Thermolysis and radiofluorination of diaryliodonium salts derived from anilines

Article abstract of DOI:10.1039/c7ob00253j

Aniline-derived diaryliodonium salts were synthesized and functionalized in good to excellent yields by judicious utilization of electron-withdrawing protecting groups. This simple approach opens another route to radiolabeling amino arenes in relatively complex molecules, such as flutemetamol.

Full text of DOI:10.1039/c7ob00253j

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Thermolysis and Radiofluorination of Diaryliodonium Salts
Derived from Anilines
Ethan J. Linstad,a,b Amy L. Vāvere,c Bao Hu,b Jayson J. Kempinger,a Scott E. Snyderc and Stephen G.
Received 00th January 20xx,
Accepted 00th January 20xx
DiMagno*b
DOI: 10.1039/x0xx00000x
Aniline-derived diaryliodonium salts were synthesized and functionalized in good to excellent yields by judicious utilization
of electron-withdrawing protecting groups. This simple approach opens another route to radiolabeling amino arenes in
relatively complex molecules, such as flutemetamol.
www.rsc.org/
transfer from the electron-rich arene ligands to iodine is the
likely cause of their rapid decomposition. A second factor
complicating the use of aniline-derived diaryliodonium salts is
that the regiochemistry of substitution is generally dictated by
electronic effects;17, 18 the C-I bond in the electron-poor aryl
substituent is cleaved preferentially.19-21 These two
characteristics conspire to make functionalization of anilines
using diaryliodonium salts difficult. Here we demonstrate that
this synthetic hurdle can be overcome by installing electron-
withdrawing protective groups on the aniline nitrogen. This
Introduction
Diaryliodonium salts are useful intermediates in the synthesis of
a variety of functionalized arenes.1-9 The high efficiency with
which nucleophiles add to them has made these aryl
electrophiles convenient precursors for the preparation of
labeled compounds, particularly 18F-fluorinated imaging agents
for positron emission tomography (PET). Uncatalyzed arylation
reactions of unsymmetrical diaryliodonium salts generally
comprise two steps: 1) ion-exchange of the incoming anionic
nucleophile for a weakly bound counterion (e.g. triflate)
followed by 2) migration of the nucleophilic group from iodine
to the ipso carbon of the more electron-poor aromatic ring.10
Treatment of diaryliodonium salts with one equivalent of
tetrabutylammonium (TBA) or tetramethylammonium (TMA)
salts of a variety of anionic nucleophiles, followed by heating
the resulting complex in acetonitrile, generally provides good
yields of the functionalized arenes. Peculiarly,11 arene
fluorination with Ar2I salts requires different conditions, in part
because the strongly basic fluoride ion induces aryl exchange
reactions in polar aprotic solvents.12 However, we have found
that the use of reduced polarity solvents increases the yield of
and selectivity with which fluoroarenes are formed from
diaryliodonium salt precursors.13
simple approach opens
functionalizing and radiolabeling aminoaryl substituents in
relatively complex molecules, and it provides viable
a
straightforward route to
a
alternative to copper-catalyzed fluorodestannylation and
fluorodeborylation reactions used previously for 18F-labeling of
anilines.22-24
Results and discussion
To test the impact of various amine protecting groups upon
functionalization of aniline-derived diaryliodonium salts, we
Scheme 1 Diaryliodonium salt synthesis
Although the scope of arene functionalization is remarkably
broad, diaryliodonium salt stability and regiochemical control
suffer when particularly electron-rich aryl groups, such as
anilines, are substituents on iodine(III). For example, (4-
dimethylamino)phenyliodonium salts have only been isolated
as relatively short-lived compounds;14-16 inner-sphere electron
a.Department of Chemistry, University of Nebraska–Lincoln, Lincoln, Nebraska
68588, USA
b.Departments of Medicinal Chemistry & Pharmacognosy and Chemistry, University
of Illinois–Chicago, Chicago, Illinois 60612, USA. Email: sdimagno@uic.edu
c. Division of Nuclear Medicine, Department of Diagnostic Imaging, St. Jude
Children’s Research Hospital, Memphis, Tennessee 38105, USA
Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization and spectral data. See DOI: 10.1039/x0xx00000x
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prepared compounds 1-7 (Scheme 1); which feature ortho-, anilines (8) in excellent average yields (92%). OVnielyw A5rt-i1cl0e %Onlionef
meta-, and para-aniline derivatives as the ultimate functionalized anisole was observed DiOnI: 1t0h.1e0s3e9/Cr7eOaBc0t0io25n3sJ.
electrophiles. The second aryl group in each case was 4- Compound
methoxyphenyl, chosen for its proven directing group ability in reaction conditions; it was recovered unchanged after it was
diaryliodonium salt thermolysis reactions, and the ease with heated at 120 °C in acetonitrile-d3 for days. The
1 alone was stable as the triflate salt under the
7
which compounds incorporating this group can be isolated and regioselectivity observed in the functionalization reaction and
crystallized. Weakly coordinating anions (hexafluorophosphate, the excellent stability of the starting diaryliodonium salt pointed
triflate) facilitate ion exchange with incoming nucleophiles. to the possibility that less electron-withdrawing and more easily
Since hexafluorophosphate undergoes fluoride ion exchange, dislodged amine protecting groups might be compatible with
triflate is preferred for 18F-labeling reactions.
this chemistry.
Diaryliodonium salts 1-6 were synthesized in good yields by
Amide acetyl protection proved to be compatible with
coupling potassium (4-methoxyphenyl)trifluoroborate with I(III) aniline functionalization at the para position. Symmetrical and
derivatives of the para-, meta-, or ortho-iodoanilines (Scheme unsymmetrical diaryliodonium salts featuring 4-(N-methyl-N-
1). This synthetic methodology has been previously acetylamino)phenyl substituents have been previously
26
demonstrated for the preparation of a wide range of reported,16,
but the reactions of these compounds with
unsymmetrical
iodophenyl)(methyl) carbamate could not be successfully that functionalization of
oxidized and coupled to form compound successfully under although with a slightly lower average yield (89%, Table 1) than
the standard conditions, likely because steric hindrance or in reactions involving
coordination from the aniline Boc protecting group interfered Since the acetyl group requires relatively aggressive
with the oxidation. Thus, we prepared a Grignard reagent from conditions for its removal, we investigated functionalization of
this iodoaniline and coupled it successfully to 4- , in which the readily hydrolyzed Boc group was installed on
methoxyphenyliodonium diacetate, forming the diaryliodonium the aniline nitrogen. Arene functionalization with to give 10
salt was efficient, but average yields were somewhat lower than
features the strongly electron-withdrawing with or (83%, Table 1). A possible explanation for the lower
phthalimide protecting group. Thermolysis of in the presence overall yields observed with is that loss of the protecting group
begins to be competitive with functionalization at elevated
temperatures (90-120 °C). To test this hypothesis, we heated
at 90 °C and 110 °C in acetonitrile-d3 in a sealed NMR tube.
While spontaneous deprotection of was slow at 90 °C, the
half-life of at 110 °C was only 30 minutes and decomposition
diaryliodonium
salts.25
t-Butyl
(2- nucleophiles have not been extensively explored. We found
2
proceeded smoothly to afford
9,
7
1
.
3
3
7
.
Compound
1
1
2
1
3
of a variety of nucleophiles (Table 1) gave the functionalized
3
Table 1 Thermolysis yields of diaryliodonium saltsa
3
3
was accompanied by evolution of isobutylene. Although
spontaneous thermal Boc deprotection of anilines is not
generally observed at such low temperatures, this reaction is
readily understood if the exceptional electron-withdrawing
ability of the I(III) substituent is considered: the Hammett sigma
value for PhI(III) (p = 1.35)27, 28 is roughly equivalent to two
nitro substituents (
p = 0.78)29.
These observations suggested that substrates featuring 4-N-
methylamide functionality should be excellent precursors for
radiolabeling using the diaryliodonium salt approach. Thus, we
synthesized a diaryliodonium salt precursor (15) of Ro 05-4865
(Scheme 2), an analogue of diazepam, which may be useful for
imaging benzodiazepine receptors to monitor brain recovery
X
N3
OAc
SCN
I
8
9
10
80
11
93
90
96
99
89
91
92
12
85
40
9c
13
90
55
65
91
71
74
78
14
87
98
98
76
98
90
90
95
89
93
85
99
89
78
88
75
35b
30b
55b
54b
31b
90
Scheme 2 Ro 05-4865 diaryliodonium salt synthesis
71
94b
82b
82b
95
49d
41d
43d
0c
Br
Cl
Fe
aYield (%) by 1H NMR (1.1 eq. of nucleophile added as TBAX or TMAX to
diaryliodonium salt in CD3CN and heated until thermolysis completed) bMix of N-
Boc & N-H product. cMostly benzoxazolium side product. d1:1 with benzoxazolium
side product. e0.25 eq. of TMAF heated in 10% CH3CN in C6D6.
2 | J. Name., 2012, 00, 1-3
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Scheme 3 Benzodiazepine radiofluorination
post-stroke and identify epileptic seizure sites.30 The aryl iodide
was oxidized with Selectfluor™ and coupled to potassium 4-
methoxyphenyltrifluoroborate, as described previously.25
Halidation (F, Cl Br, I) of 15 at 120 °C in acetonitrile for Cl, Br, I,
and in 10% acetonitrile in benzene for F gave the substituted
diazepam derivatives (16) in excellent yields (≥94%) indicating
Scheme 5 Thermolysis paths of
7
NMR spectra. The structural assignment was consistent with
the mass spectrum (calculated for C10H12ON+ [M-PF6 ] 162.09,
-
found 162.07). Importantly, heating of
at 100 °C for 2 hours provided the same benzoxazolium product
17) by internal cyclization (Scheme 4). We posited that the
4 alone in acetonitrile-d3
15 could be
a
suitable radiochemical precursor.
(
Radiofluorination (40 mCi scale) using 8 mg of 15 was carried
out using an IBA Synthera® automated radiosynthesis module
(see ESI). [18F]Fluoride substitution was complete within 10 min
after heating to 140 °C in 10% acetonitrile in toluene; the
radiochemical yield (RCY) of [18F]16 was 32.1 ± 4.0% (n = 3)
decay corrected to end of bombardment (EOB) (Scheme 3).
HPLC purification gave the product (30.2 ± 4.7% RCY) in 97%
radiochemical purity.
As the above results show, functionalization and 18F-
labeling of arenes para to protected amines are relatively
straightforward processes; the only complication was loss of
Boc at elevated temperatures. Similarly, functionalization of
meta-iodoaniline through the intermediacy of diaryliodonium
ratios of cyclization and functionalization products could be
altered significantly by either reducing the electron-density on
the amide oxygen or by using steric effects to reduce the C=O…I
interaction. To test this hypothesis, we prepared
diaryliodonium salt
trifluoracetate protecting group significantly reduce the basicity
of the carbonyl oxygen. As a result, underwent smooth
5, in which the three fluorine atoms in the
6
functionalization to give 13 with our standard subset of
nucleophiles. Although yields were generally lower (75%) than
in the p-substituted examples, in no case was a cyclized
benoxazolium product observed.
In an attempt to use steric effects to suppress internal
cyclization and benzoxazolium salt formation, the reactivity of
salts is also an efficient process. Compound
4 was smoothly
the Boc-protected diaryliodonium salt
7 was investigated. The
converted to various substituted aniline derivatives 11 (Table 1)
in high yield. In no case, even with the most basic nucleophiles
in this set, was evidence for aryne formation observed.
In contrast to the straightforward and general
functionalization of para- and meta-derivatives, substitution of
diaryliodonium salts ortho to amine nitrogen is somewhat more
nucleophiles azide and, surprisingly, fluoride were arylated with
ease at relatively low temperatures, while thermolysis reactions
featuring other nucleophiles required higher temperatures to
initiate (>80 °C) and gave rise to complex mixtures of products
(14, Table 1). Compound 7 alone proved to be relatively
unstable at elevated temperatures, losing the Boc group
completely after heating for 2 hours at 90 °C in acetonitrile-d3.
Treatment of the deprotected (N-H) diaryliodonium salt with
nucleophiles (I, Br, Cl) yielded multiple products (Scheme 5).
Thus, it seems clear that if spontaneous deprotection occurs,
the opportunity to obtain an acceptable yield of functionalized
aniline is lost. The greater fragility of the Boc protective group
complex. Diaryliodonium salt
5 (Scheme 1) was prepared
without difficulty; however, the standard thermolysis reactions
did not provide the expected functionalized products (12) in
uniformly high yields (Table 1). While highly nucleophilic azide
afforded the desired 2-azido aniline directly, a single side
product predominated in reactions featuring less nucleophilic
anions. Conspicuously, none of the desired 2-fluoro aniline was
formed with tetramethylammonium fluoride (Table 1).
in 7 compared to that in 3 was investigated using computational
chemistry (see ESI). Density functional theory (B3LYP/6-
311G(d,p)/MIDIX) calculations of aryliodonium model
compounds featuring Boc-protected amines ortho and para to
the I(III) center revealed that the ground state and transition
state structures of the ortho derivative were stabilized by
coordination of the carbamate carbonyl oxygen to the I(III). In
comparison to the para isomer, the ground state and transition
state of the ortho isomers were stabilized by 5.4 and 8.7
kcal/mol respectively, leading to a lower ΔGǂ for the ortho
isomer (∆∆Gǂ = 2.1 kcal/mol). Thus, it appears that coordination
of the Boc carbonyl to I(III) is a reasonable explanation for the
Inspection of the NMR data from these reactions revealed
that loss of starting material was correlated with the formation
of a product exhibiting a methyl singlet at 3.98 ppm, a chemical
shift indicative of a methyl iminium cation. The structure of this
product, a benzoxazolium cation, was inferred from 1H and 13
C
Scheme 4 Benzoxazolium formation mechanism
reduced stability of the ortho-N-Boc derivative
Unexpectedly, fluoridation of occurred at a much lower
temperature than was observed with 1-6 (>100 °C). We
7.
7
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Scheme 6 Calculated transition-state structure
Scheme 8 Synthesis of protected [18F]flutemetamol
postulated that the enhanced reactivity of
7 arose from a
= 3) EOB (Scheme 8). The ease with which the pharmacophore
core structure can be radiofluorinated indicates that suitably
protected diaryliodonium salts are promising precursors to
[18F]flutemetamol, which has been previously synthesized from
combination of steric and coordinative interactions of the Boc
substituent with the ortho-iodonium group. The effect of these
interactions is to rotate the nitrogen substituent out of
conjugation with the arene ring, rendering the aromatic system
much less electron-rich than in a typical protected aniline.
Notably, this congested environment appears not to interfere
with binding of and subsequent substitution by the small anions
a nitroaromatic compound32, 33
.
Conclusions
-
F- and N3 , while rate accelerations were not apparent for I-, Br-
In the course of these studies, we have identified the reaction
modes of variously protected aniline diaryliodonium salts, and
have shown that ortho-, meta-, and para-aniline derivatives
behave surprisingly differently. A key lesson from this work is
that electron-withdrawing protective groups in 4-anilino-
iodonium salts behave exactly as expected; reaction rate
acceleration is directly correlated with the electron-
withdrawing ability of the substituent. In contrast, direct
interaction of protective groups with the I(III) center in ortho-
aminophenyliodonium salts 5-7 leads to cyclization, more facile
deprotection, and enhanced reaction rates with sterically
undemanding nucleophiles. The surprising implication of these
findings is that, under the appropriate conditions, para-, meta-,
and ortho-aniline-derived diaryliodonium salts are practical
[18F]-fluorination substrates.
, Cl-, SCN-, or OAc-. Computational investigation into the
fluoridation of a model ortho-substituted iodonium salt
(Scheme 6) shows that the Boc-protected amino group is indeed
twisted out of conjugation with the aryl ring at the transition
state.
Seeking to take advantage of the smooth ortho fluoridation
of Boc-protected aniline diaryliodonium salts, we turned our
attention to the radiosynthesis of [18F]flutemetamol (Vizamyl™),
which contains aniline and benzothiazole rings with the fluoride
ortho to the amine. [18F]Flutemetamol is used for imaging β-
amyloid plaques in the brain as a diagnostic tool for Alzheimer's
disease.31 A Boc-protected precursor (18) was prepared in 5
steps from commercially available starting materials in modest
yield (Scheme 7). As was found previously for ortho-iodoaniline
derivatives, direct oxidation of I(I) to I(III) was not successful in
this hindered system, so we again employed the
transmetalation approach used to prepare 7. Fluorination of 18
Experimental section
was carried out using a sub-stoichiometric amount of TMAF in
acetonitrile-d3/benzene-d6 (60 °C, 30 min) to provide the
corresponding protected fluoroarene ([19F]19) in 83% yield,
with no fluorination of the 4-methoxyphenyl directing arene
observed.
General methods
All materials were obtained from commercial sources and used
as received unless otherwise noted. Trimethylsilyl acetate
(TMSOAc), trimethylsilyl trifluoroacetate (TMSTFA), and
trimethylsilyl triflate (TMSOTf) were distilled under reduced
pressure into flame‐dried storage tubes and stored under
nitrogen. Acetonitrile and d3‐acetonitrile (Cambridge Isotope
Laboratories) were stirred over P2O5 (12 h), distilled into flame-
dried storage tubes, and transferred into an inert atmosphere
glove box. Benzene and d6‐benzene (Sigma-Aldrich) were dried
over Na/benzophenone (12 h), distilled directly into flame‐dried
storage tubes, and stored under dry nitrogen. Tetrahydrofuran
(THF) was dried over Na/benzophenone and distilled into a
flame dried storage flask under dry nitrogen. Acetate buffer
concentration was 0.5 M HOAc and 0.5 M NaOAc unless
otherwise noted. All glassware and NMR tubes were oven dried
(140 °C) for 24 h before they were transferred into the glove box
for use. Glove box manipulations were performed under
nitrogen in an MBraun Labmaster 130, equipped with a
recirculating purifier, which removed oxygen and water. All
NMR experiments reported were performed using a Bruker
Avance 300 MHz, 400 MHz, 500 MHz, 600 MHz, or 700 MHz
NMR spectrometers in the NMR laboratory at the University of
Radiofluorination of 18 was carried out in 1 mL of a 10%
acetonitrile/toluene solution containing 4 mg of 18 and 10 mCi
of [18F]fluoride that was heated gradually to 120 °C over the
course of 10 min to produce [18F]19 in 52% RCY (51.7 ± 1.9%, n
Scheme 7 Protected [19F]flutemetamol synthesis
4 | J. Name., 2012, 00, 1-3
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Nebraska or at the University of Illinois at Chicago and from the glove box and the solvent was removed under reduced
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calibrated using residual protonated solvent. Yields from NMR pressure. The remainder was treatedDOwI:it1h0.10t3h9e/C7mOiBn0im02u5m3J
scale reactions were determined by using the residual solvent amount of acetonitrile needed to dissolve it, and this solution
peak as an internal standard. All J coupling values are given in was added to an aqueous solution of sodium
Hz. Computational work was done using the Gaussian 0934 suite hexafluorophosphate (6.7 g, 40 mmol). The solution was
of programs.
filtered, and the solid was retained. The filtrate was extracted
with CH2Cl2 (3 x 25 mL). The combined organic layers were
added to the recovered solid and the resulting solution was
Experimental
Diaryliodonium salts (except
7
,
15, and 18) were synthesized dried over sodium sulfate, filtered to remove the drying agent,
according to the method previously reported.25
and the solvent was removed by rotary evaporation. The
resulting oil was dissolved in acetonitrile (40 mL) diluted with
(2-((Boc)(methyl)amino)-5-methylphenyl)(4'-
methoxyphenyl)iodonium trifluoromethansulfonate (7). N- ethyl acetate (200 mL). MTBE was added until the solution
Boc-N-methyl-2-iodotoluidine (525 mg, 1.51 mmol) was reached the cloud point (250 mL). The solution was allowed to
dissolved in dry THF. The solution was chilled to -78 °C and iso- stand at room temperature overnight to precipitate the
propylmagnesium chloride (2 M in THF, 1.13 mL, 2.26 mmol) product. The solution was filtered, and more MTBE added until
was added slowly with stirring. This reaction mixture was stirred the solution again reached the cloud point and the process was
for 1 hour at -78 °C to effect the transmetalation. 4- repeated to obtain a second crop. The product was recovered
Methoxyphenyliodonium diacetate (1.6 g, 4.54 mmol) was as a colorless crystalline solid (3.0 g, 60%). The initially isolated
dissolved in dry THF, and this solution was also chilled to -78 °C. hexafluorophosphate salt (2 g, 3.2 mmol) was converted to the
The Grignard reagent solution was added through a chilled triflate salt using an IRA-400 ion exchange column. Removal of
cannula to the stirred solution of iodonium diacetate. The the solvent followed by recrystallization as above yielded the
1
reaction mixture was allowed to warm slowly to room colorless crystalline product (1.5 g, 75%). H NMR (CD3CN, 400
temperature overnight. The reaction was poured into acetate MHz, 25 °C): δ 8.16 (dd, J = 9.0, 2.3; 1H), 7.93 (d, J = 9.1, 2H),
buffer (50 mL), extracted with ethyl acetate (25 mL x 4), washed 7.84 (d, J = 2.2, 1H), 7.53 (t, J = 8.1, 2H), 7.45 (d, J = 7.1, 2H), 7.39
with water (10 mL), dried over sodium sulfate, and the solvents (t, J = 7.6, 2H), 7.03 (d, J = 9.1, 2H), 4.65 (d, J = 10.8, 1H), 3.86 (s,
were removed under reduced pressure. Acetonitrile (10 mL) 3H), 3.74 (d, J = 10.8, 1H), 3.33 (s, 3H). 13C NMR (CD3CN, 176
was
added
to
the
residue
and
sodium MHz, 25 °C): δ 170.3, 169.1, 164.4, 148.4, 138.9, 138.7, 138.7,
trifluoromethanesulfonate (1.3 g, 7.6 mmol, in 10 mL water) 138.0, 137.9, 132.5, 131.8, 130.4, 129.4, 126.1, 119.1, 107.4,
was added. After stirring for 1.5 hours, the acetonitrile was 102.8, 57.8, 56.8, 35.2. 19F NMR (CD3CN, 376 MHz, 25 °C): δ -
removed by rotary evaporation. The remaining aqueous 79.31 (s, 3F). HRMS (ESI) calculated for C23H20N2O2I [M-(OTf)]
solution was extracted with ethyl acetate (25 mL x 3), and the 483.0564, found 483.0569.
combined organic extracts were washed with water (10 mL),
dried over sodium sulfate, and evaporated. The residue was (4-methoxyphenyl)iodonium triflate (18). In
(2-(N-Boc-N-methyl)amino-5-(6-methoxybenzothiazolyl))
nitrogen-
a
dissolved in acetonitrile (10 mL), MTBE (25 mL) added and the charged glovebox, 2-(3-iodo-4-(N-Boc-N-methyl)phenyl)-6-
mixture was allowed to stand overnight. The solution was benzothiazole (550.14 mg, 1.11 mmol) was dissolved in 5 mL of
filtered to yield the product as colorless crystals (0.090 g, 5%). dry THF, and placed in a flame-dried 50 mL Schlenk tube. The
1H NMR (CD3CN, 700 MHz, 60 °C): δ 7.98 (d, J = 9.0, 2H), 7.62 (s, solution was chilled to -78 °C before iPrMgCl (2.0 M in THF, 1.1
1H), 7.50 (d, J = 8.1, 1H), 7.44 (d, J = 8.1, 1H), 7.09 (d, J = 9.0, mL, 2.22 mmol) was added dropwise with stirring. The solution
2H), 3.88 (s, 3H), 3.28 (s, 3H), 2.32 (s, 3H), 1.52 (br s, 9H). 13C was stirred for 5 minutes, and transferred by cannula to another
NMR (CD3CN, 175 MHz, 60 °C): δ 164.6, 142.5, 142.0, 139.5, 50
mL
flame-dried
Schlenk
tube
containing
135.7, 135.5, 128.4, 123.5, 121.7, 119.5, 102.8, 84.4, 57.1, 38.7, bis(acetoxy)iodoanisole (1.17 g, 3.33 mmol) in 10 mL of dry THF
28.8, 21.0. 19F NMR (CD3CN, 376 MHz, 25 °C): δ -79.33 (s, 3F). at -78 ˚C. The solution was stirred for 15 minutes at -78 ˚C, the
HRMS (ESI) calculated for C20H25O3NI 454.0874 [M-OTf-], found reaction vessel was shielded from light using aluminum foil, and
454.0879.
(7-Iodo-1-methyl-5-phenyl-1,3-dihydro-2H-
benzo[e][1,4]diazepin-2-one)(4'-methoxyphenyl)iodonium
the reaction mixture was allowed to warm slowly to room
temperature over the course of 12 h. The solution was
concentrated in vacuo and diluted with 15 mL of methanol.
trifluoromethansulfonate (15). In a glove box under nitrogen, Sodium triflate (1.91 g, 11.10 mmol) was dissolved in 10 mL of
7-iodo-1-methyl-5-phenyl-1,3-dihydro-2H-benzo[e][1,4] water/methanol (1:2, v/v) and added dropwise to the
diazepin-2-one (3.00 g, 7.97 mmol) and SelectfluorTM (3.67 g, vigorously stirred solution. After 30 minutes, the mixture was
10.36 mmol) were dissolved in dry acetonitrile (30 mL). TMSOAc concentrated in vacuo to remove methanol, and the remaining
(3.36 mL, 22.32 mmol) was added to the solution dropwise. The aqueous solution was transferred to a separatory funnel and
reaction mixture was heated in a sealed container at 60 °C for 3 extracted three times with DCM. The organic layers were dried
h with stirring and then allowed to cool to room temperature. over sodium sulfate, and solvent was removed in vacuo. The
Potassium (4-methoxyphenyl) trifluoroborate (1.92 g, 8.76 crude oil was sonicated with hexanes and filtered. The solid was
mmol) was added to the stirred reaction mixture, followed by sonicated in 15 mL ethyl acetate, chilled to 0 ˚C, and filtered.
dropwise addition of TMSTFA (1.38 mL, 8.0 mmol). The solution The solid was sonicated again in 15 mL ethyl acetate, chilled to
was stirred for 10 min before the reaction vessel was removed 0 ˚C, and filtered to yield a pale yellow solid (0.243 g, 29.1%). 1H
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J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
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Journal Name
NMR (CD3CN, 400 MHz, 25 °C): δ 8.36 (br s, 1H), 8.22 (dd, J = 8.5, thanks the National Natural Science Foundation ofVCiehwinAratic(leNOSnFliCne)
DOI: 10.1039/C7OB00253J
1.8, 1H), 8.08 (d, J = 9.0, 2H), 7.88 (d, J = 8.9, 1H), 7.64 (d, J = 8.5, (no. 21202148) for support.
1H), 7.54 (d, J = 2.5, 1H), 7.14 (dd, J = 8.9, 2.5, 1H), 7.12 (d, J =
9.0, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.37 (br s, 3H), 1.56 (s, 9H);
19F NMR (CD3CN, 376 MHz, 25 °C): δ -79.30 (s, 1F); 13C NMR
(CD3CN, 100 MHz, 25 °C): δ 187.3, 164.7, 164.7, 162.4, 159.5,
149.3, 139.6, 137.9, 132.7, 124.9, 123.8, 119.2, 118.4, 117.5,
105.6, 56.8, 56.7, 38.5, 28.5, 1.8, 1.6, 1.4, 1.2, 1.0; HRMS: (ESI)
calculated for C27H28IN2O4S [M-(OTf)]+ 603.0809 found
603.0795.
Notes and references
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Support for this research was provided by NIH R01EB015536
and ALSAC-St. Jude Children's Research Hospital. Bao Hu also
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DOI: 10.1039/C7OB00253J
Mechanistic and theoretical studies reveal new reactions of Ar2I salts that can interfere with radiolabeling of these substrates.