LETTER
Hydroxymethylation of Heteroaromatic Bases
875
Table 1 Hydroxymethylation of Heteroaromatic Bases by Persul-
13,
fate Oxidation of Ethylene Glycol (A), Glycerol (B) or MeOH (C)
Heteroaromatic Radical source Yields (%)
base
Selectivity
(Isomer) %
Lepidine
Lepidine
Lepidine
A
B
C
92
15
98
(2) 100
(2) 100
(2) 75 CH OH;
2
(
2) 25 CHO
Equation 5
Quinoline
Quinoline
Quinaldine(a)
A
B
A
A
76
12
98
58
(2) 61; (4) 39
(2) 63; (4) 37
(4) 85
other hand, alkoxyl radicals can undergo a fast b-scission;
for instance, the rate constant value for the b-scission of
•
6
t-BuO radical to acetone and methyl radical is about 10
Isoquinoline
(1) 100
–
1
s at 30 °C; three factors may contribute to increase in the
a
H SO (0.5 mmol) was used instead of CF COOH.
rate of b-scission of alkoxyl radicals compared to hydro-
gen abstraction: (i) the stability of the resulting radical;
2
4
3
1
0
(
ii) polar solvents; (iii) high temperature, b-scission being
With glycerol a similar clean and selective hydroxy-
a unimolecular process.
2–
methylation also occurs, but conversions based on S O8
2
Thus, we have developed a different synthetic strategy are lower, due to competitive oxidation of all the –OH
based on the oxidation of ethylene glycol by persulfate groups (Equation 7).
•
and Ag(I) catalysis, considering that CH OH is more
2
•
likely to be formed from MeOH and CH O . Since
CH OH radical is more stable than CH , b-scission
should be faster for the alkoxyl radical formed from
3
•
•
2
3
•
glycol (Equation 6) than for t-BuO . The formation of the
hydroxymethyl radical is also favoured by the polar sol-
vent (H O–OHCH CH OH, 1:1) and the high temperature
2
2
2
(
reflux).
Equation 7
No substitution takes place with the secondary ketyl radi-
Equation 6
cal formed according to Equation 7a, for two main rea-
•
sons: it is more oxidisable than CH OH and its addition
2
11
to the heterocyclic ring is more reversible, so that it is
further oxidised, with S O8 consumption.
Actually, a very selective and clean hydroxymethylation
of the heterocyclic rings, with formation of traces of alde-
hydes, occurs by persulfate oxidation of ethylene glycol in
the presence of protonated heteroaromatic bases in aque-
ous solution.
2
–
2
References
(
1) Studer, A.; Bossart, M. In Radicals in Organic Synthesis;
In addition to their synthetic interest, the results reported
in the Table 1 clarify the reaction mechanism, which in
turn can explain the high selectivity. The alkoxyl radical
of Equation 6 undergoes b-scission faster than hydrogen
abstraction from C–H bonds, leading to CH OH and sub-
sequent hydroxymethylation. Equation 6 being an elec-
tron-transfer process, the enthalpic effect is of very minor
significance, and the b-fragmentation of the alkoxyl radi-
cal is so fast that the intermolecular hydrogen abstraction
from the reaction products is minimised.
Renaud, F.; Sibi, M. P., Eds.; Wiley-VCH: New York, 2001,
74.
(2) Reviews on the subject: (a) Minisci, F.; Porta, O. In
Advances in Heterocyclic Chemistry, Vol. 16; Katritzky, A.
R., Ed.; Academic Press: New York, 1974, 123–180.
•
2
(
b) Minisci, F. Top. Curr. Chem. 1976, 62, 1. (c) Minisci,
F.; Fontana, F.; Vismara, E. J. Heterocycl. Chem. 1990, 27,
9.
7
(
3) Recent publications: (a) Cowden, C. J. Org. Lett. 2003, 5,
4497. (b) Minisci, F.; Recupero, F.; Punta, C.; Gambarotti,
C.; Pedulli, G. F.; Fontana, F. Chem. Commun. 2002, 2496.
(
c) Minisci, F.; Recupero, F.; Cecchetto, A.; Punta, C.;
1
2
Recently, Steckam has reported a mild, selective method
for the formal generation of CH OH by photoinduced
Gambarotti, C.; Pedulli, G. F.; Fontana, F. J. Heterocycl.
Chem. 2003, 40, 325.
•
2
radical electron-transfer of a-silyl ethers; this method can
be used for the hydroxymethylation of heteroaromatic
bases, even if it is somewhat more complex compared to
the methodology described in this paper.
(4) Recupero, F.; Bravo, A.; Bjorsvik, H.-R.; Fontana, F.;
Minisci, F.; Piredda, M. J. Chem. Soc., Perkin Trans. 2 1997,
2399.
Synlett 2004, No. 5, 874–876 © Thieme Stuttgart · New York