Medium Rings Bearing Bitriazolyls: Easily Accessible Structures with Superior Performance as Cu Catalyst Ligands

Article abstract of DOI:10.1021/acs.joc.8b01899

Benefiting from their unique properties, the development of structurally novel and easily accessible medium rings is of significant interest in the pharmaceutical industry and academic research. However, synthetic access to medium-ring scaffolds is very d

Full text of DOI:10.1021/acs.joc.8b01899

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Article
Medium Rings Bearing Bitriazolyls (MRBTs): Easily Accessible
Structures with Superior Performance as Cu-catalyst Ligands
Lingjun Li, Shenlong Huang, Tongpeng Shang, Bo Zhang, yuanyang guo,
Gongming Zhu, Demin Zhou, Guisheng Zhang, Anlian Zhu, and Lihe Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01899 • Publication Date (Web): 17 Oct 2018
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Medium Rings Bearing Bitriazolyls (MRBTs): Easily Accessible Structures with
Superior Performance as Cu-catalyst Ligands
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†
†
‡
Lingjun Li,*, † Shenlong Huang, Tongpeng Shang, Bo Zhang, Yuanyang Guo,†
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Gongming Zhu,† Demin Zhou,*, ‡ Guisheng Zhang,*, † Anlian Zhu† and Lihe Zhang‡
† Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals,
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry
and Chemical Engineering Henan Normal University, Xinxiang, Henan 453007 (P. R. China). E-mail:
lingjunlee@htu.cn; zgs@htu.cn;
‡ National Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking
University, Beijing 100083 (P. R. China). E-mail: deminzhou@bjmu.edu.cn.
MRBTs: (1) New easily accessible medium-ring skeleton;
(2) Superior accelerating ligands for Cu-catalyzed click reaction.
N
N
Bn
N
One-pot Triazolation Substitution, Annulation
,
!
Bn
R
N
O
N
N
R
N
N
N
n
N
A B
/
Condition
Cu1
N
R'
X
2
+
R N3
N
(
X
)
n
BTMRs
N
3aa: R' = NHCH3
;
Kobs = 1.95 M-1s-1; TON = 55,000
X = CH2, N, O;
R = alkyl, benzyl, ribosyl
3ab: ligand for site-special modification of protein
7 to 12 mumbered rings
MBP
N
CuSO4/Na scorbate
Ligand: 3ab
H
N
H
N
O
N
O
S
O
N
N
O
N3
O
N
Fluorescent alkyne
O
H
Abstract: Benefiting from their unique properties, developments of structurally novel
and easily accessible medium rings are of significant interest in pharmaceutical industry
and academic research. However, synthetic access of medium-ring scaffolds is very
difficult due to their rigid skeleton and large-angle strains. In this paper, a new class of
medium rings bearing bitriazolyls (MRBTs) was designed, synthesized and identified as a
promising new-skeleton ligand for Cu(I)-catalyzed click reaction and used in site-special
modification of protein. One of MRBTs, 3aa, exhibited as most as 55,000 turnover
number (TON) and dramatically accelerating effects (kobs = 1.95 M-1s-1) and ranked
among the most efficient CuAAC ligands. Unlike the difficult access to other known
medium rings, these 7- to 12-membered MRBTs can be prepared in one-step manner
straightforward from structurally diverse linear terminal diynes and azides. The unique
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accessibility and intriguing properties therefore imply their broad application
perspectives.
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Introduction
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Medium rings are a class of valuable structural motifs found in natural products and
artificial functional materials.1-4 The unique cyclic frames and conformational constraint
provided by medium rings afford them highly attractive bioactivities and physical
chemical properties.2 Screenings based on medium-ring scaffolds have opened intriguing
perspectives in the discovery of drug leading compounds, dyes and catalysis ligands.3
However, synthetic access of medium-ring scaffolds is very difficult due to their rigid
skeleton and large-angle strains.5 Indeed, the scarcity of structural diverse medium rings
has been considered one of the main reasons that limited their usages in both of
commercial and academic researches. For example, medium rings (8 to 12-membered)
are absent among the current top 200 brand-name drugs and top 200 generic drugs, even
if their frequent occurrence in many important bioactive natural products.6 Therefore,
developments of easily accessible new- structure medium rings are of significant interest.
1,2,3-Triazole is an unnatural heteroaryl skeleton, which has been witnessed a successful
utilization in a wide scope of chemistry and materials science in the past decades.7,8
Linear or macrocyclic compounds bearing multi/bitriazolyls moieties have been prepared
(Figure 1A).9-12 However, there is little knowledge in the design and applications about
medium rings bearing multi/bitriazolyls. Medium-ring skeletons have proved extremely
useful to organize spatial presentations of structural moieties for the design of
functionalized molecules.13 On the other hand, synergistic effects provided by
sequential assembly of multi/biheteroaryls can effectively enhance their binding
affinities.14 Therefore, equipment of medium rings with multi/bitriazolyls will be
interesting to offer a new chemical space with promising functionalities (Figure 1B).
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Bn
N
(A)
N
N
N
(B)
R1
N
N
N
N
O
N
R2
R2
CH3
n
O
N
N
N
N
O
N
N
N
N
X
( )n
N
N
+
N
N
N
Bn
N
n = 1,2,3,4,5
Medium Ring
N
N
Bn
Bitriazole
CuAAC ligands TBTA
: R1, R2 = Bn
BTTPS: R2 = t-Bu,R1 = CH2CH2CH2OSO3H
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:
Highly Efficient Nanoparticle ligands
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(J. Am. Chem. Soc. 2010, 132, 16893)
Angew. Chem. Int. Ed 2016
(
.
, 55, 3091
)
OH
N
N
N
N
HO
HO
HO
HO
O
N
N
N
N
N
O
N3
NH2
X
N
S
OH
S
( )n
N
N
N
O
N
N
N
N
N
N
N
O
N
N
HOOC (H2C)4
OH
Highly selective CA II inhibitor
2015
Medium Ring bearing Bistriazole
MRBTs
HO
(
)
Copper-chelating Azide
2014
(Angew. Chem. Int. Ed.
, 53, 5872)
(J. Med. Chem.
, 58, 1494)
Figure 1 Design of MRBTs and multi/bitriazoles9-12
The synthesis of medium ring containing biaryls/biheteroaryls is a long-term challenging
task in organic synthesis, which suffered from harsh reaction conditions, multi-step
reactions and limited scope of substrates (Figure 2A).15 Therefore, as the first part of this
work, we focused on the development of a facile chemical synthesis of MRBTs. Through
a design of in situ intramolecular oxidative coupling reaction, MRBTs can be prepared
from simple diyne and azide. In contrast to known methods for the preparation of
biaryl/biheteroaryl-containing medium rings that proceed through single sp2 C-C
bond-forming transformations, the presented approach involves one-step formation of
four C-N bonds and one intramolecular sp2 C-C bond, leading to the construction of the
biheteroaryl core with substitution and annulation all being completed by one time
(Figure 2B). This synthesis methodology presents a rare example for one-pot preparation
of biaryl/biheteroaryl-containing medium rings direct from linear hydrocarbon.
Following the facile synthetic methodology of MRBTs, we identified 7-memebered
MRBTs as the promising new-skeleton ligands for Cu(I)-catalyzed click reaction and in
site-special modification of protein (Figure 2C). Through a brand-spectrum screening on
the prepared 7-memberd MRBTs and the next structural optimizations, compound 3aa
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was exhibited as most as 55,000 turnover number (TON) and dramatically accelerating
effects (kobs = 1.95 M-1s-1), ranking among the most efficient CuAAC ligands.
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(A) Synthesis of medium ring by single sp2 C-C formation (Previous work)
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n-BuLi/i-prMgCl
for Metalation
Pd cat. for
C-H activation
Ar
Ar
Ar
Br/I
Ar
H
Ar
Ar
H
X
X
X
n
n
Organocuprate
oxidation
Br/I
n
7- to 8-membered rings
7- to 12-membered ring
(B) Synthesis of MRBTs by one-pot triazolation, substitution and annulation (This work)
N
N
N
R
R
H
H
n
X
Cu(I)
O2
To form the biheteroaryl core,
substitution and annulation in
one pot!
+
R
N3
X
2
N
N
N
MRBTs
X = CH2, N, O
R = alkyl, benzyl, ribosyl
7
11
to
membered rings
(C) Discovery of MRBTs as the superior ligands of Cu(I)-catalyzed click reaction
Applications
Optimization
Screening
MRBTs
Superior ligands for click reaction
(1) kobs = 1.95 M-1s-1
3aa
3ab
Compound
Compound
3a
Compound
as leading compounds
(2) TON = 55,000
(3) Site-specific labeling of protein
Figure 2 Synthesis and applications of MRBTs
Results and Discussion
Development of a facile synthesis of 7-membered MRBTs.
The structural rigidity imposed on medium rings prevents the use of many well-known
biaryl-coupling protocols such as palladium-catalyzed Stille, Suzuki, or Negishi reactions
for the construction of intramolecular sp2 C-C bonds in medium rings.5 Much efforts have
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be made to develop effective methods for the construction of the internal sp2 C-C bonds
in medium rings, among which the strategy based on the organocuprate are used
recently.15 Construction of intramolecular sp2 C-C bonds via oxidation of organocuprate
is effective to synthesize biaryl-containing medium rings, however, the preparation of
organocuprates usually suffered from extreme reaction conditions and poor
functional-group tolerances, which greatly limited the further use of this method in the
structurally complicated compounds. Along with our efforts to develop new chemical
transformations via copper triazolide intermediates that can be in situ prepared from
alkyne and azide under very mild conditions,16,17,18 we here attempted to utilize copper
triazolide to realize the effective construction of intramolecular sp2 C-C bond of MRBTs
(Scheme 1A).
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(A)
Retrosynthetic analysis
Cu(I) / Oxidants
?
One-pot
N
N
N
N
N
N
N
R
R
X
(
)
n
N
N
R
X
R
X
(
)
n
+
(
)
n
N
[Cu]
[Cu]
N3
R
N
N
MRBTs
X = CH2, N, O
(B)
MRBTs
Condition I for synthesis of
Chao-Jun Li's Method [19]
Bn
N
Condition I
O
Bn
N
N
Bn
N
N
Bn
N
N
2
10% CuI
DIPEA (2.2 equiv.)
20% CuSO4
40% Na-ascorbate
N
OMe
N
N
1a
N
O
+
CH3CN-H2O, 25oC, 8h
N
N
O
t-BuOH/H2O, RT
N
N
Bn N3
OMe
4a
89%
OMe
3a
86%
2a
(C)
MRBTs
Condition II for synthesis of
Burgess's Method [21]
Condition II
Bn
N
Bn
N
N
Cu(0), CuSO4,
MeCN/2M Na2CO3
CuBr, O2,
NaOEt, EtOH
N
Bn
N
Bn
N
1e
+
Bn N3
N
N
60 oC, 10h
N
25 oC, 48h.
N
2
N
N
2a
Scheme 1 Synthesis of MRBTs
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Compound 1a was taken as the donor of diyne to investigate our synthetic route of
MRBTs (Scheme 1A). Chao-Jun Li group have reported the preparation of compound 1a
and its reaction with azide to give acyclic bistriazole product 4a with 89% yield (Scheme
1B).19 Herein, we are interested to explore a new reaction condition for promoting the
reaction of 1a to produce cyclic product 3a, and then catalysts, solvents, bases were
screened and optimized (Supplementary Table S1 in supporting information). We first
found that product 3a was obtained in 31% yield after a mixture of 1a, 2a (2.2 equiv),
triethylamine (TEA; 2.2 equiv), and CuI (0.1 equiv) in THF was stirred at 25 °C under
open air for 6 h. The reactivities of copper triazolide could be regulated by the oxidant
systems, which led to different products through different reaction pathways.20 We thus
attempted to investigate roles of air as the oxidant in the cyclization reactions. After
being conducted the reaction under nitrogen atmosphere, and the reaction only produced
the acyclic bistriazole product 4a (72% yield), and production of 3a was completely
inhibited. 4a could not react itself to give 3a in the presence of CuI and DIPEA under air.
The result suggested that the sp2 C-C bond between triazolyl moieties should form prior
to protonation of copper triazolides under the current conditions. We then insert a pure
oxygen atmosphere to cyclization reaction. As expected, a mixture of diyne 1a, azide 2a,
TEA, and CuI in THF under oxygen gave 3a in a better 71% yield. The type of copper(I)
salt catalyst (10 mol %) affected the yield of 3a, with CuCl giving a 51% yield; CuBr,
69%; Cu2O, 41%; and CuI, 71%. Screening of solvents showed that the mixture of water
and CH3CN (v/v = 1:1) was the best solvents with a dramatically increasing of cyclic
products. When a mixture of 1a with CuI (0.1 equiv) as the catalyst, 2a (2.2 equiv), and
DIPEA (2.2 equiv) in CH3CN-H2O (v/v = 1:1) was stirred under oxygen at 25 °C for 12 h,
3a was obtained in 86% isolated yield (Condition I in Scheme 1B).
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After successful preparation of 3a, we attempted to apply condition I to other diynes.
Unfortunately, no cyclic products could be obtained when 1,6-heptadiyne was used. We
tried the conditions that Burgess’s group reported for the preparation of linear bistriazoles
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(Scheme 1C),21 however the same results were given without any annulation products of
1,6-heptadiyne and total recovery of starting materials. In both of reaction condition I and
Burgess’s reaction condition, the diynes used as reactants were found to have
heteroatoms (N or O) on the beta-position of alkynyl groups, which might be a reason to
facilitate the construction of medium ring. While in the case of 1,6-heptadiyne without N
or O on its beta-position, the formation of medium ring would be more difficult. We thus
went back to optimize reaction conditions with 1,6-heptadiyne as the starting material.
Reaction condition II shown in Scheme 1C was finally built as the optimal one, in which
1,6-heptadiyne reacted smoothly with azides to give target 3b in the yield of 76% after 10
hours at 60oC with CuBr as the catalyst in the presence of oxygen.
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Table 1 Synthesis of seven-membered MRBTsa,b,
Bn
Bn
N
Bn
Bn
N
N
N
N
N
N
N
Bn
N
Bn
N
Bn
N
Bn
N
N
N
N
N
N
N
N
N
Ph
O
O
N
N
N
N
N
O
EtO
3d
O
MeO
3c
O
OMe
O
O
(80%)
(88%)
3b
(82%)
3a
(86%)
N
Bn
N
N
Bn
Bn
N
N
N
N
Bn
N
Bn
N
N
Bn
N
N
N
Bn
N
N
N
Bn
N
N
N
N
N
N
CN
3g
(71%)
N
O
N
O
EtO
O
NC
c
3h
(78%)
3f
(76%)
3e
(77%)
OAc
OAc
N
Bn
N
N
AcO
Bn
N
N
N
OAc
N
O
N
O
O
N
AcO
AcO
N
N
N
N
N
OMe
N
N
N
N
N
N
N
N
O
N
MeO
3i
O
N
O
c
3l
(68%)
3k
(55%)
3j
(64%)
(88%)
a Reaction Conditions: diyne (0.15 mmol), benzyl azide (0.32 mmol), CuI (0.015 mmol),
oxygen balloon and DIPEA (0.3 mmol) were stirred in CH3CN-H2O (v/v = 1:1) (3 mL) at
b
c
room temperature for 12 h. Isolated yield. Reaction Conditions: diyne (0.15 mmol),
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benzyl azide (0.32 mmol), CuBr (0.015 mmol), oxygen balloon and NaOEt (0.3 mmol)
were stirred in ethanol (3 mL) at 60 oC for 10 h.
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Differing from the intermolecular oxidative couplings of copper triazolide, the
intramolecular cyclizations in medium-ring might be highly unpredictable because
medium rings suffer from extra transannular steric interactions that are not present in
smaller and larger rings. Furthermore, the cyclization procedures are usually subject to
unfavorable entropic effects and enthalpic effects. Additionally, there are two possible
competing reactions of the intramolecular cyclizations, protonation of copper triazolide
and the linear self-couplings during the cyclization reaction. Condition I and II therefore
supplied an efficient and concise way to realize intramolecular oxidative cyclizations on
copper triazolide.
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With condition I and II in hand, we then investigated the synthesis of diverse
seven-membered MRBTs from different diynes and azides. As shown in Table 1,
dialkynyl amines, dialkynyl ethers, and dialkynyl dicarbonyl compounds afforded the
corresponding bistriazolyl rings in good to excellent yields (3a–3i). Various
functionalities such as carbonyl, ester, ether, and cyano groups remained intact under the
reaction conditions. Anthracenylmethyl azides reacted smoothly with diynes to generate
medium rings 3j and 3l, in 64% and 68% yields. It is particularly worth noting that a
delicate ribosyl azide could also be an effective substrate for the reaction, affording the
corresponding seven-membered rings in a moderate yield (Table 1, 3k).
Preparation of 8- to 12-membered MRBTs
Different sizes of medium rings offer different properties, but they often require different
synthetic methods.22 After the facile synthesis and successful applications of our method
in 7-membered MRBTs, we turned our attention to developing a general method for
preparations of MRBTs with different ring sizes. Eight-membered rings are usually the
most difficult medium rings to form, because of energetically unfavorable transannular
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and torsional strain effects in ring-closing reactions.23 Thus, we tested our method for the
preparation of 8-membered rings as shown in Table 2. The reaction of 1,7-octydiyne with
benzyl azide proceeded smoothly in the presence of CuBr (0.1 equiv), and NaOEt (2.2
equiv) in ethanol at 60 oC for 10 h, to form eight-membered ring 3m in 67% yield. Then,
the syntheses of MRBTs with 9-membered, 10-membered, 11-membered and
12-membered rings were investigated. The nine-membered carbocycle 3n was obtained
from 1,8-nonadiyne and benzyl azide in 73% yield. Furthermore, 10-, 11-, and
12-membered rings (Table 2, 3o, 3p, and 3q) were synthesized in good yields from the
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corresponding
diynes
[1,2-bis(prop-2-yn-1-yloxy)
benzene
1l,
1,3-bis(prop-2-yn-1-yloxy)propane 1p, and 2,2’-bis(prop-2-yn-1-yloxy)-1,1’-biphenyl
1m] and benzyl azide. Additionally, the chiral diynes (R)-1n and (S)-1o, which were
prepared from (R)- and (S)-binaphthol, respectively, were used as substrates for the
synthesis of 12-membered medium rings. Compounds 3r and 3s were obtained in yields
of 86% and 83%, respectively, from benzyl azide (2.2 equiv), CuI (0.1 equiv), and NaOEt
(2.2 equiv) at 60 oC in ethanol for 10 h, with moderate diastereomeric ratios, i.e., 6:1 for
3r and 7:1 for 3s.
Table 2 Synthesis of 8 to 11-membered MRBTsa,b
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The dynes for the synthesis of 8- to 12-membered rings:
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O
O
(
)
n
O
O
n = 1, 2
9
O
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O
O
O
O
O
8- to 12-Membered MRBTs:
N
N
N
N
O
N
N
N
N
N
O
N
N
Bn
Bn
Bn
Bn
Bn
Bn
N
10
9
Bn
Bn
8
11
O
N
N
N
N
N
N
N N
O
N
N
N
N
3p
3n
3o
(73%)
(73%)
(71%)
3m
(75%)
N
N
N
N
N
N
O
N
N
N
N
Bn
Bn
Bn
Bn
O
O
O
O
Bn
Bn
12
O
N
N
N
N
N
N
N
N
3s
(73%)
3r
(69%)
3q
(64%)
diastereomeric ratio (dr) = 6:1 18
diastereomeric ratio (dr) = 7:1 18
a
b
Isolated yield. Diyne (0.15 mmol), benzyl azide (0.32 mmol), CuBr (0.015 mmol),
oxygen balloon and NaOEt (0.33 mmol) were stirred in ethanol (3 mL) at 60 oC for 10 h.
Identification of MRBTs as the ligands for copper-catalyzed click reaction
An important point of the researches in medium rings is to utilize their unique chemical
spaces to discover new functional molecules.1,3 As a class of remarkable compounds,
ligands of copper-catalyzed alkyne and azide cycloaddition (CuAAC) reaction have been
shown to improve the biocompatibility of CuAAC reaction9 as well as enhance the
reaction rate,24 drawing great attention from materials science to biomedical research.25
Using fluorescent click reaction (Figure 3A) reported by Wang and coworkers,26 we
could investigate the catalytic performances of 7-membered MRBTs. The copper
residues of 7-membered MRBTs listed in Table 1 were confirmed by atomic absorption
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spectrometer less than 0.5 ppm, and then the compounds were directly used to screen as
ligands of CuAAC. Compound 3a was found to greatly accelerate fluorescent click
reaction. In the skeleton of 3a, two triazolyl moieties and nitrogen atom in the ring might
play binding groups to Cu(I), and the ester group outside the ring offered an additional
modification site which could be modified readily (Figure 3B). Surprisingly, compound
3aa obtained by transferring methyl ester of 3a to methanamide indicated a dramatically
increase of catalytic activities. The kobs values was measured and calculated based on
reported methods.9 The kobs of 3aa was 1.95 M-1s-1, which is 5.6 times that of BTTPS9a
(0.35 M-1s-1), one of the best Cu(I) ligands for CuAAC reported to date (Figure 3C,
Supplementary Figure S4 and Supplementary Table S5 in the supporting information).
This ligand is also 12.5-fold more efficient than the classical TBTA27 ligand. When
increasing the concentration of propargyl alcohol to 300 μM under the same reaction
conditions, quantitative conversion was achieved within 5 min by using 3aa as the ligand
(Figure 3D). The catalyst loading and efficiency was then investigated as shown in Table
3. 98% yield was obtained with 0.01 mol % Cu(I) under aqueous conditions (Entry 3 in
Table 3). A 55,000 turnover number (TON) was achieved under solvent-free conditions
with 10 mmol benzyl azide, 10 mmol ethynylbenzene and 0.001 mol % Cu(I) at room
temperature (Entry 5 in Table 3), which makes 3aa one of the most efficient ligands for
copper-catalyzed click reaction (Supplementary Table S6 in the supporting information).
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No fluorescent
(A)
(B)
MRBTs
compounds
HO
II
O
O
HO
+
N3
I
Bn
N
N
fluorescent
click reaction
Bn
N
N
N
CuSO4
Na ascorbate
N
O
on
i
Buffer/DMSO 95:5
t
N
N
amina
3aa
Bn
NHCH3
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Bn
HO
O
III
O
N
N
Bn
N
N
Bn
N
N
N
N
N
hydrolysis
N
N
O
N
N
N
O
N
N
OMe
λex=404nm
λem=477nm
OH
handle for further
modification
3ab
OH
3a
(C)
(D)
3
m in
5
m in
100
1 0 0
3aa-Cu (4:1)
80
60
40
20
0
80
60
40
20
BTTPS-Cu (4:1)
TBTA-Cu (2:1)
a
a
a
A
S
A
T
S
a
T
B
P
P
3
3
T
B
T
T
T
20
40
60
T
T
B
B
t
(m in)
Figure 3 (A) Fluorescent CuAAC reaction; (B) Screening and structural optimization of
MRBTs as the ligands of copper-catalyzed click reaction. (C) Kinetics with 3aa, BTTPS
and TBTA respectively as ligands of copper-catalyzed click reaction. (D) A comparison
of the efficiency of the three ligands within 3min and 5min. The reaction conditions:
propargyl alcohol (50 μM for C, 300 μM for D), 3-azido-7-hydroxy-coumarin (100 μM),
CuSO4 (75 μM), 0.1 M PBS buffer/DMSO (95:5), sodium ascorbate (2.5 mM); 3aa-Cu
(4:1), BTTPS-Cu (4:1), TBTA-Cu (2:1).
Table 3 Test of catalyst loading of 3aa (4:1 ratio to Cu) for the reaction of
phenylacetylene (0.75 M) with benzyl azide (0.75 M), 3:1 MeOH/water, sodium
ascorbate (30 mM), 24oC.
N
N
N
Cu(I)/Ligand
Bn
+
Ph
Bn N3
Ph
Mol% Cu
Time (h)
0.1
Yield[a]
Entry
Cu source
TON
99
1
2
3
4
CuSO4/ascorbate
CuSO4/ascorbate
CuSO4/ascorbate
CuSO4/ascorbate
1
99
98
95
60
0.1
0.01
0.4
16
54
980
950
0.005
12000
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5b
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CuBr
0.001
--
24
72
55
55000
--
--/ascorbate
<5%
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a Isolated yields. b Solvent-free without ascorbate.
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After transferring methyl ester to carboxyl group, a more hydrophilic derivative 3ab
could be obtained (Figure 3B), which was then chosen to apply in the bioconjugation of
protein. Site-specific inserts of unnatural amino acid (UAA) into proteins have provided a
potent tool for the multi-purpose modifications of protein.28 The use of BTMR ligand in
the bioconjugation of protein was explored in this paper, using azide bearing maltose
binding protein (MBP-N167-N3, 45 KDa) (Figure 4A).29 A total of 100 μL of
MBP-N167-N3 (50 M) in phosphate buffered saline (PBS) buffer was reacted with 2.0
equivalents of fluorescent alkyne at room temperature for 80 min in the presence of
CuSO4 (50 μM), Ligand 3ab (300 μM), and sodium ascorbate (2.0 mM). The reaction
was terminated by the addition of 4 μL ethylenediaminetetraacetic acid (500 mM). The
samples were analyzed by SDS-PAGE (12% gel) using fluorescent imaging before
Coomassie blue staining. MBP-N167-N3 was labeled by fluorescent alkyne with
3ab/Cu(I) as the ligand. The yield of 3ab-Cu(I) was at least 6-fold higher than that
achieved by using the uncoordinated Cu(I) (Figure 4B). Besides, the best ratio of
3ab/Cu(I) is 6:1 (Supplementary Figure S6 in the supporting information), with a low
copper loading preferable for bioconjugation.30
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(A)
(B)
HN
O S O
H
N
O
N3
+
O
MBP
8
N
9
CuSO4
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Na Ascorbate
Ligand :3ab
N
H
N
O
N
N
N
O
S
O
O
N
H
MBP
Figure 4. (A) Compound 3ab as the ligand for site-specific fluorescent labeling of MBP.
(B) Images of fluorescent labeling of MBP without Cu (right), with 3ab-complexed Cu(I)
(middle) and with Cu(I) in the absence of ligand (left). MFI, means fluorescence
intensity.
Conclusion
In summary, we have reported a novel class of medium rings MRBTs in this paper.
Altering from the complex preparative procedures for medium rings, the synthesis of
MRBTs were designed to complete by a concise one-pot aerobic oxidative coupling
directly from linear diynes and azides. Merits of this method include step- and
atom-economy, readily available starting materials, the use of oxygen as a clean oxidant,
and the use of only catalytic amounts of Cu(I) salt. In addition, this synthetic
methodology could be applied in preparations of 8- to 12-membered medium rings that
were not readily available through classical methods.
We then identified one of 7-memebered MRBTs 3a as the new leading compound for the
design of CuAAC ligands by screening, and the following two superior MRBTs 3aa and
3ab could be obtained through facile structural modifications. 3aa and 3ab demonstrated
a higher reaction rate and catalysis efficiency than the well-known BTTPS ligand, and
also indicated a low catalyst loading and desirable utility in bioconjugation of the protein.
The superior performances of MRBTs as the copper-catalyzed click reaction illustrate the
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great practical value of this new medium-ring skeleton, and the further the applications of
MRBTs in the design of drug candidates and biomaterials are still undergoing in our lab.
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Experimental Section
Materials and Methods. All reactions were run with anhydrous solvents unless
otherwise noted. Tetrahydrofuran (THF) was distilled from sodium and benzophenone
immediately before use. CH3CN were distilled from CaH2. Anhydrous
dimethylformamide (DMF) was purchased from Aldrich and used as received. MeOH
and EtOH were distilled from Mg turnings and iodine immediately before use. Reactions
were monitored by thin-layer chromatography (TLC) on silica gel GF254-precoated
plates. Compounds were detected under UV light/or visualized by phosphomolybdic acid
in ethanol solution. Solvents were evaporated under reduced pressure and below 50 °C
(water bath). Mass spectra were obtained on Bruker APEX. High-resolution MS were
1
performed with Bruker BIFLEX III and Bruker Daltonics. Inc. APEX II. H NMR and
13C NMR data were recorded with an Avance 400/DPX (Bruker) spectrometer in CDCl3
solutions using the residual solvent signal or TMS as reference. Chemical shifts are
reported in parts per million and coupling constants quoted in Hz. Fluorescence spectra
were performed on a Cary Eclipse fluorescence spectrophotometer (Varian, America).
Intensity data for compound 3d and 3p were collected on a Bruker SMART6000 CCD
diffractometer.
1,6-heptadiyne(1e), Propargyl ether(1f), 1,7-octydiyne(lj) and 1,8-nonadiyne (1k)
were purchased from Alfa Aesar China Co. Ltd. (Tianjin) and used as received. Organic
azides were prepared based on our previous works or the methods in literature.18, 31
General procedure for diyne (1a)
1a was synthesis from methyl 2-(bis(3-(trimethylsilyl)prop-2-yn-1-yl)amino)acetate.19
Tetrabutylammonium fluoride (507 mg, 1.6 mmol, 2.5 equiv.) was added to methy1
2-(bis(3-trimethylsilyl)prop-2-yn-yl)amino) acetate (200 mg, 0.65 mmol) dissolved in
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5mL dry THF. The mixture was reacted with vigorous stirring under room temperature.
Upon completion of the reaction (TLC), the mixture was concentrated. The crude mixture
was purified by silica gel column chromatography using petroleum ether/ethyl acetate as
eluent to give 1a as a colorless oil (94 mg, 88%).
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General procedure for diynes (1b, 1c, 1d, 1g, 1h, 1i)
Potassium carbonate (2.5 equiv.) and tetrabutylammonium iodide (0.1 equiv.) were added
to a stirred mixture of 1,3-dicarbonyl compounds/malononitrile (1.0 equiv.) and
3-bromopropyne (2.0 equiv.) dissolved in dry DMF. The mixture was reacted with
vigorous stirring at room temperature overnight. Upon completion of the reaction (TLC),
the mixture was concentrated. Upon completion of the reaction (TLC), the reaction was
diluted with water and extracted with ethyl acetate. The organic fractions were combined,
dry over Na2SO4, evaporated under reduced pressure. The crude mixture was purified by
alumina column chromatography using petroleum ether/ethyl acetate as eluent to give
pure products.32
General procedure for diynes (1l, 1n, 1o, 1p)
Potassium carbonate (2.5 equiv.) was added to a stirred mixture of diphenol (1 equiv.)
and 3-bromopropyne (2 equiv.) dissolved in dry acetone, then the mixture was heated to
reflux for 16 hours. Upon completion of the reaction (TLC), the mixture was
concentrated. The crude mixture was purified by silica gel column chromatography using
petroleum ether/ethyl acetate as eluent to give pure products.33
Synthesis of diyne (1m)
NaH (2.5 equiv.) was added to a stirred mixture of 1,3-propylenediol (1 equiv.) and
3-bromopropyne (2 equiv.) dissolved in dry THF, then the mixture was stirred for 24
hours at room temperature. Upon completion of the reaction (TLC), the mixture was
concentrated. The crude mixture was purified by silica gel column chromatography using
petroleum ether/ethyl acetate as eluent to give pure products.34
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General procedure for MBTRs (3a-3e, 3g-3i, 3k-3l).
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The reaction flask was evacuated three times and then filled with oxygen from oxygen
balloon. Under oxygen atmosphere, di-alkynyl ether/di-alkynyl dicarbonyl compounds
(0.15 mmol), azides (0.32 mmol, 2.1 equiv.), copper(I) iodide (0.015 mmol, 0.1 equiv.)
and N,N-diisoproplyethylamine (DIPEA) (0.3 mmol, 1.2 equiv.) were added into 5 mL
dry acetonitrile. The reaction was allowed to stir at room temperature for 12 hours. Upon
completion of the reaction (TLC), reaction solvent was evaporated under reduced
pressure. The residue was diluted with water and extracted with ethyl acetate. The
organic fractions were combined, dry over Na2SO4, evaporated under reduced pressure.
The crude mixture was purified by silica gel column chromatography using petroleum
ether/ethyl acetate as eluent to give target compound.
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General procedure for MRBTs (3f, 3j, 3m-3s).
The reaction flask was evacuated three times and then filled with oxygen from oxygen
balloon. Under oxygen atmosphere, azides (0.32 mmol, 2.1 equiv.), di-alkynyl ether and
di-alkynyl dicarbonyl compounds (0.15 mmol), copper(I) bromide (0.015 mmol, 0.1
equiv.) and NaOEt (0.33 mmol, 2.2 equiv.) were added to dry ethanol. The reaction was
o
heated to 60 C for 10 hours. Upon completion of the reaction (TLC), reaction solvent
was evaporated under reduced pressure. The residue was diluted with water and extracted
with ethyl acetate. The organic fractions were combined, dry over Na2SO4, evaporated
under reduced pressure. The crude mixture was purified by silica gel column
chromatography using petroleum ether/ethyl acetate as eluent to give target compound.
Synthesis of MRBT 3aa
Compound 3a 2-(1,9-dibenzyl-1H-bis([1,2,3]triazolo)[4,5-c:4',5'-e]azepin-5(4H, 6H,
9H)-yl)-N-methylacetamide (215 mg, 0.5 mmol) was dissolved in 3 mL of solvent of
THF/MeOH/H2O (v/v/v = 1:1:2). After LiOH (42 mg, 1.0 mmol) was added, the reaction
mixture was stirred at room temperature for 1 hour. After volatiles were removed in
vacuum, the residue was purified by silica gel column chromatography using
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CH2Cl2/MeOH as eluent to pure product 3aa (182 mg, 87% yield).
Synthesis of MRBT 3ab
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9
Compound 3a (215 mg, 0.5 mmol) was dissolved in 3 mL of MeNH2 (33 wt.% in
absolute ethanol) and stirring at room temperature for 2 hours. After volatiles were
removed in vacuum, the residue was purified by silica gel column chromatography using
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petroleum ether/ethyl acetate as eluent to pure product 3ab (200 mg, 93% yield).
X-ray crystallography.
(a) Method. Single crystals of compound 3d and 3p suitable for X-ray diffraction analysis
were obtained from slow solvent evaporationin in petroleum ether/CH2Cl2 solutions at
room temperature. No solvent of crystallization was present in the lattice for any of the
structures. (b) Crystal parameters. 3d: C31H28N6O3;
colorless, block;
0.16×0.08×0.03mm; monoclinic, P21/c; a = 12.6636(2), B = 12.6670(2) and C =
17.6579(3) Å; α = 90, β = 109.067(2), and γ = 90°; V = 2677.10(8) Å3; Z = 4; T = 170K;
ρcalc = 1.321 g/cm3; Final R indexes [I> =2σ (I)], R1 = 0.0562, wR2 = 0.1742; Final R
indexes [all data], R1 = 0.0841, wR2 = 0.1789; CCDC no: 1871589. 3p: C23H24N6O2;
colorless, needle ; 0.28×0.06×0.04 mm; triclinic, P-1; a = 8.2396(2), B = 11.5901(5),and
C = 17.6579(3) Å; α = 107.523(4), β = 104.775(3), and γ = 90.140(3)°; V = 1077.91(8)
Å3; Z = 2; T = 293K; ρcalc = 1.283; Final R indexes [I> =2σ (I)], R1 = 0.0549, wR2 =
0.1661; Final R indexes [all data], R1 = 0.0738, wR2 = 0.1740; CCDC no: 1871590.
Intensity data for compound 3d and 3p were collected on a Bruker SMART6000 CCD
diffractometer using mirror-monochromated Cu Kα radiation (λ = 1.54184 Å) at
170K(for 3d) and 293 K(for 3p). The frames were integrated with the Bruker APEX2
software package using a narrow-frame algorithm. The data were corrected for decay,
Lorentz, and polarization effects as well as absorption and beam corrections based on the
multi-scan technique. The structures were solved by a combination of direct methods in
SHELXTL and the difference Fourier technique and refined by full-matrix leastsquares
procedures.
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Characterization of compounds 3a-3l
5
6
2-(1,9-Dibenzyl-1H-bis([1,2,3]triazolo)[4,5-c:4',5'-e]azepin-5(4H,6H,9H)-yl)-N-methyla
7
8
cetamide (3a)
9
Bn
N
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N
Bn
N
N
N
O
N
N
OMe
3a
The title compound was synthesized according to the general procedure, and isolated as a
pale-yellow solid (eluent PE : EtOAc = 1:2 , Rf = 0.3, 55.4 mg, 86% yield). M.p.: 52-53
oC. 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.27 (m, 6H), 6.81 – 6.79 (m, 4H), 5.56 (s, 4H),
13
4.23 (s, 4H), 3.74 (s, 3H), 3.36 (s, 2H). C NMR (100 MHz, CDCl3) δ 170.9, 147.0,
134.1, 129.2, 128.7, 126.2, 123.4, 56.6, 53.4, 52.0, 50.7. HRMS (ESI) m/z calculate for
+
(M+H+) C23H24N7O2 430.1986, Found: 430.1977.
1,1'-(1,9-Dibenzyl-4,5,6,9-tetrahydro-1H-cyclohepta[1,2-d:3,4-d']bis([1,2,3]triazole)-5,5
-diyl)diethanone (3b)
Bn
N
N
Bn
N
N
N
O
N
O
3b
The title compound was synthesized according to the general procedure, and isolated as a
pale-yellow solid (General procedure A: eluent PE : EtOAc = 1:1 , Rf = 0.4, 54.2 mg,
82% yield). M.p.: 35-36 oC. H NMR (400 MHz, CDCl3) δ 7.28 – 7.25 (m, 6H), 6.77 –
1
13
6.75 (m, 4H), 5.51 (s, 4H), 3.38 (s, 4H), 2.21 (s, 6H). C NMR (100 MHz, CDCl3) δ
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203.3, 145.4, 133.9, 129.1, 128.7, 126.3, 123.3, 74.7, 53.4, 27.7, 26.6. HRMS (ESI) m/z
5
6
+
calculate for (M+H+) C25H25N6O2 441.2034, Found: 441.2038.
7
8
9
Methyl 5-acetyl-1,9-dibenzyl-4,5,6,9-tetrahydro-1H-cyclohepta[1,2-d:3,4-d']bis ([1,
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
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42
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,3]triazole)-5-carboxylate (3c)
Bn
N
N
Bn
N
O
N
N
N
O
MeO
3c
The title compound was isolated as a pale-yellow solid (eluent PE:EtOAc = 1:1 , Rf =
0.5, 60.2 mg, 88% yield). M.p.: 34-35 oC. 1H NMR (400 MHz, CDCl3) δ 7.27 –7.25 (m,
6H), 6.80 – 6.77 (m, 4H), 5.51 (s, 4H), 3.74 (s, 3H), 3.37 (s, 4H), 2.23 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 201.2, 171.3, 145.3, 133.8, 129.1, 128.9, 128.6, 126.3, 123.3, 67.3,
+
53.4, 53.3, 28.7, 26.0. HRMS (ESI) m/z calculate for (M+H+) C26H27N6O3 471.2139,
Found: 471.2164.
Ethyl
5-benzoyl-1,9-dibenzyl-4,5,6,9-tetrahydro-1H-cyclohepta[1,2-d:3,4-d']bis
([1,2,3]triazole)-5-carboxylate (3d)
Bn
N
N
Bn
N
O
N
N
Ph
N
O
EtO
3d
The title compound was synthesized according to the general procedure, and isolated as a
white solid (eluent PE : EtOAc = 2:1 , Rf = 0.2, 63.8 mg, 80% yield). M.p.: 148- 149 oC.
1H NMR (400 MHz, CDCl3) δ 7.82 – 7.80 (m, 2H), 7.58 – 7.54 (m, 1H), 7.46 – 7.42 (m,
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2H), 7.28 – 7.24 (m, 6H), 6.82 – 6.79 (m, 4H), 5.58 – 5.49 (m, 4H), 4.12 (q, J = 7.1 Hz,
5
6
13
2H), 3.66 (d, J = 15.8 Hz, 2H), 3.46 (d, J = 15.8 Hz, 2H), 1.08 (t, J = 7.1 Hz, 3H). C
7
8
9
NMR (100 MHz, CDCl3) δ 194.0, 172.3, 145.6, 134.3, 133.9, 133.4, 129.1, 128.9, 128.8,
128.6, 126.3, 123.3, 65.2, 62.6, 53.4, 30.6, 13.8. HRMS (ESI) m/z calculate for (M+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
+
C31H29N6O3 533.2296, Found:533.2308.
1,9-Dibenzyl-1,4,6,9-tetrahydrooxepino[3,4-d:5,6-d']bis([1,2,3]triazole) (3e)
Bn
N
N
Bn
N
N
N
N
O
3e
The title compound was synthesized according to the general procedure, and isolated as a
White solid (eluent PE : EtOAc = 2:1 , Rf = 0.2, 41.4 mg, 77% yield). M. p.: 149- 150
oC.1H NMR (400 MHz, CDCl3) δ 7.31 – 7.27 (m, 6H), 6.81 – 6.79 (m, 4H), 5.58 (s, 4H),
4.98 (s, 4H). 13C NMR (100 MHz, CDCl3) δ 148.0, 134.0, 129.2, 128.8, 126.2, 123.4,
65.5, 53.4. HRMS (ESI) m/z calculate for (M+H+) C20H19N6O+ 359.1615 Found:
359.1626.
1,9-Dibenzyl-4,5,6,9-tetrahydro-1H-cyclohepta[1,2-d:3,4-d']bis([1,2,3]triazole) (3f)
Bn
N
N
Bn
N
N
N
N
3f
The title compound was synthesized according to the general procedure, and isolated as a
yellow solid (eluent PE : EtOAc = 1:1, Rf = 0.5, 40.6 mg, 76% yield). M.p.: 179- 180
oC.1H NMR (600 MHz, CDCl3) δ 7.27 – 7.23 (m, 6H), 6.82 – 6.81 (m, 4H), 5.51 (s, 4H),
2.87 (t, J = 6.8 Hz, 4H), 2.21 – 2.16 (m, 2 H). 13C NMR (150 MHz, CDCl3) δ 149.4,
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134.3, 129.1, 128.6, 126.4, 123.2, 53.2, 28.2, 23.8. HRMS (ESI) m/z calculate for (M+H+)
5
6
+
C21H21N6 357.1822, Found: 357.1853. 1
7
8
9
1,9-Dibenzyl-6,9-dihydro-1H-cyclohepta[1,2-d:3,4-d']bis([1,2,3]triazole)-5,5(4H)-dicarb
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
onitrile (3g)
Bn
N
N
Bn
N
N
N
N
CN
NC
3g
The title compound was synthesized according to the general procedure, and isolated as a
White solid (eluent PE : EtOAc = 2:1, Rf = 0.3, 43.3 mg, 71% yield). M.p.: 75- 76 oC. 1H
NMR (400 MHz, CDCl3) δ 7.31 – 7.27 (m, 6H), 6.84 – 6.82 (m, 4H), 5.59 (s, 4H), 3.51 (s,
4H). 13C NMR (150 MHz, CDCl3) δ 141.9, 133.3, 129.4, 129.2, 126.5, 123.8, 114.7, 53.9,
37.4, 33.8. HRMS (ESI) m/z calculate for (M+H+) C23H19N8 407.1727, Found:
+
407.1731.
Ethyl 1,9-dibenzyl-5-butyryl-4,5,6,9-tetrahydro-1H-cyclohepta[1,2-d:3,4-d']bis([1,2,3]
triazole)-5-carboxylate (3h)
Bn
N
N
Bn
N
N
N
N
O
EtO
O
3h
The title compound was synthesized according to the general procedure, and isolated as a
White solid (eluent PE : EtOAc = 2:1, Rf = 0.4, 58.3 mg, 78% yield). M.p.: 120- 121 oC.
1H NMR (400 MHz, CDCl3) δ 7.27 – 7.25 (m, 6H), 6.79 – 6.77 (m, 4H), 5.51 (s, 4H),
4.18 (q, J = 7.2 Hz, 2H) 3.44 – 3.33 (m, 4H), 2.50 (t, J = 7.2 Hz, 2H), 1.64 – 1.55 (m, 2H),
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1.26 (t, J = 6.8 Hz, 3H), 0.90 (t, J = 7.2Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 203.7,
5
6
171.0, 145.5, 133.9, 129.2, 128.7, 126.4, 123.3, 67.0, 62.4, 53.4, 40.3, 28.9, 17.3, 14.1,
7
8
+
13.7. HRMS (ESI) m/z calculate for (M+H+) C28H31N6O3 499.2458, Found:499.2447.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
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35
36
37
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39
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41
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43
44
45
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47
48
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53
54
55
56
57
58
59
60
Methyl
1,9-dibenzyl-5-(2-methoxyacetyl)-4,5,6,9-tetrahydro-1H-cyclohepta[1,2-d:3,
4-d']bis([1,2,3]triazole)-5-carboxylate (3i)
Bn
N
N
Bn
N
N
N
OMe
N
O
MeO
O
3i
The title compound was synthesized according to the general procedure, and isolated as a
Colorless transparent solid (eluent PE : EtOAc = 1:1 , Rf = 0.5, 64.2 mg, 88% yield).
o
1
M.p.: 68- 69 C. H NMR (400 MHz, CDCl3) δ 7.27-7.26 (m, 6H), 6.79 – 6.77 (m, 4H),
5.51 (s, 4H), 4.16 (s, 2H), 3.74 (s, 3H), 3.46 (d, J = 16.0 Hz, 2H), 3.40 (s, 3H), 3.35 (d, J
= 16.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 202.4, 170.9, 145.6, 133.9, 129.2, 128.7,
126.3, 123.4, 76.0, 64.9, 59.5, 53.4, 53.0, 28.5. HRMS (ESI) m/z calculate for (M+H+)
+
C26H27N6O4 487.2088, Found: 487.2046.
1,9-Bis(anthracen-9-ylmethyl)-4,5,6,9-tetrahydro-1H-cyclohepta[1,2-d:3,4-d']bis([1,2,3]
triazole) (3j)
N
N
N
N
N
N
3j
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2
3
4
5
6
7
8
9
The title compound was synthesized according to the general procedure, and isolated as a
white solid (eluent PE : EtOAc = 2:1 , Rf = 0.3. 53.4 mg, 64% yield). M.p.: 213- 214 oC.
1H NMR (400 MHz, CDCl3) δ 8.47 (s, 2H), 8.02 – 8.00 (m, 4H), 7.77 – 7.75 (m, 4H),
7.49 – 7.43 (m, 8H), 6.37 (s, 4H), 2.52 (t, J = 6.8 Hz, 4H), 2.01 – 1.95 (m, 2H).13C NMR
(100 MHz, CDCl3) δ 148.7, 131.4, 130.6, 130.1, 129.7, 127.4, 125.3, 123.7, 123.5, 122.8,
10
11
12
13
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17
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19
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29
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31
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40
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
47.5, 28.8, 22.7. HRMS (ESI) m/z calculate for (M+H+) C37H29N6 557.2448, Found:
557.2438.
(2R,3S,4R,5S)-5-(9-((2R,3R,4R,5R)-3,4-Diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)o
xepino[3,4-d:5,6-d']bis([1,2,3]triazole)-1(4H,6H,9H)-yl)tetrahydrofuran-2,3,4-triyl
triacetate (3k)
OAc
OAc
AcO
OAc
N
O
O
AcO
AcO
N
N
N
N
N
O
3k
The title compound was synthesized according to the general procedure, and isolated as a
colorless oil (eluent PE : EtOAc = 1:2 , Rf = 0.4, 56.1 mg, 55% yield). 1H NMR (400
MHz, CDCl3) δ 6.38 (d, J = 4.0 Hz, 2H), 6.20 – 6.18 (m, 2H), 5.85 (t, J = 5.0 Hz, 2H),
5.19 (d, J = 15.3 Hz, 2H), 4.87 (d, J = 15.3 Hz, 2H), 4.50 – 4.44 (m, 4H), 4.25 – 4.22 (m,
2H), 2.13 (s, 6H), 2.09 (s, 6H), 2.07 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 170.6, 169.5,
169.2, 147.8, 122.9, 88.2, 81.9, 74.2, 71.4, 66.3, 62.5, 20.8, 20.6, 20.5. HRMS (ESI) m/z
calculate for (M+H+) C28H35N6O15+ 695.2155, Found: 695.2168.
1,9-Bis(anthracen-9-ylmethyl)-1,4,6,9-tetrahydrooxepino[3,4-d:5,6-d']bis([1,2,3]triazole)
(3l)
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3
4
5
6
7
8
9
N
O
N
N
N
N
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
N
3l
The title compound was synthesized according to the general procedure, and isolated as a
yellow solid (eluent PE : EtOAc = 3:1 , Rf = 0.2. 56.9 mg, 68% yield). M.p.: 208- 209
oC. 1H NMR (600 MHz, CDCl3) δ 8.52 (s, 2H), 8.05 – 8.03 (m, 4H), 7.75 – 7.73 (m, 4H),
7.47 – 7.45 (m, 8H), 6.52 (s, 4H), 4.65 (s, 4H).13C NMR (100 MHz, CDCl3) δ 147.4,
131.4, 130.7, 130.4, 129.8, 127.7, 125.4, 123.9, 123.2, 122.6, 63.9, 48.1. HRMS (ESI)
m/z calculate for (M+Na+) C36H26N6NaO+ 581.2060, Found: 581.2062.
Characterization of compounds 3m-3s
1,10-Dibenzyl-1,4,5,6,7,10-hexahydrocycloocta[1,2-d:3,4-d']bis([1,2,3]triazole) (3m)
N
N
N
Bn
Bn
N
N
N
3m
The title compound was synthesized according to the general procedure, and isolated as a
pale-yellow solid (eluent PE : EtOAc = 2:1 , Rf = 0.3. 41.6 mg, 75% yield). M.p.: 164-
165 oC. 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.22 (m, 6H), 6.92 – 6.89 (m, 4H), 5.52 (d,
J = 15.2 Hz, 2H), 5.17 (d, J = 15.2 Hz, 2H), 3.08 – 3.05 (m, 2H), 1.86 – 1.83 (m, 4H),
13
1.34-1.29 (m, 2H). C NMR (100 MHz, CDCl3) δ 150.0, 133.2, 128.0, 127.8, 126.1,
120.6, 52.2, 26.7, 23.8. HRMS (ESI) m/z calculate for (M+H+) C22H23N6 Exact Mass:
+
371.1979, Found: 371.1989.
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1,11-Dibenzyl-4,5,6,7,8,11-hexahydro-1H-cyclonona[1,2-d:3,4-d']bis([1,2,3]triazole)
5
6
(3n)
7
8
N
N
9
N
Bn
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
Bn
N
N
N
3n
The title compound was synthesized according to the general procedure, and isolated as a
white solid (eluent PE : EtOAc = 2:1 , Rf = 0.4. 42.1 mg, 73% yield). M.p.: 145- 146 oC.
1H NMR (400 MHz, CDCl3) δ 7.30-7.26 (m, 6H), 6.95-6.92 (m,4H), 5.26 (d, J = 14.8 Hz,
2H), 4.66 (d, J = 14.8 Hz, 2H), 2.72 – 2.64 (m, 2H), 1.76 – 1.73 (m, 2H), 1.38 – 1.28 (m,
2H), 1.27 – 1.23 (m, 2H), 1.19 – 1.11 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 150.2,
134.3, 129.2, 129.0, 127.9, 121.1, 52.9, 27.4, 26.3, 24.8. HRMS (ESI) m/z calculate for
+
(M+H+) C23H25N6 385.2135, Found: 385.2147.
3,4-Dibenzyl-3,4,7,14-tetrahydrobenzo[2,3][1,4]dioxecino[6,7-d:8,9-d']bis([1,2,3]triazol
e) (3o)
O
N
N
N
Bn
Bn
O
N
N N
3o
The title compound was synthesized according to the general procedure, and isolated as a
pale-yellow solid (eluent PE : EtOAc = 2:1 , Rf = 0.3. 47.9 mg, 71% yield). M.p.: 18.-
187 oC. 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.26 (m, 4H), 7.24 (s, 2H), 6.92 – 6.84 (m,
4H), 6.83 – 6.79 (m, 4H), 5.29 (d, J = 14.8 Hz, 2H), 5.07 (d, J = 13.2 Hz, 2H), 4.69 (d, J
= 14.8 Hz, 2H), 4.17 (d, J = 13.2 Hz, 2H). 13C NMR (100 MHz, CDCl3 ) δ 149.1, 146.7,
132.8, 128.3, 128.2, 126.7, 123.1, 121.5, 120.2, 64.9, 52.2. HRMS (ESI) m/z calculate for
(M+H+) C26H23N6O2 451.1877, Found: 451.1856.
+
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5
6
1,13-Dibenzyl-4,6,7,8,10,13-hexahydro-1H-[1,5]dioxacycloundecino[7,8-d:9,10-d']bis([
7
8
1,2,3]triazole) (3p)
9
N
N
N
O
O
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
Bn
Bn
N
N
N
3p
The title compound was synthesized according to the general procedure, and isolated as a
white solid (eluent PE : EtOAc = 2:1 , Rf = 0.4. 45.6 mg, 73% yield). M.p.: 201- 202 oC.
1H NMR (400 MHz, CDCl3) δ 7.35 – 7.29 (m, 6H), 6.89-6.87 (m, 4H), 4.94 (d, J = 15.0
Hz, 2H), 4.57 (d, J = 15.0 Hz, 2H), 4.38 (d, J = 14Hz, 2H), 3.79 (d, J = 14 Hz, 2H), 3.25
– 3.14 (m, 4H), 1.59 – 1.54 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 148.2, 133.9, 129.3,
129.1, 127.8, 122.0, 63.5, 62.7, 52.7, 31.0. HRMS (ESI) m/z calculate for (M+H+)
+
C23H25N6O2 417.2034, Found: 417.2017.
3,4-Dibenzyl-3,4,7,18-tetrahydrodibenzo[2,3:4,5][1,6]dioxacyclododecino[8,9-d:10,11-d
']bis([1,2,3]triazole) (3q)
N
O
N
N
Bn
Bn
N
N
O
N
3q
The title compound was synthesized according to the general procedure, and isolated as a
white solid (eluent PE : EtOAc = 2:1, Rf = 0.5. 50.5 mg, 64% yield). M.p.: 273- 274 oC.
The product as a mixture of two isomers (the ratio is 0.7:1). 1H NMR (400 MHz, CDCl3)
δ 7.43 – 7.41 (m, 2H), 7.36 – 7.29 (m, 11H), 7.22 – 7.18 (m, 2H), 7.11 – 7.09 (m, 4H),
6.97 – 6.88 (m, 10H), 6.47 (d, J = 8.0 Hz, 2H), 5.30 (d, J = 14.8 Hz, 2H), 5.14 (d, J =
14.0 Hz, 1.4H), 4.93 (d, J = 14.8 Hz, 1.4H), 4.73 (d, J = 10.4 Hz, 2H), 4.61 (d, J = 14.8
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7
8
Hz, 2H), 4.47 (d, J = 14.8 Hz, 1.4H), 3.88 (d, J = 14.4 Hz, 1.4H), 3.54 (d, J = 10.4 Hz,
2H). 13C NMR (150 MHz, CDCl3) δ 156.2, 153.9, 146.9, 133.9, 133.4, 132.2, 130.4,
129.4, 129.4, 129.3, 128.6, 128.5, 128.4, 128.2, 128.1, 127.9, 122.8, 122.7, 121.1, 120.9,
9
+
110.7, 59.7, 57.4, 53.3, 53.1. HRMS (ESI) m/z calculate for (M+H+) C32H27N6O2
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
527.2190, Found: 527.2201.
15,16-Dibenzyl-12,15,16,19-tetrahydrodinaphtho[2',1':2,3;1'',2'':4,5][1,6]dioxacyclodod
ecino[8,9-d:10,11-d']bis([1,2,3]triazole) (3r)
N
N
N
Bn
Bn
O
O
N
N
N
3r
The title compound was synthesized according to the general procedure, and isolated as a
white solid. The product as a mixture of two isomers (the ratio is 6:1). (For isomer 1 (3r),
o
1
eluent PE : EtOAc = 2:1 , Rf = 0.4. 55.5 mg, 59% yield). M.p.: 134- 135 C. H NMR
(400 MHz, CDCl3) δ 7.80 – 7.77 (m, 2H), 7.71 – 7.66 (m, 4H), 7.17 – 7.08 (m, 8H), 7.06
– 7.02 (m, 2H), 6.91 – 6.89 (m, 2H), 6.71 – 6.69 (m, 4H), 5.17 (d, J = 14 Hz, 2H), 4.71 (d,
J = 14.8 Hz, 2H), 4.33 (d, J = 14.8 Hz, 2H), 3.77 (d, J = 14 Hz, 2H). 13C NMR (150 MHz,
CDCl3) δ 151.6, 146.8, 133.9, 133.3, 129.4, 129.2, 129.0, 128.3, 128.2, 126.4, 125.1,
123.5, 122.7, 119.0, 113.9, 58.3, 53.0. HRMS (ESI) m/z calculate for (M+H+)
+
C40H31N6O2 627.2503, Found: 627.2537.
(For isomer 2 (3r’), eluent PE : EtOAc = 2:1 , Rf = 0.3. 9.4 mg, 10% yield). M.p.: 134-
o
1
135 C. H NMR (400 MHz, CDCl3) δ 7.82 – 7.76 (m, 4H), 7.48 – 7.44 (m, 2H), 7.38 –
7.34 (m, 4H), 7.25 – 7.20 (m, 2H), 7.09 – 7.05 (m, 2H), 6.90 – 6.87 (m, 6H), 6.84 – 6.82
(m, 2H), 5.26 (d, J = 14.8 Hz, 2H), 4.84 (d, J = 10.8 Hz, 2H), 4.57 (d, J = 14.8 Hz, 2H),
13
3.66 (d, J = 10.8 Hz, 2H). C NMR (150 MHz, CDCl3) δ 154.3, 147.0, 134.2, 133.9,
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The Journal of Organic Chemistry
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129.5, 129.4, 129.3, 129.1, 128.2, 127.9, 126.4, 126.0, 123.6, 122.5, 118.2, 113.6, 60.8,
5
6
+
53.3. HRMS (ESI) m/z calculate for (M+H+) C40H31N6O2 627.2503, Found: 627.2507.
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15,16-Dibenzyl-12,15,16,19-tetrahydrodinaphtho[2',1':2,3;1'',2'':4,5][1,6]dioxacyclodod
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ecino[8,9-d:10,11-d']bis([1,2,3]triazole) (3s)
N
N
N
Bn
Bn
O
O
N
N
N
3s
The title compound was synthesized according to the general procedure, and isolated as a
white solid. The product as a mixture of two isomers (the ratio is 7:1). (For isomer 1 (3s),
eluent PE : EtOAc = 2:1 , Rf = 0.3. 60.1 mg, 64% yield). M.p.: 127- 128 oC. H NMR
1
(400 MHz, CDCl3) δ 7.86 – 7.83 (m, 2H), 7.77 – 7.72 (m, 4H), 7.24 – 7.16 (m, 8H), 7.13
– 7.09 (m, 2H), 6.98 – 6.96 (m, 2H), 6.78 – 6.76 (m, 4H), 5.22 (d, J = 14.2 Hz, 2H), 4.77
(d, J = 15.2 Hz, 2H), 4.39 (d, J = 15.2 Hz, 2H), 3.82 (d, J = 14.2 Hz, 2H). 13C NMR (150
MHz, CDCl3) δ 151.6, 146.8, 133.9, 133.3, 129.4, 129.2, 129.1, 128.3, 128.2, 126.4,
125.1, 123.5, 122.7, 119.1, 113.9, 58.3, 53.1. HRMS (ESI) m/z calculate for (M+H+)
+
C40H31N6O2 627.2503, Found: 627.2536.
(For isomer 2 (3s’), eluent PE : EtOAc = 2:1 , Rf = 0.4. 8.5 mg, 9% yield). M.p.: 123-124
1
oC. H NMR (400 MHz, CDCl3) δ 7.82 – 7.76 (m, 4H), 7.48 – 7.44 (m, 2H), 7.38 – 7.34
(m, 4H), 7.25 – 7.22 (m, 2H), 7.09 – 7.05 (m, 2H), 6.90 – 6.87 (m, 6H), 6.84 – 6.82 (m,
2H), 5.26 (d, J = 14.8 Hz, 2H), 4.84 (d, J = 10.8 Hz, 2H), 4.57 (d, J = 14.8 Hz, 2H), 3.66
(d, J = 10.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 154.3, 134.2, 133.9, 129.5, 129.4,
129.3, 129.2, 128.2, 127.9, 126.4, 126.0, 123.6, 122.5, 118.2, 113.6, 60.8, 53.3. HRMS
+
(ESI) m/z calculate for (M+H+) C40H31N6O2 627.2503, Found: 627.2541.
Characterization of compounds 3aa and 3ab
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