Stereoselective synthesis of β-amino ketones possessing β-[(2H-pyran-2-one)-3-Yl]-β-chlorovinyl moiety via three-component direct Mannich-type reaction, catalyzed with ZrOCl2·8H 2O

Article abstract of DOI:10.1002/jhet.363

(Chemical Presented) New Z-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3- yl)acrolein was synthesized starting from dehydroacetic acid using Vilsmeier-Haack reaction and efficiently used in three component direct Mannich-type reaction with different anil

Full text of DOI:10.1002/jhet.363

594
Stereoselective Synthesis of b-Amino Ketones Possessing
b-[(2H-Pyran-2-one)-3-Yl]-b-chlorovinyl Moiety via
Three-Component Direct Mannich-Type Reaction,
Catalyzed with ZrOCl2ꢀ8H2O
Vol 47
Aziz Shahrisa* and Maryam Zirak
Faculty of Chemistry, Department of Organic and Bioorganic Chemistry, University of Tabriz,
Tabriz, Iran
*E-mail: ashahrisa@yahoo.com
Received September 2, 2009
DOI 10.1002/jhet.363
Published online 3 May 2010 in Wiley InterScience (www.interscience.wiley.com).
New Z-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein was synthesized starting from
dehydroacetic acid using Vilsmeier–Haack reaction and efficiently used in three component direct Man-
nich-type reaction with different anilines, cyclic and acyclic ketones catalyzed with zirconium oxychlor-
ide (ZrOCl2ꢀ8H2O) in ethanol at room temperature. Also, comenic aldehyde was used in direct
Mannich-type reaction at the same conditions. The reaction proceeds rapidly and affords the correspond-
ing b-amino ketones in good to high yields with moderate to high stereoselectivity.
J. Heterocyclic Chem., 47, 594 (2010).
INTRODUCTION
plagued by a number of serious disadvantages [6].
Therefore, catalytic Mannich reactions have been
reported by several groups as an efficient method to pre-
pare b-amino carbonyl compounds [8,9d].
Because of their easy availability [10] and low toxic-
ity [11], Zr(IV) salts have recently attracted much atten-
tion as a catalyst for organic transformations [9]. To our
knowledge, there have been only a few reports on the
metal oxysalt-based organic reactions [12].
The Vilsmeier–Haack reaction is a widely used
method for the formylation of activated aromatic and
heteroaromatic compounds [1]. The reactions of ali-
phatic substrates [2], particularly carbonyl compounds
[3] with chloromethylene iminium salts are highly versa-
tile. One aspect of its importance is its reaction with a
keto methylene group to produce b-chloroacroleins [4].
b-Amino carbonyl compounds are also attractive tar-
gets for chemical synthesis because of their wide utility
as biologically active molecules [5]. The Mannich reac-
tion is a classical method for preparation of the b-amino
carbonyl compounds [5,6] and has been one of the most
important basic reactions in organic chemistry for its
use in natural product and pharmaceutical synthesis [7].
However, because of the drastic reaction conditions and
long reaction times, the classical Mannich reaction is
As part of our research on synthesis of pyrone deriva-
tives[13], herein we report a simple and environmentally
benign stereoselective synthesis of new b-amino ketones
possessing b-[(2H-pyran-2-one)-3-yl]-b-chlorovinyl or
4-oxo-4H-pyran-2-yl moiety via direct Mannich-type
reaction between Z-3-chloro-3-(4-chloro-6-methyl-2-
oxo-2H-pyran-3-yl)acrolein 2 or O-protected comenic
aldehyde 10, anilines and ketones at room temperature
using ZrOCl2ꢀ8H2O as catalyst.
C
V
2010 HeteroCorporation

May 2010
Stereoselective Synthesis of b-Amino Ketones Possessing b-[(2H-Pyran-2-one)-3-yl]-
b-chlorovinyl Moiety via Three-Component Direct Mannich-Type Reaction
595
Scheme 1. Synthesis of Z-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-py-
ran-3-yl)acrolein 2.
Figure 1. (a) HMBC correlations and (b) HMQC correlations for 2.
RESULTS AND DISCUSSION
The ZrOCl2ꢀ8H2O catalyzed Mannich reaction was
first studied with preformed imine 3. As shown in
Scheme 2, imine 3, which was synthesized by reaction
of 2 and aniline in EtOH at room temperature, was
treated with cyclohexanone in the presence of catalytic
amount of ZrOCl2ꢀ8H2O and Mannich adduct 4c was
isolated in 85% yield, with 78% anti selectivity.
A new b-chloroacrolein with 2H-pyran-2-one moiety
2 was synthesized from commercially available dehydro-
acetic acid 1 in 69.4% yield using Vilsmeier–Haack
reaction as outlined in Scheme 1.
The structure of compound 2 was established from
IR, 1H NMR, 13C NMR, 2D-NMRs (HMQC and
HMBC), and mass spectral data and elemental analyses.
Subsequently, a one-pot direct Mannich-type reaction
of 2 with anilines and cyclic ketones were investigated
(Scheme 3).
3
The values of coupling constant J of the proton signals
1
of AClC¼¼CHACOAH in the H NMR spectra equal to
6.8 Hz indicate that these atoms are located in the s-cis
position [4h,i]. It was shown by the study of isomer
composition of b-aryl-b-chloroacroleins, arising from
aryl ketones [4j,k,o] and heteroaryl ketones [4o] in the
reaction with Vilsmeier-Haack reagent, a-unsubstituted
acroleins are obtained exclusively as a Z isomer. There-
fore, 2 has s-cis-Z-configuration at the side chain. The
HMBC spectral data of 2 [Fig. 1(a)] revealed long range
correlations between the H1 (d 10.18) with C2 (at d
To examine the optimal conditions, Mannich reaction
of 2 (1 mmol), aniline (1 equiv.), and cyclohexanone (2
equiv.), using ZrOCl2ꢀ8H2O as catalyst was carried out in
different solvents such as acetonitrile, dichloromethane,
ethanol, water, and solvent-free conditions. Ethanol was
determined as a powerful solvent for high yield and anti
selectivity of reaction and environmental acceptability. In
dichloromethane, acetonitrile and under solvent-free con-
ditions, in addition to Mannich adducts, side product 5
(Fig. 2), was obtained. In water, imine 3 was isolated as a
sole product. Also 0.07 equiv. (7 mol %) of ZrOCl2ꢀ8H2O
was determined as optimum amount of catalyst.
0
132.3); H2 with C1, C3, and C2 (at d 190.6, 142.8, and
0
0
0
0
120.1, respectively); H4 (d 6.26) with C2 , C3 , C5 , and
0
C6 (at d 120.1, 150.8, 164.1, and 20.4, respectively);
0
0
0
H6 (d 2.35) with C4 and C5 (at d 107.1 and 164.1,
Eleven examples of the direct Mannich-type reaction
of 2, anilines and cyclic ketones in ethanol are listed in
Table 1. The reactions were performed by adding cyclic
ketones (2 equiv.) to a mixture of the 2 (1 mmol) and
anilines (1 equiv.) in ethanol in the presence of 0.07
equiv. of ZrOCl2ꢀ8H2O at room temperature to give the
corresponding b-amino ketones 4a–k in 40–85% yields
with moderate to high anti selectivity (Scheme 3).
0
respectively). There are no correlations between C1
(carbonyl group of a-pyrone ring) and protons. Also
HMQC spectral data of 2 was shown in Figure 1(b)
that revealed one bond correlation between H1 (d
10.18) with C1 (d 190.6); H2 (d 6.32) with C2 (d 132.3);
0
0
0
0
H4 (d 6.26) with C4 (d 107.1); H6 (d 2.35) with C6 (d
20.4).
Scheme 2. Synthesis of imine 3 and its Mannich reaction with cyclohexanone.
Journal of Heterocyclic Chemistry
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A. Shahrisa and M. Zirak
Vol 47
Scheme 3. One-pot Mannich-type reaction of 2, anilines and cyclic ketones.
3J of the proton signals of AClC¼¼CHACH¼¼ equal to
11.3 and 11.2 Hz, respectively, indicate that these atoms
are located in the s-trans position.
Unexpectedly, from reaction of aliphatic amine such
as n-butyl amine with 2 and cyclohexanone in the pres-
ence of ZrOCl2ꢀ8H2O in ethanol at room temperature, 5
was obtained as a sole product (Scheme 5). In fact, n-
butyl amine acts as a base and aldol condensation was
occurred instead of Mannich reaction.
Figure 2. Structure of side product 5.
Also, direct Mannich-type reaction of 2 and anilines
with acyclic ketones such as acetone and acetophenone
catalyzed with ZrOCl2ꢀ8H2O was investigated at room
temperature and corresponding b-amino ketones 7a–d
were obtained in good to high yields in short reaction
time. The overall reaction is best formulated in Scheme 6.
Methyl and Ethyl acetoacetate were also treated in
the direct Mannich-type reaction with 2 and aniline, cat-
alyzed with ZrOCl2ꢀ8H2O in ethanol at room tempera-
ture in 25 min, and interestingly corresponding dihydro-
pyridines 8a,b were isolated as sole products instead of
Mannich adduct 9 (Scheme 7).
According to the literature [8a,9d] anti/syn ratio was
1
determined using H NMR spectra.
Exceptionally, in the case of cyclopentanone (n ¼ 1),
in addition to Mannich adducts 4a,b the side product 6
was obtained. With increasing reaction time (over 2 h)
the Mannich adducts 4a,b were completely converted to
6 (Scheme 4). In the cases of cyclohexanone, product 4c
even after 24 h was not converted to adduct 5. This can
be attributed to more acidity of cyclopentanone protons
in comparison with cyclohexanone ones. In the 1H
NMR spectra of 5 and 6, the values of coupling constant
Table 1
Yields and selectivity of direct mannich-type reaction of b-[(2H-pyran-2-one)-3-yl]-b-chloroacrolein 2, anilines, and cyclic
ketones in the presence of ZrOCl2ꢀ8H2O.
Ketonea
ArNH2
Productb
Time (min)
Yield (%)c
Anti/Syn
n ¼ 1
n ¼ 1
n ¼ 2
n ¼ 2
n ¼ 2
n ¼ 2
n ¼ 2
n ¼ 2
n ¼ 2
n ¼ 3
n ¼ 3
C6H5NH2
4-ClC6H4NH2
C6H5NH2
4a
4b
4c
4d
4e
4f
4g
4h
4i
10
10
25
30
30
30
30
15
20
40
45
40
55
80
76
75
85
80
85
78
76
75
63:37
70:30
74:26
58:42
58:42
33:67
70:30
75:25
80:20
70:30
62:38
4-ClC6H4NH2
2-ClC6H4NH2
3,4-Cl2C6H3NH2
4-BrC6H4NH2
4-MeOC6H4NH2
4-nBuC6H4NH2
C6H5NH2
4j
4k
4-ClC6H4NH2
a Ketone ¼
.
b Product ¼
.
c Isolated yields.
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Stereoselective Synthesis of b-Amino Ketones Possessing b-[(2H-Pyran-2-one)-3-yl]-
b-chlorovinyl Moiety via Three-Component Direct Mannich-Type Reaction
597
Scheme 4. Conversion of Mannich adducts 4a,b to adduct 6.
Scheme 5. Aldol reaction of 2 with cyclohexanone in the presence of n-BuNH2/ZrOCl2ꢀ8H2O.
Scheme 6. Mannich reaction of 2, anilines and acyclic ketones.
Scheme 7. Synthesis of new N-aryl dihydropyridines possessing b-[(2H-pyran-2-one)-3-yl]-b-chlorovinyl at C4-position.
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A. Shahrisa and M. Zirak
Vol 47
Scheme 8. Mannich-type reaction of comenic aldehyde 10, anilines, and cyclohexanone.
tion mixture. After that the mixture was stirred at 45–55ꢁC for
2 h, kept over night at room temperature and poured into the
water (200 mL). The obtained solution was left at room tem-
perature. Yellowish brown crystals were filtered off and dried
Also, 5-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde
(O-protected comenic aldehyde) 10 was synthesized
according to literature [14] and used in three component
direct Mannich-type reaction with three different ani-
lines and cyclohexanone. As shown in Scheme 8,
ZrOCl2ꢀ8H2O efficiently catalyzed this reaction at room
temperature and Mannich adducts 11a–c were obtained
in high yields with moderate stereoselectivity.
in air. b-[(2H-Pyran-2-one)-3-yl]-b-chloroacrolein
2
was
obtained in 69.4% yield. Mp. 90–92ꢁC; FTIR (KBr): 3081,
3030, 2968, 2927 (CH), 2864, 2746 (CHAldehyde), 1718, 1679,
1
1616, 1545, 1304, 1248, 1121, 837, 768 cmꢂ1; H NMR (500
3
3
MHz, CDCl3): d 10.18 (d, J ¼ 6.8 Hz, 1H, CHO), 6.32 (d, J
¼ 6.8 Hz, 1H, CHVinyl), 6.26 (s, 1H, CHa-Pyrone), 2.35 (s, 3H,
CH3) ppm; 13C NMR (125 MHz, CDCl3):
d 190.6
CONCLUSIONS
(C¼¼OAldehyde), 164.1, 158.5, 150.8, 142.8, 132.3, 120.1, 107.1,
20.4 (CH3) ppm; Ms: m/z ¼ 233 ([MþH]þ, 4%; [MþHþ2]þ,
2.8%; [MþHþ4]þ, 1.3%), 205 (25%), 189 (36%), 169 (30%),
43 (100%); Anal. Calcd. for C9H6Cl2O3: C, 46.38; H, 2.60.
Found: C, 46.56; H, 2.65.
In summary, new b-[(2H-pyran-2-one)-3-yl]-b-chlor-
oacrolein was synthesized in good yield and was sub-
jected to the three-component Mannich-type reaction
with different anilines, cyclic and acyclic ketones, cata-
lyzed with ZrOCl2ꢀ8H2O in ethanol. Moderate to good
anti selectivity was observed in very short reaction times
at room temperature. Similarly, Mannich-type reaction
with protected comenic aldehyde was also investigated,
and corresponding b-amino ketones were obtained in
high yields with moderate to high stereoselectivity.
Ethyl and methyl acetoacetate were also treated with an-
iline and b-[(2H-pyran-2-one)-3-yl]-b-chloroacrolein and
interestingly corresponding dihydropyridines were syn-
thesized instead of Mannich adduct.
Synthesis of 4-chloro-3-[(1Z)-1-chloro-3-(phenylimino)-
prop-1-enyl]-6-methyl-2H-pyran-2-one
(3). b-[(2H-Pyran-2-
one)-3-yl]-b-chloroacrolein 2 (1 mmol) was treated with Ani-
line (1 mmol) in ethanol (3 mL) at room temperature for 2
min. After completion of the reaction, mixture was poured into
the water (20 mL). The resulting yellow solids were separated
by filtration and dried in air. Imine 3 was obtained in 80.8%
yield, Mp. 124–126ꢁC; FTIR (KBr): 3100, 3020, 2967, 2922,
1
1717, 1684, 1625, 1542, 1266, 1154, 821, 764, 694 cmꢂ1; H
3
NMR (400MHz, CDCl3): d 8.62 (d, J ¼ 8.5 Hz, 1H, CH¼¼N),
3
7.39–7.43 (m, 2H, CHAr), 7.22–7.30 (m, 3H, CHAr) 6.77 (d, J
¼ 8.5 Hz, 1H, CHVinyl), 6.24 (s, 1H, CHa-Pyrone), 2.33 (s, 3H,
CH3) ppm; 13C NMR(100 MHz, CDCl3): d 161.9, 157.7,
155.7, 149.8, 149.3, 132.7, 131.6, 128.2, 126.0, 119.9, 119.3,
105.7, 18.8 (CH3) ppm; Anal. Calcd. for C15H11Cl2NO2: C,
58.46; H, 3.60; N, 4.55. Found: C, 58.28; H, 3.91; N, 4.77.
General procedure for Mannich-type reaction. To a solu-
tion of b-[(2H-Pyran-2-one)-3-yl]-b-chloroacrolein 2 (1 mmol)
in ethanol (5 mL) were added aniline (1 mmol), cyclohexa-
none (2 eq), and ZrOCl2ꢀ8H2O (0.022 g), successively at room
temperature (20–25ꢁC) and stirred for 25 min. After comple-
tion of the reaction, ethanol was evaporated under reduced
pressure. The crude solid was dissolved in CH2Cl2 (10 mL)
and catalyst was removed by filtration. Filtrate was washed
with a 5% aqueous NaHCO3 solution and brine, dried over an-
hydrous Na2SO4, and concentrated to dryness. The crude mix-
ture was purified by PLC on silica gel using hexane/acetone
(20:3) to afford the final product. Specific detail was given for
each compound.
EXPERIMENTAL
General. All chemicals were purchased and used without
any further purification. Melting points were determined on a
Electrothermal MEL-TEMP apparatus (model 1202D) and are
uncorrected. FTIR spectra were obtained with a Bruker Tensor
27 spectrometer. NMR spectra were recorded at 400 and 500
MHz for proton and at 100 and 125 MHz for carbon nuclei in
CDCl3. Elemental analyses were done by a Vario EL III, Ele-
mentar. The products were purified by PLC on silica gel by
using hexane/acetone mixture as eluent. All compounds were
characterized by their spectroscopic data and elemental analysis.
Synthesis of Z-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-py-
ran-3-yl)acrolein (2). POCl3 (14.8 g, 96.4 mmol) was added
dropwise to dimethylformamide (DMF) (24 mL) with stirring
at 30–35ꢁC. The mixture was stirred at 50ꢁC for 1 h. Then a
solution of dehydroacetic acid 1 (4 g, 19.4 mmol) in least
amount of DMF was added dropwise with stirring to the reac-
(Z)-4-Chloro-3-[1-chloro-3-(2-oxocyclopentyl)-3-(phenyla-
mino)prop-1-enyl]-6-methyl-2H-pyran-2-one (4a). Anti/Syn:
63/37; Yellow solid; FTIR (KBr): 3381 (NH), 3055, 3020,
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Stereoselective Synthesis of b-Amino Ketones Possessing b-[(2H-Pyran-2-one)-3-yl]-
b-chlorovinyl Moiety via Three-Component Direct Mannich-Type Reaction
599
4
2939, 2865, 1734, 1722, 1626, 1546, 1505, 1305, 1260, 840,
750 cmꢂ1; H NMR (400 MHz, CDCl3): d 7.13–7.18 (m, 2H,
CHAr), 6.57–6.62 (m, 2H, CHAr), 6.07 (d, J ¼ 0.7 Hz, 0.58H,
CHa-Pyrone, anti), 6.06 (d, 4J ¼ 0.8 Hz, 0.42H, CHa-Pyrone
,
1
4
3
3
CHAr), 6.67–6.75 (m, 3H, CHAr), 6.10 (d, J ¼ 0.8 Hz, 0.63H,
syn), 6.03 (d, J ¼ 9.3 Hz, 0.42H, CHVinyl, syn), 5.98 (d, J ¼
CHa-Pyrone, anti), 6.05 (d, 4J ¼ 0.7 Hz, 0.37H, CHa-Pyrone
,
8.4 Hz, 0.58H, CHVinyl, anti), 4.77 (s, br, 1H, NH), 4.45 (dd,
3
3
3
3
syn), 5.93 (d, J ¼ 8.7 Hz, 0.63H, CHVinyl, anti), 5.62 (d, J ¼
3J ¼ 3.7 Hz, J ¼ 9.3 Hz, 0.42H, CHAN, syn), 4.39 (dd, J ¼
3
3
3
3
9.3 Hz, 0.37H, CHVinyl, syn), 4.70 (dd, J ¼ 3.9 Hz, J ¼ 9.3
4.6 Hz, J ¼ 8.4 Hz, 0.58H, CHAN, anti), 2.91 (dt, J ¼ 4.5
Hz, 3J ¼ 12.8 Hz, 0.42H, ACOCH<, syn), 2.80–2.85 (m,
0.58H, ACOCH<, anti), 2.23 (s, 3H, CH3), 1.65–2.42 (m, 8H,
CH2 Cyclohexanone) ppm; 13C NMR (100 MHz, CDCl3): d 212.0,
211.9 (C¼¼OCyclohexanone), 161.3, 160.9, 158.2, 149.1, 148.7,
144.3, 140.4, 138.4, 137.8, 132.9, 128.1, 127.0, 126.9, 126.7,
124.4, 121.5, 120.1, 117.1, 114.3, 105.7, 105.3, 53.5, 52.7,
41.5, 40.9, 30.4, 29.5, 26.5, 25.9, 23.8, 23.7, 18.8, 18.7 ppm;
Anal. Calcd. for C21H20Cl3NO3: C, 57.23; H, 4.57; N, 3.18.
Found: C, 57.12; H, 4.62; N, 3.43.
3
3
Hz, 0.37H, CHAN, syn), 4.53 (dd, J ¼ 7.1 Hz, J ¼ 8.6 Hz,
0.63H, CHAN, anti), 2.28 (s, 3H, CH3, (anti and syn)), 2.06–
2.35 (m, 7H, CH and CH2 Cyclopentanone, anti and syn); 13C
NMR (100 MHz, CDCl3): d 220.7, 218.7 (C¼¼OCyclopentanone),
161.1, 161.0, 158.3, 149.1, 148.9, 145.5, 136.1, 133.4, 128.1,
128.0, 123.2, 122.9, 119.8, 117.5, 117.0, 113.4, 113.1, 105.5,
105.4, 52.7, 52.2, 51.4, 50.8, 38.5, 37.9, 25.9, 25.3, 19.9, 19.7,
18.9, 18.7 ppm; Anal. Calcd. for C20H19Cl2NO3: C, 61.24; H,
4.88; N, 3.57. Found: C, 60.93; H, 5.01; N, 3.68.
(Z)-4-Chloro-3-[1-chloro-3-(4-chlorophenylamino)-3-(2-oxo-
cyclopentyl)prop-1-enyl]-6-methyl-2H-pyran-2-one (4b). Anti/
Syn: 70/30; Yellow solid; FTIR (KBr): 3378 (NH), 3070,
3061, 2940, 2860, 1733, 1724, 1630, 1545, 1508, 1306, 1263,
(Z)-4-Chloro-3-[1-chloro-3-(2-chlorophenylamino)-3-(2-oxo-
cyclohexyl)prop-1-enyl]-6-methyl-2H-pyran-2-one (4e). Anti/
Syn: 58/42; Pale yellow solid, FTIR (KBr): 3384 (NH), 3092,
2937, 2865, 1733, 1703, 1625, 1595, 1550, 1504, 1438, 1244,
1
857, 761 cmꢂ1; H NMR (400 MHz, CDCl3): d 7.08–7.12 (m,
848, 743 cmꢂ1
;
1H NMR (400 MHz, CDCl3): d 7.20–7.23 [2
3
3
2H, CHAr, anti and syn), 6.62–6.66 (m, 1.4H, CHAr, anti),
6.59–6.61 (m, 0.6H, CHAr, syn), 6.11 (d, 4J ¼ 0.7 Hz, 0.7H,
ꢃ d, 7.22 (d, Jortho ¼ 7.9 Hz, 0.42H, CHAr, syn), 7.21 (d, Jor-
¼ 7.9 Hz, 0.58H, CHAr, anti)], 7.10–7.16 (m, 1H, CHAr),
tho
4
4
3
CHa-Pyrone, anti), 6.07 (d, J ¼ 0.8 Hz, 0.3H, CHa-Pyrone, syn),
6.82 (dd, Jmeta ¼ 1.2 Hz, Jortho ¼ 8.3 Hz, 0.42H, CHAr, syn),
5.87 (d, 3J ¼ 8.7 Hz, 0.7H, CHVinyl, anti), 5.58 (d, 3J ¼ 9.4
6.77 (dd, Jmeta ¼ 1.2 Hz, Jortho ¼ 8.2 Hz, 0.58H, CHAr
,
4
3
4
Hz, 0.3H, CHVinyl, syn), 4.75–5.32 (s, br, 1H, NH, anti and
anti), 6.60–6.65 (m, 1H, CHAr), 6.07 (d, J ¼ 0.9 Hz, 0.58H,
3
3
syn), 4.63 (dd, J ¼ 3.3 Hz, J ¼ 8.9 Hz, 0.3H, CHAN, syn),
CHa-Pyrone, anti), 6.06 (d, 4J ¼ 0.9 Hz, 0.42H, CHa-Pyrone
,
3
3
3
3
4.45 (dd, J ¼ 7.5 Hz, J ¼ 8.5 Hz, 0.7H, CHAN, anti), 1.85–
2.46 (m, 7H, CH and CH2 Cyclopentanone, anti and syn), 2.25 (d,
4J ¼ 0.4 Hz, 2.1H, CH3, anti), 2.23 (d, 4J ¼ 0.6 Hz, 0.9H,
CH3, syn). 13C NMR (100 MHz, CDCl3): d 220.1, 219.3
(C¼¼OCyclopentanone), 161.2, 161.0, 158.2, 158.1, 151.3, 150.1,
145.8, 136.6, 134.0, 128.8, 128.1, 124.1, 124.0, 119.6, 118.3,
118.1, 114.0, 113.8, 105.2, 52.4, 52.1, 51.1, 50.9, 38.6, 37.9,
26.1, 25.6, 20.3, 19.7, 18.3, 18.1 ppm; Anal. Calcd. for
C20H18Cl3NO3: C, 56.29; H, 4.25; N, 3.28. Found: C, 56.01;
H, 4.23; N, 3.59.
syn), 6.05 (d, J ¼ 9.4 Hz, 0.42H, CHVinyl, syn), 6.02 (d, J ¼
8.4 Hz, 0.58H, CHVinyl, anti), 5.49 (s, br, 1H, NH), 4.57 (dd,
3J ¼ 3.5 Hz, J ¼ 9.3 Hz, 0.42H, CHAN, syn), 4.50 (dd, J ¼
4.5 Hz, 3J ¼ 8.4 Hz, 0.58H, CHAN, anti), 2.94–3.00 (m,
0.42H, ACOCH<, syn), 2.86–2.92 (m, 0.58H, ACOCH<,
3
3
4
anti), 2.23 (d, J ¼ 0.8 Hz, 3H, CH3), 1.67–2.43 (m, 8H, CH2
Cyclohexanone) ppm; 13C NMR (100 MHz, CDCl3): d 211.5,
211.4 (C¼¼OCyclohexanone), 161.0, 160.9, 158.2, 149.0, 148.8,
142.2, 141.9, 136.2, 133.0, 128.0, 126.7, 124.4, 122.9, 119.6,
119.1, 117.0, 116.9, 112.2, 111.8, 105.5, 105.4, 53.6, 52.7,
52.3, 41.54, 41.52, 30.8, 29.5, 26.8, 25.9, 23.8, 23.6, 18.7
ppm; Anal. Calcd. for C21H20Cl3NO3: C, 57.23; H, 4.57; N,
3.18. Found: C, 57.40; H, 4.69; N, 3.50.
(Z)-4-Chloro-3-[1-chloro-3-(2-oxocyclohexyl)-3-(phenylami-
no)prop-1-enyl]-6-methyl-2H-pyran-2-one (4c). Anti/Syn: 74/
26; Pale yellow solid, FTIR (KBr): 3386 (NH), 3085, 3030,
2938, 2862, 1731, 1699, 1625, 1603, 1546, 1505, 1438, 1384,
(Z)-4-Chloro-3-[1-chloro-3-(3,4-dichlorophenylamino)-3-(2-
oxocyclohexyl)prop-1-enyl]-6-methyl-2H-pyran-2-one (4f). Anti/
Syn: 33/67; Pale yellow solid, FTIR (KBr): 3395 (NH), 3048,
2934, 2863, 1730, 1702, 1621, 1546, 1488, 1439, 1249, 844,
1301, 1257, 1212, 795, 752, 694 cmꢂ1
;
1H NMR (400 MHz,
CDCl3): d 7.14–7.18 (m, 2H, CHAr), 6.68–6.73 (m, 3H, CHAr),
3
4
6.07 (d, J ¼ 9.3 Hz, 0.26H, CHVinyl, syn), 6.06 (d, J ¼ 0.8
Hz, 0.74H, CHa-Pyrone, anti), 6.05 (d, 4J ¼ 0.7 Hz, 0.26H,
CHa-Pyrone, syn), 6.03 (d, 3J ¼ 8.4 Hz, 0.74H, CHVinyl, anti),
1
796, cmꢂ1; H NMR (400 MHz, CDCl3): d 7.16–7.20 [2 ꢃ d:
3
3
7.19 (d, Jortho ¼ 8.7 Hz, 0.33H, CHAr, anti), 7.18 (d, Jortho
¼
3
3
4
4.53 (dd, J ¼ 3.7 Hz, J ¼ 9.3 Hz, 0.26H, CHAN, syn), 4.48
8.7 Hz, 0.67H, CHAr, syn)], 6.80 (d, Jmeta ¼ 2.4 Hz, 0.33H,
3
3
4
(dd, J ¼ 4.8 Hz, J ¼ 8.4 Hz, 0.74H, CHAN, anti), 2.94 (dt,
CHAr, anti), 6.78 (d, Jmeta ¼ 2.6 Hz, 0.67H, CHAr, syn),
3
3J ¼ 4.4 Hz, J ¼ 12.9 Hz, 0.26H, ACOCH<, syn), 2.83–2.89
6.50–6.56 (m, 1H, CHAr), 6.09 (s, 0.33H, CHa-Pyrone, anti),
3
(m, 0.74H, ACOCH<, anti), 2.23 (s, 3H, CH3), 1.66–2.41 (m,
8H, CH2 Cyclohexanone) ppm; 13C NMR (100 MHz, CDCl3): d
211.8 (C¼¼OCyclohexanone), 160.9, 160.8, 158.2, 148.9, 146.1,
145.7, 136.8, 133.4, 128.0, 124.0, 122.6, 120.0, 119.6, 117.0,
116.9, 113.2, 112.8, 105.4, 105.3, 53.7, 53.6, 52.6, 52.5, 41.5,
41.3, 30.6, 29.6, 26.7, 25.9, 23.8, 23.4, 18.6 ppm; Anal. Calcd.
for C21H21Cl2NO3: C, 62.08; H, 5.21; N, 3.45. Found: C,
62.07; H, 5.26; N, 3.69.
6.08 (s, 0.67H, CHa-Pyrone, syn), 5.97–6.01 [2 ꢃ d: 5.99 (d, J
3
¼ 9.4 Hz, 0.67H, CHVinyl, syn), 5.98 (d, J ¼ 8.4 Hz, 0.33H,
3
3
CHVinyl, anti)], 5.12 (s, br, 1H, NH), 4.41 (dd, J ¼ 3.7 Hz, J
¼ 9.3 Hz, 0.67H, CHAN, syn), 4.37 (dd, 3J ¼ 4.8 Hz, 3J ¼
8.5 Hz, 0.33H, CHAN, anti), 2.84–2.93 (m, 1H,
ACOCH<,antiþsyn), 2.24 (s, 3H, CH3), 1.62–2.43 (m, 8H,
CH2 Cyclohexanone) ppm; 13C NMR (100 MHz, CDCl3): d 212.1,
212.0 (C¼¼OCyclohexanone), 161.2, 161.1, 158.3, 158.2, 149.2,
148.9, 145.2, 132.3, 131.7, 131.6, 129.5, 129.4, 125.0, 119.9,
119.6, 119.5, 114.5, 112.9, 105.5, 105.4, 53.3, 53.2, 52.7, 41.5,
30.8, 29.4, 26.7, 25.8, 23.7, 23.5, 18.8 ppm; Anal. Calcd. for
C21H19Cl4NO3: C, 53.08; H, 4.03; N, 2.95. Found: C, 53.01;
H, 4.38; N, 3.21.
(Z)-4-Chloro-3-[1-chloro-3-(4-chlorophenylamino)-3-(2-oxo-
cyclohexyl)prop-1-enyl]-6-methyl-2H-pyran-2-one (4d). Anti/
Syn: 58/42; Pale yellow solid, FTIR (KBr): 3393 (NH), 3095,
3042, 2935, 2864, 1729, 1697, 1623, 1548, 1498, 1439, 1238,
1
822 cmꢂ1; H NMR (400 MHz, CDCl3): d 7.07–7.12 (m, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

600
A. Shahrisa and M. Zirak
Vol 47
(Z)-3-(3-(4-Bromophenylamino)-1-chloro-3-(2-oxocyclohex-
(Z)-4-Chloro-3-(1-chloro-3-(2-oxocycloheptyl)-3-(phenyla-
mino)prop-1-enyl)-6-methyl-2H-pyran-2-one (4j). Anti/Syn:
70/30; Pale yellow solid, FTIR (KBr): 3381 (NH), 3094, 3050,
2928, 2857, 1732, 1695, 1623, 1606, 1550, 1503, 1440, 1301,
yl)prop-1-enyl)-4-chloro-6-methyl-2H-pyran-2-one (4g). Anti/
Syn: 70/30; Pale yellow solid, FTIR (KBr): 3390 (NH), 3093,
2935, 2864, 1729, 1698, 1627, 1592, 1549, 1493, 1300, 820
cmꢂ1
;
1H NMR (400 MHz, CDCl3): d 7.21–7.25 (m, 2H,
861, 744 cmꢂ1; H NMR (400 MHz, CDCl3): d 7.13–7.17 (m,
1
4
CHAr), 6.51–6.57 (m, 2H, CHAr), 6.08 (d, J ¼ 0.6 Hz, 0.7H,
2H, CHAr), 6.65–6.70 (m, 3H, CHAr), 6.06 (s, 1H, CHa-Pyrone),
5.82 (d, 3J ¼ 9.4 Hz, 0.3H, CHVinyl, syn), 5.80 (d, 3J ¼ 8.3
4
CHa-Pyrone, anti), 6.07 (d, J ¼ 0.5 Hz, 0.3H, CHa-Pyrone, syn),
6.03 (d, 3J ¼ 9.3 Hz, 0.3H, CHVinyl, syn), 5.98 (d, 3J ¼ 8.4
Hz, 0.7H, CHVinyl, anti), 4.60 (dd, J ¼ 4.1 Hz, J ¼ 9.4 Hz,
3
3
3
3
3
3
Hz, 0.7H, CHVinyl, anti), 4.45 (dd, J ¼ 3.6 Hz, J ¼ 9.3 Hz,
0.3H, CHAN, syn), 4.52 (dd, J ¼ 5.9 Hz, J ¼ 8.3 Hz, 0.7H,
CHAN, anti), 2.98–3.08 (m, 1H, ACOCH<, antiþsyn), 2.50–
2.55 (m, 2H, ACH2COA), 2.23 (s, 3H, CH3), 1.20–2.08 (m,
8H, CH2 Cycloheptanone) ppm; 13C NMR (100 MHz, CDCl3): d
215.8, 215.1 (C¼¼OCycloheptanone), 160.9, 158.3, 148.9, 146.1,
145.4, 136.3, 133.6, 128.1, 124.3, 123.0, 119.7, 117.0, 116.8,
113.1, 112.7, 105.4, 55.3, 54.2, 54.1, 53.6, 43.3, 42.3, 28.9,
28.2, 27.9, 27.5, 27.1, 23.7, 23.1, 18.7 ppm; Anal. Calcd. for
C22H23Cl2NO3: C, 62.86; H, 5.52; N, 3.33. Found: C, 62.82;
H, 5.67; N, 3.51.
3
3
0.3H, CHAN, syn), 4.38 (dd, J ¼ 4.5 Hz, J ¼ 8.3 Hz, 0.7H,
CHAN, anti), 2.91 (dt, 3J ¼ 4.4 Hz, 3J ¼ 13.0 Hz, 0.3H,
ACOCH<, syn), 2.80–2.85 (m, 0.7H, ACOCH<, anti), 2.24
(s, 3H, CH3), 1.66–2.40 (m, 8H, CH2 Cyclohexanone) ppm; 13C
NMR (100 MHz, CDCl3): 212.0 (C¼¼OCyclohexanone), 161.0,
158.2, 149.0, 145.3, 144.8, 136.2, 132.9, 130.7, 124.5, 123.0,
119.6, 114.8, 114.5, 108.7, 108.6, 105.5, 105.4, 53.6, 53.5,
52.8, 52.6, 41.6, 41.5, 30.8, 30.5, 26.7, 25.9, 23.8, 23.5, 18.7
ppm; Anal. Calcd. for C21H20BrCl2NO3: C, 51.98; H, 4.15; N,
2.89. Found: C, 51.73; H, 4.53; N, 2.97.
(Z)-4-Chloro-3-[1-chloro-3-(4-chlorophenylamino)-3-(2-oxo-
cycloheptyl)prop-1-enyl]-6-methyl-2H-pyran-2-one (4k). Anti/
Syn: 62/38; Pale yellow solid, FTIR (KBr): 3383 (NH), 3096,
3029, 2929, 2858, 1736, 1699, 1626, 1600, 1551, 1500, 1300,
(Z)-4-Chloro-3-[1-chloro-3-(4-methoxyphenylamino)-3-(2-oxo-
cyclohexyl)prop-1-enyl]-6-methyl-2H-pyran-2-one
(4h). Anti/
Syn: 75/25; Pale yellow solid, FTIR (KBr): 3343 (NH), 3039,
2936, 2865, 1729, 1694, 1620, 1543, 1507, 1442, 1301, 1246,
1254, 861, 775, 732 cmꢂ1 1H NMR (400 MHz, CDCl3): d
;
1
850, 774, 730 cmꢂ1; H NMR (400 MHz, CDCl3): d 6.73–6.76
7.08–7.11 (m, 2H, CHAr), 6.56–6.60 (m, 2H, CHAr), 6.08 (s,
1H, CHa-Pyrone, antiþsyn), 5.78 (d, 3J ¼ 9.9 Hz, 0.38H,
(m, 2H, CHAr), 6.61–6.65 (m, 2H, CHAr), 6.04–6.07 [3 ꢃ d:
3
4
3
6.06 (d, J ¼ 9.2 Hz, 0.25H, CHVinyl, syn), 6.06 (d, J ¼ 0.8
CHVinyl, syn), 5.77 (d, J ¼ 8.2 Hz, 0.62H, CHVinyl, anti), 4.84
4
Hz, 0.75H, CHa-Pyrone, anti), 6.04 (d, J ¼ 0.8 Hz, 0.25H, CHa-
(s, br, 1H, NH), 4.53 (dd, 3J ¼ 4.0 Hz, 3J ¼ 9.5 Hz, 0.38H,
CHAN, syn), 4.45 (dd, 3J ¼ 5.8 Hz, 3J ¼ 8.3 Hz, 0.62H,
CHAN, anti), 3.03–3.07 (m, 0.62H, ACOCH<, anti), 2.95–
3.01 (m, 0.38H, ACOCH<, syn), 2.49–2.51 (m, 2H,
ACH2COA), 2.23 (s, 3H, CH3), 1.24–2.17 (m, 8H, CH2 Cyclo-
heptanone) ppm; 13C NMR (100 MHz, CDCl3): d 215.9, 215.1
(C¼¼OCycloheptanone), 161.1, 158.2, 149.0, 148.9, 144.7, 144.1,
135.8, 133.1, 127.9, 124.7, 123.4, 121.5, 121.4, 119.6, 114.2,
113.8, 105.4, 55.2, 54.4, 54.2, 53.3, 43.3, 42.4, 28.9, 28.6,
28.3, 28.2, 27.6, 27.1, 23.7, 22.9, 18.7 ppm. Anal. Calcd. for
C22H22Cl3NO3: C, 58.10; H, 4.88; N, 3.08. Found: C, 57.92;
H, 5.06; N, 3.36.
3
Pyrone, syn)], 5.99 (d, J ¼ 8.4 Hz, 0.75H, CHVinyl, anti), 4.43
3
3
(dd, J ¼ 3.7 Hz, J ¼ 9.3 Hz, 0.25H, CHAN, syn), 4.39 (dd,
3J ¼ 4.9 Hz, 3J ¼ 8.4 Hz, 0.75H, CHAN, anti), 3.71–3.72 (2 ꢃ
s, 3H, AOCH3), 2.90–2.95 (m, 0.25H, ACOCH<, syn), 2.77–
2.82 (m, 0.75H, ACOCH<, anti), 2.22 (2 ꢃ s, 3H, CH3), 1.65–
2.40 (m, 8H, CH2 Cyclohexanone) ppm; 13C NMR (100 MHz,
CDCl3): d 212.0, 211.9 (C¼¼OCyclohexanone), 160.9, 160.8, 158.2,
151.6, 151.5, 148.9, 148.6, 140.2, 139.8, 133.9, 132.0, 127.0,
126.7, 124.0, 122.8, 114.9, 114.5, 113.7, 113.6, 105.4, 105.3,
54.7, 54.6, 53.7, 52.7, 41.6, 41.4, 30.6, 29.6, 26.7, 26.0, 23.9,
23.5, 18.8, 18.7 ppm; Anal. Calcd. for C22H23Cl2NO4: C,
60.56; H, 5.31; N, 3.21. Found: C, 60.29; H, 5.70; N, 3.38.
(Z)-3-[3-(4-Butylphenylamino)-1-chloro-3-(2-oxocyclohexyl)
4-Chloro-3-[(1Z)-1-chloro-3-(2-oxocyclohexylidene)prop-1-
enyl]-6-methyl-2H-pyran-2-one (5). White solid; Mp. 154–
156ꢁC; FTIR (KBr): 3039, 2962, 2930, 2876, 1728, 1675,
prop-1-enyl]-4-chloro-6-methyl-2H-pyran-2-one
Syn: 80/20; Pale yellow solid, FTIR (KBr): 3381 (NH), 3094,
(4i). Anti/
1634, 1614, 1580, 1302, 857, 803, 775 cmꢂ1 1H NMR (400
;
3019, 2930, 2861, 1733, 1684, 1623, 1550, 1517, 1299, 829,
743 cmꢂ1
MHz, CDCl3): d 7.41–7.43 (m, 1H, CHVinyl), 6.60 (d, 3J ¼
3
4
;
1H NMR (400 MHz, CDCl3): d 6.97 (d, Jortho
¼
11.3 Hz, 1H, CHVinyl), 6.17 (s, 1H, CHa-Pyrone), 2.67 (td, J ¼
3
3
3
8.3 Hz, 2H, CHAr), 6.63 (d, Jortho ¼ 8.3 Hz, 0.4H, CHAr
,
1.9 Hz, J ¼ 7.0 Hz, 2H, CH2 Cyclohexanone), 2.49 (t, J ¼ 6.6
Hz, 2H, ACH2COA), 2.28 (s, 3H, CH3), 1.84–1.89 (m, 2H,
CH2), 1.76–1.80 (m, 2H, CH2) ppm; 13C NMR (100 MHz,
CDCl3) d 199.6 (C¼¼OCyclohexanone), 161.3, 158.2, 149.2, 138.4,
129.0, 127.0, 126.7, 120.3, 105.7, 39.2, 26.6, 22.2, 22.0, 18.8
ppm. Anal. calcd. for C15H14Cl2O3: C, 57.53; H, 4.51. Found:
C, 57.58; H, 4.69.
syn), 6.60 (d, Jortho ¼ 8.3 Hz, 1.6H, CHAr, anti), 6.07 (d, 3J
3
¼ 9.4 Hz, 0.2H, CHVinyl, syn) 6.06 (d, 4J ¼ 0.7 Hz, 0.8H,
4
CHa-Pyrone, anti), 6.05 (d, J ¼ 0.7 Hz, 0.2H, CHa-Pyrone, syn),
3
3
6.00 (d, J ¼ 8.3 Hz, 0.8H, CHVinyl, anti), 4.50 (dd, J ¼ 3.6
Hz, 3J ¼ 9.3 Hz, 0.2H, CHAN, syn), 4.44 (dd, 3J ¼ 4.8 Hz,
3J ¼ 8.3 Hz, 0.8H, CHAN, anti), 2.91–2.97 (m, 0.2H,
ACOCH<, syn), 2.79–2.85 (m, 0.8H, ACOCH<, anti), 2.47
(t, 3J ¼ 7.6 Hz, 2H, CH2 Butyl), 2.23 (s, 3H, CH3), 1.72–
2.43 (m, 8H, CH2 Cyclohexanone), 1.48–1.55 (m, 2H, CH2 Butyl),
1.26–1.34 (m, 2H, CH2 Butyl), 0.89 (t, 3J ¼ 7.4 Hz, 3H,
CH3 Butyl) ppm; 13C NMR (100 MHz, CDCl3): d 212.0
(C¼¼OCyclohexanone), 160.8, 158.2, 148.9, 143.9, 137.2, 131.5,
127.9, 122.6, 119.8, 113.4, 113.1, 105.4, 53.7, 53.0, 41.4, 33.6,
32.9, 30.6, 26.7, 26.0, 23.5, 21.2, 18.7, 12.9 ppm; Anal. Calcd.
for C25H29Cl2NO3: C, 64.94; H, 6.32; N, 3.03. Found: C,
65.03; H, 6.29; N, 3.31.
4-Chloro-3-[(1Z)-1-chloro-3-(2-oxocyclopentylidene)prop-1-
enyl]-6-methyl-2H-pyran-2-one (6). White solid, Mp. 182–
184ꢁC; FTIR (KBr): 3106, 3034, 2958, 1728, 1708, 1623,
1549, 1297, 1172, 861, 805 cmꢂ1 1H NMR (400 MHz,
;
4
3
CDCl3):d 7.34 (dt, J ¼ 2.8 Hz, J ¼ 11.2 Hz, 1H, CHVinyl),
3
4
6.52 (d, J ¼ 11.2 Hz, 1H, CHVinyl), 6.18 (d, J ¼ 0.7 Hz, 1H,
4
3
CHa-Pyrone), 2.71 (td, J ¼ 2.8 Hz, J ¼ 7.3 Hz, 2H, CH2 Cyclo-
3
4
pentanone), 2.39 (t, J ¼ 7.9 Hz, 2H, ACH2COA), 2.29 (d, J ¼
0.4 Hz, 3H, CH3), 1.95–2.03 (m, 2H, CH2 Cyclopentanone) ppm;
13C NMR (100 MHz, CDCl3): d 206.0 (C¼¼OCyclopentanone),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Stereoselective Synthesis of b-Amino Ketones Possessing b-[(2H-Pyran-2-one)-3-yl]-
b-chlorovinyl Moiety via Three-Component Direct Mannich-Type Reaction
601
161.4, 158.1, 149.2, 140.1, 129.8, 128.5, 123.7, 120.1, 105.7,
37.5, 26.6, 18.8, 18.6 ppm. Anal. Calcd. for C14H12Cl2O3: C,
56.21; H, 4.04. Found: C, 55.83; H, 4.06.
145.3, 137.6, 136.4, 133.7, 129.0, 128.8, 128.3, 127.4, 124.2,
122.9, 115.2, 106.5, 49.9, 41.5, 19.8 ppm; Anal. Calcd. for
C23H18Cl3NO3: C, 59.70; H, 3.92; N, 3.03. Found: C, 59.92;
H, 4.07; N, 3.36.
(Z)-4-Chloro-3-[1-chloro-5-oxo-3-(phenylamino)hex-1-enyl]-
6-methyl-2H-pyran-2-one (7a). Pale yellow solid, Mp. 30–
32ꢁC; FTIR (KBr): 3384 (NH), 3095, 3052, 3024, 2959, 2924,
1734, 1669, 1626, 1602, 1550, 1503, 1302, 860, 752, 694
(Z)-Dimethyl 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-
pyran-3-yl)vinyl]-2,6-dimethyl-1-phenyl-1,4-dihydropyridine-3,5-
dicarboxylate (8a). yellow solid, Mp. 54–56ꢁC; FTIR (KBr):
3096, 2948, 2926, 2852, 1734, 1694, 1629, 1586, 1551, 1290,
cmꢂ1 1H NMR (400 MHz, CDCl3): d 7.15–7.19 (m, 2H,
;
CHAr), 6.71–6.74 (m, 1H, CHAr), 6.66–6.68 (m, 2H, CHAr),
6.08 (d, 4J ¼ 0.8 Hz, 1H, CHa-Pyrone), 5.95 (d, 3J ¼ 7.9 Hz,
1H, CHVinyl), 4.70–4.74 (dt, 3J ¼ 5.2 Hz, 3J ¼ 7.9 Hz, 1H,
1208, 860, 771, 732 cmꢂ1 1H NMR (400 MHz, CDCl3): d
;
7.39–7.45 (m, 3H, CHAr), 7.10–7.13 (m, 2H, CHAr), 6.10 (s,
1H, CHa-Pyrone), 5.71 (d, 3J ¼ 9.4 Hz, 1H, CHVinyl), 5.15 (d,
3J ¼ 9.4 Hz, 1H, CHDihydropyridine), 3.77 (s, 6H, AOCH3), 2.29
(s, 3H, CH3 a-Pyrone), 1.98 (s, 6H, CH3 Dihydropyridine) ppm; 13C
NMR (100 MHz, CDCl3): d 167.2 (C¼¼OEster), 160.5, 158.3,
148.5, 147.3, 139.1, 134.5, 129.3, 128.4, 127.6, 120.9, 118.6,
105.4, 101.4, 50.3, 33.5, 18.7, 17.3 ppm; Anal. Calcd. for
C25H23Cl2NO6: C, 59.53; H, 4.60; N, 2.78. Found: C, 59.68;
H, 4.63; N, 2.88.
3
CHAN), 4.54 (s, br, 1H, NH), 2.98 (d, J ¼ 5.2 Hz, 2H, CH2),
2.24 (d, 4J ¼ 0.5 Hz, 3H, CH3 a-Pyrone), 2.23 (s, 3H,
CH3COA) ppm; 13C NMR (100 MHz, CDCl3): d 206.5
(C¼¼OKetone), 161.1, 158.2, 149.1, 145.1, 136.3, 128.2, 123.0,
119.5, 117.8, 113.4, 105.4, 48.7, 45.3, 29.5, 18.7 ppm; Anal.
Calcd. for C18H17Cl2NO3: C, 59.03; H, 4.68; N, 3.82. Found:
C, 58.91; H, 4.98; N, 4.02.
(Z)-4-Chloro-3-[1-chloro-3-(4-chlorophenylamino)-5-oxohex-
1-enyl]-6-methyl-2H-pyran-2-one (7b). Pale yellow solid, Mp.
34–36ꢁC; FTIR (KBr): 3370 (NH), 3095, 3050, 2959, 2925,
2854, 1730, 1667, 1621, 1548, 1490, 1436, 1254, 863, 821,
(Z)-Diethyl 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-py-
ran-3-yl)vinyl]-2,6-dimethyl-1-phenyl-1,4-dihydropyridine-3,5-
dicarboxylate (8b). yellow solid, Mp. 42–44ꢁC; FTIR (KBr):
3092, 3059, 2980, 2936, 1734, 1691, 1631, 1583, 1552, 1203,
1
1
773, 732 cmꢂ1; H NMR (400 MHz, CDCl3): d 7.10–7.13 (m,
742 cmꢂ1; H NMR (400 MHz, CDCl3): d 7.40–7.43 (m, 3H,
2H, CHAr), 6.61–6.65 (m, 2H, CHAr), 6.09 (d, 4J ¼ 0.7 Hz,
CHAr), 7.10–7.12 (m, 2H, CHAr), 6.10 (d, 4J ¼ 0.7 Hz, 1H,
3
3
3
1H, CHa-Pyrone), 5.92 (d, J ¼ 8.0 Hz, 1H, CHVinyl), 4.63–4.68
CHa-Pyrone), 5.71 (d, J ¼ 9.5 Hz, 1H, CHVinyl), 5.15 (d, J ¼
(ddd, 3J ¼ 4.3 Hz, 3J ¼ 6.1 Hz, 3J ¼ 7.9 Hz, 1H, CHAN),
9.5 Hz, 1H, CHDihydropyridine), 4.23 (m, 4H, CH2 Ethyl), 2.24 (s,
3
2
3
2.92–3.04 [2 ꢃ dd: 3.02 (dd, J ¼ 6.2 Hz, J ¼ 17.1 Hz, 1H,
CH2), 2.95 (dd, 3J ¼ 4.3 Hz, 2J ¼ 17.1 Hz, 1H, CH2), CH2
3H, CH3 a-Pyrone), 1.99 (s, 6H, CH3), 1.35 (t, J ¼ 7.1 Hz, 6H,
CH3 Ethyl) ppm; 13C NMR (100 MHz, CDCl3): d 166.7
(C¼¼OEster), 160.4, 158.3, 148.4, 147.1, 139.1, 134.5, 129.3,
128.3, 127.6, 120.9, 118.1, 105.4, 101.7, 59.2, 33.2, 18.7, 17.3,
13.4 ppm. Anal. Calcd. for C27H27Cl2NO6: C, 60.91; H, 5.11;
N, 2.63. Found: C, 60.93; H, 5.18; N, 2.90.
Protons], 2.24 (s, 3H, CH3 a-Pyrone), 2.22 (s, 3H,
Diastrotopic
CH3COA) ppm; 13C NMR (100 MHz, CDCl3): d 206.6
(C¼¼OKetone), 161.3, 158.2, 149.1, 143.7, 135.7, 128.0, 123.4,
122.5, 119.4, 114.6, 105.4, 48.8, 45.1, 29.6, 18.7 ppm; Anal.
Calcd. for C18H16Cl3NO3: C, 53.96; H, 4.02; N, 3.50. Found:
C, 54.07; H, 4.18; N, 3.38.
5-Benzyloxy-2-[(2-oxocyclohexyl)(phenylamino)methyl]-4H-
pyran-4-one (11a). Anti/Syn: 40/60; White solid; FTIR (KBr):
3408 (NH), 3031, 2935, 2861, 1708, 1642, 1555, 1523, 1455,
;
1246, 1208, 992 cmꢂ1 1H NMR (400 MHz, CDCl3): d 7.50
(s, 0.4H, CHPyrone 6-position, anti), 7.49 (s, 0.6H, CHPyrone 6-posi-
tion, syn), 7.28–7.37 (m, 5H, CHAr), 7.13 (m, 2H, CHAr), 6.71–
6.75 (m, 1H, CHAr), 6.59 (m, 2H, CHAr), 6.50 (s, 0.6H, CHPyr-
one 3-position, syn), 6.49 (s, 0.4H, CHPyrone 3-position, anti), 4.99–
5.00 [2 ꢃ s: 5.00 (s, 0.8H, ACH2OA, anti), 4.99 (s, 1.2H,
ACH2OA, syn), 4.64 (d, 3J ¼ 5.4 Hz, 0.4H, CHAN, anti),
4.41 (d, 3J ¼ 4.9 Hz, 0.6H, CHAN, syn), 4.20 (s, br, 1H,
NH), 2.98–3.04 (m, 0.6H, ACOCH<, syn), 2.84–2.92 (m,
0.4H, ACOCH<, anti), 2.25–2.41 (m, 2H, ACH2COA) 1.57–
2.04 (m, 6H, CH2 Cyclohexanone) ppm; 13C NMR (100 MHz,
(Z)-4-Chloro-3-[1-chloro-5-oxo-5-phenyl-3-(phenylamino)-
pent-1-enyl]-6-methyl-2H-pyran-2-one
(7c). Pale
yellow
solid, Mp. 126–128ꢁC; FTIR (KBr): 3381 (NH), 3092, 3056,
3028, 2924, 2855, 1729, 1685, 1625, 1600, 1548, 1293, 1265,
861, 751, 694 cmꢂ1 1H NMR (400 MHz, CDCl3): d 7.98–
;
8.00 (m, 2H, CHAr), 7.57–7.60 (m, 1H, CHAr), 7.46–7.51 (m,
2H, CHAr), 7.14–7.19 (m, 2H, CHAr), 6.69–6.74 (m, 3H,
CHAr), 6.07 (s, 1H, CHa-Pyrone), 6.07 (d, 3J ¼ 7.8 Hz, 1H,
CHVinyl), 4.89–4.93 (m, 1H, CHAN), 3.46–3.57 (m, 2H, CH2),
2.23 (s, 3H, CH3 a-Pyrone) ppm; 13C NMR (100 MHz, CDCl3)
d 197.7 (C¼¼OKetone), 161.0, 158.2, 149.1, 145.6, 137.1, 135.5,
132.6, 128.2, 127.7, 127.6, 127.3, 122.8, 117.3, 113.1, 105.4,
48.8, 40.6, 18.7 ppm; Anal. Calcd. for C23H19Cl2NO3: C,
64.50; H, 4.47; N, 3.27. Found: C, 64.35; H, 4.65; N, 3.55.
(Z)-4-Chloro-3-[1-chloro-3-(4-chlorophenylamino)-5-oxo-5-
phenylpent-1-enyl]-6-methyl-2H-pyran-2-one (7d). Pale yel-
low solid, Mp. 128–130ꢁC; FTIR (KBr): 3371 (NH), 3172,
3060, 3031, 2924, 2855, 1731, 1695, 1621, 1547, 1493, 1456,
CDCl3):
d
209.7, 208.4 (C¼¼O Cyclohexanone), 173.4
(C¼¼OPyrone), 166.1, 165.7, 146.0, 144.9, 144.7, 140.3, 139.8,
134.6, 128.3, 128.2, 127.7, 127.6, 127.4, 127.3, 126.6, 126.6,
118.0, 117.8, 113.0, 112.9, 112.8, 112.4, 70.8, 70.6, 54.6, 53.8,
52.2, 52.1, 41.1, 41.0, 28.2, 28.1, 26.4, 25.9, 23.6, 23.4 ppm;
Anal. calcd. for C25H25NO4: C, 74.42; H, 6.25; N, 3.47.
Found: C, 74.08; H, 6.46; N, 3.21.
1213, 811, 742 cmꢂ1 1H NMR (400 MHz, CDCl3): d 7.96–
;
7.99 (m, 2H, CHAr), 7.59–7.63 (m, 1H, CHAr), 7.47–7.53 (m,
2H, CHAr), 7.20–7.22 (m, 2H, CHAr), 6.95–6.97 (m, 2H,
5-Benzyloxy-2-[(4-chlorophenylamino)(2-oxocyclohexyl)-
methyl]-4H-pyran-4-one (11b). Anti/Syn: 55/45; White solid,
FTIR (KBr): 3333 (NH), 3088, 3034, 2933, 2861, 1708, 1644,
3
CHAr), 6.19 (d, J ¼ 8.4 Hz, 1H, CHVinyl), 6.08 (d, 4J ¼ 0.8
Hz, 1H, CHa-Pyrone), 4.90–4.95 (m, 1H, CHAN), 3.55–3.77 [2
ꢃ dd: 3.74 (dd, 3J ¼ 6.8 Hz, 2J ¼ 17.1 Hz, 1H, CH2), 3.58
1600, 1497, 1202, 816, 738 cmꢂ1 1H NMR (400 MHz,
;
CDCl3): d 7.50 (s, 0.55H, CHPyrone 6-position, anti), 7.49 (s,
0.45H, CHPyrone 6-position, syn), 7.30–7.35 (m, 5H, CHAr), 7.05–
7.08 (m, 2H, CHAr), 6.49–6.54 (m, 2H, CHAr), 6.47 (s, 0.45H,
CHPyrone 3-position, syn), 6.45 (s, 0.55H, CHPyrone 3-position, anti),
3
2
(dd, J ¼ 4.0 Hz, J ¼ 17.3 Hz, 1H, CH2), CH2 Diastrotopic Pro-
tons], 2.25 (d, 4J ¼ 0.6 Hz, 3H, CH3 a-Pyrone) ppm; 13C NMR
(100 MHz, CDCl3): d 198.7 (C¼¼OKetone), 162.2, 159.2, 150.1,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

602
A. Shahrisa and M. Zirak
Vol 47
5.00 (2 ꢃ s: 2H, ACH2OA), 4.59 (d, 3J ¼ 5.1 Hz, 0.55H,
CHAN, anti), 4.34 (d, 3J ¼ 4.8 Hz, 0.45H, CHAN, syn),
2.97–3.02 (m, 0.45H, ACOCH<, syn), 2.84–2.89 (m, 0.55H,
Trans 2 1999, 1175; (l) Kirsch, G.; Prim, D.; Leising, F.; Mignani, G.
J Heterocycl Chem 1994, 31, 1005; (m) Ziegenbein, W.; Franke, W.
Ger. Pat.1.071.684 (1959); Chem Abstr 1961, 55, 16488f; (n) Brahma,
S.; Ray, J. K. Tetrahedron 2008, 64, 2883; (o) Romagnoli, R.; Baraldi,
P. G.; Carrion, M. D.; Cara, C. L.; Cruz-Lopez, O.; Preti, D.; Tolo-
meo, M.; Grimaudo, S.; Di Cristina, A.; Zonta, N.; Balzarini, J.; Bran-
cale, A.; Sarkar, T.; Hamel, E. Bioorg Med Chem 2008, 16, 5367.
[5] Arend, M.; Westermann, B.; Risch, N. Angew Chem Int Ed
1998, 37, 1044.
ACOCH<, anti), 2.29–2.45 (m, 2H, ACH2COACyclohexanone
)
1.55–2.13 (m, 6H, CH2 Cyclohexanone) ppm; 13C NMR (100
MHz, CDCl3): d 209.7, 208.3 (C¼¼O Cyclohexanone), 173.3
(C¼¼OPyrone), 165.9, 165.6, 146.0, 143.7, 143.5, 139.9, 134.6,
134.5, 128.2, 128.1, 127.7, 127.6, 127.4, 127.3, 126.6, 122.5,
114.0, 113.4, 112.9, 112.7, 70.7, 54.8, 53.8, 52.3, 52.0, 41.2,
41.0, 28.0, 27.9, 26.5, 25.8, 23.7, 23.6 ppm; Anal. calcd. for
C25H24ClNO4: C, 68.57; H, 5.52; N, 3.20. Found: C, 68.21; H,
5.38; N, 3.18.
[6] (a) Tramontini, M.; Angiolini, L. Mannich-Bases, Chemis-
try and Uses; CRC: Boca Raton, FL, 1994 and reference cited therein;
(b) Volkmann, R. A. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.1, p 355 and
references cited therein.
5-Benzyloxy-2-[(3,4-dichlorophenylamino)(2-oxocyclohexyl)
methyl]-4H-pyran-4-one (11c). Anti/Syn: 75/25; White solid,
FTIR (KBr): 3336 (NH), 3067, 3031, 2939, 2865, 1708, 1642,
;
1595, 1476, 1208, 812, 749, 696 cmꢂ1 1H NMR (400 MHz,
[7] (a) Kleinmann, E. F. In Comprehensive Organic Synthesis;
Trost, B. M., Flemming, I., Eds.; Pergamon Press: New York, 1991;
Vol.2, Chapter 4.1; (b) Kobayashi, S.; Ishitani, H. Chem Rev 1999,
99, 1069; (c) Denmark, S.; Nicaise, O. J.-C. In Comprehensive Asym-
metric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamomoto, H., Eds.;
Springer: Berlin, 1999; Vol.2, p 93; (d) Juaristi, E., Ed. Enantioselec-
tive Synthesis of b-Amino Acids; Wiley-VCH: New York, 1997.
[8] (a) Azizi, N.; Torkiyan, L.; Saidi, M. R. Org Lett 2006, 8,
2079; (b) Wu, Y.-S.; Cai, J.; Hu, Z.-Y.; Lin, G.-X. Tetrahedron Lett
2004, 45, 8949; (c) Chen, W. Y.; Li, X.; Lu, J. Synth Commun 2008,
CDCl3): d 7.52 (s, 0.75H, CHPyrone 6-position, anti), 7.49 (s,
0.25H, CHPyrone 6-position, syn), 7.29–7.37 (m, 5H, CHAr), 7.11–
3
7.15 [2 ꢃ d: 7.14 (d, Jortho ¼ 8.7 Hz, 0.25H, CHAr, syn), 7.12
3
4
(d, Jortho ¼ 8.7 Hz, 0.75H, CHAr, anti)], 6.69 (d, Jmeta ¼ 2.7
4
Hz, 0.75H, CHAr, anti), 6.63 (d, Jmeta ¼ 2.7 Hz, 0.25H, CHAr
,
syn), 6.40–6.47 [m, 2H, (1H, CHAr) and (1H, CHPyrone
3-posi-
tion)] 5.00 (s, 2H, ACH2OA), 4.59 (d, 3J ¼ 5.1 Hz, 0.75H,
CHAN, anti), 4.30 (d, 3J ¼ 4.6 Hz, 0.25H, CHAN, syn),
3.01–3.06 (m, 0.25H, ACOCH<, syn), 2.83–2.89 (m, 0.75H,
´
38, 546; (d) Ibrahem, I.; Casas, J.; Cordova, A. Angew Chem Int Ed
2004, 43, 6528. For reviews of catalytic Mannich reactions, see: (e)
Kobayashi, S.; Ueno, M. In Comprehensive Asymmetric Catalysis,
Supplement; Springer: Berlin, 2004; Vol.1, p 143; (f) Xu, L.-W.; Xia,
C.-G.; Li, L. J Org Chem 2004, 69, 8482; (g) Josephsohn, N. S.; Snap-
per, M. L.; Hoveyda, A. H. J Am Chem Soc 2004, 126, 3734; (h)
Guo, Q.-X.; Liu, H.; Guo, C.; Luo, S.-W.; Gu, Y.; Gong, L.-Z. J Am
Chem Soc 2007, 129, 3790; (i) Dubs, C.; Hamashima, Y.; Sasamoto,
N.; Seidel, T. M.; Suzuki, S.; Hashizume, D.; Sodeoka, M. J Org
Chem 2008, 73, 5859; (j) Ferlin, M. G.; Chiarelotto, G.; Castagliuolo,
I. J Heterocycl Chem 2002, 39, 631; (k) Shi, H.; Shi, H.; Wang, Z.
J Heterocycl Chem 2001, 38, 929.
ACOCH<, anti), 2.24–2.45 (m, 2H, ACH2COACyclohexanone
)
1.53–2.12 (m, 6H, CH2 Cyclohexanone) ppm; 13C NMR (100
MHz, CDCl3): d 209.7, 208.1 (C¼¼O Cyclohexanone), 173.3
(C¼¼OPyrone), 165.7, 146.1, 146.0, 144.9, 144.7, 139.9, 134.6,
134.5, 131.9, 131.8, 129.7, 129.6, 127.7, 127.6, 127.4, 127.3,
126.7, 123.5, 120.2, 113.9, 113.3, 112.7, 112.5, 112.3, 111.9,
70.7, 54.6, 53.5, 52.2, 51.9, 41.3, 40.9, 28.0, 27.7, 26.6, 25.7,
23.6, 23.6 ppm; Anal. calcd. for C25H23Cl2NO4: C, 63.57; H,
4.91; N, 2.97. Found: C, 63.67; H, 4.89; N, 3.06.
[9] (a) Shi, M.; Cui, S. C.; Li, Q. J. Tetrahedron 2004, 60,
6679; (b) Bhanushali, M. J.; Nandurkar, N. S.; Jagtap, S. R.; Bhanage,
B. M. Synth Commun 2009, 39, 845; (c) Hashemi, M. M.; Eftekhari-
Sis, B.; Abdollahifar, A.; Khalili, B. Tetrahedron 2006, 62, 672; (d)
Eftekhari-Sis, B.; Abdollahifar, A.; Hashemi, M. M.; Zirak, M. Eur J
Org Chem 2006, 5152; (e) Smitha, S.; Reddy, C. S. Synthesis 2004,
834.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet