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Article

Regioselective Reduction of 1H-1,2,3-Triazole Diesters

by
Christopher R. Butler
,
Justin Bendesky
and
Allen Milton Schoffstall
*
Department of Chemistry and Biochemistry, University of Colorado Springs, Colorado Springs, CO 80918, USA
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(18), 5589; https://doi.org/10.3390/molecules26185589
Submission received: 30 July 2021 / Revised: 30 August 2021 / Accepted: 9 September 2021 / Published: 15 September 2021
(This article belongs to the Special Issue Heterocycles in Organic Synthesis: A Theme Issue in Honor of Prof. Dr. Albert Padwa)
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Versions Notes

Abstract

:
Regioselective reactions can play pivotal roles in synthetic organic chemistry. The reduction of several 1-substituted 1,2,3-triazole 4,5-diesters by sodium borohydride has been found to be regioselective, with the C(5) ester groups being more reactive towards reduction than the C(4) ester groups. The amount of sodium borohydride and reaction time required for reduction varied greatly depending on the N(1)-substituent. The presence of a β-hydroxyl group on the N(1)-substituent was seen to have a rate enhancing effect on the reduction of the C(5) ester group. The regioselective reduction was attributed to the lower electron densities of the C(5) and the C(5) ester carbonyl carbon of the 1,2,3-triazole, which were further lowered in cases involving intramolecular hydrogen bonding.

Graphical Abstract

1. Introduction

Sodium borohydride (NaBH4) is a mild reducing agent used widely for converting aldehydes and ketones to alcohols [1]. It has been reported that some esters can also be reduced by NaBH4 in alcohols, although higher proportions of the reagent and longer reaction times are required than for reduction of aldehydes and ketones [2,3]. Based on these reports, we developed an interest in the opportunity to prepare and selectively reduce heterocyclic diesters, which became our goal. Triazole and other five-membered ring heterocycles having vicinal diesters became available following the pioneering reports by Huisgen of 1,3-dipolar cycloaddition of a 1,3-dipolar species with an activated disubstituted alkyne [4,5]. The 1,4-disubstituted triazoles made from terminal alkynes are available by the regioselective method known as CuAAC (copper(I) azide-alkyne cycloaddition) [6,7], whereas regioselective synthesis of 1,5-disubstituted triazoles employs other catalysts [8,9,10].
Reduction of both ester groups of oxazole 2,4-diesters has been reported using NaBH4 in ethanol at room temperature [11]. Dimethyl pyrrole-2,4-dicarboxylate was selectively reduced to form ethyl 4-(hydroxymethyl)-1H-pyrrole-2-carboxylate (A of Scheme 1) using diisobutylaluminum hydride (DIBAH). The selectivity of the reduction was not as effective for dimethyl pyrrole-3,4-dicarboxylates and did not occur for dimethyl furan-2,4-dicarboxylate, suggesting a role of the pyrrole nitrogen in complexing with the reagent and a neighboring carbonyl oxygen [12]. Dimethyl pyridine-2,5-dicarboxylate has been selectively reduced at C(2) using NaBH4/CaCl2 in ethanol/THF to form methyl 6-(hydroxymethyl)-3-pyridinecarboxylate (B of Scheme 1) [13]. The distinction between the relative reactivity of unsymmetrical diesters is based upon differences in electronic factors [14], steric factors [15], or a combination of these factors [16]. Two research groups have shown there to be a difference in reactivity of bulky tert-butyl esters and methyl esters [17,18]. One of these employed sodium triacetoxyborohydride [NaBH(OAc)3] [18]. Selective reduction of diesters to form hydroxy esters using lithium borohydride (LiBH4), relying upon differences in steric effects, has been reported [19]. Another example using DIBAH was for selective reduction of diesters by formation of an aldehyde monoester [12,20]. Esters were reduced using NaBH4-CaCl2 [13,21] or by NaBH4 with added sodium methoxide (NaOMe) via sodium monomethoxyborohydride (NaBH3OCH3), wherein the authors propose that the active reagent of NaBH4 in methanol is indeed (NaBH3OCH3) [22]. The reduction of nicotinate esters with a large excess of NaBH4 at reflux [23] and nicotinate esters having other electron-withdrawing groups by an excess of reductant at room temperature [24] have been observed. Prior work on the NaBH4 reduction of diethyl 2,4-pyrroledicarboxylate took place regioselectively at the C(4) ester group. Diethyl 2,5-pyrroledicarboxylate gave predominate conversion to the diol [12].

2. Results

We elected to pursue work directed towards possible selective reduction of five-membered ring heteroaromatic diesters. As representatives of these, neither of the ester groups of dimethyl imidazole-4,5-dicarboxylate were reduced by NaBH4 in MeOH/THF, but chemoselective reduction [25] was achieved for the N(1) ketone of dimethyl 1-(2-oxo-2-phenylethyl)-1H-1,2,3-triazole-4,5-dicarboxylate (1a) (C of Scheme 1) to form dimethyl 1-(2-hydroxy-2-phenylethyl)-1H-1,2,3-triazole-4,5-dicarboxylate (2a), followed later by regioselective reduction to form methyl 5-(hydroxymethyl)-1-(2-hydroxy-2-phenylethyl)-1H-1,2,3-triazole-4-carboxylate (3a). In our earliest experiment for reaction of 1a, we anticipated the reduction with NaBH4 to reduce the ketone, but not the ester. The ketone was reduced, but some ester reduction was also observed. Adding more NaBH4 and waiting for the reaction to finish gave 3a in good yield, with the ester group at C(4) being unreactive, although initially we did not know which of the ester substituents had been reduced. This turned out to be an excellent example of a regioselective process. We chose to investigate the scope of the selectivity of diester reduction of 1a, along with related compounds. Ester reduction was understandably more likely for 1a than for the more electron-rich imidazole 4,5-diesters. An important issue was how a hydroxy group as part of the N(1) substituent might influence the outcome of the ester reduction or the reduction rate of 1a. We posited that a hydroxy group might be required in order to observe selective reduction of 1a, which turned out not to be the case.
A detailed study of a series of the 1H-1,2,3-triazole diesters revealed that a carbonyl function at N(1) was not necessary for reduction of the C(5) ester, but reduction might be enhanced via six-membered lactone formation between an OH group on an N(1) substituent and the C(5) ester prior to reduction. Five-membered lactones are known to be reduced by NaBH4 [26]. We have not investigated the possibility of lactone formation. However, evidence was not seen for formation of a reactive borate complex [27]. The C(5) ester group was found to be much more reactive with NaBH4 than a C(4) ester in the presence or absence of a carbonyl group (or a hydroxy group) at N(1). The scope of the selective ester reduction of triazole diesters at C(5) and the factors responsible for the selectivity were examined by reduction of a number of triazole esters and diesters.
Several dimethyl 1H-1,2,3-triazole-4,5-dicarboxylates (1a–f) were prepared by thermal cycloaddition [4,5] of organic azides with dimethyl acetylenedicarboxylate (DMAD). Reduction of 1a–f with NaBH4 in methanol afforded 2a and 2b in a chemoselective process after just 3 min (Table 1). The N(1) ester group of dimethyl 1-(2-ethoxy-2-oxoethyl)-1H-1,2,3-triazole-4,5-dicarboxylate (1c) was reduced faster than the C(5) ester, but not fast enough to be synthetically useful.
Additional reaction time allowed all C(5) esters to undergo reduction. The products 3a–f were formed in the times indicated, along with the number of equivalents of NaBH4 needed for the starting diesters to be fully converted to the C(4) esters 3a–f [28,29]. Notably, diesters 1d–f, containing only alkyl or aralkyl functionality at N(1), required longer times for reduction. The structures of the products were elucidated using 1D and 2D-NMR spectroscopy. As it was not clear from 1D spectroscopy alone which ester group had been reduced, 2D-NMR HMBC spectroscopy was necessary to help elucidate the product structures of 3a–f [29]. The structure of the reduction product 3f was further confirmed by X-ray crystallography, as shown in Figure 1.
Triazoles with substituents at the C(5) position were prepared using ruthenium catalysis [10] by dichloro(pentamethylcyclopentadienyl)ruthenium polymer (RuCl2CP*)x producing 1-substituted 1H-1,2,3-triazole-5-esters 4a–d, as shown in Table 2. The reduction of 4a–d with NaBH4 in methanol afforded 5a–d. The reduction of 4d required more NaBH4 and more time than 4a–c, similar to the conditions needed for the reduction of 1f. The absence of an electron-withdrawing ester group at C4 for 4a–d also slowed the reduction rate of the C5 ester group compared to the rates of 1a–f.
Triazoles with substituents at the C(4) position were prepared using copper catalysis [6,7] producing methyl 1-substituted 1H-1,2,3-triazole-4-carboxylates 6a–d, as shown in Table 3. The reduction of 6a–d with NaBH4 in methanol afforded 7a–b and 8c–d. It was observed that the reduction of the N(1) carbonyl for 6a–b occurred at an acceptable rate, but the reduction of the C(4) position ester group of 8c–d was slow and required multiple days and a large excess of NaBH4, as shown in Table 3.
Observations based on the data in Table 1, Table 2 and Table 3 are: 1. β-Ketone substituents at N(1) undergo rapid reduction as expected. 2. β-Ester substituents at N(1) undergo reduction more rapidly than C(5) ester substituents. 3. Reduction of C(5) ester substituents is facilitated by a hydroxy group at the β carbon of N(1) substituents, whereas C(5) esters having only aralkyl substituents at N(1) react slower with NaBH4. 4. A ketone substituent at N(1) facilitates reduction of a C(5) ester more than an ester at N(1) because the ketone is reduced more rapidly, exposing a facilitating hydroxy group for reduction of a C(5) ester. 5. Regardless of the substituents at N(1), C(5) ester substituents are reduced more rapidly than C(4) ester substituents. 6. The presence of a C(4) ester substituent enhances the rate of reduction of a C(5) ester substituent. Stronger reducing agents such as LiAlH4 should be chosen when complete reduction of triazole and other heteroaromatic diesters is desired.
Compounds 1a–f and 4a–d each gave reduction of the C(5) ester. The relative rates of reduction varied considerably with the nature of the N(1) substituents. An N(1) substituent containing a ketone was reduced by NaBH4 to the corresponding alcohol within a few minutes, as observed for products 2a–b. The resulting hydroxy substituent situated at the δ-position relative to the ester carbonyl undergoing reduction showed a rate-enhancing effect on the ester at C(5), such as in the reduction of 1a–b to 3a–b as compared to the reduction rates of 1d–f to 3d–f. When N(1) contained a keto or ester group, as for 1a–c and 4a–c, reduction of that keto or ester group to an alcohol was observed. The rate-enhancement was lower for the reduction of 1c because the N(1) ester group was reduced more slowly than the N(1) ketones of 1a and 1b, also observed for the reduction rate of 6b compared to that of 6a. The reduction rate of the C(5) ester group was significantly slower when the N(1) substituent contained only alkyl, alkenyl, or aralkyl groups as in 1d–f and 4d. The times necessary to complete the reactions in this study provide a clear distinction between triazole C(5) esters bearing an N(1) substituent containing a β-carbonyl group (1a–c and 4a–c) and those having N(1) alkyl or alkenyl substituents (1d–f and 4d). All ketone and ester groups of 1a–c and 4a–c were reduced to alcohols. The resulting alcohols 2a–c and 5a–c gave reduction of the C(5) ester groups more readily than C(5) esters 1d–f and 4d.
Our hypothesis to explain the difference in reactivity of the C(4) and C(5) diesters is that there are consistent differences in electron density at the ester carbonyl carbons, leading to preferred reaction of the C(5) carbonyl group of the C(5) esters. Molecular modeling studies [30] furnished insight into the preferential reduction of the C(5) esters, which indicated that the calculated electron density at the C(5) carbonyl carbon was lower than at the C(4) carbonyl carbon for 1a–f and 4a–d, supporting the observation that NaBH4 gave reduction of the C(5) ester group in preference to the C(4) ester group. Plots of electron densities of the C(5) carbonyl and C(5) carbons of 1a–f and separately 4a–d showed linear correlations with R-squared values of >0.9. When intramolecular hydrogen bonding was included in the calculations and compared to the data for no hydrogen bonding, a lower electron density was observed at C(5) and a much lower electron density at the C(5) carbonyl carbon. However, the R-squared values were only 0.87 and 0.49, respectively (See Supplementary Material).
Electron density differences and, where relevant, intramolecular hydrogen bonding, are postulated to explain the faster rates of reduction of the C(5) esters. Other possible explanations of a higher rate of reactivity at C(5) such as for 2a and 2b are the formation of a lactone intermediate [26] or a borate complex intermediate [27]. These explanations are not possible for 1d–f, which lack reducible carbonyl groups in substituents at N(1) such as in 1a–c. Similar observations were made for the modeling studies of 4a–d. The overall rates of reduction of 4a–d showed a decrease compared to those for 1a–f, indicating a favorable rate enhancement for reduction of a C(5) ester when an ester group is also present at C(4).

3. Conclusions

The regioselective NaBH4 reduction of the C(5) 1H-1,2,3-triazole esters was found to be a dependable reaction that occurred with all 1H-1,2,3-triazole 4,5-diesters examined in this study. The 1H-1,2,3-triazole 5-esters were also reduced faster than the 1H-1,2,3-triazole 4-esters. The results are supported by 2D-NMR and X-ray data. When a hydroxy substituent was available at the N(1) position by the initial reduction of a ketone or ester at N(1) of the triazole esters and diesters studied, reduction times were shorter for the C(5) esters of both triazole-4,5-diesters and triazole-5-esters. The lower electron densities found at the C(5) position for all of the 1H-1,2,3-triazole esters and diesters studied are posited as the enabling factor for reduction even in the cases when no hydroxy substituent is available at the N(1) position to assist in the regioselective reduction of the C(5) position ester. In cases where a hydroxy substituent becomes available by reduction of a group at N(1), the rate of reduction at C(5) is further increased. Intramolecular hydrogen bonding could be the reason for the high reactivity of C(5) esters where hydrogen bonding is relevant.

4. Materials and Methods

All starting materials were purchased from commercially available sources and used as obtained. All synthesized organic azides were stored at 0 °C until needed. All azides should be considered as hazardous and potentially explosive. Plastic or ceramic spoons were used when weighing solid azides. All synthesized organic azides were stored at 2–8 °C to ensure safety of potentially explosive material and to reduce degradation of the azide moiety. All reactions were performed in a ventilated hood. Thin layer chromatography (TLC) was performed on Agela Technologies aluminum-backed silica dioxide plates and products observed under 254 nm UV light. Flash column and radial chromatography (T-Squared Technology, Inc., 206 Lassen Dr., San Bruno CA 94066 USA) were performed with SiliCycle silica gel 60, 0.040−0.063 mm (230−400 mesh) using distilled ethyl acetate and distilled hexanes. Microwave-assisted synthesis was performed using a CEM Discover SP Microwave Synthesizer. NMR spectra (400 or 500 MHz for 1H and 100 MHz for 13C) were measured in CDCl3 or DMSO-d6. Chemical shifts (δ) are given in ppm relative to the resonance of their respective residual solvent peak, CHCl3 (7.27 ppm, 1H; 77.16 ppm, the middle peak, 13C). Multiplicities were described using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, m = multiplet. Regioselectivity of the reduction was determined by HSQC and HMBC correlation 2D-NMR analysis. FTIR experiments were performed on a Perkin Elmer Spectrum 1 instrument (Perkin Elmer Inc., 732 E. Utah Valley Dr., Suite 120, American Fork, UT 84003, USA) or Fisher Scientific Nicolet iS5 instrument (Thomas Scientific, PO Box 99, Swedesboro, NJ 08085, USA). Melting points were performed on a Stanford Research Systems Digimelt MPA160 SRS instrument (Stanford Research Systems, 1290-D Reamwood Ave., Sunnyvale, CA 94089, USA) and all melting points are uncorrected. All elemental analyses were performed by Atlantic Microlabs Inc., Norcross, GA. High-resolution MS experiments were recorded at 70 eV by electrospray ionization using a Voyager DE-STR MALDI-TOF (ABI) instrument (AB Sciex, LLC, 500 Old Connecticut Path, Framingham, MA 10701, USA). Single crystals of 3f suitable for X-ray crystallographic analysis were obtained by slow recrystallization from a THF solution of 3f at room temperature. X-ray diffraction data were collected using a Bruker SMART APEX CCD diffractometer (Bruker Corp., 40 Manning Rd., Billerica, MA 01821, USA).

4.1. General Procedures for the Synthesis of Organic Azides

Metal azides are shock sensitive and should be handled with smooth edged, non-metallic spoons or spatulas. Purification of initially isolated products is required to remove traces of azides.
Procedure A. To tert-butyl alcohol/water (1:1, 100 mL) in a 250 mL round-bottom flask were added 2-bromoacetophenone, cinnamyl bromide or benzyl bromide (10 mmol), and sodium azide (0.98 mg, 15 mmol) and the mixture was stirred at rt for 2 h. The mixture was extracted with ethyl acetate (3 × 25 mL), the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness, affording the organic azide in 80–95% yield. The azide was stored at 0 °C and used without further purification [29].
2-Azidoacetophenone [31]. Dark yellow oil. (1.435 g, 89.0% yield); 1H-NMR (CDCl3, 400 MHz) δ 7.92–7.90 (d, 2H), δ 7.65–7.61 (t, 1H), δ 7.52–7.48 (t, 2H), δ 4.57 (s, 2H); FTIR cm−1 3062, 2096, 1691, 1596, 1448, 1213.
Cinnamyl azide [32]. Yellow oil. (1.586 g, 99.7% yield); 1H-NMR (CDCl3, 400 MHz) δ7.41–7.38 (d, 2H), δ 7.35–7.31 (t, 2H), δ 7.29–7.25 (t, 1H), δ 6.66–6.62 (d, J = 15.6 Hz, 1H), δ 6.27–6.19 (m, 1H), δ 3.94–3.92 (d, 2H); FTIR cm−1 3027, 2090, 1654, 1598, 1448, 1234.
Benzyl azide [33]. Yellow oil. (1.187 g, 87.6%); 1H-NMR (CDCl3, 400 MHz). δ 7.39–7.29 (m, 5H), δ 4.31 (s, 2H); FTIR cm−1 3031, 2089, 1597, 1453, 1252.
Procedure B. Into a 100 mL round-bottom flask, chloroacetone, ethyl bromoacetate, or 1-bromopentane (10 mmol), DMSO (50 mL), and sodium azide (0.98 mg, 15 mmol) were added. The mixture was stirred at rt for 12 h and extracted with diethyl ether (3 × 25 mL). The combined organic layers were washed with water (2 × 25 mL), dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo, affording the organic azide in 70–85% yield. The azide was stored at 0 °C and used without further purification.
1-Azidopropan-2-one [34]. Yellow oil. (831 mg, 83.9% yield); 1H-NMR (CDCl3, 400 MHz) δ 3.99 (s, 2H), δ 2.21 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 202.0, 57.8, 27.1; FTIR cm−1 2097, 1724, 1281.
Ethyl azidoacetate [35]. Yellow oil. (1.058 g, 82.1% yield); 1H-NMR (CDCl3, 400 MHz) δ 4.28–4.21 (q, 2H), δ 3.82 (s, 2H), δ 1.34–1.26 (t, 3H); FTIR cm−1 2102, 1740, 1286, 1190.
1-Azidopentane [36]. Colorless oil. (1.120 g, 99.0% yield); 1H-NMR (CDCl3, 400 MHz) δ 3.28–3.22 (t, 2H), δ 1.66–1.56 (m, 2H), δ 1.40–1.29 (m, 4H), δ 0.95–0.88 (t, 3H); 13C-NMR (CDCl3, 100 MHz) δ 51.35, 28.75, 28.42, 22.13, 13.81; FTIR cm−1 2089.

4.2. Experimental Procedure for the Synthesis of 1H-1,2,3-Triazole-4,5-Diesters (1a–f)

Into a 100 mL round-bottom flask, the organic azide (4 mmol), tert-butyl alcohol/H2O (1:1) soln. (60 mL), dimethyl acetylenedicarboxylate (582 mg, 4.1 mmol) were added and the mixture heated under reflux for 2 h, cooled and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness. Purification was performed by recrystallization or flash column chromatography.
Dimethyl 1-(2-oxo-2-phenylethyl)-1H-[1,2,3]triazole-4,5-dicarboxylate (1a) [37].
Dimethyl 1-(2-oxopropyl)-1H-1,2,3-triazole-4,5-dicarboxylate (1b) [34]. Colorless solid, purified by flash column chromatography (1:6, ethyl acetate/hexanes). (689 mg, 71.4% yield); m.p.: 72.4–73.9 °C; 1H-NMR (CDCl3, 400 MHz) δ 5.54 (s, 2H), δ 3.98 (s, 3H), δ 3.94 (s, 3H), δ 2.32 (s, 3H); 13C-NMR (CDCl3, 100 MHz) δ 198.6, 160.3, 158.9, 140.1, 129.9, 59.1, 53.4, 52.8, 27.1; FTIR cm−1 1752, 1725 1244, 1110, 1064; Anal. Calcd. for C9H11N3O5: C, 44.82; H, 4.60; N, 17.42% Found: C, 45.09; H, 4.63; N, 17.55%.
Dimethyl 1-(2-ethoxy-2-oxoethyl)-1H-1,2,3-triazole-4,5-dicarboxylate (1c) [38]. Colorless solid, purified by recrystallization from ethanol. (881 mg, 81.2% yield); m.p.: 120.8–121.6 °C; 1H-NMR (CDCl3, 400 MHz) δ 5.44 (s, 2H), δ 4.25 (q, J = 7.1 Hz, 2H), δ 3.99 (s, 3H), δ 3.96 (s, 3H), δ 1.28 (t, J = 7.1 Hz, 3H); 13C-NMR (CDCl3, 100 Hz), δ 165.5, 160.2, 158.7, 140.2, 130.0, 62.6, 53.4, 52.8, 51.6, 14.0; FTIR cm−1 3024, 1692, 1664, 1585, 1463, 1248, 1106, 1042; Anal. Calcd. for C10H13N3O6: C, 44.28; H, 4.83; N, 15.49% Found: C, 44.30; H, 4.88; N, 15.43%.
Dimethyl 1-pentyl-1H-1,2,3-triazole-4,5-dicarboxylate (1d) [39]. Colorless oil, purified by flash column chromatography (1:10, ethyl acetate/hexanes). (819 mg, 80.3% yield); 1H NMR (CDCl3, 400 MHz) δ 4.16–4.50 (t, 2H), δ 3.97 (s, 3H), δ 3.93 (s, 3H), δ 1.93–1.81 (m, 2H), δ 1.41–1.81 (m, 4H), δ 0.85 (t, J = 7.0 Hz, 3H); 13C-NMR (CDCl3, 100 MHz) δ 160.5, 159.0, 139.8, 129.8, 53.4, 52.6, 50.6, 29.9, 28.3, 21.9, 13.7; FTIR cm−1 1729, 1212, 1127, 1060; HRMS (TOF MS ES+) m/z [m + H]+ calc. C11H17N3O4 256.1292. Found: 256.1299.
Dimethyl 1-benzyl-1H-1,2,3-triazole-4,5-dicarboxylate (1e) [40]. Light yellow solid, purified by recrystallization from ethanol/water. (982 mg, 89.2% yield); m.p.: 45.8–46.4 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.38–7.25 (m, 5H), δ 5.82 (s, 2H), δ 3.97 (s, 3H), δ 3.88 (s, 3H); FTIR cm−1 3028, 1724, 1572, 1466, 1227, 1140, 1057.
Dimethyl 1-(3-phenylprop-2-en-1-yl)-1H-1,2,3-triazole-4,5-dicarboxylate (1f) [41]. Yellow oil, purified by flash column chromatography (1:8, ethyl acetate/hexanes). (1.032 g, 85.7% yield); 1H-NMR (CDCl3, 400 MHz) δ 7.37–7.24 (m, 5H), δ 6.65–6.62 (d, J = 15.79 Hz, 1H), δ 6.29 (m, 1H), δ 5.38 (dd, J = 6.73 Hz, 2H), δ 3.97 (s, 3H), δ 3.94 (s, 3H); 13C-NMR (CDCl3, 100 MHz) δ 160.4, 159.0, 140.0, 136.0, 135.3, 129.9, 128.7, 128.6, 126.7, 121.0, 53.5, 52.8, 52.6; FTIR cm−1 3028, 1728, 1553, 1450, 1213, 1100, 1059; HRMS (TOF MS ES+) m/z [m + H]+ calc. C15H15N3O4 302.1136. Found: 302.1135.

4.3. Experimental Procedure for the Synthesis of 1H-1,2,3-Triazole Monoalcohol Esters (2a–2b)

Into a 25 mL round-bottom flask, 1H-1,2,3-triazoloester (1a or 1b, 1 mmol) and methanol (20 mL) were added, followed by NaBH4 (38 mg, 1 mmol) and the solution stirred for three min. The reaction was quenched with 1 M HCl until a pH of 6 was reached (~1.5 mL) and evaporated in vacuo to dryness. The crude product was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to dryness.
Dimethyl 1-(2-hydroxy-2-phenylethyl)-1H-1,2,3-triazole-4,5-dicarboxylate (2a) [42]. Colorless oil, purified by flash column chromatography (1:4, ethyl acetate/hexanes). (300 mg, 98.5% yield); 1H-NMR (CDCl3, 400 MHz) δ 7.42–7.37 (m, 5H), δ 5.19–5.14 (m, 1H), δ 4.86–4.83 (dd, 2H), δ 3.98 (s, 3H), δ 3.97 (s, 3H) δ 2.91 (s, 1H); 13C-NMR (CDCl3, 100 MHz) δ 160.3, 159.3, 139.6, 139.3, 131.3, 128.9, 128.7, 125.8, 72.9, 56.5, 53.5, 52.7; FTIR cm−1 3382, 2954, 1726, 1454, 1220, 1061; HRMS (TOF MS ES+) m/z [m + H]+ calc. for C14H15N3O5 306.1090 Found: 306.1087.
Dimethyl 1-(2-hydroxypropyl)-1H-1,2,3-triazole-4,5-dicarboxylate (2b). Colorless oil, purified by flash column chromatography (1:4, ethyl acetate/hexanes). (197 mg, 80.8% yield); 1H-NMR (CDCl3, 400 MHz) δ 4.52–4.57 (dd, 2H), δ 4.23–4.29 (m, 1H), δ 4.02 (s, 3H), δ 3.99 (s, 3H); 13C-NMR (CDCl3, 100 MHz) δ 160.36, 159.44, 139.46, 131.17, 66.81, 56.48, 53.49, 52.73, 20.62; FTIR cm−1 3407, 2957, 1727, 1459, 1219, 1117, 1064; HRMS (TOF MS ES+) m/z [m + H]+ calc. for C9H13N3O5 244.0928 Found: 244.0932.

4.4. Experimental Procedure for the 1H-1,2,3-Triazole Ester Reduction to Alcohols 3a–f, 5a–d, 7a–b and 8c–d

Into a 25 mL round-bottom flask, the 1H-1,2,3-triazoloester (1a–f, 4a–d, 6a–d, 2 mmol) and methanol (10 mL) were added. Sodium borohydride was added to the flask in portions (76 mg, 2 mmol) every 0.5 h until reaching the number of equivalents specified in Table 1, Table 2 and Table 3. TLC analysis was performed on the reaction mixture prior to each addition until no starting material remained in the reaction mixture. Upon completion, the methanol was evaporated in vacuo to dryness.
Methyl 5-(hydroxymethyl)-1-(2-hydroxy-2-phenylethyl)-1H-1,2,3-triazole-4-carboxylate (3a) [29]. Tan solid, purified by flash column chromatography, (1:4, ethyl acetate/hexanes). (404 mg, 72.9% yield); m.p.: 96.8–98.5 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.46–7.33 (m, 5H), δ 5.27–5.23 (d, 1H), δ 5.02–4.95 (dd, 1H), δ 4.86–4.81 (ds, 1H), δ 4.69–4.64 (dd, 1H), δ 4.51–4.46 (dd, 1H), δ 4.38–4.34 (s, 2H); 13C-NMR (CDCl3, 100 MHz) δ162.1, 142.0, 139.7, 136.0, 128.9, 128.6, 125.8, 72.8, 55.6, 53.0, 52.5; FTIR cm−1 3510, 3290, 3083, 1708, 1234, 1203, 1068, 1032; Anal. Calcd. for C13H15N3O4: C, 56.31; H, 5.45; N, 15.16% Found: C, 56.39; H, 5.44; N, 15.11%.
Methyl 5-(hydroxymethyl)-1-(2-hydroxypropyl)-1H-1,2,3-triazole-4-carboxylate (3b). Tan solid, purified by flash column chromatography, (1:4, ethyl acetate/hexanes). (334 mg, 77.7% yield); m.p.: 72.1–73.8 °C; 1H-NMR (DMSO-d6, 400 MHz) δ 5.49 (t, 1H), δ 5.12 (d, 1H), δ 4.97–4.74 (m, 2H), δ 4.50–4.28 (m, 2H), δ 4.15–3.97 (m, 1H), δ 3.84 (s, 3H), δ 1.12 (d, 3H); 13C-NMR (DMSO-d6, 100 MHz) δ 161.9, 141.9, 135.5, 65.9, 55.5, 52.2, 51.3, 21.3; FTIR cm−1 3381, 3210, 1714, 1250, 1179, 1334, 1033; Anal. Calcd. for C8H13N3O4: C, 44.650; H, 6.09; N, 19.53% Found: C, 44.58; H, 5.98; N, 19.27%
Methyl 1-(2-hydroxyethyl)-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxylate (3c). Colorless solid, initially purified by flash column chromatography (1:2.5, ethyl acetate/hexanes) and further purified by recrystallization from dichloromethane/hexanes. (205 mg, 50.9% yield); m.p.: 72.0–72.5 °C; 1H-NMR (DMSO-d6, 400 MHz) δ 5.53 (t, 1H), δ 5.09 (t, 1H), δ 4.88 (d, 2H), δ 4.53 (t, 2H), δ 3.84 (s, 3H), δ 3.80 (q, 2H); 13C-NMR (DMSO-d6, 100 MHz) δ 161.9, 141.8, 135.5, 60.4, 52.2, 51.29, 51.26; FTIR cm−1 3342, 3223, 1708, 1241, 1195, 1123, 1052; Anal. Calcd. for C7H11N3O4: C, 41.79; H, 5.51; N, 20.89% Found: C, 41.64; H, 5.36; N, 20.82%.
Methyl 5-(hydroxymethyl)-1-pentyl-1H-1,2,3-triazole-4-carboxylate (3d). Colorless solid, purified by flash column chromatography (1:5, ethyl acetate/hexanes). (234 mg, 51.4% yield); m.p.: 60.5–60.8 °C; 1H-NMR (CDCl3, 400 MHz) δ 4.89 (s, 2H), δ 4.46–4.30 (m, 2H), δ 3.97 (s, 4H), δ 1.99–1.79 (m, 2H), δ 1.42–1.18 (m, 4H), δ 0.88 (t, 3H); 13C-NMR (CDCl3, 100 MHz) δ 163.1, 140.9, 136.9, 53.2, 52.6, 48.8, 30.0, 28.5, 22.1, 13.8; FTIR cm−1 3247, 1708, 1224, 1194, 1047; Anal. Calcd. for C10H17N3O3: C, 52.85; H, 7.54; N, 18.49% Found: C, 53.00; H, 7.38; N, 18.46%
Methyl 1-benzyl-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxylate (3e). Colorless solid, purified by recrystallization from diethyl ether/hexanes. (411 mg, 83.1% yield); m.p.: 89.1–89.8 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.35–7.18 (m, 5H), δ 5.62 (s, 2H), δ 4.76 (s, 2H), δ 3.95 (s, 3H); 13C-NMR (CDCl3, 100 MHz) δ 162.9, 141.1, 137.3, 134.0, 129.2, 128.8, 127.3, 53.3, 52.7, 52.6; FTIR cm−1 3238, 3032, 1710, 1570, 1453, 1238, 1192, 1048; Anal. Calcd. for C12H13N3O3: C, 58.29; H, 5.30; N, 17.00% Found: C, 58.16; H, 5.36; N, 16.95; HRMS (TOF MS ES+) m/z [m + H]+ calc. for C12H13N3O3 248.1035 Found: 248.1042.
Methyl 5-(hydroxymethyl)-1-(3-phenylprop-2-en-1-yl)-1H-1,2,3-triazole-4-carboxylate (3f). Colorless solid, purified by recrystallization from ethyl acetate/hexanes. (345 mg, 63.1% yield); m.p.: 155.4–155.7 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.38–7.22 (m, 5H), δ 6.59 (d, J = 15.9 Hz, 1H), δ 6.3 (m, 1H), δ 5.23 (d, 2H), δ 4.96 (s, 2H), δ 3.99 (s, 3H), δ 3.55 (s, 1H); 13C-NMR (CDCl3, 100 MHz) δ 162.9, 141.1, 137.2, 135.4, 135.0, 128.7, 128.5, 126.7, 121.4, 53.3, 52.4, 50.9; FTIR cm−1 3222, 3058, 3026, 1708, 1570, 1470, 1246, 1192, 1045; Anal. Calcd. for C14H15N3O3: C, 61.530; H, 5.53; N, 15.38% Found: C, 61.53; H, 5.59; N, 15.47%.

4.5. Experimental Procedure for the Synthesis of 1H-1,2,3-Triazole-5-Monoesters (4a–d)

Into a 35 mL microwave vessel, the organic azide (4 mmol), THF (15 mL), and dichloro (pentamethylcyclopentadienyl)ruthenium polymer (91 mg, 0.31 mmol) were added, in that order. The vessel was flushed with N2, sealed, and heated at 100 °C in the CEM microwave for 20 min. Upon completion the crude mixture was purified by flash column chromatography.
Methyl 1-(2-oxopropyl)-1H-1,2,3-triazole-5-carboxylate (4a) [39].
Methyl 1-(2-ethoxy-2-oxoethyl)-1H-1,2,3-triazole-5-carboxylate (4b). Yellow oil, further purified by radial chromatography (1:8, ethyl acetate/hexanes). (378 mg, 44.3% yield); 1H-NMR (CDCl3, 400 MHz) δ 8.18 (s, 1H), δ 5.49 (s, 2H), δ 4.30–4.25 (q, 2H), δ 3.93 (s, 3H), δ 1.32–1.29 (t, 3H); 13C-NMR (CDCl3, 100 MHz) δ 166.1, 158.7, 137.3, 128.4, 62.1, 52.5, 51.1, 13.9; FTIR cm−1 3140, 1726, 1272, 1121, 1092; HRMS (TOF MS ES+) m/z [m + H]+ calc. for C8H11N3O4 214.0823 Found: 214.0822.
Methyl 1-(2-oxo-2-phenylethyl)-1H-1,2,3-triazole-5-carboxylate (4c). Tan solid, further purified by an additional flash column chromatography (1:5, ethyl acetate/hexanes). (322 mg, 32.8% yield); m.p.: 122.3–123.5 °C; 1H-NMR (CDCl3, 400 MHz) δ 8.23 (s, 1H), δ 8.04–7.99 (d, 2H), δ 7.72–7.66 (t, 1H), δ 7.60–7.53 (t, 2H), δ 6.22 (s, 2H), δ 3.88 (s, 3H); 13C-NMR (CDCl3, 100 MHz) δ 189.9, 159.1, 137.6, 134.4, 134.1, 129.1, 128.11, 128.06, 56.1, 52.6; FTIR cm−1 3140, 3022, 1731, 1699, 1596, 1460, 1226, 1131; Anal. Calcd. for C12H11N3O3: C, 58.772; H, 4.521; N, 17.134% Found: C, 59.02; H, 4.67; N, 17.05%.
Methyl 1-(3-phenylprop-2-en-1-yl)-1H-1,2,3-triazole-5-carboxylate (4d). Yellow oil, further purified by radial chromatography (1:10, ethyl acetate/hexanes). (128 mg, 13.2% yield); 1H-NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), δ 7.38–7.26 (m, 5H), δ 6.69–6.65 (d, J = 15.6, 1H), δ 6.41–6.34 (m, 1H), δ 5.51–5.49 (d, 2H), δ 3.94 (s, 3H); 13C-NMR (CDCl3, 100MHz) δ 158.8, 138.1, 135.7, 135.1, 128.6, 128.3, 127.4, 126.7, 122.2, 52.5, 52.1; FTIR cm−1 3104, 3026, 1725, 1598, 1448, 1246, 1122; HRMS (TOF MS ES+) m/z [m + Li]+ calc. for C13H13N3O2 250.1168 Found: 250.1168.
1-[5-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]propan-2-ol (5a). Colorless solid, further purified by radial chromatography (1:3, ethyl acetate/hexanes). (235 mg, 74.8% yield); m.p. 92.2–92.7 °C; 1H-NMR (DMSO-d6, 400 MHz) δ 7.57 (s, 1H), δ 5.40 (t, 1H), δ 5.07 (d, 1H), δ 4.61 (2H), δ 4.38–4.12 (m, 2H), δ 4.01 (ddd, 1H), δ 1.08 (d, 3H); 13C-NMR (DMSO-d6, 100 MHz) δ 138.6, 132.4, 66.1, 54.9, 52.6, 21.4; FTIR cm−1 3326, 3137, 3093, 1245, 1168, 1017; Anal. Calcd. for C6H11N3O2: C, 45.85; H, 7.05; N, 26.74% Found: C, 45.83; H, 6.98; N, 26.49%.
2-[5-(Hydroxymethyl)-1H-1,2,3-triazole-1-yl]ethanol (5b). Yellow oil, purified by an additional flash column chromatography (1:2, ethyl acetate/hexanes). (153 mg, 53.4% yield); 1H-NMR (DMSO-d6, 400 MHz) δ 7.58 (s, 1H), δ 5.46 (s, 1H), δ 5.09 (s, 1H), δ 4.61 (s, 2H), δ 4.40–4.37 (t, 2H), δ 3.76 (s, 2H); 13C-NMR (DMSO-d6, 100 MHz) δ 138.5, 132.5, 60.7, 52.4, 50.5; FTIR cm−1 3260, 3098, 1238, 1111, 1022; HRMS (TOF MS ES+) m/z [m + H]+ calc. C5H9N3O2 144.0773. Found: 144.0771.
2-[5-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]-1-phenyl-1-ethanol (5c). Tan solid, purified by radial chromatography (1:7, ethyl acetate/hexanes). (304 mg, 69.2% yield); m.p.: 119.1 –122.3 °C; 1H-NMR (DMSO-d6, 400 MHz) δ 7.56 (s, 1H), δ 7.36–7.27 (m, 5H), δ 5.83–5.82 (d, 1H), δ 5.45–5.42 (t, 1H), δ 5.01–4.97 (q, 1H), δ 4.55–4.42 (m, 4H); 13C-NMR (DMSO-d6, 100 MHz) δ 142.7, 138.7, 132.3, 128.7, 128.1, 126.5, 72.4, 55.1, 52.5; FTIR cm−1 3261, 3036, 1241, 1059, 1023; Anal. Calcd. for C11H13N3O2: C, 44.65; H, 6.09; N, 19.53% Found: C, 44.58; H, 5.98; N, 19.27%
1-[(3-Phenylprop-2-en-1-yl)-1H-1,2,3-triazole-5-yl]-methanol (5d). Colorless solid, further purified by recrystallization from diethyl ether/hexanes. (343 mg, 79.8% yield); m.p.: 66.1–66.6 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.51 (s, 1H), δ 7.38–7.21 (m, 5H), δ 6.57 (d, J = 15.8, 1H), δ 6.31 (dt, 1H), δ 5.19 (d, 2H), δ 4.76 (s, 2H), δ 3.71 (s, 1H); 13C-NMR (CDCl3, 100 MHz) δ 136.3, 135.6, 134.3, 133.1, 128.7, 128.4, 126.6, 122.2, 53.1, 50.7; FTIR cm−1 3229, 1621, 1593, 1470, 1188, 1045; Anal. Calcd. for C12H13N3O: C, 66.96; H, 6.09; N, 19.55% Found: C, 66.66; H, 6.09; N, 19.26%

4.6. Experimental Procedure for the Synthesis of 1H-1,2,3-Triazole-4-Monoesters (6a–d)

Into a 100 mL round-bottom flask, the organic azide (4 mmol), tert-butyl alcohol/H2O (1:1) soln. (60 mL), methyl propiolate (345 mg, 4.1 mmol), 1M copper sulfate pentahydrate solution (200 uL), and sodium ascorbate (40 mg, 0.20 mmol) were added, in that order. The mixture was refluxed for 2 h. Upon completion, the mixture was cooled to rt., 20 mL of a 10% ammonia solution added, and the mixture stirred for 5 min. The mixture was extracted ethyl acetate (20 mL × 3), the combined organic layers washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness.
Methyl 1-(2-oxo-2-phenylethyl)-1H-1,2,3-triazole-4-carboxylate (6a) [43].
Methyl 1-(2-ethoxy-2-oxoethyl)-1H-1,2,3-triazole-4-carboxylate (12b) [44]. Colorless solid, purified by recrystallization from ethanol/hexanes. (477 mg, 55.9% yield); m.p.: 105.2–105.7 °C; 1H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), δ 5.22 (s, 2H), δ 4.28 (q, 2H), δ 3.95 (s, 3H), δ 1.3 (t, 3H); 13C-NMR (CDCl3, 100 MHz) δ 165.6, 160.9, 140.4, 129.0, 62.8, 52.3, 51.0, 14.0; FTIR cm−1 3152, 3005, 1754, 1715, 1241, 1028, 1014.
Methyl 1-benzyl-1H-1,2,3-triazole-4-carboxylate (6c) [44,45].
Methyl 1-(3-phenylprop-2-en-1-yl)-1H-1,2,3-triazole-4-carboxylate (6d). Colorless solid, purified by recrystallization from ethyl acetate/hexanes. (831 mg, 85.4% yield); m.p.: 131.7 –132.5 °C; 1H-NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), δ 7.41–7.31 (m, 5H), δ 6.74–6.70 (d, J = 15.6 Hz, 1H), δ 6.38–6.31 (m, 1H), δ 5.21–5.19 (d, 2H), δ 3.95 (s, 3H); 13C-NMR (CDCl3, 100 MHz) δ 161.1, 140.2, 136.5, 135.1, 128.83, 128.80, 127.2, 126.8, 120.7, 52.6, 52.2; FTIR cm−1 3124, 3027, 1717, 1658, 1578, 1451, 1228, 1046; Anal. Calcd. for C13H13N3O2: C, 64.19; H, 5.39; N, 17.27% Found: C, 64.03; H, 5.53; N, 17.23%.
Methyl 1-(2-hydroxy-2-phenylethyl)-1H-1,2,3-triazole-4-carboxylate (7a) [29]. Colorless solid, purified by flash column chromatography (1:5, ethyl acetate/hexanes). (389 mg, 78.7% yield) m.p. 84.5–85.3 °C; 1H-NMR (CDCl3, 500 MHz) δ 8.19 (s, 1H), δ 7.45–7.30 (m, 5H), δ 5.20 (d, 1H), δ 4.69 (d, 1H), δ 4.44 (dd, 1H), δ 3.91 (s, 3H), δ 3.53 (s, 1H); 13C-NMR (CDCl3, 100 MHz) δ 161.1, 139.8, 139.4, 129.0, 128.9, 128.6, 125.8, 72.5, 57.5, 52.2; FTIR cm−1 3393, 3143, 3002, 1730, 1257, 1199, 1061; Anal. Calcd. for C13H15N3O3: C, 58.29; H, 5.30; N, 17.00% Found: C, 58.41; H, 5.18; N, 17.17%; HRMS (TOF MS ES+) m/z [m + H]+ calc. C13H15N3O3 248.1035. Found: 248.1037.
Methyl 1-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxylate (7b) [46]. Colorless solid, purified by flash column chromatography (1:4, ethyl acetate/hexanes). (293 mg, 85.7% yield) m.p. 81.3–82.7 °C; 1H-NMR (DMSO-d6, 400 MHz) δ 8.73 (s, 1H), δ 5.05 (t, 1H) δ 4.46 (t, 2H), δ 3.83–3.78 (m, 5H); 13C-NMR (DMSO-d6, 100 MHz) δ 160.8, 138.3, 129.4, 59.4, 52.4, 51.6; FTIR cm−1 3372, 3149, 1728; Anal. Calcd. for C6H9N3O3: C, 42.11; H, 5.30; N, 24.55% Found: C, 42.09; H, 5.30; N, 24.68%.
(1-Benzyl-1H-1,2,3-triazol-4-yl)methanol (8c) [44]. Colorless solid, purified by flash column chromatography (1:4, ethyl acetate/hexanes). (173 mg, 91.2% yield); m.p.: 67.9–68.6 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.50 (s, 1H), δ 7.39–7.278 (m, 5H), δ 5.51 (s, 2H), δ 4.76 (s, 2H); FTIR cm−1 3237, 3136, 1221, 1014.
1-[(3-Phenylprop-2-en-1-yl)-1H-1,2,3-triazol-4-yl]methanol (8d). Colorless solid, purified initially by flash column chromatography (1:5, ethyl acetate/hexanes) and then radial chromatography (1:8, ethyl acetate/hexanes). (87 mg, 40.4% yield); m.p.: 80.0–81.9 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), δ 7.40–7.30 (m, 5H), δ 6.70–6.66 (d, J = 15.6, 1H), δ 6.38–6.31 (dt, 1H), δ 5.15–5.13 (d, 2H), δ 4.01 (s, 2H), δ 2.03 (s, 1H); 13C-NMR (CDCl3, 100 MHz) δ 148.2, 135.45, 135.38, 128.7, 128.5, 126.7, 121.8, 121.74, 56.1, 52.34; FTIR cm−1 3279, 3121, 3078, 1220, 1039; Anal. Calcd. for C12H13N3O: C, 66.96; H, 6.09; N, 19.52% Found: C, 66.67; H, 6.07; N, 19.51%

4.7. Experimental Procedure for Reduction Completion Analyses (1a–f, 4a–d, 6a–d)

To each of 1, 4 or 6 (1 mmol) in CH3OH (10 mL), NaBH4 (1 eq) was added with stirring at rt. for 30 min. Additional NaBH4 was added in 1eq increments for 30 min periods until 1, 4 or 6 were no longer detectable by TLC analysis under UV (254 nm) light. Aliquots were spotted at the origin of a TLC plate and developed in ethyl acetate/hexanes (3/7). Towards the end of each analysis, larger aliquots were spotted (x5) and developed. Detection limits were <1% for 1a, e, f; 4c–d; and 6a, c, d and < 2% for 1b–d; 4a–b and 6b. Detection limits were determined by visualizing developed plates spotted with standard samples of 1, 4 and 6 by the same technique used for each of the reduction analyses. Spotting (x5) per standard solution gave detectable spots for 0.1 mmol/mL of 1a, e, f; 4c–d; and 6a, c, d, and 0.2 mmol/mL of 1b–d; 4a–b and 6b.

Supplementary Materials

The following are available online, The IR, 1H and 13C-NMR spectra of all numbered compounds and molecular modeling details are available in the Supplementary Material.

Author Contributions

Conceptualization, A.M.S. and C.R.B.; formal analysis, A.M.S. and C.R.B.; investigation, C.R.B. and J.B.; methodology, C.R.B. and J.B.; supervision, A.M.S.; writing—original draft preparation, A.M.S. and C.R.B.; writing—review and editing, A.M.S., C.R.B. and J.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing is not applicable.

Acknowledgments

We thank the NMR spectroscopy facility (UC Boulder) for some of the NMR spectra; the Central Analytical Mass Spectrometry Lab (UC Boulder) for high-resolution MS data; Alfred Hagedorn (UCCS) for useful discussions and for laboratory help and guidance; Gary Balaich (USAFA) for his valuable assistance in obtaining X-ray crystallography data and the associated thermal ellipsoid plots; Renee Henry (UCCS) for collaborative efforts; Brett Mayer (UCCS) for assistance with molecular modeling; and Janel Owens (UCCS) for help with LC-MS experiments.

Conflicts of Interest

The authors declare no conflict of interest. This research was not funded by external agencies. Therefore, funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The authors have no personal circumstances or interest that may be perceived as inappropriately influencing the representation or interpretation of reported research results.

Sample Availability

Samples of the benzyl and phenacyl triazole diesters are available from the authors.

References

  1. Periasamy, M.; Thirumalaikumar, M. Methods of enhancement of reactivity and selectivity of sodium borohydride for applications in organic synthesis. J. Organomet. Chem. 2000, 609, 137–151. [Google Scholar] [CrossRef]
  2. Brown, H.C.; Narasimhan, S.; Choi, Y.M. Selective Reductions. 30. Effect of cation and solvent on the reactivity of saline borohydrides for reduction of carboxylic esters. Improved procedures for the conversion of esters to alcohols by metal borohydrides. J. Org. Chem. 1982, 47, 4702–4708. [Google Scholar] [CrossRef]
  3. Soai, K.; Oyamada, H.; Ookawa, A. Sodium borohydride-t-butyl alcohol-methanol as an efficient system for the selective reduction of esters. Synth. Commun. 1982, 12, 463–467. [Google Scholar] [CrossRef]
  4. Huisgen, R. 1,3-Dipolar cycloadditions. Past and future. Angew. Chem. Int. Ed. 1963, 2, 565–598. [Google Scholar] [CrossRef]
  5. Huisgen, R. Kinetics and mechanism of 1,3-dipolar cycloadditions. Angew. Chem. Int. Ed. 1963, 2, 633–645. [Google Scholar] [CrossRef]
  6. Rostovtsev, V.V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. A stepwise Huisgen cycloaddition process: Copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem. Int. Ed. 2002, 41, 2596–2599. [Google Scholar] [CrossRef]
  7. Tornoe, C.W.; Christensen, C.; Meldal, M. Peptidotriazoles on solid phase: [1,2,3]-Triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem. 2002, 67, 3057–3064. [Google Scholar] [CrossRef]
  8. Zhang, L.; Chen, X.; Xue, P.; Sun, H.H.Y.; Williams, I.D.; Sharpless, K.B.; Fokin, V.V.; Jia, G. Ruthenium-catalyzed cycloaddition of alkynes and organic azides. J. Am. Chem. Soc. 2005, 127, 15998–15999. [Google Scholar] [CrossRef]
  9. Thomas, J.; John, J.; Parekh, N.; Dehaen, W. A metal-free three-component reaction for the regioselective synthesis of 1,4,5-trisubstituted 1,2,3-triazoles. Angew. Chem. Int. Ed. 2014, 53, 10155–10159. [Google Scholar] [CrossRef]
  10. Johansson, J.R.; Hermansson, E.; Norden, B.; Kann, N.; Beke-Somfai, T. δ-Peptides from RuAAC-derived 1,5-disubstituted triazole units. Eur. J. Org. Chem. 2014, 2014, 2703–2713. [Google Scholar] [CrossRef]
  11. Nagaraju, A.; Sandeep, K.; Swamy, K.C.K. Copper catalyzed access to functionalized oxazoles from oximes via carbenoids. Tetrahedron Lett. 2018, 59, 2238–2242. [Google Scholar] [CrossRef]
  12. Yasui, E.; Tsuda, J.; Ohnuki, S.; Nagumo, S. Selective mono-reduction of pyrrole-2,5 and 2,4-dicarboxylates. Chem. Pharm. Bull. 2016, 64, 1262–1267. [Google Scholar] [CrossRef] [Green Version]
  13. Langlois, Y.; Potier, P. Synthese totale de la descarbomethoxy-16 vobasine. Tetrahedron 1975, 31, 419–422. [Google Scholar] [CrossRef]
  14. Papavassilopoulou, E.; Christofis, P.; Terzoglou, D.; Moutevelis-Minakakis, P. Reduction of pentafluorophenyl esters to the corresponding primary alcohols using sodium borohydride. Tetrahedron Lett. 2007, 48, 8323–8325. [Google Scholar] [CrossRef]
  15. Huang, N.; Jiang, T.; Wang, T.; Soukri, M.; Ganorkar, R.; Deker, B.; Leger, J.; Madalengoitia, J.; Kuehne, M.E. The acyclic dieneamine indoloacrylate addition route to catharanthine. Tetrahedron 2008, 64, 9850–9856. [Google Scholar] [CrossRef]
  16. Yamazaki, T.; Tanii, J.; Hirai, Y.; Matoba, K. Reaction of 2,3,6-trimethylpyrimidin-4-one and dimethyl acetylenedicarboxylate. Heterocycles 1986, 24, 9–12. [Google Scholar] [CrossRef]
  17. Pasunooti, K.K.; Yang, R.; Vedachalam, S.; Gorityala, B.K.; Liu, C.; Liu, X. Synthesis of 4-mercapto-L-lysine derivatives: Potential building blocks for sequential native chemical ligation. Bioorg. Med. Chem. Lett. 2009, 19, 6268–6271. [Google Scholar] [CrossRef]
  18. Flanagan, R.C.; Xie, S.; Millar, A. A catalyzed and highly selective ester reduction in the synthesis of an N-acylpyrrolidine: Safe design through reaction calorimetry and modeling. Org. Process Res. Dev. 2008, 12, 1307–1312. [Google Scholar] [CrossRef]
  19. Kavadias, G.; Luh, B.; Saintonge, R. Synthesis of 4,5-disubstituted imidazoles. Can. J. Chem. 1982, 60, 723–729. [Google Scholar] [CrossRef]
  20. Padron, J.M.; Kokotos, G.; Martin, T.; Markidis, T.; Gibbons, W.A.; Martin, V.S. Enantiospecific synthesis of α-amino Acid semialdehydes: A key step for the synthesis of unnatural unsaturated and saturated α-amino acids. Tetrahedron Asymmetry 1998, 9, 3381–3394. [Google Scholar] [CrossRef]
  21. Vargas, D.F.; Romero, B.S.; Larghi, E.L.; Kaufman, T.S. Rhodium(III)-catalyzed C–H activation-based first total synthesis of 6-O-methyl anciscochine, an alkaloid isolated from Ancistrocladus tectorius. Synthesis 2020, 52, 119–126. [Google Scholar] [CrossRef]
  22. Prasanth, C.P.; Ebbin, J.; Abhijith, A.; Nair, D.S.; Ibrahim, I.; Jevgenij, R.; Bakthan, S. Stabilization of NaBH4 in methanol using a catalytic amount of NaOMe. Reduction of esters and lactones at room temperature without solvent-induced loss of hydride. J. Org. Chem. 2018, 83, 1431–1440. [Google Scholar]
  23. Brown, M.S.; Rapoport, H. The reduction of esters with sodium borohydride. J. Org. Chem. 1963, 28, 3261–3263. [Google Scholar] [CrossRef]
  24. Rao, N.S.L.; Rao, M.V.B.; Prasad, K.R.S. Synthesis and antibacterial evaluation of hydrazone derivatives bearing 6-chlorothieno [3,2-c]pyridine moiety. Asian J. Chem. 2019, 31, 627–632. [Google Scholar] [CrossRef]
  25. Ward, D.E.; Rhee, C.K. Chemoselective reductions with sodium borohydride. Can. J. Chem. 1989, 67, 1206–1211. [Google Scholar] [CrossRef]
  26. Chaudhuri, S.K.; Saha, M.; Saha, A.; Bhar, S. Systematic investigations on the reduction of 4-aryl-4-oxoesters to 1-aryl-1,4-butanediols with methanolic sodium borohydride. Beilstein J. Org. Chem. 2010, 6, 748–755. [Google Scholar] [CrossRef] [PubMed]
  27. Kim, J.; de Castro, K.A.; Lim, M.; Rhee, H. Reduction of aromatic and aliphatic keto esters using sodium borohydride/MeOH at room temperature: A thorough investigation. Tetrahedron 2010, 66, 3995–4001. [Google Scholar] [CrossRef]
  28. Butler, C.R.; Schoffstall, A.M.; Shoemaker, R.K. Regioselective Reduction of 1H-1,2,3-Triazoles Diesters and Triesters, Abstracts of Papers. In Proceedings of the 251st ACS National Meeting & Exposition, San Diego, CA, USA, 13–17 March 2016. CHED-21. [Google Scholar]
  29. Butler, C.R.; Schoffstall, A.M.; Shoemaker, R.K. Unequivocal Structure Proof using NMR Spectroscopy in an Organic Laboratory Project. In NMR Spectroscopy in the Undergraduate Curriculum; ACS Symposia Series; Soulsby, D., Wallner, T., Anna, L., Eds.; ACS: Washington, DC, USA, 2016; Volume 1221, pp. 151–172. [Google Scholar] [CrossRef]
  30. Wavefun.com. Available online: https://www.wavefun.com/spartan-latest-version (accessed on 20 June 2021).
  31. Wang, H.; Hou, R.; Wu, J.; Chen, L. Polymer-supported hypervalent iodine reagent mediated synthesis of α-azidoketones. J. Chin. Chem. Soc. 2007, 54, 1333–1335. [Google Scholar] [CrossRef]
  32. Balderman, D.; Kalir, A. Selective reduction of azides. Improved preparation of a,a-disubstituted benzylamines. Synthesis 1978, 1, 24–26. [Google Scholar]
  33. Alvarez, S.G.; Alvarez, M.T. A practical procedure for the synthesis of alkyl azides at ambient temperature in DMSO in high purity and yield. Synthesis 1997, 1997, 413–414. [Google Scholar] [CrossRef]
  34. Dyke, J.M.; Groves, A.P.; Morris, A.; Ogden, J.S.; Catarino, M.I.; Dias, A.A.; Oliveira, A.M.S.; Costa, M.L.; Barros, M.T.; Cabral, M.H.; et al. A study of the thermal decomposition of azidoacetone by photoelectron and matrix isolation spectroscopy. J. Phys. Chem. A 1999, 103, 8239–8245. [Google Scholar] [CrossRef]
  35. Assis, A.C.; Couto, N.; Duarte, M.F.; Rodrigues, P.; Barros, M.T.; Costa, M.L.; Cabral, B.J.C.; Fernandez, M.T. Azidoacetone as a complexing agent of transition metals Ni2+/Co2+ promoted dissociation of the C−C bond in azidoacetone. J. Mass Spectrom. 2011, 46, 696–704. [Google Scholar] [CrossRef] [PubMed]
  36. Frankowski, M.; Fox, B.S.; Smith-Gicklhorn, A.M.; Beyer, M.K.; Bondybey, V.E.; Algarra, M.; Costa, M.L.; Rodrigues, P.; Barros, M.T.; Cordeiro, M.N.D.S. Matrix-isolation FTIR study of azidoacetone and azidoacetonitrile. Low Temp. Phys. 2003, 29, 870–875. [Google Scholar] [CrossRef] [Green Version]
  37. Shanmugavelan, P.; Nagarajan, S.; Sathishkumar, M.; Ponnuswamy, A.; Yogeeswari, P.; Sriram, D. Efficient synthesis and in vitro antitubercular activity of 1,2,3-triazoles as inhibitors of Mycobacterium tuberculosis. Bioorg. Med. Chem. Lett. 2011, 21, 7273–7276. [Google Scholar] [CrossRef] [PubMed]
  38. Fisera, L.; Pavlovic, D. 1,3-Dipolar cycloaddition of heterocycles. XII. 1,3-Dipolar cycloadditions to 2,3-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]-2,5-heptadiene, 1,4-epoxy-1,4-dihydronaphthalene, and exo,endo-1,6-bis(methoxycarbonyl)-11,12-dioxatetracyclo[4.4.0.12,5.17,10]-3,8-dodecadiene. Coll. Czech. Chem. Comm. 1984, 49, 1990–2000. [Google Scholar]
  39. Butler, C.R.; Taylor, L.J.; Schoffstall, A.M. Synthesis and NMR spectroscopic characterization of 1H-1,2,3-triazoles, ACS Symposium Series 1376. In NMR Spectroscopy in the Undergraduate Curriculum, Volume 4: In-Person and Distance Learning Approaches; Soulsby, D., Wallner, T., Anna, L., Eds.; ACS: Washington, DC, USA, 2021; Chapter 4; pp. 41–65. [Google Scholar] [CrossRef]
  40. Ouali, M.S.; Vaultier, M.; Carrie, R. Thermolysis and photolysis of 1,2,3-triazolines derived from olefins trisubstituted by electroattracting groups. Preparation of aziridines. Bull. Soc. Chim. Fr. 1979, 11–12 Pt 2, 633–643. [Google Scholar] [CrossRef]
  41. Uozumi, Y.; Suzuka, T.; Kawade, R.; Takenaka, H. p-Allylic azidation in water with an amphiphilic resin-supported palladium-phosphine complex. Synlett 2006, 13, 2109–2113. [Google Scholar] [CrossRef]
  42. Tsuge, O.; Kanemasa, S.; Matsuda, K. A silyl-functionalized alkyl azide, trimethylsilylmethyl azide; synthesis and cycloaddition reaction to acetylenic dipolarophiles. Chem. Lett. 1983, 7, 1131–1134. [Google Scholar] [CrossRef] [Green Version]
  43. Xiao, L.; Cai, S.; Liu, Q.; Liao, L.; Guo, X.; Li, Y.; Jia, X.; Li, F.; Liu, L. One-step synthesis of polypyrazoles and self-assembled polypyrazole-copper catalysts for click chemistry. Polym. Chem. 2014, 5, 607–613. [Google Scholar] [CrossRef]
  44. Orgueira, H.A.; Fokas, D.; Isome, Y.; Chan, P.C.-M.; Baldino, C.M. Regioselective synthesis of [1,2,3]-triazoles catalyzed by Cu(I) generated in situ from Cu(0) nanosize activated powder and amine hydrochloride salts. Tetrahedron Lett. 2005, 46, 2911–2914. [Google Scholar] [CrossRef]
  45. Luebbe, F.; Grosz, K.P.; Hillebrand, W.; Sucrow, W. Photolysis of a 2-tetrazene from an enehydrazine. Tetrahedron Lett. 1981, 22, 227–228. [Google Scholar] [CrossRef]
  46. Das, J.; Dey, S.; Pathak, T. A Metal-free route to carboxylated 1,4-disubstituted 1,2,3-triazoles from methoxycarbonyl modified vinyl sulfone. J. Org. Chem. 2019, 84, 15437–15447. [Google Scholar] [CrossRef] [PubMed]
Molecules 26 05589 sch001 550
Scheme 1. Sodium borohydride (NaBH4) and diisobutylaluminum hydride (DIBAH) reduction reactions of heteroaromatic diesters.
Scheme 1. Sodium borohydride (NaBH4) and diisobutylaluminum hydride (DIBAH) reduction reactions of heteroaromatic diesters.
Molecules 26 05589 sch001
Molecules 26 05589 g001 550
Figure 1. X-ray crystallography-derived thermal ellipsoid plot of compound 3f.
Figure 1. X-ray crystallography-derived thermal ellipsoid plot of compound 3f.
Molecules 26 05589 g001
Table
Table 1. Preparation of dimethyl 1H-1,2,3-triazole-4,5-dicarboxylates from organic azides and dimethyl acetylenedicarboxylate (DMAD) and their reduction with sodium borohydride (NaBH4).
Table 1. Preparation of dimethyl 1H-1,2,3-triazole-4,5-dicarboxylates from organic azides and dimethyl acetylenedicarboxylate (DMAD) and their reduction with sodium borohydride (NaBH4).
Molecules 26 05589 i001
SubstrateR1Yield (%)Reduction ProductR2Yield (%)Time (h)Eq. NaBH4
1aPhCOCH2812aPhCH(OH)CH2980.051
1bCH3COCH2712bCH3CH(OH)CH2810.051
1aPhCOCH2813aPhCH(OH)CH2731.53
1bCH3COCH2713bCH3CH(OH)CH2781.53
1cEtOCOCH2813cHOCH2CH2512.55
1dCH3(CH2)3CH2803dCH3(CH2)3CH25136
1ePhCH2893ePhCH28348
1fPh(CH)2CH2863fPh(CH)2CH280714
Table
Table 2. Preparation of methyl 1-substituted-1H 1,2,3-triazole-5-carboxylates using dichloro(pentamethylcyclopentadienyl)ruthenium polymer (RuCl2CP*)x catalyst and their reduction by NaBH4.
Table 2. Preparation of methyl 1-substituted-1H 1,2,3-triazole-5-carboxylates using dichloro(pentamethylcyclopentadienyl)ruthenium polymer (RuCl2CP*)x catalyst and their reduction by NaBH4.
Molecules 26 05589 i002
SubstrateR1Yield (%)Reduction ProductR2Yield (%)Time (h)Eq. NaBH4
4aCH3COCH2445aCH3CH(OH)CH2752.55
4bEtOCOCH2335bHOCH2CH25336
4cPhCOCH2475cPhCH(OH)CH2693.57
4dPh(CH)2CH2135dPh(CH)2CH28010.521
Table
Table 3. Preparation and reduction of methyl 1-substituted 1H-1,2,3-triazole carboxylates.
Table 3. Preparation and reduction of methyl 1-substituted 1H-1,2,3-triazole carboxylates.
Molecules 26 05589 i003
SubstrateR1Yield (%)Reduction ProductR2C(4) Ester ReductionYield (%)Time (h)Eq. NaBH4
6aPhCOCH2867aPhCH(OH)CH2No790.51
6bEtOCOCH2567bHOCH2CH2No8612
6cPhCH2798cPhCH2Yes9160 a40 a
6dPh(CH)2CH2858dPh(CH)2CH2Yes4072 a,b48 a
a NaBH4 was added in portions over 3 days. b This reaction reached ~50% completion according to TLC and 1H-NMR analysis.
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Butler, C.R.; Bendesky, J.; Schoffstall, A.M. Regioselective Reduction of 1H-1,2,3-Triazole Diesters. Molecules 2021, 26, 5589. https://doi.org/10.3390/molecules26185589

AMA Style

Butler CR, Bendesky J, Schoffstall AM. Regioselective Reduction of 1H-1,2,3-Triazole Diesters. Molecules. 2021; 26(18):5589. https://doi.org/10.3390/molecules26185589

Chicago/Turabian Style

Butler, Christopher R., Justin Bendesky, and Allen Milton Schoffstall. 2021. "Regioselective Reduction of 1H-1,2,3-Triazole Diesters" Molecules 26, no. 18: 5589. https://doi.org/10.3390/molecules26185589

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