Vanadium-catalyzed solvent-free synthesis of quaternary α-trifluoromethyl nitriles by electrophilic trifluoromethylation

Article abstract of DOI:10.1002/anie.201406181

The direct electrophilic trifluoromethylation of silyl ketene imines (SKIs) with hypervalent iodine reagents leads to the formation of quaternary α-trifluoromethyl nitriles in good yields. This new reaction has been carried out with a variety of substitut

Full text of DOI:10.1002/anie.201406181

Angewandte
Chemie
DOI: 10.1002/anie.201406181
Trifluoromethylation
Hot Paper
Vanadium-Catalyzed Solvent-Free Synthesis of Quaternary a-
Trifluoromethyl Nitriles by Electrophilic Trifluoromethylation**
Natalja Frꢀh and Antonio Togni*
Abstract: The direct electrophilic trifluoromethylation of silyl
ketene imines (SKIs) with hypervalent iodine reagents leads to
the formation of quaternary a-trifluoromethyl nitriles in good
yields. This new reaction has been carried out with a variety of
substituted SKIs under solvent-free conditions using a vana-
dium(IV) catalyst (5 mol%). The corresponding products may
be transformed into useful organofluorine building blocks.
nitriles and their activated form, silyl ketene imines, caught
our attention. Nitriles are important intermediates in organic
synthesis,[8] and the cyano group is found in natural prod-
ucts,[9] as well as in an increasing number of pharmaceuti-
cals;[10] in the latter, the cyano group is typically attached to an
aromatic ring or to a fully substituted carbon atom, such as,
for example, in the calcium channel antagonist verapamil. The
reason for this is that substitution patterns potentially leading
to the formation of cyanohydrins upon metabolic oxidation
also imply the potential release of toxic cyanide. Based on
these considerations, it appeared worthwhile to investigate
the a-trifluoromethylation of secondary nitriles.
Preliminary experiments showed that simple deprotona-
tion of 2-methyl-3-phenylpropanenitrile by a strong base and
subsequent reaction with reagent 1 did not lead to product
formation, and only decomposition of 1 was observed under
various conditions. Consequently, we turned our attention to
silyl ketene imines, compounds reminiscent of the analogous
silyl ketene acetals, known to react with reagent 1. Even
though SKIs have been known for a long time,[11] their use as
nucleophiles has not been investigated as thoroughly as that
of sily ketene acetals.[12] It has been pointed out that SKIs
have significant advantages for the construction of quaternary
carbon centers compared to silyl ketene acetals because the
substituents reside in two mutually orthogonal planes.[13]
Thus, we hypothesized that silyl ketene imines might be
a suitable class of nucleophiles to react with 1 and/or 2 to form
quaternary a-trifluoromethylated nitriles.
T
he development of readily accessible and shelf-stable
hypervalent iodine reagents 1 and 2 (Figure 1) for direct
electrophilic trifluoromethylation has been a key addition to
the existing methods of organofluorine chemistry. Indeed
these compounds have become very popular since the initial
publication in 2006 by our group,[1] as evidenced by numerous
reports concerned with the trifluoromethylation of a large
variety of carbon- and heteroatom-based nucleophiles.[2]
The synthetically enabling power of reagents 1 and 2 is
illustrated by the more than 50 articles since 2012 reporting
[2,3]
À
the formation of a new C CF3 bond.
However, reactions
leading to the formation of a new quaternary carbon center
upon the trifluoromethylation of a suited substrate by 1 or 2
are still scarce. So far the only reported transformations of
this type are the synthesis of a-CF3-b-keto esters,[1,4] described
by our group and the corresponding enantioselective version
later by Gade and co-workers,[5] the related formation a-CF3-
a-nitro esters,[4a,b,6] and the preparation of a-CF3 carbonyls
from silyl ketene acetals.[4b,c,6b,7] The scarcity of such trans-
formations prompted us to investigate reactions of substrates
that would afford products containing a new quaternary
trifluoromethylated carbon center. For various reasons,
SKI 3a was chosen as a model substrate for the envisaged
trifluoromethylation using reagent 1 or 2 (Table 1).14] Indeed,
the transformation proceeded in 32% yield relative to 1 when
reagent 1 was exposed to 1.75 equivalents of SKI 3a (entry 1).
Additives known to activate our reagents[2] such as HNTf2,
Zn(NTf2)2, CuCl, and FeCl3 did not catalyze the transforma-
tion and gave only low product yields (entries 2–5). However,
when VO(salen) complex 4a was used as
a catalyst
(10 mol%), the yield increased to 89% (entry 6). Further-
more, we found that other metal catalysts with salen-type
ligands and Fe or Mn centers similarly catalyzed the reaction
(see the Supporting Information). Reagent 2 performed less
well under the same reaction conditions, product 6a being
obtained in only 7% yield (entry 7). Reducing the amount of
SKI to 1.25 equivalents led to lower conversion and after 24 h
20% of reagent 1 was found unreacted (entry 8), while
changing the solvent to CH2Cl2 gave the product in 71% yield
and full conversion after 24 h (entry 9). Further screening of
catalysts revealed that complex 4b with a more electron-rich
and bulky salen ligand increased the yield to 81% (entry 10)
and lowering the reaction temperature to 08C further
improved the yield (entry 11). To our surprise, when applying
Figure 1. Hypervalent-iodine-based electrophilic trifluoromethylation
reagents 1 and 2.[1]
[*] N. Frꢀh, Prof. Dr. A. Togni
Department Chemie und Angewandte Biowissenschaften
Eidgençssische Technische Hochschule (ETH) Zꢀrich
8093 Zꢀrich (Switzerland)
E-mail: atogni@ethz.ch
[**] This work was supported by ETH Zꢀrich. We thank E. Otth for X-ray
analysis and S. Foser for experimental assistance.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406181.
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Table 1: Reaction optimization for product 6a.[14]
Entry[a] Reagent Additive
(mol%)
Equiv
of SKI
T
Solvent Yield
[%][b]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
2
1
1
1
1
1
1
–
1.75
1.75
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
CH3CN 32
HNTf2 (20)
Zn(NTf2)2 (20) 1.75
CH3CN
CH3CN 14
CH3CN 5
9
CuCl (20)
FeCl3 (20)
4a (10)
4a (10)
4a (10)
4a (10)
4b (10)
4b (10)
4b (5)
1.75
1.75
1.75
1.75
1.25
1.25
1.25
1.25
1.25
1.25
CH3CN 19
CH3CN 89
CH3CN 7[c]
CH3CN 53[d]
CH2Cl2 71
CH2Cl2 81
9
10
11
12
13
08C to RT CH2Cl2 87
08C to RT
08C to RT
–
–
89
86
5 (5)
[a] Reaction conditions: A solution of reagent 1 (0.13 mmol, 1 equiv,
0.25m in solvent) was added to the additive under argon. A solution of
SKI 3a (0.4m in solvent) was added and the reaction mixture was stirred
at the given temperature. After 24 h C6H5CF3 (10 mL, 0.65 equiv) was
added and after vigorous stirring an aliquot was taken for 19F NMR
spectroscopy. [b] The yield was determined relative to C6H5CF3 as an
internal standard by integration of the appropriate signals. [c] Reaction
did not reach full conversion, 40% of reagent 2 was left after 24 h.
[d] Reaction did not reach full conversion, 20% of reagent 1 was left after
24 h.
Scheme 1. Reaction scope for the trifluoromethylation of SKIs.
[a] 1.75 equiv of SKI was used. [b] 19F NMR yield is given in brackets.
before purification, 1 equiv of TMSBr was added to the
reaction mixture to cleave the silyl ester.[16] After flash
column chromatography, nitrile 6a was obtained in pure form
in good yield (Scheme 1). We then explored the reaction
scope with a variety of substituted SKIs, which were prepared
by lithiation of the corresponding nitriles followed by
trapping with TBSCl.[17] The optimized reaction conditions
were applied and in all cases the corresponding a-trifluor-
omethylated nitrile was obtained in good to excellent yields
(Scheme 1). Replacement of the methyl group of 6a by
a larger substituent led to slightly decreased yields, presum-
ably due to the increased steric bulk for ethyl (6b, 59%),
cyclopropyl (6c, 53%), and benzyl (6l, 58%). Good yields
were obtained with para-, meta-, and ortho-methyl-substi-
tuted benzyl moieties (6d–6 f, 78–83%). Furthermore, naph-
thyl substitution instead of phenyl (6k) was also well
tolerated. Para-methoxy-substituted SKI 3g delivered the
corresponding nitrile 6g in excellent 93% yield. Electron-
solvent-free conditions we could even reduce the catalyst
loading to 5 mol% and the transformation still proceeded in
excellent 89% yield (entry 12). Applying the chiral oxovana-
dium complex 5, a complex known to catalyze hetero-Diels–
Alder reactions with a high degree of enantioselectivity,[15] led
under these conditions to 86% yield. Unfortunately, however,
no chiral induction was observed (entry 13). We are not aware
of any other direct electrophilic trifluoromethylation using
reagents 1 or 2 proceeding under solvent-free conditions. Also
the use of a vanadium(IV) complex as a catalyst in trans-
formations of these reagents is unprecedented.
After optimization of the reaction conditions, SKI 3a was
subjected to the reaction conditions on a preparative scale.
After 24 h the neat reaction mixture was directly subjected to
flash column chromatography and a-trifluoromethylated
nitrile 6a was obtained, albeit TBS-protected iodobenzoic
acid coeluted with the chosen solvent system. Therefore,
2
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withdrawing substituents were equally well tolerated (6h, 6i),
while a sterically more demanding substrate with a methyl
group in b-position gave the desired product in good
diastereomeric ratio (9:1 d.r.) but modest yield. Finally, the
reaction scope could be extended to substrates containing two
alkyl substituents. Thus, nitrile 6m was obtained in excellent
yield (91%). SKI 3n also underwent efficient trifluorome-
thylation but isolation of the product 6n turned out to be
difficulty due to its volatility.
A crystal of a-trifluoromethylated nitrile 6l suitable for
X-ray structure determination was obtained by slow sub-
limation under vacuum in a sealed glass tube at 708C
(Figure 2). A CCDC database search revealed no crystallo-
Scheme 2. Derivatization of a-trifluoromethylated nitrile 6a. Reaction
conditions: a) 1. LiAlH4, Et2O, RT, 16 h, 2. HCl, Et2O; b) 1. DIBAL-H,
hexanes, À788C to RT, 6 h, 2. ethyl formate, 1 h; c) H2O2, K2CO3,
DMSO, 08C to RT, 2 h; d) NaN3, Et3N·HCl, toluene, 1108C, 36 h.
DIBAL-H=diisobutylaluminum hydride.
oxidative conditions proceeds in quantitative yield. More-
over, reaction with sodium azide allowed the formation of a-
quaternary, a-CF3-substituted tetrazole 10, a scaffold with
potential applications in medicinal chemistry and agrochem-
istry.
Figure 2. ORTEP representation of compound 6I. Hydrogen atoms are
omitted for clarity and thermal ellipsoids are drawn at the 30%
probability level. Selected bond lengths [ꢁ] and bond angles [8]: C1–C2
1.5287(17), C1–C3 1.4778(15), C2–F1 1.3345(14), C3–N1 1.1425(16),
C1–C4 1.5521(16), C1–C11 1.5605(16); F1-C2-C1 113.20(10), C2-C1-C3
106.78(10), C4-C1-C11 110.16(9), C3-C1-C2-F1 172.65(10).
In conclusion, we have developed an unprecedented
trifluoromethylation of silyl ketene imines allowing the
formation of variously substituted quaternary a-trifluorome-
thylated nitriles in good to excellent yields. The reaction could
be performed on a gram scale without a decrease in yield and
the corresponding a-CF3 nitrile was converted into valuable
organofluorine building blocks. The reaction proceeds under
solvent-free reaction conditions using a vanadium catalyst,
these being two aspects that have never been applied with our
reagents before. The former aspect adds practicality to the use
of reagents 1 and 2, whereas the finding that not only copper
salts and simple complexes are able to effect catalytic
transformations of these reagents opens new venues towards
the development of new and more efficient syntheses in
trifluoromethylation chemistry.
At the present stage we do not have any experimental
evidence concerning a possible mechanism for this new
reaction. However, the fact that the best catalysts are well-
defined vanadyl(IV) systems, that is, complexes that are both
Lewis acidic and redox active, hints at a possible redox-
catalytic process. Additionally, one should also take the
silylating properties of the SKI substrates into account and
hence their ability to transfer the silyl group to reagent 1. If
this indeed happens, the resulting cationic (iodonium) species
should be able to engage the catalyst in a SET process
enabling the formation of CF3 radicals, which are rapidly
trapped by the deprotonated nitrile. The radical anionic form
of the product generated as an intermediate would then
reduce the vanadyl(V) form of the catalyst back to its original
oxidation state, thereby closing the catalytic cycle. Clearly,
this is nothing more than a reasonable conjecture guiding our
experimental scrutiny into the mechanism.
graphic data of either all-carbon-substituted a-trifluorome-
thylated nitriles or non-fluorinated analogues with the
exception of compounds of the type PhC(CN)(CF3)R,
where R is either a sulfonate or an amino group.[18] Closer
inspection of these structures showed that the geometry of the
quaternary carbon atom C1 is insignificantly affected by its
À
substitution. The C CF3 bond of 1.5287(17) ꢀ in 6l is slightly
shorter than in the two known examples (1.536(9) ꢀ[18a] and
1.541(6) ꢀ[18b]) and the CF3-C-CN angle (106.78(10)8) is
within the same range (107.5(6)8 and 105.4(4)8). As expected,
the CF3 group adopts a staggered conformation with F1 in an
antiperiplanar orientation with respect to the CN group, as
shown by the torsion angle F1-C2-C1-C3 of 172.65(10)8. This
conformation may be indicative of a hyperconjugative inter-
action s*(C2-F1)–p.
To illustrate the practicality of our reaction, we synthe-
sized a-trifluoromethylated nitrile 6a from 2 grams of the
corresponding SKI 3a in 82% yield. As mentioned above,
nitriles are valuable intermediates in organic synthesis and
hence the a-trifluoromethylated nitrile 6a was subjected to
different standard transformations (Scheme 2). Reduction of
the nitrile moiety using LAH yields b-CF3 amine hydrochlo-
ride 7 in quantitative yield after acidic workup, while
quaternary a-CF3 aldehyde 8 was obtained in 76% yield by
reduction using DIBAL-H. Quaternary a-CF3 aldehydes
were previously not accessible using a recently reported
protocol.[19] Conversion of nitrile 6a to amide 9 under
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[4] a) I. Kieltsch, P. Eisenberger, A. Togni, Angew. Chem. 2007, 119,
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Experimental Section
A flame-dried 4 mL screw-cap vial was charged with 4b (17.4 mg,
0.03 mmol, 0.05 equiv) and 1 (198 mg, 0.63 mmol, 1.00 equiv). At 08C,
silyl ketene imine 3 (0.78 mmol, 1.25 equiv) was added and the green
suspension was stirred from 08C to ambient temperature for 24 h
(500 rpm). During this time the color usually changed from green to
brown to dark-red to olive-green. After 24 h bromotrimethylsilane
(83 mL, 0.63 mmol, 1.00 equiv) was added and the mixture was stirred
for another hour at ambient temperature. The reaction mixture was
directly purified by flash column chromatography (SiO2; pentane,
then pentane/Et2O) to yield the pure product.
CCDC 1004038 (6l) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
Received: June 12, 2014
Published online: && &&, &&&&
Keywords: nitriles · quaternary centers · solvent-free processes ·
.
trifluoromethylation · vanadium
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[2] For a comprehensive review about the application of reagents
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DOI: 10.1021/cr500223h.
ˇ
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[14] Table 1 shows selected experiments; for a more extensive
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[17] See the Supporting Information for procedures and analyses.
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Trifluoromethylation
N. Frꢁh, A. Togni*
&&&& — &&&&
Vanadium-Catalyzed Solvent-Free
Synthesis of Quaternary a-
Trifluoromethyl Nitriles by Electrophilic
Trifluoromethylation
Not only copper! Oxovanadium(IV)
complexes catalyze the trifluoromethyla-
tion of silyl ketene imines with hyper-
valent iodine reagents to form quaternary
a-trifluoromethyl nitriles under solvent-
free conditions. The products, formed in
up to 93% yield, may be further trans-
formed into useful synthetic building
blocks for organofluorine chemistry.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!