A. Greenfield, C. Grosanu / Tetrahedron Letters 49 (2008) 6300–6303
6303
Table 3 (continued)
Amine
Sulfonamide
Yielda (%)
R = CH3, CF3
Methanesulfonamides
>95
Trifluoromethanesulfonamides
>95
F3C
F3C
14
15
16
O
R
HN
S
NH2
O
NH
O S O
R
>95
>95
>95
>95
>95
>90
NH2
H
N
R
NH2
O
O
S
N
N
O
O
O
17
O
O
O
HN
R
S
NH2
a
Isolated yields. All products were fully characterized. Reaction were run in a sequential manner.
below. If TLC analysis shows starting material remaining, addi-
tional amount of anhydride can be added. The reaction mixture
is stirred for half an hour allowing the temperature to reach ambi-
ent if needed, followed by the addition of 2–10 times excess of
2.5 N NaOH/methanol (1:2–3). The resulting mixture is stirred at
room temperature until conversion to the target mono-sulfon-
amide is complete (0.5–24 h). Weakly acidic work-up (pH 3–6) fol-
lowed by conventional isolation affords the desired materials with
yields greater than 90% (purity of crude material 90% or higher).
Note: When carrying out reactions in a parallel format, in order
to avoid reaction monitoring, an excess of anhydride up to
2–2.2 equiv and, correspondingly, base should be added, and the
initial temperature lowered to prevent local overheating. Typical
yields are >80%.
To evaluate the applicability of the procedure in a parallel syn-
thesis format, we compared sequential versus parallel setup on se-
lected examples (Table 2). The results presented in Table 2 suggest
this approach to be high yielding in a parallel syntheses setup de-
spite the large excess (ꢀ2.2 equiv) of sulfonylating agent used.
Application of the protocol to a diverse set of amines is shown
in Table 3. A wide range of primary amines such as anilines,
benzylamines, aliphatic, and non-chromophoric amines, and
aminoacids were investigated.
Additionally, we explored various substitution patterns on both
anilines and benzylamines, and showed that the nature of the sub-
stituent has little or no influence on the yield of the target mono-
sulfonamide. In the case of non- and weakly chromophoric amines
(Ex. 15 and 16), we modified the protocol and used 2.5 equiv of the
anhydride and 3 equiv of base in order to provide complete
conversion without monitoring. For a vast majority of amines,
the yields of corresponding sulfonamides were nearly quantitative.
The hydrolytically unstable methyl ester (Ex. 7) afforded the
corresponding acid, while 4-aminobenzamide (Ex. 8) produced
the sulfonamide in slightly lower yield presumably due to its low
solubility. Less successful sulfamidation of o-nitroaniline (Ex. 4)
was accompanied by low conversion rather than selectivity. How-
ever, even in this case, the yields of products based on consumed
starting material were ꢀ90%.
In summary, we developed a general and highly efficient one-
pot protocol for the synthesis of primary methane- and trifluoro-
methanesulfonamides that includes a simple reaction setup, offers
high product yields, facile isolation, and is applicable to a wide
range of amine substrates.
Acknowledgments
We would like to thank Drs. D. Rotella, A. Robichaud, and
R. Magolda for their support and encouragement.
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