Double Cu-Catalyzed Direct Csp3?H Azidation/CuAAC Reaction: A Direct Approach towards Demanding Triazole Conjugates

Article abstract of DOI:10.1002/chem.201806288

The first one-pot procedure for the double copper(I)-catalyzed oxidative Csp³?H azidation–CuAAC process, implying unstable azide intermediates and easy-to-remove reagents under water-tolerant conditions, is presented. The combination of tert-butyl hydroperoxide as oxidant and TMSN₃ as azide source for the C?H bond azidation, which produces harmless side-products such as tBuOH and H₂O, probed to be perfectly compatible with the following cycloaddition step. Highly demanding 1,2,3-triazoles could be then directly obtained in good overall yields by extraction or simple crystallization, thus avoiding chromatography purifications. The potential of this methodology, has also being highlighted by the successful reaction of alkynes presenting interesting complex biological moieties based for example on biotin, DNA base or cinchona alkaloid units.

Full text of DOI:10.1002/chem.201806288

A Journal of
Accepted Article
Title: Double Cu-Catalyzed Direct Csp3-H Azidation / CuAAC
Reaction: A Direct Approach towards Demanding Triazole
Conjugates
Authors: Tobias Brandhofer, Aysegül Özdemir, Andrea Gini, and Olga
García Mancheño
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To be cited as: Chem. Eur. J. 10.1002/chem.201806288
Link to VoR: http://dx.doi.org/10.1002/chem.201806288
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10.1002/chem.201806288
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Double Cu-Catalyzed Direct Csp3-H Azidation / CuAAC Reaction:
A Direct Approach towards Demanding Triazole Conjugates
Tobias Brandhofer,[a][b] Aysegül Özdemir,[b] Andrea Gini,*[b] Olga García Mancheño*[a]
Dedication ((optional))
Abstract: The first one-pot procedure for the double copper(I)-
catalyzed oxidative Csp3-H azidation – CuAAC process, implying
unstable azide intermediates and easy-to-remove reagents under
water-tolerant conditions, is presented. The combination of TBHP as
oxidant and TMSN3 as azide source for the C-H bond azidation, which
produces harmless side-products such as tBuOH and H2O, probed to
be perfectly compatible with the following cycloaddition step. Highly
demanding 1,2,3-triazoles could be then directly obtained in good
overall yields by extraction or simple crystallization, thus avoiding
chromatography purifications. The potential of this methodology, has
also being highlighted by the successful reaction of alkynes
presenting interesting complex biological moieties based for example
on Biotin, DNA base or cinchona alkaloid units.
synthetic limitation. While most of simple aliphatic azides are
particularly stable toward various reaction and storage conditions,
such as the presence of water or dioxygen,[1,4,8-9] in the cases in
which a stable radical or carbocation can be generated, the azide
unit of the C(sp3)-N3 species is promptly cleaved (Scheme 1, top).
Indeed, certain azides are sensitive to elimination under standard
functionalization reactions, such as the CuAAC, which would led
to degradation or undesired side-reactions.[10] Therefore, the in
situ generation and trapping of the azide would be essential when
the target is difficult to handle in the required environment for the
work-up, purification and following synthetic step. However, the
one-pot procedures reported in literature are essentially limited to
nucleophilic substitutions,[11] diazo transfers[12] or addition to
epoxides,[13] which required a pre-functionalization (e.g. use of an
alkyl halide, etc) on the molecule where the azide has to be
installed. Conversely, the one-pot combination of the more
convenient direct C-H bond azidation[14-16] of organic molecules
with CuAAC remains fundamentally unexplored.[17-18] This
restraint might be the result of the interaction between the copper
catalyst and the standard hypervalent iodine(III)-containing
reagents used for C-H bond azidation reactions (Scheme 1,
middle).[14] In fact, such iodine reagents and their by-products
have the potential to deactivate the copper species involved in the
CuAAC catalytic cycle.[19]
Introduction
The 1,2,3-triazole heterocycle[1] has become in the past years an
essential artificial amide bio-isosteric[2] core for the development
of novel lead-target biological active molecules for
pharmacological and agrochemical applications.[3,4] 1,2,3-
Triazole-containing molecules present hence important biological
activities,[3,4] while their synthesis can be easily achieved.[1,5] In
this regard, the copper catalyzed azide-alkyne cycloaddition
(CuAAC) reaction,[6] discovered independently by the groups of
Fokin and Sharpless, and Meldal,[7] was elevated as the most
prominent approach for the straightforward, highly efficient and
selective synthesis of 1,4-substituted 1,2,3-triazoles.[5-6,8]
Moreover, the introduction of the CuAAC reaction has also
revolutionized the area of biochemistry, since it tolerates aqueous
media and allows the orthogonal, fast generation of a large variety
of bio-conjugates upon reaction of the appropriate alkyne and
organic azide coupling partners.[3,9] However, an important aspect
to be considered is the accessibility of the azide reagent. Although
the insertion of an azide moiety into organic molecules may
appear an established procedure,[10] on a number of occasions
the synthesis and handling of organic azides might become a real
Elimination issue with "unstable" azides:
desired
reaction
side-
pathway
N3
decomposition/
undesired products
Product
unstable azide
Previous work: Typical 2-step direct oxidative aliphatic C-H bond azidation /
functionalization sequence
Isolation
1) C-H azidation
2) Click-reaction
R
N
e.g. "CuAAC"
N3
Iodo(III)-azide
species
N
H
"Cu(I)"
N
-[H]
R
+
uncompatible issues
of Iodo-containing
reagents/by-products
Not suitable for a
one-pot CuAAC
This work: One-pot C(sp3)-H bond azidation/cycloaddition reaction
[a]
[b]
T. Brandhofer, Prof. Dr. O. García Mancheño,
Organic Chemistry Institute,
Münster University,
Corrensstr. 40, 48149 Münster, Germany
E-mail: olga.garcia@uni-muenster.de
T. Brandhofer, A. Özdemir, Dr. A. Gini,
Organic Chemistry Institute,
CuAAC step
Direct azidation step
N3
R
N
Oxidant / "Cu"cat.
"N3" source
N
H
N
R
+
unreactive/compatible
oxidant by-products
Regensburg University,
Universitätstr. 31, 93053 Regensburg, Germany
E-mail: andrea.gini@unige.ch
Scheme 1. Common oxidative C-H azidation sequence reactions and our
double Cu-catalyzed one-pot approach.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201806288
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To solve the current limitations, expand the application field
of direct azidation and develop a general and robust one-pot
methodology, we envisioned a mild and facile double copper-
catalyzed approach for the oxidative Csp3-H azidation – trapping
of unstable azides by CuAAC, implying common and easy-to-
remove compatible reagents (Scheme 1, bottom).
(99% vs. 40 and 92% with Cu2O and CuSO4, respectively).
Alternatively, NaN3 was used as azide source, displaying a
notably lower reactivity (20% conversion, entry 7). Moreover, the
decrease of the equivalents of azide reagent TMSN3 from 2 to 1.2
did not show a significant effect on the performance of the
reaction, providing similar good results (entry 8). Finally, we were
pleased to observe a superior reactivity of the standard aqueous
TBHP solution compared to anhydrous TBHP (3M in isooctane),
which mainly led to the overoxidation to xanthone (entry 9).
Although the main focus was the development of the one-
pot azidation/CuAAC reaction, the applicability of the first
azidation step was also shortly explored with a few different
types of representative substrates (Scheme 2). Thus,
besides xanthene, other benzylic, alpha to an heteroatom
and even the more difficult to oxidize allylic substrates, such
as 2-methylquinoline (1b), N,N-dimethyl toluidine (1c) and
cyclohexene (1d), could be directly transformed into the
Results and Discussion
Based on the experience on Csp3-H bond functionalization of
xanthene and acridane moieties acquired in our laboratory,[20] we
decided to start our investigations with the optimization of the
reaction involving the commercially available, cheap and bench-
stable xanthene (1a) as model substrate and precursor of the
unstable azide intermediate.[18,21] To ensure the highest
conversion into the desire azide 2a[18-20] and avoiding unwanted
side-products such as xanthone (3) by over-oxidation of the
substrate, the azidation step was first investigated (Table 1).
corresponding azides
2
in good yields.
N3
Table 1. Optimization of the C-H bond azidation step.[a]
N3
N
O
2a
H
N3
O
TMSN3 (1.2 equiv.)
TBHP (1.2 equiv.)
"N3" source
2b
H
TBHP (1.2 equiv.)
80%
62%
CuBr (10 mol%)
MeCN, 50 °C
"Cu" cat. (10 mol%)
MeCN, 50 °C
- H2O; - tBuOH
O
O
O
N
N3
1a
2a
3
N3
2d
74%b
2c
Conv.
(%)[b]
99(86)[c]
--[d,e]
Ent.
“Cu” cat.
Oxidant
“N3“ (equiv.)
t (h)
90%
a Yields after work-up and extraction (see S.I.).
b
1
2
3
4
5
6
7
8
9
CuBr
CuBr
CuBr
Cu2O
CuI
TBHP
DDQ
TMSN3 (2.0)
TMSN3 (2.0)
TMSN3 (2.0)
NaN3 (2.0)
2
18
18
24
24[4]
24
24
2
Reaction at 100 °C for 4 h using 1 equiv. of TMSN3 and 5 equiv. of 1d.
Scheme 2
.
Oxidative C-H bond azidation step with some selected
PIDA
90
representative substrates
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
40
After having optimized the azidation step (TBHP 70% in
H2O, CuBr (10 mol%), TMSN3 (1.2 equiv.) in MeCN for 2 h at
50 °C), the one-pot process was studied (Table 2). Thus,
after the azidation reaction, the mixture was initially allowed
to cool down to room temperature, and the phenyl acetylene
NaN3 (2.0)
99[70]
92
CuSO4·5H2O
CuBr
TMSN3 (2.0)
NaN3 (2.0)
20
CuBr
TMSN3 (1.2)
TMSN3 (1.2)
99(80)[c]
99[e,f]
CuBr
2
(
4a) and sodium ascorbate were added. Unfortunately, only
[a] 1a (0.4 mmol, 1 equiv.), TMSN3 (2 equiv.), tBuOOH 70% in H2O (1.2
equiv.) and catalyst (10 mol%) were reacted in MeCN (0.4 M) at 50 °C. [b]
Conversion determined by 1H-NMR analysis. [c] Yield of 2a after work-up
and extraction in brackets. [d] A mixture complex was observed. [e]
traces of the desired triazole product 5aa could be then
observed (entry 1). To our delight, the simple addition of tert-
butyl alcohol as co-solvent to improve the solubility of the
reaction mixture was enough to achieve full conversion in 24
h at room temperature, providing the desire product in a
satisfying 62% yield (entry 2). The one-pot reaction with the
PIDA/TMSN3 system (for the first step see Table 1, entry 3) was
also carried out as control experiment (entry 3). However, as we
anticipated, it only led to a low 14% yield of 5aa, showing the
already mentioned incompatibility issues of the iodo-based
oxidants within the second step. Moreover, the addition of
standard ligands utilized in CuAAC processes, such as
tris(benzyltriazolylmethyl)amine (TBTA), glycol or 2,2’-bipyridine
(bpy), decreased the reactivity (entries 4-6). On the contrary, the
use of 50 °C for both steps led to an increased 68% overall yield
after 24 h (entry 7).
Xanthone (
3M in isooctane was used
3) was obtained as major product after work-up. [f] tBuOOH
.
Initially, tert-butyl hydroperoxide (TBHP) 70% in water was
employed in the presence of copper bromide as catalyst[22] and
TMSN3 as azide source. A full conversion into the desired product
was observed after 2 hours at 50 °C (entry 1). Other standard
oxidants in cross-dehydrogenative coupling (CDC)[23] of C(sp3)-H
bonds such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) and phenyliodine diacetate (PIDA) were also explored
(entries 2-3). While the formation of the product 2a could not be
observed with DDQ, a good 90% conversion over a prolonged
reaction time (18 vs. 2 h) was achieved with PIDA (entry 3). Next,
various Cu(I) species such as Cu2O and CuI, and CuSO4, as one
of the most employed Cu-catalyst in CuAAC reactions, were
tested (entries 4-6). However, all of those catalysts required
longer reaction times (24 vs. 2 h) for achieving an acceptable
conversion, being CuI among them the most competitive species
The main issue regarding the formation of the triazole ring is
the intrinsic instability of the azide intermediate 2a. Indeed, the
decomposition pathway to the corresponding xanthone (3)
become predominant as the reaction time increases. However,
under the same conditions, the reaction at 50 °C after 4 h showed
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no full conversion (entry 8). In general, the rate determining-step
moderate to good yields (54%-79%). To our delight, alkyl
acetylenes, which are known to react slower in CuAAC
processes,[4] were active under the optimized condition. Thus, the
products 5at-v were achieved in moderate but synthetically
practical yields (45-52%). However, no steric influence was
observed between n-butyl (5at, 45%), cyclohexyl (5au, 52%) and
t-butyl (5av, 47%) derivatives.
Noteworthy, the procedure proved to be very robust, providing
a similar high 85% yield of 5aa when conducting on a one-gram
scale (Scheme 3, top). Moreover, in the reaction with bis-terminal
alkynes, a controlled and complete selectivity between the mono
and bis-cyclization was obtained by a careful choice of the
stoichiometry (Scheme 3, bottom). Hence, the desire bis-click
product 6 was obtained as only product in almost quantitative
yield in the presence of 0.46 equiv. of bis-alkyne 4w as limiting
reagent (Scheme 3, entry A). Alternatively, the sole formation of
the mono cyclization product 5aw was observed when using 4w
in excess (2.4 equiv.; Scheme 3, entry B).
for the CuAAC reaction comprises
a Cu-acetylide, which
formation is influenced by the nature of the alkyne and the
presence of a base.[6,24] Therefore, in order to accelerate the
process, several bases were next investigated (entries 9-12). As
expected, all the tested bases led to a faster overall reaction and
better yields (72-82%). Diisopropylethyl amine (DIPEA) provided
the best results in term of yield and reaction time, leading to 5aa
in a good 82% yield in only 4 h (entry 9). It is interesting to note
that 2,6-lutidine gave a similar yield than DIPEA but provided a
significant higher amount of decomposition products (entry 12).
Table 2. Optimization of the one-pot sequence.[a]
Ph
N
CuBr
(10 mol%)
4a
N3
H
(1.2 equiv.)
N
N
TBHP, TMSN3
additive
MeCN
50 °C, 2 h
Na ascorb.
(0.4 equiv.)
O
O
O
T (°C), t (h)
2a
1a
5aa
Table 3. Scope of the reaction of 1a with various alkynes 4[a][b]
co-
Yield
Entry
Additive (eq.)
T (°C)
t (h)
R
solvent
--
(%)[b]
traces
62
i)
CuBr (10 mol%)
N
H
TMSN3, TBHP (1.2 equiv.)
1
2
-
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
50
50
50
50
50
24
24
24
24
24
24
24
4
N
MeCN, 50 °C, 2 h
N
-
tBuOH
tBuOH
tBuOH
glycol
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
then, ii) 4 (1.2 equiv.)
3
-
TBTA (0.3)
--
14[c]
48
O
Na ascorb. (0.4 equiv.)
DIPEA (1.5 equiv)
4
O
5
17[d]
traces
68
1a
tBuOH, 50 °C, 4-24 h
5
6
bpy (0.3)
-
R'
R'
7
82%
76%
70%
63%
70%
72%
5aa
H
R'
8
-
42[e]
82
5ab Me
5ac OMe
5ad Ph
5ae
5af CO2Me
R'
9
DIPEA (1.5)
Et3N (1.5)
K2CO3 (1.5)
2,6-lutidine (1.5)
4
N
N
5ag
5ah
Me 58%
Cl 54%
10
11
12
4
78
N
N
F
N
N
18
4
72
xanthene
xanthene
80
F3C
[a] 1a (0.4 mmol, 1 equiv.), TMSN3 (2 equiv.), TBHP 70% in H2O (1.2
equiv.) and CuBr (10 mol%) in MeCN (0.4 M) at 50 °C for 2 h; then alkyne
4a (1.2 equiv.), Na ascorbate (0.4 equiv.), the additive and tBuOH (2.5
mL/mmol) as co-solvent were added to the mixture and stirred at the
corresponding temperature. [b] Isolated yields. [c] The PIDA/TMSN3
system was used for the azidation step. [d] Glycol was used instead of
tBuOH as co-solvent. [e] No full conversion.
R'
N
CF3
R'
N
N
5ai
5aj
5ak
Me 52%
Cl 51%
CN 62%
N
N
N
N
5am
69%
5al
68%
N
N
xanthene
xanthene
xanthene
R'
OR'
S
Next, various alkynes were screened in the reaction (Table 3).
Firstly, several aryl-substituted acetylenes bearing electron-
withdrawing and donating groups, as well as substituents in the
ortho-, para- and meta-position, were tested. The method showed
a good steric and electronic functional group tolerance, providing
in all cases the substituted products 5aa-5am in good yields (up
to 82%). Even heteroarene-containing acetylenes such as
thiophene, gave the desire product 5an in a satisfactory 62%
yield. Although no clear electronic effects could be observed, the
reaction was slightly influenced by steric hindrance on the alkyne.
Hence, ortho-substituted phenyl acetylenes provided the products
(5ai-k) in lower yields than the related regioisomers (e.g. 4-
MeC6H4 5ab, 76% vs 3-MeC6H4 5ag, 58% vs 2-MeC6H4 5ai,
52%).
R'
R'
N
N
N
N
N
N
N
N
5ao
5ap
5aq
5ar
5an
62%
OH 79%
NMe2 70%
Me 54%
H
N
56%
xanthene
xanthene
xanthene
O
Ph
N
H
N
N
N
N
N
N
N
N
N
5as
69%
5at
52%
5au
47%
5av
45%
N
N
N
xanthene
xanthene
xanthene
xanthene
[a] 1a (0.4 mmol, 1 equiv.), TMSN3 (2 equiv.), TBHP 70% in H2O (1.2
equiv.) and CuBr (10 mol%) in MeCN (0.4 M) at 50 °C for 2 h; then (1.2
equiv.), Na ascorbate (0.4 equiv.), DIPEA (1.2 equiv.) and tBuOH (2.5
4
mL/mmol) were added and stirred at 50 °C. [b] Isolated yield.
Additionally, this methodology tolerates substrates bearing
demanding functional groups such as a hydroxyl (4o, 4r),
methoxide (4q), tertiary amine (4p) or amide (4s) in α to the
acetylene moiety, leading to the corresponding products 5 in
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Ph
trapping adduct of 1a could not be detected by NMR due to a fast
oxidation to xanthone 3, the formation of the more stable adduct
8c was quantitatively observed. This suggests a first radical
formation followed by a further oxidation to the corresponding
carbocation (or iminium) species, which finally react with the
nucleophilic azide reagent to form the observed products.
N
CuBr
(10 mol%)
TBHP, TMSN3
4a
(1.2 equiv.)
N
N
DIPEA
[2a]
MeCN
50 °C, 2 h
Na ascorb.
tBuOH
O
O
1a
(1 gram)
5aa
85% (1.79 grams)
Table 4. Scope: Different targets & anchoring of bio-probes[a,b]
N
N
N
R
TMSN3 (1.2 equiv.)
TBHP (1.2 equiv.)
4 (1.2 equiv.)
N
N3
H
DIPEA (1.5 equiv)
N
O
N
5aw
Na ascorb.
(0.4 equiv.)
CuBr (10 mol%)
MeCN, 50 °C
TBHP, TMSN3
(1.2 equiv.)
4w
(x equiv.)
tBuOH, 50 °C
[2a]
1a
+
5
1
2
Ph
Na ascorb.
(0.4 equiv.)
DIPEA (1.5 equiv)
tBuOH, 50 °C
N
CuBr (10 mol%)
MeCN, 50 °C
N
N
Ph
N
N
N
N
N
N
N
N
N
N
N
O
N
N
N
Ph
X
6
N
4w
5aw
6
N
Entry
N
(equiv.) Yield (%) Yield (%)
Ph
5ba[c]
R
O
OMe
84%
O
A
B
0.46
2.40
--
96
--
5ga
5ha
5ca
63%
X = Br
X = F
72%
56%
5ea
5fa
R = H
R = OMe
O
69
40%
86%
Ph
Scheme 3. Gram-scale, and mono- vs. bis-cycloaddition selectivity
5ax
N
65%
N
N
O
HO
N
The scope of the methodology was next investigated with
different type of substrates (Table 4). Whereas xanthene
derivatives 1e-h presenting electron rich groups gave the desire
products in high yields (84-86%; 5ea, 5fa), the reaction with
electron poor derivatives was slightly less efficient (56-72%; 5ga,
5ha). Furthermore, N,N-dimethylanilines could also be enrolled in
the reaction.[20] Thus, the p-toluidine derivative 1c gave the
product in a good overall 63% yield. Noteworthy, the developed
strategy allowed the transformation of the highly demanding 2-
methyl quinoline 1b,[25,26] a previously unexplored substrate in
direct azidation reactions. However, in this case the addition of a
double amount of sodium ascorbate (0.8 vs. 0.4 equiv.) was
required. In addition, the one-pot reaction with cyclohexene as
representative allylic substrate was also possible upon carrying
out the first azidation step at 100 °C (see Scheme 2), leading to
the triazole conjugate 5da in a good 69% yield. To our delight, the
reaction was also suitable for alkyne derivatives of important
bioactive compounds such as cinchona alkaloid derivatives (5ax,
65%; 5cx, 83%; and 5bx, 51%), nucleosides (5ay, 67%) or biotin
(5az, 62%).
BF4
N
N
R
N
N
5fx
83%
5bx
51%
5da
N
N
69%[d]
H
O
N
O
O
N
OH
OH
N
HN
H
NH
O
N
N
H
N
N
N
O
O
S
2
O
5ay
67%
5az
62%
O
[a] 1a (0.4 mmol, 1 equiv.), TMSN3 (2 equiv.), TBHP 70% in H2O (1.2
equiv.) and CuBr (10 mol%) in MeCN (0.4 M) at 50 °C for 2 h; then (1.2
4
equiv.), Na ascorbate (0.4 equiv.), DIPEA (1.2 equiv.) and tBuOH (2.5
mL/mmol) were added to the mixture and then stirred for 4-24 h at 50 °C.
[b] Isolated yield. [c] 0.8 equiv. of Na ascorbate was used. [d] First-step
reaction with 1d (5 equiv.), TMSN3 (1 equiv.) and TBHP (5.5M in decane)
at 100 °C for 4 h.
(1)
H
N3
TMSN3
(1.2 equiv.)
Ph3C+ClO4
-
MeCN
r.t., 1 h
O
O
O
At this stage, it is important to point out that this methodology
allows a facile isolation of the final products.[27] Thus, purification
by column chromatography could be avoided,[28] since the
evaporation and extraction or a simple precipitation of the crude
mixture provided pure products in good to excellent yields.
Motivated by these results, we subsequently carried out some
mechanistic studies for the azidation step (Scheme 4). In order to
analyze the radical or cationic character of the key intermediates
1a
7
2a
71%
(2)
H
OTEMP
not observed
(mainly xanthone 3)
CuBr (10 mol%)
TMSN3 (1.2 eq.)
tBuOOH (1.2 eq.)
TEMPO (2.0 eq.)
CD3CN, 50 °C, 4 h
O
O
1a
8a
or
or
in this reaction, the xanthene carbocation
7 was initially
N
N
O
N
synthesized by hydrogen abstraction of 1a with a trityl salt
(Ph3CClO4) (Scheme 4, eq. 1). This cationic species 7 was then
reacted with TMSN3, providing the product 2a in a good 71%. This
result indicates an ionic mechanism via 7 as electrophilic key
intermediate. Furthermore, radical trapping experiments with
2,2,6,6-tetramethyl-piperidinyloxyl radical (TEMPO) were
performed with both xanthene (1a) and the N,N-dimethylaniline
1c in MeCN-D3 (Scheme 4, eq. 2). Although the corresponding
H
1c
8c
quant.
Scheme 4. Key intermediates analysis: Isolation of a cationic species and
radical trapping studies.
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With this information, and based on related isolated Cu-
catalyzed TBHP-mediated C-H functionalization and the well-
known CuAAC processes reported in the literature,[24,29] the
postulated reaction mechanism for the double Cu-catalyzed one-
pot process is outlined in Scheme 5. Accordingly, in the first step
the Cu(I) catalyst promote the homolytic cleavage of the organic
peroxide TBHP, leading to the tert-butoxy radical (tBuO•) and
Cu(II)-OH species. The formed tBuO• is then able to abstract a
hydrogen radical from the substrate 1a to form tBuOH and the C-
centered radical intermediate I. The radical I subsequently
undergoes a SET process with the Cu(II) complex present in the
media, leading to the carbocation 7. In this step, a Cu(I) species
is also generated, closing hence the first Cu-catalytic cycle. Next,
the electrophilic intermediate 7 reacts with the TMSN3 nucleophile
to form in situ the organic azide 2a. After addition of the rest of the
reagents required for the CuAAC reaction, the Cu(I) species
interacts with the terminal acetylene 4a, giving the active Cu-
acetylide. This species undergoes a 1,3-dipolar cycloaddition
reaction with the previously formed azide 2a, providing the 1,2,3-
triazolyl cuprate III. Finally, a protolysis of III to give the product
5aa and liberation of the active Cu(I) species closes the second
Cu-catalytic cycle.
biological interesting alkynes based for example on Biotin, a DNA
base or cinchona alkaloids were successfully implemented.
Finally, due to its simplicity and the good overall yields
considering the involved sensitive intermediates, this
methodology presents a great potential for the preparation of
challenging bioconjugates.
Experimental Section
General information and materials:
1H, 13C and 19F NMR spectra were recorded in CDCl3, CD3CN and DMSO-
D6 (reference signals: 1H = 7.26 ppm, 13C = 77.16 ppm, CDCl3) on a Bruker
ARX-300, a Bruker ARX-400, Bruker Avance II 300, Bruker Avance II 400
or a Jeol JNM-ECS 400 MHz. Chemical shifts (d) are given in ppm and
spin-spin coupling constants (J) are given in Hz. Analytical thin layer
chromatography was performed using silica gel 60 F254 and I2 served as
staining agent. Column chromatography was performed on silica gel 60
(0.040-0.063 mm). Exact masses (HRMS) were recorded on an Agilent Q-
TOF 6540 UHD or Bruker MicrOTof ESI spectrometer using electrospray
ionization (ESI) techniques or on an Finnigan MAT SSQ 710
spectrometer using electron impact (EI) techniques.
A
The starting materials 3e,[20a, 29] 3f,[30] 3g and 3h,[20a, 29] 4q,[31] 4s,[32] 4w,[33]
4x[34] and 4z[35] were prepared following known literature procedures.
Alternatively, xanthenes 1 were synthetized from the corresponding
xanthones 3 in a sequential manner.[20a] CH3CN was distilled over CaH2.
Other solvents and commercially available reagents were used without
further purification.
N3
δ+ δ-
TMS-N3
Ph
δ+
N
O
O
N
DIPEA
[Cu]
N
O
δ-
Standard procedure for the tandem azidation-click-reaction:
Ph
H
7
2a
4a
CuBr (5.7 mg, 0.04 mmol, 10 mol%) and the substrate 1 (0.4 mmol, 1.0
eq) were dissolved in 1 mL CH3CN. TMSN3 (63.7 μL, 0.48 mmol, 1.2 eq)
and tBuOOH (70% in H2O; 65.7 μL, 0.48 mmol, 1.2 eq) were added and
the solution was stirred at 50 °C for 2-2.5 h. Then, sodium ascorbate (31.7
mg, 0.4 mmol, 0.4 eq), 1 mL tBuOH, DIPEA (95.2 μL, 0.3 mmol, 1.5 eq)
and the acetylene 4 (0.48 mmol, 1.2 eq) were successively added. After
stirring the mixture at 50 °C for 18 h, H2O (10 mL) and DCM (10 mL) were
added. The two phases were separated and the aqueous phase was
extracted with DCM (3x10mL). The combined organic phases were
washed with brine, dried over MgSO4 and the solvent was removed under
vacuum. The crude product was further purified by recrystallization or flash
column chromatography.
SET
II
catalytic
cycle 2
catalytic
cycle 1
- tBuOH
- OH-
CuII
CuI
Ph
[Cu]
N
III
tBuO-OH
N
N
- H
R
H
R
N H
R
O
protolysis
O
O
Analytical data of the products:
I
1a
5aa
4-Phenyl-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole (5aa): According to the
standard procedure, the crude was recrystallized from CH3CN to obtain
the product 5aa (107 mg, 0.33 mmol, 82 %) as a white solid. 1H NMR (400
MHz, CDCl3) δ 7.77 – 7.72 (m, 2H), 7.47 – 7.38 (m, 5H), 7.36 (d, J = 3.0
Hz, 2H), 7.30 (d, J = 7.8 Hz, 3H), 7.26 (s, 1H), 7.19 – 7.13 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 151.0, 130.7, 130.5, 129.7, 128.8, 128.3, 125.7,
124.3, 118.2, 118.0, 117.7, 117.4, 56.3; HRMS (ESI): m/z [M + Na]+ calcd
for C21H15N3O + Na: 348.1107; found: 348.1105.
Scheme 5. Proposed double Cu-catalyzed mechanism.
Conclusions
In conclusion, a practical and efficient one-pot double Cu(I)-
catalyzed the direct oxidative Csp3-H bond azidation / CuAAC
reaction implying unstable azides has been developed. Thus, the
combination of TBHP as oxidant and TMSN3 as simple, iodine-
free azide source for the C-H bond functionalization, which
produces harmless side-products such as tBuOH and H2O,
probed to be perfectly compatible with the next cycloaddition step.
In this manner, highly demanding 1,2,3-triazole derivatives were
directly obtained in good overall yields from a variety of substrates
presenting dibenzylic (xanthenes) or alpha to nitrogen C-H bonds
(N,N-dimethyl anilines), as well as difficult oxidizing compounds
such as 2-methyl quinolines and allylic substrates. Moreover, the
isolation of the products could be normally achieved by
evaporation and extraction or by simple crystallization/
precipitation from the crude mixture. To further highlight the
potential of this approach, not only simple but also more complex
4-(p-Tolyl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole (5ab): According to the
standard procedure, the crude was recrystallized from CH3CN to obtain
the product 5ab (103 mg, 0.30 mmol, 76 %) as a white solid. 1H NMR (400
MHz, CDCl3) δ 7.77 (s, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.40 – 7.33 (m, 4H),
7.27 (d, J = 1.0 Hz, 2H), 7.25 (d, J = 1.0 Hz, 1H), 7.20 (d, J = 7.9 Hz, 2H),
7.11 – 7.07 (m, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.4,
138.5, 132.0, 130.2, 129.6, 129.3, 129.3, 127.6, 126.0, 123.6, 118.1, 117.4,
60.5, 21.5; HRMS (ESI): m/z [M + Na]+ calcd for C22H17N3O + Na:
362.1264; found: 362.1260.
4-(4-Methoxyphenyl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole
(5ac):
According to the standard procedure, the crude was recrystallized from
CH3CN to obtain the product 5ac (100 mg, 0.28 mmol, 70 %) as a white
solid. 1H NMR (300 MHz, CDCl3) δ 7.66 – 7.61 (m, 2H), 7.39 (ddd, J = 7.8,
7.1, 4.3 Hz, 4H), 7.28 (d, J = 1.1 Hz, 1H), 7.25 (d, J = 2.2 Hz, 2H), 7.21 (s,
1H), 7.16 – 7.09 (m, 2H), 6.89 – 6.84 (m, 2H), 3.79 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.7, 150.9, 130.7, 130.1, 129.7, 127.0, 124.2, 123.3,
117.7, 117.4, 117.2, 114.2, 56.2, 55.4; HRMS (ESI): m/z [M + K]+ calcd.
for C22H17N3O2 + K: 394.0952; found: 394.0950.
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4-([1,1'-Biphenyl]-4-yl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole
(5ad):
129.4, 128.3, 128.1, 124.2, 120.9, 118.8, 117.6, 117.2, 108.7, 56.8; HRMS
(ESI): m/z [M + Na]+ calcd for C22H14N4O + Na: 373.1060; found: 373.1061.
According to the standard procedure, the crude was recrystallized from
CH3CN to obtain the product 5ad (101 mg, 0.25 mmol, 63 %) as a white
solid. H NMR (400 MHz, CDCl3) δ 7.88 – 7.84 (m, 3H), 7.69 – 7.62 (m,
1
4-(Naphthalen-2-yl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole
(5al):
According to the standard procedure, the crude was recrystallized from
CH3CN to obtain the product 5al (102 mg, 0.27 mmol, 68 %) as a white
solid. 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J = 0.8 Hz, 1H), 7.95 (s, 1H),
7.91 (d, J = 1.5 Hz, 2H), 7.86 (ddd, J = 7.3, 4.0, 2.5 Hz, 2H), 7.53 – 7.49
(m, 2H), 7.41 (ddd, J = 5.7, 1.9, 1.1 Hz, 4H), 7.33 – 7.28 (m, 2H), 7.18 (s,
1H), 7.16 – 7.09 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 151.4, 133.5, 133.3,
132.4, 130.2, 129.2, 128.6, 128.2, 127.8, 127.7, 126.5, 126.3, 124.8, 124.0,
123.6, 117.9, 117.3, 117.2, 60.6; HRMS (ESI): m/z [M + Na]+ calcd for
C25H17N3O + Na: 398.1264; found: 398.1265.
4H), 7.48 (t, J = 7.6 Hz, 2H), 7.40 (d, J = 8.6 Hz, 4H), 7.32 – 7.27 (m, 3H),
7.14 (dd, J = 15.6, 8.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 151.5, 141.3,
140.7, 130.8, 130.3, 129.7, 129.4, 129.3, 128.9, 127.6, 127.1, 126.5, 124.3,
123.6, 118.1, 117.4, 60.7; HRMS (ESI): m/z [M + Na]+ calcd for
C27H19N3NaO + Na: 424.1420; found: 424.1420.
4-(4-Fluorophenyl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole
(5ae):
According to the standard procedure, the crude was recrystallized from
CH3CN to obtain the product 5ae (96 mg, 0.28 mmol, 70 %) as a white
solid. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 2H), 7.74 – 7.69 (m, 5H), 7.41
– 7.32 (m, 11H), 7.28 (d, J = 1.1 Hz, 3H), 7.11 (dd, J = 5.7, 2.1 Hz, 7H),
7.08 – 7.06 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 161.2 (d, J = 273.9 Hz),
151.5, 147.1, 131.8, 130.3, 129.3, 127.9 (d, J = 8.2 Hz), 126.7 (d, J = 3.2
Hz), 123.6, 118.0, 117.4, 115.9 (d, J = 21.7 Hz), 60.7; 19F NMR (280 MHz,
CDCl3) δ -113.04 (tt, JF-H = 8.6, 5.3 Hz); HRMS (ESI): m/z [M + Na]+ calcd
for C21H14FN3O + Na: 366.1013; found: 366.1009.
4-(3,5-Bis(trifluoromethyl)phenyl)-1-(9H-xanthen-9-yl)-1H-1,2,3-
triazole (5am): According to the standard procedure, the crude was
purified by flash column chromatography (hexane/EtOAc, 4:1) to obtain
the product 5am (127 mg, 0.28 mmol, 69 %) as a white solid. 1H NMR (300
MHz, CDCl3) δ 8.17 (s, 2H), 7.90 (s, 1H), 7.82 (s, 1H), 7.41 (ddd, J = 8.5,
7.2, 1.6 Hz, 2H), 7.33 (ddd, J = 16.0, 8.0, 1.3 Hz, 4H), 7.17 – 7.09 (m, 3H);
13C NMR (75 MHz, CDCl3) δ 151.5, 145.3, 132.7, 132.4 (q, J = 33.5 Hz),
130.6, 129.2, 126.0, 125.1, 123.3 (q, J = 278.8 Hz), 121.9 (q, J = 2.3 Hz),
121.5, 117.5, 117.4, 61.3; 19F NMR (280 MHz, CDCl3) δ -62.90 (m); HRMS
(ESI): m/z [M + H]+ calcd for C23H13F6N3O + H: 462.1036; found: 462.0988.
Methyl 4-(1-(9H-xanthen-9-yl)-1H-1,2,3-triazol-4-yl) benzoate (5af):
According to the standard procedure, the crude was recrystallized from
CH3CN to obtain the product 5af (110 mg, 0.29 mmol, 72 %) as a white
solid. 1H NMR (400 MHz, CDCl3) δ 8.08 – 8.03 (m, 2H), 7.86 (s, 1H), 7.84
– 7.80 (m, 2H), 7.37 (ddd, J = 10.2, 7.7, 6.1 Hz, 4H), 7.29 – 7.26 (m, 2H),
7.13 – 7.08 (m, 3H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8,
151.5, 146.8, 134.8, 132.6, 130.4, 130.3, 129.9, 129.3, 125.9, 123.7, 117.8,
117.5, 60.9, 52.3; HRMS (ESI): m/z [M + K]+ calcd for C23H17N3O3 + Na:
406.1168; found: 406.1158.
4-(Thiophen-2-yl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole
(5an):
According to the standard procedure, the crude was recrystallized from
Et2O to obtain the product 5an (82 mg, 0.25 mmol, 62 %) as a white solid.
1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.63 – 7.61 (m, 1H), 7.45 (dd, J
= 5.0, 0.9 Hz, 1H), 7.43 – 7.38 (m, 3H), 7.36 (d, J = 7.8 Hz, 2H), 7.31 –
7.29 (m, 2H), 7.15 – 7.10 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 151.4,
144.0, 132.3, 131.8, 130.3, 129.3, 126.5, 126.1, 123.6, 121.8, 118.1, 117.4,
60.6; HRMS (ESI): m/z [M + Na]+ calcd for C19H13N3OS + Na: 354.0672;
found: 354.0665.
4-(m-Tolyl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole (5ag): According to
the standard procedure, the crude was recrystallized from hexane/EtOAc
(9:1) to obtain the product 5ag (79 mg, 0.23 mmol, 58 %) as a white solid.
1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.63 (s, 1H), 7.60 – 7.55 (m,
1H), 7.43 – 7.36 (m, 4H), 7.31 (dd, J = 4.3, 3.3 Hz, 2H), 7.29 (s, 1H), 7.19
– 7.16 (m, 1H), 7.16 – 7.10 (m, 3H), 2.42 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 151.4, 147.9, 138.7, 132.2, 130.3, 130.2, 129.4, 129.3, 128.8,
126.7, 123.6, 123.3, 118.1, 117.4, 60.6, 21.6; HRMS (ESI): m/z [M + Na]+
calcd for C22H17N3O + Na: 362.1264; found: 362.1257.
(1-(9H-Xanthen-9-yl)-1H-1,2,3-triazol-4-yl)methanol (5ao): According to
the standard procedure, the crude was recrystallized from Et2O to obtain
the product 5ao (87 mg, 0.32 mmol, 79 %) as a white solid. 1H NMR (300
MHz, CDCl3) δ 7.57 (s, 1H), 7.42 – 7.36 (m, 2H), 7.32 – 7.29 (m, 2H), 7.29
– 7.28 (m, 1H), 7.26 (d, J = 1.1 Hz, 1H), 7.14 – 7.08 (m, 2H), 7.07 (s, 1H),
4.73 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 151.0, 148.6, 130.8, 129.7, 126.9,
124.2, 120.2, 117.4, 56.7, 56.4; HRMS (ESI): m/z [M + Na]+ calcd for
C16H13N3O2 + Na: 302.0900; found: 302.0896.
4-(3-Chlorophenyl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole
(5ah):
According to the standard procedure, the crude was recrystallized from
CH3CN to obtain the product 5ah (78 mg, 0.22 mmol, 54 %) as a white
solid. 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.79 (d, J = 1.7 Hz, 1H),
7.63 (dt, J = 7.3, 1.5 Hz, 1H), 7.44 – 7.39 (m, 2H), 7.36 (dd, J = 7.9, 4.5
Hz, 3H), 7.32 (dd, J = 4.1, 2.3 Hz, 2H), 7.29 (d, J = 2.9 Hz, 2H), 7.14 (dd,
J = 5.2, 2.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 151.5, 134.9, 132.2,
132.2, 130.9, 130.4, 130.2, 129.3, 128.6, 126.2, 124.2, 123.7, 117.9, 117.5,
60.9; HRMS (ESI): m/z [M + Na]+ calcd for C21H14ClN3O + Na: 382.0718;
found: 382.0712.
1-(1-(9H-Xanthen-9-yl)-1H-1,2,3-triazol-4-yl)-N,N-
dimethylmethanamine (5ap): According to the standard procedure, the
crude was recrystallized from hexane/CH3CN (9:1) to obtain the product
5ap (86 mg, 0.28 mmol, 70 %) as a white solid. 1H NMR (400 MHz, CDCl3)
δ 7.34 (t, J = 7.7 Hz, 2H), 7.29 (d, J = 7.7 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H),
7.13 – 7.05 (m, 4H), 3.49 (s, 2H), 2.17 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 150.9, 130.6, 129.6, 124.1, 120.9, 117.6, 117.5, 117.3, 56.2, 54.6, 45.3;
HRMS (ESI): m/z [M + H]+ calcd for C17H19N4O + H: 307.1553; found:
307.1554.
4-(o-Tolyl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole (5ai): According to the
standard procedure, the crude was recrystallized from CH3CN to obtain
the product 5ai (71 mg, 0.21 mmol, 52 %) as a white solid. 1H NMR (400
MHz, CDCl3) δ 7.70 (s, 1H), 7.56 (dd, J = 5.8, 2.2 Hz, 1H), 7.39 (dd, J =
12.5, 4.5 Hz, 4H), 7.29 (s, 1H), 7.27 – 7.23 (m, 4H), 7.11 (dd, J = 10.8, 3.8
Hz, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.4, 147.9, 138.6,
132.2, 130.3, 130.2, 129.4, 129.3, 128.8, 126.7, 123.6, 123.3, 118.1, 117.4,
60.6, 21.6; HRMS (ESI): m/z [M + Na]+ calcd for C22H17N3O + Na:
362.1264; found: 362.1264.
4-(2-Methoxypropan-2-yl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole (5aq):
According to the standard procedure, the crude was recrystallized from
Et2O to obtain the product 5aq (68 mg, 0.22 mmol, 54 %) as a white solid.
1H NMR (300 MHz, CDCl3) δ 7.42 – 7.37 (m, 2H), 7.32 (d, J = 7.8 Hz, 2H),
7.24 (d, J = 9.0 Hz, 2H), 7.17 (s, 1H), 7.12 (dd, J = 10.5, 4.4 Hz, 2H), 7.01
(s, 1H), 3.00 (s, 3H), 1.50 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 150.9,
130.6, 129.7, 129.6, 124.2, 118.9, 117.7, 117.4, 72.9, 56.2, 50.5, 26.4;
HRMS (ESI): m/z [M + Na]+ calcd for C19H19N3O2 + Na: 344.1369; found:
344.1369.
4-(2-Chlorophenyl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole
(5aj):
According to the standard procedure, the crude was recrystallized from
CH3CN to obtain the product 5aj (73 mg, 0.20 mmol, 51 %) as a white solid.
1H NMR (300 MHz, CDCl3) δ 8.11 (dd, J = 7.8, 1.6 Hz, 1H), 7.66 (s, 1H),
7.34 – 7.26 (m, 4H), 7.20 (ddd, J = 6.2, 3.3, 2.1 Hz, 3H), 7.16 – 7.14 (m,
2H), 7.14 – 7.07 (m, 1H), 7.06 – 7.00 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 150.9, 144.9, 134.9, 131.2, 130.7, 130.2, 129.78, 129.5, 129.1, 127.1,
124.2, 121.64, 117.5, 117.4, 56.4; HRMS (ESI): m/z [M + Na]+ calcd for
C21H14ClN3O + Na: 382.0718; found: 382.0729.
2-(1-(9H-Xanthen-9-yl)-1H-1,2,3-triazol-4-yl)propan-2-ol
(5ar):
According to the standard procedure, the crude was recrystallized from
Et2O to obtain the product 5ar (69 mg, 0.22 mmol, 56 %) as a white solid.
1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.38 – 7.33 (m, 3H), 7.29 – 7.22
(m, 6H), 7.10 – 7.05 (m, 3H), 7.02 (s, 1H), 1.57 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 151.4, 137.9, 130.2, 129.2, 123.6, 118.5, 118.1, 117.4, 68.7, 60.4,
30.6; HRMS (ESI): m/z [M + Na]+ calcd for C18H17N3NaO2 + Na: 330.1213;
found: 330.1212.
2-(1-(9H-Xanthen-9-yl)-1H-1,2,3-triazol-4-yl)benzonitrile
(5ak):
N-((1-(9H-Xanthen-9-yl)-1H-1,2,3-triazol-4-yl)methyl)benzamide (5as):
According to the standard procedure, the crude was recrystallized from
CH3CN to obtain the product 5as (78 mg, 0.20 mmol, 51 %) as a white
solid. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.6 Hz, 2H), 7.56 (s, 1H),
7.49 (t, J = 7.4 Hz, 1H), 7.44 – 7.35 (m, 4H), 7.28 (d, J = 7.7 Hz, 2H), 7.24
(s, 1H), 7.08 (t, J = 7.5 Hz, 2H), 7.03 (s, 1H), 6.56 (s, 1H), 4.62 (d, J = 5.5
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 167.5, 151.4, 134.2, 133.7, 131.8,
According to the standard procedure, the crude was recrystallized from
Et2O to obtain the product 5ak (87 mg, 0.25 mmol, 62 %) as a white solid.
1H NMR (400 MHz, CDCl3 ) δ 8.19 (s, 1H), 7.89 (dd, J = 8.2, 1.2 Hz, 1H),
7.73 (dt, J = 7.7, 1.6 Hz, 1H), 7.63 – 7.58 (m, 1H), 7.41 (t, J = 1.5 Hz, 1H),
7.39 (d, J = 7.5 Hz, 4H), 7.30 – 7.27 (m, 2H), 7.17 (s, 1H), 7.14 – 7.10 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 151.0, 144.5, 133.7, 133.6, 133.3, 130.9,
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10.1002/chem.201806288
Chemistry - A European Journal
FULL PAPER
130.3, 129.3, 128.7, 128.7, 127.1, 123.7, 117.9, 117.4, 60.6, 35.5; HRMS
(ESI): m/z [M + Na]+ calcd for C23H18N4O2 + Na: 405.1322; found:
405.1321.
CH3CN to obtain the product 5da (116 mg, 0.29 mmol, 72 %) as a white
solid. 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 7.1 Hz, 2H), 7.45 (s, 1H),
7.43 – 7.31 (m, 2H), 7.27 (d, J = 6.2 Hz, 3H), 7.22 (d, J = 6.4 Hz, 1H), 7.19
(s, 1H), 7.13 – 7.05 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 154.2, 150.7,
133.9, 132.2, 131.0, 130.4, 129.6, 128.9, 128.5, 127.5, 125.8, 124.6, 119.6,
119.3, 117.9, 117.5, 117.0, 116.4, 55.8; HRMS (ESI): m/z [M + Na]+ calcd
for C21H14BrN3O + Na: 426.0218; found: 426.0204.
4-Cyclohexyl-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole (5at): According to
the standard procedure, the crude was recrystallized from CH3CN to obtain
the product 5at (69 mg, 0.21 mmol, 52 %) as a white solid. 1H NMR (300
MHz, CDCl3) δ 7.38 – 7.32 (m, 3H), 7.26 (d, J = 1.5 Hz, 1H), 7.25 – 7.21
(m, 3H), 7.11 – 7.04 (m, 2H), 7.00 (s, 1H), 2.74 – 2.63 (tt, J = 11.3, 3.5 Hz,
1H), 2.02 – 1.94 (m, 2H), 1.85 – 1.66 (m, 4H), 1.44 – 1.30 (m, 4H); 13C
NMR (75 MHz, CDCl3) δ 151.4, 130.1, 129.7, 129.2, 124.2, 123.5, 118.3,
117.3, 60.0, 35.3, 33.0, 26.2, 26.1; HRMS (ESI): m/z [M + Na]+ calcd for
C21H21N3O+ Na: 354.1577; found: 354.1579.
1-(2-Fluoro-9H-xanthen-9-yl)-4-phenyl-1H-1,2,3-triazole
(5ha):
According to the standard procedure, the crude was recrystallized from
CH3CN to obtain the product 5ea (75 mg, 0.22 mmol, 56 %) as a white
solid.). 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.9 Hz, 2H), 7.35 (t, J =
7.8 Hz, 1H), 7.28 (dd, J = 9.8, 1.2 Hz, 3H), 7.23 – 7.15 (m, 4H), 7.12 (s,
1H), 7.10 – 6.99 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7 (d, J = 243.9
Hz), 150.9, 148.9, 147.1 (d, J = 2.2 Hz), 130.9, 130.4, 129.6, 128.9, 128.4,
125.8, 124.5, 118.9 (d, J = 8.2 Hz), 118.7 (d, J = 7.6 Hz), 118.3 (d, J = 23.7
4-(tert-Butyl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole (5au): According to
the standard procedure, the crude was recrystallized from hexane/Et2O
(1:1) to obtain the product 5au (57 mg, 0.19 mmol, 47 %) as a white solid.
1H NMR (400 MHz, CDCl3) δ 7.39 (t, J = 7.6 Hz, 2H), 7.32 (d, J = 7.6 Hz,
2H), 7.25 (t, J = 6.8 Hz, 2H), 7.16 – 7.09 (m, 3H), 6.80 (s, 1H), 1.23 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 150.8, 130.4, 129.6, 125.8, 124.0,
117.9, 117.2, 116.5, 55.8, 30.8, 30.3; HRMS (ESI): m/z [M + Na]+ calcd for
C19H19N3O + Na: 328.1420; found: 328.1414
Hz), 117.9, 117.4, 116.6, 115.3 (d, J = 23.8 Hz), 56.3 (d, J = 1.2 Hz); 19
F
NMR (280 MHz, CDCl3) δ -117.80 (m); HRMS (ESI): m/z [M + Na]+ calcd
for C21H14FN3O + Na: 366.1019; found: 366.1013.
2-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)quinoline (5ba):[28] According
to the standard procedure, the crude was purified by flash column
chromatography (20% EtOAc/hexane) to obtain the product 5ga (36 %
NMR yield; CH2Br2 as internal standard). The analytical data is in
accordance with the literature.[35] 1H NMR (300 MHz, CDCl3) δ 8.08 (dd, J
= 20.4, 8.4 Hz, 2H), 7.88 (s, 1H), 7.77 (dd, J = 4.5, 2.3 Hz, 2H), 7.70 (dd,
J = 5.6, 4.1 Hz, 1H), 7.57 – 7.49 (m, 1H), 7.37 – 7.32 (m, 5H), 7.28 (dd, J
= 5.0, 3.6 Hz, 2H), 5.84 (s, 2H); HRMS (ESI): m/z [M + H]+ calcd for
C18H14N4 + H: 287.1297; found: 287.1296.
4-Butyl-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole (5av): According to the
standard procedure, the crude was recrystallized from Et2O to obtain the
product 5av (55 mg, 0.18 mmol, 45 %) as a white solid. 1H NMR (400 MHz,
CDCl3) δ 7.37 – 7.33 (m, 3H), 7.26 – 7.22 (m, 4H), 7.10 – 7.05 (m, 2H),
7.01 (s, 1H), 2.65 – 2.60 (m, 2H), 1.59 (ddd, J = 11.5, 7.7, 6.5 Hz, 2H),
1.33 (tt, J = 14.0, 7.1 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 151.3, 133.7, 130.1, 129.2, 129.1, 123.5, 118.3, 117.4, 60.0, 31.4,
25.3, 22.5, 13.9; HRMS (ESI): m/z [M + Na]+ calcd for C19H19N3O + Na:
328.1420; found: 328.1423.
N,4-Dimethyl-N-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)aniline (5ca):
According to the standard procedure, the product 5fa (70 mg, 0.25 mmol,
63 %) was obtained as yellow oil after extraction and removal of the solvent
under vacuum. 1H NMR (300 MHz, CDCl3) δ 7.82 (s, 1H), 7.77 (dd, J = 8.3,
1.3 Hz, 2H), 7.44 – 7.35 (m, 3H), 7.09 (d, J = 8.3 Hz, 2H), 7.00 – 6.96 (m,
2H), 5.87 (s, 2H), 3.21 (s, 3H), 2.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
147.7, 145.1, 131.2, 130.4, 129.7, 128.8, 128.4, 128.3, 125.9, 114.1, 71.4,
38.6, 20.4; HRMS (ESI): m/z [M + H]+ calcd for C17H18N4 + H: 279.1610;
found: 279.1608.
4-(7-Ethynylnaphthalen-2-yl)-1-(9H-xanthen-9-yl)-1H-1,2,3-triazole
(5aw): The standard procedure was differed only in the amount of the
alkyne: 2.4 equivalent of 2,7-diethynylnaphthalene 4w was used. Then the
crude was recrystallized from CH3CN to obtain the product 5aw (110 mg,
0.28 mmol, 69 %) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.17 (s,
1H), 7.97 (s, 1H), 7.83 (dd, J = 8.6, 1.6 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H),
7.73 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 8.5, 1.6 Hz, 1H), 7.45 (s, 1H), 7.44
– 7.39 (m, 4H), 7.31 – 7.27 (m, 3H), 7.15 (ddd, J = 8.2, 5.3, 1.2 Hz, 2H),
3.14 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 151.0, 148.5, 133.0, 132.8, 132.5,
130.8, 129.7, 128.9, 128.7, 128.5, 128.0, 124.9, 124.3, 124.2, 120.1, 118.5,
117.6, 117.5, 84.0, 77.8, 56.5; HRMS (EI): m/z [M]+ calcd for C16H16N4:
264,1375; found: 264.1362.
1-(Cyclohex-2-en-1-yl)-4-phenyl-1H-1,2,3-triazole (5da): According to a
modified standard procedure (first-step reaction with 1d (5 equiv.), TMSN3
(1 equiv.) and TBHP (5.5M in decane) at 100 °C for 4 h), the crude was
purified by flash column chromatography (hexane/EtOAc, 5:1) to obtain
the product 5da (62.3 mg, 0.28 mmol, 69 %) as a white solid. 1H NMR (400
MHz, CDCl3) δ 7.86 – 7.82 (m, 2H), 7.80 (s, 1H), 7.45 – 7.39 (m, 2H), 7.35
– 7.29 (m, 1H), 6.18 (dtd, J = 9.7, 3.8, 1.9 Hz, 1H), 5.85 (ddt, J = 10.0, 3.8,
2.2 Hz, 1H), 5.32 (dtq, J = 7.9, 4.2, 2.2 Hz, 1H), 2.27 – 2.14 (m, 3H), 2.07
– 1.98 (m, 1H), 1.78 – 1.70 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 147.8,
134.1, 131.0, 128.9, 128.1, 125.8, 124.3, 118.5, 56.1, 30.8, 24.8, 19.2;
HRMS (ESI): m/z [M + Na]+ calcd for C14H15N3 + Na: 248.1164; found:
248.1169.
2,7-Bis(1-(9H-xanthen-9-yl)-1H-1,2,3-triazol-4-yl)naphthalene (6): The
standard procedure was differed only in the amount of the alkyne: 0.48
equivalents of 2,7-diethynylnaphthalene 4w were used. Then the crude
was recrystallized from CH3CN to obtain the product 6 (114 mg, 0.19 mmol,
96 %) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.20 (s, 2H), 7.81 –
7.79 (m, 3H), 7.47 – 7.43 (m, 8H), 7.34 (d, J = 1.1 Hz, 2H), 7.32 – 7.29 (m,
6H), 7.18 (tdd, J = 7.1, 3.5, 1.2 Hz, 5H); 13C NMR (75 MHz, CDCl3) δ 150.9,
148.5, 134.3, 133.5, 132.8, 130.7, 129.6, 128.3, 124.5, 124.2, 124.0, 118.3,
117.5, 117.3, 56.3; HRMS (ESI): m/z [M + Na]+ calcd for C40H26N6O2 + Na:
646.2015; found: 645.2003.
(2S)-1-((1-(9H-Xanthen-9-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-((R)-
hydroxy(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium
tetrafluoroborate (5ax):[28] According to the standard procedure, the
crude was recrystallized from Et2O/CH3CN (99:1) to obtain the product 5ax
(167 mg, 0.26 mmol, 65 %) as a brown solid. 1H NMR (300 MHz, CDCl3)
δ 8.80 (d, J = 4.0 Hz, 1H), 8.59 (bs, 1H), 8.31 (d, J = 7.3 Hz, 1H), 8.24 –
8.14 (m, 1H), 7.88 (bd, J = 8.0 Hz, 1H), 7.79 (d, J = 4.1 Hz, 1H), 7.76 –
7.70 (m, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.45 – 7.36 (m, 2H), 7.30 (bs, 1H),
7.25 – 7.18 (m, 2H), 7.10 – 7.04 (m, 2H), 7.02 – 6.93 (m, 1H), 6.41 (bs,
1H), 6.12 (d, J = 13.3 Hz, 1H), 5.92 – 5.78 (m, 1H), 5.23 (bs, 1H), 5.18 (d,
J = 4.7 Hz, 1H), 5.08 (d, J = 13.2 Hz, 1H), 4.73 – 4.53 (m, 1H), 4.05 – 3.96
(m, 1H), 3.90 – 3.83 (m, 1H), 3.55 – 3.40 (m, 1H), 3.02 – 2.91 (m, 1H),
2.86 – 2.72 (m, 1H), 2.55 – 2.42 (m, 1H), 2.21 – 2.09 (m, 1H), 1.79 (bs,
1H), 1.65 – 1.56 (m, 1H), 1.35 (d, J = 6.1 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 177.2, 156.1, 151.5, 151.4, 149.7, 147.3, 144.7, 136.4, 135.3,
134.9, 130.8, 129.6, 128.7, 127.1, 126.6, 124.0, 123.9, 122.9, 121.8, 119.8,
118.0, 117.6, 117.5, 117.3, 116.8, 66.5, 65.5, 57.1, 56.6, 53.4, 38.1, 31.2,
27.1, 23.8, 21.3; HRMS (ESI): m/z [M]+ calcd for C35H34N5O2: 556.2707;
found: 556.2714.
1-(3-Methoxy-9H-xanthen-9-yl)-4-phenyl-1H-1,2,3-triazole
(5ea):
According to the standard procedure, the crude was recrystallized from
CH3CN to obtain the product 5ba (119 mg, 0.34 mmol, 84 %) as a white
solid. 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.82 – 7.78 (m, 2H), 7.42
(dddd, J = 7.9, 7.2, 4.7, 2.0 Hz, 5H), 7.30 (ddd, J = 7.8, 4.2, 2.3 Hz, 2H),
7.16 – 7.09 (m, 2H), 6.82 (t, J = 2.2 Hz, 1H), 6.72 (dd, J = 8.6, 2.5 Hz, 1H),
3.87 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.1, 152.5, 151.4, 147.7, 132.1,
130.5, 130.2, 130.1, 129.4, 129.3, 128.9, 128.5, 126.08, 123.6, 117.3,
111.3, 110.3, 101.4, 60.5, 55.6; HRMS (EI): m/z [M]+ calcd for C22H17N3O2:
355,1321; found 355.1312.
1-(3,6-Dimethoxy-9H-xanthen-9-yl)-4-phenyl-1H-1,2,3-triazole (5fa):
According to the standard procedure, the crude was recrystallized from
Et2O to obtain the product 5ca (133 mg, 0.35 mmol, 86 %) as a white solid.
1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.75 – 7.73 (m, 2H), 7.39 (dd, J
= 10.3, 4.7 Hz, 2H), 7.33 – 7.28 (m, 1H), 7.26 – 7.23 (m, 2H), 6.98 (s, 1H),
6.75 (d, J = 2.5 Hz, 2H), 6.66 (dd, J = 8.6, 2.6 Hz, 2H), 3.81 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 159.7, 150.9, 130.7, 130.1, 129.7, 127.0, 124.2,
123.3, 117.7, 117.4, 117.2, 114.2, 56.2, 55.4; HRMS (ESI): m/z [M]+ calcd
for C23H19N3O3: 385,1426; found: 385,1388.
(2S)-2-((R)-Hydroxy(quinolin-4-yl)methyl)-1-((1-((methyl(p-
tolyl)amino)methyl)-1H-1,2,3-triazol-4-yl)methyl)-5-vinylquinuclidin-
1-ium tetrafluoroborate (5cx):[28] According to the standard procedure,
the product 5fx (197 mg, 0.33 mmol, 83 %) was obtained as a brown solid
after extraction and removal of the solvent under vacuum. 1H NMR (400
MHz, CDCl3) δ 8.75 – 8.64 (m, 1H), 8.17 – 8.05 (m, 1H), 7.90 – 7.50 (m,
1-(2-Bromo-9H-xanthen-9-yl)-4-phenyl-1H-1,2,3-triazole
According to the standard procedure, the crude was recrystallized from
(5ga):
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10.1002/chem.201806288
Chemistry - A European Journal
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2H), 7.20 – 7.01 (m, 2H), 6.98 – 6.83 (m, 3H), 6.72 (d, J = 8.1 Hz, 1H),
6.67 – 6.51 (m, 1H), 6.43 – 6.31 (m, 1H), 6.26 – 6.06 (m, 1H), 5.84 – 5.52
(m, 2H), 5.32 (d, J = 12.9 Hz, 1H), 5.19 – 4.95 (m, 2H), 4.59 – 4.39 (m,
1H), 3.93 – 3.71 (m, 2H), 3.66 – 3.48 (m, 1H), 3.18 – 3.08 (m, 1H), 3.01
(bs, 2H), 2.78 – 2.60 (m, 2H), 2.62 – 2.53 (m, 1H), 2.37 – 2.20 (m, 1H),
2.15 – 1.94 (m, 6H), 1. 6 – 1.59 (m, 1H), 1.46 (bs, 1H); 13C NMR (75 MHz,
CDCl3) δ 150.0, 148.8, 147.2, 147.1, 144.8, 135.3, 130.1, 129.7, 129.6,
129.5, 127.0, 126.3, 122.9, 122.5, 118.7, 116.7, 115.4, 114.5, 114.1, 113.2,
112.5, 73.0, 71.8, 71.4, 69.0, 66.7, 65.6, 65.0, 60.4, 56.8, 52.4, 48.7, 41.0,
37.9, 36.6, 31.2, 31.0, 29.7, 27.8, 27.1, 20.4, 20.3, 18.6; HRMS (ESI): m/z
[M]+ calcd for C31H37N6O: 509.3023; found: 509.3018.
Subbotina, Z. Yacob, in Chemistry of 1,2,3,-Triazoles; Topics in
Heterocycle Chemistry, Vol. 40 (Eds. W. Dehaen, V. A. Bakulev),
Springer-Verlag, Berlin Heidelberg, 2014 .
[2]
[3]
See for example: a) N. A. Meanwell, J. Med. Chem. 2011, 54, 2529; b) I.
Mohammed, I. Reddy Kummetha, G. Singh, N. Sharova, G. Lichinchi, J.
Dang, M. Stevenson, T. M. Rana, J. Med. Chem. 2016, 59, 7677.
Selected reviews on 1,2,3-triazolee bioactive proprieties: a) S. Roper, H.
C. Kolb in Fragment-Based Approaches in Drug Discovery; Methods and
Principles in Medicinal Chemistry, Vol. 34 (Eds.: H. Baltes, W. Göpel, J.
Hesse), Wiley-VCH, Weinheim, 2006, pp. 313–339; b) K. B. Sharpless,
R. Manetsch, Expert Opin. Drug Dis. 2006, 1, 525; c) G. C. Tron, T. Pirali,
R. A. Billington, P. L. Canonico, G. Sorba, A. A. Genazzani, Med. Res.
Rev. 2008, 28, 278; d) S. G. Agalave, S. R. Maujan, V. S. Pore, Chem.
Asian J. 2011, 6, 2696; f) C.-H Zhou, Y. Wang, Curr. Med. Chem. 2012,
19, 239; g) R. S. Keri, S. A. Patil, S. Budagumpi, B. M. Nagaraja, Chem.
Biol. Drug. Des. 2015, 86, 410; h) I. Pibiri. S. Buscemi, Curr. Bioact.
Comp. 2010, 6, 208; i) S. Zhang, Z. Xu, C. Gao, Q.-C. Ren, L. Chang,
Z.-S. Lv, L.-S. Feng, Eur. J. Med. Chem. 2017, 138, 501; j) A. Lauria, R.
Delisi, F. Mingoia, A. Terenzi, A. Martorana, G. Barone, A. M. Almerico,
Eur. J. Org. Chem. 2014, 3289; k) Sahu, S. Ganguly, A. Kaushik, Chin.
J. Nat. Med. 2013, 11, 456.
(2S)-2-((R)-Hydroxy(quinolin-4-yl)methyl)-1-((1-(quinolin-2-ylmethyl)-
1H-1,2,3-triazol-4-yl)methyl)-5-vinylquinuclidin-1-ium
tetrafluoroborate (5bx):[28] According to the standard procedure, the
crude was recrystallized from Et2O/CH3CN (1:1) to obtain the product 5gx
(121 mg, 0.20 mmol, 51 %) as a brown solid. 1H NMR (400 MHz, CDCl3)
δ 8.78 (bs, 1H), 8.05 – 7.87 (m, 3H), 7.80 – 7.68 (m, 2H), 7.63 (bs, 1H),
7.52 – 7.35 (m, 2H), 7.25 – 7.15 (m, 1H), 6.55 – 6.39 (m, 1H), 6.10 (bs,
1H), 6.07 – 5.95 (m, 1H), 5.83 (bs, 2H), 5.17 (bs, 1H), 5.12 – 5.05 (m, 1H),
4.49 (bs, 2H), 3.78 (bs, 2H), 3.15 – 3.00 (m, 2H), 2.92 – 2.80 (m, 1H), 2.70
(s, 1H), 2.37 – 2.29 (m, 1H), 2.23 – 2.12 (m, 1H), 1.96 (s, 1H), 1.79 (bs,
1H), 1.63 (bs, 1H), 1.57 – 1.45 (m, 2H), 1.23 – 1.15 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 159.1, 150.1, 150.0, 148.1, 147.9, 138.8, 136.3, 135.4,
130.1, 129.7, 129.5, 129.0, 128.6, 127.6, 127.1, 126.9, 125.7, 125.3, 122.9,
122.1, 118.6, 116.0, 69.4, 60.3, 49.8, 49.1, 39.0, 31.3, 28.0, 25.4, 25.1,
19.8; HRMS (ESI): m/z [M]+ calcd for C32H33N6O: 517,2710; found:
517.2701.
[4]
Selected example of 1,2,3 triazole-containing bioactive compounds: a) R.
Alvarez, S. Velzquez, A. San-Felix, S. Aquaro, E. De Clercq, C.-F. Perno,
A. Karison, J. Balzarini, M. J. Camarasa, J. Med. Chem. 1994, 37, 4185;
b) D. H. Boschelli, D. T. Connor, D. A. Bornemeier, R. D. Dyer, J. A.
Kennedy, P. J. Kuipers, G. C. Okonkwo, D. J. Schrier, C. D. Wright, J.
Med. Chem. 1993, 36, 1802; c) M.J. Genin, D. A. Allwine, D. J. Anderson,
M. R. Barbachyn, D. E. Emmert, S. A. Garmon, D. R. Graber, K. C.
Grega, J. B. Hester, D. K. Hutchinson, J. Morris, R. J. Reischer, C. W.
Ford, G. E. Zurenko, J. C. Hamel, R. D. Schaadt, D. Stapert, B. H. Yagi,
J. Med. Chem. 2000, 43, 953-970; d) R. Alvarez, S. Velazquez, A. San-
Felix, S. Aquaro, E. De Clercq, C.-F. Perno, A. Karlsson, J. Balzarini, M.
J. Camarasa, J. Med. Chem. 1994, 37, 4185; e) A. Brik, J. Alexandratos,
Y.-C. Lin, J. H. Elder, A. J. Olson, A. Wlodawer, D. S. Goodsell, C.-H.
Wong, ChemBioChem 2005, 6, 1167; f) N. G. Aher, V. S. Pore, N. M.
Mishra, A. Kumar, P. K. Shukla, A. Sharma, M. K. Bhat, Bioorg. Med.
Chem. Lett. 2009, 19, 759; g) F. Pagliai, T. Pirali, E. Del Grosso, R. Di
Brisco, G. C. Tron, G. Sorba, A. Genazzani, J. Med. Chem. 2006, 49,
467;
5-(1-(9H-Xanthen-9-yl)-1H-1,2,3-triazol-4-yl)-1-((2R,4S,5R)-4-hydroxy-
5-(hydroxymethyl) tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
(5ay):[28] According to the standard procedure, the crude was
recrystallized from Et2O to obtain the product 5ay (127 mg, 0.27 mmol,
67 %) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J = 1.7 Hz,
1H), 7.79 – 7.75 (m, 3H), 7.60 (bs, 1H), 7.42 – 7.38 (m, 2H), 7.38 – 7.34
(m, 2H), 7.10 – 7.05 (m, 2H), 5.90 (d, J = 1.2 Hz, 1H), 5.47 (d, J = 3.5 Hz,
1H), 3.26 (d, J = 3.5 Hz, 2H), 2.98 – 2.96 (m, 1H), 1.65 – 1.50 (m, 2H); 13
C
NMR (75 MHz, CDCl3) δ 193.7, 169.7, 164.3, 140.6, 133.9, 130.5, 130.3,
129.1, 127.9, 126.5, 125.7, 125.3, 68.9, 53.8, 45.4, 39.4, 37.3, 22.0, 21.9;
HRMS (ESI): m/z [M + Na]+ calcd for C24H21N5O6 + Na: 498.1390; found:
498.1378.
(1-(9H-Xanthen-9-yl)-1H-1,2,3-triazol-4-yl)methyl5-((3aS,4S,6aR)-2-
oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate
(5az):
According to the standard procedure, the crude was recrystallized from
CH3CN to obtain the product 5az (125 mg, 0.25 mmol, 62 %) as a white
solid. 1H NMR (400 MHz, CDCl3) δ 7.50-7.41 (m, 2H), 7.41-7.32 (m, 2H),
7.28 (bs, 1H), 7.21 – 7.07 (m, 4H), 5.78 (bs, 1H), 5.20 (bs, 1H), 5.14-5.07
(m, 2H), 4.49 (bs, 1H), 4.29 (bs, 1H), 3.11 (bs, 1H), 2.90-2.85 (m, 1H),
2.75-2.65 (m, 1H), 2.40 – 2.22 (m, 2H), 1.75-1.25 (m, 7H); 13C NMR (100
MHz, CDCl3) δ 173.3, 150.9, 143.6, 130.7, 130.3, 129.6, 129.2, 124.1,
123.6, 117.4, 61.9, 60.1, 57.4, 57.3, 56.4, 55.4, 40.5, 33.6, 28.2, 24.6;
HRMS (ESI): m/z [M + Na]+ calcd for C26H27N5O4S + Na: 528.1681; found:
528.1674.
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Acknowledgements
Deutsche Forschungsgemeinschaft (DFG) and INTERREG V A,
ETZ 2014-2020 – Bayern-Czech Republic (project 41) are
gratefully acknowledged for generous support. We are also
grateful to the COST Action “C-H activation in organic Synthesis
(CHAOS)” (CA15106).
[7]
[8]
Keywords: Oxidative C-H functionalization • Azidation • Click
Chemistry • Triazole • Copper catalysis
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Tobias Brandhofer, Aysegül Özdemir,
Andrea Gini,* Olga García Mancheño*
Pim, pam, ready! An efficient novel
Direct Azidation
double copper-catalyzed one-pot
azidation/click process based on
direct C-H bond functionalization is
reported. Due to its simplicity and
efficiency, this methodology allows the
preparation of challenging triazole
conjugates via unstable azide
Page No. – Page No.
Double Cu-Catalytic Approach
R4
One-pot Double Cu-Catalyzed Direct
Csp3-H Bond Azidation / CuAAC
Reaction: A Direct Approach towards
Demanding Triazole Conjugates
N3
N
tBuOOH aq.
"Cu" cat.
H
R4
N
R3
R2
C
R3
R2
C
N
R1
R1
"N3"source
R3
R2
C
R1
+
unreactive/compatible
oxidant by-products
tBuOH / H2
O
intermediates in good overall yields.
CuAAC
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