Staudinger Reaction of Azides with Acyl Derivatives
J . Org. Chem., Vol. 61, No. 5, 1996 1699
6.84 (NH, br t, 1H, J ∼ 4-5 Hz), (CD3CN + D2O) 4.36 (s, 2H),
no NH signal, mass spectrum m/ z 249 (M+).
38 mmol) and concd H2SO4 (0.75 mL) were stirred for 1 h at
0-10 °C. R-Hydroxy-o-xylene (1.222 g, 10 mmol) in acetoni-
trile (3 mL) was added at 0-5 °C over 30 min and the solution
stirred at rt for 2 d. Some unreacted alcohol remained (TLC).
Most of the solvent was evaporated, and both 10% aqueous
KHCO3 and solid NaHCO3 were added until CO2 evolution
stopped. The precipitated sulfate was dissolved in water. This
solution and the filtrate were extracted with ethyl acetate. The
organic phase was washed with saturated NaCl solution (5
mL), dried (MgSO4), and evaporated and the residue chro-
matographed [eluant, 10% ethyl acetate-CH2Cl2] to give
R-acetamido-o-xylene (6b) (0.537 g, 3.29 mmol) (33% yield):
B. The iminophosphorane 3 was produced by stirring a
mixture of azide 1 (0.0807 g, 0.346 mmol) and Ph3P (0.0988 g,
0.377 mmol) overnight in CHCl3 (15 mL, purified by passage
through alumina). Acetyl chloride (30 µL, 0.42 mmol) in CHCl3
(10 mL) was added over 10 min, the mixture was stirred
overnight, stored in the freezer, and worked up a few days
later (TLC on silica [eluant, methanol-acetonitrile (15:85)]).
The residue showed three major compounds, Ph3PdO, amide
6, and a polar, fluorescent, iodine-positive material. Half of
the solvent was evaporated, cyclohexane added, and the
precipitate filtered off and washed successively with 0.5 mL
portions of CH2Cl2, ethyl acetate, and acetonitrile. The solid
(0.0299 g) contained chloride ion (AgNO3), was soluble in water
and methanol, and had the 1H NMR spectrum [(CD3OD) δ 1.83
(s, 3H), 1.95 (s, 3H), 2.47 (s, 3H), 4.33 (s, 2H), 5.49 (s, 1H)
ppm] of syn-(CH2NH3+Cl-,CH3)(CH3,CH3)B (9). The residue
from the filtrates was chromatographed to give (1) 0.0521 g
(0.19 mmol) of Ph3PdO (50% yield), (2) 0.021 g (0.098 mmol)
of amide 6 (eluant: acetonitrile) (28% yield), and (3) 0.0528 g
of the (N-alkylamino)phosphonium chloride 8 [eluant, metha-
nol-acetonitrile (1:9)] (29% yield) (positive chloride ion) which
formed crystals by slow evaporation of a CDCl3 solution. The
molecular weight was determined by titration with coulo-
metrically generated mercurous ions.33 An aliquot (0.9 to 1
mL) of a methanol solution (5.05 mg/5 mL) was pipetted into
the titration vessel. Perchloric acid (1.2 M, 20 drops) was
added with enough methanol (∼4 mL) to cover the electrodes.
The end point was determined potentiometrically with two
identical mercury-coated silver electrodes at constant current
(0.5 µA). The current for generating Hg(I) was 2 mA. Because
of the slow response of the electrodes, the end point lags behind
the equivalent point. A series of titrations were performed
with successive additions of new samples. The distance
between the successive end points corresponds to the current
used, with moles of Cl- given by it/F (i, current; t, time). For
a 0.9 mL aliquot, t was 84.6 s, equivalent to 1.76 × 10-6 mol
close to the value of 1.8 × 10-6 mol for a molecular weight of
503.4, consistent with structure 8.
1
mp 55 °C; H NMR (CDCl3) δ 2.02 (s, 3H), 2.33 (s, 3H), 4.435
(d, J ) 5.2 Hz, 2H), 5.56 (bs, 1H), 7.20 (s, 4H); mass spectrum
m/ z 163.2 (91.6, M+).
Rea ction of r-Azid o-o-xylen e (1b), Acetyl Ch lor id e,
a n d Tr ip h en ylp h osp h in e (Tr ia za p h osp h a d ien e Ad d u ct
P a th w a y). Triphenylphosphine (0.214 g, 0.82 mmol) was
added to a solution of the azide 1b (116 µL, 0.121 g, 0.82 mmol)
and AcCl (60 µL, 0.066 g, 0.84 mmol) in purified CHCl3 (2.5
mL), and the mixture was stirred for 1 week. A solid residue
(0.03 g) was not investigated. Using precautions against water
entry, the filtrate was evaporated and the residue distilled bulb
to bulb, bp50Torr 150 °C. The acrid odor of R-chloro-o-xylene
permeated the apparatus; the distillate had the expected mass
spectrum: m/ z 40 (100), 142 (32.6) [M+]. An NMR spectrum
showed both acetic anhydride and R-chloro-o-xylene (see
below); Ph3PdO remained undistilled.
r-Ch lor o-o-xylen e (10b). R-Hydroxy-o-xylene (0.245 g, 2
mmol) was dissolved in ether (10 mL), thionyl chloride (250
µL, 0.41 g, 3.4 mmol) was added, and the solution was stirred
for 2 d. After the solvent was removed, the residue was
distilled bulb to bulb to give R-chloro-o-xylene (10b): bp55Torr
150 °C; 1H NMR (CDCl3) δ 2.43 (s, 3H), 4.61 (s, 2H), 7.18-
7.32 (m, 4H) ppm; mass spectrum m/ z 140 (100), 142 (32.6)
[M+]. Only enough material was isolated to confirm the
identify of 10b.
Tr id eu ter ioa cetyl Ch lor id e. Thionyl chloride (9.7 g,
0.082 mol) was added dropwise to d4-acetic acid (4.40 mL, 0.078
mol) in distilled DMF at 0 °C. The reaction was left to stir for
5 min and then distilled through a long Vigreux column and
collected with a double condenser cooled by ice-water. The
product, CD3COCl (40% yield), gave no 1H NMR signals in the
methyl region. A quintet at 2.64 ppm, which remained
unchanged during all reactions, was attributed to an impurity.
NMR Kin etics Exp er im en ts. All the experiments were
carried out using 200 MHz AM, 360 MHz AMX, or 500 MHz
ARX spectrometers and the Bruker kinetics program. The
data were treated with the Bruker automatic Fourier trans-
form program. Homogeneity was established for azide in the
case of iminophosphorane (“normal”) reactions, for azide and
acyl halide in the triazaphosphadiene adduct reactions, and
for Ph3P in the case of all reactions followed by 31P NMR. To
minimize effects on homogeneity, concentrated reactants were
added and the experiment begun. The time elapsed between
these additions and the first acquired spectrum was usually
45 s. The kinetics were usually followed over a period of ca.
8 h at rt (nominally 16 °C). Each spectrum was acquired with
eight scans and 5 s relaxation delay. The spectra were spaced
at increasing intervals starting with 5 s periods. In some
cases, 31P NMR spectra were acquired alternately in the same
run with 1H NMR spectra for a better defined comparison.
Half-lives were estimated by using the integrated NMR
peaks (A) in an uncomplicated region of the spectrum with
t1/2 ) ln 2/[ln(A0/A)(t1 - t2)]. First-order (or pseudo-first-order)
kinetics were assumed, and half-lives were obtained at those
times for which competing reactions were minimal.
syn -[CH2NHP +(C6H5)3,CH3][CH3,CH3]B Cl- (8): yellow
solid, mp 80-100 °C with sublimation, MW 503.4 (Cl- titra-
tion); 1H NMR (CDCl3) δ 1.32 (s, 3H), 1.78 (s, 3H), 2.56 (s,
3H), 4.50 (s, 1H), 4.59 (s, 1H), 7.62-7.95 (m, 15H), 9.89 (bs,
1H); 31P NMR 38.96 ppm. The δ values in a series of solvents
of increasing polarity are given in Table 1.
Rea ction of syn -(Azid om eth yl,m eth yl)(m eth yl,m eth -
yl)bim a n e (1), Acetyl Ch lor id e, a n d Tr ip h en ylp h osp h in e
(Tr ia za p h osp h a d ien e Ad d u ct P a th w a y). Triphenylphos-
phine (0.0684 g, 0.261 mmol) was added all at once to a
solution of azide 1 (0.0531 g, 0.228 mmol) in purified CHCl3
(10.5 mL) and AcCl (30 µL, 0.422 mmol) and the mixture
stirred overnight. After evaporation of the solvent, the solid
residue was flash chromatographed on silica gel to give the
following materials: (1) [eluant, ethyl acetate-CH2Cl2 (5:95)]
syn-(CH2Cl,CH3)(CH3,CH3)B (13) (0.0251 g, 0.111 mmol) (50%
yield), (2) (eluant, ethyl acetate) Ph3PdO (0.039 g, 0.14 mmol)
(54%), and (3) (eluant, acetonitrile) 6 (0.0134 g, 0.054 mmol)
(24% yield). The identity of the chlorobimane26 10 was
confirmed by mp (132-4 °C), mass spectrum [m/ z 226 (100),
1
228 (33)], H NMR [δ 1.86 (s, 3H), 1.95 (s, 3H), 2.44 (s, 3H),
4.48 (s, 2H) ppm], and TLC comparison with authentic
material.
Con ver sion of r-Azid o-o-xylen e (1b) to Im in op h osp h o-
r a n e. Rea ction w ith Acetyl Ch lor id e. Triphenylphosphine
(0.124 g, 0.473 mmol) in CHCl3 (10 mL) was added to a solution
of the azide 1b (60 µL, 0.064 g, 0.43 mmol) in CHCl3 (15 mL).
The mixture was stirred for 1 week, and then AcCl (60 µL,
0.84 mmol) was added. After the mixture was stirred for 4 d,
o-xylyl-R-ammonium chloride (9b) (25.1 mg, 0.16 mmol) (37%
yield) [1H NMR (DMSO-d6) δ 2.35 (s, 3H), 4.01 (s, 2H), 7.27,
7.37 (4H), 8.27 (bs, 3H)] [positive Cl- test] was filtered off, the
filtrate evaporated, and the residue chromatographed [eluant,
10-20% ethyl acetate-CH2Cl2] to yield an inseparable Ph3PdO
and R-acetamido-o-xylene (6b) (NMR spectrum identical to
that of authentic 6b in the high field region, see below).
r-Aceta m id o-o-xylen e (6b). Acetonitrile (2 mL, 1.56 g,
Three types of reactions were studied (200 MHz, several at
500 MHz) by means of 1H and 31P NMR spectroscopy: (1) the
reaction of a phosphine and an azide to form an iminophos-
phorane, (2) the reaction of an iminophosphorane with an
acylating agent (“normal” pathway), and (3) the reaction of a
phosphine with a mixture of a reactive acyl derivative and an
azide (“triazaphosphadiene adduct” pathway, TAP).
Kin etic Stu d ies of Im in op h osp h or a n e F or m a tion . A.
1H NMR. (1) Ph3P (5.9 mg, 0.023 mmol) was added to syn-
(CH2N3,CH3)(CH3,CH3)B (1) (5.0 mg, 0.021 mmol) in CDCl3