Aryl fluoroalkanesulfonate chemistry. A new approach to labelled arene elaboration

Full text of DOI:10.1002/jlcr.1181

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 440–441.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1181
Short Research Article
Aryl fluoroalkanesulfonate chemistry. A new approach to
labelled arene elaborationy
JOHN M. HERBERT*, ANDREW D. KOHLER, FRANCK LE STRAT and DAVID WHITEHEAD
Isotope Chemistry and Metabolite Synthesis Department, sanofi-aventis, Willowburn Ave., Alnwick, Northumberland NE66 2JH, UK
Received 21 July 2006; Revised 7 November 2006; Accepted 21 November 2006
Keywords: aromatic substitution; halogenation; selective catalysis; aryl triflates; aryl nonaflates
Introduction
halogenation with an N-halosuccinimide in sulfuric
acid (Scheme 1; Table 1), in an adaptation of a reported
procedure3. Attempts to carry out Friedel-Crafts acyla-
tion of 1 were unsuccessful.
Labelled phenyl perfluoroalkanesulfonates are readily
available from labelled phenol1, and in this report, are
used to construct multiply substituted labelled arenes.
Further substitution of 2 or 4 gave 1,2,4-trisubsti-
tuted arenes in good yields (Scheme 2). Halophenyl
triflates 3 were further elaborated via the Grignard
reagent formed under Knochel conditions4 (Scheme 2;
Table 2) and it was possible to displace either bromide
or triflate selectively from 4a using previously reported
Results and discussion
Nitration of
1 to give 2
was reproducible2, and
4-halogenated products 3a and 4a were prepared by
methods (Scheme 2; Table 3)5–7
.
HNO3, H2SO4
OSO2R
NXS, acid
OSO2R
O2N
OSO2R
X
RT
RT
2a (R =CF3)
2b (R=C4F9)
3a (X = I, R = CF3); 3b (X = I, R = C4F9)
4a (X Br, R = CF3); 4b (X = Br, R = C4F9)
1a (R =CF3)
1b (R=C4F9)
Scheme 1
Table 1 Electrophilic substitution reactions of 1a and 1b
R
Electro-
phile
Acid
Reaction
time (h)
Yield
(%)
CF3
CF3
CF3
C4F9
C4F9
C4F9
HNO3
NIS
NBS
HNO3
NIS
H2SO4
CF3COOH or H2SO4
H2SO4
H2SO4
CF3COOH or H2SO4
H2SO4
6
4–6
6
4
4–6
20
90, 92
89–99
81, 94
90
86–93
36
*Correspondence to: John M. Herbert, Isotope Chemistry and Metabo-
lite Synthesis Department, sanofi-aventis, Willowburn Ave., Alnwick,
Northumberland NE66 2JH, UK.
E-mail: john.herbert@sanofi-aventis.com
yProceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
NBS
Copyright # 2007 John Wiley & Sons, Ltd.

ARYL FLUOROALKANESULFONATE CHEMISTRY 441
X = NO2, R = CF3
NYS, H2SO4, RT
X = Br, R = CF3
NIS (81-94%)
OSO2R
OTf
OTf
Br
X
O2N
Y = I (90-99%)
Y = Br (81-94%)
or NaNO3 (Y = NO2, 86%)
H2SO4, RT
3,4
Y
Y
1. i-PrMgCl, THF, -20°
2. E+
(X = I)
Nu, catalyst
(X = Br, R = CF3)
Y
+
OSO2R
E
OTf
Br
Y
6
5
Scheme 2
Table 2 Reaction of Grignard reagents derived from 3 with electrophiles
R
E+ (E)
Yield (%)
R
E+ (E)
Yield (%)
CF3 (EtCO)2O (COEt)
CF3 1-Benzyl-4-piperidinone
CF3 Benzaldehyde (CH(OH)Ph) 99
CF3 MeSO2Cl (Cl) 75
28
29
CF3 NCCOOEt (COOEt) 68
CF3 Ms2O (SO2Me)
CF3 C2Cl6 (Cl)
35
85
C4F9 NCCOOEt (COOEt) 60
Table 3 Metal-catalysed displacement reactions of 4a
Nu
Catalyst
5, 6 yields
Nu [Y]
Catalyst
Pd(dppf)2Cl2
Pd(OAc)2, AsPh3
Ni(dppf)Cl2
5, 6 yields
Zn(CN)2
Zn(CN)2
Me2Zn
Pd(dppf)2Cl2
Pd(OAc)2, AsPh3
Pd(dppe)2Cl2
0, 100%
87%, 0
72%, 25%
100%, 0
[(RO)2B]2 a[B(OR)2]
[(RO)2B]2 a[B(OR)2]
[(RO)2B]2 a[B(OR)2]
Et3SiH[H]
92%, 0
1%, 91%
50%
Me2Zn
Pd(OAc)2, AsPh3
Pd(OAc)2, dppp
55%
a Bis(pinacol)diborane.
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Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 440–441
DOI: 10.1002.jlcr