Borazine-CF3? Adducts for Rapid, Room Temperature, and Broad Scope Trifluoromethylation

Article abstract of DOI:10.1002/anie.201711316

A fluoroform-derived borazine CF₃^? transfer reagent is used to effect rapid nucleophilic reactions in the absence of additives, within minutes at 25 °C. Inorganic electrophiles spanning seven groups of the periodic table can be trifluoromethylated in high yield, including transition metals used for catalytic trifluoromethylation. Organic electrophiles included (hetero)arenes, enabling C?H and C?X trifluoromethylation reactions. Mechanistic analysis supports a dissociative mechanism for CF₃^? transfer, and cation modification afforded a reagent with enhanced stability.

Full text of DOI:10.1002/anie.201711316

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Accepted Article
Title: Borazine-CF3- Adducts for Rapid, Room Temperature, and
Broad Scope Trifluoromethylation
Authors: Jacob Benjamin Geri, Michael McCreery Wade Wolfe, and
Nathaniel Kolnik Szymczak
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201711316
Angew. Chem. 10.1002/ange.201711316
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Angewandte Chemie International Edition
10.1002/anie.201711316
COMMUNICATION
Borazine-CF -
Adducts for Rapid, Room Temperature, and
3
Broad Scope Trifluoromethylation
Jacob B. Geri, Michael M. Wade Wolfe, and Nathaniel K. Szymczak*
Abstract: We present a strategy to use a fluoroform-derived borazine
-
CF
3
transfer reagent to effect rapid nucleophilic reactions in the
absence of additives within minutes at 25 °C. Inorganic electrophiles
spanning 7 groups of the periodic table can be trifluoromethylated in
high yield, including transition metals used for catalytic
trifluoromethylation. Organic electrophiles included (hetero)arenes,
enabling C-H and C-X trifluoromethylation reactions. Mechanistic
-
analysis supports a dissociative mechanism for CF
3
transfer, and
Figure 1. Previously reported CF -
E=electrophile). Countercation in 2 is K(18-crown-6) .
sources and new borazine-CF
-
reagents
3
3
cation modification afforded a reagent with enhanced stability.
+
(
3
The trifluoromethyl (CF ) group is indispensable in organic
adduct, 2, is highly nucleophilic. Unlike SiMe
3
CF
does not present
competing nucleophilic centers, enabling reactions with hard
electrophiles such as SiMe Cl, and the Lewis acid is recyclable.
/F- (1a),
3
synthesis.[1] As the smallest fluoroalkyl group, it dramatically
-
-
B(OMe)
3
CF
3
(1b), or DMF-CF
3
(1c), 2
increases the bioavailability and metabolic stability of drug
candidates without altering their steric profile. Nucleophilic
trifluoromethylation reactions are particularly attractive; however,
3
-
[2]
-
In this communication, we show that 2 is capable of rapid and
the trifluoromethyl anion (CF
3 3
) is highly unstable. While CF
-
-
highly general CF
3
transfer to diverse transition metal, main
can be generated for in-situ use, it undergoes irreversible F
group, and organic electrophiles, experimentally interrogate its
mechanism, and present a variant with enhanced stability.
elimination at -80 °C. Lewis acids can be employed to stabilize
-
-
CF
3 3
, but stabilization comes at the cost of attenuated CF
nucleophilicity.[ As a result, currently used CF
3]
-
The reactivity profile for CF
unit is dictated by the identity of the metal center.[11]
Depending on the metal used, the CF ligand can be used to form
C-CF bonds through direct nucleophilic transfer (Zn ), radical
substitution (Ag ),
3
transfer from a transition metal-
3
reagents present
CF
3
a more limited reactivity scope than analogous Grignard and
3
organolithium reagents.
2+
[12]
-
3
The most commonly used CF
3
transfer reagent, SiMe
3
CF
3
-.
,
+
[13]
+ [14]
3+ [15]
+
or reductive elimination (Cu ,
Pd ) . We selected reactions with these metals to assess the
transmetalation activity of 2. Zn(TMEDA)(Cl) AgNO , and
Au(SiPr)Cl react with one equiv. 2 to afford M-CF products (3e:
4%, 3c: 44%, and 3d: 15%) in under 10 minutes at 25 °C (Figure
). While Ag, Au, and Zn –CF complexes are useful CF transfer
Au ,
uses a cationic Lewis acid (LA, SiMe
SiMe CF
form SiMe
3
) to stabilize CF
3
2+ [16]
-
3
3
is typically activated by a Lewis base (Nuc; e.g. F ) to
-
-
2
,
3
3
(Nuc)(CF
3
)
which can release CF
3
; however, this
intermediate is unstable above -60°C.[4] Therefore low
temperatures or activation in the presence of substrate are used,
3
7
2
3
3
but these conditions introduce operational challenges and/or
transfer selectivity.[
4c, 4d]
reagents, only Cu and Pd complexes catalyze cross-coupling with
decreased CF
3
An alternative approach
-
[4d, 5a]
CF
Pd(TMEDA)(p-tolyl)I reacted to afford CuCF
complexes in high yield (3b: 83% and 3a: 98%). The obtained
CuCF reacts with (4-Ph)PhI to afford (4-Ph)PhCF (66%).
3
.
When treated with one equiv. 2 for 10 min, CuI and
that does not require an activator is the use of neutral LAs to
-
[5]
3
and PdCF
3
generate anionic LA-CF
3
adducts. Unfortunately, previously
,[5b] BR
[6]
employed LAs are either too strong (B(OMe) ) or too
3 3
weak (DMF),[7] resulting in either low CF
-
[8]
3
3
3
nucleophilicity or low
thermal stability.[7, 9] B(OR)
-
-
Main group electrophiles in groups 13-15 are challenging
3
CF
3
and DMF-CF
3
also present
substrates due to their high oxo/fluorophilicity.[17] 2 enabled the
reactive oxyanion nucleophiles which can engage in competing
3
3
3
3
3 3
SnMe CF
,[18] and
reactions with oxophilic electrophiles.[
5b, 7]
synthesis of B(OMe)
CF
-, SiMe
CF
,
A LA with optimal
19]
PbMe
3
CF [
3
from their corresponding halides in good to excellent
strength and no competing nucleophilic sites could enable the
yield (3f: 99%, 3g: 96%, 3h: 73%, and 3i: 99% respectively) at 25
°C. Group 15 halides were also trifluoromethylated by 2; when
synthesis of potent and selective trifluoromethylation reagents.
-
We recently reported the preparation of LA-CF
fluoroform (HCF
electronically matched LA/Brønsted base pairs (Figure 1).
combined empirical/theoretical approach identified
hexamethylborazine (B
3
adducts from
3
;
an industrial waste product), using
[
10]
A
3
N
3
Me
6
) as one of the weakest LAs
-
-
capable of stabilizing CF
3
at 25 °C; the corresponding CF
3
[
*]
J. B. Geri, M. M. Wade Wolfe, Prof. N. K. Szymczak
Department of Chemistry, University of Michigan
930 N. University, Ann Arbor, MI 48109 (USA)
E-mail:nszym@umich.edu
Homepage: http://www.umich.edu/ ~ szymlab/
Figure
2.
Reactions
with
inorganic
electrophiles.
TMEDA
=
tetramethylethylenediamine, iPr = 1,3-bis(diisopropylphenyl)-imidazol-2-ylidine.
X = Cl for substrates except for Pb; X=Br and Cu; X=I. Yield determined by F-
NMR. *: as reported in reference 8.
19
Supporting information for this article is given via a link at the end of
the document.
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Angewandte Chemie International Edition
10.1002/anie.201711316
COMMUNICATION
Figure 3. Reactions with organic and inorganic chalcogens.
CF [
20]
3 2
(3j) and Bi(CF )
Cl[21] (3k)
were combined with 2, PPh
2
3
were prepared in 99% and 42% yield.
3
Figure 4. Rapid electrophilic trifluoromethylation from HCF . Isolated yield. *:
yield determined by 19F-NMR .
SCF
3
and SeCF
3
are important functional groups in medicinal
chemistry,[ and SCF
22]
- [23]
,
SeCF
- [23]
,
and TeCF
-[24]
are useful
3
3
3
synthons that must be prepared using 1a at -60 °C. In contrast, 2
reacts with S, Se, and Te within 20 minutes at 25 °C to produce
SCF (4c: 92%), SeCF (4d: 61%), and TeCF (4e: 97%); these
3 3 3
anions were alkylated in-situ in 87% (4f), 68% (4g), and 59% (4h)
combined yield. Additionally, dichalcogenides react with 2 to
afford S- and Se-ethers (79% (4a), 69% (4b)). Because 2 is
NO2 aromatic trifluoromethylation (Figure 5f). 2 reacted with
perfluorotoluene, 2-nitropyridine, and p-dinitrobenzene to afford
6l-n in modest yield (27-42%). These reactions represent new
-
-
-
general routes to Ar-CF compounds.
3
Unsubstituted heteroarenes can form σ-complexes with
strong nucleophiles, and subsequent oxidation/rearomatization
can be an attractive C-H functionalization strategy.[
Unsubstituted triazine, pyrimidine, and quinazoline compounds
selectively reacted with 2 at the 4- position to furnish σ-adducts
prepared from HCF
route to R-SCF and R-SeCF
We repeated the above reactions using anionic CF
3
, these reactions represent an economical
31]
3
3
moieties.
3
transfer
reagents: analogous to 2, these single reagent precursors require
-
no optimization of exogenous additives. 1b-c transfer CF
3
to
(Figure 6b), which were oxidized to CF -substituted products (6o-
3
inorganic electrophiles, but the reactions are conducted at high
q). Notably, 5-bromo-2-chloropyrimidine afforded 6r in 49% yield
as the sole product. In 4-Cl substituted quinazolines or triazines,
treatment with 2 afforded geminal bistrifluoromethylated amides
(6s-u). The anionic σ-adducts were functionalized at the nitrogen
temperature (1b)[ or under cryogenic conditions (1c).
5a]
[5a, 9, 23]
Efficiency was compared at 25°C (0.1 M) and yield measured
after 10 min.[ 1b only provided trace product, and 1c provided
products in lower yield than 2 for all but 2 of 14 substrates (3d:
25]
atom by introducing an electrophile (e.g. H O, benzyl bromide) to
2
5
6%, 4d 86%). We attribute the favorable reactivity of 2 to the
isolate dearomatized heterocyclic products. To demonstrate this
-
combination of fast CF
nucleophilic sites.
3
transfer and the absence of competing
selectivity, 6v was prepared in 60% yield over three steps in one
pot. These 4- selective trifluoromethylations of heteroarenes
complement meta- selective radical C-H trifluoromethylations.[32]
We hypothesized that 2 could enable selective addition reactions
with pyridines if they were first activated by LAs. Using only the
steric bulk of the activating LA to control selectivity, quinoline-LA
adducts reacted with 2 to afford σ-adducts at either the 2- (BF3)
or 4- (B(C F ) ) position. These reactions proceeded with high
Rapid synthetic procedures are required in manipulations of
18F (t
1/2=120 minutes). We used the in-situ generation of the
electrophilic trifluoromethylation reagent Togni I (5a) from HCF -
3
derived 2 to showcase the speed with which HCF
deliver CF
[26]
3
can be used to
equivalents to electron-rich substrates (Figure 4).
+
[27]
3
-
Preparation of 2 from HCF
3
, CF
3
transfer to form Togni I, and
6
5 3
addition of 1-thio-β-D-glucose tetraacetate afforded 5b in 32
minutes (43% combined yield, Figure 4). While the synthesis of
(85%; 93%) selectivity with commercially available LAs, in
3 3
contrast with a previous method that relied on larger B(C F CF )
6
4
1
9
18 [28]
for 4- selective trifluoromethylation.[33] Oxidation afforded the C-H
HC F
2
F
is challenging and there are numerous practical
18
hurdles associated with manipulations of F, the speed of our
trifluoromethylated products (6w: 27%; 6x: 61%). This
+
methodology combined with extremely rapid and selective CF
transfer from Togni may enable
radiotrifluoromethylation reactions to be explored.
3
methodology
expands
the
scope
of
2-
selective
trifluoromethylation reactions beyond pyridine N-oxides,[
enabling the inclusion of oxidizable functionalities such as an
allylic thioether (6y, 37%).[ Overall, the broad scope of 2
showcases the utility of a highly nucleophilic reagent that does not
require exogenous activators.[
34]
I
electrophilic
35]
We next explored reactions between 2 and non-enolizable
-
organic electrophiles (Figure 5a, 5b). CF
3
addition reactions have
36]
been extensively studied with carbonyl substrates and were used
to benchmark 2. Substrates containing acyl chloride, isocyanate,
aldehyde, ketone, ester, imine, and carbonate groups all afforded
addition products in good yield (6a-6k: 29-87%). In contrast to
reactions using 2, 1b provided <10% yield in all cases under
identical conditions.
To interrogate whether CF3- transfer occurs through an
associative or dissociative pathway, we determined the rate law
for CF transfer from 2 to representative electrophiles (E= 7, 8). In
3
an associative mechanism, the rate dependence for both 2 and E
would be 1st order with a negative S . In a dissociative
‡
st
Nucleophilic aromatic addition/substitution (S
N
Ar) reactions
in comparison
However, S Ar
mechanism, the rate dependence for 2 and E would be 1 /zero
[
11, 29]
‡
offer unique, orthogonal reactivity patterns
order, with a positive S . Orders consistent with a dissociative
[11]
[29b]
-
with cross-coupling and radical substitution.
N
mechanism were observed in CF transfer to 7/8, with a positive
3
-
[30]
‡
reactions with CF
that the high nucleophilicity of 2 would support S
Indeed, we found that 2 can be used for metal-free C-F and C-
3
are not well described. We hypothesized
S (+12(3) e.u.) value for 7.
N
Ar reactivity.
In addition to establishing the rate law for CF3 transfer, we
also found that thermal decomposition of 2 followed second order
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COMMUNICATION
-
-
Figure 5. a) CF
3
addition to C=O and C=N compounds. b) CF
3
addition to acyl chloride, ester, carbonate, and isocyanate compounds. c) Nucleophilic aromatic
substitution. (*: yield determined by 19F-NMR) d) Direct nucleophilic addition/oxidation. e) Geminal bistrifluoromethylations. f) 2- or 4- C-H trifluoromethylation of
quinolines.
+
indicating that the cation likely assists in rate-determining CF -
3
dissociation. This mechanistic insight suggested that 2b could be
kinetics, suggesting that an encounter between [K(18-crown-6)]
-
-
[2]
and CF
3
units promote CF
3
defluorination. This is supported by
the presence of an intermolecular K-F interaction in the solid state
activated by the addition of exogenous Lewis acids: addition of 5
structure of 2, which elongates a single C-F bond.[ Accordingly,
10]
equiv. K[B(C
reduction in yield. This provides a complementary strategy to
SiR CF reagents; activity is enhanced by addition of cationic,
6 5 4
F ) ] to 2b lead to a >40x increase in rate with no
cation Lewis acidity was found to directly influence the stability of
+
2
. Encapsulation of K with 2 equiv 18-crown-6 improved the
3
3
solution half-life at 60 °C (0.2 M) from 7 min to 18 min. Replacing
rather than anionic, activators.
+
+
K in 2a with less Lewis acidic Cs provided even higher stability
180 min). The latter variant exhibits high stability at 25 °C, with a
In summary, we have demonstrated that a recyclable and
-
(
fluoroform-derived CF
3
reagent promotes broad-scope
daily decomposition rate of 1% in solution (0.2 M THF) and 3% as
trifluoromethylation at 25 °C. 2 is an excellent transmetalation
a solid, and showed no decomposition after one month at -30 °C.
reagent, rapidly trifluoromethylating 18 different elements in high
-
The higher stability of 2b is consistent with the absence of Cs-CF
3
yield. The reagents promote CF
3
transfer reactions with diverse
interactions in its solid state structure.
The alkali metal dependence on the decomposition of
organic
electrophiles
including
carbonyl/imine
transfer follows a cation-
and
-
2
(hetero)aromatic compounds. CF
3
suggested that Lewis acids could also be used to facilitate
assisted dissociative mechanism, which enabled the design of a
weighable solid reagent with enhanced shelf-stability that could
be activated with exogenous K+.
-
dissociative CF
Me (CF
reducing electron density at the carbon atom of CF
3
transfer. We hypothesized that the
bond by
-. Reagents 2
B
3
N
3
6
3 3
)-cation interaction would labilize the B-CF
3
and 2b, in which a cation-fluorine interaction is either present or
absent, allowed us to clearly interrogate this hypothesis. In
-
nucleophilic CF
3
transfer to aldehyde 7, 2 was 3x faster than 2b,
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COMMUNICATION
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COMMUNICATION
Jacob B. Geri, Michael M. Wade Wolfe,
and Nathaniel K. Szymczak
Page No. – Page No.
-
Borazine-CF
3
Adducts for Rapid,
Room Temperature, and
Broad Scope Trifluoromethylation
A fluoroform-derived reagent facilitates the nucleophilic trifluoromethylation of a
broad array of inorganic and organic electrophiles at room temperature. The scope
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includes 18 inorganic elements, nucleophilic aromatic substitution, and CF
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addition to carbonyl and imine compounds. Kinetic analysis supports a dissociative
mechanism, and an enhanced-stability reagent is presented.
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