Acta Chim. Slov. 2006, 53, 245–256
245
Scientific Paper
Synthesis and Transformations of Some N-Substituted (1R,4S)-3-Aminomethylidene-1,7,7-trimethylbicyclo[2.2.1]-heptan-2-ones†
Uroš Grošelj, Simon Rečnik, Anton Meden, Branko Stanovnik*,
and Jurij Svete*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, P.O. Box 537,
1000 Ljubljana, Slovenia
E-mail: branko.stanovnik@fkkt.uni-lj.si and
jurij.svete@fkkt.uni-lj.si
†
Received 13-04-2006 Dedicated to the memory of Prof. Dr. Davorin Dolar
Abstract
Acid-catalysed reactions of (1R,3E,4S)-3-[(dimethylamino)methylidene]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (2) with amino acid derivatives 3a–d and pyrazolidin-3-ones 5a–e gave the substitution products 4/4’a–d and 6a–e, respectively, in 40–83% yields. Compound 4a was transformed with Bredereck’s reagent into the 3-(dimethylamino)propenoate 7/7’. Treatment of 1-{[(1R,3Z,4S)-1,7,7-trimethyl-2-oxobicyclo-[2.2.1]hept-3-ylide-ne]methyl}pyrazolidin-3-ones 6a and 6b with dimethyl acetylenedicarboxylate in refluxing anisole furnished the corresponding cycloadducts as mixtures of four diastereomers, the major endo-isomers 10/11a,b and the minor exo-isomers 12/13a,b with moderate endo-selectivity. Chromatographic separation of 10/11/12/13a,b afforded the endo/exo-pairs of diastereomers, 10/13a,b and 11/12a,b. The structures of compounds 4/4’, 6, 7/7’, and 10/11/12/13 were determined by NMR and by X-ray diffraction.
Keywords: camphor, enaminones, condensations, pyrazolidin-3-ones, pyrazolo[1,2–a]pyrazoles

1. Introduction
(+)-Camphor (1) and its derivatives belong to the most frequently employed types of ex-chiral pool starting materials, building blocks, ligands, reagents and/or catalysts, resolving agents in various asymmetric applications, and as shift reagents in NMR spectroscopy.1 For example, reaction of 3-hydroxymethylidenecamph-or2 with amines followed by reduction of the exocyclic C=C double bond leads to 3-aminomethylcamphor derivatives exhibiting local anesthetic and smooth muscle relaxant properties.3–5
On the other hand, 2-aminopyrazolo[1,2–a]-pyrazole-7-carboxylate moiety belongs to a family of conformationally constrained peptide mimetics.6 It is a constituent of biologically active compounds, such as Eli-Lilly’s ?-lactam antibiotics LY 186826, LY 193239, and LY 255262.7–11 In this context, we have previously reported preparation and synthetic utilisation of various 3-pyrazolidinone-1-azomethine imines including their regioselective and stereoselective 1,3-dipolar
cycloadditions leading to polysubstituted pyrazolo-[1,2–a]pyrazoles.12–27
Recently, a series of alkyl 2-substituted 3-(dimeth-ylamino)propenoates and analogous enaminones have been prepared as versatile reagents for the preparation of various heterocyclic systems.12,18,28 Chiral non-racemic 3-(dimethylamino)propenoate analogues, derived from ?-amino acids, have been employed in the synthesis of heterocycles, functionalised with an ?-amino acid, dipeptide, ß-amino alcohol, and related structural elements.12,14,18,28,29 Recently, our studies on ex-chiral pool derived enaminones have been extended towards the preparation and synthetic utilisation of (+)-camphor
(1) derived enaminones.30–37 In the present work, we now report reactions of (1R,3E,4S)-3-[(dimethylamino)me-thylidene]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one
(2)  with amino acid derivatives 3 and pyrazolidin-3-ones 5, and some further transformations of the substitution products 4 and 6 with bis(dimethylamino)-tert-butoxymethane (Bredereck’s reagent) and dimethyl acetylenedicarboxylate (DMAD).
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Acta Chim. Slov. 2006, 53, 245–256
2. Results and Discussion
The starting compound 2 was prepared from (+)-camphor (1) in one step according to the literature procedure.30 Treatment of enaminone 2 with amino acid derivatives 3a–d in ethanol under reflux afforded the corresponding substitution products, in all cases as mixtures of the major (E)-isomers 4a–d and the minor (Z)-isomers 4’a–d in 54–83% yields. Similarly, acid-catalysed reactions of 2 with pyrazolidin-3-ones 5a–e in acetic acid or in ethanol in the presence of equimolar amount of hydrochloric acid at room temperature or under reflux gave the corresponding substitution products 6a–e in 40–80% yields. In contrast to the amino acid derivatives 4a–d, compounds 6a–e were obtained as the (Z)-isomers, exclusively. Crystallisation of a mixture of 4a and 4’a in a ratio of 68:32, respectively, gave isomerically pure compound 4a. Similarly, chromatographic separation of 4b and 4’b in a ratio of 80:20, respectively, yielded pure (E)-isomer 4b and isomerically enriched (Z)-isomer 4’b (Z:E = 96:4). On the other hand, attempted chromatographic separation of a 70:30 mixture of 4d and 4’d failed, most probably due to the fast E/Z-isomerisation.29c,31 Reactions of 2 with chiral racemic pyrazolidin-3-ones 5d and 5e gave mixtures of two diastereoisomeric substitution products 6/6’d and 6/6’e in a ratio of 1:1, respectively. Unfortunately, these diastereomers could not be separated, neither by crystallization, nor by chromatographic techniques (CC and/or MPLC). Reaction of 4/4’a with bis(dimethylamino)-tert-butoxymethane (Bredereck’s reagent) in toluene under reflux furnished a mixture of isomeric enamino esters 7 and 7’ in a ratio of 59:41 and in 48% yield (Scheme 1, Table 1).
Table 1. Selected Experimental Data for Compounds 4, 4’, 6, and 7/7’.
Compound	R	Yield (%)	E:Z
4/4’a	CH2COOMe	76	68:32a
4/4’b	CH2CN	81	80:20
4/4’c	CH2CH2COOEt	54	97:3
4/4’d	COOEt fcOOEt	83	70:30
6a	H	46	0:100
6b	Me	80	0:100
6c	-	40	0:100
6d	-	46	0:100
6e	-	48	0:100
7/7’	-	48	59:41
aPure (E)-isomer 4a was obtained upon crystallization. bPure (E)-isomer 4b and almost pure (Z)-isomer 4’b (Z:E = 96:4) were obtained upon MPLC.
RR
4'         3"    1   V  5
r
6a (R = H) 6b (R = Me)
TT~T   h'n-I
^
NMe2
¦   I  ¦        and    Ml
\\/^r
^^^n
4a-d                    4'a-d
major (E)-isomers    minor (Z)-isomers
fi
p/TJ'nhbz
Bz = COPh          kVJ^
Ph
Ph NHBz            ^-^Ay.NHBz
and    THH^   HN-(
-N HN
ro        'o                      ~~-V"-"o        "o
6d                            I          6'd
(4R,5R,rR,3'Z,4'S)                     (4S,5S,TR,3'Z,4'S)
6d:6'd = 1:1
, NHCbz

NHCbz           ^^/^N/\1,-NHCbz
and    ¦rfC'   HN-(
6e                                  '           6'e
(4R,1'R,3'Z,4'S)                          (4S,TR,3'Z,4'S)
6e:6'e = 1:1
4i

COOMe &J 3-   NMe2
Me2N^

¦^   N       COOMe
major (2Z,3'E)-isomer
minor (2Z,3'Z)-isomer
Sheme 1. Reagents and conditions: (i) R–NH2×HCl (3a-d), EtOH, reflux; (ii) EtOH, HCl, r.t. or reflux (iii) AcOH, reflux; (iv) t-BuOCH(NMe2)2, toluene, reflux.
Treatment of 1-{[(1S,3Z,4R)-1,7,7-trimethyl-2-oxobicyclo[2.2.1]hept-3-ylidene]methyl}pyrazolidin-3-one (6a) with dimethyl acetylenedicarboxylate (DMAD) in refluxing anisole afforded (5RS)-2,3-dihydro-1-oxo-5-[(1R,3RS,4R)-2-oxo-1,7,7-trimethylbicyclo[2.2.1]hept-3-yl]-1H,5H-pyrazolo[1,2–a]pyrazole-6,7-dicarboxylate in 77% yield as a mixture of four diastereomers 10a, 11a, 12a, and 13a, in a molar ratio of 44:36:12:8, respectively. Similarly, reaction of the 5,5-dimethyl analogue 6b with DMAD furnished a mixture of four diastereomeric cycloadducts 10b, 11b, 12b, and 13b, in a molar ratio of 51:31:9:9, respectively, in 83% yield. Both mixtures of isomers, 10/11/12/13a and 10/11/12/13b, consisted of the major pair of the endo-isomers 10/11 and the minor pair of the exo-isomers 12/13. Separation of 10/11/12/13a by medium pressure liquid chromatography (MPLC) was only partial and furnished two endo/exo-mixtures of isomers: (a) a mixture of the endo-isomer 10a and the exo-isomer 13a (10a:13a = 84:16) in 15% yield and (b) a mixture of the endo-isomer 11a and the exo-isomer 12a ( 11a:12a = 79:21) in 22% yield. In the same manner, MPLC separation of 10/11/12/13b furnished two endo/exo-mixtures, 10b:13b = 77:23 and 11b:12b = 84:16, in 40% and 22% yield, respectively. In all isomeric cycloadducts 10a,b–13a,b the endo/exo-configurations at C(3’) were unambigously determined by NMR, while
R
HN
,R
3'        I
O
HN
2
COOMe
HN
4'
IV
H
and
O
7
7'
4/4'a
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Acta Chim. Slov. 2006, 53, 245–256
247
4         3m|        t    \  y
3'   HN 6' ~~V^o    2
l^k
V
7
6a (R = H)
6b (R = Me)
H V ^ -R

8a,b (Z)-isomers 8'a,b (E)-isomers
H ^ ^ -R
N
N
O e
9a,b (Z)-isomers 9'a,b (L)-isomers
COOMe MeOOCeJ/
4- h Tr n 8-^-°
sryT^i~N'      I1
"rfrL3'H 4>c 2  and
6.^4^0  R   3  R
10/11a,b
major encfo-isomers
MeOOC. H
COOMe ,   N   T
h y<c
'O R     R
12/13a,b
minor exo-isomers
MeOOC. H
COOMe
H     V^      and ¦O R     R
O
COOMe MeOOC^/
H   r     N^-.-N       [ H    ^^
•*o R    R
11/12a,b 10/13a,b
(first fraction) (second fraction)
arbitrary configurations at C(5)
Sheme 2
configurations at C(5) could not be established (for details see Structure Determination). Consequently, the configurations at C(5) in the isomeric pairs 10/13 and 11/12, as drawn in the Scheme 2, are arbitrary. They to do not necessarily correspond to the actual configurations (Scheme 2).
Compound	R	Yield (%)	Ratio of Isomers
10a/lla/12a/13a	H	77	44:36:12:8
10b/llb/12b/13b	Me	83	51:31:9:9
10a/13a	H	15	84:16
lla/12a	H	22	79:21
10b/13b	Me	40	77:23
llb/12b	Me	22	84:16
Reagents and conditions: (i) dimethyl acetylenedicarboxylate (DMAD), anisole, reflux; (ii) chromatographic separation (MPLC).
Low stereoselectivity of cycloadditions of 6a,b to DMAD could be explained by initial thermal isomerisation of the enaminone 6 into a mixture of four isomeric azomethine imines 8, 8’, 9, and 9’ as a consequence of fast E/Z-isomerisation and endo/exo-isomerisation. Consequently, 1,3-dipolar cycloaddition of DMAD to a mixture of four isomeric dipoles 8, 8’, 9, and 9’ leads to four isomeric cycloadducts 10–13 with variable configurations at positions 5 and 3’. Besides, the exo/endo-equilibration is also feasible in cycloadducts 10–13 via the enol 14. Predominant formation of the endo-isomers 10/11 is in agreement with the literature data for related ?-substituted camphor derivatives, which exist predominantly in the thermodynamically more stable endo-form because of steric repulsions between the exo-substituent and the Me–C(7) group.1,38 In contrast to the moderate endo/exo-selectivity (position 3’ in the cycloadducts),
h     e
,W?,-N.
endo/exo
H       e
T
'     8a,b
major encfo-isomers
9a,b
minor exo-isomers
MeOOC. H
MeOOC-
COOMe
-COOMe
endo/exo
10,11
major endo-isomers
COOMe
MeOOC-
endo/exo
-COOMe
MeOOC. H
COOMe
14 Sheme 3
12,13
minor exo-isomers
4
O
o
N
O
O
o
O
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Acta Chim. Slov. 2006, 53, 245–256
the facial selectivity of cycloadditions (position 5 in the cycloadducts) was almost neglible according to the ratio of epimers within the endo-pair of isomers (10:11 ~ 3:2) and the exo-pair of isomers (12:13 ~ 1:1). In addition to the above mentioned explanation by fast E/Z-isomerisation around the exocyclic C=N double bond of the intermediate azomethine imines 8 and 9, low facial selectivity might also be due to weak stereodirecting effect of the (+)-camphor residue, because of rotation around the C(3’)–C(3’’) single bond (Scheme 3).
3. Structure Determination
Structures of compounds 4a–d/4’a–d, 6a–e, 6’d,e, 7/7’, 10/11/12/13a, and 10/11/12/13b were determined by spectroscopic methods (IR, 1H NMR, 13C NMR, 2D NMR NOESY spectroscopy, MS) and by elemental analyses for C, H, and N. Compounds 4a, 4b, and 6a–d were prepared in isomerically pure form. Compounds 4c, 4d, and 7 were characterised as isomerically enriched mixtures of major (E)-isomers and the minor (Z)-isomers, whereas compounds 10/11/12/13 were characterized as mixtures of isomers. Compound 4d
was not prepared in analytically pure form. Identity of 4b was confirmed by 13C NMR and EI-HRMS.
The configuration around the C=C double bonds in isomers 7 and 7’ were determined by NMR on the basis of long-range coupling constants, 3JC–H, between the corresponding methylidene protons and the carbonyl carbon atoms, measured from the antiphase splitting of cross peaks in the HMBC spectrum. Generally, the magnitude of coupling constant, 3JC–H, for nuclei with cis-configuration around the C=C double bond are smaller (2–6 Hz) than that for trans-oriented nuclei (8–12 Hz).39–49 The magnitude of coupling constant, 3J
C(1)-H(3)
= 2.8 Hz, in the isomer 7 indicated the (2Z)-configuration. In the isomer 7’, coupling constants, 3JC(2’)–H(3’’) = 8.3 Hz and 3JC(1)–H(3) = 2.8 Hz, showed the (2Z,3Z)-configuration (Figure 1).
The (E)-configuration around the exocyclic C=C double bond in compounds 4a–c was determined by NOESY spectroscopy on the basis of n.O.e. between NH and H–C(4). On the other hand, n.O.e. between H–C(3’’) and H–C(4) in compounds 4’a, 6a–e, and 7’ were in agreement with the (3’Z)-configuration (Figure 1).
Me2NAH HN^C'™6
4'            I   ...       II
3 J-S, o
JC(1)-H(3) = 2.8 Hz (cis)
(2Z,3'E)-isomer
OJ.OMe H       C
fXl/C,     H       NMe2    ¦'"".....'"
T
2.8 Hz (cis) 3JC(2')-h(3") = 8.3 Hz (trans)
(2Z,3'Z)-isomer
n.O.e. tT%'R
H
4a-c
(E)-isomers
n.O.e. H       H
"drX h
4'a
(Z)-isomer
,R
n.O.e.
H      H     R    R
HN O
6a-e
(Z)-isomers
n.O.e. H       H
COOMe H
NMe2
7'
(2Z,3'Z)-isomer
3Jh(3>h(4') ~ 4.5 Hz 4Jh(3W) ~ 1.5 Hz 3JH(3>H(5) ~ 5 Hz or ~ 9 Hz
COOMe H    §    .H      4   L6   .COOMe
10,11
major endo-isomers
3Jh(3>H(4') ~ 0 Hz 4Jh(3)-H(5') ~ 0 Hz
3JH(3)-H(5) ~ 5 Hz or ~ 9 Hz
COOMe H     H    H     H je     COOMe

R
12,13
minor exo-isomers
Figure 1. Structure Determination by NMR Methods.
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7
5'
H
o
2
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249
The configuration at position 3’ in compounds 10– 13 was determined by NMR on the basis of multiplicity of coupling of proton H–C(3’). Following the Karplus equation50 and the possibility of a long-range coupling between H–C(3’) and Ha–C(5’) by the virtue of the “W” configuration,51 the H–C(3’) proton in major endo-isomers 9/10a,b coupled with H–C(4’), Ha–C(5’), and H–C(5), therefore appearing as a doublet of a doublet of a doublet (or a multiplet) with typical coupling constants, 3JH(3’)–H(4’) = 4.5 Hz, 4JH(3’)–H(5’) = 1.5 Hz, and 3JH(3’)–H(5) = 5.3–8.3 Hz. On the other hand, the H–C(3’) proton in the minor exo-isomers 12/13a,b coupled only with H–C(5), therefore appearing as doublet (3JH(3’)–H(5) = 7.2–9.1 Hz). Similar patterns of multiplicities and values of coupling constants were also reported in the literature for analogous compounds. 34–36,52,53 Unfortunately, the configuration at position 5 in compounds 10–13 could not be determined on the basis of the NMR data (Figure 1, Table 2).
In compounds 4/4’a–d and 7/7’, the configurations around the exocyclic C(3’)=C(3’’) double bond were correlated with chemical shifts ? for H–C(3’’) and NH. In the case of the (Z)-isomers 4’a–d and 7’, signals for H– C(3’’) appeared at higher field (6.23–6.44 ppm) than in the case of the (E)-isomers 4a–d and 7 (6.82–6.96 ppm). Signals for NH exhibited even stronger dependence of chemical shift on the configuration. Typical chemical shifts for the NH proton of the (Z)-isomers 4’a–d and 7’ were 7.53–8.19 ppm, while chemical shifts for NH protons of the (E)-isomers 4a–d and 7 were 4.13–6.58 ppm. The downfield shift of the NH proton in the (Z)-isomers 4’a–d and 7’ could be rationalised by intramolecular hydrogen bond, N–H····O=C(2’). Similarly, the downfield shift of H–C(3’’) signals of the (E)-isomers 4a–d and 7 might be attributed to the effect of the ring carbonyl group. These typical NMR data were in agreement with the previously published typical data of related ?-alkylidene substituted (1R,4S)-1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-2-ones and (1R,5S)-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones (Table 2).31
Table 2. Correlation between NMR data and configuration of compounds 4/4’, 7/7’, 10/11, and 12/13.

C10
C8XU O
I
W
^
Major Isomers 4 and 7					
Compound Solvent	8 [ppm]		Z or E		
	3"-H	NH			
4a               DMSO-d6	6.82	6.58	Ea		
4b               CDCI3	6.85	4.13	Ea,b		
4c               CDCI3	6.96	4.49	Ea		
4b               CDCI3	6.88	4.46	E		
7                 CDCI3	6.90	4.80	E,Zc		
Minor Isomers 4’ and 7’					
Compound Solvent	8 [ppm]		Z or E		
	3’’–H	NH			
4’a             DMSO-d6	6.44	7.55	Za		
4’d             CDCI3	6.23	7.53	Z		
4’c              CDCI3	6.33	7.66	Z		
4’b             CDCI3	6.26	7.74	Z		
7’                CDCI3	6.24	8.19	Z,Za,c		
Major	endo-Isomers 10 and 11				
Compound Solvent	8 [ppm]			3JH–H [Hz]	
	3'-H	5-H	3’-4’	3'-5’	3'—5
10a             CDCI3	2.81	4.44	d	d	6.4
11a             CDCI3	3.19	4.94	4.7	1.3	5.3
10b             CDCI3	2.55	4.66	4.5	1.5	8.3
lib            CDCI3	2.92	4.98	4.7	1.0	5.3
Minor exo-Isomers 12 and 13					
Compound Solvent	8 [ppm]			3JH–H [Hz]	
	3'-H	5-H	3'-4’	3'—5’	3'-5
12a             CDCI3	2.44	4.49	0	0	9.1
13a             CDCI3	2.49	4.64	0	0	7.2
12b             CDCI3	2.26	4.58	0	0	9.1
13b             CDCI3	2.17	4.59	0	0	8.9
a Determined by NOESY spectroscopy. b Determined by X-ray diffraction. c Determined by HMBC spectroscopy. d H–C(3’) appeared as multiplet.
The structure of compound 4b was also determined by X-ray diffraction (Figure 2).
C13
&mm
Figure 2. The asymmetric unit of compound 4b. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.
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Acta Chim. Slov. 2006, 53, 245–256
4. Experimental
4.1. General Procedures.
Melting points were determined on a Kofler micro hot stage. The NMR spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for 1H and 75.5 MHz for 13C nucleus, using DMSO–d6 and CDCl3 as solvents and TMS as the internal standard. Mass spectra were recorded on an AutoSpecQ spectrometer and IR spectra on a Perkin-Elmer Spectrum BX FTIR spectrophotometer. Microanalyses were performed on a Perkin-Elmer CHN Analyser 2400. Column chromatography (CC) was performed on silica gel (Fluka, silica gel 60, 40–60 µm). Medium pressure liquid chromatography (MPLC) was performed with a Büchi isocratic system with detection on silica gel (Merck, silica gel 60, 15-35 µm); column dimensions (dry filled): 15 × 460 mm; backpressure: 10–15 bar; detection: UV 254 nm; sample amount: 100–150 mg of isomeric mixture per each run. Ratio of isomers and d.e. were determined by 1H NMR.
tert-Butoxy-bis(dimethylamino)methane (Bredereck’s reagent), amino acid derivatives 3a–d, 1,2-dihydro-3H-indazol-3-one (5c), and dimethyl acetylenedicarboxylate (DMAD) are commercially available (Fluka AG).
(1R,3E,4S)-3-[(Dimethylamino)methylidene]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (2),30 pyrazolidin-3-one hydrochloride (5a),54,55 5,5-dimethylpyrazolidin-3-one (5b),56,57 rel-(4R,5R)-4-benzoylamino-5-phenylpyrazolidin-3-one (5d),22 and (RS)-4-(benzyloxycarbonylamino)-pyrazolidin-3-one (5e)58,59 were prepared according to the literature procedures.
Source of chirality: (i) (+)-Camphor (1) (Fluka AG), product number 21300, purum, natural, ? 97.0% (GC, sum of enantiomers), [?]54620 +54.5 ± 2.5 (c = 10, EtOH), [?]D20 +42.5 ± 2.5 (c = 10, EtOH), mp 176–180 °C, e.e. not specified; (ii) (S)-glutamic acid diethyl ester hydrochloride (3d) (Fluka AG), product number 49550, puriss., ? 99.0% (AT, dried material), [?]D20 +22 ± 1 (c = 5, EtOH), mp 113–115 °C, e.e. not specified; (iii) rel-(4R,5R)-4-benzoylamino-5-phenylpyrazolidin-3-one (5d), racemic compound obtained by diastereoselective synthesis;22 (iv) (RS)-4-(benzyloxycarbonylamino)pyra zolidin-3-one (5e), racemic compound obtained from
(S)-serine.58
4.2.  General Procedure for the Preparation of N-substituted (1R,4S)-3-(aminomethylidene)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones 4a–c.
Amine hydrochloride 3a–c (1 mmol) was added to a solution of compound 2 (207 mg, 1 mmol) in anhydrous ethanol (3 ml), the mixture was stirred under reflux for 3–5 h, and the volatile components were
evaporated in vacuo. The oily residue was triturated with water (10 ml) and kept at 5 °C for 24 h. The precipitate was collected by filtration to give 4a–c.
The following compounds were prepared in this manner:
4.2.1.  Methyl {([(1R,3E,4S)-1,7,7-trimethyl-2-oxobicyclo[2.2.1]hept-3-ylidene]methyl}glycinate (4a) and its (1R,3Z,4S)-isomer 4’a. Prepared from 2 and methyl glicinate hydrochloride (3a) (126 mg, 1 mmol); reflux for 5 h. Yield: 191 mg (76%) of a white solid; 4a:4’a = 68:32; mp 81–91 °C. (Found: C, 66.83; H, 8.73; N, 5.78. C14H21NO3 requires: C, 66.91; H, 8.42; N, 5.57.); IR, ?max (KBr): 3242, 2950, 1749 (C=O), 1697 (C=O), 1616, 1411, 1318, 1236, 1200, 1104, 1075 cm–1. Crystallization from a mixture of acetone and water (1:1) afforded pure compound 4a.
4.2.1.1. Data for the major (1R,3E,4S)-isomer 4a.Yield: 48 mg (19%) of a white solid; 4a:4’a = 100:0; mp 107–112 °C (from acetone–water); [?]D21 +242.5 (c = 0.31, CH2Cl2); 1H NMR (DMSO-d6): ? 0.72, 0.79, 0.86 (9H, 3s, 1:1:1, 3×CH3); 1.12–1.26, 1.51–1.62, and 1.82–1.94 (4H, 3m, 2:1:1, CH2CH2); 2.66 (1H, d, J = 3.4 Hz, H–C(4’)); 3.64 (3H, s, OCH3); 3.93 (2H, d, J = 6.0 Hz, CH2NH); 6.54–6.62 (1H, m, NH); 6.82 (1H, d, J = 12.0 Hz, H–C(3’’)).
4.2.1.2. Data for the minor (1R,3Z,4S)-isomer 4’a. 1H NMR (DMSO-d6): ? 0.74, 0.81, 0.83 (9H, 3s, 1:1:1, 3×CH3); 2.31 (1H, d, J = 3.4 Hz, H–C(4’)); 3.64 (3H, s, OCH3); 3.96 (2H, d, J = 6.4 Hz, CH2NH); 6.44 (1H, d, J = 12.4 Hz, H–C(3’)); 7.50–7.60 (1H, m, NH).
4.2.2.  ({[(1R,3E,4S)-1,7,7-Trimethyl-2-oxobicyclo-[2.2.1]hept-3-ylidene]methyl}amino)acetonitrile (4b) and its minor (1R,3Z,4S)-isomer 4’b.
Prepared from 2 and aminoacetonitrile hydrochloride (3b) (93 mg, 1 mmol); reflux for 3 h. Yield: 177 mg (81%) of a white solid; 4b:4’b = 80:20; mp 100–137 °C. (Found: C, 71.71; H, 8.48; N, 13.04. C13H18N2O requires: C, 71.53; H, 8.31; N, 12.83.). MPLC (EtOAc–hexanes, 1:2) afforded pure compound 4b (second fraction) and isomerically enriched 4’b (first fraction, 4b’:4b = 96:4).
4.2.2.1. Data for the major (1R,3E,4S)-isomer 4b. Yield: 103 mg (47%) of a white solid; 4b:4’b = 100:0; mp 130–136 °C; [?]D20 +262.5 (c = 0.28, CH2Cl2). 1H NMR (CDCl3): ? 0.83, 0.94, 0.95 (9H, 3s, 1:1:1, 3×CH3); 1.31–1.46, 1.61–1.71, 1.93–2.05 (4H, 3m, 2:1:1, CH2CH2); 2.51 (1H, d, J = 3.8 Hz, H–C(4’)); 4.06 (2H, d, J = 6.4 Hz, CH2NH); 4.13 (1H, br s, NH); 6.85 (1H, d, J = 11.3 Hz, H–C(3’’)). 13C NMR (DMSO-d6): ? 9.7, 19.1, 20.7, 27.2, 31.5, 36.0, 46.7, 48.1, 58.0, 117.0, 117.9, 134.6,
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207.4. (Found: C, 71.80; H, 8.39; N, 12.55. C13H18N20 requires: C, 71.53; H, 8.31; N, 12.83.); IR, vmax (KBr): 3338, 2959, 2249 (C=N), 1699 (C=0), 1613, 1451, 1423, 1311, 1237, 1221, 1202, 1173, 1070, 1019, 945 cm-1.
4.2.2.2. Data for the minor (1R,3Z,4S)-isomer 4’b.
Yield: 18 mg (8%) of a white solid; 4b:4’b = 4:96; mp 95-101 °C; [a]D20 +228.5 (c = 0.46, CH2C12). 1H NMR (CDC13): S 0.81, 0.90, 0.94 (9H, 3s, 1:1:1, 3xCH3); 1.31-1.41, 1.61-1.71, 1.95-2.08 (4H, 3m, 2:1:1, CH2CH2); 2.37 (1H, d, J = 3.8 Hz, H-C(4’)); 4.00 (2H, d, J = 6.0 Hz, CH2NH); 6.23 (1H, d, J = 11.7 Hz, H-C(3")); 7.53 (1H, br s, NH). 13C NMR (DMSO-d6): S 9.2, 19.1, 20.6, 28.4, 30.3, 35.9, 49.1, 49.7, 116.2, 116.5, 138.5, 209.2. (Found: C, 71.58; H, 8.58; N, 12.73. C13H18N20 requires: C, 71.53; H, 8.31; N, 12.83.); IR, vmax (KBr): 3318, 2965, 2250 (C=N), 1682 (C=0), 1623, 1467, 1416, 1370, 1279, 1225, 1161, 1107, 1068, 1030, 940 cm-1.
4.2.3. Ethyl 3-({[(lR,3E,4S)-l,7,7-trimethyl-2-oxobicyclo[2.2.1]hept-3-ylidene]methyl}amino)-propanoate (4c) and its minor (1R,3Z,4S)-isomer 4’c.
Prepared from (2) and ethyl /3-alaninate hydrochloride (3c) (154 mg, 1 mmol); reflux for 5 h. Yield: 151 mg (54%) of a white solid; 4c:4’c = 93:7; mp 83-90 °C; [a]D20 +245.4 (c = 0.39, CH2C12); 13C NMR (CDC13): S 9.5, 9.8, 14.6, 19.3, 19.6, 20.6, 20.7, 27.1, 29.0, 30.6, 31.9,
36.1,  36.7, 44.0, 44.6, 46.5, 48.3, 49.3, 50.3, 57.9, 61.1,
61.2, 111.7, 114.0, 137.5, 142.6, 171.7, 172.3, 206.8, 207.9. (Found: C, 68.73; H, 9.18; N, 5.29. CjgH^NOj requires: C, 68.79; H, 9.02; N, 5.01.); IR, vmax (KBr): 3283, 2956, 1721 (C=0), 1692 (C=0), 1619, 1580, 1452, 1369, 1318, 1260, 1196, 1169, 1086, 1072 cm-1.
4.2.3.1.  Data for the major (1R,3E,4S)-isomer 4c.
JH NMR (CDC13): S 0.81, 0.90, 0.93 (9H, 3s, 1:1:1, 3xCH3); 1.23-1.42 (2H, m, CH2CH2); 1.27 (3H, t, J = 7.2 Hz, CH2CH3); 1.58-1.67 (1H, m, 1H of CH2); 1.88-1.98 (2H, 2m, 1:1, CH2CH2); 2.42 (1H, d, J = 3.8 Hz, H-C(4’)); 2.54 (2H, t, J = 6.4 Hz, CH2COOEt); 3.42 (2H, q, J = 6.4 Hz, CH2NH); 4.17 (2H, q, J = 7.2 Hz, CH2CH3); 4.40-4.57 (1H, m, NH); 6.96 (1H, d, J = 13.6 Hz, H-C(3")).
4.2.3.2.  Data for the minor (1R,3Z,4S)-isomer 4’c. *H
NMR (CDC13): 50.79, 0.86, 0.92 (9H, 3s, 1:1:1, 3 xCH3); 2.29 (1H, d, J = 3.8 Hz, H-C(4’)); 6.33 (1H, d, J = 12.4 Hz, H-C(3")); 7.66 (1H, br s, NH).
4.3. Diethyl (2S)-2-({[(lR,3E,4S)-l,7,7-trimethyl-2-oxobicyclo[2.2.1]heptan-3-ylidene]methyl}-amino)pentanedioate (4d) and its minor (2S,VRL'Z,4’S)-isomer 4’d.
Diethyl (S)-glutaminate hydrochloride (3d)
(240 mg, 1 mmol) was added to a solution of compound 2 (207 mg, 1 mmol) in anhydrous ethanol (3 ml), the mixture was stirred under reflux for 6 h, and the volatile components were evaporated in vacuo. The oily residue was purified by CC (EtOAc–hexanes, 2:1). Fractions containing the product were combined and evaporated in vacuo to give 4d. Yield: 303 mg (83%) of a colorless oil; 4d:4’d = 70:30; [?]D20 +134.5 (c = 0.39, CH2Cl2, 4d:4’d = 48:52). EI-MS (m/z): 365 (M+); EI-HRMS (m/z): Found: 365.221050 (M+); C20H31NO5 requires: 365.220223 (M+); (Found: C, 65.16; H, 8.56; N, 4.16. C20H31NO5 requires: C, 65.73; H, 8.55; N, 3.83.); IR, ?max (NaCl): 3308, 2957, 1738 (C=O), 1689 (C=O), 1615, 1472, 1447, 1373, 1325, 1253, 1183, 1161, 1107, 1073, 1027 cm–1.
4.3.1. Data for the major (2S,1’R,3’E,4’S)-isomer 4d.
1H NMR (CDCl3): ? 0.81, 0.92, 0.94 (9H, 3s, 1:1:1, 3×CH3); 1.22–1.44 (8H, m, 2×CH2CH3 and CH2CH2); 1.54–1.69 (1H, m, 1H of CH2CH2); 1.91–2.22 (3H, m, 1H of CH2CH2 and CH2CH2COOEt); 2.31–2.51 (3H, m, CH2COOEt and H–C(4’)); 3.84–3.92 (1H, m, CH2CHNH); 4.09–4.24 (4H, m, 2×OCH2CH3); 4.46 (1H, dd, J = 8.7, 13.2 Hz, NH); 6.88 (1H, d, J = 13.2 Hz, H–C(3’’)). 13C NMR (CDCl3): ? 9.4, 14.5, 14.5, 19.5, 20.7, 28.7, 30.3, 30.5, 49.3, 50.2, 58.8, 60.1, 61.0, 61.8, 62.1, 113.5, 140.2, 171.9, 172.9, 208.4.
4.3.2. Data for the minor (2S,1’R,3’Z,4’S)-isomer 4’d.
1H NMR (CDCl3): ? 0.81, 0.88 (6H, 2s, 1:1, 2×CH3); 3.75–3.83 (1H, m, CH2CHNH); 6.26 (1H, d, J = 12.1 Hz, H–C(3’’)); 7.74 (1H, br t, J = 10.4 Hz, NH).
4.4. 1-{[(1R,3Z,4S)-1,7,7-Trimethyl-2-oxobicyclo-[2.2.1]hept-3-ylidene]methyl}pyrazolidin-3-one (6a). Pyrazolidin-3-one hydrochloride (3a) (123 mg, 1 mmol) was added to a solution of compound 2 (207 mg, 1 mmol) in anhydrous ethanol (6 ml) and the mixture was stirred under reflux for 2 h. Volatile components were evaporated in vacuo and the oily residue was purified by CC (EtOAc). Fractions containing the product were combined and evaporated in vacuo to give 6a. Yield: 114 mg (46%) of a yellow solid; mp 140–145 °C; [?]58820 = +260.8 (c = 0.291, CH2Cl2); 1H NMR (CDCl3): ? 0.87, 0.93 (9H, 2s, 2:1, 3×CH3); 1.26–1.42, 1.57–1.70, 1.96–2.04 (4H, 3m, 2:1:1, CH2CH2 of camphor); 2.31 (1H, d, J = 3.4 Hz, H–C(4’)); 2.72 (2H, t, J = 8.7 Hz, 4–CH2); 3.95 (2H, t, J = 8.7 Hz, 5–CH2); 5.99 (1H, s, H–C(3’’)); 13.15 (1H, s, H–N(2)). 13C NMR (CDCl3): ? 10.0, 19.5, 20.6, 29.1, 30.5, 31.6, 49.5, 50.0, 52.2, 59.3, 108.9, 132.1, 169.3, 205.4. (Found: C, 67.80; H, 8.32; N, 11.24. C14H20N2O2 requires: C, 67.71; H, 8.12; N, 11.28.); IR, ?max (KBr): 2959, 1704 (C=O), 1656 (C=O), 1557, 1466, 1397, 1369, 1277, 1223, 1030 cm–1.
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4.5. General Procedure for the Preparation of 1-{[(1R,3Z,4S)-1,7,7-trimethyl-2-oxobicyclo[2.2.1]hept-3-ylidene]methyl}pyrazolidin-3-ones 6b,d,e.
Hydrochloric acid (37%, 0.1 ml, ~1 mmol) was added to a solution of 2 (207 mg, 1 mmol) and pirazolidin-3-one 5b,d,e (1 mmol) in anhydrous ethanol (6 ml) and the mixture was stirred at r.t. or under reflux for 1.5–7 h. Volatile components were evaporated in vacuo and the residue was purified by CC. Fractions containing the product were combined and evaporated in vacuo to give 6b,d,e.
The following compounds were prepared in this manner:
4.5.1. 5,5-Dimethyl-1-{[(1R,3Z,4S)-1,7,7-trimethyl-2-oxobicyclo[2.2.1]hept-3-ylidene]methyl}-pyrazolidin-3-one (6b). Prepared from 2 and 5,5-dimethylpyrazolidin-3-one (5b) (114 mg, 1 mmol); r.t. for 7 h; CC: EtOAc– hexanes, 1:1. Yield: 221 mg (80%) of a yellow solid; mp 173–178 °C; [?]D20 = +250.4 (c = 0.48, CH2Cl2); 1H NMR (CDCl3): ? 0.86, 0.87, 0.93 (9H, 3s, 1:1:1, 3×CH3); 1.26–1.40 (2H, m, CH2CH2 of camphor); 1.48 (6H, s, 2×CH3); 1.56–1.68, 1.93–2.07 (2H, 2m, 1:1, CH2CH2 of camphor); 2.31 (1H, d, J = 3.8 Hz, H–C(4’)); 2.55 (2H, s, 4–CH2); 6.00 (1H, s, H–C(3’’)); 13.63 (1H, s, H–N(2)). 13C NMR (CDCl3): ? 10.1, 19.6, 20.6, 27.5, 27.6, 29.2, 30.5, 45.7, 49.5, 52.6, 59.4, 64.1, 108.1, 127.0, 167.1, 204.9. (Found: C, 69.27; H, 9.00; N, 10.33. C16H24N2O2 requires: C, 69.53; H, 8.75; N, 10.14.); IR, ?max (KBr): 2963, 1702 (C=O), 1651 (C=O), 1553, 1386, 1371, 1286, 1200, 1108, 1026 cm–1.
4.5.2.  (4R*,5R*)-4-Benzoylamino-5-phenyl-1-{[(1R,3Z,4S)-1,7,7-trimethyl-2-oxobicyclo[2.2.1]hept-3-ylidene]methyl}pyrazolidin-3-one (6/6’d). Prepared from 2 and (4R*,5R*)-4-benzoylamino-5-phenylpyrazolidin-3-one (5d) (282 mg, 1 mmol); r.t. for 4 h; CC (CHCl3–MeOH, 40:1). Yield: 204 mg (46%) of a yellow solid; 6d:6d’ = 1:1; mp 123–128 °C. EI-MS (m/z): 443 (M+); EI-HRMS (m/z): Found: 443.221760 (M+); C27H29N3O3 requires: 443.220892. (Found: C, 72.88; H, 6.70; N, 9.56. C27H29N3O3 requires: C, 73.11; H, 6.59; N, 9.47.); IR, ?max (KBr): 2958, 1724 (C=O), 1657 (C=O), 1538, 1490, 1374, 1340, 1167, 1072, 1020 cm–1.
4.5.2.1. NMR data for the first isomer. 1H NMR (CDCl3): ? 0.85, 0.89, 0.96 (9H, 3s, 1:1:1, 3×CH3); 1.22– 1.44, 1.58–1.68, 1.88–1.99 (4H, 3m, 2:1:1, CH2CH2); 2.21 (1H, br d, J = 3.4 Hz, H–C(4’)); 4.94 (1H, dd, J = 6.8, 9.0 Hz, H–C(4)); 5.09 (1H, d, J = 9.0 Hz, H–C(5)); 5.76 (1H, s, H–C(3’’)); 7.28–7.33 and 7.39–7.46 (8H, 2m, 2:6, 8H of Ph); 7.54 (1H, br d, J = 6.4 Hz, NHCH); 7.67–7.72 (2H, m, 2H of Ph); 14.19 (1H, br s, H–N(2)).
4.5.2.2. NMR data for the second isomer. 1H NMR (CDCl3): ? 0.85, 0.89, 0.96 (9H, 3s, 1:1:1, 3×CH3); 1.22–
1.44, 1.58–1.68, 1.88–1.99 (4H, 3m, 2:1:1, CH2CH2); 2.21 (1H, br d, J = 3.4 Hz, H–C(4’)); 4.77 (1H, dd, J = 6.8, 8.3 Hz, H–C(4)); 5.14 (1H, d, J = 8.3 Hz, H–C(5)); 5.79 (1H, s, H–C(3’’)); 7.28–7.33 and 7.39–7.46 (8H, 2m, 2:6, 8H of Ph); 7.50 (1H, br d, J = 6.8 Hz, H–N(4)); 7.67–7.72 (2H, m, 2H of Ph); 14.16 (1H, s, H–N(2)).
4.5.3.(4R*)-4-Benzyloxycarbonylamino-1-{[(1R,3Z,4S)-1,7,7-trimethyl-2-oxobicyclo[2.2.1]hept-3-ylidene]-methyl}pyrazolidin-3-one (6/6’e). Prepared from 2 and (4RS)-4-benzyloxycarbonyl-aminopyrazolidin-3-one (5e) (236 mg, 1 mmol); reflux for 1.5 h; CC (CHCl3– MeOH, 40:1). Yield: 191 mg (48%) of a yellow solid; 6e:6’e = 1:1; mp 60–70 °C; EI-MS (m/z) = 397 (M+); EI-HRMS (m/z): Found: 397.201250 (M+); C22H27N3O4 requires: 397.200157. (Found: C, 66.19; H, 7.10; N, 10.48. C22H27N3O4 requires: C, 66.48; H, 6.85; N, 10.57.); IR, ?max (KBr): 2958, 1717 (C=O), 1657 (C=O), 1619, 1536, 1455, 1388, 1258, 1071, 1026 cm–1.
4.5.3.1.  NMR data for the first isomer. 1H NMR (CDCl3): ? 0.88, 0.94 (9H, 2s, 2:1, 3×CH3); 1.32–1.45, 1.61–1.68, and 1.95–2.05 (4H, 3m, 2:1:1, CH2CH2); 2.35 (1H, d, J = 3.8 Hz, H–C(4’)); 3.68–3.76 (1H, m, Ha–C(5)); 4.32–4.40 (1H, m, H–C(4)); 4.49–4.57 (1H, m, Hb-C(5)); 5.11 (2H, s, OCH2Ph); 5.67 (1H, br s, NHCH); 6.04 (1H, s, H–C(3’’)); 7.27–7.41 (5H, m, Ph); 13.67 (1H, s, H–N(2)).
4.5.3.2. NMR Data for the second isomer. 1H NMR (CDCl3): ? 0.84, 0.93, 0.94 (9H, 3s, 1:1:1, 3×CH3); 1.32–
1.45, 1.61–1.68, and 1.95–2.05 (4H, 3m, 2:1:1, CH2CH2); 2.33 (1H, d, J = 3.4 Hz, H–C(4’)); 3.68–3.76 (1H, m, Ha–C(5)); 4.32–4.40 (1H, m, H–C(4)); 4.49–4.57 (1H, m, Hb-C(5)); 5.11 (2H, s, OCH2Ph); 5.67 (1H, br s, NHCH); 6.04 (1H, s, H–C(3’’)); 7.27–7.41 (5H, m, Ph); 13.61 (1H, s, H–N(2)).
4.6. 1-{[(1R,3Z,4S)-1,7,7-Trimethyl-2-oxobicyclo [2.2.1]hept-3-ylidene]methyl}-1,2-dihydro-3H-indazol-3-one (6c).
A solution of 2 (207 mg, 1 mmol) and 1,2-dihydro-3H-indazol-3-one (5c) (134 mg, 1 mmol) in acetic acid (6 ml) was stirred under reflux for 2.5 h. Volatile components were evaporated in vacuo and the residue was purified by CC (EtOAc–hexanes, 1:1). Fractions containing the product were combined and evaporated in vacuo to give 6c. Yield: 119 mg (40%) of a yellow solid; mp 173–177 °C; [?]D21 = +350.6 (c = 0.33, CHCl3); 1H NMR (CDCl3): ? 0.92, 0.97, 1.02 (9H, 3s, 1:1:1, 3×CH3); 1.42–1.58, 1.72–1.82, and 2.09–2.18 (4H, 3m, 2:1:1, CH2CH2); 2.58 (1H, d, J = 3.8 Hz, H–C(4’)); 6.75 (1H, s, H–C(3’’)); 7.23–7.29 (1H, m,
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1H of Ar); 7.33 (1H, d, J = 8.3 Hz, 1H of Ar); 7.59 and 7.91–7.94 (2H, 2m, 2H of Ar); 13.62 (1H, s, H–N(2)). 13C NMR (CDCl3): ? 9.9, 19.2, 20.9, 28.5, 30.3, 48.6, 52.5, 59.9, 109.3, 117.3, 118.8, 120.9, 123.7, 124.9, 132.9, 140.4, 160.4, 207.5. (Found: C, 72.88; H, 6.87; N, 9.70. C18H20N2O2 requires: C, 72.95; H, 6.80; N, 9.45.); IR, ?max (KBr): 2961, 1691 (C=O), 1659 (CO), 1577, 1464, 1374, 1332, 1068, 1018, 993 cm–1.
4.7. Methyl (2Z)-3-(dimethylamino)-2-({[(1R,3E,4S)-1,7,7-trimethyl-2-oxobicyclo[2.2.1]hept-3-ylidene]-methyl}amino)propenoate (7) and its (2Z,1’R,3’Z,4’S)-isomer 7’.
Bis(dimethylamino)-tert-butoxy-methane (0.31 ml, 1.5 mmol) was added to a mixture of 4/4’a (251 mg, 1 mmol, 4a:4’a = 68:32) and anhydrous toluene (5 ml) and the solution was stirred under reflux for 1 h. Volatile components were evaporated in vacuo and the residue was purified by CC (EtOAc–hexanes, 1:1). Fractions containing the product were combined and evaporated in vacuo to give 7/7’. 147 mg (48%) of a yellow solid; 7:7’ = 59:41; mp 136–144 °C (from n-hexane–CH2Cl2); [?]D20 +247.1 (c = 0.31, CH2Cl2); 13C NMR (CDCl3): ? 9.5, 9.7, 19.2, 19.5, 20.6, 20.7, 27.4, 28.9, 30.6, 31.6, 38.9, 42.7, 42.8, 46.6, 48.2, 49.3, 50.1, 51.5, 57.7, 58.7, 100.1, 101.0, 112.5, 115.1, 139.1, 144.1, 144.9, 145.7, 168.9,
170.0. 207.3, 208.0. EI-MS (m/z): 306 (M+); EI-HRMS (m/z): Found: 306.195650 (M+); C17H26N2O3 requires: 306.194343 (M+). (Found: C, 66.37; H, 8.81; N, 9.36. C17H26N2O3 requires: C, 66.64; H, 8.55; N, 9.14.); IR, ?max (KBr): 3298, 2953, 1693 (C=O), 1622, 1607, 1580, 1432, 1378, 1299, 1281, 1252, 1217, 1179, 1128, 1086, 948 cm–1.
4.7.1. NMR Data for the major (2Z,1’R,3’E,4’S)-isomer 7: 1H NMR (CDCl3): ? 0.83, 0.91, 0.94 (9H, 3s, 1:1:1, 3×CH3); 1.24–1.45, 1.55–1.68, and 1.91–2.04 (4H, 3m, 2:1:1, CH2CH2); 2.58 (1H, d, J = 3.4 Hz, H–C(4’)); 3.02 (6H, s, NMe2); 3.66 (3H, s, COOMe); 4.80 (1H, d, J = 11.3 Hz, NH); 6.90 (1H, d, J = 11.7 Hz, H–C(3’’)); 7.19 (1H, s, H–C(3)).
4.7.2. NMR Data for the minor (2Z,1’R,3’Z,4’S)-isomer 7’: 1H NMR (CDCl3): ? 0.84, 0.88, 0.93 (9H, 3s, 1:1:1, 3×CH3); 2.33 (1H, d, J = 3.4 Hz, H–C(4’)); 3.00 (6H, s, NMe2); 6.24 (1H, d, J = 12.1 Hz, H–C(3’’)); 7.16 (1H, s, H–C(3)); 8.19 (1H, d, J = 12.4 Hz, NH).
4.8. General Procedure for the Preparation of Dimethyl 2,3-dihydro-1-oxo-1H,5H-pyrazolo[1,2–a]pyrazole-6,7-dicarboxylates 10/11/12/13.
A mixture of 6a (276 mg, 1 mmol) or 6b (248 mg, 1 mmol) and DMAD (142 mg, 1 mmol) in anisole (5 ml) was stirred under reflux for 4 h. Volatile components were evaporated in vacuo and the residue was purified
by CC (EtOAc–hexanes, 1:2). Fractions containing the product were combined and evaporated in vacuo to give a mixture of four isomeric cycloadducts 10/11/12/13.
The following compounds were prepared in this manner:
4.8.1. Dimethyl (5R*)-2,3-dihydro-1-oxo-5-[(1R,3R,4R)-1,7,7-trimethyl-2-oxobicyclo[2.2.1]-hept-3-yl]-1H,5H-pyrazolo[1,2–a]pyrazole-6,7-dicarboxylates 10/11a and their (5R*,1’R,3’S,4’R)-isomers 12/13a. Prepared from 6a; CC (EtOAc–hexanes, 1:2). Yield: 301 mg (77%) of a yellow solid; 10a:11a:12a:13a = 44:36:12:8. Further chromatographic separation by MPLC (EtOAc–hexanes, 1:2) afforded a mixture of 11a and 12a (first fraction) and a mixture of 10a and 13a (second fraction).
4.8.1.1. Data for a mixture of 10a and 13a (second fraction). Yield: 59 mg (15%) of a yellow solid; 10a:13a = 84:16; mp 51–63 °C. (Found: C, 61.65; H, 6.94; N, 7.39. C20H26N2O6 requires: C, 61.53; H, 6.71; N, 7.18.); IR, ?max (KBr): 2958, 1741 (C=O), 1709 (C=O), 1635, 1438, 1394, 1361, 1251, 1199, 1166, 1121, 1094, 1030 cm–1.
4.8.1.1.1. NMR data for the major endo-isomer 10a. 1H NMR (CDCl3): ? 0.88, 0.91, 0.99 (9H, 3s, 1:1:1, 3×CH3); 1.35–1.55 and 1.61–1.91 (4H, 2m, 1:3, CH2CH2); 2.07– 2.11 (1H, m, H–C(4’)); 2.51–2.56 (1H, m, Ha–C(2)); 2.79–2.83 (1H, m, H–C(3’)); 2.85–3.18 (2H, m, Hb–C(2) and Ha–C(3)); 3.73 (3H, s, 6–COOMe); 3.93–4.00 (1H, m, Hb–C(3)); 3.95 (3H, s, 7–COOMe); 4.44 (1H, d, J = 6.4 Hz, H–C(5)).
4.8.1.1.2. NMR data for the minor exo-isomer 13a. 1H NMR (CDCl3): ? 0.96, 1.02 (6H, 2s, 1:1, 2×CH3); 2.49 (1H, d, J = 7.2 Hz, H–C(3’)); 3.57–3.63 (1H, m, Hb– C(3)); 3.74 (3H, s, 6–COOMe); 3.94 (3H, s, 7–COOMe); 4.64 (1H, d, J = 7.2 Hz, H–C(5)).
4.8.1.2.  Data for a mixture of 11a and 12a (first fraction). Yield: 86 mg (22%) of a yellow solid; 11a:12a = 79:21; mp 53–61 °C. (Found: C, 61.71; H, 6.96; N, 7.47. C20H26N2O6 requires: C, 61.53; H, 6.71; N, 7.18.); IR, ?max (KBr): 2958, 1757 (C=O), 1738 (C=O), 1707 (C=O), 1627, 1439, 1392, 1368, 1345, 1255, 1202, 1170, 1092, 1033 cm–1.
4.8.1.2.1. NMR data for the major endo-isomer 11a. 1H NMR (CDCl3): ? 0.87, 0.92, 0.99 (9H, 3s, 1:1:1, 3×CH3); 1.48–1.82 (3H, m, 3H of CH2); 1.95–2.05 (2H, m, 1H of CH2 and H–C(4’)); 2.52–2.60 (1H, m, Ha–C(2)); 2.75– 2.88 (1H, m, Hb–C(2)); 3.01–3.11 (1H, m, Ha–C(3)); 3.19 (1H, br deg dt, J = 1.3, 5.0 Hz, H–C(3’)); 3.62–3.68 (1H, m, Hb–C(3)); 3.75 (3H, s, 6–COOMe); 3.94 (3H, s, 7–COOMe); 4.94 (1H, d, J = 5.3 Hz, H–C(5)).
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4.8.1.2.2. NMR data for the minor exo-isomer 12a.
1H NMR (CDCl3): ? 0.93, 0.94 (6H, 2s, 1:1, 2×CH3); 2.17 (1H, d, J = 4.1 Hz, H–C(4’)); 2.44 (1H, d, J = 9.1 Hz, H–C(3’)); 3.76 (3H, s, 6–COOMe); 3.93 (3H, s, 7–COOMe); 4.49 (1H, d, J = 9.1 Hz, H–C(5)).
4.8.2. Dimethyl (5R*)-2,3-dihydro-5,5-dimethyl-1-oxo-3-[(1R,3R,4R)-1,7,7-trimethyl-2-oxo-bicyclo[2.2.1]hept-3-yl]-1H,5H-pyrazolo[1,2–a]pyrazole-6,7-dicarboxylates 10/11b and their (5R*,1’R,3’S,4’R)-isomers 12/13b. Prepared from 6b; CC (EtOAc–hexanes, 1:2). Yield: 347 mg (83%) of a yellow solid; 10b:11b:12b:13b = 51:31:9:9. Further chromatographic separation by MPLC (EtOAc–hexanes, 1:4) afforded a mixture of 11b and 12b (first fraction) and a mixture of 10b and 13b (second fraction).
4.8.2.1. Data for a mixture of 10b and 13b (second fraction). Yield: 167 mg (40%) of a yellow solid; 10b:13b = 77:23; mp 51–56 °C. (Found: C, 63.48; H, 7.44; N, 6.70. C22H30N2O6 requires: C, 63.14; H, 7.23; N, 6.69.); IR, ?max (KBr): 2961, 1744 (C=O), 1712 (C=O), 1630, 1438, 1374, 1346, 1292, 1272, 1231, 1199, 1167, 1115, 1034 cm–1.
4.8.2.1.1. NMR Data for major endo-isomer 10b. 1H NMR (CDCl3): ? 0.86, 0.90, 0.97, 1.04, 1.37 (15H, 5s, 1:1:1:1:1, 5×CH3); 1.25–1.48, 1.62–1.87, and 1.93–2.04 (5H, 3m, 1:2:2, CH2CH2 and H–C(4’)); 2.25 (1H, d, J = 15.5 Hz, Ha–C(2)); 2.55 (1H, ddd, J = 1.5; 4.5; 8.3 Hz, H–C(3’)); 2.87 (1H, d, J = 15.5 Hz, Hb–C(2)); 3.72 (3H, s, 6–COOMe); 3.94 (3H, s, 7–COOMe); 4.66 (1H, d, J = 8.3 Hz, H–C(5)).
4.8.2.1.2.  NMR data for minor exo-isomer 13b. 1H NMR (CDCl3): ? 0.89, 0.96, 1.01, 1.07, 1.36 (15H, 5s, 1:1:1:1:1, 5×CH3); 2.17 (1H, d, J = 8.9 Hz, H–C(3’)); 2.22 (1H, d, J = 15.4 Hz, Ha–C(2)); 2.74 (1H, d, J = 15.8 Hz, Hb–C(2)); 3.74 (3H, s, 6–COOMe); 3.93 (3H, s, 7–COOMe); 4.59 (1H, d, J = 8.8 Hz, H–C(5)).
4.8.2.2.  Data for a mixture of 11b and 12b (first fraction). Yield: 92 mg (22%) of a yellow solid; 11b:12b = 84:16; mp 46–51 °C. (Found: C, 63.23; H, 7.51; N, 6.74. C22H30N2O6 requires: C, 63.14; H, 7.23; N, 6.69.); IR, ?max (KBr): 2961, 1758 (C=O), 1744 (C=O), 1707 (C=O), 1634, 1439, 1371, 1358, 1340, 1292, 1258, 1232, 1200, 1169, 1118, 1038 cm–1.
4.8.2.2.1. NMR data for major endo-isomer 11b. 1H NMR (CDCl3): ? 0.84, 0.90, 0.99, 1.10, 1.27 (15H, 5s, 1:1:1:1:1, 5×CH3); 1.45–1.53, 1.57–1.83, and 1.96–2.08 (5H, 3m, 1:2:2, CH2CH2 and H–C(4’)); 2.25 (1H, d, J = 15.5 Hz, Ha–C(2)); 2.67 (1H, d, J = 15.5 Hz, Hb–C(2)); 2.92 (1H, br deg dt, J = 1.0, 5.0 Hz, H–C(3’)); 3.73 (3H,
s, 6–COOMe); 3.94 (3H, s, 7–COOMe); 4.98 (1H, d, J = 5.3 Hz, H–C(5)).
4.8.2.2.2. NMR data for minor exo-isomer 12b. 1H NMR (CDCl3): ? 0.91, 0.92, 0.98, 1.26, 1.43 (15H, 5s, 1:1:1:1:1, 5×CH3); 2.23 (1H, d, J = 15.8 Hz, Ha–C(2)); 2.26 (1H, d, J = 9.1 Hz, H–C(3’)); 2.84 (1H, d, J = 15.8 Hz, Hb–C(2)); 3.76 (3H, s, 6–COOMe); 3.94 (3H, s, 7–COOMe); 4.58 (1H, d, J = 9.1 Hz, H–C(5)).
4.9. X-Ray Structure Determination.
Single crystal X-ray diffraction data of compound 4b were collected at room temperature on a Nonius Kappa CCD diffractometer using the Nonius Collect
Software.60 DENZO and SCALEPACK61 were used
for indexing and scaling of the data. The structure was solved by means of SIR97.62 Refinement was done using Xtal3.463 program package and the crystallographic plot was prepared by ORTEP III.64 Crystal structure was refined on F values using the full-matrix least-squares procedure. The non-hydrogen atoms were refined anisotropically. The positions of hydrogen atoms were geometrically calculated and their positional and isotropic atomic displacement parameters were not refined. Absorption correction was not necessary. Regina65 weighting scheme was used.
The crystallographic data for compound 4b have been deposited with the Cambridge Crystallographic Data Center as supplementary material with the deposition number: CCDC 604181. These data can be obtained, free of charge via http://www.ccdc.cam.ac.uk/ conts/retrieving.html.
5. Acknowledgements
The financial support from the Ministry of Science and Technology, Slovenia through grants P0-0502-0103, P1-0179, and J1-6689-0103-04 is gratefully acknowledged.
We acknowledge with thanks the financial support from pharmaceutical companies Krka d.d. (Novo mesto, Slovenia) and Lek d.d., a new Sandoz company (Ljubljana, Slovenia).
The authors wish to express their gratitude to the Alexander von Humboldt Foundation, Germany, for the donation of a Büchi medium pressure liquid chromatograph.
Crystallographic data were collected on the Kappa CCD Nonius diffractometer in the Laboratory of Inorganic Chemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia. We acknowledge with thanks the financial contribution of the Ministry of Science and Technology, Republic of Slovenia through grant Packet X-2000 and PS-511-102, which thus made the purchase of the apparatus possible.
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Povzetek
Pri kislinsko kataliziranih reakcijah (1R,3E,4S)-3-[(dimetilamino)metiliden]-1,7,7-trimetilbiciklo-[2.2.1]heptan-2-ona (2) z ?-aminokislinskimi derivati 3a–d in pirazolidin-3-oni 5a–e poteče izmenjava dimetilaminske skupine, ki vodi do nastanka ustreznih N-substituiranih (1R,4S)-3-aminometiliden-1,7,7-trimetilbiciklo[2.2.1]heptan-2-onov 4/4’a–d in 6a–e. Izmenjave dimetilaminske skupine z ?-aminokislinskimi derivati 3a–d so vodile do zmesi večinskih (3E)-izomerov 4a–d in manjšinskih (3Z)-izomerov 4’a–d, medtem ko so bile pretvorbe enaminona 2 s pirazolidinoni 5a–e stereoselektivne saj so nastali izključno ustrezni (3Z)-izomeri 6a–e. Pretvorba spojine 4a z bis(dimetilamino)-terc-butoksimetanom (Bredereckovim reagentom) je vodila do 3-(dimetilamino)propenoata 7/7’. Izvedli smo tudi pretvorbi 1-{[(1R,3Z,4S)-1,7,7-trimetil-2-oksobiciklo[2.2.1]hept-3-iliden]metil}pirazolidin-3-onov 6a and 6b z dimetil acetilendikarboksilatom (DMAD). V obeh primerih sta nastali ustrezni zmesi štirih diastereomernih spojin, 10/11/12/13a in 10/11/12/13b, z večinskima endo-izomeroma 10 in 11 ter manjšinskima ekso-izomeroma 12 in 13. S preparativno tekočinsko kromatografijo (MPLC) smo zmesi štirih izomerov 10/11/ 12/13 uspeli ločiti na dva endo/ekso-para izomerov, 10/13 in 11/12. Strukture produktov so bile potrjene z NMR spektroskopijo in z rentgensko strukturno analizo.
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