Nitroaldol reaction of nitro[11C]methane to form 2-(hydroxymethyl)-2-nitro[2-11C]propane-1,3-diol and [ 11C]Tris

Article abstract of DOI:10.1002/jlcr.1833

The nitroaldol reaction of nitro[¹¹C]methane and formaldehyde, which yields 2-(hydroxymethyl)-2-nitro[2-¹¹C]propane-1,3-diol, is explored. The fluoride-ion-assisted nitroaldol reaction using (C ₄H₉)₄NF was rapid and provided the desired nitrotriol in more than 97% radiochemical conversion (decay-corrected) in 3 min at room temperature. Neither 2-nitro[2-¹¹C]ethanol nor 2-nitro[2-¹¹C]propane-1,3-diol was observed under the reaction conditions. The preparation of 2-amino-2-(hydroxymethyl)-[2-¹¹C] propane-1,3-diol ([¹¹C]Tris) was described, which was followed by the nitro-group reduction using NiCl₂ and NaBH₄ in aqueous MeOH. The decay-corrected radiochemical conversion to [¹¹C]Tris was 68.0±6.5% in two steps. Copyright

Full text of DOI:10.1002/jlcr.1833

Research Article
Received 20 July 2010,
Revised 15 August 2010,
Accepted 22 August 2010 Published online 29 November 2010 in Wiley Online Library
(www.wileyonlinelibrary.com) DOI: 10.1002/jlcr.1833
Nitroaldol reaction of nitro[11C]methane
to form 2-(hydroxymethyl)-2-nitro[2-11C]-
propane-1,3-diol and [11C]Tris
Ã
Koichi Kato, Ming-Rong Zhang, Katsuyuki Minegishi,
Nobuki Nengaki, Makoto Takei, and Kazutoshi Suzuki
The nitroaldol reaction of nitro[11C]methane and formaldehyde, which yields 2-(hydroxymethyl)-2-nitro[2-11C]propane-1,3-
diol, is explored. The fluoride-ion-assisted nitroaldol reaction using (C4H9)4NF was rapid and provided the desired nitrotriol
in more than 97% radiochemical conversion (decay-corrected) in 3 min at room temperature. Neither 2-nitro[2-11C]ethanol
nor 2-nitro[2-11C]propane-1,3-diol was observed under the reaction conditions. The preparation of 2-amino-2-
(hydroxymethyl)-[2-11C]propane-1,3-diol ([11C]Tris) was described, which was followed by the nitro-group reduction using
NiCl2 and NaBH4 in aqueous MeOH. The decay-corrected radiochemical conversion to [11C]Tris was 68.076.5% in two steps.
Keywords: isotopic labeling; carbon-11; nitroaldol reaction; fluoride ion; Tris
that overcome the major differences in the reaction conditions
between radiolabeling and nonradiolabeling reactions. Thus, the
Introduction
reaction can afford three nitroaldol products, 2-nitro[2-11C]etha-
The nitroaldol reaction is an important route to C–C bond
formation in organic syntheses. Nitroaldol products are used as
synthetic intermediates of versatile pharmaceuticals, including
nol (3), 2-nitro[2-11C]propane-1,3-diol (4), and 2-(hydroxymethyl)-
2-nitro[2-11C]propane-1,3-diol (5), by mono- and multiple addi-
b-aminoalcohols, which are structural components of b-
blockers.1 In general, the nitroaldol reaction is performed in
the presence of excess nitroalkane to carbonyl compounds in
order to suppress multiple addition reactions and compensate
for the low reactivity of nitroalkanes. Methods that utilize the
multiple adduct as a synthetic building block are also being
developed.2
tions in the presence of a large excess of formaldehyde [Equation
(1)]. In our previous research, we encountered the obstacle of
regulating the formation of 3. The low steric hindrance of
formaldehyde promoted multiple reactions, yielding 4 by
treatment of 2 and paraformaldehyde with EtONa in the
presence of EtOH at 01C.5 We optimized the reaction conditions
to give 3 in good radiochemical conversion by adjusting the
amount of EtONa and EtOH.5 Besides optimizing the mono-
adduct formation, we also found another difficulty relating to the
third addition to form nitrotriol 5. We did not observe the
multiple adduct yielding 5 during our previous attempt of
11C-labeled nitroaldol reactions, in contrast to the facile formation
of 4. The intra-molecular hydrogen bonding of nitronate that
renders the isolation of nitrodiol feasible under nonradiolabeling
conditions would require a longer reaction time for the
formation of 5 (Figure 1).8 Thus, we explored reaction conditions
to produce 5 rapidly for use in 11C-labeling synthesis.
Carbon-11 is a positron-emitting radionuclide that can be used
for positron emission tomography (PET) research. Iodo[11C]-
methane ([11C]H3I, 1) is a frequently used 11C-labeling agent for
PET tracer synthesis.3 Carbon-11-labeled nitromethane
([11C]H3NO2, 2) is prepared via on-line nitration of 1.4 In contrast
to the electrophilic character of 1, 2 can be used as a nucleophile
by furnishing the stabilized carbanion under mild basic condi-
tions. Thus, the umpolung strategy is available for 11C-labeling
methodologies, although there are several constraints of using a
short-lived radioisotope. When we consider the use of 2 as an
11C-labeling agent, the development of an efficient method for
the nitroaldol reaction using 2 becomes a challenging issue in
11C-labeling chemistry. Because of the short half-life of 11C, the
development of rapid reaction conditions that overcome the
considerably low reactivity of 2 is required. It is difficult to
regulate the multiple additions and the dehydration of nitroaldol
products because 11C-labeling reactions involve a large excess of
carbonyl compounds and bases.5,6 With the exception of the
reaction with formaldehyde, controlling the chiral center of
nitroaldol products is a primary concern.7
2-Amino-2-(hydroxymethyl)-[2-11C]propane-1,3-diol ([11C]Tris,
6), which can be prepared by nitro-group reduction, becomes a
target of synthetic applications of
5 because Tris is a
pharmaceutical product used for treatment of acidosis.9 Acidosis
is worthy of comment in relation to PET research because it is
Department of Molecular Probes, National Institute of Radiological Sciences,
4-9-1 Anagawa, Inage-ku, Chiba, Japan
*Correspondence to: Koichi Kato, Department of Molecular Probes, National
Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Japan 263-8555.
E-mail: katok@nirs.go.jp
The nitroaldol reaction of 2 and formaldehyde provides us
opportunities to develop appropriate 11C-labeling methodologies
J. Label Compd. Radiopharm 2011, 54 140–144
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K. Kato et al.
O-
O-
plateau of radioactivity in the reaction vessel, a gas stream was
suspended and the solution was heated up to 40 or 1001C. After
3 min, the reaction was quenched by the addition of CH3COOH
(100 mL). The reaction mixture was analyzed by HPLC under the
following conditions: column, Silica AG 80 (Shiseido Ltd.,
4.6 Â 250 mm, 5 mm); flow rate, 2 mL/min; eluent, hexane/1,4-
dioxane (65/35). The retention times for 3 and 4 were 3.6 and
5.2 min, respectively.
H
O
N+
H
O
11C
Figure 1. A structure of intra-molecular hydrogen bonding.
accompanied by inflammation. Inflammation is a common
target for diagnosis by PET as it is observed across several
diseases. In addition, the reduction of aliphatic nitro compounds
2-(Hydroxymethyl)-2-nitro[2-11C]propane-1,3-diol (5)
to corresponding amines is a difficult process under 11C-labeling Gaseous 2 was collected by a reaction vessel containing TBAF
conditions. Therefore, the development of nitroaldol reaction as (5 mmol) and paraformaldehyde 10 mmol) in THF (300 mL) with a
well as efficient nitro-group reduction provides new synthons 30 mL/min flow rate. After reaching a plateau of radioactivity in
for use in 11C-labeling. In this context, the reaction of 2 with the reaction vessel, a gas stream was suspended and the
formaldehyde to yield nitrotriol 5 and the synthesis of 6 become solution was placed at RT. After 3 min, the reaction was
topics of interest from the viewpoint of the 11C-labeling quenched by the addition of CH3COOH (100 mL). The reaction
nitroaldol reaction. We describe herein the synthesis of 6, mixture was analyzed by HPLC under the following conditions:
including simple preparation of 2, rapid nitroaldol reaction, and column, Silica AG 80 (Shiseido Ltd., 4.6 Â 250 mm, 5 mm); flow
the nitro-group reduction of 5.
rate, 2 mL/min; eluent, hexane/1,4-dioxane (65/35). The reten-
tion time for 5 was 8.1 min.
Experimental section
2-Amino-2-(hydroxymethyl)-[2-11C]propane-1,3-diol (6)
General information
To an unquenched reaction mixture of 5, a 6:4 mixture of MeOH
and H2O (500 mL) was added. The resulting solution was
transferred to the next reaction vessel containing NiCl2 (2 mg)
and NaBH4 (12 mg) by gas flow. The reaction mixture
immediately became black and bubbled vigorously, and then
it was placed for 1 min at RT and then CH3COOH (100 mL) was
added. The resulting mixture contained black precipitation and
a part of supernatant (approximately 10 mL) was mixed with the
eluent of analytical HPLC (approximately 100 mL). The resulting
clear solution was analyzed by HPLC under the following
conditions: column, J’sphere L80 (YMC Ltd., 4.6 Â 150 mm, 5 mm);
flow rate, 0.5 mL/min; eluent, MeOH/50 mM ammonium phos-
phate buffer (pH = 4) (15/85). The retention time for 6 was
4.0 min under the reverse-phase condition. The mixture was also
analyzed by liquid chromatography-mass spectrometry (LCMS)
and the retention time of 6 of radiochromatogram corre-
sponded with that of ion intensity chromatogram of MS
spectrum for nonlabeled Tris contaminated in 6. LC conditions
used were as follows; column, Atlantiss HILIC (Waters Ltd.,
4.6 Â 150 mm, 3 mm); flow rate, 0.3 mL/min; eluent, 5 mM
NH4OAc solution of CH3CN–H2O (70/30); LC-MS/MS m/z 122
(M1H) and 56.
Reagents EtONa, 1.0 M THF solution of TBAF, paraformaldehyde,
AgNO2, and aqueous 57% HI solution were purchased from
WAKO Co. Ltd. 2-Hydoroxymethyl-2-nitropropane-1,3-diol was
purchased from Aldrich Co. Ltd. A 0.05 M THF solution of lithium
aluminum hydride (LAH) was prepared by diluting a 1.0 M THF
solution purchased from Aldrich. The reaction solvents used,
THF, EtOH (used as an additive), and MeOH, were of dehydrated
grade purchased from WAKO Co. Ltd. Solvents used for HPLC,
hexane, 1,4-dioxane, MeOH, and acetonitrile, were of HPLC
grade purchased from WAKO Co. Ltd.
A CYPRIS HM-18 cyclotron (Sumitomo Heavy Industry, Tokyo)
was used for the 11C production by a 14N(p, a)11C nuclear
reaction. Purification and analysis of radioactive mixtures was
performed by HPLC with an in-line UV (210 nm) detector in
series with a NaI crystal scintillation detector.
Nitro[11C]methane (2)
[11C]Carbon dioxide was produced by the 14N(p,a)11C nuclear
reaction in a nitrogen gas containing 0.01% oxygen with 18 MeV
protons. After bombardment, [11C]O2 was transferred to the
reaction vessel where a 0.05 M THF solution of LAH (500 mL) was
placed at 01C. After evaporating THF, an aqueous 57% HI
solution (400 mL) was added to the vessel. The resulting mixture
was heated to 1501C to produce gaseous iodo[11C]methane (1).
The precursor 1 was passed through P2O5, and Ascarite then
converted to nitro[11C]methane (2) by passing at a flow rate of
30 mL/min through a plug of AgNO2 attached to a column filled
with NaHCO3. The column of AgNO2 was wound with a prior
tube line to preheat the gas stream. Both of the column and
wound tube line were covered by foil and robber heater and
heated at 1001C.
Results and discussion
According to a previous report by Shoeps et al., the 11C-labeling
agent [11C]H3NO2, 2, is prepared via nitration of [11C]H3I, 1, by
passing through a heated plug of AgNO2 in a furnace at
80–1001C.4 At lower temperatures, 1 is converted into other
radioactive compounds and the radiochemical yield of 2 is
decreased.4 Therefore,
a whole glass column of AgNO2,
including joints, should be placed in a furnace to allow the
nitration reaction to achieve better conversion while maintain-
ing the desired high reaction temperature. Using a furnace is a
reasonable approach; however, sometimes it can prove to be
cumbersome spatially. In contrast, the use of a rubber heater
Nitroaldol reaction by treatment of 2 and paraformaldehyde
with EtONa and EtOH
Gaseous 2 was collected by a reaction vessel containing EtONa makes the reaction system smaller, although it is not suitable for
(15 mmol), EtOH (10 mL), and paraformaldehyde 10 mmol) in THF covering the entire glass column and joints. This means that the
(300 mL) with a 30 mL/min flow rate at RT. After reaching a gas stream containing 1 passes through the front part of a plug
J. Label Compd. Radiopharm 2011, 54 140–144
Copyright r 2010 John Wiley & Sons, Ltd.
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K. Kato et al.
of AgNO2 without being heated sufficiently by the rubber of an 11C-labeled compound, a shorter total synthetic time should
heater. As a result, the actual reaction temperature of the be considered in order to increase the radioactivity of the final
nitration reaction becomes partially lower by using a rubber product. Besides the short reaction time of 11C-labeling, avoiding
heater, resulting in the poor conversion of 2. In fact, the time-consuming processes such as evaporation, distillation, and
radiochemical conversion of 2 was 40–70% when a rubber isolation between every reaction step helps to reduce total
heater covered the glass tube directly and heated it to 1001C. To synthetic time. For this purpose, we selected THF as the solvent for
overcome the problem of insufficient heating of the gas stream, the nitroaldol reaction because the nitro-group reduction reaction
we introduced preheating of the tube line. Thus, we wound a of 5 would not be influenced by contamination of THF.
prior tube line on to the glass column of AgNO2, covered both
In our previous study, the addition of EtOH with EtONa
of them with foil and rubber heater (Figure 2), and then heated enhanced the nitroaldol reaction of 2 and paraformaldehyde
at 1001C. After this treatment, the radiochemical conversion of 2 yielding 11C-labeled nitroethanol 3 at 0 1C.5 The radiochemical
became similar to that achieved using a furnace (around 90% conversion of 3 was 64.473.1% (Table 1). The reaction also
conversion). The pyrolysis of AgNO2 under nitration conditions is yielded 11C-labeled nitrodiol 4 in 17.073.9% radiochemical
also a problematic issue because it affords several types of acidic conversion but nitrotriol 5 was not obtained at the reaction
nitrogen oxides that retard base-promoted reactions.10 To temperature. From the viewpoint of the multiple additions
overcome this, a column containing NaHCO3 was attached reactions, pseudo-first-order conditions of the 11C-labeling
following the AgNO2 column to remove these products.11,12
reaction using 2 to formaldehyde could assist the rapid formation
The choice of solvent for the nitroaldol reaction plays an of 5. Thus, we first decided to introduce higher reaction
important role both chemically and technically because the temperatures to the above reaction conditions in order to
synthesis of [11C]Tris 6 requires two steps. For a multistep synthesis increase the total reaction rate for the formation of each
nitroaldol product. The reaction was carried out by treating 2
and paraformaldehyde (10mmol) with EtONa (15mmol), and EtOH
(17 mmol) at 401C. As a result, nitroaldol reactions forming 4 were
enhanced and radiochemical conversion was increased to
67.075.9% (entry 1). However, the desired nitrotriol 5 was not
obtained. Even though a higher temperature was introduced
(1001C), no improvement in the formation of 5 was observed
(entry 2). Stabilization by intra-molecular hydrogen bonding in
the reaction using EtONa and EtOH was too strong to allow the
formation of 5 even under two different high temperatures. Our
efforts in the preparation of 5 thus directed us toward another
approach, which was focused on the disruption of intra-molecular
hydrogen bonding of nitroaldol intermediates.
Ionic fluoride assists nucleophilic substitution of alkyl halides
by hetero atoms such as N, O, and S. The presence of strong
hydrogen bonds between fluoride and hydrogen on hetero
atoms promotes these reactions.13 We considered that the
hydrogen-bonding ability of fluoride might induce the disrup-
tion of the stabilized nitronate of 4 (Figure 3). By the way, the
strong HF bond energy allows the potential of ionic fluoride to
act as a base. Therefore, potential properties of basic fluoride
direct us toward the investigation of fluoride-promoted rapid
formation of 5. We chose tetrabutylammonium fluoride (TBAF)
as a base because of its high solubility in THF. We carried out the
reaction by treatment of 2 and paraformaldehyde (10 mmol) with
TBAF (5 mmol). The reaction gave 5 very efficiently even at RT.
The radiochemical conversion of 5 was more than 97% after
3 min (Table 1, entry 3). As the formation of 5 was sufficient for
11C-labeling syntheses and 5 mmol TBAF would not affect the
reduction of the nitro-group, we did not investigate the TBAF-
mediated reaction further. It should be noted that TBAF used in
this study was a commercially available trihydrate solution in
THF and that the reaction proceeded without any additives to
enhance nonradiolabeling reactions.14 Nagren et al. reported the
˚
nitroaldol reaction of 2 and aromatic aldehyde using solid
TBAF.6 They pointed out the increased selectivity for the
formation of nitroaldol against dehydrated products using
TBAF. However, they did not observe the multiple addition
products. In our laboratory, we observed neither 3 nor 4, nor the
dehydrated products. Compared with the reaction using
aromatic aldehydes, both the nitroaldol products and the
aldehyde of the reaction using formaldehyde are sterically less
Figure 2. Pictures and a drawing of AgNO2 column: (a) a glass column wound with
a prior tube; (b) a glass column covered with foil and a rubber heater; and (c) a
drawing of a glass column wound with a prior tube.
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Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 140–144

K. Kato et al.
a,b
Table 1. Nitroaldol reaction of 2 and (HCHO)n
NO2
NO2
NO2
11CH3NO2 + (HCHO)n
HO
HO
OH
[Eq. (1)]
11C
+
HO
OH
+
HO
2
3
4
5
Radiochemical conversion (%)c,d
Entry
Base (mmol)
Temp
401C
1001C
rt
EtOH (mL)
3
4
5
1
2
3
4e
15
15
5
10
10
—
10
29.275.2
2.971.4
0
67.075.9
85.372.1
0
0
0
974
0
15
01C
64.473.1
17.073.9
aReaction conditions: 2 (37–370 MBq); paraformaldehyde (10 mmol); THF (300 mL); reaction time (3 min).
bEach reaction was carried out more than three times.
cDetermined by a radiochromatogram of analytical HPLC after decay correction.
dSignificant amount of radioactivity was not remained in the column after each analysis.
eReference4.
-F
-O
O-
F-
1. TBAF, THF
NH2
+
rt, 3 min
H
O
N
H
O
HO
HO
OH
2 + (HCHO)n
2. NiCl2, NaBH4
MeOH-H2O (6/4)
rt, 1 min
11C
6
Figure 3. Hypothesis of fluoride-assisted disruption.
Scheme 1.
hindered. Therefore, hydrogen-bond-free nitronate and paraf- containing NiCl2hexahydrate and NaBH4. The black precipitation
ormaldehyde reacted immediately after second and third and gas evolution were observed in the reaction mixture and
additions in the presence of fluoride, as compared with the the nitro-group reduction of 5 yielded the corresponding amine
reaction of 2 and aromatic aldehyde. The rapid nitrotriol 6 after 1 min at room temperature in 61.376.3% radiochemical
formation also retards the dehydration of nitroaldols because conversion (decay-corrected, two steps).20 The less polar radio-
there are no acidic a-protons in 5. The amount of TBAF used for active byproducts, which may have been derived from the
the nitroaldol reactions we used (5 mmol) was different from that reductive amination or acetalization of 1,3-diol or incomplete
˚
used by Nagren (100 mmol). We consider that removing the reduction of nitro-group, were obtained. These side reactions
acidic nitrogen oxides derived from the preparation of 2 by arise from an excess of formaldehyde. Reducing the amount of
NaHCO3 contributes to reducing the required amount of TBAF. formaldehyde in the nitroaldol reaction could suppress these
The reduction reaction of 11C-labeled aliphatic nitro com- side reactions. However, this treatment is likely to affect the
pounds to the corresponding amines was difficult to perform conversion of the nitroaldol reaction, leading to the contamina-
when we applied it to the remote-controlled automation for PET tion of 4. The reduction of a mixture of 4 and 5 would afford
tracer syntheses. Raney Ni in HCOOH and Zn in acidic EtOH are 11C-labeled serinol and 6, but the efficient separation of serinol
effective for the reduction of a nitro group under 11C-labeling and 6 by high-performance liquid chromatography was difficult
conditions.6,15 Hydrogenation under an H2 atmosphere using Pd to achieve. It was better to keep the amount of formaldehyde and
or Pt on carbon is usually chosen under nonradiolabeling therefore another treatment was required. We alternatively
conditions.16 However, a more accessible method that assem- carried out the nitro-group reduction in aqueous methanol14
bles all the necessary reactants easily under mild conditions because we considered that the addition of water might assist
would be preferable for the reduction of the nitro group under the conversion of 6 by the hydrolysis of imine and acetal or by
the 11C-labeling conditions. Recently, we reported that the increasing the stability of Ni2B-NaBH4. In fact, the nitro-group
reduction of a nitro group using Ni2B-NaBH4 could yield amines reduction of 5 with Ni2B-NaBH4 using 60% aqueous MeOH instead
efficiently under 11C-labeling conditions.5,17 The reagent Ni2B– of 100% MeOH improved the decay-corrected radiochemical
NaBH4 is prepared by mixing NiCl2 and NaBH4 in situ, and conversion of 6 to 68.076.5% in two steps (Scheme 1).20,21
gaseous H2 is not required.18 In addition, the reduction reaction
is carried out under neutral conditions and is robust against the
contamination of water. In fact, any isolation process of the
Conclusion
reaction mixture of the nitroaldol reaction was not necessary for The fluoride-assisted nitroaldol reaction of 2 and formaldehyde
the nitro group reduction of 5.6,19 Thus, the reduction reaction was rapid and yielded nitrotriol 5 efficiently. Carbon-11 labeling
was performed by the addition of MeOH to the nitroaldol synthesis of Tris was carried out as an application of 5. The
reaction and then transferred to the next reaction vessel preparation of 2 using a rubber heater is convenient compared
J. Label Compd. Radiopharm 2011, 54 140–144
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

K. Kato et al.
with that using a furnace. The reduction by Ni2B–NaBH4 is facile
and yields the corresponding amine very efficiently under
11C-labeling conditions. We believe that the technical and
synthetic improvements described in this paper solve the
problems that hamper the utility of 2 as an 11C-labeling agent.
We anticipate that the procedures described in this paper will
allow 11C-labeling synthesis using 2 to become more accessible.
Label. Compd. Radiopharm. 1992, 31, 891–901; c) K.-O. Schoeps,
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Nucl. Med. Biol. 1993, 20, 669–678.
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49, 5837–5839.
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Acknowledgements
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This work was supported in part by a consignment grant for the
Molecular Imaging Program on Research Base for PET Diagnosis
from the Ministry of Education, Culture, Sports, Science and
Technology of the Japanese Government. We thank the staff of
the Cyclotron Operation and Radiochemistry sections for
technical support in using radio isotopes. We are also indebted
to Dr Ryuji Nakao and Mr Takehito Ito for their assistance with
the LCMS analysis.
[11] In a former report, attaching a column containing K2CO3 was
effective for trapping nitrogen oxides. However, most of radio-
activity was absorbed in K2CO3 and we could not obtain 1 in this
institute.
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