Asymmetric synthesis of tetrahydroisoquinoline derivatives through 1, 3-dipolar cycloaddition of C, N-cyclic azomethine imines with allyl alkyl ketones

Article abstract of DOI:10.3390/molecules26102969

[3 + 2] A 1, 3-Dipolar cycloaddition of C, N-cyclic azomethine imines with allyl alkyl ketones has been achieved. The reaction proceeds under mild conditions and tolerates a wide range of functional groups. An array of tetrahydroisoquinoline derivatives is generally constructed with good diastereoselectivities and enantioselectivities (up to >25:1 dr, >95% ee). Moreover, the absolute configuration of the product was previously determined by using the quantum electronic circular dichroism calculation and ECD spectrum method.

Full text of DOI:10.3390/molecules26102969

molecules
Article
Asymmetric Synthesis of Tetrahydroisoquinoline Derivatives
through 1,3-Dipolar Cycloaddition of C,N-Cyclic Azomethine
Imines with Allyl Alkyl Ketones
Guipeng Feng 1,2, Guoyang Ma 2, Wenyan Chen 2, Shaohong Xu 2, Kaikai Wang 2,
*
and Shaoyan Wang 1,
*
1
School of Chemical Engineering, University of Science and Technology Liaoning, Anshan 114051, China;
fengguipengheda@163.com
School of Pharmacy, Xinxiang University, Xinxiang 453000, China; maguoyang0903@gmail.com (G.M.);
c15736992481@163.com (W.C.); xu_shaohong@126.com (S.X.)
2
*
Correspondence: wangkaikai@xxu.edu.cn (K.W.); aswsy64@163.com (S.W.)
Abstract: A [3 + 2] 1,3-Dipolar cycloaddition of C,N-cyclic azomethine imines with allyl alkyl ketones
has been achieved. The reaction proceeds under mild conditions and tolerates a wide range of
functional groups. An array of tetrahydroisoquinoline derivatives is generally constructed with
good diastereoselectivities and enantioselectivities (up to >25:1 dr, >95% ee). Moreover, the absolute
configuration of the product was previously determined by using the quantum electronic circular
dichroism calculation and ECD spectrum method.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Keywords: 1,3-dipolar cycloaddition; asymmetric; azomethine imines
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Feng, G.; Ma, G.; Chen, W.;
Xu, S.; Wang, K.; Wang, S.
Asymmetric Synthesis of
1. Introduction
Tetrahydroisoquinoline Derivatives
through 1,3-Dipolar Cycloaddition of
C,N-Cyclic Azomethine Imines with
Allyl Alkyl Ketones. Molecules 2021,
26, 2969. https://doi.org/10.3390/
molecules26102969
A variety of isoquinoline alkaloids [1–3] exist in many natural products and drugs,
and have a broad range of clinical applications, exhibiting a broad range of biological
activities such as antitumor, anti-HIV, antibiotic, antifungal, antivirus, anti-inflammatory,
anticoagulation, and bronchodilation, and can also act on the central nervous system [4–8]
In particular, it is tremendously noteworthy that all the above-illustrated bioactive tetrahy-
droisoquinolines have a chiral stereocenter at the C1-position [ 12]. Such representative
examples include (S)-salsolidine [13], (S)-carnegine [14], (S)-xylopinine [15] (in Figure 1),
and so on. Novel C,N-cyclic azomethine imines as efficient 1,3-dipoles [16 17], are readily
accessible, stable compounds that have been employed recently in various metal-catalyzed
and organocatalytic 1,3-dipolar cycloadditions (1,3-DCs) [18 21]. These dipoles can be
.
9
–
Academic Editor: Fangrui Zhong
,
Received: 12 April 2021
Accepted: 12 May 2021
Published: 17 May 2021
–
easily prepared and give access to pharmaceutically attractive chiral substituted tetrahy-
droisoquinoline skeletons.
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
MeO
MeO
MeO
MeO
MeO
N
MeO
H
NH
N
Me
H
OMe
(S)-salsolidine
(S)-carnegine
(S)-xylopinine
OMe
Copyright:
© 2021 by the authors.
Figure 1. Examples of bioactive natural products containing chiral C1-substituted tetrahydroiso-
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
quinolines.
In 2010, the Maruoka group uncovered a promising example of using C,N-cyclic
azomethine imines as prochiral electrophiles to react with α,β-unsaturated aldehydes to
construct a tetrahydroisoquinoline scaffold catalyzed by a titanium–BINOLate complex [22].
Shortly after, the Maruoka group disclosed the first example of using of vinyl ethers and
Molecules 2021, 26, 2969. https://doi.org/10.3390/molecules26102969
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 2969
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C,N-cyclic azomethine imines catalyzed by chiral Brønsted acids to synthesize tetrahy-
droisoquinolines through the enantioselective organocatalytic inverse-electron-demand
1,3-DCs [23]. In 2014, the Wang group developed C,N-cyclic azomethine imines with
unsaturated aldehydes through dienamine-mediated enantioselective [3 + 2] 1,3-dipolar
cycloaddition catalyzed by a chiral prolinol silyl ether catalyst [24 25]. In addition, the C,N-
cyclic azomethine imine substrates were recently used in 1,3-DCs with N-arylmaleimides,
allenoates, azlactones, bromo-substituted Morita Baylis Hillman adducts of isatins,
unsaturated nitriles, 3-nitroindoles, ortho-quinone methides through [3 + 2] or [4 + 3]
annulation reactions [26 30] and catalyst free [5 + 1] cycloaddition with isocyanides [31],
and with Morita Baylis Hillman carbonates by phosphine catalysts or with N-benzyl
azomethine ylide or with azaoxyallyl cations through [3 + 3] cycloaddition [32 34], and
α,β-
,
−
−
α,β-
–
−
−
–
[3 + 1] cycloaddition with isocyanides (in Scheme 1a) [35]. However, to the best of our
knowledge, no example of a catalytic asymmetric 1,3-dipolar cycloaddition reaction using
allyl alkyl ketones with C,N-cyclic azomethine imines has been reported. Previous suc-
cess by the Chen group, using chiral primary amine catalytic asymmetric γ-regioselective
vinylogous Michael addition of allyl alkyl ketones with maleimides through dienamine
catalysis, has been developed (in Scheme 1b) [36]. Herein, we report the first chiral primary
amine-catalyzed enantioselective [3 + 2] 1,3-dipolar cycloaddition of allyl alkyl ketones
with C,N-cyclic azomethine imines to give a novel class of dinitrogen-fused heterocycles
combining the biologically important tetrahydroisoquinoline core and pyrazolidine core
(in Scheme 1c).
Scheme 1. Previous reports and our protocol.
2. Results
In our initial attempt, we first examined the reaction of N,N-cyclic azomethine imine
1
with deconjugated 3-enone 5a in the presence of DPEN catalyst C1 (Table 1) in CHCl3,
but no desired product was observed even at a higher temperature. We then turned our
attention to C,N-cyclic azomethine imines 2, 3 and 4a. Unfortunately, no matter what the
temperature of the reaction raised from rt to reflux, no desired cycloaddition adduct was
observed when we employed the
2 and 3 dipoles. To our delight, the reaction between
C,N-cyclic azomethine imine 4a and deconjugated 3-enone 5a proceeded smoothly to give
the desired product in high yield (85% yield, 62% ee and dr 3:2, entry 1, Table 1) and the
reaction could not afford the desired product if no acid or no catalyst were added to the
reaction [18] (entries 2 and 3). The results indicated that catalysts with acids are critical

Molecules 2021, 26, 2969
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for the cycloaddition reaction. In addition, the
β,
γ
-C=C bond could act as an inducing
group for the formation of more stable extended dienamine species from deconjugated
3-enone substrates 5a and activating the γ-site and furnishing the following vinylogous
1,3-DCs process.
Table 1. Optimization of reaction conditions a.
O
N
N
N
NTs
N
NBz
Ph
1
2
3
O
N
O
O
N
C (10 mol%)
N
acid (20 mol%)
N
Ph
solvent,
r.t., 12 h
O
NO2
NO2
4a
5a
Ph
6aa
Ph
H2N
Ph
NH2
Ph
Ph
Ph
Ph
C1
C7
C8
C4
C5
H2N
Ph
N
H2N HN
Ph
Ph
Ph
Ph
Ph
C2
C3
S
CF3
CF3
H2N HN
H2N HN Bn
Ph Ph
H2N HN
H2N HN
HN
Ph
Ph
C6
H2N HN
OMe
H
Ph
Ph
OTMS
N
C10
N
C9
H
NH2
N
Yield (%) b
dr d
Entry
Solvent
Catalyst
Acid
ee (%) c
1
2
3
4
5
6
7
8
9
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Toluene
DCE
CH3CN
THF
Dioxane
Et2O
EA
DCE
C1
C1
none
C2
C3
C4
C5
C6
C7
C8
C9
C10
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
benzoic acid
none
85
n.r.
n.r.
89
91
90
86
85
87
88
56
n.r.
90
91
72
65
87
62
-
-
3:2
-
-
12.5:1
>25:1
>25:1
>25:1
>25:1
>25:1
5:1
>25:1
-
1:1
25:1
2:1
6:1
1:1
-
1:1
10:1
4:1
15.7:1
6:1
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
o-fluorobenzoic acid
salicylic acid
p-nitrobenzoic acid
80
76
72
38
59
44
11
20
-
85
80
28
50
77
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
a
trace
74
70
84 (64) e
65
68
82
92 (85) e
90
DCE
DCE
DCE
82
75
p-methoxybenzoic acid
Unless noted otherwise, reactions were performed with 4a (0.1 mmol), 5a (0.2 mmol), amine
C
(10 mol%), and acid (20 mol%) in solvent
b
c
d
e
(1 mL) at rt. Isolated yield. Determined by chiral HPLC analysis. Determined by crude NMR analysis. The reaction was conducted at
0 ◦C for 24 h.

Molecules 2021, 26, 2969
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We then turned our attention towards the use of chiral primary amine catalyst to
improve the reaction enantioselectivity and diastereoselectivity. The reaction was tested
in the presence of a number of primary amine catalysts (entries 4–10). The corresponding
product 6aa was then isolated in high yield (89%), good enantioselectivity (80% ee), and
with good diastereoselectivity (dr 12.5:1) through C2 catalyst in CHCl3 at room temperature
(entry 4). In contrast, the reaction afforded poor to moderate enantioselectivity (11–76%)
when used with other catalysts (entries 5–11). The chiral prolinol silyl ethers as the
catalyst could not produce the product (entry 12). A screening of the solvents showed that
performing the reaction to improve the ee and the dr (entry 13–19) with C2 as the catalyst.
The reaction proceeded with higher yield (91%) and good enantioselectivity (80%) and
excellent diastereoselectivity (dr 25:1) in DCE at room temperature (entry 14). However,
only poor or moderate diastereoselectivities were observed in other solvents (entry 13,
15–19). Furthermore, the effect of acid additives was also studied. The presence of 20 mol%
o-fluorobenzoic acid (OFBA) enhanced the ee value to 84% and the yield also increased
to 92% (entry 20). A screening of the temperature showed that performing the reaction at
0 ◦C reduced the ee value and the yield (entry 20). The yield and stereoselectivity could
not be further improved when the reaction used the other acid additives (entries 21–23).
On the basis of the above-mentioned results, the reaction conditions were established to
1.0 equivalent of 4, 2.0 equivalents of 5, 10 mol% of C2 and 20 mol% of OFBA in DCE at
room temperature for 12 h.
3. Discussion
With the optimized conditions in hand, the generality of the reaction was evaluated. A
range of substrates was shown to be compatible with the developed protocol for the [3 + 2]
cycloaddition of C,N-cyclic azomethine imines to allyl alkyl ketone by using C2 as catalyst.
As summarized in Figure 2 (Figures S2 and S3 Supplementary Material, respectively), not
only aromatic alkyl allyl ketones but also long aliphatic chain allyl ketones could all be
employed successfully to afford the products 6aa–ah in high yields (88–96%), moderate to
high enantioselectivities (50–96%), and high diastereoselectivities (dr 10:1 to >25:1) From
these results, we found that the conditions were applicable to a wide variety of allyl alkyl
ketones. With this promising result in hand, we then investigated the generality of the
C,N-cyclic azomethine imines. The influence of the substituent of the benzoyl group on the
nitrogen was examined. The benzoyl group bearing electron-withdrawing or -donating
groups at the para position and meta position afforded the corresponding products in high
yields and steroselectivities (6ba to 6ga). We found that some electron-withdrawing groups
(
(
(
−
NO2,
CH3,
−
Cl,
−
Br) on the aromatic moiety were more effective than some donating groups
−
−
OCH3, 3,5-Me2) to afford the products in yields and steroselectivities, respectively
6aa to 6ga). From these results, it was determined that the electron density of the N’-acyl
moiety played an important role in trapping the
β
-position of the carbon carbon double
−
bond intermediate for the 1,3-DCs. This study prompted us to examine the influence of
structurally different N’-acyl moiety azomethine imines. The furoyl and naphthoyl groups
on the nitrogen were also tolerated, giving the desired products in high yields, moderate
enantioselectivities, and high diastereoselectivities, respectively (6ha 95% yield, 60% ee, dr
> 25:1 and 6ia 93% yield, 71% ee, dr > 25:1). An increase in the steric bulk of the N’-acyl
moiety was also tolerated to afford the product 6ja in high yields (90%) with 72% ee value
and dr 10:1.

Molecules 2021, 26, 2969
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a
Figure 2. Substrate scope of the double 1,3-dipolar cycloaddition a. Unless noted otherwise, reactions were performed
with 4 (0.1 mmol), 5 (0.2 mmol), amine C2 (10 mol%), and OFBA (20 mol%) in DCE (1 mL) at rt.
As we failed to obtain single crystals suitable for X-ray crystallographic analysis to
determine the absolute configuration of the products, the electronic circular dichroism
(ECD) spectrum of chiral product 6ba was recorded in methanol and compared with the
theoretically calculated results [37–39]. As depicted in Figure 3, the experimental ECD
spectrum matched quite well to the calculated one of (R,S)-6ba. Therefore, the stereogenic
center of product 6ba is probably in the (R,S) configuration.

Molecules 2021, 26, 2969
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Figure 3. Comparison of the experimental ECD spectrum of chiral 6ba (the red line) with the
calculated one of (R,S)-6ba (the blue line). The green line is the position of the peak in horizontal axis.
As shown in Scheme 2, we proposed a plausible catalytic cycle to explain the reaction
mechanism. The condensation of a chiral primary amine catalyst with allyl phenylethyl
ketone 5a would lead to the formation of the iminium-ion, which could form the dien-
amine intermediate
A [40–42]. The dienamine intermediate A reacts with the C,N-cyclic
azomethine 4a by a 1,3-dipolar cycloaddition to generate the polycyclic intermediate
B.
Subsequently, an acid-catalyzed elimination step converts intermediate
B to the final
product 6aa.
Scheme 2. Plausible mechanism.
4. Materials and Methods
NMR data were obtained for 1H at 400 MHz or 600 MHz, and for 13C at 100 MHz
or 150 MHz. The data are presented as follows: chemical shift was reported in ppm from
tetramethylsilane with the solvent resonance as the internal standard in CDCl3 solution,
integration, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet) and coupling constant in Hertz (Hz). ESI HRMS was recorded on a Waters
SYNAPT G2. In each case, enantiomeric excesses (ee) were determined by chiral high-
performance liquid chromatography (chiral HPLC) that were Daicel Chiralpak AD-H

Molecules 2021, 26, 2969
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Column (250
(250
×
4.6 mm), Chiralpak IA Column (250
4.6 mm). UV detection was monitored at 220 nm or 254 nm. Optical rotation was
×
4.6 mm), or Chiralpak IC Column
×
measured in CHCl3 solution at 20 ◦C. Column chromatography was performed on silica
gel (200–300 mesh) eluting with ethyl acetate and petroleum ether. TLC was performed
on glass-backed silica plates. UV light, I2, and solution of potassium permanganate were
used to visualize products. All chemicals were used without purification as commercially
available unless otherwise noted. Petroleum ether (PE) and ethyl acetate (EtOAc) were
distilled. THF was freshly distilled from sodium/benzophenone before use. Experiments
involving moisture and/or air sensitive components were performed under a positive
pressure of argon in oven-dried glassware equipped with a rubber septum inlet. Dried
solvents and liquid reagents were transferred by oven-dried syringes.
The 1,3-dipoles of
the literature methods. The substrates 5a−h were prepared according to the literature
procedures [36 52 57]. Catalyst C1 was commercially available. Catalysts C2 C8 were syn-
thesized according to the literature procedures [58 59]. The C,N-cyclic azomethine imines
(0.1 mmol), catalyst C2 (2.8 mg, 0.01 mmol), o-fluorobenzoic acid (2.8 mg, 0.02 mmol) were
dissolved in DCE (1.0 mL) and allyl ketone (0.2 mmol) was added. Then, the mixture
1 [43], 2 [44], 3 [45] and 4 [46–51] were synthesized according to
,
–
–
,
4
5
was stirred at rt for 12 h. After completion, the mixture was evaporated and the resulting
crude residue was purified by column chromatography on silica gel eluting with petroleum
ether/ethyl acetate (10:1 to 5:1) to afford the chiral product 6.
5. Conclusions
In conclusion, we have developed the first chiral primary amine-catalyzed enantiose-
lective [3 + 2] 1,3-dipolar cycloaddition of allyl alkyl ketones with C,N-cyclic azomethine
imines via induced dienamine catalysts to give a novel class of dinitrogen-fused heterocy-
cles combining the biologically important tetrahydroisoquinoline core and pyrazolidine
core. The reaction affords a tetrahydroisoquinoline derivative in high yield with moderate
to high enantioselectivities (up to 96%) and high diastereoselectivities. In addition, this
reaction provides an efficient method for constructing diverse and complex chiral tetrahy-
droisoquinolines compounds. Research into further applications of this enantioselective
1,3-dipolar cycloaddition with C,N-cyclic azomethine imines is in progress.
Supplementary Materials: The following are available online. Figure S1: General procedure for the
preparation of the C,N-cyclic azomethines imines and its analogs, Figure S2: General procedure for
catalytic asymmetric 1,3-DCs, Figure S3: Copies of NMR spectra and HPLC spectra.
Author Contributions: G.F., G.M., W.C. and S.X. participated in the synthesis, purification and
characterization of the new compound. K.W. and S.W. participated in the interpretation of spec-
troscopy of the new compounds and the review of the manuscript. K.W. and S.W. participated in
the interpretation of the results, writing, revision and correspondence to the Journal of Molecules
until the manuscript was accepted. All authors have read and agreed to the published version of
the manuscript.
Funding: This research was funded by the NSFC (21801214) and Funding of College Students
Innovation and Entrepreneurship Training Program of Henan province (S202011071009).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data are contained within the article or Supplementary materials.
Acknowledgments: We are grateful for the financial support from Funding of College Students
Innovation and Entrepreneurship Training Program of Henan province (S202011071009).
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or
in the decision to publish the results.
Sample Availability: Samples of the compounds are available from the authors.

Molecules 2021, 26, 2969
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References
1.
Kouznetsov, V.V.; Ortiz-Villamizar, M.C.; Mendez-Vargas, L.Y.; Puerto Galvis, C.E. A Review on Metal-Free Oxidative
α
-Cyanation
and Alkynylation of N-Substituted Tetrahydroisoquinolines as a Rapid Route for the Synthesis of Isoquinoline Alkaloids. Curr.
Org. Chem. 2020, 24, 809–816. [CrossRef]
2.
3.
4.
5.
6.
7.
8.
9.
Chrzanowska, M.; Grajewska, A.; Rozwadowska, M.D. Asymmetric Synthesis of Isoquinoline Alkaloids: 2004–2015. Chem. Rev.
2016, 116, 12369–12465. [CrossRef] [PubMed]
Bhadra, K.; Kumar, G.S. Therapeutic Potential of Nucleic Acid-Binding Isoquinoline Alkaloids: Binding Aspects and Implications
for Drug Design. Med. Res. Rev. 2011, 31, 821–862. [CrossRef] [PubMed]
Shang, X.-F.; Yang, C.-J.; MorrisNatschke, S.L.; Li, J.-C.; Yin, X.-D.; Liu, Y.-Q.; Guo, X.; Peng, J.-W.; Goto, M.; Zhang, J.-Y.; et al.
Biologically active isoquinoline alkaloids covering 2014–2018. Med. Res. Rev. 2020, 40, 2212–2289. [CrossRef] [PubMed]
Li, D.-D.; Yu, P.; Xiao, W.; Wang, Z.-Z.; Zhao, L.-G. Berberine: A Promising Natural Isoquinoline Alkaloid for the Development of
Hypolipidemic Drugs. Curr. Top. Med. Chem. 2020, 20, 2634–2647. [CrossRef]
Qing, Z.-X.; Yang, P.; Tang, Q.; Cheng, P.; Liu, X.-B.; Zheng, Y.-J.; Liu, Y.-S.; Zeng, J.-G. Isoquinoline Alkaloids and Their Antiviral,
Antibacterial, and Antifungal Activities and Structure-activity Relationship. Curr. Org. Chem. 2017, 21, 1920–1934. [CrossRef]
Iranshahy, M.; Quinn, R.J.; Iranshahi, M. Biologically active isoquinoline alkaloids with drug-like properties from the genus
Corydalis. RSC Adv. 2014, 4, 15900–15913. [CrossRef]
Maiti, M.; Kumar, G.S. Polymorphic nucleic Acid binding of bioactive isoquinoline alkaloids and their role in cancer. J. Nucleic
Acids 2010, 2010, 593408. [CrossRef]
Lu, S.M.; Wang, Y.Q.; Han, X.W.; Zhou, Y.G. Asymmetric hydrogenation of quinolines and isoquinolines activated by chlorofor-
mates. Angew. Chem. Int. Ed. 2006, 45, 2260–2263. [CrossRef]
10. Scott, J.D.; Williams, R.M. Chemistry and biology of the tetrahydroisoquinoline antitumor antibiotics. Chem. Rev. 2002, 102, 1669–
1730. [CrossRef]
11. Li, B.; Liu, R.X.; Yang, J.; Luo, J.Y.; Yao, L.; Li, M.Q.; Zheng, X.H.; Jiang, R.; Nie, H.F.; Zhang, S.Y. Iridium-Catalyzed Asymmetric
Hydrogenation of Sterically Hindered Cyclic Imines for Enantioselective Synthesis of Tetrahydroisoquinolines. Org. Lett. 2021
,
23, 140–144. [CrossRef] [PubMed]
12. Li, D.; Chen, X.C.; Gao, W. Asymmetric Synthesis of C-1-Chiral THIQs with Imines in Isoquinoline Rings. Synthesis 2020
52, 3337–3355. [CrossRef]
,
13. Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M.; Ohta, T.; Takaya, H. Asymmetric synthesis of isoquinoline alkaloids by homoge-
neous catalysis. J. Am. Chem. Soc. 1986, 108, 7117–7119. [CrossRef]
14. Pyne, S.G.; Bloem, P.; Chapman, S.L.; Dixon, C.E.; Griffith, R. Chiral sulfur compounds. 9. Stereochemistry of the intermolecular
and intramolecular conjugate additions of amines and anions to chiral (E)- and (Z)-vinyl sulfoxides. Total syntheses of (R)-(+)-
carnegine and (+)- and (−)-sedamine. J. Org. Chem. 1990, 55, 1086–1093. [CrossRef]
15. Mastranzo, V.M.; Yuste, F.; Ortiz, B.; Sanchez-Obregon, R.; Toscano, R.A.; Garcia Ruano, J.L. Asymmetric Synthesis of (S)-(-)-
Xylopinine. Use of the Sulfinyl Group as an Ipso Director in Aromatic S-E. J. Org. Chem. 2011, 76, 5036–5041. [CrossRef]
16. De, N.; Yoo, E.J. Recent Advances in the Catalytic Cycloaddition of 1,n-Dipoles. ACS Catal. 2018, 8, 48–58. [CrossRef]
17. Bao, G.; Wang, P.; Li, G.; Yu, C.; Li, Y.; Liu, Y.; He, Z.; Zhao, T.; Rao, J.; Xie, J.; et al. 1,3-Dipolar Cycloaddition between
Dehydroalanines and C,N-Cyclic Azomethine Imines: Application to Late-Stage Peptide Modification. Angew. Chem. Int. Ed.
2021, 60, 5331–5338. [CrossRef]
18. Hua, T.; Yang, Q.; Xiao, W. Recent Developments of Reactions with C,N-Cyclic Azomethine Imines. Chin. J. Org. Chem. 2020
40, 3559–3595. [CrossRef]
,
19. Qiu, G.; Kuang, Y.; Wu, J. N-Imide Ylide-Based Reactions: C-H Functionalization, Nucleophilic Addition and Cycloaddition. Adv.
Synth. Catal. 2014, 356, 3483–3504. [CrossRef]
20. Yue, G.; Liu, B. Research Progress on 3 + n (n
21. Hashimoto, T.; Maruoka, K. Recent Advances of Catalytic Asymmetric 1,3-Dipolar Cycloadditions. Chem. Rev. 2015, 115, 5366–5412.
[CrossRef] [PubMed]
≥
3) cycloaddition of 1,3-Diploes. Chin. J. Org. Chem. 2020, 40, 3132–3153. [CrossRef]
22. Hashimoto, T.; Maeda, Y.; Omote, M.; Nakatsu, H.; Maruoka, K. Catalytic Enantioselective 1,3-Dipolar Cycloaddition of
C,N-Cyclic Azomethine Imines with alpha, beta-Unsaturated Aldehydes. J. Am. Chem. Soc. 2010, 132, 4076–4077. [CrossRef]
23. Hashimoto, T.; Omote, M.; Maruoka, K. Asymmetric Inverse-Electron-Demand 1,3-Dipolar Cycloaddition of C,N-Cyclic Azome-
thine Imines: An Umpolung Strategy. Angew. Chem. Int. Ed. 2011, 50, 3489–3492. [CrossRef]
24. Li, W.; Wei, J.; Jia, Q.; Du, Z.; Zhang, K.; Wang, J. Asymmetric Synthesis of Tetrahydroquinolines through a 3 + 2 Cycloaddition
Controlled by Dienamine Catalysis. Chem. Eur. J. 2014, 20, 6592–6596. [CrossRef] [PubMed]
25. Li, W.; Jia, Q.; Du, Z.; Zhang, K.; Wang, J. Amine-Catalyzed Enantioselective 1,3-Dipolar Cycloadditions of Aldehydes to
C,N-Cyclic Azomethine Imines. Chem. Eur. J. 2014, 20, 4559–4562. [CrossRef]
26. Chen, L.; Yang, G.M.; Wang, J.; Jia, Q.F.; Wei, J.; Du, Z.Y. An efficient 4+3 cycloaddition reaction of aza-o-quinodimethanes with
C,N-cyclic azomethine imines: Stereoselective synthesis of 1,2,4-triazepines. RSC Adv. 2015, 5, 76696–76699. [CrossRef]
27. Zhan, G.; Shi, M.-L.; He, Q.; Du, W.; Chen, Y.-C. 4 + 3 Cycloadditions with Bromo-Substituted Morita-Baylis-Hillman Adducts of
Isatins and N-(ortho-Chloromethyl)aryl Amides. Org. Lett. 2015, 17, 4750–4753. [CrossRef] [PubMed]

Molecules 2021, 26, 2969
9 of 10
28. Liu, X.; Wang, Y.; Yang, D.; Zhang, J.; Liu, D.; Su, W. Catalytic Asymmetric Inverse-Electron-Demand 1,3-Dipolar Cycloaddition
of C,N-Cyclic Azomethine Imines with Azlactones: Access to Chiral Tricyclic Tetrahydroisoquinolines. Angew. Chem. Int. Ed.
2016, 55, 8100–8103. [CrossRef]
29. Liu, X.; Yang, D.; Wang, K.; Zhang, J.; Wang, R. A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and
3-nitroindoles: An easy access to five-ring-fused tetrahydroisoquinolines. Green Chem. 2017, 19, 82–87. [CrossRef]
30. Xu, J.; Yuan, S.; Peng, J.; Miao, M.; Chen, Z.; Ren, H. Base-mediated diastereoselective 4+3 annulation of in situ generated
ortho-quinone methides with C,N-cyclic azomethine imines. Org. Biomol. Chem. 2017, 15, 7513–7517. [CrossRef] [PubMed]
31. Soeta, T.; Tamura, K.; Ukaji, Y. 5 + 1 Cycloaddition of C,N-Cyclic N‘-Acyl Azomethine Imines with Isocyanides. Org. Lett. 2012
14, 1226–1229. [CrossRef] [PubMed]
,
32. Zhang, L.; Liu, H.; Qiao, G.; Hou, Z.; Liu, Y.; Xiao, Y.; Guo, H. Phosphine-Catalyzed Highly Enantioselective 3 + 3 Cycloaddition
of Morita-Baylis-Hillman Carbonates with C,N-Cyclic Azomethine Imines. J. Am. Chem. Soc. 2015, 137, 4316–4319. [CrossRef]
33. Wang, K.-K.; Li, Y.-L.; Wang, Z.-Y.; Hu, M.-W.; Qiu, T.-T.; Zhu, B.-K. Cross 1,3-dipolar cycloadditions of C,N-cyclic azomethine
imines with an N-benzyl azomethine ylide: Facile access to fused tricyclic 1,2,4-hexahydrotriazines. Org. Biomol. Chem. 2019
17, 244–247. [CrossRef] [PubMed]
,
34. Cheng, X.; Cao, X.; Xuan, J.; Xiao, W.-J. Silver(I)- and Base-Mediated 3 + 3 -Cycloaddition of C,N-Cyclic Azomethine Imines with
Aza-oxyallyl Cations. Org. Lett. 2018, 20, 52–55. [CrossRef] [PubMed]
35. Cao, W.-B.; Jiang, S.; Li, H.-Y.; Xu, X.-P.; Ji, S.-J. Synthesis of strained 1,2-diazetidines via 3 + 1 cycloaddition of C,N-cyclic
azomethine imines with isocyanides and synthetic derivation dagger. Org. Chem. Front. 2021. [CrossRef]
36. Zhan, G.; He, Q.; Yuan, X.; Chen, Y.-C. Asymmetric Direct Vinylogous Michael Additions of Allyl Alkyl Ketones to Maleimides
through Dienamine Catalysis. Org. Lett. 2014, 16, 6000–6003. [CrossRef]
37. Freedman, T.B.; Cao, X.; Dukor, R.K.; Nafie, L.A. Absolute configuration determination of chiral molecules in the solution state
using vibrational circular dichroism. Chirality 2003, 15, 743–758. [CrossRef]
38. Stephens, P.J.; Harada, N. ECD cotton effect approximated by the Gaussian curve and other methods. Chirality 2010, 22, 229–233.
[CrossRef] [PubMed]
39. Kong, F.-D.; Ma, Q.-Y.; Huang, S.-Z.; Wang, P.; Wang, J.-F.; Zhou, L.-M.; Yuan, J.-Z.; Dai, H.-F.; Zhao, Y.-X. Chrodrimanins K–N
and Related Meroterpenoids from the Fungus Penicillium sp. SCS-KFD09 Isolated from a Marine Worm, Sipunculus nudus. J.
Nat. Prod. 2017, 80, 1039–1047. [CrossRef] [PubMed]
40. Bencivenni, G.; Galzerano, P.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Direct asymmetric vinylogous Michael addition of cyclic
enones to nitroalkenes via dienamine catalysis. Proc. Natl. Acad. Sci. USA 2010, 107, 20642–20647. [CrossRef]
41. Ramachary, D.B.; Reddy, Y.V. Dienamine Catalysis: An Emerging Technology in Organic Synthesis. Eur. J. Org. Chem. 2012
2012, 865–887. [CrossRef]
,
42. Jurberg, I.D.; Chatterjee, I.; Tannert, R.; Melchiorre, P. When asymmetric aminocatalysis meets the vinylogy principle. Chem.
Commun. 2013, 49, 4869–4883. [CrossRef] [PubMed]
43. Na, R.; Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.; Zhong, J.; Wang, M.; Benitez, D.; Tkatchouk, E.; et al. Phosphine-Catalyzed
Annulations of Azomethine Imines: Allene-Dependent [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] Pathways. J. Am. Chem. Soc. 2011
133, 13337–13348. [CrossRef]
,
44. Chatzopoulou, E.; Davies, P.W. Highly regioselective synthesis of 2,4,5-(hetero)aryl substituted oxazoles by intermolecular
[3 + 2]-cycloaddition of unsymmetrical internal alkynes. Chem. Commun. 2013, 49, 8617–8619. [CrossRef] [PubMed]
45. Zhao, J.; Wu, C.; Li, P.; Ai, W.; Chen, H.; Wang, C.; Larock, R.C.; Shi, F. Synthesis of Pyrido[1,2-b]indazoles via Aryne [3 + 2]
Cycloaddition with N-Tosylpyridinium Imides. J. Org. Chem. 2011, 76, 6837–6843. [CrossRef] [PubMed]
46. Zhou, M.-Y.; Kong, S.-S.; Zhang, L.-Q.; Zhao, M.; Duan, J.-A.; Ou-yang, Z.; Wang, M. CuBr2 catalyzed bromination/oxidation of
isochromans to benzaldehyde derivatives. Tetrahedron Lett. 2013, 54, 3962–3964. [CrossRef]
47. Wang, K.-K.; Li, Y.-L.; Wang, X.-Y.; Zhu, B.-K. Catalyst-Free Synthesis of 2,3-Benzodiazepines via Tetrahydrodiazirino[3,1-
a]isoquinoline Reacts with Sulfonyl Chlorides. Chem. Sel. 2019, 4, 3340–3343. [CrossRef]
48. Hickin, J.A.; Ahmed, A.; Fucke, K.; Ashcroft, M.; Jones, K. The synthesis and structure revision of NSC-134754. Chem. Commun.
2014, 50, 1238–1240. [CrossRef]
49. Ortega, H.; Ahmed, S.; Alper, H. Facile Regioselective Synthesis of Pyrazolo[5,1-a]isoquinolines via Ring-Opening Cycliza-
tion/Oxidation Reactions of Stable Aroyldiaziridines of 3,4-Tetrahydroisoquinoline with Alkynes. Synthesis 2007, 2007, 3683–3691.
[CrossRef]
50. Koptelov, Y.B.; Saik, S.P.; Molchanov, A.P. Stable azomethine imines having a 3,4-dihydroisoquinoline fragment and their
cycloaddition to N-arylmaleimides. Russ. J. Org. Chem. 2011, 47, 537–546. [CrossRef]
51. Allen, J.M.; Lambert, T.H. Synthesis and characterization of a diaziridinium ion. Conversion of 3,4-dihydroisoquinolines to
4,5-dihydro-3H-benzo[2,3]diazepines via a formal N-insertion process. Tetrahedron 2014, 70, 4111–4117. [CrossRef]
52. Nahm, S.; Weinreb, S.M. N-methoxy-n-methylamides as effective acylating agents. Tetrahedron Lett. 1981, 22, 3815–3818. [CrossRef]
53. Larock, R.C.; Lu, Y.-d. Synthesis of allylic ketones via acylation of allylic mercurials. Tetrahedron Lett. 1988, 29, 6761–6764.
[CrossRef]
54. Shionhara, T.; Suzuki, K. Facile one-pot procedure for Et3Al-Promoted asymmetric pinacol-type rearrangement. Synthesis 2003
,
1, 141–146. [CrossRef]

Molecules 2021, 26, 2969
10 of 10
55. Lee, A.S.-Y.; Wang, S.-H.; Chang, Y.-T.; Chu, S.-F. Synthesis of
β-Amino and
β-Methoxy Ketones by Lewis Acids Promoted
β-Substitution Reactions of β,γ-Unsaturated Ketones. Synlett 2003, 2003, 2359–2363. [CrossRef]
56. Meninno, S.; Croce, G.; Lattanzi, A. Asymmetric Synthesis of Trisubstituted Tetrahydrothiophenes Bearing a Quaternary
Stereocenter via Double Michael Reaction Involving Dynamic Kinetic Resolution. Org. Lett. 2013, 15, 3436–3439. [CrossRef]
[PubMed]
57. Zhu, B.; Zhang, W.; Lee, R.; Han, Z.; Yang, W.; Tan, D.; Huang, K.-W.; Jiang, Z. Direct Asymmetric Vinylogous Aldol Reaction of
Allyl Ketones with Isatins: Divergent Synthesis of 3-Hydroxy-2-Oxindole Derivatives. Angew. Chem. Int. Ed. 2013, 52, 6666–6670.
[CrossRef]
58. Zhuo, L.-G.; Yao, Z.-K.; Yu, Z.-X. Synthesis of Z-Alkenes from Rh(I)-Catalyzed Olefin Isomerization of β,γ-Unsaturated Ketones.
Org. Lett. 2013, 15, 4634–4637. [CrossRef] [PubMed]
59. Wang, M.; Lin, L.; Shi, J.; Liu, X.; Kuang, Y.; Feng, X. Asymmetric Crossed-Conjugate Addition of Nitroalkenes to Enones by a
Chiral Bifunctional Diamine Organocatalyst. Chem. Eur. J. 2011, 17, 2365–2368. [CrossRef]