Scheme 1a
Table 1. Formation of O-Alkylhydroxylamines 5a-da
a Reagents and conditions: (a) i. BnOH, PPh3, DIAD, THF, rt;
ii. 5 mol % of 2, CH2Cl2, reflux; iii. EtOCHdCH2; iv. MeOH then
filter; (b) NH2NH2, THF, rt, 72% from BnOH.
the Grubbs benzylidene catalyst [(PCy3)2(Cl)2RudCHPh,
1].11
In the course of developing a facile route to O-alkylhy-
droxylamines,12,13 we encountered difficulty removing Mit-
sunobu byproducts. Our previous experience with the
generation of soluble, ROMP-derived sulfonamide oligo-
mers14 led us to believe that oligomers derived via ROMP
may have utility as capture-release agents due to their
tunable properties and unique solubility profiles. This
hypothesis has led to the development of the capture-
ROMP-release strategy that we now report.
The method we employ (Scheme 1) utilizes a post-capture
polymerization/filtration event that effectively removes Mit-
sunobu byproducts without the use of chromatography. The
Mitsunobu reaction is first utilized to capture a variety of
alcohols onto exo-N-hydroxy-7-oxabicyclo[2.2.1]hept-5-ene-
2,3-dicarboximide (3).15 Subjection of the crude reaction
mixture to ROM-polymerization conditions using 5 mol %
a Reactions performed as outlined in Scheme 1. b Based on original
amount of alcohol. c Determined by GC before azeotropic removal of
hydrazine. d Polymerization conducted with 2 mol % of 2. e Cleavage
withMeNH2/MeOH.
of (IMesH2)(PCy3)(Cl)2RudCHPh (2)16,17 generates a dif-
ferentially soluble polymer 4 that was isolated by precipita-
tion from methanol. Filtration away from the Mitsunobu
byproducts gave 4 as a free-flowing powder in good to
excellent yield (Table 1). Hydrazinolysis (anhydrous NH2-
NH2/THF, rt), followed by biphasic extraction (Et2O/H2O),
resulted in the release of the target O-alkylhydroxylamine 5
in good purity (Table 1). No traces of PPh3O or DIADH2
(8) Barrett, A. G. M.; Roberts, R. S.; Schro¨der, J. Org. Lett. 2000, 2,
2999-3001.
(9) (a) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J. Org.
Lett. 1999, 1, 579-582. (b) Barrett, A. G. M.; Cramp, S. M.; Roberts, R.
S. Org. Lett. 1999, 1, 1083-1086. (c) Barrett, A. G. M.; Cramp, S. M.;
Roberts, R. S.; Zecri, F. J. Org. Lett. 2000, 2, 261-264. (d) Barrett, A. G.
M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J. Comb. Chem. High Throughput
Screening 2000, 3, 131-138. (e) Arnauld, T.; Barrett, A. G. M.; Cramp, S.
M.; Roberts, R. S.; Ze´cri, F. J. Org. Lett. 2000, 2, 2663-2666. (f) Barrett,
A. G. M.; Cramp, S. M.; Hennessy, A. J.; Procopiou, P. A.; Roberts, R. S.
Org. Lett. 2001, 3, 271-273. (g) Arnauld, T.; Barrett, A. G. M.; Seifried,
R. Tetrahedron Lett. 2001, 42, 7899-7901. (h) Arnauld, T.; Barrett, A. G.
M.; Hopkins, B. T.; Ze´cri, F. J. Tetrahedron Lett. 2001, 42, 8215-8217.
(10) For use of ROM polymers as organic soluble supports for radical
reactions, see: (a) Enholm, E. J.; Gallagher, M. E. Org. Lett. 2001, 3, 3397-
3399. (b) Enholm, E. J.; Cottone, J. S. Org. Lett. 2001, 3, 3959-3962.
ROM polymers as soluble catalysts: (c) Bolm, C.; Dinter, C. L.; Seger,
A.; Ho¨cker, H.; Brozio, J. J. Org. Chem. 1999; 64, 5730-5731.
(11) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
1
were observed by GC or H NMR analysis. In addition, no
1
polymeric byproducts were observed by H NMR of the
crude, isolated O-alkylhydroxylamines.18 The major con-
taminant in all cases was residual hydrazine (5-12% by GC,
Table 1) which could be azeotropically removed with toluene
under reduced pressure.
In the area of impurity elimination, the Mitsunobu reac-
tion20 has previously been the target of several groups. A
variety of methods21 have been developed to facilitate the
separation of the Mitsunobu byproducts (Ph3PO and DEADH2)
from the desired reaction product. Our approach incorporates
(12) For other methods on the production of O-alkylhydroxylamines,
see: (a) Theilacker, W.; Ebke, K. Angew. Chem. 1956, 68, 303. (b)
Grochowski, E.; Jurczak, J. Synthesis 1976, 682-684. (c) Choong, I. C.;
Ellman, J. A. J. Org. Chem. 1999, 64, 6528-6529. (d) Foot, O. F.; Knight,
D. W. Chem. Commun. 2000, 975-976.
(13) (a) Davies, S. G.; Jones, S.; Sanz, M. A.; Teixeira, F. C.; Fox, J. F.
Chem. Commun. 1998, 2235-2236. (b) Bull, S. D.; Davies, S. G.; Jones,
S.; Ouzman, J. V. A.; Price, A. J.; Watkin, D. J. Chem. Commun. 1999,
2079-2080. (c) Koide, K.; Finkelstein, J. M.; Ball, Z.; Verdine, G. L. J.
Am. Chem. Soc. 2001, 123, 398-408.
(16) IMesH2 ) 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene.
(17) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(18) See 1H NMR spectra of crude 5a-h in the Supporting Information.
(19) High, A.; Prior, T.; Bell, R. A.; Rangachari, P. K. J. Pharmacol.
Exp. Ther. 1999, 288, 490-501.
(14) Wanner, J.; Harned, A. M.; Probst, D. A.; Poon, K. W. C.; Klein,
T. A.; Snelgrove, K. A.; Hanson, P. R. Tetrahedron Lett. 2002, 43, 917-
921.
(20) For reviews, see: (a) Mitsunobu, O. Synthesis 1981, 1-28. (b)
Hughes, D. L. Org. React. 1992, 42, 335-656. (c) Hughes, D. L. Org.
Prep. Proced. Int. 1996, 28, 127-164.
(15) Narita, M.; Teramoto, T.; Okawara, M. Bull. Chem. Soc. Jpn. 1971,
44, 1084-1089.
1008
Org. Lett., Vol. 4, No. 6, 2002