Green H 2 O-Promoted Solvent-Free Synthesis of Enaminocarbonyl Compounds with High Stereoselectivity from Electron-Deficient Terminal Alkynes

Article abstract of DOI:10.1055/s-0040-1707968

A green H ₂ O-promoted solvent-free hydroamination of electron-deficient terminal alkynes with amines has been developed. All secondary amines, including aliphatic and aromatic amines, gave the corresponding (E)-enamines in good to excellent yi

Full text of DOI:10.1055/s-0040-1707968

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
A
en
X. Y. Chen et al.
Letter
Synlett
Green H2O-Promoted Solvent-Free Synthesis of Enaminocarbonyl
Compounds with High Stereoselectivity from Electron-Deficient
Terminal Alkynes
Xiao Yun Chen*
Luming Zhang
Yaonan Tang
Shuxia Yuan
0
0
0
0-
0
0
0
2-0
4
4
3-1
3
0
5
X
R2 = alkyl
R1
N
R2
R1
H
Solvent-free
N
R2
+
X
Yields: 65–>99%
20 examples
Catalyst-free
Additive-free
Baocheng Zhu
Guang Chen
R2 = H
R1 = alkyl, aryl
R1 NH
X
X = COOR, COR, Ts
Yields: 45–65%
4 examples
Xiaofang Cheng
School of Environmental and Chemical Engineering, Jiangsu
University of Science and Technology, Mengxi Road No. 2,
Zhenjiang, 212003, P. R. of China
chenxy@just.edu.cn
Received: 27.08.2019
Accepted after revision: 12.02.2020
Published online: 03.03.2020
good stereoselectivity, a broad substrate range, and mild re-
action conditions without a solvent or catalyst would be
highly desirable.
DOI: 10.1055/s-0040-1707968; Art ID: st-2020-d0039-l
Nair's protocol:4a
Abstract A green H2O-promoted solvent-free hydroamination of elec-
tron-deficient terminal alkynes with amines has been developed. All
secondary amines, including aliphatic and aromatic amines, gave the
corresponding (E)-enamines in good to excellent yields, whereas prima-
ry aromatic amines afforded Z-configured products in moderate yields.
Propiolates, propyn-1-ones, propynamides, and 1-(ethynylsulfonyl)-4-
methylbenzene were explored in this Michael addition.
O
O
H2O, r.t.
O
H-[N]
+
OEt
[N]
OEt
+
OEt
[N]
[N] = NHR, NR2
Maurya's protocol:4e
Key words green chemistry, water catalysis, hydroamination,
alkynes, enamines
[N]
O
CuI NPs (10 mmol%)
solvent-free
H-[N]
+
R
R
O
OEt
OEt
Enaminocarbonyl compounds are widely used in syn-
theses of various heterocycles,1 including indoles,1c–e pyr-
roles,1f–h quinolines,1i and pyridines,1j,k to give bioactive
compounds and natural products2 such as alkaloids,2a,b pep-
tides,2c or amino acids,2d,e as well as their derivatives.2f,g
Therefore, extensive efforts have been devoted to the explo-
ration of new methods for synthesizing enaminocarbonyl
compounds. At present, enaminocarbonyl compounds are
mainly synthesized by direct condensation of 1,3-dicarbon-
yl compounds with amines or their derivatives.1c,3 However,
there these protocols have several disadvantages; for exam-
ple, neat -keto esters or 1,3-diketones are usually needed
as precursors, and certain catalysts are required. Recently,
due to their almost complete atom-efficiency, hydroamina-
tions of alkynes with nitrogen-containing reagents have
been used to prepare a range of enamines.1f,4 Among such
methods, a solvent-free copper-catalyzed method4e and a
water-promoted hydroamination4a show several unique ad-
vantages (Figure 1). Inspired by these protocols, and on the
basis of our experience of functionalization of unsaturated
C–C bonds,5 we considered that a green and general meth-
od for synthesizing enaminocarbonyl compounds with
R = H, Ph, CO2Et
[N] = NR'2, NR'Ar
This work:
[N]
O
H2O (11 equiv.)
H-[N]
+
R
solvent- and catalyst-free
R
O
OEt
OEt
R = H, Ph
[N] = NR'2, NR'Ar
Figure 1 Hydroaminations of electron-deficient alkynes
In Nair’s protocol,4a water was used as solvent, giving
the E-adducts in almost quantitative yield. Maurya’s
solvent-free approach with a CuI catalyst4e again led to near
quantitative formation of the E- adducts (Figure 1). These
results encouraged us to examine to the reaction of less-
reactive N-methylaniline with ethyl propiolate in the absence
of a solvent or any other additive at room temperature. Un-
fortunately, none of the desired product 3a was detected af-
ter stirring for one hour at room temperature (Table 1, en-
try 1). However, raising the reaction temperature to 80 °C
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
X. Y. Chen et al.
Letter
Synlett
resulted in a 60% yield of 3a (entry 2). On the basis of the
hypothesis that dispersion of the reactants in water might
benefit the reaction, we added 0.44 equivalents of water to
the reaction mixture, which improved the yield to 72% (en-
try 3). By changing the amount of H2O from 0.44 equiva-
lents to 11 equivalents, the yield of 3a was improved from
72 to 94% (entries 3–7). Further increases in the amount of
water from 11 to 25 equivalents had little influence on the
yield (entries 7–9). Therefore, 11 equivalents of H2O was
chosen as the optimal amount for this reaction. Next, the
reaction temperature was investigated. Raising or lowering
the temperature reduced the yield (entries 7 and 10–12).
Finally, the optimal conditions were chosen to be a mixture
of the propiolate (1 equiv) and an aniline or aromatic N-
heterocycle (1.2 equiv) with 11 equivalents of water under
stirring at 80 °C for one hour. In contrast, for aliphatic
amines, the reactions need to be performed in a water bath
at room temperature for only 10 minutes.
99% (entries 1–4). As expected, weakly nucleophilic prima-
ry anilines gave products 3e–i with a Z-configuration in low
to moderate yields of 26–65% (entries 5–9). The decreased
nucleophilicity of 3,4-dicholoroaniline as a result of the
presence of the two chloro substituents resulted in the cor-
responding product 3g being obtained in only 26% yield,
even when the reaction time was prolonged to 12 hours
(entry 7), whereas 4-chloroaniline afforded the correspond-
ing product 3f in 65% yield (entry 6).6 Due to its poor stabil-
ity, product 3h was obtained in only 47% yield, even though
the strongly nucleophilic 4-methoxyaniline was used (en-
try 8).7 1-Naphthylamine gave product 3i in a moderate 42%
yield (entry 9). Furthermore, N-containing heterocyclic
compounds, including 1H-benzo[d]imidazole, and 1H-imid-
azole, gave the corresponding products without E/Z selec-
tivity in yields of 89 and 97% yields, respectively (see Sup-
porting Information, Figure S2).8 Unfortunately, indole and
carbazole did not afford the desired products under the
standard conditions, presumably because of the lower nuc-
leophilicities of their NH groups.
Table 1 Optimization of the Reaction Conditionsa
O
Table 2 Scope of Aminesa
Ph
H2O (x equiv)
N
OEt
PhNHMe
+
CO2Et
80 °C, 1 h
O
R1
R2
NH
R2
H2O (11 equiv)
80 °C or r.t.
3a
1a
2a
+
OEt
N
R1
CO2Et
Yield (%)
94
Entry
Temp (°C)
H2O (equiv)
Yieldb (%)
2a
1
3a–p
1
2
rt
80
80
80
80
80
80
80
80
40
60
100
0
trace
60
72
78
89
90
94
93
91
63
83
68
Entry Amine 1
Product 3
0
Me
N
H
3
0.44
1
N
Me
CO2Et
4
1
5
2.2
5
1a
3a
6
Me
Me
H
7
11
N
Me
N
N
2c
65
CO2Et
8
25
55
11
11
11
Me
9
1b
3b
3c
10
11
12
NH
3c
>99
CO2Et
a Reaction conditions: ethyl propiolate (0.5 mmol), N-methylaniline (0.6
mmol, 1.2 equiv), H2O, 1 h under air.
1c
b Isolated yield.
Me
H
N
N
Me
CO2Et
4d
78
45
65
With the optimal reaction conditions in hand, we exam-
ined the reactions of various amines, including aliphatic
amines, aryl amines, and N-containing aromatic com-
pounds with ethyl propiolate (2a). Most of the amines
formed the corresponding 3-aminopropenoates 3 in good
yields (65–99%; Table 2). In general, anilines, including pri-
mary and secondary anilines, reacted smoothly to afford
the corresponding products 3a–i in yields of 26–99% (Table
2; entries 1–9). In particular, secondary anilines, including
highly sterically hindered N-isopropylaniline, gave the cor-
responding products 3a–d in good to excellent yields of 78–
MeO
1d
MeO
3d
CO2Et
H
PhNH2
N
5
Ph
1e
3e
CO2Et
NH2
H
N
6e
Cl
1f
Cl
3f
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
X. Y. Chen et al.
Letter
Synlett
Table 2 (continued)
For aliphatic secondary amines, most reactions were
performed in a water bath for 10 minutes (Table 2, entries
10–18). All secondary aliphatic amines, including highly
sterically hindered N,N-diisopropylamine, reacted efficient-
ly with ethyl propiolate (2a) to give the corresponding
products in good to excellent yields (77 to >99%). The linear
dialkylamines dipropylamine and dihexylamine performed
well, affording the desired products 3j and 3k, respectively,
in yields of 91 and 99% (Table 2, entries 10 and 11). The ste-
rically hindered N,N-diisopropylamine gave product 3l in
77% yield (entry 12), whereas dibenzylamine gave the de-
sired product 3m in almost quantitative yield (>99%) (entry
13). When 4-methylpiperidine was used, the yield of 3n
was only 78% (entry 14), similar to that obtained from with
N,N-diisopropylamine. Morpholine and pyrrolidine also
performed well in this reaction, affording the correspond-
ing products 3o and 3p quantitatively (entries 15 and 16).
Di(2-cyanoethyl)amine similarly gave product 3q in 98%
yield (entry 17). Finally, N,N′-dimethylethane-1,2-diamine
gave the (2E,2′E)-diacrylate 3r in 93% yield (entry 18).
Next, we examined the effect of changing the alkyne
component by using phenyl propiolate, propargyl ketones,
various propiolamides, and 1-(ethynylsulfonyl)-4-methyl-
benzene in the reaction (Table 3). Hept-1-yn-3-one and 1-
phenylprop-2-yn-1-one reacted smoothly to give corre-
sponding products 3s and 3t in excellent yields of 85 and
91%, respectively (Table 3, entries 1 and 2). Due to differ-
ences in the stability and electron-deficiency of the prod-
ucts, the reaction was performed at 20 °C for one hour
when hept-1-yn-3-one was used as substrate. When vari-
ous propiolamides were applied in the reaction, the best re-
sults were achieved with soluble N,N-dimethylpropan-
amide, which gave product 3u in >99% yield (entry 3).
Compared with N,N-dimethylpropanamide, N-phenyl-
propanamide and N-phenyl-N-methylpropanamide, which
were insoluble in the reaction mixture, gave 3v and 3w in
lower yields (88% in each case; entries 4 and 5). To our satis-
faction, 1-(ethynylsulfonyl)-4-methylbenzene also reacted
well to give product 3x in 93% yield after stirring for one
hour at room temperature (entry 6). Finally, the lowest
yield and the worst stereoselectivity were observed with
phenyl propiolate, which gave product 3y in 67% yield (en-
try 7).
Entry Amine 1
Product 3
Yield (%)
26
CO2Et
Cl
NH2
H
Cl
N
7e
Cl
Cl
3g
1g
CO2Et
NH2
H
N
8
476
MeO
1h
MeO
3h
NH2
9
42
NH
CO2Et
1i
3i
Pr2N
3j
NHPr2
10f
11f
12f
13f
91
>99
77
CO2Et
1j
Hex2N
3k
NHHex2
1k
CO2Et
(i-Pr)2N
3l
NH(i-Pr)2
1l
CO2Et
Bn2N
3m
NHBn2
CO2Et
>99
1m
Me
Me
14f
78
N
NH
CO2Et
1n
3n
O
O
15f
16f
17f
N
99
>99
98
NH
1o
CO2Et
CO2Et
3o
N
NH
1p
3p
NC
NC
N
NH
NC
3q
CO2Et
NC
1q
Me
NH
Me
N
CO2Et
18g
93
EtO2C
On the basis of previous related reports,9 water is con-
sidered to play a key role in promoting the protonation and
deprotonation of the intermediate formed by Michael addi-
tion of the amines.10 Subsequently, the thermodynamically
favored E-type products are formed directly when second-
ary amines are used as nucleophilic coupling partners.
When primary aromatic amines are used in the reaction, Z-
type products are formed as a result of intramolecular hy-
drogen bonding between the NH group and the carbonyl
oxygen.
HN
N
Me
1r
Me
3r
a Reaction conditions: ethyl propiolate (2a, 0.5 mmol, 1.0 equiv), amine 1
(0.6 mmol, 1.2 equiv), water (5 mmol, 11 equiv), 80 °C, 1 h, under air.
b Isolated yield.
c Reaction time 4 h.
d Stirred at r.t. for 1 h.
e Reaction time 12 h.
f Stirred at r.t. in a water bath for 10 min.
g 2 equiv ethyl propiolate.
Thieme. All rights reserved. Synlett 2020, 31, A–E

D
X. Y. Chen et al.
Letter
Synlett
Table 3 Scope of Alkynesa
Funding Information
We are grateful to the National Natural Science Foundation of China
(No. 21602085 and 51902140) and Natural Science Foundation of Ji-
H
O
N
H2O (11 equiv)
R
Me
angsu Province (No. BK20160551) for financial support.
N
ati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
6
0
2
0
8
5)Nati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(5
1
9
0
2
1
4
0)NaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
ofJi
a
n
gsuPro
v
i
n
c
e
(B
K
2
0
1
6
0
5
5)
+
N
Me
COR
80 °C or r.t.
2
3q–w
1a
Acknowledgment
Entry Alkyne 2
Product 3
Yieldb
(%)
We acknowledge helpful discussions with Dr. Jun Wang (Sun Yat-sen
University) and Dr. Long Wang (Huazhong University of Science and
Technology).
Me
N
Bu
Bu
1c
85
91
O
O
Supporting Information
2b
3s
Supporting information for this article is available online at
Me
N
https://doi.org/10.1055/s-0040-1707968.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
2d
O
O
References and Notes
2c
3t
Me
N
(1) (a) Wan, J.-P.; Gao, Y. Chem. Rec. 2016, 16, 1164. (b) Cai, X.; Yang,
M.; Guo, H. Curr. Org. Synth. 2019, 16, 70. (c) Xin, D.; Burgess, K.
Org. Lett. 2014, 16, 2108. (d) Neumann, J. J.; Rakshit, S.; Dröge,
T.; Würtz, S.; Glorius, F. Chem. Eur. J. 2011, 17, 7298. (e) Li, Y.;
Cao, X.; Liu, Y.; Wan, J.-P. Org. Biomol. Chem. 2017, 15, 9585.
(f) Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.; Rottländer, M.;
Skrydstrup, T. Org. Lett. 2009, 11, 4208. (g) Nguyen, H. H.; Kurth,
M. J. Org. Lett. 2013, 15, 362. (h) Ke, J.; He, C.; Liu, H.; Li, M.; Lei,
A. Chem. Commun. 2013, 49, 7549. (i) Toh, K. K.; Wang, Y.-F.; Ng,
E. P. J.; Chiba, S. J. Am. Chem. Soc. 2011, 133, 13942. (j) Zhao, M.;
Wang, F.; Li, X. Org. Lett. 2012, 14, 1412. (k) Toh, K. K.; Sanjaya,
S.; Sahnoun, S.; Chong, S. Y.; Chiba, S. Org. Lett. 2012, 14, 2290.
(l) Yamamoto, S.-i.; Okamoto, K.; Murakoso, M.; Kuninobu, Y.;
Takai, K. Org. Lett. 2012, 14, 3182. (m) Wan, J.-P.; Jing, Y.; Hu, C.;
Sheng, S. J. Org. Chem. 2016, 81, 6826. (n) Suri, M.; Jousseaume,
T.; Neumann, J. J.; Glorius, F. Green Chem. 2012, 14, 2193.
(o) Wan, J.-P.; Cao, S.; Liu, Y. Org. Lett. 2016, 18, 6034.
(2) (a) Ferraz, H. M. C.; de Oliveira, E. O.; Payret-Arrua, M. E.;
Brandt, C. A. J. Org. Chem. 1995, 60, 7357. (b) Comins, D. L. J. Het-
erocycl. Chem. 1999, 36, 1491. (c) Beholz, L. G.; Benovsky, P.;
Ward, D. L.; Barta, N. S.; Stille, J. R. J. Org. Chem. 1997, 62, 1033.
(d) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.;
Wang, F.; Sun, Y.; Armstrong, J. D.; Grabowski, E. J. J.; Tillyer, R.
D.; Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918.
(e) Dai, Q.; Yang, W.; Zhang, X. Org. Lett. 2005, 7, 5343. (f) Wan,
J. P.; Lin, Y.; Cao, X.; Liu, Y.; Li, W. ChemInform 2016, 52, 1270.
(g) Malawska, B. Curr. Top. Med. Chem. (Sharjah, United Arab
Emirates) 2005, 5, 69.
(3) (a) Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983, 902.
(b) Arcadi, A.; Bianchi, G.; Giuseppe, S. D.; Marinelli, F. Green
Chem. 2003, 5, 64. (c) Sridharan, V.; Avendaño, C.; Menéndez, J.
C. Synlett 2007, 881. (d) Bartoli, G.; Bosco, M.; Locatelli, M.;
Marcantoni, E.; Melchiorre, P.; Sambri, L. Synlett 2004, 239.
(e) Zhang, Z.-H.; Yin, L.; Wang, Y.-M. Adv. Synth. Catal. 2006, 348,
184.
(4) (a) Randive, N. A.; Kumar, V.; Nair, V. A. Monatsh. Chem. 2010,
141, 1329. (b) Choudhary, G.; Peddinti, R. K. Green Chem. 2011,
13, 3290. (c) Zhang, X.; Yang, B.; Li, G.; Shu, X.; Mungra, D. C.;
Zhu, J. Synlett 2012, 622. (d) He, B.; Su, H.; Bai, T.; Wu, Y.; Li, S.;
Gao, M.; Hu, R.; Zhao, Z.; Qin, A.; Ling, J.; Tang, B. Z. J. Am. Chem.
NMe2
NMe2
3
>99%
88
O
O
2d
3u
Me
N
H
H
N
N
Ph
Ph
4
O
O
2e
3v
Me
N
Me
Me
N
N
Ph
Ph
5
88
O
O
2f
3w
Me
O
O
N
S
Me
6c
93
S
Me
O
O
2g
2h
3x
3y
Me
N
O
O
7
67
O
O
a Reaction conditions: alkyne (0.5 mmol, 1.0 equiv), N-methylaniline (0.6
mmol, 1.2 equiv), H2O (5 mmol, 11 equiv), 8 h, 80 °C, under air.
b Isolated yield.
c Stirred at r.t. for 1 h.
d Stirred at 80 °C for 1 h.
In conclusion, a simple, green, water-promoted, Michael
addition has been developed. Various -enamino esters and
-enaminones were synthesized stereoselectively in mod-
erate to excellent yields (42 to >99%). (Z)--Enaminones
were obtained from primary aromatic amines, whereas
secondary amines gave (E)--enamino esters. We propose
that water promotes the reaction, not only by improving
the dispersion of the reactants, but also by assisting proton
transfers in the formation of the intermediate and the prod-
uct.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

E
X. Y. Chen et al.
Letter
Synlett
Soc. 2017, 139, 5437. (e) Nayal, O. S.; Thakur, M. S.; Kumar, M.;
Shaifali; Upadhyay, R.; Maurya, S. K. Asian J. Org. Chem. 2018, 7,
776.
(10) When D2O was used as additive in the reaction instead of H2O,
the 1H NMR spectrum of the product (Figure S3; Supporting
Information) showed that about half the double-bond protons
were replaced by deuterium. However, as hydrogen exchange
between both substrates and D2O was found to occur, the
degree of participation of H2O/D2O in protonation/deuteration
could not be conclusively demonstrated by this experiment.
(11) Ethyl (2E)-3-[Methyl(phenyl)amino]acrylate (3a); Typical
Procedure
(5) (a) Yuan, M.; Chen, X.; Lin, S. Prog. Chem. 2018, 30, 1082; DOI:
10.7536/PC171246. (b) Hou, H.; Tang, D.; Li, H.; Xu, Y.; Yan, C.;
Shi, Y.; Chen, X.; Zhu, S. J. Org. Chem. 2019, 84, 7509. (c) Chen, X.
Y.; Bohmann, R. A.; Wang, L.; Dong, S. X.; Räuber, C.; Bolm, C.
Chem. Eur. J. 2015, 21, 10330. (d) San, H. H.; Wang, S.-J.; Jiang,
M.; Tang, X.-Y. Org. Lett. 2018, 20, 4672.
(6) When the weakly nucleophilic N-methyl-p-nitroaniline was
investigated as the aminating agent, none of the desired product
was detected.
(7) When p-methoxyaniline was used, the desired product was
formed in the first hour (TLC monitoring). On prolonging the
reaction time, byproducts were detected and all the desired
product was eventually consumed.
Ethyl propiolate (0.5 mmol) was slowly added with stirring to a
mixture of N-methylaniline (0.6 mmol) and distilled H2O (0.1
mL) in a 2 mL vial, and the vial then sealed. The mixture was
heated at 80 °C with stirring for 1 h. The reaction was then
quenched with sat. brine (0.5 mL), and the mixture was cooled
to r.t. and extracted with EtOAc (3 × 1 mL) by pipette in the
same vial. The combined organic layers were dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The residue
was purified by column chromatography [silica gel, PE–EtOAc
(8:1)] to give a pale yellow oil; yield: 96.7 mg (94%).
(8) The ratio of Z/E products from 1H-benzo[d]imidazole was about
29:50. The ratio of Z/E products from 1H-imidazole was about
1
50:21. The two H NMR spectra are shown in Fig. S2 (Support-
ing Information).
1H NMR (400 MHz, CDCl3):  = 7.94 (d, J = 13.2 Hz, 1 H), 7.38–
7.31 (m, 2 H), 7.15–7.08 (m, 3 H), 4.94 (d, J = 13.2 Hz, 1 H), 4.18
(q, J = 7.1 Hz, 2 H), 3.24 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H). 13C NMR
(101 MHz, CDCl3):  = 169.3, 148.6, 146.7, 129.6, 124.3, 120.0,
90.5, 59.44, 36.7, 14.7. MS (ESI): m/z [M + H]+ calcd for
(9) (a) Khatik, G. L.; Kumar, R.; Chakraborti, A. K. Org. Lett. 2006, 8,
2433. (b) Chankeshwara, S. V.; Chakraborti, A. K. Org. Lett. 2006,
8, 3259. (c) Zhang, F.-Z.; Tian, Y.; Li, G.-X.; Qu, J. J. Org. Chem.
2015, 80, 1107. (d) Chu, X.-Q.; Xu, X.-P.; Ji, S.-J. Chem. Eur. J.
2016, 22, 14181. (e) Huang, H.-Y.; Liang, C.-F. Asian J. Org. Chem.
2018, 7, 955.
C
12H16NO2: 206.1; found: 206.1.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E