4-substituted tert-butyl phenylazocarboxylates-synthetic equivalents for the para-phenyl radical cation

Article abstract of DOI:10.1002/anie.201004508

First electrophile, then radical: 4-Substituted tert-butyl phenylazocarboxylates 1 are versatile synthetic equivalents of the para-phenyl radical cation 2. The tert-butyloxycarbonylazo group enables nucleophilic substitutions to proceed under mild conditions and can later be employed for the generation of aryl radicals. Copyright

Full text of DOI:10.1002/anie.201004508

Angewandte
Chemie
DOI: 10.1002/anie.201004508
Synthetic Equivalents
4-Substituted tert-Butyl Phenylazocarboxylates—Synthetic
Equivalents for the para-Phenyl Radical Cation**
Sarah B. Hꢀfling, Amelie L. Bartuschat, and Markus R. Heinrich*
Dedicated to Professor Samir Z. Zard on the occasion of his 55th birthday
Broadly applicable bifunctional synthetic building blocks are
of high value not only for the preparation of single molecules
but also for the modular assembly of structurally diverse
compound libraries.[1] Along the lines of our recent work in
the field of aryl radical chemistry,[2,3] we turned our interest
towards derivatives of benzene, in which the aromatic core
could be selectively modified by a nucleophilic substitu-
tion[4–7] as well as by a radical reaction. Herein we present the
results of our first investigation concerning 4-substituted tert-
butyl phenylazocarboxylates (1a–c) as synthetic equivalents
of the para-phenyl radical cation (2).
Table 1: Synthesis of 4-phenylazocarboxylic acid tert-butyl ester (PACE)
phenyl ethers from 1a and phenolates.
Entry Phenol PACE ether
Yield
[%]
4-fluorophenol
(3)
1
74[a]
l-tyrosine
methyl ester (4)
2
3
61[b]
45[a]
diethylstilb-
estrol (6)
4
5
morphine (8)
estradiol (10)
81[b]
quant.[a]
The azocarboxylates 1a and 1b were prepared in two
steps from 4-nitro- and 4-fluorophenylhydrazine, respectively,
by reaction with di-tert-butyl dicarbonate and subsequent
oxidation with manganese dioxide.[8,9] To our knowledge, no
examples have been reported for the selective nucleophilic
substitution of 1a–c or analogous esters. Importantly, under
the given reaction conditions the nucleophilic attack should
tyrosine deriva-
tive (12)
6
7
70[a]
tyrosine deriva-
tive (14)
quant.[a]
not occur at either the N N bond[10] or at the carbonyl moiety
=
of the aryl azocarboxylate.[11–13] In a first study, we therefore
investigated the reactivity of different nucleophiles towards
the nitro compound 1a.[14,15] It became apparent that pheno-
lates are particularly suitable reagents for the selective
substitution of the nitro group. The desired diphenyl ethers
were obtained as reaction products under surprisingly mild
conditions (Table 1). Comparably simple nucleophilic sub-
stitutions were observed for aliphatic amines in combination
tyrosine deriva-
tive (16)
8
66[b]
[a] Reaction conditions: Cs2CO3 (5.0 equiv), K2CO3, DMF, RT. [b] K2CO3
(5.0 equiv), [18]crown-6 (5.0 equiv), DMF, RT.
[*] S. B. Hꢀfling, A. L. Bartuschat, Prof. Dr. M. R. Heinrich
Professur fꢁr Pharmazeutische Chemie
with Sangerꢀs reagent[16] and with activated Fukuyama-type
protecting groups.[17,18]
Friedrich-Alexander-Universitꢂt Erlangen-Nꢁrnberg
Schuhstrasse 19, 91052 Erlangen (Germany)
Fax: (+49)9131-852-2585
E-mail: Markus.Heinrich@medchem.uni-erlangen.de
Homepage: http://www.medchem.uni-erlangen.de/heinrichlab/
Because the products are colored, the reactions summar-
ized in Table 1 could be monitored easily by thin-layer
chromatography. At room temperature, the formation of the
diphenyl ethers was usually complete within a few hours. The
conversion of morphine (8) to its diphenyl ether derivative 9
was possible by changing the standard conditions (Cs2CO3 in
DMF) to potassium carbonate in the presence of [18]crown-6.
Several control experiments revealed that primary or secon-
[**] The generous financial support of our research by the Deutsche
Forschungsgemeinschaft (DFG) and the FAU Erlangen-Nꢁrnberg is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004508.
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dary amines do not interfere with the phenyl ether synthesis
We then turned to investigate the generation of aryl
radicals from the previously prepared azocarboxylates. In this
context, only a few reports exist on arylazo ketones,[11a,12]
arylazo succinates,[11c] and arylazo carboxylates.[22] These
substrates, however, would not be suited for nucleophilic
substitutions since they are less stable than 1a–c.[23] The
results of our experiments are summarized in Table 3.
(Table 1, entry 2). As an example, azo compound 1a
remained stable in the presence of n-butyl amine for more
than 24 h. With thiols, in contrast, 1a was readily reduced to
hydrazine 18 (Scheme 1).[19] The unique influence of the nitro
At temperatures above 608C, trifluoroacetic acid reliably
induced the cleavage of the tert-butyloxycarbonyl (Boc)
group. In this way, the azo compounds were probably first
converted to aryl diazenes. This assumption is supported by
the remarkable influence of ambient oxygen on the reaction
Scheme 1. Selective reduction of nitro compound 1a. The fluoro
compound 1b does not react under these conditions.
group further became evident by the observation that only 18
was formed from a 1:1 mixture of 1a and 1b in the presence of
dodecane thiol or cysteine while the fluorinated compound
1b remained unchanged. Thiols can therefore be used to
selectively remove an excess of reagent 1a after completion of
a diphenyl ether synthesis.
Besides the nitro compound 1a, the fluorinated phenyl-
azocarboxylate 1b were successfully substituted by aliphatic
amines such as morpholine (19) and desipramine (21).
(Table 2, entries 1 and 2). In comparison to known reagents[16]
the azocarbonyl moiety in 1 again proved to be a highly
activating substituent for nucleophilic aromatic substitu-
tions.[20]
Table 3: Products from radical reactions of 4-substituted tert-butyl
phenylazocarboxylates.
Entry PACE compound
Product
Yield
[%]
1
2
1a
1a
57[a]
89[b]
3
4
1a
1a
64[c,h]
Table 2: Nucleophilic substitution of 1b and 1c with aliphatic and
aromatic amines.
58[d,h]
Entry
Reactants
Product
Yield [%]
90[a]
1b
5
1b
40[e]
1
+
morpholine (19)
1b
6
7
1c
1c
59[c]
67[b]
2
+
92[a]
desipramine (21)
1b
3
4
5
+
0[a]
p-anisidine (23)
8
9
73[f]
1c
+
74[b]
53[c]
p-anisidine (23)
9
15
24
57[f]
42[a]
1c
+
p-chloroaniline (25)
10
[a] Reaction conditions: DMF, RT. [b] CF3COOH, CH3CN, 808C.
[c] CF3COOH, CH3CN, RT.
11
53[g]
The aromatic amine para-anisidine (23), however, did not
react with 1b under the conditions that had been suitable for
the reactions of 19 and 21 (Table 2, entry 3). The preparation
of the desired diaryl amine 24 was instead achieved using
diphenyl ether 1c (Table 1, entry 1) in combination with the
trifluoroacetate salt of 23.[21] Even the salt of para-chloroani-
line (25) reacted with 1c.
[a] Reaction conditions: CF3COOH, BrCCl3, CH3CN, 808C. [b] CF3COOH,
I2, CH3CN, 808C. [c] CF3COOH, benzene, 808C. [d] CF3COOH, H2C
CHCN, CuCl2, MnO2, CH3CN, 658C. [e] 4-Fluoraniline, NaOH, H2O2,
(H3C)2NCOCH3, RT. [f] CF3COOH, CH3CN, EtOH, H2O, 908C.
[g] CF3COOH, TEMPO, CH3CN, 658C. [h] Reactions on a 2 mmol scale.
=
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course. As reported by Kosower[24] for phenyl diazene
For the radical reactions (Table 3), the 4-substituted tert-butyl
phenylazocarboxylate and the substrate (30 equiv) were dissolved in
acetonitrile (0.03m), and the resulting mixture was heated to 808C
and stirred under air. At this temperature, the required amount of
trifluoroacetic acid (see individual products in the Supporting
Information) was added and, the reaction was monitored by TLC.
After cooling to room temperature, the reaction mixture was diluted
with water (for some substrates, the pH was adjusted to 9 by the
addition of saturated aqueous Na2CO3) and extracted with ethyl
acetate. The combined organic phases were washed with saturated
aqueous NaCl and dried over Na2SO4. After removal of the solvents
under reduced pressure, the crude product was purified by column
chromatography.
=
(Ph-N NH), the decomposition of this type of compound
occurs instantly in the presence of oxygen (k2
ꢀ 103 LmolÀ1 sÀ1). Although quite unusual for radical reac-
tions,[25] comparative experiments proceeded best when they
were conducted under air instead of under argon. We
=
therefore assume that aryl diazenyl radicals (Ar-N NC) were
first generated from the aryl diazenes by hydrogen-atom
transfer, and these were then transformed into aryl radicals
with loss of nitrogen. Under argon, the aryl diazenes have an
increased lifetime in the reaction mixture and were therefore
able to undergo side reactions.[26] These observations are also
in agreement with mechanistic studies on the decomposition
Received: July 22, 2010
Published online: November 9, 2010
=
of alkyl diazenes (alkyl-N NH) in the presence of oxygen or
the tetramethylpiperidin-1-oxyl radical (TEMPO).[27]
The aryl radicals were used for the preparation of
brominated,[28a] iodinated,[28b,c] and arylated compounds[28a]
(Table 3, entries 1–3, 6, 7, and 10), among which the
halogenated products are well suited for further transforma-
tions.[29] Moreover, a Meerwein arylation could be achieved
employing acrylonitrile, copper(II) chloride, and manganese
dioxide as reagents (Table 3, entry 4).[2c,30] Under strongly
basic conditions[31] and in the presence of hydrogen perox-
ide,[32] the difficult radical arylation of an unprotonated
aniline derivative was realized using 4-fluoroaniline as a
sample substrate (Table 3, entry 5).[3a,33] By treatment with
trifluoroacetic acid and ethanol, we obtained the previously
unknown phenylated morphine 34 from azocarboxylate 9
without observing the apomorphine rearrangement as side
reaction (Table 3, entry 8).[34] The tyrosine derivative 15 was
reduced under comparable conditions (Table 3, entry 9). The
allyl ether 37 was converted in the presence of TEMPO to the
dihydrobenzofuran 38 by a 5-exo cyclization typical for
radicals. This result provides further support for the proposed
radical reaction mechanism (Table 3, entry 11).[35,36]
Keywords: arenes · aromatic substitution ·
nucleophilic substitution · radical reactions · synthetic methods
.
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