Cyclic thioanhydrides: Linchpins for multicomponent coupling reactions based on the reaction of thioacids with electron-deficient sulfonamides and azides

Article abstract of DOI:10.1021/ol702570x

(Chemical Equation Presented) Reaction of cyclic thioanhydrides with amines affords amides functionalized with thioacids, which can be trapped in situ with electrondeficient azides or, preferably, 2,4-dinitrobenzenesulfonamides. In this manner the cyclic thioanhydride serves as a linchpin in a three-component coupling sequence. The use of thiomaleic anhydride and a afunctional nucleophile extends the process to heterocycle synthesis, while a cyclic thioanhydride prepared from aspartic acid directly provides N-functionalized asparagine derivatives.

Full text of DOI:10.1021/ol702570x

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5323-5325
Cyclic Thioanhydrides: Linchpins for
Multicomponent Coupling Reactions
Based on the Reaction of Thioacids
with Electron-Deficient Sulfonamides
and Azides
David Crich*,† and Albert A. Bowers‡
Department of Chemistry, Wayne State UniVersity, 5101 Cass AVenue, Detroit,
Michigan 48230, and Department of Chemistry, UniVersity of Illinois at Chicago,
Chicago, Illinois 60607
Dcrich@chem.wayne.edu
Received October 22, 2007
ABSTRACT
Reaction of cyclic thioanhydrides with amines affords amides functionalized with thioacids, which can be trapped in situ with electron-
deficient azides or, preferably, 2,4-dinitrobenzenesulfonamides. In this manner the cyclic thioanhydride serves as a linchpin in a three-component
coupling sequence. The use of thiomaleic anhydride and a bifunctional nucleophile extends the process to heterocycle synthesis, while a
cyclic thioanhydride prepared from aspartic acid directly provides N-functionalized asparagine derivatives.
Thioacids are useful intermediates in organic synthesis,1
having found application in peptide synthesis,2 and as
precursors to thioesters for native chemical ligation.3 Their
long-established reaction with azides yields secondary amides
and has recently come to the fore as a versatile ligation
reaction,4 while their complementary reaction with 2,4-
dinitrobenzenesulfonamides5 has been much less widely
applied. The relatively limited application of these useful
coupling reactions can be ascribed, at least in part, to the
need to prepare all but the simplest thioacids. We conceived
that this hurdle could be overcome through the nucleophilic
ring-opening of cyclic thioanhydrides with the in situ
(4) (a) Hakimelahi, G. H.; Just, G. Tetrahedron Lett. 1980, 21, 2119-
2122. (b) Rosen, T.; Lico, I. M.; Chu, D. T. W. J. Org. Chem. 1988, 53,
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4577. (l) McKervey, M.; O’Sullivan, M. B.; Myers, P. L.; Green, R. H. J.
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† Wayne State University.
‡ University of Illinois at Chicago.
(1) (a) Niyomura, O.; Kato, S. Top. Curr. Chem. 2005, 251, 1-12. (b)
Kato, S.; Murai, T. In The Chemistry of Acid DeriVatiVes; Patai, S., Ed.;
Wiley: Chichester, 1992; Vol. 2, pp 803-847. (c) Bauer, W.; Ku¨hlein, K.
In Methoden der Organischen Chemie, 4th Ed; Falbe, J., Ed.; Thieme:
Stuttgart, 1985; Vol. E5, pp 832-890.
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392. (b) Mitin, Y. V.; Zapevalova, N. P. Int. J. Pept. Protein Res. 1990,
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Science 1994, 266, 776. (b) Dawson, P. E.; Kent, S. B. H. Annu. ReV.
Biochem. 2000, 69, 923-960. (c) Yeo, D. S. Y.; Srinivasan, R.; Chen, G.
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10.1021/ol702570x CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/03/2007

Table 1. Three-Component Coupling of Cyclic Thioanhydrides with Amines and 2,4-Dinitrobenzenesulfonamides
a Ar ) 2,4-dinitrophenyl. b Conditions: i) 1.2 equiv thioanhydride, 1 equiv amine, DMF, 30 min; ii) 1 equiv CsCO3, 1 equiv sulfonamide, DMF 1 h.
generation of a thioacid for use in a coupling reaction.
Limited precedent is provided by the opening of thiosuccinic
anhydride with amines with subsequent trapping of the
thioacid with benzyl bromide, providing a thiolester for later
use in native chemical ligation.6 Success, coupled with the
facile synthesis and stability of cyclic thioanhydrides, should
provide a new entry into multicomponent coupling reactions.7
In a first demonstration of this type commercial thiosuc-
cinic anhydride8 was treated with benzylamine in methanol
at room temperature, followed by the addition of tosyl azide
and 2,6-lutidine, leading to the isolation of the dissymmetric
succinamide 2 in quantitative yield (Scheme 1). A second
and the potential for synthesis of tertiary amides. Table 1
presents a series of examples conducted in this three-
component manner, each of which afforded excellent yields
of the products. All reactions in Table 1 were conducted
under ambient temperature conditions by addition of the
nucleophilic amine to the cyclic thioanhydride, followed by
addition of the sulfonamide and a mild base; the overall
reaction time, including workup, is less than 2 h. The reaction
sequence is not restricted to the opening of five-membered
cyclic thioanhydrides but is also suitable for thiomalonic
anhydride and thioglutaric anhydride (Table 1, entries 7 and
8) and presumably larger ring sizes, many of which are very
readily prepared.8 The functional group compatibility of the
method is highlighted by the use of carbohydrate-based
amines either as the nucleophile (Table 1, entry 4) or in the
form of the sequence-terminating sulfonamide (Table 1,
entries 5 and 6). In particular the absence of protecting groups
in the latter example is stressed; compatibility with alcohols
is further highlighted by the use of methanol as solvent. The
use of the morpholine sulfonamide in entries 7 and 8 of Table
1 leads to the formation of tertiary amides, marking the clear
difference between the azide-based chemistry and the sul-
fonamide route.
Scheme 1. Three-Component Coupling of Amines, Cyclic
Thioanhydrides, and Sulfonyl Azides
A further extension of this new multicomponent-coupling
sequence is highlighted by the reaction of thiomaleic
anhydride with a bifunctional nucleophile. In this chemistry
the softer thiol first undergoes Michael addition to the
electrophile, and this is followed by cyclization of the amine
onto the thioanhydride moiety. The overall sequence, which
results in the formation of a functionalized benzothiazinone,
is completed by trapping the thioacid with a sulfonamide
(Scheme 2), and the only byproduct is 2,4-dinitroben-
zenethiol. We anticipate that similar heterocycle-forming
example employed free glycine as the initiating nucleophile
and also proceeded in excellent yield (Scheme 1).
In general, however, we have preferred to complete our
sequences by trapping the thioacids with the versatile 2,4-
dinitrobenzenesulfonamides due to their greater versatility,9
(6) (a) Mapp, A. K.; Dervan, P. B. Tetrahedron Lett. 2000, 41, 9451-
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Natl. Acad. Sci., U.S.A. 2000, 97, 3930-3935.
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H., Eds. Multicomponent Reactions; Wiley: Weinheim, 2005.
(8) (a) Kates, M. J.; Schauble, J. H. J. Org. Chem. 1995, 60, 6676-
6677. (b) Kates, M. J.; Schauble, J. H. J. Heterocycl. Chem. 1995, 32, 971-
978.
(9) (a) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831-5834. (b) Kan, T.; Fukuyama, T. Chem.
Commun. 2004, 353-359.
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Org. Lett., Vol. 9, No. 25, 2007

Reaction of 20 with 1-glucosamine followed by trapping
with the morpholine sulfonamide gave the N-glucosyl
asparagine derivative 23 in 44% yield (Scheme 5). The
Scheme 2. Three-Component Heterocycle Synthesis
Scheme 5. Synthesis of a N-Glucosyl Asparagine Derivative
systems will be available from the employment of other
bifunctional nucleophiles in this sequence.
Next, we turned to the potential of more highly function-
alized cyclic thioanhydrides and, in particular, ones derived
from aspartic acid. Treatment of N-Cbz-L-aspartic anhydride
with Na2S, according to the procedure of Kates and Schauble,
gave 20 in 47% yield (Scheme 3).
isolation of a single diastereomer confirms the enantiomeric
purity of the thioaspartic anhydride starting material. This
last example opens the way to a new method for glycopeptide
synthesis with minimal use of protecting groups; further
investigations, aimed at optimization of the reaction sub-
strates and conditions, are in progress.11,12
Scheme 3. Synthesis of N-Cbz-Thioaspartic Anhydride
In conclusion, the reaction of readily available cyclic
thioanhydrides with amines and then 2,4-dinitrobenzene-
sulfonamides represents a very efficient multicomponent-
coupling sequence employing the cyclic thioanhydride as
linchpin. The use of unsaturated cyclic thioanhydrides and
bifunctional nucleophiles opens up the possibility of multi-
component-heterocycle synthesis, while amino acid-based
cyclic thioanhydrides have the potential to serve as linchpins
in the convergent synthesis of glycopeptides.
Treatment of 20 with aniline in DMF followed by trapping
of the intermediate thioacid with the morpholine sulfonamide
gave the fully functionalized aspartamide 21 in 63% yield
as a single regioisomer (Scheme 4), which was confirmed
Acknowledgment. A.A.B. thanks the University of
Illinois at Chicago for a Moriarty Scholarship.
Scheme 4. Synthesis of a Fully Functionalized Asparagine
Amide
Supporting Information Available: Full experimental
details and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL702570X
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on the basis of HMBC correlations. When the reaction was
conducted in benzene as solvent, a regioisomeric mixture
of products was formed in the ratio of 2.5:1 favoring 21.10
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