Diastereoselective arylation of enantiopure 3-bromopiperidin-2-one derived from (R)-(-)-2-phenylglycinol with organocuprate reagents

Article abstract of DOI:10.1016/j.tetlet.2011.08.124

The diastereoselective substitution of 3-bromolactam derived from (R)-(-)-2-phenylglycinol with a variety of arylcuprate reagents is presented. The stereochemical outcome of the substitution reaction is discussed. The method provides an efficient and stra

Full text of DOI:10.1016/j.tetlet.2011.08.124

Tetrahedron Letters 52 (2011) 5947–5950
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Diastereoselective arylation of enantiopure 3-bromopiperidin-2-one derived
from (R)-(ꢀ)-2-phenylglycinol with organocuprate reagents
Oscar Romero a, Alejandro Castro b, Joel L. Terán a, Dino Gnecco a, María L. Orea a, Ángel Mendoza a,
Marcos Flores c, Luis F. Roa d, Jorge R. Juárez a,
⇑
a Centro de Química, Benemérita Universidad Autónoma de Puebla, Edif. 103H, Complejo de Ciencias, C.U., 72570 Puebla, Pue., Mexico
b Departamento de Investigación y Posgrado, Universidad Politécnica de Tlaxcala, Av. Universidad Politécnica No. 1, San Pedro Xalcatzinco, 90199 Tepeyanco, Tlax., Mexico
c Facultad de Química, Universidad Nacional Autónoma de México, 04510 México D.F., Mexico
d División Académica de Ciencias Básicas, Universidad Juárez Autónoma de Tabasco, 86690 Cunduacán, Tab., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2011
Revised 20 August 2011
Accepted 22 August 2011
Available online 7 September 2011
The diastereoselective substitution of 3-bromolactam derived from (R)-(ꢀ)-2-phenylglycinol with a vari-
ety of arylcuprate reagents is presented. The stereochemical outcome of the substitution reaction is dis-
cussed. The method provides an efficient and straightforward route to enantiopure 3-arylpiperidines.
Ó 2011 Elsevier Ltd. All rights reserved.
A large number of piperidine-containing compounds, either
natural or synthetic, are biologically and medicinally interesting.1
As a consequence, the development of new methods for the enan-
tioselective synthesis of piperidine derivatives by stereoselective
introduction of substituents at the carbon positions of the hetero-
cycle constitutes an area of current interest.2 In the context of the
enantioselective synthesis of 3-substituted piperidines, the enolate
alkylation of the amide carbonyl of lactams derived from phenyl-
glycinol with alkyl halides takes place with high diastereoselectiv-
ity to ultimately give enantiopure 3-alkylpiperidines in good
yields.3 However, this amide-enolate alkylation method cannot
be extended to aryl halides, as a consequence the stereoselective
Ar
Br
Ar2CuMgX
Reduction
Substitution
reaction
N
N
O
OH
O
OH
Ph
Ph
3-Bromopiperidin-2-one
3-Arylpiperidin-2-ones
R
Ar
N
N
OH
Ph
arylation at the
a-position to the carbonyl group of lactams de-
3-Arylpiperidines
3-PPP analogs
rived from phenylglycinol has been limited by the lack of a suitable
approach.4 In fact, the preparation of enantiopure 3-arylpiperi-
dines derived from phenylglycinol has been achieved through the
condensation of this amino alcohol with a substrate containing
the aromatic ring at the beginning of the synthesis, which involves
that it is required to follow the entire synthesis to accomplish each
derivative.5a,b
Scheme 1. Diastereoselective arylation of an enantiopure 3-bromopiperidin-2-one
with arylcuprate reagents.
Br
Br2, s-BuLi
S
In this communication we present a novel and efficient proce-
dure for the diastereoselective arylation of an enantiopure 3-brom-
opiperidin-2-one derived from (R)-(ꢀ)-2-phenylglycinol, involving
a substitution reaction with arylcuprate reagents. To illustrate the
stereochemical outcome we have prepared enantiopure 3-arylpi-
peridines derived from phenylglycinol, which had been applied
to the synthesis of the alkaloid 3-PPP (Preclamol) and its analogs5
Scheme 1.
N
THF, -80 °C
70%
O
OH
N
O
OH
Ph
Ph
1
2
Scheme 2. Preparation of (10R,3S)-3-bromopiperidin-2-one 2.
the procedure described by Quirion and co-workers.7 Separation of
this mixture by chromatography gave (10R,3S)-3-bromolactam 2 in
70% yield as a single diastereoisomer detectable by 1H NMR
Scheme 2.
Compound 2 was obtained, starting from lactam 1,6 as a epi-
meric mixture of 3-bromopiperidin-2-ones in 95:5 ratio following
The substitution reaction of 3-bromopiperidin-2-one 2 was ini-
tially attempted with phenylmagnesium bromide, as a nucleophile,
⇑
Corresponding author.
E-mail address: jorge.juarez@correo.buap.mx (J.R. Juárez).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.124

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O. Romero et al. / Tetrahedron Letters 52 (2011) 5947–5950
Table 1
Nucleophilic substitution of 3-bromolactam 2
OH
H
S
Br
N
PhMgBr (3 equiv)
R
S
S
H
O
+
Ph
O
N
N
O
OH
N
O
OH
CuX(1.5 equiv)
24 h
OH
Ph
Ph
Ph
2
3
4
Entry Cupper(I)
source
T (°C)
Solvent
[0.05 M]
Ratioa
3:4
Yield 3/
4(%)
1
2
3
0
ꢀ57 to 25 THF
0
0b
4/87
35/53
CuIꢁS(Me)2
ꢀ57 to 25 THF/S(Me)2
5:95
40:60
CuIꢁS(Me)2
ꢀ57 to
ꢀ25
THF/S(Me)2
4
5
6
CuIꢁS(Me)2
CuIꢁS(Me)2
CuI
ꢀ57
THF/S(Me)2
THF/S(Me)2
THFc
70:30
95:5
80:20
60/24
80/2
63/14
c
ꢀ57
ꢀ57
a
Compound 3 was the single diastereoisomer detected by 1H NMR from the
reaction mixture.
b
Only PhMgBr reagent was used as the nucleophile.
The concentration of the reaction was 0.025 M.
c
Figure 1. ORTEP of piperidine 5ꢁHCl.
R
R
additionally stirred at room temperature for 12 h (Table 1, entry
1). However, treatment of lactam 2 with phenylmagnesium bro-
mide and CuIꢁ0.75S(Me)2in THF-S(Me)2 solvent under similar reac-
tion conditions gave the desired product 3-phenylpiperidin-2-one
3 although in poor yield (4%).9 The major product was dimer 4 ob-
tained in 87% yield (entry 2).10 When this arylation reaction was
performed at ꢀ57 °C for 24 h, the ratio of products 3:4 was 70:30
(entry 4). The best result was achieved when the substitution reac-
tion was carried out at ꢀ57 °C for 24 h and the concentration of the
reaction was 0.025 M to avoid the formation of dimer 4. Under
these conditions compound 3 was obtained in 80% yield and the ra-
tio 3:4 was 95:5 (entry 5).
BH3-S(Me)2 (2.6 equiv)
N
N
O
OH
THF, rt, 12 h
quantitative
OH
R
5
Ph
Ph
3
[α]D -72.5 (c 0.8, MeOH)
lit.5b [α]D -70. 7 (c 0.6, MeOH)
Scheme 3. Reduction of compound 3.
in THF at ꢀ57 °C for 12 h.8 Under these reaction conditions, only
starting material was observed, even when the reaction was
Br
PhMgX
N
O
OH
CuI . 0.75S(Me)2
Ph
2
H
Cu
N
XMg
O
Br
Ph
O
Favored
H
Cu
Mg
X
N
Disfavored
XMgO
Br
Ph
XMgO
Conformation
Inversion of configuration
A
B
Conformation
Retention of configuration
N
O
OH
Ph
3
Scheme 4. A proposed mechanism for the nucleophilic substitution of compound 2.

O. Romero et al. / Tetrahedron Letters 52 (2011) 5947–5950
5949
Table 2
Additionally, in order to examine the reactivity of the phenyl-
cuprate reagent in the absence of S(Me)2, lactam 2 was treated
with phenylmagnesium bromide and CuI, as a cooper (I) source,
in THF without S(Me)2 at ꢀ57 °C for 24 h. In this case, compound
3 was achieved in 60% yield and the ratio of compounds 3:4 was
80:20 (entry 6).11
The absolute configuration at the C-3 of piperidin-2-one 3 was
determined by reduction of the lactam carbonyl group to give
the known piperidine 5 (absolute configuration at the piperidine
3-position had previously assigned as R)5b Scheme 3.
Diastereoselective arylation of compound 2 with arylcuprate reagents
Ar
ArMgX (3 equiv)
Br
CuI.0.75S(Me)2 (1.5 equiv)
N
O
THF-S(Me)2 [0.025M]
-57 °C
N
O
OH
Ph
OH
Ph
6a-f
2
3-Arylpiperidin-2-ones
Entry
Ar
Time (h)
Producta
Yield (%)
In addition, compound 5ꢁHCl was crystallized and its X-ray
crystallographic analysis confirmed the (R) configuration at C-312
Figure 1.
OMe
1
2-Methoxyphenyl
3-Methoxyphenyl
36
45c
N
O
The stereochemical outcome of the arylation reaction can be
explained by coordination of the amide oxygen to magnesium atom
of the phenylcuprate reagent in half-chair conformation A or B. In
the conformation A the attack of the phenylcuprate reagent is hin-
dered by the axial hydrogen at the C-3. Whereas, in the conforma-
tion B the delivery of the phenyl group takes place from the same
face of the C–Br bond, affording 3-phenylpiperidone 3 with reten-
tion of the configuration at C-3 Scheme 4.
Following our finding, the efficiency of diastereoselective aryla-
tion of 3-bromopiperidin-2-one 2 with various arylcuprate re-
agents under optimized reaction conditions was investigated. All
results are summarized in Table 2.
It is worth nothing that treatment of lactam 2 with sterically
demanding nucleophiles, such as 2-methoxyphenyl- and 2-tolyl-
cuprate gave the corresponding products in moderate yields (en-
tries 1 and 4). Additionally, less sterically hindered arylcuprate
reagents provided similar yields (entries 2, 3, 5, and 6) than when
employing the phenylcuprate reagent. It is also worth mentioning
that in all cases only the (3R) diastereoisomers were identified by
1H NMR from the crude reaction mixtures.
Finally, compound 6b was employed in the synthesis of the
alkaloid (+)-3-PPP. Thus, treatment of 6b with BH3-S(Me)2 in THF
afforded compound 7 in quantitative yield. The spectroscopic data
of compound 7 are in good agreement with the data reported in the
literature for the (1R,3R) enantiomer.5a Then, starting from 7 and
following the methodology described by Marazano and co-workers
the synthesis of (+)-3-PPP was achieved in two steps in 96% yield5a
Scheme 5.
OH
Ph
Ph
6a
OMe
OMe
2
3
12
12
82b
N
O
OH
6b
4-Methoxyphenyl
85b
N
O
OH
Ph
Ph
Ph
Ph
6c
4
5
6
2-Tolyl
3-Tolyl
4-Tolyl
24
12
12
50c
85b
85b
N
O
OH
6d
N
O
OH
6e
In conclusion, an efficient method for the diastereoselective
arylation of 3-bromopiperidin-2-one derived from (R)-(ꢀ)-2-phe-
nylglycinol with arylcuprate reagents has been developed.
The stereochemical outcome has been studied and we showed
that the nucleophilic substitution occurs with the retention of con-
figuration via a coordinated transition state. Finally, to the best of
our knowledge this is the first example of a nucleophilic substitution
N
O
OH
6f
Onlythe (3R)diastereoisomers 6a–f were observed by 1H-NMR from the crude
a
of an enantiopure
a-bromolactam with an arylcuprate reagent.
reaction mixtures.
b
Ratio product/dimer 4 was 95:5.
In this case, the ratio product/dimer4 was 90:10.
c
Acknowledgments
This work was founded by projects VIEP-BUAP, PROMEP, and
CONACYT CB-2009-01/128747. O.R. and A.C. thank CONACYT for
the doctoral and postdoctoral scholarships, respectively.
OMe
OMe
OH
R
R
R
BH3-S(Me)2(2.6 eq)
Ref. 13
N
O
OH
N
N
THF, rt, 12 h
quantitative
OH
Ph
Ph
6b
7
(+)-3-PPP
Scheme 5. Synthesis of (+)-3-PPP.

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O. Romero et al. / Tetrahedron Letters 52 (2011) 5947–5950
Brewster, A. G.; Broady, S.; Davies, C. E.; Heightman, T. D.; Hermitage, S. A.;
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