Syntheses of novel N-([ 18F]fluoroalkyl)-N-nitroso-4-methyl-benzenesulfonamides and decomposition studies of corresponding 19F- and bromoanalogues: Potential new compounds for the 18F-labelling of radiopharmaceuticals

Article abstract of DOI:10.1002/jlcr.729

N-([¹⁸F]fluoroalkyl)-N-nitroso-4-methyl-benzensulfonamides [n-alkyl = (-CH₂) [^18,19F]F, n = 2-4)] were synthesized in radiochemical yields ranging from 75-90% to provide new secondary labelling precursors for the syntheses

Full text of DOI:10.1002/jlcr.729

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 959–977.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.729
Research Article
Syntheses of novel N-([18F]fluoroalkyl)-N-nitroso-
4-methyl-benzenesulfonamides and decomposition
19
studies of corresponding F- and bromo-
analogues: potential new compounds for the
18F-labelling of radiopharmaceuticals
Ralf Schirrmacher1,*, Bernd Mathiasch2, Esther Schirrmacher1,
1
1
.
Dragana Radnic and Frank Rosch
1 Institute of Nuclear Chemistry, University of Mainz,
Fritz-Strassmann-Weg 2, D-55128 Mainz, Germany
2 Institute of Inorganic Chemistry, University of Mainz,
Duesbergweg 10-14, D-55128 Mainz, Germany
Summary
N-([18F]fluoroalkyl)-N-nitroso-4-methyl-benzensulfonamides [n-alkyl = (ꢀCH2)
[
18,19F]F, n=2–4)] were synthesized in radiochemical yields ranging
from 75–90% to provide new secondary labelling precursors for the
syntheses of 18F-labelled compounds. Preliminary decomposition studies
utilizing the corresponding non-radioactive 19F-compounds as well as the
bromo containing analogous compounds were performed to evaluate their
stability regarding temperature and basicity of the labelling medium.
Furthermore, initial difficulties in labelling these compounds led to the
development of a modified labelling procedure applying nearly solvent-free
conditions. Extensive decomposition experiments of the new fluoro- as
well as the bromo-compounds were conducted under various conditions
in order to get experimental data about their stability and reactivity.
As a result, different trends for the stability of the bromo as well as
*Correspondence to: R. Schirrmacher, Institute of Nuclear Chemistry, Fritz-Strassmann-Weg 2,
D-55128 Mainz, Germany. E-mail: schirrmacher@mail.kernchemie.uni-mainz.de
Copyright # 2003 John Wiley & Sons, Ltd.
Received 14 March 2003
Revised 7 May 2003
Accepted 12 May 2003

960
R. SCHIRRMACHER ET AL.
the fluoro compounds could be observed. Copyright # 2003 John Wiley &
Sons, Ltd.
Key Words: 18F-nitroso-sulfonamides; secondary labelling precursor; decom-
position studies; 18F-fluoroalkylation
Introduction
18F-Fluoroalkylation is a useful alternative method for introducing the
18F-label into polyfunctional molecules like radiopharmaceuticals for
positron emission tomography (PET).1 Especially for H-acidic
compounds, which do not lend themselves to direct nucleophilic
fluorination, fluoroalkylation makes it possible to introduce [18F]fluor-
alkyl groups, such as C2H4[18F]F, into NH, OH, and SH functionalities
applying 2-[18F]fluoroethyltosylate.2 Bifunctional alkanes like 1-bromo-
2-[18F]fluoroethane and analogues can also be applied as precursors for
18F-fluoroalkylations, which are easily prepared via anion activated
nucleophilic 18F-substitution of the corresponding di-bromoalkanes.3
18F-Fluorobenzylation applying 4-[18F]fluorobenzylbromide has been
used for the syntheses of fluorinated radiopharmaceuticals.4 A general
drawback of these labelling precursors is their lack of selectivity with
regard to polyfunctional molecules containing HO- or NH-groups. A
selective base-supported 18F-fluoroalkylation of the H-acidic groups
like phenolic HO- or COOH-moieties can be accompanied by the
undesired alkylation of the nucleophilic NH-group, making the use
of suitable NH-protecting groups necessary. To circumvent these
difficulties, the development and search for new potential labelling
precursors with different labelling properties are of great interest in
radiopharmaceutical chemistry. The synthesis of a 4-[18F]fluorobenze-
nediazonium cation for example has recently been described for the
labelling of aromatic compounds via azo-coupling.5 N-Alkyl-N-
nitrosoamides are compounds of diminished stability and are of great
interest in medicine6, biochemistry7 and industrial chemistry.8 Espe-
cially in organic chemistry N-nitrosamides have been widely used9 and
opened a route to highly reactive carbocations. N-4-R-Benzyl-N-
nitrosopivalamide for example decomposes via a unimolecular path-
way10 to generate short-lived nitrogenous entity-separated ion-pairs,
comprising highly reactive 4-R-benzyl cations and the pivalate ion.8
When the solvent is non-nucleophilic to the carbocation, then the only
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SYNTHESES OF NOVEL . . .
961
product of significance is the ester. Since the benzyl cation is unable to
rearrange, to build fragments, and to lose protons, SN1-type reactions
with the counter ion and any sufficiently nucleophilic partner is its only
fate. Extensive studies of the electronic effects on the kinetics of thermal
deamination were reported by Darbeau et al.11 In radiopharmaceutical
chemistry the concentration of the 18F-labelling precursor is generally in
the nanomolar range and the compound which is to be labelled is
present in high molar excess. Taking this fact into consideration,
radiolabelled carbocations could become useful tools in radiochemistry
as new secondary labelling precursors (Scheme 1). Furthermore, the
syntheses of [18F]fluorodiazoalkanes for the selective alkylation of H-
acidic compounds in the presence of amines could possibly be achieved
via basic decomposition of these compounds (Scheme 1). The present
study aimed at synthesising these new N-[18F]fluoroalkyl-N-nitroso-4-
O+
O
O
N
N
N
N
N
18F
O
18F
O
18F
N+
O
S
S
n
S
n
n
O
O-
O-
n = 2-4
O
S
O
S
O-
O-
O
S
O
O
O
N
+
O
18F
N
N
+
F18
N
+
n
N2
n
n
18F
R1-NH2
R1-NH-R2
R1-SH
R1-OH
18F-labelled product
(a)
SO3H
O
N
18F
N
O
N+ N
+
-
18F
n-1
S
n
O
Ph-OH
R1-NH2
R1-COOH
R1-NH-R2
18F-labelled product
(b)
Scheme 1. (a) possible thermolytic decomposition of new N-[18F]fluoroalkyl-N-
nitroso-4-methyl-benzenesulfonamides.11b (b) possible base induced formation of
[18F]fluorodiazo-alkanes
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962
R. SCHIRRMACHER ET AL.
methyl-benzenesulfonamides as a prerequisite for further studies
concerning the labelling of organic compounds and radiopharmaceu-
ticals.
Results and discussion
Syntheses of 19F-standard compounds and labelling precursors (cf. Table 1)
The syntheses of the non-radioactive standard compounds for analytical
purposes such as high performance liquid chromatography (HPLC)-
and thin layer chromatography (TLC)-conditions as well as for
decomposition studies to prove their eligibility for the labelling was
achieved according to Scheme 2. In the case of 3, 2-fluoroethylamine
and 4-methylbenzenesulfonylchloride (1) were used for the synthesis,
whereas compounds 4 and 5 were obtained via fluoroalkylation of the
deprotonated 4-methylbenzenesulfonamide (2). The di-fluoroalkylated
by-product which was formed during the alkylation step could be
separated via column chromatography. The final nitrosation of all
fluoroalkyl-nitrosamides was performed with sodium nitrite in acetic
acid according to Hyde et al.12 to yield fluoroalkyl-nitrosamides (11–
13). The labelling precursors for the syntheses of 18F-labelled
compounds were all synthesized starting from 4-methylbenzenesulfo-
Table 1. Synthesized compounds
O
S
O
S
N
O
H
N
X1
N
X2
n
n
O
O
X1
F
X1
X1
X2
F
X2
Br
14
n
Br
6
OH
11
2
3
4
3
4
5
12
13
15
16
7
8
9
10
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 959–977

SYNTHESES OF NOVEL . . .
963
O
S
a
Cl
n = 2
O
O
S
1
2
2
O
H
O
S
N
O
b
d
S
N
F
N
F
n
NH2
NH2
n = 3
n
O
O
O
O
S
c
n = 4
O
O
S
O
S
N
O
H
N
e
h
Br
N
Br
2
3
2
O
O
S
O
O
S
f
H
N
Cl
OH
OH
O
S
N
O
i, j
O
O
O
S
1
N
Br
n
g
H
N
O
n = 3, 4
4
O
Scheme 2. Syntheses of N-(fluoroalkyl)-N-nitroso-4-methyl-benzenesulfona-
mides (11–13) and N-(bromoalkyl)-n-nitroso-4-methyl-benzenesulfonamides
(14–16) (cf. Table 1): (a) 2-fluoroethylamine hydrochloride, K2CO3, THF; (b)
NaH, Cu(I)Cl, 1-bromo-3-fluoropropane, DMF; (c) NaH, Cu(I)Cl, 1-bromo-4-
fluorobutane; (d) acetic acid, NaNO2; (e) 2-bromoethylamine hydrochloride,
NaHCO3, THF/water; (f) according to Augstein et al.13; (g) according to
Augstein et al.13; (h) acetic acid, NaNO2; (i) according to Augstein et al.13;
( j) acetic acid, NaNO2
nylchloride (1). Compound 6 was obtained by using 2-bromoethylamine
and 1 and subsequently nitrosated to yield 14. The homologous
compounds 15 and 16 were synthesized starting from the reaction of the
corresponding 3-hydroxypropylamine and 4-hydroxybutylamine with 1
to yield 913 and 10. The nitrosation of these intermediates was not
successful and lead only to the formation of by-products due to the H-
acidic conditions. Therefore, previous to the final nitrosation step, the
OH-moieties of 9 and 10 were converted into the corresponding
bromides.13 Nitrosation yielded 15 and 16 in good yields.
Radioactive labelling of N-([18F]fluoroalkyl)-N-nitroso-4-methyl benze-
nesulfonamides [n-alkyl=(–CH2)n[18F]F, n=2–4)]
Initial labelling experiments were performed applying standard condi-
tions which involved the azeotropic drying of the aqueous [18F]fluoride-
solution in the presence of Kryptofix12.2.2. and potassium carbonate
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964
R. SCHIRRMACHER ET AL.
with acetonitrile.2 After drying, a 18F-stock solution in acetonitrile was
prepared and the labelling precursors, (N-bromoalky)-N-nitroso-4-
methyl-benzensulfonamides [n-alkyl = (–CH2)Br n=2–4)]) (14–16),
dissolved in acetonitrile were added at 758C. Aliquots were taken at
several time points and the radiochemical yields (RCYs) were
determined with HPLC and TLC. The RCYs of all labelled products
(N-([18F]fluoroalkyl)-N-nitroso-4-methyl-benzensulfonamide [n-alkyl =
(–CH2)n[18F]F n=2–4)] were in the unsatisfactory range of 55% after
2 min reaction time at 758C. Neither longer reaction times nor changes
in the reaction temperature led to increased RCYs. The only way to
achieve slightly better RCYs (+2–3%) was to increase the concentra-
tion of the labelling precursors (14–16) because even after the observed
decomposition there was still enough labelling precursor left. But a
higher precursor concentration would possibly result in a more difficult
purification from the labelled product and is therefore not advisable. To
our understanding, these difficulties in labelling are in accordance with
the experimental data of the decomposition experiments we conducted
afterwards. To obtain experimental data about the behaviour of the N-
([18F]fluoroalkyl)-N-nitroso-4-methyl-benzenesulfonamides as well as
the corresponding bromo-labelling precursors under typical labelling
conditions and various temperatures we performed decomposition
studies to get information about how to modify the labelling set-up in
general to maximise RCYs.
Thermal decomposition studies of N-([19F]fluoroalkyl)-N-nitroso-4-
methyl-benzenesulfonamides (19F-standard compounds) in acetonitrile
at 758C (Figure 1(A))
To get information about the general thermal stability of the
19F-compounds 11–13 we conducted decomposition experiments with-
out adding nucleophiles or bases.
The decomposition studies of compounds 11–13 were performed
applying the dynamic 1H NMR (400 MHz) technique. All 19F-standard
compounds underwent thermal decomposition in [D3]acetonitrile at
758C. This solvent was used because it is usually applied in nucleophilic
18F-labelling reactions at temperatures between 70 and 808C. The
product distribution was determined with 1H NMR as well as FD-mass
spectrometry (at the end of experiment) focusing especially on the
protons of the aryl-groups. Plots (Figure 1) of the decomposition data
gave first order decomposition kinetics (Figure 1(A)).10 Additionally the
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SYNTHESES OF NOVEL . . .
965
(a)
(b)
(c)
(d)
(e)
Figure 1. Decomposition studies of N-(halogenoalkyl)-N-nitroso-4-methyl
benzenesulfonamides (fluoro-derivatives 11–13 and bromo-derivatives 14–16):
(a) 11–13, acetonitrile, 758C (b) 14–16, acetonitrile, 758C, (c) 11–13, acetonitrile,
258C, Kryptofix1 2.2.2./K2CO3 (d) 14–16, acetonitrile, 258C, Kryptofix1 2.2.2./
K2CO3 (e) 14–16, acetonitrile, 758C, Kryptofix1 2.2.2./K2CO3
rate constants for each decomposition were determined (Table 2). Half-
lives (t1/2) for the decomposition were calculated to be 124 min (11,
[-N-(CH2)2F]), 122 min (12, [-N-(CH2)3F]) and 60 min (13, [-N-
(CH2)4F]). These results indicate that the electron withdrawing effect
of the fluorine atom is decreasing with a longer alkyl chain and the
compound becomes less stable. This effect is not quantitatively
noticeable for the fluoroethyl and fluoropropyl compounds, as these
two are of comparable stability but it becomes more pronounced for the
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966
R. SCHIRRMACHER ET AL.
Table 2. (A) HPLC-retention times of the radio-labelled N-([18F]fluoroalkyl)-N-
nitroso-4-methyl-benzenesulfonamides and of the labelling precursors N-(bromo-
alkyl)-N-nitroso-4-methyl-benzenesulfonamides, (B) half-lifes and rate constants
A
HPLC- RCYs
retention (%)a
time
Overall
RCYs (%)b
Compound (min)
no.
11
12
13
14
15
16
16
75 ꢁ 5
85 ꢁ 4
90 ꢁ 5
}
}
}
50 ꢁ 7
59 ꢁ 4
65 ꢁ 5
}
}
}
17.2
18.4
17.8
19.7
20.4
B
Compound Decomp. Kryptofix
Kryptofix
no.
758C
2.2.2.1/K2CO3 2.2.2.1/K2CO3
258C
758C
Half-life Rate
(min)
Half-
life
(min)
Rate
constant (min)
Half-life Rate
constant
(minꢀ1
constant
(minꢀ1
)
)
(minꢀ1
)
11
12
13
14
15
16
124
122
60
57
78
0.0056
0.0055
0.0115
0.0122
0.0089
0.0068
9.5
19.3
1733
347
740
0.0734
0.036
0.0004
0.002
0.0009
0.0003
}
}
}
4.6
97
107
}
}
}
0.1497
0.0071
0.0065
102
2310
a determined via HPLC (decay corrected).
b product radioactivity after HPLC-purification referring to starting activity of used
18F]Fluoride (not decay corrected).
[
fluorobutyl compound, resulting in a diminished stability. Darbeau et al.
suggested that this observation could be related to intramolecular
electronic effects, namely that electron repulsing groups accelerate the
thermolysis of nitrosamides whereas electron withdrawing groups have
stabilising effects.11b Nevertheless, all these 19F-compounds are rela-
tively stable under thermal conditions at 758C.
Thermal decomposition studies of N-(bromoalkyl)-N-nitroso-4-methyl-
benzenesulfonamides (labelling precursors) in acetonitrile at 758C
(Figure 1 (B))
It is also of great interest whether the labelling precursors 14–16 are
stable under thermal conditions compared to the corresponding
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SYNTHESES OF NOVEL . . .
967
19F-fluoro compounds. The thermal decomposition studies of com-
1
pounds 14–16 applying the H NMR technique were performed as
described for the corresponding fluoro-compounds. The thermal
stability of the bromo compounds showed a different trend in stability,
compound 16 being the most stable. The half-lives were found to be
57 min (14, [-N-(CH2)2Br]), 78 min (15, [-N-(CH2)3Br]) and 102 min (16,
[-N-(CH2)4Br]) (Figure 1(B); rate constants cf. Table 2). It is well known
that as the alkyl fragment of the nitrosoamide becomes bulkier, the
stability of the compound decreases.14 The influence of the electron-
withdrawing bromine in these compounds is obviously not the
dominating factor governing stability. In general the bromo compounds
are less stable than the fluoro analogues.
Thermal decomposition studies of N-([19F]fluoroalkyl)-N-nitroso-4-
methyl-benzenesulfonamides (19F-standard compounds) in acetonitrile
at 25 and 758C with Kryptofix12.2.2./K2CO3-complex (Figure 1(C))
To obtain data about the time-dependent decomposition of the 19F-
standard compounds 11–13 under typical labelling conditions (acetoni-
trile as solvent, elevated temperatures, Kryptofix12.2.2./K2CO3-
complex to avoid liberation of HF and radioactivity adsorption on
the vessel surface and to enhance the nucleophilicity of the [18F]fluor-
ide), 1H NMR experiments were performed at 758C as well as 258C. At
a temperature of 758C decomposition of 11–13 was complete within
1–2 min. The fast liberation of gas (presumably nitrogen) was
1
obvious and spoiled the H NMR experiment so that no additional
data could be obtained. Even at 258C the decomposition of
1
2
1
2
compounds 11 (t = 9.4 min) and 12 (t = 19.3 min) was rather fast in
1
comparison to compound 13 (t = 1733 min) (Figure 1(C);
2
rate constants cf. Table 2). These results demonstrate the higher
stability of 13 and may provide higher RCYs during the labelling
procedure.
These experimental results supported our previous assumption
that the usually applied method of 18F-fluorination (see experimental
part) is unsuitable for the labelling of the bromo precursors to
obtain N-([18F]fluoroalkyl)-N-nitroso-4-methyl-benzenesulfonamides.
Their stability under the typical labelling conditions is not high enough
to guarantee the necessary RCYs which are required for an efficient 18F-
labelling of radiopharmaceuticals. These results demand a modification
of the labelling procedure. The reaction has to progress fast and the
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968
R. SCHIRRMACHER ET AL.
solvent volume must be minimized since the decomposition is solvent-
mediated.
Thermal decomposition studies of N-(bromoalkyl)-N-nitroso-4-methyl-
benzenesulfonamides (labelling precursors) in acetonitrile at 25 and 758C
with Kryptofix12.2.2./K2CO3-complex (Figure 1(D) and 1(E))
In addition to the decomposition studies of the fluoro compounds at
typical labelling conditions and at 258C, the stability of the bromo
bearing precursors, which are also of general interest for the planned
labelling reaction, was determined. Therefore, decomposition studies at
258C in acetonitrile with Kryptofix1 2.2.2./K2CO3 were monitored with
1H NMR. The focus was on the aromatic protons. Plots (Figure 1(D);
rate constants cf. Table 2) of the decomposition data gave first order
kinetics. When compared with the stability of the corresponding fluoro
compounds, it became quite obvious that the half-lives of 347 min
14 [-N-(CH2)2Br], 740 min 15 [-N-(CH2)3Br] and 2310 min 16 [-N-
(CH2)4Br] (Figure 1(D); rate constants cf. Table 2) reflect a diminished
base lability. It is again noticeable that compound 16 is the most stable
because of the longer bromo-alkyl chain.
When the reaction temperature is increased to 758C, compound 14
decomposes with a relatively short half-life of 4.6 min whereas 15 [-N-
(CH2)3Br] and 16 [-N-(CH2)4Br] remain comparably stable with half-
lives of 97 and 107 min (Figure 1(E); rate constants cf. Table 2).
Concerning a radioactive labelling, the 18F-fluorination of 14 might be
more difficult compared to its homologues because the reason for the
above mentioned low radiochemical yields in this case is not only
the decreased stability of the fluoro compound 11 but also that of the
precursor (14). From this point of view it is even more necessary to
establish an alternative labelling procedure.
Modified labelling procedure of N-([18F]fluoroalky)-N-nitroso-4-methyl-
benzensulfonamides [n-alkyl =(–CH2)[18,19F]F,n=2–4)] applying
nearly solvent-free conditions
Decomposition of both the labelling precursors and the 18F-labelled
products in acetonitrile under basic conditions was observed. Decom-
position of the fluoro-compounds 11–13 at typical labelling conditions
was too fast to get high radiochemical yields which are a prerequisite for
successful application in radiopharmaceutical chemistry. Therefore, we
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SYNTHESES OF NOVEL . . .
969
H218O
(p, n)
18F aq
Kryptofix 2.2.2.
K2CO3 / CH3CN
Kryptofix 2.2.2./[18F]F-/CH3CN/75˚C
O
S
O
S
N
N
O
O
N
N
nearly solvent-free conditions
18F
n
Br
O
O
n
n = 2-4
Scheme 3. Radioactive labelling of bromo precursors 14–16 applying nearly
solvent-free conditions to obtain N-([18F]fluoroalkyl)-N-nitroso-4-methyl-benze-
nesulfonamides (11–13)
established a modified labelling procedure under nearly solvent-free
conditions applying high concentrations of precursors and subsequent
fast cooling.
This method included the normal azeotropic drying procedure as
described above but no 18F-stock solution in acetonitrile was prepared
(Scheme 3). On the contrary, the [18F]fluoride/Kryptofix12.2.2-complex
remained adsorbed on the reaction vessels’ surface at a temperature of
75–808C and the precursors 14–16, dissolved in 0.2 ml acetonitrile at RT
were added quickly. After 3 min reaction time (within this time, most of
the acetonitrile evaporated into the vapour phase), ice-cold water was
added for terminating the reaction and the mixture was passed through
a solid phase cartridge (LiChrolute EN, Merck, Germany) to trap the
radio-labelled compounds via fixation. After rinsing with water and
drying with nitrogen, the cartridge was eluted with acetonitrile (408C).
The eluate was subsequently analysed via radio-HPLC and radio-TLC.
The RCYs of the N-([18F]fluoroalky)-N-nitroso-4-methyl-benzensulfo-
namides [n-alkyl = (–CH2)[18, 19F]F, n=2–4)] were between 75 and
90% (Table 2).
Experimental
Syntheses of 19F-compounds and labelling precursors
N-(2-Fluoroethyl)-4-methyl-benzenesulfonamide ð3Þ. 2-Fluoroethylam-
ine hydrochloride (2 g, 0.02 mol) and 4-methyl-benzenesulfonylchloride
(1) (2 g, 0.01 mol) were suspended in THF (20 ml), aqueous potassium
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970
R. SCHIRRMACHER ET AL.
carbonate solution (3 M, 52 ml) was added and stirred under reflux for
2 h. The progress of the reaction was monitored via TLC. After the
reaction was complete, the mixture was concentrated to a small volume
and the precipitating product was isolated via filtration. The crude
precipitate was washed with ice-water and dried under vacuum
(1 ꢂ 10ꢀ3 bar). Yield: 2.01 g (88%) of a white powder. 1H NMR
(400 MHz, CDCl3): d = 7.8 (d, 2 H, Ar–H), 7.3 (d, 2 H, Ar–H), 4.7 (t,
2 H, CH2–F), 3.2 (t, 2 H, CH2–N), 2.4 (s, 3 H, CH3) ppm. 13C NMR
(400 MHz, CDCl3): d = 143.5, 136.5, 129.0, 126.8, 82.0, 79.6, 43.3, 21.3
ppm. 19F NMR (400 MHz, CDCl3): d = ꢀ222 ppm. MS (FD): m/z (%)
= 217 (100) [M+]. Analysis: calculated. C, 49.75; H, 5.57; N, 6.45;
found. C, 49.74; H, 5.42; N, 6.59.
N-(2-Fluoroethyl)-N-nitroso-4-methyl-benzenesulfonamide ð11Þ. (3) (2 g,
9.2 mmol) was dissolved in warm acetic acid (14 ml) and 1 ml of water.
The solution was cooled to 58C and NaNO2 (2.3 g, 33 mmol) was added
in small portions. After 20 min the reaction mixture was poured into ice
water (50 ml) and extracted with dichloromethane (20 ml). The organic
phase was washed with KOH 0.5 N (3 ꢂ 20 ml), dried over Na2SO4 and
1
evaporated under vacuum. Yield: 1.97 g (86%) of a yellow powder. H
NMR (400 MHz, CDCl3): d = 7.9 (d, 2 H, Ar–H), 7.3 (d, 2 H, Ar–H),
4.4 (dt, 2 H, CH2–F, 2JHF 47 Hz), 4.1 (dt, 2 H, CH2–N, 3JHF 24 Hz), 2.3
(s, 3 H, CH3) ppm. 13C NMR (400 MHz, CDCl3): d = 146.0, 134.4,
130.0, 128.1, 79.9 (1JCF 170 Hz), 42.2 (2JCF 29 Hz), 21.5. 19F NMR
(400 MHz, CDCl3): d = ꢀ222 ppm. MS (FD): m/z (%) = 246 (100)
[M+]. Analysis: calculated. C; 43.90; H, 4.50; N, 11.38; found. C, 44.20;
H, 4.62; N, 11.49.
N-(3-Fluoropropyl)-4-methyl-benzenesulfonamide ð4Þ. 4-Methyl-benze-
nesulfonamide (2) (6 g, 35 mmol) was dissolved in DMF (100 ml) under
argon, NaH (0.42 g, 10.5 mmol) was added and the mixture was stirred
at 808C for 1 h. To the solution, Cu(I)Cl (30 mg) and 1-bromo-3-
fluoropropane were added and the mixture was heated at 808C for 12 h.
The solution was poured into water (150 ml) and extracted with ether
(3 ꢂ 100 ml). The organic layer was dried over Na2SO4 and the solvent
was removed under vacuum. The crude product was purified via column
chromatography (n-hexane/ethylacetate 4:1) on silica gel. Yield: 2.2 g
(27%) of a yellow oil. 1H NMR (400 MHz, CDCl3): d = 7.7 (d, 2 H, Ar–
H), 7.3 (d, 2 H, Ar–H), 4.5 (m, 3 H, CH2–F), 3.1 (q, 2 H, CH2–N), 2.4 (s,
3 H, CH3), 1.8 (m, 2 H, CH2) ppm. 13C NMR (400 MHz, CDCl3): 143.3,
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SYNTHESES OF NOVEL . . .
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136.5, 129.4, 126.8, 82.2, 80.6, 39.6, 21.2, 20.8, 13.9. 19F NMR
(400 MHz, CDCl3) d = ꢀ222 ppm. MS (FD): m/z (%) = 231 (100)
[M+]. Analysis: calculated. C, 51.93; H, 6.10; N, 6.06; found. C, 51.82;
H, 5.92; N, 6.29.
N-(3-Fluoropropyl)-N-nitroso-4-methyl-benzenesulfonamide ð12Þ. The
nitrosation of (4) was performed as described for compound 11. The
crude product was purified via column chromatography (n-hexane/
1
ethylacetate 4/1) on silica gel. Yield: 51% of a yellow solid. H NMR
(400 MHz, CDCl3): d = 7.9 (d, 2 H, Ar–H), 7.4 (d, 2 H, Ar–H), 4.3 (m,
2 H, CH2–F, 2JHF 47 Hz), 3.8 (q, 2 H, CH2–N), 2.4 (s, 3 H, CH3), 1.8 (m,
3
2 H, CH2, JHF 26 Hz) ppm. 13C NMR (400 MHz, CDCl3): d = 146.0,
134.4, 130.1, 127.8, 81.5, 79.9, 39.4, 28.7, 21.5 ppm. 19F NMR
(400 MHz, CDCl3): d = ꢀ222 ppm. MS (FD): m/z (%) = 260 (100)
[M+]. Analysis: calculated. C, 46.14; H, 5.03; N, 10.76; found. C, 46.28;
H, 5.14; N, 10.94
N-(4-Fluorobutyl)-4-methyl-benzenesulfonamide ð5Þ. The fluorobutyla-
tion of 4-methyl-benzenesulfonamide (2) was performed as described for
compound 4. The crude product was purified via column chromato-
1
graphy (n-hexane/ethylacetate 7/3). Yield: 60% of a yellow oil. H
NMR (400 MHz, CDCl3): d = 7.7 (d, 2 H, Ar–H), 7.3 (d, 2 H, Ar–H),
4.3–4.8 (m, 2 H, CH2–F), 3.0 (q, 2 H, CH2–N), 2.4 (s, 3 H, CH3), 1.7 (m,
4 H, 2 ꢂ CH2) ppm. 13C NMR (400 MHz, CDCl3): d = 143.2, 136.7,
129.5, 126.8, 84.0, 82.4, 60.1, 42.5, 27.2, 25.5, 21.2, 20.8, 13.9 ppm. 19F
NMR (400 MHz, CDCl3): d = ꢀ219 ppm. MS (FD): m/z (%) = 245
(100) [M+]. Analysis: calculated C, 53.86; H, 6.57; N, 5.71; found. C,
53.69; H, 6.40; N, 5.93.
N-(4-Fluorobutyl)-N-nitroso-4-methyl-benzenesulfonamide ð13Þ. The ni-
trosation of 5 was performed as described for compound 11. No
purification via column chromatography was necessary. Yield: 78% of a
yellow oil (compound solidifies at 48C). 1H NMR (400 MHz, CDCl3): d
= 7.9 (d, 2 H, Ar–H), 7.4 (d, 2 H, Ar–H), 4.2–4.5 (m, 2 H, CH2–F), 3.7
(t, 2 H, CH2–N), 2.5 (s, 3 H, CH3), 1.6 (m, 4 H, 2 ꢂ CH2) ppm. 13C
NMR (400 MHz, CDCl3): d = 145.9, 134.8, 130.0, 127.0, 83.7, 42.3,
27.5, 27.3, 23.7, 21.5 ppm. 19F NMR (400 MHz, CDCl3): d =
ꢀ219 ppm. MS (FD): m/z (%) = 274 (100) [M+], 246 (65). Analysis:
calculated. C, 48.16; H, 5.51; N, 10.21; found. C, 48.02; H, 5.36; N,
10.43.
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R. SCHIRRMACHER ET AL.
N-(2-Bromoethyl)-N-methyl-benzenesulfonamide ð6Þ. 2-Bromoethylamine
hydrobromide (10.7 g, 0.052 mol) and 4-methylbenzenensul-
fonylchloride (1) (9.9 g, 0.052 mol) were dissolved in THF (60 ml). To
the mixture, NaHCO3 (11 g) in water (80 ml) was added and the mixture
was heated for 6 h at 608C. The reaction mixture was extracted with ether
(3 ꢂ 70 ml), the organic layer was dried over Na2SO4 and the solvent was
1
removed under vacuum. Yield: 7.4 g (51%) of a white solid. H NMR
(400MHz, CDCl3):
d = 7.7 (d, 2 H, Ar–H), 7.3 (d, 2 H,
Ar–H), 3.4 (m, 4 H, 2 ꢂ CH2) ppm. 13C NMR (400 MHz, CDCl3): d =
143.6, 136.6, 129.7, 126.8, 44.3, 31.3, 21.3 ppm. MS (FD): m/z (%) = 279
(100) [M+]. Analysis: calculated. C, 38.86; H, 3.61; N, 9.12; found. C,
39.02; H, 3.74; N, 9.30.
N-(2-Bromoethyl)-N-nitroso-4-methyl-benzenesulfonamide ð14Þ. The ni-
trosation of 6 was performed as described for compound 11. No
purification via column chromatography was necessary. Yield: 46% of a
1
white solid. H NMR (400 MHz, CDCl3): d = 7.9 (d, 2 H, Ar–H), 7.4
(d, 2 H, Ar–H), 4.1 (t, 2 H, CH2–Br), 3.4 (t, 2 H, CH2–N), 2.4 (s, 3 H,
CH3) ppm. 13C NMR (400 MHz, CDCl3): d = 146.2, 134.1, 130.2,
127.9, 44.3, 25.2, 21.1 ppm. MS (FD): m/z (%) = 308 (100) [M+], 278
(25), 156 (25). Analysis: calculated. C, 35.19; H, 3.61; N, 9.12; found. C,
34.98; H, 3.32; N, 9.31.
N-(3-Hydroxypropyl)-4-methyl-benzenesulfonamide ð9Þ. This compound
was synthesized according to Augstein et al.13 In the original literature
no NMR-, MS- or elemental analyses data were presented. Yield: 78%
(63% lit.) of a white solid. 1H NMR (400 MHz, CDCl3): d = 7.7 (d, 2 H,
Ar–H), 7.3 (d, 2 H, Ar–H), 3.7 (t, 1 H, CH2–O), 2.4 (s, 3 H, CH3), 2.1 (m,
2 H, CH2–N), 1.7 (m, 2 H, CH2) ppm. 13C NMR (400 MHz, CDCl3): d
= 143, 136, 129.5, 126.8, 65.6, 40.6, 31.2, 21.3 ppm. MS (FD): m/z (%)
= 229 (100) [M+], 230 (14). Analysis: calculated. C, 52.38; H, 6.59; N,
6.11; found. C, 52.22; H, 6.53; N, 6.30.
N-(3-Bromopropyl)-4-methyl-benzenesulfonamide ð7Þ. This compound
was synthesized according to Augstein et al.13 In the original literature
no NMR-, MS- or elemental analyses data were presented either and the
crude product was not purified and used without purification. We
performed column chromatography (n-hexane/ethylacetate 1:1) and
obtained 7 as a pure compound. Yield: 29% of a white solid. 1H NMR
(400 MHz, CDCl3): d = 7.7 (d, 2 H, Ar–H), 7.3 (d, 2 H, Ar–H), 3.4 (t,
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SYNTHESES OF NOVEL . . .
973
2 H, CH2-Br), 3.1 (t, 2 H, CH2–N), 2.4 (s, 3 H, CH3), 2.0 (m, 2 H, CH2)
ppm. 13C NMR (400 MHz, CDCl3): d = 143.4, 136.4, 129,6, 126,8, 41.2,
32.1, 30.0, 21.3 ppm. MS (FD): m/z (%) = 292 (100) [M+]. Analysis:
calculated. C, 41.11; H, 4.83; N, 4.79; found. C, 40.02; H, 4.99; N, 4.82.
N-(3-Bromopropyl)-N-nitroso-4-methyl-benzenesulfonamide ð15Þ. The
nitrosation of 7 was performed as described for compound 11. No
purification via column chromatography was necessary. Yield: 75% of a
yellow oil. 1H NMR (400 MHz, CDCl3): d = 7.9 (d, 2 H, Ar–H), 7.4 (d,
2 H, Ar–H), 3.8 (t, 2 H, CH2–N), 3.3 (t, 2 H, CH2ꢀBr), 2.4 (m, 4 H,
2 ꢂ CH2), 2.0 (s, 3 H, CH3) ppm. 13C NMR (400 MHz, CDCl3):
d = 146.0, 134.3, 130.1, 127.9, 41.5, 30.4, 29.3, 21.5 ppm. MS (FD): m/z
(%) = 321 (52) [M+], 293 (100). Analysis: calculated. C, 37.39; H, 4.08;
N, 5.76; found. C, 37.25; H, 4.13; N, 5.82.
N-(4-Hydroxybutyl)-4-methyl-benzenesulfonamide ð10Þ. This compound
was synthesized as described for compound 9. 4-Aminobutan-1-ol
was used. Yield: 96% of a white solid. 1H NMR (400 MHz,
CDCl3): d = 7.7 (d, 2 H, Ar–H), 7.3 (d, 2 H, Ar–H), 3.6 (t, 2 H, CH2–
OH), 3.0 (m, 2 H, CH2–N), 2.4 (s, 3 H, CH3), 1.5 (m, 4 H, 2 ꢂ CH2)
ppm. 13C NMR (400 MHz, CDCl3): d = 143.1, 136.7, 129.5, 126.8, 61.9,
42.8, 29.3, 25.9, 21.3 ppm. MS (FD): m/z (%) = 243 (100) [M+].
Analysis: calculated. C, 54.30; H, 7.04; N, 5.76; found. C, 54.32; H, 6.97;
N, 5.84.
N-(4-Bromobutyl)-4-methyl-benzenesulfonamide ð8Þ. This compound
was synthesized as described for compound 7. Column chromatography
on silica gel (n-hexane/ethylacetate 1:1) was performed to purify the
compound. Yield: 30% of a white solid. 1H NMR (400 MHz, CDCl3): d
= 7.7 (d, 2 H, Ar–H), 7.3 (d, 2 H, Ar–H), 3.7 (m, 2 H, CH2–N), 3.2 (t,
2 H, CH2–Br), 2.4 (s, 3 H, CH3), 1.7 (m, 4 H, 2 ꢂ CH2) ppm. 13C NMR
(400 MHz, CDCl3): d = 143.2, 133.7, 129.5, 127.3, 47.7, 32.7, 27.9, 24.9,
21.3 ppm. MS (FD): m/z (%) = 307 (15) [(M+1)+], 226 (100).
Analysis: calculated. C, 43.14; H, 5.27; N, 4.57; found. C, 43.23; H, 5.20;
N, 4.64.
N-(4-Bromobutyl)-N-nitroso-4-methyl-benzenesulfonamide ð16Þ. The ni-
trosation was performed as described for compound 11. Column
chromatography on silica gel (n-hexan/ethylacetate 7:4) was performed
to purify the compound. Yield: 25% of a yellow oil. 1H NMR
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974
R. SCHIRRMACHER ET AL.
(400 MHz, CDCl3): d = 7.9 (d, 2 H, Ar–H), 7.4 (d, 2 H, Ar–H), 3.7 (t,
2 H, CH2–Br), 3.3 (t, 2 H, CH2–N), 2.4 (s, 3 H, CH3), 1.7 (m, 4 H, 2 ꢂ
CH2) ppm. 13C NMR (400 MHz, CDCl3): d = 145.9, 134.5, 130.1,
127.8, 42.0, 32.1, 29.2, 26.2, 21.5 ppm. MS (FD): m/z (%) = 336 (100)
[(M+1)+], 308 (63). Analysis: calculated. C, 39.41; H, 4.51; N, 8.38;
found. C, 39.27; H, 4.53; N, 8.46.
Radiosyntheses
N-([18F]Fluoroalkyl)-N-nitroso-4-methyl-benzensulfonamides [n-alkyl=
(–CH2)[18F]F, n=2–4)] (general procedure)
No-carrier-added (nca) aqueous [18F]fluoride (100–200 MBq, purchased
from several institutions) prepared by the 18O(p,n)18F nuclear reaction
on an enriched 18O-water (95%) target was added to a solution of
K2CO3 (15 ml (1 N)) and Kryptofix12.2.2. (10–15 mg) in acetonitrile
(800 ml). The water was removed using a stream of nitrogen at 808C and
evaporated to dryness with acetonitrile (2 ꢂ 1 ml). To the dried [18F]F-
Kryptofix12.2.2./K2CO3-complex acetonitrile (0.5 ml) was added and
precursor compounds 14–16 (10-15 mg, 32.2–48.8 mmol (14),
31.1–46.7 mmol (15), 29.8–44.7 mmol (16)) were added and heated in
a sealed vial. At several time points aliquots were taken and the RCYs
of the radio-labelled products were determined via HPLC (Sykam Pump
Model S1121, Gilching, Germany; UV-detection: UV detector Linear,
UVIS 200 (254 nm), Linear Instruments, San Jose, USA; radioactivity
detection: scintillation detector, MED Isomed 110, Nuklear-Medizin-
technik Dresden GmbH, Germany) and radio-TLC (Instant Imager,
Packard Canberra, Dreieich, Germany). After only 2 min reaction time
max. RCYs of up to 5% could be detected. These low yields led to the
development of a modified labelling procedure.
N-([18F]Fluoroalkyl)-N-nitroso-4-methyl-benzensulfonamides [n-alkyl =
(–CH2)[18F]F n=2–4)] (modified procedure)
No-carrier-added (nca) aqueous [18F]fluoride (100–200 MBq) prepared
by the 18O(p,n)18F nuclear reaction on an enriched 18O-water (95%)
target was added to a solution of K2CO3 (15 ml (1 N)) and Krypto-
fix12.2.2. (10–15 mg) in acetonitrile (800 ml). The water was removed
using a stream of nitrogen at 808C and evaporated to dryness with
acetonitrile (2 ꢂ 1 ml). To the dried Kryptofix1 2.2.2./[18F]fluoride
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SYNTHESES OF NOVEL . . .
975
(70–180 MBq) complex at 75–808C adsorbed on the sealed vessels’
surface, the labelling precursor (14–16) (10–15 mg: 32.2–48.8 mmol (14);
31.1–46.7 mmol (15); 29.8–44.7 mmol (16)) dissolved in 0.2 ml acetoni-
trile (258C) was added quickly and heated for 3 min at 75–808C. During
this time almost all of the acetonitrile evaporated into the vapour phase.
The sealed vial was cooled in an ice bed (NaCl/ice) to stop the reaction,
diluted with water (10 ml) and passed through a 18C-Sep-Pack cartridge
to fix the radio-labelled compound. The cartridge was dried with
nitrogen, eluted with acetonitrile (1 ml) and the volume was reduced to
0.5 ml. Water was added (0.5 ml) and the mixture was injected into an
HPLC system (column: Lichrospher 100RP 18EC-5, flow 1 ml/min) to
collect the radio-labelled compounds 11–13 (Table 1). After collecting
the product, the HPLC solvent was diluted with water (10 ꢂ volume of
collected HPLC solvent) loaded onto a 18C-Sep-Pack column, dried
with nitrogen and eluted with acetonitrile (1–2 ml) to yield 11–13
(70–180 MBq, not decay corrected). The total preparation time was
approximately 45 min.
1H NMR spectra, kinetic measurements
1
The H NMR spectra were recorded on a DRX 400 (Bruker Biospin)
spectrometer. In order to obtain the spectrum of the compound directly
after the solution process, the time consuming processes of temperature
equilibration, locking and shimming were done with a sample tube
containing pure deuterated acetonitrile. When the solid compound
(40 mmol) was added, the sample tube was shaken to achieve
homogeneity and the data acquisition for 16 scans (59 s) was initiated.
Two minutes as minimum time intervals are normally sufficient at the
beginning of decomposition. The evaluation of the time dependent
spectra (thermal decomposition at 258C and 758C in acetonitrile,
thermal decomposition in acetonitrile by addition of Kryptofix12.2.2./
K2CO3) shows a linear correlation with the logarithm of the normalized
integrated signal intensity within the graphs ( d = 7.85 ppm/d aromatic
region).
Determination of product distribution via 1H NMR and mass spectroscopy
Field desorption mass spectra and NMR spectra of the decomposed
species revealed a mixture of compounds. The major ones are: C7H7SO2
(m/z=155), C7H7SO3H (m/z=172) and the halogeno-alkyltosylate
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976
R. SCHIRRMACHER ET AL.
M-28 (M molecular weight) indicating the liberation of N2. The samples
examined after longer decomposition times show species such as M-29
(loss of NO and capture of H) resulting in tosylsulfonamides. Detailed
analysis of the aliphatic region in the proton NMR spectra of those
samples exhibit two principal species: one explained by the loss of N2
(vide supra) the other originating from the tosylsulfonamides as
confirmed by spectra comparison.
Conclusion
N-([18F]fluoroalkyl)-N-nitroso-4-methyl-benzensulfonamides [n-alkyl =
(–CH2)[18F]F, n=2–4)] might become a versatile new class of secondary
labelling precursors for the syntheses of PET-radiopharmaceuticals via
in situ generation of highly reactive carbocations such as [18F]fluoro-
ethyl-, [18F]fluoropropyl- and [18F]fluorobutyl-cations. The syntheses of
highly selective [18F]fluorodiazoalkanes for the 18F-fluoroalkylation of
H-acidic compounds may also be possible via base catalyzed decom-
position of the 18F-nitrosamides. The radioactive 18F-fluorination of the
corresponding bromo-precursors could be achieved in high yields of
75–90% (decay corrected) applying a modified labelling technique
under nearly solvent-free conditions to circumvent solvent- and base
mediated fast decomposition at elevated temperatures, which are
prerequisites for nucleophilic 18F-fluorinations in general. Isolation of
the 18F-compounds for further uses such as the proposed labelling of
proteins and other biomolecules, was conducted via HPLC and solid
phase fixation. Extensive decomposition experiments of the analogous
non-radioactive 19F- and the corresponding bromo-compounds under
varying conditions provided deamination chemistry with the possibility
to rationally and efficiently exploit the decomposition of nitrosamides as
a possible route to reactive carbocations. Steric as well as electronic
effects have a high impact on the stability and the handling of these new
radio-labelled nitrosamides. The general value of these new 18F-
compounds as labelling precursors in radiochemistry is currently under
investigation.
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