Rapid and convergent assembly of natural benzo[c]phenanthridines by palladium/norbornene catalysis

Article abstract of DOI:10.3987/COM-13-S(S)62

A straightforward total synthesis of a small panel of natural benzo[c]phenanthridines is described. The selective coupling of an aryl triflate with a bromobenzylamine by means of palladium/norbornene joint catalysis and a sequential transfer hydrogenation

Full text of DOI:10.3987/COM-13-S(S)62

RAPID AND CONVERGENT ASSEMBLY OF NATURAL
BENZO[c]PHENANTHRIDINES BY
PALLADIUM/NORBORNENE CATALYSIS
Pierre-Alexandre Deyris, Tatiana Cañeque, Filipe Gomes,
Vanessa Narbonne, Giovanni Maestri,* and Max Malacria*
Table of Contents
Synthesis of phenantridines 1-4
Synthesis of triflates
Synthesis of amines
Spectral data
S2
S3
S5
S7
S1

General remarks: Reagents were obtained from commercial sources and used as received. 5-
61 and 7-82 were prepared according to reported procedures. Solvents were dried using
microwave activated molecular sieves (3 Å for MeCN, 4 Å for DMF), degassed by bubbling
argon for at least 30 minutes and stored under an inert atmosphere. Cs2CO3 has been dried by
heating at 130°C under vacuum for 24 hour and was stored in a Schlenk under argon. Reactions
were carried out under argon using standard Schlenk technique. Flash column chromatography
was performed on Merck Geduran SI 60 A silica gel (40!63 "m) and thin-layer
1
chromatography on Merck 60F254 plates. H NMR and 13C NMR spectra were recorded in
DMSO-d6, CDCl3 and pyridine-d5 on a Bruker 300 AVANCE spectrometer fitted with a QNP
probehead at 300.1 and 75.4 MHz respectively, using the solvent as internal standard (8.74 ppm
1
1
for H NMR and 150.35 ppm for 13C NMR for pyridine and 2.50, 39.51 ppm for H and 13C
NMR respectively for DMSO).
Synthesis of phenantridines 1-4
General procedure in DMF: To a Schlenk-type flask were added under argon Cs2CO3 (197
mg; 0.6 mmol; 2.3 eq) and triphenylphosphine (12 mg; 0.052 mmol; 0.20 equiv). At least three
vacuum/argon cycles were made before addition via cannula of a solution containing the aryl
triflate (0.29 mmol; 1.1 equiv), the 2-bromobenzylamine (0.26 mmol; 1 equiv) and norbornene
(240 mg, 2.6 mmol; 10 equiv) in 3 mL of MeCN. A solution of Pd(OAc)2 (6 mg, 0.026 mmol;
0.1 equiv) was then eventually added. The same procedure could be adopted when using 2-
bromobenzylamines hydrochloric salts by adding 1 more equiv of base in the reaction vessel.
The resulting suspension was stirred with a magnetic bar at 90 °C until visible formation of
1
palladium black (16-48 hours). Consumption of starting materials was assessed by H NMR.
The mixture was then allowed to cool to room temperature, diluted with EtOAc (50 mL),
washed with a saturated K2CO3 solution (3 # 30 mL) and dried over MgSO4. The solvent was
removed under reduced pressure and the products were isolated by flash column
chromatography on silica gel.
2,3,8,9-Tetramethoxybenzo[c]phenanthridine (O-methylnorfagaronine) (1)
Following the general procedure, from triflate 5 (97 g)
and amine 7 (64 mg), 58 mg were obtained as solid.
(64%). Spectral data corresponds to those reported in the
literature.3 !H NMR (300 MHz, CDCl3): ! (ppm) 9.26 (s,
1H, H6), 8.74 (s, 1H), 8.31 (d, 1H, J = 8,9Hz), 7.91 (s,
1H), 7.87 (d, 1H, J = 8,9 Hz), 7.40 (s, 1H), 7.30 (s, 1H),
4.20 (s, 3H), 4.17 ppm (s, 3H), 4.10 (s, 3H), 4.08 (s, 3H). 13C NMR (75.4 MHz, CDCl3) : !
153,0, 150.0, 149,9, 149.7, 149.6 (C6), 140,3, 128.9, 128.3, 127.5, 126.1, 122.1, 119.8, 118.0,
107.3, 107.0, 104.2, 101.6, 56.2, 56.1(x2), 56.0.
2,3-dimethoxybenzo[c][1,3]dioxolo[4,5-j]phenanthridine (Norallonitidine) (2)
Following the general procedure, from triflate 5 (97 mg)
and amine 8 (60 mg), 52 mg were obtained as solid (60%).
Spectral data corresponds to those reported in the
literature.4 !H NMR (500 MHz, CDCl3): ! (ppm) 9.29 (s,
1H), 8.63 (s, 1H), 8.51 (d, 1H, J = 9.0 Hz), 8.33 (s, 1H),
7.96 (d, 1H, J = 9.0 Hz), 7.69 (s, 1H), 7.54 (s, 1H), 6.29 (s,
2H), 4.02 (s, 3H) 3.96 (s, 3H). 13C NMR (75.4 MHz, CDCl3): ! 151.5, 149.8, 149.5, 147.7,
139.6, 130.4, 128.0, 126.4, 126.1, 123.1, 119.9, 118.8, 107.5, 104.8, 103.7, 102.1, 100.0, 55.5
(x2).
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2,3-dimethoxy-[1,3]dioxolo[4',5':4,5]benzo[1,2-c]phenanthridine (Nornitidine) (3)
Following the general procedure, from triflate 6 (93 mg) and
amine 7 (64 mg), 62 mg were obtained as solid (72%).
Spectral data corresponds to those reported in the literature.5
!H NMR (300 MHz, CDCl3): ! (ppm) 9.33 (s, 1H), 8.65 (d,
1H, J = 9.0 Hz), 8.56 (s, 1H), 8.18 (s, 1H), 7.97 (d, 1H, J =
9.0 Hz), 7.73 (s, 1H), 7.53 (s, 1H), 6.22 (s, 2H), 4.10 (s, 3H), 3.99 (s, 3H). 13C NMR (75.4
MHz, CDCl3): ! 153,3, 149.7, 149,6, 148.0 (x2), 138.4, 129.3, 128.4, 127.9, 126.4, 121.8, 119.8,
119.2, 107.8, 104.5, 102.4, 101.4, 100.9, 56.2, 55,7.
[1,3]dioxolo[4',5':4,5]benzo[1,2-c][1,3]dioxolo[4,5-j]phenanthridine (Noravicine) (4)
Following the general procedure from the triflate 6 (93 mg)
and the amine 8 (60 mg), 61 mg were obtained as solid (74%).
Spectral data corresponds to those reported in the literature.6
!H NMR (500 MHz, CDCl3): ! (ppm) 9.29 (s, 1H), 8.55 (s,
1H), 8.53 (d, 1H, J = 9,2 Hz), 8.34 (s, 1H), 7.95 (d, 1H, J = 9.2
13
Hz), 7.70 (s, 1H), 7.52 (s, 1H), 6.29 (s, 2H), 6.22 ppm (s, 2H). C NMR (75.4 MHz, CDCl3): !
151.8, 149.7, 148.1, 147.9, 141.9, 130.5, 129.6, 129.4, 126.7, 123.1, 122.4, 120.3, 119.2, 104.9,
104.6, 102.2, 101.5, 101.0, 100.1.
Synthesis of triflates:
General procedure for the synthesis of epoxynaphtalenes : A dried round-bottom flask was
charged with the corresponding dibromoaryl (16.89 mmol, 1 eq) and furane (84.47 mmol, 5 eq)
in dry toluene (50 ml) under argon atmosphere. The solution was cooled at -78 ºC and n-BuLi
1.6M in THF (18.58 mmol,1.1 eq) was added dropwise to the solution. After complete addition,
the solution was warmed up to -40ºC and extracted with EtOAc (3x20 ml), dried over
magnesium sulfate and concentrated under vacuum. The residue was purified by
chormatography column (EtOAc/heptane).
1,4-dihydro-6,7-dimethoxy-1,4-epoxynaphtalene (9)
Following the general procedure, from 4,5-dibromoveratrol (5 g), 1.91 g
of 9 (56% yield) were obtained as a white solid, the product is
spectroscopically identical to the material described in the literature.7
!H-NMR (500 MHz, CDCl3): $ (ppm) 7.01 (s, 21H), 6.94 (s, 21H), 5.65
(s, 21H), 3.82 (s, 6H).
5,8-dihydro-5,8-epoxynaphto[2,3-d][1,3]dioxo (10)
Following the general procedure, from 5,6-dibromo-1,3-benzodioxole
(4.73 g) were obtained 3.17 g of 10 (81% yield) as a white solid, the
product is spectroscopically identical to the material described in the
literature.1 !H-NMR (300 MHz, CDCl3): $ (ppm) 7.07 (s, 2H), 6.86 (s, 2H), 5.96 (d, 1H, J = 1.4
Hz), 5.91 (d, 1H, J = 1.4 Hz), 5.66 (s, 2H).
General procedure for the synthesis of alcohols: To a solution of the corresponding
epoxynaphtalene (7.35 mmol) in DCE (50 ml) was added at 0°C and dropwise a solution of p-
toluenesulfonic acid (1.47 mmol, 0.2 eq.) in DCE (2 ml). The reaction mixture was stirred at r.t.
overnight. The mixture was diluted with DCM, washed with water and brine, dried over
magnesium sulfate and concentrated under vacuum. The products were used for the next step
without further purification.
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6,7-Dimethoxynaphthalen-1-ol (11)
Following the general procedure, from 9 (1.5 g), was obtained 11 as a
white solid. The product is spectroscopically identical to the material
described in the literature.8 !H-NMR (500 MHz, CDCl3) $ (ppm) 7.44 (s,
1H), 7.28 (d, 1H, J = 8.0 Hz), 7.14 (appt, 1H, J = 8.0, 7.4 Hz), 7.08 (s,
1H), 6.68 (d, 1H, J = 7.4 Hz), 5.11 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H).
Benzo[f][1,3]benzodioxol-5-ol (12)
Following the general procedure, from 10 (1.38 g), was obtained 12 as a
white solid. The product was shown to be spectroscopically identical to
the material described in the literature.1 !H-NMR (300 MHz, CDCl3) $
(ppm) 7.50 (s, 1H), 7.32-7.25 (m, 1H), 7.16 (t, 1H, J = 7.8 Hz), 7.11 (s,
1H), 6.70 (d, 1H, J = 7.4 Hz), 6.05 (s, 2H), 5.04 (s, 1H).
General procedure for the synthesis of triflates: To a solution of the corresponding naphtol
(6.86 mmol) and pyridine (13.72 mmol) in DCM (40 ml) at 0 ºC, was slowly added Tf2O (10.29
mmol). After complete addition the mixture was warmed to r.t. and stirred until complete
conversion of the starting material (1h). The mixture then was diluted with Et2O (20 ml),
quenched with 10% aq HCl and washed with sat. NaHCO3 and brine. After drying (Mg2SO4),
the solvent was removed and the residue was purified by column chromatography
(EtOAc/heptane).
6,7-Dimethoxynaphthalen-1-yltrifluoromethanesulfonate (5)
Following the general procedure, from 11 (1.40 g) were obtained 2.04 g
(89% yield) of the product as a pale yellow solid. !H-NMR (500 MHz,
CDCl3): $ (ppm) 7.67 (dd, 1H, J = 6.9, 1.6 Hz), 7.32-7.28 (m, 3H), 7.14
(s, 1H), 4.00 (s, 3H), 3.99 (s, 3H). 13C-NMR (75 MHz, CDCl3): $ (ppm)
151.1, 150.5, 144.7, 131.1, 126.6, 123.5, 122.0, 118.7 (q, JC-F = 319.8
Hz), 116.4, 106.4, 99.3, 56.0, 55.9.
Naphtho[2,3-d][1,3]dioxol-5-yltrifluoromethanesulfonate (6)
Following the general procedure, from 12 (1.29 g), were obtained 2.19 g
(89% yield) of the product as a pale yellow solid, the product is
spectroscopically identical to the material described.1 !H-NMR (500 MHz,
CDCl3) $ (ppm): 7.66 (dd, 1H, J = 5.5, 3.6 Hz), 7.33-7.31 (m, 3H), 7.16 (s,
1H), 6.11 (s, 2H). 13C-NMR (75 MHz, CDCl3): $ (ppm) 149.4, 148.8, 145.3,
132.5, 127.3, 123.8, 123.5, 118.7 (q, JC-F = 320.5 Hz), 116.4, 104.7, 101.7, 97.4.
Synthesis of amines:
General procedure for the synthesis of oximes : Hydroxylamine hydrochloride (0.775 mg;
11.15 mmol; 1.2 eq.) was added to a solution of NaHCO3 (0.915 g; 10.9 mmol; 1 eq.) in 25 mL
of water. The solution was added to a vigorously stirred suspension of a bromobenzylamine
(10.9 mmol; 1 eq.) in EtOH (25 mL). The resulting mixture was stirred for 5h and then left at
20 °C overnight. The precipitate formed was filtered, washed with a few mL of cold ethanol and
dried under vacuum to give the desired hydroxylamine, which is used without further
purification.
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2-bromo-4,5-dimethoxy-benzaldehyde oxime (13)
Following the general procedure, from 2-bromo-4,5-dimethoxy-
benzaldehyde (2.67 g), 2.72 g (96% yield) of the product were
obtained as white crystals. The product is spectroscopically
identical to the material described.9 !H NMR (300 MHz, DMSO-
d6): ! (ppm) 11.41 (s, 1H), 8.19 (s, 1H), 7.27 (s, 1H), 7.16 (s, 1H),
3.79 (s, 3H), 3.76 (s, 3H).
6-bromo-1,3-benzodioxole-5-carbaldehyde oxime (14)
Following the general procedure, from 6-bromo-1,3-benzodioxole-
5-carbaldehyde (2.50 g), 1.96 g (72% yield) of the product were
obtained as white powder. The product is spectroscopically identical
to the material described.10 !H NMR (300 MHz, CDCl3): ! (ppm)
8.44 (s, 1H), 7.29 (s, 1H), 7.00 (s, 1H), 6.01 (s, 2H).
General procedure for the synthesis of amines: To a solution of the corresponding
hydroxylamine (7 mmol, 1 eq.) in THF (80 mL) was added a 2N HCl solution (35.3 mL; 70.7
mmol, 10 eq.), followed by zinc (4.62 g, 70.7 mmol, 10 eq.). The mixture was vigorously stirred
under reflux until full conversion. The reaction mixture was cooled to room temperature,
filtered on a celite pad to remove the excess zinc and condensed under reduce pressure to
remove THF. The aqueous layer was extracted with EtOAc (30 mL) and the pH of the aqueous
layer was adjusted to >10 by addition of a saturated ammonia solution, then extracted with
EtOAc (3x 30mL). These last organic layers were combined and dried over anhydrous K2CO3,
filtered and evaporated to give a crude, which was purified by flash column chromatography on
silica gel (eluent: EtOAc/2% Et3N).
2-Bromo-4,5-dimethoxybenzylamine (7)
Following the general procedure, from 13 (1.82 g), was obtained 1.43
g (83% yield) of the product as white powder. The product is
spectroscopically identical to the material described.11 !H NMR (300
MHz, CDCl3): ! (ppm) 6.98 (s, 1H), 6.89 (s, 1H), 3.85-3.81 (m, 8H).
13C-NMR (75 MHz, CDCl3) $ (ppm) 148.5, 148.4, 134.2, 115.6,
113.2, 112.0, 56.2, 56.0, 46.6
(6-Bromobenzo[d][1,3]dioxol-5-yl)methanamine (8)
Following the general procedure, from 14 (1.71 g) was obtained 8 (1.28
g, 80%) as a pale yellow solid. The product is spectroscopically identical
to the material described.9 !H NMR (300 MHz, CDCl3): ! (ppm) 6.99 (s,
1H), 6.88 (s, 1H), 5.96 (s, 2H), 3.80 (s, 2H), 1.56 (s, 2H). 13C-NMR (75
MHz, CDCl3) $ (ppm) 147.5, 147.2, 135.5, 113.6, 112.8, 109.1, 101.7,
46.8
S5

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Spectral data for phenantridines
2,3,8,9-Tetramethoxybenzo[c]phenanthridine (O-methylnorfagaronine) (1)
S7

2,3-dimethoxybenzo[c][1,3]dioxolo[4,5-j]phenanthridine (Norallonitidine) (2)
S8

2,3-dimethoxy-[1,3]dioxolo[4',5':4,5]benzo[1,2-c]phenanthridine (Nornitidine) (3)
S9

[1,3]dioxolo[4',5':4,5]benzo[1,2-c][1,3]dioxolo[4,5-j]phenanthridine (Noravicine) (4)
S10

Spectral data for triflates
6,7-Dimethoxynaphthalen-1-yltrifluoromethanesulfonate (5)
S11

Naphtho[2,3-d][1,3]dioxol-5-yltrifluoromethanesulfonate (6)
S12

Spectral data for bromides
2-Bromo-4,5-dimethoxybenzylamine (7)
S13

(6-Bromobenzo[d][1,3]dioxol-5-yl)methanamine (8)
S14

S15