Potential nicotinic acetylcholine receptor ligands from 2,4-methanoproline derivatives

Article abstract of DOI:10.1021/jm800537a

Potential nicotinic acetylcholine receptor (nAChR) ligands have been synthesized in which a methylisoxazole substituent is attached to the 1-position (26) of the 2-azabicyclo[2.1.1]hexane ring system or separated by spacer atoms (21 and 23). With ABT-594 as a model, a range of pyridine heterocycles have been attached to the 1-position via a -CH ₂O- spacer (11, 14, and 6). The biological evaluation of target compounds showed there was no binding affinity at the α4β2 and α3β4 nAChR subtypes.

Full text of DOI:10.1021/jm800537a

J. Med. Chem. 2008, 51, 7005–7009
7005
Brief Articles
Potential Nicotinic Acetylcholine Receptor Ligands from 2,4-Methanoproline Derivatives
Anup B. Patel* and John R. Malpass
Department of Chemistry, UniVersity of Leicester, Leicester LE1 7RH, United Kingdom
ReceiVed May 9, 2008
Potential nicotinic acetylcholine receptor (nAChR) ligands have been synthesized in which a methylisoxazole
substituent is attached to the 1-position (26) of the 2-azabicyclo[2.1.1]hexane ring system or separated by
“spacer” atoms (21 and 23). With ABT-594 as a model, a range of pyridine heterocycles have been attached
to the 1-position via a -CH2O- spacer (11, 14, and 6). The biological evaluation of target compounds
showed there was no binding affinity at the R4ꢀ2 and R3ꢀ4 nAChR subtypes.
Introduction
We recently described the conversion of derivatives of the
nonproteinogenic amino acid 2,4-methanoproline (2-azabicyclo-
[2.1.1]hexane-1-carboxylic acid)1-3 into potential nicotinic ace-
tylcholine receptora (nAChR) ligands having heterocycles at-
tached to the 1-position of the 2-azabicyclo[2.1.1]hexane system
via a methylene “spacer” (1).4,5 We now describe variants in
Figure 1. Target 2,4-methanoproline derivatives.
which heterocycles are directly attached to the 1-position (2)
and examples in which the heterocycle is separated by two
spacer units (3, 4, and 5, Figure 1).
variants, we expected the rigid 2-azabicyclo[2.1.1]hexane system
to provide a framework for maintaining the structural require-
ments and orientation necessary for activity at the nAChR. We
hoped that this rigid, strained azabicyclic system might emulate
the azetidine ring of ABT-594 and that attachment of a
chloropyridyl heterocycle at the C1 position, linked by a
-CH2O- spacer (as in 6), would reproduce the key pyr-
O-CH2-CHR-NHR moiety in ABT-594 (Figure 3). It was
also anticipated that it would give extra flexibility once in the
receptor, as opposed to traditional compounds that have the
heterocycles directly attached to the bicycle. Certainly, according
to simple molecular modeling studies, the ideal internitrogen
distance for the nAChR pharmacophore may be attained.
More recent work has exploited the bioisosteric replacement
the chloropyridyl heterocycle of (()-epibatidine by the meth-
ylisoxazole group to form (()-epiboxidine ((1R,4S,6S)-6-(3-
methyl-5-isoxazolyl)-7-azabicyclo[2.2.1]heptane).40 Epiboxidine
is a potent nAChR agonist with antinociceptive activity and
binds to ganglionic R4ꢀ2 subtype receptors. More importantly,
(()-epiboxidine was 20-fold less toxic than epibatidine, dem-
onstrating that it is possible to synthesize potent compounds
with lowered toxicity. There have been reports of the construc-
tion of epiboxidine analogues41-45 of various azabicyclic sys-
tems including those from R,ꢀ-unsaturated esters.46 There have
been no recent reports of functional group interconversion at
the C1 position of the 2-azabicyclo[2.1.1] system other than our
own,4,5 and we now add to the range with examples in which
the heterocycle is attached by alkenyl and ethano linkages.
Various methods available for the construction of the
2-azabicyclo[2.1.1]hexane system exist2,6-12 and functionality
has been studied at different positions around the bicyclic
system.7,13-20 We4,5,21 used a [2 + 2] photocycloaddition22-24
strategy, as this allows incorporation of a carboxylic ester
substituent at the bridgehead (C1) position. This opens the way
for further functionalization at C1, leading to the formation of
epibatidine ((4S,6R)-6-(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]-
heptane) analogues25-28 in the search for high affinity and
subtype selectivity for nAChRs (Figure 2).29-32 We are aware
of no other examples of the incorporation of heterocycles into
this azabicyclic system as potential nAChR ligands.
There has been much recent interest concerning 3-pyridyl
ether analogues of various azabicyclic systems.33-37 Variants
synthesized at Abbott Laboratories,34,38,39 include ABT-594 (5-
([(2R)-azetidin-2-yl]methoxy)-2-chloropyridine), a first-genera-
tion nAChR agonist.35 During clinical trials, this compound was
shown to have analgesic properties with improved separation
of antinociceptive effects and nicotinic side effects. The chloro
substituent and the azetidine ring were found to be important
structural elements for potent analgesic activity. ABT-594 was
found to have high affinity for nAChRs, although it was 180-
fold less potent than (()-epibatidine in activating peripheral
skeletal muscle-type nAChRs. In designing potential ABT-594
* To whom correspondence should be addressed. Phone: +441664
501501. Fax: +441664 501483. E-mail: anup.patel@pera.com. Address:
Pera Innovation, Nottingham Road, Melton Mowbray, Leicestershire LE13
0PB, United Kingdom.
Discussion
a Abbreviations: nAChR, nicotinic acetylcholine receptor; Het, hetero-
cycle; Cbz, benzyloxycarbonyl; DEAD, diethyl azodicarboxylate; TPP,
triphenylphosphine; THF, tetrahydrofuran, TMSI, iodotrimethylsilane; DCM,
dichloromethane; Boc, t-butoxycarbonyl; DMSO, dimethylsulfoxide; TEA,
triethylamine; BuLi, t-butyllithium; HEK, human embryonic kidney; BCA,
bicinchoninic acid; SPA, scintillation proximity assay; WGA, wheat germ
agglutinin; PVT, polyvinyltoluene.
As described previously,4,5 we have utilized the [2 + 2] pho-
tocycloaddition approach established by Pirrung22 and Clardy23 to
synthesize the key precursor 7 (Figure 3).
In the approach to analogues based on structure 4, the
N-benzoyl compound 7 was converted into the N-Cbz alcohol
10.1021/jm800537a CCC: $40.75
2008 American Chemical Society
Published on Web 10/09/2008

7006 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 21
Brief Articles
Figure 2. 2,4-Methanoproline and selected current nAChR agonists.
matized intermediate has not previously been reported during
methylisoxazole synthesis. The formation of 25 was confirmed
by X-ray crystallography, which indicated hydrogen bonding
between the carbonyl-oxygen and -hydrogen from the alcohol.
This stabilization is thought to be the reason for the
interesting isolation of 25. N-Deprotection of 25 with 6 M
hydrochloric acid led to concomitant elimination of water,
achieving conversion into the target 26. Daly and co-
workers41 have reported the isolation of a minor byproduct
while constructing the methylisoxazole ring, but there are
no reports of compounds akin to 25.
Figure 3. ABT-594 analogue 6 and key precursor compound 7.
8 as described previously,4,5 and this was, in turn, reacted
with the appropriate phenol (9) under Mitsunobu conditions47
(Scheme 1).
Biological Evaluation. The p-toluenesulfonate salts of ra-
cemic ABT-594 analogues 11, 14, and 6 and hydrochloride salts
of racemic epiboxidine analogues 21, 23, and 26 were evaluated
for binding to the high affinity nicotine binding site in human
brain (at the R4ꢀ2 and R3ꢀ4 nAChR subtypes). Unexpectedly,
for all of the compounds, the Ki values could not be recorded
even at a concentration of 1000 nM, showing that there was no
significant binding at the nAChR subtypes. Membrane prepara-
tion. Cell pastes from large-scale production of HEK-293 cells
expressing cloned human R4ꢀ2 or R3ꢀ4 nAChR were homog-
enized in 4 volumes of buffer (50 mM Tris-HCl, 150 mM NaCl,
and 5 mM KCl, pH 7.4). The homogenate was centrifuged twice
(40000g, 10 min, 4 °C) and the pellets resuspended in 4 volumes
of Tris-HCl buffer after the first spin and 8 volumes after the
second spin. The resuspended homogenate was centrifuged
(100g, 10 min, 4 °C) and the supernatant kept and recentrifuged
(40000g, 20 min, 4 °C). The pellet was resuspended in Tris-
HCl buffer supplemented with 10% w/v sucrose. The membrane
preparation was stored in 1 mL aliquots at -80 °C until required.
The protein concentration of the membrane preparation was
determined using a BCA protein assay reagent kit. Nicotinic
receptor radioligand binding scintillation proximity assay (SPA).
SPA radioligand binding assays were performed in 96-well
plates in a final volume of 250 µL Tris-HCl buffer (50 mM
Tris-HCl, 150 mM NaCl, 5 mM KCl, pH 7.4) using the
following conditions: [3H]epibatidine (53 Ci/mmol; Amersham)
R4ꢀ2 ) 1 nM, R3ꢀ4 ) 2 nM; WGA-coated PVT SPA beads
(Amersham) R4ꢀ2 ) 1 mg/well, R3ꢀ4 ) 1.5 mg/ well;
membrane protein ) 30 µg/well for both assay types. Nonspe-
cific binding (<10% for both assay types) was determined using
10 µM epibatidine. Reactions were allowed to equilibrate for
2-4 h at room temperature prior to reading on a Trilux
Scintillation counter (Perkin-Elmer). Data were analyzed using
a standard 4-parameter logistic equation (Multicalc, Perkin-
Elmer) to provide IC50 values that were converted to Ki values
using the Cheng-Prusoff equation.52
Unlike previous reports concerning the formation of ABT-
594 analogues,34,36,37 we found it necessary to heat the reaction
mixture to reflux conditions to achieve coupling. The primary
alcohol group in 8 is adjacent to the bridgehead position and it
is likely that steric hindrance leads to the need for harsher
conditions and also the modest yields (22-27%) obtained. We
were pleasantly surprised to be able to achieve ready displace-
ment at the 1-methylene position. Following the successful
attachment of a phenoxy substituent, similar reaction conditions
were used to attach hydroxy-pyridine derivative (12, 15) to give
13 and 16 in similar yields. A simple deprotection step gave
the respective products 11, 14, and 6 in good yield (81-87%);
compound 6 is the desired azabicyclic analogue of ABT-594.
The literature40-46 provides a wide array of epibatidine
analogues containing the methylisoxazole heterocycle; the most
potent of these is epiboxidine. Our initial aim was to synthesize
2-azabicyclo[2.1.1]hexane epiboxidine analogues having the
methylisoxazole attached by a bis-methylene chain. The syn-
thesis of these compounds would allow us to investigate the
effects of an increase of the carbon chain length on binding to
the nAChR. The N-Boc alcohol 17 was oxidized to the aldehyde
18 using Swern conditions in 97% yield (Scheme 2).
Wittig methodology48-50 was then employed to form the R,ꢀ-
unsaturated ester 19 (24% yield). The R,ꢀ-unsaturated methyl-
isoxazole 20 was then constructed using the method of Daly
and co-workers41 in 30% yield. Deprotection of the Boc group
with 3 M hydrochloric acid gave the desired product 21 in 97%
yield. The 1H NMR spectrum confirmed the construction of the
methylisoxazole heterocycle in 20. The singlet at δ 2.21
corresponds to the methyl group, and the singlet at δ 5.95 is
the olefinic proton in the ring system. The alkene protons at δ
6.28 and 6.46 showed mutual coupling of 16 Hz, confirming
the trans stereochemistry. The double bond of 20 was selectively
reduced using potassium azodicarboxylate to give the saturated
methylisoxazole 22 in 34% yield. Removal of the Boc group
gave the product 23 in a 99% yield (Scheme 3).
Next we aimed to construct the methylisoxazole heterocycle
attached directly at the C1 position of the 2-azabicyclo[2.1.1]
hexane system (type 2). Other groups46,51 have incorporated
heterocycles directly at the bridgehead position of other azabi-
cyclic systems in an attempt to create nAChR ligands. The
methylisoxazole synthesis was attempted on the bridgehead ethyl
ester 7 in the hope of making 24 (Scheme 4).
Conclusion
In conclusion, we have been successful in the synthesis of a
range of nAChR ligands with either the pyridyl ether moiety
or the methylisoxazole heterocycle attached to the 2-azabicy-
clo[2.1.1]hexane. The Mitsunobu reaction has been effectively
performed in order to synthesize a range of ABT-594 analogues;
11, 14, and 6. Methylisoxazole compounds have also been
synthesized on the 2-azabicyclo[2.1.1]hexane framework, with
Bizarrely, we isolated the novel intermediate 25 (61% yield,
based on recovered starting material) instead; such a nonaro-

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 21 7007
Scheme 1. Synthesis of 1-Substituted 2-Azabicyclo[2.1.1]hexane Derivatives
Scheme 2. Synthesis of Methylisoxazole Compound 21
Scheme 3. Synthesis of Methylisoxazole Compound 23
Scheme 4. Attachment of a Methylisoxazole Substituent to C1
to C1) is currently under investigation in an attempt to widen
the range of potential nAChR ligands.
Experimental Section
NMR spectra were recorded at 300 MHz using a Bruker DPX
300 spectrometer and at 400 MHz using a Bruker DRX 400
spectrometer. Chemical shifts are expressed in ppm (δ) relative to
an internal standard tetramethylsilane (TMS). Signal characteristics
are described using standard abbreviations: s (singlet), d (doublet),
dd (doublet of doublets), t (triplet), q (quartet), m (multiplet), bs
(broad singlet), AB (AB-system). Signals in 13C NMR were
determined by DEPT experiments. Signals were assigned with
assistance of H-1H COSY and H-13C COSY spectra. Routine
mass spectra were measured on a Micromass Quattro LC triple
quadropole spectrometer and were obtained using ionization by
electrospray. Accurate mass measurements were measured on a
Kratos Concept 1H sector mass spectrometer and were obtained
using ionization by fast atom bombardment. Mass spectra were
determined in units of mass relative to charge (m/z). IR spectra
were recorded on a Perkin-Elmer 298 FT spectrometer. Band
intensities are described using standard abbreviations: s (strong),
m (medium), w (weak), br (broad). Flash chromatography was
carried out using silica gel (60) manufactured by Fisher. Thin layer
chromatography was conducted on standard commercial aluminum
sheets precoated with 0.2 mm layer of silica gel (Merck Kieselgel
60-254). All the target compounds were unsuitable for elemental
analysis as they were obtained as volatile and viscous oils or
1
1
differing number of carbon atoms in the chain: 21 (n ) 2
alkene), 23 (n ) 2 alkane), and 26 (n ) 0). It is perhaps
surprising that none of these compounds show binding despite
the very different conformational opportunities open to them,
as shown by modeling studies. On the route to constructing 26,
we have reported a novel intermediate, apparently stabilized
by H-bonding via a seven-membered ring. This work, together
with our earlier studies,4 has led to the synthesis of a wide range
of heterocycle-substituted derivatives of the 2-azabicyclo[2.1.1]-
hexane ring system. The incorporation of other heterocycles at
the C7 position of this bicyclic ring system (the CH2 attached

7008 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 21
Brief Articles
unstable salts. Purification by HPLC or other chromatographic
methods caused the target compounds to decompose, so were not
used.
1-[2-(3-Methyl-isoxazol-5-yl)-vinyl]-2-azabicyclo[2.1.1]hexane
(21). 20 (5 mg, 0.02 mmol) was stirred in a solution of 3 M HCl
(2 mL) made in situ (dry ethanol (0.43 mL), dry ethyl acetate (1.2
mL), and acetyl chloride (0.36 mL)) at 0 °C for 1 h. The reaction
mixture was washed with diethyl ether (3 × 0.5 mL) and then
evaporated to dryness to give the hydrochloride salt of 21 (4 mg,
0.02 mmol, 97% yield). δH (300 MHz, D2O): 1.95-2.16 (m, 4 H,
H5s, H6s, H5a, H6a), 2.04 (s, 3 H, CH3), 2.32 (m, 1 H, H4), 2.90 (m,
2 H, H3x, H3n), 6.08 (s, 1 H, dCH), 6.28 (d, J ) 16.0 Hz, 1 H,
HCdCH-CO2Et), 6.46 (d, J ) 16.0 Hz, 1 H, HCdCH-CO2Et). δC
(75.5 MHz, D2O): 10.35 (CH3), 25.69 (C4), 37.76 (C5, C6), 44.24
(C3), 102.95 (dCH), 113.04 (C8), 141.20 (C7). m/z: 191 (MH+).
C11H19N2O [MH+] requires m/z 191.17851; observed 191.17847.
1-[2-(3-Methyl-isoxazol-5-yl)-ethyl]-2-azabicyclo[2.1.1]hexane
(23). 22 (10 mg, 0.02 mmol) was stirred in a solution of 3 M HCl
(2 mL) made in situ (dry ethanol (0.43 mL), dry ethyl acetate (1.2
mL), and acetyl chloride (0.36 mL)) at 0 °C for 1 h. The reaction
mixture was washed with diethyl ether (3 × 0.5 mL) and then
evaporated to dryness to give the hydrochloride salt of 23 (8 mg,
0.02 mmol, 99% yield). δH (300 MHz, D2O): 1.49 (dd, J ) 6.1,
2.2 Hz, 2 H, H5s, H6s), 1.85 (m, 2 H, H5a, H6a), 2.10 (s, 3 H, CH3),
2.42 (t, J ) 7.8 Hz, 2 H, H7), 2.73 (m, 1 H, H4), 2.78 (t, J ) 7.8
Hz, 2 H, H8), 3.24 (s, 2 H, H3x, H3n), 6.01 (s, 1 H, dCH). m/z: 193
(MH+). C11H17N2O [MH+] requires m/z 193.13409; observed
193.13407.
1-Phenoxymethyl-2-azabicyclo[2.1.1]hexane (11). 10 (110 mg,
0.34 mmol) was dissolved in dry dichloromethane (3 mL) and
stirred under a nitrogen atmosphere. TMSI (242 µL, 1.70 mmol)
was added and stirred for 7 min, followed by hydrofluoroboric
acid-diethyl ether complex (51 µL, 0.68 mmol), stirring for a
further 6 min. The reaction mixture was quenched with water (200
µL) and the solvent removed under reduced pressure. Water (3 mL)
was added and the solution washed with petroleum ether (bp 40-60
°C) (3 × 1 mL). The solution was neutralized with solid potassium
carbonate and the product extracted with dichloromethane (6 × 5
mL). The organic layer was dried with anhydrous magnesium
sulfate, filtered, and the solvent removed under reduced pressure
to yield 11 (56 mg, 0.29 mmol, 87% yield) as an orange oil. δH
(300 MHz, CDCl3): 1.36 (dd, J ) 4.4, 1.4 Hz, 2 H, H5s, H6s), 1.71
(m, 2 H, H5a, H6a), 2.74 (m, 1 H, H4), 3.00 (s, 2 H, H3x, H3n), 4.12
(s, 2 H, CH2O), 6.82-6.89 (m, 3 H, Ph), 7.17-7.23 (m, 2 H, Ph).
δC (75.5 MHz, CDCl3): 37.69 (C4), 40.72 (C5, C6), 48.85 (C3), 68.45
(CH2O), 68.77 (C1), 114.55, 120.86, 129.44 (5 × aryl), 158.87 (aryl
C-O). νmax (CH2Cl2): 2880w (C-H), 1590w (Ph), 1490w (Ph),
1050w cm-1. m/z: 190 (MH+). C12H16NO [MH+] requires m/z
190.12311; observed 190.12319.
1-(3-Methyl-isoxazole-5-yl)-2-azabicyclo[2.1.1]hexane (26). 25
(20 mg, 0.07 mmol) was stirred in 6 M HCl (10 mL) and heated to
reflux for 48 h. The reaction mixture was washed with diethyl ether
(3 × 0.5 mL) and then evaporated to dryness to give the hy-
drochloride salt of evaporated to dryness to give the hydrochloride
salt of 26 (14 mg, 0.07 mmol, 99% yield). δH (300 MHz, D2O):
1.84-1.98, 2.08-2.26 (m, 4 H, H5s, H6s, H5a, H6a), 1.97 (s, 3 H,
CH3), 2.47 (m, 1 H, H4), 2.83 (m, 2 H, H3x, H3n), 6.04 (s, 1 H,
dCH). δC (75.5 MHz, D2O): 10.39 (CH3), 25.40 (C4), 38.99 (C5,
C6), 44.45 (C3), 68.82 (C1), 101.56 (dCH), 155.81 (C7). m/z: 165
(MH+). C9H12N2O [MH+] requires m/z 165.48922; observed
165.48910.
1-(Pyridin-3-yloxymethyl)-2-azabicyclo[2.1.1]hexane (14). 13
(101 mg, 0.31 mmol) was dissolved in dry dichloromethane (6 mL)
and stirred under a nitrogen atmosphere. TMSI (222 µL, 1.56 mmol)
was added and stirred for 7 min, followed by hydrofluoroboric
acid-diethyl ether complex (46 µL, 0.62 mmol), stirring for a
further 6 min. The reaction mixture was quenched with water (200
µL) and the solvent removed under reduced pressure. Water (5 mL)
was added and the solution washed with petroleum ether (bp 40-60
°C) (3 × 3 mL). The solution was neutralized with solid potassium
carbonate and the product extracted with dichloromethane (5 × 10
mL). The organic layer was dried with anhydrous magnesium
sulfate, filtered, and the solvent removed under reduced pressure
to yield 14 (48 mg, 0.25 mmol, 81% yield) as a yellow oil. δH
(300 MHz, CDCl3): 1.37 (dd, J ) 4.4, 2.0 Hz, 2 H, H5s, H6s), 1.72
(m, 2 H, H5a, H6a), 2.77 (m, 1 H, H4), 3.01 (s, 2 H, H3x, H3n), 4.16
(s, 2 H, CH2O), 7.14 (m, 2 H, heterocycle), 8.14 (m, 1 H,
heterocycle), 8.24 (m, 1 H, heterocycle). δC (75.5 MHz, CDCl3):
37.77 (C4), 40.65 (C5, C6), 48.73 (C3), 68.32 (CH2O), 68.89 (C1),
120.90, 123.71, 138.07, 142.14 (4 × heterocycle), 154.95 (hetero-
cycle C-O). νmax (CH2Cl2): 3000s (C-H), 2950s (C-H), 1420s,
1160s, 900s, 690br cm-1. m/z: 191 (MH+). C11H15N2O [MH+]
requires m/z 191.11844; observed 191.11840.
Acknowledgment. We thank S. Richard Baker and Adrian
Mogg, at Eli Lilly, for the biological evaluations.
Supporting Information Available: Experimental details, spec-
troscopic characterization of all new compounds, and crystal
structure data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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1-(6-Chloro-pyridin-3-yloxymethyl)-2-azabicyclo[2.1.1]hexane
(6). 16 (57 mg, 0.16 mmol) was dissolved in dry dichloromethane
(4 mL) and stirred under a nitrogen atmosphere. TMSI (113 µL,
0.79 mmol) was added and stirred for 7 min, followed by
hydrofluoroboric acid-diethyl ether complex (24 µL, 0.31 mmol),
stirring for a further 6 min. The reaction mixture was quenched
with water (100 µL) and the solvent removed under reduced
pressure. Water (10 mL) was added and the solution washed with
petroleum ether (bp 40-60 °C) (5 × 5 mL). The solution was
neutralized with solid potassium carbonate and the product extracted
with dichloromethane (5 × 10 mL). The organic layer was dried
with anhydrous magnesium sulfate, filtered, and the solvent removed
under reduced pressure to yield 6 (30 mg, 0.13 mmol, 83% yield)
as a bright-yellow oil. δH (300 MHz, CDCl3): 1.41 (dd, J ) 4.5,
1.6 Hz, 2 H, H5s, H6s), 1.74 (m, 2 H, H5a, H6a), 2.79 (m, 1 H, H4),
3.05 (s, 2 H, H3x, H3n), 4.18 (s, 2 H, CH2O), 7.15 (m, 2 H,
heterocycle), 8.00 (m, 1 H, heterocycle). δC (75.5 MHz, CDCl3):
37.68 (C4), 40.59 (C5, C6), 48.76 (C3), 68.48 (CH2O), 69.10 (C1),
124.39, 124.92, 136.77 (3 × heterocycle), 142.76 (heterocycle
C-Cl), 154.19 (heterocycle C-O). νmax (CH2Cl2): 3020s (C-H),
2990s (C-H), 2300m, 1420s, 1260s, 900s, 750br (C-Cl) cm-1
.
m/z: 225 (MH+). C11H14N2OCl [MH+] requires m/z 225.07944;
observed 225.07947.

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 21 7009
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