Click Cchemistry with O-dimethylpropargylcarbamate for preparation of pH-sensitive functional groups. A case study

Article abstract of DOI:10.1021/jo070131j

(Chemical Equation Presented) Click chemistry has became an important tool for molecular constructs such as biopolymers. During the development of biodegradable multifunctional poly(ethylene oxide) (PEO) polymers suitable for click chemistry in water, an

Full text of DOI:10.1021/jo070131j

SCHEME 1. Cycloaddition of Alkynes and Azides
Click Chemistry with
O-Dimethylpropargylcarbamate for Preparation
of pH-Sensitive Functional Groups. A Case Study
Philippe Bertrand* and Jean Pierre Gesson
Laboratoire Synthe`se et Re´actiVite´ des Substances Naturelles,
UMR CNRS 6514, 40 AVenue du Recteur Pineau,
86022 Poitiers Cedex, France
polyphenylacetylenes6 for material development, and in the field
of combinatorial chemistry.7 Biocompatible and biodegradable
polymers for therapeutic usage have been developed for many
decades8 either as carrier systems or to improve physical
properties such as solubility. Several strategies were developed
to incorporate bioactive molecules into polymers to produce
slow releasing systems based on biological transformations such
as enzymatic hydrolysis or pH variations,9 the polymer carrier
being usually decomposed. Poly(ethylene oxide) (PEO) poly-
mers have been known for a long time to be biocompatible,
nonimmunogenic, and hydrophilic, increasing water solubility,
and are approved by the FDA.10 They are themselves the major
polymeric material when higher molecular weight derivatives
are used11 or are integrated in more complex systems as
intermediate chains.12 A PEG-asparaginase bioconjugate has
been developed for the treatment of acute lymphoblastic
leukaemia.13 In a project devoted to the development of
functional PEO polymers for drug delivery, we were interested
in biodegradable modified branched PEO with a moiety
designed for the introduction of multipurpose functional groups
by click chemistry and also for drug release in biological systems
under acidic conditions.9 Polymer biodegradability can also be
obtained by integration of pH-sensitive groups (orthoesters,14
acetals15) in the polymer structure.
philippe.bertrand@uniV-poitiers.fr
ReceiVed February 1, 2007
Click chemistry has became an important tool for molecular
constructs such as biopolymers. During the development of
biodegradable multifunctional poly(ethylene oxide) (PEO)
polymers suitable for click chemistry in water, an unexpected
reaction leading to a mixture of triazole cycloadducts was
observed. This result was attributed to an intramolecular
ligand effect, and alternative conditions were evaluated. An
efficient method was then implemented allowing the access
in high yields to the expected triazolylcarbamate. pH
sensitivity of the obtained isopropyltriazolylcarbamate was
demonstrated at acidic pH.
Model compound 3 was designed (Scheme 2) to integrate
these several requirements. In this study, a minimal methoxy-
protected ethylenoxide motif is used and linked to a benzoate
ester, for the purpose of biodegradability. The phenyl ring of
the benzoate group can also be the central point of multipurpose
functionality, provided multiple substitutions. In this work we
limited these substitutions by selecting salicylic acid, the phenol
group being converted to an azidoether necessary for the click
In 1963, Huisgen reviewed the [3 + 2] cycloaddition reactions
between 1,3 dipoles and unsaturated bonds.1 When realized
under thermal conditions, this reaction generally led to two
possible regioisomeric adducts limiting the possible applications
of this reaction (Scheme 1), the ratio being governed by steric
and electronic factors. Applied to terminal alkynes and azides,
this reaction allows access to [1,4] and [1,5] disubstituted 1,2,3-
triazoles. In 2001, Sharpless showed in this latter case that the
use of Cu(I) salts gave only [1,4] cycloadducts in high yields.2
As this reaction can be realized in several solvents, including
water, and supports many functional groups, it has been widely
used in several ways as “click chemistry”. A selective [1,5]
cycloadduct formation was also proposed.3 Click chemistry has
been applied to several types of polymers such as modified
carbohydrates4 or polyamides5 for biocompatible purposes,
(5) Jang, H.; Fafarman, A.; Holub, J.; Kirshenbaum, K. Org. Lett. 2005,
7, 1951.
(6) Englert, B. C.; Bakbak, S.; Bunz, U. H. F. Macromolecules 2005,
38, 5868.
(7) (a) Tornøe, C. W.; Sanderson, S. J.; Mottram, J. C.; Coombs, G. H.;
Meldal, M. J. Comb. Chem. 2004, 6, 312. (b) Su, S.; Giguere, J. R.; Schaus,
S. E.; Porco, J. A., Jr. Tetrahedron 2004, 60, 8645. (c) Bettinetti, L.; Lo¨ber,
S.; Hu¨bner, H.; Gmeiner, P. J. Comb. Chem. 2005, 7, 309-316.
(8) (a) Ringsdorf, H. J. Polym. Sci. Polym. Symp. 1975, 51, 135. (b)
Duncan, R.; Gac-Breton, S.; Keane, R.; Musila, R.; Sat, Y. N.; Satchi, R.;
Searle, F. J. Controlled Release 2001, 74, 135. (c) Nori, A.; Kopecek, J.
AdV. Drug DeliVery ReV. 2005, 57, 609.
(9) Ulbrich, K.; Subr, V. AdV. Drug DeliVery ReV. 2004, 56, 1023.
(10) Israelachvili, J. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 8378.
(11) Conover, C. D.; Greenwald, R. B.; Pendri, A.; Gilbert, K. W.; Shum,
K. L. Cancer Chemother. Pharmacol. 1998, 42, 407.
(12) Bafaloukos, D.; Papadimitriou, C.; Linardou, H.; Aravantinos, G.;
Papakostas, P.; Skarlos, D.; Kosmidis, P.; Fountzilas, G.; Gogas, H.;
Kalofonos, C.; Dimopoulos, A. M. Br. J. Cancer 2004, 91, 1639.
(13) Mu¨ller, H.-J.; Beier, R.; da Palma, J. C.; Lanvers, C.; Ahlke, E.;
von Schu¨tz, V.; Gunkel, M.; Horn, A.; Schrappe, M.; Henze, G.; Kranz,
K.; Boos, J. Cancer Chemother. Pharmacol. 2002, 49, 149.
(14) Guo, X.; Szoka, F. C., Jr. Bioconjugate Chem. 2001, 12, 291.
(15) (a) Asokan, A.; Cho, M. J.; Bioconjugate Chem. 2004, 15, 1166.
(b) Heffernan, M. J.; Murthy, N. Bioconjugate Chem. 2005, 16, 1340.
(1) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565. (b) Huisgen, R.
Angew. Chem., Int. Ed. 1963, 2, 633.
(2) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004.
(3) Majireck, M. M.; Weinreb, S. M. J. Org. Chem. 2006, 71, 8680.
(4) (a) Wan, Qian.; Chen, J.; Chen, G.; Danishefsky, S. J. J. Org. Chem.
2006, 71, 8244. (b) Srinivasachari, S.; Liu, Y.; Zhang, G.; Prevette, L.;
Reineke, T. M. J. Am. Chem. Soc. 2006, 128, 8176.
10.1021/jo070131j CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/27/2007
3596
J. Org. Chem. 2007, 72, 3596-3599

SCHEME 2. Preparation and Hydrolysis of Model
Compound 3
SCHEME 4. Sharpless Cycloadditionsa
a Conditions: (i) CuSO4‚5H2O, Na ascorbate, tBuOH/H2O 1:1; (ii)
benzene, p-TsOH, reflux Dean-Stark, 45%.
SCHEME 3. Preparation of Intermediates 1 and 2a
SCHEME 5. Proposed Mechanism for the Rearrangement
Leading to 4, 10, and 11
a Conditions: (i) H2SO4, MeO-(CH2)2-OH, 44%; (ii) K2CO3, DMF, Br-
(CH2)4-Br, 80%; (iii) NaN3, acetone, 97%; (iv) pNO2-Ph-OCO-Cl, pyridine,
72%; (v) BnNH2, NEt3, 92%.
chemistry. The triazole ring obtained by click chemistry can
be considered as a substitute for a phenyl ring and is expected
to facilitate the acidic cleavage of the carbamate group,
especially by preparing an isopropyltriazolylcarbamate,16 which
under acidic hydrolysis will afford alcohol 4 and benzylamine
in our case. This cleavage method is an original alternative
approach compared to other N-triazole deprotections realized
under highly acidic conditions (TFA, CH2Cl2).17 Thus Sharpless
cycloaddition conditions were selected to prepare 3 from azide
1 and propargylcarbamate 2. Equivalent reactions were described
with unsubstituted O-propargylcarbamate in a ligation protocol
for the synthesis of peptides.18 Interestingly, the opposite
N-propargyl19 and N-disubstituted propargylcarbamate20 cy-
cloadditions were reported.
Esterification of salicylic acid 5 afforded phenol 6 (Scheme
3, H2SO4, CH3O-(CH2)2-OH, 44%21), which gave after etheri-
fication bromoether 7 (dibromobutane, K2CO3, acetone, 80%).
Azide 1 is finally obtained from 7 by bromine substitution
(NaN3, DMF, 97%). Carbamate 2 was prepared from butynol
8 via the paranitrophenoxycarbonate 9 (pNO2-Ph-OCO-Cl,
pyridine, 72%) followed by displacement with benzylamine
(BnNH2, NEt3, 92%); 1 and 2 were then reacted using the
Sharpless procedure (Scheme 4, CuSO4‚5H2O, NaAscorbate,
tBuOH/H2O 1:1) in order to obtain cycloadduct 3. 1H NMR of
the crude material revealed the disappearance of the terminal
alkyne hydrogen (singlet 2.8 ppm) of the alkyne 2, and several
singlets appeared around 7.5 ppm, attributed to hydrogens from
newly formed triazole rings.
polar major compounds alcohol 4 and amine 10. Identification
of 4, 10, and 11 was made by ESI MS, comparison with
literature data,22 and for 4 and 11, by cycloaddition of butynol
8 with 1 and subsequent dehydration, giving identical 1H NMR
spectra compared to the products obtained under Sharpless
conditions. Cycloaddition of carbamate 2 with azide 1 is the
first example of unexpected results obtained by click chemistry
realized in water, which is generally tolerant to various substrates
and reactions conditions.23 Two hypothesis were first considered.
Substitution of propargylic acetates by amines catalyzed by Cu-
(I) salts was described by Murahashi and co-workers24 with a
mechanism shown in Scheme 5. Thus carbocation 12 can be
formed from 2 and then be trapped either by water or by the
released benzylamine, leading to 4 and 10, respectively, after
cycloaddition. Deprotonation of 12 can also give alkene 11.
Triazoles are good copper chelators25 and could also be involved
in the rearrangement of 3 after cycloaddition. As carbamate 2
and triazole 3 were found stable in the Sharpless conditions,
both hypothesis were ruled out.
DFT studies made by Sharpless and co-workers26 showed that
a copper intermediate 13 is formed in water during the
cycloaddition process. On the other hand, Kebarle and co-
Separation allowed the NMR characterization of small
amounts of elimination product 11 and expected 3, and the more
(16) (a) Moulin, F. HelV. Chim. Acta 1952, 35, 167. (b) Voelter, W.;
Mu¨ller, J. Liebigs Ann. Chem. 1983, 248.
(17) Lo¨ber, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5,
1753.
(22) Thibault, R. J.; Takizawa, K.; Lowenheilm, P.; Helms, B.; Mynar,
J. L.; Fre´chet, J. M. J.; Hawker, C. J. J. Am. Chem. Soc. 2006, 128, 12084.
(23) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem.
2006, 1, 51.
(18) Aucagne, V.; Leigh, A. D. Org. Lett. 2006, 8, 4505.
(19) Ossipov, D. A.; Hilborn, J. Macromolecules 2006, 39, 1709.
(20) (a) Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.;
Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521. (b) Sewald, N.; Burger,
K. Liebigs Ann. Chem. 1992, 9, 947.
(24) Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi, S.-I. J. Org. Chem.
1994, 59, 2282.
(25) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
2004, 6, 2853.
(26) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210.
(21) McMillan, F. H.; King, J. A. J. Am. Chem. Soc. 1945, 67, 2271.
J. Org. Chem, Vol. 72, No. 9, 2007 3597

TABLE 1. Conditions for CuI-Catalyzed Cycloadditions of 1 with
2 and 3:10:11 Ratios Obtaineda
entry
base
solvent
3:10:11 relative %
isolated yields
30:37:11
1
2
3
4
5
DIPEAa
DMFa
toluene
toluene
toluene
pyridine
toluene
38.5:47.4:14.1c
35.7:50.0:14.3d
76.9:0:23.1d,e
97.5:0:2.5c
f
-
-
pyridinea
f
85:0:2.2
bipyridyleb
76.9:15.4:7.7d,e
-
f
FIGURE 1. Proposed bonding ligand effect.
a General conditions: 0.1 mmol alkyne, 0.1 mmol azide, 0.01 mmol CuI,
0.1 mmol amine, 1 mL of solvent. b 0.2 mmol catalyst. c Determined from
isolated products. d Determined from 1H NMR crude mixture. e Incomplete
reaction. f Not determined.
solvating effect. This latter condition was not optimized but a
complete conversion can be expected by longer reaction time
or higher bipyridile loading.
Our results can be rationalized according to Figure 1. In water,
the C-O single bond of the carbamate is probably weaker due
to donor ligand effect of the CdO bond. The formation of a
stabilized carbocation is also favored and both effects are
expected to lead to carbamate bond breaking. Using a stronger
ligand such as pyridine disrupts the carbonyl bonding to copper,
stabilizing the C-O single bond in 16. This conclusion is
consistent with the results reported in Table 1, with the following
ligand strength for our current reaction: pyridine > bypyridyle
> DMF ) DIPEA > H2O.
Having in hand a practical method to prepare carbamate 3,
acidic hydrolysis was then evaluated. Two pH buffers were
selected: pH 1 (HCl/KCl buffer, Normex dose) and pH 4 (citric
acid buffer). A 10 mg portion of 3 was mixed with 0.5 mL of
tert-butanol to help dissolution in 10 mL of buffer, and 1 mL
samples were neutralized and analyzed at 0.5, 1, 2.5, 4, 6.5,
22, 48, 72, and 96 h. Evolution of the remaining carbamate 3
was compared to the formation of alcohol 4 (3 + 4 ) 100%).
Hydrolysis at pH 1 appeared to be a fast process (Figure 3 and
4, Supporting Information), as most of the carbamate was
hydrolyzed at 0.5 h and completely disappeared after 2.5 h. At
pH 4, about 50% hydrolysis (t1/2) is obtained at 20 h, and 75%
at 72 h (3 days).
In conclusion, this work is to our knowledge the first example
of click chemistry applied to O-dimethylpropargyl carbamates.
Initial attempts to run the reaction in the water system described
by Sharpless led to unexpected products, a result attributed to
the lability of the O-propargylcarbamate group in the presence
of Cu(I) salts. The use of nonpolar solvent such as toluene with
amines or Cu(I) chelating agents highlighted the importance of
the solvating effect for this unwanted result. Changing the
reaction medium to pyridine as solvent allows the formation of
a stable copper intermediate 16, giving a practical method for
the cycloaddition of such propargylcarbamates. Hydrolysis of
carbamate 3 was then validated at acidic pH levels, showing
the potential use of such triazole systems in this kind of
applications. Work is in progress in our laboratory for the
development and optimization of these new types of pH sensitive
releasing systems for chemical or biochemical applications.
worker27 determined in the gas phase the following bonding
order for several ligands of Cu(I): amines > R-CONR′2 >
RCOOR′ > H2O. From this literature information, a mechanism
can be postulated with the formation of intermediate 14, with
carbamate bonding properties considered equivalent to those
of ester or amide and stronger than water. Thus 15 can be
formed by displacement of one molecule of water by the
carbamate group, facilitated by a possible steric hindrance of
the gem dimethyl group,28 leading to 10 by an intramolecular
rearrangement or to 4 by water trapping. Water as solvent
affording alcohol 4, other reaction conditions were consid-
ered.7,29
Toluene was selected as solvent, CuI as the catalyst, and
several amines as ligands were tested (Table 1). The best
condition was determined conveniently by the 1H NMR
spectrum of the crude material, several hydrogen signals being
easily quantified in the mixture (Figure 2, Supporting Informa-
tion). Reacting 1 and 2 in toluene, CuI, and DIPEA (Table 1,
entry 1) produced the carbamate 3, with amine 10 as the major
product, and small amounts of alkene 11. As expected, in
absence of water, alcohol 4 was not detected. DMF (Table 1,
entry 2) gave quite the same results as DIPEA, and only
Pyridine7a gave an improvement (Table 1, entry 3) with 3 being
the major product but with incomplete reaction. Interestingly,
10 was not observed in these conditions.
Higher solvatation of the copper acetylide by pyridine is
postulated according to Kebarle, by the fact that aromatic
amines, such bipyridyles, were used to improve click chemistry
applications30 and that polar organic solvents better disolved
Cu(I) salts.31 Improvement of cycloaddition between pegylated
azides and acetylenic amide in CH2Cl2/H2O due to better
solubility of organic reacting materials was also reported.32 To
increase the yield obtained with the toluene/pyridine system,
cycloaddition was then conducted in pyridine only, and 3 was
obtained in high yield, with traces of elimination product 11
(Table 1, entry 4 and Figure 2E, Supporting Information).
Alternatively, with a bipyridyle/toluene system 3 was obtained
as the major compound, with incomplete reaction (Table 1, entry
5 and Figure 2D, Supporting Information), underlining this
Experimental Section
(27) Deng, H.; Kebarle, P. J. Am. Chem. Soc. 1998, 120, 2925.
(28) da Silva, E. F.; Svendsen, H. F. Ind. Eng. Chem. Res. 2006, 45,
2497.
(29) Fazio, F.; Bryan, M. C.; Blixt, O.; Paulson, J. C.; Wong, C.-H. J.
Am. Chem. Soc. 2002, 124, 14397.
(30) (a) Meng, J.-C.; Fokin, V. V.; Finn, M. G. Tetrahedron Lett. 2005,
46, 4543. (b) Golas, P. L.; Tsarevsky, N. V.; Sumerlin, B. S.; Matyjaszewski,
K. Macromolecules 2006, 39, 6451.
(31) Girard, C.; O¨ nen, E.; Aufort, M.; Beauvie`re, S.; Samson, E.;
Herscovici, J. Org. Lett. 2006, 8, 1689.
(32) Lee, B.-Y.; Park, S. R.; Jeon, H. B.; Kim, K. S. Tetrahedron Lett.
2006, 47, 5105.
Toluene Cycloaddition Conditions. Alkyne (0.1 mmol) and
azide (0.1 mmol) were dissolved in toluene (1 mL). CuI (1.9 mg,
0.01 mmol) and amine (0.1 mmol) were then added. After stirring
overnight at ambient temperature, solvent and amine were removed
under reduced pressure at 40 °C, and the residual oil was purified
by preparative TLC (silica, AcOEt/EP 50:50). Depending on solvent
used (Table 1), amine 10, carbamate 3, and alkene 11 were obtained
in various ratios.
Pyridine Cycloaddition Conditions. Alkyne (0.1 mmol) and
azide (0.1 mmol) were dissolved in pyridine (1 mL). CuI (1.9 mg,
3598 J. Org. Chem., Vol. 72, No. 9, 2007

0.01 mmol) was then added. After stirring overnight at ambient
temperature, pyridine was removed under reduced pressure at 40
°C, and the residual oil was purified by preparative TLC (silica,
AcOEt/EP 50:50), giving carbamate 3 (43.8 mg, 85%, yellow oil)
and alkene 11 (0.85 mg, 2.4%, colorless oil).
(ESI) calcd for [M+] C26H34N4O4 466.59, found (M + Na)+
489.2485.
2-[4-(4-Isopropenyl-[1,2,3]triazol-1-yl)-butoxy]-benzoic Acid
1
2-Methoxyethyl Ester (11). H NMR (300 MHz, CDCl3) δ 1.86
(m, 2H), 2.11 (s, 3H), 2.21 (m, 2H), 3.40 (s, 3H), 3.70 (m, 2H),
4.05 (t, 2H, J ) 5.9 Hz), 4.43 (m, 2H), 4.49 (t, 2H, J ) 6.9 Hz),
5.07 (t, 1H, J ) 1.5 Hz), 5.68 (s, 1H), 6.92 (d, 1H, J ) 8.3 Hz),
7.0 (td, 1H, J ) 0.8, 7.6 Hz), 7.44 (ddd, 1H, J ) 1.7, 7.4, 9.1 Hz),
7.65 (s, 1H), 7.83 (dd, 1H, J ) 1.7, 7.8 Hz). 13C NMR (75.5 MHz,
CDCl3) δ 21.0, 26.3, 27.5, 50.2, 59.3, 64.1, 68.3, 71.0, 112.6, 113.4,
120.2, 120.6, 120.7, 132.1, 134.0, 134.1, 149.1, 158.8, 166.4. HRMS
(ESI) calcd for [M+] C26H34N4O4 359.43, found (M + Na)+
382.1743.
1
Carbamate (3). H NMR (300 MHz, CDCl3) δ 1.85 (s + m,
8H), 2.20 (m, 2H), 3.39 (s, 3H), 3.69 (m, 2H), 4.03 (t, 2H, J )
5.75 Hz), 4.24 (d, 2H, J ) 5.95 Hz), 4.44 (m, 4H), 5.2 (sb, 1H),
6.91 (d, 1H, J ) 8.28 Hz), 6.97 (t, 1H, J ) 7.67 Hz), 7.28 (m,
5H), 7.44 (ddd, 1H, J ) 1.8, 7.8, 15.7 Hz), 7.65 (s, 1H), 7.81 (dd,
1H, J ) 1.6, 7.8 Hz). 13C NMR (75.5 MHz, CDCl3) δ 26.4, 27.3,
28.1, 45.0, 50.2, 59.3, 64.1, 68.2, 70.9, 76.8, 113.4, 120.5, 120.7,
121.6, 127.7, 127.8, 128.9, 132.2, 134.0, 139.0, 152.3, 158.8, 155.7,
166.5. HRMS (ESI) calcd for [M+] C27H34N4O6 510.60, found (M
+ Na)+ 533.2358.
Acknowledgment. The authors thank CNRS for financial
2-{4-[4-(1-Benzylamino-1-methyl-ethyl)-[1,2,3]triazol-1-yl]-
butoxy}-benzoic Acid 2-Methoxyethyl Ester (10). 1H NMR (300
MHz, CDCl3) δ 1.53 (s, 6H), 1.86 (m, 2H), 1.97 (sb, 1H), 2.2 (m,
2H), 3.39 (s, 3H), 3.50 (s, 2H), 3.68 (m, 2H), 4.05 (t, 2H, J ) 5.8
Hz), 4.41 (m, 2H), 4.48 (t, 2H, J ) 7.0 Hz), 6.91 (d, 1H, J ) 8.4
Hz), 6.97 (td, 1H, J ) 0.8, 7.6 Hz), 7.22 (m, 1H), 7.27 (m, 4H),
7.43 (ddd, 1H, J ) 1.8, 7.5, 8.3 Hz), 7.56 (s, 1H), 7.83 (dd, 1H, J
) 1.8, 7.7 Hz). 13C NMR (75.5 MHz, CDCl3) δ 26.0, 27.0, 28.4,
47.9, 49.8, 52.3, 58.9, 63.7, 67.8, 70.6, 113.0, 120.1, 120.3, 126.7,
128.25, 128.31, 131.8, 133.6, 140.9, 154.7, 158.8, 166.0. HRMS
support.
Supporting Information Available: Experimental procedure
and analytical data for compounds 1, 2, 3, 4, 6, 7, 9, 10, and 11,
and acidic hydrolysis of 3. HPLC analysis of compounds 3, 4, and
10 and example of chromatograms for time-dependent acidic
hydrolysis of compound 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO070131J
J. Org. Chem, Vol. 72, No. 9, 2007 3599