Synthesis of Venlafaxine from azadiene via a Hetero-Diels-Alder approach: New microwave-assisted transketalization and hydroxymethylation reactions

Article abstract of DOI:10.1055/s-2008-1072581

Hetero-Diels-Alder (HDA) methodology has been applied to the synthesis of Venlafaxine taking advantage of a novel MW-assisted transketalization and hydroxymethylation reaction.

Full text of DOI:10.1055/s-2008-1072581

PAPER
1753
Synthesis of Venlafaxine from Azadiene via a Hetero-Diels–Alder Approach:
New Microwave-Assisted Transketalization and Hydroxymethylation
Reactions
S
ynthesis of
V
enlafaxi
a
ne via
H
D
A
u
A
pproach ro Panunzio,*a Elisa Bandini,b Antonio D’Aurizio,b Zhining Xia,c Xiaojing Muc
a
b
c
ISOF-CNR, Area della Ricerca di Bologna, Via Gobetti 101, 40129 Bologna, Italy
Institute of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044, P. R. of China
E-mail: zhnxia@yahoo.cn
Received 5 February 2008; revised 26 February 2008
be prepared from an 2-aza-1,3-diene variably substituted
in the position 1 but unsubstituted in position 4, and a ke-
tone as dienophile, including hindered ones such as men-
thone.6 These results were very interesting since the poor
reactivity of ketones compared to aldehydes in hetero-
Diels–Alder reactions is well known, owing to both steric
and electronic reasons. As a matter of fact, until recently,
only a very few examples of HDA reactions of ketones
have been reported.7 Having in hand this information, we
started our studies by preparing the intermediate azadiene
4 from (4-methoxyphenyl)acetyl chloride (2) and the tri-
methylsilylbenzaldimine 3 according to an existing
protocol1a,8 (Scheme 1).
Abstract: Hetero-Diels–Alder (HDA) methodology has been ap-
plied to the synthesis of Venlafaxine taking advantage of a novel
MW-assisted transketalization and hydroxymethylation reaction.
Key words: 1,3-aminol, hetero-Diels–Alder reaction, MAOS,
Venlafaxine, transketalization
2-Azadienes1 have been demonstrated to be versatile in-
termediates in hetero-Diels–Alder (HDA) reactions2 with
aldehydes to furnish perhydroxazin-4-ones. The latter
have been utilized for the production of the 1,3-hy-
droxyamino moiety, or skeleton, of different biologically
active compounds and of important chiral auxiliaries/
ligands in asymmetric organic synthesis.3 In the course of
our studies on these interesting intermediates, we have re-
ported on the preparation of biologically active CNS-
drugs, Prozac and Duloxetine, in racemic and optically
pure form as well, presenting a scaffold of an 1,3-aminol
unsubstituted in the 2-position and a secondary hydroxy
functionality.4 In this paper we report our attempts to ap-
ply this strategy to the synthesis of ( )-Venlafaxine (1)5
characterized by the presence of a substituent (4-meth-
oxyphenyl group) in the 2-position of the 1,3-aminol skel-
eton (Figure 1) and a tertiary hydroxy functionality. The
importance of 1 resides in the fact that, among a large
number of chemical structures found to exhibit antide-
pressant activity with diminished cardiovascular and anti-
cholinergic liability, this compound has been proven to be
the most potent antidepressant agent and has been ap-
proved by the drug agencies of many countries for the
treatment of depression thanks to its faster onset of action
and increased efficiency. From synthetic point of view,
the choice of this particular target was dictated by our at-
MeO
OH
N
( )-venlafaxine (1)
Figure 1 Venlafaxine (1)
MeO
MeO
4%
H
4%
N
Ph
1.TMSCl
2. Et3N
H
+
N
COCl
O
Ph
TMS
TMS
2
3
4
Scheme 1 Preparation of azadiene 4
tempts of rendering the HDA protocol, developed in our The necessary [4+2] HDA reaction was next attempted
laboratories, suitable for the preparation of a library of taking advantage of our recent procedure for the prepara-
variably functionalized compounds presenting the 1-hy- tion of 1,3-perhydrooxazin-4-ones by EuFod [europi-
droxy-3-amino functionalities with or without further um(III)
tris(1,1,2,2,3,3-heptafluoro-7,7-dimethyl-4,6-
substitutions in the backbone chain identified by 1,3-ami- octanedionate]-catalyzed microwave-assisted organic
nol moiety and using as carbonyl-dienophile a ketone. synthesis (MAOS).8 Accordingly, reaction of the azadiene
Previous results showed that perhydroxazin-2-ones may 4 with dienophile cyclohexanone (5) was performed, us-
ing EuFod (0.05%) as catalyst and chlorobenzene as sol-
vent under microwave irradiation (Scheme 2). Workup of
the reaction mixture showed the formation of traces of the
desired 1,3-perhydrooxazin-4-one 6 (Table 1, entry 1)
SYNTHESIS 2008, No. 11, pp 1753–1756
Advanced online publication: 07.04.2008
DOI: 10.1055/s-2008-1072581; Art ID: Z04008SS
x
x.
x
x
.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

1754
M. Panunzio et al.
PAPER
Table 1 Reaction of Azadiene 4 with Cyclohexanone (5) under Different Reaction Conditions
Entry
Diene 4
(equiv) (equiv)
5
Lewis acid
(equiv)
Solvent
Temp (°C)/
Time
Yield of 6 Yield of 7
(%)
(%)
55.0
40.0
33.0
32.0
30.0
8.0
1
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0.5
1
EuFOD (0.05)
PhCla
135 (40 min) DHb 300 W
135 (2 h) DH 300 W
135 (10 h) CHc
110 (3 h) DH 300 W
110 (20 h) CH
trace
PhCl
0
3
0.5
0.5
0.5
1
EuFOD (0.05)
EuFOD (0.05)
EuFOD (0.05)
BF3·OEt2 (1)
BF3·OEt2 (1)
BF3·OEt2 (1)
BF3·OEt2 (1)
EuFOD (0.05)
PhCl
trace
4
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CHCl3
toluene
PhCl
0
0
5
6
–78 to r.t (12 h)
–78 (8 h)
48.0
62.0
0
7
1
trace
trace
12.0
0
8
1
0 (8 h)
9
1
25 (72 h)
0
10
11
12
13
14
15
16
1
–78 (8 h)
0
1
–78 (8 h)
0
0
1
BF3·OEt2 (1)
ZnCl2 (0.05)
ZnCl2 (0.05)
TiCl4 (0.05)
AlCl3 (0.05)
25 (12 h)
0
0
0.5
0.5
0.5
0.5
110 (1 h) DH 300 W
135 (40 min) DH 300 W
135 (40 min) DH 300 W
135 (40 min) DH 300 W
0
9.0
0
14.0
11.0
17.0
PhCl
0
PhCl
0
a PhCl = chlorobenzene.
b DH = dielectric heating.
c CH = convective heating.
whereas the major product was constituted by the trans-b- dichloromethane as solvent (Table 1, entry 7).11 Once ob-
lactam ring 7, arising from a [2+2] electrocyclization (for tained, the intermediate perhydroxazin-4-one 6 was used
the sake of easy reading only one enantiomer of the race- in the synthesis of racemic 1 in a straightforward manner
mic mixtures has been depicted in Scheme 2) irrespective (Scheme 3) by taking advantage of a new MW-mediated
of the presence or not of the Lewis acid (Table 1, entry transketalization and hydroxymethylation methodologies.
2).9 Use of chloroform as solvent, which is known to pro- In detail, treatment of perhydroxazin-4-one 6 with a mix-
mote HDA via hydrogen bonding10 was unsuccessful, ture of formic acid and formaldehyde under microwave ir-
even in the presence of BF3 as Lewis acid (Table 1, entries radiation furnished the N-hydroxymethyl derivative 8 in
11 and 12).
70% yield. Further treatment of this product in the same
reaction conditions gave the transketalized derivative 9 in
58% yield. Alternatively, exhaustive treatment of 6 re-
ported as above (formic acid and formaldehyde, under
microwave irradiation) furnished directly a stable inter-
mediate 9 in 58% yield from 6. Finally, reduction of 9
with LiAlH4 in THF afforded the target racemic 1 in 66%
yield.
Further experiments, changing different reaction parame-
ters including the very nature of the Lewis acids (Table 1),
showed that the preference for a [2+2] electrocyclization
versus a [4+2] HDA is strictly dependent on the reaction
temperature used. The best results in the formation of the
HDA adduct are obtained at very low temperature
(–78 °C, 8 h) in the presence of BF3 as Lewis acid and
In summary, the synthesis of 1 through a hetero-Diels–
Alder approach has been achieved. This study has pointed
out the high competition between a [2+2] and a [4+2] re-
actions probably due to stereoelectronic reasons. Notwith-
standing, we have been able to address the formation of
the sole [4+2] product arising from a HDA pathway by the
right choice of the temperature and Lewis acid. Theoreti-
cal calculations and studies are currently in progress to
fully clarify this important aspect. The results will be re-
ported in due course.
MeO
MeO
Ph
H
O
4
+
+
N
N
O
Ph
O
H
O
5
6
7
Scheme 2 For the Lewis acids and reaction conditions used, see
Table 1 and the experimental section.
Synthesis 2008, No. 11, 1753–1756 © Thieme Stuttgart · New York

PAPER
Synthesis of Venlafaxine via HDA Approach
1755
with CH2Cl2 (3 × 10 mL). The organic layers were dried (Na2SO4)
and the solvent was removed under vacuum. The mixture was puri-
fied by flash chromatography on silica gel (cyclohexane–EtOAc,
4:6) to give 6; yield: 217 mg (62%); white solid; mp 186–188 °C.
MeO
HCHO
O
HCHO
6
IR (CHCl3): 1665 cm–1.
HCOOH, MW
70%
O
H
N
HCOOH, MW
58%
Ph
1H NMR (400 MHz, CDCl3): d = 7.56 (m, 2 H), 7.46 (m, 3 H), 7.34
(d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.25 (br s, 1 H), 5.92
(s, 1 H), 3.78 (s, 3 H), 3.35 (s, 1 H), 2.27 (d, J = 9.2 Hz, 1 H), 1.62
(m, 5 H), 1.32 (m, 3 H), 1.13 (m, 1 H).
O
8
13C NMR (100 MHz, CDCl3): d = 171.12, 158.84, 138.30, 130.47,
129.61, 129.03, 126.63, 113.80, 79.52, 76.92, 56.65, 55.21, 34.92,
33.28, 25.45, 22.08, 21.27.
MeO
MeO
MS: m/z = 352 (M + 1), 306, 253, 201, 159, 148, 120, 105, 91, 77.
O
OH
N
LiAlH4
66%
Anal. Calcd for C22H25NO3: C, 75.19, H, 7.17; N, 3.99. Found: C,
75.38; H, 7.19; N, 3.95.
O
N
H
O
(3S*,4S*)-3-(4-Methoxyphenyl)-4-phenylazetidin-2-one (7)
Table 1; Entry 1: Compound 4 (325 mg, 1 mmol) was dissolved in
anhyd chlorobenzene (5 mL). Cyclohexanone (5; 49 mg, 0.5 mmol)
and EuFOD (50 mg, 0.05 mmol) were added. The resulting mixture
was submitted to a microwave irradiation (40 min, 300 W). After
the irradiation, the solvent was removed under vacuum. The crude
mixture was purified by flash chromatography on silica gel (cyclo-
hexane–EtOAc, 7:3) to give the b-lactam 7; yield: 139 mg (55%).
9
1
Scheme 3 Synthesis of 1 from perhydrooxazinone 6
All starting compounds, unless otherwise stated, were purchased.
Reactions were run under an atmosphere of dry N2 or argon. FT-IR
spectra were recorded on a PerkinElmer IR spectrometer, mass
spectra on Finnigan MAT instrument, and NMR spectra on a Varian
Mercury 400 MHz spectrometer using the residual signal of the sol-
vent as internal standard. Chemical shifts are reported on the d scale
and coupling constants (J) in Hertz. Microwave reactions were per-
formed on a Prolabo Synthewave 402 microwave oven. Solvents
were distilled and dried according to standard procedures.
Table 1, Entries 13, 14, 15, and 16: These experiments were per-
formed following the same procedure and using the Lewis acid
shown in the table.
Table 1, Entry 5: Compound 4 (325 mg, 1 mmol) was dissolved in
anhyd toluene (10 mL), cyclohexanone (5; 49 mg, 0.5 mmol) and
EuFOD (50 mg, 0.05 mmol) were added and the mixture was re-
fluxed for 20 h. The solvent was removed under vacuum and the
mixture was purified by flash chromatography on silica gel (cyclo-
hexane–EtOAc, 7:3) to give the b-lactam 7; yield: 76 mg (30%);
white solid; mp 135–138 °C.
[(1Z,3E)-1-(4-Methoxyphenyl)-4-phenylbuta-1,3-dien-2-
yloxy]trimethylsilane (4)
An oven dried 100 mL three-necked, round-bottomed flask,
equipped with a Teflon-coated magnetic stirring bar, a spirit ther-
mometer, and a needle for nitrogen inlet was charged with anhyd
hexane (15 mL) and LiN(SiMe3)2 (1 M soln in THF; 1 mL, 1 mmol)
and placed in an ice bath. At 0 °C, benzaldehyde (0.101 mL, 1
mmol) in hexane (1 mL) was added from a dropping funnel and the
mixture was stirred for 1 h at 0 °C. A solution of Me3SiCl (0.126
mL, 1 mmol) in hexane (1 mL) was added at 0 °C and the stirring
was maintained for 1 h at r.t. A white precipitate was observed. At
0 °C were added Et3N (0.278 mL, 2 mmol) in hexane (1 mL) and (4-
methoxyphenyl)acetyl chloride (184 mg, 1 mmol) in anhyd Et2O (1
mL) and the mixture was stirred for 2 h at r.t. The mixture was fil-
tered through a Celite pad and the solvent was evaporated, furnish-
ing the azadiene 4, which was identified by 1H and 13C NMR spectra
and used as such in the following reactions; yield: 325 mg (100%);
yellow oil.
1H NMR (400 MHz, CDCl3): d = 8.45 (s, 1 H), 7.83 (m, 2 H), 7.57
(d, J = 8.8 Hz, 2 H), 7.45 (m, 3 H), 6.88 (d, J = 8.8 Hz, 2 H), 5.92
(s, 1 H), 3.82 (s, 3 H), 0.21 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 157.96, 154.45, 151.94, 136.04,
130.89, 129.84, 129.07, 128.65, 128.59, 113.58, 106.35, 55.06,
0.70.
IR (CHCl3): 1761 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35 (m, 5 H), 7.24 (d, J = 8.8 Hz,
2 H), 6.90 (d, J = 8.8 Hz, 2 H), 6.80 (br s, 1 H), 4.61 (d, J = 2 Hz, 1
H), 4.14 (d, J = 2 Hz, 1 H), 3.80 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 169.77, 159.10, 139.50, 129.99,
128.51, 128.47, 126.75, 125.48, 114.31, 65.58, 60.48, 55.23.
MS: m/z = 254 (M + 1), 210, 194, 179, 165, 148, 120, 105, 91, 77.
Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C,
75.60; H, 6.02; N, 5.48.
(2R*,5R*)-3-Hydroxymethyl-5-(4-methoxyphenyl)-2-phenyl-1-
oxa-3-azaspiro[5.5]undecan-4-one (8)
Compound 6 (120 mg, 0.34 mmol) was dissolved in toluene (2 mL),
and formic acid (0.1 mL) and formaldehyde (37% in H2O, 1 mL)
were added. The mixture was irradiated in a microwave oven (6
min, 150 W). The formic acid was removed under vacuum and the
mixture poured into sat. aq NaHCO3 (5 mL) and then extracted with
EtOAc (3 × 15 mL). The organic layers were dried (Na2SO4) and the
solvent removed under vacuum. The crude mixture was purified by
flash chromatography on silica gel to give 8; yield: 90 mg (70%);
colorless oil.
IR (CHCl3): 3350, 1641 cm–1.
(2R*,5R*)-5-(4-Methoxyphenyl)-2-phenyl-1-oxa-3-aza-
spiro[5.5]undecan-4-one (6); Table 1, Entry 7
Compound 4 (325 mg, 1 mmol) was dissolved in anhydrous CH2Cl2
(10 mL) and added to a solution of cyclohexanone (5; 98 mg, 1
mmol) and BF3·OEt2 (142 mg, 1 mmol) in CH2Cl2 (10 mL) previ-
ously cooled at –78 °C. The mixture was stirred at this temperature
for 8 h and then poured into sat. aq NaHCO3 (10 mL) and extracted
1H NMR (400 MHz, CDCl3): d = 7.56 (m, 2 H), 7.48 (m, 3 H), 7.44
(d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 6.04 (s, 1 H), 5.21 (d,
J = 11.2 Hz, 1 H), 4.14 (d, J = 11.2 Hz, 1 H), 3.78 (s, 3 H), 3.42 (s,
1 H), 2.27 (d, J = 12.0 Hz, 1 H), 1.64 (m, 5 H + OH), 1.32 (m, 1 H),
1.14 (m, 1 H).
Synthesis 2008, No. 11, 1753–1756 © Thieme Stuttgart · New York

1756
M. Panunzio et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 172.18, 158.87, 137.12, 130.54,
129.78, 129.06, 128.64, 127.95, 113.83, 83.83, 76.61, 68.42, 56.88,
55.20, 34.58, 33.00, 25.39, 22.12, 21.14.
Acknowledgment
M.P. and Z.X. are indebted to the Italian MAE and Chinese MOST
for partially funding these studies within the S & T cooperation bet-
ween the P. R. of China and the Italian Republic (12th Joint Com-
mission 2006–2009). A.D. thanks Lek Pharmaceuticals (Ljubljana,
Slovenia) for financial support. Special thanks are due to Dr. José
Ignacio Miranda, Servicio General de RMN SGIker UPV/EHU,
Universidad del Pais Vasco, San Sebastian, Spain, for the helpful
discussion on the azadiene structure determination).
MS: m/z = 352, 253, 148, 120, 91, 77.
Anal. Calcd for C23H27NO4: C, 72.42; H, 7.13; N, 3.67. Found: C,
72.18; H, 7.10; N, 3.58.
( )-3-Hydroxymethyl-5-(4-methoxyphenyl)-1-oxa-3-aza-
spiro[5.5]undecan-4-one (9) from 8
Compound 8 (170 mg, 0.45 mmol) was dissolved in formic acid (2
mL) and formaldehyde (37% in H2O, 1 mL). The mixture was irra-
diated in a microwave oven (1 min, 75 W). The formic acid was re-
moved under vacuum and the mixture poured into sat. aq NaHCO3
(5 mL) and then extracted with EtOAc (3 × 10 mL). The organic
layers were dried (Na2SO4) and the solvent removed under vacuum.
The crude mixture was purified by flash chromatography on silica
gel to give 9; yield: 80 mg (58%); colorless oil.
References
(1) (a) Panunzio, M.; Vicennati, P. In Recent Research
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Trivandrum India, 2002, 683–707. (b) Ghosez, L.; Bayard,
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1999, 32, 4. (d) Jayakumar, S.; Ishar, M. P.; Mahajan, M. P.
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IR (CHCl3): 1644, 3388 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.17 (d, J = 8.8 Hz, 2 H), 6.83 (d,
J = 8.8 Hz, 2 H), 5.06 (dd, J = 7.6, 16.0 Hz, 2 H), 4.93 (d, J = 11.2
Hz, 1 H), 4.69 (d, J = 11.2 Hz, 1 H), 3.77 (s, 3 H), 3.31 (s, 1 H), 1.95
(d, J = 13.6 Hz, 1 H), 1.56–1.10 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 170.34, 158.86, 130.66, 128.47,
113.73, 76.54, 72.86, 68.37, 57.10, 55.21, 33.16, 32.77, 25.29,
21.68, 21.11.
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MS: m/z = 306 (M + 1), 276, 177, 148, 120, 105, 91.
Anal. Calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C,
67.05; H, 7.61; N, 4.45.
(e) Ntirampebura, D.; Ghosez, L. Synthesis 2002, 2043.
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( )-3-Hydroxymethyl-5-(4-methoxyphenyl)-1-oxa-3-aza-
spiro[5.5]undecan-4-one (9) from 6
Compound 6 (100 mg, 0.28 mmol) was dissolved in formic acid (2
mL) and formaldehyde (37% in H2O, 4 mL). The mixture was irra-
diated in a microwave oven (5 min, 150 W). The formic acid was
removed under vacuum and the mixture poured into sat. aq
NaHCO3 (5 mL) and then extracted with EtOAc (3 × 10 mL). The
organic layers were dried (Na2SO4) and the solvent removed under
vacuum. The crude mixture was purified by flash chromatography
on silica gel to give 9; yield: 50 mg (58%).
(4) (a) Panunzio, M.; Rossi, K.; Tamanini, E.; Campana, E.;
Martelli, G. Tetrahedron: Asymmetry 2004, 15, 3489.
(b) Panunzio, M.; Tamanini, E.; Bandini, E.; Campana, E.;
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( )-1-[2-Dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohex-
anol (1) [( )-Venlafaxine]
Compound 9 (92 mg, 0.3 mmol) was dissolved in anhyd THF (10
mL) at 0 °C. LiAlH4 (23 mg, 0.6 mmol) was added and the mixture
was stirred for 30 min at 0 °C, and then heated at 40 °C for 2 h. Aq
1 M HCl (5 mL) was added at 0 °C and the THF was removed under
vacuum. The aqueous phase was extracted with Et2O (3 × 10 mL),
basified (pH 10) with NH4OH and extracted with CH2Cl2 (3 × 15
mL). The organic layers were dried (Na2SO4) and the solvent re-
moved under vacuum to give 1; yield: 182 mg (66%). An aliquot of
the product was dissolved in i-PrOH (5 mL) saturated with HCl gas
to prepare the hydrochloride salt of Venlafaxine·HCl, which pre-
sented spectral data identical with the literature data.5e
(6) Bandini, E.; Martelli, G.; Spunta, G.; Bongini, A.; Panunzio,
M. Synlett 1999, 1735.
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(8) Panunzio, M.; Bandini, E.; D’Aurizio, A.; Xiao, Z. Synthesis
2007, 2060.
1H NMR (400 MHz, CDCl3): d = 7.04 (d, J = 8.8 Hz, 2 H), 6.80 (d,
J = 8.8 Hz, 2 H), 3.78 (s, 3 H), 3.27 (t, J1 = 12.4 Hz, J2 = 24.8 Hz, 1
H), 2.93 (dd, J = 3.6, 12.4 Hz, 1 H), 2.31 (s, 6 H), 2.28 (dd,
J = 3.6, 24.8 Hz, 1 H), 1.50 (m, 8 H), 0.93 (m, 2 H).
(9) (a) Bongini, A.; Panunzio, M.; Piersanti, G.; Bandini, E.;
Martelli, G.; Spunta, G.; Venturin, A. Eur. J. Org. Chem.
2000, 2379. (b) Bongini, A.; Panunzio, M. Eur. J. Org.
Chem. 2006, 972.
13C NMR (100 MHz, CDCl3): d = 158.22, 132.70, 130.08, 113.27,
74.22, 61.17, 55.14, 51.60, 45.41, 38.01, 31.15, 25.95, 21.57, 21.30.
(10) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662.
(11) Bongini, A.; Panunzio, M.; Tamanini, E.; Martelli, G.;
Vicennati, P.; Monari, M. Tetrahedron: Asymmetry 2003,
14, 993.
Synthesis 2008, No. 11, 1753–1756 © Thieme Stuttgart · New York