Quinlobelane: A water-soluble lobelane analogue and inhibitor of VMAT2

Article abstract of DOI:10.1016/j.bmcl.2010.04.117

Replacing the phenyl groups in the structure of the VMAT2 inhibitor, lobelane with either pyridyl, quinolyl or indolyl groups affords novel analogues with improved water solubility. The synthetic methodologies reported herein also underscore the paucity of hydrogenation methods that offer selectivity in the synthesis of the different classes of heteroaromatic lobelane analogues. The quinolyl group was the only replacement for the phenyl group in lobelane that retained VMAT2 inhibition.

Full text of DOI:10.1016/j.bmcl.2010.04.117

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3584–3587
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Quinlobelane: A water-soluble lobelane analogue and inhibitor of VMAT2
*
Ashish P. Vartak, A. Gabriela Deaciuc, Linda P. Dwoskin, Peter A. Crooks
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Replacing the phenyl groups in the structure of the VMAT2 inhibitor, lobelane with either pyridyl, quino-
lyl or indolyl groups affords novel analogues with improved water solubility. The synthetic methodolo-
gies reported herein also underscore the paucity of hydrogenation methods that offer selectivity in the
synthesis of the different classes of heteroaromatic lobelane analogues. The quinolyl group was the only
replacement for the phenyl group in lobelane that retained VMAT2 inhibition.
Received 11 February 2010
Revised 23 April 2010
Accepted 27 April 2010
Available online 4 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Dopamine transport
VMAT2
Lobeline analogs
Lobelane (1, N-methyl-cis-2,6-diphenethylpiperidine) is a min-
or alkaloid present in Lobelia inflata, and a defunctionalized analog
of lobeline (2), the major alkaloid of L. inflata, (Fig. 1). Mid-20th
century investigations into the pharmacology of lobelane by Foster
et al. revealed a peripheral spasmolytic, ‘central stimulating’ action
using guinea pigs, and marked respiratory analeptic activity in
dogs.1 Lobeline inhibits (+)-methamphetamine (METH) self-
administration in rats, and the effect was not surmounted by
METH, indicating a noncompetitive mechanism of inhibition. Re-
peated administration of lobeline in rats prior to (+)-METH self-
administration also prevents (+)-METH-induced dopaminergic tox-
icity.2 The underlying neurochemical mechanism of action of lobe-
line is believed to be due to reversible inhibition of the vesicular
monoamine transporter-2 (VMAT2). Since VMAT2 sequesters cyto-
solic dopamine (DA) into synaptic vesicles, thereby preventing
metabolism by monoamine oxidase (MAO), VMAT2 inhibition by
lobeline leads to increased metabolism of DA into dihydroxyphenyl
acetic acid (DOPAC) and reduced levels of cytosolic DA.3 METH
inhibits VMAT2 and MAO, leading to increased cytosolic DA levels.
METH also reverses DA transporter function, leading to increases in
extracellular DA levels). The psychological excitation or ‘high’ pro-
duced by METH is the result of the increased extracellular DA con-
centrations as an outcome of the actions of METH. One possible
explanation for the lobeline-induced attenuation of METH self-
administration is that the reduction in cytosolic DA produced by
lobeline renders METH ineffective as a stimulant. As an outcome
of these preclinical studies, lobeline is currently being evaluated
in Phase II clinical trials as a treatment for METH abuse.4
The development of lobeline as a therapeutic agent to treat
METH-addiction is complicated by its additional inhibitory effects
*
*
a6 nicotinic acetylcholine receptors (nAChRs).
on the
a
4b2 and
Glennon and co-workers reported that deoxygenation and reduc-
tion of 2 attenuated its activity at nAChRs, with the fully reduced
analog 1 binding with a >10,000-fold lower affinity to nAChRs
when compared to lobeline.5 A rigorous study into the pharmacol-
ogy of 1 and its aryl-substituted analogues revealed that 1 pos-
sessed
a
fivefold improvement in affinity for the
dihydrotetrabenazine (DTBZ) binding site on VMAT2.6,7 Replace-
ment of the phenyl groups in lobelane with anisyl and naphthyl
moieties significantly improved affinity for VMAT2 with retention
of selectivity for VMAT2.8
Lobelane and its analogues were recently reported to potently
inhibit vesicular DA uptake by VMAT2, as well as inhibit METH-
evoked DA release, with lobelane being 10–15-fold more potent
than lobeline in these studies.9,10 Based on this work, lobelane
was considered a lead candidate for the development of VMAT2
inhibitors as therapeutics for psychostimulant abuse. The evalua-
tion of lobelane in vivo for its behavioral effects in rats was limited
somewhat by the low water solubility of its salt forms. A subse-
quent systematic investigation of lobelane analogues was initiated
with the aim of discovering analogs possessing improved water
solubility, as well inhibition and selectivity at VMAT2.
OH
O
N
CH3
N
CH3
1, Lobelane
2, Lobeline
* Corresponding author. Tel.: +1 859 257 1718; fax: +1 859 257 7585.
E-mail address: pcrooks@email.uky.edu (P.A. Crooks).
Figure 1. Structures of lobelane (1) and lobeline (2).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.117

A. P. Vartak et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3584–3587
3585
b
a
5
N
N
PG
N
Boc
8
N
CH3
OH Boc OH
OTs
H
OTs
N
N
N
N
6
rt, 48-72 h
rt, 8h
d or e
100%
PPh3
PPh3
+
+
OR
H
N
N
H
H
N
N
TsO
HO
H (ax)
H (eq)
P+Ph3X- PG P+Ph3X-
N
O
PG
O
N
N
3
4
O
O
O
Boc
O
O
O
10
7
9
Scheme 1. Initial synthetic plan for the preparation of heteroaromatic analogs of
lobelane; the 3-pyridyl analog is illustrated as an example.
+ 100 mol% Ts-OH
Scheme 3. Reagents and conditions for the attempted synthesis of 3: (a) NaBH4–
LiCl, DME–H2O (6:1), 50 °C, 12 h, 70%; (b) TsCl, 2,6-lutidine, CH2Cl2, 8 h, 90%; (c) 3-
picoline (2 equiv), LDA (2 equiv), THF, À78 °C to rt; (d). SOCl2, DMSO, CH2Cl2,
À78 °C, 15 min then Et3N, 15 min; (e) DMSO, DCC, CH2Cl2, 0 °C, 10 min. NOEs
considered as proof of relative configuration are depicted as biheaded arrows.
a
0.5 H2SO4
COOMe
HOOC
N
2
COOH
MeOOC
MeOOC
N
3
b,c
MeI
d
or MeOTs
N
CH3
N
MeOOC
N
COOMe
N
H
4
COOMe
X
2,6-lutidine
Boc
11a: X = I
5
11b: X =OTs
Conditions A,
(Table 1)
Het-CHO
Scheme 2. Reagents and conditions for the synthesis of 5: (a) H2SO4, dimethoxy-
propane, MeOH, reflux, 4 h, 100%; (b) H2, Pd–C, MeOH, 12 h, bicarbonate workup,
88% de; (c) crystallization from EtOAc, 70%, 100% de; (d) Boc2O (10 equiv), DMAP
(50 mol %), 8 h, 98%.
Conditions-B
(Table 1)
Het
N
CH3
Het
Het
N
CH3
Het
X
14: Het = 3-pyridyl
21: Het = 4-pyridyl
22: Het = 2-quinolyl
23: Het = 4-quinolyl
24: Het = 3-indolyl
12: X = I, Het = 3-pyridyl
This report focuses on the substitution of the side-chain phenyl
groups of lobelane with various heteroaromatic moieties and a
study of the resultant effects on water solubility and VMAT2 inhi-
bition. Initial attempts at synthesizing heteroaromatic analogues of
lobelane were focused on the development of an advanced 2,6-
disubstituted piperidine intermediate that would be amenable to
condensation with a suitably functionalized heteroaromatic ring.
Toward this end, the synthesis of either a dialdehyde such as 3,
or a phosphonium salt such as 4 was undertaken (Scheme 1).
In the synthesis of 3, the preparation of the key precursor 5
(Scheme 2), was accomplished through an adaptation of the meth-
od reported by Chenevert and Morin.11 Reduction of the ester func-
tions of 5 yielded the diol 6 (Scheme 3), which underwent
conversion over 2–3 days at ambient temperature to 7. Exposure
of 6 to silica gel during a chromatographic purification attempt
led to complete conversion to 7 within 15 min, suggesting a
Brønsted acid-mediated 5-exo-tet cyclization involving the ejec-
tion of a molecule of H2O and isobutylene. Exposure of 6 to an
equivalent of NaOCH3 in MeOH for 60 min led to negligible
amounts of 7, which precludes the possibility of a nucleophilic
mechanism that involves attack of the hydroxyl function on the
carbamate carbonyl in the spontaneous conversion of 6 to 7. Lastly,
no t-butyl alcohol was detected in the 1H NMR spectrum of a sam-
ple of 6 that had spontaneously converted into 7. Treatment of diol
6 (immediately following its preparation) with tosyl chloride and
lutidine led to the crystalline ditosylate 8, which also underwent
cyclization in both protic and aprotic solvents at ambient temper-
ature, forming 9 and an equivalent of Ts-OH (Scheme 3). The
ditosylate 8 was stable in its solid form, and could be stored in
the freezer (À20 °C). Unfortunately, a nucleophilic coupling of 8
with 2- or 3-lithio and 2- or 3-sodio picoline could not be achieved,
even in the presence of Cu+ (as CuOTf). Treatment of 8 with Ph3P at
ambient temperature did not result in the formation of the re-
quired phosphonium salt, and increasing the reaction temperature
led to rapid formation of 9. Displacement of the tosylate moieties
with halides was also accompanied by cyclization, and Swern or
13: X = OTs, Het = 3-pyridyl
15: X = OTs, Het = 4-pyridyl
16: X = OTs, Het = 2-quinolyl
17: X = OTs, Het = 4-quinolyl
18: X = OTs, Het = 3-indolyl
19: X = OTs, Het = 2-furyl
20: X = OTs, Het = 2-thienyl
Scheme 4. Synthesis of target heterocyclic analogs of 1.
Moffat oxidation of 6 led unfortunately to a mixture of the dl and
meso diastereomers of 10. Analogous sets of results were obtained
with the Cbz, acetyl and 2,2,2-trichloroethoxycarbonyl (Troc)-pro-
tected analogues of compounds 5–10. At this point, it was con-
cluded that the close proximity of the functional groups at C2-
and C6- of the piperidine ring in compounds such as 6 and 8 to
the N-protective group, and the likely existence of conformations
that favor cyclization reactions, would limit the utility of such syn-
thons in the preparation of the required heteroaromatic analogues
of 1.
These unsuccessful attempts at utilizing piperidine-based syn-
thons prompted the delay the hydrogenation of the central core
unit until the heteroaromatic appendages had been attached. Lee
and Freudenberg have synthesized analogues of 1 through the con-
densation of 2,6-lutidine with various aromatic aldehydes, forming
2,6-distyryl derivatives, followed by N-methylation and catalytic
hydrogenation.12 Since in our case, side-chain azaheteroaromatic
moieties such as pyridyl and quinolyl, would be susceptible to N-
methylation, the methiodide of 2,6-lutidine (11a) was employed
as the starting point in the synthetic sequence. Condensation of
11a with pyridine-3-carboxaldehyde proceeded quantitatively to
afford 12 as a bright yellow crystalline solid (Scheme 4).13 At-
tempts at hydrogenation of 12 revealed that the iodide counter-
ion completely poisoned both Pd- and Pt-based catalysts. Therefore
the corresponding tosylate 13, which underwent nonselective
hydrogenation in methanol, was prepared, yielding a complex mix-
ture resulting from reduction of the side-chain pyridine moiety in

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A. P. Vartak et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3584–3587
Table 1
Reagents and conditions for the synthesis of 14, and 21–24
Het
Conditions-A
Yield
Conditions-B
Yield
3-Pyridyl
4-Pyridyl
2-Quinolyl
4-Quinolyl
3-Indolyl
2-Furyl
NaOH (2 equiv), H2O, 5 min
NaOH (2 equiv), H2O, 5 min
NaOH (2 equiv), 50% EtOH, 8 h
DIPEA, 50% EtOH, 40 °C, 12 h
DIPEA, EtOH, reflux, 8 h
100% (13)
63% (15)
90% (16)
47% (17)
80% (18)
20% (19)
16% (20)
Pd–C, EtOAc, 4 h, 50 psi
Pd–C, EtOAc, 24 h, 50 psi
43% (14)14
80% (21)15
35% (22)17
52% (23)18
18% (24)19
NA
Pt sponge,16 AcOH (2 equiv), EtOH, 12 h, 30 psi
Pd–C, AcOH (2 equiv), EtOH, 72 h, 50 psi
Pd–C, NaOH (2 equiv), EtOH, 72 h, 50 psi
Unsuccessful selective reduction
Unsurmountable catalyst poisoning
NaOH (0.5 equiv), 10% EtOH, 4 h
Ac2O, TsOH, DMAP, rt, 1 h
2-Thienyl
NA
that the putative binding surface of these analogues at the
[3H]DTBZ binding site is topologically well-defined with rigid
structural requirements for ligand interaction. This bodes well for
the future design of ligands that are selective for this binding site.
The substantial inhibitory activity of the quinolyl analogues, 22
and 23, is interesting since we have previously shown that the cor-
responding naphthyl analogues also bind avidly to the [3H]DTBZ-
binding site on VMAT2.6 Thus, this indicates that the quinolyl ana-
logues interact with the binding site in a similar manner to the
naphthyl analogues and the presence of the aza atom does not
compromise the interaction with the binding site. The diminished
activity of the 3-indolyl analogue 24 may well be due to the H-
bonding donor properties of the indolyl rings, which may interfere
with binding.
The pyridinyl analogues 14 and 21 were 100-fold lower in po-
tency when compared to lobelane in inhibiting [3H]DA uptake into
synaptic vesicles (Table 2), while the 2- and 4-quinolyl analogs 22
and 23, respectively, were equipotent with lobelane. The 3-indolyl
analogue 24 also had 100-fold lower inhibitory potency when
compared to lobelane in this assay. Thus, the potency of these ana-
logues for inhibition of [3H]DA uptake into synaptic vesicles ap-
pears to depend largely on the overall stereo-character of the
heteroaromatic moiety, rather than the specific location of charge
or H-bond donor or acceptor elements.
There was no obvious relationship between the ability of ana-
logues 14 and 21–24 to bind to the [3H]DTBZ binding site on
VMAT2 and their ability to inhibit VMAT2 function. The lack of
relationship is consistent with our earlier observations in the pyr-
rolidine series of analogues of lobelane, and reinforces our earlier
inference that affinity of lobelane-derived analogues for the
[3H]DTBZ binding site does not necessarily predict their ability to
inhibit VMAT2.
The isomeric quinolines 22 and 23 exhibit pharmacological pro-
files similar to those of lobelane with regards to their interaction
with the binding site and ability to inhibit VMAT2. However, 22
and 23 have improved water solubility characteristics compared
to lobelane. In particular, the trihydrochloride salt of 23 (termed
‘Quinlobelane’) has an aqueous solubility of P20 mg/mL in water
when compared to 1, whose aqueous solubility is only 0.3 mg/
mL. Thus, one of the primary objectives of identifying analogues
of lobelane as VMAT2 inhibitors with improved water solubility
characteristics has been met, and quinlobelane has been advanced
to behavioral testing.
Table 2
Pharmacological activity at VMAT2 of analogues 14, 21–24 in comparison with 1
Analogue
[3H]-DTBZ; Ki SEM (
l
M)
VMAT2 [3H]DA uptake
Ki SEM ( M)
l
1Á0.5 H2SO4
14
21
22ÁHCl
23ÁHCl
24ÁC4H4O4
0.97 0.19
33.3 16.3
5.87 1.72
0.96 0.37
2.64 1.41
26.01 2.88
0.045 0.002
3.72 0.32
5.23 3.03
0.067 0.015
0.051 0.005
2.13 0.28
addition to the desired reduction of the central pyridinium and ole-
finic moieties. Addition of CHCl3 as an inhibitor caused a decrease
in reaction rate, but there was no indication of improved selectivity
with either Pd–C or PtO2 catalysts. The use of EtOAc as a solvent
with Pd–C as the hydrogenation catalyst, however, led to the for-
mation of 14 with negligible amounts of bi-products. These condi-
tions could be extended to the 4-pyridyl pyridinium analogue 15,
but a substantially longer reaction time was required. It was not
possible to obtain a ‘general’ set of conditions for the synthesis of
all of the target heteroaromatic analogues, as optimization or com-
plete development of reaction conditions was necessary for each
type of heterocyclic moiety (Table 1). Chemoselective hydrogena-
tion of the furyl derivative 19 was not possible, since the furyl ring
underwent preferential hydrogenation over the olefinic moieties.
Also, hydrogenation of the thienyl analogue 20 was not possible
due to strong catalyst poisoning by the divalent sulfur. This poison-
ing was insurmountable, even after addition of excess catalyst
(500 wt %), use of various Pd and Pt catalysts, and increases in reac-
tion temperature (oil bath, H2-balloon). Compounds 14, and 21–24
were converted to their hydrochloride or fumarate salts prior to
pharmacological characterization. These salts were found to be
freely soluble in water.
The current synthetic studies have been successful in affording
5 heteroaromatic analogues of lobelane, but have revealed a lack of
a general practical synthetic methodology for the preparation of
heteromeric lobelane analogues of different classes, especially with
respect to the terminal hydrogenation procedure. Particularly lack-
ing is a suitable catalyst that is resistant to the poisoning effects of
analogues containing thienyl rings.
The ability of lobelane-derived analogues to bind to the
[3H]DTBZ-binding site on VMAT2 may not be an accurate measure
of their ability to inhibit VMAT2 function.8 In light of these find-
ings, the above heteroaromatic analogues were examined for their
ability to inhibit both the uptake of [3H]DA into synaptic vesicles,
and for their affinity for the [3H]DTBZ-binding site on VMAT2 (Ta-
ble 2). The 3-pyridinyl analogue 14 was about 30-fold less potent
than lobelane in binding to the [3H]DTBZ binding site, while the
4-pyridinyl analogue 21 was marginally lower in binding affinity
when compared to lobelane. The quinolyl analogues, 22 and 23,
bound to the [3H]DTBZ binding site almost as avidly as lobelane,
with the 2-quinolyl analogue, 22, possessing submicromolar affin-
ity. The 3-indolyl analogue, 24, exhibited greatly diminished affin-
ity for the [3H]DTBZ binding site. From these data, it would seem
Acknowledgements
The authors would like to thank the National Institutes of
Health, NIDA Grant DA013519 for financial support.
References and notes
1. Foster, R. H.; Moench, K.; Lucille, J.; Clark, H. C. J. Pharmacol. 1946, 87, 73.
2. Harrod, S. B.; Dwoskin, L. P.; Crooks, P. A.; Klebaur, J. E.; Bardo, M. T. J.
Pharmacol. Exp. Ther. 2001, 298, 172.
3. Dwoskin, L. P.; Crooks, P. A. Biochem. Pharmacol. 2002, 63, 89.
4. http://clinicaltrials.gov/ct2/show/NCT00439504?term=lobeline&rank=7.

A. P. Vartak et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3584–3587
3587
5. Flammia, D.; Dukat, M.; Damaj, M. I.; Martin, B.; Glennon, R. A. J. Med. Chem.
1999, 42, 3726.
6. Miller, D. K.; Crooks, P. A.; Zheng, G.; Grinevich, V. P.; Norrholm, S. D.; Dwoskin,
L. P. J. Pharmacol. Exp. Ther. 2004, 310, 1035.
16. ‘Pt sponge’ was generated by shaking PtO2 in EtOH under an atmosphere of H2
(30 psi) for 15 min. It was observed that the use of Pt-sponge generated in this
manner, instead of co-activation with the substrate, resulted in a faster and
cleaner reaction.
7. Zheng, G.; Dwoskin, L. P.; Deaciuc, A. G.; Norrholm, S. D.; Crooks, P. A. J. Med.
Chem. 2005, 48, 5551.
8. Zheng, G.; Dwoskin, L. P.; Deaciuc, A. G.; Crooks, P. A. Bioorg. Med. Chem. Lett.
2008, 18, 6509.
9. Nickell, J. R.; Krishnamurthy, S.; Norrholm, S.; Deaciuc, G.; Zheng, G.; Crooks, P.
A.; Dwoskin, L. P. J. Pharmacol. Exp. Ther. 2009, 332, 612.
10. Vartak, A. P.; Nickell, J. R.; Chagkutip, J.; Dwoskin, L. P.; Crooks, P. A. J. Med.
Chem. 2009, 52, 7878.
17. Characterization data for 22ÁHCl: crystalline solid; mp = 102–104 °C; Rf (free
base) = 0.3 (toluene/EtOH/NH4OH, 10:1:1); 1H NMR (300 MHz, D2O) d ppm
8.41 (d, J = 2.2 Hz, 2H), 7.98 (d, J = 5.3 Hz, 2H), 7.82–7.61 (m, 6H), 7.03 (d,
J = 3.6 Hz, 2H), 2.81–2.42 (m, 4H), 2.22 (s, 3H), 2.31–2.17 (m, 2H), 1.65–1.40
(m, 10H); 13C NMR (75 MHz, D2O) d ppm 161.8, 150.2, 137.0, 131.4, 130.1,
128.5, 128.4, 125.7, 123.9, 68.8, 42.2, 34.0, 33.1, 32.6, 21.2; EI-MS m/z 409.3
(M)+, 253.2 (
a-fragmentation).
18. Characterization data for 23ÁHCl: crystalline solid; mp = 98–100 °C; Rf (free
base) = 0.25 (toluene/EtOH/NH4OH, 10:1:1); 1H NMR (300 MHz, D2O) d ppm
8.64 (d, 2H, J = 8.0 Hz), 8.22–8.19 (m, 2H), 8.02–7.91(m, 2H), 7.74–7.53 (m, 4H),
7.28 (s, br, 2H), 2.52–2.48 (m, 4H), 2.23 (s, 3H), 2.21–2.08 (m, 2H), 1.65–1.30
(m, 10H); 13C NMR (75 MHz, D2O) d ppm 152.0, 150.8, 144.6, 131.1, 130.9,
128.6, 128.2, 124.0, 120.3, 70.1, 38.2, 33.7, 32.0, 29.3, 22.4; EI-MS m/z 409.3
11. Chenevert, R.; Morin, M. Tetrahedron: Asymmetry 1996, 7, 2161.
12. Lee, J.; Freudenberg, W. J. Org. Chem. 1944, 9, 537.
13. Fichera, M.; Fortuna, C. G.; Giuseppe, I.; Musumarra, G. Eur. J. Org. Chem. 2002,
1, 145.
14. Characterization data for 14: Clear oil; Rf = 0.4 (CH2Cl2/EtOAc/Et3N, 1:1:0.2) 1
H
NMR (300 MHz, CDCl3) d ppm 8.28–8.17 (m, 4H), 7.80–7.51 (m, 2H), 7.35 (t,
J = 6.2 Hz, 2H), 2.86–2.50 (m, 6H), 2.17 (s, 3H), 1.62–1.41 (m, 10H); 13C NMR
(75 MHz, CDCl3) d ppm 149.2, 149.0, 139.5, 138.2, 128.3, 66.3, 42.8, 34.0, 32.8,
(M)+, 253.2 (
a-fragmentation).
19. Characterization data for 24ÁC4H4O4 white solid; mp = 80–82 °C, Rf (free
base) = 0.5 (EtOAc/Et3N, 9:1); 1H NMR (300 MHz, D2O) d ppm 7.64–7.04 (m,
8H), 7.20 (s, 2H), 6.63 (s, 2H, fumaric acid), 2.38–2.23 (m, 4H), 2.24 (s, 3H),
2.30–2.18 (m, 2H), 1.83–1.22 (m, 10H); 13C NMR (75 MHz, D2O) d ppm 165.8
(COOH, fumaric acid), 138.1, 128.2, 127.7, 124.2, 124.0, 120.0, 118.4, 110.3,
32.2, 22.9; EI-MS m/z 309.1 (M)+, 203.1 (
a
-fragmentation).
15. Characterization data for 21: Clear oil; Rf = 0.7 (EtOAc/EtOH/Et3N, 10:1:0.5); 1
H
NMR (300 MHz, CDCl3) d ppm 8.41 (d, J = 9.2 Hz, 4H), 7.49 (d, J = 9.2 Hz, 4H),
2.63 (t, J = 5.2 Hz, 4H), 2.20 (s, 3H), 2.34–2.07 (m, 2H), 1.71–1.39 (m, 10H); 13C
NMR (75 MHz, CDCl3) d ppm 154.1, 148.3, 123.0, 68.1, 41.5, 33.8, 33.5, 31.4,
109.5, 67.1, 41.1, 35.5, 32.1, 26.0, 21.8; EI-MS m/z 385.3 (M)+, 241.2 (
a-
fragmentation), 144.1, 116.1.
22.0; EI-MS m/z 309.1 (M)+, 203.1 (
a-fragmentation).