Thiourea: A novel cleaving agent for 1,3-dioxolanes

Full text of DOI:10.1021/jo981115c

5682
J . Org. Chem. 1999, 64, 5682-5685
Sch em e 1
Th iou r ea : A Novel Clea vin g Agen t for
1,3-Dioxola n es
Swapan Majumdar and Anup Bhattacharjya*
Indian Institute of Chemical Biology,
4 Raja S. C. Mullick Road, Calcutta 700 032, India
Received J une 10, 1998
In tr od u ction
One of the most common methods of protecting alde-
hydes, ketones, and vicinal diols involves the formation
of acetals. Aldehydes and ketones are usually protected
as their 1,3-dioxolane derivatives, and vicinal diols such
as those present in carbohydrate derivatives are pro-
tected as 2,2-dimethyl-1,3-dioxolanes. Several methods
are available for deprotecting these types of acetals,
which mostly utilize acidic cleaving methods.1 Other
cleaving methods involving the use of silica gel2 or
lithium tetrafluoroborate in wet acetonitrile3 and some
nonaqueous cleaving methods have also been reported
for this purpose.4-6 Herein we report that thiourea can
effect the cleavage of 1,3-dioxolanes derived from alde-
hydes and ketones, as well as the selective cleavage of
the 5,6-O-isopropylidene moiety in 1,2:5,6-di-O-isopro-
pylidene hexose derivatives, leading to good to excellent
yields of the parent compounds.
hydrate derivatives, because partial deprotection of such
compounds is frequently applied in carbohydrate chem-
istry. With this end in view, each of the 1,2:5,6-di-O-
isopropylidene carbohydrate derivatives 4-9 (Table 1)
was subjected to treatment with a 0.8 M solution of
thiourea in ethanol-water (1:1) under reflux. In each
case, the corresponding 5,6-deprotected compound was
formed in good to very good yields. In all cases, the 1,2-
O-isopropylidene group remained unaffected under the
1
reaction condition as revealed by the H NMR spectra of
the products. The utility of this method was immediately
apparent when it was discovered that the diisopropyl-
idene aminosugar derivative 8, which could not be de-
protected by treatment with 75% aqueous acetic acid,10
underwent cleavage by this method.
Resu lts a n d Discu ssion
The successful removal of the 5,6-O-isopropylidene
groups of the 1,2:5,6-di-O-isopropylidene carbohydrate
derivatives with thiourea suggested application of this
method for the cleavage of 1,3-dioxolanes derived from
aldehydes and ketones. The dioxolane derivative 10
(Table 2) obtained from cyclohexanone was treated with
thiourea acccording to the above procedure, and cyclo-
hexanone was indeed obtained in 87% yield as evident
from IR, NMR, and GC analyses. Similarly, the dioxo-
lanes 11-16 (Table 2) were deprotected to give the
corresponding carbonyl compounds in excellent yields.
The time required for the cleavage of the dioxolanes
listed in Table 2 was found to be shorter than that
required for the diisopropylidene carbohydrate deriva-
tives in Table 1.
The time required for the completion of the cleavage
reaction was found to depend on the concentration of
thiourea. The extent of deprotection of the diisopropyl-
idene derivative 4 was insignificant even after 20 h when
a 0.25 M solution of thiourea in ethanol-water (1:1) was
used. However, during the same period the use of a 0.5
M solution led to 50% conversion, whereas a 0.8 M
solution of thiourea afforded the cleaved product in 77%
yield. Interestingly, when the deprotection of 4 was
carried out in a 5 M solution of thiourea in water the
reaction was over in only 6 h and the 1,2-O-isopropy-
lidene glucose derivative 17 was obtained in 75% yield.
Thiourea-mediated cleavage was also found to be
effective for the removal of dimethyl acetal and THP
ether, as evident from the efficient deprotection of ben-
One of the known methods of preparation of an alkyl
thiol from an alkyl halide or sulfonate involves the
formation of the corresponding thiouronium salt by
treatment with thiourea followed by alkaline hydrolysis.7
An attempted synthesis of the thiocarbohydrate deriva-
tive 3 from the corresponding R-mesylate 18 by heating
with a 0.8 M solution of thiourea in ethanol-water (1:1)
followed by treatment with aqueous NaOH solution
resulted in a mixture of products. The 1H NMR spectrum
of one of the products, which was isolated in a very poor
yield, revealed the loss of the 5,6-O-isopropylidene group
of 1 during the reaction (Scheme 1).9 To our knowledge,
there has been no report of such cleavage by thiourea. It
was, therefore, of much interest to study whether the
method was general for the removal of the 5,6-O-
isopropylidene groups in other diisopropylidene carbo-
(1) For general methods, see: Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis; J ohn Wiley and Sons: New
York, 1991.
(2) Huet. F.; Lechevalier, A.; Pellet, M.; Conia, J . M. Synthesis 1978,
63.
(3) Lipshutz, B. H.; Harvey, D. F. Synth. Commun. 1982, 12, 267.
(4) Marcantoni, E.; Nobili, F. J . Org. Chem. 1997, 62, 4183 and
references therein.
(5) Sen, S. E.; Roach, S. L.; Boggs, J . K.; Ewing, G. J .; Magrath, J .
J . Org. Chem. 1997, 62, 6684 and references therein.
(6) Kaur, G.; Trehan, A.; Trehan, S. J . Org. Chem. 1998, 63, 2365.
(7) Speziale, A. J . Organic Synthesis; Wiley: New York, 1963;
Collect. Vol. IV, p 401.
(8) Meyer zu Reckendrof, W. Angew. Chem., Int. Ed. Engl. 1966, 5,
967.
(9) The product was assigned the structure 222 (Scheme 1) on the
basis of 1H and 13C NMR analyses. The structure of 2 was indepen-
dently verified by its preparation from 1 by removal of the 5,6-
isopropylidene group by known hydrolytic procedure10 followed by
treatment of the resulting diol with NaOEt.
(10) (a) Shing, T. K. M.; Elsley, D. A.; Gillhouley, J . G. J . Chem.
Soc., Chem. Commun. 1989, 1280. (b) Yadav, J . S.; Chander, M. C.;
Reddy, K. K. Tetrahedron Lett. 1992, 33, 135.
10.1021/jo981115c CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

Notes
Ta ble 1. Clea va ge of 5,6-Isop r op ylid en e Gr ou p s fr om
J . Org. Chem., Vol. 64, No. 15, 1999 5683
Ta ble 2. Dep r otection of Eth ylen e Aceta ls by Th iou r ea
1,2:5,6-d i-O-Isop r op ylid en e F u r a n oses
so
is involved in the hydrolytic removal of the dioxolane
moiety.12
In conclusion, thiourea-induced cleavage of 1,3-dioxo-
lanes in ethanol-water provides an efficient and opera-
tionally simple procedure for deprotection of ethylene
acetals, as well as the selective deprotection of 1,2:5,6-
diisopropylidene carbohydrate derivatives or similar
compounds. The method is expected to be one of choice
for this purpose as a result of the essentially neutral
reaction medium employed for the cleavage reaction.
zaldehyde dimethyl acetal 31 (87%) and the THP ether
of cyclohexanol 32 (86%) (Table 3). It was also established
that under the condition of the cleavage reaction dioxo-
lanes could be selectively deprotected in the presence of
two important hydroxyl protecting groups, TBDMS and
MOM, because the doubly protected derivatives 30 and
33 could be converted to the singly protected 34 and 36
without any noticeable deprotection of the other protect-
ing groups (Table 3).
(11) In control experiments, the pH of a medium consisting of alcohol
and water was adjusted to pH 6 by addition of acetic acid, and 6 (Table
1) and 15 (Table 2) were separately heated under reflux in this medium
for 10 h and 6 h, respectively. Both were observed to be completely
deprotected.
(12) Another possibility suggested by one of the referees is the
involvement of the following equilibrium:
The mechanism of the above cleavage of dioxolanes by
thiourea is not clear at present. The usual removal of
the 5,6-O-isopropylidene group in the aforementioned
carbohydrate derivatives generally requires a mildly
acidic medium. The pH values of 0.25, 0.5, and 1.0 M
thiourea in ethanol-water were found to be 6.6, 6.0, and
5.6, respectively, and that of 5.0 M thiourea in water was
5.4. The pH of the solvent medium without thiourea or
of the individual solvents was found to be nearly 7.0. It
was also observed that the deprotection did not proceed
without thiourea in the reaction medium.11 It is pos-
sible that under the condition of the reaction, the imi-
nothiol tautomer of thiourea with an acidic thiol group
However, attempted reaction of the dioxolane 16 with thiourea in
ethanol in the absence of water to isolate the corresponding N-
carbamoyl imino intermediate A failed because the starting material
remained unchanged, and the involvement of such a mechanism is
inconclusive.

5684 J . Org. Chem., Vol. 64, No. 15, 1999
Notes
Ta ble 3. Rem ova l of Oth er P r otectin g Gr ou p s by
Th iou r ea
etate (3 mL, 28.8 mmol) was added, and the reaction mixture
was heated under reflux for 15 h. After the completion of the
reaction as revealed by TLC, the reaction mixture was poured
onto ice and extracted with CHCl3 (3 × 25 mL). The combined
organic layer was washed with water (3 × 25 mL), dried, and
concentrated. The syrupy residue solidified on trituration with
cyclohexane, and crystallization from cyclohexane gave 9 as a
colorless solid (4.5 g, 60%): mp 102-103 °C; [R]24 - 3.9 (c 2.3,
D
CHCl3); IR (KBr) 2988, 1737, 1443, 1382, 1225, 1139, 1070, 1016,
883, 852, 697 cm-1; 1H NMR δ 5.90 (d, J ) 3.6 Hz, 1H), 4.71 (d,
J ) 3.6 Hz, 1H), 4.36-4.29 (m,1H), 4.26 (s, 2H), 4.14-4.09 (m,
2H), 4.03-3.96 (m, 2H), 3.77 (s, 3H), 1.49 (s, 3H), 1.42 (s, 3H),
1.35 (s, 3H), 1.32 (s, 3H); 13C NMR δ 171.0 (s), 112.2 (s), 109.4
(s), 105.6 (d), 84.1 (d), 83.7 (d), 81.5 (d), 73.0 (d), 68.7 (t), 67.7
(t), 52.3 (q), 27.2 (2q), 26.6 (q), 25.7 (q); MS (EI) m/z 317 (M+
15), 303, 259, 245, 236, 199. Anal. Calcd for C15H24O8: C, 54.20;
H, 7.27. Found: C, 53.45; H, 7.21.
-
2-(2-Meth oxym eth yloxy)eth yl-2-m eth yl-1,3-dioxolan e (33).
NaH (0.5 g) was added at
0 °C to a stirred solution of
2-(2-hydroxy)ethyl-2-methyl-1,3-dioxolane19b (1.0 g, 7.5 mmol) in
THF (20 mL). Methoxymethyl chloride (1 mL) was added to this,
and the mixture was stirred for 1 h. Excess NaH was destroyed
by the addition of crushed ice, and the residue obtained after
removal of THF was extracted with ether (3 × 20 mL). The
combined organic layer was washed with water (3 × 20 mL) and
dried, and removal of solvent gave 33 as a colorless syrup (1.1
g, 82%): IR (neat) 2954, 1442, 1216 cm-1 1H NMR δ 4.74 (s,
;
1H), 4.72 (s, 1H), 3.95 (m, 4H), 3.74 (t, 2H), 3.39 (s, 3H), 1.99 (t,
2H), 1.34 (s, 3H); 13C NMR δ 108.7 (s), 96.3 (t), 64.4 (t, 2C), 63.5
(t), 54.9 (q), 38.7 (t), 24.1 (q); MS (EI) m/z 175 (M+ - 1), 161
(M+ - 15), 114, 101, 87, 71.
Gen er a l Met h od for Clea va ge of 1,3-Dioxola n es b y
Th iou r ea . The general method is illustrated by the cleavage of
the 1,2:5,6-di-O-isopropylidene carbohydrate derivative 8.
3-Deoxy-3-N,N-d ia llyla m in o-1,2-O-isop r op ylid en e-r-D-
glu cofu r a n ose (21). A solution of 8 (1.15 g, 3.39 mmol) in 0.85
M thiourea solution in (1:1) EtOH-H2O (20 mL) was heated
under reflux for 18 h. The reaction mixture was concentrated
under reduced pressure, and the residue was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layer was washed
with water (3 × 20 mL), dried, and then concentrated to give a
brown syrup, which on chromatography over silica gel (ethyl
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded in CDCl3 solutions at 300 and 75 MHz, respectively.
Reactions were monitored by thin-layer chromatography using
Merck 60 F254 precoated silica gel plate (no. 5554). Gas-liquid
chromatography was performed using a HP-5890 series II
instrument with HP-1 (megabore) capillary column (30 m × 0.53
mm × 0.88 µm) fitted with FID, and quantitation was done using
HP integrator (HP 3396A). Silica gel of mesh size 60-120 (SRL,
India) was used for column chromatography. Organic extracts
were dried over anhydrous sodium sulfate. Alcohol was distilled
from calcium oxide prior to use. Solvents were removed in a
rotary evaporator under reduced pressure. Thiourea was crystal-
lized from dehydrated alcohol.
acetate) gave the diol 21 as a colorless syrup (0.84 g, 82%): [R]25
D
-16.0 (c 0.6, CHCl3); IR (neat) 3446 (broad), 2982, 1643, 1378,
1216, 1166, 1066 cm-1; 1H NMR δ 5.86 (d, J ) 3.9 Hz, 1H), 5.78
(m, 2H), 5.24 (m, 4H), 4.77 (d, J ) 3.9 Hz, 1H), 4.24(m,1H), 3.86
(m, 2H), 3.67 (m, 1H), 3.56 (d, J ) 5.9 Hz, 1H), 3.40 (dd, J )
13.8, 5.4 Hz, 2H), 2.97 (dd, J ) 13.8, 8.1 Hz, 2H), 1.49 (s, 3H),
1.25 (s, 3H); 13C NMR δ 134.7 (d), 119.3 (t), 111.5 (s), 106.1 (d),
79.3 (d), 71.5 (d), 67.1 (d), 65.0 (t), 55.0 (t), 27.1 (s), 26.4 (s); MS
(EI) m/z 299 (M+), 297 (M+ - 2), 284 (M+ - 15), 268, 258, 199.
Anal. Calcd for C15H25O5N: C, 60.16; H, 8.42; N, 4.68. Found:
C, 59.46; H, 8.08; N, 5.09.
All other dioxolanes were cleaved according to the above pro-
cedure. For the dioxolanes derived from aldehydes and ketones,
essentially the same procedure was adopted, except extraction
was done with hexane or ether and the purification by chroma-
tography was not necessary.
3-Deoxy-3-N,N-d ia llyla m in o-1,2:5,6-d i-O-isop r op ylid en e-
r-D-glu cofu r a n ose (8). Anhydrous K2CO3 (3.4 g, 24.6 mmol)
and allyl bromide (3 mL) were added at 25 °C to a stirred
solution of 3-deoxy-3-amino-1,2:5,6-di-O-isopropylidenegluco-
furanose13 (2.54 g, 9.8 mmol) in dry acetone (50 mL), and stirring
was continued at 50 °C for 20 h. Filtration of the mixture and
removal of solvent from the filtrate afforded a syrupy residue,
which was chromatographed on silica gel (hexanes-ethyl ac-
etate, 19:1) to give 8 as a syrupy liquid (3.1 g, 93%): [R]24D -24.6
(c 1.0, CHCl3); IR (neat) 2984, 1642, 1455, 1376, 1251, 1213,
1165, 1071 cm-1 1H NMR δ 5.81 (m, 3H), 5.32-5.11 (m, 4H),
;
4.72 (d, J ) 3.6 Hz, 1H), 4.30 (m, 1H), 4.10 (m, 2H), 3.97 (m,
1H), 3.46 (d, J ) 4.8 Hz, 1H), 3.40 (bd, J ) 13.2 Hz, 2H),
3.03 (dd, J ) 14.7, 7.2 Hz, 2H), 1.50 (s, 3H), 1.41 (s, 3H), 1.36
(s, 3H), 1.31 (s, 3H); 13C NMR δ 134.2 (d), 116.2 (t), 109.8 (s),
109.1 (s), 103.5 (d), 80.1 (d), 78.8 (d), 71.1 (d), 66.0 (t), 64.2 (d),
52.6 (t), 25.3 (q), 25.0 (q), 24.0 (q), 23.7 (q); MS (EI) m/z 339
(M+), 324 (M+ - 15), 298, 240, 169. Anal. Calcd for C18H29O5N‚
H2O: C, 60.46; H, 8.74; N, 3.92; Found: C, 60.60; H, 8.47; N,
3.57.
3-O-Allyl-1,2-isop r op ylid en e-r-D-a llofu r a n ose (18). Oil;
[R]25 +116.3 (c 0.6, CHCl3); IR (Neat) 3446, 2930, 1647, 1455,
D
1379 cm-1; H NMR δ 6.03-5.92 (m, 1H), 5.78 (d, J ) 3.6 Hz,
1
1H), 5.29 (m, 2H), 4.65 (t, J ) 3.9 Hz, 1H), 4.27 (dd, J ) 6.3, 5.4
Hz, 1H), 4.07 (m, 2H), 3.91 (dd, J ) 8.7, 4.2 Hz, 1H), 3.73 (m,
(15) Bhattacharjee, A.; Chattopadhyay, P.; Kundu, A. P.; Mukho-
padhyay, R.; Bhattacharjya, A. Indian J . Chem. 1996, 35B, 69.
(16) Brimacombe, J . S.; Ching, O. A. Carbohydr. Res. 1968, 8, 82.
(17) de Belder, A. N. Adv. Carbohydr. Chem. 1977, 34, 179.
(18) Smith, A. B., III; Rivero, R. A.; Hale, K. J .; Vaccaro, H. A. J .
Am. Chem. Soc. 1991, 113, 2092.
(19) (a) Daignault, R. A.; Eliel, E. L. Organic Synthesis; Wiley: New
York, 1973; Collect. Vol. V, pp 303-306. (b) Meskens, F. A. J . Synthesis
1981, 501.
3-O-Ca r bom eth oxym eth yl-1,2:5,6-d i-O-isop r op ylid en e-r-
D-glu cofu r a n ose (9). 1,2:5,6-di-O-isopropylidene glucose14 (5 g,
19.2 mmol) was added in portions to a suspension of NaH (1.6
g, 40% suspension in mineral oil), prewashed with hexane (2 ×
5 mL) and dried under vacuum, in THF (50 mL) and cooled to
0 °C. After the mixture was stirred for 30 min, methylbromoac-
(20) McMurry, J . E.; Erion, M. D. J . Am. Chem. Soc. 1985, 107,
2712.
(21) Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J . Org. Chem. 1977,
42, 3772.
(13) Brimacombe, J . S.; Bryan, J . G. H.; Husain, A.; Stacey, M.;
Tolley, M. S. Carbohydr. Res. 1967, 3, 318.
(14) Schimdt, O. T. Methods in Carbohydrate Chemistry; Academic
Press Inc.: New York and London, 1963; Vol. II, p 318.
(22) Buchanan, J . G.; Oakes, E. M. Carbohydr. Res. 1965, 1, 242.

Notes
J . Org. Chem., Vol. 64, No. 15, 1999 5685
1H), 2.53 (d, J ) 3.6 Hz, 1H), 2.48 (dd, J ) 7.5, 6.0 Hz, 1H),
1.59 (s, 3H), 1.36 (s, 3H); 13C NMR δ 134.2 (d), 119.1 (t), 113.6
(s), 104.5 (d), 79.3 (d), 77.8 (d), 77.7 (d), 71.7 (t), 71.3 (d), 63.4
(t), 27.1 (q), 26.9 (q); MS (EI) m/z 245 (M+ - 15), 199, 141, 127.
Anal. Calcd for C12H20O6: C, 55.35; H, 7.74. Found: C, 54.11;
H, 7.47.
3-O-Meth a n esu lfon yl-1,2-isop r op ylid en e-r-D-glu cofu r a -
n ose (20). Oil; [R]25D -49.2 (c 1.2, CHCl3 ); IR (neat) 3490, 2984,
2930, 1360, 1217, 1175, 1080, 1021, 949, 886, 784, 727 cm-1; 1H
NMR δ 5.95 (d, J ) 3.6 Hz, 1H), 5.12 (d, J ) 2.7 Hz, 1H), 4.75
(d, J ) 3.6 Hz, 1H), 4.25 (dd, J ) 9.0, 3.0 Hz, 1H), 3.89 (dd, J )
12.9, 5.5 Hz, 1H), 3.75 (m, 2H), 3.15 (s, 3H), 2.93 (d, J ) 5.4 Hz,
1H), 2.13 (bm, 1H), 1.51 (s, 3H), 1.32 (s, 3H); 13C NMR δ 113.4
(s), 105.7 (d), 84.0 (d), 82.7 (d), 79.1 (d), 68.9 (d), 64.5 (t), 38.8
(q), 27.1 (q), 26.6 (q); MS (EI) m/z 283 (M+ - 15), 237, 209, 188.
Anal. Calcd for C10H18O8S: C, 40.24; H, 6.08; Found: C, 40.14;
H, 6.16
colorless syrup (130 mg), which was found from the analysis of
the H NMR spectrum of the mixture to consist of 33 and 36 in
1
a ratio of 1:3: IR (neat, mixture) 2944, 1714, 1458, 1355, 1216,
1
1114, 992 cm-1; H NMR (mixture, data for 36) δ 4.75 (s, 1H),
4.72 (1H), 3.83 (t, 2H), 3.38 (s, 3H), 2.70 (t, 2H), 2.18 (s, 3H).
Dep r otection of 4 w ith 5 M Th iou r ea Solu tion . Com-
pound 4 (0.1 g, 0.33 mmol) was heated under reflux with aqueous
5 M thiourea solution (5 mL) for 6 h. After the completion of
the reaction as revealed by TLC, the reaction mixture was
extracted with CHCl3 (3 × 15 mL), and the combined organic
layer was washed with water (3 × 15 mL), dried, and concen-
trated to give a syrupy liquid. Chromatography of the material
over silica gel (ethyl acetate) furnished the diol 17 as a colorless
syrup (0.065 g, 75%).
Ack n ow led gm en t. A.B. is grateful to DST, India
for financial assistance. The award of a Senior Research
Fellowship by UGC, India to S.M. is gratefully acknowl-
edged. Thanks are due to Dr. V. S. Giri and Dr. Ranjan
Mukhopadhyay for NMR analysis.
3-O-Ca r bom eth oxym eth yl-1,2-isop r op ylid en e-r-D-glu co-
fu r a n ose (22). Oil; [R]25 -76.3 (c 0.6, CHCl3); IR (neat) 3446,
D
2934, 1738, 1381, 1237, 1131, 1086, 1017 cm-1; 1H NMR δ 5.94
(d, J ) 3.3 Hz, 1H), 4.73 (bs, 1H), 4.50 (d, J ) 3.3 Hz, 1H), 4.36-
3.68 (m, 7H), 3.80 (s, 3H), 1.48 (s, 3H), 1.31 (s, 3H); 13C NMR δ
172.8 (s), 112.4 (s), 105.6 (d), 83.6 (d), 82.3 (d), 80.4 (d), 69.1 (d),
66.1 (t), 64.7 (t), 53.0 (q), 27.1 (q), 26.7 (q); MS (EI) m/z 292 (M+),
277 (M+ - 15), 231, 216, 204. Anal. Calcd for C12H20O8: C, 49.29;
H, 6.90. Found: C, 49.22; H, 6.86.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 8, 9, 18, 20, 21, 22, 33, and 36. This material is
available free of charge via the Internet at http://pubs.acs.org.
4-Meth oxym eth yloxybu ta n e-2-on e (36). The deprotection
of 33 (0.2 g, 1.14 mmol) by the above method gave after 20 h a
J O981115C