Synthesis of chiral 4,4-disubstituted-dihydropyridazines

Article abstract of DOI:10.1016/j.tetasy.2007.11.026

In this paper, a novel general route to the stereospecific synthesis of chiral dihydropyridazines relying on the stereospecific formation of 1,4-diones is presented. The chirality is provided through the application of bicyclic lactams to the synthesis of

Full text of DOI:10.1016/j.tetasy.2007.11.026

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 27–30
Synthesis of chiral 4,4-disubstituted-dihydropyridazines
Paul T. Buonora,a,* Qun Zhang,b Jennifer Sawkoc and Larry J. Westrumd
aDepartment of Chemistry and Biochemistry, California State University—Long Beach, 1250 Bellflower Blvd.,
Long Beach, CA 90840-3903, USA
bDepartment of Chemistry, Lamar University, Beaumont, TX 77710, USA
cDepartment of Chemistry, University of Scranton, Scranton, PA 18510-4626, USA
dDepartment of Chemistry, 2 East South Street, Knox College, Galesburg, IL 61401-4999, USA
Received 13 September 2007; accepted 19 November 2007
Available online 4 January 2008
Abstract—In this paper, a novel general route to the stereospecific synthesis of chiral dihydropyridazines relying on the stereospecific
formation of 1,4-diones is presented. The chirality is provided through the application of bicyclic lactams to the synthesis of the required
diones. Treatment of the diones with hydrazine produces the pyridazine targets. In this report, the synthesis of four chiral 6-phenyl-4,4-
disubstituted-1,4-dihydropyridazines is also presented.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
As a part of our continuing studies directed toward the
asymmetric synthesis of the members of the pyridazine fam-
ily, we recognized that the synthesis of suitably substituted
1,4-diketones from bicyclic lactams would allow access to
chiral 4,4-disubstituted-dihydropyridazines (Scheme 2).4
The pyridazine family of heterocycles has been known for
more than a century. Testament for the diverse bioactivity
displayed by pyridazine derivatives is found in the increas-
ing number of papers and patents in the recent years.1
R1
The most common approach to the synthesis of
1,4-dihydropyridazines is the 4+2 cycloaddition of a
suitably substituted olefin with a tetrazine derivative
through the intermediacy of the 4,5-dihydropyridazine
(Scheme 1).2 Han and Ong recently reported a nice
application of tricarbonyl[(1-4-g)-2-methoxy-5-methylene-
cyclohexa-1,3-diene]iron to control the regio- and stereo-
selectivity of a spirocyclic Diels–Alder product.3 Such
methods are limited in that the substituents at the 3 and
6 positions of the product are identical as they originate
from the symmetrical tetrazine.
R1
R1
O
O
O
HN
N
N
R2
R3
R2
R3
i-Pr
O
R4
R4
Scheme 2.
Chiral bicyclic lactams have been demonstrated to be use-
ful and versatile precursors for the enantioselective synthe-
sis of a number of nitrogen heterocycles, enones, diones
and ketoacid molecular structures.5 Among the chiral
non-racemic nitrogen heterocycles produced to date are
the piperidines, pyrrolidines, pyrrolidinones and the tetra-
hydro-isoquinolines.
R1
R2
N
N
R
R1
R
N
N
R2
NH
R
R
N
Phenyl, alkyl, and hydride species have previously been uti-
lized as the bridgehead species on the bicyclic lactam. Pre-
vious conversions to diones have utilized hydrogen and
alkyl lithium species to provide a route to chiral non-race-
mic diones.6 We envisioned that the ability to vary these
fragments would allow for the formation of pyridazines
Scheme 1.
*
Corresponding author. Tel.: +1 562 985 4946; fax: +1 562 985 8557;
e-mail: pbuonora@csulb.edu
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.026

28
P. T. Buonora et al. / Tetrahedron: Asymmetry 19 (2008) 27–30
where the substituents at the 3 and 6 positions may be
varied.
Analysis of the target 1,4-dihydropyridazines 5a–d was
complicated by their air oxidation. 4,5-Unsubstituted,
monosubstituted and vicinal disubstituted dihydropyrida-
zines form pyridazines on exposure to molecular oxygen.
The geminal disubstitution in the compounds produced
in this study 5a–d precluded this reaction but did not pre-
vent other oxygen induced decomposition. The formation
of hydroperoxides and subsequent decomposition of
dihydropyridazines has previously been proposed by Baker
et al.7 By storing the compounds under an argon atmo-
sphere, we found them to be stable for at least six weeks.
2. Results and discussion
The initial phase of the study involved the synthesis of four
chiral a,a-disubstituted-c-diketones (Scheme 3). This was
achieved in a straightforward fashion via the general bicy-
clic lactam protocol developed by Meyers et al.6 The disub-
stituted bicyclic lactams 2a–d were produced in 55–78%
yield from [3.3.0] bicyclic lactam 1 following chromato-
graphic separation from the diastereomer. Treatment of
the bicyclic lactam 2 with an alkyl lithium reagent allows
for the production of the dione, which contains different
groups at the 3- and 6-positions of the final product. In
our case, n-butyl lithium was used to produce the desired
diones 3a–d after hydrolytic workup.
3. Conclusion
The protocol applied demonstrates the potential to synthe-
size differentially substituted chiral 4,4-disubstituted-1,4-
dihydropyridazines, with the advantage of being able to
control the identity of the groups at all substitution
positions.
Ph
Ph
N
Ph
O
O
Me
R
1) LDA, MeI
2) LDA, RX
1) n-BuLi
O
O
4. Experimental
4.1. General
N
1
2) H2O
Me
R
i-Pr
O
i-Pr
O
Bu
a R = Benzyl
b R = Allyl
2a 78% (85% de)
2b 75% (90% de)
2c 55% (83% de)
2d 74% (80% de)
3a 76%
3b 77%
3c 77%
3d 72%
All reactions were carried out under an atmosphere of
nitrogen in oven-dried glassware. Reagents were generally
the best quality commercial grade and used without further
purification unless otherwise indicated. Diisopropylamine
(Aldrich) was distilled and dried according to standard
procedure prior to use. Tetrahydrofuran was distilled from
sodium benzophenone ketyl. The pH 5.0 buffer consisted of
a mixture of 50 mL 0.1 M in potassium hydrogen phthalate
and 22.6 mL of 0.1 M NaOH. TLC was performed using
Whatman PE SIL G/UV 250 lm layer, polyester UV 254
silica gel plates. Radial chromatography was employed
using 1 mm or 2 mm layer rotors with silica gel GF
(ANALTECH). Column chromatography was conducted
c R = iso-Butyl
d R = n-Butyl
Scheme 3.
Diones 3 spontaneously cyclize to enones 4a–d (Scheme 4).
This observation has been taken advantage of previously
by Meyers et al.6 The diones may be stored in pure form
under refrigeration with minimal cyclization. To avoid
the formation of these self-cyclized products, the diones
were submitted to reaction with hydrazine as quickly as
possible to produce the target chiral 4,5-dihydropyrida-
zines. It was anticipated that the 4,5-dihydropyridazines
would rapidly and spontaneously tautomerize to the de-
sired 1,4-dihydropyridazines. The NMR spectra of the
reaction products show only resonances associated with
4,5- and 1,4-dihydropyridazines 5a–d and 6a–d, of which
the latter predominate as over 90% of the mixture.
˚
using 70–230 mesh, 60 A silica gel. Microanalyses were
performed by Quantitative Technologies Inc., Whitehouse,
NJ. Optical rotations were performed on a JASCO P-1010
polarimeter. Melting points are uncorrected. IR (infrared
spectra) were recorded on a Perkin–Elmer 1310 spectro-
meter. 1H and 13C NMR spectra were obtained using
a Bruker AC-250 (250 MHz for 1H and 62.9 MHz for
13C) and Techmag Apollo (400 MHz for 1H and
100 MHz for 13C) as solutions in CDCl3 (Aldrich Chemical
Company; spectra grade). Chemical shifts are reported in d
unit-parts per million (ppm) downfield from tetramethyl
silane (TMS) as the internal reference. Splitting patterns
are designated as s, singlet; br s, broad singlet; d, doublet,
t, triplet; q, quartet.
Ph
Pr
Ph
O
4a R = Benzyl
4b R = Allyl
O
O
4c R = iso-Butyl
4d R = n-Butyl
Me
Me
R
R
Bu
Ph
Ph
Ph
H2NNH2
O
O
N
N
HN
N
4.2. General protocol for a-alkyl-a-methyl bicyclic lactams
2a
Me
R
Me
R
Me
R
Bu
Bu
Bu
To an oven dried 50 mL round-bottom flask, equipped
with a stirring bar and purged with nitrogen, were added
THF (20 mL) and diisopropylamine (0.56 mL, 4.4 mmol).
The solution was cooled to 0 °C in an ice bath and 1.9 M
n-butyl lithium in hexane (2.52 mL, 4.8 mmol) was added
5a
5b
5c
5d
90%
93%
93%
95%
6a
6b
6c
6d
Scheme 4.

P. T. Buonora et al. / Tetrahedron: Asymmetry 19 (2008) 27–30
29
dropwise. After 5 min, the reaction temperature was
lowered to ꢀ78 °C in a dry ice-iso-propanol bath.
(3R,7aR)-Tetrahydro-6-methyl-3-(1-methylethyl)-7a-phenyl-
pyrrolo-[2,1-b]oxazol-5(6H)-one (0.52 g, 2 mmol) in 2 mL
of dry THF was added to the solution. The mixture was
stirred for 2–3 h at ꢀ78 °C, and alkyl iodide (6 mmol)
was added via syringe. The solution was stirred for 4–5 h
at ꢀ78 °C and then the reaction was quenched with 5–
10 mL saturated ammonium chloride aqueous solution.
After warming to room temperature, the mixture was con-
centrated under vacuum and extracted with 3 ꢁ 15 mL of
methylene chloride, dried over anhydrous sodium sulfate,
and concentrated under vacuum. Radial or flash chroma-
tography (1:9, ethyl acetate–hexane) gave pure product,
which was used in the next step.
THF and a 2 mL THF solution of dialkyl bicyclic lactam
(1.0 mmol) were added and the solution cooled to ꢀ78 °C
in the dry ice-isopropanol bath. Then 4.0 mmol of 1.9 M
n-butyl lithium in hexane added. The solution was stirred
for 1–1.5 h at ꢀ78 °C, quenched with 5 mL saturated
ammonium chloride aqueous solution, warmed to room
temperature and concentrated under vacuum. The solution
was extracted with 3 ꢁ 15 mL methylene chloride. The
organic phase was washed with saturated brine and dried
over anhydrous sodium sulfate. Evaporation of the solu-
tion gave an oil residue, which was dissolved in 30 mL of
ethanol and 30 mL of pH 5 buffer, and then heated at
reflux for 24 h. The solution was concentrated under
vacuum to remove the ethanol and extracted with
3 ꢁ 15 mL methylene chloride. The combined methylene
chloride extracts were washed with saturated brine, dried
over anhydrous sodium sulfate and concentrated under
vacuum. The crude products were purified by radial
chromatography (1:9 or 1:19 ethyl acetate–hexane).
4.2.1. (3S,6S,7aS)-Tetrahydro-6-(2-propenyl)-6-methyl-3-(1-
methylethyl)-7a-phenyl-pyrrolo[2,1-b]oxazol-5(6H)-one 2b.
Yield 82%; mp 79–80 °C; IR (CCl4 cmꢀ1) 3060, 2920,
1
1740, 1455, 768, 705; H NMR d 7.48 7.27 (m, 5H), 5.80–
5.63 (m, 1H), 5.13–5.17 (m, 2H), 4.19 (dd, J = 7.89,
8.22 Hz, 1H), 3.69–3.59 (m, 1H), 3.37 (dd, J = 7.72,
8.36 Hz, 1H), 2.61 (d, J = 14.15 Hz, 1H), 2.36 (dd,
J = 6.80, 13.73 Hz, 1H), 2.22 (dd, J = 7.78, 13.74 Hz, 1H),
1.94 (d, J = 14.10 Hz, 1H), 1.29 (s, 3H), 1.19–1.10 (m, 4H),
0.67 (d, J = 6.07 Hz, 3H); 13C NMR d 185.3, 143.4, 133.9,
128.6, 128.0, 125.1, 118.6, 99.6, 70.8, 63.2, 47.2, 46.3, 43.2,
32.6, 25.6, 21.0, 18.7. Anal. Calcd for C19H25NO2: C,
76.21; H, 8.42; N, 4.68. Found: C, 76.51; H, 8.53; N, 4.60.
4.3.1. (3S)-3-Benzyl-3-methyl-1-phenyl-1,4-octanedione 3a.
20:6
Yield 76%; ½aꢂD ¼ ꢀ20:6 (c 2.82, CHCl3) IR (film, cmꢀ1
)
3080, 3045, 2975, 1685, 1600, 1585, 1495, 755, 710. 1H
NMR d 7.90–7.86 (m, 2H), 7.57–7.50 (m, 1H), 7.46–7.39
(m, 3H), 7.30–7.21 (m, 3H), 7.10–7.05 (m, 2H), 3.52 (d,
J = 18.11 Hz, 1H), 3.12 (d, J = 18.11 Hz, 1H), 2.98 (d,
J = 12.94 Hz, 1H), 2.88 (d, J = 12.95 Hz, 1H), 2.67 (ddd,
J = 6.15, 8.56, 18.14 Hz, 1H), 2.21 (ddd, J = 6.10, 8.48,
18.15 Hz, 1H), 1.69–1.48 (m, 2H), 1.36–1.22 (m, 5H),
0.89 (t, J = 7.25 Hz, 3H); 13C NMR d 214.8, 198.1, 136.9,
133.1, 130.4, 128.5, 128.1, 128.0, 126.7, 49.3, 47.9, 45.0,
38.8, 25.5, 22.3, 21.5, 14.0. Anal. Calcd for C22H26O2: C,
81.94; H, 8.13. Found: C, 81.87; H, 8.18.
4.2.2. (3S,6S,7aS)-Tetrahydro-6-methyl-3-(1-methylethyl)-
6-(2-methylpropyl)-7a-phenyl-pyrrolo[2,1-b]oxazol-5(6H)-
20:7
one 2c. Yield 60%, ½aꢂD ¼ þ6:9 (c 1.5, CHCl3) IR (film,
1
cmꢀ1) 3080, 2920, 1740, 1455, 785, 730; H NMR d 7.49–
7.27 (m, 5H), 4.20 (dd, J = 7.69, 8.42 Hz, 1H), 3.69–3.59
(m, 1H), 3.33 (dd, J = 7.76, 8.44 Hz, 1H), 2.66 (d,
J = 14.14 Hz, 1H), 2.02 (d, J = 14.06 Hz, 1H), 1.81–1.78
(m, 1H), 1.67–1.44 (m, 2H), 1.28 (s, 3H), 1.18–1.10 (m,
4H), 0.94 (d, J = 6.57 Hz, 3H), 0.84 (d, J = 6.57 Hz, 3H),
0.67 (d, J = 6.13 Hz, 3H); 13C NMR d 186.1, 143.6,
128.5, 128.0, 125.1, 99.6, 70.8, 63.3, 47.3, 47.1, 46.7, 32.7,
26.7, 24.9, 21.0, 18.7. Anal. Calcd for C20H29NO2: C,
76.14; H, 9.27; N, 4.44. Found: C, 76.25; H, 9.42; N, 4.39.
4.3.2. (3S)-3-Allyl-3-methyl-1-phenyl-1,4-octanedione 3b.
)
20:6
Yield 77%; ½aꢂD ¼ þ36:8 (c 0.7, CHCl3) IR (film, cmꢀ1
3060, 2950, 2920, 2860, 1695, 1680, 1590, 1575, 1440,
1345, 1215, 1000, 910, 750, 685, 1H NMR d 7.94–7.89
(m, 2H), 7.58–7.51 (m, 1H), 7.46–7.40 (m, 2H), 5.81–5.64
(m, 1H), 5.11–5.02 (m, 2H), 3.51 (d, J = 17.99 Hz, 1H),
3.14 (d, J = 17.99 Hz, 1H), 2.69 (ddd, J = 7.28, 7.76,
17.86 Hz, 1H), 2.50 (ddd, J = 7.28, 7.32, 17.87 Hz, 1H),
2.36 (d, J = 7.47 Hz, 2H), 1.68–1.53 (m, 2H), 1.41–1.26
(m, 5H), 0.92 (t, J = 7.23 Hz, 3H); 13C NMR d 214.3,
198.1, 137.1, 133.2, 133.1, 128.5, 128.0, 118.9, 48.6, 47.0,
43.2, 38.0, 25.6, 22.4, 21.7, 14.0. Anal. Calcd for
C18H24O2: C, 79.36, H, 8.88. Found: C, 79.46; H, 9.03.
4.2.3. (3S,6S,7aS)-Tetrahydro-6-butyl-6-methyl-3-(1-methyl-
ethyl)-7a-phenyl-pyrrolo[2,1-b]oxazol-5(6H)-one 2d. Yield
20:6
80%; ½aꢂD ¼ þ4:5 (c 1.7, CHCl3) IR (film, cmꢀ1) 3050,
2950, 1715, 1440, 770, 705; 1H NMR d 7.48–7.27 (m,
5H), 4.19 (dd, J = 7.97, 8.13 Hz, 1H), 3.70–3.59 (m, 1H),
3.35 (dd, J = 7.83, 8.21 Hz, 1H), 2.56 (d, J = 14.15 Hz,
1H), 1.97 (d, J = 14.14 Hz, 1H), 1.63–1.24 (m, 9H), 1.17–
1.02 (m, 4H), 0.89 (t, J = 7.10 Hz, 3H), 0.67 (d,
J = 6.02 Hz, 3H); 13C NMR d 186.0, 143.6, 128.6, 128.0,
125.1, 99.5, 70.8, 63.2, 47.3, 46.7, 38.6, 32.6, 26.6, 26.1,
23.1, 21.0, 18.7, 14.0. Anal. Calcd for C20H29NO2: C,
76.14; H, 9.27; N, 4.44. Found: C, 76.26; H, 9.44; N, 4.41.
4.3.3. (3S)-3-Methyl-3-(20-methylpropyl)-1-phenyl-1,4-octane-
dione 3c. Yield 77%; IR (film, cmꢀ1) 3075, 2975, 1685,
1600, 1585, 1450, 755, 695; 1H NMR d 7.94–7.90 (m,
2H), 7.57–7.50 (m, 1H), 7.47–7.40 (m, 2H), 3.55 (d,
J = 17.83 Hz, 1H), 3.10 (d, J = 17.83 Hz, 1H), 2.71 (ddd,
J = 6.33, 8.43, 17.84 Hz, 1H), 2.50 (ddd, J = 6.44, 8.26,
17.83 Hz, 1H), 1.76–1.46 (m, 4H), 1.41–127 (m, 5H),
0.95–0.88 (m, 9H), 13C NMR d 214.8, 198.2, 137.3, 133.0,
128.5, 127.9, 49.1, 48.7, 47.7, 37.9, 25.8, 25.0, 24.8, 24.3,
22.4, 22.1, 14.0. Anal. Calcd for C19H28O2: C, 79.11; H,
9.78. Found: C, 79.22; H, 9.93.
4.3. General protocol for chiral auxiliary removal as
described for 3-alkyl-3-methyl-1-phenyl-1,4-octane-diones 3
To an oven dried 50 mL round-bottom flask, equipped
with a stirring bar and purged with nitrogen, 20 mL of
4.3.4. (3S)-3-Butyl-3-methyl-1-phenyl-1,4-octanedione 3d.
Yield 72%, IR (film, cmꢀ1) 3070, 2970, 1700, 1680, 1595,

30
P. T. Buonora et al. / Tetrahedron: Asymmetry 19 (2008) 27–30
1
1580, 1445, 750, 690; H NMR d 7.94–7.90 (m, 2H), 7.57–
7.50 (m, 1H), 7.46–7.40 (m, 2H), 3.52 (d, J = 17.84 Hz,
1H), 3.10 (d, J = 17.84 Hz, 1H), 2.71 (ddd, J = 7.27, 7.27,
17.77 Hz, 1H), 2.48 (ddd, J = 7.02, 7.26, 17.76 Hz, 1H),
1.65–1.50 (m, 4H), 1.41–1.15 (m, 9H), 0.95–0.86 (m, 6H);
13C NMR d 214.8, 198.3, 137.2, 133.0, 128.5, 128.0, 48.7,
39.5, 37.8, 26.3, 25.7, 23.3, 22.4, 21.6, 14.0, 13.9. Anal.
Calcd for C19H28O2: C, 79.11; H, 9.78. Found: C, 79.07;
H, 9.80.
7.31 (m, 5H), 6.99 (br, 1H), 4.50 (d, J = 2.06 Hz, 1H),
2.28–2.21 (m, 2H), 1.86–1.70 (m, 1H), 1.67–1.52 (m, 2H),
1.46–1.32 (m, 2H), 1.30–1.14 (m, 5H), 1.12–0.84 (m, 9H);
13C NMR d 150.6, 137.7, 135.5, 128.7, 128.2, 125.0,
101.5, 48.8, 37.5, 30.8, 29.3, 28.0, 25.2, 24.9, 24.2, 22.9,
14.1.
4.4.4. (4S)-3,4-Dibutyl-4-methyl-6-phenyl-1,4-dihydropyrid-
azine 6d. 95% IR (film, cmꢀ1) 3310, 3050, 2950, 1650,
1
1595, 1455, 755, 695. H NMR d 7.45–7.27 (m, 5H), 7.00
4.4. General protocol for 4,4-disubstituted-3-butyl-6-phenyl-
dihydropyridazines 5 and 6
(br, 1H), 4.49 (d, J = 2.08 Hz, 1H), 2.30–2.22 (m, 2H),
1.68–1.51 (m, 2H), 1.48 1.20 (m, 1H), 0.99–0.83 (m, 6H);
13C NMR d 153, 138.3, 135.5, 128.7, 128.3, 125.1, 40.3,
37.3, 30.8, 29.4, 27.2, 26.8, 23.3, 22.8, 14.12, 14.09.
To a 3 mL vial equipped with a stirring bar were added
3-alkyl-3-methyl-1-phenyl-1,4-octanedione (0.2 mmol) and
0.2 mL absolute ethanol. The vial was then purged with
nitrogen and hydrazine monohydrate (1–1.5 mmol) was
added. After being stirred at room temperature for 0.5 h,
the reaction solution was refluxed for 12 h, cooled to room
temperature, and concentrated under vacuum. This gave a
yellow oil, which was not further purified because of its
sensitivity to air. Usually, dihydropyridazines having alkyl
or aryl substituents in the ring at the 3- and 6-positions
exist in solution in an equilibrium between the 1,4-dihydro
and 4,5-dihydro tautomers. The resonances of the 1,4-
dihydropyridazine compounds predominate in the NMR
spectra. The clearly observable resonance are noted below.
Acknowledgments
P.T.B. and Q.Z. gratefully acknowledge the support of the
Robert A. Welch Foundation and the Department of
Chemistry, Lamar University-Beaumont, Beaumont,
Texas, where this work was begun. The authors also thank
the Departments of Chemistry at Knox College, Lamar
University, the University of Scranton, and the California
State University—Long Beach for resources and support.8
References
4.4.1. (4S)-4-Benzyl-3-butyl-4-methyl-6-phenyl-1,4-dihydro-
pyridazine 6a. 90% IR (film, cmꢀ1) 3320 (br), 3060, 3025,
2960, 1595, 1450, 750, 700; H NMR d 7.49–7.12 (m, 1H),
4.47 (d, J = 2.36 Hz, 1H), 2.75 (d, J = 12.72 Hz, 1H), 2.61
(d, J = 12.72 Hz, 1H), 2.26–2.20 (m, 2H), 1.73–1.64 (m,
2H), 1.50–1.35 (m, 2H), 1.32 (s, 3H), 1.00 (t, J = 7.25 Hz,
3H); 13C NMR d 149.7, 139.1, 137.3, 135.2, 130.7, 128.8,
128.4, 127.6, 126.1, 125.3, 99.8, 43.0, 38.6, 31.4, 29.1,
24.5, 22.8, 14.1.
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4.4.2. (4S)-4-Allyl-3-butyl-4-methyl-6-phenyl-1,4-dihydro-
pyridazine 6b. 93% IR (film, cmꢀ1) 3310 (br), 3060,
2950, 1635, 1585, 1460, 755, 695; H NMR d 7.47–7.31
3. Han, J. L.; Ong, C. W. Tetrahedron 2006, 62, 8169.
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Lett. 1985, 26, 2047; (c) Meyers, A. I.; Westrum, L. J.
Tetrahedron Lett. 1993, 34, 7701; (d) Hughes, R. C.; Dvorak,
C. A.; Meyers, A. I. J. Org. Chem. 2001, 66, 5545.
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(m, 5H), 7.16 (br, 1H), 5.93–5.77 (m, 1H), 5.08–5.00 (m,
2H), 4.53–4.52 (d, J = 2.22 Hz, 1H), 2.31 2.20 (m, 2H),
2.15–1.95 (m, 2H), 1.67–1.53 (m, 2H), 1.50–1.31 (m, 2H),
1.22 (s, 3H), 0.95 (t, J = 7.25 Hz, 3H); 13C NMR d 149.5,
138.7, 135.0, 134.3, 128.6, 128.2, 125.1, 117.4, 99.9, 43.6,
37.1, 30.9, 29.1, 25.2, 22.7, 13.9.
4.4.3. (4S)-3-Butyl-4-methyl-4-(20-methyl)-propyl-6-phenyl-
1,4-dihydropyridazine 6c. 93% IR (film, cmꢀ1) 3310,
8. This work includes results from the MS Thesis of Qun Zhang
and the BS Thesis of Jennifer Sawko.
1
3050, 2940, 1650, 1595, 1455, 755, 695; H NMR d 7.44–