the new reagent can be used for construction of chemical
libraries. Further modification of functional groups present in
compounds such as 10 could additionally increase the potential
for molecular diversity inherent in these, at first glance, simple
compounds.
We thank the Swedish Natural Science Research Council, the
National Board for Industrial and Technical Development and
Astra Draco AB for generous financial support.
derivative 3 with three different protecting groups. The overall
yield of 3 from 1 is 87%.†
Compound 3 easily undergoes the Mitsunobu reaction with
alcohols,6 thereby giving rise to triprotected monosubstituted
hydrazines 4 (Scheme 2). From compounds of this type the Cbs
group can be cleaved reductively with Hg-activated aluminium
to provide crystalline intermediates 5, which are alkylated as
previously described1 under phase transfer conditions to give
1,2-diprotected 1,2-disubstituted hydrazine intermediates 6.
These differ from those described earlier in one important
respect, namely, that their Boc and Z groups can be removed
selectively in optional order. So far, we prefer to remove the
Boc group first under mild acidic conditions via compounds 7
and subsequently acylate the latter to 8. Finally, these can be
deprotected under stronger acidic or catalytic hydrogenolysis
conditions to give substances 9, although we normally prefer to
acylate them without isolation directly to the final products
10.
Footnotes
* E-mail: urbki@bmc.uu.se
† Selected data for 3: 1H NMR (400 MHz, CDCl3, major conformer): d 1.34
(s, 9 H, Boc), 5.18 and 5.24 (AB quartet, J 12.1 Hz, 2 H, CH2), 7.14 (br s,
1 H, NH), 7.37 (perturbed signal, 5 H, Ph), 7.80 (d, J 8.3 Hz, 2 H, Cbs H3,5),
8.24 (d, J 8.3 Hz, 2 H, Cbs H2,6).
A relatively large number of compounds 4–10 have been
prepared to investigate and exemplify this scheme, all of which
are listed in Table 1. No indication whatsoever of incomplete
selectivity in the removal of the protecting groups in interme-
diates 4 and 6 has been detected. Alkylations and acylations of
5, 7 and 9 were performed as described previously.1 As can be
seen from the table, all steps proceed very satisfactorily and few
intermediates are obtained in less than 90% yield.
Mono- and di-alkylated hydrazines are extensively used as
precursors in the synthesis of heterocycles.7 Recently, Han and
Janda also applied this methodology in their synthesis of a-aza
amino acids.8 Highly substituted hydrazines have found a
number of practical applications.9
Although not demonstrated experimentally here, several
other reactions of the amino group in addition to alkylation and
acylation can be envisaged to be useful in this context, but we
have confined ourselves to exemplify a few additional func-
tional groups which can be introduced easily using the present
conditions. Considering the large number of alkylating and
References
1 U. Ma¨eorg, L. Grehn and U. Ragnarsson, Angew. Chem., 1996, 108,
2802; Angew. Chem., Int. Ed. Engl., 1996, 35, 2626.
2 E. Wu¨nsch, Chem. Ber., 1965, 98, 797.
3 T. Hamada and O.Yonemitzu, Synthesis, 1986, 852.
4 I. Koppel, J. Koppel, F. Degerbeck, L. Grehn and U. Ragnarsson, J. Org.
Chem., 1991, 56, 7172.
5 L. Grehn, K. Gunnarsson and U. Ragnarsson, Acta Chem. Scand., Ser. B,
1986, 40, 745.
6 O. Mitsunobu, Synthesis, 1981, 1; D. L. Hughes, Org. React., 1992, 42,
335.
7 U. Jensen-Korte and N. Mu¨ller, Methoden Org. Chem. (Houben-Weyl),
4th edn. 1952–1990, vol. E16a, pp. 807–815; J. Elguero, in Compre-
hensive Heterocyclic Chemistry, ed. A. R. Katritzky, C. W. Rees and
K. T. Potts, Pergamon, Oxford, 1984, vol. 5, pp. 291–301; J. B. Polya,
ibid., pp. 762–768.
8 H. Han and K. D.Janda, J. Am. Chem. Soc., 1996, 118, 2539.
9 A. R. Katritzky, J. Wu and S. V. Verin, Synthesis, 1995, 651.
Received in Cambridge, UK, 2nd May 1997; 7/03008H
1382
Chem. Commun., 1997
Grehn, Leif
