Organocatalyzed synthesis of chiral non-racemic 1,4-dihydropyridazines

Article abstract of DOI:10.1016/j.tetasy.2010.03.007

Chiral non-racemic 1,4-dihydropyridazines were prepared by the reaction of 1,2-diaza-1,3-dienes with arylacetaldehydes under organocatalytic conditions. l-Proline and (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine coupled with trifluoroacetic acid were used

Full text of DOI:10.1016/j.tetasy.2010.03.007

Tetrahedron: Asymmetry 21 (2010) 617–622
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Organocatalyzed synthesis of chiral non-racemic 1,4-dihydropyridazines
b
b
b
a
Giuliana Pitacco a, , Orazio A. Attanasi , Lucia De Crescentini , Gianfranco Favi , Fulvia Felluga ,
*
Cristina Forzato a, Fabio Mantellini b, Patrizia Nitti a, Ennio Valentin a, Ennio Zangrando a
a Dipartimento di Scienze Chimiche, Università di Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy
b Istituto di Chimica Organica, Università di Urbino ‘Carlo Bo’, Via I Maggetti 24, 61029 Urbino, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral non-racemic 1,4-dihydropyridazines were prepared by the reaction of 1,2-diaza-1,3-dienes with
arylacetaldehydes under organocatalytic conditions. L-Proline and (S)-(+)-1-(2-pyrrolidinylmethyl)pyr-
rolidine coupled with trifluoroacetic acid were used as organocatalysts. Enantiomeric excesses ranged
from 25% to 78%.
Received 22 February 2010
Accepted 4 March 2010
Available online 13 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Their activities can be correlated with those of 1,4-dihydropyr-
idine derivatives, such as lercanidipine and niphedipine.4 1,4-
The Michael addition of carbon and hetero-nucleophiles to
,b-unsaturated systems is one of the most important bond-
Dihydropyridazines can be prepared by many different methods
including formal [4+2] cycloadditions.5 The particular case of an in-
verse electron demand Diels–Alder reaction6 is the synthesis, car-
ried out in hexane, of the 5,6-dihydro-4H-pyridazine derivative 4
starting from DD 2a and the pyrrolidino enamine of phenylacetal-
dehyde 3. The subsequent elimination of the amino moiety and the
tert-butyloxycarbonyl group was carried out by treatment of
compound 4 with Amberlyst 15 obtaining the corresponding 1,4-
dihydropyridazine system 5 (Scheme 1). Starting from these
results, we envisaged the possibility to use asymmetric enamine
organocatalysis7 to prepare compound 5 and other 4-aryl-1,4-
dihydropyridazines in optically active forms.
a
forming processes in organic chemistry since it offers an extremely
powerful tool for the synthesis of highly functionalized molecules.1
Therefore, extensive studies have been carried out on the develop-
ment of catalytic asymmetric Michael procedures for various
useful donor–acceptor combinations.2 Functionalized 1,2-diaza-
1,3-dienes (DDs) are reactive species both as acceptors in Michael
reactions and as components in cycloadditions. In general, when
they are used as electrophilic carbon derivatives, the resulting
a
-functionalized hydrazone intermediates evolve more or less rap-
idly towards the formation of five- or six-membered heterocyclic
rings, depending on the reaction conditions, the nature of the
nucleophile and the electrophile. Among the various possible prod-
ucts that can be prepared by these methods, 1,4-dihydropyridazine
derivatives 1 (Fig. 1) are of particular interest, as some of them are
known for their biological activity. For example, they act as vasodi-
lators and coronary therapeutic agents, or as spasmolytic agents,
particularly when the substituent at C4 is aromatic.3
2. Results and discussion
L
-Proline (L-Pro) was chosen as the organocatalyst because it
was the first organocatalyst used8 and considering that many stud-
ies are present in the literature on the mechanism of its action.7a,8,9
Freshly distilled phenylacetaldehyde 6 was reacted with DD 2b in
the presence of catalytic amounts of L-Pro (20 mol %) in tetrahydro-
furan (THF), at room temperature. After 96 h, the 1H NMR analysis
of the crude reaction mixture revealed the almost complete
disappearance of 2b and the concomitant formation of ethyl 6-
methyl-4-phenyl-1,4-dihydropyridazine-5-carboxylate 5, which
was purified by column chromatography (Scheme 2).
The enantiomeric excess of (+)-5 was 39%, as determined by
HPLC on a chiral column. The reaction was also performed using
DD 2c, which furnished compound (+)-12 with 59% ee, determined
by HPLC on a chiral column. Using (S)-(+)-1-(2-pyrrolidinylmeth-
yl)pyrrolidine (2PMP) and trifluoroacetic acid (TFA) as the organo-
catalytic mixture,10 in THF, the ee of compound (+)-5 was 75%
while the ee of (+)-12 was 46%. In particular, the structure of
R
NH
N
1
Figure 1. 4-Substituted-1,4-dihydropyridazine ring.
* Corresponding author. Tel.: +39 040 558 3923; fax: +39 040 558 3903.
E-mail address: gpitacco@units.it (G. Pitacco).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.007

618
G. Pitacco et al. / Tetrahedron: Asymmetry 21 (2010) 617–622
CO2Et
CO2Et
N
Ph
CO2Et
Ph
N
CH3
CH3
H
Ph
CH3
Amberlyst 15
EtOH, rt
hexane
- 78 °C
+
N
N
N
N
NH
N
CO2But
COOBut
2a
3
4
5
Scheme 1. Formation of 1,4-dihydropyridazine 5 via reaction of 1,2-diaza-1,3-butadiene 2a and phenylacetaldehyde enamine 3.
1,4-dihydropyridazine (+)-12 was determined by X-ray spectros-
copy diffraction (Fig. 2).
Using both L-Pro and 2PMP/TFA as organocatalysts, other arylac-
etaldehydes, namely compounds 7–11, were also reacted with DD
2c, with the aim of verifying a possible electronic effect on the out-
come of the reaction and on the stability of the products. The result-
ing methyl 4-aryl-6-methyl-1,4-dihydropyridazine-5-carboxylates
(+)-13–(+)-17 were isolated as single reaction products. However,
as shown in Table 1, the yields of the products were modest for
compoundsderived from phenylacetaldehyde, 4-bromophenylacet-
aldehyde and 4-ethoxy phenylacetaldehyde (entries 1–4), whereas
the yields were much higher for those derived from nitrophenylac-
etaldehydes (entries 5–7). This is probably a consequence of the
higher stability of the more conjugated enamine intermediate when
the substituent at the phenyl ring is the nitro group.
Low catalyst turnover has already been observed in other
cases11 and it has been ascribed to the formation of unreactive
hemiaminal species of relative stability.
A reaction was also performed between phenylacetaldehyde 6
and 4-ethoxycarbonyl-3-methyl-1-phenylaminocarbonyl-2-diaza-
1,3-diene 2d, in the presence of 2PMP/TFA, with the aim of deter-
Figure 2. ORTEP drawing of compound 12.
Table 1
Reaction times, yields and ee’s for all products
CO2R1
N
Ar
Entry Product
2PMP/TFA
Yielda eeb
L
-Pro
Yielda eeb
CH3
H
Reaction
time (d)
Reaction
time (d)
+
(%)
(%)
(%)
(%)
O
1
2
3
4
5
6
7
(+)-5
4
4
5
10
7
5
35
25
23
18
70
85
87
39
59
62
66
69
52
78
4
4
5
10
10
5
40
37
32
15
36
83
62
75
46
72
28
25
35
65
N
(+)-12
(+)-13
(+)-14
(+)-15
(+)-16
(+)-17
6
Ar = C6H5-:
Ar = p-Br-C6H4-: 7
Ar = p-EtO-C6H4-: 8
Ar = p-NO2-C6H4-:
Ar = o-NO2-C6H4-:
Ar = m-NO2-C6H4-: 11
CONH2
R1 = Et: 2b
R1 = Me: 2c
9
10
7
4
a
In isolated product.
Determined by HPLC on a chiral column.
b
L-Pro,
or 2PMP/TFA
20 mol%
mining whether a substituent on the carbamic nitrogen might have
an influence on the course of the reaction. No difference was ob-
served, as the known 1,4-dihydropyridazine (+)-5 was isolated
(25% yield, 47% ee) (Scheme 3).
THF, rt, 4-10d
CO2R1
5
6
Ar
CH3
4
A possible mechanism for the enamine organocatalysis is
shown in Scheme 4, with
L
-Pro as the catalyst. Taking into account
NH
3
N
2
1
CO2Et
1
5
R = Et; Ar = C6H5-: (+)-
R1 = Me; Ar = C6H5-: (+)-12
CH3
2-PMP/TFA (20 mol%)
1
(+)-5
6
+
13
14
R = Me; Ar = p-Br-C6H4-: (+)-
THF, rt, 96 h
1
N
N
R = Me; Ar = p-EtO-C6H4-: (+)-
R1 = Me; Ar = p-NO2-C6H4-: (+)-15
CONHPh
R1 = Me; Ar = o-NO2-C6H4-: (+)-16
1
17
R = Me; Ar = m-NO2-C6H4-: (+)-
2d
Scheme 2. Organocatalyzed formation of 1,4-dihydropyridazines (+)-5, (+)-12–(+)-
17 from DDs 2b,c and arylacetaldehydes 6–11.
Scheme 3. Organocatalyzed formation of 1,4-dihydropyridazines (+)-5 from DD 2d
and phenylacetaldehyde 6.

G. Pitacco et al. / Tetrahedron: Asymmetry 21 (2010) 617–622
619
CO2R1
N
CO2R1
N
Ph
Ar
CH3
CH3
Ar
+
H
H
H
+
+
NH
O
N
COOH
N
N
COR2
O
CONHR2
COOH
2
2a-d
6
6-11
18
2b 2c
R =H:
,
2
2d
R =Ph:
base-promoted
organocatalysed
formal [4+2]
formal [3+2]
cycloaddn
cycloaddn
CO2R1
N
CO2R1
CO2R1
Ar
O
CH3
Ar
CH3
Ph
CO2R1
CH3
H2O
-OOC
Ph
CH3
- L-Pro
N
HN
N
HN
NH
N
N
CONHR2
CONHR2
NHCOR2
20
19
23
5,12
Scheme 5. Possible reaction pathways.
CO2R1
CO2R1
All optically active 1,4-dihydropyridazines (+)-5, (+)-12–(+)-17
molecules exhibited very high positive specific rotation values. A
direct comparison of the CD spectra of our 1,4-dihydropyridazines
cannot be made, owing to their different enantiopurities. However,
1,4-dihydropyridazines (+)-5, (+)-12, (+)-13, (+)-14 and (+)-17
Ar
CH3
- R2NHCOOH
H
Ar
CH3
N
HO
N
N
N
CONHR2
21
show two strong positive bands at about 250 nm and 320 nm
*
p?p transitions of the
22
(Fig. 3). These bands can be attributed to
aromatic ring and to the enaminoester moiety. A third band (shoul-
der) around 260 nm showing fine structure can also be assigned to
the aromatic ring. The p- and o-nitrophenyl derivatives (+)-15 and
(+)-16 exhibit the same bands, shifted, however, the former to
higher wavelengths, above 250 nm, and the latter to shorter wave-
lengths, around 300 nm, as a consequence of a strong electronic ef-
fect exerted by the nitro group.
(+)-5, (+)-12-(+)-17
Scheme 4. Plausible mechanism of 1,4-dihydropyridazine formation.
what is proposed by several authors,7a,9
L-Pro reacts with alde-
hydes 6–11 forming in situ their enamine derivatives 18. The reg-
ioselective Michael-type reaction of the b-carbon atom of
enamines 18 to the electrophilic terminal carbon atom of the
azo-ene system produces the zwitterionic hydrazone intermedi-
ates 19, which is then hydrolyzed in situ to give the corresponding
aldehyde 20.
20
(+)-15
(+)-13
10
Intramolecular nucleophilic attack of the nitrogen atom onto
the carbonyl group determines the formation of the tetrahydropy-
ridazine (intermediates 21). The loss of either the carbamic acid
(+)-5
(R2 = H) or its phenyl derivative (R2 = Ph), induced by
L-Pro (or by
(+)-17
(+)-12
TFA for the 2PMP-TFA pair), yields alkyl 4-aryl-6-methyl-1,
4-dihydropyridazine-5-carboxylates (+)-5 and (+)-12–(+)-17, after
rearrangement of the 4,5-dihydropyridazine intermediates 22. Un-
der our reaction conditions, no traces of oxazolidinone systems
have ever been detected, different to that found by Seebach and
Eschenmoser et al. in the reaction between cyclohexanone and
superelectrophiles such as (E)-b-nitrostyrene and chloral, organo-
0
(+)-14
(+)-16
-10
205
250
300
350
400
Wavelength [nm]
catalyzed by L
-Pro.9c
In this case the cyclization process occurred by means of formal
[4+2] cyclization and all four atoms (C@C–N@N) of the former azo-
ene system of starting DDs are incorporated into the 1,4-dihydropy-
ridazine derivatives. It is noteworthy that the base-mediated reac-
tion of the same starting phenylacetaldehyde 6 with the DDs 2a–d
produces the corresponding pyrrole derivatives 23 through formal
[3+2] cycloaddition in which three atoms (C@C–N) of the azo-ene
systemare involved.12 Thesamecompounds23wereobtainedwhen
the reaction between the DD 2a and the pyrrolidino enamine of phe-
nylacetaldehyde 3 was performed in methanol, firstly at ꢀ78 °C and
then under heating (Scheme 5).6 Under the conditions used for
organocatalysis, no traces of pyrrole derivatives were found.
Figure 3. CD spectra for 1,4-dihydropyridazines (+)-5, (+)-12–(+)-17.
The assignment of the absolute configuration to the 1,4-dihyd-
ropyridazines (+)-5 and (+)-12–(+)-17 was tentatively made as (S),
on the basis of the well-accepted catalysis mechanism of L-Pro, that
is, a preferential re–si facial attack of the enamine intermediate,
formed in situ from the aldehyde and proline (or protonated
2PMP), onto the electrophile, with formation of the transition state
24 (Fig. 4).
Transition states having 9–11-membered hydrogen-bonded ring
have already been proposed for
L-Pro and other pyrrolidine-based
organocatalysts for a variety of carbon–carbon bond formations.9a,13

620
G. Pitacco et al. / Tetrahedron: Asymmetry 21 (2010) 617–622
4. Experimental
Ar
H
CO2R1
H
H
4.1. General
H
CH3
O
N
N
Separation by column chromatography was achieved on silica gel
for flash-chromatography (BDH) with conditions described by
Still.16 Thin layer chromatograms were run on 0.25 mm EM pre-
coated plates of silica gel PolygramÒ Sil G/UV254. Light petroleum re-
fers to the fraction with bp 40–70 °C. High performance liquid
chromatograms (HPLCs) were obtained on a Hewlett Packard Series
N
O
OC
NHR2
24
Figure 4. Transition state for proline-mediated reactions of aldehydes with DDs.
1100 instrument from
a chiral column Lux 5l Cellulose-2
(Phenomenex) with a Cellulose tris(3-chloro-4-methylphenylcar-
bammate) chiral stationary phase, eluent: n-hexane/isopropanol
75:25, detector UV 220 nm. IR spectra were recorded on a Jasco
FT/IR 200 spectrophotometer. 1H NMR and 13C NMR spectra were
obtained from a Jeol EX-400 spectrometer (400 MHz for proton,
100.1 MHz for carbon) using deuteriochloroform as the solvent
and tetramethylsilane as an internal standard. Chemical shifts are
expressed in parts per million (d). Coupling constants are given in
hertz. Optical rotations were determined on a Perkin Elmer Model
241 polarimeter. CD spectra were recorded on a Jasco J-710 spectro-
polarimeter. Mass spectra were recorded on an ion trap instrument
Finnigan GCQ (70 eV). Elemental analyses were determined on a
Carlo Erba 1106 instrument at the Department of Chemical Sciences
and Technologies of the University of Udine, Italy. Phenylacetalde-
Under slightly acidic conditions, by traces of hydrochloric acid
present in chloroform, 1,4-dihydropyridazines underwent a series
of transformations that could be followed by 1H NMR. For example,
ethyl 6-methyl-4-phenyl-1,4-dihydropyridazine-5-carboxylate
5
was converted into its isomer ethyl 3-methyl-5-phenyl-1,4-dihyd-
ropyridazine-4-carboxylate 27, through protonation of C5 to yield
the intermediate 25, prototropy to 26 and loss of proton to give
compound 27. Analogous isomerization, although under basic
conditions, between methyl 3,5-dimethyl-1,4-dihydropyridazine-
4-carboxylate and methyl 4,6-dimethyl-1,4-dihydropyridazine-5-
carboxylate was proposed by Razin and co-workers.14 These latter
heterocycles can be eventually oxidized with potassium perman-
ganate to the corresponding aromatic molecules. In the present
case, the oxidation is presumably due to the air, occurring without
addition of any oxidant and giving the pyridazine derivative 28,
even in the solid state (Scheme 6).
hyde 6, L-proline and (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine
were purchased from Sigma–Aldrich; 4-bromophenylacetaldehyde
7 and 4-ethoxyphenylacetaldehyde 8 were prepared according to
the literature;17 2-nitrophenylacetaldehyde was prepared from
phenylacetaldehyde by nitration according to the literature;18
4-nitrophenylacetaldehyde 9 and 3-nitrophenylacetaldehyde 11
were prepared according to the literature;19 1-aminocarbonyl-3-
methyl-4-ethoxycarbonyl-1,2-diaza-1,3-diene 2b, 1-aminocar-
bonyl-3-methyl-4-methoxycarbonyl-1,2-diaza-1,3-diene 2c and
1-phenylaminocarbonyl-3-methyl-4-ethoxycarbonyl-1,2-diaza-
1,3-diene 2d were prepared according to the literature.20
CO2Et
CO2Et
CO2Et
Ph
CH3
Ph
CH3
H+
Ph
CH3
N
NH
N
NH
N
N
H
5
25
26
4.2. General procedure for the reactions between DDs and
arylacetaldehydes
-H+
CO2Et
4
To a solution of the appropriate aldehyde (1.0 mmol) and DD
CO2Et
Ph
CH3
(1.0 mmol)in anhydrous THF(10 mL), L-Pro (20 mol %)or2PMPasso-
5
Ph
CH3
ciated with TFA (20 mol %) was added.9c,10b The mixture was stirred
for 4–10 days, until completion of the reaction. The solvent was elim-
inatedandthecrudereactionmixturewaschromatographedonsilica
gel (eluent: light petroleum–ethyl acetate, gradient).
3
N
6
N
2
N
H
N
1
28
27
Scheme 6. Transformations of 1,4-dihydropyridazine (+)-5 under slightly acidic
conditions (CDCl3).
4.2.1. (S)-(+)-Ethyl 6-methyl-4-phenyl-1,4-dihydropyridazine-
5-carboxylate 5
Mp 132–133 °C; Rf 0.77 (eluent: ethyl acetate–light petroleum 1:1).
IR (nujol) 3322.3, 1670.4, 1604.6, 1259.7, 1100.0, 1057.6, 765.7, 724.0,
701.9 cmꢀ1;1HNMRd7.38 (br s, 1H, NH), 7.25 (m, 5H, Ph), 6.91 (d, J4.0,
1H, H-3), 4.53 (d, J 4.0, 1H, H-4), 4.09 (dq, 2H, OCH2), 2.33 (s, 3H, CH3),
1.20 (t, 3H, OCH2CH3); 13C NMR d 167.2 (s), 146.2 (s), 143.2 (s), 141.8
(d), 128.6 (2d), 127.7 (2d), 126.9 (d), 95.2 (s), 59.6 (t), 39.1 (d), 18.1
(q), 14.2 (q); MS m/z 244 (M+Å, 18), 215 (100), 198 (31), 172 (46), 167
On the other hand, the formation of the pyridazine derivatives
is a common fate for all our 1,4-dihydropyridazines, when stored
at room temperature.5b The process is more or less rapid, depend-
ing on the aryl substituent.
3. Conclusion
(68), 139 (65). 75% ee; ½a D20
ꢁ
¼ þ548:8 (c 0.25, MeOH); CD (0.001 M,
The formation of enantiomerically enriched polysubstituted
1,4-dihydropyridazines through a single reaction between DDs
and arylacetaldehydes by organocatalysis is an interesting route,
although enantiomeric excesses range from 25% to 78%. The use
of different organocatalysts should be considered. As to the abso-
lute configuration assignment, a computational investigation is
currently in progress concerning the specific rotation, as success-
fully carried out in other cases.15
MeOH)
+7.6;
D
e
e321 = +8.3;
De273 = +2.9;
De
266 = +4.1; 259 = +5.6;
D
e
De250 =
D
218 = ꢀ6.6). Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N,
11.47. Found: C, 68.10; H, 6.29; N, 12.01.
4.2.2. (S)-(+)-Methyl 6-methyl-4-phenyl-1,4-dihydropyridazine-
5-carboxylate 12
Mp 136–137 °C; Rf 0.69 (eluent: ethyl acetate–light petroleum
1:1). IR (CDCl3) 3350.6, 1678.6, 1612.7 1490.7, 1255.6, 1100.3,

G. Pitacco et al. / Tetrahedron: Asymmetry 21 (2010) 617–622
621
1061.0, 698.8 cmꢀ1
;
1H NMR (CDCl3) d 7.25 (m, 6H, Ph, NH), 6.91
(s), 133.6 (d), 131.0 (d), 127.8 (d), 124.0 (d), 94.3 (s), 51.1 (q),
(d, J 4.0, 1H, H-3), 4.52 (d, J 4.0, 1H, H-4), 3.62 (s, 3H, OCH3), 2.34
(s, 3H, CH3); 1H NMR (CD3CN) d 8.34 (br s, 1H, NH), 7.30 (m, 2H,
Ph), 7.20 (m, 3H, Ph), 6.88 (d, J 4.0, 1H, H-3), 4.47 (d, J 4.0, 1H,
H-4), 3.54 (s, 3H, OCH3), 2.30 (s, 3H, CH3); 13C NMR d 167.6 (s),
146.4 (s), 142.9 (s), 141.8 (d), 128.7 (2d), 127.6 (2d), 127.0 (d),
94.9 (s), 50.9 (q), 39.1 (d), 18.2 (q); MS m/z 230 (M+Å, 28), 215
35.0 (d), 17.9 (q); MS m/z 275 (M+Å, 8), 258 (80), 227 (10), 213
(100), 199 (60), 183 (45). 52% ee; ½a D20
ꢁ
¼ þ71:5 (c 0.595, MeOH);
CD (0.002 M, MeOH):
D
e
340 = ꢀ3.7;
D
e
294 = +6.8; 279 = +5.2;
De
D
e255 = +12.0;
D
e228 = ꢀ6.0). Anal. Calcd for C13H13N3O4: C, 56.72;
H, 4.76; N, 15.27. Found: C, 56.40; H, 4.60; N, 15.56.
(50), 198 (72), 171 (52), 153 (100). 46% ee; ½a D20
ꢁ
¼ þ211:2 (c
4.2.7. (S)-(+)-Methyl 6-methyl-4-(3-nitrophenyl)-1,4-dihydropy
ridazine-5-carboxylate 17
0.34, MeOH); CD (0.0015 M, MeOH)
De319 = +3.2; De273 = +1.0;
D
e
266 = +1.4;
D
e
249 = +2.6;
D
e
218 = ꢀ2.5). Anal. Calcd for
Mp 142–143 °C; Rf 0.54 (eluent: ethyl acetate–light petroleum
1:1). IR (CDCl3): 3350.2, 1701.6, 1650.2, 1613.8, 1530.3, 1490.1,
C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.92; H, 6.18;
N, 12.33.
1461.8, 1437.0, 1351.9, 1255.2, 1098.7, 908.7, 731.6 cmꢀ1 1H
;
NMR d 8.09 (m, 2H, ArH), 7.58 (br d, 1H, ArH), 7.48 (br d, 1H,
ArH), 7.42 (br s, 1H, NH), 6.95 (d, J 4.4, 1H, H-3), 4.69 (d, J 4.4,
1H, H-4), 3.67 (s, 3H, OCH3), 2.38 (s, 3H, CH3); 13C NMR d 167.1
(s), 148.6 (s), 147.0 (s), 144.7 (s), 140.3 (d), 133.8 (d), 129.6 (d),
122.6 (d), 122.2 (d), 94.2 (s), 51.2 (q), 38.9 (d), 18.3 (q); MS m/z
274 (M+Åꢀ1, 7), 260 (33), 258 (100), 216 (32), 202 (10), 169 (10),
4.2.3. (S)-(+)-Methyl 4-(4-bromophenyl)-6-methyl-1,4-dihyd-
ropyridazine-5-carboxylate (13)
Mp 142–143 °C; Rf 0.65 (eluent: ethyl acetate–light petroleum
1:1). IR (CDCl3) 3337.8, 1679.5, 1613.5, 1485.1, 1254.2, 1099.6,
1067.0, 1010.4 cmꢀ1; 1H NMR d 7.41 (br d, 2H, ArH), 7.32 (br s, 1H,
NH), 7.09 (br d, 2H, ArH), 6.89 (d, J 4.1, 1H, H-3), 4.49 (d, J 4.1, 1H,
H-4), 3.64 (s, 3H, OCH3), 2.33 (s, 3H, CH3); 13C NMR d 167.4 (s),
146.5 (s), 141.8 (s), 141.2 (d), 131.7 (2d), 129.3 (2d), 120.9 (s), 94.7
(s), 51.0 (q), 38.6 (d), 18.2 (q); MS m/z 308, 310 (M+Å, 58), 293, 295
(50), 276, 278 (23), 249, 251 (38), 229 (15), 197 (30), 169 (22), 153
153 (32), 121 (12). 78% ee; ½a D20
ꢁ
¼ þ419:9 (c 0.18, MeOH); CD
270 = +0.7; 247 = +6.6;
(0.0006 M, MeOH):
D
e314 = +8.2;
D
e
De
De225 = +2.4). Anal. Calcd for C13H13N3O4: C, 56.72; H, 4.76; N,
15.27. Found: C, 56.22; H, 4.15; N, 15.53.
(100). 72% ee; ½a D20
ꢁ
¼ þ403:3 (c 0.45, MeOH), ½a D25
ꢁ
¼ þ404:4 (c
4.2.8. Ethyl 3-methyl-5-phenyl-1,4-dihydropyridazine-4-car-
boxylate 27
0.045, MeOH); CD (0.0015 M, MeOH):
De318 = +7.2; De252 = +11.7;
D
e
210 = ꢀ8.5). Anal. Calcd for C13H13BrN2O2: C, 50.50; H, 4.24; N,
On standing in chloroform solution for 48 h, compound 5 was
partially transformed into its isomer 27 and the oxidation product
28. Although not isolated, its signals are given separately, for the
sake of clarity. 1H NMR 7.03 (d, 1H, H-6), 4.32 (s, 1H, H-4), 4.17
(dq, 2H, OCH2), 2.15 (s, 3H, CH3), 1.24 (t, 3H, OCH2CH3); 13C NMR
d 170.4 (s), 137.9 (s), 136.8 (s), 128.5 (2d), 126.0 (d), 124.9 (d),
124.0 (2d), 102.1 (s, C-5), 61.4 (t), 45.1 (d, C-4), 22.4 (q), 13.7 (q).
Aromatic and NH protons are hidden under the signals of com-
pounds 5 and 28.
9.06. Found: C, 50.42; H, 4.16; N, 9.28.
4.2.4. (S)-(+)-Methyl 4-(4-ethoxyphenyl)-6-methyl-1,4-dihydro-
pyridazine-5-carboxylate 14
Oil; Rf 0.61 (eluent: ethyl acetate–light petroleum 1:1). IR (neat)
3342.1, 1734.4, 1682.8, 1608.7, 1510.4, 1477.4, 1259.0, 1096.6,
1045.4, 799.8 cmꢀ1 1H NMR d 7.42 (br s, 1H, NH), 7.04 (br d, 2H,
;
ArH), 6.85 (d, J 4.0, 1H, H-3), 6.80 (br d, 2H, ArH), 4.42 (d, J 4.0,
1H, H-4), 3.98 (q, 2H, OCH2), 3.62 (s, 3H, OCH3), 2.25 (s, 3H, CH3),
1.38 (t, 3H, OCH2CH3); 13C NMR d 167.7 (s), 158.0 (s), 146.3 (s),
142.0 (d), 135.2 (s), 128.6 (2d), 114.5 (2d), 95.1 (s), 63.3 (t), 51.0
(q), 38.1 (d), 18.2 (q), 14.8 (q); MS m/z 273 (M+Åꢀ1, 18), 258 (85),
4.2.9. Ethyl 3-methyl-5-phenyl-pyridazine-4-carboxylate 28
1H NMR d 9.17 (s, 1H, H-6), 7.49 (m, 3H, Ph), 7.41 (m, 2H, Ph),
4.22 (dq, 2H, OCH2), 2.80 (s, 3H, CH3), 1.08 (t, 3H, OCH2CH3); 13C
NMR d 166.6 d (s), 155.5 (s), 150.0 (d), 136.0 (s), 134.0 (s), 129.8
(s), 129.6 (d), 129.0 (2d), 127.9 (2d), 62.2 (t), 20.3 (q), 14.1 (q). After
10 days, conversion of the two isomers 5 and 27 into compound 28
was complete.
227 (40), 213 (100), 199 (60), 183 (48). 66% ee; ½a D20
ꢁ
¼ þ198:0
(c 0.295, MeOH); CD (0.0011 M, MeOH)
D
e
316 = +3.3;
D
e
279 = +2.0;
D
e
262 = +3.3;
D
e
230 = ꢀ2.9). Anal. Calcd for C15H18N2O3: C, 65.68;
H, 6.61; N, 10.21. Found: C, 65.72; H, 6.30; N, 10.28.
4.2.5. (S)-(+)-Methyl 6-methyl-4-(4-nitrophenyl)-1,4-dihydro-
pyridazine-5-carboxylate 15
4.2.10. Crystal data for compound 12
C13H14N2O2, M = 230.26, orthorhombic, space group P 212121,
Mp 148–149 °C; Rf 0.50 (eluent: ethyl acetate–light petroleum
1:1). IR (CDCl3) 3337.1, 3107.7, 1681.8, 1604.7, 1518.7, 1489.8,
a = 7.337(2), b = 9.362(3), c = 17.081(4) Å, V = 1173.3(6) Å3, Z = 4,
q
calcd = 1.304 g/cm3, ) = 0.727 mmꢀ1, F(0 0 0) = 488. Final
l(Mo Ka
1252.9, 1188.0, 1101.5, 854.9 cmꢀ1 1H NMR d 8.16 (br d, 2H,
;
R = 0.0429, wR2 = 0.1182, S = 1.093 for 156 parameters and 9238
reflections, 1757 unique [R(int) = 0.0620], of which 1617 with
ArH), 7.38 (br d, 3H, ArH, NH), 6.91 (d, J 4.0, 1H, H-3), 4.68 (d, J
4.0, 1H, H-4), 3.65 (s, 3H, OCH3), 2.36 (s, 3H, CH3); 13C NMR d
167.1 (s), 149.8 (s), 147.0 (s), 146.9 (s), 140.1 (d), 128.4 (2d),
124.0 (2d), 94.1 (s), 51.2 (q), 39.2 (d), 18.2 (q); MS m/z 275
(M+Åꢀ1, 15), 260 (100), 246 (10), 216 (30), 198 (10), 153 (25),
I > 2r(I), max positive and negative peaks in DF map 0.118,
ꢀ0.115 e Åꢀ3. Absolute structure parameter 0.5(3).22
Diffraction data were collected at room temperature by using a
Brucker Kappa CCD imaging plate mounted on a Nonius FR591
121 (10). 69% ee; ½a D20
ꢁ
¼ þ492:7 (c 0.055, MeOH); CD (0.0002 M,
265 = +3.0;
rotating anode (Cu K
a radiation, k = 1.54178 Å). Cell refinement,
MeOH)
D
e
299 = +19.2;
D
e
D
e
239 = ꢀ8.9. Anal. Calcd for
indexing and scaling of the data sets were carried out using DENZO
C13H13N3O4: C, 56.72; H, 4.76; N, 15.27. Found: C, 56.34; H, 4.26;
23
and SCALEPACK
.
The structure was solved by direct methods and
N, 15.13.
Fourier analyses and refined by the full-matrix least-squares meth-
od based on F2.24 All the calculations were performed using the
WINGX System, Ver 1.80.05.25
4.2.6. (S)-(+)-Methyl 6-methyl-4-(2-nitrophenyl)-1,4-dihydropy
ridazine-5-carboxylate 16
Crystallographic data (excluding structure factors) for the struc-
ture reported have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication number CCDC
764970. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: +44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
Mp 148–149 °C; Rf 0.57 (eluent: ethyl acetate–light petroleum
1:1). IR (nujol) 3335.7, 1697.2, 1613.6 1525.6, 1251.8, 1187.8,
1098.4, 736.3 cmꢀ1 1H NMR d 7.82 (dd, 1H, ArH), 7.55 (br dt, 2H,
;
ArH, NH), 7.42 (dd, 1H, ArH), 7.36 (dt, 1H, ArH), 7.08 (d, J 4.1, 1H,
H-3), 5.12 (d, J 4.1 Hz, 1H, H-4), 3.50 (s, 3H, OCH3), 2.39 (s, 3H,
CH3); 13C NMR d 166.9 (s), 148.4 (s), 147.6 (s), 140.8 (d), 137.6

622
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Barbas, C. F., III Org. Lett. 2001, 3, 3737–3740.
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Int. Ed. 2004, 43, 6532–6535; (b) Isshiki, K.; Tanaka, H.; Nakashima, T.;
Yoshioka, T. EP 0636611 B1, 1995.