Solvent-Directed Click Reaction between Active Methylene Compounds and Azido-1,3,5-triazines

Article abstract of DOI:10.1021/acs.orglett.9b02089

A novel solvent-directed click reaction between active methylene compounds and azido-1,3,5-triazines has been developed. In aqueous solution, the regiospecific trisubstituted 1,2,3-triazole products are quickly synthesized in high yields under mild conditions and easy to separate without column chromatography. This click reaction is controlled by the protonation of a nitrogen anion intermediate, and the postulated mechanism is substantiated by DFT calculations.

Full text of DOI:10.1021/acs.orglett.9b02089

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Solvent-Directed Click Reaction between Active Methylene
Compounds and Azido-1,3,5-triazines
†
†
Ziqiang Yan, Yuanheng Li, and Mingming Ma*
CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at Microscale, University of Science
and Technology of China, Hefei, Anhui 230026, China
*
S Supporting Information
ABSTRACT: A novel solvent-directed click reaction between
active methylene compounds and azido-1,3,5-triazines has
been developed. In aqueous solution, the regiospecific
trisubstituted 1,2,3-triazole products are quickly synthesized
in high yields under mild conditions and easy to separate
without column chromatography. This click reaction is
controlled by the protonation of a nitrogen anion
intermediate, and the postulated mechanism is substantiated
by DFT calculations.
lick reactions refer to a group of organic reactions that
Scheme 1. Different Synthesis Methods of 1,2,3-Triazole
C
are fast, simple to use, easy to purify, and regiospecific
and give high product yields. Click reactions are widely utilized
for conjugating substrates with different functions and display
1
2
significant impacts on bioconjugation, drug discovery, and
3
material science. Azide−alkyne Huisgen cycloaddition is one
of the most deployed click reactions. However, the
4
completion of this reaction under mild conditions still requires
5
transition-metal catalysts (Scheme 1a), which greatly hinders
6
its applications in living systems. Using a highly strained
cyclooctyne can achieve metal-free strain-promoted azide−
7
alkyne cycloaddition, but the difficulties of synthesizing the
strained alkynes also limit its broad applications.
On the other hand, 1,2,3-triazoles are the product of azide−
alkyne cycloaddition, which have shown wide applications in
8
9
10
medicinal, material, and synthetic organic chemistry. For
example, some 1,2,3-triazoles show a broad spectrum of
biological activities such as antifungal, antiviral, antiallergic,
11
anti-HIV, and antimicrobial activities. Therefore, the fast
synthesis of diverse 1,2,3-triazoles has gained much attention.
12
Since the azide−alkyne Huisgen cycloaddition typically
produces regiospecific disubstituted 1,2,3-triazole, the regio
selective synthesis of trisubstituted 1,2,3-triazole needs new [3
+
2] cycloaddition reactions (Scheme 1b) between azide and
13 14 15
carbonyl compounds, nitroalkenes, N-tosylhydrazones, or
enol ethers. However, the uncompromising standards of click
reactions are rarely met by these new cycloaddition reactions
because of their requirement of excessively harsh conditions,
relatively slow reaction rate, or inconvenience in purification.
Herein, we report a novel solvent-directed, metal-free click
reaction between active methylene compounds and azido-
1
6
4
17
18
aprotic solvent such as DMSO, a diazo-transfer reaction
proceeds to give high yields of diazo compounds; in aqueous
solution, a regiospecific [3 + 2] cycloaddition reaction
proceeds to give a high yield of trisubstituted 1,2,3-triazole.
1
,3,5-triazines, swiftly yielding regiospecific trisubstituted 1,2,3-
triazoles with high efficiency under mild conditions. 1,3,5-
Triazine is an electron-deficient aromatic ring that serves as an
electron-withdrawing group to activate the azido group.
Interestingly, the reaction pathway is directed by solvents: in
Received: June 17, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02089
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The choice of reaction pathway is determined by the
protonation of a common nitrogen anion intermediate by
acidic α-hydrogen (leading to diazo-transfer reaction) or by
solvent (leading to cycloaddition reaction).
found as the sole product. The isolation yield of triazole was
91% with Et N as the base (Table 1, entry 7). With the most
3
optimized solution in hand, optimization of the base was
commenced again. The selection of base displayed few
differences among the different entries. Although with
NaHCO3 as the base, the yield of triazole was slightly
increased from 92% to 94% (Table 1, entry 8) compared to
K CO (Table 1, entry 9), the full conversion in room
Previously, we reported an efficient diazo-transfer reaction
between 2-azido-4,6-dimethoxy-1,3,5-triazines (ADT) and 1,3-
19
diketo compounds. The yield of this reaction is highly
dependent to its solvent: diazo transfer is more likely to occur
in solvents with high polarity; thus, DMSO was selected as the
best solvent for this reaction.
2
3
temperature would require a longer time. Therefore, a 1:1
mixture of H O and DMSO was selected as the most preferred
2
During the optimization of this diazo-transfer reaction, a
trisubstituted 1,2,3-triazole was initially discovered as the
byproduct when 0.6 mmol (1.2 equiv) of ADT and 0.5 mmol
solvent, K CO as the base, and 20 min as the reaction time.
2
3
When the equivalence of ADT was decreased from 1.2 to 1
compared to 2a and the reaction time was reduced to 10 min,
the isolation yield of 1,2,3-triazole remained unchanged (Table
1, entry 10), indicating a highly atom-economical cyclo-
addition reaction between ADT and 2a. After the reaction was
completed, 10 mL of water was added to the mixture and white
solid precipitated out, which can be isolated by filtration and
water washing as the products with sufficient purity.
(
1.0 equiv) of ethyl acetoacetate were used as the substrate, 2
mL of DMSO was used as the solvent, and 40 mol % Et N was
3
used as the base. After 1 h at room temperature, the NMR
yields of 2-diazo-1,3-dione and 1,2,3-triazole produced are 70%
and 20%, respectively (Table 1, entry 1). We hypothesized that
a
Table 1. Optimization of the Cycloaddition Reaction
To probe the general applicability and the regiospecificity of
this cycloaddition reaction, we investigated a wide range of
asymmetric substrates containing carbonyl groups with an
activated α-methylene (Scheme 2, compound 2a−l) as the
triazole
diazo
time
(3aa)
(4aa)
b
b
entry solvent
base
(min) yield (%) yield (%)
replacement to ethyl acetoacetate under the optimal conditions
1
2
DMSO
DMSO
Et N
60
60
20
17
70
3
2
(
Scheme 2). When R was an electron-donating group, such as
4-
methylmorpholine
OEt (2a and 2d), OMe (2c), and O-tBu (2b), the reaction
gave the triazole product with an excellent yield of 88−94%
and excellent regiospecificity. In alkyl acetoacetates, the keto
group is more electron-deficient than ester groups, and the
cycloaddition only occurs on the keto group, with the ester
group left. Changing the polarity of the reactant by substituting
3
4
5
6
7
DMSO
DMSO
DMSO
DMSO
pyridine
KOAc
60
60
60
60
30
trace
trace
trace
trace
86
86
96
K CO
2
3
NaHCO3
c
H O/
Et N
3
91
2
DMSO
1
R with longer alkyl chains (2c) or adding halide atom to the
c
8
9
1
H O/
NaHCO3
K CO
90
20
10
94
2
alkyl chain has little effect on the regiospecificity or the yield of
the reaction. When a phenyl group was attached to the keto
group (2f,g), the yields of triazoles slightly decreased, but the
regiospecificity of the reaction wasn’t affected. We believe that
this phenomenon occurred because the conjugation of the
phenyl with a keto group decreases the electron deficiency on
the keto group, and the steric hindrance may also reduce the
activity of the keto group, making it harder to be attacked by
DMSO
c
H O/
92
2
2
3
DMSO
c
0
H O/
K CO
92
2
2
3
DMSO
a
Reaction conditions: ethyl acetoacetate 2a (0.5 mmol), ADT 1a (0.6
b
mmol), and base (0.2 mmol) in solvent (4 mL), at 25 °C. The yield
was determined by using H NMR with mesitylene as the internal
standard. Isolation yield.
1
c
1
nitrogen. Noticeably, when R was substituted by an electron-
withdrawing −PhNO group (2h), the yield of the
2
this yield of 1,2,3-triazole would also be affected by the base
and the polarity of the solvent. Therefore, the optimization of
cycloaddition reaction between ADT (1a) and 1,3-diketo (2a)
was initially commenced by screening the base and the solvent
corresponding triazole did not increase. The reason is likely
due to the high reactivity of nitro group to carbanions. Upon
addition of base in the solution of 2h, the mixture would
immediately turn red, indicating the generation and reaction of
carbanions from 2h. The fact that the corresponding 1,2,3-
triazole product is still acquirable from 2h proves the
advantages of the reaction between ADT and 2h. When the
ester group was replaced by amide group that is more electron-
donating (2j,k), the activity of the methylene group is further
reduced. Therefore, the reaction with ADT required a slightly
higher temperature (40 °C) and longer reaction time (2 h) to
form corresponding triazoles. Besides diketo compounds, other
active methylene compounds have also been examined. When
the α-methylene of ketone is adjacent to a phenyl group (2l),
the acidity of α-methylene is too low to be deprotonated by
K CO . In this case, a stronger base KOH is used to replace
(Table 1). 4-Methylmorpholine was initially deployed as the
replacement of Et N, and the conversion of 2a was limited. No
3
diazo compound was discovered, and triazole (3aa) had a 17%
1
yield, determined by H NMR (Table 1, entry 2). When a
weaker organic base, pyridine, was added, no reaction between
ADT and 2a was observed (Table 1, entry 3), which indicated
that a stronger base might be more preferred. Therefore,
stronger inorganic bases were used for further optimization.
However, although inorganic bases were able to boost the
conversion of 2a, the main product remains diazo, as only trace
of or no triazole was observed (Table 1, entry 4−6).
As mentioned above, the diazo-transfer reaction between
ADT and 2a is favored in organic solvents with high polarity,
such as DMSO. Since DMSO is aprotic solvent, we sought to
add protic solvent into DMSO. Surprisingly, as we added water
into DMSO to form a mixed solvent, the yield of diazo
compounds dramatically decreased, while the 1,2,3-triazole was
2
3
K CO , and the diphenyl-substituted product (3al) can be
2
3
obtained at 40 °C within 2 h. Besides carbonyl compounds, the
α-methylene of nitriles (5) can be deprotonated by KOH and
react with ADT at 40 °C smoothly, as shown in Scheme 3. The
cyano group was attacked by the nitrogen to give
B
DOI: 10.1021/acs.orglett.9b02089
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Reactions between ADT and Carbonyl-Activated
Methylene Compounds
Scheme 3. Reactions between ADT and Cyano-Activated
Methylene Compounds
a,
b
a
a
Reaction conditions: ADT 1a (0.5 mmol), active methylene
compounds 5 (0.5 mmol), and KOH (0.2 mmol) in DMSO/H O
2
=
1:1 (4 mL), at 40 °C for 1 h. Isolation yields are provided.
a
Scheme 4. Scope of Azido-1,3,5-triazines
a
Reaction condition: ADT 1a (0.5 mmol), active methylene
compounds 2 (0.5 mmol) and K CO (0.2 mmol) in DMSO/H O
2
3
2
b
c
=
4
1:1 (4 mL), at room temperature for 20 min. Isolation yields. At
0 °C for 2 h. With KOH (0.2 mmol) as the base, at 40 °C for 2 h.
d
corresponding triazole products in good yields. Surprisingly,
the obtained products (6aa−ac) were all the Dimroth-
5d
rearranged products with a 1,2-disubstituted triazole ring,
which are confirmed by their HNMR in DMSO-d showing the
6
characteristic NH on triazole ring at δ in the range of 11−15
ppm (see the SI). In the cases of 5a and 5b, only the cyano
group was attacked by the nitrogen, rather than the less active
amide group. When two cyano groups are present, the reaction
between ADT and malononitrile (5c) gives 6ac with one
cyano group left, and 5c can emit bright blue-color
fluorescence.
The scope of azido-1,3,5-triazines was explored with
acetylacetone as the reactant, demonstrated in Scheme 4.
Besides the alkoxy groups (1a,b,d), the 1,3,5-triazine can also
be substituted by amino (1c) and thiol (1e,f) groups. These
substitution groups change the electron density of 1,3,5-
triazine ring, which tune the activity of the azido-1,3,5-
triazines: with alkoxy > thiol > amino substitution. Under
a
Reaction condition: azide 1 (0.5 mmol), acetylacetone 2e (0.5
mmol), and K CO (0.2 mmol) in DMSO/H O = 1:1 (4 mL), at 25
2
3
2
b
c
°
C. Isolation yields. At 40 °C.
optimal reaction conditions, all of these azido-1,3,5-triazines
(1a−f) could provide the corresponding triazole products with
good to excellent yields. The ester group in 1b−f could be
C
DOI: 10.1021/acs.orglett.9b02089
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
easily modified to conjugate with other functional molecules.
Therefore, this cycloaddition click reaction could be utilized to
conjugate different substrates.
A postulated cycloaddition mechanism is depicted in
Scheme 5. Initially, the active methylene is converted to
Scheme 5. Proposed Mechanism for the Solvent-Directed
Cycloaddition Reaction
Figure 1. Energy profile and molecular configuration of the
cycloaddition between ADT and acetylacetone.
proposed mechanism is further substantiated by DFT
calculation. We chose the cycloaddition between ADT (1a)
and acetylacetone (2e) as the model reaction. The DFT
calculation was performed at the M06-2X/6-311+ G(d,p) level
with D3 dispersion correction in 1:1 H O and DMSO mixed
2
solvent. The rate-determining step of the cycloaddition
reaction was found as the conversion from TI 3 to TI 4,
whose energy profile is depicted in Figure 1. The conversion
from TI 3 to TI 4 can be separated into two steps, the
nucleophilic addition of secondary amine and the proton
transfer from N to O. IRC scanning demonstrated an unstable
reactive intermediate with a low energy barrier to converse
back to TI 3 with an estimated relative free energy of about 24
kcal/mol. The four-membered-ring transition state TS is then
formed with an energy barrier of 39.5 kcal/mol and proton
transfer then occurs to form TI 4 with an energy release of
5
1.9 kcal/mol. Thus, from TI 3 to TI 4, 12.4 kcal/mol free
energy is released, which drives the cycloaddition reaction to
proceed.
In conclusion, we have developed a solvent-directed click
reaction between active methylene compounds and azido-
1
,3,5-triazines. According to the experiment results, this
enolate TI 1 by base, whose formation is accelerated in a polar
solvent. Undergoing a nucleophilic addition, TI 1 reacts with
the azido group on azido-1,3,5-triazine (1) to afford
intermediate TI 2. In an aprotic solution with high polarity
reaction displays high tolerance to many functional groups
and effectiveness of join substrates with specific functional
groups under mild conditions with excellent yield, great
regiospecificity, and facileness of purification, which meets the
standard of click reactions. We have also offered a plausible
mechanism for this reaction, and the mechanism is further
substantiated with DFT calculations, which allow better
optimization and development of new methodologies.
(
such as DMSO or DMF), TI 2 then grabs a proton from the
α-methylene to form intermediate TI 6, which undergoes
diazo-transfer steps to give diazo compounds as the final
1
9
product. Nevertheless, in a protic solvent, the nitrogen anion
is more likely to capture a proton from the solvent to give
intermediate TI 3. Therefore, the diazo-transfer reaction does
not occur in protic solvents. The excellent regiospecificity of
the cycloaddition reaction is believed to be determined by the
electron deficiency of the carbonyl groups. The more electron-
deficient carbonyl is attacked by the lone-pair electrons on the
nitrogen atom of the secondary amine, which affords a N−C−
O−H four-membered ring transition state (Figure 1, TS). The
proton transfers from N to O and the bond formation between
N and C take place simultaneously, producing the intermediate
TI 4. After a series of proton-transfer and elimination
reactions, trisubstituted 1,2,3-triazole is formed as the final
product. With nitriles as the reactants, similar intermediate TI
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02089.
General procedures for the synthesis of azide com-
1
pounds and azido compounds, calculation details, H
13
and C NMR spectra, and mass spectra of all
synthesized compounds (PDF)
AUTHOR INFORMATION
3
′ is formed and the nitrogen atom would attack the cyano
■
Corresponding Author
group to give intermediate TI 4′, which proceeds through
Dimroth rearrangement to give the final product 6. The
*E-mail: mma@ustc.edu.cn.
D
DOI: 10.1021/acs.orglett.9b02089
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ORCID
(13) (a) Wang, L.; Peng, S.; Danence, L. J.; Gao, Y.; Wang, J. Chem.
Eur. J. 2012, 18, 6088−93. (b) Shashank, A. B.; Karthik, S.;
-
Mingming Ma: 0000-0002-7967-8927
Author Contributions
†Z.Y. and Y.L. contributed equally to this work.
Madhavachary, R.; Ramachary, D. B. Chem. - Eur. J. 2014, 20, 16877−
16881. (c) Danence, L. J.; Gao, Y.; Li, M.; Huang, Y.; Wang, J. Chem.
- Eur. J. 2011, 17, 3584−7. (d) Ramachary, D. B.; Reddy, G. S.;
Peraka, S.; Gujral, J. ChemCatChem 2017, 9, 263−267. (e) Wan, J. P.;
Cao, S.; Liu, Y. Org. Lett. 2016, 18, 6034−6037.
Notes
The authors declare no competing financial interest.
(14) Quan, X. J.; Ren, Z. H.; Wang, Y. Y.; Guan, Z. H. Org. Lett.
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(
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15) (a) Chen, Z. K.; Yan, Q. Q.; Liu, Z. X.; Xu, Y. M.; Zhang, Y. H.
ACKNOWLEDGMENTS
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This work was supported by the National Natural Science
Foundation of China (21722406) and the Fundamental
Research Funds for the Central Universities
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