A facile route to the deprotection of sulfonate esters and sulfonamides with low valent titanium reagents

Article abstract of DOI:10.1055/s-2000-7614

A novel method for the cleavage of N/O-tosyl bonds by low-valent titanium is reported. TBDPS ether, THP ether, and olefin are found to be compatible under the reaction conditions.

Full text of DOI:10.1055/s-2000-7614

PAPER
1575
A Facile Route to the Deprotection of Sulfonate Esters and Sulfonamides with
Low Valent Titanium Reagents
Sandip K. Nayak*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Fax +91 22 5505151; E-mail: sknayak@magnum.barc.ernet.in
Received 1 March 2000; revised 8 June 2000
Abstract: A novel method for the cleavage of N/O-tosyl bonds by
low-valent titanium is reported. TBDPS ether, THP ether, and ole-
fin are found to be compatible under the reaction conditions.
Key words: p-toluenesulfonate ester, p-toluenesulfonamide, depro-
tection, low-valent titanium, TBDPS ether, THP ether
Development of mild and selective methods for protection
of functional groups and deprotection of protected deriv-
atives continue to be significant aspects in the synthesis of
polyfunctional molecules. Alcohols and amines are often
protected by p-toluenesulfonyl (Ts) group due to the crys-
talline nature of these derivatives. However, methods for
their deprotection usually suffer from poorer yields or
harsh reaction conditions.1 Therefore, there has been con-
siderable interest in the development of facile methods for
the deprotection of tosylate esters and tosylamides. Con-
sequently, some useful reagents such as TMsCl/NaI,2
SmI2,3 TBAF,4 etc. have been developed for this purpose
in recent years. This paper reports a new protocol for the
facile deprotection of tosylate esters and tosylamides us-
ing low-valent titanium reagents (Scheme) at ambient
temperature.
Reductive deoxygenation of carbonyl compounds to ole-
fins under the influence of low-valent titanium (LVT) re-
agents, commonly referred to as “McMurry reaction”, has
been tremendously exploited by synthetic chemists since
its debut in the early 1970s.5 In our continuing exploration
of the synthetic utility of LVT reagents, we have discov-
Scheme
ered that these reagents are also equally efficient in the
deprotection of benzyl/allyl/propargyl ethers and amines6
(by SET mechanism). As an extension of this work, it was
this in view, other LVT reagents were used to improve the
of interest to investigate the effect of LVT reagents on
yield of the above reaction. It was observed that with LVT
other SET mediated reactions.
reagent (prepared from TiCl3-Li-THF), 1a underwent
Since the cleavage of O-tosyl and N-tosyl bonds by Na/
complete deprotection to yield 1b in good yield (76%) un-
liquid ammonia is reported,7 these bonds, in principle,
der refluxing conditions (Table, entry 2). Moreover, a
comparable yield (75%) of 1b was also achieved when the
reaction was carried out at ambient temperature (Table,
entry 3). These results are in contrast to the reported com-
should be cleaved by LVT reagents which are rich source
of electrons. Thus, a model reaction was carried out with
4-methyl-(4-methylphenylsulfonyloxy)benzene (1a) and
LVT reagent (prepared from TiCl3-Mg-THF) under re-
patibility of tosylate esters with LVT reagents.9 Based on
fluxing conditions (18 hours) when a mixture of the
the above result, subsequent studies were carried out with
LVT reagent generated from TiCl3-Li-THF.
deprotected product 1b (32%) along with the starting ma-
terial 1a (48%) was isolated (Table, entry 1). The result
To explore the synthetic scope of this LVT reagent,
was encouraging albeit the yield of the reaction was mod-
various other substrates were used. Thus, 4-chloro-(4-
methylphenylsulfonyloxy)benzene (2a), 2,3,5-trimethyl-
(4-methylphenylsulfonyloxy)benzene (3a) and 2-(4-
est. Earlier, we have observed that the activity of LVT re-
agents largely depends on their method of preparation
(reducing metal, solvent, external ligands, etc.).8 Keeping
Synthesis 2000, No. 11, 1575–1578 ISSN 0039-7881 © Thieme Stuttgart · New York

1576
S. K. Nayak
PAPER
Table Deprotection of Tosylate Esters and Tosylamides with Low-
Valent Titanium Reagent
In conclusion, a facile route to the hitherto unknown
cleavage of O-tosyl and N-tosyl bonds of tosylate esters
and tosylamides with LVT reagent at ambient temperature
has been demonstrated. Selective deprotection of tosyl
group in the presence of THP ether, TBDPS ether, and
olefin was also observed. Thus, the present method further
enhances the utility of LVT reagents in organic synthesis.
Entry Substrate Reagent (Conditions)
Product
(% Yield)a
1
2
1a
1a
TiCl3-Mg-THF (reflux, 18 h)
TiCl3-Li-THF (reflux, 18 h)
TiCl3-Li-THF (25°C, 18 h)
TiCl3-Li-THF (25°C, 18 h)
TiCl3-Li-THF (25°C, 18 h)
TiCl3-Li-THF (25°C, 18 h)
TiCl3-Li-THF (25°C, 18 h)
TiCl3-Li-THF (25°C, 18 h)
TiCl3-Li-THF (25°C, 18 h)
TiCl3-Li-THF (25°C, 18 h)
TiCl3-Li-THF (25°C, 18 h)
TiCl3-Li-THF (25°C, 18 h)
TiCl3-Li-THF (25°C, 18 h)
1b (32)b
1b (76)
1b (75)
2b (83)
3b (91)
4b (61)
5b (67)
6b (72)
7b (78)
8b (43)
10b (73)
11b (76)
12b (68 )
3
1a
FT-IR spectra were obtained on a Nicolet spectrophotometer (mod-
el 410).1H NMR were recorded on a Bruker AC 300 (300 MHz) or
Varian EM 360 (60 MHz) spectrometer with TMS as internal stan-
dard. Microanalyses were performed with a Carlo Erba elemental
analyser (model 1110). All reactions were carried out under Ar atm.
TiCl3 was obtained from Aldrich Chemical Co. U.S.A. THF was
distilled freshly from Na-benzophenone ketyl prior to use. The to-
sylate esters and tosylamides were prepared according to the litera-
ture procedure.12
4
2a
5
3a
6
4a
7
5a
8
6a
9
7a
Sulfonate Esters and Sulfonamides; Typical Procedure
A solution of 4-methylphenol (1b) (1.08 g, 10 mmol) in CHCl3 (10
mL) was cooled in an ice bath, dry pyridine (1.6 mL, 20 mmol) was
added, followed by the addition of p-toluenesulfonylchloride (2.29
g, 12 mmol) in small portions. The reaction mixture was stirred at
ice temperature and completed after 3 h (monitored by TLC). Ether
(30 mL) and H2O (10 mL) were added, the organic layer was
washed successively with 2 N HCl (5 mL), 5% NaHCO3 (5 mL),
H2O, brine, and dried (Na2SO4). The solvent was removed under re-
duced pressure and the crude tosylate was crystallised from MeOH
to yield 1a.
10
11
12
13
8a
10a
11a
12a
a Isolated yield.
b 48% of 1a was recovered.
4-Methyl-(4-methylphenylsulfonyloxy)benzene (1a)
Colourless solid; yield: 2.3 g, 88%.
Mp: 67-68°C (Lit.13 mp: 68-69°C).
IR (KBr): v = 1376, 1175 cm-1.
1H NMR (60 MHz, CCl4): d = 2.37 (s, 3H), 2.50 (s, 3H), 6.73-7.80
(m, 8H)
methylphenylsulfonyloxy)naphthalene (4a) underwent
smooth deprotection in good to high yields (Table, entries
4-6) with LVT reagent. Similarly, aliphatic tosylate ester
such as 1-(4-methylphenylsulfonyloxy)hexadecane (5a)
underwent facile deprotection to 5b in good yield (Table,
entry 7).
4-Chloro-(4-methylphenylsulfonyloxy)benzene (2a)
Yield: 85%.
Mp: 71°C (Lit.13 mp: 73°C).
IR (KBr): v = 1399, 1173 cm-1.
Influence of LVT on sulfonamides was also investigated.
Thus, N,N-diphenyl-4-methylbenzenesulfonamide (6a)
and
N-methyl-N-phenyl-4-methylbenzenesulfonamide
(7a) could be easily deprotected with LVT to give the
amines 6b and 7b, respectively, in good yields (Table, en-
tries 8 and 9). Similarly, aliphatic sulfonamide N-decyl-4-
methylbenzenesulfonamide (8a) was deprotected to n-de-
cylamine (8b) in modest yield (entry 10).
1H NMR (60 MHz, CCl4): d = 2.47 (s, 3H), 6.73-7.63 (m, 8H).
2,3,5-Trimethyl-(4-methylphenylsulfonyloxy)benzene (3a)
Yield: 85%.
Mp: 81°C.
IR (KBr): v = 1364, 1190 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.92 (s, 3H), 2.17 (s, 3H), 2.21 (s,
3H), 2.45 (s, 3H), 6.67 (s, 1H), 6.86 (s, 1H), 7.31 (d, 2H, J = 8 Hz),
7.74 (d, 2H, J = 8.2 Hz).
Selectivity in the deprotection of tosyl group in the pres-
ence of other functional groups was also investigated.
Thus, 1-(4-methylphenylsulfonyloxy)-8-(2-tetrahydropy-
ranyloxy)octane (10a) and 1-((1,1-dimethylethyl)diphe-
nylsilyloxy)-8-(4-methylphenylsulfonyloxy)octane (11a)
underwent facile deprotection to 8-(2-tetrahydropyranyl-
oxy)octan-1-ol (10b)10 and 8-((1,1-dimethylethyl)diphe-
nylsilyloxy)octan-1-ol (11b),11 respectively, in good
yields (entries 11 and 12). The p-toluenesulfonate ester of
oleyl alcohol (12a) was deprotected to oleyl alcohol (12b)
in good yield (entry 13). The above experiments clearly
indicate the compatibility of THP ether, TBDPS ether,
and olefin functionalities during the cleavage of O-Ts
bonds with LVT reagent.
Anal. Calcd for C16H18O3S: C, 66.2; H, 6.24; S, 11.03. Found: C,
66.5; H, 6.22; S, 10.96.
2-(4-Methylphenylsulfonyloxy)naphthalene (4a)
Yield: 82%.
Mp: 126°C (Lit.13 mp: 125°C).
IR (KBr): v = 1377, 1175 cm-1.
1H NMR (60 MHz, CCl4): d = 2.40 (s, 3H), 6.90-7.77 (m, 11H).
Synthesis 2000, No. 11, 1575–1578 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Facile Route to the Deprotection of Sulfonate Esters
1577
1-(4-Methylphenylsulfonyloxy)hexadecane14 (5a)
Yield: 78%.
1-((1,1-Dimethylethyl)diphenylsilyloxy)-8-(4-methylphenylsul-
fonyloxy)octane (11a)
To a solution of 9 (0.9 g, 3 mmol) in dry DMF (1 mL), TBDPSCl
(0.86 mL, 3.3 mmol) and imidazole (409 mg, 6 mmol) were added
and the mixture was stirred at 25 °C. After 30 min (monitored by
TLC), the solution was diluted with Et2O (20 mL), quenched with
sat. NaHCO3 (2 mL), and extracted with Et2O (2 ¥ 10 mL). The or-
ganic layer was dried and concentrated under reduced pressure to
give a thick oil, which on purification by column chromatography
(silica gel, hexane/EtOAc, 6:1) yielded 11a as a colourless oil, yield
93%.
Mp: 42°C.
IR (KBr): v = 1359, 1173 cm-1.
1H NMR (60 MHz, CCl4): d = 0.9 (br t, 3H, J = 6.5 Hz), 1.20 (s,
28H), 2.37 (s, 3H), 3.83 (t, 2H, J = 6 Hz), 7.13 (d, 2H, J = 8 Hz),
7.57 (d, 2H, J = 8 Hz).
N-(4-Methylphenylsulfonyloxy)diphenylamine (6a)
Yield: 68%.
Mp: 142°C (Lit.13 mp: 141°C).
IR (KBr): v = 1357, 1165 cm-1.
IR (film): v = 1361, 1177 cm-1.
1H NMR (CDCl3): d = 1.05 (s, 9H), 1.21-1.65 (m, 12H), 2.44 (s,
3H), 3.64 (t, 2H, J = 6.5 Hz), 4.00 (t, 2H, J = 6.5 Hz), 7.32-7.45 (m,
7H), 7.65-7.81 (m, 7H).
1H NMR (60 MHz, CCl4): d = 2.33 (s, 3H), 6.97-7.87 (m, 14H).
N-Methyl-N-(4-methylphenylsulfonyloxy)aniline (7a)
Yield: 73%.
Mp: 93°C (Lit.13 mp: 94°C).
IR (KBr): v = 1345, 1191 cm-1.
1H NMR (60 MHz, CCl4): d = 2.30 (s, 3H), 3.0 (s, 3H), 6.77-7.37
(m, 9H).
Deprotection of Sulfonate Esters and Sulfonamides; Typical
Procedure
A mixture of TiCl3 (1.23 g, 8 mmol) and Li (196 mg, 28 mmol) in
dry THF (30 mL) was refluxed (80 °C, 3 h) under Ar. The LVT re-
agent thus prepared16 was cooled to ambient temperature (25 °C)
and a solution of 4-methyl-(4-methylphenylsulfonyloxy)benzene
(1a, 524 mg, 2 mmol) in THF (5 mL) was added, and the solution
was stirred at 25 °C for 18 h. After completion of the reaction
(TLC), the reaction mixture was diluted with Et2O (10 mL),
quenched with aqueous 10% K2CO3 (1 mL) and stirred (5 min). The
black mixture was passed through Celite, washed with Et2O (2 ¥ 10
mL), and the collected extract was dried (Na2SO4). The solvent was
evaporated in vacuo and the crude product was purified by prepar-
ative TLC (silica gel; hexane/EtOAc = 19:1) to yield pure 4-meth-
ylphenol (1b, 162 mg, 75%).
N-(4-Methylphenylsulfonyloxy)decylamine (8a)
Yield: 80%.
Mp: 61°C (Lit.15 mp: 62-63°C).
IR (KBr): v = 1327, 1161 cm-1.
1H NMR (300 MHz, CDCl3): d = 0.87 (t, 3H, J = 6.2 Hz), 1.20 (br
s, 14H), 1.41-1.43 (m, 2H), 2.42 (s, 3H), 2.92 (q, 2H, J = 5.6 Hz),
4.35 (br s, 1H), 7.3 (d, 2H, J = 8.0 Hz), 7.74 (d, 2H, J = 7.9 Hz).
8-(2-Tetrahydropyranyloxy)octan-1-ol10 (10b)
Yield: 73%.
8-(4-Methylphenylsulfonyloxy)-1-octanol (9)
IR (film): v = 3397 cm-1.
1H NMR (CDCl3): d = 1.33 (br s, 8H), 1.52-1.82 (m, 10H), 3.34-
3.87 (m, 6H), 4.57 (t, 1H, J = 2.7 Hz).
Colourless oil, yield: 70%.
IR (film): v = 3383, 1358, 1176 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.26 (br s, 8H), 1.50-1.64 (m,
4H), 2.44 (s, 3H), 3.61 (t, 2H, J = 6.5 Hz), 4.0 (t, 2H, J = 6.5 Hz),
7.33 (d, 2H, J = 8.0 Hz), 7.78 (d, 2H, J = 7.8 Hz).
8-((1,1-Dimethylethyl)diphenylsilyloxy)octan-1-ol11 (11b)
Yield: 76%.
IR (film): v = 3353, 1111, 702 cm-1.
1-(4-Methylphenylsulfonyloxy)-(9Z)-octadecene (12a)
Colourless oil, yield 81%.
IR (film): v = 1364, 1177 cm-1.
1H NMR (300 MHz, CDCl3): d = 0.86 (br t, 3H), 1.25 (br s, 22H),
1.56-1.63 (m, 2H), 1.99 (br s, 4H), 2.45 (s, 3H), 4.01 (t, 2H, J = 6.5
Hz), 5.34 (br s, 2H), 7.34 (d, 2H, J = 8.0 Hz), 7.79 (d, 2H, J = 8.2
Hz).
1H NMR (CDCl3): d = 1.04 (s, 9H), 1.25-1.38 (m, 8H), 1.53-1.58
(m, 4H), 3.63–3.67 (m, 4H), 7.37-7.42 (m, 6H), 7.65-7.68 (m,
4H).
References
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991.
(2) Sabitha, G.; Subba Reddy, B. V.; Abraham, S.; Yadav, J. S.
Tetrahedron Lett. 1999, 40, 1569.
(3) Knowles, H.; Parsons, A. F.; Pettifer, R. M. Synlett 1997, 271.
(4) Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595.
(5) McMurry, J. E. Chem. Rev. 1989, 89, 1513.
Fürstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468.
Fürstner, A.; Ernst, A. Tetrahedron 1995, 51, 773.
Fürstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem. 1995,
60, 6637.
1-(4-Methylphenylsulfonyloxy)-8-(2-tetrahydropyranyloxy)oc-
tane (10a)
To a solution of 9 (0.9 g, 3 mmol) and PPTS (76 mg, 0.3 mmol) in
dry CH2Cl2 (10 mL), 3,4-dihydro-2-H-pyran (0.3 mL, 3.3 mmol)
was added at r.t. After 30 min (monitored by TLC), the solution was
diluted with Et2O (20 mL), and washed with 50% sat. brine (to re-
move PPTS). The solvent was dried and evaporated to give a crude
oil, which on purification by column chromatography (silica gel,
hexane/EtOAc, 7:1) yielded 10a as a colourless oil, yield 91%.
IR (film): v = 1361, 1199 cm-1.
(6) Kadam, S. M.; Nayak, S. K.; Banerji, A. Tetrahedron Lett.
1992, 33, 5129.
1H NMR (CDCl3): d = 1.25 (br s, 8H), 1.53-1.83 (m, 10H), 2.45 (s,
3H), 3.34-4.03 (m, 6H), 4.56 (br s, 1H), 7.33 (d, 2H, J = 7.4 Hz),
7.78 (d, 2H, J = 6.5 Hz).
Nayak, S. K.; Kadam, S. M.; Banerji, A. Synlett 1993, 581.
Talukdar, S.; Banerji, A. Synth. Commun. 1996, 26, 1051.
Rele, S.; Talukdar, S.; Banerji, A. Tetrahedron Lett. 1999, 40,
767.
Synthesis 2000, No. 11, 1575–1578 ISSN 0039-7881 © Thieme Stuttgart · New York

1578
S. K. Nayak
PAPER
(7) Roemmele, R. C.; Rapaport, H. J. Org. Chem. 1988, 53, 2367;
and references cited therein.
(8) Balu, N.; Nayak, S. K.; Banerji, A. J. Am. Chem. Soc. 1996,
118, 5932.
Banerji, A.; Nayak, S. K. J. Chem. Soc., Chem. Commun.
1991, 1432.
(9) Castedo, L.; Saa, J. M.; Suau, R.; Tojo, G. J. Org. Chem. 1981,
46, 4292.
(10) Nishiguchi, T.; Kawamine, K.; Ohtsuka, T. J. Chem. Soc.,
Perkin Trans. I 1992, 153.
(11) Chandra, P.; Saleh, S.; Blair, I. A. Tetrahedron Lett. 1989, 30,
19.
(12) Fieser, L. F.; Fieser, M. Reagent for Organic Synthesis, Vol.
1; Wiley: New York, 1967; pp 1179-1184.
March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New
York, 1992, pp 352-354.
(15) Hutchins, R. O.; Kandasamy, D.; Dux, F.; Maryanoff, C. A.;
Rotstein, D.; Goldsmith. B.; Burgoyne, W.; Cistone, F.;
Dalissandro, J.; Puglis, J. J. Org. Chem. 1978, 43, 2259.
(16) LVT reagent was generated from the reduction of TiCl3 with
3.5 equiv of Li in THF (Rieke’s method). TiCl3:substrate was
kept at 4:1 in all the cases. Use of less than 4 equiv of TiCl3
with respect to the substrate led to the isolation of unreacted
starting material. This could be attributed to the consumption
of LVT for further reduction of p-toluenesulfonyl group
(formed during the cleavage) to the corresponding sulfide.
After stirring the reaction mixture at 25 °C for 4 h, TLC
showed about 40-50% consumption of the starting materials.
No significant improvement in the reaction kinetics was
observed by carrying out the reactions at reflux temperature.
Therefore, in all cases, the reaction mixture was stirred
overnight (18 h) at 25 °C for completion.
(13) Rappoport, Z. Handbook of Tables for Organic Compound
Identification, 3rd ed.; The Chemical Rubber Co.: Ohio, 1967.
(14) Beak, P.; Covington, J. B.; Smith, S. G.; White. J. M.; Zeigler,
J. M. J. Org. Chem. 1980, 45, 1354.
Article Identifier:
1437-210X,E;2000,0,11,1575,1578,ftx,en;Z01300SS.pdf
Synthesis 2000, No. 11, 1575–1578 ISSN 0039-7881 © Thieme Stuttgart · New York