Ring Opening of Epoxides with Sodium Azide in Water. a Regioselective pH-Controlled Reaction

Full text of DOI:10.1021/jo990368i

6094
J . Org. Chem. 1999, 64, 6094-6096
Ta ble 1. Azid olysis by Sod iu m Azid e of
Ep oxycycloh exa n e in Aqu eou s Med iu m
Rin g Op en in g of Ep oxid es w ith Sod iu m
Azid e in Wa ter . A Regioselective
p H-Con tr olled Rea ction
Francesco Fringuelli,* Oriana Piermatti,
Ferdinando Pizzo,* and Luigi Vaccaro
productsa (%)
T (°C) time (h) azido alcohol diol
Dipartimento di Chimica, Universita` degli Studi di Perugia,
entry pH
salt
via Elce di Sotto 8, 06123 Perugia, Italy
1
2
3
4
5
6
7
8
9
9.5
9.5
9.5
9.5
16
30
30
30
30
16
30
30
30
30
20
12
12
6
6
1.2
0.5
4
0.5
0.5
95
100b
100
100
97
5
Received March 2, 1999
c
Yb(OTf)3
d
LiClO4
1,2-Azido alcohols are compounds of interest in organic
synthesis as either precursors of vicinal amino alcohols
or in the chemistry of carbohydrates and nucleosides.1
They are usually prepared through ring opening of
epoxides by using different azides in suitable solvents.
The classical protocol uses1a,b,2,3a NaN3 as reagent and
NH4Cl as coordinating salt in alcohol-water at 65-80
°C. Under these conditions, azidolysis is generally carried
out over a long reaction time (12-48 h), and the azidohy-
drin is often accompanied by isomerization, epimeriza-
tion, and rearrangement products.1a,b
9.5
CTABre
3
8
4.2f
4.2f
4.2g
3.5f
2.5g
92
100b
100
87
13
32
10
68
a
GC ratios of the products.The epoxide conversion is quantita-
tive. 90% yield of isolated product. c 0.2 mol/equiv. 5 mol/equiv;
b
d
the starting pH was 8.4, and it was adjusted to 9.5 by adding
NaOH. e 1 mol/equiv. f By using AcOH. By using H2SO4.
g
reverse the regioselectivity have had little success3b,g,f,5a
with the exception of azidolysis that uses Et3Al/HN3 in
dry toluene at -70 °C.5b
The rate of reaction is not significantly improved by
using NaN3 in anhydrous CH3CN in the presence of salts
such as LiOTf3a or Mg(ClO4)2 or by using Me3SiN3 with
3a
Azidolysis of epoxides carried out in water only is a
3e
Yb(Oi-Pr)3,3b Ti(Oi-Pr)4,3c,d and V(Oi-Pr)3 in organic
rarity.1b,6
solvent. A good acceleration of the reaction is obtained
by using Bu3SnN3,3f SnCl2‚2H2O-Mg/NaN3-H2O/THF,3g
a recently reported system that permits working at room
temperature, and titanium,4a aluminum,4b and tin4c
azides in organic solvents. NaN3 supported on porous
solid acids (zeolite, alumina, and silica gel) has also been
used;4d the rate of the reaction depends on the organic
solvent used and on the amount of water impregnating
the supports. High enantioselective azidolyses of meso
epoxides have been achieved with Me3SiN3 in the pres-
ence of chromium (salen) complexes using ethereal
solvents.4e
Organic reactions in water have received much atten-
tion in the past decade.7 Water is surprisingly amenable
to many more types of reactions than chemists had once
imagined and also offers economical advantages and
cleaner chemical production methods.
We have performed aldol-like condensations8 and
oxidation8 and cycloaddition reactions9 in aqueous me-
dium and have pointed out that the control of pH is
crucial in order to obtain high yields and high selectivi-
ties.10 In this paper, we report the azidolysis of epoxides
1-7 in water. The results show that both the reactivity
and regioselectivity of the epoxide ring cleavage reaction
in water and the competition of azido ion with the water
or with hydroxide ion can be controlled by working at a
suitable pH value.11 Epoxycyclohexane (1) was chosen as
a representative compound (Table 1). Azidolysis of 1 in
aqueous 2.5 M NaN3 (pH ) 9.5) proceeded for 12 h at 30
°C and trans-azidohydrin was the sole reaction product
that was isolated in pure form in 90% yield (Table 1,
Azidolysis of unsymmetrical epoxides occurs with the
attack of the azide ion on the less substituted carbon,
except for the aryl-substituted epoxides.1 Attempts to
(1) (a) The Chemistry of the Azido Group; Patai, S., Ed.; Wiley: New
York, 1971. (b) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88,
297. (c) Coe, D. M.; Myers, P. L.; Parry, D. M.; Roberts, S. M.; Storer,
R. J . Chem. Soc., Chem. Commun. 1990, 151. (d) J acobs, G. A.; Tino,
J . A.; Zahler, R. Tetrahedron Lett. 1989, 30, 6955.
(2) (a) Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.; Pineschi,
M. Eur. J . Org. Chem. 1998, 5, 1675. (b) Nugent, T. C.; Hudlicky, T.
J . Org. Chem. 1998, 63, 510. (c) Swift, G.; Swern, D. J . Org. Chem.
1967, 32, 511.
(3) (a) Chini, M.; Crotti, P.; Macchia, F. Tetrahedron Lett. 1990, 31,
5641. (b) Meguro, M.; Asao, N.; Yamamoto, Y. J . Chem. Soc. Chem.
Commun. 1995, 1021. (c) Caron, M.; Sharpless, K. B. J . Org. Chem.
1985, 50, 1557. (d) Sinou, D.; Emziane, M. Tetrahedron Lett. 1986,
27, 4423. (e) Blandy, C.; Choukroun, R.; Gervais, D. Tetrahedron Lett.
1983, 24, 4189. (f) Saito, S.; Yamashita, S.; Nishikawa, T.; Yokoyama,
Y.; Inaba, M.; Moriwake, T. Tetrahedron Lett. 1989, 30, 4153. (g)
Sarangi, C.; Das, N. B.; Nanda, B.; Nayak, A.; Sharma, R. P. J . Chem.
Res., Synop. 1997, 378.
(6) (a) Guy, A.; Doussot, J .; Garreau, R.; Godefroy-Falguieres, A.
Tetrahedron: Asymmetry 1992, 3, 247. (b) DeMarinis, R. M.; Berchtold,
G. A. J . Am. Chem. Soc. 1969, 91, 6525.
(7) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie
Academic and Professional: Glasgow, 1998. (b) Li, C. J .; Chan, T. H.
Organic Reactions in Aqueous Media; Wiley: New York, 1997.
(8) Fringuelli, F.; Piermatti, O.; Pizzo, F. In Organic Synthesis in
Water; Grieco, P. A., Ed.; Blackie Academic and Professional: Glasgow,
1998; pp 223-244 and 250-261.
(9) Fringuelli, F.; Piermatti, O.; Pizzo, F. In Targets in Heterocyclic
Systems; Attanasi, O. A., Spinelli, D., Eds.; SCI: Rome, 1997; pp 57-
73.
(4) (a) Caron, M.; Carlier, P. R.; Sharpless, K. B. J . Org. Chem. 1988,
53, 5185. (b) Youn, Y. S.;. Cho, I. S.; Chung, B. Y. Tetrahedron Lett.
1998, 39, 4337. (c) Saito, S.; Nishikawa, T.; Yokoyama, Y.; Moriwake,
T. Tetrahedron Lett. 1990, 31, 221. (d) Onaka, M.; Sugita, K.; Izumi,
Y. J . Org. Chem. 1989, 54, 1116. (e) Martinez, L. E.; Leighton, J . L.;
Carsten, D. H.; J acobsen, E. N. J . Am. Chem. Soc. 1995, 117, 5897.
(5) (a) Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.; Pineschi,
M. Tetrahedron Lett. 1996, 37, 1675. (b) Mereyala, H. B.; Frei, B. Helv.
Chim. Acta 1986, 69, 415.
(10) (a) Fringuelli, F.; Germani, R.; Pizzo, F.; Santinelli, F.; Savelli,
G. J . Org. Chem. 1992, 57, 1198. (b) Fringuelli, F.; Pellegrino, R.; Pizzo,
F. Synth. Commun. 1993, 23, 3157. (c) Ye, D.; Fringuelli, F.; Piermatti,
O.; Pizzo, F. J . Org. Chem. 1997, 62, 3748.
(11) (a) Blum12a carried out the azidolysis of benzanthracene oxides
with NaN3 in H2O-acetone ca. 1:1.8, adjusting the pH of the mixture
to 8 with H2SO4: (b) Recently, Whalen12b carefully studied the kinetics
of aminolysis and azidolysis of benzo[a]pyrene diol epoxide in 1:9
dioxane/water at several pH values.
10.1021/jo990368i CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/14/1999

Notes
Ta ble 2. Azid olysis by Sod iu m Azid e of Ep oxid es in
J . Org. Chem., Vol. 64, No. 16, 1999 6095
of all the epoxides with the exception of styrene oxide
(3), in which the nucleophile predominantly attacked the
more substituted benzylic R-carbon.3g 1H and 13C NMR
data of the reaction products and a comparison with
authentic samples indicate that the ring opening of 2 and
6 was diastereoselective, and trans-azidohydrins were the
sole products.
Aqu eou s Med iu m a t 30 °C
Under acidic conditions (pH 4.2), compounds 2, 5, 6,
and 7 gave a reversed regioselectivity, while the attack
of the azide ion on the more substituted R-carbon of 1,2-
epoxyoctane (4) increased from 10% to 30%. No change
of regioselectivity was observed in the azidolysis of 3.
Again, the ring opening of 2 and 6 was completely anti
stereoselective. Thus, it was possible to change the
regioselectivity in the azidolysis of R-disubstituted ep-
oxides by simply working in aqueous medium and chang-
ing the reaction conditions from basic to acidic and or
vice versa.
The 1,2-epoxy-2-methylheptane (5) and the azido al-
cohols from epoxide 5 and 6 are new compounds, and
1
their structures are supported by H and 13C NMR data
(see the Experimental Section) and previous work in this
field.15,16
The regioselectivity under acidic conditions can be
explained by considering that the attack of the azide ion
on the more substituted R-carbon arises from the prior
protonation of epoxide, which produces a considerably
more positive charge on the tertiary R-carbon of 2, 5, 6,
and 7 than on the secondary â-carbon of 2 and 6 or the
primary â-carbon of 5 and 7. The R/â ratios of azidolyses
of constitutional isomers 4 and 5 gave quantitative
information about the protonation effect on the competi-
tive attacks of secondary and tertiary carbon atoms
compared with a primary carbon. The azide ion attack
on secondary R-carbon of 4 at pH 4.2 and in the presence
of CTABr is 11 times more favored than that observed
in azidolysis carried out under basic conditions, while the
nucleophilic attack on tertiary R-carbon of 5 under acidic
conditions is 283 times more favored and causes an
inversion of regioselectivity.
To our knowledge, this is the first reported investiga-
tion on the regioselectivity of azidolysis of epoxides
carried out in aqueous acidic medium. The procedure is
easy and is particularly useful for synthesizing tertiary
azides that cannot be easily obtained by other methods.
Thus, working under acidic conditions, the (+)-epoxycar-
ane 6 is converted with good yield into the optically pure
(-)-3â-azido-4R-hydroxy-trans-carane, which can then be
easily reduced to the corresponding amino alcohol, which
is a promising chiral auxiliary.
a
GC ratios of products. The epoxide conversion is quantitative
if not otherwise specified. b R-azido-â-hydroxy + â-azido-R-hydroxy
derivative. c Yield of main isolated product. By using AcOH. e At
d
16 °C. f By using H2SO4. Conversion 50%. With CTABr, 1 mol/
g
h
i
j
k
equiv. At 100 °C. Conversion 44%. At 70 °C.
entry 2). At lower temperature, the nucleophilic attack
of hydroxide ion was detectable, and 5% diol accompanied
the azido alcohol (Table 1, entry 1). The presence of Yb-
(OTf)3 did not affect the reaction rate, while LiClO4 and
cetyltrimethylammonium bromide (CTABr) accelerated
azidolysis13 (Table 1, entries 3-5). Under acidic condi-
tions, the reaction was strongly accelerated. The best
reaction conditions were pH 4.2 at 30 °C (Table 1, entry
7); at lower pH and temperature values there was
competition from the nucleophilic attack of the water
(Table 1, entries 6, 9, and 10). The use of acetic acid as
acidifying agent was essential because it allowed the
reaction to be performed in a buffered medium.14 When
H2SO4 was used, the starting pH 4.2 increased over time
because the azido alcoholate consumed a proton equiva-
lent, and the reaction rate slowed (Table 1, entry 8).
Table 2 illustrates the azidolysis of representative
epoxides 2-7.
Reexamining the classical protocol for the azidolysis
of unfunctionalized epoxides 1-4 and 7 reported in the
literature1b,2c,3a and considering the results of this study,
it is clear that in the classical method the reaction time
is too long, the temperature is too high, and NH4Cl and
the alcoholic cosolvent are unnecessary. For example, the
azidolysis of 2 in 8:1 methanol-water and in the presence
of NH4Cl (2.2 equiv) requires only 2 h at 80 °C and occurs
At pH 9.5, the attack of azide ion preferentially
occurred, as expected, on the less substituted â-carbon
(12) (a) Blum, J .; Ben-Shoshan, S. J . Heterocycl. Chem. 1983, 20,
1461. (b) Lin, B.; Islam, N.; Friedman, S.; Yagi, H.; J erina, D. M.;
Whalen, D. L. J . Am. Chem. Soc. 1998, 120, 4327.
(13) The reaction could occur in the pseudomicellar phase where
the hydroxide counterion makes the pH higher than that of the aqueous
phase.
(14) (a) The pKa values of HN3 and AcOH in water at 25 °C are 4.7
and 4.8, respectively.1a,14b A commercial buffered solution at pH 4.2
cannot be used because the addition of 5 mol/equiv of NaN3 signifi-
cantly increases the pH of the medium. (b) Handbook of Chemistry
and Physics, 78th ed.; Lide, D. R., Ed.; CRC Press: New York, 1997-
98; pp 8-45.
(15) (a) Fringuelli, F.; Germani, R.; Pizzo, F.; Savelli, G. Tetrahedron
Lett. 1989, 30, 1427. (b) Fringuelli, F.; Pizzo, F.; Germani, R.; Savelli,
G. Org. Prep. Proced. Int. 1989, 30, 757.
(16) (a) Fringuelli, F.; Piermatti, O.; Pizzo, F. Gazz. Chim. Ital. 1995,
125, 195. (b) Fringuelli, F.; Gottlieb, H. B.; Hagaman, E. W.; Taticchi,
A., Wenkert, E.; Workulich, P. M. Gazz. Chim. Ital. 1975, 105, 1215.
(c) Fringuelli, F.; Moreno, L. N.; Taticchi, A.; Wenkert, E. J . Org. Chem.
1977, 42, 3168.

6096 J . Org. Chem., Vol. 64, No. 16, 1999
Notes
1H NMR δ 0.84 (t, J ) 6.7 Hz, 3H), 1.13-1.57 (m, 8H), 1.25 (s,
3H), 2.51 (d, J ) 4.9 Hz, 1H), 2.55 (d, J ) 4.9 Hz, 1H); 13C NMR
δ 13.9, 20.8, 22.5, 24.8, 31.8, 36.6, 53.8, 56.9. Anal. Calcd for
C8H16O: C, 74.94; H, 12.58. Found: C, 74.82; H, 12.30.
in 12 h at room temperature, giving in all cases practi-
cally the same regioselectivity observed as when working
in water only (12 h at room temperature, R/â ) 35/65).
In 1989, we reported15 that the epoxidation of alkenes
could be carried out in water only by using peroxyacids.
Coupling that procedure with the azidolysis here re-
ported, it is possible to prepare azido alcohols from
alkenes by a one-pot procedure. For example, the trans-
2-azidocyclohexanol can be obtained in pure form from
cyclohexene with 74% yield.
1-Azid o-2-h yd r oxy-2-m eth ylh ep ta n e. Prepared in 90%
yield, under basic conditions (pH 9.5, 28 h, 30 °C, CTABr 1 mol/
equiv, Table 2 footnote h): oil; 1H NMR δ 0.89 (t, J ) 6.9 Hz,
3H), 1.17-1.56 (m, 8H), 1.19 (s, 3H), 2.01 (sb, 1H), 3.23 (d, J )
12.1 Hz, 1H), 3.28 (d, J ) 12.1 Hz, 1H); 13C NMR δ 13.9, 22.5,
23.3, 24.4, 32.2, 39.6, 60.8, 72.8. Anal. Calcd for C8H17N3O: C,
56.11; H, 10.01; N, 24.54. Found: C, 56.20; H, 10.03; N, 24.51.
2-Azid o-1-h yd r oxy-2-m eth ylh ep ta n e. Prepared in 70%
yield, under acidic conditions (pH 4.2, 3 h, 30 °C, Table 2,
1
footnote d): oil; H NMR δ 0.89 (t, J ) 7.0 Hz, 3H), 1.17-1.56
Exp er im en ta l Section
(m, 8H), 1.26 (s, 3H), 2.11 (sb, 1H), 3.43 (d, J ) 11.3 Hz, 1H),
3.49 (d, J ) 11.3 Hz, 1H); 13C NMR δ 13.9, 19.8, 22.5, 23.3, 32.1,
36.3, 65.1, 68.7. Anal. Calcd for C8H17N3O: C, 56.11; H, 10.01;
N, 24.54. Found: C, 56.22; H, 9.98; N, 24.61.
Gen er a l P r oced u r es. All chemicals were purchased and
used without any further purification. GC analyses were per-
formed with an SPB-5 fused silica capillary column (30 m, 0.25
mm diameter), an “on column” injector system, an FID detector,
and hydrogen as carrier gas. GC-MS analyses were carried out
with 70 eV electron energy. Column chromatographies were
carried out on silica gel (0.04-0.063 mm, 230-400 mesh ASTM).
1H and 13C NMR spectra were recorded at 400 and 100.6 MHz,
respectively, in CDCl3 as solvent and TMS as internal standard.
pH measures were performed by using a combination refillable
pH electrode. The azido alcohols from epoxides 1,3g 2,3a,5b 3,3a
4,5d and 73a,5b are known. The epoxide 5 and the azido alcohols
from epoxides 5 and 6 are new compounds and are described
below.
(-)-3â-Azid o-4R-h yd r oxy-tr a n s-ca r a n e. Prepared in 70%
yield, under acidic conditions (pH 4.2, 48 h, 30 °C, Table 2,
footnote d): mp 34-35 °C, from n-hexane-Et2O; [R]D -50.2° (c
1
) 0.82, CHCl3); H NMR δ 0.69-0.80 (m, 2 H, 1-H, 6-H), 0.95
(s, 3 H, 8-CH3), 1.00 (s, 3 H, 9-CH3), 1.32 (dd, J ) 14.6, 4.2 Hz,
1 H, 2-Hâ), 1.33 (s, 3 H, 10-CH3), 1.68 (ddd, J ) 14.6, 10.2, 7.8
Hz, 1 H, 5-HR), 1.89 (sb, 1 H, 4-OH), 2.06 (dd, 1 H, J ) 14.6, 7.3
Hz, 5-Hâ), 2.09 (dd, J ) 14.6, 9.4 Hz, 1 H, 2-HR), 3.34 (dd, J )
10.2, 7.3 Hz, 1 H, 4-H); 13C NMR δ 15.0, 15.7, 18.0, 18.6, 20.8,
26.3, 28.5, 31.0, 65.3, 72.8. Anal. Calcd for C10H17N3O: C, 61.51;
H, 8.78;, N, 21.52. Found: C, 61.50; H, 8.75; N, 21.54.
Azid olysis a t p H ) 9.5. Epoxide (5 × 10-3 mol) was added
at the indicated temperature (Tables 1 and 2) to an aqueous
solution of sodium azide (25 × 10-3 mol in 10 mL of water) and
the heterogeneous mixture stirred for the time reported in Tables
1 and 2. The starting pH was 9.5, and it increased by 0.5-0.7
units during the reaction. The mixture was extracted with Et2O
(2 × 25 mL), saturated with NaCl, and extracted once again with
Et2O (25 mL). The extracts were dried (Na2SO4) and concen-
trated under reduced pressure to give the crude azido alcohol,
which was purified by column chromatography (eluent n-hex-
anes-ethyl acetate 95:5). The reaction yield is reported in Tables
1 and 2. When the azidolysis was executed in the presence of
salt, the molar ratio salt/epoxide indicated in Table 1 (see
footnotes) was used.
(+)-4â-Azido-3R-h ydr oxy-cis-car an e. Prepared in 55% yield,
under basic conditions (pH 9.5, 60 h, 100 °C, Table 2, footnote
i): oil; [R]D ) +146.6° (c ) 1.22, CHCl3); 1H NMR δ 0.63 (ddd, J
) 9.0, 8.8, 2.8 Hz, 1 H, 6-H), 0.70 (ddd, J ) 9.2, 9.0, 6.0 Hz, 1 H,
1-H), 1.03 (s, 6 H, 8- CH3, 9- CH3), 1.25 (dd, J ) 15.2, 6.0 Hz, 1
H, 2-Hâ), 1.21 (s, 3 H, 10- CH3), 1.60 (ddd, J ) 16.1, 3.2, 2.8 Hz,
1 H, 5-Hâ), 1.78 (ddd, J ) 15.2, 9.2, 1.4 Hz, 1 H, 2-HR), 2.07 (sb,
1 H, 3-OH), 2.38 (ddd, J ) 16.1, 8.8, 7.7 Hz, 1 H, 5-HR), 3.39
(ddd, J ) 7.7, 3.2, 1.4 Hz, 1 H, 4-H); 13C NMR δ 14.9, 17.2,
17.3, 18.2, 22.0, 25.9, 28.5, 28.6, 63.9, 70.5. Anal. Calcd for
C10H17N3O: C, 61.51; H, 8.78; N, 21.52. Found: C, 61.55; H,
8.73; N, 21.58.
Azid olysis a t p H ) 4.2. Epoxide (5 × 10-3 mol) was added
at the indicated temperature (Tables 1 and 2) to an aqueous
solution of sodium azide (25 × 10-3 mol in 8 mL of water and
4.6 mL of glacial acetic acid) and the heterogeneous mixture
stirred for the time reported in Tables 1 and 2. The starting pH
was 4.2, and it remained practically constant during the reaction.
The mixture was extracted with Et2O (2 × 25 mL), saturated
with NaCl, and extracted once again with Et2O (25 mL). The
extracts were washed with 10% aqueous NaOH, dried (Na2SO4),
and concentrated under reduced pressure to give the crude azido
alcohol, which was purified by column chromatography (eluent
n-hexanes-ethyl acetate 95:5). The reaction yield is reported
in Tables 1 and 2.
On e-P ot Syn th esis of tr a n s-2-Azid ocycloh exa n ol fr om
Cycloh exen e. Pure, powdered m-CPBA (2.2 × 10-3 mol) was
added to a cold (1-3 °C), well-stirred suspension of cyclohexene
(2.0 × 10-3 mol) in a 1 N solution of NaHCO3 (12 mL) over a
period of 3 min. The heterogeneous mixture was stirred for 40
min at room temperature. Powdered NaN3 (9.0 × 10-3 mol) was
then added, and the stirring was continued for 12 h at 30 °C.
The mixture was then saturated (NaCl) and extracted with Et2O
(3 × 15 mL). The organic phase was dried (Na2SO4) and
concentrated under reduced pressure, furnishing 0.180 g of
trans-2-azidocyclohexanol3g GC 98% pure, yield 74%.
Ack n ow led gm en t. This work was supported by the
Consiglio Nazionale delle Ricerche (CNR) and Univer-
sita` degli Studi di Perugia.
1,2-Ep oxy-2-m eth ylh ep ta n e (5). Prepared in 94% yield by
epoxidation with m-CPBA in water of 2-methyl-1-heptene:15a oil;
J O990368I