mg (65%), white solid; mp 147-148 °C (EtOAc).
IR (KBr): nmax = 3291, 3126, 3054, 2968, 2935, 1647, 1545, 1467,
1435, 1216, 989, 946, 868, 808, 610 cm-1.
IR (KBr): nmax = 3260, 3070, 2912, 1637, 1549, 1490, 1460, 1439
1H NMR (CDCl3, 400 MHz): d = 1.26 (t, 3H, J = 7.5 Hz, CH3-CH2),
2.17 (s, 3H, CH3), 2.60 (q, 2H, J = 7.6 Hz, CH2CH3), 5.90 (s, 1H,
CH-C-NH), 6.21 (s, 1H, CH-CO).
13C NMR (CDCl3, 400 MHz): d = 12.7 (CH3CH2), 21.7 (CH3C),
26.1 (CH2CH3), 106.6 (CH-C-N), 115.5 (CH-CO), 150.0 (C-
CH2CH3), 153.6 (C-CH3), 165.8 (CO).
EIMS: m/z (%) = 137 (M+, 99), 136 (M-1, 100), 118 (10), 109 (M-
CO, 22), 94 (M-CO-CH3, 43).
HRMS: m/z calc for C8H11NO (M+) 137.084064. Found:
1258, 1165, 1028, 948, 937, 831, 756, 721 cm-1.
1H NMR (CDCl3, 400 MHz): d = 2.21 (s, 3H, CH3), 2.34 (s, 3H,
CH3-Carom.), 6.00 (s, 1H, CH-C-NH), 6.25 (s, 1H, CH-CO), 7.25-
7.34 (m, 4H, 4 CHarom.).
13C NMR (CDCl3, 400 MHz) d = 19.9 (CH3-Carom.), 21.6 (CH3),
109.5 (CH-C-N), 117.0 (CH-CO), 126.1, 129.1, 129.5, 130.9,
134.1, 135.9 (6 Carom.), 146.0 (C-Carom.), 152.8 (C-CH3), 164.6 (CO).
EIMS: m/z (%) = 199 (M+, 91), 198 (M-1, 100), 184 (M-CH3, 31),
156 (M-CH3-CO, 10).
HRMS: m/z calc for C13H13NO (M+) 199.099714. Found:
137.083742.
199.099108.
Synthesis 2000, No. 2, 273–280 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A New Synthetic Method to 2-Pyridones
277
3-Ethyl-2,5,6,7-tetrahydro-1H-cyclopenta[c]pyridin-1-one
(10b)
From 2-methylcyclopent-1-ene carboxylic acid 4 (284 mg, 2.25
mmol) and propionitrile b (0.16 mL, 2.25 mmol), the mixture was
stirred at r.t. for 24 h. Yield: 220 mg (60%), white prisms; mp 179-
80 °C (acetone).
HRMS: m/z calcd for C14H1237ClNO (M+) 247.057792. Found:
247.055699. m/z calcd for C14H1235ClNO (M+) 245.060742. Found:
245.059894.
Anal: C14H12ClNO (245.7): Calc C, 68.44; H, 4.92; N, 5.70. Found
C, 68.43; H, 4.97; N, 5.75.
IR (KBr): nmax = 3280, 2937, 2876, 1636, 1562, 1462, 951, 822, 629
3-Ethyl-1,2-dihydroisoquinolin-1(2H)-one (11b)
599 cm-1.
From o-toluic acid 5 (306 mg, 2.25 mmol) and propionitrile b (0.16
mL, 2.25 mmol), the mixture was stirred at r.t. for 24 h. Yield: 156
mg (40%), white prisms; mp 139-140 °C (acetone).
1H NMR (CDCl3, 400 MHz): d = 1.25 (t, 3H, J = 7.4 Hz, CH3-CH2),
2.05 [m, 2H, CH2(CH2)2], 2.60 (q, 2H, J = 7.6 Hz, CH2CH3), 2.80 (t,
4H, J = 7.6 Hz, 2 CH2C=), 6.02 (s, 1H, CH-C-NH).
13C NMR (CDCl3, 300 MHz): d = 12.7 (CH3CH2), 23.5
[CH2(CH2)2], 26.2 (CH2CH3), 29.3 (CH2CCO), 34.3 (CH2C=CCO),
102.2 (CH-C-N), 128.7 (=C-CO), 148.9 (C=C-CO), 157.5 (C-
CH2CH3), 162.9 (CO).
IR (KBr): nmax = 3293, 3163, 2976, 1657, 1605, 1554, 1475, 1376,
1347, 1257, 1130, 952, 903, 826, 747, 580 cm-1.
1H NMR (CDCl3, 400 MHz): d = 1.35 (t, 3H, J = 7.5 Hz, CH3-CH2),
2.85 (q, 2H, J = 7.5 Hz, CH2CH3), 6.31 (s, 1H, CH-C-NH), 7.42
(dd, 1H, J = 7.5, 7.4 Hz, CHarom.), 7.48 (d, 1H, J = 7.8 Hz, CHarom.),
7.62 (dd, 1H, J = 8.0, 7.4 Hz, CHarom.), 8.39 (d, 1H, J = 8.1 Hz,
CHarom.).
EIMS: m/z (%) = 163 (M+, 68), 162 (M-1, 100), 148 (M-CH3, 7),
134 (M-1-CH3, 12).
13C NMR (CDCl3, 400 MHz): d = 12.4 (CH3CH2), 26.4 (CH2CH3),
102.9 (CH-C-N), 124.4 ( = C-CO), 125.7 (2 CHarom.), 127.2, 132.5
(2 CHarom.), 138.7 (C=C-CO), 143.3 (C-CH2CH3), 164.6 (CO).
EIMS: m/z (%) = 173 (M+, 68), 172 (M-1, 72), 158 (M-CH3, 49),
145 (M-CO, 14), 131 (16).
HRMS: m/z calc for C10H13NO (M+) 163.099714. Found:
163.099106.
Anal: C10H13NO (163.1): CalcC, 73.59; H, 8.03; N, 8.58. Found C,
73.42; H, 8.17; N, 8.60.
3-Isopropyl-2,5,6,7-tetrahydro-1H-cyclopenta[c]pyridin-1-one
(10c)
HRMS: m/z calcd for C11H11NO (M+) 173.084064. Found:
173.084484.
From 2-methylcyclopent-1-ene carboxylic acid 4 (284 mg, 2.25
mmol) and isobutyronitrile c (0.20 mL, 2.25 mmol); the mixture
was stirred at r.t. for 24 h. Yield: 287 mg (72%), white prisms; mp
184-5 °C.
Anal: C11H11NO (173.2): Calc. C, 76.28; H, 6.40; N, 8.09. Found C,
76.40; H, 6.43; N, 8.15.
3-Isopropyl-1,2-dihydroisoquinolin-1(2H)-one (11c)
From o-toluic acid 5 (306 mg, 2.25 mmol) and isobutyronitrile c
(0.20 mL, 2.25 mmol), the mixture was stirred at r.t. for 21 h. Yield:
353 mg (84%), white solid; mp 192-193 °C.
IR (KBr): nmax = 3271, 3132, 2960, 2920, 2874, 1645, 1628, 1570,
1456, 1391, 1121, 1058, 946, 818 cm-1.
1H NMR (CDCl3, 300 MHz): d = 1.25 (d, 6H, J = 6.6 Hz, 2 CH3-
CH), 2.05 [m, 2H, CH2(CH2)2], 2.80 [m, 5H, 2 CH2C= and
CH(CH3)2], 6.02 (s, 1H, CH-C-NH).
IR (KBr): nmax = 3162, 3008, 2967, 2871, 1661, 1637, 1607, 1554,
1477, 1349, 1256, 1170, 983, 906, 821, 754 637 cm-1.
13C NMR (CDCl3, 300 MHz): d = 21.8 (2 CH3), 23.5 [CH2(CH2)2],
29.2 (CH2CCO), 31.8 [CH(CH3)2], 34.3 (CH2C=CCO), 100.4 (CH-
C-N), 128.6 ( =C-CO), 153.8 (C=C-CO), 157.4 [C-CH(CH3)2],
162.9 (CO).
EIMS: m/z (%) = 177 (M+, 86), 162 (M-CH3, 100), 149 (M-CO,
15), 134 (M-CH3-CO, 13).
1H NMR (CDCl3, 400 MHz): d = 1.35 (d, 6H, J = 6.8 Hz, 2 CH3-
CH), 2.85 [m, 1H, CH(CH3)2], 6.31 (s, 1H, CH-C-NH), 7.42 (ddd,
1H, J = 8.0, 6.8, 1.2 Hz, CHarom.), 7.49 (d, 1H, J = 8.0 Hz, CHarom.),
7.62 (ddd, 1H, J = 7.6, 6.4, 1.2 Hz, CHarom.), 8.37 (dd, 1H, J = 7.6,
1.2 Hz, CHarom.).
13C NMR (CDCl3, 400 MHz): d = 21.4 (2 CH3), 32.2 [CH(CH3)2],
101.4 (CH-C-N), 125.7, 125.9 (2 CHarom.), 127.3 ( =C-CO), 132.5 (2
CHarom.), 138.7 (C=C-CO), 147.3 [C-CH(CH3)2], 164.5 (CO).
EIMS: m/z (%) = 187 (M+, 89), 186 (M-1, 16), 172 (M-CH3, 100),
154(18), 145 (5).
HRMS: m/z calc for C12H13NO (M+) 187.099714. Found:
HRMS: m/z calc for C11H15NO (M+) 177.115364. Found:
177.115068.
Anal: C11H15NO (177.1): Calc C, 74.54; H, 8.53; N, 7.90. Found C,
74.32; H, 8.47; N, 7.94.
3-(p-Chlorophenyl)-2,5,6,7-tetrahydro-1H-cyclopenta[c]pyri-
din-1-one (10d)
From 2-methylcyclopent-1-ene carboxylic acid 4 (284 mg, 2.25
mmol) and p-chlorobenzonitrile d (309.5 mg, 2.25 mmol), the mix-
ture was stirred at r.t. for 24 h. Yield: 452 mg (82%), white solid;
mp dec. (aq EtOH).
187.099202.
Anal: C12H13NO (187.1): Calc C, 76.98; H, 7.00; N, 7.48. Found C,
76.90; H, 7.03; N, 7.59.
3-(p-Chlorophenyl)isoquinolin-1(2H)-one (11d)
From o-toluic acid 5 (306 mg, 2.25 mmol) and p-chlorobenzonitrile
d (309.5 mg, 2.25 mmol), the mixture was stirred at r.t. for 24 h.
Yield: 340 mg (62%), yellow solid (acetone); mp 268-270 °C.
IR (KBr): nmax = 3127, 3072, 2959, 2917, 1633, 1608, 1495, 1464,
1092, 1012, 817, 818 578 cm-1.
1H NMR (CDCl3, 300 MHz): d = 2.11 [m, 2H, CH2(CH2)2], 2.88 (t,
4H, J = 8.7 Hz, 2 CH2C = ), 6.44 (s, 1H, CH-C-NH), 7.44 (d, 2H,
J = 8.7 Hz, 2 CHarom.), 7.58 (d, 2H, J = 8.7 Hz, 2 CHarom.).
13C NMR (CDCl3, 300M Hz): d = 23.4 [CH2(CH2)2], 29.5
(CH2CCO), 34.4 (CH2C = CCO), 103.1 (CH-C-N), 122.1 ( = C-
CO), 127.4, 129.4 (4 CHarom.), 132.5, 135.8 (2 Carom.), 143.4 (C-Car-
om.), 157.0 (C = C-CO), 162.1 (CO).
IR (KBr): nmax = 3165, 3038, 1664, 1607, 1487, 1349, 1093, 862,
806 680 cm-1.
1H NMR (DMSO-d6, 300 MHz): d = 6.93 (s, 1H, CH-C-NH), 7.48
(m, 1H, CHarom.); 7.54 (d, 2H, J = 8.4, 2 CHarom. disubstituted), 7.70
(m, 2H, CHarom.); 7.79 ((d, 2H, J = 8.4, 2 CHarom. disubstituted), 8.18
(d, 1H, J = 7.8 Hz, CHarom.-C-CONH).
13C NMR (DMSO-d6, 300 MHz): d = 104.3 (CH-C-N), 115.8 (Car-
om.), 125.6 (Carom.), 127.3 (2 CHarom.), 127.5 (2 CHarom.), 129.2 (2
(EIMS: m/z (%) = 247 (37ClM+, 37), 245 (35ClM+, 100), 230 (M-
CH3), 218 (48), 173 (6), 137 (10).
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278
E. M. Brun et al.
PAPER
CHarom.), 129.4 (2 CHarom.), 133.4 (CHarom.), 134.6 (Carom.), 138.4
(Carom.), 139.5 ( = C-NH), 163.4 (CO).
IR (film): nmax = 3411, 2929, 2859, 1620, 1597, 1457, 1297, 1152,
968, 840 697 cm-1.
EIMS: m/z (%) = 258 (37ClM+1, 8), 257 (37ClM+, 8), 256 (35ClM+1,
1H NMR (CDCl3, 300 MHz): d = 0.93 (t, 3H, J = 6.0 Hz, CH3-CH2),
1.34 (m, 2H, CH3CH2CH2), 1.56 (m, 2H, CH2CH2CH2), 2.28 (s, 3H,
CH3-Carom.), 2.52 (t, 2H, J = 7.5 Hz, CH2CH2Carom.), 5.00 (br s, 1H,
OH), 6.48 (s, 2H, 2 CHarom.), 6.59 (s, 1H, CHarom.).
13C NMR (CDCl3, 300 MHz): d = 13.9 (CH3-CH2), 21.3 (CH3-Car-
om.), 22.4 (CH3CH2CH2), 33.5 (CH2CH2CH2), 35.5 (CH2CH2Carom.),
112.4, 113.3, 121.9 (3 CHarom.), 139.4, 144.7, 152.4 (3 Carom.).
EIMS): m/z (%) = 165 (M++1, 8), 164 (M+, 52), 149 (M-CH3, 9),
135 (M-CH2CH3, 60), 121(M-CH3CH2CH2, 96), 107 (M-
CH3CH2CH2CH2, 94), 91 (86), 56 (100).
24), 255 (35ClM+, 15), 239 (37ClM-H2O, 100).
HRMS: m/z calc for C15H1035ClNO (M+) 255.045092. Found:
255.045659.
6-Isopropyl-4-(2-oxopropyl)pyridin-2(1H)-one (12)
From 4,6-dimethyl-2H-pyran-2-one (6) (279 mg, 2.25 mmol) and
isobutyronitrile c (0.20 mL, 2.25 mmol), the mixture was stirred at
r.t. for 24 h. Yield: 139 mg (32%), yellow oil.
IR (film): nmax = 3123, 2970, 1716, 1651, 1546, 1456, 1360, 1214,
1160, 961, 869 737 cm-1.
HRMS: m/z calc for C11H16O (M+) 164.120115. Found:
164.119589.
1H NMR (CDCl3, 400 MHz): d = 1.28 (d, 6H, J = 6.9 Hz, 2 CH3-
CH), 2.21 (s, 3H, CH3CO), 2.84 [m, 1H, CH(CH3)2], 3.53 (s, 2H,
CH2CO), 5.93 (s, 1H, CH-C-NH), 6.27 (s, 1H, CHCO).
2-(2-Cyanobenzyl)but-3-enoic Acid (16)
Yield: 212 mg (47%), yellow oil (by column chromatography).
13C NMR (CDCl3, 400 MHz): d = 21.6 (2 CH3), 29.7 (CH3CO),
32.2 [CH(CH3)2], 50.7 (CH2CO), 104.2 (CH-C-N), 117.1 ( =C-CO),
149.2 (C=C-CO), 155.0 [C-CH(CH3)2], 165.2 (CON), 202.3 (CO
ketone).
EIMS: m/z (%) = 193 (M+, 76), 178 (M-CH3, 46), 165 (M-CO, 7),
151(M-CH3CCH3, 100), 136 (20).
IR (film): nmax = 3070, 2226, 1697, 1485, 1422, 1287, 1213, 929,
763 cm-1.
1H NMR (CDCl3, 300 MHz): d = 3.08 (dd, 1H, J = 13.9, 7.6 Hz,
CH2Carom.), 3.29 (dd, 1H, J = 13.8, 7.6 Hz, CH2Carom.), 3.42 (m, 1H,
CHCO2H) 5.07 (d, 1H, J = 17.2 Hz, =CH2trans), 5.14 (d, 1H,
J = 10.2 Hz, =CH2cis), 5.85 (ddd, 1H, J = 17.2, 10.2, 8.5 Hz,
CH = CH2), 7.1-7.5 (m, 4H, 4 CHarom.).
13C NMR (CDCl3, 300 MHz): d = 36.2 (CH2-Carom.), 50.8
(CHCO2H), 112.8 (Carom.CN), 117.9 (CN), 119.0 ( = CH2), 128.3,
130.2, 132.8 (4 Carom.), 133.7 (CH = CH2), 142.2 (Carom.), 178.0
(CO2H).
HRMS: m/z calc for C11H15NO2 (M+) 193.110279. Found:
193.110328.
2-[2-Amino-2-(2-methylphenyl)-1-ethenyl]benzonitrile (13)
Yield: 123 mg (47%), yellow solid; mp 192-193 °C (by column
chromatography).
IR (film): nmax = 3359, 3292, 3005, 2921, 2840, 2219, 1647, 1463,
EIMS: m/z (%) = 201 (M+, 7), 183 (M-H2O, 27), 155 (M-H2O-
CO, 68), 116 (M-C4H5O2, 100).
HRMS: m/z calc for C12H11NO2 (M+) 201.078979. Found:
1223, 987, 965, 935, 817, 615, 564 530 cm-1.
1H NMR (CDCl3, 400 MHz): d = 2.30 (s, 3H, CH3-Carom.), 5.25 (br
s, 2H, NH2), 6.90 (s, 1H, CH= ), 7.05 (m, 3H, CHarom.), 7.45 (m, 2H,
CHarom.), 7.60 (t, 1H, J = 6.0 Hz, CHarom.), 7.65 (d, 1H, J = 6.0 Hz,
CHarom.), 7.75 (d, 1H, J = 6.0 Hz, CHarom.).
13C NMR (CDCl3, 400 MHz): d = 20.8 (CH3), 112.6 (Carom.CN),
116.8 (CN), 123.0, 126.1, 126.3, 127.7, 128.2, 130.0, 130.6, 131.0,
136.4, 138.3, 141.3, 152.4 (11Carom. and CH = ), 155.8 ( =C-NH2).
201.078447.
2-(2-Cyanobenzyl)-2-methylbut-3-enoic Acid (17)
Yield: 199 mg (44%), yellow solid (by column chromatography);
mp 93-94ºC.
IR (KBr): nmax = 3068, 2983, 2939, 2226, 1707, 1691, 1487, 1289,
1221, 926, 767, 662 cm-1.
EIMS: m/z (%) = 234 (M+, 56), 233 (M-1, 100), 216 (M-NH4 ,
+
+
17), 90 (M-NH4 -CN, 5).
1H NMR (CDCl3, 300 MHz): d = 1.32 (s, 3H, CH3), 3.24 (d, 1H,
J = 13.4 Hz, CH2Carom.), 3.34 (d, 1H, J = 13.4 Hz, CH2Carom.), 5.12
(d, 1H, J = 17.4 Hz, = CH2trans), 5.23 (d, 1H, J = 10.8 Hz
, = CH2cis), 6.13 (dd, 1H, J = 17.4, 10.8 Hz, CH = ), 7.29 (m, 2H, 2
CHarom.), 7.47 (t, 1H, J = 6.0 Hz, CHarom.), 7.62 (d, 1H, J = 6.6 Hz,
CHarom.).
HRMS: m/z calc for C16H14N2 (M+) 234.115699. Found:
234.114879.
1-(2-Methylphenyl)pentan-1-one (14)
Yield: 12 mg (3%), yellow oil (by column chromatography).
13C NMR (CDCl3, 300 MHz): d = 19.4 (CH3), 42.3 (CH2-Carom.),
50.0 (C-CO), 114.3 (Carom.CN), 115.8 (CH2 = ), 118.5 (CN), 127.3,
131.1, 132.3, 132.9, 139.5, 140.8 (5 Carom. and CH = CH2), 180.3
(CO2H).
EIMS: m/z (%) = 215 (M+, 1), 197 (M-H2O, 8), 170 (M-CO2H,
10), 157 (17), 116 (M-C5H7O2, 100).
IR (film): nmax = 2959, 2929, 2872, 1733, 1688, 1601, 1456, 1286,
1073, 967, 755 cm-1.
1H NMR (CDCl3, 400 MHz): d = 0.93 (t, 3H, J = 7.6 Hz, CH3-CH2),
1.38 (m, 2H, CH3CH2CH2), 1.66 (m, 2H, CH2CH2CH2),. 2.48 (s,
3H, CH3-Carom.), 2.88 (t, 2H, J = 7.2 Hz, CH2CH2CO), 7.25 (m, 2H,
CHarom.), 7.35(t, 1H, J = 7.2 Hz, CHarom.), 7.60 (d, 1H, J = 6.4 Hz,
CHarom.).
13C NMR (CDCl3, 400 MHz): d = 13.9 (CH3-CH2), 21.1 (CH3-Car-
om.), 22.4 (CH3CH2CH2), 26.5 (CH2CH2CH2), 41.4 (CH2CH2CO),
125.6, 128.2, 131.0, 131.9 (4 CHarom.), 137.8, 138.1 (2 Carom.), 205.4
(CO).
EIMS: m/z (%) = 177 (M++1, 16), 176 (M+, 7), 161 (M-CH3, 6),
147 (M-CH2CH3, 2), 119 (M-butyl, 100).
HRMS: m/z calc for C12H16O (M+) 176.120115. Found:
176.120586.
HRMS: m/z calc for C13H13NO2 (M+) 215.094629. Found:
215.095664.
2-(2-Cyanobenzyl)-3-methylbut-3-enoic Acid (18)
Yield: 320 mg (63%), yellow solid (by column chromatography);
mp 92-93ºC.
IR (KBr): nmax = 2969, 2736, 2650, 2223, 1702, 1640, 1441, 1418,
1248, 936, 897, 765, 547 cm-1.
1H NMR (CDCl3, 300 MHz): d = 1.84 (s, 3H, CH3C= ), 3.13 (dd,
1H, J = 14.1, 6.9 Hz, CH2Carom.), 3.34 (dd, 1H, J = 14.1, 8.4 Hz,
CH2Carom.), 3.49 (dd, 1H, J = 8.4, 6.9 Hz, =CCHCH2), 4.91 (d, 1H,
J = 0.6 Hz, =CH2), 4.95 (d, 1H, J = 1.2 Hz, =CH2), 7.32 (m, 2H, 2
3-Butyl-5-methylphenol (15)
Yield: 100 mg (27%), yellow oil (by column chromatography).
Synthesis 2000, No. 2, 273–280 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A New Synthetic Method to 2-Pyridones
279
CHarom.), 7.47 (dt, 1H, J = 7.5, 1.5 Hz, CHarom.), 7.63 (dd, 1H,
J = 7.8, 0.6 Hz, CHarom.),
13C NMR (CDCl3, 300 MHz): d = 19.8 (CH3), 30.8 (CH2-Carom.),
46.5 (CH-CO), 111.1 (Carom.CN), 114.9 (CH2 = ), 117.9 (CN),
126.4, 129.4, 132.0, 132.4, 140.5, 141.3 (5 Carom. and C=CH2),
178.3 (CO2H).
EIMS: m/z (%) = 215 (M+, 2), 197 (M-H2O, 25), 182 (M-H2O-
CH3, 7), 169 (M-H2O-CO, 14), 154 (M-H2O-CO-CH3, 21), 116
(M-C5H7O2, 65), 99 (C5H7O2, 100).
13C NMR ((E)-isomer, CDCl3, 300 MHz): d = 19.0 (CH3), 32.5
(CH2-Carom.), 41.9 (CH2CH = ), 112.2 (Carom.CN), 116.2
(C = CHCO), 117.8 (CN), 125.6, 127.0, 129.4, 132.8, 132.9, 144.6
(5 Carom. and C = CHCO), 171.3 (CO2H).
EIMS: m/z (%) = 215 (M+, 8), 197 (M-H2O, 100), 182 (M-H2O-
CH3, 13), 169 (M-H2O-CO, 36), 154 (M-H2O-CO-CH3, 30),
116 (M-C5H7O2, 99).
HRMS: m/z calc for C13H13NO2 (M+) 215.094629. Found:
215.095117.
HRMS: m/z calcd for C13H13NO2 (M+) 215.094629. Found:
215.094605.
Acknowledgement
(E)-5-(2-Cyanophenyl)pent-2-enoic Acid (19)
Yield: 105 mg (23%), yellow oil (by column chromatography).
The research was financed by DCICYT (PB-95-1121-C02-01). One
of us (E.M.B.) acknowledges a grant by DGICYT.
IR (film): nmax = 2930, 2858, 2225, 1695, 1493, 1410, 1320, 1220,
1101, 870, 740 cm-1.
References and Notes
1H NMR (CDCl3, 300 MHz): d = 2.60 (m, 2H, CH2CH = ), 2.92 (m,
2H, Carom.CH2), 5.85 (d, 1H, J = 17.2 Hz, = CH 6.92 (t, 1H, J = 7.5
Hz, CH = ), 7.32 (m, 2H,. CHarom.), 7.52 (dt, 1H, J = 7.8, 1.5 Hz,
CHarom.), 7.63 (dd, 1H, J = 7.5. 1.5 Hz, CHarom.).
13C NMR (CDCl3, 300 MHz): d = 30.5 (CH2CH = ), 33.2 (CH2-Car-
om.), 112.2 (Carom.CN), 117.9 (CN), 126.8, 129.4, 129.8, 132.9,
133.8, 142.9, 143.9 (5 Carom. and CH = CHCO), 171.4 CO2H).
(1) Schultz, A. G. Chem. Rev. 1973, 73, 385.
Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114, 5863.
(2) Kelly, T. R.; Bell, S. H.; Ohashi, N.; Armstrong-Chong, J. J.
Am. Chem. Soc. 1988, 110, 6471.
(3) Williams, D. R; Lowder, P. D.; Gu, Y-G. Tetrahedron Lett.
1997, 38, 327.
(4) Kozikowski, A. P.; Campiani, G.; Sun, L-Q.; Wang, S.;
Saxena, A.; Doctor, B. P. J. Am. Chem. Soc. 1996, 118, 11357.
(5) Brickner, S. J. Chemistry and Industry 1997, 131.
(6) Murray, T. J.; Zimmerman, S. C. Tetrahedron Lett. 1995, 36,
7627.
EIMS: m/z (%) = 201 (M+, 5), 183 (M-H2O, 78), 155 (M-H2O-
CO, 30), 116 (100).
HRMS: m/z calc for C12H11NO2 (M+) 201.078979. Found:
201.078633.
Lee, L. F.; Normansell, J. E. J. Org. Chem. 1990, 55, 2964.
(7) Meislich, H. In Pyridine and its Derivatives, Vol. 3;
Klingsberg, E., Ed.; Interscience: New York, 1962; p 509-
890.
(E)-5-(2-cyanophenyl)-2-methylpent-2-enoic Acid (20)
Yield: 156 mg (34%), yellow solid (by column chromatography);
mp 101-102ºC.
IR (KBr): nmax = 2928, 2867, 2224, 1685, 1637, 1425, 1304, 1270,
Jones, G. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A.; Rees, C. W.; Scriven, E. F., Eds.; Pergamon
Press: Oxford, 1996; p 395-510.
1075, 943, 759, 750, 616, 552 cm-1.
1H NMR (CDCl3, 300 MHz): d = 1.76 (s, 3H, CH3), 2.62 (dt, 2H,
J = 7.8, 7.5 Hz, CH2CH2CH = ), 3.00 (t, 2H, J = 7.8 Hz, Car-
om.CH2CH2), 6.92 (t, 1H, J = 7.5 Hz, CH = ), 7.32 (m, 2H, CHarom.),
7.52 (dt, 1H, J = 7.8, 1.5 Hz, CHarom.), 7.63 (dd, 1H, J = 7.5. 1.5 Hz,
CHarom.).
13C NMR (CDCl3, 300 MHz): d = 11.9 (CH3), 29.8 (CH2CH = ),
33.2 (CH2-Carom.), 112.3 (Carom.CN), 117.8 (CN), 126.9, 128.6,
129.6, 132.9, 133.0, 142.1, 144.7 (5 Carom. and CH = CCO), 173.2
CO2H).
Wenner, W.; Plati, J. T. J. Chem. Soc. 1946, 751.
(8) Jain, R.; Roschangar, F.; Ciufolini, M. A. Tetrahedron Lett.
1995, 36, 3307.
Tohda, Y.; Yanagidani, T.; Hiramatsu, S-i.; Nishiwaki, N.;
Tani, K.; Ariga, M. Bull. Chem. Soc. Jpn. 1997, 70, 2781.
(9) Brun, E. M.; Gil, S.; Mestres, R.; Parra, M. Synlett 1999, 1088.
(10) Mekelburger, H. B.; Wilcox, C. S. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; p 99-101.
EIMS: m/z (%) = 215 (M+, 3), 197 (M-H2O, 83), 182 (M-H2O-
CH3, 5), 169 (M-H2O-CO, 21), 157 (46), 116 (M-C5H7O2, 100).
HRMS: m/z calc for C13H13NO2 (M+) 215.094629. Found:
Thomson, C. M. Dianion Chemistry in Organic synthesis;
CRS Press: Boca Raton, FL, 1994; p 88-129.
Aurell, M. J.; Gaviña, P.; Mestres, R. Tetrahedron 1994, 50,
2571.
Brun, E. M.; Gil, S.; Mestres, R.; Parra, M.; Villar, F.
Tetrahedron Lett. 1998, 39, 1055.
215.093983.
5-(2-Cyanophenyl)-3-methylpent-2-enoic Acid (21)
Yield: 112 mg (22%), waxy material (by column chromatography).
Aurell, M. J.; Ceita, L.; Mestres, R.; Parra, M.; Tortajada, A.
Tetrahedron 1995, 51, 3915.
IR (KBr): nmax = 2938, 2225, 1692, 1666, 1637, 1488, 1449, 1434,
1410, 1380, 1246, 1161, 862, 761 cm-1.
(11) Cainelli, G.; Cardillo, G.; Contento, M.; Umani-Ronchi, A.
Gazz. Chim. Ital. 1974, 104, 625.
Katzenellenbogen, J. A.; Savu, P. M. J. Org. Chem. 1981, 239.
(12) Brun, E. M.; Gil, S.; Mestres, R.; Parra, M. Tetrahedron 1998,
54, 15305.
(13) Cainelli, G.; Cardillo, G.; Contento, M.; Umani-Ronchi, A. J.
Chem. Soc., Perkin Trans I 1973, 400.
Johnson, P. R; White, J. D. J. Org. Chem. 1984, 49, 4424.
(14) Parra, M.; Mestres, R.; Aparicio, D.; Durana, N.; Rubiales, G.
J. Chem. Soc., Perkin Trans. I 1989, 327.
1H NMR ((Z)-isomer, CDCl3, 300 MHz): d = 1.96 (s, 3H, CH3),
2.20-2.40 (m, 4H, Carom.CH2CH2C = ), 5.91 (d, 1H, J = 1.5 Hz,
CH = ), 7.27 (m, 2H,. CHarom.), 7.51 (m, 1H, CHarom.), 7.60 (m, 1H,
CHarom.).
1H NMR ((E)-isomer, CDCl3, 300 MHz): d = 2.23 (s, 3H, CH3),
2.50 (t, 2H, J = 7.5 Hz, CH2CH2C = ), 3.01 (t, 2H, J = 7.5 Hz, Car-
om.CH2CH2), 5.67 (d, 1H, J = 0.9 Hz, CH = ), 7.27 (m, 2H,. CHarom.),
7.51 (m, 1H, CHarom.), 7.60 (m, 1H, CHarom.).
13C NMR ((Z)-isomer, CDCl3, 300 MHz): d = 24.6 (CH3), 43.0
(CH2-Carom.), 49.1 (CH2CH = ), 112.3 (Carom.CN), 117.9 (CN),
125.4, 126.8, 129.5, 129.8, 132.9, 133.1, 144.1 (5-Carom. and
C = CHCO), 171.6 (CO2H).
(15) Ballester, P.; Garcia-Raso, A.; Mestres, R. Synthesis 1985,
802.
(16) Brun, E. M.; Casades, I.; Gil, S.; Mestres, R.; Parra, M.
Tetrahedron Lett. 1998, 39, 5443
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PAPER
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Tetrahedron 1994, 50, 5109.
Article Identifier:
1437-210X,E;2000,0,02,0273,0280,ftx,en;P04299SS.pdf
(18) Harding, K. E.; Clement, R. S.; Gilbert, J. L.; Wiechman, B.
J. Org. Chem. 1984, 49, 2049.
Synthesis 2000, No. 2, 273–280 ISSN 0039-7881 © Thieme Stuttgart · New York