Synthesis of amino-1,2,4-triazoles by reductive ANRORC rearrangements of 1,2,4-oxadiazoles

Article abstract of DOI:10.1021/jo102049r

The reaction of various 1,2,4-oxadiazoles with an excess of hydrazine in DMF has been investigated. 3-Amino-1,2,4-triazoles are produced through a reductive ANRORC pathway consisting of the addition of hydrazine to the 1,2,4-oxadiazole followed by ring-opening, ring-closure, and final reduction of the 3-hydroxylamino-1,2,4-triazole intermediate. The general applicability of 1,2,4-oxadiazoles ANRORC reactivity is demonstrated also in the absence of C(5)-linked electron-withdrawing groups.

Full text of DOI:10.1021/jo102049r

pubs.acs.org/joc
SCHEME 1. ANRORC of 1,2,4-Oxadiazoles with
Dinucleophiles
Synthesis of Amino-1,2,4-triazoles by Reductive
ANRORC Rearrangements of 1,2,4-Oxadiazoles
Antonio Palumbo Piccionello, Annalisa Guarcello,
ꢀ
Silvestre Buscemi, Nicolo Vivona, and Andrea Pace*
ꢀ
ꢀ
Dipartimento di Chimica Organica “E. Paterno”, Universita
degli Studi di Palermo, Viale delle Scienze - Parco d’Orleans II,
I-90128 Palermo, Italy
five-membered heterocycles and are recently gaining impor-
tance from both a mechanistc and synthetic point of view.3-13
These include reactions on electron-poor five-membered sys-
tems such as 1,3,4-oxadiazoles,3 1,3,4-thiadiazoles,4 nitro-
imidazoles,3,5 bis(1,3,4-thiadiazol-2-yl)-1,3,5-triazinium
halides,6 isothiazole,7 and isoxazoles.8 Recently, by taking
advantage of 1,2,4-oxadiazoles reactivity and their high
tendency to rearrange into more stable heterocycles,1,14 we
have reported several ANRORC rearrangements of fluori-
nated-1,2,4-oxadiazoles as a valid approach for the obtain-
ing fluorinated heterocycles such as 1,2,4-triazoles,9 1,2,4-
oxadiazoles,10 1,2,4-triazines,9b,11 1,2,4-oxadiazinones,12 and
indazoles.13 In all of these reactions the 1,2,4-oxadiazole
substrate acts as a dielectrophile and at least one of its ring
atoms, generally the C(5), undergoes nucleophilic attack by
the bidentate reagent. The product is a function of the leaving
group, which could be internal, i.e. the O(1)-N(2) moiety
leading to loss of hydroxylamine,9,10 or part of the C(3)-11,12
or C(5)-linked13 side chain. On the other hand, the effect of a
leaving group directly linked to C(3) has not been studied.
In this context, ANRORC reactivity of 1,2,4-oxadiazoles has
been so far ascribed to the presence of a strongly electron-
withdrawing fluorinated group (RF) linked at the C(5).
Moreover, the identity of the final ring depended on the
nature of the side chain (SC) (Scheme 1). However, the pos-
sibility to exploit ANRORC of differently substituted
(or nonfluorinated) 1,2,4-oxadiazoles was never evaluated.
Here we report the study of the hydrazinolysis reaction of
1,2,4-oxadiazoles 4a-m15 as a function of solvent, of the
nature of the C(3)-linked leaving group (LG), and of the
C(5)-linked substituent (Chart 1).
pace@unipa.it
Received October 15, 2010
The reaction of various 1,2,4-oxadiazoles with an excess
of hydrazine in DMF has been investigated. 3-Amino-
1,2,4-triazoles are produced through a reductive ANRORC
pathway consisting of the addition of hydrazine to the
1,2,4-oxadiazole followed by ring-opening, ring-closure,
and final reduction of the 3-hydroxylamino-1,2,4-triazole
intermediate. The general applicability of 1,2,4-oxadia-
zoles ANRORC reactivity is demonstrated also in the
absence of C(5)-linked electron-withdrawing groups.
Heterocyclic rearrangements represent a powerful tool for
the synthesis of heterocycles which are difficult to obtain
through classical methodologies.1,2 In this context, ANRORC
(Addition of a Nucleophile, Ring-Opening and Ring-Closure)
reactions represent a useful strategy for ring transformation
of heterocyclic systems.2 ANRORC rearrangements of six-
membered heterocycles have been extensively studied by Van
der Plas and co-workers.2 Whether classified as ANRORC
or not, similar ring transformations have been reported for
(9) (a) Buscemi, S.; Pace, A.; Pibiri, I.; Vivona, N.; Spinelli, D. J. Org.
Chem. 2003, 68, 605–608. (b) Buscemi, S.; Pace, A.; Palumbo Piccionello, A.;
Pibiri, I.; Vivona, N.; Giorgi, G.; Mazzanti, A.; Spinelli, D. J. Org. Chem.
2006, 71, 8106–8113. (c) Palumbo Piccionello, A.; Pace, A.; Buscemi, S.;
Vivona, N. ARKIVOC 2009, vi, 235–244.
(10) Buscemi, S.; Pace, A.; Pibiri, I.; Vivona, N.; Lanza, C. Z.; Spinelli, D.
Eur. J. Org. Chem. 2004, 974–980.
(11) Buscemi, S.; Pace, A.; Palumbo Piccionello, A.; Macaluso, G.;
Vivona, N.; Spinelli, D.; Giorgi, G. J. Org. Chem. 2005, 70, 3288–3291.
(12) Palumbo Piccionello, A.; Pace, A.; Buscemi, S.; Vivona, N.; Giorgi,
G. Tetrahedron Lett. 2009, 50, 1472–1474.
(13) (a) Palumbo Piccionello, A.; Pace, A.; Pibiri, I.; Buscemi, S.; Vivona,
N. Tetrahedron 2006, 62, 8792–8797. (b) Palumbo Piccionello, A.; Pace, A.;
Pierro, P.; Pibiri, I.; Buscemi, S.; Vivona, N. Tetrahedron 2009, 65, 119–127.
(14) Pace, A.; Pierro, P. Org. Biomol. Chem. 2009, 7, 4337–4348.
(15) (a) Eloy, F.; Deryckere, A.; Van Overstraeten, A. Bull. Soc. Chim.
Belg. 1969, 78, 47–53. (b) Westphal, G.; Schmidt, R. Z. Chem. 1974, 14, 94
(Chem, Abstr., 1974, 81, 13443). (c) Buscemi, S.; Cicero, M. G.; Vivona, N.
J. Chem. Soc., Perkin I 1988, 1313–1315. (d) Buscemi, S.; Pace, A.; Frenna,
V.; Vivona, N. Heterocycles 2002, 57, 811–823. (e) Choi, P.; Rees, C. W.;
Smith, E. H. Tetrahedron Lett. 1982, 23, 125–128. (f) Palumbo Piccionello,
A.; Pace, A.; Buscemi, S.; Vivona, N. Org. Lett. 2009, 11, 4018–4020.
(1) See, for example: (a) Ruccia, M.; Vivona, N.; Spinelli, D. Adv. Heterocycl.
Chem. 1981, 29, 141–169. (b) Vivona, N.; Buscemi, S.; Frenna, V.; Cusmano, G.
Adv. Heterocycl. Chem. 1993, 56, 49–154. (c) Pace, A.; Pibiri, I.; Buscemi, S.;
Vivona, N. Heterocycles 2004, 63, 2627–2648. (d) Katritzky, A. R.; Ramsden,
C. A.; Scriven, E. F. V.; Taylor, R. J. K., Eds. Comprehensive Heterocyclic
Chemistry III; Pergamon: Oxford, UK, 2008.
(2) Van der Plas, H. C. Adv. Heterocycl. Chem. 1999, 74, 1–253.
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(3) (a) Hetzheim, A.; Mockel, K. Adv. Heterocycl. Chem. 1966, 7, 183–
224. (b) Reid, J. R.; Heindel, N. D. J. Heterocycl. Chem. 1976, 13, 925–926.
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(4) Sandstrom, J. Adv. Heterocycl. Chem. 1968, 9, 165–209.
(5) Suwinski, J.; Pawlus, W.; Salwinska, E.; Swierczek, K. Heterocycles
1994, 37, 1511–1520.
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(8) (a) Adamo, M. F. A.; Duffy, E. F.; Donati, D.; Sarti-Fantoni, P.
Tetrahedron 2007, 63, 2047–2052. (b) Adamo, M. F. A.; Duffy, E. F.; Donati,
D.; Sarti-Fantoni, P. Tetrahedron 2007, 63, 2684–2688. (c) Adamo, M. F. A.;
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8724 J. Org. Chem. 2010, 75, 8724–8727
Published on Web 11/16/2010
DOI: 10.1021/jo102049r
r
2010 American Chemical Society

Palumbo Piccionello et al.
JOCNote
CHART 1
SCHEME 2. Reaction of Oxadiazoles 4 with Hydrazine
Selected 3-chloro derivatives 4a and 4f-m, variously
substituted at C(5), were obtained from the corresponding
3-amino-1,2,4-oxadiazoles.15
When compound 4a15a was reacted according to pre-
viously reported conditions,9a i.e., in methanol at room tem-
perature and in the presence of a 5-fold excess of hydrazine,
no product formation was observed. Moreover, when reacted in
DMF with a stoichiometric amount of hydrazine, compound
4a remained essentially unchanged.16 Nevertheless, optimi-
zation of reaction conditions, which considered various sol-
vents, temperatures, and reaction times (see the Supporting
Information), indicated DMF as an ideal solvent to perform
room temperature hydrazinolysis reaction with a 40-fold
excess of hydrazine.
The observed reactivity is illustrated in Scheme 2 for all
substrates and results are summarized in Table 1.
The isolation of 3-aminotriazoles 8 is likely a consequence
of the reductive reaction environment that transforms the
3-hydroxylamino moiety of intermediate 7 into the 3-amino
group of the final product. We were able to isolate a very low
amount (5%) of intermediate 7 (R = Ph) under milder
conditions from the reaction of the 3-chloro derivative 4a
with hydrazine (5 equiv) in THF. In turn, in a separate
reaction with hydrazine, compound 7 (R = Ph) was immedi-
ately and quantitatively transformed into the corresponding
3-aminotriazole 8a.
From a mechanistic point of view and according to reported
reactivity of structurally similar isothiazoles7 and oxa-
diazoles,3,9-13 the formation of aminotriazoles 8 could be
explained on the basis of two different ANRORC reaction
paths involving initial attack of hydrazine on the oxadiazole
ring. In route a (Scheme 2), and in analogy to ANRORC
reported for 5-perfluoroalkyl-1,2,4-oxadiazoles, the initial
nucleophilic attack on the C(5) of the oxadiazole ring causes
ring-opening into intermediate 5. Subsequent ring-closure
involving the former C(3) of the oxadiazole with loss of the
leaving group leads to hydroxylaminotriazole 7, which is
then reduced into aminotriazole 8. In route b (Scheme 2), the
initial attack involves the C(3) of the oxadiazole leading to
the dihydrooxadiazole derivative 6. This intermediate can
produce 7 through nucleophilic attack at C(5), ring-opening
TABLE 1. Reaction of 4 with hydrazine in DMF
compd
LG
R
time (h) conv (%)
yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
Cl
OMe
N(Me)NH2 Ph
NH2
N(Me)2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Ph
Ph
2
48
48
72
72
2
2
2
2
2
100
84
8a
8a
8a
8a
8a
8b
8c
8d
8e
8f
90
69
51
21
8
85
80
75
71
72
93
86
78
57
35
12
Ph
Ph
4-MePh
4-MeOPh
4-ClPh
4-CF3Ph
benzyl
2-furanyl
2-thiophenyl
4-pyridyl
100
100
100
100
100
100
100
100
4j
4k
4l
2
2
2
8g
8h
8i
4m
Cl
and ring-closure involving either the intramolecular 3-hydrazino
moiety or another external hydrazine molecules.
Theoretically, the two proposed routes (Scheme 2) could
be concurrent; however, any attempt to isolate 3-hydrazino
adduct 6 failed. Surprisingly, the expected formation of
3-hydrazino-1,2,4-oxadiazoles was not evidenced in any of
the tested reactions. Such compounds, if formed, should have
shown a reactivity similar to that of compound 4c, which was
reported as the exclusive product from the reaction of 4a with
methylhydrazine.15f
Compared with 3-chloro-derivative 4a, instead, 3-methoxy-,
3-amino-, 3-N-amino-N-methylamino- and 3-dimethylami-
no-derivatives showed prolonged reaction times, lower
(16) Trace amounts of 3-N,N-dimethylamino-5-phenyl-1,2,4-oxadiazole,
originating from a nucleophilic aromatic substitution of the 3-chloro sub-
stituent by the solvent released dimethylamine, were observed.
J. Org. Chem. Vol. 75, No. 24, 2010 8725

Palumbo Piccionello et al.
JOCNote
CHART 2
with MgSO4 and filtered, and the solvent was evaporated under
reduced pressure. Chromatography of the residue allowed iso-
lation of the corresponding 3-chloro-1,2,4-oxadiazoles 4i-m in
good yields.
3-Chloro-5-(4-trifluoromethylphenyl)-1,2,4-oxadiazole, 4i: 1.93 g,
68%; mp 66-67 °C (petroleum ether); 1H NMR (300 MHz,
CDCl3) δ 7.81 (d, 2H, J = 11.4 Hz), 8.24 (d, 2H, J = 11.4 Hz);
13C NMR (62.5 MHz, CDCl3) δ123.2 (q, J= 271 Hz), 126.3, 128.1,
128.5, 135.0 (q, J = 32.8 Hz), 162.2, 175.8; IR (Nujol) 1616,
1592 cm-1; GC-MS (m/z) 250 [(M þ 2)þ, 34%], 248
(Mþ, 100%). Anal. Calcd for C9H4ClF3N2O: C, 43.48; H, 1.62;
N, 11.27. Found: C, 43.50; H, 1.60; N, 11.25.
conversion of starting oxadiazole, and lower yield of final
triazoles 8. Therefore, the observed reactivity 4a > 4b >
4c > 4d > 4e seems to be strongly dependent on the leaving
group ability of the C(3) substituent rather than on its electronic
effect. Indeed, neither 3,5-diphenyl-, bearing a conjugating
C(3) substituent, nor 3-trifluoromethyl-5-phenyl-1,2,4-oxa-
diazole, bearing an electron-withdrawing C(3) substituent,
reacted under similar conditions.9a
On the other hand, there appears to be no correlation
between isolated yields of triazoles 8a-i and the type of
substitution at the C(5) of the oxadiazole’s ring. In fact, all
3-chloro-derivatives 4a and 4f-m reacted quantitatively
within 2 h without any significant difference in the time
required to observe complete conversion of the substrate.
In conclusion, the hydrazinolysis of 1,2,4-oxadiazole de-
rivatives 4 containing a leaving group directly linked at the
C(3) of the ring was investigated and an easy rearrangement
into amino-triazoles 8 through a reductive ANRORC was
evidenced. While previous studies have limited the application
of ANRORC rearrangements of 1,2,4-oxadiazoles to fluo-
rinated substrates, the reported results introduce the first
ANRORC reaction of nonfluorinated 1,2,4-oxadiazoles.
Besides opening the way to further mechanistic studies, the
high yields obtained suggest considering this methodology as
a general approach for the designed synthesis of functiona-
lized aminotriazoles which are well-known for their biological
activity.17
1
3-Chloro-5-benzyl-1,2,4-oxadiazole, 4j: 1.14 g, 59%; oil; H
C
NMR (300 MHz, CDCl3) δ 4.21 (s, 2H), 7.30-7.35 (m, 5H); 13
NMR (62.5 MHz, CDCl3) δ 33.3, 128.0, 129.0, 129.1, 132.5,
161.4, 180.2; IR (Nujol) 1568 cm-1; GC-MS (m/z) 196
[(M þ 2)þ, 32%], 194 (Mþ, 100%). Anal. Calcd for C9H7ClN2O:
C, 55.54; H, 3.63; N, 14.39. Found: C, 55.50; H, 3.60; N, 14.40.
3-Chloro-5-(2-furanyl)-1,2,4-oxadiazole, 4k: 1.26 g, 74%; mp
83-84 °C (petroleum ether); 1H NMR (300 MHz, CDCl3) δ 6.63
(dd, 1H, J1 = 3.6 Hz, J2 = 1.5 Hz), 6.35 (d, 1H, J = 3.6 Hz), 7.69
(d, 1H, J = 1.5 Hz); 13C NMR (62.5 MHz, CDCl3) δ 112.8,
118.0, 139.1, 147.6, 161.7, 168.8; IR (Nujol) 3111, 1624,
1540 cm-1; GC-MS (m/z) 172 [(M þ 2)þ, 33%], 170
(Mþ, 100%). Anal. Calcd for C6H3ClN2O2: C, 42.25; H, 1.77;
N, 16.43. Found: C, 42.25; H, 1.80; N, 16.40.
3-Chloro-5-(2-thiophenyl)-1,2,4-oxadiazole, 4l: 1.60 g, 81%;
mp 37-39 °C (petroleum ether); 1H NMR (300 MHz, CDCl3) δ
7.21-7.24 (m, 1H), 7.71 (d, 1H, J = 5.1 Hz), 7.93 (d, 1H, J =
3.6 Hz); 13C NMR (62.5 MHz, CDCl3) δ 124.5, 128.8, 132.9,
133.4, 161.6, 172.8; IR (Nujol) 3080, 1684, 1647, 1593,
1578 cm-1; GC-MS (m/z) 188 [(M þ 2)þ, 33%], 186
(Mþ, 100%). Anal. Calcd for C6H3ClN2OS: C, 38.62; H, 1.62;
N, 15.01. Found: C, 38.65; H, 1.60; N, 15.00.
3-Chloro-5-(4-pyridyl)-1,2,4-oxadiazole, 4m: 1.05 g, 58%; mp
96-97 °C (petroleum ether); 1H NMR (300 MHz, CDCl3) δ 7.96
(d, 2H, J = 3.0 Hz), 8.90 (d, 1H, J = 3.0 Hz); 13C NMR
(62.5 MHz, CDCl3) δ 121.0, 130.0, 151.3, 162.4, 175.3; IR
(Nujol) 1610, 1578, 1543 cm-1; GC-MS (m/z) 183 [(M þ 2)þ,
34%], 181 (Mþ, 100%). Anal. Calcd for C7H4ClN3O: C, 46.30;
H, 2.22; N, 23.14. Found: C, 46.40; H, 2.20; N, 23.20.
Experimental Section
General Procedure for the Reaction of 1,2,4-Oxadiazoles
4a-m with Hydrazine. A 2 mL sample of hydrazine hydrate
(41 mmol) was added to a stirred solution of oxadiazole 4
(1 mmol) in dry DMF (2 mL) and the mixture was kept at rt for
the time reported in Table 1. The solvent was then evaporated
under reduced pressure and the residue treated with water,
neutralized with 1 M aqueous HCl, and extracted with EtOAc.The
organic layer was dried over MgSO4 then filtered, and the solvent
was removed under reduced pressure. Chromatography of the
residue allowed isolation of the corresponding 3(5)-amino-5(3)-
aryl-1,2,4-triazoles 8 (Table 1). For compounds 8a-d,18 8f,19
and 8g-i18 spectroscopic data matched those reported in the
cited literature.
Materials and Methods. Melting points were determined on a
hot-stage apparatus and are uncorrected. FT-IR spectra were
registered in Nujol mull. 1H NMR and 13C NMR spectra were
recorded at 300 and 62.5 MHz, respectively, using TMS as an
internal standard. Flash chromatography was performed by
using silica gel (0.040-0.063 mm) and mixtures of ethyl acetate
and petroleum ether (fraction boiling in the range of 40-60 °C)
in various ratios. Compounds 4a,b,15a 4c,15f 4d,15b 4e,15e and
4f-h15a were obtained as previously reported.
General Procedure for the Synthesis of 3-Chloro-1,2,4-oxadia-
zoles 4i-m. Compounds 4i-m were obtained adapting a pre-
viously reported method.15a
To a stirred solution of the appropriate amine 9a-e15b-d
(Chart 2) (10 mmol) in concentrated HCl (50 mL) at 0 °C was
added NaNO2 (11 mmol, 0.759 g) portion wise during 1 h. The
mixture was kept at rt until gas evolution ceased. Reaction
mixture was extracted with CHCl3, the organic phase was dried
3(5)-Amino-5(3)-(4-trifluoromethylphenyl)-1,2,4-triazole, 8e:
1
162 mg, 71%; mp 222-223 °C (EtOH); H NMR (300 MHz,
DMSO-d6) δ 6.26 (s, 2H, exch. with D2O), 7.81 (d, 2H, J =
8.4 Hz), 8.14 (d, 2H J = 8.4 Hz), 12.34 (s, 1H, exch. with D2O);
13C NMR (62.5 MHz, DMSO-d6) δ 129.5 (q, J = 270 Hz), 130.5,
131.0, 133.6 (q, J = 32 Hz), 141.2, 162.4, 162.9; IR (Nujol) 3420,
3291, 3188, 1679, 1640 cm-1; GC-MS (m/z) 228 (Mþ, 100%).
Anal. Calcd for C9H7F3N4: C, 47.37; H, 3.09; N, 24.55. Found:
C, 47.40; H, 3.10; N, 24.50.
(17) See among others: (a) Chen, C.; Dagnino, R., Jr.; Huang, C. Q.;
McCarthy, J. R.; Grigoriadis, D. E. Bioorg. Med. Chem. Lett. 2001, 11, 3165–
3168. (b) Lowe, R. F.; Nelson, J.; Dang, T. N.; Crowe, P. D.; Pahuja, A.;
McCarthy, J. R.; Grigoriadis, D. E.; Conlon, P.; Saunders, J.; Chen, C.;
Szabo, T.; Kung Chen, T.; Bozigian, H. J. Med. Chem. 2005, 48, 1540–1549.
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Shafieea, A. Bioorg. Med. Chem. 2003, 11, 769–773. (d) Naito, Y.; Akahoshi,
F.; Takeda, S.; Okada, T.; Kajii, M.; Nishimura, H.; Sigiura, M.; Fukaya, C.;
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Synthesis of 3(5)-Hydroxylamino-5(3)-phenyl-1,2,4-triazole, 7. A
0.24 mL sample of hydrazine hydrate (5 mmol) was added to a
stirred solution of oxadiazole 4a (1 mol, 0.180 g) in THF (10 mL)
and the mixture was kept at rt for 24 h. The solvent was then
evaporated under reduced pressure and the residue was treated with
water, neutralized with 1 M aqueous HCl, and extracted with
EtOAc. The organic layer was dried over MgSO4 then filtered,
and the solvent was removed under reduced pressure. Chromatog-
raphy of the residue produced unreacted 4a (81 mg, 45%), 8a
(74 mg, 46%), and 3(5)-hydroxylamino-5(3)-phenyl-1,2,4-
triazole (7) (9 mg, 5%).
Reduction of 3(5)-Hydroxylamino-5(3)-phenyl-1,2,4-triazole
(7) with Hydrazine. To a stirred solution of 7 (5 mg, 0.3 mmol)
in dry DMF (1 mL) was added hydrazine hydrate (40 equiv,
55 μL) and the mixture was stirred at rt for 1 h. The solvent was
then evaporated under reduced pressure and the residue was
treated with water, neutralized with 1 M aqueous HCl, and
extracted with EtOAc.The organic layer was dried over MgSO4
then filtered, and the solvent was removed under reduced pressure.
Chromatography of the residue over preparative TLC plates yielded
3(5)-amino-5(3)-phenyl-1,2,4-triazole (8a) (4.5 mg, 100%).
3(5)-Hydroxylamino-5(3)-phenyl-1,2,4-triazole, 7: mp 238 °C
dec (EtOH); 1H NMR (300 MHz, DMSO-d6) δ 7.38-765
(m, 3H), 7.92 (m, 2H), 9.09 (s, 1H, exch. with D2O), 9.35
(s, 1H, exch. with D2O), 12.98 (s, 1H, exch. with D2O); 13C
NMR (62.5 MHz, DMSO-d6) δ 125.5, 128.3, 128.5, 132.5, 157.4,
158.6; IR (Nujol) 3220, 1577 cm-1; GC-MS (m/z) 176 (Mþ, 8%),
160 (M - 16, 100%). Anal. Calcd for C8H8N4O: C, 54.54; H,
4.58; N, 31.80. Found: C, 54.60; H, 4.70; N, 31.90.
Acknowledgment. Financial support through the Univer-
sity of Palermo and Italian MIUR through the FIRB “Futuro in
Ricerca” Grant no. RBFR08A9 V1 is gratefully acknowledged.
Supporting Information Available: Experimental details and
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 24, 2010 8727