Hydrogenative dearomatization of pyridine and an asymmetric aza-Friedel-Crafts alkylation sequence

Article abstract of DOI:10.1002/anie.201309876

Highly efficient synthesis of enantiomerically enriched substituted piperidines has been realized via chiral phosphoric acid catalyzed cascade hydrogenative dearomatization of substituted pyridines and aza-Friedel-Crafts reaction in good to excellent yiel

Full text of DOI:10.1002/anie.201309876

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Angewandte
Communications
DOI: 10.1002/anie.201309876
Asymmetric Catalysis
Hydrogenative Dearomatization of Pyridine and an Asymmetric Aza-
Friedel–Crafts Alkylation Sequence**
Shuo-Guo Wang and Shu-Li You*
Abstract: Highly efficient synthesis of enantiomerically
enriched substituted piperidines has been realized via chiral
phosphoric acid catalyzed cascade hydrogenative dearomati-
zation of substituted pyridines and aza-Friedel-Crafts reaction
in good to excellent yields and enantioselectivity.
omatization of pyridine/asymmetric aza-Friedel–Crafts
sequence (pyrrole as the nucleophile[7]) could provide effi-
cient access to a chiral piperidine scaffold (Scheme 1). It is
noteworthy that the pyrrole core is also a prominent feature
in numerous biologically interesting natural products and
pharmaceuticals. Therefore, the synthesis of compounds with
such embedded motifs is highly desirable.[8]
P
iperidine represents an intriguing scaffold widely distrib-
uted in natural products having significant biological activ-
ities, and therapeutic agents[1] (Figure 1). Therefore, tremen-
dous effort has been devoted to the development of efficient
methods for the synthesis of this privileged structure.[2]
Despite extensive efforts, catalytic asymmetric synthesis of
Scheme 1. The design of a CPA-catalyzed cascade reaction. CPA=chi-
ral phosphoric acid.
Figure 1. Selected natural products and a drug containing a piperidine
motif.
We began our study by choosing 2-phenylpyrrole (3a) and
3-benzoylpyridine (4a) as the model substrates, and subjected
them to the Hantzsch ester 2 with a chiral phosphoric acid as
the catalyst (Table 1). In the presence of 10 mol% (S)-binol-
TRIP (1a) in dichloromethane at room temperature, the
reaction proceeded smoothly to afford the desired product 5a
in 64% yield and 57% ee within 24 hours (entry 1, Table 1).
To increase the enantioselectivity of this cascade reaction,
various chiral phosphoric acids were tested. To our great
delight, when (R)-spinol-TRIP (1j)[9] was employed as the
catalyst, the reaction gave the best enantioselectivity
(entry 10, Table 1).
Further screening of solvents (entries 1–7, Table 2)
revealed that dichloromethane remained the optimal solvent
in terms of enantioselectivity. Interestingly, molecular sieves
significantly accelerated the reaction rate to afford a high
conversion. With 4 ꢀ molecular sieves as an additive and
a prolonged reaction time, the yield increased to 94% without
affecting the enantioselectivity of the reaction (entry 12,
Table 2). Further efforts were made to improve the enantio-
selectivity by lowering the reaction temperature to 08C,
however, the reaction was sluggish under these conditions.
Only 20% yield of 5a, albeit with an improved enantiose-
lectivity (92% ee), could be obtained even with a prolonged
reaction time (entry 14, Table 2).
substituted piperidines by direct functionalization of pyridine
remains scarce. In this regard, catalytic asymmetric nucleo-
philic additions to the pyridinium salts[3] and reduction of
substituted pyridines[4] are frequently utilized strategies.
Asymmetric additions to the pyridinium salts are limited to
the nucleophiles such as cyanide,[3a] alkynes,[3b,c] dialkylzinc,[3d]
and boronic acid.[3e] For direct asymmetric reduction of the
pyridine core, precious metals such as iridium, rhodium,
ruthenium, and palladium are in general required to assure
the efficiency.[4c–i] Meanwhile, organocatalytic enantioselec-
tive transfer hydrogenation of pyridines using a Hantzsch
ester as a hydrogen source has witnessed significant pro-
gress.[5] With our continuing interest in asymmetric dearoma-
tization reactions,[6] we envisaged that a hydrogenative dear-
[*] S.-G. Wang, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: slyou@sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn/
[**] We thank the National Basic Research Program of China (973
Program 2010CB833300), NSFC (21025209, 21121062, 21332009),
and the Chinese Academy of Sciences for generous financial
support.
Under the optimal reaction conditions, the substrate
scope was explored to test the generality of the reaction.
The results are summarized in Table 3. The cascade reaction
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309876.
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Table 1: Screening of chiral phosphoric acid catalysts.
Table 3: Substrate scope for the cascade reaction.
Entry[a]
Ar
R
t [h]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
4-FC6H4
2-ClC6H4
2-FC6H4
3-MeC6H4
Ph
Ph
Ph
Ph
60
72
72
60
60
60
48
72
72
60
60
72
60
72
72
72
72 (5b)
70 (5c)
93 (5d)
95 (5e)
94 (5 f)
74 (5g)
73 (5h)
70 (5i)
91 (5j)
92 (5k)
93 (5l)
93 (5m)
95 (5n)
78 (5o)
94 (5p)
90 (5q)
85
88
87
87
82
89
87
90
86
87
90
89
89
89
96
83
4-MeOC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-naphthyl
4-tBuC6H4
1-naphthyl
4-FC6H4
4-MeOC6H4
4-BrC6H4
4-MeC6H4
3-NO2C6H4
2-thienyl
Me
9
10
11
12
13
14
15
16
Entry[a]
1
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1 f
1g
1h
1i
64
75
85
74
73
85
84
47
90
33
57
13
30
60
4
29
6
23
26
88
Et
[a] Reactions were performed with 3-benzoylpyridine (0.2 mmol),
Hantzsch ester 2 (0.24 mmol), 2-phenylpyrrole (0.24 mmol), 1j
(10 mol%), and 4 ꢀ M.S. (100 mg) in 2 mL CH2Cl2. [b] Yield of isolated
product. [c] Determined by HPLC.
1j
[a] Reactions were performed with 3-benzoylpyridine (0.2 mmol),
Hantzsch ester 2 (0.24 mmol), 2-phenylpyrrole (0.24 mmol),
1 (10 mol%) in 2 mL CH2Cl2. [b] Yield of isolated produt. [c] Determined
by HPLC.
tolerated a wide range of 2-arylpyrroles bearing either an
electron-donating or electron-withdrawing substituent on the
aryl group. The reactions of 3-benzoylpyridine with the 2-
arylpyrroles 3b–f were tested. In all cases, good to excellent
yields and enantioselectivity were achieved (5b–f; Table 3).
In addition, the reactions of various 3-acylpyridines were also
carried out. High yields and enantioselectivity were obtained
for 3-acylpyridines bearing either an electron-rich aryl group
(4-tBuC6H4, 4-MeOC6H4, 4-MeC6H4) or electron-poor aryl
group (4-FC6H4, 4-BrC6H4, 3-NO2C6H4). Moreover, both
naphthalen-2-yl(pyridin-3-yl)methanone and naphthalen-1-
yl(pyridin-3-yl)methanone were suitable substrates for the
cascade reaction (5g and 5i). The substrate 4o with a 2-thienyl
group was also well tolerated, and the corresponding product
was obtained in 78% yield and 89% ee. To our delight, the
asymmetric cascade reaction of 3-acetylpyridine led to the
product in 94% yield and 96% ee (5p). When 3-propionyl-
pyridine was used, the reaction also proceeded smoothly in
90% yield and 83% ee (5q). The absolute configuration of
enantiopure 5l, recrystallized from petroleum ether and
dichloromethane, was confirmed by an X-ray crystallographic
analysis as R.[10]
Regarding the mechanism of this cascade reaction, it is
proposed that the first step is protonation of the pyridine by
the phosphoric acid catalyst to generate the pyridinium salt A
(Scheme 2). Then, the reduction of A by 1,4-hydride transfer
from the Hantzsch ester 2 generates the enamine intermedi-
ate B, which then isomerizes to the iminium C in the presence
of phosphoric acid. Subsequent asymmetric aza-Friedel–
Crafts reaction will generate the desired product and then
release the phosphoric acid.
Table 2: Screening of solvents, additives, and reaction temperature.
Entry[a]
Solvent/additive
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
CH2Cl2
toluene
ClCH2CH2Cl
CH3CN
CHCl3
24
24
24
24
24
24
24
24
24
24
24
36
48
84
33
63
45
15
42
10
53
52
81
52
36
94
95
20
88
77
69
57
67
69
81
89
89
89
88
88
88
92
THF
PhCl
CH2Cl2/3 ꢀ M.S.
CH2Cl2/4 ꢀ M.S.
CH2Cl2/5 ꢀ M.S.
CH2Cl2/MgSO4
CH2Cl2/4 ꢀ M.S.
CH2Cl2/4 ꢀ M.S.
CH2Cl2/4 ꢀ M.S.
9
10
11
12
13
14d
[a] Reactions were performed with 3-benzoylpyridine (0.2 mmol),
Hantzsch ester 2 (0.24 mmol), 2-phenylpyrrole (0.24 mmol), 1j
(10 mol%), and additive (100 mg) in 2 mL solvent at room temperature.
[b] Yield of isolated product. [c] Determined by HPLC. [d] The reaction
was carried out at 08C. M.S.=molecular sieves, THF=tetrahydrofuran.
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2-arylpyrrole 3 (0.24 mmol), and 4 ꢀ M.S. (100 mg) were dissolved in
CH2Cl2 (2 mL). The reaction mixture was stirred at room temper-
ature. After the reaction was complete (as monitored by TLC), the
reaction mixture was quenched with aq. NaHCO3 and extracted with
CH2Cl2. The dichloromethane layer was washed with brine, dried over
Na2SO4, and filtrated. After the solvent was removed under reduced
pressure, the residue was purified by silica gel column chromato-
graphy (acetone/petroleum ether 1:4) to afford product 5.
Received: November 13, 2013
Published online: January 27, 2014
Keywords: asymmetric catalysis · heterocycles ·
.
organocatalysis · reduction · synthetic methods
Scheme 2. Plausible catalytic cycle. HB*=chiral phosphoric acid.
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a nucleophile.
77% ee. Interestingly, in the absence of an additional
nucleophile, the product 6b, containing a dipiperidine frame-
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In summary, we have developed a highly efficient syn-
thesis of enantiomerically enriched substituted piperidines by
the chiral phosphoric acid catalyzed hydrogenative dearoma-
tization /aza-Friedel–Crafts sequence of substituted pyridines
with up to 95% yield and 96% ee. The newly developed
methodology features readily available starting materials and
mild reaction conditions. The results from the current study
provide a new synthetic route for chiral piperidines and novel
concepts in desigining catalytic cascade reactions. Further
applications of this cascade into other transformations are
currently underway in our laboratory.
Experimental Section
In a Schlenk tube, the catalyst (R)-1j (14.3 mg, 0.02 mmol), sub-
stituted pyridine 4 (0.2 mmol), Hantzsch ester 2 (60.7 mg, 0.24 mmol),
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