A new approach to di- And tetrasubstituted 2,3-dihydropyridin-4(1H)-ones through aza-diels-alder reaction promoted by silicon tetrachloride

Article abstract of DOI:10.1055/s-0028-1087677

Silicon tetrachloride promotes an aza-Diels-Alder reaction with a range of imines and Danishefsky's diene or an alkylated derivative, giving the desired products in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087677

PAPER
643
A New Approach to Di- and Tetrasubstituted 2,3-Dihydropyridin-4(1H)-ones
through Aza-Diels–Alder Reaction Promoted by Silicon Tetrachloride
A
za-Diels–Alde
r
R
n
eaction Prom
t
oted b
o
y
Silicon
T
e
n
trachloride io Massa,*a Vincenzo de Sio,a Rosaria Villano,a,b M. Rosaria Acocella,a Laura Palombi,a Giusi Sellitto,c
Antonella Peduto,c Rosanna Filosa,c Paolo De Capraris,c Arrigo Scettria
a
Dipartimento di Chimica, Università di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy
Fax +39(089)969603; E-mail: amassa@unisa.it
Istituto di Chimica Biomolecolare-CNR, Trav. La Crucca, 07040 Li Punti, Sassari, Italy
Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy
b
c
Received 18 September 2008
Moreover, the study of the reactivity of alkylated
Danishefsky diene, 2, allowed an easy approach to new
tetrasubstituted 2,3-dihydropyridin-4(1H)-ones.
Abstract: Silicon tetrachloride promotes an aza-Diels–Alder reac-
tion with a range of imines and Danishefsky’s diene or an alkylated
derivative, giving the desired products in good to excellent yields.
We first investigated the reaction of the representative
imine 3a with diene 1 in the presence of silicon tetrachlo-
ride according to Scheme 1. In the absence of silicon tet-
rachloride, the desired product was not detected and we
recovered the unreacted imine 3a (Table 1, entry 1), while
the use of silicon tetrachloride gave the cyclic product 4a
in 72% yield in reasonable time (entry 2). The activation
of silicon tetrachloride with a Lewis base like methyl p-
tolyl sulfoxide (entry 3) was not necessary, giving almost
unchanged yield. Interestingly, we observed also in our
previous work on vinylogous aldol reactions a not negli-
gible reactivity of Danishefsky’s diene and masked forms
of acetoacetate esters in the presence of nonactivated sili-
con tetrachloride.13,14 At the end of the process, the use of
trifluoroacetic acid was necessary to obtain the final ad-
duct in high yield. In the absence of the acidic treatment,
neutral aqueous workup afforded a complex mixture of
products, which tended to decompose in the course of
chromatography. The failure to isolate any intermediate
did not allow to ascertain the mechanism for the formation
of the dihydropyridinones through a [4+2] cycloaddition
or a Mukaiyama vinylogous imino-aldol reaction.2c
Key words: aza-Diels–Alder reaction, heterocycles, silicon tetra-
chloride
The aza-Diels–Alder reaction is a powerful method for the
construction of six-membered nitrogen heterocycles.1,2
Recent advances have been made in a number of Lewis
acid catalyzed aza-Diels–Alder reactions in organic sol-
vents,3 aqueous media,4 and ionic liquids.5 Moreover, the
use of Brønsted acid6 and hydrogen-bond catalysis7 pro-
vides an alternative to the use of metal catalysts. Asym-
metric versions of this transformation have also been
reported with several chiral metal complexes8,9 or chiral
Brønsted acid catalysts.6
Many examples of aza-Diels–Alder reactions in the pres-
ence of simple Danishefsky’s diene 1 (Figure 1) have
been reported, but surprisingly less attention has been
paid to the reactivity of alkylated 2 and, to the best of our
knowledge, the only diastereoselective versions reported
in the literature concern the use of chiral or activated
aldimines10 and/or the use of alkylated dienes different
from 2.9f,11
O
Ph
OTMS
OTMS
OTMS
1) SiCl4, i-Pr2NEt,
CH2Cl2, –78 °C, 4 h
N
+
OMe
2: alkylated Danishefsky's diene
OMe
OMe
Ph
2) TFA, –78 °C
N
Ph
3a
1
Ph
4a
1: Danishefsky's diene
Figure 1
Scheme 1
Very recently the activation of the mild Lewis acid silicon
tetrachloride with strong neutral Lewis bases, was intro-
duced by Denmark in a number of very important carbon–
carbon bond-forming reactions like aldol-type reactions.12
With these results in hand we further examined the possi-
bility of developing a one-pot process with the combina-
tion of the synthesis of imine, in the presence of activated
molecular sieves, and the following aza-Diels–Alder reac-
tion (Table 2, entry 1, Scheme 2).
Now we report a new application of silicon tetrachloride
in a versatile and efficient aza-Diels–Alder reaction of a
range of imines with the Danishefsky dienes 1 and 2.
In this way the adduct 4a was obtained in comparable
yield and in shorter reaction time (1 h), while longer reac-
tion time gave almost quantitative yield (entry 2). Several
imines were reacted according to the modified one-pot
procedure.
SYNTHESIS 2009, No. 4, pp 0643–0649
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x
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x
x
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Advanced online publication: 27.01.2009
DOI: 10.1055/s-0028-1087677; Art ID: P10008SS
© Georg Thieme Verlag Stuttgart · New York

644
A. Massa et al.
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Table 2 Aza-Diels–Alder Reaction with Danishefsky’s Diene (1)
Table 1 Aza-Diels–Alder Reaction of 3a with Danishefsky’s Diene
(1)
Entry
1c
2
Aldehyde, R
Yield (%)a,b of 4
Entry
MeS(O)(4-MeC6H4)
(equiv)
SiCl4
(equiv)
Yield
(%)a,b
5a
5a
5b
5c
5d
5e
5f
Ph
4a
4a
4b
4c
4d
4e
4f
73
95
83
95
94
77
–
Ph
1
2
3
–
–
1
1
–
3
4-ClC6H4
2-furyl
–
72
73
4
0.1
a All the yields refer to isolated chromatographically pure compounds.
b The product was characterized by comparison of spectroscopic data
with those reported in literature.
5
2-pyridyl
4-F3CC6H4
PhCH=CH
PhCH2CH2
4-O2NC6H4
4-O2NC6H4
4-MeC6H4
4-FC6H4
4-MeOC6H4
6
7d
8d
9
O
5g
5h
5h
5i
4g
4h
4h
4i
–
NH2
26
93
66
40
–
O
1) 4 Å MS, CH2Cl2, r.t., 1 h
N
R
+
10d
11
12
13
2) SiCl4, i-Pr2NEt, 1, –78 °C, 4 h
R
3) TFA, –78 °C, 10 min
5
6a
5j
4j
4
5k
4k
Scheme 2
a All the yields refer to isolated chromatographically pure compounds.
b The products were characterized by comparison of spectroscopic
data with those reported in literature.
The reported data show a very good reactivity for several
aromatic and heteroaromatic imines, while imines derived
from unsaturated or aliphatic aldehydes did not react
(Table 2, entries 7 and 8) even after the activation of sili-
con tetrachloride by methyl p-tolyl sulfoxide. A different
behavior was shown by imines both with the strong elec-
tron-withdrawing nitro group and with electron-releasing
groups on the aromatic ring (entries 9–13). The presence
of a nitro group on the aldehyde aromatic moiety of the
imine decreased the reactivity (entry 9) and the activation
of silicon tetrachloride was required to obtain higher yield
(entry 10). The lower reactivity of aldimines 5i, 5j, and
5k and their order of reactivity, respectively 4-Me > 4-F >
4-MeO, can reasonably be attributed to the effect of the
electron-releasing groups that decrease the electrophilici-
ty of carbonyl compounds and imines (entries 11–13).
c Reaction time = 1 h.
d The reactions were performed using 0.1 equiv of methyl p-tolyl sul-
foxide.
Table 3 Aza-Diels Alder Reaction of 4-Methoxy Derivative 5k
with Danishefsky’s Diene 1
Entry Amine, Ar
MeS(O)
Yield (%)a of 4
(4-MeC6H4)
(equiv)
1
6a
6a
6b
6c
6c
Ph
–
4ka
4ka
4kb
4kc
4kc
–
2
Ph
0.1
–
27
32
47
70
3
2-MeOC6H4
4-O2NC6H4
4-O2NC6H4
4
–
The problem of the low reactivity of 4-MeO derivatives of
5k (Table 3, entries 1 and 2) was resolved using an imine
activated by a strong electron-withdrawing group on the
aromatic ring of parent amine. In fact, the corresponding
pyridinone 4kc could be isolated in good yield by per-
forming the reaction at –50 °C on the imine derived from
4-nitroaniline 6c and in the presence of the methyl p-tolyl
sulfoxide for the activation of silicon tetrachloride
(Table 3, entry 5, Scheme 3).
5b
0.1
a All the yields refer to isolated chromatographically pure compounds.
b Reaction temperature = –50 °C.
In the optimized reaction conditions of the one-pot proce-
dure, the alkylated diene 2 was successfully used in the
formation of a new cyclic tetrasubstituted adducts 7
(Table 4, Scheme 4). In preliminary experiments we
O
O
1) 4 Å MS, CH2Cl2, r.t., 1 h
2) i-Pr2NEt, SiCl4, 1, –78 °C, 4 h
3) TFA, –78 °C
+
ArNH2
N
MeO
Ar
OMe
5k
6
4k
Scheme 3
Synthesis 2009, No. 4, 643–649 © Thieme Stuttgart · New York

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Aza-Diels–Alder Reaction Promoted by Silicon Tetrachloride
645
O
noted a lower reactivity of 2 with respect to the simple di-
ene 1, (entries 1 and 2, Table 4). The cyclic adducts were
obtained in satisfactory yield only when silicon tetrachlo-
ride was activated by methyl p-tolyl sulfoxide. The ob-
served diastereoselectivity was found to be 66:34 in favor
of the trans diastereomer. The two diastereomers were
generally separated by chromatography. The cis relation-
ship was assigned on the basis of a larger JH-5,H-6
(Scheme 4), according to what was reported for the oxy-
genated analogous pyranones.15 After these preliminary
results, we examined the reactivity of several imines ob-
tained by the combination of several amines and alde-
hydes. The presence of a 4-methoxy group on the
aromatic ring bound to the nitrogen atom completely de-
activated the imine (entry 3), even after Lewis base acti-
vation of silicon tetrachloride (entry 4). In the presence of
a nitro group we obtained high yields (entries 5–7), but
unfortunately, at the expense of the diastereoselectivity.
Then, we turned the attention to the influence of different
substituents on the aromatic ring of the aldehyde moiety
of the imines. In these cases, we noted again a strong elec-
tronic effect on the reactivity.
O
H5
H6
1) 4 Å MS, CH2Cl2, r.t., 1 h
+ Ar2NH2
2) i-Pr2NEt, Lewis base,
SiCl4, 2, –78 °C, 4 h
3) TFA, –78 °C
Ar1
N
Ar2
6
Ar1
5
7
Scheme 4
pletely inhibited the reactivity (entries 11 and 12). Con-
cerning the diastereoselectivity, substituents in the para
position gave a slight excess of the cis product (entries 8–
10). However, in the presence of substituents in the ortho
position, the ratio was significantly inverted in favor of
the trans diastereomer (entries 13–17). This effect was
minimized in the presence of 2-cyano (entry 13), a group
with a well-known coordination ability.12a
Different Lewis bases like DMF and pyridine N-oxide
were also effective in the activation of silicon tetrachlo-
ride and they gave the adduct 7j in slightly higher yields
and with a slight decrease of diastereoselectivity with re-
spect to methyl p-tolyl sulfoxide (entries 16 and 17).
Under the standard reaction conditions, electron-
withdrawing groups gave higher yield (entries 8–10 and
13–17), while substituents like methyl and methoxy com-
In summary, we have described here a new application of
silicon tetrachloride in aza-Diels–Alder reaction of sever-
al imines with Danishefsky’s dienes 1 and 2. The cyclic
Table 4 Aza-Diels–Alder Reaction on Different Aldimines with Diene 2
Entry
1
Ar1 of aldehyde
Ph
Ar2 of amine
Lewis base (0.1 equiv)
–
Yield (%)a
cis/transb
–
Ph
7a
7a
–
–
2
Ph
Ph
MeS(O)(4-MeC6H4)
–
82
–
66:34
–
3
Ph
4-MeOC6H4
4
Ph
4-MeOC6H4
MeS(O)(4-MeC6H4)
–
–
–
–
5
Ph
4-O2NC6H4
7b
7c
7c
7d
7e
7f
7g
7h
7i
86
50
95
96
65
73
0
55:45
55:45
50:50
68:32
67:33
68:32
–
6
4-Cl
4-O2NC6H4
MeS(O)(4-MeC6H4)
MeS(O)(4-MeC6H4)
MeS(O)(4-MeC6H4)
MeS(O)(4-MeC6H4)
MeS(O)(4-MeC6H4)
MeS(O)(4-MeC6H4)
MeS(O)(4-MeC6H4)
MeS(O)(4-MeC6H4)
MeS(O)(4-MeC6H4)
MeS(O)(4-MeC6H4)
pyridine N-oxide
DMF
7c
8
4-Cl
4-O2NC6H4
4-O2NC6H4
4-NCC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
2-NCC6H4
2-ClC6H4
2-O2NC6H4
2-ClC6H4
2-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9
10
11
12
13
14
15
16
17
0
–
90
60
73
73
70
42:58
24:76
20:80
27:73
27:73
7j
7k
7j
7j
a All the yields refer to isolated chromatographically pure compounds.
b The cis/trans diastereoisomeric ratios were determined by 1H NMR analysis (400 MHz) on the crude products.
c Reaction temperature = –50 °C.
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646
A. Massa et al.
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ESI-MS: m/z = 278 (M + 1).
Anal. Calcd for C19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C,
adducts were obtained in good to excellent yields. Partic-
ular attention was paid to the synthesis of novel tetrasub-
stituted 2,3-dihydropyridin-4(1H)-one using alkylated 82.47; H, 6.72; N, 5.23.
Danishefsky’s diene 2. In this case the observed diastereo-
trans-2,3-Dihydro-3,5-dimethyl-1,2-diphenylpyridin-4(1H)-one
(trans-7a)
The title compound was obtained as a yellow wax-like solid in 28%
yield; Rf = 0.35 (PE–EtOAc, 7:3).
IR (KBr): 697, 756, 1207, 1312, 1385, 1494, 1594, 1614, 2924 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.37 (d, J = 7.5 Hz, 3 H, CHCH3),
1.77 (s, 3 H, CH3), 2.78 (dq, J = 2.1, 7.5 Hz, 1 H, CHCH3), 4.88 (br
d, J = 2.1 Hz, 1 H, CHCH), 6.99–7.08 (m, 3 H, ArH), 7.24–7.32 (m,
7 H, ArH), 7.53 (s, 1 H, C=CH).
13C NMR (100 MHz, CDCl3): d = 12.8, 18.3, 47.6, 68.0, 108.2,
117.7, 123.5, 126.0, 127.5, 128.7, 129.4, 137.8, 144.0, 145.5, 194.5.
selectivity was only moderate, but significantly dependent
on the substitution pattern of the aldehyde moiety of the
imine. Moreover an efficient one-pot procedure was de-
veloped with the combination of the synthesis of imine
and the following aza-Diels–Alder reaction in the pres-
ence of activated molecular sieves.
All reactions were performed in oven-dried (140 °C) or flame-dried
glassware under dry N2. All the solvents for the reactions were of
reagent grade and were dried and distilled immediately before use
(CH2Cl2 from CaH2). Column chromatographic purification of
products was carried out using silica gel 60 (70–230 mesh, Merck).
The reagents (Aldrich and Fluka) were used without further purifi-
cation. Petroleum ether (PE) used refers to the fraction boiling in the
range 40–60 °C. The NMR spectra were recorded on a Bruker DRX
400 spectrometer (400 MHz, 1H; 100 MHz, 13C). Spectra were ref-
ESI-MS: m/z = 278 (M + 1).
Anal. Calcd for C19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C,
82.40; H, 6.79; N, 5.24.
cis-2,3-Dihydro-3,5-dimethyl-1-(4-nitrophenyl)-2-phenylpyri-
din-4(1H)-one (cis-7b)
1
erenced to residual CHCl3 (7.26 ppm, H, 77.23 ppm, 13C). Cou-
pling constants J are reported in Hz. Yields are given for isolated
products showing one spot on a TLC plate and no impurities detect-
able in the NMR spectrum. IR spectra were recorded on a Bruker
Vector 22 (frequencies 400–4000 cm–1, resolution 2 cm–1). Mass
spectral analyses were carried out using an electrospray spectrome-
ter, Waters 4 micro quadrupole. Elemental analyses were performed
with FLASHEA 1112 series-Thermo Scientific for CHNS-O appa-
ratus.
The title compound was obtained as a yellow wax-like solid in 47%
yield; Rf = 0.44 (PE–EtOAc, 7:3).
IR (KBr): 693, 750, 843, 1111, 1202, 1318, 1500, 1587, 2924 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.06 (d, J = 6.9 Hz, 3 H, CHCH3),
1.89 (s, 3 H, CH3), 3.43 (quint, J = 6.9 Hz, 1 H, CHCH3), 5.10 (d,
J = 6.8 Hz, 1 H, CHCH), 7.06 (d, J = 7.3 Hz, 2 H, ArH), 7.30 (m, 5
H, ArH), 7.63 (s, 1 H, C=CH), 8.13 (d, J = 7.3 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 11.0, 12.9, 43.9, 67.5, 112.6,
One-Pot Aza-Diels–Alder Reaction of Danishefsky’s Diene 1 (or
Diene 2); General Procedure
115.7, 125.5, 127.4, 128.5, 129.0, 135.1, 141.9, 142.8, 149.5, 193.4.
ESI-MS: m/z = 323 (M + 1).
In a flame-dried, 2-necked, round-bottomed flask, aldehyde 5 (0.66
mmol) and aniline 6 (0.70 mmol) were added to activated 4 Å MS
(0.7 g) in anhyd CH2Cl2 (2 mL) under argon. The reaction mixture
was stirred at r.t. for 1 h. Then the mixture was diluted with anhyd
CH2Cl2 (2 mL) and the temperature was lowered to –78 °C. At this
temperature, activator (0.066 mmol, if required), i-Pr2NEt (0.66
mmol), SiCl4 (0.66 mmol, 1.0 M in CH2Cl2) and Danishefsky’s di-
ene 1 (or 2, 0.71 mmol) were successively added. At the end of the
reaction, the mixture was treated with a solution of trifluoroacetic
acid (0.1 mL) in CH2Cl2 (1 mL). After about 15 min, the reaction
was quenched with aq sat. NaHCO3 (10 mL), extracted with CH2Cl2
(50 × 3 mL), and the combined organic extracts were dried
(Na2SO4). After removal of the solvent under reduced pressure, the
crude oil was purified by silica gel flash chromatography with PE–
EtOAc mixture (from 9:1 to 7:3) for adducts 4 and with PE–EtOAc
mixture (from 95:5 to 8:2) to afford the pure cyclic adducts 7.
Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C,
70.56; H, 5.45; N, 8.85.
trans-2,3-Dihydro-3,5-dimethyl-1-(4-nitrophenyl)-2-phenylpy-
ridin-4(1H)-one (trans-7b)
The title compound was obtained as a yellow solid in 39% yield;
mp 147 °C; Rf = 0.35 (PE–EtOAc, 7:3).
IR (KBr): 700, 780, 849, 959, 1121, 1242, 1344, 1490, 1579, 2936,
2987 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.38 (d, J = 7.4 Hz, 3 H, CHCH3),
1.80 (s, 3 H, CH3), 2.88 (dq, J = 1.9, 7.4 Hz, 1 H, CHCH3), 4.98 (br
d, J = 1.9 Hz, 1 H, CHCH), 7.05 (d, J = 7.5 Hz, 2 H, ArH), 7.99 (d,
J = 7.2 Hz, 2 H, ArH), 7.26–7.30 (m, 3 H, ArH), 7.58 (s, 1 H,
C=CH), 8.17 (d, J = 7.5 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 12.9, 18.2, 47.8, 67.7, 112.2,
The products 4a–k are known compounds and were characterized
by comparison of their spectroscopic data with those reported in the
literature.5,6
116.0, 125.6, 125.7, 128.1, 129.1, 136.4, 140.6, 142.3, 150.0, 194.7.
ESI-MS: m/z = 323 (M + 1).
Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C,
70.59; H, 5.50; N, 8.53.
cis-2,3-Dihydro-3,5-dimethyl-1,2-diphenylpyridin-4(1H)-one
(cis-7a)
The title compound was obtained as a yellow wax-like solid in 54%
yield; Rf = 0.41 (PE–EtOAc, 7:3).
cis-2-(4-Chlorophenyl)-2,3-dihydro-3,5-dimethyl-1-(4-nitro-
phenyl)pyridin-4(1H)-one (cis-7c)
The title compound was obtained as a yellow solid in 48% yield;
mp 196 °C; Rf = 0.40 (PE–EtOAc, 7:3).
IR (KBr): 698, 756, 1188, 1258, 1305, 1498, 1593, 1621, 1651,
2863, 2938, 2981 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.03 (d, J = 7.0 Hz, 3 H, CHCH3),
1.85 (s, 3 H, CH3), 3.37 (quint, J = 7.0 Hz, 1 H, CHCH3), 5.01 (d,
J = 7.0 Hz, 1 H, CHCH), 6.99–7.05 (m, 4 H, ArH), 7.23–7.32 (m, 6
H, ArH), 7.52 (s, 1 H, C=CH).
IR (KBr): 790, 869, 979, 1132, 1248, 1350, 1470, 1559, 1600, 2940,
2999 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.05 (d, J = 6.9 Hz, 3 H, CHCH3),
1.87 (s, 3 H, CH3), 3.41 (quint, J = 6.9 Hz, 1 H, CHCH3), 5.09 (d,
13C NMR (100 MHz, CDCl3): d = 11.2, 12.8, 43.6, 67.6, 108.3,
118.1, 123.4, 127.7, 127.9, 128.6, 129.3, 136.3, 145.2, 145.6, 193.4.
Synthesis 2009, No. 4, 643–649 © Thieme Stuttgart · New York

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Aza-Diels–Alder Reaction Promoted by Silicon Tetrachloride
647
J = 6.9 Hz, 1 H, CHCH), 7.03 (d, J = 9.1 Hz, 2 H, ArH), 7.26 (m, 4
H, ArH), 7.60 (s, 1 H, C=CH), 8.11 (d, J = 9.1 Hz, 2 H, ArH).
cis-2-(4-Cyanophenyl)-2,3-dihydro-3,5-dimethyl-1-phenylpyri-
din-4(1H)-one (cis-7e)
The title compound was obtained as a yellow solid in 44% yield; mp
142 °C; Rf = 0.35 (PE–EtOAc, 7:3).
13C NMR (100 MHz, CDCl3): d = 11.0, 12.8, 43.7, 66.7, 112.7,
115.8, 125.5, 128.8, 129.1, 133.6, 134.4, 141.7, 142.1, 149.2, 193.0.
IR (KBr): 689, 756, 991, 1138, 1285, 1365, 1478, 1539, 1622, 2215,
2870, 2966, 2989 cm–1.
ESI-MS: m/z = 357 (M + 1).
Anal. Calcd for C19H17ClN2O3: C, 63.69; H, 4.80; N, 7.85. Found:
C, 63.78; H, 4.65; N, 7.71.
1H NMR (400 MHz, CDCl3): d = 1.03 (d, J = 7.0 Hz, 3 H, CHCH3),
1.84 (s, 3 H, CH3), 3.39 (quint, J = 7.0 Hz, 1 H, CHCH3), 5.08 (d,
J = 7.0 Hz, 1 H, CHCH), 6.93 (d, J = 7.8 Hz, 2 H, ArH), 7.06 (t,
J = 7.4 Hz, 1 H, ArH), 7.24–7.28 (m, 2 H, ArH), 7.42 (d, J = 8.2 Hz,
2 H, ArH), 7.51 (s, 1 H, C=CH), 7.58 (d, J = 8.3 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 11.1, 12.7, 43.2, 67.1, 108.7,
111.7, 118.3, 118.5, 123.9, 128.5, 129.4, 132.3, 141.6, 144.3, 145.3,
192.3.
trans-2-(4-Chlorophenyl)-2,3-dihydro-3,5-dimethyl-1-(4-nitro-
phenyl)pyridin-4(1H)-one (trans-7c)
The title compound was obtained as a yellow solid in 47% yield;
mp 198 °C; Rf = 0.33 (PE–EtOAc, 7:3).
IR (KBr): 791, 866, 989, 1135, 1260, 1355, 1476, 1549, 1605, 2930,
3000 cm–1.
ESI-MS: m/z = 303 (M + 1).
1H NMR (400 MHz, CDCl3): d = 1.38 (d, J = 7.3 Hz, 3 H, CHCH3),
1.81 (s, 3 H, CH3), 2.86 (dq, J = 1.7, 7.2 Hz, 1 H, CHCH3), 4.98 (br
d, J = 1.7 Hz, 1 H, CHCH), 7.05 (d, J = 9.2 Hz, 2 H, ArH), 7.16 (d,
J = 8.4 Hz, 2 H, ArH), 7.32 (d, J = 8.4 Hz, 2 H, ArH), 7.58 (s, 1 H,
C=CH), 8.17 (d, J = 9.2 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 13.0, 18.2, 47.7, 67.3, 112.5,
116.1, 125.8, 127.3, 129.5, 134.1, 135.2, 140.5, 142.6, 149.9, 194.4.
Anal. Calcd for C20H18N2O: C, 79.44; H, 6.00; N, 9.26. Found: C,
79.56; H, 6.12; N, 9.09.
trans-2-(4-Cyanophenyl)-2,3-dihydro-3,5-dimethyl-1-phe-
nylpyridin-4(1H)-one (trans-7e)
The title compound was obtained as a yellow solid in 21% yield; mp
149 °C; Rf = 0.29 (PE–EtOAc, 7:3).
ESI-MS: m/z = 357 (M + 1).
IR (KBr): 655, 688, 790, 1144, 1251, 1300, 1377, 1485, 1533, 1600,
2198, 2981 cm–1.
Anal. Calcd for C19H17ClN2O3: C, 63.69; H, 4.80; N, 7.85. Found:
C, 63.91; H, 4.62; N, 7.68.
1H NMR (400 MHz, CDCl3): d = 1.38 (d, J = 7.2 Hz, 3 H, CHCH3),
1.76 (s, 3 H, CH3), 2.74 (dq, J = 2.2, 7.2 Hz, 1 H, CHCH3), 4.91 (br
d, J = 2.2 Hz, 1 H, CHCH), 6.95 (d, J = 7.8 Hz, 2 H, ArH), 7.10 (t,
J = 7.4 Hz, 1 H, ArH), 7.25–7.37 (m, J = 8.0 Hz, 4 H, ArH), 7.52 (s,
1 H, C=CH), 7.60 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 12.7, 18.1, 47.2, 67.5, 108.7,
111.6, 117.6, 118.2, 124.0, 127.0, 129.6, 132.6, 143.6, 143.7, 145.3,
193.7.
cis-2,3-Dihydro-3,5-dimethyl-2-(4-nitrophenyl)-1-phenylpyri-
din-4(1H)-one (cis-7d)
The title compound was obtained as a yellow solid in 65% yield;
mp 142 °C; Rf = 0.38 (PE–EtOAc, 7:3).
IR (KBr): 753, 790, 849, 1190, 1234, 1308, 1359, 1510, 1581, 2933
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.03 (d, J = 7.0 Hz, 3 H, CHCH3),
1.83 (s, 3 H, CH3), 3.39 (quint, J = 7.0 Hz, 1 H, CHCH3), 5.16 (d,
J = 7.0 Hz, 1 H, CHCH), 6.93 (d, J = 8.0, 2 H, ArH), 7.04 (t, J = 8.0
Hz, 1 H, ArH), 7.24 (t, J = 8.0 Hz, 2 H, ArH), 7.48 (d, J = 8.6 Hz, 2
H, ArH), 7.53 (s, 1 H, C=CH), 8.11 (d, J = 8.6 Hz, 2 H, ArH).
ESI-MS: m/z = 303 (M + 1).
Anal. Calcd for C20H18N2O: C, 79.44; H, 6.00; N, 9.26. Found: C,
79.29; H, 6.15; N, 9.49.
cis-2-(4-Chlorophenyl)-2,3-dihydro-3,5-dimethyl-1-phenyl-
pyridin-4(1H)-one (cis-7f)
The title compound was obtained as a yellow wax-like solid in 50%
13C NMR (100 MHz, CDCl3): d = 11.1, 12.7, 40.7, 66.8, 108.7,
118.4, 123.7, 124.0, 128.7, 129.4, 143.8, 144.5, 145.5, 147.5, 192.5.
ESI-MS: m/z = 323 (M + 1).
yield; Rf = 0.54 (PE–EtOAc, 7:3).
Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C,
70.92; H, 5.81; N, 8.55.
IR (KBr): 655, 670, 756, 889, 1150, 1288, 1268, 1370, 1452, 1577,
1627, 2863, 2999 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.02 (d, J = 7.0 Hz, 3 H, CHCH3),
1.83 (s, 3 H, CH3), 3.35 (quint, J = 7.0 Hz, 1 H, CHCH3), 5.00 (d,
J = 7.3 Hz, 1 H, CHCH), 6.96–7.06 (m, 3 H, ArH), 7.24–7.27 (m, 6
H, ArH), 7.50 (s, 1 H, C=CH).
13C NMR (100 MHz, CDCl3): d = 11.1, 12.7, 43.4, 66.9, 108.4,
118.9, 123.7, 128.7, 129.1, 129.3, 133.8, 134.8, 144.9, 145.5, 193.0.
trans-2,3-Dihydro-3,5-dimethyl-2-(4-nitrophenyl)-1-phenylpy-
ridin-4(1H)-one (trans-7d)
The title compound was obtained as a yellow wax-like solid in 31%
yield; Rf = 0.23 (PE–EtOAc, 7:3).
IR (KBr): 700, 780, 849, 959, 1121, 1242, 1344, 1490, 1579, 2936,
2987 cm–1.
ESI-MS: m/z = 312 (M + 1).
1H NMR (400 MHz, CDCl3): d = 1.39 (d, J = 7.3 Hz, 3 H, CHCH3),
1.77 (s, 3 H, CH3), 2.76 (dq, J = 2.2, 7.3 Hz, 1 H, CHCH3), 4.96 (br
d, J = 2.2 Hz, 1 H, CHCH), 6.95 (d, J = 7.8 Hz, 2 H, ArH), 7.10 (t,
J = 7.3 Hz, 1 H, ArH), 7.30 (t, J = 7.8 Hz, 2 H, ArH), 7.43 (d,
J = 8.6 Hz, 2 H, ArH), 7.54 (s, 1 H, C=CH), 8.16 (d, J = 8.6 Hz, 2
H, ArH).
Anal. Calcd for C19H18ClNO: C, 73.19; H, 5.82; N, 4.49. Found: C,
73.31; H, 5.68; N, 4.29;
trans-2-(4-Chlorophenyl)-2,3-dihydro-3,5-dimethyl-1-phe-
nylpyridin-4(1H)-one (trans-7f)
The title compound was obtained as a yellow wax-like solid in 23%
yield; Rf = 0.44 (PE–EtOAc, 7:3).
13C NMR (100 MHz, CDCl3): d = 12.7, 18.1, 47.2, 67.4, 108.8,
117.7, 123.7, 124.0, 127.2, 129.6, 143.4, 144.5, 145.5, 147.5, 193.6.
IR (KBr): 672, 758, 882, 1148, 1227, 1332, 1490, 1584, 1624, 2944,
2987 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.35 (d, J = 7.2 Hz, 3 H, CHCH3),
1.76 (s, 3 H, CH3), 2.72 (dq, J = 2.1, 7.2 Hz, 1 H, CHCH3), 4.84 (br
d, J = 2.1 Hz, 1 H, CHCH), 6.97 (d, J = 8.0 Hz, 2 H, ArH), 7.08 (t,
ESI-MS: m/z = 323 (M + 1).
Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C,
70.64; H, 5.48; N, 8.85.
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648
A. Massa et al.
PAPER
J = 7.3 Hz, 1 H, ArH), 7.17 (d, J = 8.0 Hz, 2 H, ArH), 7.25–7.32 (m,
J = 7.3 Hz, 1 H, ArH), 7.15–7.41 (m, 6 H, ArH), 7.43 (s, 1 H,
4 H, ArH), 7.50 (s, 1 H, C=CH).
C=CH).
13C NMR (100 MHz, CDCl3): d = 12.7, 18.1, 47.5, 67.3, 108.4,
13C NMR (100 MHz, CDCl3): d = 12.8, 18.6, 45.4, 65.2, 107.7,
117.4, 118.3, 123.6, 126.9, 127.0, 129.0, 129.5, 130.5, 135.2, 144.6,
145.7, 194.5.
117.7, 123.7, 126.0, 127.5, 128.9, 133.2, 136.4, 143.8, 145.3, 194.2.
ESI-MS: m/z = 312 (M + 1).
ESI-MS: m/z = 312 (M + 1).
Anal. Calcd for C19H18ClNO: C, 73.19; H, 5.82; N, 4.49. Found: C,
73.30; H, 5.65; N, 4.66.
Anal. Calcd for C19H18ClNO: C, 73.19; H, 5.82; N, 4.49. Found: C,
73.31; H, 5.69; N, 4.69;
cis-2-(2-Cyanophenyl)-2,3-dihydro-3,5-dimethyl-1-phenylpyri-
din-4(1H)-one (cis-7i)
The title compound was obtained as a yellow wax-like solid in 38%
cis-2,3-Dihydro-3,5-dimethyl-2-(2-nitrophenyl)-1-phenylpyri-
din-4(1H)-one (cis-7k)
yield; Rf = 0.42 (PE–EtOAc, 7:3).
The title compound was obtained as a yellow wax-like solid in 15%
yield; Rf = 0.40 (PE–EtOAc, 7:3).
IR (KBr): 698, 756, 1188, 1258, 1305, 1498, 1593, 1621, 1651,
2210, 2863, 2938, 2981 cm–1.
IR (KBr): 734, 788, 845, 1003, 1190, 1234, 1358, 1365, 1532, 1600,
2943, 2978 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.05 (d, J = 7.0 Hz, 3 H, CHCH3),
1.87 (s, 3 H, CH3), 3.48 (quint, J = 7.0 Hz, 1 H, CHCH3), 5.63 (d,
J = 7.5 Hz, 1 H, CHCH), 6.99–7.01 (m, 2 H, ArH), 7.08 (t, J = 7.4
Hz, 1 H, ArH), 7.27 (m, 2 H, ArH), 7.35 (m, 1 H, ArH), 7.47–7.49
(m, 2 H, ArH, C=CH), 7.60–7.80 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 10.2, 12.8, 42.5, 64.2, 108.0,
112.3, 117.5, 118.0, 118.8, 124.2, 127.7, 128.6, 129.5, 132.9, 133.6,
141.4, 145.9, 192.5.
1H NMR (400 MHz, CDCl3): d = 0.97 (d, J = 7.0 Hz, 3 H, CHCH3),
1.84 (s, 3 H, CH3), 3.98 (quint, J = 7.0 Hz, 1 H, CHCH3), 6.24 (d,
J = 7.5 Hz, 1 H, CHCH), 7.04–7.08 (m, 3 H, ArH), 7.27 (t, J = 8.4
Hz, 2 H, ArH), 7.39–7.46 (m, 2 H, ArH), 7.55 (s, 1 H, C=CH), 7.73
(d, J = 7.8 Hz, 1 H, ArH), 7.81 (d, J = 8.0 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 9.7, 12.8, 43.3, 59.6, 108.2, 118.8,
124.1, 124.7, 128.9, 129.4, 131.3, 133.2, 138.1, 144.4, 146.0, 149.2,
192.5.
ESI-MS: m/z = 303 (M + 1).
ESI-MS: 323 (M + 1).
Anal. Calcd for C20H18N2O: C, 79.44; H, 6.00; N, 9.26. Found: C,
79.58; H, 6.21; N, 9.08.
Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C,
70.64; H, 5.75; N, 8.50.
trans-2-(2-Cyanophenyl)-2,3-dihydro-3,5-dimethyl-1-phe-
nylpyridin-4(1H)-one (trans-7i)
The title compound was obtained as a yellow wax-like solid in 52%
yield; Rf = 0.33 (PE–EtOAc, 7:3).
trans-2,3-Dihydro-3,5-dimethyl-2-(2-nitrophenyl)-1-phenylpy-
ridin-4(1H)-one (trans-7k)
The title compound was obtained as a yellow wax-like solid in 58%
yield; Rf = 0.34 (PE–EtOAc, 7:3).
IR (KBr): 688, 743, 1100, 1232, 1320, 1377, 1490, 1594, 1632,
2200, 2932, 2958 cm–1.
IR (KBr): 710, 782, 849, 1120, 1223, 1370, 1434, 1559, 1600, 2965,
2997 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.44 (d, J = 7.2 Hz, 3 H, CHCH3),
1.81 (s, 3 H, CH3), 2.83 (dq, J = 2.5, 7.2 Hz, 1 H, CHCH3), 5.23 (br
d, J = 2.5 Hz, 1 H, CHCH), 6.94 (d, J = 7.9 Hz, 2 H, ArH), 7.09 (t,
J = 7.3 Hz, 1 H, ArH), 7.31–7.26 (m, 2 H, ArH), 7.36–7.45 (m, 3 H,
ArH), 7.48 (s, 1 H, C=CH), 7.50 (d, J = 7.3 Hz, 1 H, ArH).
13C NMR (100 MHz CDCl3): d = 12.9, 18.5, 47.2, 66.5, 108.3,
110.7, 116.9, 118.2, 119.0, 124.3, 126.5, 128.4, 129.7, 133.1, 134.0,
142.7, 144.9, 193.7.
1H NMR (400 MHz CDCl3): d = 1.41 (d, J = 7.2 Hz, 3 H, CHCH3),
1.80 (s, 3 H, CH3), 2.59 (dq, J = 1.1, 7.2 Hz, 1 H, CHCH3), 5.81 (br
d, J = 1.1 Hz, 1 H, CHCH), 6.95 (d, J = 7.8 Hz, 2 H, ArH), 7.07 (t,
J = 7.3 Hz, 1 H, ArH), 7.29 (m, 2 H, ArH), 7.42–7.46 (m, 1 H, ArH),
7.52 (m, 2 H, ArH), 7.64 (s, 1 H, C=CH), 8.10 (d, J = 8.0 Hz, 1 H,
ArH).
13C NMR (100 MHz, CDCl3): d = 12.7, 19.2, 46.9, 63.7, 108.9,
117.5, 123.9, 126.4, 127.7, 128.9, 129.6, 133.7, 134.0, 144.4, 144.9,
147.3, 194.3.
ESI-MS: m/z = 303 (M + 1).
Anal. Calcd for C20H18N2O: C, 79.44; H, 6.00; N, 9.26. Found: C,
79.60; H, 6.19; N, 9.08.
ESI-MS: m/z = 323 (M + 1).
Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C,
70.93, H, 5.44; N, 8.51.
cis-7j
We were not able to separate the minor cis diastereomer from the
trans. It was obtained as an inseparable mixture with the trans iso-
mer in 35% total yield.
Note Added in Proof
This paper is published despite the effects of the Italian law 133/08.
This law drastically reduces public funds to public Italian universi-
ties, which is particularly dangerous for scientific free research, and
will prevent young researchers from getting a position, either tem-
porary or tenured, in Italy. One of the authors (A.M.) is protesting
against this law to obtain its cancellation.
trans-2-(2-Chlorophenyl)-2,3-dihydro-3,5-dimethyl-1-phe-
nylpyridin-4(1H)-one (trans-7j)
The title compound was obtained as a yellow wax-like solid in 38%
yield; Rf = 0.46 (PE–EtOAc, 7:3).
IR (KBr): 718, 862, 1148, 1232, 1256, 1312, 1380, 1480, 1544,
1634, 2930, 2977 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.40 (d, J = 7.3 Hz, 3 H, CHCH3),
1.82 (s, 3 H, CH3), 2.80 (dq, J = 1.7, 7.2 Hz, 1 H, CHCH3), 5.22 (br
d, J = 1.7 Hz, 1 H, CHCH), 6.93 (d, J = 8.4 Hz, 2 H, ArH), 7.04 (t,
Acknowledgment
We are grateful to MIUR for financial support.
Synthesis 2009, No. 4, 643–649 © Thieme Stuttgart · New York

PAPER
Aza-Diels–Alder Reaction Promoted by Silicon Tetrachloride
649
(7) Chiral Brønsted acid catalyzed aza-Diels–Alder reaction:
Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem. Int. Ed.
2006, 45, 4796.
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