Catalytic Michael/Ring-Closure Reaction of α,β-Unsaturated Pyrazoleamides with Amidomalonates: Asymmetric Synthesis of (?)-Paroxetine

Article abstract of DOI:10.1002/chem.201603056

A highly enantioselective tandem Michael/ring-closure reaction of α,β-unsaturated pyrazoleamides and amidomalonates has been accomplished in the presence of a chiral N,N′-dioxide–Yb(OTf)₃complex (Tf: trifluoromethanesulfonyl) to give various substituted chiral glutarimides with high yields and diastereo- and enantioselectivities. Moreover, this methodology could be used for gram-scale manipulation and was successfully applied to the synthesis of (?)-paroxetine. Further nonlinear and HRMS studies revealed that the real catalytically active species was a monomeric L-PMe₂–Yb³⁺complex. A plausible transition state was proposed to explain the origin of the asymmetric induction.

Full text of DOI:10.1002/chem.201603056

DOI: 10.1002/chem.201603056
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Asymmetric Catalysis
Catalytic Michael/Ring-Closure Reaction of a,b-Unsaturated
Pyrazoleamides with Amidomalonates: Asymmetric Synthesis of
(À)-Paroxetine
Yu Zhang, Yuting Liao, Xiaohua Liu,* Qian Yao, Yuhang Zhou, Lili Lin, and Xiaoming Feng*[a]
Abstract: A highly enantioselective tandem Michael/ring-clo-
sure reaction of a,b-unsaturated pyrazoleamides and amido-
malonates has been accomplished in the presence of
a chiral N,N’-dioxide–Yb(OTf)3 complex (Tf: trifluoromethane-
sulfonyl) to give various substituted chiral glutarimides with
high yields and diastereo- and enantioselectivities. Moreover,
this methodology could be used for gram-scale manipula-
tion and was successfully applied to the synthesis of (À)-pa-
roxetine. Further nonlinear and HRMS studies revealed that
the real catalytically active species was
a monomeric
L-PMe2–Yb3+ complex. A plausible transition state was pro-
posed to explain the origin of the asymmetric induction.
Introduction
tion (Scheme 1). Although Michael additions of malonates with
a,b-unsaturated aldehydes[6b,c] or nitroalkenes[6d] have been
well reported, a reductive amination cyclization step was re-
quired to construct the lactam structure enantioselectively.
Subsequently, Rios and co-workers used amidomalonate as an
alternative nucleophile that could undergo an intramolecular
hemiaminal formation to form the heterocycle.[6e,f] However,
good results were given in the presence of the unusual solvent
trifluoroethanol, which restricted the reaction’s execution for
scaled-up production. Therefore, the development of a concise
synthetic methodology to form substituted piperidines was in
high demand.
Substituted piperidines are endowed with properties that
make them of interest for biological and medicinal applica-
tions.[1] For instance, the trans-3,4-disubstituted piperidine
(À)-paroxetine (Paxil R) has emerged as a selective serotonin
re-uptake inhibitor for the treatment of depression, anxiety,
and panic disorders (Figure 1).[2] The asymmetric synthesis of
Figure 1. Selected biologically active compounds containing piperidines.
this heterocyclic scaffold has attracted significant interest for
a long time.[3] Several catalytic enantioselective synthetic meth-
ods have been developed, such as allylic alkylation,[4] hydroge-
nation,[5] and Michael addition.[6] Among them, Michael addi-
tion is an efficient and straightforward technique with the ad-
vantage of accessible starting materials and convenient opera-
[a] Y. Zhang, Y. Liao, Prof. Dr. X. Liu, Q. Yao, Y. Zhou, Dr. L. Lin,
Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology, Ministry of Education
College of Chemistry, Sichuan University
Chengdu 610064 (P.R. China)
Fax: (+86)2885418249
E-mail: liuxh@scu.edu.cn
xmfeng@scu.edu.cn
Scheme 1. Catalytic asymmetric reactions for the synthesis of (À)-paroxetine.
PG: protecting group; LG: leaving group; EWG: electron-withdrawing group;
TMS: trimethylsilyl; Tf: trifluoromethanesulfonyl.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201603056.
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a,b-Unsaturated pyrazoleamides are useful Michael accept-
ors, in which the pyrazole unit could act as both a good direct-
ing group and a leaving group.[7] In the light of the advance of
in situ cyclization of a,b-unsaturated amides,[8] we reasoned
that the catalytic asymmetric reaction between a,b-unsaturat-
ed pyrazoleamides and amidomalonates would provide
a straightforward access to the piperidine-2,6-dione backbone,
a key intermediate for (À)-paroxetine and its analogues (+)-fe-
moxetine and roche-1 as well. Here, we report a diastereo- and
enantioselective Michael/ring-closure reaction of a,b-unsaturat-
ed pyrazoleamides with amidomalonates. The reaction per-
formed well in the presence of a chiral N,N’-dioxide–Yb(OTf)3
complex (Tf: trifluoromethanesulfonyl)[9] to furnish a wide
range of chiral glutarimides in high yields and diastereo- and
enantioselectivities (up to 99% yield, >95:5 d.r., 98% ee).
(À)-Paroxetine could be obtained in 66% overall yield and
98% ee through a four-step transformation.
albeit with a lower yield (Table 1, entry 2). The yield was slight-
ly improved when the amount of Et3N was increased (Table 1,
entry 3). Next, a detailed screening of chiral N,N’-dioxide li-
gands revealed that L-PiMe2 could provide a comparable out-
come of 22% yield and 97% ee (Table 1, entries 4–7). In order
to improve the reaction yield, the modulation of other reaction
parameters, including by fixing the ratio of metal/L-PiMe2, by
adding 3 ꢁ molecular sieves, by raising the temperature, and
by increasing the concentration, clearly improved the reactivity
without erosion of the diastereo- and enantioselectivity
(Table 1, entries 8 and 9). Finally, product 3aa was isolated in
90% yield, 96:4 d.r., and 98% ee. Moreover, a change of the
solvent to ClCH2CH2Cl had no obvious effect on the result
(Table 1, entry 10). We therefore chose these reaction condi-
tions (Table 1, entry 9) for further studies.
We next explored the scope of amidomalonates that could
participate in this transformation (Table 2). N-Benzyl-substitut-
ed ones also afforded the corresponding glutarimides in excel-
lent yields (89–93%) and enantioselectivities (94–98% ee).
Results and Discussion
We selected the addition reaction of a,b-unsaturated pyra-
zoleamide 1a and ethyl-N-methylmalonamide 2a as a model
reaction to optimize the reaction conditions, as summarized in
Table 1. A preliminary study showed that lanthanide metal
salts in combination with the chiral N,N’-dioxide L-PiEt2Me
were effective to promote the transformation to generate the
desired trans-3,4-disubstituted glutarimide 3aa (Table 1, en-
tries 1 and 2). Yb(OTf)3 gave a result of 96% ee and 94:6 d.r.,
Table 2. Substrate scope of the amidomalonates 2.[a]
Table 1. Optimization of the reaction conditions.[a]
[a] Reaction conditions: The same as in Table 1, entry 9. [b] Determined
after derivation (see the Supporting Information).
Variation in the size of the ester group did not affect the out-
come. Notably, product 3ae, which could be further trans-
formed into (À)-paroxetine, was generated with good results
under the optimal reaction conditions. The reaction was also
tolerable on a gram scale, and 80% yield, 94:6 d.r., and 97%
ee were obtained. With consideration of the ease for industrial
manipulation, this gram-scale transformation also proceeded
smoothly if ClCH2CH2Cl was used instead of CH2Cl2, to provide
the corresponding product 3aa in 90% yield, 96:4 d.r., and
97% ee (Scheme 2).
Entry
Ligand
Metal salt
Yield [%][b]
d.r.[c]
ee [%][d]
1[e]
2[e]
3
4
5
6
7
8[f]
9[f,g]
10[f,h]
L-PiEt2Me
L-PiEt2Me
L-PiEt2Me
L-PiPr2
La(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
24
10
21
27
22
22
10
36
90
90
94/6
94/6
95/5
95/5
92/8
95/5
93/7
95/5
96/4
96/4
89
96
96
80
94
97
89
97
98
97
L-PiEt2
L-PiMe2
L-PrMe2
L-PiMe2
L-PiMe2
L-PiMe2
The generality of the a,b-unsaturated pyrazoleamides was
then tested (Table 3). A b-aryl group bearing electron-with-
drawing or -donating substituents at various positions could
be tolerated in the reaction, and the related products were iso-
lated in 87–99% yields with 93–97% ee (Table 3, entries 1–11).
The diastereoselectivity dropped a little when substrates bear-
ing a 2-substituted aryl group were used (Table 3, entries 7 and
8). Moreover, if a,b-unsaturated pyrazoleamides containing
fused ring, heteroaromatic, or alkyl groups at the b position
were employed in the transformation, the catalyst could pro-
[a] Unless otherwise noted, the reactions were carried out with 1a
(0.2 mmol), 2a (0.3 mmol), L/metal salt (1:1.2, 10 mol%), and Et3N
(1.0 equiv) in CH2Cl2 (1.0 mL) at 358C for 3 d. [b] Yield of isolated product.
[c] Determined by 1H NMR spectroscopic analysis. [d] Determined by chiral
HPLC analysis after flash column chromatography purification. [e] Et3N
(0.2 equiv). [f] At 408C. [g] L/metal salt (1:1, 10 mol%), 3 ꢁ molecular sieves
(40 mg) in CH2Cl2 (0.4 mL). [h] L/metal salt (1:1, 10 mol%), 3 ꢁ molecular
sieves (40 mg) in ClCH2CH2Cl (0.4 mL).
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To show the synthetic utility of current catalyst system, the
synthesis of (À)-paroxetine was performed from the piperi-
dine-2,6-dione product 3ae, in accordance with to a previous
report.[3b] Initially, the reduction of 3ae with LiAlH4 followed by
methanesulfonylation provided the intermediate mesylate. In-
stallation of the seamol fragment gave the N-Bn product 6ae
in 68% overall yield. Finally, the target compound was ob-
tained in nearly quantitative yield after removal of the benzyl
group by hydrogenation. Thus, (À)-paroxetine could be effi-
ciently attained in 66% total yield with >95/5 d.r. and 98% ee
in four steps (Scheme 3a). (+)-Femoxetine and roche-1 possess
Scheme 2. Experimental procedure for the scale-up reactions.
Table 3. Substrate scope for the a,b-unsaturated pyrazoleamides 1.[a]
Entry
R3
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
4-ClC6H4
4-BrC6H4
4-F3CC6H4
4-NCC6H4
4-MeC6H4
4-MeOC6H4
2-BrC6H4
2-MeOC6H4
3-MeC6H4
3,4-Cl2C6H3
Ph
99 (3bb)
99 (3cb)
96 (3db)
98 (3eb)
97 (3 fb)
90 (3gb)
87 (3hb)
96 (3ib)
97 (3jb)
97 (3kb)
97 (3lb)
94 (3mb)
58 (3nb)
75 (3ob)
>95/5
>95/5
95/5
>95/5
95/5
>95/5
85/15
85/15
91/9
92/8
91/9
91/9
92/8
97
97
95
96
97
96
94
95
94
93
96
90
85
91[e]
9
10
11
12
13
14
Scheme 3. The application of the catalytic asymmetric reaction for the syn-
thesis of (À)-paroxetine, (+)-femoxetine, and roche-1. Ms: methanesulfonyl.
2-naphthyl
2-thienyl
2-furyl
89/11
the opposite enantiomeric configuration to (À)-paroxetine and
also exhibit very important pharmaceutical activities.[11] For in-
stance, (+)-femoxetine is used in the treatment of depression,
obsessive-compulsive disorder, and panic attacks. The synthesis
of the corresponding trans-piperidine core structures was car-
ried out by the use of the chiral N,N’-dioxide ent-PiMe2, pre-
pared from d-pipecolic acid. The reactions of a,b-unsaturated
pyrazoleamide 1l and 1b with ethyl-N-methylmalonamide 2a
were successful and afforded the related glutarimides ent-3la
and ent-3ba in good yields and excellent diastereo- and enan-
tioselectivities (97 and 98% ee, respectively; Scheme 3b and
3c). The intermediates could undergo similar transformations
to those described for (À)-paroxetine to synthesize (+)-femox-
etine and roche-1.
15
16
78 (3pb)
67 (3qb)
77/23
88/12
89
92
17
51 (3rb)
99 (3cb)
89/11
95/5
86
88
18[f]
4-BrC6H4
[a] Reaction conditions: The same as Table 1, entry 9. [b] Yield of isolated
product. [c] Determined by 1H NMR spectroscopic analysis. [d] Deter-
mined by chiral HPLC analysis after flash column chromatography purifi-
cation. [e] Determined from a derivative of 3ob (see the Supporting Infor-
mation). [f] 1s was used as the starting material.
duce the corresponding products with moderate to good
yields and stereoselectivities (Table 3, entries 12–15). The cata-
lyst was also suitable for a,b,g,d-unsaturated pyrazoleamides
1q and 1r, bearing a conjugated alkene substituent, and gen-
erated only the 1,4-addition/cyclization products in moderate
yields with good diastereo- and enantioselectivities (Table 3,
entries 16 and 17). The pyrazole substituent obviously affected
the enantioselectivity, and the ee value decreased to 88% if an
unsubstituted pyrazole group was introduced into the sub-
strate (Table 3, entry 18). The absolute configuration of the
major isomer of the product 3aa was unambiguously estab-
lished as 3S,4R, in accordance with the previous report.[10]
For further understanding of the reaction process, the rela-
tionship between the ee values of ligand L-PiMe2 and product
3aa was explored.[12] A nonlinear effect was not observed,
which suggests that L-PiMe2 coordinated with the Yb3+ ions in
a 1:1 ratio (Figure 2). Additionally, this could be verified
through HRMS experiments, in which ESI-MS species assigned
to [L-PiPr2+Yb3++ÀOTf]2+ (m/z 429.6121) were detected from
the mixture of the catalyst system (see the Supporting Infor-
mation). Operand IR experiments were also carried out. As the
peaks at n˜ =1381 and 1728 cmÀ1, which are related to the sub-
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nates to the Yb3+ ion in a bidentate manner. Malonamide 2a
attacks the Re face of pyrazoleamide 1a because the Si face is
shielded by the neighboring 2,6-dimethylphenyl group on
ligand L-PiMe2. Thereby, (3S,4R)-3aa is obtained with simulta-
neous liberation of the catalyst.
Conclusions
In summary, we have described a highly enantioselective Mi-
chael addition with one-step ring closure of a,b-unsaturated
pyrazoleamides and amidomalonates catalyzed by a chiral
N,N’-dioxide–Yb(OTf)3 complex. The desired glutarimides with
C3 and C4 chiral centers were afforded with high enantioselec-
tivities and reactivity (up to 98% ee and 99% yield). This new
procedure has been successfully applied to the enantioselec-
tive synthesis of the antidepressant drug (À)-paroxetine. The
application of the N,N’-dioxide/metal catalyst system in the
synthesis of other pharmaceuticals was also explored.
Figure 2. Exploration of the nonlinear effect on the catalytic asymmetric
tandem Michael/ring-closure reaction of 1a with 2a.
strates, gradually decreased in intensity, the peak of the Mi-
chael/ring-closure product 3ba at n˜ =1678 cmÀ1 increased
(Figure 3). No additional peaks related to Michael addition in-
termediates were detected, which indicated that the rate of
the ring-closure step was faster than that of the Michael addi-
tion step. This result implied that the Michael addition step
might be the rate-determining step.
Experimental Section
General procedure for the preparation a,b-unsaturated pyr-
azoleamides
All of the a,b-unsaturated pyrazoleamides were prepared by similar
procedures to those in the literature.[7]
Based on our previous work and the absolute configuration
of the product 3aa, a transition state was proposed to ration-
alize the stereoinduction (Figure 4). In the proposed model,
both the N,N’-dioxide and amide oxygen atoms of L-PiMe2 co-
ordinate to the Yb3+ ion in a tetradentate manner to form two
six-membered chelate rings. Pyrazoleamide 1a then coordi-
General procedure for the preparation of amidomalonates
A mixture of amine (25 mmol) and 4 ꢁ molecular sieves (2.00 g)
was dropwise added to a solution of dialkylmalonate (50 mmol) in
toluene (30 mL) at room temperature. After the reaction mixture
had been heated to reflux for 5 h, the resultant suspension was fil-
tered and concentrated in vacuo. The crude product was purified
by flash column chromatography to afford the desired product.
General procedure for the catalytic asymmetric reactions
Yb(OTf)3 (12.4 mg, 0.02 mmol), L-PiMe2 (10.7 mg, 0.02 mmol), 3 ꢁ
molecular sieves (40.0 mg), a,b-unsaturated pyrazoleamide
(0.20 mmol), and CH2Cl2 (0.4 mL) were added to an oven-dried re-
action tube under a nitrogen atmosphere. After the mixture had
been stirred for 30 min at 358C, amidomalonates (0.30 mmol) and
Et3N (28.0 mL, 0.2 mmol) were subsequently added. The reaction
mixture was stirred at 408C for 72 h and directly purified by flash
column chromatography (ethyl acetate/petroleum ether, 1:6–1:2)
to afford the desired product.
Figure 3. Operando IR experiments.
Typical characterization of 3aa: White solid; m.p. 112–1158C; 90%
1
yield; 96:4 d.r. by H NMR spectroscopy; 98% ee; [a]1D4 =À55.7 (c=
0.56 in CH2Cl2); HPLC: DAICEL CHIRALCEL ADH column, n-hexane/
2-propanol=80/20, flow rate=1.0 mLminÀ1
,
l=210 nm, tR
(major)=11.77 min, tR (minor)=18.90 min; 1H NMR (400 MHz,
CDCl3): d=7.24–7.16 (m, 2H), 7.09–7.00 (m, 2H), 4.19–4.02 (m, 2H),
3.83–3.74 (m,1H), 3.73–3.62 (m, 1H), 3.21 (s, 3H), 3.06–2.96 (m,
1H), 2.87–2.76 (m, 1H), 1.11 ppm (t, J=7.2 Hz, 3H); 13C NMR
(101 MHz, CDCl3): d=170.4, 168.6, 167.6, 162.3 (d, J=248.2 Hz),
134.5 (d, J=3.2 Hz), 128.6 (d, J=8.3 Hz), 116.2 (d, J=21.6 Hz), 61.9,
56.4, 38.9, 37.7, 27.0, 13.9 ppm; HRMS (ESI-TOF): m/z calcd for
C15H16FNO4Na+ [M+Na+]: 316.0956; found: 316.0965.
Figure 4. Plausible transition state for the reaction.
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tR (minor)=8.05 min, tR (major)=8.97 min; 1H NMR (400 MHz,
CDCl3): d=7.19–7.09 (m, 2H), 7.00–6.91 (m, 2H), 6.60 (d, J=8.4 Hz,
1H), 6.32 (d, J=2.0 Hz, 1H), 6.10 (dd, J=8.4, 2.0 Hz, 1H), 5.84 (s,
2H), 3.54 (dd, J=9.2, 2.0 Hz, 1H), 3.48–3.32 (m, 2H), 3.18–3.10 (m,
1H), 2.83–2.49 (m, 3H), 2.09–1.98 (m, 1H), 1.83–1.75 (m, 1H), 1.74–
1.65 (m, 1H), 1.64–1.49 ppm (m, 1H); 13C NMR (101 MHz, CDCl3):
d=161.4 (d, J=245.2 Hz), 154.4, 148.1, 141.5, 140.0 (d, J=3.2 Hz),
128.8 (d, J=7.8 Hz), 115.4 (d, J=21.1 Hz), 107.8, 105.5, 101.0, 97.9,
69.5, 50.4, 47.1, 44.6, 43.0, 35.4 ppm; HRMS (ESI-TOF): m/z calcd for
C19H20FNO3Na+ [M
Synthesis of (À)-paroxetine
See ref. [3c] for a previous synthesis of (À)-paroxetine in the litera-
ture.
(3S,4R)-[1-Benzyl-4-(4-fluorophenyl)piperidin-3-yl]-methanol
(4ae): Lithium aluminum hydride (228 mg, 6.0 mmol) was added
to a mixture of tetrahydrofuran (6.0 mL) at 08C and stirred for
15 min. A solution of 3ae (397 mg, 1.0 mmol) in tetrahydrofuran
(3.0 mL) was added slowly with a syringe, over 5 min. The mixture
was warmed up to 608C and continuously stirred for 4 h. After re-
action completion, the resulting solution was cooled to 08C,
quenched with EtOAc (20 mL) and H2O (0.52 mL), and stirred for
a further 20 min. The resulting colorless suspension was filtered
through Celiteꢂ and washed with CH2Cl2 (40 mL). The organic por-
tions were dried with Na2SO4 and concentrated in vacuo to afford
the alcohol as a colorless oil. This material was directly used in the
next stage without further purification.
Na+]: 352.1319; found: 352.1319.
Acknowledgements
We thank the National Natural Science Foundation of China
(nos. 21372162, 21432006, and 21321061) for financial support.
(À)-N-Benzylparoxetine (6ae): Et3N (0.21 mL, 1.5 mmol) and MsCl
(0.11 mL, 1.5 mmol) were added sequentially, with a syringe, to an
ice-cooled (08C) solution of the crude alcohol in anhydrous CH2Cl2
(4.0 mL), which resulted in the immediate formation of a colorless
precipitate. The mixture was stirred at room temperature for
20 min, diluted with water (30 mL) and saturated aqueous NaHCO3
(50 mL), and extracted with CH2Cl2 (3ꢃ40 mL). The combined or-
ganic portions were dried with Na2SO4 and concentrated in vacuo
to afford the mesylate as a yellow solid. NaH (60% dispersion in
mineral oil, 80 mg, 2.0 mmol) was added to a solution of seamol
(277 mg, 2.0 mmol) in anhydrous DMF (4.0 mL), and the resulting
mixture was stirred at room temperature for 20 min. The mesylate
in DMF (6.0 mL) was then added, and the mixture was heated at
908C for 15 h. The mixture was then cooled to room temperature,
diluted with EtOAc (100 mL), and washed sequentially with water
(50 mL), aqueous 1m NaOH (2ꢃ50 mL), and brine (50 mL). The or-
ganic portion was dried (Na2SO4) and concentrated in vacuo to
afford a residue (d.r.=90/10 and the isomers were separable),
which was purified by flash column chromatography (ethyl ace-
tate/petroleum ether, 1:6) to separate the major isomer N-benzyl-
paroxetine (6ae; 286 mg, 68% yield for 3 steps) as a pale yellow
Keywords: asymmetric synthesis
reactions · paroxetine · ring-closure reactions
· heterocycles · Michael
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1
oil; H NMR (400 MHz, CDCl3): d=7.27–7.18 (m, 4H), 7.16–7.11 (m,
1H), 7.06–2.99 (m, 2H), 6.88–6.76 (m, 2H), 6.48 (d, J=8.4 Hz, 1H),
6.21 (d, J=2.4 Hz, 1H), 5.98 (dd, J=8.4, 2.4 Hz, 1H), 5.70 (s, 2H),
3.52 (d, J=13.2 Hz, 1H), 3.46–3.36 (m, 2H), 3.35–3.27 (m, 1H),
3.18–3.08 (m, 1H), 2.91–2.81 (m, 1H), 2.45–2.26 (m, 1H), 2.16–2.03
(m, 1H), 2.02–1.89 (m, 2H), 1.80–1.60 ppm (m, 2H); 13C NMR
(101 MHz, CDCl3): d=161.6 (d, J=245.0 Hz), 154.4, 148.2, 141.6,
139.9 (d, J=3.1 Hz), 138.3, 129.3, 128.9 (d, J=7.7 Hz), 128.3, 127.1,
115.4 (d, J=21.1 Hz), 107.9, 105.6, 101.1, 98.0, 69.6, 63.4, 57.6, 53.8,
44.1, 42.2, 34.4 ppm; HRMS (ESI-TOF): m/z calcd for C26H26FNO3Na+
[M+Na+]: 442.1789; found: 442.1789.
(À)-Paroxetine: A suspension of 10% Pd/C (50 mg) and N-benzyl-
paroxetine (6ae; 150 mg, 0.36 mmol) in AcOH (1.4 mL) and iPrOH
(3.5 mL) was sealed inside a hydrogenation bomb. The vessel was
purged with hydrogen (6 purge cycles at 6 bar) and heated at
508C for 15 h. The mixture was cooled to room temperature and
then depressurized, filtered through Celiteꢂ, washed with AcOH
(20 mL), MeOH (20 mL), and CH2Cl2 (20 mL), and concentrated in
vacuo to afford a colorless oil. It was dissolved in saturated aque-
ous Na2CO3 solution (20 mL) and extracted with CH2Cl2 (3ꢃ25 mL).
The organic extracts were dried (Na2SO4) and concentrated in
vacuo to afford the free amine (115 mg, 97% yield) as a colorless
ˇ
ˇ
´
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1
oil; >95:5 d.r. by H NMR spectroscopy; 98% ee; [a]2D3 =À77.5 (c=
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Received: June 27, 2016
Published online on && &&, 0000
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FULL PAPER
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Asymmetric Catalysis
Y. Zhang, Y. Liao, X. Liu,* Q. Yao, Y. Zhou,
L. Lin, X. Feng*
&& – &&
Catalytic Michael/Ring-Closure
Reaction of a,b-Unsaturated
Pyrazoleamides with
Amidomalonates: Asymmetric
Synthesis of (À)-Paroxetine
Tandem heterocycle formation: A
tandem Michael/ring-closure reaction of
a,b-unsaturated pyrazoleamides and
amidomalonates has been accom-
plished in the presence of a chiral N,N’-
dioxide–Yb(OTf)3 complex to give the
chiral glutarimides with high yields and
diastereo- and enantioselectivities (see
scheme: Tf=trifluoromethanesulfonyl;
M.S.=molecular sieves). The methodol-
ogy was successfully applied to the syn-
thesis of (À)-paroxetine.
Chem. Eur. J. 2016, 22, 1 – 7
www.chemeurj.org
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ