Preparation of hydroxy-substituted hexahydrophthalazinones from cyclohexane- and norbornanelactones or ketallactones

Article abstract of DOI:10.1007/s007060200001

Cyclohexane- and norbomanelactones (1, 5) as well as ketallactones (3, 7) and their hydrolytic products (2, 4a,b, 8) react with hydrazine hydrate to yield the hydroxy-substituted hexahydrophthalazinones 9-12. In the cyclizations, the configurations of the

Full text of DOI:10.1007/s007060200001

Monatshefte fuÈr Chemie 133, 241±248 ꢀ2002)
Preparation of Hydroxy-Substituted
Hexahydrophthalazinones from Cyclohexane-
and Norbornanelactones or Ketallactones
2;Ã
2
1;Ã
     Â
Jozsef A. Szabo ,Pa l Sohar ,Antal Csa mpai , and Geza Stajer
Â1
1
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, Hungary
2
Research Group for Structural Chemistry and Spectroscopy, Hungarian Academy of Sciences ±
 
 Â
 
Eotvos Lorand University and Department of General and Inorganic Chemistry, Eotvos Lorand
University, H-1518 Budapest, Hungary
Summary. Cyclohexane- and norbornanelactones ꢀ1, 5) as well as ketallactones ꢀ3, 7) and their
hydrolytic products ꢀ2, 4a,b, 8) react with hydrazine hydrate to yield the hydroxy-substituted
hexahydrophthalazinones 9±12. In the cyclizations, the con®gurations of the bridgehead atoms remain
unaltered, and the hydroxy group retains its original position in the hydrazinolysis of 5 and 7. The
compounds were characterized by IR, 1H, and 13C NMR spectroscopy.
Keywords. Amino acids; Heterocycles; Ketones; Phthalazinones; Hydrazinolysis.
Introduction
No simple method for the preparation of 2-substituted 4- or 5-hydroxycyclo-
hexane- or -norbornanecarboxylic acids has been described in the literature. One of
the known procedures applies electrophilic addition to substituted cis- or trans-4-
cyclohexenecarboxylic acids followed by lactonization and elimination of the
undesired group [1±4]. Another route is the Baeyer-Villiger oxidation of 2-endo-
substituted norbornane-7-ones with m-chloroperbenzoic acid which results in two
isomeric lactones; however, separation of these has not been satisfactorily achieved
on a preparative scale [5]. 2-Aroylcyclohexane derivatives yield suitable products
upon reaction with aryllithium; the oxo or hydroxy functions have to be in-
corporated in subsequent steps in this case [6, 7].
By employing Friedel-Crafts reactions, we recently have devised a new and sim-
ple method for the transannular hydroxylation of aroylcyclohexane- and norbornane-
carboxylic acids. The aroyllactones and ketallactones prepared this way [8] seemed
to be suitable starting compounds for the above functionalized cyclohexane- and
norbornanehydroxy derivatives. As the lactones can be viewed as precursors of the
ꢀ-oxo-cycloalkanecarboxylic acids, they were also used for the preparation of cy-
cloalkane-condensed dihydropyridazinones or their methylene-bridged derivatives.
Ã
Corresponding author. E-mail: stajer@pharma.szote.u-szeged.hu

ꢀ
J. A. Szabo et al.
242
Results and Discussion
In neutral or acidic ethanolic solution, lactone 1 does not undergo hydrolysis. Treat-
ment of 1 in ethanol with aqueous NaOH followed by acidi®cation affords
the 2t-aroyl-5c-hydroxy-1r-cyclohexanecarboxylic acid 2 ꢀScheme 1); in deut-
eriochloroform, 2 exists predominantly as the more stable conformer containing
equatorial carboxyl, aroyl, and hydroxy groups.
Scheme 1. a: EtOH=H2O, b: NaOH=H2O, c: HCl=H2O, d: H2NNH2 Á H2O; Ar ˆ p-tolyl
On warming to 80ꢀC in aqueous ethanol, 3 readily hydrolyses to 2c-aroyl-4c-
hydroxy-1r-cyclohexanecarboxylic acid ꢀ4a), all three substituted carbons retain-
ing their original con®guration ꢀScheme 2). In CDCl3 at room temperature, NMR
measurements show a predominant conformation of 4a with axial carboxyl and
equatorial aroyl and hydroxy groups. Upon standing at room temperature or
Scheme 2. a: EtOH=H2O, b: NaOH=H2O, c: HCl=H2O, d: H2NNH2 Á H2O; Ar ˆ p-tolyl

Synthesis of Hydroxylated Hexahydrophthalazinones
243
warming in EtOAc, 4a quickly recycles to ketallactone 3. However, hydrolysis
with base results in 2t-aroyl-4c-hydroxy-1r-cyclohexanecarboxylic acid 4b with
axial hydroxy and equatorial aroyl and carboxyl groups.
Similar to 1, lactone 5 does not undergo hydrolysis in aqueous ethanol
ꢀScheme 3). In the presence of acid, 5 isomerizes to 6 which contains an exo aroyl
group. In basic solution, the lactone opens to the aroylhydroxycarboxylate ꢀin
which both the hydroxy and the carboxylate groups are endo and the aroyl group is
presumably exo); acidi®cation leads to the exo aroyl compound 6 [8]. These
examples illustrate the facile endo ! exo isomerization of the aroyl group at the
norbornane skeleton.
Scheme 3. a: EtOH=H2O, b: NaOH=H2O, c: HCl=H2O, d: H2NNH2 Á H2O; Ar ˆ p-tolyl
Unlike 3, ketallactone 7 does not undergo hydrolysis in neutral aqueous eth-
anolic solution, even on warming ꢀ80ꢀC) for a prolonged time ꢀ10 h). Under basic
conditions, 7 furnishes 8 in which both the hydroxy and carboxyl groups retain their
original endo positions, but the aroyl group has been isomerized from endo to exo.
With hydrazine, lactones 1 and 5 and ketallactones 3 and 7 react analogously
to ꢀ-oxo-carboxylic acids to furnish pyridazinones [9±13]. As the position of the
hydroxy group in the products may be questionable, both lactones and hydrolytic
products were applied in the reactions ꢀthe latter only when the steric positions of
the carboxyl and oxo groups allows cyclization).
With hydrazine hydrate in ethanol, both lactone 1 and 2t-aroyl-5c-hydroxy-1r-
cyclohexanecarboxylic acid ꢀ2) react. The reaction of 1 yields phthalazinone 9a
containing a cis-condensed hetero ring and a 7-cis-hydroxy group in an equatorial
position. The reaction of 2 results in 9b with a diequatorial trans-condensed hetero
ring and the hydroxy group in the cis-equatorial position to the lactam carbon
bond. With hydrazine, ketallactone 3 and its hydrolysis product 4a give the same
phthalazinone 10a in which the rings are cis-annelated with axial carbonyl and
equatorial CˆN groups. The hydroxy group is cis-oriented with respect to the
carbonyl group and hence occupies an equatorial position. However, 4b gives the
diequatorial trans-fused compound 10b with an axial hydroxy group.

ꢀ
J. A. Szabo et al.
244
On hydrazinolysis, both norbornane lactone 5 and ketallactone 7 lead to
methylene-bridged di-endo-fused phthalazinones 11 and 12 in which the hydroxy
group occupies an endo-orientation.
Structure determination
The spectroscopic data1 ꢀTables 1±3) shed light on the spatial structures of the new
compounds. Whereas all three substituents on the cyclohexane ring are equatorial
in 2, one of them ꢀthe carboxyl group in 4a and the hydroxy group in 4b) becomes
axial in 4a,b. Due to the more strained structures in 4a,b, the sums of the carbon
chemical shifts of the cyclohexane ring in these compounds is signi®cantly smaller
ꢀ245.9 and 242.9 ppm, respectively) than that for 2 ꢀ261.3 ppm) [14a].
For 4b, the equatorial orientation of H-6 follows from the higher chemical shift
ꢀ3.87 ppm) as compared with that of H-6 in 4a ꢀ3.69 ppm) and that of H-7 in 2
ꢀꢁ3.4 ppm). The 1,3-diaxial interactions with the hydroxy group are revealed in
the up®eld shifts of the signals of C-4a and C-8 relative to the corresponding posi-
tions in 2 ꢀC-8a,5) and 4a ꢀC-4a,8) by 2.9 and 4.8 ppm ꢀ2) and 3.9 and 1.3 ꢀ4a),
respectively, and are caused by the steric compression shift ꢀ®eld effect [14b, 15]).
Similarly, the axial position of the carboxyl group in 4a is obvious from the
down®eld shift of the signal of the equatorial H-8a atom ꢀ2.90 ppm; 2.68 and
2.59 ppm for 2 and 4b) and from the small splittings ꢀquartet, 4.1 Hz) of this signal,
thus excluding diaxial-type couplings [16, 17]. The ®eld effects on the C-7,8a
signals are 4.8 and 3.2 ppm as compared to 4b.
The same principles were used to determine the stereostructures of the further
compounds. Additionally, it is to be noted that the sum of the chemical shifts of the
cyclohexane carbons of 9a and 9b differ signi®cantly ꢀ224.3 and 244.5 ppm)
because of the strained cis-annelation in 9a leading to up®eld shifts of the lines in
question. The difference in the annelation in 10a,b, however, is not re¯ected in a
similar way ꢀthe sum of the shifts are 227.3 and 226.5 ppm) because the sterically
more favourable trans-annelation in 10b is compensated by the 1,3-diaxial in-
teractions of the hydroxy group which is equatorial in 10a. Consequently, the ®eld
effect of different origin in 10b on the one hand and in 9a and 10a on the other is
manifested in similar up®eld shifts of the cyclohexane carbon lines for both
isomers 10a,b as well as for 9a. The anisotropy of the carbonyl group [14c] in the
1,3-diaxial position leads to a signi®cant down®eld shift of the H-7 signal in 9a
ꢀ3.92 ppm; 9b: 3.30 ppm).
The di-endo annelation of the hetero ring and the norbornane moiety is shown by
the double doublet splittings of the signals of the annelational hydrogens 4a,8a in 11
and 12 in accordance with earlier ®ndings [18, 19] due to the signi®cant H-4a,5 and
H-8,8a couplings ꢀin contrast to the di-exo analogues where these couplings are
insigni®cant and only the H-4a,8a interaction leads to doublet splittings of the H-
4a,8a signals). In the exo-endo-type 8, the hydrogen on the endo-substituted C-8a
gives a ddd signal, whereas the signal of H-4a attached to the exo-substituted carbon
appears as a doublet.
1
For comparison of the analogous data, the numbering of 9a and 10a ꢀScheme 1 and 2) was applied

Synthesis of Hydroxylated Hexahydrophthalazinones
245

ꢀ
J. A. Szabo et al.
246
Table 3. Characteristic IR frequencies ꢀcmÀ1) of compounds 2, 4a,b, 8, 9a,b, 10a,b, 11, and 12 ꢀKBr
pellets)
ꢃꢀOH) band
ꢀsharp)a
ꢃꢀOH) or ꢃꢀNH) band
ꢀbroad or diffuse)b
ꢃꢀCˆX)
ꢃꢀCˆO) or
ꢀꢀCArH)
bandd
bandc
amide-I band
2
3450
3420
3365
3376
3500
3478
3460
3320
3471
3404
3400±2500
3400±2500
3400±2500
3400±2500
3225
1702
1701
1733
1697
1613
1614
1669
1678
1655
1670
1672
1683
1659
1674
1669
1645
820
4a
4b
8
812
822
824
9a
9b
10a
10b
11
12
835, 819
816
3237
3245
822
3195
823
3203
1619
1622
831
3250
825
a
ꢃꢀOH) band of the alcohol group; b carboxylic OH group for 2, 4a,b, and 8, ꢃꢀNH) band for 9a,b,
10a,b, 11, and 12; c ꢃꢀCˆO) band ꢀXˆO) for 2, 4a,b, and 8, ꢃꢀCˆN) band ꢀXˆN) for 9a,b, 10a,b, 11,
d
and 12; split band for 9a
NOE measurements [14d, 20] on 12 demonstrated the endo-position of the
hydroxy group. Irradiation of H-6 caused an enhancement of the intensity of H-9-
exo at 1.27 ppm. For the endo-counterpart, the doublet of the latter hydrogen
responded in another NOE experiment when the H-4a signal was saturated. This is
a direct proof of the di-endo-annelation of the hetero ring and the norbornane
skeleton. The anisotropy of the close-lying benzene ring [14e] is seen in an up®eld
shift of the hydroxy signal for 12 ꢀ4.32 ppm; 11: 4.70 ppm).
Experimental
IR spectra were determined in KBr discs on a Bruker IFS-55 FT-spectrometer controlled by Opus 2.0
software. 1H and 13C NMR spectra were recorded in CDCl3 solution in 5 mm tubes at room
temperature on a Bruker DRX-500 FT spectrometer at 500 ꢀ1H) and 126 ꢀ13C) MHz, respectively,
using the deuterium signal of the solvent as the lock and TMS as internal standard. DEPT spectra were
run in a standard way, using only the ꢂ ˆ 135ꢀ pulse to separate the CH=CH3 and CH2 lines phased up
and down, respectively. For NOE difference, COSY, HMQC, and HMBC measurements, the standard
Bruker pulse programs were used. The results of elemental analyses agreed satisfactorily with the
calculated values.
5c-Hydroxy-2t-p-toluoyl-1r-cyclohexanecarboxylic acid ꢀ2; C15H18O4)
A solution of 3.0 g lactone 1 [8] in a mixture of 3.0 g KOH and 30 cm3 MeOH was re¯uxed for 1 h
and then evaporated to dryness. The residue was dissolved in 50 cm3 H2O and acidi®ed with 36%
HCl to pH 3. The separated solid was ®ltered off by suction, washed with 20 cm3 H2O, and dried to
give 2.5 g product ꢀ78%) which was crystallized from n-hexane±acetone. M.p.: 115±118ꢀC.
4c-Hydroxy-2c-p-toluoyl-1r-cyclohexanecarboxylic acid ꢀ4a; C15H18O4)
A solution of 1.5 g 3 [8] in a mixture of 50 cm3 EtOH and 20 cm3 H2O was re¯uxed for 4 h. After
evaporation to dryness, the residue was crystallized from EtOAc to give 1.04 g ꢀ65%) 4a. M.p.:
159±162ꢀC.

Synthesis of Hydroxylated Hexahydrophthalazinones
247
4c-Hydroxy-2t-p-toluoyl-1r-cyclohexanecarboxylic acid ꢀ4b; C15H18O4)
A mixture of 2.0 g 3 and 1.0 g KOH in 10 cm3 MeOH was warmed at 80ꢀC for 1 h, cooled, acidi®ed
to pH 4 by dropwise addition of 36% HCl, and evaporated to dryness. The residue was suspended in
10 cm3 H2O, and the solid ꢀ1.92 g, 89%) was ®ltered off by suction, washed with 5 cm3 H2O, dried,
and crystallized from EtOAc. M.p.: 172±173ꢀC.
5-endo-Hydroxy-3-exo-p-toluoylbicyclo[2.2.1]heptane-2-endo-carboxylic acid ꢀ8; C16H18O4)
A solution of 0.1 g 7 [8] in a mixture of 0.1 g KOH and 5 cm3 MeOH was re¯uxed for 1 h and
evaporated to dryness. The residue was dissolved in 2 cm3 H2O and acidi®ed to pH 3 by dropwise
addition of 36% HCl. After ®ltration by suction, the solid ꢀ0.08 g, 75%) was washed with 3 cm3 H2O,
dried, and crystallized from EtOAc. M.p.: 193±195ꢀC.
General procedure for the preparation of 9a,b, 10a,b, 11, and 12
A mixture of lactone, ketallactone, or their hydrolysis products ꢀg) in MeOH ꢀcm3) was re¯uxed for
2 h with 90% N2H4 Á H2O ꢀg) ꢀ1: 1.2 g, 20 cm3, 1.3 g; 2: 0.65 g, 10 cm3, 0.5 g; 3: 1.2 g, 20 cm3, 1.2 g;
4a: 0.9 g, 15 cm3, 0.4 g; 4b: 0.41 g, 5 cm3, 0.4 g; 5: 0.61 g, 10 cm3, 0.6 g; 7: 0.55 g, 10 cm3, 0.8 g).
After evaporation, 15 cm3 H2O was added to the residue, and the solid was ®ltered off by suction,
washed with water, dried, and crystallized.
7c-Hydroxy-4-p-tolyl-4ar,5,6,7,8,8ac-hexahydrophthalazin-112H)-one ꢀ9a; C15H18N2O2)
Yield: 0.9 g ꢀ71%); m.p.: 221±223ꢀC ꢀMeOH).
7c-Hydroxy-4-p-tolyl-4ar,5,6,7,8,8at-hexahydrophthalazin-112H)-one ꢀ9b; C15H18N2O2)
Yield: 0.5 g ꢀ78%); m.p.: 218±220ꢀC ꢀMeOH).
6c-Hydroxy-4-p-tolyl-4ar,5,6,7,8,8at-hexahydrophthalazin-112H)-one ꢀ10a; C15H18N2O2)
From 3: yield: 1 g ꢀ79%); from 4a: yield: 0.77 g ꢀ87%), m.p.: 233±235ꢀC ꢀMeOH).
6c-Hydroxy-4-p-tolyl-4ar,5,6,7,8,8at-hexahydrophthalazin-112H)-one ꢀ10b; C15H18N2O2)
Yield: 0.35 g ꢀ88%); m.p.: 207±208ꢀC ꢀEtOH).
7-endo-Hydroxy-5t,8t-methano-4-p-tolyl-4ar,5,6,7,8,8ac-hexahydrophthalazin-112H)-one
ꢀ11; C16H18N2O2)
Yield: 0.42 g ꢀ66%); m.p.: 288±291ꢀC ꢀEtOH).
6-endo-Hydroxy-5t,8t-methano-4-p-tolyl-4ar,5,6,7,8,8ac-hexahydrophthalazin-112H)-one
ꢀ12; C16H18N2O2)
Yield: 0.40 g ꢀ69%); m.p.: 258±260ꢀC ꢀEtOH).
Acknowledgements
Â
The authors are indebted to Mrs. Csiszar-Makra for the typing of the manuscript. Grants: OTKA
T 25415, OTKA T 29651, and FKFP-0200=2000.

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J. A. Szabo et al.: Synthesis of Hydroxylated Hexahydrophthalazinones
248
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Received September 3, 2001. Accepted October 8, 2001