Rapid synthesis of aliphatic amides by reaction of carboxylic acids, grignard reagent and amines: Application to the preparation of [11C]amides

Article abstract of DOI:10.1039/a702897k

Aliphatic amides have been prepared in moderate to good yields (30-70%) by treatment in THF of magnesium halide carboxylates with amines in the presence of 2.5 equivalents of alkylmagnesium halide. The reaction is rapid (<30 min) and has been successfully

Full text of DOI:10.1039/a702897k

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Rapid synthesis of aliphatic amides by reaction of carboxylic acids,
Grignard reagent and amines: application to the preparation of
[11C]amides
Catherine Aubert, Cécile Huard-Perrio and Marie-Claire Lasne*
Laboratoire de Chimie Moléculaire et Thioorganique (UMR CNRS 6507), Institut des
Sciences de la Matière et du Rayonnement, Université de Caen-Basse Normandie,
6 Bd Maréchal Juin, 14050 Caen Cedex, and Centre Cyceron, France
Aliphatic amides have been prepared in moderate to good yields (30–70%) by treatment in TH F of
magnesium halide carboxylates with amines in the presence of 2.5 equivalents of alkylmagnesium halide.
The reaction is rapid (<30 min) and has been successfully applied to the synthesis of amides labelled with
carbon-11 (âϩ, t : 20.4 min). [11C]Aliphatic amides have been obtained in 15–60% radiochemical yields
¹
¯
²
[decay corrected to end of bombardment (EOB), 5 min amidation reaction time].
metric29,37–42 amounts, have also been found to promote amid-
Introduction and background information
ations. Recently, zirconium(), titanium() or tantalium()
carboxylates were isolated and transformed into amides in good
yields.40,41 In some other cases, amines were activated as organo-
metallic complexes.43–51
The development of in vivo studies of biological processes in
living animals or humans using positron emission tomography
(PET) is strongly dependent on the availability of new tracers
labelled with a positron emitter such as carbon-11, fluorine-18,
oxygen-15 or nitrogen-13. Although carbon-11 is the most
widely used radioisotope, radiosyntheses of 11C-compounds
are always a challenge. Only two cyclotron-produced labelled
precursors are available ([11C]CO2 and [11C]CH4). Due to the
short half-life (20.4 min), preparation of 11C-labelled com-
pounds require minimum-step synthesis, very rapid and effi-
cient reactions and simple handling and transfers. Moreover,
specific activity, stoichiometry, purification methods and radi-
ation protection are additional considerations.1
Recently, we observed that the direct reaction of the [11C]ac-
etate and butanoate with 1,2,3,4-tetrahydroisoquinoline yielded
the corresponding [11C]amides.52 To our knowledge, such a
reactivity of carboxymagnesium halides towards amines for
amides synthesis has never been studied. Here we report our
results for the one-step conversion of carboxymagnesium hal-
ides into amides by reaction with a free amine both in stable
isotope and carbon-11 chemistries (Scheme 1).
11C]-CO2
A large variety of radiopharmaceuticals include an amide2–5
or an amine function. This latter is often obtained by reduc-
tion 6,7 or by pyrolysis8,9 of the suitable amide. Several [11C]-
alkylamides,10–12 cyclopropanecarboxamide,10,11 acrylamides,13
benzamide14 and N,N-disubstituted benzamides15 have been
described. The preparations are based on two different
approaches. In the first one, [11C]CO2 is trapped with a Grig-
nard reagent and the resulting [11C]carboxylate is then trans-
formed into an [11C]acid chloride2–9,10–13 or into an activated
form of the [11C]acid 15 before its reaction with an amine. This
method requires at least three steps from [11C]CO2. In the
second route, [11C]benzonitrile, obtained by a palladium-
catalysed reaction of [11C]cyanide anion with bromobenzene, is
hydrolysed. This route leads only to non-substituted [11C]benz-
amide.14 Among the readily available labelled precursors, [11C]-
carboxymagnesium halides are attractive by being obtained
efficiently by carboxylation of Grignard reagents with [11C]-
CO2.16–18 Up to now, they were only used as intermediates for
preparing labelled reagents such as [11C]carboxylic acids,18–20
[11C]acid chlorides2–9,10–13 or [11C]alkyl iodides19,21–26 via the cor-
responding alcohols. Development of a new general synthetic
procedure for the preparation of amides using directly the
[11C]carboxylates as reactive intermediates is therefore essential.
In stable isotope chemistry, many procedures to obtain
amides from carboxylic acids are known.27–29 The most com-
mon methods are based on the conversion of the acid into a
more reactive functional intermediate (isolated or formed in
situ29,32) like an acyl chloride, mixed carboxylic anhydride, acyl
azide or active ester before reaction with an amine. The direct
reaction between an acid itself and a free amine is of limited
scope due to the high temperatures it requires.30,31 Several
metallic compounds used in catalytic29,33–36 or stoichio-
[
R1-CO2H
i
iii
1
or [11C]-1
[R1-CO2MgX]
R1COCl
ii
ii
i
3
or [11C]-3
R1-CO2H
R1CONR3R4
1
10–15
or [11C]-10–15
R1-CO2H 1, R1MgX or R2MgX 2
a
b
c
d
e
f
R
1 or R2 Pr Et Me Pri But Ph
R3R4NH
R1CONR3R4
1,2,3,4-Tetrahydroisoquinoline 4 10
Butanamine 5
Dipropylamine 6
Morpholine 7
Aniline 8
11
12
13
14
15
1-Phenylethylamine 9
Scheme 1 Reagents: i, R1MgX or R2MgX 2; ii, R3R4NH 4–9, then
aq. HCl; iii, aq. NH4Cl
Results and discussion
Amides in stable isotope chemistry
Carboxymagnesium halides 3 were prepared in situ by reaction
of a Grignard reagent 2 with a carboxylic acid 1 at 70 ЊC in
THF for 15 min. The Grignard reagent 2 was used in a stoichio-
metric amount or in excess compared to the acid 1 (Table 1).
After addition of the amine 4–9, the reaction mixture was
treated under the conditions reported in Tables 2, 3 or 4. The
structures of the different reaction products obtained after
J. Chem. Soc., Perkin Trans. 1, 1997
2837

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Table 1 Amide 10a from PrCO2H 1a (2 mmol), PrMgBr 2a and amine
4.a Yields as a function of the ratio 2a/4.
Table 2 Amide 10a from PrCO2H 1a (2 mmol), amine 4 (2 mmol) and
EtMgBr 2b (5 mmol).a Yields as a function of the solvent.
PrMgBr 2a
Amine 4
10a Yieldsb
Entry
Solvent
10a Yieldsb (%)
Entry
(mmol)
(mmol)
(%)
1
2
3
4
5
6
THF
Et2O
49–52
45
20
15
0
1
2
3
4
5
6
7
8
9
0
2
2
3
4
5
5
5
10
15
2
2
5
2
2
2
5
8
5
2
0
0
0
THF/Dioxanec
THF/DME c,d
THF/DMF c,e
THF/HMPA c, f
0
16
50
49
54
65
59
0
a
At the reflux temperature of the solvent for 60 min reaction time.
c
b Isolated yields. THF/co-solvent = 70/30 (v:v). d Dimethoxyethane.
e N,N-dimethylformamide. f Hexamethylphosphoramide.
10
The solvent effect on the yield of the amide 10a was studied
in the reactions using butanoic acid 1a (2 mmol), tetrahydro-
isoquinoline 4 (2 mmol) and ethylmagnesium bromide 2b (5
mmol) (Table 2). THF gave the best results compared to Et2O
and a mixture of THF–dioxane (entries 1, 2 and 3). Addition of
a polar solvent 53 to THF inhibited the amidation (entries 4, 5
and 6).
The effect of the reaction time was studied in the syntheses of
the amides 10a, 10b, 10c and 11a using a 2:2:5 molar ratio of
acid/amine/Grignard reagent (Table 3, entries 1, 3, 5 and 6).
Yields were found to be optimum in less than 30 min and often
after 2–5 min only. When we increased the Grignard reagent
amount, we observed that the best yields could be reached after
a shorter reaction time (Table 3, entries 2 and 4).
Finally, the scope of the reaction was studied and some
results are presented in Table 4. Generally the aliphatic amides
10a, 10b, 10c, 10d, 11a, 12a, 13a and 15a were obtained in low
to moderate yields (entries 1, 2, 3, 4, 7, 9, 10 and 12) whereas
attempted preparation of the amides 10e, 10f, 11f and 14a
failed (entries 5, 6, 8 and 11). The reaction conditions (short
reaction time, excess of Grignard reagent versus acid) led us to
apply this method to the synthesis of the corresponding
[11C]amides.
a
In refluxing THF for 60 min. b Isolated yields.
hydrolysis were assigned from the spectroscopic data of pure
isolated compounds. These reaction products were found to be
the expected amides 10–15, the starting amines 4–9 and traces
of non-identified compounds. An independent synthesis of the
expected amides 10–15 was also carried out using the acid
chloride method to have authentic samples and spectroscopic
data as references (Scheme 1).
The influence of the amounts of the organomagnesium hal-
ide and the amine was studied for optimizing the preparation of
the amide 10a from butanoic acid 1a or its salt 3a (pre-formed
by reaction of propylmagnesium bromide 2a with the acid 1a)
and tetrahydroisoquinoline 4. All experiments were carried out
in THF for 60 min (Table 1). As expected, no reaction was
observed between the free acid 1a and the amine 430,31 (entry 1).
The synthesis starting from the salt 3a (obtained by reaction of
1 equivalent of the acid 1a with 1 to 2 equivalents of propyl-
magnesium bromide 2a) did not lead to the amide 10a (entries
2, 3 and 4). Formation of the amide 10a was effected when the
ratio of Grignard reagent versus acid 1a was higher than 2.5
(entry 6). Yields were not significantly improved by using a
larger amount of Grignard reagent (entry 10) and they were not
changed by using ethylmagnesium bromide instead of propyl-
magnesium bromide. The use of an excess of the amine 4 had
no effect on the yields (entries 7 and 8) except when the reaction
was carried out in presence of a large excess of Grignard
reagent (entry 9).
Amides labelled with carbon-11
The reaction of carboxylates [11C]-3 with the amines 4–9 was
carried out as follows. Cyclotron produced [11C]carbon dioxide
was bubbled through a solution of organomagnesium halide 2
in THF or Et2O at 0 ЊC for 3 min. [11C]Carbon dioxide was
trapped in 80–97% yield. The resulting carboxylate solution
was transferred under nitrogen into a second reaction vessel
containing the appropriate amine, 4–9, and eventually a further
reagent was added (listed in Table 6). The reaction mixture was
treated under the conditions described in Tables 5, 6 and 7. The
crude product obtained after hydrolysis was analysed by radio
TLC and eventually by HPLC. Reactions were always found to
lead to a mixture of the desired amides [11C]-10–15 and the
carboxylic acids [11C]-1 resulting from hydrolysis of the
unchanged carboxylates [11C]-3. Identification of the [11C]car-
boxylic acids was achieved after their unambiguous synthesis
by hydrolysis of the carboxylates [11C]-3 (Scheme 1). It is note-
worthy that [11C]carbon dioxide is always used in very small
amounts (< µmol).13 We can consider that carboxylates [11C]-3
are present in similar quantities. Usually 0.1–0.5 mmol of
alkylmagnesium halides and amines were used respectively to
trap [11C]carbon dioxide17 and to synthesize amides via
[11C]acid chlorides.11 Here, the Grignard reagent 2a and tetra-
hydroisoquinoline 4 were used in a 104 to 105 excess over the
carboxylate [11C]-3a (Table 5). The highest yields were reached
when an excess of the amine 4 versus the Grignard reagent was
used (entry 3) as seen previously (Table 1, entry 9). However,
use of the small amount of amine 4 was found to give the amide
[11C]-10a in a higher purity after HPLC (entry 1).
The need to have a 1:1:1.5 molar ratio of carboxylate/
amine/organomagnesium halide could be related to the con-
ditions described for the preparation of amides from mag-
nesium halide amide (2 mol equiv.) and ester (1 mol equiv.).50,51
We suggest that the formation of the amide 10a involves the
intermediate 16 (Scheme 2). The latter, obtained by reaction of
R2
O
O
H
O
MgX
i
R1
OMgX
R1
NR3R4
OMgX
NR3R4
R1
3
16
10
Scheme 2 Reagents: i, R3R4NH 4–9, R2MgX 2
the carboxylate 3a with the amine 4, is decomposed by a nucleo-
philic attack of the alkylmagnesium halide present in excess
according to a six-centred mechanism.
Classically, Lewis acids [TiCl4, Ti(PriO)4, BBr3, AlCl3 etc.]
used in catalytic or stoichiometric amounts29,32–40 are known to
be very efficient for the conversion of esters into amides,
lactams or for transamidations. Attempts to use different Lewis
acids (BCl3, ZnBr2, HgCl2 or TiCl4) in excess compared to the
carboxylate 3a failed. No amide 10a was formed by reaction of
the carboxylic acid 1a (2 mmol) with tetrahydroisoquinoline 4
(2 mmol), ethylmagnesium bromide 2b (5 mmol) and one of
these Lewis acids (5–10 mmol) in THF for 60 min. The starting
amine 4 was quantitatively recovered.
In our search for reagents useful in amide bond formation,
we have investigated the reaction in the presence of Et3N,54 1,8-
diazabicyclo[5.4.0]undec-7-ene54 (DBU) or a pyridine deriv-
2838
J. Chem. Soc., Perkin Trans. 1, 1997

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Table 3 Reaction of R1CO2H 1 with amines 4 or 5 in the presence of a Grignard reagent in THF at 70 ЊC: yields as a function of time
Entry
1
R1CO2H (mmol)
R2MgBr (mmol)
Amine (mmol)
Reaction time (min)
Amide
Yieldsa (%)
1a (2)
2a (5)
4 (2)
5
60
180
5
10a
10a
10a
10a
11a
11a
11a
11a
10b
10b
10b
10c
10c
10c
45
51
54
56
11
37
39
32
8
13
12.5
28
22
11
2
3
1a (2)
1a (2)
2a (10)
2b (5)
4 (2)
5 (2)
5
30
180
5
2
5
15
2
5
4
5
1a (2)
1a (2)
2b (10)
2b (5)
5 (2)
4 (2)
6
1c (2)
2b (5)
4 (2)
30
a
Isolated yields.
Table 4 Synthesis of the amides 10–15
Entry Amine R1CO2MgX Time (min)
Amide
Yieldsa (%)
1
2
3
4
5
6
7
8
9
4
3a
3b
3c
3d
3e
3f
3a
3f
3a
3a
3a
3a
60
5
2
10a
10b
10c
10d
10e
10f
11a
11f
12a
13a
14a
15a
65b
13c
28c
28c
60
60
60
60
60
30
60
60
5
0c,d
0c
39c
0c
5
6
7
8
9
37c
28.5d
0d
10
11
12
32c
a
b,c,d
Isolated yields.
2:2:5, 2:2:10.
Acid/amine/EtMgBr (mmol) respectively 2:5:10,
ative55–59 (Table 6). When the [11C]amidations were carried out
in the presence of a pyridinium salt, Et3N or DBU for 10 min,
only a small amount of the expected amide [11C]-10a was
formed (entries 1, 2, 3 and 4). The reactions carried out in the
presence of pyridine or 2,6-di-tert-butylpyridine led to the
amide [11C]-10a in satisfactory yields only if the reaction time
was higher than 5 min (entries 5 and 6). The optimum yields
were obtained when 2-chloropyridine was employed whatever
the reaction time tested (entry 7). However, the improvements
in the yields due to the presence of 2-chloropyridine compared
to those observed for reactions carried out without any added
reagent were not significant (entry 8). Moreover, for ease of
purification by HPLC, reactions without 2-chloropyridine were
found to be preferable.
Fig. 1 Preparative HPLC chromatogram of the crude product con-
taining butyric acid [11C]-1a and amide [11C]-10a
The results presented above showed that the amide [11C]-10a
could be efficiently formed in a reaction time of 10 min and that
good yields were already obtained after 1 min (Table 6, entry 8).
Because of the half-life of carbon-11, reaction times longer
than 10 min were not studied and 5 min was found to be
adequate.
ent, the shorter the reaction time could be, the yields being
unchanged.
These conditions were successfully applied to the synthesis
of [11C]amides. Reactions of [11C]carboxymagnesium halides
yielded the corresponding [11C]amides in 15–60% radio-
chemical yields (decay corrected to EOB) in 5 min reaction
time. This reaction should be considered as a simple method for
the synthesis of [11C]amides and presents several advantages.
The procedure is extremely easy (it requires only the addition of
the amine and no added catalyst). The reaction time is short (5
min). The complete synthesis can be carried out in THF, the
solvent generally used to prepare the Grignard reagent.
Work is now in progress to improve yields in aliphatic amides
and to prepare aromatic amides by using activated amines both
in carbon-11 and stable isotope chemistries.
Finally, in Table 7 we present the different [11C]amides pre-
pared with this method. In a typical example, the amide [11C]-
10a was obtained after HPLC purification (Fig. 1) in 25%
radiochemical yield (decay corrected to EOB) and in 30 min
total synthesis time. Starting from [11C]CO2 (280 MBq), 20–30
µg of stable amide 10a was obtained.
Conclusion
In summary, we have shown that Grignard reagents promoted a
rapid reaction of simple carboxylic acids with various aliphatic
amines. The conditions required a 2.5 ratio Grignard reagent
versus acid and THF as the solvent. Aliphatic amides were
obtained in moderate to good yields (30–70%) in a short time
(5–30 min). The greater the amount of Grignard reagent pres-
Experimental
THF was dried by reflux over benzophenone and sodium and
distilled under a nitrogen atmosphere. Et2O was dried by reflux
J. Chem. Soc., Perkin Trans. 1, 1997
2839

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Table 5 Amide [11C]-10a. Yields as a function of PrMgBr 2a and
1,2,3,4-tetrahydroisoquinoline 4 amounts.
CH2CO), 2.87 (2H, m, CH2Ar), 3.68 (1.3H, t, J 6, CH2CH2N),
3.81 (0.7H, t, J 6, CH2CH2N), 4.62 (0.7H, s, ArCH2N), 4.73
(1.3H, s, ArCH2N) and 7.12–7.2 (4H, m, C6H4); δC(CDCl3) (2
conformers) 14.1 (CH3), 18.7 and 18.8 (CH2CH2CO), 28.7 and
29.7 (CH2CO), 35.7 and 35.9 (CH2CH2N), 39.7 and 43.3
(CH2CH2N), 44.3 and 47.5 (ArCH2N), 126.1, 126.4, 126.5,
126.7, 126.8, 126.9, 128.4, 129.1, 132.8, 133.8, 134.2 and 135.2
(C6H4), 172.0 and 172.1 (CO); m/z 203 (Mϩ, 38%), 132
PrMgBr 2a
(mmol)
Amine 4
(mmol)
Crude yieldsa
(%)
Purityb
(%)
Entry
1
2
3
4
0.275
0.275
0.275
0.0275
0.0375
0.275
0.375
52 ± 4
38 ± 17
63 ± 2
32 ± 17
98 ± 2
87 ± 13
98 ± 2
75 ± 15
0.0375
ϩ
(C9H10Nϩ, 36), 104 (C8H8 , 51), 91 (37), 77 (100), 71 (C4H7Oϩ,
32), 57 (68), 43 (C3H7ϩ, 59) and 41 (C3H5ϩ, 72).11
a
After work-up and before HPLC from the starting carboxylate [11C]-
3a (decay corrected to EOB, mean values of 2 or 3 runs, reaction in
THF for 5 min. b Percent of the amide [11C]-10a in the crude product
determined by radio TLC.
N-Propionyl-1,2,3,4-tetrahydroisoquinoline 10b. Purified by
chromatography with ethyl acetate–light petroleum (30:70) as
eluent to give the pure title compound 10b (0.359 g, 95%) as a
yellow oil, Rf 0.3 (ethyl acetate–light petroleum, 30:70);
νmax(NaCl)/cmϪ1 1644, 1434 and 1212;11 δH (CDCl3) (2 con-
formers) 1.12 (3H, t, J 7.4, CH3), 2.35 (0.6H, q, J 7.4, COCH2),
2.38 (1.4H, q, J 7.4, COCH2), 2.8 (0.6H, t, J 5.9, CH2CH2N),
2.82 (1.4H, t, J 5.9, CH2CH2N), 3.61 (1.4H, t, J 5.9,
CH2CH2N), 3.76 (0.6H, t, J 5.9, CH2CH2N), 4.54 (1.4H, s,
ArCH2N), 4.66 (0.6H, s, ArCH2N) and 7.0–7.15 (4H, m, C6H4);
δC(CDCl3) (2 conformers) 9.47 and 9.56 (CH3), 26.9 and 27.1
(CH2CO), 28.6 and 29.6 (CH2CH2N), 39.7 and 43.2
(CH2CH2N or ArCH2N), 44.3 and 47.3 (CH2CH2N or
ArCH2N), 126.1, 126.4, 126.5, 126.6, 126.7, 126.9, 128.4, 129.1,
132.8, 133.8, 134.2 and 135.2 (C6H4) and 172.8 (CO); m/z 189
(Mϩ, 100%), 174 (C11H12NOϩ, 60), 117 (C9H9ϩ, 28) and 104
(C8H8ϩ, 28).11
N-Acetyl-1,2,3,4-tetrahydroisoquinoline 10c. Purified by
chromatography with ethyl acetate–light petroleum (20:80) as
eluent to give the pure title compound 10c (0.353 g, 95%) as
a yellow oil, Rf 0.35 (ethyl acetate–light petroleum, 30:70);
νmax(NaCl)/cmϪ1 1620, 1434, 1250 and 1224; δH (CDCl3) (2 con-
formers) 2.18 (1.8H, s, CH3), 2.19 (1.2H, s, CH3), 2.85 (1.2H, t,
J 6, CH2CH2N), 2.91 (0.8H, t, J 6, CH2CH2N), 3.68 (1.2H, t, J
6, CH2N), 3.82 (0.8H, t, J 6, CH2N), 4.62 (0.8H, s, ArCH2N),
4.73 (1.2H, s, ArCH2N) and 7.12–7.21 (4H, m, C6H4);62
δC(CDCl3) (2 conformers) 21.7 and 21.9 (CH3), 28.6 and 29.5
(CH2CH2N), 39.7 and 44.1 (CH2CH2N or ArCH2N), 44.2 and
48.2 (CH2CH2N or ArCH2N), 126.1, 126.5, 126.6, 126.8, 127.1,
127.5, 128.4, 129.6, 132.5, 133.5, 134.1 and 135.2 (C6H4), 169.8
and 169.9 (CO); m/z 175 (Mϩ, 8%), 132 (C9H10NOϩ, 19), 117
(24), 104 (33), 77 (C6H5ϩ, 42), 63 (17), 51 (36) and 43 (C2H3Oϩ,
100).62,63
over LiAlH4 and distilled under a nitrogen atmosphere. 1,2,3,4-
Tetrahydroisoquinoline was purchased from Aldrich Chem.
Co. Inc. and used as received. All other reagents were used
as obtained from commercial sources (purity > 98% Janssen
Chimica, Aldrich or Sigma). Solutions of organomagnesium
halides were prepared from magnesium turnings and alkyl or
aryl halides in freshly distilled tetrahydrofuran (THF ) or
diethyl ether (Et2O) under nitrogen.60 They were titrated with
menthol in the presence of phenanthroline.61 IR spectra were
recorded on a Perkin-Elmer 16 PC FT-IR spectrometer. 1H
NMR and 13C NMR spectra were obtained from solutions in
deuteriochloroform on a Bruker AC-250 spectrometer (250
MHz 1H, 62 MHz 13C) with tetramethylsilane as internal stand-
ard. All chemical shifts (δ) are quoted in parts per million. All J
values are in Hz. Mass spectra were recorded on a Nermag R10
(EI, 70 eV). Column chromatography was carried out on Silica
Gel 60 (70–230 mesh ASTM, Merck). Thin layer chromatog-
raphy was performed on Silica Gel 60F254 (0.1 mm, Merck).
[11C]Carbon dioxide was prepared by the 14N (p, α) 11C
nuclear reaction using a nitrogen gas target and a baby cyclo-
tron (CGR MeV 325). Bombardment was carried out for 1 min
with a 1.5 µA beam of 16 MeV protons. Radioactivity
determinations were carried out by a Capintec Radioisotope
Calibrator (CRC-12). Identification of the labelled compounds
and measures of the radiochemical purities were determined by
radio TLC using a Berthold automatic TLC-linear analyser and
authentic stable isotope samples as reference. The plates were
developed in pentane–ethyl acetate (70:30, eluent A) or in
methanol–ethyl acetate (50:50, eluent B). Preparative HPLC
was carried out on a Merck HPLC system consisting of in-
telligent pump (L-6200), UV detector (L-4000), chromato-
integrator (D-2500) in series with a scintillation detector (Nar-
deux). Separations were performed on a reversed-phase column
(Waters µ-Bondapak C18, 300 × 7.8 mm) eluted at 3 ml minϪ1
with methanol–water (70:30) at λ = 254 nm.
N-(2-Methylpropionyl)-1,2,3,4-tetrahydroisoquinoline
10d.
Purified by chromatography with ethyl acetate–light petroleum
(85:15) as eluent to give the pure title compound 10d (0.507 g,
80%) as a yellow oil, Rf 0.65 (ethyl acetate–light petroleum,
85:15); νmax(NaCl)/cmϪ1 1642 and 1436; δH (CDCl3) (2 con-
formers) 1.14 (1.65H, d, J 5.0, CH3), 1.16 (1.35H, d, J 5.0,
CH3), 2.83 (3H, m, CH2CH2N and CH), 3.73 (1.1H, t, J 6.1,
CH2CH2N), 3.83 (0.9H, t, J 6.1, CH2CH2N), 4.67 (0.9H, s,
ArCH2N), 4.73 (1.1H, s, ArCH2N) and 7.10–7.21 (4H, m,
C6H4); δC(CDCl3) (2 conformers) 19.4 and 19.5 (2 CH3), 28.5
and 29.9 (CH), 30.6 and 30.8 (CH2CH2N), 40.0 and 43.1
(CH2CH2N or ArCH2N), 47.4 and 47.9 (CH2CH2N or
ArCH2N), 126.1, 126.4, 126.5, 126.6, 126.8, 126.9, 128.4, 129.1,
132.9, 133.8, 134.1 and 135.3 (C6H4) and 176.0 (CO); m/z 204
(Mϩ, 45%), 104 (51), 91 (41), 77 (100), 71 (35) and 57 (69).
N-Benzoyl-1,2,3,4-tetrahydroisoquinoline 10f. Purified by
chromatography with ethyl acetate–light petroleum (50:50) as
eluent to give the pure title compound 10f (0.436 g, 92%) as a
colourless solid (mp 128 ЊC),64 Rf 0.8 (ethyl acetate–light pet-
roleum, 50:50); νmax(NaCl)/cmϪ1 1634, 1446, 1434, 1300, 1288,
1256 and 1236; δH (CDCl3) (2 conformers) 2.87–2.99 (2H, m,
CH2CH2N), 3.60–3.71 (1.2H, m, CH2CH2N), 3.98–4.08 (0.8H,
m, CH2CH2N), 4.50–4.68 (0.8H, m, ArCH2N), 4.89–4.98
(1.2H, m, ArCH2N), 7.17–7.20 (4H, m, C6H4) and 7.44 (5H, s,
C6H5);62 δC(CDCl3) (2 conformers) 28.4 and 29.7 (CH2CH2N),
44.9 and 45.4 (CH2CH2N), 49.9 and 53.6 (ArCH2N), 126.7, 127,
128.6, 128.7, 129.0, 129.9, 130.6, 133.1, 134.7 and 136.2 (C6H4
Preparation of the amides 10–15 from acid chlorides
General procedure. The appropriate acid chloride (0.002 mol)
was added dropwise to the amine 4, 5, 6, 7 or 9 (0.002 mol) and
triethylamine (0.695 cm3, 0.005 mol) in dichloromethane (10
cm3) with stirring under nitrogen. A yellow precipitate was
formed immediately. The mixture was refluxed for 60 or 180
min, cooled to room temperature and then washed with aque-
ous hydrochloric acid (10%; 20–30 cm3). The mixture was
extracted with dichloromethane (2 × 20 cm3) and the extract
dried (MgSO4), filtered and evaporated. The crude product was
purified by column chromatography on silica gel using ethyl
acetate–light petroleum as eluent.
N-Butyryl-1,2,3,4-tetrahydroisoquinoline 10a. Purified by
chromatography with ethyl acetate–light petroleum (30:70)
as eluent to give the pure title compound 10a (0.406 g, 100%) as
a yellow oil, Rf 0.3 (ethyl acetate–light petroleum, 30:70);
νmax(NaCl)/cmϪ1 1652, 1646, 1456 and 1436;11 δH (CDCl3) (2
conformers) 0.98 (1H, t, J 7.5, CH3), 0.99 (2H, t, J 7.5, CH3),
1.69 (0.7H, sext, J 7.5, CH3CH2), 1.71 (1.3H, sext, J 7.5,
CH3CH2), 2.38 (0.7H, t, J 7.5, CH2CO), 2.39 (1.3H, t, J 7.9,
2840
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
Table 6 The amide [11C]-10a from the amine 4 (0.375 mmol) and [1-11C]-PrCO2MgBr 3a:a yields as a function of the presence of a potentially
activating agent (0.375 mmol)
Crude yield b (%)
Purityc (%)
1 min
Entry
Added reagent
1 min
5 min
10 min
5 min
10 min
1
2
3
4
5
6
7
8
1-Methyl-2-chloropyridinium iodide
2-Chloropyridinium chloride
Et3N
DBU
Di-tert-butylpyridine
Pyridine
2-Chloropyridine
None
—
—
—
—
27 ± 1
47 ± 17
64 ± 1
56 ± 3
—
—
—
—
77 ± 1
65 ± 2
68 ± 1
60 ± 2
9 ± 1
21 ± 2
26 ± 1
37 ± 1
65 ± 2
62 ± 1
79 ± 1
76 ± 2
—
—
—
—
94 ± 2
80 ± 20
95 ± 4
96 ± 1
—
—
—
—
92 ± 6
87 ± 5
90 ± 2
98 ± 2
19 ± 2
98 ± 2
99 ± 1
85 ± 13
90 ± 10
93 ± 3
95 ± 4
96 ± 3
a
[1-11C]-PrCO2MgBr 3a was prepared from [11C]-CO2 and PrMgBr (0.275 mmol). b After work-up and before HPLC from the starting carboxylate
[11C]-3a (decay corrected to EOB, mean values of 2 or 3 runs). c Percent of the amide [11C]-10a in the crude product determined by radio TLC.
Table 7 The synthesis of the amides [11C]-10–12a
Crude yield b Purityc
Table 8 Rf Values of [11C]carboxylic acids and [11C]amides
Eluent A
Eluent B
Entry Amine R1CO2MgX Amides
(%)
(%)
Carboxylic acids
Amides
[11C]-1a
[11C]-1b
[11C]-1c
[11C]-1f
0.10
0.15
0.10
0.30
0.30
0.20
0.20
0.30
0.75
0.75
0.55
0.40
0.30
0.65
0.80
0.85
0.75
0.90
0.90
0.90
1
2
3
4
5
6
4
[11C]-3a
[11C]-3b
[11C]-3c
[11C]-3f
[11C]-3a
[11C]-3a
[11C]-10a
[11C]-10b
[11C]-10c
[11C]-10f
[11C]-11a
[11C]-12a
52 ± 4
40 ± 2
68 ± 1
23 ± 2
32 ± 2
42 ± 2
98 ± 2
77 ± 5
67 ± 2
14 ± 2
42 ± 2
45 ± 5
[11C]-10a
[11C]-10b
[11C]-10c
[11C]-10f
[11C]-11a
[11C]-12a
5
6
a
Amine/R1MgX = 0.0375/0.275 (mmol) in THF for 5 min. b After
work-up and before HPLC from the starting carboxylate [11C]-3 (decay
corrected to EOB, mean values of 2 or 3 runs). c Percent of the [11C]-
amide in the crude product determined by radio TLC.
N-(Methylbenzyl)butanamide 15a. Purified by chromatog-
raphy with ethyl acetate–light petroleum (50:50) as eluent to
give the pure title compound 15a (0.286 g, 75%) as a colourless
oil, Rf 0.32 (ethyl acetate–light petroleum, 50:50); νmax(NaCl)/
cmϪ1 1636 and 1540; δH (CDCl3) 0.92 (3H, t, J 7.4, CH2CH3),
1.48 (3H, d, J 7, CHCH3), 1.68 (2H, sext, J 7.4, CH2CH3), 2.14
(2H, t, J 7.4, CH2CO), 5.13 (1H, qt, J 7, CH3CH), 5.80 (1H, s,
NH) and 7.27–7.33 (5H, m, C6H5); δC(CDCl3) 13.8 (CH2CH3),
19.3 (CH2CH3), 21.8 (CH3CH), 38.9 (CH2CO), 48.6 (CHCH3),
126.3, 127.4, 128.4 and 143.4 (C6H5) and 172.1 (CO); m/z 191
(Mϩ, 66%), 165 (57), 152 (C12H17NOϩ, 100), 149 (C9H10NOϩ,
62), 109 (65), 105 (C8H9ϩ, 67), 77 (C6H5ϩ, 65), 71 (43), 55 (42),
43 (C3H7ϩ, 97) and 41 (C3H5ϩ, 73).
and C6H5); m/z 237 (Mϩ, 77%), 236 ([M Ϫ 1]ϩ, 55), 132
(C9H10Nϩ, 32), 117 (C9H9ϩ, 48), 105 (C7H5Oϩ, 100) and 104
(C8H8NOϩ, 33).11,62
N-Butylbutanamide 11a. Purified by chromatography with
ethyl acetate–light petroleum (50:50) as eluent to give the pure
title compound 11a (0.2 g, 70%) as a colourless oil, Rf 0.65
(ethyl acetate–light petroleum, 50:50); νmax(NaCl)/cmϪ1 1646
and 1264; δH (CDCl3) 0.85 (3H, t, J 7.3, CH3), 0.87 (3H, t, J 7.3,
CH3), 1.18–1.48 (4H, m, CH2CH2CH2NH), 1.59 (2H, sext, J
7.3, CH2CH2CO), 2.07 (2H, t, J 7.3, CH2CO), 3.18 (2H, q, J
6.6, CH2NH) and 5.4 (1H, s, NH); δC(CDCl3) 13.8 (2 CH3), 19.3
(CH2CH2CO), 20.1 (CH2CH2CH2N), 31.8 (CH2CH2N), 38.9
(CH2CO), 39.3 (CH2N) and 173 (CO).65
N,N-Dipropylbutanamide 12a. Purified by chromatography
with ethyl acetate–light petroleum (50:50) as eluent to give the
pure title compound 12a (0.273 g, 80%) as a colourless oil, Rf
0.65 (ethyl acetate–light petroleum, 50:50); νmax(NaCl)/cmϪ1
1642, 1464 and 1380; δH (CDCl3) 0.88 (3H, t, J 7.5, CH3), 0.92
(3H, t, J 7.5, CH3), 0.96 (3H, t, J 7.5, CH3), 1.47–1.72 (6H, m, 3
CH2CH3), 2.27 (2H, t, J 7.5, CH2CO) and 3.15–3.30 (4H, m,
2 CH2N); δC(CDCl3) 11.3 and 11.5 (2 CH3CH2CH2N), 14.1
(CH3CH2CH2CO), 19.0 (CH2CH2CO), 21.1 and 22.4 (2
CH2CH2N), 35.1 (CH2CO), 47.5 and 49.7 (2 CH2N) and 172.7
(CO);66 m/z 172 (Mϩ ϩ Hϩ, 17.6%), 171 (Mϩ, 19), 128
(C7H14NOϩ, 18.4), 115 (32.5), 114 (37), 101 (82.9), 100
(C6H14Nϩ, 60.9), 86 (C4H7NOϩ ϩ Hϩ, 25.2), 72 (64.9), 71 (19.7)
and 45 (100).
N-Butyrylmorpholine 13a. Purified by chromatography with
ethyl acetate–light petroleum (50:50) as eluent to give the pure
title compound 13a (0.250 g, 79.6%) as a colourless oil, Rf 0.35
(ethyl acetate–light petroleum, 50:50); νmax(NaCl)/cmϪ1 1644,
1456, 1436 and 1116; δH (CDCl3) 0.97 (3H, t, J 7.4, CH3), 1.66
(2H, sext, J 7.4, CH2CH3), 2.30 (2H, t, J 7.4, CH2CO) and 3.46–
3.69 (8H, m, 2 OCH2CH2N); δC(CDCl3) (2 conformers) 13.7
and 14.0 (CH3), 18.4 and 18.7 (CH2CH3), 35.1 and 35.9
(CH2CO), 41.9 and 46.1 (CH2N), 66.7 and 67.0 (CH2O), 172.0
and 177.6 (CO); m/z 157 (Mϩ, 100%), 142 (C7H12NO2ϩ, 34) and
129 (C6H11NO2ϩ, 56).
Synthesis of the amides 10–15 from carboxymagnesium halides
3: general procedure
To a solution of alkylmagnesium halide 2 (0.002, 0.003, 0.004,
0.005, 0.01 or 0.015 mol), the carboxylic acid 1 (0.002 mol) was
added at 0 ЊC under nitrogen. After the reaction mixture had
been stirred at 70 ЊC for 15 min, the amine 4–9 (0.002, 0.005 or
0.008 mol) was added at 0 ЊC. The reaction vessel was heated at
70 ЊC for 2, 5, 30 or 180 min. The mixture was quenched with
aqueous hydrochloric acid (10%; 25 cm3) at 0 ЊC and extracted
with dichloromethane (2 × 20 cm3). The combined extracts
were dried (MgSO4), filtered and concentrated. The residue
was chromatographed on silica gel with ethyl acetate–light pet-
roleum as eluent.
Synthesis of carboxylic acids [11C]-1: general procedure
[11C]Carbon dioxide was bubbled at 0 ЊC for 5 min through a
THF or Et2O (0.1 cm3) solution of alkylmagnesium halide
(1.47  in THF or Et2O; 0.2 or 0.02 cm3). The mixture was then
hydrolysed at 0 ЊC with aqueous ammonium chloride (satur-
ated solution; 1.5 cm3). The crude reaction mixture was ana-
lysed by radio TLC (Table 8).
Synthesis of amides [11C]-10–15: general procedure
To the solution of the carboxymagnesium halide [11C]-3 in THF
prepared as described earlier, the amine 4–6 (0.0375, 0.275,
J. Chem. Soc., Perkin Trans. 1, 1997
2841

View Article Online
21 B. Langström, G. Antoni, P. Gullberg, C. Halldin, K. Nagren,
0.375 mmol) was added, followed by the reagent listed in Table
6 (0.375 mmol) and THF (0.2 cm3). The reaction mixture was
heated at 70 ЊC for 1, 5 or 10 min. After cooling at 0 ЊC, the
mixture was hydrolysed with aqueous hydrochloric acid (2 ; 1
cm3). The organic and aqueous layers were separated, counted
and analysed. Analysis of the organic layer revealed the pres-
ence of a mixture of [11C]amide and [11C]carboxylic acid in the
ratios shown in Table 7.
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Purification of [1Ј-11C]butyryl-1,2,3,4-tetrahydroisoquinoline
10a
The amide [11C]-10a was prepared according to the method
described earlier (see above). After hydrolysis with 2  aqueous
hydrochloric acid, the mixture was loaded onto a C18 Sep-Pak
[pre-wet with methanol (10 cm3) and then with water (10 cm3)].
The Sep-Pak was rinsed with water (0.8 cm3) and dried under
nitrogen. The amide [11C]-10a was eluted with THF (1.5 cm3).
Solvent was removed from the eluted fractions at 80 ЊC under
nitrogen and after cooling at 0 ЊC, the radioactive residue was
taken up into methanol–water (70:30) and injected via a filter
(Millipore, Millex-HV13, 0.45 mm, 13 mm) onto an HPLC col-
umn. The amide [11C]-10a (tr = 7.70 min; 25.3 MBq; 20–30 µg
calculated from a calibration curve in HPLC; >99% radio-
chemical purity) was collected in 25% yield (decay corrected to
EOB starting from 280 MBq of [11C]-CO2) and within 30 min.
35 T. Ogawa, T. Hikasa, T. Ikegami, N. Ono and H. Suzuki, Chem.
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1990, 31, 7281.
Acknowledgements
We thank Mr David Turmel for his help in the non-radioactive
chemistry and Louisa Barré’s CEA research group (Cyceron
Center) for advice and technical support in radioactive
chemistry.
42 K. Joshi, J. Bao, A. S. Goldman and J. Kohn, J. Am. Chem. Soc.,
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Paper 7/02897K
Received 28th April 1997
Accepted 2nd June 1997
2842
J. Chem. Soc., Perkin Trans. 1, 1997