A mild method for the cleavage of the 4-picolyloxy group with magnesium under neutral conditions

Article abstract of DOI:10.1055/s-0031-1290092

A mild and efficient method for the selective hydrolysis of 4-picolyl esters with magnesium in methanol or water in the presence of other esters and sensitive protecting groups is described. 4-Picolyl aryl ethers and thioethers are also smoothly deprotected to give the corresponding phenols and thiophenols. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1290092

142
LETTER
A Mild Method for the Cleavage of the 4-Picolyloxy Group with Magnesium
under Neutral Conditions
Jianwei Zhu,a Wenjun Miao,a Lingling Bao,a Tao Ji,a Guo Tang,*a Pengxiang Xu,a Yufen Zhaoa,b
a
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. of China
Fax +86(592)2185780; E-mail: t12g21@xmu.edu.cn
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University,
b
Beijing 100084, P. R. of China
Received 16 August 2011
corresponding products in excellent yields. The protected
Abstract: A mild and efficient method for the selective hydrolysis
substrates, in most cases, released nearly quantitative
of 4-picolyl esters with magnesium in methanol or water in the pres-
yields based on converted 4-picolyl benzoate.
ence of other esters and sensitive protecting groups is described. 4-
Picolyl aryl ethers and thioethers are also smoothly deprotected to
give the corresponding phenols and thiophenols.
Magnesium in methanol was chosen as a deprotection
agent for 4-picolyl esters in the present study because of
Key words: hydrolysis, 4-picolyloxy group, magnesium, protect-
ing groups, phenols
the mild reaction conditions and apparent compatibility
with acid-sensitive functionalities.15,16 Using 4-picolyl
benzoate as a model substrate, we have studied the effect
of solvent effect on the deprotection process (Table 1). Of
the solvents used, methanol was the most efficient (reac-
tion time 4 h) and gave a high yield (Table 1, entry 1). A
good yield (86%) was also achieved when water was used
as solvent.
The 4-picolyl group has been shown to be useful in the
protection of carboxyl groups in organic synthesis. In the
segment-condensation peptide synthesis method, seg-
ments are protected as 4-picolyl esters at the carboxyl ter-
mini.1 In addition, in the solid-phase peptide synthesis, 4-
picolyl groups have been used as key intermediates to an-
chor the amino acid to the polymer support.2,3 The pres-
ence of this basic functional group also offers potential
advantages for purification of products by
electrophoresis4 or ion-exchange chromatography.5
Screening of other alcohols showed that methanol is the
most efficient solvent for this reaction (Table 1, entries 1–4).
Table 1
Solvent Effects in Cleavage 4-Picolyloxy Group
O
O
Mg
O
Owing to the pyridine ring, the 4-picolyl esters is stable
under harsh conditions, such as in trifluoroacetic acid,
hydrofluoric acid (25 °C, 20%, 1 h), and even in high
concentrations of hydrochloric acid (0 °C, 2 h) or hydro-
bromic acid (0 °C, 2 h). 4-Picolyl esters are also stable in
Et3N (25 °C, 1 h). Due to the lack of a highly efficient and
selective deprotection method, little attention has been
paid to the 4-picolyl group introduced by the Young
group6 in 1968 in solution peptide synthesis. It was also
reported that the 4-picolyl groups were deprotected by a
light-absorbing photosensitizer.7 An excellent yield for
the free carboxylate has been obtained using visible-light-
absorbing citrate-stabilized metal complexes to mediate
electron transfer between dithiothreitol and an N-meth-
ylpicolinium ester in aqueous solution by Falvey’s group.8
OH
+
N
N
solvent
Entry
1
Solvent
Time (h)
Yield (%)a
MeOH
EtOH
4
16
16
16
24
24
16
16
16
16
4
92
2
30
3
i-PrOH
t-BuOH
THF
28
4
30
5
n.r.b
n.r.b
90
6
1,4-dioxane
7
MeOH (10%)–THF
MeOH (10%)–MeCN
H2O (10%)–THF
H2O (10%)–1,4-dioxane
H2O
8
95
Our continued interest in peptide synthesis recently
prompted us to explore the efficient deprotection of 4-pi-
colyl esters.9,10 Removing a protecting group by treating a
compound with magnesium has good applications in or-
ganic synthesis.11–14 We found that the hydrolysis of 4-pi-
colyl esters using magnesium in methanol gives the
9
92
10
11
12
93
86
MeOH (20%)–H2O
4
90
a Isolated yield.
b No reaction.
SYNLETT 2012, 23, 142–144
Advanced online publication: 09.12.2011
x
x.
x
x.
2
0
1
1
DOI: 10.1055/s-0031-1290092; Art ID: W17911ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
143
In the nonprotonic solvent, the reaction did not proceed As shown in Table 2, in all the magnesium-deprotection
(Table 1, entries 5, 6). However, when only 10% of meth- products the same rotation was measured indicating that
anol or water was added into the aprotic solvents, the no significant racemization of the amino acids occurs dur-
cleavage of the 4-picolyloxy group of 4-picolyl benzoate ing these reactions. To corroborate this observation, 4-pi-
was completed within 16 hours in the mixture of solvents, coly ester was removed from the synthesized dipeptide
and the reaction gave benzoic acid in 85–93% yield Boc-(L)-Ala-(L)-Val-OPic. After Boc deprotection, the
(Table 1, entries 7–10).
resulting free dipeptide was analyzed by HPLC. Only a
small peak (0.2%) was detected at the time corresponding
to the (L)-Ala-(D)-Val-OH isomer when compared to con-
trol chromatograms of (L)-Ala-(L)-Val-OH (tR = 8.63
min) and (L)-Ala-(D)-Val-OH (tR = 7.74 min) isomers.
This fact indicates that no significant racemization took
place during derivatization with 4-picoly ester and subse-
quent deprotection.
Pyridin-4-ylmethanol can be coupled to carboxylic acids,
protected amino acids, phenols, and benzenethiols using
standard ester synthesis techniques, described in detail in
the typical procedure.17,18 We tried to reduce 4-picolyl es-
ters of common Cbz, Boc, and Fmoc N-protected amino
acids and cinnamic acid with magnesium in methanol.
The results obtained are summarized in Table 2. In these
reactions, the acid-sensitive Cbz and Boc groups and the
basic-sensitive Fmoc group were unaffected. Deprotec-
tion of 4-picolyl cinnamate, which has a potentially re-
duceable a,b-unsaturated system, was unaffected when
treated with magnesium in methanol, even after long reac-
tion times (24 h at r.t., Table 2, entry 16). Thus, a remark-
able specificity is observed.
Table 3 Removal of the Protecting Groups for the Phenols and Ben-
zenethiols
Entry Starting material
Product
Yield (%)
88
O
H
O
1
2
3
H
OH
OH
O
N
Table 2 Removal of Protection for the Carboxyl Groupa
O
Mg, MeOH
X
AA
O
C
N
X
AA OH +
N
89
90
solvent
NC
H2
NC
X = Boc, Cbz, Fmoc
N
Entry Starting material
Product
[a]D20 (c = 1, AcOH)
S
Reaction Standard
SH
1
2
3
4
5
6
7
8
9
Boc-Phe-OPic
Boc-Val-OPic
Boc-Ala-OPic
Boc-Phe-OH
Boc-Val-OH
Boc-Ala-OH
4.1
–6.0
4.2
–5.9
N
S
–24.4
–24.6
–19.8
–23.9
–23.6
–63.2
–21.0
–28.4
–4.6
4
92
SH
Boc-Asp(Bn)-OPic Boc-Asp(Bn)-OH –19.5
N
Boc-Leu-OPic
Boc-Ile-OPic
Boc-Pro-OPic
Boc-Trp-OPic
Cbz-Met-OPic
Boc-Leu-OH
Boc-Ile-OH
Cbz-Pro-OH
Boc-Trp-OH
Cbz-Met-OH
Cbz-Val-OH
Cbz-Ala-OH
Cbz-Phe-OH
Cbz-Ile-OH
Cbz-Gly-OH
Fmoc-Met-OH
–23.9
–23.4
–63.1
–20.9
–28.3
–4.5
In our ongoing efforts to explore this Mg/MeOH method-
ology, we found it to be very effective for deprotecting 4-
picolyl ethers. Preliminary experiments have given very
satisfactory results (Table 3).18 Thus, aryl ethers and thio-
ethers are smoothly deprotected to give the corresponding
phenols and thiophenols.
10 Cbz-Val-OPic
11 Cbz-Ala-OPic
12 Cbz-Phe-OPic
13 Cbz-Ile-OPic
14 Cbz-Gly-OPic
15 Fmoc-Met-OPic
In summary, a simple and efficient method for the cleav-
age of the 4-picolyloxy group by treatment with magne-
sium in methanol has been developed. The reaction does
not produce byproducts other than the salts generated. Fi-
nally, the deprotection reaction can be performed in H2O
or MeOH. We anticipate its widespread applicability and
usefulness in organic synthesis.
–13.8
5.1
–13.9
4.9
–18.2
–
–18.3
–
–19.5
–19.4
Supporting Information for this article is available online at
O
O
16
–
–
http://www.thieme-connect.com/ejournals/toc/synlett.
Pic
H
Ph
O
Ph
O
Primary Data for this article are available online at http://
www.thieme-connect.com/ejournals/toc/synlett and can be cited
using the following DOI: 10.4125/pd0022nd.
a Starting material (2 mmol), Mg (288 mg, 12 mmol), MeOH (20 mL),
r.t., 4 h.
© Thieme Stuttgart · New York
Synlett 2012, 23, 142–144

144
J. Zhu et al.
LETTER
(16) Pak, C. S.; Lim, D. S. Synth. Commun. 2001, 34, 2209.
(17) Protective Groups in Organic Synthesis, 3rd ed.; Green, T.
W.; Wuts, P. G. M., Eds.; Wiley: New York, 1999, 373–377.
(18) Typical Procedure A: Protection
Acknowledgment
We acknowledge financial support from the Chinese National
Natural Science Foundation (20732004, 20972130, 21075103,
21173178) and NFFTBS (J1030415).
A solution of N-Boc-L-alanine-L-valine (0.864 g, 3 mmol),
4-picolyl chloride hydrochloride (0.50 g, 3 mmol), and Et3N
(0.606 g, 6 mmol) in DMF (10 mL) was heated at 90 °C for
3 h, till TLC showed the absence of 4-picolyl chloride. The
solvent was distilled off, and EtOAc (10 mL) was added to
the residue. The solution was washed with sat. NaHCO3
(3 × 10 mL), H2O (2 × 10 mL), and brine (10 mL), and then
dried over MgSO4. After evaporation of the solvent, the dark
brown solid was purified by column chromatography using
EtOAc–PE (1:1). The filtrate was evaporated in vacuo, and
the product was purified by column chromatography using
EtOAc–PE (1:1). Yield 0.852 g (75%); [a]D20 –24.6 (c 1,
DMF). ESI-MS: m/z = 380.2 [M + H]+, 402.2 [M + Na]+.
ESI-HRMS: m/z calcd for [C19H29N3O5 + H]+: 380.2185;
found: 380.2181; m/z calcd for [C19H29N3O5Na]+: 402.2005;
found: 402.2002. 1H NMR (400 MHz, CDCl3): d = 0.90 (d,
J = 7.0 Hz, 3 H), 0.95 (d, J = 7.0 Hz, 3 H), 1.35 (d, J = 6.9
Hz, 3 H), 1.44 (s, 9 H), 2.20–2.24 (m, 1 H), 4.23 (s, 1 H),
4.61 (t, J = 5.0, 9.0 Hz, 1 H), 5.18 (s, 2 H), 5.28 (d, J = 7.9
Hz, 1 H), 7.26–7.30 (m, 2 H), 8.61 (m, 2 H). 13C NMR (100
MHz, CDCl3): d = 17.5, 18.9, 28.1, 30.9, 49.8, 57.0, 64.7,
80.0, 121.8, 140.2, 149.9, 155.6, 171.3, 172.7.
References and Notes
(1) Camble, R.; Garner, R.; Young, G. T. Nature (London)
1968, 217, 2471.
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Typical Procedure B: Deprotection
To a solution of picolyl N-Boc-L-alanine-L-valinate (0.76 g,
2 mmol) in MeOH (20 mL) magnesium turnings (288 mg, 12
mmol) were added. After stirring for 4 h at r.t. the reaction
mixture was filtered. The filtrate was concentrated in vacuo,
and the residue was diluted with 5% NaHCO3 (10 mL) and
EtOAc (10 mL), and the organic layer was extracted with 5%
NaHCO3 (2 × 10 mL). The aqueous extract was acidified to
pH 2–3 with sat. KHSO4 and extracted with EtOAc (2 × 10
mL). The organic layer was washed with brine (2 × 10 mL),
dried with Na2SO4, and filtered. The residue was purified by
silica gel column chromatography using EtOAc–PE. Yield
0.518 g (90%); [a]D20 8.7 (c 1, CHCl3).
(12) (a) Tang, G.; Ji, T.; Hu, A. F.; Zhao, Y. F. Synlett 2008,
1907. (b) Zhao, Y. F.; Tang, G.; Zhou, N. US 7163917B2,
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1994, 59, 1428.
Synlett 2012, 23, 142–144
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