Late-Stage Derivatization of Buflavine by Nickel-Catalyzed Direct Substitution of a Methoxy Group via C-O Bond Activation

Article abstract of DOI:10.1055/a-1467-2494

The nickel-catalyzed cross-coupling of methoxyarenes was applied to buflavine, which allows for the selective monosubstitution of one of the two methoxy groups in the molecule, leading to the formation of 2- and 3-substituted isomers. Trimethylsilylmethyl (TMSCH ₂), phenyl, and alkynyl groups can be introduced into buflavine using this method. The resulting TMSCH ₂analogue of buflavine can also be converted into several other derivatives.

Full text of DOI:10.1055/a-1467-2494

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–H
special topic
A
Bond Activation – in Honor of Prof. Shinji
R. Shimazumi et al.
Special Topic
Synthesis
Late-Stage Derivatization of Buflavine by Nickel-Catalyzed Direct
Substitution of a Methoxy Group via C–O Bond Activation
Ryoma Shimazumia
MeO
derivatization
cat.
Ni(OAc)2/ICy
MeO
Kosuke Moritab
Tomoki Yoshidaa
Kosuke Yasuia
3
MeO
NMe
2
NMe
TMS
MgCl
TMS
Mamoru Tobisu*a,c
0
0
0
0
-
0
0
0
2
-
8
4
1
5-2
2
2
5
C–OMe activation
buflavine
a Department of Applied Chemistry, Graduate School of Engineering,
Osaka University, Suita, Osaka 565-0871, Japan
tobisu@chem.eng.osaka-u.ac.jp
+ 3-substituted isomer
b Nada High School, Kobe, Hyogo 658-0082, Japan
c Innovative Catalysis Science Division, Institute for Open and Transdisci-
plinary Research Initiatives (ICS-OTRI), Osaka University, Suita, Osaka
565-0871, Japan
Dedicated to Professor Shinji Murai for his contribution to bond activation.
Published as part of the Special Topic Bond Activation – in Honor of Prof. Shinji Murai
Corresponding Author
Received: 10.03.2021
Accepted after revision: 25.03.2021
Published online: 25.03.2021
we4 and others5 demonstrated that nickel-catalyzed cross-
coupling can be used to functionalize monomethoxy-sub-
stituted natural products. However, naturally occurring
compounds often contain multiple methoxy groups, and
their selective monoderivatization is a challenge, especially
when the methoxy groups are located in a similar electron-
ic and steric environment. Buflavine (1)6,7 represents a rela-
tively simple natural product that contains two methoxy
groups with no steric and electronic bias. Herein, we report
on the nickel-catalyzed alkylation of buflavine (1), in which
one of the two methoxy groups is substituted by an incom-
ing nucleophile to provide an array of buflavine derivatives
in a divergent fashion (Scheme 1).
DOI: 10.1055/a-1467-2494; Art ID: ss-2021-f0122-st
Abstract The nickel-catalyzed cross-coupling of methoxyarenes was
applied to buflavine, which allows for the selective monosubstitution of
one of the two methoxy groups in the molecule, leading to the forma-
tion of 2- and 3-substituted isomers. Trimethylsilylmethyl (TMSCH2),
phenyl, and alkynyl groups can be introduced into buflavine using this
method. The resulting TMSCH2 analogue of buflavine can also be con-
verted into several other derivatives.
Key words C–O bond activation, cross-coupling, nickel, natural prod-
uct, late-stage functionalization
MeO
MeO
The derivatization of natural products allows for librar-
ies of such derivatives to be created, which often leads to
the discovery of drugs with improved potency, selectivity,
and/or pharmacokinetic profiles. In addition, natural prod-
uct derivatives can be used to accelerate the discovery and
the pharmacological study of new biological targets.1 How-
ever, the limited scope of the methods that are currently
available for derivatizing natural products confines the
chemical space to be explored, and therefore, new reliable
methods applicable for this purpose are required. In this
context, modern C–H functionalization chemistry has
emerged as a powerful tool for the late-stage derivatization
of natural products.2 We envisioned that our previously re-
ported nickel-catalyzed cross-coupling of methoxy-substi-
tuted arenes3 has some potential for use in rapidly increas-
ing the diversity of natural products, given that a methoxy-
arene is a common motif found in natural products. In fact,
3
3
Nu
MeO
Nu
NMe
NMe
cat. Ni(OAc)2/ICy
2
2
N
N
buflavine (1)
+
3-substituted isomer
ICy
Scheme 1 Nickel-catalyzed functionalization of buflavine (1)
We initiated our study by examining the nickel-cata-
lyzed cross-coupling of 1,2-dimethoxyarene derivative 2, as
a model compound of 1, with the alkyl Grignard reagent 3,
based on our previous success in the monoselective alkyla-
tion of 1,2-dimethoxybenzene with this nucleophile.4a,b The
use of an N-cyclohexyl-substituted N-heterocyclic carbene
(NHC) ligand (i.e., ICy) led to the formation of the mono-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
R. Shimazumi et al.
Special Topic
Synthesis
alkylated product 4 in 83% isolated yield with two regioiso-
mers being obtained in a ratio of 1.4:1 (Table 1, entry 1).
Other NHC ligands, including IPr (entry 2), IMes (entry 3),
and SIMes (entry 4), as well as PCy3 (entry 6), also promot-
ed this alkylation reaction, although the yields were lower
than that obtained with ICy. Notably, the use of IMesMe, the
4,5-dimethyl-substituted analogue of IMes,8 afforded 4 in
an excellent yield (entry 5). Based on these results, we used
the commercially available ICy as the ligand in the subse-
quent studies.
in a ratio of 3:1, and the structure of the major isomer 5a
was unambiguously determined by HSQC and HMBC mea-
surements (see the Supporting Information for details). Al-
though a high regioselectivity is desired in target-oriented
synthesis, the formation of isomeric mixtures can also be
advantageous in diversity-oriented synthesis. For example,
in the late-stage derivatization of drug candidates, each
product isomer serves as an additional derivative that can
be obtained without the need for costly and laborious de
novo synthesis.
MeO
TMS
MgCl
Table 1 Optimization of Nickel-Catalyzed Cross-Coupling Using the
Model Substrate 2a
3
3 (1.5 equiv)
MeO
NMe
2
Ni(OAc)2 (10 mol%)
ICy•HCl (20 mol%)
TMS
MgCl
toluene
80 °C, 18 h
MeO
3 (1.5 equiv)
Ni(OAc)2 (10 mol%)
ligand (20 mol%)
3
MeO
buflavine (1)
2
NMe2
MeO
toluene
80 °C, 18 h
TMS
3
3
2
2
MeO
NMe
NMe
2
TMS
+
MeO
TMS
MeO
3
2
+
TMS
NMe2
NMe2
5a
5b
4a
4b
72% (3:1)
Scheme 2 Nickel-catalyzed cross-coupling of buflavine (1) with 3. Re-
agents and conditions: 1 (0.20 mmol), 3 (0.30 mmol), Ni(OAc)2 (0.020
mmol), ICy·HCl (0.040 mmol), toluene (1.0 mL), 80 °C, 18 h.
Me
N
Me
N
N
N
R
N
N
Ar
R
Ar
Ar
Ar
X
Cl
Cl
IMesMe·HCl
SIMes·HCl
ICy·HBF4: R = cyclohexyl, X = BF4
IPr·HCl: R = 2,6-iPr2C6H3, X = Cl
IMes·HCl: R = 2,4,6-Me3C6H2, X = Cl
The successful cross-coupling of a methoxy group of 1
with TMSCH2MgCl prompted us to examine the issue of
whether 1 could also be functionalized with other nucleo-
philes (Scheme 3). Although Suzuki–Miyaura-type cross-
coupling with PhB(nep)2 (nep = neopentylglycolate) using a
Ni/ICy catalyst4c failed, it was possible to synthesize the
phenylated buflavine 6 using PhMgBr as a nucleophile, af-
fording a mixture of two regioisomers (isomeric ratio = 1:1)
in 31% yield (Scheme 3a). Moreover, the alkynylated bufla-
vine 7 can be synthesized by Ni/ICy-catalyzed cross-cou-
pling using a triisopropylsilyl-protected alkynyl Grignard
reagent (Scheme 3b).4b We also examined cross-coupling of
1 with a -hydrogen-containing alkyl group using our pre-
viously reported Ni/dcype system,4e but the desired product
8 was not formed (Scheme 3c).
The TMSCH2 group in 5 serves as a versatile handle for
the further derivatization of buflavine (Scheme 4). For ex-
ample, the benzylsilane moiety in 5 can function as a ben-
zyl anion equivalent in the presence of a suitable fluoride
activator, thus allowing for the reaction with electrophiles.9
In fact, treatment of 5 with tetrabutylammonium difluorot-
riphenylsilicate (TBAT) in the presence of an aldehyde or an
imine afforded buflavine derivatives bearing a pendant al-
cohol (i.e., 9) or an amine (i.e., 10) group. The in situ gener-
ated benzyl anion can be protonated when 5 is treated with
Ar = 2,4,6-Me3C6H2
Entry
Ligand
Conv. (%) of 2
Yield (%) of 4 (4a/4b)b
1c
2
3
4
5
6
ICy·HBF4
IPr·HCl
>99
66
67
58
92
78
83 (1.4:1)d
39 (1.3:1)
51 (1:1.5)
32 (1:2.3)
99 (1:1.7)
68 (1:1.6)
IMes·HCl
SIMes·HCl
IMesMe·HCl
PCy3
a Reaction conditions: 2 (0.30 mmol), 3 (0.45 mmol), Ni(OAc)2 (0.030
mmol), ligand (0.060 mmol), toluene (1.0 mL), 18 h, 80 °C.
b Determined by GC using pentadecane as an internal standard.
c Run on a 1.0 mmol scale.
d Isolated yield.
With the optimized reaction conditions in hand, we
next investigated the alkylative cross-coupling of buflavine
(1) with 3 (Scheme 2). The reaction of 1 with 3 in the pres-
ence of Ni(OAc)2 (10 mol%) and ICy·HCl (20 mol%) in tolu-
ene at 80 °C for 18 hours afforded the monoalkylated prod-
ucts 5 in 72% isolated yield, and no dialkylated product was
observed, as was the case when the model substrate 2 was
used. The product consisted of two regioisomers 5a and 5b
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H

C
R. Shimazumi et al.
Special Topic
Synthesis
tion of a methyl group via nickel-catalyzed methoxy-substi-
tution reactions would be useful in this context. The -ex-
tended analogue 12 of buflavine could be synthesized by
the addition to an aldehyde, followed by acid-mediated de-
hydration.
(a) Arylation
MeO
PhMgBr (1.5 equiv)
3
2
Ni(OAc)2 (15 mol%)
ICy•HBF4 (20 mol%)
NMe
1
+ 3-substituted
isomer
toluene
80 °C, 18 h
In summary, we have demonstrated that nickel-cata-
lyzed cross-coupling of methoxyarenes can be used to elab-
orate the methoxy-substituted natural product buflavine.
TMSCH2, aryl, and alkynyl groups can be introduced into 1
by using the corresponding Grignard reagents. The TMSCH2
group on the buflavine skeleton is also amenable to further
transformations, thus allowing a variety of derivatives of 1
to be generated. The findings reported in this study indicate
that such methoxy cross-coupling reactions are potential
and powerful tools for rapidly increasing the diversity of
natural products.
6 31% (1:1)
(b) Alkynylation
TIPS
H
(2.0 equiv)
MeO
Ni(cod)2 (10 mol%)
ICy•HBF4 (20 mol%)
EtMgBr (2.0 equiv)
3
2
TIPS
NMe
1
+ 3-substituted
isomer
dioxane
120 °C, 18 h
7 27% (1.6:1)
(c) Alkylation
nC5H11MgBr (1.5 equiv)
MeO
Ni(cod)2 (10 mol%)
dcype (10 mol%)
MgI2 (1.5 equiv)
3
1H (400 or 600 MHz) and 13C (101 or 150 MHz) NMR spectra were re-
corded on a JEOL ECS-400 spectrometer or Bruker Avance III spec-
trometer, in CDCl3 with tetramethylsilane as the internal standard.
The chemical shifts in 1H NMR spectra were recorded relative to ei-
ther CHCl3 ( 7.26) or tetramethylsilane ( 0.00). The chemical shifts
in 13C NMR spectra were recorded relative to CDCl3 ( 77.00). The data
are reported as follows: chemical shift () in ppm, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling
constant (Hz), and integration. IR spectra were obtained using a
JASCO FT/IR-4200 spectrophotometer. Absorption is reported in re-
ciprocal centimeters (cm–1) with the following relative intensities: s
(strong), m (medium), or w (weak). High-resolution mass spectra
(HRMS) were obtained using a JEOL JMS-700 spectrometer. Analytical
GC was carried out on a Shimadzu GC-2014 gas chromatograph,
equipped with a flame ionization detector. Column chromatography
was performed with silica gel (SiliCycle SiliaFlash F60, 230–400 mesh)
or NH2 silica gel (Kanto Chemical Co., Inc., NH2 Silica Gel 60, spherical,
particle size 40–50 m).
2
nC5H11
NMe
1
toluene
80 °C, 14 h
8 0%
Scheme 3 Scope of nucleophiles [TIPS: triisopropylsilyl; dcype:
1,2-bis(dicyclohexylphosphino)ethane]
TBAF in the absence of added electrophiles to form the
methylated analogue 11 of buflavine which could not be ac-
cessed directly by cross-coupling with MeMgX under the
nickel-catalyzed conditions. Given the fact that a methyl
group can have a profound impact on the various aspects of
biological activity of a molecule,10 the late-stage introduc-
MeO
MeO
NMe
Me
NMe
Br
a
c
OH
MeO
9 63%
(9a/9b = 3:1)
NMe
11 79%
(11a/11b = 3:1)
TMS
MeO
MeO
d
b
NMe
5
NMe
Cl
(5a/5b = 3:1)
NH
12 51%
(12a/12b = 3:1)
10 69%
(10a/10b = 3:1)
Scheme 4 Derivatization of 5. The corresponding 3-substituted isomers were also formed in each reaction. Reagents and conditions: (a) 5 (0.19 mmol),
4-bromobenzaldehyde (0.4 mmol), TBAT (0.10 mmol), 4 Å MS (200 mg), THF (2.0 mL), 12 h, 70 °C; (b) 5 (0.20 mmol), benzylideneaniline (0.4 mmol),
TBAT (0.10 mmol), 4 Å MS (200 mg), THF (2.0 mL), 12 h, 70 °C; (c) 5 (0.15 mmol), 1 M TBAF in THF (0.3 mL), THF (2.0 mL), 12 h, rt; (d) 5 (0.20 mmol),
4-chlorobenzaldehyde (0.4 mmol), TBAT (0.10 mmol), 4 Å MS (200 mg), THF (2.0 mL), 1 h, 75 °C; p-TsOH·H2O (0.80 mmol), toluene (2.0 mL), 1 h,
120 °C (TBAT: tetrabutylammonium difluorotriphenylsilicate).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H

D
R. Shimazumi et al.
Special Topic
Synthesis
Toluene, 1,4-dioxane, and THF (dehydrated) were purchased from
Wako Chemicals and used as received. Ni(cod)2 (Strem), ICy·HCl (TCI),
ICy·HBF4 (TCI), IMes·HCl (TCI), IPr·HCl (TCI), SIMes·HCl (TCI), and PCy3
(Aldrich) were purchased from commercial suppliers and used as re-
ceived. IMesMe·HCl11 [1118916-80-5] and buflavine (1)12 [65762-70-1]
were prepared according to literature procedures. (Trimethyl-
silyl)methylmagnesium chloride (1.0 M in THF, Aldrich), ethynyltri-
isopropylsilane (TCI), and ethylmagnesium bromide (1.0 M in THF,
Aldrich) were purchased from commercial suppliers and used as re-
ceived. Anhydrous Ni(OAc)2 was prepared by heating Ni(OAc)2·4 H2O
(Wako) at 100 °C under vacuum until the color changed from green-
ish blue (hydrate) to greenish yellow (anhydride). Tetrabutylammoni-
um fluoride (1.0 M in THF, TCI), tetrabutylammonium difluorotriphe-
nylsilicate (TCI), p-toluenesulfonic acid monohydrate (TCI), 4-bromo-
benzaldehyde (TCI), 4-chlorobenzaldehyde (TCI), and benzylidene-
aniline (TCI) were purchased from commercial suppliers and used as
received.
1-(4-Methoxy-5-((trimethylsilyl)methyl)-[1,1′-biphenyl]-2-yl)-
N,N-dimethylmethanamine (4a)
Yield: 161 mg (49%); colorless oil; Rf = 0.16 (EtOAc, on silica gel).
IR (ATR): 2947 (w), 2813 (w), 1486 (m), 1245 (m), 849 (s), 700 (m)
cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.40–7.30 (m, 5 H), 7.02 (s, 1 H), 6.87
(s, 1 H), 3.85 (s, 3 H), 3.35 (s, 2 H), 2.15 (s, 6 H), 2.10 (s, 2 H), –0.01 (s,
9 H).
13C NMR (101 MHz, CDCl3):  = 155.81, 141.69, 134.22, 132.87,
130.92, 129.83, 127.75, 127.49, 126.25, 110.72, 60.92, 55.15, 45.35,
20.12, –1.57.
MS: m/z (%) = 327 (M+, 31), 326 (19), 313 (28), 312 (100), 296 (10),
284 (23), 283 (19), 282 (13), 268 (13), 267 (15), 254 (10), 253 (12),
252 (36), 179 (23), 73 (61), 58 (37).
HRMS (DART): m/z calcd for C20H30NOSi [M + H+]: 328.2091; found:
328.2089.
1-(4,5-Dimethoxy-[1,1′-biphenyl]-2-yl)-N,N-dimethylmethan-
amine (2)
1-(5-Methoxy-4-((trimethylsilyl)methyl)-[1,1′-biphenyl]-2-yl)-
N,N-dimethylmethanamine (4b)
This compound was prepared based on a reductive amination reac-
tion procedure reported in the literature.13 In a round-bottom two-
necked flask, 4,5-dimethoxy-[1,1′-biphenyl]-2-carbaldehyde14 (1.45
g, 6.0 mmol) was dissolved in THF (50 mL). HNMe2·HCl (978 mg, 12
mmol), NaOAc (788 mg, 9.6 mmol), and AcOH (0.2 mL) were then
added. The mixture was cooled to 0 °C, and NaBH(OAc)3 (2.8 g, 13.2
mmol) was added portionwise. After stirring the mixture at rt for 12
h, solvent was removed in vacuo. The residue was then dissolved in
Et2O and extracted with 10% citric acid solution (3 × 30 mL). The
aqueous layer was neutralized with KOH at 0 °C and extracted with
Et2O (3 × 30 mL). The combined organic layer was dried (Na2SO4) and
concentrated in vacuo to give the desired product 2.
Yield: 110 mg (34%); colorless oil; Rf = 0.28 (EtOAc, on silica gel).
IR (ATR): 2922 (m), 2853 (w), 1222 (w), 850 (w), 772 (s), 700 (w) cm–1
1H NMR (400 MHz, CDCl3):  = 7.40–7.33 (m, 5 H), 7.11 (s, 1 H), 6.67
(s, 1 H), 3.77 (s, 3 H), 3.26 (s, 2 H), 2.13 (s, 6 H), 2.13 (s, 2 H), 0.01 (s, 9
H).
13C NMR (101 MHz, CDCl3):  = 154.97, 141.97, 139.03, 130.93,
129.73, 128.11, 127.79, 127.58, 126.51, 111.39, 60.45, 54.97, 45.16,
20.20, –1.46.
MS: m/z (%) = 327 (M+, 25), 326 (16), 313 (17), 312 (62), 284 (14), 283
(39), 269 (12), 268 (10), 267 (22), 253 (19), 252 (53), 251 (11), 179
(27), 178 (14), 73 (100), 59 (16), 58 (40), 45 (12).
.
Yield: 1.52 g (93%); colorless solid; mp 92.1 °C.
HRMS (DART): m/z calcd for C20H30NOSi [M + H+]: 328.2091; found:
328.2094.
IR (ATR): 1219 (w), 772 (s), 599 (w) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.41–7.31 (m, 5 H), 7.11 (s, 1 H), 6.74
(s, 1 H), 3.94 (s, 3 H), 3.87 (s, 3 H), 3.31 (s, 2 H), 2.13 (s, 6 H).
Nickel-Catalyzed Alkylation of 14a
13C NMR (101 MHz, CDCl3):  = 148.18, 147.25, 141.36, 134.62,
129.75, 128.74, 127.91, 126.65, 112.79, 112.23, 60.51, 56.03, 55.87,
45.29.
MS: m/z (%) = 271 (M+, 33), 270 (19), 257 (14), 256 (79), 240 (10), 228
(24), 227 (73), 226 (15), 212 (22), 197 (22), 196 (100), 195 (12), 181
(21), 165 (13), 153 (13), 152 (11), 141 (10), 115 (14), 58 (67), 42 (11).
A 10 mL sample vial with a Teflon-sealed screw cap was placed in a
nitrogen-filled glovebox. Ni(OAc)2 (3.5 mg, 0.020 mmol), ICy·HCl (11
mg, 0.040 mmol), 1 (55 mg, 0.20 mmol), and 3 (1.0 M in THF; 0.30 mL,
0.30 mmol) were then added sequentially to the vial, and the result-
ing mixture was stirred at rt for 3 min. The THF was then removed in
vacuo to give a residue, which was dissolved in toluene (1.0 mL). The
vial was then sealed and the contents were stirred at 80 °C for 18 h.
The reaction mixture was then treated with saturated aqueous NH4Cl
(5.0 mL) to give a biphasic mixture. The resulting aqueous layer was
collected and extracted with EtOAc (3 × 15 mL). The combined organ-
ic extracts were then washed with brine and dried (Na2SO4) before
being evaporated to dryness to give a residue, which was purified by
flash column chromatography over NH silica gel (hexane 100% to hex-
ane/EtOAc 3:1) to give a mixture of 5a and 5b (5a/5b = 3:1, deter-
mined by 1H NMR). A part of 5a was obtained in a pure form.
HRMS (DART): m/z calcd for C17H22NO2 [M + H+]: 272.1645; found:
272.1647.
Nickel-Catalyzed Cross-Coupling of 2 with 3
A 10 mL sample vial with a Teflon-sealed screw cap was placed in a
nitrogen-filled glovebox. Ni(OAc)2 (17.6 mg, 0.10 mmol), ICy·HBF4
(64.0 mg, 0.20 mmol), 2 (272 mg, 1.0 mmol), and 3 (1.0 M in THF;
1.50 mL, 1.5 mmol) were then added sequentially to the vial, and the
resulting mixture was stirred at rt for 3 min. The THF was then
removed in vacuo to give a residue, which was dissolved in toluene
(3.0 mL). The vial was then sealed and the contents were stirred at
80 °C for 18 h. The reaction mixture was then treated with saturated
aqueous NH4Cl (5.0 mL) to give a biphasic mixture. The resulting
aqueous layer was collected and extracted with EtOAc (3 × 15 mL).
The combined organic extracts were then washed with brine and
dried (Na2SO4) before being evaporated to dryness to give a residue,
which was purified by flash column chromatography over silica gel
(hexane/EtOAc 4:1 to EtOAc 100%) to give 4a and 4b.
3-Methoxy-6-methyl-2-((trimethylsilyl)methyl)-5,6,7,8-tetra-
hydrodibenzo[c,e]azocine (5a)
Yield: 48.6 mg (72%) as a mixture with 5b; yellow oil; Rf = 0.44 (hex-
ane/EtOAc 1:1, on NH silica gel).
IR (ATR, 5a + 5b): 1604 (w), 1590 (w), 1560 (w), 1232 (w), 1209 (w),
781 (s) cm–1
.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H

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R. Shimazumi et al.
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Synthesis
1H NMR (400 MHz, CDCl3):  = 7.32–7.22 (m, 4 H), 6.90 (s, 1 H), 6.81
(s, 1 H), 3.85 (s, 3 H), 3.52 (d, J = 13.6 Hz, 1 H), 3.30–3.25 (m, 1 H), 3.06
(d, J = 13.6 Hz, 1 H), 2.75–2.70 (m, 1 H), 2.56–2.51 (m, 5 H), 2.11 (s, 2
H), –0.03 (s, 9 H).
MS: m/z (%) = 330 (11), 329 (M+, 43), 328 (21), 314 (23), 287 (25), 286
(100), 285 (31), 271 (20), 270 (17), 256 (14), 255 (37), 254 (12), 253
(21), 252 (31), 241 (14), 240 (11), 239 (18), 209 (10), 165 (15), 119
(11), 115 (16), 91 (16), 42 (14).
13C NMR (101 MHz, CDCl3):  = 156.02, 141.20, 140.29, 134.14,
132.45, 130.26, 129.28, 129.15, 128.37, 127.51, 125.97, 111.95, 58.94,
58.83, 54.96, 46.18, 32.69, 20.31, –1.55.
HRMS (DART): m/z calcd for C23H24NO [M + H+]: 330.1852; found:
330.1850.
Nickel-Catalyzed Alkynylation of 14b
MS: m/z (%) = 339 (M+, 18), 324 (19), 281 (37), 266 (14), 191 (12), 179
(10), 178 (21), 165 (12), 73 (100), 59 (11), 45 (28), 44 (11), 42 (10).
HRMS (DART): m/z calcd for C21H30NOSi [M + H+]: 340.2091; found:
340.2091.
A 10 mL sample vial with a Teflon-sealed screw cap was placed in a
nitrogen-filled glovebox and charged with ethynyltriisopropylsilane
(72 mg, 0.40 mmol). EtMgBr (1.0 M in THF, 0.40 mL, 0.40 mmol) was
then added to the magnetically stirred material in a dropwise manner
at rt. The resulting mixture was stirred at rt for 5 min. Ni(cod)2 (11
mg, 0.040 mmol), ICy·HBF4 (22 mg, 0.080 mmol), and 1 (57 mg, 0.20
mmol) were then added sequentially to the vial, and the resulting
mixture was stirred at rt for 3 min. The THF was then removed in vac-
uo, and the resulting residue was dissolved in dioxane (1.0 mL). The
vial was then sealed and the contents were heated with stirring at
120 °C for 18 h. After allowing the reaction mixture to cool to rt, the
solvent was removed in vacuo to give a residue, which was purified by
flash column chromatography over silica gel (CHCl3 100% to CHCl3/
MeOH 20:1) to give 7a and 7b.
2-Methoxy-6-methyl-3-((trimethylsilyl)methyl)-5,6,7,8-tetra-
hydrodibenzo[c,e]azocine (5b)
Yield: 48.6 mg (72%) as a mixture with 5a; yellow oil; Rf = 0.60
(hexane/EtOAc 1:1, on NH silica gel).
Spectroscopic data were collected with a 3:1 (5a/5b) mixture.
1H NMR (400 MHz, CDCl3):  (selected peaks assigned to 5b) = 6.96 (s,
1 H), 6.70 (s, 1 H), 3.79 (s, 3 H), 3.56 (d, J = 13.6 Hz, 1 H), 3.13 (d, J =
13.6 Hz, 1 H), 2.69 (m, 5 H), 0.06 (s, 9 H); other peaks of 5b are over-
lapped with those of 5a.
13C NMR (101 MHz, CDCl3):  (peaks assigned to 5b) = 155.39, 141.55,
140.69, 134.20, 132.30, 130.26, 129.35, 129.22, 128.39, 127.75,
125.84, 110.75, 58.38, 57.32, 55.02, 44.10, 31.63, 20.15, –1.46.
MS: m/z (%) (5a + 5b) = 340 (18), 339 (M+, 63), 338 (15), 325 (16), 324
(60), 282 (25), 281 (100), 266 (33), 265 (19), 207 (11), 191 (13), 178
(14), 73 (72), 45 (12).
3-Methoxy-6-methyl-2-((triisopropylsilyl)ethynyl)-5,6,7,8-tetra-
hydrodibenzo[c,e]azocine (7a)
Yield: 14.5 mg (17%); colorless oil; Rf = 0.65 (hexane/EtOAc 1:1, on NH
silica gel).
IR (ATR, 7a + 7b): 2939 (m), 2862 (m), 1461 (w), 882 (w), 760 (s) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.39 (s, 1 H), 7.34–7.26 (m, 3 H), 7.21
(d, J = 7.2 Hz, 1 H), 6.87 (s, 1 H), 3.92 (s, 3 H), 3.55 (d, J = 13.2 Hz, 1 H),
3.25 (dd, J = 7.6, 6.8 Hz, 1 H), 3.14 (d, J = 13.2 Hz, 1 H), 2.68 (dd, J = 7.6,
6.8 Hz, 1 H), 2.56 (t, J = 10.4 Hz, 1 H), 2.48–2.43 (m, 4 H), 1.13 (m, 21
H).
13C NMR (150 MHz, CDCl3):  = 160.07, 141.28, 139.13, 134.68,
133.05, 129.41, 129.25, 128.03, 126.13, 113.40, 112.10, 102.97, 94.94,
58.72, 58.60, 56.06, 45.49, 32.33, 29.71, 18.69, 11.40.
MS: m/z (%) = 434 (37), 433 (M+, 100), 432 (29), 419 (25), 418 (81),
405 (13), 403 (11), 402 (33), 391 (23), 390 (67), 375 (11), 374 (13),
362 (15), 360 (11), 349 (10), 348 (38), 347 (29), 334 (13), 333 (24),
332 (54), 320 (21), 319 (10), 305 (21), 304 (21), 291 (20), 290 (52),
289 (39), 287 (10), 277 (18), 276 (14), 275 (19), 263 (23), 262 (21),
261 (20), 249 (13), 248 (10), 247 (18), 229 (12), 215 (15), 207 (15),
203 (10), 202 (20), 166 (13), 159 (22), 152 (20), 145 (29), 144 (11),
138 (28), 137 (10), 130 (23), 129 (12), 124 (16), 123 (20), 115 (12), 73
(17), 59 (22), 57 (11), 44 (31).
HRMS (DART): m/z (5a + 5b) calcd for C21H30NOSi [M + H+]: 340.2091;
found: 340.2093.
Nickel-Catalyzed Phenylation of 14a
In a nitrogen-filled glovebox, Ni(OAc)2 (5.5 mg, 0.030 mmol, 0.15
equiv), ICy·HBF4 (12.8 mg, 0.040 mmol, 0.20 equiv), and 1.0 M PhMg-
Br in THF (0.30 mL, 0.30 mmol, 1.5 equiv) were added to a 10 mL
screw-capped vial. After removing all volatiles, 1 (56.7 mg, 0.20
mmol, 1.0 equiv) and toluene (1.0 mL) were added and the vial was
sealed with the cap. The vial was then removed from the glovebox.
The resulting mixture was stirred at 80 °C for 18 h. After allowing the
reaction mixture to cool to rt, the solvent was removed and the resi-
due was purified by flash column chromatography over silica gel
(CHCl3/MeOH) to give phenylated buflavine 6 as a 1:1 mixture of re-
gioisomers (determined by 1H NMR).
3-Methoxy-6-methyl-2-phenyl-5,6,7,8-tetrahydrodibenzo[c,e]-
HRMS (DART): m/z calcd for C28H40NOSi [M + H+]: 434.2874; found:
azocine and Its Regioisomer (6)
Yield: 20.2 mg (31%); colorless oil; Rf = 0.52 and 0.44 (CHCl3/MeOH
434.2877.
4:1, on silica gel).
2-Methoxy-6-methyl-3-((triisopropylsilyl)ethynyl)-5,6,7,8-tetra-
Spectroscopic data were collected with a 1:1 mixture of regioisomers.
hydrodibenzo[c,e]azocine (7b)
IR (ATR): 1219 (w), 771 (s), 719 (w), 699 (w) cm–1
.
Yield: 8.9 mg (10%); colorless oil; Rf = 0.52 (hexane/EtOAc 1:1, on NH
silica gel).
1H NMR (400 MHz, CDCl3):  = 7.61–7.56 (m, 5 H), 7.45–7.24 (m, 15
H), 7.01 (s, 1 H), 6.91 (s, 1 H), 3.90 (s, 3 H), 3.83 (s, 3 H), 3.62 (t, J = 12.6
Hz, 2 H), 3.32–3.25 (m, 2 H), 3.16 (dd, J = 13.5, 1.2 Hz, 2 H), 2.65–2.50
(m, 9 H), 2.47 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 155.9, 155.3, 141.4, 141.2, 140.9,
140.1, 139.7, 138.1, 137.9, 133.7, 133.2, 131.8, 129.8, 129.7, 129.54,
129.51, 129.4, 129.2, 129.1, 128.2, 127.98, 127.96, 127.8, 127.0, 126.1,
113.3, 112.0, 58.9, 58.8, 58.4, 57.5, 55.7, 55.6, 46.2, 44.9, 32.8, 32.1.
1H NMR (400 MHz, CDCl3):  = 7.47 (s, 1 H), 7.37–7.35 (m, 1 H), 7.29–
7.23 (m, 3 H), 6.77 (s, 1 H), 3.87 (s, 3 H), 3.53 (d, J = 13.6 Hz, 1 H), 3.24
(dd, J = 8.4, 6.8 Hz, 1 H), 3.03 (d, J = 13.6 Hz, 1 H), 2.69 (dd, J = 8.4, 6.8
Hz, 1 H), 2.54–2.45 (m, 5 H), 1.15 (m, 21 H).
13C NMR (150 MHz, CDCl3):  = 159.56, 142.07, 141.29, 139.94,
136.39, 129.57, 128.88, 128.45, 127.17, 112.42, 111.75, 102.90, 95.29,
58.48, 57.26, 56.02, 45.34, 32.25, 18.71, 18.68, 11.41.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H

F
R. Shimazumi et al.
Special Topic
Synthesis
MS: m/z (%) = 434 (32), 433 (M+, 100), 432 (58), 419 (11), 418 (33),
391 (13), 390 (23), 348 (17), 347 (27), 333 (11), 332 (31), 319 (10),
305 (22), 304 (13), 291 (19), 290 (46), 289 (25), 277 (17), 275 (12),
263 (12), 261 (10), 207 (14), 159 (13), 145 (10), 138 (12), 73 (10), 44
(18).
rt, the solvent was removed in vacuo. The residue was purified by
flash column chromatography over NH silica gel (hexane/EtOAc 1:1)
to give amine 10 as a mixture of regioisomers (10a/10b = 3:1).
N-(2-(3-Methoxy-6-methyl-5,6,7,8-tetrahydrodibenzo[c,e]azocin-
2-yl)-1-phenylethyl)aniline and Its Regioisomer (10)
HRMS (DART): m/z calcd for C28H40NOSi [M + H+]: 434.2874; found:
434.2876.
Yield: 61.4 mg (69%); pale yellow oil; Rf = 0.29 (hexane/EtOAc 1:1, on
NH silica gel).
Addition of 5 to Aldehyde9a
Spectroscopic data were collected with a 3:1 mixture of regioisomers.
Each regioisomer of 10 exists as a mixture of two diastereomers,
probably based on the axial chirality of the restricted biaryl moiety.15
To a nitrogen-filled 10 mL screw-capped vial, 5 (5a/5b = 3:1; 64.5 mg,
0.19 mmol) and 4-bromobenzaldehyde (74.0 mg, 0.40 mmol, 2.0
equiv) were added. THF (2.0 mL) was added. To the resulting mixture,
4 Å MS (200 mg) were added and the reaction was then stirred at rt
for several minutes. TBAT (54.9 mg, 0.10 mmol, 0.50 equiv) was added
and the vial was sealed with a cap. The mixture was stirred at 70 °C
overnight. After cooling to rt, the solvent was removed in vacuo. The
residue was purified by flash column chromatography over silica gel
(CHCl3/MeOH 19:1 to 4:1) and over NH silica gel (hexane/EtOAc 1:1 to
EtOAc 100%) to give alcohol 9 as a mixture of regioisomers (9a/9b =
3:1).
IR (ATR): 1219 (w), 772 (s), 719 (w) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.47–7.22 (m, 8 H, 10a and 9 H, 10b),
7.12–7.01 (m, 3 H, 10a and 10b), 6.91–6.86 (m, 2 H, 10a), 6.77 (d, J =
4.8 Hz, 1 H, 10b), 6.60–6.57 (m, 1 H, 10a and 10b), 6.45–6.39 (m, 2 H,
10a and 10b), 4.94–4.65 (m, 1 H, 10a and 10b), 4.56–4.55 (m, 1 H, 10a
and 10b), 4.00 and 3.98 (s, 3 H, 10a), 3.92 and 3.91 (s, 3 H, 10b), 3.52
(d, J = 13.2 Hz, 1 H, 10a and 10b), 3.26–2.95 (m, 4 H, 10a and 10b),
2.72–2.32 (m, 6 H, 10a and 10b).
13C NMR (101 MHz, CDCl3):  = 157.1, 157.0, 156.4, 147.7, 147.63,
147.58, 144.3, 144.1, 144.0, 141.3, 141.2, 140.32, 140.29, 140.11,
140.08, 139.7, 139.6, 137.3, 137.2, 134.1, 133.9, 133.0, 132.9, 132.3,
132.1, 129.44, 129.36, 129.3, 129.1, 129.0, 128.91, 128.88, 128.6,
128.5, 128.4, 128.1, 127.8, 126.84, 126.78, 126.4, 126.33, 126.26,
126.03, 125.98, 125.9, 125.8, 116.8, 116.7, 113.3, 113.2, 113.13,
113.09, 112.6, 111.4, 111.3, 59.8, 59.52, 59.50, 59.0, 58.84, 58.81,
58.75, 58.68, 58.3, 57.2, 55.4, 46.2, 46.1, 44.6, 40.0, 39.7, 39.6, 32.7,
32.6, 31.8.
1-(4-Bromophenyl)-2-(3-methoxy-6-methyl-5,6,7,8-tetrahydro-
dibenzo[c,e]azocin-2-yl)ethan-1-ol and Its Regioisomer (9)
Yield: 54.3 mg (63%); colorless solid; mp 98.0–107.2 °C; Rf = 0.44
(CHCl3/MeOH 4:1, on silica gel).
Spectroscopic data were collected with a 3:1 mixture of regioisomers.
Each regioisomer of 9 exists as a mixture of two diastereomers, prob-
ably based on the axial chirality of the restricted biaryl moiety.15
IR (ATR): 1219 (w), 771 (s) cm–1
.
MS: m/z (%) (10a + 10b) = 448 (M+, 0), 267 (43), 183 (14), 182 (100),
1H NMR (400 MHz, CDCl3):  = 7.46–7.40 (m, 2 H, 9a and 9b), 7.38–
7.17 (m, 5 H, 9a and 6 H, 9b), 7.13–7.01 (m, 1 H, 9a and 9b), 6.88–6.84
(m, 2 H, 9a), 6.78 (d, J = 4.8 Hz, 1 H, 9b), 4.98–4.86 (m, 1 H, 9a and 9b),
3.90 and 3.89 (s, 3 H, 9a), 3.84 and 3.81 (s, 3 H, 9b), 3.52–3.49 (m, 1 H,
9a and 9b), 3.23–2.91 (m, 5 H, 9a and 9b), 2.70–2.61 (m, 1 H, 9a and
9b), 2.51–2.37 (m, 2 H, 9a and 9b), 2.47 (s, 3 H, 9a), 2.33 (s, 3 H, 9b).
13C NMR (101 MHz, CDCl3):  = 157.0, 156.4, 143.8, 143.7, 143.5,
143.4, 141.3, 141.1, 141.0, 140.3, 140.2, 140.0, 139.5, 137.3, 134.3,
133.0, 132.6, 132.4, 131.2, 131.11, 131.07, 129.4, 129.3, 129.1, 128.9,
128.8, 128.1, 127.8, 127.7, 127.5, 127.5, 126.0, 125.7, 125.4, 125.1,
125.0, 120.9, 120.80, 120.75, 120.7, 112.6, 111.2, 111.1, 73.54, 73.45,
73.2, 58.72, 58.66, 58.6, 58.4, 58.3, 57.5, 57.3, 55.50, 55.47, 46.0, 45.3,
44.8, 40.9, 40.8, 32.6, 32.5, 32.1, 32.0.
MS: m/z (%) = 453 (M++2, 19), 452 (16), 451 (M+, 21), 438 (19), 436
(19), 267 (27), 266 (44), 252 (26), 236 (11), 225 (12), 224 (58), 223
(100), 222 (11), 209 (20), 194 (10), 193 (45), 191 (14), 179 (27), 178
(75), 166 (10), 165 (37), 115 (11), 78 (23), 77 (44), 57 (14), 44 (40), 42
(19).
HRMS (DART): m/z calcd for C25H27NO279Br [M + H+]: 452.1219;
found: 452.1216.
104 (28), 77 (28), 44 (22).
HRMS (DART): m/z calcd for C31H33N2O [M + H+]: 449.2587; found:
449.2591.
Desilylation of 5
To a 30 mL flask, 5 (5a/5b = 3:1; 50.9 mg, 0.15 mmol) and THF (2.0
mL) were added. TBAF (1 M in THF; 0.3 mL, 0.3 mmol, 2.0 equiv) was
then added and the solution stirred at rt overnight. After stirring, the
volatiles were removed in vacuo. The residue was purified by flash
column chromatography over NH silica gel (hexane/EtOAc 3:7 to 1:1)
to give desilylated 11 as a mixture of regioisomers (11a/11b = 3:1).
3-Methoxy-2,6-dimethyl-5,6,7,8-tetrahydrodibenzo[c,e]azocine
and Its Regioisomer (11)
Yield: 31.8 mg (79%); colorless oil; Rf = 0.44 and 0.32 (hexane/EtOAc
1:1, on NH silica gel).
Spectroscopic data were collected with a 3:1 (11a/11b) mixture of
regioisomers.
IR (ATR): 1215 (m), 770 (s), 747 (s), 719 (w), 668 (w) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.37–7.21 (m, 4 H, 11a and 4 H, 11b),
7.18 (s, 1 H, 11b), 7.08 (s, 1 H, 11a), 6.85 (s, 1 H, 11a), 6.74 (s, 1 H,
11b), 3.91 (s, 3 H, 11a), 3.84 (s, 3 H, 11b), 3.55 (d, J = 13.2 Hz, 1 H,
11a), 3.54 (d, J = 13.2 Hz, 1 H, 11b), 3.29–3.23 (m, 1 H, 11a and 1 H,
11b), 3.11 (d, J = 13.2 Hz, 1 H, 11a), 3.06 (d, J = 13.2 Hz, 1 H, 11b),
2.74–2.68 (m, 1 H, 11a and 1 H, 11b), 2.57–2.48 (m, 5 H, 11a and 5 H,
11b), 2.26 (s, 3 H, 11b), 2.25 (s, 3 H, 11a).
Addition of 5 to Imine9b
To a nitrogen-filled 10 mL screw-capped vial, 5 (5a/5b = 3:1; 67.8 mg,
0.20 mmol) and benzylideneaniline (72.5 mg, 0.40 mmol, 2.0 equiv)
were added, followed by THF (2.0 mL). To the resulting mixture, 4 Å
MS (200 mg) were added and the solution was stirred at rt for several
minutes. After adding TBAT (54.9 mg, 0.10 mmol, 0.50 equiv), the vial
was sealed with a cap and stirred at 70 °C overnight. After cooling to
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H

G
R. Shimazumi et al.
Special Topic
Synthesis
13C NMR (101 MHz, CDCl3):  = 157.3, 156.7, 141.21, 141.17, 140.0,
139.0, 135.7, 133.4, 132.6, 131.6, 129.4, 129.3, 129.2, 129.0, 128.0,
127.6, 126.1, 126.0, 125.7, 112.1, 110.6, 58.8, 58.6, 58.5, 57.5, 55.4,
55.3, 45.9, 45.5, 32.5, 32.3, 15.9, 15.9.
Conflict of Interest
The authors declare no conflict of interest.
MS: m/z (%) (11a + 11b) = 268 (15), 267 (M+, 82), 266 (29), 253 (13),
252 (74), 236 (13), 225 (17), 224 (58), 223 (19), 210 (20), 209 (100),
208 (12), 194 (13), 193 (12), 190 (10), 181 (13), 179 (10), 178 (17),
166 (25), 165 (41), 44 (11).
Funding Information
This work was supported, in part, by the SEEDS program from Osaka
University.Osa
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iversiyt()
HRMS (DART): m/z (major) calcd for C18H22NO [M + H+]: 268.1696;
found: 268.1698.
Acknowledgment
Olefination of 516
We thank the Instrumental Analysis Center, Faculty of Engineering,
Osaka University, for their assistance with HRMS.
Compound 5 (5a/5b = 3:1; 67.8 mg, 0.20 mmol) and 4-chlorobenzal-
dehyde (56.2 mg, 0.40 mmol) were dissolved in THF (2.0 mL). Then, 4
Å MS (200 mg) were added to the resulting mixture and the reaction
was stirred at rt for 30 min, after which, TBAT (54.0 mg, 0.10 mmol)
was added. The mixture was stirred at 75 °C for 1 h and then cooled to
rt. After, stirring, 4 M HCl (0.10 mL) was added and the mixture was
stirred at rt for 20 min. After removing the THF under reduced pres-
sure, the residue was dissolved in toluene (2.0 mL) and p-TsOH·H2O
(152 mg, 0.80 mmol) was added. The mixture was stirred at 120 °C for
1 h, then cooled to rt and diluted with Et2O (5.0 mL). The solution was
washed with water (1.0 mL), saturated aqueous NaHCO3 (1.0 mL), and
brine (1.0 mL) in that order. The solvent was then removed in vacuo to
give a residue, which was purified by flash column chromatography
over NH silica gel (hexane 100% to hexane/EtOAc 1:1) to give 12 as a
mixture of regioisomers (12a/12b = 3:1).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1467-2494. Su
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gInformatio
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ortingInformatio
n
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(E)-2-(4-Chlorostyryl)-3-methoxy-6-methyl-5,6,7,8-tetrahydro-
dibenzo[c,e]azocine and Its Regioisomer (12)
Yield: 39.7 mg (51%); yellow oil; Rf = 0.14 and 0.16 (hexane/EtOAc 2:1,
on NH silica gel).
Spectroscopic data were collected with a 3:1 (12a/12b) mixture of re-
gioisomers.
IR (ATR): 2933 (w), 1487 (s), 1236 (w), 812 (w), 754 (s), 731 (w) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.61 (t, J = 8.0 Hz, 1 H, 12a), 7.50–7.24
(m, 8 H, 12a and 10 H, 12b), 7.18–7.14 (m, 2 H, 12b), 7.09 (d, J = 16.8
Hz, 1 H, 12a), 6.93 (s, 1 H, 12a), 6.83 (s, 1 H, 12b), 3.97 (s, 3 H, 12a),
3.91 (s, 3 H, 12b), 3.88 (d, J = 17.2 Hz, 1 H, 12b), 3.62 (d, J = 13.6 Hz, 1
H, 12b), 3.56 (d, J = 13.6 Hz, 1 H, 12a), 3.29–3.23 (m, 1 H, 12a and 1 H,
12b), 3.13 (d, J = 13.2 Hz, 1 H, 12a), 3.12 (d, J = 13.2 Hz, 1 H, 12b),
2.76–2.69 (m, 1 H, 12a and 1 H, 12b), 2.58–2.47 (m, 5 H, 12a and 4 H,
12b).
13C NMR (101 MHz, CDCl3):  = 156.40, 155.82, 141.26, 141.21,
140.04, 139.72, 138.30, 136.50, 135.87, 134.87, 133.24, 132.81,
129.83, 129.76, 129.56, 129.43, 129.27, 129.15, 128.90, 128.70,
128.28, 127.93, 127.77, 127.65, 127.30, 126.13, 125.32, 125.04,
123.58, 113.13, 111.69, 60.38, 58.82, 58.65, 58.49, 57.65, 55.60, 45.91,
45.34, 32.58, 32.23.
MS: m/z (%) (12a + 12b) = 391 (M++2, 31), 390 (32), 389 (M+, 97), 388
(24), 376 (25), 375 (18), 374 (66), 361 (10), 360 (14), 358 (22), 349
(10), 348 (35), 347 (28), 346 (100), 305 (14), 303 (37), 296 (10), 281
(16), 278 (13), 268 (34), 267 (26), 266 (12), 265 (23), 253 (28), 252
(26), 221 (11), 219 (10), 208 (11), 207 (27), 193 (11), 191 (30), 165
(11), 147 (11), 140 (15), 139 (13), 138 (15), 132 (22), 131 (14), 127
(13), 126 (27), 125 (30), 73 (16), 44 (39).
HRMS (DART): m/z calcd for C25H25NO35Cl [M + H+]: 390.1619; found:
390.1618.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H

H
R. Shimazumi et al.
Special Topic
Synthesis
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H