Monoligated Pd(0)-catalyzed intramolecular ortho- and para-arylation of phenols for the synthesis of aporphine alkaloids. Synthesis of (-)-lirinine

Article abstract of DOI:10.1016/j.tet.2011.12.022

An intramolecular palladium(0)-mediated ortho-arylation of phenols applied to the synthesis of various substituted aporphines is reported. Most significantly, the efficiency of the transformation was enhanced by the use of monoligated Pd(0) complexes. This methodology was extended to para-arylation of phenols and employed in the synthesis of the aporphine alkaloid (-)-lirinine.

Full text of DOI:10.1016/j.tet.2011.12.022

Tetrahedron 68 (2012) 1674e1681
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Tetrahedron
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Monoligated Pd(0)-catalyzed intramolecular ortho- and para-arylation of phenols
for the synthesis of aporphine alkaloids. Synthesis of (ꢀ)-lirinine
*
Malik Hellal, Shambhavi Singh, Gregory D. Cuny
Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women’s Hospital and Harvard Medical School, 65 Landsdowne Street,
Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An intramolecular palladium(0)-mediated ortho-arylation of phenols applied to the synthesis of various
substituted aporphines is reported. Most significantly, the efficiency of the transformation was enhanced
by the use of monoligated Pd(0) complexes. This methodology was extended to para-arylation of phenols
and employed in the synthesis of the aporphine alkaloid (ꢀ)-lirinine.
Received 9 November 2011
Received in revised form 7 December 2011
Accepted 9 December 2011
Available online 14 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aporphines
Alkaloids
Catalysis
Palladium
Phenol
1. Introduction
OH
MeO
ortho-Arylation of phenols represents a strategy for constructing
arylearyl bonds. Several approaches have been described in the
literature to mediate this process, including Pd-catalyzed,1 Rh-
catalyzed,2 base-mediated,3 enzymatic,4 photochemical,5 or oxi-
dative reactions,6 and using the PinheyeBarton route.7 Many of
these methods have limited applicability due to lack of functional
group tolerance to the required harsh reaction conditions, such as
strong base or high temperature. Although Pd-mediated methods
represent a promising route for intramolecular ortho-arylations of
phenols, prolonged heating (24e48 h) and high catalyst loadings
(20e50 mol %) have previously been necessary for this process,
even with aryl iodides.1
Aporphine alkaloids are a class of natural products that have
demonstrated interesting and assorted biological activities,8 such
as the non-selective dopamine agonist (ꢀ)-apomorphine used in
the treatment of Parkinson’s disease and (ꢀ)-lirinine (also known
as 3-hydroxynuciferine), which was isolated from the leaves of
Liriodendron tulipifera and exerts spasmolytic and hypotensive
properties (Fig. 1).9,10 The prominence of aporphines has attracted
significant interest by the synthetic organic chemistry community
resulting in the development of numerous methods for their
N
NH
N
Me
MeO
Me
HO
HO
aporphine
(-)-apomorphine
(-)-lirinine
Fig. 1. Aporphine scaffold and examples of aporphine alkaloids.
preparation.11 Furthermore, the ortho- or para-aryl phenol motifs
found among many members of the aporphines makes this scaffold
interesting for studying intramolecular arylation of phenols. Herein
is reported a convenient method for the synthesis of various
aporphines using an efficient intramolecular phenol ortho-aryla-
tion reaction. This process was then extended to para-arylation of
phenols and applied to the synthesis of the aporphine alkaloid
(ꢀ)-lirinine.
Buchwald and co-workers recently reported the development of
a new class of air- and moisture-stable Pd-precatalysts that are
activated under standard reaction conditions and ensure the for-
mation of the monoligated active complex of Pd(0) (Fig. 2).12 The
L1Pd(0) species generated by the precatalysts presents the advan-
tage to be less sterically hindered and highly reactive, which we
hypothesized may be beneficial for mediating the intramolecular
ortho-arylation of phenols. Thus, the exploration of these pre-
catalysts for the synthesis of aporphines was undertaken.
* Corresponding author. Tel.: þ1 617 768 8640; fax: þ1 617 768 8606; e-mail
address: gcuny@rics.bwh.harvard.edu (G.D. Cuny).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.022

M. Hellal et al. / Tetrahedron 68 (2012) 1674e1681
1675
Table 1
OMe
Optimization of the intramolecular ortho-arylation of phenolsa
PCy2
i-Pr
MeO
i-Pr
PCy2
i-Pr
PCy2
OMe
NH
i-Pr
Pd
MeO
[Pd]
N
N
Cl
L
HO
Ts
HO
Ts
i-Pr
i-Pr
X
precatalyst
BrettPhos
XPhos
SPhos
6a X=Br
7 X=Cl
8a
Fig. 2. Structure of Pd-precatalysts and various associated ligands (L).
Entry
Substrate
Catalyst
Yieldb (%)
2. Results and discussion
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6a
6a
6a
7
Pd(OAc)2 (20%), PCy3 (40%)
XPhos precat. (5%)
Pd(OAc)2 (5%), XPhos (10%)
BrettPhos precat. (5%)
SPhos precat. (5%)
XPhos precat. (1%)
XPhos precat. (3%)
XPhos precat. (5%)
56c
93
0c
2.1. Preparation of tetrahydroisoquinolines 6aef and 7
20c
83
9c
The sulfonamides 4aec were obtained in a three-step process
involving a Henry reaction of benzaldehydes,13 followed by re-
duction of the nitrostyrene and reaction with p-toluenesulfonyl
chloride (Scheme 1). The substrate tetrahydroisoquinolines 6aef
and 7 were prepared utilizing a PicteteSpengler cyclization of the
sulfonamides 4aec and acetaldehydes 5aee under acidic condition.
Acetaldehydes 5aee were synthesized using various methods.
60d
0c
a
Reaction condition: 6a or 7 (1 equiv), [Pd] (mol %), Cs2CO3 (3 equiv), DMA,
110 ꢁC, 1 h.
b
c
Isolated yield.
110 ꢁC for 24 h.
110 ꢁC for 3 h.
d
R1
R1
MeNO
BrettPhos or SPhos (entries 4 and 5). Decreasing the catalyst
loading to 1 or 3 mol % also resulted in lower yields of 9% and 60%,
respectively (entries 6 and 7). Furthermore, no reaction was ob-
served with chlorine substrate 7 (entry 8).
R2
R3
CHO
R2
R3
NO2
2
LiAlH
4
52-69%
65-79%
1a R =OH, R =R =H
2a R =OH, R =R =H
1
2
3
1
2
3
1b R =OH, R =R =OMe
2b R =OH, R =R =OMe
1
2
3
1
2
3
2.3. Substrate scope of intramolecular ortho- and para-
arylation of phenols
R1
With optimized conditions identified, the phenol arylation was
extended to the synthesis of various aporphines. As shown in Table
2, electron-donating and electron-withdrawing groups were tol-
erated in this process and gave the expected aporphines in good
yields (entries 1 and 2). Moreover, a homoaporphine, representing
a related class of natural products,14 was also synthesized in 76%
yield using the same reaction conditions (entry 3). Next the use of
this methodology was extended to para-arylation of phenols. Using
the same reaction conditions, an aporphine was synthesized via
a phenol para-arylation in 88% yield (entry 4). However, with
a substrate containing a methoxy group ortho to the arylation site,
the process required 10 mol % of catalyst, presumably due to in-
creased steric hindrance for CeC bond formation (entry 5).
R1
H
N
Ts-Cl
R2
R3
NH2
R2
R3
Ts
79-90%
3a R =OH, R =R =H
3b R =OH, R =R =OMe
1
2
3
4a R =OH, R =R =H
1
1
1
2
2
3
3
4b R =OH, R =R =OMe
1
2
3
4c R =R =H, R =OH
3c R =R =H, R =OH
2
3
1
2
3
R1
R2
R3
[ ]
O
R6
R5
n
TFA
N
+
Ts
X
40-78%
[ ]
n
R6
R5
Table 2
R4
Substrate scope and limitations of ortho- and para-arylation of phenolsa
X
R1
R1
R4
5a X=Br, n=1, R =R =R =H
4
5
6
R2
R2
5b X=Cl, n=1, R =R =R =H
4
5
6
6a-f X=Br
7 X=Cl
5c X=Br, n=2, R =R =R =H
N
4
5
6
N
R3
R4
Ts
R3
Ts
5d X=Br, n=1, R =R =-O-CH -O-, R =H
4
5
2
6
[Pd]
[ ]n
[ ]n
5e X=Br, n=1, R =R =H, R =Cl
R6
R5
4
5
6
Scheme 1. Synthesis of the tetrahydroisoquinolines using PicteteSpengler reactions.
R5
Br
R6
R4
2.2. Optimization of phenol ortho-arylation conditions
6b-f
8b-f
Entry
R1, R2, R3
R4, R5, R6
n
Product
Yieldb (%)
As previously reported, 6a could be converted to 8a in moderate
yield using a high loading of Pd(OAc)2 and PCy3 and with prolonged
heating (Table 1, entry 1).1a However, with the XPhos precatalyst
1
2
3
4
5
H, H, OH
H, H, OH
H, H, OH
OH, H, H
eOeCH2eOe, H
H, H, Cl
H, H, H
H, H, H
H, H, H
1
1
2
1
1
8b
8c
8d
8e
8f
78
77
76
(5 mol %), Cs2CO3 (3 equiv) in dimethylacetamide (DMA) at 110 ꢁ
C
88
98c
for only 1 h aporphine 8a was obtained in 93% yield (entry 2). For
comparison, ortho-arylation was not observed using Pd(OAc)2 and
XPhos, showing the remarkable effect of the precatalyst (entry 3).
Further investigation revealed that the reaction was dependent on
the choice of ligand. For example, lower yields were observed with
OH, OMe, OMe
a
Reaction condition: 6bef (1 equiv), XPhos precat. (5 mol %), Cs2CO3 (3 equiv),
DMA, 110 ꢁC, 1 h.
b
Isolated yield.
XPhos precat. (10 mol %).
c

1676
M. Hellal et al. / Tetrahedron 68 (2012) 1674e1681
2.4. Synthesis of the aporphine alkaloid (L)-lirinine
4. Experimental section
With the methodology established for the intramolecular para-
arylation of phenols, this process was applied to the synthesis of the
aporphine alkaloid (ꢀ)-lirinine (Scheme 2). The key steps in the
synthetic strategy were to prepare and use an enantiomerically
pure N-sulfinylamine tetrahydroisoquinoline intermediate in the
PicteteSpengler reaction.15
4.1. General information and materials
All reactions were carried out under an atmosphere of argon in
flame dried or oven-dried glassware with magnetic stirring. Purifi-
cation of products was performed on an automated system using
disposable silica gel columns. Analytical thin layer chromatography
OBn
OBn
O
MeO
MeO
CHO
MeO
MeO
a
OBn
OBn
H
9
10
MeO
MeO
N
p-Tol
MeO
MeO
N
O
p-Tol
S
c
S
d
O
:
:
i-Pr
O
p-Tol
H2N p-Tol
14
13
S
b
S
O
:
O
:
Me
11
12
OBn
OH
OH
OR
MeO
MeO
MeO
MeO
MeO
MeO
MeO
h
e
N
f
i
N
N
p-Tol
N
Ts
MeO
R
S
Ts
O
:
Br
Br
(R)-8f
15 (dr = 94:6)
17 R = H
(-)-lirinine R = Me
16 R = Bn
g
j
(R)-6f R = H
Scheme 2. Synthesis of (ꢀ)-lirinine. Reagents and conditions: (a) 1. ClPh3PCH2OCH3, KOtBu; 2. HCl, 83% over two steps; (b) LiHMDS, 91%; (c) Ti(OEt)4, 64%; (d) NaBH4, 80%; (e) 5a,
BF3$Et2O, 53%, dr: 94:6; (f) m-CPBA, 99%; (g) HCl, 64%; (h) XPhos precat. (10 mol %), 98%; (i) Na/Naphthalene, 94%; (j) CH2O, then NaBH4, 95%.
Homologation of benzaldehyde 9 was performed by a Wittig
reaction, followed by enol ether hydrolysis in 83% yield over two
steps. Acetaldehyde 10 was converted to the chiral sulfinylamide
14 by addition of (ꢀ)-sulfinylamine 10 in the presence of Ti(OEt)4
in 64% yield, followed by imine reduction with NaBH4 in 80% yield.
Then, a diastereoselective PicteteSpengler reaction between 14
and 2-bromophenylacetaldehyde 5a gave the tetrahy-
droisoquinoline 15 in 53% yield and with good diastereomeric
selectivity (dr¼94:6 as determined by 1H NMR). This selectivity
was notably higher than a similar reported substrate, which lacked
the ortho-bromine.15 Tetrahydroisoquinoline 15 (dr¼94:6) was
quantitatively oxidized with m-CPBA to the corresponding N-tosyl
tetrahydroisoquinoline 16. Then, removal of the benzyl group
under acidic conditions furnished the phenol intermediate (R)-6f.
The intramolecular para-arylation was performed with Xphos
precatalyst (10 mol %) to give (R)-8f in 98% yield. The N-tosyl
group was removed under sodium naphthalide conditions to give
17 in 94% yield and 89% ee.16 Finally, reductive amination fur-
nished (ꢀ)-lirinine in 95% yield. NMR spectral data for the syn-
thetic material was in agreement with that previously reported for
the isolated natural product.9a,11f,17
was performed on 0.25 mm silica gel 60-F plates. Visualization was
accomplished with UV light and ninhydrin solution, KMnO4 or ani-
saldehyde staining followed by heating. 1H NMR spectra were
recorded on a 400 or 500 MHz spectrometer and are reported in
parts per million using solvent as the internal standard (CDCl3 at
7.26 ppm or DMSO-d6 at 2.54 ppm). Data are reported as: (br¼broad,
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet; in-
tegration; coupling constant(s) in hertz). 13C NMR spectra were
recorded on a 100 or 125 MHz spectrometer. Chemical shifts are
reported in ppm from tetramethylsilane, with the solvent resonance
employed as the internal standard (CDCl3 at 77.0 ppm or DMSO-d6 at
39.0 ppm). High-resolution mass spectra were obtained on MALDI-
FT-ICR MS, using 150 mg/mL 2,5-dihydroxybenzoic acid dissolved in
MeOH/H2O (50:50) as matrix.
All reagents and solvents were purchasedfromcommercial sources
and used without further purification. The following starting materials
were made according to literature procedures: 2-(2-nitrovinyl)phenol
2a,18 2,3-dimethoxy-6-(2-nitrovinyl)-phenol 2b,19 N-(4-hydroxy
phenethyl)-p-toluenesulfonamide 4c,1a 2-(2-bromophenyl)acetalde-
hyde 5a,20 2-(2-chlorophenyl)-acetaldehyde 5b,21 3-(2-bromo-phe-
nyl)propanal 5c,22 1-(2-bromobenzyl)-2-p-toluenesulfonamide-1,2,3,
4-tetrahydroisoquinolin-7-ol 6a,1a 2-(benzyloxy)-3,4-dimethoxy-
benzaldehyde 9,13 (S)-(þ)-p-toluenesulfinamide 12.23
3. Conclusion
In summary, a monoligated Pd(0) catalyst has shown remark-
able reactivity in the ortho-arylation of phenols. Low catalyst
loading (5 mol %) and short reaction times (1e3 h) were sufficient
to perform this process for most substrates generating various
aporphines in good to excellent yields. The methodology was ex-
tended for the first time to the para-arylation of phenols for the
construction of aporphines and used for the synthesis of
(ꢀ)-lirinine.
4.2. Synthesis of amines 3a and b
4.2.1. 2-(2-Aminoethyl)phenol (3a)24. A solution of 2-(2-nitrovinyl)
phenol 2a (860 mg, 5.21 mmol) in THF (12 mL) was added dropwise
(over 1 h) to a stirred and cooled (0 ꢁC) suspension of LiAlH4 (479 mg,
17.18 mmol) in THF (6 mL). Stirring was continued for 2 h at room
temperature. The reaction mixture was cooled to 0 ꢁC and thenwater
was added. The organic solvent was removed in vacuo. The residue

M. Hellal et al. / Tetrahedron 68 (2012) 1674e1681
1677
was dissolved in HCl (10%, 40 mL) and washed twice with EtOAc
(20 mL). The combined organic layers were extracted twice with HCl
(10%, 20mL). The combinedaqueouslayerswere treatedwithtartaric
acid (4 equiv) and the pH was adjusted to >10 with concd NH3 and
the aqueous layers were extracted three times with chloroform
(30 mL). The combined organic layers were washed with water and
brine, driedoveranhydrous Na2SO4, andevaporated. Theresiduewas
purified by chromatography on silica gel using 3e10% 2 M NH3 in
MeOH in CH2Cl2 toyield 3a asawhite solid (464 mg, 3.38 mmol, 65%).
chromatography on silica gel using 0e10% EtOAc in cyclohexane to
give the corresponding vinyl ether.
The vinyl ether was dissolved in THF (5 mL) and cooled to 0 ꢁC,
then treated with 6 M H2SO4 (2.5 mL). The resulting mixture was
heated to 50 ꢁC for 4 h. After cooling, the reaction was added
dropwise in a saturated solution of NaHCO3 (20 mL) and extracted
twice with EtOAc (20 mL). The organic layers were combined,
washed with brine (10 mL), dried over anhydrous MgSO4, filtered,
and concentrated.
1H NMR (500 MHz, CDCl3):
d
7.12 (ddd, J¼8.0, 8.0,1.5 Hz,1H), 6.99 (dd,
J¼7.5, 1.5 Hz, 1H), 6.90 (dd, J¼8.0, 1.0 Hz, 1H), 6.76 (ddd, J¼7.5, 7.5,
1.0 Hz, 1H), 5.40 (br, 1H), 3.09e3.07 (m, 2H), 2.80e2.78 (m, 2H).
4.4.1. (2-Bromo-3,4-methylenedioxyphenyl)acetaldehyde (5d). The
residue was purified by chromatography on silica gel using 0e10%
EtOAc in cyclohexane to give 5d (244 mg, 1.0 mmol, 78%) as
a moderately unstable white solid. 1H NMR (500 MHz, CDCl3):
4.2.2. 6-(2-Aminoethyl)-2,3-dimethoxyphenol (3b). The same pro-
cedure as for 3a was used. The residue was purified by chroma-
tography on silica gel 3e10% 2 M NH3 in MeOH in CH2Cl2 to yield 3b
as a white solid (739 mg, 3.75 mmol, 78%). 1H NMR (500 MHz,
d
9.74 (t, J¼1.5 Hz, 1H), 7.08 (d, J¼8.5 Hz, 1H), 6.67 (d, J¼8.5 Hz, 1H),
6.00 (s, 2H), 3.82 (d, J¼1.5 Hz, 2H). 13C NMR (125 MHz, CDCl3):
d
197.4, 147.9, 147.0, 125.4, 116.3, 114.9, 109.1, 102.1, 44.2.
CDCl3):
d
6.70 (d, J¼8.5 Hz, 1H), 6.36 (d, J¼8.5 Hz, 1H), 5.11 (br, 3H),
3.89 (s, 3H), 3.84 (s, 3H), 3.04e3.01 (m, 2H), 2.78e2.73 (m, 2H). 13C
4.4.2. (2-Bromo-5-chlorophenyl)acetaldehyde (5e)25. The residue
was purified by chromatography on silica gel using 0e10% EtOAc in
cyclohexane to give 5e (276 mg, 1.2 mmol, 70%) as moderately
NMR (125 MHz, CDCl3):
d 152.2, 150.3, 137.8, 124.8, 121.5, 102.7,
55.9, 42.3, 60.6, 35.4. HRMS (MALDI-TOF) C10H16NO3 [MþH]þ:
198.1125; found: 198.1128.
unstable a white solid. 1H NMR (500 MHz, CDCl3):
d 9.76 (t,
J¼1.5 Hz, 1H), 7.54 (d, J¼8.5 Hz, 1H), 7.24 (d, J¼2.5 Hz, 1H), 7.18 (dd,
4.3. Synthesis of sulfonamides 4a and b
J¼8.5, 2.5 Hz, 1H), 3.85 (d, J¼1.5 Hz, 2H).
4.3.1. N-(2-Hydroxyphenethyl)-p-toluenesulfonamide (4a). To a so-
lution of 3a (370 mg, 2.70 mmol) in 6 mL of DMF at 0 ꢁC under argon
was added tosyl chloride (540 mg, 2.80 mmol) followed by diiso-
4.5. Preparation of tetrahydroisoquinolines 6bef and 7,
exemplified for 1-(2-chlorobenzyl)-2-p-toluenesulfonyl-
1,2,3,4-tetrahydroisoquinolin-7-ol (7)
propylethylamine (473 mL, 2.80 mmol). The solution was stirred at
room temperature for 4 h. The reaction was concentrated, and then
diluted in HCl 1 N (10 mL), extracted twice with EtOAc (20 mL). The
organic layers were combined, washed with brine (10 mL), dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was pu-
rified by chromatography on silica gel using CH2Cl2/cyclohexane/
EtOAc (60/35/5) to give 4a (620 mg, 2.13 mmol, 79%) as an orange oil.
Into a flask was added aldehyde 5b (80 mg, 0.51 mmol), sul-
fonamide 4c (100 mg, 0.34 mmol), and TFA (1 mL). The solution was
heated to 70 ꢁC for 5 h. After cooling, the reaction mixture was
diluted with water (10 mL) and neutralized with saturated NaHCO3.
The mixture was extracted twice with EtOAc (20 mL). The organic
extracts were combined, washed with brine (10 mL), dried over
anhydrous Na2SO4, filtered, and concentrated. The crude product
was purified by chromatography on silica gel using 10e30% EtOAc
in cyclohexane to give 7 (103 mg, 0.24 mmol, 70%) as a pale yellow
1H NMR (500 MHz, CDCl3):
d
7.67 (d, J¼8.0 Hz, 2H), 7.24 (d, J¼8.0 Hz,
2H), 7.09 (ddd, J¼8.0, 8.0,1.5 Hz,1H), 6.98 (dd, J¼7.5,1.5 Hz,1H), 6.82
(ddd, J¼8.0, 8.0, 1.0 Hz, 1H), 6.75 (dd, J¼7.5, 1.0 Hz, 1H), 5.50 (br, 1H),
4.86 (t, J¼6.0 Hz,1H), 3.21 (q, J¼6.5 Hz, 2H), 2.79 (t, J¼6.5 Hz, 2H), 2.40
solid. 1H NMR (500 MHz, CDCl3):
d
7.39 (d, J¼8.0 Hz, 2H), 7.29 (dd,
(s, 3H). 13C NMR (125 MHz, CDCl3):
d
154.0, 143.6, 136.8, 131.2, 129.9,
J¼7.5, 1.5 Hz, 1H), 7.20e7.10 (m, 3H), 7.04 (d, J¼8.0 Hz, 2H), 6.86 (d,
J¼3.0 Hz, 1H), 6.63 (dd, J¼5.5, 2.5 Hz, 1H), 6.47 (d, J¼2.5 Hz, 1H),
5.23 (dd, J¼5.5, 4.0 Hz, 1H), 4.52 (s, 1H), 3.88e3.83 (m, 1H),
3.67e3.56 (m, 1H), 3.23e3.11 (m, 2H), 2.74e2.68 (m, 1H), 2.60e2.55
128.4, 127.3, 124.6, 121.3, 115.8, 43.7, 30.7, 21.7. HRMS (MALDI-TOF)
C15H17NNaO3S [MþNa]þ: 314.0821; found: 314.0835.
4.3.2. N-(2-Hydroxy-3,4-dimethoxyphenethyl)-p-toluenesulfona-
mide (4b). The same procedure as for 4a was used. The residue was
purified by chromatography on silica gel using 25e50% EtOAc in
cyclohexane to give 4b (319 mg, 0.91 mmol, 90%) as a white solid.
(m,1H). 2.32 (s, 3H). 13C NMR (125 MHz, CDCl3):
d 153.7,142.9,137.1,
136.9, 135.5, 134.5, 132.1, 130.1, 126.7, 129.4, 129.3, 128.1, 127.1, 125.1,
114.6, 113.5, 56.1, 41.0, 39.3, 26.9, 26.1, 21.4. HRMS (MALDI-TOF)
C23H22ClNNaO3S [MþNa]þ: 450.0901; found: 450.0904.
1H NMR (500 MHz, CDCl3):
d
7.67 (d, J¼8.5 Hz, 2H), 7.25 (d, J¼8.5 Hz,
2H), 6.66 (d, J¼8.5 Hz, 1H), 6.37 (d, J¼8.5 Hz, 1H), 5.87 (s, 1H), 4.59
4.5.1. 1-(2-Bromo-3,4-methylenedioxybenzyl)-2-p-toluenesulfonyl-
1,2,3,4-tetrahydroisoquinolin-7-ol (6b). The same procedure as for 7
was used. The crude product was purified by chromatography on
silica gel using 10e30% EtOAc in cyclohexane to give 6b (158 mg,
0.31 mmol, 61%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3):
(t, J¼6.0 Hz,1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.20 (q, J¼6.5 Hz, 2H), 2.71
(t, J¼6.5 Hz, 2H), 2.41 (s, 3H). 13C NMR (125 MHz, CDCl3):
d 151.5,
147.5, 143.3, 137.2, 135.6, 129.8, 127.2, 125.1, 117.1, 103.9, 61.1, 56.0,
43.3, 30.1, 21.7. HRMS (MALDI-TOF) C17H21NNaO5S [MþNa]þ:
374.1033; found: 374.1046.
d
7.38 (d, J¼8.0 Hz, 2H), 7.04 (d, J¼8.0 Hz, 2H), 6.97 (d, J¼8.0 Hz, 1H),
6.89 (d, J¼8.5 Hz,1H), 6.70 (d, J¼2.5 Hz,1H), 3.91e3.87 (m, 1H), 6.65
(dd, J¼5.5, 2.5 Hz, 1H), 6.56 (d, J¼8.0 Hz, 1H), 5.84 (d, J¼1.5 Hz, 1H),
5.80 (d, J¼1.5 Hz, 1H), 5.29 (dd, J¼7.0, 4.0 Hz, 1H), 4.74 (br, 1H),
3.70e3.64 (m, 1H), 3.25e3.20 (m, 1H), 2.97 (dd, J¼10.0, 4.0 Hz, 1H),
2.82e2.75 (m, 1H), 2.60e2.56 (m, 1H), 2.33 (s, 3H). 13C NMR
4.4. Preparation of phenylacetaldehydes 5d and e
A solution under argon of methoxymethyl-triphenylphospho-
nium chloride (2.2 equiv) in dry THF (4 mL) at 0 ꢁC was treated
dropwise with a solution of KOtBu 1 M in THF (2 equiv). The
resulting mixture was allowed to warm to room temperature and
stirred under argon for 30 min, then treated with a solution of al-
dehyde (1 equiv) in dry THF (4 mL) and stirred at room temperature
for 3 h. The reaction was quenched by the addition of brine (10 mL),
extracted with EtOAc (3ꢂ10 mL), dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The residue was purified by
(100 MHz, CDCl3):
d 153.9, 148.1, 146.7, 143.0, 137.7, 137.4, 130.5,
129.5, 127.1, 125.5, 125.1, 119.9, 116.6, 114.9, 113.5, 108.3, 106.8, 101.7,
55.2, 39.2, 37.2, 26.6, 21.6. HRMS (MALDI-TOF) C24H22BrNNaO5S
[MþNa]þ: 538.0294; found: 538.0291.
4.5.2. 1-(2-Bromo-5-chlorobenzyl)-2-p-toluenesulfonyl-1,2,3,4-
tetrahydroisoquinolin-7-ol (6c). The same procedure as for 7 was

1678
M. Hellal et al. / Tetrahedron 68 (2012) 1674e1681
used. The crude product was purified by chromatography on silica
gel using 10e30% EtOAc in cyclohexane to give 6c (126 mg,
0.25 mmol, 50%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3):
38.3, 26.9, 21.4, 20.7. HRMS (MALDI-TOF) C25H26BrNNaO5S
[MþNa]þ: 554.0607; found: 554.0626.
d
7.40e7.30 (m, 3H), 7.07e7.01 (m, 4H), 6.90 (d, J¼8.0 Hz, 1H), 6.65
4.6. General procedure for the ortho- and para-arylation of
phenols
(dd, J¼5.5, 2.5 Hz, 1H), 6.61 (d, J¼7.5 Hz, 1H), 4.79 (br, 1H), 5.22 (dd,
J¼5.5, 4.5 Hz, 1H), 3.95e3.91 (m, 1H), 3.59e3.53 (m, 1H), 3.18e3.03
(m, 2H), 2.84e2.77 (m,1H), 2.63e2.58 (m,1H), 2.34 (s, 3H). 13C NMR
A reaction tube was charged with tetrahydroisoquinoline 8aef
(1 equiv), Xphos precat. (1e10 mol %) and Cs2CO3 (3 equiv). The
tube was evacuated and backfilled with argon (three times), and
then dry DMA (1 mL/0.1 mmol of starting material) was added. The
mixture was sparged with argon for 5 min and then heated at
110 ꢁC for 1 h. After cooling at room temperature, the reaction
mixture was quenched with 1 N HCl. The reaction mixture was
extracted three times with ethyl acetate. The organic extracts were
combined, washed with brine, dried over anhydrous Na2SO4, fil-
tered, and concentrated. The crude product was purified by chro-
matography on silica gel using CH2Cl2/cyclohexane/EtOAc (60:35:5)
as eluent to yield a white solid.
(100 MHz, CDCl3):
d 154.0, 143.2, 139.1, 137.1, 136.8, 133.9, 133.3,
132.0, 130.4, 129.6, 128.6, 127.2, 125.4, 123.1, 115.0, 113.5, 56.0, 43.4,
39.6, 26.5, 21.7. HRMS (MALDI-TOF) C23H21BrClNNaO3S [MþNa]þ:
528.0006; found: 528.0025.
4.5.3. 1-(2-Bromophenethyl)-2-p-toluenesulfonyl-1,2,3,4-tetrahydro-
isoquinolin-7-ol (6d). The same procedure as for 7 was used. The
crude product was purified by chromatography on silica gel using
10e30% EtOAc in cyclohexane to give 6d (87 mg, 0.18 mmol, 52%) as
a pale yellow solid. 1H NMR (500 MHz, CDCl3):
d
7.62 (d, J¼8.0 Hz,
2H), 7.50 (dd, J¼8.0, 1.0 Hz, 1H), 7.27 (ddd, 1H, J¼8.0, 8.0, 2.0 Hz, 1H),
7.22 (ddd, 1H, J¼7.5, 7.5, 1.0 Hz, 1H), 7.12 (d, J¼8.5 Hz, 2H), 7.04 (ddd,
J¼7.5, 7.5, 1.5 Hz, 1H), 6.73 (d, J¼8.0 Hz, 1H), 6.55 (dd, J¼8.0, 2.5 Hz,
1H), 6.52 (d, J¼2.5 Hz, 1H), 5.02 (dd, 1H, J¼5.5, 4.5 Hz, 1H), 4.55 (br,
1H), 3.95e3.90 (m, 1H), 3.56e3.50 (m, 1H), 3.02e2.83 (m, 2H),
2.46e2.43 (m, 2H), 2.33 (s, 3H), 2.13e1.95 (m, 2H). 13C NMR
4.6.1. 5,6,6a,7-Tetrahydro-6-p-toluenesulfonyl-4H-dibenzo-[de,g]
quinolin-1-ol (8a). 1H NMR (500 MHz, CDCl3):
d
8.13 (d, J¼8.0 Hz,
1H), 7.69 (d, J¼8.0 Hz, 2H), 7.38e7.34 (m, 2H), 7.29e7.28 (m, 1H),
7.23 (d, J¼8.0 Hz, 2H), 6.85 (d, J¼8.5 Hz, 1H), 6.74 (d, J¼8.5 Hz, 1H),
5.19 (s, 1H), 4.11e4.07 (m, 1H), 4.66 (dd, J¼14.0, 4.5 Hz, 1H),
3.27e3.21 (m, 1H), 3.16 (dd, J¼14.0, 4.5 Hz, 1H), 3.02 (t, J¼14.0 Hz,
1H), 2.48e2.43 (m, 1H), 2.38 (s, 3H), 2.36e2.31 (m, 1H).
(125 MHz, CDCl3):
d 153.9, 143.3, 141.3, 138.0, 137.7, 133.0, 130.7,
130.2, 129.6, 127.9, 127.7, 127.2, 124.8, 124.5, 114.5, 113.4, 56.8, 39.3,
37.7, 33.8, 27.1, 25.5, 21.6. HRMS (MALDI-TOF) C24H24BrNNaO3S
[MþNa]þ: 508.0552; found: 508.0558.
4.6.2. 10,11-Methylenedioxy-5,6,6a,7-tetrahydro-6-p-toluene-
4.5.4. 1-(2-Bromobenzyl)-2-tosyl-1,2,3,4-tetrahydroisoquinolin-5-ol
(6e). Into a flask was added 5a (90 mg, 0.45 mmol), sulfonamide 4a
(88 mg, 0.30 mmol), and TFA (1 mL). The solution was stirred at
room temperature for 1 h. Then, the reaction mixture was diluted
with water (10 mL) and neutralized with saturated NaHCO3. The
mixture was extracted twice with EtOAc (20 mL). The organic ex-
tracts were combined, washed with brine (10 mL), dried over an-
hydrous Na2SO4, filtered, and concentrated. The crude product was
purified by chromatography on silica gel using 10e30% EtOAc in
cyclohexane to give 6e (57 mg, 0.12 mmol, 40%) as a white solid. 1H
sulfonyl-4H-dibenzo[de,g]-quinolin-1-ol (8b). 1H NMR (400 MHz,
CDCl3):
d
7.71 (d, J¼8.5 Hz, 2H), 7.64 (d, J¼8.5 Hz, 1H), 7.25e7.23 (m,
2H), 6.82 (d, J¼8.0 Hz, 1H), 6.74 (d, J¼8.0 Hz, 1H), 6.07 (d, J¼1.5 Hz,
1H), 6.01 (d, J¼1.5 Hz, 1H), 5.27 (s, 1H), 5.30 (s, 1H), 4.66 (dd, J¼14.0,
4.5 Hz, 1H), 4.10e4.06 (m, 1H), 3.36 (dd, J¼14.0, 4.5 Hz, 1H),
3.25e3.19 (m, 1H), 2.69 (t, J¼14.0 Hz, 1H), 2.47e2.43 (m, 1H), 2.38
(m, 3H), 2.36e2.32 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 151.1,
146.9,143.5,138.3,133.2,130.1,128.4,127.1,125.9,125.8,121.2,120.7,
118.1, 116.1, 106.8, 101.6, 53.2, 41.1, 30.2, 28.3, 21.7. HRMS (MALDI-
TOF) C24H21NNaO5S [MþNa]þ: 458.1033; found: 458.1043.
NMR (500 MHz, CDCl3):
d
7.47 (dd, J¼7.5, 1.0 Hz, 1H), 7.37 (d,
J¼8.0 Hz, 2H), 7.19 (ddd, J¼7.5, 7.5, 1.0 Hz, 1H), 7.14e7.07 (m, 2H),
7.04e6.98 (m, 3H), 6.72 (d, J¼7.5 Hz, 1H), 6.59 (d, J¼8.0 Hz,1H), 5.32
(dd, J¼10.0, 5.0 Hz, 1H), 4.65 (br, 1H), 4.03e3.98 (m, 1H), 3.63e3.57
(m, 1H), 3.24e3.11 (m, 2H), 2.64e2.61 (m, 2H), 2.32 (s, 3H). 13C NMR
4.6.3. 9-Chloro-5,6,6a,7-tetrahydro-6-p-toluenesulfonyl-4H-dibenzo
[de,g]quinolin-1-ol (8c). 1H NMR (400 MHz, CDCl3):
d 8.17 (d,
J¼9.5 Hz, 1H), 7.69 (d, J¼8.5 Hz, 2H), 3.00 (t, J¼14.0 Hz, 1H),
7.32e7.29 (m, 2H), 7.24 (d, J¼8.5 Hz, 2H), 6.85 (d, J¼8.0 Hz, 1H), 6.69
(d, J¼8.0 Hz,1H), 5.19 (s, 1H), 4.64 (dd, J¼14.0, 4.5 Hz,1H), 4.11e4.07
(m, 1H), 3.25e3.19 (m, 1H), 3.14e3.10 (m, 1H), 2.48e2.44 (m, 1H),
(125 MHz, CDCl3):
d 153.3, 143.0, 137.5, 137.3, 132.9, 132.3, 129.5,
128.5, 127.5, 127.3, 126.7, 125.3, 120.3, 119.7, 113.2, 55.8, 43.3, 38.5,
27.1, 21.6, 21.2. HRMS (MALDI-TOF) C23H22BrNNaO3S [MþNa]þ:
494.0396; found: 494.0419.
2.38 (s, 3H), 2.35e2.31 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 151.4,
143.6, 138.4, 138.1, 134.0, 133.1, 130.1, 129.3, 129.1, 128.7, 127.3, 127.1,
126.0, 120.5, 116.2, 53.4, 41.2, 37.4, 28.3, 21.7. HRMS (MALDI-TOF)
C23H20ClNNaO3S [MþNa]þ: 448.0745; found: 448.0762.
4.5.5. 1-(2-Bromobenzyl)-6,7-dimethoxy-2-p-toluenesulfon-yl-
1,2,3,4-tetrahydroisoquinolin-5-ol (6f). Into a flask was added al-
dehyde 5a (255 mg, 1.28 mmol), sulfonamide 4b (300 mg,
0.84 mmol), and TFA (2 mL). The solution was stirred at room
temperature for 1 h. The reaction mixture was diluted with water
(20 mL) and neutralized with saturated NaHCO3. The mixture was
extracted twice with EtOAc (40 mL). The organic extracts were
combined, washed with brine (20 mL), dried over anhydrous
Na2SO4, filtered, and concentrated. The crude product was purified
by chromatography on silica gel using CH2Cl2/cyclohexane/EtOAc
(60:35:5) to give 6f (353 mg, 0.66 mmol, 78%) as a yellowish solid.
4.6.4. 4,5,6,6a,7,8-Hexahydro-6-p-toluenesulfonyl-benzo [6,7] cyclo-
hept[1,2,3-ij] isoquinoline-1-ol (8d). 1HNMR(500MHz,CDCl3):
d7.48
(d, J¼8.0 Hz, 2H), 7.37e7.44 (m, 4H), 7.11 (d, J¼8.0 Hz, 2H), 6.88e6.84
(m, 2H), 5.26 (s, 1H), 4.63 (dd, J¼11.0, 6.5 Hz, 1H), 3.95e3.90 (m, 1H),
3.45e3.39 (m, 1H), 2.68e2.61 (m, 1H), 2.58e2.5 (m, 2H), 2.45e2.38
(m, 2H), 2.34 (s, 3H), 2.24e2.18 (m, 1H). 13C NMR (125 MHz, CDCl3):
d
150.0,143.2,140.5,138.2,133.4,130.0,129.8,129.6,129.3,128.1,127.7,
127.0,124.4,115.1, 52.9, 38.9, 38.4, 30.5, 27.1, 21.6. HRMS (MALDI-TOF)
C24H23NNaO3S [MþNa]þ: 428.1291; found: 428.1302.
1H NMR (500 MHz, CDCl3):
d
7.48 (dd, J¼8.0, 1.0 Hz, 1H), 7.43 (d,
J¼8.0 Hz, 2H), 7.19 (ddd, J¼7.5, 7.5, 1.0 Hz, 1H), 7.12e7.07 (m, 2H),
7.05 (d, J¼8.0 Hz, 2H), 6.01 (s, 1H), 5.74 (s, 1H), 5.22 (t, J¼8.0 Hz, 1H),
3.97e3.93 (m, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 3.60e3.54 (m, 1H),
3.21e3.13 (m, 2H), 2.64e2.53 (m, 2H), 2.32 (s, 3H). 13C NMR
(125 MHz, CDCl3):
131.2, 129.3, 128.3, 127.3, 127.1, 125.2, 112.9, 102.2, 61.0, 55.7, 43.1,
4.6.5. 5,6,6a,7-Tetrahydro-6-p-toluenesulfonyl-4H-dibenzo [de,g]qui-
nolin-3-ol (8e). 1H NMR (500 MHz, CDCl3):
d
7.71 (d, J¼8.5 Hz, 2H),
7.66 (d, J¼8.0 Hz), 7.47 (d, 1H, J¼8.0 Hz), 7.33e7.28 (m, 2H),
7.25e7.22 (m, 3H), 6.71 (d, 1H, J¼8.5 Hz, 1H), 4.77 (dd, J¼14.0,
5.0 Hz, 1H), 4.70 (s, 1H), 4.17e4.13 (m, 1H), 3.30e3.23 (m, 2H), 3.09
(t, J¼14.0 Hz, 1H), 2.76e2.72 (m, 1H), 2.38 (s, 3H), 2.16e2.10 (m, 1H).
d 150.0, 146.5, 142.8, 137.3, 133.9, 132.7, 132.2,

M. Hellal et al. / Tetrahedron 68 (2012) 1674e1681
1679
13C NMR (125 MHz, CDCl3):
130.1, 129.2, 127.8, 127.5, 127.1, 123.4, 123.1, 121.1, 113.6, 53.3, 40.8,
37.1, 22.2, 21.7. HRMS (MALDI-TOF) C23H21NNaO3S [Mþ]þ:
414.1134; found: 414.1142.
d
152.3, 143.6, 138.1, 134.7, 133.9, 133.5,
(2 mL) under argon at 0 ꢁC was added sodium borohydride (18 mg,
0.47 mmol). After stirring for 30 min, acetone (2 mL) was added and
the reaction was stirred another 5 min. The solvent was removed in
vacuo and the residue was dissolved in EtOAc (10 mL), washed with
water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by chroma-
tography on silica gel using 10e30% EtOAc in cyclohexane to afford
14 (80 mg, 0.19 mmol, 80%) as a thick pale yellow oil. 1H NMR
4.6.6. 1,2-Dimethoxy-5,6,6a,7-tetrahydro-6-p-toluenesulfonyl-4H-
dibenzo[de,g] quinolin-3-ol (8f). 1H NMR (500 MHz, CDCl3):
d 8.24
(d, J¼8.0 Hz, 1H), 7.69 (d, J¼8.5 Hz, 2H), 7.32e7.28 (m, 2H),
7.24e7.20 (m, 3H), 5.83 (s, 1H), 4.58 (dd, J¼14.0, 4.5 Hz, 1H),
4.12e4.08 (m, 1H), 3.96 (s, 3H), 3.68 (s, 3H), 3.26e3.20 (m, 1H),
3.14e3.11 (m, 1H), 3.02 (t, J¼14.0 Hz, 1H), 2.77e2.73 (m, 1H), 2.38 (s,
(400 MHz, CDCl3):
d
7.48 (d, J¼8.0 Hz, 2H), 7.42e7.31 (m, 5H), 7.23
(d, J¼8.0 Hz, 2H), 6.79 (d, J¼8.5 Hz, 1H), 6.62 (d, J¼8.5 Hz, 1H),
5.05e4.99 (m, 2H), 4.08 (t, J¼6.0 Hz, 1H), 3.86 (s, 6H), 3.30e3.24 (m,
1H), 2.99e2.92 (m, 1H), 2.70 (t, J¼7.0 Hz, 2H), 2.38 (s, 3H). 13C NMR
3H), 2.14e2.07 (m, 1H). 13C NMR (125 MHz, CDCl3):
d 149.3, 145.9,
143.4, 139.0, 138.2, 135.9, 131.7, 130.1, 129.5, 128.7, 127.6, 127.2, 127.1,
120.1, 116.3, 61.2, 60.3, 53.4, 40.5, 37.7, 22.1, 21.7. HRMS (MALDI-
TOF) C25H25NNaO5S [MþNa]þ: 474.1346; found: 474.1353.
(100 MHz, CDCl3): d 152.9, 151.1, 142.7, 141.5, 141.2, 137.9, 130.3,
129.7, 128.7, 128.3, 128.2, 126.2, 125.0, 124.8, 124.7, 107.7, 75.4, 61.1,
56.3, 41.8, 31.2, 21.5. HRMS (MALDI-TOF) C24H27NNaO4S [MþNa]þ:
448.1559; found: 448.1574. ½a D20
þ41.5 (c 0.2, CHCl3).
ꢃ
4.7. Synthesis of (L)-lirinine
4.7.4. (þ)-1-(2-Bromobenzyl)-5-benzyloxy-6,7-dimethoxy-2-p-tol-
uenesulfinyl-1,2,3,4-tetrahydroisoquinoline (15). A solution of 14
(185 mg, 0.43 mmol) and aldehyde 5a (173 mg, 0.87 mmol) in dry
4.7.1. 2-(2-(Benzyloxy)-3,4-dimethoxyphenyl)acetaldehyde (10)26. A
solution under argon of methoxymethyl-triphenylphosphonium
chloride (3.50 g, 9.9 mmol) in dry THF (12 mL) at 0 ꢁC was
treated dropwise with KOtBu (1 M in THF, 9.9 mL, 9.9 mmol). The
resultant mixture was allowed to warm to room temperature and
stirred for 30 min, then treated with a solution of benzaldehyde 9
(1.29 g, 4.7 mmol) in dry THF (6 mL) and stirred at room temper-
ature under argon for 14 h. The reaction was quenched by the ad-
dition of brine (10 mL), extracted with EtOAc (3ꢂ20 mL), dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The residue
was purified by chromatography on silica gel using 0e10% EtOAc in
cyclohexane to afford the enol ether (1.41 g, 4.7 mmol, 100%) as
a pale yellow solid.
The enol ether (1.41 g, 4.7 mmol) was dissolved in acetone
(10 mL) and cooled at 0 ꢁC, then treated with a solution HCl (6 N,
10 mL). The resultant mixture was stirred for 1 h at room temper-
ature, extracted with EtOAc (4ꢂ30 mL), dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by chromatography on silica gel using 0e10% EtOAc in cyclo-
hexane to afford 10 (1.13 g, 3.94 mmol, 83%) as a moderately
unstable colorless oil (stored under argon at 0 ꢁC). 1H NMR
CH2Cl2 (4 mL) under argon was cooled to ꢀ78 ꢁC. BF3$Et2O (110
mL,
0.87 mmol) was added, and the reaction mixture was stirred at
ꢀ78 ꢁC for 18 h. The reaction was quenched with triethylamine
(121 mL, 0.87 mmol), and then the solvent was removed in vacuo.
The residue was purified by chromatography on silica gel using
10e40% EtOAc in cyclohexane to give 15 (139 mg, 0.23 mmol, 53%)
as a pale yellow solid. 1H NMR (400 MHz, CDCl3):
d
7.44 (d, J¼8.5 Hz,
2H), 7.40e7.31 (m, 4H), 7.24 (d, J¼8.5 Hz, 2H), 7.16 (ddd, J¼7.5, 7.5,
1.5 Hz, 1H), 7.09e7.03 (m, 3H), 6.89 (dd, 1H, J¼7.5, 1.5 Hz), 6.09 (s,
1H), 5.04 (s, 2H), 4.74 (t, J¼7.0 Hz, 1H), 3.85 (s, 3H), 3.72e3.64 (m,
2H), 3.62 (s, 3H), 3.15e3.04 (m, 2H), 2.79e2.76 (m, 2H), 2.37 (s, 3H).
13C NMR (100 MHz, CDCl3):
d 150.1, 141.1, 140.8, 140.2, 138.1, 137.7,
133.0, 132.7, 129.6, 128.6, 128.4, 128.2, 127.3, 126.0, 125.4, 120.6,
106.2, 74.8, 61.1, 55.8, 55.0, 43.7, 41.3, 23.5, 21.6. HRMS (MALDI-TOF)
C32H32BrNNaO4S [MþNa]þ: 628.1128; found: 628.1147. ½a 2D0
þ51.0
ꢃ
(c 0.2, CHCl3).
4.7.5. (R)-1-(2-Bromobenzyl)-5-benzyloxy-6,7-dimethoxy-2-p-tol-
uenesulfonyl-1,2,3,4-tetrahydroisoquinoline (16). To a solution of 15
(130 mg, 0.21 mmol) in dry CH2Cl2 (3 mL) under argon at 0 ꢁC was
added m-CPBA (71 mg, 0.32 mmol), and the reaction mixture was
stirred at this temperature for 1 h. Next, a solution of saturated
aqueous NaHCO3 (3 mL) was added and the resulting solution was
vigorously stirred for 30 min. The reaction mixture was diluted
with CH2Cl2 (10 mL). The organic phase was separated, washed
with H2O (5 mL), brine (5 mL), dried over anhydrous MgSO4, fil-
tered, and concentrated. The residue was purified by chromatog-
raphy on silica gel using 10e40% EtOAc in cyclohexane to give 16
(132 mg, 0.21 mmol, 99%) as a white solid. 1HH NMR (400 MHz,
(500 MHz, CDCl3):
d
9.54 (t, J¼2.0 Hz, 1H), 7.41e7.31 (m, 5H), 6.81
(d, J¼8.5 Hz, 1H), 6.68 (d, J¼8.5 Hz, 1H), 5.08 (s, 2H), 3.90 (s, 3H),
3.88 (s, 3H), 3.51 (d, J¼2.0 Hz, 2H).
4.7.2. (R)-N-2-(2-(Benzyloxy)-3,4-dimethoxyphenyl)ethyl-idene]-p-
toluene sulfinamide (13). To a solution of acetaldehyde 10 (1.02 g,
3.56 mmol) in CH2Cl2 (35 mL) under argon was added sulfinamide
12 (553 mg, 3.56 mmol) and Ti(OEt)4 (3.73 mL, 17.81 mmol). The
reaction mixture was refluxed 4 h, and then cooled to 0 ꢁC and
quenched with H2O (10 mL). The turbid solution was filtered
through Celite, and the filter cake was washed with CH2Cl2
(2ꢂ10 mL). The phases were separated and the aqueous layer was
washed with CH2Cl2 (10 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated. The resi-
due was purified by chromatography on silica gel using 0e20%
EtOAc in cyclohexane to afford 13 (1.03 g, 2.44 mmol, 69%) as a pale
CDCl3):
d
7.49 (d, J¼7.5 Hz, 1H), 7.45 (d, J¼8.5 Hz, 2H), 7.39e7.31 (m,
5H), 7.20 (ddd, J¼7.5, 7.5, 1.0 Hz, 1H), 7.10 (d, J¼7.5 Hz, 2H), 7.06 (d,
J¼8.5 Hz, 2H), 6.15 (s, 1H), 5.20 (t, J¼7.5 Hz, 1H), 4.87 (AB, 2H,
J¼108.0, 11.0 Hz, 2H), 3.83 (s, 3H), 3.82e3.77 (m, 1H), 3.66 (s, 3H),
3.54e3.47 (m, 1H), 3.17 (d, J¼7.5 Hz, 2H), 2.59e2.46 (m, 2H), 2.30 (s,
3H). 13C NMR (100 MHz, CDCl3):
d 151.7, 150.0, 143.1, 141.3, 137.8,
yellow solid. 1H NMR (400 MHz, CDCl3):
d
8.15 (t, J¼5.0 Hz, 1H), 7.51
137.5, 132.9, 132.4, 131.0, 129.5, 128.5, 128.3, 127.6, 127.4, 125.5,
120.2, 106.4, 74.9, 61.1, 56.3, 56.0, 43.4, 39.1, 21.6. HRMS (MALDI-
(d, J¼8.0 Hz, 2H), 7.35e7.30 (m, 5H), 7.24 (d, J¼8.0 Hz, 2H), 6.79 (d,
J¼8.5 Hz, 1H), 6.64 (d, J¼8.5 Hz, 1H), 4.98 (s, 2H), 3.87 (s, 3H), 3.86
(s, 3H), 3.65 (t, J¼5.0 Hz, 1H), 2.37 (s, 3H). 13C NMR (100 MHz,
TOF) C32H32BrNNaO5S [MþNa]þ: 644.1077; found: 644.1089. ½a 2D0
ꢃ
ꢀ70.3 (c 0.3, CHCl3).
CDCl3):
d 153.3, 150.9, 142.6, 141.7, 141.6, 137.5, 129.7, 128.4, 128.2,
128.0, 124.8, 124.6, 121.2, 107.6, 75.2, 60.9, 56.1, 36.6, 21.4. HRMS
4.7.6. (R)-1-(2-Bromobenzyl)-6,7-dimethoxy-2-p-toluenesulfonyl-
1,2,3,4-tetrahydroisoquinolin-5-ol [(R)-6f]. To a solution of 16
(180 mg, 0.29 mmol) in DME (2 mL) was added dropwise concd HCl
(2 mL). The mixture was heated to 80 ꢁC for 1 h. After cooling, the
reaction mixture was poured in a saturated solution of NaHCO3
(10 mL), extracted with EtOAc (2ꢂ10 mL). The organic layers were
(MALDI-TOF) C24H26NO4S [MþH]þ: 424.1577; found: 424.1593.
½
a 2D0
ꢃ
þ229 (c 0.3, CHCl3).
4.7.3. (R)-N-2-(2-(Benzyloxy)-3,4-dimethoxyphenyl)ethyl]-p-toluene
sulfinamide (14). To a solution of 13 (100 mg, 0.24 mmol) in CH3OH

1680
M. Hellal et al. / Tetrahedron 68 (2012) 1674e1681
combined, washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated. The residue was purified by chromatog-
raphy on silica gel using 10e30% EtOAc in cyclohexane gave (R)-6f
(98 mg, 0.18 mmol, 64%) as a pale yellow solid. 1H NMR (500 MHz,
CDCl3):
d
8.19 (d, J¼8.0 Hz,1H), 7.28 (ddd, J¼8.0, 7.5, 1.0 Hz, 1H), 7.24
(d, J¼7.5 Hz, 1H), 7.18 (ddd, J¼7.5, 7.5, 1.0 Hz, 1H), 5.86 (br, 1H), 3.98
(s, 3H), 3.72 (s, 3H), 3.11e3.08 (m, 2H), 3.01 (dd, J¼13.5, 3.0 Hz, 1H),
2.92e2.88 (m, 1H), 2.78 (dd, J¼17.0, 4.0 Hz, 1H), 2.60 (t, J¼13.5 Hz,
1H), 2.55 (s, 3H), 2.45 (ddd, J¼12.0, 12.0, 4.0 Hz, 1H). 13C NMR
CDCl3):
d
7.48 (dd, 1H, J¼8.0, 1.0 Hz), 7.43 (d, J¼8.0 Hz, 2H), 7.19 (dt,
J¼7.5, 1.0 Hz, 1H), 7.12e7.07 (m, 2H), 7.05 (d, J¼8.0 Hz, 2H), 6.01 (s,
1H), 5.74 (s, 1H), 5.22 (t, J¼8.0 Hz, 1H), 3.99e3.91 (m, 1H), 3.85 (s,
3H), 3.67 (s, 3H), 3.60e3.51 (m, 1H), 3.21e3.12 (m, 2H), 2.62e2.51
(100 MHz, CDCl3): d 148.7, 146.0, 138.5, 135.6, 132.2, 127.8, 127.3,
126.9, 126.4, 118.9, 116.0, 62.6, 61.1, 60.3, 52.9, 44.0, 34.8, 23.3.
HRMS (MALDI-TOF) C19H22NO3 [MþH]þ: 312.1594; found:
(m, 2H), 2.33 (s, 3H). ½a D20
ꢃ
ꢀ129 (c 0.3, CHCl3).
312.1598. ½a 2D0
ꢃ
ꢀ52.0 (c 0.1, CHCl3), [lit.11f ꢀ83.7 (c 1.0, CHCl3)].
4.7.7. (R)-1,2-Dimethoxy-5,6,6a,7-tetrahydro-6-p-toluenesulfonyl-
4H-dibenzo[de,g] quinolin-3-ol [(R)-8f]. A reaction tube was
charged with (R)-6f (53 mg, 0.1 mmol), Xphos precatalyst (7.4 mg,
0.01 mmol), Cs2CO3 (97 mg, 0.3 mmol). The tube was evacuated and
backfilled with argon (three times), and then dry DMA (1 mL/
0.1 mmol of starting material) was added. The mixture was sparged
with argon for 5 min and then heated at 110 ꢁC for 1 h. The reaction
mixture was allowed to cool, and then quenched with 1 N HCl
(5 mL), extracted with ethyl acetate (3ꢂ10 mL). The organic extracts
were combined, washed with brine (20 mL), dried over anhydrous
MgSO4, filtered, and concentrated. The residue was purified by
chromatography on silica gel using CH2Cl2/cyclohexane/EtOAc (60/
35/5) to give (R)-8f (44 mg, 0.097 mmol, 98%) as a pale yellow solid.
Acknowledgements
The authors appreciate financial support from the Harvard
NeuroDiscovery Center. The authors also thank Prof. Stephen L.
Buchwald for providing the precatalysts.
Supplementary data
Description of the general experimental procedures and NMR
spectra of the compounds is provided. Supplementary data asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.tet.2011.12.022.
1H NMR (500 MHz, CDCl3):
d
8.24 (d, J¼8.0 Hz, 1H), 7.69 (d,
References and notes
J¼8.5 Hz, 2H), 7.32e7.27 (m, 2H), 7.24e7.20 (m, 3H), 5.83 (s, 1H),
4.59 (dd, J¼14.0, 4.5 Hz, 1H), 4.12e4.07 (m, 1H), 3.96 (s, 3H), 3.68 (s,
3H), 3.26e3.19 (m, 1H), 3.14e3.10 (m, 1H), 3.02 (t, J¼14.0 Hz, 1H),
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addition of saturated NaHCO3 (100 mL). Anhydrous K2CO3 (547 mg)
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94%) as a pale yellow solid. The %ee was determined to be 89%.16 1H
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d
8.98 (s, 1H), 8.08 (d, J¼8.0 Hz, 1H),
7.26e7.20 (m, 2H), 7.13 (ddd, J¼8.0, 8.0, 1.0 Hz,1H), 3.76 (s, 3H), 3.65
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d 148.7, 146.5,
138.6, 135.4, 133.1, 132.4, 127.7, 127.3, 126.9, 126.4, 118.5, 116.2, 61.1,
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298.1438; found: 298.1439. ½a D20
ꢀ35.0 (c 0.1, CHCl3).
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