Ti(O-i-Pr)4/Me3SiCl/Mg-mediated reductive cleavage of sulfonamides and sulfonates to amines and alcohols

Article abstract of DOI:10.1021/ol200740r

A low-valent titanium generated in situ from Ti(O-i-Pr)₄, Me₃SiCl, and Mg powder in THF reacted with aryl- and alkyl-sulfonamides of aryl and alkyl amines in a reductive N-S/S-O/S-C bond cleaving pathway to provide the corresponding amines and hydrocarbons (and thiols) derived from the sulfonyl moiety. The reagent could also cleave sulfonates to the corresponding alcohols.

Full text of DOI:10.1021/ol200740r

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2626–2629
Ti(O-i-Pr)4/Me3SiCl/Mg-Mediated
Reductive Cleavage of Sulfonamides and
Sulfonates to Amines and Alcohols
Noriaki Shohji, Tsuyoshi Kawaji, and Sentaro Okamoto*
Department of Material and Life Chemistry, Kanagawa University, 3-27-1
Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
okamos10@kanagawa-u.ac.jp
Received March 19, 2011
ABSTRACT
A low-valent titanium generated in situ from Ti(O-i-Pr)4, Me3SiCl, and Mg powder in THF reacted with aryl- and alkyl-sulfonamides of aryl and alkyl
amines in a reductive NÀS/SÀO/SÀC bond cleaving pathway to provide the corresponding amines and hydrocarbons (and thiols) derived from
the sulfonyl moiety. The reagent could also cleave sulfonates to the corresponding alcohols.
Protection/deprotection of amine functionality is of impor-
tance for synthesizing nitrogen-containing compounds invol-
ving biologically active substances. One of the most versatile
protecting groups for amines is based on formation/disconnec-
tion of sulfonamides,1 which are readily prepared, often bring
an easiness of purification, and have reasonable stability under
various reaction conditions. However, the requirement of the
robust conditions for their deprotection is a major disadvan-
tage. The traditional way is hydrolysis with strong acids such as
HBr or HClO4. Reductive cleavage through a single-electron
transfer (SET) process from alkali metals is commonly used.
However, these suffer from harsh reaction conditions, which
often affect other functional groups present in the substrate.
The methods reported to mediate p-toluenesulfonamide (Ts-
amide) cleavage under milder conditions are as follows:
electrolysis,2 Ni(acac)2/i-PrMgCl,3 n-Bu3SnH/AIBN,4 TiCl4/
Zn,4a TiCl3/Li,5a mischmetal/TiCl4,5b Mg/MeOH,6 Mg/
Me3CoLi,7 alkali metals on silica,8 TMSI,9 SmI2,10
photolysis,11 TBAF,12 and phase-transfer catalyst.13 How-
ever, many of these methods are not necessarily general
€
(5) (a) Nayak, S. K. Synthesis 2000, 1575. (b) Vellemae, E.; Lebedev,
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r
10.1021/ol200740r
Published on Web 04/21/2011
2011 American Chemical Society

and/or require toxic, expensive reagents and special
equipment.
Table 1. Reductive Cleavage of Various Sulfonamides Mediated
by Ti(O-i-Pr)4/Me3SiCl/Mga
Recently, we have developed a new protocol for deal-
lylation and depropargylation of allyl and propargyl ethers
to the parent alcohols by employing a low-valent titanium
(LVT)14 derived in situ from Ti(O-i-Pr)4, Me3SiCl, and Mg
powder in THF.15 The reaction proceeded with a stoichio-
metric or catalytic amount of the LVT reagent at room
temperature. We now found that a Ti(O-i-Pr)4/Me3SiCl/
Mg reagent reacts with sulfonamides 1 to produce the
corresponding amines 2 in good to excellent yields, where
the sulfonyl moiety was reduced to hydrocarbons and/
or thiols (Scheme 1). The reagent also cleaved sulfonates
3 to 4.
Scheme 1. Low-Valent Titanium-Mediated Cleavage of Sulfon-
amides and Sulfonates
The results of the reaction of amides 1 with various
substituents on the nitrogen as well as on the sulfur atom
are summarized in Table 1. As revealed from runs 1À8,
sufonamides of dialkylamine (dibenzylamine) with a vari-
ety of sulfur substituents (R3) reacted with a Ti(O-i-Pr)4/
Me3SiCl/Mg (1/1.5/5) reagent to provide dibenzylamine in
good to excellent yields: Amides with a bulky substituent
were cleaved efficiently (run 3À5). It was noteworthy that
the method could cleave aliphatic sulfonamides as shown
in runs7, 8 and 12, albeit insomewhat low yield due toslow
reaction rate. In addition to sulfonamides of aliphatic
secondary amines, those of aromatic secondary and pri-
mary amines (aniline derivatives, run 9 and 10) as well as
aliphatic primary amines (run 11) were good substrates.
Thus, the method could cleave a variety of sulfonamides
reductively to amines, although the results ofrun 13show a
limitation of the method that aliphatic sulfonamides of
aliphatic primary amines could not react.
a A mixture of 1 (1.0 mmol), Ti(O-i-Pr)4 (1.0 mmol), Me3SiCl (1.5
mmol), and Mg powder (5.0 mmol) in THF (5 mL) was stirred at 50 °C.
b Reaction time. c Unless otherwise indicated, 1H NMR yield was
determined using an internal standard. d Isolated yield. e 34% of 1g
remained. f 13% of 1h remained. g 45% of 1l remained.
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The reaction of non- and monosubstituted benzenesulfon-
amides (runs 1, 2 and 6) gave a mixture of the correspond-
ing thiols and hydrocarbons as co-products. Meanwhile,
interestingly, trisubstituted phenyl and naphthalene-1-sul-
fonamide derivatives were reduced to nearly completely
produce the corresponding trisubstituted benzenes or
naphthalene (runs 3À5). As illustrated in Scheme 2, after
aqueous workup of the reaction mixture derived from 1d
Bogdanovic, B. Angew. Chem., Int. Ed. 1996, 35, 2442. Ephritikhine, M.
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Org. Lett., Vol. 13, No. 10, 2011
2627

and 1n, 1,3,5-triisopropylbenzene and 1-dimethylamino-
naphthalene were respectively obtained quantitatively.
Thus, with choosing an appropriate sulfonyl group and
reaction conditions, the method can provide a non- (or
less-)smelling deprotection procedure suitable for large-
scale manufacturing in certain cases. It was found that
aliphatic sulfonamides such as 1h (run 8) gave the corre-
sponding thiol (35%) and n-hexadecane (8%), the latter of
which might form through coupling of n-octyl radical
intermediates.
Table 2. Reaction of Sulfonamides 1 of Cyclic and Functiona-
lized Aminesa
Scheme 2. Reaction of Aromatic Sulfonamides with Ti(O-i-Pr)4/
Me3SiCl/Mg
Table 2 shows the representative results of the reaction
of tosylamides derived from cyclic and functionalized
amines. The amides of anilines with an electron-donating
and -withdrawing group were good substrates (runs 1À3).
The NÀS bond in sulfonamides of indole and hydroquino-
line was readily cleaved (runs 4À7). Functional groups
such as benzyl ether (run 1), aromatic chloride (run 2),
ketal (run 3), and silyl ether (run 8) were tolerated under
the conditions. It is noteworthy that the reaction condi-
tions retained benzyl ethers of aliphatic and aromatic
alcohols, which may be disconnected under the conditions
by SET from alkali metals (Birch conditions). As well as
tosylamides, mesitylamides (runs 5 and 7) could smoothly
be deprotected.
As shown in Scheme 3, a Ti(O-i-Pr)4/Me3SiCl/Mg re-
agent could also cleave the OÀS bond of sulfonates.
p-Toluene sulfonate of 2-naphthol (3a) reacted with the
reagent at 50 °C for 12 h to provide 2-naphthol in good
yield. The reaction of methanesulfonate derivative 3b also
provided 2-naphthol, albeit in low yield due to the slow
reaction rate. Phenol tosylates 3c and 3d smoothly reacted
to furnish the corresponding phenols without any damage
of their functional groups. Meanwhile, the reaction of
tosylate of 1-octanol (3e) with Ti(O-i-Pr)4/Me3SiCl/Mg
(1/1.5/5) yielded desired 1-octanol (4e) and p-tolyl n-octyl
sulfide (7e) in a ratio of 71:27. The results can be explained
by assuming that the thiolate anion, p-Tol-SÀ, generated in
situ, reacts competitively with remaining 3e. To avoid this,
excess amount of Me3SiCl (4 equiv) was used, expect-
ingthe formationof non-nucleophilc silyl etherofthe thiol,
p-Tol-S-SiMe3. Thus, the reaction gave quantitatively
a A mixture of 1 (1.0 mmol), Ti(O-i-Pr)4 (1.0 mmol), Me3SiCl (1.5
mmol), and Mg powder (5.0 mmol) in THF (5 mL) was stirred at 50 °C
for 12 h. b Isolated yield. c NMR yield.
1-octanol but not the sulfide. Meanwhile, the reaction of
1-naphthalene sulfonate of primary alcohol (3f) produced
naphthalene nearly quantitatively, where CÀS cleavage
occurred faster than thiolate formation. This may also
provide a method for desulfonation of aromatic sulfonic
acid derivatives.
The reported LVT reagents utilized for deprotection of
sulfonamides have been prepared prior to the reaction by
reduction of TiCl4 or TiCl3 with Zn,4a Li,5a or mischmetal5b
in THF under refluxing conditions, which are heteroge-
neous colloidal slurries of activated titanium. The cleavage
of sulfonamides needed an excess amount (3À4 equiv) of
these reagents. Meanwhile, the present method could be
performed simply by mixing the substrate and the reagent
comprising 1 equiv of Ti(O-i-Pr)4 in THF at 50 °C, the
mixture of which remains homogeneous, except for Mg
powder, to all appearances. It can be postulated that a
LVT(s) could be generated from Ti(O-i-Pr)4/Me3SiCl/Mg
2628
Org. Lett., Vol. 13, No. 10, 2011

may be repeated with the gradual generation of
Ti(III) and lower-valent titanium species (Scheme 4).
These processes might enable a facile generation of
LVT(s) and an operationally simple procedure. The
fact that the reaction did not proceed in the absence
Scheme 3. Reaction of Sulfonates with Ti(O-i-Pr)4/Me3SiCl/Mg
of Me3SiCl may suggest that the generation of ClnTiIV
-
(O-i-Pr)4Àn might be essential to reduction of the titanium
by Mg.16
Scheme 4. Generation of LVTs
In conclusion, we have developed a mild protocol for
deprotection of sulfonamide to amines, which was mediated
by a low-valent titanium reagent, Ti(O-i-Pr)4/Me3SiCl/Mg,
in THF at 50 °C. The method can be used for NÀS cleavage
of a wide range of aromatic and aliphatic sulfonamides with
a reasonable functional compatibility. Choice of the appro-
priate sulfonyl groups and reaction conditions enables a
non- (or less-)smelling deprotection procedure, which may
be useful for a large-scale production in certain cases, by
co-producing the corresponding hydrocarbon material in-
stead of a thiol. The reagent could also cleave sulfonates to
the corresponding alcohols.
Acknowledgment. This work was supported by a Grants-
in-Aid for Scientific Research (22550103) from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT).
Supporting Information Available. Detailed experimen-
tal section including experimental procedures and spec-
troscopic data of compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
through the following reaction pathway: (i) titanium iso-
propoxide reacts with silyl chloride to afford a titanium
chloride compound(s) and i-PrOSiMe3, (ii) the resulting
titanium chloride(s) can be reduced by the reaction with Mg
to generate a lower-valent species, (iii) these processes
€
(16) Furstner, A.; Bogdanovic, B. Angew. Chem., Int. Ed. Engl. 1996,
35, 2443. Ladipo, F. T. Current Org. Chem. 2006, 10, 965.
Org. Lett., Vol. 13, No. 10, 2011
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