An efficient synthesis of an 8-phenoxy aporphine derivative utilizing mono-ligated palladium ortho-phenol arylation

Article abstract of DOI:10.1016/j.tet.2019.04.011

8-Aryloxy aporphines are a structurally diverse subset of alkaloids that display an array of biological activities. An efficient synthesis of an 8-phenoxy aporphine model compound has been developed utilizing Pictet-Spengler cyclization followed by biaryl bond formation using Pd-XPhos catalyzed ortho-phenol arylation. Biaryl bond formation using direct arylation is also compared. Finally, the stability of the 8-phenoxy aporphine model compound is discussed with potential implications for the isolation, structure elucidation and pharmacognosy of 7-dehydroaporphine natural products.

Full text of DOI:10.1016/j.tet.2019.04.011

Accepted Manuscript
An efficient synthesis of an 8-phenoxy aporphine derivative utilizing mono-ligated
palladium ortho-phenol arylation
Ghada Ali, Gregory D. Cuny
PII:
S0040-4020(19)30401-6
https://doi.org/10.1016/j.tet.2019.04.011
TET 30256
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 February 2019
Revised Date: 28 March 2019
Accepted Date: 2 April 2019
Please cite this article as: Ali G, Cuny GD, An efficient synthesis of an 8-phenoxy aporphine derivative
utilizing mono-ligated palladium ortho-phenol arylation, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.04.011.
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Leave this area blank for abstract info.
An Efficient Synthesis of an 8-Phenoxy
Aporphine Derivative Utilizing Mono-ligated
Palladium ortho-Phenol Arylation
Ghada Ali and Gregory D. Cuny*
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An Efficient Synthesis of an 8-Phenoxy Aporphine Derivative Utilizing Mono-ligated
Palladium ortho-Phenol Arylation
Ghada Ali1, Gregory D. Cuny*2
2
1Department of Chemistry and Department of Pharmacological and Pharmaceutical Sciences,
University of Houston, College of Pharmacy, Houston, Texas 77204, United States
Keywords: aporphine, 7-dehydroaporphine, phenoxy, arylation, palladium
*Corresponding author. E-mail address: gdcuny@central.uh.edu
Abstract
8-Aryloxy aporphines are a structurally diverse subset of alkaloids that display an array
of biological activities. An efficient synthesis of an 8-phenoxy aporphine model compound has
been developed utilizing Pictet-Spengler cyclization followed by biaryl bond formation using
Pd-XPhos catalyzed ortho-phenol arylation. Biaryl bond formation using direct arylation is also
compared. Finally, the stability of the 8-phenoxy aporphine model compound is discussed with
potential implications for the isolation, structure elucidation and pharmacognosy of 7-
dehydroaporphine natural products.
1. Introduction
Aporphines are a family of alkaloids consisting of a four-membered fused-ring system
with rings A and B comprising an embedded tetrahydroisoquinoline (Figure 1). Representative
members possess diverse and interesting biological utilities, such as anticancer,1-2 antimicrobial,3
anti-inflammatory,4 and antiplatelet5 activities. More recently, aporphines have emerged as
ligands for human and parasitic serotonin (5-HT) receptors.6-8 The array of biological properties
demonstrated by aporphines has helped elevate this class of natural products to privileged
scaffold status.9 Over the past several years our laboratory has been interested in exploiting
aporphines as a conformational restricted framework for pharmacological space exploration.
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This has included an initial focus on 7-oxygenated10 and 6a-methyl11 aporphine alkaloids. These
studies resulted in the discovery that the non-natural enantiomer (1) of (−)-nornuciferidine was a
potent β1- and β2-adrenergic receptor ligand antagonizing adenylyl cyclase (IC50 = 0.017 and
0.0069 µM, respectively) that can be useful for refining the understanding of ligand binding
modes to this class of G-protein coupled receptors.12
Figure 1. The aporphine alkaloid scaffold with numbering and β1/β2-adrenergic receptor
antagonist (R,R)- nornuciferidine (1).
Another subset of alkaloids possesses aryloxy groups on carbon-8 of the aporphine
scaffold (Figure 2). A recent example includes thaliculine (2).13 In addition, an array of
aporphine-benzylisoquinoline dimeric alkaloids ether-linked at the 8-position of the aporphines
have been isolated.14-26 For example, thalifaboramine (3a)17 and thalicultratine A (3b)22 were
found in Thalictrum genus. A number of these aporphine-benzylisoquinoline dimeric alkaloids
demonstrated potent cytotoxicity activities.22-26 However, approaches to the syntheses of 8-
aryloxy aporphines are lacking, except for the photolysis of proaporphines.27 Herein, we report
an efficient synthetic route to this class of aporphines using a model substrate. In addition,
observations regarding the stability of this class of compounds, as well as potential implications
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for the isolation, structure elucidation and pharmacognosy of 7-dehydroaporphines, a related
class of natural products, are discussed.
Figure 2. Examples of an 8-phenoxy aporphine thaliculine (2) and aporphine-benzylisoquinoline
dimeric alkaloids thalifaboramine (3a) and thalicultratine A (3b).
Our strategy for constructing the 8-phenoxy aporphine model substrate 4 is outlined in
the retrosynthetic analysis depicted in Figure 3, with the latter phase of the synthesis anticipated
to use either palladium-catalyzed ortho-phenol arylation28-31 or direct arylation32-33 of 1-
benzyltetrahydroisoquinoline substrates. These materials would be obtained via Pictet-Spengler
cyclization of phenethylamine carbamates and vinyl ethers, which would arise from mono-
nucleophilic aromatic substitution (SNAr) of commercially available 2,6-dihaloaldehydes.
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O
O
O
R1
N
N
O
Me
CO2Me
X
Ph
O
Ph
O
4
R1 = H or Me
X = Br or Cl
O
NHCO2Me
O
NH2
HO
HO
and
and
X
X
O
Ph
O
X
O
Figure 3. Retrosynthetic analysis for 8-phenoxy aporphines.
2. Results and discussion
2.1. Synthesis of the Pictet-Spengler reaction components
The requisite methyl carbamate 7, required for the Pictet-Spengler reaction, was
previously prepared using a five-step method.34-35 We initially explored the possibility of
selective protection of the amine without carbonate formation using two equivalents of base and
one equivalent of methyl chloroformate. However, only inseparable mixtures of 6 and 7 were
obtained. Using one equivalent each of base and methyl chloroformate gave the desired product
7 exclusively, albeit in only 48% yield. Given these results, a two-step process was devised
(Scheme 1) where both the amine and phenol were protected using three and two equivalence of
base and methyl chloroformate, respectively, followed by selective base hydrolysis of the
carbonate to provide 7 in quantitative yield.
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Scheme 1. Synthesis of methyl carbamate 7 and vinyl ethers 10a and 10b required for the Pictet-
Spengler reaction.
The second required components for the Pictet-Spengler reaction, vinyl ethers 10a and
10b, were obtained by initial SNAr reaction of 2,6-dihalobenzaldehydes 8a and 8b with phenol36
to generate the phenoxy substituted benzaldehydes 9a and 9b in moderate yields (Scheme 1).
This mono-SNAr reaction was difficult to control with significant formation of the di-ether
product 9c. Reaction optimization using 8a revealed that selectivity toward the desired product
9a decreases by increasing reaction temperature and time. Carrying out the reaction at 165 °C for
two hours using one equivalent of K2CO3 afforded 9a and 9c in 42% and 25% yield, respectively
(Table 1, entry 1). Screening different bases highlighted K2CO3 as the best (entries 2-4). Next,
o
the reaction temperature was assessed. At 155 C the desired product yield increased to 60%,
while the yield of 9b was reduced to 10% (entry 5). Slow addition of the phenol to 8a over four
hours and then maintaining the reaction mixture for an additional two hours gave a poor result
(entry 6). Further reduction of the reaction temperature to 145 oC (entry 7), slightly improved the
yield of 9a compared to conditions described in entry 5. Using two equivalents of base did not
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improve the yield (entry 8). Increasing the reaction time also did not help (entry 9). Further
o
reduction of temperature to 130 C, resulted in low yield of 9a, but no formation of unwanted
o
product 9c (entry 10). However, extending the reaction time at 130 C resulted in increased
formation of 9c (entry 11). With 9a and 9b in hand, obtained using the reaction conditions
highlighted in entry 7, the materials were subjected to Wittig reactions34 to furnish the desired
vinyl ethers 10a and 10b in 82% and 91% yields, respectively (Scheme 1).
Table 1. Optimization of the SNAr reaction of 8a with phenol.
Entry
Base
Temp Time
Yield
(%)a
(oC)
(h)
9a (9c)
42 (25)
5 (24)
NRd
1
2
K2CO3
165
2
2
Cs2CO3 165
3
Li2CO3
CaCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
165
165
155
155
145
145
145
130
130
24
24
2
4
NR
5
6b
60 (10)
38 (20)
65 (5)
64 (6)
57 (11)
18 ( 0)
55 (15)
6
7
2
8c
9
2
4
10
11
2
18
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a Isolated yield.
b Slow addition of phenol to the aldehyde over 4 hours and then additional 2 hours of reaction time at 155
°C.
c 2 equivalents of base.
d NR = no reaction.
2.2. Synthesis 8-phenoxy aporphine 4
Pictet-Spengler cyclization34 of 7 with 10a or 10b proceeded efficiently to form
tetrahydroisoquinolines 11a and 11b in 96% and 92% yields, respectively (Scheme 2). The latter
materials were transformed into their methoxy analogues 13a and 13b in excellent yields. These
four 1-benzyl tetrahydroisoquinoline carbamates displayed hindered rotation evidenced by their
NMR spectra. Next, formation of the aporphine core structure was examined. Basis on our prior
work in the area of aporphine synthesis, we envisioned using Pd-Xphos precatalysts developed
29
by Buchwald37-38 to mediate the ortho-phenol arylation10-12,
of substrates 11a and 11b.
Alternatively, direct arylations of methyl ethers 13a and 13b were also pursued based on the
precedence of several groups, including Fagnou,32 as well as our own previous experiences in the
synthesis of diastereomers of the aporphine alkaloid artabonatine A.10 To our delight, ortho-
phenol arylation of 11a and 11b using 10 mol% Pd-XPhos precatalyst G1 under basic condition
for only one hour furnished the desired arylated product 12 in 90% and 83% yields, respectively.
These results highlighted that introduction of steric hindrance via the phenoxy was not
detrimental to ortho-arylation reactions. Subsequent methylation of 12 generated 14 in 95%
yield. In order to assess the effectiveness of direct arylation, the non-phenolic substrates 13a and
13b were treated with Pd-XPhos precatalyst G1 under basic condition, again for just one hour, to
provide 14, but in significantly lower yields (22% from 13a and trace amounts from 13b). These
results further underscored the importance of the phenol hydroxyl group for activating the ortho-
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position of the substrate to facilitate coupling. Finally, reduction of 14 with lithium aluminum
hydride (LAH) gave the 8-phenoxy aporphine model substrate 4 in 94% yield.
Scheme 2. Synthetic pathway for preparation of 8-phenoxy aporphine 4. Also shown in the
structure of Pd-XPhos precatalyst G1.
Surprisingly, during analytical characterization of the 8-phenoxy aporphine 4, the
compound was found to be quite unstable, decomposing to a mixture of products. This occurs in
the solid state or in solution. For example, after standing in air at room temperature for several
hours or under an argon atmosphere at -20 °C for several days, decomposition products were
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observed. This compound’s instability appeared to result from the strong electron donating 8-
phenoxy substituent, since similar phenomenon with other aporphines prepared in our laboratory
have not been observed. Suspicion to the identity and formation of the major decomposition
product was oxidation of the C ring generating the corresponding 7-dehydroaporphine 15, a
known class of related alkaloids. After extensive purification, 15 was indeed confirmed as the
major product. To further examine the oxidation of 4 to 15, more controlled and efficient
experimental conditions were employed. Freshly prepared 4 was oxidized in the presence of
1
iodine39 to give 15 in 78% isolated yield. The H- and 13C-NMR spectra of 15 matched the
major isolated decomposition product and was consistent with a 7-dehydroaporphine.
Interestingly, a number of research groups have reported the isolation of 8-aryloxy-7-
dehydroaporphines along with 8-aryloxy aporphines.13, 20-22 For example, Li, et al. highlighted
the isolation of several 7-dehydroaporphine-benzylisoquinoline ether-linked dimers and the
corresponding aporphine-benzylisoquinoline ether-linked dimers from Thalictrum cultratum
Wall.22 The instability observed with 4 raises the possibility that some 8-aryloxy-7-
dehydroaporphines may form via oxidation of the corresponding 8-aryloxy aporphines during
various collection, storage and/or processing maneuvers.
3. Conclusion
A convenient method for the synthesis of 8-phenoxy aporphine model substrate 4 was
achieved in six steps and overall isolated yields of 41% or 25% starting with 2,6-dibromo or 2,6-
dichlorobenzaldehydes, respectively. The synthetic route employed three key transformations: 1)
SNAr mediated installation of the phenoxy during preparation of vinyl ether substrates; 2) Pictet-
Spengler cyclization for tetrahydroisoquinoline formation; and 3) mono-ligated palladium-
catalyzed ortho-phenol arylation. This latter reaction for constructing the biaryl bond proved
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more efficient than palladium-mediated direct arylation of the corresponding ortho-methoxy
ether. The synthetic strategy outlined can be applied to naturally occurring 8-aryloxy aporphines,
as well as other non-natural derivatives furthering the pharmacological exploration of this
privileged scaffold. Finally, the instability of 8-phenoxy aporphine 4 was also highlighted,
raising a cautionary note for the isolation and structure elucidation of 8-aryloxy-7-
dehydroaporphines, particularly when the corresponding 8-aryloxy aporphines are also observed.
4. Experimental section
4.1. General information and materials
All reactions were carried out under an argon atmosphere in oven-dried glassware with
rubber septa and magnetic stirring. All commercially available chemicals and solvents were used
directly without further purification. Reactions were monitored by thin-layer chromatography
(TLC) on Baker-flex® silica gel plates IB2-F. Visualization was accomplished with UV light
(254 and 365 nm) or visualizing agents (e.g. phosphomolybdic acid stain). Flash chromatography
was conducted on a silica gel (40−60 ꢀm). Melting points were measured using Thomas Hoover
Uni-Melt capillary melting point apparatus and are uncorrected. 1H NMR spectra were recorded
at room temperature on 500 or 600 MHz spectrometer with tetramethylsilane (TMS) as an
internal standard. Chemical shifts (δ) were given in parts per million (ppm) with reference to
TMS.13C NMR spectra were recorded on a 101 or 126 MHz spectrometer with reference to
CDCl3 (77.0 ppm). Signal patterns were reported as s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, and br = broad. Coupling constants (J) were given in Hz. In case of
rotamers, NMR data were reported as major [minor] if the corresponding peaks were separated
from each other or they were written as a range for both of the major and minor rotamers if the
peaks were overlapping. Note, in the 13C NMR spectra of the minor rotamers some carbons were
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not resolved. High resolution mass spectra (HRMS) were performed by the University of Texas
Mass Spectrometry facility using a quadrupole time-of-flight (Q-TOF) mass spectrometer or by
the University of Houston Mass Spectrometry laboratory using an Orbitrap mass
spectrometer equipped with a TriVersa NanoMate nano-electrospray (nESI) source. The spectra
were reported as m/z (relative intensity) for the molecular ion [M].
4.2. Synthesis of Pictet-Spengler cyclization components
Methyl 3-methoxy-4-((methoxycarbonyl)oxy)phenethylcarbamate (6): Triethylamine (313.6
mg, 3.1 mmol) was added to a solution of 4-(2-aminoethyl)-2-methoxyphenol hydrochloride 5
(203.6 mg, 1 mmol) in anhydrous DMF (3 mL) under an argon atmosphere. The resulting
solution was cooled to 0 °C and then methylchloroformate (207.9 mg, 2.2 mmol) was added
dropwise. The reaction mixture was stirred at room temperature for 3 h and then quenched with 1
N aqueous HCl. The aqueous layer was extracted with ethyl acetate (3 × 30 mL). The combined
organic extracts were washed with saturated aqueous NaHCO3 and brine, dried over anhydrous
Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography
on silica gel (EtOAc/hexane, 35:65) to afford 6 (280.4 mg, 99% yield) as a white solid; mp: 76–
78 °C; 1H-NMR (500 MHz, CDCl3): δ = 7.05 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 6.75 (d, J = 8.0,
1H), 4.82 (brs, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.66 (s, 3H), 3.43 (td, J = 6.5, 6.5 Hz, 2H), 2.79 (t,
J = 6.7 Hz, 2H) ppm; 13C-NMR (126 MHz, CDCl3): δ = 156.92, 153.95, 150.99, 138.55, 138.03,
122.25, 120.69, 112.91, 55.85, 55.45, 52.00, 42.01, 36.01ppm; HRMS (ESI) m/z calculated for
C13H18NO6 [M + H]+: 284.1129, found: 284.1127.
Methyl 4-hydroxy-3-methoxyphenethylcarbamate (7): To a solution of 6 (283.2 mg, 1 mmol)
in methanol (5 mL) was added KOH (207.9 mg, 2 mmol). The reaction mixture was heated
under reflux for 4 h and then concentrated. The residue was neutralized with 1N aqueous HCl.
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The aqueous layer was extracted with ethyl acetate (3 × 30 mL). The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue
was purified by column chromatography on silica gel (EtOAc/hexane, 35:65) to afford 7 (220.7
mg, 98% yield) as a white solid; mp: 66–68 °C; 1H-NMR (500 MHz, CDCl3): δ = 6.84 (d, J = 8.0
Hz, 1H), 6.68-6.66 (m, 2H), 5.66 (s, 1H), 4.76 (brs, 1H), 3.86 (s, 3H), 3.66 (s, 3H), 3.41 (td, J =
7.0, 6.0 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H) ppm; 13C-NMR (126 MHz, CDCl3): δ = 156.98, 146.55,
144.19, 130.50, 121.31, 114.41, 111.17, 55.84, 52.02, 42.35, 35.76 ppm; HRMS (ESI) m/z
calculated for C11H16NO4 [M + H]+: 226.1074, found: 226.1075.
General procedure for 2-halo-6-phenoxybenzaldehyde: K2CO3 (138.2 mg, 1 mmol) was
added to a solution of 2,6-dihalobenzaldehyde (1 mmol) and phenol (94.11 mg, 1 mmol) in
anhydrous DMA (4 mL) under an argon atmosphere. The resulting mixture was heated at 145 °C
for 2 h. The reaction mixture was allowed to cool to room temperature and quenched by addition
of water and then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by flash column chromatography on silica gel (EtOAc/hexane, 1: 99) to afford 9a or 9b
and the byproduct 9c.
2-Bromo-6-phenoxybenzaldehyde (9a):
(180 mg, 65% yield), pale yellow oil; 1H-NMR (500 MHz, CDCl3): δ = 10.46 (s, 1H), 7.39-7.36
(m, 3H), 7.25-7.29 (t, J = 8.2 Hz, 1H), 7.19-7.16 (m, 1H), 7.03 (dd, J = 8.5, 1.0 Hz, 2H), 6.85 (d,
J = 8.0, Hz, 1H) ppm; 13C-NMR (126 MHz, CDCl3): δ = 189.59, 160.11, 155.95, 134.59, 130.09,
128.97, 125.46, 124.56, 124.12, 119.46, 117.90 ppm; HRMS (CI) m/z calculated for C13H8BrO2
[M - H]+: 274.9708, found: 274.9713.
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2-Chloro-6-phenoxybenzaldehyde (9b):
1
(93 mg, 40% yield) pale yellow oil; H-NMR (500 MHz, CDCl3): δ = 10.56 (s, 1H), 7.41-7.34
(m, 3H), 7.21-7.17 (m, 2H), 7.05-7.03 (m, 2H), 6.80 (d, J = 9.0, 1H) ppm; 13C-NMR (101 MHz,
CDCl3): δ = 188.48, 160.18, 155.80, 135.96, 134.37, 130.06, 125.50, 124.57, 124.15, 119.47,
117.03 ppm; HRMS (CI) m/z calculated for C13H8ClO2 [M - H]+: 231.0213, found: 231.0212.
2,6-diphenoxybenzaldehyde (9c):
(14.5 mg, 5% yield) white solid; mp: 89–90 °C; 1H-NMR (500 MHz, CDCl3): δ = 10.61 (s, 1H),
7.41-7.37 (m, 4H), 7.32 (t, J = 8.0 Hz, 1H), 7.20-7.16 (m, 2H), 7.10-7.07 (m, 4H), 6.57 (d, J =
8.0 Hz, 2H) ppm; 13C-NMR (126 MHz, CDCl3): δ = 188.23, 159.90, 156.10, 135.14, 129.97,
124.34, 119.65, 118.39, 112.66 ppm; HRMS (ESI) m/z calculated for C19H15O3 [M + H]+:
291.1016, found: 291.1016.
General procedure for 1-halo-2-(2-methoxyvinyl)-3-phenoxybenzene: LDA (2 M solution in
THF/heptane/ethylbenzene, 1.0 mL, 2 mmol) was added dropwise to a solution of
(methoxymethyl)triphenylphosphonium chloride (684.9 mg, 2 mmol) in anhydrous THF (2 mL)
at 0 °C. The mixture was stirred at the same temperature for 20 min then a solution of 9a, or 9b
(1 mmol) in anhydrous THF (0.5 mL) was added dropwise. The resulting mixture was allowed to
warm to room temperature and then stirred for an additional 3 h. The reaction mixture was
quenched with 1 N aqueous HCl and then extracted with ethyl acetate (3 × 30 mL). The
combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by column chromatography on silica gel (hexane) to
furnish 10a or 10b, each as a mixture of cis- and trans-isomers.
1-Bromo-2-(2-methoxyvinyl)-3-phenoxybenzene (10a):
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(251.8 mg, 82% yield) colorless viscous liquid; 1H-NMR (500 MHz, CDCl3) of trans-isomer : δ
= 7.39-7.30 (m, 4H), 7.08 (t, J = 7.5 Hz, 1H), 6.93-6.90 (m, 3H), 6.83 (d, J = 8.0 Hz, 1H), 5.91
(d, J = 12.5 Hz, 1H), 3.65 (s, 3H) ppm; 13C-NMR (126 MHz, CDCl3): δ = 156.82, 154.19,
153.99, 129.77, 128.46, 128.29, 126.59, 124.54, 123.14, 119.06, 118.05, 100.24, 56.22 ppm;
HRMS (CI) m/z calculated for C15H13ClO2 [M]+: 260.0604, found:260.0605.
1-Chloro-2-(2-methoxyvinyl)-3-phenoxybenzene (10b):
1
(239.5 mg, 91% yield) colorless liquid; H-NMR (600 MHz, CDCl3) of trans-isomer: δ = 7.43
(d, J = 12.6 Hz, 1H), 7.33-7.30 (m, 2H), 7.16 (dd, J = 7.8, 0.9 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H),
6.97 (t, J = 8.1 Hz, 1H), 6.93 (d, J = 7.8 Hz, 2H), 6.77 (d, J = 7.8 Hz, 1H), 5.95 (d, J = 13.2 Hz,
1H), 3.65 (s, 3H) ppm; 13C-NMR (151 MHz, CDCl3): δ = 156.81, 154.41, 154.02, 133.59,
129.79, 126.67, 126.03, 125.17, 123.17, 118.28, 118.11, 97.60, 56.23 ppm; HRMS (CI) m/z
calculated for C15H13BrO2 [M]+: 304.0099, found: 304.0094.
4.3. Synthesis of 8- phenoxy aporphine 4
General procedure for methyl 1-(2-halo-6-phenoxybenzyl)-7-hydroxy-6-methoxy-3,4-
dihydroisoquinoline-2(1H)-carboxylate: To a solution of 7 (225.2 mg, 1 mmol) and 10a or
10b (1.2 mmol) in anhydrous DCM (10 mL) under an argon atmosphere was added phosphoryl
trichloride (1533 mg, 11 mmol). The reaction mixture was stirred at room temperature for 18 h
and then 10% aqueous ammonium hydroxide (50 mL) was added and the resulting mixture
stirred vigorously for 5 minutes. The resulting aqueous solution was extracted with ethyl acetate
(3 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 20:80) to furnish 11a or 11b.
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Methyl
1-(2-bromo-6-phenoxybenzyl)-7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-
2(1H)-carboxylate (11a):
1
(478.5 mg, 96% yield) white solid; mp: 150–153 °C; H-NMR (500 MHz, CDCl3) for major
[minor] rotamers: δ = 7.38-7.29 (m, 3H), 7.15-7.08 (m, 1H), 7.03-6.95 (m, 3H), 6.91[6.87] (s,
1H), [6.71] 6.66 (d, J = 8.0 Hz, 1H), 6.57 [6.52] (s, 1H), 5.63 [5.59] (s, 1H), [5.66] 5.54 (dd, J =
11.0, 3.0 Hz, 1H), 4.28 (ddd, J = 13.5, 5.7, 2.0 Hz, 1H) [3.96 (dq, J = 13.0, 3.0 Hz)], 3.85 [3.83]
(s, 3H), 3.52-3.40 (m, 2H), [3.55] 3.21 (s, 3H), 3.18-3.12 (m, 1H), 2.89-2.75 (m, 1H), 2.65-2.59
(m, 1H) ppm; 13C-NMR (126 MHz, CDCl3) for major [minor] rotamers: δ = 157.08, [156.71],
[156.63], 156.11, 155.89, [155.83], 145.41, [145.30], 143.90, [143.83], 129.93, [129.75],
[129.54], 129.41, 129.07, [128.36], 128.22, [127.32], 126.72, 126.41, [126.35], 125.75, [125.51],
123.87, [123.39], 119.40, [118.70], [116.51], 115.71, [112.86], 112.52, 110.65, [110.44], 55.86,
[55.82], [53.46], 53.12, [52.41], 51.99, [38.32], 37.68, 36.33, [36.15], [28.31], 28.24 ppm;
HRMS (ESI) m/z calculated for C25H25BrNO5 [M + H]+: 498.0911, found: 498.0909.
Methyl
1-(2-chloro-6-phenoxybenzyl)-7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-
2(1H)-carboxylate (11b):
1
(417.5 mg, 92% yield) white solid; mp: 76–79 °C; H-NMR (500 MHz, CDCl3) for major
[minor] rotamers: δ = 7.38-7.32 (m, 2H), 7.15-7.09 (m, 2H), 7.08-699 (m, 3H), 6.85 [6.82] (s,
1H), [6.67] 6.63 (d, J = 8.0, 1H), 6.57 [6.52] (s, 1H), [5.62] 5.50 (dd, J = 10.8, 3.4 Hz, 1H), 5.55
[5.51] (s, 1H), 4.28 (ddd, J = 13.5, 6.0, 2.0 Hz, 1H) [3.96 (dq, J = 13.5, 3.0 Hz)], 3.85 [3.84] (s,
1H), [3.55] 3.21 (s, 1H), 3.51-3.36 (m, 2H), 3.18-3.13 (m, 1H), 2.89-2.76 (m, 1H), 2.66-2.59 (m,
1H) ppm; 13C-NMR (126 MHz, CDCl3) for major [minor] rotamers: δ = 157.17, [156.74],
156.15, 155.89, [155.82], 145.41, [145.30], 143.91, [143.84], 135.97, 129.93, [129.76], 129.47,
[127.97], 127.88, 127.75, [127.58], 125.75, [125.50], [124.01], 123.86, 123.47, [123.39], 119.38,
16

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[118.74], [115.90], 115.14, [112.91], 112.58, 110.67, [110.46], 55.87, [53.53], 53.25, [52.41],
52.00, [38.17], 37.55, 33.89, [33.67], [28.30], 28.23 ppm; HRMS (ESI) m/z calculated for
C25H25ClNO5 [M + H]+: 454.1416, found: 454.1417.
Methyl 1-hydroxy-2-methoxy-8-phenoxy-6a,7-dihydro-4H-dibenzo[de,g]quinoline-6(5H)-
carboxylate (12): To a mixture of 11a or 11b (0.5 mmol), Cs2CO3 (488.7 mg, 1.5 mmol) and
Pd-XPhos G1 (37 mg, 0.05 mmol) under an argon atmosphere was added anhydrous DMA (3
mL). The reaction was then heated in an oil bath (110 °C) for 1 h. After quenching the reaction
by the addition of 1 N aqueous HCl, the aqueous layer was extracted with ethyl acetate (3 × 20
mL). The combined organic extracts were washed with saturated aqueous NaHCO3 and brine,
dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to column
chromatography on silica gel (EtOAc/hexane, 20:80) to give 12 (187.8 mg, 90% yield using 11a)
as a white solid; mp: 193–195 °C; 1H-NMR (600 MHz, CDCl3): 8.29 (d, J = 8.4 Hz, 1H), 7.32 (t,
J = 8.1 Hz, 1H), 7.28 (t, J = 7.8 Hz, 2H), 7.01 (t, J = 7.2 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.91
(d, J = 7.8 Hz, 2H), 6.62 (s, 1H), 6.27 (s, 1H), 4.71 (brs, 1H), 4.41 (brs, 1H), 3.91 (s, 3H), 3.59
(s, 3H), 3.31 (s, 1H), 2.92 (t, J = 12.3 Hz, 1H), 2.83 (t, J = 15, 1H), 2.60 (d, J = 15 Hz, 1H), 2.42
(t, J = 14.1 Hz, 1H) ppm; 13C-NMR (151 MHz, CDCl3): δ = 158.34, 145.68, 141.87, 133.78,
129.55, 128.91, 127.28, 126.01, 124.97, 124.83, 122.08, 119.63, 116.74, 109.79, 56.19, 52.45,
51.22, 38.83, 29.87, 27.84 ppm (two quaternary and one non-quaternary carbons are not
observed); HRMS (ESI) m/z calculated for C25H24NO5 [M + H]+: 418.1649, found: 418.1650.
General
procedure
for
Methyl
1-(2-halo-6-phenoxybenzyl)-6,7-dimethoxy-3,4-
dihydroisoquinoline-2(1H)-carboxylate: A mixture of 11a or 11b (0.2 mmol) and Cs2CO3
(97.7 mg, 0.3 mmol) in anhydrous DMF (600 ꢀL) under an argon atmosphere was stirred at
room temperature for 5 min. Iodomethane (34 mg, 0.24 mmol) was added and the mixture was
17

ACCEPTED MANUSCRIPT
stirred at room temperature for 2 h. After completion of the reaction, it was quenched by addition
of water and then extracted with ethyl acetate (3 × 10 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was
subjected to column chromatography on silica gel (EtOAc/hexane, 20:80) to give 13a or 13b.
Methyl 1-(2-bromo-6-phenoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-
carboxylate (13a):
(99.4 mg, 97% yield) white solid; mp: 65– 67 °C; 1H-NMR (500 MHz, CDCl3) for major [minor]
rotamers: δ = 7.37-7.28 (m, 3H), 7.14-7.08 (m, 1H), 7.03-6.94 (m, 3H), 6.75-6.71 (m, 1H), 6.71
[6.63] (s, 1H), 6.59 [6.54] (s, 1H), [5.65] 5.54 (dd, J = 10.5, 4.0 Hz, 1H), 4.29 (ddd, J = 13.5, 4.0,
2.0 Hz, 1H) [3.98 (dq, J = 13.5, 3.0 Hz)], 3.84 [3.83] (s, 3H), 3.77 [3.70] (s, 3H), [3.59] 3.26 (s,
3H), 3.56-3.40 (m, 2H), 3.22 [3.17] (dd, J = 13.5, 3.5 Hz, 1H), 2.90-2.77 (m, 1H), 2.68-2.62 (m,
1H) ppm; 13C-NMR (126 MHz, CDCl3) for major [minor] rotamers: δ = 156.79, [156.43],
[156.32], 155.86, 147.77, [147.61], 147.33, [147.20], [130.05], 129.97, [129.80], 129.66,
[129.06], 128.60, [128.46], 128.35, [127.54], 127.08, 126.43, 126.34, [126.26], [126.11], 123.76,
[123.36], 118.88, [118.35], [116.99], 116.39, 111.26, [111.01], [109.92], 109.65, 55.87, 55.83,
[53.77], 53.50, [52.48], 52.05, [38.34], 37.69, 36.46, [36.10], 28.10 ppm; HRMS (ESI) m/z
calculated for C26H27BrNO5 [M + H]+: 512.1067, found: 512.1063.
Methyl 1-(2-chloro-6-phenoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-
carboxylate (13b):
(91.7 mg, 98% yield) white solid; mp: 56 –58 °C; 1H-NMR (500 MHz, CDCl3) for major [minor]
rotamers: δ = 7.37-7.31 (m, 2H), 7.16-7.06 (m, 3H), 7.00 [6.96] (d, J = 8.0 Hz, 2H), 6.72-6.69
(m, 1H), 6.64 [6.57] (s, 1H), 6.59 [6.54] (s, 1H), [5.62] 5.50 (dd, J = 10.5, 3.5 Hz, 1H), 4.28
18

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(ddd, J = 13.5, 6.0, 2.5 Hz, 1H) [3.97 (dq, J = 13.5, 3.2 Hz)], 3.85 [3.83] (s, 3H), 3.77 [3.71] (s,
3H), [3.59] 3.27 (s, 3H), 3.55-3.40 (m, 2H), 3.22-3.14 (m, 1H), 2.91-2.76 (m, 1H), 2.68-2.62 (m,
1H) ppm; 13C-NMR (126 MHz, CDCl3) for major [minor] rotamers: δ = 156.81, [156.51],
156.35, [155.88], 155.84, 147.75, [147.60], 147.31, [147.19], 135.90, 129.94, [129.78], [129.07],
128.61, [128.39], 128.09, [127.96], 127.87, 126.40, [126.08], [124.22], 123.82, 123.70, [123.32],
118.79, [118.32], [116.39], 115.83, 111.26, [111.01], [109.93], 109.66, [55.87], 55.82, 55.79,
[53.77], 53.55, [52.47], 52.06, [38.21], 37.57, 33.96, [33.59], 28.06 ppm; HRMS (ESI) m/z
calculated for C26H257ClNO5 [M + H]+: 468.1572, found: 468.1568.
Methyl
1,2-dimethoxy-8-phenoxy-6a,7-dihydro-4H-dibenzo[de,g]quinoline-6(5H)-
carboxylate (14):
Method A: A mixture of 12 (208.7 mg, 0.5 mmol) and Cs2CO3 (244.3 mg, 0.75 mmol) in
anhydrous DMF (1.5 mL) under an argon atmosphere was stirred at room temperature for 5 min.
Iodomethane (85 mg, 0.6 mmol) was added and the reaction mixture was stirred at room
temperature for 2 h. After completion of the reaction, it was quenched by addition of water and
then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to
column chromatography on silica gel (EtOAc/hexane, 15:85) to give 14 (205 mg, 95% yield)
Method B: Following the procedure for synthesis of 12 but using 13a or 13b to furnish 14.
White solid; mp: 192–194 °C; 1H-NMR (600 MHz, CDCl3): δ = δ 8.29 (d, J = 7.8 Hz, 1H), 7.33-
7.28 (m, 3H), 7.04 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 7.8 Hz, 2H), 6.70 (s,
1H), 4.68 (brs, 1H), 4.43 (brs, 1H), 3.90 (s, 3H), 3.69 (s, 3H), 3.57 (brs, 3H), 3.31 (brs, 1H), 2.95
(t, J = 12.0 Hz, 1H), 2.86 (td, J = 13.8 Hz, 1H), 2.65 (d, J = 15.0 Hz, 1H), 2.44 (t, J = 13.8 Hz,
19

ACCEPTED MANUSCRIPT
1H) ppm; 13C-NMR (151 MHz, CDCl3): δ = 158.26, 152.04, 145.58, 133.56, 129.65, 129.59,
129.23, 127.52, 127.26, 125.93, 124.69, 122.23, 120.04, 116.88, 111.71, 60.04, 55.90, 52.45,
51.22, 38.67, 30.13, 27.94 ppm (one quaternary and one non-quaternary carbons were not
observed); HRMS (ESI) m/z calculated for C26H26NO5 [M + H]+: 432.1805, found: 432.1809.
1,2-Dimethoxy-6-methyl-8-phenoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline (4): To
a suspension of LAH (37.9 mg, 1 mmol) in anhydrous THF (1 mL) at 0 °C under an argon
atmosphere was added a solution of 14 (43.1 mg, 0.1 mmol) in anhydrous THF (2 mL) dropwise.
The reaction mixture was then heated under reflux for 1 h before quenching by the addition of
water and 10% aqueous ammonium hydroxide solution, respectively. The resulting mixture was
filtered through celite to remove a fine yellow precipitate. The filtrate was extracted with DCM
(3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated. The crude residue was purified with column chromatography
1
on silica gel (EtOAc/DCM, 30:70) to give 4 (36.8 mg, 94% yield) as a viscous liquid; H-NMR
(600 MHz, CDCl3): δ = 8.20 (d, J = 7.8 Hz, 1H), 7.31-7.27 (m, 3H), 7.04 (t, J = 7.2 Hz, 1H),
6.94-6.92 (m, 3H), 6.65 (s, 1H), 3.89 (s, 3H), 3.69 (s, 3H), 3.48 (dd, J = 14.4, 3.9 Hz, 1H), 3.16-
3.11 (m, 1H), 3.00 (dd, J = 11.4, 5.4 Hz, 1H), 2.93 (dd, J = 13.5, 3.9 Hz, 1H), 2.67 (dd, J = 16.2,
3.6 Hz, 1H), 2.47 (td, J = 12.0, 3.6 Hz, 1H), 2.38 (s, 3H), 2.14 (t, J = 14.1 Hz, 1H) ppm; 13C-
NMR (126 MHz, CDCl3): δ = 158.21, 152.62, 151.90, 145.09, 134.05, 129.66, 128.72, 128.59,
127.91, 127.36, 126.58, 124.40, 122.34, 119.17, 117.12, 111.43, 61.92, 60.29, 55.82, 53.19,
43.90, 29.18, 27.05 ppm; HRMS (ESI) m/z calculated for C25H26NO3 [M + H]+: 387.1908,
found: 388.190
1,2-Dimethoxy-6-methyl-8-phenoxy-5,6-dihydro-4H-dibenzo[de,g]quinoline (15): To
a
refluxing suspension of 4 (13.5 mg, 0.035 mmol) and anhydrous sodium acetate (11.4 mg, 0.14
20

ACCEPTED MANUSCRIPT
mmol) in anhydrous 1,4-dioxane (1 mL) under an argon atmosphere was added dropwise a
solution of I2 (8.8 mg, 0.035 mmol) in anhydrous 1,4-dioxane (1 mL). Refluxing was continued
for an additional hour and then the solvent was evaporated under reduced pressure. To the
resulting residue was added saturated aqueous solution of Na2S2O3 (3 mL) and then the mixture
was extracted with ethyl acetate (3 × 5 mL). The combined organic extracts were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to
column chromatography on silica gel (EtOAc/hexane, 5:95) to give 15 (10.5 mg, 78% yield) as a
greenish yellow solid; mp: 160–162 °C; 1H-NMR (600 MHz, CDCl3): δ = 9.32 (d, J = 9 Hz, 1H),
7.32-7.27 (m, 3H), 7.09 (d, J = 7.2 Hz, 1H), 7.06-7.02 (m, 4H), 6.91 (s, 1H), 4.02 (s, 3H), 3.90
(s, 3H), 3.36 (t, J = 6.0 Hz, 2H), 3.26 (t, J = 6.0 Hz, 2H), 2.98 (s, 3H) ppm; 13C-NMR (126 MHz,
CDCl3): δ = 158.75, 151.14, 150.56, 145.61, 143.51, 129.58, 129.47, 128.11, 125.97, 125.68,
123.77, 122.23, 122.11, 119.12, 117.71, 116.81, 111.56, 94.58, 59.81, 56.34, 50.24, 40.41, 31.10
ppm; HRMS (ESI) m/z calculated for C25H24NO3 [M + H]+: 386.1751, found: 386.1752.
Acknowledgements
The authors would like to thank the Welch Foundation (E-1916-20170325) for financial support
of this research.
Dedication
GDC would like to dedicate this paper to Prof. Stephen Buchwald in honor of him being a joint
recipient of the 2018 Tetrahedron Prize for Creativity in Organic Chemistry. Steve has been an
inspiration, mentor and friend, for which I am grateful.
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