11C-C bond formation by palladium-mediated cross-coupling of alkenylzirconocenes with [11C]methyl iodide

Article abstract of DOI:10.1002/jlcr.1044

A novel ¹¹C-C bond formation based on the palladium-mediated cross-coupling reaction of alkenylzirconocenes with [¹¹C]methyl iodide is described. The conversion of internal alkynes into the corresponding alkenylzirconocenes followed by transmetalation with Pd(PPh₃) ₄ and subsequent cross-coupling with [¹¹C]methyl iodide gave several ¹¹C-labelled α,α′-dimethyl-substituted alkenes. The palladium complex Pd(PPh₃)₄ proved to be superior to Pt(PPh₃)₄ or Ni(PPh₃)₄ as transition metal complex. The scope and limitations of the novel palladium-mediated cross-coupling reaction of alkenylzirconocenes with [ ¹¹C]methyl iodide were tested with various internal alkynes. After heating at 60°C for 6 min radiochemical yields of up to 75% (based upon [¹¹C]methyl iodide) could be achieved. Copyright

Full text of DOI:10.1002/jlcr.1044

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 91–100.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1044
11C–C bond formation by palladium-mediated
cross-coupling of alkenylzirconocenes with
[11C]methyl iodide
Frank R. Wuest* and Mathias Berndt
Institut fur Bioanorganische und Radiopharmazeutische Chemie, FZ-Rossendorf e.V.,
¨
Dresden, Germany
Summary
A novel 11C–C bond formation based on the palladium-mediated cross-coupling
reaction of alkenylzirconocenes with [11C]methyl iodide is described. The conversion
of internal alkynes into the corresponding alkenylzirconocenes followed by
transmetalation with Pd(PPh3)4 and subsequent cross-coupling with [11C]methyl
11
iodide gave several C-labelled a,a0-dimethyl-substituted alkenes. The palladium
complex Pd(PPh3)4 proved to be superior to Pt(PPh3)4 or Ni(PPh3)4 as transition
metal complex.
The scope and limitations of the novel palladium-mediated cross-coupling reaction
of alkenylzirconocenes with [11C]methyl iodide were tested with various internal
alkynes. After heating at 608C for 6 min radiochemical yields of up to 75%
(based upon [11C]methyl iodide) could be achieved. Copyright # 2006 John Wiley &
Sons, Ltd.
Key Words: 11C–C bond formation; [11C]methyl iodide; alkenylzirconcenes
Introduction
The 3,3-dimethylallyl moiety, also referred to as prenyl group, is known as an
important structural building block in many natural and medicinal products.
Prominent examples comprise the naturally occurring linear isoprenoids
geranyl pyrophosphate and farnesyl pyrophosphate. Moreover, as key
intermediates in the isoprenoid pathway they are involved in the biosynthesis
of a broad range of compounds such as steroids, carotenoids and terpenes.1
The isotopic substitution of one of the two methyl groups with a [11C]methyl
group would provide an access to a large number of interesting 11C-labelled
*Correspondence to: Frank R. Wust, Institute of Bioinorganic and Radiopharmaceutical Chemistry,
¨
FZ-Rossendorf, PF 51 01 19. 01314 Dresden, Germany. E-mail: f.wuest@fz-rossendorf.de
Contract/grant sponsor: Deutsche Forschungsgemeinschaft
Copyright # 2006 John Wiley & Sons, Ltd.
Received 27 September 2005
Revised 12 December 2005
Accepted 13 December 2005

92
F. R. WUEST AND M. BERNDT
compounds. A commonly employed strategy to form a,a0-dimethyl-substituted
alkenes comprises, the formation of alkenylzirconocenes by the syn-insertion
of a C–C triple bond into the Zr–H bond of Schwartz reagent [Cp2Zr(H)Cl]
followed by metal-mediated C–C bond formation with electrophiles under
retention of the configuration of the C–C douple bond.2,3 The insertion of the
C–C triple bond into the Zr–H bond represents the key step for the
preparation of synthetically useful alkenylzirconocenes. The process is closely
related to the hydroboration reaction with alkynes. In principle, the formation
of alkenylzirconocenes by syn-addition of one equivalent Schwartz reagent
onto unsymmetrically-substituted internal alkynes may lead to a mixture of
regioisomers enriched in the regioisomer where the zirconium–carbon bond is
placed geminal to the sterically less demanding substituent. However, further
treatment with Schwartz reagent readily isomerises the mixture of regioi-
somers presumably via a dimetalated intermediate to favour the formation of
the thermodynamically stable isomer.
Alkenylzirconocenes generated in situ by hydrozirconation of alkynes
readily undergo transmetalation reactions with several transition metal
complexes M(PPh3)4 enabling subsequent cross-coupling reactions of the
formed organometallic reagent with organic halides R1-X. This also includes
the use of [11C]methyl iodide as electrophile in cross-coupling reactions to give
the corresponding 11C-labelled compounds (Figure 1).
In this paper, we describe a novel 11C–C bond formation based upon the
transition metal-mediated cross-coupling reaction between alkenylzircono-
cenes and [11C]methyl iodide. Scope and limitations of the reaction were
studied by screening several internal alkynes in terms of functional group
compatibility.
Results and discussion
In a first set of reactions, the principle feasibility of the approach was
elaborated by the synthesis of 2-[11C]methylpropenyl benzene [11C]3 via
M(L)n
R1
H
R
H
R
R1-X
M(PPh3)4
Zr
H
R
Cl
M = Pd, Pt, Ni
11CH3
H
R
[
11C]MeI
Figure 1. Transmetalation of alkenylzirconocenes and subsequent cross-coupling
reaction with organic halides R1-X, including [11C]methyl iodide
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CROSS-COUPLING OF ALKENYLZIRCONOCENES
93
transition metal complex-mediated hydrozirconation/11C-methylation of
prop-1-ynyl-benzene 1 with [11C]methyl iodide as a model reaction (Figure 2).
The reaction conditions were optimized by the variation of different group
10 transition metal complexes. Prop-1-ynyl-benzene 1 was treated with 1.2
equiv. of Schwartz reagent in THF at room temperature. Due to the steric
bulk of the phenyl group a slight 1.2 equivalent excess of Schwartz reagent is
sufficient to give the thermodynamically stable alkenylzirconocene 2 exclu-
sively. Formation of alkenylzirconocene 2 could be monitored by formation of
a clear orange-coloured solution.
Alkenylzirconocene 2 was treated with 5 mol% M(PPh3)4 (M ¼ Ni, Pd, Pt)
prior to distillation of [11C]methyl iodide into the solution. The reaction
mixture was heated at 608C for 6 min. Aliquots of the reaction mixture were
taken for radio-HPLC analysis. The determined radiochemical yield represents
the percentage of radioactivity area of the 11C-labelled product [11C]3 related
to the total radioactivity area. The results are summarized in Table 1.
Transition metal complexes Ni(PPh3)4 or Pt(PPh3)4 gave only 4 and 11%
radiochemical yield, respectively, whereas sufficient radiochemical yields of up
to 70% could be obtained when Pd(PPh3)4 was used. Besides the desired cross-
coupled product [11C]3, only unreacted [11C]methyl iodide could be found in
the reaction mixture as detected by radio-HPLC. The low radiochemical yield
of 4% obtained with Ni(PPh3)4 is somewhat surprising since nickel-mediated
cross-coupling reactions according to a Negishi reaction are known to proceed
in high chemical yields.4 However, the transmetalation of internal alkenyl
units with Ni(PPh3)4 was shown to proceed very slowly in the cross-coupling
process.2,3 This fact along with the known air and moisture sensitivity of
11CH3
M(PPh3)4
11C]MeI
M = Pd, Pt, Ni
Zr
Cp2ZrHCl
Cl
[
[
11C]3
1
2
Figure 2. Hydrozirconation of prop-1-ynyl-benzene 1 followed by transition
metal-mediated cross-coupling with [11C]methyl iodide
Table 1. Radiochemical yields of transition metal-mediated cross-coupling reaction of
alkenylzirconocene 2 with [11C]methyl iodide
Transition metal complex
Radiochemical yield (%)
Ni(PPh3)4
Pt(PPh3)4
Pd(PPh3)4
4
11
70
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94
F. R. WUEST AND M. BERNDT
Ni(PPh3)4, which makes the handling of this transition metal complex
especially difficult during the radiosynthesis with [11C]methyl iodide, may
explain the observed low radiochemical yield. On the other hand, the more
stable Pd(PPh3)4 complex was found to be a suitable metal complex for
sufficient cross-couplings of alkenylzirconocene 2 with [11C]methyl iodide.
Reduction of the reaction time from 6 to 3 min led to lower radiochemical
yields of 29%. A direct cross-coupling between alkenylzirconocene complex 2
and [11C]methyl iodide was not possible as demonstrated in a control
experiment without a transition metal complex. In this experiment, only
[11C]methyl iodide was found in the reaction mixture.
The scope and limitations of the elaborated novel radiolabelling method
were tested using other methyl-substituted alkynes (4, 6, 8, 10, 12, 14, 16).
Optimized reaction conditions were applied to the radiosynthesis of other
11C-labelled alkenes bearing a prenyl group ([11C]5, [11C]7, [11C]9, [11C]11,
[11C]13, [11C]15, [11C]17).
The results are summarized in Table 2.
In contrast to the hydrozirconation reaction employing model compound 1,
a total amount of 2.5 equivalents of Schwartz reagent was used in the case of
sterically less-hindered internal alkynes 4, 6, 8, 10 and 14 to force the
hydrozirconation reaction in favour to thermodynamically controlled regios-
electivity. For this purpose, additional 1.5 equivalents of Schwartz reagent
were added to the reaction mixture containing a mixture of alkenylzirconocene
regioisomers as described in Figure 1. This procedure provided the formation
of the preferred thermodynamically stable isomer. Subsequent transmetalation
with Pd(PPh3)4 and treatment with [11C]methyl iodide gave the desired cross-
coupled products [11C]5, [11C]7, [11C]9 and [11C]11 in good radiochemical
yields of up to 75% based upon [11C]methyl iodide. The obtained low
radiochemical yield (5%) of 4-nitrophenyl compound [11C]15 is an example for
the incompatibility of Schwartz reagent towards nitro groups. In the case of
butynol 12, a larger excess of 5.0 equivalents of Schwartz reagent had to be
used to compensate the reaction of Schwartz reagent with the free OH-group.
The first equivalent of the hydrozirconation reagents is reacting with the free
OH-group of 12 to form a zirconium–alkoxide intermediate. This intermediate
can accommodate further Schwartz reagent according to the desired syn-
addition to the triple bond. The resulting alkenylzirconocene compound
undergoes transmetalation with Pd(PPh3)4 and cross-coupling with
[11C]methyl iodide to afford prenyl alcohol [11C]13 after hydrolysis in good
radiochemical yield of 62% (Figure 3).
In order to avoid an expected competitive reduction reaction of the ester
group in compound 16, only 1.2 equivalents of Schwartz reagent were used for
the radiosynthesis of ester [11C]17. However, treatment of compound 16 with
1.2 equivalents of Schwartz reagent gave a pale yellow turbid solution instead
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CROSS-COUPLING OF ALKENYLZIRCONOCENES
95
Table 2. Radiochemical yield (RCY) determined by analytical radio-HPLC referring to
as the percentage of the total amount of radioactivity in the reaction mixture
Alkyne
Equiv.
Cp2ZrClH (%)
RCY Unreacted
[11C]methyl
iodide (%)
Product
O
11CH3
O
2.5
65
35
[11C]5
4
11CH3
2.5
2.5
75
50
25
50
[11C]7
6
11CH3
[11C]9
8
O
11CH3
Si
O
2.5
70
30
Si
[11C]11
10
11CH3
HO
HO
5
62
38
95
12
[11C]13
O
11CH3
O
2.5
5
[11C]15
O2N
O2N
14
11CH3
O
O
O
O
1.2
0
>95
[11C]17
16
of a clear orange-coloured solution. This might be an indicator that the
formation of the desired alkenylzirconocene has failed due to undesired side
reactions of Schwartz reagent with the ester group. Consequently, no product
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F. R. WUEST AND M. BERNDT
Zr
Cp2ZrHCl
HO
Cp2ZrHCl
Cl
O
12
11CH3
HO
1. Pd(PPh3)4, [11C]MeI
2. Hydrolysis
Cl
Zr
O
Cl
Zr
[
11C]13
Figure 3. Radiosynthesis of prenyl alcohol [11C]13
formation of [11C]17 was observed when the reaction mixture was treated with
Pd(PPh3)4 and [11C]methyl iodide. For all other compounds (4, 6, 8, 10, 12 and
to a lower extent for compound 14) conversion of alkynes into the
corresponding alkenylzirconocene complexes could be monitored by the
formation of a clear orange-coloured solution.
In summary, we have elaborated a novel 11C–C bond forming reaction
based upon the palladium-mediated cross-coupling between alkenylzircono-
cenes with [11C]methyl iodide. The excellent regioselectivity of the formed
alkenyl–zirconocene complexes makes this approach a promising route for the
convenient preparation of 11C-labelled compounds containing a prenyl group.
However, easily reducible functional groups such as nitro groups or esters are
not compatible with the reaction conditions employing Schwartz reagent for
the hydrozirconation reaction of internal alkynes.
Experimental
General
1H-NMR spectra were recorded on a Varian Inova-400 at 400 MHz. Chemical
shifts (d) are determined relative to the solvent and converted to the TMS
scale. Melting points were determined on a Galen III melting point apparatus
(Cambridge Instruments). Elemental analysis were obtained on a LECO
CHNS 932 elemental analyser. Flash chromatography was conducted
according to Still et al.5 Analytical HPLC was conducted using LaChrom
systems from Merck-Hitachi.
Thin-layer chromatography (TLC) was performed on Merck silica gel F-254
plastic plates, with visualization under UV (254 nm). Compounds 1, 3, 6, 7, 8,
9, 12 and 13 were purchased from Aldrich. References to previous syntheses of
known compounds for comparing analytical results have been listed.
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CROSS-COUPLING OF ALKENYLZIRCONOCENES
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Chemical syntheses
General procedure for the synthesis of arylethers 4, 5, 14 and 15
Phenol or 4-nitrophenol (3.0 mmol), 2-butyne-1-ol or 3-methyl-2-butene-1-ol
(4.5 mmol) and triphenylphosphine (3.6 mmol) were dissolved in 40 ml of THF
and cooled to 08C by means of an ice bath. DIAD (4.8 mmol) was slowly
added via syringe. The resulting clear yellow–orange-coloured solution was
stirred at room temperature for 2 h. The volume of the solution was reduced
by evaporation of THF. The residue (2–3 ml) was purified by flash
chromatography (10% EtOAc/hexane) to give the desired compounds 4, 5,
14 and 15.
1
But-2-ynyloxy-benzene 4. Pale yellow oil. Yield: 63%. H-NMR (CDCl3):
d 1.87 (t, J ¼ 2:4 Hz, 3H; CH3), 4.65 (q, J ¼ 2:4 Hz, 2H; CH2), 6.96–7.00
(m, 3H; Ar-H), 7.28–7.32 (m, 2H; Ar-H).6
1
(3-Methyl-but-2-enyloxy)-benzene 5. Pale yellow oil. Yield: 86%. H-NMR
(CDCl3): d 1.77 (s, 3H; CH3), 1.82 (s, 3H; CH3), 4.53 (d, J ¼ 6:6 Hz, 2H; CH2),
5.53 (m, 1H), 6.93–6.98 (m, 3H; Ar-H), 7.28–7.32 (m, 2H; Ar-H).7
1-But-2-ynyloxy-4-nitrobenzene 14. Yellow solid. Yield: 75%. Melting point
125–1278C. 1H-NMR (CDCl3): d 1.87 (t, J ¼ 2:4 Hz, 3H; CH3), 4.75
(q, J ¼ 2:4 Hz, 2H; CH2), 7.03 and 8.21 (2d of AA0BB0 system, J ¼ 9:3 Hz,
4H; Ar-H). Analytically calculated for C10H9NO3: C, 62.82; H, 4.47; N, 7.33.
Found C, 62.51; H, 4.05; N, 6.98.
(3-Methyl-but-2-enyloxy)-4-nitrobenzene 15. Yellow oil. Yield: 71%.
1H-NMR (CDCl3): d 1.77 (s, 3H; CH3), 1.82 (s, 3H; CH3), 4.61
(d, J ¼ 6:8 Hz, 2H; CH2), 5.47 (m, 1H), 6.95 and 8.19 (2d of AA0BB0 system,
J ¼ 9:3 Hz, 4H; Ar-H).8
General procedure for the synthesis of silyl ethers 10 and 11. A mixture of
2-butyne-1-ol or 3-methyl-2-butene-1-ol (10 mmol), TBDMSCl (1.81 g,
12 mmol) and i-PrNEt (1.95 ml, 20 mmol) in CH2Cl2 (10 ml) was stirred at
room temperature for 6 h. The mixture was washed with saturated solutions of
NH4Cl and NaHCO3 and brine. The organic layer was dried and the solvent
was evaporated in vacuo. The residue was purified by flash chromatography
(10% ETOAc/hexane) to give silyl ethers 10 and 11.
1
tert.-Butyl-but-2-ynyloxy-dimethyl-silane 10. Yield: 89%. H-NMR (CDCl3):
d 0.10 (s, 6H; Si(CH3)2), 0.89 (s, 9 H; C(CH3)3), 1.82 (t, J ¼ 2:4 Hz, 3H; CH3),
4.62 (q, J ¼ 2:4 Hz, 2H; CH2).9
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F. R. WUEST AND M. BERNDT
tert.-Butyl-dimethyl-(3-methyl-but-2-enyloxy)-silane
11. Yield:
94%.
1H-NMR (CDCl3): d 0.08 (s, 6H; Si(CH3)2), 0.90 (s, 9 H; C(CH3)3), 1.61
(s, 3H; CH3), 1.70 (s, 3H; CH3), 4.15 (d, J ¼ 6:3 Hz, 2H; CH2), 5.29 (m, 1H).10
General procedure for the synthesis of benzoic esters 16 and 17
2-Butyne-1-ol or 3-methyl-2-butene-1-ol (10 mmol) was dissolved in dry
pyridine (2 ml). Benzoylchloride (12 mmol) was slowly added and the mixture
was stirred for 30 min at room temperature. Then the mixture was poured into
ice-water and 1 M HCl was added. Extraction with EtOAc, evaporation of the
solvent under reduced pressure and subsequent flash chromatography (10%
EtOAc/hexane) gave benzoic esters 16 and 17.
Benzoic acid but-2-ynyl ester 16. Pale yellow oil. Yield: 70%. 1H-NMR
(CDCl3): d 1.88 (t, J ¼ 1:9 Hz, 3H; CH3), 4.89 (q, J ¼ 1:9 Hz, 2H; CH2), 7.44
(m, 2H, Ar-H), 7.60 (m, 1H; Ar-H), 8.07 (m, 2H; Ar-H).11
Benzoic acid 3-methyl-but-2-enyl ester 17. Pale yellow oil. Yield: 89%.
1H-NMR (CDCl3): d 1.80 (s, 3H; CH3), 1.85 (s, 3H; CH3), 4.11 (d,
J ¼ 6:6 Hz, 2H; CH2), 5.42 (m, 1H), 7.41 (m, 2H, Ar-H), 7.56 (m, 1H;
Ar-H), 8.06 (m, 2H; Ar-H).12
Radiochemical syntheses
[11C]CO2 was produced by the 14N(p,a)11C reaction on a IBA CYCLONE
18/9 cyclotron. The synthesis was carried out in a remotely controlled synthesis
apparatus by Nuclear Interface (Munster). [11C]Methyl iodide was prepared
¨
according to Crouzel et al.13 [11C]Methyl iodide was transferred in a stream of
nitrogen into the reaction vessel at room temperature. After completion of the
transfer, the reaction vessel was heated and aliquots were taken for radio-
HPLC analysis after the indicated time. Radio-HPLC analyses were carried
out with Phenomenex RP 18 column (LUNA C18(2) 4.6 ꢀ 250 mm, 5 mm)
using an indicated isocratic eluent with a flow rate of 1.0 ml/min. The products
were monitored by an UV detector L4500 (Merck, Hitachi) at 240 nm and by
g-detection with a scintillation detector GABI (X-RAYTEST).
Optimization of reaction conditions for the transition metal-mediated cross-
coupling of alkenylzirconocenes with [11C]methyl iodide
Prop-1-ynyl-benzene 1 (21.4 ml, 0.17 mmol) and Schwartz reagent (53 mg,
0.2 mmol) were dissolved in dry THF (1 ml) under argon atmosphere. After
being stirred for 3 h at room temperature the clear orange-coloured solution
was treated with the metal complex M(PPh3)4 (4.5 mmol). 400 ml of the solution
was added to the synthesis module. After [11C]methyl iodide transfer and
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99
subsequent heating for 6 min at 608C, aliquots were taken for radio-HPLC
analysis.
2-[11C]methylpropenyl benzene ½11Cꢁ3. HPLC analysis: CH3CN/0.1 M ammo-
nium formate (70/30), tR ¼ 13:4 min.
Radiosyntheses of compounds ½11Cꢁ5, ½11Cꢁ7, ½11Cꢁ9, ½11Cꢁ11 and
½11Cꢁ15. Schwartz reagent (0.5 mmol) was dissolved in dry THF (1 ml).
Alkyne 4, 6, 8, 10 or 14 (0.2 mmol) was added. After 3 h, Pd(PPh3)4 (5.0 mmol)
was added to the clear orange-coloured solution. Four hundred microlitres of
the solution was added to the synthesis module. After [11C]methyl iodide
transfer and subsequent heating for 6 min at 608C, aliquots were taken for
radio-HPLC analysis.
3-([11C]methyl-but-2-enyloxy)-benzene ½11Cꢁ5. Yield (based upon [11C]methyl
iodide: 65%. HPLC analysis: CH3CN/0.1 M ammonium formate (70/30),
tR ¼ 9:3 min.
2,4,4-[11C]trimethyl-pent-2-ene ½11Cꢁ7. Yield (based upon [11C]methyl
iodide: 75%. HPLC analysis: CH3CN/0.1 M ammonium formate (80/20),
tR ¼ 5:4 min.
2-[11C]methyl-hex-2-ene ½11Cꢁ9. HPLC analysis: CH3CN/0.1 M ammonium
formate (80/20), tR ¼ 10:2 min.
Tert.-butyl-dimethyl-(3-[11C]methyl-but-2-enyloxy)-silane ½11Cꢁ11. Yield (based
upon [11C]methyl iodide: 70%. HPLC analysis: CH3CN/0.1 M ammonium formate
(80/20), tR ¼ 9:0 min.
3-([11C]methyl-but-2-enyloxy)-4-nitrobenzene ½11Cꢁ15. Yield (based upon
[11C]methyl iodide: 5%. HPLC analysis: CH3CN/0.1 M ammonium formate
(70/30), tR ¼ 10:2 min.
Radiosyntheses of 3-[11C]methyl-but-2-en-1-ol ½11Cꢁ13
Schwartz reagent (1.0 mmol) was dissolved in dry THF (1 ml). Butynol 12
(0.2 mmol) was added. After 3 h, Pd(PPh3)4 (5.0 mmol) was added. 400 ml of the
solution was added to the synthesis module. After [11C]methyl iodide transfer
and subsequent heating for 6 min at 608C, aliquots were taken for radio-HPLC
analysis.
3-[11C]methyl-but-2-en-1-ol ½11Cꢁ13. Yield (based upon [11C]methyl iodide:
62%. HPLC analysis: CH3CN/0.1 M ammonium formate (70/30),
tR ¼ 3:8 min.
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F. R. WUEST AND M. BERNDT
Radiosyntheses of benzoic acid 3-[11C]methyl-but-2-enyl ester ½11Cꢁ17
Schwartz reagent (0.5 mmol) was dissolved in dry THF (1 ml). Ester 18
(0.4 mmol) was added. After 3 h, Pd(PPh3)4 (5.0 mmol) was added. Four
hundred microlitres of the solution was added to the synthesis module. After
[11C]methyl iodide transfer and subsequent heating for 6 min at 608C, aliquots
were taken for radio-HPLC analysis.
3-[11C]methyl-but-2-enyl ester ½11Cꢁ17. Yield (based upon [11C]methyl iodide:
0%.
Acknowledgements
Financial support from the Deutsche Forschungsgemeinschaft (to F. W.) is
gratefully acknowledged. The authors wish to thank S. Preusche for
radioisotope production, and H. Kasper, P. Mading and T. Krauss for
¨
technical assistance.
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