Probes for narcotic receptor mediated phenomena. 47.1 Novel C4a- and N-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols

Article abstract of DOI:10.1016/j.bmc.2013.02.060

A series of N-methyl rac-cis-4a-aralkyl- and alkyl-substituted-1,2,3,4,4a, 9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols have been prepared (2a-l) using a simple previously designed synthetic route, in order to find a ligand that would interact with both μ- and δ-opioid receptors. A C4a-phenethyl derivative 2a, was found to have modest receptor affinity both at μ- (K _i = 60 nM) and δ-opioid receptors (K_i = 64 nM). The N-methyl substituent of 2a and that of other ligands in the series was then modified to obtain compounds with different N-substituents that might provide higher affinity at both receptors. A number of compounds differently substituted at C4a and N were synthesized and evaluated. Binding studies and functional assays revealed a moderately selective δ-antagonist (2l), selective μ-δ antagonists (3d, 3g), and a μ-κ antagonist (3f).

Full text of DOI:10.1016/j.bmc.2013.02.060

Bioorganic & Medicinal Chemistry 21 (2013) 3298–3309
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Bioorganic & Medicinal Chemistry
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Probes for narcotic receptor mediated phenomena. 47.1 Novel
C4a- and N-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]
pyridin-6-ols
Malliga R. Iyer a, Richard B. Rothman b, Christina M. Dersch b, Arthur E. Jacobson a, Kenner C. Rice a,
⇑
a Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and The National Institute on Alcohol Abuse and Alcoholism,
National Institutes of Health, Department of Health and Human Services, 5625 Fishers Lane, Room 4N03, Bethesda, MD 20892-9415, USA
b Clinical Psychopharmacology Section, Chemical Biology Research Branch, National Institute on Drug Abuse, Addiction Research Center, National Institutes of Health, Department of
Health and Human Services, Baltimore, MD 21224, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of N-methyl rac-cis-4a-aralkyl- and alkyl-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-
c]pyridin-6-ols have been prepared (2a–l) using a simple previously designed synthetic route, in order
Received 18 December 2012
Revised 20 February 2013
Accepted 27 February 2013
Available online 3 April 2013
to find a ligand that would interact with both
2a, was found to have modest receptor affinity both at
l
- and d-opioid receptors. A C4a-phenethyl derivative
(Ki = 60 nM) and d-opioid receptors
l
-
(Ki = 64 nM). The N-methyl substituent of 2a and that of other ligands in the series was then modified
to obtain compounds with different N-substituents that might provide higher affinity at both receptors.
A number of compounds differently substituted at C4a and N were synthesized and evaluated. Binding
Keywords:
Synthesis
studies and functional assays revealed a moderately selective d-antagonist (2l), selective
(3d, 3g), and a antagonist (3f).
l–d antagonists
Opioid receptor binding
cis-1,2,3,4,4a,9a-Hexahydrobenzofuro[2,3-
c]pyridin-6-ols
l–j
Published by Elsevier Ltd.
Opioid agonists and antagonists
Oxide-bridged phenylmorphans
1. Introduction
affinity based on N-variations on the piperidine ring, we thought
it would be of interest to explore the effect of C4a group as well
as the importance of the ethyl group at this position on opioid
receptor affinity. As part of our continuing interest in the benzof-
uro[2,3-c]pyridin-ol series of compounds, we had devised a sim-
pler route for the synthesis of these compounds.6 This new
synthetic route offered us the flexibility to design and study com-
pounds with a variety of substituents in the C4a-position as well as
on the piperidine nitrogen atom in the rac-cis-benzofuro[2,3-
c]pyridin-6-ol series of compounds. In our present study we ini-
tially examined the effect of chain length and substitution at the
C4a-position. The N-methyl-C4a-alkyl and aralkyl-derivatives (2)
were synthesized and their affinity for opioid receptors was deter-
mined. In the second part of this study we selected a promising
compound bearing an N-methyl group from the above series of
compounds (2), and designed a variety of substituents to replace
the methyl moiety. The N-methyl-C4a phenethyl-compound (2,
cis-1,2,3,4,4a,9a-Hexahydrobenzofuro[2,3-c]pyridin-6-ols
with suitable substitution on the nitrogen have been shown to
have high affinity for -, d- and
-opioid receptors.2 Benzof-
(1)
l
j
uro[2,3-c]pyridinols are partial structures of oxide-bridged
phenylmorphans. Although they appear to be structurally similar
to the d-series of the oxide-bridged phenylmorphans,3–5 the pres-
ence of a truncated C4a group gives the benzofuropyridinols a flex-
ibility that is lacking in the rigid oxide-bridged phenylmorphans.
This flexibility may enable them to assume a conformation that
is closer to morphine than the oxide-bridged phenylmorphans
are able to assume, and their opioid affinity and activity may be
correlated with their ability to attain this conformation.6 Hutchi-
son et al.2 found that the C4a-ethyl-substituted N-phenethyl- and
N-cyclopropylmethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-
c]pyridin-6-ols (1a and 1b, respectively), had high affinity for
l-
opioid receptors (Ki = 0.9 and 4 nM, respectively) and were potent
antinociceptives. While Hutchison’s work focused on the opioid
R = phenethyl) having similar (albeit moderate)
and negligible -affinity was chosen for further manipulation to
obtain compounds based on 3, where R is not Me, with the hope
l- and d-affinity
j
of obtaining compounds that interact with both
with higher affinity and potency.
l- and d-receptors
⇑
Corresponding author. Tel.: +1 301 496 1856; fax: +1 301 402 0589.
E-mail address: kr21f@nih.gov (K.C. Rice).
0968-0896/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmc.2013.02.060

M. R. Iyer et al. / Bioorg. Med. Chem. 21 (2013) 3298–3309
3299
Scheme 1. Reagents and conditions: (a) n-BuLi, aralkyl or alkyl Br; (b) (1) NBS, (2) NaBH3CN; (c) HBr, reflux; (d) Et3N, sealed tube, 100 °C. Yields are shown in Table 1.
Mixed
l
Àd ligands are currently of great interest7,8 as potential
Table 1
Yields of N-methyl substituted compounds
analgesics with fewer side-effects. However, the correct ratio of a
ligand’s affinities at
l and d has not been determined that would
Compd
R
5 (%)
6 (%)
7 (%)
2 (%)
allow it to act as a potent analgesic with, for example, decreased
respiratory depression, physical dependence, and abuse liability.
Binding studies and functional assays on the synthesized com-
pounds revealed interesting trends, which are discussed below.
a
b
c
d
e
f
g
h
i
PhCH2
76
42
96
64
a
Ph(CH2)2
Ph(CH2)3
Ph(CH2)4
Ph(CH2)5
CH3
41
49
70
81
85
63
30
83
83
86
94
49
83
c
c
67
b
2. Chemistry
CH2CH3
(CH2)2CH3
(CH2)3CH3
(CH2)4CH3
4-F-Ph(CH2)2
2-F-Ph(CH2)2
45
82
69
35
34
48
48
39
75
82
87
76
92
65
62
64
c
The synthesis developed earlier6 enabled the preparation of
compounds with new alkyl or aralkyl moieties at C-4a. We decided
to explore the receptor affinity of compounds with a benzyl, phen-
ethyl, phenylpropyl, phenylbutyl and phenylpentyl group as the
aralkyl group, and methyl, propyl, butyl and pentyl, along with
the previously known ethyl group, were chosen as alkyl moieties
at the C4a position. A general route for the synthesis of the N-
methyl compounds in the hexahydrobenzofuro[2,3-c]pyridin-6-ol
series is shown in Scheme 1. We previously found, in the hexa-
hydrobenzofuro[2,3-c]pyridin-8-ol series of compounds,9 that
although a C4a-methyl-N-p-fluorophenethyl compound showed
c
j
k
l
80
95
See Iyer et al.6
a
b
c
See Hutchison et al.2
Taken directly to next step (diol not purified).
alization at the C4a position was achieved under Evans
conditions,10 leading to enamines 5a–l. The desired intermediates
possessing an ethyl group, or any alkyl or aralkyl group at C4a were
easily obtained using this method. A simple two-step procedure6
involving bromination of the alkene with NBS followed by NaC-
NBH3 reduction in acidic medium gave the late stage intermediates
6a–l. Hydrobromic acid-assisted deprotection of the two aromatic
O-methyl groups gave the diols 7a–l (Scheme 1), the needed tem-
plates for the base-mediated oxide-ring formation. Heating the diol
in methanolic Et3N in a sealed tube gave the N-methyl substituted
2a–l (Scheme 1) in excellent yield. The yields of the N-methyl
substituted compounds are shown in Table 1. The depicted config-
very weak
l- and d-affinity, it had better affinity than any of the
other substituents examined in that series. We thought it would
be of interest, then, to incorporate a 2-fluorophenethyl and a 4-flu-
orophenethyl moiety in the molecule, at C4a in the N-methyl com-
pounds 2k and 2l, and as the N-substituent in 3c and 3d (in the
C4a-phenethyl compound).
The starting substrate 4-(2,5-dimethoxyphenyl)-1-methyl-
1,2,3,6-tetrahydropyridine (4, Scheme 1) was assembled via
known literature procedures.3 With compound 4 in hand, function-

3300
M. R. Iyer et al. / Bioorg. Med. Chem. 21 (2013) 3298–3309
Scheme 2. Reagents and conditions: (a) Ac2O (neat), reflux, 71%; (b) (1) proton sponge, Troc-Cl, (2) K2CO3, MeOH, (3) Zn, AcOH, 77%; (c) (1) RBr, DMF, NaHCO3, (2) K2CO3,
MeOH, 38–56% (see Section 5 for details).
Table 2
Opioid receptor binding studies
Compd
Ki (nM SD)
R
R1
la
db
jc
l
/d
j/
l
j/d
2a
2b
2c
2d
2e
2f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph(CH2)2
PhCH2
Ph(CH2)3
Ph(CH2)4
(CH2)5Ph
CH3
60
66
165 18
45
28
425 45
19 0.5
84 10
97
91
166 14
96
9
49
22
7
5
5
64
551 37
5
2882 259
3544 167
238 10
0.9
0.1
5
48
54
1.4
4
3
>10
>263
20
20
11
17
23
81
14
33
118
307
3
3
11
45
6
7
36
29
75
>10,000
212 13
479 29
207 21
33 3.3
2
1
4
5
2
163 19
2
6
71
9
0.4
0.04
0.09
0.2
0.5
3
0.95
>0.4
>23
3
9
29
22
43
19
6
21
32
95
4182 240
>5000
2gd
2h
2i
CH2CH3
(CH2)2CH3
(CH2)3CH3
(CH2)4CH3
4-F-Ph(CH2)2
2-F-Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
1651 162
1913 70
971 55
2879 131
2217 90
730 48
670 26
721 40
826 67
2459 222
16 0.75
5
5
2j
2k
2l
128
52
39
8
2
4
1.3
2
8
0.8
3
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph(CH2)2
Ph(CH2)3
4-F-Ph(CH2)2
2-F-Ph(CH2)2
4-CF3-Ph(CH2)2
CPMe
CH2CH@CH2
2-CF3-Ph(CH2)2
3-CF3-Ph(CH2)2
Morphine
DAMGO
U69,593
0.2
0.4
0.7
0.3
0.3
0.2
0.4
1.3
0.3
111 11
3
34
26
26
24
55
136 14
63
605 36
3
1
2
2
4
0.43
0.4
0.36
2
8
5
0.7
1.5
14
23
174 17
16
2.6 0.01
1.2 0.1
>2
80
3
1922 144
541 44
299 49
2
5
34
9
1500 170
>12
l
M
lM
3.5 0.3
Assays were conducted using CHO cells that were stably transfected and express the
l
-, d-, or j-opioid receptors, respectively. All results n = 3.
a
[3H]DAMGO binding.
b
[3H]DADLE binding.
c
[3H]U69,593 binding.
d
Data from Hutchison et al.2
e
CPM = cyclopropylmethyl.
uration of the compounds in Schemes 1 and 2 was based on the X-
ray crystallographic determination of the structures of related
compounds in the pyrindin-8-ol series, compounds 6a, 7a, and
2a,6 as well as 2g and 6g.9
3. Results and discussion
The opioid receptor binding affinities of the compounds are
shown in Table 2. Except for compound 3f, with an N-cyclopro-
Synthesis of compounds 3a–3i was carried out as shown in
Scheme 2. Acetate protection of the phenol 2a gave 8. Sequential
treatment of 8 with Troc-Cl, deprotection of the acetate, and Zn-
dust mediated removal of the Troc group gave the N-nor
compound 9. Compound 9 was alkylated at the N-position to give
compounds 3a–3i.
pylmethyl group (Ki = 16 nM at
j
), few of the compounds had
<100 nM affinity for the -opioid receptor. The
j
l-receptor affinity
of the compounds in Table 2 ranged from affinities comparable to
morphine (Ki = 5 or 7–8 nM, for 3f, 3d and 3e, respectively) to those
with very poor affinity (Ki = 425 nM, for 2f). The d-receptor
affinities ranged from Ki = 24–26 nM for 3d–f, to inactive

M. R. Iyer et al. / Bioorg. Med. Chem. 21 (2013) 3298–3309
3301
Table 3
Agonist (ED50, nM, and Emax) and antagonist (Ke, nM) activities from [35S]GTP-
c
-S functional assays
a
a
a
Compd
R
l
ED50 & Emax
567 93
75
1186 211
43
248 35
82
2149 556
d ED50 & Emax
j
ED50 & Emax
l
Ke
d Ke
j Ke
3a
Ph(CH2)2
395
29
6
1
ND
ND
ND
ND
229 10
258 45
ND
3
3c
3d
3e
3f
4-F-Ph(CH2)2
2-F-Ph(CH2)2
4-CF3-Ph(CH2)2
CPMb
350 110
218 15
213 17
ND
2
29
N
1
48
8
37
7
2160 252
ND
2
1250 261
111 13
827 97
64 10
60
N
5
46
N
3
135 36
18 0.01
ND
8
1
32
8
3g
3i
CH2CH@CH2
3-CF3-Ph(CH2)2
N
N
ND
ND
37
248 36
7
43
455 47
3
ND
ND
ND
DAMGO
34
100
4
2
SNC80
55 10
104
1
(À)-U50,488
Naloxone
27
99
3
2
2.3 0.3
ND = not determined; N = no agonist activity.
a
CPM = cyclopropylmethyl.
Emax = the percent the compound stimulated GTP-
b
c-S binding as compared to the stimulation produced by 1000 nM DAMGO, 500 nM SNC80 or 500 nM (À)-U50,488
(when the% stimulation is considerably less than 100%, the compound is said to be a partial agonist).
(Ki > 10
l
M) for 2f. The compounds with appreciable affinity at an
the hope of finding compounds with suitably mixed l- and d-
receptor affinities. Toward that end, the C4a-phenethyl substituent
in 2a was chosen as the fixed moiety for the present study. Thus, 2a
opioid receptor were further evaluated using the [35S]GTP-
say (Table 3).
c
-S as-
Initially we varied the C4a-substituent to see if we could obtain
a compound with at least moderate affinity at both the - and d-
receptors. In the N-methyl, C4a-aralkyl series 2a–e, with the
with equivalent, if moderate, l–d binding affinity, and negligible j
l
affinity (Table 2), was used as the template for modification of the
N-substituent. A variety of N-substituents were chosen (phen-
ylalkyl, flurophenylalkyl, trifluoromethylphenylalkyl, allyl and
cyclopropylmethyl) to examine their effect on the opioid receptor
affinity of compounds bearing the C4a-phenethyl moiety (Table
2, 3a–3i). The N-benzyl compounds were not prepared because
previous work had shown that opioids with an N-benzyl substitu-
ent were inactive; for example, an N-4-fluorobenzyl compound in
the pyridine-8-ol series had almost no affinity for opioid
receptors.9
exception of the C4a-phenylpropyl compound 2c that had little
affinity for the
l-opioid receptor, increasing the C4a-chain length
resulted in only
a
moderate increase in -affinity (from
l
Ki = 66 nM for the C4a-benzyl compound 2b to 28 nM for the
C4a-phenylpentyl compound 2e). In that series there was great
variability in d-receptor affinity. The affinity for d-receptors peaked
with the C4a-phenylbutyl compound (Ki = 29 nM at d) in 2a–e.
None of these compounds were further evaluated in the functional
assay.
Compounds 3a, 3c, 3d, 3e and 3i had good to moderate affinity
In the C4a-alkyl, N-methyl series 2f–j, the affinity for
l
recep-
at
(Table 3). Compound 3f was more promiscuous and showed good
or moderate binding at all three receptors. The jl and d ratios
for 3d and 3e were promising and hence were evaluated in the
35S]GTP-
-S functional assay along with compounds 3a, 3c, 3f,
3g and 3i. The functional assays showed that none of the com-
pounds had any appreciable agonist activity. Compounds 3a–3e
were all found to be partial, and very weak, agonists (Table 3).
Most interesting was 3d with an o-fluorophenethyl N-substituent
and 3g with an N-allyl substituent both of which were found to
l- and d-receptors and much less affinity for kappa receptors
tors was optimal when C4a was ethyl, in 2g, as found by Hutchison
et al.,2 and the compound with the highest affinity at d-receptors
was determined to be 2j, with a C4a-pentyl group (Ki = 33 nM, Ta-
ble 1). The affinity increased with chain-length, from propyl (2h,
Ki = 479 nM) to butyl (2i, Ki = 207 nM) to pentyl (2j, Ki = 33 nM).
Thus, a 14.5-fold increase in affinity was seen when the C4a-alkyl
group chain-length went from C4a-propyl (2h) to pentyl (2j).
Attachment of C4a-fluorophenethyl (para or ortho, 2k or 2l, respec-
j
[
c
tively) did not improve affinity or selectivity for the
l- or d-recep-
tors. Functional studies ([35S]GTP-
c
-S assay) of 2c–2e, 2j and 2l
have moderate l- and d-antagonist activity, and the N-cyclopro-
revealed that compound 2l had moderate antagonist activity
(Ke = 29 nM), 2c had less antagonist activity (Ke = 88 nM) than 2l
at the d-receptor, and the others were essentially inactive
(Ke > 200 nM).
The second part of the study involved selecting a specific C4a-
substituent from the N-methyl substituted compounds 2a–l with
pylmethyl compound 3f, which was determined to be a moder-
ately potent non-selective antagonist. The antagonist activity of
these compounds was in marked contrast with the agonist activity
found in the compounds of Hutchison et al.2 We have discovered
that a change in the substituent at C4a from ethyl to phenethyl
completely modified activity in this 1,2,3,4,4a,9a-hexa-
hydrobenzofuro[2,3-c]pyridin-6-ol series of compounds. For exam-
ple, a compound with a C4a-ethyl and an N-cyclopropylmethyl
good affinity for both the
l- and d-receptors. The C4a-substituent
would then be held constant and the N-substituent modified with

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M. R. Iyer et al. / Bioorg. Med. Chem. 21 (2013) 3298–3309
moiety was formerly found2 to be a potent
l
-agonist in vivo, with
20 °C for 1 h and the solvent was removed to give a brown oil.
moderate affinity for
(Ki = 4, 34 and 53 nM for
ever, when the C4a-ethyl group was changed to the C4a-phenethyl
group, as in 3f, we obtained a moderately potent opioid antagonist
with similar receptor affinity and selectivity (Ki = 8, 32 and 64 nM
to the l-, j- and d-receptor, respectively); a remarkable change in
activity, but not in receptor affinity or selectivity, induced by the
substituent at C4a.
j
- and somewhat less affinity for d-receptors
The crude product was suspended in MeOH and 37% HCl (1 mL)
was added to the suspension. Solid NaBH3CN (1.5 equiv) was
added and the reaction mixture was stirred at room temperature
for 30 min. The reaction mixture was then diluted with aqueous
saturated NaHCO3 and the organic layer was washed with H2O
and extracted into CH2Cl2. Evaporation of the solvent gave a brown
oil. Purification of the crude product by column chromatography
using 30% hexanes in Et2O gave either sticky oils or crystalline sol-
ids 6.
l
-, - and d-receptor, respectively). How-
j
4. Conclusion
5.1.3. General procedure C
To 6 was added 48% HBr (20 mL) and the emulsion was refluxed
for 10 h. After completion of the reaction, the excess HBr was re-
moved by distillation to give 7 as a brown solid. Neutralization
of the HBr salt by partitioning between NaHCO3 and CHCl3 gave
the free base. A small batch of 7 was recrystallized from MeOH
to give crystalline 7 as a free base that could be converted to the
pure HBr salt.
We evaluated the effect of alkyl and aralkyl chain-length at the
C4a position of the N-methyl benzofuropyridin-6-ol series of com-
pounds. We found that increasing the chain length from benzyl to
phenylpentyl gave a moderate improvement of
affinity was found to be highest with the C4a-phenylbutyl group.
However, with the C4a-alkyl groups, the highest -affinity resides
l-affinity. The d-
l
with C4a-ethyl and C4a-pentyl substituents, and these gave better
d-affinity, as well. Except for phenylpentyl, the compounds in the
5.1.4. General procedure D
N-methyl series had little or no affinity for
tion of an o-fluoro group on the aromatic ring of the C4a-phen-
ethyl-subsitutent (3d) yielded moderately selective d-
j-receptors. Introduc-
Compound 7 was treated with MeOH (1 mL) and excess Et3N
(15 mL). The reaction mixture was placed in a sealed tube and
heated at 100 °C for 3 h. The reaction mixture was cooled, and
the excess Et3N removed to give a brown solid. Silica-gel column
chromatography of the brown solid using 15% MeOH in CH2Cl2
gave an off-white solid 2.
a
antagonist. A considerably more potent antagonist had an N-cyclo-
propylmethyl group, 3f (Ke = 8 nM); it was also more promiscuous,
with affinity for all of the opioid receptors. Our search among the
C4a-phenethyl compounds with a variety of N-substituents for a
selective
opioid antagonist activity at both
l
-agonist d-antagonist resulted in compounds that had
- and d-receptors. Efforts are
5.1.5. General procedure E
l
A mixture of the amine 9, alkyl bromide (1.2 equiv) and NaHCO3
(2 equiv) in DMF (20 mL) was heated at 50 °C for 20 h. After cooling
to room temperature, the reaction mixture was poured into ice-
H2O, and the product was extracted with Et2O. The ethereal ex-
tracts were washed with saturated NH4Cl solution. After drying
over Na2SO4, the solvent was removed in vacuo to afford an oil.
The crude oil was subjected to flash chromatography on silica gel
using 75% EtOAc in hexanes as the eluent to give the compounds
3a–h as a solid.
underway to study compounds with a more promising N-substitu-
ent, changing the C4a-substituent to yet untried moieties. The re-
sults from that study will be reported in due course.
5. Experimental
5.1. Chemistry
Mass spectra (CIMS) were obtained using a Finnigan 4600 mass
spectrometer unless otherwise noted. 1H nuclear magnetic reso-
nance (1H NMR, 500 MHz) was recorded on a Bruker Avance 500
instrument in deuterated solvents (Cambridge Isotope Laborato-
ries, Inc.) as specified. TMS was used as an internal standard. IR
spectra were recorded on a Beckman IR 4230 spectrometer. Col-
umn chromatography was performed with the use of 230–400-
mesh EM silica gel. Melting points were determined on a Buchi
B-545 melting point apparatus and are uncorrected. Combustion
analyses were determined at Micro-Analysis, Inc., Wilmington,
DE or at Atlantic Microlabs, Atlanta, GA.
5.1.6. 4-Benzyl-4-(2,5-dimethoxyphenyl)-1-methyl-1,2,3,4-
tetrahydropyridine (5a)
Using general procedure A, 12.75 g of 4 was converted to 5a
(13.4 g, 76%). 1H NMR (500 MHz; CDCl3): d 7.02 (d, J = 6.1 Hz,
4H), 6.81–6.76 (m, 3H), 6.71 (d, J = 3.1 Hz, 1H), 6.63 (dd, J = 8.7,
3.1 Hz, 1H), 5.84 (d, J = 8.1 Hz, 1H), 4.54–4.52 (m, 1H), 3.82 (s,
3H), 3.60 (s, 3H), 3.51 (d, J = 12.9 Hz, 1H), 2.86 (d, J = 12.9 Hz,
1H), 2.69 (dt, J = 11.2, 3.7 Hz, 1H), 2.60 (dt, J = 13.4, 2.1 Hz, 1H),
2.46–2.42 (m, 3H), 1.91–1.85 (m, 1H). 13C NMR (126 MHz, CDCl3):
d 152.9, 151.7, 139.3, 137.3, 136.4, 130.5, 127.4, 125.6, 119.8,
111.7, 110.4, 110.3, 103.8, 55.6, 55.4, 47.0, 45.6, 42.4, 41.9, 33.6.
HRMS (TOF MS ES+) calcd for C21H26NO2 (M+H)+: 324.1964; found:
324.1957. Anal. Calcd for (C21H25NO2Á0.1H2O): C, 77.55; H, 7.81; N,
4.31; found: C, 77.44; H, 7.82; N, 4.18.
5.1.1. General procedure A
A solution of 4 in dry THF was stirred under argon at À20 °C. A
solution of n-butyllithium, 2.5 M in hexane (1.5 equiv), was added
to the reaction, producing a deep red color. The mixture was stirred
at À20 °C for 2 h. Alkyl bromide (1.5 equiv) was added, producing a
yellow solution, which was then stirred and brought to 20 °C over
1 h. The reaction mixture was then treated with saturated NH4Cl
solution. The reaction mixture was partitioned between Et2O and
H2O. The organic layer was dried over anhyd Na2SO4 and removal
of the solvent gave an orange oil. Column chromatography of the
crude material using 20% hexanes in Et2O gave compound 5 as a
pure yellow oil.
5.1.7. 4-Benzyl-3-bromo-4-(2,5-dimethoxyphenyl)-1-
methylpiperidine (6a)
Using general procedure B, 13.4 g of 5a was converted to 6a
(7.0 g, 42%). IR (neat) 2941 cmÀ1 1H NMR (500 MHz, CDCl3,) d
;
7.04 (m, 3H), 6.89 (d, 1H, J = 9.0 Hz), 6.76 (dd, 1H, J = 2.0 and
8.5 Hz), 6.58 (d, 2H, J = 7.0 Hz), 6.24 (s, 1H), 5.66 (s, 1H), 3.96 (s,
3H), 3.63 (s, 3H), 3.45 (d, 1H, J = 15.0 Hz), 3.24 (d, 1H,
J = 13.5 Hz), 3.18 (d, 1H, J = 13.0 Hz), 3.02 (d, 2H, J = 13.5 Hz), 2.66
(t, 1H, J = 12.0 Hz), 2.45 (s, 3H), 2.36 (t, 1H, J = 9.5 Hz), 1.70 (d,
1H, J = 13.0 Hz); 13C NMR (126 MHz, CDCl3) d 153.2, 152.7, 137.9,
135.1, 130.3, 127.5, 126.2, 115.8, 111.7 111.2, 110.5, 58.9, 58.0,
56.0, 55.7, 51.8, 46.4, 45.7, 36.8, 27.4; HRMS (TOF MS ES+) calcd
5.1.2. General procedure B
To a solution of 5 in dry THF at À78 °C was added N-bromosuc-
cinimide (1 equiv) in dry THF (15 mL). The mixture was stirred at

M. R. Iyer et al. / Bioorg. Med. Chem. 21 (2013) 3298–3309
3303
for C21H27NBrO2 (M+H)+: 404.1225; found: 404.1206. Anal. Calcd
for (C21H26NBrO2): C, 62.38; H, 6.48; N, 3.46; found: C, 62.44; H,
6.39; N, 3.55.
5.1.12. 2-(3-Bromo-1-methyl-4-(3-phenylpropyl)piperidin-4-
yl)benzene-1,4-diol (7c)
Using general procedure C, 15.5 g of 6c was converted to 7c
(12.0, 83%). 1H NMR (500 MHz; CDCl3): d 7.19 (t, J = 7.1 Hz, 3H),
7.10 (t, J = 6.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 2H), 6.58 (d, J = 10.4 Hz,
2H), 6.45 (s, 1H), 5.91 (s, 1H), 3.96 (d, J = 14.1 Hz, 1H), 3.75 (d,
J = 14.1 Hz, 1H), 3.48 (s, 1H), 3.31–3.23 (m, 3H), 2.96 (s, 3H),
2.58–2.44 (m, 3H), 2.20 (d, J = 14.2 Hz, 1H), 2.00–1.98 (m, 1H),
1.43–1.42 (m, 1H), 1.07 (s, 1H). 13C NMR (126 MHz, CD3OD): d
150.7, 149.9, 143.2, 131.7, 129.3, 129.2, 126.7, 117.5, 115.6,
115.3, 107.8, 57.9, 55.0, 51.8, 49.5, 49.32, 49.26, 49.14, 49.10,
48.9, 48.80, 48.76, 44.6, 44.1, 36.8, 30.6, 28.5, 26.4. HRMS (TOF
MS ES+) calcd for C21H27NBr79O2 (M+H)+: 404.1225; found:
404.1206. Anal. Calcd for (C21H26BrNO2ÁHBrÁ0.75H2O): C, 50.56;
H, 5.76; N, 2.80; found: C, 50.59; H, 5.88; N, 2.80.
5.1.8. 2-(4-Benzyl-3-bromo-1-methylpiperidin-4-yl)benzene-
1,4-diol (7a)
Using general procedure C, 2.7 g of 6a was converted to 7a
(2.4 g, 96%). 1H NMR (500 MHz; CD3OD): d 7.00 (d, J = 7.4 Hz,
3H), 6.66 (t, J = 8.4 Hz, 3H), 6.51 (dd, J = 8.5, 2.7 Hz, 1H), 6.03 (d,
J = 2.5 Hz, 1H), 5.89 (s, 1H), 3.65 (d, J = 13.1 Hz, 1H), 3.35 (m, 2H),
3.25 (t, J = 11.4 Hz, 1H), 3.00 (dd, J = 28.1, 10.7 Hz, 2H), 2.52 (s,
3H), 2.28 (td, J = 13.2, 4.3 Hz, 1H), 1.68 (d, J = 13.6 Hz, 1H). 13C
NMR (126 MHz, CD3OD): d 150.3, 150.2, 139.2, 133.3, 131.4,
128.4, 127.1, 117.2, 116.2, 114.7, 59.2, 58.1, 52.3, 49.8, 49.5, 49.3,
48.6, 48.5, 46.2, 45.7, 36.6, 27.4. HRMS (TOF MS ES+) calcd for
C
19H23N81BrO2 (M+H)+: 378.0892; found: 378.0901.
5.1.13. 2-Methyl-4a-(3-phenylpropyl)-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (2c)
5.1.9. (4a-Benzyl-2-methyl-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (2a)
Using general procedure D, 2.4 g of 7a was converted to 2a
Using general procedure D, 12.0 g of 7c was converted to 2c
(8.0 g, 83%). Mp 180–183 °C; IR (neat) 3055 cmÀ1
;
1H NMR
(1.2 g, 64%). Mp 148–151 °C; IR (neat) 3055 cmÀ1
;
1H NMR
(500 MHz, CD3OD) d 7.24 (t, 2H, J = 7.0 Hz), 7.13 (m, 3H), 6.56 (m,
3H), 4.38 (t, 1H, J = 6.0 Hz), 2.74 (dd, 1H, J = 5.0 and 12.5 Hz), 2.54
(t, 2H, J = 7.0 Hz), 2.46 (dd, 1H, J = 5.5 and 11.0 Hz), 2.30 (dd, 1H,
J = 7.0 and 12.5 Hz), 2.21 (s, 3H), 2.14 (dt, 1H, J = 2.5 and
11.5 Hz), 2.00 (m, 1H), 1.71–1.77 (m, 2H), 1.53–1.59 (m, 3H); 13C
NMR (126 MHz, CD3OD) d 153.1, 152.9, 143.4, 135.7, 129.4,
129.3, 126.8, 115.2, 111.42, 111.37, 107.9, 85.3, 57.1, 52.7, 46.6,
46.2, 39.8, 37.2, 33.6, 27.1; HRMS (TOF MS ES+) calcd for
(500 MHz, CD3OD)
d 7.18 (d, 3H, J = 7.5 Hz), 6.95 (d, 2H,
J = 6.5 Hz), 6.55 (m, 2H), 6.35 (s, 1H), 4.43 (t, 1H, J = 6.0 Hz), 2.87
(s, 2H), 2.77 (dd, 1H, J = 5.5 and 12.5 Hz), 2.49 (dd, 1H, J = 5.5 and
11.5 Hz), 2.22 (m, 1H), 2.19 (s, 3H), 2.09 (dt, 1H, J = 3.5 and
11.5 Hz), 1.94 (m, 2H); 13C NMR (126 MHz, CD3OD) d 152.7,
152.3, 137.9, 134.9, 131.6, 128.7, 127.3, 115.3, 112.0, 111.4,
107.6, 84.2, 56.8, 52.4, 46.0, 45.9, 32.7; HRMS (TOF MS ES+) calcd
for C19H22NO2 (M+H)+: 296.1651; found: 296.1640. Anal. Calcd
for (C19H21NO2Á0.25H2O): C, 76.52; H, 7.54; N, 4.46; found: C,
76.30; H, 7.47; N, 4.56.
C
21H26NO2 (M+H)+: 324.1964; found: 324.1961. Anal. Calcd for
(C21H25NO2Á0.25H2O): C, 76.91; H, 7.83; N, 4.27; found: C, 77.20;
H, 7.73; N, 4.31.
5.1.10. 4-(2,5-Dimethoxyphenyl)-1-methyl-4-(3-phenylpropyl)-
1,2,3,4-tetrahydropyridine (5c)
5.1.14. 4-(2,5-Dimethoxyphenyl)-1-methyl-4-(4-phenylbutyl)-
1,2,3,4-tetrahydropyridine (5d)
Using general procedure A, 5.0 g of 4 was converted to 5c (3.0 g,
41%). 1H NMR (500 MHz; CDCl3): d 7.30 (t, J = 7.4 Hz, 2H), 7.19 (dd,
J = 20.6, 7.3 Hz, 3H), 7.11 (d, J = 2.8 Hz, 1H), 6.82–6.73 (m, 2H), 6.00
(d, J = 8.0 Hz, 1H), 4.74 (d, J = 7.9 Hz, 1H), 3.82 (s, 3H), 3.73 (s, 3H),
2.80 (d, J = 11.1 Hz, 1H), 2.63 (d, J = 14.9 Hz, 4H), 2.59–2.54 (m, 3H),
2.37 (td, J = 12.7, 4.1 Hz, 1H), 1.96 (t, J = 12.5 Hz, 1H), 1.74 (td,
J = 12.6, 4.0 Hz, 1H), 1.61 (dd, J = 12.6, 6.0 Hz, 1H), 1.30 (dd,
J = 12.2, 7.4 Hz, 1H). 13C NMR (126 MHz, CDCl3): d 152.8, 151.8,
142.9, 137.7, 136.2, 128.5, 128.1, 125.4, 119.7, 111.8, 109.9,
104.5, 55.5, 55.33, 55.32, 47.0, 42.4, 40.8, 39.60, 39.61, 39.59,
39.58, 36.6, 36.57, 36.52, 33.80, 33.78, 26.51, 26.48, 26.46, 26.44.
HRMS (TOF MS ES+) calcd for C23H30NO2 (M+H)+: 352.2277; found:
352.2288. Anal. Calcd for (C23H29NO2): C, 78.59; H, 8.32; N, 3.99;
found: C, 78.38; H, 8.39; N, 3.98.
Using general procedure A, 15.0 g of 4 was converted to 5d
(11.5 g, 49%). 1H NMR (500 MHz, CDCl3): d 7.29 (t, J = 7.4 Hz, 3H),
7.18 (dd, J = 15.1, 7.3 Hz, 2H), 7.08 (d, J = 3.0 Hz, 1H), 6.81 (d,
J = 8.7 Hz, 1H), 6.73 (dd, J = 8.7, 3.0 Hz, 1H), 5.98 (d, J = 8.0 Hz,
1H), 4.70 (d, J = 8.0 Hz, 1H), 3.81 (s, 6H), 2.79 (d, J = 10.9 Hz, 1H),
2.60 (s, 3H), 2.58–2.52 (m, 3H), 2.29 (td, J = 12.7, 4.3 Hz, 1H),
1.96–1.91 (m, 1H), 1.73 (dt, J = 12.6, 6.3 Hz, 1H), 1.57 (dd,
J = 12.7, 6.3 Hz, 2H), 1.31 (q, J = 6.7 Hz, 2H), 1.01 (dt, J = 12.3,
5.0 Hz, 1H). 13C NMR (126 MHz, CDCl3): d 152.9, 151.9, 143.1,
138.0, 136.2, 128.4, 128.2, 125.5, 119.8, 111.9, 110.0, 104.8, 55.6,
55.5, 47.1, 42.5, 41.0, 39.8, 35.9, 33.8, 32.4, 24.5, 14.3. HRMS
(TOF MS ES+) calcd for C24H32NO2 (M+H)+: 366.2069; found:
366.2061. Anal. Calcd for (C24H31NO2): C, 78.86; H, 8.55; N, 3.83;
found: C, 78.47; H, 8.67; N, 3.65.
5.1.11. 3-Bromo-4-(2,5-dimethoxyphenyl)-1-methyl-4-(3-
phenylpropyl)piperidine (6c)
5.1.15. 3-Bromo-4-(2,5-dimethoxyphenyl)-1-methyl-4-(4-
phenylbutyl)piperidine (6d)
Using general procedure B, 3.0 g of 5c was converted to 6c
(3.0 g, 81%). 1H NMR (500 MHz; CDCl3): d 7.16–7.14 (m, 1H),
7.01–6.97 (m, 4H), 6.87 (d, J = 8.6 Hz, 1H), 6.81–6.78 (m, 2H),
5.46 (s, 1H), 3.87 (s, 4H), 3.81 (s, 4H), 3.02 (dd, J = 23.2, 12.3 Hz,
2H), 2.81 (d, J = 13.4 Hz, 1H), 2.56 (dd, J = 13.0, 3.4 Hz, 1H),
2.49–2.38 (m, 6H), 2.20 (dd, J = 11.9, 9.0 Hz, 1H), 2.02 (d,
J = 12.9 Hz, 1H), 1.90 (t, J = 10.4 Hz, 1H). 13C NMR (126 MHz,
CD3OD): d 162.0, 160.1, 153.3, 152.7, 135.4, 130.7, 130.6, 129.5,
129.4, 127.64, 127.58, 124.1, 124.0, 115.8, 115.4, 115.2, 111.9,
110.6, 110.5, 76.8, 58.4, 58.2, 55.9, 55.7, 51.2, 46.2, 44.6, 32.3,
27.5, 25.6. HRMS (TOF MS ES+) calcd for C23H31BrNO2 (M+H)+:
Using general procedure B, 9.4 g of 5d was converted to 6d
(9.7 g, 85%). 1H NMR (500 MHz, CDCl3): d 7.24–7.19 (m, 3H), 7.12
(t, J = 6.9 Hz, 1H), 7.04 (d, J = 7.5 Hz, 3H), 6.78 (d, J = 8.8 Hz, 1H),
6.73–6.71 (m, 1H), 6.65 (s, 1H), 5.45 (s, 1H), 3.79 (s, 3H), 3.74 (s,
3H), 3.03 (d, J = 13.3 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 2.82 (d,
J = 13.4 Hz, 1H), 2.43 (t, J = 8.0 Hz, 2H), 2.35 (s, 3H), 2.30 (t,
J = 12.1 Hz, 1H), 2.10–2.05 (m, 1H), 1.93–1.83 (m, 1H), 1.46 (q,
J = 7.5 Hz, 2H), 1.12 (t, J = 6.3 Hz, 1H), 0.67 (d, J = 4.3 Hz, 1H). 13C
NMR (126 MHz, CDCl3): d 153.0, 152.4, 142.4, 135.8, 128.2, 128.1,
125.5, 115.5, 111.8, 110.1, 105.6, 58.39, 58.36, 55.8, 55.4, 51.1,
46.0, 44.3, 35.4, 31.9, 31.0, 27.4, 24.7. HRMS (TOF MS ES+) calcd
for C24H33NBrO2 (M+H)+: 446.1695; found: 446.1685. Anal. Calcd
for (C24H32NBrO2Á0.75H2O): C, 62.57; H, 7.34; N, 3.05; found: C,
62.51; H, 7.46; N, 3.15.
432.1538;
found:
432.1529.
Anal.
Calcd
for
(C23H30BrNO2Á0.25H2O): C, 63.22; H, 7.03; N, 3.20; found: C,
63.35; H, 7.16; N, 3.46.

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M. R. Iyer et al. / Bioorg. Med. Chem. 21 (2013) 3298–3309
5.1.16. 2-(3-Bromo-1-methyl-4-(4-phenylbutyl)piperidin-4-
yl)benzene-1,4-diol (7d)
5.1.20. 2-Methyl-4a-(5-phenylpentyl)-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (2e)
Using general procedure C, 9.0 g of 6d was converted to 7d
(7.0 g, 83%). 1H NMR (500 MHz, CD3OD): d 6.99 (t, J = 7.5 Hz, 3H),
6.90 (t, J = 7.4 Hz, 2H), 6.85 (d, J = 7.6 Hz, 2H), 6.45 (d, J = 8.5 Hz,
1H), 6.39 (dd, J = 8.6, 2.6 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 5.75 (s,
1H), 3.86 (d, J = 14.1 Hz, 1H), 3.58 (d, J = 14.3 Hz, 1H), 3.36–3.33
(m, 1H), 3.21–3.19 (m, 1H), 2.81 (s, 3H), 2.32–2.26 (m, 4H), 1.99
(d, J = 14.6 Hz, 1H), 1.85 (dt, J = 12.0, 6.3 Hz, 1H), 1.40–1.38 (m,
1H), 1.33–1.30 (m, 1H), 1.02 (t, J = 6.3 Hz, 1H), 0.62–0.58 (m, 1H).
13C NMR (126 MHz, CD3OD): d 150.6, 149.8, 143.6, 132.0, 129.3,
129.2, 126.5, 117.6, 115.6, 115.2, 57.9, 55.1, 51.8, 44.7, 44.2, 36.3,
32.8, 30.7, 26.4, 25.9. HRMS (TOF MS ES+) calcd for C22H29NBrO2
(M+H)+: 418.1382; found: 418.1376. Anal. Calcd for
(C22H28NBrO2.1.5HBr): C, 48.96; H, 5.51; N, 2.60; found: C, 48.60;
H, 5.22; N, 2.55.
Using general procedure C and D, 4.7 g of 6e was converted to 2e
(2.9 g, 81%). Mp 182–185 °C; 1H NMR (500 MHz, CDCl3): d 7.22 (t,
J = 7.4 Hz, 2H), 7.11 (d, J = 7.5 Hz, 3H), 6.58–6.55 (m, 3H), 4.38 (t,
J = 5.9 Hz, 1H), 2.77 (dd, J = 12.4, 5.1 Hz, 1H), 2.56 (t, J = 7.6 Hz,
3H), 2.50 (t, J = 5.8 Hz, 1H), 2.37 (dd, J = 12.3, 6.7 Hz, 1H), 2.26 (s,
3H), 2.20–2.15 (m, 1H), 2.00 (ddd, J = 13.9, 5.9, 3.0 Hz, 1H), 1.81–
1.68 (m, 2H), 1.57 (q, J = 7.3 Hz, 3H), 1.34–1.27 (m, 3H). 13C NMR
(126 MHz, CD3OD): d 153.1, 152.8, 143.7, 135.9, 129.4, 129.3,
126.7, 115.2, 111.44, 111.37, 85.2, 57.0, 52.7, 46.7, 46.2, 39.9, 36.6,
33.63, 33.60, 33.2, 24.6. HRMS (TOF MS ES+) calcd for C23H30NO2
(M+H)+: 352.2277; found: 352.2287. Anal. Calcd for (C23H29NO2):
C, 78.59; H, 8.32; N, 3.99; found: C, 78.31; H, 8.22; N, 3.94.
5.1.21. 4-(2,5-Dimethoxyphenyl)-1,4-dimethyl-1,2,3,4-
tetrahydropyridine (5f)
5.1.17. 2-Methyl-4a-(4-phenylbutyl)-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (2d)
Using general procedure A, 7.0 g of 4 was converted to 5f (5.0 g,
67%). 1H NMR (500 MHz, CDCl3): d 7.07 (d, J = 3.2 Hz, 1H), 6.78 (d,
J = 8.7 Hz, 2H), 6.68 (dd, J = 8.8, 3.1 Hz, 1H), 5.89 (d, J = 7.9 Hz, 1H),
4.53–4.52 (m, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 2.74 (dd, J = 7.3, 4.0 Hz,
1H), 2.55 (s, 3H), 2.49–2.44 (m, 1H), 1.83 (ddd, J = 13.4, 11.6, 3.2 Hz,
1H), 1.45 (s, 3H). 13C NMR (126 MHz, CD3OD): d 153.2, 152.3,
139.7, 136.0, 118.7, 112.6, 110.5, 107.6, 56.0, 55.9, 47.6, 42.8,
37.5, 35.2, 28.9. HRMS (TOF MS ES+) calcd for C15H22NO2 (M+H)+:
248.1645; found: 248.1651.
Using general procedure D, 6.8 g of 7d was converted to 2d
(4.5 g, 86%). Mp 175–178 °C; 1H NMR (500 MHz, CDCl3): d 7.24 (t,
J = 7.5 Hz, 2H), 7.14–7.13 (m, 4H), 6.61–6.56 (m, 2H), 4.39 (t,
J = 5.9 Hz, 1H), 2.75 (dd, J = 12.3, 5.1 Hz, 1H), 2.56 (t, J = 7.6 Hz,
3H), 2.49–2.47 (m, 1H), 2.37 (dd, J = 12.3, 6.6 Hz, 1H), 2.25 (s,
2H), 2.20–2.15 (m, 1H), 2.03–2.00 (m, 1H), 1.81–1.79 (m, 1H),
1.67–1.52 (m, 3H), 1.29 (t, J = 1.2 Hz, 3H). 13C NMR (126 MHz,
CD3OD): d 153.1, 152.7, 143.8, 136.0, 129.4, 129.2, 126.6, 115.2,
111.4, 111.3, 110.4, 85.3, 57.1, 52.7, 46.7, 46.2, 40.0, 36.7, 33.8,
32.5, 30.7, 24.9. HRMS (TOF MS ES+) calcd for C22H28NO2 (M+H)+:
338.2120; found: 338.2111. Anal. Calcd for (C22H27NO2): C,
78.30; H, 8.06; N, 4.15; found: C, 78.17; H, 8.06; N, 4.21.
5.1.22. 3-Bromo-4-(2,5-dimethoxyphenyl)-1,4-
dimethylpiperidine (6f)
Using general procedure B, 5.0 g of 5f was converted to 6f (2.0 g,
30%). 1H NMR (500 MHz, CDCl3): d 6.82 (d, J = 8.7 Hz, 1H), 6.73 (dd,
J = 13.1, 4.3 Hz, 2H), 5.45 (s, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.03 (d,
J = 13.4 Hz, 1H), 2.94 (d, J = 12.1 Hz, 1H), 2.74 (d, J = 13.4 Hz, 1H),
2.62 (td, J = 12.7, 3.8 Hz, 1H), 2.40 (d, J = 11.7 Hz, 1H), 2.36 (s,
3H), 1.68 (d, J = 12.7 Hz, 1H), 1.46 (s, 3H). 13C NMR (126 MHz,
CD3OD): d 153.7, 152.8, 138.9, 114.2, 112.4, 110.5, 59.0, 58.1,
56.2, 55.9, 51.8, 46.5, 41.2, 32.2, 22.1. HRMS (TOF MS ES+) calcd
for C15H23NBr79O2 (M+H)+: 328.0912; found: 328.0875. Anal. Calcd
for (C15H22NBrO2Á0.5H2O): C, 53.42; H, 6.87; N, 4.15; found: C,
53.12; H, 6.86; N, 4.12.
5.1.18. 4-(2,5-Dimethoxyphenyl)-1-methyl-4-(5-phenylpentyl)-
1,2,3,4-tetrahydropyridine (5e)
Using general procedure A, 6.0 g of 4 was converted to 5e (6.8 g,
70%). 1H NMR (500 MHz, CDCl3): d 7.25–7.22 (m, 3H), 7.12 (t,
J = 7.7 Hz, 2H), 7.01 (d, J = 3.1 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H),
6.66 (dd, J = 8.7, 3.1 Hz, 1H), 5.90 (d, J = 8.0 Hz, 1H), 4.64 (dd,
J = 8.0, 1.0 Hz, 1H), 3.74 (d, J = 2.7 Hz, 4H), 2.73–2.70 (m, 1H),
2.53 (s, 3H), 2.50 (d, J = 7.7 Hz, 3H), 2.46–2.44 (m, 2H), 2.17 (td,
J = 12.4, 4.3 Hz, 1H), 1.88–1.83 (m, 1H), 1.59–1.51 (m, 3H), 1.22
(td, J = 9.1, 5.8 Hz, 3H), 0.90 (d, J = 5.8 Hz, 2H). 13C NMR
(126 MHz, CD3OD): d 152.8, 151.9, 143.0, 138.1, 136.2, 128.5,
128.2, 125.5, 119.8, 111.9, 109.9, 104.9, 55.60, 55.56, 47.1, 42.5,
41.0, 39.9, 36.0, 33.8, 31.4, 30.0, 24.4. HRMS (TOF MS ES+) calcd
for C25H34NBrO2 (M+H)+: 380.2590; found: 380.2589. Anal. Calcd
for (C25H33NBrO2Á0.5H2O): C, 63.96; H, 7.51; N, 2.98; found: C,
64.12; H, 7.51; N, 2.84.
5.1.23. 2,4a-Dimethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-
c]pyridin-6-ol (2f)
Using general procedure C and D, 2.0 g of 6f was converted to 2f
(0.65 g, 49%). Mp 275–278 °C 1H NMR (500 MHz, CDCl3): d 6.75–
6.63 (m, 3H), 4.40 (d, J = 0.4 Hz, 1H), 3.84 (d, J = 0.4 Hz, 1H), 3.55
(dd, J = 13.9, 2.4 Hz, 1H), 3.31 (s, 3H), 3.27–3.22 (m, 2H), 2.97 (s,
3H), 2.05–2.01 (m, 1H), 1.90–1.89 (m, 1H). 13C NMR (126 MHz,
CD3OD): d 153.6, 151.5, 138.4, 115.6, 111.7, 110.4, 85.5, 53.0,
51.0, 44.0, 41.6, 34.0, 20.4. HRMS (TOF MS ES+) calcd for
5.1.19. 3-Bromo-4-(2,5-dimethoxyphenyl)-1-methyl-4-(5-
phenylpentyl)piperidine (6e)
C
13H18NO2 (M+H)+: 220.1338; found: 220.1335. Anal. Calcd for
Using general procedure B, 6.8 g of 5e was converted to 6e
(5.2 g, 63%). 1H NMR (500 MHz, CDCl3): d 7.28–7.25 (m, 1H), 7.18
(d, J = 7.0 Hz, 1H), 7.11 (d, J = 7.3 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H),
6.76–6.73 (m, 1H), 6.69 (s, 1H), 5.46 (s, 1H), 3.83 (s, 3H), 3.78 (s,
3H), 3.05 (d, J = 13.4 Hz, 1H), 2.92 (d, J = 11.0 Hz, 1H), 2.84 (d,
J = 13.4 Hz, 1H), 2.49 (t, J = 7.6 Hz, 3H), 2.44 (d, J = 12.3 Hz, 1H),
2.37 (d, J = 7.9 Hz, 2H), 2.07–2.02 (m, 1H), 1.89–1.87 (m, 2H),
1.49 (t, J = 7.5 Hz, 3H), 1.20 (dd, J = 16.1, 7.8 Hz, 2H), 1.10 (t,
J = 6.2 Hz, 1H), 0.64 (s, 1H). 13C NMR (126 MHz, CD3OD): d 153.1,
152.6, 142.7, 136.1, 128.4, 128.3, 125.6, 115.7, 111.9, 110.1,
105.7, 58.6, 58.5, 56.0, 55.5, 51.2, 46.2, 44.5, 35.8, 31.3, 31.1,
29.7, 27.5, 24.9. HRMS (TOF MS ES+) calcd for C25H35NBrO2
(M+H)+: 460.1851; found: 460.1837. Anal. Calcd for
(C25H34NBrO2Á0.25H2O): C, 78.19; H, 8.79; N, 3.65; found: C,
78.34; H, 8.76; N, 3.25.
(C13H17NO2ÁHBr): C, 52.01; H, 6.04; N, 4.67; found: C, 51.73; H,
6.12; N, 4.65.
5.1.24. 4-(2,5-Dimethoxyphenyl)-1-methyl-4-propyl-1,2,3,4-
tetrahydropyridine (5h)
Using general procedure A, 7.5 g of 4 was converted to 5h (4.0 g,
45%). 1H NMR (500 MHz, CDCl3): d 7.02 (d, J = 3.0 Hz, 1H), 6.78 (s,
2H), 6.68 (d, J = 3.0 Hz, 2H), 5.91 (d, J = 8.0 Hz, 1H), 4.66 (d,
J = 8.0 Hz, 1H), 3.77 (d, J = 9.5 Hz, 6H), 2.75–2.72 (m, 1H), 2.55 (s,
3H), 2.51–2.45 (m, 2H), 2.16 (td, J = 12.7, 4.1 Hz, 2H), 1.87 (td,
J = 12.2, 2.2 Hz, 1H), 1.57 (td, J = 12.5, 4.2 Hz, 1H), 1.16 (s, 1H),
0.80 (t, J = 7.1 Hz, 1H). 13C NMR (126 MHz, CDCl3): d 153.2, 152.4,
138.6, 136.5, 120.1, 112.4, 110.3, 105.4, 55.98, 55.96, 47.5, 42.9,
42.8, 41.4, 34.2, 18.3, 15.3. HRMS (TOF MS ES+) calcd for
C
17H26NO2 (M+H)+: 276.1964; found: 276.1964.

M. R. Iyer et al. / Bioorg. Med. Chem. 21 (2013) 3298–3309
3305
5.1.25. 3-Bromo-4-(2,5-dimethoxyphenyl)-1-methyl-4-
propylpiperidine (6h)
(s, 3H), 3.12 (d, J = 13.2 Hz, 1H), 2.98 (d, J = 10.5 Hz, 1H), 2.92 (d,
J = 13.3 Hz, 1H), 2.51 (s, 1H), 2.43 (d, J = 11.1 Hz, 4H), 2.12 (s, 2H),
1.97–1.94 (m, 2H), 1.24 (dd, J = 14.8, 7.4 Hz, 2H), 1.10 (t,
J = 6.0 Hz, 1H), 0.85 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CD3OD):
d 153.0, 152.5, 136.1, 115.5, 111.8, 110.0, 58.6, 58.5, 55.8, 55.4,
51.1, 46.1, 44.3, 31.1, 31.0, 27.3, 23.2, 13.9. Using general proce-
dure B, 10.4 g of 5i was converted to 6i (6.0 g, 48%). HRMS (TOF
MS ES+) calcd for C18H29NBrO2 (M+H)+: 370.1382; found:
370.1393. Anal. Calcd for (C18H28NBrO2Á0.5H2O): C, 56.99; H,
7.71; N, 3.69; found: C, 57.27; H, 7.43; N, 3.53.
Using general procedure B, 4.0 g of 5h was converted to 6h
(2.5 g, 48%). Mp 120–124 °C; 1H NMR (500 MHz, CDCl3): d 6.79
(d, J = 8.8 Hz, 1H), 6.72 (dd, J = 8.8, 2.8 Hz, 1H), 6.66 (s, 1H), 5.44
(s, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.04 (d, J = 13.3 Hz, 1H), 2.87
(dd, J = 33.7, 12.1 Hz, 2H), 2.43 (td, J = 12.9, 2.2 Hz, 1H), 2.36–2.31
(m, 5H), 1.98 (td, J = 12.7, 3.8 Hz, 1H), 1.86 (td, J = 12.5, 3.7 Hz,
2H), 1.07 (t, J = 6.2 Hz, 1H), 0.76 (t, J = 7.2 Hz, 2H), 0.60 (d,
J = 5.5 Hz, 1H). 13C NMR (126 MHz, CD3OD): d 153.2, 152.7, 136.3,
115.7, 112.1, 110.2, 58.6, 56.1, 55.6, 51.3, 46.3, 44.6, 34.0, 27.6,
18.6, 14.8. HRMS (TOF MS ES+) calcd for C17H27NBrO2 (M+H)+:
356.1225; found: 356.1222. Anal. Calcd for (C17H26NBrO2): C,
57.31; H, 7.36; N, 3.93; found: C, 57.39; H, 7.61; N, 3.90.
5.1.30. 4a-Butyl-2-methyl-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (2i)
Using general procedure C and D, 12.75 g of 6i was converted to
2i (13.4 g, 76%). Mp 176 °C; 1H NMR (500 MHz, CDCl3): d 6.63 (d,
J = 9.1 Hz, 1H), 6.57 (dd, J = 7.0, 2.2 Hz, 2H), 4.45 (t, J = 6.0 Hz,
1H), 2.81–2.79 (m, 1H), 2.48 (t, J = 5.5 Hz, 1H), 2.36 (s, 1H), 2.28
(s, 3H), 2.16 (t, J = 9.0 Hz, 1H), 1.98 (ddd, J = 10.4, 6.3, 3.4 Hz, 1H),
1.83–1.81 (m, 1H), 1.63–1.61 (m, 1H), 1.48 (t, J = 3.2 Hz, 1H), 1.21
(ddd, J = 7.0, 5.8, 5.1 Hz, 4H), 0.85–0.82 (m, 3H). 13C NMR
(126 MHz, CDCl3): d 152.4, 150.6, 135.2, 114.5, 111.5, 111.0,
110.7, 84.5, 56.3, 51.9, 45.8, 45.7, 39.2, 32.6, 26.3, 23.4, 14.1. HRMS
(TOF MS ES+) calcd for C16H24NO2 (M+H)+: 262.1807; found:
262.1815. Anal. Calcd for (C16H23NO2): C, 73.53; H, 8.87; N, 5.36;
found: C, 73.23; H, 8.90; N, 5.40.
5.1.26. 2-(3-Bromo-3-propyl-1-methylpiperidin-4-yl)benzene-
1,4-diol (7h)
Using general procedure C, 2.5 g of 6h was converted to 7h
(2.0 g, 87%). 1H NMR (500 MHz, CD3OD): d 6.56 (d, J = 8.4 Hz, 1H),
6.51 (d, J = 8.5 Hz, 1H), 6.41 (s, 1H), 5.89 (s, 1H), 3.98 (d,
J = 14.2 Hz, 1H), 3.73 (d, J = 14.2 Hz, 1H), 3.50 (d, J = 12.5 Hz, 1H),
3.37 (t, J = 13.2 Hz, 1H), 2.96 (s, 3H), 2.43 (t, J = 13.8 Hz, 1H), 2.29
(t, J = 12.7 Hz, 1H), 2.17 (d, J = 14.8 Hz, 1H), 1.96–1.91 (m, 1H),
1.12 (t, J = 6.0 Hz, 1H), 0.80 (t, J = 6.9 Hz, 3H), 0.73–0.69 (m, 1H).
13C NMR (126 MHz, CD3OD): d 150.7, 149.8, 132.1, 117.6, 115.6,
115.1, 57.9, 55.2, 51.9, 44.7, 44.1, 33.5, 26.5, 19.9, 14.8. HRMS
(TOF MS ES+) calcd for C15H23NBr79O2 (M+H)+: 328.0912; found:
328.0875. Anal. Calcd for (C15H22NBrO2ÁHBr): C, 44.03; H, 5.67; N,
3.42; found: C, 44.15; H, 5.79; N, 3.35.
5.1.31. 4-Pentyl-4-(2,5-dimethoxyphenyl)-1-methyl-1,2,3,4-
tetrahydropyridine (5j)
Using general procedure A, 10.0 g of 4 was converted to 5j
(9.0 g, 69%). 1H NMR (500 MHz, CDCl3): d 7.06 (d, J = 3.1 Hz, 1H),
6.80 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 3.1 Hz, 1H), 5.95 (d, J = 8.0 Hz,
1H), 4.70–4.69 (m, 1H), 3.81 (s, 6H), 2.78–2.76 (m, 1H), 2.59 (s,
3H), 2.52 (t, J = 13.4 Hz, 3H), 2.22 (d, J = 4.4 Hz, 2H), 1.90 (d,
J = 7.1 Hz, 2H), 1.64–1.59 (m, 1H), 1.45 (d, J = 7.1 Hz, 1H), 0.85 (t,
J = 7.0 Hz, 5H). 13C NMR (126 MHz, CD3OD): d 152.8, 152.0, 138.2,
136.1, 119.8, 114.7, 111.9, 109.9, 105.1, 55.58, 55.56, 47.1, 42.5,
41.0, 40.0, 33.8, 32.7, 32.6, 30.4, 24.3, 22.6, 22.0, 14.19, 14.00.
HRMS (TOF MS ES+) calcd for C19H30NO2 (M+H)+: 304.2277; found:
304.2273. Anal. Calcd for (C19H29NO2Á0.5H2O): C, 73.04; H, 9.68; N,
4.48; found: C, 73.07; H, 9.56; N, 4.27.
5.1.27. 2-Methyl-4a-propyl-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (2h)
Using general procedure D, 0.7 g of 7h was converted to 2h
(0.4 g, 76%). Mp 179 °C; 1H NMR (500 MHz, CDCl3): d 6.57 (q,
J = 8.1 Hz, 3H), 4.39 (t, J = 5.9 Hz, 1H), 2.75 (dd, J = 12.4, 5.2 Hz,
1H), 2.49–2.46 (m, 1H), 2.35 (dd, J = 12.4, 6.7 Hz, 1H), 2.24 (s,
3H), 2.19–2.14 (m, 1H), 2.03–2.00 (m, 1H), 1.80 (td, J = 9.4,
4.5 Hz, 1H), 1.65 (td, J = 12.9, 4.7 Hz, 1H), 1.51 (td, J = 12.8,
4.4 Hz, 1H), 1.27 (ddd, J = 25.4, 12.9, 6.4 Hz, 2H), 0.88 (t,
J = 7.3 Hz, 3H). 13C NMR (126 MHz, CD3OD): d 153.1, 152.7, 136.0,
115.1, 111.4, 111.3, 85.3, 57.1, 52.7, 49.5, 48.5, 46.7, 46.2, 42.6,
41.4, 37.2, 36.8, 33.9, 33.77, 33.75, 29.0, 18.4, 15.0. HRMS (TOF
MS ES+) calcd for C15H22NO2 (M+H)+: 248.1651; found: 248.1655.
Anal. Calcd for (C15H21NO2): C, 72.84; H, 8.56; N, 5.66; found: C,
72.82; H, 8.53; N, 5.62.
5.1.32. 3-Bromo-4-pentyl-4-(2,5-dimethoxyphenyl)-1-
methylpiperidine (6j)
Using general procedure B, 9.0 g of 5j was converted to 6j (4.5 g,
39%). Mp 219 °C; 1H NMR (500 MHz, CD3OD): d 6.77 (d, J = 8.8 Hz,
1H), 6.72–6.69 (m, 1H), 6.65 (d, J = 2.0 Hz, 1H), 5.43 (s, 1H), 3.80 (s,
3H), 3.75 (s, 3H), 3.02 (d, J = 13.4 Hz, 1H), 2.89 (d, J = 11.1 Hz, 1H),
2.83–2.80 (m, 1H), 2.40 (dd, J = 12.8, 2.8 Hz, 1H), 2.34 (s, 3H), 2.30
(d, J = 12.5 Hz, 1H), 2.03–1.99 (m, 2H), 1.86 (dd, J = 12.4, 3.6 Hz,
2H), 1.15–1.02 (m, 5H), 0.76 (t, J = 6.9 Hz, 3H). 13C NMR
(126 MHz, CD3OD): d 153.1, 152.6, 136.2, 115.6, 111.9, 110.1,
58.7, 58.5, 55.9, 55.5, 51.2, 46.2, 44.4, 32.4, 31.3, 27.5, 24.8, 22.4,
14.1. HRMS (TOF MS ES+) calcd for C19H31NBr79O2 (M+H)+:
384.1538; found: 384.1537. Anal. Calcd for (C19H30NBrO2Á0.5H2O):
C, 58.01; H, 7.94; N, 3.56; found: C, 58.29; H, 8.03; N, 3.49.
5.1.28. 4-Butyl-4-(2,5-dimethoxyphenyl)-1-methyl-1,2,3,4-
tetrahydropyridine (5i)
Using general procedure A, 8.5 g of 4 was converted to 5i (9.0 g,
82%). 1H NMR (500 MHz, CDCl3): d 7.04 (d, J = 3.0 Hz, 1H), 6.79 (d,
J = 8.7 Hz, 1H), 6.70 (dd, J = 8.7, 3.1 Hz, 1H), 5.94 (d, J = 8.0 Hz, 1H),
4.68 (d, J = 8.0 Hz, 1H), 3.79 (d, J = 6.6 Hz, 6H), 2.77–2.75 (m, 1H),
2.57 (s, 3H), 2.54–2.48 (m, 2H), 2.22 (dt, J = 12.5, 6.3 Hz, 1H),
1.92–1.87 (m, 1H), 1.62 (dt, J = 12.6, 6.4 Hz, 1H), 1.24–1.20 (m,
4H), 0.83 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3): d 152.8,
152.0, 138.2, 136.2, 119.8, 112.0, 109.9, 105.8, 105.1, 55.62,
55.59, 47.2, 42.5, 41.0, 39.8, 33.8, 26.9, 23.5, 14.2. HRMS (TOF MS
ES+) calcd for C18H28NO2 (M+H)+: 290.2120; found: 290.2104. Anal.
Calcd for (C18H27NO2): C, 74.70; H, 9.40; N, 4.84; found: C, 74.46; H,
9.57; N, 4.48.
5.1.33. 4a-Pentyl-2-methyl-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (2j)
Using general procedure C and D, 4.5 g of 6j was converted to 2j
(1.5 g, 47%). Mp 185–188 °C; 1H NMR (500 MHz, CDCl3): d 6.57 (q,
J = 8.2 Hz, 3H), 4.39 (t, J = 5.9 Hz, 1H), 4.39 (t, J = 5.9 Hz, 1H), 2.75
(dd, J = 12.4, 5.1 Hz, 1H), 2.49–2.46 (m, 1H), 2.36 (dd, J = 12.4,
6.7 Hz, 1H), 2.25 (s, 3H), 2.17 (td, J = 10.4, 2.9 Hz, 1H), 2.02 (ddd,
J = 14.2, 6.3, 3.4 Hz, 1H), 1.80 (td, J = 9.4, 4.5 Hz, 1H), 1.67–1.64
(m, 1H), 1.54 (d, J = 11.6 Hz, 1H), 1.27 (dt, J = 24.2, 5.1 Hz, 5H),
0.87 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CD3OD): d 153.0,
5.1.29. 3-Bromo-4-butyl-4-(2,5-dimethoxyphenyl)-1-
methylpiperidine (6i)
Using general procedure B, 10.4 g of 5i was converted to 6i
(6.0 g, 48%). 1H NMR (500 MHz, CDCl3): d 6.88 (d, J = 8.7 Hz, 1H),
6.81 (d, J = 8.7 Hz, 1H), 6.75 (s, 1H), 5.53 (s, 1H), 3.90 (s, 3H), 3.84

3306
M. R. Iyer et al. / Bioorg. Med. Chem. 21 (2013) 3298–3309
152.6, 135.9, 115.1, 111.34, 111.27, 85.3, 57.0, 52.7, 49.5, 48.4,
46.6, 46.19, 46.16, 40.0, 33.7, 33.5, 24.8, 23.5, 14.3. HRMS (TOF
MS ES+) calcd for C17H26NO2 (M+H)+: 276.1964; found: 276.1951.
Anal. Calcd for (C17H25NO2): C, 74.14; H, 9.15; N, 5.09; found: C,
73.89; H, 9.12; N, 5.02.
57.1, 46.9, 46.2, 42.79, 33.7, 30.8; HRMS (TOF MS ES+) calcd for
20H23NFO2 (M+H)+: 328.1713; found: 328.1702. Anal. Calcd for
(C20H22FNO2.0.25H2O): C, 72.37; H, 6.83; N, 4.22; found: C,
72.61; H, 6.89; N, 4.28.
C
5.1.38. 4-(2,5-Dimethoxyphenyl)-4-(2-fluorophenethyl)-1-
methyl-1,2,3,4-tetrahydropyridine (5l)
5.1.34. 4-(2,5-Dimethoxyphenyl)-4-(4-fluorophenethyl)-1-
methyl-1,2,3,4-tetrahydropyridine (5k)
Using general procedure A, 12.75 g of 4 was converted to 5l
(13.4 g, 76%). 1H NMR (500 MHz, CDCl3): d 7.12–7.08 (m, 3H),
6.98 (dt, J = 25.8, 8.3 Hz, 2H), 6.80 (d, J = 8.7 Hz, 1H), 6.73 (dd,
J = 8.7, 3.1 Hz, 1H), 6.00 (d, J = 8.0 Hz, 1H), 4.78 (dd, J = 8.0, 1.0 Hz,
1H), 3.81 (s, 3H), 3.80 (s, 3H), 2.77 (dt, J = 7.2, 3.7 Hz, 1H), 2.60
(d, J = 8.1 Hz, 4H), 2.55–2.46 (m, 3H), 2.23 (td, J = 12.7, 4.3 Hz,
1H), 1.96–1.86 (m, 2H). 13C NMR (126 MHz, CD3OD): d 162.1,
160.2, 152.9, 152.0, 137.2, 136.6, 130.69, 130.65, 130.5, 130.4,
127.1, 127.0, 123.84, 123.81, 120.0, 115.2, 115.0, 111.7, 110.5,
110.3, 104.0, 55.7, 55.4, 47.0. HRMS (TOF MS ES+) calcd for
Using general procedure A, 12.75 g of 4 was converted to 5k
(13.4 g, 76%). 1H NMR (500 MHz, CDCl3): d 7.12 (d, J = 3.1 Hz, 1H),
7.05 (dd, J = 8.3, 5.7 Hz, 2H), 6.92 (t, J = 8.7 Hz, 2H), 6.81 (d,
J = 8.8 Hz, 1H), 6.74 (dd, J = 8.7, 3.1 Hz, 1H), 6.01 (d, J = 8.0 Hz,
1H), 4.74 (dd, J = 8.0, 1.3 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 2.78
(dt, J = 7.5, 3.6 Hz, 1H), 2.62–2.58 (m, 3H), 2.58–2.52 (m, 3H),
2.52–2.43 (m, 1H), 2.18 (td, J = 12.9, 4.4 Hz, 1H), 1.92 (dtd,
J = 17.2, 12.8, 4.1 Hz, 2H). 13C NMR (126 MHz, CD3OD): d 162.0,
160.1, 152.9, 151.9, 139.31, 139.29, 137.3, 136.6, 129.7, 129.6,
120.0, 114.9, 114.77, 111.8, 110.2, 104.0, 55.6, 55.4, 47.0, 42.5,
42.3, 41.1, 33.9, 30.6. HRMS (TOF MS ES+) calcd for C22H27FNO2
(M+H)+: 356.2026; found: 356.2024. Anal. Calcd for
(C22H26FNO2Á0.25H2O): C, 73.41; H, 7.42; N, 3.89; found: C,
73.36; H, 7.30; N, 3.73.
C
22H27FNO2 (M+H)+: 356.2026; found: 356.2024. Anal. Calcd for
(C22H26FNO2Á0.25H2O): C, 73.41; H, 7.42; N, 3.89; found: C,
73.36; H, 7.30; N, 3.73.
5.1.39. 3-Bromo-4-(2,5-dimethoxyphenyl)-4-(2-
fluorophenethyl)-1-methylpiperidine (6l)
5.1.35. 3-Bromo-4-(2,5-dimethoxyphenyl)-4-(4-
fluorophenethyl)-1-methylpiperidine (6k)
Using general procedure B, 12.75 g of 5l was converted to 6l
(13.4 g, 76%). Mp °C; IR (neat) 2941 cmÀ1
;
1H NMR (CDCl3,
Using general procedure B, 12.75 g of 5k was converted to 6k
500 MHz) d 7.13 (q, 1H, J = 7.0 Hz), 6.99 (m, 2H), 6.85 (d, 2H,
J = 8.5 Hz), 6.77 (m, 2H), 5.43 (s, 1H), 3.84 (s, 3H), 3.78 (s, 3H),
3.03 (d, 1H, J = 13.5 Hz), 2.98 (d, 1H, J = 11.0 Hz), 2.79 (d, 1H,
J = 13.5 Hz), 2.56 (dt, 1H, J = 3.5 and 12.5 Hz), 2.43 (m, 2H), 2.38
(m, 1H), 2.33 (s, 3H), 2.22 (dd, 1H, J = 2.5 and 9.0 Hz), 2.00 (d, 1H,
J = 13.0 Hz), 1.93 (t, 1H, J = 9.0 Hz); 13C NMR (CDCl3, 126 MHz) d
162.0, 160.1, 153.3, 152.7, 135.4, 130.7, 130.6, 129.5, 129.4,
127.64, 127.58, 124.1, 124.0, 115.8, 115.4, 115.2, 111.9, 110.6,
110.5, 58.4, 58.2, 55.9, 55.6, 51.2, 46.2, 44.6, 32.3, 27.5,
25.6,153.23, 152.53, 142.56, 135.52, 128.34 (2C), 128.24 (2C),
125.74, 115.67, 111.92, 110.42, 58.36, 58.15, 55.90, 55.53, 51.12,
46.10, 44.55, 33.76, 31.97, 27.45; HRMS (TOF MS ES+) calcd for
(13.4 g, 76%). IR (neat) 2941 cmÀ1 1H NMR (500 MHz, CDCl3) d
;
6.86 (m, 4H), 6.77 (d, 1H, J = 8.5 Hz), 6.68 (m, 2H), 5.35 (s, 1H),
3.72 (s, 3H), 3.70 (s, 3H), 2.96 (d, 1H, J = 13.0 Hz), 2.94 (d, 1H,
J = 11.0 Hz), 2.73 (d, 1H, J = 13.5 Hz), 2.46 (dt, 1H, J = 3.0 and
13.0 Hz), 2.34 (m, 2H), 2.28 (s, 3H), 2.22 (m, 1H), 2.11 (dt, 1H,
J = 4.5 and 12.5 Hz), 1.88 (d, 1H, J = 13.0 Hz), 1.81 (dt, 1H, J = 3.0
and 11.5 Hz); 13C NMR (126 MHz, CDCl3) d 162.2, 160.3, 153.3,
152.6, 138.22, 138.20, 135.5, 129.7, 129.6, 115.8, 115.2, 115.0,
112.0, 110.5, 58.4, 58.1, 56.0, 55.6, 51.2, 46.2, 44.6, 33.1, 31.3,
27.5; HRMS (TOF MS ES+) calcd for C22H28NFBrO2 (M+H)+:
436.1287; found: 436.1288. Anal. Calcd for (C22H27NBrFO2): C,
60.55; H, 6.24; N, 3.21; found: C, 60.59; H, 6.24; N, 3.26.
C
22H28NFBr9O2 (M+H)+: 436.1287; found: 436.1288. Anal. Calcd
for (C22H27NBrFO2): C, 60.55; H, 6.24; N, 3.21; found: C, 60.59; H,
6.24; N, 3.26.
5.1.36. 2-(3-Bromo-4-(4-fluorophenethyl)-1-methylpiperidin-
4-yl)benzene-1,4-diol (7k)
Using general procedure C, 12.75 g of 6k was converted to 7k
(13.4 g, 76%). 1H NMR (500 MHz, CDCl3): d 7.07 (t, J = 6.8 Hz, 2H),
6.92 (t, J = 8.7 Hz, 3H), 6.67 (d, J = 8.5 Hz, 1H), 6.62–6.60 (m, 1H),
6.53 (s, 1H), 5.92 (s, 1H), 4.01–3.98 (m, 1H), 3.76 (d, J = 14.0 Hz,
1H), 3.59–3.56 (m, 1H), 3.50–3.45 (m, 1H), 3.00 (s, 3H), 2.69–2.65
(m, 1H), 2.59–2.54 (m, 1H), 2.42 (d, J = 4.9 Hz, 1H), 2.31 (s, 1H),
2.04 (dd, J = 11.7, 2.0 Hz, 1H). 13C NMR (126 MHz, CD3OD): d
163.6, 161.7, 150.9, 149.8, 139.12, 139.10, 131.6, 131.1, 131.0,
117.7, 115.9, 115.8, 115.7, 115.5, 108.3, 107.9, 57.9, 54.9, 51.8,
49.5, 49.3, 48.5, 44.9, 44.1, 33.4, 32.3, 26.4. HRMS (TOF MS ES+)
calcd for C20H22FBrNO2 (M+H)+: 406.0818; found: 406.0798. Anal.
Calcd for (C20H21FBrNO2.HBr): C, 49.10; H, 4.94; N, 2.86; found:
C, 48.89; H, 4.86; N, 2.88.
5.1.40. 2-(3-Bromo-4-(2-fluorophenethyl)-1-methylpiperidin-4-
yl)benzene-1,4-diol (7l)
Using general procedure C, 12.75 g of 6l was converted to 7l
(13.4 g, 76%). 1H NMR (500 MHz, CDCl3): d 7.08 (s, 1H), 6.96 (d,
J = 6.1 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.62 (t, J = 5.8 Hz, 2H), 6.56
(t, J = 1.8 Hz, 1H), 6.50 (s, 1H), 5.87–5.86 (m, 1H), 3.94 (d,
J = 12.7 Hz, 1H), 3.72–3.69 (m, 1H), 3.57 (d, J = 0.7 Hz, 1H), 3.38
(t, J = 1.8 Hz, 1H), 3.16 (d, J = 1.0 Hz, 2H), 2.95 (s, 3H), 2.65–2.64
(m, 1H), 2.54 (d, J = 1.4 Hz, 1H), 2.40–2.39 (m, 1H), 2.31–2.28 (m,
1H), 2.18 (s, 1H), 1.97 (d, J = 0.7 Hz, 1H). 13C NMR (126 MHz,
CD3OD): d 163.0, 161.05, 161.04, 150.6, 149.8, 131.73, 131.70,
131.1, 129.7, 129.5, 128.8, 128.7, 125.08, 125.05, 117.5, 115.9,
115.7, 115.5, 115.4, 107.70, 57.8, 54.6, 51.7, 49.29, 49.1, 49.0,
48.8, 48.69, 48.65, 48.6, 48.52, 48.49, 48.33, 48.28, 44.6, 44.21,
44.19, 31.7, 26.2, 26.1. HRMS (TOF MS ES+) calcd for C20H24FBrNO2
(M+H)+: 406.0818; found: 406.0798. Anal. Calcd for
(C20H23FBrNO2Á1.5HBr): C, 45.35; H, 4.66; N, 2.64; found: C,
45.57; H, 4.76; N, 2.70.
5.1.37. 4a-(4-Fluorophenethyl)-2-methyl-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (2k)
Using general procedure D, 12.75 g of 7k was converted to 2k
(13.4 g, 76%). Mp 207–210 °C; IR (neat) 3055 cmÀ1
;
1H NMR
(500 MHz, CD3OD)
d 7.13 (t, 2H, J = 8.0 Hz), 6.95 (d, 2H,
J = 8.5 Hz), 6.66 (s, 1H), 6.60 (m, 2H), 4.49 (t, 1H, J = 5.5 Hz), 2.83
(dd, 1H, J = 5.0 and 12.5 Hz), 2.58 (m, 3H), 2.35 (dd, 1H, J = 7.0
and 12.5 Hz), 2.26 (s, 3H), 2.15 (dt, 1H, J = 2.5 and 11.0 Hz), 2.09
(m, 1H), 1.94 (dt, 1H, J = 5.0 and 13.5 Hz), 1.76–1.86 (m, 2H); 13C
NMR (126 MHz, CD3OD) d 153.2, 152.9, 139.47, 139.45, 135.3,
130.84, 130.77, 125.4, 116.0, 115.8, 115.4, 111.5, 111.4, 85.1,
5.1.41. 4a-(2-Fluorophenethyl)-2-methyl-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (2l)
Using general procedure D, 12.75 g of 7l was converted to 2l
(13.4 g, 76%). Mp 218–221 °C; IR (neat) 3055 cmÀ1
;
1H NMR
(500 MHz, CD3OD)
d 7.17 (t, 2H, J = 6.5 Hz), 7.06 (t, 1H,
J = 7.0 Hz), 6.99 (t, 1H, J = 9.0 Hz), 6.68 (s, 1H), 6.61 (m, 2H), 4.51

M. R. Iyer et al. / Bioorg. Med. Chem. 21 (2013) 3298–3309
3307
(t, 1H, J = 6.0 Hz), 2.81 (dd, 1H, J = 4.5 and 11.5 Hz), 2.62 (dt, 1H,
J = 5.0 and 13.0 Hz), 2.53 (m, 2H), 2.40 (dd, 1H, J = 6.5 and
11.5 Hz), 2.26 (s, 3H), 2.16 (m, 1H), 2.09 (m, 1H), 1.94 (dt, 1H,
J = 5.0 and 13.0 Hz), 1.76–1.87 (m, 2H); 13C NMR (126 MHz,
CD3OD) d 152.9, 152.5, 134.9, 131.4, 131.3, 129.8, 128.61, 128.55,
125.04, 125.01, 116.0, 115.8, 115.3, 111.4, 111.3, 107.6, 84.8,
56.9, 52.5, 46.6, 46.2, 35.6, 24.8; HRMS (TOF MS ES+) calcd for
1H), 1.99 (td, J = 13.1, 5.0 Hz, 1H), 1.90–1.80 (m, 1H), 1.65–1.56
(m, 3H). 13C NMR (126 MHz, CD3OD): d 153.1, 150.0, 142.2,
140.3, 134.7, 128.8, 128.56, 128.54, 128.4, 126.2, 126.0, 114.7,
110.9, 84.9, 60.6, 54.7, 49.9, 46.7, 42.1, 33.6, 32.9, 30.6. HRMS
(TOF MS ES+) calcd for C27H30NO2 (M+H)+: 400.2277; found:
400.2271. Anal. Calcd for (C27H29NO2Á0.5H2O): C, 79.38; H, 7.40;
N, 3.43; found: C, 79.31; H, 7.34; N, 3.60.
C
20H23NFO2 (M+H)+: 328.1713; found: 328.1702. Anal. Calcd for
(C20H22FNO2Á0.1H2O): C, 72.97; H, 6.79; N, 4.25; found: C, 72.84;
5.1.45. 4a-Phenethyl-2-(3-phenylpropyl)-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (3b)
H, 6.72; N, 4.19.
Using general procedure E, 9 (50 mg, 0.17 mmol) was converted
to 3b (27 mg, 39%). Mp 137–141 °C; 1H NMR (500 MHz, CDCl3): d
7.18–7.05 (m, 8H), 6.97 (d, J = 7.4 Hz, 2H), 6.58 (d, J = 8.4 Hz, 1H),
6.54 (d, J = 2.2 Hz, 1H), 6.49 (dd, J = 8.4, 2.3 Hz, 1H), 4.47 (t,
J = 6.6 Hz, 1H), 2.85 (dd, J = 12.0, 5.6 Hz, 1H), 2.48 (dq, J = 25.9,
6.7 Hz, 4H), 2.37 (td, J = 13.0, 4.4 Hz, 1H), 2.29 (d, J = 4.6 Hz, 2H),
2.19 (dd, J = 12.0, 7.6 Hz, 1H), 2.04–1.97 (m, 2H), 1.75 (m, 6H).
13C NMR (126 MHz, CDCl3): d 152.7, 150.5, 142.2, 141.9, 134.3,
128.5, 128.4, 126.0, 125.9, 114.9, 111.1, 110.9, 84.6, 58.0, 54.6,
49.9, 46.7, 42.3, 33.8, 32.1, 30.5, 28.2. HRMS (TOF MS ES+) calcd
for C28H32NO2 (M+H)+: 414.2433; found: 414.2457. Anal. Calcd
for (C28H31NO2): C, 81.32; H, 7.56; N, 3.39; found: C, 81.41; H,
7.56; N, 3.35.
5.1.42. 2-Methyl-4a-phenethyl-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-yl acetate (8)
Compound 2a was treated with acetic anhydride (10 mL) and
heated to reflux. After completion of the reaction the acetic anhy-
dride was evaporated off to give a sticky solid. This solid was ap-
plied to silica-gel column and the desired product was eluted
using 75% EtOAc in hexanes to give a sticky solid 8. 1H NMR
(500 MHz, CDCl3): d 7.26 (t, J = 7.0 Hz, 2H), 7.18 (d, J = 6.8 Hz,
1H), 7.12 (d, J = 6.8 Hz, 2H), 6.88–6.81 (m, 3H), 4.59 (d, J = 4.7 Hz,
1H), 2.80 (t, J = 6.1 Hz, 1H), 2.58–2.53 (m, 2H), 2.43 (dt, J = 13.8,
6.4 Hz, 2H), 2.29 (d, J = 7.1 Hz, 6H), 2.19 (t, J = 10.2 Hz, 1H), 2.10
(d, J = 14.5 Hz, 1H), 2.04–1.96 (m, 1H), 1.91–1.85 (m, 2H). 13C
NMR (126 MHz, CD3OD): d 170.0, 156.5, 144.7, 142.0, 134.7,
128.5, 128.3, 126.0, 121.1, 116.6, 110.9, 85.2, 56.5, 56.4, 51.85,
51.83, 46.3, 45.8, 41.3, 33.20, 33.18, 33.1, 30.6, 21.3. HRMS (TOF
MS ES+) calcd for C22H26NO3 (M+H)+: 352.1913; found: 352.1901.
Anal. Calcd for (C22H25NO3): C, 75.19; H, 7.17; N, 3.99; found: C,
74.96; H, 7.35; N, 3.99.
5.1.46. 2-(4-Fluorophenethyl)-4a-phenethyl-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (3c)
Using general procedure E, 9 (50 mg, 0.17 mmol) was converted
to 3c (28 mg, 40%). Mp 194–197 °C; 1H NMR (500 MHz, CDCl3): d
7.26–7.23 (m, 3H), 7.16 (s, 1H), 7.11 (dd, J = 12.2, 6.4 Hz, 3H),
6.95 (t, J = 8.7 Hz, 2H), 6.71–6.62 (m, 3H), 4.56 (t, J = 6.2 Hz, 1H),
2.96 (dd, J = 11.4, 5.7 Hz, 1H), 2.76 (t, J = 8.1 Hz, 2H), 2.61–2.49
(m, 4H), 2.40 (dd, J = 12.0, 7.2 Hz, 1H), 2.27–2.22 (m, 1H), 2.12
(ddd, J = 13.8, 4.9, 3.5 Hz, 1H), 1.99 (td, J = 13.1, 4.9 Hz, 1H), 1.91–
1.80 (m, 3H). 13C NMR (126 MHz, CD3OD): d 162.5, 160.6, 153.1,
150.1, 142.2, 135.9, 134.6, 130.2, 130.1, 128.5, 128.4, 126.0,
115.4, 115.2, 114.7, 110.9, 110.8, 84.9, 60.5, 54.7, 49.9, 46.6, 42.1,
32.8, 30.6. HRMS (TOF MS ES+) calcd for C27H29NFO2 (M+H)+:
418.2182; found: 418.2163. Anal. Calcd for (C27H28NFO2Á0.5H2O):
C, 77.84; H, 6.81; N, 3.32; found: C, 76.75; H, 6.68; N, 3.40.
5.1.43. 4a-Phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-
c]pyridin-6-ol (9)
Compound 8 was treated with Troc-Cl and proton sponge in
dichloroethane and stirred overnight. After completion of the reac-
tion, the organic layer was evaporated and the reaction mixture
was taken in water and treated with 1 M HCl (1 mL). The organic
layer was then extracted with ethyl acetate (20 mL), dried over
Na2SO4 and solvent evaporated to give a pale yellow oil. The com-
pound was dissolved in MeOH and H2O (1:1) and treated with ex-
cess K2CO3 and stirred for 2 h. The organic layer was then extracted
into CH2Cl2, washed with water and dried over Na2SO4. The organic
layer was then evaporated to give a brown oil. This oil was treated
with AcOH (6 mL) and powdered Zn dust () and stirred for 2 h.
After completion of the reaction, the organic layer was filtered over
cotton and washed with CH2Cl2. The excess AcOH was quenched
with satd. NaHCO3 dried over Na2SO4 and solvent evaporated. This
solid was applied to silica-gel column and the desired product was
eluted using 15% MeOH in CH2Cl2 to give an off-white solid 9. 1H
5.1.47. 2-(2-Fluorophenethyl)-4a-phenethyl-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (3d)
Using general procedure E, 9 (50 mg, 0.17 mmol) was converted
to 3d (32 mg, 42%). Mp 209–213 °C; 1H NMR (500 MHz, CDCl3): d
7.27–7.24 (m, 3H), 7.18 (t, J = 8.0 Hz, 3H), 7.11 (d, J = 7.3 Hz, 2H),
7.03 (dt, J = 24.5, 8.2 Hz, 2H), 6.71 (d, J = 8.4 Hz, 1H), 6.67–6.62
(m, 1H), 4.57 (t, J = 6.2 Hz, 1H), 3.00 (dd, J = 11.6, 5.2 Hz, 1H),
2.84 (t, J = 7.9 Hz, 2H), 2.67–2.56 (m, 4H), 2.50 (td, J = 13.0,
4.6 Hz, 1H), 2.41 (dd, J = 11.8, 7.3 Hz, 1H), 2.29–2.25 (m, 1H),
2.15–2.12 (m, 1H), 1.99 (td, J = 13.1, 5.0 Hz, 1H), 1.92–1.80 (m,
3H). 13C NMR (126 MHz, CD3OD): d 162.3, 160.3, 160.2, 153.1,
150.1, 142.2, 134.6, 131.1, 128.5, 128.0, 126.0, 124.2, 115.5,
115.3, 114.7, 110.94, 110.85, 110.6, 84.9, 58.8, 54.58, 49.8, 46.7,
42.2, 32.8, 30.6, 26.8. HRMS (TOF MS ES+) calcd for C27H29NFO2
(M+H)+: 418.2182; found: 418.2163. Anal. Calcd for (C27H28NFO2):
C, 77.67; H, 6.76; N, 3.35; found: C, 77.41; H, 6.68; N, 3.32.
NMR (500 MHz, CDCl3):
d 7.21 (t, J = 7.4 Hz, 2H), 7.10 (t,
J = 8.9 Hz, 3H), 6.65–6.58 (m, 3H), 4.37 (t, J = 5.1 Hz, 1H), 3.07
(dd, J = 13.7, 4.6 Hz, 1H), 2.79 (dd, J = 13.5, 5.7 Hz, 2H), 2.56 (dt,
J = 11.7, 5.4 Hz, 2H), 2.45 (td, J = 12.8, 4.4 Hz, 1H), 1.99–1.89 (m,
3H), 1.79 (dtd, J = 31.2, 11.3, 4.5 Hz, 2H). 13C NMR (126 MHz,
CD3OD):
d 153.5, 152.9, 143.6, 135.8, 129.4, 129.3, 126.82,
126.80, 115.4, 111.4, 84.7, 49.5, 49.4, 49.2, 49.0, 48.8, 48.7, 48.5,
47.8, 46.8, 42.6, 42.4, 34.2, 31.6. HRMS (TOF MS ES+) calcd for
C
19H22NO2 (M+H)+: 296.1651; found: 296.1651.
5.1.48. 4a-Phenethyl-2-(4-(trifluoromethyl)phenethyl)-
5.1.44. 2,4a-Diphenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-
c]pyridin-6-ol (3a)
1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (3e)
Using general procedure E, 9 (50 mg, 0.17 mmol) was converted
to 3e (32 mg, 40%). Mp 163–166 °C; 1H NMR (500 MHz, CDCl3): d
7.52 (d, J = 7.9 Hz, 2H), 7.25 (q, J = 8.7 Hz, 5H), 7.16 (t, J = 7.3 Hz,
1H), 7.10 (d, J = 7.3 Hz, 2H), 6.71–6.61 (m, 2H), 4.56 (t, J = 5.8 Hz,
1H), 2.99–2.96 (m, 1H), 2.84 (d, J = 7.7 Hz, 2H), 2.58 (dt, J = 14.0,
7.4 Hz, 4H), 2.52–2.42 (m, 2H), 2.26 (t, J = 9.2 Hz, 1H), 2.13–2.10
(m, 1H), 1.98 (td, J = 13.0, 5.0 Hz, 1H), 1.91–1.80 (m, 3H). 13C
Using general procedure E, 9 (50 mg, 0.17 mmol) was converted
to 3a (38 mg, 56%). Mp 205–208 °C; 1H NMR (500 MHz, CDCl3): d
7.21 (dt, J = 25.8, 8.6 Hz, 8H), 7.10 (d, J = 7.2 Hz, 3H), 6.71–6.61
(m, 2H), 4.77 (d, J = 0.4 Hz, 1H), 4.58–4.56 (m, 1H), 3.00–2.96 (m,
1H), 2.80 (t, J = 7.9 Hz, 2H), 2.62–2.53 (m, 1H), 2.50 (td, J = 13.0,
4.5 Hz, 1H), 2.43–2.41 (m, 1H), 2.27–2.24 (m, 1H), 2.15–2.11 (m,

3308
M. R. Iyer et al. / Bioorg. Med. Chem. 21 (2013) 3298–3309
NMR (126 MHz, CD3OD): d 153.1, 150.2, 142.1, 129.1, 128.6, 128.4,
126.0, 125.5, 114.8, 110.92, 110.86, 84.8, 59.9, 54.53, 54.51, 49.8,
46.7, 42.0, 33.4, 32.7, 30.6. HRMS (TOF MS ES+) calcd for
C
C
1H), 2.19–2.17 (m, 1H), 1.96 (dddd, J = 50.0, 26.9, 13.3, 7.3, 6.1 Hz,
3H). 13C NMR (126 MHz, CD3OD): d 152.8, 150.3, 142.1, 141.0,
134.4, 132.2, 130.9, 130.6, 128.9, 128.5, 128.3, 125.9, 125.5,
123.11, 123.08, 114.8, 110.93, 110.88, 84.6, 59.9, 54.5, 49.8, 46.6,
42.0, 33.3, 32.5, 30.5. HRMS (TOF MS ES+) calcd for C28H29NF3O2
(M+H)+: 468.2150; found: 468.2139. Anal. Calcd for (C28H28NF3O2):
C, 71.93; H, 6.04; N, 3.00; found: C, 71.80; H, 6.13; N, 2.93.
28H29NF3O2 (M+H)+: 468.2150; found: 468.2139. Anal. Calcd for
28H28NF3O2: C, 71.93; H, 6.04; N, 3.00; found: C, 72.16; H, 6.22;
N, 3.07.
5.1.49. 2-(Cyclopropylmethyl)-4a-phenethyl-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-6-ol (3f)
5.2. Pharmacology
Using general procedure E, 9 (200 mg, 0.68 mmol) was con-
verted to 3f (90 mg, 38%). Mp 170–173 °C; 1H NMR (500 MHz,
CDCl3): d 7.17 (t, J = 6.8 Hz, 3H), 7.09 (d, J = 7.0 Hz, 1H), 7.02 (d,
J = 6.9 Hz, 2H), 6.60 (dd, J = 26.5, 11.2 Hz, 2H), 4.52 (d, J = 5.8 Hz,
1H), 3.01 (t, J = 5.8 Hz, 1H), 2.65 (d, J = 5.4 Hz, 1H), 2.47 (dd,
J = 38.2, 6.3 Hz, 2H), 2.28–2.14 (m, 4H), 2.06–2.04 (m, 1H), 1.88
(dd, J = 13.4, 4.1 Hz, 2H), 1.75 (dd, J = 12.4, 3.8 Hz, 2H), 0.8 (br s,
1H), 0.5 (d, J = 1.0 Hz, 2H), 0.06 (br s, 2H). 13C NMR (126 MHz,
CD3OD): d 165.5, 152.9, 150.3, 142.2, 136.4, 134.5, 128.5, 128.4,
125.9, 115.9, 114.8, 111.0, 110.9, 84.8, 63.7, 54.6, 50.0, 46.7, 42.2,
32.4, 30.5, 8.2, 4.2. HRMS (TOF MS ES+) calcd for C23H28NO2
(M+H)+: 350.2120; found: 350.2117. Anal. Calcd for
(C23H27NO2Á0.25H2O): C, 78.04; H, 7.83; N, 3.95; found: C, 78.16;
H, 7.95; N, 3.89.
5.2.1. Opioid binding affinity
As previously described,1,11 the recombinant CHO cells (hMOR-
CHO, hDOR-CHO and hKOR-CHO) were produced by stable trans-
fection with the respective human opioid receptor cDNA, and pro-
vided by Dr. Larry Toll (SRI International, CA). The cells were grown
in plastic flasks in DMEM (90%) (hDOR-CHO and hKOR-CHO) or
DMEM/F-12 (45/45%) medium (hMOR-CHO) containing 5% FBS
(Invitrogen), 5% FetalClone II (HyClone), and Geneticin (G-418:
0.10–0.2 mg/ml) (Invitrogen) under 95% air/5% CO2 at 37 °C. Cell
monolayers were harvested and frozen in À80 °C. The hKOR-
CHO, hMOR-CHO and hDOR-CHO cells are used for opioid binding
experiments. For the [35S]-GTP-
c-S binding experiments, we use
hKOR-CHO and hMOR-CHO cells for assaying KOR and MOR recep-
tor function. Currently, we use the NG108-15 neuroblastoma  gli-
5.1.50. 2-Allyl-4a-phenethyl-1,2,3,4,4a,9a-
oma cell for the DOR [35S]-GTP-
c-S binding assay, and obtain an
hexahydrobenzofuro[2,3-c]pyridin-6-ol (3g)
excellent signal-to-noise ratio. In summary, we use the hDOR-
Using general procedure E, 9 (50 mg, 0.17 mmol) was converted
to 3g (22 mg, 39%). Mp 155–158 °C; 1H NMR (500 MHz, CDCl3): d
7.21–7.17 (m, 2H), 7.11 (d, J = 7.0 Hz, 1H), 7.04 (d, J = 7.5 Hz, 3H),
6.64–6.56 (m, 2H), 5.79 (t, J = 8.3 Hz, 1H), 5.12–5.09 (m, 2H), 4.48
(t, J = 6.2 Hz, 1H), 2.93 (t, J = 7.9 Hz, 2H), 2.84 (dd, J = 11.8, 5.3 Hz,
1H), 2.50–2.40 (m, 2H), 2.25 (dd, J = 11.9, 6.9 Hz, 1H), 2.09–2.02
(m, 2H), 1.94–1.88 (m, 2H), 1.82–1.71 (m, 3H). 13C NMR
(126 MHz, CD3OD): d 153.1, 150.1, 142.2, 134.8, 128.5, 128.4,
126.0, 118.5, 114.7, 110.9, 110.8, 84.9, 61.8, 54.5, 49.8, 46.6, 42.0,
32.8, 30.6. HRMS (TOF MS ES+) calcd for C22H26NO2 (M+H)+:
336.1964; found: 336.1962. Anal. Calcd for (C22H25NO2): C,
78.77; H, 7.51; N, 4.18; found: C, 78.88; H, 7.54; N, 4.16.
CHO cells for DOR binding assays, and the NG108-15 cells for the
DOR [35S]-GTP-
c-S binding assay.
As noted formerly,1,12 [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin
([3H]DAMGO, SA = 44–48 Ci/mmol) was used to label MOR,
[3H][D-Ala2,D-Leu5]enkephalin ([3H]DADLE, SA = 40–50 Ci/mmol)
to label DOR and [3H](À)-U69,593 (SA = 50 Ci/mmol) to label KOR
binding sites. On the day of the assay, cell pellets were thawed
on ice for 15 min then homogenized with a polytron in 10 mL/pel-
let of ice-cold 10 mM Tris–HCl, pH 7.4. Membranes were then cen-
trifuged at 30,000Âg for 10 min, resuspended in 10 ml/pellet ice-
cold 10 mM Tris–HCl, pH 7.4 and again centrifuged 30,000Âg for
10 min. Membranes were then resuspended in 25 °C 50 mM Tris–
HCl, pH 7.4 (ꢀ100 mL/pellet hMOR-CHO, 50 mL/pellet hDOR-CHO
and 120 mL/pellet hKOR-CHO). All assays took place in 50 mM
Tris–HCl, pH 7.4, with a protease inhibitor cocktail [bacitracin
5.1.51. 4a-Phenethyl-2-(2-(trifluoromethyl)phenethyl)-
1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (3h)
Using general procedure E, 9 (350 mg, 1.18 mmol) was con-
verted to 3h (210 mg, 38%). Mp 180–183 °C; 1H NMR (500 MHz,
CD3OD): d 7.60 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.31–
7.23 (m, 5H), 7.16 (d, J = 7.3 Hz, 1H), 7.10 (d, J = 7.2 Hz, 2H),
6.71–6.61 (m, 2H), 4.57 (t, J = 6.3 Hz, 1H), 3.01–2.95 (m, 4H),
2.66–2.57 (m, 4H), 2.47 (dt, J = 31.1, 6.2 Hz, 2H), 2.30–2.25 (m,
1H), 2.15–2.12 (m, 1H), 2.02–1.80 (m, 2H). 13C NMR (126 MHz,
CD3OD): d 153.1, 150.1, 142.2, 138.9, 134.6, 131.9, 131.8, 128.5,
128.4, 126.4, 126.14, 126.09, 126.0, 114.7, 111.0, 110.9, 105.8,
84.9, 77.4, 60.3, 54.5, 49.7, 46.7, 42.1, 32.8, 30.6, 30.1. HRMS (TOF
MS ES+) calcd for C28H29NF3O2 (M+H)+: 468.2150; found:
468.2139. Anal. Calcd for (C28H28NF3O2): C, 71.93; H, 6.04; N,
3.00; found: C, 71.65; H, 5.98; N, 2.96.
(100
statin (2
tion curves were made up with buffer containing 1 mg/mL BSA.
Nonspecific binding was determined using 20 M levallorphan
([3H]DAMGO and [3H]DADLE) and
(À)-U69,593 (for
lg/mL), bestatin (10
lg/mL), leupeptin (4 lg/mL) and chymo-
lg/mL)], in a final assay volume of 1.0 mL. All drug dilu-
l
1 lM
[3H]U69,593 binding). [3H]Radioligands were used at ꢀ2 nM con-
centrations. Triplicate samples were filtered with Brandel Cell Har-
vesters (Biomedical Research & Development Inc., Gaithersburg,
MD), over Whatman GF/B filters, after a 2 h incubation at 25 °C.
The filters were punched into 24-well plates to which was added
0.6 mL of LSC-cocktail (Cytoscint). Samples were counted, after
an overnight extraction, in a Trilux liquid scintillation counter at
44% efficiency. Opioid binding assays had ꢀ30
lg protein per assay
tube. Inhibition curves were generated by displacing a single con-
centration of radioligand by 10 concentrations of drug. The pooled
data of three experiments (typically 30 data points) were fit to the
two-parameter logistic equation for the best-fit estimates of the
IC50 and N values: Y = 100/(1+([INHIBITOR]/IC50)N), where ‘Y’ is
the percent of control value. Ki values for test drugs are calculated
according to the standard equation: Ki = IC50/(1+[radioligand]/Kd]).
For the [3H]radioligands, the following Kd values (nM SD, n = 3)
were used in the Ki calculation: [3H]DAMGO (0.93 0.04), [3H]DA-
DLE (1.9 0.3) and [3H](À)-U69,593 (11 0.6).
5.1.52. 4a-Phenethyl-2-(3-(trifluoromethyl)phenethyl)-
1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (3i)
Using general procedure E, 9 (350 mg, 1.18 mmol) was con-
verted to 3i (240 mg, 43%). Mp 168–171 °C; 1H NMR (500 MHz,
CDCl3): d 7.52–7.48 (m, 2H), 7.42 (dt, J = 16.4, 8.0 Hz, 2H), 7.30
(dd, J = 14.2, 6.9 Hz, 3H), 7.22 (d, J = 7.2 Hz, 1H), 7.15 (d,
J = 7.5 Hz, 2H), 6.77–6.67 (m, 2H), 4.63 (t, J = 6.3 Hz, 1H), 3.05
(dd, J = 12.0, 5.4 Hz, 1H), 2.91 (t, J = 8.0 Hz, 2H), 2.67 (dt, J = 16.9,
9.1 Hz, 4H), 2.53 (ddd, J = 38.7, 12.3, 5.9 Hz, 2H), 2.34–2.30 (m,

M. R. Iyer et al. / Bioorg. Med. Chem. 21 (2013) 3298–3309
3309
5.2.2. [35S]GTP-
c-S binding assays
Acknowledgments
As previously described,1,12 the assays were conducted with
minor modifications of published methods.13 In this description,
buffer ‘A’ is 50 mM Tris–HCl, pH 7.4, containing 100 mM NaCl,
This research was supported by the NIH Intramural Research
Programs of the National Institute on Drug Abuse, and the National
Institute of Alcohol Abuse and Alcoholism, NIH, DHHS. We thank
Noel Whittaker and Dr. John Lloyd (Mass Spectrometry Facility,
NIDDK) for the mass spectral data, and Drs. Klaus Gawrisch and
Walter Teague (Laboratory of Membrane Biochemistry and Bio-
physics, NIAAA) for NMR spectroscopic data.
10 mM MgCl2, 1 mM EDTA and buffer ‘B’ is buffer
1.67 mM DTT and 0.15% BSA. On the day of the assay, cells were
thawed on ice for 15 min and homogenized using a polytron in
A plus
50 mM Tris–HCl, pH 7.4, containing 4
l
g/mL leupeptin, 2
lg/mL
chymostatin, 10 g/mL bestatin and 100
l
l
g/mL bacitracin. The
homogenate was centrifuged at 30,000Âg for 10 min at 4 °C, and
the supernatant discarded. The membrane pellets were resus-
References and notes
pended in buffer B and used for [35S]GTP-
c
-S binding assays. Test
tubes received the following additions: 50 L buffer A plus 0.1%
BSA, 50 L GDP in buffer A/0.1% BSA (final concentration = 40 M),
50 L drug in buffer A/0.1% BSA, 50 -S in buffer A/
L [35S]-GTP-
0.1% BSA (final concentration = 50 pM), and 300 L of cell mem-
branes (50 g of protein) in buffer B. The final concentrations of re-
agents in the [35S]GTP-
-S binding assays were: 50 mM Tris–HCl,
pH 7.4, containing 100 mM NaCl, 10 mM MgCl2, 1 mM EDTA,
1 mM DTT, 40 M GDP and 0.1% BSA. Incubations proceeded for
3 h at 25 °C. Nonspecific binding was determined using GTP- -S
(40 -S was separated by vacuum
M). Bound and free [35S]GTP-
1. Li, F.; Deck, J. A.; Dersch, C. M.; Rothman, R. B.; Deschamps, J. R.; Jacobson, A. E.;
Rice, K. C. Eur. J. Med. Chem. 2012, 58, 557.
2. Hutchison, A. J.; de Jesus, R.; Williams, M.; Simke, J. P.; Neale, R. F.; Jackson, R.
H.; Ambrose, F.; Barbaz, B. J.; Sills, M. A. J. Med. Chem. 1989, 32, 2221.
3. Burke, T. R., Jr.; Jacobson, A. E.; Rice, K. C.; Weissman, B. A.; Huang, H. C.;
Silverton, J. V. J. Med. Chem. 1986, 29, 748.
4. Linders, J. T. M.; Mirsadeghi, S.; Flippen-Anderson, J. L.; George, C.; Jacobson, A.
E.; Rice, K. C. Helv. Chim. Acta 2003, 86, 484.
5. Kurimura, M.; Liu, H.; Sulima, A.; Przybyl, A. K.; Ohshima, E.; Kodato, S.;
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A. E.; Rice, K. C. Bioorg. Med. Chem. 2010, 18, 91.
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Chem. Soc. 1980, 102, 5955.
l
l
l
l
l
c
l
l
c
l
c
l
c
filtration (Brandel) through GF/B filters. The filters were punched
into 24-well plates to which was added 0.6 mL LSC-cocktail (Cyto-
scint). Samples were counted, after an overnight extraction, in a
Trilux liquid scintillation counter at 27% efficiency.
For the [35S]GTP- -S binding experiments,1,12 Ke values were
c
determined using the ‘shift’ experimental design, agonist (DAMGO)
dose-response curves were generated, using hMOR-CHO cells, in
the absence and presence (ten points/curve) of a test compound.
The data of several experiments, three or more, were pooled, and
the Ke values were calculated according to the equation: [Test
drug]/(EC50-2/EC50-1 – 1), where EC50-2 is the EC50 value in the pres-
ence of the test drug and EC50-1 is the value in the absence of the
test drug.
11. Fontana, G.; Savona, G.; Rodriguez, B.; Dersch, C. M.; Rothman, R. B.; Prisinzano,
T. E. Tetrahedron 2008, 64, 10041.
12. Iyer, M. R.; Lee, Y. S.; Deschamps, J. R.; Dersch, C. M.; Rothman, R. B.; Jacobson,
A. E.; Rice, K. C. Eur. J. Med. Chem. 2012, 50, 44.
13. Xu, H.; Hashimoto, A.; Rice, K. C.; Jacobson, A. E.; Thomas, J. B.; Carroll, F. I.; Lai,
J.; Rothman, R. B. Synapse 2001, 39, 64.