Regio- and stereoselective allylic trifluoromethylation and fluorination using CuCF3 and CuF reagents

Article abstract of DOI:10.1021/jo4010074

Copper-mediated trifluoromethylation of allylic chlorides and trifluoroacetates was performed using a convenient Cu-CF₃ reagent. The reaction is suitable for selective synthesis of allyl trifluoromethyl species. Mechanistic studies indicate that the reaction proceeds via a nucleophilic substitution mechanism involving allyl copper intermediates. The analogous Cu-F reagent was suitable for fluorination of allyl chlorides. Stereodefined cyclic substrates reacted regio- and stereoselectively.

Full text of DOI:10.1021/jo4010074

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Note
Regio- and Stereoselective Allylic Trifluoromethylation
and Fluorination using CuCF3 and CuF Reagents
Johanna M. Larsson, Stalin R. Pathipati, and Kalman J. Szabo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4010074 • Publication Date (Web): 20 Jun 2013
Downloaded from http://pubs.acs.org on June 24, 2013
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Regio- and Stereoselective Allylic Trifluoromethylation and Fluorination using CuCF3 and
CuF Reagents
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Johanna M. Larsson, Stalin R. Pathipati and Kálmán J. Szabó*
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Department of Organic Chemistry, Stockholm University, SE-106 91 Stockholm, Sweden
*E-mail: kalman@organ.su.se
Copper-mediated trifluoromethylation of allylic chlorides and trifluoroacetates was performed
using a convenient Cu-CF3 reagent. The reaction is suitable for selective synthesis of allyl
trifluoromethyl species. Mechanistic studies indicate that the reaction proceeds via a nucleophilic
substitution mechanism involving allyl copper intermediates. The analogous Cu-F reagent was
suitable for fluorination of allyl chlorides. Stereodefined cyclic substrates reacted regio- and
stereoselectively.
The trifluoromethyl group is a privileged structural motif in pharmaceutical and agrochemical
products.1 Therefore, the development of new methods for introduction of CF3 groups has
attracted considerable recent attention.1,2 Most efforts have been concentrated on introducing the
CF3 functional group into aryl,2-10 alkene11-18 and alkyne19,20 substrates. In recent years two main
strategies have been developed for these reactions: i) nucleophilic functionalization based on
electron-rich trifluoromethylating reagents, such as complexes 1a-b;3,7,19 and ii) electrophilic
trifluoromethylation using electron-deficient CF3 reagents, such as the Togni8 or other oxidative
reagents.5,11,13-15 Particularly useful methods have appeared for allylic C-H functionalization
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using the latter method (see for example reference15). Although C-H functionalization is one of
the most efficient and atom economic strategies for the introduction of new functional groups,
some of the allylic (and other) trifluoromethylation methods suffer from regio-, stereo-selectivity
and functional group compatibility problems. Therefore, there is still room for development of
new substitution methods based on prefunctionalized substrates.16-18,21
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Figure 1. Convenient nucleophilic CF3 and F transfer reagents.
Recently, Grushin3 and we19 have reported efficient methods for the synthesis of
organotrifluoromethylated compounds using convenient Cu-CF3 reagent 1a. We have shown19
that propargylic halides and trifluoroacetates can be converted to allenyl- or propargyl-CF3
derivatives under mild, neutral conditions by 1a, which is easily accessed via a simple two step
synthesis reported by Grushin and co-workers.3 We have now found that the same method can be
extended to allylic derivatives (Scheme 1, Table 1). Allylic halides 2a-j can be efficiently and
regioselectively trifluoromethylated by copper reagent 1a in CDCl3 (use of deuterated solvent
facilitated the careful analysis of the crude product by 1H NMR). The reaction provides the linear
allylic regioisomer usually with high yield. The reactions can be conducted under mild, neutral
conditions (typically at room temperature) without any additives.
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Scheme 1. Allylic trifluoromethylation with 1a
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Cinnamyl chloride 2a and its analogs 2b-e reacted smoothly. The aromatic chloro substituent
survived the reaction as only the allylic chloride in 2b was trifluoromethylated to give 4b (entry
4). Both linear (2c) and branched (2d) para-nitro cinnamyl chloride gave the corresponding
linear regiosiomer 4c (entries 5-6) suggesting that allylic rearrangement may take place during
the trifluoromethylation process. The cinnamyl substrate containing an electron-donating
methoxy group (2e) reacted faster and with higher yield than its counterpart with an electron-
withdrawing nitro group (2c). Alkyl substituted allylic halides 2f-g also reacted with high regio-
and stereoselectivity (entries 8 and 10). Geranyl bromide 2h reacted with excellent
regioselectivity to give 4g; however, the E/Z forms were obtained in a 3:1 ratio. Silyl derivative
2i reacted with poor yield, affording 4h. In this process an interesting side reaction was observed,
which inspired us to develop a method for allylic fluorination (vide supra). Terpene chloride 2j
could also be converted to trifluoromethyl derivative 4i without changing the stereogenic carbon.
We have also studied application of non-halide leaving groups for the trifluoromethylation
reaction. Allylic acetates (such as cinnamyl acetate) did not react under our conditions or using
elevated temperatures. However, allylic trifluoroacetates reacted with 1a with the same regio-
and stereoselectivity as allylic halides. For example, 3a and 3b gave the linear regiosiomer 4a
similarly to 2a. The trifluoroacetates are less reactive than the halides, and therefore slightly
elevated temperature (55 °C) had to be applied. In some cases (such as for 3c), yields with the
trifluoroacetate substrate were lower than with the corresponding halides.
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Table 1. Synthesis of Allylic-CF3 Compounds from Allylic Halides and Trifluoroacetates.a
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a
A mixture of 2 or 3 (0.15 mmol) and 1a (1.1 equiv) in CDCl3 (0.6 mL) was stirred for 18 h at
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room temperature (2) or at 55 °C (3). The reaction was repeated on 1.6 mmol scale.
Linear/branched ratio of the substrate 6:1. d Linear/branched ratio of the substrate 1:3.
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The reaction can easily be scaled up. When we increased the scale of the reaction from 0.15 to
1.6 mmol (11 times) the yield was, in fact slightly increased from 68% to 76%. As mentioned
above, the yield for trifluoromethylation of 2i (entry 12) was unexpectedly low (41%). Analysis
of the reaction mixture by 19F NMR showed that part of the starting material underwent
fluorodesilylation to give PhMe2Si-F. Moreover, careful analysis of the reaction mixture of the
trifluoromethylation of 3c showed that allylic fluorination affording 5a′ also occurred using 1a
(Scheme 2). The fluorine in these processes apparently originated from the CF3 group. We
reasoned that probably -fluoride elimination of the Cu-CF3 occurred to give Cu-F and CF2. -
Fluoride elimination is a well-known process6,22 for Cu-CF3 complexes without PPh3 or other
strongly coordinating ligands. These findings gave us the idea to attempt fluorination reactions
with the fluoro analog of 1a (Table 2). Reagent 1c23 is readily available as an intermediate in the
synthesis of 1a.3
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Scheme 2. Allylic Trifluoromethylation and Fluorination with 1a.
Selective allylic fluorination reactions have attracted much attention in the last couple of years.24-
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These reactions are very challenging as some of the allylic fluorides are unstable27 and the
control of the regio- and stereoselectivity of the process is usually very difficult. In general, the
Pd- and Ir-catalyzed reactions are suitable for achieving high levels of selectivity.24-26 However,
the Cu-catalyzed/mediated allylic fluorination is rather unusual. During the revision of this paper
an independent study on copper-catalyzed fluorination of allyl chlorides and bromides was
published by Guosheng Liu and co-workers.28
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The fluorination of allylic halides with 1c (Table 2) required higher temperature (80 °C) than the
corresponding trifluoromethylation (room temperature). When 2f was employed the linear
product 5a was formed (Table 2, entry 1). Cyclic allylic bromide 2k reacted readily with high
NMR yield to give 5b. As 5b is both volatile and unstable,27 it was not isolated. However, cyclic
allylic fluorides with electron-withdrawing substituents, such as 5c-d, are stable compounds that
are fairly easy to isolate. When stereodefined allylic chlorides29 2l-m were reacted with 1c, we
obtained allylic fluorides 5c-d stereoselectively. Formation of methoxy ether byproducts from
reaction of 2l with MeOH coordinated to 1c somewhat lowered the yield of 5c (Table 2, entry 3).
Gouverneur and co-workers30 found that 5c undergoes Pd-catalyzed allylic nucleophilic
substitution with malonate derivatives. However, according to our studies allylic fluoride 5c does
not undergo the analogous reaction with MeOH, and thus the methoxy byproduct is proposed to
form from allylic chloride 2l. Replacement of MeOH with CHCl3 in 1c eliminated this side
reaction and the yield of 5c thereby increased (Table 2, entry 4). Additionally, the
stereoselectivity of formation of 5d was somewhat dependent on the solvents coordinated to 1c.
In the case of MeOH coordination (entry 6) the trans/cis ratio was higher (8:1) than with
coordinated CHCl3 (entry 5) (4:1). The reactions (entries 3-6) proceeded with inversion of
configuration in a formal SN2 reaction. Palladium-catalyzed synthesis of 5c from allylic
chlorides was previously described by Doyle and Katcher.24 This reaction proceeds via allyl
palladium intermediates by (overall) retention of configuration.24
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Table 2. Fluorination of Allylic Halides with 1c.a
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a A mixture of 2 (0.30 mmol) and 1c (1.4-1.8 equiv) in CDCl3 (0.5 mL) was stirred for 2.5 h at 80
°C. b Solvent (X) coordinated to 1c. c The reaction was conducted at rt for 10 min, 5b is unstable,
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therefore 1H NMR yield is given. The isolated product contained 15% of the other regioisomer
(2-fluorocyclohex-3-en-1-yl acetate).
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Gouverneur and co-workers30 described the synthesis of 5d from the corresponding allylic silane
and Selectfluor, which reacts through an SE2’ mechanism. Thus, our copper-mediated process
complements the stereochemistry of the Pd-catalyzed reaction to 5c and somewhat simplifies
access to 5d via substitution of easily accessible allylic chloride29 2m (entries 5-6). When the
reaction was attempted with 2m and simple inorganic fluoride salts, such as CsF and LiF, no
reaction took place. Using AgF a complex mixture including 5d and its possible regio- and
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stereoisomers was obtained. Application of CuF2 and PPh3 resulted in formation of 5d and its
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stereoisomer, albeit in low (1H NMR) yield (28%).
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When cyclic substrates 2k and 2m were reacted with CF3 complex 1a mainly fluorinated
products 5b and 5d were obtained, albeit with much lower conversion than with fluoride complex
1c. Under the applied reaction conditions allylic trifluoroacetates did not give allyl fluoride
products with 1c. The trifluoromethylation of 2a was also attempted using complex 1b.7
However, the (1H NMR) yield (30%) was much lower than with 1a. Interestingly, we could
observe formation of allylic fluorides even with this reagent.
We have briefly studied the mechanistic aspects of the trifluoromethylation reaction. Addition of
PPh3 to the trifluoromethylation of 2a (Table 1, entry 1, Table 3) strongly inhibited the reaction,
suggesting that the substitution is initiated by PPh3 dissociation followed by coordination of the
allylic halide. This is in line with the findings by Grushin3 for trifluoromethylation of aromatic
halides with 1a.
Table 3. Inhibition experiment with PPh3.
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Suprisingly, including TEMPO (6) in the trifluoromethylation resulted in formation of TEMPO
derivatives 7 and 8 and a decrease in the yield of 4a (Scheme 3). Although formation of 7-8 may
indicate a radical process, two equivalents of TEMPO did not completely inhibit the reaction, as
in the oxidative trifluoromethylation.11 Furthermore, control experiments showed that 2a or 1a
alone do not react with TEMPO. This suggests formation of a reaction intermediate from 1a and
2a, which could react with TEMPO (6).
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Scheme 3. Inhibition experiment with TEMPO 6.
Considering the fact that allylic isomers 2c-d and 3a-b regioselectively gave linear products 4c
and 4b, respectively, we suggest that the allylic substrate 2 and 1a form an allyl copper
intermediate, such as 9a (Scheme 4). This complex may rearrange to the 3-allyl form 9b, and
thus the unsubstituted terminus may approach the CF3 group. Product 4 is proposed to be formed
by reductive elimination. Complex 9a may undergo a single-electron reduction to form Cu(II)
complexes and CF3 or allylic radicals. This process may be promoted in the presence of radical
acceptors, such as TEMPO (6). However, we suggest that formation of the allyl-CF3 products 4
proceeds via an ionic mechanism.
Scheme 4. Suggested mechanism for the trifluoromethylation.
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This conclusion is also supported by our competition experiments (Scheme 5). Thus, the reaction
is faster with a substrate bearing an electron-donating substituent (2e) than with a substrate with
an electron-withdrawing substituent (2c). This suggests that CF3 is transferred in a nucleophilic
substitution process. However, it should be noted that the difference in the rate of
trifluoromethylation between the p-methoxy (2e) and the p-nitro substituted (2c) cinnamyl
derivatives is relatively small (about 2.5 times), which means that a radical mechanism cannot be
excluded.
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Scheme 5. Competition experiments. All components have been used in equal amounts.
In summary, we have shown that allylic chlorides and trifluoroacetates can be trifluoromethylated
by reagent 1a. The reaction is highly stereo- and regioselective and tolerates several functional
groups. At elevated temperature 1a undergoes -elimination to give 1c, which has proved to be a
useful fluorinating reagent. Using complex 1c, regio- and stereoselective fluorination of some
stereodefined allylic chlorides could be performed. Our procedure broadens the reagent scope in
trifluoromethylation and fluorination methods, and complements the chemo- and stereoselectivity
of existing methods.
Experimental Part
General information. Starting materials 1a,3 3a,31 2b,32 2c,33 2d,33 2e,32 2f,32 3c,31 2g,34 2i,34
2j,35 2l,36 and 2m,29 were prepared according to literature procedures. All other chemicals were
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obtained from commercial suppliers and were used without further purification. All reactions
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were prepared in a glovebox and performed under argon unless otherwise stated. H NMR, C
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NMR and 19F NMR spectra were recorded in CDCl3 on 400 or 500 MHz instruments. All H
NMR spectra are measured relative to the signals for residual CHCl3 (7.26 ppm) and all 13C NMR
spectral data are reported relative to CDCl3 (77.16 ppm). For 19F NMR, α,α,α-trifluorotoluene
was used as an external standard (-63.7 ppm). HRMS data were recorded on a micrOTOF
instrument using ESI technique. Attempts to obtain a HRMS spectrum was unsuccessful because
of a combination of low polarity and high volatility for compounds 4e, 4f, 4h, 4i, and 5a. All
column chromatography was performed using silica gel (35-70 microns).
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General procedure for trifluoromethylation of 2a-2j, 3a-3c. To a screw top vial were added 2
or 3 (0.15 mmol), (PPh3)3CuCF3 (1a, 152 mg, 0.165 mmol) and CDCl3 (0.6 mL) inside the
glovebox. The reaction mixture was stirred for 18 hours at room temperature for substrates 2 and
at 55 C for substrates 3. The crude mixture was thereafter purified by column chromatography.
General procedure for fluorination of 2f, 2k-2m. To a screw top vial were added 2 (0.30
mmol), (PPh3)3CuF (1b, 1.4 equiv/0.43 mmol or 1.8 equiv/0.54 mmol) and CDCl3 (1 mL) inside
the glovebox. The number of solvent molecules coordinated to (PPh3)3CuF was determined by 1H
NMR spectroscopy in CDCl3 or C6D6. Using this information the molecular weights of
(PPh3)3CuF·xMeOH and (PPh3)3CuF·xCHCl3 were calculated (see below). The reaction mixture
was heated at 80 C for 2.5 h. The solvent volume was thereafter reduced under vacuum and
pentane was added. The organic solvent was separated from the precipitated PPh3 and the solid
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was washed with pentane 2 additional times. The organic phases were then joined and the
product was purified by column chromatography.
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Modified synthesis of 1c. Complex 1c was synthesized according to a previously reported
literature procedure37 or with a slight modification in the purification process. Using the original
procedure37 we obtained (PPh3)3CuF·2.8MeOH in which the MeOH is coordinated to the
complex. It has previously been noted23 that the number of MeOH molecules retained in the
product, (PPh3)3CuF·xMeOH, after prolonged drying under vacuum at room temperature varies.
A value of x less than one could not be achieved. However, the coordinated MeOH could be
removed using a modified purification method. After completion of the reaction, the crude was
concentrated at reduced pressure and thereafter dissolved in CHCl3. To ensure complete removal
of MeOH, the solvent was ones again removed at reduced pressure. Recrystallization of the
residue from CHCl3/pentane produced (PPh3)3CuF·0.46CHCl3 (1c) in 54% (4.997 g, 5.406 mmol,
MW = 924.31 g/mol) yield. The number of CHCl3 molecules coordinated to 1c after drying the
complex overnight in vacuum varied from two to complete removal of the solvent. The amounts
of the coordinated solvent molecules were determined by 1H NMR. The spectral data for 1c is in
agreement with previously reported literature values.23,37
(E)-(4,4,4-Trifluorobut-1-en-1-yl)benzene (4a). The product was synthesized from 2a (0.15
mmol, 23 mg and 1.6 mmol, 258 mg) according to the general procedure for trifluoromethylation.
The title compound was purified by column chromatography (pentane) and isolated as an oil in
68% yield (19 mg and 232 mg in the scaled-up version of the reaction). Compound 4a was also
synthesized from allylic trifluoroacetates 3a (0.15 mmol, 35 mg) and 3b (0.15 mmol, 35 mg)
according to the general procedure for trifluoromethylation. Additionally, in the
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trifluoromethylation of 3b 1.2 equiv (0.18 mmol) of 1a was used. The title compound was
purified by column chromatography (pentane) and isolated in 53% yield (15 mg) from 3a and in
61% yield (17 mg) from 3b. The NMR data obtained are in agreement with literature values.15
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Spectral data for 4a: H NMR (400 MHz, CDCl3) δ 7.41-7.36 (m, 2H), 7.36-7.30 (m, 2H), 7.30-
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7.24 (m, 1H), 6.61 (d, J = 15.8 Hz, 1H), 6.11 (dt, J = 15.8, 7.3 Hz 1H), 3.06-2.93 (m, 2H); C
NMR (100 MHz, CDCl3) δ 136.8, 136.4, 128.8, 128.3, 126.6, 126.1 (q, JC-F = 277.2 Hz), 117.3
(q, JC-F = 3.6 Hz), 37.8 (q, JC-F = 29.9 Hz); 19F NMR (376 MHz, CDCl3) δ -66.2 (t, J = 10.7 Hz).
(E)-1-Chloro-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (4b). The product was synthesized from
2b (0.15 mmol, 28 mg) according to the general procedure for trifluoromethylation. The title
compound was purified by column chromatography (pentane) and isolated as an oil in 85% yield
(28 mg). The NMR data obtained are in agreement with literature values.16 Spectral data for 4b:
1H NMR (400 MHz, CDCl3) δ 7.30 (br s, 4H), 6.56 (d, J = 15.8 Hz, 1H), 6.09 (dt, J = 15.8, 7.3
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Hz, 1H), 3.06-2.92 (m, 2H); C NMR (100 MHz, CDCl3) δ 135.6, 134.8, 134.0, 129.0, 127.8,
125.9 (q, JC-F = 277.2 Hz), 118.1 (q, JC-F = 3.6 Hz), 37.8 (q, JC-F = 30.0 Hz); 19F NMR (376 MHz,
CDCl3) δ -66.2 (t, J = 10.6 Hz).
(E)-1-Nitro-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (4c). The product was synthesized from 2c
(0.15 mmol, 30 mg) and 2d (0.15 mmol, 30 mg) according to the general procedure for
trifluoromethylation except that pentane was added to the reaction mixture after completion of
the reaction. The organic solvent was separated from the precipitated PPh3 and the solid was
washed with pentane two additional times. The organic phases were then joined and the product
was purified by column chromatography (pentane/diethylether 10:1) and isolated as an oil in 51%
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yield (18 mg) from 2c and in 62% (22 mg) yield from 2d. Spectral data for 4c: H NMR (400
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MHz, CDCl3) δ 8.24-8.16 (m, 2H), 7.56-7.48 (m, 2H), 6.69 (d, J = 15.9, 1H), 6.30 (dt, J = 15.9,
7.2 Hz, 1H), 3.13-2.99 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 147.5, 142.5, 134.8, 127.2, 125.7
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(q, JC-F = 276.8 Hz), 124.2, 122.3 (q, JC-F = 3.6 Hz), 37.9 (q, JC-F = 30.3 Hz); F NMR (376
MHz, CDCl3) δ -65.9 (t, J = 10.5 Hz); HRMS (ESI): m/z calcd. for [C10H8F3NO2Na]+ 254.0399,
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found 254.0391.
(E)-1-methoxy-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (4d). The product was synthesized
from 2e (0.15 mmol, 27 mg) according to the general procedure for trifluoromethylation except
that pentane was added to the reaction mixture after completion of the reaction. The organic
solvent was separated from the precipitated PPh3 and the solid was washed with pentane two
additional times. The organic phases were then joined and the product was purified by column
chromatography (pentane/diethylether 20:1) and isolated as an oil in 79% yield (26 mg). The
NMR data obtained are in agreement with literature values.20 Spectral data for 4d: 1H NMR (500
MHz, CDCl3) δ 7.35-7.29 (m, 2H), 6.89-6.83 (m, 2H), 6.54 (d, J = 15.9 Hz, 1H), 5.96 (dt, J =
15.9, 7.3 Hz, 1H), 3.81 (s, 3H), 3.01-2.91 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 159.7, 136.2,
129.2, 127.8, 126.1 (q, JC-F = 276.6 Hz), 115.0 (q, JC-F = 3.6 Hz), 114.2, 55.5, 37.8 (q, JC-F = 29.8
Hz); 19F NMR (376 MHz, CDCl3) δ -66.3 (t, J = 10.7 Hz).
(E)-(6,6,6-Trifluorohex-3-en-1-yl)benzene (4e). The product was synthesized from 2f (0.15
mmol, 27 mg) according to the general procedure for trifluoromethylation. The title compound
was purified by column chromatography (pentane) and isolated in 75% yield (24 mg). Compound
4e was also synthesized from allylic trifluoroacetate 3c (0.15 mmol, 39 mg) according to the
general procedure for trifluoromethylation except that pentane was added to the reaction mixture
after completion of the reaction. The organic solvent was separated from the precipitated PPh3
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and the solid was washed with pentane two additional times. The organic phases were then
collected and 4e was purified by column chromatography (pentane) and isolated as an oil in 30%
yield (10 mg). Compound 5a′ was isolated in 32% yield (8 mg). The spectral data for this
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compound is in agreement with previously reported literature values.26 Spectral data for 4e: H
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NMR (400 MHz, CDCl3) δ 7.32-7.27 (m, 2H), 7.23-7.16 (m, 3H), 5.75 (dt, J = 15.4, 6.7 Hz, 1H),
5.41 (dtt, J = 15.4, 7.0, 1.5 Hz, 1H), 2.85-2.67 (m, 4H), 2.45-2.34 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 141.6, 137.5, 128.6, 128.5, 126.2 (q, JC-F = 276.5 Hz), 124.8, 118.5 (q, JC-F = 3.6 Hz),
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37.5 (q, JC-F = 29.6 Hz), 35.5, 34.4; F NMR (376 MHz, CDCl3) δ -66.7 (t, J = 10.8 Hz); (EI):
m/z (rel intens) 213 (M+, 10), 181 (31), 131 (23), 117 (8), 91 (100).
(E)-(4,4,4-Trifluorobut-1-enyl)cyclohexane (4f). The product was synthesized from 2g (0.15
mmol, 24 mg) (linear/branched isomeric ratio 6:1) according to the general procedure for
trifluoromethylation. The title compound was purified by column chromatography (pentane) and
isolated in as an oil 59% yield (17 mg). Spectral data for 4f: 1H NMR (400 MHz, CDCl3) δ 5.65
(dd, J = 15.5, 6.7 Hz, 1H), 5.33 (dtd, J = 15.5, 7.0, 1.4 Hz, 1H), 2.81-2.69 (m, 2H), 2.04-1.92 (m,
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1H), 1.79-1.69 (m, 4H), 1.69-1.61 (m, 1H), 1.37-1.01 (m, 5H); C NMR (100 MHz, CDCl3) δ
144.3, 126.3 (q, JC-F = 276.5 Hz), 115.2 (q, JC-F = 3.5 Hz), 40.8, 37.6 (q, JC-F = 29.4 Hz), 32.8,
26.3, 26.1; 19F NMR (376 MHz, CDCl3) δ -66.8 (t, J = 10.8 Hz); (EI): m/z (rel intens) 191 (M+,
16), 109 (6), 97 (3), 83 (5), 67 (100).
(E)-9,9,9-Trifluoro-2,6-dimethylnona-2,6-diene (4g). The product was synthesized from 2h
(0.15 mmol, 33 mg) according to the general procedure for trifluoromethylation. The title
compound was purified by column chromatography (pentane) and isolated as an oil in 90% yield
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(28 mg, E/Z ratio 3:1, determined from F NMR spectroscopy). The NMR data obtained are in
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agreement with literature values.16 Spectral data for (E)-4g: H NMR (400 MHz, CDCl3) δ 5.26-
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5.01 (m, 2H), 2.87-2.72 (m, 2H), 2.16-2.02 (m, 4H), 1.69 (s, 3H), 1.66 (s, 3H), 1.60 (s, 3H); C
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NMR (100 MHz, CDCl3) δ 142.5, 132.0, 126.7 (q, JC-F = 276.6 Hz), 123.8, 112.0 (q, JC-F = 3.4
Hz), 39.7, 33.1 (q, JC-F = 29.3 Hz), 26.5, 25.8, 17.8, 16.5; 19F NMR (376 MHz, CDCl3) δ -66.4 (t,
J = 11.0 Hz).
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(E)-Dimethyl (phenyl)(4,4,4-trifluorobut-1-en-1-yl)silane (4h). The product was synthesized
from 2i (0.15 mmol, 32 mg) according to the general procedure for trifluoromethylation. The title
compound was purified by column chromatography (pentane) and isolated as an oil in 41% yield
(15 mg). The compound PhMe2Si-F38 was observed to form as a by-product (ratio 4h: PhMe2Si-F
1:1.3 determined from 19F NMR analysis of the crude reaction mixture). Spectral data for 4h: 1H
NMR (400 MHz, CDCl3) δ 7.54-7.48 (m, 2H), 7.40-7.34 (m, 3H), 6.11 (d, J = 18.5 Hz, 1H), 6.00
(dt, J = 18.5, 6.2 Hz, 1H), 3.00-2.86 (m, 2H), 0.36 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 138.0,
137.3, 135.0 (q, JC-F = 3.4 Hz), 133.9, 129.3, 128.0, 125.9 (q, JC-F = 277.1 Hz), 41.2 (q, JC-F = 28.9
Hz), -2.7; 19F NMR (376 MHz, CDCl3) δ -66.0 (t, J = 10.8 Hz).
(R)-4-(Prop-1-en-2-yl)-1-(2,2,2-trifluoroethyl)cyclohex-1-ene (4i). The product was
synthesized from 2j (linear/branched isomeric ratio 1:3, 0.15 mmol, 26 mg) according to the
general procedure for trifluoromethylation. The title compound was purified by column
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chromatography (pentane) and isolated as an oil in 56% yield (17 mg). Spectral data for 4i: H
NMR (400 MHz, CDCl3) δ 5.73-5.66 (m, 1H), 4.76-4.68 (m, 2H), 2.71 (q, J = 11.2 Hz, 2H),
13
2.24-2.05 (m, 4H), 2.05-1.91 (m, 1H), 1.88-1.78 (m, 1H), 1.74 (s, 3H), 1.56-1.43 (m, 1H); C
NMR (100 MHz, CDCl3) δ 149.6, 128.8, 127.5 (q, JC-F = 2.6 Hz), 126.4 (q, JC-F = 277.8 Hz),
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109.0, 41.9 (q, JC-F = 28.7 Hz), 40.5, 31.0, 29.3, 27.7, 20.9; 19F NMR (376 MHz, CDCl3) δ -64.8
(t, J = 11.2 Hz).
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(E)-(5-Fluoropent-3-en-1-yl)benzene (5a). The product was synthesized from 2f (0.15 mmol, 27
mg) according to the general procedure for fluorination except that the reaction was performed at
half the scale. The copper reagent used, (PPh3)3CuF (1.8 equiv, 0.27 mmol, 235 mg, MW =
869.40 g/mol), had no solvent molecule coordinated in solid form. The title compound was
purified by column chromatography (pentane/chloroform 9:1) and isolated as an oil in 53% yield
1
(13 mg). Spectral data for 5a: H NMR (400 MHz, CDCl3) δ 7.33-7.27 (m, 2H), 7.23-7.17 (m,
3H), 5.94-5.83 (m, 1H), 5.79-5.67 (m, 1H), 4.80 (dd, J = 47.4, 6.2 Hz, 1H), 2.77-2.70 (m, 2H),
2.46-2.38 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 141.5, 136.4 (d, JC-F = 12.0 Hz), 128.54,
128.52, 126.1, 125.3 (d, JC-F = 16.5 Hz), 83.7 (d, JC-F = 160.6 Hz), 35.3 (d, JC-F = 3.2 Hz), 34.1
(d, JC-F = 2.1 Hz); 19F NMR (376 MHz, CDCl3) δ -208.3 (tm, J = 47.4 Hz); (EI): m/z (rel intens)
164 (M, 7), 131 (51), 104 (5), 91 (100), 77 (3).
3-Fluorocyclohex-1-ene (5b). The product was synthesized from 2k (0.30 mmol, 48 mg) in a
soda lime reaction vial according to the general procedure for fluorination using the copper
reagent (PPh3)3CuF·0.5CHCl3 (1.8 equiv, 0.54 mmol, 500 mg, MW = 924.31 g/mmol) except
that the reaction was run at room temperature for 10 min. The title compound was formed in 92%
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NMR yield according to H NMR using 1,3,5-trimethyoxybenzene as an internal standard. The
NMR data obtained are in agreement with literature values.27
Cis-(methyl 5-fluorocyclohex-3-enecarboxylate) (5c). The product was synthesized from 2l
(trans/cis 15:1, 0.30 mmol, 52 mg) according to the general procedure for fluorination and the
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product was purified by column chromatography (pentane/diethylether 10:1). Depending on the
purification method for 1c (see above) the complex contained varying amounts of coordinated
solvent molecules (MeOH or CHCl3). When using copper reagent (PPh3)3CuF·2.8MeOH (1.4
equiv, 0.43 mmol, 417 mg, MW = 959.11 g/mol) the product was isolated as an oil in 57% yield
(27 mg, cis/trans 4:1) together with methoxy derivative (methyl-5-methoxycyclohex-3-ene-1-
carboxylate)39 in 23% yield (12 mg, cis/trans 1.5:1). When using copper reagent
(PPh3)3CuF·0.8CHCl3 (1.8 equiv, 0.54 mmol, 528 mg, MW = 964.9 g/mol) the product was
isolated in 76% yield (36 mg, cis/trans 4:1). The isomeric ratios were determined from 1H and 19F
NMR of the crude reaction mixtures. The NMR data obtained are in agreement with literature
values.30 Spectral data for cis-5c: 1H NMR (500 MHz, CDCl3) δ 5.92-5.84 (m, 1H), 5.83-5.75 (m,
1H), 5.13 (dm, J = 48.9 Hz, 1H), 3.69 (s, 3H), 2.71-2.61 (m, 1H), 2.47-2.22 (m, 3H), 1.98-1.86
(m, 1H); 13C NMR (126 MHz, CDCl3) δ 174.4, 130.0 (d, JC-F = 9.7 Hz), 126.9 (d, JC-F = 20.8 Hz),
87.3 (d, JC-F = 163.9 Hz), 52.0, 37.4 (d, JC-F = 8.2 Hz), 31.6 (d, JC-F = 20.3 Hz), 27.3 (d, JC-F = 2.1
Hz); 19F NMR (376 MHz, CDCl3) δ -173.0 (tm, J = 48.9 Hz).
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Trans-(4-fluorocyclohex-2-en-1-yl acetate) (5d). The product was synthesized from 2m
(cis/trans 24:1, 0.30 mmol, 52 mg) according to the general procedure for fluorination and the
product was purified by column chromatography (pentane/diethylether 9:1). When using copper
reagent (PPh3)3CuF·2.8MeOH (1.4 equiv, 0.43 mmol, 417 mg, MW = 959.11 g/mol) the product
was isolated as an oil in 62% yield (30 mg, cis/trans 8:1). When using copper reagent
(PPh3)3CuF·0.5CHCl3 (1.8 equiv, 0.54 mmol, 500 mg, MW = 924.31 g/mol) the product was
isolated in 77% yield together with the regioisomer of 5d: 2-fluorocyclohex-3-en-1-yl acetate (37
mg, cis-5d/trans-5d/regioisomer of 5d 16:68:17). The isomeric ratio was determined from 19F
NMR of the crude reaction mixture. The NMR data obtained are in agreement with literature
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values.40 Spectral data for trans-5d: 1H NMR (500 MHz, CDCl3) δ 6.05-5.96 (m, 1H), 5.96-5.89
(m, 1H), 5.37-5.24 (m, 1H), 5.05 (dm, J = 47.8 Hz, 1H), 2.21-2.09 (m, 2H), 2.04 (s, 3H), 1.92-
1.79 (m, 1H), 1.72-1.59 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 170.6, 131.1 (d, JC-F = 9.6 Hz),
130.2 (d, JC-F = 19.1 Hz), 85.6 (d, JC-F = 164.5 Hz), 67.5 (d, JC-F = 2.6 Hz), 26.7 (d, JC-F = 20.0
Hz), 25.3 (d, JC-F = 5.2 Hz), 21.3; 19F NMR (376 MHz, CDCl3) δ -172.2 (m).
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Competition experiments (Scheme 5). The reaction was performed according to the general
procedure for trifluroromethylation using a combination of 2a (0.15 mmol, 23 mg) and 2e (0.15
mmol, 27 mg) or 2c (0.15 mmol, 30 mg) as starting materials and trifluoromethylating reagent
(PPh3)3CuCF3 (1a, 0.15 mmol, 138 mg) in 0.8 mL CDCl3. The ratios between the products
formed were determined using 19F NMR to be 4a/4d 1:1.8 and 19F NMR to be 4a/4c 1:0.7.
Inihibition expertiment with PPh3 (Table 3). The reaction was performed according to the
general procedure for trifluroromethylation using 2a (0.15 mmol, 23 mg) as starting material
except that the reaction was performed in 0.5 mL of CDCl3 for 5 h and that different amounts of
PPh3 (0, 1, 2 or 10 equiv) were added. The ratios between the products formed were determined
using 1H NMR analysis of the crude reaction mixtures.
Inihibition expertiment with radical scavenger TEMPO (Scheme 3). The reaction was
performed according to the general procedure for trifluoromethylation using 2a (0.15 mmol, 23
1
mg) as starting material in the presence of TEMPO (6) (2 equiv, 0.3 mmol, 47 mg). As the H
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NMR shifts of 7 and 8 are overlapping, we used both H and F spectroscopy to determine the
yields. From the ratio of 4a and 8 in 1H-NMR and from 19F NMR (using α,α,α-trifluorotoluene as
an internal standard) the yields were determined to be 44% of 4a, 37% of 841 (with respect to the
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amount of 2a employed) and 19% of 7 (with respect to the amount of 1a employed). Spectral
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data for 8: H NMR (400 MHz, CDCl3) δ 7.43-4.37 (m, 2H), 7.34-7.28 (m, 2H), 7.25-7.20 (m,
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1H), 6.60 (d, J = 16.0 Hz, 1H), 6.29 (dt, J = 16.0, 5.9 Hz, 1H), 4.45 (dd, J = 5.9, 1.5 Hz, 2H),
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1.64-1.53 (m, 1H), 1.51-1.44 (m, 4H), 1.39-1.30 (m, 1H), 1.21 (s, 6H), 1.14 (s, 6H); C NMR
(100 MHz, CDCl3) δ 137.3, 131.5, 128.6, 127.6, 126.6, 125.8, 78.2, 60.0, 39.9, 33.2, 20.4, 17.3.
Control experiments with TEMPO. The reaction was performed according to the general
procedure for trifluoromethylation but without allylic substrate and with the addition of TEMPO
(6) (0.3 mmol, 47 mg). According to 19F NMR analysis (using α,α,α-trifluorotoluene as an
internal standard) <0.5% of 7 was formed. Additionally, only unreacted 1a can be observed in the
crude reaction mixture by 19F NMR in more than trace amounts. The reaction was performed
according to the general procedure for trifluoromethylation using 2a as starting material with the
addition of TEMPO (6) (2 equiv, 0.3 mmol, 47 mg) but without copper complex 1a. According to
1H NMR analysis 2a is still intact after the reaction and other products were not formed in more
than trace amounts.
Investigation into the formation of methoxy ether byproduct 10 during the fluorination of
2l. To a screw top vial were added 2l (0.04 mmol, 7 mg), (PPh3)3CuF·2.8MeOH (1.4 equiv, 0.056
mmol, 54 mg, MW = 959.11 g/mol) and CDCl3 (0.15 mL) inside the glovebox. An internal
standard was included in the reaction mixture (1,3,5-trimethyoxybenzene) and the clear solution
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was heated at 80 C for 2.5 h. Analysis by H NMR spectroscopy revealed that all 2l had been
consumed. Ratios: 5c/10 3.5:1 and cis-5c/trans-5c 3.6:1. MeOH was thereafter added to the
reaction mixture (approx. 1.6 equiv, 2 mg) and the solution was heated at 80 C for another 2.5 h.
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1H NMR analysis revealed that no decomposition of 5c and 10 had occurred (by comparing the
integrals with the integrals of the internal standard) and that the cis-5c/trans-5c ratio of 3.6:1 was
maintained. These results shows that 10 forms from 2l and not from 5c.
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Acknowledgements. The authors thank the financial support of the Swedish Research Council
(VR) and the Knut och Alice Wallenbergs Foundation via the Center of Molecular Catalysis at
Stockholm University (CMCSU).
Supporting information available. The NMR spectra of the products are given. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(2) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475.
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Chem. Int. Ed. 2011, 50, 7655.
(4) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science
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