Approach to 3-(Cyclo)alkylpiperidines through 'sp3-sp3 via sp2-sp3' Coupling

Article abstract of DOI:10.1055/s-0034-1379502

The idea of introducing (cyclo)alkyl substituents at the C-3 atom of the piperidine ring, that is, formal sp³-sp³ retrosynthetic disconnection, is implemented through a two-step reaction sequence including directed ortho metalation of a pyridine derivative and the subsequent quenching with a carbonyl compound, followed by catalytic hydrogenation. This robust but very efficient method allows for multigram preparation of sp³-rich 3-(cyclo)alkylpiperidines, which are valuable building blocks for medicinal chemistry and other areas.

Full text of DOI:10.1055/s-0034-1379502

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2015, 26, 408–411
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letter
Synlett
A. I. Subota et al.
Letter
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Approach to 3-(Cyclo)alkylpiperidines through ‘sp –sp via
2
3
sp –sp ’ Coupling
Andrii I. Subotaa
Oleksandr O. Grygorenkob
Yevheniia B. Valterb
Maxim A. Tairova
Oleksiy S. Artamonova
Dmitriy M. Volochnyuka
Sergey V. Ryabukhin*b
a
Institute of Organic Chemistry, National Academy of Sciences
of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
National Taras Shevchenko University of Kyiv, Volodymyrska
b
Street 64, Kyiv 01601, Ukraine
s.v.ryabukhin@gmail.com
Received: 01.10.2014
Accepted after revision: 30.10.2014
Published online: 05.12.2014
low for the extensive use in drug-discovery programs (Table
1). The major issue was that unique synthetic sequence was
DOI: 10.1055/s-0034-1379502; Art ID: st-2014-d0832-l
applied in each particular case, thus none of these methods
can be considered as general practical approach to 3-al-
kylpiperidines. Moreover, some of the compounds were
disclosed only in patents without detailed characterization.
Abstract The idea of introducing (cyclo)alkyl substituents at the C-3
3
3
atom of the piperidine ring, that is, formal sp –sp retrosynthetic dis-
connection, is implemented through a two-step reaction sequence in-
cluding directed ortho metalation of a pyridine derivative and the sub-
sequent quenching with a carbonyl compound, followed by catalytic
hydrogenation. This robust but very efficient method allows for multi-
Alkyl
–
+
Alkyl+
3
gram preparation of sp -rich 3-(cyclo)alkylpiperidines, which are valu-
N
N
H
H
able building blocks for medicinal chemistry and other areas.
1
Scheme 1 Retrosynthetic disconnection of 3-(cyclo)alkylpiperidines
Key words heteroaliphatic compounds, alicyclic compounds, lead-
oriented synthesis, catalytic hydrogenation, piperidines
The challenge of lead-oriented synthesis (LOS) which
gained a foothold in medicinal chemistry in the last decade1
has called for rethinking of synthetic methods available for
generation of good starting points for drug discovery. Po-
tential lead compounds as well as building blocks for their
construction are subject to rigorous criteria imposed by
H
N
N
OMe
OH
N
O
D4 receptor ligand
analgesic
3
2
LOS, including high sp atom fraction and limited confor-
F
F
3
mational flexibility, among others. Meanwhile, most syn-
N
N
N
3
thetic approaches to mounting substituents onto sp -
N
F
enriched conformationally restricted cores rely on carbon–
N
N
2
2
2
heteroatom bond formation; unlike their sp –sp and sp –
NH
3
3
3
4,5
sp counterparts, sp –sp C–C couplings are less common.
In this work, we were interested in practical implemen-
O
N
3
3
15-HPGD inhibitor
PKC inhibitor
tation of sp –sp retrosynthetic disconnection at the C-3
atom of the piperidine ring (Scheme 1). Piperidines are rec-
ognized for their superior developability in drug-discovery
programs as compared to other saturated heterocycles.6
Piperidines with cycloalkyl substituents are especially
promising since six-membered rings linked with other cy-
cles through a single C–C bond are found among top ten
privileged Bemis–Murcko frameworks for medicinal chem-
Figure 1 Biologically active derivatives of 3-(cyclo)alkylpiperidines
In design of the method for the implementation of the
above-mentioned retrosynthetic disconnection, we have
taken advantages of catalytic reduction of pyridine deriva-
tives as an approach to the generation of the piperidine
ring. This would allow reducing the problem of formal sp –
sp coupling to much better developed sp –sp C–C bond
3
7
3
2
3
istry. 3-(Cyclo)alkylpiperidines have approved their utility
for the search of biologically active compounds (Figure 1).8
Nevertheless, their synthetic accessibility remains far too
formation (‘sp –sp via sp –sp ’ coupling). Since electrophil-
ic reagents for introducing alkyl substituents are more con-
3
3
2
3
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Table 1 Literature Data on the Synthesis of Selected 3-Alkylpiperidines
1
cooled to –78 °C and added in one portion at this tempera-
ture. Optimization of the reagent ratio showed that using
twofold excess of the ketone is optimal (Table 2). Quenching
of the reaction mixture after addition of the electrophile
Alkyl
No. of methodsa
The most high-yielding sequence
No. of steps
Yield (%)
should be performed by addition of aqueous NaHCO at –
3
7
8 °C to diminish self-condensation of the excessive re-
Me
>50
1
2
6
2
–
2
3
–
1009
1110
7211
17
agent. This procedure was applied for the reaction of 3-
lithio-2-bromopyridine with a number of aldehydes and
ketones (Scheme 3), and the corresponding products 2a–i
were obtained in 40–67% yield. It should be noted that in
the reaction with nonenolizable benzadehyde, the highest
yield of the product 2i was obtained (67%), and only 1.1-
fold excess of the aldehyde was sufficient.
i-Prb
i-Bu
1
cyclobutyl
cyclopentyl
cyclohexyl
cycloheptyl
0
–
2512
1
3
5613
–
0
a
According to the Reaxys® database.
S-Enantiomer.
O
R1
R2
b
Li
1.
R1
R2
LDA
OH
THF, –78 °C
THF, –78 °C
. aq NaHCO3
–78 °C to r.t.
N
Br
N
Br
venient and common, the generation of organometallic
species the at C-3 atom of an appropriate pyridine deriva-
tive would be a reaction of choice for the key step of the se-
quence. This can be achieved via directed ortho metalation
N
Br
2
3
2
(
DOM) of 2-substituted pyridines. To minimize the number
OH
Br
OH
OH
of steps in the reaction sequence, the DOM-directing group
at C-2 position should be easily removed upon catalytic hy-
drogenation conditions. In this view, DOM of 2-bromopyri-
dine followed by quenching with an appropriate electro-
N
N
Br
N
Br
2
a, 40%
2b, 41%
2c, 56%
Me
N
14,15
phile would be beneficial.
Since we were especially in-
terested in introducing alicyclic substituents into the final
products, we have thought of aldehydes and ketones as pos-
OH
OH
OH
15
sible electrophilic reagents. The hydroxy group which is
also introduced in the molecule could be removed upon the
catalyic hydrogenation step (Scheme 2). Thus, three reac-
tions – removal of the DOM-directing group, reductive de-
hydroxylation at the benzylic-type position, and reduction
of the pyridine ring – are expected to occur upon hydroge-
nation.
N
Br
N
Br
N
Br
2
d, 54%
2e, 55%
2f, 54%
OH
OH
Ph
OH
Ph
N
Br
N
Br
N
Br
2
g, 49%
2h, 60%
2i, 67%
R1
R1
R2
Scheme 3 Synthesis of pyridines 2a–i
1. DOM lithiation
[H]
R2
OH
O
2.
N
Br
N
Br
N
Our initial attempts of catalytic reduction of the pyri-
H
R1
R2
2
1
dine 2a (40–60 bar of H , Pd/C, MeOH, 85 °C) led to complex
2
Scheme 2 Design of the reaction sequence for the synthesis of 3-al-
kylpiperidines
mixtures of the products. Optimization of the reaction con-
ditions showed that piperidine 1a is formed as the only
18
isolated product (87% yield) if the hydrogenation is per-
For the first step of the reaction sequence, we have ad-
opted the procedure mentioned in the patent literature.16
Generation of 3-lithio-2-bromopyridine (3) from 2-bro-
mopyridine was achieved upon action of LDA in THF at –78 °C
Table 2 Optimization of the Reagent Ratio in the Reaction of 3 and
Cyclopentanone
15,16
(Scheme 3).
Quenching of the organometallic interme-
Entry
Ratio of cyclopentanone/3
Yield (%)
diate with cyclopentanone used as the model substrate was
accompanied by self-condensation of the ketone induced by
strongly basic nucleophile 3, especially on a large scale. Af-
ter some experimentation, it was found that this side reac-
tion is diminished if the solution of the electrophile is
1
2
3
1:1
2:1
3:1
26
40
42
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A. I. Subota et al.
Letter
formed in the presence of ca. 30 mol% of concentrated
aqueous HCl. The procedure19 worked well with all the pyr-
idines 2 shown in Scheme 4, except compound 2f contain-
ing the tertiary amine function. To obtain the correspond-
ing diamine 1f, conversion of 2f into hydrobromide salt was
necessary prior to hydrogenation.
(5) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(6) Ritchie, T. J.; Macdonald, S. J. F.; Peace, S.; Pickett, S.; Luscombec,
C. N. Med. Chem. Commun. 2012, 3, 1062.
(
(
7) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887.
8) (a) Macchia, M.; Cervetto, L.; Demontis, G. C.; Longoni, B.;
Minutolo, F.; Orlandini, E.; Ortore, G.; Papi, C.; Sbrana, A.;
Macchia, B. J. Med. Chem. 2003, 46, 161. (b) Morie, T.; Adachi, K.;
Niidome, K.; Kawashima, K.; Shimizu, I.; Ishii, D. EP 1403235,
2004. (c) Duveau, D. Y.; Yasgar, A.; Wang, Y.; Hu, X.;
Kouznetsova, J.; Brimacombe, K. R.; Jadhav, A.; Simeonov, A.;
Thomas, C. J.; Maloney, D. J. Bioorg. Med. Chem. Lett. 2014, 24,
630.
R1
R1 R2
H2, Pd/C
R2
OH
1
2 M HCl
N
Br
N
(30 mol%)
H
(9) Zacharie, B.; Moreau, N.; Dockendorff, C. J. Org. Chem. 2001, 66,
264.
2
1
MeOH
5
(10) Pedrosa, R.; Andrés, C.; Duque-Soladana, J. P.; Rosón, C. D. Tetra-
hedron: Asymmetry 2000, 11, 2809.
(11) (a) Cheng, Y.-X.; Luo, X.; Tomaszewski, M. US 2007259888,
2
007. (b) Gedig, T.; Dettner, K.; Seifert, K. Tetrahedron 2007, 63,
N
H
N
H
N
H
2670.
1
a, 87%
1b, 83%
1c, 80%
(12) Bourrain, S.; Hunt, P.; Huscroft, I.; Kulagowski, J.; London, C.;
Naylor, E.; Raubo, P.; Seward, E. US 2004229864, 2004.
Me
N
(13) (a) Macchia, M.; Cervetto, L.; Demontis, G. C.; Longoni, B.;
Minutolo, F.; Orlandini, E.; Ortore, G.; Papi, C.; Sbrana, A.;
Macchia, B. J. Med. Chem. 2003, 46, 161. (b) Ablordeppey, S. Y.;
Fischer, J. B.; Law, H.; Glennon, R. A. Bioorg. Med. Chem. 2002,
10, 2759. (c) Liu, C.; Han, N.; Song, X.; Qiu, J. Eur. J. Org. Chem.
N
H
N
N
H
H
2010, 5548.
1d, 74%
1e, 90%
1f, 45%
(see the SI)
(14) (a) Melnyk, P.; Gasche, J.; Thal, C. Synth. Commun. 1993, 23,
2
727. (b) Gallagher, T.; Karig, G.; Spencer, J. A. Org. Lett. 2001, 3,
Ph
Ph
835.
(
15) (a) Marsais, F.; Laferdrix, B.; Gungor, T.; Mallet, M.; Queguiner,
G. J. Chem. Res., Miniprint 1982, 2863. (b) Couture, A.;
Grandclaudon, P.; Huguerre, E. Synthesis 1989, 456. (c) Romero,
D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.; May, P. D.; Palmer,
J. R.; Johnson, P. D.; Smith, H. W.; Busso, M.; Tan, C. K.; Voorman,
R. L.; Reusser, F.; Althaus, I. W.; Downey, K. M.; So, A. G.;
Resnick, L.; Tarpley, W. G.; Aristoff, P. A. J. Med. Chem. 1994, 37,
N
H
N
N
H
H
1g, 71%
1h, 66%
1i, 85%
Scheme 4 Synthesis of piperidines 1a–i
In conclusion, a convenient two-step reaction sequence
was developed for introducing (cyclo)alkyl substituents at
the C-3 position of the piperidine ring, which allowed for
the multigram preparation of 3-(cyclo)alkylpiperidines.
The method is an illustration of ‘sp –sp via sp –sp ’ cou-
pling concept, which should be re-evaluated for other areas
of organic chemistry in order to achieve the goals of lead-
oriented synthesis.
9
99.
(16) Bridger, G.; McEachern, E.; Skerlj, R.; Schols, D. US 2004209921,
2004.
(
17) Representative Procedure for the Preparation of 21-(2-Bro-
3
3
2
3
mopyridin-3-yl)cyclopentanol (2a)
To a cooled (–78°С) solution of diisopropylamine (18.3 g, 25.4
mL, 0.181 mol) in absolute THF (700 mL), n-BuLi (69 mL, 23% in
hexane, 2.5 M, 0.172 mol) was added dropwise under argon
atmosphere. The mixture was stirred at –78 °C for 1 h, and a
solution of 2-bromopyridine (23.1 g, 14.3 mL, 0.146 mmol) in
dry THF (150 mL) was added dropwise over 20 min. The reac-
tion mixture was kept at –78 °С for 90 min, and precooled (–78 °С)
solution of cyclopentanone (26.6 g, 28 mL, 0.316 mol) in dry
THF (70 mL) was added in one portion. The mixture was stirred
at –78 °С for additional 80 min and quenched with sat. aq
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379502.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
NaHCO (140 mL) at –78°С, then warmed to r.t. and diluted with
3
EtOAc (1 L). The organic phase was separated, washed with sat.
aq NaHCO (2 × 150 mL) and brine (200 mL), dried over Na SO ,
References and Notes
3
2
4
and concentrated in vacuo to give 22.5 g of residue. The product
was purified by flash chromatography (gradient hexane–EtOAc
as an eluent), followed by recrystallization from pentane. The
sample of 2a of analytical purity was obtained by additional
recrystallization from hexanes. Yield 14.2 g (40%); white nee-
(
1) Nadin, A.; Hattotuwagama, C.; Churcher, I. Angew. Chem. Int. Ed.
2012, 51, 1114.
(
2) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752.
3) Mann, A. In Practice of Medicinal Chemistry; Wermuth, C. G., Ed.;
Academic Press/Elsevier: Amsterdam, 2008, 3rd ed.; 363–379.
4) Aldeghi, M.; Malhotra, S.; Selwood, D. L.; Chan, A. W. Chem. Biol.
Drug. Des. 2014, 83, 450.
(
+
dles; mp 80–82 °C (hexanes). MS (ESI): m/z = 242/244 [MH ].
(
Anal. Calcd for C10H12BrNO: C, 49.61; H, 5.00; Br, 33.00; N, 5.79.
1
Found: C, 49.37; H, 5.27; Br, 32.74; N, 5.70. H NMR (400 MHz,
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 408–411

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A. I. Subota et al.
Letter
CDCl ): δ = 8.22 (d, J = 3.6 Hz, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.31–
in H O (150 mL), 20% aq NaOH (50 mL) was added, and the
3
2
7
2
.19 (m, 1 H), 2.65 (br s, 1 H), 2.39–2.25 (m, 2 H), 2.18–2.05 (m,
H), 2.05–1.93 (m, 2 H), 1.91–1.80 (m, 2 H). C NMR (101 MHz,
mixture was extracted with hexanes (2 × 80 mL). The combined
organic phases were dried over NaOH and evaporated in vacuo.
The crude product was distilled in vacuo (bp 94–96 °C/10 mbar)
to give the product 1a; yield 13.8 g (87%); colorless liquid; bp
13
CDCl ): δ = 147.5 (CH), 141.6 (C), 140.9 (C), 135.8 (CH), 122.18
3
(
CH), 82.2 (C), 39.3 (CH ), 23.7 (CH ).
2
2
+
(
18) The detailed results on the optimization will be published in
the upcoming full paper.
19) Representative Procedure for the Preparation of 13-Cyclo-
pentylpiperidine (1a)
94–96 °C/10 mbar. MS (ESI): m/z = 154 [MH ]. Anal. Calcd for
C10H19N: C, 78.37; H, 12.50; N, 9.14. Found: C, 78.03; H, 12.71;
1
(
N, 8.96. H NMR (400 MHz, CDCl ): δ = 3.07–2.99 (m, 1 H), 2.97–
3
2.89 (m, 1 H), 2.46 (td, J = 11.9, 2.9 Hz, 1 H), 2.21 (dd, J = 11.9,
10.4 Hz, 1 H), 2.04 (br s, 1 H), 1.85–1.77 (m, 1 H), 1.75–1.63 (m,
2 H), 1.63–1.48 (m, 3 H), 1.48–1.31 (m, 4 H), 1.20–1.10 (m, 1 H),
A mixture of 10% Pd/C (5.0 g, 50% wet with H O for safety, unre-
duced), MeOH (400 mL), pyridine 2a (25.1 g, 0.103 mol), and
concentrated aq HCl (2.5 mL, 0.03 mol), was placed in an auto-
2
13
1.10–0.93 (m, 3 H). C NMR (101 MHz, CDCl ): δ = 51.9 (CH ),
3
2
clave and hydrogenated at 40 bar of H and 85 °C for 64 h. The
46.7 (CH ), 44.0 (CH), 42.9 (CH), 30.2 (CH ), 30.1 (CH ), 30.0
2
2
2
2
catalyst was filtered off, and the filtrate was evaporated under
reduced pressure to give 24.6 g of the residue. It was dissolved
(CH ), 26.5 (CH ), 24.9 (CH ), 24.7 (CH ).
2
2
2
2
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 408–411

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