Pd(0)-Mediated 11C-Carbonylation of Aryl(mesityl)iodonium Salts as a Route to [11C]Arylcarboxylic Acids and Derivatives

Article abstract of DOI:10.1021/acs.joc.7b01704

Pd(0)-mediated ¹¹C-carbonylation of aryl(mesityl)iodonium salts followed by suitable quench provides a rapid room-temperature two-pot procedure for labeling arylcarboxylic acids and amide derivatives with the short-lived positron emitter carbon

Full text of DOI:10.1021/acs.joc.7b01704

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Note
Pd(0)-Mediated 11C-Carbonylation of Aryl(mesityl)iodonium
Salts as a Route to [11C]Arylcarboxylic Acids and Derivatives
Stefano Altomonte, Sanjay Telu, Shuiyu Lu, and Victor W Pike
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01704 • Publication Date (Web): 03 Oct 2017
Downloaded from http://pubs.acs.org on October 4, 2017
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Pd(0)ꢀMediated 11CꢀCarbonylation of Aryl(mesityl)iodonium Salts as a Route
to [11C]Arylcarboxylic Acids and Derivatives
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Stefano Altomonte, Sanjay Telu*, Shuiyu Lu and Victor W. Pike
Molecular Imaging Branch, NIMH, NIH, Bethesda, MD 20892, USA
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Abstract: Pd(0)ꢀmediated 11Cꢀcarbonylation of aryl(mesityl)iodonium salts followed by
aqueous quench provides a rapid roomꢀtemperature twoꢀpot procedure for labeling
arylcarboxylic acids and amide derivatives with the shortꢀlived positronꢀemitter carbonꢀ11 (t1/2
=
20.4 min) in generally good to high yields (up to 71%). High product ringꢀselectivity ( 13) was
≥
achieved when using mesityl as a spectator group in the diaryliodonium salt precursors. This
process has potential for preparing new radiotracers for molecular imaging with positron
emission tomography.
Carboxylic acids and their derivatives, when labeled with the shortꢀlived positronꢀemitter
carbonꢀ11 (t1/2 = 20.4 min), are potential radiotracers for use in positron emission tomography
(PET), a molecular imaging technology with expanding utility in biomedical research, drug
development and clinical diagnosis.1–3 Novel radiotracers are continuously in demand for
biomedical research and for drug development. Generally, [11C]arylcarboxylic acids have been
synthesized from aryl halides, arylboronic acids or arylboronic esters with either [11C]carbon
monoxide or [11C]carbon dioxide as a labeling synthon.4–7 However, most of the known methods
suffer drawbacks, such as air/moisture sensitivity5, use of high temperatures,6 or use of high
amounts of precursor4.
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Carbonꢀ11 is produced from biomedical cyclotrons as either [11C]methane or [11C]carbon
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dioxide through the N(p,α)11C nuclear reaction on nitrogen in the presence of hydrogen (10%)
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or oxygen (1%), respectively.8 Either labeled compound can be obtained in high yield and high
molar activity [ratio of radioactivity (Bq) to amount of compound (mol)]. In addition,
[11C]carbon monoxide has been gaining importance as a labeling synthon because of: i) easy
highꢀyield and high molar activity synthesis by passage of [11C]carbon dioxide over heated
molybdenum (875 °C);9 (ii) the development of new apparatus10–15 and techniques16–20 for
increasing [11C]carbon monoxide availability in small volumes of organic solvents; (iii) the
expansion of strategies for transitionꢀmetal mediated insertion of [11C]carbon monoxide into
radiotracers;21–25 and (iv) the generally high functional group tolerance of the transition metalꢀ
mediated reactions.
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Aryliodine(III) compounds are useful arylation reagents.26 As examples, diaryliodonium
salts (ArI+Ar1X−) may be readily synthesized as quite stable but reactive compounds. Generally,
diaryliodonium salts show greater reactivity than the corresponding iodoarenes. In fact, the
phenyliodonio group (PhI+−) has106 times higher nucleofugacity than the widely used triflate
leaving group.27 Diaryliodonium salts have become widely used as precursors for labeling
arenes with [18F]fluoride ion and other radioactive nucleophiles.28–30 Salts with dissimilar aryl
rings (unsymmetrical salts) are generally preferred as precursors for ease of synthesis and
reagent economy. The possibility to use reactive unsymmetrical diaryliodonium salts for other
types of labeling reaction has been little explored. Exceptionally, AlꢀQahtani and Pike reported
that the Pdꢀmediated 11Cꢀcarbonylation of diaryliodonium salts (ArI+Ar1X−) in the presence of
arylstannanes (Ar2SnR3) at room temperature rapidly produces pairs of 11Cꢀlabeled diaryl
ketones i.e., Ar11COAr2 plus Ar1−11COAr2.31 In that study, [11C]arylcarboxylic acids were
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observed as minor byproducts due to high water content in the reaction medium (DME: H2O; 4:
1 v/v). Therefore, we envisaged that diaryliodonium salts might also serve as effective
precursors for the rapid synthesis of [11C]arylcarboxylic acids and derivatives under mild
conditions from [11C]carbon monoxide, provided that high ringꢀselectivity for the desired
product could be attained. Here we describe our progress towards developing the ringꢀselective
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Pdꢀmediated Cꢀcarbonylation of substituted diaryliodonium salts as a rapid roomꢀtemperature
route for producing [11C]arylcarboxylic acids and derivatives.
We report that
aryl(mesityl)iodonium salts are especially effective precursors for this radiochemistry.
AlꢀQahtani and Pike31 reported that the electronꢀrich 2ꢀanisyl ring introduces some ringꢀ
selectivity into the Pdꢀmediated 11Cꢀcarbonylation of 2ꢀanisyl(phenyl)iodonium tosylate (1) by
directing [11C]carbon monoxide incorporation preferentially to the phenyl ring. Thus, the 2ꢀ
anisyl group acted as a weak ‘spectator group’. To investigate whether the choice of palladium
11
reagent might increase ringꢀselectivity in the Cꢀcarbonylation of 1, different palladium(0) and
palladium(II) species were tested at 100 °C (Table 1).
Table 1. Screening of Palladium Reagents for the 11C-Carbonylation of 1.
entry
Pd
oxidation
state
Pd reagent
sonication
timea
I
YA of
[11C]3:
[11C]acids [11C]2 ratio
(%)b
(min)
(%)
II
II
II
II
II
0
0.5
0.5
0.5
0.5
0.5
5
1
2
3
4
5
6
PdCl2
[PdCl(C3H5)]2
(NHC)Pd(allyl)Clc
Pd(OAc)2
48
53
24
42
47
23
39
49
18
27
38
16
1.4
1.2
1.1
0.8
1.7
16
Pd(PPh3)2Cl2
Pd(PPh3)4
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0
0
0
0
0
0
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8
Pd[(o-tolyl)3P]2
Pd[P(Cy)3]2
Pd[(t-Bu)3P]2
Pd(dppe)2
62
27
12
45
44
47
49
12
9
3.6
2.5
1.4
1.0
1.1
0.9
5
9
5
10
11
12
32
39
37
0.5
0.5
Pd(dba)2
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Pd2(dba)3
a Of 1 with Pd-reagent preceding 11C-carbonylation.
b Aggregate yields (YA) are based on [11C]CO incorporation (I) and HPLC analysis, as described in the text.
c NHC = bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
Briefly, [11C]carbon monoxide was carried by helium into a sealed miniꢀautoclave.12
Then a preꢀsonicated32 mixture of diaryliodonium salt (3.8 µmol; 1.5−2.3 mg) and Pd reagent (~
0.5 mg), in DMF−water (4: 1, v/v; 100 µL), was pumped into the autoclave and allowed to react
at a set temperature for 2 min. The reactor contents were then transferred to a vented Vꢀvial (5ꢀ
mL). The radioactivity in the vial was measured. The vial was then purged with helium (10
mL/min) for 2 min to remove unreacted [11C]carbon monoxide, and the residual radioactivity
was recorded. The percent incorporation of [11C]carbon monoxide (I%) was measured as the
ratio of the final and initial radioactivity multiplied by 100. Control experiments showed that
negligible radioactivity was lost before the helium purge.
An aliquot of each quenched reaction mixture was analyzed with gradient reverse phase
HPLC. No radioactivity was left on the HPLC column at the end of analysis. All radioactive
peak areas were decayꢀcorrected. The aggregate yield of [11C]carboxylic acids (YA%) was
measured as the sum of peak areas corresponding to the two expected [11C]carboxylic acids
divided by the sum of peak areas for all detected radioactivity, multiplied by I%. The yield of a
single [11C]carboxylic acid or [11C]amide was measured analogously from its chromatographic
peak area and I%. Ringꢀselectivity was defined as the ratio of the yield of the desired
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[11C]carboxylic acid divided by the yield of the [11C]carboxylic acid derived from the spectator
ring. Labeled products were identified by coinjection with nonꢀradioactive standards.
In the screening reactions, except for that using an Nꢀheterocyclic carbene (NHC)ꢀbased
reagent (Table 1, entry 3), all the tested Pd(II) reagents (entries 1, 2, 4 and 5) gave 42−53%
[11C]carbon monoxide incorporation. In most cases, formation of [11C]benzoic acid ([11C]3) was
slightly preferred over [11C]2ꢀmethoxybenzoic acid ([11C]2). Among Pd(0) reagents (entries
6−12), Pd(PPh3)4 uniquely showed very high selectivity for formation of [11C]3 (16ꢀfold; entry
6), although [11C]carbon monoxide incorporation was low (23%). The more bulky phosphines
[e.g., tri(oꢀtolylphosphine)] gave much higher [11C]carbon monoxide incorporation (62%) and
about 4ꢀfold ringꢀselectivity for [11C]3 (entry 7).
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In view of the high ringꢀselectivity achieved with Pd(PPh3)4, we sought to improve yields
with its use in the 11Cꢀcarbonylation of 1. Interestingly, when reactions were conducted in
anhydrous DMF and quenched with waterꢀMeCN in a 2ꢀpot procedure, there were fewer and
lower levels of unknown radioactive byproducts, and the aggregate yield of [11C]carboxylic acids
increased over twoꢀfold (from 16 to 36%; Table entry 1 vs. entry 2). Basic (aq. 0.5 M NaOH or
aq. 1 M NH4OH in MeCN, 1: 1 v/v), or acidic (aq. 1 M HCl in MeCN, 1: 1 v/v) quenching
agents were also examined. Neutral or basic quench conditions were well tolerated. NH4OH
gave the best reproducibility and ringꢀselectivity (entry 3).
Table 2. Effects of Pd-Ligand System, Temperature, and Quenching Agent on 11C-
Carbonylation of 1 in One-pot and Two-pot Procedures.
entry
reaction
temp.
I
quench method
agentb temp.
YA of
[11C]3:
[11C]2
ratio
Pd−ligand
system
[11C]acids c
(°C)
(%)a
(%)a
(°C)
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d
1
2
Pd(PPh3)4
100
100
100
RT
23
37
-
-
16
36
16
8
Pd(PPh3)4
Pd(PPh3)4
A
B
A
B
B
A
A
B
-
100
RT
100
100
RT
RT
50
50
-
3
37
35
20
11
17
10
6
4
Pd(PPh3)4
35 ± 0
36
30 ± 1
29
5
Pd(PPh3)4
RT
6
Pd(PPh3)4
RT
30 ± 4
57
22 ± 1
33
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7
RT
Pd(PPh3)4−Xantphos
Pd(PPh3)4−Xantphos
Pd(PPh3)4−Xantphos
Pd(PPh3)4−Xantphosd
8
RT
62 ± 3
64 ± 3
36
43 ± 3
51 ± 5
10
12
15
7
9
RT
10
RT
a Values are means ± SEMs for n ≥ 2 or otherwise n = 1.
b A: H2O–MeCN (500 µL; 1: 1 v/v) for 2 min; B: 1 M NH4OH–MeCN (500 µL; 1: 1 v/v) for 2 min.
c Aggregate yields (YA) are based on [11C]CO incorporation (I) and HPLC analysis, as defined in the text.
d One-pot procedure. Other entries are two-pot.
In general, lowering the reaction temperature from 100 °C to room temperature did not
greatly affect the radioactive product outcome (Table 2, c.f., entries 2 and 3 with entries 4 and 6,
respectively). However, when radiosyntheses were performed at room temperature, a quench
temperature of at least 50 °C was found to avoid some unknown radioactive byproducts.
Bidentate phosphines, particularly Xantphos with a large bite angle (110°), are efficient
ligands in aminocarbonylation reactions.19,33 Hence, we examined the Pd(PPh3)4−Xantphos pair
for effect on [11C]carbon monoxide incorporation. In the twoꢀpot procedure with reaction at
room temperature, addition of Xantphos gratifyingly gave almost 2ꢀfold higher [11C]carbon
monoxide incorporation than when absent (Table 2, entries 4−6 vs entries 7−9). Surprisingly,
Xantphos had little effect on [11C]carbon monoxide incorporation in the oneꢀpot process (entry
10).
In search of increased ringꢀselectivity, we examined different ‘spectator groups’ (Table
3). The best ring selectivities were obtained with 2,4,6ꢀtriꢀsubstituted aryl groups. Despite
giving a slightly lower aggregate yield of the [11C]acids, a salt with a mesityl spectator group (5)
gave complete conversion into the desired [11C]benzoic acid ([11C]3). A salt with a 2,4,6ꢀ
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trimethoxyphenyl (TMP) group (6) gave comparable results, but required longer initial
sonication of the reaction mixture (10 min vs 5 min) for complete dissolution of reagents.
Notably, little ringꢀselectivity was observed in the reaction of the phenyl(2ꢀthienyl)iodonium salt
(7).
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Table 3. Spectator Group Effect on Yields and Ring-
Selectivities
in
the
11C-Carbonylation
of
Aryl(phenyl)iodonium Salts with the RT Two-pot
Procedure.
salta
Ar
(spectator
group)
2-An
I
YA of
[11C]acids
(%)b,c
51 ± 5
73
56 ± 4
64 ± 3
58
[11C]3:
Ar11CO2H
ratio
15
(%)b
64 ± 3
87
69 ± 1
70 ± 2
61
1
4
5
6
7
8
4-An
1.6
Mes
[11C]3 only
20
TMPd
2-Thi
DMUe
0.8
0.1
86
83
a All salts were tosylates, except 8 which was a triflate.
b Values are means ± SEMs for n = 2 or otherwise n = 1.
c
All reactions were quenched with Method B, except for those of 4
and 7 which were quenched with Method A. Aggregate yields (YA)
are measured from [11C]CO incorporation (I) and HPLC analysis, as
defined in the text.
d Sonication time: 10 min; 5 min was used for other entries.
e DMU: 1,3-dimethyl-urac-5-yl.
A 1,3ꢀdimethylꢀuracꢀ5ꢀyl (DMU) ring has been used as a spectator group in arylation
reactions.34 However, here this group failed as a spectator group: the 11Cꢀcarbonylation of
DMU(phenyl)iodonium triflate (8)35 gave mostly [11C]1,3ꢀdimethylꢀuracilꢀ5ꢀcarboxylic acid
([11C]13) (Table 3, entry 8).
We investigated the substrate scope and limitations of the room temperature twoꢀpot 11Cꢀ
carbonylation procedure with various substituted aryl(mesityl)iodonium salts (5, 14a−14n) that
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had been synthesized by known methods.36,37 Electronꢀwithdrawing or electronꢀdonating groups
in meta or para position gave good [11C]carbon monoxide incorporation (> 60%) and moderate
to high yields of the desired [11C]carboxylic acids (47−71%), with the exception of 4ꢀ
iodophenyl(mesityl)iodonium triflate, which gave [11C]4ꢀiodobenzoic acid ([11C]15e) in low
yield (11%). The mesityl group always acted as a highly effective spectator group, driving all
the 11Cꢀcarbonylation reactions almost exclusively to the desired aryl ring with ringꢀselectivities
usually far exceeding 13 (Table 4).
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4
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Table 4. Substrate Scope for Substituted Aryl(mesityl)iodonium Salts.
1) 11CO
R
Pd(PPh3)4 Xanthphos
DMF, RT, 2 min
R
TsO
11CO2H
+
Mes11CO2H
2) quench
Mes
[11C]2, [11C]3,
[11C]9,
[11C]10
5, 14a 14n
[11C]15a [11C]15n
salt
R
desired
product
I
ring-selectivityb
yield of
desired
product
(%)c
(%)a
5
H
[11C]3
69 ± 1 [11C]3 only
72 ± 3 13
56 ± 4
55 ± 0
65 ± 7
61 ± 4
63 ± 1
11 ± 4
47 ± 6
60 ± 1
71 ± 9
46 ± 3
59 ± 2
23 ± 1
12 ± 0
1 ± 0
14a
14b
14c
14d
14ed,e
14f
3-SF5
3-CN
3-Me
4-SF5
[11C]15a
[11C]15b
[11C]15c
[11C]15d
[11C]15e
82 ± 1 [11C]15b only
78 ± 4 > 183
77 ± 0 16
4-I
80 ± 3 [11C]15e only
60 ± 3 > 61
4-OMe [11C]9
14g
14h
14ie
14j
4-Me
4-CF3
2-iPr
2-Me
[11C]15g
77 ± 3 > 40
77 ± 8 > 72
[11C]15h
[11C]15i
[11C]15j
53 ± 1 > 66
72 ± 5 [11C]15j only
43 ± 1 > 23
14k
14l
2-OMe [11C]2
2-CN
2-CF3
2-F
[11C]15l
[11C]15m
[11C]15n
37 ± 10 33
14m
14nd
41 ± 11 n.d.f
30 ± 2 [11C]15n only
5 ± 2
a Values are means ± SEMs for n = 2
b For desired product versus [11C]10.
c Yields are based on [11C]CO incorporation (I) and HPLC analysis, as defined in the text, and
are means ± SEMs for n = 2.
dTriflate; other salts are tosylates.
e14e, 14i, and 14n were quenched with method A; the remaining reactions were quenched
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with method B.
f n.d. = not determined.
5
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8
Substituent electronics, more so than size, dictated 11Cꢀcarbonylation yield for ortho
substituted aryl(mesityl)iodonium salts (Table 4). For example, moderate yields of
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[11C]carboxylic acids were obtained from salts with an electronꢀdonating ortho methyl or ortho
isopropyl substituent ([11C]15j and [11C]15i; 59 and 46%; respectively). By contrast, salts with
small electronꢀwithdrawing substituents, such as nitrile or fluoro, gave low yields of the desired
[11C]carboxylic acids (12% for [11C]15l and 5% for [11C]15n). The salt with a bulkier and
stronger electronꢀwithdrawing ortho trifluoromethyl substituent gave only 1% of labeled acid
([11C]15m). [11C]Carbon monoxide incorporation into the Pdꢀiodonium center was low with
ortho electronꢀwithdrawing substituents; more than 60% of radioactivity was lost in the helium
purging of the reaction mixtures. Moreover, many unidentified radioactive products formed.
11CꢀCarbonylation at an sp2 carbon proceeded smoothly in (E)ꢀphenyl(styryl)iodonium
tosylate38 (16) to give [11C](E)ꢀcinnamic acid ([11C]18) in good yield and selectivity (Table 5).
This method was also effective for preparing a nonꢀconjugated vinylic [11C]carboxylic acid
([11C]19) from 17 (Table 5).
Table 5. 11C-Carbonylations at Vinylic Carbons.
salt
16
R
[11C]vinylic
acid
I
[11C]vinylic [11C]vinylic acid
acid: [11C]3
ratio
yield
(%)a,b
69 ± 5
32 ± 4
(%)a
Ph
[11C]18
[11C]19
92 ± 0
68 ± 1
10
1.4
17 cyclohexyl
a Values are means ± SEMs for n = 2.
b Yields are based on [11C]CO incorporation (I) and HPLC analysis, as defined in the text.
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Finally, we explored the mild twoꢀpot 11Cꢀcarbonylation procedure for the synthesis of
[11C]Nꢀmethylamides (Table 6). When the probable intermediates (arylꢀPdꢀ11CO) from the
reactions of [11C]carbon monoxide with the diaryliodonium salts 14b, 14g, and 14i were
quenched with methylamine (2 M in THF), amides [11C]20a−c, were obtained in moderate yields
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4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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32
33
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60
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(25−30%) under nonꢀoptimized conditions. These results suggest that the Cꢀcarbonylation of
diaryliodonium salts may be applied readily to synthesize derivatives of [11C]carboxylic acids
thereby extending the scope of this methodology.
Table 6. Examples of the Syntheses of [11C]Amides.
[11C]amide
I
salt
R
[11C]amide
yield
(%)a
30
28
25
(%)
14b
14g
14i
3-CN
4-Me
2-iPr
[11C]20a
[11C]20b
[11C]20c
81
73
53
a Yields are based on I and HPLC, and are for n = 1.
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In summary, the Cꢀcarbonylation of diaryliodonium salts constitutes a new and viable
method for the synthesis of [11C]arylcarboxylic acids and derivatives.
Experimental Section
Materials and Methods
Arylcarboxylic acids, 4ꢀiodophenyl(mesityl)iodonium triflate (14e), other chemicals, and
solvents were purchased commercially. All other diaryliodonium salts were synthesized
according to literature methods.35–37 (E)ꢀPhenyl(styryl)iodonium tosylate (16) and (E)ꢀ(2ꢀ
cyclohexylvinyl)(phenyl)iodonium tosylate (17) were synthesized by treatment of the
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corresponding boronic acids with Koser’s reagent,38 as described below. Some salts required
additional purification by crystallization. In those cases, salts were dissolved in a minimal
volume of MeCN or MeOH and precipitated by slow addition of diethyl ether and allowed to
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stand in a refrigerator for about 0.5 h. 1H (400.13 MHz), C (100.62 MHz), and 19F (376.47
MHz) NMR spectra were recorded on an Avance 400 instrument (Bruker) at RT in deuterated
solvents. 1H and 13C NMR signals are reported as δ (ppm) downfield from the signal for
tetramethylsilane. 19F NMR signals are reported as δ (ppm) downfield from the signal for
trichlorofluoromethane. HRMS data (ESIꢀTOF) were obtained at the Bioorganic Chemistry
Laboratory of NIDDK (NIH). Melting points were measured with a Digital SMP20 (Stuart)
melting point apparatus. Radiochemistry was performed in a leadꢀshielded hotꢀcell for protection
of personnel from radiation.
Synthesis of diaryliodonium salts
General method A. Koser’s reagent (0.78 g, 2 mmol) was added in one portion to an arene (2
mmol) in DCMꢀCF3CH2OH (10 mL, 10: 1, v/v) at RT. The resulting mixture was stirred at RT
for 24 h. Solvent was evaporated off and the crude mixture was triturated in diethyl ether (30
mL) for 30 min. The white solid was filtered off, washed with diethyl ether, and dried in vacuo.
General Method B. TsOH·H2O (0.38 g, 2 mmol) in MeCN (2 mL) was added to a solution of
(diacetoxyiodo)arene (2 mmol) in DCMꢀCF3CH2OH (10 mL, 10: 1, v/v) at 0 °C or CHCl3 (15
mL). In the case of reaction in DCMꢀCF3CH2OH, the obtained pale yellow solution was stirred
for 10 min and an arene (5 mmol) was added. The mixture was then warmed to RT and stirred
until it gave a negative KIꢀstarch paper test result. In the case of reaction in CHCl3, the mixture
was heated at 60 °C for 3 h. At the end of reactions, solvent was evaporated off and the crude
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mixture was triturated in diethyl ether (30 mL) for 30 min. The white solid was filtered off,
washed with diethyl ether and dried in vacuo.
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General Method C. TsOH·H2O (0.38 g, 2 mmol) was added to a solution of iodoarene (2 mmol)
and mCPBA (0.49 g, 2.2 mmol) in MeCN (10 mL) and the reaction mixture was heated at 77 °C
for about 0.5 h. Mesitylene (0.5 mL) was added to the reaction mixture and heating was
continued until the reaction mixture gave a negative KIꢀstarch paper test result (0.5−4 h).
Solvent was evaporated off and the crude mixture was triturated in diethyl ether (30 mL) for 30
min. The white solid was filtered off, washed with diethyl ether and dried in vacuo.
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(2ꢀMethoxyphenyl)(phenyl)iodonium tosylate (1). Method B, using phenyltributylstannane in
1
place of arene, gave 1 as a white solid (0.67 g, 70%). mp = 119−121 °C; H NMR (CDCl3) δ
7.94 (d, J = 8.0 Hz, 2H), 7.65–7.73 (m, 1H), 7.58–7.65 (m, 2H), 7.54 (d, J = 7.2 Hz, 2H), 7.39 (t,
J = 8.0 Hz, 2H), 7.07 (d, J = 7.6 Hz, 2H), 7.02 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 3.90
13
(s, 3H), 2.32 (s, 3H). C{1H}NMR (CDCl3), δ 156.8, 142.8, 139.2, 136.3, 135.3, 134.4, 131.7,
131.6, 128.4, 126.0, 123.8, 114.2, 112.4, 104.6, 56.8, 21.3. HRMS Calc'd. for C13H12OI+[M–
OTs]+ 310.9933, found 310.9937.
(4ꢀMethoxyphenyl)(phenyl)iodonium tosylate (4). Method A gave 4 as a white solid (0.9 g,
93%). mp = 163−166 °C; 1H NMR (CD3OD) δ 8.13–8.08 (m, 2H), 8.08–8.04 (m, 2H), 7.68 (d, J
= 8.2 Hz, 2H), 7.67–7.61 (m, 1H), 7.53–7.46 (m, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 9.1
13
Hz, 1H), 7.03 (q, J = 5.5 Hz, 1H), 3.82 (s, 3H), 2.35 (s, 3H). C{1H}NMR (CD3OD) δ 164.5,
143.6, 141.7, 138.6, 136.0, 133.4, 133.0, 129.8, 127.0, 118.8, 116.6, 104.5, 56.4, 21.3. HRMS
Calc'd. for C13H12OI+ [M–OTs]+ 310.9933, found 310.9935.
Mesityl(phenyl)iodonium tosylate (5). Method A gave 5 as a white solid (0.81 g, 82%). mp =
1
175−177 °C; H NMR (CD3OD) δ 7.91–7.86 (m, 2H), 7.69–7.60 (m, 3H), 7.52–7.46 (m, 2H),
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7.24–7.17 (m, 4H), 2.64 (s, 6H), 2.36 (s, 3H), 2.35 (s, 3H). 13C{1H}NMR (CD3OD) δ 145.9,
143.7, 143.6, 141.8, 135.4, 133.4, 133.3, 131.4, 129.9, 127.1, 122.5, 114.3, 27.2, 21.5, 21.1.
HRMS Calc'd. for C15H16I+ [M–OTs]+ 323.0297, found 323.0302.
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Phenyl(2,4,6ꢀtrimethoxyphenyl)iodonium tosylate (6). Method A gave 6 as a white solid (1 g,
1
92%). mp = 198−199 °C; H NMR (CD3OD) δ 7.94 (dd, J = 8.4, 1.1 Hz, 2H), 7.68 (d, J = 8.2
Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.48–7.41 (m, 2H), 7.20 (d, J = 7.9 Hz, 2H), 6.40 (s, 2H), 3.96
13
(s, 6H), 3.88 (s, 3H), 2.35 (s, 3H). C{1H}NMR (CD3OD) δ 168.9, 161.6, 143.8, 141.7, 135.9,
133.2, 132.9, 129.9, 127.1, 116.0, 93.0, 86.3, 57.9, 56.8, 21.5. HRMS Calc'd. for C15H16O3I+ [M–
OTs]+ 371.0144, found 371.0145.
Phenyl(thiophenꢀ2ꢀyl)iodonium tosylate (7). Method A gave 7 as a white solid (0.28 g, 61%, 1
mmol scale). mp = 141−143 °C; 1H NMR (CD3OD) δ 8.19–8.11 (m, 2H), 7.99 (dd, J = 3.8, 1.2
Hz, 1H), 7.87 (dd, J = 5.4, 1.2 Hz, 1H), 7.71–7.63 (m, 3H), 7.54–7.47 (m, 2H), 7.21 (d, J = 7.9
13
Hz, 2H), 7.15 (dd, J = 5.4, 3.8 Hz, 1H), 2.35 (s, 3H). C{1H}NMR (CD3OD) δ 143.7, 142.3,
141.8, 138.7, 135.9, 133.8, 133.2, 131.0, 130.0, 127.1, 119.2, 99.2, 21.5. HRMS Calc'd. for
C10H8SI+ [M–OTs]+ 286.9391, found 286.9393.
(1,3ꢀDimethylꢀuracꢀ5ꢀyl)(phenyl)iodonium triflate (8). TfOH (0.36 mL, 4 mmol) was added
dropwise to a solution of (diacetoxyiodo)benzene (0.66, 2 mmol) in DCM (10 mL) at – 40 °C
and the resulting yellow solution was stirred for 0.5 h. 1,3ꢀDimethyluracil (0.28 g, 2 mmol) was
added to this stirred solution which was further stirred at – 40 °C for 0.5 h. The mixture was
warmed to RT and stirred for another 0.5 h. Solvent was evaporated off and the residue was
triturated in diethyl ether (30 mL) for 30 min. The solid was filtered off, washed with diethyl
ether (15 mL × 2) and dried in vacuo to give 8 as a white solid (0.85 g, 86%). mp = 168−170 °C;
1H NMR (CD3CN) δ 8.59 (s, 1H), 8.11–8.04 (m, 2H), 7.70 (tt, J = 7.1, 1.1 Hz, 1H), 7.57–7.50
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(m, 2H), 3.41 (s, 3H), 3.26 (s, 3H). C{1H}NMR (CD3CN) δ 160.1, 156.1, 151.9, 136.4, 134.0,
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4
5
6
133.1, 121.3 (q, J = 320.6 Hz), 114.9, 86.6, 38.6, 30.0. 19F{1H} NMR (CD3CN) δ −79.34 (s).
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8
9
+
HRMS Calc'd. for C12H12IN2O2 [M−OTf]+ 342.9944, found 342.9939.
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3ꢀPentafluorosulfanylphenyl(mesityl)iodonium tosylate (14a). Method C gave 4 as a white
1
solid (0.61 g, 53%)
.
mp = 193−195 °C; H NMR (CD3OD) δ 8.42 (s, 1H), 8.10 (d, J = 8.3 Hz,
1H), 7.99 (d, J = 8.0 Hz, 1H), 7.73–7.61 (m, 3H), 7.26 (s, 2H), 7.20 (d, J = 8.0 Hz, 2H), 2.64 (s,
6H), 2.37 (s, 3H), 2.35 (s, 3H). 13C{1H}NMR (CD3OD) δ 156.1 (quint, J = 19.2 Hz), 146.5,
143.8, 143.6, 141.8, 138.3, 134.2, 132.54 (quint, J = 4.5 Hz), 131.7, 130.7 (quint, J = 4.5 Hz),
19
129.9, 127.1, 122.8, 113.9, 27.2, 21.5, 21.2. F{1H} NMR (CD3OD) δ 79.99 (quint, J = 150.6
Hz), 61.45 (d, J = 148.7 Hz). HRMS Calc'd. for C15H15F5IS+ [M–OTs]+ 448.9859, found
448.9863.
(3ꢀCyanophenyl)(mesityl)iodonium
tosylate
(14b).
Method
B,
from
(4ꢀ
diacetoxyiodo)benzonitrile and mesitylene gave 14b as an offꢀwhite solid (0.65 g, 63%). mp =
1
177−178 °C; H NMR (DMSOꢀD6) δ 8.56 (t, J = 1.5 Hz, 1H), 8.23 (dq, J = 8.3, 1.0 Hz, 1H),
8.09 (dt, J = 7.8, 1.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.21 (s, 2H),
13
7.10 (d, J = 7.8 Hz, 2H), 2.59 (s, 6H), 2.29 (s, 3H), 2.28 (s, 3H). C{1H}NMR (DMSOꢀD6) δ
145.4, 143.2, 141.7, 138.9, 137.6, 135.3, 132.3, 129.7, 127.9, 125.4, 122.8, 116.8, 114.5, 113.9,
26.3, 20.7, 20.4. HRMS Calc'd. for C16H15IN+ [M–OTs]+ 348.0249, found 348.0254.
Mesityl(mꢀtolyl)iodonium tosylate (14c). Method C gave 14c as a white solid (0.77 g, 76%).
1
mp = 159−161 °C; H NMR (CD3OD) δ 7.73 (s, 1H), 7.66 (d, J = 6.8 Hz, 2H), 7.65 (d, J = 7.6
Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.21 (s, 2H), 7.19 (d, J = 7.9 Hz, 2H),
2.63 (s, 6H), 2.35 (s, 9H). 13C{1H}NMR (CD3OD) δ 145.7, 144.3, 143.6, 143.5, 141.6, 135.4,
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134.0, 132.9, 132.2, 131.3, 129.8, 127.0, 122.2, 114.0, 27.1, 21.33, 21.27, 21.1. HRMS Calc'd.
for C16H18I+ [M–OTs]+ 337.0453, found 337.0449.
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8
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4ꢀPentafluorosulfanylphenyl(mesityl)iodonium tosylate (14d). Method C gave 14d as a white
solid (0.33 g, 29%). mp = 162−163 °C;1H NMR (CD3OD) δ 8.05 (d, J = 8.7 Hz, 2H), 7.94 (d, J
= 9.0 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.26 (s, 2H), 7.20 (d, J = 8.0 Hz, 2H), 2.64 (s, 6H), 2.37
(s, 3H), 2.36 (s, 3H).13C{1H}NMR (CD3OD) δ 157.1 (quint, J = 18.5 Hz), 146.4, 143.7, 143.5,
141.7, 135.9, 131.6, 130.6 (quint, J = 4.6 Hz), 129.8, 127.0, 122.5, 117.6, 27.1, 21.3, 21.1.
19F{1H} NMR (CD3OD) δ 80.10 (quint, J = 150.4 Hz), 61.11 (d, J = 148.5 Hz). HRMS Calc'd.
for C15H15F5IS+ [M–OTs]+ 448.9859, found 448.9857.
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Mesityl(4ꢀmethoxyphenyl)iodonium
tosylate
(14f).
Method
B,
using
(diacetoxyiodo)mesitylene and anisole, gave 14f as a white solid (0.6 g, 57%). mp = 191−192
°C; 1H NMR (CD3OD) δ 7.84 (q, J = 5.6 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 8.2 Hz,
2H), 7.21 (d overlapped with singlet up field, J = 8.2 Hz, 2H), 7.18 (s, 2H), 7.02 (q, J = 5.6 Hz,
1H), 7.02 (d, J = 9.2 Hz, 1H), 3.82 (s, 3H), 2.65 (s, 6H), 2.35 (s, 3H), 2.33 (s, 3H). 13C{1H}NMR
(CD3OD) δ 164.3, 145.6, 143.8, 143.4, 141.7, 137.6, 131.3, 129.9, 127.1, 123.0, 119.0, 102.8,
56.5, 27.1, 21.5, 21.2). HRMS Calc'd. for C16H18IO+ [M–OTs]+ 353.0402, found 353.0403.
Mesityl(pꢀtolyl)iodonium tosylate (14g). Method C gave 14g as a white solid (0.62 g, 61%).
mp = 171−172 °C; 1H NMR (CD3OD) δ 7.76 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 7.5 Hz, 2H), 7.30
(d, J = 7.7 Hz, 2H), 7.20 (s, 4H), 2.63 (s, 6H), 2.40–2.32 (m, 9H). 13C{1H}NMR (CD3OD) δ
145.7, 144.6, 143.6, 143.4, 141.6, 135.3, 134.0, 131.3, 129.8, 127.0, 122.4, 110.4, 27.0, 21.3,
21.3, 21.1. HRMS Calc'd. for C16H18I+ [M–OTs]+ 337.0453, found 337.0447.
Mesityl(4ꢀ(trifluoromethyl)phenyl)iodonium tosylate (14h). Method C gave 14h as a white
solid (0.36 g, 64%). mp = 164−166 °C; 1H NMR (CD3OD) δ 8.05 (d, J = 8.0 Hz, 2H), 7.77 (d, J
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= 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.24 (s, 2H), 7.19 (d, J = 8.0 Hz, 2H), 2.64 (s, 6H), 2.36
5
6
13
(s, 3H), 2.35 (s, 3H). C{1H}NMR (CD3OD) δ 146.2, 143.7, 143.6, 141.7, 135.9, 134.8 (q, J =
7
8
9
34.2 Hz), 129.8, 129.7 (q, J = 3.0 Hz), 126.9, 124.7 (q, J = 272.7 Hz), 122.5, 118.0, 27.1, 21.3,
21.1. 19F{1H} NMR (CD3OD) δ – 64.7. HRMS Calc'd. for C16H15F3I+ [M–OTs]+ 391.0171,
found 391.0172.
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(2ꢀIsopropylphenyl)(mesityl)iodonium tosylate (14i). Method C gave 14i as a white solid
(0.35 g, 33%). mp = 146−149 °C; 1H NMR (CD3OD) δ 7.89 (d, J = 8.1 Hz, 1H), 7.69–7.63 (m,
3H), 7.60 (t, J = 7.9 Hz, 1H), 7.28 (t, J = 7.1 Hz, 1H), 7.24–7.17 (m, 4H), 3.03 (sept, J = 6.8 Hz,
1H), 2.60 (s, 6H), 2.35 (s, 6H), 1.19 (d, J = 6.4 Hz, 6H). 13C{1H}NMR (CD3OD) δ 151.9, 145.8,
143.7, 143.6, 141.6, 137.7, 134.4, 131.6, 131.1, 130.1, 129.8, 127.0, 121.4, 118.0, 39.3, 26.8,
24.0, 21.3, 21.0. HRMS Calc'd. for C18H22I+ [M–OTs]+ 365.0766, found 365.0769.
Mesityl(oꢀtolyl)iodonium tosylate (14j). Method B, using (2ꢀdiacetoxyiodo)toluene and
mesitylene in CHCl3 at 60 °C with 3 h reaction time, gave 14j as an offꢀwhite solid (0.67 g,
66%). mp = 172−173 °C; 1H NMR (CD3OD) δ 7.83 (d, J = 7.9 Hz, 1H) 7.66 (d, J = 8.2 Hz, 2H),
7.56–7.52 (m, 2H), 7.28–7.16 (m, 5H), 2.61 (s, 6H), 2.60 (s, 3H), 2.36 (s, 3H), 2.35 (s, 3H).
13C{1H}NMR (CD3OD) δ 145.8, 143.8, 143.7, 142.5, 141.7, 137.3, 134.1, 133.5, 131.6, 130.8,
129.9, 127.1, 121.7, 118.5, 27.1, 25.2, 21.5, 21.1. HRMS Calc'd. for C16H18I+ [M–OTs]+
337.0453, found 337.0456.
Mesityl(2ꢀmethoxyphenyl)iodonium tosylate (14k).
Method C was used with slight
modification. Thus, TsOH·H2O (0.98 g, 4 mmol) was added to a solution of 2ꢀiodoanisole (0.94
g, 4 mmol) and mCPBA (0.98 g, 4.4 mmol) in CHCl3 (20 mL) at RT and stirred for 10 min.
Mesitylboronic acid (0.66 g, 4 mmol) was added to the mixture and stirred for 1 h at RT. Work
1
up was as in method C and gave 14k as white crystals (1.44 g, 69%). mp = 178−179 °C. H
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NMR (CD3OD) δ 7.87 (dd, J = 8.0, 1.5 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.63–7.60 (m, 1H),
7.25 (dd, J = 8.4, 1.1 Hz, 1H), 7.19 (d, J = 7.9 Hz, 2H), 7.16 (s, 2H), 7.06 (td, J = 7.9, 1.3 Hz,
1H), 3.91 (s, 3H), 2.63 (s, 6H), 2.34 (s, 3H), 2.33 (s, 3H). 13C{1H}NMR (CD3OD) δ 158.6,
145.5, 143.9, 143.8, 141.7, 137.4, 136.0, 131.2, 129.9, 127.1, 124.9, 121.1, 114.4, 103.3, 57.6,
26.9, 21.5, 21.1. HRMS Calc'd. for C16H18OI+ [M–OTs]+ 353.0402, found 353.0406.
(2ꢀCyanophenyl)(mesityl)iodonium tosylate (14l). Method C gave 14l as a white solid (0.17 g,
16%). mp = 187−190 °C; 1H NMR (CD3OD) δ 8.25 (dd, J = 8.1, 0.9 Hz, 1H), 8.03 (dd, J = 7.7,
1.6 Hz, 1H), 7.84 (td, J = 7.7, 1.1 Hz, 1H), 7.76 (td, J = 7.9, 1.7 Hz, 1H), 7.66 (d, J = 8.2 Hz,
2H), 7.22 (s, 2H), 7.21 (d overlapped with the down field singlet, J = 8.0 Hz, 2H), 2.69 (s, 6H),
2.36 (s, 3H), 2.35 (s, 3H). 13C{1H}NMR (CD3OD) δ 146.3, 143.9, 143.7, 141.7, 138.9, 137.3,
137.1, 134.4, 131.7, 129.9, 127.1, 123.4, 119.2, 118.6, 117.2, 27.3, 21.4, 21.1. HRMS Calc'd. for
C16H15IN+ [MꢀOTs]+ 348.0249, found 348.0254.
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Mesityl(2ꢀ(trifluoromethyl)phenyl)iodonium tosylate (14m). Method C gave 14m as a white
solid (0.53 g, 47%). mp = 150−152 °C; 1H NMR (CD3OD) δ 8.05–7.99 (m, 2H), 7.85 (t, J = 7.7
Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.25 (s, 2H), 7.19 (d, J = 8.4 Hz, 2H),
2.61 (s, 6H), 2.37 (s, 3H), 2.35 (s, 3H). 13C{1H}NMR (CD3OD) δ 146.6, 144.0, 143.5, 141.7,
138.7, 137.0, 134.2, 132.1 (q, J = 32.6 Hz), 131.8, 130.6 (q, J = 5.1 Hz), 129.8, 126.9, 124.2 (q, J
= 273.6 Hz), 123.3, 109.3, 27.0, 21.3, 21.1. 19F{1H} NMR (CD3OD) δ ꢀ60.83 (s). HRMS Calc'd.
for C16H15F3I+ [M–OTs]+ 391.0171, found 391.0173.
(2ꢀFluorophenyl)(mesityl)iodonium tosylate (14n). Method C gave 14n as a white solid (0.55
g, 54%). mp = 167−168 °C; 1H NMR (CD3OD) δ 8.12 (dd, J = 7.7, 5.9, 1.5 Hz, 1H), 7.73–7.68
(m, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.44 (td, J = 8.7, 1.3 Hz, 1H), 7.32 (td, J = 8.1, 1.3 Hz, 1H),
7.21 (d overlapped with up field singlet, J = 8.5 Hz, 2H), 7.18 (s, 2H), 2.66 (s, 6H), 2.35 (s, 3H),
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2.32 (s, 3H). 13C{1H}NMR (CD3OD) δ 161.7 (d, J = 250.3 Hz), 145.8, 143.5, 141.7, 138.3,
136.9, 136.8, 131.3, 129.8, 128.8 (d, J = 3.2 Hz), 126.9, 122.6, 118.4 (d, J = 22.5 Hz), 100.9 (d, J
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= 23.3 Hz), 26.8 (d, J = 1.9 Hz), 21.3, 21.0. F{1H} NMR (376 MHz, CD3OD) δ −98.34 (s).
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HRMS Calc'd. for C15H15FI+ [M–OTs]+ 341.0203, found 341.0206.
(E)ꢀPhenyl(styryl)iodonium tosylate (16). Koser’s reagent (0.392 g, 1 mmol) was added to a
solution of (E)ꢀstyrylboronic acid (0.15 g, 1 mmol) in DCMꢀCF3CH2OH (10 mL; 9: 1 v/v) at 0
°C. The mixture was stirred overnight. Solvent was then evaporated off, and the residue was
triturated in diethyl ether (25 mL). The solid was filtered off and recrystallized to give 16 as offꢀ
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white crystals (0.38 g; 79%). mp = 147−148 °C. H NMR (CD3OD) δ 8.14 (d, J = 7.6 Hz, 2H),
7.92 (d, J = 14.4 Hz, 1H), 7.81 (d, J = 14.4 Hz, 1H), 7.65–7.73 (m, 3H), 7.55 (t, J = 8.0 Hz, 2H),
7.49–7.55 (m, 2H), 7.38–7.47 (m, 3H), 7.20 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H), 13C{1H}NMR
(CD3OD) δ 152.0, 143.6, 141.7, 136.6, 135.9, 133.6, 133.2, 132.2, 130.2, 129.9, 128.9, 127.0,
114.2, 99.9, 21.3. HRMS Calc’d for C14H12I+ [M−OTs]+ 306.9984, found 306.9987.
(E)ꢀ(2ꢀCyclohexylvinyl)(phenyl)iodonium tosylate (17). The method for 16 was applied to
(E)ꢀ(2ꢀcyclohexylvinyl)boronic acid (1.5 mmol) and gave 17 as a white solid (0.57 g; 79%). mp
= 85−87 °C. 1H NMR (CD3OD) δ 8.05 (dd, J = 7.6 Hz, 2H), 7.75–7.66 (m, 3H), 7.55 (t, J = 8.0
Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.98–7.07 (m, 2H), 2.36 (s, 3H), 2.25–2.36 (m, 1H), 1.73 (d, J
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= 10.4 Hz, 4H), 1.65 (d, J = 12.8 Hz, 1H), 1.10–1.38 (m, 5H). C{1H}NMR (CD3OD) δ 160.4,
143.7, 141.7, 136.5, 133.5, 133.1, 129.9, 127.0, 113.7, 99.8, 45.2, 32.6, 26.8, 26.6, 21.4. HRMS
Calc'd. for C14H18I+ [M−OTs]+ 313.0453, found 313.0455.
Synthesis of amides (20 a−c). SOCl2 (1.1 eq) was added to an aryl acid (2ꢀisopropylbenzoic
acid, 3ꢀcyanobenzoic acid or 4ꢀtoluic acid) in toluene (0.3 M) and the reaction mixture was
heated at reflux for 3 h. The solvent and residual SOCl2 were evaporated off in vacuo and the
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residue was dissolved in anhydrous THF. A THF solution of Nꢀmethylamine (2 M, 2.3 eq) was
added and the reaction mixture was stirred at RT for 16 h. The mixture was concentrated to
dryness in vacuo and the crude product was purified with flash chromatography on normal phase
silica gel with DCM and methanol as a gradient starting at 0% methanol and increased to 5%.
Thus were prepared:
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3ꢀCyanoꢀNꢀmethylbenzamide (20a). White solid. mp = 136−138 °C. H NMR (CDCl3) δ
8.09–8.04 (m, 1H), 8.01 (dt, J = 7.8, 1.3 Hz, 1H), 7.77 (dt, J = 7.8, 1.4 Hz, 1H), 7.57 (t, J = 7.8
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Hz, 1H), 6.41 (bs, 1H), 3.03 (d, J = 4.9 Hz, 3H). C{1H}NMR (CDCl3) δ 166.0, 135.8, 134.6,
131.3, 130.6, 129.6, 118.0, 112.9, 27.4. HRMS Calc’d. for C9H9N2O [M+H]+ 161.0715, found
161.0717.
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4ꢀMethylꢀNꢀmethylbenzamide (20b). White solid. mp = 137−138 °C. H NMR (CDCl3) δ
7.66 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 6.17 (bs, 1H), 3.00 (d, J = 4.8 Hz, 3H), 2.38 (s,
13
3H). C{1H}NMR (CDCl3) δ 168.2, 141.7, 131.8, 129.2, 126.8, 26.8, 21.4. HRMS Calc’d. for
C9H12NO [M+H]+ 150.0919; found 150.0918.
2ꢀIsopropylꢀNꢀmethylbenzamide (20c). Offꢀwhite solid (~ 90% pure by HPLC). mp = 73−75
°C. 1H NMR (CDCl3) δ 7.36 (s, 2H), 7.31–7.21 (m, 1H), 7.20–7.11 (m, 1H), 5.74 (bs, 1H), 3.31
(sept, J = 6.8 Hz, 1H), 3.00 (d, J = 4.8 Hz, 3H), 1.26 (d, J = 4 Hz, 6H). 13C{1H}NMR (CDCl3) δ
171.3, 146.6, 136.2, 129.9, 126.5, 126.0, 125.6, 29.9, 26.7, 24.2. HRMS Calc’d. for C11H16NO
[M+H]+ 178.1232; found 178.1233.
Radiochemistry
Noꢀcarrierꢀadded [11C]CO2 was prepared with the 14N(p,α)11C nuclear reaction by bombarding a
nitrogenꢀ1% oxygen gas target (initial pressure 300 p.s.i.) with a proton beam (16 MeV, 5 or 10
µA) from a cyclotron (PETrace; GE) for 5 or 10 min. Radiochemistry was performed in a leadꢀ
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shielded hotꢀcell on a modified Synthia platform controlled by inꢀhouse developed software
based on Labview.39,40 [11C]CO2 was first collected in a stainless steel tube trap filled with
molecular sieves (13X or 4Å) at RT. The trap was purged with helium at 80 mL/min for 45 s to
remove oxygen. [11C]CO2 was then released in a helium stream (16 mL/min) at 270°C and
concentrated in a cryogenic trap filled with silica gel. [11C]CO2 was then released from the
cryotrap in helium (10 mL/min) by warming the trap with a halogen lamp and then passed over
molybdenum wire (99.97%, 0.05 mm diameter, Strem Chemicals, Newburyport, MA) in a quartz
tube (22 cm length, 0.7 cm i.d.) heated at 875 °C to produce [11C]CO. The [11C]CO was first
concentrated cryogenically on silica gel in a stainless steel trap cooled with liquid nitrogen and
then released in helium into the autoclave by warming the trap with a halogen lamp.
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One-pot 11C-carbonylation method: Diaryliodonium salt 1 (3.8 µmol; ~ 1.8 mg) and Pd reagent
(~ 0.5 mg) in DMF−H2O (4: 1 v/v, 100 µL) were sonicated for 30 s or 5 min and loaded into an
autoclave. The mixture was allowed to react with [11C]CO at a set temperature for 2 min, and
then collected in a vented glass vial (5ꢀmL). Radioactivity in the vial was measured before and
after helium purge for 2 min. An aliquot (50 µL) was then diluted with MeCNꢀH2O (1: 1 v/v;
500 µL) and analyzed with reverse phase HPLC.
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Two-pot C-carbonylation method: Precursor (1, 4−8, 14a–14n, 16, or 17; 3.8 µmol; ~ 1.5−2.3
mg, plus Pd(PPh3)4 (0.5 mg) with Xantphos (0.5 mg) or without in DMF (80 µL) were sonicated
for 5 min and treated with [11C]CO in an autoclave at a set temperature for 2 min. The reaction
mixture was then transferred to a vented glass vial and purged with helium for 2 min. An aliquot
(50 µL) was then mixed with aq. NH4OH (1 M)–MeCN or water–MeCN and allowed to react at
RT, 50 or 100 °C for 2 min preceding HPLC analysis.
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Two-pot 11C-amidation method: The reaction mixture containing precursors (14b, 14g, or 14i;
3.8 µmol), Pd(PPh3)4 (0.5 mg) and Xantphos (0.5 mg) in DMF (80 µL) was sonicated for 5 min
and treated with [11C]CO in an autoclave at ambient temperature for 2 min. The reaction mixture
was then transferred to a vented glass vial and purged with helium for 2 min. NꢀMethylamine in
THF (2 M, 100 µL) was added to an aliquot of the reaction mixtre (50 µL) and the mixture was
heated at 50 °C for 2 min. The reaction mixture was cooled to RT and analysed with HPLC.
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Radioactivity was measured with a calibrated AtomlabTM 300 dose calibrator (Biodex
Medical Systems; Shirley, NY), and corrected for background and physical decay of carbonꢀ11.
RadioꢀHPLC analysis
HPLC was performed on a system comprising a Gold 126 solvent module (Beckman Coulter;
Fullerton, CA) coupled with a 166 or 168 UV absorbance detector plus a Flowꢀcount
radioactivity PMT detector (Bioscan, Washington, DC). An aliquot of the quenched reaction
mixture was injected onto a reverse phase column (Luna C18, 10 µm, 100 Å, 250 × 4.6 mm i.d.;
Phenomenex, Torrance, CA) eluted at 2 mL/min with a linear gradient of aqueous 0.1% TFA
(A)–MeCN (B), starting with 10% B and increasing to 50% B in 10 min, held for 5 min, then
increased to 80% B in 2 min and held for 5 min at 80% B. Eluate was monitored for
radioactivity and absorbance at 231 or 254 nm. Radiochemical product identities were
confirmed by comparison of HPLC retention times with nonꢀradioactive standards. In some
examples, labeled products were collected and coꢀinjected with reference standards.
AUTHOR INFORMATION
Stefano Altomonte 0000ꢀ0002ꢀ3897ꢀ8421.
Sanjay Telu: 0000ꢀ0001ꢀ5300ꢀ8725.
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Shuiyu Lu: 0000ꢀ0003ꢀ0310ꢀ4318.
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Victor William Pike: 0000ꢀ0001ꢀ9032ꢀ2553.
Corresponding Author
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*Eꢀmail: telus@mail.nih.gov
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Intramural Research Program of the National Institutes of
Health (NIMH; project ZIA MH002793). We are grateful to the NIH Clinical Center (Chief Dr.
P. Herscovitch) for cyclotron production of carbonꢀ11.
ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge on the ACS Publications website at DOI:
Examples of radioꢀHPLC chromatograms, and 1Hꢀ, 13C{1H}ꢀ, 19F{1H)}ꢀNMR spectra.
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