Stereoselective nucleophilic addition reactions to cyclic n-acyliminium ions using the indirect cation pool method: Elucidation of stereoselectivity by spectroscopic conformational analysis and dft calculations

Article abstract of DOI:10.3762/bjoc.14.100

In this study, six-membered N-acyliminium ions were generated by the “indirect cation pool” method and reacted with several nucleophiles. These reactions afforded disubstituted piperidine derivatives with high diastereoselectivities and good to excellent

Full text of DOI:10.3762/bjoc.14.100

Stereoselective nucleophilic addition reactions to cyclic
N-acyliminium ions using the indirect cation pool method:
Elucidation of stereoselectivity by spectroscopic
conformational analysis and DFT calculations
Koichi Mitsudo1, Junya Yamamoto1, Tomoya Akagi1, Atsuhiro Yamashita1,
Masahiro Haisa1, Kazuki Yoshioka1, Hiroki Mandai1, Koji Ueoka2, Christian Hempel2,
Jun-ichi Yoshida2 and Seiji Suga*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1192–1202.
1Division of Applied Chemistry, Graduate School of Natural Science
and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku,
Okayama 700-8530, Japan and 2Department of Synthetic Chemistry
and Biological Chemistry, Graduate School of Engineering, Kyoto
University, Nishikyo-ku, Kyoto 615-8510, Japan
doi:10.3762/bjoc.14.100
Received: 29 December 2017
Accepted: 26 April 2018
Published: 24 May 2018
Email:
This article is part of the Thematic Series "Electrosynthesis II".
Guest Editor: S. R. Waldvogel
Seiji Suga* - suga@cc.okayama-u.ac.jp
* Corresponding author
© 2018 Mitsudo et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
cation pool; conformation; electroorganic synthesis; N-acyliminium
ion; NMR analysis; piperidine
Abstract
In this study, six-membered N-acyliminium ions were generated by the “indirect cation pool” method and reacted with several
nucleophiles. These reactions afforded disubstituted piperidine derivatives with high diastereoselectivities and good to excellent
yields. The conformations of the obtained N-acyliminium ions were studied by low temperature NMR analyses and DFT calcula-
tions and were found to be consistent with the Steven’s hypothesis.
Introduction
Cyclic amines are significant key motifs in pharmaceutical and iminium ions in relatively high concentrations by low tempera-
natural products because a variety of compounds bearing those ture electrolysis [6-10]. The N-acyliminium ions thus generated
moieties exhibit physiological and pharmacological activities can directly react with a variety of carbon nucleophiles to very
[1-3]. As many of these compounds feature asymmetric carbon efficiently yield carbon–carbon bond-formation products. In ad-
atoms at the α-position of the cyclic amine, the stereoselective dition, this research lead to the development of an indirect
carbon–carbon bond formation at this position is of great impor- cation pool method that enables the creation of the cation pool
tance from the perspective of drug discovery [4,5]. Meanwhile by reacting a cation precursor having a C–S bond with an elec-
the “cation pool” method can realize the generation and accu- trochemically generated ArS(ArSSAr)+ as the cation-gener-
mulation of highly reactive cationic species such as N-acyl- ating reagent. For example, a pool of alkoxycarbenium ions
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Beilstein J. Org. Chem. 2018, 14, 1192–1202.
can be rapidly generated by the reaction of thioacetals and able for the generation and accumulation of N-acyliminium
ArS(ArSSAr)+ (Ar = p-FC6H4, Scheme 1) [11].
ions. Therefore, the reaction of N-Boc-4-phenyl-2,3,4,5-tetra-
hydropyridin-1-ium (C1) derived from precursor 1a and
The cation pool method is advantageous over the conventional ArS(ArSSAr)+ (Ar = p-FC6H4) generated by the low tempera-
Lewis acid promoted generation of carbocation species because ture electrolysis was first performed with several nucleophiles
the reactive cationic species can be detected by spectroscopy (Table 1). The starting 1a and other N-acyliminium ion precur-
such as NMR and IR measurements. For this research, the reac- sors were synthesized by the modified Beak’s protocol [12] (see
tion of six-membered N-acyliminium ions having a substituent Supporting Information File 1). As observed in our previous
in the 4-, 5-, or 6-position were generated by the indirect cation studies, the Boc protecting group was found not suitable for the
pool method and examined in the reaction with several nucleo- direct cation pool method due to its cleavage by protic acid
philes to give the disubstituted piperidine derivatives in an generated during the electrolysis of the cation precursor. How-
excellent diastereoselective manner (Scheme 1). This result ever, it can be utilized in the indirect cation pool method as
inspired us to investigate the stereochemistry of the N-acyl- diaryldisulfides are the exclusive side products formed during
iminium ions by means of NMR spectroscopy, which is chal- carbocation generation. Thus, the reaction of acyliminium ion
lenging to achieve without using cation pool methods. The cur- C1 with Me3Al afforded trans-1-(tert-butoxycarbonyl)-2-
rent report presents the diastereoselective synthesis of disubsti- methyl-4-phenylpiperidine (2aa) in a good yield and virtually
tuted piperidine derivatives by the indirect cation pool method complete diastereoselectivity (cis/trans = <1:99). Similarly, the
and the elucidation of the stereoselectivity based on both NMR reaction of C1 with diethylzinc or allyltributylstannane gave pi-
analyses of the cyclic N-acyliminium ions and DFT calcula- peridine derivatives 2ab and 2ac with high yields and trans-
tions.
selectivity (Table 1, entries 2 and 3). Also, the introduction of
phenyl or cyano groups in the piperidine core proceeded in a
highly regioselective manner and good to high yields (Table 1,
Results and Discussion
N-Acyliminium ions obtained from N-Boc-piperidines are entries 4 and 5).
attractive intermediates because they easily can be transformed
to a variety of alkaloids having a piperidine skeleton. In our pre- Next, we examined the reaction of N-Boc-4-methyl-2,3,4,5-
liminary study, we found the indirect cation pool method suit- tetrahydropyridin-1-ium (C2) with nucleophiles (Table 2).
Scheme 1: Generation and reaction of cationic species generated by “indirect cation pool” methods.
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Beilstein J. Org. Chem. 2018, 14, 1192–1202.
Table 1: Reaction of N-acyliminium ion C1 with several nucleophiles.
Table 2: Reaction of N-acyliminium ion C2 with several nucleophiles.
entry
Nu−
2
yield (%)a cis/transb
entry
Nu−
2
yield (%)a cis:transb
Me3Al
(5.0 equiv)
Me3Al
(2.5 equiv)
1
85
89
<1:99
1
86
95
95
93
89
<1:99
<1:99
<1:99
3:97
2aa
2ab
2ac
2ad
2ae
2ba
2bb
2bc
2bd
2be
Et2Zn
(2.5 equiv)
Et2Zn
(5.0 equiv)
2
3
4
5
3:97
2
3
4
5
(allyl)SnBu3
(3.0 equiv)
(allyl)SnBu3
(2.5 equiv)
>99
<1:99
15:85
<1:99
PhMgBr
(2.0 equiv)
PhMgBr
(2.5 equiv)
87
TMSCN
(5.0 equiv)
TMSCN
(5.0 equiv)
99
<1:99
aIsolated yield. bDetermined by GC analysis.
aIsolated yield. bDetermined by GC analysis.
Both, the reactivity and diastereoselectivity of the reactions and all products 2da–dc were obtained in high to excellent cis-
were similar to those of C1 and the disubstituted piperidine de- diastereoselectivities (Table 4).
rivatives 2ba–be were obtained in good to high yields with
excellent diastereoselectivities.
The tendency of the reactions of the 6-phenyl-substituted
N-acyliminium cation C5 with nucleophiles was slightly differ-
Then, the reaction of 5-phenyl-substituted N-acyliminium ent compared to those of C1–C4 (Table 5). The reactions
cation C3 was performed (Table 3). Interestingly, all reactions proceeded in a cis-selective manner, however, the selectivity
led to the 2,5-disubstituted piperidine derivatives 2ca–ce in very was not high except in case of product 2ed (Table 5, entry 4).
good yields and high cis-selective manner. A similar trend is The low yield of 2ed was due to the generation of an enamine
observed for the reactions of the 5-methyl-substituted cation C4 as a byproduct. While the reason of the low selectivity has not
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Beilstein J. Org. Chem. 2018, 14, 1192–1202.
Table 3: Reaction of N-acyliminium ion C3 with several nucleophiles.
entry
Nu−
2
yield (%)a
cis:transb
Me3Al
(2.5 equiv)
1c
89
94:6
2ca
2cb
2cc
2cd
2ce
Et2Zn
(2.5 equiv)
2
3c
4
99
97
97
96
96:4
98:2
96:4c
98:2
(allyl)SnBu3
(2.5 equiv)
PhMgBr
(2.5 equiv)
TMSCN
(5.0 equiv)
5
aIsolated yield. bDetermined by GC analysis. cDetermined by 1H NMR analysis.
been clear, it is probably due to steric repulsion between the Hd (3.10 ppm) exhibited an axial–axial coupling (J > 10 Hz)
phenyl and Boc groups. A distortion of the Boc group in C5 and 7.1% ROE was observed between Hd and Hg. These results
was also suggested by DFT calculation (see Supporting Infor- suggest that Hd adopts an axial and the phenyl group a pseudo-
mation File 1). The reaction of 6-methyl-substituted N-acyl- equatorial position at low temperature.
iminium cation C6 bearing a methyl group, which is smaller
than a phenyl group, gave the corresponding cis-products with The low temperature NMR analysis of C3, which has a phenyl
high diastereoselectivities (Table 6).
group at 5-position, was next performed and the 1H NMR spec-
trum is depicted in Figure 2. An axial–axial coupling between
As mentioned, the reaction between the cyclic N-acyliminium He and Hf was observed, suggesting that these two protons
ions C1–C6 and several nucleophiles proceeded diastereoselec- were located at axial positions. This result indicates that the
tively. To clarify the reason of the observed selectivity, phenyl group of C3 was located in the pseudo-equatorial posi-
1H NMR analyses of C1–C6 were performed at low tempera- tion.
ture (Figures 1–3, see also Supporting Information File 1). All
protons on the piperidine ring in C1 (Ha–Hh) have been The conformation of C5, an N-acyliminium ion bearing a phe-
assigned by H–H COSY (Figure 1). In addition, the signal of nyl group in the 6-position, was also examined by NMR analy-
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Beilstein J. Org. Chem. 2018, 14, 1192–1202.
Table 4: Reaction of N-acyliminium ion C4 with several nucleophiles.
entry
1
Nu−
2
yield (%)a
73
cis:transb
Me3Al
98:2
2da
2db
2dc
2dd
2de
2
3
4
5
Et2Zn
(allyl)SnBu3
PhMgBr
82
90
83
98
95:5
98:2
91:9
96:4
TMSCN
aIsolated yield. bDetermined by GC analysis.
Table 5: Reaction of N-acyliminium ion C5 with several nucleophiles.
entry
1
Nu−
2
yield (%)a
40
cis:transb
Me3Al
63:37
2ea
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Beilstein J. Org. Chem. 2018, 14, 1192–1202.
Table 5: Reaction of N-acyliminium ion C5 with several nucleophiles. (continued)
2
3
4
5
Et2Zn
(allyl)SnBu3
PhMgBr
90
94
56
85
76:24
72:28
92:8
2eb
2ec
2ed
2ee
TMSCN
64:36
aIsolated yield. bDetermined by GC analysis.
Table 6: Reaction of N-acyliminium ion C6 with several nucleophiles.
entry
1
Nu−
2
yield (%)a
49
cis:transb
Me3Al
82:18
2fa
2fb
2fc
2fd
2
3
4
Et2Zn
(allyl)SnBu3
PhMgBr
46
87
87
96:4
96:4
96:4
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Beilstein J. Org. Chem. 2018, 14, 1192–1202.
Table 6: Reaction of N-acyliminium ion C6 with several nucleophiles. (continued)
5
TMSCN
90
>99:1
2fe
aIsolated yield. bDetermined by GC analysis.
Figure 1: (a) 1H NMR of N-acyliminium ion C1 in CD2Cl2 at −80 °C (600 MHz). (b) Preferred conformation of C1.
sis (Figure 3). The signal of Hf was observed as a triplet due to pseudo-axial). Although the conformation of C4 could not be
the axial–axial coupling with He and the geminal coupling with determined by the NMR analysis, the conformation is assumed
Hg, and these results indicate that the phenyl group of C5 is to be similar to that of C3 (pseudo-equatorial), because both
placed in the pseudo-axial position. The low temperature NMR ions led to similar stereoselectivities in the reactions with
measurements of N-acyliminium ions C2, C4, and C6 were also nucleophiles. As mentioned, the conformation of N-acyl-
performed. The conformations of C2 and C6 were similar to iminium cation C1–C4 was pseudo-equatorial and that of C5
those of C1 and C5, respectively (C2: pseudo-equatorial, C6: and C6 was pseudo-equatorial (Figure 4).
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Beilstein J. Org. Chem. 2018, 14, 1192–1202.
Figure 2: (a) 1H NMR spectrum of C3 in CD2Cl2 at −60 °C (400 MHz). (b) Preferred conformation of C3.
Figure 3: (a) 1H NMR spectrum of C5 in CD2Cl2 at −60 °C (400 MHz). (b) Preferred conformation of C5.
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Beilstein J. Org. Chem. 2018, 14, 1192–1202.
N-acyliminium ion would be a half-chair form and that the
attack of the nucleophile proceeds from that side that generates
a stable chair form product, because an attack from another side
would lead to a more unstable product with a twist form [13].
As a close study, Woerpel reported a diastereoselective substi-
tution reaction for synthesizing disubstituted tetrahydropyrans
via six-membered oxocarbenium ions generated in situ from
tetrahydropyran acetals [14]. If the Stevens’ hypothesis is true,
a nucleophilic reaction with C1, having a pseudo-equatorial
phenyl group, should give a trans-2,4-disubstituted product
(Figure 5). Similarly, acyliminium ions C3 and C5 should give
the cis-2,5- or cis-2,6-disubstituted piperidine derivatives, re-
spectively. These explanations are consistent with above
mentioned conformational analyses results, and the hypothesis
was in agreement with the experimental results (Figure 6).
Figure 4: Summary of the conformations of N-acyliminium ions
C1–C6.
It is commonly assumed that the diastereoselectivity of the
disubstituted piperidine derivatives 2a–f was influenced by the
conformation of the N-acyliminium ions C1–C6. In this context
Stevens proposed that the conformation of the six-membered
Figure 5: Stevens’ hypothesis on the tendency of the addition of
nucleophiles to N-acyliminium ions. The substituent at the nitrogen
atom is omitted for clarity.
Figure 6: A plausible mechanism of the observed diastereoselective reaction of the N-acyliminium ions.
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Beilstein J. Org. Chem. 2018, 14, 1192–1202.
To obtain further insight in the conformation of the cyclic the preferred conformations of C2, C4, and C6 were similar to
N-acyliminium ions, DFT calculations of C1–C6 were per- those of C1, C3, and C5.
formed (Figure 7). First, ΔG of pseudo-equatorial and pseudo-
axial conformations of C1 was calculated at the B3LYP/6- Conclusion
31G(d) level of theory. The pseudo-equatorial conformation of In this study, we presented an efficient method for the highly
C1 was more stable than the pseudo-axial conformation by diastereoselective synthesis of disubstituted piperidine deriva-
1.27 kcal/mol. Similarly, DFT calculations of C3 and C5 were tives through the reaction of N-acyliminium ions with nucleo-
performed, and the results show that the pseudo-equatorial con- philes. The starting N-acyliminium ions were generated by the
formation of C3 and the pseudo-axial conformation of C5 were indirect cation pool method and their conformations were con-
more stable than the other conformations, respectively. The firmed by low temperature NMR analyses for the first time. The
more stable conformations that the calculations implied are experimental results were fully consistent with DFT calcula-
consistent with the conformations determined by the low tem- tions. The correlation between the stereochemistry of the
perature NMR analyses, and the DFT calculations suggest that N-acyliminium ions and the reaction products is in agreement
Figure 7: Comparison of ΔG for the pseudo-equatorial and pseudo-axial conformations of C1–C6 at the B3LYP/6-31G(d) level.
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Beilstein J. Org. Chem. 2018, 14, 1192–1202.
10.Yoshida, J.-i.; Suga, S. Chem. – Eur. J. 2002, 8, 2650.
with common interpretation and further synthetic applications
and more detailed investigations of the reaction mechanism are
in progress in our laboratory.
doi:10.1002/1521-3765(20020617)8:12<2650::AID-CHEM2650>3.0.C
O;2-S
11.Suga, S.; Matsumoto, K.; Ueoka, K.; Yoshida, J.-i. J. Am. Chem. Soc.
2006, 128, 7710. doi:10.1021/ja0625778
12.Beak, P.; Lee, W.-K. Tetrahedron Lett. 1989, 30, 1197.
doi:10.1016/S0040-4039(00)72714-6
Supporting Information
13.Stevens, R. V. Acc. Chem. Res. 1984, 17, 289.
doi:10.1021/ar00104a005
Supporting Information File 1
Experimental details, ORTEP drawings of 1a, 1b, 1d–1f,
theoretical calculations of C1–C6, and NMR spectra of all
new compounds and C1–C6.
14.Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.;
Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521.
doi:10.1021/ja037935a
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-100-S1.pdf]
Supporting Information File 2
License and Terms
X-ray structure analysis data for 1a (CCDC-1813600), 1b
(CCDC-1813582), 1d (CCDC-1813594), 1e
(CCDC-1813595), 1f (CCDC-1813596). These data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre via
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
http://www.ccdc.cam.ac.uk/data_request/cif.
X-ray analysis of 1a–f.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-100-S2.cif]
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The definitive version of this article is the electronic one
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Acknowledgements
This work was supported in part by JSPS KAKENHI (No.
doi:10.3762/bjoc.14.100
16H01155, No. 16K05777), and by JST, ACT-C, Japan.
ORCID® iDs
Koichi Mitsudo - https://orcid.org/0000-0002-6744-7136
Hiroki Mandai - https://orcid.org/0000-0001-9121-3850
Jun-ichi Yoshida - https://orcid.org/0000-0001-8439-2272
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