Efficient regioselective synthesis of 6-amino-5-benzoyl-1-substituted 2 (1H)-pyridinones

Article abstract of DOI:10.1021/jo0515428

A regioselective and efficient approach toward 6-amino-5-benzoyl-1- substituted 2(1H)-pyridinones by reaction of acyclic ketene aminals with propiolic acid ester was developed. The effect of the solvent and temperature on the regioselectivity of the react

Full text of DOI:10.1021/jo0515428

Efficient Regioselective Synthesis of
6-Amino-5-benzoyl-1-Substituted 2(1H)-Pyridinones
Hartmut Schirok,* Cristina Alonso-Alija, Jordi Benet-Buchholz,† Andreas H. Go¨ller,
Rolf Grosser, Martin Michels, and Holger Paulsen
Bayer HealthCare AG, Pharma Research, D-42096 Wuppertal, Germany
hartmut.schirok@bayerhealthcare.com
Received July 25, 2005
A regioselective and efficient approach toward 6-amino-5-benzoyl-1-substituted 2(1H)-pyridinones
by reaction of acyclic ketene aminals with propiolic acid ester was developed. The effect of the
solvent and temperature on the regioselectivity of the reaction and the compatibility of the target
compounds to functional group manipulations was examined. Substrates with an ortho substituent
build atropisomers due to the restricted rotation around the C-N bond. The enantiomers were
separated, and the barrier of rotation was determined experimentally. Quantum chemical
calculations allowed a ranking of the barrier heights, and a new mechanism of rotation by
deformation of the central pyridinone moiety is proposed.
Introduction
pyrrolones 7-9,7 and 3-hydroxy-5-imino-1,5-dihydro-2H-
pyrrol-2-ones 10.8 Furthermore, seven-membered 1H-
imidazo[1,2-b][2]benzazepin-5-ones 11 are obtained with
2-(bromomethyl)benzoate.9
Ketene aminals are powerful and versatile intermedi-
ates in heterocyclic synthesis. Reactions of cyclic ketene
aminals of the general formula 1 with 1,2- and 1,3-
bisacceptor substrates leading to five- and six-membered
heterocycles have been reported repeatedly during the
past three decades (Figure 1).1 Depending on the elec-
trophile used, a vast number of different heterocyclic
structures is accessible. Among the six-membered ring
systems, hydropyridines and pyridinones such as 2-ami-
notetrahydropyridines 2,2 6-aminodihydropyridinones 3,3
6-aminopyridinones 4,4 and dihydropyridine-2-amines 55
have been synthesized, while the group of five-membered
heterocycles includes aminopyrroles 6,6 5-aminodihydro-
The two electron-donating amino groups on the one end
and the electron-withdrawing effect of the carbonyl
moiety on the other end of the ketene aminal system 1
cause a strong polarization of the remarkably long (1.38-
1.47 Å) carbon-carbon double bond in the push-pull
ethylene.10 This determines the reactivity of the com-
pound class 1, which is characterized by the fact that the
enaminic R-carbon atom is more nucleophilic than the
two nitrogen atoms.11 For example, simple electrophiles
such as benzylic halides react selectively at the carbon
atom (Figure 1, 1 f 12).7a,12
* To whom correspondence should be addressed.
† Bayer Industry Services, Analytics, X-ray Laboratory, D-51368
Leverkusen, Germany. Present address: Institut Catala` d’Investigacio´
Qu´ımica (ICIQ), Avgda. Pa¨ısos Catalans, s/n, 43007 Tarragona, Spain.
(1) For reviews, see: (a) Huang, Z.; Wang, M. Heterocycles 1994,
37, 1233-1262. (b) Wang, M.; Huang, Z. Prog. Natl. Sci. 2002, 12, 249-
257. For a more recent work, see: Sharon, A.; Maulik, P. R.; Roy, R.;
Ram, V. J. Tetrahedron Lett. 2004, 45, 5815-5818.
(6) Nie, X.-P.; Wang, M.-X.; Huang, Z.-T. Synthesis 2000, 10, 1439-
1443.
(7) (a) Gupta, A. K.; Ila, H.; Junjappa, H. Synthesis 1988, 284-286.
(b) Huang, Z.-T.; Liu, Z.-R. Chem. Ber. 1989, 122, 95-100. (c) Zhang,
J.-H.; Wang, M.-X.; Huang, Z.-T. J. Chem. Soc., Perkin Trans. 1 1999,
321-326.
(8) Yu, C.-Y.; Wang, L.-B.; Li, W.-Y.; Huang, Z.-T. Synthesis 1996,
959-962.
(9) Xu, Z.-H.; Jie, Y.-F.; Wang, M.-X.; Huang, Z.-T. Synthesis 2002,
523-527.
(2) Jones, R. C. F.; Patel, P.; Hirst, S. C.; Turner, I. Tetrahedron
1997, 53, 11781-11790.
(3) (a) Huang, Z.-T.; Liu, Z.-R. Heterocycles 1986, 24, 2247-2254.
(b) Jones, R. C. F.; Smallridge, M. J. Tetrahedron Lett. 1988, 29, 5005-
5008. (c) Jones, R. C. F.; Patel, P.; Hirst, S. C.; Smallridge, M. J.
Tetrahedron 1998, 54, 6191-6200.
(4) (a) Huang, Z.-T.; Tzai, L.-H. Chem. Ber. 1986, 119, 2208-2219.
(b) Huang, Z.-T.; Liu, Z.-R. Synth. Commun. 1989, 19, 1801-1812. (c)
Huang, Z.-T.; Wang, M.-X. J. Chem. Soc., Perkin Trans. 1 1993, 1085-
1090. (d) Zhao, M.-X.; Wang, M.-X.; Huang, Z.-T. Tetrahedron 2002,
58, 1309-1316.
(5) Zhang, J.-H.; Wang, M.-X.; Huang, Z.-T. J. Chem. Soc., Perkin
Trans. 1 1999, 2087-2094.
(10) (a) Destro, R.; Cosentino, U.; Moro, G.; Ortoleva, E.; Pilati, T.
J. Mol. Struct. 1989, 212, 97-111. (b) Wang, X.-J.; Zhu, M.-J.; Guo,
F.; Liu, Z.-R.; Huang, Z.-T. J. Struct. Chem. 1991, 10, 103-105. (c)
Jones, R. C. F.; Martin, J. N.; Smith, P.; Gelbrich, T.; Light, M. E.;
Hursthouse, M. B. Chem. Commun. 2000, 1949-1950. (d) Jones, R.
C. F.; Dimopoulos, P. Tetrahedron 2000, 56, 2061-2074. (e) Sottofat-
tori, E.; Anzaldi, M.; Balbi, A.; Artali, R.; Bombieri, G. Helv. Chim.
Acta 2002, 85, 1698-1705.
(11) Huang, Z.-T.; Liu, Z.-R. Synthesis 1987, 357-362.
10.1021/jo0515428 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/19/2005
J. Org. Chem. 2005, 70, 9463-9469
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Schirok et al.
SCHEME 2. Preparation of Ketene Aminalsa
a Reagents and conditions: (a) Corresponding aniline, salicylic
aldehyde (cat.), piperidine (cat.), ethanol, reflux. (b) p-Chlo-
rothiophenol, ethanol/chloroform, HCl (gas), rt. (c) Corresponding
aniline, acetic acid, 80 °C.
Results and Discussion
Synthesis of Amino 2(1H)-Pyridinones. For the
intended approach we desired a general and convenient
method to the ketene aminals 13 allowing the incorpora-
tion of various anilinic residues. The synthesis of 3-amino-
3-anilino-1-phenylprop-2-en-1-ones 13 in a single step
from benzoylacetonitrile 17 and anilines in ethanol
employing a catalytic system comprising salicyclic alde-
hyde and piperidine has been described in the literature
(Scheme 2, pathway a).15 In our hands this procedure led
to the desired ketene aminals 13 in satisfactory yields
in several cases (Table 1, method A). However, the
addition became very sluggish in instances of sterically
hindered anilines bearing substituents in an ortho posi-
tion (Table 1, 13x) with the exception of electron-rich
anilines such as 2,4-dimethoxyaniline (13z) and failed
in the presence of certain functional groups such as
hydroxyl groups (see 13r). Literature precedent exists for
an alternative two-step route leading to the same net
product.16,17 The required intermediate 18 was generated
by nucleophilic addition of the thiophenol to the nitrile
17 in a mixture of diethyl ether and chloroform saturated
with hydrogen chloride (Scheme 2).18 The subsequent
substitution with anilines was performed in acetic acid
at 80 °C. This protocol proved to be a robust and reliable
method to generate the ketene aminals 13. It was done
easily in high yields even on a multigram scale and
tolerated numerous functional groups on the aniline, such
as ethers, thioethers, amines, amides, phosphonates,
carboxylic esters, alcohols, and phenol moieties (Table
1, method B). The sterically hindered ortho-substituted
anilines such as o-methyl- (13x), o-isopropyl- (13y), and
FIGURE 1. Heterocycles derived from cyclic ketene aminals.
SCHEME 1. Reaction of Noncyclic Ketene
Aminals 13 with Propiolic Ester 14
By the reaction of ketene aminals 1 with methyl
propiolate, a pyridinone moiety is formed (Figure 1, 1 f
4). An aza-ene mechanism has been proposed for this
reaction.3a,4c,5 However, it is difficult to rule out other
pathways comprising a Michael addition13 or a [2+2]
cycloaddition with a subsequent rearrangement.
In connection with a recent medicinal chemistry pro-
gram, we required a practical synthesis of 6-aminopyri-
dinones of the generic structure 15 (Scheme 1).14 There-
fore, we envisioned the cyclization of mono-N-substituted
ketene aminals 13 with propiolic acid methyl ester 14 to
be a suitable route to the desired structures in analogy
to the preparation of 4 (Figure 1). However, in contrast
to the application of cyclic aminals 1, very little is known
about the reactivity of monosubstituted and therefore
noncyclic ketene aminals of the generic structure 13.
Depending on the relative nucleophilicity of the primary
compared to the secondary amino function, we expected
mixtures of regioisomers 15 and 16.
(15) (a) Krishnamurti, P. J. Chem. Soc. 1928, 415-417. (b) Veer,
W. L. C. Recl. Trav. Chim. Pays-Bas 1950, 69, 1118-1121.
(16) (a) Meier, E.; Glockner, H.; Kuffner, K.; Boie, I. â-Amino-â-imino
acid esters. British Patent DT 1,409,987, Jan 31, 1974. (b) Todo, Y.;
Yamafuji, T.; Nagumo, K.; Kitayama, I.; Nagaki, H.; Miyajima, M.;
Konishi, Y.; Narita, H.; Takano, S.; Saikawa, I. Nicotinic acid deriva-
tives. U.S. Patent 4,851,535, Jul 25, 1989.
(17) An alternative synthesis was published in the following: Wood-
man, D. J.; Murphy, Z. L. J. Org. Chem. 1969, 34, 3451-3456. For
further methods for N,N′-disubstituted ketene aminals from activated
methylene compounds and isothiocyanates, see: (a) Barun, O.; Ila, H.;
Junjappa, H.; Singh, O. M. J. Org. Chem. 2000, 65, 1583-1587. (b)
Shi, Y.; Zhang, J.; Grazier, N.; Stein, P. D.; Atwal, K. S.; Traeger, S.
C.; Callahan, S. P.; Malley, M. F.; Galella, M. A.; Gougoutas, J. Z. J.
Org. Chem. 2004, 69, 188-191 and references therein.
(18) The chloroform must be ethanol free. When ethanol-stabilized
chloroform was used, the product contained a substantial amount of
the ethyl imidoate. This compound was transformed into the desired
amidine in low yield, see also ref 11 and Shilcrat, S. C.; Mokhallalati,
M. K.; Fortunak, J. M. D.; Pridgen, L. N. J. Org. Chem. 1997, 62, 8449-
8454.
(12) Li, Z.-J.; Smith, C. D. Synth. Commun. 2001, 31, 527-533.
(13) Kno¨lker, H.-J.; Boese, R.; Hitzemann, R. Heterocycles 1989, 29,
1551-1558.
(14) The synthesis of 6-amino-5-benzoyl-4-methyl-1-phenylpyridin-
2(1H)-one was described in the following: Wardakhan, W. W.; Agami,
S. M. Egypt J. Chem. 2001, 44, 315-333.
9464 J. Org. Chem., Vol. 70, No. 23, 2005

Synthesis of Substituted 2(1H)-Pyridinones
TABLE 1. Isolated Yields of Ketene Aminals 13 and Cyclized Products 15
a Synthesis of the ketene aminal: Method A, directly from benzoylacetonitriles 17; Method B, by substitution of p-chlorothiophenol.
Cf. Scheme 2. b Cyclization in methanol with methyl propiolate at reflux for 1.5-3 h. Yields given are isolated yields. c Substantial amount
of the regioisomer 16 was detected by HPLC but not isolated.
o-morpholinoaniline (13bb) yielded the desired aminals
in almost 90% yield. Even the electron-poor 2,6-difluoro
aniline derivative (13aa) was prepared in 73% yield using
the two-step method. With 2,6-difluorobenzene-1,4-di-
amine we isolated exclusively the product resulting from
the reaction of the less hindered 4-amino group (13w).
J. Org. Chem, Vol. 70, No. 23, 2005 9465

Schirok et al.
SCHEME 3. Goldberg Reaction Leading to
6-Anilinopyridin-2(1H)-one 21a
FIGURE 2. NMR data of the regioisomers 15 and 16.
a Reagents: (a) 0.05 equiv of CuI, 0.2 equiv of trans-1,2-
The subsequent cyclization of the aminals 13 with
propiolic acid methyl ester 14 to the target pyridinones
15 was next investigated (Scheme 1). To the best of our
knowledge, such asymmetric ketene aminal substrates
have not been used in this reaction so far. However,
similar reactions of cyclic ketene aminals4 and phenyl-
acetylimidazoles,13,19 both containing two equivalent ni-
trogens, have been reported.20 Alternatively to propiolic
acid methyl ester 14, propiolic acid with carbonyldi-
imadazole as activator is used very often.3c,21
diaminocyclohexane, 2.0 equiv of K3PO4, 35% yield.
SCHEME 4. Model System for Examination of the
Reaction Conditions
On the basis of previous studies, cyclization of ketene
aminals 13 was expected but with uncertain regioselec-
tivity. We were then pleased to find out that heating of
ketene aminal 13a with methyl propiolate in methanol
resulted in a single isolated compound in 83% yield.
Many functional groups were compatible with the cy-
clization conditions, including alkyl, halogen, ether, and
thioether moieties, amines, amides, carboxylates, phos-
phonates, alcohols, and phenols. However, if ortho-
substituted anilines were built in the ketene aminal, the
regioselectivity of the cyclization dropped. For example,
the crude product of the cyclization of 13y was a 4:1
mixture of regioisomers as determined by LC-MS. In
some cases the minor component 16 was isolated for
structure assignment. As such the 2,6-difluoro derivative
13aa gave 43% of the desired compound 15aa ac-
companied by 4% of its regioisomer 16aa. The o-mor-
pholino-substituted substrate 13bb yielded a 3:2 mixture
of regioisomers 15bb and 16bb.
TABLE 2. Variations of the Reaction Conditions and
Product Distribution (HPLC)
temp., time,
%
%
%
%
entry
solvent
°Ca
h
13z 15z 16z 22z
1
MeOH
65
40
rt
40
rt
65
65
65
65
65
65
65
65
2
2
60
52
67
69
78
5
13
8
16
33
22
25
18
89
2
MeOH
2
2
3
MeOH
20
4
6
3
4
MeOH/H2O (5:1)
MeOH/H2O (5:1)
EtOH
2
4
5
24
2
2
2
6
4
2
7
HOAc
2
63
<5
15
3
8
8
DMF
2
3
1
5
1
1
2
3
84
83
62
95
95
94
9
EtOAc
2
1
10
11
12
13
DMSO
2
5
THF
2
4
acetone
toluene
2
4
2
4
The structures of the regioisomeric pyridinones 15 and
16 were unambiguously assigned by NMR after isolation
of both compounds. Without exception, in compounds of
general structure 15 the 1H NMR signal of the 3-H next
to the pyridinone carbonyl appears in the range of 5.65-
a The reactions were performed with methyl propiolate (R′ )
Me) on a 50 mg scale in sealed pressure test tubes. The temper-
ature given is the temperature of the preheated oil bath.
the solvent. In a series of reactions using 13z (Scheme
4) as a test system we analyzed the reaction mixtures
by HPLC. After 2 h in refluxing methanol (Table 2, entry
1) we detected traces of starting material, 60% of the
desired isomer 15z, 13% of the regioisomer 16z, and 16%
of the noncyclized intermediate 22z. As expected, the
product distribution (15z:16z ) 4.6:1 at 65 °C) was
shifted to product 15z when the reaction temperature
was lowered to 40 °C (15z:16z ) 6.5:1, entry 2). Running
the reaction at room temperature resulted in a high
regioselectivity of 22:1, but a 10-fold extended reaction
time was needed to reach the same conversion (entry 3).
The addition of water to the solvent had a beneficial
effect. In a methanol-water mixture (5:1) the product
distribution changed from 17:1 at 40 °C (entry 4) to 39:1
at room temperature with a prolonged reaction time
(entry 5). Cyclization did not occur in other solvents. Even
in ethanol instead of methanol we detected almost
exclusively the intermediate product 22z (entry 6).
Similar results were obtained using dipolar aprotic
solvents such as dimethylformamide, ethyl acetate, di-
3
5.74 ppm (Figure 2). The J coupling constant (between
3-H and 4-H) was determined to be 9.6-9.8 Hz. For the
corresponding regioisomers 16 the 3-H signal is shifted
consistently downfield to above 5.9 ppm. Evidence for the
correct assignment comes from the analysis of the model
system 21 which was synthesized in a Goldberg reaction22
from 6-aminopyridin-2(1H)-one 20 as depicted in Scheme
3. Its analogous proton produces a resonance peak at 5.92
ppm. Furthermore, the X-ray structure of (S)-15z con-
firmed this assignment (see Supporting Information).
Reaction Conditions and Product Distribution.
During our investigations we studied the product distri-
bution dependence on the reaction conditions, especially
(19) Dzvinchuk, I. B.; Vypirailenko, A. V.; Lozinskii, M. O. Chem.
Heterocycl. Compd. (Engl. Transl.) 2001, 37, 1096-1101.
(20) For a similar reaction of enaminones with propiolic ester leading
to N-aryl pyridinones, see: Savarin, C. G.; Murry, J. A.; Dormer, P.
G. Org. Lett. 2002, 4, 2071-2074.
(21) We reported on the application of in-situ-generated propiolic
acid chloride in a similar reaction, see: Schirok, H.; Alonso-Alija, C.;
Michels, M. Synthesis 2005, in press.
9466 J. Org. Chem., Vol. 70, No. 23, 2005

Synthesis of Substituted 2(1H)-Pyridinones
TABLE 3. Influence of the Alcohol Residue in the
Propiolic Ester on the Product Distributiona
entry
R′ (14)
% 13z
% 15z
% 16z
% 22z′
1
2
3
4
Me
Et
iPr
tBu
<5
<5
60
46
33
13
13
34
24
16
36
17
56
<5
FIGURE 3. Methaqualone 23 and 4,6-dimethyl-1-phenylpy-
rimidin-2(1H)-ones 24.
a All reactions were performed on a 50 mg scale in methanol at
65 °C for 2 h in sealed pressure test tubes.
the enantiomeric excess appeared to be much slower and
could be followed accurately in a time frame of days.24
For 15z the half-life at 100 °C was determined to be 15
days. The energy barrier of rotation was calculated to be
139.0 kJ mol-1, which corresponds to a half-life of 4050
years at room temperature.25 This energy barrier is
methyl sulfoxide, tetrahydrofuran, and acetone (entries
8-12) and in toluene (entry 13). In the latter three
solvents product 22z was obtained in high purity. The
1
vinylic coupling constant of 15.7 Hz in the H NMR of
22z proves the E configuration of the double bond R,â to
the ester as depicted in Scheme 4. When 22z was heated
in methanol at 65 °C we obtained a 4.5:1 mixture of 15z
and 16z very similar to entry 1. This shows that a facile
E/Z isomerization must occur under the cyclization
conditions. In acetic acid most of the starting material
13z was not consumed (entry 7).
The influence of the alkyl group R′ in the propiolic ester
14 was also examined (Table 3). With ethyl instead of
methyl propiolate as reagent a product distribution of
15z:16z of 3.5:1 was found after 2 h at 65 °C in methanol
(entry 2). In the case of isopropyl propiolate, a 1:1 mixture
of 15z and 16z was obtained (entry 3). When tert-butyl
propiolate was used, the cyclization step slowed signifi-
cantly. In this case product 15z was not detected (entry
4).
similar to that reported for 23 (131.6 kJ mol-1 26
and 24
)
(114-126 kJ mol-1 27
(Figure 3).
)
The absolute configuration of (S)-15z ([R]D20.5 ) -30.6°,
c ) 0.665, DCM) was assigned by X-ray analysis (see
Supporting Information).
Mechanism of Rotation. Rotational barriers may be
resolved by computational approaches. Force fields, as
used for 24 (R1 ) OMe, Figure 3),27a calculate only steric
hindrance and neglect any stabilizing electronic effects.
Pure ab initio Hartree-Fock as calculated for derivatives
of 23 (Figure 3, HF/6-31G*)26b accounts for steric hin-
drance but neglects the electron correlation part of
electronic interactions.28 Quantitative values could be
obtained by hybrid density functional or highly correlated
ab initio methods but are not feasible due to computa-
tional limitations. We used semiempirical AM1 theory29
to rank compounds qualitatively by relative barrier
(VAMP6.5,30 details are given in the Supporting Informa-
tion).
From o-pyridine to o-isopropyl the barrier increases
continuously with increasing size of the substituent.
There is mostly no effect with introduction of a p-methoxy
group and some lowering with introduction of a m-
methoxy residue. The ranking is in line with the occur-
rence of separable enantiomers.
Atropisomerism and Absolute Configuration. For
highly congested systems comprised of ortho-substituted
aryl pyridinones, the question arose whether rotation
around the C-N bond forming the biarylic axis was
1
restricted. In the H NMR spectrum of 15y two doublet
signals for the methyl groups of the o-isopropyl substitu-
ent appear at 1.09 and 1.19 ppm. Similarly, in the 13C
NMR spectrum the signals of the two methyl groups on
the isopropyl moiety are distinguishable at 23.1 and 23.4
ppm. This pattern is characteristic for diastereotopic
groups, thus indicating a stereogenic element in the
molecule. In the case of a hindered rotation of the aryl
ring around the inter-ring C-N bond, a stereogenic axis
is defined by this bond, thus explaining the phenomenon
The coarse correlation between barrier heights and
inter-ring dihedrals clearly suggests that electronic ef-
fects have only a negligible role compared with steric
effects. Therefore, the question for the mechanism of
1
through the existence of atropisomers. In the H NMR
(24) Time vs ee: 0 day, 98.2% ee; 2 days, 91.1% ee; 4 days, 79.7%
ee; 7 days, 70.4% ee; 9 days 65.2% ee; 11 days, 59.3% ee; 14 days, 51.3%
ee; 16 days, 47.0% ee; 21 days, 38.3% ee; 23 days, 33.2% ee. Linear
regression of ln(ee(o)/ee) vs t: y ) 5.3423E-7, R2 ) 0.998. k )
2.671E-7 [1/s]. ∆Gq ) 139.0 kJ mol-1. t1/2 (100 °C) ) 15 days, t1/2 (25
°C) ) 4054 years.
of the o-morpholino compound 15bb a similar effect is
observed. The hydrogens of the morpholino group nor-
mally show up as two multiplets at 3.2 and 3.7 ppm, as,
for example, in the meta-regioisomer 15s. In case of the
o-morpholino residue in compound 15bb clearly resolved
signals at 2.73 (2H), 2.87 (2H), and 3.48 (4H) ppm are
observed.
The enantiomers of the ortho-substituted derivatives
were separable by preparative chiral HPLC (15y, 15z).23
In the case of the meta-substituted analogue 15m no
separation was achieved at room temperature. Enan-
tiopure 15z was completely racemized in DMSO solution
at 160 °C within 2 h. In boiling water the decrease of
(25) Ernst, L. ChiuZ 1983, 17, 21-30.
(26) (a) Mannschreck, A.; Koller, H.; Stu¨hler, G.; Davies, M. A.;
Traber, J. Eur. J. Med. Chem. Chim. Ther. 1984, 19, 381-383. (b)
Azanli, E.; Rothchild, R.; Sapse, A.-M. Spectrosc. Lett. 2002, 35, 257-
274.
(27) (a) Kashima, C.; Katoh, A. J. Chem. Soc., Perkin Trans. 1 1980,
1599-1602. (b) Roussel, C.; Adjimi, M.; Chemlal, A.; Djafri, A. J. Org.
Chem. 1988, 53, 5076-5080. (c) Sakamoto, M.; Utsumi, N.; Ando, M.;
Saeki, M.; Mino, T.; Fujita, T.; Katoh, A.; Nishio, T.; Kashima, C.
Angew. Chem. 2003, 115, 4496-4499; Angew. Chem., Int. Ed. 2003,
42, 4360-4363.
(28) (a) Go¨ller, A.; Grummt, U.-W. Chem. Phys. Lett. 2000, 321, 399-
405. (b) Go¨ller, A.; Grummt, U.-W. Chem. Phys. Lett. 2002, 354, 233-
242.
(22) (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421-7428. (b) Li, C. S.; Dixon, D. D. Tetrahedron Lett.
2004, 45, 4257-4260.
(23) Column: KBD 6175, 250 mm × 20 mm. Eluent: isohexane/
ethyl acetate 60:40. Temperature: 23 °C. Flow: 15 mL/min. UV
detection: 254 nm.
(29) Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P.
J. Am. Chem. Soc. 1985, 107, 3902-3909.
(30) Clark, T.; Alex, A.; Beck, B.; Burckhardt, F.; Chandrasekhar,
J.; Gedeck, P.; Horn, A.; Hutter, M.; Martin, B.; Rahut, G.; Sauer, W.;
Schindler, T.; Steinke, T. VAMP 8.0; Erlangen, 2001.
J. Org. Chem, Vol. 70, No. 23, 2005 9467

Schirok et al.
Synthetic Functionalization. As an additional as-
pect we became interested in the reactivity of the common
core of the compounds and its compatibility with func-
tional group interconversions. Concerning the amino
group we knew from the X-ray structure as well as from
the 1H NMR spectra that a strong hydrogen bond toward
the carbonyl oxygen is formed. We therefore questioned
whether we could alkylate or acylate the amino function.
Our attempts to benzylate or benzoylate the nitrogen
failed. However, with the very reactive bromoacetic acid
tert-butylester we were able to get the desired product
25 in 72% yield. The ester moiety was subsequently
cleaved with trifluoroacetic acid almost quantitatively,
and the resulting acid 26 was coupled to amides 27a-c
(Scheme 5).
The low reactivity of the amino group encouraged us
to evaluate transformations that are not compatible with
a nucleophilic nitrogen. In this way we managed to
mesylate the benzylic alcohol 15q in the presence of the
unprotected amino function in 89% yield. The resulting
building block gave us access to a variety of benzylic
amines 29a-c (Scheme 6).
FIGURE 4. Ground-state and transition-state structures of
15a, and the numbering schemes for the inter-ring dihedral
C-N-C-C and out-of-plane deformation C-N-C (see Sup-
porting Information).
Amides may also be generated on a benzoic acid
moiety. The acid 30 was liberated by hydrolysis of the
methyl ester 15p with lithium hydroxide in 96% yield.
Starting with this benzoic acid, amides 31a-c were
generated in high yields with amines and anilines using
polymer bound DCC and hydroxybenzotriazole. Dimer
formation was not observed (Scheme 7).
rotation arises. While in the literature, on one hand, a
pronounced C-N bond elongation for the transition
states27a and, on the other hand, a 3,3-electrocyclic reac-
tion with ring opening and closure has been suggested,27b
we propose a different mechanism: The rotational barrier
is significantly lowered by a pronounced deplanarization
of the central pyridinone ring, thereby bending the
rotating phenyl ring out of the plane in the one and the
coplanar 1,3-amino carbonyl group in the other direction.
The angles C-N-C (defined in Figure 4) for all com-
pounds vary only slightly around 150°; for 15y, with the
highest barrier, it is 144°.
Conclusions
The cyclization of noncyclic ketene aminals of the
general structure 13 with methyl propiolate in methanol
provides a versatile short synthesis of 6-amino-5-benzoyl-
SCHEME 5. Derivatization of 15 with Bromoacetatea
a Reagents and conditions: (a) tert-Butyl bromoacetate, K2CO3, acetone, reflux. (b) Trifluoroacetic acid, DCM, rt. (c) DCC, HOBt, DCM,
DMF, corresponding amine, rt.
SCHEME 6. Alkylation of Mesylate 28a
a Reagents and conditions: (a) MsCl, TEA, DCM, 0 °C f rt. (b) Corresponding amine, THF, rt.
SCHEME 7. Syntheses of Amides 31a
a Reagents and conditions: (a) LiOH, methanol/water, 35 °C. (b) DCC, HOBt, DCM, DMF, corresponding amine, rt.
9468 J. Org. Chem., Vol. 70, No. 23, 2005

Synthesis of Substituted 2(1H)-Pyridinones
1-substituted 2(1H)-pyridinones 15 under mild condi-
tions. The predominant product results from the reaction
of the arylated nitrogen of the aminal. Only methanol or
methanol/water mixtures were found to be suitable
solvents for formation of the target compounds. As
expected for a kinetically controlled product distribution,
by lowering the reaction temperature from reflux to room
temperature, the regioselectivity increases while the
speed of the reaction slows down. The selectivity is also
dependent on the size of the ester group. Presumably due
to steric repulsion in the ring-forming step, the product
distribution can be shifted to the isomeric product 16 with
bulkier esters. In unsymmetrically ortho-substituted
derivatives the barrier of rotation around the C-N-bond
in the N-aryl pyridinones is high enough to isolate the
atropisomers at room temperature. The experimental
examination of the racemization reveals a barrier height
of 139 kJ/mol for 15z. We proposed a probable mechanism
of rotation which comprises the deformation of the central
pyridinone moiety in the transition state. The reactivity
of the amino function is very low, allowing functional
group interconversions which are normally not possible
in the presence of an amino function.
Acknowledgment. We thank Dr. P. Schmitt, C.
Streich, and D. Bauer for recording NMR spectra and
helpful discussions. In addition, we are grateful to M.
Stoltefuâ, G. Wiefel-Hu¨bschmann, and S. Brauner for
HRMS measurements.
Supporting Information Available: ORTEP-plot of (S)-
15z; details on computations; experimental methods and
compound data; 1H and 13C NMR spectra of compounds 15b-
h,j-k,n-z,aa,bb,cc, 18b, 21, 22z, 25, 26, 27a-c, 29a-c, and
31a-c; X-ray crystallographic data (CIF file) of compound (S)-
15z. This material is available free of charge via the Internet
at http://pubs.acs.org. The supplementary crystallographic
data for this paper (CCDC 273344) can also be obtained free
of charge via www.cc.dc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12, Union
road, Cambridge CB2 1EZ, U.K. Fax: +44 1223 336033.
E-mail: deposit@ccdc.cam.ac.uk).
JO0515428
J. Org. Chem, Vol. 70, No. 23, 2005 9469