Nucleophile assisting leaving groups: A strategy for aliphatic 18F-fluorination

Article abstract of DOI:10.1021/jo900700j

(Chemical Equation Presented) A series of arylsulfonate nucleophile assisting leaving groups (NALGs) were prepared in which the metal chelating unit is attached to the aryl ring via an ether linker. TheseNALGs exhibited significant rate enhancements in halogenation reactions using metal halides. Studies with a NALG containing a macrocyclic ether unit suggest that rate enhancements of these nucleophilic halogenation reactions are facilitated by stabilization of charge in the transition state rather than through strong precomplexation with metal cation. In several cases, a primary substrate containing one of the new leaving groups rivaled or surpassed the reactivity of triflates when exposed to nucleophile but was otherwise highly stable and isolable. These and previously disclosed chelating leaving groups were used in ¹⁸F-fluorination reactions using no-carrier-added [ ¹⁸F]fluoride ion (t_1/2 = 109.7 min, β⁺ = 97%) in CH₃CN. Under microwave irradiation and without the assistance of a cryptand, such as K2.2.2, primary substrates with select NALGs led to a substantial improvement (2-3-fold) in radiofluorination yields over traditional leaving groups.

Full text of DOI:10.1021/jo900700j

pubs.acs.org/joc
Nucleophile Assisting Leaving Groups: A Strategy for Aliphatic
18F-Fluorination
Shuiyu Lu,*,† Salvatore D. Lepore,*,‡ Song Ye Li,‡ Deboprosad Mondal,‡
Pamela C. Cohn,‡ Anjan K. Bhunia,‡ and Victor W. Pike†
†Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health,
Bethesda, Maryland 20892-1003, and ‡Department of Chemistry, Florida Atlantic University,
Boca Raton, Florida 33431
slepore@fau.edu; shuiyu.lu@mail.nih.gov
Received April 4, 2009
A series of arylsulfonate nucleophile assisting leaving groups (NALGs) were prepared in which the
metal chelating unit is attached to the aryl ring via an ether linker. These NALGs exhibited significant
rate enhancements in halogenation reactions using metal halides. Studies with a NALG containing a
macrocyclic ether unit suggest that rate enhancements of these nucleophilic halogenation reactions
are facilitated by stabilization of charge in the transition state rather than through strong
precomplexation with metal cation. In several cases, a primary substrate containing one of the
new leaving groups rivaled or surpassed the reactivity of triflates when exposed to nucleophile but
was otherwise highly stable and isolable. These and previously disclosed chelating leaving groups
were used in 18F-fluorination reactions using no-carrier-added [18F]fluoride ion (t1/2 =109.7 min,
βþ=97%) in CH3CN. Under microwave irradiation and without the assistance of a cryptand, such as
K2.2.2, primary substrates with select NALGs led to a substantial improvement (2-3-fold) in
radiofluorination yields over traditional leaving groups.
Introduction
neutral precursor ligand B (Scheme 1).4 Depending on the
specific nucleophilic reaction mechanism, metal chelation in
the transition state should reduce the energy of activation (Ea1)
of NALG substrates relative to substrates containing tradi-
tional leaving groups. Without the added stabilizing effect of
nucleophilic salt chelation with a nearby multidentate ligand,
the energy of activation (Ea2) for reactions involving tradi-
tional leaving groups (leading to a transition state such as D) is
expected to be higher (Ea2>Ea1).
Our initial arylsulfonate NALG design E consisted of an
oligoether (also macrocyclic) unit connected to the aryl ring
ortho to the sulfonate via an ester linking unit (Scheme 1).
NALGs E were prepared in one pot starting from very low
cost materials and proved to be useful leaving groups in a
number of reactions1,2,5 and in a recent total synthesis.6
We have previously reported on the development of new
chelating leaving groups capable of facilitating nucleophilic
reactions involving metal salts1 and titanium(IV) complexes.2
We have termed such groups nucleophile assisting leaving
groups (NALGs), arguing that the rate enhancement afforded
by these designed leaving groups is primarily due to stabilizing
interactions with a metal-nucleophile pair in the course of a
reaction to lower the transition state energy of the rate-limiting
step.3 Forexample, in the case of substrateA, it is expected that
the negative charge imparted to the leaving group moiety (LG)
by an incoming nucleophile (Nuc-)intransitionstateC should
provide a more favorable chelation complex relative to its
(1) Lepore, S. D.; Bhunia, A. K.; Cohn, P. C. J. Org. Chem. 2005, 70,
8117–8121.
(2) (a) Lepore, S. D.; Bhunia, A. K.; Mondal, D.; Cohn, P. C.; Lefkowitz,
C. J. Org. Chem. 2006, 71, 3285–3286. (b) Lepore, S. D.; Mondal, D.; Li, S.
Y.; Bhunia, A. K. Angew. Chem., Int. Ed. 2008, 47, 7511–7514. (c) Li, S. Y.;
Lepore, S. D. Encylcopedia of Reagents for Organic Synthesis, 2nd ed.; Wiley:
New York, 2008; Vol. 8, pp 6629.
(4) Cacciapaglia, R.; Van Doorn, A. R.; Mandolini, L.; Reinhoudt, D.
N.; Verboom, W. J. Am. Chem. Soc. 1992, 114, 2611–2617.
(5) Braddock, D. C.; Hermitage, S. A.; Kwok, L.; Pouwer, R.; Redmond,
J. M.; White, A. J. P. Chem. Commun. 2009, 1082–1084.
(6) Park, J.; Kim, B.; Kim, H.; Kim, S.; Kim, D. Angew. Chem., Int. Ed.
2007, 46, 4726–4728.
(3) Lepore, S. D.; Mondal, D. Tetrahedron 2007, 63, 5103–5122.
5290 J. Org. Chem. 2009, 74, 5290–5296
Published on Web 07/02/2009
DOI: 10.1021/jo900700j
r
2009 American Chemical Society

Lu et al.
JOCArticle
SCHEME 1. Rationale for Rate Enhancement Observed with
Nucleophile Assisting Leaving Groups (NALGs) and Strategies
for Improvement
TABLE 1. Bromination Reaction Times with 3-Phenylpropyl Substrates
Containing Various Leaving Groups
However, crystal structure studies of these original NALGs
demonstrated that the carbonyl of the ester linker is out of
conjugation with the arylsulfonyl ring.1 We argued that,
since this chelated conformation is not ideal, further nucleo-
philic reaction rate gains might be realized with NALG
systems devoid of the ester carbonyl. Also, the aryl ether
linker in F should possess broader chemical stability than a
carboxyl ester for applications as a leaving group in complex
synthesis. In this report, we describe the synthesis and
nucleophilic reaction performance of new NALGs F where-
by the chelating moiety is connected to an arylsulfonyl ring
by an ether linkage. These new ether-linked NALGs, along
with others that we have previously described, have been
examined for their effectiveness in nucleophilic radiofluori-
nation using K18F for eventual application in preparing
radiotracers for positron emission tomography (PET).
aAll brominations were carried out in acetone-d6 noting the time of
reaction completion by the disappearance of starting material resonance
peaks in the 1H NMR.
Results and Discussion
salt (LiBF4). Our titration curves following known proto-
cols8 clearly established that 1 rapidly chelated the lithium
cation (Scheme 2). Thus, we conclude that the superior
chelating ability of 12-crown-4 over tetraethylene glycol
holds in our NALG systems.
Evidence for Stabilized TS Hypothesis. Our previous stu-
dies with NALG systems suggest their rate of reaction with
metal halides to produce alkyl halides is not heavily depen-
dent on the chelating ability of the ortho-oligoether unit
attached to the leaving group. A useful comparison would be
NALG 1 containing a 12-crown-4 chelating unit with NALG
10, which possesses a linear unit containing the same number
of Lewis basic oxygens (Table 1, entries 6 and 7). The time
required for both substrates to be completely converted to
bromide product 2 indicates that they proceed at very similar
rates despite the substantial difference (103) in their intrinsic
lithium cation chelating abilities.
One explanation for this small rate difference in the
bromination reactions of NALGs 1 and 10 might be that
the 12-crown-4 unit of 1 is hindered from effectively
chelating lithium cation by its arylsulfonate unit. Other
lariat systems have been known to exhibit similar side arm
restrictions relative to their parent crown compounds.7
To explore this possibility, NALG 1 was examined by
1H NMR in the presence of a non-nucleophilic lithium
The lithium cation is expected to be available for chela-
tion of the sulfonate unit of 1 in the transition state since
12-crown-4 is known to hold this cation in a perched rather
than buried position.6 Therefore, we surmise that the failure
of NALG 1 to provide highly superior leaving group ability
over linear NALG systems such as 10 may be due to an
inability of the crown ether to effectively present the lithium
cation in transition states such as C (Scheme 1). Others have
observed a preference for straight-chain chelators (podands)
over crown ethers in nucleophilic processes, arguing that
a chelating macrocycle draws a cation into its cavity and
away from the reactive site.9 Another possibility may be that
the carbonyl group linking the 12-crown-4 unit to phenyl
(8) (a) Cudic, P.; Vigneron, J.-P.; Lehn, J.-M.; Cesario, M.; Prange, T.
Eur. J. Org. Chem. 1999, 10, 2479–2484. (b) Cudic, P.; Kranz, J. K.; Behenna,
D. C.; Kruger, R. G.; Tadesse, H.; Wand, A. J.; Veklich, Y. I.; Weisel, J. W.;
McCafferty, D. G. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 7384–7389.
(9) Lu, T.; Yoo, H. K.; Zhang, H.; Bott, S.; Atwood, J. L.; Echegoyen, L.;
Gokel, G. W. J. Org. Chem. 1990, 55, 2269–2270.
(7) Torun, L.; Robison, T. W.; Krzykawski, J.; Purkiss, D. W.; Bartsch,
R. A. Tetrahedron 2005, 61, 8345–8350.
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SCHEME 2. Evidence for Lithium Chelation with NALG 1
SCHEME 3. Synthesis of Second Generation NALGs
isolated and purified by aqueous workup followed by silica
gel flash chromatography, leading to high isolated yields
(72-88%).
Using 3-phenylpropanol as a model substrate for a
series of reaction rate studies, attempts to form sulfonates
11-18 with DMAP activation were unsuccessful. How-
ever, the conversion of 3-phenylpropanol to the alkoxide
using NaH followed by addition of 4 and DMAP gave
good yields of sulfonates 11-18 (and 11a-18a). This
procedure has also been used with success to form a wide
variety of sulfonates from hindered secondary alcohols.2
Despite the high reactivity of these aryl ether NALGs
toward metal halides, they are remarkably stable com-
pounds. By contrast, triflates (especially primary) are
generally more reactive toward Lewis basic agents and
some are not isolable by silica gel chromatography.
NALG substrates, on the other hand, are easily purified
by flash chromatography and can be stored for extended
periods at room temperature.
In order to easily rank a variety of leaving groups using
room temperature reactions in a convenient solvent such as
acetone, we chose to study bromination reactions of sub-
strates 11-19 to form 3-phenyl-1-bromopropane (2) using
the quite soluble LiBr salt. For ready comparison, we also
examined the brominations of our previously disclosed ester
NALG system (compounds 7-10 and 1)1 under the same
conditions. Despite the near ubiquity of bromination reac-
tions with LiBr, conditions involving even nonhindered
primary tosylate substrates are often quite forcing10 even
with highly polar solvents such as DMF or NMP.11 Indeed,
primary tosylate 5 required 32 h for conversion to the
corresponding bromide 2 in acetone at room temperature.12
Substrate 6 containing the triflate leaving group, which is
considered to be among the best nucleofuges,13 required 2 h
sulfonate in 1 does not afford the conformation mobility
required for the macrocyclic chelating unit to assist in the
nucleophilic reaction. In this regard, the superior flexibility of
our NALGs containing acyclic chelating units may be better
poised to stabilize the growing negative charge in transition
state C despite their poor chelating abilities. Nonetheless, we
surmised that even the acyclic chelator systems would benefit
from a change in linkage to the arylsulfonyl moiety.
New Aryl Ether NALGs. As an alternative to the carbonyl
linker of our previous NALGs, we turned to aryl ether
systems in an effort to develop simple and convenient
chelating leaving groups. Although this type of connection
might diminish the electron-withdrawing capacity of the
arylsulfonyl moiety, it was thought that the Lewis basicity
of the aryl ether oxygen would provide additional chelating
ability, possibly offsetting its negative electronic effect.
Beginning with cheap and commercially available 4-
substituted and 2,4-disubstituted phenols, a series of small
oligoethyleneglycol tosylates were appended to the pheno-
lic hydroxyl group to give aryl ethers 3 in good yields
(Scheme 3). With the para-position blocked by either a
tert-butyl or a fluoro group, the reaction of 3 with chlor-
osulfonic acid initially gave desired product 4 in low yields
(20-40%), most likely due to the formation of a significant
amount of sulfonic acid product. The addition of a chlor-
inating agent (thionyl chloride) significantly improved the
yields, presumably by converting sulfonic acid products
to desired sulfonyl chlorides 4. Intermediates 4 were then
(10) For some recent examples, see (a) Fujita, K.; Yorimitsu, H.;
Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2004, 126, 6776–6783.
(b) Nguyen, T. B.; Castanet, A.-S.; Nguyen, T.-H.; Nguyen, K. P. P.;
Bardeau, J.-F.; Gibaud, A.; Mortier, J. Tetrahedron 2006, 62, 647–651.
(11) For some recent examples, see (a) Rezanka, T.; Sigler, K. Eur. J.
Org. Chem. 2006, 18, 4277–4284. (b) Racouchot, S.; Sylvestre, I.; Ollivier, J.;
Kozyrkov, Y. Yu.; Pukin, A.; Kulinkovich, O. G.; Salaun, J. Eur. J. Org.
Chem. 2002, 13, 2160–2176.
(12) All brominations were carried out in acetone-d6 noting the time of
reaction completion by the disappearance of starting material resonance
peaks in the 1H NMR.
(13) Netscher, T. Rec. Res. Dev. Org. Chem. 2003, 7, 71.
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under the same conditions although other analogous bromi-
nations sometimes entail refluxing in acetone.14
applications in preparing radiotracers for PET. PET is a
powerful imaging modality for clinical research15 and drug
development.16 Fluorine-18 (18F, t1/2=109.7 min) is one of
the most widely used positron-emitting radioisotopes be-
cause [18F]fluoride ion in large quantity and high specific
radioactivity can be made from a cyclotron through the
proton irradiation of 18O-enriched water.17 Nucleophilic
radiofluorination of aliphatic compounds remains an im-
portant labeling method.17,18
A number of strategies have been used to overcome the
inherent limitation of fluoride ion as a nucleophile, including
the use of phase transfer catalysts such as the widely used
amino ether cryptand Kryptofix 2.2.2 (K2.2.2), which serves
tocapture the metalcounterion(generally Kþ) andtoseparate
itfrom[18F]fluoride ion, therebyenhancing itsnucleophilicity.
K2.2.2 must be removed from the final product due to its
toxicity.19 A few recent reports describe successful fluori-
nation strategies that involve a significant deviation from
the widely used and standard 18F-, K2.2.2-Kþ/CH3CN con-
ditions.17 These include tert-butylammonium fluoride20
(TBAF) in tertiary alcohol solvents21 and KF with imidazo-
lium ionic liquids.22 However, we reasoned that a well-de-
signed leaving group may obviate the need for cryptand and
solvent substitutions relative to the 18F-, K2.2.2-Kþ/CH3CN
system while still achieving rapid 18F-incorporation.
Our initial studies involved the use of the NALG esters of
3-phenylpropanol. However, the fluorination product
proved too volatile (bp=70 °C/10 mmHg) for convenient
handling in our radiosynthesis apparatus, where the reaction
was heated for 5ꢀ2 min at 90 W (reaching 130 °C) under
microwave condition or at 130 °C for 10 min under thermal
condition. Thus we prepared analogues of compounds 1, 5,
7-11, 13, 16, and 19 containing a 4-tert-butyl group on the
phenyl ring (Table 2). As expected, radiofluorinated product
20, resulting from the tert-butyl containing substrates, was
far easier to handle and measure.
In general, the bromination reaction of NALGs 11-13
containing a tert-butyl group para to the oligoethylene oxide
chelating unit (Table 1, entries 8-10) reacted more slowly
than their ester analogues (entries 3-5). This modest rate
decrease was likely due to the fact that both the tert-butyl and
ether linkage in 11-13 release electron density into the
arylsulfonyl ring, destabilizing partial negative charge of
the sulfonate leaving group in the transition state. These
experiments also indicate that the carbonyl unit in NALGs
such as 7-10 likely contributes a modest electron-withdraw-
ing effect even though our previous crystallographic studies
demonstrated that the carbonyl lies orthogonal to the plane
of the aryl ring.1
As observed in our previous studies with ester NALGs,1
an increase in the number of ether oxygens of the NALG side
arm translates into stepwise increases in the rate of bromina-
tion. In each series (Table 1), 7-10, 11-13, 14-16, and
17-18, addition of the second ethylene oxide unit exerts the
greatest rate enhancement, leading to between double and
triple the reaction rate. However, the addition of a fourth
ethylene oxide unit gives only a relatively moderate rate
enhancement (compare 9 and 10).
Our original hypothesis that reaction rate gains would
result from the replacement of a carboxyl linker with an ether
does not appear to be supported by our data. Nonetheless,
we reasoned that the more robust aryl ether NALG could be
made practical through the introduction of electron-with-
drawing groups to offset the electron-donation property of
the ether linker. Indeed, the introduction of fluoro groups
(NALGs 14-18) led to substantial gains in the bromination
reaction rate relative to tert-butyl NALGs (11-13). The
combination of one or two fluoro groups with a chelating
arm of three ethylene glycol units, NALGs 16 and 18 (entry
15), led to a reaction rate nearly 20 times greater than that of
tosylate 5 and equivalent to that of triflate 6.
In the three aryl ether series of compounds (Table 1), 11-
13, 14-16, and 17-18, the rate of bromination is influenced
by the substituent on aromatic ring meta to the sulfonyl
group and follows the order: tert-butyl<mono-F<di-F. As
may be expected, an electron-donating group reduces
while an electron-withdrawing group accelerates the rate of
bromination.
Typical 18F radiosynthesis procedures call for the use of
M18F obtained by adding poorly nucleophilic and weak
bases to the proton-irradiated [18O]water.23
In our previous work, we demonstrated that NALGs
1 containing a 12-crown-4 moiety exhibited a substantial
rate enhancement with lithium halide salts over sodium or
(15) (a) Czernin, J.; Phelps, M. E. Annu. Rev. Med. 2002, 53, 89–112.
(b) Wagner, H. N. J. Nucl. Med. 1991, 32, 561–564.
(16) (a) Comar, D., Ed. PET for Drug Development and Evaluation. In
Developments in Nuclear Medicine, No. 26; Kluwer Academic Publishers:
Dordrecht, The Netherlands, 1995. (b) Burns, H. D.; Hamill, T. H.; Eng, W. S.;
Francis, B.; Fioravanti, C.; Gibson, R. E. Curr. Opin. Chem. Biol. 1999, 3, 388–
394.
We recently described stereoretentive halogenation and
azidation reactions using Ti(IV) reagents with the 8-quino-
line sulfonate (quisylate) leaving group.2b While this leaving
group only possesses one chelating heteroatom, the rigid
geometry of the 8-quinoline system appears to allow for
more ideal chelation. The reaction of phenylpropyl quisylate
substrate 19 with LiBr gave a significantly enhanced bromi-
nation rate of 4.5 h (entry 16), rivaling ester and ether
NALGs containing two ethylene oxide units.
(17) Cai, L. S.; Lu, S. Y.; Pike, V. W. Eur. J. Org. Chem. 2008, 17, 2853–
2573.
ꢀ
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(18) Lasne, M.-C.; Perrio, C.; Rouden, J.; Barre, L.; Roeda, D.; Dolle, F.;
Crouzel, C. Top. Curr. Chem. 2002, 222, 201–258.
(19) Alexoff, D. L.; Fowler, J. S.; Gatley, S. J. Appl. Radiat. Isot. 1991, 42,
1189–1193.
(20) Sun, H; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050–2051.
(21) Kim, D. W.; Ahn, D.-S.; Oh, Y.-H.; Lee, S.; Kil, H. S.; Oh, S. J.; Lee,
S. J.; Kim, J. S.; Ryu, J. S.; Moon, D. H.; Chi, D. Y. J. Am. Chem. Soc. 2006,
128, 16394–16397.
(22) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Am. Chem. Soc. 2002, 124,
10278–10279.
(23) Qaim, S. M.; Clark, J. C.; Crouzel, C.; Guillaume, M.; Helmeke, H.
Application to 18F-Labeling. The substantially enhanced
rate observed in the reaction of NALG containing substrates
toward bromination especially in aryl ether systems (such as
16) encouraged us to test whether such advantages might
also be realized in nucleophilic radiofluorination for possible
€
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W., Eds.; Kluwer Academic Publisher: Dordrecht, The Netherlands, 1993;
(14) Polla, M. O.; Tottie, L.; Norden, C.; Linschoten, M.; Musil, D.;
Trumpp-Kallmeyer, S.; Aukrust, I. R.; Ringom, R.; Holm, K. H.; Neset, S.
M.; Sandberg, M.; Thurmond, J.; Yu, P.; Hategan, G.; Anderson, H. Bioorg.
Med. Chem. 2004, 12, 1151–1175.
pp 1-43.
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TABLE 2.
[
18F]Fluorination of Various NALG Containing Substrates to Yield 20 under Thermal and Microwave Heating Conditions
c
aAverage decay-corrected radiochemical yield (n g 2). bNo product with thermal conditions in the absence of K2.2.2. Unidentified radioactive
prodcut (7%) obtained at retention time of 14-16 min.
potassium salts.1 NALGs containing linear oligoether arms
also showed some preference for the lithium cation. Thus we
adapted standard procedures to form Li18F and reacted this
with several NALGs under various conditions in an attempt
to produce 20 (Table 2). Contrary to our results using LiBr in
acetone (Table 1), we observed no fluorination product using
Li18F with substrates 5a, 1a, and 16a in acetone, acetonitrile,
DMF, or DMSO. In the reaction of 1a in acetonitrile, several
bases were used to prepare Li18F including Li2CO3, LiOH,
and LiOAc, none yielding desired product 20.
ortho chelating units of our NALG substrates sterically
hinder the approach of the K2.2.2/K18F complex to the
electrophilic site of the substrate. As expected, the radio-
chemical yields were much better with microwave irradiation
than under thermal heating.24 Here, as well, the phase
transfer catalyst K2.2.2 canceled the NALG effect. In the
absence of K2.2.2, product 20 was only obtained under
microwave conditions (Table 2). Our benchmark substrate
5a gave a radiochemical yield (RCY) of 9% under these
conditions (Table 2, entry 1).
We have previously observed that highly polar solvents cancel
the “NALG effect” by effectively competing with the oligoether
arm of a NALG in chelating the metal of a nucleophilic salt.
A highly solvated cation is not likely to participate in stabilizing
transition states such as C (Scheme 1). Thus we interpret the
poor reactivity of 1a and 16a in DMF and DMSO to be the
result of over-solvation. In less polar solvents such as acetoni-
trile and acetone, the poor reactivity of 1a and 16a was likely due
to the poor solubility of Li18F or the formation of tighter ion
pair in these solvents.
With K2CO3 and K2.2.2, desired product 20 was obtained
with a variety of NALG substrates under both thermal and
microwave conditions (Table 2) in good radiochemical yields
(decay-corrected, ng2). In most cases, NALGs performed
significantly worse than the tosylate leaving group. With the
cryptand tightly complexing the potassium cation of K18F,
In general, we found that our chelating groups provided
significantly less rate enhancement with K18F in acetonitrile
than our previous studies with LiBr in acetone (Table 1).
NALG 1a was essentially unreactive toward potassium
fluoride even under microwave conditions. It is likely that
the macrocycle unit only served to provide steric hindrance
to the nucleophilic salt given the very poor affinity of 12-
crown-4 for the potassium cation. With ester NALGs 7a-
10a, we observed a marked preference for three ethylene
oxide units in the side chain. Thus, 9a gave an average RCY
of 22% (entry 4), a 2-3-fold enhancement relative to tosylate
(24) (a) Elander, N.; Jones, J. R.; Lu, S. Y.; Stone-Elander, S. Chem. Soc.
Rev. 2000, 29, 239–249. (b) Stone-Elander, S.; Elander, N. J. Labelled
Compd. Radiopharm. 2002, 45, 715–746. (c) Jones, J. R.; Lu, S. Y. In
Microwaves in Organic Chemistry, 2nd ed.; Loupy, A., Eds.; Wiley-VCH:
Weinheim, Germany, 2006; pp 820-859.
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Lu et al.
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5a (entry 1). Importantly, attempts to fluorinate the triflate
of 3-(tert-butylphenyl)propanol were hampered by the in-
stability of this compound to purification25 and to reaction
conditions. This underscores the utility of our chelating
leaving groups whose reactivity is more directed toward
the nucleophilic salt. To our knowledge, the fluorination of
9a is the highest reported radiochemical yield of a primary
substrate using K18F/CH3CN unassisted by additives, such
as a cryptand.
Although the reasons for additional rate enhancement
afforded by three ethylene oxide units in 9a are unclear, a
similar preference was observed with the aryl ether NALGs
(entry 8 vs 7). However, the addition of an electron-with-
drawing fluorineinNALG 16a (alsocontainingthree ethylene
oxide units) did not improve the radiochemical yield (entry
9 vs 8). Similar to our bromination experiments (Table 1),
quisylate 19a significantly enhanced fluorination of the pri-
mary substrate relative to tosylate, giving an RCY of 19%.
chromatography using hexane/ethyl acetate as the eluent. Reac-
tion yields varied from 90 to 95%.
General Procedure for Preparation of Sulfonyl Chloride Deri-
vatives 4. Aryl ether derivative (1.0 equiv) was added over
30 min to neat chlorosulfonic acid (5.0 equiv) cooled to 0 °C.
After complete addition, the reaction mixture was stirred at
room temperature for 3-6 h. The reaction mixture was then
recooled to 0 °C, and N,N-dimethylformamide (5.5 equiv) was
added slowly followed by thionyl chloride (10.0 equiv). The
reaction mixture was heated at 60-65 °C for 2 h and cooled to
0 °C and then added slowly to a mixture of ice and ether with
constant stirring. The ether layer was extracted, and the aqueous
layer was washed twice with ether. The ether washings were
collected, washed with saturated sodium bicarbonate solution,
and dried over anhydrous sodium sulfate. Purified product was
obtained by flash column chromatography using hexane/ethyl
acetate as the eluent. Reaction yields varied from 72 to 88%.
2-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy-5-fluorobenzene-1-
1
sulfonyl chloride: H NMR (400 MHz, CDCl3) δ 7.69-7.67
(dd, J=7.45, 3.15 Hz, 1H), 7.41-7.36 (m, 1H), 7.18-7.15 (dd,
J=9.22, 3.93 Hz, 1H), 3.35-3.33 (m, 2H), 3.97-3.95 (m, 2H),
3.79-3.77 (m, 2H), 3.67-3.63 (m, 4H), 3.56-3.53 (m, 2H),
3.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.2, 153.7,
153.1-153.0 (d, J=2.50 Hz, 1C), 123.9-123.7 (d, J=22.85 Hz,
1C), 116.3-116.1 (d, J = 27.31 Hz, 1C), 116.0-115.9 (d,
J=7.28 Hz, 1C), 71.7, 70.8, 70.5, 70.3, 70.0, 69.1, 58.9; HRMS
(CIþ) calcd for C13H18ClFNaO6S [M þ Na]þ 379.0389, found
379.0393.
Conclusion
Studies with substrate 1 containing a 12-crown-4 moiety
accord with the concept that a NALG chelating unit en-
hances metal halide substitution reactions through stabiliza-
tion of charge in the transition state rather than through
strong precomplexation with metal cations. On the basis of
this principle, the ideal NALG should contain a linker which
allows its chelating unit to stabilize the transition state
effectively. To this end, a new series of NALGs were synthe-
sized in which the chelating units were attached to the aryl
ring via an ether linkage. In addition, we prepared NALGs
with electron-withdrawing fluorines on the aryl ring. In some
cases, these new NALGs were more reactive toward LiBr
than our previous systems, suggesting that future variation of
the linker element may provide additional rate enhance-
ments. These and previously disclosed NALGs were then
evaluated for their effectiveness in 18F-fluorination, an ap-
plication requiring fast and high yield reactions. Under
microwave irradiation, several NALGs, especially those with
three ethylene oxide units in the chelating arm, exhibited
useful reactivity toward K18F. Importantly, this reactivity
was achieved in the absence of a cryptand, which significantly
increases the efforts necessary to purify radiolabeled samples
for use in medical imaging applications. With this stand-
alone reactivity, we believe that our NALG systems hold
promise for solid phase applications, especially those invol-
ving the synthesis of 18F-labeled PET imaging agents.
General Procedure for Esterification Reactions To Give 11-
18. To a cooled (0 °C) suspension of sodium hydride (2.0 equiv)
in dichloromethane (0.2 M) was added 3-phenyl-1-propanol
(1.5 equiv) under argon. After 1 h of stirring, arylsulfonyl
chloride (1.0 equiv) and 4-(dimethylamino)pyridine (1.0 equiv)
were added to the previous solution. The reaction was main-
tained at room temperature for 4-6 h. Following completion,
the reaction mixture was quenched with DI water and extracted
several times with dichloromethane. The collected organic
extracts were concentrated, and the resulting oil was purified
by silica gel chromatography (using ethyl acetate/hexanes as
eluent). Reaction yields varied from 72 to 80%. 3-Phenylpropyl-
2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy-5-fluorobenzene-1-sul-
1
fonate (16) H NMR (400 MHz, CDCl3) δ 7.68-7.66 (dd, J=
7.79, 3.17 Hz, 1H), 7.33-7.26 (m, 3H), 7.22-7.19 (m, 1H),
7.16-7.14 (m, 2H), 7.12-7.09 (dd, J=9.15, 3.98 Hz, 1H), 4.28-
4.26 (m, 2H), 4.23-4.20 (t, J=6.20 Hz, 2H), 3.93-3.90 (m, 2H),
3.76-3.73 (m, 2H), 3.65-3.62 (m, 4H), 3.56-3.54 (m, 2H), 3.38
(s, 3H), 2.74-2.71 (t, J=7.39 Hz, 2H), 2.06-2.00 (m, 2H); 13
C
NMR (100 MHz, CDCl3) δ 156.7, 154.3, 153.0 (d, J=2.26 Hz,
C), 140.3, 128.3, 128.2, 126.0, 122.0-121.8 (d, J=22.82 Hz, 1C),
118.0-117.7 (d, J=26.47 Hz, 1C), 115.5-115.4 (d, J=7.41 Hz,
1C), 71.7, 70.7 (2), 70.5, 70.3, 69.7, 69.2, 58.9, 31.3, 30.6; HRMS
(ESIþ) calcd for C22H29FNaO7S [M þ Na]þ 479.1510, found
479.1507.
Experimental Section
General Procedure for Substitution Reactions (Table 1). To a
solution of lithium bromide (4.0 equiv) at rt in acetone-d6 (0.08 M)
were added NALG esters (1.0 equiv). The reaction was main-
tained atroom temperatureuntil completion (2-12 h; see Table 1),
which was determined by the point at which starting material
General Procedure for Preparation of Aryl Ether Derivatives 3.
To an ice-cooled suspension of NaH (1.5 equiv) in N,N-
dimethylformamide was slowly added the phenol derivative
(1.0 equiv) followed by stirring for 30-60 min. The tosylate
derivative (1.5 equiv) of oligoethylene glycol was then added,
and the reaction mixture was heated to 60-65 °C for 16-18 h
followed by cooling and quenching with aqueous HCl (2 M) and
water dilution. The mixture was extracted three times with ether.
The organic layer was dried over anhydrous sodium sulfate and
concentrated. Purified product was obtained by flash column
1
resonance peaks were no longer visible in the H NMR of the
reaction mixture. Following completion, the reaction mixture was
concentrated under vacuum, quenched with DI water, and ex-
tracted several times with ether. The collected organic extracts
were concentrated, and the resulting oil was purified by silica gel
chromatography (using pure hexane as eluent). Reaction yields
were >95%.
General Procedure for [18F]Fluoride Ion Drying and Fluorina-
tion of NALGs under Microwaves (Table 2). A model 521 instru-
ment for accelerated microwave chemistry cavity (Resonance
(25) Although the crude yield of the triflate was satisfactory, conven-
tional silica gel flash chromatography resulted in very poor isolated yields
(<5%) under a variety of conditions.
J. Org. Chem. Vol. 74, No. 15, 2009 5295

Lu et al.
JOCArticle
Instruments, Inc.) was securely mounted on the Synthia MKII
platform inside a lead-shielded hot cell.26 The time and power
control was located outside the hot cell and linked
to the cavity through a RF coaxial cable. A glass reaction V-vial
(1 mL) was equipped with a screw-on cap and Tuf-Bond Teflon/
silicone septum and a vent needle that was connected to a glass vial
(20 mL) to collect the solvents and a charcoal trap to retain any
volatile breakthrough radioactivity. The V-vial containing NCA
(no-carrier-added) [18F]fluoride ions (10-100 mCi) in H218O (20-
100 μL, obtained by irradiating 95 atom % [18O]water for 120 min
with a 17 MeV, 20 μA proton beam), K2CO3/K2.2.2 or K2CO3
only (100-600 μL stock solution of 0.5 mg K2CO3 and 5.0 mg
K2.2.2, or 0.5 mg K2CO3 only in 9:1 CH3CN and H2O mixture)
and CH3CN (400 μL) was placed in the microwave cavity.
Microwave heating at 90 W in 3 ꢀ 2 min pulses was applied under
N2 gas flow (200 mL/min) which speeded up the removal of
azeotropic mixture of H2O and CH3CN. The temperature reading
by the IR sensor reached 130 °C when the liquid volume was over
0.5 mL. The temperature readinggraduallydecreasedto50-60 °C
as solvents evaporated. The heating cycle was repeated twice, and
each time fresh CH3CN (500 μL) was added. At the end of drying,
the vent needle was removed. NALG precursor (5.0 mg) in
CH3CN was introduced in the closed V-vial and irradiated
with 90 W microwave power in 5 ꢀ 2 min pulses. The reaction
temperature reached 130 °C during microwave irradiation and
decreased to 60-70 °C when microwave irradiation ceased. The
reaction mixture was diluted with water (0.7 mL) and purified by
˚
HPLC on a reverse phase column (Luna C18, 10 μ, 100 A, 250 ꢀ
10 mm i.d.). The flow rate was 4 mL/min. The mobile phase was
isocratic CH3CN/10 mM aqueous HCOONH4 (65:35 v/v). The
retention time of the radiolabeled product, 1-(3-[18F]fluoropro-
pyl)-4-tert-butyl benzene, was 25 min and was authenticated by
coelution from the column with the corresponding nonradioactive
standard, 1-(3-fluoropropyl)-4-tert-butyl benzene. Radiochemical
yield (decay-corrected) was calculated from the radioactivity of
the HPLC fraction at 24-26 min compared to the total radio-
activity introduced into the V-vial.
Acknowledgment. We thank the National Institute of
Mental Health (66963-01), General Medical Science
(073621-01), and NSF (0311369) for financial support. Re-
search by S.Y.L. and V.W.P. was supported by the Intra-
mural Research Program (Project Z01-MH-002793) of the
NIMH, NIH. We also thank Prof. Predrag Cudic for helpful
discussions.
Supporting Information Available: Copies of 1H NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
ꢀ
(26) Lazarova, N.; Simeon, F. G.; Musachio, J. L.; Lu, S. Y.; Pike, V. W.
J. Labelled Compd. Radiopharm. 2007, 50, 463–465.
5296 J. Org. Chem. Vol. 74, No. 15, 2009