The neighboring group effect of fluorine in the tritium labeling of organic substrates with [Cp*(PMe3)IrMe(CH2Cl 2)]+ [BArf]-, a cationic iridium(III) complex

Article abstract of DOI:10.1002/jlcr.1072

The cationic Ir(III) complex, [Cp*(PMe₃)IrMe(CH ₂Cl₂)][BAr_f] (1, Cp* = η⁵-C₅Me₅, BAr_f = MeB(C ₆F₅)₃), has been shown to be a useful reagent in the tritium and deuterium labeling of organic substrates. During a recent reaction of 1 with a fluorinated molecule, we observed an unusually high incorporation of tritium ortho to the aromatic fluorines. To probe whether this was an isolated incident or a more general phenomenon, we have investigated the application of 1 towards the tritiation of simple fluorinated organic substrates. Our results indicate that aromatic fluorine indeed does exhibit a neighboring group effect in terms of directing ortho H/T exchange. The directing influence appears to be at least as strong as the hydroxyl moiety reported in previous works. Copyright

Full text of DOI:10.1002/jlcr.1072

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 623–634.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1072
Research Article
The neighboring group effect of fluorine in the tritium
labeling of organic substrates with
[Cp*(PMe3)IrMe(CH2Cl2)]+[BArf]ꢀ, a cationic
iridium(III) complex
Marc B. Skaddan1,* and Robert G. Bergman2
1 Pfizer Global Research and Development, Pfizer Inc., 2800 Plymouth Road,
Ann Arbor, MI 48105, USA
2 Department of Chemistry, University of California and Division of Chemical Sciences,
Lawrence Berkeley National Laboratories, Berkeley, CA 94720, USA
Summary
The cationic Ir(III) complex, [Cp*(PMe3)IrMe(CH2Cl2)][BArf] (1, Cpꢁ ¼ Z5-C5Me5,
BArf ¼ MeBðC6F5Þ3), has been shown to be a useful reagent in the tritium and
deuterium labeling of organic substrates. During a recent reaction of 1 with
a fluorinated molecule, we observed an unusually high incorporation of tritium ortho
to the aromatic fluorines. To probe whether this was an isolated incident or a more
general phenomenon, we have investigated the application of 1 towards the tritiation
of simple fluorinated organic substrates. Our results indicate that aromatic fluorine
indeed does exhibit a neighboring group effect in terms of directing ortho H/T
exchange. The directing influence appears to be at least as strong as the hydroxyl
moiety reported in previous works. Copyright # 2006 John Wiley & Sons, Ltd.
Received 20 February 2006; Revised 21 March 2006; Accepted 21 March 2006
Key Words: iridium; fluorine; tritium; exchange; Bergman; neighboring group effect
Introduction
The C–H bond activation of organic substrates with highly active
Ir(III) complexes, such as [Cp*(PMe3)IrMe(CH2Cl2)][BArf] (1, Figure 1, Cpꢁ ¼
Z5-C5Me5, BArf ¼B½3; 5-ðCF3Þ2C6H3ꢂ4, has been extensively studied,1–12 and
the application to tritium and deuterium labeling of both simple organic
*Correspondence to: M. B. Skaddan, Pfizer Inc., 2800 Plymouth Road, B28, Room 2028E, Ann Arbor,
MI 48105, USA. E-mail: marc.b.skaddan@pfizer.com
Contract/grant sponsor: U.S. Department of Energy; contract/grant number: DE-AC02-05CH11231
Copyright # 2006 John Wiley & Sons, Ltd.

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M. B. SKADDAN AND R. G. BERGMAN
Figure 1.
molecules and more complex pharmaceutical templates has been recently
demonstrated by our groups.13,14 We found that 1 exchanges tritium most
easily with the protons of aromatic rings. Exchange was also observed in
simple alkyl groups that are activated by electron-withdrawing heteroatoms,
such as nitrogen or oxygen, though to a lesser degree. In general, 1 is a
sterically sensitive complex, with labeling occurring meta or para to a
substituent on an aromatic ring. Thus far, the lone exception appeared to be
phenyl groups containing hydroxyl or methoxy groups, where significant
labeling occurred ortho to the substituent. It was reasoned that this might be
due to coordination of the oxygen to the Ir metal, which in turn directs the
activation ortho analogous to previously reported methods using Ir(I)
catalysts.
In a recent study designed to examine the mechanism of methyl/arene
exchange in C–H activating Ir cations, Tellers and coworkers conducted
kinetic experiments using Cp*(PMe3)IrMeOTf and 1,2-difluorobenzene as the
substrate.3 They observed the 1,2,3- and 1,3,4-trisubstituted arene in a 1:2
ratio, respectively (Scheme 1). This regioselectivity is in line for what one
would expect if purely steric factors guided the substitution process. We now
report that H/T exchange reactions carried out on simple fluorinated benzenes
with 1 show dramatically different regioselectivity.
Results and discussion
The reactive Ir complex 1 was prepared by stirring the precursor,
Cp*(PMe3)IrMeCl (2), with NaBArf in an inert atmosphere as reported
previously.13 Complex 1 was then mixed in a 1.1:1 ratio with the appropriate
fluorinated substrate from Table 1. All substrates were commercially available
except N-(2-fluoro-6-hydroxyphenyl)acetamide, which was prepared from 2,6-
difluoronitrobenzene in a four-step reaction sequence adapted from Erikkson
et al. (Scheme 2).15 After 20 min of stirring, the Ir–substrate complex was
exposed to a mixture of T2 and H2 gas, then worked up by removing base-
exchangeable tritiums and purifying by solid-phase extraction.
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NEIGHBORING GROUP EFFECT FLUORINE TRITIUM LABELING IRIDIUM
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Scheme 1.
Results of the tritiation experiments are shown in Table 1. Entries 1–5
describe the outcome of the reaction of 1 with simple fluorinated acetanilides
(entries 1 and 2), acetophenone (entry 3), or difluorobenzene (in comparison to
the Tellers experiment, entries 4 and 5), while entries 6–8 display the results
from molecules designed to probe how fluorine influences tritiation (‘internal
competition’) in the presence of free phenyl groups (entry 6) or hydroxyl
moieties (entries 7 and 8). For 3-fluoroacetanilide (entry 1), there is no labeling
ortho to the acetamide substituent, which is consistent with the pattern seen
previously for acetanilide substrates.13 The remaining two positions sets up a
competition between a relatively unhindered positon meta to the acetamide
and fluorine moieties and a position ortho to the fluorine. The results clearly
show the preference of the position ortho to the fluorine (57%) relative to the
unhindered meta position (43%). Once again, one would expect to see a
substitution pattern heavily skewed towards the meta position if purely steric
factors dominated, as Tellers observed. Entry 2 (2,6-difluoroacetamide)
corroborates these findings by once again showing an inclination towards
substitution ortho to the fluorines (77% – a random distribution would be
66%) vs the relatively unhindered position meta to the fluorines (23%). Entries
4 and 5 attempt to recreate the Tellers experiment using 1,2-difluorobenzene as
the substrate. In this case, we observed an almost equal distribution of tritium
label ortho and meta to the fluorines. Using a T2/H2 mixture or no carrier-
added T2 produces a statistically equivalent distribution of tritium. This is in
contrast to the Tellers experiment, where distribution of the Ir isomers was
heavily skewed towards the meta-substituted Ir complex. For entry 6, a direct
competition is arranged in a benzophenone template between a phenyl ring
with no fluorines and one with two fluorines. In this case, the sterically
benevolent positions on the free phenyl ring are favored (accounting for 79%
of the tritium) and the label is equally distributed amongst the meta and para
positions. However, even in the difluorinated ring it can be seen that there is a
clear preference for the label to be incorporated ortho to the fluorine –
absolutely none occurs meta to the fluorines.
As mentioned before, hydroxyl (and to a lesser extent methoxy) moieties
appear to be exceptions to the steric model for tritium substitutions invol-
ving 1 in terms of their ability to direct ortho exchange. Entries 7 and 8 pit
fluorine against hydroxyl in a disubstituted acetanilide and benzophenone,
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M. B. SKADDAN AND R. G. BERGMAN
Table 1. Tritiation of fluorinated phenyl substrates
Entry
1
Substrate
NHAc
T Positiona
(43%) T
NHAc
(57%)
T
F
F
F
F
NHAc
F
NHAc
F
2
(23%)
T
(77%)
T
(13%)
COCH3
F
COCH3
F
F
F
3
(87%)
T
F
F
F
F
F
F
F
4
(54%)
T
(46%)
T
F
F
T
5b
F
(49%)
T
(51%)
O
F
O
F
F
(21%)
T
6
(26%)
T
F
T
(53%)
F
F
(33%) T
NHAc
OH
NHAc
OH
7
(38%)
T
T
(29%)
O
O
(47%)
(53%) T
HO
T
F
8
HO
F
aTritium location and percent distribution determined by 3H NMR.
bCarrier-free T2 used.
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NEIGHBORING GROUP EFFECT FLUORINE TRITIUM LABELING IRIDIUM
627
Scheme 2.
respectively. The results show that fluorine is almost equal to hydroxyl in
terms of its ‘directing power’. In entry 7, 33% of the label is ortho to fluorine,
while 29% is ortho to the hydroxyl moiety. For the benzophenone substrate
(entry 8), the results are similar – 53% of the label is ortho to the hydroxyl vs
47% for fluorine.
Several conclusions can be drawn from these data. First, there is a clear
neighboring group effect of fluorine on H/T exchange. Tritiations ortho to
fluorine occur at a relative rate more rapid than that which would be expected
from steric factors, or even a random distribution of tritium. Substitution
ortho to the fluorine is often favored, not just tolerated. Second, when there
exists both unhindered protons on a free phenyl ring and protons ortho to
fluorines on a different ring, exchange at the free phenyl ring is favored (entry
4). The obvious warning is that this is based on a singular example in which
the fluorines are located in a 2,6-disubstitution pattern in benzophenone.
Third, fluorine has about the same ‘directing power’ or neighboring group
effect as hydroxyl (entries 5 and 6).y
The exact mechanism of this fluorine-based directing influence on H/T
exchange is not clear. It is unlikely that a simple electronic effect can be
invoked (i.e. fluorine’s high electronegativity and subsequent decrease of
electron density at the ortho position increase the reactivity of the ortho C–H
bond), since at least one study suggests that more electron-deficient arenes
react more slowly with 1 than more electron-rich arenes.3 A more likely set of
scenarios using 1,2-difluorobenzene as an example substrate is illustrated in
Scheme 3.
In the first scenario (A), the meta-substituted Ir complex under-
0
goes decomposition faster than the ortho-substituted congener ðkD > kDÞ.
This would have the net effect of preferential accumulation of the ortho Ir
complex and subsequently a higher proportion of ortho-tritiated product. In
the second scenario (B), differing tritiation/hydrogenation rates lead to the
disparate distribution of products (since the majority of these experiments
were carried out using tracer quantities of T2 gas). In other words, if
0
0
kT=kH >> kT =kH , one would expect a preferential accumulation of the ortho-
tritiated product. However, the fact that the tritium distribution for
y In making these conclusions, it should be noted that no attempts were made to monitor the extent of
tritiation over time; therefore, the authors cannot verify that the exchange process has come to equilibrium.
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M. B. SKADDAN AND R. G. BERGMAN
Scheme 3.
1,2-difluorobenzene is statistically indistinguishable whether tracer or no
carrier-added T2 was used (Table 1, entries 4 and 5) strongly suggests that this
scenario is unlikely.
A more probable situation (C) is that fluorine is weakly coordinating via its
p-type lone pairs (‘secondary bonding’) to the Ir metal. The reversible
coordination directs the Ir to activate the C–H bond ortho to the C–F bond in
the arene. Cotton et al. have reported bromocarbon and fluorocarbon binding
to various transition metal cations, including Ir(III).16,17 Crabtree and
coworkers have also shown that cationic Ir(I) and – (III) complexes can bind
the halogens of halocarbons, including fluorine.18–20 Interestingly, they found
that the iodo-, bromo-, and chlorocarbon Ir–X distance is equal to the sum
of the covalent radii, while the Ir–F distance in the 8-fluoroquinoline complex
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NEIGHBORING GROUP EFFECT FLUORINE TRITIUM LABELING IRIDIUM
629
lies between the sum of the covalent radii and the sum of the van der Waals
radii. This intermediate distance suggests that the interaction is weaker than
that of a full covalent bond.18 The fact that we have not observed the same
effect with other halogens could mean that there is a delicate interplay bet-
ween the relatively small size of fluorine and its more reversible mode of
coordination to Ir, which in turn allows it to direct ortho H/T exchange in
a more facile nature.
Conclusions
We have treated a series of fluorinated organic substrates with 1 and T2 gas to
investigate the fluorine-directing potential of H/T exchange. Our results
indicate that fluorine exerts a clear neighboring group influence on the C–H
bond ortho to the fluorines in these substrates, with incorporation exceeding
that predicted by random exchange or that predicted intuitively from previous
studies on Ir(III)-mediated C–H activation ortho to arene substituents,
including halogens. Fluorine’s ‘directing influence’ seems to be at least as
strong as the hydroxyl moiety. Mechanistic understanding of why this occurs
is at this point lacking. An experiment comparing tritiated product ratios using
tracer and no carrier-added T2 suggest that the effect is not due to differing
tritiation vs hydrogenation rates of the substituted Ir complex intermediates.
Alternatively, the literature suggests that Ir–F coordination is a more plausible
explanation. These results not only further our understanding of this labeling
system, but also its application to drug substrates in light of the ubiquitous
presence of fluorine in many pharmaceutical libraries.
Experimental
The CH2Cl2 used for the stoichiometric tritiations was purchased from J. T.
Baker (BakerDRYTM, catalog No. 9295-10) without further purification. 20,60-
Difluorobenzophenone, 2,6-difluoronitrobenzene, 1,2-difluorobenzene and
3-fluoroacetanilide were purchased from Aldrich, 4-fluoro-40-hydroxybenzo-
phenone from TCI America, 2,4,6-trifluoroacetophenone from Matrix
Scientific, and 2,6-difluoroacetanilide from SynQuest. All reagents were used
without further purification. Mass spectrometric data were collected on a
Waters Micromass ZQ (ESI). Thin-layer chromatography (Analtech scored
glass 10 cm ꢃ 20 cm hard TLC plates) was used to assess the Sep-Pak1 eluent
1
3
profile and to determine final radiochemical purity. H, H, and 13C NMR
spectra were obtained on a Bruker 300 or 400 MHz Ultrashield spectrometer.
Resonances are reported in parts per million relative to the incomplete
deuteration signal from the NMR solvent. For the tritiated compounds,
3
percentages in the H NMR data correspond to the fraction of the total
integrated signal. Tritium NMR integration error limits are on the order
of ꢄ 1%, as determined by three consecutive 4096 scan experiments on 5 mCi
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630
M. B. SKADDAN AND R. G. BERGMAN
of [3H]1,2-difluorobenzene (1.11 Ci no carrier-added T2 run, vide infra).
Radioactivity measurements were made on a Packard Tricarb 1900CA liquid
scintillation analyzer. Radio-TLC analysis was performed on a Bioscan AR-
2000 Imager using WinScan 2.2 software.
General procedure for stoichiometric H/T exchanges
All manipulations prior to Trisorber use were performed in a N2 dry box.
Cp*Ir(PMe3)MeCl6 (5.20–5.42 mmol, 1.10 equiv.) was added to an oven-dried
2.5 ml round-bottom flask with stir bar, then NaBArf (5.20–5.42 mmol,
1.10 equiv.) was added. The dry mixture was solubilized in CH2Cl2
(150 ml), creating a dark orange solution. The flask was capped and stirred
vigorously for 10 min. A solution of the substrate (4.73–4.93 mmol, 1.00 equiv.)
in CH2Cl2 (150 ml) was added to the Ir solution. The flask was fitted with an
oven-dried 2-way stopcock valve (stopcock in closed position), and the
reaction mixture was stirred for 20 min at 258C. The assembly was removed
from the dry box and attached to an IN/US Trisorber TS-1000 manifold
(IN/US Systems Inc., Tampa, FL). The solution was degassed by freeze-
pump-thaw (1 cycle). The sensitive volume (the volume of gas to be opened to
the reaction flask ¼ Ve, 3.08 ml) was loaded with 5 torr T2 (48.4 mCi), and the
manifold volume (Va, 9.99 ml) was loaded with 152 torr H2 (tracer chemistry
was used to minimize waste and maximize safety). The two chambers were
quickly mixed, resulting in 119 torr H2/T2 (19.7 mmol, 7.99–8.33 equiv.) in
the sensitive volume, Ve. The sensitive volume was opened to the flask and the
reaction was stirred vigorously for 2 h. The reaction mixture was frozen and
the excess gas transferred to a uranium oxide waste bed. The manifold and
flask were backfilled with He and the flask/stopcock assembly removed from
the Trisorber manifold.
For substrates in table entries 1, 2, 7 and 8, exchangeable tritium was
removed by adding 0.3 ml ethanol and distilling the solvents under vacuum.
The crude material was redissolved in 250 ml of the mobile phase, and loaded
onto 2 tandem SiO2 Sep-Paks (Waters, WAT051910). The eluent was collected
in 1.5–3 ml fractions and the activity and purity of the fractions was monitored
by LSC and TLC, respectively. The appropriate fractions were then evapo-
rated under nitrogen and a final purity assessed by TLC (reported values are
final purities).
For [3H]2,4,6-trifluoroacetophenone and 1,2-difluorobenzene (Table entries
4 and 5), the crude reaction was vacuum distilled bulb-to-bulb without the
addition of ethanol. For the experiment involving no carrier-added T2, 1.11 Ci
was used. 3H NMR experiments were performed by diluting a 2–5 mCi sample
of the distillate with 600 ml CD2Cl2.
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NEIGHBORING GROUP EFFECT FLUORINE TRITIUM LABELING IRIDIUM
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[3H]3-Fluoroacetanilide (Table Entry 1)
Addition of the substrate to the Ir/NaBArf solution produced an orange
solution. The color changed to yellow upon exposure to H2/T2 gas. SPE
solvent system: Et2O. Radio-TLC purity ¼ 99%. Activity in crude, post-
distillation: 3.87 mCi. Activity in distillate: 11.1 mCi. Activity of pure tritiated
substrate recovered from crude: 1.64 mCi. 3H NMR (CD2Cl2, 320 MHz) d 6.93
(d, JT2F ¼ 8:8 Hz, 57%), 7.39 (d, JT2F ¼ 6:8 Hz, 43%).
[3H] 2,6-Difluoroacetanilide (Table Entry 2)
Addition of the substrate to the Ir/NaBArf solution produced an orange
solution. The color changed to yellow upon exposure to H2/T2 gas. SPE
solvent system: Et2O. Radio-TLC purity ¼ 97%. Activity in crude, post-
distillation: 1.41 mCi. Activity in distillate: 15.8 mCi. Activity of pure tritiated
3
substrate recovered from crude: 0.554 mCi. H NMR (CDCl3, 320 MHz) d
7.08 (d, JT2F ¼ 9:2 Hz, 77%), 7.32 (m, 23%).
[3H]2,4,6-Trifluoroacetophenone (Table Entry 3)
Note: due to the volatility of this compound, exchangeable tritiums were not
removed prior to SPE purification. Evaporations under N2 were done with the
vial containing the compound in an ice bath to prevent excess evaporation of
tritrated compound. Addition of the substrate to the Ir/NaBArf solution
produced an orange solution. The color remained orange upon exposure to
H2/T2 gas. SPE solvent system: 10% Et2O/Pentane. Radio-TLC purity ¼ 82%
(difficult to assess due to volatility). Activity in crude: 17.4 mCi. Activity of
3
pure tritiated substrate recovered from crude: 1.40 mCi. H NMR (CD3OD,
320 MHz) d 2.62 (s, 13%), 7.08 (t, JT2F ¼ 10:1 Hz, 87%).
[3H]1,2-Difluorobenzene (Table Entries 4 and 5)
Addition of the substrate to the Ir/NaBArf solution produced an
orange solution. The color changed to yellow upon exposure to H2/T2
gas, and was unchanged for the no carrier-added T2 experiment. Tracer
Run Data: Activity in crude, prior to distillation: 29.2 mCi. Activity in crude,
post-distillation: 8.98 mCi. Activity in distillate: 16.7 mCi. 3H NMR
(CDCl3, 320 MHz) d 7.24 (s, 46%), 7.31 (app. dd, JT2F ¼ 11:0,
9.0 Hz, 54%). N.C.A. T2 Run Data: Activity in crude, prior to distillation:
102.3 mCi. Activity in crude, post-distillation: 55.8 mCi. Activity in distillate:
3
44.0 mCi. H NMR (CDCl3, 320 MHz, average of three successive acquisi-
tions at 4096 scans each) d 7.24 (app. s, 51%), 7.31 (dd, JT2F ¼ 11:0,
8.9 Hz, 49%).
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[3H] 20,60-Difluorobenzophenone (Table Entry 6)
Addition of the substrate to the Ir/NaBArf solution produced an orange
solution. The color changed to a lighter orange upon exposure to H2/T2 gas.
SPE solvent system: 10% Et2O/Pentane. Radio-TLC purity ¼ 100%. Activity
in crude, post-distillation: 6.30 mCi. Activity in distillate: 14.9 mCi. Activity of
3
pure tritiated substrate recovered from crude: 4.23 mCi. H NMR ([2H6]ace-
tone, 320 MHz) d 7.33 (d, JT2F ¼ 9:2 Hz, 21%), 7.71 (s, 53%), 7.85 (s, 26%).
[3H]2-Fluoro-6-hydroxyacetanilide (Table Entry 7)
Addition of the substrate to the Ir/NaBArf solution produced an orange
solution. The color changed to yellow upon exposure to H2/T2 gas. SPE
solvent system: Et2O. Radio-TLC purity ¼ 94%: Activity in crude, post-
distillation: 4.62 mCi. Activity in distillate: 27.3 mCi. Activity of pure tritiated
substrate recovered from crude: 0.98 mCi. 3H NMR (CDCl3, 320 MHz) d 6.78
(d, JT2F ¼ 11:0 Hz, 33%), 6.93 (s, 29%), 7.17 (d, JTꢀF ¼ 7:1 Hz, 38%).
[3H]4-Fluoro-40-hydroxybenzophenone (Table Entry 8)
Addition of the substrate to the Ir/NaBArf solution produced a very dark
orange solution. The color changed to yellow upon exposure to H2/T2 gas.
SPE solvent system: 50% Et2O/Pentane. Radio-TLC purity ¼ 98%. Activity
in crude, post-distillation: 6.42 mCi. Activity in distillate: 22.4 mCi. Activity
of pure tritiated substrate recovered from crude: 4.05 mCi. 3H NMR
([2H6]acetone, 320 MHz) d 7.08 (s, 53%), 7.41 (d, JT2F ¼ 9:0 Hz, 47%).
3-Fluoro-2-nitrophenol (3)
Following a procedure adapted from Eriksson,15 sodium metal (81.9 mg,
2.56 mmol) was added to a 15 ml round bottom flask containing 3.6 ml
anhydrous methanol at 08C. The solution was stirred until the sodium had
completely dissolved. This NaOMe solution was added dropwise to a solution
of 2,6-difluoronitrobenzene (2, 501 mg, 3.15 mmol) in 9 ml anhydrous MeOH.
The reaction turned a yellow-orange color and was stirred overnight at RT.
TLC showed conversion of most of the starting material to a more polar spot.
The MeOH was evaporated in vacuo and the residue was partitioned between
water (5 ml) and diethyl ether (10 ml). The layers were separated and the
aqueous layer was extracted two more times with ether (10 ml each). The
organics were combined, dried with Na2SO4, and evaporated in vacuo to give
the crude 1-fluoro-3-methoxy-2-nitrobenzene as a pinkish yellow solid
(540 mg). This was used in the deprotection without further purification.
For the deprotection, the crude 1-fluoro-3-methoxy-2-nitrobenzene was
dissolved in anhydrous CH2Cl2 (6.2 ml) and cooled to 08C. To this was added
a 1M solution of BBr3 in CH2Cl2 (8.00 ml, 8.00 mmol) dropwise. The reaction
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NEIGHBORING GROUP EFFECT FLUORINE TRITIUM LABELING IRIDIUM
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was warmed to RT and the dark red solution was allowed to stir overnight.
LC-MS showed complete conversion of the starting material to the product.
The reaction was cooled to 08C and was quenched slowly with 6 ml water and
stirred for 1 h, during which time a chunky, red suspension formed. The
suspension was filtered through a course fritted funnel, and the biphasic
filtrate was separated. The aqueous layer was extracted with ether (3 ꢃ 5 ml),
and the organics were combined and evaporated in vacuo to a brown residue.
The residue was dissolved in 10 ml ether and extracted with 2M NaOH
(3 ꢃ 1.7 ml) and water (1 ml). The combined basic extracts were neutralized
with 6M HCl, then extracted with ether (3 ꢃ 8 ml). The combined ether
extracts were dried with Na2SO4 and evaporated in vacuo to an orange solid
(481 mg). The crude material was purified by flash chromatography (SiO2,
30% EtOAc/Hex) to give 3 (446 mg, 90%). MS (ESI neg) m/z 156 (M-H, 100).
2-Amino-3-fluorophenol (4)
To a solution of 3 (446 mg, 2.84 mmol) in EtOH (20 ml) was added Pd/C
(90 mg). The flask was evacuated of air and filled/purged with H2 gas three
times. The reaction was stirred vigorously under H2 balloon pressure
overnight. The suspension was then filtered through a short pad of Celite to
remove the Pd/C, and the orange filtrate was evaporated in vacuo to a solid
1
(426 mg). H NMR (CDCl3, 300 MHz) d 2.20 (s, 1H), 6.57–6.71 (m, 3H); MS
(ESI neg) m/z 126 (M-H, 100).
N-(2-fluoro-6-hydroxyphenyl)acetamide (5)
To a solution of 4 (300 mg, 2.36 mmol) in EtOAc (2.4 ml) at 08C was added
acetic anhydride (560 ml, 5.9 mmol) dropwise. The reaction was warmed to RT
and stirred overnight, then poured into a separatory funnel containing 5 ml
saturated NaHCO3. The layers were separated and the organic layer was
washed two more times with saturated NaHCO3 (2 ꢃ 5 ml), then dried with
Na2SO4 and evaporated in vacuo to a solid. The crude solid was purified by
flash chromatography (SiO2, 30–60% EtOAc/Hex) to give the title compound
as a slightly yellow solid (220 mg, 55%), as well as the N,O-diacetylated
product (148 mg, 30%). 1H NMR (CD3OD, 400 MHz) d 2.07 (s, 3H),
6.51–6.60 (m, 2H), 6.95–7.02 (m, 1H); 13C NMR (CD3OD, 100 MHz) d 22.6
(107.3, 107.5; JC2F ¼ 21:1 Hz), (113.38, 113.41; JC2F ¼ 3:0 Hz), 114.4, 128.9,
155.2 (158.3, 160.7; JC2F ¼ 247 Hz), 173.1; MS (ESI neg) m/z 168 (M-H, 100).
Acknowledgements
We gratefully acknowledge the radiosynthesis group at Pfizer for helpful
discussions and input. The work at UC Berkeley was supported by the
Director, Office of Energy Research, Office of Basic Energy Sciences, Chemical
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 623–634
DOI: 10.1002/jlcr

634
M. B. SKADDAN AND R. G. BERGMAN
Sciences Division, of the U.S. Department of Energy under Contract no.
DE-AC02-05CH11231.
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