Synthesis of 6-Substituted Piperidin-3-ones via Rh(II)-Catalyzed Transannulation of N-Sulfonyl-1,2,3-triazoles with Electron-Rich Aromatic Nucleophiles

Article abstract of DOI:10.1021/acs.orglett.7b01180

A highly diastereoselective rhodium(II)-catalyzed transannulation of aldehyde-tethered N-sulfonyl triazoles with electron-rich aromatic nucleophiles is reported for the first time to afford functionalized 6-substituted piperidin-3-ones. The reaction has a broad substrate scope including both aliphatic and aromatic N-sulfonyl-1,2,3-triazoles together with various aromatic nucleophiles. The addition of a catalytic amount of Lewis acid has proven to be crucial for the yield improvement. By employing this methodology, hardly accessible piperidin-3-ones bearing quaternary carbons could be obtained.

Full text of DOI:10.1021/acs.orglett.7b01180

Letter
pubs.acs.org/OrgLett
Synthesis of 6‑Substituted Piperidin-3-ones via Rh(II)-Catalyzed
Transannulation of N‑Sulfonyl-1,2,3-triazoles with Electron-Rich
Aromatic Nucleophiles
Yang Li,† Ran Zhang,† Arshad Ali,† Jing Zhang,† Xihe Bi,*,†,‡ and Junkai Fu*,†
†Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal
University, Changchun 130024, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A highly diastereoselective rhodium(II)-cata-
lyzed transannulation of aldehyde-tethered N-sulfonyl triazoles
with electron-rich aromatic nucleophiles is reported for the
first time to afford functionalized 6-substituted piperidin-3-
ones. The reaction has a broad substrate scope including both
aliphatic and aromatic N-sulfonyl-1,2,3-triazoles together with
various aromatic nucleophiles. The addition of a catalytic
amount of Lewis acid has proven to be crucial for the yield improvement. By employing this methodology, hardly accessible
piperidin-3-ones bearing quaternary carbons could be obtained.
iridium-catalyzed hydrogenation of 3-hydroxypyridinium salts,
but this reaction is restricted to the formation of 6-H-piperidin-
3-ones (eq 2 in Figure 1).8 Moreover, to the best of our
knowledge, the synthesis of piperidin-3-ones bearing quaternary
carbons are still unexplored. In this context, the search for a
step-economical and efficient system to generate structural
diversity of piperidin-3-ones is of great value.
he piperidin-3-one is a frequently encountered inter-
Tmediate in the synthesis of alkaloid natural products and
pharmaceutical agents.1 This moiety could be easily converted
into diversely functionalized compounds, such as piperidin-3-ol,
a versatile building block in organic synthesis,2 as well as
piperidin-3-amine via reductive amination.3 However, a
practical and efficient access to piperidin-3-one remains scarce.
The aza-Achmatowicz reaction is a general method for the
preparation of this scaffold, which requires multiple steps and
affords 6-alkoxy or hydroxyl piperidin-3-ones (eq 1 in Figure
1).4 Other methods including ring expansion of cyclo-
propanes,5 [1, 2]-shift of ammonium ylides,6 and modification
of amino acids7 usually need particular precursors to generate
specific piperidin-3-ones. Recently, Zhou et al. reported an
The N-sulfonyl triazole chemistry has attracted much
attention in recent years.9 Disclosed initially by Fokin,
Gevorgyan and co-workers,10 the N-sulfonyl-1,2,3-triazoles
have emerged as stable and readily available precursors of α-
imino metal carbenes11 and have proven to be an excellent
nitrogen source for the construction of numerous hetero-
cycles.9d The Shi and Huang groups independently reported
the synthesis of a mixture of 1,2-dihydroisoquinolines and 1-
indanones from N-sulfonyl 1,2,3-triazoles bearing an ether
tether upon treatment with a rhodium(II) catalyst.12 Quite
recently, Li and co-workers disclosed the rhodium-catalyzed
intramolecular reaction of benzyl bromide and N-sulfonyl
triazoles to afford versatile 4-bromo-1,2-dihydroisoquinolines,
and a bromonium ylide was proposed as the key intermediate.13
In continuation of our interest in the development of novel
carbene transformations involving N-sulfonyl triazoles,14 we
present herein a diastereoselective rhodium(II)-catalyzed
intermolecular transannulation of N-sulfonyl triazoles with
electron-rich aromatic nucleophiles to construct diversely
functionalized 6-substituted piperidin-3-ones, including these
with quaternary carbons.
Received: April 19, 2017
Figure 1. Different strategies for the construction of piperidin-3-ones.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01180
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Organic Letters
Letter
In alignment with our previous work, the reaction of N-
sulfonyl triazole 1a and 1,3,5-trimethoxybenzene 2 in chloro-
form at 120 °C in the presence of catalytic Rh2(Oct)4 was
selected as a model system (Table 1).14b To our delight, the
Scheme 1. Substrate Scope of Aliphatic N-Sulfonyl-1,2,3-
triazoles
ab
,
a
Table 1. Optimization of the Reaction Conditions
temp
(°C)
yield
b
entry
catalyst
solvent
additive
(%)
1
2
3
4
5
6
7
8
9
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(OAc)4
none
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCE
120
120
100
80
none
10
35
47
39
20
0
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
100
100
100
100
100
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
28
25
78
toluene
CHCl3
MgSO4/Sc(OTf)3
(2 mol %)
10
11
12
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
CHCl3
CHCl3
CHCl3
100
100
100
MgSO4/Cu(OTf)2
(2 mol %)
71
69
50
MgSO4/Yb(OTf)3
(2 mol %)
MgSO4/Sc(OTf)3
(10 mol %)
a
All reactions were carried out in 0.04 M solvent with 5 mol % catalyst
b
and 5.0 equiv of nucleophile under a nitrogen atmosphere. Isolated
yields.
a
Reaction conditions: 1 (0.20 mmol), aromatic nucleophile (1.0
mmol), Rh2(Oct)4 (10 μmol), Sc(OTf)3 (4.0 μmol), and MgSO4
desired 6-substituted piperidin-3-one 3a was detected albeit in
just 10% yield (entry 1), and its structure was further confirmed
by X-ray crystallographic analysis.15 The addition of anhydrous
magnesium sulfate into the reaction mixture would improve the
yield up to 35%, suggesting that water could compete with the
aromatic nucleophile to take part in the reaction (entry 2).
Screening the reaction temperature showed that 100 °C was
the best choice (entries 3 and 4), and the product was obtained
in 47% yield. Replacing Rh2(Oct)4 with other rhodium(II)
catalysts, such as Rh2(OAc)4, gave a lower yield (entry 5).
When the reaction was carried out without a metal catalyst, no
desired product could be detected, indicating that Rh2(Oct)4
played an essential role (entry 6). Other solvents, for instance,
1,2-dichloroethane or toluene, all gave unsatisfactory yields
(entries 7 and 8). Lewis acids have been used as efficient
promoters for some N-sulfonyl triazole reactions,14b,16 so we
tested different kinds of Lewis acids. Delightedly, the yield of 3a
was dramatically improved, and when 2 mol % Sc(OTf)3 was
employed, a yield of 78% was obtained (entries 9−11). Further
increasing the amount of Sc(OTf)3 up to 10 mol %, in contrast,
made the yield drop to 50% (entry 12).
With the optimized reaction conditions secured, we explored
the scope and generality of the reaction with a variety of
aliphatic N-sulfonyl triazoles. As shown in Scheme 1, the
substrates with either dimethyl groups or different rings,
including four-, five-, and six-membered rings, at the C5
position could be transformed into the corresponding products
3b−e in excellent yields. Functional groups, such as a double
bond and heteroatom, could also be tolerated under the
reaction conditions to give 3f−h. Especially, all these formed
products contain quaternary carbons, which could not be
b
(0.40 g) in CHCl3 (5.0 mL) at 100 °C for 2 h. Isolated yields.
c
d
Reaction for 6 h. Without Sc(OTf)3.
accessed by a normal aza-Achmatowicz reaction. When the C5
position of the substrate was monosubstituted by n-butyl,
benzyl, various phenyl, or isopropyl groups, the desired
products 3i−n were obtained as single trans-isomers. The
relative stereochemistry of 3j was established by X-ray
crystallographic analysis.15 The C4 position of the substrate
could be substituted with a variety of groups as well, including
dimethyl groups, cyclohexane, and an isopropyl group, to give
products 3o−q in good yields. Besides 1,3,5-trimethoxyben-
zene, other electron-rich aromatic compounds could also serve
as good nucleophiles. For 1,3-dimethoxy- and 1,2,4-trimethox-
ybenzene, the products 3r and 3t were isolated in 61% and 77%
yields respectively, while 1,3-dimethoxy-5-methylbenzene gave
isomers 3s and 3s′ in nearly equal yields. When 3-dimethyl-
aminoanisole was employed, the desired product 3u was
obtained in just 59% yield in the absence of a Lewis acid.17 The
aromatic nucleophiles with less electron-rich substituent
groups, such as anisole and N,N-dimethylaniline, did not give
the corresponding products. It is noteworthy that, during all the
above cases, β-H elimination or [1, 2]-alkyl migration,18 which
potentially occurs along with alphatic rhodium carbenoid
intermediates, was not observed.19
Later, the aromatic N-sulfonyl triazoles were found to be
suitable substrates for this transannulation (Scheme 2). When
2-triazole-benzaldehyde was employed as the substrate, the
product 5a was isolated in 84% yield, and the structure of 5a
B
DOI: 10.1021/acs.orglett.7b01180
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope of Aromatic N-Sulfonyl-1,2,3-
triazoles
Scheme 3. Proposed Mechanism
a b
,
3 or 5. On the other hand, path b involving demetalation,
followed by a formal [1, 4]-migration and isomerization to
product 3 or 5, could also not be ruled out. However, previous
reports show that a formal [1, 3]-migration is possible for
intermediate G.14c,21 In this case, path a is more favorable.
In conclusion, a novel rhodium(II)-catalyzed intermolecular
transannulation of aldehyde-tethered N-sulfonyl triazoles with
electron-rich aromatic nucleophiles has been developed for the
first time. This methodology provides a step-economical and
practical access to functionalized 6-substituted piperidin-3-ones,
especially to these with quaternary carbons, which are not easily
obtained through other methods. A mechanism involving
oxonium ylide formation, Lewis acid assisted C−O cleavage,
C−N recombination, and enol isomerization has been
proposed. The broad substrate scope for both aliphatic and
aromatic N-sulfonyl triazoles together with the high diaster-
eoselectivity make this reaction promising for the construction
of useful scaffolds in biomedical research and drug discovery.
a
Reaction conditions: 4 (0.20 mmol), aromatic nucleophile (1.0
mmol), Rh2(Oct)4 (10 μmol), Sc(OTf)3 (4.0 μmol), and MgSO4
b
(0.40 g) in CHCl3 (5.0 mL) at 100 °C for 2 h. Isolated yields.
was confirmed by X-ray crystallographic analysis.15 The effect of
substituents on the phenyl ring was evaluated. Both electron-
donating (Me−, MeO−, BnO−, 3,4-(MeO)2−, or −OCH2O−)
and electron-withdrawing (Cl− or F−) groups were tolerated
well to give the desired products 5b−i in excellent yields. The
1,3-dimethoxy- and 1,2,4-trimethoxybenzene could also be
efficiently used as nucleophiles affording 5j and 5l in 72% and
80% yields, respectively. For 1,3-dimethoxy-5-methylbenzene,
the major product was 5k, along with minor isomer 5k′ which
was generated from the nucleophilic attack of the N-sulfonyl
triazole via the C2 position of 1,3-dimethoxy-5-methylbenzene.
The ratio of the isomers was proposed due to the stronger
electron effect of the para-methoxyl group compared to the
ortho-methoxyl group.
ASSOCIATED CONTENT
■
S
* Supporting Information
Based on the above results, a proposed mechanism is
illustrated in Scheme 3. Upon treatment with the rhodium(II)
catalyst, N-sulfonyl triazole 1 or 4 decomposes into the
corresponding α-imino metal carbene, which could be further
trapped by the intramolecular aldehyde to form oxonium ylide
A.14b,20 Nucleophilic addition of an electron-rich aromatic
nucleophile to the oxonium intermediate affords zwitterion B,
which releases a proton to generate intermediate C. There are
two plausible pathways for the subsequent transformations. In
path a, the oxygen atom bearing lone pair electrons coordinates
to the Lewis acid, and subsequent C−O bond cleavage takes
place under the simultaneous action of the electron-rich
aromatic ring to give zwitterion E. Release of the rhodium
catalyst and recombination of the nitrogen atom with the
benzylic carbon center deliver the cycloadduct F, which after
protonation would isomerize into 6-substituted piperidin-3-one
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01180.
Experimental procedures and spectra copies (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: fujk109@nenu.edu.cn.
*E-mail: bixh507@nenu.edu.cn.
ORCID
Junkai Fu: 0000-0002-7714-8818
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b01180
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(12) (a) Sun, R.; Jiang, Y.; Tang, X.-Y.; Shi, M. Chem. - Eur. J. 2016,
22, 5727. (b) Yu, Y.; Zhu, L.; Liao, Y.; Mao, Z.; Huang, X. Adv. Synth.
Catal. 2016, 358, 1059.
(13) He, J.; Shi, Y.; Cheng, W.; Man, Z.; Yang, D.; Li, C.-Y. Angew.
Chem., Int. Ed. 2016, 55, 4557.
(14) (a) Fu, J. K.; Shen, H. J.; Chang, Y. Y.; Li, C. C.; Gong, J. X.;
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(15) CCDC 1539648 (3a), CCDC 1539578 (3j), and CCDC
1539582 (5a) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk.
(16) (a) Zhang, Y.-S.; Tang, X.-Y.; Shi, M. Org. Chem. Front. 2015, 2,
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(17) When the reaction was carried out in the presence of Sc(OTf)3,
piperidin-3-one bearing two 3-dimethylaminoanisole moieties at C6
and C2 position could be obtained in 64% yield.
(18) (a) Miura, T.; Biyajima, T.; Fujii, T.; Murakami, M. J. Am. Chem.
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would suppress the potential side reactions.
ACKNOWLEDGMENTS
■
This work was supported by the NSFC (21522202, 21372038),
the Ministry of Education of the People’s Republic of China
(NCET-13-0714), the Jilin Provincial Research Foundation for
Basic Research (20140519008JH), and the Fundamental
Research Funds for the Central Universities (2412015BJ005).
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