Free-radical cyclizations onto differently substituted 1,2,3-triazoles installed in sugar templates

Article abstract of DOI:10.1021/jo001550i

The synthesis and manipulation of differently substituted 1,2,3-triazoles (7-11 and 12-16) installed in sugar templates gave compounds 29-34 and 44-50, after reaction with tributyltin hydride or tris(trimethylsilyl)silane. Following standard procedures compound 44 was transformed into piperidinose derivative 54. These compounds are chiral, useful building blocks for the synthesis of glycosidase inhibitors of the fused-azole piperidinose type.

Full text of DOI:10.1021/jo001550i

J . Org. Chem. 2001, 66, 3717-3725
3717
F r ee-Ra d ica l Cycliza tion s on to Differ en tly Su bstitu ted
1,2,3-Tr ia zoles In sta lled in Su ga r Tem p la tes
J ose´ Marco-Contelles* and Mercedes Rodr´ıguez-Ferna´ndez
Laboratorio de Radicales Libres, IQOG (CSIC), C/ J uan de la Cierva 3, 28006-Madrid, Spain
iqoc21@iqog.csic.es
Received November 1, 2000
The synthesis and manipulation of differently substituted 1,2,3-triazoles (7-11 and 12-16) installed
in sugar templates gave compounds 29-34 and 44-50, after reaction with tributyltin hydride or
tris(trimethylsilyl)silane. Following standard procedures compound 44 was transformed into
piperidinose derivative 54. These compounds are chiral, useful building blocks for the synthesis of
glycosidase inhibitors of the fused-azole piperidinose type.
In tr od u ction
Several azoles1-3 fused to furanoses or pyranoses have
been identified as good, selective, and potent glycosidase
inhibitors (GI).4 This is the case of compounds 1, 2, and
nagstatin (3) (Figure 1). Several synthetic approaches
have been described for the preparation of these aza-
sugars and related molecules. Most of these syntheses5
have relied either on the intramolecular 1,3-dipolar
cycloaddition (1,3-DC) of δ-azidonitriles1b or δ-azido-R,â-
unsaturated esters2 derived from sugars, by intra-
molecular SN2 reaction on tethered azole-triflate sugar
derivatives,6 or from gluconolactams by annulation strat-
egies.7 Despite these efforts, new synthetic alternatives
are sought due to the potential biological activity and
F igu r e 1. Fused-azole piperidinoses 1-3.
therapeutic profile of new target molecules.4
Sch em e 1. Gen er a l Str a tegy for th e Syn th esis of
F u sed Azoles (D) via F r ee-Ra d ica l Cycliza tion of
In ter m ed ia te B (P ) P r otectin g Gr ou p ; X )
Lea vin g Gr ou p ; Y ) N, O, S, CH; n ) 0, 1)
In this context, in the last years we have been explor-
ing a new approach for the synthesis of fused-azole
piperidinoses, annulated onto furanose templates.8,9 The
basis of this strategy is shown in Scheme 1 and consists
of the following: (a) the introduction of an N-azole at C3
in an hexofuranose starting material (A) and (b) the
5-exo-trig or the 6-exo-trig cyclization of a carbon (at C5
or C6)-centered radical species onto an heterocyclic ring
system in intermediates (B). This process should give
new and interesting azaannulated sugars of type C. It is
expected that further standard synthetic transformations
* To whom correspondence should be addressed. Fax: 34 91 564 48
53. Tel: 34 91 562 29 00.
(1) (a) Heightman, T. D.; Vasella, A.; Tsitsanou, K. E.; Zographos,
S. E.; Skamnaki, V.; Oikonomakos, N. G. Helv. Chim. Acta 1998, 81,
853. (b) Ermett, P.; Vasella, A. Helv. Chim. Acta 1991, 74, 2043.
(2) Kru¨lle, T. M.; de la Fuente, C.; Pickering, L.; Aplin, R. T.;
Tsitsanou, K. E.; Zographos, S. E.; Oikonomakos, N. G.; Nash, R. J .;
Griffiths, R. C.; Fleet, G. W. J . Tetrahedron: Asymmetry 1997, 8, 3807.
(3) Aoyama, T.; Naganawa, H.; Suda, H.; Uoptani, K.; Aoyagi, T.;
Takeuchi, T. J . Antibiot. 1992, 45, 1557.
as hydrolysis of the isopropylidene acetal at carbons C1/
C2, followed by 1,2-diol cleavage and hydride reduction,
would afford fused-azole pyrrolidinoses or piperidinoses
of type (D).
The key step in this approach is the free-radical
cyclization onto a heterocycle. Examples of this type of
cyclization10 are known in the synthesis of functionalized
indoles,11 imidazoles and benzimidazoles,12 or pyrroles.13
However, similar free-radical cyclizations onto triazole
ring systems were unprecedented. This fact coupled with
(4) (a) Elbein, A. D. Annu. Rev. Biochem. 1987, 56, 497. (b)
Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed. Engl. 1999,
38, 750.
(5) Bols, M. Acc. Chem. Res. 1998, 31, 1.
(6) (a) Frankowski, A.; Seliga, C.; Bur, D.; Streith, J . Helv. Chim.
Acta 1991, 74, 934. (b) Frankowski, A.; Deredas, D.; Streith, J .;
Tschamber, T. Tetrahedron 1998, 54, 9033 (c) Siendt, H.; Tschamber,
T.; Streith, J . Tetrahedron Lett. 1999, 40, 5191.
(7) Granier, T.; Gaiser, F.; Hintermann, L.; Vasella, A. Helv. Chim.
Acta 1997, 80, 1443.
(8) Marco-Contelles, J .; J ime´nez, C. A. Rev. Soc. Quim. Mex. 1999,
43, 83.
(9) Marco-Contelles, J .; J ime´nez, C. A. Carbohydr. Polymer, in press.
10.1021/jo001550i CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/28/2001

3718 J . Org. Chem., Vol. 66, No. 11, 2001
Marco-Contelles and Rodr´ıguez-Ferna´ndez
Sch em e 2. Syn th esis of F u sed -Azole Tr ia zole
P ip er id in oses fr om
1,2:5,6-Di-O-isop r op ylid en e-r-D-a llofu r a n ose8,9
F igu r e 2. Radical precursors for 5-exo-trig (7-11) and 6-exo-
trig (12-16) cyclizations.
Resu lts a n d Discu ssion
the potential biological interest of the resulting molecules
prompted us to start a project on the synthesis of fused
triazoles on D-glucose templates in the furanose form.
Until now, we have explored the 6-exo-trig free-radical
cyclization14 on radical precursors having difunctionalized
1,2,3-triazoles with alkoxycarbonyl groups at C4 and C5,
functionalized with only one alkoxycarbonyl group at C4,
or unsubstituted 1,2,4-triazoles. As a result, we have
prepared the fused-triazole piperidinoses 4-6 from 1,2:
5,6-di-O-isopropylidene-R-D-allofuranose in a short syn-
thetic scheme and in good overall chemical yield, featur-
ing unprecedented carbocyclization protocols (Scheme
2).8,9
A. Syn th esis of F u sed -Tr ia zole P yr r olid in oses in
F u r a n ose Tem p la t es b y 5-Exo-Tr ig F r ee-R a d ica l
Cycliza tion . A1. Syn th esis of th e Ra d ica l P r ecu r -
sor s 7-11. The synthesis of these precursors was achieved
from commercially available 1,2:5,6-di-O-isopropylidene-
R-D-allofuranose as shown in Schemes 3 and 4 (see the
Supporting Information). Tosylate 1716 was submitted to
the “one-pot two-step” sodium periodate oxidation plus
sodium borohydride reduction to give alcohol 18, which
was transformed into azide 19. This compound was also
prepared from known azide 2017 using the same protocol
(Scheme 3). All new molecules showed good spectroscopic
and analytical data. According to our strategy (Scheme
1), the incorporation of the 1,2,3-triazole ring at C3 was
attempted via 1,3-DC of an azide with the selected
acetylene.18
Using trimethylsilylacetylene, ethyl propiolate, or di-
ethyl acetylenedicarboxylate, compounds 21-23, 24/25,
and 26 were obtained from azide 19, respectively, in good
chemical yield (Scheme 3). As expected from the litera-
ture19 and by comparison with the 1H NMR spectroscopic
data, the 4-substituted 1,2,3-triazoles were isolated as
the major isomers in the reaction with monosubstitued
acetylenes. Structural analysis was straightforward as
it is well-known that H5 in 4-substituted 1,2,3-triazoles
resonates at higher chemical shifts than H4 in 5-substi-
tuted 1,2,3-triazoles.19 In agreement with this, in adduct
24 the signal for H5 appeared at 8.18 ppm, while in
product 25 H4 was observed at 8.09 ppm (see the
Continuing with these attempts, and in order to see
the scope of the present methodology, we prepared and
submitted to free-radical cyclization new radical precur-
sors. These compounds (7-16) (Figure 2) have been
designed in order to explore the 5-exo-trig and the 6-exo-
trig free-radical cyclization onto differently substituted
1,2,3-triazoles. In this paper, we describe the results that
we obtained in these transformations.15
(10) For reviews, see: (a) Aldabbagh, T.; Bowman, W. R. Contemp.
Org. Synth. 1997, 4, 261. (b) Bowman, W. R.; Bridge, C. F.; Brookes,
P. J . Chem. Soc, Perkin Trans. 1 2000, 1.
(11) (a) Caddick, S.; boutayab, K.; West, R. Synlett 1993, 231. (b)
Artis, D. R.; Cho, I.-S.; Figueroa, S. J .; Muchowski, J . M. J . Org. Chem.
1994, 59, 9, 2456. (c) Moody, C. J .; Norton, C. L. Tetrahedron Lett.
1995, 36, 9051.
(12) (a) Aldabbagh, F.; Bowman, W. R. Tetrahedron Lett. 1997, 38,
3793. (b) Aldabbagh, F.; Bowman, W. R.; Mann, E. Tetrahedron Lett.
1997, 38, 7937. (c) Aldabbagh, F.; Bowman, W. R. Tetrahedron 1999,
35, 4109.
(13) (a) Antonio, Y.; de la Cruz, E.; Galeazzi, E.; Guzma´n, A.; Bray,
B. L.; Greenhouse, R.; Kurz, L. J .; Lustig, D. A.; Maddox, M. L.;
Muchowski, J . M. Can, J . Chem. 1994, 72, 15. (b) Aldabbagh, F.;
Bowman, W. R.; Mann, E.; Slawin, A. M. Z. Tetrahedron 1999, 55, 8111.
(14) (a) Giese, B. Radicals in Organic Synthesis: Fomation of
Carbon-Carbon Bonds; Pergamon Press: New York, 1986. (b) J as-
perse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237. (c)
Motherwell, W. B.; Crich, D. Free Radical Chain Reactions in Organic
Synthesis; Academic Press: London, 1992.
(15) For a preliminary report, see: Marco-Contelles, J ., Rodr´ıguez-
Ferna´ndez, M. Tetrahedron Lett. 2000, 41, 381.
(16) Heap, J . M.; Owen, L. N. J . Chem. Soc. C 1970, 707.
(17) Gurjar, M. K.; Patil, V. J . Pawar, S. M. Indian J . Chem. 1987,
26B, 1115.
(18) Sheradsky, T. The Chemistry of the Azido Group; Patai, S., Ed.;
Interscience: London, 1971; p 377.
(19) (a) Stephani, E. Bull. Soc. Chim. Fr. 1978, 364. (b) Ha¨bich, D.;
Barth, W. Heterocycles 1989, 29, 2083. (c) Chre´tien, F.; Gross, B. J .
Heterocycl. Chem. 1982, 19, 263.

Free-Radical Cyclizations onto Substituted 1,2,3-Triazoles
J . Org. Chem., Vol. 66, No. 11, 2001 3719
documented in a related transformation.21 It is interest-
ing to note that in compound 21 the proton at H5 was
observed at 7.53 ppm, while in compound 22, the 5-sub-
stituted 1,2,3-triazole appeared at 7.65 ppm. This is just
the reverse trend observed in the series with alkoxy-
carbonyl groups (see above for products 24 and 25), and
it is probably due to the different electronic properties
of the silyl group. Finally, product 26 was also prepared
by an alternative route involving compound 28, readily
obtained from azide 2722 as described,23 after periodic acid
oxidation followed by sodium borohydride reduction
(Scheme 4).
Sch em e 3. Syn th esis of P r ecu r sor s 7-11a
Following with our plan, the final iodination of alcohols
(21 and 23-26) under Garegg’s conditions24 gave the
desired radical precursors 7-11 (Scheme 3). It is inter-
esting to note that in the 13C NMR spectra of these
iodides the chemical shifts for CH2(C5′)I appear unusu-
ally low (around -2.0/-3.0 ppm). This is probably due
to the strong shielding effect of the spatially near
orientated aromatic 1,2,3-triazole nucleus regarding the
methylene group at C5′; this behavior has been previ-
ously observed by us in other related molecules in these
series.9
A2. Th e F r ee-Ra d ica l Cycliza tion of P r ecu r sor s
7-11. With these molecules in hand, the free-radical
cyclization was attempted and we obtained the results
shown in Scheme 5. Under our experimental conditions,
using procedure A (AIBN, HSnBu3) or procedure B
(AIBN, HSnBu3, Bu3SnCl) (see the Experimental Sec-
tion), the cyclization of substrates 7, 8, and 10 afforded
the corresponding reduced, uncyclized material. This was
1
evident from simple inspection of the H NMR spectrum,
observing that the signals for the group ICH2(5′) were
absent, appearing as a doublet at high field, integrating
for three protons instead. In the case of compound 7, we
could also isolate traces of product 30, the reduced
uncyclized desilylated material. The yields of the cycliza-
tion products are low, probably due to extensive decom-
position or polymerization.
a
Reagents: (a) ref 16; (b) (i) NalO4, (ii) NaBH4 (17 to 18, 83%),
20 to 19 [65% (74%)]; (c) NaN3, DMF (74%); (d) trimethylsilyl-
acetylene, toluene, 110 °C (21, 55%; 22, 4%; 23, 14%); (e) ethyl
propiolate, toluene, 110 °C (24, 56%; 25, 43%); (f) diethyl acety-
lenedicarboxylate, toluene, 110 °C (26, 69%); (g) I2, Ph3P, toluene,
110 °C (7, 87%; 8, 62%; 9, 62%; 10, 77%; 11, 89%).
Sch em e 4. Syn th esis of In ter m ed ia te 26 via a n
Alter n a tive Rou tea
Only in activated 1,2,3-triazoles having one ethoxy-
carbonyl group at C4 (9) or two ethoxycarbonyl groups
at C4/C5 (11) was the 5-exo-trig cyclization possible,
providing the same adduct 31, in low yields, along with
significant and major quantities of the reduced, uncyc-
lized derivatives 32 or 34, respectively. Full spectroscopic
and analytical data clearly supported this structure; in
particular, in the 1H NMR spectrum of compound 31
(sugar numbering) no aromatic protons were obtained
and only one ethoxycarboyl was noticed; in addition, the
typical set of signals for the “furanose” ring system was
clearly detected. In the 13C NMR/DEPT spectra a signal
for a methylene (29.4 ppm) was correlated with the
protons at 3.29 and 3.19 ppm in the HMQC experiment.
In summary, all these data point out that this compound
was the expected pyrrolidinose fused-triazole derivative.
a
Reagents: (a) ref 23; (b) (i) HlO4, THF, (ii) NaBH4, EtOH [53%
(65%) overall yield from diol 28].
Supporting Information). Contrary to previous reports,20
when using trimethylsilyacetylene, in addition to the
normal major product 21, we have also detected the
5-substituted 1,2,3-triazole (22) and a third product,
which was identified as the unsubstituted substrate 23
(Scheme 3). This compound was obtained from major
isomer 21 by desilylation with tetrabutylammonium
fluoride. The reasons for this “spontaneous” desilylation
are not clear to us, but this is a fact that was previously
In Scheme 6, we show a possible mechanism for this
free-radical ring annulation. The high yield of the reduced
uncyclized material (34) shows that radical E is quite
(21) Wigerink, P.; Van Aerschot, Claes, P.; Balzarini, J .; De Clercq,
E.; Herdewijn, P. J . Heterocycl. Chem. 1989, 26, 1635.
(22) (a) Richardson, A. C. Methods Carbohydr. Chem. 1972, 6, 218.
(b) Chen, H.; Guo, Z.; Liu, H.-w. J . Am. Chem. Soc. 1998, 120, 9951.
(23) Marco-Contelles, J .; J ime´nez, C. A. Tetrahedron 1999, 55,
10526.
(20) AÄ lvarez, R.; Vela´zquez, S.; San-Fe´lix, A.; Aquaro, S.; De Clercq,
E.; Perno, C.-F.; Karlsson, A.; Balzarini, J .; Camarasa, M. J . J . Med.
Chem. 1994, 37, 4185.
(24) Garegg, P. J .; Samuelson, B. J . Chem. Soc., Perkin Trans. 1
1980, 2866.

3720 J . Org. Chem., Vol. 66, No. 11, 2001
Marco-Contelles and Rodr´ıguez-Ferna´ndez
Sch em e 5. 5-Exo-Tr ig F r ee-Ra d ica l Cycliza tion of
P r ecu r sor s 7-11a
radical captures a proton from (TMS)3SiH, reinitiating
the free-radical chain reaction. The final result is the so-
called ipso substitution of the ethoxycarbonyl group at
C5 in the radical precursor, a well-known process previ-
ously described by Bowman and co-workers in 2-substi-
tuted (thiophenyl or sulfonyl) benzimidazoles and imi-
dazoles in free-radical mediated intramolecular cycliza-
tions.12c
From these results, we can conclude that 5-exo-trig
cyclizations onto the 1,2,3-triazole nucleus are only
possible for very activated heterocyclic ring systems with
the substituent at the appropriate position. In these
cases, the formation of very strained fused ring as-
semblies possibly is the reason of the low chemical yields,
the major product being the reduced uncyclized material.
In the absence of these activating moieties, the ring
annulation is absolutely impossible.
B. Syn th esis of F u sed -Tr ia zole F u r a n oses by
6-Exo-Tr ig F r ee-Ra d ica l Cycliza tion . B1. Syn th esis
of th e Ra d ica l P r ecu r sor s 12-16. The synthesis of the
radical precursors 12-16 has been achieved as shown
in Scheme 7 (see the Supporting Information). For
precursors 12 and 13, we chose sugars 20 and 27 as
starting materials. Compound 2722 (see Scheme 4) af-
forded adducts 35-37 after 1,3-DC reaction with trim-
ethylsilylacetylene. Compound 38 was obtained by acid
hydrolysis of intermediate 35 and from diol 2017 (see
Scheme 3) by reaction with trimethylsilylacetylene.
Tosylation of compound 38 afforded derivative 41, whose
SN2 reaction with sodium iodide gave radical acceptor 12,
which upon acetylation afforded precursor 13. In the 1,3-
DC of compound 20,17 besides to adduct 38, we also
isolated compounds 39 and 40. Compound 40 was syn-
thesized by desilylation of product 38. Pursuing on with
our plan, the 1,3-DC reaction of bromide 428 with
trimethylsilylacetylene gave the 4-substituted 1,2,3-
triazole 14, along with minor amounts of other products,
probably the 5-substituted isomer and the desilylated
derivative, which were not isolated.20 The acetylated
derivative 43 provided adducts 15 and 16 in the 1,3-DC
reaction with trimethylsilylacetylene. As in the previous
series (see preparation of radical precursors 7-11) major
4-substituted isomers along with minor quantities of the
desilylated derivatives were isolated in the 1,3-DC reac-
tions. The full spectroscopic and analytical data coupled
to the data from literature and our own previous work
confirmed this assignment (Scheme 7).
a
Reagents: (a) (TMS)3SiH, AlBN (procedure A); (b) (TMS)3SiH,
AlBN, Bu3SnCl (procedure B).
Sch em e 6. Mech a n ism for F r ee-Ra d ica l
Cycliza tion of P r ecu r sor 11
B2. Th e F r ee-Ra d ica l Cycliza tion of P r ecu r sor s
12-16. In the next free-radical cyclization and having
in mind the results of the previous 5-exo-trig cyclizations,
we observed that the incorporation of additives as Bu3-
SnCl (procedure B) (see the Experimental Section)25
usually gave better yields of the cyclization products and
cleaner reactions (Scheme 8). For instance, for compound
12 in the absence of additive (procedure A), compounds
44 and 45 were isolated in in 9% and 29% yields,
respectively. This changed dramatically using procedure
B, where the yields of the same reaction products (44 and
45) were instead 53% and 34%, respectively.
For the analogous acetyl derivative 13, an unseparable
mixture of products 46 and 47 was detected and trans-
formed in mild, basic hydrolysis conditions into products
44 and 45. Using procedure A, the yields were 39% and
19%, respectively, while changing to procedure B these
reluctant to undergo cyclization. However, this is a
possible radical process, and after 5-exo-trig cyclization
onto carbon C5 of the heterocyclic ring, an allylic radical
species F results that gives product 31 after ethyl radical
formation and carbon dioxide elimination; the ethyl
(25) Sibi, M. P.; J i, J . J . Am. Chem. Soc. 1996, 118, 3063.

Free-Radical Cyclizations onto Substituted 1,2,3-Triazoles
J . Org. Chem., Vol. 66, No. 11, 2001 3721
Sch em e 7. Syn th esis of P r ecu r sor s 12-16a
Sch em e 8. 5-Exo-Tr ig F r ee-Ra d ica l Cycliza tion of
P r ecu r sor s 12-16a
a
Reagents: (a) trimethylsilylacetylene, toluene, 110 °C (35,
62%; 36, 5%; 37, 30%), (38, 54%; 39, 2%; 40, 43%), (14, 69%), (15,
59%; 16, 19%); (b) AcOH/H2O, rt (38, 63% from 35; 40, 96% from
37); (c) TBAF, THF, rt (91%); (d) ClTs, py, (Bu3Sn)2O (87%); (e)
Nal, DMF (84%); (f) Ac2O, py (13, 84%; 43, 87%).
results were better amounting to 45% and 9%. The power
of tris(trimethylsilyl)silane (procedure B) was obvious
when we compared it with procedure C (identical, but
using HSnBu3 as reducing agent); in this case, products
44 and 45 were isolated in very poor yields of 11% and
5%, respectively.
For the silyl containing precursor 14, we tested only
procedure A. This gave the expected 6-exo-trig cyclization
product 48 in 36% yield (61% taking into account the
recovered starting material) and the reduced, uncyclized
derivative 49 in 11% yield (19% taking into account the
recovered starting material).
Under the same experimental conditions, precursor 15
afforded compound 50 in a clean but low yieldind reaction
(32%).
Finally, for precursor 16, only procedure A was tested
with the same results observed in the cyclization of
compound 13 using procedure B. This fact shows that in
a
Key: (a) procedure A: (TMS)3SiH, AlBN; (b) procedure B:
(TMS)3SiH, Bu3SnCl, AlBN; (c) procedure C: Bu3SnH, Bu3SnCl,
AlBN.
this case the structure of the product overrides other
influences due to the reagents used.
In all the cases studied, the H and 13C NMR spectra
1
of the cyclized derivatives, along with complementary
1H-1H COSY and H-13C HMQC experiments confirmed
1
the proposed structure and the chemical shifts or cou-
pling constants assigned to the corresponding protons
and carbons.
In summary, from these results, it is clear that the
6-exo-trig cyclization onto 1,2,3-triazole ring systems is
possible affording moderate yields of the cyclic deriva-
tives, even if no activated substituents have been incor-
porated in the heterocyclic ring.9

3722 J . Org. Chem., Vol. 66, No. 11, 2001
Marco-Contelles and Rodr´ıguez-Ferna´ndez
Sch em e 9a
Exp er im en ta l Section
Gen er a l Meth od s. See ref 28.
Gen er a l Meth od for F r ee-Ra d ica l Ca r bocycliza tion
Rea ction s. P r oced u r e A. To a solution of the radical precur-
sor in toluene (0.02 M) (previously deoxygenated by passing
through the solution a current of argon during 20 min) under
argon and at reflux was slowly added a solution of (TMS)3SiH
(2.14 equiv) and AIBN (0.1 equiv) in toluene over 11 h via
syringe pump. After addition, the reaction was heated at this
temperature for 36 h. The mixture was cooled, and the solvent
was removed in a vacuum. The residue was submitted to
chromatography eluting with hexane/EtOAc mixtures.
P r oced u r e B. As in procedure B but using Bu3SnCl (1
equiv) as additive.
P r oced u r e C. As in procedure B but using HSnBu3.
Gen er a l Met h od for Acid H yd r olysis of 1,2-O-Iso-
p r op ylid en e Aceta ls. The product was cooled at 0 °C and
treated with a mixture of trifluoroacetic acid/water (60%).The
reaction was warmed at room temperature for 24 h. The
solvent was removed and the residue submitted to chroma-
tography eluting with hexane/ethyl acetate mixtures.
Gen er a l Meth od for Desilyla tion s. The product was
dissolved in dry THF (0.05 M), and the solution was treated
at room temperature with a solution of tetrabutylammonium
fluoride in THF (1.5 equiv, 1.0 M). After the mixture was
refluxed for 3 h, the solvent was removed in a vacuum and
the residue was submitted to flash chromatography eluting
with hexane/ethyl acetate mixtures.
Gen er a l Meth od for Acetyla tion s. The alcohol was
treated with a mixture of acetic anhydride/pyridine (v/v, 1/1)
at room temperature overnight. The solvent was eliminated
in a vacuum, and the residue was submitted to flash chroma-
tography eluting with hexane/ethyl acetate mixtures.
Gen er a l Meth od for Ba sic Hyd r olysis of Aceta tes. The
compound was dissolved in a mixture of methanol/water/
triethylamine in the usual ratio of (5:1:4 v/v/v). After complete
reaction, the solvents were removed, and the residue was
submitted to flash chromatography eluting with hexane/ethyl
acetate mixtures.
a
Reagents: (a) NaH, BnBr, THF (80%); (b) TFA/H2O (60%); (c)
(i) NaBH4, MeOH, (ii) Ac2O, py.
C. F in a l Tr a n sfor m a tion of In ter m ed ia te 44. With
compound 44 in hand, we have performed some experi-
ments in order to evaluate the viability of the strategy
shown in Scheme 1 for the synthesis of modified furanose
fused systems of type D. After some experimentation, it
was soon evident that the protection of the hydroxyl
group was necessary for a successful approach (see the
Experimental Section). Then, we benzylated this group
to provide compound 51 (Scheme 9); the acid hydrolysis
of this compound afforded lactol 52 as a mixture of
anomers at C1 which, without separation, was submitted
to reaction with sodium borohydride followed by acety-
lation. Two products (53 and 54) were obtained after
workup and chromatography. Compound 53 was the
peracetylated derivative of 52; this means that product
52 was stable as the ring-closed hemi-acetal and there-
fore stable to the borohydride reduction conditions.Com-
pound 54 was the expected fused 1,2,3-triazole piperidi-
nose, whose structure was established by detailed and
extensive spectroscopic analysis.
F r ee-R a d ica l Cycliza t ion of P r ecu r sor 7. Following
gen er a l p r oced u r e A for ca r bocycliza tion , compound 7
(118 mg, 0.28 mmol) afforded products 29 (8 mg, 10%) and 30
(2 mg, 3%), after chromatography (hexane/EtOAc, from 9:1 to
3:2). 29: mp 140-143 °C; [R]20D +38 (c 0.8, CH3OH); IR (KBr)
1
ν 2961, 1387, 1250, 1083 cm-1; H NMR (CDCl3, 400 MHz) δ
In summary, we have extended our previous successful
results8,9 on the free-radical cyclization onto 1,2,3-triazole
ring systems in sugar templates, analyzing 5-exo-trig and
6-exo-trig cyclization protocols on conveniently function-
alized sugar derivatives having activated or not hetero-
cyclic ring systems. As a result, we observed that the
strain associated with the resulting 5-exo-trig products
is a major impediment for clean and good yielding
reactions, a problem that can be partially solved by
substituting the ring with alkoxycarbonyl groups as
activating moieties for the free radical cyclization. Con-
versely, the 6-exo-trig examples studied revealed that
nonsubstituted or silyl containing nucleus are moderately
efficient in giving reasonable yields of cyclized deriva-
tives. Finally, we succeeded in designing a simple route
to transform these annulated furanoses (44)26 into fused
triazole piperidinoses (54) of potential biological inter-
est.27
7.35 (s, 1 H, H5), 6.16 (d, J 1′,2′ ) 3.8 Hz, 1 H, H1′), 5.04 (d,
J 4′,3′ ) 3.8 Hz, 1 H, H3′), 4.88 (d, J 1′,2′ ) 3.8 Hz, 1 H, H2′), 4.66
(qd, J 4′,5′ ) 6.3 Hz, J 4′,3′ ) 3.8 Hz, 1 H, H4′), 1.58, 1.35 [2 s, 2
× 3 H, -OC(CH3)2O-], 0.91 (d, J 4′,5′ ) 6.3 Hz, 3 H, H5′), 0.31
[s, 9 H, (CH3)3 Si]; 13C NMR (CDCl3, 50 MHz) δ 147.9 (C4),
128.4 (C5), 112.1 [-OC(CH3)2O-], 105.0 (C1′), 84.5 (C2′), 75.1
(C4′), 67.3 (C3′), 26.6, 26.2 [OC(CH3)2O], 13.4 (C5′), -1.1
[(CH3)3 Si]; MS (70 eV) m/z 282 (11), 170 (11), 152 (37), 99
(60), 43 (100. 30: mp 160-163 °C; [R]20 +56 (c 8.9, CH3OH);
D
IR (KBr) ν 3096, 2988, 1630, 1378, 1220, 1018 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 7.73 (d, J ) 0.9 Hz, 1 H, H5), 7.48 (d, J )
0.9 Hz, 1 H, H4), 6.15 (d, J 1′,2′ ) 3.8 Hz, 1 H, H1′), 5.02 (d,
J 4′,3′ ) 3.8 Hz, 1 H, H3′), 4.91 (d, J 1′,2′ ) 3.8 Hz, 1 H, H2′), 4.67
(dq, J 4′,5′ ) 6.6 Hz, J 4′,3′ ) 3.8 Hz, 1 H, H4′), 1.57, 1.35 [s, s, 2
× 3 H, -OC(CH3)2O-], 0.90 (d, J 4′,5′ ) 6.6 Hz, 3 H, H5′); 13C
NMR (CDCl3, 50 MHz) δ 134.0 (C4), 123.3 (C5), 112.2
[-OC(CH3)2O-], 104.9 (C1′), 84.4 (C2′), 75.0 (C4′), 67.6 (C3′),
26.4, 26.1 [OC(CH3)2O, 13.3 (C5′); MS (70 eV) m/z 226 (12),
181 (27), 123 (100), 99 (70), 41 (79). Anal. Calcd for C10H15
-
N3O3: C, 53.32; H, 6.71; N, 18.66. Found: C, 53.51; H, 6.78;
N, 18.57.
F r ee-R a d ica l Cycliza t ion of P r ecu r sor 8. Following
gen er a l p r oced u r e A for ca r bocycliza tion , compound 8
(56 mg, 0.16 mmol) afforded product 30 (11 mg, 31%), after
chromatography (hexane/EtOAc, from 9:1 to 3:2).
(26) Marco-Contelles, J .; Alhambra, C., Mart´ınez-Grau, A. Synlett
1998, 693 (Corrigendum: Synlett 1999, 376).
(27) The glycosidase inhibition of the azole-fused piperidinoses
described in this paper has been carried out by Dr. Raynald Demange
in Professor Pierre Vogel’s laboratory, in Lausanne University (section
de Chimie) (Switzerland). These molecules showed a weak activity in
a large series of enzymatic assays. The authors would like to thank
these colleagues for kindly performing these experiments.
(28) Marco-Contelles, J .; Pozuelo, C.; J imeno, M. L.; Mart´ınez, L.;
Mart´ınez-Grau, A. J . Org. Chem. 1992, 57, 2625.

Free-Radical Cyclizations onto Substituted 1,2,3-Triazoles
J . Org. Chem., Vol. 66, No. 11, 2001 3723
F r ee-R a d ica l Cycliza t ion of P r ecu r sor 9. Following
gen er a l p r oced u r e B for ca r bocycliza tion , compound 9
(100 mg, 0.24 mmol) afforded products 31 (7 mg, 7%) and 32
(31 mg, 45%), after chromatography (from hexane to hexane/
cycliza tion , compound 12 (96 mg, 0.25 mmol) afforded
products 44 (34 mg, 53%) and 45 (22 mg, 34%), after chroma-
tography (from hexane to hexane/EtOAc, 1:4). 44: oil; [R]20
D
+60 (c 4.6, CHCl3); IR (KBr) ν 3500-3400, 2920, 1600, 1340,
1
EtOAc, 9:1). 31: mp 139-142 °C; [R]20 +34 (c 5.5, CHCl3);
1225, 1050 cm-1; H NMR (CDCl3, 400 MHz) δ 7.40 (s, 1 H,
D
IR (KBr) ν 2984, 1719, 1586, 1375, 1135, 1079, 1024 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 5.83 (d, J 1,2 ) 3.8 Hz, 1 H, H1),
5.54 (t, J 4,5B ) J 4,3 ) 4.2 Hz, 1 H, H4), 5.28 (d, J 1,2 ) 3.8 Hz,
1 H, H2), 4.97 (d, J 4,3 ) 4.2 Hz, 1 H, H3), 4.37 (q, J ) 7.1 Hz,
2 H, COOCH2CH3), 3.29 (d, J 5A,5B ) 17.9 Hz, 1 H, H5A), 3.19
(dd, J 5A,5B ) 17.9 Hz, J 4,5B ) 4.2 Hz, 1 H, H5B), 1.54, 1.35 [2
s, 2 × 3 H, -OC(CH3)2O-], 1.37 (q, J ) 7.1 Hz, 3 H,
COOCH2CH3); 13C NMR (CDCl3, 50 MHz) δ 160.6 (COOCH2-
CH3), 145.2 (C7), 133.7 (C6), 112.9 [-OC(CH3)2O-], 106.3 (C1),
86.9 (C4), 81.8 (C2), 68.8 (C3), 61.1 (COOCH2CH3), 29.4 (C5),
26.9, 26.5 [OC(CH3)2O], 14.3 (COOCH2CH3); MS (70 eV) m/z
296 (5), 280 (70), 250 (28), 179 (86), 122 (35), 122 (26), 106
(56), 94 (62), 43 (100). Anal. Calcd for C13H17N3O5: C, 52.88;
H, 5.80; N, 14.23. Found: C, 53.07; H, 5.75; N, 14.12. 32: mp
196-199 °C; [R]20D +96 (c 3.4, CH3OH); IR (KBr) ν 3112, 2977,
1727, 1453, 1383, 1127, 1049 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 7.96 (s, 1 H, H5), 6.12 (d, J 1′,2′ ) 3.8 Hz, 1 H, H1′), 5.03 (d,
J 4′,3′ ) 3.7 Hz, 1 H, H3′), 4.86 (d, J 1′,2′ ) 3.8 Hz, 1 H, H2′), 4.65
(qd, J 4′,5′ ) 6.4 Hz, J 4′,3′ ) 3.7 Hz, 1 H, H4′), 4.39 (q, J ) 7.1
Hz, 2 H, COOCH2CH3), 1.55, 1.33 [2 s, 2 × 3 H, -OC(CH3)2O-
], 1.38 (t, J ) 7.1 Hz, 3 H, COOCH2CH3), 0.91 (d, J 4′,5′ ) 6.4
Hz, 3 H, H5′); 13C NMR (CDCl3, 50 MHz) δ 160.5 (COOCH2-
CH3), 140.6 (C4), 127.0 (C5), 112.5 [-OC(CH3)2O-], 104.8
(C1′), 84.3 (C2′), 74.7 (C4′), 68.2 (C3′), 61.5 (COOCH2CH3),
26.3, 26.0 [OC(CH3)2O], 14.3 (COOCH2CH3), 13.2 (C5′); MS (70
eV) m/z 298 (5), 282 (22), 195 (57), 122 (33), 95 (100), 43 (69).
Anal. Calcd for C13H19N3O5: C, 52.52; H, 6.44; N, 14.13.
Found: C, 52.65; H, 6.60; N, 13.99.
H8), 5.74 (d, J 1,2 ) 3.5 Hz, 1 H, H1), 5.20 (d, J 1,2 ) 3.5 Hz, 1
H, H2), 4.88 (d, J 4,3 ) 3.9 Hz, 1 H, H3), 4.82 (br dd, J 4,5 ) 5.9
Hz, J 4,3 ) 3.9 Hz, 1 H, H4), 4.11 (ddd, J 4,5 ) 5.9 Hz, J 6B,5
)
15.6 Hz, J 6A,5 ) 10.9 Hz, 1 H, H5), 3.15 (dd, J 6A,6B ) 15.6 Hz,
J 6A,5 ) 10.9 Hz, 1 H, H6A), 2.83 (dd, J 6A,6B ) 15.6 Hz, J 6B,5
)
5.6 Hz, 1 H, H6B), 2.29 (br s, 1 H, OH), 1.54, 1.29 [2 s, 2 × 3
H, -OC(CH3)2O-]; 13C NMR (CDCl3, 50 MHz) δ 132.2 (C7),
130.7 (C8), 112.9 [-OC(CH3)2O-], 104.9 (C1), 84.5 (C2), 77.3
(C4), 65.7 (C5), 63.2 (C3), 26.6, 26.2 [OC(CH3)2O], 24.2 (C6);
MS (70 eV) m/z 253 (26), 238 (100), 195 (13), 137 (69), 112
(51), 81 (36). Anal. Calcd for C11H15N3O4: C, 52.17; H, 5.97;
N, 16.59. Found: C, 52.35; H, 6.17; N, 16.40. 45: mp 153-
155 °C; [R]20 +37 (c 7.4, CH3OH); IR (KBr) ν 3530, 3400-
D
3320, 3040, 2920, 1600, 1365-1355, 1200, 885 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 7.74 (d, J ) 1.0 Hz, 1 H, H5), 7.65 (d, J )
1.0 Hz, 1 H, H4), 6.25 (d, J 1′,2′ ) 3.7 Hz, 1 H, H1′), 5.21 (d,
J 4′,3′ ) 3.6 Hz, 1 H, H3′), 5.09 (d, J 1′,2′ ) 3.7 Hz, 1 H, H2′), 4.22
(dd, J 4′,5′ ) 9.0 Hz, J 4′,3′ ) 3.6 Hz, 1 H, H4′), 2.89 (m, 1 H, H5′),
1.61, 1.38 [2 s, 2 × 3 H, -OC(CH3)2O-], 1.71 (d, J ) 4.5 Hz,
1 H, OH), 1.27 (d, J 6′,5′ ) 6.1 Hz, 3 H, H6′); 13C NMR (CDCl3,
50 MHz) δ 133.5 (C4), 124.8 (C5), 112.5 [-OC(CH3)2O-], 105.9
(C1′), 83.7 (C2′), 83.5 (C4′), 65.5 (C3′), 65.2 (C5′), 26.6, 26.2
[OC(CH3)2O], 21.2 (C6′); MS (70 eV) m/z 240 (14), 142 (22),
123 (35), 113 (71), 85 (51), 43 (100). Anal. Calcd for
C
11H17N3O4: C, 51.76; H, 6.71; N, 16.46. Found: C, 51.89; H,
6.98; N, 16.27.
Tr a n sfor m a tion of Com p ou n d 44. (a ) Ben zyla tion of
P r od u ct 44. To a solution of compound 44 (33 mg, 0.13 mmol)
in dry THF (2 mL), under argon and at 0 °C sodium hydride
(5.4 mg, 0.13 mmo, 60% dispersion in oil), were added catalytic
amounts of tetrabutylammonium iodide and benzyl bromide
(18.8 µL, 0.16 mmol, 1.2 equiv). The mixture was warmed at
room temperature for 20 h. Then, two drops of acetic acid were
added, the crude was filtered over Celite-545, and the cake
was washed with methylene chloride. The solvent was evapo-
rated and the residue submitted to chromatography (hexane/
F r ee-R a d ica l Cycliza t ion of P r ecu r sor 10. Following
gen er a l p r oced u r e B for ca r bocycliza tion , compound 10
(100 mg, 0.24 mmol) afforded product 33 (16 mg, 23%), after
chromatography (from hexane to hexane/EtOAc, 7:3), and a
more polar product whose structure has not been established.
33: mp 62-64 °C; [R]20D +153 (c 5.0, CH3OH); IR (KBr) ν 2982,
1727, 1529, 1375, 1066, 1015 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 8.12 (s, 1 H, H4), 6.21 (d, J 1′,2′ ) 3.8 Hz, 1 H, H1′), 5.74 (d,
J 4′,3′ ) 3.8 Hz, 1 H, H3′), 5.13 (d, J 1′,2′ ) 3.8 Hz, 1 H, H2′), 4.72
(qd, J 4′,5′ ) 6.4 Hz, J 4′,3′ ) 3.8 Hz, 1 H, H4′), 4.38 (q, J ) 7.1
Hz, 2 H, COOCH2CH3), 1.57, 1.35 [2 s, 2 × 3 H, -OC(CH3)2O-
], 1.38 (t, J ) 7.1 Hz, 3 H, COOCH2CH3), 0.81 (d, J 4′,5′ ) 6.4
Hz, 3 H, H5′); 13C NMR (CDCl3, 50 MHz) δ 158.5 (COOCH2-
CH3), 137.3 (C4), 128.7 (C5), 111.8 [-OC(CH3)2O-], 105.5
(C1′), 84.4 C2′), 75.6 (C4′), 66.3 (C3′), 61.9 (COOCH2CH3), 26.6,
26.1 [OC(CH3)2O], 14.0 (COOCH2CH3), 13.3 (C5′); MS (70 eV)
m/z 299 (1), 282 (39), 253 (10), 195 (64), 122 (37), 95 (100).
Anal. Calcd for C13H19N3O5: C, 52.52; H, 6.44; N, 14.13.
Found: C, 52.43; H, 6.70; N, 13.95.
ethyl acetate, 3/2) to give product 51 (36 mg, 80%): oil; [R]20
D
-49 (c 6.2, CHCl3); IR (KBr) ν 2989, 1455, 1375, 1218, 1020,
816 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.45 (s, 1 H, H8), 7.37-
7.27 (m, 5 H, -OCH2C6H5), 5.81 (d, J 1,2 ) 3.6 Hz, 1 H, H1),
5.23 (d, J 1,2 ) 3.6 Hz, 1 H, H2), 4.90 (br s, 1 H, H4), 4.86 (d,
J 4,3 ) 3.7 Hz, 1 H, H3), 4.73 (s, 2 H, -OCH2C6H5), 3.92 (ddd,
J 4,5 ) 3.9 Hz, J 6B,5 ) 5.7 Hz, J 6A,5 ) 10.6 Hz, 1 H, H5), 3.17
(dd, J 6A,6B ) 15.7 Hz, J 6B,5 ) 5.7 Hz, 1 H, H6B), 3.02 (dd, J 6A,6B
) 15.7 Hz, J 6A,5 ) 10.6 Hz, 1 H, H6B), 1.59, 1.36 [2 s, 2 × 3 H,
-OC(CH3)2O-]; 13C NMR (CDCl3, 75 MHz) δ 137.1 (C7), 130.8
(C8), 132.2-127.8 (-OCH2C6H5), 112.6 [-OC(CH3)2O-], 105.1
(C1), 83.9 (C2), 74.8 (C4), 71.4 (C5), 71.3 (-OCH2C6H5), 63.5
(C3), 26.6, 26.2 [OC(CH3)2O], 21.4 (C6); MS (70 eV) m/z 344
(1), 328 (19), 252 (2), 237 (71), 121 (17), 108 (29), 91 (100).
Anal. Calcd for C18H21N3O4: C, 62.96; H, 6.16; N, 12.24.
Found: C, 62.73; H, 6.27; N, 12.55.
F r ee-R a d ica l Cycliza t ion of P r ecu r sor 11. Following
gen er a l p r oced u r e A for ca r bocycliza tion , compound 11
(109 mg, 0.22 mmol) afforded products 31 (9 mg, 14%) and 34
(26 mg, 33%), after chromatography (hexane/EtOAc, from 9:1
to 7:3). 34: oil; [R]20D +87 (c 9.2, CHCl3); IR (KBr) ν 2985, 1731,
1554, 1374, 1211, 1016 cm-1
;
1H NMR (CDCl3, 300 MHz) δ
(b) Hyd r olysis of Aceta l 51. Following the gen er a l
m eth od for a cid h yd r olysis of 1,2-O-isop r op ylid en e a c-
eta ls, compound 51 (92 mg, 0.27 mmol) gave product 52 (73
mg, 89%) isolated as an unseparable mixture of anomers (R/
â: 2/1) after chromatography (hexane/ethyl acetate, 1/4): 1H
NMR (CD3OD, 300 MHz) (major isomer) δ 7.51 (s, 1 H, H8),
7.43-7.28 (m, 5 H, -OCH2C6H5), 5.29 (d, J 1,2 ) 4.3 Hz, 1 H,
H1), 5.07 (br s, 1 H, H2), 4.98 (br s, 1 H, H3), 4.91 (s, 2 H,
-OCH2C6H5), 4.68 (dd, J 4,5 ) 3.6 Hz, J 4,3 ) 3.9 Hz, 1 H, H4),
3.95 (ddd, J 4,5 ) 3.6 Hz, J 6B,5 ) 3.7 Hz, J 6A,5 ) 4.9 Hz, 1 H,
H5), 3.19 (dd, J 6A,6B ) 14.9 Hz, J 6B,5 ) 3.7 Hz, 1 H, H6B), 3.05
(dd, J 6A,6B ) 14.9 Hz, J 6A,5 ) 4.9 Hz, 1 H, H6B); 13C NMR (CD3-
OD, 75 MHz) δ 139.3 (C7), 130.8 (C8), 135.1-128.9 (-OCH2-
C6H5), 104.6 (C1), 81.5 (C2), 77.4 (C4), 74.2 (C5), 72.1
(OCH2C6H5), 65.5 (C3), 22.3 (C6). Anal. Calcd for C15H17N3O4:
C, 59.40; H, 5.65; N, 13.85. Found: C, 59.43; H, 5.70; N, 13.95.
(c) Sod iu m Bor oh yd r id e Red u ction + Acetyla tion of
P r od u ct 52. Lactol 52 (52 mg, 0.17 mmol) dissolved in ethanol
6.20 (d, J 1′,2′ ) 3.8 Hz, 1 H, H1′), 5.34 (d, J 4′,3′ ) 4.0 Hz, 1 H,
H3′), 5.11 (d, J 1′,2′ ) 3.8 Hz, 1 H, H2′), 4.71 (qd, J 4′,5′ ) 6.3 Hz,
J 4′,3′ ) 4.0 Hz, 1 H, H4′), 4.43 (q, q, J ) 7.3 Hz, 4 H, 2 ×
COOCH2CH3), 1.57, 1.36 [2 s, 2 × 3 H, -OC(CH3)2O-], 1.38
(t, t, J ) 7.3 Hz, 6 H, 2 × COOCH2CH3), 0.87 (d, J 4′,5′ ) 6.3
Hz, 3 H, H5′); 13C NMR (CDCl3, 50 MHz) δ 160.1, 158.5 (2 ×
COOCH2CH3), 130.4 (C4), 121.9 (C5), 112.0 [-OC(CH3)2O-],
105.5 (C1′), 84.4 (C2′), 75.4 (C4′), 67.1 (C3′), 63.1, 62.0 (2 ×
COOCH2CH3), 26.6, 26.1 [OC(CH3)2O], 14.1, 13.8 (2
×
COOCH2CH3), 13.5 (C5′); MS (70 eV) m/z 370 (3), 354 (26),
324 (12), 267 (35), 214 (41), 194 (100), 167 (50), 139 (17), 122
(40), 99 (66). Anal. Calcd for C16H23N3O7: C, 52.03; H, 6.28;
N, 11.38. Found: C, 52.33; H, 6.40; N, 13.65.
F r ee-R a d ica l Cycliza t ion of P r ecu r sor 12. Following
gen er a l p r oced u r e A for ca r bocycliza tion , compound 12
(46 mg, 0.12 mmol) afforded products 44 (3 mg, 9%) and 45 (9
mg, 29%). Following gen er a l p r oced u r e
B for ca r bo-

3724 J . Org. Chem., Vol. 66, No. 11, 2001
Marco-Contelles and Rodr´ıguez-Ferna´ndez
(3 mL) was treated with a solution of sodium borohydride (6.4
mg, 0.17 mmol, 1 equiv) in ethanol (1 mL). The mixture was
stirred at 0 °C for 15 min and warmed at room temperature
for 2 h. Sodium borohydride (9.6 mg, 0.25 mmol, 1.5 equiv)
was added again and stirred for 4 h more. A saturated aqueous
solution of ammonium chloride was added and the ethanol
removed. The crude was treated according to the gen er a l
m eth od for a cetyla tion s. and the residue was submitted to
chromatography (hexane/ethyl acetate, from 2:3 to 1:4) to give
product 53 (40 mg, 61%) [isolated as an unseparable mixture
F ollow in g th e gen er a l m eth od for a cetyla tion , alcohol
45 (13 mg, 0.05 mmol) gave compound 47 (10 mg, 67%). 47:
IR (KBr) ν 3088, 1737, 1379, 1222, 945 cm-1; 1H NMR (CDCl3,
200 MHz) δ 7.75 (d, 1 H, H5), 7.45 (d, 1 H, H4), 5.25 (d, J 1′,2′
) 3.6 Hz, 1 H, H1′), 5.24 (d, J 4′,3′ ) 3.7 Hz, 1 H, H3′), 4.91 (d,
J 1′,2′ ) 3.6 Hz, 1 H, H2′), 4.47 (dd, J 4′,5′ ) 8.7 Hz, J 4′,3′ ) 3.7
Hz, 1 H, H4′), 4.21 (dd, J 4′,5′ ) 8.7 Hz, J 5′,6′ ) 6.1 Hz, 1 H,
H5′), 2.01 (s, 3 H, OCOCH3), 1.63, 1.39 [2 s, 2 × 3 H, -OC-
(CH3)2O-], 1.27 (d, J 6′,5′ ) 6.1 Hz, 3 H, H6′); 13C NMR (CDCl3,
50 MHz) δ 169.0 (OCOCH3), 134.1 (C4), 123.3 (C5), 112.6
[-OC(CH3)2O-], 105.4 (C1′), 84.3 (C2′), 80.9 (C4′), 67.5 (C3′),
65.5 (C5′), 26.6, 26.1 [OC(CH3)2O], 20.9 (C6′), 17.6 (OCOCH3);
MS (70 eV) m/z 282 (14), 123 (37), 83 (11), 43 (100). Anal. Calcd
for C13H19N3O5: C, 52.52; H, 6.44; N, 14.13. Found: C, 52.44;
H, 6.68; N, 13.95.
of anomers (R/â: 14/1)] and 54 (13 mg, 19%). 53: oil; [R]20
D
+50 (c 22.3, CHCl3); IR (KBr) ν 2940, 1755, 1431, 1375, 1238,
1
1013, 820 cm-1; H NMR (CDCl3, 300 MHz) (major isomer) δ
7.44 (s, 1 H, H8), 7.36-7.30 (m, 5 H, -OCH2C6H5), 6.50 (d,
J 1,2 ) 4.7 Hz, 1 H, H1), 5.54 (dd, J 2,3 ) 5.8 Hz, J 1,2 ) 4.7 Hz,
1 H, H2), 5.24 (dd, J 2,3 ) 5.8 Hz, J 3,4 ) 7.2 Hz, 1 H, H3), 4.86
(dd, J 4,5 ) 3.5 Hz, J 4,3 ) 7.2 Hz, 1 H, H4), 4.66 (s, 2 H,
F r ee-R a d ica l Cycliza t ion of P r ecu r sor 14. Following
gen er a l p r oced u r e A for ca r bocycliza tion , compound 14
(72 mg, 0.18 mmol) afforded products 48 [21 mg, 36% (61%
taking into account the recovered starting material)] and 49
[7 mg, 11% (19% taking into account the recovered starting
material)], after chromatography (from hexane to hexane/
-OCH2C6H5), 3.99 (dt, J 4,5 ) 3.5 Hz, J 6B,5 ) 3.5 Hz, J 6A,5
)
7.1 Hz, 1 H, H5), 3.12 (dd, J 6A,6B ) 16.2 Hz, J 6A,5 ) 7.1 Hz, 1
H, H6A), 2.85 (dd, J 6A,6B ) 16.2 Hz, J 6B,5 ) 3.5 Hz, 1 H, H6B),
2.15, 2.09 (2 s, 2 × OCOCH3); 13C NMR (CDCl3, 50 MHz) δ
169.5, 169.2 (2 × OCOCH3), 137.2 (C7), 131.3 (C8), 131.3-
127.8 (-OCH2C6H5), 93.9 (C1), 75.6 (C2), 74.1 (C4), 72.2
(OCH2C6H5), 71.5 (C5), 59.7 (C3), 21.9 (C6), 21.0, 20.5 (2 ×
OCOCH3); MS (70 eV) m/z 359 (3), 344 (1), 328 (25), 299 (17),
268 (31), 211 (12), 91 (100). Anal. Calcd for C19H21N3O5: C,
61.45; H, 5.70; N, 11.31. Found: C, 61.43; H, 5.70; N, 11.26.
EtOAc, 1:4). 48: 145-147 °C; [R]20 -31 (c 7.7, CH3OH); IR
D
(KBr) ν 3350, 2940, 1490, 1350, 1225, 1035 cm-1
;
1H NMR
(CDCl3, 200 MHz) δ 5.81 (d, J 1,2 ) 3.6 Hz, 1 H, H1), 5.26 (d,
J 1,2 ) 3.6 Hz, 1 H, H2), 4.95 (d, J 4,3 ) 3.6 Hz, 1 H, H3), 4.88
(br s, 1 H, H4), 4.18 (m, 1 H, H5), 3.24 (dd, J 6A,6B ) 15.6 Hz,
J 6B,5 ) 5.7 Hz, 1 H, H6B), 2.90 (dd, J 6A,6B ) 15.6 Hz, J 6A,5
)
54: mp 193-195 °C; [R]20 +14 (c 1.4, CH3OH); IR (KBr) ν
11.0 Hz, 1 H, H6A), 2.69 (br d, J ) 9.2 Hz, 1 H, OH), 1.60,
D
2989, 1754, 1371, 1218, 1020 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 7.42 (s, 1 H, H8), 7.38-7.28 (m, 5 H, -OCH2C6H5), 5.95 (dt,
J 1A,2 ) J 1B,2 ) 3.7 Hz, J 2,3 ) 6.2 Hz, 1 H, H2), 5.88 (m, 1 H,
H4), 4.87 (dd, J 2,3 ) 6.0 Hz, J 3,4 ) 3.8 Hz, 1 H, H3), 4.75 and
4.53 (AB system, d, J ) 11.6 Hz, 2 H, -OCH2C6H5), 4.39 (dd,
1.36 [2 s, 2 × 3 H, -OC(CH3)2O-], 0.34 [s, 9 H, (CH3)3Si]; 13
C
NMR (CDCl3, 50 MHz) δ 141.9 (C8), 137.7 (C7), 112.9
[-OC(CH3)2O-], 105.0 (C1), 84.7 (C2), 77.3 (C4), 65.9 (C5),
63.1 (C3), 26.6, 26.3 [OC(CH3)2O], 25.4 (C6), -1.1 [(CH3)3Si];
MS (70 eV) m/z 326 (1), 297 (10), 181 (13), 126 (63), 100 (18),
73 (100). Anal. Calcd for C14H23N3O4Si: C, 51.67; H, 7.12; N,
12.91. Found: C, 51.95; H, 7.40; N, 12.65. 49: mp 113-115
J 1A,2 ) 3.7 Hz, J 1A,1B ) 12.3 Hz, 1 H, H1A), 4.32 (dd, J 1B,2
)
3.7 Hz, J 1A,1B ) 12.3 Hz, 1 H, H1B), 3.90 (dd, J 6A,5 ) 5.9 Hz,
J 6B,5 ) 9.6 Hz, 1 H, H5), 3.14 (dd, J 6A,6B ) 16.4 Hz, J 6A,5 ) 9.6
Hz, 1 H, H6A), 2.99 (dd, J 6A,6B ) 16.4 Hz, J 6B,5 ) 9.6 Hz, 1 H,
H6B), 2.13, 2.09, 2.07 (3 s, 3 × OCOCH3); 13C NMR (CDCl3,
50 MHz) δ 170.6, 170.2, 169.7 (3 × OCOCH3), 136.9 (C7), 130.8
(C8), 132.2-127.9 (-OCH2C6H5), 72.7 (C5), 71.5 (OCH2C6H5),
69.7 (C2), 65.9 (C4), 63.2 (C1), 57.8 (C3), 23.0 (C6), 20.9 (3 ×
OCOCH3); MS (70 eV) m/z 344 (3), 325 (7), 301 (7), 266 (69),
224 (22), 194 (12), 135 (26), 91 (100). Anal. Calcd for
°C; [R]20 +41 (c 1.8, CH3OH); IR (KBr) ν 3450, 3020, 2930,
D
1360, 1220, 820 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.52 (s, 1
H, H5), 6.23 (d, J 1′,2′ ) 3.7 Hz, 1 H, H1′), 5.24 (d, J 4′,3′ ) 3.7
Hz, 1 H, H3′), 5.03 (d, J 1′,2′ ) 3.7 Hz, 1 H, H2′), 4.22 (dd, J 4′,5′
) 9.0 Hz, J 4′,3′ ) 3.7 Hz, 1 H, H4′), 2.84 (dq, J 4′,5′ ) 9.0 Hz,
J 6′,5′ ) 6.1 Hz, 1 H, H5′), 1.61, 1.38 [s, 2 × 3 H, -OC(CH3)2O-
], 1.27 (d, J 6′,5′ ) 6.1 Hz, 3 H, H6′), 0.34 [s, 9H, (CH3)3 Si]; 13
C
NMR (CDCl3, 50 MHz) δ 146.0 (C4), 129.6 (C5), 112.4
[-OC(CH3)2O-], 105.8 (C1′), 83.7 (C3′), 83.6 (C4′), 65.1 (C2′,
C5′), 26.6, 26.2 [OC(CH3)2O], 21.0 (C6′), -1.1 [(CH3)3 Si]; EM
(70 eV) m/z 312 (13), 283 (5), 184 (32), 142 (40), 98 (51), 73
(100). Anal. Calcd for C14H25N3O4Si: C, 51.35; H, 7.70; N,
12.83. Found: C, 51.71; H, 7.98; N, 12.57.
F ollow in g th e gen er a l m eth od for d esilyla tion , com-
pound 48 (26 mg, 0.079 mmol) gave compound 44 (20 mg,
99%).
C
21H25N3O7: C, 58.46; H, 5.84; N, 9.74. Found: C, 58.44; H,
5.71; N, 9.95.
F r ee-R a d ica l Cycliza t ion of P r ecu r sor 13. Following
gen er a l p r oced u r e A for ca r bocycliza tion , compound 13
(71 mg, 0.17 mmol) afforded a crude (46 + 47) that was
submitted to b a sic h yd r olysis follow in g t h e gen er a l
p r oced u r e to give products 44 (17 mg, 39%) and 45 (8 mg,
19%). Following gen er a l p r oced u r e B for ca r bocycliza -
tion , compound 13 (180 mg, 0.42 mmol) afforded a crude (46
+ 47) that was submitted to ba sic h yd r olysis follow in g th e
gen er a l m eth od to give products 44 (48 mg, 45%) and 45 (9
mg, 9%). Following gen er a l p r oced u r e C for ca r bocycliza -
tion , compound 13 (65 mg, 0.15 mmol) afforded a crude (46 +
47) that was submitted to ba sic h yd r olysis follow in g th e
gen er a l m eth od to give products 44 (5 mg, 11%) and 45 (2
mg, 5%), after chromatography (hexane/EtOAc, from 2:3 to
1:4).
F r ee-R a d ica l Cycliza t ion of P r ecu r sor 15. Following
gen er a l p r oced u r e A for ca r bocycliza tion , compound 15
(69 mg, 0.15 mmol) afforded product 50 [8 mg, 32% (78%
taking into account the recovered starting material)] after
chromatography (hexane/EtOAc, from 9:1 to 3:2). 50: 111-
113 °C; [R]20D +1 (c 7.3, CH3OH); IR (KBr) ν 3040, 2940, 1720,
1460, 1350, 1275, 1040 cm-1 1H NMR (CDCl3, 400 MHz) δ
;
5.79 (d, J 1,2 ) 3.6 Hz, 1 H, H1), 5.25 (d, J 1,2 ) 3.6 Hz, 1 H,
H2), 5.23 (ddd, J 4,5 ) 1.9 Hz, J 6A,5 ) 11.3 Hz, Hz, J 6B,5 ) 5.9
Hz, 1 H, H5), 4.96 (d, J 4,3 ) 3.6 Hz, 1 H, H3), 4.87 (m, 1 H,
H4), 3.18 (dd, J 6A,6B ) 15.4 Hz, J 6B,5 ) 5.9 Hz, 1 H, H6B), 3.03
(dd, J 6A,6B ) 15.4 Hz, J 6A,5 ) 11.3 Hz, 1 H, H6A), 2.17 (s, 3 H,
OCOCH3), 1.57, 1.33 [2 s, 2 × 3 H, -OC(CH3)2O-], 0.32 [s, 9
H, (CH3)3Si]; 13C NMR (CDCl3, 50 MHz) δ 170.3 (OCOCH3),
142.2 (C7), 136.8 (C8), 112.8 [-OC(CH3)2O-], 105.3 (C1), 84.1
(C2), 74.8 (C4), 67.0 (C5), 63.4 (C3), 26.5, 26.1 [OC(CH3)2O],
21.9 (C6), 21.0 (OCOCH3), -1.1 [(CH3)3Si]; MS (70 eV) m/z 368
(4), 307 (88), 279 (13), 189 (11), 163 (29), 114 (45), 43 (100).
Anal. Calcd for C16H25N3O5Si: C, 52.30; H, 6.86; N, 11.43.
Found: C, 52.44; H, 6.98; N, 11.29.
F ollow in g th e gen er a l m eth od for a cetyla tion , alcohol
44 (11 mg, 0.04 mmol) gave compound 46 (10 mg, 67%). 46:
mp 57-60; [R]20 -35 (c 4.3, CH3OH); IR (KBr) ν 2940, 1738,
D
1376, 1231, 1085 cm-1; H NMR (CDCl3, 300 MHz) δ 7.44 (s,
1
1 H, H8), 5.78 (d, J 1,2 ) 3.7 Hz, 1 H, H1), 5.23 (m, 2 H, H2,
H5), 4.96 (d, J 4,3 ) 3.7 Hz, 1 H, H3), 4.86 (d, J 4,3 ) 3.7 Hz, 1
H, H4), 3.11 (dd, J 6A,6B ) 15.4 Hz, J 6A,5 ) 5.7 Hz, 1 H, H6A),
3.02 (dd, J 6A,6B ) 15.4 Hz, J 6B,5 ) 11.4 Hz, 1 H, H6B), 2.12 (s,
3 H, OCOCH3), 1.57, 1.32 [2 s, 2 × 3 H, -OC(CH3)2O-]; 13C
NMR (CDCl3, 50 MHz) δ 170.2 (OCOCH3), 131.4 (C7), 130.8
(C8), 112.8 [-OC(CH3)2O-], 105.1 (C1), 83.9 (C2), 74.8 (C4),
66.7 (C5), 63.5 (C3), 26.4, 26.0 [OC(CH3)2O], 20.9 (OCOCH3),
17.5 (C6); MS (70 eV) m/z 296 (13), 280 (39), 235 (56), 179 (18),
151 (54), 119 (90), 43 (100). Anal. Calcd for C13H17N3O5: C,
52.88; H, 5.80; N, 14.23. Found: C, 52.51; H, 5.77; N, 13.89.
F r ee-R a d ica l Cycliza t ion of P r ecu r sor 16. Following
gen er a l p r oced u r e A for ca r bocycliza tion , compound 16
(34 mg, 0.09 mmol) afforded a crude (46 + 47) that was
submitted to b a sic h yd r olysis follow in g t h e gen er a l

Free-Radical Cyclizations onto Substituted 1,2,3-Triazoles
J . Org. Chem., Vol. 66, No. 11, 2001 3725
m eth od to give products 44 (11 mg, 48%) and 45 (3.5 mg,
15%), after chromatography (hexane/EtOAc, from 2:3 to 1:4).
Su p p or tin g In for m a tion Ava ila ble: General methods
andexperimental procedures for the synthesis of the radical
precursors 7-16, with full spectroscopic and analytical data.
This material is available free of charge via the Internet at
http:/pubs.acs.org.
Ack n ow led gm en t. This work was supported by
CICYT (Petri 95-0248-OP), CAM, and COST Action No.
D12 (European Union). M.R.-F. is an Associate Profes-
sor of UAM (Department of Organic Chemistry).
J O001550I