C O M M U N I C A T I O N S
Alternatively, when starting with nonamethyltrisilazane (2, R )
Tms), the reaction with 1 failed to progress appreciably in CDCl3
at reflux, whereas in tetrachloroethylene at reflux a similar
decomposition to TmsCl (2 equiv), COS, S, and HNCO-related
products16 occurred without evidence of cyclization to the hoped-
for 3 (R ) Tms).
Another generalization involved reaction of 1 with the “tethered”
N,N-bis(silylated) amino acid derivative ethyl 2,2,5,5-tetramethyl-
1-aza-2,5-disilacyclopentane-1-acetate (STABASE-GlyOEt),17 which
readily produced DtsGlyOEt3,4e along with 1,2-bis(chlorodimeth-
ylsilyl)ethane.17
To achieve Dts formation by the aforementioned chemistry, it
was important that both free valences of nitrogen be silylated. To
reinforce results already cited for 2 (R ) H), the rapid, exo-
thermic reactions of 1 or 10 with N-trimethylsilyl N-benzylamine
(14)13 were studied. Reactions of 14 with 10 smoothly gave
CCl3SS(CdO)NHBn (15) plus TmsCl (4), establishing the highly
selective net replacement of Tms instead of a proton.18 In the same
vein, reactions of 14 with 1 gave TmsCl (4) plus chlorocarbonyl
carbamoyl disulfane Cl(CdO)SS(CdO)NHBn (16), which did not
progress to Dts derivative 3 (R ) Bn).
Mechanisms of Silylamine Acylation and Dts Heterocycliza-
tion. The central finding of this work is that whereas simple primary
amines upon reaction with bis(chlorocarbonyl)disulfane (1) form
isocyanates 9 and related derivatives rather than the anticipated Dts-
amines 3, the same chemistry carried out on bis(silyl)amine
substrates [e.g., 2, STABASE] indeed provides 3 in respectable
yields and purities, with negligible amounts of 9 and related
compounds.
of the manuscript, and Drs. Kate and Michael Ba´ra´ny for long-
standing encouragement. Supported by NIH Grants AM 01260, GM
28934, GM 42722, and GM 43552.
Supporting Information Available: Experimental procedures,
NMR characterization, representative kinetics (8 pages, print/PDF). This
References
(1) The name dithiasuccinoyl-amine derives from the conceit that the
heterocycle is the sulfurized analogue of a succinimide that represents a
protected amine derivative. The present contribution introduces the first
synthesis of Dts-amines that follows the intuitive notion that an analogue
of succinyl chloride could be used to establish amino protection.
(2) Zumach, G.; Ku¨hle, E. Angew. Chem., Int. Ed. Engl. 1970, 9, 54-63.
(3) (a) Barany, G. Ph.D. Thesis, The Rockefeller University, 1977, Disserta-
tion Abstr. 38, 5893-B. (b) Barany, G.; Merrifield, R. B. J. Am. Chem.
Soc. 1977, 99, 7363-7365.
(4) (a) Barany, G.; Merrifield, R. B. Anal. Biochem. 1979, 95, 160-170.
(b) Barany, G.; Merrifield, R. B. J. Am. Chem. Soc. 1980, 102, 3084-
3095. (c) Barany, G. Int. J. Pept. Protein Res. 1982, 19, 321-324.
(d) Słomczyn´ska, U.; Barany, G. J. Heterocyclic Chem. 1984, 21, 241-
246. (e) Zalipsky, S.; Albericio, F.; Słomczyn´ska, U.; Barany, G. Int. J.
Pept. Protein Res. 1987, 30, 740-783. (f) Hammer, R. P.; Albericio, F.;
Gera, L.; Barany, G. Int. J. Pept. Protein Res. 1991, 36, 31-45. (g) Chen,
L.; Thompson, T. R.; Hammer, R. P.; Barany, G. J. Org. Chem. 1996,
61, 6639-6645. (h) Barany, G.; Barany, M. J.; Chen, L.; Eastep, S. J.;
Hammer, R. P.; Hanson, M. C.; Majerle, R. S.; Mott, A. W.; Słomczyn´ska,
U. (alphabetical), currently being readied for publication.
(5) (a) Barany, G.; Albericio, F. J. Am. Chem. Soc. 1985, 107, 4936-4942.
(b) Albericio, F.; Barany, G. Int. J. Pept. Protein Res. 1987, 30, 177-
205.
(6) (a) Meinjohanns, E.; Vargas-Berenguel, A.; Meldal, M.; Paulsen, H.; Bock,
K. J. Chem. Soc., Perkin Trans. 1 1995, 2165-2175 and follow-up papers
by this group. (b) Jensen, K. J.; Hansen, P. R.; Venugopal, D.; Barany,
G. J. Am. Chem. Soc. 1996, 118, 3148-3155.
(7) Planas, M.; Bardaji, E.; Jensen, K. J.; Barany, G. J. Org. Chem. 1999,
64, 7281-7289.
(8) (a) Xu, Q.; Musier-Forsyth, K.; Hammer, R. P.; Barany, G. In Peptides:
Chemistry, Structure and Biology. Proceedings of the Fourteenth American
Peptide Symposium; Kaumaya, P. T. P., Hodges, R. S., Eds.; Mayflower
Scientific Ltd.: Kingswinford, U.K., 1996; pp 123-124. (b) Xu, Q.;
Musier-Forsyth, K.; Hammer, R. P.; Barany, G. Nucleic Acids Res. 1996,
24, 1602-1607 and references therein.
Two separate stages of the process must be considered. Acylation
of mono(trimethylsilyl)amines, i.e., TmsNHR or Tms-NR1R2, is
precedented,4c,e,12 and even bis(acylation) of Tms2NR [requiring heat
and Lewis acid catalysis] has been described.19 Evidence provided
herein, as well as previously,3a,4h suggests that chlorocarbonyl
carbamoyl disulfane intermediates (like 5 and 16) are indeed
generated from 1 plus amine derivatives and are surprisingly stable;
yet the success or failure of cyclization to Dts is contingent on
whether the carbamoyl nitrogen bears a trimethylsilyl group [TmsCl
(4) formed as final coproduct] or a proton [HCl produced, but no
cyclization]. We now conclude that when there is a proton on the
amino nitrogen, its removal (either spontaneous or promoted
intentionally) initiates a cascade of nonproductive side reactions.
Formation of these byproducts is precluded when the proton is
replaced by a bulky Tms group; in this case, the only accessible
pathway for loss of TmsCl is coupled to the heterocyclization that
gives Dts-amines 3.
Summary and Conclusions. Dts-amines can be synthesized
directly in a simple and robust reaction that uses the trimethylsilyl
group as a “large proton” to circumvent extant synthetic problems.
This simplification and improvement in the synthesis of 1,2,4-
dithiazolidine-3,5-diones promises to open up new avenues for the
application of Dts-based protection strategies to meet a wide
spectrum of goals in synthetic organic and biological chemistry
research.
(9) Wood, M. E.; Cane-Honeysett, D. J.; Dowle, M. D.; Coles, S. J.;
Hursthouse, M. B. Org. Biomol. Chem. 2003, 1, 3015-3023 and two
earlier communications by this group.
(10) For a review of Gabriel synthesis of amines [alkylation of phthalimide
salts, followed by dephthaloylation], see: Gibson, M. S.; Bradshaw, R.
W. Angew. Chem., Int. Ed. Engl. 1968, 7, 919-930.
(11) (a) Kobayashi, N.; Osawa, A.; Fujisawa, T. Chem. Lett. 1973, 1315-
1318. (b) Haas, A.; Helmbrecht, J.; Klug, W.; Koch, B.; Reinke, H.;
Sommerhoff, J. J. Fluorine Chem. 1973/74, 3, 383-395. (c) Barany, G.;
Schroll, A. L.; Mott, A. W.; Halsrud, D. A. J. Org. Chem. 1983, 48, 8,
4750-4761.
(12) Silylated amines can be acylated, in some cases more selectively and in
higher yield than the corresponding free amines: (a) Birkofer, L.; Ritter,
A. Angew. Chem., Int. Ed. Engl. 1965, 4, 417-429. (b) Klebe, J. F. AdV.
Org. Chem. 1972, 8, 98-178. (c) Kricheldorf, H. R. Liebigs Ann. Chem.
1972, 763, 17-38. (d) Mironov, V. F.; Sheludyakov, V. D.; Kozyukov,
V. P. Russ. Chem. ReV. 1979, 48, 473-489 (Engl. trans.).
(13) Substrates 2 are made either by exhaustive silylation of the corresponding
primary amine or by silylation of an isolated monosilylamine intermediate,
which is in turn made readily from amine plus TmsCl, or by SN2 reaction
of alkyl/aryl halides/tosylates with metal bis(trimethylsilyl)amides. General
review: Tamao, K.; Kawachi, A. In Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations; Fleming, I., Ed.; Georg Thieme
Verlag: New York, 2001; Vol. 4, pp 451-472.
(14) Byproducts 8 and/or 9 may be transformed further to ureas or are
hydrolyzed back to the parent amines upon aqueous workup.
(15) Harris, J. F., Jr. J. Am. Chem. Soc. 1960, 82, 155-158.
(16) These results are not surprising, given the difficulty, discussed in refs 2
and 4g, in preparing 3 (R ) H) by methods that suffice to elaborate 3 for
most other substituents R. In the case under consideration, initial nitrogen/
silicon-containing products could be Tms-NdCdO [matches authentic
standard] and/or TmsNH(CdO)Cl.
(17) Djuric, S.; Venit, J.; Magnus, P. Tetrahedron Lett. 1981, 22, 1787-1790.
(18) Reference 12d shows that reaction of Tms-NH-R with R′(CdO)Cl (but
not COCl2) gives predominantly R′(CdO)NH-R + TmsCl. Thus, while
it was conceivable that reaction of Tms-NH-Bzl with 1 could lead to 5 +
HCl (if 1 reacted like COCl2), in fact, 1 reacts exclusively via N-Tms
bond cleavage to give 16 + HCl, and heterocyclization does not occur.
(19) Ru¨hlmann, K. Chem. Ber. 1961, 94, 2311-2313.
Acknowledgment. We thank Lori J. Enloe and Drs. Alayne L.
Schroll and Fernando Albericio (1982), and Dana M. Baas, Megan
M. Corey, Eric P. Gillis, Michael C. Hanson, Isaac D. Mitchell,
Abraham Tsehaye, James W. Wollack, Abehayeu Yilma, and Dr.
Mian Liu (2004) for assistance in preparing key starting materials,
Drs. Paul C. Ewbank, Jed Fisher, Craig J. Forsyth, Rita S. Majerle,
and Simon K. Shannon for valuable discussions and critical reading
JA0455446
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