Modified Synthesis of NOP Receptor Antagonist SB612111

Article abstract of DOI:10.1055/s-0036-1588379

SB612111 [(5S,7S)-7-{[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl}-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol] is a potent and selective antagonist of the nociception/orphanin FQ peptide (NOP) receptor. In the process of synthesizing cis-SB612111 to support ongoing animal studies, several key steps of the published syntheses in the patent literature proceeded in low yields in our hands, particularly in the route to the key intermediate 4-(2,6-dichlorophenyl)piperidine, the reduction of 7-[4-(2,6-dichlorophenyl)piperidine-1-carbonyl]-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, the formation of (±)-6-methyl-12-oxatricyclo[8.2.1.0^2,7]trideca-2,4,6-trien-11-one, and the final reductive amination between (±)-6-methyl-12-oxatricyclo[8.2.1.0^2,7]trideca-2,4,6-trien-11-ol and 4-(2,6-dichlorophenyl)piperidine in the diastereoselective synthesis. We have thus explored various reaction conditions and successfully improved the yields for the necessary synthetic steps. We herein report our modified synthesis of SB612111 as the cis-diastereomers.

Full text of DOI:10.1055/s-0036-1588379

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
D. A. Perrey et al.
Paper
Synthesis
Modified Synthesis of NOP Receptor Antagonist SB612111
David A. Perreya
Jun-Xu Lib
O
OH
Yanan Zhang*a
OH
Cl
a Research Triangle Institute, Research Triangle
Park, NC 27709, USA
reductive
amination
Cl
HO
yzhang@rti.org
b Department of Pharmacology and Toxicology,
University at Buffalo, Buffalo, NY 14214, USA
N
improved
from 5%
to 67%
Cl
O
Cl
Cl
cis-SB612111
Cl
HN
Received: 09.09.2016
Accepted after revision: 27.11.2016
Published online: 19.12.2016
these, SB612111 [(5S,7S)-7-{[4-(2,6-dichlorophenyl)piperidin-
1-yl]methyl}-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]an-
nulen-5-ol, 1, Figure 1] developed by GlaxoSmithKline
(GSK), is one of the most potent and selective non-peptide
NOP antagonists discovered to date.18 SB612111 was once
proposed for phase I clinical trials in the treatment of
Parkinson’s disease, but was not further developed.19
DOI: 10.1055/s-0036-1588379; Art ID: ss-2016-m0600-op
Abstract SB612111 [(5S,7S)-7-{[4-(2,6-dichlorophenyl)piperidin-1-
yl]methyl}-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol] is a
potent and selective antagonist of the nociception/orphanin FQ pep-
tide (NOP) receptor. In the process of synthesizing cis-SB612111 to sup-
port ongoing animal studies, several key steps of the published synthe-
ses in the patent literature proceeded in low yields in our hands,
particularly in the route to the key intermediate 4-(2,6-dichlorophe-
nyl)piperidine, the reduction of 7-[4-(2,6-dichlorophenyl)piperidine-1-
carbonyl]-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, the
formation of (±)-6-methyl-12-oxatricyclo[8.2.1.02,7]trideca-2,4,6-trien-
11-one, and the final reductive amination between (±)-6-methyl-12-ox-
atricyclo[8.2.1.02,7]trideca-2,4,6-trien-11-ol and 4-(2,6-dichlorophe-
nyl)piperidine in the diastereoselective synthesis. We have thus ex-
plored various reaction conditions and successfully improved the yields
for the necessary synthetic steps. We herein report our modified syn-
thesis of SB612111 as the cis-diastereomers.
F
F
N
Cl
O
S
O
N
N
OH
N
N
N
N
OH
J-113,397
LY-2940094
Key words NOP, antagonist, modified synthesis, SB612111
N
The nociception/orphanin FQ peptide (NOP) receptor,
previously called the opioid receptor-like receptor (ORL1,
XOR1, and LC132) was discovered in 1994.1–5 The NOP re-
ceptor has been recognized by the International Union of
Pharmacology as the fourth member of the opioid receptor
family,3,6 although many classical opioid receptor ligands do
not bind with high affinity to the NOP receptor.7–9 The NOP
receptor is widely distributed in the central (CNS) and pe-
ripheral nervous system, specifically in regions associated
with mood disorders and obesity, as well as other areas
such as the cardiovascular and immune systems.10,11 NOP
has been linked to a broad range of physiological and be-
havioral functions, such as pain, anxiety, depression, an-
orexia, obesity, and drug abuse.10–12
O
Cl
N
N
H
Cl
NH2
HO
O
SB612111
JTC-801
Figure 1 Representative NOP antagonists
In an effort to investigate the potential role of the NOP
receptor in drug addiction, particularly in mediating re-
lapse of drugs such as nicotine,20,21 access to grams of
SB612111 was required. We initially aimed to prepare the
more accessible cis-diastereomeric mixture of 1 following
procedures described in a patent by GSK (Scheme 1).22 Ac-
A number of agonists and antagonists selective for the
NOP receptor have been developed in order to study the bi-
ological role of this receptor system (Figure 1).13–17 Among
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
D. A. Perrey et al.
Paper
Synthesis
cording to the patent, enantiomerically pure SB612111 (1)
was attained by amide coupling of benzocycloheptanoic
acid 2 with 4-(2,6-dichlorophenyl)piperidine (3), followed
by reduction of both the ketone and amide and then sepa-
ration of the resulting diastereomers by chiral separation
(Scheme 1). In our attempt to follow these procedures, the
synthesis proceeded well in general, with yields in most of
the steps comparable to the original patent. However, sev-
eral key steps afforded rather low yields in our hands that
prevented a practical preparation of gram quantities of cis-
1. We have thus explored alternate reaction conditions in
these steps and successfully improved the yields. Hereby
we present these findings and our solutions to the encoun-
tered issues.
ing from 12–38%. We found that purification of the acid 8
prior to the cyclization resulted in a cleaner Friedel–Crafts
reaction and improved yields (51% for the cyclization step
and 39% over 3 steps).
MsCl
Na, EtOH
OH
OMs
Et3N
CH2Cl2
CH2(CO2Et)2
4
5
97% over 2 steps
O
tBu
O
BrCH2CO2tBu
TFA
77%
CO2Et
CO2Et
CO2Et
NaH
THF
CO2Et
6
84%
7
O
O
(i) (COCl)2
CH2Cl2
HO
CO2Et
CO2Et
CO2Et
CO2Et
OH
(ii) AlCl3
CH2Cl2
51%
8
9
O
O
6 N HCl
CO2H
O
dioxane
quant.
OH
2
Cl
2
Scheme 2 Synthesis of benzoheptanone acid 2
Cl
HO
The synthesis of piperidine 3,22,23 however, had immedi-
ate problems in the first step. Condensation between benz-
aldehyde 10 and two equivalents of ethyl acetoacetate in
absolute ethanol, only afforded the desired cyclohexanone
11 in 23% yield after chromatography (Scheme 3). This was
in contrast to the patent report where the reaction gave
high yield by simple precipitation of the product with di-
ethyl ether after removal of reaction solvents. Replacing ab-
solute ethanol with 96% ethanol, as per the original proce-
dure did not alter the results. Purification of ethyl acetoace-
tate and piperidine by distillation did not afford any
improvement, and extended reaction times also did not af-
ford any improvement.
N
chiral separation
Cl
1
Cl
HN
3
Cl
O
Cl
Scheme 1 Synthetic approach to SB612111
O
O
O
O
Cl
O
EtO2C
Cl
OH
OEt
Cl
NaOH
The synthesis of acid 2 proceeded as expected in similar
yields following the patent procedure (Scheme 2), starting
from commercially available 2-(2-methylphenyl)ethanol
(4).22 Mesylation of the alcohol and displacement of the re-
sulting mesylate 5 with malonate provided intermediate 6,
alkylation of which with tert-butyl bromoacetate gave the
triester 7 in high yield (81% over 3 steps, vs. 65% reported).
After removal of the tert-butyl group of 7 with TFA and con-
version into the acid chloride, Friedel–Crafts acylation pro-
vided the benzoheptanone 9, which underwent decarbox-
ylation to give acid 2. This 3-step sequence proceeded in
27% in the original report. While the tert-butyl ester hydro-
lysis and decarboxylation steps proceeded in high yields in
our hands, the yield of cyclization appeared variable, rang-
OH
piperidine
EtOH
EtOH
H2O
Cl
CO2Et
CO2H
Cl
11
Cl
quant.
Cl
68%
10
12
O
NH
NH4OH
34%
BH3.SMe2
NH
Cl
·HCl
O
THF
87%
Cl
3·HCl
Cl
13
Scheme 3 Synthesis of 4-arylpiperidine 3
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
D. A. Perrey et al.
Paper
Synthesis
The 2,6-dichlorobenzaldehyde was newly purchased
and used as received. While the NMR spectrum of this alde-
hyde did not show any impurities, we suspected that a trace
amount of the corresponding carboxylic acid from oxida-
tion of the aldehyde could be present, possibly generated
during the reaction via oxidation by the oxygen present in
the nitrogen gas used as the inert gas. Since the piperidine
was catalytic and only 0.2 equivalents were used as sug-
gested by the original report, the benzoic acid could react
with piperidine, rendering it unavailable as the catalyst.
Therefore, we investigated the stoichiometry of the piperi-
dine added to the reaction. We found that the subsequent
addition of another 0.2 equivalents of piperidine improved
the yield from 23% to 68% without chromatography purifi-
cation. Further increasing the amount of piperidine did not
result in improvement, consistent with the fact that only
trace amount of benzoic acid was present.
Hydrolysis of the diester 11 to the diacid 12 with sodi-
um hydroxide proceeded in quantitative yield. Condensa-
tion of 12 with ammonium hydroxide at 190 °C gave the
imide 13 in 34% without chromatography required. Finally,
reduction of 13 to the piperidine 3 with borane–dimethyl
sulfide proceeded in 87% yield with the piperidine isolated
as the hydrochloride salt. This three-step sequence pro-
ceeded with similar yields as reported.22
With both components 2 and 3 in hand, amide coupling
via the acid chloride (Scheme 4) gave the penultimate prod-
uct 14 in 45% yield. Lithium aluminum hydride reduction in
the presence of aluminum trichloride, however, gave rather
poor yields (5–14%) of the desired cis-diastereomers of 1 af-
ter chromatographic separation from the trans-diastereo-
mers. This yield was even lower than the literature yield
(25%). Modifications to the work-up procedure to increase
recovery of product from the aluminates did not improve
the yield. Such a poor yield at the final step precluded pro-
duction of enough material for the animal studies, thus an
alternate approach was sought.
The same GSK group later reported a modified diastereo-
selective synthesis in another patent.24 Instead of diastereo-
meric separation of the final product, the new diastereose-
lective synthesis converted acid 2 into a lactone 17 (Scheme
5). Since only the cis-diastereomer could cyclize, this con-
version allows for the facile separation from the trans ana-
logues, which would remain as the hydroxy ester. Thus, acid
2 was converted into the methyl ester 15 and the ketone
was reduced to alcohol 16. The literature method utilized
sodium hydride activation to afford the next cyclization
step to form the lactone 17; however, no conversion was
observed in our hands under these conditions with only
starting material recovered. We instead found that catalytic
4-toluenesulfonic acid25 gave excellent conversion into 17
(84% conversion, 42% yield from the mixture of diastereo-
mers), which was readily separated from the uncyclized
material. It should be noted the unreacted trans-16 could
be converted into the cis-isomer via hydroxyl inversion
(e.g., via Mitsunobu reaction) and then to cis-17 to improve
material conversion. Diisobutylaluminum hydride reduc-
tion gave the lactol 18 in 75% yield.
O
O
(COCl)2
MeOH
BH3·SMe2
THF
CO2Me
CO2H
CH2Cl2
99%
81%
15
2
HO
O
O
TsOH
DiBAL-H
CO2Me
toluene
75%
CH2Cl2
42%
cis-17
16
O
Cl
reductive
amination
OH
Cl
HO
(see Table 1)
HO
OH
N
cis-18
cis-1
19
Scheme 5 Diastereoselective synthesis of SB612111 via lactone
Cl
For the final reductive amination step, the literature
procedure24 preformed the imine in methanol at 50 °C for 2
hours followed by reduction with sodium borohydride at 0
°C. Surprisingly, under these conditions, the desired cis-1
was obtained in only 5% yield. Instead, diol 19 was isolated
as the main product (Table 1, entry 1) after chromatograph-
ic separation, with piperidine 3 recovered. Although diol 19
could potentially be converted into 1 (e.g., via selective to-
sylation of the primary alcohol and displacement with the
piperidine), effort was focused on improving the conversion
of 18 into 1. Suspecting the imine did not form appropriate-
ly under the reported conditions, we then examined anoth-
er solvent, 2,2,2-trifluoroethanol, which has been reported
to favor imine formation.26 Under these conditions, 18 and
O
(i) (COCl)2
Cl
CH2Cl2
O
CO2H
(ii)
3
N
O
iPr2EtN
CH2Cl2
45%
2
14
Cl
LiAlH4
AlCl3
Cl
HO
Et2O
N
5–14%
cis-1
Scheme 4 SB612111 synthesis via amide
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
D. A. Perrey et al.
Paper
Synthesis
Table 1 Comparison of Reductive Amination Conditions To Form cis-1
Entry Ratio of 18/3 Conditions
Reducing agent (equiv) Solvent
Isolated yield (%)
5
1
2
3
4
2:3
1:1
1:1
3:2
1. preformed imine (50 °C, 2 h)
2. NaBH4, 0 °C then r.t., 16 h
NaBH4 (1)
MeOH
1. preformed imine (40 °C, 5 min)
2. NaBH4, r.t., 16 h
NaBH4 (2)
CF3CH2OH
<5
<5
40
1. preformed imine (40 °C, 5 min)
2. NaBH3CN, r.t., 16 h
NaBH3CN (2)
NaBH3CN (4)
CF3CH2OH
all reagents mixed (ratio 18/3 1:1); at 16 h, 18 (0.5 equiv) added;
AcOH (2 equiv), MeOH
then stirring 24 h
5
6
7
8
3:2
1:1
1:1
1:1
all reagents mixed; r.t., 16 h
NaBH3CN (4)
AcOH (2 equiv), MeOH
28
40
52
67
all reagents mixed; r.t., 16 h
NaBH(OAc)3 (2)
NaBH(OAc)3 (4)
NaBH(OAc)3 (4)
DCE
DCE
DCE
all reagents mixed; r.t., 16 h
all reagents mixed; r.t., 16 h; aq NaHCO3 quench
3 were mixed and stirred at 40 °C for 5 minutes to preform
the imine before addition of sodium borohydride. But again,
diol 19 was obtained as the major product (entry 2). We
next investigated sodium cyanoborohydride as the reduc-
ing agent in 2,2,2-trifluoroethanol; however, only trace
amount of the desired cis-1 was isolated (entry 3).
lactone 17, and the final reductive amination between 18
and 3. Possible explanations of the differences include dif-
ferent batches of reagents used and scale of the reactions.
We have thus explored various reaction conditions that re-
sulted in significantly improved yields in these key steps.
The modified reactions are amenable to scale-up for gram
quantity preparation of SB612111.
Given the unsatisfactory results with the preformation
of the imine, we next examined the in situ formation of the
imine in methanol in the presence of acetic acid with in-
creased amount of reducing agent (entry 4). The reaction
was carefully monitored by TLC and mass spectrometry.
When partial conversion was observed with piperidine 3
still present after 16 hours, an additional 0.5 equivalent of
lactol 18 was added. Encouragingly, significantly enhanced
conversion was observed under the new conditions (40%,
entry 4). When the reaction was started with 1.5 equiva-
lents of lactol 18, it gave a lower yield (28%, entry 5). This is
possibly the result of competition between reduction of the
lactol and reductive amination under the reaction condi-
tions, where the excess of the lactol was reduced more rap-
idly.
All solvents and chemicals were reagent grade. Unless otherwise
mentioned, all were purchased from commercial vendors and used as
received. Flash column chromatography was done on a Teledyne ISCO
CombiFlash Rf system using prepacked columns. Solvents used were
hexane, EtOAc, and CH2Cl2. Purity and characterization of compounds
was established by a combination of TLC, MS, and NMR analysis. 1H
NMR spectra were recorded on a Bruker Avance DPX-300 (300 MHz)
spectrometer and were determined in CDCl3 with TMS (δ = 0.00) or
solvent peaks as the internal reference. TLC was done on EMD pre-
coated silica gel 60 F254 plates, and spots were visualized with UV
light or iodine staining. LR-MS were obtained using a Waters Alliance
HT/Micromass ZQ system (ESI).
2-(2-Methylphenyl)ethyl Methanesulfonate (5)
Finally, sodium triacetoxyborohydride was explored as
the reducing agent, with 1,2-dichloroethane as the solvent.
Encouragingly, 2 equivalents of triacetoxyborohydride af-
forded the product in 40% yield (entry 6), similar to the best
results with cyanoborohydride. Increasing the reducing
agent to 4 equivalents further improved the yield to 52%
(entry 7). Finally, the work-up procedure was altered from
a simple aqueous work up to a hydrogen carbonate quench
and this modification further improved yield to 67% (entry
8).
In summary, modifications and improvements have
been made to the previously reported synthesis of the NOP
receptor antagonist SB612111 in order to support ongoing
behavioral studies. While in general the reported synthesis
proceeded as expected, several key steps only gave modest
to very low yields under the reported conditions, including
synthesis of piperidine 3, the acid-catalyzed formation of
To a solution of 2-(2-methylphenyl)ethanol (4, 5.0 g, 36.71 mmol) in
anhyd CH2Cl2 (100 mL) cooled in ice under N2 was added Et3N (5.94 g,
8.2 mL, 58.74 mmol) then a solution of MsCl (6.73 g, 4.5 mL, 58.74
mmol) in CH2Cl2 (50 mL) was added slowly via addition funnel. This
resulting solution was allowed to warm to r.t. overnight. Water was
added and the layers separated. The organic fraction was concentrat-
ed in vacuo then redissolved in Et2O. The solution was washed with 2
N HCl solution and NaHCO3 solution, and dried (MgSO4); the solvent
removed under reduced pressure to give the desired sulfonate (7.87 g,
100%) as a clear liquid.
1H NMR (300 MHz, CDCl3): δ = 7.13–7.20 (m, 4 H), 4.39 (t, J = 7.3 Hz, 2
H), 3.08 (t, J = 7.3 Hz, 2 H), 2.85 (s, 3 H), 2.35 (s, 3 H).
Diethyl 2-[2-(2-Methylphenyl)ethyl]propanedioate (6)
Na metal (1.55 g, 67.58 mmol) was dissolved in abs EtOH (50 mL)
then diethyl malonate (16.24 g, 15.4 mL, 101.36 mmol) was added
slowly to the solution at r.t. under N2. The resulting mixture was
stirred at r.t. for 30 min. A solution of the methanesulfonate 5 (7.24 g,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
D. A. Perrey et al.
Paper
Synthesis
33.79 mmol) in EtOH (25 mL) was added dropwise via addition fun-
nel. Upon complete addition, the mixture was heated at reflux for 3 h.
The mixture was cooled and the solvent removed under reduced pres-
sure. The crude was diluted with water and extracted Et2O (3 ×). The
combined extracts were washed with 2 N HCl and brine, and dried
(MgSO4); the solvent was removed under reduced pressure. Excess di-
ethyl malonate was removed via N2 blowdown to give the diester
(9.13 g, 97%).
1-Methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-car-
boxylic Acid (2)
6 N HCl (95 mL) was added to a solution of diester 9 (3.30 g, 10.37
mmol) in 1,4-dioxane (30 mL) and the mixture was heated at reflux
overnight. It was cooled and diluted with water, then extracted with
Et2O (3 ×). The combined extracts were dried (MgSO4) and the solvent
was removed under reduced pressure to give the acid 2 (2.26 g, 100%)
as an off-white solid.
1H NMR (300 MHz, CDCl3): δ = 7.08–7.19 (m, 4 H), 4.21 (q, J = 7.2 Hz, 4
H), 3.34–3.44 (m, 1 H), 2.60–2.69 (m, 2 H), 2.31 (s, 3 H), 2.10–2.21 (m,
2 H), 1.28 (t, J = 7.2 Hz, 6 H).
1H NMR (300 MHz, CDCl3): δ = 7.45 (d, J = 7.5 Hz, 1 H), 7.31 (d, J = 7.3
Hz, 1 H), 7.15–7.23 (m, 1 H), 2.95–3.11 (m, 3 H), 2.76–2.92 (m, 2 H),
2.37 (s, 3 H), 2.06–2.28 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 203.8, 178.8, 139.3, 138.0, 135.9, 134.1,
126.7, 126.3, 42.4, 38.1, 27.5, 25.9, 19.6.
2-tert-Butyl 1,1-Diethyl 1-[2-(2-Methylphenyl)ethyl]ethane-1,1,2-
tricarboxylate (7)
To a solution of NaH (as a 60% dispersion in mineral oil, 3.45 g, 86.22
mmol) in anhyd THF (140 mL) was slowly added a solution of diester
6 (8.0 g, 28.74 mmol) in THF (60 mL). The mixture was stirred at r.t.
under N2 for 30 min then tert-butyl bromoacetate (7.01 g, 5.3 mL,
35.93 mmol) was added dropwise and the resulting cloudy solution
was stirred at r.t. under N2 overnight. The mixture was cooled in ice
and quenched with water, then extracted with Et2O (2 ×). The com-
bined extracts were dried (MgSO4) and the solvent was removed
under reduced pressure. Purification by chromatography (silica gel,
CH2Cl2) gave the triester 5 (9.42 g, 84%) as a clear liquid.
Diethyl 2-(2,6-Dichlorophenyl)-4-hydroxy-4-methyl-6-oxocyclo-
hexane-1,3-dicarboxylate (11)
2,6-Dichlorobenzaldehyde (10, 5.0 g, 28.57 mmol) and ethyl acetoace-
tate (7.44 g, 7.2 mL, 57.14 mmol) were combined in abs EtOH (20 mL),
then piperidine (0.49 g, 0.6 mL, 5.71 mmol) was added dropwise. The
mixture was stirred under N2 overnight, then an additional aliquot of
piperidine (0.6 mL) was added. After stirring for a further 24 h, the
solvent was removed under reduced pressure and the viscous oil al-
lowed to stand until the whole oil solidified (approx. 24–48 h). The
solid was rinsed with Et2O and collected by filtration to give the prod-
uct (8.10 g, 68%). 1H NMR data matches that in the literature.21
1H NMR (300 MHz, CDCl3): δ = 12.51 (br s, 1 H), 7.19–7.30 (m, 2 H),
7.03–7.12 (m, 1 H), 5.03 (d, J = 11.1 Hz, 1 H), 3.82–4.14 (m, 5 H), 3.12
(d, J = 11.1 Hz, 1 H), 2.50 (s, 2 H), 1.34 (s, 3 H), 1.00 (t, J = 7.1 Hz, 3 H),
0.87 (t, J = 7.2 Hz, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.07–7.15 (m, 4 H), 4.23 (q, J = 7.2 Hz, 4
H), 3.00 (s, 2 H), 2.51–2.59 (m, 2 H), 2.29 (s, 3 H), 2.16–2.24 (m, 2 H),
1.43 (s, 9 H), 1.28 (t, J = 7.2 Hz, 6 H).
3,3-Bis(ethoxycarbonyl)-5-(2-methylphenyl)pentanoic Acid (8)
TFA (20 mL) was added to triester 7 (12.85 g, 32.80 mmol) and the
mixture stirred at r.t. for 90 min. Solvent was removed under reduced
pressure and the crude diluted with water. It was extracted with Et2O
(3 ×), then the combined extracts were dried (MgSO4) and the sol-
vents removed under reduced pressure. The crude material was puri-
fied by chromatography (silica gel, 0–10% MeOH/CH2Cl2) to give the
acid 6 (8.53 g, 77%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.06–7.16 (m, 4 H), 4.24 (q, J = 7.1 Hz, 4
H), 3.13 (s, 2 H), 2.51–2.62 (m, 2 H), 2.28 (s, 3 H), 2.20–2.30 (m, 2 H),
1.28 (t, J = 7.2 Hz, 6 H).
3-(2,6-Dichlorophenyl)pentanedioic Acid (12)
A solution of NaOH (8.09 g, 202 mmol) in water (30 mL) was added to
diester 11 (4.22 g, 10.11 mmol) in EtOH (30 mL) and the mixture
heated at reflux for 3 h. The mixture was cooled, the EtOH was re-
moved under reduced pressure, and the aqueous solution was acidi-
fied with 6 N HCl. The solution was extracted with EtOAc (3 ×), the
combined extracts were dried (MgSO4), and the solvent was removed
under reduced pressure to give the diacid (2.80 g, 100%) as a brown
solid. 1H NMR data matches that in the literature.21
1H NMR (300 MHz, CDCl3): δ = 9.77 (br s, 2 H), 7.36 (d, J = 8.1 Hz, 1 H),
7.21–7.32 (m, 1 H), 7.07–7.18 (m, 1 H), 4.81 (tt, J = 10.6, 3.7 Hz, 1 H),
3.33 (dd, J = 15.3, 10.7 Hz, 2 H), 2.67 (dd, J = 15.3, 3.8 Hz, 2 H).
Diethyl 1-Methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-
7,7-dicarboxylate (9)
To acid 8 (6.80 g, 20.22 mmol) in CH2Cl2 (100 mL) cooled in ice under
N2 was added a drop of DMF then oxalyl chloride (7.70 g, 5.1 mL,
60.65 mmol) was added slowly and the mixture was stirred at r.t. for
3 h. All solvents were removed under reduced pressure and the crude
redissolved in CH2Cl2 (30 mL). This solution was added slowly via an
addition funnel to a solution of AlCl3 (10.78 g, 80.86 mmol) in CH2Cl2
(70 mL) cooled in ice under N2, and the resulting mixture was allowed
to warm up to r.t. overnight. The mixture was quenched cautiously
with water then made acidic with 2 N HCl. The layers were separated
and the aqueous portion extracted with CH2Cl2 (1 ×). The combined
organics were dried (MgSO4) and the solvent was removed under re-
duced pressure. The crude was purified by chromatography (silica gel,
0–30% EtOAc/hexane) to give the product (3.30 g, 51%) as a clear oil.
4-(2,6-Dichlorophenyl)piperidine-2,6-dione (13)
Diacid 12 (3.58 g, 12.92 mmol) was suspended in concd NH4OH solu-
tion (28–30%, 80 mL), dissolved as far as possible via sonication and
mixing. The mixture was stirred for 45 min then heated to boil away
the liquid. The remaining dry residue was heated at 190 °C for 3 d.
The mixture was cooled and the residue dissolved in CH2Cl2. The solu-
tion was washed with 0.1 N NaOH solution and dried (MgSO4); the
solvent was removed under reduced pressure to give the product
(1.12 g, 34%) as a brown solid. 1H NMR data matches that in the litera-
ture.21
1H NMR (300 MHz, CDCl3): δ = 8.25 (br s, 1 H), 7.29–7.45 (m, 2 H),
7.16–7.23 (m, 1 H), 4.39 (tt, J = 13.7, 4.4 Hz, 1 H), 3.62 (dd, J = 17.7,
13.8 Hz, 2 H), 2.71 (dd, J = 17.5, 4.3 Hz, 2 H).
1H NMR (300 MHz, CDCl3): δ = 7.46 (d, J = 7.7 Hz, 1 H), 7.25–7.31 (m, 1
H), 7.12–7.19 (m, 1 H), 4.05 (q, J = 7.2 Hz, 2 H), 4.04 (q, J = 7.1 Hz, 2 H),
3.31 (s, 2 H), 2.92–3.00 (m, 2 H), 2.52–2.59 (m, 2 H), 2.36 (s, 3 H), 1.18
(t, J = 7.2 Hz, 6 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
D. A. Perrey et al.
Paper
Synthesis
4-(2,6-Dichlorophenyl)piperidine Hydrochloride (3·HCl)
1H NMR (300 MHz, CDCl3): δ = 7.44 (d, J = 7.5 Hz, 1 H), 7.30 (d, J = 7.2
Hz, 1 H), 7.15–7.22 (m, 1 H), 3.62 (s, 3 H), 2.95–3.07 (m, 3 H), 2.77–
2.89 (m, 2 H), 2.37 (s, 3 H), 2.02–2.30 (m, 2 H).
To a solution of imide 13 (1.12 g, 4.34 mmol) in anhyd THF (50 mL)
cooled in ice under N2 was added dropwise 2 M BH3·SMe2 in THF (21.7
mL, 43.4 mmol). Upon completion of the addition, the mixture was
warmed to r.t. then heated at reflux for 3 h. The mixture was then
cooled in ice and carefully quenched with 2 N HCl, then heated at re-
flux again for 3 h. The mixture was cooled and the volatile solvents
were removed under reduced pressure. The mixture was diluted with
water, the pH adjusted to >7 with 2 N NaOH solution then extracted
with EtOAc (3 ×). The combined extracts were dried (MgSO4) and the
solvent was removed under reduced pressure. The crude was taken
up in CH2Cl2 and 2 N HCl in Et2O was added until acidic, then all the
solvents were removed under reduced pressure. The residue was trit-
urated (Et2O) and the solid formed was collected by filtration as the
piperidine 3 (1.01 g, 87%). 1H and 13C NMR data match that in the lit-
erature.21
Methyl 5-Hydroxy-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]an-
nulene-7-carboxylate (16)
To a solution of ketone 15 (0.92 g, 3.99 mmol) in THF (20 mL) cooled
in ice under N2 was added slowly BH3·SMe2 (2 M in THF; 2 mL, 3.99
mmol). The mixture was stirred at r.t. overnight. The reaction was
quenched carefully with MeOH and then all solvents were removed
under reduced pressure. The crude was redissolved in MeOH and con-
centrated again, then this was repeated once more. The crude was pu-
rified by chromatography (silica gel, 0–100% EtOAc/hexane) to give
1
the product (0.75 g, 81%) as a clear oil. H NMR data matches that in
the literature.22
1H NMR (300 MHz, CDCl3): δ = 7.02–7.42 (m, 3 H), 4.97–5.09 (m, 1 H),
3.64–3.70 (m, 2 H), 2.99–3.23 (m, 1 H), 2.86 (ddd, J = 15.3, 8.0, 3.1 Hz,
1 H), 2.50 (dd, J = 14.7, 11.7 Hz, 1 H), 2.32 (s, 3 H), 2.10–2.31 (m, 2 H),
1.97–2.10 (m, 2 H), 1.84–1.92 (m, 1 H), 1.67–1.81 (m, 1 H).
1H NMR (300 MHz, CDCl3): δ = 9.53–10.01 (m, 2 H), 7.22–7.37 (m, 2
H), 7.11 (t, J = 8 Hz, 1 H), 3.71–3.84 (m, 1 H), 3.57–3.71 (m, 2 H), 2.91–
3.19 (m, 4 H), 1.82 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 137.0, 135.3, 130.3, 128.6, 44.8, 38.3,
(±)-6-Methyl-12-oxatricyclo[8.2.1.02,7]trideca-2,4,6-trien-11-one
(17)
24.8.
7-[4-(2,6-Dichlorophenyl)piperidine-1-carbonyl]-1-methyl-
6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (14)
To a solution of hydroxyl ester 16 (0.75 g, 3.20 mmol) (as a mixture of
diastereomers) in CH2Cl2 (10 mL) was added TsOH·H2O (1.02 g, 5.12
mmol) and the solution stirred at r.t. for 6 h. Water was added, the
layers separated and the aqueous layer extracted with CH2Cl2. The
combined organic fractions were washed with brine and dried
(MgSO4), and the solvent was removed under reduced pressure. Puri-
fication by chromatography (silica gel, 0–2% EtOAc/CH2Cl2) gave the
product (0.27 g, 42%) as a white solid. 1H NMR data matches that in
the literature.22
1H NMR (300 MHz, CDCl3): δ = 7.10–7.18 (m, 1 H), 7.06 (t, J = 7.5 Hz, 1
H), 6.96–7.02 (m, 1 H), 5.44 (d, J = 8.5 Hz, 1 H), 3.15 (dt, J = 16.4, 3.9
Hz, 1 H), 2.96–3.03 (m, 1 H), 2.72–2.91 (m, 2 H), 2.36–2.47 (m, 1 H),
2.35 (s, 3 H), 1.96 (d, J = 12.4 Hz, 1 H), 1.87 (tdd, J = 13.8, 3.1, 1.6 Hz, 1
H).
To acid 2 (0.15 g, 0.687 mmol) in CH2Cl2 (10 mL) cooled in ice under
N2 was added oxalyl chloride (0.262 g, 0.17 mL, 2.062 mmol). The
mixture was allowed to warm slowly to r.t. overnight then all solvents
were removed under reduced pressure. The residue was redissolved
in CH2Cl2 (5 mL) then added slowly to a solution of piperidine 3 (0.183
g, 0.687 mmol) and i-Pr2EtN (0.266 g, 0.36 mL, 2.062 mmol) in CH2Cl2
(5 mL) cooled in ice under N2. The mixture was allowed to warm to r.t.
slowly overnight. Water was added and the layers separated. The or-
ganic phase was washed with 1 N HCl solution and dried (MgSO4),
and then the solvent removed under reduced pressure. The crude was
then purified by chromatography (silica gel, 0–50% EtOAc/hexane) to
give the amide (0.133 g, 45%) as a tan solid.
1H NMR (300 MHz, CDCl3): δ = 7.56 (d, J = 5.5 Hz, 1 H), 7.28–7.37 (m, 2
H), 7.16–7.25 (m, 2 H), 7.03–7.12 (m, 1 H), 4.81 (d, J = 12.4 Hz, 1 H),
3.90 (d, J = 12.6 Hz, 1 H), 3.70–3.83 (m, 1 H), 3.20–3.35 (m, 1 H), 2.94–
3.19 (m, 4 H), 2.72–2.84 (m, 1 H), 2.59–2.71 (m, 1 H), 2.50 (qd, J =
12.7, 4.0 Hz, 2 H), 2.38 (d, J = 4.0 Hz, 3 H), 2.12–2.32 (m, 1 H), 1.86–
2.02 (m, 1 H), 1.64 (d, J = 13.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 204.2, 172.5, 139.3, 138.3, 136.0, 133.9,
130.5, 128.7, 128.1, 126.5, 126.4, 46.5, 43.8, 43.1, 40.4, 35.1, 26.1,
20.0.
13C NMR (75 MHz, CDCl3): δ = 179.7, 139.4, 137.5, 137.4, 131.2, 126.6,
126.1, 84.7, 40.9, 37.3, 31.9, 26.3, 21.2.
(±)-6-Methyl-12-oxatricyclo[8.2.1.02,7]trideca-2,4,6-trien-11-ol
(18)
To a solution of lactone 17 (1.32 g, 6.53 mmol) in toluene (40 mL)
cooled to –60 °C was added 1 M DIBAL-H in toluene (6.5 mL, 6.53
mmol). The mixture was stirred at –60 °C for 1 h, then MeOH (50 mL)
was added at –50 °C, followed by sat. potassium sodium tartrate solu-
tion (100 mL) and the mixture allowed to warm up to r.t. The layers
were separated, the aqueous portion was extracted with EtOAc (3 ×),
the combined organics were dried (MgSO4), and the solvent was re-
moved under reduced pressure to give the lactol (1.00 g, 75%) as a
white solid. 1H NMR data matches that in the literature.22
1H NMR (300 MHz, CDCl3): δ = 6.96–7.07 (m, 2 H), 6.90–6.95 (m, 1 H),
5.57 (d, J = 3.0 Hz, 1 H), 5.20 (d, J = 8.9 Hz, 1 H), 2.78–3.03 (m, 3 H),
2.68 (dddd, J = 11.9, 8.7, 6.7, 1.7 Hz, 1 H), 2.50–2.58 (m, 1 H), 2.31 (s, 3
H), 2.04–2.16 (m, 1 H), 1.53–1.68 (m, 1 H).
Methyl 1-Methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-
7-carboxylate (15)
To a solution of acid 2 (2.26 g, 10.36 mmol) in CH2Cl2 (50 mL) cooled
in ice under N2 was added oxalyl chloride (3.94 g, 2.6 mL, 31.07
mmol) and after the initial reaction had subsided, the mixture was
stirred at r.t. overnight. Solvents were removed under reduced pres-
sure, the residue was redissolved in CH2Cl2 (50 mL) and cooled in ice.
MeOH (20 mL) was added and the mixture stirred at r.t. for 1.5 h. The
mixture was diluted with water and the layers separated. The aque-
ous portion was extracted with CH2Cl2, the combined organic por-
tions were dried (MgSO4), and the solvent was removed under re-
duced pressure to give the methyl ester (2.41 g, quant.). 1H NMR data
matches that in the literature.22
13C NMR (75 MHz, CDCl3): δ = 142.9, 138.1, 136.8, 129.8, 125.5, 125.4,
102.0, 84.5, 43.8, 37.4, 30.2, 25.4, 21.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
D. A. Perrey et al.
Paper
Synthesis
(±)-cis-7-{[4-(2,6-Dichlorophenyl)piperidin-1-yl]methyl}-1-meth-
yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol (1)
Supporting Information
Supporting information for this article is available online at
Method 1 (from amide 14): A solution of AlCl3 (0.173 g, 1.298 mmol)
in Et2O (8 mL) was added dropwise via addition funnel to a solution of
LiAlH4 (0.047 g, 1.236 mmol) in Et2O (8 mL) cooled in ice under N2.
The resulting mixture was stirred for 10 min then a solution of amide
14 (0.133 g, 0.309 mmol) in Et2O (8 mL) was added dropwise. The
mixture was warmed up to r.t. and stirred for 4 h. The mixture was
cooled again in ice and quenched by the addition of water, 2 N NaOH
solution, and water. The layers were separated and the aqueous por-
tion was extracted with Et2O. The combined organic fractions were
dried (MgSO4) and the solvent was removed under reduced pressure.
The crude was purified by chromatography (silica gel, 0–40%
EtOAc/hexane) to obtain the cis-isomer (0.018 g, 14%).
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References
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1H NMR (300 MHz, CDCl3): δ = 7.43 (d, J = 7.3 Hz, 1 H), 7.19–7.34 (m, 2
H), 7.10–7.18 (m, 1 H), 7.00–7.10 (m, 2 H), 5.04 (d, J = 10.2 Hz, 1 H),
3.48 (tt, J = 12.5, 3.7 Hz, 1 H), 3.14 (dd, J = 14.8, 7.4 Hz, 1 H), 2.92–3.04
(m, 2 H), 2.56–2.72 (m, 2 H), 2.46 (dd, J = 14.5, 11.9 Hz, 1 H), 2.33 (s, 3
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H), 1.29–1.40 (m, 1 H), 0.78–0.93 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 145.1, 139.8, 138.2, 134.8, 130.2, 128.6,
127.5, 125.8, 120.6, 71.7, 65.6, 55.2, 55.2, 42.7, 40.8, 38.4, 31.0, 27.9,
27.3, 20.3.
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(±)-cis-7-(Hydroxymethyl)-1-methyl-6,7,8,9-tetrahydro-5H-ben-
zo[7]annulen-5-ol (19)
1H NMR (300 MHz, CDCl3): δ = 7.42 (d, J = 7.5 Hz, 1 H), 7.10–7.18 (m, 1
H), 7.03–7.10 (m, 1 H), 5.04 (d, J = 10.4 Hz, 1 H), 3.41–3.52 (m, 2 H),
3.15 (dd, J = 14.6, 7.8 Hz, 1 H), 2.48 (dd, J = 14.7, 11.9 Hz, 1 H), 2.33 (s,
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Acknowledgment
This work was supported in part by National Institute on Drug Abuse,
National Institutes of Health, USA (grants DA040693 and DA032837).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G