Hydrogen peroxide promoted hydroxylation of haloarenes and heteroarenes

Article abstract of DOI:10.1016/j.tetlet.2006.04.020

Addition of aqueous hydrogen peroxide significantly accelerates the substitution reactions of hydroxide salts with haloarenes bearing electron withdrawing substituents. A similar effect is observed in the reactions of hydroxide salts with halogenated heteroarenes. Reactions are carried out in water or water-THF at ambient temperature or at 50-60 °C.

Full text of DOI:10.1016/j.tetlet.2006.04.020

Tetrahedron Letters 47 (2006) 4249–4251
Hydrogen peroxide promoted hydroxylation
of haloarenes and heteroarenes
*
William R. Cantrell, Jr., William E. Bauta and Tracy Engles
Genzyme Corporation, Therapeutics Manufacturing and Development, 14805 Omicron Drive, San Antonio, TX 78245, USA
Received 15 March 2006; revised 3 April 2006; accepted 6 April 2006
Abstract—Addition of aqueous hydrogen peroxide significantly accelerates the substitution reactions of hydroxide salts with halo-
arenes bearing electron withdrawing substituents. A similar effect is observed in the reactions of hydroxide salts with halogenated
heteroarenes. Reactions are carried out in water or water–THF at ambient temperature or at 50–60 ꢀC.
ꢁ
2006 Elsevier Ltd. All rights reserved.
1
. Introduction
NH2
N
N
N
Displacement of halogens by hydroxide anion on aro-
matic and heteroaromatic rings is often a difficult trans-
formation. Even in the case of haloarenes which are
NaOH, 1M aq
HO
N
Cl
1
F
85 °C
O
predisposed to S Ar reactivity by the presence of
N
strongly electron withdrawing functionalities, forcing
conditions are generally required. Alternatives to
hydroxide in such reactions have been developed, for
OH
1
NH2
N
N
N
other
2
+
example, by use of 2-butyn-1-ol, 2-(methylsulfonyl)eth-
HO
N
H
O
degradants
3
4
F
anol, or sodium trimethylsilanoate. Palladium cata-
O
lyzed reactions to form t-butyl-aryl ethers have also
5
been developed. These t-butyl-aryl ethers can be readily
OH
2
(<10%)
cleaved to the corresponding phenols.
Scheme 1. Base degradation of clofarabine.
2
. Results and discussion
converted to the corresponding xanthines by the action
During the course of our studies on the alkaline degra-
dation of clofarabine (1), we observed conversion to a
number of degradants upon prolonged heating with
aqueous sodium hydroxide. One of these degradants,
the isoguanine nucleoside (2), resulting from formal
SNAr reaction, was only produced as a small proportion
of the mixture (Scheme 1). A review of the literature
revealed a previous report by Rai c´ -Mali c´ and co-work-
ers, where 2-fluoro-9H-purine-6-thiol derivatives were
of hydrogen peroxide in dilute ammonium hydroxide
6
at room temperature. Thus a formal double S
Ar
N
displacement on the 2 and 6 positions of the purine ring
had been achieved. However, when these reaction condi-
tions were attempted with clofarabine (1), no significant
production of 2 was observed. This result was not
entirely unexpected, given the very high reactivity of
7
2-fluoropurines in comparison with other halopurines.
Also, Heller and Weiler had reported on the hydrogen
peroxide accelerated displacement of nitro groups from
ortho- and para-dinitrobenzenes to the corresponding
8
phenols with sodium hydroxide in aqueous dioxane.
Aryl hydroperoxide intermediates were detected in
these reactions. We thus decided to study hydrogen
Keywords: Accelerated S
*
N
Ar; Mild conditions.
Corresponding author. Tel.: +1 210 949 8481; fax: +1 210 949
649; e-mail: william.bauta@genzyme.com
8
peroxide-promoted S Ar reactions in selected aromatic
N
0040-4039/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.020

4250
W. R. Cantrell, Jr. et al. / Tetrahedron Letters 47 (2006) 4249–4251
and heteroaromatic systems under various reaction
conditions.
20 min to high conversion, affording the corresponding
phenol (entry 13).
An aqueous suspension of clofarabine was treated with
lithium hydroxide (3 mol equiv) and hydrogen peroxide
M a˛ kosza and Sienkiewicz have reported the vicarious
nucleophilic substitution reactions of electron deficient
(
2 mol equiv) with vigorous stirring. After 17 h at room
temperature, HPLC analysis showed 29% conversion to
. The mixture was heated to 60 ꢀC for 5 h, whereupon
aromatic systems with t-butyl hydroperoxide in liquid
9
ammonia. While these authors observed S Ar substi-
N
2
tution in the case of 4-fluoronitrobenzene, vicarious
nucleophilic substitution products resulted with 3-flu-
oronitrobenzene, 3-chloronitrobenzene, and 1,3-dinitro-
benzene (entry 14). Under our conditions we observed no
reaction.
the reaction was 86% complete by HPLC analysis.
Workup and isolation afforded nucleoside 2 in 48%
yield. Interestingly, use of catalytic (0.11 equiv) hydro-
gen peroxide led to a low (6.8%) conversion to 2. Thus,
a reactivity enhancement had been observed by addition
of hydrogen peroxide.
Some p-deficient heterocyclic systems were investigated
(
Scheme 2). 2-Fluoro pyridine (3) reacted to afford 2-
1
0
The conversion of 4-nitrofluorobenzene to 4-nitrophe-
pyridone (4) in 47% yield (82% conv). But 3-fluoro-
2
–4,9
nol has been accomplished using various methods.
We found that the reaction could be carried out with
LiOH (3 equiv) and HOOH (2 equiv) in THF–water
LiOH (3 eq)
(
Table 1, entry 1). Alternatively, a biphasic mixture of
water and toluene could be used (entry 2), or in water
alone (entry 3). Sodium hydroxide worked well in water
HOOH (2 eq),
H O, 50 C, 21 h
2
N
F
F
N
H
O
o
3
4
(47%)
(
entry 4) but both sodium and potassium hydroxide
afforded lower yield and conversion in THF–water (en-
tries 4–6). Consistent with the clofarabine result, ammo-
nium hydroxide gave low conversion (entry 7). As a
control, the reaction proceeded to only 3% conversion
in the absence of hydrogen peroxide (entry 8).
LiOH (3 eq)
OH
HOOH (2 eq),
N
5
N
o
H O, 50 C, 17 h
2
6
(0%)
2
(
1
-Nitrofluorobenzene reacted smoothly to 2-nitrophenol
entry 9) but 3-nitrofluorobenzene failed to react (entry
0). 2-Chloro and 4-chloronitrobenzene were unreactive
LiOH (3 eq)
N
N
N
Cl HOOH (2 eq),
N
H
8
O
o
under our usual reaction conditions but also when
DMSO was used as a co-solvent (entries 11–12). Highly
reactive 1-chloro-2,4-dinitrobenzene proceeded within
H
2
O, 50 C, 16 h
7
(67%)
Scheme 2. Reactions of other halo heteroarenes.
Table 1. Hydrogen peroxide-promoted S
N
Ar reactions of haloaromatic compounds
R2
R2
R1
R3
HOOH, MOH
R1
R3
X
H
2
O, solvent
OH
a
b
Entry
R
1
R
2
R
3
X
M
Solvent
THF–H
Conv (%)
Yield (%)
1
2
3
4
5
6
7
8
9
NO
NO
NO
NO
NO
NO
NO
NO
H
H
NO
H
NO
NO
2
2
2
2
2
2
2
2
H
H
H
H
H
H
H
H
H
NO
H
H
H
H
H
H
H
H
H
H
H
H
NO
H
H
NO
NO
NO
F
F
F
F
F
F
F
F
F
F
Cl
Cl
Cl
H
Li
Li
Li
Na
Na
K
NH
Li
Li
Li
Li
Li
Li
Li
2
O
99
n.d.
76
52
60
59
19
28
c
PhMe–H
2
O
H
H
2
O
O
98
93
35
52
2
2
THF–H
THF–H
2
O
O
2
d
4
H
2
O
n.i.
e
THF–H
2
O
3
n.i.
57
n.i.
n.i.
n.i.
73
2
H
H
2
O
O
90
0
10
11
12
13
14
2
2
2
DMSO–H
DMSO–H
2
O
O
Trace
Trace
98
2
2
2
2
2
2
THF–H O
2
THF
0
n.i.
a
b
c
HPLC conversion.
Isolated yield.
Not determined.
Not isolated.
d
e
2 2
No H O added.

W. R. Cantrell, Jr. et al. / Tetrahedron Letters 47 (2006) 4249–4251
4251
MeCN (v/v), isocratic) to give 2 as a white solid
HO OH
+
M
OH
M
O OH
+
+
H O
2
1
(
0.16 g, 0.56 mmol, 48% yield). Mp = 292 ꢀC (dec). H
NMR (DMSO-d ) 10.74 (br s, 1H), 7.84 (1H, d,
6
J = 2.2 Hz), 7.80 (br s, 2H), 6.13 (1H, dd, J = 4.2,
Ar
X
+
M
O OH
OH
Ar O OH
MX
15.6 Hz), 5.93 (1H d, J = 5.1 Hz), 5.09 (1H, dt,
J = 3.9, 52.5 Hz), 5.13 (1H, br s), 4.35 (1H, ddd,
J = 4.8, 8.4, 18.7 Hz), 3.79 (1H, q, J = 4.6 Hz), 3.80–
Ar O OH
+
M
Ar-O
+
M
O OH
3
1
2
.56 (2H, m). IR (KBr) 3371s br, 1675s, 1643s, 1606s,
Scheme 3. Proposed mechanism for hydrogen peroxide-promoted
hydroxylation.
À1
519w, 1379m, 1094m cm . UV (H O/MeOH) k
2
max1
46.9 nm, kmax2 291.7 nm. Mass spec. (electrospray,
+
positive) m/e [M+H] = 287. Anal. Calcd for
C H FN O : C, 42.11; H, 4.24; F, 6.66; N, 24.55.
pyridine (5), was unreactive.11 Under similar conditions,
1
0
12
5
4
2
-chloropyrimidine (7) afforded 2-pyrimidone (8) in 67%
Found: C, 41.96; H, 4.00; F, 6.43; N, 24.57.
1
2
yield (100% conv).
A possible mechanism for hydrogen peroxide-promoted
SNAr reactions is outlined in Scheme 3. In the presence
of hydroxide, hydrogen peroxide is converted to the
Acknowledgements
The authors thank Dr. Jim Goebel, for mass spectral
data and useful discussions. We also thank Dr. Phil
Bauer, for his support and advice.
1
3
more reactive hydrogen peroxide anion and displaces
the halogen to generate an intermediate aryl hydroper-
oxide, which further reacts with hydroxide to regenerate
the peroxide anion and the desired product. We did not
detect the aryl hydroperoxides by HPLC during the
course of our study and did not see evidence for the for-
mation of diarylhydroperoxide products, which would
result from condensation of the aryl hydroperoxide an-
ion with the haloarene. According to this mechanism,
the reaction can be catalytic in hydrogen peroxide.
However, we did not find this to be practical, probably
owing to the modest stability of hydrogen peroxide
under the reaction conditions.
References and notes
1. Smith, M. B.; March, J. March’s Advanced Organic
Chemistry, 5th ed.; Wiley Inter-Science: NY, 2001, p
8
61.2.
. Levin, J. I.; Du, M. T. Synth. Commun. 2002, 32, 1401–
406.
. Rogers, J. F.; Green, D. M. Tetrahedron Lett. 2002, 43,
585–3587.
. Krapcho, A. P.; Waterhouse, D. Synth. Commun. 1998,
8, 3415–3422.
. (a) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J.
F. J. Am. Chem. Soc. 1999, 121, 3224–3225; (b) Parrish, C.
A.; Buchwald, S. A. J. Org. Chem. 2001, 66, 2498–2500.
. Prekupec, S.; Svedru zˇ i c´ , D.; Gazivoda, T.; Mrvo sˇ -Sermek,
D.; Nagl, A.; Grdi sˇ a, M.; Paveli c´ , K.; Balzarini, J.;
De Clerq, E.; Folkers, G.; Scapozza, L.; Mintas, M.;
Rai c´ -Mali c´ , S. J. Med. Chem. 2003, 46, 5763–5772.
2
3
4
5
1
3
2
3. Conclusion
6
In summary, we have demonstrated that aqueous hydro-
gen peroxide promotes the S Ar reactions of hydroxide
N
salts with various electron deficient aromatic and het-
eroaromatic systems under mild reaction conditions.
These reactions were generally clean and not accompa-
nied by vicarious nucleophilic substitution products.
7
. Gester, J. F.; Robins, R. K. J. Org. Chem. 1966, 31, 3258–
3
262.
8
9
. Heller, R. A.; Weiler, R. Can. J. Chem. 1987, 65, 251–255.
. M a˛ kosza, M.; Sienkiewicz, K. J. Org. Chem. 1990, 55,
4979–4981.
10. The reaction of 2-fluoropyridine with aqueous hydrochlo-
ric acid to afford 2-pyridone has been reported: Bradlow,
H. L.; Vander Werf, C. A. J. Org. Chem. 1949, 14, 509–
A representative procedure is as follows. A 50 mL flask
was charged with clofarabine (1, 0.352 g, 1.159 mmol),
H O (6 mL), LiOH (0.083 g, 3.48 mmol), and H O
2
2
2
(
30 wt %, 0.24 mL, 2.32 mmol). The mixture was stirred
5
15.
at 60 ꢀC for 24 h. HPLC analysis showed 88% conver-
sion. The reaction was worked up. A solution of
Na S O in H O was added until the peroxide test
1
1. 2-Fluoropyridine has been converted to 3-methoxypyri-
dine with sodium methoxide and 18-crown-6 with micro-
wave irradiation: Lloung, M.; Loupy, A.; Marque, S.;
Petit, Alain. Heterocycles 2004, 63, 297–308.
2. 2-Chloropyrimidine was converted in two steps to 2-
pyrimidone via the 2-ethoxy ether: Al-Awadi, N.; Taylor,
R. J. Chem. Soc., Perkin Trans. 2 1986, 1255–1258.
2
2
3
2
(
starch–iodide paper) was negative. Acetic acid was
added until the pH was 4–5. The volatiles were removed
under vacuum. The residue was purified by reverse
phase preparative HPLC chromatography (Waters
1
Atlantis C18 OBD, 5 lm, 19 · 100 mm, 95% H O, 5%
13. See Ref. 1, p 445.
2