The thorpe-ingold effect in glutarimide derivatives. Part II

Article abstract of DOI:10.3987/com-04-10120

Differently substituted glutarimides, 3-methylglutarimide (12), 3,3-dimethylglutarimide (14) and 3,3,4,4-tetramethylglutarimide (18) were prepared and their reactivity towards aryllithiums was investigated. The influence of Thorpe-Ingold effect on the dis

Full text of DOI:10.3987/com-04-10120

HETEROCYCLES, Vol. 65, No. 1, 2005
9
HETEROCYCLES, Vol. 65, No. 1, 2005, pp. 9 - 22
Received, 13th May, 2004, Accepted, 12th November, 2004, Published online, 16th November, 2004
THE THORPE-INGOLD EFFECT IN GLUTARIMIDE
DERIVATIVES. PART II†
Michał Pawłowski,a Jan K. Maurin,b,c Andrzej Leniewski,a Krystyna
Wojtasiewicz,a and Zbigniew Czarnocki*a
a Faculty of Chemistry, Warsaw University, Pasteur St. 1, 02-093 Warsaw, Poland,
E-mail: czarnoz@chem.uw.edu.pl
b National Institute of Public Health, Chełmska 30/34, 00-750 Warsaw, Poland,
c Institute of Atomic Energy, 05-400 Otwock-Świerk, Poland
Abstract – Differently substituted glutarimides, 3-methylglutarimide (12),
3,3-dimethylglutarimide (14) and 3,3,4,4-tetramethylglutarimide (18) were
prepared and their reactivity towards aryllithiums was investigated. The influence
of Thorpe-Ingold effect on the distribution of products in tautomeric equilibrium
was observed together with a total regioselectivity of the process. For imide (12)
only keto amide (13) was isolated. Imide (14) resulted in formation both hydroxy
lactam (16) and keto amide (15), and imide (18) gave only hydroxy lactam (24).
INTRODUCTION
Reactions between cyclic imides (such as succinic and glutaric imides) and organometallic compounds
(such as Grignard and lithium compounds) are well-known synthetic procedures for the preparation of
1,4- and 1,5-dicarbonyl derivatives. The N-methylated or N-phenylated imides are in most cases used as
starting materials. Numerous examples of this type of reaction can be found in the literature, including
those leading to quite complex1 or sensitive products.2 Also, other nucleophiles (amines, hydroxylamines,
hydrazines and alkoxides) were often employed.3 Frequently, a selective reduction of the carbonyl group
(with NaBH4/H+ or Zn(BH4)2/H+) in the imide moiety is applied, leading to N-acyliminium intermediates
of immense synthetic potential.
† Part I see ref. 12

10
HETEROCYCLES, Vol. 65, No. 1, 2005
In the case of five-membered ring imide derivative reaction leads surprisingly often to compounds having
a hydroxy lactam (1) structure.
OH
Ph
O
N
H
NH2
O
O
Ph
1
2
A reaction of a Grignard compound with (S)-1-benzyl-4-benzyloxy-2,5-pyrrolidinedione (3) that gave
1-benzyl-4-benzyloxy-5-hydroxy-5-(4-methoxybenzyl)pyrrolidin-2-one (4) as a sole product4 is a good
example. Another salient feature of this reaction is the observed regioselectivity. The formation of
1-benzyl-4-benzyloxy-5-hydroxy-5-(4-methoxybenzyl)pyrrolidin-2-one 4 as the only product4 means that
surprisingly the more hindered carbonyl group in (S)-1-benzyl-4-benzyloxy-2,5-pyrrolidinedione (3)
underwent a nucleophilic attack.
Ph
Ph
O
O
OH
Ph
O
O
O
N
N
Ph
Ph
3
4
An attack on the more or less hindered site of the imide molecule depends on both the structure of the
imide moiety and the type of nucleophilic reagent used in the reaction. In almost all cases described, not
only 4- monosubstituted but sometimes also 4,4-disubstituted 2,5-pyrolidinediones and hence even much
more crowded ones were formed.5-7 An interesting explanation of this unusual behavior was offered.6
In the case of six membered imide ring (glutarimide) derivatives the regioselectivity appears to be
governed by much more complicated factors. In some instances, nucleophiles like hydrazine hydrate react
at the less hindered site, as observed in the case of 3-ethyl-3-phenylpiperidine-2,6-dione.8 Surprisingly,
the introduction of fluorine at the aromatic ring changes the regiochemistry in favor of an attack at the
more hindered site. The methoxide ion seems to behave in a similar manner.9 The problem of the product

HETEROCYCLES, Vol. 65, No. 1, 2005
11
structure of the nucleophile action on glutarimide molecule seems to be even more complicated. Both
open-chain (keto amide) (2)3 and cyclic (hydroxy lactam) (1)10 structures, sometimes being in tautomeric
relationship, were detected. During our studies, we have gained some evidences for the presence of the
tautomeric equilibrium between these forms.11,12 The predominance of the particular form is strongly
affected by stereoelectronic factors in the molecule – mainly the Thorpe-Ingold effect (gem-dialkyl effect)
which is known to facilitate the cyclisation.13,14 At least three explanations of this effect can be found in
the literature. According to one of them, a gem-substitution of the methylene hydrogens causes
compression of the internal angle of the carbon chain, pushing the reactive centers closer together.15
Another rationale proposed for the effect is called a “reactive rotamer effect”, according to which a ring
closure reaction proceeds at a higher rate on geminally substituted reactant because of the resultant
decrease in the disfavored rotamer distribution.16 A higher rate for the cyclic transition state formation in
the case of gem-dimethyl compounds has recently been supported by quantum chemical methods.17
The problem of the ring-chain tautomerism has far-reaching implications for chemical processes.
Speckamp et al.14 demonstrated that existence of the keto amide (2) form in the selective reduction of
glutarimides causes overreduction of the carbonyl group in this tautomer.
In our previous publications we have demonstrated the significant influence of the Thorpe-Ingold effect
on the structure of products derived from the action of phenyllithium on selected glutarimides.12
O
O
PhLi
Ph
NH2
O
N
H
O
6
5
O
O
PhLi
HO
Ph
NH2
N
O
O
N
H
O
Ph
H
7
8
9
PhLi
HO
Ph
O
N
H
O
N
O
H
10
11
In the case of 4,4-dimethylglutarimide (7), the stereoelectronic stabilization is sufficiently strong to allow
the separation and full spectroscopic characterization of both tautomers (8) and (9). The addition of

12
HETEROCYCLES, Vol. 65, No. 1, 2005
another pair of geminal methyls to the glutarimide ring completely shifts the tautomeric equilibrium
towards the cyclic form (11), making the open-chain congener undetectable.12 Following our earlier
findings, we present here a further elaboration of the reactivity of the glutarimide system bearing various
number of methyl substituents. That allows both the study of the regioselectivity of nucleophilic addition,
and also the Thorpe-Ingold effect.
RESULTS AND DISCUSSION
Several non-symmetrically substituted glutarimides, namely: 3-methyl-, 3,3-dimethyl-, and
3,3,4,4-tetramethylglutarimide (12, 14, 18) were prepared, mostly by using well-known methods. They
were subsequently treated with a multi-molar excess of phenyllithium and the compositions of the
reaction mixtures were analysed after a standard workup.
In the case of 3-methylglutarimide (12), only one product was obtained in a 9% yield and the starting
material was recovered. The open chain structure of the product has already been proven.18 A similar
result was obtained when m-tolyllithium was used in this reaction. The product was isolated in a 17%
yield along with approx. 80% of the recovered starting imide (12). Relatively low chemical yields
obtained in the above mentioned reactions might be explained by the preliminary formation of the lithium
salt at the imide nitrogen which decreased the electrophylicity in both carbonyls. Compound (12) revealed
1
comparable spectral features to those obtained previously. Thus, in an aromatic region of H NMR
spectrum two groups of signals (7.33-7.39 and 7.75-7.76 ppm) were observed which are often attributed
to the ortho deshielding effect of the carbonyl group attached to the aromatic ring. That supports the
assignment of the open-chain structure (13) for this compound. The presence of the carbonyl carbon atom
signal in 13C NMR spectrum at 200.3 ppm is also consistent with this assignment.
O
O
m-TolLi
Me
NH2
O
N
H
O
13
12
The above was additionally confirmed by the X-Ray crystallographic analysis of product (13). The
experimental and refinement data are given in Table 1. The molecular structure obtained from
crystallographic studies is shown in Figure 1. In the crystal structure two types of NH···O hydrogen
bonds of similar dimensions which involve two amide hydrogen atoms and both carbonyl oxygens are
observed.

HETEROCYCLES, Vol. 65, No. 1, 2005
13
Figure 1. Molecular structure of 13. The non hydrogen atoms are shown as 20% probability ellipsoids.
No other tautomeric forms were detected by spectroscopic methods.
An additional unexpected feature of this type of reaction is a high degree of regioselectivity observed.
Compound (13) was the only product indicated by high field NMR spectra of the crude reaction mixture.
Therefore it is not surprising that in the case of 3,3-dimethylglutarimide (14) again only one carbonyl
group was attacked by phenyllithium under the same conditions. Interestingly, two compounds (15) and
(16) were formed in 38% and 19% yields, respectively.
O
O
PhLi
HO
Ph
Ph
NH2
N
H
O
O
N
H
O
15
14
16
BF3 etherate
Ph
N
O
H
17
No traces of other regioisomers were detected. In the case of compound (15), a very similar shape of the
1H NMR spectrum was observed. Again, an ortho deshielding effect in the aromatic region (signals at
7.40-7.59 and 7.94-7.99 ppm), together with the presence of carbonyl group resonance at 200.0 ppm

14
HETEROCYCLES, Vol. 65, No. 1, 2005
showed up in 13C NMR spectrum. Careful column chromatography allowed the separation of compounds
(15) and (16). An X-Ray analysis of a single crystal of 15 proved its open chain structure, also in the solid
state. The experimental and refinement data are shown in Table 1. The molecular structure of 15
observed in the crystalline state is shown in Figure 2. The crystal shows considerable thermal motions in
the phenyl ring region which might be interpreted as librations and shown as a partial disorder of this
region (see Figure 2). Although the bond dimensions in the phenyl ring region are somewhat distorted by
thermal motion, the whole molecular structure seems rational and similar to 13. Also the hydrogen bonds
characteristic of (13), NH···O intermolecular interactions, are observed and all donor and acceptor
functions are employed.
Figure 2. Molecular structure of 15. The non hydrogen atoms are shown as 20% probability ellipsoids.
Two alternative positions of the disordered phenyl ring are visualized.
Despite repeated efforts we were unable to obtain a single crystal of 16 suitable for X-Ray analysis.
1
However, in our opinion both H and 13C NMR spectrum unambiguously pointed the hydroxy lactam
structure of 16. Quite indicative was the absence of the ortho deshielding effect, the presence of both
methyl groups as singlets at 0.80 ppm and 0.99 ppm in 1H NMR spectrum, together with the extinction of
13
the carbonyl carbon group signal in C NMR spectrum at 200.0 ppm in favor of the appearance of a
tertiary alcohol resonance at 88.8 ppm. An additional drawback in handling compounds (15) and (16) was
the fact that both of them existed in a relatively fast tautomeric relationship, accompanied by a facile
dehydration process that brought about the formation of enamide (17) whose structure was confirmed by

HETEROCYCLES, Vol. 65, No. 1, 2005
15
the presence of the olefin hydrogen triplet (5.39 ppm, J=5 Hz) in 1H NMR spectrum and the olefin carbon
signal at 101.7 ppm in 13C NMR spectrum.
The presence of hydroxy lactam structure (16) derived from compound (14) seems to be the consequence
of the Thorpe-Ingold effect. A similar behaviour has previously been observed in the case of
4,4-dimethylglutarimide.12
Analogously, we prepared 3,3,4,4-tetramethylglutarimide (18) according to the modified procedure given
by Ingold19 in which dibromophorone (19) (obtained from phorone (20)) was subjected to cyclisation by
hydroiodic acid – red phosphorus treatment. The cyclopentanone derivative (21) thus formed was
subsequently oxidized by HNO3 followed by the anhydride (22) formation from acid (23). The reaction
with aqueous ammonia and pyrolysis of the salt produced imide (18) in a moderate yield.
Br
a,b
c
d
O
O
O
Br
21
20
19
d
e
f
CO2H CO2H
O
N
H
O
O
O
O
23
22
18
Reagents and conditions: (a) Br2, CCl4, 95%; (b) pyridine, 0oC, 24 h, 85%; (c) HI, Pred, reflux, 42%; (d)
HNO3, reflux, 67%; (e) AcCl, reflux, 98%; (f) NH3(aq.), 230oC, 2 h, 90%.
The introduction of yet another pair of methyl groups to the imide ring of 18 shifts the tautomeric
equilibrium between the cyclic and the open-chain forms even further. Thus, when (18) was used, the
only product detected after the reaction with phenyllithium was the hydroxy lactam (24), which was
formed in a 59% yield.
PhLi
HO
N
H
O
Ph
N
H
O
O
N
H
O
Ph
18
24
25

16
HETEROCYCLES, Vol. 65, No. 1, 2005
This compound was extremely prone to the dehydration process and even carefully purified solvents
promoted its transformation into 25. The result of the X-Ray structure analysis of this product is shown in
Figure 3, whereas the experimental and refinement details are given in Table 1. The crystal structure is
build up from molecular hydrogen bonded dimers bonded via pairs of NH···O hydrogen bonds between
symmetry related molecules.
Figure 3. The molecular structure of 25 together with the numbering scheme. The non-hydrogen atoms
are shown as 30% probability ellipsoids
We managed to collect spectral data for compound (24) in which similar phenomena to those for 16 were
1
observed. In H NMR the presence of four methyl resonances (at 0.54, 0.86, 1.02 and 1.15 ppm)
13
confirmed the cyclic structure of this compound. Also, in C NMR spectrum there was a signal at 84.0
ppm, which was indicative of a tertiary hydroxy group. The ortho deshielding effect in 1H NMR spectrum
and a carbonyl carbon atom resonance at 200.0 ppm in 13C NMR spectrum were not present for this
compound, which excluded the open-chain tautomer structure. We were unable to detect any traces of the
other regioisomer of compound (24) in the crude reaction mixture. We obtained a monocrystal of
compound (24). Its X-Ray analysis is in full accordance with all previous assignments. To prevent the
crystal from decomposition, the crystallographic measurements were performed at a low temperature. The
molecular structure of 24 is shown in Figure 4 whereas the experimental and refinement data are given in
Table 1. In the crystal structure strong OH···O hydrogen bonds between hydroxyl hydrogen and carbonyl
oxygen atoms from symmetry related molecules are present. Some much weaker CH···O and CH···π
interactions are also visible.

HETEROCYCLES, Vol. 65, No. 1, 2005
17
Figure 4. Molecular structure of 24 together with the numbering scheme. The non-hydrogen atoms are
shown as 30% probability ellipsoids.
EXPERIMENTAL
GENERAL
The NMR spectra were recorded on a Varian Unity Plus spectrometer operating at 500 MHz or 200 MHz
for 1H NMR and 125 MHz or 50 MHz for 13C NMR, respectively. Tetramethylsilane (TMS) was used as
the internal standard. Chemical shifts are reported in ppm. Coupling constants (J) are reported in hertz.
Melting points are uncorrected. Column chromatographic separations were carried out on silica gel
(70-230 mesh or 230-400 mesh) or on neutral aluminum oxide (activity III) and were monitored by TLC
on silica gel or aluminum oxide plates, which were visualized by UV radiation and/or iodine vapours.
Diethyl ether was distilled from CaH2 before use. Bromobenzene and chloroform were also distilled
before use. In the case of sensitive compounds solvents for chromatography were redistilled and stored
over neutral aluminum oxide. Most of the X-Ray crystallographic data were collected at room
temperature on a Kuma KM4 single crystal κ-axis diffractometer using MoKα radiation. The data for 24,
however, were collected at 143 K using a Kuma KM4CCD apparatus. The data were corrected for
Lorentz and polarization effects but not for absorption. Crystal structures were solved using dirrect
methods from SHELXS9722 and refined by the application of the SHELXL97 23 software. X-Ray data are
collected in Table 1.

18
HETEROCYCLES, Vol. 65, No. 1, 2005

HETEROCYCLES, Vol. 65, No. 1, 2005
19
3,3,4,4-Tetramethylcyclopentanone (21). According to modified Ingold’s procedure,19
3,5-dibromo-2,6-dimethylhepta-2,5-dien-4-one (α,α’-dibromophorone 19, 25 g, 85 mmol), hydriodic acid
(250 mL, 54 wt. %) and red phosphorus (30 g, 1 mol) were gently refluxed for 4 h. After cooling down to
rt, 1 L of water was added and the mixture was steam distilled. A first 250 mL portion of the distillate
was collected and extracted with dichloromethane (5×25 mL). Combined organic layers were dried over
anhydrous MgSO4 and concentrated. The residue was chromatographed on silica gel using
dichloromethane/hexane (2:1 v/v) as an eluent resulting in compound (21) (5 g, 42%) as a white solid, mp
1
130-131°C (lit.,19 mp 130°C). H NMR (CDCl3, 500 MHz) δ 1.03 (s, 12H), 2.20 (s, 4H); 13C NMR
(CDCl3, 125 MHz) δ 23.93, 40.22, 52.48, 218.83.
2,2,3,3-Tetramethylpentanedioic acid (23). Compound (21) (5 g, 36 mmol), 10 mL of water and 10 mL
of 68% nitric acid were mixed and the reaction mixture was refluxed until the evolution of brown
nitrogen oxides ceased. After cooling down to rt a white solid was obtained (4.5 g, 67%), mp 144-145°C
(lit.,19 mp 144°C). 1H NMR (CDCl3, 200 MHz) δ 1.15 (s, 6H) 1.19 (s, 6H) 2.47 (s, 2H), 10.0 (br s, 2H,
disappeared with D2O); 13C NMR (CDCl3, 50 MHz) δ 21.0, 22.9, 37.7, 42.3, 48.4, 179.1, 183.4; MS (ES)
(m/z) [M+Na]+ = 211, [M-H]- = 187; IR (KBr, cm-1) 2980, 1695, 1290.
3,3,4,4-Tetramethyldihydro-2H-pyran-2,6(3H)-dione (22). Compound (23) (4 g, 21 mmol) and acetyl
chloride (30 mL, 420mmol) were gently refluxed for 2 h. Then volatile reagents were removed in vacuo
and the resulting precipitate was recrystallized from hexane to give compound (22) (3.3 g, 98%) mp
183-184°C (lit.,19 mp 184°C). 1H NMR (CDCl3, 500 MHz) δ 1.08 (s, 6H), 1.30 (s, 6H), 2.70 (s, 2H); 13C
NMR (CDCl3, 125 MHz) δ 20.3, 23.8, 34.1, 42.4, 45.8, 166.0, 172.7; IR (KBr, cm-1) 3440, 2985, 1805,
1770, 1175, 1050, 1005.
GENERAL PROCEDURE OF IMIDES PREPARATION.
To a solution of acid anhydride (24 mmol) in dioxane (10 mL) concentrated aqueous ammonia (20 mL)
was added. After 30 min all solvents were evaporated under vacuum and the residue was heated neat at
230°C for 2 h. The resulting brownish solid was chromatographed on silica gel using chloroform as an
eluent to afford an appropriate imide. Each sample of imide taken to the subsequent step was vacuum
dried over P2O5.
3-Methylpiperidine-2,6-dione (12). mp 92-93°C (lit.,20 mp 91-92°C). Yield 89%. Spectral data were in
accordance with the literature.20
3,3-Dimethylpiperidine-2,6-dione (14). mp 142-143°C (lit.,21 mp 137-144°C). Yield 94%. Spectral data
were in accordance with the literature.21
1
3,3,4,4-Tetramethylpiperidine-2,6-dione (18). mp 202-203°C (lit.,19 mp 202°C). Yield 90%. H NMR
13
(CDCl3, 200 MHz) δ1.05 (s, 6H), 1.24 (s, 6H), 2.53 (s, 2H), 8.29 (br s, 1H, disappeared with D2O); C
NMR (CDCl3, 50 MHz) δ 20.3, 24.0, 35.2, 44.0, 45.6, 171.5, 178.9; IR (KBr, cm-1) 3205, 2990, 2965,

20
HETEROCYCLES, Vol. 65, No. 1, 2005
1725, 1680, 1285; MS (EI) m/z (rel intensity in %) 169 (M+, 49), 154 (11), 113 (42), 110 (10), 100 (15),
87 (31), 86 (29), 84 (76), 83 (100), 70 (37), 69 (47), 57 (12), 56 (11), 55 (31).
GENERAL PROCEDURE FOR REACTIONS BETWEEN IMIDES AND PHENYLLITHIUM.
To the lithium turnings (250 mg, 36 mmol) in 30 mL of ether either bromobenzene or m-bromotoluene
(54 mmol) in 5 mL of ether was slowly added at rt with stirring during a period of 1 h. After additional 1
h the solution was cooled down to -78°C and an appropriate imide (3.6 mmol) suspended in 5 mL of
anhydrous ether was added in one portion. After 30 min of stirring at -78°C the mixture was allowed to
reach rt overnight. 5 mL of water was carefully added and the reaction mixture was evaporated and
extracted with ethyl acetate (5x20 mL). Combined organic layers were evaporated and the residue was
chromatographed giving the following products:
2-Methyl-5-(3-methylphenyl)-5-oxopentanamide (13). Obtained from imide (12) (457 mg, 3.6 mmol)
and isolated by column chromatography on basic aluminum oxide using chloroform as eluent with yield
17% (124 mg) along with 361 mg (79%) of the recovered imide (12). Recrystallized from CHCl3 mp
128-129ºC. 1H NMR (CDCl3, 500 MHz) δ 1.21 (d, J=7 Hz, 3H), 1.87 (m, 1H), 2.05 (m, 1H), 2.41(s, 3H),
2.45 (app. sextet, 1H), 2.98 (m, 1H), 3.11 (m, 1H), 5.70 and 5.75 (two br s, 2H, s-cis NH and s-trans NH),
7.36 (m, 2H), 7.76 (d, J= 9 Hz, 1H), 7.77 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 17.9, 21.4, 28.6, 35.9,
39.6, 125.3, 128.5, 128.6, 134.0, 136.7, 138.4, 178.6, 200.3; MS (ES) [M+H]+ = 220, [M+Na]+ = 242;
HRMS m/z calcd for C13H17NO2Na 242.1157 found 242.1136.Anal. Calcd for C13H17NO2: C 71.21, H
7.81, N 6.39. Found: C 71.28, H 7.69, N 6.27.
2,2-Dimethyl-5-oxo-5-phenylpentanamide (15) and 6-hydroxy-3,3-dimethyl-6-phenylpiperidin-2-one
(16). The products (15) and (16) were prepared from 14 (508 mg, 3.6 mmol) and isolated by column
chromatography on neutral aluminum oxide using chloroform as eluent: 15 with yield 38% (300 mg), mp
133-134°C and 16 with yield 19% (150 mg), mp 155-156°C along with 208 mg (41%) of recovered imide
(14).
1
2,2-Dimethyl-5-oxo-5-phenylpentanamide (15). Recrystallized from ethyl acetate. H NMR (CDCl3,
200 MHz) 1.27 (s, 6H), 1.94 (m, 2H), 3.01 (m, 2H), 5.87 and 6.17 (two br s, 2H, s-cis NH and s-trans
NH), 7.40 – 7.60 (m, 3H), 7.97 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 25.6, 34.4, 35.0, 41.6, 128.1, 128.5,
133.0, 136.7, 180.2, 200.0; IR (KBr, cm-1) 3425, 3160, 1670, 1445 MS; (ES) [M+Na]+ = 242; HRMS m/z
calcd for C13H17NO2Na 242.1157 found 242.1146. Anal. Calcd for C13H17NO2: C 71.21, H 7.81, N 6.39.
Found: C 71.31, H 7.72, N 6.30.
1
6-Hydroxy-3,3-dimethyl-6-phenylpiperidin-2-one (16). Recrystallized from CHCl3. H NMR (CDCl3,
200 MHz) 0.79 (s, 3H), 0.98 (s, 3H), 1.43 (m, 1H), 2.30 – 2.60 (m, 3H), 3.88 (s, 1H, disappeared with
D2O), 6,37 (br s, 1H, disappeared with D2O), 7.30 – 7.40 (m, 3H), 7.40 – 7.50 (m, 2H); 13C NMR (CDCl3,
50 MHz) δ 23.0, 23.8, 28.6, 31.0, 36.9, 88.8, 127.5, 127.7, 127.8, 128.3, 128.4, 141.0, 174.1; IR (KBr,
cm-1) 3320, 2925, 1640, 1390; MS (EI) m/z (rel intensity in %) 219 (M+, 15), 218(100), 202 (42), 190

HETEROCYCLES, Vol. 65, No. 1, 2005
21
(25), 177(12), 176 (44), 162 (13), 148 (22), 136 (33), 134 (14), 122 (37), 105 (80), 104 (33), 77 (37), 56
(12), 55 (11), 51 (10), 41 (17); HRMS m/z calcd for C13H17NO2Na 242.1147 found 242.1169. Anal.
Calcd for C13H17NO2: C 71.21, H 7.81, N 6.39. Found: C 71.25, H 7.74, N 6.14.
6-Hydroxy-3,3,4,4-tetramethyl-6-phenylpiperidin-2-one (24). Obtained from compound (18) (608 mg,
3.6 mmol) and purified by column chromatography on silica gel using benzene and ethyl acetate as
eluents, starting from pure benzene to benzene:ethyl acetate (1:1 v/v). It gave 525 mg of 24, 59%, mp
1
143-144°C. Recrystallized from benzene. H NMR (benzene-d6, 500 MHz) δ 0.54 (s, 3H), 0.86 (s, 3H),
1.02 (s, 3H), 1.15 (s, 3H), 1.85 (qAB, J=14.5 Hz), 5.00 (s, 1H, disappeared with D2O), 7.08 (tt, 1H, J1=7.8,
J2=1.5 Hz), 7.17 (td, 2H, J1=7.8, J2=1.5 Hz), 7.29 (s, 1H, disappeared with D2O), 7.55 (dt, 2H, J1=7.7,
J2=1.5 Hz); 13C NMR (benzene-d6, 125 MHz) δ 19.3, 23.2, 24.7, 26.2, 35.6, 44.4, 48.0, 84.0, 125,4, 127.8,
128.6, 148.5, 179.6; MS (EI) m/z (rel intensity in %) 247 (M+, 4), 230 (39), 229 (23), 215 (16), 214 (100),
199(11), 191 (18), 170 (21), 160 (23), 128 (10), 122 (18), 105 (19), 104 (10), 84 (82), 83 (10), 77 (21), 70
(12), 69 (41), 55 (12), 41 (24); IR (KBr, cm-1) 3295, 2975, 1655, 1625, 1405, 1170; HRMS m/z calcd for
C15H21NO2Na 270.1470 found 270.1476. Anal. Calcd for C15H21NO2: C 72.84, H 8.56, N 5.66. Found: C
73.01, H 8.66, N 5.48.
3,3-Dimethyl-6-phenyl-3,4-dihydropyridin-2(1H)-one (17). Keto amide (15) (100 mg, 0.46 mmol) was
dissolved in 5 mL of chloroform and one drop of BF3 etherate was added. After 30 min the solvents were
removed and a short-path chromatography on neutral aluminum oxide was performed with chloroform as
1
eluent, giving compound (17) (90 mg, 98%), mp 143°C. Recrystallized from CHCl3. H NMR (CDCl3,
500 MHz) δ 1.25 (s, 6H), 2.37 (d, J=5.0 Hz, 2H), 5.41 (td, 1H, J1=5.0, J2=1.8 Hz), 7.10 (br s, 1H,
disappeared with D2O), 7.40 (m, 5H); 13C NMR (CDCl3, 125 MHz) δ 24.5, 36.0, 36.9, 101.7, 124.7,
128.7, 128.9, 135.0, 136.3, 177.1; MS (ES) [M+H]+ = 202. Anal. Calcd for C13H15NO: C 77.58, H 7.51,
N 6.96. Found: C 77.42, H 7.39, N 6.61.
3,3,4,4-tetramethyl-6-phenyl-3,4-dihydropyridin-2(1H)-one (25). Attempted purification of compound
(24) (100 mg, 0,4 mmol) by recrystallization from chloroform gave compound 25 (92 mg, 99%), mp
1
137°C. H NMR (CDCl3, 200 MHz) δ 1.09 (s, 6H), 1.17 (s, 6H), 5.17 (d, 1H, J=1.8 Hz), 7.11 (bs, 1H,
13
disappeared with D2O), 7.34-7.41 (m, 5H); C NMR (CDCl3, 50 MHz) δ 19.2, 23.0, 37.4, 44.3, 114.5,
124.7, 128.6, 128.9, 133.0, 134.9, 178.0; IR (KBr, cm-1) 3200, 3105, 2975, 1675, 1660, 1345; MS (EI)
m/z (rel intensity in %) 229 (M+, 30), 215 (15), 214 (100), 199 (12), 160 (22), 143 (10); HRMS m/z for
C15H19NONa 252.1364 found 252.1335. Anal. Calcd for C15H19NO: C 78.56, H 8.35, N 6.11. Found: C
78.65, H 8.21, N 5.89.
ACKNOWLEDGEMENTS
We are very grateful to Prof. K. Woźniak from Warsaw University, Faculty of Chemistry, Laboratory of
Crystallochemistry, for making the X-Ray measurement for compound (24).

22
HETEROCYCLES, Vol. 65, No. 1, 2005
REFERENCES
1. R. Lukeš, L. Havliĉkova, and V. Dudek, Collect. Czech. Chem. Commun., 1961, 26, 1719.
2. A. Castello, J. Cervello, J. Marquet, M. Moreno-Manas, and X. Sirera, Tetrahedron, 1986, 42, 4073.
3. J. P. Devlin, W. D. Ollis, J. E. Thorpe, R. J. Wood, B. J. Broughton, P. J. Warren, K. R. Wooldridge,
and D. E. Wright, J. Chem. Soc., Perkin Trans. I, 1975, 830.
4. P. Q. Huang, S. L. Wang, J. L. Ye, Y. P. Ruan, Y. Q. Huang, H. Zheng, and J. X. Gao, Tetrahedron,
1998, 54, 12547.
5. J. C. Gramain and R. Remuson, Tetrahedron Lett., 1985, 26, 4083.
6. J. B. P. A. Wijnberg, H. E. Schoemaker, and W. N. Speckamp, Tetrahedron, 1978, 34, 179.
7. A. M. Hamersma and W. N. Speckamp, Tetrahedron, 1982, 38, 3255.
8. A. B. Foster, M. Jarman, Ch-S. Leung, M. G. Rowlands, and G. N. Taylor, J. Med. Chem., 1983, 26,
50.
9. W. H. Soine, C. F. Yu, D. Thomas, S. L. Cao, R. B. Westkaemper, and T. D. Williams, Med. Chem.
Res., 1996, 6, 174.
10. H. Suzuki, S. Aoyagi, and C. Kibayashi, J. Org. Chem., 1995, 60, 6114.
11. Z. Czarnocki and J. T. Wróbel, Bull. Pol. Acad. Sci., Chem., 1984, 32, 335.
12. J. K. Maurin, Z. Czarnocki, B. Paluchowska, and M. Winnicka-Maurin, Acta Cryst., 1997, B53, 719.
13. E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley & Sons, New York,
1994.
14. J. C. Hubert, J. B. P. A. Wunberg, and W. N. Speckamp, Tetrahedron, 1975, 31, 1437.
15. P. v.R. Schleyer, J. Am. Chem. Soc., 1961, 83, 1368.
16. T. C. Bruice and U. K. Pandit, J. Am. Chem. Soc., 1960, 82, 5858.
17. A. L. Parrill and D. P. Dolata, J. Mol. Struct. (Theochem), 1996, 370, 187.
18. G. D. Andreetti, G. Bocelli, J. Cybulski, Z. Dąbrowski, and J. T. Wróbel, J. Mol. Struct., 1985, 128,
259.
19. K. U. Ingold and C. W. Shoppee, J. Chem. Soc., 1928, 396.
20. Z. Dąbrowski and J. Cybulski, Bull. Pol. Acad. Sci., Chem., 1981, 29, 11.
21. R. Tlumak, J. Day, J. Slanga, and P. J. Skell, J. Am. Chem. Soc., 1982, 104, 7257.
22. G. M. Sheldrick, Acta Cryst., 1990, A46, 467.
23. G. M. Sheldrick, SHELXL97. Program for the Refinement of Crystal Structures., 1997 Univ. of
Göttingen, Germany.