Chemoselective O-methylation of N-acylated/sulfonylated tyrosine derivatives

Article abstract of DOI:10.1016/S0040-4039(01)02349-8

Methyl ethers (6a and 6b) of N-trifluoroacetyl- and N-(m-trifluoromethyl) phenylsulfonyl-6-nitro-tyrosine t-butyl ester were readily prepared by modified Mitsunobu reaction (DPPE, DIAD, MeOH). Williamson (MeI, K₂CO₃ or Li₂CO₃ or NaOH under phase transfer) and classical Mitsunobu conditions (PPh₃, DEAD, MeOH) gave O,N-dimethylated derivatives (7a and 7b) as side or main products. O- versus N-selectivity in tyrosine methylation reactions depends on both pK_a values and steric factors.

Full text of DOI:10.1016/S0040-4039(01)02349-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1187–1188
Chemoselective O-methylation of N-acylated/sulfonylated
tyrosine derivatives
Mireille Attolini, Thierry Boxus, Ste´phane Biltresse and Jacqueline Marchand-Brynaert*
Unite´ de Chimie Organique et Me´dicinale, Universite´ Catholique de Louvain, Baˆtiment Lavoisier, Place L. Pasteur no. 1,
B-1348 Louvain-la-Neuve, Belgium
Received 27 September 2001; accepted 6 December 2001
Abstract—Methyl ethers (6a and 6b) of N-trifluoroacetyl- and N-(m-trifluoromethyl) phenylsulfonyl-6-nitro-tyrosine t-butyl ester
were readily prepared by modified Mitsunobu reaction (DPPE, DIAD, MeOH). Williamson (MeI, K2CO3 or Li2CO3 or NaOH
under phase transfer) and classical Mitsunobu conditions (PPh3, DEAD, MeOH) gave O,N-dimethylated derivatives (7a and 7b)
as side or main products. O- versus N-selectivity in tyrosine methylation reactions depends on both pKa values and steric factors.
© 2002 Elsevier Science Ltd. All rights reserved.
O-Alkylation of tyrosine derivatives is usually per-
formed by the Williamson reaction.1 However, depend-
ing on the acidity of the N-protected function,
N-alkylation can occur in competition with the forma-
tion of phenolic ether.2 The Mitsunobu reaction has
been scarcely applied in this case.3
The required precursors 2a and 2b were obtained in two
steps from tyrosine t-butyl ester (TyrOtBu).4
Williamson etherification of 2a with methyl iodide in
the presence of potassium carbonate led to a mixture of
O-methyl and O,N-dimethyl derivatives 6a and 7a
(Table 1, entry 1). Similar reaction of methyl iodide and
lithium carbonate applied to precursor 2b gave exclu-
sively O,N-dimethyl derivative 7b (entry 2). Under
phase transfer conditions, the same result was obtained
(entry 3). Therefore, we turned to the Mitsunobu reac-
tion and systematically examined the O/N chemoselec-
tivity of precursors 1–2. The reactions were performed
During the search of RGD peptidomimetic com-
pounds,4 we were interested in the preparation of
methyl ethers of N-trifluoroacetyl- and N-(m-trifluoro-
methyl)phenylsulfonyl-6-nitro-tyrosine t-butyl ester 6a
and 6b (Scheme 1), respectively.
t
t
O2N
CO2 Bu
CO2 Bu
iii
Alkylation
see Table 1
i
TyrOtBu
NH-R
NH-R
HO
HO
or ii
1 a, R= COCF3;
2
b, R= SO2PhmCF3
1
5
8
3
t
t
t
2
6
X
4
CO2 Bu
X
CO2 Bu
X
CO2 Bu
+
NH-R
N-R
N-R
+
9
MeO
MeO
HO
7
Me
Me
3 (X = H); 6 (X = NO2)
4 (X = H); 7 (X = NO2)
5 (X = H); 8 (X = NO2)
Scheme 1. O/N-Methylation of tyrosine derivatives. Reagents and conditions: (i) trifluoroacetic anhydride (1 equiv.), CH2Cl2,
20°C, 2 h, 95% yield; (ii) mCF3PhSO2Cl (1.1 equiv.), pyridine (1.2 equiv.), CH2Cl2, 20°C, 5 h, 48% yield; (iii) HNO3 (1.2 equiv.),
HOAc, 16°C, 1 h, 95% yield.
* Corresponding author. Tel.: +32 10 472740; fax: +32 10 474168; e-mail: marchand@chim.ucl.ac.be
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02349-8

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M. Attolini et al. / Tetrahedron Letters 43 (2002) 1187–1188
Table 1. O/N selectivity
Entry
Conditions (conversion ratio of 100%)
Products (ratio)a
1H NMR (l)
OMe
NMe
1
2
3
4
5
6
7
8
2a; MeI, K2CO3, CH3CN, reflux
2b; MeI, Li2CO3, DMF, 40°C
6a/7a (75/25)
7b (100)
7b (100)
3a/4a (84/16)
6a/7a (86/14)
6a/7a (96/4)
6a (100)
4b/5b (65/35)
7b (100)
3.93 (6a); 3.84 (7a)
3.95
3.95
3.80 (3a); 3.79 (4a)
3.80 (3a); 3.79 (4a)
3.80 (3a); 3.79 (4a)
3.80 (3a); 3.79 (4a)
3.79 (4b)
2.98
2.90
2.90
2.94
2.94
2.94
2.94
2.90
2.90
2.90
2.92
2b; MeI, NaOH, BTBACl, CH2Cl2, H2O, 20°C
1a; PPh3, DEAD, MeOH, 20°C
2a; PPh3, DEAD, MeOH, 20°C
2a; DPPE, DEAD, MeOH, 20°C
2a; DPPE, DIAD, MeOH, 20°C
1b; PPh3, DEAD, MeOH, 20°C
2b; PPh3, DEAD, MeOH, 20°C
2b; DPPE, DEAD, MeOH, 20°C
2b; DPPE, DIAD, MeOH, 20°C
9
10
11
3.79 (4b)
3.95 (6b)
3.95 (6b)
6b/7b/8b (66/27/7)
6b/7b/8b (51/30/18)
a Determined by 1H NMR analysis of the crude mixtures.
in methanol (0.4 M) at 20°C with diethyl azodicarboxy-
late (DEAD, 1.1 equiv.) and triphenylphosphine (1.1
equiv.).
(sulfonamide series) gave O-methyl product 6b as the
major compound (entries 10 and 11), but N-methyl-
and O,N-dimethyl derivatives 8b and 7b were still
present. Nevertheless, the desired methyl ether 6b could
be obtained in about 60% yield, although it was not
formed under Williamson or classical Mitsunobu condi-
tions. Thus, steric factors10 dramatically changed the
O/N selectivities of the methylation reaction.
In the trifluoroacetamide series (1a, 2a), O-methylation
was always preferred over O,N-dimethylation (entries 4
and 5); at the end of the reaction, 84:16 and 86:14
mixtures of 3a:4a and 6a:7a were recovered. However, a
98:2 selectivity of 3a:4a and 6a:7a could be observed for
conversion ratios of 60 and 80%, respectively. On the
other hand, in the m-(trifluoromethyl)phenyl sulfon-
amide series (1b, 2b), O-monomethylation was never
observed (entries 8 and 9). Due to the high acidity of
NH proton, N-methylation occurred faster, leading to a
35:65 mixture of N-methyl (5b) and O,N-dimethyl (4b)
derivatives of 1b at 100% of conversion ratio. When the
acidity of the phenol moiety increased, due to the
ortho-nitro substitution, O,N-dimethyl (7b) derivative
of 2b was the only formed product at the end of the
reaction. Indeed, sulfonamides are known to be good
substrates of Mitsunobu reaction.5,6
References
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Since the differences of pKa values of the competing
functions were not sufficiently marked for complete
selectivity,7 we speculated that steric effects could help.
By using 1,2-bis(diphenylphosphino)ethane8 (DPPE) in
replacement of triphenylphosphine, reaction of 2a (tri-
fluoroacetamide series) furnished a 96:4 mixture of
6a:7a (entry 6). The next replacement of DEAD by
diisopropyl azodicarboxylate9 (DIAD) gave 6a as single
product (entry 7). Application of these modified Mit-
sunobu conditions to methylation of compound 2b