BF 3 ·oEt 2 -Catalyzed Synthesis of anti -β-(N -Arylamino)-α-hydroxynitriles by Regio- And Diastereospecific Ring Opening of 3-Aryloxirane-2-carbonitriles with Anilines

Article abstract of DOI:10.1055/s-0039-1690243

A safe and convenient synthetic method to anti -β-(N -arylamino)-α-hydroxynitriles from 3-aryloxirane-2-carbonitriles and anilines was developed under the catalysis of BF ₃ ·OEt ₂ in ethanol. In this method, BF ₃ ·OEt ₂ first reacts with ethanol to produce the true catalyst of super- acid H[B(OEt)F ₃], followed by an acid-catalyzed regio- and diastereospecific ring opening of oxirane-2-carbonitriles with anilines, generating anti -β-(N -arylamino)-α-hydroxynitriles. The method features the advantages of non-metal catalysis, short reaction times, and easy operation, and uses an environmentally friendly solvent.

Full text of DOI:10.1055/s-0039-1690243

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
paper
A
en
C. Xu et al.
Paper
Synthesis
BF3·OEt2-CatalyzedSynthesisofanti--(N-Arylamino)--hydroxynitriles
by Regio- and Diastereospecific Ring Opening of 3-Aryloxirane-2-car-
bonitriles with Anilines
Chuangchuang Xu
Ar
NH
O
Yang Lu
Kaini Xu
Jiaxi Xu*
BF3•OEt2 (0.1 equiv)
CN
ArNH2
+
CN
R
R
EtOH, MW, 100 °C, 40 min
OH
trans
anti
State Key Laboratory of Chemical Resource Engineering,
Department of Organic Chemistry, College of Chemistry,
Beijing University of Chemical Technology, Beijing
100029, People’s Republic of China
♦ 16 examples, up to 96% yield
♦ enviromentally friendly solvent
♦ regio- and diastereospecificity
♦ metal-free reaction
♦ short reaction time
♦ microwave acceleration
jxxu@mail.buct.edu.cn
Received: 13.08.2019
Accepted after revision: 15.10.2019
Published online: 05.11.2019
-Aminocyanohydrins, derivatives of cyanohydrins, are
also proven to be biologically active compounds3,5 and have
prevalent applications in the synthesis of -amino--
hydroxycarboxylic acid derivatives11 and heterocyclic com-
pounds.2,3 However, there are few investigations on the syn-
thesis of -aminocyanohydrins, all of which involve the ad-
dition of highly toxic cyanide sources to the corresponding
N-protected -aminoaldehydes (Scheme 1a).5,11,12 More
recently, we reported a new method for the synthesis of
2-arylindoles from vicinal 3-aryloxirane-2-carbonitriles
and anilines, and showed that -(N-arylamino)cyanohy-
drins are important intermediates (Scheme 1b).2 Inspired
by our previous work,2 a microwave-assisted BF3·OEt2-cata-
lyzed synthesis of anti--(N-arylamino)--hydroxynitriles
through regio- and diastereospecific ring opening of ox-
DOI: 10.1055/s-0039-1690243; Art ID: ss-2019-h0449-op
Abstract A safe and convenient synthetic method to anti--(N-aryl-
amino)--hydroxynitriles from 3-aryloxirane-2-carbonitriles and anilines
was developed under the catalysis of BF3·OEt2 in ethanol. In this meth-
od, BF3·OEt2 first reacts with ethanol to produce the true catalyst of
super acid H[B(OEt)F3], followed by an acid-catalyzed regio- and diaste-
reospecific ring opening of oxirane-2-carbonitriles with anilines, gener-
ating anti--(N-arylamino)--hydroxynitriles. The method features the
advantages of non-metal catalysis, short reaction times, and easy oper-
ation, and uses an environmentally friendly solvent.
Key words amino-hydroxynitrile, boron trifluoride, ring opening,
regiospecificity, diastereospecificity, oxiranecarbonitrile, aniline
Considerable effort has continually been devoted to the
development of new synthetic methodology in basic organ-
ic synthesis to cater for the needs of the synthesis or modi-
fication of drugs, natural products, and organic functional
materials. Cyanohydrins are versatile building blocks in
synthetic organic chemistry in which the two functional
groups hydroxyl and cyano group connect to the same car-
bon nucleus, making them not only possessing the ability to
participate in monofunctional group conversion reactions,1
but also bifunctional group conversion reactions.2–4 Fur-
thermore, cyanohydrins are also proven to be biological ac-
tive molecules3,5,6 and have certain biological applications.7
Traditional methods for the synthesis of cyanohydrins and
their O-protected derivatives involved the addition of high-
ly toxic cyanide to aldehydes or ketones.6,8 These methods
are generally dangerous to operate, and this limits their ap-
plications. To overcome these disadvantages, Orru9 and
Lian10 achieved the synthesis of O-protected cyanohydrins
by employing low or nontoxic trityl isocyanide and malono-
nitriles, respectively. As a result, the development of novel,
safe, and practical methods for construction of cyanohy-
drins still is an issue to deeply investigate.
a) Nucleophilic addition of cyanide to N-protected aminoaldehydes.
R2
R2
NH
CN– resource
NH
CN
R1
O
R1
OH
CN– source: TMSCN, KCN, Bu3SnCN, acetone cyanohydrin
b) Synthesis of 3-arylindoles from 3-aryloxirane-2-carbonitriles and anilines
via β-(N-arylamino)cyanohydrin intermediates - Our previous work
R2
H
O
N
Lewis acids
alcohols
R2
CN
R4
R3
R1
+
R3
R1
N
R4
R3
R4
N
R2
CN
R1
OH
c) Synthesis of β-(N-arylamino)cyanohydrins from 3-aryloxirane-2-carbonitriles
and anilines - This work
NHAr
O
BF3•OEt, EtOH
CN
ArNH2
+
CN
R
R
MW, 100 °C, 40 min
OH
(
)
(
)
Scheme 1 Methods of synthesis of -aminocyanohydrins
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G
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B
C. Xu et al.
Paper
Synthesis
irane-2-carbonitriles with anilines in ethanol was devel-
oped (Scheme 1c). The reaction is of synthetic importance
and has the advantages of short reaction times, non-metal
catalysis, a cyanide-free reagent, and an environmentally
friendly solvent.
the reaction time was also investigated. Shortening the re-
action time to 20 minutes gave 3a in a lower NMR yield of
61% (Table 1, entry 6), but prolonging the reaction time to
40 minutes gave 3a in a higher NMR yield of 97% and 96%
isolated yield (Table 1, entry 7). Further prolonging of the
reaction time did not improve the yield (Table 1, entries 8
and 9). Finally, the number of equivalents of aniline and
BF3·OEt2 was adjusted slightly, however neither increasing
nor decreasing them improved the yield (Table 1, entries
10–13). Overall, the best reaction conditions are 1a (112
mg, 0.5 mmol), aniline (65 mg, 0.7 mmol), and BF3·OEt2 (7
L, 0.05 mmol) in 3 mL of commercial ethanol stirred at
100 °C for 40 minutes under microwave irradiation in a
sealed vessel, giving the product anti--(N-arylamino)cy-
anohydrin 3a in 96% yield.
Table 1 Optimization of the Reaction Conditionsa
Ph
O
NH
BF3•OEt2, EtOH
MW, temp., time
NH2
CN
CN
OH
Br
Br
(
)-3a
(
)-1a
2a
Entry
Equiv of 2a
Time (min)
Temp (°C)
Yield (%) of 3a
1
2
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.3
1.5
30
30
30
30
30
20
40
50
60
40
40
40
40
78
90
61
With the established conditions in hand, the scope and
generality of the reaction were investigated and the results
are summarized in Scheme 2. First of all, the reactions of
different of anilines with trans-3-(4-bromophenyl)oxirane-
2-carbonitrile (1a) were investigated. Both electron-rich
and electron-deficient anilines 2a–f and even N-alkylani-
lines 2g and 2h, were well suited for the reaction and gave
the corresponding products 3a–h in satisfactory to excel-
lent yields. For anilines with electron-donating groups, p-
toluidine (2b) gave the corresponding anti--(N-arylami-
no)cyanohydrin 3b in 68% yield. However, electron-rich 4-
methoxyaniline (2c) could not generate the desired anti--
(N-arylamino)cyanohydrin 3c, but gave 2-(4-bromophe-
nyl)-5-methoxy-1H-indole in 16% yield. Based on the mech-
anism of our previous work,2 we thought that the formation
of indole was possible due to the electron-rich aromatic
ring of 3c, making it easier to undergo an annulation pro-
cess to generate the indole species. Besides, the lower yields
of electron-rich anilines probably are attributed to their
stronger basicity and the formation of indoles. The stronger
basic anilines favor an acid-base reaction with H[B(OEt)F3]
and related acids, decreasing the catalyst activity. Further-
more, halogen-substituted anilines were also tested. 4-Flu-
oroaniline (2d), 4-chloroaniline (2e), and 4-bromoaniline
(2f) were suitable for the reaction, giving the desired prod-
ucts anti--(N-arylamino)cyanohydrins 3d–f in 91%, 67%,
and 78% yields, respectively. Additionally, N-methylaniline
(2g) and 1,2,3,4-tetrahydroquinoline (2h) were also used to
generate 3g and 3h in 91% and 58% yields. Besides, the reac-
tions of different trans-3-aryloxirane-2-carbonitriles 1b–f
with aniline (2a) were also conducted, producing the corre-
sponding anti--(N-arylamino)cyanohydrins 3i–m in mod-
erate to good yields. trans-3-Phenyloxirane-2-carbonitrile
(1b) and trans-3-(p-tolyl)oxirane-2-carbonitrile (1c) gave
the corresponding products 3i and 3j in 71% and 61% yields,
respectively. In addition, halogen-substituted 3-arylox-
irane-2-carbonitriles trans-3-(4-fluorophenyl)oxirane-2-
carbonitrile (1d) and trans-3-(4-chlorophenyl)oxirane-2-
carbonitrile (1e) generated 3k and 3l in 78% and 85% yields,
respectively. Next, electron-deficient trans-3-(4-cyanophe-
65
3
100
110
120
100
100
100
100
100
100
100
100
92
4
90
5
88
6
61
7
97 (96b)
86
8
9
90
10c
11d
12
13
82
44
83
85
a Reaction conditions: 1a (0.5 mmol), BF3·OEt2 (0.1 equiv), commercial
EtOH (3 mL), microwave irradiation, sealed vessel; yields determined by 1H
NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.
b Yield of isolated product is indicated.
c BF3·OEt2 (0.2 equiv) was employed.
d Reaction was performed without BF3·OEt2.
We started our studies by using trans-3-(4-bromophe-
nyl)oxirane-2-carbonitrile (1a) and aniline (2a) as the mod-
el substrates. After preliminary screening of the reaction
conditions with different solvents, acids, and its equiva-
lents, loading of aniline, and reaction times [for details, see
Table S1 in the Supporting Information (SI)], we found that
when 1a (0.5 mmol, 112 mg), aniline (0.7 mmol, 65 mg),
and BF3·OEt2 (0.05 mmol, 7 L) in 5 mL of commercial etha-
nol were refluxed for 11 hours, anti-3-(4-bromophenyl)-2-
hydroxy-3-(phenylamino)propanenitrile (3a) was obtained
in the highest NMR yield of 88% [Table S1 (SI), entry 37]. To
get a better yield, the reaction was performed under micro-
wave irradiation in a sealed vessel (Table 1). Stirring 1a (0.5
mmol, 112 mg), aniline (0.7 mmol, 65 mg), and BF3·OEt2
(0.05 mmol, 7 L) in 3 mL of commercial ethanol at 78 °C for
30 minutes under microwave irradiation in a sealed vessel
afforded the product 3a in 61% NMR yield (Table 1, entry 1).
Furthermore, screening of the reaction temperature indi-
cated that the reaction performed better at 100 °C, afford-
ing 3a in 92% NMR yield (Table 1, entries 2–5). Moreover,
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

C
C. Xu et al.
Paper
Synthesis
nyl)oxirane-2-carbonitrile (1f) was investigated and gave
anti--(N-arylamino)cyanohydrin 3m in 77% yield. Besides,
trans-3-(naphthalen-2-yl)oxirane-2-carbonitrile (1g) and
trans-3-(naphthalen-1-yl)oxirane-2-carbonitrile (1h) were
also examined, affording anti--(N-arylamino)cyanohy-
drins 3n and 3o in 69% and 72% yields, respectively. Finally,
alkyl-substituted oxiranes, anti-3-phenethyloxirane-2-car-
bonitrile (1i) was also utilized and gave the corresponding
product 3p in 17% yield. As is described above, we can con-
clude that the reaction has a wide substrate scope. For elec-
tron-deficient substrates, both 3-aryloxirane-2-carbonitrile
and anilines, have a little better reactivity than that of elec-
tron-rich substrates.
stronger basicity of aliphatic amines than anilines, making
them capture H+ and lower both their reactivity and also
that of the oxiranes.
To examine the synthetic utility of the reaction, based
on our previous work,2 -(N-Arylamino)cyanohydrins could
be transformed into the corresponding indoles under the
catalysis by concentrated HCl in refluxing 2,2,2-trifluo-
roethanol for 30 hours. The reactions of 3a and syn-3a car-
ried out under above conditions were investigated, giving
the product 2-(4-bromophenyl)-1H-indole (4) in 9% and
45% yields, respectively (Scheme 3b and 3c). The results in-
dicates that -(N-arylamino)cyanohydrins have great po-
tential application value in synthesis of indoles.
To better understand the reaction mechanism, some
control experiments were taken into account (Scheme 4):
the reaction of trans-3-(4-bromophenyl)oxirane-2-carbo-
nitrile (1a) and aniline (2a) under the optimal conditions
without BF3·OEt2 only gave 3a in 44% yield (Scheme 4a), the
results illustrated that the use of BF3·OEt2 is advisable for
this reaction. Next, inorganic protic acid HCl (using
PhNH2·HCl as a HCl source) was utilized as the catalyst in
the model reaction, producing 3a in 53% yield, indicating
proton (H+) partly performed as the true catalyst (Scheme
4b). Furthermore, to examine whether trialkyl borate,
which was possibly generated from the interaction be-
tween BF3·OEt2 and alcohol, contributed to the reaction or
not, B(OMe)3 was employed as catalyst in the model reac-
tion and only gave 3a in 23% yield, lower than the reaction
without catalyst (Scheme 4a). PhNH2·HCl and B(OMe)3 as
co-catalysts were also investigated and gave 3a in 57% yield,
similar to the PhNH2·HCl-catalyzed reaction (Scheme 4b).
The results indicates that B(OMe)3 did not have any catalyt-
ic activity for this reaction (Schemes 4c and 4d). Finally,
HBF4 was examined and gave the product in 99% yield
(Scheme 4e), which indicated that H[B(OEt)F3] might be the
true catalyst in the reaction.
R2
O
BF3•OEt2 (0.1 equiv)
NH2
NH
R2
CN
R1
CN
MW, sealed vessel
EtOH (3 mL)
100 °C, 40 min
R1
OH
(
)-1 (0.5 mmol)
2 (1.4 equiv)
(
)-3
F
MeO
NH
NH
NH
NH
CN
CN
CN
CN
OH
OH
OH
OH
Br
Cl
Br
Br
Br
(
)-3a 96%
(
)-3b 68%
(
)-3c ND
(
)-3d 91%
Br
NH
NH
N
N
CN
CN
CN
OH
CN
CN
OH
OH
OH
)-3h 58%
NHPh
Br
Br
Br
Br
(
(
)-3e 67%
(
)-3g 91%
(
)-3f 78%
NHPh
NHPh
NHPh
CN
CN
CN
OH
OH
OH
OH
F
Cl
(
)-3i 71%
(
)-3j 61%
(
)-3k 78%
(
)-3l 85%
NHPh
NHPh
OH
NHPh
CN
NHPh
CN
CN
CN
OH
)-3p 17%
OH
Ph
OH
NC
In our previous work,2 3-aryloxirane-2-carbonitriles re-
acted with anilines under the catalysis of BF3·OEt2 (0.16
(
)-3m 77%
(
)-3n 69%
(
(
)-3o 72%
Scheme 2 Scope of the reaction. Reagents and conditions: 1 (0.5
mmol), 2 (0.7 mmol), BF3·OEt2 (7 L, 0.05 mmol), commercial EtOH
(3 mL), stirring, 100 °C, 40 min, microwave irradiation, sealed vessel.
Yields of isolated products are indicated.
Ph
O
NH
a)
NH2
BF3•OEt2, (0.1 equiv)
CN
OH
)-syn-3a 43%
CN
+
EtOH, MW, 100 °C, 40 min
Br
The reaction of cis-3-(4-bromophenyl)oxirane-2-carbo-
nitrile (cis-1a) and aniline (2a) was also investigated and
the corresponding product syn-3-(4-bromophenyl)-2-
hydroxy-3-(phenylamino)propanenitrile (syn-3a) was ob-
tained in 43% yield (Scheme 3a). The yield of syn-3a is obvi-
ously lower than that of 3a possible due to the cis-cyano
group, which makes the molecule more polar. The higher
polarity makes cis-1a less reactive than its trans-isomer 1a.
For examination of the scope of amines, we examined
two representative aliphatic amines, primary amine BnNH2
and secondary amine Et2NH, but neither of them gave the
corresponding products. That is possibly attributed to the
Br
(
)-cis-1a
2a 1.4 equiv.
(
Ph
b)
NH
HCl concd (0.3 equiv)
Br
CN
N
CF3CH2OH, reflux, 30 h
H
OH
Br
4 9%
(
)-3a
Ph
c)
NH
HCl concd (0.3 equiv)
Br
CN
OH
)-syn-3a
N
CF3CH2OH, reflux, 30 h
H
Br
4 45%
(
Scheme 3 Applications of the reaction
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

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C. Xu et al.
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Synthesis
In our previous work,2 -(N-arylamino)cyanohydrins
could further generate the corresponding indole com-
pounds catalyzed by proton acid, which is possibility
caused by the stronger acidity of trifluoroethanol than eth-
anol. Thus, trifluoroethanol has stronger reactivity with
Ph
O
O
O
NH
NH2
CN
CN
CN
CN
CN
a)
EtOH, MW, 100 °C, 40 min
OH
Br
Br
Br
(
)-1a
2a 1.4 equiv
(
)-3a 44%
Ph
NH
NH2
PhNH2•HCl (0.3 equiv)
BF3·OEt2
and
generates
stronger
proton
acid
b)
Br
EtOH, MW, 100 °C, 40 min
H[B(OCH2CF3)F3], which not only could accelerate the regio-
and diastereospecific SN2-type ring-opening process, but
also promote the intramolecular aromatic electrophilic
substitution process, giving the products of indoles.
OH
(
)-1a
)-1a
2a 1.1 equiv
(
)-3a 53%
Ph
NH
NH2
B(OMe)3 (0.1 equiv)
CN
c)
EtOH, MW, 100 °C, 40 min
In summary, a microwave-assisted BF3·OEt2-catalyzed
synthesis of anti--(N-arylamino)cyanohydrins from 3-aryl-
oxirane-2-carbonitriles and anilines in ethanol was devel-
oped. In this reaction, BF3·OEt2 firstly reacts with the sol-
vent ethanol to produce the true catalysts, super acids
H[B(OEt)nF4-n] (n = 1 to 4). Then an acid-catalyzed SN2-type
regio- and diastereospecific ring opening of 3-aryloxirane-
2-carbonitriles with anilines occurs in the presence of
H[B(OEt)nF4-n]. The reaction employed 3-aryloxirane-2-car-
bonitriles readily accessible from aromatic aldehydes and
2-chloroacetonitrile by Darzens reaction and anilines as the
starting materials, avoiding the use of highly toxic cyanide
reagents, making the reaction safe. As a result, the reaction
features advantages of readily accessible starting materials,
non-metal catalysis, short reaction times, cyanide-free re-
agents, and an environmentally friendly solvent.
OH
Br
Br
(
2a 1.4 equiv
(
)-3a 23%
Ph
B(OMe)3 (0.1 equiv),
PhNH2•HCl (0.3 equiv)
O
O
NH
NH2
CN
CN
CN
CN
d)
Br
EtOH, MW, 100 °C, 40 min
OH
Br
Br
(
)-1a
)-1a
2a 1.1 equiv
(
)-3a 57%
Ph
NH
NH2
HBF4 (50% w/w aq.)
e)
Br
EtOH, MW, 100 °C, 40 min
OH
(
2a 1.4 equiv
(
)-3a 99%
Scheme 4 Control experiments
equiv) or AlCl3 (0.10 equiv) in the presence of 2,2,2-trifluo-
roethanol, producing indoles. On the basis of the control ex-
periments and previously reported work,2 a plausible
mechanism is proposed (Scheme 5). First, BF3·OEt2 reacts
with the solvent ethanol to generate the true catalyst of
H[B(OEt)F3], which subsequently reacts with ethanol to
yield H[B(OEt)2F2], H[B(OEt)3F], and H[B(OEt)4] acidic spe-
cies as catalysts. H[B(OEt)nF4-n] (n = 1 to 4) species activate
epoxides 1 via protonation, forming intermediates I. Next,
intermediates I undergo a regio- and diastereospecific SN2-
type ring opening of oxirane-2-carbonitriles with anilines
2, generating intermediates II. The ring opening of proton-
ated aryloxiranes regiospecifically occurs on their benzylic
carbon atoms.13 Finally, intermediates II give the product
anti--(N-arylamino)cyanohydrins 3 after proton transfer
to H[B(OEt)2F2]–, regenerating the catalysts for the next cat-
alytic cycle.
Unless otherwise noted, all materials were purchased from commer-
cial sources, and commercially available reagents were used without
further purification. All reactions were performed under microwave
irradiation in a sealed vessel using a CEM Discover microwave reactor.
Column chromatography was carried out on silica gel (200–300
mesh) from Branch of Qingdao Haiyang Chemical Industry. Petroleum
ether (PE) used for column chromatography was bp 60–90 °C. Reac-
tions were monitored by TLC on silica gel GF254 coated 0.2-mm
plates from the Institute of Yantai Chemical Industry. The plates were
visualized under UV light. Melting points were measured on a Yanaco
MP-500 melting point apparatus and are uncorrected. 1H, 13C, and 19
F
NMR spectra were recorded on a Bruker 400 MHz NMR spectrometer
in CDCl3 and DMSO-d6 with TMS as an internal standard. IR spectra
(KBr pellets) were taken on a Nicolet 5700 FT-IR spectrophotometer.
HRMS were obtained under ESI ionization using an agilent LC/MSD
TOF mass spectrometer.
BF3•OEt2
EtOH
Ar2
OEt2
NH
(
)-1
-(N-Arylamino)cyanohydrins 3; General Procedure
CN
H[B(OEt)F3]
Ar1
(
A solution of 3-aryloxirane-2-carbonitrile 1 (0.5 mmol), aniline (0.7
mmol), and BF3·OEt2 (7 L, 0.05 mmol) in commercial EtOH (3 mL)
was stirred at 100 °C for 40 min under microwave irradiation in a
sealed vessel. The mixture was cooled to r.t., and then the solution
was transferred into a 25-mL flask and concentrated in vacuo. The
residue was purified by flash column chromatography (silica gel,
PE/EtOAc 10:1) to afford the corresponding -(N-arylamino)cyanohy-
drins 3.
OH
)-3
[B(OEt)F3]-
Ar2
Ar1
(
H
O+
NH2
OH
CN
Ar1
CN
(
)-I
SN2-type
ring-opening
)-II
Ar2NH2
H[B(OEt)2F2], H[B(OEt)3F], and H[B(OEt)4]
can serve as catalysts as well
anti-3-(4-Bromophenyl)-2-hydroxy-3-(phenylamino)propane-
nitrile (3a)
Scheme 5 Proposed mechanism
Colorless oil; yield: 153 mg (96%); Rf = 0.21 (33% EtOAc/PE).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

E
C. Xu et al.
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Synthesis
IR (KBr): 1010, 1072, 1385, 1405, 1436, 1501, 1602, 2246, 3385 cm–1
.
IR (KBr): 1011, 1072, 1180, 1271, 1294, 1313, 1406, 1494, 1600, 2252,
3385 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.53 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4
Hz, 2 H), 7.17 (t, J = 8.0 Hz, 2 H), 6.82 (t, J = 7.4 Hz, 1 H), 6.66 (d, J = 8.0
Hz, 2 H), 4.78 (d, J = 6.4 Hz, 1 H), 4.77 (dd, J = 8.0, 6.4 Hz, 1 H), 4.45 (s,
1 H), 3.17 (d, J = 8.0 Hz, 1 H).
1H NMR (400 MHz, CDCl3):  = 7.51 (d, J = 8.4 Hz, 2 H), 7.26 (d, J = 8.4
Hz, 2 H), 7.09 (d, J = 8.8 Hz, 2 H), 6.53 (d, J = 8.8 Hz, 2 H), 4.72 (s, 1 H),
4.67 (s, 1 H), 4.53 (s, 1 H), 3.38 (s, 1 H).
13C NMR (101 MHz, CDCl3):  = 145.3, 134.8, 132.4, 129.5, 128.7,
13C NMR (101 MHz, CDCl3):  = 144.0, 134.4, 132.4, 129.3, 128.7,
123.0, 120.0, 117.2, 114.8, 65.8, 60.4.
124.5, 123.1, 117.2, 115.9, 65.6, 60.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H14BrN2O: 317.0284; found:
HRMS (ESI): m/z [M + H]+ calcd for C15H13BrClN2O: 350.9894; found:
317.0280.
350.9897.
syn-3-(4-Bromophenyl)-2-hydroxy-3-(phenylamino)propane-
nitrile (syn-3a)2
anti-3-(4-Bromophenyl)-3-[(4-bromophenyl)amino]-2-hydroxy-
propanenitrile (3f)
Colorless oil; yield: 68 mg (43%); Rf = 0.21 (33% EtOAc/PE).
The residue was subjected to silica gel column chromatography
(PE/EtOAc 15:1) to give the desired product as a colorless solid; yield:
154 mg (78%); mp 140–142 °C; Rf = 0.34 (33% EtOAc/PE).
1H NMR (400 MHz, CDCl3):  = 7.51 (d, J = 8.2 Hz, 2 H), 7.31 (d, J = 8.2
Hz, 2 H), 7.15 (t, J = 7.8 Hz, 2 H), 6.79 (t, J = 7.2 Hz, 1 H), 6.61 (d, J = 8.0
Hz, 2 H), 4.67 (d, J = 6.0 Hz, 1 H), 4.64 (d, J = 6.0 Hz, 1 H), 4.11 (br s, 2
H).
13C NMR (101 MHz, CDCl3):  = 145.3, 135.7, 132.3, 129.4, 129.1,
123.0, 119.5, 117.8, 114.6, 65.1, 60.6.
IR (KBr): 1011, 1073, 1313, 1405, 1491, 1594, 2251, 3388 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 7.53 (d, J = 8.4 Hz, 2 H), 7.40 (d, J =
8.4 Hz, 2 H), 7.16 (d, J = 8.8 Hz, 2 H), 6.78 (d, J = 6.4 Hz, 1 H), 6.60 (d, J =
8.8 Hz, 2 H), 6.56 (d, J = 8.4 Hz, 1 H), 4.74–4.66 (m, 2 H).
13C NMR (101 MHz, DMSO-d6):  = 146.0, 138.2, 131.4, 131.0, 130.2,
120.9, 120.0, 115.4, 107.7, 63.9, 58.6.
anti-3-(4-Bromophenyl)-2-hydroxy-3-(p-tolylamino)propane-
nitrile (3b)
HRMS (ESI): m/z [M + H]+ calcd for C15H13Br2N2O: 394.9389; found:
394.9393.
Yellowish oil; yield: 112 mg (68%); Rf = 0.35 (33% EtOAc/PE).
IR (KBr): 1010, 1071, 1268, 1299, 1487, 1518, 1617, 2246, 3385 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.52 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.4
Hz, 2 H), 6.98 (d, J = 8.4 Hz, 2 H), 6.58 (d, J = 8.4 Hz, 2 H), 4.73 (d, J = 4.0
Hz, 1 H), 4.72 (d, J = 4.0 Hz, 1 H), 4.34 (s, 1 H), 3.43 (s, 1 H), 2.23 (s, 3
H).
anti-3-(4-Bromophenyl)-2-hydroxy-3-[methyl(phenyl)ami-
no]propanenitrile (3g)
Colorless oil; yield: 150 mg (91%); Rf = 0.46 (33% EtOAc/PE).
IR (KBr): 1011, 1074, 1142, 1181, 1384, 1402, 1450, 1501, 1598, 2246,
13C NMR (101 MHz, CDCl3):  = 142.9, 134.9, 132.3, 130.0, 129.4,
3406 cm–1
.
128.7, 122.9, 117.4, 115.1, 65.7, 60.7, 20.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H16BrN2O: 331.0441; found:
331.0437.
1H NMR (400 MHz, CDCl3):  = 7.50 (d, J = 8.0 Hz, 2 H), 7.31 (t, J = 7.6
Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 6.97 (d, J = 8.0 Hz, 2 H), 6.92 (t, J = 7.6
Hz, 1 H), 5.19 (d, J = 6.8 Hz, 1 H), 5.07 (t, J = 6.4 Hz, 1 H), 3.10 (d, J = 7.6
Hz, 1 H), 2.78 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 150.1, 133.6, 132.0, 129.5, 129.2,
anti-3-(4-Bromophenyl)-2-hydroxy-3-[(4-methoxyphenyl)ami-
no]propanenitrile (3c)
122.5, 120.0, 118.9, 115.5, 65.9, 62.0, 34.3.
HRMS (ESI): m/z [M + H]+ calcd for C16H16BrN2O: 331.0441; found:
661.0438.
Not detected, but 16% of 2-(4-bromophenyl)-5-methoxy-1H-indole
was obtained.2
anti-3-(4-Bromophenyl)-3-[(4-fluorophenyl)amino]-2-hydroxy-
propanenitrile (3d)
anti-3-(4-Bromophenyl)-3-[3,4-dihydroquinolin-1(2H)-yl]-2-hy-
droxypropanenitrile (3h)
Yellowish oil; yield: 152 mg (91%); Rf = 0.38 (33% EtOAc/PE).
IR (KBr): 1011, 1072, 1221, 1406, 1488, 1510, 1604, 2250, 3386 cm–1
Colorless oil; yield: 103 mg (58%); Rf = 0.46 (33% EtOAc/PE).
.
IR (KBr): 1010, 1073, 1192, 1307, 1345, 1400, 1455, 1494, 1601, 2249,
3418 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.53 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.4
Hz, 2 H), 6.88–6.83 (m, 2 H), 6.61–6.55 (m, 2 H), 4.73 (d, J = 4.0 Hz, 1
H), 4.67 (d, J = 4.0 Hz, 1 H), 4.41 (s, 1 H), 3.46 (s, 1 H).
13C NMR (101 MHz, CDCl3):  = 157.0 (d, JC-F = 239.4 Hz), 141.57 (d,
JC-F = 3.0 Hz), 134.7, 132.4, 128.7, 123.0, 117.3, 116.1 (d, JC-F = 2.0 Hz),
115.9 (d, JC-F = 13.1 Hz), 65.7, 61.1.
1H NMR (400 MHz, CDCl3):  = 7.51 (d, J = 8.0 Hz, 2 H), 7.27 (d, J = 8.0
Hz, 2 H), 7.09 (t, J = 7.8 Hz, 1 H), 7.02 (d, J = 7.2 Hz, 1 H), 6.84 (d, J = 7.6
Hz, 1 H), 6.72 (t, J = 7.2 Hz, 1 H), 5.33 (d, J = 6.4 Hz, 1 H), 5.13 (t, J = 7.0
Hz, 1 H), 3.33 (ddd, J = 11.2, 7.6, 2.8 Hz, 1 H), 3.15 (ddd, J = 11.2, 7.6,
3.2 Hz, 1 H), 2.96 (d, J = 8.0 Hz, 1 H), 2.77 (d, J = 6.0 Hz, 1 H), 2.76 (d, J =
6.4 Hz, 1 H), 1.96–1.87 (m, 1 H), 1.78–1.69 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 144.8, 134.2, 132.1, 130.0, 129.4,
127.4, 124.2, 122.5, 118.7, 118.1, 112.0, 63.0, 61.9, 44.8, 28.0, 21.9.
HRMS (ESI): m/z [M + H]+ calcd for C18H18BrN2O: 357.0597; found:
19F NMR (377 MHz, CDCl3):  = –124.52.
HRMS (ESI): m/z [M + H]+ calcd for C15H13BrFN2O: 335.0190; found:
335.0184.
357.0591.
anti-3-(4-Bromophenyl)-3-[(4-chlorophenyl)amino]-2-hydroxy-
propanenitrile (3e)
The residue was subjected to silica gel column chromatography
(PE/EtOAc 15:1) to give the desired product as a yellowish oil; yield:
118 mg (67%); Rf = 0.40 (33% EtOAc/PE).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

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C. Xu et al.
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Synthesis
anti-2-Hydroxy-3-phenyl-3-(phenylamino)propanenitrile (3i)
HRMS (ESI): m/z [M + H]+ calcd for C15H14ClN2O: 273.0789; found:
273.0786.
The residue was subjected to silica gel column chromatography
(PE/EtOAc 15:1) to give the desired product as a colorless solid; yield:
85 mg (71%); mp 98–100 °C; Rf = 0.44 (33% EtOAc/PE).
anti-4-[2-Cyano-2-hydroxy-1-(phenylamino)ethyl]benzonitrile
(3m)
IR (KBr): 1030, 1075, 1182, 1274, 1315, 1435, 1454, 1501, 1603, 2248,
3387 cm–1
.
The residue was subjected to silica gel column chromatography
(PE/EtOAc 6:1) to give the desired product as a yellowish oil; yield:
101 mg (77%); Rf = 0.22 (33% EtOAc/PE).
1H NMR (400 MHz, CDCl3):  = 7.43–7.33 (m, 5 H), 7.17 (dt, J = 7.6, 0.8
Hz, 2 H), 6.81 (t, J = 7.2 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 2 H), 4.84 (dd, J =
7.2, 3.6 Hz, 1 H), 4.77 (dd, J = 8.4, 3.6 Hz, 1 H), 4.48 (d, J = 7.2 Hz, 1 H),
3.29 (d, J = 8.8 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 145.7, 135.6, 129.4, 129.2, 128.9,
126.9, 119.8, 117.5, 114.9, 66.1, 61.0.
IR (KBr): 1074, 1272, 1314, 1413, 1436, 1503, 1603, 2232, 3380 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.67 (d, J = 8.0 Hz, 2 H), 7.57 (d, J = 8.4
Hz, 2 H), 7.16 (t, J = 8.0 Hz, 2 H), 6.81 (t, J = 7.6 Hz, 1 H), 6.61 (d, J = 8.0
Hz, 2 H), 4.83 (d, J = 4.0 Hz, 1 H), 4.81 (d, J = 4.0 Hz, 1 H), 4.60 (s, 1 H),
3.62 (s, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H15N2O: 239.1179; found:
239.1179.
13C NMR (101 MHz, CDCl3):  = 145.1, 141.8, 132.8, 129.5, 128.2,
119.8, 118.3, 117.1, 114.5, 112.4, 65.1, 60.5.
anti-2-Hydroxy-3-(phenylamino)-3-(p-tolyl)propanenitrile (3j)
HRMS (ESI): m/z [M + H]+ calcd for C16H14N3O: 264.1131; found:
264.1139.
The residue was subjected to silica gel column chromatography
(PE/EtOAc 15:1) to give the desired product as a colorless oil; yield: 77
mg (61%); Rf = 0.45 (33% EtOAc/PE).
anti-2-Hydroxy-3-(naphthalen-2-yl)-3-(phenylamino)propane-
nitrile (3n)
IR (KBr): 1071, 1181, 1273, 1315, 1380, 1436, 1504, 1603, 2247, 3387
cm–1
.
The residue was subjected to silica gel column chromatography
(PE/EtOAc 15:1) to give the desired product as a colorless oil; yield: 77
mg (69%); Rf = 0.37 (33% EtOAc/PE).
1H NMR (400 MHz, CDCl3):  = 7.29 (d, J = 8.0 Hz, 2 H), 7.20 (d, J = 8.0
Hz, 2 H), 7.17 (t, J = 8.0 Hz, 2 H), 6.80 (t, J = 7.6 Hz, 1 H), 6.70 (d, J = 7.6
Hz, 2 H), 4.81 (s, 1 H), 4.74 (d, J = 4.0 Hz, 1 H), 4.45 (s, 1 H), 3.27 (s, 1
H), 2.34 (s, 3 H).
IR (KBr): 1072, 1129, 1273, 1314, 1374, 1435, 1504, 1602, 2247, 3388
cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.88 (d, J = 8.8 Hz, 2 H), 7.84 (d, J = 6.4
Hz, 1 H), 7.83 (d, J = 6.0 Hz, 1 H), 7.52–7.50 (m, 3 H), 7.16 (t, J = 8.0 Hz,
2 H), 6.80 (t, J = 7.6 Hz, 1 H), 6.73 (d, J = 7.6 Hz, 2 H), 4.96 (d, J = 4.0 Hz,
1 H), 4.82 (d, J = 4.0 Hz, 1 H), 4.62 (s, 1 H), 3.49 (s, 1 H).
13C NMR (101 MHz, CDCl3):  = 145.8, 138.8, 132.5, 129.9, 129.4,
126.8, 119.7, 117.6, 114.9, 66.2, 60.7, 21.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H17N2O: 253.1335; found:
253.1336.
13C NMR (101 MHz, CDCl3):  = 145.8, 133.4, 133.2, 133.2, 129.4,
129.1, 128.1, 127.7, 126.6, 126.4, 124.3, 119.6, 117.6, 114.8, 66.0, 61.0.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2O: 289.1335; found:
anti-3-(4-Fluorophenyl)-2-hydroxy-3-(phenylamino)propane-
nitrile (3k)
289.1336.
Colorless oil; yield: 100 mg (78%); Rf = 0.33 (33% EtOAc/PE).
IR (KBr): 1071, 1158, 1225, 1314, 1436, 1509, 1603, 2248, 3396 cm–1
.
anti-2-Hydroxy-3-(naphthalen-1-yl)-3-(phenylamino)propane-
nitrile (3o)
1H NMR (400 MHz, CDCl3):  = 7.41–7.37 (m, 2 H), 7.18 (t, J = 7.6 Hz, 2
H), 7.08 (t, J = 7.6 Hz, 2 H), 6.82 (t, J = 7.2 Hz, 1 H), 6.66 (d, J = 7.8 Hz, 2
H), 4.79 (s, 1 H), 4.73 (d, J = 4.0 Hz, 1 H), 4.49 (s, 1 H), 3.46 (d, J = 1.8
Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 162.8 (d, JC-F = 249.5 Hz), 145.5, 131.5
(d, JC-F = 3.0 Hz), 129.4, 128.8 (d, JC-F = 8.1 Hz), 119.8, 117.5, 116.2 (d,
JC-F = 22.2 Hz), 114.8, 65.9, 60.2.
The residue was subjected to silica gel column chromatography
(PE/EtOAc 15:1) to give the desired product as a colorless solid; yield:
104 mg (72%); mp 147–149 °C; Rf = 0.43 (33% EtOAc/PE).
IR (KBr): 1065, 1167, 1269, 1314, 1383, 1435, 1503, 1602, 2248, 3387
cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.08 (d, J = 8.8 Hz, 1 H), 7.95 (d, J = 8.0
Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.68–7.63 (m, 2 H), 7.57 (dt, J = 8.0,
0.8 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.14 (t, J = 8.0 Hz, 2 H), 6.79 (t, J =
7.4 Hz, 1 H), 6.72 (d, J = 7.6 Hz, 2 H), 5.68 (dd, J = 9.6, 3.6 Hz, 1 H), 4.96
(dd, J = 9.6, 3.6 Hz, 1 H), 4.66 (d, J = 9.2 Hz, 1 H), 3.50 (d, J = 10.0 Hz, 1
H).
13C NMR (101 MHz, CDCl3):  = 145.5, 134.1, 130.6, 130.5, 129.7,
129.5, 129.5, 127.2, 126.1, 125.7, 124.2, 121.1, 120.0, 117.3, 115.1,
65.8, 57.1.
19F NMR (377 MHz, CDCl3):  = –112.64.
HRMS (ESI): m/z [M + H]+ calcd for C15H14FN2O: 257.1085; found:
257.1084.
anti-3-(4-Chlorophenyl)-2-hydroxy-3-(phenylamino)propane-
nitrile (3l)
Colorless oil; yield: 116 mg (85%); Rf = 0.33 (33% EtOAc/PE).
IR (KBr): 1014, 1073, 1092, 1271, 1315, 1408, 1435, 1495, 1603, 2248,
3388 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2O: 289.1335; found:
1H NMR (400 MHz, CDCl3):  = 7.39–7.34 (m, 4 H), 7.17 (t, J = 7.6 Hz, 2
H), 6.81 (t, J = 7.2 Hz, 1 H), 6.66 (d, J = 7.6 Hz, 2 H), 4.80 (dd, J = 8.0, 3.6
Hz, 1 H), 4.75 (s, 1 H), 4.46 (d, J = 8.0 Hz, 1 H), 3.28 (s, 1 H).
289.1334.
anti-2-Hydroxy-5-phenyl-3-(phenylamino)pentanenitrile (3p)
Colorless oil; yield: 29 mg (17%); Rf = 0.47 (33% EtOAc/PE).
13C NMR (101 MHz, CDCl3):  = 145.4, 134.8, 134.2, 129.5, 129.4,
128.4, 119.9, 117.3, 114.8, 65.8, 60.3.
IR (KBr): 694, 750, 1075, 1316, 1498, 1510, 1601, 2251, 2854, 2925,
3394 cm–1
.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

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C. Xu et al.
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Synthesis
1H NMR (400 MHz, CDCl3):  = 7.29–7.25 (m, 2 H), 7.22–7.18 (m, 3 H),
7.09 (dd, J = 8.0, 1.2 Hz, 1 H), 6.83 (t, J = 7.6 Hz, 1 H), 6.67 (dd, J = 8.4,
0.8 Hz, 2 H), 4.54 (s, 1 H), 3.69 (td, J = 6.8, 4.2 Hz, 1 H), 3.13 (d, J = 7.2
Hz, 1 H), 2.78 (dt, J = 14.0, 7.2 Hz, 1 H), 2.69 (dt, J = 14.0, 8.0 Hz, 1 H),
2.03 (q, J = 7.2 Hz, 2 H), 1.59 (s, 1 H).
13C NMR (101 MHz, CDCl3):  = 146.7, 140.2, 129.6, 128.6, 128.4,
126.4, 119.7, 118.2, 114.5, 64.4, 56.9, 33.4, 32.0.
(2) Xu, C. C.; Xu, J. X. J. Org. Chem. 2018, 83, 14733.
(3) Ma, Y.; Shang, C.; Yang, P.; Li, L.; Zhai, Y.; Yin, Z.; Wang, B.;
Shang, L. J. Med. Chem. 2018, 61, 10333.
(4) (a) Sasaki, M.; Ando, M.; Kawahata, M.; Yamaguchi, K.; Takeda,
K. Org. Lett. 2016, 18, 1598. (b) Wang, N.; Li, L.; Li, Z. L.; Yang, N.
Y.; Guo, Z.; Zhang, H. X.; Liu, X. Y. Org. Lett. 2016, 18, 6026.
(c) Ritzen, B.; van Oers, M. C.; van Delft, F. L.; Rutjes, F. P. J. Org.
Chem. 2009, 74, 7548. (d) Kurz, T.; Widyan, K. J. Org. Chem. 2005,
70, 3108.
(5) Zhai, Y.; Zhao, X.; Cui, Z.; Wang, M.; Wang, Y.; Li, L.; Sun, Q.;
Yang, X.; Zeng, D.; Liu, Y.; Sun, Y.; Lou, Z.; Shang, L.; Yin, Z.
J. Med. Chem. 2015, 58, 9414.
HRMS (ESI): m/z [M + H]+ calcd for C17H19N2O: 267.1492; found:
267.1490.
2-(4-Bromophenyl)-1H-indole (4)2
A solution of 3-(4-bromophenyl)-2-hydroxy-3-(phenylamino)pro-
panenitrile 3a or syn-3a (159 mg, 0.5 mmol) and concd HCl (12.5 L,
0.15 mmol) in commercial 2,2,2-trifluoroethanol (5 mL) was refluxed
for 30 h under open-air conditions. The mixture was cooled to r.t., and
then the crude solution was quenched with water (10 mL) and ex-
tracted with EtOAc (2 × 10 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel, PE/EtOAc 30:1)
to afford 2-(4-bromophenyl)-1H-indole (4)2 as a beige solid; yield: 12
mg (9% from 3a); 61 mg (45% from syn-3a).
1H NMR (400 MHz, CDCl3):  = 8.27 (s, 1 H), 7.63 (d, J = 8.0 Hz, 1 H),
7.57 (d, J = 8.4 Hz, 2 H), 7.52 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 8.0 Hz, 1 H),
7.23–7.19 (m, 1 H), 7.15–7.11 (m, 1 H), 6.82 (s, 1 H).
13C NMR (101 MHz, CDCl3):  = 136.9, 136.67, 132.2, 131.3, 129.2,
126.6, 122.7, 121.5, 120.8, 120.5, 110.9, 100.5.
(6) Gregory, R. J. H. Chem. Rev. 1999, 99, 3649.
(7) (a) Liu, X.; Xiang, M.; Tong, Z.; Luo, F.; Chen, W.; Liu, F.; Wang,
F.; Yu, R. Q.; Jiang, J. H. Anal. Chem. 2018, 90, 5534. (b) Cioni, J.
P.; Doroghazi, J. R.; Ju, K. S.; Yu, X.; Evans, B. S.; Lee, J.; Metcalf,
W. W. J. Nat. Prod. 2014, 77, 243. (c) Peterson, C. J.; Tsao, R.;
Coats, J. R. Pest Manage. Sci. 2000, 56, 615.
(8) (a) Murtinho, D.; Serra, M. Curr. Organocatal. 2014, 1, 87.
(b) Sofighaderi, S.; Setamdideh, D. Orient. J. Chem. 2013, 29,
1135. (c) Feng, X.; Chen, F.-X. Synlett 2005, 892. (d) North, M.;
Usanov, D. L.; Young, C. Chem. Rev. 2008, 108, 5146. (e) Kurono,
N.; Ohkuma, T. ACS Catal. 2016, 6, 989. (f) Qin, B.; Liu, X.; Shi, J.;
Zheng, K.; Zhao, H.; Feng, X. J. Org. Chem. 2007, 72, 2374. (g) Li,
Y.; He, B.; Qin, B.; Feng, X.; Zhang, G. J. Org. Chem. 2004, 69,
7910. (h) Zheng, S.; Yuan, X.; Wang, W.; Liang, C.; Cao, F.; Zhang,
R. J. Anal. Toxicol. 2016, 40, 388.
(9) Cioc, R. C.; Schuckman, P.; Preschel, H. D.; Vlaar, T.; Ruijter, E.;
Orru, R. V. Org. Lett. 2016, 18, 3562.
(10) Zhang, D.; Lian, M.; Liu, J.; Tang, S.; Liu, G.; Ma, C.; Meng, Q.;
Peng, H.; Zhu, D. Org. Lett. 2019, 21, 2597.
Funding Information
(11) (a) Sendzik, M.; Janc, J. W.; Cabuslay, R.; Honigberg, L.;
Mackman, R. L.; Magill, C.; Squires, N.; Waldeck, N. Bioorg. Med.
Chem. Lett. 2004, 14, 3181. (b) Ziora, Z.; Kasai, S.; Hidaka, K.;
Nagamine, A.; Kimura, T.; Hayashi, Y.; Kiso, Y. Bioorg. Med.
Chem. Lett. 2007, 17, 1629. (c) Tasic, G.; Matovic, R.; Saicic, R.
J. Serb. Chem. Soc. 2004, 69, 981. (d) Hook, D. F.; Gessier, F.; Noti,
C.; Kast, P.; Seebach, D. ChemBioChem 2004, 5, 691.
This work was supported by the National Natural Science Foundation
of China (Nos. 21572017 and 21772010) and the Fundamental Re-
search Funds for the Central Universities (XK1802-6).
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Supporting Information
(12) Herranz, R.; Castro-Pichel, J.; García-López, T. Synthesis 1989,
703.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690243.
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(13) (a) Zhou, C.; Xu, J. X. Prog. Chem. 2011, 23, 165. (b) Li, X. Y.; Yang,
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© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G