Highly enantioselective [4+2] annulation via organocatalytic Mannich-reductive cyclization: One-pot synthesis of functionalized piperidines

Article abstract of DOI:10.1039/c3cc42431f

A new method for one-pot synthesis of 2,3-substituted piperidine from N-PMP aldimine and aqueous glutaraldehyde via formal [4+2] cycloaddition is reported. This reaction involves organocatalytic direct Mannich reaction-reductive cyclization with high yields (up to 90%) and excellent enantioselectivities (up to >99%). The practicability of this method is also shown at a gram scale as well as through the synthesis of functionalized (-)-anabasine.

Full text of DOI:10.1039/c3cc42431f

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Highly enantioselective [4+2] annulation via
organocatalytic Mannich-reductive cyclization:
Cite this: DOI: 10.1039/c3cc42431f
one-pot synthesis of functionalized piperidines†
Indresh Kumar,*a Panduga Ramaraju,a Nisar A. Mir,a Deepika Singh,b
Vivek K. Guptac and Rajnikantc
Received 5th April 2013,
Accepted 3rd May 2013
DOI: 10.1039/c3cc42431f
www.rsc.org/chemcomm
A new method for one-pot synthesis of 2,3-substituted piperidine
from N-PMP aldimine and aqueous glutaraldehyde via formal [4+2]
cycloaddition is reported. This reaction involves organocatalytic
direct Mannich reaction–reductive cyclization with high yields (up
to 90%) and excellent enantioselectivities (up to >99%). The
practicability of this method is also shown at a gram scale as well
as through the synthesis of functionalized (À)-anabasine.
Functionalized saturated piperidines are increasingly common
scaffolds widely distributed in a number of biologically active
natural and synthetic compounds.1 Among several known efforts,
cycloaddition reactions are the most efficient methods for the
synthesis of a cyclic ring system, because of their atom-economy.2
Notably, [4+2] cycloaddition–annulation reactions such as (i) imino-
Diels–Alder reaction,3 and (ii) phosphine catalyzed in situ generated
1,4-carbon dipole and a subsequent reaction with imines4 are the
important methods to synthesize piperidines. Despite high utility,
more strictly, these two methods gave only direct access to tetra-
hydropyridines instead of piperidines. On the other hand, comple-
mentary [4+2] annulation of suitable all-carbon 1,4-dipoles with
imines to synthesize piperidines directly has not been studied
extensively due to the unavailability of suitable 1,4-dipoles. To
the best of our knowledge, the only report on in situ generation
of 1,4-carbon dipole via the metal-catalyzed decarboxylative ring-
opening of g-methylidene-d-valerolactones and subsequent [4+2]
annulation with imines to synthesize 2,3-substituted piperidines
in a non-asymmetric fashion was developed by Prof. T. Hayashi’s
group in 2009 (eqn (1), Scheme 1).5 Hence, the development of a
catalytic asymmetric method for 2,3-substituted piperidines through
Scheme 1 1,4-Carbon donor–acceptor approach with imine as formal [4+2]
cycloaddition for piperidines.
1,4-carbon donor–acceptor annulation with imines, from simple and
easily available materials, is still in very high demand. Additionally,
a 2,3-substituted piperidine skeleton present in a number of
compounds having biological significance (Fig. 1), though lengthy,
and limited methods are available for the synthesis of this ring
system.6
The last few years have witnessed the impressive growth of the
organocatalytic cascade or tandem transformations, which are now
considered to be the most effective ways to design new catalytic
asymmetric synthetic routes.7 Recently, a number of attractive
organocatalytic cascade approaches have been reported by different
groups to synthesize optically enriched piperidines.8 Herein, we
report a proficient one-pot organocatalytic Mannich-reductive
a Department of Chemistry, Birla Institute of Technology and Science,
Pilani 333 031, Rajasthan, India. E-mail: indresh.chemistry@gmail.com,
indresh.kumar@pilani.bits-pilani.ac.in; Fax: +91 1596 244183;
Tel: +91 1596 515707
b Instrumentation Division, IIIM-CSIR Lab, Jammu 180 001, India
c X-ray Crystallography Laboratory, Post-Graduate Department of Physics &
Electronics, University of Jammu, Jammu 180 006, India
† Electronic supplementary information (ESI) available: CCDC 930264 (7t). For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc42431f
Fig. 1 Representative examples of bioactive 2,3-substituted piperidines.
c
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cyclization sequence for the asymmetric synthesis of 2,3-substituted reaction temperature (entry 13, Table 1) and catalyst loading
piperidines from imines and aqueous glutaraldehyde 5 (eqn (2), (entry 14, Table 1) led to the prolonged reaction with reduced
Scheme 1). Although glutaraldehyde 5 has been used earlier for yields. Thus, we preferred to perform this one-pot cascade
N-substituted piperidine synthesis9 it has recently been employed sequence with optimized conditions (entry 12, Table 1).
in several other organocatalytic transformations.10
With the optimal conditions in hand, we further explored the
In continuation of our interests in nitrogen heterocyclic com- scope of the proline 1 catalyzed asymmetric [4+2] annulation
pounds,11 we have recently presented the organocatalytic [3+2] reaction with regard to a variety of preformed N-PMP aldimines 6
annulation between succinaldehyde and N-PMP aldimines for the and the results are summarized in Table 2. In general, all the N-PMP
synthesis of substituted pyrrolidines and pyrroles.12 Here, we antici- aldimines derived from corresponding aromatic aldehydes worked
pated that glutaraldehyde 5, a synthetically useful 1,5-dicarbonyl well and provided a series of 2,3-substituted piperidines 7 in
compound, could be explored as an in situ 1,4-carbon donor–acceptor moderate to high yields (up to 90%) with high diastereo- (>25 : 1)
precursor with imines 6 to synthesize piperidines. This reaction and excellent enantioselectivities (up to >99% ee) under optimized
involves a proline catalyzed direct Mannich reaction and acid conditions (Table 2). In the case of electron-deficient aryl-imines,
catalyzed intramolecular reductive cyclization as one pot formal reactions proceeded very well (entries 1–14, Table 2), however the
[4+2] cycloaddition. The screening of catalysts, solvents, and reactions were rather slow in the case of imines preformed from
temperature with N-PMP aldimine 6c as a model substrate was 2-substituted aldehydes (entries 1, 4, 7, and 10, Table 2) and
investigated and is summarized in Table 1.
naphthaldehydes (entries 16 and 17, Table 2) leading to lower
Our initial experimentations showed that among the amine yields, possibly because of the steric crowding. In addition,
catalysts that were screened (entries 1–4, Table 1), proline 1 efficiently imines derived from hetero-aromatic aldehydes also resulted in the
catalyzed the direct Mannich reaction of aqueous glutaraldehyde 5 corresponding products in good yields and enantioselectivities
(25% sol.) with imine 6c, which on acid catalyzed reductive cycliza- (entries 18–22, Table 2). In the case of an alkenyl imine 6w,
tion afforded substituted piperidine 7c with good yield and selectivity derived from a-b-unsaturated aldehyde, the reaction proceeded
(entry 1, Table 1). Solvent screening (entries 5–11, Table 1) with good yields and low enantioselectivity (entry 23, Table 2).
revealed that polar aprotic solvents were optimal for this one- A clean transformation to highly functionalized 7x was observed
pot transformation and particularly DMSO was preferred as
the solvent. Gratifyingly, enhancement in the yield (90%) and
enantioselectivity (98%) was observed, when the reaction was
Table 2 Generality of formal [4+2] cycloaddition for piperidine synthesis
carried out at 10 1C (entry 12, Table 1). Further decreasing the
Table 1 Optimization of reaction conditionsa
Entrya
R
Timeb (h)
7
Yieldc (%) drd
eee
1
2
3
4
5
6
7
8
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
2-FC6H4
3-FC6H4
4-FC6H4
9
8
6
9
8
8
9
8
8
10
9
9
8
8
9
9
9
8
9
8
9
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
72
81
90
79
83
80
69
80
79
68
75
81
>25 : 1 >99
>25 : 1 >99
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
n.d.
98
92
91
75
96
89
88
96
97
90
92
97
73
81
94
80
81
90
80
68
68
99
n.d.
n.d.
2-Cl-C6H4
3-ClC6H3
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
3-Br-4-FC6H3
4-CNC6H4
Ph
1-Naphthyl
2-Naphthyl
2-Pyridyl
3-Pyridyl
4-Pyridyl
4-Thiophene
4-Furan
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24 f
25
26g
7j
7k
7l
Entry
Cat.
Conditionsa
Yieldb (%)
drc
eed (%)
7m 62
1
2
3
4
5
6
7
8
1
2
3
4
1
1
1
1
1
1
1
1
1
1
DMSO, rt, 4 h
DMSO, rt, 5 h
DMSO, rt, 7 h
DMSO, rt, 10 h
Toluene, rt, 12 h
CH3CN, rt, 8 h
THF, rt, 7 h
CH2Cl2, rt, 12 h
1,4-Dioxane, rt, 10 h
DMF, rt, 6 h
81
72
65
n.r.
n.r.
58
40
n.r.
46
71
65
>20 : 1
>20 : 1
>20 : 1
n.d.
94
93
82
n.d.
n.d.
90
85
n.d.
88
92
95
98
98
7n
7o
7p
7q
7r
7s
7t
7u
7v
7w 61
7x
7y
7z
82
61
58
64
72
65
81
72
63
n.d.
10 : 1
10 : 1
n.d.
10 : 1
>20 : 1
>20 : 1
>25 : 1
>25 : 1
>25 : 1
9
10
11
12
13
14e
(E)-CHCHC6H4 10
CO2Et
4-Ome-C6H4
Me
6
20
20
90
n.r.
n.r.
NMP, rt, 5 h
DMSO, 10 8C, 6 h
DMSO, 5 1C, 10 h
DMSO, 10 1C, 9 h
90
75
68
n.d.
96
a
(i) Imine 6 (0.3 mmol), 5 (25% aqueous sol., 0.9 mmol), 1 (20 mol%),
a
b
(i) Imine 6c (0.3 mmol), 5 (25% aqueous sol., 0.9 mmol), catalyst DMSO (3.0 mL), (ii) H2O (2.0 mL). Time for the Mannich reaction
b
c
d
(20 mol%), solvent (3.0 mL) (ii) H2O (2.0 mL). Isolated yield refer to 7c catalyzed by 1 (20 mol%). Isolated yield refer to 7. Determined by
(after two steps in one pot operation). Determined by 1H-NMR. 1H-NMR. Determined by HPLC analysis using CHIRALPAK-IA and IB
c
e
d
f
columns using iPrOH–hexane as solvents. Reaction was carried out
without water. Aldimine was prepared in situ.
Determined by HPLC analysis using a CHIRALPAK-IA column using
e
g
iPrOH–hexane as solvents. Catalyst 1 (10 mol%).
c
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Notes and references
1 (a) M. Rubiralta, E. Giralt and A. Diez, Piperidine: Structure, Preparation,
Reactivity, and Synthetic Applications of Piperidine and Its Derivatives,
Elsevier, Amsterdam, 1991; (b) M. G. P. Buffat, Tetrahedron, 2004,
60, 1701; (c) C. Escolano, M. Amat and J. Bosch, Chem.–Eur. J., 2006,
12, 8198.
2 (a) Cycloaddition Reactions in Organic Synthesis, ed. S. Kobayashi and
K. A. Jørgensen, Wiley-VCH, Weinheim, Germany, 2002; (b) K. A.
Jørgensen, Angew. Chem., Int. Ed., 2000, 39, 3558; (c) P. Buonora,
J.-C. Olsen and T. Oh, Tetrahedron, 2001, 57, 6099.
3 (a) P. D. Bailey, P. A. Millwood and P. D. Smith, Chem. Commun.,
1998, 633; (b) N. S. Josephsohn, M. L. Snapper and A. H. Hoveyda,
J. Am. Chem. Soc., 2003, 125, 4018; (c) U. K. Tambar, S. K. Lee and
J. L. Leighton, J. Am. Chem. Soc., 2010, 132, 10248; (d) R.
Wakabayashi, T. Kurahashi and S. Matsubara, Org. Lett., 2012,
14, 4794; (e) For the recent review; see: G. Masson, C. Lalli,
M. Benohoud and G. Dagousset, Chem. Soc. Rev., 2013, 42, 902.
4 (a) X.-F. Zhu, J. Lan and O. Kwon, J. Am. Chem. Soc., 2003, 125, 4716;
(b) R. P. Wurz and G. C. Fu, J. Am. Chem. Soc., 2005, 127, 12234;
(c) H. Xiao, Z. Chai, H.-F. Wang, X.-W. Wang, D.-D. Cao, W. Liu,
Y.-P. Lu, Y.-Q. Yang and G. Zhao, Chem.–Eur. J., 2011, 17, 10562;
(d) For recent review: Q.-Y. Zhao, Z. Lian, Y. Wei and M. Shi, Chem.
Commun., 2012, 48, 1724.
5 R. Shintani, M. Murakami and T. Hayashi, Org. Lett., 2009, 11, 457.
6 For recent syntheses of 2,3-substituted piperidines: (a) P. R. Sultane and
R. G. Bhat, J. Org. Chem., 2012, 77, 11349; (b) A. C. Cutter, I. R. Miller,
J. F. Keily, R. K. Bellingham, M. E. Light and R. C. D. Brown, Org. Lett.,
2011, 13, 3988; (c) M. Ahari, A. Perez, C. Menant, J.-L. Vasse and J.
Szymoniak, Org. Lett., 2008, 10, 2473; (d) M. Takahashi and G. C.
Macalizio, J. Am. Chem. Soc., 2007, 129, 7514; (e) R. M. de Figueiredo,
Scheme 2 Application at gram-scale synthesis (1); synthesis of functionalized
(À)-anabasine (2).
with high yields (90%) and excellent selectivities (>25 : 1 dr, 99% ee),
when activated imine 6x was utilized without water (entry 24,
Table 2). The reactions failed in the case of electron-rich arylimine
and in situ generated alkyl imine from acetaldehyde, similar to our
previous results (entries 25 and 26, Table 2).12a
The relative stereochemistry of C2 and C3 as trans- and
absolute as (2S, 3S) was confirmed by determination of the
coupling constant and comparing the [a]D of one of our
compounds 7o with literature data (see ESI†).6e Single crystal
X-ray study of 7t further confirmed the stereochemical outcome,13
as expected through the L-proline 1 catalyzed syn-Mannich reaction,
followed by cyclization; the stereochemistry of all other products
was assigned through analogy. A plausible mechanism has been
proposed, which rationalizes the high stereochemical outcome of
this transformation (see ESI†).
To demonstrate the practical utility of our [4+2] annulation
protocol, we examined the reaction on a gram scale. While,
a somewhat longer reaction time was required, aldimine 6c
(1.0 g scale) could be transformed into 7c (1.14 g) without much
reduction in yields and with the same selectivity (eqn (1),
Scheme 2). These substituted piperidines are versatile building
blocks in organic synthesis and can be readily converted into
important products. For example, compound 7s contains
the basic skeleton of anabasine, a tobacco alkaloid obtained
from Nicotiana tobacum, known to possess nicotinic receptor
agonist activity,14 which was easily converted to functionalized
(À)-anabasine 8 (eqn (2), Scheme 2).
¨
R. Frohlich and M. Christmann, J. Org. Chem., 2006, 71, 4147.
7 For the recent reviews, see: (a) Ł. Albrecht, H. Jiang and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2011, 50, 8492;
(b) C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167;
(c) D. Enders, C. Grondal and M. R. M. Hu¨ttl, Angew. Chem., Int. Ed.,
2007, 46, 1570; (d) H. Pellissier, Adv. Synth. Catal., 2012, 354, 237.
8 (a) Y. Wang, S. Zhu and D. Ma, Org. Lett., 2011, 13, 1602;
(b) M. R. Monaco, P. Renzi, D. M. S. Schietroma and M. Bella, Org.
Lett., 2011, 13, 4546; (c) Y. Wang, D.-F. Yu, Y.-Z. Liu, H. Wei,
Y.-C. Luo and P.-F. Xu, Chem.–Eur. J., 2010, 16, 3922;
(d) T. Urushima, D. Sakamoto, H. Ishikawa and Y. Hayashi, Org.
Lett., 2010, 12, 4588; (e) Y. Hayashi, H. Gotoh, R. Masui and
H. Ishikawa, Angew. Chem., Int. Ed., 2008, 47, 4012; ( f ) M. Terada,
K. Machioka and K. Sorimachi, J. Am. Chem. Soc., 2007, 129, 10336;
(g) E. C. Carlson, L. K. Rathbone, H. Yang, N. D. Collett and
´
R. G. Carter, J. Org. Chem., 2008, 73, 5155; (h) S. Cıhalov,
´
G. Valero, J. Schimer, M. Humpl, M. Dracınsky, A. Moyano,
R. Rios and J. Vesely, Tetrahedron, 2011, 67, 8942.
9 Y. Watanabe, S. C. Shim, T.-A. Mitsudo, M. Yamashita and
Y. Takegami, Bull. Chem. Soc. Jpn., 1976, 49, 2302.
10 (a) X.-F. Huang, Z.-M. Liu, Z.-C. Geng, S.-Y. Zhang, Y. Wang and
X.-W. Wang, Org. Biomol. Chem., 2012, 10, 8794; (b) Z.-Q. He, B. Han,
R. Li, L. Wu and Y.-C. Chen, Org. Biomol. Chem., 2010, 8, 755;
(c) R.-G. Han, Y. Wang, Y.-Y. Li and P.-F. Xu, Adv. Synth. Catal., 2008,
350, 1474; (d) B.-C. Hong, R. Y. Nimje, A. A. Sadani and J.-H. Liao,
Org. Lett., 2008, 10, 2345; (e) B.-C. Hong, P. Kotame and J.-H. Liao,
Org. Biomol. Chem., 2011, 9, 382; ( f ) Y. Hayashi, T. Okano, S. Aratake
and D. Hazelard, Angew. Chem., Int. Ed., 2007, 46, 4922;
(g) D. Hazelard, H. Ishikawa, D. Hashizume, H. Koshino and
Y. Hayashi, Org. Lett., 2008, 10, 1445.
11 (a) I. Kumar, N. A. Mir, C. V. Rode and B. P. Wakhloo, Tetrahedron:
Asymmetry, 2012, 23, 225; (b) I. Kumar and C. V. Rode, Tetrahedron:
Asymmetry, 2010, 21, 2703; (c) I. Kumar, S. Rana, J. W. Cho and
C. V. Rode, Tetrahedron: Asymmetry, 2010, 21, 352; (d) I. Kumar and
C. V. Rode, Tetrahedron: Asymmetry, 2007, 18, 1975; (e) I. Kumar,
S. R. Bhide and C. V. Rode, Tetrahedron: Asymmetry, 2007, 18, 1210.
12 (a) I. Kumar, N. A. Mir, V. K. Gupta and Rajnikant, Chem. Commun.,
2012, 48, 6975; (b) I. Kumar, N. A. Mir, P. Ramaraju and
B. P. Wakhloo, RSC Adv., 2012, 2, 8922.
In conclusion, we have developed the first organocatalytic
asymmetric two component direct synthesis of 2,3-substituted
piperidines. The present one-pot cascade sequence involves a
direct Mannich reaction of glutaraldehyde with various N-PMP
aldimines, followed by acid catalyzed reductive cyclization,
through a 1,4-carbon donor–acceptor strategy as formal [4+2]
cycloaddition under very mild conditions. The viability of this
method was established through (i) the reaction proceeding
efficiently at a gram scale, and (ii) one step synthesis of a basic
skeleton of (À)-anabasine alkaloid. Further applications of this
methodology for the synthesis of related alkaloids are currently
under investigation and will be presented in due course.
We acknowledge the financial support from BITS-Pilani
and DST-New Delhi. Instrumental support from Dr S. Aravinda
(Scientist), IIIM-Jammu (CSIR-Lab), is also acknowledged. Mr P.
Ramaraju thanks UGC-New Delhi for Junior Research Fellowship.
13 See ESI;† CCDC 930264 for (7t).
14 (a) E. Leete and M. E. Mueller, J. Am. Chem. Soc., 1982, 104, 6440;
(b) L. P. Dwoski, L. Teng, S. T. Buxton, A. Ravard, N. Deo and
P. A. Crooks, Eur. J. Pharmacol., 1995, 276, 195; (c) Chem. Abstr.,
1998, 128, 321802v.
c
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