triphenylphosphine dibromide. Unlike the preparation of
other hydrazine reagents,1 only one step is required here to
obtain the starting material in a yield of 78-87%.5
In the earlier studies,2a,b,3 the removal of the triphenylphos-
phonium moiety required several hours of heating with a
strong base. We have found that corresponding salts 3 can
be easily deprotected within 2-3 min at rt in the system
dichloromethane/2 M NaOH. Probably, phase transfer ca-
talysis takes place here and the starting phosphonium salt
serves as a catalyst, so the equimolar mixture of deprotected
hydrazine 4 and triphenylphosphine oxide is obtained.
Further, this mixture can be brought to acylation without
separation into components. Amide nitrogen is not acylated
under typical conditions (1.1 equiv of RCOCl or maleic
anhydride in pyridine solution, 10-15 min). Also, reaction
of the mixture of 4 and triphenylphosphine oxide in acetic
anhydride is a very effective (95%), clean, and fast method
for acetylation. After column chromatography the corre-
sponding hydrazines 5 were obtained in yields of 70-86%
over two steps (R2CO ) PhCO, CH3CO, COCHdCHCOOH).
These substances can be further used for introduction of
additional alkyl and acyl substituents using the previously
illustrated methodology.1a,b For example, the compound 6
where R3 ) allyl was readily synthesized (97%) by our
standard PTC alkylation procedure.1a
Because of the great difference in acidities of the NH
hydrogens in 1, the phosphinimine 2 is readily and selectively
obtained by the action of 1 equiv of BuLi. The following
alkylation is carried out as a one-pot synthesis without
isolation of the phosphinimine. During the reaction the
resulting phosphonium salts 3 precipitate from the reaction
mixture and thus can be easily isolated in good yield, pure
by TLC and NMR spectra. Also, an additional amount of
product can be precipitated by adding ether to the solution.6
However, in the case of 3c and 3f this fraction was
contaminated and therefore not included in the overall yield
given in Table 1. Probably the lower steric hindrance of the
Table 1. The Synthesis of Phosphonium Salts 3
compound no.
R1
reaction time, h yield, %
3a
3b
3c
3d
3e
3f
methyl
benzyl
4-nitrobenzyl
n-butyla
propargyl
ethoxycarbonylmethyl
allyl
4
5
22
50
7
75
76
62
72
68
67
71
The selective substitution of the PNH hydrogen in reagent
1 is evident from an analysis of the NMR spectra of products
3
3. The values of JPH are in the range of 5.2-6.2 Hz and
20
7
2
those of JPC in the range of10.8-15.7 Hz, thus being in
3g
good agreement with previously reported experimental
values.3b To further demonstrate the regioselective alkylation
of 1, compound 11, which is isomeric to 5a (R1 ) R2 )
CH3), was synthesized. For this purpose we used our earlier
developed strategy1a as illustrated in Scheme 2. One Boc-
a 10 equiv of RX was used.
methyl group enables the formation of the 1:1 THF solvate
(calculated by intensities of signals of NMR spectra) in the
case of 3a, since it was not observed in the case of other
salts 3. We failed to introduce the sec-butyl group using the
same procedure. The phosphinimine 2 does not react with
sec-BuBr and causes extensive elimination of the corre-
sponding sec-BuI, resulting in the starting material 1 as a
1:1 THF solvate.
Scheme 2a
(4) (a) Walker, C. C.; Shechter, H. J. Am. Chem. Soc. 1968, 90, 5626-
5627. (b) Merrill, G. B.; Shechter, H. Tetrahedron. Lett. 1975, 4527-4530.
(c) Frøyen, P. A. Phosphorus, Sulfur, Silicon Relat. Elem. 1991, 57, 11-
15.
(5) Reagent 1. The experiment and the weighing of dibromotri-
phenylphosphorane were carried out under argon. To the suspension of Ph3-
PBr2 (4.103 g, 9.72 mmol) in toluene (∼15 mL) was added triethylamine
(1.36 mL, 1 equiv), followed by a solution of tert-butyl carbazate in toluene
(1.284 g, 1 equiv). The reaction was monitored by TLC (EtOAc/chloroform
1:1 as the mobile phase). When the reaction was complete (∼6 h), cold
water was added to the reaction mixture. The insoluble product was isolated
by suction and carefully washed many times with water and toluene, yielding
4.007 g (87%) of white solid 1, pure by TLC. The solid was recrystallized
from acetonitrile for further use, mp 184-185 °C (dec). 1H NMR (CD3-
OD): δ ) 1.46 (s, 9H, Boc), 7.9-8.2 (m, 15H, 3 × Ph). 13C NMR (CD3-
OD): δ ) 28.6 (s, Boc), 83.0 (s, Cq, Boc), 121.1 (d, Ph, JPC ) 102.2),
131.4 (d, Ph, JPC ) 13.1), 135.7 (d, Ph, JPC ) 10.9), 137.0 (s, Ph), 158.2
(CO).
(6) All experiments were carried out in a flask sealed with a septum and
under argon. A typical procedure is given below using 3b as an example:
1.370 g (2.894 mmol) of fine-grained 1 was suspended in THF (17 mL).
On ice cooling and stirring, 1.48 mL of 1.96 M BuLi/hexane (1 equiv) was
introduced dropwise by syringe within 30 min. After another 30 min, benzyl
bromide (0.34 mL, 1 equiv) was added and the ice-bath was removed. After
5 h of stirring, the solid precipitate was isolated by suction and washed
with THF. A total of 1.046 g (64%) of 3b was obtained, pure by TLC
(EtOH/CH2Cl2 1:7). An additional amount of product (0.191 g, pure by
TLC) was precipitated by adding ether to the original THF solution, and
thus the overall yield was 76%.
a (a) CH3I, NaOH/K2CO3, TBAHS, toluene, rt; (b, d) Mg(ClO4)2,
MeCN, 50 °C; (c) Ac2O, Py, 50 °C.
group can be cleaved very selectively in the presence of Mg-
(ClO4)2 from tert-butyl imidodicarbonate 8 and tert-butyl
acylcarbamate 10 as well.1b,7 Under forcing conditions
(excess of acetic anhydride and pyridine in the presence of
8% DMAP for ∼5 days) the amide nitrogen of 9 can be
successfully acetylated, furnishing pure 10. A comparison
of the 1H NMR spectra of 11 and 5a enables one to conclude
that these compounds are isomers but not identical sub-
stances. As the acetyl group is more electronegative than
(7) Stafford, J. A.; Brackeen, M. F.; Karanewsky, D. S.; Valvano, N. L.
Tetrahedron Lett. 1993, 34, 7873-7876.
2298
Org. Lett., Vol. 3, No. 15, 2001
Tsubrik, Olga
