Synthesis and study of a heterocyclic receptor designed for carboxylic acids

Article abstract of DOI:10.1016/j.tet.2004.03.045

The synthesis of a tricyclic receptor having a bowl shape and three binding points for carboxylic acids has been achieved starting from readily available 1-tetralone derivatives according to two different methods. This host possesses a six-membered lactam

Full text of DOI:10.1016/j.tet.2004.03.045

Tetrahedron 60 (2004) 4197–4204
Synthesis and study of a heterocyclic receptor designed for
carboxylic acids
*
¨
Gregory Moore, Cyril Papamicael, Vincent Levacher, Jean Bourguignon and Georges Dupas
´ ´ ´
Laboratoire de Chimie Organique Fine et Heterocyclique UMR 6014, IRCOF-INSA, B.P. 08, 76131 Mont-Saint-Aignan Cedex, France
Received 24 November 2003; revised 9 March 2004; accepted 17 March 2004
Abstract—The synthesis of a tricyclic receptor having a bowl shape and three binding points for carboxylic acids has been achieved starting
from readily available 1-tetralone derivatives according to two different methods. This host possesses a six-membered lactam moiety and a
carboxamide at the end of a flexible arm. Association constant with benzoic acid and stoichiometry of the complex have been determined
using 1H NMR dilution experiments.
q 2004 Published by Elsevier Ltd.
1. Introduction
2. Results and discussion
2.1. Design of the hosts
In a previous paper,1 we described the synthesis of a
heterocyclic receptor for carboxylic acids. The design of
this receptor is outlined in Figure 1. The three binding points
are ensured by a five or a six-membered lactam and a remote
carboxamide incorporated on the benzene ring of an
heterocyclic structure having a bowl shape. In order to
obtain this bowl shape, ring B must be saturated and a cis-
fusion between rings B and C is required. In this preliminary
communication, we gave only few details concerning the
design and the synthetic pathway.
We performed first some molecular mechanic calculations
(MM2 force field as implemented in PCMODELw and
CVFF force field as implemented in CERIUS2). We selected
acetic acid as a model and tried the five and six-membered
lactams 2a and 2b (Fig. 2).
Figure 2. Selected five and six-membered lactams.
In these two cases, three hydrogen bonds can be obtained
(structures depicted respectively in Figs. 3 and 4). We also
performed some calculations at the PM3 level of theory on
the six-membered lactam 2b. Energy of the molecule was
computed as a function of the dihedral angle u between the
benzene ring and the carboxamide group. As it can be seen
in Figure 5, rotation about the flexible arm induces a
maximum variation of 2 kcal mol21. As a consequence, it
could be expected that the formation of a third
hydrogen bond would be possible because the correspond-
ing decreasing of the energy is larger than this variation.
Figure 1. Cleft receptor design (left) and proposed receptor design (right).
The aim of this paper is to provide full details concerning
both the design and the syntheses of this new kind of acids
receptors.
Keywords: Molecular recognition; Carboxylic acids; Molecular modelling;
Coupling reactions.
In order to verify this hypothesis, it is necessary to compare
the binding properties of receptors 1a,b (two binding points)
*
Corresponding author. Tel.: þ33-235-522-474; fax: þ33-235-522-962;
e-mail address: georges.dupas@insa-rouen.fr
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.03.045

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G. Moore et al. / Tetrahedron 60 (2004) 4197–4204
and receptors 2a,b (three binding points). We decided first
to synthesize the five-membered lactams.
2.2. Towards the synthesis of the five-membered lactams
We selected the method used by Ennis et al.2 in the
b-tetralone series (Scheme 1). For this purpose, we needed
an a-tetralone substituted at the 7-position by a group
allowing further functional group interconversion leading to
the carboxamide at the end of the flexible arm. The
7-benzyloxy-1-tetralone 3c seemed to be a good choice
since it could be obtained from the commercially available
7-methoxy-1-tetralone 3b. Cleavage of the methoxy group
of 3b according to the procedure described by Chakrabotri
et al.3 and subsequent reaction with benzyl chloride under
basic conditions afforded the required 7-substituted-1-
tetralone 3c. Tetralones 3a,c where deprotonated with
LDA and alkylated with ethyl bromoacetate in THF at
278 8C. While this work was in progress, Ennis and
co-workers reported the same reaction on 1-tetralone 3a.4
The keto-esters 4a,b thus obtained were then hydrolysed
into the corresponding keto-acids 5a,b and subsequent
reaction with (R)-phenylglycinol led to the bis-lactams 6a,b.
As Ennis et al.2 ring opening of bis-lactam 6a proceeded
smoothly but the same reaction on 6b was more difficult and
the yield was lower (67% for 6a and 25% for 6b). While
dehydration of the alcohol 7a led to the 7-unsubstituted
lactam 8 in a 60% yield, only tarry material was obtained
with the benzyloxy derivative. This first route being
unsuccessful, we decided to focus our interest on the
synthesis of the six-membered lactam.
Figure 3. Molecular modelling of the five-membered lactam 2a and its
interactions with acetic acid.
2.3. Synthesis of the six-membered lactam ring
The selected precursors were again 7-substituted-1-tetra-
lones 3a-f. They were reacted with methacrylamide under
conditions published by Corriu’s group5 (Scheme 2). No
reaction occurred with 7-nitro-1-tetralone 3e and
7-hydroxy-1-tetralone 3f, but benzo[h]quinolinones 9a-d
could be obtained in medium yields starting from tetralones
3a-d. We tried to improve these yields by performing the
reaction in various solvents but no significant improvement
could be obtained. Having at hand the 7-substituted-1-
tetralone 9d, it was necessary to introduce the carboxamide
group at the end of the flexible arm. We tried first the
cuprous iodide catalysed reaction of the bromo derivative
9d with diethyl malonate as described in our previous paper1
(Scheme 3).
Figure 4. Molecular modelling of the six-membered lactam and its
interactions with acetic acid.
This method led to the targeted host 2b. Careful
1
examination of the H NMR spectra of 2b showed two
signals corresponding to the N–H lactam and two signals
for the methyl group at the 3-position. This fact could be
explained by the epimerisation of the 3-position during the
course of the synthesis. During the catalytic hydrogenation
reaction of 13b into 14, the two hydrogen atoms attack the
less hindered side of the molecule say anti to the methyl
group leading to a racemic mixture of a single diastereo-
isomer. The ring junction is cis as showed by the small value
of the coupling constant between the corresponding two
hydrogen atoms (J¼4 Hz). Moreover, a single signal is
observed for the methyl group at the 3-position. However,
epimerisation seems to occur during the decarboxylation
Figure 5. PM3 molecular modelling of host 2b as a function of dihedral
angle u.

G. Moore et al. / Tetrahedron 60 (2004) 4197–4204
4199
Scheme 1. Reagents, conditions and yields. (a) 1) PhSH, K2CO3, NMP, 30 min, 190 8C (80%). 2) K2CO3, Benzyl chloride, DMF, 4 h, 100 8C (90%);
(b) 1) LDA, THF, 30 min, 278 8C. 2) Br–CH2CO2Et, 18 h, 278 8C!rt (40% for 4a, 45% for 4b); (c) KOH, EtOH, 2 h, reflux (85% for 5a and 5b);
(d) (R)-phenylglycinol, toluene, 12 h, reflux (73% for 6a and 72% for 6b); (e) Et3SiH, TiCl4, CH2Cl2, 2 h, 278 8C (70% for 7a and 25% for 7b); (f) LiOH, H2O,
DMSO, 72 h, 100 8C (60%); (g) HCl, THF, H2O, 8 h, reflux (40%).
synthesis involving the cross coupling reaction of the
enoxysilane 17 with the triflate 16c (Scheme 4). The
required triflate 16b was obtained within two steps starting
from the benzyloxy derivative 9c. Deprotection of the
phenol and reduction of the C4a–C10b double bond of 9c
were achieved in the same pot via catalytic hydrogenation
with 10% Pd–C and the phenol 16a was converted into the
triflate 16c with ditriflimide under basic conditions. Cross
coupling of the enoxysilane 17 with this triflate under
conditions published by us6 afforded ester 18a. This ester
was hydrolysed and the resulting intermediate carboxylic
acid was converted into one of the stereoisomers 2b0 of the
targeted host 2b.
Scheme 2. Reagents, conditions and yields. (a) methacrylamide, Si(OMe)4,
CsF, 5 h, 80 8C (30–60%).
2.4. Binding properties of the hosts 1b0 and 2b0
step which is carried out under basic conditions as shown by
the duplication of the signal corresponding to the methyl
group in the 1H NMR spectrum of 15. In order to avoid this
troubleshooting decarboxylation step, we tried another
We first performed some dilution experiments in order to
study the self-association of the hosts 1b0 and 2b0. They
Scheme 3. Reagents, conditions and yields. (a) CH3I for 10a and PMBCl for 10b, KOH, DMSO, 30 min, rt (40% for 10a, 60% for 10b); (b) 1) n-BuLi, THF,
10 min, 278 8C. 2) tert-BuLi, 1 h, 278 8C. 3) MeOD for 11a and I2 for 11b, 2 h, 278 8C (100% for 11a by 1H NMR, 70% for isolated 11b); (c) same reagents
and conditions as in a (40% for 12a and 60% for 12b); (d) EtOOC–CH2–COOEt, NaH, CuI, dioxane, 5 h, reflux (40% for 13a, 50% for 13b); (e) H2, Pd–C
10%, EtOH, 1 bar, 12 h, rt (45%); (f) 1) 3% NaOH, EtOH, 15 h, rt. 2) HCl, pH¼2. 3) CuI, CH3CN, 1 h, 60 8C (100% by 1H NMR); (g) n-propylamine, EDCI,
HOBt, MeCN, 72 h, rt (35%). 2) CAN, H2O, MeCN, 5 h, rt (35%).

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G. Moore et al. / Tetrahedron 60 (2004) 4197–4204
Figure 7. Titration of host 1b0 with benzoic acid. The initial guest
concentration was 0.0204 mol L21
. Aliquots of a guest solution
(0.287 mol L21) were added and the chemical shift of the lactam proton
was monitored.
Scheme 4. Reagents, conditions and yields. (a) H2, Pd–C 10%, EtOH,
1 bar, 12 h, rt (80% for 1b0 from 9a, 85% for 16a from 9c); (b) Ditriflimide,
DMF, NEt3, 4 h 30, 0 8C!rt (40%); (c) Pd(PPh3)4, CH3COOLi, THF, 21 h,
reflux (40%); (d) 3% NaOH, EtOH, 15 h, rt (89%); (e) n-propylamine,
EDCI, HOBt, MeCN, 72 h, rt (65%).
were dissolved in chloroform-d and on dilution, an upfield
chemical shift of the lactam N–H proton could be observed.
Classical Horman and Dreux7 analysis of these shift values
gave a Kd value (dimerisation constant) of about 20 M21 for
2b0. However, the method did not converge in the case of
1b0. These two hosts were then titrated with benzoic acid. In
order to specify the stoichiometry of the complexes formed,
we first performed Job plots8 (Fig. 6 for 1b0 and Fig. 8 for
2b0). These plots clearly show the formation of 1/1
complexes (maximum value at x¼0.5).
Figure 8. Job plot of host 2b0. The sum of host and guest concentrations was
constant (C0¼0.0135 mol L21, guest concentration¼xC0) and the chemical
shift of the lactam proton was monitored.
The association constants Ka were then determined
assuming a 1/1 complexation process and neglecting the
dimerisation process for 2b0. Ka values of 80 and 200 M21
were obtained for 1b0 and 2b0 respectively (Fig. 7 for 1b0 and
Fig. 9 for 2b0).
Figure 9. Titration of host 2b0 with benzoic acid. The initial guest
concentration was 0.0193 mol L21
. Aliquots of a guest solution
(0.304 mol L21) were added and the chemical shift of the lactam proton
was monitored. Owing to the complexity of spectra, some chemical shifts
could not be measured.
or a six-membered lactam could be incorporated in the
tricyclic part. Unfortunately the synthesis of the selected
hosts was impossible in the case of a five membered la0ctam.
However, it was possible to obtain the hosts 2b and 2b with
a six-membered lactam according to two different routes. A
NMR study with monitoring of the lactam proton of 2b0 as a
function of host and guest concentrations was then
undertaken.
Figure 6. Job plot of host 1b0. The sum of host and guest concentrations was
constant (C0¼0.0135 mol L21, guest concentration¼xC0) and the chemical
shift of the lactam proton was monitored.
The lactam moiety of host 1b0 is able to bind with benzoic
acid with an association constant of 80 M21 in good
agreement with a two binding points process. Addition of a
third binding point (in 2b0) ensures a significant increasing
of the association constant and confirms that the flexible arm
is really involved in the binding process.
3. Conclusion
Our initial goal was to design a new kind of host for
carboxylic acids. We selected a tricyclic structure with a
bowl shape and a carboxamide moiety at the end of a
flexible arm. We first checked this design with molecular
and quantum mechanics calculations. Calculations were in
good agreement with this design and showed that both a five
We are now trying to incorporate an amine receptor in the
flexible arm in order to obtain a receptor able to promote the

G. Moore et al. / Tetrahedron 60 (2004) 4197–4204
4201
reaction between an acid and an amine via a supramolecular
process.
J¼1.5 Hz). 13C NMR (CDCl3, 75.5 MHz) d 28.9, 29.9, 35.5,
44.9, 70.5, 110.9, 123.0, 127.9, 128.5, 129.0, 130.5, 133.1,
137.0, 137.3, 157.9, 178.4, 198.8. A solution of the above
ketoacid 5b (200 mg, 0.64 mmol) and (R)-phenylglycinol
(172 mg, 1.28 mmol) in toluene (3.2 mL) was heated to
reflux for 12 h in a flask fitted with a Dean Stark trap. After
cooling to rt, the toluene was removed under reduced
pressure and the residue was purified by flash chromato-
graphy on silica gel (cyclohexane/ethyl acetate 8/2, Rf¼0.4)
to afford 190 mg (72%) of compound 6b as a brown oil. IR
4. Experimental
4.1. General details
The infra-red spectra were recorded on a Beckmann IR 4250
1
spectrometer. The H and 13C NMR spectra were recorded
1
(KBr) 1497, 1714 cm21. H NMR (CDCl3, 300 MHz) d
on a 200 or 300 MHz Bruker apparatus. Spectra were
recorded in deuteriochloroform or in hexadeuteriodimethyl-
sulfoxide (DMSO-d6). Chemical shifts are given in ppm
with TMS or HMDS as internal reference. Chemicals were
purchased from Aldrich Co. and Janssen Co. and, unless
otherwise stated, were used without further purification.
Flash chromatography was performed with silica 60
(70–230 mesh from Merck) and monitored by thin layer
chromatography (TLC) with silica plates (Merck, Kieselgel
60 F254).
1.40 (m, 1H), 2.25 (m, 1H), 2.41 (m, 1H), 2.70 (m, 3H), 2.70
(m, 1H), 3.89 (d, 1H, J¼16.1 Hz), 4.10 (d, 1H, J¼16.1 Hz),
4.08 (dd, 1H, J¼8.7, 8.7 Hz), 4.59 (dd, 1H, J¼8.7, 8.7 Hz),
5.25 (t, 1H, J¼8.7 Hz), 6.42 (d, 1H, J¼1.5 Hz), 6.75 (dd,
1H, J¼6.5, 1.5 Hz), 6.98–7.36 (m, 11H). 13C NMR (CDCl3,
75.5 MHz) d 27.5, 28.9, 41.2, 44.1, 58.8, 69.4, 71.5, 111.7,
117.4, 127.0, 127.8, 128.0, 128.2, 128.8, 129.3, 139.9,
179.6. Anal. Calcd for C27H25NO3: C, 78.81; H, 6.12; N,
3.40. Found: C, 78.95; H, 6.2; N, 3.45.
4.1.3. 8-Benzyloxy-1-(3-hydroxy-1-phenylpropyl)-
1,3,3a,4,5,9b-hexahydro-benz[g]indol-2-one (7b). To a
cooled (278 8C) solution of bis-lactam 6b (194 mg,
0.47 mmol) in dichloromethane (2 mL), triethylsilane
(335 mL, 2.07 mmol) was added. The mixture was stirred
at 278 8C for 15 min and titanium tetrachloride (228 mL,
2.07 mmol) was slowly added. The solution was stirred
278 8C for 2 h, allowed to warm to rt and hydrolized with a
saturated aqueous solution of ammonium chloride. The
aqueous layer was extracted with dichloromethane. The
organic layer was washed with water, dried on magnesium
sulfate and evaporated to dryness. The residue was purified
by flash chromatography on silica gel (cyclohexane/ethyl
acetate 2/8, Rf¼0.4) to afford 50 mg (25%) of compound 7b
as an amorphous solid. IR (KBr) 1659, 3266 cm21. 1H NMR
(CDCl3, 300 MHz) d 1.65 (m, 2H), 2.30 (dd, 1H, J¼18.0,
3.6 Hz), 2.49–2.82 (m, 3H), 2.85 (dd, 1H, J¼18.0, 8.9 Hz),
3.75 (m, 2H), 4.10 (m, 1H), 4.52 (m, 1H), 4.31 (d, 1H,
J¼9.1 Hz), 5.05 (m, 2H), 6.40 (m, 1H), 6.61 (m, 1H), 6.92
(m, 2H), 7.11–7.25 (m, 9H). 13C NMR (CDCl3, 75.5 MHz)
d 26.6, 29.9, 31.3, 60.9, 62.0, 62.5, 64.9, 116.0, 117.3,
127.3, 127.8, 128.1, 128.2, 129.1, 129.3, 130.1, 132.1,
133.4, 137.3, 154.9, 177.0. Anal. Calcd for C27H27NO3: C,
78.42; H, 6.58; N, 3.39. Found: C, 78.61; H, 6.44; N, 3.31.
4.1.1. Ethyl (7-benzyloxy-1-oxo-1,2,3,4-tetrahydro-
naphthalen-2-yl)acetate (4b). To a cooled (278 8C)
solution of LDA (1.58 mmol, freshly prepared from
diisopropylamine and n-butyllithium) in THF (1 mL), a
solution of tetralone 3c (400 mg, 1.58 mmol) in THF (1 mL)
was slowly added. After 30 min stirring at 278 8C, a
solution of ethyl bromoacetate (210 mL, 1.9 mmol) in THF
(3.2 mL) was added. The resulting mixture was allowed to
warm to rt and stirred for 18 h. The solvent was removed
under reduced pressure and the residue was dissolved in
ethyl acetate. The organic layer was successively washed
with water, an aqueous solution of sodium hydrogencarbo-
nate (5%) and an aqueous solution of hydrochloric acid
(5%). After drying on magnesium sulfate, the solvent was
removed under reduced pressure. Flash chromatography on
silica gel (cyclohexane/dichloromethane 8/2, Rf¼0.3)
afforded 241 mg (45%) of compound 4b as a pale yellow
oil. IR (KBr) 1682, 1732 cm21
.
1H NMR (CDCl3,
300 MHz) d 1.22 (t, 3H, J¼7.2 Hz), 1.92 (m, 1H), 2.18
(m, 1H), 2.34 (m, 1H), 2.99 (m, 4H), 4.11 (q, 2H,
J¼7.2 Hz), 5.02 (s, 2H), 7.09 (m, 2H), 7.22–7.39 (m,
5H), 7.51 (d, 1H, J¼1.5 Hz). 13C NMR (CDCl3, 75.5 MHz)
d 14.7, 28.9, 29.9, 35.6, 45.1, 60.9, 70.5, 110.9, 122.8,
127.9, 128.4, 129.0, 130.4, 133.3, 137.0, 137.3, 151.9,
172.9, 198.7. Anal. Calcd for C21H22O4: C, 74.54; H, 6.55.
Found: C, 74.41; H, 6.42.
4.2. General procedure for the Corriu’s reaction of
1-tetralones with methacrylamide
4.1.2. 7-Benzyloxy-11-phenyl-2,2a,3,4,10,11-hexahydro-
9-oxa-11a-aza-pentaleno[6a,1-a]naphthalen-1-one (6b).
To a solution of ester 4b (250 mg, 0.74 mmol) in ethanol
(2.1 mL), potassium hydroxide (45.4 mg, 0.8 mmol) in
ethanol (0.4 mL) was added and the resulting mixture was
heated to reflux for 2 h. After cooling to rt, the solution was
extracted with dichloromethane and the aqueous layer was
acidified with diluted hydrochloric acid. Extraction with
dichloromethane followed by drying on magnesium sulfate
and removal of solvents under reduced pressure afforded
195 mg (85%) of crude (7-benzyloxy-1-oxo-1,2,3,4-tetra-
hydronaphth-2-yl)acetic acid 5b as a white solid. IR (KBr)
1680, 1712, 3082 cm21. 1H NMR (CDCl3, 300 MHz) d 1.92
(m, 1H), 2.18 (m, 1H), 2.34 (m, 1H), 2.99 (m, 4H), 5.02 (s,
2H), 7.09 (m, 2H), 7.22–7.39 (m, 5H), 7.51 (d, 1H,
Cesium fluoride must be dried on phosphoric anhydride,
under vacuum at 100 8C. Under a stream of nitrogen, cesium
fluoride, 7-substituted-1-tetralone, methacrylamide and
tetramethoxysilane were introduced into a flask. The
resulting mixture was heated at 80 8C for 5 h. The mixture
was then cooled to rt, triturated with ethyl acetate and
filtered on a celite pad. The solution was washed with water,
dried on magnesium sulfate and the solvent was removed
under reduced pressure. The final product was recrystallized
or chromatographed on silica gel.
4.2.1. 3-Methyl-3,4,5,6-tetrahydro-1H-benzo[h]quinolin-
2-one (9a). According to the general procedure, 1-tetralone
3a (3.2 g, 22 mmol), cesium fluoride (5.35 g, 35 mmol),

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G. Moore et al. / Tetrahedron 60 (2004) 4197–4204
methacrylamide (1.9 g, 22 mmol) and tetramethoxysilane
(5.15 mL, 35 mmol) afforded 1.8 g (40%) of 9a after
recrystallization from ethyl acetate. Mp 174 8C (lit.5
.
173 8C). IR (KBr) 1660, 3245 cm21 1H NMR (CDCl3,
(0.96 mL, 2.2 mmol) was added and the solution was stirred
for 10 min at 278 8C. tert-Butyllithium (1 M solution,
3.4 mL, 3.4 mmol) was then added and the appropriate
electrophile was added after 1 h stirring at 278 8C.
300 MHz) d 1.20 (d, 3H, J¼7.2 Hz), 2.15–2.61 (m, 5H),
2.69–2.77 (m, 2H), 7.02 (m, 4H), 7.39 (s, 1H, NH). 13C
NMR (CDCl3, 75.5 MHz) d 15.9, 27.0, 28.6, 34.6, 35.4,
114.4, 119.2, 127.1, 127.7, 128.4, 129.7, 136.1, 174.8. Anal.
Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C,
78.8; H, 7.1; N, 6.6.
4.3.1. 9-Deutero-3-methyl-3,4,5,6-tetrahydro-1H-
benzo[h]quinolin-2-one (11a). The electrophile was
methanol-d (1 mL, 2.4 mmol). After 2 h stirring at
278 8C, hydrolysis was carried out with a saturated aqueous
solution of NH4Cl. The solution was allowed to warm at rt
and extracted with dichloromethane. The combined extracts
were dried on magnesium sulfate and concentrated under
reduced pressure to afford 0.214 mg of crude product 11a
which was not further purified. 1H NMR (CDCl3, 200 MHz)
d 1.30 (d, 3H, J¼6.5 Hz), 2.4–2.8 (m, 7H), 7.30 (s, 3H),
7.90 (s, 1H).
4.2.2. 9-Methoxy-3-methyl-3,4,5,6-tetrahydro-1H-
benzo[h]quinolin-2-one (9b). According to the general
procedure, 7-methoxy-1-tetralone 3b (0.39 g, 2.2 mmol),
cesium fluoride (2.68 g, 17.5 mmol), methacrylamide
(0.95 g, 2.2 mmol) and tetramethoxysilane (2.58 mL,
17.5 mmol) afforded 0.146 g (60%) of 9b after recrystal-
lization from ethyl acetate. Mp 114 8C. IR (KBr) 1672,
4.3.2. 9-Iodo-3-methyl-3,4,5,6-tetrahydro-1H-benzo[h]-
quinolin-2-one (11b). The electrophile was a solution of
iodine (0.86 g, 3.4 mmol) in THF (8.6 mL). After 2 h
stirring at 278 8C, hydrolysis was carried out with a
saturated aqueous solution of sodium thiosulfate until
disappearance of the red colour. The solution was allowed
to warm at rt and extracted with dichloromethane. The
combined extracts were dried on magnesium sulfate and
concentrated under reduced pressure to afford 0.237 mg
(70%) of 11b after recrystallization from ethyl acetate. Mp
1
3220 cm21. H NMR (CDCl3, 200 MHz) d 1.20 (d, 3H,
J¼7.5 Hz), 2.10–2.60 (m, 7H), 3.60 (s, 3H), 6.60 (d, 1H,
J¼1.5 Hz), 6.75 (dd, 1H, J¼7.0, 1.5 Hz), 6.95 (d, 1H,
J¼7.0 Hz). 13C NMR (CDCl3, 75.5 MHz) d 18.15, 29.62,
29.96, 36.96, 37.70, 58.18, 107.88, 114.98, 116.51, 129.10,
130.21, 131.47, 132.57, 160.95, 176.01. HRMS. Calcd for
C15H17NO2: 243.1259. Found: 243.1250.
4.2.3. 9-Benzyloxy-3-methyl-3,4,5,6-tetrahydro-1H-
benzo[h]quinolin-2-one (9c). According to the general
procedure, 7-benzyloxy-1-tetralone 3c (0.555 g, 2.2 mmol),
cesium fluoride (2.68 g, 17.5 mmol), methacrylamide
(0.95 g, 2.2 mmol) and tetramethoxysilane (2.58 mL,
17.5 mmol) afforded 0.282 g (40%) of 9c after flash
chromatography on silica gel (cyclohexane/dichloro-
methane 3/7, Rf¼0.4). Mp 159 8C (ethyl acetate). IR
225 8C. IR (KBr) 1670, 3240 cm21 1H NMR (CDCl3,
.
200 MHz) d 1.29 (d, 3H, J¼6.5 Hz), 2.35–2.80 (m, 7H),
6.92 (d, 1H, J¼6.5 Hz), 7.47 (d, 1H, J¼6.5 Hz), 7.52 (s,
1H), 7.79 (s, 1H). 13C NMR (CDCl3, 75.5 MHz) d 15.9,
26.8, 28.1, 34.6, 35.3, 91.9, 115.9, 127.7, 128.6, 130.0,
131.9, 135.5, 136.4, 174.8. Anal. Calcd for C14H14INO: C,
49.58; H, 4.16; N, 4.13. Found: C, 49.6; H, 4.2; N, 4.2.
1
(KBr) 1660, 3240 cm21. H NMR (CDCl3, 200 MHz) d
1.20 (d, 3H, J¼7.4 Hz), 2.10–2.70 (m, 7H), 5.00 (s, 2H),
6.70 (m, 2H), 6.95 (d, 1H, J¼8.1 Hz), 7.20–7.40 (m, 5H).
13C NMR (CDCl3, 75.5 MHz) d 15.9, 27.3, 27.7, 34.6, 35.4,
70.6, 106.7, 113.5, 115.3, 127.8, 128.4, 128.9, 129.1, 130.8,
137.1, 137.3, 158.2, 174.8. Anal. Calcd for C21H21NO2: C,
78.97; H, 6.63; N, 4.39. Found: C, 79.05; H, 6.7; N, 4.3.
4.4. General procedure for the protection of the N–H
lactam
Potassium hydroxide (0.224 g, 4 mmol, previously dried
under vacuum) was dissolved in freshly distilled DMSO
(3 mL). The lactam and the alkylation reagent were then
added. The mixture was stirred at rt for 30 min. Water was
then added and the resulting solution was extracted with
dichloromethane. The extracts were washed with water,
dried and concentrated under reduced pressure.
4.2.4. 9-Bromo-3-methyl-3,4,5,6-tetrahydro-1H-benzo-
[h]quinolin-2-one (9d). According to the general pro-
cedure, 7-bromo-1-tetralone 3d (5 g, 22 mmol), cesium
fluoride (5.35 g, 35 mmol), methacrylamide (1.9 g,
22 mmol) and tetramethoxysilane (5.15 mL, 35 mmol)
afforded 1.9 g (30%) of 9d after recrystallization from
4.4.1. 9-Bromo-1,3-dimethyl-3,4,5,6-tetrahydro-1H-
benzo[h]quinolin-2-one (10a). According to the general
procedure, compound 9d (0.292 g, 1 mmol) and methyl
iodide (0.25 mL, 4 mmol) afforded 0.123 g (40%) of
N-protected compound 10a as a yellow solid after
purification by flash chromatography on silica gel (cyclo-
hexane/ethyl acetate 7/3, Rf¼0.3). Mp (ethyl acetate)
1H NMR (CDCl3,
1
ethyl acetate. Mp 212 8C. IR (KBr) 1670, 3230 cm21. H
NMR(CDCl3, 300 MHz)d1.28(d, 3H, J¼7.4 Hz), 2.27–2.80
(m, 7H), 7.00 (d, 1H, J¼8.1 Hz), 7.29 (d, 1H, J¼8.1 Hz), 7.46
(s, 1H), 8.45 (s, 1H). 13C NMR (CDCl3, 75.5 MHz) d 15.3,
26.3, 27.4, 34.0, 34.7, 115.4, 120.2, 122.5, 127.5, 129.2, 129.7,
131.2, 134.3, 174.5. Anal. Calcd for C14H14BrNO: C, 57.55;
H, 4.83; N, 4.79. Found: C, 57.4; H, 4.9; N, 4.6.
124 8C. IR (KBr) 1670 cm21
.
300 MHz) d 1.28 (d, 3H, J¼7.4 Hz), 2.27–2.80 (m, 7H),
3.12 (s, 3H), 7.0 (d, 1H, J¼8.1 Hz), 7.29 (d, 1H, J¼8.1 Hz),
7.46 (s, 1H). 13C NMR (CDCl3, 75.5 MHz) d 15.3, 26.3,
27.4, 34.0, 34.7, 36.1, 115.4, 120.2, 122.5, 127.5, 129.2,
129.7, 131.2, 134.3, 174.5. Anal. Calcd for C15H16BrNO: C,
58.84; H, 5.27; N, 4.57. Found: C, 58.9; H, 5.45; N, 4.6.
4.3. General procedure for the halogen–lithium exchange
reaction on 9-bromo-3-methyl-3,4,5,6-tetrahydro-1H-
benzo[h]quinolin-2-one (9d)
In a flask flushed with nitrogen, the bromo derivative
(0.292 g, 1 mmol) was dissolved in THF (6 mL) and the
solution was cooled at 278 8C. Then, n-butyllithium
4.4.2. 9-Iodo-1,3-dimethyl-3,4,5,6-tetrahydro-1H-
benzo[h]quinolin-2-one (12a). According to the general

G. Moore et al. / Tetrahedron 60 (2004) 4197–4204
4203
procedure, compound 11b (0.339 g, 1 mmol) and methyl
iodide (0.25 mL, 4 mmol) afforded 0.142 g (40%) of
N-protected compound 12a as a pale yellow solid after
purification by flash chromatography on silica gel (cyclo-
hexane/ethyl acetate 7/3, Rf¼0.3). Mp (ethyl acetate)
1H NMR (CDCl3,
300 MHz) d 1.17 (d, 3H, J¼7.2 Hz), 2.10–2.60 (m, 7H),
3.12 (s, 3H), 6.80 (d, 1H, J¼7.0 Hz), 7.28 (d, 1H,
J¼1.5 Hz), 7.41 (dd, 1H, J¼7.0, 1.5 Hz). 13C NMR
(CDCl3, 75.5 MHz) d 15.4, 28.2, 28.3, 33.4, 34.5, 35.9,
91.5, 125.3, 129.8, 131.7, 132.9, 134.4, 135.7, 136.3, 175.7.
Anal. Calcd for C15H16INO: C, 51.01; H, 4.57; N, 3.97.
Found: C, 51.1; H, 4.7; N, 4.0.
diethyl ester (13b). According to the general procedure,
reaction of sodium hydride (0.088 g, 2 mmol) in dioxane
(1.2 mL) with diethyl malonate (0.34 mL, 2 mmol), cuprous
iodide (0.38 g, 2 mmol) and lactam 12b (0.46 g, 1 mmol)
afforded 0.246 g (50%) of 13b as a pale brown oil after flash
chromatography on silica gel (cyclohexane/ethyl acetate
8/2, Rf¼0.3). IR (KBr) 1674, 1732 cm21. 1H NMR (CDCl3,
300 MHz) d 1.17 (d, 3H, J¼7.0 Hz), 1.24 (m, 6H), 2.02–
2.55 (m, 7H), 3.65 (s, 3H), 4.15 (m, 4H), 4.46 (s, 1H), 4.57
(d, 1H, J¼16.0 Hz), 5.20 (d, 1H, J¼16.0 Hz), 6.63 (d, 2H,
J¼11.0 Hz), 6.83 (d, 2H, J¼11.0 Hz), 7.18 (m, 3H). Anal.
Calcd for C29H33NO6: C, 70.86; H, 6.77; N, 2.85. Found: C,
70.95; H, 6.8; N, 2.9.
136 8C. IR (KBr) 1670 cm21
.
4.4.3. 9-Iodo-1-(4-methoxybenzyl)-3-methyl-3,4,5,6-
tetrahydro-1H-benzo[h]quinolin-2-one (12b). According
to the general procedure, compound 11b (0.339 g, 1 mmol)
and 4-methoxybenzyl chloride (0.205 mL, 1.5 mmol)
afforded 0.176 g (60%) of N-protected compound 12b as a
brown solid after purification by flash chromatography on
silica gel (cyclohexane/ethyl acetate 85/15, Rf¼0.3). Mp
4.6. General procedure for the catalytic hydrogenation
reaction of benzo[h]quinolin-2-ones
The compound to reduce was dissolved in ethanol in a
pressure vessel and palladium on carbon (10%) was added
under nitrogen. The vessel was flushed with hydrogen and
the mixture was stirred for 12 h at 1 bar. The mixture was
filtered on a celite pad and the solvent was removed under
reduced pressure.
(ethyl acetate) 102 8C. IR (KBr) 1667 cm21 1H NMR
.
(CDCl3, 300 MHz) d 1.17 (d, 3H, J¼7.1 Hz), 2.01–2.48 (m,
7H), 3.68 (s, 3H), 4.52 (d, 1H, J¼11.8 Hz), 5.13 (d, 1H,
J¼11.8 Hz), 6.61 (m, 2H), 6.83 (m, 3H), 7.29 (d, 1H,
J¼1.5 Hz), 7.41 (dd, 1H, J¼8.0, 1.5 Hz). 13C NMR (CDCl3,
75.5 MHz) d 15.3, 28.1, 28.3, 33.3, 36.4, 47.4, 55.6, 91.4,
113.9, 127.9, 129.7, 129.8, 130.5, 131.7, 133.0, 133.3,
135.7, 136.4, 159.0, 175.8. Anal. Calcd for C22H22INO2: C,
57.53; H, 4.83; N, 3.05. Found: C, 57.40; H, 4.78. N, 2.99.
4.6.1. 2-[1-(4-Methoxybenzyl)-3-methyl-2-oxo-1,2,3,
4,4a,5,6,10b-octahydro-benzo[h] quinolin-9-yl]-malonic
acid diethyl ester (14). According to the general procedure,
compound 13b (0.49 g, 1 mmol) in ethanol (50 mL)
containing 10% Pd–C (0.245 g) afforded 0.22 g (45%) of
1
crude 14 as a yellow solid. H NMR (CDCl3, 300 MHz) d
1.20 (m, 9H), 1.26 (m, 1H), 1.65 (m, 1H), 1.85 (m, 1H), 1.96
(m, 1H), 2.29 (m, 1H), 2.42 (m, 1H), 2.6–2.8 (m, 2H), 3.65
(s, 3H), 4.11 (m, 4H), 4.21 (m, 1H), 4.45 (s, 1H), 5.65 (m,
2H), 6.68 (m, 2H), 7.05 (m, 5H).
4.5. General procedure for the copper catalysed coupling
reactions with diethyl malonate
To a suspension of sodium hydride (55% dispersion in
mineral oil) in dry dioxane freshly distilled diethyl malonate
was added under nitrogen. Cuprous iodide and the iodo
derivative were then added and the mixture was heated to
reflux for 5 h. After hydrolysis with a small amount of ice-
water, the solvent was removed under reduced pressure and
the residue was dissolved in dichloromethane. After
filtration, the organic extract was washed with a saturated
aqueous solution of sodium thiosulfate. After drying on
magnesium sulfate, the solvent was removed under reduced
pressure.
4.6.2. 3-Methyl-3,4,4a,5,6,10b-hexahydro-1H-benzo[h]-
quinolin-2-one (1b0). According to the general procedure,
compound 9a (0.64 g, 3 mmol) in ethanol (65 mL) contain-
ing 10% Pd–C (0.48 g) afforded 0.52 g (80%) of 1b0 as a
yellow solid after recrystallization from ethyl acetate. Mp
122 8C. IR (KBr) 1670, 3240 cm21 1H NMR (CDCl3,
.
300 MHz) d 1.05 (d, 3H, J¼5.0 Hz), 1.26 (m, 1H), 1.65 (m,
1H), 1.85 (m, 1H), 1.96 (m, 1H), 2.29 (m, 1H), 2.42 (m, 1H),
2.6–2.8 (m, 2H), 4.45 (dd, 1H, J¼5.2, 3.2 Hz), 6.45 (m,
1H), 7.05–7.23 (m, 4H). 13C NMR (CDCl3, 75.5 MHz) d
16.7, 27.1, 27.6, 32.9, 33.6, 35.6, 53.0, 126.9, 127.8, 128.3,
129.2, 136.3, 136.9, 176.2. Anal. Calcd for C14H17NO: C,
78.10; H, 7.96; N, 6.51. Found: C, 78.0; H, 8.0; N, 6.55.
4.5.1. 2-(1,3-Dimethyl-2-oxo-1,2,3,4,5,6-hexahydro-
benzo[h]quinolin-9-yl)-malonic acid diethyl ester (13a).
According to the general procedure, reaction of sodium
hydride (0.088 g, 2 mmol) in dioxane (1.2 mL) with diethyl
malonate (0.34 mL, 2 mmol), cuprous iodide (0.38 g,
2 mmol) and lactam 12a (0.353 g, 1 mmol) afforded
0.154 g (40%) of 13a as a brown oil after flash chromato-
graphy on silica gel (cyclohexane/ethyl acetate 8/2,
4.6.3. 9-Hydroxy-3methyl-3,4,4a,5,6,10b-hexahydro-1H-
benzo[h]quinolin-2-one (16a). According to the general
procedure, compound 9c (0.16 g, 0.5 mmol) in ethanol
(10 mL) containing 10% Pd–C (0.08 g) afforded 0.098 g
1
(85%) of crude 16a as a white solid. H NMR (DMSO-d6,
1
Rf¼0.3). IR (KBr) 1674, 1732 cm21. H NMR (CDCl3,
300 MHz) d 1.02 (d, 3H, J¼7.2 Hz), 1.18 (m, 1H), 1.61 (m,
1H), 1.84 (m, 1H), 1.96 (m, 1H), 2.29 (m, 1H), 2.52 (m, 1H),
2.65 (m, 2H), 4.35 (d, 1H, J¼3.2 Hz), 6.51–6.68 (m, 2H),
6.82 (d, 1H, J¼8.7 Hz).
300 MHz) d 1.16 (m, 9H), 2.15–2.61 (m, 7H), 3.06 (s, 3H),
4.13 (m, 4H), 4.53 (s, 1H), 6.85 (d, 1H, J¼6.5 Hz), 7.30 (s,
1H), 7.40 (d, 1H, J¼6.5 Hz). Anal. Calcd for C22H27NO5:
C, 68.55; H, 7.06; N, 3.63. Found: C, 68.45; H, 6.99; N,
3.70.
4.6.4. Trifluoromethanesulfonic acid 3-methyl-2-oxo-
1,2,3,4,4a,5,6,10b-octahydro-benzo[h]quinolin-9-yl ester
(16b). To a cooled solution (0 8C) of the crude phenol 16a
(0.76 g, 3.28 mmol) in freshly distilled DMF (22 mL)
4.5.2. 2-[1-(4-Methoxybenzyl)-3-methyl-2-oxo-1,2,3,
4,5,6-hexahydrobenzo[h]quinolin-9-yl]malonic acid

4204
G. Moore et al. / Tetrahedron 60 (2004) 4197–4204
containing triethylamine (1.15 mL, 8.2 mmol), ditriflimide
(2.6 g, 7.22 mmol) was added. The mixture was stirred at
0 8C for 30 min and then at rt for 4 h. The solvent was
removed under reduced pressure (1 mm Hg) and the residue
was dissolved in diethyl ether. The solution was washed
with water and the organic layer was dried on magnesium
sulfate. The solvent was removed and the excess of
ditriflimide was removed by recrystallization in cyclo-
hexane. The ditriflimide was carefully washed with
cyclohexane and the resulting organic layer was washed
with water and dried on magnesium sulfate. After removing
of the solvent, the residue was recystallized in cyclohexane
to afford 0.48 g (40%) of triflate 16b as a white solid. Mp
The solution was acidified to pH¼2 with diluted hydro-
chloric acid and ethanol was evaporated. The solution was
filtered and the solid was collected to afford 79 mg (89%) of
1
crude 18b as a white solid. H NMR (CDCl3, 300 MHz) d
1.07 (d, 3H, J¼6.8 Hz), 1.18 (m, 1H), 1.37 (m, 1H), 1.65–
1.73 (m, 2H), 1.91 (m, 1H), 2.30–2.43 (m, 2H), 2.53–2.72
(m, 2H), 3.52 (d, 1H, J¼16.0 Hz), 3.63 (d, 1H, J¼16.0 Hz),
4.47 (m, 1H), 6.97 (s, 2H), 7.36 (s, 1H), 9.28 (s, 1H). 13C
NMR (CDCl3, 75.5 MHz) d 16.9, 25.7, 27.1, 31.5, 32.2,
36.0, 41.4, 53.4, 128.9, 129.0, 129.2, 133.1, 134.5, 136.7,
176.9, 178.3.
4.6.7. 2-(3-Methyl-2-oxo-1,2,3,4,4a,5,6,10b-octahydro-
benzo[h]quinolin-9-yl)-N-propyl-acetamide (2b0).
1
171 8C. IR (KBr) 1418, 1443, 1668, 3074, 3226 cm21. H
A
NMR (CDCl3, 300 MHz) d 1.11 (d, 3H, J¼7.4 Hz), 1.22 (m,
1H), 1.69 (m, 1H), 1.89 (m, 1H), 1.91 (m, 1H), 2.29 (m, 1H),
2.42 (m, 1H), 2.61–2.88 (m, 2H), 4.47 (d, 1H, J¼3.2 Hz),
6.61 (s, 1H), 7.19 (m, 3H). 13C NMR (CDCl3, 75.5 MHz) d
16.8, 26.7, 26.8, 32.4, 33.1, 35.9, 53.0, 120.7, 120.9, 130.9,
133.6, 137.3, 139.2, 148.5, 176.1. 19F (CDCl3, 282.4 MHz)
d 73.3. Anal. Calcd for C15H16F3NO4S: C, 49.58; H, 4.44;
N, 3.85. Found: C, 49.65; H, 4.51; N, 3.78.
solution of acid 18b (0.039 g, 0.14 mmol), n-propylamine
(0.012 mL, 0.14 mmol), HOBT (0.019 g, 0.14 mmol) and
EDCI (0.027 g, 0.14 mmol) in acetonitrile (5 mL) was
stirred at rt for 72 h. The mixture was diluted with ethyl
acetate, washed with a 2M aqueous solution of HCl and then
with a 2M aqueous solution of NaOH. After drying on
magnesium sulfate, the solvent was removed under reduced
pressure. The product was purified by flash chromatography
on silica gel (ethyl acetate/methanol 9/1, Rf¼0.5) to afford
0
1
4.6.5. (3-Methyl-2-oxo-1,2,3,4,4a,5,6,10b-octahydro-
benzo[h]quinolin-9-yl)-acetic acid methyl ester (18a).
Enoxysilane 176 (0.366 g, 2.5 mmol corresponding to the
O-silylated product) was added to a solution of triflate 16c
(0.363 g, 1 mmol), lithium acetate (0.2 g, 3 mmol),
Pd(PPh3)4 (0.173 g, 0.15 mmol) in THF (20 mL) under a
nitrogen atmosphere. The mixture was heated to reflux for
16 h. After cooling at rt, an other amount of catalyst was
added (0.023 g, 0.02 mmol) and the mixture was heated to
reflux for 5 h. The solvent was removed under reduced
pressure. The residue was purified by flash chromatography
on silica gel (ethyl acetate, Rf¼0.3). After removal of the
eluent, the residue was dissolved in dichloromethane,
washed with water, dried on magnesium sulfate. Removal
of the solvent followed by recrystallization in ethyl acetate
afforded 0.115 g (40%) of compound 18a as a white solid.
0.029 g (65%) of compound 2b as a pale yellow solid. H
NMR (CDCl3, 300 MHz) d 0.77 (t, 3H, J¼7.3 Hz), 1.09 (d,
3H, J¼7.2 Hz), 1.18–1.28 (m, 1H), 1.37 (qt, 2H, J¼7.3,
6.9 Hz), 1.60–171 (m, 1H), 1.76–1.95 (m, 2H), 2.10 (s,
1H), 2.25–2.46 (m, 1H), 2.56–2.79 (m, 2H), 3,07 (t, 2H,
J¼6.9 Hz), 3.42 (s, 2H), 4.44 (m, 1H), 5.71 (m, 1H), 6.80
(m, 1H), 7.03 (m, 2H), 7.17 (m, 1H). 13C NMR (CDCl3,
75.5 MHz) d 11.7, 16.8, 23.1, 27.0, 27.1, 32.7, 33.2, 35.7,
41.7, 43.9, 53.0, 128.7, 129.3, 129.8, 133.9, 135.6, 136.9,
171.3, 176.2. Anal. Calcd for C19H26N2O2: C, 72.58; H,
8.33; N, 8.91. Found: C, 72.7, H, 8.45; N, 8.95.
References and notes
1
Mp 114 8C. IR (KBr) 1652, 1742, 3190 cm21. H NMR
1. Moore, G.; Levacher, V.; Bourguignon, J.; Dupas, G.
Tetrahedron Lett. 2001, 42, 261–263, and references cited
therein.
(CDCl3, 300 MHz) d 1.12 (d, 3H, J¼5.0 Hz), 1.22 (m, 1H),
1.63 (m, 1H), 1.82 (m, 1H), 1.99 (m, 1H), 2.30 (m, 1H), 2.43
(m, 1H), 2.59–2.81 (m, 2H), 3.53 (s, 2H), 3.62 (s, 3H), 4.42
(m, 1H), 6.04 (m, 1H), 7.00–7.11 (m, 3H). 13C NMR
(CDCl3, 75.5 MHz) d 16.6, 27.1, 27.4, 32.9, 33.7, 35.5,
41.1, 52.5, 52.9, 128.9, 129.2, 129.6, 132.7, 135.9, 136.3,
172.4, 176.0. Anal. Calcd for C17H21NO3: C, 71.06; H, 7.37;
N, 4.87. Found: C, 71.1; H, 7.4; N, 4.7.
2. Ennis, M. D.; Hoffman, R. L.; Ghazal, N. B.; Old, D. W.;
Mooney, P. A. J. Org. Chem. 1996, 61, 5813–5817.
3. Nayak, M. K.; Chakraborti, A. K. Tetrahedron Lett. 1997, 38,
8749–8752.
4. Nieman, J. A.; Ennis, M. D. Org. Lett. 2000, 2, 1395–1397.
5. Corriu, R. J. P.; Perz, R. Tetrahedron Lett. 1985, 26,
1311–1314. Chuit, C.; Corriu, R. J. P.; Perz, R.; Reye, C.
Tetrahedron 1986, 2293, 2301.
4.6.6. 3-Methyl-2-oxo-1,2,3,4,4a,5,6,10b-octahydro-
benzo[h]quinolin-9-yl acetic acid (18b). To a solution of
ester 18a (93 mg, 0.32 mmol) in ethanol (1 mL), sodium
hydroxide (38.8 mg, 0.97 mmol) in ethanol (0.25 mL) was
added and the resulting mixture was stirred at rt for 15 h.
` ´
6. Briere, J. F.; Dupas, G.; Queguiner, G.; Bourguignon, J.
Tetrahedron 2000, 56, 8679–8688.
7. Horman, I.; Dreux, B. Helv. Chim. Acta 1984, 67, 754–764.
8. Job, A. Ann. Chim. (10th series) 1928, 9, 113–203.