Chiral Synthesis of McGeachin-Type Bisaminals

Article abstract of DOI:10.1021/acs.joc.9b03362

Bridged [3.3.1]-bisaminal structures, namely 6,12-epiminodibenzo[b,f][1,5]diazocines, are herein named McGeachin-Type bisaminals. The TsOH-catalyzed chiral synthesis of McGeachin-Type bisaminals is first developed by condensation of two molecules of 2-(methylamino)benzaldehyde and one molecule of chiral amines. Two chiral diastereomers are generated simultaneously and are isolated by column chromatography in a total yield of up to 99%. The absolute structure of one stereoisomer was determined by X-ray crystallography.

Full text of DOI:10.1021/acs.joc.9b03362

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Article
Chiral Synthesis of McGeachin-type Bisaminals
Yang Chen, Siqi Li, Shili Hou, Jiaxi Xu, and Zhanhui Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03362 • Publication Date (Web): 30 Jan 2020
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The Journal of Organic Chemistry
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Chiral Synthesis of McGeachin-type Bisaminals
Yang Chen †, Siqi Li †,§, Shili Hou ⊥, Jiaxi Xu *† and Zhanhui Yang *†
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†State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, College of Chemistry, Beijing
University of Chemical Technology, Beijing 100029, P. R. China
§ Research Institute of Jilin Petrochemical Company, PetroChina, Jilin 132021, China
⊥Guangxi Key Laboratory of Electrochemical and Magnetochemical Functional Materials, College of Chemistry and Bioen-
gineering, Guilin University of Technology, Guangxi 541004, China
Supporting Information Placeholder
ABSTRACT: The bridged [3.3.1]-bisaminal structures, 6,12-epiminodibenzo[b,f][1,5]diazocines, are herein named as McGeachin-
type bisaminals. A TsOH-catalyzed chiral synthesis of McGeachin-type bisaminals is first developed by condensation of two mole-
cules of 2-(methylamino)benzaldehyde and one molecule of chiral amines. Two chiral diastereomers are generated simultaneously,
and are isolated by column chromatography in up to total 99% yields. The absolute structure of one stereoisomer was determined
by X-ray crystallography.
of o-aminobenzaldehyde or using different acid catalysts,9
Molina’s, Ukhin’s, Yu and Wang’s, and Sridharan’s groups
8
INTRODUCTION
In 1926, Seidel first claimed that a trimer and a tetramer of o-
aminobenzaldehyde were obtained, and proposed linear struc-
tures for them (Figure 1a, I and II).1 It must be noted that the-
se compounds were not first observed by Seidel.2 However, it
was Seidel that first conceived the correct composition. An
eight-membered structural proposal was subsequently pro-
posed by Bamberger in 1927 (Figure 1b, III and IV).3 In 1966,
McGeachin proposed bridged cyclic structures with two
bridged carbon atoms and one apical nitrogen atom (Figure 1c,
V and VI).4a In the same year, Albert and Yamamoto inde-
pendently proposed similar structures but with two bridged
nitrogen atoms and one apical carbon atom (Figure 1d, VII
and VIII).4b McGeachin’s structural proposal was proved cor-
rect; thus, we herein name the aminals with the structural sub-
units of iminodibenzodiazocine IX (Figure 1e) to McGeachin-
type bisaminals. In previous synthetic reports, these bases
developed different synthetic routes to McGeachin-type bis-
aminals with functionalities at the apical nitrogen (Scheme 1a).
In the above reports, primary aryl amines (ArNH2) and α-
substituted methylamines (R’CH2NH2) were used. Zonta and
Figure 1. Different structural proposals for McGeachin-type
bisaminals in history.
5a
were classified into pseudo-Troger’s bases or Troger’s base
analogues,5b although they contain different structural motifs
(Figure 1e, X). McGeachin-type bisaminals have been used as
ligand backbones in some transition metal complexes.6 Addi-
tionally, their antibacterial bioactivity was also explored by
Son and coworkers.7
There exist limited methods to synthesize McGeachin-type
bisaminals. The facile trimerization of o-aminobenzaldehyde
implies that the condensation between two molecules of o-
aminobenzaldehyde with one molecule of primary amines
constitutes an efficient method. By using different surrogates
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coworkers achieved the synthesis by a metal-free cyclization
Page 2 of 9
solvent, either under reflux conditions (entries 11-13) or in a
sealed tube (entry 14). Tetrahydrofuran (THF) and acetonitrile
were not effective (entries 15 and 16), although the latter was
used as a very good solvent in Sridharan’s work.9b Raising the
temperature gave a higher 69% yield (entry 17). The Lewis
acids explored all gave unsatisfactory yields (entries 18-24).
1
2
3
4
5
6
7
8
of 2-aminophenyl ketimines with the corresponding 2-
aminophenyl ketones as catalysts (Scheme 1b).5b In addition,
occasional observations of McGeachin-type bisaminals were
also reported by Aube,10b,c Loh,10f Menendez,10g our group,11
and others.10 However, the reported synthetic efforts all ig-
nored the stereocenters (6- and 12-positions) of McGeachin-
type bisaminals, and racemates were generated in all cases. It
is of great importance to synthesize chiral McGeachin-type
bisaminals, which may act as potential chiral catalysts or lig-
and backbones due to their unique structures.11 Herein, we
present the first chiral synthesis of McGeachin-type bisami-
nals from 2-(methylamino)benzaldehyde (1) and chiral amines
(2), giving two diastereomeric chiral products 3 and 4, which
are isolated by column chromatography (Scheme 1c).
o
Finally, heating in toluene at 150 C for 48 h in a sealed tube
with 20 mol % of TsOH·H2O gave desired products in 99%
total yield in 40:60 d.r. (entry 25). The absolute structure of 3a
was determined by XRD analysis.
9
Scheme 2. Reaction of o-aminobenzaldehyde with (S)-1-
phenylethylamine.
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Scheme 1. Previous racemic syntheses and present chiral syn-
theses.
Table 1. Optimization of reaction conditions
Yield
(%)a
0
Temp.
(oC)
Entry Cat.
Ratiob
1c
-
125
125
125
125
125
125
125
125
125
125
rfx
-
2c
PPTS
0
-
RESULTS AND DISCUSSION
3c
PhCO2H
0
-
We first tried the reaction of o-aminobenzaldehyde (5) with
(S)-1-phenylethylamine (2a). (Scheme 2). After heating 5 and
2a in toluene at 125 oC in a sealed tube for 12 h, desired prod-
uct 6 and undesired trimer 7 were observed, together with an
imine product (see Figures S1–S4 in the Supporting Infor-
mation). However, products 6 and 7 could not be isolated. In
Yu and Wang’s work,9a the reactions of o-aminobenzaldehyde
(5) with arylamines (ArNH2) gave fused aminals that were
formally derived from trimer 7 and arylamines, while the reac-
tions with α-substituted methylamines (R’CH2NH2) gave
McGeachin-type bisaminals. Based on their results, we postu-
lated that the steric effect of the secondary alkyl group (1-
phenylethyl) in amine 2a disfavored the formation of 6. To
improve the chemoselectivity toward desired products, we
must suppress the undesired trimerization. Pleasingly, Sri-
dharan’s work provided us a good solution by adding an alkyl
group to the amino group of o-aminobenzaldehyde.9b So 2-
(methylamino)benzaldehyde (1) was selected as the model
substrate to perform the condition optimization (Table 1). Di-
rect condensation of 1 and 2a in the presence of MgSO4 as
desiccant did not give any product (entry 1). Initial screening
of a number of Bronsted acids (entries 1-9) revealed that
TsOH·H2O was optimal. Without addition of MgSO4, the
4c
CSA
0
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5c
Et3N·HCl
4-ClC5H4N·HCl
CF3CO2H
TsOH·H2O
4-O2NC6H4CO2H
TsOH·H2O
TsOH·H2O
4-O2NC6H4CO2H
2,4-(O2N)2C6H3CO2H
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
Sc(OTf)3
0
-
6c
0
-
7c
0
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8c
52
21
51
17
2
41:59
42:58
41:59
41:59
50:50
46:54
43:57
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9c
10
11d
12d
13d
14e
15f
16g
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rfx
rfx
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23
0
150
100
100
150
150
150
150
150
150
0
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69
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21
9
40:60
43:57
43:57
44:56
42:58
45:55
Yb(OTf)3
ZnCl2
FeCl3
24
9
yield was not affected (entry 10 vs entry 8). In contrast to Zon-
5b
ta’s
and Bergman’s work,10e xylenes were not a suitable
AlCl3
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Cu(OTf)2
PhB(OH)2
150
150
150
17
0
47:53
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cases, no MgSO4 was added. dXylenes as solvent, and reaction
e
1
2
3
4
5
6
7
refluxed in open air for 10 h. Xylenes as solvent in a sealed
24
25 h
h
tube. fTHF as solvent. gMeCN as solvent. Reaction time 48 h.
TsOH·H2O
99
40:60
PPTS = Pyridinium p-toluenesulfonate; CSA = Camphorsul-
fonic acid; rfx = reflux.
aDetermined by H NMR of the crude reaction mixtures with
4-nitroiodobenzene as an internal standard. Ratio of 3a:4a
determined by H NMR of the crude reaction mixtures. In
these cases, 1.5 equiv of MgSO4 was added, while in the rest
1
b
1
c
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Table 2. Preparation of various chiral McGeachin-type bisaminalsa
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1
aIsolated yields after column chromatography, and the d.r. values were determined by the H NMR of the crude reaction mixtures.
bYields in the parentheses were obtained from 1-mmol scale reactions. c1 equiv of triethylamine to chiral amine was added.
Various McGeachin-type bisaminals were prepared under
the optimal conditions from chiral amines and 2-
(methylamino)benzaldehyde (1) (Table 2). The reaction of S-
1-phenylethylamine (2a) gave (6R,12R,1’S)-3a and its dia-
stereomer (6S,12S,1’S)-4a in 37 and 53% yields, respectively.
By using (R)-1-phenylethylamine (2b) as chiral source,
2
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(6S,12S,1’R)-3b and its diastereomer (6R,12R,1’R)-4b were
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(PhMgBr or MeMgBr) failed (Scheme 4b). We also tried to
remove the chiral (S)-1-phenylethyl auxiliary with Pd/C-H2 or
1-chloroethyl chloroformate,12 but the results were not so sat-
isfactory (Scheme 4c). The thermal equilibrium between the
two chiral diastereomers were investigated (Scheme 4d).
Treating 3f under optimal conditions gave a mixture of 3f and
4f in 43:57 ratio, while the same treatment of 4f gave a mix-
ture in 45:55 ratio. Similar diastereomeric ratios were also
observed in Table 1 and Table 2. Thus, the diastereoselectivity
in the chiral synthesis of McGeachin-type bisaminals is proba-
bly thermodynamically controlled. The results in Scheme 1d
also implied that once the chiral auxiliary was removed, race-
mization might occur under acidic conditions. Molina and
1
2
3
4
5
6
7
8
synthesized in 44 and 55% yields, respectively. Notably, 3a
and 3b, and 4a and 4b are two pairs of enantiomers. Similar
results were also obtained from the reactions of chiral amines
2c-h, with desired products isolated in 54-99% total yields and
around 45:55 d.r. values. The lower total yields of 3c and 4c
(54%), and 3h and 4h (56%) were attributed to the very close
polarity of the diastereomeric products during the purification
by column chromatography. Sterically larger (S)-1-
phenylpropan-1-amine (2i) also readily underwent the cascade
reaction to deliver (6R,12R,1’S)-3i and (6S,12S,1’S)-4i in total
90% yields. Methyl L-phenylalaninate (2j) and methyl L-
methioninate (2k) were also suitable substrates to prepare the
corresponding McGeachin-type bisaminals, although the de-
sired products were obtained in moderate yields.
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coworkers first observed the racemization of
a chiral
McGeachin-type bisaminal.5a In a gram-scale synthesis, de-
sired products 3e and 4e were isolated in 33% (0.50 g) and 40%
(0.62 g) yields, respectively (Scheme 4e).
When N-allyl aldehyde (8) was used, imine 9 was observed
predominantly (Scheme 3). Desired McGeachin-type products
(3l and 4l) were only isolated in a trace amount, and were
identified by HRMS analysis. This reaction indicated the
strong steric effect of the N-alkyl group on the chiral synthesis.
A tentative mechanism for the chiral synthesis of McGeachin-
type bisaminals is proposed (Scheme 5). Proton-catalyzed
condensation between 2-(methylamino)benzaldehyde (1) and
chiral amine 2 gives an iminium intermediate A. Subsequent
addition of a second molecular of 1 to A might occur from
either Re or Si face of the iminium moiety. The Re addition
delivers ammonium B1, while the Si addition gives B2.
Through the same sequence of intramolecular proton transfer
(C1 and C2), amine-aldehyde condensation (D1 and D2),
amine-iminium addition and deprotonation, B1 and B2 finally
evolve to 3 and 4, respectively. We suggest that the Si or Re
addition of 1 to A is the diastereo-determining step, although
the d.r. values are ultimately regulated by a thermodynamical
control. The thermal equilibrium investigation in Scheme 4d
indicated that the reaction might be reversible. According to
the mechanism, pure 3f or 4f go reversely through the se-
quence (from D1 or D2 to A) to regenerate intermediate A,
which then go through the sequence (from A to 3 and 4) a
second time to reproduce a mixture of 3f and 4f in almost
identical ratios (substrate 2f in Table 2 vs Scheme 4d).
Scheme 3. Reaction of o-(allylamino)benzaldehyde
Scheme 4. Further manipulations and Gram-scale Synthesis
Scheme 5. Proposed mechanism
The current protocol is also applicable to the synthesis of
racemic McGeachin-type bisaminals from aryl and alkyl
amines. For example, under the optimal conditions, the reac-
tions of p-tolylamine (11a) and methyl glycinate hydrochlo-
Further modification of the synthesized McGeachin-type
bisaminals were performed. The Suzuki coupling of 3f gave
desired product 10 in 72% yield (Scheme 4a). However, modi-
fication of the ester group of 3j with Grignard reagents
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ride (11b) delivered desired products 12a and 12b in 70% and
To a heavy-wall reaction tube charged with a magnetic stirring
bar was sequentially added 2-(methylamino)benzaldehyde (1)
(68 mg, 0.5 mmol), amine 2 (0.25 mmol), triethylamine (0.25
mmol, only for 2j, 2k, and 11b), TsOH·H2O (9.5 mg, 0.1
mmol), and dry toluene (2.5 ml). Then the tube was sealed by
a polytetrafluoroethylene screw cap, and was immersed into a
1
2
3
4
5
6
7
8
61% isolated yields, respectively (Scheme 6).
Scheme 6. TsOH-catalyzed synthesis of racemic McGeachin-
type bisaminals from aryl and alkyl amines
o
preheated 150 C heating-mantle for 48 h. The solvent was
removed under reduced pressure. The crude residue was puri-
fied by silica gel column chromatography to give a pair of
diastereomers 3 and 4.
9
(6R,12R)-5,11-Dimethyl-13-((S)-1-phenylethyl)-5,6,11,12-
tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine (3a)
10
11
12
13
14
15
16
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Yield: 32.9 mg (37%); white solid, m.p.: 166–168 °C; Rf =
0.50 (PE:EA = 5:1, v/v); [α]2D5 = 79.1 (c, 1.0, CH2Cl2). 1H NMR
(400 MHz, CDCl3, δ): 7.43–7.30 (m, 5H), 7.12 (ddd, J = 8.5,
7.4, 1.6 Hz, 2H), 6.97 (dd, J = 7.4, 1.6 Hz, 2H), 6.66–6.57 (m,
4H), 4.75 (s, 2H), 3.67 (q, J = 6.5 Hz, 1H), 2.90 (s, 6H), 1.49
(d, J = 6.5 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3, δ):
143.6, 143.5, 128.7, 128.4, 127.8, 127.5, 127.3, 71.6, 56.8,
CONCLUSION
In summary, we have developed a TsOH-catalyzed chiral
synthesis of McGeachin-type bisaminals from 2-
(methylamino)benzaldehyde and chiral amines. A pair of chi-
ral diastereomers are generated simultaneously in about 40:60
d.r.. The two diastereomers are isolated by column chromatog-
raphy in up to 99% yields. The steric hindrance between the
secondary N-alkyl of chiral amine and the N-alkyl of 2-
(alkylamino)benzaldehyde is crucial to the occurrence of the
chiral condensation. Preliminary results show that the
McGeachin-type bisaminals show very weak nucleophilicity
and basicity. We hope the unique bridged cyclic structures of
our synthesized chiral McGeachin-type bisaminals will enable
their applications as chiral catalyst or ligand backbones in the
future.
+
36.2, 21.1. HRMS (ESI) m/z: [M + H]+ calcd for C24H26N3 ,
356.2121; found, 356.2115.
(6S,12S)-5,11-Dimethyl-13-((S)-1-phenylethyl)-5,6,11,12-
tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine (4a)
Yield: 47.0 mg (53%); white solid, m.p.: 148–150 °C; Rf =
1
0.50 (PE:EA = 5:1, v/v); [α]2D5 = -145.7 (c, 1.0, CH2Cl2). H
NMR (400 MHz, CDCl3, δ): 7.41–7.29 (m, 5H), 7.16–7.09 (m,
2H), 7.01 (dd, J = 7.4, 1.6 Hz, 2H), 6.66 (t, J = 7.3 Hz, 2H),
6.60 (d, J = 8.2 Hz, 2H), 4.81 (s, 2H), 3.64 (q, J = 6.5 Hz, 1H),
2.95 (s, 6H), 1.52 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3, δ): 143.9, 128.6, 128.5, 127.7, 127.5, 127.2,
120.7, 116.4, 111.8, 71.6, 57.1, 36.4, 21.8. HRMS (ESI) m/z:
EXPERIMENTAL SECTION
General Information
All the reactions were performed in dry toluene under nitrogen
atmosphere, and the reaction tubes were flame-dried prior to use.
Column chromatography was performed on silica gel (200–300
mesh) from Anhui Liangchen silicon source material Co., Ltd,
+
[M + H]+ calcd for C24H26N3 , 356.2121; found, 356.2128.
(6S,12S)-5,11-Dimethyl-13-((R)-1-phenylethyl)-5,6,11,12-
tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine (3b)
Yield: 39.0 mg (44%); white solid; m.p.: 97–100 °C; Rf =
1
0.50 (PE:EA = 5:1, v/v); [α]2D5 = -71.8 (c, 1.0, CH2Cl2). H
o
and petroleum ether (PE, b.p. 60–90 C) and ethyl acetate (EA,
NMR (400 MHz, CDCl3, δ): 7.43–7.28 (m, 5H), 7.16–7.09 (m,
2H), 6.97 (dd, J = 7.4, 1.6 Hz, 2H), 6.67–6.56 (m, 2H), 4.75 (s,
2H), 3.67 (q, J = 6.5 Hz, 1H), 2.91 (s, 6H), 1.49 (d, J = 6.5 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3, δ): 143.5, 128.7, 128.4,
127.9, 127.5, 127.3, 120.2, 116.2, 111.5, 71.6, 56.7, 36.2, 21.1.
commercially received) were used as eluents. Reactions were
monitored by thin-layer chromatography on silica gel from Anhui
Liangchen silicon source material Co., Ltd. The plates were visu-
alized under UV light. Melting points were obtained on a melting
point apparatus and were uncorrected. The specific rotation analy-
sis was measured by Anton Paar MCP200 Pa polarimeter. 1H and
13C NMR spectra were recorded on a Bruker 400 MHz spectrome-
ter in CDCl3 with TMS as an internal standard, and the chemical
shifts (δ) were reported in part(s) per million (ppm). The high-
resolution mass analyses were performed under ESI ionization
using a Thermoscientific Q Exactive spectrometer (only for 12a
and 12b) and an Agilent LC/MSD TOF mass spectrometer. The
GC-MS analyses were performed on a Thermo Sscientific tandem
equipment.
+
HRMS (ESI) m/z: [M + H]+ calcd for C24H26N3 , 356.2121;
found, 356.2122.
(6R,12R)-5,11-dimethyl-13-((R)-1-phenylethyl)-5,6,11,12-
tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine (4b)
Yield: 48.8 mg (55%); white solid; m.p.: 134–136 °C; Rf =
1
0.50 (PE:EA = 3:1, v/v); [α]2D5 = 137.5 (c, 1.0, CH2Cl2). H
NMR (400 MHz, CDCl3, δ): 7.38–7.23 (m, 5H), 7.09 (td, J =
7.6, 1.6 Hz, 2H), 6.97 (dd, J = 7.4, 1.6 Hz, 2H), 6.62 (td, J =
7.4, 1.1 Hz, 2H), 6.56 (dd, J = 8.2, 1.1 Hz, 2H), 4.78 (s, 2H),
3.61 (q, J = 6.5 Hz, 1H), 2.91 (s, 6H), 1.48 (d, J = 6.5 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3, δ): 143.9, 128.6, 128.45,
127.7, 127.5, 127.2, 120.7, 116.4, 111.8, 71.56, 57.1, 36.4,
All the chiral amines were commercially available. 2-
(Methylamino)benzaldehyde
(2)13
and
2-
(allylamino)benzaldehyde (8)14 were prepared according to pub-
1
lished procedures, and their H NMR spectra were identical with
those reported.
+
General Procedure for Synthesis of McGeachin-type bisami-
nals
21.8. HRMS (ESI) m/z: [M + H]+ calcd for C24H26N3 ,
356.2121; found, 356.2130.
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(6R,12R)-13-((S)-1-(4-methoxyphenyl)ethyl)-5,11-
dimethyl-5,6,11,12-tetrahydro-6,12-
epiminodibenzo[b,f][1,5]diazocine (3c)
Page 6 of 9
Yield: 41.8 mg (43%); yellow solid; m.p.: 191–193 °C; Rf =
0.60 (PE:EA = 5:1, v/v); [α]2D5 = 36.1 (c, 1.0, CH2Cl2). 1H NMR
(400 MHz, CDCl3, δ): 7.38–7.30 (m, 4H), 7.16–7.08 (m, 2H),
6.97 (dd, J = 7.5, 1.5 Hz, 2H), 6.64 (td, J = 7.4, 1.1 Hz, 2H),
6.59 (d, J = 8.2 Hz, 2H), 4.72 (s, 2H), 3.67 (q, J = 6.5 Hz, 1H),
2.91 (s, 6H), 1.45 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3, δ): 143.4, 142.3, 132.9, 129.2, 128.2, 1286,
127.5, 120.0, 116.4, 111.6, 71.5, 56.1, 36.2, 21.1. HRMS (ESI)
1
2
3
4
5
6
7
8
Yield: 21.2 mg (22%); white solid; m.p.: 138–140 °C; Rf =
0.50 (PE:EA = 5:1, v/v); [α]2D5 = 23.5 (c, 0.8, CH2Cl2). 1H NMR
(400 MHz, CDCl3, δ): 7.33–7.27 (m, 2H), 7.13–7.06 (m, 2H),
6.95 (dd, J = 7.4, 1.6 Hz, 2H), 6.90–6.84 (m, 2H), 6.64 – 6.53
(m, 4H), 4.72 (s, 2H), 3.83 (s, 3H), 3.60 (q, J = 6.5 Hz, 1H),
2.89 (s,6H), 1.45 (d, J = 6.4 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3, δ): 158.8, 143.5, 135.7, 129.0, 128.7, 127.5,
120.2, 116.2, 113.7, 111.5, 71.6, 56.0, 55.3, 36.2, 21.1. HRMS
(ESI) m/z: [M + H]+ calcd for C25H28N3O+, 386.2227; found,
386.2221.
m/z: [M + H]+ calcd for C24H25ClN3 , 390.1732 found,
390.1735.
+
9
10
11
12
13
14
15
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19
20
21
22
23
24
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26
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36
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(6S,12S)-13-((S)-1-(4-Chlorophenyl)ethyl)-5,11-dimethyl-
5,6,11,12-tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine
(4e)
(6S,12S)-13-((S)-1-(4-Methoxyphenyl)ethyl)-5,11-
dimethyl-5,6,11,12-tetrahydro-6,12-epiminodibenzo
[b,f][1,5]diazocine (4c)
Yield: 53.4 mg (55%); white solid; m.p.: 129–132 °C; Rf =
1
0.70 (PE:EA = 5:1, v/v); [α]2D5 = -158.7 (c, 1.0, CH2Cl2). H
NMR (400 MHz, CDCl3, δ): 7.31 (s, 4H), 7.13 (td, J = 8.6, 1.5
Hz, 2H), 7.00 (d, J = 7.6 Hz, 2H), 6.66 (t, J = 7.6 Hz, 2H),
6.60 (d, J = 8.2 Hz, 2H), 4.77 (d, J = 1.7 Hz, 2H), 3.62 (qd, J =
6.5, 1.6 Hz, 1H), 2.94 (s, 6H), 1.48 (d, J = 6.5, 3H). 13C{1H}
NMR (101 MHz, CDCl3, δ): 143.8, 143.2, 132.7, 128.8, 128.7,
128.7, 127.7, 120.5, 116.5, 111.8, 71.6, 56.6, 36.3, 21.8.
Yield: 30.8 mg (32%); white solid; m.p.: 138–140 °C; Rf =
1
0.50 (PE:EA = 5:1, v/v); [α]2D5 = -80.2 (c, 0.48, CH2Cl2). H
NMR (400 MHz, CDCl3, δ): 7.26–7.22 (m, 2H), 7.09 (td, J =
8.0, 1.5 Hz, 2H), 6.97 (dd, J = 7.5, 1.6 Hz, 2H), 6.88–6.82 (m,
2H), 6.62 (td, J = 7.4, 1.1 Hz, 2H), 6.56 (d, J = 8.2 Hz, 2H),
4.77 (s, 2H), 3.81 (s, 3H), 3.55 (t, J = 6.5 Hz, 1H), 2.92 (s, 6H),
1.47 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3, δ):
158.7, 143.9, 136.5, 128.6, 128.5, 127.7, 120.7, 116.4, 113.8,
111.8, 71.5, 56.3, 55.2, 36.4, 21.7. HRMS (ESI) m/z: [M +
H]+ calcd for C25H28N3O+, 386.2227; found, 386.2235.
+
HRMS (ESI) m/z: [M + H]+ calcd for C24H25ClN3 , 390.1732;
found, 390.1730.
(6S,12S)-13-((R)-1-(4-Bromophenyl)ethyl)-5,11-dimethyl-
5,6,11,12-tetrahydro-6,12-
epiminodibenzo[b,f][1,5]diazocine(3f)
(6R,12R)-5,11-Dimethyl-13-((S)-1-(p-tolyl)ethyl)-
5,6,11,12-tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine
(3d)
Yield: 41.1 mg (38%); white solid; m.p.: 203–205 °C; Rf =
1
0.55 (PE:EA = 3:1, v/v); [α]2D5 = -24.5 (c, 1.0, CH2Cl2). H
NMR (400 MHz, CDCl3, δ): 7.53–7.44 (m, 2H), 7.31–7.26 (m,
2H), 7.15–7.09 (m, 2H), 6.97 (dd, J = 7.4, 1.6 Hz, 2H), 6.63
(td, J = 7.4, 1.1 Hz, 2H), 6.58 (d, J = 8.3 Hz, 2H), 4.72 (s, 2H),
3.65 (q, J = 6.5 Hz, 1H), 2.90 (s, 6H), 1.44 (d, J = 6.5 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3, δ): 143.4, 142.8, 131.6 ,
129.6, 128.8, 127.5, 121.0, 120.0, 116.4, 111.6, 71.5, 56.2,
Yield: 32.3 mg (35%); yellow solid; m.p.: 130–132 °C; Rf =
0.50 (PE:EA = 5:1, v/v); [α]2D5 = 55.8 (c, 0.4, CH2Cl2). 1H NMR
(400 MHz, CDCl3, δ): 7.29 (d, J = 8.0 Hz, 2H), 7.16 (d, J =
7.8 Hz, 2H), 7.11 (td, J = 8.8, 1.6 Hz, 2H), 6.62 (td, J = 7.4,
1.1 Hz, 2H), 6.58 (dd, J = 8.2, 1.0 Hz, 4H), 4.75 (s, 2H), 3.63
(q, J = 6.5 Hz, 1H), 2.90 (s, 6H), 2.38 (s, 3H), 1.47 (d, J = 6.5
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3, δ): 143.5, 140.6,
136.9, 129.1, 128.7, 127.8, 127.5, 120.2, 116.2, 111.5, 71.6,
56.4, 36.2, 21.2. HRMS (ESI) m/z: [M + H]+ calcd for
+
36.2, 21.1. HRMS (ESI) m/z: [M + H]+ calcd for C24H25BrN3 ,
434.1226; found, 434.1221.
(6R,12R)-13-((R)-1-(4-Bromophenyl)ethyl)-5,11-dimethyl-
5,6,11,12-tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine
(4f)
+
C25H28N3 , 370.2278; found, 370.2277.
(6S,12S)-5,11-Dimethyl-13-((S)-1-(p-tolyl)ethyl)-5,6,11,12-
tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine (4d)
Yield: 66.0 mg (61%); yellow solid; m.p.: 165–167 °C; Rf =
1
0.75 (PE:EA = 5:1, v/v); [α]2D5 = 165.0 (c, 1.0, CH2Cl2). H
NMR (400 MHz, CDCl3, δ): 7.48–7.42 (m, 2H), 7.29–7.22 (m,
2H), 7.15–7.09 (m, 2H), 7.00 (dd, J = 7.5, 1.6 Hz, 2H), 6.65
(td, J = 7.4, 1.1 Hz, 2H), 6.59 (d, J = 8.2 Hz, 2H), 4.76 (s, 2H),
3.60 (d, J = 6.5 Hz, 1H), 2.94 (s, 6H), 1.47 (d, J = 6.5 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3, δ): 143.9, 143.8, 131.7,
129.3, 128.8, 127.8, 120.9, 120.5, 116.6, 111.9, 71.6, 56.7,
Yield: 50.7 mg (55%); yellow solid; m.p.: 54–56 °C; Rf =
1
0.50 (PE:EA = 3:1, v/v); [α]2D5 = -151.3 (c, 0.6, CH2Cl2). H
NMR (400 MHz, CDCl3, δ): 7.24–7.20 (m, 2H), 7.14–7.06 (m,
4H), 6.97 (dd, J = 7.4, 1.6 Hz, 2H), 6.62 (td, J = 7.4, 1.1 Hz,
2H), 6.56 (dd, J = 8.2, 1.1 Hz, 2H), 4.78 (s, 2H), 3.57 (q, J =
6.5 Hz, 1H), 2.92 (s, 6H), 2.35 (s, 3H), 1.47 (d, J = 6.5 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3, δ): 143.9, 141.5, 136.7,
129.1, 128.6, 127.7, 127.4, 120.7, 116.4, 111.7, 71.5, 56.7,
36.4, 21.8, 21.1. HRMS (ESI) m/z: [M + H]+ calcd for
+
36.4, 21.8. HRMS (ESI) m/z: [M + H]+ calcd for C24H25BrN3 ,
434.1226; found, 434.1226.
(6R,12R)-5,11-Dimethyl-13-((S)-1-(naphthalen-2-yl)ethyl)-
5,6,11,12-tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine
(3g)
+
C25H28N3 , 370.2278; found, 370.2283.
(6R,12R)-13-((S)-1-(4-Chlorophenyl)ethyl)-5,11-dimethyl-
5,6,11,12-tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine
(3e)
Yield: 31.4 mg (31%); white solid; m.p.: 68–70 °C; Rf =
1
0.65 (PE:EA = 5:1, v/v); [α]2D5 = 23.3 (c, 0.54, CH2Cl2). H
NMR (400 MHz, CDCl3, δ): 7.87–7.79 (m, 4H), 7.59 (dd, J =
8.4, 1.7 Hz, 1H), 7.48 (dd, J = 6.2, 3.2 Hz, 2H), 7.11 (td, J =
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The Journal of Organic Chemistry
8.4, 1.6 Hz, 2H), 6.92 (dd, J = 7.4, 1.6 Hz, 2H), 6.64–6.57 (m,
= 10.3, 3.7 Hz, 2H), 2.88 (s, 6H), 2.09 (ddq, J = 18.4, 11.2, 3.6
Hz, 1H), 1.84 (ddq, J = 13.2, 10.1, 7.5 Hz, 1H), 0.62 (t, J = 7.4
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3, δ): 143.6, 141.1,
128.9, 128.7, 128.2, 127.5, 127.3, 120.4, 116.2, 111.5, 71.8,
63.5, 36.2, 26.4, 10.6. HRMS (ESI) m/z: [M + H]+ calcd for
1
2
3
4
5
6
7
8
4H), 4.77 (s, 2H), 3.83 (q, J = 6.5 Hz, 1H), 2.89 (s, 6H), 1.54
(d, J = 6.5 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3, δ):
143.5, 141.3, 133.5, 133.1, 128.8, 128.31 , 127.9, 127.7, 127.5,
126.7, 126.0, 125.9, 125.8, 120.2, 116.4, 111.6, 71.7, 56.9,
+
+
36.6, 21.2. HRMS (ESI) m/z: [M + H]+ calcd for C28H28N3 ,
C25H28N3 , 370.2278; found, 370.2278.
406.2278; found, 406.2279.
(6S,12S)-5,11-Dimethyl-13-((S)-1-phenylpropyl)-5,6,11,12-
tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine (4i)
(6S,12S)-5,11-dimethyl-13-((S)-1-(naphthalen-2-yl)ethyl)-
5,6,11,12-tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine
(4g)
9
Yield: 54.5 mg (59%); yellow solid; m.p.: 98–100 °C; Rf =
1
0.50 (PE:EA = 5:1, v/v); [α]2D5 = -71.8 (c, 1.0, CH2Cl2). H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield: 56.7 mg (56%); yellow solid; m.p.: 66–68 °C; Rf =
NMR (400 MHz, CDCl3, δ): 7.34–7.27 (m, 5H), 7.09 (td, J =
8.2, 7.8, 1.6 Hz, 2H), 6.97 (dd, J = 7.4, 1.6 Hz, 2H), 6.63 (t, J
= 7.4, 2H), 6.57 (d, J = 8.2 Hz, 2H), 4.79 (s, 2H), 3.42 (dd, J =
9.5, 3.8 Hz, 1H), 2.92 (s, 6H), 2.09 (ddq, J = 19.2, 11.6, 4.0
Hz, 1H), 1.86–1.72 (m, 1H), 0.64 (t, J = 7.4 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3, δ): 144.0, 141.8, 128.6, 128.2, 127.7,
127.2, 120.8, 116.4, 111.8, 71.7, 63.1, 36.5, 26.4, 10.2. HRMS
1
0.50 (PE:EA = 5:1, v/v); [α]2D5 = -106.1 (c, 0.28, CH2Cl2). H
NMR (400 MHz, CDCl3, δ): 7.87–7.77 (m, 3H), 7.73 (s, 1H),
7.61 (dd, J = 8.5, 1.7 Hz, 1H), 7.48 (dd, J = 6.2, 3.3 Hz, 2H),
7.13 (td, J = 8.0, 1.6 Hz, 2H), 6.99 (dd, J = 7.4, 1.6 Hz, 2H),
6.65 (td, J = 7.4, 1.1 Hz, 2H), 6.60 (d, J = 8.5 Hz, 2H), 4.85 (s,
2H), 3.81 (q, J = 6.5 Hz, 1H), 2.93 (s, 6H), 1.58 (d, J = 6.5 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3, δ): 143.9, 142.1, 133.5,
133.0, 128.7, 128.3, 127.8, 127.8, 1276, 126.1, 125.9, 125.7,
125.6, 120.7, 116.5, 111.8, 71.6, 57.3, 36.4, 21.8. HRMS (ESI)
+
(ESI) m/z: [M + H]+ calcd for C25H28N3 , 370.2278; found,
370.2283.
+
m/z: [M + H]+ calcd for C28H28N3 , 406.2278; found, 406.2281.
(R)-2-((6S,12S)-5,11-Dimethyl-5,6,11,12-tetrahydro-6,12-
epiminodibenzo[b,f][1,5]diazocin-13-yl)-3-phenylpropanoate
(3j)
(6R,12R)-5,11-Dimethyl-13-((S)-1-(naphthalen-1-yl)ethyl)-
5,6,11,12-tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine
(3h)
Yield: 33.0 mg (32%); yellow solid; m.p.: 144–146 °C; Rf =
0.55 (PE:EA = 5:1, v/v); [α]2D5 = -2.4 (c, 1.0, CH2Cl2). 1H NMR
(400 MHz, CDCl3, δ): 7.25–7.14 (m, 5H), 7.09 (td, J = 8.2, 1.6
Hz, 2H), 7.04 (dd, J = 7.5, 1.6 Hz, 2H), 6.66 (td, J = 7.4, 1.1
Hz, 2H), 6.57 (d, J = 8.2 Hz, 2H), 4.93 (s, 2H), 3.72 (dd, J =
9.8, 5.4 Hz, 1H), 3.34 (s, 3H), 3.29 (dd, J = 13.0, 5.4 Hz, 1H),
3.14 (dd, J = 13.0, 9.8 Hz, 1H), 2.98 (s, 6H). 13C{1H} NMR
(101 MHz, CDCl3, δ): 172.5, 143.6, 137.0, 129.1, 128.8, 128.4,
127.4, 126.7, 120.8, 117.0, 112.4, 72.5, 64.7, 51.5, 37.4, 36.6.
Yield: 30.4 mg (30%); yellow solid; m.p.: 138–140 °C; Rf =
0.50 (PE:EA = 5:1, v/v); [α]2D5 = 69.0 (c, 0.4, CH2Cl2). 1H NMR
(400 MHz, CDCl3, δ): 8.21 (s, 1H), 7.92 (dd, J = 8.0, 1.5 Hz,
3H), 7.83 (d, J = 8.2 Hz, 3H), 7.52–7.43 (m, 3H), 7.16 (td, J =
8.4, 1.6 Hz, 2H), 6.97 (dd, J = 7.4, 1.6 Hz, 2H), 6.65 (td, J =
7.3, 1.1 Hz, 2H), 6.62 (dd, J = 8.3, 1.0 Hz, 2H), 4.86 (s, 2H),
4.56 (s, 1H), 2.81 (s, 6H), 1.61 (d, J = 6.5 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3, δ): 143.5, 139.7, 133.9, 131.5, 128.8,
127.6 (d, J = 2.4 Hz), 125.7, 125.7, 125.4, 120.4, 116.3, 111.6,
71.7, 36.3, 21.0. HRMS (ESI) m/z: [M + H]+ calcd for
+
HRMS (ESI) m/z: [M + H]+ calcd for C26H28N3O2 , 414.2176;
found, 414.2182.
+
(R)-2-((6R,12R)-5,11-Dimethyl-5,6,11,12-tetrahydro-6,12-
epiminodibenzo[b,f][1,5]diazocin-13-yl)-3-phenylpropanoate
(4j)
C28H28N3 , 406.2278; found, 406.2279.
(6S,12S)-5,11-dimethyl-13-((S)-1-(naphthalen-1-yl)ethyl)-
5,6,11,12-tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine
(4h)
Yield: 28.8 mg (28%); yellow solid; m.p.: 115–117 °C; Rf =
1
0.75 (PE:EA = 5:1, v/v); [α]2D5 = 0.6 (c, 1.0, CH2Cl2). H NMR
Yield: 26.3 mg (26%); white solid; m.p.: °C; Rf = 0.65
(400 MHz, CDCl3, δ): 7.24–7.17 (m, 3H), 7.14–7.07 (m, 4H),
7.02 (dd, J = 7.5, 1.6 Hz, 2H), 6.65 (td, J = 7.4, 1.1 Hz, 2H),
6.56 (d, J = 8.3 Hz, 2H), 4.96 (s, 2H), 3.65 (t, J = 7.5 Hz, 1H),
3.35 (s, 3H), 3.16 (d, J = 7.5 Hz, 2H), 2.97 (s, 6H). 13C{1H}
NMR (101 MHz, CDCl3, δ): 172.1, 143.3, 137.3, 129.2, 128.8,
128.3, 127.2, 126.6, 120.8, 116.7, 112.1, 72.6, 64.2, 51.3, 37.5,
1
(PE:EA = 5:1, v/v); [α]2D5 = -85.3 (c, 0.6, CH2Cl2). H NMR
(400 MHz, CDCl3, δ): 8.15-7.65 (m, 4H), 7.56–7.44 (m, 2H),
7.37 (td, J = 8.4, 1.5 Hz, 1H), 7.16 (td, J = 7.7, 1.5 Hz, 2H),
6.98 (dt, J = 7.8, 1.5 Hz, 2H), 6.69–6.61 (m, 4H), 4.92 (d, J =
1.5 Hz, 2H), 4.53 (s, 1H), 2.97 (s, 6H), 1.65 (d, J = 6.6 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3, δ): 144.0, 140.4, 133.9,
131.5, 128.7, 128.6, 127.9, 127.4, 125.9, 125.6, 125.3, 120.9,
116.4, 111.7, 71.7, 36.4, 21.2. HRMS (ESI) m/z: [M + H]+
+
36.6. HRMS (ESI) m/z: [M + H]+ calcd for C26H28N3O2 ,
414.2176; found, 414.2177.
+
Methyl (S)-2-((6R,12R)-5,11-dimethyl-5,6,11,12-
tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocin-13-yl)-4-
(methylthio)butanoate (3k)
calcd for C28H28N3 , 406.2278; found, 406.2278.
(6R,12R)-5,11-Dimethyl-13-((S)-1-phenylpropyl)-
5,6,11,12-tetrahydro-6,12-epiminodibenzo[b,f][1,5]diazocine
(3i)
Yield: 16.8 mg (17%); yellow liquid; Rf = 0.50 (PE:EA =
1
5:1, v/v); [α]2D5 = -2.7 (c, 0.62, CH2Cl2). H NMR (400 MHz,
Yield: 28.6 mg (31%); yellow solid; m.p.: 52–54 °C; Rf =
0.50 (PE:EA = 5:1, v/v); [α]2D5 = 4.3 (c, 0.32, CH2Cl2). 1H NMR
(400 MHz, CDCl3, δ): 7.39–7.28 (m, 5H), 7.12 (td, J = 8.8 Hz,
1.6 Hz, 2H), 6.96 (dd, J = 7.4, 1.6 Hz,2H), 6.63 (td, J = 7.4,
1.1 Hz,2H), 6.58 (d, J = 8.2 Hz, 2H), 4.77 (s, 2H), 3.41 (dd, J
CDCl3, δ): 7.13–7.04 (m, 2H), 7.04 (dd, J = 7.5, 1.5 Hz, 2H),
6.65 (td, J = 7.4, 1.1 Hz, 2H), 6.56 (d, J = 8.1 Hz, 2H), 4.85 (s,
2H), 3.59 (dd, J = 7.4, 5.6 Hz, 1H), 3.49 (s, 3H), 3.01 (s, 6H),
2.59–2.45 (m, 2H), 2.26–2.13 (m, 2H), 2.09 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3, δ): 172.7, 143.6, 128.7, 127.4, 120.9,
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116.9, 112.4, 72.5, 61.7, 51.7, 36.7, 30.0, 29.9, 15.5. HRMS
7.13 (t, J = 7.7 Hz, 2H), 6.99 (d, J = 7.4 Hz, 2H), 6.64 (t, J
= 7.4 Hz, 2H), 6.60 (d, J = 8.2 Hz, 2H), 4.80 (s, 2H), 3.73
(q, J = 6.4 Hz, 1H), 2.93 (s, 6H), 1.52 (d, J = 6.5 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3, δ): 143.5, 142.7, 140.8,
140.1, 128.7, 128.3, 127.5, 127.2, 127.1, 127.0, 120.1,
116.3, 111.5, 71.6, 56.4, 36.2, 21.1. HRMS (ESI) m/z: [M +
(ESI) m/z: [M + H]+ calcd for C22H28N3O2S+, 398.1897; found,
1
2
3
4
5
6
398.1900.
Methyl (S)-2-((6S,12S)-5,11-dimethyl-5,6,11,12-tetrahydro-
6,12-epiminodibenzo[b,f][1,5]diazocin-13-yl)-4-
(methylthio)butanoate (4k)
+
H]+ calcd for C30H30N3 , 432.2434; found, 432.2437.
7
8
9
Yield: 14.9 mg (15%); yellow liquid; Rf = 0.75 (PE:EA =
Procedure for the isomerization investigation of 3f and 4f
1
5:1, v/v); [α]2D5 = 1.4 (c, 0.22, CH2Cl2). H NMR (400 MHz,
To a dry reaction tube charged with a magnetic stirring bar
was added 3f or 4f (21.7 mg, 0.05 mmol), TsOH·H2O (2 mg,
0.01 mmol, 20 mol %), and dry toluene (1 ml). The tube was
sealed and was heated for 1 h at 150 °C in a heating-mantle.
The solvent was removed under reduced pressure. The crude
CDCl3, δ): 7.14–7.08 (m, 2H), 7.07 (dd, J = 7.5, 1.6 Hz, 2H),
6.68 (td, J = 7.4, 1.1 Hz, 2H), 6.58 (dd, J = 8.2, 1.0 Hz, 2H),
4.93 (s, 2H), 3.60 (dd, J = 8.0, 5.7 Hz, 1H), 3.47 (s, 3H), 3.00
(s, 6H), 2.58 (ddd, J = 13.1, 7.1, 4.4 Hz, 1H), 2.49 (ddd, J =
13.2, 8.5, 6.4 Hz, 1H), 2.23–2.11 (m, 2H), 2.09 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3, δ): 172.5, 143.4, 128.7, 127.1, 121.1,
116.8, 112.2, 72.5, 60.9, 51.4, 36.7, 30.3, 29.8, 15.4. HRMS
(ESI) m/z: [M + H]+ calcd for C22H28N3O2S+, 398.1897; found,
398.1892.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
residue was submitted to H NMR to measure the diastere-
ometic ratio.
ASSOCIATED CONTENT
Supporting Information
Copies of 1H and 13C NMR, MS, and HRMS spectra, and CIF file
of 3a. These material is available free of charge via the Internet at
http://pubs.acs.org.
5,11-Dimethyl-13-(p-tolyl)-5,6,11,12-tetrahydro-6,12-
epiminodibenzo[b,f][1,5]diazocine (12a)
Yield: 60.1 mg (70%); white solid, m.p.:65–67 °C; Rf =
0.60 (PE:EA = 5:1, v/v). 1H NMR (400 MHz, CDCl3, δ): 7.23–
7.13 (m, 4H), 7.11–6.98 (m, 4H), 6.73 (td, J = 7.4, 1.0 Hz, 2H),
6.64 (d, J = 8.2 Hz, 2H), 5.55 (s, 2H), 3.09 (s, 6H), 2.29 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3, δ): 144.7, 143.6, 130.8,
129.6, 128.8, 127.1, 121.1, 118.5, 116.7, 112.4, 73.2, 36.7,
AUTHOR INFORMATION
Corresponding Author
* jxxu@mail.buct.edu.cn (J.X.)
* zhyang@mail.buct.edu.cn (Z.Y.)
+
20.5. HRMS (ESI) m/z: [M + H]+ calcd for C23H24N3 ,
342.1965; found, 342.1956.
ORCID
Zhanhui Yang: 0000-0001-7050-8780
Jiaxi Xu: 0000-0002-9039-4933
Notes
The authors declare no competing financial interest.
Author Contribution
Y.C. and S.L. contributed equally.
Methyl
2-(5,11-dimethyl-5,6,11,12-tetrahydro-6,12-
epiminodibenzo[b,f][1,5]diazocin-13-yl)acetate (12b)
Yield: 49.3 mg (61%); white solid, m.p.:45–47 °C; Rf =
1
0.40 (PE:EA = 2:1, v/v). H NMR (400 MHz, CDCl3, δ): 7.14
(td, J = 8.0, 1.6 Hz, 2H), 7.09 (dd, J = 7.5, 1.5 Hz, 2H), 6.68 (t,
J = 7.4 Hz, 2H), 6.61 (d, J = 8.2 Hz, 2H), 4.91 (s, 2H), 3.76 (s,
3H), 3.64 (d, J = 16.9 Hz, 1H), 3.36 (d, J = 16.9 Hz, 1H), 3.04
(s, 6H). 13C{1H} NMR (101 MHz, CDCl3, δ): 170.8, 143.1,
128.9, 127.7, 119.9, 116.7, 112.0, 74.2, 51.9, 51.6, 36.5.
ACKNOWLEDGMENT
This work is financially supported by Beijing Natural Science
Foundation (no. 2202041, to Z.Y.), the National Natural Science
Foundation of China (no. 21602010, to Z.Y.), and the Fundamen-
tal Research Funds for the Central Universities (no. XK1802-6, to
Z.Y. and J.X.; no. 12060093063, to Z.Y.). We sincerely thank Dr.
Mingwu Yu from Ludong University for HRMS determination
during revision of the manuscript.
+
HRMS (ESI) m/z: [M + H]+ calcd for C19H22N3O2 , 324.1707;
found, 324.1696.
Procedure for the Suzuki-Coupling of 3f
To a dry reaction tube charged with a magnetic stirring bar
was added 3f (43.3 mg, 0.1 mmol), PhB(OH)2 (18.3 mg, 0.15
mmol), K3PO4 (42.5 mg, 0.2 mmol), Pd(PPh3)4 (4 mg, 3.25
mol, 3.5 mol %), and dry toluene (1.5 ml) under a nitrogen
atmosphere. The tube was sealed and the mixture was stirred
for 20 h at 100 °C in a heating-mantle. The solvent was re-
moved by distillation under reduced pressure. The crude resi-
due was purified by silica gel column chromatography to give
desired product 10.
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