Utilization of Borane-Catalyzed Hydrosilylation as a Dearomatizing Tool: Six-Membered Cyclic Amidine Synthesis from Isoquinolines and Pyridines

Article abstract of DOI:10.1055/s-0040-1707323

In this study, a convenient strategy to synthesize six-membered?? cyclic amidines from isoquinolines and pyridines has been developed. Borane-catalyzed hydrosilylation of each N-heteroarene was utilized as a dearomatizing tool. Substrate scope is broad with respect to both isoquinolines and pyridines, with various reaction pathways depending on the substitution pattern of the N-heteroarenes. The reaction mechanism and reactivity of each class of N-heteroarenes has been discussed. The resulting six-membered (Z)-sulfonyl amidine products are rarely reported and are mostly unprecedented. The scalability of this method and versatility of the cyclic amidine products are also presented.

Full text of DOI:10.1055/s-0040-1707323

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–K
paper
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de
V. D. Cao et al.
Paper
Synthesis
Utilization of Borane-Catalyzed Hydrosilylation as a Dearomatizing
Tool: Six-Membered Cyclic Amidine Synthesis from Isoquinolines
and Pyridines
Vinh Do Cao◊
Dong Geun Jo◊
N
SO2Ar
R
R
N
N
H
Huiae Kim
SiRR'H
R
B(C6F5)3
cat.
H
N
Changeun Kim
Seula Yun
ArSO2N3
H
R
– N2
R
RR'SiH2
R
then, MeOH
Seewon Joung*
N
N
N
N
H
SO2Ar
Department of Chemistry, Mokpo National University, Muan,
Jeonnam, 58554, South Korea
SiRR'H
seewonjoung@mokpo.ac.kr
◊These authors contributed equally
Corresponding Author
Received: 18.08.2020
Accepted after revision: 09.09.2020
Published online: 12.10.2020
the other strategies had produced (E)-sulfonylamidines as a
major product,3a,7 our approach could selectively achieve
(Z)-sulfonylamidines. This E/Z selectivity originated from
the unique concerted mechanism during the [3+2] cyclo-
addition step. Moreover, since only a few examples of the
synthesis of six-membered (Z)-sulfonyl amidines have been
reported to date, this approach could enlarge the molecular
library for organic and medicinal chemistry society. In the
same vein, utilization of this strategy for the construction
of new cyclic amidines from other N-heteroarenes would
also be important. Moreover, during this study, various
mode of reaction of each N-heteroarene will be discussed.
Herein, we report an extensive application of our dearoma-
tization strategy to synthesize cyclic (Z)-sulfonyl amidines
from isoquinolines and pyridines (Scheme 1b).
DOI: 10.1055/s-0040-1707323; Art ID: ss-2020-f0434-op
Abstract In this study, a convenient strategy to synthesize six-
membered cyclic amidines from isoquinolines and pyridines has been
developed. Borane-catalyzed hydrosilylation of each N-heteroarene was
utilized as a dearomatizing tool. Substrate scope is broad with respect
to both isoquinolines and pyridines, with various reaction pathways de-
pending on the substitution pattern of the N-heteroarenes. The reac-
tion mechanism and reactivity of each class of N-heteroarenes has been
discussed. The resulting six-membered (Z)-sulfonyl amidine products
are rarely reported and are mostly unprecedented. The scalability of
this method and versatility of the cyclic amidine products are also pre-
sented.
Key words cyclic amidine, hydrosilylation, N-heteroarenes, dearoma-
tization, [3+2] cycloaddition, B(C6F5)3
Ar
H
Cl
Cyclic amidine is an important structural motif in or-
ganic synthesis and medicinal chemistry because of its
ubiquitous presence in natural and pharmaceutical mole-
cules.1 The biological activities of the six-membered cyclic
amidines have been widely studied and evaluated as human
iNOS inhibitor, mRNA modulator, proapoptotic agent, anti-
inflammatory agent, hBGT1 inhibitor, and matriptase inhib-
itor (Figure 1).2 As a result, various synthetic strategies to-
ward the six-membered cyclic amidines have been report-
ed.3 As part of this effort, our group recently reported a new
synthetic strategy toward the six-membered cyclic ami-
dines from readily available quinolines and sulfonyl azides
(Scheme 1a).4 We utilized the borane (B(C6F5)3, BCF) cata-
lyzed 1,4-hydrosilylation of quinoline 1 as a dearomatizing
tool.5 The resulting N-silyl enamine intermediate 2 was
then reacted with organic azide via [3+2] cycloaddition to
achieve a six-membered sulfonyl amidine 3.6 While most of
R
R
N
N
H
N
H
NH
N
N
H
H
human iNOS inhibitor
mRNA modulator
proapoptotic agent
O
H
N
R
N
S
NR2
COOH
O2
NH
R
H2N
H2N
N
N
Ar
antiinflammatory &
analgesic
hBGT1 inhibitor
matriptase inhibitor
NH2
HN
Figure 1 Selected six-membered cyclic amidine compounds with bio-
logical activities
Before we commenced our study, we carefully com-
pared the reactivity of each target class of N-heteroarenes
with quinolines. Isoquinoline was chosen as the initial sub-
strate. Compared to hydrosilylation of quinoline with
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
V. D. Cao et al.
Paper
Synthesis
a) Our previous work: Tandem dearomative cyclic amidine synthesis of quinolines
H
B(C6F5)3 (5 mol%)
PhMeSiH2 (1.2 eq.)
TsN3 (1.0 eq.)
(10a)
N
Ts
R
B(C6F5)3 (5 mol%)
R
CDCl3
ArSO2N3
0 °C to RT, 2 h
then, MeOH
N
N
NH
R
R
110 °C, time
R
Ph2SiH2 (1.2 eq.)
65 °C, overnight
SiMePhH
N
H
N
– N2
N
N
6
H
SO2Ar
then, MeOH
3
isolated yield
SiPh2H
1
2
4
5
(crude yieldb)
Br
N
b) This work: Expansion to other isoquinolines, pyridines and sulfonyl azides
R
N
N
Ts
Ts
Ts
N
Ts
NH
NH
N
NH
Br
SO2Ar
NH
R
Br
N
SiRR'H
R
NH
N
6a, 63% (n.d.)
6b, 78% (81%)
6c, 81% (85%)
6d, 88% (91%)
H
H
6
8 h
2 h
2 h
2 h
B(C6F5)3 (5 mol%)
RR'SiH2 (1.2 eq.)
5
ArSO2N3
4
TMS
– N2
then, MeOH
R
R
Cl
OTIPS
N
R
N
Ts
N
N
N
N
Ts
Ts
NH
N
N
TIPSO
H
SO2Ar
NH
NH
Ts
7
SiRR'H
8
9
NH
6e, 87% (95%)
6f, 54% (64%)
6g, 80% (85%)
6h, 81% (95%)a
Scheme 1 Six-membered cyclic amidine synthesis by using dearoma-
tive hydrosilylation strategy
2 h
15 h
15 h
9 h
F3C
CF3
Br
Ph
N
diphenylsilane at 65 °C, hydrosilylation of the isoquinoline
required more reactive methylphenylsilane and higher tem-
perature (110 °C) to obtain reasonable conversion.4 This
distinction originated from the reactivity difference be-
tween the 1,2-hydrosilylation of isoquinoline and 1,4-hy-
drosilylation of quinolines.5a In situ NMR monitoring of the
reaction mixture clearly showed the slower 1,2-hydrosilyla-
tion.8 The structure of the resulting conjugated enamine in-
termediate 5 from isoquinoline was also contrasted to that
of the unconjugated enamine intermediate 2 from the quin-
olines. To examine the reactivity differences from these as-
pects, we investigated the substrate scope of the reaction
with respect to isoquinolines and tosyl azide 10a (Scheme
2). Note that all reactions were conducted in chloroform-d
in the NMR cell so that we could observe the conversion of
each step by using in situ 1H NMR analysis.
Under the optimized conditions for the synthesis of iso-
quinolines, dearomative hydrosilylation of isoquinoline 4a
produced the conjugated enamine 5a in 8 h. The subse-
quent addition of tosyl azide 10a induced [3+2] cycloaddi-
tion, hydride shift, and a nitrogen extrusion process to pro-
duce the desired cyclic amidine in excellent conversion
from the enamine intermediate. Note that an ice bath was
required for the second step due to the vigorous exothermic
reaction. Next, the dearomative hydrosilylation of 5-bro-
moisoquinoline (4b) produced the desired enamine inter-
mediate 5b with excellent conversion in 2 h. Subsequent
addition of tosyl azide 10a resulted in formation of the cy-
clic amidine in excellent yield. Since the 7-bromo- and 8-
bromo-isoquinolines 4c and 4d showed similar high reac-
tivity toward the hydrosilylation, the electron-withdrawing
effect of the bromides might have increased the reactivity.
Similarly, the dearomative hydrosilylation of 5-chloroiso-
quinoline 4e also resulted in rapid conversion into the re-
spective enamine intermediate 5e. The following addition
of azide 10a resulted in formation of the desired cyclic ami-
N
N
N
4i
4j
4k
4l
Scheme 2 Substrate scope of the reaction with respect to isoquino-
lines. Reagents and conditions: 4 (0.5 mmol), B(C6F5)3 (0.025 mmol), and
MePhSiH2 (0.6 mmol) were heated in CDCl3 (0.5 mL) in a screw-capped
NMR tube. a Required 1.7 equiv of silane for full conversion. b Deter-
mined by 1H NMR analysis of the crude mixture (internal standard:
tetrachloroethane).
dine product 6e in good yield. The reactions of the electron-
donating silyloxy-substituted isoquinolines 4f and 4g also
resulted in good to excellent yields, although longer reac-
tion time was required. Additionally, reaction of substrate
4h, bearing an alkyne functional group, resulted in forma-
tion of the desired product 6h without undesired hydrosi-
lylation on the alkyne.9 With respect to these results, 4-bro-
moisoquinoline 4i was also tested in our cascade process.
The first dearomative hydrosilylation of 4i led to its conver-
sion into enamine intermediate 5i, like the other halogen-
substituted isoquinolines. However, the ensuing azide addi-
tion resulted in a complex mixture. The halogen on the
enamine intermediate may participate in other side reac-
tions by acting as a leaving group during the [3+2] cycload-
dition, hydride shift, and nitrogen gas extrusion process. Af-
ter that, the reactivity of the 1-methylisoquinoline 4j was
also tested under the dearomative hydrosilylation condi-
tions. Although 4j was reactive enough for the dearomati-
zation, the N–Si bond of the enamine intermediate from 5j
was too unstable for this stepwise process and resulted in a
complex mixture. Note that this result is similar to the over-
reduction of 2-methylquinoline.10 6-Phenylisoquinoline
(4k) was also tested for our process. However, it was not re-
active towards the dearomative hydrosilylation. The hydro-
silylation of the electron-deficient aryl isoquinoline 4l
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

C
V. D. Cao et al.
Paper
Synthesis
resulted in the same. The extended conjugation from the
additional aryl group might stabilize 4k and 4l and deacti-
vate it.
As initial reaction conditions, we chose diphenylsilane
at 85 °C for the dearomative hydrosilylation of 3-chloropyr-
idine (7a) and 3-bromopyridine (7b). The resulting enam-
ine intermediates were converted into cyclic amidines 9a
and 9b via regioselective [3+2] cycloaddition with tosyl
azide 10a. Interestingly, the reaction rate for the cycloaddi-
tion step was much slower than for the other N-het-
eroarenes. On the other hand, 3-bromo-5-methylpyridine
7c had lower reactivity than the 3-halopyridines toward the
dearomatization step. Therefore, we changed the silane to
more reactive methylphenylsilane so as to achieve moder-
ate yield of cyclic amidine 9c. Note that the azide preferred
to react with 2-methylenamine rather than 2-bromoenam-
ine of 8c. Eventually, we increased the temperature of the
dearomative hydrosilylation to 110 °C to achieve reasonable
conversion of the rest of our pyridines (7d–g). Both 3-meth-
ylpyridine 7d and 3-phenylpyridine 7e showed moderate
conversion during the dearomative hydrosilylation step, but
the additional side reactions during the second step with
azide 10a led to lower yield of 9d.12 The reaction of 3,5-di-
methylpyridine 7f produced 9f in a low yield, but the reac-
tion of 3-methyl-5-phenylpyridine 7g resulted in a moder-
ate yield of 9g. Note that the azide preferred to react with
the 2-methylenamine over 2-phenylenamine of intermedi-
ate 8g. More interestingly, we could obtain double hydrosi-
lylation intermediate 8d′ from 3-methylpyridine 7d by add-
ing more silane (2.5 equiv).5b Subsequent addition of azide
10a resulted in silylated cyclic amidine 9h as the major
product along with diastereomer 9h′ as the minor product.
The major diastereomer was trans since the azide ap-
proached from the other side of the methyl substituent.13
After exploring the substrate scope of the reaction with
pyridines and tosyl azide 10a, we thought that the longer
reaction time during the cycloaddition step could allow side
reactions to occur. Therefore, 4-(trifluoromethyl)benzene-
sulfonyl azide (10b) was applied to reduce the reaction
time of the second step. This electron-deficient azide exhib-
ited higher reactivity than 10a.4 After the dearomative hy-
drosilylation of 7, 10b was added to the reaction mixture
instead of 10a. The dienamine intermediates were quickly
converted into cyclic amidines within 2 h (Scheme 3, bot-
tom). The isolated yields of the new cyclic amidines from
10b (11a–g) were similar to or higher than the correspond-
ing amidines from 10a. The crystal structure of 11g (CCDC
1987424) was also obtained,14 which supported the (Z)-sul-
fonyl amidine structure of 9 and 11. The modified proce-
dure to obtain silylated cyclic amidine 11h and 11h′ from
the doubly hydrosilylated intermediate 8d′ was also applied
successfully with 10b.
We then turned our attention to the pyridines. A bo-
rane-catalyzed multiple hydrosilylation of the pyridines
had been discussed by Chang and Park.5b Dearomative hy-
drosilylation of simple pyridine and 2-substituted pyridines
with 1.0 equiv of the silane resulted in a complex mixture.11
We believe that the substituent near the nitrogen of the
pyridine affected the stability of the N-silyl enamine inter-
mediates. In the case of the 4-substituted pyridines, double
hydrosilylation was too fast to capture the N-silyl enamine
intermediate. Therefore, we decided to focus on the 3-sub-
stituted pyridines to determine the pyridine substrate
scope (Scheme 3, top).
B(C6F5)3 (5 mol%)
R'
silane (1.2 eq.)
ArSO2N3 (1.0 eq.)
R'
R
R'
R
R
(10)
N
N
RT, YY h
then, MeOH
CDCl3
temp., time
N
N
H
SO2Ar
SiRR'H
9 or 11
7
8
isolated yield (crude yieldb)
Ar = 4-CH3-C6H4 (10a), YY h = overnight
Cl Br
Br
CH3
Me
N
N
N
N
N
N
N
N
H
H
H
H
Ts
Ts
Ts
Ts
9a, 74% (74%)
Ph2SiH2
9b, 56% (60%)
Ph2SiH2
9c, 47% (n.d.)
MePhSiH2
9d, 17% (n.d.)
MePhSiH2
85 °C, 12 h
85 °C, 12 h
85 °C, 12 h
110 °C, 4 h
Ph
H3C
CH3
Ph
Me HPhMeSi
Me
*
N
N
N
N
N
N
N
N
H
H
H
H
Ts
Ts
Ts
Ts
9e, 41% (42%)
MePhSiH2
110 °C, 4 h
9f, 23% (23%)
MePhSiH2
110 °C, 18 h
9g, 32% (38%)
MePhSiH2
110 °C, 18 h
9h, 23%/9h', 3%a
MePhSiH2
110 °C, 18 h
Ar = 4-CF3-C6H4 (10b), YY h = 2 h
Cl Br
Br
CH3
Me
N
N
N
N
N
N
N
N
H
H
H
H
SO2Ar
SO2Ar
SO2Ar
SO2Ar
11a, 65% (n.d.)
Ph2SiH2
11b, 60% (n.d.)
Ph2SiH2
11c, 55% (56%)
MePhSiH2
11d, 23% (26%)
MePhSiH2
85 °C, 12 h
85 °C, 12 h
85 °C, 12 h
110 °C, 4 h
Ph
H3C
CH3
Ph
Me HPhMeSi
Me
*
N
N
N
N
N
N
N
N
H
H
H
H
SO2Ar
SO2Ar
SO2Ar
SO2Ar
11e, 42% (45%)
MePhSiH2
110 °C, 4 h
11f, 48% (n.d.)
MePhSiH2
110 °C, 18 h
11g, 40% (45%)
MePhSiH2
110 °C, 18 h
11h, 25%/11h', 2%a
MePhSiH2
110 °C, 18 h
Scheme 3 Substrate scope of the reaction with respect to pyridines.
Reagents and conditions: 7 (0.5 mmol), B(C6F5)3 (0.025 mmol), and
silane (0.6 mmol) were heated in CDCl3 (0.5 mL) in a screw-capped
NMR tube. a 1.25 mmol (2.5 equiv) of silane was added. b Determined
by 1H NMR analysis of the crude mixture (internal standard: tetrachlo-
roethane).
After exploring the substrate scope of the isoquinolines
and pyridines, we compared the reaction mechanism and
reactivity of the N-heteroarenes (Scheme 4).15 The previ-
ously reported quinoline is also presented for comparison
(Scheme 4a). The quinoline was dearomatized by borane
catalyzed 1,4-hydrosilylation. The resulting unconjugated
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

D
V. D. Cao et al.
Paper
Synthesis
a)4
was not effective on the aryl isoquinolines, the hydrosilyla-
tion of electron-deficient and electron-donating isoquino-
lines generally resulted in the formation of enamine 5 with
good conversion. Note that the hydrosilylation of electron-
deficient isoquinolines were faster than of electron-rich
isoquinolines. Subsequent addition of the tosyl azide result-
ed in cyclic amidine 6 with excellent conversion from 5.
Note that the conjugated enamine 5 had higher reactivity
toward azide than that of the isolated enamine from quino-
line 2.
In the case of the 3-substituted pyridines 7 (Scheme 4c),
1,4-hydrosilylation dominated. Again, the electron-defi-
cient pyridines were more reactive than the electron-rich
pyridines toward the 1,4-hydrosilylation. The reaction of
the resulting dihydropyridine 8 with sulfonyl azide showed
interesting regioselectivity. The azide preferred to react
with sterically less hindered enamine rather than more hin-
dered enamine of the dienamine 8. Compared to the iso-
quinolines, the electron density of the reactive enamine ni-
trogen might be decreased due to the additional conjuga-
tion toward the other alkene; this, in turn, may slow the
second [3+2] cycloaddition step.
HPh2Si
H
B(C6F5)3
B(C6F5)3
1,4-hydrosilylation
[H-B(C6F5)3]-
SiPh2H
N
N
HPh2Si
H
1a
3a
N
N
1) H– shift, – N2
2) MeOH
TsN3
[3+2]
N
N
N
N
H
N
H
Ts
2a' SiPh2H
2a SiPh2H
Ts
b)
HPh2Si
HPh2Si
H B(C6F5)3
1,2-hydrosilylation
N
N
SiMePhH
H
B(C6F5)3
R
R
R
[(C6F5)3B-H]–
4
N
N
N
N
1) H– shift, – N2
2) MeOH
TsN3
[3+2]
Ts
Ts
H
NH
N
N
SiMePhH
R
R
SiMePhH
5
H
6
5'
c)
R
R
HR'RSi
HR'RSi
H
B(C6F5)3
B(C6F5)3
1,4-hydrosilylation
[H-B(C6F5)3]–
+
N
N
SiRR'H
H
7
Finally, the synthetic utility of this method was investi-
gated (Scheme 5). To test the scalability of this process, we
performed gram-scale reactions of the representative iso-
quinoline and pyridine (Scheme 5a). Isoquinoline 4a (10
mmol) was converted into N-silyl enamine intermediate 5a,
then subsequent addition of the azide resulted in the for-
mation to 1.6 g of the cyclic amidine 6a. The 10 mmol scale
hydrosilylation of the 3-phenylquinoline 7e resulted in N-
silyl-dienamine intermediate 8e with moderate conversion.
Subsequent addition of the tosyl azide resulted in 1.3 g of
9e. The yield of the 10 mmol scale reactions were similar to
those of the 0.5 mmol scale reactions (Scheme 2, Scheme 3)
and proved the scalability of this process. The resulting cy-
clic amidine product 6a and 9e could be further functional-
ized to lactam 12 and 13 in moderate to good yields
R
R
N
R
1) H– shift, – N2
2) MeOH
TsN3
[3+2]
N
N
N
N
N
N
H
Ts
8'
SiRR'H
H
Ts
9
8
SiRR'H
Scheme 4 Comparison of the proposed mechanisms of the cyclic ami-
dine synthesis from N-heteroarenes
N-silylenamine 2a was subjected to [3 + 2] cycloaddition
with 10a, hydride shift, and nitrogen extrusion process to
produce cyclic amidine 3a after methanol quenching. In the
case of isoquinoline 4 (Scheme 4b), 1,2-hydrosilylation oc-
curred because C1 is the only electropositive reaction site
on 4. An elevated temperature was required for this 1,2-hy-
drosilylation. Although the dearomative hydrosilylation
a)
TsN3 (1.0 eq.)
B(C6F5)3 (5 mol%)
MePhSiH2 (1.2 eq.)
N
(10a)
Ts
N
N
CHCl3
0 °C to RT, 2 h
then, MeOH
NH
110 °C, 8 h
SiMePhH
H
6a
53% (1.6 g)
4a
10 mmol
5a
Ph
Ph
Ph
TsN3 (1.0 eq.)
B(C6F5)3 (5 mol%)
MePhSiH2(1.2 eq.)
(10a)
N
N
H
N
N
CHCl3
110 °C, 4 h
RT, overnight, then,
MeOH
Ts
SiPhMeH
7e
10 mmol
9e
8e
39% (1.3 g)
b)
Ph
Ph
N
O
concd HCl
concd HCl
Ts
THF/MeOH/H2O
65 °C, 2.5 h
NH
NH
12, 72%
N
H
9e
N
N
H
O
MeOH/H2O
85 °C, 5 h
Ts
6a
13, 36%
Scheme 5 Practical application of the cyclic amidine synthesis from isoquinolines and pyridines
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

E
V. D. Cao et al.
Paper
Synthesis
(Scheme 5b).16 Since the synthetic utility of the lactams
have been widely studied, including ring-opening path-
ways,17 this suggests the possible application of this strate-
gy for the synthesis of linear structures from the novel N-
heteroarenes.
equiv) was subsequently added to the reaction mixture, which was
then heated to 110 °C in an oil bath for the indicated time. The result-
ing mixture was subjected to NMR analysis to monitor the conver-
sion.
Step 2: To the resulting mixture from the first step in an NMR cell was
added tosyl azide 10a (0.5 mmol, 1.0 equiv) at 0 °C and the mixture
was warmed to r.t. (N2 bubbling was observed) with NMR spectra re-
corded every 2 h. The reaction was quenched with MeOH and the
mixture was filtered through silica with CH2Cl2 washing. The result-
ing crude mixture was purified by column chromatography.
In conclusion, we have synthesized various six-mem-
bered (Z)-sulfonyl amidines by using borane-catalyzed hy-
drosilylation of N-heteroarenes as a dearomatizing tool to
access the key N-silyl enamine intermediate. The resulting
N-silyl enamine intermediates were converted into cyclic
amidine via a [3+2] cycloaddition with sulfonyl azide, hy-
dride shift, and nitrogen gas extrusion mechanism. This
strategy is widely applicable to various N-heteroarenes and
is scalable. This report expands the molecular library and
synthetic utility of (Z)-sulfonyl cyclic amidines, which were
rarely synthesized by previous methods. The reactivity of
each step of this process was examined in detail in an effort
to expand the application of the strategy. Further applica-
tions of this strategy with other classes of substrates are
under investigation in our laboratory.
N-(1,4-Dihydroisoquinolin-3(2H)-ylidene)-4-methylbenzene-
sulfonamide (6a)
Compound 6a was prepared from 4a according to the general proce-
dure for 8 h; eluent: EtOAc/hexane/CH2Cl2 = 20:80:20.
Yield: 95.2 mg (63%); yellowish solid; mp 140–142 °C.
IR (neat): 3322, 1606, 1392, 1265, 1145, 1070, 930, 910, 805, 727,
660, 599, 533 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.96 (s, 1 H), 7.82 (d, J = 8.3 Hz, 2 H),
7.30–7.21 (m, 4 H), 7.20–7.12 (m, 2 H), 4.49 (s, 2 H), 3.64 (s, 2 H), 2.38
(s, 3 H).
13C NMR (125 MHz, CDCl3):  = 165.1, 142.8, 139.4, 130.7, 130.3, 129.3
(2C), 128.0, 127.5, 127.2, 126.3 (2C), 125.2, 45.5, 36.6, 21.5.
HRMS (EI): m/z [M]+ calcd for C16H16N2O2S: 300.0932; found:
300.0930.
Unless otherwise stated, all catalytic reactions were carried out under
an argon atmosphere. Chloroform-d from Eurisotop and dichloro-
methane-d2 from Deutero were used as solvent without additional
purification for optimization, substrate scope, and mechanistic stud-
ies. Tris(pentafluorophenyl)borane was purchased from TCI or Alfa
Aesar and stored at –15 °C. All other reagents were directly used as
purchased without further purification unless otherwise stated.
N-(5-Bromo-1,4-dihydroisoquinolin-3(2H)-ylidene)-4-methyl-
benzenesulfonamide (6b)
Compound 6b was prepared from 4b according to the general proce-
dure for 2 h; eluent: EtOAc/hexane/acetone = 35:65:5.
Analytical thin-layer chromatography (TLC) was performed on pre-
coated silica gel 60 F254 plates. Visualization on TLC was achieved by
the use of UV light (254 nm), and by exposure to acidic p-anisalde-
hyde stain followed by heating. Column chromatography was under-
taken on silica gel (400–630 mesh) using a suitable eluent. 1H NMR
was recorded with a Jeol ECZ-500R (CDCl3 or CD2Cl2 in 500 MHz) for
characterization of compounds. 13C{1H} NMR was recorded with a Jeol
ECZ-500R (CDCl3 or CD2Cl2 in 125 MHz) and was fully decoupled by
broad-band proton-decoupling. Chemical shifts are quoted in parts
per million (ppm) referenced to tetramethylsilane or to the appropri-
ate solvent peak (1H NMR of CHCl3 in CDCl3:  = 7.24 ppm (singlet),
and CH2Cl2 in CD2Cl2:  = 5.32 ppm (triplet); 13C NMR of CDCl3:  =
77.0 ppm (triplet), and CD2Cl2:  = 53.1 ppm (quin)). Infrared (IR)
spectra were recorded with a Perkin Elmer Frontier ATR-FT-IR spec-
trophotometer, max in cm–1. High-resolution mass spectra were ob-
tained by using the EI method from Korea Basic Science Institute
(Daegu). X-ray diffraction data were collected with a Bruker D8
QUEST; samples were coated with Parabar oil under a stream of N2 (g)
at 173 K.
Yield: 148.7 mg (78%); yellowish solid; mp 161–163 °C.
IR (neat): 3243, 1626, 1296, 1284, 1149, 1136, 920, 662, 593, 551 cm–1
1H NMR (500 MHz, CDCl3):  = 9.13 (s, 1 H), 7.86 (d, J = 8.1 Hz, 2 H),
7.51 (d, J = 3.1 Hz, 1 H), 7.29 (d, J = 7.8 Hz, 2 H), 7.20–7.05 (m, 2 H),
4.56 (s, 2 H), 3.76 (s, 2 H), 2.41 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 164.3, 143.1, 139.2, 132.2, 131.9,
129.8, 129.5 (2C), 128.5, 126.5 (2C), 124.5, 123.3, 45.6, 36.2, 21.5.
HRMS (EI): m/z [M]+ calcd for C16H15BrN2O2S: 378.0038; found:
378.0035.
.
N-(7-Bromo-1,4-dihydroisoquinolin-3(2H)-ylidene)-4-methyl-
benzenesulfonamide (6c)
Compound 6c was prepared from 4c according to the general proce-
dure for 2 h; eluent: EtOAc/hexane = 35:65.
Yield: 152.7 mg (81%); yellowish solid; mp 180–182 °C.
IR (neat): 3300, 1627, 1601, 1257, 1134, 1070, 899, 813, 703, 676,
552, 535 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.00 (s, 1 H), 7.83 (d, J = 8.3 Hz, 2 H),
7.40 (dd, J = 8.1, 2.0 Hz, 1 H), 7.34 (d, J = 2.0 Hz, 1 H), 7.28 (d, J = 7.7 Hz,
2 H), 7.04 (d, J = 8.0 Hz, 1 H), 4.47 (s, 2 H), 3.60 (s, 2 H), 2.40 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 164.5, 143.1, 139.2, 132.9, 131.1, 129.5
(2C), 129.4, 129.1, 128.3, 126.4 (2C), 120.9, 45.0, 36.2, 21.6.
Synthesis of Cyclic Amidines 6 from Isoquinolines 4 and Tosyl
Azide 10a (Scheme 2); General Procedure
Step 1: Tris(pentafluorophenyl)borane (B(C6F5)3) catalyst (0.025
mmol, 5 mol%) in an NMR tube was dissolved in CDCl3 (0.5 mL) under
argon atmosphere. MePhSiH2 (0.6 mmol, 1.2 equiv) was added at r.t.
(H2 bubbles were evolved), and TCE (0.3 mmol) was added into the re-
action mixture as internal standard. Isoquinoline 4a–k (0.5 mmol, 1.0
HRMS (EI): m/z [M]+ calcd for C16H15BrN2O2S: 378.0038; found:
378.0034.
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V. D. Cao et al.
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Synthesis
N-(8-Bromo-1,4-dihydroisoquinolin-3(2H)-ylidene)-4-methyl-
benzenesulfonamide (6d)
1H NMR (500 MHz, CDCl3):  = 8.89 (s, 1 H), 7.83 (d, J = 8.0 Hz, 2 H),
7.27 (d, J = 8.3 Hz, 2 H), 7.00 (d, J = 8.4 Hz, 1 H), 6.79 (dd, J = 8.1, 2.6 Hz,
1 H), 6.70 (d, J = 2.5 Hz, 1 H), 4.44 (s, 2 H), 3.58 (s, 2 H), 2.40 (s, 3 H),
1.30–1.19 (m, 3 H), 1.09 (d, J = 7.4 Hz, 18 H).
Compound 6d was prepared from 4d according to the general proce-
dure for 2 h; eluent: EtOAc/hexane = 30:70.
13C NMR (125 MHz, CDCl3):  = 165.4, 155.2, 142.8, 139.4, 131.6, 129.4
(2C), 128.5, 126.4 (2C), 122.4, 119.6, 116.5, 45.6, 36.0, 21.5, 17.9 (6C),
12.6 (3C).
HRMS (EI): m/z [M]+ calcd for C25H36N2O3SSi: 472.2216; found:
472.2213.
Yield: 167.0 mg (88%); yellowish solid; mp 207–209 °C.
IR (neat): 3336, 1615, 1255, 1139, 1075, 1065, 821, 805, 790, 692,
590, 537, 524 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.95 (s, 1 H), 7.86–7.82 (m, 2 H), 7.48
(dd, J = 7.8, 1.3 Hz, 1 H), 7.30–7.25 (m, 2 H), 7.16 (dd, J = 7.7, 7.7 Hz, 1
H), 7.11 (dd, J = 7.6, 1.2 Hz, 1 H), 4.58 (s, 2 H), 3.69 (s, 2 H), 2.40 (s, 3
H).
13C NMR (125 MHz, CDCl3):  = 164.3, 143.0, 139.2, 132.3, 131.1,
130.3, 129.4 (2C), 129.3, 126.7, 126.4 (2C), 121.1, 45.9, 36.3, 21.5.
4-Methyl-N-(5-((trimethylsilyl)ethynyl)-1,4-dihydroisoquinolin-
3(2H)-ylidene)benzenesulfonamide (6h)
Compound 6h was prepared from 4h, MePhSiH2 (0.85 mmol, 1.7
equiv) and 10a according to the general procedure for 9 h; eluent:
EtOAc/hexane = 30:70.
HRMS (EI): m/z [M]+ calcd for C16H15BrN2O2S: 378.0038; found:
378.0036.
Yield: 159.7 mg (81%); yellowish solid; mp 185–187 °C.
IR (neat): 3252, 2959, 2901, 2150, 1627, 1496, 1417, 1296, 1149,
N-(5-Chloro-1,4-dihydroisoquinolin-3(2H)-ylidene)-4-methyl-
benzenesulfonamide (6e)
1080, 919, 837, 658, 588, 553 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.18 (s, 1 H), 7.86 (d, J = 8.4 Hz, 2 H),
7.40 (d, J = 7.3 Hz, 1 H), 7.27 (d, J = 8.1 Hz, 2 H), 7.18 (dd, J = 7.7, 7.7 Hz,
1 H), 7.10 (d, J = 7.8 Hz, 1 H), 4.51 (s, 2 H), 3.84 (s, 2 H), 2.39 (s, 3 H),
0.26 (s, 9 H).
13C NMR (125 MHz, CDCl3):  = 164.8, 142.8, 139.4, 131.8, 131.7,
130.4, 129.3 (2C), 126.7, 126.3 (2C), 125.3, 122.0, 101.4, 100.5, 45.2,
34.3, 21.4, –0.1 (3C).
Compound 6e was prepared from 4e according to the general proce-
dure for 2 h; eluent: CH2Cl2/acetone = 100:1.
Yield: 145.0 mg (87%); yellowish solid; mp 154–156 °C.
IR (neat): 3244, 1627, 1298, 1286, 1151, 1143, 920, 664, 594, 542 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.22 (s, 1 H), 7.90–7.83 (m, 2 H), 7.32–
7.25 (m, 3 H), 7.18 (dd, J = 7.9, 7.9 Hz, 1 H), 7.06 (dd, J = 7.6, 3.0 Hz, 1
H), 4.56 (s, 2 H), 3.76 (s, 2 H), 2.40 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 164.2, 143.0, 139.2, 133.0, 132.1, 129.5
(2C), 128.5, 128.2, 128.0, 126.5 (2C), 123.8, 45.4, 33.4, 21.5.
HRMS (EI): m/z [M]+ calcd for C21H24N2O2SSi: 396.1328; found:
396.1330.
HRMS (EI): m/z [M]+ calcd for C16H15ClN2O2S: 334.0543; found:
334.0545.
Synthesis of Cyclic Amidines 9 from Pyridines 7 and Tosyl Azide
10a (Scheme 3); General Procedure
Step 1: B(C6F5)3 catalyst (0.025 mmol, 5 mol%) in an NMR tube was
dissolved in CDCl3 (0.5 mL) under argon atmosphere. Silane (0.6
mmol, 1.2 equiv) was added at r.t. (H2 bubbles were evolved) and TCE
(0.3 mmol) was added into the reaction mixture as internal standard.
Pyridine 7a–h (0.5 mmol, 1.0 equiv) was subsequently added and the
mixture was heated to the indicated temperature in an oil bath for the
indicated time. The resulting mixture was subjected to NMR analysis
to monitor the conversion.
4-Methyl-N-(5-((triisopropylsilyl)oxy)-1,4-dihydroisoquinolin-
3(2H)-ylidene)benzenesulfonamide (6f)
Compound 6f was prepared from 4f according to the general proce-
dure for 15 h; eluent: CH2Cl2/EtOAc = 98:2.
Yield: 128.1 mg (54%); yellowish solid; mp 144–146 °C.
IR (neat): 3319, 2944, 2866, 1615, 1268, 1142, 1038, 785, 660, 546
cm–1
.
Step 2: To the resulting mixture from the first step in an NMR cell was
added tosyl azide 10a (0.5 mmol, 1.0 equiv) at r.t. After standing over-
night, an NMR spectrum was recorded, and the reaction was
quenched with MeOH. The mixture was filtered through silica with
CH2Cl2 washing, and the resulting crude mixture was purified by col-
umn chromatography.
1H NMR (500 MHz, CDCl3):  = 9.08 (s, 1 H), 7.84 (d, J = 8.0 Hz, 2 H),
7.26 (d, J = 7.3 Hz, 2 H), 7.10 (dd, J = 8.0, 8.0 Hz, 1 H), 6.85–6.70 (m, 2
H), 4.51 (s, 2 H), 3.67 (s, 2 H), 2.40 (s, 3 H), 1.38–1.25 (m, 3 H), 1.08 (d,
J = 8.1 Hz, 18 H).
13C NMR (125 MHz, CDCl3):  = 165.4, 153.1, 142.7, 139.7, 131.3, 129.3
(2C), 127.7, 126.4 (2C), 120.4, 117.5, 116.8, 45.4, 30.6, 21.5, 18.0 (6C),
13.0 (3C).
N-(5-Chloro-3,4-dihydropyridin-2(1H)-ylidene)-4-methyl-
benzenesulfonamide (9a)
HRMS (EI): m/z [M]+ calcd for C25H36N2O3SSi: 472.2216; found:
472.2217.
Compound 9a was prepared from 7a, Ph2SiH2 (0.6 mmol, 1.2 equiv)
and 10a according to the general procedure for 12 h at 85 °C; eluent:
EtOAc/hexane = 25:75.
4-Methyl-N-(7-((triisopropylsilyl)oxy)-1,4-dihydroisoquinolin-
3(2H)-ylidene)benzenesulfonamide (6g)
Yield: 106.0 mg (74%); yellowish solid; mp 194–196 °C.
Compound 6g was prepared from 4g according to the general proce-
dure for 15 h; eluent: EtOAc/hexane = 25:75.
IR (neat): 3177, 3088, 2948, 1575, 1409, 1286, 1132, 912, 844, 740,
673, 590, 552 cm–1
.
Yield: 189.1 mg (80%); yellowish solid; mp 156–158 °C.
IR (neat): 3296, 2942, 2865, 1611, 1248, 1060, 817, 661 cm–1
1H NMR (500 MHz, CDCl3):  = 9.47 (s br, 1 H), 7.78 (d, J = 8.3 Hz, 2 H),
7.27 (d, J = 8.0 Hz, 2 H), 6.26 (d, J = 4.4 Hz, 1 H), 2.72 (t, J = 8.8 Hz, 2 H),
2.53 (dd, J = 7.8, 1.4 Hz, 2 H), 2.40 (s, 3 H).
.
13C NMR (125 MHz, CDCl3):  = 160.0, 143.5, 138.5, 129.5 (2C), 126.5
(2C), 120.7, 116.3, 30.5, 26.7, 21.5.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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V. D. Cao et al.
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Synthesis
HRMS (EI): m/z [M]+ calcd for C12H13ClN2O2S: 284.0386; found:
284.0388.
IR (neat): 3228, 1557, 1282, 1147, 1131, 1079, 899, 751, 701, 654,
573, 549 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.68 (s, 1 H), 7.85 (d, J = 6.8 Hz, 2 H),
7.38–7.23 (m, 7 H), 6.52 (s, 1 H), 2.81–2.72 (m, 2 H), 2.71–2.67 (m, 2
H), 2.42 (s, 3 H).
N-(5-Bromo-3,4-dihydropyridin-2(1H)-ylidene)-4-methyl-
benzenesulfonamide (9b)
13C NMR (125 MHz, CDCl3):  = 268.2, 143.3, 138.9, 137.3, 129.5 (2C),
128.8 (2C), 127.5, 126.6 (2C), 124.5 (2C), 121.0, 119.7, 29.9, 21.9, 21.6.
HRMS (EI): m/z [M]+ calcd for C18H18N2O2S: 326.1089; found:
326.1090.
Compound 9b was prepared from 7b, Ph2SiH2 (0.6 mmol, 1.2 equiv)
and 10a according to the general procedure for 12 h at 85 °C; eluent:
CH2Cl2.
Yield: 92.1 mg (56%); white solid; mp 166–168 °C.
IR (neat): 3173, 1574, 1286, 1155, 1132, 1084, 910, 735, 666, 641, 551
cm–1
N-(3,5-Dimethyl-3,4-dihydropyridin-2(1H)-ylidene)-4-methyl-
.
1H NMR (500 MHz, CDCl3):  = 9.49 (s, 1 H), 7.81 (d, J = 8.1 Hz, 2 H),
7.30 (d, J = 8.0 Hz, 2 H), 6.39 (s, 1 H), 2.73 (s, 2 H), 2.65 (t, J = 7.5 Hz, 2
H), 2.42 (s, 3 H).
benzenesulfonamide (9f)
Compound 9f was prepared from 7f, MePhSiH2 (0.6 mmol, 1.2 equiv)
and 10a according to the general procedure for 18 h at 110 °C; eluent:
EtOAc/hexane = 20:80.
13C NMR (125 MHz, CDCl3):  = 160.5, 143.6, 138.5, 129.6 (2C), 126.6
(2C), 123.4, 103.9, 30.6, 28.5, 21.6.
Yield: 31.8 mg (23%); white solid; mp 104–106 °C.
HRMS (EI): m/z [M]+ calcd for C12H13BrN2O2S: 327.9881; found:
327.9883.
IR (neat): 3328, 1588, 1422, 1270, 1134, 1079, 923, 881, 680, 589, 549
cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.33 (s, 1 H), 7.84–7.80 (m, 2 H), 7.29–
7.27 (m, 2 H), 5.88–5.82 (m, 1 H), 2.65–2.56 (m, 1 H), 2.41 (s, 3 H),
2.34 (dd, J = 17.1, 7.0 Hz, 1 H), 1.91 (dd, J = 17.0, 7.6 Hz, 1 H), 1.73 (s, 3
H), 1.17 (d, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 164.9, 142.9, 139.3, 129.4 (2C), 126.3
(2C), 117.5, 117.2, 34.3, 32.1, 21.5, 19.6, 16.7.
N-(5-Bromo-3-methyl-3,4-dihydropyridin-2(1H)-ylidene)-4-
methylbenzenesulfonamide (9c)
Compound 9c was prepared from 7c, MePhSiH2 (0.6 mmol, 1.2 equiv)
and 10a according to the general procedure for 12 h at 85 °C; eluent:
EtOAc/hexane = 10:90.
HRMS (EI): m/z [M]+ calcd for C14H18N2O2S: 278.1089; found:
278.1092.
Yield: 80.8 mg (47%); white solid; mp 117–119 °C.
IR (neat): 3313, 1584, 1282, 1133, 1081, 817, 701, 578, 547 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.53 (s, 1 H), 7.82 (d, J = 8.3 Hz, 2 H),
7.30 (d, J = 8.5 Hz, 2 H), 6.39 (s, 1 H), 2.95–2.67 (m, 2 H), 2.56–2.32 (m,
4 H), 1.23 (d, J = 6.5 Hz, 3 H).
4-Methyl-N-(3-methyl-5-phenyl-3,4-dihydropyridin-2(1H)-
ylidene)benzenesulfonamide (9g)
Compound 9g was prepared from 7g, MePhSiH2 (0.6 mmol, 1.2 equiv)
and 10a according to the general procedure for 18 h at 110 °C; eluent:
EtOAc/hexane = 25:75.
13C NMR (125 MHz, CDCl3):  = 163.5, 143.4, 138.6, 129.5 (2C), 126.4
(2C), 122.9, 103.1, 36.2, 35.8, 21.6, 16.8.
HRMS (EI): m/z [M]+ calcd for C13H15BrN2O2S: 342.0038; found:
342.0040.
Yield: 55.1 mg (31%); white solid; mp 130–132 °C.
IR (neat): 3316, 1582, 1399, 1264, 1124, 1076, 924, 881, 761, 683,
591, 549 cm–1
.
4-Methyl-N-(5-methyl-3,4-dihydropyridin-2(1H)-ylidene)-
1H NMR (500 MHz, CDCl3):  = 9.68 (s, 1 H), 7.86 (d, J = 8.3 Hz, 2 H),
7.47–7.23 (m, 7 H), 6.48 (d, J = 4.6 Hz, 1 H), 2.84–2.75 (m, 2 H), 2.49–
2.43 (m, 1 H), 2.42 (s, 3 H), 1.25 (d, J = 6.7 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 164.8, 143.2, 139.0, 137.6, 129.4 (2C),
128.8 (2C), 127.4, 126.4 (2C), 124.5 (2C), 119.9, 119.0, 34.5, 29.7, 21.6,
16.7.
benzenesulfonamide (9d)
Compound 9d was prepared from 7d, MePhSiH2 (0.6 mmol, 1.2 equiv)
and 10a according to the general procedure for 4 h at 110 °C; eluent:
EtOAc/hexane = 15:85.
Yield: 22.6 mg (17%); white solid; mp 166–168 °C.
IR (neat): 3311, 1584, 1271, 1072, 893, 732, 670, 592, 553, 525 cm–1
1H NMR (500 MHz, CDCl3):  = 9.34 (s, 1 H), 7.83 (d, J = 7.1 Hz, 2 H),
7.30 (d, J = 7.2 Hz, 2 H), 5.89 (d, J = 5.2 Hz, 1 H), 2.61 (t, J = 7.7 Hz, 2 H),
2.43 (s, 3 H), 2.20 (t, J = 7.7 Hz, 2 H), 1.74 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 162.2, 143.1, 139.2, 129.4 (2C), 126.4
(2C), 118.7, 117.9, 29.7, 24.2, 21.6, 19.4.
HRMS (EI): m/z [M]+ calcd for C13H16N2O2S: 264.0932; found:
264.0934.
.
HRMS (EI): m/z [M]+ calcd for C19H20N2O2S: 340.1245; found:
340.1247.
4-Methyl-N-((3S,5S,Z)-3-methyl-5-((S)-methyl(phenyl)silyl)piperi-
din-2-ylidene)benzenesulfonamide (9h)
Compound 9h was prepared from 7d, MePhSiH2 (1.25 mmol, 2.5
equiv) and 10a according to the general procedure for 12 h at 110 °C;
eluent: EtOAc/hexane = 25:75.
Yield: 45.1 mg (23%), 1:1 diastereomeric mixture of Si stereogenic
center; yellowish liquid.
4-Methyl-N-(5-phenyl-3,4-dihydropyridin-2(1H)-ylidene)-
benzenesulfonamide (9e)
IR (neat): 3290, 2924, 2116, 1599, 1392, 1253, 1140, 1079, 813, 723,
Compound 9e was prepared from 7e, MePhSiH2 (0.6 mmol, 1.2 equiv)
and 10a according to the general procedure for 4 h at 110 °C; eluent:
CH2Cl2/EtOAc = 99:1.
665, 579 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.56 (d, J = 7.5 Hz, 1 H), 7.83–7.74 (m, 2
H), 7.50–7.45 (m, 2 H), 7.44–7.35 (m, 3 H), 7.24 (d, J = 8.0 Hz, 2 H),
4.34–4.25 (m, 1 H), 3.44–3.30 (m, 1 H), 3.27–3.16 (m, 1 H), 2.61–2.52
Yield: 66.2 mg (41%); white solid; mp 196–198 °C.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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V. D. Cao et al.
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Synthesis
(m, 1 H), 2.39 (s, 3 H), 1.77–1.71 (m, 1 H), 1.63 (dddd, J = 18.4, 13.8,
4.8, 2.8 Hz, 1 H), 1.51 (dddd, J = 17.8, 12.7, 5.3, 2.8 Hz, 1 H), 1.21 (dd,
J = 9.2, 7.4 Hz, 3 H), 0.39 (dd, J = 5.7, 4.0 Hz, 3 H).
1H NMR (500 MHz, CD2Cl2):  = 9.39 (s, 1 H), 8.03 (d, J = 8.0 Hz, 2 H),
7.78 (d, J = 8.1 Hz, 2 H), 6.35–6.28 (m, 1 H), 2.81–2.73 (m, 2 H), 2.65–
2.55 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = (169.6, 169.6), 142.4, 139.9, (134.5,
134.4) (2C), 132.7, 130.1, 129.2 (2C), 128.2 (2C), 126.1 (2C), (44.5,
44.3), 34.4, (28.3, 28.2), 21.4, (19.5, 19.5), (14.7, 14.6), (–7.9, –8.0).
13C NMR (125 MHz, CD2Cl2):  = 160.7, 144.2, 133.6 (q, J = 32.5 Hz),
126.7 (2C), 125.7 (q, J = 3.8 Hz, 2C), 123.1 (q, J = 270.0 Hz), 120.1,
116.8, 30.3, 26.3.
IR: 3290, 2924, 2116, 1599, 1392, 1253, 1140, 1079, 813, 723, 665,
HRMS (EI): m/z [M]+ calcd for C12H10ClF3N2O2S: 338.0104; found:
338.0102.
579 cm–1
.
HRMS (EI): m/z [M]+ calcd for C20H26N2O2SSi: 386.1484; found:
386.1484.
N-(5-Bromo-3,4-dihydropyridin-2(1H)-ylidene)-4-(trifluoro-
methyl)benzenesulfonamide (11b)
Compound 11b was prepared from 7b, Ph2SiH2 (0.6 mmol, 1.2 equiv)
and 10b according to the general procedure for 12 h at 85 °C; eluent:
CH2Cl2/hexane/acetone = 40:60:5.
4-Methyl-N-((3R,5S,Z)-3-methyl-5-((S)-methyl(phenyl)silyl)piperi-
din-2-ylidene)benzenesulfonamide (9h′)
Compound 9h′ was prepared from 7d, MePhSiH2 (1.25 mmol, 2.5
equiv) and 10a according to the general procedure for 12 h at 110 °C;
eluent: EtOAc/hexane = 25:75.
Yield: 114.5 mg (60%); white solid; mp 177–179 °C.
IR (neat): 3177, 3070, 1576, 1406, 1322, 1156, 1130, 1060, 914, 843,
Yield: 5.1 mg (3%), 1:1 diastereomeric mixture of Si stereogenic cen-
ter; yellowish liquid.
740, 709, 613, 570 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.42 (s, 1 H), 8.03 (d, J = 8.3 Hz, 2 H),
7.78 (d, J = 8.1 Hz, 2 H), 6.42 (d, J = 4.9 Hz, 1 H), 2.82–2.71 (m, 2 H),
2.71–2.66 (m, 2 H).
IR (neat): 3290, 2926, 2116, 1598, 1392, 1260, 1127, 1081, 896, 868,
725, 575 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.59 (s, 1 H), 7.78 (d, J = 8.0 Hz, 2 H),
7.52–7.46 (m, 2 H), 7.44–7.36 (m, 3 H), 7.24 (d, J = 8.1 Hz, 2 H), 4.28
(tt, J = 7.4, 3.9 Hz, 1 H), 3.47–3.33 (m, 1 H), 3.22 (td, J = 12.9, 4.0 Hz, 1
H), 2.46–2.41 (m, 1 H), 2.39 (s, 3 H), 1.97 (dddt, J = 18.2, 13.7, 6.2, 2.3
Hz, 1 H), 1.42 (dddt, J = 15.4, 10.8, 5.3, 2.7 Hz, 1 H), 1.35–1.23 (m, 1 H),
1.19 (dd, J = 9.1, 6.9 Hz, 3 H), 0.40 (dd, J = 4.0 Hz, 4.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 161.7, 144.8, 133.5 (q, J = 32.5 Hz),
126.7 (2C), 125.7 (q, J = 3.9 Hz, 2C), 123.1 (q, J = 270.0 Hz), 122.8,
104.4, 30.7, 28.0.
HRMS (EI): m/z [M]+ calcd for C12H10BrF3N2O2S: 381.9598; found:
381.9595.
13C NMR (125 MHz, CDCl3):  = 169.0, 142.3, 140.2, (134.6, 134.5)
(2C), (132.8, 132.7), 130.2, 129.2 (2C), 128.3 (2C), 126.1 (2C), (44.9,
44.7), 36.8, (30.6, 30.6), 21.5, (20.1, 20.0), (18.3, 18.2), (–7.9, –8.0).
HRMS (EI): m/z [M]+ calcd for C20H26N2O2SSi: 386.1484; found:
386.1484.
N-(5-Bromo-3-methyl-3,4-dihydropyridin-2(1H)-ylidene)-4-(tri-
fluoromethyl)benzenesulfonamide (11c)
Compound 11c was prepared from 7c, MePhSiH2 (0.6 mmol, 1.2
equiv) and 10b according to the general procedure for 12 h at 85 °C;
eluent: EtOAc/hexane = 20:80.
Yield: 108.8 mg (55%); yellow solid; mp 126–128 °C.
Synthesis of Cyclic Amidines 11 from Pyridines 7 and 4-(Trifluoro-
methyl)benzenesulfonyl Azide 10b (Scheme 3); General Procedure
IR (neat): 3305, 1593, 1403, 1321, 1264, 1169, 1122, 930, 822, 717,
622, 550 cm–1
.
Step 1: B(C6F5)3 catalyst (0.025 mmol, 5 mol%) in an NMR tube was
dissolved in CDCl3 (0.5 mL) under argon atmosphere. Silane (0.6
mmol, 1.2 equiv) was added at r.t. (H2 bubbles were evolved) and TCE
(0.3 mmol) was added into the reaction mixture as internal standard.
Pyridine 7a–h (0.5 mmol, 1.0 equiv) was subsequently added and the
mixture was heated to the indicated temperature in an oil bath for the
indicated time. The resulting mixture was subjected to NMR analysis
to monitor the conversion.
1H NMR (500 MHz, CDCl3):  = 9.45 (s, 1 H), 8.07 (d, J = 8.2 Hz, 2 H),
7.78 (d, J = 8.2 Hz, 2 H), 6.40 (dd, J = 4.7, 1.4 Hz, 1 H), 2.85–2.75 (m, 2
H), 2.50–2.39 (m, 1 H), 1.25 (d, J = 6.8 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 164.3, 144.9, 134.2 (q, J = 32.9 Hz),
127.0 (2C), 126.0 (q, J = 3.4 Hz, 2C), 123.30 (q, J = 271.8 Hz), 122.73,
104.01, 36.11, 35.82, 16.72.
HRMS (EI): m/z [M]+ calcd for C13H12BrF3N2O2S: 395.9755; found:
395.9753.
Step 2: To the resulting mixture from the first step in an NMR cell was
added 4-(trifluoromethyl)benzenesulfonyl azide 10b (0.5 mmol, 1.0
equiv) at r.t. (N2 bubbling was observed) and an NMR spectrum was
recorded after 2 h. The reaction was quenched with MeOH, and the
mixture was filtered through silica, and washed with CH2Cl2. The re-
sulting crude mixture was purified by column chromatography.
N-(5-Methyl-3,4-dihydropyridin-2(1H)-ylidene)-4-(trifluoro-
methyl)benzenesulfonamide (11d)
Compound 11d was prepared from 7d, MePhSiH2 (0.6 mmol, 1.2
equiv) and 10b according to the general procedure for 4 h at 110 °C;
eluent: EtOAc/hexane = 15:85.
N-(5-Chloro-3,4-dihydropyridin-2(1H)-ylidene)-4-(trifluoro-
methyl)benzenesulfonamide (11a)
Yield: 36.6 mg (23%); white solid; mp 155–157 °C.
IR (neat): 3374, 3094, 1576, 1406, 1318, 1156, 1127, 1061, 927, 842,
Compound 11a was prepared from 7a, Ph2SiH2 (0.6 mmol, 1.2 equiv)
and 10b according to the general procedure for 12 h at 85 °C; eluent:
CH2Cl2/hexane/acetone = 60:40:5.
719, 606, 524 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.33 (s, 1 H), 8.07 (d, J = 8.1 Hz, 2 H),
7.76 (d, J = 8.0 Hz, 2 H), 5.91 (s, 1 H), 2.63 (t, J = 8.3 Hz, 2 H), 2.21 (t, J =
8.3 Hz, 2 H), 1.74 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 162.5, 145.5, 134.0 (q, J = 32.7 Hz),
127.0 (2C), 126.0 (q, J = 3.8 Hz, 2C), 123.4 (q, J = 272.8 Hz), 119.50,
117.8, 29.7, 24.1, 19.4.
Yield: 109.8 mg (65%); white solid; mp 230–232 °C.
IR (neat): 3183, 3075, 1575, 1406, 1290, 1131, 1060, 918, 843, 710,
598, 573 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

I
V. D. Cao et al.
Paper
Synthesis
HRMS (EI): m/z [M]+ calcd for C13H13F3N2O2S: 318.0650; found:
N-((3S,5S,Z)-3-Methyl-5-((S)-methyl(phenyl)silyl)piperidin-2-ylid-
318.0652.
ene)-4-(trifluoromethyl)benzenesulfonamide (11h)
Compound 11h was prepared from 7d, MePhSiH2 (1.25 mmol, 2.5
equiv) and 10b according to the general procedure for 12 h at 110 °C;
eluent: EtOAc/hexane = 20:80.
N-(5-Phenyl-3,4-dihydropyridin-2(1H)-ylidene)-4-(trifluoro-
methyl)benzenesulfonamide (11e)
Compound 11e was prepared from 7e, MePhSiH2 (0.6 mmol, 1.2
equiv) and 10b according to the general procedure for 4 h at 110 °C;
eluent: EtOAc/hexane = 20:80.
Yield: 55.2 mg (25%), 1:1 diastereomeric mixture of Si stereogenic
center; white solid; mp 98–100 °C.
IR (neat): 3296, 2924, 2108, 1621, 1394, 1321, 1273, 1154, 1103,
1059, 728, 710, 697, 613, 602 cm–1
Yield: 80.0 mg (42%); white solid; mp 195–197 °C.
.
1H NMR (500 MHz, CDCl3):  = 8.67–8.56 (m, 1 H), 8.02 (d, J = 8.1 Hz, 2
H), 7.71 (d, J = 8.2 Hz, 2 H), 7.50–7.46 (m, 2 H), 7.44–7.35 (m, 3 H),
4.35–4.26 (m, 1 H), 3.48–3.33 (m, 1 H), 3.30–3.18 (m, 1 H), 2.58 (tdd,
J = 13.5, 6.5, 2.7 Hz, 1 H), 1.85–1.73 (m, 1 H), 1.67–1.60 (m, 1 H), 1.58–
1.47 (m, 1 H), 1.22 (dd, J = 9.2, 7.4 Hz, 3 H), 0.40 (dd, J = 5.9, 3.8 Hz, 3
H).
13C NMR (125 MHz, CDCl3):  = (170.4, 170.3), 146.2, (134.5, 134.4),
133.5 (q, J = 32.5 Hz), 132.55, 130.14 (2C), 128.23 (2C), 126.61 (2C),
125.7 (q, J = 3.8 Hz, 2C), 123.4 (q, J = 271.3 Hz), (44.7, 44.5), 34.5,
(28.3, 28.1), (19.5, 19.4), (14.8, 14.6), (–7.9, –8.0).
IR (neat): 3189, 1569, 1405, 1321, 1156, 1131, 1061, 991, 909, 751,
715, 612, 566 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.61 (s, 1 H), 8.10 (d, J = 8.5 Hz, 2 H),
7.78 (d, J = 2.9 Hz, 2 H), 7.49–7.12 (m, 5 H), 6.51 (d, J = 4.0 Hz, 1 H),
3.20–2.39 (m, 4 H).
13C NMR (125 MHz, CDCl3):  = 162.3, 145.2, 137.0, 134.2 (q, J = 32.6
Hz), 128.8 (2C), 127.7, 127.1 (2C), 126.0 (q, J = 6.3 Hz, 2C), 124.6 (2C),
123.3 (q, J = 271.3 Hz), 121.8, 119.3, 30.0, 21.9.
HRMS (EI): m/z [M]+ calcd for C18H15F3N2O2S: 380.0806; found:
380.0804.
HRMS (EI): m/z [M]+ calcd for C20H23F3N2O2SSi: 440.1202; found:
440.1202.
N-(3,5-Dimethyl-3,4-dihydropyridin-2(1H)-ylidene)-4-(trifluoro-
methyl)benzenesulfonamide (11f)
N-((3R,5S,Z)-3-Methyl-5-((S)-methyl(phenyl)silyl)piperidin-2-ylid-
ene)-4-(trifluoromethyl)benzenesulfonamide (11h′)
Compound 11f was prepared from 7f, MePhSiH2 (0.6 mmol, 1.2 equiv)
and 10b according to the general procedure for 18 h at 110 °C; eluent:
EtOAc/hexane = 15:85.
Compound 11h′ was prepared from 7d, MePhSiH2 (1.25 mmol, 2.5
equiv) and 10b according to the general procedure for 12 h at 110 °C;
eluent: EtOAc/hexane = 20:80.
Yield: 67.5 mg (48%); white solid; mp 123–125 °C.
IR (neat): 3331, 1590, 1432, 1321, 1267, 1116, 1061, 927, 888, 716,
Yield: 5.1 mg (2%), 1:1 diastereomeric mixture of Si stereogenic cen-
ter; white solid; mp 144–146 °C.
622, 598 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.34 (s, 1 H), 8.07 (d, J = 7.9 Hz, 2 H),
7.76 (d, J = 8.3 Hz, 2 H), 5.89–5.86 (m, 1 H), 2.71–2.59 (m, 1 H), 2.39–
2.30 (m, 1 H), 1.99–1.91 (m, 1 H), 1.75 (s, 3 H), 1.18 (d, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 165.6, 145.6, 133.9 (q, J = 32.9 Hz),
126.9 (2C), 125.9 (q, J = 4.0 Hz, 2C), 123.4 (q, J = 272.8 Hz), 118.4,
117.1, 34.4, 32.1, 19.6, 16.6.
IR (neat): 3294, 2929, 2120, 1598, 1391, 1320, 1262, 1126, 1084,
1061, 899, 870, 829, 715, 612 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.63 (s, 1 H), 8.02 (d, J = 8.2 Hz, 2 H),
7.71 (d, J = 8.3 Hz, 2 H), 7.52–7.47 (m, 2 H), 7.46–7.34 (m, 3 H), 4.34–
4.25 (m, 1 H), 3.51–3.36 (m, 1 H), 3.25 (td, J = 12.9, 3.9 Hz, 1 H), 2.50–
2.38 (m, 1 H), 2.05–1.92 (m, 1 H), 1.49–1.39 (m, 1 H), 1.36–1.24 (m, 1
H), 1.19 (dd, J = 9.2, 6.9 Hz, 3 H), 0.41 (t, J = 4.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 169.7, 146.4, (134.6, 134.5) (2C), 133.5
(q, J = 32.5 Hz), (132.6, 132.5), 130.2, 128.3 (2C), 126.6 (2C), 125.8 (q,
J = 3.6 Hz, 2C), 123.4 (q, J = 272.5 Hz), (45.1, 44.9), 36.9, (30.5, 30.4),
(20.1, 20.0), (18.2, 18.1), (–7.9, –8.0).
HRMS (EI): m/z [M]+ calcd for C14H15F3N2O2S: 332.0806; found:
332.0807.
N-(3-Methyl-5-phenyl-3,4-dihydropyridin-2(1H)-ylidene)-4-(tri-
fluoromethyl)benzenesulfonamide (11g)
Compound 11g was prepared from 7g, MePhSiH2 (0.6 mmol, 1.2
equiv) and 10b according to the general procedure for 18 h at 110 °C;
eluent: EtOAc/hexane = 20:80.
HRMS (EI): m/z [M]+ calcd for C20H23F3N2O2SSi: 440.1202; found:
440.1202.
Yield: 78.5 mg (40%); white solid; mp 143–145 °C.
Synthesis of 1,4-Dihydroisoquinolin-3(2H)-one (12) from Cyclic
IR (neat): 3312, 1586, 1445, 1399, 1260, 1124, 1083, 1060, 932, 888,
Amidine 6a (Scheme 5)
835, 718, 691, 624, 555 cm–1
.
A round-bottom flask was charged with amidine 6a (0.18 mmol, 54
mg), then MeOH (1.6 mL), H2O (0.4 mL), and conc. HCl (0.1 mL) were
added sequentially at r.t. and the reaction mixture was stirred and
heated to 85 °C for 5 h (12) before sat. NaHCO3 solution was added to
neutralize the mixture. After evaporation of MeOH, the resulting
aqueous layer was extracted with EtOAc and the organic layer was
dried over MgSO4, and evaporated under reduced pressure. The crude
mixture was purified by column chromatography on silica gel with
EtOAc/hexane.
1H NMR (500 MHz, CDCl3):  = 9.67 (s, 1 H), 8.11 (d, J = 8.1 Hz, 2 H),
7.77 (d, J = 8.2 Hz, 2 H), 7.42–7.26 (m, 5 H), 6.49 (d, J = 5.3 Hz, 1 H),
2.89–2.78 (m, 2 H), 2.55–2.43 (m, 1 H), 1.27 (d, J = 6.7 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 165.5, 145.3, 137.3, 134.04 (q, J = 32.5
Hz), 128.8 (2C), 127.63, 127.0 (2C), 126.00 (q, J = 4.0 Hz, 2C), 124.6
(2C), 123.3 (q, J = 271.3 Hz), 120.8, 118.7, 34.5, 29.7, 16.6.
HRMS (EI): m/z [M]+ calcd for C19H17F3N2O2S: 394.0963; found:
394.0962.
EtOAc/hexane = 70:30.
Yield: 19.2 mg (72%); white solid; mp 154–156 °C.
IR (neat): 3185, 3029, 1652, 1496, 1429, 1396, 1345, 1327, 833, 742,
550, 457 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

J
V. D. Cao et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3):  = 7.34 (s, 1 H), 7.28–7.22 (m, 2 H), 7.20–
7.14 (m, 2 H), 4.51 (d, J = 2.3 Hz, 2 H), 3.59 (s, 2 H).
13C NMR (125 MHz, CDCl3):  = 172.2, 131.8, 131.1, 127.8, 127.5,
126.7, 125.4, 45.3, 36.6.
HRMS (EI): m/z [M]+ calcd for C9H9NO: 147.0684; found: 147.0684.
(d) Diana, G. D.; Hinshaw, W. B.; Lape, H. E. J. Med. Chem. 1977,
20, 449. (e) Calas, M.; Ouattara, M.; Piquet, G.; Ziora, Z.; Bordat,
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6307. (f) Penning, T. D.; Khilevich, A.; Chen, B. B.; Russell, M. A.;
Boys, M. L.; Wang, Y.; Duffin, T.; Engleman, V. W.; Finn, M. B.;
Freeman, S. K.; Hanneke, M. L.; Keene, J. L.; Klover, J. A.; Nickols,
G. A.; Nickols, M. A.; Rader, R. K.; Settle, S. L.; Shannon, K. E.;
Steininger, C. N.; Westlin, M. M.; Westlin, W. F. Bioorg. Med.
Chem. Lett. 2006, 16, 3156. (g) Blériot, Y.; Dintinger, T.; Genre-
Grandpierre, A.; Padrines, M.; Tellier, C. Bioorg. Med. Chem. Lett.
1995, 5, 2655. (h) Christoff, J. J.; Bradley, L.; Miller, D. D.; Lei, L.;
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Synthesis of 5-Phenyl-3,4-dihydropyridin-2(1H)-one (13) from
Cyclic Amidine 9e (Scheme 5)
A round-bottom flask was charged with amidine 9e (0.18 mmol, 59
mg), then THF (0.8 mL), MeOH (1.0 mL), H2O (0.1 mL), and HCl conc.
(0.05 mL) were added sequentially at r.t. The reaction mixture was
stirred and heated to 65 °C for 2.5 h before sat. NaHCO3 solution was
added to neutralize the mixture. After evaporation of THF and MeOH,
the resulting aqueous layer was extracted with EtOAc and the organic
layer was dried over MgSO4, and evaporated under reduced pressure.
The crude product was purified by column chromatography on silica
gel with EtOAc/hexane.
(2) (a) Guthikonda, R. N.; Shah, S. K.; Pacholok, S. G.; Humes, J. L.;
Mumford, R. A.; Grant, S. K.; Chabin, R. M.; Green, B. G.; Tsou, N.;
Ball, R.; Fletcher, D. S.; Luell, S.; MacIntyre, D. E.; MacCoss, M.
Bioorg. Med. Chem. Lett. 2005, 15, 1997. (b) Delcros, J.-G.;
Tomasi, S.; Duhieu, S.; Foucault, M.; Martin, B.; Le Roch, M.;
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(c) Lee, E.; Han, S.; Jin, G. H.; Lee, H. J.; Kim, W.-Y.; Ryu, J.-H.;
Jeon, R. Bioorg. Med. Chem. Lett. 2013, 23, 3976. (d) Glushkov, V.
A.; Anikina, L. V.; Vikharev, Y. B.; Feshina, E. V.; Shklyaev, Y. V.
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EtOAc/hexane = 50:50.
Yield: 11.2 mg (36%); white solid; mp 120–122 °C.
IR (neat): 3196, 3076, 2945, 1682, 1645, 1594, 1388, 1295, 1212,
1144, 752, 693, 577, 514, 499, 460 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.71 (s, 1 H), 7.38–7.28 (m, 4 H), 7.26–
7.19 (m, 1 H), 6.50 (d, J = 4.6 Hz, 1 H), 2.79 (dd, J = 8.6, 7.4 Hz, 2 H),
2.65 (dd, J = 8.9, 7.2 Hz, 2 H).
13C NMR (125 MHz, CDCl3):  = 170.8, 138.3, 128.7 (2C), 126.7, 124.3
(2C), 121.3, 117.5, 30.3, 23.4.
HRMS (EI): m/z [M]+ calcd for C11H11NO: 173.0841; found: 173.0841.
Funding Information
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(b) Tsuritani, T.; Yamamoto, Y.; Kawasaki, M.; Mase, T. Org. Lett.
2009, 11, 1043. (c) Chang, S.; Lee, M.; Jung, D. Y.; Yoo, E. J.; Cho,
S. H.; Han, S. K. J. Am. Chem. Soc. 2006, 128, 12366. (d) Golovko,
T. V.; Solov’eva, N. P.; Anisimova, O. S.; Granik, V. G. Chem. Het-
erocycl. Compd. 2003, 39, 344. (e) Xu, Y.; Zhu, S. Tetrahedron
2001, 57, 4337.
This research was supported by the National Research Foundation of
Korea (NRF-2018R1D1A1B07045397) and Korea Basic Science Insti-
tute (KBSI) National Research Facilities & Equipment Center (NFEC)
grant funded by the Korea government (Ministry of Education) (no.
2019R1A6C1010005). This work was carried out by the convergence
Research Laboratory established by the Mokpo National University
(MNU) Innovation Support Project.
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oreaBasi
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Org. Lett. 2020, 22, 515.
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Acknowledgment
We thank Dr. Dongwook Kim (KAIST) for the X-ray diffraction analy-
sis.
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Supporting Information
(8) See the Supporting Information for details.
Supporting information for this article is available online at
(9) Curless, L. D.; Ingleson, M. J. Organometallics 2014, 33, 7241.
(10) Gandhamsetty, N.; Park, S.; Chang, S. Synlett 2017, 28, 2396.
(11) See the Supporting Information for details.
https://doi.org/10.1055/s-0040-1707323. Su
p
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ortingInformationS
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p
p
ortingI
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formatio
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(12) We observed double hydrosilylation as well as [3+2] cycloaddi-
tion of the 2-methylenamine.
References
(13) See the Supporting Information for a detailed mechanism
describing the stereoselectivity.
(14) CCDC 1987424 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K