Nickel-catalyzed asymmetric arylative cyclization of N-alkynones: Efficient access to 1,2,3,6-tetrahydropyridines with a tertiary alcohol

Article abstract of DOI:10.1016/j.cclet.2021.06.006

Nickel/(S)-t-Bu-PHOX complex catalyzed asymmetric arylative cyclization of N-alkynones has been achieved, delivering 1,2,3,6-tetrahydropyridines containing a chiral tertiary alcohol in high yields and excellent enantioselectivities, which provides efficient access to chiral tetrahydropyridine and piperidine analogues.

Full text of DOI:10.1016/j.cclet.2021.06.006

ARTICLE IN PRESS
JID: CCLET
[m5G;June 27, 2021;10:40]
Chinese Chemical Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Nickel-catalyzed asymmetric arylative cyclization of N-alkynones:
Efficient access to 1,2,3,6-tetrahydropyridines with a tertiary alcohol
Jiangyan Tiana, Wendian Lia, Ruihao Lia, Lin Heb, Hui Lva,b,∗
a key Laboratory of Biomedical Polymers of Ministry of Education & College of Chemistry and Molecular Sciences, Engineering Research Center of
Organosilicon Compounds & Materials, Ministry of Education, Sauvage Center for Molecular Sciences, Wuhan University, Wuhan 430072, China
b Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University,
Shihezi 832000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Nickel/(S)-t-Bu-PHOX complex catalyzed asymmetric arylative cyclization of N-alkynones has been
achieved, delivering 1,2,3,6-tetrahydropyridines containing a chiral tertiary alcohol in high yields and ex-
cellent enantioselectivities, which provides efficient access to chiral tetrahydropyridine and piperidine
analogues.
Received 21 March 2021
Revised 3 June 2021
Accepted 3 June 2021
Available online xxx
© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia
Medica, Chinese Academy of Medical Sciences.
Keywords:
Asymmetric catalysis
Alkynones
Cyclization
Nickel
Enantioselective construction of high valuable chiral heterocy-
cles in an atom economy and step economy manner is one of
the most important goals of chemists pursued [1,2]. To this end,
the transition-metal-catalyzed intramolecular cyclization of alky-
nals/alkynones, one of the most straightforward methods for the
efficient construction of five- to six-membered heterocycles bear-
ing a tertiary alcohol, has been widely investigated [3-5]. As a re-
sult, cyclization of alkynals/alkynones has been achieved by various
kinds of transition-metal catalysts, such as rhodium [6-15], ruthe-
nium [16], nickel [17-23] or palladium complexes [24-28], which
greatly promoted the development of intramolecular cyclization of
alkynals/alkynones. However, most of these approaches involved
an exo-trig pathway, affording five-membered heterocycles con-
taining an exocyclic olefin (Scheme 1a) [29-31]. By comparison, the
endo-trig cyclization of alkynals/alkyones to generate endocyclic
alkenes was rarely reported, although it provides concise access
to some valuable molecules. In 2016, Lam group reported their
pioneer work on Ni-catalyzed desymmetrization of 1,3-diketones,
which achieved endo-trig cyclization of alkynones, giving fused bi-
cycles efficiently [32]. Nevertheless, only cyclic 1,3-diketones with
relatively high activity could be tolerated in this transformation,
which limited its applications in construction of chiral heterocy-
cles. Thus, it is highly desirable to develop new methodology to
expand the generality of endo-trig cyclization of alkynones [33].
Scheme 1. Transition metal catalyzed arylative cyclization of alkynones.
In the past decades, nickel catalyzed asymmetric reactions has
emerged as a powerful strategy for construction of chiral molecules
[34-38]. In this context, our group reported nickel-catalyzed in-
tramolecular asymmetric reductive cyclization of aryl halides with
unactivated ketones through the addition of aryl nickel species to
carbonyl group [39]. Inspired by this result, we envision that the
vinyl nickel species may also react with unactivated ketones to
generate chiral heterocycles efficiently. Herein, we report a highly
enantioselective intramolecular arylative cyclization of N-alkynones
to furnish chiral tetrahydropyridines containing a tertiary allylic al-
cohol in high yields and excellent enantioselectivities (Scheme 1b),
∗
Corresponding author.
E-mail address: huilv@whu.edu.cn (H. Lv).
https://doi.org/10.1016/j.cclet.2021.06.006
1001-8417/© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Please cite this article as: J. Tian, W. Li, R. Li et al., Nickel-catalyzed asymmetric arylative cyclization of N-alkynones: Efficient access to
1,2,3,6-tetrahydropyridines with a tertiary alcohol, Chinese Chemical Letters, https://doi.org/10.1016/j.cclet.2021.06.006

ARTICLE IN PRESS
JID: CCLET
[m5G;June 27, 2021;10:40]
J. Tian, W. Li, R. Li et al.
Chinese Chemical Letters xxx (xxxx) xxx
Table 1
which are important structural motifs widely existed in natural
products and biologically active compounds [40-42].
Optimization for nickel-catalyzed arylative cyclization of 1a and 2a.a
Our initial study began with nickel-catalyzed arylative cycliza-
tion of N-alkynone (1a) with phenylboronic acid (2a) in the pres-
ence of 10 mol% Ni(OAc)2•4H2O in DCE. Firstly, a series of com-
mercial available chiral oxazoline ligands were evaluated. As shown
in Table 1, Pybox (L1), Pyox (L2), and Box (L3) did not exhibit
any catalytic activity in this transformation (entries 1–3). When
phosphine-oxazoline ligand L4 was employed, it delivered target
product in 50% yield with 14% ee (entry 4). Increasing the steric
hindrance of oxazoline, the enantioselectivity was greatly proved,
but the yield was decreased gradually (entries 5 and 6). Consid-
ering the excellent enantiocontrol ability of (S)-t-Bu-PHOX, it was
chosen as the best ligand for further optimization. Subsequently,
the solvent effects were investigated, and the results disclosed that
toluene and methanol were detrimental to the conversion, which
lead to a totally inhibition of this transformation. The yields in-
creased when 1,4-dioxane, CH3CN and 2-methyltetrahydrofuran (2-
MeTHF) were used as solvent, while the enantioselectivities de-
creased to some extent (entries 7–11). Interestingly, a little water
can improve the yield and has little impact on the enantioselectiv-
ity (entry 12). To our delight, the yield was increased to 95% when
Ni(TFA)2 was used as metal precursor in presence of 2 equiv. water
(entry 13). Increasing the temperature to 90 °C, a full conversion
was obtained, affording target product 3a in 99% yield with 99% ee
(entry 14).
Entry
L
Solvent
Metal salt
Yield (%)b
ee (%)c
1
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
L6
L6
DCE
Ni(OAc)2•4H2O
Ni(OAc)2•4H2O
Ni(OAc)2•4H2O
Ni(OAc)2•4H2O
Ni(OAc)2•4H2O
Ni(OAc)2•4H2O
Ni(OAc)2•4H2O
Ni(OAc)2•4H2O
Ni(OAc)2•4H2O
Ni(OAc)2•4H2O
Ni(OAc)2•4H2O
Ni(OAc)2•4H2O
Ni(TFA)2
NR
NA
NA
NA
14
84
99
86
NA
NA
83
88
99
99
99
2
DCE
NR
3
DCE
NR
4
DCE
50
5
DCE
29
6
DCE
19
7
1,4-Dioxane
Toluene
MeOH
CH3CN
2-MeTHF
DCE
68
8
trace
trace
52
9
10
11
12d
13d
44
31
DCE
95
99 (93)f
14d,
DCE
Ni(TFA)2
e
a
Reaction conditions: 1a (0.05 mmol), 2a (0.15 mmol), nickel salt (10
mol%), ligand (11 mol%), solvent (1 mL), 80 °C, under Ar atmosphere.
Determined by 1H NMR using 3,5-dimethylpyrazole as internal standard.
b
c
Determined by chiral HPLC.
d
H2O (0.10 mmol).
e
The reaction was performed at 90 °C.
f
The isolated yield.
ally, the reaction had a broad substrate scope and exhibited good
tolerance to various substituted arylboronic acids and N-alkynones.
As shown in Scheme 2, different kinds of arylboronic acids, no
matter the position and the electronic nature of substituent, are
well tolerated in this transformation, giving target products in high
With the optimal conditions in hand, we surveyed the general-
ity of nickel-catalyzed arylative cyclization of N-alkynones. Gener-
Scheme 2. Substrate scope. Unless otherwise noted, the reactions were performed with 1 (0.1 mmol), 2 (0.3 mmol), Ni(TFA)2 (10 mol%), (S)-t-Bu-PHOX (11 mol%) and H2O
(0.2 mmol, 5.5 mol/L in dioxane) in DCE (2 mL) at 90 °C for 36 h under Ar atmosphere. Yields of isolated product 3. Enantiomeric excess was determined by chiral HPLC.
The absolute configuration of 3k was confirmed to be R by X-ray, the other configurations follows that of 3k.
2

ARTICLE IN PRESS
JID: CCLET
[m5G;June 27, 2021;10:40]
J. Tian, W. Li, R. Li et al.
Chinese Chemical Letters xxx (xxxx) xxx
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.cclet.2021.06.006.
References
[1] M.G. Vinogradov, O.V. Turova, S.G. Zlotin, Adv. Synth. Catal. 363 (2021)
1466–1526.
[2] R.M. Philip, S. Radhika, P.V. Saranya, G. Anilkumar, RSC Adv. 10 (2020)
42441–42456.
Scheme 3. Gram scale reaction.
[3] I. Ojima, M. Tzamarioudaki, Z. Li, R.J. Donovan, Chem. Rev. 96 (1996) 635–662.
[4] J. Montgomery, Acc. Chem. Res. 33 (2000) 467–473.
[5] W.W. Chen, M.H. Xu, Org. Biomol. Chem. 15 (2017) 1029–1050.
[6] I. Ojima, M. Tzamarioudaki, C.Y. Tsai, J. Am. Chem. Soc. 116 (1994) 3643–3644.
[7] B. Bennacer, M. Fujiwara, S.Y. Lee, I. Ojima, J. Am. Chem. Soc. 127 (2005)
17756–17767.
yields and excellent enantioselectivities (3a-3l). Notably, the reac-
tion shows excellent compatibility to a series of functional groups,
such as aldehyde (3f), ester (3g), cyano group (3h), hydroxyl group
(3i), and there was no significant impact on the yield and enantios-
electivity. When R1 is substituted aryl group or naphthyl group, the
reaction proceeded very smoothly, delivering desired products 3m-
3r with high yields and excellent enantioselectivities. It is worth
noting that the reaction was also compatible with alkyl substi-
tuted N-alkynone, furnishing 3s in 87% yield with 87% ee. When
R2 is substituted benzene group, it afforded target products with
high yields and excellent ee values (3t-3v). Replacing R2 by a het-
eroaryl, the yield and enantioselectivity decreased to some extent
(3w). The ether-tethered substrate was also tolerated, but the ee
value dropped dramatically (88% yield and 66% ee, see Supporting
information).
[8] R. Shintani, K. Okamoto, Y. Otomaru, K. Ueyama, T. Hayashi, J. Am. Chem. Soc.
127 (2005) 54–55.
[9] J.U. Rhee, M.J. Krische, J. Am. Chem. Soc. 128 (2006) 10674–10675.
[10] X. Fang, C. Li, X. Tong, Chem. Commun. (2009) 5311–5313.
[11] R. Tanaka, K. Noguchi, K. Tanaka, J. Am. Chem. Soc. 132 (2010) 1238–1239.
[12] K. Masuda, N. Sakiyama, R. Tanaka, K. Noguchi, K. Tanaka, J. Am. Chem. Soc.
133 (2011) 6918–6921.
[13] J. Keilitz, S.G. Newman, M. Lautens, Org. Lett. 15 (2013) 1148–1151.
[14] F. Serpier, J.L. Brayer, B. Folléas, S. Darses, Org. Lett. 17 (2015) 5496–5499.
[15] A. Selmani, S. Darses, Org. Lett. 22 (2020) 2681–2686.
[16] A. Saxena, F. Perez, M.J. Krische, Angew. Chem. Int. Ed. 55 (2016) 1493–1497.
[17] X.Q. Tang, J. Montgomery, J. Am. Chem. Soc. 121 (1999) 6098–6099.
[18] Y. Ni, K.K.D. Amarasinghe, J. Montgomery, Org. Lett. 4 (2002) 1743–1745.
[19] R.D. Baxter, J. Montgomery, J. Am. Chem. Soc. 133 (2011) 5728–5731.
[20] A.D. Jenkins, A. Herath, M. Song, J. Montgomery, J. Am. Chem. Soc. 133 (2011)
14460–14466.
To demonstrate the synthetic utility of the current method-
ology, a gram-scale reaction was conducted under the standard
condition, affording desired product 3a in 88% yield with 98% ee,
which indicated that the method has a potential application in
construction of chiral molecules with a tetrahydropyridine motif.
In conclusion, nickel-catalyzed asymmetric cyclization of N-
alkynones with arylboronic acids has been achieved, offering
1,2,3,6-tetrahydropyridines bearing a chiral tertiary alcohol in ex-
cellent yields with excellent enantioselectivities (up to 99% yield,
up to 99% ee). This reaction proceeded through an endo-trig path-
way, which provides efficient access to heterocycles with an endo-
cyclic allylic alcohol. Moreover, the potential utility of this method
was demonstrated by a gram-scale reaction without loss of yield
and enantioselectivity. Further development and application of this
reaction is underway in our laboratories.
[21] M.T. Haynes, P. Liu, R.D. Baxter, et al., J. Am. Chem. Soc. 136 (2014)
17495–17504.
[22] H. Wang, S. Negretti, A.R. Knauff, J. Montgomery, Org. Lett. 17 (2015)
1493–1496.
[23] Z. Zhou, W. Liu, W. Kong, Org. Lett. 22 (2020) 6982–6987.
[24] K. Shen, X. Han, X. Lu, Org. Lett. 15 (2013) 1732–1735.
[25] J. Song, Q. Shen, F. Xu, X. Lu, Org. Lett. 9 (2007) 2947–2950.
[26] L. Zhao, X. Lu, Angew. Chem. Int. Ed. 41 (2002) 4343–4345.
[27] H. Wang, X. Han, X. Lu, Tetrahedron 66 (2010) 9129–9134.
[28] X. Han, X. Lu, Org. Lett. 12 (2010) 108–111.
[29] Y. Li, M.H. Xu, Org. Lett. 16 (2014) 2712–2715.
[30] W. Fu, M. Nie, A. Wang, Z. Cao, W. Tang, Angew. Chem. Int. Ed. 54 (2015)
2520–2524.
[31] G. Liu, W. Fu, X. Mu, et al., Commun. Chem. 1 (2018) 90.
[32] C. Clarke, C.A. Incerti-Pradillos, H.W. Lam, J. Am. Chem. Soc. 138 (2016)
8068–8071.
[33] H. Green, S.P. Argent, H.W. Lam, Chem. Eur. J. (2021), doi:10.1002/chem.
202100143.
[34] Z. Lu, X.D. Hu, H. Zhang, et al., J. Am. Chem. Soc. 142 (2020) 7328–7333.
[35] W. Wang, C. Ding, G. Yin, Nat. Catal. 3 (2020) 951–958.
[36] Y. Cai, L.X. Ruan, A. Rahman, S.L. Shi, Angew. Chem. Int. Ed. 60 (2021)
5262–5267.
[37] Y.Q. Li, G. Chen, S.L. Shi, Org. Lett. 23 (2021) 2571–2577.
[38] P. Ye, X. Liu, G. Wang, L. Liu, Chin. Chem. Lett. 32 (2021) 1237–1240.
[39] Y. Li, W. Li, J. Tian, G. Huang, H. Lv, Org. Lett. 22 (2020) 5353–5357.
[40] M.M. Khan, S. Khan, S. Saigal, Iqbal, RSC Adv. 6 (2016) 42045–42061.
[41] S. Hanessian, A.K. Chattopadhyay, Org. Lett. 16 (2014) 232–235.
[42] O.G. Mancheño, R. Gómez Arrayás, J. Adrio, J.C. Carretero, J. Org. Chem. 72
(2007) 10294–10297.
Declaration of competing interest
The authors declare no conflict of interest.
Acknowledgments
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 22071188, 21871212), the open
foundation of CAS Key Laboratory of Molecular Recognition and
Function, the "Double First-Class" Project of Shihezi University.
3