Azide and Cyanide Displacements via Hypervalent Silicate Intermediates

Article abstract of DOI:10.1021/jo982302d

Hypervalent azido- and cyanosilicate derivatives, prepared in situ by the reaction of trimethylsilyl azide or trimethylsilyl cyanide, respectively, with tetrabutylammonium fluoride, are effective sources of nucleophilic azide or cyanide. Primary and secondary alkyl halides and sulfonates undergo rapid and efficient azide or cyanide displacement in the absence of phase transfer catalysts with the silicate derivatives. Application of these reagents to the stereoselective synthesis of glycosyl azide derivatives is reported.

Full text of DOI:10.1021/jo982302d

J . Org. Chem. 1999, 64, 3171-3177
3171
Azid e a n d Cya n id e Disp la cem en ts via Hyp er va len t Silica te
In ter m ed ia tes†
Eric D. Soli, Amy S. Manoso, Michael C. Patterson, and Philip DeShong*,‡
Department of Chemistry and Biochemistry, The University of Maryland, College Park, Maryland 20742
David A. Favor, Ralph Hirschmann, and Amos B. Smith, III
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323
Received November 23, 1998
Hypervalent azido- and cyanosilicate derivatives, prepared in situ by the reaction of trimethylsilyl
azide or trimethylsilyl cyanide, respectively, with tetrabutylammonium fluoride, are effective sources
of nucleophilic azide or cyanide. Primary and secondary alkyl halides and sulfonates undergo rapid
and efficient azide or cyanide displacement in the absence of phase transfer catalysts with the
silicate derivatives. Application of these reagents to the stereoselective synthesis of glycosyl azide
derivatives is reported.
Nucleophilic substitution is one of the most prized and
useful transformations in the chemical arsenal. At the
practical level, however, nucleophilic displacements often
require relatively harsh reaction conditions with high
reaction temperatures, polar solvents such as DMSO,
HMPA, or DMF, and a large excess of the nucleophile if
high yields of product are to be achieved. Recently, we
reported the use of tetrabutylammonium triphenyldif-
luorosilicate (TBAT, 1a ) as a source of nucleophilic
fluoride for SN2 displacement of primary and secondary
alkyl substrates (Scheme 1)1 and for silicon-carbon bond
cleavage.2 TBAT is an excellent fluoride surrogate when
compared to alkali metal fluorides or tetraalkylammo-
nium fluorides because TBAT is crystalline, soluble in a
wide range of organic solvents, nonbasic, and nonhygro-
scopic. Having demonstrated that hypervalent silicate
derivatives are practical reagents for the delivery of
fluoride anion,1-3 extension of this strategy to deliver
other nucleophiles was investigated. In this paper, we
report that trimethylsilyl azide (TMS-N3) and trimeth-
ylsilyl cyanide (TMS-CN) underwent reaction with tet-
rabutylammonium fluoride (TBAF) to generate the re-
spective hypervalent trimethylfluorosilicate (1b or 1c) in
situ. Analogous with the observations using TBAT,
silicates 1b and 1c were extremely reactive alternates
of azide and cyanide anion, respectively, for SN2 displace-
ment (Scheme 1). Using the in situ generated silicates,
it was possible to perform displacements under milder
conditions than typically required (vide infra). Takaya
has also published a preliminary report in which azides
are prepared in this manner.4
those typically employed demonstrate the effectiveness
of the silicate strategy. Especially noteworthy is the
reaction of silicates 1b/1c with phenethyl bromide be-
cause the substrate is prone to base-catalyzed elimination
to afford styrene. Displacements employing alkali metal
salts in polar solvents consistently afforded more elimi-
nation products than the silicate method (vide supra).
Cya n id e Disp la cem en ts
The major advantage of the silicate method with these
substrates was the rate of cyanide displacement in
acetonitrile. The silicate-based displacements occurred
rapidly, whereas the displacements using alkali metal
salts of cyanide were sluggish (typically >12 h) (Scheme
2). For example, the silicate-based displacement of benzyl
bromide occurred in less than 5 min in refluxing aceto-
nitrile, compared with the crown ether procedure that
required 24 h under identical conditions (eq 1, Scheme
2). Results for the cyanide displacement with a variety
of primary and secondary substrates bearing halide or
sulfonate leaving groups are summarized in Table 1.
Several features of the results in Table 1 are notewor-
thy; although displacement was predictably longer for
benzyl chloride (Table 1, entry b) than for the bromo ana-
logue (entry a), the chloride underwent cyanide displace-
ment in comparable yield. Previous methods, while
achieving similar yield, required longer reaction times,
painstakingly dried reagents, DMSO as the solvent, or
toxic 18-crown-6 as a phase transfer catalyst.5-7 Primary
alkyl iodide (entry c), bromide (entry d), chloride (entry
e), and mesylate (entry f) were efficiently converted to
the corresponding nitrile 3, where the relative order of
reactivity was as follows: I ≈ OMs > Br > Cl. Again,
the yield of displacement product was comparable to tra-
ditional methodologies; however, these more traditional
methods employed either high temperatures and lengthy
reaction time or required DMF as the solvent.8,9 Phen-
As noted in Scheme 2, silicates 1b and 1c are potent
azide and cyanide anion surrogates. Comparison of the
reaction conditions for nucleophilic displacement with
† This paper is dedicated to Professor J ack Baldwin on the occasion
of his 60th birthday.
‡ Phone: 301-405-1892. Fax: 301-314-9121. Email: pd10@umail.umd.
edu.
(1) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J . Am. Chem. Soc.
1995, 117, 5166-5167.
(2) Pilcher, A. S.; DeShong, P. J . Org. Chem. 1996, 61, 6901-6905.
(3) Loezos, P.; Pilcher, A. S.; DeShong, P., unpublished results.
(4) Ito, M.; Koyakumaru, K.-i.; Ohta, T.; Takaya, H. Synthesis 1995,
376-378.
(5) Harusawa, S.; Yoneda, R.; Omori, Y.; Kurihara, T. Tetrahedron
Lett. 1987, 28, 4189-4190.
(6) Cook, F. L.; Bowers, C. W.; Liotta, C. L. J . Org. Chem. 1974, 39,
3416-3418.
(7) Friedman, L.; Shechter, H. J . Org. Chem. 1960, 25, 877-879.
10.1021/jo982302d CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/09/1999

3172 J . Org. Chem., Vol. 64, No. 9, 1999
Soli et al.
Sch em e 1
Sch em e 2
fluxing acetonitrile, no appreciable amount of nitrile
product formed from exo-norbornyl bromide (entry l);
however, in refluxing dioxane, displacement of the exo-
bromide occurred in good yield to give endo-nitrile, albeit
sluggishly. This reaction occurred predominantly with
inversion of configuration, supporting our proposed SN2
displacement mechanism. We have not yet been able to
determine whether the small amount of exo-nitrile ob-
tained is the result of epimerization of the halide prior
to displacement or is due to an SN1-like process. As ex-
pected, the cyclohexyl halides were less ideal substrates
for the displacement reaction even with the silicate
derivative. Cyclohexyl bromide (entry m) failed to give
the displacement product and gave the alkene instead,
mirroring the results of previous researchers.6,12,13 (-)-
Menthyl chloride (entry n) was similarly unreactive,
presumably due to steric hindrance. However, it is
noteworthy that the reagent did not induce elimination
under these reaction conditions.
Cyanide is an ambident nucleophile and is known to
react as a carbon nucleophile to give nitriles (R-CN) or
as a nitrogen nucleophile to yield isocyanides (R-NC).14
Traditionally, NaCN or KCN has been used to form
nitriles, and AgCN has been used to form isocyanides.15
It has been rationalized that alkali metal cyanide dis-
sociates to give “free” CN ion which attacks with its more
basic carbon end, whereas AgCN does not entirely
dissociate, leaving Ag+ complexed to the carbon of the
nucleophile, so that only nitrogen is available for nucleo-
philic attack.16 We hypothesized that the silicon would
function analogously, so that C-complexation to silicon
would leave the cyano nitrogen available to act as a
nucleophile. However, no traces of isonitrile products
were detected in the reaction mixtures. Whether this
result is an indication of the bonding in the hypervalent
species or a function of reaction conditions is under
investigation.
ethyl bromide (entry g), which should be more prone to
elimination than the dodecyl substrates, gave no elimina-
tion products with silicate 1c, again attesting to the
nonbasic nature of the reagent. Predictably, secondary
halides and sulfonates reacted slower with competing
elimination, lowering the yields of nitrile. For example,
silicate 1c rapidly converted 2-iodooctane (entry h),
bromide (entry i), and tosylate (entry j) to the nitrile in
good yield (76-83%), although the alkene byproduct was
also observed.
For secondary substrates, the silicate methodology is
superior to prior methods with regard to yield and reac-
tion conditions. Regen and co-workers reported the dis-
placement of the primary bromide in entry d in quantita-
tive yield using NaCN-coated alumina in refluxing
toluene for 24 h. However, under the same conditions,
Regen reported that the secondary bromide in entry i
gave only 27% of the corresponding nitrile after 40 h.8
The Bram group was able to perform the same transfor-
mation in 72% yield, but only under aqueous phase-
transfer conditions.10 Finally, secondary benzylic bromide
(entry k) underwent smooth conversion to the corre-
sponding nitrile upon treatment with cyanosilicate with-
out the formation of the elimination product. Again the
yield was superior to that previously reported.11 In re-
Azid e Disp la cem en ts
Our primary interest in the azide displacement was
for the synthesis of glycosyl azide derivatives, which are
important precursors of N-linked glycoconjugates.17 For
(8) Regen, S. L.; Quici, S.; Liaw, S.-J . J . Org. Chem. 1979, 44, 2029-
2030.
(9) White, D. A.; Baizer, M. M. J . Chem. Soc., Perkin Trans. 1 1973,
2230-2236.
(10) Bram, G.; Loupy, A.; Pedoussaut, M. Bull Chim. Soc. Fr. 1986,
124-128.
(11) Saito, K.; Harada, K. Bull. Chem. Soc. J pn. 1989, 62, 2562-
2566.
(12) Shaw, J . E.; Hsia, D. Y.; Parries, G. S.; Sawyer, T. K. J . Org.
Chem. 1978, 43, 1017-1018.
(13) Thoman, C. J .; Habeeb, T. D.; Huhn, M.; Korpusik, M.; Slish,
D. F. J . Org. Chem. 1989, 54, 4476-4478.
(14) Black, T. H. Org. Prep. Proced. Int. 1989, 21, 179-217.
(15) Brown, B. R. The Organic Chemistry of Aliphatic Nitrogen
Compounds; Oxford University Press: New York, 1994; Vol. 28.
(16) Carretero, J . C.; Garc´ıa Ruano, J . L. Tetrahedron Lett. 1985,
26, 3381-3384.

N3 and CN Displacements via Silicate Intermediates
J . Org. Chem., Vol. 64, No. 9, 1999 3173
Ta ble 1. Rea ction of Silica te An ion 1c w ith Alk yl Ha lid esa
a
The indicated substrate, Me3SiCN, and TBAF (1:1.5:1.5 molar ratio) in acetonitrile were allowed to react at the given temperature,
b
unless otherwise noted. Isolated yield after purification. The yield determined by gas chromatographic analysis of the crude reaction
mixture (vs an internal standard) is reported in parentheses. c No reaction was observed. Reaction was performed in dioxane.
d
Sch em e 3
example,glycosylamines,17,18glycolipids,19-22glycopeptides,23-25
heterocyclic N-glycosides,26,27 and combinatorial librar-
ies28,29 have been prepared from glycosyl azide deriva-
tives. It was found that a wide variety of glycosyl ana-
logues underwent reaction with the silicate generated in
situ from trimethylsilyl azide in the presence of a fluoride
source, affording the corresponding glycosyl azides in
high yield. The yield of azides obtained by this methodol-
ogy exceed or are comparable to those reported by other
activating agents such as: tin(IV),30,31 hexamethylphos-
methods while avoiding the use of toxic reagents or
phorictriamide,32,33 in situ brominating reagents,34 or
(17) Nolte, R. J . M.; van Zomeren, J . A. J .; Zwikker, J . W. J . Org.
Chem. 1978, 43, 1972-1975.
(18) Sproviero, J . F.; Salinas, A.; Bertiche, E. S. Carbohydr. Res.
1971, 19, 81-86.
(19) Kameyama, A.; Ishida, H.; Kiso, M.; Hasegawa, A. J . Carbo-
large excess of alkali metal azide salt.35,36
The general transformation for azide displacement is
outlined in Scheme 3 and involved nucleophilic displace-
ment of bromide, chloride, triflate, tosylate, trichloroimi-
date, and isoxazoline leaving groups. Of particular con-
cern was the ability to retain the protecting groups of
the glycosyl derivatives during the displacement. Previ-
ous studies in our group had demonstrated that azide
hydr. Chem. 1994, 13, 641-654.
(20) Iida, M.; Endo, A.; Fujita, S.; Numata, M.; Sugimoto, M.;
Nunomura, S.; Ogawa, T. J . Carbohydr. Chem. 1998, 17, 647-672.
(21) Kwon, O.; Danishefsky, S. J . J . Am. Chem. Soc. 1998, 120,
1588-1599.
(22) Deshpande, P. P.; Kim, H. M.; Zatorski, A.; Park, T.-K.;
Ragupathi, G.; Livingston, P. O.; Live, D.; Danishefsky, S. J . J . Am.
Chem. Soc. 1998, 120, 1600-1614.
(23) Garcia, J .; Urp´ı, F.; Vilarrasa, J . Tetrahedron Lett. 1984, 25,
4841-4844.
(24) Inazu, T.; Kobayashi, K. Synlett 1993, 869-870.
(25) Kunz, H. Angew. Chem., Int. Ed. Engl. 1987, 26, 294-308.
(26) Garc´ıa-Lo´pez, M. T.; Garc´ıa-Mun˜oz, G.; Iglesias, J .; Madron˜ero,
R. J . Heterocycl. Chem. 1969, 6, 639-642.
(27) Earl, R. A.; Townsend, L. B. Can. J . Chem. 1980, 58, 2550-
2561.
(30) Matsubara, K.; Mukaiyama, T. Chem. Lett. 1994, 247-250.
(31) Meinjohanns, E.; Meldal, M.; Paulsen, H.; Bock, K. J . Chem.
Soc., Perkin Trans. 1 1995, 405-415.
(32) Takeda, T.; Sugiura, Y.; Ogihara, Y.; Shibata, S. Can. J . Chem.
1980, 58, 2600-2603.
(33) Ogawa, T.; Nakabayashi, S.; Shibata, S. Agric. Biol. Chem.
1983, 47, 281-285.
(34) Saito, A.; Saito, K.; Tanaka, A.; Oritani, T. Tetrahedron Lett.
1997, 38, 3955-3958.
(28) Roberge, J . Y.; Beebe, X.; Danishefsky, S. J . J . Am. Chem. Soc.
1998, 120, 3915-3927.
(29) Drouillat, B.; Kellam, B.; Dekany, G.; Starr, M.; Toth, I. Bioorg.
Med. Chem. Lett. 1997, 7, 2247-2250.
(35) Szarek, W. A.; Achmatowicz, O.; Plenkiewicz, J .; Radatus, B.
Tetrahedron 1978, 34, 1427-1433.
(36) Sabesan, S.; Neira, S. Carbohydr. Res. 1992, 223, 169-85.

3174 J . Org. Chem., Vol. 64, No. 9, 1999
Soli et al.
Sch em e 4
completely stereoselective and gave azide 9R,â in 95%
yield as a mixture of anomers (R: â ) 85:10).
Perbenzylated glycosyl donors are known to be more
reactive than their acetylated counterparts and the
R-chloro derivative gave the â-azido product stereoselec-
tively (entry f). However, the much less stable R-trichlor-
oimidate analogue 16 underwent azide displacement with
silicate 1b to afford a 1:1 mixture of anomeric azides.
The final glycosyl derivatives investigated was the
N-acetylglucosamine family (entries h and i). Treatment
of oxazoline 17 with silicate 1b afforded exclusively
â-azide 18 in good yield. This result was particularly
pleasing since the oxazoline derivative is known to be
hydrolytically unstable. Alternatively, R-chloride 19, a
much more robust analogue of N-acetylglucosamine, un-
derwent azide displacement in only 1.5 h to give exclu-
sively 18.
The advantage of the silicate-based displacements is
demonstrated in the following example from the Hirsh-
mann-Smith laboratory (Scheme 5). Standard methods
for direct conversion of the primary neopentyl carbinol
(-)-20 to its corresponding azide proved to be ineffec-
tive.41-43 The most promising of these methods appeared
to be the Mitsunobu conditions with diphenyl phosphoryl
azide (DPPA) as the azide source.43 On one occasion,
these conditions afforded desired azide (-)-21 in a low
30% yield, but this result was irreproducible. However,
treatment of triflate 22 with the in situ generated
azidosilicate 1b in acetonitrile afforded azide (-)-21 in
60% yield.
displacements using the alkali metal salts resulted in
removal of acetoxy groups under the strongly basic and
nucleophilic reaction conditions (see Scheme 4).37 Acetoxy
or benzyl ether protected sugars bearing an appropriate
leaving group underwent efficient azide displacement
with a slight excess of silicate 1b in THF at moderate
temperatures to afford glycosyl azides in good to excellent
yield. As noted in Table 2, the displacement occurred
predominately with inversion of configuration and no
deprotected or glycal elimination products were observed.
Peracetylmannose 6-tosylate 4 was prepared and sub-
jected to typical azide displacement conditions (Scheme
4). Even under optimized conditions, the displacement
required 6 equiv of sodium azide for 48 h in warm DMF.
The yields were unreliable at best, and the azidation was
accompanied by loss of the anomeric acetate and ano-
merization.37 In addition, a second acetate was lost (pre-
sumably from the C-2 position). In contrast, when tosy-
late 4 was treated with TMS-N3/TBAF, the displacement
proceeded in dramatically improved yield and all the
protecting groups as well as the configuration at the ano-
meric center were preserved. In addition, as was observed
in cyanide displacements noted above, the rate of the
displacement of tosylate by azide was enhanced by
comparison with typical azide displacement conditions.
In addition to primary leaving groups, displacement
at a more hindered secondary center occurred with equal
facility (Table 2). For example, mannosyl triflate 638
(entry a) gave 2-azidoglucopyranose 7 in 73% yield with
complete inversion of configuration. Again, the anomeric
configuration and integrity of the protecting groups were
unaffected using these conditions.
Con clu sion
Treatment of trimethylsilyl cyanide and azide with
TBAF resulted in the in situ generation of silicates 1c
and 1b, respectively. The resulting silicates have been
shown to be highly effective as nucleophilic cyanide and
azide donors under extremely mild conditions. Extension
of this strategy for the nucleophilic transfer of other
groups will be reported in due course.
Exp er im en ta l Section
1
Gen er a l. All H and 13C NMR spectra were recorded on a
400 MHz spectrometer in CDCl3 unless otherwise indicated.
Chemical shifts are reported in parts per million (δ), and
coupling constants (J values) are given in hertz (Hz). Infrared
absorbances are reported in reciprocal centimeters (cm-1). Gas
chromatography was performed on an instrument equipped
with a flame ionization detector using a 25 m capillary column
coated with cross linked methyl silicone.
Tetrahydrofuran (THF) and dioxane were distilled from
sodium/benzophenone ketyl. Pyridine, acetonitrile (MeCN),
and methylene chloride (CH2Cl2) were distilled from calcium
hydride. Dimethylformamide (DMF) was distilled from mo-
lecular sieves. Methanol (MeOH) was dried and stored over
molecular sieves. Glassware used in the reactions was dried
overnight in an oven at 120 °C. All reactions were performed
under an atmosphere of nitrogen unless noted otherwise.
Tetrabutylammonium fluoride (TBAF) was used as a 1.0 M
solution in THF. All materials were purchase from Aldrich and
used as received, with the following exceptions. 2-Iodooctane
(Table 1, entry h) was synthesized from the corresponding
alcohol using Olah’s method.44 In the case of sulfonates (Table
Silicate 1b could also be employed for the synthesis of
1-azido glycosyl derivatives from the corresponding pre-
cursors. For example, azide 9â, which serves as a
precursor to glycopeptide derivatives, was prepared from
commercially available R-bromide 8.39 Similarly, R-chlo-
ride 1040 underwent displacement to afford 9â. Note that
the reactions occurred by SN2 displacement, as evidenced
by complete inversion at the reaction center. On the other
hand, displacement of â-chloro anomer 1141 was not
(37) Patterson, M. C.; Vepachedu, S. R.; DeShong, P., unpublished
results.
(38) 1,3,4,6-Tetra-O-acetyl-2-O-trifluormethanesulfonyl-â-D-man-
nopyranose [cat. no. 31,025-5] was purchased from Aldrich Chemical
Co. and used without further purification.
(39) 2,3,4,6-Tetra-O-acetyl-R-D-glucopyranosyl bromide [cat. no. 27093-
0100] was purchased from Acros Organics and recrystallized from
diisopropyl ether prior to use.
(40) Lemieux, R. U. In Methods in Carbohydrate Chemistry; Whis-
tler, R. L., Wolfram, M. L., BeMiller, J . N., Eds.; Academic Press: New
York, 1963; Vol. 2, 223-224.
(41) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre,
D. J .; Grabowski, E. J . J . J . Org. Chem. 1993, 58, 5886-5888.
(42) Viaud, M. C.; Rollin, P. Synthesis 1990, 130-132.
(43) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahe-
dron Lett. 1977, 1977-1980.
(44) Olah, G. A.; Narang, S. C.; Balaram Gupta, B. G.; Malhotra,
R. J . Org. Chem. 1979, 44, 1247-1251.

N3 and CN Displacements via Silicate Intermediates
J . Org. Chem., Vol. 64, No. 9, 1999 3175
Ta ble 2. Rea ction of Silica te An ion 1b w ith Glycosyl Accep tor sa
a
b
All reactions were performed using 1.2 equiv of silicate 1b, generated in situ, in THF at the indicated temperature. Isolated material.
All known compounds exhibited physical and spectroscopic properties identical to those reported in the literature. See Experimental
Section for details.
Sch em e 5
1, entries f and j) the appropriate sulfonate was synthesized
from the alcohol immediately before use using the literature
method,45,46 and the crude isolated sulfonate was used without
further purification. 2,3,4,6-Tetra-O-acetyl-R-D-glucopyranosyl
bromide (8) was purchased from Acros Organics and recrystal-
lized from diisopropyl ether prior to use. All compounds were
P h en yla ceton itr ile (Table 1, entries a and b). Trimethyl-
silyl cyanide (200 µL, 1.50 mmol) and TBAF (1.5 mL, 1.5
mmol) were added to a stirring solution of benzyl bromide
(119µL, 1.00 mmol) in 10 mL of acetonitrile under an atmo-
sphere of nitrogen. The reaction was complete by GC analy-
sis in 0.1 h. The light yellow reaction mixture was concen-
trated in vacuo, and the resulting syrup was purified by
flash chromatography (9:1, pentane/CH2Cl2) to afford 111 mg
(95%) of phenylacetonitrile as a colorless oil. The IR and 1H
and 13C NMR data were identical to those of an authentic
sample purchased from Aldrich, as well as published spectral
data.47,48
1
determined to be >95% pure by GC and H NMR spectroscopy.
Gen er a l P r oced u r e for Syn th esis of Nitr iles 3. Nitrile
preparations and product isolations were performed under
identical reaction conditions, the only variable being the
reaction time and solvent as outlined in Table 1. The following
example is illustrative.
(45) Wawzonek, S.; Klimstra, P. D.; Kallio, R. E. J . Org. Chem. 1960,
25, 621-623.
(46) Schleyer, P. v. R. In Reagents for Organic Synthesis; Fieser, L.
F., Fieser, M., Eds.; J ohn Wiley and Sons: New York, 1967; Vol. 1, pp
1180-1181.
(47) Pouchert, C. J . The Aldrich Library of FT-IR Spectra, 1st ed.;
Aldrich Chemical Company: Milwaukee, 1985; Vol. 2.
(48) Pouchert, C. J .; Behnke, J . The Aldrich Library of 13C and 1H
FT NMR Spectra, 1st ed.; Aldrich Chemical Co.: Milwaukee, 1993;
Vol. 2.

3176 J . Org. Chem., Vol. 64, No. 9, 1999
Soli et al.
Tr id eca n en itr ile (Table 1, entries c-f): colorless oil.; IR
(thin film) 2246; 1H NMR, 400 MHz (CDCl3) δ 2.33 (t, J ) 7.2,
2H), 1.62 (p, 2H), 1.51-1.39 (m, 2H), 1.38-1.17 (m, 16H), 0.84
(t, J ) 7.6, 3H); 13C NMR (CDCl3) δ 120.1, 32.1, 29.8, 29.7,
29.5, 29.0, 28.9, 25.6, 22.8, 17.3, 14.3. The IR was identical to
the published spectrum.49
Hyd r ocin n a m on itr ile (Table 1, entry g): colorless oil. The
IR and 1H and 13C NMR data were identical to those of an
authentic sample purchased from Aldrich, as well as published
spectral data.48,49
2-P h en ylp r op ion itr ile (Table 1, entry k): colorless oil. The
IR and 1H and 13C NMR data were identical to those of an
authentic sample purchased from Aldrich, as well as published
spectral data.48,49
en d o/exo-2-Nor bor n a n e Ca r bon itr ile (Table 1, entry l).
The IR and 1H and 13C NMR data were identical, except for
the endo/ exo ratio, to those of an authentic sample purchased
from Aldrich, as well as published spectral data.47,48,50 The
endo/ exo ratio was determined by integration of the 13C NMR
spectrum.
1,2,3,4-Tet r a -O-a cet yl-6-a zid o-6-d eoxy-â-D-glu cop yr a -
n ose (5r). Tosylate 4 (500 mg, 1.24 mmol) was dissolved in
10 mL of anhydrous DMF. Sodium azide (810 mg, 12.5 mmol)
was added, and the solution was stirred at 56 °C for 48 h. The
reaction mixture was poured into brine and extracted with
ethyl acetate 5 times. The combined ethyl acetate extracts were
concentrated in vacuo. The residue was dissolved in 10 mL of
anhydrous pyridine, DMAP (20 mg, 0.16 mmol) and acetic
anhydride (500 µL, 5.30 mmol) were added, and the mixture
was stirred at room temperature for 4 h. The reaction was
poured into 10 mL of ice water and extracted with ethyl
acetate. The combined ethyl acetate extracts were washed with
brine, dried over Na2SO4, and evaporated in vacuo. The residue
was chromatographed (1:9, EtOAc/CH2Cl2) to yield 262 mg
(55%) of azide 5R as an oil: IR (neat) 2106, 1756;1H NMR
(CDCl3) δ 6.08 (d, J ) 1.6 Hz, 1H), 5.35-5.21 (m, 3H), 4.03-
3.92(m, 1H), 3.43-3.22 (m, 2H), 2.16 (s, 3H), 2.15 (s, 3H), 2.04
(s, 3H), 1.99 (s, 3H); 13C NMR (CDCl3) δ 169.8, 169.5, 169.4,
167.8, 90.1, 71.7, 68.4, 66.1, 66.3, 50.5, 20.8, 20.7, 20.6, 20.4;
LRMS (EI), m/z (rel int) 314 (M+ - OAc) (18), 286 (10), 214
(5), 97 (100); HRMS (M+ - OAc) m/z calcd for C12H16O7N3
314.0988, found 314.0989.
1,2,3,4-Tet r a -O-a cet yl-6-a zid o-6-d eoxy-â-D-glu cop yr a -
n ose (5â). Trimethylsilyl azide (40 µL, 0.300 mmol) and TBAF
(300 µL, 0.310 mmol) were added to an argon-blanketed
solution of tosylate 4 (109 mg, 0.217 mmol) in 4 mL of CH3CN.
The reaction was heated at reflux for 6 h. Over this time, the
solution turned from colorless to clear yellow. The mixture was
allowed to return to room temperature, and 10 mL of water
was added. This material was extracted with ethyl acetate.
The organic extracts were combined, dried over Na2SO4, and
filtered. Solvent was removed in vacuo to afford a light yellow
oil. The oil was purified by flash chromatography (2:1, EtOAc/
hexane) to yield 62 mg (77%) of azide 5â as a colorless oil: IR
(CCl4) 2106, 17569; 1H NMR (CDCl3) δ 5.84 (d, J ) 1.2 Hz,
1H), 5.46 (dd, J ) 3.1, 1.2, 1H), 5.24 (dd, J ) 9.6, 9.6, 1H),
5.09 (dd, J ) 9.6, 3.1, 1H), 3.74 (ddd, J ) 9.6, 5.5, 3.5, 1H),
3.42-3.34 (m, 2H), 2.20 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H),1.99
(s, 3H); 13C NMR (CDCl3) δ 170.2, 169.8, 169.7, 168.4, 90.1,
74.4, 70.5, 68.0, 66.4, 50.7, 20.8, 20.7, 20.6, 20.5.
J ) 8.8), 5.10 (t, J ) 9.5), 5.05 (t, J ) 9.5), 4.31 (dd, J ) 4.8,
12.5), 4.09 (dd, J ) 2.0, 12.5), 3.79 (ddd, J ) 9.5, 4.8, 2.0),
3.65 (dd, J ) 9.5, 8.8), 2.18 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H),
2.01 (s, 3H). The spectra for the anomeric mixture has been
previously reported.51
2,3,4,6-Tet r a -O-a cet yl-â-D-glu cop yr a n osyl Azid e (9â).
Meth od
a (Entry b, Table 2). 2,3,4,6-Tetra-O-acetyl-R-D-
glucopyranosyl bromide (8) (89 mg, 0.22 mmol) was dissolved
at 25 °C in 3 mL of THF. Trimethylsilyl azide (40 µL, 0.3 mmol)
was added via syringe followed by TBAF (0.3 mL, 0.3 mmol).
The solution was stirred at 25 °C for 3 h. The organic solution
was filtered through a plug of silica gel, dried over Na2SO4,
and concentrated in vacuo to give a yellow amorphous solid.
The residue was crystallized from absolute ethanol to afford
75 mg (93%) of azide 9â as a white solid: mp 126-127 °C (lit.33
mp 126-128 °C). Physical and spectroscopic properties of 9â
were identical to previously reported data.33,36
Meth od b (Entry c, Table 2). 2,3,4,6-Tetra-O-acetyl-R-D-
glucopyranosyl chloride40 (10) (80 mg, 0.22 mmol) was dis-
solved at 25 °C in 3 mL of THF. Trimethylsilyl azide (40 µL,
0.3 mmol) was added via syringe followed by TBAF (0.3 mL,
0.3 mmol). The solution was stirred for 29 h at 65 °C. The
reaction was cooled to ambient temperature, filtered through
a plug of silica gel, dried over Na2SO4, and concentrated in
vacuo to give a yellow oil. The oil was crystallized from
absolute ethanol to afford 69 mg (85%) of azide 9â as a white
solid: mp 126-126.5 °C (lit.33 mp 126-128 °C). Physical and
spectroscopic properties of 9â were in agreement with previ-
ously reported values.33,36
Meth od c (Entry e, Table 2). 2,3,4,6-Tetra-O-acetyl-R-D-
glucopyranosyl trichloroimidate52 (12) (240 mg, 0.49 mmol) was
dissolved at 25 °C in 4 mL of THF. Trimethylsilyl azide (90
µL, 0.68 mmol) was added via syringe followed by TBAF (0.68
mL, 0.68 mmol). The solution was stirred for 22 h at 65 °C.
The reaction was cooled to ambient temperature, filtered
through a plug of silica gel, dried over Na2SO4, and concen-
trated in vacuo to give a yellow oil. The oil was crystallized
from acetone and recrystallized from Et2O/petroleum ether (1:
1) to afford 150 mg (88%) of hydrolyzed sugar 13 as a white
solid with no traces of sugar azide. 13: mp 130-132 °C (lit.53
mp 132-134 °C); IR (CCl4) 3462, 1759; 1H NMR (CDCl3) 5.27
(t, J ) 9.7), 5.09 (t, J ) 9.7), 4.89 (dd, J ) 9.7, 8.2), 4.75 (dd,
J ) 8.7, 8.2), 4.26 (dd, J ) 12.3, 4.7), 4.15 (dd, J ) 12.3, 2.3),
4.75 (ddd, J ) 9.7, 4.7, 2.4), 3.62 (d J ) 8.7), 2.07 (s, 3H), 2.06
(s, 3H), 2.00 (s, 3H), 1.99 (s, 3H).
2,3,4,6-Tet r a -O-a cet yl-D-glu cop yr a n osyl Azid e (9r/â).
2,3,4,6-Tetra-O-acetyl-â-D-glucopyranosyl chloride54 (11) (80
mg, 0.22 mmol) was dissolved at 25 °C in 3 mL of THF.
Trimethylsilyl azide (40 µL, 0.3 mmol) was added via syringe
followed by TBAF (0.3 mL, 0.3 mmol). The solution was stirred
for 46 h at 65 °C. The reaction was cooled to ambient
temperature, filtered through a plug of silica gel, dried over
Na2SO4, and concentrated in vacuo to give a yellow amorphous
material which was crystallized from absolute ethanol. The
crude reaction mixture was a 9:1 (R/â) anomeric mixture of
2,3,4,6-tetra-O-acetyl-D-glucopyranosyl azide as determined by
1H NMR. The anomeric mixture was separated by column
chromatography (4:1, hexanes/EtOAc) and crystallized from
absolute ethanol to afford 8 mg (10%) of azide 9â as a white
solid and 69 mg (90%) of azide 9R as a white solid (overall
yield of 95%) with melting point of 98-99 °C (lit.2 mp 98-
99.5 °C). Physical and spectroscopic properties of azide 9R were
identical to previously reported values.33,36
1,3,4,6-Tet r a -O-a cet yl-2-a zid o-2-d eoxy-â-D-glu cop yr a -
n ose (7). 1,3,4,6-Tetra-O-acetyl-2-O-trifluormethanesulfonyl-
â-D-mannopyranose (6) (53 mg, 0.11 mmol) was dissolved at
25 °C in 3 mL of THF. Trimethylsilyl azide (19 µL, 0.15 mmol)
was added via syringe followed by TBAF (150 µL, 0.15 mmol).
The solution was stirred at 25 °C for 22 h. The reaction mixture
was filtered through a plug of silica gel and concentrated in
vacuo to give a yellow oil which was chromatographed (2:1,
hexanes/EtOAc) to afford 30 mg (73%) of â-anomer 7 as a
2,3,4,6-Tetr a -O-ben zyl-â-D-glu cop yr a n osyl Azid e (15â).
Meth od
a (Entry f, Table 2). 2,3,4,6-Tetra-O-benzyl-R-D-
glucopyranosyl chloride55 (14) (100 mg, 0.18 mmol) was dis-
(51) Vasella, A.; Witzig, C.; Chiara, J .-L.; Martin-Lomas, M. Helv.
Chim. Acta 1991, 74, 2073-2077.
1
(52) Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 1249-
colorless oil.: IR (CCl4) 2113, 1762; H NMR (CDCl3) 5.56 (d,
1256.
(53) McCloskey, C. M.; Pyle, R. E.; Coleman, G. H. J . Am. Chem.
Soc. 1944, 66, 349-350.
(54) Lemieux, R. U. In Methods in Carbohydrate Chemistry; Whis-
tler, R. L., Wolfram, M. L., BeMiller, J . N., Eds.; Academic Press: New
York, 1963; Vol. 2, pp 224-225.
(49) Pouchert, C. J . The Aldrich Library of Infrared Spectra, 3rd
ed.; Aldrich Chemical Co.: Milwaukee, 1981.
(50) Grutzner, J . B.; J autelat, M.; Dence, J . B.; Smith, R. A.; Roberts,
J . D. J . Am. Chem. Soc. 1970, 92, 7107-7120.

N3 and CN Displacements via Silicate Intermediates
J . Org. Chem., Vol. 64, No. 9, 1999 3177
solved at 25 °C in 3 mL of THF. Trimethylsilyl azide (32 µL,
0.25 mmol) was added via syringe followed by TBAF (0.25 mL,
0.25 mmol). The solution was stirred for 5 h at 65 °C. The
reaction was cooled to ambient temperature, filtered through
a plug of silica gel, dried over Na2SO4, and concentrated in
vacuo to give a yellow oil. The oil was chromatographed (9:1,
hexanes/EtOAc) to afford 94 mg (92%) of azide 15â as a
colorless oil. Physical and spectroscopic properties of azide 15â
were identical to previously reported values.33
Meth od b (Entry g, Table 2). 2,3,4,6-Tetra-O-benzyl-R-D-
glucopyranosyl trichloroimidate56 (16) (790 mg, 0.1.15 mmol)
was dissolved at 25 °C in 30 mL of THF. Trimethylsilyl azide
(0.21 mL, 1.58 mmol) was added via syringe followed by TBAF
(1.58 mL, 1.58 mmol). The solution was stirred for 48 h at 65
°C. The reaction was cooled to ambient temperature, filtered
through a plug of silica gel, dried over Na2SO4, and concen-
trated in vacuo to give a yellow oil. The oil was chromato-
graphed (9:1, hexanes/EtOAc) to give 310 mg (48%) of an
inseparable anomeric mixture (1:1, R/â) of azide 15 as a
colorless oil. Spectroscopic and physical properties of the
anomeric mixture were in agreement with previously reported
values.33
2-Aceta m id o-3,4,6-tr i-O-a cetyl-2-d eoxy-â-D-glu cop yr a -
n osyl Azid e (18). Meth od a (Entry h, Table 2). 2-Methyl-
(3,4,6-tri-O-acetyl-1,2-dideoxy-R-D-glucopyrano)-[2,1-d]-2-ox-
azoline57,58 (17) (110 mg, 0.33 mmol) was dissolved at 25 °C in
3 mL of THF. Trimethylsilyl azide (60 µL, 0.44 mmol) was
added via syringe followed by TBAF (0.44 mL, 0.44 mmol).
The solution was stirred for 22 h at 65 °C. The reaction was
cooled to ambient temperature, filtered through a plug of silica
gel, dried over Na2SO4, and concentrated in vacuo to give a
yellow oil. The oil was crystallized from EtOAc/petroleum ether
to afford 89 mg (73%) of azide 18 as a white solid. Physical
and spectroscopic properties of 18 were identical to previously
reported data.36
trated in vacuo to give a yellow-brown oil. The oil was
chromatographed (10:1, CH2Cl2/MeOH) to afford a white solid
which was recrystallized from EtOAc/petroleum ether to afford
72 mg (89%) of azide 18 as a white solid. Physical and
spectroscopic properties of 18 were identical to previously
reported data.36
Oxa zolid in on e Azid e (-)-21. Carbinol (-)-2062 (1.01 mL,
3.36 mmol) and 2,6-di-tert-butyl-4-methylpyridine (1.17 g, 5.71
mmol) were dissolved in 34 mL of CH2Cl2. Trifluoromethane-
sulfonic anhydride (0.79 mL, 4.70 mmol) was added at 0 °C.
After 1 h at 0 °C, the reaction was quenched with saturated
aqueous NaHCO3 (20 mL), washed with CH2Cl2, dried over
MgSO4, and concentrated in vacuo. The residue was chromato-
graphed (4:1, hexanes/EtOAc) to gave 1.23 g (85%) of triflate
(-)-22 as a clear coloress oil. This was used immediately in
the following step. Triflate (-)-22 (1.23 g, 2.85 mmol) was
dissolved in dry CH3CN (20 mL). Trimethylsilyl azide (508 µL,
4.41 mmol) was added via syringe followed by TBAF (4.13 mL,
4.13 mmol). The solution was stirred at reflux for 12 h. The
reaction was cooled to room temperature, water was added
(30 mL), the solution was extracted with EtOAc, and the
combined organics were washed with brine (50 mL), dried over
MgSO4, and concentrated in vacuo. The residue was chromato-
graphed (4:1, hexanes/EtOAc) to afford 590 mg (63%) of azide
(-)-21 as a white solid: mp 35-36 °C; [R]20 -9.7° (c 0.59,
D
CHCl3); IR (CHCl3) 3020, 2980, 2110, 1785, 1715; 1H NMR (500
MHz, CDCl3) δ 5.93 (ddt, J ) 17.1, 10.5, 6.2, 1 H), 5.60 (s, 1
H), 5.35 (dd, J ) 17.1, 1.2, 1 H), 5.28 (d, J ) 10.4, 1 H), 4.68
(dd, J ) 12.8, 6.0, 1 H), 4.58 (dd, J ) 12.6, 6.3, 1 H), 2.26
(septet, J ) 7.0, 1 H), 1.13 (d, J ) 7.0, 6 H), 0.98 (s, 9 H); 13C
NMR (125 MHz, CDCl3) δ 172.7, 155.0, 131.6, 119.6, 95.6, 68.8,
67.1, 51.2, 37.4, 34.6, 25.8, 18.7, 17.8; high-resolution mass
spectrum (CI, NH3) m/z 325.1879 [(M + H)+; calcd for
C
15H25O4N4 325.1876].
Meth od b (Entry i, Table 2). 2-Acetamido-3,4,6-tri-O-acetyl-
2-deoxy-R-D-glucopyranosyl chloride59 (19) (79 mg, 0.22 mmol)
was dissolved at 25 °C in 3 mL of THF. Trimethylsilyl azide
(58 µL, 0.43 mmol) was added via syringe followed by TBAF
(0.43 mL, 0.43 mmol). The solution was stirred for 1.5 h at 65
°C. The reaction was cooled to ambient temperature, filtered
through a plug of silica gel, dried over Na2SO4, and concen-
Ack n ow led gm en t. We thank Dr. Yui-Fai Lam and
Ms. Caroline Ladd for their assistance in obtaining
NMR and mass spectral data. The financial support of
the University of Maryland is acknowledged. Professor
Amos Smith, III, would like to acknowledge generous
financial support from the Public Health Service
(AI/GM-42010-01-04).
(55) Grynkiewicz, G.; BeMiller, J . N. Carbohydr. Res. 1984, 131,
273-276.
J O982302D
(56) Schmidt, R. R.; Michel, J . Angew. Chem., Int. Ed. Engl. 1980,
19, 731-732.
(60) Shimizu, S.; Kito, K.; Sasaki, Y.; Hirai, C. J . Chem. Soc., Chem.
Commun. 1997, 1629-1630.
(57) Nakabayashi, S.; Warren, C. D.; J eanloz, R. W. Carbohyd. Res.
1986, 150, C7-C10.
(58) J ha, R.; Davis, J . T. Carboydr. Res. 1995, 277, 125-134.
(59) Heidlas, J . E.; Lees, W. J .; Pale, P.; Whitesides, G. M. J . Org.
Chem. 1992, 57, 146-151.
(61) Hudlicky, T.; Endoma, M. A. A.; Butora, G. J . Chem. Soc.,
Perkin Trans. 1 1996, 2187-2192.
(62) Alcohol (-)-20 was prepared according to the method of Favor:
Favor, D. A. Ph.D. Thesis, Univeristy of Pennsylvania, 1999.