Conversion of N-aromatic amides to O-aromatic esters

Article abstract of DOI:10.1021/ol026051d

(Matrix Presented) N-Aromatic secondary amides can be transformed into O-aromatic esters in high yield via N-nitrosamide intermediates. The amides can be generated in situ from the corresponding aromatic amines or nitro compounds, and phenols can easily be made from the esters. The reaction can be modified by addition of methyl methacrylate or toluene at 0 °C to give polymerization or deamination, respectively. The rearrangement mechanism may involve radical formation and recombination.

Full text of DOI:10.1021/ol026051d

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2349-2352
Conversion of N-Aromatic Amides to
O-Aromatic Esters
Daniel T. Glatzhofer,* Raymond R. Roy, and Kimberly N. Cossey
Department of Chemistry and Biochemistry, The UniVersity of Oklahoma,
Norman, Oklahoma 73019
dtglatzhofer@chemdept.chem.ou.edu
Received April 20, 2002
ABSTRACT
N-Aromatic secondary amides can be transformed into O-aromatic esters in high yield via N-nitrosamide intermediates. The amides can be
generated in situ from the corresponding aromatic amines or nitro compounds, and phenols can easily be made from the esters. The reaction
can be modified by addition of methyl methacrylate or toluene at 0 °C to give polymerization or deamination, respectively. The rearrangement
mechanism may involve radical formation and recombination.
The oxygenation of aromatic rings is a useful synthetic
transformation, but direct methods to accomplish this in a
controlled fashion are rare. A common strategy is nitration
of an aromatic ring, followed by reduction of the nitro group,
diazotization of the resulting amino group, and finally
decomposition of the diazo group in the presence of water
to give the desired phenol. While the nitration, reduction,
and diazotization steps are generally straightforward, even
a brief survey of the literature shows that the decomposition
of diazonium salts in water gives highly variable yields of
phenols ranging from excellent to none, depending on the
other functional groups present, and a variety of techniques
have been developed in an effort to improve yields.1,2
Therefore, development of alternative general methods to
replace N-aromatic nitrogen with O-aromatic oxygen is
desirable.
studies were carried out on this unusual reaction, and it was
postulated that decomposition occurred by loss of nitrogen
to give a carbocation and acyloxy anion, which quickly
recombine to give the ester. While interesting,10 this specific
transformation is of limited synthetic utility as O-aliphatic
esters and their corresponding aliphatic alcohols are readily
available through other synthetic methods. In contrast, the
analogous reaction of N-aromatic secondary amides to give
O-aromatic esters would be a useful alternative to the
decomposition of aromatic diazonium salts to give phenols
because the O-aromatic esters can generally be quantitatively
converted to phenols, if desired, by base-catalyzed trans-
esterification or saponification/protonation.11 However, White
reported that attempts to convert N-aromatic secondary
amides to O-aromatic esters by thermal decomposition of
the corresponding N-nitrosamides were unsuccessful,5 pre-
Several decades ago, White and co-workers showed that
N-aliphatic secondary amides could be converted to N-
nitrosamides, which would thermally rearrange to acyloxy-
azoaliphatics and decompose in inert solvents to give
O-aliphatic esters and nitrogen (Scheme 1).3-9 Mechanistic
Scheme 1
(1) Horning, D. E.; Ross, D. A.; Muchowski, J. M. Can. J. Chem. 1973,
51, 2347.
(2) Cohen, T.; Dietz, A. G., Jr.; Miser, J. R. J. Org. Chem. 1977, 42,
2053.
(3) White, E. H. J. Am. Chem. Soc. 1954, 76, 4497.
(4) White, E. H. J. Am. Chem. Soc. 1955, 77, 6008.
10.1021/ol026051d CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/08/2002

Table 1. Conversion of N-Aromatic Amides (R-NHCOR′) to O-Aromatic Esters (RO2CR′) via N-Nitrosamide Rearrangement
example
R
R′
ester yield, %a
mp, °C
lit. mp, °Cb
purity, %c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
p-nitrophenyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
phenyl
p-methoxyphenyl
methyl
methyl
trifluoromethyl
methyl
methyl
93
80
92
88
94
82
83
94
91
91
91
83
94
72
76
81-82
81-82
p-methoxyphenyl
p-bromophenyl
p-cyanophenyl
p-phenylphenyl
p-methylphenyl
m-methylphenyl
o-tert-butylphenyl
phenyl
p-cyanophenyl
1-naphthyl
8-acetamido-1-naphthyl
p-phenylphenyl
2-pyridyl
98
21-23
63-65
87-88
21.5
63
88-89
97
91
24-26
68-70
60
47-49
146-148
34-36
24.3
68-70
6019
47-49
147-148
34-3618
8521
4-[2.2]paracyclophanyl
134-135
132.5-13411
a Yield refers to isolated, purified product in the case of solids; for liquid esters yield refers to total isolated yield corrected for purity. b All mp’s were
taken from ref 16 unless otherwise noted. c Purities of liquid esters were determined by semiquantitative GC-MS; mass spectra matched literature values
taken from ref 17 unless otherwise as noted.
sumably as a result of the difficulty of forming the
intermediate phenyl carbocation.
titatively converted to 4-hydroxy[2.2]paracyclophane by
hydroxide-catalyzed transesterification in methanol.11,13 This
surprising result provided the impetus to investigate the scope
and synthetic utility of this transformation.
Literature descriptions of the conversion of 4-amino-[2.2]-
paracyclophane to 4-hydroxy[2.2]paracyclophane by the
diazotiation/decomposition routes reported relatively low
yields,11-13 and repetition in our laboratory gave uniformly
unacceptable results (<10% yield). Therefore, treatment of
N-acetyl-4-amino[2.2]paracyclophane14 with excess sodium
nitrite in 2:1 acetic anhydride/acetic acid at 0 °C (to generate
+NO in situ), followed by warming to room temperature,
was carried out to form the corresponding N-nitrosamide,4
which was to be isolated, transferred to an inert solvent, and
thermolyzed in an attempt to generate 4-acetoxy[2.2]-
paracyclophane (Scheme 2). However, the isolated product
The results of conversion of a variety of N-aromatic
secondary amides to O-aromatic esters are shown in Table
1.15 Solid products were characterized by melting points16
and liquid esters by GC-MS.17 Yields were uniformly very
good to excellent, and the technique is clearly tolerant of a
wide range of functional groups and their position on the
aromatic rings, most notably the excellent yield (94%) for
(11) Norcross, B. E.; Becker, D.; Cukier, R. I.; Schultz, R. M. J. Org.
Chem. 1967, 32, 220.
(12) Cram, D. J.; Allinger, N. L. J. Am. Chem. Soc. 1955, 77, 6289.
(13) Cipiciani, A.; Fringuelli, F.; Mancini, V.; Piermatti, O.; Pizzo, F.;
Ruzziconi, R. J. Org. Chem. 1997, 62, 3744.
(14) Falk, H.; Reich-Rohrwig, P.; Schlo¨gl, K. Tetrahedron 1970, 26, 511.
(15) The desired acetamide (1-3 mmol) is placed in a flask and dissolved
in 15 mL of a 2:1 mixture of acetic anhydride and acetic acid. The flask is
cooled to 0 °C in an ice bath. While the mixture is being slowly stirred
magnetically, solid sodium nitrite (2 equiv, 1.6 equiv if the molecule has a
nitrile group) is added to the mixture, and the vessel is lightly capped.
Evolution of a brown gas occurs, the solution may change color, and
sometimes a solid comes out of solution. The flask is kept in the ice bath
for 2 h and allowed to warm to room temperature, where it is typically
kept for 24 h, although the reaction may be complete much sooner. The
solution may darken on standing. The mixture is poured into ice/water,
and for solid samples, the resulting solid that forms is collected by suction
filtration. Prolonged stirring is sometimes needed to sufficiently hydrolyze
acetic anhydride, which can contribute to oil formation. Traces of acetic
acid/anhydride can often be removed from the solid by dissolving in ethanol,
pouring into ice/water, and collecting the resulting solid by suction filtration.
The samples can be recrystallized from appropriate solvents as needed. For
liquid or low melting point esters, the aqueous mixture from quenching the
reaction is extracted with methylene chloride (3 × 50 mL). The combined
methylene chloride extracts are washed with saturated sodium bicarbonate
solution (3 × 50 mL) and dried using anhydrous magnesium sulfate.
Methylene chloride is removed under reduced pressure to give the desired
crude ester.
Scheme 2
was shown not to be the N-nitrosamide but rather the desired
4-acetoxy[2.2]paracyclophane11,13 in 76% yield (Table 1,
example 15).15 The 4-acetoxy[2.2]paracyclophane was quan-
(5) White, E. H. J. Am. Chem. Soc. 1955, 77, 6011.
(6) White, E. H. J. Am. Chem. Soc. 1955, 77, 6014.
(7) White, E. H.; Elliger, C. A. J. Am. Chem. Soc. 1967, 89, 165.
(8) White, E. H. Organic Syntheses; Wiley: New York, 1973; Collect.
Vol. V, p 336.
(9) White, E. H.; Dzadzic, P. M. J. Am. Chem. Soc. 1976, 98, 4020.
(10) For other recent research concerning N-nitrosamide rearrangements,
see: Darbeau, R. W.; Perez, E. V.; Sobieski, J. I.; Rose, W. A.; Yates, M.
C.; Boese, B. J.; Darbeau, N. R. J. Org. Chem. 2001, 66, 5679 and references
therein.
(16) Literature mp’s were taken from The Dictionary of Organic
Compounds, 6th ed.; Chapman and Hall: New York, 1996 unless otherwise
noted.
(17) Unless otherwise noted, mass spectra were correlated with standard
spectra available on the SDBS website, http://www.aist.go.jp/RIODB/SDBS/
(20Dec2001).
2350
Org. Lett., Vol. 4, No. 14, 2002

the sterically hindered o-tert-butylphenyl acetate (Table 1,
example 8). The carboxyl moiety (R′ in Table 1) can also
be varied to yield O-aromatic benzoate or trifluoroacetate
esters (Table 1, examples 9, 10, and 1318), showing that ester
formation occurs by recombination of fragments rather than
by reaction of the aromatic fragment with solvent. Two other
specific examples of the synthetic utility of this reaction are
the formation of p-cyanophenyl p-methoxybenzoate (Table
1, example 10), a liquid crystalline compound,19 and 1,8-
bisacetoxynaphthalene (Table 1, example 12), a convenient
precursor to 1,8-dihydroxynaphthalenes, which are of interest
as unusual ligands20 but are otherwise difficult to access
synthetically. Heterocycles can also be used as substrates as
shown for the synthesis of 2-acetoxypyridine21 (Table 1,
example 14), which is essentially 2-hydroxypyridine that is
protected from tautomerization to 2(1H)-pyridone. Such
molecules can be difficult to access by conventional routes.
The synthetic utility of this reaction can be expanded.
Aromatic amines may be converted to O-aromatic acetates
in a one-pot reaction by in situ generation of the amides,
simply by dissolving the amine in acetic anhydride and
heating briefly, followed by cooling and addition of ap-
propriate amounts of acetic acid and sodium nitrite.22 Further,
aromatic amines are often generated by catalytic hydrogena-
tion (Pd/C) of aromatic nitro compounds. By carrying out
the hydrogenation in acetic anhydride, the amide can be
generated in situ after reduction.23 The catalyst can be
removed by filtration, the solution cooled, appropriate
amounts of acetic acid and sodium nitrite added, and after
reaction and warming to room temperature, the O-aromatic
acetate may be generated. This latter reaction sequence
constitutes a two-step, essentially one-pot conversion of
aromatic nitro compounds to aromatic acetates.24 The yield
advantage of carrying out this reaction sequence versus
stepwise synthesis was demonstrated for the synthesis of
4-acetoxybiphenyl from 4-nitrobiphenyl (Scheme 3). Isolat-
ing both 4-aminobiphenyl and 4-acetamidobiphenyl in the
reaction sequence before conversion to 4-acetoxybiphenyl
gave an overall yield of 79%. Isolating the 4-aminobiphenyl
but generating the 4-acetamidobiphenyl in situ before
Scheme 3a
a (a) H2, Pd/C, ethanol; (b) Ac2O, heat; (c)15 2:1 Ac2O/AcOH,
NaNO2, 0 °C f rt; (d)22 (1) Ac2O, heat, (2) AcOH, NaNO2, 0 °C
f rt; (e)24 (1) H2, Pd/C, 2:1 Ac2O/AcOH, (2) filter, (3) NaNO2, 0
°C f rt.
conversion to 4-acetoxybiphenyl gave an overall yield of
87%. However, carrying out the reaction sequence without
isolating any of the intermediate compounds gave 4-acetoxy-
biphenyl in 97% yield.
White postulated that decomposition of aliphatic nitrosa-
mides generated carbocation/anion pairs. However, yields
for the conversion of N-aromatic amides to O-aromatic esters
were uniformly high regardless of the electron-donating/-
withdrawing character of the substituents (Table 1), casting
doubt on a carbocation/anion pair mechanism and suggesting
decomposition via either a radical or cyclic, concerted
mechanism (Scheme 4). Indeed, a homolytic radical cleavage
Scheme 4
(18) Ayres, D. C.; Levy, D. P. Tetrahedron 1986, 42, 4259.
(19) Kimura, T.; Duan, X.; Kato, M.; Matsuda, H.; Fuduka, T.; Yamaca,
S.; Okada, S.; Nakanishi, H. Mol. Cryst., Liq. Cryst. 1988, 164, 77.
(20) Poirier, M.; Simard, M.; Wuest, J. D. Organometallics 1996, 15,
1296.
(21) Cohen, T.; Deets, G. L. J. Org. Chem. 1972, 37, 55.
(22) 4-Aminobiphenyl (2.56 g, 15.1 mmol) was placed in a 250-mL
round-bottom flask and dissolved in 60 mL of acetic anhydride. The flask
was fitted with a condenser, and the solvent was heated to reflux for 30
min and allowed to cool to room temperature. Acetic acid (30 mL) was
added, and the flask was cooled to 0 °C in an ice bath. Reaction with sodium
nitrite (2.04 g, 30.0 mmol) and workup was carried out as described above15
to give 3.06 g (96%) of 4-biphenylacetate, mp 87-88 °C (lit. mp 88-89
°C).16
mechanism has been postulated for the decomposition of
N-aromatic nitrosamides in aromatic solvents for the syn-
thesis of biaryls.25 White usually generated nitrosamides
using N2O4 and isolated them before allowing them to
rearrange. The reaction conditions presented here allow for
in situ generation of nitrosamides, and the solvent must
provide a nonreactive environment that facilitates the rear-
rangement. Disruption of the inert solvent environment by
reactive moieties would allow trapping of reactive intermedi-
ates.
(23) Rylander, P. N. Hydrogenation Methods; Academic Press: Orlando,
1985; p 105.
(24) 4-Nitrobiphenyl (0.307 g, 1.54 mmol) was placed in a hydrogenation
flask and dissolved in 20 mL of acetic anhydride and 10 mL of acetic acid.
Palladium (10% on C, 30 mg) was added, and the bottle was attached to a
Parr hydrogenation apparatus. Hydrogenation was carried out with shaking
for 3 h at 25 psi H2. The catalyst was removed by filtration through filter-
aid, and the solution was cooled in an ice bath for 30 min. Reaction with
sodium nitrite (0.212 g, 3.08 mmol) and workup was carried out as described
above15 to give 0.317 g (97%) of 4-biphenylacetate, mp 87-89 °C (lit. mp
88-89 °C).16
Evidence for the role of solvent came from two experi-
ments. In the first experiment, the N-nitrosamide of N-(4-
nitrophenyl)acetamide, isolated at low temperature, was used
as an initiator for methyl methacrylate (MMA) polymeriza-
(25) Bachman, W. E.; Hoffman, R. A. Org. React. 1944, 2, 224-261.
Org. Lett., Vol. 4, No. 14, 2002
2351

tion,26 which will occur radically but not cationically. UV-
visible spectroscopy showed that p-nitrophenyl moieties were
present in the polymer. Generation of the N-nitrosamide in
situ at low temperature and use of the solution as an initiator
also gave polymer, while a blank containing all of the
reaction components except N-(4-nitrophenyl)acetamide failed.
In summary, the method for conversion of N-aromatic
secondary amides to O-aromatic esters presented here is
inexpensive and convenient, carried out in low environmental
impact solvents, using minimal equipment, and not requiring
isolation of intermediate N-nitrosamides or diazonium salts.
We have scaled-up the reaction without difficulty to effect
multigram conversions. Yields are uniformly high (although
conditions were not optimized), and the reaction can be
carried out with a variety of functional groups present in
the substrate. The method can be simply modified to be
carried out directly on aromatic amines and in some cases
can be extended to be carried out on aromatic nitro
compounds. Phenols can easily be generated from the
resulting esters, and workup procedures could be easily
developed to obtain the phenol without isolating the ester.
While the results presented here are suggestive of radical
intermediates, further studies will needed to elucidate the
exact nature of the mechanisms of these reactions.
In a second experiment, the N-nitrosamide of 4-acetami-
dobiphenyl was generated as usual at 0 °C. Before allowing
the reaction mixture to warm, a large excess of toluene was
added.27 After reaction, the two major isolated products were
biphenyl and bibenzyl, with only traces of 4-acetoxybiphenyl.
Such a result could be explained by the generation of
biphenyl radicals, followed by benzylic hydrogen abstraction
from the toluene to form biphenyl and benzyl radicals. The
benzyl radicals would combine to form bibenzyl. A cationic
reactive intermediate would be expected to generate mainly
benzyltoluenes, which were not observed. This reaction may
be a useful alternative to reduction of diazonium salts for
the deamination of aromatic primary amines.28
Acknowledgment. We thank Prof. R. W. Darbeau for
introducing us to N-nitrosamide chemistry and valuable
discussions. We also thank the University of Oklahoma and
the National Science Foundation (EPS-9720651, DMR-
0072544, and CHE-9820544) for support.
(26) N-p-Nitrophenylacetamide (0.138 g, 0.765 mmol) was treated as
described for the synthesis of esters,15 except that the reaction was quenched
before warming by pouring into ice/water and kept at 0 °C with stirring
until a solid formed. The solid was collected quickly by suction filtration
to give 0.135 g of the corresponding crude N-nitrosamide. This N-
nitrosamide was added to 30 mL of distilled methyl methacrylate in a large
test tube. The tube was capped, covered with foil, and allowed to stand at
room temperature for 48 h. The resulting viscous sample was dissolved in
chloroform and added dropwise to methanol to precipitate polymer. The
polymer was purified by reprecipitating twice from chloroform into
methanol, collection by suction filtration, and air-drying to a constant weight
of 1.251 g. In a separate set of experiments, N-p-nitrophenylacetamide (0.093
g, 0.52 mmol) was dissolved in 2 mL of acetic anhydride and 1 mL of
acetic acid, chilled in ice bath for 30 min, and 0.071 g NaNO2 (1.3 mmol)
and allowed to remain at 0 °C for 2 h. A blank was prepared using the
same amounts of acetic anhydride, acetic acid, and NaNO2 under identical
conditions. Each solution was added separately to test tubes containing 30
mL of methyl methacrylate (which had been filtered through neutral alumina
to remove inhibitors and was shown not to contain polymer) each. Reaction
and purification was carried out as above to give 0.227 g of polymer from
the initiator containing the acetamide. Polymer was not obtained from the
blank.
OL026051D
(27) 4-Acetamidobiphenyl (0.217 g, 1.02 mmol) was placed in a 125-
mL Erlenmeyer flask and dissolved in 10 mL of acetic anhydride and 5
mL of acetic acid. The flask was cooled to 0 °C in an ice bath. While the
mixture was being slowly stirred magnetically, solid sodium nitrite (0.142
g, 2.05 mmol) was added to this mixture, and the vessel was lightly capped.
Evolution of a brown gas occurred, and the solution turned lime green.
The flask was kept in the ice bath for 2 h. Toluene (70 mL) was added,
and the flask was kept in the ice bath for 10 min. The flask was allowed to
warm to room temperature and was kept there for 24 h. Water (50 mL)
was added, and the toluene layer was separated, washed 3× with sat.
NaHCO3, once with water, and dried over MgSO4. Filtration and removal
of solvent under reduced pressure gave 0.181 g of product (mp 60-83 °C).
Semiquantitative GC-MS16 showed that the sample contained 64%
bibenzyl, 34% biphenyl, and 1% 4-biphenylacetate.
(28) Kornblum, N. Org. React. 1944, 2, 262.
2352
Org. Lett., Vol. 4, No. 14, 2002