Microwave-accelerated fluorodenitrations and nitrodehalogenations: expeditious routes to labeled PET ligands and fluoropharmaceuticals

Article abstract of DOI:10.1016/j.tetlet.2010.02.042

Methods for the expeditious fluorination of arenes have been investigated, using readily available fluoride sources. An optimized procedure for microwave-accelerated fluorodenitration has been developed, giving good to excellent yields in less than 10 min, rendering it practical for use in the preparation of F¹⁸ labeled ligands for PET imaging. Application of the method in the synthesis of CNS agents is demonstrated, and a practical method for the preparation of substrates is also presented.

Full text of DOI:10.1016/j.tetlet.2010.02.042

Tetrahedron Letters 51 (2010) 1906–1909
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-accelerated fluorodenitrations and nitrodehalogenations:
expeditious routes to labeled PET ligands and fluoropharmaceuticals
Paul LaBeaume, Michael Placzek, Mathew Daniels, Ian Kendrick, Patrick Ng, Melissa McNeel,
Roushan Afroze, Abigail Alexander, Rhiannon Thomas, Amy E. Kallmerten , Graham B. Jones
*
Bioorganic and Medicinal Chemistry Laboratories, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Methods for the expeditious fluorination of arenes have been investigated, using readily available fluo-
ride sources. An optimized procedure for microwave-accelerated fluorodenitration has been developed,
giving good to excellent yields in less than 10 min, rendering it practical for use in the preparation of
Received 24 December 2009
Revised 3 February 2010
Accepted 5 February 2010
Available online 11 February 2010
F
18 labeled ligands for PET imaging. Application of the method in the synthesis of CNS agents is demon-
strated, and a practical method for the preparation of substrates is also presented.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Fluorodenitration
Microwave
F18
PET
Haloperidol
Donepezil
Nitrodehalogenation
1. Introduction
of end product. Cyclotron chemistry makes 18Fꢀ available rou-
tinely, so we opted to investigate microwave-mediated fluoroden-
itration of substrates using commonly available fluoride sources
under a variety of conditions. Fluorodenitration of 1 and heterocy-
clic variants has been reported using a range of different condi-
tions, principal limitations being the need for highly activated
substrates and degradation of desired products 2 into the phenols
3 (Scheme 1).7 Kuduk reported facile fluorodenitration of cyano-
pyridine 4 using a reagent grade TBAF but in the case of 5, using
dry TBAF observed conversion to phenol 6.8 In a series of reports,
DiMagno describes remedy in the use of specially prepared anhy-
drous (as opposed to spray dried) TBAF, which promotes facile flu-
orodenitration of a range of substrates including unactivated
arenes such as 7.9 Prior to this work, a traditionally exploited route
Methods for the introduction of fluorine into arenes and hetero-
arenes are significant components of contemporary medicinal
chemistry due to its often striking physicochemical and metabolic
impact on drug candidates.1 A large number of blockbuster agents
possess the fluoroarene motif ranging from antimicrobials (e.g.,
Ciprofloxacin), antifungals (e.g., Diflucan), CNS agents (e.g., Halo-
peridol, Risperidone) to antimetabolites (e.g., Fludarabine), and
statins (e.g., Lipitor).2 Interest in the development of fluorination
methodologies has been bolstered with the advent of positron
emission tomography (PET) imaging, and the attractiveness of F18
labeled ligands (e.g., Fluorodeoxyglucose—‘FDG’).3
Given the F18 t1/2 (119 min) efficient synthetic methodologies
are required, which has served to limit the scope of ligand develop-
ment.4 We became interested in developing expeditious methodol-
ogy for fluorodenitration of arenes using microwave-accelerated
processes, a field which has grown considerably in recent years,5
and which we have enjoyed success with a variety of transforma-
tions.6 To be generally useful for the preparation of F18 labeled
ligands, methodology needs to be robust, efficient in terms of
chemical and radiochemical yield, and allow effortless purification
O
H2O
O
F
NO2
OH
N
R
R
R
F
OH
(M) F
2
3
1
NO2
N
OH
CN
NO2
CN
NC
NO2
N
N
CN
7
6
* Corresponding author. Tel.: +1 617 373 8619; fax: +1 617 373 8795.
E-mail addresses: gr.jones@neu.edu, grjones@lynx.neu.edu (G.B. Jones).
2009 M. J. Collins Innovation Awardee (CEM Corp).
5
4
Scheme 1. Fluorodenitration pathways using nucleophilic fluoride sources.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.042

P. LaBeaume et al. / Tetrahedron Letters 51 (2010) 1906–1909
1907
involved the use of dried KF in combination with K2CO3 and the
phase transfer agent 4,7,13,16,21,24-hexa-oxa-1,10-diazabicy-
clo[8.8.8]-hexacosane (Kryptofix 222).7 In an attempt to achieve
a degree of consistency, and with a view to developing micro-
wave-based protocols for the production of radiolabeled variants
(which might be subsequently amenable to automated production
methods) we studied a number of substrates using three represen-
tative conditions (Chart 1).10
experiments using cyclotron generated 18Fꢀ/K222 a radiochemical
yield of >75% was attained with substrate 11 on a preparative scale.
In cases where low yields of fluorinated product 2 were obtained
using method B, the balance of material (up to 95%) was the de-
rived phenols 3, advocating the need for specially prepared anhy-
drous TBAF (method C).
With economic and expeditious routes to fluoroarenes secured,
we wished to highlight application of the method with a synthesis
F
O
N
F
F
F
COOH
F
N
N
N
N
N
OH
N
N
O
OH
O
HN
N N
N
N
N
O
Cl
Ciprofloxacin
Haloperidol
Diflucan
Risperidone
A series of activated heteroarene and bicyclic arene substrates
were assessed to evaluate and compare reaction times, in most
cases resulting in smooth conversion to the fluorinated product
in less than 10 min (cf. up to ꢁ4 h using conventional heating) as
shown in Chart 1. Though the ready availability of KF in 18F labeled
form is to be noted (relevant to method A), the most reproducible
results were with anhydrous TBAF (method C) and the availability
of conventionally prepared 18F TBAF bodes well for cases where
methods B and C are comparable.11 Reactions are routinely con-
ducted on 100 mg scale, however the scalability of the process
was confirmed with preparative scale versions using substrates
10–15 giving equivalent yields.12 Additionally, in preliminary
of an
F
19-substituted CNS agent, and selected HaloperidolÒ
(Scheme 2). The original Janssen route to this commonly pre-
scribed anti-psychotic involves late-stage coupling of a substituted
piperidine onto an
stration of proof of concept, the corresponding nitroacylarene 35
was prepared by Pd-mediated alkyl coupling followed by deprotec-
tion of the TBS-protected iodoalkane, which was then subjected to
amination with 37 via mesylate 36 (Scheme 2).14 Finally, the key
microwave-mediated fluorodenitration of 38 was investigated.
Using the KF/K222 in DMF, ether linked side products were formed
contributing to the moderate yields of product attained (ꢁ25%).
x
-chlorinated flouroarene.13 For the demon-
NO2
NO2
NO2
NO2
NO2
O
H
CN
10
9
8
N
COOH
COOMe
13
11
12
A= <5 %
A= 65%
B= 5%
CHO
A= <5 %
B= >95 %
A= <5 %
A= <5 %
B= >95 %
A= 20%
NO2
B= 50%
NO2
15
NO2
NO2
O
NO2
CHO
NO2
N
COOMe
N
COOH
14
A= >95 %
B= 85 %
16
18
17
19
A= 30%
B= <5 %
COMe
B= <5 %
CO2Me
B= <5 %
NO2
B= <5 %
B= <5 %
NO2
O
O
O
NO2
NO2
NO2
NO2
CN
NO2
23
32
20
22
A= <5 %
B= > 95%
C= > 95%
CF3
21
B= 29 %
C= >95 %
NO2
B= <5 %
B= ~5 %
B= 93 %
NO2
OCH3
25
27
NO2
24
NO2
Cl
N
26
Br
N
N
NO2
NO2
33
H
N
CN
C= >95%
C= >95 %
C= > 95 %
C= > 95%
NO2
A= 57 %
B= <5 %
C= >95 %
NO2
F
F
NO2
NO2
29
N
CN
30
Cl
Cl
28
Legend (all MW, 10 min)
31
F
F
CO2Me
C= > 95 %
A = KF/K222/ DMF or DMSO
B = TBAF, THF or DMSO
C= TBAF(anhyd), THF or DMSO
NO2
C= >95 %
CN
C= > 95 %
C= > 95 %
Chart 1. Comparative fluorodenitrations.

1908
P. LaBeaume et al. / Tetrahedron Letters 51 (2010) 1906–1909
O
O
I
OTBS
(47%)
1.
2.
OH
Zn/Cu, Pd(PPh3)4
Cl
(74%)
35
TBAF, THF
O2N
34
O2N
Ms-Cl, Et3N
0oC
Haloperidol
160oC
(84%)
anhydrous
TBAF/DMSO
10 min MW
99% (75%
conversion)
Cl
DMF, Et3N
O
O
OH
OMs
Cl
HO
N
37
(55%)
HN
O2N
38
O2N
36
Scheme 2. Synthesis of haloperidol through microwave halodenitration.
O
NO2
O
H
O
O2N
MeO
MeO
MeO
MeO
LDA, THF
HMPA
(30%)
N
N
40
41
39
O
F19
130 C 5min MW
anhydrous TBAF/DMSO
65% (40% conversion)
MeO
MeO
N
42
Scheme 3. Microwave-accelerated denitration route to fluorinated donepezil analogues.
Table 1
With the conventional TBAF in THF yields of up to 30% could be ob-
tained on prolonged heating (2 min heat/2 min pause cycles over a
30-min period). However, using anhydrous TBAF very clean con-
version to the desired product was effected within minutes, with
30% conversion within 3 min and 75% within 10 min (2 min heat/
2 min pause cycles). Given the importance of this agent, it is thus
expected that a route to the corresponding F18 labeled PET ligand
can be developed using the methodology outlined herein. Though
instructive, we also wished to demonstrate fluorodenitration in a
non-activated substrate and developed a synthesis of a fluorinated
analogue of the acetyl cholinesterase inhibitor donepezil (Scheme
3).15 Coupling of the enolate derived from 40 with 39 afforded ad-
vanced intermediate 41, which underwent fluorodenitration using
anhydrous TBAF to give analogue 42 in good yield within 5 min
(followed by 5-min pause cycle).
Microwave-accelerated Cu-catalyzed nitrodehalogenations
O2N
Br
20 min. 25%
(85%)
N
N
H
H
X
R
Time (min)
Yield (%)
Conventional (21–27 h) (%)
I
I
I
I
I
I
I
I
I
4-MeO
4-Me
3-MeO
H
3-Me
H
3-Me
4-CF3
2-Pyridine
17
20
20
16
20
1
1
15
10
88
50
84
85
84
58
49
10
15
81
25
65
65
69
65
69
ꢁ5
ꢁ5
With the microwave-mediated fluorodenitration process estab-
lished, we have also begun to investigate methods for the introduc-
tion of the key leaving group. Based on observed leaving group
patterns of I > F > NO2, we were motivated to investigate micro-
wave-accelerated nitro de-iodination, and have subsequently iden-
tified conditions which are far superior to the conventional
thermolyses in terms of both time and conversion efficiency
(Scheme 4).16 Using a range of substrates, the process is effective
in <20 min (all uninterrupted heating cycles) to give a variety of
useful building blocks (Table 1), which makes the prospect of
transformations of I > F feasible in labeling studies. This is espe-
cially relevant in cases where one needs to study under SPECT
and PET imaging methods, where the 123I/125I and 18F counter-
parts are obvious choices. The conditions are also applicable for
the preparation of 5-nitroindoles, key building blocks for CNS
agents, from the corresponding bromo substrate. The yield based
on recovered substrate (85% at 20 min) suggests considerable opti-
mization may be possible, making the sequence Ar-Br?Ar-F a
practical, two-step possibility.
2. Representative procedures
2.1. 4-Nitroanisole
H
N
N
H
R
nBu4NNO2, DMF
R
NO2
X
4-Iodoanisole (0.0581 g, 0.25 mmol), copper powder (0.0095 g,
0.15 mmol), and tetrabutylammoniumnitrite(0.1442 g, 0.50 mmol)
were added to a flame-dried 14 ꢂ 86 mm (OD) glass microwave tube
Cu powder, MW 110oC
Scheme 4. Microwave-accelerated nitrodeiodinations.

P. LaBeaume et al. / Tetrahedron Letters 51 (2010) 1906–1909
1909
and charged with argon. Freshly distilled DMF (0.5 mL) was added
References and notes
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column chromatography (9:1 hexanes/ethyl acetate) and concen-
trated in vacuo to yield the title compound (0.0330 g, 88%) as a
yellow oil.
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We thank the Alzheimer’s Drug Discovery Foundation (ADDF)
and the Institute for the Study of Aging (ISOA) Inc. for financial
support of this work (project #281004).
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