Microwave accelerated three-component fluoroalkylations: Expeditious routes to fluoropharmaceuticals and PET ligands

Article abstract of DOI:10.1016/j.tetlet.2010.11.056

One-pot three-component coupling methods have been developed to allow in situ preparation of fluoroalkylated arenes and hydrocarbon chain analogs. The methods, which are accelerated under microwave irradiation gives access to ω-fluorinated alkyl, alkenyl, and alkynyl substituted arenes from readily available precursors. The methods involve late stage introduction of the fluorine and are well suited to application in the synthesis of ¹⁸F labeled PET imaging agents.

Full text of DOI:10.1016/j.tetlet.2010.11.056

Tetrahedron Letters 52 (2011) 332–335
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave accelerated three-component fluoroalkylations: expeditious routes
to fluoropharmaceuticals and PET ligands
Michael Placzek, Paul LaBeaume, Luke Harris, Patrick Ng, Mathew Daniels, Amy 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:
One-pot three-component coupling methods have been developed to allow in situ preparation of fluor-
oalkylated arenes and hydrocarbon chain analogs. The methods, which are accelerated under microwave
Received 7 October 2010
Revised 5 November 2010
Accepted 10 November 2010
Available online 18 November 2010
irradiation gives access to
x-fluorinated alkyl, alkenyl, and alkynyl substituted arenes from readily avail-
able precursors. The methods involve late stage introduction of the fluorine and are well suited to appli-
cation in the synthesis of 18F labeled PET imaging agents.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Fluoroalkylation
Microwave
18F
PET
Sonogashira
Negishi
Heck
Hiyama
1. Introduction
and BMS747158-02, which were developed for myocardial perfu-
sion imaging,6 the
a4b2 nicotinic receptor targeted nifrolidine
Fluorination methods are important aspects of contemporary
medicinal chemistry due to the often striking physicochemical
and metabolic properties of fluorinated drug candidates.1 In addi-
tion to the growing number of fluorinated blockbuster drugs,2
development of fluorination methodologies has been bolstered
by the use of 18F labeled ligands in positron emission tomography
(PET) imaging (e.g., Fluorodeoxyglucose—‘FDG’).3 Given the 18F t1/2
(119 min) to be generally useful, fluorination methods need to be
robust, efficient in terms of chemical and radiochemical yield,
and allow effortless purification of the end product.4 We recently
demonstrated a microwave accelerated fluorodenitration process,
and applied the methodology to the synthesis of a number of fluo-
rinated CNS agents.5 Though a number of aryl fluorination methods
are available, they are far more restricted for fluoroalkanes, typi-
cally limited to late stage nucleophilic displacement of tosyloxy
groups.4 Expanding the repertoire of available methods would be
of benefit, as a growing number of pre-clinical and investigation
agents for PET imaging possess (18F) fluoroalkyl chains. These in-
clude the mitochondrial complex 1 (MC-1), inhibitors RP1005,
and the dopamine receptor targeting agent fallypride,7 both of
which are used in Alzheimers disease (AD) PET imaging studies.8
A key to developing CNS targeted imaging agents is optimizing
lipophilicity of the drug to maximize blood brain barrier penetra-
tion (and, conversely for cardiovascular agents) and this typically
requires re-synthesis, as the addition of even a single methylene
spacer can have a profound impact on transport properties.6 With
this backdrop we have been investigating means to develop effi-
cient coupling methods, which (1) allow effective coupling of func-
tionalized hydrocarbon chains onto readily available arenes (2)
where chain length and hybridization can be modified at ease
and (3) where the 18F can be introduced in situ at the final stage
of the process.
We were initially drawn to reports from the Fu laboratories
wherein conditions for Pd/phosphine mediated Hiyama cross-cou-
plings of trialkoxysilanes are effective with alkyl halides but alkyl
tosylates are poor electrophiles.9 Given that fluoride can be used
to catalyze the Hiyama reactions, we envisioned that
a–x bromo
tosylates would be excellent substrates for a three component cou-
pling, involving in situ fluoride exchange on the coupled aryl-alkyl
tosylate as a final step. Additionally routes to 18F TBAF and its func-
tional equivalents are available,10 as is a route to the powerfully
nucleophilic anhydrous TBAF.11 Initial results using test substrates
⇑
Corresponding author. Fax: +1 617 373 8795.
E-mail address: gr.jones@neu.edu (G.B. Jones).
2009 M. J. Collins Innovation Awardee (CEM Corp).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.056

M. Placzek et al. / Tetrahedron Letters 52 (2011) 332–335
333
O
O
O
Cl
N
N
F
O
S
F
O
BMS 747158-02
RP 1005
H
H
N
O
N
O
OMe
OMe
F
N
H
F
N
Nifrolidine
Fallypride
triethoxysilane (1) with tosyloxy 6-bromohexanol (2) were prom-
ising (Scheme 1) providing proof of principle for the strategy
which, under pressing conditions were giving appreciable yields
of product 4 (Table 1).12 Traces of byproduct (<5%) stemming from
elimination to form 5 were observed at extended reaction times
(>5 min), and the coupled tosylate 3 at lower reaction times
(<2 min.), but the major product in all cases was the desired fluo-
roalkane 4. Control reactions using conventional thermal heating
underscored the microwave effect—for example, entry 1, whose
counterpart thermal reactions take >12 h to achieve comparable
yield at room temperature.9
Optimal temperature was 80 °C (entry 3) and increasing
catalyst loading led to yet higher conversions (cf. entries 6–7). As
expected, reactions were equally effective using 6-fluoro-1-bromo-
hexane as the substrate. Though encouraging, practical consider-
ations stemming from the need to introduce the trialkoxysilane
group in late stage syntheses and the air sensitivity of the catalytic
cycle led us to pursue variants (vide infra).
We next turned attention to vinyl linked fluoroalkyls and inves-
tigated conditions for Heck type coupling (Scheme 2).13 Iodoben-
Si(OEt)3
PdBr2
P(tBu)2MeBF4
MW 2 min.
Bu4NF THF
Table 2
Br
TsO
Heck cross-coupling fluorinationsa
1
TsO
2
3
Entry
5 (R)
Temp (°C)
Time (min)
Yield 7%
Yield 8%
1
2
3
4
5
6
7
8
9
H
100
90
90
15
5
5
35
52
48
56
24
0
22
47
45
43
9
4
5
2-MeO
3-MeO
4-MeO
2-MeCO
3-MeCO
4-MeCO
2-NH2
3-NH2
4-NH2
+
90
5
5
F
100
100
100
100
100
100
40
40
40
15
15
15
12
10
9
13
11
9
5
4
Scheme 1. Tandem Hiyama coupling route to aryl fluoroalkanes.
10
Table 1
Tandem Hiyama cross-coupling fluoroalkylationsa
a
Reactions used 2 equiv TBAF and 6 in 1,4-dioxane, 0.05 equiv Pd cat and
0.1 equiv phosphine. E/Z ratios of 7–8:1.
Entry
% Pd cat
Time (min)
Temp (°C)
%Yield 4
1
2
3
4
5
6
7
8
10
10
10
10
10
20
30
30
2
2
2
2
2
2
2
5
60
70
80
90
110
80
51
55
61
45
14
76
87
85
I
Pd(PPh3)2Cl2
CuI, Et3N
MW
Bu4NF THF
R
TosO
R
9
10
11
80
80
F
a
Scheme 3. Tandem Sonogashira coupling route to aryl fluoroalkynes.
Reactions used 2 equiv TBAF in THF with 2.5 equiv phosphine.
I
Ni(PPh3)2Cl2
Zn dust, DMA
then TBAF, MW
Cl
I
Pd(OAc)2
13
F
7
12
R
R
Br
Cl
P(o-tol)3
(iPr)2NEt
TBAF
5
R
Tos
6
15
8
14
F
Scheme 2. Tandem Heck coupling route to aryl fluoroalkenes.
Scheme 4. Tandem Negishi coupling-fluorination.

334
M. Placzek et al. / Tetrahedron Letters 52 (2011) 332–335
O
O
O
Cl
Br
Cl
DMA, I2, Zn
Ni(PPh3)2Cl2 MW 80oC 10 min
O
S
S
RP1005
then TBAF 125o C 10 min
I
17
16
Scheme 5. Negishi coupling route to RP 1005.
DMA, I2, Zn
Ni(PPh3)2Cl2 MW 80oC 10 min
O
Br
18
O
F
Cl
N
N
Br
H
then TBAF 125o C 10 min
Boc
19
N
N
then TFA 125o C 10 min
Scheme 6. Negishi coupling route to nifrolidine homolog.
scope, using this initial screening, suggests that this could develop
into a widely applicable strategy for a range of arene and heteroa-
rene substrates, and is worthy of fuller optimization, though it is evi-
dent that subtle variations in reactions temperature or reaction time
have a marked impact on product yield (entries 4–6). Given the
initial success of the tandem coupling procedures, we became inter-
ested in application of the technology to synthesis of fluorinated
medicinal agents. Using RP1005 and nifrolidine as benchmarks, in
order to form fluoroalkyl derivatives it is evident that re-tooling of
the original syntheses is required in order to install the requisite
siloxane for the Hiyama coupling. Given the availability of haloge-
nated intermediates in the synthesis of these agents, an alternate
coupling in the form of the Negishi process was investigated
(Scheme 4).15 In this, a bromo-chloroalkane would be coupled and
subjected to in situ halogen exchange via microwave irradiation.
Using iodobenzene as the test substrate under standard condi-
tions, within 10–15 min 4-chloro-1-bromobutane coupled to form
intermediate 13, which was subjected to in situ fluorination to give
14 with appreciable conversion, together with varying quantities
of elimination product 15 (Table 4). Elevated temperatures re-
sulted in increase in elimination, optimal conditions being 80 °C
with 2 equiv of TBAF. Direct halex displacement from isolated
intermediate 13 was effective and the tandem one pot sequence
proved comparable to the Hiyama process, and could be conducted
without the need for glove box handling.16
With the conditions developed, we were able to apply immedi-
ately to the synthesis of RP 1005. Iodoarene intermediate 16
underwent Negishi coupling to give 17 and was followed by
in situ halex fluorination to give the desired product in moderate
yield (ꢀ20% over two steps) in a one pot process (Scheme 5).6
Though substantially higher yields are attainable through optimi-
zation with these substrates (cf. Table 4) we were motivated to
identify conditions that minimize the formation of alkene (elimi-
nation) byproducts, to make the process more amenable to an
18F labeled variant for PET imaging, sequential introduction of
TBAF for example minimizing elimination products. In a similar
vein, an advanced intermediate in the synthesis of nifrolidine,
the readily available pyridyl bromide 18, was coupled successfully
to give, following fluorination and in situ deprotection, the four
carbon chain nifrolidine analog 19 in good yield (35% over three
steps based on 18) as shown in Scheme 6.7
Table 3
Sonogashira cross-coupling fluorinationsa
Entry
9
Temp
Time
Yield 11
1
2
3
4
5
6
7
8
9
H
50
70
70
70
90
70
70
70
70
70
70
70
10
10
10
10
10
15
10
10
10
10
10
10
86
93
88
91
62
86
79
82
73
90
91
89
2-CH3CO
3-CH3CO
4-CH3CO
4-CH3CO
4-CH3CO
2-MeO
3-MeO
4-MeO
2-iodopyridine
3-iodopyridine
4-iodopyridine
10
11
12
a
Reactions used 2 equiv TBAF, 1.1 equiv 10 (9:1 THF/Et3N) with 0.05 equiv Pd
and Cu cat.
Table 4
Tandem Negishi cross-coupling fluorinationsa
Entry
Temp (°C)
Time (min)
TBAF (equiv)
%Yield 14
%Yield 15
1
2
3
4
5
6
7
8
9
70
80
15
5
2
2
63
54
62
65
55
52
53
59
56
22
10
8
80
80
80
90
10
15
20
5
2
2
2
2
11
11
18
15
14
17
15
25
90
90
100
100
10
15
15
10
2
2
2
3.5
10
a
Reactions used 2 equiv 12, 0.1 equiv I2, 3 equiv Zn in DMA, with 0.05 equiv Ni
cat.
zene was effective under forcing conditions but moving to an acti-
vated substrate led to appreciable conversion to the fluorinated
product 7 (Table 2, entries 2–4). Elevated temperatures and reac-
tion times led to increased formation on elimination product 8,
but in most cases the balance of material was recovered. Arene 5,
which for subsequent radiolabeling purposes (using 18F TBAF)
can be easily separated from the desired product chromatographi-
cally. Electron deficient substrates were inferior substrates and
anilines moderately effective at higher temperatures and extended
reaction times (entries 5–10) warranting additional investigation.
In summary, methods have been developed for in situ fluor-
oalkylation, fluorovinylation, and fluoroalkynylation of arenes.
The methods, which exploit microwave heating,17 give good yields
with short reaction times, and provides a potentially attractive
route for the preparation of 18F labeled radiopharmaceuticals.4 To
this end, one of the methods has been applied to two classes of
PET image contrast agents of current interest.
Finally
a series of Sonogashira couplings were developed
(Scheme 3).14 Various iodoarenes 9 were coupled with tosyloxy sub-
strate 10, giving appreciableconversion to products 11 (Table 3). The

M. Placzek et al. / Tetrahedron Letters 52 (2011) 332–335
335
8. Kallmerten, A. E.; Jones, G. B. Curr. Alzheimer Res. 2010, 7, 251.
9. Lee, J.-Y.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 5616.
Acknowledgment
10. Kim, D. W.; Jeong, H. J.; Lim, S. T.; Sohn, M. H. Angew. Chem., Int. Ed. 2008, 47,
8404.
11. Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050; Sun, H.; DiMagno, S.
G. Angew. Chem., Int. Ed. 2006, 45, 2720.
12. All compounds were fully characterized by appropriate spectroscopic and
analytical techniques.
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).
13. Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442.
14. Sonogashira, K.; Tohda, T.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467.
15. Smith, S. W.; Fu, G. C. Angew. Chem., Int. Ed. 2008, 47, 9334.
16. Attempts to utilize with 3 and 2 carbon chain substrates was as expected
unsuccessful, resulting in formation of cyclopropane and ethane, respectively.
The scope of this and the related Hiyama, Sonogahsira, and Heck type
couplings will be reported in a full account of this work. For synthesis of 19
iodine and zinc dust are added to degassed solution of bromochlorobutane
(DMA), heated to 80 °C for 3.5 h and cooled to 25 °C. A degassed solution of 18
in DMA is added (cannula) then Ni(PPh3)2Cl2, and the mixture irradiated
(80 °C,10 min). TBAF (1 M, THF) is directly injected, the mixture irradiated
(125 °C, 10 min) then TFA added and re-irradiated (125 °C, 10 min). The
mixture is diluted (DCM), poured onto Na2CO3 (satd soln), extracted (DCM),
dried (MgSO4), concentrated in vacuo and purified by chromatography.
17. (a) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38, 653; (b) Kappe, C. O.
Angew. Chem., Int. Ed. 2004, 43, 6250; (c) Larhed, M.; Moberg, C.; Hallberg, A.
Acc. Chem. Res. 2002, 35, 717; (d) Kuhnert, N. Angew. Chem., Int. Ed. 2002, 47,
1863; (e) Avery, K. B.; Devine, W. G.; Kormos, C. M.; Leadbeater, N. E.
Tetrahedron Lett. 2009, 50, 2851.
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