Regioselective N-Alkylation of Ethyl 4-Benzyloxy-1,2,3-triazolecarboxylate: A Useful Tool for the Synthesis of Carboxylic Acid Bioisosteres

Month 2018

Regioselective N-Alkylation of Ethyl 4-Benzyloxy-1,2,3-

triazolecarboxylate: A Useful Tool for the Synthesis of Carboxylic Acid

Bioisosteres

Stefano Sainas,^a

Agnese C. Pippione,^aAlessandro Giraudo,^aKatia Martina,^aFederica Bosca,^aBarbara Rolando,^a

Alessandro Barge,^aAlex Ducime,^aAntonella Federico,^aStuart J. Grossert,^bRobert L. White,^bDonatella Boschi,^aand

a

*

Marco L. Lolli

^aDipartimento di Scienza e Tecnologia del Farmaco (DSTF), Università degli Studi di Torino, via Pietro Giuria 9, Turin

10125, Italy

^bDepartment of Chemistry, Dalhousie University, 6274 Coburg Road, Halifax, Nova Scotia B3H 4R2, Canada

*E-mail: marco.lolli@unito.it

Received June 29, 2018

DOI 10.1002/jhet.3426

Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).

Acidic 4-hydroxy-1,2,3-triazole is a proven bioisostere of acidic functions that has recently been used to

replace the acidic moieties of biologically active leads. Straightforward chemical strategies for the synthesis

of the three possible N-alkylated 4-hydroxy-1,2,3-triazole regioisomers have been designed and reported

herein, by identifying the optimal conditions under which the alkylation of ethyl 4-benzyloxy-1,2,3-

triazolecarboxylate (compound 19) can be regiodirected to the triazole N(b) position and thus produce the

only isomer that cannot be obtained via the cycloaddition reaction. Furthermore, an innovative platform

for parallel synthesis, called Arachno and which has been patented by the authors’ group, has been used

to speed up the process, and an NMR study has been carried out to better understand the reactivity of com-

pound 19 towards the N(b) position. A library of benzyloxy protected 4-hydroxy-1,2,3-triazoles has been

prepared using the two strategies: regiodirection for the N(b) and N(c) isomers and cycloaddition for the

N(a) isomers; the processes are described herein. The three N-alkylated regioisomer series have been char-

acterized spectroscopically (NMR and MS). The subsequent catalytic hydrogenation of the 4-benzyloxy pro-

tective group on the N-alkylated-4-benzyloxy-5-ethoxycarbonyl-1,2,3-triazoles provided the corresponding

substituted 4-hydroxy-1,2,3-triazoles.

J. Heterocyclic Chem., 00, 00 (2018).

INTRODUCTION

[8,9]. Unlike with other hydroxyazole systems that

are frequently used to mimic the carboxylic function

[10–17], regio-substitution at the nitrogen atoms of the

hydroxytriazole ring allows for improved exploration

of the chemical space of the biological target [18].

The effective application of this system in designing

biologically active compounds requires the development

of straightforward chemical strategies for the synthesis

of the three possible 4-hydroxy-1,2,3-triazole N-

substituted regioisomers. In this work, N ring positions

are labeled (a), (b), and (c), according to structure B in

Figure 1, so as to easily identify the three regioisomers.

Besides a few studies into general solutions for the

synthesis of N(a)-alkylated triazoles, that are most

accessible via cycloaddition reactions [19–21], there are

not many that report general methods for the synthesis

of complementary N(b)-substituted and N(c)-substituted

regioisomers [22–24]. In fact, the alkylation of 4,5-

dicarboxylated 1,2,3-triazole always shows modest

regioselectivity [23].

Bio(iso)steric replacement is an approach that is widely

used in medicinal chemistry to improve the bioavailability,

selectivity, potency, and other properties of a lead

compound [1]. This powerful strategy requires the

continuous development of new and highly chemodiverse

isosteres if the requirements of speciﬁc targets are to

be satisﬁed. The 1,2,3-triazole is a well-known and

thoroughly reviewed bioisostere of the peptide bond that

is often used as a hydrophobic linker with the ability to

participate in hydrogen bonding and π-interactions [2,3].

Its 4-hydroxy derivative (A, Fig. 1) has recently been

successfully used to mimic the carboxylic function in the

design of new potential drugs, as it can be deprotonated

at physiological pH [4,5]. As the search for new agents

that are active in the central nervous system gathers pace,

this moiety has led to promising glutamate analogues [4],

novel sortilin inhibitors [5], new anticancer drugs [6,7],

and new immunosuppressive agents being produced

S. Sainas, A. C. Pippione, A. Giraudo, K. Martina, F. Bosca, B. Rolando, A. Barge,

A. Ducime, A. Federico, S. J. Grossert, R. L. White, D. Boschi, and M. L. Lolli

Vol 000

Figure 1. Protected hydroxytriazole building blocks of general structure B. [Color ﬁgure can be viewed at wileyonlinelibrary.com]

We have recently reported the preparation of N-alkyl

derivatives of ethyl 4-benzyloxy-1,2,3-triazolcarboxylate

19 in ACN and potassium carbonate in which it was

shown that alkylation only occurred on N(b) and N(c)

[4,6,9], while the N(b)/N(c) alkylation ratio was governed

by a combination of the electronic and steric effects of

the alkyl bromine (Scheme 1).

We herein systematically investigate the N-alkylation

of 19 to identify the principle parameters (temperature,

solvent, base, and alkylating reagent) involved in the

reaction mechanism, with the aim of driving future

reactions towards the desired regioisomer. We also

present a detailed general strategy for the production of

N(b)-alkylated and N(c)-alkylated triazole isomers that

cannot be obtained via the cycloaddition reaction. A

small library of protected hydroxy-1,2,3-triazoles

(building blocks of general structure B, Fig. 1) has

been prepared to validate the general regio-synthetic

method.

The resulting hydroxy-protected N-alkyl substituted

triazoles are to be considered a shortlist of building

blocks that may be useful to the study of benzyloxy/

hydroxytriazole systems and their potential applications

in drug design. Besides containing a benzyl-protected

hydroxy group (the precursor to the bioisosteric acidic

function in the ﬁnal drug), these building blocks contain

also an esteriﬁed carboxylic group which can be used to

link the moiety to a drug backbone.

RESULTS AND DISCUSSION

Optimization of the regio-alkylation of 19. Producing 19

in an adequate yield is clearly necessary if its N regio-

alkylation is to be effectively investigated. Several

strategies to increase the yield of the synthesis of

compound 19, from its N-(4-methoxybenzyl) protected

derivative 7a (Scheme 2), have been investigated herein

as previous experience only provides modest yields

(35%) [4]. In fact, the yield of 19 rise to 71% upon

changing the ACN/H₂O ratio in the solvent mixture from

9/1 to 1/1, applying longer reaction times (from few

hours to more than 12 h) and purifying the reaction

mixture with Amberlyst A21 free base resin, in order to

retain the by-product 4-methoxybenzoic acid. Once

sufﬁcient yield of 19 had been secured, variations in the

reaction conditions for its N-alkylation (including

temperature, solvent, base, and alkylating reagent) were

studied using parallel syntheses and the Arachno device.

Arachno is a parallel-synthesis-friendly and low-cost

technology that can speed up investigations, which was

designed and patented [25] by the authors’ group and is

reported for the ﬁrst time herein. Scheme 2 and the

video in Data S1 show the use of Arachno in the

identiﬁcation of the optimal conditions for obtaining

the N(b)-alkylated isomer from 19. The study involved

up to 36 different reaction conditions (solvent, base,

and temperature) and identiﬁed the best parameter

Scheme 1. The alkylation pattern of ethyl 4-benzyloxy-1,2,3-triazolecarboxylate 19. i) RX, K₂CO₃, ACN.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2018

Hydroxytriazoles are Useful Tools in Bioisosteric Replacement of Acidic Functions: Strategies

for the Preparation of a Library of Protected Hydroxytriazole Building Blocks are Described

Scheme 2. Use of Arachno parallel synthesis technology to obtain N(b,c)-alkylated isomers, 2b,c and 6b,c, from 19. i) 7a (1.0 mmol), cerium (IV)

ammonium nitrate (2.5 mmol), ACN/H₂O 50:50 v/v, rt. [Color ﬁgure can be viewed at wileyonlinelibrary.com]

combination with which to obtain the N(b) and N(c)

alkylates in the highest yields.

2.0 eq of base, and compound 19 was dissolved in the

solvent at a 40-mM concentration. The reaction was left at

room temperature for 16 h. Conversions were >95%

across all the experiments. However, 20 / 30% mixtures of

hydrolyzed carboxylic acid (20 Scheme 2) were obtained

when the reactions were performed in the presence of

water. As depicted in Figure 2, N(b) regioselectivity (N(b)/

[N(b) + N(c)]%) reached its highest value when the

reaction was carried out in ACN and in the presence of

either sodium or potassium carbonate. Cesium carbonate

appears to be less efﬁcient in promoting N(b) alkylation in

all the solvents used.

Position N(a) never reacts with the alkylating agent

under the explored conditions, given the steric hindrance

of the benzyloxy moiety. N(b) selectivity is in agreement

with previous accounts and can be ascribed to its higher

nucleophilicity [23], which is caused by the stability of

Benzyl bromide was selected as the ﬁrst model alkylating

agent to produce the previously investigated compounds,

6b–c [4]. The reactions were carried out in the presence of

sodium, potassium, or cesium carbonate in either ACN,

dimethylformamide (DMF), a dioxane/water (8/2 v/v)

mixture, or a tetrahydrofuran (THF)/water (8/2 v/v) mixture

(Fig. 2), at room temperature. The use of Arachno allows in

a lab stirring plate the performance of six experiments,

meaning that optimization cycles of 12 parallel experiments,

each testing different solvent, alkylating ratio and base

choice conditions, were easily run. Alkylation only occurred

on N(b) and N(c) under all the investigated experimental

conditions. The N(b)/N(c) ratio was either determined by

GC–MS or HPLC–MS. The alkylation reactions were

performed in the presence of 2.0 eq of benzyl bromide and

Figure 2. N(b) regioselectivity of triazole benzylation in the presence of various solvents and bases. Reaction conditions: 19 (1.0 mmol), benzyl bromide

(2.0 mmol), base (2.0 mmol), solvent, rt, 16 h. [Color ﬁgure can be viewed at wileyonlinelibrary.com]

Journal of Heterocyclic Chemistry

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S. Sainas, A. C. Pippione, A. Giraudo, K. Martina, F. Bosca, B. Rolando, A. Barge,

A. Ducime, A. Federico, S. J. Grossert, R. L. White, D. Boschi, and M. L. Lolli

Vol 000

the isomer ii (in Scheme 3) due to the intramolecular

hydrogen bond with the ester group. Moreover, N(c) and

the ester group should own the capacity to coordinate

cations (iv in Scheme 3). Indeed, in either DMF,

dioxane/water or THF/water, instead of ACN, the

solvent’s ability to form hydrogen bonds is enhanced and

thus competes with intramolecular hydrogen bonding.

This increases the concentration of 2H-1,2,3-triazole form

i and consequently the reactivity of the N(c) position.

The ¹H-NMR spectra of 19, in dimethyl sulfoxide

(DMSO, Fig. 3b) and in CDCl₃(Fig. 3a), support this

hypothesis. The mobile proton region of the ¹H-NMR

spectrum, recorded in DMSO, only show the presence of

two signals (Fig. 3b), which can be assigned to the

protons in positions (b) and (c), assuming that the third

tautomer iii is not favored. We can surmise that the most

intense signal is caused by the proton in the (c) position

and that it is probably involved in the most stable

hydrogen bond network. However, the presence of

DMSO also allows the protonation of N(b) to occur

because of the solvent’s ability to compete with

intramolecular hydrogen bond formation. Interestingly,

Scheme 3. Possible tautomers of 19 and its salt.

Figure 3. ¹H-NMR mobile proton region of 19 recorded in CDCl₃(a) and in DMSO (b).

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2018

Hydroxytriazoles are Useful Tools in Bioisosteric Replacement of Acidic Functions: Strategies

for the Preparation of a Library of Protected Hydroxytriazole Building Blocks are Described

only one species is detected (Fig. 3a), when the same

spectrum is recorded in CDCl₃, a solvent not able to form

hydrogen bonds. The absence of competition between the

solvent and the intramolecular hydrogen bond formation

probably shifts the equilibrium depicted in Scheme 3 A

to the right (structure ii).

In the presence of carbonate, the alkylation may involve

the partial deprotonation of the triazole ring (pKa ~ 9.3)

[23], while the ester group can coordinate the metal ion

and block the reactivity of the N(c) position (structure iv,

Scheme 3 B). As depicted in Figure 2, increased N(b)

selectivity was observed in the presence of sodium and

potassium salts, as compared to the cesium salt.

regioselectivity was increased, as compared to benzyl

bromide alkylation, while Cs₂CO_3,NaH, and t-BuOK

were conﬁrmed as the most selective towards N(b)

substitution. Despite some impurities being observed

when the reaction was performed with t-BuOK, the

regioselectivity trend caused by the cationic counterion

was maintained. The general enhancement in

regioselectivity is probably a consequence of the lower

reaction rate observed when ethyl bromide is used instead

of benzyl bromide. Indeed, the alkylation reaction seems

to be much slower than the interconversion between the

two isomers depicted in Scheme 3, meaning that

alkylation proceeds towards the most thermodynamically

stable isomer.

When the reaction was performed in THF, using either

Cs₂CO₃, NaH, DBU, t-BuOK, LDA, or Et₃N as the base,

the highest selectivity for the N(b) position was achieved

when either the sodium or potassium salts were used

(Fig. 4). Lithium diisopropylamide (LDA), Cs₂CO_3,

Finally, the role that temperature plays in regioselectivity

was investigated. The reactions were carried out using NaH

at different temperature values (up to 70°C), but no

variation in regioselectivity was observed. This behavior

may be caused by the very low inﬂuence that temperature

has on the equilibrium between the two species depicted in

DBU, and Et₃N yielded

a mixture of the two

regioisomers with much lower N(b) regioselectivity; this

is probably because they show lower coordinating-atom

afﬁnity (high charge density and small ionic radius).

In order to conﬁrm this behavior, the previously

described set of reactions was performed in dry THF with

ethyl bromide and 6 eq of the alkylating agent to ensure

complete conversion. As showed in Figure 5, average

1

Scheme 3A. In order to conﬁrm this hypothesis, H-NMR

spectra of 19 were recorded at a variety of temperatures.

The mobile proton region is characterized by two signals

whose line width increases with temperature (as the

exchange rate is increased), but their area ratio remains

unchanged (Data S1). This conﬁrms that temperature

Figure 4. A screening of the inﬂuence of the choice of base on the benzylation of triazole 19. Reaction conditions: 19 (1.0 mmol), benzyl bromide

(2.0 mmol), base (2.0 mmol) in dry THF, rt, 16 h. (a) N(b) /N(c) alkylation regioselectivity; (b) % of starting material conversion. [Color ﬁgure can be

viewed at wileyonlinelibrary.com]

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

S. Sainas, A. C. Pippione, A. Giraudo, K. Martina, F. Bosca, B. Rolando, A. Barge,

A. Ducime, A. Federico, S. J. Grossert, R. L. White, D. Boschi, and M. L. Lolli

Vol 000

Figure 5. A screening of the inﬂuence of the base on the ethylation of triazole 19: N(b) and N(c) regioselectivity are presented in the graph. Reaction

conditions: 19 (1.0 mmol), ethyl bromide (6.0 mmol), base (1.1 mmol) in dry THF, rt, 24 h. [Color ﬁgure can be viewed at wileyonlinelibrary.com]

affects the exchange rate between the two positions, but not

the relative populations, leaving the regioselectivity of

alkylation reaction unaltered.

Synthesis of N(a), N(b), and N(c)-alkylated triazoles.

Synthesis of N(b) triazoles.

The optimized procedure

was repeated to obtain a set of eight N(b) triazoles (Table 1).

Table 1

Synthesis of N(b) regio-substituted triazoles.

Cpd

RX

Yield (Conv^a%)

N(b)/[N(b) + N(c)]%

94

1b^b

71 (>95)

2b^b

9b^b

5b^b

69 (80)

66 (>95)

56 (>95)

>95

10b^b

6b

25 (35)

>95

75 (>95)

93

11b

12b

74 (>95)

78 (>95)

89

90

Reaction conditions: 19 (1.0 mmol), RX (2.5 mmol), NaH (1.2 mmol) in dry THF, rt, 24 h.

^aDetermined by LC–MS.

^bThe reactions were carried out with 6.0 mmol of RX.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2018

Hydroxytriazoles are Useful Tools in Bioisosteric Replacement of Acidic Functions: Strategies

for the Preparation of a Library of Protected Hydroxytriazole Building Blocks are Described

As depicted in Table 1, the reaction shows high

regioselectivity both with primary and secondary alkylating

agents when performed in THF in the presence of NaH.

Methyl, ethyl, and n-propyl bromides gave only a small

quantity of the N(c)-substituted derivative. Regioselectivity

was found to be consistently higher than 89% when a set

of three benzyl bromides was used as the alkylating agents.

Synthesis of N(a) triazoles.

The triazole N(a) atom

cannot be alkylated using the previously described

methods, meaning that a different approach (Scheme 4a,

b) was used to collect a complete set of the respective

N(a)-alkylated triazoles, 1a–8a.

Two synthetic strategies have been designed. The ﬁrst

(Scheme 4a) is an alternative of the well-known methods

involving dangerous low-molecular-weight alkylazides

[19]. The previously described procedure [20] was used

to provide primary ammonium salts of 1-alkyl-1,2,3-

triazol-5-ols (compounds 1d–6d), by reacting diethyl

diazomalonate with a proper amine. The intermediate

was O-alkylated with benzyl bromide in DMF, in the

presence of Cs₂CO₃, in order to avoid handling the

unstable ethyl 4-hydroxy-1-alkyltriazol-5-carboxylates

[20], giving compounds 1a–6a in moderate yields. In the

second strategy, the synthesis of 6a–8a (Scheme 4b) passes

through the base-catalyzed reaction of less dangerous

Synthesis of N(c) triazoles.

Because the alkylation

reaction carried out in DMF and in the presence of

Cs₂CO₃gave the higher N(c)/N(b) ratio (Fig. 2), these

condictions where applied to 19 to synthesize N(c)-

alkylated triazoles. As showed in Table 2, the N(c)

regioisomer was obtained in a 40% yield with methyl

iodide and the benzyl bromides, whereas ethyl, propyl,

and isopropyl bromide gave N(c) in lower yields. As

expected, steric hindrance means that the secondary

halide isopropyl bromide shows a signiﬁcant preference

for the N(b) position.

Table 2

Regioselectivity of alkylation reaction in the presence of Cs₂CO_3,DMF.

Cpd

RX

Yield (Conv^a) %

N(b) Yield %

52

N(c) Yield %

42

1b–1c^b

94 (>95)

2b–2c^b

9b–9c^b

92 (>95)

76 (>95)

61 (70)

65

55

47

27

21

14

,

5b–5c^{b c}

10b–10c^b

6b–6c

84 (>95)

71

44

13

40

11b–11c

12b–12c

93 (>95)

82 (>95)

52

42

41

40

Reaction conditions: 19 (1.0 mmol), RX (2.5 mmol), Cs₂CO₃(2.5 mmol) in dry DMF, room temperature, 24 h.

^aDetermined by LC–MS.

^bReactions were carried out with 6.0 mmol of RX.

^cThe reaction mixture was stirred at 50°C for 3 days in order to obtain these products.

Journal of Heterocyclic Chemistry

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A. Ducime, A. Federico, S. J. Grossert, R. L. White, D. Boschi, and M. L. Lolli

Vol 000

Scheme 4. Synthesis of N(a)-alkylated triazoles. (i) selected amine, toluene, rt; (ii) BnBr, Cs₂CO₃, dry DMF; (iii) diethyl malonate, EtO^ÀNa⁺, EtOH

reﬂux.

benzylic azides with diethyl malonate [26] to give 16a, 17a,

and 18a (in 70%, 71%, and 65% yields, respectively). These

hydroxytriazoles were further converted to the respective O-

benzylated compounds 6a–8a. The benzyl analogue 6a was

prepared using both approaches (Schemes 4a,b), and the

overlapped spectra of the products conﬁrmed the

regioselectivity of both procedures.

With the aim of obtaining all the 4-hydroxy-1,2,3-

triazole isomers, the respective benzylated derivatives 6b

and 6c were subjected to deprotection to give 16b and

16c (Scheme 5), as 16a was directly obtained by the

cycloaddition reaction (Scheme 4b).

NMR and MS studies on hydroxy-1,2,3-triazoles. 2D-

NMR was used to univocally assign the structure of the

three benzyl isomers 6a, 6b, and 6c (Supporting

Information pages S19–S26). In terms of ¹³C- chemical

shifts, the signal of the C(d) carbon of the N(c)-

substituted benzyl isomer 6c (110.8 ppm, Table 3) was

observed at higher ﬁeld than the corresponding resonance

in the N(a) or N(b)-substituted isomers 6a and 6b

(124.2 ppm). A similar, although smaller, shift was also

observed in the C(h) peak of 6c (158.5 ppm in compound

6c, vs 161.0 and 160.5 ppm, for 6a and 6b, respectively),

while the chemical shift of C(e) was upﬁeld when N(a)

was substituted (152.5 ppm in compound 6a vs 161.0

and 161.3, for 6b and 6c, respectively, Table 3). Similar

results were found for the ¹³C signals of C(d), C(e), and

C(h) (Table 3) of the other members of the 1–8 series. In

this sense, the relative chemical shifts of these three key

positions can be used to assign the isomeric pattern.

When considering the hydroxytriazole N(b)-alkylated

structures, the tautomeric equilibrium between forms A

and B (Scheme 6) cannot be ignored. Indeed, a

considerable excess (or total dominance) in one of the

two tautomers can govern the interaction of the ﬁnal drug

with its proper target. A ¹H-NMR analysis of mobile

proton chemical shifts has been performed on compound

16b in order to attempt to determine which species is

most abundant in solution.

1

Interestingly, the H-NMR spectrum of compound 16b

shows a mobile-proton signal at 11.41 ppm (at 25°C, in

DMSO) that is less shifted than that of compound 19

(14.9 ppm), which is relative to a heterocyclic N position.

Seeing as no other mobile-proton signal is visible, it

would appear that only one tautomer is present, and it is

possible to surmise that the predominant (the only

visible) tautomer in these conditions is A.

Scheme 5. Synthesis of 16b and 16c. (i) 6b or 6c (1.0 mmol), H₂, Pd/C

10% w/w, dry THF, rt.

Structural characterization is also supported by

electrospray ionization (ESI) mass spectrometry data.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

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Hydroxytriazoles are Useful Tools in Bioisosteric Replacement of Acidic Functions: Strategies

for the Preparation of a Library of Protected Hydroxytriazole Building Blocks are Described

Scheme 6. Tautomeric equilibrium for 16b.

Ethyl 1-benzyl-5-hydroxy-1H-1,2,3-triazole-4-carboxylate

16a and its two isomers 2-benzyl 16b and 3-benzyl 16c

were readily ionized in both positive and negative

ionization modes, ESI(+) and ESI(À) (Fig. 6a,b). The

preferential formation of sodiated ions over protonated

species upon ESI(+) is consistent with the presence of

favorable bidentate binding that involves two proximate

heteroatoms [27]. From a classical resonance structure

point of view (Supporting Information Scheme S1), the

alkylated nitrogen in each of the triazoles 16a–c is

electron deﬁcient and less likely to bind a sodium ion.

When the sodiated and deprotonated triazoles were

subjected to tandem mass spectrometry with collision-

induced dissociation (MS/MS, CID), the ion spectra of

the resulting products for the three isomers were clearly

different, indicating that isomer speciﬁc fragmentation

processes occurred.

For the N(a) and N(b) isomers 16a and 16b, the

chelation of a sodium cation between the carbonyl

oxygen [27] and N(c) would orient the ethoxylic oxygen

atom towards the hydroxyl group for hydrogen bonding

and the subsequent proton transfer needed for the

elimination of ethanol (Scheme 7, A and B). The

formation of a second product ion (m/z 196), from

sodiated 16a (Fig. 6a), indicates that the subsequent loss

of carbon monoxide occurred, while the binding of the

sodium cation to the two adjacent nitrogen atoms stays

favorable [27]. N(c) is alkylated in 16c, and chelation of

the sodium cation by the ester and hydroxy groups is

more probable (Scheme 7C). These complexed groups,

however, cannot align for ethanol elimination and the

alternative release of the benzyl cation from sodiated 16c

strengthens the bonding to sodium (Scheme 7C).

Dissociation to the sodium ion was not observed in the

CID spectra of sodiated 16c (Fig. 6a), unlike in the other

isomeric ions 16a and 16b.

The ESI(À) CID spectra of the isomeric

hydroxytriazoles 16a–c (Fig. 6b) showed neutral losses

that can be attributed to benzylazide, a benzyl radical,

and dinitrogen. In the hydroxy anion of 16c, the double

bond between N(a) and N(b) is appropriately positioned

for the release of dinitrogen upon the formation of a

carbonyl at C(e) (Scheme 7D). This process is analogous

to Grob fragmentation and the favorable decarboxylative

Journal of Heterocyclic Chemistry

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S. Sainas, A. C. Pippione, A. Giraudo, K. Martina, F. Bosca, B. Rolando, A. Barge,

A. Ducime, A. Federico, S. J. Grossert, R. L. White, D. Boschi, and M. L. Lolli

Vol 000

Figure 6. Product-ion spectra collected on a triple quadrupole mass spectrometer (15 V cone. 15 eV CID). (a) sodiated hydroxytriazoles; (b) deprotonated

hydroxytriazoles collected on a triple quadrupole mass spectrometer (20 V cone. 15 eV CID). A: compound 16a; B: compound 16b; and C: compound

16c. [Color ﬁgure can be viewed at wileyonlinelibrary.com]

Scheme 7. Fragmentation pathways of sodiated hydroxytriazoles 16a (A), 16b (B), 16c (C), and deprotonated 16c (D).

elimination found in β-substituted propanoate ions [28].

The minor and major ions, at m/z 190 and 91

respectively, are consistent with subsequent losses of

carbon monoxide and ethyl cyanoformate that occur with

the formation of a benzyl anion. The fragmentation of

deprotonated 16a is equivalent to a retro azide-alkyne

Journal of Heterocyclic Chemistry

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Hydroxytriazoles are Useful Tools in Bioisosteric Replacement of Acidic Functions: Strategies

for the Preparation of a Library of Protected Hydroxytriazole Building Blocks are Described

cycloaddition [29] yielding benzylazide and an alkyne

oxide ion at m/z 113. The structure of 16a, and not that

of 16c, matches the regioselectivity observed for the

reaction of benzylazide with an α-carbonyl alkyne [30].

The loss of a benzyl radical from deprotonated 16b

leaves N(b) with a single electron that is stabilized by

delocalization onto the ester carbonyl. By contrast, the

charge on the ionized hydroxyl group in deprotonated

16a and 16c is conjugated to the ester carbonyl. Overall,

the results of the ESI(+) and ESI(À) fragmentation

processes are unique for each of the three structural

isomers and support the structures that were assigned

after analysis of the NMR results.

interchangeable. Compounds 1a–c and 6a–c were also

checked using HSQC and HMBC 2D-NMR experiments.

The IR spectra of solid compounds (hydroxytriazole

derivatives) were recorded on an FTIR (PerkinElmer

SPECTRUM BXII, KBr dispersions), using diffuse

reﬂectance apparatus DRIFT ACCY. ESI mass spectra

were obtained on a Waters Quattro LC triple quadrupole

mass spectrometer, using the ﬂow injection (20 μL/min)

of compounds dissolved in methanol–water (1:1, v/v) at

0.2 mg/mL. HRMS spectra were recorded on a LTQ

Orbitrap mass spectrometer (Thermo Scientiﬁc, Bremen,

Germany), equipped with an atmospheric pressure

interface and an ESI ion source instrument. The entire

sample batch described showed purities of >95%, which

were conﬁrmed using two HPLC analytical methods.

HPLC analyses were performed on an UHPLC chromato-

graphic system (Perkin Elmer, Flexar). The analytical

column was an UHPLC Acquity CSH Fluoro-Phenyl

(2.1 × 100 mm, 1.7-μm particle size) (Waters). Com-

pounds were dissolved in ACN and injected through a

20-μL loop. The mobile phase consisted of ACN/water

with 0.1% triﬂuoroacetic acid (ratio between 60/40 and

40/60, depending on the compound’s retention factor).

HPLC retention times (tR) were obtained at ﬂow rates of

0.5 mL/min, and the column efﬂuent was monitored at

215 and 254 nm, referenced against a 360-nm wavelength.

MPLC puriﬁcation was performed on a CombiFlash Rf

200 (Teledyne Isco), at 5–200 mL/min, 200 psi (with auto-

matic injection valve), using RediSep Rf Silica columns

(Teledyne Isco), with the eluents indicated. Flash column

chromatography was performed on silica gel (Merck

Kieselgel 60, 230–400 mesh ASTM), using the eluents

indicated. Thin-layer chromatography (TLC) on silica gel

was carried out on 5 × 20-cm plates with 0.25-mm layer

thickness; when necessary they were developed with

iodine and KMnO₄. Anhydrous Na₂SO₄was used as the

drying agent for the organic phases. No commercially

available reagent (Sigma Aldrich, Alfa Aesar) was puriﬁed

prior to use. Analytical grade solvents [petroleum ether (b.

p. 40–60°C), EtOAc, diisopropyl ether, acetone, diethyl

ether, dichloromethane (DCM), methanol (MeOH), and

ethanol 96% v/v] were used without further puriﬁcation.

When needed, solvents were dried on 4-Å molecular

sieves. THF was distilled from Na and benzophenone un-

der N₂immediately prior to use. Reactions were performed

in ﬂame-dried or oven-dried glassware under positive dry

nitrogen pressure. The Arachno parallel synthesis platform

was purchased from FALC (https://www.falcinstruments.

it/en/).

CONCLUSIONS

We have recently demonstrated that the regio-

substituted hydroxytriazole scaffold is an effective

bioisosteric scaffold with a wide range of applications for

drug design [4,6,9]. We herein describe a variety of

optimized strategies for the preparation of regio-

substituted hydroxytriazole derivatives that can be used

as useful building blocks. The regioselective N(b)-

substitution

of

4-benzyloxy-5-ethoxycarbonyl-1,2,3-

triazole with alkyl/aryl halides in the presence of either

NaH or t-BuOK in dry THF produced N(b)-substituted-4-

benzyloxy-5-ethoxycarbonyl-1,2,3-triazoles as the major

products in good to excellent regioselectivity. NMR

spectroscopy and mass spectrometry were used to

conﬁrm the chemical structures of bexyloxy/hydroxy

triazole derivatives that are substituted on either N(a),

N(b), or N(c) and their tautomeric forms in solution. The

availability of the current synthetic route to the individual

isomers facilitates the rational use of hydroxy-1,2,3-

triazole based building blocks in future bioisosteric

applications.

EXPERIMENTAL

General information.

Melting points (m.p.) were

measured on capillary apparatus (Büchi 540). Final m.p.

determination was achieved by placing the sample in a

bath at a temperature 10°C below the m.p. and applying a

heating rate of 2°C min^À1. All compounds were routinely

1

checked using H-NMR and ¹³C-NMR (Bruker Avance

300 and JEOL ECZR600) and mass spectrometry

(Finnigan-Mat TSQ-700, 70 eV, direct inlet). The

following abbreviations are used for coupling patterns:

br = broad, s = singlet, d = doublet, dd = doublet of

doublets, t = triplet, q = quartet, m = multiplet. Chemical

shifts (δ) are given in parts per million (ppm).

The chemical shifts marked with an asterisk are

General procedure for preparation of N(a) triazole salts 1–

6d. A solution of diazodiethyl malonate [31] (5 mmol),

and the desired amine (3 eq or more), in toluene (or, for

volatile amines, a commercially available solution of the

amine), was stirred at room temperature for about 48 h.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

S. Sainas, A. C. Pippione, A. Giraudo, K. Martina, F. Bosca, B. Rolando, A. Barge,

A. Ducime, A. Federico, S. J. Grossert, R. L. White, D. Boschi, and M. L. Lolli

Vol 000

iPr₂O was added to the resulting suspension, and the

solid was collected by ﬁltration and well washed with

iPr₂O to afford the corresponding 1-alky-lH-1,2,3-triazol-

5-ol alkylammonium salt as a white solid.

1-Methyl-5-hydroxy-4-ethoxycarbonyl-1H-1,2,3-triazole

methylammonium salt (1d). MeNH₂33% w/w (20 eq), in

3.75 (2H, d, J = 7.3 Hz, -NCH₂-), 4.27 (2H, q,

J = 7.1 Hz, -OCH₂CH₃), 4.94 (3H, br s, -NH⁺₃);

¹³C-NMR (75 MHz, CD₃OD): δ 14.0 (-OCH₂CH₃), 20.1,

20.3 (2 x -CH (CH₃)₂), 28.1, 29.8 (2 x -CH (CH₃)₂), 47.7

(-CH₂NH⁺₃), 51.8 (g), 60.2 (-OCH₂CH₃), 119.0 (d), 161.0

(e), 164.9 (h). ESI-HRMS (m/z) [M + H]⁺calcd for

absolute ethanol, was used as reactant and solvent. The

reaction mixture was stirred for 2 h at room temperature.

C₉H₁₆N₃O₃214.1186, obsd. 214.1184.

1-(Cyclopropylmethyl)-5-hydroxy-4-ethoxycarbonyl-1H-

1,2,3-triazole cyclopropylmethylammonium salt (4d). White

1

White solid (m.p. 191.9–192.7°C). Yield 79%. H-NMR

(300 MHz, CD₃OD): δ 1.33 (3H, t, J = 7.1 Hz,

-OCH₂CH₃), 2.56 (3H, s, CH₃NH⁺₃), 3.56 (3H, s,

-NCH₃), 4.26 (2H, q, J = 7.1 Hz, -OCH₂CH₃), 4.90 (3H,

br s, -NH⁺₃); ¹³C-NMR (75 MHz, CD₃OD): δ 14.9

(-OCH₂CH₃), 25.4 (-CH₃NH⁺₃), 30.6 (g), 60.2

(-OCH₂CH₃), 119.0 (d), 161.1 (e), 164.7 (h). IR (KBr) ν

(cm^À1): 2978, 2881, 2784, 2619, 2511, 2151 (w), 1714,

1698, 1563, 1470, 1310, 1185, 1159; ESI-HRMS (m/z)

[M + H]⁺calcd for C₆H₁₀N₃O₃172, 0717, obsd. 172.0698.

On this occasion, the free hydroxytriazole form was

isolated and characterized: ethyl 5-hydroxy-1-methyl-1H-

1,2,3-triazole-4-carboxylate (1). The methylammonium

salt 1d (100 mg) was suspended in EtOAc (10 mL); the

suspension was treated with 0.5 M HCl (10 mL); the

organic layer was separated, dried, and evaporated under

reduced pressure to afford the desired compound as a

white solid (m.p. 102.0–104.2°C). Quantitative yield.

¹H-NMR (300 MHz, DMSO): δ 1.28 (3H, t, J = 7.1 Hz,

-CH₂CH₃), 3.73 (3H, s, -NCH₃), 4.26 (2H, q, J = 7.1 Hz,

solid (m.p. 153.9–154.8°C). Yield 54%. ¹H-NMR

(300 MHz, CD₃OD):

δ

0.30–0.44 (4H, m,

-CH₂CH(CH₂)₂), 0.44–0.74 (4H, m, -CH₂CH(CH₂)₂),

0.98–1.16 (1H, m, -CH₂CH(CH₂)₂), 1.21–1.42 (4H, m

and t overlapped, -CH₂CH(CH₂)₂and -OCH₂CH₃), 2.81

(2H, d, J = 7.5 Hz, -CH₂NH⁺₃), 3.81 (2H, d, J = 7.0 Hz,

-NCH₂-), 4.27 (2H, q, J = 7.1 Hz, -OCH₂CH₃), 4.93 (3H,

br s, -NH⁺₃); ¹³C-NMR (75 MHz, CD₃OD): δ 4.1, 4.38

(-CH₂CH(CH₂)₂), 9.6, 11.9 (-CH₂CH(CH₂)₂), 15.0

(-OCH₂CH₃), 45.7 (-CH₂NH⁺₃), 48.9 (g), 60.2

(-OCH₂CH₃), 119.0 (d), 160.8 (e), 165.0 (h). ESI-HRMS

(m/z) [M + H]⁺calcd for C₉H₁₄N₃O₃212.1030, obsd.

212.1027.

1-(Cyclohexylmethyl)-5-hydroxy-4-ethoxycarbonyl-1H-1,2,3-

triazole cyclohexhylmethylammonium salt (5d). White solid

(m.p. 112.1–113.8°C). Yield 17%. H-NMR (300 MHz,

1

CD₃OD): δ 0.85–1.44 (13H, m and t overlapped, -

CH₂C₆H₁₁), 1.50–1.99 (12H, m, -CH₂C₆H₁₁), 2.78 (2H,

d, J = 7.0 Hz, -CH₂NH₃⁺), 3.77 (2H, d, J = 7.2 Hz,

NCH₂-), 4.27 (2H, q, J = 7.1 Hz, -OCH₂CH₃), 4.92 (3H,

br s, -NH⁺₃); ¹³C-NMR (75 MHz, CD₃OD): δ 14.9

(-OCH₂CH₃), 26.6, 26.9, 27.1, 27.5, 31.3, 31.7, 37.3,

39.1 (-CH₂C₆H₁₁), 46.4 (-CH₂NH⁺₃), 50.6 (g), 60.2

(-OCH₂CH₃), 119.0 (d), 161.1 (e), 164.8 (h). ESI-HRMS

(m/z) [M À H]^Àcalcd for C₁₂H₁₈N₃O₃252.1354, obsd.

-CH₂CH₃); ¹³C-NMR (75 MHz, DMSO):

δ 14.2

(-CH₂CH₃), 31.9 (g), 59.7 (-CH₂CH₃), 119.1 (C (d)),

152.1 (C (h)), 160.6 (C (e)); MS (CI) 172 (M + 1); IR

(KBr) ν (cm^À1): 2980, 1718, 1598, 1508, 1475, 1383,

1230, 1158, 1061; ESI-HRMS (m/z) [M + H]⁺calcd for

C₆H₁₀N₃O₃172.0717, obsd. 172.0712.

1-Ethyl-5-hydroxy-4-ethoxycarbonyl-1H-1,2,3-triazole

ethylammonium salt (2d). The reaction was carried out in a

252.1356.

1-Benzyl-5-hydroxy-4-ethoxycarbonyl-1H-1,2,3-triazole

benzylammonium salt (6d).

White solid (m.p. 146.8–

sealed tube using 2.0 M ethylamine in THF (20 eq), and by

stirring the reaction mixture for 4 days at room

temperature. White solid (m.p. 131.0–132.6°C). Yield

148.4°C). Yield 78%. ¹H-NMR (300 MHz, DMSO): δ

1.22 (3H, t, J = 6.6 Hz, -OCH₂CH₃), 4.00 (2H, s,

-CH₂NH⁺₃), 4.11 (2H, q, J = 6.6 Hz, -OCH₂CH₃), 4.95

(2H, s, -NCH₂-), 7.17–7.44 (10H, m, aromatic protons),

8.50 (3H, br s, -NH₃⁺); ¹³C-NMR (75 MHz, DMSO): δ

14.7 (-OCH₂CH₃), 42.4(-CH₂NH⁺₃), 45.6 (g) 57.5

(-OCH₂CH₃), 115.9 (d), 126.8, 127.1, 128.1, 128.4,

128.7, 134.4 and 138.5 (C ipso), 159.7 (e), 162.8 (h); MS

(CI) m/z: 248 (M + H); IR (KBr) ν (cm-1): 2980, 1694,

1567, 1448, 1261, 1166. ESI-HRMS (m/z) [M + H]⁺

calcd for C₁₂H₁₄N₃O₃248.1030, obsd. 248.1031.

1

32%. H-NMR (300 MHz, CD₃OD): δ 1.20–1.42 (9H, m,

3 x -CH₂CH₃), 2.99 (2H, q, J = 7.3 Hz, -CH₂NH⁺₃), 3.99

(2H, q, J = 7.2 Hz, -NCH₂-), 4.27 (2H, q, J = 7.1 Hz,

-OCH₂CH₃), 4.90 (3H, br s, -NH⁺₃); ¹³C-NMR (75 MHz,

CD₃OD): δ 12.9, 14.9, 15.1 (3 x CH₃), 36.0 (-CH₂NH⁺₃),

39.6 (g), 60.2 (-OCH₂CH₃), 119.2 (d), 160.4 (e), 164.8

(h). ESI-HRMS (m/z) [M + H]⁺calcd for C₇H₁₂N₃O₃

186.0873 obsd. 186.0870.

1-(2-Methylpropyl)-5-hydroxy-4-ethoxycarbonyl-1H-1,2,3-

triazole 2-methylpropylammonium salt (3d). White solid (m.

The free hydroxytriazole form was isolated and

characterized: ethyl 1-benzyl-5-hydroxy-1H-1,2,3-triazole-

4-carboxylate (16a). The benzylammonium salt 6d

(100 mg) was suspended in EtOAc (10 mL); the

suspension was treated with 0.5 M HCl (10 mL), and the

organic layer was separated, dried, and evaporated under

p. 140.7–143.0°C). Yield 76%. ¹H-NMR (300 MHz,

CD₃OD): δ 0.92 (6H, d, J = 6.7 Hz, -CH (CH₃)₂), 1.00

(6H, d, J = 6.7 Hz, -CH (CH₃)₂), 1.34 (3H, t, J = 7.1 Hz,

-OCH₂CH₃), 1.94 (1H, m, -CH₂CH(CH₃)₂), 2.18 (1H, m,

-CH₂CH(CH₃)₂), 2.78 (2H, d, J = 7.1 Hz, -CH₂NH⁺₃),

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2018

Hydroxytriazoles are Useful Tools in Bioisosteric Replacement of Acidic Functions: Strategies

for the Preparation of a Library of Protected Hydroxytriazole Building Blocks are Described

reduced pressure to afford the desired compound as a white

solid. Quantitative yield. ¹H-NMR, ¹³C-NMR, IR, and MS

spectra overlap with the spectra of 16a, obtained using the

azide methodology: diethyl malonate (1.71 mL,

11.3 mmol) was added to a stirred solution of sodium

(259 mg, 11.3 mmol), in ethanol (25 mL). After 20 min,

a freshly prepared solution of benzyl azide (1.00 g,

7.52 mmol), in ethanol (2 mL), was added dropwise

under stirring. The resulting mixture was reﬂuxed for 5 h.

After cooling, the mixture was concentrated in vacuo and

then diluted with water (20 mL). Acidiﬁcation to pH 2,

by adding dilute hydrochloric acid, afforded a crystalline

precipitate; this was isolated by ﬁltration, washed with

water, and dried in vacuo. Recrystallization by addition

of petroleum ether to a saturated solution of crude in

chloroform afforded compound 16a as a white solid (m.p.

101.8–102.9°C). Yield 70%. ¹H-NMR (300 MHz,

CDCl₃): δ 1.33 (3H, t, J = 7.2 Hz, -CH₂CH₃), 4.35 (2H,

q, J = 7.2 Hz, -CH₂CH₃), 5.36 (2H, s, -NCH₂-), 7.27–

7.38 (5H, m, aromatic protons), 8.91 (1H, br s, -OH);

¹³C-NMR (75 MHz, CDCl₃): δ 14.2 (-CH₂CH₃), 49.9

(g), 61.4 (-OCH₂CH₃), 119.1 (d), 128.4, 128.5, 128.9,

134.1 (C ipso), 153.8 (e), 163.2 (h); MS (CI) m/z: 248

(M + H); IR (KBr) ν (cm^À1): 2987, 1700, 1603, 1424,

1189; ESI-HRMS (m/z) [M + H]⁺calcd for C₁₂H₁₄N₃O₃

248.1030, obsd. 248.1030.

aromatic protons); ¹³C-NMR (75 MHz, CDCl₃): δ 14.5,

14.7 (-OCH₂CH₃and NCH₂CH₃), 41.7 (g), 61.3 (-

OCH₂CH₃), 77.7 (f), 124.3 (d), 129.0, 129.1, 129.4,

135.0 (C ipso), 152.2 (e), 161.2 (h). ESI-HRMS (m/z)

[M + H]⁺calcd for C₁₄H₁₈N₃O₃276.1343, obsd.

276.1339.

Ethyl

5-benzyloxy-1-(2-methylpropyl)-1H-1,2,3-triazole-4-

carboxylate (3a).

Colorless oil. Yield: 70%. Flash

chromatography eluent: petroleum ether/EtOAc 85/15 v/

v. ¹H-NMR (300 MHz, CDCl₃): δ 0.83 (6H, d,

J = 6.7 Hz, -CH₂CH(CH₃)₂), 1.44 (3H, t, J = 7.1 Hz, -

OCH₂CH₃), 2.26–1.92 (1H, m, -CH₂CH(CH₃)₂), 3.77

(2H, d, J = 7.3 Hz, -CH₂CH(CH₃)₂), 4.45 (2H, q,

J = 7.1 Hz, -OCH₂CH₃), 5.54 (2H, s, -OCH₂-), 7.36–7.38

(5H, m, aromatic protons); ¹³C-NMR (75 MHz, CDCl₃):

δ 14.7 (-OCH₂CH₃), 19.8 (-CH₂CH(CH₃)₂), 28.6 (-

CH₂CH(CH₃)₂), 53.5 (g), 61.3 (-OCH₂CH₃), 77.6 (f),

123.9 (d), 128.9, 128.9, 129.3, 135.0 (C ipso), 152.7 (e)

161.2 (h). ESI-HRMS (m/z) [M + H]⁺calcd for

C₁₆H₂₂N₃O₃304.1656, obsd. 304.1652.

Ethyl 5-benzyloxy-1-cyclopropylmethyl-1H-1,2,3-triazole-4-

carboxylate (4a).

Colorless oil. Yield: 61%. Flash

chromatography eluent: petroleum ether/EtOAc 85/15 v/

v. ¹H-NMR (300 MHz, CDCl₃): δ 0.29 (2H, q,

J = 5.2 Hz, -CH₂CH(CH₂)₂) 0.50 (2H, q, J = 6.1 Hz, -

CH₂CH(CH₂)₂), 1.44 (3H, t, J = 7.1 Hz, -OCH₂CH₃),

1.61–1.47 (1H, m, -CH₂CH(CH₂)₂), 3.83 (2H, d,

J = 7.3 Hz, -CH₂CH(CH₂)₂), 4.45 (2H, q, J = 7.1 Hz, -

OCH₂CH₃), 5.55 (2H, s, -OCH₂-), 7.33–7.39 (5H, m,

aromatic protons); ¹³C-NMR (75 MHz, CDCl₃): δ 4.6 (-

CH₂CH(CH₂)₂, 11.2 (-CH₂CH(CH₂)₂, 14.9 (-OCH₂CH₃),

51.8 (g), 61.7 (-OCH₂CH₃), 78.1 (f), 124.5 (d), 128.9,

129.0, 129.3, 135.4 (C ipso), 152.8 (e), 161.7 (h). ESI-

HRMS (m/z) [M + H]⁺calcd for C₁₆H₂₀N₃O₃302.1499,

obsd. 302.1497.

General procedure for preparation of N(a) 1a–6a

isomers. Cs₂CO₃(4.4 eq) and benzyl bromide (4.4 eq)

were added to a solution of the salt (compounds 1–5d,

5 mmol) in dry DMF. The resulting mixture was stirred

at room temperature for a few hours, and the reaction

progress was periodically checked by TLC. The reaction

mixture was poured into water and extracted twice with

diethyl ether. The organic layers were collected, dried,

and concentrated under reduced pressure. The crude

material was puriﬁed by ﬂash chromatography to afford

the title compound.

Ethyl

5-benzyloxy-1-cyclohexylmethyl-1H-5-hydroxy-1H-

1,2,3-triazole-4-carboxylate (5a).

Colorless oil. Yield:

57%. Flash chromatography eluent: petroleum

1

Ethyl

5-benzyloxy-1-methyl-1,2,3-triazole-4-carboxylate

ether/EtOAc 85/15 v/v. H-NMR (300 MHz, CDCl₃): δ

0.72–1.18 (5H, m, -NCH₂C₆H₁₁), 1.39–1.79 (9H, m, -

OCH₂CH₃and -NCH₂C₆H₁₁), 3.79 (2H, d, J = 7.3 Hz, -

NCH₂C₆H₁₁), 4.46 (2H, q, J = 7.1 Hz, -OCH₂CH₃), 5.54

(2H, s, -OCH₂-), 7.33–7.39 (5H, m, aromatic protons);

¹³C-NMR (75 MHz, CDCl₃): δ 14.5 (-OCH₂CH₃), 25.5,

26.1, 30.4, 37.8 (-NCH₂C₆H₁₁), 52.4 (g), 61.3 (-

OCH₂CH₃), 77.6 (f), 123.9 (d), 129.2, 129.3, 129.6, 135.1

(C ipso), 152.8 (e), 161.3 (h). ESI-HRMS (m/z) [M + H]⁺

(1a). Colorless oil. Yield: 63%. Flash chromatography

eluent: petroleum ether/EtOAc 80/20 v/v. ¹H-NMR

(300 MHz, CDCl₃): δ 1.45 (3H, t, J = 7.1 Hz, -

OCH₂CH₃), 3.62 (3H, s, -NCH₃), 4.47 (2H, q,

J = 7.1 Hz, -OCH₂CH₃), 5.55 (2H, s, -OCH₂-), 7.33–7.42

(5H, m, aromatic protons); ¹³C-NMR (75 MHz, CDCl₃):

δ 14.5 (-OCH₂CH₃), 32.9 (g), 61.4 (-OCH₂CH₃), 77.7

(f), 124.6 (d), 129.3, 129.4, 129.8, 135.3 (C ipso), 152.7

(e), 161.1 (h).

calcd for C₁₉H₂₆N₃O₃344.1969, obsd. 344.1965.

Ethyl 1-benzyl-5-benzyloxy-1H-1,2,3-triazole-4-carboxylate

(6a). K₂CO₃was used instead Cs₂CO₃for this reaction.

Ethyl

5-benzyloxy-1-ethyl-1H-1,2,3-triazole-4-carboxylate

(2a). Colorless oil. Yield: 47%. Flash chromatography

eluent: petroleum ether/EtOAc 80/20 v/v. ¹H-NMR

(300 MHz, CDCl₃): δ 1.27 (3H, t, J = 7.3 Hz, -

NCH₂CH₃), 1.44 (3H, t, J = 7.1 Hz, -OCH₂CH₃), 4.00

(2H, q, J = 7.3 Hz, -NCH₂CH₃), 4.45 (2H, q, J = 7.1 Hz,

-OCH₂CH₃), 5.54 (2H, s, -OCH₂-), 7.41–7.29 (5H, m,

Colorless oil. Yield 83%. Flash chromatography eluent:

1

petroleum ether/EtOAc 70/30 v/v. H-NMR (300 MHz,

CDCl₃): δ 1.35 (3H, t, J = 7.1 Hz, -CH₂CH₃), 4.37 (2H,

q, J = 7.1 Hz, -CH₂CH₃), 5.12 (2H, s, -NCH₂-), 5.32

(2H, s, -OCH₂-), 7.07–7.26 (10H, m, aromatic protons);

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

S. Sainas, A. C. Pippione, A. Giraudo, K. Martina, F. Bosca, B. Rolando, A. Barge,

A. Ducime, A. Federico, S. J. Grossert, R. L. White, D. Boschi, and M. L. Lolli

Vol 000

¹³C-NMR (75 MHz, CDCl₃): δ 14.4 (-CH₂CH₃), 50.4 (g),

61.3 (-CH₂CH₃), 77.5 (f), 124.2 (d), 127.9, 128.5, 128.8,

128.9 (2C arom overlapped), 129.2, 134.4 (C ipso -

NCH₂Ph), 134.8 (C ipso -OCH₂Ph), 152.5 (e), 161.0 (h);

MS (CI) 338 (M + H); ESI-HRMS (m/z) [M + H]⁺calcd

for C₁₉H₂₀N₃O₃338.1499, obsd. 338.1452.

MS (CI) m/z: 368 (M + H); ESI-HRMS (m/z) [M + H]⁺

calcd for C₂₀H₂₂N₃O₄368.1605, obsd. 368.1598.

In analogy with earlier results [32], the alkylation of 17a

afforded the desired compound 7a together with a

by-product. The by-product eluted with a more polar

eluent (DCM/MeOH 95/5 v/v) and was structurally

characterized using heteronuclear 2D-NMR (HSQC and

HMBC, Data S1), that allowed its identiﬁcation as 3-

benzyl-4-(ethoxycarbonyl)-1-(4-methoxybenzyl)-1H-1,2,3-

triazol-3-ium-5-olate (23). ¹H-NMR (300 MHz, DMSO): δ

1.18 (3H, t, J = 6.9 Hz, -CH₂CH₃), 2.73 (3H, s, -CH₃

DMF), 2.89 (3H, s, -CH₃DMF). 3.74 (3H, s, -OCH₃),

4.19 (2H, q, J = 6.9 Hz, -CH₂CH₃), 5.17 (2H, s, -

NCH₂PhOCH₃), 5.79 (2H, s, -NCH₂Ph), 6.92 (2H, d,

J = 15.6 Hz, aromatic protons), 7.23–7.40 (7H, m,

aromatic protons), 7.96 (1H, s, -CHO DMF). ¹³C-NMR

(75 MHz, DMSO): δ 14.2 (-CH₂CH₃), 30.8 (-CH₃DMF),

35.8 (-CH₃DMF), 46.8 (-CH₂PhOCH₃), 55.1 (-OCH₃),

56.3 (-CH₂Ph), 60.0 (-CH₂CH₃), 107.3 (C (d)), 114.1,

127.4 (C ipso -PhOCH₃), 127.5, 128.4, 128.7, 129.5,

134.3 (C ipso -Ph), 155.3 (C (e)), 158.5 (C(h)), 159.0,

Ethyl

5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-

carboxylate (17a). The title compound was synthesized

according to the azide methodology (see compound 16a).

White solid (m. p. 112.0–112.8°C from chloroform-

petroleum ether). Yield 71%. ¹H-NMR (300 MHz,

DMSO): δ 1.27 (3H, t, J = 7.1 Hz, -CH₂CH₃), 3.73 (3H,

s, -OCH₃), 4.26 (2H, q, J = 7.1 Hz, -CH₂CH₃), 5.26 (2H,

s, -NCH₂-), 6.92–7.21 (4H, m, aromatic protons); ¹³C-

NMR (75 MHz, DMSO): δ 14.2 (-CH₂CH₃), 47.9 (g),

55.0 (-OCH₃), 59.6 (-CH₂CH₃), 113.8, 119.2 (d), 127.4

(C ipso), 129.0, 151.8 (e), 158.8, 160.5 (h); MS (CI) m/z:

278 (M + H); IR (KBr) ν (cm^À1): 2958, 1696, 1609,

1512, 1424, 1248, 1124; ESI-HRMS (m/z) [M + H]⁺

calcd for C₁₃H₁₆N₃O₄278.1135, obsd. 278.1129.

Ethyl 5-hydroxy-1-(3,4-dimethoxybenzyl)-1H-1,2,3-triazole-

4-carboxylate (18a). The title compound was synthesized

162.3 (-CHO (DMF)); MS (CI) m/z: 368 (M + H).

Ethyl 5-benzyloxy-1-(3,4-dimethoxybenzyl)-1H-1,2,3-triazole-

according to the azide methodology (see compound 16a).

However, after the acidiﬁcation of the quenched reaction

mixture to pH 4, via the addition of 6 M HCl, the

resulting solution was extracted twice with DCM. The

combined organic layer was washed with brine, dried

with MgSO₄, and concentrated under reduced pressure.

The resulting crude material was puriﬁed by ﬂash

chromatography (eluent: petroleum ether/EtOAc 95/5 v/v)

to afford 18a as a pale orange solid (m.p. 90.6–93.2°C).

4-carboxylate (8a).

Obtained as 6a, starting from 18a.

Flash chromatography eluent: petroleum ether/EtOAc

70/30 v/v. Colorless oil, yield 36%.

Compound 8a was also obtained, but in a higher yield

(86%), from azide 15 using a modiﬁed procedure that

avoided the isolation of 18a under acidic conditions:

diethyl malonate (4.48 g, 28.5 mmol) was added to a

stirred solution of sodium (650 mg, 28.5 mmol), in

ethanol (100 mL). After 1 h, a freshly prepared solution of

3,4-dimethoxybenzyl azide (5 g, 25.9 mmol), in ethanol

(5 mL), was added dropwise under stirring. The resulting

mixture was reﬂuxed overnight. After cooling the mixture

to rt, 7.16 g (51.8 mmol) of K₂CO₃and 6.16 mL

(51.8 mmol) of benzyl bromide were added, and the

mixture was stirred at rt overnight. The solvent was

evaporated under reduced pressure; the residue was taken

with EtOAc (50 mL), and the resulting solution was

washed ﬁrst with 2 M HCl (30 mL) and then with 2 M

NaOH (30 mL). The organic phase was dried and

concentrated under reduced pressure, giving a colorless

oil. This latter was puriﬁed by ﬂash chromatography

(eluent: petroleum ether/EtOAc 70/30 v/v), to obtain 8a

1

Yield 69%. H-NMR (300 MHz, DMSO): δ 1.23 (3H, t,

J = 7.1 Hz, -CH₂CH₃), 3.72–3.68 (6H, m, -OCH₃), 4.16

(2H, q, J = 7.0 Hz, -CH₂CH₃), 5.02 (2H, s, -NCH₂-),

6.97–6.64 (3H, m, aromatic protons); ¹³C-NMR

(75 MHz, DMSO): δ 14.4 (-OCH₂CH₃), 47.2 (g), 55.8,

55.9 (-OCH₃), 59.3 (-OCH₂CH₃), 111.9, 112.1, 117.9

(d), 120.2, 130.0, 148.6, 149.0, 151.1 (e), 162.8 (h). ESI-

HRMS (m/z) [M À H]^Àcalcd for C₁₄H₁₆N₃O₅306.1096,

obsd. 306.1100.

Ethyl 5-(benzyloxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-

4-carboxylate (7a).

Obtained as 6a, starting from 17a.

Flash chromatography eluent: petroleum ether/EtOAc

70/30 v/v. Colorless oil, yield 55%. The structure was

determined unequivocally using heteronuclear 2D-NMR

(HSQC and HMBC, Data S1). ¹H-NMR (300 MHz,

CDCl₃): δ 1.43 (3H, t, J = 7.2 Hz, -CH₂CH₃), 3.76 (3H,

s, -OCH₃), 4.45 (2H, q, J = 7.2 Hz, -CH₂CH₃), 5.14 (2H,

s, -NCH₂-), 5.41 (2H, s, -OCH₂Ph), 6.81–7.13 (4H, m,

aromatic protons), 7.28–7.36 (5H, m, aromatic protons);

¹³C-NMR (75 MHz, CDCl₃): δ 14.4 (-OCH₂CH₃), 49.9

(g), 55.3 (-OCH₃), 61.2 (-OCH₂CH₃), 77.5 (f), 114.2,

124.1 (d), 126.4 (C ipso -PhOCH₃), 128.7, 128.9, 129.1,

129.4, 134.8 (C ipso -Ph), 152.3 (e), 159.6, 161.0 (h);

1

(colorless oil). Yield 86%. H-NMR (300 MHz, CDCl₃):

δ 1.52–1.31 (3H, m, -OCH₂CH₃), 3.74 (3H, s, -OCH₃),

3.86 (3H, s, -OCH₃), 4.45 (2H, q, J = 7.1 Hz,

-OCH₂CH₃), 5.16 (2H, s, -NCH₂-), 5.42 (2H, s,

-OCH₂Ph), 6.78–6.67 (3H, m, aromatic protons), 7.39–

7.21 (5H, m, aromatic protons); ¹³C-NMR (75 MHz,

CDCl₃): δ 14.4, (-OCH₂CH₃), 50.4 (g), 55.8, 55.9

(-OCH₃), 61.3 (-OCH₂CH₃), 77.5 (f), 110.9, 111.0, 120.5,

124.8 (d), 126.7, 128.7, 128.8, 129.1, 134.8 (C ipso -Ph),

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2018

Hydroxytriazoles are Useful Tools in Bioisosteric Replacement of Acidic Functions: Strategies

for the Preparation of a Library of Protected Hydroxytriazole Building Blocks are Described

149.1, 149.2, 152.4 (e), 161.0 (h). ESI-HRMS (m/z)

(-OCH₂CH₃), 72.7 (f), 124.3 (d), 128.5, 128.9, 129.2,

137.4 (C ipso), 160.6 (h), 161.6 (e); MS (CI) m/z: 262

(M + H); IR (KBr) ν (cm^À1): 2996, 1723, 1545, 1465,

1368, 1286, 1152; ESI-HRMS (m/z) [M + H] + calcd for

[M + H]⁺calcd for C₂₁H₂₄N₃O₅398.1711, obsd. 398.1707.

5-(Benzyloxy)-1H-1,2,3-triazole-4-carboxylate (19).

A

solution of cerium ammonium nitrate (17.9 g,

32.7 mmol), in 50 mL of water, was added dropwise to a

solution of 7a (5 g, 13.6 mmol), in 50 mL of CH₃CN.

The mixture was vigorously stirred at room temperature

for 12 h and then evaporated under reduced pressure. The

residue was diluted with 0.5 M HCl. The resulting

solution was extracted with EtOAc (3 × 50 mL), and the

combined organic layer was washed with brine, dried,

and concentrated under reduced pressure. The subsequent

ﬂash chromatography (eluent: DCM/EtOAc 90/10 v/v)

yielded a mixture of the desired compound and 4-

methoxybenzoic acid. The mixture was dissolved in

100 mL of DCM, and 1.5 eq of Amberlyst A21 free base

resin were added; the resulting mixture was stirred for

30 min and ﬁltered (this step was repeated ﬁve times).

The combined organic layer was evaporated under

reduced pressure to yield compound 19 as a white solid

(m.p. 92.8–93.5°C). Yield 71%. ¹H-NMR (300 MHz,

DMSO): δ 1.23 (3H, t, J = 7.1 Hz, -OCH₂CH₃), 4.22

(2H, q, J = 7.1 Hz, -OCH₂CH₃), 5.29 (2H, s, -OCH₂-),

7.23–7.50 (5H, m, aromatic protons); ¹³C-NMR

C₁₃H₁₆N₃O₃262.1186, obsd. 262.1192.

Ethyl 5-(benzyloxy)-2-ethyl-2H-1,2,3-triazole-4-carboxylate

(2b).

Colorless oil. Yield 69%. ¹H-NMR (300 MHz,

CDCl₃): δ 1.28 (3H, t, J = 7.1 Hz, -CH₂CH₃), 1.42 (3H, t,

J = 7.3 Hz, -NCH₂CH₃), 4.30 (2H, q, J = 7.3 Hz,

-CH₂CH₃), 4.61 (2H, q, J = 7.1 Hz, -NCH₂CH₃), 5.25

(2H, s, -OCH₂-), 7.21–7.39 (5H, m, aromatic protons);

¹³C-NMR (75 MHz, CDCl₃): δ 14.4* (-NCH₂CH₃), 14.6*

(-OCH₂CH₃), 51.1 (g), 61.0 (-OCH₂CH₃), 72.2 (f), 123.5

(d), 127.7, 128.2, 128.5, 136.1 (C ipso), 160.5* (h),

160.7* (e); MS (CI) m/z: 276 (M + H); ESI-HRMS (m/z)

[M + H]⁺calcd for C₁₄H₁₈N₃O₃276.1343, obsd. 276.1335.

Ethyl 5-(benzyloxy)-2-(cyclohexylmethyl)-2H-1,2,3-triazole-

4-carboxylate (5b).

The mixture was stirred at 50°C

overnight in order to complete the reaction. Colorless oil.

Yield 56%. ¹H-NMR (300 MHz, CDCl₃): δ 0.91–1.29

(5H, m, -NCH₂C₆H₁₁), 1.39 (3H, t, J = 7.1 Hz,

-CH₂CH₃), 1.53–1.73 (5H, m, -NCH₂C₆H₁₁), 2.00 (1H,

m, -NCH₂C₆H₁₁), 4.12 (2H, d,

J

=

7.5 Hz,

-NCH₂C₆H₁₁), 4.40 (2H, q, J = 7.1 Hz, -CH₂CH₃), 5.36

(2H, s, -OCH₂-), 7.31–7.49 (5H, m, aromatic protons);

¹³C-NMR (75 MHz, CDCl₃): δ 14.5 (-OCH₂CH₃), 25.6,

26.2, 30.4, 38.4 (4 x -NCH₂C₆H₁₁), 61.1 (-OCH₂CH₃),

62.0 (g), 72.3 (f), 123.5 (d), 127.8, 128.2, 128.5, 136.1

(C ipso), 160.62* (e), 160.64* (h); MS (CI) m/z: 344

(75 MHz, DMSO):

δ

14.1 (-OCH₂CH₃), 60.2

(-OCH₂CH₃), 71.5 (f), 122.7 (d), 127.6, 128.0, 128.3,

136.2 (C ipso), 156.9* (e), 160.0* (h). MS (CI) m/z: 248

(M + H); IR (KBr) ν (cm^À1): 3190, 1682, 1547, 1455,

1371, 1137. ESI-HRMS (m/z) [M + H]⁺calcd for

C₁₂H₁₄N₃O₃248.1030, obsd. 248.1027.

(M + H); ESI-HRMS (m/z) [M + H]⁺calcd for

C₁₉H₂₆N₃O₃344.1969, obsd. 344.1967.

General selective procedure for preparation of N(b)

triazoles. NaH (1.2 mmol) was added to a solution of

Ethyl 2-benzyl-5-(benzyloxy)-2H-1,2,3-triazole-4-carboxylate

(6b).

Colorless oil. Yield 75%. The structure was

19 (1.00 mmol), in dry THF (8 mL). The resulting

mixture was stirred at room temperature for 5 min under

inert atmosphere. Then, the selected alkylating agent

(6.00 or 2.5 mmol, Table 1) was added, and the mixture

was stirred at room temperature overnight. When the

reaction was complete, the mixture was poured into 1 M

HCl (30 mL) and extracted with EtOAc (3 × 50 mL).

The combined organic layer was washed with brine,

dried with Na₂SO₄, and concentrated under reduced

pressure. The resulting crude material was puriﬁed by

ﬂash chromatography (eluent: petroleum ether/EtOAc

90/10 v/v) to afford the title compound.

determined unequivocally using heteronuclear 2D-NMR

(HSQC and HMBC, Data S1). ¹H-NMR (300 MHz,

CDCl₃): δ 1.38 (3H, t, J = 7.2 Hz, -CH₂CH₃), 4.40 (2H,

q, J = 7.2 Hz, -CH₂CH₃), 5.33 (2H, s, -OCH₂-), 5.45

(2H, s, -NCH₂-), 7.25–7.45 (10H, m, aromatic protons);

¹³C-NMR (75 MHz, CDCl₃): δ 14.3 (-OCH₂CH₃), 59.6

(g), 61.1 (-OCH₂CH₃), 72.3 (f), 124.2 (d), 127.8, 128.1,

128.2, 128.5, 128.6, 128.8, 134.5 (C ipso -NCH₂Ph),

136.0 (C ipso -OCH₂Ph), 160.5 (h), 161.0 (e); MS (CI)

m/z: 338 (M + H); ESI-HRMS (m/z) [M + H]⁺calcd for

C₁₉H₂₀N₃O₃338.1499, obsd. 338.1465.

Ethyl 5-benzyloxy-2-propyl-2H-1,2,3-triazole-4-carboxylate

(9b).

Colorless oil Yield 66%. ¹H-NMR (300 MHz,

Ethyl 5-(benzyloxy)-2-methyl-2H-1,2,3-triazole-4-carboxylate

(1b).

White solid (m. p. 51.9–56.2°C, triturated

CDCl₃): δ 0.90 (3H, t, J = 7.4 Hz, -NCH₂CH₂CH₃),

1.38 (3H, t, J = 7.1 Hz, -OCH₂CH₃), 1.88–2.03 (2H, m,

with diisopropyl ether). Yield 71%. The structure was

determined unequivocally using heteronuclear 2D-NMR

(HSQC and HMBC, Supporting Information S37 and

S38). ¹H-NMR (300 MHz, (CD₃)₂CO): δ 1.32 (3H, t,

J = 7.2 Hz, -CH₂CH₃), 4.09 (3H, s, -NCH₃), 4.30 (2H, q,

J = 7.2 Hz, -CH₂CH₃), 5.33 (2H, s, -OCH₂-), 7.34–7.52

(5H, m, aromatic protons); ¹³C-NMR (75 MHz,

-NCH₂CH₂CH₃), 4.26 (2H, t,

J

=

7.1 Hz,

-NCH₂CH₂CH₃), 4.40 (2H, q, J = 7.1 Hz, -OCH₂CH₃),

5.35 (2H, s, -OCH₂-), 7.24–7.53 (5H, m, aromatic

protons); ¹³C-NMR (75 MHz, CDCl3):

δ

11.0

(-NCH₂CH₂CH₃), 14.5 (-OCH₂CH₃), 23.0 (-NCH₂CH₂CH₃),

57.7 (-NCH₂CH₂CH₃), 61.1 (-OCH₂CH₃), 72.3 (-OCH₂-),

123.5 (d), 127.8, 128.2, 128.5, 136.2 (C ipso), 160.7 (h),

(CD₃)₂CO):

δ

14.6 (-OCH₂CH₃), 42.9 (g), 60.9

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

S. Sainas, A. C. Pippione, A. Giraudo, K. Martina, F. Bosca, B. Rolando, A. Barge,

A. Ducime, A. Federico, S. J. Grossert, R. L. White, D. Boschi, and M. L. Lolli

Vol 000

160.8 (e). ESI-HRMS (m/z) [M + H] + calcd for

C₁₅H₂₀N₃O₃290.1499, obsd. 290.1498.

compound was always found to be the alkylation product

on N(c) of the triazole ring; the second eluted compound

was alkylated on N(b).

Ethyl 4-(benzyloxy)-1-methyl-1H-1,2,3-triazole-5-carboxylate

(1c) and ethyl 5-(benzyloxy)-2-methyl-2H-1,2,3-triazole-4-

Ethyl 4-benzyloxy-2-isopropyl-2H-1,2,3-triazole-5-carboxylate

1

(10b).

Colorless oil. Yield 25%. H-NMR (600 MHz,

CDCl₃): δ 1.37 (3H, t, J = 7.1 Hz, -OCH₂CH₃), 1.52 (6H,

d, J = 6.7 Hz, -NCH (CH₃)₂), 4.38 (2H, q, J = 7.1 Hz,

-OCH₂CH₃), 4.69 (1H, hept, J = 6.7 Hz, -NCH (CH₃)₂),

5.35 (2H, s, -OCH₂-), 7.30 (1H, t, J = 7.4 Hz, aromatic

proton), 7.35 (2H, t, J = 7.4 Hz, aromatic protons), 7.47

(2H, d, J = 7.1 Hz, aromatic protons); ¹³C-NMR

(151 MHz, CDCl3): δ 14.5 (-OCH₂CH₃), 22.0 (-NCH

(CH₃)₂), 58.5 (-NCH (CH₃)₂), 61.0 (-OCH₂CH₃), 72.2

(-OCH₂-), 123.1 (d), 127.9, 128.2, 128.5, 136.3 (C ipso),

160.6 (h), 160.8 (e).

carboxylate (1b).

(1c) White solid (m. p. 75.9–79.7°C,

triturated with diisopropyl ether). Yield 42%. The structure

was determined unequivocally using heteronuclear 2D-

NMR (HSQC and HMBC). ¹H-NMR (300 MHz,

(CD₃)₂CO): δ 1.35 (3H, t, J = 7.2 Hz, -CH₂CH₃), 4.21

(3H, s, -NCH₃), 4.34 (2H, q, J = 7.2 Hz, -CH₂CH₃), 5.48

(2H, s, -OCH₂-), 7.32–7.54 (5H, m, aromatic protons);

¹³C-NMR (75 MHz, (CD₃)₂CO): δ 14.5 (-OCH₂CH₃),

39.1 (g), 61.6 (-OCH₂CH₃), 71.9 (f), 112.4 (d), 128.4,

128.8, 129.2, 137.8 (C ipso), 159.2 (h), 161.6 (e); MS (CI)

m/z: 262 (M + H); IR (KBr) ν (cm^À1): 2977, 1700, 1570,

1423, 1366, 1304, 1146; ESI-HRMS (m/z) [M + H]⁺calcd

for C₁₃H₁₆N₃O₃262.1186, obsd. 262.1188.

Ethyl

5-(benzyloxy)-2-[(4-methylphenyl)methyl]-2H-1,2,3-

triazole-4-carboxylate (11b).

Colorless oil. Yield 74%.

¹H-NMR (600 MHz, CDCl₃): δ 1.38 (3H, t, J = 7.1 Hz,

-OCH₂CH₃), 2.33 (3H, s, À CH₃), 4.39 (2H, q, J = 7.1 Hz,

-OCH₂CH₃), 5.32 (2H, s, -OCH₂-), 5.41 (2H, s, -NCH₂-),

7.10–7.28 (4H, m, aromatic protons), 7.29–7.40 (3H, m,

aromatic protons), 7.40–7.49 (2H, m, aromatic protons);

¹³C-NMR (151 MHz, CDCl₃): δ 14.5 (-OCH₂CH₃), 21.3

(-CH₃), 59.5 (g), 61.4 (-OCH₂CH₃), 72.6 (f), 124.2 (d),

127.2, 127.9, 128.2, 128.5, 129.5, 131.5, 136.1, 138.5,

160.1 (h), 161.0 (e). ESI-HRMS (m/z) [M + H]⁺calcd for

C₂₀H₂₂N₃O₃352.1655, obsd. 352.1653.

(1b) White solid. Yield 52%. H-NMR, ¹³C-NMR, IR,

and MS spectra overlap with the spectra of 1b, obtained

using the selective procedure for the preparation of N(b)

triazoles.

Ethyl 4-(benzyloxy)-1-ethyl-1H-1,2,3-triazole-5-carboxylate

(2c) and ethyl 5-(benzyloxy)-2-ethyl-2H-1,2,3-triazole-5-

1

carboxylate (2b).

(2c) Colorless oil. Yield 27%.

¹H-NMR (300 MHz, CDCl₃): δ 1.29 (3H, t, J = 7.1 Hz,

-NCH₂CH₃), 1.42 (3H, t, J = 7.2 Hz, -CH₂CH₃), 4.30

(2H, q, J = 7.2 Hz, -CH₂CH₃), 4.60 (2H, q, J = 7.1 Hz,

-NCH₂CH₃), 5.45 (2H, s, -OCH₂-), 7.24–7.43 (5H, m,

aromatic protons); ¹³C-NMR (75 MHz, CDCl₃): δ 14.3

(-OCH₂CH₃), 15.5 (-NCH₂CH₃), 47.1 (g), 61.3

(-CH₂CH₃), 71.5 (f), 111.7 (d), 127.6, 128.1, 128.5,

136.5 (C ipso), 158.7 (h), 161.3 (e); MS (CI) m/z: 276

(M + H); ESI-HRMS (m/z) [M + H]⁺calcd for

C₁₄H₁₈N₃O₃276.1343, obsd. 276.1335.

Ethyl 5-benzyloxy-2-[(4-nitrophenyl)methyl]-2H-1,2,3-triazole-

1

4-carboxylate (12b).

Pale yellow solid. Yield 82%. H-

NMR (600 MHz, CDCl₃): δ 1.39 (3H, t, J = 7.1 Hz, -

OCH₂CH₃), 4.41 (2H, q, J = 7.1 Hz, -OCH₂CH₃), 5.34

(2H, s, -OCH₂-), 5.55 (2H, s, -NCH₂-), 7.29–7.50 (7H, m,

aromatic protons), 8.16–8.20 (2H, m, aromatic protons);

¹³C-NMR (151 MHz, CDCl₃): δ 14.5 (-OCH₂CH₃), 58.6

(g), 61.4 (-OCH₂CH₃), 72.6 (f), 124.2, 125.1 (d), 127.8,

128.4, 128.6, 128.9, 135.9, 141.4, 148.1, 160.3 (h), 161.2

(e). ESI-HRMS (m/z) [M + H]⁺calcd for C₂₀H₁₉N₄O₅

383.1349, obsd. 383.1348.

(2b) Colorless oil. Yield 65%. ¹H-NMR, ¹³C-NMR, IR,

and MS spectra overlap with the spectra of 2b, obtained

using the selective procedure for the preparation of N(b)

General procedure for preparation of both N(b) and N(c)

triazoles.

Cs₂CO₃(2.50 mmol) and the selected

Ethyl 4-(benzyloxy)-1-(2-methylpropyl)-1H-1,2,3-triazole-5-

carboxylate (3c) and ethyl 5-(benzyloxy)-2-(2-methylpropyl)-

2H-1,2,3-triazole-4-carboxylate (3b).

alkylating agent (2.5 mmol, Table 2) were added to a

solution of 19 (1.00 mmol), in dry DMF (10 mL). The

resulting mixture was stirred at room temperature (some

reactions were carried out at higher temperature). When

the reaction was complete, the mixture was poured into

H₂O (60 mL); the pH was adjusted to 7 using 1 M HCl,

and the mixture was extracted with EtOAc (3 × 50 mL).

The combined organic layer was washed with brine,

dried with Na₂SO₄, and concentrated under reduced

pressure to afford a colorless oil. This latter showed two

spots on TLC (eluent: petroleum ether/EtOAc 90/10 v/v),

which can be attributed to the two triazole isomers. The

mixture was separated using ﬂash chromatography

(petroleum ether/EtOAc 90/10 v/v). A common feature in

all these experiments was the fact that the ﬁrst eluted

The mixture was

stirred at 50°C for 3 days in order to complete the reaction.

(3c) Colorless oil. Yield 11%. ¹H-NMR (300 MHz,

CDCl₃): δ 0.93 (6H, d, J = 6.7 Hz, -CH₂CH(CH₃)₂),

1.38 (3H, t, J = 7.1 Hz, -CH₂CH₃), 2.23 (1H, m,

-CH₂CH(CH₃)₂), 4.36 (2H, q, J = 7.1 Hz, -CH₂CH₃),

4.45 (2H, d, J = 7.4 Hz, -CH₂CH(CH₃)₂), 5.53 (2H, s,

-OCH₂-), 7.32–7.51 (5H, m, aromatic protons);

¹³C-NMR - (75 MHz, CDCl₃): δ 14.2 (-OCH₂CH₃), 19.7

(-CH₂CH(CH₃)₂), 29.4 (-CH-), 58.3 (g), 61.1

(-OCH₂CH₃), 71.5 (f), 110.9 (d), 127.5, 128.0; 128.4,

136.4 (C ipso), 158.8 (h), 161.1 (e); MS (CI) m/z: 304

(M + H); ESI-HRMS (m/z) [M + H]⁺calcd for

C₁₆H₂₂N₃O₃304.1656, obsd. 304.1654.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2018

Hydroxytriazoles are Useful Tools in Bioisosteric Replacement of Acidic Functions: Strategies

for the Preparation of a Library of Protected Hydroxytriazole Building Blocks are Described

(3b) Colorless oil. Yield 40%. ¹H-NMR (300 MHz,

CDCl₃): δ 0.91 (6H, d, J = 6.7 Hz, -CH₂CH(CH₃)₂), 1.39

(3H, t, J = 7.1 Hz, À CH₂CH₃), 2.33 (1H, m,

(M + H); ESI-HRMS (m/z) [M + H]⁺calcd for

C₁₉H₂₆N₃O₃344.1969, obsd. 344.1964.

(5b) Colorless oil. Yield 47%. ¹H-NMR, ¹³C-NMR, IR,

and MS spectra overlap with the spectra of 5b, obtained

using the selective procedure for the preparation of N(b)

-CH₂CH(CH₃)₂), 4.10 (2H, d,

J

=

7.4 Hz,

-CH₂CH(CH₃)₂), 4.40 (2H, q, J = 7.1 Hz, -CH₂CH₃),

5.36 (2H, s, -OCH₂-), 7.31–7.49 (5H, m, aromatic

triazoles.

protons); ¹³C-NMR (75 MHz, CDCl₃):

δ

14.4

Ethyl 1-benzyl-4-(benzyloxy)-1H-1,2,3-triazole-5-carboxylate

(6c) and ethyl 1-benzyl-4-(benzyloxy)-1H-1,2,3-triazole-5-

(-OCH₂CH₃), 19.7 (-CH₂CH(CH₃)₂), 29.2 (-CH-), 61.0

(-OCH₂CH₃), 63.0 (g), 72.2 (f), 123.4 (d), 127.7, 128.1,

128.4, 136.0 (C ipso), 160.5* (h), 160.6* (e); MS (CI)

m/z: 304 (M + H); ESI-HRMS (m/z) [M + H]⁺calcd for

carboxylate (6b).

(6c) Colorless oil. Yield 40%. The

structure

was

determined unequivocally using

heteronuclear 2D-NMR (HSQC and HMBC, Data S1)

1

techniques. H-NMR (300 MHz, CDCl₃): δ 1.31 (3H, t,

C₁₆H₂₂N₃O₃304.1656, obsd. 304.1663.

J = 7.2 Hz, -CH₂CH₃), 4.30 (2H, q, J = 7.2 Hz,

-CH₂CH₃), 5.53 (2H, s, -OCH₂-), 5.82 (2H, s, -NCH₂-),

7.26–7.49 (10H, m, aromatic protons); ¹³C-NMR

(75 MHz, CDCl₃): δ 14.2 (-OCH₂CH₃), 54.6 (g), 61.2

(-OCH₂CH₃), 71.5 (f), 110.8 (d), 127.7, 128.0, 128.2,

128.4, 128.5, 128.8, 135.1 (C ipso -NCH₂Ph), 136.3 (C

ipso -OCH₂Ph), 158.5 (h), 161.3 (e); MS (CI) m/z: 338

(M + H); ESI-HRMS (m/z) [M + H]⁺calcd for

C₁₉H₂₀N₃O₃338.1499, obsd. 338.1471.

Ethyl 4-benzyloxy-1-(cyclopropylmethyl)-1H-1,2,3-triazole-5-

carboxylate (4c) and ethyl 5-benzyloxy-2-(cyclopropylmethyl)-

2H-1,2,3-triazole-4-carboxylate (4b).

The mixture was

stirred at 50°C overnight.

(4c) Colorless oil. Yield 38%, ¹H-NMR (300 MHz,

CDCl₃): δ 0.43–0.48 (2H, m, -CH₂CH(CH₂)₂), 0.51–0.59

(2H, m, -CH₂CH(CH₂)₂), 1.35–1.45 (4H, t and m

overlapped, -OCH₂CH₃and -CH₂CH(CH₂)₂), 4.38 (2H,

q, J = 7.1 Hz, -OCH₂CH₃), 4.48 (2H, d, J = 7.3 Hz,

-CH₂CH(CH₂)₂), 5.54 (2H, s, -OCH₂-), 7.30–7.54 (5H,

m, aromatic protons); ¹³C-NMR (75 MHz CDCl₃): δ

4.0 (-CH₂CH(CH₂)₂), 11.3 (-CH₂CH(CH₂)₂), 14.2

(-OCH₂CH₃), 56.2 (g), 61.2 (-OCH₂CH₃), 71.5 (f), 110.6

(d), 127.6, 128.0, 128.4, 136.5 (C ipso), 158.9 (h), 161.1

(e); ESI-HRMS (m/z) [M + H]⁺calcd for C₁₆H₂₀N₃O₃

302.1499, obsd. 302.1497.

(6b) Colorless oil. Yield 44%. ¹H-NMR, ¹³C-NMR, IR,

and MS spectra overlap with the spectra of 6b, obtained

using the selective procedure for the preparation of N(b)

triazoles.

Ethyl 4-(benzyloxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-

5-carboxylate

(7c)

and

ethyl

5-(benzyloxy)-2-(4-

methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate (7b).

The

product was puriﬁed using ﬂash chromatography (eluent:

petroleum ether/EtOAc 95/5 v/v).

(4b) Colorless oil. Yield 58%. ¹H-NMR (300 MHz,

CDCl₃): δ 0.37–0.47 (2H, m, -CH₂CH(CH₂)₂), 0.55–0.65

(2H, m, -CH₂CH(CH₂)₂), 1.31–1.46 (4H, t and m

overlapped, -OCH₂CH₃and -CH₂CH(CH₂)₂), 4.15 (2H,

d, J = 7.3 Hz, -CH₂CH(CH₂)₂), 4.41 (2H, q, J = 7.1 Hz,

-OCH₂CH₃), 5.37 (2H, s, -OCH₂-), 7.32–7.51 (5H,

m, aromatic protons); ¹³C-NMR (75 MHz CDCl₃): δ

3.9 (-CH₂CH(CH₂)₂), 10.8 (-CH₂CH(CH₂)₂), 14.4

(-OCH₂CH₃), 60.6 (g), 61.0 (-OCH₂CH₃), 72.2 (f), 123.5

(d), 127.7, 128.1, 128.4, 136.1(C ipso), 160.6*(h),

(7c) White solid (m.p. 76.5–78.7°C). Yield 36%.

¹H-NMR (300 MHz, DMSO): δ 1.24 (3H, t, J = 7.1 Hz,

-OCH₂CH₃), 3.72 (3H, s, -OCH₃), 4.27 (2H, q,

J = 7.1 Hz, -OCH₂CH₃), 5.45 (2H, s, -OCH₂-), 5.73 (2H,

s, -NCH₂-), 6.90 (2H, d, J = 8.5 Hz, aromatic protons),

7.18 (2H, d, J = 8.7 Hz, aromatic protons), 7.29–7.50

(5H, m, aromatic protons); ¹³C-NMR (DMSO): δ 13.9

(-OCH₂CH₃), 53.5 (g), 55.1 (OCH₃), 61.1 (-OCH₂CH₃),

71.1 (f), 110.4 (d), 114.1, 127.5, 127.6, 128.1, 128.4,

129.1, 136.4 (C ipso), 157.7 (h), 159.1, 160.6 (e).

ESI-HRMS (m/z) [M + H]⁺calcd for C₂₀H₂₂N₃O₄

368.1605, obsd. 368.1602.

160.7*(e); ESI-HRMS (m/z) [M

C₁₆H₂₀N₃O₃302,1499, obsd. 302.1497.

+

H]⁺calcd for

Ethyl 4-(benzyloxy)-1-(cyclohexylmethyl)-1H-1,2,3-triazole-5-

carboxylate (5c) and ethyl 5-(benzyloxy)-2-(cyclohexylmethyl)-

2H-1,2,3-triazole-5-carboxylate (5b).

The mixture was

(7b) White solid (m.p. 80.7–81.7°C, from ethanol).

Yield 60%. H-NMR (300 MHz, DMSO): δ 1.26 (3H, t,

1

stirred at 50°C for 3 days in order to complete the reaction.

(5c) Colorless oil. Yield 14%. ¹H-NMR (300 MHz,

CDCl₃): δ 0.93–1.18 (5H, m, -NCH₂C₆H₁₁), 1.31 (3H, t,

J = 7.1 Hz, -CH₂CH₃), 1.47–1.65 (5H, m, -NCH₂C₆H₁₁),

1.82 (1H, m, NCH₂C₆H₁₁), 4.29 (2H, q, J = 7.1 Hz

-CH₂CH₃), 4.39 (2H, d, J = 7.3 Hz, -NCH₂C₆H₁₁), 5.45

(2H, s, -OCH₂-), 7.24–7.43 (5H, m, aromatic protons);

¹³C-NMR (75 MHz, CDCl₃): δ 14.3 (-OCH₂CH₃), 25.7,

26.2, 30.4, 38.4 (4 x NCH₂C₆H₁₁), 57.3 (g), 61.2

(-OCH₂CH₃), 71.5 (f), 111.0 (d), 127.6, 128.1, 128.5,

136.5 (C ipso), 158.9 (h), 161.2 (e); MS (CI) m/z: 344

J = 7.1 Hz, -OCH₂CH₃), 3.74 (3H, s, -OCH₃), 4.25 (2H,

q, J = 7.1 Hz, -OCH₂CH₃), 5.30 (2H, s, -OCH₂-), 5.48

(2H, s, -NCH₂-), 6.92 (2H, d, J = 8.6 Hz, aromatic

protons), 7.27 (2H, d, J = 8.6 Hz, aromatic protons),

7.31–7.49 (5H, m, aromatic protons); ¹³C-NMR

(DMSO): δ 14.0 (-OCH₂CH₃), 55.0 (OCH₃), 58.3 (g),

60.3 (-OCH₂CH₃), 71.7 (f), 113.9, 123.0 (d), 126.7,

127.8, 128.06, 128.2, 129.5, 135.8 (C ipso), 159.1, 159.4

(h), 160.1 (e). ESI-HRMS (m/z) [M + H]⁺calcd for

C₂₀H₂₂N₃O₄368.1605, obsd. 368.1602.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

S. Sainas, A. C. Pippione, A. Giraudo, K. Martina, F. Bosca, B. Rolando, A. Barge,

A. Ducime, A. Federico, S. J. Grossert, R. L. White, D. Boschi, and M. L. Lolli

Vol 000

Ethyl

triazole-5-carboxylate (8c) and ethyl 5-(benzyloxy)-2-(3,4-

dimethoxybenzyl)-2H-1,2,3-triazole-4-carboxylate (8b).

product was puriﬁed using ﬂash chromatography (eluent:

petroleum ether/EtOAc 80/20 v/v).

4-(benzyloxy)-1-(3,4-dimethoxybenzyl)-1H-1,2,3-

-OCH₂CH₃), 1.59 (6H, d, J = 6.7 Hz, -NCH (CH₃)₂), 4.37

(2H, q, J = 7.1 Hz, -OCH₂CH₃), 5.42 (1H, hept,

J = 6.7 Hz, -NCH (CH₃)₂), 5.53 (2H, s, -OCH₂-), 7.32

(1H, t, J = 7.4 Hz, aromatic proton), 7.38 (2H, t,

J = 7.5 Hz, aromatic protons), 7.50 (2H, d, J = 7.3 Hz,

aromatic protons); ¹³C-NMR (151 MHz, CDCl3): δ 14.3

(-OCH₂CH₃), 22.4 (-NCH (CH₃)₂), 53.7 (-NCH (CH₃)₂),

61.2 (-OCH₂CH₃), 71.5 (-OCH₂-), 110.5 (d), 127.7,

128.1, 128.5, 136.7 (C ipso), 159.1 (h), 161.4 (e).

The

(8c) The two isomers were separated using ﬂash

chromatography

(eluent:

petroleum

ether/EtOAc

80/20 v/v). White solid (m.p. 80.6–81.7°C). Yield 31%.

¹H-NMR (300 MHz, CDCl₃): δ 1.34 (3H, t, J = 7.1 Hz,

-OCH₂CH₃), 3.83 (3H, s, -OCH₃), 3.85 (3H, s, -OCH₃),

4.33 (2H, q, J = 7.1 Hz, -OCH₂CH₃), 5.52 (2H, s,

-OCH₂-), 5.75 (2H, s, -NCH₂-), 6.79 (1H, d, J = 8.2 Hz,

aromatic proton), 6.86–7.00 (2H, m, aromatic protons),

7.28–7.55 (5H, m, aromatic protons); ¹³C-NMR

(75 MHz, CDCl₃): δ 14.2 (-OCH₂CH₃), 54.4 (g), 55.9 (2

x OCH₃), 61.3 (-OCH₂CH₃), 71.6 (f), 110.6 (d), 111.0,

111.3, 121.1, 127.6, 127.7, 128.5, 136.4 (C ipso), 149.1,

149.2, 158.9 (h), 161.1 (e). ESI-HRMS (m/z) [M + H]⁺

calcd for C₂₁H₂₄N₃O₅398.1711, obsd. 398.1709.

1

(10b) Colorless oil. Yield 71%. H-NMR, ¹³C-NMR,

IR, and MS spectra overlap with the spectra of 10b,

obtained using the selective procedure for the preparation

of N(b) triazoles.

Ethyl

4-(benzyloxy)-1-[(4-methylphenyl)methyl]-1H-1,2,3-

triazole-5-carboxylate (11c) and ethyl 5-(benzyloxy)-2-[(4-

methylphenyl)methyl]-2H-1,2,3-triazole-5-carboxylate (11b).

(11c) Colorless oil. Yield 41%. ¹H-NMR (600 MHz,

CDCl₃): δ 1.32 (3H, t, J = 7.1 Hz, -OCH₂CH₃), 2.31

(3H, s, À CH₃), 4.31 (2H, q, J = 7.1 Hz, -OCH₂CH₃),

5.52 (2H, s, -OCH₂-), 5.77 (2H, s, -NCH₂-), 7.08–7.22

(4H, m, aromatic protons), 7.29–7.40 (3H, m, aromatic

protons), 7.45–7.49 (2H, m, aromatic protons); ¹³C-NMR

(151 MHz, CDCl₃): δ 14.3 (-OCH₂CH₃), 21.3 (-CH₃),

59.5 (g), 61.3 (-OCH₂CH₃), 71.6 (f), 110.8 (d), 127.7,

128.1, 128.2, 128.6, 129.5, 132.2, 136.5, 138.3, 158.7

(h), 161.4 (e). ESI-HRMS (m/z) [M + H]⁺calcd for

C₂₀H₂₂N₃O₃352.1656, obsd. 352.1655.

(8b) White solid (m.p. 95.8–97.6°C). Yield 41%.

¹H-NMR (300 MHz, CDCl₃): δ 1.38 (3H, t, J = 7.1 Hz,

-OCH₂CH₃), 3.82 (3H, s, -OCH₃), 3.87 (3H, s, -OCH₃),

4.40 (2H, q, J = 7.1 Hz, -OCH₂CH₃), 5.33 (2H, s,

-OCH₂-), 5.38 (2H, s, -NCH₂-), 6.69–6.96 (3H, m,

aromatic protons), 7.28–7.52 (5H, m, aromatic protons);

¹³C-NMR (75 MHz, CDCl₃): δ 14.3 (-OCH₂CH₃), 56.0,

56.1 (2 x OCH₃), 59.5 (g) 61.2 (-OCH₂CH₃), 72.2 (f),

111.1, 111.3, 121.1, 124.0 (d)126.9, 127.7, 128.2, 128.6,

136.0 (C ipso), 149.0, 149.4, 160.5* (h), 161.0* (e ESI-

HRMS (m/z) [M + H]⁺calcd for C₂₁H₂₄N₃O₅398.1711,

obsd. 398.1707.

1

(11b) Colorless oil. Yield 52%. H-NMR, ¹³C-NMR,

IR, and MS spectra overlap with the spectra of 11b,

obtained via the selective procedure for the preparation of

N(b) triazoles.

Ethyl 4-benzyloxy-1-[(4-nitrophenyl)methyl]-1H-1,2,3-triazole-

5-carboxylate (12c) and ethyl 4-benzyloxy-1-[(4-nitrophenyl)

Ethyl 4-benzyloxy-1-propyl-1H-1,2,3-triazole-5-carboxylate

(9c) and ethyl 5-benzyloxy-2-propyl-2H-1,2,3-triazole-5-

methyl]-1H-1,2,3-triazole-5-carboxylate (12b).

(12c) Pale

carboxylate (9b).

(9c) White solid (m.p. 70.2–73.1°C,

1

yellow solid. Yield 40%. H-NMR (600 MHz, DMSO): δ

1.18 (3H, t, J = 7.1 Hz, -OCH₂CH₃), 4.22 (2H, q,

J = 7.1 Hz, -OCH₂CH₃), 5.34 (2H, s, -OCH₂-), 5.55 (2H,

s, -NCH₂-), 7.28–7.51 (7H, m, aromatic protons), 7.46–

7.51 (2H, m, aromatic protons); ¹³C-NMR (151 MHz,

DMSO): δ 13.9 (-OCH₂CH₃), 53.5 (g), 61.1 (-OCH₂CH₃),

71.2 (f), 111.0 (d), 123.9, 127.6, 128.1, 128.3, 128.4,

136.3, 143.1, 147.1, 157.4 (h), 160.5 (e). ESI-HRMS (m/z)

[M + H]⁺calcd for C₂₀H₁₉N₄O₅383.1349, obsd. 383.1350.

(12b) Pale yellow solid. Yield 42%. ¹H-NMR,

¹³C-NMR, IR, and MS spectra overlap with the spectra

of 12b, obtained using the selective procedure for the

preparation of N(b) triazoles.

General hydrogenation procedure to obtain compounds 16b

and 16c. Palladium on carbon (Pd/C, 45 mg) was added

to a solution of the appropriate protected triazole

(compounds 6b and 6c, 0.300 mmol), in dry THF

(15 mL). The resulting mixture was vigorously stirred

under a hydrogen atmosphere for 1 h. The suspension

was ﬁltered through Celite, and the cake was washed

with methanol. The ﬁltrate was concentrated under

triturated with diisopropyl ether). Yield 21%. ¹H-NMR

(300 MHz, CDCl₃): δ 0.87 (3H, t, J = 7.4 Hz,

-NCH₂CH₂CH₃), 1.31 (3H, t, J = 7.1 Hz, -OCH₂CH₃),

1.75–1.91 (2H, m, -NCH₂CH₂CH₃), 4.29 (2H, q,

J = 7.1 Hz, -OCH₂CH₃), 4.50 (2H, t, J = 7.1 Hz,

-NCH₂CH₂CH₃), 5.45 (2H, s, -OCH₂-), 7.17–7.46 (5H, m,

aromatic protons); ¹³C-NMR (75 MHz, CDCl3): δ 11.0

(-NCH₂CH₂CH₃), 14.3 (-OCH₂CH₃), 23.6 (-NCH₂CH₂CH₃),

53.2 (-NCH₂CH₂CH₃), 61.3 (-OCH₂CH₃), 71.6 (-OCH₂-

), 110.9 (d), 127.7, 128.1, 128.5, 136.6 (C ipso), 158.8

(h), 161.3 (e). ESI-HRMS (m/z) [M + H] + calcd for

C₁₅H₂₀N₃O₃290.1499, obsd. 290.1495.

(9b) Colorless oil. Yield 55%. ¹H-NMR, ¹³C-NMR, IR,

and MS spectra overlap with the spectra of 9b, obtained

using the selective procedure for the preparation of N(b)

triazoles.

Ethyl 4-benzyloxy-1-isopropyl-1H-1,2,3-triazole-5-carboxylate

(10c) and ethyl 5-benzyloxy-2-isopropyl-2H-1,2,3-triazole-5-

carboxylate (10b).

(10c) White solid. Yield 13%.

¹H-NMR (600 MHz, CDCl₃): δ 1.39 (3H, t, J = 7.1 Hz,

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Month 2018

Hydroxytriazoles are Useful Tools in Bioisosteric Replacement of Acidic Functions: Strategies

for the Preparation of a Library of Protected Hydroxytriazole Building Blocks are Described

reduced pressure. When necessary, the obtained solid was

further puriﬁed by ﬂash chromatography.

Ramondetti, C.; Buccinna, B.; Al-Karadaghi, S.; Boschi, D.; Saglio, G.;

Lolli, M. L. J Med Chem 2018, 61, 6034.

[9] Sainas, S.; Pippione, A. C.; Giorgis, M.; Lupino, E.; Goyal, P.;

Ramondetti, C.; Buccinnà, B.; Piccinini, M.; Braga, R. C.; Andrade, C.

H.; Andersson, M.; Moritzer, A.-C.; Friemann, R.; Mensa, S.; Al-

Kadaraghi, S.; Boschi, D.; Lolli, M. L. Eur J Med Chem 2017, 129, 287.

[10] Lolli, M. L.; Hansen, S. L.; Rolando, B.; Nielsen, B.;

Wellendorph, P.; Madsen, K.; Larsen, O. M.; Kristiansen, U.; Fruttero,

R.; Gasco, A.; Johansen, T. N. J Med Chem 2006, 49, 4442.

[11] Lolli, M. L.; Giordano, C.; Pickering, D. S.; Rolando, B.;

Hansen, K. B.; Foti, A.; Contreras-Sanz, A.; Amir, A.; Fruttero, R.;

Gasco, A.; Nielsen, B.; Johansen, T. N. J Med Chem 2010, 53, 4110.

[12] Tosco, P.; Lolli, M. L. J Mol Model 2008, 14, 279.

[13] Giorgis, M.; Lolli, M. L.; Rolando, B.; Rao, A.; Tosco, P.;

Chaurasia, S.; Marabello, D.; Fruttero, R.; Gasco, A. Eur J Med Chem

2011, 46, 383.

[14] Pippione, A. C.; Federico, A.; Ducime, A.; Sainas, S.; Boschi,

D.; Barge, A.; Lupino, E.; Piccinini, M.; Kubbutat, M.; Contreras, J.-M.;

Morice, C.; Al-Karadaghi, S.; Lolli, M. L. Med Chem Commun 2017,

8, 1850.

[15] Giraudo, A.; Krall, J.; Nielsen, B.; Sørensen, T. E.; Kongstad,

K. T.; Rolando, B.; Boschi, D.; Frølund, B.; Lolli, M. L. Eur J Med Chem

2018, 158, 311.

Ethyl

(16b).

2-benzyl-5-hydroxy-2H-1,2,3-triazole-4-carboxylate

White solid. Yield 92%. ¹H-NMR (300 MHz,

CDCl₃): δ 1.40 (3H, t, J = 6.9 Hz, -OCH₂CH₃), 4.42

(2H, q, J = 6.9 Hz, -OCH₂CH₃), 5.43 (2H, s, -NCH₂-),

7.25–7.48 (5H, m, aromatic protons);¹³C-NMR (75 MHz,

CDCl₃): δ 14.3 (-OCH₂CH₃), 59.7 (-NCH₂-), 61.8

(-OCH₂CH₃), 122.2 (d), 128.3, 128.6, 128.8, 134.1 (C

ipso), 162.2 (h), 163.3 (e). MS (CI) 248 (M + 1). IR

(KBr) ν (cm^À1): 3399, 2984, 1684, 1544, 1526, 1458,

1328, 1182, 1149.

Ethyl

(16c).

3-benzyl-5-hydroxy-1H-1,2,3-triazole-4-carboxylate

White solid (m.p. 147.5–150.2°C). Yield 89%.

¹H-NMR (300 MHz, CDCl₃): δ 1.36 (3H, t, J = 7.1 Hz,

-OCH₂CH₃), 4.38 (2H, q, J = 7.1 Hz, -OCH₂CH₃), 5.80

(2H, s, -NCH₂-), 7.28–7.34 (5H, m, aromatic

protons);¹³C-NMR (75 MHz, CDCl₃):

δ

14.2

(-OCH₂CH₃), 54.9 (-NCH₂-), 61.6 (-OCH₂CH₃), 109.5

(d), 127.9, 128.5, 128.8, 134.6 (C ipso), 158.8 (h), 161.5

(e). MS (CI) 248 (M + 1). IR (KBr) ν (cm^À1): 2988,

1715, 1603, 1518, 1438, 1334, 1138, 1105.

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Acknowledgments. This research was supported by funding

from the University of Turin, Ricerca Locale 2015 and 2016

(grant numbers LOLM_RILO_17_01 and BOSD_RILO_17_01),

PRIN 2015 (LOLM_PRIN_2015_16_01), and the Natural

Sciences and Engineering Research Council of Canada (NSERC

to R. L. W.). The authors also wish to thank several people who

have contributed to this work. In particular, we would like to

mention: Prof. A. A. Doucette for use of the Quattro LC mass

spectrometer and A. Crowell and X. Feng for maintenance of the

instrument. Annalisa Costale is thanked for performing all the

UPLC analyses and Livio Stevanato for maintaining the NMR

instrumentation.

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SUPPORTING INFORMATION

Additional supporting information may be found online

in the Supporting Information section at the end of the

article.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

Article Doi

Regioselective N-Alkylation of Ethyl 4-Benzyloxy-1,2,3-triazolecarboxylate: A Useful Tool for the Synthesis of Carboxylic Acid Bioisosteres

DOI: 10.1002/jhet.3426

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Full text of DOI:10.1002/jhet.3426

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