Highly selective deblocking of propargyl carbonates in the presence of propargyl carbamates with tetrathiomolybdate

Article abstract of DOI:10.1021/jo048777o

(Chemical Equation Presented) Propargyloxycarbonyl chloride, 1, has been used to protect the hydroxyl and amino functionalities of amino alcohols and aminophenols in one pot using triethylamine or pyridine as a base. The increased reactivity of benzyltriethylammonium tetrathiomolybdate, 2, toward propargyl carbonates over propargyl carbamates is studied in detail and has been exploited further to develop an orthogonal protection strategy for the hydroxyl and amino functionalities. For example, 2-amino-1-butanol, 6a, was treated with 1 to get the N,O-diPoc compound 7a in 90% yield, which when treated with 1.1 equiv of 2 at room temperature removes the Poc group attached to oxygen while leaving the one attached to nitrogen intact to yield compound 8a in 85% yield. This particular observation offers a new protecting strategy where an amine and an alcohol group can be protected simultaneously in one pot, and in a later synthetic step, if the alcohol group has to be deprotected selectively, it can be achieved with 1 equiv of 2.

Full text of DOI:10.1021/jo048777o

Highly Selective Deblocking of Propargyl Carbonates in the
Presence of Propargyl Carbamates with Tetrathiomolybdate
R. Ramesh, Ramakrishna G. Bhat, and Srinivasan Chandrasekaran*,†
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
scn@orgchem.iisc.ernet.in
Received July 17, 2004
Propargyloxycarbonyl chloride, 1, has been used to protect the hydroxyl and amino functionalities
of amino alcohols and aminophenols in one pot using triethylamine or pyridine as a base. The
increased reactivity of benzyltriethylammonium tetrathiomolybdate, 2, toward propargyl carbonates
over propargyl carbamates is studied in detail and has been exploited further to develop an
orthogonal protection strategy for the hydroxyl and amino functionalities. For example, 2-amino-
1-butanol, 6a, was treated with 1 to get the N,O-diPoc compound 7a in 90% yield, which when
treated with 1.1 equiv of 2 at room temperature removes the Poc group attached to oxygen while
leaving the one attached to nitrogen intact to yield compound 8a in 85% yield. This particular
observation offers a new protecting strategy where an amine and an alcohol group can be protected
simultaneously in one pot, and in a later synthetic step, if the alcohol group has to be deprotected
selectively, it can be achieved with 1 equiv of 2.
Introduction
use of this reagent for protection of the amino group in
peptide synthesis4 and for the hydroxyl function in
carbohydrate synthesis2 has already been demonstrated.
The propargyloxy carbonyl (Poc) group is stable to a
variety of acidic and basic conditions. For instance, it has
been shown that methyl esters of Poc-protected amino
acids could be hydrolyzed with methanolic NaOH in good
yields, keeping the Poc group intact.4 The orthogonality
of the Poc group with a number of acid- and base-labile
protecting groups used commonly in carbohydrate syn-
thesis has also been reported.2 However, propargyl
carbonates/carbamates are deprotected effectively using
benzyltriethylammonium tetrathiomolybdate 2 as the
reagent2-5 (Figure 1). It has also been shown that most
of the commonly used protecting groups for amines and
alcohols, including the allyloxycarbonyl group, do not
react with 2.
One of the most convenient methods used for the
protection of amines is by forming the corresponding
carbamates.1 tert-Butyl, benzyl, and 9-fluorenylmethyl
carbamates are by far the most commonly used as Boc,
Cbz, and Fmoc, respectively. Alcohols are generally
protected as the corresponding ethers, esters, acetals, or
ketals.1 Protection of alcohols as carbonates is not
uncommon. Carbonates are relatively less stable than
carbamates, and most of them are not sufficiently stable
to a variety of conditions to meet the needs of a protecting
group. The increased stability of carbamates over carbon-
ates has not been comprehensively studied to develop a
methodology for orthogonal protection in the case of such
protecting groups.
We have earlier reported our results on the protection
of alcohols and amines as propargyl carbonates2 and
carbamates,3 respectively. The protection is achieved by
treating the alcohol or amine with propargyloxycarbonyl
chloride (PocCl, 1) in the presence of a suitable base. The
Results and Discussion
We decided to carry out a systematic study of depro-
tection of propargyl carbonates and propargyl carbamates
* To whom correspondence should be addressed. Tel: +91-80-2293
2404. Fax: +91-80-2360 0529.
(3) Sinha, S.; Ilankumaran, S.; Chandrasekaran, S. Tetrahedron
† Honorary Professor, Jawaharlal Nehru Center for Advanced
Scientific Research, Jakkur, Bangalore.
Lett. 1999, 40, 771.
(4) Bhat, R. G.; Sinha, S.; Chandrasekaran, S. Chem. Commun.
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons, Inc.: New York, 1999.
(2) Sridhar, P. R.; Chandrasekaran, S. Org. Lett. 2002, 4, 4731.
2002, 8, 812.
(5) Ramesha, A. R.; Chandrasekaran, S. Synth. Commun. 1992, 22,
3277.
10.1021/jo048777o CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/07/2005
J. Org. Chem. 2005, 70, 837-840
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Ramesh et al.
FIGURE 1. Protection of an amine or alcohol with propargyloxycarbonyl chloride, 1, and subsequent deprotection of Poc group
with benzyltriethylammonium tetrathiomolybdate, 2.
TABLE 1. Preparation of Propargyl Carbonates and
Carbamates
SCHEME 1. Comparison of the Reactivity of 2
with Propargyl Carbonates and Propargyl
Carbamates (28 °C, CH3CN)
with benzyltriethylammonium tetrathiomolybdate 2 with
a view to develop a simple protocol for orthogonal
protection. Propargyl carbonates have been shown to
react with 2 at a faster rate than propargyl carbamates,
and the difference in reactivity is marked. Generally, the
reaction times are less than an hour for propargyl
carbonates, and it varies from 6 h to 1 day for propargyl
carbamates. For example, phenyl propargyl carbonate 4a
reacts with 1 equiv of 2 to give phenol in almost
quantitative yield (20 min, rt), whereas p-toluidylpro-
pargyl carbamate 4f takes about 6 h for complete
deprotection, and interestingly, the carbamate 5 did not
react completely even after 36 h3 with 2 under the same
reaction conditions (Scheme 1).
However, the carbamates 4f and 5 cleaved readily to
give the corresponding amines 3f and 5a in very good
yields when treated with 1 equiv of 2 under ultrasoni-
cation (ultrasonic cleaning bath, 28 °C, CH3CN, 30-45
min). It is to be noted that the same results cannot be
achieved by increasing the temperature. Though the
reaction is faster at elevated temperatures, it is observed
that increasing the temperature above 60 °C results in
gradual decomposition of the reagent 2. There are reports
dealing with the deprotection of Poc group with trifluo-
roacetic acid in the presence of metal complexes such as
Co2(CO)8, but no difference in the reactivities of propargyl
carbonates and carbamates has been observed.6
2, as evident from Scheme 1, prompted us to study the
selective deblocking of propargyl carbonates in the pres-
ence of propargyl carbamates. We began our experiments
by treating 1 equiv each of phenyl propargyl carbonate
4a and p-toluidyl propargyl carbamate 4f with 1.1 equiv
of 2 in dry acetonitrile at room temperature. The reaction
was monitored by thin-layer chromatography (TLC) until
the carbonate 4a disappeared completely (25 min) to give
phenol 3a (89%) and the unreacted carbamate 4f (87%)
as shown in Scheme 2.
A few simple propargyl carbonates and carbamates
were prepared for further study by treating the corre-
sponding alcohols, or phenols, and amines with 1 (CH2-
Cl2, Et3N). The desired carbonates 4a-d and carbamates
4e-h were obtained in excellent yields (Table 1).
The selective deblocking of carbonates 4a-d in the
presence of carbamates 4e-h using 2 was studied with
different combinations of substrates. In all cases, pro-
pargyl carbonates 4a-d could be deblocked completely
(15-45 min) and propargyl carbamates 4e-h could be
recovered in high yields, as listed in Table 2. The general
observation is that the deprotection of alkyl propargyl
carbonates 4b and 4d takes longer time than aryl
propargyl carbonates 4a and 4c, when treated with 2.
The drastic difference in the reactivity of propargyl
carbonates and carbamates toward tetrathiomolybdate
SCHEME 2. Selective Reaction of 2 with Propargyl Carbonate in the Presence of Propargyl Carbamate
838 J. Org. Chem., Vol. 70, No. 3, 2005

Selective Deblocking of Propargyl Carbonates
TABLE 4. Selective Deprotection of Propargyl
Carbonates with 2
SCHEME 3. Simultaneous Protection of Amino
and Hydroxyl Groups as Corresponding
Carbamate and Carbonate
SCHEME 4. Selective Deprotection of Propargyl
Carbonate in the Presence of Propargyl
Carbamate Using 2
TABLE 2. Selective Deblocking of Propargyl
Carbonates in the Presence of Propargyl Carbamates
with 2
entry carbonate + carbamate time (min)
productsa
i
4a + 4e
4c + 4e
4a + 4h
4c + 4g
4c + 4h
4b + 4e
4b + 4f
4b + 4g
4d + 4h
4d + 4f
25
15
25
15
15
35
35
35
45
45
3a (89) + 4e (87)
3c (88) + 4e (91)
3a (89) + 4h (88)
3c (88) + 4h (90)
3c (89) + 4h (88)
3b (89) + 4e (86)
3b (89) + 4f (88)
3b (90) + 4g (92)
3d (88) + 4h (85)
3d (88) + 4f (84)
ii
iii
iv
v
vi
vii
viii
ix
x
protected amino groups, we decided to study the reaction
of 7a, with 2, where both the amino and hydroxyl groups
are protected with a Poc group. The protected derivative
7a was easily prepared (90%) by the reaction of 2-ami-
nobutanol 6a with 1 (Scheme 3).
The protected derivative 7a was then treated with 2
(1.1 equiv, 25 min, 28 °C, CH3CN) to yield 8a (85%),
where the propargyl carbonate alone was deblocked
leaving the propargyl carbamate unaffected (Scheme 4).
To ascertain the scope of this methodology a number
of amino alcohols 6b-h were converted to the corre-
sponding Poc-protected derivatives 7b-h, respectively,
in very good yields (Table 3).
a Percentage yields for the products are given in parentheses.
TABLE 3. Di-Poc Derivatives of Amino Alcohols and
Aminophenols
The selective deblocking of these di-Poc derivatives
7b-h with 2 was then studied under similar conditions
(1.1 equiv, rt, 20-30 min), and in all cases the reaction
was quite selective and efficient to produce the corre-
sponding alcohols 8b-h respectively in excellent yields.
These results are summarized in Table 4.
Conclusion
In conclusion, the utility of propargyloxycarbonyl
chloride in simultaneous protection of alcohols and
amines has been explored and the selective deblocking
of propargyl carbonates in the presence of propargyl
carbamates with benzyltriethylammonium tetrathiomo-
lybdate 2 under mild conditions has been achieved. These
results add a new dimension to selective protection
strategies by providing an efficient method for the one
pot protection of alcohol and amine functionalities with
the same reagent 1. In a later synthetic step, if the
alcohol group has to be deprotected selectively it can be
achieved with 1 equiv of 2, leaving the amino protection
intact, which can then be removed at a later step with
an additional 1 equiv of 2 under ultrasonic conditions.
However, all the propargyl carbonates are completely
deblocked in less than 45 min.
Encouraged by the success achieved in selective de-
blocking of Poc-protected hydroxyl groups over Poc-
Experimental Section
General Procedure for the Protection of Amines,
Alcohols, and Phenols with PocCl, 1. To a well-stirred
solution of phenol (10 mmol) and triethylamine (10.5 mmol)
(6) Fukase, Y.; Fukase, K.; Kusumoto, S. Tetrahedron Lett. 1999,
40, 1169.
J. Org. Chem, Vol. 70, No. 3, 2005 839

Ramesh et al.
in anhydrous dichloromethane (30 mL), at -78 °C, was added
dropwise PocCl (10 mmol). The reaction mixture was stirred
at the same temperature until completion of the reaction (as
shown by TLC). It was then washed with water and dried over
anhydrous Na2SO4. The carbonate 4a was then purified, to
get a pale yellow oil, using flash column chromatography on a
silica gel (230-400 mesh) column using 10% ethyl acetate in
hexane for elution.
(t, J ) 2.4, 1H), 2.5 (t, J ) 2.1, 1H), 1.48-1.69 (m, 2H), 0.97
(t, J ) 7.2, 3H). 13C NMR (CDCl3): δ 155.0, 154.3, 78.0, 76.7,
75.8, 74.6, 69.2, 55.3, 52.4, 51.5, 24.2, 10.1. IR (neat): 3295
(s), 2129 (w), 1747 (s), 1714 (s). ESMS: HRMS calcd for C12H15-
NO5 + Na 276.0848, found 276.0851.
Procedure for the Selective Deblocking of Propargyl
Carbonates from Di-Poc-Protected Amino Alcohols and
Aminophenols. To a stirred solution of 7a (2 mmol) in
anhydrous CH3CN (1.5 mL) at room temperature was added
tetrathiomolybdate 2 (2.2 mmol). The reaction mixture was
stirred until the disappearance of the starting material (25
min, as shown by TLC). The solvent was removed under
vacuum. The residue was extracted with a 9:1 mixture of
dichloromethane and diethyl ether three times and filtered
over a Celite pad. The compound 8a was purified, to get a
colorless oil, by flash column chromatography on a silica gel
(230-400 mesh) column using 20% ethyl acetate in hexane
for elution.
1H NMR (CDCl3): δ 7.37-7.15 (m, 5H), 4.8 (d, J ) 2.7, 2H),
2.6 (t, J ) 2.7, 1H). 13C NMR (CDCl3): δ 152.8, 150.7, 129.3,
126.0, 120.7, 76.4, 76.1, 55.6. IR (neat): 3293 (s), 3069 (w),
2130 (w), 1759 (s). ESMS: HRMS calcd for C10H8O3 + Na
199.0371, found 199.0390.
Procedure for the Selective Deblocking of Propargyl
Carbonates in the Presence of Propargyl Carbamates.
To a solution of propargyl carbonate and carbamate (2 mmol
each) in anhydrous CH3CN (2 mL) was added tetrathiomo-
lybdate 2 (2.2 mmol) at room temperature (28 °C). Reaction
was monitored using TLC. On complete disappearance of the
propargyl carbonate, stirring was stopped and the solvent was
removed under vacuum. The residue was extracted with a 9:1
mixture of dichloromethane and diethyl ether three times and
filtered over a Celite pad. The compounds were separated by
flash column chromatography on silica gel (230-400 mesh)
using a ethyl acetate/hexane solvent system.
1H NMR (CDCl3): δ 5.3 (sb, 1H), 4.6 (sb, 2H), 3.55-3.69
(m, 3H), 3.1 (sb, 1H), 2.5 (sb, 1H), 1.42-1.62 (m, 2H), 0.95 (t,
J ) 6.9, 3H). 13C NMR (CDCl3): δ 155.8, 78.1, 74.7, 64.5, 54.7,
52.5, 24.2, 10.3. IR: 3404 (s), 3297 (s), 2966 (m), 2127 (w), 1714
(s), 1697 (s). IR (neat): 3395 (br), 2131(w), 1714 (s). ESMS:
HRMS calcd for C8H13NO3 + Na 194.0793, found 194.0795.
General Procedure for the Preparation of 7a-h. To a
well-stirred solution of the 2-amino-1-butanol 6a (5 mmol) and
triethylamine (11 mmol) in anhydrous dichloromethane (20
mL) at -78 °C was added dropwise PocCl, 1 (10.5 mmol). The
reaction mixture was stirred at the same temperature until
completion of the reaction (as shown by TLC). It was then
washed with water and dried over anhydrous Na2SO4. The
diprotected compound 7a was then purified to get a pale yellow
oil, using flash column chromatography on a silica gel (230-
400 mesh) column using 20% ethyl acetate in hexane for
elution.
Acknowledgment. R.R. thanks CSIR, New Delhi,
for a research fellowship, and R.G.B thanks IISc for
financial assistance. Financial support from the Volks-
wagen Foundation, Germany, is gratefully acknowl-
edged.
Supporting Information Available: Characterization
1
data and H and 13C spectra for reference compounds 4a-h,
7a-h and 8a-h and experimental procedures including those
for the synthesis of 1 and 2. This material is available free of
charge via the Internet at http://pubs.acs.org.
1H NMR (CDCl3): δ 5.2 (db, J ) 8.4, 1H), 4.7 (d, J ) 2.4,
2H), 4.7 (sb, 2H), 4.2 (d, J ) 4.2, 2H), 3.77-3.87 (m, 1H), 2. 6
JO048777O
840 J. Org. Chem., Vol. 70, No. 3, 2005