Chemoselective deprotection of cyclic N,O-aminals using catalytic bismuth(III) bromide in acetonitrile

Article abstract of DOI:10.1021/jo050228a

Cyclic N,O-aminals can be chemoselectively and efficiently deprotected using a catalytic amount of bismuth(III) bromide in acetonitrile at room temperature. This selectivity was also achieved in the presence of terminal O,O-acetal functionality. The susce

Full text of DOI:10.1021/jo050228a

SCHEME 1
Chemoselective Deprotection of Cyclic
N,O-Aminals Using Catalytic Bismuth(III)
Bromide in Acetonitrile
Xin Cong,†,‡ Fang Hu,‡ Ke-Gang Liu,‡
Qing-Jiang Liao,† and Zhu-Jun Yao*,‡
age between cyclic O,O-acetals and N,O-aminals would
be difficult.
Department of Medicinal Chemistry, China Pharmaceutical
University, 24 Tong Jia Xiang Road,
Recently, considerable effort has been focused on
developing mild, selective methods for acetal deprotec-
tion. Several methods have been reported for cleaving
acetals and ketals under nearly neutral conditions,
wherein mild Lewis acids are often adopted instead of
strong acids. For example, PdCl2(MeCN) in moist aceto-
nitrile or in acetone can deprotect acetals and ketals
efficiently. However, these hydrolyses are not consistently
reproducible and must be shielded from light.9 Selective
deprotection of acyclic acetals has been reported using
Bi(NO3)3‚5H2O in CH2Cl2.10 Several cyclic O,O-acetals
have been deprotected utilizing catalytic Bi(OTf)3‚4H2O
in refluxing THF/H2O (4:1).11 Bismuth(III) compounds
are attractive because they have suitable acidity yet are
nontoxic, easy to handle, and inexpensive.12
Nanjing 210009, China, and State Key Laboratory of
Bioorganic and Natural Product Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, China
yaoz@mail.sioc.ac.cn
Received February 4, 2005
We report herein that bismuth(III) bromide in aceto-
nitrile is a highly efficient catalytic system for selective
deprotection of cyclic N,O-aminals (Scheme 1). Since few
mild methods exist for the selective deprotection of N,O-
aminals, we examined the use of this system on a variety
of other functionalities. It was found that the method
proved to be highly efficient and easy to apply; further-
more, chemoselective deprotection of cyclic N,O-aminals
was achieved in the presence of cyclic O,O-acetals. The
reactions proceeded very well in acetonitrile with a
catalytic amount of bismuth(III) bromide at room tem-
perature.
Cyclic N,O-aminals can be chemoselectively and efficiently
deprotected using a catalytic amount of bismuth(III) bromide
in acetonitrile at room temperature. This selectivity was also
achieved in the presence of terminal O,O-acetal functional-
ity. The susceptibility of various other groups to cleavage
was also investigated. This method has advantages of ease
of operation and use of nontoxic and inexpensive reagents
in catalytic amounts.
Serine and its derivatives are frequently used in the
course of many syntheses as N,O-aminal-protected chi-
rons such as the Garner aldehyde.1 However, the related
cyclic O,O-acetals are also commonly used protecting
groups for 1,2- or 1,3-diols. To our knowledge, cyclic
acetals are usually more resistant to cleavage than the
corresponding acyclic acetals. Methods of deprotecting
cyclic O,O-acetals can often be applied to cleaving cyclic
N,O-aminals and acyclic acetals as well. Although nu-
merous approaches have been developed for deprotection
of cyclic O,O-acetals,2 few examples3 have been reported
where N,O-aminals are selectively deprotected in the
presence of O,O-acetals. Typical conditions for acid-
catalyzed deprotection of acetals include DOWEX 50 W
(H+) resin/methanol,4 trifluoroacetic/H2O,5 p-TsOH/metha-
nol,6 aqueous 60-80% AcOH,7 Amberlyst 15/methanol,
or Amberlyst 15/acetone/H2O.8 However, many of these
involve strong acids, corrosive reagents, and elevated
temperatures. Under such conditions, selectivity in cleav-
Protected cyclic N,O-aminals were conveniently pre-
pared from L-Garner’s aldehyde13 through reduction and
protection of the resultant primary alcohols. As shown
(4) (a) Ho, P.-T. Tetrahedron Lett. 1978, 19, 1623-1626. (b) Devel,
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K. T.; Robert, J. W.; Norman, L. Synthesis 1994, 31-33.
† China Pharmaceutical University.
‡ Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences.
(1) Coppola, G. M.; Schuster, H. F. Asymmetric SynthesissCon-
struction of Chiral Molecules Using Amino Acids; John Wiley & Sons:
New York, 1987.
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Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
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10.1021/jo050228a CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/12/2005
4514
J. Org. Chem. 2005, 70, 4514-4516

TABLE 1. Deprotection of Cyclic N,O-Aminals Using BiBr3 in MeCN
a All substrates and products were fully characterized by spectroscopic methods (see Supporting Information). b Reaction was carried
out following the general procedure described in this paper. c Isolated yields.
SCHEME 2
in Table 1, deprotection of the cyclic N,O-aminals was
achieved in excellent yields. Amine protecting groups
such as Boc and Cbz were stable under the conditions
used. MOM (entries 1 and 4) and TBDPS (entry 7)
groups, as well as acetate (entries 3 and 6) and unsatur-
ated ester functionalities (entry 8), were also stable under
the reaction conditions. However, the TBDMS groups
(entries 2 and 5) were simultaneously cleaved using this
protocol.13 The reaction rate decreased when the pre-
ferred solvent (MeCN) was replaced with acetone or CH2-
Cl2. In the latter cases, significant quantities of unreacted
starting materials were indicated by TLC monitoring. It
is noteworthy here that the reaction rates could be
accelerated by adding a catalytic amount of H2O such
that reaction times could be reduced to 1 h. However,
under these conditions the reaction system becomes
weakly acidic.14
examined (Scheme 2). Treatment of 19 with 10 mol %
To ascertain the reactivity of O,O-acetals under the
BiBr3 in MeCN at room temperature for 48 h afforded
only 16% yield of diol 20. The results were slightly
above conditions, the reaction of cyclic O,O-acetal 19 was
improved (up to 35% yield) when 20 mol % BiBr3 was
used at room temperature. However, the reactions led
(14) Joginder, S. B.; Jame, V.; Joel, S.; Oljan, R.; Thomas, B.
Tetrahedron Lett. 2000, 41, 6021-6024.
J. Org. Chem, Vol. 70, No. 11, 2005 4515

saturated aqueous NaHCO3 (2 mL). The layers were separated,
and the aqueous layer was extracted with ethyl acetate (3 × 10
mL). The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated in vacuo to give the crude
product, which was purified by flash column chromatography
on silica gel (petroleum ether/ethyl acetate ) 2:1) to give 4 (47
mg, 97%) as a white wax. [R]22D: 1.4 (c 1.18, CH2Cl2). IR (neat):
to more complex mixtures if the amount of BiBr3 was
increased to 50 mol % or the reaction temperature was
elevated to reflux. These results indicated that selective
deprotection of the cyclic N,O-aminals using a lower
amount of BiBr3 in MeCN at room temperature might
be achieved in the presence of cyclic O,O-acetals. Thus,
substrate 21 embodying both a cyclic N,O-aminal and a
cyclic O,O-acetal was prepared from alcohol 2215 and
examined (Scheme 2). Treatment of 21 with 20 mol %
BiBr3 in MeCN for 4 h at room temperature afforded
alcohol 22 (69%) and triol 23 (21%). These results indicate
that BiBr3 in MeCN may be a practical choice for selective
removal of N,O-aminals in the presence of O,O-acetals.
In summary, we have demonstrated that the use of
catalytic amounts (10-20 mol %) of bismuth(III) bromide
in acetonitrile at room temperature provides a mild and
effective method for selective deprotection of cyclic N,O-
aminals. These cyclic N,O-aminals can be converted to
the corresponding amino alcohols in satisfactory to excel-
lent yields in the presence of MOM, TBDPS, acetate, and
cyclic O,O-acetal groups. Advantages of this method
include the simplicity of procedure and the use of
inexpensive, nontoxic reagents in catalytic amounts.
1
3360, 1945, 2883, 1719, 1561, 1500, 1213, 1147, 1030 cm-1. H
NMR (300 MHz, CDCl3): δ 2.69 (br, 1H), 3.34 (s, 3H), 3.63-3.89
(m, 5H), 4.61 (s, 2H), 5.10 (brs, 2H), 5.45 (d, J ) 7.2 Hz,1H),
7.31-7.37 (m, 5H) ppm. 13C NMR (75 MHz, CDCl3): δ 52.1, 55.4,
63.2, 66.9, 67.9, 96.81, 128.1 (2C), 128.2, 128.5 (2C), 136.3, 156.4
ppm. ESIMS (m/z, %): 292.2 (M + Na+, 100%). HR-ESI-MS calcd
for C13H19NO5Na (M + Na+), 292.1155; found, 292.1151.
N-((R)-2-Hydroxy-1-((4R,5S)-2,2-dimethyl-5-((R)-2,2-di-
methyl-1,3-dioxolan-4-yl)-1,3-dioxolan-4-yl)ethyl)acet-
amide (22)15 and Triol 23. Compound 21 (100 mg, 0.29 mmol)
was converted to amino alcohol 22 and triol 23 by the above
general procedure using 20 mol % BiBr3. The crude products
were separated by flash column chromatography on silica gel
(petroleum ether/ethyl acetate ) 4:1) to give pure alcohol 22 (61
mg, 69%) as a colorless oil and triol 23 (16 mg, 21%) as a colorless
wax. Data for 22: [R]24D: 14.4 (c 1.36, CHCl3). 1H NMR (300
MHz, CDCl3): δ 1.38 (s, 6H), 1.41 (s, 3H), 1.43(s, 3H), 2.02 (s,
3H), 3.20 (br, 1H), 3.84-3.93 (m, 4H), 4.01-4.06 (m, 1H), 4.08-
4.10 (m, 2H), 4.18 (dd, J ) 8.4 Hz, 1H) ppm. Data for 23: [R]24
:
D
15.6 (c 1.30, CH3OH). IR (neat): 3318, 2988, 2939, 2887, 1653,
1555, 1374, 1239, 1214, 1081, 1060 cm-1 1H NMR (300 MHz,
.
CD3OD): δ 1.36 (s, 3H), 1.38 (s, 3H), 1.98 (s, 3H), 3.51-3.81 (m,
5H), 3.92 (dd, J ) 7.2 Hz, 1H), 4.02-4.08 (m, 1H), 4.13 (dd, J )
7.5 Hz, 1H), 6.42 (brs, 1H) ppm. 13C NMR (75 MHz, CD3OD): δ
23.2, 27.9, 28.0, 56.6, 62.4, 65.0, 75.1, 80.2, 80.5, 111.3, 173.8
ppm. ESI-MS (m/z, %): 264.1 (M + H+, 20%), 286.1 (M + Na+,
100%). HR-ESI-MS calcd for C11H21NO6Na (M + Na+), 286.1261;
found, 286.1260.
Experimental Section
General Procedure for Deprotection of Cyclic N,O-
Aminals. To a solution of cyclic N,O-aminal 1 (1.0 mmol) in
MeCN (10 mL) was added bismuth(III) bromide (45 mg, 0.1
mmol) at room temperature. The reaction mixture was stirred
at room temperature, and the progress of the reaction was
monitored by TLC. When all starting material had disappeared,
the reaction mixture was quenched by adding saturated aqueous
NaHCO3 (5 mL). The layers were separated, and the aqueous
layer was extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over Na2SO4, and concen-
trated. The residue was purified by flash column chromatogra-
phy on silica gel to afford the pure product 2.
Benzyl (S)-1-Hydroxy-3-(methoxymethoxy)propan-2-yl-
carbamate (4). To a solution of (S)-benzyl 4-((methoxymethoxy)-
methyl)-2,2-dimethyloxazolidine-3-carbomate (3) (56 mg, 0.18
mmol) in MeCN (1.8 mL) was added bismuth(III) bromide (8
mg, 0.018 mmol) at room temperature. The reaction mixture was
stirred at room temperature for 5 h. When all starting material
had disappeared, the reaction mixture was quenched by adding
Acknowledgment. This work was financially sup-
ported by the Major State Basic Research and Develop-
ment Program (G2000077500), NSFC (20425205 and
20321202), the Chinese Academy of Sciences (KGCX2-
SW-209), and Shanghai Municipal Commission of Sci-
ence and Technology (03DZ19203 and 04DZ14901). The
authors thank Dr. Terrence R. Burke, Jr. for his help
with manuscript preparation.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Liu, K.-G.; Yan, S.; Wu, Y.-L.; Yao, Z.-J. J. Org. Chem. 2002,
67, 6758-6763.
JO050228A
4516 J. Org. Chem., Vol. 70, No. 11, 2005