Studies on bicyclo[3.3.1]nonanes for synthesis of cyclooctenes

Article abstract of DOI:10.1081/SCC-120004065

This paper describes a full conformational and stereochemical study of bicylo[3.3.1]nonanes, obtained from the reaction between cinnamaldehyde and 1-morpholine 1-cyclohexene. NMR data and stereochemistry were unequivocally established and assigned by two-

Full text of DOI:10.1081/SCC-120004065

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
STUDIES ON BICYCLO[3.3.1]NONANES FOR
SYNTHESIS OF CYCLOOCTENES
David Díez , Margarita Parra , Sonia G. San Feliciano , Isidro S. Marcos ,
Narciso M. Garrido , Pilar Basabe , Alicia Jiménez , Howard B. Broughton &
Julio G. Urones
To cite this article: David Díez , Margarita Parra , Sonia G. San Feliciano , Isidro S. Marcos ,
Narciso M. Garrido , Pilar Basabe , Alicia Jiménez , Howard B. Broughton & Julio G. Urones
(2002) STUDIES ON BICYCLO[3.3.1]NONANES FOR SYNTHESIS OF CYCLOOCTENES, Synthetic
Communications, 32:12, 1829-1839, DOI: 10.1081/SCC-120004065
To link to this article: http://dx.doi.org/10.1081/SCC-120004065
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SYNTHETIC COMMUNICATIONS, 32(12), 1829–1839 (2002)
STUDIES ON BICYCLO[3.3.1]NONANES
FOR SYNTHESIS OF CYCLOOCTENES
David Dıez,1, Margarita Parra,2
*
Sonia G. San Feliciano,1 Isidro S. Marcos,1
1
Narciso M. Garrido,1 PilarBasabe, Alicia Jimenez,3
Howard B. Broughton,4 and Julio G. Urones1
1Dpto. Quımica Organica, Universidad de Salamanca,
37008, Salamanca, Spain
2Dpto. Quımica Organica, Universidad de Valencia,
Valencia, Spain
3Servicio de Rayos X, Universidad de Salamanca,
Salamanca, Spain
4Merck Sharp & Dohme, Harlow, Essex, UK
ABSTRACT
This paper describes a full conformational and stereochemical
study of bicylo[3.3.1]nonanes, obtained from the reaction
between cinnamaldehyde and 1-morpholine 1-cyclohexene.
NMR data and stereochemistry were unequivocally estab-
lished and assigned by two-dimensional experiments and
single-crystal X-ray analysis. The crystal structure of a
minor compound, 4, is reported. Cyclooctenes, which are
present in natural products with biological activities, were
synthesized from the bicyclononanes via the Wharton
fragmentation.
*Corresponding author. Fax: 00 34 923294474; E-mail: ddm@gugu.usal.es
1829
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1830
DIEZ ET AL.
Key Words: Bicyclo[3.3.1]nonanes; Cyclooctenes synthetic
methods; Wharton; Molecular modelling
INTRODUCTION
Compounds with eight-membered rings are widely distributed in
Nature, principally in higher plants and marine organisms.[1] Some of
them exhibit interesting biological activities: for example, taxol, used in
the treatment of ovarian and other types of cancers,[2] and dibenzocyclo-
octadiene lignanes, which possess antileukemic activity, and are found in the
steganone family.[3]
Bicyclic[3.3.1]nonane systems bearing a keto group at C-9 and a leav-
ing group ꢀ to the bridge position undergo a facile cleavage of the C9–C1 or
C9–C5 bond to produce an eight membered ring in basic conditions. This
reaction, a variant of the Grob fragmentation known as the Wharton frag-
mentation, has been used for many years in order to obtain these struc-
tures,[4] along with the Haller–Bauer reaction.[5]
Recently a renewed interest in the synthesis and use of bicyclo[3.3.1]-
nonane systems has been demonstrated.[6–8] This has induced us to publish
our preliminary studies in this area.
It is known that enamines and ꢀ-ꢁ unsaturated aldehydes react to give
bicyclo[3.3.1]nonanes.[9] In particular, the reaction between 1-morpholine-1-
cyclohexene and cinnamaldehyde has been studied several times by different
groups,[10–13] due to the biological properties of the compounds obtained
with this methodology.[14] Single crystal X-ray analysis established the
stereochemistry of the major product, and the group of Trivedi carried
out the conformational studies;[11] but the two minor bicyclic products
remain insufficiently described. In this paper, we describe a complete
experimental and theoretical study of this reaction revising some 13C assign-
ments worked out by Trivedi’s research group. The three bicyclo[3.3.1]no-
nanes obtained were transformed under basic conditions into the respective
cis and trans cyclooctenes, in order to corroborate the stereochemistry of the
starting materials.
RESULTS AND DISCUSSION
In the reaction of cinnamaldehyde and 1-morpholine-1-cyclohexene,
only three bicyclic compounds of the four possible products were identified
(65% in total) together with a byproduct 5 (5%). The ratios of the products
are shown in Scheme 1.

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BICYCLO[3.3.1]NONANES
1831
Scheme 1.
Rationalisation of the Results Obtained
1. Structural Analyses
The conformation of compound 1 has been previously considered, and
there is even a single crystal X-ray analysis.[10] In the 1H-NMR, more notice-
able signals are: firstly, the hydrogen in the axial position on C-3 (Hax on
C-3) that shows an apparent quartet at 1.41 ppm with J ¼ 13.0 Hz, which
supports a chair–boat conformation; and secondly, two double triplets
corresponding to hydrogen on C-2and hydrogen on C-4 at 3.05 ppm
(H on C-2, dt, J ¼ 12.7 and 4.0 Hz) and 3.02 ppm (H on C-2, dt, J ¼ 12.7
and 4.0 Hz) respectively. The 13C NMR assignment is shown unequivocally
in Table 1.
In the literature, only the melting points of the other products, 2 and
4,[10] are given. We therefore decided to find out the conformation of both.
The bicyclic structure 3 was never detected. In both the products we were
able to isolate, the conformation is chair–chair, as deduced from the lack of
upfield signals for the hydrogen on C-3.
The stereochemistry of 2 was assigned on the following basis: a doub-
let at 3.43 ppm (J ¼ 8.1 Hz) assigned to hydrogen on C-4 (dihedral angle
with the other two hydrogen atoms ꢀ90ꢁ), implies an axial position for
the phenyl, and thus equatorial for the morpholine group, which has to
be a different compound from 1.
On the other hand, the phenyl group in the structure 4 is equatorial.
This was determined on the basis of the hydrogen on C-4 in 1H NMR, which
appears as a double triplet at 3.14 ppm with J ¼ 13.6 and 4.8 Hz. An n.O.e.

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1832
DIEZ ET AL.
Table 1. 13C NMR 100 MHz (The Assignment Has Been
Done by 2D Heteronuclear Experiments (1H/13C HCCORR)
1
2
4
C-1
48.87
63.30
32.89
43.78
53.51
34.89
16.58
34.30
219.85
146.57
127.03
126.58
128.73
49.30
67.04
48.10
65.49
32.75
46.88
50.99
36.29
20.43
28.67
219.85
146.33
126.94
126.18
128.53
50.7251.03
66.96
47.70
C-265.66
C-3
C-4
C-5
C-6
30.09
44.60
52.19
28.38
20.80
27.70
218.71
141.14
127.67
126.85
128.58
C-7
C-8
C-9
C-10
C-20, 60
C-400
C-3 , 50
C-100, 400
C-200, 300
67.02
between the hydrogen on C-2and the hydrogen on C-4 places the morpho-
line group equatorial as well. We could confirm this stereochemistry in 4
due to the axial hydrogen on C-3, that appears as a quartet at 2.38 ppm with
J ¼ 13.5 Hz similar to the one in the structure 1, except for the shielding.
The structure 4 was confirmed by a single X ray analysis, and it is shown in
Figure 1.
2. Molecular Modelling Analyses
The formation of the above products in the ratio of 61 : 16 : 0 : 23 calls
for some comment. While the stereochemistry of the initial Michael addition
has been explained previously,[11] it is not immediately clear what factors
give rise to the ratios of the pairs of cyclisation products arising from each of
these intermediates (1 : 2 and 3 : 4). These molecules do not equilibrate under
conditions very similar to those used in their formation. As a study has been
done using isolated isomers to dope the reaction, it is likely that the product
ratio is the result of kinetic effects during the ring closure step, in which an
enol or enolate closes onto the iminium group of the precursor. We there-
fore undertook a molecular modelling study to see whether the reaction
profile in the gas phase was consistent with the observed product ratios.
For each of the above molecules, several models were constructed as initial

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BICYCLO[3.3.1]NONANES
1833
Figure 1. X-Ray of compound 4.
starting points. Each of the two cyclohexanone rings in each molecule can
exist as boat or chair, and all four possibilities were studied. The bond to the
nitrogen of the morpholine can take an axial or equatorial orientation with
respect to the morpholine, and each of these was also studied for all four
ring-flips of the bicycle. The initial conformations were minimised by mol-
ecular mechanics using the Tripos force field, and then each system was
optimised with MOPAC using the AM1 Hamiltonian and precise conver-
gence criteria, with the eigenvector following optimisation method. The
resulting structures were submitted to a systematic conformational search
in which the bonds between the bicycle and the phenyl ring, and that
between the bicycle and the morpholine, were explored in 15 degree incre-
ments. An hydrogen was also attached to the carbonyl oxygen, with a
dihedral angle of 80 degrees with respect to the bridge head, such that it
lay over the substituted side of the bicycle and slightly toward the morpho-
line. This was done so that the reverse reaction would ‘‘give rise to’’ the enol,
the condensation of an enolate on an iminium ion often being a barrierless
process at least in the gas phase.
The lowest-energy structure by molecular mechanics was then
re-optimised with MOPAC as before (with a charge of þ1 since the carbonyl
was protonated) and then the bond formed during the final step of the
reaction was stretched in 0.05 A increments between 1.5 and 2.5 A. This
permitted the location of structures close to the transition state for each
starting conformer. Those structures where the approximate transition state
thus located had the lowest energy observed for the reaction processes

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1834
DIEZ ET AL.
involved in formation of 1 to 4 were then subjected to the MOPAC transi-
tion state search using eigenvector following until the transition state was
located. This was also done for a few other low-lying transition states for
alternate conformers of some of the systems, confirming that the approx-
imate method had indeed located transition states close to those found by
the TS routine. On this basis, selection of structures from the reaction
coordinate study for full transition state optimisation based on the relative
energies from the reaction coordinate was valid.
The relative energies and dipoles of the various transition states located
in this experiment are given below. For the transition states, the lowest cal-
culated Gibbs free energy for a transition state giving rise to each possible
product based on vibrational analysis at 300 K is also given. The free energy is
calculated from the result of a THERMO and FORCE calculation done on
the transition state geometry previously found, by using ÁG ¼ ÁH ꢂ TÁS
and substituting in the values for enthalpy and entropy calculated by
MOPAC with the THERMO, FORCE, ROT ¼ 1 and TRANS keywords.
These values are indeed consistent with the major product of each cyclisation,
though the differences are not sufficient to explain the complete absence of 3.
This could be because of entropic differences between the conformations
required, increasing the difference in barrier heights relative to those calcu-
lated here, to solvation effects, to further reaction of the product 3, to failure
to find the lowest-energy transition state for the case 4, or simply to the
inadequacy of gas-phase AM1 to model accurately such systems. Table 2.
In order to corroborate the stereochemistry of the compounds 1, 2 and
4, and to obtain cyclooctenes for further synthesis of biologically active
compounds, they were submitted to the Wharton conditions, leading to
the cyclic products 6 and 7 (Scheme 2).
We could obtain the structure 6 from compounds 1 and 2 in 50% and
58% yield respectively, while compound 4 gave the cyclooctene 7 in 52%
yield, the remainder being recovered starting material. Taking into account
Table 2.
Open
Chain
H.o.F.
Open
Chain
Dipole
TS
Free
Energy
Ring
Closed
H.o.F.
Ring
Closed
Dipole
TS
H.o.F.
TS
Dipole
(Kcal/mol) (Debye) (Kcal/mol) (Kcal/mol) (Debye) (Kcal/mol) (Debye)
1
2
3
4
89.86
91.25
91.31
90.73
6.68
5.46
6.69
7.05
30.06
29.45
29.82
30.00
108.44
111.74
110.02
111.17
3.30
3.15
4.25
4.25
103.07
106.94
101.72
106.13
7.53
7.57
6.79
7.82

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BICYCLO[3.3.1]NONANES
1835
Scheme 2.
the coupling constants of the different hydrogen atoms and with the help of
n.O.e. experiments, we proposed one conformation of the products 6 and 7,
as shown in the above figure. The 13C NMR data are given in experimental
section, and they were assigned unequivocally by HMQC and HMBC
experiments.
CONCLUSION
In summary, our goal was to complete the previous studies done in this area,
which we presumed would be very helpful for research groups working in
this area. We have done a full conformational and stereochemical study of
bicyclo[3.3.1]nonates, obtained from the reaction between cinnamaldehyde
and 1-morpholine 1-cyclohexene, and the synthesis of the cyclooctenes by
submission to the Wharton fragmentation. NMR data and stereochemistry
were unequivocally established and assigned by two-dimensional experi-
ments and single X-ray analysis.
EXPERIMENTAL SECTION
General remarks: Melting points were determined on a hot-stage appa-
1
ratus. The H and 13C NMR spectra were recorded in CDCl3 solution on
Bruker Avance 400 MHz DRX spectrometer; using residual isotopic solvent
(CHCl3, ꢂH ¼ 7.26 ppm; CHCl3, ꢂC ¼ 77 ppm) as the references. IR
spectra were obtained as thin films using a BOMEM FT MB-100 spectrom-
eter. Mass spectra were recorded using VG TS-250, 70 eV instrument.

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DIEZ ET AL.
All reactions were monitored by TLC. Flash column chromatography was
carried out using silica gel 60 (0.040–0.063 mm Merck). Organic extracts
were dried with anhydrous Na2SO4 and evaporated under reduced pressure
below 40ꢁC. All crystalline products were crystallised from methanol.
X-Ray analysis was recorded on SEIFERT XRD 3003 SC diffractometer.
Reaction between 1-morpholino-1-cyclohexene and cinnamaldehyde:
1-morpholino-1-cyclohexene (5.6 ml, 33.25 mmol) was added at 0ꢁC with
stirring under argon to a solution of cinnamaldehyde (870 mg, 6.60 mmol)
and a catalytic amount of 2,6-diterc-butyl-4-methyl-phenol as radical inhi-
bitor in dry CH2Cl2 (14 ml). The resulting mixture was gradually warmed to
rt and stirred for 22 h, and then, H2O (2ml) was added. It was extracted
several times with AcOEt, washed with H2O and brine, and then, dried
(Na2SO4). Evaporation of the solvent left a crude product of three bicy-
clo[3,3,1]nonanes 1 (785 mg, 2.62 mmol, 40%), 2 (200 mg, 0.66 mmol, 10%),
4 (293 mg, 0.97 mmol, 15%) and the by product 5 (70 mg, 0.33 mmol, 5%)
and the excess of the starting enamine, which were separated by flash chro-
matography using hexane–ethyl acetate (8 : 2) as the eluent.
2-cinnamylidencyclohexanone 5 was first eluted as a crystalline
product: m.p. 110–113ꢁC; ꢃmax/cmꢂ1: 2934, 1669, 1578, 1241, 1146, 976,
754; ꢂH (CDCl3, 400 MHz): 7.25 (2H, m, H-60 and H-80, Ar), 7.15 (3H, m,
H-50, H-90 and H-80 Ar), 6.98 (1H, dd, J ¼ 14.67 and 25 Hz, H-20), 6.98 (1H, d,
J ¼ 9.98 Hz, H-30), 2.73 (2H, t, J ¼ 5.87 Hz, H-3), 2.48 (2H, t, J ¼ 6.46 Hz,
1
H-6), 1.86 (4H, m, H-4 and H-5); ꢂC (CDCl3, 100 MHz, H-decoupled):
0
200.46 (1C, C-1), 140.81 (CH, C-10), 136.72(C-ipso Ar, C-4 ), 135.29 (CH,
C-20), 135.05 (1C, C-2), 128.75 (2CH meta Ar, C-60 and C-80), 128.75 (CH, C-
30), 127.10 (2CH ortho Ar, C-50 and C-90), 123.14 (1CH para Ar, C-70), 39.94
(CH2, C-3), 26.90 (CH2, C-6), 23.33 (CH2, C-5), 23.03 (CH2, C-4); HRMS:
212.1176 (C15H16O1 requires 212.1201), m/z (Mþ, 7%) 153 (14%), 136 (11%),
107 (52%), 89 (31%), 77 (100%), 63 (23%).
The second compound was identified as the crystalline bicycle [3,3,1]
nonane, 2R*-morpholine-4S*-phenyl-bicyclo[3,3,1]nonan-9-one, 4: m.p.
135–140ꢁC; ꢃmax/cmꢂ1: 2955, 2855, 1715, 1452, 1275, 1121, 702; ꢂH
(CDCl3, 400 MHz): 7.25 (2H, m, H-50 and H-30, Ar), 7.15 (2H, m, H-20
and H-60, Ar), 7.15 (1H, m, H-40, Ar), 3.75 (4H, m, H-200 and H-300), 3.14
(1H, dt, J ¼ 13.6 and 4.8 Hz, H-4ꢁ), 2.75 (1H, m, H-1ꢀ), 2.53 (4H, m, H-100
and H-400), 2.5 (1H, m, H-5ꢀ), 2.49 (1H, m, H-2ꢁ), 2.45 (1H, m, H-8ꢀ), 2.38
(1H, q, J ¼ 13.5 Hz, H-3ꢀ), 2.14 (1H, dt, J ¼ 13.4 and 5.4 Hz, H-3ꢁ), 2.00
(1H, m, H-7ꢀ), 1.9 (1H, m, H-6ꢀ), 1.8 (1H, m, H-8ꢁ), 1.75 (1H, m, H-6ꢁ),
1
1.50 (1H, m, H-7ꢁ); ꢂC (CDCl3, 100 MHz, H-decoupled): Table 1; HRMS:
299.1913 (Mþ, 7%, C19H25NO2 requires 299.1885), m/z: 299 (Mþ, 13%) 230
(24%), 202 (100%), 181 (53%), 150 (46%), 98 (74%); The third compound
was an oily product identified as 2R*-morpholine-4R*-phenyl-bicy-

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BICYCLO[3.3.1]NONANES
1837
clo[3,3,1]nonan-9-one, 2: ꢃmax/cmꢂ1; 2995, 2853, 1713, 1452, 1277, 1121;
ꢂH (CDCl3, 400 MHz): 7.25 (2H, m, H-50 and H-30, Ar), 7.15 (2H, m, H-20
and H-60, Ar), 7.15 (1H, m, H-40, Ar), 3.65 (4H, m, H-200 and H-300), 3.43
(1H, d, J ¼ 8.1 Hz, H-4ꢀ), 2.75 (1H, wide s, H-5ꢀ), 2.68 (1H, m, H-2ꢁ), 2.65
(1H, wide s, H-1ꢀ), 2.4 (4H, m, H-100 and H-400), 2.5 (1H, m, H-3ꢀ), 2.5 (1H,
m, H-8ꢀ), 2.15 (1H, m, H-3ꢁ), 2.15 (1H, m, H-6ꢀ), 2.15 (1H, m, H-6ꢁ), 2.15
(1H, m, H-7ꢀ), 1.8 (1H, m, H-8ꢁ), 1.58 (1H, m, H-7ꢁ); ꢂC (CDCl3, 100 MHz,
1H-decoupled): Table 1; HRMS: 299.1871 (Mþ, C19H25NO2, requires
299.1885), m/z: 299 (Mþ, 2%), 219 (2%), 202 (100%), 129 (43%), 107
(17%), 84 (86%).
The fourth one was a crystalline bicyclo[3,3,1]nonane identified as 2S*-
morpholine-4R*-phenyl-bicycle [3,3,1] nonan-9-one, 1: m.p. 118–120ꢁC;
ꢃ
max/cmꢂ1: 2940, 2885, 1711, 1451, 117, 702; ꢂH (CDCl3, 400 MHz): 7.25
(2H, m, H-50 and H-30, Ar), 7.17 (2H, m, H-20 and H-60, Ar), 7.17 (1H, m, H-
40, Ar), 3.66 (4H, t, J ¼ 4.71 Hz, H-200 and H-300), 3.05 (1H, dt, J ¼ 12.8 and
4.0 Hz, H-2ꢀ), 3.02(1H, dt, J ¼ 14.1 and 4.0 Hz, H-4ꢀ), 2.58 (1H, m, H-1ꢀ),
2.58 (1H, m, H-5ꢀ), 2.52 (4H, t, J ¼ 4.7 Hz, H-100 and H-400), 2.0 (1H, m, H-
3ꢀ), 2.0 (1H, m, H-6ꢀ), 2.0 (1H, m, H-7ꢀ), 2.0 (2H, m, H-8), 18.5 (1H, m, H-
6ꢁ), 1.62(1H, m, H-7 ꢁ), 1.41 (1H, q, J ¼ 13.1 Hz, H-3ꢁ); ꢂC (CDCl3,
100 MHz, 1H-decoupled): Table 1; HRMS: 299.1861 (Mþ, C19H25NO2,
requires 299.1885), m/z: 299 (Mþ, 2%), 256 (3.5%), 202 (6%), 153 (35%),
107 (56%), 77 (100%).
Wharton Fragmentation: MeI (4 ml) was added dropwise to the pur-
ified bicyclo[3,3,1]nonane, 1, 2 or 4 (200 mg, 0.7 mmol) at rt under argon.
The mixture was stirred and gradually warmed to MeI reflux for 22 h. After
that, the evaporation of the MeI in excess left the corresponding salt, which
was never isolated or purified, but 5 ml of 15% KOH solution were added
on it. The new mixture was stirred and warmed at reflux (100ꢁC) for 20 h,
and then extracted with AcOEt. The extract was washed with H2O and
brine, and then dried. The solvent was evaporated, and in all cases the
cyclooctenes were purified by flash column chromatography, and obtained
6 in 50% yield from 1 and in 58% from 2, and 7 in 52% from 4.
2R*-phenyl-4-cycloocten-1S*-carboxylic acid, 6: m.p.: 138–140ꢁC;
ꢃ
max/cmꢂ1; 3200–2900, 1710, 1452, 1246, 700; ꢂH (CDCl3, 400 MHz): 7.25
(5H, m, Ar), 5.92(1H, ddd, J ¼ 15.2, 10.4 and 7.6 Hz, H-5), 5.74 (1H, m,
H-4), 3.38 (1H, dt, J ¼ 13.2and 4.8 Hz, H-2 ꢀ), 3.10 (1H, t, J ¼ 4.8 Hz, H-
1ꢀ), 2.89 (1H, ddd, J ¼ 13.2, 13.2 and 10 Hz, H-3ꢁ), 2.35 (1H, m, H-6ꢁ), 2.21
(1H, m, H-6ꢀ), 2.2 (1H, m, H-3ꢀ), 2.2 (1H, m, H-8ꢁ), 1.85 (1H, m, H-8ꢀ),
1.85 (1H, m, H-7ꢁ), 1.31 (1H, m, H-7ꢀ); ꢂC (CDCl3, 100 MHz,
1H-decoupled): 182.08 (1C, C1-COOH), 141.85 (C-ipso Ar), 132.40 (CH,
C5), 128.66 (2CH meta Ar), 128.66 (CH, C-4) 128.21 (2CH ortho Ar), 126.73
(1CH para Ar), 46.87 (CH, C-1), 45.74 (CH, C-2), 30.94 (CH2, C-3), 28.30

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1838
DIEZ ET AL.
(CH2, C-7), 27.45 (CH2, C-6), 24.91 (CH2, C-8); HRMS: 230.1296
(Mþ, C15H18O2, requires 230.1306), m/z 230 (Mþ, 32%), 104 (100%), 91
(99%), 78 (53%), 67 (34%).
2S*-phenyl-4-cycloocten-1S*-carboxylic acid, 7: m.p.: 118–120ꢁC;
ꢃ
max/cmꢂ1; 3200–2900, 1705, 1452, 1246, 700; ꢂH (CDCl3, 400 MHz): 7.23
(2H, m, Ar), 7.15 (3H, m, Ar), 5.82 (1H, ddd, J ¼ 15.6, 10.0 and 8 Hz, H-4),
5.64 (1H, ddd, J ¼ 16.4, 10.0 and 6.4 Hz, H-5), 3.09 (1H, ddd, J ¼ 16.4 Hz,
10.8 and 5.2Hz, H-2 ꢁ), 2.85 (1H, ddd, J ¼ 11.2, 6.4 and 1.2 Hz, H-1ꢀ), 2.70
(1H, m, ddd, J ¼ 14, 9.6 and 4.8 Hz, H-3ꢀ), 2.25 (2H, m, H-6), 2.25 (1H, m, H-
3ꢁ), 1.91 (1H, m, H-8ꢀ), 1.81 (1H, m, H-8ꢁ), 1.81 (1H, m, H-7ꢁ), 1.65 (1H, m,
H-7ꢀ); ꢂC (CDCl3, 100 MHz, 1H-decoupled): 182.24 (1C, C1-COOH), 144.10
(C-ipso Ar), 131.38 (CH, C-4), 128.24 (2CH meta Ar), 128.00 (CH, C5) 127.36
(2CH ortho Ar), 126.35 (1CH para Ar), 48.82(CH, C-1), 47.66 (CH, C-2),
32.17 (CH2, C-3), 31.03 (CH2, C-8), 28.90 (CH2, C-7), 26.02 (CH2, C-6);
HRMS: 230.1307 (Mþ, C15H18O2 requires 230.1306), m/z 230 (Mþ, 6%),
153 (19%), 136 (16%), 107 (38%), 91 (47%), 77 (100%), 67 (31%).
Crystal data for 4: C19H25NO2, M ¼ 299.4, orthorhombic, space group
P212121 (no. 19), ꢀ ¼ 7.0505 (3), ꢁ ¼ 15.705 (1), ꢄ ¼ 29.235(3) A, ꢀ ¼ 90ꢁ,
ꢁ ¼ 90ꢁ, ꢄ ¼ 90ꢁ, V ¼ 3237.1(2) A3, Z ¼ 8, DC ¼ 1.229 Mg/m3, ꢅ (Cu–Ka) ¼
0.619 mmꢂ1, F(000) ¼ 1296. Data (3165 independent reflections, theta range
ꢁ
3.02to 65.00 ) were measured on a Seifer 3003 SC rotating anode diffract-
ometer with Cu–Ka radiation (graphite monochromator) using 20-! scans.
The structure was solved by direct methods and the non-hydrogen atoms
were refined anisotropically by full-matrix least squares based on F2
to give, R1 ¼ 0.0372, !R2 ¼ 0.0784 [I>2sigma(1)]. Hydrogen atoms were
geometrically constrained and allowed to ride over the atoms to which
they are attached.
ACKNOWLEDGMENTS
We thank the CICYT, Junta de Castilla y Leon (SA 13/00B), MEC
(SGSF) and Generalitat Valenciana (PM) (POST-CB-11-101) for financial
support of this research. We gratefully acknowledge the NMR Spectrometry
Service of University of Salamanca for providing NMR spectra.
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Received in the UK April 26, 2001