Triazolyl derivatives for acidic release of alcohols

Article abstract of DOI:10.1002/ejoc.201001677

New triazolyl-based carbonates and ethers have been investigated as potential alcohol-releasing systems under mild acidic conditions. Triazolyl carbonates could not be prepared because of their apparent instability, whereas ethers were successfully obtained. The rate of hydrolysis of these ethers ramged from a few hours to several days. A theoretical investigation demonstrated that the acidic release of alcohols from triazole derivatives proceeds first by protonation of the triazole ring followed by proton transfer from the triazole ring to the carbonyl group of the carbonates or to the oxygen atom of the ether derivatives. The rate of the decomposition reaction was shown to depend on the length of the N3-H···O hydrogen bond in the intermediate C-NH⁺/E-NH⁺ structures and on the stability of the triazole carbocation, which is closely related to the π-donating effect of its R² and R³ substituents. Copyright

Full text of DOI:10.1002/ejoc.201001677

FULL PAPER
DOI: 10.1002/ejoc.201001677
Triazolyl Derivatives for Acidic Release of Alcohols
Martine Mondon,[a] Régis Delatouche,[a] Christian Bachmann,[b] Gilles Frapper,*[b]
Christophe Len,[c] and Philippe Bertrand*[a]
Keywords: pH-Sensitive systems / Protecting groups / Hydrogen bonds / Carbonates / Heterocycles / Alcohols / Click
chemistry
New triazolyl-based carbonates and ethers have been inves-
tigated as potential alcohol-releasing systems under mild
acidic conditions. Triazolyl carbonates could not be prepared
because of their apparent instability, whereas ethers were
successfully obtained. The rate of hydrolysis of these ethers
ramged from a few hours to several days. A theoretical inves-
tigation demonstrated that the acidic release of alcohols from
triazole derivatives proceeds first by protonation of the tri-
azole ring followed by proton transfer from the triazole ring
to the carbonyl group of the carbonates or to the oxygen atom
of the ether derivatives. The rate of the decomposition reac-
tion was shown to depend on the length of the N3–H···O hy-
drogen bond in the intermediate C-NH+/E-NH+ structures
and on the stability of the triazole carbocation, which is
closely related to the π-donating effect of its R2 and R3 sub-
stituents.
(PEO), polylactic acid (PLA) or polyglutamic acid (PGA).
To exploit the increasing acidity of endocytosis, ortho es-
ters,[5] acetals[6] or polyurethanes[7] have been proposed as
acid-sensitive vectors designed to reach the lysosomal stage
before being degraded. When covalent links between the bio-
active molecules and vectors are involved, hydrazone,[8]
benzaldehyde[9] and trityl[10,11] groups have been used for
targeting biomolecules with amines or alcohols. These con-
structs must be rapidly cleaved at mild acidic pH values to
exploit endosome maturation, a process that is completed
in less than 1 hour.[12] This objective can be achieved by
systems generating positive species on protonation such as
carbocations. The more stabilized the species, the faster the
acidic hydrolysis should be. For the trityl-like groups, and
especially with p-methoxy-substituted phenyl rings,[13] the
mesomeric effect gives a highly stabilized dianisylphenyl
Introduction
Drug delivery based on nanoparticle vectors such as
polymers,[1] liposomes or polyplexes is a well-known pro-
cess in which the vectors are internalized by cellular endo-
cytosis,[2] a natural process that allows cells to internalize
bulky objects, such as nutriments, for their needs. The pro-
cess starts with the encapsulation, by the membrane, of the
object to be internalized, with subsequent generation of an
intracellular vesicle called endosome at a mildly acidic in-
ternal pH (pH = 6). On maturation endosomes give more
acidic lysosome vesicles (pH 4–5),[3] responsible for the de-
gradation of the internalized objects. This mechanism has
been exploited for the cellular internalization of various
drug delivery systems prepared through two different ap-
proaches. The first approach relies on non-covalent as-
sembly between the vectors and cargos, as in the case of
the polyaminated polyplexes used for carrying DNA. The
second approach is based on covalent objects into which
acid-sensitive bonds are introduced. Many polymeric vec-
tors have been designed in this way, for instance HPMA, as
proposed by Kopececk and Duncan,[4] polyethylene oxides
carbocation (Scheme 1, DAP+: R1 = vector, R2 = R3
=
OMe). Thus, dimethoxytrityl derivatives have been particu-
[a] Laboratoire Synthèse et Réactivité des Substances Naturelles,
UMR CNRS 6514,
40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France
Fax: +33-05-49453502
E-mail: philippe.bertrand@univ-poitiers.fr
[b] Laboratoire Catalyse en Chimie Organique, UMR CNRS 6503,
Université de Poitiers,
40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France
E-mail: gilles.frapper@univ-poitiers.fr
[c] Université de Technologie de Compiègne (UTC), ESCOM,
1, Allée du réseau Jean-Marie Buckmaster, 60200 Compiègne,
France
Scheme 1. Example and principle for the design of trityl-like sensi-
tive groups.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001677.
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G. Frapper, P. Bertrand et al.
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larly developed for the acidic pH release of nucleosides, as
exemplified in Scheme 1 with the 5-O-trityl ether 1 of thym-
idine 2.[11]
Results and Discussion
Alcohol 5 was selected as a standard aliphatic alcohol
model and uridine 2Ј,3Ј-acetonide 6 for potential applica-
tion with nucleoside derivatives. Azide 4 used in this work
has already been described by us.[20] The carbonates were
synthesized based on two possible routes from alcohols 3
(Scheme 3). Alcohols 3 could be converted into triazolyl
carbonates 11/12 via propargyl carbonates 9/10 or via
alcohols 13. Non-commercial propargylic alcohols 3c,d
were prepared by a known procedure from ketones 7c,d.[21]
Alcohols 3 were then tentatively converted into the corre-
sponding carbonates. Alcohol 3a was successfully converted
into the intermediate carbonate 8a prior to nucleophilic
substitution with alcohol 5 to afford 9a. Initial attempts to
directly use the unprotected uridine to prepare unprotected
uridine carbonate 8a failed due to its low solubility in or-
ganic solvent. The corresponding soluble 2Ј,3Ј-acetonide
6[22] was finally prepared and allowed the synthesis of car-
bonate 10a in good yields. Attempts to convert alcohols 3b–
d into the corresponding carbonates 9b–d and 10b–d failed.
The two propargyl carbonates 9a and 10a were then sub-
mitted to the cycloaddition reaction with azide 4 under
various copper catalysis conditions.
To achieve conjugation to the vectors, one of the phenyl
groups was substituted with an electron-withdrawing amide
(R1) to link the trityl group to the vector via a spacer. This
synthetic strategy can be improved by recently developed
ligation methods. Cycloaddition reactions have been intro-
duced for bioconjugation to several types of nanopar-
ticles.[14] The Huisgen azide–alkyne cycloaddition[15] im-
proved by Sharpless and co-workers[16] is now commonly
used in the popular concept of click chemistry when applied
to terminal alkynes and azides. It allows the selective syn-
thesis of 1,4-disubstituted triazole rings under copper catal-
ysis. When used for bioconjugation, the resulting aromatic
triazole ring has rarely been exploited.[17–19]
We have recently proposed this chemistry for a biocon-
jugation process leading at the same time to a new type of
acid-sensitive group,[20] with the triazole group considered
as a possible substituent for one of the phenyl groups in the
trityl structure, as in generic compounds A (Scheme 2, R2
= R3 = Ph). In this way, cycloaddition with convenient 1,1-
disubstituted propargyl alcohols 3 and alkyl azide 4 should
lead to both ligation and the formation of a pH-sensitive
system. On acidic hydrolysis, a dialkyltriazolylmethyl-stabi-
lized carbocation (T+) should be formed. We have already
successfully developed this concept with benzylamine, pro-
ducing a carbamate cleaved at mildly acidic pH 4 with a
half-life of 22 h.[20] We now propose to use this strategy to
prepare “protected” alcohol derivatives for the release of
bioactive molecules with hydroxy functional groups. Car-
bonates were investigated (Scheme 2) by analogy to our car-
bamates but ether versions were also considered, in accord
with existing literature. In addition to the synthetic work
and hydrolysis experiments, molecular modelling was per-
formed to find the correlation between the stability of the
resulting carbonates and ethers in acidic environments and
the experimental half-lives of the protected molecules and
to explore the possible participation of the triazole ring in
such a hydrolysis.
Scheme 3. Reagents and conditions: i) THF, Li–CϵC–TMS, –60
to 0 °C overnight; ii) p-NO2PhCOCl, NEt3, CH2Cl2; iii) CH2Cl2,
pyridine, DMAP, 25 °C; iv) CuSO4·5H2O + NaAscorbate or CuI,
THF/H2O, 1:1, 25 °C.
Unfortunately, only the cycloadduct 11a was detected in
the crude and subsequent purification led to decomposition
whereas none of the other carbonates were observed. The
instability of the propargylic carbonates 9 and 10 during
cycloaddition prompted us to investigate prior cycload-
dition between alcohols 3 and azide 4 and subsequent func-
tionalization. Alcohols 3 were treated with azide 4 using
Scheme 2. Dialkyltriazolylmethane as trityl analogues.
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Triazolyl Derivatives for Acidic Release of Alcohols
CuSO4·5H2O in THF/H2O. In our case, THF was found reaction with the resulting water molecule as the dianisyltri-
more convenient in relation to compound solubility and af- azolyl carbocation may be more sensitive to less nucleo-
forded the cycloadducts 13 in good-to-high yields. The vari- philic compounds.[24] This etherification procedure ap-
ous methods used to try and activate the alcohols 13 (ni- peared to be very convenient and practical in such cases. It
trophenyl formate, prior deprotonation with bases) were also appeared to be more efficient than previously reported
unsuccessful and we were not able to prepare the desired methods in which trityl alcohols were first converted into
triazolyl carbonates 11 or 12 from 13.
halogen derivatives prior to substitution. The acetonide
We then investigated the preparation of the ether ver- protecting group was found to be stable under these condi-
sions (Scheme 2, X = no atom) using an analogous strategy. tions.
The ethers could also be obtained as a propargylic interme-
Having obtained four molecules 14c,d and 15c,d as po-
diate prior to cycloaddition or could be prepared after cy- tential acidic releasing systems, the rate of hydrolysis of
cloaddition. According to our application and the difficult- these compounds was studied. Preliminary tests revealed
ies encountered in the synthetic path with propargylic deriv- that the solubility was not complete in aqueous buffered
atives, we focused on the preparation of ethers 14 and 15 solutions (pH 1, HCl/KCl; pH 4, citrate buffer). The use of
via alcohols 13 (Scheme 4). Several methods have been used co-solvents was then investigated: acetonitrile, methanol
to prepare trityl ethers. Patel et al.[10] proposed an initial and dimethoxydiethylene glycol [(DME)2O]. The hydrolysis
conversion to the corresponding chloride (AcCl, reflux). In at pH = 1 of ethers 15c,d was at this stage monitored by
our hands, this procedure and others [SOCl2/pyridine, THF, TLC to obtain indicative rates as a function of the co-sol-
DMF, (COCl)2/CH2Cl2 or toluene, PCl3/Benzene] failed vent (Table 1). In all cases, compound 15d was rapidly hy-
when applied to alcohols 13. Recently, Lewis acid catalysis drolysed. Acetonitrile appeared to give increased solubility
with B(C6F5)3 as the catalyst has been described for the and faster hydrolysis for compound 15c, confirming the
preparation of ethers from two alcohols, one of which is a correlation between rate of hydrolysis and solubility. An
good nucleophile and the other is able to generate a stable 80:20 mixture of buffer/CH3CN was consequently selected
carbocation under Lewis acid catalysis.[23] This procedure to precisely determine the values of t1/2 for the rate of hy-
was first investigated with alcohol 5 to prepare ethers 14 drolysis of the ethers 14 and 15 in buffered solutions at
(Scheme 4). As expected, no reaction occurred with alcohol pH 1 and 4. In the latter case, addition of CH3CN gave a
13a, the two methyl groups not being able to sufficiently final pH of 4.3. This value is in agreement with the known
stabilize the potential carbocation and alcohol 13a being lysosomal pH (range 4–5), the cellular vesicles where our
itself probably as nucleophilic as the other alcohol 5. compounds should be cleaved by an acidic reaction to re-
Alcohol 13b gave a mixture of ether 14b and alkene 16b, lease the alcohols. Reaction mixtures were neutralized at
which were difficult to separate. Alkene 16 was observed indicated times and the formation of released alcohols (13
only starting from alcohol 13b as a result of proton loss or 5/6) from the initial ethers followed over time (see Hy-
from the carbocation. This was facilitated by the resulting drolysis Experiments in the Supporting Information).
conjugation, not possible for the other alcohols 13. Ethers
Table 1. Rates of hydrolysis of ethers 15 in pH 1 buffered solutions.
14c,d were obtained in high yields, which confirms the im-
portance of the aromatic effect for the cation stabilization
in this type of reaction. This protocol was applied to the
preparation of ethers 15c,d, which were obtained in good-
to-high yields. The lower yield found for ether 15d was the
result of an incomplete reaction, as unreacted materials
were recovered. This has been attributed to a competitive
Head 1[a] 15c, R2,R3 = Ph [%] 15d, R2,R3 = MeOC6H4 [%]
Time
(DME)2O 20 min
3 h
–
7
9
100
n.d.[a]
n.d.[a]
100
MeOH
3 h
CH3CN
20 min
3 h
n.d.[a]
53
n.d.[a]
[a] n.d.: not determined.
The observed half-lives are reported in Table 2. 1H NMR
signals of compounds 5/6, 13 and 14/15 were selected to
monitor the hydrolysis (Figure 1). Attempts to quantify
more precisely the hydrolysis rates by HPLC were not suc-
cessful due to co-elution of alcohols 13 and 14 or 15. All
ethers were rapidly hydrolysed at pH = 1, making such di-
aryltriazolylmethyl ether derivatives suitable protecting
groups for alcohols. The nucleoside 6 was released at pH 4.3
without degradation of the acetonide group, as shown in
the 1H NMR spectrum of the crude. A comparison between
the ethers 14c/15c and 14d/15d showed that, as expected,
the d compounds are hydrolysed more rapidly, a result di-
rectly correlated to the stabilization effect of the two anisyl
groups compared with the phenyl ones. At physiological pH
(buffer TRISMA/CH3CN, 80:20), ethers 15 were stable over
Scheme 4. Reagents and conditions: i) B(C6F5)3, CH2Cl2, reflux.
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8 d. In the case of ether 14c, the system used to evaluate at pH = 1 and 4. These results are consistent with the mod-
the hydrolysis rate was not optimal with partial precipi- erate solubility of the c series compared with the d series
tation and this may explain the differences observed with and may also be explained by possible side-protonations on
the corresponding nucleoside 15c, which is slowly hydro- the nucleoside moiety in compounds 15, whereas ethers 14
lysed. The opposite result was observed for compounds 14d have only one protonation site. At pH = 1, the acidity could
and 15d, with the propanol ether more rapidly hydrolysed compensate this side-protonation for 15, whereas at pH =
4, this is not possible. In our hands, the dianisyltriazolylme-
thyl ethers appeared to be suited to the preparation of acid
pH-sensitive protecting groups that may be used for hy-
droxy-drug release.
Table 2. Determination of t1/2 for the hydrolysis of ethers 14c,d and
15c,d in buffered solutions at pH 1 and 4 with acetonitrile as co-
solvent.
To rationalize our experimental kinetic data and to eluci-
date the hydrolysis mechanism, we performed molecular
DFT B3LYP/6-31G(d,p) gas-phase calculations. This theo-
retical level[25] of calculation is widely used and has been
proven to give reliable results in a number of mechanistic
studies.[26] Acidic protonation of triazoles has also been ex-
tensively studied[27] by this method for various substituted
pH
t1/2
14c
[a]
14d
15c
15d
1
4.3
7.3
Ͻ20 min
6–7 h
3 h
Ͻ20 min
60 h
ϱ[b]
n.d.[d]
Ͼ60 h[c]
Stable[e]
n.d.[d]
Stable[e]
[a] Inadequate solubility. [b] Not hydrolysed. [c] 15% hydrolysed at
60 h. [d] n.d.: not determined. [e] After 8 d.
Figure 1. 1H NMR monitoring of the hydrolysis of ether 15d with citrate buffer/CH3CN 4:1 (pH = 4.3). A) Crude reaction mixture from
hydrolysis with pH = 4.3 citrate buffer. B) Alcohol 13d. C) Ether 15d. D) Uridine acetonide 6.
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Triazolyl Derivatives for Acidic Release of Alcohols
triazoles and 1,4-disubstituted triazoles. Preferential pro- site was the most reactive, additive calculations were per-
tonation sites were shown to be the N3 nitrogen atom and formed on model compounds MeO–CO–OMe and 1,4-di-
then N2 (Scheme 2, see compound A). To account for the methyltriazolyl (Scheme 6). The results showed that proton-
medium sensitivity of these reactions, solvent effects were ation of the carbonyl oxygen atom of MeO–CO–OMe was
included in the energy calculations using the SMD contin- not as favoured as the protonation of the N3 atom of the
uum model.[28] B3LYP/6-31G(d,p) geometries and SMD- 1,4-dimethyltriazolyl model compound by as much as
B3LYP/6-31G(d)//B3LYP/6-31G(d,p) aqueous free energies 42 kcal/mol. Even though these model compounds differ
can be found in the Supporting Information. We have cho- from the carbonates studied, such a high energy separation
sen to discuss the aqueous solution Gibbs’ free energies. allowed us to conclude that the first protonation occurs at
Several pairs of substituents R2 and R3 were investigated the N3 atom of the triazolyl (C-NH+ in Scheme 5) and re-
for both the triazolyl carbonates and triazolyl ethers series, vealed the particular role of the triazolyl ring acting as a
although some of the compounds calculated were not ob- protonated vector in this hydrolysis reaction. Thus, in an
tained (Table 3). R1 = R4 = methyl substituents were used acidic medium (pH = 4), the protonated carbonates have
to reduce calculation times. All calculations were performed structures analogous to the one displayed in Figure 2a
with the Gaussian 09 package[29] and computational details (structural parameters are given in the Supporting Infor-
are described in the Exp. Section. Let us first start our dis- mation). An interesting common feature can be reported
cussion with carbonate derivatives even if half-live measure- for C-NH+ intermediates: the distance between the proton
ments could not be achieved for these compounds. We per- fixed on the N3 atom and the oxygen atom of the carbonyl
formed theoretical calculations on these systems to gain a group is ranked between 1.65 and 1.70 Å due to the non-
better understanding of their apparent instability. First, the planar seven-membered H–N3–C–C–O–C=O ring and the
protonation step was studied (Scheme 5). In Scheme 6, the nucleophilic lone-pair on the carbonyl oxygen atom. This
stability of the protonated species are given relative to N1 very short distance allows a smooth intramolecular proton
in model a. In agreement with previous calculations,[27] the shift, leading to the formation of the carbocation T+ and
protonation of the triazole N2 atom is less favoured by the MeO–CO–OH species.[30]
about 18 kcal/mol than the N3 site (water phase free en-
ergy).
Table 3. Computed aqueous free energies (ΔGcalc in) for protonated
triazolyl carbonates C-NH+ and triazolyl ethers E-NH+ decompo-
sition reactions.
R2
R3
ΔGcalcd. [kcal/mol]
Scheme 6. Relative free energies [kcal/mol] determined at the
B3LYP/6-31G(d,p) level of theory for protonation of the (a) tri-
azole, (b) carbonate and (c) ether models.
C-NH+
E-NH+
Me
Me
Me
Ph
+1.1
–4.0
+5.8
+2.3
–5.7
Ph
Ph
–10.6
–13.8
–17.4
Tol[a]
An[a]
Tol[a]
An[a]
–8.9
–12.5
[a] An = Anisyl = 4-MeOPh; Tol = 4-MePh.
Scheme 5. Proposed mechanism for acidic release of alcohol from
carbonates.
Figure 2. Selected distances [Å] for (a) protonated carbonate C-
NH+ and (b) ether E-N3H+ (R1 = R2 = Me) optimized structures
at the B3LYP/6-31G(d,p) level of theory.
Thus, only two protonation sites were considered for
these systems: the N3 atom of the triazolyl and the oxygen
atom of the carbonyl. Protonation of the most basic nitro-
gen atom of the triazole ring gave the C-NH+ carbocation
This decomposition process is the next step of our pro-
intermediate (local minimum on the potential energy sur- posed hydrolysis mechanism (Scheme 5). The free energies
face). The attempt to protonate the oxygen atom of the car- of these decomposition steps, ΔGcalcd., are reported in
bonyl group resulted in C–O bond dissociation and the re- Table 3. As expected, ΔGcalcd. correlates to the π-donating
lease of carbocation T+. To determine which protonation effect of the R2 and R3 substituents. Thus, the more π-do-
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nating the R2 and R3 substituents, the more stable is the the carbonyl nucleophilic site could be much closer to the
carbocation T+. In our experiments, the carbonates could triazolyl protonated site than the oxygen of the ether group.
not be observed, except for propargylic derivatives with R2 The shorter the hydrogen bond, the faster the proton trans-
= R3 = Me, which decomposed when we tried to conduct fer leading to the release of alcohols. It can be postulated
the cycloaddition reaction. The instability of the carbonate from our results that a six- or seven-membered hydrogen-
compounds could originate from an easy intramolecular bond-containing ring can be used to design a cleavable sys-
proton shift from the N3 atom to the oxygen atom of the tem linked to a triazolyl ring. Such work is one of our forth-
carbonyl, facilitated by the short distance noted above.
Turning now to the ether compounds, two protonation
sites were also considered: the N3 atom of the triazolyl and
the oxygen atom of the ether. The attempt to protonate this
oxygen atom leads to C–O bond dissociation and the for-
mation of the carbocation T+ as well as MeOH. However,
an additional calculation performed for the protonation of
the oxygen atom of the dimethyl ether model showed that
this is not as favoured as the protonation of the N3 atom of
the 1,4-dimethyltriazolyl compound by about 59 kcal/mol
(Scheme 6). Once again, despite these model compounds
differing from the ethers investigated here, the protonation
energies are so different that we can postulate that the N3
atom is protonated first (E-NH+ in Scheme 7). For these
ether compounds, the R2 and R3 substituents were the same
as for the carbonate series (Table 3). Five protonated species
(E-NH+) were fully optimized and, in contrast to the car-
coming goals.
Scheme 7. Proposed mechanism for the acidic release of alcohol
from ethers.
Conclusions
The design of new pH-sensitive protecting groups based
bonate species, the calculated distance between the proton on diaryltriazolylmethyl ethers and carbonates has been in-
fixed on the N3 atom and the ether oxygen atom appears vestigated. The synthesis of such derivatives exploited the
to be significantly longer (2.20–2.40 Å, see Figure 2, b) due elegant regioselective cycloaddition of alkynes and azides,
to the presence of a shorter –C(R2R3)–O– chain in the resulting in a short and modular synthesis for further devel-
ethers compared with –C(R2R3)–O–C=O in the carbonates. opment. This synthetic strategy was expected to allow the
This observation could explain the relative stability of the preparation of pH-sensitive vector linkers during the conju-
ether compounds relative to the carbonate compounds. The gation to the vector. Ethers were found particularly useful
intramolecular proton shift from the N3 atom to the ether for an expected application as acid-sensitive protecting
oxygen atom then leads to the formation of the carbocation groups. These ethers were prepared by direct association of
T+ and MeOH species. The free energies of these decompo- two alcohols, one nucleophilic and the other obtained by
sition reactions, ΔGcalcd., were calculated using the same cycloaddition and generating a stable carbocation easily by
procedure as for the carbonate species and are reported in Lewis acid catalysis. This overall synthesis for the prepara-
Table 3. Similar trends are observed concerning the π-do- tion of ethers as acid-sensitive systems represents an im-
nating effect of the R2 and R3 substituents. The negative provement over known literature procedures and has been
values of ΔGcalcd. for R2 = R3 = Ph, C6H4Me (tolyl) and successfully applied to an advanced model of the nucleo-
C6H4OMe (anisyl) are consistent with our experimental ob- side. The determination of the rate of hydrolysis of these
servations as compounds 14c, 14d, 15c and 15d are all hy- ethers in acidic environments has shown that a more acidic
drolysed under mild acidic conditions. Moreover, the half- pH can be used for fast hydrolysis, ranging from under
lives of these compounds at pH 1 and 4 (Table 2) correlate 20 min to several hours. At a milder pH, the hydrolysis still
to ΔGcalcd.: compounds 14d and 15d (R2 = R3 = anisyl, required several hours for the most sensitive compound and
ΔGcalcd. = –12.5 kcal/mol) have shorter half-lives than com- days for our nucleoside model, a result that must be im-
pounds 14c and 15c (ΔGcalcd. = –5.7 kcal/mol). For reac- proved for biological applications. For both carbonates and
tions following the same mechanism, the most exergonic is ethers, theoretical investigations demonstrated that a pro-
likely to be the fastest, that is, the one with the lowest bar- ton transfer from the triazole ring to the carbonyl of the
rier and therefore the shortest half-life. These theoretical carbamate group or to the oxygen atom of the ether group
investigations demonstrated that the acidic release of was the initial step towards hydrolysis. The kinetics of the
alcohols from triazole derivatives proceeds first by the pro- reaction may be related to the distance between the leaving
tonation of the triazole ring followed by a proton transfer proton and the accepting nucleophilic site in the C-NH+/E-
from the triazole ring to the carbonyl group of the carbon- NH+ carbocation intermediate. The shorter the intermo-
ates or the oxygen atom of the ether derivatives. The rate lecular hydrogen bond, the faster was the hydrolysis reac-
of the decomposition reaction has been shown to depend tion. This structural effect is under investigation for the de-
on the length of the N3–H···O hydrogen bond in the C- sign of more efficient acid pH-sensitive protecting groups
NH+/E-NH+ intermediate structures. As the carbonate based on diaryltriazolylmethyl ethers. Moreover, molecular
groups are longer and more flexible than the ether groups, modelling revealed the importance of the π-donating effect
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Triazolyl Derivatives for Acidic Release of Alcohols
6.97 (td, J = 7.6, 0.9 Hz, 1 H), 6.90 (d, J = 8.2 Hz, 1 H), 4.42 (t, J
= 7.2 Hz, 2 H, CH2), 4.34 (m, 2 H, CH2), 4.03 (t, J = 5.8 Hz, 2 H,
CH2), 3.64 (m, 2 H), 3.44 (t, J = 6.3 Hz, 2 H, CH2), 3.36 (s, 3 H,
OMe), 2.69 (m, 2 H, CH2), 2.16 (m, J = 7.2 Hz, 2 H, CH2), 1.90
(m, 4 H, 2 CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.9
(CO), 158.4 (C), 151.3 (C), 144.5 (C), 142.3 (C), 133.6 (CH), 131.9
(CH), 128.4 (CH), 128.2 (CH), 128.0 (CH), 127.92 (CH), 127.87
(CH), 127.2 (CH), 127.1 (CH), 125.6 (CH), 124.2 (CH), 120.3 and
120.1 (CH or C), 113.0 (CH), 81.1 (C), 70.5 (CH2), 67.8 (CH2),
63.7 (CH2), 63.4 (CH2), 58.9 (OCH3), 49.8 (CH2), 32.6 (CH2), 31.8
(CH2), 27.1 (CH2), 26.0 (CH2) ppm. HRMS (TOF-MS ES+):
calcd. for C38H41N3O5Na [M + Na]+ 642.2944; found 642.2944.
of the substituents on the stability of the carbocation inter-
mediate: the more π-donating the R3/R4 substituents, the
more stable is the carbocation. A subtle balance between
carbocation stability/reactivity and the nucleophilic charac-
ter of the carbonates/ethers explains the results observed
during hydrolysis.
Experimental Section
Abbreviations used: EA = ethyl acetate, PE = petroleum ether,
DMAP = 4-(dimethylamino)pyridine.
2-Methoxyethyl 2-(4-{4-[(3-Phenylpropoxy)bis(4-methoxyphenyl)-
methyl]-1H-1,2,3-triazol-1-yl}butoxy)benzoate (14d): B(C6F5)3
(6 mol-%) was added to a solution of alcohol 13d (326 mg,
0.581 mmol) and 3-phenyl-1-propanol (79 mg, 0.581 mmol) in
CH2Cl2 (8 mL). After stirring overnight at reflux, the reaction mix-
ture was diluted with CH2Cl2 and washed with water. The organic
phase was dried with MgSO4 and concentrated in vacuo. The resi-
due was purified by flash chromatography on a silica gel column
(20–30% gradient EA in PE) to afford the corresponding ether 14d
as an oil (352 mg, 89%). TLC (PE/EA): 50:50, Rf = 0.37. 1H NMR
(400 MHz, CDCl3): δ = 6.79–7.45 (m, 17 H, 16 Ar-H and 1-H,
triazole), 4.34–4.40 (m, 4 H, 2 CH2), 4.02 (t, J = 6.0 Hz, 2 H, CH2),
3.78 (s, 6 H, 2 OMe), 3.64 (m, 2 H, CH2), 3.39 (m, 5 H, CH2 and
OMe), 2.69 (m, 2 H, CH2), 2.15 (m, 2 H, CH2), 1.86 (m, 4 H,
2CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.9 (CO), 158.6
(C), 158.4 (C), 152.0 (C), 142.3 (C), 136.8 (C), 133.6 (CH), 131.9
(CH), 129.2 (CH), 128.5 (CH), 128.43 (CH), 128.4 (CH), 128.2
(CH), 125.6 (CH), 123.8 (CH), 120.2 (CH), 113.2 and 113.1 (2 CH
and 1 C), 113.0, 80.7 (C), 70.6 (CH2), 67.9 (CH2), 63.7 (CH2), 63.2
(CH2), 58.9 (OMe), 55.2 (OMe), 49.7 (CH2), 32.6 (CH2), 31.9
(CH2), 27.1 (CH2), 26.1 (CH2) ppm. HRMS (TOF-MS ES+):
calcd. for C40H45N3O7Na [M + Na]+ 702.3155; found 702.3135.
1,1-Dimethylprop-2-ynyl 3-Phenylpropyl Carbonate (9a): A solution
of carbonate 8a (700 mg, 2.81 mmol) in CH2Cl2 (8 mL) was treated
with alcohol 5 (383 mg, 2.81 mmol) in the presence of pyridine
(0.25 mL, 3.09 mmol) and of a catalytic amount of DMAP. After
stirring 48 h at room temperature, the mixture was extracted with
CH2Cl2 and washed with water. The organic phase was dried with
MgSO4 and concentrated in vacuo. Purification by flash
chromatography of the residue (EA/PE, 5:95 to 20:80) gave com-
pound 9a (430 mg, 62%) as an oil with the presence of starting
1
material (73 mg, 9.6%). TLC (PE/EA): 90:10, Rf = 0.34. H NMR
(400 MHz, CDCl3): δ = 7.17–7.31 (m, 5 H, Ar), 4.15 (t, J = 6.6 Hz,
2 H, CH2), 2.71 (dd, J = 8.0, 7.5 Hz, 2 H, CH2), 2.57 (s, 1 H, H-
Cϵ), 2.00 (m, 2 H, CH2), 1.72 (s, 6 H, 2CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 153.1 (CO), 141.1 (C), 128.5 (CH), 128.4
(CH), 126.1 (CH), 84.2 (Cϵ), 73.8 (C), 72.8 (HCϵ), 67.0 (CH2),
32.0 (CH2), 30.3 (CH2), 28.8 (2CH3) ppm. HRMS (TOF-MS ES+):
calcd. for C15H18O3Na [M + Na]+ 269.11536; found 269.1148.
1,1-Dimethylprop-2-ynyl 2Ј,3Ј-O-Isopropylideneuridin-5Ј-yl Carbon-
ate (10a): A solution of carbonate 8a (117.5 mg, 0.471 mmol) in
CH2Cl2 (2 mL) was treated with uridine acetonide 6 (134 mg,
0.471 mmol) in the presence of pyridine (42 μL, 0.52 mmol) and
of a catalytic amount of DMAP. After stirring overnight at room
temperature the mixture was extracted with CH2Cl2 and washed
with water. The organic phase was dried with MgSO4 and concen-
trated in vacuo. Purification by flash chromatography of the residue
(EA/PE, 10:90 to MeOH/CH2Cl2, 2:98) gave compound 10a as a
white solid (120 mg, 64.5%, m.p. 80–82 °C). TLC (MeOH/
2-Methoxyethyl 2-(4-{4-[(2Ј,3Ј-O-Isopropylideneuridin-5Ј-yloxy)di-
phenylmethyl]-1H-1,2,3-triazol-1-yl}butoxy)benzoate
(15c):
B-
(C6F5)3 (6 mol-%) was added to a solution of alcohol 13c
(403.7 mg, 0.805 mmol) and acetonide 6 (229 mg, 0.805 mmol) in
CH2Cl2 (10 mL). After stirring overnight at reflux, the reaction
mixture was diluted with CH2Cl2 and washed with water. The or-
ganic phase was dried with MgSO4 and concentrated in vacuo. The
residue was purified by flash chromatography on a silica gel column
(1% gradient MeOH in CH2Cl2) to afford the corresponding ether
15c as a white solid which precipitated in Et2O (m.p. 72–75 °C,
558 mg, 90%). TLC (PE/EA): 50:50, Rf = 0.05; TLC (CH2Cl2/
MeOH): 95:5, Rf = 0.36. 1H NMR (400 MHz, CDCl3): δ = 8.54 (s,
1 H, NH), 7.82 (dd, J = 7.6, 2.0 Hz, 1 H, CH), 7.65 (d, J = 8.1 Hz,
1 H, CH), 7.43 (ddd, J = 8.4, 7.6, 1.6 Hz, 1 H, CH), 7.29 (m, 10
H, Ar-H), 7.13 (s, 1 H, NCH=C), 6.96 (td, J = 7.6, 0.8 Hz, 1 H,
CH), 6.91 (d, J = 8.4 Hz, 1 H, CH), 5.95 (d, J = 1.6 Hz, 1 H, CH),
5.25 (dd, J = 8.1, 2.4 Hz, 1 H, =CH), 4.81 (m, 2 H, 2 CH), 4.44 (t,
J = 7.2 Hz, 2 H, CH2), 4.37 (m, 1 H), 4.33 (m, 2 H, CH2), 4.05 (m,
2 H, CH2), 3.83 (m, 2 H, CH2), 3.65 (m, 2 H, CH2), 3.37 (s, 3 H,
OMe), 2.16 (m, 2 H, CH2),1.84 (m, 2 H, CH2), 1.56 (s, 3 H, CH3),
1.33 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.9
(CO), 162.8 (CO), 158.4 (C), 150.5 (C), 149.9 (C), 143.5, 142.6,
141.1 (CH), 133.6 (CH), 131.9 (CH), 128.14 (CH), 128.11 (CH),
127.9 (CH), 127.8 (CH), 124.7 (NCH), 120.4 (CH), 120.0 (C), 114.1
(C), 113.0 (CH), 101.5 (CH), 92.1 (CH), 85.9 (CH), 85.1 (CH), 82.0
(C), 80.8 (CH), 70.5 (CH2), 67.9 (CH2), 64.5 (CH2), 63.7 (CH2),
58.9 (OMe), 49.9 (CH2), 27.3 (CH3), 27.2 (CH2), 26.0 (CH3), 25.4
(CH2) ppm. HRMS (TOF-MS ES+): calcd. for C41H46N5O10 [M
+ H]+ 768.3245; found 768.3237.
1
CH2Cl2): 5:95, Rf = 0.46. H NMR (400 MHz, CDCl3): δ = 8.43
(br. s, 1 H, NH), 7.34 (d, J = 8.2 Hz, 1 H, CH=), 5.77 (d, J =
2.3 Hz, 1 H, 1Ј-H), 5.72 (dd, J = 8.2, 2.3 Hz, 1 H, -CH=), 4.94 (dd,
J = 6.3, 2.3 Hz, 1 H, 2Ј-HЈ), 4.83 (dd, J = 6.3, 3.5 Hz, 1 H, 3Ј-H),
4.11–4.44 (m, 3 H, 2ϫ5Ј-H and 4Ј-H), 2.58 (s, 1 H, H-Cϵ), 1.70
(s, 6 H, 2 CH3), 1.57 (s, 3 H, CH3), 1.36 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 163.7 (CO), 152.4 (C), 142.0 (C-6), 114.6
(C), 102.6 (C-5), 94.1 (C-1Ј), 84.8 (C-4Ј), 84.6 (C-2Ј), 83.7 (Cϵ),
80.9 (C-3Ј), 74.5 (C), 73.3 (H-Cϵ), 66.9 (C-5Ј), 28.7 (CH3), 28.6
(CH3), 27.1 (CH3), 25.3 (CH3) ppm. HRMS (TOF-MS ES+):
calcd. for C18H22N2O8Na [M + Na]+ 417.12739; found 417.1277.
2-Methoxyethyl
2-(4-{4-[(3-Phenylpropoxy)diphenylmethyl]-1H-
1,2,3-triazol-1-yl}butoxy)benzoate (14c): B(C6F5)3 (6 mol-% ) was
added to a solution of azide alcohol 13c (424 mg, 0.846 mmol) and
3-phenyl-1-propanol (115 mg, 0.846 mmol) in CH2Cl2 (10 mL). Af-
ter being stirring overnight at reflux, the reaction mixture was di-
luted with CH2Cl2 and washed with water. The organic phase was
dried with MgSO4 and concentrated in vacuo. The residue was
purified by flash chromatography on a silica gel column (5–30%
gradient EA in PE, m.p. 66–66.5 °C) to afford the corresponding
ether 14c as a white solid (475 mg, 90%) after recrystallization in
1
diethyl ether. TLC (PE/EA): 50:50, Rf = 0.5. H NMR (400 MHz,
CDCl3): δ = 7.82 (dd, J = 7.6,1.8 Hz, 1 H), 7.14–7.47 (m, 17 H),
Eur. J. Org. Chem. 2011, 2111–2119
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2117

G. Frapper, P. Bertrand et al.
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163.4 (CO), 158.9 (C), 158.4 (C), 151.1 (C), 150.2 (C), 141.1 (CH),
135.9 (C), 134.9 (C), 133.6 (CH), 131.9 (CH), 129.5 (CH), 129.3
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www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2111–2119

Triazolyl Derivatives for Acidic Release of Alcohols
T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M.
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The MeO–CO–OH compound is expected to be unstable. Its
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[30]
Received: December 14, 2010
Published Online: March 7, 2011
Eur. J. Org. Chem. 2011, 2111–2119
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2119