An efficient synthesis of thalifoline

Article abstract of DOI:10.1055/s-2002-34844

An efficient multi-step approach for the synthesis of the isoquinolin-1-one alkaloid thalifoline (1) is described. The key intermediate carbamate 8a underwent a modified Bischler-Napieralski-type cyclization using Banwell's Tf₂O/DMAP conditions to form the lactam 9a under mild conditions and in excellent yield.

Full text of DOI:10.1055/s-2002-34844

PAPER
2187
An Efficient Synthesis of Thalifoline
An
E
fficient Synth
o
esis of
T
hali
u
foline -Chu Wang, Paris E. Georghiou*
Chemistry Department, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, A1B 3X7, Canada
E-mail: parisg@mun.ca
Received 11 June 2002; revised 27 July 2002
present in only minor amounts. Based upon the few bio-
genetic studies that have been conducted, they are pre-
sumed to result from the biochemical oxidation of the
more prevalent alkaloid components including benzyltet-
rahydroisoquinoline units.2,3 Thalifoline is structurally re-
lated to a subunit of more complex alkaoids such as
baluchistanamine (2)4,5 and (–)-tejedine (3).5 We herein
describe an efficient multi-step synthesis of thalifoline
from vanillin (4). Using modified Bischler–Napieralski
cyclization conditions developed by Banwell et al.,6 thal-
ifoline was obtained in 37% overall yield from vanillin.
The methodology reported herein appears to be a general
one which could be applicable to other 6,7-disubstituted
3,4-tetrahydroisoquinolin-1-ones.
Abstract: An efficient multi-step approach for the synthesis of the
isoquinolin-1-one alkaloid thalifoline (1) is described. The key in-
termediate carbamate 8a underwent a modified Bischler–Napieral-
ski-type cyclization using Banwell’s Tf2O/DMAP conditions to
form the lactam 9a under mild conditions and in excellent yield.
Key Words: alkaloids, thalifoline, quinolines, heterocycles, iso-
quinoline, ring closure, cyclizations
Thalifoline (1),1 first isolated from Thalictrum minus L.
var. adiantifolium Hort by Doskotch et al. in 1969, is a
member of a small group of naturally-occurring tetrahy-
droisoquinolones (Figure 1). This group of alkaloids is
Figure 1
CHO
ii
MeO
RO
NO2
MeO
MeO
BnO
iii
NHR
BnO
6
7
R = H
R = CHO
5
4
R = H
iv
i
4a R = Bn
v
7a R = CH3
vi
MeO
BnO
MeO
BnO
vii
N
NCO2Et
R
R
viii
O
9a R =CH3
9b R = H
1
8a R = CH3
8b R = H
Scheme 1 Reagents and conditions: i) BnBr/K2CO3, acetone, reflux (98%); ii) MeNO2/NH4Ac, HOAc, reflux (90%); iii) LiAlH4, THF, reflux
(used directly in step iv); iv) HCO2Et, reflux (78% from steps iii and iv); v) BH3 THF/BF3 Et2, THF, reflux (used directly in step vi); vi)
ClCO2Et/NaHCO3, CH2Cl2–H2O, 0 °C (60% from steps v and vi); vii) 8a + Tf2O/DMAP, CH2Cl2, 0 °C, (90%); viii) 9a + H2/Pd/C, MeOH
(>98%).
Synthesis 2002, No. 15, Print: 29 10 2002.
Art Id.1437-210X,E;2002,0,15,2187,2190,ftx,en;M02302SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2188
Y.-C. Wang, P. E. Georghiou
PAPER
The conversion of vanillin to 4-benzyloxy-3-methoxy- of 1 have been reported by Kametani et al.18 in which 1
phenethylamine (6) was achieved in 84% overall yield us- was produced from a minor by-product of a photo-Pschorr
ing a standard procedure (Scheme 1). Benzylation of reaction; and by Irie et al.19 via 3,4,5-trimethoxyphenethyl
vanillin with benzyl bromide using K2CO3 in refluxing ac- isocyanate in 16% yield.
etone afforded 4a in 98% yield. Condensation of 4a with
nitromethane using either aqueous sodium hydroxide at
All reactions were performed under N2 or Ar. All compounds were
0 °C,7 methylammonium chloride and Na2CO3 in etha-
purified by either flash chromatography using Scientific Adsorbents
nol,8 or, dimethylammonium chloride and KF in toluene,9
Inc. (SAI) silica gel (63–200 m) or preparative thin layer chroma-
tography (PLC) plates, which were made from SAI silica gel (5–15
) with gypsum. TLC was performed on precoated silica gel 60 F254
(SAI). Chemical reagents were purchased from Sigma–Aldrich.
Solvents were dried using standard procedures. Mps were deter-
mined on a Fisher–Johns apparatus and are uncorrected. IRspectra
were recorded on a Mattson Polaris FT instrument. MS data were
only afforded the -nitrostyrene 5 in less than 50% yields
and presented difficulties in purifying the product. The re-
action of 4a with nitromethane in refluxing acetic acid
with ammonium acetate however, produced crystalline 5
in 90% yield. Reduction of 5 using LiAlH4 in refluxing
THF10 afforded 6 in 84% overall yield from vanillin.
Without further purification, 6 was converted to N-
formyl-N-4-benzyloxy-3-methoxyphenethylamine (7) in
78% yield by reaction with ethyl formate in refluxing con-
1
presented as follows: m/z, intensity. H NMR spectra were at 300
MHz or 500 MHz, and chemical shifts are relative to internal TMS.
13C NMR spectra were recorded at 75 MHz or 125 MHz and chem-
ical shifts are relative to the solvent ( = 77.0 for CDCl3).
11
ditions. Reduction of 7 using LiAlH4 afforded the
O-Benzylvanillin (4a)
desired N-methyl-N-4-benzyloxy-3-methoxyphenethyl-
amine (7a) in only low yields. However with BH3 THF/
BF3 OEt2 in refluxing THF,12 7a could be obtained in
>90% yields and pure enough to be used directly in the
subsequent step. Schotten–Baumman reaction with ethyl
chloroformate13 afforded the key intermediate N-ethoxy-
carbonyl-N-methyl-4-benzyloxy-3-methoxyphenethyl-
amine (8a) in 60% overall yield from 7.
A solution of anhyd K2CO3 (31 g, 0.23 mol) in CHCl3 (60 mL) and
MeOH (30 mL) was refluxed for 15 min and then vanillin 4 (7.6 g,
0.05 mol) and benzyl bromide (8.9 mL, 0.08 mol) were added. After
heating at reflux for 4 h, the reaction mixture was filtered, the or-
ganic phase was washed with water, dried (MgSO4), filtered, and
concentrated in vacuo. The product was recystallized from hexane–
CH2Cl2 to give pure 4a.
Yield: 12 g (96%); crystalline needles; mp 63–64 °C (lit.20 61–
64 °C).
Cyclization of either carbamates 8a or 8b, or formamide
7 under typical, or modified Bischler–Napieralski condi-
tions proved to be difficult. These substrates were treated
with P2O5/POCl3 (2:1) as described by Wang.14 Such con-
ditions reportedly usually give cyclized isoquinolin-1-
ones in yields as high as 98% with o-, m- or p-(mono)sub-
stituted phenethyl carbamates. In our cases only polar, in-
tractable mixtures were obtained. Other conditions
employed with similar results included: heating at 150 °C
in polyphosphoric acid;15 treating with POCl3 in refluxing
benzene;16 or reacting with Eaton’s acid (P2O5/
MeSO3H).17 From the 1H NMR spectra of the crude reac-
tion products it was obvious that the benzyl protecting
group was not inert to the relatively harsh reagents and re-
action temperature conditions that were required to effect
the Bischler–Napieralski cyclization.
4-Benzyloxy-3-methoxy- -nitrostyrene (5)
A mixture of O-benzylvanillin (4.0 g, 16.5 mmol), ammonium ace-
tate (1.2 g, 15.1 mmol), nitromethane (6 mL, 87.3 mmol), and gla-
cial HOAc was refluxed for 1.5 h. After cooling to r.t., the
crystalline product was filtered and recrystallized from EtOH to af-
ford 5.
Yield: 3.2 g (90%); mp 121–122 °C (lit.21 122–123 °C).
4-Benzyloxy-3-methoxyphenethylamine (6)
A solution of 4-benzyloxy-3-methoxy- -nitrostyrene (5) (1.0 g, 3.5
mmol) in anhyd THF (5 mL) was added dropwise to a stirred solu-
tion of LiAlH4 (0.7 g, 17.5 mmol) in anhyd THF (15 mL). The re-
action mixture was refluxed for 3 h followed by addition of aq KOH
(20%) to destroy the excess LiAlH4. The mixture was then extracted
with EtOAc (3 20 mL), washed with brine (3 20 mL), dried
(K2CO3), concentrated in vacuo. The oily residue was used directly
in the next step.
Efficient cyclization of 8a to afford 9a however was
achieved by using the trifluoromethanesulfonic anhy-
dride/DMAP procedure developed by Banwell et al.6 in
their total synthesis of Amaryllidaceae alkaloids. Cycliza-
tion of 8a proceeded cleanly in CH2Cl2 at 0 °C to form the
O-benzylated thalifoline 9a in 90% yields. On the other
hand, when these same conditions were employed with 8b
or with 7, the desired cyclization failed, affording only in-
tractable mixtures.
N-Formyl-N-(4-benzyloxy-3-methoxy)phenethylamine (7)
3-Methoxy-4-benzyloxyphenethylamine (6) (890 mg, 3.5 mmol)
was dissolved in ethyl formate (40 mL), and the reaction mixture
was refluxed for 1 h. After removal of the solvent, the residue was
purified by flash chromatography (silica gel; CH2Cl2–MeOH, 96:4)
to afford 7.
Yield: 775 mg (78%); colorless oil.
1H NMR (CDCl3, 500 MHz): = 2.51 (q, J = 7.0 Hz, 2 H), 2.75 (t,
J = 7.0 Hz, 2 H), 3.86 (s, 3 H), 5.11 (s, 2 H), 5.72 (br s, 1 H), 6.65
(dd, J = 1.5, 8.0 Hz), 6.73 (d, J = 1.5 Hz, 1 H), 6.81 (d, J = 8.0 Hz,
1 H), 7.29–7.43 (m, 5 H), 8.08 (s, 1 H).
13C NMR (CDCl3, 125 MHz): = 35.5, 37.8, 39.7, 43.6, 53.9, 56.5,
71.6, 112.9, 113.1, 114.8, 114.9, 121.1, 121.3, 127.6, 128.3, 129.0,
131.2, 132.2, 137.6, 137.6, 147.3, 147.6, 150.3, 150.3, 161.6, 164.8.
Catalytic hydrogenation of 9a near-quantitatively afford-
ed the target molecule thalifoline whose physical proper-
ties are in agreement with those reported.1,18,19 It should be
noted that Doskotch et al. synthesized 1 using a seven-step
synthesis which also commenced with vanillin, but in-
volved a final oxidation step to form the target molecule
resulting in a less than 10% overall yield. Other syntheses
MS: m/z (%) = 285 (M+, 6), 240 (14), 149 (20), 91 (100).
Synthesis 2002, No. 15, 2187–2190 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Efficient Synthesis of Thalifoline
2189
HRMS: m/z calcd for C17H19NO3: 285.1372; found: 285.1380.
manner, to give a light brown solid. Purification by flash column
chromatography (hexanes–EtOAc, 1:1) afforded 9a.
N-Ethoxycarbonyl-N-methyl-4-benzyloxy-3-methoxypheneth-
ylamine (8a)
Yield: 90%; colorless solid; mp 114–115 °C.
1H NMR (CDCl3, 500 MHz): = 2.91 (t, J = 6.0 Hz, 2 H), 3.12 (s,
3 H), 3.51 (t, J = 6.0 Hz, 2 H), 3.89 (s, 3 H), 5.17 (s, 2 H), 6.63 (s, 1
H), 7.27–7.47 (m, 5 H), 7.67 (s, 1 H).
13C NMR (CDCl3, 125 MHz): = 28.0, 35.5, 48.8, 56.5, 71.3,
110.1, 113.2, 122.4, 128.0, 128.3, 129.0, 132.3, 137.3, 147.5, 152.7,
165.2.
To a solution of 7 (775 mg, 2.72 mmol) in THF (20 mL) under Ar
was added BF3 OEt2 (0.14 mL, 1.09 mmol) via syringe. The solu-
tion was heated to a gentle reflux and then BH3 THF (7 mL 6.80
mmol) was added dropwise with stirring. The solution was refluxed
for 2 h, cooled to 0 °C, and quenched with aq HCl (20%). The mix-
ture was stirred at 0 °C for 1 h, then at 25 °C for 1 h. The mixture
was concentrated on a rotary evaporator, then cooled to 0 °C and
made basic to pH 13 using solid KOH. Water and CH2Cl2 were add-
ed to the resulting basic mixture to dissolve the potassium salts and
the amine. The mixture was extracted with CH2Cl2 (4 20 mL), and
the organic extracts were combined, dried (MgSO4), filtered and
evaporated to dryness on a rotary evaporator to afford the crude
amine 7a which was used without further purification directly in the
next step.
MS: m/z (%) = 297 (M+, 3), 296 (19), 206 (7), 192 (4), 183 (17), 135
(9), 91 (100).
APCI HRMS: m/z calcd for C18H19NO3: 297.1364; found:
297.1365.
Thalifoline (1)
To a solution of 9a (650 mg, 2.2 mmol) in EtOH (10 mL) was added
10% Pd/C (130 mg), and the resulting mixture was stirred under H2
at atmospheric pressure for 2 h. The reaction mixture was filtered
through Celite, and the precipitate was washed with EtOH (2 10
mL). The EtOH was evaporated to afford 1. The spectral data are in
agreement with those reported in ref.19
Sat. aq NaHCO3 (6 mL) was added to a solution of the crude amine
7a in CH2Cl2 (4 mL). The resulting two-phase system was stirred
vigorously at 0 °C, and ethyl chloroformate (0.26 mL, 2.72 mmol)
in CH2Cl2 (1 mL) was added dropwise. The reaction mixture was al-
lowed to warm to r.t. and stirred for a further 3 h. The CH2Cl2 layer
was separated, and the aq phase was extracted with CH2Cl2 (2 10
mL). The combined organic layers were dried (MgSO4), filtered and
concentrated in the usual manner. The resulting residue was puri-
fied by flash chromatography (hexanes–EtOAc, 9:1), to afford 8a.
Yield: 437 mg (96%); colorless solid; mp 211–212 °C (hexane–
CH2Cl2) (lit.1 210–212 °C; lit.19 211–212 °C).
1H NMR (CDCl3, 500 MHz): = 2.92 (t, J = 7.0 Hz, 2 H), 3.12 (s,
3 H), 3.53 (t, J = 7.0 Hz, 2 H), 3.92 (s, 3 H), 5.71 (s, 1 H), 6.61 (s, 1
H), 7.67 (s, 1 H).
13C NMR (CDCl3, 125 MHz): = 28.1, 35.6, 48.9, 56.4, 109.1,
114.7, 123.2, 131.3, 145.0, 149.7, 165.1.
MS: m/z (%) = 207 (M+, 75), 164 (99), 136 (100).
Yield: 569 mg (61%); colorless oil, which by NMR is a mixture of
two rotamers.
1H NMR (CDCl3, 500 MHz): = 1.23 (m, 3 H), 2.13 (m, 2 H), 2.79
(br s, 2 H), 2.87 (m, 3 H), 3.47 (s, 2 H), 3.91 (s, 3 H), 5.15 (s, 2 H),
6.67–6.85 (m, 3 H), 7.30–7.47 (m, 4 H).
13C NMR (CDCl3, 125 MHz): = 15.2, 34.1, 34.5, 34.9, 35.2, 51.0,
51.4, 56.4, 61.6, 71.6, 113.1, 114.9, 121.2, 127.7, 128.2, 128.9,
132.8, 137.8, 147.2, 150.1, 156.8.
Acknowledgment.
The NSERC/CRD Program and Prime Pharmaceutical Company
are thanked for financial support to Y. W.
MS: m/z (%) = 343 (M+, 10), 298 (3), 240 (14), 227 (4), 116 (100),
91 (98).
HRMS: m/z calcd for C20H25NO4: 343.1765; found: 343.1747.
References
N-Methyl-4-benzyloxy-3-methoxyphenethylamine (8b)
Compound 8b was prepared using the same procedure used for 8a.
Compound 6 (890 mg, 3.5 mmol) afforded 8b.
(1) Doskotch, R. W.; Schiff, P. L. Jr.; Beal, J. L. Tetrahedron
1969, 25, 469.
(2) Cava, M. P.; Bessho, K.; Douglas, B.; Markey, S.;
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Yield: 820 mg (71%); colorless oil.
1H NMR (CDCl3, 500 MHz): = 1.23 (t, J = 7.0 Hz, 3 H), 2.74 (t,
J = 7.0 Hz, 2 H), 3.40 (m, 2 H), 3.88 (s, 3 H), 4.10 (q, J = 7.0 Hz, 2
H), 4.65 (br s, 1 H), 5.13 (s, 2 H), 6.56 (d, J = 8.5 Hz, 1 H), 6.73 (br
s, 1 H), 6.8 (d, J = 8.5 Hz, 1 H), 7.28–7.44 (m, 5 H).
13C NMR (CDCl3, 125 MHz): = 15.1, 36.2, 42.6, 56.4, 61.2, 71.6,
113.0, 114.8, 121.1, 127.7, 128.2, 128.9, 132.4, 137.7, 147.3, 150.2,
157.0.
MS: m/z (%) = 329 (M+, 8), 240 (13), 227 (4), 137 (46), 91 (100).
HRMS: m/z calcd for C19H23NO4: 329.1622; found: 329.1617.
Cyclization of 8a
(7) Worrall, D. E. Org. Synth., Coll. Vol. 1; J. Wiley and Sons:
Chichester, 1941, 413.
A solution of trifluoromethanesulfonic anhydride (Tf2O) (1.10 M;
13 mL, 13.7 mmol) in anhyd CH2Cl2 (70 mL) was added over a
period of 15 min to a solution, maintained at 0 °C, of 8a (940 mg,
2.74 mmol) and DMAP (1.0 g, 8.22 mmol) in CH2Cl2 (50 mL). The
reaction mixture was allowed to warm to r.t. and was stirred for 24
h. It was then diluted with CH2Cl2 (30 mL), washed with sat. aq
Na2CO3 (3 30 mL), aq HOAc (20%; 3 30 mL), and then aq
Na2CO3 (1 30 mL) before being dried (MgSO4). The reaction
mixture was filtered and the solvent was evaporated in the usual
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Synthesis 2002, No. 15, 2187–2190 ISSN 0039-7881 © Thieme Stuttgart · New York

2190
Y.-C. Wang, P. E. Georghiou
PAPER
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Synthesis 2002, No. 15, 2187–2190 ISSN 0039-7881 © Thieme Stuttgart · New York