Convenient Reductive Deamination of Aromatic Amines
J . Org. Chem., Vol. 66, No. 25, 2001 8295
Ta ble 2. Red u ctive Dea m in a tion of F u n ction a lized
Ar yla m in es
at -10 °C for 30 min. An aliquot of the ethereal chloroamine
solution could be iodometrically titrated using potassium iodide
and sodium thiosulfate to accurately determine the chloro-
amine concentration in the organic solution (see Supporting
Information). The typical yield of chloroamine in solution using
this procedure was 5.0 mmol. Not e: Although no problems
were experienced in the preparation and handling of chloro-
amine using this procedure, it should be noted that only dilute
solutions of chloroamine should be prepared. More concen-
trated solutions readily decompose potentially creating a safety
hazard.14 The preparation and reactions of chloroamine should
also be carried out in a well-ventilated hood.
Gen er a l Ar yla m in e Hyd r od ea m in a tion P r oced u r e.
Methanesulfonyl chloride (0.92 mL, 12 mmol) was added to a
cooled 0 °C stirred solution of the arylamine (12 mmol) in
pyridine (1.09 mL) and dichloromethane (35 mL), keeping the
temperature below 10 °C. The mixture was allowed to come
to room temperature overnight and then quenched with 6 N
NaOH and enough water to dissolve the resulting solid. Phases
were separated, and the aqueous phase was extracted with
dichloromethane. The aqueous phase was cooled to 0° C and
acidified with concentrated HCl. The resulting solid methane-
sulfonamide was filtered and dried under reduced pressure.
The crude dried product was generally adequately pure for
subsequent reactions.
The methanesulfonamide (3 mmol) in DMF (15 mL) was
stirred and cooled to 0 °C under a positive nitrogen atmo-
sphere. Sodium hydride (95%, 152 mg, 6 mmol) was added and
the mixture stirred for an additional 2 h. The freshly prepared
chloroamine solution (5 mmol) was added and the mixture
stirred at 0° C for 4 h and allowed to come to room temperature
with stirring overnight. The mixture was then poured into ice-
water (50 mL) and extracted with hexanes (2 × 50 mL), and
the combined hexane extracts were consecutively washed with
1 M HCl, 3 M NaOH, water, and saturated sodium chloride.
Concentration afforded the desired reduction products in good
to excellent yields as described in Tables 1 and 2. All products
are known compounds with spectra and physical constants
identical to those reported in the literature.
4-Meth a n esu lfon a m id oben zoic Acid . To a stirred cooled
(0 °C) solution of 4-aminobenzoic acid (1.37 g, 10 mmol) in THF
(35 mL) was added alternately in portions NaOH (1.7 M, 15
mL) and methanesulfonyl chloride (1.13 mL, 15 mmol), keep-
ing the pH 9-11. The mixture was stirred 5 h at 0 °C and
allowed to come to room temperature overnight. The mixture
was cooled in an ice bath and slowly acidified to pH 2 with
cold 1.0 M sulfuric acid. The mixture was extracted with ethyl
acetate (3 × 30 mL), and the combined organic extracts were
washed with water and brine. Drying with MgSO4 and
concentration afforded the crude sulfonamide, 1.59 g (74%
yield), mp 119-121 °C (lit.15 mp 121-123 °C), which was of
satisfactory purity for direct use in the deamination reaction.
R ed u ct ion of 4-Met h a n esu lfon a m id ob en zoic Acid .
4-Methanesulfonamidobenzoic acid (430 mg, 2 mmol) stirred
in DMF (15 mL) at 0 °C was treated with NaH (95%, 173 mg,
6.8 mmol), and stirring continued for 2h at 0 °C. Chloroamine
solution (3.3 mmol) was added, keeping the temperature at 0
°C for 3 h and then allowing the mixture to come to room
temperature overnight. The mixture was then acidified to pH
2 with 1 M HCl and extracted with dichloromethane (3 × 30
mL). Drying over sodium sulfate and concentration afforded
benzoic acid, 200 mg, 82% yield, identical in all respects to
authentic material.
a
d
Reference 8. b Reference 15. c Reference 16. This work. e Ref-
erence 17.
reaction conditions, benzamide could only be recovered
in 62% yield.
The mild conditions necessary for the deamination
sequence appear to be ideal for the reduction of complex
arylamines.13 The ready formation of the required inter-
mediate methanesulfonylhydrazines using the proce-
dures described here may lead to a greatly expanded
utility for other functionalizing deamination reactions.
Related work in these areas is currently in progress.
Exp er im en ta l Section
1H spectra were recorded on a 300-MHz spectrometer.
Infrared spectra were recorded using KBr or neat liquid
samples. Mass spectrometric determinations, and purity as-
sessments were carried out using GC-MS. Melting points are
uncorrected. Elemental analyses were carried out by Desert
Analytics, Tucson, AZ. Unless otherwise described, commercial
reagents were used without further purification.
Ch lor oa m in e (Mod ifica t ion of t h e P r oced u r e of
Sch m itz a n d Co-Wor k er s).12 Ammonium chloride (0.707 g,
13.2 mmol) was added to a 2.0 M aqueous ammonia solution
(4.35 mL, 8.7 mmol), and the mixture was cooled in an ice bath.
To this cooled mixture was added dropwise 5.25% (0.76 M)
aqueous sodium hypochlorite (commercial bleach) (18.8 mL,
14.3 mmol) over 15 min and the mixture stirred an additional
15 min at 0 °C. The aqueous solution was extracted with a
cold (0 °C) mixture of dichloromethane (12 mL) and ether (10
mL) and then with another portion of cold dichloromethane
(12 mL). The combined organic extracts were dried with CaCl2
Redu ction of 4-Meth an esu lfon am idoph en ol. To a stirred
cooled (0 °C) solution of 4-methanesulfonamidophenol16 (561
(14) Goehring, R. R. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L., Ed.; Wiley: New York, 1995; pp 1052-1053.
(15) Hu, H.; Mendoza, J . S.; Lowden, C. T.; Ballas, L. M.; J anzen,
W. P. Bioorg. Med. Chem. 1997, 5, 1873-1882.
(13) Although direct comparisons between the methods reported
here and standard deamination methods described in the literature
are possibly unreliable, the overall yields described in this work are
comparable or superior to deaminations previously reported. (e.g.,
p-toluidine: yield, this work 84%, reported 77-83%;18 2-aminonaph-
thalene, this work 75%, reported 35-45%;18 4-aminobenzoic acid, this
work 61%, reported 68%;19 methyl 4-aminobenzoate, this work, 87%,
(16) Belyaev, A.; Zhang, X.; Augustyns, K.; Lambeir, A.-E. De
Meester, I.; Vedernikova, I.; Scharpe, S.; Haemers, A. J . Med. Chem.
1999, 42, 1041-1052.
(17) Wazeer, M. I. M.; Ali, S. A. Magn. Reson. Chem. 1990, 28, 601-
605.
reported 54%.19
)
(18) Kornblum, N. Org. React. 1944, 2, 262-340.