A new practical one-pot conversion of phenols to anilines

Article abstract of DOI:10.1021/ol051080k

(Chemical Equation Presented) A novel one-pot synthesis of anilines from phenols was developed. Using this methodology, anilines are produced in good yield (86%) by a reaction of phenols with 2-bromo-2-methylpropionamide and NaOH in DMA via Smiles rearrangement. Phenols, which are substituted electron-withdrawing groups, are more reactive for Smiles rearrangement. Thiophenols are also converted to anilines. The process is a convenient, safe, and inexpensive method for large-scale preparation of anilines.

Full text of DOI:10.1021/ol051080k

ORGANIC
LETTERS
2
005
Vol. 7, No. 17
629-3631
A New Practical One-Pot Conversion of
Phenols to Anilines
3
Masahiro Mizuno* and Mitsuhisa Yamano
Chemical DeVelopment Laboratories, Pharmaceutical Production DiVision,
Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome,
Yodogawa-ku, Osaka, 532-8686, Japan
Mizuno_Masahiro@takeda.co.jp
Received May 10, 2005
ABSTRACT
A novel one-pot synthesis of anilines from phenols was developed. Using this methodology, anilines are produced in good yield (86%) by a
reaction of phenols with 2-bromo-2-methylpropionamide and NaOH in DMA via Smiles rearrangement. Phenols, which are substituted electron-
withdrawing groups, are more reactive for Smiles rearrangement. Thiophenols are also converted to anilines. The process is a convenient,
safe, and inexpensive method for large-scale preparation of anilines.
Several methods have been developed for the direct conver-
sion of phenols to anilines, because phenols are generally
more available than the corresponding anilines.
Another method, which has been used for the conversion
of phenols to anilines, is an alkylation-Smiles rearrange-
4
ment -hydrolysis sequence. (Scheme 1) The phenol 1 was
These methods include the well-known Bucherer reaction,1
etherified to 2-aryloxy-2-methylpropionamide 3 with 2-bromo-
2
and activation of phenols with 4-chloro-2-phenylquinazoline
3
or diethyl chlorophosphate. However, all of them suffer from
particular drawbacks. The Bucherer reaction is restricted to
naphthalenes and related heterocycles, whereas benzene
derivatives are much less reactive. Rearrangement of aryl-
oxyquinazoline, prepared from 4-chloro-2-phenylquinazoline,
requires extremely high temperatures (ca. 300 °C) and strong
basic conditions. Preparation of aryl diethyl phosphate esters
requires toxic diethyl chlorophosphate and potassium metal
in liquid ammonia.
Scheme 1. Alkylation-Smiles Rearrangement-Hydrolysis
Sequence
(
1) (a) Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49. (b) Wagner, R. B.;
Zook, H. D. Synthetic Organic Chemistry; John Wiley and Sons: New York,
953; p 670. (c) Schroter, R. Houben-Weyl-Muller 1957, 11, 143. (d) Rieche,
A.; Seeboth, H. Ann. 1960, 638, 66.
2) (a) Morrow, D. F.; Hofer, R. M. J. Med. Chem. 1966, 9, 249. (b)
1
(
Conrow, R. B.; Bernstein, S. Steroids 1968, 11, 151. (c) Scherrer, R. A.;
Beatty, H. R. J. Org. Chem. 1972, 37, 1681. (d) Matsumoto, K.; Stark, P.;
Meister, R. G. J. Med. Chem. 1977, 20, 17. (e) Sadek, S. A.; Shaw, S. M.;
Kessler, W. V.; Wolf, G. C. J. Org. Chem. 1981, 46, 3259.
(3) Rossi, R. A.; Bunnett, J. F. J. Org. Chem. 1972, 37, 3570.
1
0.1021/ol051080k CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/21/2005

2
-methylpropionamide 2 in dioxane. This underwent Smiles
The starting compound, 6-hydroxy-1-tetralone 6, was
prepared from commercially available 6-methoxy-1-tetralone
quantitatively by acid hydrolysis.
First, we tried the Weidner method, which is a three-
step, two-pot process; then, we confirmed that the alkylation
and Smiles rearrangement proceeded successfully. However,
the above-mentioned combination of sodium hydride and
N,N-dimethylformamide used in this method could be
dangerous.
rearrangement to give the N-aryl-2-hydroxypropionamide 4.
Then, hydrolysis of 4 gave the aniline 5.
4
f
However, this method also has some difficulties. This
4
e
sequence consists of a three-step, three-pot process or a
three-step, two-pot process4f and requires sodium hydride
and N,N-dimethylformamide, which has a threat of uncon-
trollable exothermic reaction.
5
Recently, palladium-catalyzed amination of aryl sulfonates,
6
We have studied the modification of bases and solvents
e.g., aryl triflates and aryl nonaflates, has been investigated.
(Table 1) and discovered that an alkali metal hydroxide in a
However, this method needs to derive aryl sulfonates from
phenols and has serious problems with respect to cost and
remaining of palladium.
We report herein the development of a novel three-step,
one-pot Smiles rearrangement process to prepare anilines
from phenols, which have electron-withdrawing groups.
Table 1. Reaction Conditions of Smiles Rearrangement
We selected 6-amino-1-tetralone 9 as a target aniline,
which is an important intermediate for medicines and
chemicals. Until now, aniline 9 has been synthesized by two
general synthetic methods.7
,8
yield (%)a
The first of these involves a Friedel-Crafts ring-closure
step near the end of the synthesis. â-Benzoylpropionic acid
as a starting material is nitrated to give the meta-nitro
compound and is then reduced to the amine. Acetylation of
the amino group and hydrogenolysis of the ketonic oxygen
entry
base
NaH
NaOH
NaOH
NaOH
NaOH
NaOMe
NaOMe
Na2CO3
Na2CO3
solvent
temp./time
7
8
1
2
3
4
5
6
7
8
9
DMA
DMA
DMA
MeOH
MeOH
MeOH
MeOH
DMA
rt/0.5 h
rt/0.5 h
rt/2 h
rt/2 h
reflux/2 h
rt/2 h
reflux/1 h
rt/2 h
140 °C/1 h
ndb
22
nd
96
75
98
56
99
27
89
73
94
0.3
13
0.1
26
nd
72
gives the acetamido acid. Friedel-Crafts cyclization gives
7
6-acetamido-1-tetralone, which is hydrolyzed to aniline 9.
The alternative synthetic method involves the introduction
of ketonic oxygen into the saturated side chain as a key step.
Tetralin as a starting material is acetylated to give 6-acetyl-
tetralin and then provides the oxime. Beckmann rearrange-
ment of the oxime gives 6-acetamidetetralin. Selective
oxidation gives 6-acetamido-1-tetralone, which is hydrolyzed
DMA
a
Yield based on quantitative HPLC analysis. b nd ) not detected.
8
dipolar aprotic solvent, for example, sodium hydroxide in
N,N-dimethylacetamide (DMA), is a mild and safe combina-
tion for the Smiles rearrangement. Furthermore, we found
that the combination of an alkali metal hydroxide in a dipolar
aprotic solvent is successful not only in the Smiles rear-
rangement but also in the O-alkylation and the hydrolysis
reaction. As a result, it is possible to make a three-step
process in one-pot.
to aniline 9.
These two general methods require many steps to produce
aniline 9. Our novel three-step, one-pot Smiles rearrangement
process should be a very useful method.
(
4) (a) Bayles, R.; Johnson, M. C.; Maisey, R. F.; Turner, R. W. Synthesis
1
1
2
1
1
977, 31, 33. (b) Fitzgerald, L. R.; Blakeley, R. L.; Zerner, B. Chem. Lett.
984, 29. (c) Coutts, I. G. C.; Southcott, M. R. J. Chem. Res., Synop. 1988,
41. (d) Coutts, I. G. C.; Southcott, M. R. J. Chem. Res., Miniprint 1988,
921. (e) Coutts, I. G. C.; Southcott, M. R. J. Chem. Soc., Perkin Trans. 1
990, 767. (f) Weidner, J. J.; Weintraub, P. M.; Schnettler, R. A.; Peet, N.
The phenol 6, 3 equiv of 2-bromo-2-methylpropionamide
, and 3 equiv of sodium hydroxide in DMA were stirred at
2
P. Tetrahedron 1997, 53, 6303. (g) Beier, P.; Mindl, J.; Sterba, V.; Hanusek,
J. Org. Biomol. Chem. 2004, 2, 562.
room temperature to produce 2-aryloxy-2-methylpropiona-
mide 7. Sodium hydroxide (9 equiv) was added to this
solution, and then the mixture was stirred at 50 °C to produce
N-aryl-2-hydroxypropionamide 8. Water was added to this
solution, and then the mixture was refluxed to produce the
aniline 9. At the end of the reaction, addition of water gave
a 59% yield of 9, which crystallized directly from the reaction
solution. (Scheme 2)
We isolated 7 and 8, which are novel intermediates, by
addition of water in each step of the reaction mixture. We
obtained a 47% yield of 7 and a 76% yield of 8, which
crystallized directly from the reaction solution mixture.
N-Aryl-2-hydroxypropionamide 8 is an amino-protected
compound of aniline 9, which allows us to modify and later
hydrolyze 8.
(
5) (a) Buckley, J.; Webb, R. L.; Laird, T.; Ward, R. J. Chem. Eng. News
982, 60 (28), 5. (b) De Wall, G. Chem. Eng. News 1982, 60 (37), 5, 43.
6) (a) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1264. (b)
Louie, J.; Driver, M. S.; Hamann, B. C.; Hartwig, J. J. Org. Chem. 1997,
2, 1268. (c) Ahman, J.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6363.
d) Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L.
1
(
6
(
Tetrahedron Lett. 1997, 38, 6367. (e) Wolfe, J. P.; Tomori, H.; Sadighi, J.
P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158. (f) Ullrich, T.;
Giraud, F. Tetrahedron Lett. 2003, 44, 4207. (g) Anderson, K. W.; Mendez-
Perez, M.; Piego, J.; Buchwald, S. L. J. Org. Chem. 2003, 68, 9563. (h)
Rahman, O.; Kihlberg, T.; Langstroem, B. Org. Biomol. Chem. 2004, 2,
1
612.
7) (a) Somerville, L. F.; Allen, C. F. H. Organic Syntheses; Wiley: New
(
York, 1943; Collect. Vol. II, p 81. (b) Allinger, N. L.; Jones, E. S. J. Org.
Chem. 1962, 27, 70.
(
8) (a) Newman, M. S.; Zahm, H. V. J. Am. Chem. Soc. 1943, 65, 1097.
(
b) Schofield, K.; Swain, T.; Theobald, R. S. J. Chem. Soc. 1949, 2399. (c)
Allinger, N. L.; Jones, E. S. J. Org. Chem. 1962, 27, 70. (d) Biggs, D. F.;
Casy, A. F.; Chu, Ih; Coutts, R. T. J. Med. Chem. 1976, 19, 472.
3630
Org. Lett., Vol. 7, No. 17, 2005

Scheme 2. Novel Synthesis of 6-Amino-1-tetralonea
Table 2. One-Pot Syntheses of Anilines from Phenols
(Thiophenols)
a
Isolated yield ) 59% (three-step, one-pot, only filtration).
Using our protocol, we were able to produce a variety of
phenols or thiophenols. (Table 2) Phenols or thiophenols,
which have electron-withdrawing groups, converted to
anilines particularly smoothly, and the anilines were isolated
in good yield by filtration.
a
This three-step, one-pot method for the conversion of
phenols to anilines is the most convenient, safe, and
inexpensive compared to other methods.
Conversion based on quantitative HPLC analysis (not optimized).
b
Isolated yield (products separated as crystals from reaction mixture by
filtration).
In summary, we have described a three-step, one-pot
alkylation-rearrangement-hydrolysis procedure for the
conversion of 6-hydroxy-1-tetralone 6 to 6-amino-1-tetralone
Acknowledgment. The authors thank Mr. Kokichi Yoshi-
da and Dr. Kiminori Tomimatsu for helpful discussions.
9. This is the simplest method to prepare 9. We then extended
this method to the conversion of phenols or thiophenols to
anilines, which have electron-withdrawing groups. This
method produces a convenient, inexpensive, and scalable
method of preparation of anilines. Additional examples of
this three-step, one-pot alkylation-rearrangement-hydroly-
sis procedure will be the subject of a subsequent report.
Supporting Information Available: Detailed experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL051080K
Org. Lett., Vol. 7, No. 17, 2005
3631