Cleavage of N′,N′-dialkylhydrazides with Phl(OH)OTs

Article abstract of DOI:10.1021/ol0060477

equation presented N′,N′-Dimethylhydrazides are efficiently cleaved to give the carboxylic acid upon treatment with Phl(OH)OTs in water or water/CH₂Cl₂ mixtures. The reaction occurs with the evolution of a gas.

Full text of DOI:10.1021/ol0060477

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2139-2140
Cleavage of N ′,N ′-Dialkylhydrazides
with PhI(OH)OTs
Peter G. M. Wuts* and Michael P. Goble
Chemical Process Research and DeVelopment, 1500-91-201, Pharmacia and Upjohn,
Kalamazoo, Michigan 49001
peter.g.wuts@am.pnu.com
Received May 11, 2000
ABSTRACT
N′,N′-Dimethylhydrazides are efficiently cleaved to give the carboxylic acid upon treatment with PhI(OH)OTs in water or water/CH Cl2 mixtures.
2
The reaction occurs with the evolution of a gas.
We have recently been investigating the use of N′,N′-
dialkylhydrazide for directed orthometalations1 and found
that there are few methods to cleave these derivatives. The
available methods to achieve cleavage were developed by
Barton2 and Ho.3 Barton showed, in the context of the
protection of penicillic acids, that N′,N′-dialkylhydrazides
could be cleaved with Pb(OAc)4 or MnO2, and Ho showed
that dimethylhydrazides could be cleaved in low yield using
NaOCl. We have recently shown that periodic acid or CuCl2
can also be used to cleave dimethylhydrazides.1a The cupric
chloride method has the advantage that it is compatible with
the presence of sulfur.
We now describe a new and mild method for the cleavage
of N′,N′-dialkylhydrazides that should greatly extend the
utility of this group both in its use as a protective group4
and as a directing group in the orthometalation reaction. As
illustrated in Scheme 1, treatment of a hydrazide with PhI-
(OH)OTs in an aqueous/organic medium at temperatures
between -50 °C and rt very cleanly releases the acid from
the hydrazide. During the course of this work, we noticed
that the reaction occurs with the evolution of gas. Attempts
to identify the gas by capturing it in an IR cell and recording
its infrared spectrum were unsuccessful because of high
background levels of water and CO2. We surmise that the
gas is probably nitrogen and methane resulting from the
decomposition of 4 through the diimide. The heat of reaction
was measured in a CRC-90 calorimeter and found to be -88
kcal/mol (-372.3 kJ/mol) with the evolution of gas con-
firmed. On a 100 mg scale, this produced an adiabatic
temperature rise of 18 °C, indicating that scale-up of this
chemistry will require careful temperature control.
The use of alcoholic solvents results in the formation of
mixtures of the acid and ester presumably because of
competition in the hydrolysis of intermediate 2. The reaction
also works well in 10% aqueous NaOH and 10% HCl,
acetonitrile, methylene chloride, or mixtures of water and
methylene chloride. The reaction is fastest in water, with
CH2Cl2 being the slowest (9% starting material remaining
Scheme 1
(1) (a) Pratt, S. A.; Goble, M. P.; Mulvaney, M. J.; Wuts, P. G. M.,
Tetrahedron Lett., 2000, in press. (b) McCombie, W. W.; Lin; S.-I.; Vice,
S. F. Tetrahedron Lett., 1999, 40, 8767.
(2) Oliveira Baptista, M. J. V.; Barrett, A. G. M.; Barton, D. H. R.;
Girijavallabhan, M.; Jennings, R. C.; Kelly; J.; Papadimtriou; V. J.; Turner,
J. V.; Usher, N. A., J. Chem. Soc., Perkin Trans I 1977 1477.
(3) Ho, T.-L.; Wong, C. M. Synth. Commun. 1974, 4, 347.
(4) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, Wiley: New York, 1999.
10.1021/ol0060477 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

after 10 min of reaction). Reaction times for the individual
substrates were not optimized.
A testament to the mildness of the reaction is illustrated with
the 3-trimethylsilylfuroic acid derivative, which cleanly gives
the acid without the intervention of furan oxidation. The
cleavage of the cyclohexene derivative is also noteworthy
because of the well-known ability of hypervalent iodine
derivatives to react with alkenes.5 In this case, the lower yield
may be attributed to some overoxidation of the alkene. Sulfur
derivatives are not compatible with this chemistry because
they are oxidized to the sulfoxide.6,7
The reaction can also be used to hydrolyze the N-
phenylhydrazide and the morpholino derivative. No other
hydrazides were examined, but others should work equally
well.
Table 1. Cleavage of Dialkylhydrazides with PhI(OH)OTs
equiv of
% yield
of acid
hydrazidea,e
PhI(OH)OTs
solvent
benzoic
2
1
1.3
1.3
1.3
2
2
1.3
1.3
water
water
water
water
water
water
water
water
CH2Cl2
water
water
CH2Cl2
water
CH2Cl2
water
91
59
80
80
73
91
64
80
80
benzoicb
benzoicc
octanoic
4-methoxybenzoic
4-nitrobenzoic
cyclohexene carboxylic
octanoic
Acknowledgment. We thank Sean Lapikas for running
the CRC-90 calorimetry experiment.
3-TMS-furoic
2-iPrS-benzoic
hydrocinnamic
d
55
OL0060477
2
2
(5) A review: Wirth, T. Hirt, U. H. Synthesis 1999, 1271.
(6) Xia, M.; Chen, Z.-C. Synth. Commun., 1997, 27, 1315.
Naproxen
71
(7) Sample experimental: To a solution of N,N-dimethylbenzoic hy-
drazide (0.500 g, 3.04 mmol) in 5 mL of water was added [hydroxy-
(tosyloxy)]iodobenzene (2.38 g, 6.08 mmol) at once. The reaction was stirred
for 3 h (not optimized), and then 25 mL of CH2Cl2 and 20 mL water were
added. The layers were separated, and the aqueous was extracted with 3 ×
10 mL of CH2Cl2. The organic layer was concentrated to 10 mL and
extracted with 3 × 10 mL of 10% NaOH. The aqueous was acidified to a
pH of 2 and extracted with 3 × 20 mL of CH2Cl2. The organic was then
dried with sodium sulfate. The solids were removed by filtration, and the
solvent was removed by rotary evaporation to yield 338 mg (91%) of
benzoic acid.
a All hydrazides were the dimethylhydrazide unless otherwise noted. b N-
Phenyl hydrazide was used. c The morpholino hydrazide was used. d Oxi-
dation of the sulfur to the sulfoxide occurs. e Satifactory spectroscopic data
was obtained for all new compounds.
Table 1 give the results for a series of hydrazides. The
efficiency of the reaction is quite good with few limitations.
2140
Org. Lett., Vol. 2, No. 14, 2000