Synthesis of novel C2-symmetric 1,3-bis{(1S,2R,3S,4R)-1,7,7-trimethyl-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-yl}benzoimidazolium tetrafluoroborates

Article abstract of DOI:10.1016/j.tetasy.2008.01.005

Two new C₂-symmetric benzoimidazolium tetrafluoroborates 19 and 20 were prepared from (1S)-(+)-camphorquinone 1 in seven and eight steps, respectively. Thus, N¹-((1S,2R,3S,4R)-1,7,7-trimethyl-4′-methylenedihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-yl)benzene-1,2-diamine 11, available in three steps from 1, was first condensed with 1 to afford amino imines 12 and 13/13′. [3 + 2] Cycloaddition of trimethylenemethane (TMM) to 12 or 13/13′ gave cycloadduct 17, which was successfully reduced to diamine 4 using NaCNBH₃. Catalytic hydrogenation of methylene groups of 4 gave the methyl analogue 18. Finally, cyclization of diamines 4 and 18 with triethyl orthoformate furnished the desired C₂-symmetric benzoimidazolium tetrafluoroborates 19 and 20, respectively. The structures were determined by NMR techniques, NOESY spectroscopy, and X-ray diffraction.

Full text of DOI:10.1016/j.tetasy.2008.01.005

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 330–342
Synthesis of novel C2-symmetric 1,3-bis{(1S,2R,3S,4R)-1,7,7-
trimethyl-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-yl}-
benzoimidazolium tetrafluoroborates
*
ˇ
ˇ
Uros Groselj, Anton Meden, Branko Stanovnik and Jurij Svete
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkercˇeva 5, PO Box 537, 1000 Ljubljana, Slovenia
Received 26 November 2007; accepted 8 January 2008
Abstract—Two new C2-symmetric benzoimidazolium tetrafluoroborates 19 and 20 were prepared from (1S)-(+)-camphorquinone 1 in
seven and eight steps, respectively. Thus, N1-((1S,2R,3S,4R)-1,7,7-trimethyl-40-methylenedihydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-
furan]-3-yl)benzene-1,2-diamine 11, available in three steps from 1, was first condensed with 1 to afford amino imines 12 and 13/130.
[3 + 2] Cycloaddition of trimethylenemethane (TMM) to 12 or 13/130 gave cycloadduct 17, which was successfully reduced to diamine
4 using NaCNBH3. Catalytic hydrogenation of methylene groups of 4 gave the methyl analogue 18. Finally, cyclization of diamines 4
and 18 with triethyl orthoformate furnished the desired C2-symmetric benzoimidazolium tetrafluoroborates 19 and 20, respectively. The
structures were determined by NMR techniques, NOESY spectroscopy, and X-ray diffraction.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
with N-substituents containing terpene based centers of
chirality. (ꢀ)-Isopinocamphenylamine and (+)-bornyl-
amine based imidazolium salts were tested as stereodirect-
ing ligands in the palladium-catalyzed asymmetric oxindole
reaction with ee’s up to 76%.27,28 Some examples of chiral
NHC ligands are depicted in Figure 1.
Camphor and its derivatives belong among the most fre-
quently employed types of chiral starting materials, build-
ing blocks, resolving agents, shift reagents in NMR
spectroscopy, and ligands in various asymmetric reagents
and/or catalysts.1–4
Over the last decade, our studies on the preparation and
synthetic applications of 3-(dimethylamino)propenoates
and related enaminones29–31 have been extended to chiral
non-racemic enaminones, available from a-aminoacids29–35
and (+)-camphor.31,36–45 Within this context, (+)-cam-
phor derived enaminones have been used as key-intermedi-
ates in the synthesis of various terpene functionalized
heterocycles.36–45 Recently, our attention was focused on
(1S)-(+)-camphorquinone 1 derived imines as valuable chi-
ral building blocks. Thus, 3-aryliminocamphors were used
as dipolarophiles in stereospecific [3 + 2] cycloadditions to
trimethylenemethane (TMM) leading to spiro[bicy-
clo[2.2.1]heptane-2,20-furans] and spiro[bicyclo[2.2.1]hep-
tane-3,20-pyrrolidines],46 which underwent stereoselective
[4 + 2] cycloadditions to 1,2,4,5-tetrazines to furnish
11:14-isopropylidene-2,3-diaza-8-oxadispiro[5.1.5.2]penta-
deca-1,4-dienes and 11:14-isopropylidene-2,3,8-triazadispi-
ro[5.1.5.2]pentadeca-1,4-dienes as novel dispiro (hetero)-
cyclic systems.47 Reductions of spiro[bicyclo[2.2.1]hep-
tane-2,20-furans] and spiro[bicyclo[2.2.1]heptane-3,20-pyr-
Another group of interesting compounds are enantiomeri-
cally pure 1,2-diamines, which have attracted considerable
attention as chiral ligands in a variety of transition metal-
catalyzed asymmetric processes.5–19 Chiral and achiral di-
amines are also frequently used as starting materials for
the synthesis of (benz)imidazolium salts, the precursors
for the corresponding N-heterocyclic carbenes.20–22 Ever
since the pioneering report by Herrmann et al.23 on the first
application of N-heterocyclic carbene (NHC) palladium
complexes as catalysts in 1995, the use of NHC ligands
as phosphine mimetics has been found in all areas of transi-
tion metal catalysis.20 Currently, the field of stereoselective
catalysis based on N-heterocyclic carbenes is in the process
of rapid expansion.20,23–26 Surprisingly, there are, to the
best of our knowledge, only a few reports of NHC ligands
*
Corresponding author. Tel.: +386 1 2419 100; fax: +386 1 2419 220;
e-mail: jurij.svete@fkkt.uni-lj.si
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.005

U. Grosˇelj et al. / Tetrahedron: Asymmetry 19 (2008) 330–342
331
Ph
Ph
N
N
N
N
HO
BF4
N
Cl
OH
N
Cl
N
N
N
N
BF4
BF4
Figure 1. Some examples of chiral NHC ligands.
rolidines] afforded novel non-racemic amines, diamines, and
amino alcohols.46 In continuation of our work on stereo-
selective transformations of 3-iminocamphor derivatives,
we herein report the synthesis of novel C2-symmetric benz-
imidazolium tetrafluoroborates 19 and 20, the precursors
for the corresponding N-heterocyclic carbenes as ligands
in transition metal catalysis. The synthetic route to benzim-
idazolium tetrafluoroborates 19 and 20 produced a number
of new chiral non-racemic diamines and aminoimines, as
potential ligands in asymmetric processes.
tion was not selective and afforded three condensation
products 12, 13, and 130 in a ratio of 26:44:30, respectively.
Using chromatographic techniques, this mixture was par-
tially separated into the pure compound 12 and a mixture
of epimeric compounds 13 and 130 in a ratio of 60:40,
respectively. Further reduction of a-iminoketone 12 with
NaCNBH3 was chemo- and stereoselective and furnished
the a-amino ketone 14 in 70% yield and in 100% de. Isola-
tion of epimeric compounds 13 and 130 was somewhat sur-
prising, yet explainable by the initial formation of a deeply
orange-red a-iminoketone 12, which undergoes either a
double [1,5] sigmatropic hydrogen shift via the intermedi-
ate 15, or an intramolecular hydride shift to give colorless
C-3 epimeric a-aminoketones 13 and 130. Equilibration be-
tween epimers 13 and 130 is feasible via the enol form 16
(Scheme 2, Table 1).
2. Results and discussion
Our primary goal was to synthesize N1,N2-
bis{(1S,2R,3S,4R)-1,7,7-trimethyl-40-methylenedihydro-30H-
spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-yl}benzene-1,2-di-
amine 4, a novel bulky C2-symmetric chiral diamine, as a
precursor for the corresponding benzoimidazolium tetra-
fluoroborate. The original synthetic approach was based
on a recently developed method for the preparation of clo-
sely analogous amines46 comprising of a three step trans-
formation of (1S)-(+)-camphorquinone 1 into 4 via acid-
catalyzed condensation with benzene-1,2-diamine 1?2,
[3 + 2] cycloaddition of trimethylenemethane (TMM)
2?3, and reduction with LiAlH4 3?4. Unfortunately, this
strategy failed at the very beginning, since condensation of
1 with 0.5 equiv of benzene-1,2-diamine yielded a quinoxa-
line derivative 5 instead of the desired diimine 2. An alter-
native synthetic approach starting from spirofuran 8
followed by condensation of 8 with benzene-1,2-diamine
8?3, and endo-stereoselective reduction of diimine 3
(3?4) was then envisaged. The starting spirofuran 8 was
prepared in three steps from (1S)-(+)-camphorquinone 1
according to literature procedures.46 Condensation of
spirofuran 8 with 0.5 equiv of benzene-1,2-diamine in
refluxing toluene in the presence of catalytic amounts of
p-toluenesulfonic acid failed to give the expected diimine
3 (Scheme 1, Table 1).
Treatment of 12 with a large excess (5 equiv) of TMM gave
the desired cycloadduct 17 in 69% yield. Similarly, the
reaction of a mixture of a-aminoketone epimers 13 and
130 with a slight excess (1.4 equiv) of TMM followed by
chromatographic workup yielded isomerically pure cyclo-
adduct 17 in 32% yield and the unreacted mixture of
starting compounds 13 and 130 in a ratio of 2:98, respec-
tively, in 22% yield. Crystallization of 130/13 from dichloro-
methane–n-heptane gave isomerically pure epimer 130.
The lower reactivity of epimer 130 in the cycloaddition to
trimethylenemethane (TMM) could be attributed to steric
hindrance from both faces of 130 imposed by the secondary
amine (endo-face) and the two methyl groups (exo-face).
Attempt to reduce imine 17 with LiAlH4 resulted in a dis-
appointingly low conversion into the desired ligand 4,
which was isolated in only 10% yield. Reduction of 17 with
NaCNBH3, however, proceeded smoothly to give the
desired C2-symmetric diamine 4 in quantitative yield.
Additions of TMM and NaCNBH3 or LiAlH4 to the
exocyclic C@N double bond of 12, 13, and 17 afforded
kinetically controlled exo-isomers 4 and 17, exclusively.
No endo-epimers of compounds 4 and 17 were observed
1
in the H NMR spectra of the crude reaction mixtures.
The predominant attack of both reagents from the less
hindered endo-face of the bicyclic system was in accor-
dance with the previously reported results (Scheme 3,
Table 1).46,47
On the other hand, acid-catalyzed condensation of diamino-
furan 11, available in three steps from (1S)-(+)-camphor-
quinone 1,46 did take place when treated with (1S)-(+)-
camphorquinone 1 in refluxing toluene. However, the reac-

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U. Grosˇelj et al. / Tetrahedron: Asymmetry 19 (2008) 330–342
N
H2N
NH2
N
5
O
O
(0.5 equiv.)
i
TMM =
O
O
1
N
N
2
TMM
H2N
NH2
(0.5 equiv.)
i
O
N
O
N
LiAlH4
O
HN
O
NH
O
O
8
3
4
iii TMM
Ref. 46
NH2
O
N
O
N
O
(1 equiv.)
i
ii
O
Ref. 46
Ref. 46
1
6
7
Scheme 1. Reagents and conditions: (i) p-toluenesulfonic acid (cat.), toluene, reflux; (ii) [2-(acetoxymethyl)allyl]trimethylsilane (1.4 equiv), Pd(OAc)2,
(i-PrO)3P, toluene, reflux; HCl–H2O, MeOH, rt.
lized into the corresponding benzoimidazolium tetrafluoro-
borates 19 and 20, respectively, using triethyl orthoformate
and ammonium tetrafluoroborate in the presence of a cat-
alytic amount of formic acid (Scheme 4, Table 1).
Table 1. Selected experimental data for compounds 4, 5, 12–14, 17–20,
130, and 180
Reaction
Product
Yield (%)
dea (%)
1?5
5
81
31
36
70
69
32
22
100
100
34
100
100
100
96
100
100
70
100b
100
100
11?12 + 13/130
12
13
14
17
17
130
4
3. Structure determination
12?14
12?17
The structures of compounds 4, 5, 12, 13, 130, 14, 17, 18,
180, 19, and 20 were determined by spectroscopic methods
(IR, 1H and 13C NMR, NOESY spectroscopy, MS) and by
elemental analyses for C, H, and N. Compounds 5, 12, 130,
and 17–20 were prepared in isomerically pure form. Com-
pound 13 could not be prepared in isomerically pure form
and was characterized by 1H NMR, 13C NMR, and by EI-
HRMS as a mixture of epimers 13 and 130. The minor iso-
13/130?17 + 130
17?4
10 (Procedure A)
88 (Procedure B)
100
44b
61
4
4?18/180
18
18b
19
20
4?19
18?20
42
a Determined by 1H NMR.
b After chromatographic separation.
1
mer 180 was characterized only by H NMR. Compounds
4, 5, 130, 19, and 20 were not prepared in analytically pure
form; their identities were confirmed by 13C NMR and EI-
HRMS.
Catalytic hydrogenation of diamine 4 gave a mixture of
fully saturated 1,2-diaminobenzenes 18 and 180 in a ratio
of 85:15 in quantitative yield. Further chromatographic
purification afforded isomerically pure compound 18 in
44% yield. Diamines 4 and 18 were then successfully cyc-
The configuration at the 3-position in secondary amines 4,
12, 13, 130, 14, 17, 18, and 180 was determined by 1H NMR
on the basis of vicinal coupling constants (3JH(3)–H(4)) and

U. Grosˇelj et al. / Tetrahedron: Asymmetry 19 (2008) 330–342
333
H2N
NO2
O
N
iii
ii
O
N
O
O
(1 equiv.)
Ref. 46
Ref. 46
i
NO2
NO2
Ref. 46
1
9
10
O
NH
NH2
O
11
O
NH HN
O
O
i, iv
v
14
1
O
O
O
O
O
O
N
O
N
and
NH
N
N
HN
HN
and
13'
12
13
O
O
O
N
H
[1,5]-H shift
[1,5]-H shift
N
N
13/13'
H
H
12
15
HO
HN
H
O
H
O
O
O
N
O
hydride shift
N
H
N
N
N
H
13
12
16
Scheme 2. Reagents and conditions: (i) p-toluenesulfonic acid (cat.), toluene, reflux; (ii) [2-(acetoxymethyl)allyl]trimethylsilane, Pd(OAc)2, (i-PrO)3P,
toluene, reflux; (iii) LiAlH4, Et2O–THF, 55 °C; (iv) chromatographic separation; (v) NaCNBH3, MeOH, AcOH, rt.
multiplicities for proton H–C(3). The dihedral angles be-
tween H–C(3) and H–C(4) in the secondary exo-amines
4, 12, 13, 14, 17, 18, and 180 are close to 90° and, following
the Karplus equation,48 no appreciable coupling between
these protons would be expected. Accordingly, negligible
appearing as a triplet (J = 3.7 Hz). Similar patterns of
multiplicities for H–C(3) and magnitudes of coupling con-
stants, JH(3)–H(4), have also been reported in the literature
3
for analogous compounds.36,39,40,42–44,46,47,49,50 The config-
uration at 3-position in secondary amines 4, 12, 14, and 17
was additionally confirmed by NOESY spectroscopy. The
NOE between H–C(3) and Ha–C(40) and NOE between
H–N and the bridge methyl group in compounds 4, 12,
14, and 17 supported the proposed exo-configuration
(Fig. 2).
3
coupling constants, JH(3)–H(4) ꢁ 0 Hz, were observed in
1H NMR spectra of the secondary exo-amines 4, 12, 13,
14, 17, 18, and 180. Signals for H–C(3) appeared either as
doublets (coupled with H–N protons) or singlets (lack of
coupling with H–N protons). Similarly, the H–C(3) in
endo-benzoimidazolium tetrafluoroborates 19 and 20 does
not couple with H–C(4) and, therefore, appears as a singlet.
In endo-amine 130, however, the dihedral angle between H–
C(3) and H–C(4) is smaller (ꢁ30°) and proton H–C(3) cou-
ples with H–C(4) as well as with H–N proton, therefore
The structures of compounds 12, 130, and 20 were deter-
mined by X-ray diffraction analysis (Figs. 3–5). On the ba-
sis of X-ray diffraction data, the (E)-configuration around
the exocyclic C@N double bond in compounds 12 and

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U. Grosˇelj et al. / Tetrahedron: Asymmetry 19 (2008) 330–342
O
O
NH
O
NH
O
N
O
O
i
ii or iii
N
NH HN
12
17
4
O
O
O
N
O
N
O
HN
O
N
i, iv
HN
HN
and
13/13'
17
13'
hindered
O
O
NH
NH
N
H
H
N
O
O
endo-approach
less hindered
TMM
13
17
hindered
O
no conversion
hindered
HN
N
O
13'
Scheme 3. Reagents and conditions: (i) [2-(acetoxymethyl)allyl]trimethylsilane, Pd(OAc)2, (i-PrO)3P, toluene, reflux; (ii) NaCNBH3, MeOH, AcOH, rt;
(iii) LiAlH4, THF, 55 °C (Ref. 36); (iv) chromatographic separation.
130 was established (cf. Figs. 3 and 4). Since the (E)-config-
uration imposes lesser steric strain than the (Z)-configura-
tion around the exocyclic C@N double bond, it is safe to
assume the (E)-configuration also for the other imines 13
and 17.
(b) an acid-catalyzed condensation of 11 with 1 to give iso-
meric imino ketones 12 and 13/130, (c) a stereoselective
[3 + 2] cycloaddition of trimethylenemethane (TMM) to
the C@O bonds of 12 or 13 leading to cycloadduct 17,
(d) a stereoselective reduction of the C@N bond of 17 to
give diamine 4, and (e) a cyclization of N1,N2-disubstituted
benzene-1,2-diamine 4 with HC(OEt)3–NH4BF4 in the
presence of a catalytic amount of formic acid into benzoim-
idazolium tetrafluoroborate 19. Catalytic hydrogenation of
4 furnished the saturated diamine 18, which was then cyc-
lized into the corresponding benzoimidazolium salt 20. The
initially intended synthesis of 19 from 1 or 8 via bis-con-
densation of benzene-1,2-diamine failed. In contrast to
their simpler analogues,46 the C@N double bond in imine
12 was quite resistant for reduction with LiAlH4 in THF,
yet it reacted smoothly with NaCNBH3 in MeOH–AcOH
to give the corresponding diamine 4 as a single diastereomer.
4. Conclusion
Two novel chiral non-racemic C2-symmetric benzoimi-
dazolium tetrafluoroborates 19 and 20 were prepared in
several steps from commercially available (1S)-(+)-cam-
phorquinone 1 in 3.8% and 1.1% overall yields, respec-
tively. The synthetic approach comprises of (a) a three
step preparation of N1-{(1S,2R,3S,4R)-1,7,7-trimethyl-40-
methylenedihydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-fur-
an]-3-yl}benzene-1,2-diamine 11 from 1 and 2-nitroaniline,

U. Grosˇelj et al. / Tetrahedron: Asymmetry 19 (2008) 330–342
335
O
O
O
O
O
O
i
and
NH HN
NH HN
NH HN
4
18
18'
ii
ii
BF4
BF4
O
O
O
O
N
N
N
N
19
20
Scheme 4. Reagents and conditions: (i) H2, 10% Pd–C, EtOH, then chromatographic separation; (ii) HC(OEt)3, HCOOH, NH4BF4, 120 °C.
BF4
O
O
O
O
3
3 O
NHR
3
N
N
3
R
4
H
H
NHR
N 3'''
H
H
4
4
4
H
H
H
H
H
H
H
19, 20
13'
13, 14
4, 12, 17, 18, 18'
3JH3-H4 ~ 0 Hz
3JH3-H4 ~ 3.7 Hz
3JH3-H4 ~ 0 Hz
3JH3-H4 ~ 0 Hz
CH3
H3C
n.O.e.
CH3
H3C
O
4'
O
Hb
4
3H
NH
R
Ha
H
N
R
H
n.O.e.
4, 12, 14, 17
4, 12, 17
Figure 2. Structure determination by 1H NMR and NOESY spectroscopy.
In conclusion, we have developed the synthesis of novel
chiral non-racemic C2-symmetric diamines 4 and 18 and
their respective benzoimidazolium tetrafluoroborates 19
and 20, which might be useful ligands in asymmetric pro-
cesses. Our current studies are focused on possible applica-
tions of these chiral compounds.
13C nucleus, using DMSO-d6 and CDCl3, with TMS as
the internal standard, as solvents. All NMR experiments
were carried out at 23 °C. Optical rotations were measured
on a Perkin–Elmer 241MC Polarimeter. Mass spectra were
recorded on an AutoSpecQ spectrometer, IR spectra on a
Perkin–Elmer Spectrum BX FTIR spectrophotometer.
Microanalyses were performed on a Perkin–Elmer CHN
Analyzer 2400. Column chromatography (CC) was per-
formed on silica gel (Fluka, Silica Gel 60, 0.04–0.06 mm).
5. Experimental
5.1. General methods
1
The ratio of the isomers and de were determined by H
NMR.
Melting points were determined on a Kofler micro hot
(1S)-(+)-Camphorquinone 1, benzene-1,2-diamine, p-tolu-
enesulfonic acid monohydrate, [2-(acetoxymethyl)allyl]-
trimethylsilane, Pd(OAc)2, (i-PrO)3P, LiAlH4, and
1
stage. The H NMR spectra were obtained on a Bruker
1
Avance DPX 300 at 300 MHz for H and 75.5 MHz for

336
U. Grosˇelj et al. / Tetrahedron: Asymmetry 19 (2008) 330–342
Figure 3. The asymmetric unit of compound 12. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.
Figure 4. The asymmetric unit of compound 130. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.
NaCNBH3 are commercially available (Fluka AG).
[bicyclo[2.2.1]heptane-2,20-furan]-3-one 8 and N1-((1S,2R,
3S,4R)-1,7,7-trimethyl-40-methylenedihydro-30H-spiro[bi-
(1S,2R,4R)-1,7,7-Trimethyl-40-methylenedihydro-30H-spiro-

U. Grosˇelj et al. / Tetrahedron: Asymmetry 19 (2008) 330–342
337
Figure 5. The asymmetric unit of compound 20. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.
cyclo-[2.2.1]heptane-2,20-furan]-3-yl)benzene-1,2-diamine 11
(NaCl) 3064, 2961, 2929, 2872, 1580, 1513, 1472, 1453,
were prepared according to literature procedures.46
1405, 1391, 1380, 1371, 1362, 1334, 1267, 1173,
1134, 1118, 1109, 1073, 1053, 1018, 999, 914, 868, 829,
Source of chirality: (1S)-(+)-camphorquinone 1, 99%,
762 cmꢀ1
.
20
(Fluka AG), product number 27,207-8, ½aꢂD ¼ þ100 (c
1.9, toluene), mp 200–202 °C.
5.3. Synthesis of N1-[(1S,3E,4R)-2-oxo-1,7,7-trimethylbicy-
clo[2.2.1]hept-3-ylidene]-N2-{(1S,2R,3S,4R)-1,7,7-trimethyl-
40-methylenedihydro-30H-spiro[bicyclo[2.2.1]- heptane-2,20-
furan]-3-yl}benzene-1,2-diamine 12, N1-[(1S,3S,4R)-2-oxo-
1,7,7-trimethylbicyclo[2.2.1]hept-3-yl]-N2-{(1S,2R,4R)-
1,7,7-trimethyl-40-methylenedihydro-30H-spiro[bicy-
clo[2.2.1]heptane-2,20-furan]-3-ylidene}benzene-1,2-diamine
13, and N1-[(1S,3R,4R)-2-oxo-1,7,7-trimethylbicy-
clo[2.2.1]hept-3-yl]-N2-{(1S,2R,4R)-1,7,7-trimethyl-40-
methylenedihydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-
furan]-3-ylidene}benzene-1,2-diamine 130
5.2. Synthesis of (1S,4R)-1,11,11-trimethyl-1,2,3,4-tetra-
hydro-1,4-methanophenazine 5
A
mixture of (1S)-(+)-camphorquinone 1 (3 mmol,
499 mg), benzene-1,2-diamine (1.5 mmol, 163 mg), and
p-toluenesulfonic acid monohydrate (0.3 mmol, 58 mg) in
anhydrous toluene (35 mL) was heated at reflux for 6 h.
A Dean–Stark water trap was used to remove water during
the reaction. The reaction mixture was cooled to 5 °C,
poured into a cooled saturated aq NaHCO3 (150 mL,
5 °C) and the product was extracted with EtOAc
(2 ꢃ 100 mL). The organic phases were combined, dried
over anhydrous Na2SO4, filtered, and the filtrate was evap-
orated in vacuo. The residue was purified by CC (EtOAc–
hexanes, 1:80). Fractions containing the product were com-
bined and evaporated in vacuo to give 5. Yield: 0.290 g
A mixture of N1-((1S,2R,3S,4R)-1,7,7-trimethyl-40-methy-
lenedihydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-
yl)benzene-1,2-diamine 11 (6.33 mmol, 1978 mg), (1S)-(+)-
camphorquinone 1 (6.33 mmol, 1053 mg), and p-toluene-
sulfonic acid monohydrate (0.32 mmol, 61 mg) in anhy-
drous toluene (60 mL) was heated at reflux for 4 h. A
Dean–Stark water trap was used to remove water during
the reaction. The reaction mixture was cooled to room tem-
perature, poured into ethyl acetate (300 mL), and the
resulting mixture was washed with saturated aq NaHCO3
(100 mL) and water (100 mL). The organic phase was
dried over anhydrous Na2SO4, filtered, and the filtrate
was evaporated in vacuo to give a mixture of compounds
12, 13, and 130 in a ratio of 26:44:30, respectively, which
was separated by CC (EtOAc–hexanes, 1:20). A mixture
of compounds 13 and 130 was eluted first, followed by
21
1
(81%) of a yellow oil; ½aꢂ589 ¼ ꢀ29:0 (c 0.30, CHCl3). H
NMR (CDCl3): d 0.63, 1.12, 1.44 (9H, 3s, 1:1:1, 3 ꢃ Me);
1.37–1.47, 1.99–2.13, 2.23–2.38 (4H, 3m, 2:1:1, 2 ꢃ CH2);
3.07 (1H, d, J = 4.5 Hz, H–C(4)); 7.62–7.68, 7.96–8.08
(4H, 2m, 1:1, 4H of Ar). 13C NMR (CDCl3): d 10.1,
18.6, 20.4, 24.7, 31.9, 53.4, 53.8, 54.3, 128.09, 128.11,
128.7, 128.8, 141.4, 141.6, 163.8, 165.5. m/z (EI) = 238
(M+); m/z (HRMS) found: 238.146320 (M+); C16H18N2 re-
quires: m/z = 238.146999. (C16H18N2 requires: C, 80.63; H,
7.61; N, 11.75. Found: C, 79.67; H, 8.06; N, 11.55.); mmax

338
U. Grosˇelj et al. / Tetrahedron: Asymmetry 19 (2008) 330–342
the elution of compound 12. Fractions containing the
products were combined and evaporated in vacuo to give
pure compound 12 and a mixture of compounds 13 and
130 in a ratio of 60:40. Crystallization of 13/130 from etha-
nol afforded a mixture of compounds 13 and 130 in a ratio
of 67:33.
5.4. Synthesis of N1-{(1S,2R,3S,4R)-1,7,7-trimethyl-40-
methylenedihydro-30H-spiro[bicyclo[2.2.1]-heptane-2,20-
furan]-3-yl}-N2-{(1S,2R,3E,4R)-1,7,7-trimethyl-40-methyl-
enedihydro-30H-spiro[bicyclo-[2.2.1]heptane-2,20-furan]-3-
ylidene}benzene-1,2-diamine 17
Procedure A: Compound 12 (0.1 mmol, 46 mg) and [2-
(acetoxymethyl)allyl]trimethylsilane (0.5 mmol, 94 mg)
were dissolved in anhydrous toluene (2 mL) under argon
and heated at reflux. Then, a solution of Pd(OAc)2
(0.036 mmol, 8 mg) and (i-PrO)3P (0.215 mmol, 0.05 mL,
d240 ¼ 0:905 g=L) in anhydrous THF (0.5 mL) was added
and the reaction mixture was heated at reflux for 3 h. Vol-
atile components were evaporated in vacuo and the residue
was purified by CC (EtOAc–hexanes, 1:30). Fractions
containing the product were combined and evaporated
in vacuo to give 17.
5.3.1. Data for compound 12. Yield: 0.904 g (31%) of an
18
orange red solid; mp 168–175 °C; ½aꢂ589 ¼ ꢀ854:4 (c 0.09,
1
CHCl3). H NMR (CDCl3): d 0.80, 0.88, 0.99, 1.10, 1.15
(18H, 5s, 1:2:1:1:1, 6 ꢃ Me); 1.11–1.21, 1.30–1.39, 1.42–
1.53 (3H, 3m, 3H of CH2); 1.56–1.89 (5H, m, 4H of CH2,
H–C(41)); 2.04–2.18 (1H, m, 1H of CH2); 2.37 (1H, dd,
J = 1.1; 15.9 Hz, Ha–C(40)); 2.85 (1H, br d, J = 15.4 Hz,
Hb–C(40)); 3.06 (1H, d, J = 4.5 Hz, H–C(42)); 3.11 (1H,
d, J = 6.8 Hz, H–C(3)); 4.28–4.35 (1H, m, Ha–C(20));
4.42 (1H, br d, J = 12.8 Hz, Hb–C(20)); 4.70 (1H, d,
J = 1.5 Hz, Ha–C(300)); 4.87 (1H, d, J = 1.5 Hz, Hb–
C(300)); 5.27 (1H, d, J = 6.8 Hz, NH); 6.43–6.47, 6.51–
6.57 (2H, 2m, 1:1, 2H of Ar); 6.64 (1H, dd, J = 1.5;
7.5 Hz, 1H of Ar); 7.04–7.10 (1H, m, 1H of Ar). 13C
NMR (CDCl3): d 9.2, 9.9, 17.7, 20.9, 21.7, 22.3, 24.4,
26.1, 30.3, 31.7, 43.1, 44.7, 49.1, 49.3, 50.1, 52.1, 57.8,
68.7, 72.9, 93.8, 104.2, 110.3, 114.3, 119.2, 127.9, 133.7,
142.6, 146.9, 169.6, 205.8. m/z (EI) = 460 (M+); m/z
(HRMS) found: 460.310320 (M+); C30H40N2O2 requires:
m/z = 460.308979. (C30H40N2O2 requires: C, 78.22; H,
8.75; N, 6.08. Found: C, 78.03; H, 8.95; N, 6.01.); mmax
(KBr) 3409, 2953, 2882, 1749 (C@O), 1653, 1647, 1595,
1504, 1484, 1456, 1425, 1400, 1390, 1371, 1330, 1320,
1295, 1257, 1194, 1157, 1073, 1060, 1040, 1012, 971, 882,
Procedure B: A mixture of compounds 13 and 130 in a ratio
of 67:33 (2 mmol, 922 mg) and [2-(acetoxymethyl)allyl]tri-
methylsilane (2.8 mmol, 522 mg) was dissolved in anhy-
drous toluene (6 mL) under argon and heated at reflux.
Then, a solution of Pd(OAc)2 (0.2 mmol, 46 mg) and
(i-PrO)3P (1.3 mmol, 0.3 mL, d20 ¼ 0:905 g=L) in anhy-
4
drous THF (2 mL) was added and the reaction mixture
was heated at reflux for 2 h. Volatile components were
evaporated in vacuo and the residue was purified by CC.
Product 17 was eluted with EtOAc–hexanes (1:40), fol-
lowed by the elution of a mixture of the unreacted 13/130
with EtOAc–hexanes (1:10). Fractions containing the prod-
uct were combined and evaporated in vacuo to give 17 and
a mixture of unreacted 13 and 130 (13:130 = 98:2), respec-
tively. Further recrystallization of the mixture of com-
pounds 13 and 130 from n-heptane/CH2Cl2 gave pure
compound 130.
743 cmꢀ1
.
5.3.2. Data for a mixture of compounds 13 and 130. Yield:
1.060 g (36%) of a grayish-white solid; 13:130 = 67:33; mp
18
5.4.1. Data for compound 17. Yield: 0.029 g (69%, Proce-
185–193 °C; ½aꢂ589 ¼ ꢀ11:3 (c 0.20, 13:130 = 73:27, CHCl3).
13C NMR (CDCl3): d 9.4, 9.5, 18.9, 19.5, 19.9, 20.6, 20.8,
22.2, 22.4, 23.97, 24.04, 26.4, 28.8, 31.6, 31.7, 32.8, 39.9,
40.0, 44.2, 46.7, 47.57, 47.60, 48.3, 48.7, 51.0, 51.2, 51.8,
51.9, 56.7, 58.4, 62.3, 64.8, 72.5, 72.6, 90.1, 90.2, 103.5,
104.1, 110.3, 110.5, 116.96, 117.04, 118.5, 118.6, 124.9,
125.0, 137.09, 137.12, 140.46, 140.48, 147.4, 148.1, 187.0,
187.5, 217.0, 218.1. m/z (EI) = 460 (M+); m/z (HRMS)
found: 460.310120 (M+); C30H40N2O2 requires: m/z =
460.308979. (C30H40N2O2 requires: C, 78.22; H, 8.75; N,
6.08. Found: C, 78.48; H, 9.08; N, 6.03.); mmax (KBr)
3448, 2960, 2870, 1751 (C@O), 1686 (C@N), 1595, 1504,
1483, 1456, 1390, 1372, 1324, 1296, 1263, 1191, 1156,
dure A) or 0.334 g (32%, Procedure B) of a yellowish solid;
18
1
mp 123–126 °C; ½aꢂ589 ¼ ꢀ115:0 (c 0.21, CHCl3). H NMR
(CDCl3): d 0.79, 0.86, 0.90, 0.95, 1.07, 1.13 (18H, 6s,
1:1:1:1:1:1, 6 ꢃ Me); 1.15–1.21, 1.32–1.57, 1.59–1.79,
1.82–1.93 (8H, 4m, 1:4:2:1, 4 ꢃ CH2); 1.86 (1H, d,
J = 4.5 Hz, H–C(41)); 2.39 (1H, d, J = 15.1 Hz, Ha–
1
2
0
0
C(4 )); 2.59 (1H, d, J = 15.8 Hz, Ha–C(4 )); 2.69 (1H, d,
J = 5.1 Hz, H–C(42)); 2.76 (1H, br dd, J = 1.1; 15.9 Hz,
1
2
0
0
Hb–C(4 )); 2.86 (1H, br d, J = 15.3 Hz, Hb–C(4 )); 3.13
(1H, d, J = 7.0 Hz, H–C(3)); 4.41 (1H, br d, J = 12.8 Hz,
Ha–C(2 )); 4.46–4.54 (2H, m); 4.69 (1H, d, J = 0.9 Hz,
1
0
00
1
1
2
00
00
Ha–C(3 )); 4.85 (2H, br s, Hb–C(3 ), Ha–C(3 )); 4.94–
4.99 (2H, m); 5.07 (1H, br d, J = 7.0 Hz, NH); 6.35 (1H,
d, J = 7.9 Hz, 1H of Ar); 6.47–6.53 (2H, m, 2H of Ar);
6.91–7.00 (1H, m, 1H of Ar). 13C NMR (CDCl3): d 9.5,
10.0, 19.1, 21.5, 22.3, 22.5, 24.3, 26.1, 31.71, 31.74, 39.5,
43.2, 47.6, 48.3, 49.1, 51.4, 51.8, 52.2, 68.4, 72.8, 73.3,
90.6, 93.7, 103.5, 104.1, 109.5, 114.2, 119.2, 125.4, 135.8,
140.8, 147.0, 147.9, 185.9. m/z (EI) = 514 (M+); m/z
(HRMS) found: 514.357320 (M+); C34H46N2O2 requires:
m/z = 514.355929. (C34H46N2O2 requires: C, 79.33; H,
9.01; N, 5.44. Found: C, 79.35; H, 9.23; N, 5.39.); mmax
(KBr) 3425, 2988, 2950, 1668 (C@N), 1592, 1503, 1482,
1454, 1423, 1389, 1371, 1326, 1293, 1262, 1239, 1192,
1065, 1040, 1019, 884, 740 cmꢀ1
.
5.3.3. 1H NMR data for compound 13. 1H NMR (CDCl3):
d 0.87, 0.93, 0.94, 0.95, 0.97, 1.16 (18H, 6s, 1:1:1:1:1:1,
6Me); 1.18–1.31 (1H, m, 1H of CH2); 1.35–1.51 (1H, m,
1H of CH2); 1.56–1.87 (5H, m, 5H of CH2); 1.99–2.14
(1H, m, 1H of CH2); 2.19 (1H, d, J = 4.5 Hz, H–C(41));
2.45–2.50 (1H, m); 2.64 (1H, J = 4.9 Hz, H–C(42)); 2.71–
2.83 (1H, m); 3.36 (1H, d, J = 2.6 Hz, H–C(3)); 4.46–4.58
(2H, m); 4.77–4.84 (1H, m); 4.87–5.01 (2H, m); 5.08–5.11
(1H, m); 6.50–6.59, 6.63–6.69, 6.94–7.01 (4H, 3m, 2:1:1,
4H of Ar).
1155, 1065, 1044, 1018, 884, 737 cmꢀ1
.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 19 (2008) 330–342
339
5.4.2. Data for compound 130. Procedure B, 0.207 g (22%)
of a white solid; 13:130 = 98:2. Crystallization from n-hep-
tane/CH2Cl2 gave pure compound 130; mp 203–205 °C;
217.7. m/z (EI) = 463 (MH+); m/z (HRMS) found:
463.3308 (MH+); C30H43N2O2 requires: m/z = 463.3325.
(C30H42N2O2 requires: C, 77.88; H, 9.15; N, 6.05. Found:
C, 77.75; H, 9.39; N, 5.97.); mmax (KBr) 3404, 2957, 2875,
1749 (C@O), 1599, 1515, 1481, 1446, 1430, 1390, 1371,
18
1
½aꢂ589 ¼ ꢀ71:9 (c 0.21, CHCl3). H NMR (CDCl3): d 0.87,
0.94, 0.98, 1.01, 1.04, 1.10 (18H, 6s, 1:1:1:1:1.1, 6 ꢃ Me);
1.23–1.31, 1.34–1.44, 1.52–1.87 (8H, 3m, 1:1:6, 4 ꢃ CH2);
2.49 (1H, t, J = 4.2 Hz, H–C(41)); 2.60 (1H, d,
J = 4.9 Hz, H–C(42)); 2.61 (1H, d, J = 15.1 Hz, Ha–
C(40)); 2.78 (1H, br d, J = 15.5 Hz, Hb–C(40)); 3.95 (1H,
t, J = 3.7 Hz, H–C(3)); 4.50 (1H, d, J = 4.0 Hz, NH);
4.54 (1H, br d, J = 13.0 Hz, Ha–C(20)); 4.88–4.99 (3H, m,
Hb–C(20), H2C(300)); 6.53–6.59 (2H, m, 2H of Ar); 6.65,
6.96 (2H, 2dt, 1:1, J = 1.1; 7.5 Hz, 2H of Ar). 13C NMR
(CDCl3): d 9.4, 9.5, 18.96, 18.99, 19.5, 19.9, 22.3, 24.0,
31.8, 32.8, 39.9, 44.3, 47.6, 48.7, 51.2, 51.8, 58.4, 62.3,
72.6, 90.2, 103.6, 110.5, 117.0, 118.7, 124.9, 137.1, 140.5,
148.1, 187.5, 218.2. m/z (EI) = 460 (M+); m/z (HRMS)
found: 460.309560 (M+); C30H40N2O2 requires: m/z =
460.308979. (C30H40N2O2 requires: C, 78.22; H, 8.75; N,
6.08. Found: C, 78.64; H, 8.97; N, 6.06.); mmax (KBr)
3400, 2988, 2961, 2870, 1737 (C@O), 1690 (C@N), 1597,
1509, 1482, 1459, 1441, 1389, 1374, 1326, 1294, 1277,
1265, 1190, 1154, 1066, 1058, 1038, 1018, 1004, 878,
1329, 1312, 1264, 1242, 1074, 1040, 1027, 886, 733 cmꢀ1
.
5.6. Synthesis of N1,N2-bis{(1S,2R,3S,4R)-1,7,7-trimethyl-
40-methylenedihydro-30H-spiro[bicyclo-[2.2.1]heptane-2,20-
furan]-3-yl}benzene-1,2-diamine 4
Procedure A: To a solution of compound 17 (0.5 mmol,
258 mg) in anhydrous THF (15 mL) under argon was
added a solution of LiAlH4 (5 mmol, 5 mL, 1 M in THF)
and the reaction mixture was heated at 55 °C for 7 h. The
reaction mixture was cooled to 0 °C and the unreacted
LiAlH4 was carefully quenched with saturated aq Na2SO4
(just enough to quench all LiAlH4). The reaction mixture
was filtered, the solid residue thoroughly washed with
CH2Cl2 (100 mL), the filtrate evaporated in vacuo, and
the residue was purified by CC (PhMe–hexanes, 1:1). Frac-
tions containing the products were combined and evapo-
rated in vacuo to give 4. Further elution with EtOAc–
hexanes (1:1) followed by evaporation afforded the unre-
acted compound 17.
747 cmꢀ1
.
5.5. Synthesis of N1-[(1S,3S,4R)-2-oxo-1,7,7-trimethylbicy-
clo[2.2.1]hept-3-yl]-N2-{(1S,2R,3S,4R)-1,7,7-trimethyl-40-
methylenedihydro- 30H-spiro[bicyclo[2.2.1]heptane-2,20-
furan]-3-yl}benzene-1,2-diamine 14
Procedure B: NaCNBH3 (2 mmol, 126 mg) was added to a
solution of compound 17 (0.5 mmol, 258 mg) in anhydrous
MeOH (70 mL) under argon followed by the addition of
glacial acetic acid (0.2 mL) and the reaction mixture was
stirred at room temperature for 20 h. Volatile components
were evaporated in vacuo and the residue was purified by
CC (PhMe–hexanes, 2:1). Fractions containing the product
were combined and evaporated in vacuo to give 4.
NaCNBH3 (1.71 mmol, 108 mg) was added to a solution of
compound 12 (0.57 mmol, 263 mg) in anhydrous MeOH
(70 mL) under argon followed by the addition of glacial
acetic acid (0.2 mL) and the reaction mixture was stirred
at room temperature for 3 h. Afterwards, water (30 mL)
was added and the reaction mixture was stirred at room
temperature for 1 h. MeOH was evaporated in vacuo from
the reaction mixture, water (70 mL) was added to the resi-
due, and the resulting mixture was extracted twice with
CH2Cl2 (100 mL). The combined organic phases were dried
over anhydrous Na2SO4, filtered, and the filtrate was evap-
orated in vacuo. The residue was purified by CC (EtOAc–
hexanes, 1:20). Fractions containing the product were
combined and evaporated in vacuo to give 14. Yield:
0.185 g (70%) of a grayish-white solid; mp 117–120 °C;
Yield: 0.026 g (10%, Procedure A) or 0.228 g (88%, Proce-
22
dure B) of a grayish-white solid; mp 70–76 °C; ½aꢂ589
¼
1
þ189:0 (c 0.17, CHCl3). H NMR (CDCl3): d 0.80, 0.91,
1.19 (18H, 3s, 1:1:1, 6 ꢃ Me); 1.15–1.27, 1.33–1.54, 1.70–
1.81 (8H, 3m, 2:4:2, 4 ꢃ CH2); 1.89 (2H, d, J = 4.5 Hz,
2 ꢃ H–C(4)); 2.41, 2.89 (4H, 2br d, 1:1, J = 15.2 Hz,
2 ꢃ H2C(40)); 3.14 (2H, d, J = 5.7 Hz, 2 ꢃ H–C(3)); 3.95
(2H, br d, J = 5.7 Hz, 2 ꢃ NH); 4.40–4.50 (4H, m,
2 ꢃ H2C(20)); 4.74, 4.88 (4H, 2br s, 1:1, 2 ꢃ H2C(300));
6.35–6.41, 6.63–6.69 (4H, 2m, 1:1, 4H of Ar). 13C NMR
(CDCl3): d 10.1, 21.8, 22.5, 26.1, 31.7, 43.1, 48.4, 49.4,
52.4, 69.0, 73.3, 94.3, 104.6, 110.1, 117.2, 135.7, 146.8.
m/z (EI) = 516 (M+); m/z (HRMS) found: 516.373050
(M+); C34H48N2O2 requires: m/z = 516.371579. (C34H48-
N2O2 requires: C, 79.02; H, 9.36; N, 5.42. Found: C,
79.57; H, 10.43; N, 4.88.); mmax (KBr) 3406, 2953, 2886,
1670, 1596, 1517, 1481, 1446, 1430, 1401, 1389, 1371,
1330, 1310, 1268, 1245, 1194, 1152, 1073, 1040, 996, 885,
21
1
½aꢂ589 ¼ þ42:2 (c 0.06, CHCl3). H NMR (CDCl3): d 0.82,
0.89, 0.94, 0.99, 1.02, 1.23 (18H, 6s, 1:1:1:1:1:1, 6 ꢃ Me);
1.14–1.27 (1H, m, 1H of CH2); 1.32–1.49, 1.59–1.65 (4H,
2m, 1:1, 2 ꢃ CH2); 1.68–1.81 (3H, m, 2H of CH2, H–
C(41)); 2.03–2.15 (1H, m, 1H of CH2); 2.20 (1H, d,
J = 4.2 Hz, H–C(42)); 2.39 (1H, dd, J = 1.2; 15.3 Hz, Ha–
C(40)); 2.89 (1H, br d, J = 15.3 Hz, Hb–C(40)); 3.08 (1H,
d, J = 4.2 Hz, H–C(31)); 3.38 (1H, s, H–C(32)); 3.58 (1H,
s, H–N1); 4.22–4.28 (2H, m, Ha–C(20), H–N2); 4.40 (1H,
br d, J = 12.6 Hz, Hb–C(20)); 4.74 (1H, d, J = 1.2 Hz,
Ha–C(300)); 4.88 (1H, s, Hb–C(300)); 6.44 (1H, d,
J = 7.8 Hz, 1H of Ar); 6.50 (1H, d, J = 7.5 Hz, 1H of
Ar); 6.66 (1H, dt, J = 1.2; 7.5 Hz, 1H of Ar); 6.82 (1H,
dt, J = 1.2; 7.5 Hz, 1H of Ar). 13C NMR (CDCl3): d 9.4,
10.1, 20.8, 20.9, 21.9, 22.4, 25.9, 26.4, 29.0, 31.7, 43.1,
46.9, 47.0, 49.2, 49.5, 52.6, 56.9, 64.3, 69.0, 73.1, 94.1,
104.7, 110.3, 112.1, 116.7, 120.5, 135.0, 137.9, 146.5,
730 cmꢀ1
.
5.7. Synthesis of N1,N2-bis{(1S,2R,3S,4R,40R)-1,40,7,7-
tetramethyldihydro-30H-spiro[bicyclo[2.2.1]-heptane-2,20-
furan]-3-yl}benzene-1,2-diamine 18 and its
(1S,2R,3S,4R,40S)-epimer 180
A mixture of compound 4 (0.63 mmol, 326 mg), ethanol
(50 mL), and 10% Pd–C (100 mg) was hydrogenated (3

340
U. Grosˇelj et al. / Tetrahedron: Asymmetry 19 (2008) 330–342
bar of H2) at room temperature for 10 h. The reaction mix-
ture was filtered through a short pad of CeliteÒ, washed
with dichloromethane (100 mL), and the filtrate evaporated
in vacuo to give a mixture of epimers 18 and 180 in a ratio
of 85:15, which was purified by CC (PhMe–hexanes, 1:2).
Fractions containing the product were combined and evap-
orated in vacuo to give compound 18.
(2H, br s, 2 ꢃ Hb–C(300)); 7.64–7.70, 7.93–7.98 (4H, 2m,
1:1, 4H of Ar); 9.31 (1H, s, 1H of Ar). 13C NMR (CDCl3):
d 9.8, 22.3, 23.7, 28.2, 30.2, 41.7, 49.7, 51.0, 54.5, 72.5, 73.4,
95.9, 106.4, 114.5, 127.2, 131.7, 139.1, 144.5. m/z
(EI) = 527 (M-87+); m/z (HRMS) found: 527.364900 (M-
87+); C35H47N2O2 requires: m/z = 527.363754. (C35H47-
BF4N2O2 requires: C, 68.40; H, 7.71; N, 4.56. Found: C,
67.77; H, 7.86; N, 4.65.); mmax (KBr) 3422, 3210, 2952,
2930, 2872, 1636, 1617, 1549, 1481, 1458, 1449, 1394,
1373, 1320, 1244, 1235, 1196, 1168, 1123, 1083, 1063,
5.7.1. Data for compound 18. Yield: 0.145 g (44%) of a
21
greenish-white solid; mp 163–173 °C; ½aꢂ589 ¼ þ93:1 (c
1032, 899, 765, 752 cmꢀ1
.
1
0.12, CHCl3). H NMR (CDCl3): d 0.79, 0.84, 1.18 (18H,
3s, 1:1:1, 6 ꢃ Me); 0.84 (6H, d, J = 6.9 Hz, 2 ꢃ H3C–
C(30)); 1.20–1.27, 1.42–1.47 (6H, 2m, 1:2, 3 ꢃ CH2); 1.58
(2H, dd, J = 3.6; 12.9 Hz, 2 ꢃ Ha–C(40)); 1.67–1.78 (2H,
m, CH2); 1.84 (2H, d, J = 4.5 Hz, 2 ꢃ H–C(4)); 2.12–2.26
(2H, m, 2 ꢃ H–C(30)); 2.42 (2H, dd, J = 7.8; 12.9 Hz,
2 ꢃ Hb–C(40)); 3.15 (2H, d, J = 3.3 Hz, 2 ꢃ H–C(3)); 3.58
(2H, dd, J = 3.6; 8.1 Hz, 2 ꢃ Ha–C(20)); 3.93 (2H, dd,
J = 6.0; 8.1 Hz, 2 ꢃ Hb–C(20)); 4.43 (2H, br s, 2 ꢃ NH);
6.33–6.39, 6.62–6.68 (4H, 2m, 1:1, 4H of Ar). 13C NMR
(CDCl3): d 10.3, 18.4, 21.9, 22.7, 25.8, 31.4, 33.5, 44.3,
48.7, 49.4, 52.8, 68.9, 77.1, 93.2, 109.0, 116.8, 135.5. m/z
(EI) = 520 (M+); m/z (HRMS) found: 520.404120 (M+);
C34H52N2O2 requires: m/z = 520.402879. (C34H52N2O2 re-
quires: C, 78.41; H, 10.06; N, 5.38. Found: C, 78.63; H,
10.34; N, 5.38.); mmax (KBr) 3385, 2963, 2937, 2873, 1595,
1518, 1481, 1455, 1445, 1426, 1387, 1366, 1352, 1312,
1274, 1261, 1247, 1150, 1116, 1072, 1047, 1042, 1024,
5.8.2. 1,3-Bis{(1S,2R,3S,4R,40R)-1,40,7,7-tetramethyldihy-
dro-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-yl}-1H-ben-
zo[d]imidazol-3-ium tetrafluoroborate 20. Prepared from
compound 16; 0.110 g (42%) of a dirty-white solid; mp
22
333–337 °C; ½aꢂ589 ¼ þ54:7 (c 0.09 CHCl3). 1H NMR
(DMSO-d6): d 0.68 (6H, d, J = 6.9 Hz, 2 ꢃ H3C–C(30));
0.89, 0.90, 1.19 (18H, 3s, 1:1:1, 6 ꢃ Me); 1.50–1.76, 1.82–
1.93 (8H, 2m, 3:1, 4 ꢃ CH2); 2.04 (2H, dd, J = 6.3;
13.5 Hz, 2 ꢃ Ha–C(40)); 2.12 (2H, d, J = 4.2 Hz, 2 ꢃ H–
C(4)); 2.18–2.29 (2H, m, 2 ꢃ H–C(30)); 2.62 (2H, dd,
J = 7.5; 13.5 Hz, 2 ꢃ Hb–C(40)); 3.11 (2H, dd, J = 6.0;
7.8 Hz, 2 ꢃ Ha–C(20)); 3.88 (2H, dd, J = 6.3; 7.8 Hz,
2 ꢃ Hb–C(20)); 4.91 (2H, s, 2 ꢃ H–C(3)); 7.76–7.82, 8.00–
8.06 (4H, 2m, 1:1, 4H of Ar); 10.05 (1H, s, 1H of Ar).
13C NMR (DMSO-d6): d 10.0, 17.0, 21.7, 22.2, 27.0, 30.1,
32.5, 42.8, 49.4, 51.3, 53.9, 71.6, 76.5, 95.2, 114.5, 127.1,
131.6, 141.0. m/z (EI) = 531 (Mꢀ87+); m/z (HRMS)
found: 531.3944 (Mꢀ87+); C35H51N2O2 requires: m/z =
531.3951. (C35H51BF4N2O2 requires: C, 67.96; H, 8.31;
N, 4.53. Found: C, 67.41; H, 8.45; N, 4.61.); mmax (KBr)
3447, 3227, 2977, 2964, 2940, 2891, 1636, 1534, 1489,
1459, 1391, 1323, 1313, 1237, 1168, 1123, 1081, 1053,
1013, 994, 967, 936, 738 cmꢀ1
.
5.7.2. Data for compound 180. 1H NMR (CDCl3): d 0.88
(6H, s, 2 ꢃ Me); 0.92 (6H, d, J = 6.3 Hz, 2 ꢃ H3C–C(30));
1.16 (6H, s, 2 ꢃ Me); 2.03–2.13 (2H, m, 2 ꢃ H–C(30));
3.04 (2H, s, 2 ꢃ H–C(3)); 3.24 (2H, dd, J = 7.8; 10.8 Hz);
4.05 (2H, t, J = 7.5 Hz); 4.20 (2H, br s, 2 ꢃ NH).
1032, 989, 980, 942, 779, 766 cmꢀ1
.
5.9. X-ray structure analysis for compounds 12, 130, and 20
5.8. General procedure for the preparation of benzo[d]-
imidazolium tetrafluoroborates 19 and 20
Single crystal X-ray diffraction data of compounds 12, 130,
and 20 were collected at room temperature on a Nonius
Kappa CCD diffractometer using the Nonius Collect Soft-
Two drops of formic acid were added to a mixture of di-
amine 4 (0.218 g, 0.42 mmol) or 18 (0.220 g, 0.42 mmol)
and NH4BF4 (0.42 mmol, 45 mg) in triethyl orthoformate
(3 mL) under argon. The reaction mixture was heated at
120 °C for 3 h. Upon cooling to room temperature, Et2O
(10 mL) was added, and the resulting precipitate was col-
lected by filtration, and washed with Et2O (10 mL) to give
product 19 or 20, respectively. Compounds 19 and 20 were
prepared in this manner.
52
ware.51 DENZO and SCALEPACK were used for indexing
and scaling of the data and the structures were solved by
means of SIR97.53 Refinement was done using XTAL3.454
program package and the crystallographic plots were pre-
pared by ORTEP III.55 Crystal structures were refined on F
values using the full-matrix least-squares procedure. The
non-hydrogen atoms were refined anisotropically in all
cases, while the positions of hydrogen atoms were geomet-
rically calculated and their positional and isotropic atomic
displacement parameters were not refined. Absorption cor-
rection was not necessary. Regina56 weighting scheme was
used in all cases.
5.8.1. 1,3-Bis{(1S,2R,3S,4R)-1,7,7-trimethyl-40-methylenedi-
hydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-yl}-1H-
benzo[d]imidazol-3-ium tetrafluoroborate 19. Prepared
from 4; 0.158 g (61%) of a dirty-white solid; mp 219–
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary
publication numbers CCDC 668594–668596. Copies of
the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
[fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.cam.
ac.uk.
23
225 °C; ½aꢂ589 ¼ þ64:8 (c 0.23, CHCl3). 1H NMR
(DMSO-d6): d 0.90, 0.95, 1.23 (18H, 3s, 1:1:1, 6 ꢃ Me);
1.53–1.69, 1.86–1.98 (8H, 2m, 3:1, 4 ꢃ CH2); 2.32 (2H, d,
J = 4.5 Hz, 2 ꢃ H–C(4)); 3.08, 3.23 (4H, 2br d, 1:1,
J = 17.0 Hz, 2 ꢃ H2C(40)); 3.66 (2H, dd, J = 0.9; 12.9 Hz,
2 ꢃ Ha–C(20)); 4.25 (2H, d, J = 12.9 Hz, 2 ꢃ Hb–C(20));
4.74 (2H, s, 2 ꢃ Ha–C(300)); 4.88 (2H, s, 2 ꢃ H–(3)); 5.04

U. Grosˇelj et al. / Tetrahedron: Asymmetry 19 (2008) 330–342
341
22. Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc.
2006, 128, 1840–1846.
Acknowledgments
23. Herrmann, W. A.; Elison, M.; Fischer, J.; Ko¨cher, C.;
Arthus, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2371.
24. Perry, M. C.; Burgess, K. Tetrahedron: Asymmetry 2003, 14,
951.
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 the financial support from pharmaceuti-
cal 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 Alex-
ander von Humboldt Foundation, Germany, for the dona-
tion of a Buchi 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 Technol-
ogy, University of Ljubljana, Slovenia. We acknowledge
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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