Total synthesis of (±)-paroxetine by diastereoconvergent cobalt-catalysed arylation

Article abstract of DOI:10.1002/ejoc.201402108

A total synthesis of paroxetine is reported, with a diastereoselective and diastereoconvergent cobalt-catalysed sp³-sp² coupling reaction involving a 3-substituted 4-bromo-N-Boc-piperidine (Boc = tert-butoxycarbonyl) substrate as a key step. A 9:1 diastereoselectivity was obtained, while a control experiment involving a conformationally locked 3-substituted 4-bromo-tert-butyl cyclohexane ring proceeded with essentially complete stereoselectivity.

Full text of DOI:10.1002/ejoc.201402108

FULL PAPER
DOI: 10.1002/ejoc.201402108
Total Synthesis of (؎)-Paroxetine by Diastereoconvergent Cobalt-Catalysed
Arylation
[a]
[b]
[a]
[a]
Carole F. Despiau, Andrew P. Dominey, David C. Harrowven, and Bruno Linclau*
Keywords: Total synthesis / Homogeneous catalysis / Nitrogen heterocycles / Cross-coupling / Cobalt / Radicals
A total synthesis of paroxetine is reported, with a diastereo- step. A 9:1 diastereoselectivity was obtained, while a control
3
2
selective and diastereoconvergent cobalt-catalysed sp –sp
experiment involving a conformationally locked 3-substi-
tuted 4-bromo-tert-butyl cyclohexane ring proceeded with
essentially complete stereoselectivity.
coupling reaction involving a 3-substituted 4-bromo-N-Boc-
piperidine (Boc = tert-butoxycarbonyl) substrate as a key
Introduction
Recent years have seen a marked rise in the use of
cheaper transition metals for catalytic C–C bond formation.
Iron and cobalt are particularly attractive for large-scale
metal catalysis as they have far lower toxicities than nickel
or palladium. Recent demonstrations of their ability to cat-
alyse the union of aryl Grignard reagents with unactivated
secondary alkyl halides represent a significant advance in
[
1,2]
the synthetic potential of these emerging protocols.
To date, investigations into the diastereoselectivity of
Scheme 1. Diastereoconvergent coupling reactions;[3a,3b] a) FeCl
5 mol-%), ArMgBr (1.3 equiv.), TMEDA (1.2 equiv.), THF, room
3
such cross-couplings are limited.[ With 3- and 4-substi-
3]
(
tuted bromocyclohexane derivatives, a number of reports temp., 30 min; b) CoCl2 (5 mol-%), PhMgBr (1.2 equiv.), (R,R)-
have demonstrated the preferential incorporation of the N,N,NЈ,NЈ-tetramethyl-1,2-cyclohexanediamine (6 mol-%), THF,
25 °C, 15 min.
“nucleophilic” component into the less encumbered equato-
rial position in iron-catalysed cross-coupling reactions [e.g.,
[
3a]
Similar observations have been made for efficiently catalyse cross-coupling reactions.[5] An alkyl radi-
Scheme 1 (i)].
the analogous cobalt-catalysed reactions, with bicyclohept- cal (II) can then be generated by reaction of the reduced
[
6]
anes exo-3 and endo-3 both giving exo-4 when treated with ferrate complex with the alkyl bromide. Recombination of
PhMgBr [Scheme 1 (ii)].[
3b]
the alkyl radical with the metal complex to give III, fol-
Mechanistically, the stereochemical outcome has been lowed by reductive elimination, would liberate the cross-
explained by the involvement of a radical intermediate, as coupling product. Similar mechanisms have been proposed
[
3c,4]
[3b,7]
seen in the proposed mechanism shown in Scheme 2.
Ferrate complexes (I) have been proposed as the reactive well as for a cobalt-catalysed tandem cyclisation and aryl-
for the cobalt-catalysed allylation of alkyl halides,
as
[
8]
species when the Grignard reagent involved is unable to un- ation reaction. The configurational lability of the radical
dergo β-hydride elimination. Indeed, such complexes have intermediate (II) nicely accounts for the formation of the
been prepared by Fürstner et al., who showed that they
[
[
a] Chemistry, University of Southampton, Highfield,
Southampton SO17 1BJ, UK
E-mail: bruno.linclau@soton.ac.uk
www.southampton.ac.uk/chemistry/about/staff/linclau.page
b] GlaxoSmithKline, Medicines Research Centre,
Gunnels Wood Road, Stevenage SG1 2NY, UK
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402108.
©
2014 The Authors. Published by Wiley-VCH Verlag GmbH &
Co. KGaA. This is an open access article under the terms of
the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the
original work is properly cited.
Scheme 2. Proposed mechanism for the cross-coupling reaction.[3–8]
SET = single-electron transfer.
Eur. J. Org. Chem. 2014, 4335–4341
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4335

C. F. Despiau, A. P. Dominey, D. C. Harrowven, B. Linclau
FULL PAPER
Scheme 3. Retrosynthetic analysis. Boc = tert-butoxycarbonyl.
most stable diastereoisomer (e.g., trans-2, exo-4). A late
transition state for the reductive elimination step has also
been invoked to explain the bias towards production of the
thermodynamic product.[
1,3]
In this paper, we report a successful application of this
diastereoconvergent cross-coupling methodology in a short
®
[9]
synthesis of paroxetine 5 (Paxil , Scheme 3). Paroxetine
is a potent inhibitor of serotonin reuptake, and is widely
prescribed for the treatment of depression, obsessive-com-
pulsive disorder, panic disorder, social and anxiety disorder,
and post-traumatic stress disorder.[
10]
Scheme 4. Synthesis of the cross-coupling precursor; DMAP = 4-
(
dimethylamino)pyridine.
Results and Discussion
Our retrosynthetic analysis is shown in Scheme 3, with
secondary bromide 6 as a key intermediate for the introduc-
We were now in a position to examine our key cross-
tion of the aryl residue. As the coupling is expected to be coupling step with p-fluorophenylmagnesium bromide. For
diastereoconvergent, our strategy allows for its production completeness, we decided to separate the diastereoisomers
as a mixture of diastereomers. Consequently, the synthesis of 6 in order to rigorously establish diastereoconvergence
of 6 can be envisioned from commercially available 8 using for each stereoisomer. To that end, the cis and trans dia-
standard chemistry.
stereomers of alcohol 10 were separated by chromatog-
A literature survey revealed that N-protected 4-bromopi- raphy, then each was brominated to give trans- and cis-6,
peridine derivatives have been used as substrates in iron/ respectively. However, it proved more convenient to sepa-
cobalt-catalysed coupling reactions,[ yet none of the ex- rate cis and trans bromides 6 by selective precipitation from
11]
amples reported featured α-alkyl substitution. Moreover, hexane/Et O.
2
cross-couplings on six-membered rings with α-alkyl substit-
The optimisation studies for the cross-coupling of brom-
uents have little precedent.[
12,13]
Hence, both the reactivity ides 6 with 4-fluorophenylmagnesium bromide are summa-
and the stereochemical outcome of our key step would be rised in Table 1. Preliminary studies with iron(III) chloride/
instructive, given that substituted piperidines are ubiquitous TMEDA (N,N,NЈ,NЈ-tetramethylethylenediamine; Table 1,
in natural products and medicines.[
9j,14,15]
entries 1 and 2) and (FeCl ) (TMEDA) (Table 1, entry 3)
[4]
3 2 3
The synthesis of bromide precursor 6 was readily ac- mainly returned unreacted starting material. However, a
[
16]
complished in three steps from known diol 7 (Scheme 4).
switch to iron(III) acetylacetonate (acac) in combination
Regioselective tosylation of 7 (dr 58:42) proceeded in good with TMEDA and hexamethylenetetramine (HMTA)[
yield using triethylamine (2.1 equiv.) as the base. Introduc- showed some promise, with cis-6 giving a 16% yield of cou-
tion of the sesamol group with Cs CO in DMF gave ad- pling product 11 as a 78:22 mixture of trans/cis isomers
4]
2
3
duct 10 in 51% yield. This yield improved to 76% when a (Table 1, entry 4). The same reaction using trans-6 gave a
toluene solution of 9 and sesamol was exposed to aqueous lower yield, with a similar ratio of trans- and cis-11 (Table 1,
NaOH using tetrabutylammonium hydroxide as phase- entry 5). Hence, these results demonstrate the expected dia-
transfer catalyst. Finally, conversion of alcohol 10 into stereoconvergence.
bromide 6 was achieved in 65% yield through the action of
Increasing the temperature and the amount of Grignard
bromotriphenylphosphonium bromide. Bromination of the reagent used led to a modest increase in yield (Table 1, en-
electron-rich sesamol ring was never observed with this rea- try 6), but the product mixture now contained significant
gent, in contrast to related procedures using triphenylphos- levels of elimination product 12. It is unclear whether 12
phine and bromine, where it proved to be a minor side- was formed by a reductive elimination process, or by degra-
reaction (10% yield).
dation of the starting material. The formation of thermody-
4336
www.eurjoc.org
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2014, 4335–4341

Total Synthesis of (Ϯ)-Paroxetine
Table 1. Investigation of the cross-coupling step.
Entry
dr of 6[a,b] Catalyst (equiv.)
Additive (equiv.)
ArMgBr
Conditions
dr of 11[a,c] Ratio 6:11:12[d] Yield [%][e]
[
equiv.]
TMEDA[f] (1.2)
TMEDA (1.2)
–
1.2
[g]
THF, 0.5 h, 0 °C
THF, 18 h, 0 °C to r.t.
THF, 0.5 h, r.t.
–
–
–
–
72:Ͻ1:27
–
Ͻ1
Ͻ1
0
1
2
3
Ͻ1:99
59:41
Ͼ99:1
FeCl
FeCl
3
3
(0.05)
(0.05)
) (TMEDA) ]
3 2 3
1.2[
1.3[
g]
g]
[(FeCl
0.05)
(
4
5
6
7
Ͻ1:99
Ͼ99:1
11:89
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
3
(0.05)
(0.05)
(0.1)
TMEDA (0.1),
HMTA[ (0.05)
TMEDA (0.1),
HMTA (0.05)
TMEDA (0.1),
HMTA (0.05)
TMEDA (0.1),
HMTA (0.05)
NMP (5.8)
1.3[g]
1.3[g]
2.0[g]
1.3[g]
THF,
0.5 h, 0 °C
THF,
4 h, 0 °C
THF,
23 h, r.t.
78:22
79:21
77:23
74:26
67:32:Ͻ1
73:27:Ͻ1
46:45:9
16
7
h]
3
3
3
3
20
Ͻ1:99
(0.05)
(0.1)
Et
2
O,
69:23:8
Ͻ10
4 h, 0 °C
THF, 7 h, 0 °C
MeTHF,
3.2[
g]
66:34
68:32
85:10:5
67:15:18
3
12
8
9
Ͻ1:99
30:70
1.5[
i]
bmim-FeCl
4
(0.05)
–
0
.5 h, 0 °C to r.t.
THF,
0 min, 0 °C
THF,
h, 0 °C
2
O,
1
1
1
1
1
1
1
1
1
0
Ͼ99:1
Ͻ1:99
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
30:70
Co(acac)
Co(acac)
Co(acac)
Co(acac)
Co(acac)
Co(acac)
Co(acac)
Co(acac)
Co(acac)
3
3
3
3
3
3
3
3
3
(0.05)
(0.05)
(0.05)
(0.05)
(0.1)
TMEDA (0.05)
TMEDA (1.0)
TMEDA (0.05)
1.1[g]
2.1[g]
2.0[g]
2.0[i]
2.0[i]
2.0[i]
2.0[j]
2.0[i]
2.0[i]
83:17
87:13
79:21
89:11
90:10
88:12
88:12
71:29
88:12
69:25:6
46:53:Ͻ1
71:29:Ͻ1
45:50:5
20
31
n.d.
43
77
26
26
4
4
1
3
Et
1
2
h, 0 °C
3
TMEDA (0.5),
HMTA (0.1)
TMEDA (0.5),
HMTA (0.5)
TMEDA (0.5),
HMTA (0.5)
TMEDA (0.5),
HMTA (0.5)
bpy[ (0.5),
MeTHF,
2 h, 0 °C to r.t.
MeTHF,
2 h, 0 °C to r.t.
MeTHF,
2 h, –5 °C
MeTHF,
2 h, 0 °C to r.t.
MeTHF,
2 h, 0 °C to r.t.
MeTHF,
4
15:80:5
5
(0.1)
43:51:6
6
(0.1)
58:29:14
89:8:3
k]
7
Ͼ99:1
30:70
(0.1)
HMTA (0.5)
TMEDA (0.5),
HMTA (0.5)
8[l]
(0.1)
11:88:Ͻ1
76
5 h, 0 °C to r.t.
a] trans/cis. [b] Determined by H NMR spectroscopy. [c] Determined by 19F NMR spectroscopy of the crude material. [d] Determined
1
[
1
by H NMR spectroscopy of the crude material. [e] Isolated yield of 11. [f] N,N,NЈ,NЈ-Tetramethylethylenediamine. [g] Added as a 1 m
solution in THF. [h] Hexamethylenetetramine. [i] Added as a 1 m solution in MeTHF. [j] Added as a 0.5 m solution in MeTHF. [k] 2,2Ј-
Bipyridine. [l] Reaction carried out on 1.05 g (2.53 mmol) of 6.
namically more stable alkene 12 as the only observed elimi-
nation product suggests that the latter process predomi- reactive Co catalysts. Pleasingly, our first reaction with
nates. In the iron-catalysed coupling reaction between tolyl- Co(acac) /TMEDA,
At this juncture we decided to examine the use of more
III
[
19]
gave 11 in 20% yield (Table 1, en-
3
magnesium bromide and 5-phenyl-1-bromopentane, Na- try 10) with an improved selectivity for trans-11. The yield
gano and Hayashi described that the reaction was improved was elevated to 31% by using a molar equivalent of
[
17]
by using diethyl ether as the solvent instead of THF. Un- TMEDA and 2.1 equiv. of ArMgBr (Table 1, entry 11). As
fortunately, in our case, switching the solvent to diethyl with the iron-catalysed examples, the selectivity dropped
ether (Table 1, entry 7), lowered both the yield and the when diethyl ether was used as solvent (Table 1, entry 12),
selectivity, as did the use of N-methyl-2-pyrrolidone (NMP) although it improved slightly when cat. HMTA was used in
in combination with THF (Table 1, entry 8).[ The pro- MeTHF (Table 1, entry 13).
18]
cedure of Bica and Gaertner, i.e., the use of the ionic liquid
A step change in performance was noted when we em-
[
11b]
bmim-FeCl as an iron source, was also investigated,
but ployed 10 mol-% of Co(acac)3 with a combination of
4
this too gave low yields and poor selectivities (Table 1, en- TMEDA and HMTA as additives in MeTHF (Table 1, en-
[
4]
try 9).
try 14). Under these conditions, the desired product (i.e.,
Eur. J. Org. Chem. 2014, 4335–4341
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4337

C. F. Despiau, A. P. Dominey, D. C. Harrowven, B. Linclau
FULL PAPER
1
1) was obtained in 77% yield with a trans/cis ratio of 90:10 quantitative yield as off-white crystals by recrystallisation
[
20b]
(Table 1, entry 14). The yield dropped significantly when from 2-propanol.
All spectroscopic data matched litera-
[
20b]
the reaction was carried out at lower temperature (Table 1, ture values.
entry 15), though the same product ratio was obtained.
Attempts to increase the selectivity by adding a more dilute
solution of the Grignard reagent (Table 1, entry 16) or by Conclusions
substituting TMEDA with bpy (Table 1, entry 17) were also
In conclusion, we have developed a short route to (Ϯ)-
paroxetine using a cobalt-mediated cross-coupling reaction
to construct the 3,4-disubstituted piperidine scaffold. The
key step is notable for being diastereoconvergent, consistent
with reported mechanistic studies. Importantly, for bromo-
cyclohexane 13, the diastereoselectivity was essentially com-
plete, whereas for N-Boc-piperidine 6 it dropped to 9:1. No-
tably, our synthesis of (Ϯ)-paroxetine 5 is unique in that the
p-fluorophenyl ring is introduced in the penultimate step.
An enantioselective total synthesis is currently under inves-
tigation.
unsuccessful. Pleasingly, using our optimised conditions on
a gram scale (Table 1, entry 18) with a diastereoisomeric
mixture of bromide 6 gave paroxetine precursor 11 as a sep-
arable 88:12 mixture of trans and cis diastereomers in 76%
yield. Comparison between Table 1, entries 14 and 18 again
confirmed the diastereoconvergence of the process.
Although the diastereoselectivity was satisfactory, it did
not match the levels obtained with locked cyclohexyl deriv-
ative cis-1 (i.e., 96:4; Scheme 1). As a control experiment,
we decided to prepare cyclohexyl analogue cis-13 and test
it, using our optimised conditions, in a cross-coupling reac-
tion with (4-fluorophenyl)magnesium bromide (Scheme 5).
Surprisingly, it gave trans-14 as the sole reaction product,
1
19
Experimental Section
as judged by H and F NMR spectroscopic analysis. The
strong conformational lock imposed by the tert-butyl group
N-Boc-4-hydroxy-3-(tosyloxymethyl)piperidine (9): A solution of p-
provides a possible explanation for the improved diastereo- toluenesulfonyl chloride (1.26 g, 6.61 mmol, 1.1 equiv.) in anhy-
Cl (11 mL) was added to a solution of N-Boc-3-
selectivity obtained in this system compared to the N-Boc- drous CH
2
2
piperidine substrates (see Table 1). However, it is also plaus- hydroxymethyl-4-piperidol 7 (1.39 g, 6.01 mmol, 1 equiv.), dry tri-
ethylamine (1.76 mL, 12.62 mmol, 2.1 equiv.), and DMAP (73 mg,
ible that N-Boc chelation prior to the reductive elimination
provides additional stabilisation for an axial organocobalt
intermediate.
2 2
0.60 mmol, 0.1 equiv.) in dry CH Cl (22 mL) under argon at room
temp. The reaction mixture was stirred at room temp. After 23 h,
water (36 mL) was added, and the product was extracted with
2 2
CH Cl (3ϫ 36 mL). The combined organic layers were washed
with brine (36 mL), dried with magnesium sulfate, and concen-
trated under reduced pressure. The crude mixture was purified by
column chromatography (petroleum ether/acetone, from 80:20 to
7
0:30) to give 9 [1.79 g, 77%, 67:33 dr (trans:cis)] as a colourless
oil. The two diastereoisomers could be separated by HPLC
hexane/acetone 80:20).
(
Scheme 5. Control experiment with a conformationally locked cy-
clohexane derivative.
Data for trans diastereoisomer: R
f
(hexane/acetone, 80:20): 0.18. IR
Finally, the synthesis of (Ϯ)-paroxetine was completed by
(
neat): ν˜ = 3424 (br. w), 2975 (w), 2929 (w), 1694 (m), 1669 (m),
removal of the Boc protecting group (Scheme 6). Following
–
1 1
1
428 (br. m), 1175 (s), 959 (br. w) cm . H NMR (400 MHz, [D
DMSO, 343 K): δ = 7.78 (d, J = 8.2 Hz, 2 H, 9-H or 10-H), 7.49
d, J = 8.1 Hz, 2 H, 9-H or 10-H), 4.24 (dd, J = 10.0, 3.8 Hz, 1 H,
6
]-
Jacobsen’s conditions,[
20a]
our target 5·HCl was obtained in
(
7
4
-H), 3.98 (dd, J = 10.0, 8.1 Hz, 1 H, 7-H), 3.86 (br. ddd, J = 13.4,
.0, 1.8 Hz, 1 H, 2eq-H), 3.78 (dtd, J = 13.4, 4.3, 1.9 Hz, 1 H, 6eq
-
H), 3.34 (td, J = 9.5, 4.4 Hz, 1 H, 4ax-H), 2.77 (ddd, J = 13.5, 11.6,
.0 Hz, 1 H, 6ax-H), 2.57 (dd, J = 13.1, 10.5 Hz, 1 H, 2ax-H), 2.43
3
(
(
4
s, 3 H, 12-H), 1.74 (dq, J = 12.9, 3.7 Hz, 1 H, 5eq-H), 1.52–1.64
m, 1 H, 3-H), 1.39 (s, 9 H, 15-H), 1.24 (dddd, J = 12.9, 11.6, 10.0,
.5 Hz, 1 H, 5ax-H) ppm. C NMR + DEPT 135 (100 MHz, [D ]-
6
1
3
DMSO, 343 K): δ = 153.6, 144.5 (C, C-8, C-13), 132.4 (C, C-11),
29.8, 127.1 (CH, C-9, C-10), 78.5 (C, C-14), 69.7 (CH , C-7), 66.4
, C-6), 33.2
1
2
(
(
CH, C-4), 43.6 (CH
2
, C-2), 42.9 (CH, C-3), 41.5 (CH
, C-15), 20.7 (CH , C-12) ppm. MS (ES ):
2
+
CH
2
, C-5), 27.7 (CH
3
+
3
+
+
6
m/z = 408.2 [M + Na] . HRMS (ES ): calcd. for C18H27NNaO S
Scheme 6. Completion of the synthesis.
338
[M + Na]+ 408.1451; found 408.1454.
4
www.eurjoc.org
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2014, 4335–4341

Total Synthesis of (Ϯ)-Paroxetine
1
1
05.9 (CH, C-14), 100.6 (CH
6), 67.9 (CH , C-7), 66.9 (CH, C-4), 44.2 (CH
, C-6), 33.3 (CH , C-5), 27.7 (CH
ES ): m/z = 374.2 [M + Na] . HRMS (ES ): calcd. for
2
, C-11), 97.7 (CH, C-9), 78.3 (C, C-
, C-2), 43.2 (CH,
, C-17) ppm. MS
2
2
C-3), 41.4 (CH
(
C
2
2
3
+
+
+
18 6
H25NNaO
[M + Na]+ 374.1574; found 374.1577.
+
f
Data for cis diastereoisomer: R (hexane/acetone, 80:20): 0.21. IR
(
neat): ν˜ = 3425 (br. w), 2975 (w), 2927 (w), 1694 (m), 1670 (m),
–1 1
1
428 (br. m), 1175 (s), 959 (br. w) cm . H NMR (400 MHz, [D
DMSO, 363 K): δ = 7.77 (d, J = 8.3 Hz, 2 H, 9-H or 10-H), 7.48
d, J = 8.1 Hz, 2 H, 9-H or 10-H), 4.13 (dd, J = 9.9, 5.2 Hz, 1 H,
-H), 3.92 (dd, J = 9.9, 9.4 Hz, 1 H, 7-H), 3.84 (q, J = 4.0 Hz, 1
H, 4eq-H), 3.49 (dd, J = 13.1, 3.8 Hz, 1 H, 2eq-H), 3.43 (dt, J =
3.3, 4.8 Hz, 1 H, 6eq-H), 3.23 (ddd, J = 13.3, 7.6, 5.8 Hz, 1 H, 6ax
6
]-
(
7
1
-
H), 3.04 (app. dd, J = 12.9, 9.3 Hz, 1 H, 2ax-H), 2.44 (s, 3 H, 12-
H), 1.87 (tdt, J = 9.4, 5.2, 3.8 Hz, 1 H, 3ax-H), 1.46–1.53 (m, 2 H,
2
Data for cis diastereoisomer: R
f
(hexane/EtOAc, 60:40): 0.24. IR
(
1
neat): ν˜ = 3446 (br. w), 2974 (w), 2928 (w), 1665 (br. m), 1489 (s),
183 (br. s), 1038 (m) cm . H NMR (400 MHz, [D
5-H), 1.39 (s, 9 H, 15-H) ppm. 13C NMR + DEPT 135 (100 MHz,
–1
1
6
]DMSO,
6
[D ]DMSO, 343 K): δ = 153.7, 144.4 (C, C-8, C-13), 132.5 (C, C-
363 K): δ = 6.77 (d, J = 8.6 Hz, 1 H, 13-H), 6.57 (d, J = 2.5 Hz, 1
1
6
3
1), 129.8, 127.1 (CH, C-9, C-10), 78.3 (C, C-14), 69.5 (CH
3.5 (CH, C-4), 40.7 (CH , C-2), 39.7 (CH, C-3), 38.7 (CH
1.4 (CH , C-5), 27.7 (CH , C-15), 20.7 (CH
2
, C-7),
, C-6),
, C-12) ppm. MS
H, 9-H), 6.37 (dd, J = 8.6, 2.5 Hz, 1 H, 14-H), 5.93 (s, 2 H, 11-H),
2
2
4.56 (br. d, J = 3.5 Hz, 1 H, OH), 3.99 (dd, J = 9.9, 5.3 Hz, 1 H,
7-H), 3.94 (app. t, J = 3.5 Hz, 1 H, 4eq-H), 3.76 (dd, J = 9.6, 8.6 Hz,
1 H, 7-H), 3.58 (br. d, J = 12.6, 3.5 Hz, 1 H, 2eq-H), 3.46 (dt, J =
12.9, 4.9 Hz, 1 H, 6eq-H), 3.32 (m, 1 H, 6-H), 3.20 (m, 1 H, 2-H),
2
3
3
+
+
+
(ES ): m/z = 408.2 [M + Na] . HRMS (ES ): calcd. for
+
+
C
18 6
H27NNaO S [M + Na] 408.1451; found 408.1458.
N-Boc-3-{[3,4-(methylenedioxy)phenoxy]methyl}piperidin-4-ol (10): 1.96 (m, 1 H, 3-H), 1.51–1.62 (m, 2 H, 5-H), 1.37 (s, 9 H, 17-H)
1
3
NaOH (50% aq.; 2.9 mL) was added to a mixture of N-Boc-4- ppm. C NMR + DEPT 135 (100 MHz, [D
hydroxy-3-[(tosyloxy)methyl]piperidine 9 (cis and trans; 591 mg,
154.0, 153.8, 147.6, 140.8 (C, C-15, C-8, C-10, C-12), 107.5 (CH,
.53 mmol, 1 equiv.), tetra-n-butylammonium hydroxide (1.0 m in
C-13), 105.9 (CH, C-14), 100.5 (CH , C-11), 97.6 (CH, C-9), 78.1
O; 77 μL, 0.08 mmol, 0.05 equiv.), and sesamol (233 mg, (C, C-16), 67.4 (CH , C-7), 64.0 (CH, C-4), 41.3 (CH , C-2), 40.2
.69 mmol, 1.1 equiv.) in toluene (5.7 mL). The reaction mixture
(CH, C-3), 38.9 (CH , C-6), 31.6 (CH , C-5), 27.7 (CH , C-17)
ppm. MS (ES ): m/z = 374.2 [M + Na] . HRMS (ES ): calcd. for
6
]DMSO, 353 K): δ =
1
H
1
2
2
2
2
2
2
+
3
+
+
was stirred at 70 °C. After 25 h, the aqueous and organic phases
+
[M + Na]+ 374.1574; found 374.1580.
were separated. The aqueous phase was extracted with EtOAc (3ϫ
C
18
H
25NNaO
N-Boc-4-bromo-3-{[3,4-(methylenedioxy)phenoxy]methyl}piperidine
6): A mixture of N-Boc-3-{[3,4-(methylenedioxy)phenoxy]-
methyl}piperidin-4-ol 10 (1.29 g, 3.67 mmol, 1.0 equiv.) and imid-
azole (300 mg, 4.41 mmol, 1.2 equiv.) in dry dichloromethane
8.5 mL) was cooled to 0 °C. A solution of bromotriphenylphos-
phonium bromide (1.704 g, 4.04 mmol, 1.1 equiv.) in dry CH Cl
9.1 mL) was stirred at room temp. for 15 min, and then added
dropwise to the starting material. The reaction mixture was stirred
in the dark for 24 h at room temp., then it was diluted with water
6
20 mL), then the combined organic phases were dried with magne-
sium sulfate and concentrated under reduced pressure. The crude
mixture was purified by column chromatography (petroleum ether/
EtOAc, 60:40) to give 10 (412 mg, 76%) as a yellow oil. The two
diastereoisomers were separated by HPLC (hexane/EtOAc, 60:40)
to give the trans diastereoisomer (280 mg, 52%) as a pale yellow
oil, and the cis diastereoisomer (128 mg, 24%) as a colourless
oil.
(
(
2
2
(
(
2 2
25 mL) and extracted with CH Cl (3ϫ 70 mL). The organic layer
was dried with sodium sulfate and concentrated under reduced
pressure. The crude mixture was purified by column chromatog-
raphy (petroleum ether/EtOAc, 90:10) to give 6 [1.521 g, 65%,
70:30 dr (cis/trans)] as a colourless oil. The two diastereoisomers
could be separated by selective precipitation of cis-6 from hexane/
diethyl ether (90:10).
Data for trans diastereoisomer: R
f
(hexane/EtOAc, 50:50): 0.27. IR
(
(
neat): ν˜ = 3049 (br. w), 2975 (w), 2927 (br. w), 1686 (br. s), 1670
–1 1
br. s), 1489 (s), 1182 (br. s), 1038 (m) cm . H NMR (400 MHz,
]DMSO, 363 K): δ = 6.77 (d, J = 8.5 Hz, 1 H, 13-H), 6.58 (d,
J = 2.5 Hz, 1 H, 9-H), 6.38 (dd, J = 8.5, 2.5 Hz, 1 H, 14-H), 5.93
s, 2 H, 11-H), 4.56 (d, J = 5.4 Hz, 1 H, OH), 4.12 (dd, J = 9.9,
[D
6
(
3
3
1
2
9
1
.7 Hz, 1 H, 7-H), 4.00 (ddd, J = 13.3, 4.3, 1.9 Hz, 1 H, 2eq-H),
.84 (dd, J = 10.0, 8.0 Hz, 1 H, 7-H), 3.81 (dtd, J = 13.3, 4.3,
.8 Hz, 1 H, 6eq-H), 3.50 (tdd, J = 9.2, 5.3, 4.8 Hz, 1 H, 4ax-H), Data for trans diastereoisomer: R
.88 (ddd, J = 13.4, 11.1, 3.2 Hz, 1 H, 6ax-H), 2.78 (dd, J = 13.3, EtOAc, 90:10): 0.20. IR (neat): ν˜ = 2957 (w), 1698 (m), 1489 (m),
.9 Hz, 1 H, 2ax-H), 1.81 (dtd, J = 12.9, 4.3, 3.5 Hz, 1 H, 5eq-H), 1264 (s), 1184 (br. w), 730 (br. s), 703 (m), 651 (w) cm . H NMR
.71 (ddddd, J = 9.9, 9.2, 8.0, 4.3, 3.7 Hz, 1 H, 3ax-H), 1.40 (s, 9 (400 MHz, [D ]DMSO, 373 K): δ = 6.78 (d, J = 8.3 Hz, 1 H, 13-
f
(petroleum ether 40–60 °C/
–
1 1
6
H, 17-H), 1.33 (dddd, J = 12.9, 11.1, 9.2, 4.3 Hz, 2 H, 5ax-H) ppm.
H), 6.60 (d, J = 2.4 Hz, 1 H, 9-H), 6.41 (dd, J = 8.3, 2.4 Hz, 1 H,
14-H), 5.94 (s, 2 H, 11-H), 4.41 (td, J = 9.7, 4.3 Hz, 1 H, 4ax-H),
4.11 (dd, J = 10.1, 3.6 Hz, 1 H, 7-H), 4.05 (ddd, J = 13.6, 4.2,
13
C NMR + DEPT 135 (100 MHz, [D
6
]DMSO, 343 K): δ = 154.0,
153.7, 147.6, 140.9 (C, C-15, C-8, C-10, C-12), 107.6 (CH, C-13),
Eur. J. Org. Chem. 2014, 4335–4341
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4339

C. F. Despiau, A. P. Dominey, D. C. Harrowven, B. Linclau
FULL PAPER
2.0 Hz, 1 H, 2eq-H), 3.98 (dd, J = 10.2, 7.0 Hz, 1 H, 7-H), 3.78 353 K): δ = 7.27 (dd, J = 8.8, 5.6 Hz, 2 H, 16-H), 7.08 (t, J =
(dtd, J = 13.5, 4.4, 1.9 Hz, 1 H, 6eq-H), 2.98–3.09 (m, 2 H, 2-H, 6- 8.8 Hz, 2 H, 17-H), 6.70 (d, J = 8.4 Hz, 1 H, 13-H), 6.40 (d, J =
H), 2.28 (dtd, J = 13.2, 4.3, 3.2 Hz, 1 H, 5eq-H), 2.06–2.17 (m, 1
2.5 Hz, 1 H, 9-H), 6.18 (dd, J = 8.6, 2.5 Hz, 1 H, 14-H), 5.90 (s, 2
H, 11-H), 4.30 (ddd, J = 13.1, 4.0, 1.5 Hz, 1 H, 2eq-H), 4.06 (ddt,
1
3
H, 3-H), 1.84–1.97 (m, 1 H, 5-H), 1.42 (s, 9 H, 17-H) ppm.
NMR + DEPT 135 (100 MHz, [D
C
6
]DMSO, 353 K): δ = 153.5, J = 13.1, 4.0, 2.0 Hz, 1 H, 6eq-H), 3.58 (dd, J = 10.1, 3.5 Hz, 1 H,
53.5, 147.6, 141.2 (C, C-15, C-8, C-10, C-12), 107.6 (CH, C-13), 7-H), 3.53 (dd, J = 10.1, 7.6 Hz, 1 H, 7-H), 2.83 (td, J = 12.9,
06.1 (CH, C-14), 100.6 (CH , C-11), 97.8 (CH, C-9), 78.7 (C, C- 3.0 Hz, 1 H, 4ax-H), 2.75 (dd, J = 13.1, 11.1 Hz, 1 H, 2ax-H), 2.68
6), 69.1 (CH , C-7), 51.6 (CH, C-4), 45.2 (CH
, C-6), 35.5 (CH , C-5), 27.6 (CH
ES ): m/z = 436.1, 438.0 [M + Na] . HRMS (ES ): calcd. for
1
1
1
2
2
2
, C-2), 44.1 (CH,
3
, C-17) ppm. MS
(m, 1 H, 6ax-H), 2.02 (tdt, J = 11.1, 7.6, 3.9 Hz, 1 H, 3ax-H), 1.73
(dtd, J = 13.1, 3.5, 2.5 Hz, 1 H, 5eq-H), 1.62 (qd, J = 12.6, 4.5 Hz,
C-3), 43.0 (CH
(
2
2
+
+
+
13
1 H, 5ax-H), 1.44 (s, 9 H, 21-H) ppm. C NMR + DEPT 135
79
+
+
C
18
H24 BrNNaO
5
[M + Na] 436.0730; found 436.0733.
6
(100 MHz, [D ]DMSO, 353 K): δ = 160.5 (C, d, J = 241.0 Hz, C-
18), 154.3, 153.6, 147.5, 141.0 (4 C, C-19, C-8, C-10, C-12), 139.3
(
(
C, d, J = 2.9 Hz, C-15), 128.7 (CH, d, J = 7.8 Hz, C-16), 114.7
CH, d, J = 21.4 Hz, C-17), 107.5 (CH, C-13), 105.8 (CH, C-14),
1
7
00.5 (CH
), 46.4, 43.6 (CH
, C-5), 27.8 (CH
DMSO, 298 K): δ = –116.2 (s, 1 F) ppm.
؎)-Paroxetine Hydrochloride Salt (5·HCl): trans-N-Boc-4-(p-fluoro-
phenyl)-3-[3,4-(methylenedioxy)phenoxymethyl]piperidine (trans-
1; 286 mg, 0.67 mmol, 1 equiv.) was dissolved in 2-propanol
(3.3 mL). Concentrated hydrochloric acid (101 μL, 1.00 mmol,
.5 equiv.) was added, and the solution was stirred for 5 h at 75 °C.
2
, C-11), 97.6 (CH, C-9), 78.3 (C, C-20), 68.9 (CH
2
, C-
2
, C-2, C-6), 43.1 (CH, C-4), 40.8 (CH, C-3), 33.2
1
9
(CH
2
3 6
, C-21) ppm. F NMR (282 MHz, [D ]-
(
Data for cis diastereoisomer: R
f
(petroleum ether 40–60 °C/EtOAc,
1
9
1
0:10): 0.17. IR (neat): ν˜ = 2958 (w), 1696 (m), 1489 (m), 1265 (s),
–1
1
183 (br. m), 732 (br. s), 702 (m), 650 (w) cm . H NMR
]DMSO, 353 K): δ = 6.78 (d, J = 8.6 Hz, 1 H, 13-
H), 6.61 (d, J = 2.5 Hz, 1 H, 9-H), 6.40 (dd, J = 8.6, 2.5 Hz, 1 H,
1
(400 MHz, [D
6
The resulting mixture was cooled to room temp. and concentrated
under reduced pressure. The residue was dried by azeotroping with
absolute ethanol (3ϫ 3 mL) to give 5·HCl (243 mg, Ͼ 99%) as an
off-white solid, which was recrystallised from 2-propanol.
14-H), 5.94 (s, 2 H, 11-H), 4.86 (app. q, J = 3.2 Hz, 1 H, 4eq-H),
3.81–3.96 (m, 3 H, 2-H, 2 7-H), 3.77 (dt, J = 13.4, 4.2 Hz, 1 H,
6eq-H), 3.21 (ddd, J = 13.8, 10.0, 4.0 Hz, 1 H, 6ax-H), 2.97 (br. dd,
J = 13.1, 10.1 Hz, 1 H, 2ax-H), 1.95–2.17 (m, 3 H, 3-H, 2 5-H),
+
+
1
.40 (s, 9 H, 17-H) ppm. MS (ES ): m/z = 436.1, 438.2 [M + Na] .
+
79
+
+
HRMS (ES ): calcd. for C18
found 436.0729.
5
H24 BrNNaO [M + Na] 436.0730;
N-Boc-4-(p-fluorophenyl)-3-[3,4-(methylenedioxy)phenoxymethyl]-
piperidine (11): N-Boc-4-bromo-3-{[3,4-(methylenedioxy)phenoxy]-
methyl}piperidine (6) (1.049 g, 2.53 mmol, 1 equiv.), Co(acac)
3
(
0
90 mg, 0.25 mmol, 0.1 equiv.), TMEDA (190 μL, 1.27 mmol,
.5 equiv.), HMTA (177 mg, 1.27 mmol, 0.5 equiv.), and MeTHF
1
M.p. 124–126 °C (iPrOH). H NMR (400 MHz, CDCl
3
): δ = 9.94
(
br. s, 2 H, NH
2
), 7.22 (dd, J = 8.3, 5.3 Hz, 2 H, 16-H), 6.99 (t, J
8.6 Hz, 2 H, 17-H), 6.62 (d, J = 8.6 Hz, 1 H, 13-H), 6.33 (d, J =
.5 Hz, 1 H, 9-H), 6.12 (dd, J = 8.3, 2.3 Hz, 1 H, 14-H), 5.88 (s, 2
H, 11-H), 3.63–3.83 (m, 2 H, 2-H, 6-H), 3.60 (br. dd, J = 9.6,
.0 Hz, 1 H, 7-H), 3.48 (dd, J = 9.3, 4.8 Hz, 1 H, 7-H), 3.17 (br. t,
J = 12.4 Hz, 1 H, 2-H), 3.04 (br. t, J = 12.1 Hz, 1 H, 6-H), 2.91
td, J = 11.9, 3.0 Hz, 1 H, 4-H), 2.68 (m, 1 H, 3-H), 2.42 (m, 1 H,
-H), 2.03 (br. d, J = 13.6 Hz, 1 H, 5-H) ppm. C NMR + DEPT
35 (100 MHz, CDCl ): δ = 161.9 (d, J = 245.9 Hz, C, C-18), 153.7,
48.2, 142.1 (C, C-8, C-10, C-12), 137.0 (d, J = 2.9 Hz, C, C-15),
28.9 (d, J = 8.8 Hz, CH, C-16), 115.8 (d, J = 22.0 Hz, CH, C-17),
(5.1 mL) were put into a flame-dried two-necked round-bottomed
=
2
flask. The reaction mixture was cooled to 0 °C, then a solution
of 4-fluorophenylmagnesium bromide (1.0 m in MeTHF; 5.1 mL,
5
complete, the reaction mixture was stirred for 1 h at 0 °C, and then
for 1 h at room temp. Then the mixture was quenched with aqueous
HCl (1 m aq.; 7.3 mL). The aqueous layer was extracted with di-
ethyl ether (3ϫ 28 mL), and the combined organic layers were
dried with magnesium sulfate and concentrated under reduced
pressure. The crude mixture [88:12 dr (trans:cis)] was purified by
column chromatography (pentane/acetone, 94:6) to give 11
.1 mmol, 2.0 equiv.) was added over 3 h. After the addition was
2
(
1
3
5
1
1
1
1
6
3
3
07.9, 105.6 (CH, C-13, C-14), 101.2 (CH
7.4 (CH , C-7), 46.8 (CH , C-2), 44.5 (CH
), 39.4 (CH, C-4), 30.0 (CH
): δ = –115.2 (s, 1 F, F18) ppm. The spectra are consistent
2
, C-11), 97.9 (CH, C-9),
(826 mg, 76%) as a colourless oil, in a mixture with unreacted start-
2
2
2
1
, C-6), 41.7 (CH, C-
ing material 6. The mixture was purified by HPLC (pentane/acet-
one, 94:6) to give trans-11 (722 mg, 66%) as a colourless oil, which
solidified on standing and was recrystallised from pentane, and cis-
9
2
, C-5) ppm. F NMR (282 MHz,
CDCl
with reported data.
3
[20b]
1
1 (46 mg, 4%) as a colourless oil.
Supporting Information (see footnote on the first page of this arti-
cle): General information and experimental procedures; room-tem-
perature NMR spectra of 6, 9, 10, trans-11, and 5·HCl; determi-
nation of product ratios; characterisation of all other compounds;
copies of NMR spectra of all compounds.
Acknowledgments
C. D. would like to thank GlaxoSmithKline and Engineering and
Physical Sciences Research Council (EPSRC) for providing a stu-
dentship from the Doctoral Training Account.
Data for trans diastereoisomer: R
f
(pentane/acetone, 94:6): 0.13,
]DMSO,
m.p. 96.0–97.0 °C (pentane). 1H NMR (400 MHz, [D
6
4340
www.eurjoc.org
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2014, 4335–4341

Total Synthesis of (Ϯ)-Paroxetine
2008, 10, 1389–1391; i) A. Ma, S. Zhu, D. Ma, Tetrahedron
Lett. 2008, 49, 3075–3077; j) Review: C. De Risi, G. Fanton,
G. P. Pollini, C. Trapella, F. Valente, V. Zanirato, Tetrahedron:
Asymmetry 2008, 19, 131–155.
[
1] Recent reviews and perspectives: a) S. Borman, Chem. Eng.
News 2013, 91 (50), p. 27; b) R. Jana, T. P. Pathak, M. S. Sig-
man, Chem. Rev. 2011, 11, 1417–1492; c) G. Cahiez, A.
Moyeux, Chem. Rev. 2010, 110, 1435–1462; d) E. Nakamura,
N. J. Yoshikai, Org. Chem. 2010, 75, 6061–6067; e) A. Rudolph,
M. Lautens, Angew. Chem. Int. Ed. 2009, 48, 2656–2670; An-
gew. Chem. 2009, 121, 2694–2708; f) A. Fürstner, Angew. Chem.
Int. Ed. 2009, 48, 1364–1367; Angew. Chem. 2009, 121, 1390–
[
10] a) N. S. Gunasekara, S. Noble, P. Benfield, Drugs 1998, 55, 85–
1
20; b) A. J. Wagstaff, S. M. Cheer, A. J. Matheson, D. Orm-
rod, K. L. Goa, Drugs 2002, 62, 655–703.
3f]
[
11] a) See ref.[ ; b) K. Bica, P. Gaertner, Org. Lett. 2006, 8, 733–
735; c) M. Nakamura, S. Ito, K. Matsuo, E. Nakamura, Synlett
2
005, 1794–1798; d) A. Guérinot, S. Reymond, J. Cossy, An-
1393; g) W. M. Czaplik, M. Mayer, J. Cvengros, A. Ja-
gew. Chem. Int. Ed. 2007, 46, 6521–6524; Angew. Chem. 2007,
cobi von Wangelin, ChemSusChem 2009, 2, 396–417; h) B. D.
Sherry, A. Fürstner, Acc. Chem. Res. 2008, 41, 1500–1511; i)
C. Gosmini, J.-M. Bégouin, A. Moncomble, Chem. Commun.
119, 6641–6644; e) T. Hatakeyama, N. Nakagawa, M. Naka-
mura, Org. Lett. 2009, 11, 4496–4499; f) T. Hatakeyama, Y.
Okada, Y. Yoshimoto, M. Nakamura, Angew. Chem. Int. Ed.
2008, 3221–3233.
2
011, 50, 10973–10976; Angew. Chem. 2011, 123, 11165–11168;
g) T. Hashimoto, T. Hatakeyama, M. Nakamura, J. Org. Chem.
012, 77, 1168–1173; h) T. Hatakeyama, T. Hashimoto,
[
[
2] B. Plietker, Synlett 2010, 2049–2058.
3] For examples, see: a) M. Nakamura, K. Matsuo, S. Ito, E.
Nakamura, J. Am. Chem. Soc. 2004, 126, 3686–3687; b) H.
Ohmiya, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2006,
2
K. K. A. D. S. Kathriarachchi, T. Zenmyo, H. Seike, M. Naka-
mura, Angew. Chem. Int. Ed. 2012, 51, 8834–8837; Angew.
Chem. 2012, 124, 8964–8967; i) M. Guisan-Ceinos, F. Tato, E.
Bunuel, P. Calle, D. J. Cardenas, Chem. Sci. 2013, 4, 1098–
1104.
1
28, 1886–1889; c) R. B. Bedford, M. Betham, D. W. Bruce,
A. A. Danopoulos, R. M. Frost, M. Hird, J. Org. Chem. 2006,
7
1
1, 1104–1110; d) B. Saito, G. C. Fu, J. Am. Chem. Soc. 2007,
29, 9602–9603; e) P. M. Perez Garcia, T. Di Franco, A. Or-
[12] a) Z. Lu, G. C. Fu, Angew. Chem. Int. Ed. 2010, 49, 6676–6678;
[
7]
sino, P. Ren, X. Hu, Org. Lett. 2012, 14, 4286–4289; f) H.
Ohmiya, H. Yorimitsu, K. Oshima, Org. Lett. 2006, 8, 3093–
Angew. Chem. 2010, 122, 6826–6828 (Ni, Ͼ95:5); b) see ref.
[13] For halocyclohexanes with α-ether substituents, see: a) see
ref.[
12a]
(Ni, Ͼ20:1); b) A. K. Steib, T. Thaler, K. Komeyana,
3
096; g) X. Yu, T. Yang, S. Wang, H. Xu, H. Gong, Org. Lett.
2011, 13, 2138–2141.
P. Mayer, P. Knochel, Angew. Chem. Int. Ed. 2011, 50, 3303–
3307; Angew. Chem. 2011, 123, 3361–3365 (Fe, Ͼ95:5).
[14] a) J. Cossy, Chem. Rec. 2005, 5, 70–80; b) D. O’Hagan, Nat.
Prod. Rep. 2000, 17, 435–446.
[4] G. Cahiez, V. Habiak, C. Duplais, A. Moyeux, Angew. Chem.
Int. Ed. 2007, 46, 4364–4366; Angew. Chem. 2007, 119, 4442–
4444.
[
15] For reviews, see: a) A. Cochi, D. Gomez Pardo, J. Cossy, Eur.
J. Org. Chem. 2013, 809–829; b) M. A. Wijdeven, J. Willemsen,
F. P. J. T. Rutjes, Eur. J. Org. Chem. 2010, 2831–2844; c) S.
Källström, R. Leino, Bioorg. Med. Chem. 2008, 16, 601–635;
d) M. G. P. Buffat, Tetrahedron 2004, 60, 1701–1729; e) P. M.
Weintraub, J. S. Sabol, J. M. Kane, D. R. Borcherding, Tetrahe-
dron 2003, 59, 2953–2989; f) F.-X. Felpin, J. Lebreton, Eur. J.
Org. Chem. 2003, 3693–3712; g) S. Laschat, T. Dickner, Synthe-
sis 2000, 1781–1813.
[
5] a) A. Fürstner, H. Krause, C. W. Lehmann, Angew. Chem. Int.
Ed. 2006, 45, 440–444; Angew. Chem. 2006, 118, 454–458; b)
A. Fürstner, R. Martin, H. Krause, G. Seidel, R. Goddard,
C. W. Lehmann, J. Am. Chem. Soc. 2008, 130, 8773–8787.
6] Early CIDNP (chemically induced dynamic nuclear polariza-
tion) experiments showing iron-catalysed radical formation
from an alkyl halide in the presence of a Grignard reagent: a)
R. B. Allen, R. G. Lawler, H. R. Ward, J. Am. Chem. Soc. 1973,
[
9
1
5, 1692–1693; b) R. G. Lawler, P. Livant, J. Am. Chem. Soc.
976, 98, 3710–3712.
[
16] a) J. Lázár, G. Bernáth, J. Heterocycl. Chem. 1990, 27, 1885–
1
892; b) P. C. Ting, J. F. Lee, J. Wu, S. P. Umland, R. Aslanian,
[
7] Co-catalysed coupling involving trans-2-(1-octynyl)-3-iodo-
tetrahydropyran gave an 86:14 trans/cis selectivity: T. Tsuji, H.
Yorimitsu, K. Oshima, Angew. Chem. Int. Ed. 2002, 41, 4137–
J. Cao, Y. Dong, C. G. Garlisi, E. J. Gilbert, Y. Huang, J. Jak-
way, J. Kelly, Z. Liu, S. McCombie, H. Shah, F. Tian, Y. Wan,
N.-Y. Shih, Bioorg. Med. Chem. Lett. 2005, 15, 1375–1378; c)
K. Soai, H. Oyamada, Synthesis 1984, 605–607.
4139; Angew. Chem. 2002, 114, 4311–4313.
[
[
8] K. Wakabayashi, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc.
[
[
17] T. Nagano, T. Hayashi, Org. Lett. 2004, 6, 1297–1299.
18] a) S. Guelak, A. Jacobi von Wangelin, Angew. Chem. Int. Ed.
2001, 123, 5374–5375.
9] Recent syntheses of paroxetine include, see: a) D. A. Devalan-
2012, 51, 1357–1361; Angew. Chem. 2012, 124, 1386–1390; b)
kar, P. U. Karabal, A. Sudalai, Org. Biomol. Chem. 2013, 11,
A. Fürstner, A. Leitner, M. Méndez, H. Krause, J. Am. Chem.
Soc. 2002, 124, 13856–13863; c) A. Fürstner, A. Leitner, Angew.
Chem. Int. Ed. 2002, 41, 609–612; Angew. Chem. 2002, 114,
632–635.
1
280–1285; b) N. R. Chaubey, S. K. Ghosh, Tetrahedron:
Asymmetry 2012, 23, 1206–1212; c) Z.-T. He, Y.-B. Wei, H.-J.
Yu, C.-Y. Sun, C.-G. Feng, P. Tian, G.-Q. Lin, Tetrahedron
2
ˇ
012, 68, 9186–9191; d) S. Cíhalová, G. Valero, J. Schimer, M.
[
19] L. Nicolas, P. Angibaud, I. Stansfield, P. Bonnet, L. Meerpoel,
S. Reymond, J. Cossy, Angew. Chem. Int. Ed. 2012, 51, 11101–
Humpl, M. Dra cˇ ínský, A. Moyano, R. Rios, J. Vesely, Tetrahe-
dron 2011, 67, 8942–8950; e) S. Somaiah, S. Sashikanth, V.
Raju, K. V. Reddy, Tetrahedron: Asymmetry 2011, 22, 1–3; f)
M.-H. Kim, Y. Park, B.-S. Jeong, H.-G. Park, S.-S. Jew, Org.
Lett. 2010, 12, 2826–2829; g) G. Valero, J. Schimer, I. Cisarova,
J. Vesely, A. Moyano, R. Rios, Tetrahedron Lett. 2009, 50,
1
1104.
20] a) M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2003, 125,
1204–11205; b) J. F. Bower, T. Riis-Johannessen, P. Szeto, A. J.
[
1
Whitehead, T. Gallagher, Chem. Commun. 2007, 728–730.
Received: February 19, 2014
1943–1946; h) P. S. Hynes, P. A. Stupple, D. J. Dixon, Org. Lett.
Published Online: May 27, 2014
Eur. J. Org. Chem. 2014, 4335–4341
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4341