Synthesis of polyhydroxylated 2H-azirines and 2-halo-2H-azirines from 3-azido-2,3-dideoxyhexopyranoses by alkoxyl radical fragmentation

Article abstract of DOI:10.1021/jo800182y

(Chemical Equation Presented) The reaction of 3-azido-2,3-dideoxypyranose and 3-azido-2,3-dideoxy-2-halohexopyranose compounds with (diacetoxyiodo)benzene and iodine generated 2-azido-1,2-dideoxy-1-iodoalditols and 2-azido-1,2-dideoxy-1-halo-1-iodoalditols, respectively. These β-iodo azides could be transformed by chemoselective dehydroiodination into 2-azido-1,2-dideoxy-4-O-formyl-pent-1-enitols and (Z,E)-2-azido-1,2-dideoxy-1- halo-4-O-formyl-pent-1-enitols in good yields. Thermolysis and photochemical studies of these vinyl azides and 1-halovinyl azides for the synthesis of polyhydroxylated 3-alkyl-2H-azirines and the hitherto unknown 2-halo-3-alkyl-2H-azirines have also been accomplished.

Full text of DOI:10.1021/jo800182y

Synthesis of Polyhydroxylated 2H-Azirines and 2-Halo-2H-azirines
from 3-Azido-2,3-dideoxyhexopyranoses by Alkoxyl Radical
Fragmentation
Carmen R. Alonso-Cruz,† Alan R. Kennedy,‡ Mar´ıa S. Rodr´ıguez,*,† and Ernesto Sua´rez*,†
Instituto de Productos Naturales y Agrobiolog´ıa del C.S.I.C., Carretera de La Esperanza 3,
38206 La Laguna, Tenerife, Spain, and WestCHEM Department of Pure and Applied Chemistry,
UniVersity of Strathclyde, Glasgow G1 1XL, United Kingdom
esuarez@ipna.csic.es
ReceiVed January 28, 2008
The reaction of 3-azido-2,3-dideoxypyranose and 3-azido-2,3-dideoxy-2-halohexopyranose compounds
with (diacetoxyiodo)benzene and iodine generated 2-azido-1,2-dideoxy-1-iodoalditols and 2-azido-1,2-
dideoxy-1-halo-1-iodoalditols, respectively. These ꢀ-iodo azides could be transformed by chemoselective
dehydroiodination into 2-azido-1,2-dideoxy-4-O-formyl-pent-1-enitols and (Z,E)-2-azido-1,2-dideoxy-1-
halo-4-O-formyl-pent-1-enitols in good yields. Thermolysis and photochemical studies of these vinyl
azides and 1-halovinyl azides for the synthesis of polyhydroxylated 3-alkyl-2H-azirines and the hitherto
unknown 2-halo-3-alkyl-2H-azirines have also been accomplished.
Introduction
Products possessing stabilized 2H-azirine systems have also been
isolated from natural sources.4 The asymmetric syntheses of two
of them, dysidazirine and azirinomycin, have been accom-
plished.5 On the other hand, the corresponding and even more
reactive 2-halo-2H-azirines have been much less studied. As
far as we know, there exists no general method to prepare
disubstituted 3-alkyl-2-halo-2H-azirines and they are expected
to be highly unstable on the basis of previous studies of related
azirines.6
2H-Azirines, since first reported by Neber et al.,1 have
received a great deal of attention from theoretical and experi-
mental chemists.2 The highly strained imine bond confined in
a three-membered ring confers unique properties to these
heterocycles.3 They can act as nucleophiles, electrophiles, and
also as dienophiles and diporalophiles in cycloaddition pro-
cesses. As a consequence of this reactivity, they are precursors
of an impressive number of more elaborate heterocyclic systems.
* Corresponding author. Fax: +34 922 260135.
(4) (a) Miller, T. W.; Tristram, E. W.; Wolf, F. J. J. Antibiot. 1971, 24, 48–
50. (b) Stapley, E. O.; Hendlin, D.; Jackson, M.; Miller, A. K.; Hernandez, S.;
Mata, J. M. J. Antibiot. 1971, 24, 42–47. (c) Molinski, T. F.; Ireland, C. M. J.
Org. Chem. 1988, 53, 2103–2105. (d) Salomo´n, C. E.; Williams, D. H.; Faulkner,
D. J. J. Nat. Prod. 1995, 58, 1463–1466.
† Instituto de Productos Naturales y Agrobiolog´ıa.
‡ University of Strathclide.
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Mart´ınez de Marigorta, E.; de los Santos, J. M. Org. Prep. Proced. Int. 2002,
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Woolhouse, A. D. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R.,
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D. J.; Hassner, A. Synthesis 1975, 483–495.
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4116 J. Org. Chem. 2008, 73, 4116–4122
10.1021/jo800182y CCC: $40.75 2008 American Chemical Society
Published on Web 04/26/2008

Synthesis of 2-Azido-1-alkenes
SCHEME 1. ꢀ-Fragmentation of
Vinyl azides are also useful intermediates in the synthesis
of heterocycles, with versatility endowed by being precursors of
vinyl nitrenes.7 Since the pioneering work on the addition
of iodine azide to olefins and the subsequent elimination of
hydrogen iodine by Hassner and co-workers,8 several methods
for the synthesis of these compounds have been developed.7,9
Comparatively, the synthesis of halovinyl azides whose halogen
atom offers another reaction site has received much less
attention. Although they can also be prepared by addition of
halogen azides to vinyl halides,10 other syntheses have been
developed to avoid the use of these highly reactive and
dangerous reagents: (a) the reaction of R-oxophosphonium ylides
with N-halosuccinimides in the presence of azidotrimethylsi-
lane11 and (b) the addition of hydrazoic acid to some allenyl
halides.12 However, access to halovinyl azides by these methods
is limited to specific structures; e.g., none of them could
apparently be used for the synthesis of fluorovinyl azides or
for substances with a terminal 2-azido-1-halo-1-alkene arrange-
ment. Indeed, there exists no general method to prepare 2-azido-
1-halo-1-alkenes, the only report being on the isolation of the
R-azido-ꢀ-chloro- and R-azido-ꢀ-bromostyrene from the reaction
of (haloethynyl)benzene with sodium azide in low yield.13 One
of the most interesting features of vinyl azides is their easy
thermal or photochemical transformation into 2H-azirines.8a–c,14
3-Azido-2,3-dideoxyhexopyranoses and
3-Azido-2,3-dideoxy-2-halohexopyranosesa
a ARF ) alkoxyl radical fragmentation reaction; R ) protective groups.
It should be possible, using this methodology and taking into
account the availability of the 3-azido-2,3-dideoxyhexopyranose
Ia compounds, to synthesize chiral ꢀ-iodo azides IIa and
hence vinyl azides IIIa and 2H-azirines IVa from carbohy-
drates (Scheme 1, X ) H). 3-Azido-2,3-dideoxyhexopyranose
compounds were conveniently prepared in high yield by acid-
catalyzed reaction of 2-deoxyhex-1-enitol derivatives (glycals) with
NaN3. The reaction proceeded through Michael addition of the
azide anion over an R,ꢀ-unsaturated aldehyde intermediate.17
This methodology could be extended to the preparation of
polyhydroxylated 2-azido-1-halo-1-alkenes IIIb starting from
halohydrins Ib and after chemoselective dehydroiodination of
the 1,1-dihalo alditol IIb intermediate. In addition, the ther-
molysis or photolysis of these halovinyl azide IIIb offers an
unrivaled opportunity to study the properties and stability of
the hitherto unknown 3-alkyl-2-halo-2H-azirines IVb (Scheme
1, X ) Hal).
Earlier work from our laboratory revealed hypervalent iodine
reagents in the presence of molecular iodine to be a valuable
oxidation system for the formation of anomeric alkoxyl radicals
from carbohydrate alcohols.15 The glycopyran-1-O-yl radical
thus formed triggers the facile radical ꢀ-fragmentation of the
C1-C2 bond to give a C2 radical.16 An electron-withdrawing
group at this position inhibits the oxidation of the C-radical,
which is finally trapped by an atom of iodine from the reaction
medium. This should also occur in the case of 2-deoxy
carbohydrates, allowing for the efficient synthesis of 1-iodoaldi-
tols with one carbon less than the starting carbohydrate.
(7) For reviews, see: (a) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V.
Angew. Chem., Int. Ed. 2005, 44, 5188–5240. (b) Scriven, E. F. V.; Turnbull,
K. Chem. ReV. 1988, 88, 297–368. (c) Hassner, A. In Azides and Nitrenes:
ReactiVity and Utility; Scriven, E. F. V., Ed.; Academic Press: Orlando, 1984;
pp 35-94. (d) L’abbe´, G. Angew. Chem., Int. Ed. Engl. 1975, 14, 775–782. (e)
L’abbe´, G.; Hassner, A. Angew. Chem., Int. Ed. Engl. 1971, 10, 98–104. (f)
Smolinsky, G.; Pryde, C. A. In The Chemistry of the Azido Group; Patai, S.,
Ed.; John Wiley and Sons: London, 1971; pp 555-585. For recent references,
see: (g) Singh, P. N. D.; Carter, C. L.; Gudmundsdottir, A. D. Tetrahedron Lett.
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Lett. 2003, 44, 5339–5341. (i) Mazal, C.; Jonas, J.; Za´k, Z. Tetrahedron 2002,
58, 2729–2733.
Results and Discussion
To assess the potential scope and limitations of this method,
experiments were carried out using a variety of 3-azido-2,3-
dideoxyhexopyranose compounds 7-12 as outlined in Table
1. In previous communications, we described the preliminary
results obtained,18 and we now disclose herein the full details
of these experiments. The reaction of glycals 1-6 with NaN3
in the presence of HgSO4 and H2SO4 afforded 1,3-hydroxy
azides 7-12 in good yields as diastereoisomeric mixtures at
(8) (a) Hassner, A.; Levy, L. A. J. Am. Chem. Soc. 1965, 87, 4203–4204. (b)
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T. J. Org. Chem. 2007, 72, 1534–1537. (b) Zhu, W.; Ma, D. W. Chem. Commun.
2004, 888–889.
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Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001; Vol. 2, pp 246-278. (c) Sua´rez, E.; Rodr´ıguez, M. S. In
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Weinheim, 2001; Vol. 2, pp 440-454. (d) Robertson, J.; Pillai, J.; Lush, R. K.
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1979, 44, 3281–3287. (c) Gallagher, T. C.; Sasse, M. J.; Storr, R. C. J. Chem.
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565–581. (f) Hartung, J.; Gottwald, T.; Spehar, K. Synthesis 2002, 1469–1498.
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T. M. V. D.; Gilchrist, T. L. Synthesis 1997, 673–676.
(g) Cekovic, Z Tetrahedron 2003, 59, 8073–8090.
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2003, 338, 795–799. (b) Liberek, B.; Dabrowska, A.; Frankowski, R.; Matusze-
wska, M.; Smiatacz, Z Carbohydr. Res. 2002, 337, 1803–1810. (c) Dabrowska,
A.; Dokurno, P.; Konitz, A.; Smiatacz, Z. Carbohydr. Res. 2000, 323, 230–234.
(d) Wengel, J.; Pedersen, E. B. Synthesis 1991, 451–454. (e) Wengel, J.; Lau,
J.; Pedersen, E. B.; Nielsen, C. M. J. Org. Chem. 1991, 56, 3591–3594. (f)
Abbaci, B.; Florent, J.-C.; Monneret, C. J. Chem. Soc., Chem. Commun. 1989,
1896–1897. (g) Florent, J.-C.; Monneret, C. J. Chem. Soc., Chem. Commun.
1987, 1171–1172.
(12) Fotsing, J. R.; Banert, K. Synthesis 2006, 261–272.
(13) Tanaka, R.; Yamabe, K. J. Chem. Soc., Chem. Commun. 1983, 329–
330.
(14) Smolinsky, G. J. Org. Chem. 1962, 27, 3557–3559.
(15) (a) Armas, P.; Francisco, C. G.; Sua´rez, E. Angew. Chem., Int. Ed. Engl.
1992, 31, 772–774. (b) Armas, P.; Francisco, C. G.; Sua´rez, E. J. Am. Chem.
Soc. 1993, 115, 8865–8866. (c) Herna´ndez, R.; Leo´n, E. I.; Moreno, P.; Sua´rez,
E. J. Org. Chem. 1997, 62, 8974–8975. (d) Francisco, C. G.; Freire, R.; Gonza´lez,
C. C.; Sua´rez, E. Tetrahedron: Asymmetry 1997, 8, 1971–1974. (e) Francisco,
C. G.; Mart´ın, C. G.; Sua´rez, E. J. Org. Chem. 1998, 63, 2099–2109. (f)
Francisco, C. G.; Mart´ın, C. G.; Sua´rez, E. J. Org. Chem. 1998, 63, 8092–8093.
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J. Org. Chem. Vol. 73, No. 11, 2008 4117

Alonso-Cruz et al.
TABLE 1. Alkoxyl Radical Fragmentation Reaction of 3-Azido-2,3-dideoxy-hexopyranosesa
a Reagents and conditions per mmol of substrate: HgSO4 (0.047 mmol), H2SO4 (5 mM, 27 mmol), 1,4-dioxane, 30 °C, then NaN3 (10 mmol), AcOH
(1.35 mL). b Reagents and conditions per mmol of substrate: (diacetoxyiodo)benzene (1.5 mmol), I2 (1.5 mmol), CH2Cl2, reflux. c Reagents and
conditions per mmol of substrate: DBU (2.5 mmol), PhH, reflux. d For brevity, in this case ꢀ-D-Gal refers to the peracetylated moiety of galactose.
C3.17 In all cases, except for previously described compounds
717c and 10,17a,b the mixtures were partially resolved by
chromatography and the azide stereochemistry determined by
with (diacetoxyiodo)benzene and iodine in CH2Cl2 at reflux
temperature. The reaction proceeded smoothly in high yield,
and as observed, the di-tert-butylsilanediyl protective group and
the sensitive glycosidic linkage survived the reaction conditions
(entries 2 and 3, respectively). The stereochemistries of the
ꢀ-iodo azides 13-18 were then unambiguously determined by
individually submitting the γ-hydroxy azides to the ARF
reaction. The integrity of the adjacent azide stereogenic center
was preserved during the reaction, and no generation of
diastereoisomers at this carbon atom (C-3) was detected. From
a practical point of view, the ARF was best accomplished with
the mixture of the γ-hydroxy azides followed by a much more
efficient chromatographic separation at the ꢀ-iodo azide stage.
1
means of H NMR spectroscopy by a careful analysis of the
vicinal coupling constants (in particular J2a,3 and J2e,3). It is
noteworthy to mention that the major anomer of pentopyranose
12L-Thr adopts preferentially a 1C4 conformation with the azido
group in equatorial position and the anomeric alcohol in axial
position, whereas the major anomer of compound 12L-Ery
4
exists in a C1 conformation leaving also the azide equatorial
and the anomeric alcohol in axial position.
The alkoxyl radical fragmentation (ARF) reactions were
performed under the conditions stated in Table 1 (entries 1-6),
4118 J. Org. Chem. Vol. 73, No. 11, 2008

Synthesis of 2-Azido-1-alkenes
TABLE 2. Thermolysis of Vinyl Azides 19-24a
the corresponding 2H-azirines 25-30 were isolated in good yields.
The azirines 25-29 were sufficiently stable to be isolated and
purified by silica gel chromatography and can be stored for months
in a freezer at -25 °C without significant decomposition. The
azirine 30 could be isolated and fully characterized spectroscopi-
cally after aqueous workup but could not withstand silica gel
chromatographic purification, probably because of its lower steric
demand. The somewhat lower yields observed for azirines 26, 27,
and 29 (entries 2, 3, and 5) are probably due to thermal instability
of the three-membered ring at this temperature. Under photolytic
conditions at room temperature, a much smoother reaction ensued,
for example, irradiation of vinyl azide 22 with the unfiltered light
using a 450 W Hanovia medium-pressure lamp afforded azirine
28 in 94% yield.
The isolation of azirine 26 in crystalline form suitable for
X-ray diffraction provides an opportunity to probe its solid-
state structure.20 Although a crystallographic analysis was
performed on the palladium(II) complex of 3-(p-methoxyphe-
nyl)-2H-azirine, the molecular structure of simple 3-alkylmono-
substituted-2H-azirines has not been determined.21
Although several examples of monosubstituted 3-alkyl-
2H-azirines can be found in the literature,,7h,14 22 as far as
we know, no examples of the monosubstituted 3-alkyl-2H-
azirines possessing an R-hydroxyl derivative have been
reported to date. Closely related stabilized 2H-azirine-3-
carboxylic esters have been recently synthesized and used
as dienophiles in aza-Diels-Alder cycloaditions or as radical
acceptors.23
The next goal of our work was to extend this protocol to a
simple general procedure for the synthesis of 2-azido-1-halo-
1-alkenes of the IIIb type (X ) F, Cl, Br, and I) (Scheme 1).
Previous studies in this laboratory explored the feasibility of
1,1-dihalo- and 1,1,1-trihaloalditols formation from carbohydrate
halohydrin systems using the ARF reaction as the key step.24
(20) X-ray data for compounds 26 and 38d-Z have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication nos.
CCDC 222314 and 648303, respectively. Copies of the data may be obtained
free of charge from the CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K.
Fax: (+44) 1223-336-033. E-mail: deposit@ccdc.cam.ac.uk.
(21) (a) Hassner, A.; Bunnell, C. A.; Haltiwanger, K J. Org. Chem. 1978,
43, 57–61. For recent crystallographic studies with other than 3-monosubstituted
2H-azirines, see: (b) Piquet, V.; Baceiredo, A.; Gornitzka, H.; Dahan, F.; Bertrand,
G. Chem. Eur. J. 1997, 3, 1757–1764. (c) Alcaraz, G.; Wecker, U.; Baceiredo,
A.; Dahan, F.; Bertrand, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1246–1248.
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Kanehisa, N.; Yasuoka, N.; Kasai, N.; Isomura, K.; Taniguchi, H. J. Chem. Soc.,
Chem. Commun. 1980, 98–99.
a Toluene (12 mL/mmol), reflux. b Benzene (30 mL/mmol), reflux. c For
brevity, in this case ꢀ-D-Gal refers to the peracetylated moiety of galactose.
d By irradiation in C6D6 (0.07 mM) with
a 450 W ACE-Hanovia
medium-pressure mercury lamp, the yield was 94%. e Unstable; could not
withstand chromatographic purification, crude yield.
The yields shown in Table 1 were determined using chromato-
graphic homogeneous hydroxy azide mixtures giving correct
elemental analysis, and in all cases complete consumption of
the starting material was observed. The dehydroiodination of
the ꢀ-iodo azides with DBU in benzene at reflux temperature
afforded vinyl azides 19-24 in good yield. It is worth noting
the stability of the sensitive formyl ester under the reaction
conditions. The separation of the isomeric ꢀ-iodo azides was
unnecessary; the synthesis could be realized directly from the
diastereoisomeric mixture.
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Under thermolysis conditions and in accord with the rules
proposed by Hassner,19 acyclic vinyl azides with this 3-monoalkyl
substitution pattern should give 2H-azirines. Indeed, when the vinyl
azides shown in Table 2 were refluxed in the specified solvent,
(24) (a) Gonza´lez, C. C.; Kennedy, A. R.; Leo´n, E. I.; Riesco-Fagundo,
C.; Sua´rez, E. Angew. Chem., Int. Ed. 2001, 40, 2326–2328. (b) Gonza´lez,
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J. 2003, 9, 5800–5809. (c) Francisco, C. G.; Gonza´lez, C. C.; Paz, N. R.; Sua´rez,
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A. R.; Paz, N. R.; Sua´rez, E. Tetrahedron: Asymmetry 2004, 15, 11–14.
(19) Hassner, A.; Wiegand, N. H.; Gottlieb, H. E. J. Org. Chem. 1986, 51,
3176–3180.
J. Org. Chem. Vol. 73, No. 11, 2008 4119

Alonso-Cruz et al.
TABLE 3. Synthesis of 2-Azido-1,2-dideoxy-1-halopent-1-enitol Compounds
a Reagents and conditions per mmol of substrate. Fluorohydrins: Selectfluor (1.5 mmol), nitromethane, H2O, rt then reflux. Chlorohydrins:
N-chlorosuccinimide (2 mmol), THF, H2O, 50 °C. Bromohydrins: N-bromoacetamide (1.5 mmol), THF, H2O, rt. Iodohydrins: N-iodosuccinimide (1.2
mmol), THF, H2O, rt. b Reagents and conditions per mmol of substrate: (diacetoxyiodo)benzene (1.5 mmol), I2 (1.5 mmol), CH2Cl2, hν, reflux.
c Reagents and conditions per mmol of substrate: DBU (2.5 mmol), PhH, rt. d 25% of a mixture of E- and Z-vinyl iodides is also obtained. e Inseparable
mixture of isomers. f 40% of a mixture of E- and Z-vinyl iodides is also obtained.
To achieve this objective, we decided to prepare 3-azido-
2,3-dideoxyhex-1-enitols 3125 and 3526 utilizing procedures to
those previously reported (Table 3). The syntheses of both
compounds led to diastereoisomeric mixtures of azides. In the
case of 35 the isomers could be separated and although it is
not strictly necessary since C-3 is not a stereogenic center in
the final product, for the sake of convenience, the study was
carried out with the major isomer, which corresponds to a
D-arabino-hex-1-enitol stereochemistry.
The 1,2-halohydrins were synthesized as outlined in Table
3. 1,2-Fluorohydrins (32a, 36a), 1,2-chlorohydrins (32b, 36b),
1,2-bromohydrins (32c, 36c), and 1,2-iodohydrins (32d, 36d)
were prepared from the corresponding 2-deoxyhex-1-enitol (31,
35) by reaction with Selectfluor,27 N-chlorosuccinimide,28
N-bromoacetamide,29 and N-iodosuccinimide,30 respectively.
The ARF reactions were performed under the conditions
stated in Table 3, with DIB and molecular iodine in CH2Cl2 at
reflux temperature and irradiation with two 80 W tungsten
filament lamps. The ARF reactions proceeded smoothly, and
the 1-iodo-1-halo azides 33 and 37 were obtained in high yields
and with modest diastereoselectivity (dr for 37a-37c of 6:4-
7:3).31 The dehydroiodination of the dihalo azides 33 and 37with
DBU in benzene at room temperature afforded halo vinyl azides
34 and 38 in good yields. As expected, the reaction occurred with
high chemoselectivity except for 1-bromo-1-iodo azides 33c and
37c which gave significant amounts of vinyl iodides, 25% and 40%,
respectively, by competitive dehydrobromination.
The stereochemistry of the double bond was assigned on the
basis of 2D NOESY experiments,32 and furthermore, the
structure and stereochemistry of 38d-Z were determined un-
ambiguously by single-crystal X-ray crystallography.20
The synthesis of the halo vinyl azides 34 and 38 proceeded
efficiently through the three steps, but in general with poor
(25) Glycal 31 was prepared from 7 by dehydration of the anomeric alcohol
with Tf2O and s-collidine: Charette, A. B.; Coˆte´, B. J. Org. Chem. 1993, 58, 933–
936. See also: Guthrie, R. D.; Irvine, R. W. Carbohydr. Res. 1980, 82,
207–224. Kawabata, H.; Kubo, S.; Hayashi, M. Carbohydr. Res. 2001, 333, 153–
158 .
(26) Glycal 35 was prepared starting from 1,5-anhydro-4,6-O-benzylidene-
2-deoxy-D-arabino-hex-1-enitol: Chambers, D. J.; Evans, G. R.; Fairbanks, A. J.
Tetrahedron: Asymmetry 2003, 14, 1767–1769, that was transformed into 1-O-
benzoyl-4,6-O-benzylidene-2,3-dideoxy-D-erythro-hex-2-enopyranose by a Ferrier
rearrangement under Mitsunobu conditions (Guthrie, R. D.; Irvine, R. W.;
Davison, E. B.; Henrick, K.; Trotter, J. J. Chem. Soc., Perkin Trans. 2 1981,
468–472) and finally to the required 35 by treatment with NaN3 in HMPA
(Guthrie, R. D.; Irvine, R. W.; Jenkins, I. D. Aust. J. Chem. 1980, 33, 2499–2508).
See also: Guthrie, R. D.; Irvine, R. W. Carbohydr. Res. 1980, 82, 225–236.
(27) (a) Vincent, S. P.; Burkart, M. D.; Tsai, C.-Y.; Zhang, Z.; C.-H.; Wong,
C.-H. J. Org. Chem. 1999, 64, 5264–5279. (b) Albert, M.; Dax, K.; Ortner, J.
Tetrahedron 1998, 54, 4839–4848. (c) Burkart, M. D.; Zhang, Z.; Hung, S.-C.;
Wong, C.-H. J. Am. Chem. Soc. 1997, 119, 11743–11746.
(31) The reaction yields were determined using chromatographically homo-
geneous halohydrin mixtures giving correct elemental analyses and in all cases
complete consumption of the starting material was observed.
(32) A NOE interaction was observed between H-C-1 and H-C-3 in the 34-Z
and 38-Z isomers, although such an interaction was not observed for the
E-isomers. Product structures were also established by spectroscopic (1H, 13C,
and 19F NMR) correlation among Z-and E-isomers, e.g., in the 19F NMR spectra
a difference of 8-10 ppm can be observed in the chemical shift of fluorine
atoms between the Z - and E-isomers of fluoro vinyl azides 34a and 38a. For
NOE-based stereochemistry of related trisubstituted vinyl halides, see:(a) Kim,
J.; Zhang, Y.; Ran, C.; Sayre, L. M. Bioorg. Med. Chem. 2006, 14, 1444–1453.
(b) Kattuboina, A.; Kaur, P.; Timmons, C.; Li, G. Org. Lett. 2006, 8, 2771–
2774. (c) Cheng, C.; Shimo, T.; Somekawa, K.; Baba, M. Tetrahedron 1998,
54, 2031–2040. (d) Manfre, F.; Kern, J.-M.; Biellmann, J.-F. J. Org. Chem. 1992,
57, 2060–2065. (e) McCarthy, J. R.; Matthews, D. P.; Stemerick, D. M.; Huber,
E. W.; Bey, P.; Lippert, B. J.; Snyder, R. D.; Sunkarall, P. S. J. Am. Chem. Soc.
1991, 113, 7439–7440.
(28) Rodriguez, J.; Dulce`re, J.-P. Synthesis 1993, 1177–1205.
(29) Marzabadi, C. H.; Spilling, C. D. J. Org. Chem. 1993, 58, 3761–3766.
(30) Smietana, M.; Gouverneur, V.; Mioskowski, C. Tetrahedron Lett. 2000,
41, 193–195.
4120 J. Org. Chem. Vol. 73, No. 11, 2008

Synthesis of 2-Azido-1-alkenes
TABLE 4. Thermolysis and Photolysis of 2-Azido-1,2-dideoxy-1-halopent-1-enitol Compounds
a Method A: Thermal conditions. All reactions were carried out in benzene (0.1 mM); the thermolysis of the Z-isomers was carried out in a
heavy-walled Pyrex tube, sealed with a screw cap fitted with a Teflon gasket. Method B: Photochemical conditions. All reactions proceeded in C6D6
(0.03 mM) under irradiation with a 450 W ACE-Hanovia medium-pressure mercury lamp. Due to instability of the products on silica gel yields were not
calculated. b Similar results were obtained using method B, rt, 0.5 h. c These conditions gave mainly insoluble brown tar material.
diastereoselectivity. Only when the steric volume of the alkyl group
and the halogen increased did the diastereoselectivity improve
significantly (Table 3, compare drs of 34d with 38d or 38c with
38d).
vinyl azides.33 Neither the stereochemistry of the double bond
nor the reaction method used appear to greatly influence the
stereochemical outcome at the halogen center (e.g., entries 1,
2, and 3 or 4, 5 and 6).
The synthetic usefulness of these compounds for the synthesis
of heterocycles has been preliminarily assessed through ther-
molysis (method A) and photolysis (method B) experiments,
and the results are summarized in Table 4. Two series of
halovinyl azides 34 and 38 with different substituents at the
adjacent carbon were studied. According to Hassner, thermolysis
of these vinylhalo azides with this 3-monoalkyl substitution
pattern should also give 3-alkyl-2-halo-2H-azirines.19 As far as
we know, no examples of these disubstituted 3-alkyl-2-halo-
2H-azirines have been reported to date, and they are expected
to be highly reactive and unstable on the basis of previous
studies of related azirines.6
Unfortunately, we were unable to obtain 2H-azirines 41 (X
) Br) and 42 (X ) I) from the thermolysis of 34c and 34d,
respectively (entries 7, 9, and 11). On heating in benzene,
increasing amounts of polymeric substances were observed and
the substrate completely decomposed at reflux temperature.
Therefore, the preparation of 2-halo-2H-azirines from halo vinyl-
azides was most conveniently achieved by irradiation with an
unfiltered UV light using a medium-pressure mercury lamp (450
W) at room temperature (entries 3, 6, 8, 10, and 12). This was
especially facile with the Z-isomers or when the halogen atom
was bromine or iodine.
All of the 2-halo-2H-azirines 39-46 synthesized proved to
be unstable, could not withstand chromatographic purification,
and decomposed gradually, as dilute benzene solutions, within
a few days in a freezer (-25 °C) under nitrogen. Notwithstand-
ing, the instability increases in both series from 2H-azirines 39,
As is evident from Table 4, thermolyses of the E-isomers
occurred faster and at a lower temperature than those of the
Z-isomers (entries 1 and 2, 4 and 5, or 13 and 14), a fact that
has already been reported for the thermolysis of dehalogenated
J. Org. Chem. Vol. 73, No. 11, 2008 4121

Alonso-Cruz et al.
vacuum. Column chromatography (hexanes-EtOAc, mixtures) of
the residue afforded the required vinyl azides.
43 (X ) F) to 42, 46 (X ) I). We managed to fully characterize
2H-azirines 39, 43 (X ) F) and 40, 44 (X ) Cl) since the crude
1
General Procedure for the Synthesis of 2H-Azirines 25-30.
A solution of the vinyl azide (1 mmol) in dry toluene (12 mL) was
heated at reflux temperature under nitrogen for a specific period of
time (Table 2). After concentration under vacuum, the residue was
purified by Chromatotron chromatography (hexanes-EtOAc, mix-
tures) to give the required 2H-azirines.
General Procedure for the Preparation of Fluorohydrins
32a and 36a. To a solution of the corresponding 3-azido-2,3-
dideoxyhex-1-enitol (1 mmol) in nitromethane (10 mL) were added
H2O (1.5 mL) and F-TEDA-BF4 (Selectfluor) (1.5 mmol) and the
mixture stirred at room temperature for a specific period of time
(Table 3) until the disappearance of the starting material was noted
by TLC. The reaction mixture was then heated to reflux for 0.5 h,
poured into brine, and extracted with EtOAc. The organic layer
was dried over Na2SO4 and concentrated under reduced pressure.
Chromatography of the residue (hexanes-EtOAc mixtures) afforded
the required fluorohydrin compounds.
reaction products were sufficiently pure to give clean H and
13C NMR spectra, HRMS, and correct elemental analyses. From
the most unstable 2H-azirines 41, 45 (X ) Br) and 42, 46 (X
1
) I) only H NMR spectra could be obtained.
In summary, we have developed a new general methodology
for the synthesis of polyhydroxylated 2-azido-1-alkenes from
2-deoxycarbohydrates making use of the ARF reaction. This
methodology, which avoids the use of halogen azides, has been
extended to a general synthesis of 1-fluoro-, 1-chloro-, 1-bromo-,
and 1-iodo-2-azido-1-alkenes under mild conditions compatible
with common carbohydrate protecting groups. These carbohy-
drate-derived 2-azido-1-deoxy-1-iodo-alditols, 2-azido-1,2-
dideoxy-pent-1-enitols, and 2-azido-1,2-dideoxy-1-halo-pent-1-
enitols may be of interest as chiral synthons for the preparation
of polyhydroxylated heterocyclic systems.
General Procedure for the Preparation of Chlorohydrins
32b and 36b. A solution of the corresponding 3-azido-2,3-
dideoxyhex-1-enitol (1 mmol) in THF (20 mL) and H2O (10 mL),
containing N-chlorosuccinimide (2 mmol), was stirred at 50 °C for
a specific period of time (Table 3). The reaction mixture was then
poured into water, extracted with EtOAc, and washed with Na2S2O3.
The organic layer was dried and concentrated under reduced
pressure.Chromatotronchromatographyoftheresidue(hexanes-EtOAc
mixtures) afforded the required chlorohydrin compounds.
General Procedure for the Preparation of Bromohydrins
32c and 36c. A solution of the corresponding 3-azido-2,3-
dideoxyhex-1-enitol (1 mmol) in THF (34 mL) and H2O (4 mL),
containing recently crystallized N-bromoacetamide (1.5 mmol), was
stirred at room temperature for a specific period of time (Table 3).
The reaction mixture was then poured into brine and extracted with
CH2Cl2. The organic layer was dried over Na2SO4 and concentrated
under reduced pressure. Chromatotron chromatography of the
residue (hexanes-EtOAc mixtures) afforded the required bromo-
hydrin compounds.
General Procedure for the Preparation of Iodohydrins 32d
and 36d. A solution of the corresponding 3-azido-2,3-dideoxyhex-
1-enitol (1 mmol) in THF (10 mL) and H2O (10 mL), containing
N-iodosuccinimide (1.2 mmol), was stirred at room temperature
for 1 h. The reaction mixture was then poured into 10% aqueous
sodium thiosulfate and extracted with EtOAc. The organic layer
was dried over Na2SO4 and concentrated under reduced pressure.
Chromatotron chromatography of the residue (hexanes-EtOAc
mixtures) afforded the required iodohydrin compounds.
Experimental Section
CAUTION: Azide compounds can be toxic and potentially
explosive. In particular, the reaction of glycals with NaN3 in the
presence of catalytic amounts of HgSO4 and H2SO4 has the potential
to form mercuric azide which is highly susceptible to spontaneous
detonation. We have never encountered any problem when using
the reaction scales and general procedures described below, but
recommend special care be taken.
General Procedure for the Synthesis of 3-Azido-2,3-dideoxy-
aldoses 7-12 .17b,c A solution of the corresponding 2-deoxyhex-
1-enitol (1 mmol) in 1,4-dioxane (1.35 mL) containing HgSO4
(0.047 mmol) and aqueous H2SO4 (5 mM, 5.4 mL) was stirred at
30 °C for 1-5 h. Then NaN3 (10 mmol) and AcOH glacial (1.35
mL) were added, and the stirring continued for 1.5 h. The reaction
mixture was then poured into water and extracted with CH2Cl2.
The organic layer was dried over Na2SO4 and concentrated under
vacuum and the residue purified by column chromatography
(hexanes-EtOAc, mixtures) to give the required 3-azido compounds.
General Procedure for the Synthesis of ꢀ-Iodo Azides
13-18, 33, and 37. A solution of the 3-azido-2,3-dideoxy
compounds (1 mmol) in CH2Cl2 (25-50 mL) containing (diac-
etoxyiodo)benzene (1.5 mmol) and iodine (1.5 mmol) was irradiated
with two 80 W tungsten-filament lamps at reflux temperature for a
specific period of time (Tables 1 and 3). The reaction mixture was
then poured into water and extracted with CH2Cl2. The organic
layer was washed with 10% aqueous sodium thiosulfate, dried, and
concentrated in vacuo. Chromatotron chromatography of the residue
(hexanes-EtOAc, mixtures) afforded the required iodo azides.
General Procedure for the Synthesis of Vinyl Azides 19-24.
To a solution of the ꢀ-iodo azide (1 mmol) in dry benzene (34
mL) was added DBU (2.5 mmol) and the mixture stirred at 90 °C
for a specific period of time (Table 1). After this time, the reaction
mixture was poured into a saturated solution of NaHSO4 and
extracted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, and concentrated under vacuum. Column
chromatography (hexanes-EtOAc, mixtures) of the residue afforded
the required vinyl azides.
General Procedure for the Preparation of 2-Halo-2H-azir-
ine Compounds 39-46 under Photolytic Conditions. The cor-
responding halo vinyl azide was dissolved in C6D6 (0.03 mM) and
placed in a NMR tube. The reaction mixture was irradiated with
the unfiltered light of a 450 W ACE-Hanovia medium-pressure
mercury at 10 cm and the course of the reaction was monitored by
1H NMR until complete conversion (approximately 30 min).
Acknowledgment. This work was supported by Research
Programs Nos. CTQ2004-06381/BQU and CTQ2004-02367/
BQU of the Ministerio de Educacio´n y Ciencia, Spain, cofi-
nanced by the Fondo Europeo de Desarrollo Regional (FEDER).
C.R.A.-C. thanks the I3P-CSIC Program for a fellowship.
General Procedure for the Synthesis of Vinyl Azides 34
and 38. To a solution of the ꢀ-iodo azide (1 mmol) in dry benzene
(34 mL) was added DBU (2.5 mmol) and the mixture stirred at
room temperature for a specific period of time (Table 3). After
this time, the reaction mixture was poured into a saturated solution
of NaHSO4 and extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, and concentrated under
Supporting Information Available: Detailed experimental
procedures and spectral and analytical data for all new com-
pounds. X-ray crystallographic files (CIF) for compounds 26
and 38d-Z. Copies of 1H and 13C NMR spectra for compounds
13-30, 34a-34c, and 37d-38d. This material is available free
of charge via the Internet at http://pubs.acs.org.
(33) (a) Yamabe, T.; Kaminoyama, M.; Minato, T.; Hori, K.; Isomura, K.;
Taniguchi, H. Tetrahedron 1984, 40, 2095–2099. (b) Isomura, K.; Taniguchi,
H.; Mishima, M.; Fujio, M.; Tsuno, Y. Org. Magn. Reson. 1977, 9, 559–562.
JO800182Y
4122 J. Org. Chem. Vol. 73, No. 11, 2008