Exploration of the scope of Pt-catalyzed C-F activation

Article abstract of DOI:10.1002/ejoc.201100478

We recently reported methods for the catalytic methylation and methoxylation of polyfluoroaryl imines utilizing [Pt₂Me ₄(SMe₂)₂] as a precatalyst. These methodologies provide a novel route to partially functiona

Full text of DOI:10.1002/ejoc.201100478

FULL PAPER
DOI: 10.1002/ejoc.201100478
Exploration of the Scope of Pt-Catalyzed C–F Activation
Lauren Keyes,[a] Alex D. Sun,[a] and Jennifer A. Love*[a]
Keywords: Platinum / Fluorine / C–F activation / Arenes / Polyfluoroarenes
We recently reported methods for the catalytic methylation
and methoxylation of polyfluoroaryl imines utilizing
[Pt2Me4(SMe2)2] as a precatalyst. These methodologies pro-
vide a novel route to partially functionalized aryl fluorides,
which have potential utility as building blocks for the synthe-
sis of pharmaceuticals and materials. We report herein efforts
to expand the scope of these processes, particularly the
choice of directing group. Comparisons to the previously re-
ported scope of PtII-catalyzed methylation and methoxylation
are described.
systems has also been explored. Nevertheless, it would be
valuable to replace fluorine with substituents other than hy-
drogen.
Introduction
The incorporation of fluorine into chemical structures
results in increases in metabolic stability, solubility and li-
pophilicity.[1] Consequently, fluorine substituents are
emerging as common structural motifs in pharmaceuticals
and agrochemicals, with approximately half of new drugs
containing a fluoroarene.[1,2] Indeed, as of 2009 two of the
five top-selling pharmaceuticals in the US (Pfizer’s Lipitor
and GlaxoSmithKline’s Advair) contain an aryl fluoride.[2]
Moreover, aryl fluorides are increasingly used in materials
and in ligands for transition metals.[3] Because there are no
naturally occurring sources of aryl fluorides, these building
blocks must be generated through chemical synthesis.[4]
One general strategy for the synthesis of fluoroaromatics
has been the selective incorporation of fluorine into a pre-
viously non-fluorinated position on an aromatic ring using
a transition metal. In this regard, important work on the
use of electrophilic fluorinating agents has been devel-
oped.[5] Methodologies that utilize nucleophilic fluorine
sources in conjunction with transition metal catalysts have
also been developed. A significant advance, reported by
Buchwald, is the Pd-catalyzed conversion of aryl triflates
into aryl fluorides using inexpensive and commercially
available fluoride salts.[6]
In this regard, stoichiometric C–F activation involving
Ni,[8] Pd,[9] Pt[10] and Rh[11] complexes have been extensively
explored.[12] Despite various reports of stoichiometric C–F
activation, examples of catalytic C–C bond forming reac-
tions are relatively rare.[13] To this end, the NiII-catalyzed
cross-coupling of fluorobenzene with Grignard reagents
was the first reported example of a catalytic C–C bond
forming reaction involving aryl fluorides.[13a] Methodolo-
gies for the catalytic C–F activation of mono and polyfluo-
roarenes based on group 7[14] and 8[15] metals have been
developed but to a much lesser extent. The products of
these transformations are partially-functionalized aryl fluo-
rides which have the potential for further use as synthetic
building blocks. Of particular interest are late-transition
metals capable of C–F activation due to the functional
group tolerance of such systems.
With this goal in mind, we have discovered the first ex-
amples of Pt-catalyzed methylation and methoxylation of a
variety of polyfluoroaryl imines.[16] This methodology is
based on the report by Crespo and Martinez that a Pt-di-
mer, [Me2Pt(μ-SMe2)]2, effects the stoichiometric C–F acti-
vation of
a series of polyfluoroaryl imines [Equa-
tion (1)].[10a]
Hydrodefluorination of perfluoroarenes is another ap-
proach to the construction of novel polyfluorinated aro-
matics.[7] Milstein reported the first example of catalytic de-
fluorination of perfluoroarenes.[7a,7b] More recently, Whit-
tlesey and co-workers disclosed a very effective RuII system
for catalytic defluorination.[7j–7l] The use of early-transition
metals[7m–7q] as well as main group elements[7r–7u] in such
The methylation and methoxylation methodologies pro-
vide access to a variety of partially-functionalized aryl fluo-
rides in high yields with high selectivity for ortho-function-
alization. Furthermore, the majority of these products can-
not be obtained from conventional C–Br, –I, or –Cl cross-
coupling as the necessary starting materials are not com-
[a] Department of Chemistry, University of British Columbia,
2036 Main Mall, Vancouver, British Columbia, Canada V6T
1Z1
Fax: +1-604-822-3187
E-mail: jenlove@chem.ubc.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100478.
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L. Keyes, A. D. Sun, J. A. Love
FULL PAPER
mercially available. Throughout the course of our investi- The reaction was selective for functionalization in the ortho
gations of PtII-catalyzed C–F activation we sought to ex- position. Importantly, a significantly weaker carbon–bro-
plore and compare the reactivity of different PtII complexes mine bond was left untouched (entry 2). Substrates 1d and
as well as a variety of polyfluoroarenes. We report herein 1e (entries 3 and 4, respectively) reacted exclusively at the
the results of these investigations.
ortho site with an adjacent fluoride, consistent with the
selectivity observed in stoichiometric C–F activation.[10a]
A
variety of substitution patterns can also be tolerated (en-
tries 3–6). In general, the reaction was selective for mono-
methylation because the methylated products were less-sus-
ceptible to oxidative addition than the starting materials.
If the initially formed methylated product had a sufficient
number of fluorine substituents, di-methylation could be
achieved (entry 6).
Results and Discussion
Reaction Design
Our investigation of PtII-catalyzed C–F activation began
with the development of a methodology for the methylation
of polyfluoroaryl imines. Specifically, use of a catalytic
amount (5 mol-%) of the Pt-dimer resulted in complete con-
version of N-(2,4,6-trifluorobenzylidene)benzylamine (1a)
to the corresponding methylated imine (2a) [Equa-
tion (2)].[16a]
Table 1. Imine scope of PtII-catalyzed methylation.
The development of this methodology was based on pre-
vious work by Crespo and Martinez regarding stoichiomet-
ric C–F activation with the Pt-dimer [Me2Pt(μ-SMe2)]2.[10a]
On the basis of this result, we proposed that the resulting
Pt–F species could undergo transmetalation with a suitable
organometallic reagent; subsequent reductive elimination
would lead to C–C bond formation. To this end, treatment
of the PtIV–F complex 3 with dimethylzinc resulted in suc-
cessful transmetalation to give the Me3PtIV complex 4
(Scheme 1). Upon heating, complex 4 underwent clean re-
ductive elimination to give the methylated imine product
2a.
1
[a] Yield based on H NMR spectroscopy using 1,3,5-trimethoxy-
benzene as an internal standard. [b] Taken from ref.[16a]; conditions:
0.6 equiv. Me2Zn, 8 h. [c] Taken from ref.[16b]; conditions: 1.2 equiv.
Me2Zn, 12 h. [d] Taken from ref.[16c]; conditions: 1.2 equiv. Me2Zn,
12 h. [e] Addition of a second equivalent of Me2Zn after 12 h re-
sulted in dimethylation.
Scheme 1. Transmetalation and reductive elimination of PtIV com-
plexes.
Based on the reactivity of the Pt-dimer [Me2Pt(μ-
SMe2)]2, we were interested in exploring the potential of
other related PtII complexes to promote this reactivity. We
discovered two additional PtII complexes {[PtCl2-
(SMe2)2][16b] and [PtCl2(DMSO)2][16c]} that catalyzed the
methylation of the same series of polyfluoroaryl imines. The
Methylation of Fluoroarylimines – Scope
Having demonstrated the feasibility of this process, we yields with all three catalysts are included for comparative
then explored the substrate scope. The reaction was quite purposes in Table 1. Preliminary mechanistic investigations
successful for a series of polyfluoroaryl imines (Table 1). revealed that all three likely generate the same active cata-
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Exploration of the Scope of Pt-Catalyzed C–F Activation
lyst in the presence of Me2Zn. Of the PtII complexes we lytic reactivity[16a] [see Equation (3)] and also failed to un-
investigated, [Me2Pt(μ-SMe2)] remains the most active cata- dergo stoichiometric C–F activation [see Equation (4)].[10a]
lyst over a range of polyfluoroaryl imine substrates.
In addition, the requirement of at least three electron-with-
drawing groups in addition to the imine functionality for
significant catalytic reactivity was demonstrated by this
substrate. A similar dependence was reported by Crespo
and Martinez.[10a]
Methylation of Fluoroarylimines – Mechanism
Mechanistic analysis of PtII-catalyzed methylation indi-
cated that the reaction proceeds through a standard cross-
coupling mechanism involving oxidative addition, trans-
metalation and reductive elimination (Scheme 2).[17] Of
note is that the reaction requires a directing group to pro-
Methylation with Other Directing Groups
The wide range of applications for aryl fluorides necessi-
mote intramolecular C–F activation, providing high selec- tates development of a methodology with a broad substrate
tivity for the ortho position. Furthermore, mechanistic in- scope. Unfortunately, attempts to expand the nucleophile
vestigations found C–F activation to occur on a different scope of PtII-catalyzed C–F activation beyond that of meth-
timescale compared to either transmetalation or reductive ylation and methoxylation (vide infra) have been largely un-
elimination, but on a similar timescale as the overall cata- successful. Instead, we sought to explore the potential for
lytic reaction.[18] These results indicate that C–F activation a variety of ortho-directing groups to undergo catalytic C–
is rate-determining (at least for most substrates).
F activation utilizing the platinum dimer, given the impor-
tant role that directing group plays in reaction mechanism.
We began our investigations by preparing a series of
2,4,6-trifluoro-substrates with a series of different directing
groups that have literature precedent for directed carbon-
atom bond activations.[19] The 2,4,6-trifluoro substitution
pattern was selected based on its excellent performance in
both PtII-catalyzed methylation and methoxylation (see
Tables 1 and 4).[16a,16d]
Investigations of the reactivity of all substrates towards
catalytic methylation were performed at 60 °C in [D3]aceto-
nitrile using 1.2 equiv. of dimethylzinc and 5 mol-% of the
Pt-dimer (Table 2). These conditions were selected based on
previous optimization studies for methylation of polyfluo-
roaryl imines (Table 1).[16a] Under these conditions the ox-
Table 2. Directing group scope of PtII-catalyzed methylation.
Scheme 2. Mechanism of PtII-catalyzed methylation of polyfluo-
roaryl imines.
Importantly, during the course of establishing the sub-
strate scope of this methodology we noticed similarities be-
tween the catalytic reactivity of a given imine and its ability
to undergo stoichiometric C–F activation. Specifically, 2,6-
difluoroimine substrate 1g was found to have limited cata-
[a] Conversion was determined based on 1H NMR spectroscopy.
In cases that resulted in product formation, the conversions are the
average of three independent experiments. [b] Unidentified precipi-
tate formed.
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L. Keyes, A. D. Sun, J. A. Love
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azoline substrate 1h was converted into the corresponding
Interestingly, other heterocyclic directing groups such as
ortho-methylated product in 52% conversion (entry 2; pyridine or imidazole rings displayed unusual reactivity.
Table 2). Importantly, there was no reactivity in the absence More specifically, addition of dimethylzinc to a solution of
of Pt-catalyst for either imine-based (1a, given in entry 1 imidazole substrate (1i) or pyridine substrate (1j) resulted
for comparison) or oxazoline-based substrates 1h. Neither in immediate formation of intractable precipitates. The lack
imidazole nor pyridine directing groups provided the de- of solubility of both precipitates has prevented their defin-
sired product (entries 3 and 4, respectively), although the itive identification and characterization. For the imidazole
substrates did undergo reaction (vide infra). A variety of substrate, the precipitate presumably results from deproton-
other nitrogen and/or oxygen-based directing groups were ation of the imidazole ring. Consistent with this assump-
explored but were found to be unreactive towards catalytic tion, addition of dimethylzinc resulted in the formation of
methylation. Examples include aldehyde, amide and ester bubbles. Formation of a precipitate from the pyridine sub-
functionalities as well as stronger directing groups such as strate is unlikely a result of deprotonation. Instead, we pos-
methoxymethyl ether as well as N and O-carbamates. Given tulate that nucleophilic addition of a methyl group from
that C–F activation is the rate-determining step for the dimethylzinc to the pyridine ring generates a Meisenheimer
catalytic methylation of 2,4,6-trifluoroarenes, failure of a complex.[21]
given substrate to promote catalytic methylation could be
the result of an ability of the same substrate to achieve C–
F activation and, thus, gain entry into the catalytic cycle.
Attempts were made to further optimize the methylation
of the oxazoline substrate by varying temperature, solvent
and catalyst loading (Table 3). We anticipated that other
polar, coordinating solvents such as [D6]acetone and [D6]-
DMSO would be successful; however, these resulted in little
or no reactivity (entries 1 and 2, Table 3). Non-polar sol-
vents also resulted in negligible conversion to product (en-
tries 3–5; Table 3). In addition, neither increased tempera-
ture nor increased catalyst loading led to increased conver-
sion to product (entries 8–9; Table 3). Lower overall conver-
sion at increased temperature is likely the result of catalyst
decomposition upon several hours of heating at elevated
temperatures.[20] Furthermore, the addition of a second
equivalent of dimethylzinc with, or without, catalyst also
failed to increase conversion to product.
Methoxylation of Fluoroarylimines – Scope
On the other hand, preliminary investigations have indi-
cated the mechanism of PtII-catalyzed methoxylation to be
a PtII-catalyzed process mechanistically distinct from the
analogous methylation reaction.[22] Of particular signifi-
cance is that a different catalytic cycle is indicative of cataly-
Table 4. Imine scope of PtII-catalyzed methoxylation.
Table 3. Optimization of conditions for oxazoline directed cross-
coupling.
1
[a] Conversion based on 19F NMR spectroscopy and are the result
of a single experiment. [b] Compound was only partially soluble.
[a] Yield based on H NMR spectroscopy using 1,3,5-trimethoxy-
benzene as an internal standard. [b] As reported in ref.[15d]
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Exploration of the Scope of Pt-Catalyzed C–F Activation
sis proceeding via a different PtIV species. Therefore, sub- of directing both catalytic methylation and methoxylation.
strates which were not found capable of stoichiometric C– Interestingly, the imidazole substrate 1i displayed reason-
F activation may still be active in catalytic methoxylation.
able reactivity towards catalytic methoxylation resulting in
Initial substrate scope investigations made use of the 69% conversion to the methoxylated product (entry 3;
same series of polyfluoroaryl imine substrate as were uti- Table 5). As before, other substrates containing both nitro-
lized in the analogous methylation reaction.[16d] Similar re- gen and oxygen-based directing groups were found to be
activity towards PtII-catalyzed methoxylation was obtained catalytically inactive. Control experiments showed no reac-
for several imines (entries 1–3; Table 4). However, several tivity in the absence of Pt-catalyst for all substrates.
important differences in reactivity were noted. Substrates
Efforts to optimize the reactivity of oxazoline 1h and
which deviated from the 2,4,6-trifluorosubstitution pattern imidazole 1i substrates were based on varying solvent, tem-
(entries 3–6; Table 4) displayed significantly lower catalytic perature and catalyst loading. Initial screening revealed the
activity compared to what was observed with catalytic ability of an oxazoline ring to direct catalytic methoxylation
methylation (entries 3–6; Table 1). This result is of particu- achieving 76% conversion to the corresponding meth-
lar significance as it seems to suggest that an alternate oxylated product (entry 1; Table 6). Increasing the tempera-
mechanism may be operable.
ture from 35–60 °C resulted in an increased conversion to
product (entry 2; Table 6). However, increasing catalyst
loading (5–10 mol-%) had a negligible effect (entry 3;
Table 6). [D2]Dichloromethane and [D3]acetonitrile were
also capable of promoting this reaction giving similar re-
sults to THF (entries 4 and 5; Table 6). [D6]Acetone and
[D6]DMSO proved to be poor solvents for this reaction (en-
tries 6 and 7; Table 6). Interestingly, dichloromethane and
acetonitrile were identified as reasonable solvents during
the previous optimization of the methoxylation of poly-
fluoroaryl imines.[16d]
Methoxylation with Other Directing Groups
On the basis of these reactivity differences, we were
prompted to investigate the scope of PtII-catalyzed meth-
oxylation with the same series of non-imine based sub-
strates. As before, the conditions utilized for screening sub-
strates for catalytic reactivity were the conditions previously
optimized for the imine-based substrates –35 °C, [D8]THF,
1.2 equiv. of Si(OMe)4.[16d]
Once again, oxazoline substrate 1h was found capable of
directing catalytic methoxylation resulting in 80% conver-
sion to the methoxylated product under the optimized con-
ditions (entry 2; Table 5). However, the oxazoline ring is the
only directing group in addition to imine that is capable
Table 6. Optimization of conditions for oxazoline directed cross-
coupling.
Table 5. Directing group scope of PtII-catalyzed methoxylation.
[a] Conversion based on 19F NMR spectroscopy and are the result
of a single experiment.
For the imidazole substrate, the optimized conditions
were found to be THF, 60 °C and 10 mol-% Pt-catalyst (en-
try 1; Table 7). Notably, increasing the catalyst loading from
5–10 mol-% did result in a significant increase in conversion
to product (entries 1–2; 3–4; Table 7). All other solvents
were unable to promote this reactivity.
The reactivity of the imidazole substrate 1i in catalytic
methoxylation is a particularly interesting result as this sub-
strate was not capable of stoichiometric C–F activation; yet
was found to have reasonable reactivity in catalytic meth-
[a] Conversion was determined based on 1H NMR spectroscopy.
In cases that resulted in product formation, the conversions are the
average of three independent experiments. [b] Conversion at 35 °C.
[c] Conversion of imine substrate at 60 °C was 61%. [d] Isolated
yield. [e] Compound volatility resulted in a low yield of isolated
product; see Supporting Information for details.
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L. Keyes, A. D. Sun, J. A. Love
Table 8. Sequential methylation/methoxylation.
FULL PAPER
Table 7. Optimization of conditions for imidazole directed cross-
coupling.
[a] Conversion based on 19F NMR spectroscopy and are the result
of a single experiment. [b] Compound was only partially soluble.
[a] Conditions: Me2Zn (1.2 equiv.), CD3CN, 60 °C, 24 h. [b] Condi-
tions: Si(OMe)4 (1.2 equiv.), [D8]THF, 35 °C. [c] Conversion based
on 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an in-
ternal standard. [d] Methoxylation was performed at 60 °C.
oxylation (entry 3; Table 5). Clearly, the reactivity of a given
substrate in catalytic methylation does not, necessarily, im-
ply that the same reactivity will be observed in the analo-
gous catalytic methoxylation reaction. As such, a mecha-
nism for PtII-catalyzed methoxylation which does not in-
voke C–F activation as the entrance into the catalytic cycle
would explain these results.
More specifically, catalytic methylation requires a certain
minimum number of electron-withdrawing functionalities
on the aromatic ring in order to ensure reasonable reactivity
[see Equation (4)]. However, substrate reactivity is seem-
ingly not dependent on the substitution pattern of the elec-
tron-withdrawing groups. To this end, imine substrates with
2,5,6-trifluoro (1d and 1e) as well as pentafluoro substitu-
tion patterns display excellent reactivity (entries 4–6;
Sequential Methylation/Methoxylation – Scope
Having established the scope of PtII-catalyzed methyl- Table 1). On the other hand, the opposite trend was ob-
ation and methoxylation reactions, it was of interest to ex- served for catalytic methoxylation. Indeed, it was observed
plore the potential for sequential methylation/meth- that a 2,4,6-substitution pattern on the aromatic ring was a
oxylation. The substrates chosen were those which dis- requirement for substrate reactivity (Table 4).
played relatively high reactivity in either the methylation
and/or methoxylation reactions (see Tables 1 and 4; respec- lytic system, only methylation/methoxylation would be ex-
tively). pected to result in successful di-functionalization. Meth-
On the basis of the observed constraints for each cata-
The catalytic reactions were performed using the opti- oxylation of the 2,4,6-trifluoro-substituted substrates,
mized conditions for each respective reaction. Due to the though successful, would reduce the number of electron-
differences in the solvents required for these conditions withdrawing groups below the minimum requirement for
(acetonitrile and THF for methylation and methoxylation; catalytic methylation. As a result, methylation of such sub-
respectively), the acetonitrile was removed after completion strates proved to be unsuccessful. Conversely, catalytic
of the methylation reaction and replaced with THF for the methoxylation of mono-methylated products was found to
subsequent methoxylation reaction.
be reasonably successful (Table 8). This can be rationalized
The results clearly indicate that substrates which show on the basis that the ortho-methylated products still main-
high reactivity in both catalytic reactions are able to un- tain the 2,4,6-substitution pattern required for catalytic
dergo sequential methylation/methoxylation (entries 1 and methoxylation.
2; Table 8). Of note is that the reverse process (sequential
Of the substrates examined, 4-bromo-2,6-difluoroimine
methoxylation/methylation) failed to provide the desired di- substrate 1b is particularly interesting as the product of
functionalized products in all cases. This is postulated to be these sequential reactions has only a para-bromo substitu-
the result of two mechanistically distinct catalytic processes. ent as the only halogen remaining on the aryl ring. This
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Exploration of the Scope of Pt-Catalyzed C–F Activation
Materials and Methods: Deuterated solvents were purchased from
Cambridge Isotopes Inc. and degassed prior to use. Acetonitrile
was dried by refluxing over calcium hydride, stored over molecular
sieves and degassed prior to use. Tetrahydrofuran was dried on
molecular sieves and degassed prior to use. All organic reagents
were obtained from commercial sources and used as received. 1,3,5-
trimethoxybenzene was sublimed prior to use. K2PtCl4was pur-
chased from Strem Chemicals and was used without further purifi-
could serve as a versatile synthetic handle due to the
number of Pd and Ni-catalyzed cross-coupling reactions
which utilize aryl bromides. The low reactivity of 6-chloro-
2,5-difluoroimine substrate 1c (entry 3; Table 8) can be ra-
tionalized on the basis that this substrate was highly active
in catalytic methylation (95% conversion) but demonstrated
limited reactivity in the methoxylation reaction (ca. 15%
conversion). Non-imine-based oxazoline substrate 1h (entry
4; Table 8) was also capable of sequential catalysis giving a
[24]
cation. [PtCl2(SMe2)2],[23] and Pd(PPh3)4 were prepared by pre-
viously reported procedures. [Me2Pt(μ-SMe2)] was prepared based
19% overall conversion to the di-functionalized product on a modification of a previously reported procedure[23] as de-
scribed in the Supporting Information. All substrates were pre-
pared based on previously reported procedures as indicated below.
Dimethylzinc (1.2 m solution in toluene) was purchased from Ald-
rich and titrated with LiCl and I2 before use.[25] Si(OMe)4 was pur-
chased from Alfa Aesar and degassed prior to use.
(entry 4; Table 8). These results are noteworthy as the po-
tential for a substrate to undergo sequential catalytic reac-
tions results in di-functionalized products which could be
difficult to obtain via other synthetic methodologies.
N-(2,4,6-Trifluorobenzylidene)benzylamine (1a): As described in the
literature procedure.[16a] Pale yellow oil, 1.03 g, 85% yield. Charac-
terization data matches previously reported data.[15a] See Support-
ing Information for details.
Conclusions
The reactivity of a series of 2,4,6-trifluoroarenes contain-
ing a variety of ortho-directing functionalities has been ex-
amined. The ability of an oxazoline ring to direct both cata-
lytic reactions has been demonstrated. In addition, the anal-
ogous imidazole functionality was found to have reactivity
exclusive to catalytic methoxylation. Polyfluoroaryl imines
remain the optimal substrates for both methylation and
methoxylation, with reactions proceeding to greater than
95% conversion to product in both cases. However, the de-
pendence on an imine-directing motif is not necessarily a
significant limitation as these functionalities are versatile
synthetic intermediates. In addition to their biological rele-
vance, a variety of C–O and C–N containing functionalities,
such as aldehydes, alcohols and imines, can be readily ac-
cessed via the imine functionality. Finally, throughout the
course of these investigations differences in substrate reac-
tivity in PtII-catalyzed methylation from that of PtII-cata-
lyzed methoxylation were uncovered. Specifically, the imid-
azole-based substrate which did not undergo stoichiometric
N-(4-Bromo-2,6-difluorobenzylidene)benzylamine (1b): As described
in the literature procedure.[16a] Light yellow solid, 1.89 g, 90% yield.
Characterization data matches previously reported data.[15a] See
supplementary data for details.
N-(2-Chloro-3,6-difluorobenzylidene)benzylamine (1c): As described
in the literature procedure.[16a] Yellow oil, 0.88 g, 78% yield. Char-
acterization data matches previously reported data.[15a] See Sup-
porting Information for details.
2-(2,4,6-Trifluorophenyl)oxazoline (1h): As described in the litera-
ture procedure.[26] White solid, 1.54 g, 54% yield. Characterization
data matches previously reported data.[26] See Supporting Infor-
mation for details.
2-(2,4,6-Trifluorophenyl)-4,5-dihydro-1H-imidazole (1i): As de-
scribed in the literature procedure.[27] Yellow solid, 0.52 g, 84%
yield. 1H NMR ([D3]acetonitrile, 300 MHz): δ = 6.91 (t, J = 8.1 Hz,
2 H, 2-H), 3.66 (s, 4 H, -CH2CH2-) ppm. 19F NMR ([D3]acetoni-
trile, 282 MHz): δ = –107.9 (q, J = 7.5 Hz, 1 F, 1-F), –109.8 (t, J
= 7.2 Hz, 2 F, 3-F) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ =
C–F activation was found to promote PtII-catalyzed meth- 163.3 (dt, J = 252.0, J = 16.5 Hz, 1-C), 161.4 (ddd, J = 252.0, 15.0,
9.0 Hz, 3-C), 155.6 (t, J = 2.4 Hz, 5-C), 106.0 (dt, J = 16.5, J =
6.0 Hz, 4-C), 101.0 (dt, J = 25.5, 3.0 Hz, 2-C) ppm. HRMS (ESI
positive ion mode): m/z calcd. for C9H8F3N2: 201.0640; found
201.0636.
oxylation. These results imply distinct mechanisms for these
two processes. In addition, we have determined that sequen-
tial methylation and methoxylation can be achieved. De-
tailed mechanistic analysis of PtII-catalyzed methoxylation
is underway.
2-(2,4,6-Trifluorophenyl)pyridine (1j): As described in the literature
procedure.[28] The amount of Pd(PPh3)4 was increased from 5–
10 mol-% to obtain comparable yields; yellow solid, 0.80 g, 40%
yield. Characterization data matches previously reported data. See
Supporting Information for details.
Experimental Section
General Procedures: Manipulation of organometallic compounds
was performed using standard Schlenk techniques under an atmo-
sphere of dry nitrogen or in a nitrogen-filled Vacuum Atmospheres
drybox (O2 Ͻ 2 ppm). NMR spectra were recorded on Bruker Av-
ance 300, Bruker Avance 400 or Bruker Avance 600 spectrometers.
1H, 19F and 13C{1H} chemical shifts are reported in parts per mil-
lion (ppm) and referenced to residual solvent when applicable. Cou-
pling constant values were extracted assuming first-order coupling.
General Procedure for Catalytic Reactions
NMR Scale Reactions: In the glovebox, a 20 mL glass vial was
charged with 0.034 mmol substrate, 0.034 mmol (0.0059 mg) 1,3,5-
trimethoxybenzene and dissolved in 1.0 mL of degassed, deuterated
solvent. In a separate 20 mL vial was weighed 0.017 mmol of
[Me2Pt(μ-SMe2)]2 which was subsequently dissolved in 1.0 mL of
degassed, deuterated solvent; 100 μL of the resulting Pt solution
The multiplicities are abbreviated as follows: s = singlet, d = doub- was added to the vial containing substrate. The resulting solution
let, t = triplet, m = multiplet. All spectra were obtained at 25 °C.
Mass spectra were recorded on Kratos MS-50 and Waters/Micro-
mass LCT mass spectrometers. Elemental analyses were performed
using a Carlo–Erba Elemental Analyzer EA 1108.
was transferred to an NMR tube with a screw-cap containing a
septum. Me2Zn (0.041 mmol, 37 μL of ≈ 1.2 m solution in toluene;
titrated according to literature procedure; 1.2 equiv.) or Si(OMe)4
(6.2 μL, 0.040 mmol, 1.2 equiv.) was added via microsyringe. The
Eur. J. Org. Chem. 2011, 3985–3994
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3991

L. Keyes, A. D. Sun, J. A. Love
FULL PAPER
NMR tube was sealed, removed from the glovebox and placed in
an oil bath at the indicated temperature (see text). Reaction pro-
gress was monitored over time via 1H and 19F NMR spectroscopy.
Analytical Data for N-(4-Bromo-6-methoxy-2-methylbenzylidene)-
benzylamine (6b): Based on in-situ NMR spectroscopic characteri-
zation. 58% yield based on integration of the H NMR spectrum
1
relative to an internal standard (1,3,5-trimethoxybenzene). 1H
NMR ([D3]acetonitrile, 300 MHz): δ = 8.75 (s, 1 H), 7.38–7.22
(overlapping peaks, aryl-H), 4.64 (s, 2 H, -CH2-), 3.65 (s, 3 H,
OCH3), 2.49 (s, 3 H, CH3) ppm. 19F NMR ([D3]acetonitrile,
282 MHz): δ = –119.6 (q, J = 7.9 Hz, 1 F) ppm.
Preparative Scale Reactions: In a 20 mL vial, substrate (0.4 mmol)
and [Me2Pt(μ-SMe2)]2 (11.5 mg, 0.02 mmol, 0.05 equiv.) were dis-
solved in CH3CN (4–5 mL). The resulting solution was transferred
into a test tube fitted with a screw cap containing a septum. Me2Zn
(0.480 mmol, 433 μL of ca. 1.2 m solution in toluene) or Si(OMe)4
(0.480 mmol, 73 μL) was then added by microsyringe. The resulting
solution was heated at the indicated temperature for 8–24 h (see
text). The solution was cooled to room temperature and the solvent
was removed by rotary evaporation. The residue was extracted with
petroleum ether (3ϫ20 mL). The combined organic extracts were
filtered through Celite. The filtrate was concentrated by rotary
evaporation to provide the crude product. Further column
chromatography (details included in Supporting Information) pro-
vides clean products. Functionalized products were found to be
particularly volatile making purification difficult and low yielding.
The methoxylated oxazoline 5h and imidazole 5i compounds were
isolated by combining and leaving the relevant column fractions to
evaporate in air.
Analytical Data for N-(4-Fluoro-6-methoxy-2-methylphenyl)-2-ox-
azoline (6c): Based on in-situ NMR spectroscopic characterization.
1
19% yield based on integration of the H NMR spectrum relative
to an internal standard (1,3,5-trimethoxybenzene). 1H NMR ([D3]-
acetonitrile, 300 MHz): δ = 6.49–6.46 (overlapping peaks, aryl H),
4.45–4.40 (overlapping peaks, -OCH2CH2N-), 4.10–4.07 (overlap-
ping peaks, -OCH2CH2N-), 3.81 (s, OCH3), 2.23 (s, CH3) ppm. 19
F
NMR ([D3]acetonitrile, 282 MHz): δ = –112.7 (q, J = 6.9 Hz, 1 F)
ppm.
Supporting Information (see footnote on the first page of this arti-
cle): Complete experimental details and spectra of all isolated com-
pounds.
Analytical Data for 2-(2,4-Difluoro-6-methylphenyl)oxazoline (2h):
Acknowledgments
Based on in-situ NMR spectroscopic characterization. 52% yield
1
based on integration of H NMR spectrum relative to an internal
standard (1,3,5-trimethoxybenzene). 1H NMR ([D3]acetonitrile,
300 MHz): δ = 6.77–6.67 (m, aryl-H), 4.43 (t, 2 H, J = 8.7 Hz,
-OCH2CH2N-), 4.10 (t, 2 H, J = 8.7 Hz, -OCH2CH2N-), 2.40 (s,
CH3). 19F NMR ([D3]acetonitrile, 282 MHz): δ = –108.1 (q, J =
9.0 Hz, 1 F), –109.4 (t, J = 9.0 Hz, 1 F) ppm.
We thank the following for support of this research: NSERC Col-
laborative Research and Development Grant (Research Tools and
Instrumentation Grants), AstraZeneca Canada (2008 Award in
Chemistry), and the University of British Columbia.
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Received: April 4, 2011
Published Online: June 7, 2011
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