Rapid room-temperature 11C-methylation of arylamines with [ 11C]methyl iodide promoted by solid inorganic-bases in DMF

Article abstract of DOI:10.1002/ejoc.201101499

[¹¹C]Methyl iodide is the most widely used reagent for labeling radiotracers with carbon-11 (t_1/2 = 20.4 min) for molecular imaging with positron emission tomography. However, some substrates for labeling, especially primary arylamin

Full text of DOI:10.1002/ejoc.201101499

FULL PAPER
DOI: 10.1002/ejoc.201101499
11
Rapid Room-Temperature C-Methylation of Arylamines with [11C]Methyl
Iodide Promoted by Solid Inorganic-Bases in DMF
Lisheng Cai,*[a] Rong Xu,[a] Xuelei Guo,[a] and Victor W. Pike[a]
Keywords: Methylation / Arylamine / Ultrasound / Isotopic labeling / Carbon-11 / Radiopharmaceuticals / Synthesis design
[
11C]Methyl iodide is the most widely used reagent for label-
DMF were converted into their corresponding formanilides,
and that these were readily N-methylated with [11C]methyl
iodide, which preceded easy basic hydrolysis to the desired
ing radiotracers with carbon-11 (t1/2 = 20.4 min) for molecular
imaging with positron emission tomography. However, some
substrates for labeling, especially primary arylamines and
pyrroles, are sluggishly reactive towards [11C]methyl iodide.
We found that insoluble inorganic bases, especially Li3N or
Li2O, effectively promote rapid reactions (Յ 10 min) of such
substrates with no-carrier-added [11C]methyl iodide in N,N-
dimethylformamide (DMF) at room temperature to give 11C-
methylated products in useful radiochemical yields. In par-
ticular, we discovered that some primary arylamines in Li3N/
[
11C]N-methyl secondary arylamines. The use of a solid base
permitted selective reaction at an arylamino group and, in
some cases, avoided undesirable side reactions, such as ester
group hydrolysis. An ultrasound device proved useful to pro-
vide remote and constant agitation of the radioactive hetero-
geneous reaction mixtures but imparted no ultrasound-spe-
cific chemical effect.
amyloid plaque radioligands, [11C]1a and [11C]1b, and of a
prospective protein kinase C (PKC) receptor radioligand,
[11C]2 (Figure 1).
Introduction
11C-Methylation is an important method to prepare ra-
diotracers for application with positron emission tomogra-
phy (PET).[1–3] As carbon-11 has a very short half-life of
20.4 min, 11C-methylation procedures must be efficient over
short periods, typically less than 10 min.[4,5] [11C]Methyl
iodide[6–9] and [11C]methyl triflate[10] are the most accessible
and widely used 11C-methylation agents. However, these
reagents have some limitations for the 11C-N-methylation of
arylamines. [11C]Methyl iodide is often poorly effective.[11]
The more reactive [11C]methyl triflate can be generated sim-
ply by passing [11C]methyl iodide over heated silver tri-
flate[10] and is especially useful for the 11C-methylation of
arylamines, where the nucleophilicity of the amino group is
reduced by conjugation to the ring.[12,13] However, if the
electron density of the aryl group in a primary arylamine is
further reduced by an electron-withdrawing group even
[11C]methyl triflate may fail to react.
In our program of developing radiotracers for PET im-
aging, we have encountered several arylamines that show
only low or moderate reactivity towards either [11C]methyl
iodide or [11C]methyl triflate under conventional heated ba-
sic conditions. Moreover, these relatively harsh conditions
often lead to the decomposition of substrate and/or prod-
uct. These amines include precursors for the prospective β-
Figure 1. Some known[11] and prospective radiotracers that have
sluggishly reactive precursors in labeling reactions with [11C]methyl
iodide.
In view of reports that describe the successful use of solid
base/solvent combinations to achieve methylation or other
alkylation reactions at anilines and pyrroles,[14,15] we de-
cided to explore this approach for the 11C-methylation of
such substrates with [11C]methyl iodide. We also aimed to
explore ultrasound to achieve constant agitation with the
potential to increase reaction yields as documented for sev-
eral types of organic reactions,[16,17] which include methyl-
ation reactions.[18,19] In this study, we found that the use of
agitated solid inorganic-bases paired with N,N-dimethyl-
formamide (DMF) could overcome the sluggish reactivity
of arylamines and permit rapid 11C-methylation at room
temperature. For certain arylamines, this process was found
to occur through unexpected N-formyl intermediates.
[a] Molecular Imaging Branch, National Institute of Mental
Health, National Institutes of Health,
10 Center Drive, Building 10, Room B3 C346A, Bethesda MD
20892, USA
Fax: +1-301-480-5112
E-mail: LishengCai@mail.nih.gov
Eur. J. Org. Chem. 2012, 1303–1310
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Cai, R. Xu, X. Guo, V. W. Pike
FULL PAPER
of choice. We limited all reaction times to 10 min or less
to avoid excessive physical decay of carbon-11 during the
Results and Discussion
The aim of this study was to explore the use of solid reaction.
inorganic-bases to promote rapid reactions of [11C]methyl
Simple anilines, in particular anilines that carry a p-nitro
iodide with primary arylamines and a pyrrole (Figure 1) at or other electron-withdrawing group, are well-known to be
room temperature using ultrasound to agitate the hetero- poorly reactive towards alkyl halides, even in the presence
geneous reaction mixture. Our major findings were: i) that of strong bases.[26–29] For example, alkylations of aniline in
the use of Li3N/DMF or Li2O/DMF provided useful hydrocarbon solvents promoted by alumina or zeolites take
(Ͼ 5%) decay-corrected radiochemical yields (RCYs) of several hours at elevated temperatures.[15] We first tested the
11C-N-methylated products, which included unexpected N- 11C-methylation of simple anilines in Li3N/DMF. m-Nitro-
formyl compounds, ii) that formanilides were themselves aniline gave a very low yield (3%) of [11C]N-methyl-m-nitro-
useful reactive precursors for the rapid preparation of [11C]- aniline ([11C]4a, Table 1, Entry 1) whereas o- and p-nitro-
N-methylarylamines, and iii) that ultrasound was useful for aniline gave high (62%) and moderate yields (37%) of the
heterogeneous reaction agitation but did not impart an ul- respective [11C]N-methyl products, [11C]4b and [11C]4c
trasound-specific chemical effect.
(Table 1, Entries 2 and 3). Such reactions might be expected
Ultrasound is known to accelerate many types of organic to proceed through deprotonation of the weakly acidic
chemical reaction,[16,17] especially those that occur at solid– amino group to create a highly nucleophilic anion.[30] How-
liquid interfaces.[20,21] Microbubbles formed during the ever, the RCYs in these reactions appear opposite to the
ultrasonication of liquid–solid mixtures may collapse at the expected rank of basicities and nucleophilicities of the
phase interface to generate a local temperature of up to anions (m-nitroaniline Ͼ p-nitro ≈ o-nitro). A possible ex-
5000 °C within a fraction of a millisecond.[16,22–24] Further- planation is that the generated concentration of the anion
more, ultrasound between 5 and 24 kHz transfers energy to decreased with the increase in the pKa of the amine for pro-
reactants without dramatically changing the temperature of ton loss, although we also note evidence for the N-alk-
the bulk medium,[24] which is an attractive feature for reac- ylation of weak N–H acids in the presence of a solid base
tions that involve compounds with thermally sensitive to occur by complex catalytic mechanisms independent of
groups. Despite the widespread use of ultrasound as an en- amine deprotonation.[31] Aniline was unexpectedly con-
ergy source in general synthetic organic chemistry, ultra- verted in high RCY (68%) into the 11C-methylated form-
sound has not been considered previously to promote label- amide ([11C]5d) (Table 1, Entry 4), whereas no labeled form-
ing reactions with short-lived isotopes such as carbon-11. amide derivatives were produced from nitroanilines
In view of the possible advantages, we decided to explore (Table 1, Entries 1–3). This may suggest that the anion of
ultrasound for the constant agitation of heterogeneous reac- aniline (aniline pKa = 30.7)[32] and not any of the anions of
tion mixtures and to promote 11C-methylation reactions at the nitroanilines (p-nitroaniline pKa = 20.9)[32] is sufficiently
sluggishly reactive amino groups.
nucleophilic to displace Me2NH from DMF. DMF has
[11C]Methyl iodide was chosen for this study over the been reported to act as a source of the formyl group in a
more reactive [11C]methyl triflate to avoid unwanted side number of reactions,[33] which include the N-formylation of
reactions. Inorganic bases were selected i) to be strong
enough to deprotonate the weakly acidic amino group to
Table 1. RCYs of labeled products from the reactions of anilines
be labeled, ii) to have a large lattice energy in the solid form
with [11C]methyl iodide in the presence of Li3N/DMF after ultra-
sonication for 10 min at room temp.
to prevent the base serving as a nucleophile, and iii) to be
insoluble in the liquid phase in order to prevent other pos-
sible side reactions such as substrate decomposition or di-
rect reaction with [11C]methyl iodide. For the methylation
of arylamines, we focused on the use of solid Li3N, Li2O,
BaO, or KOH as the base. For the 11C-methylation of the
pyrrole 12 (Scheme 1), we used solid K2CO3.
In the choice of a supporting liquid phase for the reac-
tions, protic solvents and those capable of reacting with
strong bases were excluded. Solvents with low water-solu-
bility were avoided so that labeled products could be puri-
fied by reverse phase HPLC. Tetrahydrofuran (THF) is
known to participate in chemical reactions under strongly
Entry Precursor Amine
product [%]
RCY[a]
Amide
product
[11C]5a
[11C]5b
[11C]5c
[11C]5d
RCY
[%]
basic conditions,[25] and we found that some substrates de-
composed extensively in THF within 10 min of ultra-
sonication (unpublished results). Hexamethylphosphor-
amide and pyridine were found to give only very low RCYs
(Ͻ 1%) for reactions of the primary aromatic amines 7a
and 7b in the presence of Li3N, and hence their use was not
1
2
3
4
3a
3b
3c
3d
[11C]4a
3
0
0
0
68
[11C]4b 62Ϯ3 (59)
[11C]4c
[11C]4d
37Ϯ2 (25)
4
[a] Values are mean Ϯ range for n = 2. Values in parentheses are
further explored. Therefore, DMF became the liquid phase for shaken “silent” reactions.
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Eur. J. Org. Chem. 2012, 1303–1310

Room-Temperature 11C-Methylation of Arylamines with [11C]Methyl Iodide
halo and carboxyl anilines in DMF under reflux in the pres- had a negligible effect on the yield of [11C]1a (Entry 2).
ence of sodium methoxide.[34]
The closely related arylamine 7b gave similar yields of the
A low RCY (4%) of [11C]N-methylaniline ([11C]4d) was corresponding [11C]N-formyl and [11C]N-methyl products,
coproduced in the reaction of aniline (Table 1, Entry 4). We [11C]8b and [11C]1b, respectively, under these conditions
wondered if this product may have been generated from an- (Entry 3). As the major products were [11C]8a from 7a and
iline directly or from the major N-formyl product [11C]5d [11C]8b from 7b, DMF clearly acted as a source of the for-
during the aqueous quench of the reaction. Accordingly, we myl group as in the reaction of aniline.
tested the influence of the N-formyl group on radiolabeling.
All the tested formanilides 6a–6d gave aggregate 11C-N-
methylation (Table 2) in higher yields than the correspond-
ing anilines (3a–3d, Table 1). The most significant difference
Table 3. RCYs of labeled products from the reaction of 7a and 7b
with [11C]methyl iodide in the presence of solid inorganic-base/
DMF under ultrasonication at room temp.
arose between N-formyl-m-nitroaniline (6a) and m-nitro-
aniline (3a), which gave 45% 11C-methylation with 6a and
only 3% with 3a (cf. Table 2, Entry 1 with Table 1, Entry
1). For p-nitroaniline, no radiolabeled formamide was pres-
ent after product isolation, probably because of the high
reactivity of any formamide towards the LiOH that would
have been generated in situ from Li3N upon quenching with
water. Formanilides and N-methylformanilides are known
to be readily hydrolyzed in alkaline solution and both N-
methylformanilide (5d) and N-methyl-m-nitroformanilide
(5a) are much less prone to alkaline hydrolysis than N-
methyl-p-nitroformanilide (5c).[35] These facts appear re-
markably consistent with our findings in Table 2.
Entry Precursor Solid Time Amine
base [min] product
RCY[a]
[%]
Amide
product
RCY[a]
[%]
Table 2. RCYs of labeled products from the reactions of simple
formanilides with [11C]methyl iodide in the presence of Li3N/DMF
after ultrasonication for 10 min at room temp.
1
7a
7a
7b
7a
7a
7b
Li3N
5
[
11C]1a
11C]1a
6
[
11C]8a
11C]8a
8
2
3
4[d]
5[d]
6[d]
Li3N 10
Li3N 10
Li3N 10
[
6Ϯ0.1
[
9Ϯ0.1[b]
[
11C]1b 4Ϯ2 (9)
[
11C]8b 9Ϯ10[c] (2)
[
[
11C]1a
11C]1a
11C]1b
3
2
2
[
[
[
11C]8a
11C]8a
11C]8b
25
22
19
Li2O
Li2O
10
10
[
[a] Values in parentheses are for shaken reactions. [b] Values are
mean Ϯ range for n = 2. [c] Mean Ϯ standard deviation for n = 4.
[d] The precursor and Li3N/DMF were sonicated for 30 min before
[11C]methyl iodide was introduced.
Interestingly, for 7a, ultrasonication of the reaction mix-
ture for 30 min before the addition of [11C]methyl iodide
gave a much higher yield of radiolabeled products (28%),
with the [11C]N-formyl compound much more prevalent
than the [11C]N-methyl compound (Table 3, Entry 4). Re-
placement of Li3N with Li2O resulted in similar radioactive
product distribution and yields (Entry 5). Arylamine 7b
gave similar results to 7a under these conditions with the
Entry Precursor
Amine
product
[11C]4a
[11C]4b
[11C]4c
[11C]4d
RCY
[%]
Amide
product
[11C]5a
[11C]5b
[11C]5c
[11C]5d
RCY
[%]
1
2
3
4
6a
6b
6c
6d
0
20
76
0
45
61
0
77
We are developing prospective radiotracers for imaging N-formyl compound, [11C]8b, as the major radioactive
brain β-amyloid with PET, such as [11C]1a and [11C]1b, product (Entry 6). Our interpretation of these results is that
which are structurally related to the prototypical radio- presonication in DMF likely generated substantial concen-
tracer [11C]PIB ([11C]1c)[11] (Figure 1). In view of our find- trations of the formanilides, which reacted more readily
ings on the 11C-methylation of the simple nitroanilines than the parent amines with [11C]methyl iodide under basic
(Table 1), we were interested to test the same procedure to conditions. Again the reactions likely proceeded through
prepare the structurally more complex targets, [11C]1a and the generation of nucleophilic anions. Consideration of re-
[11C]1b. For the reaction of the primary arylamine 7a with ported pKa values suggests that anions of formanilide inter-
[11C]methyl iodide under ultrasonication for 5 min, Li3N in mediates would be formed much more easily than anions
DMF gave the highest aggregate yield of labeled products of the parent anilines. Thus, the pKa of formanilide (19.4)
(14%), in this case [11C]1a as minor product and the N-
is much lower than that of aniline (30.7),[32] and that of
[35]
formyl derivative [11C]8a as major product (Table 3, Entry p-nitroformanilide (12.5)[36] is much lower than that of p-
1). An increase in ultrasonication time from 5 to 10 min nitroaniline (20.9).[32]
Eur. J. Org. Chem. 2012, 1303–1310
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L. Cai, R. Xu, X. Guo, V. W. Pike
FULL PAPER
We obtained evidence that the N-formyl compounds method to prepare [11C]N-methylanilines under mild condi-
[11C]8a and [11C]8b were progenitors of the labeled amines tions.
[11C]1a and [11C]1b, respectively. Thus, after exposure of 7a
We have explored p-aminobenzoic acid esters as prospec-
and 7b in DMF to [11C]methyl iodide and ultrasound, we tive radioligands for imaging serotonin subtype-4 receptors
isolated the respective N-formyl compounds [11C]8a and with PET.[39] A method to label such compounds with car-
[11C]8b and showed that each was readily hydrolyzed with bon-11 in the N-methyl group would be useful. We therefore
1 m KOH at room temperature for 5 min to give the target next attempted the 11C-N-methylation of p-aminobenzoic
11C-N-methyl compounds, [11C]1a and [11C]1b.
acid methyl esters 10a–e in DMF under ultrasonic condi-
Our results and other reports,[37] which describe the tions to assess whether methylation could be achieved with-
ready alkylation of lithium salts of formanilides, prompted out accompanying ester hydrolysis. Li3N gave no labeled
us to prepare the formanilides 9a and 9b (Table 4) to test product from methyl p-aminobenzoate (10a, Table 5, Entry
their susceptibilities to 11C-N-methylation. We found that 1), whereas Li2O gave a modest RCY (15%) of the desired
7a and 7b could be converted into their corresponding non- [11C]11a (Entry 2). Li3N also gave extremely low or negligi-
radioactive formanilides, 9a and 9b, with formic acid under ble yields from the aryl ring methoxy-substituted substrates
microwave irradiation.[38] Ultrasonication of 9a or 9b with 10b (Entry 3) and 10c (Entry 4), whereas Li2O gave a small
[11C]methyl iodide in the presence of Li3N/DMF gave high yield from 10c (Entries 5 and 6). The aminobenzodioxan
aggregate yields of labeled products (68 and 50%, respec- 10d gave a higher yield (14%) of [11C]11d with Li3N (Entry
tively), in each case composed of a mixture of the [11C]N- 7) and no yield with Li2O (Entry 8). For anilines 10a–d
methyl derivative with the desformyl analog (Table 4, En- RCYs therefore depended on the steric and electronic fea-
tries 1 and 2). Presumably, [11C]1a and [11C]1b were pro- tures of the aryl ring substituents and their effects on amino
duced by hydrolysis of the major products [11C]8a or group acidity, which may be expected to determine the ef-
[11C]8b, respectively. Use of the base/solvent pair KOH/ fective concentration of the nucleophilic anion. A methoxy
DMF with 9a or 9b cleanly gave useful RCYs (66 and 32%) substituent located ortho to the ester group likely prevented
of [11C]1a or [11C]1b (Entries 3 and 4). These results further the coplanar arrangement of the ester group with the aryl
emphasize the strong utility of the N-formyl group to acti- ring, which in turn reduced the electron-withdrawing power
vate primary arylamines for 11C-N-methylation. Import- of the ester group on the amino group. An electron-donat-
antly, from these results, the 11C-N-methylation of formanil-
ides followed by alkaline hydrolysis emerged as a new rapid
Table 5. RCYs of labeled products from the reaction of variously
substituted 4-aminobenzoic acid methyl esters with [11C]methyl
iodide in the presence of solid inorganic-base/DMF with ultra-
sonication at room temp.
Table 4. RCYs of labeled products from the reaction of 9a and 9b
with [11C]methyl iodide in the presence of solid inorganic-base/
DMF with ultrasonication for 10 min at room temp.
Entry Precursor Ring
Solid
Time Product RCY
substituent base
[min]
[%]
1
2
3
4
5
6
7
8
10a
10a
10b
10c
10c
10c
10d
10d
10e
10e
10e
10e
10e
None
None
Li3N
Li2O
Li3N
Li3N
Li2O
Li2O
10
10
10
10
6
10
10
6–10
2
[
11C]11a
0
[
11C]11a 15Ϯ1[a]
3-MeO
2-MeO
2-MeO
2-MeO
O(CH2)2O Li3N
O(CH2)2O Li2O
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
[
[
[
[
[
[
[
[
11C]11b 4Ϯ3
11C]11c
11C]11c 6Ϯ1[a]
11C]11c
11C]11d 14
11C]11d 0[a]
11C]11e 21Ϯ10[a]
11C]11e 31Ϯ18[b]
11C]11e 16Ϯ13[b]
11C]11e
11C]11e 11
0
7
Entry Precursor
Solid
base
Amine
product
RCY[a]
[%]
Amide
product
RCY[a]
[%]
9
Li2O
Li2O
Li2O
BaO
Li3N
10
11
12
13
6
1
2
3
4
9a
9b
9a
9b
Li3N
Li3N
KOH
KOH
[
11C]1a
25 (21)
9 (23)
66 (53)
32 (35)
[
[
[
[
11C]8a
11C]8b
11C]8a
11C]8b
43 (45)
41 (50)
0 (0)
10
10
12
[
[
[
[
11C]1b
8
[
11C]1a
11C]1b
[
0 (0)
[a] Values are mean Ϯ range for n = 2. [b] Mean Ϯ standard devia-
tion for n Ͼ 5.
[a] Values in parentheses are for shaken “silent” reactions.
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Room-Temperature 11C-Methylation of Arylamines with [11C]Methyl Iodide
ing methoxy group ortho to the amino group would also
Overall, moderate but useful RCYs of [11C]N-methyl
have reduced anion availability. In 10d both effects oper- compounds were obtained from quite unreactive substrates
ated. By contrast, if a chloro substituent was ortho to the by brief treatment with 11C-methyl iodide in solid base/
amino group, as in 10e, a useful RCY (up to 31%) of [11C]- DMF at room temperature under the influence of ultra-
11e was obtained (Entries 9–11). In Li2O/DMF the yield of sound. However, we wished to establish whether the ultra-
[11C]11e was maximal after 6 min of sonication (Entry 10). sound imparted a specific effect in these reactions other
The specific radioactivity of [11C]11e was found to be than achieving desired reaction mixture agitation. For this
6.1 Ci/μmol at the end of radiosynthesis, an acceptably high reason, we conducted control reactions in the absence of
value for PET applications. BaO and Li3N gave much lower ultrasound but with occasional shaking to promote uni-
RCYs (Table 5, Entries 12 and 13, respectively).
formity in the heterogeneous reaction mixture. We found
Remarkably, no ester hydrolysis was observed for sub- that the yields of labeled products in nearly all cases were
strates 10a–e under the labeling conditions. The chosen so- comparable to those achieved under ultrasonication
lid inorganic-bases showed selectivity for imparting amino (Table 1, Entries 2 and 3; Table 3, Entry 3; Table 4, Entries
group deprotonation vs. ester hydrolysis. We attribute the 1–4). This strongly indicates that in this study the major
lack of nucleophilicity of the bases to their high lattice ener- role imparted by ultrasound was mainly limited to constant
gies and their insolubility in the reaction solvents.
agitation and promotion of reaction mixture uniformity.
Pyrrole nitrogen atoms are weakly acidic (e.g. 1H-di- Nonetheless, the apparatus employed here proved attractive
benzo[a,i]carbazole pKa = 17.7)[30] and recognized to be po- for this purpose as it can be operated remotely at room
orly reactive towards methyl iodide. We were interested to temperature and with full radiation safety in a lead-shielded
produce the [11C]N-methylpyrrole [11C]2 as a prospective hot-cell.
radiotracer to image PKC, by 11C-N-methylation of pyrrole
12.[40] We have previously observed that strong bases elimin-
Conclusions
ate acrylonitrile from 12 (reverse Michael addition,
Scheme 1). Even with the weak base K2CO3 in the absence
of ultrasound but at elevated temperature (80 °C), elimi-
nation was complete within 10 min. If an N-methyl group
was also present, as in 2, steric crowding further favored
elimination under thermal conditions. However, we found
that the reaction of 12 with [11C]methyl iodide in DMF/
K2CO3 with ultrasound at room temperature reduced elimi-
nation significantly (Scheme 1). In fact only about 50% of
the labeled product underwent elimination, and the target
[11C]2 was obtained in appreciable RCY (25%). This prod-
uct was obtained with a specific radioactivity of 2.1 Ci/
μmol at end of radiosynthesis.
The use of inorganic base/DMF proved especially effec-
tive for the rapid 11C-N-methylation of sluggishly reactive
arylamines and a pyrrole at room temperature with no-car-
rier-added [11C]methyl iodide. The bases effectively removed
protons at weakly acidic nitrogen atoms and were inactive
in the hydrolysis of sensitive benzoic acid esters. Further-
more, this study revealed formanilides to be useful precur-
sors to secondary [11C]N-methylarylamines. Additionally,
the ultrasound device was found to be a convenient means
for heterogeneous radioactive reaction mixture agitation.
Experimental Section
Materials: The following solid inorganic bases were purchased
from Aldrich (St. Louis, MO): Li3N (80 mesh), Li2O (97%,
60 mesh), BaO (technical grade, 90%, powder), KOH (85% pas-
tilles, crushed in glovebox), and K2CO3 (anhydrous powder,
crushed in glovebox). DMF was purchased from Alfa Aesar (Ward
Hill, MA). m-Nitroaniline (3a), o-nitroaniline (3b), p-nitroaniline
(3c), aniline (3d), N-methyl-3-nitroaniline (4a), N-methyl-2-nitro-
aniline (4b), N-(2-nitrophenyl)formamide (6b), N-(4-nitrophenyl)-
formamide (6c), methyl 4-aminobenzoate (10a), methyl 4-amino-
2-methoxybenzoate (10c), methyl 4-amino-3-chlorobenzoate (10e),
and methyl 4-(methylamino)-3-chlorobenzoate (11e) were pur-
chased from Aldrich (St. Louis, MO). N-Methyl-4-nitroaniline (4c),
N-(3-nitrophenyl)formamide (6a), and methyl 4-(methylamino)-
benzoate (11a) were obtained from Alfa Aesar (Ward Hill, MA).
N-Methylaniline (4d) was obtained from TCI (Portland, OR). N-
Methyl-N-phenylformamide (5d) and N-phenylformamide (6d)
were purchased from Acros (Pittsburgh, PA). Methyl 4-amino-3-
methoxybenzoate (10b) was purchased from Ryan Scientific (Mt.
Pleasant, SC).
General Methods and Instruments: Nonradioactive compounds
were analyzed with HPLC with an X-bridge C18 column (5 μm;
10ϫ250 mm; Waters Corp., Milford, MA) eluted with aqueous
NH4OH (0.025% v/v)/MeCN at 6.2 mL/min. Eluates were moni-
Scheme 1. Labeling of 2 with carbon-11 by treatment of 12 with
[11C]methyl iodide in K2CO3/DMF for 10 min at room temp. with
ultrasonication.
Eur. J. Org. Chem. 2012, 1303–1310
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1307

L. Cai, R. Xu, X. Guo, V. W. Pike
FULL PAPER
tored for absorbance at 254 nm (System Gold 168 detector;
Beckman, Fullerton, CA). The purity of each compound was ex-
from 9b (20 mg, 0.07 mmol). The crude product was dissolved in
DMF (2.0 mL) and purified by HPLC (aqueous NH3/MeCN, 73:27
v/v). Purity Ͼ 99%; yield 4.8 mg, 23%. 1H NMR (CDCl3): δ = 8.62
1
pressed as its area percentage of all chromatogram peak areas. H
NMR (400 MHz) and proton-decoupled 13C NMR (100 MHz) (s, 1 H, CHO), 8.09 (dm, 3JHH = 8.8 Hz, 2 H, Ar-H), 7.95 (d, 3JHH
4
spectra were acquired with an Avance 400 instrument (Bruker,
Billerica, MA) using the chemical shifts of residual deuterated sol-
vent as internal standard. Chemical shift (δ) data for the proton
and carbon resonances are reported in parts per million (ppm)
downfield relative to Me4Si; s, d, dd, brs, and dm denote singlet,
doublet, double doublet, broad singlet, and double multiplet,
respectively. LC–MS spectra were acquired with an LCQDECA in-
strument (Thermo Fisher Scientific, Waltham, MA) fitted with a
Luna C18 column (5 μm; 2.0ϫ150 mm; Phenomenex, Torrance,
CA) eluted at 150 μL/min with MeOH/H2O. HRMS were acquired
with either electron or electron spray ionization at the Mass Spec-
trometry Laboratory, University of Illinois at Urbana-
Champaign (Urbana, IL). An industrial ultrasonic processor
= 9.0 Hz, 1 H, Ar-H), 7.37 (d, JHH = 2.5 Hz, 1 H, Ar-H), 7.29
3
3
4
(dm, JHH = 8.8 Hz, 2 H, Ar-H), 7.11 (dd, JHH = 9.0, JHH
=
2.6 Hz, 1 H, Ar-H), 3.90 (s, 3 H, OCH3), 3.37 (s, 3 H, NCH3) ppm.
13C NMR (CDCl3): δ = 163.8 (CHO), 161.7, 157.7, 148.4, 143.6,
136.2, 131.4, 128.2, 123.5, 121.5, 115.6, 104.0, 55.6 (OCH3), 31.5
(NCH3) ppm. MS (TOF): m/z (%) = 301.1 (8), 300.1 (23), 299.0
(98) [M + H]+. HRMS: calcd. for C16H15N2O2S [M + H]+
299.0854; found 299.0850. Error (ppm): –1.3.
N-[4-(6-Bromobenzo[d]thiazol-2-yl)phenyl]formamide (9a): 4-(6-
Bromobenzo[d]thiazol-2-yl)aniline (7a, 20 mg, 0.06 mmol) was dis-
solved with ultrasonication in formic acid (1.0 mL). The solution
was placed in a microwave apparatus (Discover CEM, Matthews,
NC) at 120 °C for 10 min using 30 W power and a pressure limit
of 200 psi. After the reaction was complete, the solvent was evapo-
rated. The residue was washed with anhydrous diethyl ether to af-
ford crude 9a, which was dissolved in DMF (2.0 mL) and purified
by HPLC (aqueous NH3/MeCN, 17:83 v/v). Purity Ͼ 99%; yield
instrument (UIS250L, 250 W, 24 kHz; for
a
description,
see: http://downloads.german-pavilion.com/downloads/pdf/
exhibitor_19738.pdf), was used to agitate heterogeneous radioac-
tive reaction mixtures in closed vials. These vials (1 mL volume)
and their caps were custom-made from inert fluoropolymers. The
reaction vial was designed to fit snugly into the port of the instru-
ment so that ultrasound was efficiently transmitted to the reaction
mixture. In order to allow reagents to be added and reaction mix-
tures to be sampled, the septum liner of the vial cap was designed
to withstand multiple needle punctures without leaking.
1
5.5 mg, 25%. H NMR (CDCl3): δ = 10.6 (br. s, 1 H, NH), 8.44
3
3
(d, JHH = 1.9 Hz, 1 H, CHO), 8.37 (d, JHH = 1.6 Hz, 1 H, Ar-
3
3
H), 8.07 (d, JHH = 8.7 Hz, 2 H, Ar-H), 7.96 (d, JHH = 8.6 Hz, 1
H, Ar-H), 7.79 (d, JHH = 8.7 Hz, 2 H, Ar-H), 7.68 (dd, JHH
3
3
=
8.7, JHH = 2.0 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 167.8
(CHO), 160.1, 152.6, 141.2, 136.3, 129.7, 128.3, 124.8, 124.1, 119.5,
117.8, 117.3 ppm. MS (TOF): m/z (%) = 336.9 (5), 335.9 (21), 334.9
(98), 332.9 (93) [M + H]+. HRMS: calcd. for C14H10BrN2OS [M +
H]+ 332.9697; found 332.9697. Error (ppm): 0.
4
Chemical Syntheses: The following compounds were synthesized
as published: 4-(6-bromobenzo[d]thiazol-2-yl)-N-methylaniline
(1a),[11] 4-(6-methoxybenzo[d]thiazol-2-yl)-N-methylaniline (1b),[11]
3-(13-methyl-7-oxo-6,7-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]-
carbazol-12(13H)-yl)propanenitrile (2),[41,42] N-methyl-4-nitro-
aniline (4c),[43] N-methyl-N-(3-nitrophenyl)formamide (5a),[44] N-
methyl-N-(2-nitrophenyl)formamide (5b),[45] N-methyl-N-(4-ni-
trophenyl)formamide (5c),[44] 4-(6-bromobenzo[d]thiazol-2-yl)-
aniline (7a),[11] 4-(6-methoxybenzo[d]thiazol-2-yl)aniline (7b),[11]
methyl 8-amino-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate
(10d),[45] methyl 3-methoxy-4-(methylamino)benzoate (11b),[46–48]
methyl 2-methoxy-4-(methylamino)benzoate (11c),[46,47] methyl 8-
(methylamino)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate
(11d),[44,45] and 3-(7-oxo-6,7-dihydro-5H-indolo[2,3-a]pyrrolo-
[3,4-c]carbazol-12(13H)-yl)propanenitrile (12).[41,42]
N-[4-(6-Methoxybenzo[d]thiazol-2-yl)phenyl]formamide (9b): The
method used to synthesize 9a was used with 4-(6-methoxybenzo-
[d]thiazol-2-yl)aniline (7b, 20 mg, 0.07 mmol) to give crude 9b,
which was dissolved in DMF (2.0 mL) and purified by HPLC
(aqueous NH3/MeCN, 13:87 v/v). Purity Ͼ 99%; yield 5.3 mg,
1
3
24%. H NMR (MeOD): δ = 8.66 (s, 1 H, CHO), 8.12 (dm, JHH
3
= 8.7 Hz, 2 H, Ar-H), 7.91 (d, JHH = 9.0 Hz, 1 H, Ar-H), 7.56 (d,
4JHH = 2.5 Hz, 1 H, Ar-H), 7.49 (dm, JHH = 8.7 Hz, 2 H, Ar-H),
3
3
4
7.15 (dd, JHH = 9.0, JHH = 2.6 Hz, 1 H, Ar-H), 3.92 (s, 3 H,
OCH3) ppm. 13C NMR (CD3OD): δ = 166.1 (CHO), 164.2, 159.8,
149.5, 145.6, 138.6, 132.6, 129.4, 124.3, 123.2, 117.3, 105.3, 56.4
(OCH3) ppm. MS (TOF): m/z (%) = 362.1 (25), 360.1, 324.1 (100),
285.1 (90) [M + H]+. HRMS: calcd. for C15H13N2O2S [M]+
285.0698; found 285.0696. Error (ppm): –0.7.
N-[4-(6-Bromobenzo[d]thiazol-2-yl)phenyl]-N-methylformamide (8a):
N-Formylarylamine 9a (20 mg, 0.06 mmol), Li3N (5 mg,
0.14 mmol), and CH3I (5 μL, 0.08 mmol) were suspended in DMF
(0.5 mL). The suspension was placed in the ultrasonic device, which
was set at full power level for half of a 30 min period. The reaction
mixture was then quenched with aqueous HCOONH4 (5 m,
0.5 mL). The solvent was evaporated, and the residue was dissolved
in DMF. The product 8a was separated by HPLC (aqueous
General Radiochemistry Procedure: No-carrier-added (NCA) [11C]-
carbon dioxide was prepared by the 14N(p,α)11C nuclear reaction
by irradiation of nitrogen gas (164 psi) that contained oxygen (1%)
with protons (16.5 MeV, 45 μA) generated with a cyclotron (PET-
trace 200; GE Healthcare, Milwaukeee, WI). Radiochemistry was
performed in lead-shielded hot-cells for radiation protection to per-
sonnel. The [11C]carbon dioxide was converted in an automated
apparatus (PETrace MeI MicroLab; GE) into [11C]methyl iodide
by reduction to [11C]methane followed by a gas-phase reaction with
iodine. Within an inert glovebox (oxygen Ͻ 10 ppm and moist-
ure Ͻ 0.5 ppm), solid inorganic-base (ca. 5 mg), substrate (1.0 mg)
and solvent (0.3 mL) were loaded into a fluoropolymer reaction
vial (volume 1 mL) and the vial crimp-sealed with a fluoropolymer
septum. NCA [11C]methyl iodide (ca. 100 mCi) in nitrogen carrier
gas was then bubbled into the reaction mixture. The sealed vial was
placed in the port of the ultrasound apparatus (Ultrasonic Proces-
sor, UIS250L) and irradiated at full power for 50% of the time,
unless otherwise indicated, for a set period (Յ 10 min). The reac-
1
NH4OH/MeCN, 49:51 v/v). Purity Ͼ 98%; yield 4.2 mg, 20%. H
3
NMR (CDCl3): δ = 8.65 (s, 1 H, CHO), 8.12 (dm, JHH = 8.6 Hz,
4
3
2 H, Ar-H), 8.05 (d, JHH = 1.8 Hz, 1 H, Ar-H), 7.92 (d, JHH
=
3
4
8.6 Hz, 1 H, Ar-H), 7.61 (dd, JHH = 8.7, JHH = 1.9 Hz, 1 H, Ar-
H), 7.30 (dm, JHH = 8.6 Hz, 2 H, Ar-H), 3.41 (s, 3 H, NCH3)
3
ppm. 13C NMR (CDCl3): δ = 167.1 (CHO), 161.9, 153.0, 144.6,
136.7, 130.9, 130.1, 128.8, 124.3, 124.2, 121.7, 119.0, 31.7 (NCH3)
ppm. MS (TOF): m/z (%) = 163.0 (5), 350.9 (5), 165.0 (7), 381.2
(13), 349.9 (21), 346.9 (98) [M + H]+. HRMS: calcd. for
C15H12BrN2OS [M + H]+ 346.9854: found 346.9850. Error (ppm):
–1.2.
N-[4-(6-Methoxybenzo[d]thiazol-2-yl)phenyl]-N-methylformamide
(8b): The method used to synthesize 8a was used to prepare 8b
1308
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1303–1310

Room-Temperature 11C-Methylation of Arylamines with [11C]Methyl Iodide
tion mixture was filtered through a celite plug to obtain a clear
solution (syntheses of [11C]11a–11e only) or quenched by the ad-
dition of water (0.5 mL). The radioactive product was then sepa-
rated by reverse phase HPLC eluted with 0.1 m HCOONH4/MeCN,
with eluate monitored for radioactivity and absorbance, as detailed
below. The identities of labeled products were confirmed chromato-
graphically by observation of coelution with nonradioactive refer-
ence compounds in HPLC and/or by LC–MS of the associated
carrier. Decay-corrected RCYs of measured isolated radioactive
product were calculated from the amount of [11C]methyl iodide
added to the reaction vial. The specific radioactivities (Ci/μmol) of
some products were calculated by measurement of the mass of car-
rier with calibrated analytical HPLC through absorbance detection
and measurement of the associated radioactivity. Some reactions
were performed with ultrasound irradiation before addition of [11C]
methyl iodide. Some control reactions were performed without ul-
trasound irradiation, but with shaking at 0, 5 and 10 min. Thus,
were prepared:
[11C]N-Methyl-N-phenylformamide ([11C]5d): HPLC isolation:
Luna C18 column (5 μm, 10ϫ250 mm) eluted with gradient of
HCOONH4/MeCN (30% MeCN for 1 min increased linearly to
50% MeCN at 30 min, v/v) at 6.2 mL/min (λ = 254 nm) (tR
=
7.8 min).
[11C]N-[4-(6-Bromobenzo[d]thiazol-2-yl)phenyl]-N-methylformamide
([11C]8a): HPLC isolation: Luna C18 column (5 μm, 10ϫ250 mm)
eluted with HCOONH4/MeCN (3:7 v/v) at 6.2 mL/min (λ =
350 nm) (tR = 8.7 min).
[
11C]N-[4-(6-Methoxybenzo[d]thiazol-2-yl)phenyl]-N-methyl-
formamide ([11C]8b): HPLC isolation: Luna C18 column (5 μm,
10ϫ250 mm) eluted with HCOONH4/MeCN (2:3 v/v) at 6.2 mL/
min (λ = 350 nm) (tR = 7.0 min).
[11C]Methyl 4-(Methylamino)benzoate ([11C]11a): HPLC isolation:
Gemini-NX C18 column (5 μm, 10ϫ250 mm) eluted with
HCOONH4/MeCN (1:1 v/v) at 6 mL/min (λ = 254 nm) (tR
=
5.4 min).
[11C]4-(6-Bromobenzo[d]thiazol-2-yl)-N-methylaniline
HPLC isolation: Luna C18 column (5 μm, 10ϫ250 mm) eluted
with HCOONH4/MeCN (3:7 v/v) at 6.2 mL/min (λ = 350 nm) (tR
= 13.0 min).
([11C]1a):
[11C]Methyl 3-Methoxy-4-(methylamino)benzoate ([11C]11b): HPLC
isolation: Gemini-NX C18 column (5 μm, 10ϫ250 mm) eluted
with HCOONH4/MeCN (1:1 v/v) at 6 mL/min (λ = 254 nm) (tR
=
6.7 min).
[11C]4-(6-Methoxybenzo[d]thiazol-2-yl)-N-methylaniline ([11C]1b):
HPLC isolation: Luna C18 column (5 μm, 10ϫ250 mm) eluted
with HCOONH4/MeCN (2:3 v/v) at 6.2 mL/min (λ = 350 nm) (tR
= 10.0 min).
[11C]Methyl 2-Methoxy-4-(methylamino)benzoate ([11C]11c): HPLC
isolation: Gemini-NX C18 column (5 μm, 10ϫ250 mm) eluted
with HCOONH4/MeCN (3:2 v/v) at 4 mL/min (λ = 254 nm) (tR
=
7.4 min).
[11C]3-[13-Methyl-7-oxo-6,7-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]-
carbazol-12(13H)-yl]propanenitrile ([11C]2): HPLC isolation: Luna
C18 column (5 μm, 10ϫ250 mm) eluted with HCOONH4/MeCN
(9:11 v/v) at 6.2 mL/min (λ = 292 nm) (tR = 7.5 min); elimination
side product (tR = 8.3 min).
[11C]Methyl
8-(Methylamino)-2,3-dihydrobenzo[b][1,4]dioxine-5-
carboxylate ([11C]11d): HPLC isolation: Gemini-NX C18 column
(5 μm, 10ϫ250 mm) eluted with HCOONH4/MeCN (3:2 v/v) at
5 mL/min (λ = 254 nm) (tR = 7.6 min).
[11C]Methyl 3-Chloro-4-(methylamino)benzoate ([11C]11e): HPLC
isolation: Gemini-NX C18 column (5 μm, 10ϫ250 mm) eluted
with HCOONH4/MeCN (1:1 v/v) at 6 mL/min (λ = 254 nm) (tR
[11C]N-Methyl-3-nitroaniline ([11C]4a): HPLC isolation: Luna C18
column (5 μm, 10ϫ250 mm) eluted with HCOONH4/MeCN (3:2
v/v) at 6.2 mL/min (λ = 254 nm) (tR = 13.2 min).
=
9.5 min).
[11C]N-Methyl-2-nitroaniline ([11C]4b): HPLC isolation: Luna C18
column (5 μm, 10ϫ250 mm) eluted with HCOONH4/MeCN (1:3
v/v) at 6.2 mL/min (λ = 254 nm) (tR = 6.1 min) or on the same
column eluted at 6.2 mL/min with a gradient of HCOONH4/
MeCN (30% MeCN for 1 min increased linearly to 50% MeCN at
30 min) (λ = 254 nm) (tR = 21.4 min).
Acknowledgments
This research was supported by the Intramural Research Program
of the National Institutes of Health (NIH) (National Institute of
Mental Health). We are grateful to the NIH Clinical Center PET
Department (Chief: Dr. P. Herscovitch) for the production of car-
bon-11.
[11C]N-Methyl-4-nitroaniline ([11C]4c): HPLC isolation: Luna C18
column (5 μm, 10ϫ250 mm) eluted with HCOONH4/MeCN (3:2
v/v) at 6.2 mL/min (λ = 254 nm) (tR = 9.4 min) or on the same
column eluted at 6.2 mL/min with a gradient of HCOONH4/
MeCN (30% MeCN for 1 min increased linearly to 50% MeCN at
30 min) (λ = 254 nm) (tR = 12.6 min).
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Eur. J. Org. Chem. 2012, 1303–1310
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Published Online: January 9, 2012
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