Phenol-containing macrocyclic diamides as new catalysts in the highly regioselective conversion of epoxides to β-hydroxy thiocyanates

Article abstract of DOI:10.1021/jo0103266

The regioselective ring-opening reactions of some epoxides with ammonium thiocyanate in the presence of a series of new phenol-containing macrocyclic diamides and also dibenzo-18-crown-6-, 18-crown-6-, benzo-15-crown-5-, and pyridine-containing macrocyclic diamide have been studied. The epoxides were subject to cleavage by NH₄SCN in the presence of these catalysts under mild reaction conditions in various aprotic solvents. In this study, reagents and conditions have been discovered with which the individual β-hydroxy thiocyanates can be synthesized in high yield and with more than 90% regioselectivity. The results can be discussed in terms of a four-step mechanism: (1) formation of complex between catalyst and NH₄SCN, (2) release of SCN^- nucleophile from the complex, (3) reaction of the active nucleophile at the less sterically hindered site in the epoxide, and (4) regeneration of catalyst. The major advantages of this method are as follows: (1) high regioselectivity, (2) simple regeneration of catalyst, (3) its reuse through several cycles without a decrease in activity, and (4) ease of workup of the reaction.

Full text of DOI:10.1021/jo0103266

J . Org. Chem. 2001, 66, 7287-7293
7287
P h en ol-Con ta in in g Ma cr ocyclic Dia m id es a s New Ca ta lysts in th e
High ly Regioselective Con ver sion of Ep oxid es to â-Hyd r oxy
Th iocya n a tes
Hashem Sharghi,* Mohammad Ali Nasseri, and Khodabakhsh Niknam†
Department of Chemistry, Shiraz University, Shiraz 71454, I.R. Iran, and Department of Chemistry,
Persian Gulf University, Bushehr 75168, I.R. Iran
sharghi@chem.susc.ac.ir
Received March 26, 2001
The regioselective ring-opening reactions of some epoxides with ammonium thiocyanate in the
presence of a series of new phenol-containing macrocyclic diamides and also dibenzo-18-crown-6-,
18-crown-6-, benzo-15-crown-5-, and pyridine-containing macrocyclic diamide have been studied.
The epoxides were subject to cleavage by NH4SCN in the presence of these catalysts under mild
reaction conditions in various aprotic solvents. In this study, reagents and conditions have been
discovered with which the individual â-hydroxy thiocyanates can be synthesized in high yield and
with more than 90% regioselectivity. The results can be discussed in terms of a four-step
mechanism: (1) formation of complex between catalyst and NH4SCN, (2) release of SCN- nucleophile
from the complex, (3) reaction of the active nucleophile at the less sterically hindered site in the
epoxide, and (4) regeneration of catalyst. The major advantages of this method are as follows: (1)
high regioselectivity, (2) simple regeneration of catalyst, (3) its reuse through several cycles without
a decrease in activity, and (4) ease of workup of the reaction.
In tr od u ction
reported in the literature for the synthesis of â-hydroxy
thiocyanates. In one method, thiocyanohydrins are pre-
pared by opening of a cyclic sulfate with NH4SCN to
form the corresponding â-sulfate, which is hydrolyzed to
the thiocyanohydrines. A second method employed the
addition to the epoxide of thiocyanic acid generated in
situ at low temperature.18-21 For these syntheses, it has
been reported that the presence of some hydroquinone
or DDQ are required to stabilize the produced â-hydroxy
thiocyanate and inhibit its conversion to thiirane.16,22
Although the reagents such as Ti (O-i-Pr)4,23 Ph3P-
Epoxides are one of the most versatile intermediates
in organic synthesis, and a large variety of reagents are
known for the ring opening of these compounds.1 Their
electrophilic reaction with different nucleophilic anions
has been an interesting subject in organic synthesis.2-7
Between these anions, the reaction of thiocyanate ion
with epoxides, in the absence or in the presence of
catalyst, is a widely studied and suitable method for the
preparation of thiiranes.8-15 The formation of thiiranes
from the reaction of epoxides and thiocyanate ion has
been proposed to occur through the intermediacy of the
corresponding â-hydroxy thiocyanate, but this intermedi-
ate has not been isolated due to its rapid conversion to
the corresponding thiirane.13-17 There are two methods
(SCN)2,24 TiCl3 (or ZnCl2),25 and Pd(PPh3)4 are useful,
26
they are limited to specific oxiranes and are not ap-
plicable as versatile reagents in preparation of â-hydroxy
thiocyanates.27
In conjunction with the ongoing work in our laboratory
on the synthesis and complex formation of macrocyclic
compounds with different molecules,28-32 we found that
† Persian Gulf University.
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J . G. Synthesis 1984, 629.
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1247.
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Synlett 1991, 403. (b) Guy, A.; Doussot, J .; Ferroud, C.; Godefroy-
Falguieres, A. Synthesis 1992, 821.
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1 1981, 1577.
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22, 2517.
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1990, 20, 2313.
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(29) Gangali, M. R.; Eshghi, H.; Sharghi, H.; Shamsipour, M. J .
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10.1021/jo0103266 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/10/2001

7288 J . Org. Chem., Vol. 66, No. 22, 2001
Sharghi et al.
Sch em e 1
Sch em e 2
phenol-containing macrocyclic diamides efficiently cata-
lyzed the addition of ammonium thiocyanate to epoxide
to form â-hydroxy thiocyanate. Five new phenol-contain-
ing macrocyclic diamides as well as dibenzo-18-crown-
6-, 18-crown-6-, benzo-15-crown-5-, and pyridine-contain-
ing macrocyclic diamide 1933 were selected as catalysts
in these reactions.
Discu ssion
Sch em e 3
(A) P r ep a r a tion of Ca ta lyst. Although macrocyclic
amides are originally regarded as intermediates to
prepare aza crowns, only a few procedures have been
developed for their preparations. Among these, carboxylic
acid derivatives, such as malonic and R,ω-dicarboxylic
acid esters,34 labile diacid dichlorides,35,36 and bis(R-chloro-
amide)compounds,37-39 were allowed to react with various
diamides under high dilution or for long reaction periods.
In previous studies,28,31 we reported a new efficient
synthesis of macrocyclic diamides. No high-dilution tech-
nique was required in this method. We applied this
approach to the synthesis of dilactams 11-15 which
contain phenolic groups (Scheme 1).
As shown in Scheme 1, p-methoxyphenol was reacted
with hexamine in trifluoroacetic acid to give yellow
needles of 2,6-diformyl-4-methoxyphenol 1 in 32% yield.40
Dicarboxylic acid 2 was obtained as a pale yellow solid
in 60% yield by oxidation of dialdehyde 1 in the presence
of Ag2O in aqueous NaOH solution. Treatment of 2 with
thionyl chloride gave 86% yield of dicarboxylic acid
dichloride 3.
the presence of sodium hydroxide followed by protection
of the phenolic group with dimethyl sulfate. Treatment
of 5 with PBr3 gave the dibromide 6, which reacted with
o-nitrophenol to afford dinitro compound 7.
The diamino compounds 10a -d were obtained by
reduction of the corresponding dinitro compounds 9a -d
(Scheme 3). o-Nitrophenol reacted with the dichlorides
of oligoethylene glycols in the presence of potassium
carbonate in dimethylformamide to give the correspond-
ing dinitro compounds 9a -d in the range of 67-85%
yields.41 The cyclization reaction between diacid dichlo-
ride 3 and the diamines 8 and 10a -d was performed
without using high-dilution techniques. In a preliminary
study, the effect of some solvents (CHCl3, CH3CN, CH2-
Cl2, C6H6, acetone) on the yield of the macrocyclization
reaction has been investigated, and CH2Cl2 has been
chosen as the most suitable solvent for these macro-
cyclization reactions. In addition, the cyclization reaction
was carried out with fast addition of a solution of diamine
(2 mmol) in dry CH2Cl2 (10 mL) into a solution of
dicarboxylic acid dichloride 3 (2 mmol) in dry CH2Cl2
(10 mL) over 5 s with vigorous stirring at room temper-
ature. The reaction mixture was stirred for further 20
min to give macrocyclic dilactams 11-15 in good yields
(Scheme 3).
The diamine 8 was obtained by reduction of the cor-
responding dinitro compound 7 with palladium on carbon
(5%) and hydrazine in 81% yield (Scheme 2). p-Bromo-
phenol reacted with formaline (37% aqueous solution) in
(31) Sharghi, H.; Massah, A. R.; Eshghi, H.; Niknam, Kh. J . Org.
Chem. 1998, 63, 1455.
(32) Sharghi, H.; Niknam, K.; Massah, A. R. J . Heterocycl. Chem.
1999, 36, 601.
(33) Si, J .; Wu, Y.; Cai, L.; Lin, Y., Du, B.; Xu, T.; An, J . J . Inclusion
Phenom. Mol. Recognit. Chem 1994, 17, 249.
(34) (a) Tabushi, I.; Taniguchi, Y.; Kato, H. Tetrahedron Lett. 1977,
1049. (b) Tabushi, I.; Okino, H.; Kuroda, Y. Tetrahedron Lett. 1976,
4339.
(35) (a) Pentranek, J .; Ryba, O. Collect. Czech. Chem. Commun.
1980, 45, 1567. (b) Pentranek, J .; Ryba, O. Collect. Czech. Chem.
Commun. 1983, 48, 1945.
(36) (a) Pellisard, D.; Louris, R. Tetrahedron Lett. 1972, 4589. (b)
Dietrich, B.; Lehn, J . M.; Sauvage, J . P.; Blanzat, J . Tetrahedron 1973,
29, 1629.
(37) Krakowiak, K. E.; Bradshaw, J . S.; Izatt, R. M. J . Org. Chem.
1990, 55, 3364.
(38) Bradshaw, J . S.; Krakowiak, K. E.; Izatt, R. M.; Zamecka-
Krakowiak. D. J . Tetrahedron Lett. 1990, 31, 1077.
(39) (a) Krakowiak, K. E.; Bradshaw, J . S.; Izatt, R. M. J . Heterocycl.
Chem. 1990, 27, 1585. (b) Bradshaw, J . S.; Krakowiak, K. E.; An. H.;
Izatt, R. M. J . Heterocycl. Chem. 1990, 27, 2113.
(40) Lindoy, L. F.; Meehan, G. V.; Svenstrup, N. Synthesis 1998,
1029.
Crown ethers 16-19 were also used as catalysts in
thiocyanation of epoxides.
(B) Th iocya n a tion of Ep oxid es. Epoxides of conve-
nient volatility to allow GC analysis were chosen for
study. As catalysts, some phenol-containing macrocyclic-
(41) Dutasta, T. P.; Dechlercq, J . P.; Esteban-Calderon, C.; Tinant,
B. J . Am. Chem. Soc. 1989, 111, 7136.

Conversion of Epoxides to â-Hydroxy Thiocyanates
J . Org. Chem., Vol. 66, No. 22, 2001 7289
Ta ble 1. Th iocya n a tive Clea va ge of Styr en e Oxid e
w ith NH4SCN in th e P r esen ce of Va r iou s Ma cr ocyclic
Com p ou n d s in Differ en t Solven t u n d er Reflu x Con d ition
Sch em e 4
catalyst
(0.01 mol %)
time
(min)
yielda
(%)
entry
solvent
CH3CN
1
2
3
4
5
6
7
8
9
11
12
13
14
15
16
17
18
19
35
40
50
50
90
85
70
90
70
190b
70
60
60
65
70
70
93
93
90
85
55
70
75
65
70
c
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Et2O
t-BuOH
EtOH
THF
CH2Cl2
1,4-dioxane
10
11
12
13
14
15
16
diamides that were synthesized according to Scheme 4
were used. Also, dibenzo-18-crown-6 16, 18-crown-6 17,
benzo-15-crown-5 18, and pyridine-containing macro-
cyclic diamide 19 were selected to represent some com-
11
11
11
11
11
11
d
50
40
30
<20
40
a
b
Determined by GC. In the presence of excess of NH4SCN.
c 35% of the corresponding thiirane was obtained. 25% of the
d
corresponding thiirane was obtained.
hand, some other methods for conversion of epoxides into
the corresponding thiocyanohydrins are given in Table
2 (entries 4-6, 8, and 12). When epoxides were allowed
to react in the presence of our catalysts, the yield and
the regioselectivity were higher than the observed in all
of the reactions conditions studied. An alternative prepa-
ration of â-hydroxy thiocyanate by the reaction of styrene
oxide with KSCN/18-crown-6 17 was examined. This
route, however, is not a good one for the synthesis of
â-hydroxy thiocyanates and gave a 15% of the corre-
sponding thiirane (Table 2, entry 7).
Generally, the optimum amounts of the catalysts were
found to be 0.01 mol for 1 mol of epoxides and NH4SCN.
However, other factors can exert a controlling influence,
such as (1) steric hindrance of epoxides, (2) the nature
of solvent, and (3) electron-donating or -withdrawing
groups bonded to the epoxide. Each one can have a pro-
nounced effect on the observed ratio of thiocyanohydrin
isomers and overall yield.
The reaction exhibited a stereoselectivity anti as shown
for cyclohexene oxide (Table 2, entry 11) in which only
the trans isomer was detected. The anti Markovnikov-
type39 regioselectivity was generally observed in these
reactions, except for the reactions of styrene oxide (Table
2, entry 1) and indene oxide (Table 2, entry 19), which
produced 18% and 20% of the other regioisomer, respec-
tively. The reactions of other epoxides were found to be
highly regioselective, and only one isomer was obtained.
In these reactions a 5-10% of the corresponding thiiranes
was also formed, which could easily isolated by column
chromatography.
mon crown ether catalysts. The results of the reaction of
styrene oxide with thiocyanate ion in the presence of
the above catalysts are summarized in Table 1. In each
case, cleavage of the epoxide ring occurs, and upon
workup, the corresponding thiocyanohydrin was ob-
tained. The catalyst was easily recovered and could
be reused several times. By comparison, the cleavage
of the styrene oxide with ammonium thiocyanate in the
absence of catalyst is given in entry 10 of Table 1. As
shown in Table 1, yields of thiocyanation with this new
methodology were quite good. Catalysts 11 and 12 were
the most effective, and the reactions were completed in
35 and 40 min in the presence of these catalysts respec-
tively (Table 1, entries 1 and 2). In the presence of other
catalysts 13-19, the reaction times for thiocyanation at
80 °C are in the rang 50-90 min. However, the reaction
of the styrene oxide with an excess of ammonium thio-
cyanate in the absence of catalyst afforded the corre-
sponding thiirane in 35% yield when the reaction mixture
was refluxed for 3 h.
The results of the ring opening of styrene oxide in the
presence of macrocycle 11 using various solvents are
summarized in Table 1. Thiocyanation reactions proceed
very cleanly employing CH3CN, while those performed
in Et2O and CH2Cl2 led to a lower yield of the thiocyano-
hydrin.
The regiochemical mode of epoxide cleavage by am-
monium thiocyanate in the presence of macrocycle cata-
lyst can be viewed as occurring via nucleophilic attack
by thiocyanate ion on the less sterically hindered epoxide
carbon. This mechanism closely resembles the SN2 model
for aliphatic nucleophilic displacement. On the basis of
our previous study on macrocycle diamides and other
works on the complexation of crown ethers and azophe-
nol-dyed crown ethers with elemental halogens, alkaline
The results obtained with some representative epox-
ides in the presence of macrocycles 11 and 18-crown-6
17 as catalyst are summarized in Table 2. On the other

7290 J . Org. Chem., Vol. 66, No. 22, 2001
Ta ble 2. Rea ction of Ep oxid es w ith NH4SCN in th e P r esen ce of th e Rep r esen ta tive Ca ta lyst
Sharghi et al.
a
b
Determined by GC. Hydroquinone has been used to stabilize 2-hydroxycyclohexyl thiocyanate (see ref 19).
metal ions, ammonium cation, and alkylamines,28-32,42-45
conversion of epoxide to â-hydroxy thiocyanate occurs
according to the following four-step mechanism: The first
step involves the formation of a 1:1 molecular complex

Conversion of Epoxides to â-Hydroxy Thiocyanates
J . Org. Chem., Vol. 66, No. 22, 2001 7291
F igu r e 1. Absorption spectra from bottom to top refer to NH4SCN, catalyst 11, and catalyst 11 in the presence of NH4SCN, in
CH3CN solution.
between macrocycle and NH4SCN in which thiocyanate
ion (SCN-) exist as a contact ion pair:
these reactions. According to the mechanism, in both
macrocycles 11 and 12 a complexation with NH4SCN and,
hence, liberation of SCN- occurred much faster than with
other catalysts. In support of this mechanism, interaction
of catalyst 11 with NH4SCN was followed by UV spec-
troscopy (Figure 1). This figure shows the electronic
absorption spectra of NH4SCN, catalyst 11, and catalyst
11 in the presence of NH4SCN in CH3CN solution. As
we can see, addition of NH4SCN to catalyst 11 results in
the appearance of a new absorption maximum at 485 nm.
As is obvious, the catalyst 11/NH4SCN interaction will
result in a strong absorption shift of about 15 nm toward
shorter wavelengths.
macrocycle + NH4SCN h
[macrocycle....NH4+]SCN- (1)
In the second step, this complex is further decomposed
to release SCN- ion into solution as:
(macrocycle....NH4+)SCN-
f
[macrocycle....NH4+] + SCN- (2)
Therefore, in this way, SCN- ion is produced as a
nucleophilic species in the presence of a suitable macro-
cycle, and in the third step, this ion participates in the
ring-opening reaction of epoxides:
In conclusion, we have found that suitable macrocyclic
compounds can catalyze the regioselective ring opening
of epoxides by ammonium thiocyanate under mild reac-
tion conditions.
Especially noteworthy are the ease of catalyst regen-
eration and reuse, the compatibility of these reaction
conditions with a variety of sensitive functional groups,
as well as the convenience of this procedure, which make
this synthetic technique highly useful.
Finally, the catalyst is regenerated in step 4:
Exp er im en ta l Section
Elemental analyses were performed at the National Oil Co.
of Iran, Tehran Research Center.
P r ep a r a t ion of 2,6-Difor m yl-4-m et h oxyp h en ol (1).
4-Methoxyphenol (5.243 g, 42.2 mmol) and hexamethelene-
tetramine (11.95 g, 55.1 mmol) were dissolved in anhydrous
trifluroacetic acid (60 mL) under N2 and the mixture stirred
for 24 h. The mixture was poured into 4 M HCl (200 mL) and
stirred for 10 min, after which time it was extracted with CH2-
Cl2. The combined organic extracts were washed with 4 M HCl,
water, and saturated brine, dried (Na2SO4), and evaporated
to give a yellow crystalline residue. The product was purified
by column chromatography to remove baseline impurities and
trace amounts of 5-methoxysalicylaldehyde. This gave 1 as
yellow needles: yield 2.4 g (32%); mp ) 135-136 °C (lit.40 mp
135-136 °C); IR (KBr) 1144, 1471, 1600, 1675, 1686, 2872,
These steps occur continuously until all of the epoxides
and ammonium thiocyanate are consumed, and after
workup, the catalyst can be recovered easily.
The variation in yield and rate of epoxide ring opening
by SCN- in the presence of different catalyst 11-19 can
be rationalized in terms of the suggested mechanism. The
macrocycles 11 and 12 are the most active catalysts in
(42) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry, 3rd ed.; Harper & Row: New York, 1987; pp
327-423.
(43) Semnani, A.; Shamsipur, M. J . Chem. Soc., Dalton Trans. 1996,
2215.
(44) Misumi, S. Top. Curr. Chem. 1993, 165, 163.
(45) Misumi, S. J . Pure Appl. Chem. 1990, 62, 493.
1
2978, 3067, 3350 cm-1; H NMR (CDCl3, 250 MHz) δ 3.85 (s,
3H), 7.50 (s, 2H), 10.21 (s, 2H), 11.11 (s, 1H); 13C NMR (CDCl3,
62.9 MHz) δ 56.5, 122.8, 123.9, 153.0, 158.4, 192.3.

7292 J . Org. Chem., Vol. 66, No. 22, 2001
Sharghi et al.
P r epar ation of 4-Meth oxyph en ol-2,6-dicar boxylic Acid
(2).46 To a mixture of silver oxide (6.5 g, 0.028 mol) and sodium
hydroxide (5.7 g, 0.14 mol) in water (50 mL), warmed to 55-
60 °C, was added 2,6-diformyl-4-methoxyphenol 1 (2.5 g, 0.014
mol) with stirring. The silver oxide was transformed to fluffy
metallic silver, and considerable heat was evolved. Stirring
was continued for 10 min, the mixture was filtered, and the
precipitated silver was washed with 100 mL of hot water. The
solution was acidified with hydrochloric acid and cooled at 10-
15 °C. The precipitate was filtered and dried. After recrystal-
lization from ethanol a pale brown solid of dicarboxylic acid 2
was obtained in 60% yield (1.76 g): mp ) 148-150 °C dec; IR
refluxed for 24 h. After cooling, the mixture was poured into
ice, and the precipitate was filtered off. The precipitate was
washed with distilled water, and the crude product was
purified by column chromatography using petroleum ether/
ethyl acetate as eluent (2:1) to give white solid 7 (16 g): yield
66%; mp ) 185-187 °C; IR (KBr) 670, 741, 778, 865, 1005,
1055, 1091, 1170, 1218, 1285, 1351, 1380, 1461, 1526, 1588,
1608, 2842, 2938, 3072 cm-1 1H NMR (CDCl3, 250 MHz) δ
;
3.86 (s, 3H,), 5.23 (s, 4H), 7.06-7.18 (m, 4H). 7.55 (dt, 2H, J 1
) 7.3 Hz, J 2 ) 1.7 Hz), 7.7 (s, 2H), 7.88 (dd, 2H, J 1 ) 8.0 Hz,
J 2 ) 1.6 Hz); 13C NMR (CDCl3, 62.9 MHz) δ 63.0, 65.8, 114.9,
118.0, 121.0, 125.9, 131.0, 132.8, 134.0, 141.0, 151.6, 155.0;
UV (CHCl3) λ (ꢀmax) 321, 346 nm. Anal. Calcd for C21H17-
BrN2O7: C, 51.53; H, 3.48; Br, 16.36; N, 5.73. Found: C, 51.23;
H, 3.62; Br, 16.57; N, 5.53.
(KBr) 1152, 1595, 1703, 2820, 3300 cm-1
;
1H NMR (DMSO-
d6, 250 MHz) δ 3.72 (s, 3H), 7.47 (s, 2H); 13C NMR (DMSO-d6,
62.9 MHz) δ 56.0, 117.9, 120.8, 150.4, 156.0, 169.2.
P r epar ation of 4-Meth oxyph en ol-2,6-dicar boxylic Acid
Dich lor id e (3).46 4-Methoxyphenol-2,6-dicarboxylic acid 2 (2
g, 0.009 mol) was heated in thionyl chloride (10 mL) for 4 h at
50-60 °C. The thionyl chloride was evaporated at low tem-
perature to give 3 as a brown viscous oil in 86% yield (2 g):
IR (CH2Cl2) 1154, 1460, 1585, 1778, 2958, 3074 cm-1; 1H NMR
(CDCl3, 250 MHz) δ 3.8 (s, 3H), 7.6 (s, 2H); 13C NMR (CDCl3,
62.9 MHz) δ 57.0, 120.0, 123.6, 152.0, 162.4, 178.2.
4-Br om o-2,6-bis(h yd r oxym eth yl)p h en ol (4). To an aque-
ous solution of NaOH (25%, 50 mL) containing p-bromophenol
(17.3 g, 0.1 mol) and methanol (25 mL) was added formalde-
hyde (38%, 90 mL) and the mixture stirred for 12 d at room
temperature. Then, a mixture of water (50 mL) and acetic acid
(15 mL) was added. The reaction mixture was stirred for 4 h
at room temperature to give a yellow precipitate. Filtration
gave 20 g (86%) of the solid (mp ) 155-160 °C). The
precipitate was dissolved in 10% aqueous NaOH and decol-
orized with active charcoal (0.5 g). The filtrate was acidified
with 2 M HCl to give crystals that were filtered, washed with
water, and dried. The crude product was recrystallized from
hot water to gave pale yellow precipitate (10.9 g, 47%): mp )
162-164 °C (lit.47 mp 163-164 °C); IR (KBr) 1070, 1480, 1590,
3318, 3420 cm-1; 1H NMR (acetone-d6, 60 MHz) δ 2.39 (s, 2H),
4.78 (s, 4H), 7.30 (s, 2H).
Gen er a l P r oced u r e for th e P r ep a r a tion of Dia m in o
Com p ou n d s 8 a n d 10a -c. In a two-necked round-bottomed
flask equipped with a reflux condenser and a dropping funnel
was prepared a suspension of dinitro compound 7 (5.87 g, 0.012
mol) or 9a -c (0.012 mol), palladium on carbon 5% (0.4 g), and
absolute ethanol (200 mL). The mixture was warmed, and
while the mixture was stirred magnetically, hydrazine hydrate
80% (10 mL) in ethanol (20 mL) was added dropwise over a
1.5 h period through the dropping funnel with the tempera-
ture maintained at about 50 °C. The reaction mixture was
refluxed for 2 h and filtered while hot. On cooling, the filtrate
gave the corresponding diamino compound after vacuum
drying.
2,6-Bis[2-(o-a m in op h en oxy)m et h yl]-4-b r om o-1-m et h -
oxyb en zen e (8): white crystals; yield 4.14 g, 81%; mp )
105-106 °C; IR (KBr) 746, 992, 1005, 1041, 1137, 1210, 1282,
1378, 1457, 1505, 1592, 1610, 2880, 2940, 3038, 3382, 3478
cm-1; 1H NMR (CDCl3, 250 MHz) δ 3.65 (s, 4H), 3.82 (s, 3H,),
5.1 (s, 4H), 6.6-6.8 (complex, 6H), 6.95 (d, 2H, J ) 7.5) 7.47
(d, 2H, J ) 7.5); 13C NMR (CDCl3, 62.9 MHz) δ 63.4, 65.9,
112.6, 115.7, 118.9, 122.1, 125.0, 130.6, 131.0, 137.0, 146.8,
157.1; MS m/z 430 (M+ + 2, 0.7), 428 (M+, 0.7), 350 (19), 242
(14), 210 (100), 182 (23), 133 (32), 122 (26), 119 (39), 91 (79);
UV (CHCl3) λ (ꢀmax) 309 nm. Anal. Calcd for C21H21BrN2O3:
C, 58.74; H, 4.90; Br, 18.65; N, 6.53. Found: C, 58.61; H, 5.12;
Br, 18.83; N, 6.44.
4-Br om o-2,6-bis(h yd r oxym eth yl)a n isole (5). To a solu-
tion of 4-bromo-2,6-bis(hydroxymethyl)phenol (4), (2.6 g, 11
mmol) in 5% aqueous NaOH (10 mL) was added dropwise
dimethyl sulfate (1.5 mL, 15 mmol). After being stirred at 30
°C for 2 h, the reaction mixture was allowed to stand overnight
at room temperature. The precipitate was collected by filtra-
tion, washed with water, and redissolved in hot water. After
removal of the insoluble oil, the clear solution was cooled. The
product (1.6 g, 58%) crystallized as white needles: mp ) 126-
128 °C; after recrystallization from water mp ) 130 °C (lit.48
1,5-Bis(o-a m in op h en oxy)-3-oxa p en t a n e (10a ):50 white
crystals; yield 94%; mp ) 65-66 °C; IR (KBr) 1138, 1508, 1605,
1
3321, 3388 cm-1; H NMR (CDCl3, 250 MHz) δ 3.58 (s, 4H),
3.88 (t, 4H, J ) 4.6 Hz), 4.12 (t, 4H, J ) 4.6 Hz), 6.59-6.78
(m, 8H).
1,8-Bis(o-a m in op h en oxy)-3,6-d ioxa octa n e (10b):50 white
crystals; yield 93%; mp ) 48-50 °C; IR (KBr) 1140, 1510, 1608,
1
3370, 3470 cm-1; H NMR (CDCl3, 250 MHz) δ 3.67 (s, 4H),
1
mp 130 °C); IR (KBr) 1067, 1455, 3030, 3270 cm-1; H NMR
3.77 (s, 4H), 3.85 (t, 4H, J ) 4.5 Hz), 4.2 (t, 4H, J ) 4.5 Hz),
6.54-6.77 (m, 8H); MS m/z 333 (M+ + 1, 7), 332 (M+, 32), 224
(17), 153 (12), 136 (49), 109 (57), 92 (38), 80 (53), 65 (30), 44
(100).
(CDCl3, 250 MHz) δ 3.75 (s, 3H), 4.49 (s, 4H), 7.52 (s, 2H).
4-Br om o-2,6-bis(br om om eth yl)a n isol (6). To a solution
stirred at room temperature of 5 (5.5 g, 22.5 mmol) in 100 mL
of dioxane was added over a 30 min period a solution of PBr3
(50 mmol) in 10 mL of dioxane. After 20 h, 15 mL of H2O and
200 mL of CHCl3 were added, and the mixture was stirred for
5 min and then neutralized with saturated NaHCO3. The
CHCl3 extracts were dried (Na2SO4), and after removal of the
solvent the residue was purified by column chromatography
using petroleum ether (bp ) 60-80 °C) as eluent: white
crystals (5.11 g); yield 61%; mp ) 80-81 °C (lit.49 82-83 °C);
1,5-Bis(o-a m in op h en oxy)-3-th iop en ta n e (10c):50 white
crystals; yield 89%; mp ) 28-29 °C; IR (KBr) 1017, 1508, 1608,
1
3328, 3408 cm-1; H NMR (CDCl3, 250 MHz) δ 3.03 (t, 4H, J
) 6.5 Hz), 3.73 (b, 4H), 4.20 (t, 4H, J ) 6.5 Hz), 6.66-6.84 (m,
8H); MS m/z 304 (M+, 3), 196 (13), 168 (23), 123 (18), 105 (100),
80 (32), 61 (53), 45 (65).
N-ter t-Bu tylbis[2-(o-am in oph en oxy)eth yl]am in e (10d).51
The dinitro compound 9d (4.0 g, 0.01 mmol) was reduced in a
stirred refluxing solution of tin(II) chloride dihydrate (15 g,
0.65 mol) in concentrated hydrochloric acid (50 mL). After 7
h, the reaction mixture was cooled and the precipitate was
filtered. A solution of sodium hydroxide (5 N, 200 mL) was
added to the filtrate and extracted with CH2Cl2. The organic
layer was washed with water, dried with sodium sulfate, and
evaporated. The residue was crystallized from ethanol to give
diamine 10d as white crystals in 54% (6 g) yield: mp ) 50-
52 °C; IR (KBr) 1508, 1615, 3355, 3428 cm-1; 1H NMR (CDCl3,
1
IR (KBr) 778, 867, 1204, 1580, 3022 cm-1; H NMR (CDCl3,
250 MHz) δ 4.0 (s, 3H,), 4.46 (s, 4H), 7.48 (s, 2H).
2,6-Bis[2-(o-n itr oph en oxy)m eth yl]-4-br om o-1-m eth oxy-
ben zen e (7). A mixture of o-nitrophenol (14 g, 0.1 mol) and
potassium carbonate (14 g) was stirred in DMF (100 mL) for
2 h. Then, 4-bromo-2,6-bis(bromomethyl)anisol 6 (0.05 mol,
18.65 g) was added dropwise during 1 h, and the mixture was
(46) Kudau, N. A.; Trivedi, B. K.; Kulkarni, A. B. Indian J . Chem.
1974, 12, 1045.
(47) Moshfegh, A. A.; Mazandarani, B.; Nahid, A.; Hakimelahhi, H.
Helv. Chim. Acta 1982, 65, 1229.
(48) Hu, H.; Zhang, Z. Chem. J . Chin. Univ. 1984, 1, 65.
(49) Tashiro, M.; Mataka, S.; Tamato, T. J . Org. Chem. 1989, 54(2),
451.
(50) Sharghi, H.; Niknam, K.; Pooyan, M. Tetrahedron 2001, 57,
6057.
(51) Chen, Z.; Wu, C. Huaxue Shiji 1996, 18, 136; Chem. Abstr. 1996,
126, 18606g.

Conversion of Epoxides to â-Hydroxy Thiocyanates
J . Org. Chem., Vol. 66, No. 22, 2001 7293
1
250 MHz) δ 1.13 (s, 9H), 3.03 (t, 4H, J ) 6.6 Hz), 3.80 (b, 4H),
4.01 (t, 4H, J ) 6.6 Hz), 6.55-6.80 (m, 8H).
2925, 3314 cm-1; H NMR (CDCl3, 250 MHz) δ 3.75 (s, 3H),
4.04 (s, 3H), 4.92 (d, 2H, J ) 9.7 Hz), 5.42 (d, 2H, J ) 9.7 Hz),
6.99-7.04 (m, 6H), 7.94 (d, 2H, J ) 3.2 Hz), 8.41 (s, 2H), 8.62
(s, 2H), 10.83 (s, 2H), 14.64 (s, 1H); MS m/z 608 (M+, 7), 512
(14), 511 (40), 510 (57), 496 (3), 402 (4), 372 (6), 359 (7), 344
(7), 270 (51), 268 (51), 255 (11), 241 (10), 226 (35), 212 (8), 210
(12), 198 (7), 169 (13), 163 (16), 133 (43), 119 (38), 109 (46),
105 (42), 91 (100), 78 (25); UV (CHCl3) λ (ꢀmax) 374 (8129), 259
nm (19280). Anal. Calcd for C30H25BrN2O7: C, 59.51; H, 4.16;
Br, 13.20; N, 4.63. Found: C, 59.87; H, 3.94; Br, 13.51; N, 4.37.
Gen er a l P r oced u r e for Con ver sion of Ep oxid es to
â-Hyd r oxy Th iocya n a te Usin g Ma cr ocyclic Dia m id e a s
Ca ta lyst. To a mixture of epoxide (10 mmol) and NH4SCN
(10 mmol, 0.76 g) in acetonitrile (30 mL) was added a solution
of catalyst (0.1 mmol) in CH2Cl2 (5 mL), and the mixture was
stirred under reflux conditions for 35-90 min. The reaction
was monitored by TLC or GC. After completion of the reaction,
the mixture was filtered and the solvent was evaporated.
Chromatography of the crude product was performed on a
column of silica gel eluted first with n-hexane in the reaction
mixture followed by using CCl4/CH2Cl2 (1:1) for the separation
of â-hydroxy thiocyanate as a pale yellow liquid.
Gen er a l P r oced u r e for t h e Syn t h esis of P h en ol-
Con ta in in g Ma cr ocyclic Dia m id es (11-15). A solution of
diamine (2 mmol) in dry CH2Cl2 (50 mL) was added quickly
to a vigorously stirred solution of 4-methoxyphenol-2,6-dicar-
boxylic acid dichloride 3 (2 mmol) in dry CH2Cl2 (50 mL) at
room temperature. The mixture was stirred for a further 20
min and then was washed with bicarbonate solution and
water. The organic layer was dried over magnesium sulfate,
and the solvent was evaporated to give an oily product. The
crude product was purified by column chromatography using
petroleum ether (bp ) 60-80 °C)/ethyl acetate as eluent.
3,15-Dia za -4,5;13,14-d iben zo-21-h yd r oxy-19-m eth oxy-
6,9,12-tr ioxa bicyclo[15.3.1]h en eicosa -1(21),17,19-tr ien e-
2,16-d ion e (11): red viscous oil; yield 68%; IR (neat) 749, 1051,
1259, 1454, 1535, 1602, 1662, 2925, 3288 cm-1 1H NMR
;
(CDCl3, 250 MHz) δ 3.86 (s, 3H), 4.04 (s, 4H), 4.28 (s, 4H),
6.92-7.05 (m, 6H), 8.10 (d, 2H, J ) 3.3 Hz), 8.69 (m, 4H), 11.73
(s, 1H); MS m/z 450 (12), 449 (29), 448 (82), 341 (14), 340 (51),
314 (30), 284 (9), 270 (17), 268 (14), 255 (19), 241 (13), 226
(24), 212 (12), 177 (7), 163 (30), 149 (27), 135 (17), 120 (48),
109 (26), 91 (16), 77 (30), 43 (100); UV (CHCl3) λ (ꢀmax) 245
(15744), 293.5 nm (9796). Anal. Calcd for C25H24N2O7: C,
64.65; H, 5.21; N, 6.03. Found: C, 64.97; H, 5.55; N, 5.76.
3,18-Dia za -4,5;16,17-d iben zo-24-h yd r oxy-22-m eth oxy-
6,9,12,15-t et r a oxa b icyclo[18.3.1]t et r a eicosa -1(24),20,22-
tr ien e-2,19-d ion e (12): red viscous oil; yield 64%; IR (neat)
749, 1051, 1118, 1252, 1461, 1535, 1595, 1662, 2932, 3308
Select ed Sp ect r a l Da t a for â-H yd r oxy Th iocya n -
a tes.16,24,27 (a ) 2-Hyd r oxy-2-p h en yleth yl th iocya n a te: IR
(neat) ν SCN (2160 cm-1); H NMR (CDCl3, 250 MHz) δ 7.3
1
(5H, m), 5.0 (1H, dd), 3.1-3.3 (2H, m), 2.4-2.9 (1H, brs); 13C
NMR (CDCl3, 62.9 MHz) δ 135.8, 129.5, 128.3, 126.2, 113.0,
72.9, 42.4.
(b) 2-Hyd r oxycycloh exyl th iocya n a te: IR (neat) ν SCN
cm-1; H NMR (CDCl3, 250 MHz) δ 3.80 (s, 4H), 3.88 (s, 3H),
(2165 cm-1); H NMR (CDCl3, 250 MHz) δ 2.95 (1H, m), 2.35
1
1
3.97 (t, 4H, J ) 4.0 Hz), 4.25 (t, 4H, J ) 4.0 Hz), 6.89-7.10
(m, 6H), 8.08 (d, 2H, J ) 1.9 Hz), 8.53 (s, 2H), 8.60 (d, 2H, J
(1H, m), 2.15 (1H, s), 1.80 (2H, m), 1.65 (2H, m), 1.20-1.50
(4H, m); 13C NMR (CDCl3, 62.9 MHz) δ 110.0, 72.0, 55.0, 34.5,
32.5, 30.5, 27.0.
(c) 3-P h en oxy-2-h yd r oxyp r op yl th iocya n a te: IR (neat)
ν SCN (2163 cm-1); 1H NMR (CDCl3, 250 MHz) δ 7.27 (2H,
m), 6.92 (3H, m), 5.0 (1H, m), 4.2 (2H, d), 3.64 (2H, d); 13C
NMR (CDCl3, 62.9 MHz) δ 158.0, 130.0, 122.0, 115.1, 114.9,
78.2, 67.2, 33.6.
(d ) 3-Allyloxy-2-h yd r oxyp r op yl th iocya n a te: IR (neat)
ν SCN (2158 cm-1); 1H NMR (CDCl3, 250 MHz) δ 5.81 (1H,
m), 5.1-5.25 (2H, m), 4.7 (1H, brs), 3.98 (3H, m), 3.6 (2H, d),
3.36 (2H, d); 13C NMR (CDCl3, 62.9 MHz) δ 134.2, 118.0, 117.0,
80.2, 72.9, 69.2, 32.5.
) 7.8 Hz), 10.84 (s, 1H); MS m/z 510 (M+ + 2, 8), 509 (M+
+
1, 21), 508 (M+, 32), 493 (8), 492 (8), 384 (5), 374 (3), 356 (5),
312 (5), 296 (2), 285 (4), 268 (15), 241 (4), 226 (6), 203 (19),
177 (100), 163 (5), 153 (7), 135 (10), 120 (20), 109 (17), 93 (33),
77 (6); UV (CHCl3) λ (ꢀmax) 247 (14838), 351 nm (8584). Anal.
Calcd for C27H28N2O8: C, 63.77; H, 5.55; N, 5.51. Found: C,
63.42; H, 5.91; N, 5.62.
3,15-Dia za -4,5;13,14-d iben zo-21-h yd r oxy-19-m eth oxy-
9-th ia -6,12-d ioxa bicyclo[15.3.1]h en eicosa -1(21),17,19-tr i-
en e-2,16-d ion e (13): red solid; mp ) 154-156 °C; yield 66%;
IR (KBr) 749, 1051, 1252, 1454, 1535, 1602, 1662, 2918, 3301
1
cm-1; H NMR (CDCl3, 250 MHz) δ 3.31 (t, 4H, J ) 6.3 Hz),
(e) 3-Isop r op yloxy-2-h yd r oxyp r op yl th iocya n a te: IR
1
3.86 (s, 3H), 4.37 (t, 4H, J ) 6.3 Hz), 7.03-7.06 (m, 6H), 8.08
(s, 2H), 8.65 (m, 4H), 11.7 (s, 1H); MS m/z 480 (M+, 5), 466
(4), 465 (31), 464 (100), 357 (11), 356 (92), 328 (4), 296 (27),
270 (61), 268 (32), 241 (16), 226 (39), 179 (22), 178 (17), 163
(50), 152 (28), 135 (4), 120 (32), 109 (17), 93 (11), 87 (89), 77
(15); UV (CHCl3) λ (ꢀmax) 249.5 (38208), 378 (10480), 510 nm
(3792). Anal. Calcd for C25H24N2O6S: C, 62.49; H, 5.03; N, 5.83;
S, 6.67. Found: C, 62.17; H, 5.38; N, 5.52; S, 6.92.
(neat) ν SCN (2170 cm-1); H NMR (CDCl3, 250 MHz) δ 3.74
(1H, m), 3.57 (3H, m), 3.33 (2H, d), 3.17 (1H, brs), 1.1 (6H, d,
J ) 6 Hz); 13C NMR (CDCl3, 62.9 MHz) δ 114.5, 79.4, 73.2,
67.6, 38.2, 23.0, 22.0.
(f) 3-Ch lor o-2-h yd r oxyp r op yl th iocya n a te: IR (neat) ν
1
SCN (2168 cm-1); H NMR (CDCl3, 250 MHz) δ 4.1 (1H, m),
3.7 (4H, m), 2.64 (1H, brs); 13C NMR (CDCl3, 62.9 MHz) δ
117.8, 71.2, 46.1, 43.4.
9-ter t-Bu tyl-3,9,15-tr ia za -4,5;13,14-d iben zo-21-h yd r oxy-
19-m eth oxy-6,12-dioxabicyclo[15.3.1]h en eicosa-1(21),17,19-
tr ien e-2,16-d ion e (14): red viscous oil; yield 58%; IR (neat)
749, 1044, 1252, 1508, 1602, 1662, 2925, 3361 cm-1; 1H NMR
(CDCl3, 250 MHz) δ 3.85 (t, 4H, J ) 4.5 Hz), 4.11 (s, 3H), 4.17
(t, 4H, J ) 4.5 Hz), 6.97-7.08 (m, 6H), 8.11 (d, 2H, J ) 3.3
Hz), 8.64-8.69 (m, 4H), 12.08 (s, 1H); MS m/z 519 (M+, 5),
505 (12), 504 (38), 503 (16), 489 (4), 447 (6), 339 (50), 325 (12),
296 (17), 282 (18), 270 (66), 255 (13), 241 (10), 226 (14), 212
(6), 177 (4), 163 (33), 148 (5), 135 (9), 120 (19), 109 (18), 91
(8), 77 (14), 41 (100); UV (CHCl3) λ (ꢀmax) 246 (19358), 326
(11175), 507 nm (6015). Anal. Calcd for C29H33N3O6: C, 67.04;
H, 6.40; N, 8.09. Found: C, 67.51; H, 6.72; N, 7.67.
(g) 2-Hyd r oxyocta n th iocya n a te: IR (neat) ν SCN (2162
1
cm-1); H NMR (CDCl3, 250 MHz) δ 3.91 (1H, m), 3.15 (1H,
dd, J ) 13 J ) 3.5 Hz), 2.95 (1H, dd, J ) 13 J ) 7.5 Hz), 2.69
(1H, brs), 1.2-1.6 (10H, m), 0.88 (3H, m); 13C NMR (CDCl3,
62.9 MHz) δ 113.2, 70.6, 41.5, 36.3, 32.0, 29.4, 25.8, 22.9, 14.4.
(h ) 2-Hyd r oxy-1-th iocya n a toin d a n : IR (neat) ν SCN
1
(2160 cm-1); H NMR (CDCl3, 250 MHz) δ 7.2-7.5 (4H, m),
5.0 (1H, d), 4.8 (1H, m), 3.55 (2H, d), 3.2-3.5 (1H, brs); 13C
NMR (CDCl3, 62.9 MHz) δ 139.0, 130.0, 128.0, 126.0, 124.0,
120.0, 112.4, 83.7, 50.1, 39.4.
Ack n ow led gm en t. We gratefully acknowledge the
support of this work by the Shiraz University Research
Council and Professor N. Iranpoor for his helpful
comments.
10-Br om o-3,18-diaza-4,5;16,17-diben zo-24-h ydr oxy-13,22-
d im e t h oxy-6,15-d ioxa -t r icyclo[12.3.3.1.1]t e t r a e icosa -
1(24),8,10,12,20,22-h exa en e-2,19-d ion e (15): red viscous oil;
yield 67%; IR (neat) 749, 1004, 1252, 1454, 1535, 1595, 1662,
J O0103266