Diastereoselectively Complementary C-H Functionalization Enables Access to Structurally and Stereochemically Diverse 2,6-Substituted Piperidines

Article abstract of DOI:10.1021/acs.orglett.6b03372

The preparation of 2,6-substituted piperidine derivatives through diastereoselective C-H functionalization of corresponding nitrogen heterocycles represents an appealing protocol and yet remains a formidable challenge. Here, we describe a stereochemically complementary oxidative C-H functionalization of N-carbamoyl tetrahydropyridines with a wide variety of building blocks, providing either the cis- or trans-2,6-substituted piperidines with diverse patterns of functionalities. The mild metal-free process exhibits excellent regio- and diastereoselectivities as well as functional group tolerance. The synthetic utilities in natural product and analogue syntheses are also described.

Full text of DOI:10.1021/acs.orglett.6b03372

Letter
pubs.acs.org/OrgLett
Diastereoselectively Complementary C−H Functionalization Enables
Access to Structurally and Stereochemically Diverse 2,6-Substituted
Piperidines
Gang Wang,† Ying Mao,† and Lei Liu*,†,‡
†School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
‡School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
S
* Supporting Information
ABSTRACT: The preparation of 2,6-substituted piperidine
derivatives through diastereoselective C−H functionalization
of corresponding nitrogen heterocycles represents an appeal-
ing protocol and yet remains a formidable challenge. Here, we
describe a stereochemically complementary oxidative C−H
functionalization of N-carbamoyl tetrahydropyridines with a
wide variety of building blocks, providing either the cis- or
trans-2,6-substituted piperidines with diverse patterns of
functionalities. The mild metal-free process exhibits excellent regio- and diastereoselectivities as well as functional group
tolerance. The synthetic utilities in natural product and analogue syntheses are also described.
We envisioned that the direct oxidative C−H functionaliza-
tion of N-acyltetrahydropyridines would be an attractive
solution for the objective because the alkene moiety would
act not only as an activating group for the oxidative C−H
cleavage but also as an outstanding functional handle for
structurally diverse piperidines. As part of our ongoing interest
in developing a practical synthetic method through oxidative
C−H functionalization strategy,7f we now report the first
stereochemically complementary intermolecular C−H func-
tionalization of N-carbamoyl tetrahydropyridines with a wide
variety of building blocks, providing either cis- or trans-2,6-
substituted piperidine derivatives with excellent diastereocon-
trol.
Initially, the alkynylation of tetrahydropyridine 1a with
potassium trifluoroborate 2a was chosen as the model reaction
for optimization (Table 1). No expected 3a was observed when
common oxidants including DDQ, TBHP, Ph3CBF4, and
PhI(OAc)2 were used (entry 1, Table 1). Gratifyingly,
TEMPO+OTf− (TEMPO oxoammonium trifluoromethanesul-
fonate) can promote the reaction, giving the 2,6-substituted 3a
in 50% yield with a cis/trans ratio of 7:1, together with the
undesired bis-functionalized 3′a in 25% yield (entry 2).8
Subjecting 3a to the reaction system did not give any 3′a,
indicating that 3′a should not originate from the overoxidation
of 3a. While the potential 1,4-adduct 3″a was not detected, we
still envisioned that 3a′ might derive from the overoxidation of
3″a because enamide 3″a possesses lower oxidation potential
than allylic amides 1a and 3a.2k Therefore, once the 3″a was
formed, it might further undergo a second C−H oxidation
Cis- or trans-2,6-substituted tetrahydropyridines and piperidines
are key units spread across numerous bioactive natural products
and synthetic pharmaceuticals.1 Their prevalent syntheses
mainly focus on the diastereoselective heterocycle construction
strategy that relies on functional group transformations.2 On
the other hand, the method through the direct stereocontrolled
C−H functionalization of easily accessible α-substituted
piperidine derivatives represents a more economical and
topologically obvious alternative.3 Important progress has
been achieved in the diastereoselective C−H functionalization
of α-substituted piperidines through the α-amino anion and C−
H activation pathways.4,5 However, the former always requires
more than a stoichiometric amount of strongly basic organo-
lithium reagents, and the latter often suffers from modest
stereocontrol, extra efforts to remove heterocyclic directing
groups, limited functionality (aryl group) introduced into the
α-position, and the prerequisite metal catalyst. Moreover, both
approaches always provide trans-2,6-substituted products as the
major isomer, with no direct access to the cis-isomer.
Metal-free oxidative C−H functionalization of nitrogen
heterocycles through an α-amino cation pathway is an attractive
alternative.6 However, the overwhelming majority of these
studies have focused on cyclic and benzylic amines, especially
on N-arylated tetrahydroisoquinolines, and thus, the inter-
molecular diastereoselective approach has been rarely estab-
lished.7 To our knowledge, the diastereoselective bimolecular
oxidative C−H functionalization of simplified carbamates has
never been established to date. Therefore, identifying a
practical, predictable, and stereochemically complementary
C−H functionalization method to rapidly prepare structurally
and stereochemically diverse 2,6-substituted piperidine deriva-
tives is highly desirable.
Received: November 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03372
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Reaction Condition Optimization
Scheme 2. Scope of C−H Allylation
b
c
entry
oxidant
oxidant
yield (%) of 3a/3″a
dr
d
1
<5
n.a.
7:1
2
3
4
TEMPO+OTf−
50/25
66/12
76/<5
73/13
68/17
55/21
81/<5
TEMPO+ClO4
10:1
12:1
16:1
>20:1
11:1
>20:1
−
TEMPO+BF4
−
e
TEMPO+BF4
−
5
cis-2,6-substituted 5a−c as a single isomer. Common functional
groups such as silyl ethers (5d and 5e), acetates (5f), and
benzoates (5g) were well tolerated in high stereocontrol for
further manipulations. The ability to deliver diverse function-
alities into the core skeleton indicates that the C−H
functionalization approach should be applicable to complex
molecule synthesis and library construction.
f
TEMPO+BF4
−
6
g
TEMPO+BF4
−
7
8 ,
TEMPO+BF4
f h
−
a
1a (0.1 mmol), 2a (0.15 mmol), and oxidant (0.13 mmol) in CH2Cl2
b
c
1
(1.0 mL) at rt. Yield of isolated product. Determined by H NMR
d
spectroscopy. DDQ, TBHP, Ph3CBF4, or PhI(OAc)2 as an oxidant.
e
f
Cbz as the amine protecting group (3b). Boc as the amine protecting
g
h
The scope of tetrahydropyridines was next explored (Scheme
3). The efficiency and dr were not sensitive to the length of the
group (3c). SO2Me as the protecting group (3d). CH3CN as the
solvent.
followed by 1,2-addition to give bis-functionalized 3′a. The
Scheme 3. Scope of Tetrahydropyridines
counterions of the TEMPO oxoammonium salt were screened,
−
and when TEMPO+BF4 was employed, the undesired 1,4-
addition process was supremely suppressed, with 3a isolated in
76% yield with a dr of 12:1 (entries 2−4).9 Increasing the size
of the amide protecting groups proved to have a beneficial
effect on the dr (entries 4−7). Solvent optimization identified
CH3CN as the ideal choice in terms of the regioselectivity
(entry 8).
The scope of the stereoselective C−H alkynylation was then
explored (Scheme 1). A wide range of electronically varied aryl
Scheme 1. Scope of C−H Alkynylation
alkyl side chain (7a and 7b). The highly stereoselective C−H
functionalization exhibited excellent compatibility with a broad
range of unsaturations in the alkyl side chain, such as aryls (7c
and 7d), terminal alkenes (7e), and terminal alkynes (7f). The
process was also well tolerated with diverse oxygen- and
nitrogen-containing moieties, such as esters (7g), amides (7h),
silyl ethers (7i and 7j), acetates (7k), and halides (7l) as
additional functional handles. The substrates with unsaturated
side chains such as aryls (7m−o), alkenyls (7p and 7q), and
alkynyls (7r) were also well tolerated with overwhelming
selectivity at the less sterically hindered secondary C−H bond.
The facile access to cis-2,6-substituted tetrahydropyridines
prompted us to further explore the direct preparation of trans-
isomers through the oxidative C−H functionalization method.
Excitedly, the stereoselective C−H allylation and alkynylation
of bicyclic tetrahydropyridine 8 went smoothly, generating
alkynyl trifluoroborate salts with different substituent patterns
participated in the stereoselective C−H alkynylation of 1c,
giving cis-2,6-substituted 3c−j in good to excellent yields as a
single stereoisomer. Simple alkyl-substituted alkynyl boronate
3k was also well tolerated. Notably, such excellent cis-2,6-
stereoselectivity has never been achieved in the existing C−H
functionalization studies for piperidine derivatives.3−5 Aryl,
alkenyl, and benzyl trifluoroborates did not give any desired
product.
The scope of the diastereoselective C−H allylation of 1c with
allyltrimethylsilanes 4 was then explored (Scheme 2). Simple
allyltrimethylsilane 4a together with phenyl- and alkyl-
substituted 4b and 4c were suitable components, affording
B
DOI: 10.1021/acs.orglett.6b03372
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
trans-2,6-substituted 9a−h in excellent yields as a single
diastereomer (Scheme 4). The completely inverted stereo-
16b through the cross metathesis with the unsaturation in
tetrahydropyridine ring intact (eq 5).
The oxidative C−H functionalization was not affected by
addition of stoichiometric radical inhibitors such as TEMPO or
BHT, thus indicating that a radical process might not be
involved. Such observation coincides with the mechanistic
study on TEMPO oxoammonium salt mediated oxidative
cleavage of benzylic ethers.10 Therefore, we envisioned that the
N-acyliminium 19 might be generated through a direct hydride
transfer from tetrahydropyridine 17 to the oxygen of the
oxoammonium salt 18, perhaps involving prior complexation of
17 with 18 to form an electron donor−acceptor (19) (Scheme
6).10,11 The excellent cis-selectivity observed for the C−H
Scheme 4. Stereoselective Access to Trans-2,6-Substituted
Tetrahydropyridinesa
Scheme 6. Proposed Mechanism and Explanation on the
Complementary Diastereoselectivity
selectivity will not only allow for pharmaceutically important
bicyclic indolizidine- and quinolizidine-type alkaloid synthesis
but also provide a route to access simple trans-2,6-substituted
piperidine derivatives simply by cleaving the amide bond.
The diastereoselectively complementary C−H functionaliza-
tion method can facilely provide diverse cis- or trans-2,6-
substituted piperidine derivatives. For example, hydrogenation
of 7a afforded cis-dialkyl-substituted piperidine 10, a known
precursor for natural product dihydropinidine (Scheme 5, eq
Scheme 5. Synthetic Applications
functionalization of simple tetrahydropyridines could be
explained in the following manner. The α,β-unsaturated N-
acyliminium 20 would exist as a flat chair (21a) with the R
group in the pseudoaxial orientation to avoid the allylic 1,2-
strain between the R group and the acyl moiety.12 Stereo-
electronically preferred axial attack of the nucleophile at C2 of
21a provides the observed cis-2,6-substituted tetrahydropyr-
idine 22 as the major product. With respect to the bicyclic
tetrahydropyridines like 23, a completely inverted stereo-
selectivity was observed, which might also be ascribed to the
stereoelectronically preferred axial attack to C2 of N-
acyliminium 24 through 25, leading to trans-2,6-substituted
26 as the major isomer.
In summary, a predictable and diastereoselectively comple-
mentary oxidative C−H functionalization of N-carbamoyl
tetrahydropyridines with a wide assortment of components at
ambient temperature has been established, stereoselectively
providing either cis- or trans-2,6-substituted tetrahydropyridines
and piperidines with diverse patterns of functionalities. The
practical metal-free method has excellent regio- and diaster-
eoselectivity and is well tolerated for diverse functional groups.
The synthetic utilities in structurally and stereochemically
diverse 2,6-substituted piperidine derivatives were also
demonstrated. We envision that the practical method outlined
herein will have broad applications in natural product and
library synthesis for drug discovery.
1). trans-Bicyclic 9e−g were sequentially reduced by H2 and
LiAlH4, respectively, affording epi-indolizidine 167B (11a) and
its analogues 11b and 11c as a single diastereomer (eq 2). The
diastereoselectively divergent synthesis of the cis-analogue 13a
and trans-analogue 13b of natural product methyl palustramate
was also accomplished starting from a common substrate 12 in
two and three steps, respectively (eqs 3 and 4). The terminal
olefin in tetrahydropyridine 7b can also act as a powerful
handle for diversity-oriented synthesis, as exemplified by the
efficient formation of diversely functionalized alkenes 16a and
C
DOI: 10.1021/acs.orglett.6b03372
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Z.; Liu, L.; Chen, W.; Zheng, H.; Xu, Q.; Yuan, H.; Lou, H. Angew.
Chem., Int. Ed. 2014, 53, 3904. (f) Liu, X.; Meng, Z.; Li, C.; Lou, H.;
Liu, L. Angew. Chem., Int. Ed. 2015, 54, 6012. (g) Yan, C.; Liu, Y.;
Wang, Q. Org. Lett. 2015, 17, 5714.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03372.
■
S
(8) Bobbitt, J. M.; Bruckner, C.; Merbouh, N. Oxoammonium and
̈
Nitroxide-Catalyzed Oxidations of Alcohols in Organic Reactivity;
Denmark, S. E., Ed.; Wiley: New York, 2009; Vol. 74, p 103.
(9) (a) Olah, G. A. J. Org. Chem. 2005, 70, 2413. (b) Shibuya, M.;
Tomizawa, M.; Iwabuchi, Y. J. Org. Chem. 2008, 73, 4750.
(10) (a) Pradhan, P. P.; Bobbitt, J. M.; Bailey, W. F. Org. Lett. 2006,
8, 5485. (b) Hamlin, T. A.; Kelly, C. B.; Ovian, J. M.; Wiles, R. J.;
Tilley, L. J.; Leadbeater, N. E. J. Org. Chem. 2015, 80, 8150.
(11) Takahashi, Y.; Sankararaman, S.; Kochi, J. K. J. Am. Chem. Soc.
1989, 111, 2954.
Experimental details and spectral data for new com-
pounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: leiliu@sdu.edu.cn.
ORCID
(12) (a) Johnson, F. Chem. Rev. 1968, 68, 375. (b) Brown, J. D.;
Foley, M. A.; Comins, D. L. J. Am. Chem. Soc. 1988, 110, 7445.
(c) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841. (d) Unsworth, W. P.;
Taylor, R. J. K. Synlett 2016, 27, 2051.
Lei Liu: 0000-0002-0839-373X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Science Foundation of
China (21472112), the Program for New Century Excellent
Talents in University (NCET-13-0346), Fok Ying Tung
Education Foundation (151035), the Shandong Science Fund
for Distinguished Young Scholars (JQ201404), and the
Fundamental Research Funds of Shandong University
(2015JC035).
REFERENCES
■
(1) (a) Comprehensive Heterocyclic Chemistry III; Katritzky, A. R.,
Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier:
Oxford, 2008. (b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
(2) (a) Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383.
(b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199. (c) Aahman,
J.; Somfai, P. J. Am. Chem. Soc. 1994, 116, 9781. (d) Kuethe, J. T.;
Comins, D. L. Org. Lett. 2000, 2, 855. (e) Wright, D. L.; Schulte, J. P.,
II; Page, M. A. Org. Lett. 2000, 2, 1847. (f) Shu, C.; Liebeskind, L. S. J.
Am. Chem. Soc. 2003, 125, 2878. (g) Amos, D. T.; Renslo, A. R.;
́
Danheiser, R. L. J. Am. Chem. Soc. 2003, 125, 4970. (h) Toure, B. B.;
Hall, D. G. Angew. Chem., Int. Ed. 2004, 43, 2001. (i) Barbe, G.; St-
Onge, M.; Charette, A. B. Org. Lett. 2008, 10, 5497. (j) Bates, R. W.;
Lu, Y. Org. Lett. 2010, 12, 3938. (k) Brizgys, G. J.; Jung, H. H.;
Floreancig, P. E. Chem. Sci. 2012, 3, 438. (l) Cuthbertson, J. D.;
Taylor, R. J. K. Angew. Chem., Int. Ed. 2013, 52, 1490.
(3) (a) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069. (b) Mitchell,
E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes, B. U. W. Chem. -
Eur. J. 2012, 18, 10092.
(4) (a) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109. (b) Stead,
D.; Carbone, G.; O’Brien, P.; Campos, K. R.; Coldham, I.; Sanderson,
A. J. Am. Chem. Soc. 2010, 132, 7260.
(5) (a) Davies, H. M. L.; Venkataramani, C.; Hansen, T.; Hopper, D.
́
W. J. Am. Chem. Soc. 2003, 125, 6462. (b) Prokopcova, H.; Bergman,
S. D.; Aelvoet, K.; Smout, V.; Herrebout, W.; Van der Veken, B.;
Meerpoel, L.; Maes, B. U. W. Chem. - Eur. J. 2010, 16, 13063.
(c) Yoshikai, N.; Mieczkowski, A.; Matsumoto, A.; Ilies, L.; Nakamura,
E. J. Am. Chem. Soc. 2010, 132, 5568. (d) Kamijo, S.; Hoshikawa, T.;
Inoue, M. Org. Lett. 2011, 13, 5928.
(6) (a) Li, C. J.; Li, Z. Pure Appl. Chem. 2006, 78, 935. (b) Murahashi,
S.; Zhang, D. Chem. Soc. Rev. 2008, 37, 1490. (c) Li, C. J. Acc. Chem.
Res. 2009, 42, 335. (d) Klussmann, M.; Sureshkumar, D. Synthesis
2011, 2011, 353. (e) Rohlmann, R.; García Mancheno, O. Synlett
̃
2012, 24, 6.
(7) (a) Murahashi, S. I.; Komiya, N.; Terai, H.; Nakae, T. J. Am.
Chem. Soc. 2003, 125, 15312. (b) Li, Z.; Li, C. J. J. Am. Chem. Soc.
2004, 126, 11810. (c) Richter, H.; García Mancheno, O. Eur. J. Org.
̃
Chem. 2010, 4460. (d) Boess, E.; Sureshkumar, D.; Sud, A.; Wirtz, C.;
̀
Fares, C.; Klussmann, M. J. Am. Chem. Soc. 2011, 133, 8106. (e) Xie,
D
DOI: 10.1021/acs.orglett.6b03372
Org. Lett. XXXX, XXX, XXX−XXX