Copper-mediated cyanotrifluoromethylation of styrenes using the Togni reagent

Article abstract of DOI:10.1021/jo401831t

Styrenes with an electron-deficient double bond undergo cyanotrifluoromethylation with a trifluoromethylated hypervalent iodine reagent in the presence of CuCN. The reaction proceeds under mild conditions in the presence of bulky phosphines or B₂pin₂ additives. The process is highly regioselective and involves the consecutive formation of two C-C bonds in a single addition reaction. In the presence of a p-methoxy substituent in the styrene, oxytrifluoromethylation occurs instead of the cyanotrifluoromethylation.

Full text of DOI:10.1021/jo401831t

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Note
Copper Mediated Cyano-trifluoromethylation
of Styrenes using the Togni Reagent
Nadia O. Ilchenko, Pär G. Janson, and Kalman J. Szabo
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 Sep 2013
Downloaded from http://pubs.acs.org on October 1, 2013
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Copper Mediated Cyano-trifluoromethylation of Styrenes using the Togni Reagent
Nadia O. Ilchenko, Pär G. Janson 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
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Styrenes with an electron deficient double bond undergo cyano-trifluoromethylation with a
trifluoromethylated hypervalent iodine reagent in the presence of CuCN. The reaction proceeds
under mild conditions in the presence of bulky phosphines or B2pin2 additives. The process is
highly regioselective and involves a consecutive formation of two C-C bonds in a single addition
reaction. In the presence of para-methoxy substituent in the styrene oxytrifluoromethylation
occurs instead of the cyano-trifluoromethylation.
Trifluoromethylated compounds represent an important class of bioactive intermediates in
pharmaceutical and agrochemical industries.1 As a consequence, there is a large demand for new
methods for selective synthesis of functionalized trifluoromethylated compounds.2-5 Recently,
new and powerful methodologies have appeared in the literature to introduce the trifluoromethyl
functionality using oxidative reagents, such as Togni reagents 1a-b and Umemoto reagent 1c.6-22
Figure 1. Examples for oxidative CF3 transfer reagents.
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We8 and others9-12,17,20 have shown that efficient oxytrifluoromethylation of styrenes and other
species lacking β-hydrogens can be carried out by using 1a. In a standard reaction with 1a the
trifluoromethyl group is usually introduced to the terminal position of the styrene,8,9 while the
iodobenzoate (arising from 1a) is introduced to the other carbon atom of the alkene. However, a
few examples are reported,8,23 when the second group introduced was a halogenide (instead of
iodobenzoate) from the applied CuX mediator of the reaction. In this Note, we present our results
using CuCN as mediator for the trifluoromethylation reaction. We have found that using
appropriate reaction conditions this copper salt in combination with 1a is suitable for selective
introduction of the CF3 and CN groups to styrenes, thus to create two C-C bonds in a single
addition reaction (Table 1). Remarkably, in a very recent publication Akita and co-workers16
reported a similar reaction with completely different outcome. These authors employed 1c and
organonitriles for bifunctionalization of styrenes under photoredox conditions. This reaction
resulted in aminotrifluoromethylation involving C-C and C-N bond formation.
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Table 1. Variation of the Reaction Conditions for Cyano-trifluoromethylation.
The best results for the presented cyanotrifluoromethylation reaction were achieved using
electron deficient styrenes, such as 2a, with 1a as CF3 source in the presence of catalytic amounts
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of PCy3 (5)13 and stoichimetric amounts of CuCN (4). Under these conditions cyano-
trifluoromethylated product 3a was formed with high regioselectivity and in good yield (entry 1).
Addition of PCy3 was essential, as in the absence of this bulky/electron rich phosphine formation
of 3a was not observed in the crude reaction mixture (entry 2). Replacement of PCy3 with PtBu3
lead to formation of 3a but with lower yield (entry 3). Application of PPh3 was inefficient. The
reaction occured with acceptable yield (52%) using B2pin2 instead of PCy3. Recently, we have
reported that B2pin2 has an activating effect in Cu-mediated trifluoromethylation of quinones.14 A
similar effect was observed for the above cyano-trifluoromethylation reaction. Other CF3 sources,
such as 1b or 1c could not be used instead of 1a (entry 5). The reaction obviously requires
stoichimetric amounts of cyanide. However, the cyanide component does not necessarily comes
from CuCN (4). Catalytic amounts (10 mol%) of CuCN is sufficient in the presence of
stoichimetric amounts of Bu4N-CN or other cyanide sources (entries 6-7). However, the yield is
lower with Bu4N-CN (47%) than with stoichimetric amounts of CuCN (c.f. entries 1 and 6).
Application of catalytic amounts of CuCN with stoichimetric amount of KCN gave even lower
yield (entry 7) than the reaction with Bu4N-CN (entry 6) possibly due to the poor solubility of
KCN in the reaction medium. Considering this, and the fact that CuCN is less expensive than
Bu4N-CN, we employed stoichimetric amounts of CuCN in the further studies. In the absence of
CuCN using only Bu4N-CN we did not observe any reaction of 2a. We also briefly screened
other solvents for the process. However, the yield was substantially decreased, when the reaction
was conducted in MeOH, DMF, DMSO or THF instead of CDCl3 (the reactions were conducted
in deuterated solvents to directly study the crude reaction mixture with 1H and 19F NMR).
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Table 2. Cyano-trifluoromethylation of various Styrene Derivatives.a
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a
A mixture of styrene 2 (0.1 mmol), 1a (0.15 mmol), CuCN (0.1 mmol) and PCy3 (0.01 mmol,
10 mol%) was dissolved in CDCl3 under Ar. The reaction mixture was stirred at room
temperature for 18h. b Ar = 2-iodophenyl.
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We also attempted the reaction using CuOAc in place of CuCN. In this process most of the
starting material (2a) remained intact and according to 19F NMR only traces of
trifluoromethylated product was formed, i.e. oxytrifluoromethylated product did not form either.
This is in line with our previous studies8 that styrenes with electron withdrawing groups reluctant
to undergo oxytrifluoromethylation at room temperature.
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Subsequently, we explored the synthetic scope of the reactions (Table 2). Styrenes with electron-
withdrawing group proved to be particularly useful substrates for cyano-trifluoromethylation
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(entries 1-7). Inspection of the crude reaction mixtures by F NMR indicated formation of the
desired cyanotrifluoromethylated products together with other CF3 species. For example, in some
of the reactions small traces of oxytrifluoromethylation products was probably also formed. We
did not attempt to isolate these trace amounts of oxytrifluoromethylation products. The relatively
low yield in some reactions (e.g. entries 4, 5, 9) is a consequence of the formation of
oxotrifluoromethylated and other byproducts, which could easily be removed by column
chromatography. Para-chloro, -bromo and -trifluoromethyl substituted styrenes (entries 2, 3 and
5) all gave good yields similarly to the fluoro substituted analog (entry 1). Ortho-substituted
substrates (entries 4 and 6) also reacted smoothly indicating that the reaction is not sensitive to
steric hindrance. Even styrenes with weakly electron withdrawing phenyl and aryl substituents
could be applied in the cyano-trifluoromethylation. Para-phenyl substituted styrene 2g and 2-
vinylnaphthalene 2h gave the corresponding bifunctionalized products 3g-h in relatively good
yields (71 and 58% respectively). When tBu substituted styrene 2i was reacted (entry 9) mainly 3i
was formed together with a substantial amount of another trifluoromethylated product, probably
the oxytrifluoromethylated analog. Therefore, the yield (51%) was lowered and it could not be
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improved by further optimization, for example by increasing the amount of cyanide salts in the
reaction mixture. Even 3-methoxystyrene 2j gave the corresponding cyano-trifluoromethylated
product 3j in 59% yield. However, reacting the para-methoxy analog 2k under the standard
reaction conditions we obtained oxytrifluoromethylated product 6 in high yield. In this reaction
only traces, if any, cyano-trifluoromethylated product was formed. Thus, the cyano-
trifluoromethylation reaction with CuCN and 1a as CF3 source seems to be limited to styrenes
with electron-withdrawing para- and ortho-substituents, such as F, Cl, Br, CF3, Ph, aryl groups
or, in the case of methoxy groups, meta-substition. In the presence of the para-tBu substituent
(entry 9) the cyano-trifluorometylation still dominates but in this reaction substantial amounts of
another product was also formed. In the presence of a strong π-electron donor group, such as
para-methoxy, the chemoselectivity is shifted from cyano-trifluoromethylation to
oxytrifluoromethylation. The synthetic scope of the process under the applied reaction conditions
is probably limited to the above or related styrene derivatives. Other type of substrates with an
electron poor double bond, such as methyl acrylate or methyl vinyl ketone, do not undergo
trifluoromethylation reaction under the above conditions.
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The exact mechanism of the cyano-trifluoromethylation reaction is not known. However, the
electronic control of the chemoselectivity to obtain cyano-trifluoromethylated (3a-j) vs.
oxytrifluoromethylated (6) product under the same reaction conditions is interesting. A plausible
explanation for this chemoselectivity control is given in Figure 2. As mentioned previously the
reaction can also be carried out using catalytic amounts of CuCN in the presence of other cyanide
sources (Table 1, entries 1, 6 and 7). However, because of the low price of CuCN and the good
yield of the reaction, we employed stoichiometric amounts of it.
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Figure 2. Plausible Reaction Mechanism
The initial steps of the reaction are probably identical to the previously reported Cu-catalyzed
oxytrifluoromethylation8-11 and the closely related allylic/vinylic C-H activation14,24-26 reactions
using 1 as CF3 source. Thus, we suggest that 1a undergoes oxidative addition with CuCN to form
complex 7. In this complex the Cu-CF3 bond may undergo homolytic cleavage to give a CF3
radical and Cu(II) complex 8 in a doublet electronic state. The applied PCy3 ligand probably
facilitates this process by increasing the electron density on Cu. A Bpin ligand formed by
transmetallation27 of CuCN by B2pin2 (Table 1, entry 4) may have a similar effect. The CF3
radical may add to the double bond of the styrene substrate to give 9. We suggest that
recombination of radical 9 with Cu(II) complex 8 gives complex 10. The styrene substrate (η1-
benzyl moiety) with an electron withdrawing group (Z = EWG) is supposed to occupy the
position trans to the electron rich and bulky PCy3. Both ligands are sterically demanding
rendering them to a trans geometry. This geometry is probably also stabilized by the trans
influence involving an electron donating PCy3 ligand and an electron deficient η1-benzyl moiety.
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The sterically non-demanding cyano group may occupy a cis position to the η1-benzyl moiety,
and, thus it may undergo a facile reductive elimination affording product 3. Coordination of the
relatively bulky 2-iodo-benzoyl ligand is less favorable and probably its reductive elimination is
slower than for the CN ligand. In case of a styrene with electron donating OMe group in the
para-position (Z = OMe) the recombination of 8 and 9 is probably not favored. The trans
coordination of the bulky PCy3 and η1-benzyl (Z = OMe) moieties is supposed to be destabilizing
because of the “transphobia”28,29 occurring between the two electron rich ligands. Instead, radical
9 probably undergoes a single electron oxidation by copper, forming a stabilized carbocation,
followed by nucleophilic attack of the iodobenzoate anion. An alternative mechanism could be
that the cyano radical recombines with 9. This, however would be less probable with styrenes
bearing electron withdrawing substituents, which is in contrast with the above findings.
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We postulate that similar type of trifluoromethylation reactions can be developed using other
appropriate Cu-salts. For example, when the process was attempted using CuI instead of CuCN
using 2a as substrate we could isolate an unstable compound, which according to NMR and MS
analysis was identified as iodo-derivative 11 (Figure 3). Compound 11 can be regarded as a
product of a Cu-mediated iodotrifluoromethylation reaction. This process has a much lower yield
than the cyano-trifluoromethylation, which is probably due to fact the C-I bond of 11 is much
weaker than the C-CN bonding in 2a.
Figure 3. Iodotrifluoromethylation using CuI.
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In summary, we have shown that using 1a as CF3 and CuCN as cyanide sources various styrene
derivatives undergo cyano-trifluoromethylation reactions. The addition is highly regio- and
chemoselective involving formation of two C-C bonds in a single addition reaction. Thus, the
above cyano-trifluoromethylation is suitable for bifunctionalization of styrenes by late
introduction of the CF3 functionality.4 Both para- and ortho-substituted electron deficient
styrenes react readily and selectively. Under the same reaction conditions, when the para-
substituent is changed to a methoxy group oxytrifluoromethylation reaction occurs instead of
cyano-trifluoromethylation. The switch of the chemoselectivity was explained by the substituent
effects of styrene on the stability of the reaction intermediate formed prior to the product forming
step.
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Experimental Part
1
General information. H NMR, 13C NMR and 19F NMR spectra were recorded in CDCl3
(internal standard: 7.26 ppm, 1H; 77.16 ppm, 13C, external standard α,α,α-trifluorotoluene (-63.73
ppm) 19F)) using a 400 MHz spectrometer. HRMS data were recorded on a micrOTOF instrument
using ESI technique. The reported melting points are not corrected. For column chromatography,
silica gel (35-70 microns) was used.
3-Vinylanisole (2j). This compound was synthesized according to a known literature procedure
from 3-anisaldehyde.30 Isolated by column chromatography using pentane:diethyl ether, 9:1 as a
colorless oil (77 %). The NMR data obtained for 2j are in agreement with literature values.31 1H-
NMR (400 MHz, CDCl3) δ 7.27 (at, 1H), 7.06-7.02 (m, 1H), 6.99-6.97 (m, 1H), 6.84 (ddd, JHH
=
8.2, 2.6, 0.9 Hz, 1H), 6.72 (dd, JHH = 17.6, 10.9 Hz, 1H), 5.77 (dd, JHH = 17.6, 0.9 Hz, 1H), 5.28
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(dd, JHH = 10.9, 0.9 Hz, 1H), 3.84 (s, 3H), C-NMR (100 MHz, CDCl3) δ 159.9, 139.2, 136.9,
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129.6, 119.0, 114.2, 113.6, 111.7, 55.3. HRMS (ESI): m/z calcd. for [C9H10O+Na]+ 157.0624,
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found: 157.0618.
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General Procedure for Cyano-trifluoromethylation of Styrenes: To a 3 mL screwtop vial was
added copper cyanide 4 (9.0 mg, 0.1 mmol, 1 equiv.) and trifluoromethylating agent 1a (47 mg,
0.15 mmol, 1.5 equiv.). The vial was subsequentially brought into a glovebox and
tricyclohexylphosphine 5 (3 mg, 0.01 mmol, 10 mol %), the corresponding styrene 2 (0.1 mmol,
1 equiv.) and CDCl3 (0.5 mL) was added. The vial was equipped with a stirring bar, screwed shut
and stirred at room temperature for 18 h. The products were isolated by column chromatography.
4,4,4-Trifluoro-2-(4-fluorophenyl)butanenitrile (3a). The product was isolated as transparent
1
oil using pentane:dichloromethane, 1:1 as eluent system (16.5 mg, 73 %). H-NMR (400 MHz,
CDCl3) δ 7.39-7.33 (m, 2H), 7.16-7.09 (m, 2H), 4.10 (dd, JHH = 9.0, 5.5 Hz, 1H), 2.90-2.75 (m,
1H), 2.66-2.51 (m, 1H). 19F-NMR (376 MHz, CDCl3) δ -64.96 (t, JHF = 9.6 Hz), -111.91
̶ -
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112.00 (m). C-NMR (100 MHz, CDCl3) δ 163.0 (d, JCF = 249.1 Hz), 129.4 (d, JCF = 3.4 Hz),
129.2 (d, JCF = 8.4 Hz), 124.9 (q, JCF = 277.7 Hz), 118.5, 116.8 (d, JCF = 22.1 Hz), 39.9 (q, JCF
=
29.4 Hz), 30.8 (q, JCF = 3.1 Hz). HRMS (ESI): m/z calcd. for [C10H7F4N+Na]+ 240.0412, found:
240.0401.
2-(4-Chlorophenyl)-4,4,4-trifluorobutanenitrile (3b). The product was isolated as transparent
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oil using pentane:dichloromethane, 3:1 as eluent system (13.0 mg, 56 %). H-NMR (400 MHz,
CDCl3) δ 7.47-7.41 (m, 2H), 7.37-7.31 (m, 2H), 4.11 (dd, JHH = 9.1, 5.4 Hz, 1H), 2.93-2.78 (m,
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1H), 2.68-2.54 (m, 1H). F-NMR (376 MHz, CDCl3) δ -64.93 (t, JHF = 9.6 Hz). C-NMR (100
MHz, CDCl3) δ 135.3, 131.9, 129.8, 128.6, 124.6 (q, JCF =277.5 Hz), 118.1, 39.6 (q, JCF = 29.7
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Hz), 30.8 (q, JCF = 3.2 Hz). HRMS (ESI): m/z calcd. for [C10H7ClF3N+Na]+ 256.0111, found:
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256.0105.
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2-(4-Bromophenyl)-4,4,4-trifluorobutanenitrile (3c). The product was isolated as transparent
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oil using pentane:dichloromethane, 1:1 as eluent system (19.9 mg, 72 %). H-NMR (400 MHz,
CDCl3) δ 7.59-7.55 (m, 2H), 7.28-7.24 (m, 2H), 4.07 (dd, JHH = 9.1, 5.5 Hz, 1H), 2.90-2.75 (m,
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1H), 2.65-2.51 (m, 1H). F-NMR (376 MHz, CDCl3) δ -64.93 (t, JHF = 9.5 Hz). C-NMR (100
MHz, CDCl3) δ 133.0, 132.6, 129.1, 124.4 (q, JCF = 277.7 Hz), 123.5, 118.2, 39.7 (q, JCF = 29.7
Hz), 31.0 (q, JCF = 3.2 Hz). HRMS (ESI): m/z calcd. for [C10H7BrF3N+Na]+ 299.9606, found:
299.9595.
2-(2-Bromophenyl)-4,4,4-trifluorobutanenitrile (3d). The product was isolated as transparent
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oil using pentane:dichloromethane, 2:1 as eluent system (14.0 mg, 50 %). H-NMR (400 MHz,
CDCl3) δ 7.66-7.61 (m, 2H), 7.46-7.40 (m, 1H), 7.30-7.24 (m, 1H), 4.61 (dd, JHH = 9.9, 4.3 Hz,
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1H), 2.81-2.58 (m, 2H). F-NMR (376 MHz, CDCl3) δ -65.12 (t, JHF = 9.6 Hz). C-NMR (100
MHz, CDCl3) δ 134.0, 132.9, 130.9, 129.3, 128.9, 124.7 (q, JCF = 278.4 Hz), 122.8, 118.1, 38.2
(q, JCF = 29.9 Hz), 31.5 (q, JCF = 3.1 Hz). HRMS (ESI): m/z calcd. for [C10H7BrF3N+Na]+
299.9606, found: 299.9618.
4,4,4-Trifluoro-2-(4-(trifluoromethyl)phenyl)butanenitrile (3e). The product was isolated as
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transparent oil using pentane:dichloromethane, 1:1 as eluent system (13.4 mg, 50 %). H-NMR
(400 MHz, CDCl3) δ 7.76-7.71 (m, 2H), 7.56-7.53 (m, 2H), 4.21 (dd, JHH = 9.0, 5.5 Hz, 1H),
2.97-2.82 (m, 1H), 2.72-2.58 (m, 1H). 19F-NMR (376 MHz, CDCl3) δ -62.93 (s), -64.89 (t, JHF
=
9.5 Hz). 13C-NMR (100 MHz, CDCl3) δ 137.4 (q, JCF = 1.2 Hz), 131.7 (q, JCF = 32.9 Hz), 128.0,
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126.8 (q, JCF = 3.7 Hz), 124.5 (q, JCF = 277.7 Hz), 123.8 (q, JCF = 272.5 Hz), 117.9, 39.7 (q, JCF
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29.9 Hz), 31.3 (q, JCF = 3.2 Hz). HRMS (ESI): m/z calcd. for [C11H7F6N+Na]+ 290.0375, found:
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290.0363.
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4,4,4-Trifluoro-2-(2-(trifluoromethyl)phenyl)butanenitrile (3f). The product was isolated as
white solids using pentane:dichloromethane, 1:1 as eluent system (18.3 mg, 68 %). Melting point
43.9-46.3 °C. 1H-NMR (400 MHz, CDCl3) δ 7.78-7.73 (m, 2H), 7.72-7.66 (m, 1H), 7.57-7.50 (m,
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1H), 4.52 (dd, JHH = 10.4, 3.9 Hz, 1H), 2.88-2.73 (m, 1H), 2.66-2.53 (m, 1H). F-NMR (376
MHz, CDCl3) δ -59.16 (s), -65.52 (t, JHF = 9.7 Hz). 13C-NMR (100 MHz, CDCl3) δ 133.4 (q, JCF
= 1.0 Hz), 132.4 (q, JCF = 1.4 Hz), 129.7, 129.6, 127.9 (q, JCF = 30.7 Hz), 127.1 (q, JCF = 5.6 Hz),
124.4 (q, JCF = 277.8 Hz), 123.9 (q, JCF = 273.7 Hz), 118.3, 39.8 (q, JCF = 30.1 Hz), 27.91-27.70
(m). HRMS (ESI): m/z calcd. for [C11H7F6N+Na]+ 290.0375, found: 290.0375.
2-([1,1'-Biphenyl]-4-yl)-4,4,4-trifluorobutanenitrile (3g). The product was isolated as white
solids using pentane:dichloromethane, 1:1 as eluent system (19.7 mg, 71 %). Melting point 87.2-
90.5 °C. 1H-NMR (400 MHz, CDCl3) δ 7.67-7.63 (m, 2H), 7.60-7.56 (m, 2H), 7.49-7.43 (m, 4H),
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7.41-7.36 (m, 1H), 4.17 (dd, JHH = 9.4, 5.1 Hz, 1H), 2.95-2.80 (m, 1H), 2.71-2.58 (m, 1H). F-
NMR (376 MHz, CDCl3) δ -65.03 (t, JHF = 9.6 Hz). 13C-NMR (100 MHz, CDCl3) δ 142.3, 140.0,
132.5, 129.1, 128.4, 128.0, 127.8, 127.3, 124.8 (q, JCF = 282.8 Hz), 118.7, 39.9 (q, JCF = 29.6
Hz), 31.1 (q, JCF = 3.2 Hz). HRMS (ESI): m/z calcd. for [C16H12F3N+Na]+ 298.0814, found:
298.0815.
4,4,4-Trifluoro-2-(naphthalen-2-yl)butanenitrile (3h). The product was isolated as transparent
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oil using pentane:dichloromethane, 1:1 as eluent system (14.4 mg, 58 %). H-NMR (400 MHz,
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CDCl3) δ 7.92 (d, JHH = 8.5 Hz, 1H), 7.89-7.84 (m, 3H), 7.59-7.52 (m, 2H), 7.42 (dd, JHH = 8.5,
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1.9 Hz, 1H), 4.27 (dd, JHH = 9.5, 5.1 Hz, 1H), 2.99-2.85 (m, 1H), 2.77-2.63 (m, 1H). F-NMR
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(376 MHz, CDCl3) δ -65.02 (t, JHF = 9.9 Hz). 13C-NMR (100 MHz, CDCl3) δ 133.4, 133.3,
130.8, 129.9, 128.1, 128.0, 127.3, 127.3, 126.8, 124.9 (q, JCF = 277.6 Hz), 124.2, 118.7, 39.9 (q,
JCF = 29.6 Hz), 31.6 (q, JCF = 3.2 Hz). HRMS (ESI): m/z calcd. for [C14H10F3N+Na]+ 272.0658,
found: 272.0662.
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2-(4-(tert-Butyl)phenyl)-4,4,4-trifluorobutanenitrile (3i). The product was isolated as
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transparent oil using pentane:diethyl ether, 9:1 as eluent system (13.1 mg, 51 %). H-NMR (400
MHz, CDCl3) δ 7.46-7.41 (m, 2H), 7.31-7.27 (m, 2H), 4.07 (dd, JHH = 9.7, 4.9 Hz, 1H), 2.89-2.75
(m, 1H), 2.65-2.51 (m, 1H), 1.32 (s, 9H). 19F-NMR (376 MHz, CDCl3) δ -65.18 (t, JHF = 9.8 Hz).
13C-NMR (100 MHz, CDCl3) δ 152.3, 130.4, 126.9, 126.5, 124.9 (q, JCF = 277.7 Hz), 118.7, 39.9
(q, JCF = 29.5 Hz), 34.7, 31.2, 30.8 (q, JCF = 3.2 Hz). HRMS (ESI): m/z calcd. for
[C14H16F3N+Na]+ 278.1127, found: 278.1139.
4,4,4-Trifluoro-2-(3-methoxyphenyl)butanenitrile (3j). The product was isolated as colorless
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oil using pentane:dichloromethane, 1:1 as eluent system (13.5 mg, 59 %). H-NMR (400 MHz,
CDCl3) δ 7.36-7.31 (m, 1H), 6.96-6.88 (m, 3H), 4.06 (dd, JHH = 9.6, 4.9 Hz, 1H), 3.83 (s, 3H),
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2.90-2.76 (m, 1H), 2.66-2.53 (m, 1H). F-NMR (376 MHz, CDCl3) δ -65.14 (t, JHF = 9.9 Hz).
13C-NMR (100 MHz, CDCl3) δ 160.5, 135.0, 130.8, 124.8 (q, JCF = 276.8 Hz), 119.5, 118.6,
114.5, 113.2, 55.6, 39.9 (q, JCF = 29.6 Hz), 31.4 (q, JCF = 3.2 Hz). HRMS (ESI): m/z calcd. for
[C11H10F3NO+Na]+ 252.0607, found: 252.0615.
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3,3,3-Trifluoro-1-(4-methoxyphenyl)propyl 2-iodobenzoate (6). The product was isolated as
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colorless oil using pentane:diethyl ether, 19:1 as eluent system (39.1 mg, 87 %). H-NMR (400
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3H), 7.20-7.14 (m, 1H), 6.99-6.89 (m, 2H), 6.31 (dd, JHH = 8.9, 4.4 Hz, 1H), 3.80 (s, 3H), 3.09-
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2.95 (m, 1H), 2.75-2.59 (m, 1H). F-NMR (376 MHz, CDCl3) δ -63.75 (t, JHF = 10.2 Hz). C-
NMR (100 MHz, CDCl3) δ 164.9, 160.0, 141.5, 134.4, 132.9, 131.0, 130.2, 128.2, 128.0, 125.3
(q, JCF = 277.5 Hz), 114.2, 94.2, 70.7 (q, JCF = 3.2 Hz), 55.3, 40.2 (q, JCF = 28.2 Hz). HRMS
(ESI): m/z calcd. for [C17H14F3IO3+Na]+ 472.9832, found: 472.9814.
3-(4-fluorophenyl)-3-iodopropanenitrile (11). The product was synthesized according to the
general procedure except copper iodide (19 mg, 0.1 mmol, 1 equiv.) was used instead of copper
cyanide. The compound was isolated as colorless oil using pentane:dichloromethane, 20:1 as
eluent system (4.1 mg, 13 %). This product was unstable and decomposed within a couple of
hours turning to a pink oil. 1H-NMR (400 MHz, CDCl3) δ 7.42-7.36 (m, 2H), 7.05-6.97 (m, 2H),
5.30 (dd, JHH = 9.4, 6.1 Hz, 1H), 3.30-3.09 (m, 2H). 19F-NMR (376 MHz, CDCl3) δ -64.45 (t, JHF
= 9.5Hz), -112.30
̶
-112.39 (m). 13C-NMR (100 MHz, CDCl3) δ 162.5 (d, JCF =248.9 Hz), 138.3
(d, JCF =3.5 Hz), 128.7 (d, JCF = 8.4 Hz), 124.9 (q, JCF = 278.9 Hz), 115.9 (d, JCF = 21.9 Hz), 46.0
(q, JCF = 28.3 Hz), 16.4 (q, JCF = 3.1 Hz). (EI) m/z (rel intens) 191 (M+- I, 83), 127 (100). Because
of instability of 11 we were not able to perform HRMS analysis.
Acknowledgement. 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).
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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.
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