Synthesis of 1,4,5-trisubstituted triazoles by [3+2] cycloaddition of a ruthenium azido complex with ynoate esters

Article abstract of DOI:10.1016/j.jorganchem.2019.06.013

The [3 + 2] cycloaddition reactions of a series of ynoate esters with a ruthenium azido complex [Ru]?N₃ (1, [Ru] = (η⁵-C₅H₅)(dppe)Ru, dppe = Ph₂PCH₂CH₂PPh₂) were inves

Full text of DOI:10.1016/j.jorganchem.2019.06.013

Accepted Manuscript
Synthesis of 1,4,5-trisubstituted triazoles by [3+2] cycloaddition of a ruthenium azido
complex with ynoate esters
Chao-Wan Chang, Gene-Hsiang Lee
PII:
S0022-328X(19)30252-9
DOI:
https://doi.org/10.1016/j.jorganchem.2019.06.013
JOM 20825
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 12 April 2019
Revised Date: 10 June 2019
Accepted Date: 12 June 2019
Please cite this article as: C.-W. Chang, G.-H. Lee, Synthesis of 1,4,5-trisubstituted triazoles by [3+2]
cycloaddition of a ruthenium azido complex with ynoate esters, Journal of Organometallic Chemistry
(2019), doi: https://doi.org/10.1016/j.jorganchem.2019.06.013.
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ACCEPTED MANUSCRIPT
Synthesis of 1,4,5-trisubstituted triazoles by [3+2] cycloaddition of a
ruthenium azido complex with ynoate esters
Chao-Wan Chang*a and Gene-Hsiang Leeb
Division of Preparatory Programs for Overseas Chinese Students, National Taiwan
Normal University, Linkou, New Taipei City, Taiwan 24449, ROC
bInstrumentation Center, National Taiwan University, Taipei, Taiwan 10617, ROC
ABSTRACT
The [3+2] cycloaddition reactions of a series of ynoate esters with a ruthenium
azido complex [Ru]−N3 (1, [Ru] = (
investigated. The reaction products, metal-bound heterocyclic complexes such as the
triazolato complexes [Ru]N3C2(CO2Et)2 (2), [Ru]N3C2(CO2Et)(CF3) (3),
η
5-C5H5)(dppe)Ru, dppe = Ph2PCH2CH2PPh2) were
[Ru]N3C2(CO2Me)(Ph) (4) and [Ru]N3C2(CO2Et)(CH3) (5) were produced from diethyl
acetylene dicarboxylate, ethyl 4,4,4-trifluoro-2-butynoate, methyl phenylpropiolate and
ethyl 2-butynoate, respectively. The complexes were all structurally characterized as
being N(2)-bound. The alkylation of 2 with organic halides resulted in the cleavage of
the
Ru−N
bond
and
the
formation
of
a
series
of
1-alkylated-4,5-bis(ethoxycarbonyl)-1,2,3-triazoles N3(CH2R)C2(CO2Et)2 (6a, R = H;
6b, R = C6F5; 6c, R = Ph; 6d, R = 4-CH2Br-C6H4; 6e, R= 4-CN-C6H4). The high
regioselective
alkylation
of
4
with
organic
halides
gave
a
1-alkylated-4-phenyl-5-methoxycarbonyl-1,2,3-triazoles N3(CH2C6F5)C2(Ph)(CO2Me)
(N3-7a). The structures of complexes 2, 3, 4, 5 and N3-7a were confirmed by
single-crystal X-ray diffraction analysis.
Keywords: [3+2] cycloaddition; ruthenium azide; ruthenium triazolate; internal alkynes;
ynoate esters; 1,4,5-trisubstituted 1,2,3-triazole
1. Introduction
The 1,2,3-triazole structure, a nitrogen-containing heterocycle found in
biomolecules [1-3], has found widespread applications in agricultural [4-7], medicinal
[8-14] and material [15-18] chemistry during the past decades. In recent years, the
chemistry of triazole and derivatives thereof have been heavily studied, given the
pharmacological importance of the heterocyclic nucleus and because of their diverse
biological activities [19,20]. Such 1,2,3-triazole derivatives are typically prepared by the
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Huisgen 1,3-dipolar cycloaddition of azides and alkynes [21]. Metal catalyzed
cycloaddition reactions [22-26] have also been employed in recent years and based on
the so called “click chemistry” concept [27], a huge number of reports dealing with
copper-catalyzed azide-alkyne cycloaddition (CuAAC) [28] and ruthenium-catalyzed
azide-terminal-alkyne cycloaddition (RuAAC) [29] reactions to give 1,4-disubstituted
and 1,5-disubstituted 1,2,3-triazoles have appeared. On the contrary, the application of a
[3+2] cycloaddition strategy for the synthesis of fully substituted 1,4,5-trisubstituted
1,2,3-triazoles has not been found to be generally applicable, since the final products are
frequently mixtures of regioisomers [30]. Internal alkynes are not ideal staring products,
because they do not easily react with azides to give fully substituted triazoles due to
their weak activity and difficulties associated with controlling the regiochemistry of the
reactions. As a result, only few examples of the regiospecific synthesis of fully
substituted triazoles by CuACC have been reported [31].
The [3+2] cycloaddition reaction between a metal-coordinated azide group and an
alkyne was first reported by Fehlhammer’s group for the reaction of (Ph3P)2Pd(N3)2
with dimethylacetylene dicarboxylate (DMAD) [32i]. Reactions of azido metal
complexes with alkynes has attracted the interest of various research groups for decades,
and many metal azides have been shown to give 1,2,3-triazolato complexes [32]. In
most cases, the activated alkynes used as dipolarophiles are limited to highly
electron-poor alkynes such as dialkylacetylene dicarboxylate, CF3C≡CCF3 and
HC≡CCN [32]. The formation of an N-coordinate metal triazolato complex by the [3+2]
cycloaddition of a metal-coordinated azide with a less electron-poor internal alkyne,
such as CH3C≡CCO2Et and PhC≡CCO2Me, is rare [32a]. In a previous study, we
reported on the [3＋2] cycloaddition of a ruthenium azido complex with excess amounts
of alkenes and alkynes to form a variety of ruthenium triazolato complexes [33] and
successfully developed a reaction cycle for the synthesis of organic triazoles [34]. Our
continuing interest in ruthenium triazolato complexes involves the synthesis of
functionalized organic 1,2,3-triazoles and the development of reaction cycles involve
regiospecific alkylation and the subsequent Ru-N bond cleavage of various ruthenium
triazolato complexes. Herein we report on our recent findings regarding the reactivity of
ruthenium azide toward a series of ynoate esters, α,β-unsaturated carboxylic esters with
the general formula R1C≡C‒CO2R2 (R2 ≠ H) in which the ester C=O function is
conjugated to a C≡C triple bond located at the α, β position. We now report on the
results of detailed synthetic and structural investigations into this reaction. A
preliminary account of the steric and electronic effects for the structures and the
reactivity of the thus formed triazolato complexes with organic halides are reported.
2. Experimental section
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2.1. General procedures
All solvents and reagents were of reagent grade and were used without further
purification. Elemental analyses were performed on a Perkin-Elmer 2400 CHN
elemental analyzer. HR & LR-FAB mass spectra were conducted on a JMS-700 double
focusing mass spectrometer (JEOL, Tokyo, Japan) with a resolution of 8000(3000) (5%
valley definition). IR spectra were measured on a Perkin-Elmer Paragon 1000 FT-IR
spectrometer in the range of 4000-400 cm-1 using KBr pellets. NMR spectra were
recorded on Bruker AV3-400 and AVA-300 NMR spectrometers at room temperature
and are reported in units of δ with residual protons in the solvents as an initial standard
(CDCl3, δ 7.24; CD3OD, δ 3.35). Complexes [Ru]-N3 (1, [Ru] = (η
5-C5H5)(dppe)Ru,
dppe = Ph2PCH2CH2PPh2) [33], were prepared following methods reported in the
literature. Elemental analyses were carried out at the Institute of Chemistry, Academia
Sinica. X-ray diffraction studies were carried out at the Instrumentation Center located
at the National Taiwan University.
2.2. Synthesis of Cp(dppe)RuN3C2(CO2Et)2 (2)
To a Schlenk flask charged with 1 (300.0 mg, 0.495 mmol), diethyl
acetylenedicarboxylate (252 mg, 237 µL, 1.485 mmol) and CHCl3 (30 mL) were added.
The mixture was stirred at room temperature for 36 h and the volume of solvent was
reduced to 2 mL under a rotary evaporator. To the residue, 20 mL of n-pentane was
added to give a yellow precipitate. After isolation the precipitate on a filter, it was
washed with 2×5 mL of n-pentane and dried under a vacuum to give 2 (357.3 mg, 0.46
mmol, 93 % yield). Spectroscopic data for 2 are as follows: IR (KBr, cm−1): ν(C=O)
-
1
1708 (vs), ν(N=N) 1431 (s), ν(C−O) 1285 (m), 1077 (s), ν(COO ) 693 (s), 528 (s). H
NMR (CDCl3): δ7.46-7.13 (m, 20H, Ph), 4.65 (Cp), 4.19 (q, 4H, JH−H = 7.20 Hz, OCH2),
3.25, 2.52 (2m, PCH2CH2P), 1.19 (t, 6H, JH−H = 7.20 Hz, CH3). 31P NMR (CDCl3):
13
δ 87.2. C NMR (CDCl3): δ 161.8 (CO2), 142.2 (CCO2), 142.4-127.0 (Ph), 81.9 (Cp),
59.8 (OCH2), 28.5 (t, PCH2CH2P, JC-P = 23.1 Hz), 14.2 (CH3). c 777.1 (M+), 565.1
(M+−triazolato ring). Anal. Calcd. for C39H39N3O4P2Ru: C, 60.30; H, 5.06; N, 5.41
Found: C, 60.32; H, 5.07; N, 5.39.
2.3. Synthesis of Cp(dppe)RuN3C2(CO2Et) (CF3) (3)
To a Schlenk flask charged with 1 (198 mg, 0.327 mmol), ethyl
4,4,4-trifluoro-2-butynoate (233.5 µL , 271 mg, 1.634 mmol) and CH2Cl2 (20 mL) were
3

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added. The mixture was stirred at room temperature for 24 h and the volume of solvent
was then reduced to 2 mL under a rotary evaporator. To the residue, 20 mL of n-pentane
was added to give a yellow precipitate. After isolating the precipitate on a filter, it was
washed with 2×5 mL of n-pentane and dried under a vacuum to give 3 (232.1 mg, 0.301
mmol, 92 % yield). Spectroscopic data for 3 are as follows: IR (KBr, cm−1): ν(C=O)
1720 (vs), ν(N=N) 1435 (s), ν(C−O) 1310 (m), 1184 (vs), 1127 (vs), 1160 (vs), 1050
-
1
(vs), ν(COO ) 695 (s), 528 (s). H NMR (CDCl3): 7.68-7.13 (m, 20H, Ph), 4.66 (Cp),
4.15 (q, 4H, JH−H = 7.20 Hz, OCH2), 3.20, 2.55 (2m, PCH2CH2P), 1.22 (t, 6H, JH−H
=
31
13
7.20 Hz, CH3). P NMR (CDCl3): 87.0. C NMR (CDCl3): 160.5 (CO2), 137.6 (q,
JCCF = 37.2 Hz, CCF3), 135.4 (CCO2), 121.0 (q, JCF = 267.6 Hz, CF3), 142.2-127.7 (Ph),
81.9 (Cp), 59.9 (OCH2), 28.5 (t, PCH2CH2P, JC-P = 22.6 Hz), 14.0 (CH3). MS (m/z,
Ru102): 773.2 (M+), 565.1 (M+−triazolato ring). Anal. Calcd. for C37H34F3N3O2P2Ru: C,
57.51; H, 4.44; N, 5.44 Found: C, 57.66; H, 4.43; N, 5.40.
2.4. Synthesis of N(2)-bound Cp(dppe)RuN3C2(CO2Me)(Ph) (4)
To a Schlenk flask charged with 1 (524.1 mg, 0.865 mmol), methyl phenylpropiolate
(834 mg, 780 µL, 4.32 mmol) and benzene (10 mL) were added. The mixture was
heated to reflux for 48 h and the volume of solvent was then reduced to 2 mL under a
rotary evaporator. To the residue, 20 mL of n-hexane was added to give a yellow
precipitate. After isolating the precipitate on a filter, it was washed with 2×3 mL of
n-hexane and dried under a vacuum to give 4 (623.0 mg, 0.813 mmol, 94 % yield).
Spectroscopic data for 4 are as follows: IR (KBr, cm−1): 2917 (m), ν(C=O) 1700 (vs),
1536 (m), 1477 (s), ν(N=N) 1433 (s), 1397 (m), ν(C−O) 1312 (m), 1295 (m), 1184 (m),
1098 (vs), ν(COO-) 705 (vs), 526 (s). 1H NMR (CDCl3): δ 7.56-6.65 (m, 25H, Ph), 4.62
(Cp), 3.69 (s, 3H, CH3), 3.18, 2.60 (2m, PCH2CH2P). 31P NMR (CDCl3): δ 86.9. 13C
NMR (CDCl3): δ 162.8 (CO2), 149.1 (CCO2), 142.9-119.5 (Ph, N3CPh), 82.0 (Cp), 51.0
(OCH3), 28.9 (t, PCH2CH2P, JC-P = 22.6 Hz). MS (m/z, Ru102): 767.1 (M+), 565.1
(M+−triazolato ring). Anal. Calcd. for C41H37N3O2P2Ru: C, 64.22; H, 4.86; N, 5.48
Found: C, 64.32; H, 4.88; N, 5.45.
2.5. Synthesis of Cp(dppe)RuN3C2(CO2Et)(CH3) (5)
To a Schlenk flask charged with 1 (127.2 mg, 0.177 mmol), ethyl 2-butynoate (198.6
mg, 211 µL, 98% purity, 1.77 mmol) and toluene (10 mL) were added. The mixture was
heated under a 120°C silicone oil bath for 48 h and the volume of solvent was then
reduced to 1 mL under a rotary evaporator. To the residue, 10 mL of n-pentane was
added to give a yellow precipitate. After isolationg the precipitate on a filter, it was
4

ACCEPTED MANUSCRIPT
washed with 2×3 mL of n-pentane and dried under a vacuum to give the 5 (106.8 mg,
0.149 mmol, 84 % yield). Spectroscopic data for 5 are as follows: IR (KBr, cm−1):
ν(C=O) 1700 (vs), 1529 (m), ν(N=N) 1433 (s), 1384 (s), ν(C−O) 1314 (m), 1273 (m),
1128 (m), 1071 (vs), ν(COO-) 700 (vs), 527 (s). 1H NMR (CDCl3): δ 7.46-7.11 (m, 20H,
Ph), 4.58 (Cp), 4.06 (q, 2H, JH−H = 7.2 Hz, OCH2), 3.24, 2.52 (2m, PCH2CH2P), 1.20 (t,
3H, JH−H = 7.2 Hz, CH3). 31P NMR (CDCl3): δ 87.6. 13C NMR (CDCl3): δ 162.7 (CO2),
146.2 (CCO2), 143.1-127.4 (Ph, N3CCH3), 81.7 (Cp), 58.8 (OCH3), 28.7 (t, PCH2CH2P,
JC-P = 22.6 Hz). MS (m/z, Ru102): 719.1 (M+), 565.1 (M+−triazolato ring). Anal. Calcd.
for C37H37N3O2P2Ru: C, 61.83; H, 5.19; N, 5.85 Found: C, 61.95; H, 5.20; N, 5.82.
2.6. Synthesis of N3(CH3)C2(CO2Et)2 (6a) and other organic triazoles
To a Schlenk flask charged with 2 (100.1 mg, 0.129 mmol) and CH3I (82 µL, 182.9
mg, 1.288 mmol) was added CHCl3 (20 mL). The resulting solution was warmed under
a 50 °C silicone oil bath for 24 h and the solvent and the excess CH3I were then removed
by vacuum evaporation. To the residue was added 10 mL of cold n-pentane. After
filtration, the orange precipitate was washed with 2×10 mL of n-pentane and dried under
a vacuum to give [Ru]-I (81.9 mg, 0.118 mmol, 92 % yield). The filtrate was dried and
extracted with 2×5 mL of cold n-pentane. The extract was filtered and the filtrate was
dried under a vacuum to give a colorless liquid, which is the organic triazole
N3(CH3)C2(CO2Et)2 (6a, 17.6 mg, 0.077 mmol, 60 %). Spectroscopic data for 6a are as
1
follows: H NMR (C6D6): δ 4.24, 4.10 (2q, 4H, JH−H = 7.2 Hz, OCH2), 3.44 (s, 3H,
NCH3), 1.12, 1.07 (2t, 6H, JH−H = 7.2 Hz, CH3). 13C NMR (C6D6): δ 160.9, 158.5 (CO2),
141.6, 129.7 (CCO2), 62.2, 61.5 (OCH2), 22.7 (NCH3), 14.2, 13.8 (CH3). MS (m/z):
228.1 (M++1). HRMS (m/z) calcd for C9H13N3O4 [M+H]+ 228.0981, found 228.0983.
Complexes
N3(CH2Ph)C2(CO2Et)2
(6b),
N3(CH2C6F5)C2(CO2Et)2
(6c),
N3[CH2(4-CN-C6H4)]C2(CO2Et)2 (6d) and N3[CH2(4-CH2Br-C6H4)]C2(CO2Et)2 (6e)
were prepared with similar procedure as that of 6a to give a mixture of the organic
triazole and organic bromides. Spectroscopic data for 6b (colorless liquid) are as follows:
1H NMR (CDCl3): δ 7.31, 7.30, 7.27 (Ph), 5.08 (s, 2H, NCH2), 4.44 (q, 2H, JH−H = 6.9
Hz, OCH2), 4.34 (q, 2H, JH−H = 7.2 Hz, OCH2), 1.41 (t, 3H, JH−H = 7.2 Hz, CH3), 1.28 (t,
3H, JH−H = 6.9 Hz, CH3). 13C NMR (CDCl3): δ 160.0, 158.4 (CO2), 140.4, 133.9 (CCO2),
129.8, 129.3, 128.8, 127.9 (Ph), 62.7, 61.8 (OCH2), 53.7 (NCH2), 14.1, 13.7 (CH3). MS
+
1
(m/z): 306.1 (M +1). Spectroscopic data for 6c (colorless liquid) are as follows: H
NMR (CDCl3): δ 7.86, 7.40, 7.25, 7.13 (m, Ph), 5.88 (s, 2H, NCH2), 4.46 (q, 2H, JH−H
=
7.2 Hz, OCH2), 4.42 (q, 2H, JH−H = 7.2 Hz, OCH2), 1.41 (t, 3H, JH−H = 7.2 Hz, CH3),
1.40 (t, 3H, JH−H = 7.2 Hz, CH3). 13C NMR (CDCl3): δ 160.5, 158.3 (CO2), 147.2, 143.0,
140.4, 139.9, 133.9, 129.9, 107.6 (CCO2 and Ph), 63.2, 62.0 (OCH2), 41.1 (NCH2), 14.1,
5

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13.8 (CH3). MS (m/z): 394.1 (M++1). Spectroscopic data for 6d (white solid) are as
follows: 1H NMR (CDCl3): δ 7.87-7.08 (m, Ph), 5.84 (s, 2H, NCH2), 4.41 (q, 2H, JH−H
=
7.2 Hz, OCH2), 4.32 (q, 2H, JH−H = 7.2 Hz, OCH2), 1.38 (t, 3H, JH−H = 7.2 Hz, CH3),
1.28 (t, 3H, JH−H = 7.2 Hz, CH3). 13C NMR (CDCl3): δ 160.1, 158.2 (CO2), 142.8, 141.1,
139.1 (CN and CCO2), 134.0, 131.4, 128.9, 128.0 (Ph), 63.0, 62.1 (OCH2), 53.1 (NCH2),
14.2, 13.8 (CH3). MS (m/z): 329.1 (M++1). Spectroscopic data for 6e (milk-white solid)
are as follows: 1H NMR (CDCl3): δ 7.86-7.07 (m, Ph), 5.76 (s, 2H, NCH2), 4.42 (s, 2H,
CH2Br), 4.40 (q, 2H, JH−H = 7.1 Hz, OCH2), 4.30 (q, 2H, JH−H = 7.1 Hz, OCH2), 1.37 (t,
3H, JH−H = 7.1 Hz, CH3), 1.27 (t, 3H, JH−H = 7.1 Hz, CH3). 13C NMR (CDCl3): δ 160.0,
158.4 (CO2), 140.5, 138.4, 134.1, 133.9131.3, 128.9, 128.4, 127.9 (CCO2 and Ph), 62.8,
61.8 (OCH2), 53.3 (NCH2), 31.8 (CH2Br), 14.1, 13.7 (CH3). MS (m/z): 396.1 (M++1).
3
1
Spectroscopic data for N3(CH2C6F5)C(CO2Me)C(Ph) (N -7a) are as follows: H NMR
(CDCl3): δ 7.69-7.41 (m, 2H, Ph), 7.43-7.41 (m, 3H, Ph), 6.00 (s, 2H, NCH2), 3.87 (s,
3H, OCH3). 13C NMR (CDCl3): δ 159.6 (CO2), 150.4 (CCO2), 147.3, 143.8, 140.2,
133.9, 133.0, (5m, C6F5), 129.7, 129.35, 129.2, 128.1 (C6H5), 108.3 (t, C6F5), 52.6
(OCH3), 42.0 (NCH2). MS (m/z): 384.1 (M++1). HRMS: calc. for C17H10F5N3O2: m/z
383.0691, found 383.0693.
2.7. X-ray analysis
Single crystals suitable for X-ray diffraction study were grown as mentioned above.
The chosen single crystal was glued to a glass fiber and mounted on a Bruker SMART
APEX diffractometer equipped with graphite monochromatic Mo-Kα radiation (λ =
0.71073Å). Data collection was executed using the SMART program; cell refinement
and data reduction were performed with the SAINT program [35]. The structure was
determined by the SHELXTL/PC [36] program and refined by the full-matrix
least-squares methods on F2. Hydrogen atoms were placed geometrically using the
riding model with thermal parameters set to 1.2 times that for the atoms to which the
hydrogen is attached and 1.5 times that for the methyl hydrogens. Crystal data of
complex 2, 3, 4, 5 and N3-7a are listed in Table 1.
CCDC 1891931, 1891932, 1891933, 1891934 and 1907581 contains the
supplementary crystallographic data for this paper.
Table 1
Crystal and intensity collection data for complexes 2, 3, 4, 5 and N3-7a
N3
-7a
2
3
4
5
Empirical formula
C39H39N3O4P2Ru
C37H34F3N3O2P2Ru C41H37N3O2P2Ru
C37H37N3O2P2Ru
C17H10F5N3O2
6

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Formula wight
T (K)
776.74
772.68
766.74
718.70
383.28
150(2)
150(2)
150(2)
150(2)
150(2)
Wavelength, Å
Cryst syst
0.71073
0.71073
0.71073
0.71073
1.54178
Monoclinic
P21/c
Orthorhombic
Pnma
Monoclinic
P21/c
Monoclinic
P21/n
Monoclinic
P21/n
Space group
a, Å
9.4876(2)
21.7420(6)
16.7037(4)
97.6614(7)
3414.87(14)
4
22.1330(7)
16.0430(5)
9.4444(3)
90
11.6658(2)
19.1128(4)
16.8525(4)
109.9796(5)
3531.39(13)
4
9.4817(5)
21.7681(10)
16.0285(8)
91.8215(12)
3306.6(3)
4
14.5885(4)
7.4116(2)
28.8007(7)
93.4111(8)
3108.53(14)
8
b, Å
c, Å
β, deg
V, Å3
3353.51(18)
4
Z
Density (calcd), Mg/m3
Absorption coeff., mm-1
F(000)
1.511
1.530
1.442
1.444
1.638
0.600
0.618
0.575
0.609
1.326
1600
1576
1576
1480
1552
2.360 to 27.489
23784
2.236 to 27.481
22759
2.489 to 29.998
33805
2.262 to 27.443
7494
3.319 to 74.996
20912
θ range, deg
Reflections collected
Independent reflections
GOFa on F2
R (I > 2σ(I))
7831
3982
10289
7494
6397
1.050
1.294
1.057
1.064
1.052
bR1 = 0.0250,
wR2 = 0.0588
R1 = 0.0302,
wR2 = 0.0626
0.367, -0.400
R1 = 0.0887,
wR2 = 0.2036
R1 = 0.0920,
wR2 = 0.2058
1.840, -0.943
R1 = 0.0305,
wR2 = 0.0640
R1 = 0.0378,
wR2 = 0.0673
0.463, -0.646
R1 = 0.0482,
wR2 = 0.1160
R1 = 0.0628
wR2 = 0.1283
1.480, -0.756
R1 = 0.0361,
wR2 = 0.0918
R1 = 0.0417,
wR2 = 0.0988
R (all data)
Peak, hole, e Å-3
0.315, -0.278
b
aGOF = [Σ[w(F2 -F2 )2]/(n-p)]1/2; n = number of reflections, p = number of parameters refined. R1 =
o
c
2
4 1/2
(Σ||Fo|−|Fc||)/Σ|Fo|, wR2 = [Σ[w(Fo -Fc2)2]/Σ[wFo ] .
3. Results and discussion
3.1. Preparation of triazolato complexes 2-5
Treatment of 1 with a 5-fold excess of diethyl acetylene dicarboxylate in CHCl3 at
room temperature under an atmosphere of air for 36 hours afforded a [3+2] dipolar
cycloaddition product, the N(2)-bound 4,5-bis(ethoxycarbonyl)-1,2,3-triazolato complex
[Ru]N3C2(CO2Et)2 (2), in 93 % isolated yield (Scheme 1). A molecular ion peak at m/z
777.1 (M+) in the FAB mass spectrum of 2 was observed. The structure of 2 was clearly
1
established as the N(2)-bound isomer based on its H NMR spectrum, which showed a
quartet signal centered at δ 4.19 (q, 2H, JH-H = 7.2 Hz) and a triplet signal centered at δ
7

ACCEPTED MANUSCRIPT
1.19 (t, 3H, JH-H = 7.2 Hz), attributed to the two anisochronous ethoxycarbonyl protons
1
of 2. The H spectrum of an N(1)-bound isomer would show two sets of AX pattern
resonances for its two asynchronous ethoxycarbonyl groups. It should be noted that the
triazole and tetrazole anion could be coordinated to the metal through either its N(1) or
N(2) nitrogen atom [37], which are essentially isoenergetic, as evidenced by molecular
orbital calculations [38]. The evidence obtained to date indicates that either the two
N(1)- and N(2)-bonded isomers are formed simultaneously or that the N(2)-bound
isomer is the exclusive product [37, 38]. In our case, the time-elapsed 31P NMR study of
the formation of 2 did not provide any evidence for the formation of the N(1)-bound
isomer during the reaction.
Scheme 1.
Treatment of 1 with a 5-fold excess of ethyl 4,4,4-trifluoro-2-butynoate in CHCl3
at
room
temperature
for
24
hours
afforded
the
N(2)-bound
4-ethoxycarbonyl-5-trifluoromethyl-1,2,3-triazolato complex [Ru]N3C2(CO2Et)(CF3)
31
(3), in 92 % isolated yield (Scheme 1). When the reaction was monitored by P NMR
1
spectroscopy, only one new singlet resonance at δ 87.0 was observed. In the H NMR
spectrum, a quartet signal centered at δ 4.15 and a triplet signal centered at δ 1.22
attributed to the ethoxycarbonyl protons of 3 appeared. The FAB mass spectrum of 3
displayed a molecular ion peak at m/z 773.2 (M+). Analogous [3+2] cycloadditions of
methyl phenylpropiolate and ethyl 2-butynoate with 1 cleanly produced the triazolates
[Ru]N3C2(CO2Me)(Ph) (4) [Ru]N3C2(CO2Et)(CH3) (5) and in 94 % and 84 % isolated
yields, respectively. Both of the reactions did not proceed at room temperature. The
preparation of [Ru]N3C2(CO2Me)(Ph) (4) was accomplished by treating 1 with a 5-fold
excess of methyl phenylpropiolate in refluxing benzene (b.p. 80.1 °C) for 48 hours. The
preparation of 5 was accomplished in a more vigorous condition. When 1 was treated
with a 10-fold excess of ethyl 2-butynoate in refluxing toluene (b.p. 110.6 °C) for 12
hours, the resonance of 1 at δ 81.5 in the 31P NMR spectrum became smaller and a new
peak at δ 87.6, attributed to 5 appeared. The reaction was completed in 48 hours.
All four triazolate complexes 2, 3, 4 and 5 obtained by [3+2] cycloaddition with the
internal alkynes exhibit an N(2)-coordination of the five-membered ring and
8

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time-elapsed 31P NMR studies of the formation of 2-5 did not provide any evidence for
the formation of the N(1)-bound isomer during the reaction. In most cases, the activated
alkynes used as dipolarophiles are limited to highly electron-poor alkynes. The
formation of an N-coordinate metal triazolato complex by the [3+2] cycloaddition of a
metal-coordinated azide with a less electron-poor internal alkyne, such as
PhC≡CCO2Me and CH3C≡CCO2Et, is rare [32a]. To the best of our knowledge,
compound 5 prepared using 2-butynoate is the first example of the preparation of an
N-coordinated metal triazolato complex.
In this study, the different reaction times and reaction temperatures indicate that the
reactivity of dipolar [3+2] cycloaddition reactions is highly related to the nature of the
alkyne being used and is highly temperature dependent. Diethyl acetylene dicarboxylate
and ethyl 4,4,4-trifluoro-2-butynoate, internal alkynes with two strong
electron-withdrawing groups, participated smoothly in a [3+2] cycloaddition with
[Ru]-N3 (1) at room temperature and the reaction was complete in 48 and 24 hours,
respectively. Methyl phenylpropiolate and ethyl 2-butynoate, less electron-poor alkynes,
failed to react with 1 at room temperature and more drastic, vigorous conditions were
needed to complete the reaction. These results indicate that the ynoate ester with a CF3
substituent showed best reactivity, and the trend was CF3 > CO2Et > > C6H5 > CH3,
which is directly proportional to their electron-withdrawing ability.
The molecular structures of the triazolato complexes 2-5 have been established by
single crystal X-ray diffraction analysis. Diffraction-quality crystals were obtained by
allowing n-hexane to diffuse into CHCl3 solutions of 2-5. ORTEP drawings are shown
in Figure 1-4, respectively. Crystallographic and refinement data for 2-5 are
summarized in Table 1. Selected bond distances and angles are given in Table 2.
Table 2
Selected Bond Distances (Å) and Angles (deg) for 2, 3, 4 and 5
2
3
4
5
2.2878(4)
2.2940(4)
2.0869(13)
1.3316(19)
1.3397(19)
1.351(2)
1.396(2)
1.341(2)
2.2847(18)
2.2847(18)
2.167(7)
1.299(12)
1.263(12)
1.366(12)
1.394(15)
1.334(12)
2.2808(4)
2.2712(4)
2.0748(13)
1.3446(19)
1.3276(19)
1.362(2)
1.401(2)
1.343(2)
2.2790(11)
2.2823(12)
2.071(3)
1.347(4)
1.322(4)
1.349(5)
1.395(6)
1.344(5)
Ru−P1
Ru−P2
Ru−N2
N1−N2
N2−N3
N3−C2
C1−C2
N1−C1
83.386(15)
84.29(9)
85.201(16)
84.14(4)
P1−Ru−P2
9

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89.50(4)
88.1(2)
87.90(4)
90.54(9)
86.27(9)
124.1(2)
122.9(2)
105.4(3)
112.9(3)
105.8(3)
107.3(3)
108.6(3)
N2−Ru−P1
N2−Ru−P2
N1−N2−Ru
N3−N2−Ru
N2−N3−C2
N1−N2−N3
N2−N1−C1
N1−C1−C2
N3−C2−C1
85.69(4)
88.1(2)
87.57(4)
122.18(10)
124.91(11)
105.10(13)
112.83(13)
106.18(13)
107.66(14)
108.22(14)
119.6(6)
121.7(8)
103.3(8)
119.1(8)
102.4(8)
108.7(9)
106.4(9)
128.31(10)
124.92(10)
104.86(13)
113.13(23)
106.17(13)
107.19(14)
108.55(14)
The triazolate ligands in 2-5 are all bonded to the Ru via their N(2) atom. For 2, the
coordination with ruthenium is a distorted piano-stool geometry, with three facial sites
being occupied by the C5H5 ligand (Ru-C = 2.2878(4)-2.2034(18) Ǻ ; average 2.2088 Ǻ);
the other three positions are occupied by two phosphine ligands (Ru-P1 = 2.2878(4) Ǻ;
Ru-P2 = 2.2940(4) Ǻ) and the triazolate group (Ru-N2 =2.0869(13) Ǻ), which are
comparable to those in other ruthenium triazolato complexes [33, 34]. The inter-atomic
distances within the five-membered triazole ring (N1-N2 (1.3316(19)Å), N2-N3
(1.3397(19)Ǻ), N1-C1 (1.341(2)Ǻ), N3-C2 (1.351(2)Ǻ) and C1-C2 (1.396(2)Ǻ)), are
typical, consistent with the delocalization of the electrons within the heterocycle. The
bond angles of N1-N2-N3 (112.83(13)O), N2-N3-C2 (105.10(13)O), N3-C2-C1
(108.22(14)O), N1-C1-C2 (107.66(14)O) and N2-N1-C1 (106.18(13)O) are all in the range
of C(sp2) and N(sp2) hybridization of a five-membered heterocycle ring. The
five-membered triazole ring exhibits an irregular pentagonal structure and is essentially
planar.
10

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Fig. 1. ORTEP drawing of 2; thermal ellipsoids are drawn at the 50% probability level.
The molecular structures of complexes 3-5 are identical to 2, which can be
described as distorted piano-stool geometry, with the central atom being surrounded by
C5H5, triazolate and two phosphine ligands. The bond lengths and angles of 4 and 5 are
essentially identical to 2 and those of the triazole rings of 2, 4 and 5 are with derivatives
below 0.02 Å and 0.3°, respectively, indicating that the electronic and steric influences
of substituents in the 4- and 5- position on the triazolate rings of 2, 4 and 5 on the
parameters are negligible. The steric effects between the CO2Et, C6H5 and CH3 groups
are only slightly different and have no obvious effects on the structures of 2, 4 and 5.
The electron withdrawing and donating ability of the three substrates on the tetrazolates
seems have no obvious effects on the structures neither. It is worth noting that the bond
lengths and angles of 3 are slightly different from the others. For 3, the Ru-N2 bond
distance (2.167(7) Å) is slightly longer than those in compound 2, 4 and 5, which can be
attributed to the larger steric effects between the CF3 group of the triazole ring ligand
and the bulky dppe ligand. The N1-N2, N2-N3 and N1-C1 distances of 1.299(12),
1.263(12) and 1.334(12), respectively, are slightly shorter than those of 2, 4 and 5,
indicating a marginally smaller structure of the triazolate ring of 3. The inter-atomic
bond angles N1-N2-N3 (119.1(8)O), N2-N3-C2 (103.3(8)O), N3-C2-C1 (106.4(9)O),
N1-C1-C2 (108.7(9)O) and N2-N1-C1 (102.4(8)O) of the triazolate ring of 3 are slightly
deviated from those of of 2, 4 and 5, indicating that the shape of the five-membered
triazole ring of 3 is slightly distorted in comparison with those of 2, 4 and 5, which
could be due to the more steric-expulsive CF3 substituent on the triazolate ligand of 3.
Apparently, the steric effects appear to be the major determinant for the N(2)-bonding
mode and structures of 2-5 but that electronic effects appear to account for their
conformation.
11

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Fig. 2. ORTEP drawing of 3; thermal ellipsoids are drawn at the 50% probability level.
Fig. 3. ORTEP drawing of 4; thermal ellipsoids are drawn at the 50% probability level.
Fig. 4. ORTEP drawing of 5; thermal ellipsoids are drawn at the 50% probability level.
3.2. Reactions of 2-5 with electrophiles
The treatment of 2 with a 10-fold excess of CH3I in CHCl3 at room temperature for
one week or at 60°C in a silicone oil bath for 24 h resulted in the cleavage of the Ru-N
bond and the formation of [Ru]-I and
a
colorless liquid, which is
1-methyl-4,5-bis(ethoxycarbonyl)-1,2,3-triazole N3(CH3)C2(CO2Et)2 (6a), in 60 %
isolated yield (Scheme 2). The reaction was monitored by NMR spectroscopy. When 2
was treated with CH3I in CDCl3 at 60°C for 24 h, the 31P NMR spectral resonance for 2
12

ACCEPTED MANUSCRIPT
at δ 87.9 disappeared and a peak at δ 79.0, attributed to [Ru]-I, appeared. In the 1H NMR
spectrum a singlet resonance appeared at δ 4.50, attributed to the Cp of [Ru]-I, and two
quartet signals centered at δ 4.24, 4.10 (q, 2H, JH-H = 7.2 Hz) and two triplet signals
centered at δ 1.12, 1.07 (t, 3H, JH-H = 7.2 Hz) appeared, which are attributed to the
formation of the free organic triazole 6a. The FAB mass spectrum of the crude mixture
displayed molecular ion peaks at m/z 720.2 and 228.1, attributed to [Ru]−I and 6a,
respectively. A similar reaction of 2 with other organic bromides resulted in Ru-N bond
cleavage to give a series of 1,4,5-trisubstituted-1,2,3-triazole complexes. The cleavage
of the Ru-N bond of 2 was a very slow process at room temperature, requiring more than
7 days to reach completion. We accelerated the reaction by conducting the reaction at
60°C in
a
silicone oil bath for 24-48 hours, which afforded the
1-alkylated-4,5-bis(ethoxycarbonyl)-1,2,3-triazole N3(R)C2(CO2Et)2 (6b, R = CH2C6F5;
6c, R = CH2Ph; 6d, R = CH2(4-CN-C6H4); 6e, R = CH2(4-CH2Br-C6H4) and [Ru]-Br
(Scheme 2). The structure of these free triazoles were clearly established as
1
N(1)-alkylated based on their H NMR spectra, which exhibited two sets of AB pattern
proton resonances for their anisochronous ethoxycarbonyl groups. [Ru]−Br is easily
isolated as an orange-yellow precipitate in a cold n-pentane solution with a high
recycling ratio but the organic triazoles 6b-6e, which were mixed with the excess
organic bromide in n-pentane, were difficult to isolate in pure form. Nelson and
co-workers [39] examined the alkylation of the cobalt triazolato complexes, but the
isolation of the free triazole was also not successful.
Scheme 2.
Complexes 2 and the triazoles 6a-6e are stable in air and in solution, which
permitted these reactions to be carried out under an atmosphere of air. The [Ru]-Br,
which, on reacting with sodium azide, would afford [Ru]-N3 (1) thus forming a reaction
cycle (Scheme 3). Most of the procedures in this cycle could be carried out under an
atmosphere of air, thus providing an economical and convenient approach for the
synthesis of functionalized 1,4,5-trisubstituted 1,2,3-triazoles and derivatives thereof. In
13

ACCEPTED MANUSCRIPT
addition, the 1,2,3-triazole and derivatives prepared in CuAAC and RuAAC reactions
are largely limited to 1,4-disubstituted and 1,5-disubstituted 1,2,3-triazoles. The reaction
reported here, therefore, represents a complementary method for the synthesis of fully
decorated 1,4,5-trisubstituted 1,2,3-triazoles.
Scheme 3.
We recently reported [34] that the triazolato complex [Ru]N3C2HCO2Et reacts with
a series of alkyl halides to regiospecifically alkylate the triazole ring. Since all of the
triazolate complexes 3-5 contain an N(2)-bound triazolate, this prompted us to
determine if they would react similarly to produce regiospecifically alkylated triazoles.
Accordingly, complexes 3-5 were reacted with alkyl halides in CDCl3 in a 5-mm NMR
1
31
tube, and the progress of the reaction was followed by H and P NMR spectroscopy.
No alkylation was observed when 3 was treated with an excess of an electrophile such
as BrCH2C6F5, BrCH2Ph and CH3I, even under drastic, vigorous conditions.
Treatment of 4 with a 10-fold excess of BrCH2C6F5 in C6D6 on an 60°C silicon oil
bath for 48 h afforded a N3-alkylated triazole N3(CH2C6F5)C2(CO2Me)(Ph) (N3-7a) and
1
a trace amount of N1-alkylated regioisomer. The reaction was monitored by H NMR
spectroscopy. When 4 was treated with a 10-fold excess of BrCH2C6F5 in C6D6 on an
1
60°C silicon oil bath, in the H NMR two set of singlet resonances of NCH2 and CCH3
appeared at δ 6.00, 3.87 and δ 5.15 and 3.82, attributed to of the N3-alkylated triazole,
the major produt, and the N1-alkylated triazole, the minor product, respectively, in a
ratio of ca. 8:1. The FAB mass spectrum of the crude mixture displayed parent peaks at
m/z 646.1 and 384.1, attributed to [Ru]-Br and the 1,4,5-trisubstituted triazole
N3(CH2C6F5)C2(CO2Me)(Ph) (7a), respectively. Colorless crystals of N3-7a were
formed by slow evaporation of the solvent of the crude mixture. The structure of N3-7a
was determined by a single crystal X-ray diffraction analysis. Although the unit cell of
N3-7a contains two crystallographically different molecules, only one molecule is
14

ACCEPTED MANUSCRIPT
displayed due to the difference being insignificant. An ORTEP drawing is shown in Fig.
5 and the selected bond distances and angles are listed in Table 3. In N3-7a, the
4-phenyl-5-methoxycarbonyl-triazole moiety is N(1)-alkylated by the pentafluorobenzyl
group. The N1–N2, N2–N3, N1–C1, N3–C2 and C1–C2 bond lengths of 1.3348(16),
1.3133(16), 1.3625(17), 1.3621(17) and 1.3852(17) Å, respectively, all displaying
partial double-bond character, are indicative of several resonance contributions and the
five-membered triazole ring is essentially planar and aromatic. The N1–N2–N3,
N2–N3–C2, N2–N1–C1, N1–C1–C2 and N3–C2–C1 bond angles of 107.72(11)°,
109.40(11)°, 110.76(11)°, 104.47(11)° and 107.65(12)°, respectively, are indicative of
the irregular pentagonal structure of the triazole ring.
Fig. 5. ORTEP drawing of N3-7a; thermal ellipsoids are drawn at the 50% probability
level.
Table 3
Selected bond distances (Å) and angles (o) for N3-7a
1.3348(16)
1.3625(17)
1.3852(18)
1.2059(16)
1.4785(17)
1.3133(16)
1.3621(17)
1.4798(18)
1.2032(17)
1.3253(18)
N1−N2
N1−C1
C1−C2
C1−C9
N1−C11
N2−N3
N3−C2
C2−C3
O1−C9
O2−C9
107.72(11)
110.76(11)
104.47(11)
130.30(11)
118.93(11)
134.91(13)
109.40(11)
107.65(12)
117.91(11)
134.42(12)
120.57(12)
123.35(13)
N1−N2−N3
N2−N1−C1
N1−C1−C2
C1−N1−C11
N2−N1−C11
C2−C1−C9
N2−N3−C2
N3−C2−C1
N3−C2−C3
C1−C2−C3
N1−C1−C9
C1−C9−O1
15

ACCEPTED MANUSCRIPT
125.37(13)
111.28(11)
O1−C9−O2
O2−C9−O1
Similar reaction of 4 with BrCH2Ph and CH3I both afforded N3- and N1-alkylated
triazole N3(CH2R)C2(Ph)(CO2Me) in a ratio of ca. 6:1 and 4:1 (calculated from the
1
integration of the NCH2 signals of the two regioisomers in the H NMR spectra and
assigned by comparing with the NCH2 signals of 6a-6e and 7a), respectively. The two
regioisomers could be produced by electrophilic attack of CH2R+ at both the N1 and N3
nitrogen and the subsequent liberation of the alkylated trazolates gave two triazole
regioisomers (Scheme 4). The results indicate that the alkylation of 4 is not
regiospecific, but highly regioselective.
Scheme 4.
When 5 was treated with a 10-fold excess of CH3I in CDCl3 at room temperature
for 3 days, two sets of characteristic singlet resonances at δ 4.24, 2.50 and 3.96, 2.54,
attributed to NCH3, CCH3 of two regioisomers of the organic 1,4,5-trisubstituted
1
triazole, respectively, appeared at the same time in the H NMR spectrum. The ratio of
the two regioisomers was determined to be ca. 1:2. Similar alkylation reactions of 5
with BrCH2Ph and BrCH2C6F5 at room temperature resulted in Ru-N bond cleavage and
both afforded two regioisomers in ratios of ca. 1:2 and 2:3, respectively. The results of
the NMR experiments indicate that the alkylation of the triazolato complex 5 is not
regiospecific and regioselectivity is low.
The different alkylation reaction temperatures between complexes 2-5 indicate that
the reactivity of these systems is highly related to these substituents on the triazole rings
of complexes being used. The steric hindrance of a bulkier CF3 group substituted on the
triazole ring of 3 appears to disfavor the electrophilic attack of organic halides, since no
reaction was observed, even at temperatures of 100°C or above. The alkylation of 4,
which is substituted with a moderately steric bulky phenyl group, was activated at
higher temperature with more regioselectivity but no regiospecificity. The least steric
hindered CH3 group substituted on the triazole ring of 5 favors an electrophilic attack
even at room temperature but lacks regioselectivity. These results indicated that the
16

ACCEPTED MANUSCRIPT
steric effects of these substituents on the triazole rings of complexes 2-5 are the
predominant factor and electronic effects are the minor factor for the reactivity and
regioselectivity of the alkylation reaction.
3.3. Conclusion
We successfully synthesized a series of triazolato complexes by [3+2] cycloaddition
reactions of ynoate esters with a ruthenium azido complex. The reaction products,
metal-bound heterocyclic complexes such as the triazolato complexes
[Ru]N3C2(CO2Et)2 (2), [Ru]N3C2(CO2Et)(CF3) (3), [Ru]N3C2(CO2Me)(Ph) (4) and
[Ru]N3C2(CO2Et)(CH3) (5) were produced from diethyl acetylene dicarboxylate, ethyl
4,4,4-trifluoro-2-butynoate, methyl phenylpropiolate and ethyl 2-butynoate, respectively.
The resulting triazolato complexes, which were characterized by X-ray structure
analysis, confirms the N(2)-bonding type of the addition products. In the study, we
demonstrated that the steric effects appear to be the major determinant for the
N(2)-bonding mode and structures of 2-5 but that electronic effects appear to account for
their conformation. The Ru-N bond-cleavage of 2 occurred in the presence of an excess
amount
of
organic
halides,
affording
a
series
of
1-alkylated-4,5-bis(ethoxycarbonyl)-1,2,3-triazoles and [Ru]-X (X = I or Br), which, on
reaction with sodium azide, gave the [Ru]-N3 (1) thus forming a reaction cycle.
Monitoring the alkylation reactions of organic halides with 4 and 5 by NMR indicated
that, both gave two regioisomers of 1,4,5-trisubstituted 1,2,3-triazoles in different ratios,
indicating that the alkylation reactions of both 4 and 5 are not regiospecific. Steric
effects account for the electrophilic attack of ruthenium triazolato complexes and appear
to be a determining factor for the conformation of the thus formed 1,4,5-trisubstituted
1,2,3-triazoles. We are currently in the process of further exploring the synthesis and the
reactivity of new ruthenium triazolato complexes and new triazole derivatives. Studies
of related reactions and applications of these complexes are currently underway.
Acknowledgements
The authors wish to thank Prof. Shie-Ming Peng, the head of Instrumentation Center
located in National Taiwan University, for technical assistance from the Instrumentation
Center and we wish to thank the Ministry of Science and Technology of Taiwan for
financial support.
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Highlights
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ò
[3+2] Cycloaddition of a ruthenium azido complex with four ynoate esters.
Synthesis, characterization and reactivity study of novel ruthenium
triazolates.
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The first example of the preparation of an N-coordinated metal triazolato
complex using 2-butynoate.
ò
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A reaction cycle to form 1,4,5-trisubstituted 1,2,3-triazoles.
The X-ray structures of four ruthenium triazolates and one organic triazole
were determined.