Synthesis of C-homoaporphines via microwave-assisted direct arylation

Article abstract of DOI:10.1016/j.tet.2010.11.059

Representatives of the C-homoaporphine class of alkaloids have shown interesting biological activities. To date the synthesis of these molecules has never been attempted via a direct-arylation strategy. We report herein the first Pd-mediated intramolecula

Full text of DOI:10.1016/j.tet.2010.11.059

Tetrahedron 67 (2011) 569e575
Contents lists available at ScienceDirect
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Synthesis of C-homoaporphines via microwave-assisted direct arylation
*
Sandeep Chaudhary, Wayne W. Harding
Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, New York, NY 10065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Representatives of the C-homoaporphine class of alkaloids have shown interesting biological activities.
To date the synthesis of these molecules has never been attempted via a direct-arylation strategy. We
report herein the first Pd-mediated intramolecular direct arylation in the synthesis of C-homoaporphines
via the use of microwaves. Use of tricyclohexylphosphine tetrafluoroborate as ligand gave good per-
centage conversions and suppressed competing debromination with the substrates evaluated. This
arylation strategy should be broadly useful in the synthesis of C-homoaporphine alkaloids as demon-
strated herein in the synthesis of (ꢀ)-homonantenine.
Received 29 September 2010
Received in revised form 13 November 2010
Accepted 16 November 2010
Available online 20 November 2010
Keywords:
Homoaporphine
Aporphine
Ó 2010 Elsevier Ltd. All rights reserved.
Alkaloid
Microwave-assisted
Direct arylation
1. Introduction
Owing to the interesting biological activities exhibited by these
compounds and the limited access from natural sources, the de-
C-Homoaporphine alkaloids (1) are structurally-related to
aporphine alkaloids (2, Fig. 1); as compared to aporphines these
compounds have an additional carbon atom in the C ring. The
analogous B-homoaporphines are relatively rare in the literature
and have not been reported to occur in nature. Members of the C-
homoaporphine series occur naturally in plants of the Liliaceae
family, specifically the Merendera, Colchicum, Kreysigia, Andro-
cymbium, Bulbocodium, Iphigenia and Gloriosa genera.1 With
regards to biological activity, some C-homoaporphines have been
reported to exhibit acetylcholinesterase and butylcholinesterase
inhibitory activities and smooth muscle relaxing effects.2
velopment of rapid and efficient methods to prepare libraries of
these compounds is desirable.
A number of approaches to the synthesis of C-homoaporphines
have been reported. The majority of these methods involve metal-
mediated biaryl cyclization of a phenolic or phenol ether tetrahy-
droisoquinoline precursor as a key step in construction of the
homoaporphine core (Fig. 1).3 This approach is generally undesir-
able since toxic metal reagents are used and yields are sometimes
quite low. A more recent approach uses a photostimulated intra-
molecular ortho-arylation of a phenol with an activated aryl ring to
construct the biaryl bond.4 Acid treatment of p-quinol acetates,
(prepared from phenethylisoquinolines via lead tetraacetate oxi-
dation) has also been employed to prepare C-homoaporphines.5
A
fourth approach to the preparation of these molecules, is via ring-
expansion of dehydroaporphines.6
* Corresponding author. E-mail address: whardi@hunter.cuny.edu (W.W.
Harding).
Fig. 1. Approaches to the synthesis of homoaporphines.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.059

570
S. Chaudhary, W.W. Harding / Tetrahedron 67 (2011) 569e575
Table 1
Microwave promoted reactions have become increasingly pop-
Initial conditionsdmicrowave-assisted direct arylation on 10
ular in the literature since the use of microwaves can enhance re-
action rates and yields of several reactions.7aec The generation of
large compound libraries for medicinal chemistry efforts has
benefited from advances made in microwave-assisted chemistry.7d
The use of microwaves is also a valuable tool for reaction optimi-
zation studies.7aec
O
O
O
Pd(OAc)2, ligand,
base, pivalic acid,
NCO2Et
NCO2Et
+
O
10
DMSO, 130 °C,
MW, 15 min
O
O
O
O
11
12
The synthesis of C-homoaporphines by direct arylation has
never been reported in the literature. In fact, direct arylation for the
synthesis of seven-membered rings via coupling of two arene
partners is particularly rare.8 We recently reported a microwave-
assisted direct arylation protocol for the rapid synthesis of apor-
phines.9 Perceived challenges notwithstanding and based on our
earlier work, we envisaged that microwave-assisted direct aryla-
tion might also be applicable to the preparation of C-homo-
aporphines from tetrahydroisoquinoline precursors. Our efforts in
this regard are reported herein.
PCy2
PPh2
HBF4
P
Me2N
P
Me2N
HBF4
C
D
B
A
Entry
Ligand
Base
Ratio 11:12a
Yield of 11 (%)b
1
2
3
4
5
A
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
1:5
0:1
0:1
1:1
16
0
0
13
36
B
Cc
D
D
2. Results and discussion
1:1.5
The phenethyl tetrahydroisoquinoline 10 was prepared as
a substrate for studying the microwave-assisted direct arylation
reaction (Scheme 1). This substrate was also chosen since it would
allow for the synthesis of the ring C-homolog (3) of the aporphine
alkaloid nantenine (4) as part of our continuing structureeactivity
relationship studies on aporphine derivatives at human 5-HT2A
receptors.9,10 Thus phenethylamine 5 was coupled to the bromoacid
6 to give amide 8. BischlereNapieralski cyclization of 8 furnished an
intermediate imine, which was subjected to NaBH4 reduction to
afford amine 9. N-protection of 9 as an ethyl carbamate in the
subsequent step gave the arylation substrate 10.
a
Based on isolated yields of 11 and 12.
Isolated yield.
Ligand:Pd ratio used was 1:1.
b
c
Table 2
Microwave-assisted direct arylation optimization study with substrate 13
Entry
Ligand
Base
Ligand:Pda
Ratio 14:15:13b
1
2
3
4
5
6
7
8
A
E
F
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Ag2CO3
K2CO3
4:2
4:2
4:2
4:2
4:2
4:2
4:2
4:1
8:4
4:2
4:2
1:1
1:1:1
1:4:6
1:1:8
2:1:2
1:3:0
3:1:16
4:1:0
6:1:0
1:1:1
1:4:7
1:6:0
2:1:3
Scheme 1. Synthesis of arylation substrate 10.
G
H
I
D
D
D
D
D
D
To initiate our study, we then attempted the microwave-assisted
direct arylation on 10 using similar conditions as we recently
reported for the synthesis of 4 and other aporphines (Table 1).8
These conditions (Table 1, entry 1) furnished the expected
cyclized product 11 as well as debrominated product 12 in a ratio of
1:5 giving 11 in only 16% isolated yield. Two biphenyl phosphine
ligands B and C were also screened based on the reported utility of
these ligands in the synthesis of the structurally similar seven-
membered ring containing allocolchicinoids.8 Unfortunately, only
debrominated product 12 (Table 1, entries 2 and 3) was obtained
with these ligands. However, we were pleased to find that ligand D
gave us a slight improvement in the product ratio as compared to
ligand A, when either K2CO3 or Cs2CO3 was used as base (Table 1,
entries 4 and 5). Spurred by the preceding, we decided to continue
our examination of this reaction with other substrates. Our prior
success with benzyl ether substrates in the synthesis of nantenine
analogs, prompted us to consider similar substrates for this study.8
Thus, compound 13 (Table 2) was prepared from readily available
starting materials using a similar route as delineated above for
compound 10. We decided to screen a number of ligands for the
direct arylation of 13. With ligand A, we obtained the desired
9
10
11
12
a
Ratio relative to starting material.
Determined by HPLC.
b
cyclized product 14 and the debrominated by-product 15 in addi-
tion to starting material (Table 2, entry 1). Although we could
chromatographically separate compound 13 from a mixture of 14/
15, the mixture of compounds 14 and 15 could not be separated
with a variety of chromatographic procedures attempted.
At this juncture, we decided to investigate other bulky alkylte-
trafluoroborate phosphine ligands. In this examination, ligands E,F
and ligand H gave poor resultsdlow conversion of starting material
and/orsub-optimal ratios of 14:15 (Table 2, entries 2, 3 and 5). Ligand
G gave a slightly better 14:15 product ratio of 2:1 (Table 2, entry 4).
Marginal improvement in this product ratio (3:1) was observed with
the N-heterocyclic carbene ligand I, but the conversion was too low

S. Chaudhary, W.W. Harding / Tetrahedron 67 (2011) 569e575
571
to consider for further investigation (Table 2, entry 6). However, we
were excited to find that ligand D gave a 4:1 ratio of 14:15 (Table 2,
entry 7) with complete consumption of starting material. This ratio
improved to 6:1 when a 4:1 ratio of ligand/Pd was employed (Table
2, entry 8). The 14/15 mixture upon hydrogenolysis furnished
a mixture of 16a and 16b, which was purified by column chroma-
tography to furnish the cyclized phenol 16a in 71% yield over two
steps from 13. Other bases were ineffective in improving the product
ratio or yields of 14 (Table 2, entries 10 and 11). The cyclization of
similar substrates in direct arylation reactions is known to be sus-
ceptible to changes in the ligand/Pd ratio.8a Therefore we decided to
investigate the effectof the ligand/Pd ratio. This brief study indicated
that a 1:1 ratio or 8:4 ratio of ligand/Pd was notoptimal in improving
the product ratio (Table 2, entries 9 and 12).
transformation. An improved route to 3 was executed wherein
compound 20b was sequentially O-methylated (22), Boc-depro-
tected, and N-methylated (Scheme 2).
In further examinations of the substrate scope of the micro-
wave-assisted arylation protocol, we prepared arylation substrates
17aec using similar methods as above, and subjected these sub-
strates to our optimal conditions (Table 3). As in the case of 13,
mixtures of desired cyclized products (18) and the corresponding
debrominated products (19) were obtained; no starting material
(17) was detected in these reactions.
Scheme 2. Synthesis of Homonantenine (3).
3. Conclusions
Table 3
Direct arylation with other substrates
This is the first report on the use of a microwave-assisted direct-
arylation strategy for the synthesis of C-homoaporphine alkaloids.
Of several ligands screened, ligand D, (tricyclohexylphosphine
tetrafluoroborate) proved to be effective for cyclization of a variety
of substrates. N-ethyl carbamate and N-Boc protecting groups are
tolerated with the conditions used. Based on the substrates in-
vestigated, it is apparent that unsubstituted or oxygenated func-
tionalities in the incipient homoaporphine ring D and phenol ether
or phenolic moieties in ring A, are also well tolerated. As compared
to our previously reported aporphine-targeted arylation, the
present method requires slightly longer reaction times (5 min vs
15 min). This is not surprising given the greater entropic cost in
cyclizing a seven-membered versus a six-membered ring. This
arylation methodology should find general applicability in the
synthesis of naturally occurring and biologically active C-homo-
aporphine alkaloids as well as their analogs. Furthermore, these
conditions form a framework for optimizing the challenging seven-
membered ring construction in other chemotypes.
O
O
O
NR3
NR3
NR3
Pd(OAc)2, ligand D,
RO
RO
RO
Br
K2CO3, pivalic acid
+
DMSO, 130 °C,
MW, 15 min
R1
R1
R1
17
18
19
R2
R2
R2
17a R = Bn, R1 = R2 = H, R3 = CO2Et
17b R = Bn, R1 = R2 = OCH2O, R3 = Boc
18a, 19a R = Bn, R1 = R2 = H, R3 = CO2Et
18b, 19b R = Bn, R1 = R2 = OCH2O, R3 = Boc
17c
R = Bn, R1 = R2 = OMe, R3 = CO2Et
18c, 19c
R = Bn,
R
1 = R2 = OMe, R3 = CO2Et
H2/ Pd-C, rt, 2h
O
O
NR3
NR3
HO
+
HO
R1
R1
20
21
R2
R2
20a, 21a R1 = R2 = H, R3 = CO2Et
20b, 21b R1 = R2 = OCH2O, R3 = Boc
20c, 21c
R
1 = R2 = OMe, R3 = CO2Et
O
N
O
Pd(OAc)2, ligand D,
HO
Br
K2CO3, pivalic acid
4. Experimental
O
16a + 16b
DMSO, 130 °C,
MW, 15 min
O
4.1. General experimental procedures
O
17d
All glass apparatus were oven dried prior to use. A CEM Discover
microwave reactor was used to carry out all direct arylation re-
actions. HRESIMS spectra were obtained using an Agilent 6520 Q-
TOF instrument. 1H NMR and 13C NMR spectra were recorded using
Bruker DPX-500 spectrometer (operating at 500 MHz for 1H;
125 MHz, respectively, for 13C) using CDCl3 as solvent. Tetrame-
Entry
Substrate
Ratio (18:19/16a:16b)a
Yield of 20/16a (%)
1
2
3
4
17a
17b
17c
17d
6:1
7:1
5:1
5:1
72b
85b
70b
69c
a
thylsilane (
d
0.00 ppm) served as an internal standard in 1H NMR
No starting material detected.
Isolated yield over two steps from 17aec.
Isolated yield over single step from 17d.
b
c
and CDCl3
(
d
77.0 ppm) in 13C NMR as solvent unless stated oth-
erwise. Chemical shift (d 0.00 ppm) values are reported in parts per
million and coupling constants in hertz (Hz). Splitting patterns are
described as singlet (s), doublet (d), triplet (t), and multiplet (m).
Melting points were obtained on a Mel-Temp capillary electro-
thermal melting point apparatus. Reactions were monitored by TLC
with Whatman Flexible TLC silica gel G/UV 254 precoated plates
(0.25 mm). TLC plates were visualized by UV (254 nm) and by
staining with vanillin spraying reagent (2 gm vanillin in 1 L of 10%
H2SO4) followed by heating. Flash column chromatography was
performed with silica gel 60 (EMD Chemicals, 230e400 mesh,
Debenzylation of the 18/19 product mixtures followed by
chromatographic purification of the resultant phenols gave the
desired cyclized products in good yields. Cyclization of the phenol
17d could also be affected in overall yield comparable to that of the
phenol ether substrates (Table 3, entry 4).
Following the development of successful microwave-promoted
arylation conditions, we then proceeded to prepare (ꢀ)-homo-
nantenine (3). At the outset, this seemed easiest via LAH reduction
of compound 11; however, we obtained only a 19% yield of 3 in this
0.04e0.063
mm particle size). All chemicals and reagents were

572
S. Chaudhary, W.W. Harding / Tetrahedron 67 (2011) 569e575
obtained from SigmaeAldrich and Fischer Scientific (USA) and
were used without further purification.
1.09 mmol), and potassium carbonate (0.228 mg, 1.63 mmol) at room
temperature. The reaction mixture was stirred at the same tempera-
ture for 12 h, quenched with satd NH4Cl solution (10 mL), and
extracted with dichloromethane (3ꢂ20 mL). The organic layer was
washed with water (10 mL), dried over anhyd Na2SO4 and concen-
trated under reduced pressure. The resultant crude product, on col-
umn chromatography over silica gel using EtOAc/Hexanes (20:80) as
eluant furnished a rotameric mixture of 10 (0.497 g, 92% yield) as
4.2. Experimental procedures and characterization data
4.2.1. Synthesis of 3-(6-bromobenzo[d][1,3] dioxol-5-yl)-N-(3,4-dime-
thoxyphenethyl) propanamide (8). A solution of 6 (1.375 gm, 5.1 mmol)
and 1,10-carbonyldiimidazole (0.745 gm, 4.6 mmol, CDI) in anhyd THF
(40 mL) was stirred at 0 ꢁC for 1.5 h and then, at room temperature for
1 h. The mixture was cooled in an ice-bath and stirred for 1 h; then 3,
4-dimethoxyphenethylamine (5) (0.762 mL, 4.6 mmol) was added
and the solution was stirred at 0 ꢁC for 4 h and left stirring overnight
at room temperature. The reaction mixture was evaporated under
reduced pressure and the residue was dissolved in ethyl acetate and
extracted with 1 N HCl (25 mL), washed with water (50 mL), satd
NaHCO3 solution (25 mL), then with water (50 mL), and finally with
brine (50 mL). The organic layer was dried over anhyd Na2SO4 and
concentrated under reduced pressure. The crude product was crys-
tallized from EtOAc/Diethylether to furnish amide 8 as a white solid
a viscous oil. 1H NMR (500 MHz, CDCl3):
d 6.95 (s, 1H), 6.78e6.72 (m,
1H), 6.58 (s, 2H), 5.91 (s, 2H), 5.91 (s, 2H), 5.16 (d, 2H, J¼5.5 Hz),
4.31e4.10 (m, 3H), 3.84 (s, 3H), 3.36e3.27 (m, 1H), 2.92e2.86 (m, 1H),
2.75 (br s, 2H), 2.65 (d, 1H, J¼15.8 Hz), 2.07e2.01 (m, 1H), 1.97 (br s,
1H), 1.30 (t, 3H, J¼6.9 Hz); 13C NMR (125, MHz, CDCl3):
d 156.0 and
155.8 (2ꢂC), 147.8 and 147.7 (2ꢂC), 147.4 and 147.4 (2ꢂC), 146.7 (C),
134.4 and 134.1 (2ꢂC), 129.7 and 129.2 (2ꢂC), 126.2 and 125.8 (2ꢂC),
114.2 and 114.1 (2ꢂC), 112.8 and 112.7 (2ꢂCH), 111.6 and 111.4 (2ꢂCH),
110.1 and 110.0 (2ꢂCH), 109.8 (CH), 101.6 (CH2), 61.5 and 61.4 (2ꢂCH2),
56.0 and 55.9 (2ꢂCH3), 54.2 (CH), 38.1 and 37.5 (2ꢂCH2), 37.2 and 37.0
(2ꢂCH2), 33.4 (CH2), 28.1 and 27.8 (2ꢂCH2), 14.8 and 14.2 (2ꢂCH3);
HRESIMS calculated for C23H26BrNO6 [Mþ]: 491.0944; found 491.0943.
1
(1.538 gm, 77% yield). Mp: 148e150 ꢁC; H NMR (500 MHz, CDCl3):
d
6.96 (s, 1H), 6.79 (d, 1H, J¼8.1 Hz), 6.75 (s, 1H), 6.68 (d, 1H, J¼1.8 Hz),
6.65 (dd,1H, J¼8.1, 1.8 Hz), 5.93 (s, 2H), 5.37 (br t, 1H), 3.86 (s, 6H), 3.47
(dd, 1H, J¼12.9, 6.8 Hz), 2.97e2.94 (m, 2H), 2.71 (t, 2H, J¼6.8 Hz),
4.2.4. Typical microwave-assisted direct arylation procedure for ethyl
11,12-dimethoxy-1,2,4,5-tetrahydro-[1,3] dioxolo [400,500:40,50] benzo
[10,20:6,7] cyclohepta [1,2,3-ij] isoquinoline-3 (3aH)-carboxylate (11). In
a microwave reaction vial, compound 10 (50.0 mg, 0.10 mmol), Pd
(OAc)2 (4.57 mg, 0.02 mmol), ligand D (14.9 mg, 0.04 mmol), K2CO3
(42.2 mg, 0.30 mmol), and pivalic acid (3.1 mg, 0.03 mmol) were
added and dissolved in Ar-purged anhyd DMSO (0.5 mL). The mix-
ture was irradiated in the CEM microwave reactor for 15 min at
130 ꢁC with the power level at 200 W. After cooling to room tem-
perature, the reaction mixture was loaded directly onto a deactivated
silica gel column and eluted with 10% EtOAc/hexanes to furnish
a rotameric mixture of compound 11 (15.2 mg, 36% yield) as a viscous
2.39e2.36 (m, 2H); 13C NMR (125 MHz, CDCl3):
d 171.8 (C), 149.2 (C),
147.9 (C), 147.6 (C), 147.1 (C), 133.2 (C), 131.4 (C), 120.8 (CH), 114.3 (C),
112.8 (CH), 111.9 (CH2), 111.5 (CH), 110.5 (CH), 101.8 (CH2), 56.1 (CH3),
56.0 (CH3), 40.8 (CH2), 36.9 (CH2), 35.4 (CH2), 32.3 (CH2); HRESIMS
calculated for C20H22BrNO5 [Mþ]: 435.0681; found 435.0684.
4.2.2. Synthesis of 1-(2-(6-bromobenzo[d][1,3] dioxol-5-yl) ethyl)-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9). To a magnetically
stirred ice-cooled solution of 8 (0.50 g,1.15 mmol) in dry DCM (25 mL)
was added solid phosphorus pentachloride (0.358 g, 1.71 mmol) in
several portions over 10 min. The reaction mixture was stirred at 0 ꢁC
for 1 h and then left to stir at room temperature for 20 h. The reaction
mixture was then poured onto a saturated solution of satd NaHCO3
(20 mL) and the contents of the flask were stirred for 1 h. The aqueous
layer was extracted with dichloromethane (3ꢂ20 mL). The combined
organic layer was washed with satd NaHCO3 solution (2ꢂ20 mL),
washed with brine (10 mL), dried over anhyd Na2SO4, and concen-
trated under reduced pressure. The crude product was purified by
flash column chromatography over deactivated silica gel using 0.7%
MeOH/DCM as eluant to furnish a crude imine product as a white
solid. To a magnetically stirred ice-cooled solution of this crude imine
in a mixture of dry MeOH (20 mL) and dry DCM (20 mL), was added
powdered NaBH4 (0.437 g, 11.5 mmol) in three portions over 10 min.
The reaction mixture was stirred at 0 ꢁC for 2 h. The mixture was di-
lutedwithwaterandextractedwithdichloromethane(3ꢂ20mL). The
combined organic layer was washed with brine (10 mL), dried over
anhyd Na2SO4, and concentrated in vacuo. The crude product was
purified by flash column chromatography over deactivated silica gel
using 0.7% MeOH/DCM as eluant to furnish pure 9 as a white solid
(0.45 g, 93% yield from 8). Mp: 82e84 ꢁC; 1H NMR (500 MHz, CDCl3):
oil. 1H NMR (500 MHz, CDCl3):
d
6.98 and 6.93 (2ꢂs, 1H), 6.75 and
6.72 (2ꢂs, 1H), 6.68 and 6.65 (2ꢂs, 1H), 6.02e5.94 (m, 2H), 4.74 and
4.60 (2ꢂdd, 1H, J¼10.7, 6.9, 10.6, 7.5 Hz), 4.32 and 4.16 (2ꢂdd, 1H,
J¼13.2, 5.8, 13.5, 5.5 Hz), 4.15e4.01 (m, 2H), 3.88 (s, 3H), 3.49 (s, 3H),
3.26 and 3.17 (2ꢂdt, 1H, J¼12.8, 3.4, 12.9, 3.2 Hz), 2.99e2.88 (m, 1H),
2.74e2.69 (m, 1H), 2.46e2.21 (m, 3H), 2.06e2.01 (m, 1H), 1.19 (2ꢂt,
3H, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
d
155.4 and 155.0 (2ꢂC),
151.9 and 151.8 (2ꢂC), 147.2 and 147.1 (2ꢂC), 146.0 and 144.5 (2ꢂC),
133.1 and 133.0 (2ꢂC), 132.3 and 132.0 (2ꢂC), 129.3 and 128.8 (2ꢂC),
128.2 and 127.9 (2ꢂC), 127.7 (C), 127.1 and 126.5 (2ꢂC), 111.8 and
111.6 (2ꢂCH), 111.1 (CH), 108.5 and 108.2 (2ꢂCH), 101.1 and 101.0
(2ꢂCH2), 61.4 (CH2), 60.6 (CH3), 56.0 (CH3), 50.8 and 50.6 (2ꢂCH),
37.4 and 37.1 (2ꢂCH2), 36.9 and 36.6 (2ꢂCH2), 30.5 and 29.9
(2ꢂCH2), 29.3 and 29.1 (2ꢂCH2), 14.8 and 14.2 (2ꢂCH3); HRESIMS
calculated for C23H25NO6 [Mþ]: 411.1682; found 411.1682.
4.2.5. General procedure for the synthesis of direct arylation substrates
13,17a,17b and 17c: (Compound 13 as representative). To a solution of
the secondary amine precursor (2.876 g, 5.8 mmol) dissolved in dry
dichloromethane (25 mL) was added ethyl chloroformate (0.630 mL,
7.8 mmol), and potassium carbonate (1.204 mg, 8.7 mmol) at room
temperature. The reaction mixture was stirred at the same temper-
ature for 12 h, quenched with satd NH4Cl solution (50 mL) and
extracted with dichloromethane (3ꢂ50 mL). The organic layer was
washed with water (50 mL), dried over anhyd Na2SO4 and concen-
trated under reduced pressure. The resultant crude product, on
column chromatography over silica gel using EtOAc/hexanes (20:80)
as eluant, furnished a rotameric mixture of 13 (2.571 g, 78% yield) as
a white solid.
d
6.97 (s,1H), 6.81 (s,1H), 6.61 (s,1H), 6.57 (s,1H), 5.93 (dd, 2H, J¼2.6,
1.1 Hz), 4.08 (t, 1H, J¼5.5 Hz), 3.85 (s, 3H), 3.84 (s, 3H), 3.36e3.31 (m,
1H), 3.09e3.04 (m, 1H), 2.82 (m, 3H, J¼2.6 Hz), 2.73 (td, 1H, J¼16.1,
5.1 Hz), 2.0 (dd, 2H, J¼14.3, 8.0 Hz); 13C NMR (125MHz, CDCl3):
d 147.7
(C), 147.6 (C), 147.5 (C), 146.8 (C), 134.6 (C), 126.8 (C), 114.3 (C), 112.8
(CH), 111.8 (CH), 110.3 (CH), 109.3 (CH), 101.7 (CH2), 56.2 (CH3), 56.0
(CH3), 55.2 (CH), 41.1 (CH2), 36.4 (CH2), 32.8 (CH2), 28.9 (CH2); HRE-
SIMS calculated for C20H22BrNO4 [Mþ]: 419.0732; found 419.0726.
4.2.3. Synthesis of ethyl 1-(2-(6-bromobenzo[d][1,3] dioxol-5-yl) ethyl)-
6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (10). To
a
4.2.5.1. Ethyl 7-(benzyloxy)-1-(2-(6-bromobenzo[d][1,3] dioxol-5-yl)
solution of compound 9 (0.46 g, 1.09 mmol) dissolved in dry
dichloromethane (25 mL) was added ethyl chloroformate (0.10 mL,
ethyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (13). Mp:
85e87 ꢁC; 1H NMR (500 MHz, CDCl3):
d
7.41 (d, 2H, J¼6.7 Hz),

S. Chaudhary, W.W. Harding / Tetrahedron 67 (2011) 569e575
573
7.35e7.32 (m, 2H), 7.27e7.25 (m,1H), 6.96 (d,1H, J¼7.7 Hz), 6.72e6.58
(m, 3H), 5.93 (s, 2H), 5.12e5.00 (m, 3H), 4.25e4.06 (m, 3H), 3.85 (s,
3H), 3.29 (m,1H), 2.90e2.84 (m,1H), 2.65e2.61 (m, 3H), 1.99e1.91 (m,
1H), 1.82e1.78 (m, 1H), 1.28 (t, 3H, J¼7.1 Hz); 13C NMR (125 MHz,
(17d). Mp: 128e130 ꢁC; 1H NMR (500 MHz, CDCl3):
d
6.96e6.56 (m,
4H), 5.92 (s, 2H), 5.55 (s, 1H), 5.17e5.05 (m, 1H), 4.36e4.18 (m, 3H),
3.84 (br s, 3H), 3.33e3.25 (m, 1H), 2.89e2.87 (m, 1H), 2.72e2.60 (m,
3H), 2.53e2.46 and 2.29e2.24 (2ꢂm, 1H), 2.02e1.96 (m, 2H),
CDCl3):
d
156.1 and 155.9 (2ꢂC),148.7 and 148.5 (2ꢂC),147.5 (C),146.7
1.30e1.287 (m, 3H); 13C NMR (125 MHz, CDCl3):
d 155.9 (C),147.5 and
and 146.7 (2ꢂC), 146.6 (C), 137.2 (C), 134.5 and 134.2 (2ꢂC), 129.7 and
129.3 (2ꢂC), 128.7 (CH), 128.0 (CH), 127.5 (CH), 127.1 and 126.7 (2ꢂC),
114.4 (C), 113.3 and 113.2 (2ꢂCH), 112.9 and 112.8 (2ꢂCH), 112.2 and
112.1 (2ꢂCH),110.2 and 109.9 (2ꢂCH),101.7 (CH2), 71.5 (CH2), 61.6 and
61.5 (2ꢂCH), 56.2 (CH3), 54.2 (CH), 38.2 and 37.6 (2ꢂCH2), 37.2 and
37.1 (2ꢂCH2), 33.4 (CH2), 28.3 and 28.0 (2ꢂCH2), 14.9 (CH3); HRESIMS
calculated for C29H30BrNO6 [Mþ]: 567.1257; found 567.1260.
147.5 (2ꢂC), 147.4 and 147.3 (2ꢂC), 146.6 (C), 146.6 and 145.6 (2ꢂC),
145.5 and 145.5 (2ꢂC), 145.3 (C), 143.9 (C), 135.9 and 135.6 (2ꢂC),
134.4 and 134.1 (2ꢂC), 130.4 and 130.0 (2ꢂC), 125.5 and 125.2
(2ꢂCH), 121.0 (CH), 114.2 and 114.1 (2ꢂC), 113.0 and 112.9 (2ꢂCH),
112.7 and 112.7 (2ꢂCH), 112.6 (C), 110.8 and 110.7 (2ꢂCH), 110.1 and
110.0 (2ꢂCH), 109.7 (CH), 108.8 and 108.2 (2ꢂCH), 101.6 and 100.6
(2ꢂCH2), 68.5 (CH2), 61.4 and 61.4 (2ꢂCH), 55.9 (CH3), 54.0 and 53.9
(2ꢂCH), 38.8 and 38.1 (2ꢂCH2), 37.5 and 37.1 (2ꢂCH2), 33.3 and 32.4
(2ꢂCH2), 28.2 and 27.9 (2ꢂCH2), 14.7 (CH3); HRESIMS calculated for
C22H24BrNO6 [Mþ]: 477.0787; found 477.0792.
4.2.5.2. Ethyl 7-(benzyloxy)-1-(2-bromophenethyl)-6-methoxy-
3,4-dihydroisoquinoline-2(1H)-carboxylate (17a). Mp: 71e73 ꢁC; 1H
NMR (500 MHz, CDCl3):
d 7.52e7.51 (m, 1H), 7.41 (m, 2H), 7.33 (t,
2H, J¼7.1 Hz), 7.24e7.15 (m, 3H), 7.06e7.04 (m, 1H), 6.61e6.59 (m,
2H), 5.15e5.04 (m, 3H), 4.29e4.07 (m, 3H), 3.85 (s, 3H), 3.36e3.24
(m, 1H), 2.93e2.75 (m, 3H), 2.65e2.62 (m, 1H), 2.04e2.00 (m, 1H),
1.87 (m, 1H), 1.28 (t, 3H, J¼7.1 Hz); 13C NMR (125 MHz, CDCl3):
4.2.6. General procedure for the microwave-assisted direct arylation
for the synthesis of 16a, 20a, 20b and 20c (Table 2, entry 8, com-
pound 16a as representative). In a microwave reaction vial, com-
pound 17 (50.0 mg, 0.088 mmol), Pd(OAc)2 (1.98 mg, 8.8 mmol),
d
156.1 and 156.0 (2ꢂC), 148.7 and 148.5 (2ꢂC), 146.6 (C), 141.5 and
ligand D (12.98 mg, 0.035 mmol), K2CO3 (48.74 mg, 0.35 mmol), and
pivalic acid (3.60 mg, 0.035 mmol) were added and dissolved in Ar-
purged anhyd DMSO (1.0 mL). Themixturewas irradiated in the CEM
microwave reactor for 15 min at 130 ꢁC with the power level at
200 W. After cooling to room temperature, the reaction mixture was
loaded directly onto a deactivated silica gel column and eluted with
15% EtOAc/hexanes to furnish compounds 14 and 15 in a ratio of 6:1.
This mixture on debenzylation with palladiumecharcoal furnished
the crude cyclized and debrominated mixture of 16a and 16b, which
on flash column chromatography over silica gel using EtOAc/DCM
(5: 95) as eluant, furnished a rotameric mixture of homoaporphine
phenol 16a (25.0 mg, 71% yield from 17) as a white solid.
141.3 (2ꢂC), 137.2 (C), 133.0 and 132.9 (2ꢂCH), 130.6 and 130.2
(2ꢂCH), 129.7 and 129.3 (2ꢂC), 128.7 (CH), 128.0 (CH), 127.8 and
127.7 (2ꢂCH), 127.6 and 127.5 (2ꢂCH), 127.1 and 126.7 (2ꢂC), 124.6
and 124.5 (2ꢂC), 113.3 and 113.2 (2ꢂCH), 112.2 and 112.1 (2ꢂCH),
71.58 and 71.52 (2ꢂCH2), 61.6 and 61.5 (2ꢂCH2), 56.2 (CH3), 54.3
and 54.2 (2ꢂCH), 38.2 and 37.6 (2ꢂCH2), 37.2 and 36.9 (2ꢂCH2),
33.5 (CH2), 28.3 and 28.1 (2ꢂCH2), 14.9 (CH3); HRESIMS calculated
for C28H30BrNO4 [Mþ]: 523.1358; found 523.1365.
4.2.5.3. tert-Butyl 7-(benzyloxy)-1-(2-(6-bromobenzo[d][1,3] di-
oxol-5-yl) ethyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxyl-
ate (17b). Mp: 74e76 ꢁC; 1H NMR (500 MHz, CDCl3):
d 7.41 (br s, 2H),
7.31 (t, 2H, J¼7.2 Hz), 7.25e7.23 (m, 1H), 6.94 (d, 1H, J¼8.6 Hz),
6.62e6.61 (m, 3H), 5.87 (s, 2H), 5.11e5.06 (m, 3H), 4.27e4.03 (2ꢂd,
1H, J¼9.8, 10.4 Hz), 3.82 (s, 3H), 3.28e3.15 (m, 1H), 2.88e2.82 (m,
1H), 2.68e2.59 (m, 3H), 1.97e1.89 (m, 1H), 1.84 (m, 1H), 1.49 (s, 9H);
4.2.6.1. Ethyl 11-hydroxy-12-methoxy-1,2,4,5-tetrahydro-[1,3] di-
oxolo [400,500:40,50] benzo [10,20:6,7] cyclohepta [1,2,3-ij] isoquinoline-3
(3aH)-carboxylate (16a). Mp: 140e142 ꢁC; 1H NMR (500 MHz,
CDCl3):
d
7.05 and 6.99 (2ꢂs, 1H), 6.77 and 6.74 (2ꢂs, 1H), 6.63 and
13C NMR (125 MHz, CDCl3):
d
155.0 and 154.7 (2ꢂC), 148.4 and 148.2
6.60 (2ꢂs, 1H), 6.03e5.95 (m, 2H), 5.69 and 5.66 (2ꢂs, 1H), 4.78 and
4.64 (2ꢂdd, 1H, J¼10.8, 7.5, 10.4, 7.6 Hz), 4.32 and 4.15 (2ꢂdd, 1H,
J¼13.1, 5.6,13.0, 5.6 Hz), 4.11e4.00 (m, 2H), 3.91 (s, 3H), 3.28 and 3.19
(dt, 1H, J¼12.8, 3.4 Hz), 2.97e2.86 (m, 1H), 2.69 (t, 1H, J¼13.0 Hz),
2.44e2.42 (m, 2H), 2.37e2.21 (m, 1H), 2.04e1.99 (m, 1H), 1.23 and
(2ꢂC), 147.3 (C), 146.5 and 146.4 (2ꢂC), 137.1 (C), 134.4 and 134.1
(2ꢂC), 129.7 and 129.2 (2ꢂC), 128.5 (CH), 127.8 (CH), 127.4 and 127.3
(2ꢂCH), 127.1 and 126.7 (2ꢂC), 114.2 and 114.1 (2ꢂC), 113.1 (CH),
112.6 and 112.6 (2ꢂCH), 112.1 and 111.9 (2ꢂCH), 110.0 and 109.5
(2ꢂCH), 101.5 (CH2), 79.9 and 79.5 (2ꢂC), 71.3 (CH2), 55.9 (CH3), 54.3
and 53.3 (2ꢂCH), 38.3 and 36.9 (2ꢂCH2), 37.2 and 36.8 (2ꢂCH2), 33.3
and 31.5 (2ꢂCH2), 28.5 (CH3), 28.2 and 28.0 (2ꢂCH2); HRESIMS
calculated for C31H34BrNO6 [Mþ]: 595.1570; found 595.1569.
1.14 (t, 3H, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
d 155.4 and 155.0
(2ꢂC), 147.1 and 147.1 (2ꢂC), 145.9 and 145.9 (2ꢂC), 145.8 (C), 140.5
and 140.5 (2ꢂC), 133.5 and 133.4 (2ꢂC), 127.2 and 127.1 (2ꢂC), 126.7
(C), 124.7 and 124.3 (2ꢂC), 124.1 and 123.8 (2ꢂC), 110.9 and 110.9
(2ꢂCH), 110.0 and 109.9 (2ꢂCH), 108.9 and 108.7 (2ꢂCH), 101.1 and
101.0 (2ꢂCH2), 61.4 (CH2), 56.2 (CH3), 50.8 and 50.7 (2ꢂCH), 37.5 and
37.3 (2ꢂCH2), 37.0 and 36.8 (2ꢂCH2), 30.5 and 29.9 (2ꢂCH2), 29.0
and 28.9 (2ꢂCH2), 14.7 and 14.7 (2ꢂCH3); HRESIMS calculated for
C22H23NO6 [Mþ]: 397.1525; found 397.153.
4.2.5.4. Ethyl-7-(benzyloxy)-1-(2-bromo-4,5-dimethox-
yphenethyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate
(17c). Mp: 76e78 ꢁC; 1H NMR (500 MHz, CDCl3):
d 7.41e7.40 (m, 2H),
7.33 (t, 2H, J¼7.0 Hz), 7.26e7.25 (m, 1H), 6.98 (s, 1H), 6.79e6.58 (m,
3H), 5.14e5.05 (m, 3H), 4.30e4.06 (m, 3H), 3.84 (s, 6H), 3.83 (s, 3H),
3.37e3.24 (m, 1H), 2.94e2.85 (m, 1H), 2.69e2.62 (m, 3H), 2.04e2.00
(m, 1H), 1.93e1.85 (m, 1H), 1.29 (t, 3H, J¼7.0 Hz); 13C NMR (125 MHz,
4.2.6.2. Ethyl
[6,7] cyclohepta [1,2,3-ij] isoquinoline-3 (3aH)-carboxylate
(20a). Mp: 68e70 ꢁC; 1H NMR (500 MHz, CDCl3):
7.53 (d, 1H,
10-hydroxy-11-methoxy-1,2,4,5-tetrahydrobenzo
CDCl3):
d
156.1 and 155.9 (2ꢂC), 148.7 and 148.5 (2ꢂC), 148.0 and
d
147.9 (2ꢂC), 146.6 (C), 137.2 (C), 133.4 and 133.2 (2ꢂC), 129.7 and
129.3 (2ꢂC), 128.6 (CH), 128.0 (CH), 127.5 (CH),127.1 and 126.7 (2ꢂC),
115.7 and 115.6 (2ꢂCH), 114.1 and 113.9 (2ꢂC), 113.4 and 113.2
(2ꢂCH),112.9 and 112.2 (2ꢂCH),112.1 and 112.1 (2ꢂCH), 71.5 and 71.5
(2ꢂCH2), 61.6 and 61.5 (2ꢂCH2), 56.3 (CH3), 56.2 (CH3), 56.1 (CH3),
54.4 and 54.1 (2ꢂCH), 38.2 and 37.6 (2ꢂCH2), 37.4 and 36.9 (2ꢂCH2),
33.3 and 33.2 (2ꢂCH2), 28.2 and 28.0 (2ꢂCH2), 14.9 (CH3); HRESIMS
calculated for C30H34BrNO6 [Mþ]: 583.1570; found 583.1571.
J¼7.5 Hz), 7.35e7.29 (m, 2H), 6.64 (s, 1H), 5.66 (s, 1H), 4.78 and 4.63
(2ꢂdd, 1H, J¼10.5, 7.5, 10.2, 8.0 Hz), 4.32 and 4.16 (2ꢂdd, 1H,
J¼13.0 Hz, 5.8 Hz, J¼13.1, 5.5 Hz), 4.09e3.97 (m, 2H), 3.92 (s, 3H),
3.29 and 3.20 (dt, 1H, J¼12.7, 3.2 Hz), 2.98e2.88 (m, 1H), 2.73e2.67
(m, 1H), 2.57e2.48 (m, 2H), 2.35 and 2.26 (m, 1H), 2.14e2.04 (m,
1H), 1.23 and 1.09 (t, 3H, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
d
155.4 (C), 146.0 and 145.9 (2ꢂC), 140.6 (C), 139.5 and 139.4 (2ꢂC),
134.4 and 134.3 (2ꢂC), 130.5 and 130.4 (2ꢂCH), 131.1 and 130.6
(2ꢂC), 128.6 and 128.3 (2ꢂCH), 128.2 and 128.1 (2ꢂCH), 127.1 and
126.7 (2ꢂC), 126.2 and 126.1 (2ꢂC), 124.7 and 124.3 (2ꢂC), 110.3
and 110.1 (2ꢂCH2), 61.3 (CH2), 56.2 (CH3), 50.8 and 50.6 (2ꢂCH),
4.2.5.5. Ethyl 1-(2-(6-bromobenzo[d][1,3]dioxol-5-yl)ethyl)-7-hy-
droxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

574
S. Chaudhary, W.W. Harding / Tetrahedron 67 (2011) 569e575
37.5 and 37.1 (2ꢂCH2), 37.0 and 36.5 (2ꢂCH2), 29.9 (CH2), 29.1 and
28.9 (2ꢂCH2), 14.8 and 14.8 (2ꢂCH3); HRESIMS calculated for
C21H23NO4 [Mþ]: 353.1627; found 353.1628.
29.7 (2ꢂCH2), 29.2 and 29.0 (2ꢂCH2); HRESIMS calculated for
C25H29NO6 [Mþ]: 439.1995; found 439.1994.
4.2.8. Preparation of (ꢀ)-Homonantenine 11,12-dimethoxy-3-methyl-
1, 2,3,3a,4,5-hexahydro [1,3] dioxolo [400,500:40,50] benzo [10,20:6,7]
cyclohepta [1,2,3-ij] isoquinoline (3). To a solution of 22 (9.0 mg,
0.02 mmol) in dry dichloromethane (10 mL), was added dry zinc
bromide (18.46 mg, 0.08 mmol). The reaction mixture was allowed
to stir at room temperature for 45 min. The reaction was quenched
with water (10 mL) and extracted with dichloromethane (3ꢂ10 mL).
The combined organic layer was washed with water (10 mL), then
with brine (10 mL), dried over anhyd Na2SO4, and concentrated to
give the crude amine. To a solution of this amine in dichloromethane
(10 mL) was added 37% formaldehyde solution (0.017 mL,
0.607 mmol) and sodium triacetoxyborohydride (21.8 mg,
0.10 mmol). The reaction mixture was allowed to stir at room tem-
perature for 1 h. The reaction was quenched with water (10 mL) and
extracted with dichloromethane (3ꢂ10 mL). The combined organic
layer was washed with water (10 mL), then with brine (10 mL), dried
over anhyd Na2SO4, and concentrated to give crude 3, which on
column chromatography over deactivated silica gel using methanol/
dichloromethane (2:98) as eluant, furnished 3 (4.5 mg, 66% yield) as
4.2.6.3. tert-Butyl 11-hydroxy-12-methoxy-1,2,4,5-tetrahydro-[1,3]
dioxolo [400,500:40,50] benzo [10,20:6,7] cyclohepta [1,2,3-ij] isoquinoline-3
(3aH)-carboxylate (20b). Mp: 58e60 ꢁC; 1H NMR (500 MHz, CDCl3):
d
7.05 and 6.99 (2ꢂs,1H), 6.76 and 6.73 (2ꢂs,1H), 6.63 and 6.60 (2ꢂs,
1H), 5.96 (t, 2H, J¼16.8 Hz), 5.69 and 5.66 (2ꢂs, 1H), 4.76 and 4.57
(2ꢂdd, 1H, J¼10.8, 7.2, 10.4, 7.6 Hz), 4.26 and 4.10 (2ꢂdd, 1H, J¼12.8,
5.8, 13.3, 5.5 Hz), 3.91 (s, 3H), 3.24 and 3.13 (2ꢂdt, 1H, J¼12.8, 3.7,
12.7, 3.6 Hz), 2.92 and 2.86 (dt, 1H, J¼19.5, 6.2, 12.5, 5.9 Hz),
2.72e2.64 (m, 1H), 2.45e2.41 (m, 2H), 2.38e2.21 (m, 1H), 2.02e1.98
(m, 1H), 1.42 (s, 5H), 1.33 (s, 4H); 13C NMR (125 MHz, CDCl3):
d 154.6
and 154.2 (2ꢂC), 147.1 and 147.0 (2ꢂC), 145.9 and 145.9 (2ꢂC), 145.8
and 145.7 (2ꢂC), 140.4 (C), 133.6 and 133.5 (2ꢂC), 127.5 and 127.3
(2ꢂC), 127.2 and 126.9 (2ꢂC), 124.7 and 124.4 (2ꢂC), 124.2 and 123.8
(2ꢂC), 110.9 and 110.8 (2ꢂCH), 110.0 and 109.9 (2ꢂCH), 109.0 and
108.4 (2ꢂCH), 101.0 (CH2), 79.7 (C), 56.2 (CH3), 51.1 and 50.1 (2ꢂCH),
37.8 and 37.1 (2ꢂCH2), 36.8 and 36.4 (2ꢂCH2), 30.6 (CH2), 29.9 and
29.8 (2ꢂCH2), 29.1 and 29.0 (2ꢂCH2), 28.6 and 28.5 (2ꢂCH3); HRE-
SIMS calculated for C24H27NO6 [Mþ]: 425.1838; found 425.1869.
a viscous oil. 1H NMR (500 MHz, CDCl3):
d 6.98 (s, 1H), 6.73 (s, 1H),
4.2.6.4. Ethyl 10-hydroxy-7,8,11-trimethoxy-1,2,4,5-tetrahydrobenzo
[6,7] cyclohepta [1,2,3-ij] isoquinoline-3 (3aH)-carboxylate (20c). Mp:
6.66 (s,1H), 5.98 (dd, 2H, J¼12.1,1.1 Hz), 3.88 (s, 3H), 3.48 (s, 3H), 3.27
(dd, 1H, J¼11.1, 6.8 Hz), 3.15 (dt, 1H, J¼11.4, 3.8 Hz), 3.06e2.99 (m,
1H), 2.81 (dd, 1H, J¼12.0, 5.2 Hz), 2.66e2.63 (br s, 1H), 2.46 (dd, 1H,
J¼12.9, 5.6 Hz), 2.40 (s, 3H), 2.32 (dt, 1H, J¼12.9, 6.7 Hz), 2.06e2.00
208e210 ꢁC; 1H NMR (500 MHz, CDCl3):
d
7.11 and 7.06 (2ꢂs,1H), 6.80
and 6.77 (2ꢂs, 1H), 6.64 and 6.61 (2ꢂs, 1H), 5.68 and 5.65 (2ꢂs, 1H),
4.79 and 4.63 (2ꢂdd, 1H, J¼10.7, 7.3, 10.4, 7.6 Hz), 4.33 and 4.16 (2ꢂdd,
1H, J¼13.1, 5.8, 13.6, 5.8 Hz), 4.14e4.07 and 4.04e4.00 (m, 2H), 3.94
and 3.91 (s, 3H), 3.92 and 3.92 (s, 3H), 3.88 and 3.85 (s, 3H), 3.28 and
3.19 (dt, 1H, J¼12.9, 3.4 Hz), 2.98e2.87 (m, 1H), 2.73e2.67 (m, 1H),
2.50e2.46 (m, 1H), 2.41e2.33 and 2.31e2.23 (m, 1H), 2.12e2.09 (m,
(m, 1H); 13C NMR (125 MHz, CDCl3):
d 151.4 (C), 146.7 (C), 145.6 (C),
144.1 (C), 133.1 (C), 132.3 (C), 130.0 (C), 127.9 (C), 111.4 (CH), 110.7
(CH), 108.0 (CH), 100.8 (CH2), 60.3 (CH3), 58.10 (CH), 55.8 (CH3), 45.0
(CH2), 41.7 (CH3), 34.7 (CH2), 30.3 (CH2), 29.7 (CH2); HRESIMS cal-
culated for C21H23NO4 [Mþ]: 353.1627; found 353.1627.
1H), 1.23 and 1.11 (t, 3H, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
d 163.9
(C), 159.5 (C), 155.2 (C), 148.4 and 148.2 (2ꢂC), 146.9 and 146.8 (2ꢂC),
145.8 and 145.7 (2ꢂC),140.2 (C),132.2 and 132.1 (2ꢂC),127.1 (C),126.6
(C), 126.0 and 125.9 (2ꢂC), 124.7 (C), 124.2 (C), 123.8 (C), 113.7 and
113.6 (CH), 111.6 and 111.3 (CH), 109.8 and 109.6 (2ꢂCH), 61.2 (CH2),
56.1 and 56.0 (2ꢂCH3), 56.0 (CH3), 55.9 and 55.8 (2ꢂCH3), 50.8 and
50.6 (2ꢂCH), 37.3 and 37.2 (2ꢂCH2), 36.8 and 36.8 (2ꢂCH2), 30.1 and
29.7 (2ꢂCH2), 28.9 and 28.7 (2ꢂCH2), 14.7 (CH3); HRESIMS calculated
for C23H27NO6 [Mþ]: 413.1838; found 413.1846.
4.3. HPLC and microwave conditions
HPLC was conducted with an Agilent 1200 system with the
following conditions: flow rate: 1 mL/min; detection wavelength:
254 nm; retention times: Compound 14: 8.33 min, Compound 15:
9.08 min, Compound 13: 11.27 min; Column: Agilent Eclipse XDB-
C18; Eluant 80:20 (Water: Methanol).
Microwave reactions were conducted in closed vessel in a CEM
Discover microwave using the following conditions: temperature:
130 ꢁC; power: 200 W; pressure: 175 Psi; mode: Standard.
4.2.7. Preparation of tert-butyl 11, 12-dimethoxy-1,2,4,5-tetrahydro-
[1,3] dioxolo [400,500:40,50] benzo [10,20:6,7] cyclohepta [1,2,3-ij] isoquino-
line-3(3aH)-carboxylate (22). To
a solution of 20b (0.025 g,
Acknowledgements
0.058 mmol) and methyl iodide (0.073 mL, 1.17 mmol) dissolved in
dry acetone (20 mL) was added potassium carbonate (0.081 gm,
0.58 mmol) and potassium iodide (0.097 g, 0.58 mmol), and the
mixture refluxed for 6 h. The acetone was evaporated; water (10 mL)
was added to the residue and extracted with dichloromethane
(3ꢂ10 mL). The combined organic layer was dried over anhyd
Na2SO4 and concentrated under reduced pressure. The crude prod-
uct on flash column chromatography over deactivated silica gel using
EtOAc/Hexane (1: 9) as eluant, furnished 22 (0.0215 g, 83% yield) as
a white solid (mixture of rotamers). Mp: 74e76 ꢁC; 1H NMR
This publication was made possible by Grant Number RR03037
and R03DA025910 from the National Center for Research Resources
(NCRR) and National Institute of Drug Abuse (NIDA), respectively,
components of the National Institutes of Health. Its contents are
solely the responsibility of the authors and do not necessarily
represent the official views of the NIH or its divisions.
Supplementary data
(500 MHz, CDCl3):
d
6.97 and 6.92 (2ꢂs,1H), 6.75 and 6.72 (2ꢂs,1H),
1H NMR and 13C NMR spectra of compounds 8e11, 13, 16a,
17aed, 20aec, 22 and 3. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2010.11.059. These data include MOL files and InChiKeys of the
most important compounds described in this article.
6.68 and 6.65 (2ꢂs, 1H), 5.98e5.91 (s, 2H), 4.73 and 4.53 (2ꢂdd, 1H,
J¼11.1, 7.1, 10.7, 7.3 Hz), 4.26 and 4.10 (2ꢂdd, 1H, J¼13.0 Hz, 5.4 Hz,
J¼13.1 Hz, 5.8 Hz), 3.88 (s, 3H), 3.49 (s, 3H), 3.23 and 3.12 (2ꢂdt, 1H,
J¼12.9, 3.6, 12.7, 3.4 Hz), 2.96e2.84 (m, 1H), 2.75e2.67 (m, 1H),
2.47e2.43 (m, 2H), 2.41e2.28 (m,1H), 2.02e1.98 (m,1H),1.42 (s, 6H),
1.33 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 154.3 (C), 151.6 and 151.5
References and notes
(2ꢂC), 146.9 (C), 145.8 (C), 144.3 (C), 132.8 and 132.1 (2ꢂC), 128.7 and
127.5 (2ꢂC), 127.1 and 126.5 (2ꢂC), 111.4 and 111.0 (2ꢂCH), 108.3 and
107.7 (2ꢂCH), 100.8 (CH2), 79.5 (C), 60.4 (CH3), 55.8 (CH3), 50.8 and
49.9 (2ꢂCH), 37.5 and 36.6 (2ꢂCH2), 36.3 and 36.1 (2ꢂCH2), 30.3 and
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