Enaminones as building blocks in heterocyclic syntheses: Reinvestigating the product structures of enaminones with malononitrile. A novel route to 6-substituted-3-oxo-2,3-dihydropyridazine-4-carboxylic acids

Article abstract of DOI:10.3390/molecules14010068

The reported structures of reaction products of enaminones with malononitrile in ethanolic piperidine are revised. A novel route to 2,3-dihydropyridazine-4-carboxylic acids 4a-c via reactions of 2-cyano-5-(dimethylamino)-5-arylpenta-2,4-dienamides 8a-c wi

Full text of DOI:10.3390/molecules14010068

Molecules 2009, 14, 68-77; doi:10.3390/molecules14010068
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Enaminones as Building Blocks in Heterocyclic Syntheses:
Reinvestigating the Product Structures of Enaminones with
Malononitrile. A Novel Route to 6-Substituted-3-Oxo-2,3-
Dihydropyridazine-4-Carboxylic Acids
1
1
Abdul-aziz Alnajjar , Mervat Mohammed Abdelkhalik 1,*, Amal Al-Enezi and Mohamed
Hilmy Elnagdi 2
1
Applied Science Department, College of Technological Studies, Public Authority for Applied
Education and Training, P. O. Box 42325 Safat, 70654, Kuwait
2
Chemistry Department, Kuwait University, P.O. Box 5969 Safat, 13060, Kuwait
* Author to whom correspondence should be addressed; E-mail: mervatak@yahoo.com.
Received: 16 November 2008; in revised form: 15 December 2008 / Accepted: 17 December 2008 /
Published: 29 December 2008
Abstract: The reported structures of reaction products of enaminones with malononitrile
in ethanolic piperidine are revised. A novel route to 2,3-dihydropyridazine-4-carboxylic
acids 4a-c via reactions of 2-cyano-5-(dimethylamino)-5-arylpenta-2,4-dienamides 8a-c
with nitrous acid or with benzenediazonium chloride is reported. Compounds 8a-c are
converted to 1,2-dihydropyridine-3-carboxylic acid and 1,2-dihydropyridine-3-carbonitrile
derivatives upon reflux in EtOH/ HCl and in AcOH.
Keywords: Enaminones; 2-Cyano-5-(dimethylamino)-5-arylpenta-2,4-dienamide; DEPT;
Experiments; X-ray crystal structure.
Introduction
Enaminones are polydentate reagents that have been utilized extensively in this decade as building
blocks in organic synthesis [1-6]. In previous work at our laboratories, we reported several efficient
routes to polyfunctionally substituted heterocycles utilizing enaminones as starting materials [7-11].
We have also reported that the reaction of 1a with malononitrile in ethanolic sodium ethoxide afforded

Molecules 2009, 14
69
2a in good yield [12], while reacting 1a-c with malononitrile in ethanolic piperidine was believed to
afford 3a-c [13] (cf. Scheme 1). In continuation to this work, the chemical reactivity of the products
believed to be 3a-c was reinvestigated. The work has led us to revise the initially proposed structures
of these products.
Scheme 1. Reported structures for the products of reaction of enaminones 1a-c and malononitrile.
OEt
CN
NaOEt
N
O
R
NC
R
2a
CONH2
CH2(CN)2
+
R
NMe2
1a, R = Ph
b, R = 2-Furyl
c, R = 2-Thienyl
EtOH/
Piperidine
NMe2
3a-c
Results and Discussion
The reaction of 1a-c with malononitrile in ethanolic piperidine afforded products of molecular
formulae corresponding to the formation of 1:1 adducts. As reported earlier [13], the reaction products
1
showed in the H-NMR spectrum, in addition of the dimethylamino moiety, two olefinic proton
doublets at δH = ca. 5.77 and 7.23 ppm with J = 13 Hz, which fits well with the previously assumed
initial 1,2-addition of malononitrile at the carbonyl moiety. Subsequent water elimination and
hydrolysis of one of the cyano groups into an amide yielded 3a-c. However, treating these reaction
products with sodium nitrite in EtOH/HCl in presence of sodium acetate affords products for which
structures 4a-c are assigned, based on X-ray crystal structure determination [14]. Although the
described conditions may not normally lead to hydrolysis of nitriles, however a ready hydrolysis in this
case may be prompted by the stabilization of products by potential hydrogen bonding and high
reactivity of the nitrile group as part of a π-deficient system. Quite unexpectedly, coupling the
products, obtained from the reaction of malononitrile with enaminones 1a-c, with benzenediazonium
chloride in dioxane/AcONa resulted in the formation of the same products 4a-c, in good yields.
There is indication of extensive delocalization of N-1 lone-pair at carbonyl carbon. Thus N-3 bond
angles are more like those of sp2 nitrogen, while those of N-7-C10-C8 are more like sp3 carbon (cf.
Figure 1 and Table 1).

Molecules 2009, 14
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Figure 1. X-Ray crystal structure of 4b.
O
O
O
R
OH
N
N
H
4a, R = Ph
b, R = 2-Furyl
c, R = 2-Thienyl
Table 1. Selected bond lengths and angles for compound 4b.
Bond
Bond length Ao
1.224 (4)
Bond
Bond angle
122.5 (3)
116.6 (3)
114.6 (4)
O2-C14
N3-N7
N7-N3-C14
N3-N7-C10
N7-C10-C8
1.390 (3)
N3-C14
C6-C14
N7-C10
1.357 (4)
1.447 (5)
1.306 (4)
Disconnection of 4a-c and consideration of the reported data has led us to believe that the products
initially thought to be 3a-c are in fact 8a-c, which are formed via initial 1,4-addition of malononitrile
across the double bond to yield 5 that cyclized to 6 then rearranged to 7, that finally afforded 8 via an
allowed 1,3-nitrogen shift (cf. Scheme 2). However, a possible conversion of 3 to 8 involving
migration of R via a 1,3 shift should not be overlooked. We wish to state that both 8 and 3 have the
same molecular formulae and same spectral data, which after further inspection, established the
structures 8a-c. Thus, assuming that H-4 are shielded by nitrogen lone pair anisotropic effect, while H-
3 are deshielded by electron attracting substituents; it is hence logic to assign the doublets at δH = ca.
5.68 ppm to H-4, while the doublets at δH = ca. 7.39 ppm would correspond to H-3. If the reaction
products were 3a-c, then H-4 in these assumed structures are shielded and H-5 are deshielded. We note
that the deshielded doublet for 8a at δH = ca. 7.39 ppm are correlated in the HMBC experiments with
the amide carbonyl group at δC = ca. 164.90 ppm. If the reaction product was 3a, such a correlation
should not exist. Moreover, the methyl protons at δH = ca. 2.99 ppm show a cross peak correlation with
C-5 at δC = ca. 157.93 ppm. This carbon was proven by DEPT experiments to be quaternary, consistent
with structure 8a. If, on the other hand, the reaction product were 3a, then the methyl protons should
be correlated with a carbon bearing a proton.

Molecules 2009, 14
Scheme 2. Proposed mechanism for the formation of 2-cyano-5-(dimethylamino)-5-aryl-
71
penta-2,4-dienamides 8a-c.
NC
R
CONH2
O
NMe2
CH2(CN)2
NMe2
3a-c
R
NH2
EtOH/
Piperidine
NC
CN
1a, R = Ph
CN
O
b, R = 2-Furyl
c, R = 2-Thienyl
O
R
NMe2
R
NMe2
6
5
1,3-shift
NH2
NMe2
CN
O
CN
R
R
CONH2
Me2N
8a-c
7
Scheme 3. Proposed mechanism for the nitrozation and coupling reactions of 2-cyano-5-
(dimethylamino)-5-phenylpenta-2,4-dienamides 8a-c.
NMe
Cl
2
NMe2
NaNO2/HCl
CONH2
CN
R
R
or PhN NCl
N
CN
CONH2
HX
8a-c
9
X = O; NPh
O
O
O
COOH
O
CONH2
COOH
O
R
O
X
R
H2O
N
H2N
N
HX
R
N
H
N
4a, R = Ph
10
11
b, R = 2-Furyl
c, R = 2-Thienyl

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Consequently, a plausible mechanism for the formation of compounds 4a-c is illustrated in Scheme
3. It is assumed that the initially formed 9 is subject to an intramolecular cyclization to 10, which is
further hydrolysed into 11 under the reaction conditions. Finally, the lone pairs on the amide nitrogen
then react with the oxime nitrogen or the hydrazone nitrogen kicking out either a water molecule or
aniline, thus producing 4a-c. To our knowledge, this is the first reported cyclization via aniline
elimination in such a system. It is worth mentioning that condensing 3-aroyl-2-(2-
phenylhydrazono)propanals 12a,b with cyanoacetamide has been reported to yield the 2,3-
dihydropyridazine-4-carboxamides 14a,b [15] (cf. Scheme 4).
Scheme 4. Reported synthesis of 2,3-dihydropyridazine-4-carboxamides 14a,b from the
condensation of arylhydrazonals 12a,b with cyanoacetamide.
CN
O
O
O
CH2
CHO
CN
PhN NCl
CONH2
R
O
R
R
NMe2
N
N
CONH2
1a,b
NHPh
NHPh
12a,b
13a,b
CONH2
NH
R
N
N
Ph
14a,b
Conversions of 8a-c into nicotinic acid derivatives 15a-c were achieved by boiling in EtOH/HCl.
When however compounds 8a-c are heated under reflux in AcOH, nicotinic nitrile derivatives 16a-c
are obtained (cf. Scheme 5).
Scheme 5. Synthesis of 1,2-dihydropyridine-3-carboxylic acids 15a-c and 1,2-
dihydropyridine-3-carbonitriles 16a-c.
COOH
EtOH/HCl
NMe2
R
R
N
O
H
CN
15
R
CONH2
CN
O
AcOH
8a-c
N
H
16

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It has been reported earlier [16] that hydrolysis of 18 obtained via condensation of 17 with
dimethylformamide dimethylacetal afforded the pyridone derivatives 19. We have repeated this
experiment and came to the conclusion that hydrolysis of 18 in KOH affords in fact isomeric pyridone
19, which in turn gives spectra very similar to those of 16. Indeed, the mixed m.p. of the two products
proves that they are different (cf. Scheme 6).
Scheme 6. Reported synthesis of isomeric pyridones 13a-c.
O
NC
R
CN
Me
NC
R
CN
NC
R
KOH
DMF DMA
NH
NMe2
17a, R = Ph
18
19
b, R = 2-Furyl
c, R = 2-Thienyl
Conclusions
We are now able to correct a previously reported initial 1,2-addition of malononitrile at the carbonyl
moiety of enaminones 1a-c and suggest instead the novel compounds 8a-c as precursors for syntheses
of pyridazinones and pyridones derivatives.
Experimental
General
Melting points were determined on a Shimadzu-Gallenkamp apparatus and are uncorrected.
Elemental analyses were obtained by means of a LECO CHNS-932 Elemental Analyzer. NMR spectra
were measured in DMSO-d6 using a Bruker DPX 400 MHz superconducting spectrometer; HMQC,
DEPT and NOE spectra were measured using Bruker Avance II 600 MHz superconducting
spectrometer, and FT-IR measurements were from a Perkin Elmer 2000 FT-IR system. Mass
spectrometric analysis was carried out on a VG-Autospec-Q high performance tri-sector GC/MS/MS.
General procedure for the preparation of compounds 8a-c
A mixture of equimolecular amounts of each of enaminones 1a-c (10 mmol) and malononitrile (10
mmol, 066 g) in EtOH (10 mL) was refluxed for 1 hr in the presence of few drops of piperidine. Upon
cooling to r.t. a solid product precipitated, which was collected by filtration and crystallized from
dioxane.
2-Cyano-5-(dimethylamino)-5-phenylpenta-2,4-dienamide (8a): Yellow crystals, yield (72 %, 1.77 g);
mp 257-258 oC; IR (cm-1): 3435 and 3334 (NH2), 2195 (CN) and 1666 cm-1 (CO); MS m/z (M)+ = 241;
1H-NMR: δ = 2.78 (s, 3H, NCH3), 3.14 (s, 3H, NCH3), 5.64 (d, 1H, J = 12.8 Hz, H-4), 6.82 (s, 2H,

Molecules 2009, 14
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NH2), 7.13 (d, 1H, J = 12.8 Hz, H-3), 7.25-7.28 (m, 2H, phenyl-H), 7.34-7.65 (m, 3H, phenyl-H); 13C-
NMR: δ = 165.08 (CONH2), 164.59 (C-5), 153.27 (C-3), 133.99, 129.56, 128.76, 128.72, 118.90,
96.91, 87.57, 41.92 (N(CH3)2); Anal. calcd. for C14H15N3O: (241.12): C, 69.69; H, 6.27; N, 17.41.
Found: C, 69.55; H, 6.07; N, 17.29.
2-Cyano-5-(dimethylamino)-5-(furan-2-yl)penta-2,4-dienamide (8b): Brownish red crystals, yield (75
%, 1.73 g); mp 245-246 oC; IR (cm-1): 3331 and 3292 (NH2), 2190 (CN) and 1671 cm-1 (CO); MS m/z
(M)+ = 231; 1H-NMR: δ = 2.97 (s, 6H, N(CH3)2), 5.59 (d, 1H, J = 12.5 Hz, H-4), 6.72 (d, 1H, J = 5.0
Hz, furyl H-3), 6.78 (d, 1H, J = 5.0 Hz, furyl H-5), 7.02 (s, 2H, NH2), 7.56 (d, 1H, J = 12.5 Hz, H-3),
13
7.99 (t, 1H, J = 5.0 Hz, furyl H-4); C-NMR: δ = 164.49 (CONH2), 153.40 (C-5), 151.73, 145.37,
144.80, 118.38, 115.75, 111.53, 98.31, 90.40, 40.77; Anal. calcd. for C12H13N3O2: (231.10): C, 62.33;
H, 5.67; N, 18.17. Found: C, 61.97; H, 5.61; N, 18.21.
2-Cyano-5-(dimethylamino)-5-(thiophen-2-yl)penta-2,4-dienamide (8c): Yellow crystals, yield (72 %,
o
1.77 g); mp 258-259 C; IR (cm-1): 3403 and 3328 (NH2), 2196 (CN) and 1669 cm-1 (CO); MS m/z
1
(M)+ = 247; H-NMR: δ = 2.99 (s, 6H, N(CH3)2), 5.68 (d, 1H, J = 12.5 Hz, H-4), 6.94 (s, 2H, NH2),
7.18 (d, 1H, J = 5.0 Hz, thienyl H-3), 7.23 (t, 1H, J = 5.0 Hz, thienyl H-4), 7.39 (d, 1H, J = 12.5 Hz,
H-3), 7.88 (d, 1H, J = 5.0 Hz, thienyl H-5); 13C-NMR: δ = 164.90 (CONH2), 157.93 (C-5), 153.06 (C-
3), 133.66, 131.21, 130.16, 128.14, 119.04 (CN), 99.29 (C-4), 89.99 (C-2), 41.46 (N(CH3)2); Anal.
calcd. for C12H13N3OS: (247.08): C, 58.28; H, 5.30; N, 16.99; S, 12.97. Found: C, 58.23; H, 5.29; N,
16.85; S, 12.74.
General procedure for the preparation of compounds 4a-c
Procedure A: To a solution of each of compound 8a-c (10 mmol) in dioxane (15 mL) and HCl (2 mL),
was added dropwise a prepared solution of NaNO2 (0.85 g, 10 mmol) and sodium acetate (15 mmol) in
water (10 mL). The mixture was stirred for 1h. and allowed to warm up to r.t. During this time a
precipitate is formed. The reaction mixture is then filtered off and recrystallized from dioxane.
Procedure B: Coupling reaction was carried out following procedure described earlier [17], which
involves coupling each of compounds 8a-c with phenyldiazonium chloride in dioxane /AcONa.
6-Benzoyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (4a): Greenish crystals, yield (78 %, 1.90 g);
mp 186-187 oC; IR (cm-1): 3420 (OH), 3240 (NH), 1737, 1678 and 1661 cm-1 (3 CO); MS m/z (M)+ =
1
244; H-NMR: δ = 7.59-7.62 (t, 2H, J = 7.2 Hz, phenyl-H), 7.75 (t, 2H, J = 7.2 Hz, phenyl-H), 7.96
(br. s, 1H, OH, D2O exchangeable), 8.03 (s, 1H, pyridazinyl H-5), 8.05-8.06 (m, 2H, phenyl-H), 8.25
(br. s, 1H, NH, D2O exchangeable); 13C-NMR: δ = 187.43 (ketone CO), 162.42 (carboxylic acid CO),
161.22 (ring CO), 154.14, 134.93, 134.46, 132.70, 129.10, 129.01, 128.72; Anal. calcd. for
C12H8N2O4: (244.05): C, 59.02; H, 3.30; N, 11.47. Found: C, 58.95; H, 3.29; N, 11.52
6-(Furan-2-carbonyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (4b): Beige crystals, yield (75
%,1.75 g); mp 213-214 oC; IR (cm-1): 3419 (OH), 3202 (NH), 1744, 1688 and 1657 cm-1 (3 CO); MS

Molecules 2009, 14
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m/z (M)+ = 234; 1H-NMR: δ = 6.86 (t, 1H, J = 4.5 Hz, furyl H-4), 7.77 (d, 1H, J = 4.3 Hz, furyl H-3),
7.96 (br. s, 1H, OH, D2O exchangeable), 8.03 (s, 1H, pyridazinyl H-5), 8.26 (br. s, 1H, NH, D2O
exchangeable), 8.27 (d, 1H, J = 4.5 Hz, furyl H-5); Anal. calcd. for C10H6N2O5: (234.03): C, 51.29; H,
2.58; N, 11.96. Found: C, 51.34; H, 2.61; N, 12.03.
3-Oxo-6-(thiophene-2-carbonyl)- 2,3-dihydropyridazine-4-carboxylic acid (4c): Yellow crystals, yield
(72 %, 1.80 g); mp 201-202 oC; IR (cm-1): 3434 (OH), 3220 (NH), 1776, 1746 and 1693 cm-1 (3 CO);
1
MS m/z (M)+ = 250; H-NMR: δ = 7.37 (t, 1H, J = 4.3 Hz, thienyl H-4), 7.97 (br. s, 1H, OH, D2O
exchangeable), 8.04 (s, 1H, pyridazinyl H-5), 8.21 (d, 1H, J = 4.3 Hz, thienyl H-3), 8.27 (m, 2H,
thienyl H-5 and NH); Anal. calcd. for C10H6N2O4S: (250.00): C, 48.00; H, 2.42; N, 11.20; S, 12.81.
Found: C, 48.05; H, 2.40; N, 11.01; S, 12.72.
General procedure for the preparation of compounds 15a-c
Each of compounds 8a-c (10 mmol) was refluxed in an EtOH/HCl mixture (3:1, 10 mL) for 30 min.
Upon cooling to r.t. a solid product precipitated that was collected by filtration and recrystallized from
EtOH.
2-Oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid (15a): Beige crystals, yield (89 %, 1.91 g); mp
o
1
260-262 C; IR (cm-1): 3380 (NH), and 1725 cm-1 (CO); MS m/z (M)+ = 215; H-NMR: δ = 6.84 (d,
1H, J = 8.8 Hz, pyridyl H-5), 7.50-7.627 (m, 3H, phenyl-H), 7.79-7.80 (m, 2H, phenyl-H), 8.20 (d,
1H, J = 8.8 Hz, pyridyl H- 4), 12.79 (s, 1H, NH); Anal. calcd. for C12H9NO3: (215.20): C, 66.97; H,
4.22; N, 6.51. Found: C, 67.03; H, 4.20; N, 6.56.
6-(Furan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (15b): Brownish crystals, yield (90 %,
1.85 g); mp 268-269 oC; IR cm-1: 3387 (NH), and 1730 cm-1 (CO); MS m/z (M)+ = 205; 1H-NMR: δ =
6.81 (t, 1H, J = 4.3 Hz, furyl H-4), 6.98 (d, 1H, J = 7.6 Hz, pyridyl H-5), 7.34 (d, 1H, J = 4.3 Hz, furyl
H-3), 7.84 (br. s, 1H, OH, D2O exchangeable), 7.94 (br. s, 1H, NH, D2O exchangeable), 8.07 (d, 1H, J
= 4.5 Hz, furyl H-5), 8.41 (d, 1H, J = 7.6 Hz, pyridyl H-4); Anal. calcd. for C10H7NO4: (205.04): C,
58.54; H, 3.44; N, 6.83. Found: C, 58.31; H, 3.44; N, 7.05.
2-Oxo-6-(thiophen-2-yl)-1,2-dihydropyridine-3-carboxylic acid (15c): Brownish crystals, yield (93 %,
2.0 g); mp 266-268 oC; IR (cm-1): 3398 (NH) and 1721 cm-1 (CO); MS m/z (M)+ = 221; 1H-NMR: δ =
7.18 (d, 1H, J = 7.4 Hz, pyridyl H-5), 7.30 (t, 1H, J = 4.5 Hz, thienyl H-4), 7.82 (br. s, 1H, OH, D2O
exchangeable), 7.94 (br. s, 1H, NH, D2O exchangeable), 7.95 (d, 1H, J = 4.5 Hz, thienyl H-3), 7.99 (d,
1H, J = 4.5 Hz, thienyl H-5), 8.39 (d, 1H, J = 7.4 Hz, pyridyl H-4). Anal. calcd. for C10H7NO3S:
(221.01): C, 54.29; H, 3.19; N, 6.33; S, 14.49. Found: C, 54.14; H, 3.39; N, 6.63; S, 14.56.
General procedure for the preparation of compounds 16a-c
Each of compounds 8a-c (10 mmol) was refluxed in AcOH (10 mL) for 30 min. Upon cooling to r.t.
a solid product precipitated that was collected by filtration and crystallized from AcOH.

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2-Oxo-6-phenyl-1,2-dihydropyridine-3-carbonitrile (16a): White crystals, yield (92 %, 1.80 g); mp
292-294 oC; IR (cm-1): 3151 (NH), 2226 (CN) and 1660 cm-1 (CO); MS m/z (M)+ = 196; 1H-NMR: δ =
6.74 (d, 1H, J = 8.8 Hz, pyridyl H-5), 7.51-7.57 (m, 3H, phenyl-H), 7.80-7.82 (m, 2H, phenyl-H), 8.22
(d, 1H, J = 8.8 Hz, pyridyl H- 4), 12.81 (s, 1H, NH); Anal. calcd. for C12H8N2O: (196.06): C, 73.46;
H, 4.11; N, 14.28. Found: C, 73.43; H, 4.00; N, 14.20.
6-(Furan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (16b): Beige crystals, yield (94 %, 1.75 g);
mp 298-300 oC; IR (cm-1): 3163 (NH), 2230 (CN) and 1661 cm-1 (CO); MS m/z (M)+ = 186; 1H-NMR:
δ = 6.72 (d, 1H, J = 8.8 Hz, pyridyl H-5), 6.78 (t, 1H, J = 5.0 Hz, furyl H-4), 7.62 (d, 1H, J = 5.0 Hz,
furyl H-3), 8.03 (d, 1H, J = 5.0 Hz, furyl H-5), 8.16 (d, 1H, J = 8.8 Hz, pyridyl H-4), 12.82 (s, 1H,
NH). Anal. calcd. for C10H6N2O2: (186.04): C, 64.52; H, 3.25; N, 15.05. Found: C, 64.48; H, 3.14; N,
15.10.
2-Oxo-6-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (16c): Yellowish crystals, yield (95 %,
1.92 g); mp 300-302 oC; IR (cm-1): 3093 (NH), 2226 (CN) and 1651 cm-1 (CO); MS m/z (M)+ = 202;
1H-NMR: δ = 6.70 (d, 1H, J = 8.6 Hz, pyridyl H-5), 7.25 (t, 1H, J = 4.5 Hz, thienyl H-4), 7.88 (d, 1H,
J = 4.5 Hz, thienyl H-3), 8.01 (d, 1H, J = 4.5 Hz, thienyl H-5), 8.13 (d, 1H, J = 8.6 Hz, pyridyl H-4),
12.82 (s, 1H, NH); Anal. calcd. for C10H6N2OS: (202.02): C, 59.39; H, 2.99; N, 13.85; S, 15.86.
Found: C, 59.35; H, 3.09; N, 13.90; S, 15.79.
Acknowledgements
This research was done by the financial support of the Public Authority for Applied Education and
Training (Transform grant TS-07-11) of Kuwait.
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Sample Availability: Samples of the compounds 4a-c, 8a-c, 15a-c and 16a-c are available from
authors.
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