NMR-Spectroscopic, computational and mass-spectrometric investigations on the cis/trans analogues of 2,3,4-trihydronaphthalene-1-one

Article abstract of DOI:10.1016/S0040-4020(03)00026-7

NMR-Spectroscopic, computational and mass-spectrometric studies of the cis/trans isomers of N-[8-(acetylamino)-4-(2,2-dimethyl-1,1-diphenyl-silapropoxy)-6-fluoro-5- methyl-1-one-2,3,4-trihydronaphthyl]acetamide (1a and 1b), obtained as intermediates in the synthesis of an important class of alkaloid molecules, are reported. ¹H and ¹³C NMR analyses show an unusual axial preference of the TBDPSi- (tert-butyldiphenylsilyl) group in position 4 in both the isomers. Mass spectrometric evidence demonstrates that trans isomer has a higher affinity for ammonium ions than the cis isomer and that only the ammonium adduct [1b+NH₄]⁺ and the protonated molecule [1b+H]⁺ show the fragmentation in which loss of benzene is observed. Moreover, molecular mechanics and semi-empirical calculations indicate that a group of trans conformers tend to place one of the phenyl rings of the TBDPSiO- group in a offset π-stacked geometry with the compound's aromatic ring. The combination and the detailed analyses of these experimental and theoretical results could support the π-π interaction obtained as a conformational preference in the trans isomer.

Full text of DOI:10.1016/S0040-4020(03)00026-7

Tetrahedron 59 (2003) 1309–1316
NMR-Spectroscopic, computational and mass-spectrometric
investigations on the cis/trans analogues
of 2,3,4-trihydronaphthalene-1-one
*
Antonella Cartoni, Andrea Madami, Daniela Palomba, Marco Marras, Marco Berettoni,
Lauso Olivieri, Alessandro Ettorre, Amalia Cipollone, Fabio Animati, Carlo Alberto Maggi
and Edith Monteagudo
Department of Chemistry and Drug Design Menarini Ricerche S.p.A., Via Tito Speri 10, I-00040 Pomezia, Roma, Italy
Received 27 May 2002; revised 4 December 2002; accepted 19 December 2002
`
This paper is dedicated to the memory of Professor Dr Marina Attina
Abstract—NMR-Spectroscopic, computational and mass-spectrometric studies of the cis/trans isomers of N-[8-(acetylamino)-4-(2,2-
dimethyl-1,1-diphenyl-silapropoxy)-6-fluoro-5-methyl-1-one-2,3,4-trihydronaphthyl]acetamide (1a and 1b), obtained as intermediates in
the synthesis of an important class of alkaloid molecules, are reported. 1H and 13C NMR analyses show an unusual axial preference of the
TBDPSi– (tert-butyldiphenylsilyl) group in position 4 in both the isomers. Mass spectrometric evidence demonstrates that trans isomer has a
higher affinity for ammonium ions than the cis isomer and that only the ammonium adduct [1bþNH4]þ and the protonated molecule
[1bþH]þ show the fragmentation in which loss of benzene is observed. Moreover, molecular mechanics and semi-empirical calculations
indicate that a group of trans conformers tend to place one of the phenyl rings of the TBDPSiO– group in a offset p-stacked geometry
with the compound’s aromatic ring. The combination and the detailed analyses of these experimental and theoretical results could support the
p–p interaction obtained as a conformational preference in the trans isomer. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
account for the conformational preferences of isomers 1a
and 1b.
Non-covalent bonding interactions and their influence in
molecular organisation, recognition and fragmentation have
been the subject of many studies.1 These interactions define
and rule the spatial arrangements adopted by different
important molecules and biomolecules and in particular
aromatic interactions have been shown to play an important
role in many cases.2
It is important to emphasize that the characterization of a
large molecule such as 1, via a combination of different
techniques, while not always easy, is fundamental since a
detailed understanding of the non-covalent interactions that
rule the conformational preferences of the cis/trans isomers
of 1 could lead to a model compound for the rational design
of new molecules with specific conformations.
In this paper we report the preparation and structural
characterisation of the cis/trans isomers of 1 obtained as
intermediates in the synthesis of an important class of
alkaloid molecules (Fig. 1B).3 A conformational analysis of
1 has been performed using 1H and 13C NMR spectroscopy,
molecular mechanics and semi-empirical calculations.
Electrospray ionisation mass spectrometry (ESI-MS) and
low-energy collision-induced dissociation (CID) experi-
ments complete the structural investigation of 1. The
influence of different interactions has been analysed to
The present study can be seen as a particular example of the
importance of p–p and cation–p interactions in defining
the spatial arrangements adopted by the molecules.
2. Results
2.1. Synthesis
The cis/trans isomers of N-[8-(acetylamino)-4-(2,2-
dimethyl-1,1-diphenyl-silapropoxy)-6-fluoro-5-methyl-1-
one-2,3,4-trihydronaphthyl]acetamide (1a and 1b) were
synthesised from methyl 4-(4-fluoro-3-methyl-6-nitro-
phenyl)butanoate (2) by a multistep sequence and each
Keywords: cation(p)–p interaction; mass spectrometric, NMR and
computational studies; tetralone.
*
Corresponding author. Tel.: þ39-06-91184421; fax: þ39-06-9106137;
e-mail: cartoni@virgilio.it
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00026-7

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A. Cartoni et al. / Tetrahedron 59 (2003) 1309–1316
Figure 1. (A) Details of the atoms of 1a and 1b used for NMR experiments. (B) Numbering of 1 and bonds (indicated with arrows) used for the conformational
studies.
step was repeated several times (Scheme 1).4 Compound 2
was easily synthesised from 2-fluorotoluene as already
described in literature.5
2.3. Theoretical results
The conformational analysis of 1a and 1b gives two groups
of conformers A and B for both isomers. The values of the
torsions f (C4–C3–C2–H2, C2–C3–C4–H4, H4–C4–C3–
H3(pR), H4 –C4 –C3 –H3(pS), H2 –C2 –C3 –H3(pR),
H2–C2–C3–H3(pS), see Fig. 1A) obtained as the average
of the values for the structures belonging to the same group,
are reported in Tables 2 and 3. The dihedral angles f of each
conformer present in groups A and B were used as inputs in
the specific Karplus-type equations6,7 and average values of
2.2. NMR results
The cis and trans geometries of compounds 1a and 1b were
1
1
established using H–1H and H–13C coupling constant
data, considering a simple conformational model. An
envelope with carbons 1, 2, 9, 10 and 4 in the same plane
and C3 out of the plane was obtained as displayed in
Figure 1A.
3
3JCH and JHH coupling constants were calculated and are
reported in Tables 2 and 3. As shown in bold characters in
Tables 2 and 3, experimental 3JCH and 3JHH obtained in the
NMR studies (Table 1) could be satisfactorily explained
considering only the conformers of group B for both the cis
and the trans isomers (Fig. 2).
The small value for 3JC4H2 (2.0–2.5 Hz) and the large value
for JC2H4 (9.5–10.0 Hz) defined the trans geometry for
3
compound 1b (Table 1) and indicated the axial position of
H2 and the equatorial position of H4 (Fig. 1A). This
information was further confirmed by the large axial–axial
coupling between H2 and H3pR (3JH2H3(pR)¼12.5 Hz) and
2.4. Mass spectrometric results
3
the two small couplings between H4 and H3 (3JH4H3(pS)¼
JH4H3(pR)¼2.2 Hz).
The structural characterisation of organic molecules is an
important application of mass spectrometry. In many cases
mass spectrometry is able to elucidate the stereochemistry
of a compound under investigation since the sterically
controlled ionic fragmentations involve a transition state
easily accessible to one of the stereoisomers.8 To enhance
the stereochemical effects it is important to control the
Two similar coupling constants (3JC4H2¼6.0 Hz and
3JC2H4¼6.5–7.0 Hz) for C4H2 and C2H4 were in agree-
ment with a cis configuration for compound 1a. Also the
1H–1H coupling constants confirmed this assignment
(Table 1).

A. Cartoni et al. / Tetrahedron 59 (2003) 1309–1316
1311
The ESI-MS spectra of the isomers 1a and 1b are
strongly affected by the cone voltage differences (C.V.)
between the sample cone and the skimmer of the ion
source. In Figure 3 the compared ESI-MS spectra of the
cis (a) and trans (b) isomers at 45 V potential difference
are shown. The loss of benzene, giving the ion at m/z 469
[MþH278]þ, is observed exclusively in the trans isomer
at any value of the C.V. used, while the ions at m/z 291
and 273 are always present in both spectra. The same
results were obtained performing the ESI-MS experi-
ments with the VG Quattro mass spectrometer, changing
the C.V. up to 60 V [spectra not reported], and in the
low-energy CID measurements of the mass selected m/z
547 [1þH]þ and m/z 564 [1þNH4]þ obtained using
VG Quattro mass spectrometer as Triple Quadrupole
(Fig. 4).
The MS experiments show clearly that the loss of benzene
from the protonated [1bþH]þ and the ammonium adduct
[1bþNH4]þ of trans isomer is a stereospecific fragmenta-
tion process. Moreover, the trans isomers apparently have a
higher affinity for the ammonium ion than cis isomers (Fig. 3
and data not shown). The ions at m/z 569 and m/z 585 are
referred to the adducts between 1 and Naþ and Kþ,
respectively.
Scheme 1.
Relative to the precursor ion [1þH]þ at m/z 547, the ions of
m/z 291 and 273 from both isomers 1a and 1b, have been
examined with the energy resolved mass spectrometry
(ERMS) curve obtained with in source CID experiments
(data not shown)10 and with low-energy CID measurements.
As expected, the ions at m/z 273 are generated from the ions
of m/z 291 in both isomers.
internal energy excess of the precursor ion. Consequently
soft-ionisation techniques and low-energy CID experiments
have to be used.9 Furthermore, in the last few years, ESI-MS
has become another convenient tool to perform low-energy
CID experiments (in source CID)10 aimed at structural
elucidation and compares favourably with other established
methods.10–12
1
Table 1. H–1H (^0.1 Hz) and 1H–13C (^0.5 Hz) coupling constants (in Hz) of compounds 1a and 1b in CDCl3 at 298 K
Isomers
3JC4H2
3JC2H4
3JH4H3(pR)
3JH4H3(pS)
3JH2H3(pR)
3JH2H3(pS)
cis 1a
trans 1b
6.0
2.0–2.5
6.5–7.0
9.5–10.0
2.4
2.2
4.1
2.2
7.2
12.5
3.0
5.1
Table 2. trans Isomer. Torsions f (8) for the conformers in groups A and B. 3JCH (Hz) and 3JHH (Hz) calculated from the values of f using specific Karplus
equations.6,7 Only the data obtained for group B conformers are in agreement with NMR (CDCl3) experimental results (values in bold)
C4–C3–C2–H2
C2–C3–C4–H4
3JC2H4
0.5
H4–C4–C3–
H3(pR)
H4–C4–C3–
H3(pS)
H2–C2–C3–
H3(pR)
H2–C2–C3–
H3(pS)
f (8)
3JC4H2
f (8)
f (8)
3JH4H3
f (8)
3JH4H3
f (8)
3JH2H3
f (8)
3JH2H3
Group A
Group B
NMR (CDCl3)
2178
259
9.4
2.2
285
37
256
5.5
3.2
2.2
155
63
8.8
2.5
2.2
60
2174
2.8
10.2
12.5
257
62
3.1
2.6
5.1
171
9.2
9.5–10.0
2.0–2.5
Table 3. cis Isomer. Torsions f (8) for the conformers in groups A and B. 3JCH (Hz) and 3JHH (Hz) calculated from the values of torsion using specific Karplus
equations.6,7 Only the data obtained for group B conformers are in agreement with NMR (CDCl3) experimental results (values in bold)
C4–C3–C2–H2
C2–C3–C4–H4
H4–C4–C3–
H3(pR)
H4–C4–C3–
H3(pS)
H2–C2–C3–
H3(pR)
H2–C2–C3–
H3(pS)
f (8)
3JC4H2
f (8)
3JC2H4
f (8)
3JH4H3
f (8)
3JH4H3
f (8)
3JH2H3
f (8)
3JH2H3
Group A
Group B
NMR (CDCl3)
250
2154
3.2
7.8
6
82
2172
0.5
9.2
6.5–7.0
239
59
5.2
2.9
2.4
2156
259
8.9
2.9
4.1
70
234
1.9
5.8
7.2
2172
84
10.1
1.4
3.0

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A. Cartoni et al. / Tetrahedron 59 (2003) 1309–1316
Figure 2. Conformers of group B for cis and trans isomers of 1. trans Conformers show a preference to place one of the phenyl rings of the TBDPSiO– group
˚
in an offset p-stacked geometry with the compound’s aromatic ring. The distance between the centroids of aromatic rings is 4.1 A.
Figure 3. ESI mass spectra of cis (a) and trans (b) isomers of compound 1 recorded at C.V. 45 V.
3. Discussion
both isomers (Fig. 1A). This axial preference for the most
sterically demanding group of compound 1 can be
rationalised by the unfavourable interaction between
TBDPSiO– group in the equatorial position 4 and the
methyl group in position 5 (Fig. 1B).13,14
A combination of different techniques (ESI-MS/MS,
1H–13C NMR and theoretical methods) have been used to
investigate the structure of compounds 1a and 1b. The cis
and trans isomers were characterised via 1H and 13C NMR
spectroscopy. NMR data (Table 1) indicated the axial
preference of the bulky TBDPSiO– group in position 4 in
The conformational analysis of 1a and 1b performed using
molecular mechanics and semi-empirical methods rendered
Figure 4. Typical low-energy CID spectrum of the mass selected [1þH]þ ions from cis (a) and trans (b) isomers recorded in Argon at C.V.¼20 V and C.E.
(collision energy)¼40 V.

A. Cartoni et al. / Tetrahedron 59 (2003) 1309–1316
1313
of each technique a combination of different methods
were used for the structural investigation of 1. Only mass
spectrometric results, supported by semi-empirical study,
show clearly that 1b isomer must have conformations in
solution, not present in 1a, that favour the interactions with
cations. These conformations allow easy formation of
[1bþH]þ and [1bþNH4]þ ion adducts in solution, which
are able to lose benzene in the fragmentation process. We
think that these conformations could be those obtained by
theoretical calculations where one of the phenyl rings of the
TBDPSiO– group is in an offset p-stacked geometry with
the compound’s aromatic ring.
4. Conclusions
In conclusion, the axial preference of the bulky TBDPSiO–
group in 1a and 1b observed by NMR studies can be
explained by the unfavourable steric interaction between
the methyl and the TBDPSiO– group in the equatorial
position. Mass spectrometric evidence suggests a p–p
interaction between one of the phenyl rings of TBDPSiO–
group and the compound’s aromatic ring in the trans isomer
pointing to a higher affinity for the ammonium ion and a
characteristic fragmentation pathway in 1b (Scheme 2).
Theoretical results support this view showing that a group of
trans conformers could tend to place one of the phenyl rings
of the TBDPSiO– group in a offset p-stacked geometry
with the compound’s aromatic ring.
Scheme 2. Schematic repþresentation of the possible fragmentation
pathways for ions [1bþNH4] to give fragments at m/z¼469 [MþH278]þ.
two groups of conformers A and B. The experimental NMR
data obtained for these compounds suggested the preference
for group B conformers in CDCl3 (Tables 2 and 3). The
results indicated that a group of trans conformers have a
tendency to place one of the phenyl rings of the TBDPSiO–
group in an offset p-stacked geometry with the compound’s
aromatic ring (Fig. 2).15 On the other hand, ESI-MS and
low-energy CID experiments showed that the loss of
benzene from the ammonium adduct [1þNH4]þ and the
protonated molecule [1þH]þ was a peculiar feature of the
trans isomer (Figs. 3 and 4). This observation pointed out
there must be reacting conformations for ions at m/z 547
[1bþH]þ and 564 [1bþNH4]þ, but not for cis adduct ions,
that favour the characteristic fragmentation pathway.
5. Experimental
5.1. General information (for preparation of compounds
3–6)
All reactions involving air- or moisture-sensitive reagents
and intermediates were carried out under a nitrogen atmos-
phere. Dry solvents were from Fluka, and triethylamine
(Et3N) was distilled from CaH2 and stored under argon over
KOH pellets. All the other reagents and solvents were used
as received from Aldrich and Fluka. All reactions were
monitored by thin layer chromatography, which was carried
out on Merck 60 PF254 silica gel-coated aluminium sheets.
In other mass spectrometric experiments carried out under
electron ionisation (EI) conditions (data not shown), where
a [1b] radical cation was generated, ions at m/z 469 were not
observed. These mass spectrometric results suggest a
(NHþ4 /Hþ)–p interaction (Scheme 2) in the trans isomer
that favours the loss of benzene to form a silylium ion
stabilised by a cation–p interaction with the compound’s
aromatic ring.16 Moreover, the observed higher affinity for
the NHþ4 cation of 1b (m/z¼564) rather than that of the 1a
isomers17 (Fig. 3 and data not shown) and semi-empirical
results for 1b are consistent with the p–p interaction
obtained as a conformational preference in the trans isomer
(Fig. 2). NMR data, although fundamental in defining the
spatial arrangement of the bulky TBDPSiO– group and in
theoretical study, were not useful in studying the p–p
interaction in trans isomer. 1H NMR chemical shifts of H7
(d 1.80) and of CH3 (d 8.40) in C5 have the same values in
both trans and cis isomers. However it is well known25 that
the NMR study of weak attractive intramolecular inter-
actions in relatively flexible organic molecules such as 1 are
most valid at low temperature since these interactions are
entropically disfavoured in solution at room temperature.
For this reason and to eliminate the inevitable limitations
Proton NMR spectra of the reaction intermediates (3–6) and
carbon NMR spectra of 1b were obtained on a 300 MHz
Varian Gemini (BB) instrument at 298 K using the solvent
1
resonance (CDCl3 or Me2SO-d6) as internal standard. H
NMR of 1a and 1b and 13C NMR of 1a were recorded on a
400 MHz Avance Bruker spectrometer. Chemical shifts are
reported in ppm (d). ESIþ/MS spectra of intermediates
(3–6) were carried out using a Single (ZMD, Micromass,
UK) Quadrupole at low C.V. Elemental analyses were
carried out by REDOX snc (Milan, Italy).
Matrix assisted laser desorption ionization (MALDI) mass
spectra of 1a and 1b were obtained on a Reflex IV time of
flight (TOF) mass spectrometer (Bruker Daltonics, Bremen,
Germany) equipped with a SCOUT source. Data were
acquired in the positive reflectron delayed extraction mode
of operation. High-resolution mass spectra of 1a and
1b were recorded on a Micromass Analytical Autospec

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A. Cartoni et al. / Tetrahedron 59 (2003) 1309–1316
spectrometer in EIþ condition and the m/z of the fragment
1.9 mmol). This was dissolved in anhydrous CH2Cl2
(15 mL) and a mixture of imidazole (IMID., 0.48 g,
7 mmol), 4-(dimethylamino)pyridine (DMAP., 23 mg,
0.19 mmol) and tert-butyldiphenylsilyl chloride19 (1.2 mL,
4.5 mmol) was added at room temperature. After 20 h the
solution was diluted with CH2Cl2, washed with 1 M HCl
solution and saturated NaCl. The organic extracts were
dried (Na2SO4), evaporated in vacuo and the residue
triturated with diethyl ether/acetone (2:1), filtered and
dried to give a white solid (0.72 g, 1.6 mmol, yield 80%).
The latter was used without purification in the successive
ion at 273 is reported.
5.1.1. Preparation of methyl 4-(6-acetylamino-4-fluoro-
3-methyl)butanoate (3). To a solution of compound 2
(1.1 g, 4.3 mmol) in CH3OH (75 mL) and HCl 1 M (19 mL)
was added Ni2B (1.3 g, 10.3 mmol), freshly prepared as
described in literature.18 After stirring for 30 min at 608C,
the reaction mixture was diluted with water and the pH was
approximately adjusted to a value of 8 with 15% NH3
solution. The mixture was extracted with Et2O, dried with
Na2SO4 and evaporated in vacuo. The residue, a yellow oil
(0.88 g, 3.9 mmol) was dissolved in CH2Cl2 (150 mL) and
Et3N (0.67 mL) and Ac2O (0.46 mL) were added under
stirring. After 1 h, the solution was diluted with CHCl3,
washed with 0.1 M HCl, saturated NaHCO3 and saturated
NaCl. The mixture was dried (Na2SO4) and concentrated in
vacuo to give 3 as yellow oil (0.94 g, 3.5 mmol, yield 90%).
The latter was used without purification in the successive
1
reaction. H NMR (Me2SO-d6); 1.04 (9H, m, (CH3)3CSi),
1.46 (2H, m, –CH2–CH2–CH2–), 1.69 (3H, s, ArCH3),
1.80 (2H, m, –CH2CHO), 2.15 (3H, s, CH3CON), 2.78 (2H,
3
m, ArCH2–), 4.64 (1H, t, J¼3 Hz, –CHO), 7.34 (1H, d,
3J¼12 Hz, ArH), 7.40–7.77 (10H, m, (Ar)2Si), 9.21 (1H, bs,
NH). ESI-MS: m/z 493 [MþNH4]þ (100%). Anal. calcd (%)
for C29H34NO2FSi: C 72.22; H 7.05; N 2.90; F 3.94. Found:
C 72.49; H 7.19: N 2.91; F 3.67.
1
reaction. H NMR (CDCl3); 1.78 (2H, m, –CH2–CH2–
CH2–) 2.21 (3H, s, CH3CON), 2.34 (3H, s, ArCH3), 2.36
(2H, m, –CH2CO2–), 2.60 (2H, m, ArCH2–), 3.81 (3H, s,
–CO2CH3), 6.95 (1H, d, 3J¼9 Hz), 7.87 (1H, d, 3J¼12 Hz),
8.38 (1H, bs, NH); ESI-MS: m/z 268.0 [MþH]þ (100%)
285.0 [MþNH4]þ (55%). Anal. calcd (%) for C14H18NO3F:
C 61.47; H, 6.58 N 5.12; F 6.94. Found: C 61.95; H 6.85; N
4.98; F 6.77.
5.1.4. Preparation of 8-acetylamino-4-(2,2-dimethyl-1,1-
diphenyl-silapropoxy)-6-fluoro-5-methyl-1-one-2,3,4-
tetrahydronaphthalene (6). To a solution of 5 (0.13 g,
0.27 mmol) in acetone (6.4 mL) and 15% aqueous MgSO4
(0.64 mL) was added KMnO4 (210 mg, 1.4 mmol) in
portions at 08C. After stirring for 2 h at room temperature
the reaction mixture was diluted with water and extracted
with CHCl3. The organic phase was washed with saturated
NaHCO3 and saturated NaCl, dried (Na2SO4) and evapo-
rated. The crude material was purified by flash chromatog-
raphy (Merck silica gel 60, 230–400 mesh) using petroleum
ether–ethyl acetate (1:4) as eluent to give compound 6
(93 mg, 0.2 mmol, yield 74%). The latter was used without
further purification in the successive reaction. 1H NMR
(Me2SO-d6); 1.03 (9H, m, (CH3)3CSi), 1.62 (3H, s, ArCH3),
2.08 (2H, m, –CH2CHO), 2.19 (3H, s, CH3CON), 3.11 (2H,
m, –CH2CO), 5.25 (1H, bs, -CHO), 7.34–7.67 (10H, m,
(Ar)2Si), 8.29 (1H, d, 3J¼12 Hz, ArH), 11.86 (1H, bs, NH).
ESI-MS: m/z 507 [MþNH4]þ (100%). Anal. calcd (%) for
C29H32NO3FSi: C, 71.22; H 6.55; N 2.87; F 3.89. Found: C
71.49; H 6.68: N 2.84; F 3.77.
5.1.2. Preparation of 5-acetylamino-7-fluoro-8-methyl-1-
tetralone (4). To a solution of compound 3 (1.2 g,
4.5 mmol) in CH3OH (10 mL) was added 10% NaOH
(3.5 mL). The mixture was stirred for 20 h at room
temperature, concentrated and acidified with 37% HCl
solution to give a white precipitate that was filtered, washed
with water and dried. The residue (1.0 g, 3.9 mmol) was
slowly added to preheated (1108C) polyphosphoric acid
(PPA, 16 mL) and the mixture stirred for 2 h at 1008C. The
reaction was cooled at room temperature and carefully
quenched by the slow addition of ice–water and the
mixture extracted with ethyl acetate, washed with saturated
NaHCO3 and saturated NaCl. The organic phase was dried
(Na2SO4), evaporated in vacuo and the residue was
triturated with CCl4, filtered and dried to give a pale yellow
solid (0.5 g, 2.1 mmol, yield 54%). The latter was used
5.1.5. Preparation of N-[8-(acetylamino)-4-(2,2-di-
methyl-1,1-diphenyl-silapropoxy)-6-fluoro-5-methyl-1-
one-2,3,4-trihydronaphthyl]-acetamide (1a and 1b). To a
solution of compound 6 (480 mg, 0.98 mmol) in anhydrous
THF (10 mL) was added a suspension of NaH (35 mg,
1.5 mmol) in anhydrous THF (5 mL). After stirring under a
nitrogen atmosphere for 1 h, n-butyl nitrite (n-BuONO,
0.25 mL) was added. After 2 h the yellow–orange reaction
mixture was acidified with 1 M HCl solution and diluted
with CHCl3. The organic phase was washed with saturated
NaCl, dried (Na2SO4) and evaporated in vacuo. The residue
(415 mg, 0.80 mmol) was dissolved in AcOH/Ac2O (1:1;
18 mL) and zinc powder (630 mg, 9.6 mmol) was added.
After stirring for 40 h the reaction mixture was carefully
filtered and the grey solid was successively washed with
AcOH and CHCl3. The combined filtrate was evaporated to
dryness and the residue was dissolved in CHCl3, washed
with saturated NaCl, dried (Na2SO4) and concentrated in
vacuo. Flash chromatography of the residue on silica gel
using petroleum ether–ethyl acetate (from 1:1 to 1:4) as
eluent gave the mixture of the diasteroisomers 1a, 1b
1
without purification in the successive reaction. H NMR
(CDCl3); 2.12 (2H, m, –CH2–CH2–CH2–), 2.32 (3H, s,
CH3CON), 2.48 (3H, s, ArCH3), 2.59 (2H, m, –CH2CO),
2.83 (2H, m, ArCH2–), 7.01 (1H, bs, NH), 7.57 (1H, d,
3J¼12 Hz, ArH);); ESI-MS: m/z 235.8 [MþH]þ (100%)
252.9 [MþNH4]þ (20%). Anal. calcd for C13H14NO2F: C,
66.31; H, 5.95; N, 5.95; F, 8.08. Found: C, 66.93: H, 6.10;
N, 5.27; F, 7.99.
5.1.3. Preparation of 5-acetylamino-1-(2,2-dimethyl-1,1-
diphenyl-silapropoxy)-7-fluoro-8-methyl-1,2,3,4-tetra-
hydronaphthalene (5). To a stirred solution of compound 4
(0.6 g, 2.6 mmol) in absolute EtOH (12 mL) and THF
(1 mL) at room temperature was added NaBH4 (97 mg,
2.6 mmol). After 2 h the reaction mixture was diluted with
CHCl3, shaken for 20 min with 10% citric acid and washed
with saturated NaCl. The organic phase was dried (Na2SO4)
and evaporated in vacuo. The residue was triturated with
CCl4, filtered and dried to give a white solid (0.46 g,

A. Cartoni et al. / Tetrahedron 59 (2003) 1309–1316
1315
(232 mg, 0.42 mmol, yield 53%). Further purification
by semi-preparative HPLC [Merck column, LiChrosphere
100 RP-18 (10 mm), 250£10 mm, CH3CNþ0.1% TFA:
H2Oþ0.1% TFA, 80:20 at the flow rate of 3.5 mL/min] gave
the separate stereoisomers 1a and 1b (Fig. 1 and Scheme 1).
Figure 1B. The conformers’ energy was then minimised
with molecular mechanics and after removing duplicate
minima, 39 conformers for 1a and 32 for 1b were obtained.
Molecular mechanics calculations were performed in
Sybyl21 with the Tripos force field22 using the vacuum
dielectric constant and without non-bonded cut off.
Geometries of the molecular mechanics minima were then
optimised with the semi-empirical AM123 method using PC
Spartan Pro24 software. For parameters affecting SCF and
geometry optimisation Spartan default values were used
except for the application of mmok and hess¼unit options.
Removing duplicate structures after semi-empirical geome-
try optimisation 27 conformers for 1a and 26 for 1b were
obtained. Final structures were grouped considering the
similarity of the dihedral angles (f) C4–C3–C2–H2 and
C2–C3–C4–H4 (Fig. 1). Two groups of conformers (named
A and B) were obtained for both isomers 1a (15 conformers
for A and 12 conformers for B) and 1b (11 conformers for
A and 15 conformers for B).
1
cis 1a. H NMR (CDCl3); 0.90 (9H, m, (CH3)3CSi), 1.80
(3H, s, CH3Ar), 2.10 (3H, s, CH3CONHCH), 2.15 (1H, m,
3J¼15.0, 2.4, 7.2 Hz, H3pR), 2.20 (3H, s, CH3CONHAr),
2.80 (1H, dt, 3J¼15.0, 3.0, 4.1 Hz, H3pS), 4.85 (1H, m, 3J¼
3
8.2, 7.2, 3.0 Hz, H2), 5.30 (1H, dd, J¼4.1, 2.4 Hz, H4),
3
6.60 (1H, d, J¼8.2 Hz, CHNHCOCH3), 7.29–7.76 (10H,
3
m, (Ar)2Si), 8.40 (1H, d, J¼12 Hz, H7), 11.10 (1H, s,
ArNHCOCH3). 13C NMR (Me2SO-d6): 10.0 (CH3Ar), 19.0
(CH3)3CSi), 22.3 (–CHNHCOCH3), 25.0 (ArNHCOCH3),
26.3 ((CH3)3CSi), 35.8 (C3), 51.3 (C2), 65.7 (C4), 106.0
(C7), 117.0 (C9); 127.5, 127.8, 134.0, 134.8, 135.0
((Ar)2Si); 139.0 (C8), 147.0 (C5), 149.0 (C10), 163.0
(C6), 169.0 (CONH), 197.0 (C1). MALDI MS: m/z: found
569.24 [MþNaþ]. HR-MS: m/z: found 273.1030, calcd for
C15H14FN2Oþ2 : 273.1039.
5.4. Mass spectrometry
trans 1b. 1H NMR (CDCl3); 1.00 (9H, m, (CH3)3CSi), 1.80
(3H, s, CH3Ar), 2.10 (3H, s, CH3CONHCH), 2.20 (3H, s,
CH3CONHAr), 2.45 (2H, m, H3pS and H3pR), 5.15 (1H, t,
ESI/MS and low-energy CID measurements in the positive
ion-mode were carried out using a Single (ZMD, Micro-
mass, UK) and a Triple (TQ, VG Quattro, Micromass, UK)
Quadrupole mass spectrometers, respectively.
3
3J¼2.2 Hz, H4), 5.55 (1H, m, J¼12.5, 6.5, 5.1 Hz, H2),
3
6.15 (1H, d, J¼6.5 Hz, CHNHCOCH3), 7.30–7.78 (10H,
3
m, (Ar)2Si), 8.50 (1H, d, J¼12 Hz, H7), 11.10 (1H, s,
The cis and trans isomers of 1 were separately dissolved in
CH3CN or CH3OH (0.5 mg/mL) and 50 mL of this solution
was added to a mixture of CH3CN/H2O (1:1) containing
CH3COONH4 (2 mM). The sample was introduced into the
source in the infusion mode (syringe pump Harvard
Apparatus, Model 11) at a flow rate of 7 mL/min. The
ESI-MS spectra of both isomers were recorded under the
same experimental conditions (source temperature and
desolvation temperature¼1008C, cone N2 flow¼98 L/h,
desolvation N2 flow¼488 L/h and capillary voltage¼3.67
kV) changing only the sampling cone voltage from 10to 90 V.
ArNHCOCH3). 13C NMR (Me2SO-d6): 10.2 (CH3Ar), 19.7
(CH3)3CSi), 23.3 (–CHNHCOCH3), 26.0 (ArNHCOCH3),
27.1 ((CH3)3CSi), 37.0 (C3), 50.7 (C2), 66.0 (C4), 106.5
(C7), 117.0 (C9); 128.3, 130.9, 132.9, 135.1, 135.9,
((Ar)2Si); 142.0 (C8), 146.0 (C5), 151.0 (C10), 164.5
(C6); 170.5, 171.0 (CONH), 200.0 (C1). MALDI MS: m/z:
found 569.20 [MþNaþ]. HR-MS: found 273.1043, calcd for
C15H14FN2Oþ2 : 273.1039.
5.2. NMR spectroscopy
1H NMR spectra of 1a and 1b were recorded in CDCl3
(Aldrich), on a 400 MHz Avance Bruker spectrometer,
equipped with z-shielded gradient inverse detection probe,
using tetramethylsilane (0.00 ppm, H NMR) as internal
standard. Chemical shifts (d, ppm) in the case of multiplets
are measured from the approximated centre.
In the low-energy CID experiments the ions generated in
the ESI source (source temperature¼858C, desolvation N2
flow¼150 L/h, nebulizing N2¼10 L/h and capillary
voltage¼3.80 kV) were mass selected in the first quadrupole
(Q1) and allowed to collide with Argon in the RF-only
Hexapolar Cell (Q2) at a collision energy (C.E.) of up to
90 V (lab Frame). The charged products were analysed at
the frequency of 400 amu/s in MCA (Multi Channel
Analysis) mode.
1
1H–13C coupling constants were measured applying the
phase-sensitive HMBC experiment described in Ref. 20 on
a 5 mM sample of 1a and 1b in CDCl3, at 298 K. The
acquisition times t2 and t1 were 1.3 s (spectral width
6410 Hz, 8 K complex data points) and 3 ms (spectral width
20, 100 Hz, 64 real data points), respectively. The relaxation
delay was 2 s; 80 scans were accumulated per t1 increment.
Acknowledgements
We thank Professor Fulvio Cacace and Dr Christopher
Fincham for proof-reading the manuscript and Dr Meri
Gabrielli for acquiring MALDI mass spectra. Financial
support by A. Menarini (Industrie Farmaceutiche Riunite) is
gratefully acknowledged.
5.3. Computational methods
The conformational preferences of cis 1a and trans 1b
molecules were investigated using a combination of
molecular mechanics and semi-empirical methods. For
both 1a and 1b two structures were built with C3 out of
plane by þ558 and 2558, respectively. The four structures
were employed as starting points to perform a systematic
search, in steps of 308, for the four bonds indicated in
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