Unprecedented directing group ability of cyclophanes in arene fluorinations with diaryliodonium salts

Article abstract of DOI:10.1021/ol201080c

For the first time it is shown that exceptionally electron-rich arene rings can be fluorinated exclusively during the reductive elimination reactions of diaryliodonium fluorides. The 5-methoxy[2.2]paracyclophan-4-yl directing group simultaneously reduces unproductive aryne chemistry and eliminates ligand exchange reactions by a combination of steric and electronic effects. Use of the cyclophane directing group permits an unprecedented degree of control in fluorination reactions of diaryliodonium salts.

Full text of DOI:10.1021/ol201080c

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3158–3161
Unprecedented Directing Group Ability of
Cyclophanes in Arene Fluorinations with
Diaryliodonium Salts
Joseph W. Graskemper, Bijia Wang, Linlin Qin, Kiel D. Neumann, and Stephen G. DiMagno*
Department of Chemistry and Nebraska Center for Materials and Nanoscience,
University of Nebraska, Lincoln, Nebraska 68588-0304, United States
sdimagno1@unl.edu
Received April 25, 2011
ABSTRACT
For the first time it is shown that exceptionally electron-rich arene rings can be fluorinated exclusively during the reductive elimination reactions
of diaryliodonium fluorides. The 5-methoxy[2.2]paracyclophan-4-yl directing group simultaneously reduces unproductive aryne chemistry and
eliminates ligand exchange reactions by a combination of steric and electronic effects. Use of the cyclophane directing group permits an
unprecedented degree of control in fluorination reactions of diaryliodonium salts.
Rapid late-stage introduction of fluorine into biologi-
cally active compounds is essential for the synthesis of 18F-
labeled radiotracers for positron emission tomography.1ꢀ3
Although significant advances in electrophilic radiofluor-
ination have been made recently,4 nucleophilic, fluoride-
based approaches to radiotracers are preferred in imaging
applications where radiochemical purity is essential.5 For
aromatic compounds bearing electron-withdrawing groups,
nucleophilic aromatic substitution (SNAr) of halide, nitro,
or trimethylamine leaving groups by fluoride is a highly
efficient process.6ꢀ10 However, functionalization of elec-
tron-rich arenes with fluoride requires mediation by transi-
tion metal11 or hypervalent main group atoms.
The reductive elimination of aryl fluorides from diary-
liodonium salts was pioneered by Pike for arene
radiofluorination.12ꢀ14 Aided by our access to anhydrous
fluoride reagents,15 we were able to demonstrate that
removal of inorganic salts from the reaction medium and
the use of relatively nonpolar solvents dramatically in-
creasethe yieldsof fluorinated arenesfromdiaryliodonium
fluorides.16 Here we address some of the remaining road-
blocks to efficient fluorination using I(III) compounds.
(1) Positron Emission Tomography: Basic Sciences; Bailey, D. L.,
Townsend, D. W., Falk, P. E., Maisey, M. N., Eds.; Springer: London, 2005.
(2) Welch, M. J.; Redvanly, C. S. Handbook of Radiopharmaceuticals
- Radiochemistry and Applications; Wiley: Chichester, 2003.
(3) Fluorine in Pharmaceutical and Medicinal Chemistry: From Bio-
physical Aspects to Clinical Applications; Gouverneur, V., Mueller, K.,
Eds.; World Scientific: 2011.
(4) Teare, H.; Robins, E. E.; Kirjavainen, A.; Forsback, S.; Sandford,
G.; Solin, O.; Luthra, S. K.; Gouverneur, V. Angew. Chem., Int. Ed.
2010, 49, 6821.
(5) Cai, L.; Lu, S.; Pike, V. W. Eur. J. Org. Chem. 2008, 2853.
(6) Sun, H.; DiMagno, S. G. Angew. Chem., Int. Ed. 2006, 45, 2720.
(7) Sun, H.; DiMagno, S. G. J. Fluorine Chem. 2007, 128, 806.
(8) Adams, D. J.; Clark, J. H. Chem. Soc. Rev. 1999, 28, 225.
(9) Boechat, N.; Clark, J. H. J. Chem. Soc., Chem. Commun. 1993,
921.
(10) Maggini, M.; Passudetti, M.; Gonzales-Trueba, G.; Prato, M.;
Quintily, U.; Scorrano, G. J. Org. Chem. 1991, 56, 6406.
(11) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garcia-
Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
(12) Pike, V. W.; Aigbirhio, F. I. J. Chem. Soc., Chem. Commun.
1995, 2215.
(13) Shah, A.; Pike, V. W.; Widdowson, D. A. J. Chem. Soc., Perkin
Trans. 1 1997, 2463.
(14) Shah, A.; Pike, V. W.; Widdowson, D. A. J. Chem. Soc., Perkin
Trans. 1 1998, 2043.
(15) Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050.
(16) Wang, B.; Qin, L.; Neumann, K. D.; Uppaluri, S.; Cerny, R. L.;
DiMagno, S. G. Org. Lett. 2010, 12, 3352.
r
10.1021/ol201080c
Published on Web 05/17/2011
2011 American Chemical Society

The reductive elimination regiochemistry of diaryliodo-
nium fluorides is generally controlled by electronic substituent
effects; the most electron-poor ring is fluorinated selectively,
and the electron-rich aryl iodide is eliminated. However, the
extent to which electronic control can be utilized is limited,
since highly electron-rich rings promote nonproductive de-
composition reactions of diaryliodonium salts, presumably
by inner-sphere redox processes. As an example, diaryliodo-
nium salts featuring 4-(dialkylamino)phenyl groups have
not been isolated, despite attempts to do so.17 A second
consideration is the surprisingly labile nature of aryl rings on
I(III) fluorides; we demonstrated recently that rapid aryl
group exchange among diaryliodonium fluorides occurs at
room temperature in acetonitrile.18 Here we show that
appropriately substituted cyclophane ligands on iodine solve
simultaneously the ligand exchange and regiospecificity pro-
blems by means of the same stereoelectronic effect.
Paracyclophane substituents have been shown to be
superior directing groups for reductive elimination reactions
of diaryliodonium salts;19 regiospecificity is obtained even
when electron-rich aryl rings, such as 4-methoxyphenyl, are
functionalized. Significant out of plane steric bulk provided
by the “capping” aryl ring results in a highly congested,
strongly destabilized (by >4 kcal/mol) transition state for
cyclophane functionalization. A rise in the free energy of
activation for cyclophane functionalization steers the nucleo-
phile toward the second aryl substituent. Regiospecific arene
functionalization was demonstrated with the weakly basic
azide, acetate, phenoxide, thiocyanate, and thiophenoxide
nucleophiles. However, regiocontrol was lost when the more
strongly basic trifluoroethoxide nucleophile was used; this
basic group appeared to promote a mode of decomposition
that involved formation of aryne intermediates.19 The similar
basicities of fluoride and trifluoroethoxide in polar aprotic
solvents (CF3CH2OH, pKa = 23.5; HF, pKa = 15 in
DMSO)20 implied that aryne chemistry could also be a
significant side reaction in cyclophane directed fluorinations
of diaryliodonium salts.
(4-Methoxyphenyl)([2.2]paracyclophan-4-yl)iodonium
hexafluorophosphate 1(PF6) and (4-methoxyphenyl)-
((7-methoxy[2.2]paracyclophan-4-yl)iodonium hexafluoro-
phosphate 2(PF6) (Figure 1) were prepared as described
previously19 and converted to the fluoride salts by ion
exchange with anhydrous tetramethylammonium fluo-
ride21 (TMAF) in acetonitrile. The residual TMAPF6 was
removed by evaporation of the solvent, suspension of the
remaining solid in benzene, and passage of this solution
through a 0.2 μm PTFE filter. NMR (1H and 19F) and
ES-MS spectra of 1(F) and 2(F) were consistent with a single
species in solution, indicating that fluoride-promoted aryl
group exchange in diaryliodonium fluorides is suppressed
by the cyclophane substituent. Thermal decomposition
Figure 1. Numbering of the [2.2]paracyclophane ring system and
the structures of the diaryliodonium hexafluorophosphate salts
discussed in this work.
reactions of 1(F) and 2(F) (140°C, d6-benzene, 15 min) gave a
mixture of fluorinated products (Figure 2). The relatively
poor selectivity observed for arene fluorination contrasts
strongly with the excellent selectivity observed previously
for weakly basic nucleophiles (Table 1). Tellingly, roughly
equal amounts of 4-fluoro-7-methoxy[2.2]paracyclophane
and 4-fluoro-8-methoxy[2.2]paracyclophane were formed
during the thermal decomposition reaction of 2(F), implicat-
ing arynes as likely reactive intermediates. Although the
greater susceptibility of the relatively electron-rich cyclo-
phane ligand to deprotonation is not well understood cur-
rently, we pursued a simple blocking strategy to suppress
aryne formation and to restore regiocontrol.
(4-Methoxyphenyl)(5-methoxy[2.2]paracyclophan-4-yl)-
iodonium hexafluorophosphate, 3(PF6), in which both sites
ortho to the I(III) center are substituted, was synthesized
from 4-bromo[2.2]paracyclophane,22 as is shown in Figure 3.
Metalꢀhalogen exchange yielded the organolithium reagent,
which was quenched with trimethylborate and oxidized with
hydrogen peroxide.23 To introduce a halogen atom at the
(17) Beringer, F. M.; Chang, L. L. J. Org. Chem. 1972, 37, 1516.
(18) Wang, B.; Cerny, R. L.; Uppaluri, S.; Kempinger, J. J.; DiMagno,
S. G. J. Fluorine Chem. 2010, 131, 1113.
(19) Wang, B.; Graskemper, J. W.; Qin, L.; DiMagno, S. G. Angew.
Chem., Int. Ed. 2010, 49, 4079.
(20) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(21) Christe, K. O.; Wilson, W. W.; Wilson, R. D.; Bau, R.; Feng,
J. A. J. Am. Chem. Soc. 1990, 112, 7619.
(22) Cram, D. J.; Day, A. C. J. Org. Chem. 1966, 31, 1227.
(23) Krohn, K.; Rieger, H.; Hopf, H.; Barrett, D.; Jones, P. G.;
Doering, D. Chem. Ber. 1990, 123, 1729.
Org. Lett., Vol. 13, No. 12, 2011
3159

Figure 3. Synthesis of 3(PF6).
3(PF6) was converted to 3(F) by ion exchange with
anhydrous TMAF in acetonitrile and desalted according
to the procedure described previously for 2(F). 1H NMR
spectra of 3(F) in both acetonitrile and benzene showed no
evidence of aryl group exchange.
Figure 2. Thermal decomposition of [2.2]paracyclophane-sub-
stituted diaryliodonium fluorides 1(F) and 2(F).
Thermal decomposition of 3(F) at 140 °C (15 min)
gave a mixture of 4-fluoro- (72%) and 3-fluoroanisole
(15%). Small amounts of inorganic silicon fluorides
were also formed, presumably from the reaction of free
fluoride or bifluoride with the borosilicate glass NMR tube.
No fluorinated cyclophane was detected in the reaction
mixture, supporting the hypothesis that aryne formation
was largely responsible for the fluorocyclophanes observed
during the thermal decomposition of 2(F), and confirming
Chun and co-workers’ observations that the methoxy group
is not an effective ortho-director.27
In an attempt to gauge the temperature-dependence of
the fluorination selectivity, thermolysis reactions of 3(F)
were also conducted at 80 °C in benzene (6 h). Reactions
run at this temperature were a bit more selective, but
production of 3-fluoroanisole could not be suppressed
completely (Figure 4).
Table 1. Yieldsa of Reductive Elimination Products from 1(X)
and 2(X) with Various Nucleophiles
1(X)
2(X)
X
MeOPh-Xa Cyc-Xa
MeOPh-X
96
Cyc-X
N3
86
81
51
43
68
19
7
14
18
40
52
31
39
73
0
0
0
0
0
SCN
OPh
SPh
92
84
82
51
OAc
OCH2CF3
F
42b (22þ 20) 37b (18 þ 19)
37b (30 þ 7)
55b (29 þ 26)
a All yields were determined by 1H NMR spectroscopy and con-
firmed by GC-MS. The products are functionalized anisoles(MeOPh-X)
and functionalized paracyclophanes (Cyc-X). b Total amount of two
different regioisomers. Numbers in parentheses refer to the total amount
of expected and rearranged functionalized product, respectively
The generation of significant amounts of 3-fluoroanisole
from the decomposition of 3(F) contrasts with the trace
amounts formed under identical conditions from the
symmetrical compound bis(4-methoxyphenyl)iodonium
fluoride, 4(F). However, the more closely related, unsym-
metrically substituted iodonium salt, (2-methoxyphenyl)(4-
methoxyphenyl)iodonium fluoride, 5(F), provides 2-fluor-
oanisole (59%), 3-fluoroanisole (15%), and 4-fluoroanisole
(25%) at high temperature (benzene, 140 °C, 15 min), and
2-fluoroanisole (65%), 3-fluoroanisole (9%), and 4-fluor-
oanisole (23%) at 80 °C. These results suggest that a
methoxy group ortho to the I(III) center promotes aryne
formation. Modeling (B3LYP/DGDZVP, ZPE, and ther-
mal corrections) of the ground state structures of the 4(F)
and 5(F) along with the structures of the corresponding
diaryliodonium cations (Figure 5) indicates that an ortho
5-position, ortho-lithiation required installation of the dieth-
ylcarbamoyl directing group, as was reported previously.24,25
(Direct lithiation of 4-methoxy-[2.2]paracyclophane was not
successful in our hands; modeling indicated that steric con-
gestion forces the methyl group above the cyclophane ring,
thereby aligning the oxygen lone pairs in an inappropriate
geometry to coordinate an incoming organolithium reagent.)
Transmetalation with zinc chloride was essential for success-
ful introduction of the 4-methoxyphenyliodonium diacetate
moiety; the corresponding cyclophanyltributylstannane
could not be coaxed to “transmetalate” with 4-methoxyphe-
nyliodonium diacetate under any standard conditions.26
(24) Hopf, H.; Barrett, D. G. Liebigs Ann. 1995, 449.
(25) Wack, H.; France, S.; Hafez, A. M.; Drury, W. J., III;
Weatherwax, A.; Lectka, T. J. Org. Chem. 2004, 69, 4531.
(26) Pike, V. W.; Butt, F.; Shah, A.; Widdowson, D. A. J. Chem. Soc.,
Perkin Trans. 1 1999, 245.
(27) Chun, J.-H.; Lu, S.; Lee, Y.-S.; Pike, V. W. J. Org. Chem. 2010,
75, 3332.
3160
Org. Lett., Vol. 13, No. 12, 2011

Figure 4. Thermal decomposition of 3(F).
methoxy substituent stabilizes an I(III) center to a greater
extent than a para methoxy group and reduces the gas
phase fluoride ion affinity of the I(III) by 1.52 kcal/mol.
Weaker IꢀF interactions should lead to an increase in
fluoride ion basicity, leading, in turn, to a more accessible
aryne pathway.
Figure 5. Calculated (B3LYP/DGDZVP) optimized structures
and relative energies of the (2-methoxyphenyl)4-methoxyphe-
nyliodonium cation (top right), the bis(4-methoxyphenyl)
iodonium cation (top left), 4(F) (bottom left), and 5(F), bottom
right.
In summary, here we have demonstrated that cyclo-
phane-derived diaryliodonium salts bearing the electron-
rich 4-methoxyphenyl substituent can yield fluorinated
anisoles exclusively. Previously, the 4-methoxyphenyl
group was considered to be the “gold-standard” directing
group for radiochemical fluorinations of diaryliodonium
salts, and 4-fluoroanisole could not be obtained except in
low yield from the symmetrical iodonium salt.12 The
cyclophane ligand in 2(F) was shown to be resistant to
fluorination through a reductive elimination pathway, but
the combination of cyclophane steric demand and electron
donation of the p-methoxy substituent enables easy access
to a competing aryne fluorination pathway. Blocking of
the position ortho to the I(III) center in 3(F) precludes
cyclophane aryne formation and results in exclusive fluor-
ination of the anisole ring. The use of cyclophane as a
directing group for I(III)-mediated fluorinations is a pro-
mising approach, particularly if highly electron-rich
fluorinated aromatic compounds are the targets. Efforts
are underway to streamline the synthesis of cyclophane-
substituted diaryliodonium salts tomakethese compounds
more accessible.
Acknowledgment. We thank the National Science
Foundation (CHE 0717562) for support and the National
Institutes of Health (RR016544-01) for infrastructure to
conduct this research.
Supporting Information Available. Experimental pro-
cedures and analytical data for all new compounds and
synthetic intermediates. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 12, 2011
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