Synthesis and the keto-enol equilibrium of 2-acyl lactams

Article abstract of DOI:10.1023/B:RUCB.0000012373.06094.ff

Condensation of N-substituted lactams with carboxylic acid esters was studied. A wide range of substituted 2-acyl lactams with different ring sizes were synthesized. The structure of 2-acyl lactams (primarily, the ring size) was found to influence the ket

Full text of DOI:10.1023/B:RUCB.0000012373.06094.ff

Russian Chemical Bulletin, International Edition, Vol. 52, No. 11, pp. 2473—2482, November, 2003
2473
Synthesis and the ketoꢀenol equilibrium of 2ꢀacyl lactams
V. G. Nenajdenko,ꢀ A. M. Gololobov, E. P. Zakurdaev, and E. S. Balenkova
Department of Chemistry, M. V. Lomonosov Moscow State University,
Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (095) 932 8846. Eꢀmail: nen@acylium.chem.msu.ru
Condensation of Nꢀsubstituted lactams with carboxylic acid esters was studied. A wide
range of substituted 2ꢀacyl lactams with different ring sizes were synthesized. The structure of
2ꢀacyl lactams (primarily, the ring size) was found to influence the ketoꢀenol tautomerism.
Key words: lactams, protective groups, Claisen condensation, 2ꢀacyl lactams, ketoꢀenol
tautomerism.
Nitrogenꢀcontaining heterocycles are the most wideꢀ
spread heterocyclic compounds involved in the majority
of alkaloids, many biologically active compounds, and
pharmaceuticals.1 Analysis of the data published in the
literature demonstrates that the synthetic potential of
lactams (many of which are commercially available) was
employed to only a small extent. However, the use of
lactams offers considerable possibilities both for the conꢀ
struction of fiveꢀ, sixꢀ, and sevenꢀmembered heterocyclic
compounds and the design of other products valuable
from the viewpoint of organic synthesis and medicinal
chemistry.
2ꢀAcyl lactams containing the 1,3ꢀdicarbonyl system
are of particular interest in this respect. The carbonyl
groups in these compounds differ substantially in the reꢀ
activity, which opens up possibilities for chemoꢀ and
regioselective heterocyclization of unsymmetrical biꢀ
nucleophiles.
Condensation of lactams with carboxylic acid esters is
one of the most convenient approaches to the synthesis of
2ꢀacyl lactams, in which readily accessible and inexpenꢀ
sive Nꢀvinylpyrrolidone is generally used. Data on the
synthesis of sixꢀ or sevenꢀmemberedꢀring 2ꢀacyl lactams
are lacking in the literature (or they are episodic). Conꢀ
densations based on Nꢀvinylpyrrolidone have also not reꢀ
ceived systematic investigation. In the present study, we
examined Claisen condensation with protected fiveꢀ, sixꢀ,
and sevenꢀmembered lactams with the aim of developing
a general procedure for the synthesis of 2ꢀacyl lactams
containing aliphatic, aromatic, or heteroaromatic subꢀ
stituents.
Available Nꢀvinylpyrrolidone and Nꢀvinylcaprolactam
were chosen as precursors. In the case of valerolactam,
the corresponding Nꢀvinyl derivative is inaccessible. Howꢀ
ever, the diethoxymethyl protection of valerolactam has
recently been described.26
A series of procedures were developed for the syntheꢀ
sis of 2ꢀacyl lactams. Among these methods, Cꢀacylation
of Nꢀsubstituted lactams and intraꢀ and intermolecular
condensation are of most importance. Anhydrides,2
chloroanhydrides,2 fluoroanhydrides,3 carboxylic acids,4
ethyl chloroformate,5 diketene,6 lactams,7 and carboxylic
acid esters8 are used as acylating agents. Derivatives of
2ꢀoxopyrrolidineꢀ3ꢀcarboxylic acid can be prepared by
intraꢀ or intermolecular condensation.9—13 Alternative apꢀ
proaches are based on the following processes: the cleavꢀ
age and recyclization of 2ꢀaminoꢀ4ꢀoxoꢀ3ꢀsubstituted
furans14 or isooxazolinium salts,15 the addition of βꢀketo
amides at the activated double bond,16 carbonylation of
cyclic amines,17 photochemical or rhodium(II)ꢀcataꢀ
lyzed18—20 rearrangements of diazo compounds,21 and reꢀ
actions catalyzed by palladium22 and manganese23 salts.
Procedures were also developed for the synthesis of 2ꢀacyl
lactams by oxidation of 3ꢀhydroxymethylpyrrolidinꢀ
2ꢀones24 and acid hydrolysis of 2ꢀcyanolactams.25
It appeared that the reaction has a general character.
This reaction can be carried out with esters containing
various substituents, among which are electronꢀdonating
and ꢀwithdrawing (het)aromatic and aliphatic (primary,
secondary, and tertiary) substituents as well as sterically
hindered and cage substituents. Condensation can be used
for the preparation of a wide range of fiveꢀ, sixꢀ, or sevenꢀ
memberedꢀring 2ꢀacyl lactams in high yields (Scheme 1,
Table 1). This method proved to be convenient, efficient,
and easily scalable. The exceptions are nitro derivatives.
Thus, attempts to perform condensation of Nꢀvinylꢀ
pyrrolidone with ethyl 4ꢀnitrobenzoate did not lead to the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2338—2347, November, 2003.
1066ꢀ5285/03/5211ꢀ2473 $25.00 © 2003 Plenum Publishing Corporation

2474
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Nenajdenko et al.
desired result; instead, the reaction gave rise to a complex
mixture of products.
protective vinyl group appeared to be stable enough for
condensation and isolation of 2ꢀacyl lactam. By contrast,
the protective diethoxymethyl group is subjected to parꢀ
tial hydrolysis giving rise to the Nꢀformyl derivative in the
course of quenching of the reaction mixture and isolation
of the final product. For comparison, condensation of
fiveꢀ and sixꢀmembered Nꢀmethyl lactams with ethyl benꢀ
zoate (compounds 16 and 19) afforded products in higher
yields.
Scheme 1
In many cases, the synthesis procedure described in
the literature (method A) gave unsatisfactory results.
Therefore, in some cases we optimized the reaction conꢀ
ditions. It appeared that the use of more than 1.35 equiv.
of sodium hydride was inefficient and led to resinification.
The reaction can be accelerated using a higherꢀboiling
solvent (for example, xylenes). To the contrary, the use of
benzene substantially decreases the reaction rate (toluene
i. 1) NaH, PhMe, ∆; 2) satur. NH4Cl; 50—97% yield.
We found that the yield depends on the ring size. The
sevenꢀmemberedꢀring products were prepared in lower
yields compared to the fiveꢀmemberedꢀring analogs. The
Table 1. Acylation of Nꢀprotected lactams with esters
Comꢀ
pound
n
R1
R2
R3
R4
Method
Yield
(%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
1
Ph
3,4ꢀCl2ꢀС6H3
3,5ꢀ(МеO)2ꢀС6H3
3ꢀMe2NꢀС6H4
3ꢀpy
4ꢀClꢀС6H4
4ꢀFꢀС6H4
4ꢀMe2NꢀС6H4
4ꢀMeOꢀС6H4CH2
4ꢀMeOꢀС6H4
4ꢀPhꢀС6H4
4ꢀpy
Et
Et
Et
Et
Et
Et
Et
Et
Et
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
Me
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
Me
CH2=CH
CH2=CH
Me
CHO
CHO
CHO
CHO
CHO
H
A
B
A
A
B
B
B
A
B
A
A
B
A
B
B
A
A
A
A
A
A
A
B
A
A
B
A
A
B
B
A
B
B
B
A
A
79
88
75
84
82
87
83
84
77
92
70
92
97
62
74
91
72
63
76
73
73
71
77
84
85
89
82
83
85
77
76
69
64
65
75
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
Et
Et
Ме
Et
Ме
Ме
Et
Ме
Et
Et
Et
Et
Ме
Et
Ме
Et
Ме
Ме
Et
Et
Et
Et
Et
Me
Et
Et
Bn
Ме
MeSCH2
Ph
1ꢀAd
But
CH2=CH
CH2=CH
Mе
Ph
Ph
CH(OEt)2
CH(OEt)2
CH(OEt)2
CH(OEt)2
CH(OEt)2
CH(OEt)2
CH(OEt)2
CH(OEt)2
CH(OEt)2
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
CH2=CH
3ꢀBrꢀС6H4
1ꢀMeOꢀnaphthalenꢀ2ꢀyl
2ꢀPhꢀquinolinꢀ4ꢀyl
3ꢀMeOꢀnaphthalenꢀ2ꢀyl
4ꢀMe2NꢀС6H4
4ꢀpy
5ꢀBrꢀ2ꢀMeOꢀС6H3
5ꢀClꢀ2ꢀMeOꢀС6H3
2ꢀpy
CH(OEt)2
CHO
CHO
CH2=CH
CH2=CH
CH2=CH
Н
CH2=CH
CH2=CH
CH2=CH
CH2=CH
3ꢀpy
4ꢀMeꢀС6H4
cycloꢀC6H11
cycloꢀC3H5
Et
Ph
4ꢀNO2ꢀС6H4
Et

Synthesis and ketoꢀenol tautomerism of 2ꢀacyl lactams Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2475
proved to be the solvent of choice). The addition of MeOH
(5 mol.%) at the beginning of the reaction makes it posꢀ
sible to initiate the reaction without sudden boiling of the
reaction mixture and increases the yields. On the whole,
it was found that methyl carboxylates are more reactive
than ethyl carboxylates.
of isolation of 2ꢀacyl lactams. Complete hydrolysis of this
group can also take place (refluxing with 1% HCl)
(Scheme 3).
Scheme 3
All esters used in this reaction can be divided into four
groups according to their nature:
1) aliphatic primary and secondary (with the αꢀCH
proton) and benzylic (with the ortho or para substituents
exhibiting the –M effect);
2) aliphatic tertiary (devoid of the αꢀCH proton) and
benzylic (with meta substituents exhibiting the –M effect);
3) aromatic containing electronꢀdonating substituents
and benzylic (with ortho or para substituents exhibiting
the +M effect);
4) (het)aromatic electronꢀwithdrawing and benzylic
(with meta substituents exhibiting the +M effect).
It was found that the condensation rate and the yields
increase successively on going from the first to fourth
group. The reactions with esters belonging to the fourth
group are accompanied by acylation of the sodium salt of
the resulting 2ꢀacyl lactam with the second equivalent of
ester as the major side process27 (Scheme 2).
i. 1% HCl, EtOH, 2 h, 20 °C. ii. 1% HCl, EtOH, ∆.
This method can also be used for removing the vinyl
group from fiveꢀ or sevenꢀmembered acyl lactams. This
made it possible to prepare a number of acyl lactams
devoid of protective groups at the nitrogen atom. A preꢀ
parative procedure was also developed for removing proꢀ
tective groups (vinyl, diethoxymethyl, and formyl) from
the nitrogen atom of fiveꢀ, sixꢀ, and sevenꢀmembered
2ꢀacyl lactams in quantitative yield. It should be noted
that the lactamꢀring opening did not occur under these
conditions.
Scheme 2
i. NaH, PhMe, ∆.
The reactions with esters belonging to the second or
third group proceed more slowly and require prolonged
heating, which leads to partial resinification and a deꢀ
crease in the yields. The reactions with esters belonging
to the first group are accompanied by ester condensation
as the side process resulting in a decrease in the yield.
To minimize selfꢀcondensation and additional acylaꢀ
tion in the case of substituents of the first and fourth
groups, respectively, esters were slowly added to a mixꢀ
ture of Nꢀprotected lactam and NaH in refluxing toluene
(method B).
The reaction mixtures were decomposed according to
two procedures, a saturated aqueous solution of NH4Cl
(2 equiv. with respect to NaH) and 20% AcOH (1 equiv.)
being used in two approaches. The first method is softer,
but gives rise to certain amounts of Schiff's bases, whereas
the second method leads to partial hydrolysis of protecꢀ
tive groups.
n = 1 (36), 3 (37)
i. 1% HCl, ∆, EtOH.
Interesting results were obtained in spectroscopic studꢀ
ies of sixꢀmembered 2ꢀacyl lactams in CDCl3. The
1H NMR spectra have a signal at low field (δ ∼13.5—15)
with a unit integral intensity. At the same time, the signal
corresponding to the proton of C(3)H at δ ∼4—5 (by
analogy with fiveꢀ and sevenꢀmembered acyl lactams) is
absent or corresponds to the minor tautomer. These facts
indicate that sixꢀmembered 2ꢀacyl lactams exist predomiꢀ
nantly in the enol form in which the double bond is conꢀ
jugated with the aromatic ring and the amide carbonyl
group. In the 13C NMR spectrum, a signal corresponding
to the tertiary carbon atom is absent (by analogy with
fiveꢀ and sevenꢀmembered rings, at δ ∼45—55); instead,
another signal corresponding to the enol form is present at
δ 90—100. The enol form can exist as cis and trans isomers.
We found that the protective diethoxymethyl group
was partially hydrolyzed to the formyl group in the course

2476
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Nenajdenko et al.
1
However, according to the H and 13C NMR spectroꢀ
scopic data, only one isomer is present because the
cis arrangement of the carbonyl groups is stabilized by an
intramolecular hydrogen bond.
To summarize, we systematically studied condensaꢀ
tion of Nꢀsubstituted fiveꢀ, sixꢀ, and sevenꢀmembered
lactams with various esters. The procedure developed in
the present study enables one to synthesize the desired
2ꢀacyl lactams with different ring sizes containing various
substituents and protective groups in high yields. It was
found that 2ꢀacyl lactams can exist in equilibrium with
the enol form, which depends, primarily, on the ring size.
A method was developed for the synthesis of Nꢀunsubꢀ
stituted 2ꢀacyl lactams.
We qualitatively studied the dependence of this equiꢀ
librium on the ring size and the nature of the acyl and
protective groups. It appeared that in none of the cases
did the reactions of sevenꢀmembered acyl lactams afford
enols. The reactions with fiveꢀmembered lactams gave
rise to enol as the minor tautomer. Apparently, the forꢀ
mation of enol depends primarily on the ring size of acyl
lactam and the strength of the electronꢀwithdrawing propꢀ
erties of the group at the acyl substituent. Upon the forꢀ
mation of a new sixꢀmembered ring involving the hydroꢀ
gen atom of enol, the geometry of 2ꢀacyl lactams is, apꢀ
parently, least distorted in the case of sixꢀmembered
piperidinꢀ2ꢀones.
Qualitatively, the influence on the shift of the equilibꢀ
rium toward enol changes in the following series: a sixꢀ
membered ring >> a fiveꢀmembered ring >> a sevenꢀmemꢀ
bered ring.
The substituent at the nitrogen atom of 2ꢀacyl lactam
influences the ketoꢀenol tautomerism to a lesser degree.
Polar electronꢀwithdrawing groups increase the percentꢀ
age of enol in the following series: CHO > CH(OEt)2 >
> Me ≈ vinyl > H (Table 2).
Experimental
The 1H and 13C NMR spectra were recorded on a Varian
VXRꢀ400 spectrometer (400 and 100 MHz, respectively) in
CDCl3 with HMDS as the internal standard; the chemical shifts
are given in the δ scale relative to HMDS with an accuracy of
0.01 ppm. The IR spectra were measured on a URꢀ20 spectroꢀ
photometer in a thin layer (for liquids) or Nujol mulls (for
solids). The TLC analysis was performed on Silufol UVꢀ254
plates; visualization was carried out using an acidified KMnO4
solution, iodine vapor, and a UV lamp. Preparative chromatogꢀ
raphy was performed on columns with silica gel (60—200 mesh,
Merck).
Synthesis of 2ꢀacyl lactams (general procedure). Method A.
A 60% NaH suspension in mineral oil (26.7 g, 0.6675 mol) was
placed in a twoꢀneck roundꢀbottom flask equipped with a reflux
condenser, a dropping funnel, and a mechanical stirrer, after
which anhydrous toluene (450 mL) was added and then MeOH
(2 mL) was added dropwise. The reaction mixture was brought
to reflux, after which a mixture of Nꢀprotected lactam (0.5 mol)
and ester (0.5 mol) was added with vigorous stirring for 1 h at a
rate such that toluene vapor, which was swept away by H2 that
eliminated, was completely condensed in a reflux condenser
(solid esters were dissolved in anhydrous toluene (100 mL)).
The reaction mixture was refluxed for 10 h and cooled to 0 °C.
Then a solution of AcOH (40 g) in water (150 mL) was rapidly
added with cooling. The reaction mixture was stirred for 10 min.
The upper layer was separated (if required, the mixture was
filtered off from polymers, which hindered separation of layers).
The aqueous phase was extracted with CH2Cl2 (150 mL). The
extracts were combined with the organic phase, dried with
Na2SO4, and concentrated. Small amounts of the products were
purified by column chromatography (CH2Cl2 as the eluent) or
recrystallization (PriOH—hexane, 1 : 4).
Method B. Analogously, MeOH (2 mL) was added dropwise
to a mixture of 60% NaH (26.7 g, 0.6675 mol), anhydrous toluꢀ
ene (450 mL), and Nꢀprotected lactam (0.5 mol). The reaction
mixture was brought to reflux, and ester (0.5 mol) was added
with vigorous stirring for 1—2 h. The reaction mixture was reꢀ
fluxed for 10 h and then cooled to ∼20 °C. Further treatment of
the reaction mixture was carried analogously to that described in
method A.
The yields and physicochemical properties of the compounds
are given in Table 3. The spectroscopic characteristics are listed
in Table 4.
The IR spectra of all compounds have bands at 1710—1690
and 1615—1590 cm–1 corresponding to the carbonyl and amide
groups, respectively. The IR spectra of the Nꢀformyl derivatives
R4 = CHO, CH(EtO)2, Me, H
n = 1, 2
Table 2. Ketoꢀenol tautomerism of 2ꢀacyl lactams (according to
1H NMR spectroscopic data)
Comꢀ
pound
R1
R4
Ring
size
Content
(%)
Ketone
Enol
2
5
3,4ꢀCl2ꢀС6H3
CH2=CH
CH2=CH
CH2=CH
CH2=CH
Me
Me
CHO
CHO
H
CH(EtO)2
CHO
CHO
CH2=CH
H
5
5
5
5
5
6
6
6
6
6
6
6
7
7
80
100
50
87
100
27
13
20
100
20
10
20
0
50
13
0
73
87
80
0
80
90
91
0
3ꢀpy
4ꢀpy
Me
Ph
Ph
12
14
16
19
20
21
25
26
Ph
3ꢀBrꢀС6H4
4ꢀMe2NꢀС6H4
4ꢀpy
27 2ꢀMeOꢀ5ꢀBrꢀС6H3
28 5ꢀClꢀ2ꢀMeOꢀС6H3
35
37
9
100
100
Ph
Ph
0

Synthesis and ketoꢀenol tautomerism of 2ꢀacyl lactams Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2477
Table 3. Yields and physicochemical properties of 2ꢀacyl lactams
ComꢀMethod Yield M.p. Found
Molecular
formula
ComꢀMethod Yield M.p. Found
Molecular
formula
(%)
H
(%)
H
poꢀ
(%)
/°C
Calculated
poꢀ
(%)
/°C
Calculated
und
und
C
C
1
A
79
70—71
(lit.
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
A
A
A
A
A
B
A
A
B
A
A
B
B
A
B
B
B
A
88
76
73
73
71
76
84
85
89
82
83
85
77
76
69
64
65
75
66—67 67.80 8.53 C11H17NO2
67.66 8.78
87.5— 72.10 6.81 C13H15BrNO2
data8:
66.5—
69.5)
88.5
77—
78.5
89—
90.5
71.87 6.96
67.70 5.82 C13H13NO3
67.52 5.67
50.57 3.78 C13H12BrNO3
50.34 3.90
2
B
A
A
B
B
B
A
B
A
A
B
B
B
B
A
A
88
75
91
82
87
83
84
77
84
70
92
78
62
74
91
72
99.5— 54.80 3.99 C13H11Cl2NO2
100.5 54.95 3.90
88.0— 65.53 6.34 C15H17NO4
89.0 65.44 6.22
124.5— 69.81 6.95 C15H18N2O2
125.5 69.74 7.02
88.0— 66.87 5.41 C12H12N2O2
89.5
81—
82.5
61—
62.5
125— 69.84 7.14 C15H18N2O2
126
71—
72.5
58—59 68.81 6.34 C14H15NO3
68.56 6.16
100— 78.48 5.92 C19H17NO2
101
72—
73
3
90.5— 69.41 5.55 C18H17NO4
91.5 69.44 5.50
133— 73.56 5.17 C22H18N2O3
134.5 73.73 5.06
144— 69.49 5.61 C18H17NO4
146 69.44 5.50
207— 68.46 7.29 C14H18N2O2
208.5 68.27 7.37
79.5— 62.80 7.08 C16H22N2O4
81 62.73 7.24
99.0— 49.49 4.02 C14H14BrNO4
4
5
66.65 5.59
62.46 4.94 C13H12ClNO2
62.53 4.84
66.76 5.04 C13H12FNO2
66.94 5.19
6
7
8
69.74 7.02
69.57 6.73 C15H17NO3
69.48 6.61
9
100.5
88—
89.5
49.43 4.15
56.77 4.89 C14H14ClNO4
56.86 4.77
10
11
12
13
14
15
16
17
134— 68.73 6.80 C14H16N2O2
135.5
98—
99
68.83 6.60
68.61 6.85 C14H16N2O2
68.83 6.60
78.33 5.88
66.50 5.42 C12H12N2O2
66.65 5.59
73.68 6.65 C14H15NO2
73.34 6.59
62.77 7.31 C8H11NO2
62.73 7.24
54.18 6.73 C9H13NO2S
54.25 6.58
71.18 6.29 C12H13NO2
70.92 6.45
108.5— 74.57 7.48 C16H19NO2
109.5 74.68 7.44
129— 72.32 9.29 C15H23NO2
Oil
Oil
Oil
130.5
61—
62
72.25 9.30
69.13 8.70 C12H17NO2
69.54 8.27
46.5— 67.49 8.92 C11H17NO2
47 67.66 8.78
157.5— 74.22 6.87 C15H17NO2
158 74.05 7.04
49—
50
67.5— 74.45 8.77 C17H23NO2
68 74.69 8.48
have an additional band at 1580—1565 cm–1. In the spectra of
Acyl lactams devoid of protective groups can also be preꢀ
the Nꢀunsubstituted 2ꢀacyl lactams, the NH absorption band is
pared by decomposition of the reaction mixture (see methods A
and B) with acetic acid at 40 °C. This method was used for the
preparation of 3ꢀ[4ꢀ(dimethylamino)benzoyl]piperidinꢀ2ꢀone
(25) and 3ꢀ(cyclohexylcarbonyl)ꢀ1ꢀvinylazepanꢀ2ꢀone (32).
3ꢀBenzoylpyrrolidinꢀ2ꢀone (36). The yield was 100%, m.p.
107.5—108.5 °C. 1H NMR, δ: 2.23—2.35 and 2.57—2.67
(both m, 1 H each, NCH2CH2); 3.30—3.38 and 3.45—3.53
(both m, 1 H each, NCH2CH2); 4.38 (dd, 1 H, O=C—CH, J =
9.2 Hz, J = 5.8 Hz); 7.16 (br.s, 1 H, NH); 7.45 (t, 2 H, HAr(3)
and HAr(5), J = 7.3 Hz); 7.55 (t, 1 H, HAr(4), J = 7.3 Hz); 8.06
(dt, 2 H, HAr(2) and HAr(6), J = 7.8 Hz, J = 1.4 Hz). 13C NMR,
δ: 24.78 (NCH2CH2); 40.94 (NCH2CH2); 49.64 (O=C—CH);
128.45, 129.27 (CAr(3) and CAr(5) and CAr(2) and CAr(6));
133.36 (CAr(4)); 136.16 (CAr(1)); 174.27 (O=C—NH); 196.25
observed at 2860—2980 cm–1
.
Removal of protective groups from the nitrogen atom of 2ꢀacyl
lactams. 2ꢀAcyl lactam (0.01 mol) containing the protective
vinyl, formyl, or diethoxymethyl group at the nitrogen atom was
refluxed in a mixture of 95% EtOH (20 mL) and concentrated
HCl (0.5 mL). The course of the reaction was monitored by
chromatography (hexane—ethyl acetate (1 : 1) or CH2Cl2 were
used as the eluents). The solution was concentrated to dryness
on a rotary evaporator. The residue was dissolved in CH2Cl2.
The resulting solution was washed with water (200 mL), filtered
through a silica gel layer, and concentrated on a rotary evaporaꢀ
tor to obtain an impurityꢀfree crystalline compound in quantitaꢀ
tive yield.

2478
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Nenajdenko et al.
Table 4. 1H and 13C NMR spectroscopic data for 2ꢀacyl lactams
Comꢀ
pound
NMR spectroscopy
(δ, J/Hz)
1H
13C
2
3
2.22—2.35, 2.68—2.79 (both m, 1 H each, NCH2CH2);
3.50—3.73 (m, 2 H, NCH2CH2); 4.43—4.54 (m, 3 H,
CH=CH2, O=C—CH); 6.97 (dd, 1 H, CH=CH2, J = 16.0,
J = 9.1); 7.55 (d, 1 H, HAr(5), J = 8.4); 7.94 (dd, 1 H,
20.80 (NCH2CH2); 43.39 (NCH2CH2); 51.36 (O=C—CH);
96.03 (CH=CH2); 128.68, 129.00, 130.54, 131.36,
133.15, 135.41, 138.22 (CAr, CH=CH2);
167.71 (N—C=O); 192.85 (Ar—C=O)
H
Ar(6), J = 8.4, J = 2.0); 8.17 (d, 1 H, HAr(2), J = 2.0)
2.22—2.34, 2.57—2.68 (both m, 1 H each, NCH2CH2);
3.47—3.56, 3.60—3.70 (both m, 1 H each, NCH2CH2);
3.79 (s, 6 H, OMe); 4.44 (d, 1 H, transꢀCH=CH2,
J = 16.0); 4.45—4.50 (m, 2 H, cisꢀCH=CH2, O=C—CH);
6.64 (t, 1 H, HAr(4), J = 2.3); 6.99 (dd, 1 H, CH=CH2,
J = 16.0, J = 9.4); 7.20 (d, 2 H, HAr(2), HAr(6), J = 2.3)
2.25—2.36, 2.60—2.70 (both m, 1 H each, NCH2CH2);
2.99 (s, 6 H, N(Me)2); 3.50—3.59, 3.65—3.74
21.59 (NCH2CH2); 43.38 (NCH2CH2); 51.21 (O=C—CH);
55.41 (OMe); 95.42 (CH=CH2); 105.98 (CAr(4));
107.04 (CAr(2), CAr(6)); 129.10 (CH=CH2); 137.75
(CAr(1)); 160.64 (CAr(3), CAr(5)); 168.38 (N—C=O);
195.04 (Ar—C=O)
4
5
21.83 (NCH2CH2); 40.40 (N(Me)2); 43.55 (NCH2CH2);
51.21 (O=C—CH); 95.31 (CH=CH2); 129.07, 129.28,
112.34, 117.59, 117.83, 136.63, 150.52 (CAr, CH=CH2);
168.84 (N—C=O); 196.13 (Ar—C=O)
(both m, 1 H each, NCH2CH2); 4.46 (d, 1 H,
transꢀCH=CH2, J = 16.1); 4.48 (d, 1 H, cisꢀCH=CH2,
J = 9.0); 4.56 (dd, 1 H, O=C—CH, J = 9.9, J = 4.9);
6.92—6.97 (m, 1 H, HAr(4)); 7.04 (d, 1 H, CH=CH2,
J = 16.0, J = 9.0); 7.33 (t, 1 H, HAr(5), J = 8.1);
7.40—7.44 (m, 2 H, HAr(2), HAr(6))
2.24—2.32, 2.55—2.67 (both m, 1 H each, NCH2CH2);
3.44—3.70 (m, 2 H, NCH2CH2); 4.34 (dd, 1 H,
cisꢀCH=CH2, J = 9.7, J = 1.7); 4.38 (dd, 1 Н, O=C—CH,
J = 9.7, J = 1.7); 4.48 (dd, 1 Н, transꢀCH=CH2, J = 16.1,
J = 1.7); 6.95 (dd, 1 Н, CH=CH2, J = 16.1, J = 9.7);
7.33 (dd, 1 Н, HAr(5), J = 8.0, J = 4.7); 8.22 (ddd, 1 Н,
20.27 (NCH2CH2); 43.15 (NCH2CH2); 51.27
(O=C—СН); 95.84 (CH=CH2); 123.09 (CAr(5)); 128.71
(CH=CH2); 130.19 (CAr(3)); 136.69 (CAr(4)); 150.54
(CAr(2)); 153.43 (CAr(6)); 167.61 (O=C—N); 193.92
(Py—C=O)
H
Ar(4), J = 8.0, J = 2.1, J = 1.8); 8.76 (dd, 1 Н, HAr(2),
J = 4.7, J = 1.4); 9.20 (d, 1 H, Ar(6), J = 1.8)
6
7
2.23—2.35, 2.69—2.79 (both m, 1 H each, NCH2CH2);
3.52—3.62 (m, 2 H, NCH2CH2); 4.44—4.54 (m, 3 H,
CH=CH2, O=C—CH); 6.99 (dd, 1 H, cisꢀCH=CH2,
J = 16.0, J = 9.1); 7.45 (d, 2 H, HAr(3), HAr(5), J = 8.6);
8.06 (d, 2 H, HAr(2), HAr(6), J = 8.6)
2.24—2.35, 2.71—2.80 (both m, 1 H each, NCH2CH2);
3.53—3.62, 3.68—3.75 (both m, 1 H each, NCH2CH2);
4.48 (dd, 1 H, transꢀCH=CH2, J =16.0, J = 0.9);
4.51 (dd, 1 Н, cisꢀCH=CH2, J = 9.1, J = 0.9); 4.53 (dd,
1 Н, O=C—CH, J =9.2, J = 4.8); 7.01 (dd, 1 H,
CH=CH2, J =16.0, J = 9.1); 7.16 (t, 2 H, HAr(3), HAr(5),
J =8.8); 8.13—8.18 (m, 2 H, HAr(2), HAr(6))
21.06 (NCH2CH2); 43.52 (NCH2CH2); 51.28 (O=C—CH);
95.84 (CH=CH2); 128.84 (CAr(3), CAr(5)); 129.16
(CH=CH2); 131.01 (CAr(2), CAr(6)); 134.20 (CAr(1));
140.25 (CAr(4)); 168.12 (N—C=O); 193.81 (Ar—C=O)
21.15 (NCH2CH2); 43.58 (NCH2CH2); 51.26 (O=C—CH);
95.84 (CH=CH2); 115.70 (d, СAr(3), СAr(5), J = 22.2);
129.21 (CH=CH2); 132.36 (СAr(2), СAr(6)); 132.45
(СAr(1)); 166.57 (d, СAr(4), J = 345.6); 167.40 (N—C=O);
193.40 (Ar—C=O)
8
9
2.19—2.31, 2.62—2.72 (both m, 1 H each, NCH2CH2);
3.04 (s, 6 H, N(Me)2); 3.47—3.56, 3.63—3.73 (both m,
1 H each, NCH2CH2); 4.42 (d, 1 H, transꢀCH=CH2,
J = 16.0); 4.44 (d, 1 H, cisꢀCH=CH2, J = 9.0);
21.53 (NCH2CH2); 39.90 (N(Me)2); 43.68 (NCH2CH2);
50.28 (O=C—CH); 94.96 (CH=CH2); 110.58 (СAr(3),
СAr(5)); 123.67 (CH=CH2); 129.40 (СAr(1)); 131.76
(СAr(2), СAr(6)); 153.73 (СAr(4)); 169.47 (N—C=O);
192.57 (Ar—C=O)
4.47 (dd, 1 H, O=C—CH, J = 9.4, J = 4.7); 6.65 (d, 2 H,
H
Ar(3), HAr(5), J = 9.0); 7.02 (dd, 1 H, CH=CH2,
J = 16.0, J = 9.0); 7.98 (d, 1 H, HAr(2), HAr(6), J = 9.0)
1.96—2.06, 2.50—2.61 (both m, 1 H each, NCH2CH2);
3.35—3.54 (m, 2 H, NCH2CH2); 3.73—3.79 (m, 1 H,
O=C—CH); 3.75 (s, 3 H, OMe); 4.01 (d, 2 H, ArCH2,
J = 5.8); 4.42 (d, 1 H, transꢀCH=CH2, J = 16.2);
4.48 (d, 1 H, cisꢀCH=CH2, J = 9.1); 6.83 (d, 2 H, HAr(3),
HAr(5), J = 8.8); 7.00 (dd, CH=CH2, J = 16.1, J = 9.1);
7.14 (d, 2 H, HAr(2), HAr(6), J = 8.8)
19.09 (NCH2CH2); 42.95 (NCH2CH2); 48.22 (ArCH2);
53.94 (OMe); 55.08 (O=C—CH); 95.69 (CH=CH2);
114.00 (СAr(3), СAr(5)); 125.44 (СAr(1)); 129.06
(CH=CH2); 130.65 (СAr(2), (6)); 158.58 (СAr(4));
168.15 (N—C=O); 202.53 (Ar—C=O)
(to be continued)

Synthesis and ketoꢀenol tautomerism of 2ꢀacyl lactams Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2479
Table 4 (continued)
Comꢀ
pound
NMR spectroscopy
(δ, J/Hz)
1H
13C
10
11
2.13—2.22, 2.54—2.62 (both m, 1 H each, NCH2CH2);
3.40—3.46, 3.54—3.61 (both m, 1 H each, NCH2CH2);
3.75 (s, 3 Н, OMe); 4.37 (d, 1 H, transꢀCH=CH2,
J = 15.9); 4.39 (d, 1 Н, cisꢀCH=CH2, J = 9.2);
21.03 (NCH2CH2); 43.24 (NCH2CH2); 50.42 (O=C—СН);
55.17 (OMe); 95.09 (CH=CH2); 113.44 (CAr(3), CAr(5));
128.63 (CAr(1)); 128.92 (CH=CH2); 131.59 (CAr(2),
CAr(6)); 163.65 (CAr(4)); 168.59 (O=C—N); 193.28
(Ar—C=O)
4.43 (dd, 1 Н, O=C—CH, J = 9.3, J = 5.1); 6.86 (d, 2 Н,
H
Ar(3), HAr(5), J = 9.1); 6.93 (dd, 1 Н, CH=CH2,
J = 15.9, J = 9.2); 7.99 (d, 2 Н, HAr(2), HAr(6), J = 9.1)
2.26—2.37, 2.69—2.79 (both m, 1 H each, NCH2CH2);
3.53—3.61, 3.68—3.76 (both m, 1 H each, NCH2СH2);
4.49 (d, 1 H, transꢀCH=CH2, J = 15.7); 4.51 (d, 1 H,
cisꢀCH=CH2, J = 9.0); 4.61 (dd, 1 H, O=C—CH,
J = 9.2, J = 4.9); 7.04 (dd, 1 H, CH=CH2, J = 15.8,
J = 9.0); 7.36—7.42 (m, 1 H, HAr); 7.43—7.48, 7.59—7.64,
21.29 (NCH2CH2); 43.56 (NCH2CH2); 51.16 (O=C—CH);
95.68 (CH=CH2); 127.14, 127.22, 128.24, 128.87, 129.21,
130.12, 134.50, 139.68, 146.25 (CAr, CH=CH2); 168.59
(N—C=O); 194.69 (Ar—C=O)
7.68—7.73, 8.15—8.20 (all m, 2 H each, HAr
)
12
13
2.25—2.36, 2.70—2.79 (both m, 1 H each, NCH2CH2);
3.52—3.74 (m, 2 H, NCH2CH2); 4.44—4.55 (m, 3 H,
CH=CH2, O=C—CH); 6.97 (dd, 1 H, CH=CH2,
J = 16.1, J = 9.2); 7.86—7.92 (m, 2 H, HAr(3), HAr(5));
8.79—8.85 (m, 2 H, HAr(2), HAr(6))
1.91—2.02, 2.47—2.58 (both m, 1 H each, NCH2CH2);
3.31—3.50 (m, 2 H, NCH2CH2); 3.72 (dd, 1 Н,
O=C—CH, J = 9.3, J = 6.0); 4.04 (d, 2 H, PhCH2,
J = 7.4); 4.38 (dd, 1 H, transꢀCH=CH2, J = 16.1,
J = 0.9); 4.44 (dd, 1 Н, cisꢀCH=CH2, J = 9.0,
J = 0.9); 6.97 (dd, 1 Н, CH=CH2, J = 16.1, J = 9.0);
22.24 (NCH2CH2); 42.86 (NCH2CH2); 51.72 (O=C—CH);
96.21 (CH=CH2); 120.97 (CAr(3), CAr(5)); 129.01
(CH=CH2); 141.66 (CAr(4)); 150.81 (CAr(2), CAr(6));
171.43 (N—C=O); 194.77 (Ar—C=O)
19.07 (NCH2CH2); 42.97 (NCH2CH2); 49.14 (PhCH2);
54.17 (O=C—СH); 95.78 (CH=CH2); 127.01 (CAr(4));
128.60 (CAr(3), CAr(5)); 128.99 (CH=CH2); 129.68
(CAr(2), CAr(6)); 133.5 (CAr(1)); 168.09 (O=C—N); 202.19
(Bn—C=O)
7.16—7.28 (m, 5 Н, HAr
)
14
15
1.99—2.10, 2.48—2.58 (both m, 1 H each, NCH2CH2);
2.34 (s, 3 H, Me—C=O); 3.34—3.50 (m, 2 H, NCH2CH2);
3.62 (dd, 1 H, O=C—CH, J = 5.8, J = 9.4); 4.37 (dd,
1 H, transꢀСH=CH2, J = 16.1, J = 0.8); 4.42 (dd, 1 Н,
cisꢀCH=CH2, J = 9.0, J = 0.9); 6.92 (dd, 1 Н, CH=CH2,
J = 16.1, J = 9.1)
2.00 (s, 3 H, S—Me); 2.10—2.20, 2.52—2.63 (both m,
1 H each, NCH2CH2); 3.30—3.78 (m, 4 H, SCH2,
NCH2CH2); 4.11 (dd, 1 H, O=C—CH, J = 9.0, J = 6.6);
4.42 (d, 1 H, transꢀCH=CH2, J = 16.2); 4.46 (d, 1 H,
cisꢀCH=CH2, J = 9.2); 6.95 (dd, 1 H, CH=CH2,
J = 16.1, J = 9.1)
18.86 (NCH2CH2); 29.65 (O=C—Me); 42.86 (NCH2CH2);
56.03 (O=C—CH); 95.57 (CH=CH2); 128.89 (CH=CH2);
168.03 (N—C=O); 202.41 (CH3—C=O)
15.46 (SMe); 19.15 (NCH2CH2); 42.12 (SCH2); 42.92
(NCH2CH2); 56.89 (O=C—CH); 95.75 (CH=CH2); 128.90
(CH=CH2); 168.09 (N—C=O); 198.88 (Alk—C=O)
16
17
1.85—1.94, 2.22—2.29 (both m, 1 H each, NCH2CH2);
2.52 (s, 3 H, Me—N); 3.01—3.06, 3.20—3.26 (both m,
1 H each, NCH2CH2); 4.12 (m, 1 Н, O=C—CH);
7.14 (t, 2 Н, HAr(3), HAr(5), J = 7.65); 7.33 (t, 1 Н,
HAr(4), J = 7.7); 7.77 (d, 2 Н, HAr(2), HAr(6), J = 7.1)
1.26—1.35, 2.11—2.23 (both m, 1 H each, NCH2CH2);
1.62—2.08 (m, 15 Н, HAd); 3.42—3.49, 3.60—3.66
(both m, 2 H each, NCH2CH2); 4.10—4.15 (m, 1 Н,
O=C—CH); 4.40 (d, 1 H, transꢀCH=CH2,
21.61 (NCH2CH2); 29.65 (N—Me); 47.78 (NCH2CH2);
50.15 (O=C—СН); 128.19, 129.19 (СAr(2), СAr(6), СAr(3),
СAr(5)); 133.14, 135.97 (СAr(1), СAr(4));
169.82 (O=C—N); 196.15 (Ph—C=O)
23.11 (NCH2CH2); 27.64 (CAd(3), CAd(5), CAd(7));
36.34 (CAd(4), CAd(6), CAd(10)); 37.35 (CAd(2), CAd(8),
CAd(9)); 43.64 (NCH2CH2); 47.23 (CAd(1)); 48.55
(O=C—CH); 95.07 (CH=CH2); 129.15 (CH=CH2); 169.82
(O=С—N); 211.88 (Ad—С=О)
J = 15.9); 4.44 (d, 1 H, cisꢀCH=CH2, J = 9.0); 6.98 (dd,
1 Н, CH=CH2, J = 15.9, J = 9.0)
(to be continued)

2480
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Nenajdenko et al.
Table 4 (continued)
Comꢀ
pound
NMR spectroscopy
(δ, J/Hz)
1H
13C
18
1.17 (s, 9 H, (Me)3С); 2.17—2.22 (m, 2 Н, NCH2CH2);
23.35 (NCH2CH2); 25.60 ((СH3)3C); 43.52 (NCH2CH2);
3.43—3.47, 3.59—3.62 (both m, 1 H each, NCH2CH2); 4.08 44.89 ((Me)3C); 49.30 (O=C—CH); 95.04 (CH=CH2);
(dd, 1 Н, O=C—CH, J = 8.0, J = 7.3); 4.39 (dd, 1 H,
transꢀCH=CH2, J = 16.1, J = 0.8); 4.42 (dd, 1 H,
cisꢀCH=CH2, J = 9.1, J = 0.8); 6.96 (dd, 1 Н, CH=CH2,
J = 16.1, J = 9.1)
129.16 (CH=CH2); 169.66 (O=С—N); 212.30 (Alk—С=О)
19
20
21
22
1.69—1.86 (m, 2 H, NCH2CH2); 2.01—2.09, 2.14—2.24
(both m, 1 H each, NCH2CH2CH2); 3.03 (s, 3 H, Me);
3.27—3.47 (m, 2 H, NCH2); 7.42—7.48 (m, 2 H, HAr(3),
HAr(5)); 7.43—7.49 (m, 1 H, HAr(4)); 7.96—8.02
(m, 2 H, HAr(2), HAr(6))
1.71—1.82 (m, 2 H, NCH2CH2); 2.47—2.55 (m, 2 H,
NCH2CH2CH2); 3.60—3.68 (m, 2 H, NCH2); 7.38—7.54
(m, 5 H, HAr); 9.57 (s, 1 H, N—CHO); 14.84
(s, O=C—C=C—OH)
20.67 (NCH2CH2); 25.20 (NCH2CH2CH2); 34.85
(N—Me); 49.66 (NCH2); 49.84 (O=C—CH); 128.45,
128.95 (CAr(2), CAr(6), CAr(3), CAr(5)); 133.09, 136.37
(CAr(1), CAr(4)); 166.76 (N—C=O); 198.36 (Ph—C=O)
21.64 (NCH2CH2); 24.79 (NCH2CH2CH2); 41.09
(NCH2); 97.25 (N—C(=O)—C); 128.08, 128.12
(CAr(2), CAr(6), CAr(3), CAr(5)); 130.32, 134.43
(CAr(1), (CAr(4)); 162.07 (N—CHO); 172.92
(N—C(=O)—C); 174.74 (O=C—C=C—OH)
21.70 (NCH2CH2); 24.82 (NCH2CH2CH2); 41.16 (NCH2);
97.89 (N—C(=O)—C); 126.86, 127.49, 129.78, 131.20,
133.36, 136.67 (CAr); 162.13, 162.43
1.76—1.85 (m, 2 H, NCH2CH2); 2.48—2.54 (m, 2 H,
NCH2CH2CH2); 3.63—3.70 (m, 2 H, NCH2); 7.31 (t, 1 H,
HAr(5), J = 7.81); 7.45 (dt, 1 H, HAr(6), J = 7.80, J = 1.23);
7.55—7.60 (m, 1 H, HAr(4)); 7.67 (t, 1 H, HAr(2), J = 1.80); (O=C—C=C, N—CHO); 172.87 (O=C—C=C—OH)
9.58 (s, N—CHO); 14.77 (s, O=C—C=C—OH)
1.71—1.80 (m, 2 H, NCH2CH2); 2.25—2.34 (m, 2 H,
NCH2CH2CH2); 3.63—3.70 (m, 2 H, NCH2); 3.97 (s, 3 H,
OMe); 7.39 (d, 1 H, HAr(4), J = 8.68); 7.53—7.59 (m, 2 H,
HAr(6), HAr(7)); 7.65 (d, 1 H, HAr(3), J = 8.69);
7.83—7.88 (m, 1 H, HAr(5)); 8.18—8.24 (m, 1 H, HAr(8));
9.64 (s, 1 H, N—CHO); 14.62 (s, 1 H, O=C—C=C(OH))
1.70—1.79 (m, 2 H, NCH2CH2); 2.14—2.21 (m, 2 H,
NCH2CH2CH2); 3.63—3.70 (m, 2 H, NCH2); 7.44—7.60
(m, 4 H, HAr); 7.73—7.80 (m, 1 H, HAr); 7.85 (s, 1 H,
HAr); 7.91 (d, 1 H, HAr, J = 8.48); 8.15—8.20 (m, 2 H,
21.32 (NCH2CH2); 23.72 (NCH2CH2CH2); 41.32
(NCH2); 63.07 (OMe); 99.73 (O=C—C=C);
122.58, 122.73, 123.85, 125.54, 126.51, 127.49, 127.75,
127.89, 135.49, 154.00 (CAr); 162.24 (N—CHO); 172.62
(O=C—C=C); 173.31 (O=C—C=C(OH))
23
24
21.35 (NCH2CH2); 24.02 (NCH2CH2CH2); 41.12
(NCH2); 99.89 (O=C—C=C); 117.75, 123.20, 124.47,
127.30, 127.42, 128.89, 129.71, 130.21, 130.36, 138.81,
140.62, 148.55, 156.79 (CAr) 161.99 (N—CHO);
171.78 (O=C—C=C(OH)); 172.58 (O=C—C=C(OH))
H
Ar); 8.23 (d, 1 H, HAr, J = 8.49); 9.66 (s, 1 H, N—CHO);
14.68 (s, 1 H, O=C—C=C(OH))
0.82—0.93, 1.22—1.34 (both m, 1 H each, NCH2CH2);
1.68—1.79 (m, 2 H, NCH2CH2CH2); 2.15—2.19 (m, 2 H,
NCH2); 3.94 (s, 3 H, OMe); 7.20 (s, 1 H, HAr(4));
7.34—7.40 (m, 1 H, HAr(6)); 7.46—7.52 (m, 1 H, HAr(7));
7.72—7.81 (m, 3 H, HAr(1), HAr(5), HAr(8));
9.62 (s, 1 H, N—CHO)
21.24 (NCH2CH2); 23.70 (NCH2CH2CH2); 41.18 (NCH2);
55.58 (OMe); 99.52 (O=C—C=C); 105.98, 124.31, 125.29,
126.49, 127.49, 127.93, 128.02, 129.37, 135.00, 153.98
(CAr); 162.19 (N—CHO); 172.40 (O=C—C=C(OH));
172.96 (O=C—C=C(OH))
25
26
1.66—1.79, 1.91—2.19 (both m, 4 H each, NCH2CH2CH2); 20.21 (NCH2CH2CH2); 25.40 (NCH2CH2); 39.93
3.03 (s, 6 H, N(Me)2); 3.26—3.44 (m, 2 H, NCH2);
4.29—4.35 (m, 1 H, O=C—CH); 6.63 (d, 2 H, HAr(3),
HAr(5), J = 8.46); 7.88 (d, 2 H, HAr(2), HAr(6), J = 8.46)
1.22 (t, 6 H, NCH(OCH2CH3)2, J = 7.02); 1.68—1.78
(m, 2 H, NCH2CH2); 2.43 (t, 2 H, NCH2CH2CH2,
J = 7.19); 3.34 (t, 2 H, NCH2, J = 5.71); 3.47—3.57,
3.60—3.70 (both m, 2 H each, NCH(OCH2CH3); 6.41
(s, 1 H, NCH(OEt)2); 7.33—7.37 (m, 2 H, HAr(3), HAr(5));
8.62—8.66 (m, 2 H, HAr(2), HAr(6)); 15.18 (s, 1 H,
O=C—C=C—OH)
(N(Me)2); 42.18 (NCH2); 48.93 (O=C—CH); 110.62
(СAr(3), СAr(5)); 123.81 (СAr(1)); 131.23 (СAr(2), СAr(6));
153.50 (СAr(4)); 169.90 (N—C=O); 195.72 (Ar—C=O)
14.82 (NCH(OCH2CH3)2); 22.35 (NCH2CH2);
25.11 (NCH2CH2CH2); 39.42 (NCH2); 62.37
(NCH(OCH2CH3)2); 99.15 (NCH(OEt)2); 121.79
(O=C—C=C); 122.47 (CAr(3), CAr(5)); 149.8 (CAr(2),
CAr(6)); 150.78 (CAr(4)); 166.17 (N—C=O); 171.04
(O=C—C=C—OH)
(to be continued)

Synthesis and ketoꢀenol tautomerism of 2ꢀacyl lactams Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2481
Table 4 (continued)
Comꢀ
pound
NMR spectroscopy
(δ, J/Hz)
1H
13C
27
28
29
1.72—1.81 (m, 2 H, NCH2CH2); 2.15—2.24 (m, 2 H,
NCH2CH2CH2); 3.59—3.68 (m, 2 H, NCH2); 3.82 (s, 3 H,
OMe); 6.83 (d, 1 H, НAr(3), J = 8.97); 7.41 (d, 1 H,
НAr(6), J = 2.51); 7.48 (dd, 1 H, НAr(4), J = 8.94,
J = 2.53); 9.58 (s, 1 H, N—CHO); 14.41 (s, 1 H,
O=C—C=C—OH)
1.70—1.79 (m, 2 H, NCH2CH2); 2.14—2.23
(m, NCH2CH2CH2); 3.57—3.67 (m, 2 H, NCH2);
3.81 (s, 3 H, OMe); 6.87 (d, 1 H, НAr(3), J = 8.87);
7.26 (d, 1 H, НAr(6), J = 2.74); 7.33 (dd, 1 H, НAr(4),
J = 8.87, J = 2.75); 9.56 (s, 1 H, N—CHO); 14.40
(O=C—C=C—OH)
21.24 (NCH2CH2); 23.61 (NCH2CH2CH2);
41.22 (NCH2); 55.90 (OMe); 99.76 (O=C—C=C);
112.70, 113.02, 125.52, 131.94, 133.99, 155.26 (CAr);
162.19 (N—CHO); 171.05 (O=C—C=C(OH));
172.40 (O=C—C=C(OH))
21.20 (NCH2CH2); 23.56 (NCH2CH2CH2);
55.91 (NCH2); 55.91 (OMe); 99.73 (O=C—C=C);
112.55, 125.02, 125.55, 129.07, 130.98, 154.73 (CAr);
162.15 (N—CHO); 171.10 (O=C—C=C—OH);
172.39 (O=C—C=C—OH)
1.43—1.57 (m, 1 H, NCH2CH2CH2); 1.61—1.87 (m,
24.88 (NCH2CH2CH2); 26.82 (NCH2CH2);
1 H each, NCH2CH2, NCH2CH2CH2); 1.91—2.01 (m, 1 H, 28.18 (NCH2CH2CH2CH2); 43.89 (NCH2); 51.21
NCH2CH2CH2CH2); 2.03—2.13 (m, 1 H, NCH2CH2);
2.27—2.36 (m, 1 H, NCH2CH2CH2CH2); 3.70—3.80,
3.83—3.93 (both m, 1 H each, NCH2); 4.43 (d, 1 H,
cisꢀCH=CH2, J = 9.4); 4.54 (d, 1 H, transꢀCH=CH2,
J = 16.2); 5.20 (d, 1 H, O=С—CH, J = 11.3);
(O=С—CH); 93.37 (CH=CH2); 121.95 (СAr(3));
126.87 (CH=CH2); 131.53, 136.87, 148.69, 153.10
(СAr); 172.35 (N—C=O); 197.15 (Py—C=O)
7.26 (dd, 1 H, CH=CH2, JH,H = 16.2, JH,H = 9.4);
7.38—7.44 (m, 1 H, HAr(5)); 7.81 (dt, 1 H, HAr(4),
J = 7.7, J = 1.5); 8.09 (d, 1 H, HAr(3), J = 7.7);
8.58 (d, 1 H, HAr(6), J = 4.6)
30
1.39—1.93 (4 H, NCH2CH2CH2CH2); 1.99—2.05,
2.24—2.32 (both m, 1 H each, NCH2CH2); 3.54—3.60,
3.81—3.86 (both m, 1 H each, NCH2); 4.44 (dd, 1 H,
cisꢀCH=CH2, J = 9.3, J = 1.6); 4.48 (dd, 1 Н, O=C—CH,
J = 10.6, J = 2.1); 4.53 (dd, 1 Н, transꢀCH=CH2, J = 16.1,
J = 1.3); 7.11 (dd, 1 Н, CH=CH2, J = 16.1, J = 9.3); 7.33
(dd, 1 Н, НAr(5), J = 8.0, J = 4.7); 8.12 (dt, 1 Н, НAr(4),
J = 8.0, J = 2.1, J = 1.82); 8.66 (dd, 1 Н, НAr(2), J = 4.7,
J = 1.4); 9.0 (d, 1 H, НAr(6), J = 1.8)
24.83 (NCH2CH2CH2); 26.45 (NCH2CH—CH2CH2);
27.72 (NCH2CH2); 43.85 (NCH2); 53.10 (O=C—СН);
94.49 (CH=CH2); 123.45 (CH—Pyꢀ5); 131.14 (CH=CH2);
131.10, 135.31, 149.23, 152.96 (CAr); 171.11 (O=C—N);
194.41 (Py—C=O)
31
1.44—1.70 (m, 2 H, NCH2CH2CH2); 1.78—2.97 (m, 2 H,
NCH2CH2); 2.00—2.10, 2.24—2.35 (both m, 1 H each,
NCH2CH2CH2CH2); 2.37 (s, 3 H, Me); 3.58—3.67,
3.83—3.93 (both m, 1 H each, NCH2); 4.46 (dd, 1 H,
cisꢀCH=CH2, J = 9.3, J = 1.4); 4.51—4.58 (m, 2 H,
transꢀCH=CH2, CH—C=O); 7.21 (d, 2 H, НAr(3),
21.58 (Me); 25.26 (NCH2CH2CH2); 26.65 (NCH2CH2);
27.77 (NCH2CH2CH2CH2); 43.79 (NCH2); 52.96
(CH—C=O); 93.87 (CH=CH2); 128.17, 129.26 (CAr(3),
CAr(5), CAr(2), CAr(6)); 131.66 (CH=CH2); 134.25
(CAr(1)); 143.67 (CAr(4)); 171.58 (N—C=O); 195.21
(Ar—C=O)
Н
Ar(5), J = 8.1); 7.31 (dd, 1 H, CH=CH2, J = 16.1,
J = 9.4); 7.77 (d, 2 H, НAr(2), НAr(6), J = 8.1)
1.08—2.00 (m, 16 H, cycloꢀC6H11, NCH2CH2CH2CH2);
2.41—2.51 (m, 1 H, O=С—CH—C(=O)—CH);
3.15—3.23 (m, 2 H, NCH2); 3.64 (d, 1 H,
O=С—CH—C(=O)—CH, J = 9.1)
32
33
24.68 (NCH2CH2CH2); 25.25 (cycloꢀC6H11); 25.73, 25.84
(cycloꢀC6H11); 27.74 (NCH2CH2CH2CH2); 28.40
(NCH2CH2); 29.01, 29.12 (cycloꢀC6H11); 42.33(NCH2);
50.21 (O=C—CH—C(=O)—CH); 55.24 (O=C—CH—
C(=O)—CH); 176.30 (O=C—N); 209.91 (CH—CO—CH)
11.00, 11.18 (cycloꢀC3H5); 20.23 (cycloꢀC3H5); 24.63
(NCH2CH2CH2); 26.28 (NCH2CH2CH2CH2); 26.98
(NCH2CH2); 43.26 (NCH2); 58.46 (O=C—СН); 93.60
(CH=CH2); 131.23 (CH=CH2); 171.23 (O=C—N); 205.92
(cycloꢀC3H5—C=O)
0.75—1.07 (m, 4 Н, cycloꢀC3H5); 1.33—2.09 (m, 7 H,
NCH2CH2CH2CH2, cycloꢀC3H5); 3.38—3.48, 3.58—3.67
(both m, 1 H each, NCH2); 3.81 (dd, 1 Н, O=C—CH,
J = 10.2, J = 2.6); 4.47 (dd, 1 H, cisꢀCH=CH2, J =
9.3, J = 1.3); 4.56 (dd, 1 Н, transꢀCH=CH2, J = 16.1,
J = 1.0); 7.35 (dd, 1 Н, CH=CH2, J = 16.1, J = 9.3)
(to be continued)

2482
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Nenajdenko et al.
Table 4 (continued)
Comꢀ
pound
NMR spectroscopy
(δ, J/Hz)
1H
13C
34
1.31—2.08 (m, 6 H, NCH2CH2CH2CH2); 2.29—2.40,
2.50—2.62 (both m, 1 H each, CH3CH2); 3.36—3.45,
3.63—3.71 (both m, 1 H each, NCH2); 3.68 (dd, 1 H,
O=C—CH, J = 10.6, J = 2.6); 4.47 (dd, 1 H, cisꢀCH=CH2,
J = 9.3, J = 1.4); 4.55 (dd, 1 Н, transꢀCH=CH2, J = 16.2,
J = 1.1); 7.31 (dd, 1 Н, CH=CH2, J = 16.2, J = 9.4)
7.68 (СH3CH2); 24.67 (NCH2CH2CH2); 26.39
(NCH2CH2CH2CH2); 27.40 (NCH2CH2); 35.11
(CH3CH2); 43.53 (NCH2);57.23 (O=C—СН); 93.87
(CH=CH2); 131.27 (CH=CH2); 171.60 (O=C—N);
206.63 (Et—C=O)
35
1.44—1.72, 1.81—1.99 (both m, 2 H each, NCH2CH2CH2CH2); 25.22 (NCH2CH2CH2); 26.55 (NCH2CH2CH2CH2);
2.03—2.12, 2.22—2.35 (both m, 1 H each, NCH2CH2);
3.59—3.68, 3.85—3.94 (both m, 1 H each, NCH2); 4.48 (dd,
1 H, cisꢀCH=CH2, J = 9.37, J = 1.46); 4.53—4.60 (m, 2 Н,
transꢀCH=CH2, O=C—CH); 7.31 (dd, 1 Н, CH=CH2,
J = 16.1, J = 9.4); 7.42 (t, 2 Н, HAr(3), HAr(5), J = 7.5);
7.52 (tt, 1 Н, HAr(4), J = 7.3, J = 1.2); 7.85—7.90 (m,
2 Н, HAr(2), HAr(6))
27.74 (NCH2CH2); 43.76 (NCH2); 52.83 (O=C—СН);
93.95 (CH=CH2); 127.96, 128.63 ((СAr(2), СAr(6),
СAr(3), СAr(5)); 131.45 (CH=CH2); 132.79(СAr(4));
136.66 (СAr(1)); 171.48 (O=C—N); 195.56 (Ph—C=O)
(Ph—C=O). Found (%): C, 69.70; H, 6.14. C11H11NO2. Calcuꢀ
lated (%): C, 69.83; H, 5.86.
10. J. Ji, D. M. Barnes, J. Zhang, S. A. King, S. J. Wittenberg,
and H. E. Morton, J. Am. Chem. Soc., 1999, 121, 10215.
11. J. Colonge and F. Guigues, Bull. Chem. Soc. France,
1967, 4308.
12. G. H. Hakimelahi and G. Just, Tetrahedron Lett., 1979,
38, 3645.
13. K. J. Lindstrom and S. L. Grooks, Synth. Commun., 1990,
20, 2335.
14. L. Capuano and W. Fisher, Chem. Ber., 1976, 109, 212.
15. P. DeShong, N. E. Lowmaster, and O. Baralt, J. Org. Chem.,
1983, 48, 1150.
16. S. G. Alexeev, V. N. Charushin, O. N. Chupakhin, and
G. G. Alexandrov, Tetrahedron Lett., 1988, 29, 1431.
17. D. Roberto and H. Alper, J. Am. Chem. Soc., 1989, 111, 7539.
18. M. P. Doyle, J. Taunton, and H. Q. Pho, Tetrahedron Lett.,
1989, 30, 5397.
3ꢀBenzoylazepanꢀ2ꢀone (37). The yield was 100%,
m.p. 191.5—192.5 °C. 1H NMR, δ: 1.44—1.62 (m, 2 H,
NCH2CH2CH2); 1.78—1.94 (m, 2 H, NCH2CH2CH2CH2);
2.02—2.12 and 2.17—2.26 (both m, 2 H each, NCH2CH2);
3.25—3.41 (m, 2 H, NCH2); 4.36 (dd, 1 H, O=C—CH, J =
10.4 Hz, J = 1.8 Hz); 6.48 (br.s, 1 H, NH); 7.42 (t, 2 H, HAr(3)
and HAr(5), J = 7.4 Hz); 7.51 (tt, 1 H, HAr(4), J = 7.4 Hz, J =
1.2 Hz); 7.89 (dd, 2 H, HAr(2) and HAr(6), J = 7.5 Hz, J =
1.2 Hz). 13C NMR, δ: 25.40 (NCH2CH2CH2); 28.69
(NCH2CH2CH2CH2); 29.24 (NCH2CH2); 42.64 (NCH2); 52.92
(O=C—CH); 128.13, 128.51 (CAr(3) and CAr(5) and CAr(2) and
C
Ar(6)); 132.85 (CAr(4)); 136.76 (CAr(1)); 175.91 (O=C—NH);
196.39 (Ph—C=O). Found (%): C, 72.01; H, 6.87. C13H15NO2.
Calculated (%): C, 71.87; H, 6.96.
19. A. Padwa, D. J. Austin, S. F. Hornbuckle, and M. A.
Semones, J. Am. Chem. Soc., 1992, 114, 1974.
20. A. G. H. Wee, B. Liu, and L. Zhang, J. Org. Chem., 1992,
57, 4404.
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Received July 18, 2003;
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in revised form October 24, 2003