Reliable and general method for the cleavage of α-arylheteroatom- substituted carboxylic acids

Article abstract of DOI:10.1055/s-2007-990967

Bonds between arylheteroatom moieties and α-carbons of carboxylic acids are efficiently cleft by azide transfer and subsequent Curtius rearrangement. The scope of the one-pot protocol covers differently substituted carboxylic acids and heteroatoms like O, S, Se, and N. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990967

3042
LETTER
Reliable and General Method for the Cleavage of a-Arylheteroatom-
Substituted Carboxylic Acids
Cleavage of
a
-Ar
y
n
lheteroatom-
k
Substituted C
e
arboxylic
Acids Spurg, Siegfried R. Waldvogel*
Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universität Bonn,
Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
E-mail: waldvogel@uni-bonn.de
Received 24 September 2007
i ) azide transfer
ii) KOH, H2O, EtOH,
glycerol
iii) citric acid
Abstract: Bonds between arylheteroatom moieties and a-carbons
of carboxylic acids are efficiently cleft by azide transfer and subse-
quent Curtius rearrangement. The scope of the one-pot protocol
covers differently substituted carboxylic acids and heteroatoms like
O, S, Se, and N.
O
X
OH
Ar–XH
Ar
R
1
2
Key words: azides, cleavage, carboxylic acids, arenes, rearrange-
ment
X = O, S, Se, N
R = H, Me; Ph
Figure 1 Cleavage of a-arylheteroatom-substituted carboxylic
acids
Aryloxy acetates exhibit an extraordinary stability to-
wards electrophilic conditions,1 since the strong electron-
withdrawing effect of the carbonyl group onto the methyl-
ene moiety avoids a heterolytic cleavage with a positive
charge on the methylene group. Therefore, typical electro-
philic conditions for the dealkylation of phenylethers do
not affect this particular moiety,2 whereas a methoxy
group undergoes such a cleavage in a smooth manner.3
Furthermore, aryloxy acetates are a common motif in
plant-growth modulators,4 which exhibit also a high met-
abolic stability.5 The alkoxycarbonylmethyl group repre-
sents a recognition site for some electrophilic reagents and
can consequently be exploited for side-chain-directed
transformations, e.g., the direct chlorination of iodo are-
nes by MoCl5.1a
sized followed by saponification which provided the acid
upon workup. The deprotected compounds 2 (Figure 1)
were identical in all aspects with the commercially avail-
able compounds.16
Since O-alkoxycarbonylmethyl-protected phenols are su-
perb substrates for the MoCl5-mediated aryl coupling re-
action,1b chiral analogues were subjected to the
deprotection sequence. First, we focussed on substrates
derived from naturally occurring a-hydroxy acids like lac-
tic or mandelic acids. These substrates were prepared ac-
cording to standard procedures.17 The lactic acid
derivative is liberated to the corresponding 2,4-dichlo-
rophenol in 91% yield (Table 1, entry 1). Analogous man-
delic acid derivatives can also be cleft in good to excellent
yields (Table 1, entries 2 and 3). The more polar and vol-
atile 4-chlorothymol renders a slightly depressed yield be-
cause of the workup conditions. In order to demonstrate
the generality of this deprotection sequence we subjected
substrates with other heteroatoms than oxygen. A variety
of anilines were tested but lead to low yields since the
workup seems to be inappropriate. Therefore, more lipo-
philic amides can serve as substrates to remove a N-gly-
cine moiety in moderate yield (Table 1, entry 4). The
displacement of the carboxymethyl group from the nitro-
gen atom of carbazole was achieved in significantly better
yields (Table 1, entry 5). However, addition of glycerol on
a later stage in the workup turns out to be beneficial in or-
der to avoid side reactions.
In order to circumvent the very drastic reaction
conditions6 for a chemical cleavage of aryloxy acetates we
developed a mild strategy.7 The one-pot method consists
of an azide transfer with a subsequent Curtius rearrange-
ment followed by a hydrolytic workup. The initial proto-
col was limited to about 60% yield for an individual
cleavage. The mild conditions even gave access to labile
iodo phenols, but for multiple deprotection sequences the
loss of material is unacceptable. The ameliorated proce-
dure employs diethylphosphoryl azide (DEPA)8 instead of
diphenylphosphoryl azide (DPPA)9 as azide-transfer re-
agent and glycerol as additive in the hydrolytic workup.10
The cleavage is then compatible to a broad scope of O-
carboxymethyl-substituted phenols and is performed in
excellent yields.11 We found that this methodology has a
more general nature than previously described.
The protocol was tested on the sulfur congeners of phen-
oxyacetates. A variety of thiophenol derivatives (1f–h)
were deprotected by the original protocol using DPPA.
Because of the volatility and sensibility towards atmo-
spheric conditions, the thiophenols were oxidized to the
corresponding disulfides by iodine upon the workup
(Table 1, entry 6–8). The substitution pattern on the
thiophenol does not have an obvious impact on the yield.
The employed acids have been prepared by known proce-
dures or analogously.15 In general, the ester was synthe-
SYNLETT 2007, No. 19, pp 3042–3044
x
x
.x
x
.2
0
0
7
Advanced online publication: 08.11.2007
DOI: 10.1055/s-2007-990967; Art ID: G30107ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cleavage of a-Arylheteroatom-Substituted Carboxylic Acids
3043
Table 1 Cleavage of Heteroatom–a-Carbon Bonda
Additionally, the sequence was applied to the correspond-
ing selenium derivative; the phenyl selenol was isolated in
excellent yield (Table 1, entry 9).
Entry Substrate
Azide-transfer Yield
reagent
(%)b
In conclusion, the removal of carboxy methyl fragments
from various heteroatoms can be achieved by a one-pot
sequence including azide transfer, Curtius rearrangement,
and hydrolytic workup. The general and reliable method
is applicable to heteroatoms like O, N, S, and Se. Further-
more, a-substituted carboxylic acids like lactic and man-
delic acid are splendid substrates for this reaction
sequence. In particular, these chiral auxiliaries can be en-
visioned for an asymmetric biaryl formation when the ap-
propriate reagent is direct by this specific side chain.
1
2
DEPA
91
Cl
O
CO2H
Cl
1a12
DEPA
96
CO2H
i-Pr
O
Ph
Cl
1b
t-Bu
Acknowledgment
3
4
DEPA
DEPA
99
46
O
CO2H
The studies were supported by the University of Bonn. A.S. is gra-
teful for a fellowship by the Theodor-Laymann-Foundation.
Ph
t-Bu
1c
References and Notes
O
(1) (a) Mirk, D.; Kataeva, O.; Fröhlich, R.; Waldvogel, S. R.
Synthesis 2003, 2410. (b) Kramer, B.; Fröhlich, R.;
Bergander, K.; Waldvogel, S. R. Synthesis 2003, 91.
(c) Mirk, D.; Willner, A.; Fröhlich, R.; Waldvogel, S. R.
Adv. Synth. Catal. 2004, 346, 675.
(2) (a) Kocienski, P. J. Protecting Groups, 3rd ed.; Thieme:
Stuttgart, 2004. (b) Protective Groups in Organic Synthesis,
3rd ed.; Greene, T. W.; Wuts, P. G. M., Eds.; Wiley: New
York, 1999.
t-Bu
N
H
COOH
t-Bu
N
1d
5
DEPA
66d
CO2H
(3) Sobotka, H.; Austin, J. J. Am. Chem. Soc. 1952, 74, 3813.
(4) (a) Davies, P. J. In Plant Hormones: Physiology,
Biochemistry and Molecular Biology; Davies, P. J., Ed.;
Kluwer: Dordrecht, 1995, 1–12. (b) Kepinski, S.; Leyser, O.
Nature (London) 2005, 435, 446; and references cited
therein. (c) Würzer, B. Naturwissenschaften 1969, 56, 452.
(5) Norris, L. A.; Freed, V. H. Weed Res 1966, 6, 212.
(6) (a) Thermal (>270 °C): Kruber, O.; Schmitt, A. Ber. Dtsch.
Chem. Ges. B 1931, 64, 2270. (b) Photochemical: Shiraishi,
Y.; Saito, N.; Hirai, T. J. Am. Chem. Soc. 2005, 127, 12820.
(c) Photochemical: Rajesh, C. S.; Thanulingam, T. L.; Das,
S. Tetrahedron 1997, 53, 16817.
1e
6
7
DPPA
DPPA
73c
88c
S
CO2H
1f13
S
CO2H
Cl
1g13
(7) Mirk, D.; Waldvogel, S. R. Tetrahedron Lett. 2004, 45,
7911.
8
9
DPPA
DEPA
65c
93
S
CO2H
CO2H
(8) Shi, E.; Pei, C. Synth. Commun. 2005, 35, 669.
(9) (a) Wolff, O.; Waldvogel, S. R. Synthesis 2004, 1303.
(b) Shioiri, T.; Yamada, S. Org. Synth. 1984, 62, 187.
(c) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc.
1972, 94, 6203.
1h13
Se
(10) General Procedure for the Cleavage Sequence
The substrate (0.60 mmol) is dissolved in anhyd toluene (1.5
mL) and anhyd DMF (0.15 mL). After addition of Et3N (1.01
equiv) and azide-transfer reagent (1.1 equiv, DPPA or
DEPA) the mixture was stirred for 30 min at ambient
temperature and then brought to reflux for 3 h. Then, KOH
solution (0.7 mL, 50 wt% in H2O), EtOH (1.5 mL), and
glycerol (0.8 mL) were added to the reaction mixture before
refluxing for 2 h. For workup, the reaction mixture was
brought to pH 5 by the addition of a sat. citric acid solution.
Subsequently, the aqueous layer was extracted with EtOAc
(3 × 25 mL). The combined organic fractions are washed two
times with brine (25 mL), dried over MgSO4, and
concentrated under reduced pressure. Purification was
performed by column chromatography.
1i14
a Reagents and conditions: i) 1, DEPA or DPPA, Et3N, DMF, toluene,
30 min, 25 °C, then 3 h reflux, ii) glycerol, KOH/H2O, EtOH, 2 h re-
flux; iii) citric acid, H2O.
b Isolated yields.
c During workup, iodine (0.51 equiv) was added. Yield corresponds to
disulfides.
d Glycerol was added after 1.5 h reflux with EtOH, KOH/H2O.
Synlett 2007, No. 19, 3042–3044 © Thieme Stuttgart · New York

3044
A. Spurg, S. R. Waldvogel
LETTER
(11) Spurg, A.; Waldvogel, S. R. Eur. J. Org. Chem. 2007, in
press.
(12) Burkard, U.; Effenberger, F. Chem. Ber. 1986, 119, 1594.
(13) Srinivasan, C.; Pitchumani, K. J. Magn. Reson. 1982, 46,
134.
(14) Bhalla, A.; Sharma, S.; Bhasin, K. K.; Bari, S. S. Synth.
Commun. 2007, 37, 783.
(15) (a) Nazare, M.; Waldmann, H. Chem. Eur. J. 2001, 7, 3363.
(b) Smith, A. B. III.; Chen, S. S.-Y.; Nelson, F. C.; Reichert,
J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1997, 119, 10935.
(16) Structural identity was proven by consistent NMR and MS
spectra. Additionally, GC was performed for assessment of
purity.
(17) Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1986, 51, 3664.
Synlett 2007, No. 19, 3042–3044 © Thieme Stuttgart · New York

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