Instantaneous deprotection of tosylamides and esters with Sml 2/amine/water

Article abstract of DOI:10.1021/ol802243d

(Chemical Equation Presented) Sml₂/amine/water mediates instantaneous cleavage of tosyl amides and tosyl esters. Highly hindered, sensitive and functionalized substrates were successfully deprotected in near quantitative yield.

Full text of DOI:10.1021/ol802243d

ORGANIC
LETTERS
2009
Vol. 11, No. 3
503-506
Instantaneous Deprotection of
Tosylamides and Esters with SmI2/
Amine/Water
Tobias Ankner and Go¨ran Hilmersson*
Department of Chemistry, UniVersity of Gothenburg, KemiVa¨gen 10, SE-412 96
Go¨teborg, Sweden
hilmers@chem.gu.se
Received September 26, 2008
ABSTRACT
SmI2/amine/water mediates instantaneous cleavage of tosyl amides and tosyl esters. Highly hindered, sensitive and functionalized substrates
were successfully deprotected in near quantitative yield.
Protection and subsequent deprotection of amines and
alcohols is a routine procedure employed in almost any
multistep synthesis and one of the most versatile protecting
groups for amines and alcohols are based on sulfonamide/
ester formation (-Ts). The sulfone amides and sulfone esters
display desirable properties such as stability under a range
of reaction conditions and ease of purification. However, the
robustness, especially for the tosyl amides derived from
alkylamines, can be a major disadvantage since it can be
notoriously difficult to efficiently deprotect the amines. The
traditional deprotection protocols involve the use of lithium
or sodium as one-electron donors in combination with various
electron carriers. There are also several known methods that
are based on acid hydrolysis of the ester or amide bond with
strong acids like HBr or HClO4. However, both methods of
deprotection suffer from the harsh reaction conditions which
likely affects other sensitive functional groups present in the
protected compound.1
Mg/Me3CoLi,7 and Na/K metal on silica.8 Deprotection of
tosyl amides employing SmI2/HMPA or SmI2/DMPU in
refluxing THF have also been reported,9 and there are
examples of deprotections of N-acyl N-tosyl amides using
SmI2 or SmI2 in combination with aliphatic alcohols.10 Thus,
the primary literature contains a large number of methods
indicating the importance of facile deprotection protocols.
(2) (a) Maia, H. L. S.; Medeiros, M. J.; Montenegro, M. I.; Court, D.;
Pletcher, D. J. Electroanal. Chem. 1984, 164, 347. (b) Civitello, E. R.;
Rapoport, H. J. Org. Chem. 1992, 57, 834. (c) Coeffard, V.; Thobie-Gautier,
C.; Beaudet, I.; Le Grognec, E.; Quintard, J. P. Eur. J. Org. Chem. 2008,
383.
(3) Millburn, R. R.; Snieckus, V. Angew. Chem., Int. Ed. 2004, 43, 892.
(4) Knowles, H. S.; Parsons, A. F.; Pettifer, R. M.; Rickling, S.
Tetrahedron 2000, 56, 979.
(5) Vellema¨e, E.; Lebedev, O.; Ma¨eorg, U. Tetrahedron Lett. 2008, 49,
1373.
(6) (a) Nyasse, B.; Ragnarsson, U. Chem. Commun. 1997, 1017. (b)
Sridhar, M.; Kumar, B. A.; Narender, R. Tetrahedron Lett. 1998, 39, 2847.
(7) Uchiyama, M.; Matsumoto, Y.; Nakamura, S.; Ohwada, T.; Koba-
yashi, N.; Yamashita, N.; Matsumiya, A.; Sakamoto, T. J. Am. Chem. Soc.
2004, 126, 8755.
(8) Lefenfeld, M.; Dye, J. L.; Nandi, P.; Jackson, J. PCT Intl. Appl.
2007, WO 2007095276.
Hence, there has been much interest in the development
of alternative methods where milder and possibly more
selective reagents are employed. Among those methods
reported to mediate tosyl cleavage are: electrolysis,2 Ni(0)acac/
iPrMgCl,3 Bu3SnH/AIBN,4 Mischmetal/TiCl4,5 Mg/MeOH,6
(9) (a) Vedejs, E.; Lin, S. J. Org. Chem. 1994, 59, 1602. (b) Alonso,
D. A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455. (c) Fujihara, H.;
Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055. (d) Hayashi,
T.; Kawai, M.; Tokunaga, N. Angew. Chem., Int. Ed. 2004, 43, 6125. (e)
Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.; Tomioka, K. J. Am. Chem.
Soc. 2004, 126, 8128. (f) Grach, G.; Santos, J. S. O.; Lohier, J.; Mojovic,
L.; Ple´, N.; Turck, A.; Reboul, V.; Metzner, P. J. Org. Chem. 2006, 71,
9572–9579. (g) Duan, H.; Jia, Y.; Wang, L.; Zhou, Q. Org. Lett. 2006, 8,
2567.
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe groups in organic
synthesis, 4th ed; John Wiley & Sons: New York, 2007.
10.1021/ol802243d CCC: $40.75
Published on Web 01/05/2009
 2009 American Chemical Society

Even so, many of these methods are nongeneral, are
irreproducible, or require special equipment.
of the initial S-N bond cleavage are reduced more rapidly
than the tosyl amide itself. Hence the reaction requires a large
excess of SmI2 for completion. In the reaction mixture after
complete deprotection of the tosyl amide we observed
4-methylbenzenethiol and the corresponding disulfide.12
Recently we have found that the combination of the mild
reducing agent SmI2, an aliphatic amine (typically pyrroli-
dine, triethylamine or isopropyl amine) and water is a very
powerful reductant that shares properties with the Birch
reagent and might therefore serve as an alternative for
deprotection of the tosyl group.11 Herein we wish to
communicate our findings that a mixture of SmI2/amine and
water in THF instantaneously deprotects aryl sulfonate esters
and amides in unprecedented high yields.
At first we optimized the reaction conditions for the SmI2/
R3N/H2O mediated cleavage of the tosyl group from simple
amines and alcohols. For this we studied two tosylated
amines and a tosylated alcohol, which upon deprotection give
fairly nonvolatile compounds, with a minimum risk of
mechanical loss during work up (Table 1). Increasing
The reductive cleavage of the tosyl group occurs instan-
taneously at room temperature, within seconds the amide or
ester is consumed according to GC analysis, and the reaction
appears to be quantitative. The reaction does not seem to
suffer from steric hindrance (dicyclohexyl amine) and in
addition the deprotection works equally well for both primary
and secondary tosyl amides (Table 1, entries 1-6). Analo-
gous result was obtained for the tosyl protected alcohol
(Table 1, entries 7-9).
We observed no difference in reactivity between aromatic,
benzylic or aliphatic amines and found that these model
substrates responded equally well to the reagent furnishing
the free amines after workup (Table 2, entries 1-3).
Although SmI2/R3N/H2O is known to be a powerful reductant
that reacts with most functional groups, in practice only
carbonyl and related groups (e.g., ketone, aldehyde, nitriles
and nitro groups) undergo instantaneous reduction.11a,b,e,f,h,k
Thus, based on a large difference in kinetics a very high
degree of chemoselectivity can still be observed, for example,
we know that an alkyl iodide is dehalogenated in the presence
of an N-Boc group.13 Furthermore, an aliphatic nitro group
is reduced to the amine in precence of an aromatic chlorine
with SmI2/pyrrolidine/H2O.11k
Table 1. Optimization of the Reaction Conditionsa
To test the selectivity toward other functional groups, we
prepared a range of tosyl amides containing additional
functional groups such as aromatic chlorine, N-Boc, and
ketone masked as an ethylene acetal (Table 2, entries 4-6).
Pleasingly, deprotection with these functional groups present
was successful, and the resulting amines were recovered in
close to quantitative yield.
a To a solution of SmI2 in THF (4 mL, 0.13 M, 0.52 mmol) the tosylester
was added followed by water (3 equiv relative SmI2) and pyrrolidine (2
equiv relative SmI2). b Isolated yields. c Experiment performed with 2.6
mmol SmI2.
In the course of this work we also examined the cleavage
of the N-S bond in N-tosylaziridines as they are considered
notoriously difficult to deprotect giving various ring opened
byproduct with traditional methods. Vedejs and Lin reported
successful cleavage of very sterically hindered tosyl aziri-
dines with SmI2/DMPU, but with the less hindered N-tosyl-
2-phenylaziridine they observed a fast reaction but they could
not isolate any of the expected aziridine. Alonso and
Andersson have reported that tosyl aziridines undergo a rapid
ring opening reaction with the SmI2/DMPU system, while
the use of Mg/MeOH for deprotection gave according to their
findings much better results.9b
amounts of samarium diiodide, pyrrolidine and water were
used in the reaction and the optimum yield in the deprotection
was reached with 6 equivalents of SmI2, 12 equiv of
pyrrolidine and 18 equiv of water. In theory, 2 equiv of SmI2
is needed for breaking the N-S bond, therefore the products
(10) (a) Knowles, H.; Parsons, A. F.; Pettifer, R. M. Synlett 1997, 3,
271. (b) Fresneda, P.; Molina, P.; Sanz, M. Tetrahedron Lett. 2001, 42,
851. (c) Wang, S.; Dilley, A.; Poullennec, K.; Romo, D. Tetrahedron 2006,
62, 7155. (d) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128, 6054.
(e) Moussa, Z.; Romo, D. Synlett 2006, 19, 3294. (f) Kumar, V.; Ramesh,
N. G. Chem. Commun. 2006, 4952. (g) Kumar, V.; Ramesh, N. G. Org.
Biomol. Chem. 2007, 5, 3847.
To our delight, we found that both N-tosyl-2-phenylaziri-
dine and N-tosyl-2-benzylaziridine underwent clean and
instantaneous deprotection giving nearly quantitative yield
of the N-H aziridine using SmI2/Et3N/H2O. We also found
that the amine used as an additive had a large impact on the
outcome of the deprotection of N-tosylaziridines. The use
of pyrrolidine and isopropylamine gave no isolated product
(11) (a) Dahle´n, A.; Hilmersson, G. Tetrahedron Lett. 2002, 43, 7197.
(b) Dahle´n, A.; Hilmersson, G. Chem.-Eur. J. 2003, 9, 1123. (c) Dahle´n,
A.; Hilmersson, G. Tetrahedron Lett. 2003, 44, 2661. (d) Dahle´n, A.;
Hilmersson, G.; Knettle, B. W.; Flowers, R. A., II. J. Org. Chem. 2003,
68, 4870. (e) Dahle´n, A.; Petersson, A.; Hilmersson, G. Org. Biomol. Chem.
2003, 1, 2423. (f) Kim, M.; Dahle´n, A.; Hilmersson, G.; Knettle, B. W.;
Flowers, R. A., II. Tetrahedron 2003, 59, 10397. (g) Dahle´n, A.; Sundgren,
A.; Lahmann, M.; Oscarson, S.; Hilmersson, G. Org. Lett. 2003, 5, 4085.
(h) Davis, T. A.; Chopade, P. R.; Hilmersson, G.; Flowers, R. A., II. Org.
Lett. 2005, 7, 119. (i) Dahle´n, A.; Hilmersson, G. J. Am. Chem. Soc. 2005,
127, 8340. (j) Dahle´n, A.; Nilsson, Å.; Hilmersson, J. Org. Chem. 2006,
71, 1576. (k) Ankner, T.; Hilmersson, G. Tetrahedron Lett. 2007, 48, 5707.
(12) Rosencrantz, D. R.; Dolby, L. J. J. Org. Chem. 1963, 28, 1888.
(13) Granander, J.; Sott, R.; Hilmersson, G. Chem.-Eur. J. 2006, 12,
4191.
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Org. Lett., Vol. 11, No. 3, 2009

Table 2. SmI2/Pyrrolidine/Water Mediated Cleavage of Tosyl
Amides
Table 3. SmI2/Pyrrolidine/Water Mediated Cleavage of Tosyl
Esters
a Yields determined with GC/MS analysis comparing to an internal
standard.
the acetal was hydrolyzed during the acidic workup used
for the tosyl ester substrates.
a Yield determined with GC/MS analysis comparing to an internal
standard. b Isolated yield. c Performed with 2.6 mmol SmI2. d Triethylamine
was used instead of pyrrolidine.
To investigate the scope even further for this cleavage
reaction, a series of different sulfonate esters and amides
were synthesized and we found that the methyl and triflu-
oromethyl (mesyl- and triflyl- respectively) derivatives gave
no detectable product formation (Table 4, entries 1 and 2).
The bulkier and more electron-rich sulfone amides (Table
4, entries 3-5) displayed properties similar to -Ts but they
were cleaved with slighly lower effeciency. The GC/MS
analysis after work up of entries 3-5 in Table 4 revealed
that much of the sulfide was desulfurized yielding mesitylene,
triisopropylbenzene and anisole in the reaction mixture. This
side reaction clearly demands more SmI2, and therefore, the
yield is slightly lower.
while triethylamine as additive afforded the wanted product
in excellent yield (Table 2, entries 7 and 8).
Both tosyl protected alipahtic and aromatic alcohols were
efficiently cleaved, leaving the alcohol in excellent yield
(Table 3). Electronic properties does not seem to influence
the reaction, as there is no difference in yield between the
4-methoxy and 4-fluoro substituted phenyl tosyl esters (Table
3, entries 4-5). This is in contrast to Narender et al. that
previously reported that electron-poor aromatics are cleaved
with lower effeciency with Mg/MeOH.6b Again we prepared
a series of protected phenols with slightly more sensitive
functionalities (Table 3, entries 6-8) and found that a benzyl
ether, an aromatic chlorine and a benzylic ethylene acetal
are all compatible with the reaction conditions. Conveniently,
The facile cleavage of the aromatic sulfone amides and
esters while mesyl amides and mesyl esters are stable to the
reagent mixture indicate that the practical reduction potential
of SmI2/R3N/H2O is within this regime.11j Mechanistically
Org. Lett., Vol. 11, No. 3, 2009
505

Table 4. SmI2/pyrrolidine/water Mediated Cleavage of Alkyl
and Aryl Sulfonates
Figure 1. Proposed mechanism for the reductive cleavage of tosyl
amides.
To conclude we have developed a highly useful procedure
for efficient and very rapid deprotection of tosyl amides and
esters to form the corresponding amines and alcohols. The
method appears to be general and give consistently high
yields with all substrates tested including sterically hindered
aliphatic tosyl amides as well as highly sensitive ones like
the tosylated aziridines.
a Yield determined with GC/MS comparing to an internal standard.
we propose that one electron is transferred from Sm(II) to
the aromatic ring of the sulfone. This may rearrange and
accept one more electron leading to fission of the N-S bond
(Figure 1). The nonaromatic sulfone amides (i.e., mesylate
and triflate) are not capable of this, thus no cleavage reaction
is observed.
A new synthetic procedure will never have any impact if
it is not practically useful and scalable hence we also
demonstrated that this deprotection can be carried out at a
larger scale and under standard laboratory conditions. A THF
solution of SmI2 (20 mL, 2.6 mmol, 0.13 M) was freshly
prepared from samarium (3.2 mmol) and diiodoethane (2.6
mmol) in a septum capped vial using undried reagents. The
vial was loaded with water and the tosyl amide (0.43 mmol)
before the amine was added. Immediately after the addition
the reaction mixture was subjected to standard workup and
the amine was recovered in nearly quantitative yield.
Acknowledgment. Financial support from the Swedish
Natural Science Council is gratefully acknowledged. Prof.
¨
Per-Ola Norrby and Prof. Ojvind Davidsson are acknowl-
edged for valuable comments.
Note Added after Print Publication. Author I. Beaudet’s
name was misspelled in ref 2c in the version published
January 5, 2009. The correct version was published on the
Web March 27, 2009, and an Addition and Correction
appears in the April 16, 2009 issue (Vol. 11, No. 8).
Supporting Information Available: A complete descrip-
tion of experimental details and spectral charateristics of
staring materials and products. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 11, No. 3, 2009