Intramolecular ortho-arylation of phenols utilized in the synthesis of the aporphine alkaloids (±)-lirinidine and (±)-nuciferine

Article abstract of DOI:10.1016/j.tetlet.2003.09.026

A palladium-mediated intramolecular phenol ortho-arylation reaction applied to the construction of aporphine alkaloids is reported. Most significantly, the efficiency of this transformation was enhanced by the utilization of trialkylphosphine (i.e. tricyc

Full text of DOI:10.1016/j.tetlet.2003.09.026

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8149–8152
Intramolecular ortho-arylation of phenols utilized in the synthesis
of the aporphine alkaloids ( )-lirinidine and ( )-nuciferine
Gregory D. Cuny*
Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women’s Hospital and Harvard Medical School,
65 Landsdowne St., Cambridge, MA 02139, USA
Received 11 August 2003; accepted 2 September 2003
Abstract—A palladium-mediated intramolecular phenol ortho-arylation reaction applied to the construction of aporphine
alkaloids is reported. Most significantly, the efficiency of this transformation was enhanced by the utilization of trialkylphosphine
(i.e. tricyclohexylphosphine) or trialkylphosphonium salts (i.e. di-tert-butylmethyl-phosphonium tetrafluoroborate) as co-catalysts
in the presence of cesium carbonate. This methodology was employed in the syntheses of the aporphine alkaloids ( )-lirinidine and
( )-nuciferine.
© 2003 Elsevier Ltd. All rights reserved.
Ortho-aryl phenols are an important structural compo-
nent found in a wide array of organic compounds. One
of the most attractive strategies for constructing this
molecular motif involves the direct ortho-arylation of
phenols with aryl halides. Several approaches have been
described to mediate this type of process, including
enzymatic,1 photochemical,2 and oxidative.3 Multi-step
processes, including most notably the Pinhey–Barton
aryl-lead coupling route, have also been described.4
carbonate in dimethylacetamide (DMA) to yield a vari-
ety of ortho-aryl phenol containing heterocycles and
carbocycles.5d Similarly, a palladium-mediated cycliza-
tion of an aryl iodide and a phenol, in the presence of
the base t-BuCO2Na, was utilized in the synthesis of
pradimicinone.5a Recently, transition metal mediated
ortho-arylation of phenols has been extended to inter-
molecular couplings employing a rhodium catalyst
(RhCl(PPh3)3) in the presence of aryl dialkylphos-
phinite co-catalysts.6
Recently, the utilization of transition metals to affect
this transformation has been explored.5,6 For example,
an anion-accelerated intramolecular coupling of phe-
nols with aryl halides was accomplished with a palla-
dium complex (Herrmann’s catalyst) and cesium
Scheme 1.
Keywords: palladium; ortho-arylation; phenol; aporphine; lirinidine; nuciferine.
* Tel.: +1-617-768-8640; fax: +1-617-768-8606; e-mail: gcuny@rics.bwh.harvard.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)02110-5

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G. D. Cuny / Tetrahedron Letters 44 (2003) 8149–8152
Scheme 2. Reagents and conditions: (i) 6, HBTU, i-Pr2EtN, CH2Cl2, rt, 18 h, 100%; (ii) POCl3, CH3CN, D, 1.5 h, 86%; (iii)
NaBH4, MeOH, rt, 1 h; (iv) ClC(O)OMe, THF, rt, 1 h, 76% for two steps.
The ortho-aryl phenol motif is found among many
members of the aporphine alkaloid class of natural
products.7 Apomorphine, 1, is an example of a
molecule from this class that has a variety of pharma-
cological effects rendering it potentially useful for the
treatment of maladies such as erectile dysfunction and
Parkinson’s Disease.8 Other aporphine alkaloids that
contain an ortho-aryl phenol (or alkylated phenol)
include lirinidine9 and nuciferine.10 The thesis of this
communication is that transition metal mediated
intramolecular ortho-arylation of phenols provides an
efficient means to construct aporphine alkaloids, such
as ( )-lirinidine, 2, and ( )-nuciferine, 3.5e
Herrmann’s catalyst was tried without success (Entry
1). However, in the presence of Pd(OAc)2,
triphenylphosphine and anhydrous sodium acetate in
DMA 10 was obtained in low yield (Entry 2). The
remaining material was unreacted starting material. A
further increase in yield was obtained when the
triphenylphosphine ligand was replaced with tricyclo-
hexylphosphine (Entry 3). Recently, the utilization of
trialkylphosphine ligands in metal mediated processes
has proven very successful.14 Furthermore, air and
moisture stable di-tert-butylmethylphosphonium tetra-
fluoroborate could also serve as co-catalyst with equal
efficiency (Entry 4).15 Addition of 4 A powdered molec-
,
ular sieves to the Pd(OAc)2/Cy3P conditions did not
have any noticeable effect on the reaction (Entry 5).
Increasing the amount of palladium to sub-stoichiomet-
ric quantities further improved the yield of 10 (Entry 6).
Utilization of Pd2(dba)3 (Entry 7) or an imidazolium
ligand
(Entry
8;
IMesHCl:
1,3-bis(2,4,6-
trimethylphenyl)imidazolium chloride) were found to
be disadvantageous. Replacing sodium acetate with
potassium tert-butoxide was also found to be detrimen-
tal (Entry 9) to the yield of 10. However, substituting
sodium acetate with cesium carbonate improved the
yield (Entry 10).16 Addition of lithium iodide to the
reaction completely inhibited coupling (Entry 11). A
similar observation has been reported for some Heck
reactions.17 In light of the detrimental effects from
lithium iodide, the reaction was conducted in the pres-
ence of silver nitrate in order to sequester the bromide
produced. This strategy has proven useful in some
Pd-mediated coupling reactions.18 However, in the
A retrosynthetic analysis of 2 is shown is Scheme 1.
Disconnection of the ortho-aryl phenol gives a benzyl
tetrahydroisoquinoline derivative 4. Further disconnec-
tions lead to readily available phenethyl amine 5 and
phenyl acetic acid 6.
Utilizing O-benzotriazol-1-yl-N,N,N%,N%-tetramethyl-
uronium tetrafluoroborate (HBTU), 5 and 6 were cou-
pled in the presence of diisopropylethylamine to give a
quantitative yield of amide 7 (Scheme 2).11 The amide
was subjected to a Bischler–Napieralski cyclization
upon treatment with phosphorous oxychloride in
refluxing acetonitrile to yield the dihydroisoquinoline
8.12 Sodium borohydride reduction of 8 in methanol
gave the amine 9, which was subsequently treated with
methyl chloroformate in tetrahydrofuran to give the
tetrahydroisoquinoline 4 in 76% yield over the two
steps.13
Various conditions were evaluated to facilitate the
intramolecular ortho-arylation of 4 to yield the apor-
phine compound 10 (Scheme 3 and Table 1). Initially,
Scheme 3. Reagents and conditions: (i) see Table 1; (ii) MeI,
K2CO3, DMF, rt, 4 h, 68%; (iii) LiAlH4, THF, D, 22 h, 86%;
(iv) CH2N2, MeOH/Et2O (1:1), rt, 6 h, 80%.

G. D. Cuny / Tetrahedron Letters 44 (2003) 8149–8152
8151
Table 1.
Entry
Pd source (mol%)
Ligand (mol%)
Base (equiv.)
Additive
Isolated yield of 10 (%)
1
2
3
4
5
6
7
8
Hermann’s (5)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (50)
Pd2(dba)3 (10)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
PdBr2 (20)
–
Cs2CO3 (3)
–
–
–
–
0
15
45
43
46
64
19
<10
24
58
0
PPh3 (40)
PCy3 (40)
(t-Bu)2MePHBF (40)
NaOAc (3.2)
NaOAc (3.2)
NaOAc (3.2)
NaOAc (3.2)
NaOAc (3.2)
NaOAc (3.2)
NaOAc (3.2)
KO-t-Bu (1.5)
Cs2CO3 (3.2)
Cs2CO3 (3.2)
Cs2CO3 (3.2)
Cs2CO3 (3.2)
4
,
PCy3 (40)
PCy3 (100)
PCy3 (40)
IMesHCl (40)
PCy3 (40)
PCy3 (40)
PCy3 (40)
PCy3 (40)
PCy3 (40)
4 A mol. sieves
–
–
–
–
–
LiI (3.2 equiv.)
AgNO3 (1.0 equiv.)
–
9
10
11
12
13
17
49
Temp.: 110°C; solvent: DMA; time: 24 h; atmosphere: Ar.
present case 10 was only obtained in 17% yield (Entry
12). Finally, using PdBr2 in place of the Pd(OAc)2 was
found to have a slight negative effect on the reaction
(Entry 13). It is noteworthy that in all the conditions
evaluated, neither de-brominated nor salutaridine-like
products were isolated.5e
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moderate yield, the syntheses of the natural products 2
and 3 were completed (Scheme 3). The carbamate 10
was reduced with lithium aluminum hydride (LAH) in
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In conclusion, a palladium-mediated intramolecular
phenol ortho-arylation reaction was demonstrated as an
efficient means to construct aporphine alkaloids. Most
significantly, the efficiency of this transformation was
enhanced by the utilization of trialkylphosphine or
trialkylphosphonium salts as co-catalysts in the presence
of the base anhydrous cesium carbonate. This method-
ology was employed in the syntheses of two aporphine
alkaloids, ( )-lirinidine, 2, and ( )-nuciferine, 3. Further
optimization of this methodology and applications of
the strategy described herein to the synthesis of other
aporphine alkaloids as well as other classes of natural
and non-natural compounds is underway.
Acknowledgements
Financial support was provided by the Harvard Center
for Neurodegeneration and Repair (HCNR).

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(100.5 MHz, CDCl3): l 29.08, 35.18, 44.10, 53.67, 56.37,
62.54, 109.64, 119.57, 123.97, 126.90, 127.14, 128.04,
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4 (23.3 mg, 0.0576 mmol), tricyclo-
hexylphosphine (6.9 mg, 0.0246 mmol), anhydrous cesium
carbonate (60 mg, 0.184 mmol, finely ground powder) and
palladium acetate (2.8 mg, 0.0123 mmol) in DMA (1 mL)
under an argon atmosphere was heated at 110°C for 24 h.
The reaction mixture was allowed to cool and then
carefully diluted with 1N HCl. The reaction mixture was
extracted several times with ethyl acetate. The organic
extracts were combined, washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated. The
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10.9 mg of 10 (58%) as a white solid. 1H NMR (500 MHz,
CDCl3): l 2.62 (m, 1H); 2.83–2.88 (m, 2H); 2.96–3.01 (m,
2H); 3.78 (s, 3H); 3.98 (s, 3H); 4.45–4.49 (bm, 1H);
4.74–4.80 (bm, 1H); 6.17 (s, 1H); 6.62 (s, 1H); 7.23 (dt,
1H, J1=7 Hz, J2=1Hz); 7.27 (d, 1H, J=7 Hz); 7.34 (dt,
1H, J1=8.5 Hz, J2=1 Hz); 8.43 (d, 1H, J=8.5 Hz); 13C
NMR (100.5 MHz, CDCl3): l 30.29, 35.42, 39.31, 51.87,
52.86, 56.47, 109.80, 120.25, 125.08, 126.48, 126.92,
127.46, 128.52, 128.87, 132.12, 136.62, 142.13, 145.95,
156.23; HRESMS [M+H]+: 326.1393 (calculated for
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(m, 1H); 3.65 (s, 3H); 3.89 (s, 3H); 6.64 (s, 1H); 7.20–7.34
(m, 3H); 8.36 (d, 1H, J=8.0 Hz); 13C NMR (100.5 MHz,
CDCl3): l 29.15, 35.12, 43.92, 53.42, 56.07, 60.44, 62.51,
111.45, 127.12, 127.27, 127.59, 127.68, 128.08, 128.55,
128.66, 132.29, 136.42, 145.45, 152.32; HRESMS [M]+:
295.1580 (calculated for [C19H21NO2]+: 295.1572).
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