Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2009.01.067

A series of new benzolactam derivatives was synthesized and the derivatives were evaluated for their affinities at the dopamine D₁, D₂, and D₃ receptors. Some of these compounds showed high D₂ and/or D₃

Full text of DOI:10.1016/j.bmcl.2009.01.067

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1773–1778
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, binding affinity and SAR of new benzolactam derivatives
as dopamine D3 receptor ligands
b
b
b
Raquel Ortega a, Enrique Raviña a, Christian F. Masaguer a, , Filipe Areias , José Brea , María I. Loza ,
*
Laura López c, Jana Selent c, Manuel Pastor c, Ferran Sanz c
a Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain
b Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain
c Research Unit on Biomedical Informatics (GRIB), IMIM, Universitat Pompeu Fabra, Dr. Aiguader 88, E-08003 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new benzolactam derivatives was synthesized and the derivatives were evaluated for their
affinities at the dopamine D1, D2, and D3 receptors. Some of these compounds showed high D2 and/or
D3 affinity and selectivity over the D1 receptor. The SAR study of these compounds revealed structural
characteristics that decisively influenced their D2 and D3 affinities. Structural models of the complexes
between some of the most representative compounds of this series and the D2 and D3 receptors were
obtained with the aim of rationalizing the observed experimental results. Moreover, selected compounds
showed moderate binding affinity on 5-HT2A which could contribute to reducing the occurrence of extra-
pyramidal side effects as potential antipsychotics.
Received 25 November 2008
Revised 20 January 2009
Accepted 22 January 2009
Available online 27 January 2009
Keywords:
Dopamine receptors
Antipsychotics
Structure-activity relationship
Benzolactams
Ó 2009 Elsevier Ltd. All rights reserved.
Arylpiperazines
Dopamine (DA) is a major neurotransmitter in the central ner-
vous system (CNS) that plays important roles in behaviour and
cognition, ranging from movement to emotion, sensitization to
addiction, and development to plasticity. All DA receptors belong
to a superfamily of large peptides that are coupled to G-proteins
and modified by attached carbohydrate, lipid–ester or phosphate
groups. They are characterized by having seven hydrophobic trans-
membrane-spanning regions, as well as a functionally critical third
intracytoplasmic loop that interacts with G-proteins and other
effector molecules to mediate the physiological and neurochemical
effects of the receptors. Based on their pharmacological profiles,
including their effects on different signal transduction cascades,
these receptors are currently divided into two families: the D1-like
family or adenylyl-cyclase stimulators, which includes D1 and D5
receptors, and the D2-like family or adenylyl-cyclase inhibitors,
which includes D2, D3 and D4 receptors.1
The D3 dopamine receptor was first identified and clonated by
Sokoloff et al.2 in 1990 and has been shown to be an interesting
target for different CNS diseases. Although its structure and phar-
macology are very similar to dopamine D2, the D3 receptor is gen-
erally less abundant than the D2 receptor, and the difference is
particularly striking in the caudate putamen, where D2 receptors
are densest and D3 receptors are poorly represented.3 Moreover,
D3-binding sites and mRNA encoding D3 receptors are concen-
trated in the limbic brain areas known to be associated with cogni-
tive and emotional functions.4 Due to this, the D3 receptor has been
suggested to be a potential target in the treatment of neurological
disorders such as schizophrenia, and drug abuse.5 In schizophrenia,
a blockade of D2 receptors has been considered to be the main
mechanism responsible for the efficacy of antipsychotics,6 but
the complex profiles of some atypical drugs challenged this
assumption, that is, clozapine exhibits activity at multiple recep-
tors.7 Now there is an increasing body of clinical evidence that sup-
ports the notion that multi-target ligands may be more efficacious
than strictly selective agents in the treatment of schizophrenia and
other CNS disorders.8 Among multiple receptor subtypes, D3 recep-
tors have been proposed as putative targets for atypical antipsy-
chotic drugs, and thus, some works suggest that D3 antagonism
may cause cognitive enhancement9 and a lack of catalepsy.10
In an attempt to prove these hypotheses, an intensive effort has
been directed toward the development of selective ligands for
dopamine D3 receptors.11 Some of these D3 ligands are now in
ongoing clinical development as potential therapeutics for the
aforementioned disorders. The compound BP 897 (Fig. 1), which
was initially identified as a partial agonist but later displayed an
antagonist property in other experiments, could reduce cocaine-
seeking behaviour in rats.12 The superpotent benzothiophene der-
ivate FAUC 365 displays neutral antagonistic behaviour and a
7200-fold selectivity over the D2 subtype.13 Another D3 versus D2
* Corresponding author. Tel.: +34 981563100; fax: +34 981594912.
E-mail address: christianf.masaguer@usc.es (C.F. Masaguer).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.01.067

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R. Ortega et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1773–1778
Figure 1. Structures of the D3 receptor ligands BP 897, FAUC 365 and S33138.
receptor antagonist is S33138, which is now in Phase IIb clinical
trials for schizophrenia.14
Today there is an urgent need for more selective molecular tools
to help definitively separate D3 actions from those mediated by the
D2 receptors, in order to elucidate the function and potential ther-
apeutic advantages of targeting D3 receptors.
In an attempt to design a novel class of D3 ligands to study this
receptor system, we report herein the synthesis and binding affin-
ity of a new series of potential D3 receptor ligands (Fig. 2). This no-
vel series is based on the benzolactam scaffold and maintains three
characteristic elements of many dopamine D3 receptor antago-
nists: (1) an amine moiety, (2) a spacer, usually a linear alkyl chain,
and (3) a hydrophobic residue, often connected through an amide
bond.15 The size of the lactam cycle varied from a six to eight-
membered ring, the length of the alkyl spacer, from propyl to pen-
tyl, and the aryl substituent of the piperazine ring was varied to
achieve a set of compounds that allows us to evaluate some of
the structural requirements for high binding affinity and selectivity
on the D3 receptor.
The synthetic route for the preparation of the target aryl-
piperazinylalkylbenzolactams started from a commercially avail-
able benzocycloalkanone (indanone, tetralone or benzosuberone),
with the aim of achieving the corresponding benzolactam by a
Schmidt rearrangement (Scheme 1). The Schmidt reaction, accord-
ing to the literature, gives benzolactam 3 as the major product;
however, by changing the reaction medium from trichloroacetic
acid,16 polyphosphoric acid17 or sulfuric acid18 to concentrated
hydrochloric acid,19 the desired benzolactams 2 can be obtained
in moderate yields (42%). This reaction was optimized by adding
two equivalents of the sodium azide,20 and it resulted in a 75–
85% yield of the benzolactam type 2. Nevertheless, this technique
was not useful in case the of the benzosuberone, where the benzo-
lactam 2c was obtained in only a 7% yield, whereas 3c was ob-
tained in an 87% yield.
Scheme 1. Reagents and conditions: (a) 2 equiv NaN3, HCl conc.
in Scheme 2. In the case of a propyl spacer (method A), chlorides
4a–f were prepared from commercially available piperazines by
alkylation with 1-bromo-3-chloropropane in acetone using 25%
aqueous NaOH as a base. The corresponding N-(3-chloropro-
pyl)piperazines 4a–f were obtained with 60–80% yields. Alkylation
of the benzolactams 2a–c was achieved when they were treated
with the different chloropropylpiperazines 4a–f in anhydrous ben-
zene after deprotonation with NaH, resulting in the final com-
pounds 5a–f, 6a–f and 7b in a 60–85% yield.
Alkylation of piperazines with 1-bromo-4-chlorobutane or 1-
bromo-5-chloropentane, following method A (Scheme 2), pro-
duced an azaspiroazonium salt. Although the reaction of this salt
with imides has been described in the literature,21 in our case
the desired products were obtained in very low yields. Conse-
quently, method B (Scheme 2) was applied for the synthesis of
N-arylpiperazinylbutyl- and pentyl-benzolactams. Alkylation of
the benzolactams 2a,b with 1-bromo-4-chlorobutane or 1-bro-
mo-5-chloropentane in anhydrous benzene using sodium hydride
as a base gave the corresponding amides 8–10 in acceptable yields,
depending on the size of the benzolactam ring. Higher yields were
obtained with the six-membered benzolactams 822 (62%) and 10
(75%), and lower yields with the seven-membered benzolactam
922 (50%). For alkylation of piperazines, the best results were ob-
tained by reacting the arylpiperazine and chloroalkylbenzolactam
with potassium carbonate as a base and potassium iodide as a cat-
alyst in methylisobutylketone. The alkylated benzolactams 11a–h,
12a–f and 13a were obtained in a 30–75% yield.
Depending on the length of the spacer, one of two synthetic
routes was used starting from the benzolactams 2a–c, as shown
The affinity of the new compounds for cloned human D1, D2 and
D3 receptors was evaluated in in vitro binding assays using
Figure 2. General structure of new benzolactam derivatives.

R. Ortega et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1773–1778
1775
Scheme 2. Reaction conditions: (a) 1-bromo-3-chloropropane, NaOH, acetone; (b) 2a–c, NaH, benzene, reflux; (c) 1-bromo-4-chlorobutane or 1-bromo-5-chloropentane,
NaH, benzene, reflux; and (d) arylpiperazine, K2CO3, IK, methyl isobutylketone, reflux.
[3H]SCH23390 for labelling D1 receptors and [3H]spiperone for
labelling D2 and D3 receptors, according to our previously de-
scribed procedures.23 Ki values (expressed as pKi) were calculated
according to the Cheng–Prusoff equation.24 For the compounds
that showed little affinity, a percentage of inhibition at the highest
for the observed pharmacological results. A full description of the
methods used for the building of such models is provided as Sup-
plementary data and can also be found in Selent et al.25 For the
description of these models here, the residues in the transmem-
brane domains (TM) will be named using the Ballesteros and
Weinstein indexing system.26
concentration tested (10 lM) is reported. The in vitro receptor
binding data are summarized in Table 1.
One of the points studied here is the length of the linker be-
tween the lactam and the piperazine ring. Available data indicate
that the length of this bridge decisively influences the affinity of
these compounds to the D2 and D3 receptors, whereas on the D1
receptor the length of the bridge seems to have little influence.
Lengthening the bridge from propyl to butyl resulted in a beneficial
effect on the affinity at the D2 and D3 receptors. Propyl derivatives
such as 5a or 6a, with modest D2 and D3 affinities became high
affinity ligands when transformed into their butyl analogues 11a
With the aim of rationalizing the observed experimental results,
structural models of the complexes between some of the most rep-
resentative compounds of this series and the D2 and D3 receptors
were obtained. It must be stressed that such models were built
using computational methods and therefore do not have the value
of an experimental result (e.g., a crystallographic structure). Even
so, the inspection of such structures allows us to formulate an
interesting hypothesis about the physicochemical justifications
Table 1
Human D1–D3 receptor binding affinities of new compounds (pKi or percent displacement at 10 l
M)a
O
N
N
m
N
Ar
n
Compound
Code
m
n
Ar
D1
D2
D3
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
USC-A301
USC-A302
USC-A303
USC-A304
USC-A305
USC-A306
USC-B301
USC-B302
USC-B303
USC-B304
USC-B305
USC-B306
USC-C302
USC-A401
USC-A402
USC-A403
USC-A404
USC-A406
USC-A407
USC-A408
USC-B401
USC-B402
USC-B403
USC-B404
USC-B406
USC-A501
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
3
1
1
1
1
1
1
2
2
2
2
2
2
3
1
1
1
1
1
1
1
2
2
2
2
2
1
2-Methoxyphenyl
4-Methoxyphenyl
2-Pyridyl
59.47% 6.87
43.45% 5.89
5.77 0.37
40.82% 0.79
5.76 0.29
5.84 0.17
5.60 0.10
42.83% 3.40
57.00% 9.75
46.01% 6.74
5.31 0.50
50.42% 2.80
1.35% 6.95
12.40% 0.52
0.36% 6.95
52.38% 0.73
59.87% 4.77
6.10 0.07
1.10% 1.51
26.26% 0.00
36.44% 0.31
55.46% 0.62
6.66 0.05
13.13% 1.35
7.91 0.30
33.25% 2.59
57.54% 0.31
60.51% 0.12
7.94 0.52
7.45 0.10
6.80 0.11
8.44 0.17
59.02% 0.73
6.64 0.05
6.82 0.24
7.44 0.07
7.69 0.09
5.80 0.15
5.00 0.37
5.08 0.11
4.61 0.20
5.62 0.24
6.68 0.49
6.68 0.16
5.96 0.34
5.38 0.32
5.08 0.32
5.98 0.18
6.41 0.14
5.05 0.14
8.58 0.16
6.31 0.19
7.92 0.21
5.82 0.12
6.79 0.26
8.17 0.16
7.39 0.14
8.80 0.35
7.39 0.08
6.40 0.21
6.20 0.16
7.84 0.17
7.49 0.18
2-Pyrimidyl
3-Trifluoromethylphenyl
2,3-Dichlorophenyl
2-Methoxyphenyl
4-Methoxyphenyl
2-Pyridyl
2-Pyrimidyl
3-Trifluoromethylphenyl
2,3-Dichlorophenyl
4-Methoxyphenyl
2-Methoxyphenyl
4-Methoxyphenyl
2-Pyridyl
5.62 0.13
7b
58.85% 4.65
61.10% 5.76
34.16% 0.79
5.69 0.10
31.56% 0.12
5.75 0.19
6.46 0.22
6.37 0.30
5.57 0.26
47.47% 5.10
6.55 0.34
11a
11b
11c
11d
11f
11g
11h
12a
12b
12c
12d
12f
13a
2-Pyrimidyl
2,3-Dichlorophenyl
2-Chlorophenyl
3-Methoxyphenyl
2-Methoxyphenyl
4-Methoxyphenyl
2-Pyridyl
2-Pyrimidyl
2,3-Dichlorophenyl
2-Methoxyphenyl
5.06 0.14
5.76 0.31
6.01 0.12
a
All values are means of two or three separate competition experiments.

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R. Ortega et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1773–1778
or 12a, respectively. While the affinity for D2 receptors increased
with the linker extension, selectivity by the D3 receptors de-
creased. In the only pentyl case studied (13a), the use of a five car-
bon bridge produced a decrease in the affinity for the D3 receptors
and a moderate increase in the affinity for the D1 receptor, when
compared with the butyl compound 11a.
The analysis of the structural models obtained for the com-
plexes between ligands of the propyl and butyl series and the D2
and D3 receptors suggests an explanation for the experimental re-
sults observed. In all of the structures obtained, the same key inter-
actions were observed: besides the well-known salt bridge (D3.32),
which is essential for ligand binding, the aryl ring is fixed in a
hydrophobic sandwich consisting of V3.33 and F6.52 and the polar
aryl substituents interact with the Ser residues in TM5. The benzo-
lactam ring is directed towards the TM 2, 1, 7 regions and is later-
ally stabilized by a hydrophobic interaction with L2.64 and Y7.35
in both sides of the pocket. In the ligands with a butyl linker (like
11a in Fig. 3, in grey), the benzolactam ring can establish a H-bond
between the carbonyl oxygen of the benzolactam and the side
chain of H-bond donor residues in TM7 (T7.39 in D2 and S7.36 in
D3). On the other hand, the compounds with a propyl linker (like
5a in Fig. 3, in green) orient the benzolactam carbonyl oxygen in
a different position from which it is not possible to establish an
equivalent H-bond neither in the D2 nor in the D3 receptor. As a
consequence of this lack of polar anchorage, the docking simula-
tion results suggest alternate poses for some propyl compounds,
in which the lactam moiety is directed either upwards or down-
wards and out of the common binding pocket.
Another aim of this work was to study the influence of the lac-
tam ring size on the affinity of the dopamine receptors and the
selectivity of these compounds. On D3 receptors, increasing the
size of the lactam ring from 6 to 7 members produced, in all cases
of available data (except 11c ? 12c), a slightly positive effect on
affinity. In addition, the series 5b ? 6b ? 7b seems to indicate that
the optimum size of the lactam ring for affinity to the D3 receptors
would be 7 members. On D2 receptors, the effect is similar to the
previous case: increasing the size of the lactam ring from 6 to 7
produces an advantageous effect on affinity. One exception is the
compound 11f, where the expansion of its lactam ring from 6 to
7 members resulted in a drop in the affinity. As for the effect on
the D1 receptors, we can say that, in most cases, there was no sig-
nificant change in the affinity. As regards the selectivity, the com-
pounds bearing a six-membered lactam were generally more D3
selective than derivatives with a lactam of seven members. The
exception was found in the derivative 12b, which has a relatively
high affinity for D3 (Ki = 40 nM, pKi = 7.39) while lacking an affinity
for D1 or D2 receptors.
Figure 4. Complex of D2 receptor with 11a (in grey) and 12a (in green, with a CPK
representation superimposed). The seven member lactam ring present in 12a
interacts better with the hydrophobic residues shown in the figure (V2.61, L2.64
and I183).
An observation of the structural models obtained for the com-
plexes suggested that the minor positive effect of the lactam ring
size (six- or seven-membered ring) on the D2 and D3 receptor affin-
ity could be explained by the slightly more favourable contacts of
the seven-membered lactam ring compounds with the nearby
hydrophobic residues than the equivalent six-membered ring com-
pounds. This is illustrated in Figure 4, the structure of 11a (grey)
and 12a (green) in complex with D2. The aliphatic carbons of the
seven-membered ring are located closer to the V2.61, L2.64 and
the I1.83, located in the extracellular loop 2 (the residue of the
binding site not conserved between the D2 and D3 receptors). Inter-
estingly, the effect on the antagonist affinity of V2.61F27 and
L2.64S27 mutations in the D2 receptor supports our finding. Fur-
thermore, mutational studies of the I1.83 indicate that, due to
the observed impact on the ligand binding, this residue should
be close to the core of the binding pocket.28
In looking at the influence of the phenylpiperazine moiety, we
haveanalysedeightN-substitutedpiperazineswitharylorheteroaryl
groups: 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,
2-pyridyl, 2-pyrimidyl, 3-trifluoromethylphenyl, 2-chlorophenyl,
and 2,3-dichlorophenyl. The aryl groups that produced a greater
affinity for the D3 receptor were the 2-methoxyphenyl, 2-chloro-
phenyl and 2,3-dichlorophenyl. Moreover, the substituents of the
piperazine ring that led to a greater selectivity of the D3 over D2 were
2-pymimidyl, and especially 4-methoxyphenyl.
Figure 3. (a) Complexes of the D2 receptor with 11a (in grey) and 5a (in green). (b) Complex of the D3 receptor with 11a (in grey) and 5a (in green). The figure illustrates how
compounds with a butyl linker (like 11a) are able to establish H-bonds with polar residues of the seventh helix in both the D2 (T7.39) and the D3 receptors (S7.36), which are
not observed in complexes of compounds with a propyl linker (like 5a). The position of the residue D3.32 is shown as reference.

R. Ortega et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1773–1778
1777
In the compounds bearing a methoxyphenylpiperazine, the po-
sition of the methoxy group in the aromatic group critically influ-
ences the selectivity and affinity for dopamine receptors. For
example, on the D2 receptor, the pKi values of the 2-methoxyphe-
nylpiperazines 11a and 12a were 7.91 and 8.44, respectively, while
its position isomers, the 4-methoxyphenylpiperazines 11b and
12b, showed no affinity for this receptor. The same can be said
for the isomers 6a (pKi = 6.10) and 6b (pKi < 4), which carry a pro-
pyl bridge. Displacement of the methoxy group in the aromatic
ring from position 2 to 4 produced, in all cases, a decrease in the
affinity for the three receptors, though selectivity of the D3 recep-
tors increased significantly. This indicates that the change of the
location of the methoxy group is far more detrimental for D1 and
D2 than for D3 receptor binding.29 Thus, the compound that was
most selective for D3 was 12b, as it had an affinity for this receptor
more than 1000-fold higher than it had for D1 or D2. The location of
the methoxy in position 3 leads to a compound (11h) with D2 and
D3 affinities that are intermediate between those of its position 2
(11a) and position 4 (11b) isomers.
Considering that serotonin antagonism at 5-HT2A receptors has
been reported to improve the negative symptoms of schizophrenia
and to reduce the occurrence of extrapyramidal side effects30 and
bearing in mind that a preferential blockade of D3 versus D2 recep-
tors is associated with a relatively benign effect upon motor func-
tion as compared with drugs possessing D2/D3 or principally D2
antagonist properties,5,31 compounds 11a, 11g, 12a and 12f32 were
selected among the new compounds. This is because (a) their Ki
values <50 nM (or pKi > 7.30) at both D2 and D3 receptors, and
(b) they have a higher affinity to D3 than to D2 receptors (2.2- to
5.2-fold). These chosen compounds were examined further for
binding affinity toward 5-HT2A receptors by competing against
[3H]ketanserin (Table 2).
tivity over the D1 receptor. Moreover, 12b displayed a D3 affinity in
the nanomolar range and a high selectivity over D1 and D2. The SAR
study on these compounds revealed that both the length of the
bridge between the benzolactam and the piperazine and the size
of the lactam ring decisively influenced their D2 and D3 affinities.
Selected compounds showed moderate 5-HT2A binding affinity,
which could help to reduce the occurrence of extrapyramidal side
effects should the compounds be used as antipsychotics. These
data significantly improve our understanding of the D3 pharmaco-
phore and are expected to lead to novel approaches for the treat-
ment of schizophrenia. Further optimization of this series will be
reported in due course.
Acknowledgments
This work was supported in part by grants from the CICYT
(Spain, SAF2005-08025-C03) and by the Xunta de Galicia (Spain,
PIDIT06PXIB203173PR), as well as by the HERACLES and COMBIO-
MED networks from Instituto de Salud Carlos III. J. Brea received
financial support from the Programa Isabel Barreto (Xunta de Gali-
cia, Spain).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.01.067.
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In summary, we have synthesized a series of 26 new com-
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the D1, D2, and D3 receptors. Some of these compounds, for exam-
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Table 2
Human D2, D3 and 5-HT2A receptor binding affinities (pKi) of compounds 11a, 11g,
12g, and 12fa
Compound
D2
D3
D2/D3 Ki ratio
5-HT2A
11a
11g
12a
12f
7.91 0.30
7.45 0.10
8.44 0.17
7.44 0.07
8.58 0.16
8.17 0.16
8.80 0.35
7.84 0.17
4.7
5.2
2.2
2.5
6.32 0.07
7.02 0.05
6.75 0.27
7.98 0.06
a
All values are means of two or three separate competition experiments.
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(57), 231 (100), 209 (84), 160 (34).Compound 12a: Yellow solid, mp 107–
108 °C; IR (KBr) 2929, 1626, 1475, 1362, 1240; 1H NMR (CDCl3) d 7.22 (dd,
1H, J = 7.2, 1.8), 7.38–7.28 (m, 2H), 7.14–7.11 (m, 1H), 7.02–6.88 (m, 3H),
6.87–6.84 (m, 1H), 3.86 (s, 3H), 3.63–3.58 (m, 2H), 3.21 (t, 2H, J = 6.4), 3.11
(b.s., 4H), 2.79 (t, 2H, J = 7.1), 2.67 (b.s., 4H), 2.50–2.46 (m, 2H), 2.03 (q, 2H,
J = 6.8), 1.75–1.50 (m, 4H); 13C NMR (CDCl3) d 171.1, 153.1, 140.1, 136.0,
137.5, 131.2, 128.9, 128.7, 127.4, 124.1, 121.5, 119.1, 111.7, 58.1, 55.8, 53.3,
49.2, 46.9, 46.7, 30.7, 30.3, 26.9, 25.9; APEI-MS m/z 407 (M+, 8), 392 (33), 245
(100), 205 (92), 162 (20), 128 (40), 91 (30).Compound 12f: Brownish oil; IR
(film) 2938, 2821, 1635, 1574, 1451; 1H NMR (CDCl3) d 7.65 (dd, 1H, J = 7.21,
1.8), 7.37–7.28 (m, 2H), 7.14–7.10 (m, 3H), 6.95 (dd, 1H, J = 6.2, 3.3), 3.59 (t,
2H, J = 7.1), 3.20 (t, 2H, J = 6.4), 3.09 (d., 4H, J = 4.5), 2.78 (t, 2H, J = 7.1), 2.67
(b.s., 4H), 2.53–2.48 (m, 2H), 2.02 (q, 2H, J = 6.8), 1.70–1.61 (m, 4H); 13C NMR
(CDCl3) d 162.0, 151.5, 137.6, 136.5, 134.5, 131.1, 128.9, 128.7, 128.5, 127.8,
127.3, 125.0, 119.0, 58.62, 53.7, 51.8, 51.6, 47.5, 46.6, 30.7, 30.4, 24.6; APEI-
MS m/z 445 (M+, 0.28), 245 (100), 174 (20).
32. Data for selected compounds: Compound 11a: Yellow solid, mp 107–108 °C
(cyclohexane); IR (KBr) 2933, 2817, 1647, 1499, 1307, 1240: 1H NMR (CDCl3)
d 8.06 (dd, 1H, J = 7.6, 1.5), 7.41–7.31 (m, 2H), 7.15 (dd, 1H, J = 7.4, 0.6), 6.98–
6.82 (m, 4H), 3.84 (s, 3H), 3.61–3.52 (m, 4H), 3.07 (b.s., 4H), 2.96 (t, 2H,
J = 6.6), 2.63 (b.s., 4H), 2.47–2.42 (m, 2H), 1.70–1.58 (m, 4H); 13C NMR (CDCl3)
d 164.7, 152.7, 141.7, 138.3, 131.9, 130.0, 128.6, 127.4, 127.2, 123.3, 121.4,
118.6, 111.6, 58.8, 55.7, 53.8, 51.0, 47.7, 46.5, 28.6, 26.2, 24.3; APEI-MS m/z
393 (M+, 14), 378 (36), 231 (100), 205 (82), 180 (35), 160 (19).Compound
11g: Yellow-orange oil; IR (film) 2938, 2818, 1708, 1646, 1586, 1481, 1448,
1341, 1307, 1231; 1H NMR (CDCl3) d 8.04 (dd, 1H, J = 7.6, 1.2), 7.38–7.28 (m,
3H), 7.19–1.11 (m, 2H), 6.99 (dd, 1H, J = 8.1, 1.4), 6.91 (td, 1H, J = 7.6, 1.4),
3.59–3.55 (m, 4H), 3.53–3.48 (m, 2H), 3.04 (s, 4H), 2.94 (t, 2H, J = 6.6), 2.61 (s,
4H), 2.45–2.41 (m, 2H), 1.68–1.53 (m, 4H); 13C NMR (CDCl3) d 164.0, 149.0,
137.7, 131.2, 130.3, 129.4, 128.4, 127.9, 127.3, 126.7, 123.4, 120.1, 58.0, 53.1,
51.2, 50.9, 46.9, 45.8, 27.9, 25.5, 24.0; APEI-MS m/z 397 (M+, 5), 382 (16), 257
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