Concurrent pathway and unexpected products in the CuAAC reaction of ethyl prop-2-ynyl methylphosphonate with aromatic azides

Article abstract of DOI:10.1007/s10593-019-02467-9

[Figure not available: see fulltext.] The CuI-mediated click reaction of aromatic azides, containing the carboxyl moiety in the ortho position to the azido group, with ethyl prop-2-ynyl methylphosphonate proceeded via a concurrent pathway whereby the form

Full text of DOI:10.1007/s10593-019-02467-9

DOI 10.1007/s10593-019-02467-9
Chemistry of Heterocyclic Compounds 2019, 55(4/5), 374–378
Concurrent pathway and unexpected products in the CuAAC reaction
of ethyl prop-2-ynyl methylphosphonate with aromatic azides
Nazariy T. Pokhodylo1*, Olga Ya. Shyyka1, Mykola A. Tupychak1,
Yurii I. Slyvka2, Mykola D. Obushak1
1 Department of Organic Chemistry, Ivan Franko National University of Lviv,
6 Kyryla i Mefodiya St., Lviv 79005, Ukraine; e-mail: pokhodylo@gmail.com
2 Department of Inorganic Chemistry, Ivan Franko National University of Lviv,
6 Kyryla i Mefodiya St., Lviv 79005, Ukraine; e-mail: yura_slyvka@ukr.net
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(4/5), 374–378
Submitted December 17, 2018
Accepted January 14, 2019
The CuI-mediated click reaction of aromatic azides, containing the carboxyl moiety in the ortho position to the azido group, with ethyl
prop-2-ynyl methylphosphonate proceeded via a concurrent pathway whereby the formation of acrylamides predominated over
"classical" cycloaddition products 1,2,3-triazoles. The reaction appears to be specific toward the ortho-carboxyl-substituted aromatic
azides, while aryl azides with other substituents do not give the "reduction" products, but form the expected click products: (1-aryl-1H-
1,2,3-triazol-4-yl)methyl ethyl methylphosphonates. The reaction mechanism is discussed.
Keywords: azides, phosphonates, 1,2,3-triazoles, click reaction, unexpected product.
The intensive application in synthetic, biological chemistry
and materials science of the Huisgen dipolar azide/alkyne
cycloaddition catalyzed by Cu(I) salts (CuAAC) as one of
the most convenient click reactions is overviewed in
numerous publications and summarized in several recent
reviews.1 Moreover, a separate issue in the Chemical Society
Reviews, edited by M. G. Finn, is devoted to this topic.2 The
CuAAC reaction is applicable for the large range of azides
and terminal alkynes,1 occurs under mild conditions, and
may be used in biological objects.3
The diversity of Cu(I)-based catalytic systems used in
the CuAAC reactions allows to find the required conditions
depending on the reactants.1 One of the most effective and
currently one of the most commonly used catalyst in such
reactions is CuI due to its high catalytic activity, as well as
moderate solubility in many organic solvents.4 In our
recent work on new 1,2,3-triazole synthesis, we showed the
high efficiency of CuI in the reaction of norbornyl azide
with phenylacetylene, as well as in the one-pot three-
component reaction of alkyl 3-aryl-2-bromopropanoates
with sodium azide and phenylacetylene.5 At the same time,
this catalytic system is not universal and there are some
examples where the reaction did not occur or side products
formed.6
Our ongoing research in the area of CuAAC involves the
construction of small molecules for anticancer studies.7 For
this purpose, the phosphonate moiety was proposed to be
added to the triazole scaffold. It should be mentioned that
examples of the application of alkynes with phosphonate
moiety in the CuAAC are limited. For instance, the
cycloaddition of fluoroalkyl propargyl methylphosphonates
to various azidopeptides was demonstrated by obtaining the
corresponding triazoles which were screened for the inhibi-
tory activity toward acetylcholinesterase, butyrylcholin-
esterase, and carboxylesterase.8 In another example, cyclo-
addition of azidoalkylphosphonates to the propargylated
nucleotides affords several nucleoside phosphonates and
their antiviral properties were studied.9 Finally, a series of
bis- and tris[3- and 24-(5β-cholanetriazolyl)] derivatives of
phosphorus acids containing anion-binding triazolium sites
and hydrophobic cholane residues were synthesized and the
binding properties of such ligands for inorganic and organic
anions were studied.10 The limited use of phosphorus-
containing compounds in CuAAC may be due to the
0009-3122/19/55(4/5)-0374©2019 Springer Science+Business Media, LLC
374

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 374–378
Scheme 1
complexation of phosphorus moiety with copper(I), thereby
affecting the cyclization process.
Taking into account the lack of such studies, in our
present work we have synthesized ethyl prop-2-ynyl
methylphosphonate (2) and studied its reaction with a
number of aromatic azides. In our first attempts, the
CuAAC of aryl azides 1a–f with ethyl prop-2-ynyl
methylphosphonate (2) in the presence of CuI–Et3N
catalytic system proceeded with the formation of triazoles
3a–f in good to excellent yields (Scheme 1, A). Such a
result was expected and is fully consistent with "classical"
mechanism of this reaction (Scheme 2, path a). However,
when, in order to explore the scope of the reaction, a set of
azides 1g–i containing the ester group in the ortho position
was used, the cycloaddition to ethyl prop-2-ynyl methyl-
phosphonate (2) did not give the expected 1,2,3-triazole,
but instead acrylamides 4a–c were isolated in 64–73%
yields (Scheme 1, B). Such an outcome can be formally
considered as the reduction of the azido group to amino.
The electrons in redox process are balanced by the
elimination of the nitrogen molecule and addition of water.
The structures of the synthesized products were
confirmed by NMR spectra, mass spectra, and single
crystal X-ray diffraction. The latter experiment revealed a
similar geometry of compounds 3a,b (Fig. 1). The plane of
the aryl ring in crystal structures 3a,b is slightly rotated
relatively to 1H-1,2,3-triazole plane by 15.7(3)° and 22.9(5)°,
respectively. The distorted tetrahedral surrounding of
phosphorus atom (τ4 0.91 for compound 3a and 0.92 for
compound 3b, τ4 – four-coordinated geometry index)
includes two bridging O atoms, one terminal O atom, and
carbon atom of the methyl group. Phosphorus polyhedron
is raised relative to the triazole ring planes (torsion angle
P–O(1)–C(6)–C(4) in structures 3a and 3b equal to
155.5(2)° and 156.6(4)°, respectively).
Figure 1. The structures of ethyl (1-aryl-1H-1,2,3-triazol-4-yl)-
methyl methylphosphonates 3a (left) and 3b (right) with atoms
represented by thermal vibration ellipsoids of 50% probability.
cited works,6,11 as well as in our case (compounds 4),
azides bearing in the ortho position fragments suitable for
Cu(I) complexation were used.
It is most likely that in our case the concurrent reaction
occurred in a similar way as previously reported for
sulfonyl azides via the formation of ketenimine inter-
mediates.12,13 Reaction started from "classical" intermediate
complexes A, generated by the action of copper acetylide
(from alkyne 2 and CuI) on azide 1. According to the
CuAAC mechanism1g (Scheme 2, path a), the complex A
undergoes cycloaddition likely through intermediate B, and
the resulting triazolyl-cuprate C upon protonation yields
triazoles 3a–f. Probably, in case of azides 1g–i bearing
carboxyl moiety in the ortho position to the azido group the
formation of transitional state B is unfavorable due to steric
effects or additional bidental bonding of a copper atom in
complexes A. In such case, upon elimination of N2 ynamide D
or it isomeric ketenimine E or their copper complexes were
formed (Scheme 2, path b). Alternatively, the formation of
the ketenimine intermediate E may be presumed via
1,2,3-triazole ring cleavage of triazolyl cuprate C and N2
elimination. Nucleophilic addition to a highly reactive
ketenimine would lead to the formation of carbanion F
which is stabilized by phosphonate elimination and after
rearrangement gives acrylates 4a–c. The possibility that
both pathways a and b are realised at the same time, as well
The mechanism of the alternative reaction pathway is
not obvious and requires a detailed study as no similar
results for aromatic azides were mentioned in the literature.
As an example of anomalous CuAAC, some recent results
could be mentioned whereby azido compound gave the
corresponding amine rather than the desired cycloaddition
product.6,11 In these examples, solvent plays the role of
hydrogen donor (reduction agent). Additionally, in the
375

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 374–378
Scheme 2
as other mechanisms that lead to the formation of acrylates
4, cannot be completely excluded at present.
mixture. The product was extracted with CH2Cl2 (3×10 ml),
the extract was dried with Na2SO4 and evaporated. The
solid products were recrystallized from hexane.
In summary, an unusual pathway in the CuAAC reaction
was observed and unexpected noncyclic products were
isolated. The concurrent pathway is strictly controlled by
the presence in the ortho position to azide a substituent
having the tendency to coordinate the copper(I) atom. Such
exceptions allow understanding the reaction mechanism
and nature of copper(I) coordination in the catalytic cycle
and to make prospects for controlling the reaction products
formation.
Ethyl [1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl
methylphosphonate (3a). Yield 254 mg (85%), white
1
solid, mp 95–97°С. H NMR spectrum (400 MHz), δ, ppm
(J, Hz): 8.89 (1H, s, H triazole); 7.95 (2H, dd, J = 8.6,
J = 4.4, H-2,6 Ar); 7.47 (2H, t, J = 8.6, H-3,5 Ar); 5.12
(2H, d, JPH = 7.9, CH2); 4.09–3.91 (2H, m, CH3CH2); 1.50
(3H, d, JPH = 17.3, CH3P); 1.23 (3H, t, J = 6.8, CH3CH2).
13C NMR spectrum (101 MHz), δ, ppm (J, Hz): 162.2 (d,
3
Experimental
1JCF = 245.7, C-4 Ar); 144.4 (d, JCP = 7.0, C-4 triazole);
1H and 13C NMR spectra were recorded on Varian
Mercury 400 (400 and 101 MHz, respectively) and Bruker
Avance 500 (500 and 126 MHz, respectively) spectro-
meters in DMSO-d6 using TMS or the deuterated solvent
133.6 (d, 4JCF = 2.6, C-1 Ar); 123.6 (C-5 triazole); 123.1 (d,
3JCF = 8.9, C-2,6 Ar); 117.3 (d, 2JCF = 23.3, C-3,5 Ar); 61.5
2
2
(d, JCP = 6.0, CH2O); 58.1 (d, JCP = 5.3, CH2O); 16.6 (d,
3JCP = 6.2, CH3); 11.1 (d, JCP = 140.0, CH3P). Mass
1
1
(δ 2.50 and 39.5 ppm, for H and 13C nuclei, respectively)
spectrum m/z (Irel, %): 300 [M+H]+ (100). Found, %:
C 48.05; H 5.11; N 14.23. C12H15FN3O3P. Calculated, %:
C 48.17; H 5.05; N 14.04.
as internal reference. Mass spectral analyses were performed
using an Agilent 1100 series LC/MSD instrument in
API-ES/APCI mode (200 eV). Elemental analyses were
carried out using a Carlo Erba 1106 instrument. Melting
points were determined on a Boetius melting point
apparatus. Progress of reactions and purity of the
synthesized compounds were examined by TLC on Silufol
UV-254 plates, and visualization was performed using
UV lamp (254 nm) or I2 vapor.
[1-(3-Bromophenyl)-1H-1,2,3-triazol-4-yl]methyl ethyl
methylphosphonate (3b). Yield 285 mg (79%), white
solid, mp 81–82°С. H NMR spectrum (500 MHz), δ, ppm
1
(J, Hz): 8.98 (1H, s, H triazole); 8.18 (1H, s, H-2 Ar); 7.97
(1H, d, J = 8.0, H Ar); 7.71 (1H, d, J = 7.9, H Ar); 7.56
(1H, t, J = 8.1, H-5 Ar); 5.21–5.05 (2H, m, CH2); 4.07–
3.93 (2H, m, CH3CH2); 1.50 (3H, d, JPH = 17.4, CH3Р);
1.22 (3H, t, J = 7.0, CH3CH2). 13C NMR spectrum
(126 MHz), δ, ppm (J, Hz): 144.5 (d, 3JCP = 7.1, C-4 triazole);
138.1; 132.3; 132.0; 123.4; 123.2; 122.9; 119.6; 61.5 (d,
Ethyl prop-2-ynyl methylphosphonate (2) was
synthesized according to a procedure reported previously.14
1H NMR spectrum (500 MHz), δ, ppm (J, Hz): 4.63 (2H,
dd, J = 10.3, J = 2.4, ≡CCH2); 4.05–3.97 (2H, m,
CH3CH2); 3.63 (1H, t, J = 2.4, ≡CH); 1.49 (3H, d,
2
2JCP = 6.1, CH2O); 58.1 (d, JCP = 5.0, CH2O); 16.6 (d,
1
3JCP = 5.9, CH3); 11.1 (d, JCP = 139.9, CH3P). Mass
J
PH = 17.5, CH3P); 1.25 (3H, t, J = 7.0, CH3CH2).
spectrum, m/z (Irel, %): 360 [М(79Br)+H]+ (100), 362
[М(81Br)+H]+ (97). Found, %: C 40.11; H 4.34; N 11.73.
C12H15BrN3O3P. Calculated, %: C 40.02; H 4.20; N 11.67.
Ethyl {1-[3-(trifluoromethyl)phenyl]-1H-1,2,3-triazol-
4-yl}methyl methylphosphonate (3с). Yield 304 mg (87%),
Synthesis of triazoles 3a–f and acrylates 4a–c
(General method). An appropriate azide 1a–f (1.0 mmol)
and ethyl prop-2-ynyl methylphosphonate (2) (162 mg,
1.0 mmol) were dissolved in t-BuOH (5 ml). Water
(approx. 0.4 ml) was added dropwise to the solution until
an emulsion formed. After that, Et3N (0.4 ml, 2.8 mmol)
and CuI (19 mg, 0.1 mmol) were added. The reaction mixture
was stirred at room temperature until TLC (eluent hexane–
EtOAc, 5:1) indicated that all starting material had dis-
appeared (approximately 12 h). H2O (15 ml) and concen-
trated aqueous NH3 solution (5 ml) were added to the
1
yellow oil. H NMR spectrum (500 MHz), δ, ppm (J, Hz):
9.09 (1H, s, H triazole); 8.30 (1H, s, H-3 Ar); 8.27 (1H, d, J
= 7.7, H-6 Ar); 7.90–7.83 (2H m, H-4,5 Ar); 5.19–5.09
(2H, m, CH2); 4.07–3.94 (2H, m, CH3CH2); 1.50 (3H, d,
J
PH = 17.4, CH3Р); 1.22 (3H, t, J = 7.0, CH3CH2). 13C NMR
3
spectrum (126 MHz), δ, ppm (J, Hz): 144.6 (d, JCP = 7.2,
C-4 triazole); 137.4; 131.8; 131.0 (q, 2JСF = 32.6, C-3 Ar);
376

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 374–378
125.8 (q, 3JСF = 3.7, C-2 Ar); 124.5; 124.0 (q, 1JСF = 272.2,
spectrum (126 MHz), δ, ppm (J, Hz): 167.5; 163.3; 139.3;
3
CF3); 123.6 (C-5 triazole); 117.3 (q, JСF = 3.9, C-4 Ar);
133.8; 132.2; 130.5; 127.5; 123.5; 121.3; 118.0; 52.4. Mass
spectrum, m/z (Irel, %): 206 [M+H]+ (100). Found, %:
C 64.48; H 5.37; N 6.94. C11H11NO3. Calculated, %:
C 64.38; H 5.40; N 6.83.
61.5 (d, 2JCP = 6.1, CH2O); 58.1 (d, 2JCP = 5.2, CH2O); 16.6
3
1
(d, JCP = 6.2, CH3); 11.1 (d, JCP = 140.0, CH3P). Mass
spectrum, m/z (Irel, %): 350 [M+H]+ (100). Found, %:
C 44.77; H 4.30; N 11.92. C13H15F3N3O3P. Calculated, %:
C 44.71; H 4.33; N 12.03.
Methyl 2-acrylamido-5-bromobenzoate (4b). Yield
207 mg (73%), white solid, mp 83–84°С. 1H NMR
spectrum (400 MHz), δ, ppm (J, Hz): 10.71 (1H, s, NH);
8.20 (1H, d, J = 8.9, H-3 Ar); 7.99 (1H, d, J = 2.1, H-6 Ar);
7.80 (1H, dd, J = 8.9, J = 2.0, H-4 Ar); 6.43 (1H, dd,
J = 16.8, J = 10.2, CH=); 6.28 (1H, d, J = 16.8) and 5.85
(1H, d, J = 10.2, CH2=); 3.85 (3H, s, CH3O). 13C NMR
spectrum (126 MHz), δ, ppm (J, Hz): 166.7; 163.9; 138.7;
136.8; 133.1; 132.4; 128.4; 124.2; 121.3; 115.6; 53.2. Mass
spectrum, m/z (Irel, %): 284 [М(79Br)+H]+ (100), 286
[М(81Br)+H]+ (95). Found, %: C 46.55; H 3.49; N 4.98.
C11H10BrNO3. Calculated, %: C 46.50; H 3.55; N 4.93.
Methyl 3-acrylamidothiophene-2-carboxylate (4c).
Yield 139 mg (64%), white solid, mp 146–147°С. 1H NMR
spectrum (500 MHz), δ, ppm (J, Hz): 10.21 (1H, s, NH);
8.00 (1H, d, J = 5.4, H Th); 7.93 (1H, d, J = 5.4, H Th);
6.60 (1H, dd, J = 16.9, J = 10.3, CH=); 6.32 (1H, d, J = 17.0)
and 5.88 (1H, d, J = 10.3, CH2=); 3.86 (3H, s, CH3O).
13C NMR spectrum (101 MHz), δ, ppm (J, Hz): 163.8;
162.9; 143.9; 133.4; 131.9; 129.0; 123.0; 111.7; 52.6. Mass
spectrum, m/z (Irel, %): 212 [M+H]+ (100). Found, %:
C 51.11; H 4.38; N 6.71. C9H9NO3S. Calculated, %:
C 51.17; H 4.29; N 6.63.
Single crystal X-ray diffraction study of compounds
3a,b. Crystals were obtained by crystallization from hexane.
Diffraction data for compounds 3a,b were collected on a
Kuma KM-4-CCD diffractometer with MoKα radiation
(λ 0.71073 Å). The diffraction data were processed with
the CrysAlis PRO program.16 The structures were solved
by ShelXT and refined by least-squares method on F2 by
ShelXL programs with the following graphical user inter-
face of Olex.17,18 Atomic displacements for non-hydrogen
atoms were refined using an anisotropic model. Hydrogen
atoms were placed in ideal positions and refined as riding
atoms with relative isotropic displacement parameters. The
complete crystallographic datasets were deposited at the
Cambridge Crystallographic Data Center (deposits CCDC
1885238 (compound 3a) and CCDC 1885239 (compound
3b)).
Ethyl [1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl]methyl
methylphosphonate (3d). Yield 287 mg (88%), white solid,
1
mp 129–130°С. H NMR spectrum (500 MHz), δ, ppm
(J, Hz): 9.13 (1H, s, H triazole); 8.46 (2H, d, J = 8.2, H-3,5 Ar);
8.24 (2H, d, J = 8.3, H-2,6 Ar); 5.27–5.03 (2H, m, CH2);
4.09–3.90 (2H, m, CH3CH2); 1.51 (3H, d, JPH = 17.3,
CH3Р); 1.23 (3H, t, J = 6.8, CH3CH2). 13C NMR spectrum
3
(126 MHz), δ, ppm (J, Hz): 146.8; 144.5 (d, JCP = 7.0,
C-4 triazole); 140.7; 125.6 (2C); 123.2 (C-5 triazole);
2
120.7 (2C); 61.1 (d, 2JCP = 6.1, CH2O); 57.5 (d, JCP = 5.2,
3
1
CH2O); 16.1 (d, JCP = 6.7, CH3); 10.6 (d, JCP = 139.8,
CH3Р). Mass spectrum, m/z (Irel, %): 327 [M+H]+ (100).
Found, %: C 44.05; H 4.70; N 17.21. C12H15N4O5P.
Calculated, %: C 44.18; H 4.63; N 17.17.
[1-(2-Cyanophenyl)-1H-1,2,3-triazol-4-yl]methyl ethyl
methylphosphonate (3e). Yield 220 mg (72%), yellow oil.
1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 8.85 (1H, s,
H triazole); 8.14 (1H, d, J = 7.6, H-6 Ar); 7.96 (1H, t, J = 7.7,
H-4 Ar); 7.88 (1H, d, J = 8.0, H-3 Ar); 7.77 (1H, t, J = 7.6,
H-5 Ar); 5.18 (2H, d, JPH = 8.5, CH2); 4.07–3.95 (2H, m,
CH3CH2); 1.51 (3H, d, JPH = 17.3, CH3Р); 1.22 (3H, t, J = 7.0,
CH3CH2). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm
3
(J, Hz): 144.2 (d, JCP = 6.9, C-4 triazole); 138.2; 135.3;
2
135.2; 130.9; 126.4; 126.1; 116.2; 107.7; 61.6 (d, JCP = 6.2,
2
2
CH2O); 58.0 (d, JCP = 5.2, CH2O); 16.6 (d, JCP = 5.9,
1
CH3); 11.2 (d, JCP = 140.0, CH3Р). Mass spectrum, m/z
(Irel, %): 307 [M+H]+ (100). Found, %: C 50.90; H 4.99;
N 18.21. C13H15N4O3P. Calculated, %: C 50.98; H 4.94;
N 18.29.
[1-(2-Acetylphenyl)-1H-1,2,3-triazol-4-yl]methyl ethyl
methylphosphonate (3f). Yield 226 mg (70%), yellow oil.
1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 8.69 (1H, s,
H triazole); 7.84 (1H, d, J = 7.5, H-6 Ar); 7.74 (1H, t,
J = 7.5, H-5 Ar); 7.71–7.63 (2H, m, H-3,4 Ar); 5.13 (2H, d,
JPH = 8.5, CH2); 4.08–3.94 (2H, m, CH3CH2); 2.21 (3H, s,
CH3CO); 1.49 (3H, d, JPH = 17.4, CH3Р); 1.22 (3H, t,
J = 6.9, CH3CH2). 13C NMR spectrum (126 MHz), δ, ppm
3
(J, Hz): 199.9; 144.0 (d, JCP = 6.7, C-4 triazole); 136.1;
134.1; 132.7; 130.4; 129.4; 126.2; 126.1; 61.5 (d,
The authors are grateful to the Ministry of Education
and Science of Ukraine for financial support of this work
(grant No. 0118U003610).
2
2JCP = 6.1, CH2O); 58.1 (d, JCP = 5.2, CH2O); 29.7; 16.6
3
1
(d, JCP = 5.8, CH3); 11.2 (d, JCP = 139.8, CH3Р). Mass
spectrum, m/z (Irel, %): 324 [M+H]+ (100). Found, %:
C 52.05; H 5.57; N 13.14. C14H18N3O4P. Calculated, %:
C 52.01; H 5.61; N 13.00.
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