Extending triazolyl-based release under mildly acidic conditions to give aniline derivatives

Article abstract of DOI:10.1055/s-0031-1289719

Triazolyl derivatives of anilines were prepared and evaluated as releasing systems at mildly acidic pH values. Two triazolyl derivatives showed convenient pH sensitivity, being stable at pH 7.3 and rapidly hydrolyzed at pH values below 5. A generalized me

Full text of DOI:10.1055/s-0031-1289719

1090
PAPER
Extending Triazolyl-Based Release under Mildly Acidic Conditions To Give
Aniline Derivatives
A
cidic Triazolyla
é
niline Rele
g
a
se is Delatouche, Christian Bachmann, Gilles Frapper, Philippe Bertrand*
Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), UMR 7285 CNRS-Université de Poitiers, 4 rue Michel Brunet,
Bâtiment B27, 86022 Poitiers cedex, France
Fax +33(5)49453501; E-mail: philippe.bertrand@univ-poitiers.fr
Received 8 December 2011; revised 19 January 2012
higher yield than that obtained using path A. The synthe-
Abstract: Triazolyl derivatives of anilines were prepared and eval-
ses of carbamates 4b–d remained problematic. Alcohol
uated as releasing systems at mildly acidic pH values. Two triazolyl
5b gave carbamate 4b together with the inseparable alk-
ene 8b. For alcohols 5c and 5d, two rearranged amine de-
rivatives 6c and 6d were isolated in very high yields
instead of the expected carbamates 4c and 4d. The struc-
tures of alkylamines 6c and 6d were confirmed by their
preparation from alcohols 5 (path B), via chlorides 7 and
substitution with aniline (Scheme 2, iii–v). Since dianisyl
chlorides can easily be converted into alcohols,9 this may
explain the low yields observed with the chlorination
method. Amines 6c and 6d were obtained in moderate
yields compared to the in situ rearrangement of carbam-
ates 4c and 4d. Derivatives 6a and 6b were not prepared
because they were expected to be stable at low pH. The
syntheses of amines 6c and 6d appeared to be more effec-
tive via the rearrangement of carbamates 4c and 4d, which
are probably formed in situ.
derivatives showed convenient pH sensitivity, being stable at
pH 7.3 and rapidly hydrolyzed at pH values below 5. A generalized
mechanism is proposed from additional theoretical investigations.
Key words: hydrolysis, alkynes, azides, cycloaddition, amines,
protonation
Drug delivery systems (DDS) are developed to exploit
endocytosis1 and enhance permeability and retention ef-
fects,2 with progressive or differentiated release being ex-
tensively investigated.3 Covalent acid-sensitive linkers
are used to connect drugs to vectors4 to exploit the acidic
process of endocytosis. We recently described amine5 and
alcohol6 release (Scheme 1, X = NH or O respectively)
based on an acid-sensitive triazolyl system obtained by
click chemistry7 and report herein new findings for the re-
lease of aniline.
The carbamate 4a and alkylamines 6c and 6d were sub-
mitted to acidic hydrolysis (citrate buffer for pH 4.3 and
TRIZMA buffer for physiological pH). Half-lives (t1/2) are
R1
+
R1
R2
X
H+
R3
R2
XH
3
R4
R1
O
R2
R1
O
R2
N1 R
N3 N2
R1
O
R2
R4
Y
+ Y +
N
i
ii
H
R3
N
N
N
path A
N
a R1 = R2 = Me
b R1 = Me, R2 = Ph
c R1 = R2 = Ph
1a–d
N
T+
X = O, NH
A, Y = CO2
B, Y = no atom
PhHN
4a, 19%
O
PhHN
O
2a: 67%
2c: 93%
d R1 = R2 = p-MeOC6H4
4c, not isolated
ii
path B
R2
Scheme 1 Principle of triazolyl-based acid-sensitive systems
R1
R2
R1
R3
i
Two synthetic pathways were investigated to prepare
aniline carbamates A (Scheme 1, Y = CO2, R4 = Ph) and
alkylanilines B (Scheme 1, Y = no atom, R4 = Ph). In
path A (Scheme 2), propargylic carbamates 2 were pre-
pared from alcohols 1. The reaction with alcohols 1a and
1c proceeded in good yields, however, although alcohols
1b and 1d were consumed, the corresponding carbamates
2b and 2d were probably unstable and could not be isolat-
ed.8 Cycloaddition of 2a with azide 3 gave carbamate 4a
in modest yield. The cycloaddition of 2c resulted in de-
composition. In path B, the known alcohols 5a–d were
prepared in high yields and reacted with phenyl isocyan-
ate to give carbamates 4. Carbamate 4a was isolated in
PhHN
R3
N
4a, 81%
O
H
N
N
N
for 5a,c,d
N
N
6c (via 4c): 92%
6d (via 4d): 70%
5a–d
R1
Cl
R2
N
R3
iii or iv
path B
v
N
6c : 34% (iv)
6d : 45% (v)
5c,d
N
7c,d
a: R 1 = R 2 = Me
b: R 1 = Me, R 2 = Ph
c: R 1 = R 2 = Ph
O
O
Me
Ph
O
R3
O
R3
=
N
d: R 1 = R 2 = p-MeOC6H4
N
N
8b
Scheme 2 Reagents and conditions: (i) PhNCO, heptane, Et3N cat.,
reflux, 30 min; (ii) azide 3 (R3N3), CuI, THF–H2O (1:1), 24 h, 20 °C;
(iii) HCl, CH2Cl2, reflux; (iv) SOCl2, CH2Cl2, reflux; (v) aniline,
overnight.
SYNTHESIS 2012, 44, 1090–1094
Advanced online publication: 24.02.2012
DOI: 10.1055/s-0031-1289719; Art ID: T113611SS
© Georg Thieme Verlag Stuttgart · New York
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x.
x
x.
2
0
1
2

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Acidic Triazolylaniline Release
1091
R1
X
R4
R2
N
reported for carbamate 4a and amines 6c and 6d
(Table 1). The carbamate 4a was stable at all pH values.
The amine derivatives 6c and 6d were rapidly hydrolyzed
at pH 4.3 and stable at pH 7.3, which indicates that these
compounds are very good candidates for further develop-
ment; acidic maturation during endocytosis being around
one hour. These findings prompted us to make additional
theoretical calculations for these new derivatives.5
R1
O
R2
N3
R3
R3
N1
N2
B
N
A
X
R4
N
O
X = O, NH
R1
X
R4
R2
N
R1
O
R2
N+
+
R3
R3
N
AN3H+
H
N
BXH+
X
R4
N
N
O
H
Table 1 Half-Life Values (t1/2) for Carbamate 4a and Amines 6c
and 6d
C–X cleavage
C–O cleavage
R4-X-COOH
Aniline
Y
R1
R2
t1/2 (min)
T+
+
T+
R4-XH
+
pH 4.3
pH 7.3
stable
stable
– R4XH
– CO2
+ H2O
– H+
– R4XH
+ H2O
– H+
4a
6c
6d
CO2
–
Me
Ph
Me
Ph
43200
77.3
2
Scheme 3 Proposed generalized hydrolysis mechanism for triazolyl
derivatives A and B
–
p-MeOC6H4 p-MeOC6H4
0.35 stable
approach was planned with 2-substituted aniline linked to
the releasing system 5 to provide advanced intermediates
11 or 13 (Scheme 4). We selected the isocyanate 9 as
starting material because the nitro group is reducible and
because direct use of 2-aminoaniline was not suitable for
isocyanate preparation. Isocyanate 9 was reacted with al-
cohols 1a–d as depicted in path A (Scheme 4), to give car-
bamate 10a in good yield; carbamate 10b was obtained as
a mixture, whereas 10c and 10d were not obtained. Car-
bamate 10a was found to be unstable during the click re-
action, regardless of the conditions used. Path B was then
investigated using the alcohol 5d only, because of its ex-
pected rapid release as demonstrated for aniline. Isocyan-
ate 9 was reacted with alcohol 5d and carbamate 11d
(which was not observed directly) was again converted
into nitroaniline 12d in situ. The lower yield of the latter
compared to that obtained with the unsubstituted aniline
was due to difficulties during purification, and compound
12d was finally isolated along with trace amounts of the
starting alcohol 5d. Its reduction to the corresponding
amino derivative 13d led to only decomposed products
under SnCl2 conditions.
Calculations indicated that the preferred protonation sites
were the N-3 nitrogen atom for carbamates 4 and the
amine nitrogen atom for amines 6 (Figure 1). Compared
to previous results obtained with benzylamine,5 the pref-
erences for site-specific protonation of carbamates 4 and
amines 6 were less pronounced; aniline being less nucleo-
philic. Initial N-3 protonation of 4 activates the hydrolysis
by a proton transfer to the carbonyl group. This participa-
tion appeared critical and general (Scheme 3). To account
for the medium sensitivity of carbamate 4 and alkylamine
6, the free energies (DGAwater for 4 and DGBwater for 6) were
computed according to Equation 1.
After the initial protonation, the decomposition of A-N3H+
and B-NH+ species to the carbocation T+ (Scheme 3,
X = NH) is correlated with the electron-donating effect of
the R1 and R2 groups (Table 2).
We then applied these results to substituted aniline. Be-
cause our group has been working on the design of HDAC
inhibitors,10 we focused on 2-substituted aniline, which is
a key functional group in this class of inhibitors. A general
The hydrolysis was measured for 12d only in pH 4.3 buff-
er containing acetonitrile, and the t1/2 (after subtraction of
the initial residual alcohol 5d) was estimated to be
150 min (Figure 2, left). This slower release, compared
Me
Me
+22.2
Me
Me
N1 Me
O
Ph
H
Ph
H
N3 N2
N
N1 Me
N3 N2
N
O
0.0
0.0
+18.4
Table 2 Computed Aqueous Solution Free Energies (DGwater in
kcal/mol) for Protonated Triazolylaniline Carbamates A-N3H+ and
Triazolylalkylanilines B-NH+ Decomposition Reactions
H-shift toward N3
+2.7
(b)
(a)
Figure 1 Relative free energies of protonation sites (kcal/mol) at
the B3LYP/6-31G(d,p) level for (a) aniline carbamate 4 and (b) al-
kylkaniline 6 models (R1 = R2 = Me; R3 = Me)
Series
R1
R2
4, A-N3H+ 6, B-NH+
DGA DGB
water
water
a
b
c
e
d
Me
Me
+1.0
+4.0
Me
Ph
–4.0
–10.2
–14.3
–17.6
–1.9
–10.9
–14.0
–17.7
A-N3H+
B-NH+
with:
→
→
Ph-NH-CO2H + T+ ΔGA
water
water
Ph-NH2 + T+
ΔGB
Ph
Ph
ΔGAwater = G(T+)water + G(Ph-NH-CO2H)water – G(A-N3H+)water
ΔGBwater = G(T+)water + G(Ph-NH2)water – G(B-NH+)water
p-MeC6H4
p-MeOC6H4
p-MeC6H4
p-MeOC6H4
Equation 1
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1090–1094

1092
R. Delatouche et al.
PAPER
i
well as other functional groups are being developed. The-
oretical calculations allowed generalization of the pro-
posed hydrolysis mechanism, the triazole ring being
critical for carbamates. Complementary mechanistic in-
vestigations are warranted, which should clarify the de-
gree of water assistance and establish more precise energy
barriers and substituent effects for anilines.
R1
O
10a, 65%
R2
10b, inseparable mixture
1a–d
NCO
N
H
O
R1, R2 = 4-MeOC6H4
NO2
NO2
9
R1
O
R2
N
ii
i
5d
R3
X
N
H
O
N
NO2
11a
N
After work up, the organic layers were dried with MgSO4, filtered,
and concentrated under vacuum unless otherwise noted. Purifica-
tions were achieved by flash chromatography, with EtOAc and PE
on silica gel. Petroleum ether (PE), where used, had boiling range
35–60 °C. Melting points were determined with a Kofler apparatus.
1H and 13C NMR spectra were recorded with a Bruker Avance DPX
at 400 and 100 MHz, respectively. NMR spectra were recorded in
CDCl3 or acetone-d6 and chemical shifts are given in ppm relative
to TMS. High-resolution mass spectra were obtained at CRMPO,
Rennes, France.
iii
X
R1
R1
R2
[11d]
R2
R3
R3
N
H
N
N
N
H
NH2
N
NO2
N
N
N
13d
12d, 34%
Scheme 4 Reagents and conditions: (i) heptane, Et3N cat., reflux,
30 min; (ii) azide 3 (R3N3), CuI, solvents, 20 °C; (iii) SnCl2, EtOH.
1,1-Dimethylprop-2-ynyl Phenylcarbamate (2a)
To a solution of 1a (580 mL, 5.61 mmol) in heptane (30 mL) was
added Et3N (390 mL, 2.81 mmol). The solution was heated at reflux
and phenyl isocyanate (300 mL, 2.81 mmol) was added. After heat-
ing to reflux for 2 h, the solution was cooled to r.t., dissolved in
Et2O (25 mL) and washed with KHSO4 (1 M, 3 × 20 mL), and brine
(2 × 25 mL), dried, filtered, concentrated and purified by flash chro-
matography (PE–EtOAc, 9:1) to afford 2a.
Yield: 390 mg (67%); white solid.
1H NMR (400 MHz, CDCl3): d = 7.37 (d, J = 7.9 Hz, 2 H), 7.26 (m,
2 H), 7.03 (m, 1 H), 6.54 (s, 1 H), 2.56 (s, 1 H), 1.73 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 151.6, 137.8, 129.0, 123.4, 118.6,
84.9, 72.4, 72.2, 29.2.
HRMS (ESI): m/z [M + Na]+ calcd for C12H13NO2Na: 226.08440;
Figure 2 Hydrogen bond in compound 12d and hydrolysis determi-
found: 226.0846.
nation at pH 4.3
1,1-Diphenyl-prop-2-ynyl Phenylcarbamate (2c)
with aniline derivatives 6d, can be explained by the effect
of the nitro group, where the electron-withdrawing effect
and an intramolecular hydrogen bond11 (Figure 2, right)
To a solution of 1c (0.60 g, 2.88 mmol) in heptane (20 mL) was add-
ed Et3N (200 mL, 1.44 mmol). The solution was heated at reflux and
phenyl isocyanate (160 mL, 1.44 mmol) was added. The solution
participate in reducing the nucleophilic character of the was heated at reflux for 2 h more until a white precipitate appeared.
The solution was extracted with Et2O (10 mL) and washed with
amine, decreasing the protonation efficiency and, in turn,
increasing the acidity of the hydrogen atom. This increase
KHSO4 (1 M, 3 × 10 mL), then brine (2 × 10 mL). The organic layer
was dried, filtered, concentrated, and purified by flash chromatog-
in acidity was confirmed by the 1H NMR signal of this hy-
raphy (PE–EtOAc, 100:0–60:40) to afford 2c.
drogen atom, which was observed at d = 9.6 ppm, instead
Yield: 440 mg (93%); white solid.
1H NMR (400 MHz, CDCl3): d = 7.56 (m, 4 H), 7.36 (m, 7 H), 7.28
(m, 3 H), 7.04 (t, J = 7.4 Hz, 1 H), 6.84 (s, 1 H), 3.05 (s, 1 H).
of being close to d = 6 ppm observed for the NH signals in
compounds 6. These results indicate that, in the case of
aniline, the reaction has an additional parameter resulting
from mesomeric effects originating from the aniline sub- 13C NMR (100 MHz, CDCl3): d = 150.5, 141.9, 137.5, 128.9, 128.5,
128.3, 128.1, 126.1, 123.5, 82.5, 79.6, 78.3.
HRMS (ESI): m/z [M + Na]+ calcd for C22H17NO2Na: 350.1157;
found: 350.1160.
stituents, and probably also its position on the aniline ring.
In summary, an efficient, tunable release of aniline from a
triazolyl-based acid-sensitive system has been developed.
This work confirmed the rearrangement of aromatic car-
2-Methoxyethyl 2-{4-[4-(1-Methyl-1-phenylcarbamoyloxyeth-
bamates 4 (or 11) into the corresponding amines 6 (or 12)
in high yields, and has shown the approach to be a practi-
cal strategy for unsubstituted aniline. Direct linking of
substituted anilines to our system (path B) should be a
more general route when the isocyanate strategy is not ap-
plicable, despite the moderate yields obtained. Recycling
of the unreacted material should be possible. Biological
yl)[1,2,3]triazol-1-yl]butoxy}benzoate (4a)
Prepared as described for 2c from 5a (0.2 g, 0.53 mmol), heptane
(20 mL), THF (5 mL), Et3N (15 mL, 0.11 mmol), and PhNCO (75
mL, 0.69 mmol). Purified by flash chromatography (PE–EtOAc,
90:10–0:100).
Yield: 214 mg (81%); colorless oil.
1H NMR (400 MHz, acetone-d6): d = 8.57 (s, 1 H), 7.99 (s, 1 H),
applications with relevant bioactive substituted anilines as 7.72 (dd, J = 1.7, 7.7 Hz, 1 H), 7.49 (m, 3 H), 7.24 (m, 2 H), 7.08
(dd, J = 0.9, 8.5 Hz, 1 H), 6.98 (m, 2 H), 4.51 (t, J = 7.1 Hz, 2 H),
Synthesis 2012, 44, 1090–1094
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Acidic Triazolylaniline Release
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4.38 (m, 2 H), 4.08 (t, J = 6.0 Hz, 2 H), 3.65 (m, 2 H), 3.32 (s, 3 H),
(m, 2 H), 4.01 (t, J = 6.0 Hz, 2 H), 3.74 (s, 6 H), 3.62 (m, 2 H), 3.30
2.17 (m, 2 H), 1.85 (s, 3 H), 1.80 (m, 2 H).
(s, 3 H), 2.10 (m, 2 H), 1.66 (m, 2 H).
13C NMR (100 MHz, acetone-d6): d = 166.9, 159.1, 153.2, 152.3,
140.4, 134.2, 132.0, 129.5, 123.2, 122.4, 121.8, 120.9, 119.1, 114.2,
77.4, 71.2, 68.7, 64.4, 58.8, 50.3, 28.1, 27.9, 26.9.
13C NMR (100 MHz, acetone-d6): d = 166.8, 159.4, 159.2, 153.3,
147.4, 138.5, 134.2, 132.0, 130.4, 128.8, 125.2, 121.7, 120.9, 117.7,
117.1, 114.2, 113.9, 71.2, 68.7, 65.3, 64.4, 58.9, 55.5, 50.2, 27.9,
26.6.
HRMS (ESI): m/z [M + Na] calcd for C26H32N406Na: 519.22195;
found: 519.2210.
HRMS (ESI): m/z [M + Na]+ calcd for C37H40N4O6Na: 659.28401;
found: 659.2838.
2-Methoxyethyl 2-{4-[4-(Diphenylphenylaminometh-
yl)[1,2,3]triazol-1-yl]butoxy}benzoate (6c);
Method A (via Carbamate)
1,1-Dimethyl-prop-2-ynyl 2-Nitrophenylcarbamate (10a)
Prepared as described for 2a from 1a (1.16 mL, 11.12 mmol), hep-
tane (100 mL), Et3N (313 mL, 2.24 mmol) and 2-nitrophenylisocy-
anate (1.00 g, 6.09 mmol). Purification by flash chromatography
(PE–EtOAc, 9:1) afforded carbamate 10a.
To a solution of heptane (40 mL) and anhydrous THF (5 mL) under
a nitrogen atmosphere were added 5c (0.3 g, 0.6 mmol) and Et3N
(17 mL, 0.12 mmol). The solution was heated at reflux and PhNCO
(130 mL, 1.2 mmol) was added. After heating a reflux for 2 h, a
white precipitate could be observed. The solution was cooled, dilut-
ed with EtOAc (25 mL) and washed with brine (2 × 20 mL). The or-
ganic layer was dried, filtered, concentrated and purified by flash
chromatography (PE–EtOAc) to afford the triazolyl amine 6c as a
yellow oil.
Yield: 983 mg (65%); yellow solid; mp 108 °C.
1H NMR (400 MHz, CDCl3): d = 9.81 (s, 1 H), 8.61 (d, J = 8.6 Hz,
1 H), 8.20 (d, J = 8.5 Hz, 1 H), 7.62 (dd, J = 7.6, 8.5 Hz, 1 H), 7.13
(dd, J = 7.5, 8.2 Hz, 1 H), 2.62 (s, 1 H), 1.78 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 151.3, 136.1, 135.9, 135.4, 125.9,
122.3, 120.8, 84.4, 73.2, 72.9, 29.1.
HRMS (ESI): m/z [M + Na]+ calcd for C12H12N2O4Na: 271.06948;
found: 271.0696.
Method B (via Chloride)
To a mixture of 5c (0.2 g, 0.4 mmol) in anhydrous CH2Cl2 (10 mL)
under a nitrogen atmosphere was added HCl (2 M in Et2O, 299 mL,
0.6 mmol). The solution was heated at reflux for 1 h, then Et3N (139
mL, 1.0 mmol) and aniline (55 mL, 0.60 mmol) were added. The
mixture was heated at reflux for 2 h and then cooled. The solvent
was removed and the residue was purified by flash chromatography
(PE–EtOAc + 1% Et3N) to afford 6c as a colorless oil.
2-Methoxyethyl 2-(4-{4-[Bis(4-methoxyphenyl)-2-nitrophenyl-
aminomethyl]-[1,2,3]triazol-1-yl}butoxy)benzoate (12d)
Prepared as described for 6d from 5d (280 mg, 0.5 mmol), heptane
(35 mL), anhydrous THF (7 mL), Et3N (14 mL, 100 mmol), and 2-
nitrophenylisocyanate (123 mg, 0.75 mmol). Purification by flash
chromatography (PE–EtOAc, 80:20→30:70 and 2% Et3N) afforded
12d with traces of starting 5d.
Yield (method A): 319 mg (92%).
Yield (method B): 79 mg (34%).
1H NMR (400 MHz, acetone-d6): d = 7.79 (s, 1 H), 7.71 (dd, J = 1.8,
7.7 Hz, 1 H), 7.55 (m, 4 H), 7.48 (m, 1 H), 7.27 (m, 4 H), 7.20 (m,
2 H), 7.07 (d, J = 8.3 Hz, 1 H), 6.99 (dt, J = 0.8, 7.6 Hz, 1 H), 6.87
(m, 2 H), 6.48 (m, 3 H), 6.01 (s, 1 H), 4.49 (t, J = 6.9 Hz, 2 H), 4.31
(m, 2 H), 4.02 (t, J = 6.0 Hz, 2 H), 3.62 (m, 2 H), 3.30 (s, 3 H), 2.10
(m, 2 H), 1.65 (m, 2 H).
13C NMR (100 MHz, acetone-d6): d = 166.8, 159.1, 152.5, 147.3,
146.3, 134.2, 132.0, 129.2, 128.8, 128.7, 127.6, 125.6, 121.7, 120.9,
117.9, 117.2, 114.2, 71.1, 68.7, 66.3, 64.4, 58.8, 50.2, 27.9, 26.5.
Yield: 124 mg (34%).
1H NMR (400 MHz, acetone-d6): d = 9.62 (s, 1 H), 8.13 (dd, J = 8.6,
1.52 Hz, 1 H), 7.89 (s, 1 H), 7.75 (m, 2 H), 7.51 (m, 2 H), 7.09 (m,
2 H), 7.01 (td, J = 7.5, 1.0 Hz, 2 H), 6.90 (d, 4 H), 6.64 (ddd,
J = 8.4, 7.0, 1.2 Hz, 1 H), 6.5 (dd, J = 8.8, 1.1 Hz, 1 H), 4.53 (t,
J = 7.0 Hz, 2 H), 4.31 (m, 2 H), 4.06 (t, J = 6.0 Hz, 2 H), 3.79 (s,
6 H), 3.64 (t, J = 8.3 Hz, 2 H), 3.33 (s, 3 H), 2.16 (m, 2 H), 1.73 (m,
2 H).
13C NMR (100 MHz, acetone-d6): d = 166.5, 159.8, 159.5, 152.2,
145.0, 140.5, 137.0, 135.1, 134.2, 132.0, 130.1, 126.4, 125.1, 120.9,
120.1, 116.8, 114.4, 114.3, 114.2, 74.5, 71.1, 68.8, 64.4, 58.8, 50.4,
27.8, 26.6.
HRMS (ESI): m/z [M + Na]+ calcd for C35H36N4O4Na: 599.26288;
found: 599.2629.
2-Methoxyethyl 2-(4-{4-[Bis(4-methoxyphenyl)phenylamino-
methyl][1,2,3]triazol-1-yl}butoxy)benzoate (6d);
Method A (via Carbamate)
Prepared as described for 6c from 5d (0.216 g, 0.38 mmol), heptane
(30 mL), anhydrous THF (5 mL), Et3N (11 mL, 0.077 mmol) and
PhNCO (63 mL, 0.58 mmol).
HPLC Monitoring
A solution of 4a/6c/6d (0.4 mL of a 0.5 mg/mL solution in MeCN)
were added to citrate buffer (1.6 mL) under vigorous stirring. Sam-
ples were injected at different times and analyzed with an automat-
ed Waters LaChrom Elite equipped with a diode-array detector
(DAD Hitachi L-2455; 200–400 nm), an autosampler (Hitachi L-
2200), a pump (Hitachi L-2130), and a reversed-phase HPLC col-
umn (Lichrocart 150–4,6 purospher STAR).
Method B (via Chloride)
Prepared as described for 6c from 5d (0.2 g, 0.36 mmol), CH2Cl2
(15 mL), SOCl2 (30 mL, 0.42 mmol) and Et3N (150 mL, 1.07 mmol).
Purified by flash chromatography (two times; PE–EtOAc, 80:20 →
30:70 and 2% Et3N) to afford 6d with traces of starting 5d.
1H NMR Monitoring
Hydrolysis of 12d was followed by H NMR spectroscopic analy-
1
sis. A reaction mixture (10 mL) was prepared using the same con-
centration ratios used for HPLC monitoring (buffer, MeCN).
Samples (1 mL) were collected at regular times from this reaction
mixture, neutralized with 1 M KHCO3, extracted with EtOAc (3 × 5
mL), dried, and concentrated to give a crude material, which was
directly analyzed by 1H NMR. Typical 1H NMR signals from the tri-
azole (C-H) and anisyl (Ar-H and OMe) groups were different in
compound 12d and released alcohol 5d and were used to obtain av-
Yield (method A): 170 mg (70%).
Yield (method B): 114 mg (50%).
1H NMR (400 MHz, acetone-d6): d = 7.73 (m, 2 H), 7.47 (ddd, J =
1.8, 7.4, 8.5 Hz, 1 H), 7.43 (m, 4 H), 7.05 (dd, J = 0.6, 8.5 Hz, 1 H),
6.99 (dt, J = 1.0, 7.6 Hz, 1 H), 6.88 (dd, J = 7.3, 8.7 Hz, 2 H), 6.81
(m, 4 H), 6.49 (m, 3 H), 5.91 (s, 1 H), 4.47 (t, J = 7.0 Hz, 2 H), 4.32
erage values for t1/2
.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1090–1094

1094
R. Delatouche et al.
PAPER
(4) (a) Patel, V. F.; Hardin, J. N.; Mastro, J. M.; Law, K. L.;
Theoretical Calculations
All structures were studied using the B3LYP method as previously
Zimmermann, J. L.; Ehlhardt, W. J.; Woodland, J. M.;
Starling, J. J. Bioconjugate Chem. 1996, 7, 497. (b)Fréchet,
J. M. J.; Gillies, E. R.; Goodwin, A. P. Bioconjugate Chem.
2004, 15, 1254.
described,5 with the Gaussian 09 package.
Acknowledgment
(5) Delatouche, R.; Mondon, M.; Gil, A.; Frapper, G.;
Bachmann, C.; Bertrand, P. Tetrahedron 2011, 67, 401.
(6) Mondon, M.; Delatouche, R.; Bachmann, C.; Frapper, G.;
Len, C.; Bertrand, P. Eur. J. Org. Chem. 2011, 2111.
(7) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
(b) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 633.
(c) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.
Int. Ed. 2001, 40, 2004. (d) Bertrand, P.; Gesson, J.-P.
J. Org. Chem. 2007, 72, 3596.
(8) Gooding, O. W.; Beard, C. C.; Jackson, D. Y.; Wren, D. L.;
Cooper, G. F. J. Org. Chem. 1991, 56, 1083.
(9) Streidl, N.; Antipova, A.; Mayr, H. J. Org. Chem. 2009, 74,
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The authors thank the Centre National de la Recherche Scientifique
(CNRS) and the Agence National de la Recherche (ANR) for finan-
cial support and ANR for a grant to R.D.
References
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Synthesis 2012, 44, 1090–1094
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