Mild and reliable cleavage sequence for phenoxy acetates

Article abstract of DOI:10.1016/j.tetlet.2004.08.147

A novel combination of reliable transformations like ester saponification and subsequent Curtius-rearrangement employing mild reaction conditions, offers the first synthetically interesting strategy for the removal of methoxycarbonylmethyl groups from phenolic oxygens. This methodology gives also access to labile iodosubstituted phenols. A novel combination of reliable transformations like ester saponification and subsequent Curtius-rearrangement employing mild reaction conditions, offers the first synthetically interesting strategy for the removal of methoxycarbonylmethyl groups from phenolic oxygens. This methodology gives also access to labile iodosubstituted phenols.

Full text of DOI:10.1016/j.tetlet.2004.08.147

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7911–7914
Mild and reliable cleavage sequence for phenoxy acetates
Daniela Mirk and Siegfried R. Waldvogel*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-Universita¨t Mu¨nster, Corrensstrasse 40, D-48149 Mu¨nster, Germany
Received 2 July 2004; revised 24 August 2004; accepted 24 August 2004
Available online 11 September 2004
Abstract—A novel combination of reliable transformations like ester saponification and subsequent Curtius-rearrangement employ-
ing mild reaction conditions, offers the first synthetically interesting strategy for the removal of methoxycarbonylmethyl groups from
phenolic oxygens. This methodology gives also access to labile iodosubstituted phenols.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Phenoxy acetates are very robust moieties towards var-
ious harsh reaction conditions. The stability is docu-
mented by numerous transformations on the aryl
system without affecting the side chain. This alkoxy moi-
ety turned out to be beneficial for oxidative transforma-
tions with strong Lewis acids like MoCl51 or hypervalent
iodine reagents2 and can be exploited as a directing side
chain for chlorination processes.3 However, in both
transformations this particular moiety serves as splendid
and superior permanent protective group for the phe-
nolic oxygen without having any tool for the cleavage
of the phenoxy alkyl bond.4,5
Due to the robust character of the phenoxy derivatives
the cleavage occurs only as a side reaction under harsh
and prolonged reaction conditions.7 Other methods
involve very high temperatures (>270ꢁC),8 gas phase
chemistry,9 electrochemical procedures,10 or irradiation
techniques.11 Fries-rearrangements on the aromatic moi-
ety and a broad product distribution result in syntheti-
cally unattractive yields.12 The displacement of a
carboxy methoxy group on a very electron deficient
arene can be realized by a nucleophilic aromatic substi-
tution reaction.13 For simple systems a reductive cleav-
age with sodium in liquid ammonia might be
successful.14
The strong electron withdrawing effect of the carbonyl
system on the methylene group (Fig. 1) makes it less
prone for a heterolytic removal of the phenoxy system
and may explain the stability especially under cationic
conditions. Therefore, rather a methoxy group under-
goes the cleavage than the corresponding carboxy meth-
oxy moiety on the arene system.6
Apparently, arenes with sensitive substituents and com-
plex molecular structures are not anticipated to be
compatible with the reported methods. Therefore, we
developed a reliable and easy to perform two-step se-
quence for the removal of the alkoxy carbonyl methyl
group under mild conditions giving access to the corre-
sponding phenols (Scheme 1). Starting from known sub-
strates,15 except for 1f,16 we applied this protocol on
a variety of different substituted phenoxy acetates
(Table 1).
δ
O
O
OCH3
The first step of the reaction sequence is the saponifica-
tion of the ester moieties to the corresponding carboxy-
lic acids 2 under standard conditions.17 The isolated
yields of the products were excellent in almost all the
cases, even the biscarboxylic acid 2g is obtained quanti-
tatively. For 2a–e the structures were proven by
NMR techniques and mass spectrometry and the ana-
lytical data match with the data given in literature;18
2f and 2g are novel compounds and therefore fully
characterized.19
δ
R
1
Figure 1. Polarization of methyl phenoxy acetates.
Keywords: Deprotection; Phenoxy acetates; Protecting groups; Cleav-
age; Curtius-rearrangement; Azide.
*
Corresponding author. Tel.: +49 251 8333278; fax: +49 251
8339772; e-mail: waldvog@uni-muenster.de
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.147

7912
D. Mirk, S. R. Waldvogel / Tetrahedron Letters 45 (2004) 7911–7914
OH
O
O
R'
O
OH
O
O
DPPA, NEt3
NaOH, EtOH
then acidic
work-up
R
R
R
1a-g
2a-g
3a-g
Scheme 1. Deprotection sequence.
Table 1. Isolated yields following the deprotection sequence (Scheme
1)
the reaction mixture and acidic work-up leads to phen-
oxy methylamines, which are not stable in aqueous media.
Subsequent hydrolysis of the aminal moiety provides the
free phenol 3 in good to moderate isolated yields.
Entry Substrate
2: Yield 3: Yield
(%) (%)
O
O
CO2CH3
This two-step sequence allows a variety of sensitive sub-
stituents on the arene. The parent phenol derivative 1a
undergoes the deprotection protocol as well as electron
rich derivatives, involving additional methoxy and alkyl
moieties (entries 2 and 3). Even two tert-butyl groups
adjacent to the hydroxy function are compatible with
this sequence in spite of their steric hindrance and acid
lability (entry 6). Interestingly, a valuable iodo substitu-
ent is not lost during the transformation (entries 4 and
5). Applying this methodology on the dimeric acid 2g re-
sults the corresponding biaryl 3g, offering an unusual
substitution pattern on the aromatic scaffold exhibiting
hydroxy substituents in the position meta to the aryl–
aryl bond. The deprotection of a single phenol moiety
occurs in 62%. Compound 3g is not known in literature
so far and therefore fully characterized.22 Analytical
data of phenols 3a–f correspond to the data of samples
of the commercially available phenols.
1
2
97 (2a) 63 (3a)
1a
1b
CO2CH3
OCH3
93 (2b) 62 (3b)
O
CO2CH3
OCH3
3
1c
95 (2c)
59 (3c)
CH3
O
CO2CH3
4
5
6
1d
1e
99 (2d) 55 (3d)
I
O
CO2CH3
I
The amount of DPPA has to be carefully controlled
since an excess of the reagent leads to the formation of
a triphenyl phosphate derivative 4 (Fig. 2), which was
identified by 31P NMR and mass spectrometry and
diminishes the yield significantly. This might explain
the lower yield of 3e, wherein the formation of this par-
ticular by-product could not be avoided even when
using less amounts of DPPA.23
88 (2e)
99 (2f)
43 (3e)a
O
CO2Et
t-Bu
t-Bu
1f
60 (3f)
OCH3
O
CO2CH3
OCH3
CH3
7
1g 99 (2g) 31 (3g)b
O
R
CH3
P(OPh)2
O
H3CO
H3CO2C
O
4
a Formation of a by-product.
b 62% yield corresponds to one hydroxy moiety.
Figure 2. Triphenyl phosphate derivatives 4.
In conclusion, we developed the first reliable deprotec-
tion strategy for methoxycarbonylmethyl moieties. This
methodology results the corresponding phenols in good
and synthetically interesting yields and allows a large
variety in the aromatic substitution pattern. This two-
step protocol is easy to perform under mild reaction
conditions and offers a broad application in the selective
deprotection of phenolic oxygens. Moreover, sensitive
substituents on the aromatic core like iodo or tert-butyl
moieties are fully compatible with the herein presented
The second step of the deprotection sequence for the
phenolic oxygen involves a Curtius-degradation. The
carboxylic acid 2 was transformed into a carbonyl azide,
which directly undergoes the rearrangement forming the
corresponding isocyanate using diphenylphosphoryl
azide (DPPA) and triethylamine under reflux condi-
tions.20 The Curtius-rearrangement is performed with
DPPA, a mild and less harmful azide transfer reagent
that is available in large scale.21 Addition of water to

D. Mirk, S. R. Waldvogel / Tetrahedron Letters 45 (2004) 7911–7914
7913
17. General procedure: Substrate 1 was dissolved in a 1:1
mixture of EtOH and aqueous NaOH solution (20%) (20–
60mL) and stirred for 72h at 25ꢁC. After adjusting to
pH1 the precipitated colorless carboxylic acids 2 were
filtered off. If necessary the filtrate was extracted with
EtOAc (3 · 50mL). The combined organic phases were
washed with brine (2 · 50mL), dried over anhydrous
MgSO4, and evaporated, yielding colorless or off-white,
analytically pure solids.
cleavage sequence whereas oxidative or reductive meth-
ods fail.
Acknowledgements
This work was supported by the Fonds der Chemischen
Industrie and by the International Graduate College
ÔTemplate-Directed Chemical SynthesisÕ.
18. Compound 2a: Villemin, D.; Hammadi, M. Synth. Com-
mun. 1996, 26, 4337–4342; Compound 2b: Deffieux, D.;
Fabre, I.; Courseille, C.; Quideau, S. J. Org. Chem. 2002,
67, 4458–4465; Compound 2c: Freudenberg, K.; Muller,
¨
References and notes
H. G. Justus Liebigs Ann. Chem. 1953, 584, 40–53;
Compounds 2d and 2e: Koelsch, F. J. Am. Chem. Soc.
1931, 53, 304–305; Compound 2c: 1H NMR (300MHz,
CDCl3): d = 2.29 (s, 3H, CH3); 3.84 (s, 3H, OCH3); 4.63 (s,
1. Kramer, B.; Fro¨hlich, R.; Bergander, K.; Waldvogel, S. R.
Synthesis 2003, 91–96.
2. Mirk, D.; Willner, A.; Fro¨hlich, R.; Waldvogel, S. R. Adv.
Synth. Catal. 2004, 346, 675–681.
3
4
2H, OCH2); 6.67 (dd, 1H, J5,6 = 8.1Hz, J3,5 = 1.6Hz, 5-
4
H); 6.71 (d, 1H, J3,5 = 1.6Hz, 3-H); 6.79 (d, 1H,
3. Mirk, D.; Kataeva, O.; Fro¨hlich, R.; Waldvogel, S. R.
Synthesis 2003, 2410–2414.
3J5,6 = 8.1Hz, 6-H); 10.06 (br s, 1H, COOH). 13C NMR
(75MHz, CDCl3): d = 21.06 (CH3); 55.82 (OCH3); 67.78
(OCH2); 113.24 (C6); 116.42 (C3); 121.25 (C5); 133.45
(C4); 144.95 (C1); 149.52 (C2); 173.21 (CO). MS (EI,
70eV): m/z (%) = 196 (100) [M+]; 137 (87)
[M+ꢀCH2COOH]; 123 (12) [M+ꢀCH2COOHꢀCH2]; 109
(39) [M+ꢀCH2COOHꢀCO]; 91 (35) [C7Hþ7 ]; 77 (22)
[C6Hþ5 ]; 65 (18) [C5H5þ]; 51 (10) [C4Hþ3 ]. Compound
2d: 1H NMR (300MHz, CD3CN): d = 4.75 (s, 2H, OCH2);
´
4. Kocienski, P. J. Protecting Groups, 3rd ed.; Georg Thieme:
Stuttgart, 2004.
5. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
6. Sobotka, H.; Austin, J. J. Am. Chem. Soc. 1952, 74, 3813–
3815.
7. Bernard, A. M.; Ghiani, M. R.; Piras, P. P.; Rivoldini, A.
Synthesis 1989, 287–289.
3
3
6.86 (d, 2H, J2,3 = 9.0Hz, 2-H); 7.72 (d, 2H, J2,3
=
8. Kruber, O.; Schmitt, A. Chem. Ber. 1931, 64, 2270–2277.
9. Chuchani, G.; Doinguez, R. M.; Rotinov, A.; Martin, I. J.
Phys. Org. Chem. 1999, 12, 612–618.
10. Deffieux, D.; Fabre, I.; Courseille, C.; Quideau, S. J. Org.
Chem. 2002, 67, 4458–4465.
11. (a) Peller, J.; Wiest, O.; Kamat, P. V. J. Phys. Chem. 2001,
105, 3176–3181; (b) Rajesh, C. S.; Thanulingam, T. L.;
Das, S. Tetrahedron 1997, 53, 16817–16834.
12. Boule, P.; Zeral, A.; Sehili, T. Z. Phys. Chem. (Munich)
1999, 213, 87–92.
9.0Hz, 3-H); 9.36 (br s, 1H, COOH). 13C NMR (75MHz,
CD3CN): d = 65.62 (OCH2); 84.12 (C4); 117.78 (C2);
139.46 (C3); 159.00 (C1); 170.10 (CO). MS (EI, 70eV): m/z
(%) = 278 (100) [M+]; 233 (31) [M+ꢀCOOH]; 219 (21)
[M+ꢀCH2COOH]; 203 (31) [M+ꢀOCH2COOH]. Com-
1
pound 2e: H NMR (300MHz, CD3CN): d = 4.73 (s, 2H,
3
4
OCH2); 6.78 (ddd, 1H, J3,4 = 3J4,5 = 7.7Hz, J4,6
1.2Hz, 4-H); 6.85 (dd, 1H, J5,6 = 8.3Hz, J4,6 = 1.2Hz,
=
3
4
3
6-H); 7.34 (ddd, 1H, J4,5 = 7.7Hz; J5,6 = 8.3Hz,
3
4J3,5 = 1.5Hz, 5-H); 7.81 (dd, 1H, J3,4 = 7.7Hz, J3,5
=
3
4
13. Christiansen, W. G. J. Am. Chem. Soc. 1926, 48, 460–468.
14. Birch, A. J. J. Chem. Soc. 1947, 102–104.
1.5Hz, 3-H); 9.52 (br s, 1H, COOH). 13C NMR (75MHz,
CD3CN): d = 66.44 (OCH2); 86.39 (C2); 113.62 (C6);
124.50 (C4); 130.79 (C5); 140.77 (C3); 157.72 (C1); 169.88
(CO). MS (EI, 70eV): m/z (%) = 278 (82) [M+]; 233 (14)
[M+ꢀCOOH]; 203 (28) [M+ꢀOCH2COOH]; 151 (100)
[M+ꢀI]; 105 (49) [C8H9þ]; 77 (67) [C6Hþ5 ].
15. Compound 1a: Belleney, J.; Vebrel, J.; Cerutti, E. J.
Heterocycl. Chem. 1984, 21, 1431–1435; Compound 1b:
Ahvonen, T.; Brunow, G.; Kristersson, P.; Lundquist, K.
Acta Chem. Scand. Ser. B 1983, 37, 845–850; Compound
1c: see Ref. 1; Compound 1d: Baliah, V.; Gurumurthy, R.
Indian J. Chem. Sect. B 1981, 20, 629–631; Compound 1e:
Green, S. P.; Whiting, D. A. J. Chem. Soc. Perkin Trans. 1
1998, 193–202; Compound 1g: see Ref. 1.
19. Compound 2f: Mp 117ꢁC (Et2O). 1H NMR (400MHz,
CDCl3): d = 1.42 (s, 18H, CH3); 3.78 (s, 3H, OCH3); 4.42
(s, 2H, OCH2); 6.81 (s, 2H, 3-H). 13C NMR (100MHz,
CDCl3): d = 32.01 (C(CH3)3); 36.06 (C(CH3)3); 55.32
(OCH3); 72.24 (OCH2); 112.33 (C3); 144.37 (C2); 149.27
(C1); 155.21 (C4); 172.46 (CO). MS (EI, 70eV): m/z
(%) = 294 (92) [M+]; 235 (54) [M+ꢀCH2COOH]; 179 (46)
[M+ꢀCH2COOHꢀC4H9]; 57 (100) [C4Hþ9 ]. Anal. Calcd
for C17H26O4 (294.39): C, 69.36; H, 8.90. Found: C, 69.19;
H, 8.90. Compound 2g: Mp 154ꢁC (Et2O). 1H NMR
(300MHz, CD3CN): d = 1.98 (s, 6H, CH3); 3.85 (s, 6H,
OCH3); 4.60 (s, 4H, OCH2); 6.59 (s, 2H, 3-H); 6.90 (s, 2H,
6-H). 13C NMR (75MHz, CD3CN): d = 19.61 (CH3);
56.67 (OCH3); 67.17 (OCH2); 115.15 (C6); 117.36 (C3);
131.14 (C1); 134.10 (C2); 145.96 (C5); 149.60 (C4); 170.70
(CO). MS (EI, 70eV): m/z (%) = 390 (100) [M+]. HRMS:
m/z Calcd for C20H22NaO8 (M+Na+): 413.1207. Found:
413.1224.
16. 2,6-Di-tert-butyl-4-methoxyphenol (9.45g; 40.0mmol) was
dissolved in DMF (50mL). K2CO3 (13.8g; 100mmol) and
bromoacetic acid methyl ester (5.5mL; 45.0mmol) were
added. After stirring at 25ꢁC overnight, Et2O (200mL)
was added and the mixture was washed several times with
water and brine, dried over anhydrous MgSO4, and
concentrated in vacuum. 5.26g (16.3mmol; 41%) of 1f
were obtained as red oil, which was separated from solid
starting material. 1H NMR (300MHz, CDCl3): d = 1.32 (t,
3
3H, J7,8 = 7.2Hz, CH3); 1.44 (s, 18H, C(CH3)3); 3.77 (s,
3H, OCH3); 4.29 (q, 2H, 3J7,8 = 7.2Hz, COOCH2); 4.36 (s,
2H, OCH2); 6.82 (s, 2H, Ar–H). 13C NMR (75MHz,
CDCl3): d = 14.04 (CH3); 31.87 (C(CH3)3); 35.84
(C(CH3)3); 55.01 (OCH3); 60.68 (COOCH2); 72.74
(OCH2); 111.96 (C3); 144.27 (C2); 149.98 (C1); 154.82
(C4); 168.42 (CO). MS (EI, 70eV): m/z (%) = 322 (100)
[M+]; 235 (72) [M+ꢀCH2CO2CH2CH3]; 207 (15)
[235ꢀCO]; 179 (67) [235ꢀC4H9]; 57 (99) [C4Hþ9 ]. Anal.
Calcd for C19H30O4 (322.44): C, 70.77; H, 9.38. Found: C,
70.65; H, 9.34.
20. General procedure: Substrate 2 (500mg) was dissolved in
anhydrous toluene (30mL) and DMF (3mL). Et3N (1.00–
1.15equiv) and DPPA (0.90–1.05equiv) were added and
the mixture was refluxed for 3h and again for 1–2h after
addition of water (30mL). The solution was acidified with
2N HCl solution (50mL) and extracted with EtOAc

7914
D. Mirk, S. R. Waldvogel / Tetrahedron Letters 45 (2004) 7911–7914
(3 · 50mL). The combined organic phases were washed
OCH3); 5.48 (br s, 2H, OH); 6.68 (s, 2H, 3-H); 6.73 (s,
2H, 6-H). 13C NMR (75MHz, CDCl3): d = 19.32 (CH3);
55.93 (OCH3); 112.13 (C6); 115.83 (C3); 127.53 (C1);
134.05 (C2); 143.01 (C5); 145.39 (C4). MS (EI, 70eV): m/z
(%) = 274 (100) [M+]. HRMS: m/z Calcd for C16H18NaO4
(M+Na+): 297.1097. Found: 297.1061.
with brine, dried over anhydrous MgSO4, and evaporated.
Phenols 3 were purified via column chromatography on
silica with cyclohexane and EtOAc as eluents.
21. (a) Wolff, O.; Waldvogel, S. R. Synthesis 2004, 1303–1305;
(b) Shioiri, T.; Yamada, S. Org. Synth. 1990, 187–
190.
23. Phenols 3 could not be separated from the by-products 4
by column chromatography. Therefore, 3e was purified by
distillation in high vacuum.
22. Compound 3g: Mp 137–139ꢁC (Et2O). 1H NMR
(300MHz, CDCl3): d = 1.99 (s, 6H, CH3); 3.90 (s, 6H,