Probes for narcotic receptor mediated phenomena. 40. N-Substituted cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols

Article abstract of DOI:10.1016/j.bmc.2009.11.022

A series of N-substituted rac-cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols have been prepared using a simple synthetic route previously designed for synthesis of related cis-2-methyl-4a-alkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-o ls. The new phenolic compounds, where the aromatic hydroxy moiety is situated ortho to the oxygen atom in the oxide-bridged ring, do not interact as well as the pyridin-6-ols with opioid receptors. The N-para-fluorophenethyl derivative had the highest μ-opioid receptor affinity of the examined compounds (K_i = 0.35 μM).

Full text of DOI:10.1016/j.bmc.2009.11.022

Bioorganic & Medicinal Chemistry 18 (2010) 91–99
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Probes for narcotic receptor mediated phenomena. 40. N-Substituted
cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols q
Malliga R. Iyer a, Yong Sok Lee b, Jeffrey R. Deschamps c, Richard B. Rothman d, Christina M. Dersch d,
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 Center for Molecular Modeling, Division of Computational Bioscience, CIT, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
c Laboratory for the Structure of Matter, Naval Research Laboratory, Washington, DC 20375, USA
d 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-substituted rac-cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols have
been prepared using a simple synthetic route previously designed for synthesis of related cis-2-
methyl-4a-alkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols. The new phenolic compounds,
where the aromatic hydroxy moiety is situated ortho to the oxygen atom in the oxide-bridged ring, do
not interact as well as the pyridin-6-ols with opioid receptors. The N-para-fluorophenethyl derivative
Received 10 September 2009
Revised 5 November 2009
Accepted 6 November 2009
Available online 18 November 2009
had the highest l-opioid receptor affinity of the examined compounds (Ki = 0.35 lM).
Keywords:
Synthesis
Published by Elsevier Ltd.
Opioid receptor binding
N-substituted cis-4a-ethyl-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-8-ols
Oxide-bridged phenylmorphans
Geometry optimization
Superposition
1. Introduction
hydroxy group is also oriented in a meta-position with respect to the
piperidine ring in the hexahydrobenzofuro[2,3-c]pyridin-6-ols (2,
Fig. 1), and para to the oxygen atom in the dihydrofuran ring of the
epoxymorphinans. In the hexahydrobenzofuro[2,3-c]pyridin-8-ols
(1a–f, Fig. 1), as in the hexahydrobenzofuro[2,3-c]pyridin-6-ols,
the phenolic hydroxyl moiety is meta-oriented to the piperidine ring
and, unlike the pyridin-6-ols, oriented ortho to the oxygen atom in
the dihydrofuran ring. Both the pyridin-6-ols and the pyridin-8-ols
might also be expected to show similar affinity for opioid receptors
if the meta-orientation to the piperidine ring is essential for interac-
tion with opioid receptors. Also, a 7,8-dimethoxy compound in a
hexahydrobenzofuro[2,3-c]pyridine structure (2a, Fig. 1), where
the methoxy groups are meta- and para-oriented to the piperidine
ring and ortho- and meta-oriented to the oxygen in the dihydrofuran
ring, was noted, in a patent by Koelsch in 1957,16,17 to have ‘analge-
sic’ action. Some ostensibly similar C-6 and C-8 hydroxy substituted
Hexahydrobenzofuro[2,3-c]pyridin-8-ols (1a–f, Fig. 1) and hexa-
hydrobenzofuro[2,3-c]pyridin-6-ols1,2 (2, Fig. 1) are partial struc-
tures of the oxide-bridged phenylmorphan class of opioids
(Fig. 1)3–14 and although they appear to be structurally similar to
the d-series of the oxide-bridged phenylmorphans (3a, Fig. 1)1 we
have found that they can assume a conformation that is closer to
morphine than to the oxide-bridged phenylmorphans and that their
l
-opioid affinity and activity is likely to be due to their ability to
attain that conformation.1 Hutchison et al.2 found that N-phenethyl-
and N-cyclopropylmethyl-substituted 1,2,3,4,4a,9a-hexahydro-
benzofuro[2,3-c]pyridin-6-ols, had high affinity for
l-opioid
receptors (Ki = 0.9 and 4 nM, respectively) and were potent antinoci-
ceptives. We have determined that the high affinity of the N-phen-
ethyl analogue was ascribable to the 4aS,9aR enantiomer (Ki =
0.7 nM).1 In most of the well-known epoxymorphinans, morphin-
ans, 6,7-benzomorphans, and 5-phenylmorphans,15 the phenolic
hydroxyl moiety is situated meta to the piperidine ring. The phenolic
oxide-bridged phenylmorphans (3) have been found to be
nists (N-phenethyl substituted para-e and para-f oxide-bridged
phenylmorphans, Fig. 1) and -antagonists (N-phenethyl substi-
l-ago-
j
tuted ortho-b and ortho-f oxide-bridged phenylmorphans,
Fig. 1).13,14 Based on the data in the Koelsch patent16 and on our work
with oxide-bridged phenylmorphans, we thought that it would be of
interest to examine N-substituted hexahydrobenzofuro[2,3-c]pyri-
q
See Ref. 1.
* 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.
doi:10.1016/j.bmc.2009.11.022

92
M. R. Iyer et al. / Bioorg. Med. Chem. 18 (2010) 91–99
(e.g., aralkyl amides19 at C-6, cinnamoyl esters20 or phenylpropyl
4
3
ethers21 at C-14, or various other substituents on the nitrogen
atom).22–24
2
5
N
1
4a
9a
4a
9a
R
HO
N
R
6
7
4b
6
4b
H
9 O
H
O
8
8
2. Results and discussion
2.1. Chemistry
OH
2: Pyridin-6-ols
1a-f: Pyridin-8-ols
R4
The basic route for assembling the cis-benzofuropyridin-8-ol
system (1a–f, Fig. 1) was initially based on the method developed
by Hutchison et al.2 Starting from the known hydroxypropiophe-
none 4 (Scheme 1),25 alkylation with ethyl bromoacetate in DMF
with K2CO3 afforded the ester 5 in 91% yield. This material was
subjected to the Horner–Emmons reaction with diethyl(cyanome-
thy1)phosphonate and NaH in THF to give the alkenic cyano ester 6
in 90% yield as a mixture of alkene stereoisomers (Scheme 1). The
isomeric mixture was carried through without separation and trea-
ted with fresh sodium ethoxide to yield the benzofuronitrile 7 via
an intramolecular Michael addition as a 1:l mixture of diastereo-
mers in 82% yield. These diastereomers were subjected to hydroge-
nation under pressure with platinum oxide in acetic acid to afford a
separable mixture of cis-lactam 10 in 38% yield and trans-amine es-
ter 9 in 15% yield. As reported by the Hutchison group,2 the cis-
amine 8 cyclizes in situ under the acidic reaction conditions to give
the cis-lactam 10 whereas trans-amine 9 fails to undergo a similar
cyclization to form the presumably strained trans-lactam under the
same conditions. Upon subjecting the trans-amine 9 to epimerizing
conditions (sodium ethoxide in refluxing ethanol), cis-lactam 10
could be isolated in 82% yield, and the trans-lactam was not
observed. Though an appreciable amount of the cis-lactam was ob-
tained for the synthesis, the inconsistent yields from the hydroge-
nation step pointed to the need for some modification of the
synthetic route. The stereochemistry of the ring junction for ben-
zofurolactam 10 as well as for all subsequent intermediates was
assigned on the basis of the 1H NMR spectra of 10 in which the pro-
ton on C-9a showed JAX = JBX = 5.0–6.0 Hz, a result consistent with a
cis ring junction. Additionally, 2D NOESY experiments provided
further proof for the cis stereochemistry. Lactam 10 was reduced
under refluxing LAH conditions to the amine 11, which represents
the common intermediate from which the new racemic com-
pounds 1a–1f are derived.
N
R3
O
R1O
OR2
2a
R1= R2 = Alkyl
R3 = Alkyl
4 = Alkyl, Aryl, Aralkyl, Cycloalkyl
R
R3
e
R2
d
R2
R1
N
f
N
R3
c
a
R1
O
O
3a
b
3
Oxide-bridged phenylmorphans
ortho-d: R1 = OH, R2 = H
para-d: R1 = H, R2 = OH
Oxide-bridged phenylmorphan
isomers a-f: R3 = Me or phenethyl
ortho isomer: R1 = OH, R2 = H
para isomer: R1 = H, R2 = OH
Figure 1. General structures.
din-8-ols (1a–f, Fig. 1) to see if they interacted with opioid receptors.
These compounds were prepared both by the well-known route and
by an improved, relatively simple, synthetic procedure that was de-
vised for related compounds.18 This procedure also enables the syn-
thesis of compounds with new alkyl, or aralkyl moieties at C-4a. In
addition to the C4a ethyl group, we prepared one new compound
with a phenethyl moiety at that position, as a proof of concept.
The phenethyl moiety was chosen because aromatic rings in an aral-
kyl moiety are known to influence opioid receptor binding and phar-
macological activity when present in a morphinan-like structure
CN
O
O
a
b
OH
OCH2CO2Et
OCH2CO2Et
OMe
c
OMe
OMe
CN
CO2Et
6
4
5
NH2
NH2
O
O
d
+
O
O
O
OEt
OEt
OMe
OMe
OMe
8
9 (15%)
7
38%
NH
NH
O
f
e
O
O
H
H
OMe
OMe
11
10
Scheme 1. Synthesis of rac-4a-ethyl-8-methoxy-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridine. Reagents and conditions: (a) K2CO3, BrCH2CO2Et, DMF, reflux, 91%; (b)
NaH, (OEt)2OPCH2CN, 90%; (c) NaOEt, EtOH, reflux, 82%; (d) Pt/C, AcOH, H2, 50 psi; (e) NaOEt/EtOH, 82%; (f) LAH, THF, reflux, 92%.

M. R. Iyer et al. / Bioorg. Med. Chem. 18 (2010) 91–99
93
Toward that end the starting alkene substrate 13 (Scheme 3)
was assembled via known literature procedures.6 With the alkene
13 in hand, functionalization leading to the enamine 14 bearing the
desired ethyl group, or any alkyl or aralkyl group was easily
achieved using the method of Evans et al.26 and earlier reports
from our laboratory.6,7,9–11 A simple two-step procedure, originally
conceived for the synthesis of the pyridin-6-ols,18 involved bro-
mination of the alkene with NBS followed by NaCNBH3 reduction
in acidic medium and gave the late stage intermediate 15. The rel-
ative stereochemistry of the bromo compound 15a was deter-
mined by single crystal X-ray diffraction analysis of the salt
15aÁHCl (Fig. 2).
NH
N
a
Me
O
H
O
H
OMe
11
OH
1a
b
N
R
Hydrobromic acid-assisted deprotection of the two aromatic
O-methyl groups gave the diol 16 (Scheme 3) that is the needed
template for the base-mediated oxide-ring formation. The base
Et3N worked well in this reaction. Refluxing the diol in methanolic
Et3N gave 1a (Scheme 3) in excellent yield. The same route was put
to use in the synthesis of 12. Following similar manipulations
noted in Scheme 3, the analogue 12 was synthesized and its stereo-
chemistry was confirmed by X-ray diffraction analysis (Fig. 2).
O
H
OH
1b-1f
1b: R = CH2CH2Ph 49%
1c: R = p-NO2CH2CH2Ph 28%
1d: R = CH2Cyclopropyl 53%
1e: R = p-FCH2Ph 31%
yield over two steps
1f: R = p-FCH2CH2Ph 24%
Scheme 2. Synthesis of rac-N-substituted 4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzof-
uro[2,3-c]pyridin-8-ols. Reagents and conditions: (a) (1) HCHO/MeOH/PtO2, H2,
1 atm; (2) BBr3, 53% over two steps; (b) (1) alkyl bromide/NaHCO3; (2) BBr3.
2.2. Opioid receptor binding studies
The N-methyl substituted pyridin-8-ol, 1a, had little affinity
for opioid receptors (Ki = 795 nM, Table 1). It had 40 times less
The conversion of amine 11 to cis-benzofuropyridin-8-ols la and
1b–1f is shown in Scheme 2. Analogue la was prepared by the
treatment of amine with HCHO in MeOH under hydrogenating
conditions in presence of catalytic Pd/C, followed by subsequent
O-demethylation. Analogues 1b–1f were obtained by directly
alkylating the amine with an alkyl halide/NaHCO3 in DMF system
followed by BBr3 deprotection of the aromatic methoxy group
(see General Method for the synthesis of 1b–f in the Section 4).
Since the hydrogenation step gave inconsistent yields, we
focused on modifying the synthesis of 1a, using a procedure that
would enable introduction of alkyl or aralkyl substituents at
C-4a, to obtain, for example, compound 12.
affinity for l-receptors than the comparable pyridin-6-ol. Even
a greater difference between the pyridin-8- and 6-ols was seen
with the N-cyclopropylmethyl and N-phenethyl analogues
(Ki = 4670 and 1630 nM, respectively, in Table 1), both of these
pyridin-8-ols showing about three orders of magnitude less affin-
ity for
l-receptors than the comparable pyridin-6-ols. Clearly,
interaction with the
l
-receptor was greatly facilitated by a phe-
nolic hydroxyl at the C-6 position. We formerly observed, in
overlay studies with the pyridin-6-ols, that the likely pharmaco-
logically active conformer of 4aS,9aR-(À)-cis-4a-ethyl-2-(2-phen-
ylethyl)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (17,
Table 1) had its aromatic hydroxyl group is in the same general
area of three-dimensional space as that of morphine.1 In order
to map the spatial region of these phenolic hydroxyl groups with
respect to the phenolic hydroxyl group of morphine, geometry
optimization on compound 1b and its superposition onto mor-
phine were carried out as previously noted.1 While the backbone
of both 1b and 17 has considerable overlap with morphine, it can
be seen in Figure 3 that the overlap between the phenolic hydro-
xy groups of compound 17 and morphine cannot be attained
Ph
N
Me
O
H
HO
12
by compound 1b. The effect of the N-substituent on
l-receptor
R
a
R
b
N Me
N Me
N Me
MeO
OMe
13
MeO
OMe
MeO
OMe Br
14a: R = Et (84%)
14b: R = CH2CH2Ph (55%)
15a: R = Et (2 steps, 69%)
15b: R = CH2CH2Ph (2 steps, 76%)
R
R
c
d
N Me
N
Me
O
H
HO
OH Br
HO
16a: R = Et (80%)
16b: R = CH2CH2Ph (78%)
1a: R = Et (88%)
12: R = CH2CH2Ph (62%)
Scheme 3. Simplified synthesis of rac-hexahydrobenzofuro[2,3-c]pyridin-8-ols. Reagents and conditions: (a) n-BuLi À40 °C, alkyl bromide; (b) (1) NBS, THF; (2) NaCNBH3,
HCl; (c) 48% HBr, reflux; (d) Et3N, 100 °C, sealed tube.

94
M. R. Iyer et al. / Bioorg. Med. Chem. 18 (2010) 91–99
Figure 3. Overlay of the piperidine ring of conformers of compounds 1b and 171
onto that of morphine, illustrating the topographical similarity of the high affinity
ligand 17 with morphine, and the lack of overlap of the oxygen atoms in 1b, a
compound with little affinity for
l-opioid receptors. The distance between the
phenolic oxygen atoms of 17 and morphine is 1.4 Å, and it is 4.5 Å between the
phenolic oxygen atoms in 1b and morphine.
affinity in the pyridin-8-ols was relatively slight, and the bulky
phenethyl moiety at C-4a in 12 (Ki = 740 nM) did not appear to
have much influence on affinity, possibly because of the
overwhelming detrimental effect of the poorly situated phenolic
hydroxyl group. Compared with the ethyl group in 1a
(Ki = 795 nM); the phenethyl’s aromatic ring in the spatial area
around C4a did not appear to influence interaction with the
opioid receptor. Of the compounds examined, the N-p-fluoro-
phenethyl substituted pyridin-8-ol (1f) had the highest affinity
Figure 2. X-ray crystal structure of 2-methyl-4a-phenethyl-1,2,3,4,4a,9a-hexa-
hydrobenzofuro[2,3-c]pyridin-8-ol (12, top) and 3-bromo-4-(2,3-dimethoxyphenyl)-
4-ethyl-1-methylpiperidine hydrochloride (15aÁHCl, bottom). Displacement ellipsoids
are shown at the 50% level.
Table 1
[3H] Binding data for rac-cis-benzofuro[2,3-c]pyridin-8-ols
for the
l-receptor, it had five fold better affinity than the unsub-
stituted N-phenethyl compound 1b (Ki = 354 nM vs 1630 nM for
1b). The fluorine atom in the phenyethyl moiety at C4a increased
receptor affinity in the pyridin-8-ols. That finding is of interest
and will be explored in further studies in the pyridin-6-ol series.
R1
N R2
Ph
N
HO
O
H
O
H
OH
3. Conclusion
rac-1a-f, 12
4aS,9aR-171
A surprisingly large difference in binding affinity was found be-
tween comparably substituted pyridin-6-ol and pyridin-8-ol com-
pounds. Some showed about a thousand-fold difference in their
Cmpd R1
R2
Ki (nM SD)
la
db
jc
1a
1b
1c
1d
1e
1f
Et
Et
Et
Et
Et
Et
Me
795 65
7480 890 >10,000
ability to bind to
l-opioid receptors. As we discussed with the
CH2CH2Ph
1630 170 7210 670 2220 290
670 50 2260 145 720 40
Cyclopropylmethyl 4670 350 6150 470 10,000 1500
pyridin-6-ols,1 compound 17 was able to reach a conformation in
which its phenolic hydroxyl group was in the same vicinity as that
of morphine, whereas compound 1b could not attain such overlap.
Thus, it is apparent that the spatial location of the phenolic hydro-
xyl in these cis-4a-alkyl or aralkyl-1,2,3,4,4a,9a-hexahydrobenzof-
uro[2,3-c]pyridin-6 and -8-ols, not just the meta-orientation to the
piperidine ring as in the well-known epoxymorphinans, morphin-
ans, 6,7-benzomorphans, and 5-phenylmorphans, is one of the
most important factors in determining their ability to interact with
opioid receptors.
p-NO2CH2CH2Ph
p-FCH2Ph
p-FCH2CH2Ph
>2700
354 45
740 86
>4500
>4500
>4300
3380 205
935 60
2880 259
12
PhEt Me
—
171
—
0.70 0.06 75 8.8
88
8
Assays were conducted using CHO cells, which were stably transfected and express
the
l-, d- or
j
-opiate receptors, respectively. All results n = 3.
[3H]DAMGO binding.
[3H]DADLE binding.
[3H]U69,593 binding.
a
b
c

M. R. Iyer et al. / Bioorg. Med. Chem. 18 (2010) 91–99
95
ice water, and the product was treated with 37% HCl (5 mL) to neu-
tralize the excess base. The organic layer was extracted with Et2O
(2 Â 200 mL), and after drying over MgSO4 the solvent was removed
in vacuo to give a dark oil. Purification by flash chromatography
using 50% EtOAc in hexanes gave 14.0 g (82%) of isomeric mixture
4. Experimental
4.1. Chemistry
4.1.1. General
7 as a sticky solid. IR (neat) 1755, 1493 cmÀ1 1H NMR (CDCl3,
;
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 Atlantic Microlabs, Atlanta, GA.
500 MHz) d (single isomer) 6.96 (t, 1H, J = 7.5 Hz), 6.85 (t, 2H,
J = 7.5 Hz), 5.07 (s, 1H), 4.35 (m, 2H), 3.89 (s, 3H), 2.99 (d, 1H,
J = 16.5 Hz), 2.89 (d, 1H, J = 16.5 Hz), 1.86 (m, 1H), 1.67 (m, 1H),
1.33 (t, 3H, J = 7.5 Hz), 0.80 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3,
125 MHz) d single isomer) 168.03, 146.54, 145.07, 129.77, 122.84,
116.98, 115.34, 112.86, 87.40, 61.95, 56.07, 51.62, 26.83, 14.36,
14.34; HRMS (TOF MS ES+) calcd for C16H20NO4 (M+H)+: 290.1392;
found: 290.1382. Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N,
4.84. Found: C, 66.42; H, 6.60; N, 4.84.
4.1.5. General procedure for the synthesis of ethyl 3-(2-
aminoethyl)-3-ethyl-7-methoxy-2,3-dihydrobenzofuran-2-
carboxylate (9) and 4a-ethyl-8-methoxy-2,3,4,4a-
4.1.2. Ethyl 2-(2-methoxy-6-propionylphenoxy)acetate (5)
A mixture of 1-(2-hydroxy-3-methoxyphenyl)propan-1-one (4)
(50.0 g, 0.28 mol),25 ethyl bromoacetate (37.0 mL, 0.33 mol) and
powdered K2CO3 (77.4 g, 0.56 mol) in dry DMF (750 mL) was vigor-
ously stirred at 90 °C for 6 h. The reaction mixture was cooled and
then poured onto ice water (200 mL) and the product was extracted
with Et2O (2 Â 300 mL). After drying over MgSO4, the solvent was re-
moved in vacuo and the residue was distilled under aspirator pres-
sure at 200 °C to give 67.7 g (91%) of 5 as a colorless viscous oil. IR
(neat): 1756, 1683 cmÀ1; 1H NMR (CDCl3, 300 MHz) d 7.12 (dd, 2H,
J = 2.0 and 8.0 Hz), 7.01 (dd, 1H, J = 2.0 and 7.5 Hz), 4.67 (s, 2H),
4.22 (q, 2H, J = 7.0 Hz), 3.85 (s, 3H), 3.05 (q, 2H, J = 7.0 Hz), 1.26 (t,
3H, J = 7.0 Hz), 1.15 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 75 MHz) d
204.06, 169.21, 152.14, 145.54, 134.67, 124.54, 120.77, 115.26,
69.83, 61.14, 56.07, 36.79, 14.23, 8.31; HRMS (TOF MS ES+) calcd
for C14H19O5 (M+H)+: 267.1232; found: 267.1227. Anal. Calcd for
C14H18O5: C, 63.15; H, 6.81. Found: C, 63.04; H, 6.88.
tetrahydrobenzofuro[2,3-c]pyridin-1(9aH)-one (10)
A mixture of the nitrile 7 (3.4 g, 11.7 mmol) and PtO2 (0.5 g) in
acetic acid (50 mL) was hydrogenated at 50 psi at room tempera-
ture for 6 h. After filtration, the solvent was removed in vacuo
and the reaction mixture was poured on an ice water and NH4OH
mixture, the product was extracted with CHCl3 (2 Â 100 mL) and
washed with a saturated NaHCO3 solution. After drying over
Na2SO4, the solvent was removed in vacuo and the residue was
subjected to flash chromatography on silica gel with 90:9:1
CH2Cl2/MeOH/NH4OH to give 1.1 g of the cis-lactam 10 in 38% yield
as a sticky foam. Eluting the above column with 50% MeOH in
CH2Cl2 gave 0.5 g (15%) of 9 as a sticky solid.
4.1.5.1. Ethyl 3-(2-aminoethyl)-3-ethyl-7-methoxy-2,3-dihydro-
benzofuran-2-carboxylate (9). IR (neat) 3278, 1746 cmÀ1
;
1H
NMR (CDCl3, 300 MHz) d 6.96 (t, 1H, J = 7.5 Hz), 6.85 (d, 1H,
J = 8.1 Hz), 6.76 (d, 1H, J = 7.2 Hz), 5.17 (br s, 2H), 5.08 (s, 1H), 4.38
(m, 2H), 3.96 (s, 3H), 2.88 (m, 2H), 2.19 (m, 2H), 1.83 (m, 1H), 1.58
(m, 1H), 1.41 (t, 1H, J = 7.2 Hz), 0.86 (t, 3H, J = 7.2 Hz);13C NMR (CDCl3,
75 MHz) d 170.93, 148.05, 146.06, 133.47, 123.02, 117.13, 113.67,
88.27, 62.46, 56.64, 53.71, 40.33, 38.19, 30.23, 14.51, 8.78; HRMS
(TOF MS ES+) calcd for C16H24NO4 (M+H)+: 294.1705; found:
294.1711. Anal. Calcd for C16H23NO4Á0.75H2O: C, 62.62; H, 8.04; N,
4.56. Found: C, 62.95; H, 7.87; N, 4.62.
4.1.3. Ethyl 2-(2-(1-cyanobut-1-en-2-yl)-6-methoxyphenoxy)acetate
(6)
To an ice-cooled suspension of 60% NaH (3.6 g, 90.0 mmol),
which had been washed free of oil with hexane in THF (300 mL),
was
added
diethyl(cyanomethy1)phosphonate
(13.2 mL,
82.5 mmol) in a dropwise fashion. After 15 min at room tempera-
ture, a solution of 5 (20.0 g, 75.0 mmol) in THF (350 mL) was added
dropwise at 0 °C. After 2 h at 0 °C, the reaction mixture was poured
on ice water and the product was extracted with Et2O. After drying
over MgSO4, the solvent was removed in vacuo to give a dark yel-
low oil. Purification by flash chromatography using 30% EtOAc in
hexanes gave 19.5 g (90%) of an isomeric mixture 6 as a yellow
4.1.5.2. 4a-Ethyl-8-methoxy-2,3,4,4a-tetrahydrobenzofuro[2,3-
c]pyridin-1(9aH)-one (10). Compound 10 was alternatively ob-
tained from compound 9. The trans amino ester 9 (500 mg,
1.76 mmol) was carefully added to a solution of freshly cut sodium
metal (23 mg, 1.0 mmol) in EtOH (5 mL). The mixture was heated
at 80 °C for 90 min. After cooling to room temperature, the reaction
mixture was poured onto ice water, and the product was treated
with 37% HCl (2 mL) to neutralize the excess base. The organic
layer was extracted with CHCl3 (2 Â 30 mL), and after drying over
Na2SO4 the solvent was removed in vacuo to give a dark oil. Puri-
fication by flash chromatography using 90:9:1 CH2Cl2/MeOH/
NH4OH gave 345 mg (82%) of 10 as a foam. IR (neat) 3211,
oil. IR (neat) 1746, 1460 cmÀ1 1H NMR (CDCl3, 300 MHz) d (mix-
;
ture of isomers) 7.20 (m, 1H), 7.02 (m, 1H), 6.84 (m, 1H), 5.53 (s,
1H), 4.64 (s, 2H), 4.36 (m, 2H), 3.95 (s, 3H), 3.03 (q, 2H,
J = 7.2 Hz), 1.38 (m, 3H), 1.15 (t, 3H); 13C NMR (CDCl3, 75 MHz) d
(mixture of isomers) 168.86, 165.80, 152.13, 144.27, 132.53,
124.648, 124.53, 12 152.133, 204.06, 169.21, 152.14, 145.54,
134.67, 124.64, 124.53, 121.08, 120.88, 116.93, 113.43, 113.25,
98.28, 96.65, 69.79, 61.08, 55.92, 55.83, 31.24, 28.67, 14.23,
12.73, 120.77, 115.26, 69.83, 61.14, 56.07, 36.79, 14.23, 8.31;
HRMS (TOF MS ES+) calcd for C16H20NO4 (M+H)+: 290.1392; found:
290.1390. Anal. Calcd for C16H19NO4Á0.25H2O: C, 65.40; H, 6.69; N,
4.77. Found: C, 65.36; H, 6.78; N, 4.46.
1678 cmÀ1 1H NMR (CDCl3, 500 MHz) d 8.02 (br s, 1H), 6.85 (t,
;
1H, J = 7.5 Hz), 6.73 (t, 1H, J = 8.0 Hz), 6.62 (d, 1H, J = 7.5 Hz), 4.64
(s, 1H), 3.80 (s, 3H), 3.17 (ddd, 1H, J = 4.5, 9.0 and 17.0 Hz), 3.05
(t, 1H, J = 10.5 Hz), 2.16 (m, 2H), 1.71 (m, 2H), 0.80 (t, 3H,
J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) d 169.25, 147.86, 144.63,
131.86, 121.97, 114.9, 112.08, 99.34, 85.47, 55.94, 50.00, 38.30,
32.78, 8.26; HRMS (TOF MS ES+) calcd for C14H18NO3 (M+H)+:
248.1287; found: 248.1295. Anal. Calcd for C14H17NO3Á0.1H2O: C,
67.51; H, 6.96; N, 5.62. Found: C, 67.43; H, 6.95; N, 5.43.
4.1.4. Ethyl 3-(cyanomethyl)-3-ethyl-7-methoxy-2,3-dihydro-
benzofuran-2-carboxylate (7)
Compound 6 (17.0 g, 58.8 mmol) in 20 mL EtOH was carefully
added to a solution of freshly cut sodium metal (850 mg, 37.0 mmol)
in EtOH (20 mL). The mixture was heated at 80 °C for 90 min. After
cooling to room temperature, the reaction mixture was poured onto

96
M. R. Iyer et al. / Bioorg. Med. Chem. 18 (2010) 91–99
4.1.6. 4a-Ethyl-8-methoxy-1,2,3,4,4a,9a-hexahydrobenzofuro-
[2,3-c]pyridine (11)
3019, 1264 cmÀ1 1H NMR (CD3OD, 500 MHz) d 7.24 (t, 2H,
;
J = 7.5 Hz), 7.15 (m, 3H), 6.72 (t, 1H, J = 8.0 Hz), 6.63 (d, 1H,
J = 7.0 Hz), 6.59 (d, 1H, J = 7.5 Hz), 4.61 (br s, 1H), 4.48 (t, 1H,
J = 6.0 Hz), 2.94 (dd, 1H, J = 5.5 and 12.5 Hz), 2.77 (m, 2H), 2.63
(m, 1H), 2.56 (d, 1H, J = 8.0 Hz), 2.42 (dd, 1H, J = 7.0 and 12.0 Hz),
2.22 (ddd, 1H, J = 2.5, 10.0 and 12.0 Hz), 2.05 (ddd, 1H, J = 3.0, 5.5
and 14.0 Hz), 1.78 (ddd, 1H, J = 4.0, 9.5 and 14.0 Hz), 1.70 (m,
1H), 1.59 (m, 1H), 0.80 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3,
125 MHz) d 145.02, 141.56, 136.30, 132.71, 128.80 (2C), 128.76
(2C), 126.99 122.65, 116.78, 114.46, 81.719, 59.06, 50.03, 48.62,
46.31, 30.66, 30.33, 30.31, 29.65, 8.42; HRMS (TOF MS ES+) calcd
for C21H26NO2 (M+H)+: 324.1964; found: 324.1972. Anal. Calcd
for C21H25NO2Á0.25H2O: C, 76.91; H, 7.83; N, 4.27. Found: C,
77.02; H, 7.84; N, 4.22.
To a solution of LAH (1.8 g, 4.25 mmol) in THF (30 mL) was added
cis-lactam 10 (3.0 g, 1.21 mmol) in THF (20 mL) and the reaction
mixture was refluxed for 2 h. After cooling to room temperature,
the reaction was quenched with EtOAc and treated with 50% NaOH,
the organic layer was then extracted with CHCl3 (2 Â 50 ml), dried
over Na2SO4 and the solvent was removed in vacuo to afford a brown
oil. Purification on a silica gel column using 90:10 CH2Cl2/MeOH
gave 2.6 g (92%) of compound 11 as a pale yellow oil. IR (neat)
2938, 1489 cmÀ1
; d 6.97 (t, 1H,
1H NMR (CDCl3, 500 MHz)
J = 7.5 Hz), 6.86 (dd, 1H, J = 1.2 and 8.1 Hz), 6.79 (dd, 1H, J = 1.5 and
7.5 Hz), 4.47 (t, 1H, J = 4.5 Hz), 3.99 (s, 3H), 3.21 (d, 1H, J = 4.5 Hz),
2.88 (m, 1), 2.80 (m, 1H), 1.75–1.93 (m, 4H), 0.96 (t, 3H, J = 7.5 Hz);
13C NMR (CDCl3, 75 MHz) d 147.23, 144.98, 135.70, 121.28, 115.17,
111.08, 84.37, 59.97, 55.85, 46.68, 46.11, 41.63, 33.96, 30.79,
29.74, 8.69; HRMS (TOF MS ES+) calcd for C14H20NO2 (M+H)+:
234.1494; found: 234.1491. Anal. Calcd for C14H19NO2: C, 72.07; H,
8.21; N, 6.00. Found: C, 72.00; H, 7.90; N, 5.70.
4.2. 4a-Ethyl-2-(4-nitrophenethyl)-1,2,3,4,4a,9a-hexahydro-
benzofuro[2,3-c]pyridin-8-ol (1c)
Using the general method of 4.1.9, amine 11 (600 mg, 2.57 mmol)
1-(2-bromoethyl)-4-nitrobenzene (651 mg, 2.83 mmol) and subse-
4.1.7. 4a-Ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro-
[2,3-c]pyridin-8-ol (1a)
quent treatment with BBr3 (977
over two steps) of 1c as a pale yellow crystalline solid, mp 144–
146 °C. IR (neat) 3020, 1214 cmÀ1 1H NMR (CDCl3, 500 MHz) d
lL, 10.3 mmol) gave 270 mg (28%
A deoxygenated solution of compound 11 (600 mg, 2.57 mmol),
HCHO (2 mL) and 10% Pd on carbon (20 mg) in MeOH (10 mL) was
stirred at room temperature under H2 at 1 atm for 2 h. The resultant
mixture was filtered through Celite and concentrated in vacuo to give
a yellow oil. The oil was taken up in CHCl3 and treated with neat BBr3
(0.97 mL, 10.3 mmol) and refluxed for 2 h. The reaction mixture was
cooled and treated with MeOH to quench the excess BBr3, poured in
to a mixture of water and NH4OH and extracted with CH2Cl2. After
evaporation of the solvent in vacuo the crude compound was sub-
jected to flash chromatography on silica gel using 5% MeOH in CH2Cl2
as the eluent to give 1a (320 mg, 53% over two steps) as a pale yellow
;
8.10 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.0 Hz), 6.82 (t, 1H,
J = 7.5 Hz), 6.79 (d, 1H, J = 8.0 Hz), 6.64 (d, 1H, J = 7.0 Hz), 4.56 (t,
1H, J = 5.5 Hz), 2.94 (d, 1H, J = 7.5 Hz), 2.89 (t, 1H, J = 7.5 Hz), 2.63
(d, 1H, J = 6.5 Hz), 2.48 (dd, 1H, J = 6.5 and 11.0 Hz), 2.27 (t, 1H,
J = 9.5 Hz), 2.08 (dt, 1H, J = 4.5 and 10.5 Hz), 1.83 (t, 1H, J = 9.5 Hz),
1.70 (m, 1H), 1.60 (m, 1H), 0.83 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3,
125 MHz) d 148.12, 146.69, 145.63, 141.26, 134.36, 129.62 (2C),
123.81 (2C), 121.75, 115.53, 115.12, 85.47, 59.49, 54.57, 49.74,
47.12, 33.35, 32.30, 32.12, 8.54 145.66, 141.99, 134.27, 121.67,
115.90, 114.61, 85.08, 56.65, 52.04, 46.52, 46.15, 32.70, 31.80,
8.54; HRMS (TOF MS ES+) calcd for C21H25N2O4 (M+H)+: 369.1814;
found: 369.1816. Anal. Calcd for C21H24N2O4: C, 68.46; H, 6.57; N,
7.60. Found: C, 68.24; H, 6.70; N, 7.51.
solid, mp 158–160 °C. IR (neat) 2983, 1732 cmÀ1 1H NMR (CDCl3,
;
500 MHz) d 6.82 (t, 1H, J = 7.5 Hz), 6.76 (d, 1H, J = 8.0 Hz), 6.62 (d,
1H, J = 7.0 Hz), 4.65 (t, 1H, J = 6.0 Hz), 2.97 (dd, 1H, J = 5.5 and
11.5 Hz), 2.57 (dd, 1H, J = 6.0 and 11.5 Hz), 2.26 (m, 1H), 2.21 (s,
3H), 2.11 (m, 2H), 1.89 (ddd, 1H, J = 3.5, 11.0 and 15.0 Hz), 1.70 (m,
1H), 1.56 (m, 1H), 0.83 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz)
d 145.66, 141.99, 134.27, 121.67, 115.90, 114.61, 85.08, 56.65,
52.04, 46.52, 46.15, 32.70, 31.80, 8.54; HRMS (TOF MS ES+) calcd for
C14H20NO2 (M+H)+: 234.1494; found: 234.1505. Anal. Calcd for
C14H19NO2Á0.2H2O: C, 70.97; H, 8.25; N, 5.91. Found: C, 71.17; H,
8.12; N, 5.91.
4.2.1. 2-(Cyclopropylmethyl)-4a-ethyl-1,2,3,4,4a,9a-hexahydro-
benzofuro[2,3-c]pyridin-8-ol (1d)
Using the general method of 4.1.9, amine 11 (320 mg,
1.37 mmol) (bromomethyl)cyclopropane (147
subsequent treatment with BBr3 (520 L, 5.48 mmol) gave
200 mg of 1d (53% over two steps) as a pale yellow solid, mp
139–141 °C. IR (neat) 3019 cmÀ1 1H NMR (CDCl3, 500 MHz) d
lL, 1.51 mmol) and
l
;
6.80 (t, 1H, J = 7.5 Hz), 6.77 (d, 1H, J = 8.0 Hz), 6.61 (d, 1H,
J = 7.0 Hz), 4.83 (t, 1H, J = 7.0 Hz), 3.35 (dd, 1H, J = 6.0 and
10.5 Hz), 2.89 (d, 1H, J = 10.0 Hz), 2.32 (dd, 1H, J = 6.5 and
12.5 Hz), 2.23 (dd, 1H, J = 6.5 and 12.5 Hz), 2.16 (m, 3H), 2.00
(ddd, 1H, J = 4.0, 11.0 and 15.0 Hz), 1.64 (m, 1H), 1.54 (m, 1H),
0.84 (m, 1H), 0.79 (t, 3H, J = 7.5 Hz) 0.45 (t, 2H, J = 3.5 Hz), 0.03
(d, 2H, J = 3.5 Hz); 13C NMR (CDCl3, 125 MHz) d 145.88, 142.30,
133.81, 121.66, 116.41, 114.52, 84.83, 63.56, 54.65, 50.03, 47.28,
33.83, 30.52, 8.38, 7.59, 4.29, 4.27; HRMS (TOF MS ES+) calcd for
C17H24NO2 (M+H)+: 274.1807; found: 274.1814. Anal. Calcd for
C17H23NO2Á0.25H2O: C, 73.48; H, 8.52; N, 5.04. Found: C, 73.11;
H, 8.50; N, 4.93.
4.1.8. General method for the synthesis of 1b through 1f
A mixture of the amine 11, alkyl bromide (1.2 equiv) and NaH-
CO3 (2 equiv) in DMF (20 mL) was heated at 100 °C for 3 h. After
cooling to room temperature, the reaction mixture was poured
on ice water, and the product was extracted with Et2O. The ethe-
real extracts were washed with a saturated NH4Cl solution. After
drying over Na2SO4, the solvent was removed in vacuo to afford
an oil. This oil was taken up in CHCl3 and treated with neat BBr3
(4 equiv) and refluxed for 2 h. The reaction mixture was cooled
and treated with MeOH to quench the excess BBr3, poured in to a
mixture of H2O and NH4OH and extracted with CH2Cl2. After evap-
oration of the solvent in vacuo the crude compound was subjected
to flash chromatography on silica gel using 5% MeOH in CH2Cl2 as
the eluent to give the compounds 1b–f as a solid.
4.2.2. 4a-Ethyl-2-(4-fluorobenzyl)-1,2,3,4,4a,9a-hexahydro-
benzofuro[2,3-c]pyridin-8-ol (1e)
Using the general method of 4.1.9, amine 11 (233 mg, 1 mmol),
4.1.9. 4a-Ethyl-2-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro-
[2,3-c]pyridin-8-ol (1b)
Using the general method of 4.1.9, the amine 11 (1.1 g,
4.85 mmol), 2-bromoethylbenzene (0.78 mL, 5.82 mmol) and sub-
sequent treatment with BBr3 (1.84 mL, 19.4 mmol) gave 0.76 g of
1b (49% over two steps) as a white solid, mp 195–198 °C. IR (neat)
1-(bromomethyl)-4-fluorobenzene (147
quent treatment with BBr3 (379 L, 4 mmol) gave 60 mg of 1e
(31% over two steps) as light white crystals, mp 138–140 °C. IR
(neat) 3019, 1214 cmÀ1 1H NMR (CDCl3, 500 MHz) d 7.24 (m,
2H), 6.97 (t, 2H, J = 8.5 Hz), 6.79 (t, 1H, J = 7.5 Hz), 6.76 (d, 1H,
J = 7.0 Hz), 6.63 (d, 1H, J = 7.0 Hz), 5.51 (br s, 1H), 4.52 (t, 1H,
lL, 1.2 mmol) and subse-
l
;

M. R. Iyer et al. / Bioorg. Med. Chem. 18 (2010) 91–99
97
J = 6.0 Hz), 3.44 (m, 2H), 2.88 (dd, 1H, J = 5.0 and 11.5 Hz), 2.53 (dd,
1H, J = 5.5 and 11.0 Hz), 2.26 (dd, 1H, J = 7.5 and 12.0 Hz), 2.04–
2.13 (m, 2H), 1.80 (ddd, 1H, J = 3.5, 10.0 and 13.5 Hz), 1.68 (m,
1H), 1.55 (m, 1H), 0.81 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3,
and the organic layer was washed with H2O (50 mL) and extracted
into CH2Cl2 (150 mL). Removal of the solvent in vacuo gave a brown
oil. Purification of the crude product by column chromatography
using 30% hexanes in Et2O gave a pale yellow solid (9.0 g, 69% over
two steps). A small batch of the yellow solid was dissolved in MeOH
and treated with 37% HCl to give white crystals of 15aÁHCl that were
used for X-ray crystallography (Fig. 2). Mp 220–223 °C; IR (neat)
2937 cmÀ1; 1H NMR (CDCl3, 500 MHz) d 6.99 (t, 1H, J = 8.0 Hz), 6.88
(d, 1H, J = 8.0 Hz), 6.69 (d, 1H, J = 7.5 Hz), 5.29 (s, 1H), 3.97 (s, 3H),
3.86 (s, 3H), 3.15 (d, 1H, J = 13.0 Hz), 3.00 (m, 2H), 2.50 (t, 1H,
J = 14.0 Hz), 2.47 (s, 3H), 2.43 (m, 1H), 2.05 (m, 2H), 1.92 (d, 1H,
J = 12.5 Hz), 0.51 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) d
152.67, 147.92, 138.72, 122.79, 120.01, 111.48, 60.33, 58.46, 55.78
(2C), 51.14, 46.13, 45.13, 26.77, 24.86, 9.65; HRMS (TOF MS ES+) calcd
for C16H25NBr79O2 (M+H)+: 342.1069; found: 342.1055. Anal. Calcd
for C16H24NBrO2ÁHCl: C, 50.74; H, 6.65; N, 3.70. Found: C, 50.74; H,
6.71; N, 3.74.
125 MHz)
d 163.16, 161.21, 145.70, 141.25, 134.43, 133.63,
130.80, 130.73, 121.56, 115.363, 115.27, 115.18, 115.10, 85.76,
62.12, 54.75, 49.73, 47.25, 32.77, 31.94, 8.48; HRMS (TOF MS ES+)
calcd for C20H23FNO2 (M+H)+: 328.2713; found: 328.1706. Anal.
Calcd for C20H22FNO2: C, 73.37; H, 6.77; N, 4.28. Found: C, 73.34;
H, 6.78; N, 4.30.
4.2.3. 4a-Ethyl-2-(4-fluorophenethyl)-1,2,3,4,4a,9a-
hexahydrobenzofuro[2,3-c]pyridin-8-ol (1f)
Using the general method of 4.1.9, amine 11 (288 mg, 1.23 mmol),
1-(2-bromoethyl)-4-fluorobenzene (208
lL, 1.48 mmol) and subse-
quent treatment with BBr3 (467 L, 4.92 mmol) gave 100 mg of 1f
l
(24% over two steps) as a light yellow crystalline compound, mp
156–158 °C. IR (neat) 3019, 1214 cmÀ1; 1H NMR (CDCl3, 500 MHz) d
7.10 (t, 2H, J = 8.0 Hz), 7.10 (d, 2H, J = 8.5 Hz), 6.80 (t, 1H, J = 7.5 Hz),
6.77 (d, 1H, J = 7.5 Hz), 6.65 (d, 1H, J = 7.0 Hz), 5.15 (br s, 1H), 4.55 (t,
1H, J = 6.0 Hz), 2.92 (dd, 1H, J = 5.0 and 12.0 Hz), 2.75 (t, 2H,
J = 8.0 Hz), 2.54 (m, 3H), 2.46 (dd, 1H, J = 7.0 and 12.0 Hz), 2.25 (dd,
1H, J = 3.0 and 12.0 Hz), 2.08 (ddd, 1H, J = 3.5, 5.5 and 14.0 Hz), 1.81
(ddd, 1H, J = 3.5, 9.0 and 13.5 Hz), 1.73 (m, 1H), 1.61 (m, 1H), 0.82 (t,
3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) d 162.51, 160.57, 145.63,
141.23, 135.89, 134.65, 130.18, 130.11, 121. 65, 115.38, 115.32,
115.22, 115.16, 85.72, 60.57, 54.61, 49.88, 47.11, 32.78, 32.50,
32.08, 8.60; HRMS (TOF MS ES+) calcd for C21H25NFO2 (M+H)+:
342.1869; found: 342.1857. Anal. Calcd for C21H24NFO2: C, 73.88; H,
7.09; N, 4.10. Found: C, 73.99; H, 7.08; N, 4.29.
4.2.6. 2-(3-Bromo-4-ethyl-1-methylpiperidin-4-yl)benzene-1,2-
diol (16a)
To compound 15a (7.5 g, 21.9 mmol) in a clean round-bottom
flask was added 48% HBr (30 mL) and the emulsion was refluxed
at 105 °C for 10 h. After completion of the reaction, the excess
HBr was removed by distillation to leave 16aÁHBr as a pale yellow
solid (7.0 g, 80%). A small batch was recrystallized from MeOH to
give off-white crystals of 16aÁHBr, mp 248–251 °C. IR (neat)
3458 cmÀ1 1H NMR (CD3OD, 500 MHz) d 6.76 (d, 1H, J = 7.0 Hz),
;
6.65 (t, 1H, J = 8.0 Hz), 6.51 (d, 1H, J = 7.0 Hz), 5.95 (s, 1H), 4.04
(d, 1H, J = 14.0 Hz), 3.81 (d, 1H, J = 14.0 Hz), 3.54 (d, 1H,
J = 12.0 Hz), 3.41 (t, 1H, J = 16.5 Hz), 3.00 (s, 3H), 2.50 (dt, 1H,
J = 3.5 and 14.5 Hz), 2.45 (dd, 1H, J = 7.0 and 13.5 Hz), 2.28 (d,
1H, J = 14.5 Hz), 2.08 (m, 1H) 0.63 (t, 3H, J = 7.0 Hz); 13C NMR
(CD3OD, 125 MHz) d 146.06, 145.10, 130.77, 119.55, 119.47,
114.89, 57.95, 55.19, 51.80, 45.22, 44.14, 25.86, 23.85, 10.04;
HRMS (TOF MS ES+) calcd for C14H21NBrO2 (M+H)+: 314.0756;
found: 314.0744. Anal. Calcd for C14H20NBrO2ÁHBr: C, 42.56; H,
5.36; N, 3.54. Found: C, 42.59; H, 5.42; N, 3.55.
4.2.4. 4-(2,3-Dimethoxyphenyl)-4-ethyl-1-methyl-1,2,3,4-tetra-
hydropyridine (14a)
A solution of 13 (33.0 g, 141 mmol) in dry THF (350 mL) was
stirred under argon at À40 °C. A solution of n-butyllithium, 2.5 M
in hexane (113 mL, 283 mmol), was added to the reaction, produc-
ing a deep red color. The mixture was stirred at À40 °C for 3 h. Bro-
moethane (21.1 mL, 283 mmol) 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 aqueous
NH4Cl solution (40 mL). The reaction mixture was partitioned be-
tween Et2O (2 Â 300 mL) and H2O (300 mL). The organic layer
was dried over anhydrous Na2SO4 and removal of the solvent in va-
cuo gave an orange oil. Column chromatography of the crude
material using 10% hexanes in Et2O gave 31.0 g (84%) of 14a as a
4.2.7. 4a-Ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro-
[2,3-c]pyridin-8-ol (1a)
Compound 16a (2.0 g, 6.37 mmol) (free base was obtained after
neutralization of the HBr salt of 16a partitioned between NaHCO3
and CHCl3) was treated with excess Et3N (30 mL). The reaction
mixture was placed in a sealed tube and heated at 100 °C for 4 h.
Cooling of the reaction mixture, followed by evaporation of the ex-
cess Et3N gave a brown solid. This solid was subject to silica gel col-
umn chromatography and the desired product 1a was eluted using
15% MeOH in CH2Cl2 to give an off-white solid (1.3 g, 88%), mp
pure yellow oil. IR (neat) 2932, 1637 cmÀ1 1H NMR (CDCl3,
;
300 MHz) d 7.09 (m, 2H), 6.90 (d, 1H, J = 7.8 Hz), 6.02 (d, 1H,
J = 7.8 Hz), 4.82 (d, 1H, J = 7.8 Hz), 4.00 (s, 6H), 2.89 (d, 1H,
J = 10.5 Hz), 2.65 (s, 3H), 2.59 (m, 2H), 2.24 (m, 1H), 2.02 (t, 1H,
J = 12.0 Hz), 1.84 (m, 1H), 0.79 (t, 3H, J = 7.2 Hz); 13C NMR (CDCl3,
;
158–160 °C. IR (neat) 2983, 1732 cmÀ1 1H NMR (CDCl3,
500 MHz) d 6.82 (t, 1H, J = 7.5 Hz), 6.76 (d, 1H, J = 8.0 Hz), 6.62 (d,
1H, J = 7.0 Hz), 4.65 (t, 1H, J = 6.0 Hz), 2.97 (dd, 1H, J = 5.5 and
11.5 Hz), 2.57 (dd, 1H, J = 6.0 and 11.5 Hz), 2.26 (m, 1H), 2.21 (s,
3H), 2.11 (m, 2H), 1.89 (ddd, 1H, J = 3.5, 11.0 and 15.0 Hz), 1.70
(m, 1H), 1.56 (m, 1H), 0.83 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3,
75 MHz)
d 153.12, 147.53, 141.32, 135.89, 124.09, 122.36,
110.54, 105.07, 60.07, 55.73, 47.20, 42.47, 41.37, 34.49, 33.56,
9.13; HRMS (TOF MS ES+) calcd for C16H24NO2 (M+H)+: 262.1807;
found: 262.1820. Anal. Calcd for C16H24NO2: C, 73.53; H, 8.87; N,
5.08. Found: C, 73.42; H, 8.89; N, 5.36.
125 MHz)
d 145.66, 141.99, 134.27, 121.67, 115.90, 114.61,
85.08, 56.65, 52.04, 46.52, 46.15, 32.70, 31.80, 8.54; HRMS (TOF
MS ES+) calcd for C14H20NO2 (M+H)+: 234.1470; found: 234.1480.
Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C,
71.85; H, 8.10; N, 6.00.
4.2.5. 3-Bromo-4-(2,3-dimethoxyphenyl)-4-ethyl-1-methyl-
piperidine (15a)
To a solution of compound 14a (10.0 g, 38.0 mmol) in dry THF
(75 mL)atÀ78 °C was added N-bromosuccinimide (6.8 g, 38.0 mmol)
in dry THF (40 mL). The mixture was stirred at 20 °C for 1 h and then
evaporated to an orange oil. The crude product was taken in MeOH
(75 mL) and 37% HCl (2 mL) was added to the suspension. To this sus-
pension was added solid NaBH3CN (2.4 g, 38.0 mmol), and the reac-
tion mixture was stirred at room temperature for 45 min. The
reaction mixture was then diluted with aqueous saturated NaHCO3
4.2.8. 4-(2,3-Dimethoxyphenyl)-1-methyl-4-phenethyl-1,2,3,4-
tetrahydropyridine (14b)
A solution of 13 (10.0 g, 42.9 mmol) in dry THF (100 mL) was
stirred under argon at À40 °C. A solution of n-butyllithium, 2.5 M
in hexane (34.5 mL, 85.8 mmol), was added to the reaction, pro-
ducing a deep red color. The mixture was stirred at À40 °C for

98
M. R. Iyer et al. / Bioorg. Med. Chem. 18 (2010) 91–99
2 h. Phenethyl bromide (11.7 mL, 85.8 mmol) was added, produc-
ing a yellow solution, which was then stirred and brought to
20 °C over 1 h. The reaction mixture was then treated with satu-
rated NH4Cl solution (15 mL). The reaction mixture was parti-
tioned twice between Et2O (100 mL) and H2O (100 mL). The
organic layer was dried over anhydrous Na2SO4 and removal of
the solvent gave an orange oil. Column chromatography of the
crude material using 20% hexanes in Et2O gave 8.0 g (55%) of com-
145.17, 143.22, 130.94, 129.47 (2C), 129.30 (2C), 126.81, 119.75,
119.39, 115.13, 57.87, 55.06, 51.84, 45.06, 44.16, 33.54, 33.21,
26.50; HRMS (TOF MS ES+) calcd for C20H25NBr79O2 (M+H)+:
390.1069; found: 390.1070. Anal. Calcd for C20H24NBrO2ÁHBrÁH2O:
C, 49.10; H, 5.56; N, 2.86. Found: C, 48.90; H, 5.62; N, 2.77.
4.3.1. 2-Methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzo-
furo[2,3-c]pyridin-8-ol (12)
pound 14b as pure yellow oil. IR (neat) 2929, 1496 cmÀ1
;
1H NMR
Compound 16b (820 mg, 2.1 mmol) 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. Cooling of the reaction
mixture followed by evaporation of the excess Et3N gave a brown
solid. This solid was subjected to silica gel column chromatography
and the desired product was eluted using 15% MeOH in CH2Cl2 to
give an off-white solid 12 (400 mg, 62%), mp 187–189 °C. IR (neat)
3020 cmÀ1. The X-ray crystallographic analysis confirmed the
molecular structure (Fig. 2). 1H NMR (CDCl3, 500 MHz) d 7.23 (t,
2H, J = 7.0 Hz), 7.15 (t, 1H, J = 7.0 Hz), 7.08 (d, 2H, J = 7.5 Hz), 6.86
(t, 1H, J = 7.5 Hz), 6.80 (d, 1H, J = 8.0 Hz), 6.71 (d, 1H, J = 7.0 Hz),
4.68 (t, 1H, J = 5.5 Hz), 2.90 (dd, 1H, J = 4.0 and 11.5 Hz), 2.55 (m,
3H), 2.42 (dd, 1H, J = 7.0 and 11.5 Hz), 2.28 (s, 3H), 2.23 (t, 1H,
J = 11.0 Hz), 2.14 (m, 1H), 1.97 (m, 2H), 1.85 (dt, 1H, J = 5.0 and
13.0 Hz); 13C NMR (CDCl3, 125 MHz) d 145.62, 142.17, 141.79,
134.34, 128.54 (2C), 128.37 (2C), 125.99, 122.00, 115.92, 114.68,
85.25, 56.37, 51.87, 46.36, 46.20, 41.56, 32.85, 30.68; HRMS (TOF
MS ES+) calcd for C20H24NO2 (M+H)+: 310.1807; found: 310.1817.
Anal. Calcd for C20H23NO2Á0.25 H2O: C, 76.52; H, 7.54; N, 4.46.
Found: C, 76.70; H, 7.33; N, 4.52.
(CDCl3, 500 MHz) d 7.20 (t, 2H, J = 7.5 Hz), 7.12 (d, 3H, J = 7.5 Hz),
7.05 (d, 1H, J = 7.5 Hz), 6.97 (t, 1H, J = 7.5 Hz), 6.83 (d, 1H,
J = 8.0 Hz), 5.95 (d, 1H, J = 8.0 Hz), 4.79 (d, 1H, J = 7.5 Hz), 3.87 (s,
3H), 3.86 (s, 3H), 2.78 (dd, 1H, J = 4.0 and 8.0 Hz), 2.56 (s, 3H),
2.43–2.51 (m, 4 H), 2.39–2.43 (m, 2 H), 2.26 (dt, 1H, J = 5.5 and
12.5 Hz), 1.98 (dt, 1H, J = 3.0 and 12.0 Hz); 13C NMR (CDCl3,
75 MHz) d 153.22, 147.69, 143.46, 141.16, 128.46 2C, 128.28 2C);
HRMS (TOF MS ES+) calcd for C22H28NO2 (M+H)+: 338.2120; found:
338.2113.
4.2.9. 3-Bromo-4-(2,3-dimethoxyphenyl)-1-methyl-4-phen-
ethylpiperidine (15b)
To a solution of compound 14b (9.5 g, 28.1 mmol) in dry THF
(75 mL) at À78 °C was added N-bromosuccinimide (5.0 g,
28.1 mmol) in dry THF (30 mL). The mixture was stirred at 20 °C
for 1 h and the solvent was removed to give a brown oil. The crude
product was placed in MeOH (75 mL) and 37% HCl (2 mL) was
added to the suspension. To this suspension was added solid
NaBH3CN (1.76 g, 28.1 mmol), and the reaction mixture was stirred
at room temperature for 30 min. The reaction mixture was then di-
luted with aqueous saturated NaHCO3 and the organic layer was
washed with H2O (50 mL) and extracted into CH2Cl2 (150 mL). Re-
moval of the solvent gave a brown oil. Purification of the crude
product by column chromatography using 30% hexanes in Et2O
gave 15b (9.0 g, 76% over two steps) as a white crystalline solid,
4.3.2. X-ray crystal structures (Fig. 2) of 2-methyl-4a-phen-
ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ol (12)
and 3-bromo-4-(2,3-dimethoxyphenyl)-4-ethyl-1-methyl-
piperidine hydrochloride (15aÁHCl)
Single-crystal X-ray diffraction data on compounds 12 and
mp 132–135 °C. IR (neat) 2940 cmÀ1
;
1H NMR (CDCl3, 500 MHz)
15aÁHCl were collected using MoKa radiation and a Bruker APEX
d 7.24 (t, 2H, J = 7.5 Hz), 7.15 (t, 1H, J = 7.5 Hz), 7.04 (d, 3H,
J = 7.0 Hz), 6.92 (d, 1H, J = 8.0 Hz), 6.78 (d, 1H, J = 7.5 Hz), 5.29 (s,
1H), 4.00 (s, 3H), 3.89 (s, 3H), 3.09 (d, 1H, J = 13.5 Hz), 2.99 (d,
1H, J = 11.0 Hz), 2.88 (d, 1H, J = 13.0 Hz), 2.60 (dt, 1H, J = 2.5 and
12.5 Hz), 2.47 (t, 1H, J = 11.5 Hz), 2.38 (s, 3H), 2.27 (m, 3H), 2.03
(dt, 1H, J = 13.0 Hz), 1.90 (dt, 1H, J = 3.0 and 11.0 Hz); 13C NMR
(CDCl3, 125 MHz) d 152.69, 148.08, 142.37, 138.82, 128.38 (2C),
128.32 (2C), 125.81, 122.79, 119.77, 111.77, 60.27, 8.95, 58.44,
55.81, 51.13, 46.11, 44.87, 34.56, 31.92, 27.69; HRMS (TOF MS
ES+) calcd for C22H29NBr79O2 (M+H)+: 418.1382; found: 418.1382.
Anal. Calcd for C22H28NBrO2: C, 63.16; H, 6.75; N, 3.35. Found: C,
63.22; H, 6.78; N, 3.40.
2 CCD area detector. The structures was solved by direct methods
and refined by full-matrix least squares on F2 values using the pro-
grams found in the SHELXTL suite (Bruker, SHELXTL v6.10, 2000,
Bruker AXS Inc., Madison, WI). Parameters refined included atomic
coordinates and anisotropic thermal parameters for all non-hydro-
gen atoms. Hydrogen atoms on carbons were included using a rid-
ing model [coordinate shifts of C applied to H atoms] with C–H
distance set at 0.96 Å. Atomic coordinates for these compounds
have been deposited with the Cambridge Crystallographic Data
Centre (deposition numbers 729148 and 729149 for compounds
12 and 15aÁHCl, respectively). Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk.
4.3. 2-(3-Bromo-1-methyl-4-phenethylpiperidin-4-yl)benzene-
1,2-diol (16b)
Acknowledgments
To compound15b (2.2 g, 5.26 mmol) in a round-bottomflask was
added 48% HBr (25 mL) and the emulsion was refluxed at 105 °C for
10 h. After completion of the reaction, the excess HBr was removed
by distillation to leave compound 16bÁHBr as a light brown solid.
Neutralization of the HBr salt by partitioning between NaHCO3 and
CHCl3 gave 1.6 g (78%) of the free base. A small batch of 16bÁHBr
was recrystallized from MeOH to give white crystals of 16bÁHBr,
mp 190–193 °C. IR (neat) 3479 cmÀ1; 1H NMR (CD3OD, 500 MHz) d
7.20 (t, 2H, J = 7.5 Hz), 7.12 (d, 1H, J = 7.0 Hz), 7.07 (d, 2H,
J = 7.5 Hz), 6.82 (d, 1H, J = 7.5 Hz), 6.70 (t, 1H, J = 8.0 Hz), 6.58 (d,
1H, J = 8.0 Hz), 5.92 (s, 1H), 4.02 (d, 1H, J = 14.5 Hz), 3.76 (d, 1H,
J = 14.0 Hz), 3.56 (d, 1H, J = 12.0 Hz), 3.44 (t, 1H, J = 13.0 Hz), 2.98
(s, 3H), 2.75 (dt, 1H, J = 3.5 and 12.5 Hz), 2.56 (dt, 1H, J = 2.0 and
13.0 Hz), 2.41 (dt, 1H, J = 7.5 and 13.0 Hz), 2.31 (m, 2H), 2.03 (dt,
1H, J = 3.5 and 12.0 Hz); 13C NMR (CD3OD, 125 MHz) d 146.17,
We would like to thank Dr. Klaus Gawrisch and Dr. Walter Tea-
gue of the Laboratory of Membrane Biochemistry and Biophysics
(LMBB) in NIAAA for NMR spectral data. The authors also express
their thanks to Noel Whittaker and Wesley White of the Laboratory
of Analytical Chemistry for mass spectral data and 1H NMR spectral
data, and we thank NIDA for support of the X-ray crystallographic
studies (NIDA contract Y1-DA6002). The work of the Drug Design
and Synthesis Section, CBRB, NIDA, & NIAAA, was supported by
the NIH Intramural Research Programs of the National Institute
on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse
and Alcoholism. The quantum chemical study utilized PC/LINUX
clusters at the Center for Molecular Modeling of the NIH (http://
cit.nih.gov), and this research was supported by the NIH Intramural
Research Program through the Center for Information Technology.

M. R. Iyer et al. / Bioorg. Med. Chem. 18 (2010) 91–99
99
11. Linders, J. T. M.; Mirsadeghi, S.; Flippen-Anderson, J. L.; George, C.; Jacobson, A.
E.; Rice, K. C. Helv. Chim. Acta 2003, 86, 484.
Supplementary data
12. Zezula, J.; Jacobson, A. E.; Rice, K. C. Heterocycles 2007, 71, 881.
13. Zezula, J.; Singer, L. B.; Przybyl, A. K.; Hashimoto, A.; Dersch, C. M.; Rothman, R.
B.; Deschamps, J.; Lee, Y. S.; Jacobson, A. E.; Rice, K. C. Org. Biomol. Chem. 2008,
6, 2868.
14. Kurimura, M.; Liu, H.; Sulima, A.; Przybyl, A. K.; Ohshima, E.; Kodato, S.;
Deschamps, J. R.; Dersch, C.; Rothman, R. B.; Lee, Y. S.; Jacobson, A. E.; Rice, K. C.
J. Med. Chem. 2008, 51, 7866.
Supplementary data (atomic coordinates and crystallographic
data for compounds 15aÁHCl and 12) associated with this article
can be found, in the online version, at doi:10.1016/j.bmc.2009.
11.022.
15. May, E. L. J. Org. Chem. 1956, 21, 899.
16. Koelsch, C. F. U.S.A. Patent 2,809,201, 1957, 8.
References and notes
17. Koelsch, C. F. Chem. Abstr. 1958, 52, 3871f.
18. Iyer, M. R.; Deschamps, J. R.; Jacobson, A. E.; Rice, K. C. Heterocycles 2009, 79,
1. Zhang, Y.; Lee, Y. S.; Rothman, R. B.; Dersch, C. M.; Deschamps, J. R.; Jacobson, A.
E.; Rice, K. C. J. Med. Chem. (2009), doi:10.1021/jm9004225.
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.; Silverton, J. V. In
Problems of Drug Dependence 1983; Harris, L. S., Ed.; National Institute on Drug
Abuse Research Monograph 49; DHHS ((ADM) 84-1316): Washington, DC,
1984; Vol. 49, 109.
4. Burke, T. R., Jr.; Jacobson, A. E.; Rice, K. C.; Silverton, J. V. J. Org. Chem. 1984, 49,
1051.
5. Burke, T. R., Jr.; Jacobson, A. E.; Rice, K. C.; Silverton, J. V. J. Org. Chem. 1984, 49,
2508.
6. 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.
7. Yamada, K.; Flippen-Anderson, J. L.; Jacobson, A. E.; Rice, K. C. Synthesis-
Stuttgart 2002, 2359.
8. Kodato, S.; Linders, J. T. M.; Gu, X.-H.; Yamada, K.; Flippen-Anderson, J. L.;
Deschamps, J. R.; Jacobson, A. E.; Rice, K. C. Org. Biomol. Chem. 2004, 2, 330.
9. Hashimoto, A.; Przybyl, A. K.; Linders, J. T. M.; Kodato, S.; Tian, X. R.;
Deschamps, J. R.; George, C.; Flippen-Anderson, J. L.; Jacobson, A. E.; Rice, K.
C. J. Org. Chem. 2004, 69, 5322.
1061.
19. Cami-Kobeci, G.; Neal, A. P.; Bradbury, F. A.; Purington, L. C.; Aceto, M. D.;
Harris, L. S.; Lewis, J. W.; Traynor, J. R.; Husbands, S. M. J. Med. Chem. 2009, 52,
1546.
20. Moynihan, H.; Jales, A. R.; Greedy, B. M.; Rennison, D.; Broadbear, J. H.;
Purington, L.; Traynor, J. R.; Woods, J. H.; Lewis, J. W.; Husbands, S. M. J. Med.
Chem. 2009, 52, 1553.
21. Greiner, E.; Spetea, M.; Krassnig, R.; Schullner, F.; Aceto, M.; Harris, L. S.;
Traynor, J. R.; Woods, J. H.; Coop, A.; Schmidhammer, H. J. Med. Chem. 2003, 46,
1758.
22. May, E. L.; Jacobson, A. E.; Mattson, M. V.; Traynor, J. R.; Woods, J. H.; Harris, L.
S.; Bowman, E. R.; Aceto, M. D. J. Med. Chem. 2000, 43, 5030.
23. May, E. L.; Aceto, M. D.; Bowman, E. R.; Bentley, C.; Martin, B. R.; Harris,
L. S.; Medzihradsky, F.; Mattson, M. V.; Jacobson, A. E. J. Med. Chem. 1994,
37, 3408.
24. McLamore, S.; Ullrich, T.; Rothman, R. B.; Xu, H.; Dersch, C.; Coop, A.;
Davis, P.; Porreca, F.; Jacobson, A. E.; Rice, K. C. J. Med. Chem. 2001, 44,
1471.
25. Parker, K. A.; Petraitis, J. J. Tetrahedron Lett. 1981, 22, 397.
26. Evans, D. A.; Mitch, C. H.; Thomas, R. C.; Zimmerman, D. M.; Robbey, R. L. J. Am.
Chem. Soc. 1980, 102, 5955.
10. Tadic, D.; Linders, J. T. M.; Flippen-Anderson, J. L.; Jacobson, A. E.; Rice, K. C.
Tetrahedron 2003, 59, 4603.