Denitrogenative Hydrotrifluoromethylation of Benzaldehyde Hydrazones: Synthesis of (2,2,2-Trifluoroethyl)arenes

Article abstract of DOI:10.1002/chem.201902818

Reacting hydrazones of arylaldehydes with Togni's CF₃-benziodoxolone reagent, in the presence of potassium hydroxide and cesium fluoride, induces a denitrogenative hydrotrifluoromethylation event to produce (2,2,2-trifluoroethyl)arenes. This novel reaction was tolerant to many electronically-diverse functional groups and substitution patterns, as well as naphthyl- and heteroaryl-derived substrates. Advantages of this process include the easy access to hydrazone precursors on a large scale, speed and operational simplicity, and being transition metal-free.

Full text of DOI:10.1002/chem.201902818

A Journal of
Accepted Article
Title: Denitrogenative Hydrotrifluoromethylation of Benzaldehyde
Hydrazones: Synthesis of (2,2,2-Trifluoroethyl)arenes
Authors: Zhensheng Zhao, Kevin C.Y. Ma, Claude Y Legault, and
Graham K. Murphy
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To be cited as: Chem. Eur. J. 10.1002/chem.201902818
Link to VoR: http://dx.doi.org/10.1002/chem.201902818
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10.1002/chem.201902818
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Denitrogenative Hydrotrifluoromethylation of Benzaldehyde
Hydrazones: Synthesis of (2,2,2-Trifluoroethyl)arenes
Zhensheng Zhao,[a] Kevin C.Y. Ma,[a] Claude Y. Legault*[b] and Graham K. Murphy*[a]
In memory of Dr. Carey Bissonnette.
Abstract: Reacting hydrazones of arylaldehydes with Togni’s CF3-
benziodoxolone reagent, in the presence of potassium hydroxide and
cesium fluoride, induces a denitrogenative hydrotrifluoromethylation
event to produce (2,2,2-trifluoroethyl)arenes. This novel reaction was
tolerant to a large number of electronically-diverse functional groups
and substitution patterns, as well as naphthyl- and heteroaryl-derived
substrates. Favorable attributes of this process include easy access
to hydrazone precursors on a large scale, speed and operational
simplicity, and being transition metal-free.
iodonium salts, via electrophilic coupling with arenes (Scheme 1b,
i).[18] Togni’s CF3-containing HVI reagent (2)[19] has also been
used in the synthesis of 1, via the radical trifluoromethylation of
benzylic C-H bonds (Scheme 1b, ii).[20] We were interested in
exploiting the electrophilic nature of 2[21] to develop a transition
metal-free synthesis of 1, by exposing it to a suitable benzylic
nucleophile such as
a
hydrazone.[22] Arylaldehyde-derived
hydrazones readily undergo trifluoromethylation at the
azomethine carbon,[23] but to the best of our knowledge, this
reactivity has not been coupled with a denitrogenation event.
Given our interest in HVI-mediated gem-difunctionalization
reactions of diazo compounds and hydrazones,[24] we wished to
Organofluorine compounds play critical roles in many areas of
modern research, from medicinal chemistry to agrochemistry, and
from materials science to medical imaging,[1] so the continued
development of new fluorination methodologies is critical. Among
the myriad important organofluorine motifs, (2,2,2-trifluoroethyl)-
arenes (1) have received considerable attention from the
synthetic community, owing to their favorable biological properties
including their increased metabolic stability over alkyl groups.[2]
Synthetic strategies towards this motif are plentiful, and span a
wide range of general synthetic strategies. They are prepared
interrupt
a Wolff-Kishner reduction by having an anionic
intermediate engage 2 instead of a proton, leading to 1 upon loss
of N2 (Scheme 1c). We report here the results of this study, in
which we were able to rapidly and efficiently convert aldehyde-
derived hydrazones (3) to (2,2,2-trifluoroethyl)arenes by
subjecting them to Togni’s reagent (2) under basic conditions at
room temperature.
We began this study by combining hydrazone 3a with 2 and
2.2 equiv of K2CO3 in acetonitrile, from which a trace of the
from aldehydes via
a
multi-step sequence involving
trifluoromethylation and deoxygenation, (Scheme 1a, i),[3, 4] and
also from b, b-difluorostyrenes via hydrofluorination (Scheme 1a,
ii).[5] Nucleophilic displacement on a variety of activated benzylic
compounds is achieved with in situ-generated “CuCF3”[6,7]
(Scheme 1a, iii). Metal-mediated cross-coupling strategies[8]
between arenes or heteroarenes and 2,2,2-trifluoroethyl-based
reagents have been achieved with Cu-,[9] Ni-,[10] Co-,[11] Zn-,[12]
Ir-,[13] and Pd-based[14,15] catalysts (Scheme 1a, iv) and
arylboronic acids have also been effectively coupled with 2,2,2-
trifluorodiazoethane (Scheme 1a, v).[16]
a) Strategies for the synthesis of 1:
i)
ii)
O
F2C
KF
1. TMSCF3, TBAF
2. Deoxygenation
H
R
R
F
R3SiCF3
KF / CuX
iii)
F F
X
R
“CuCF3” in-situ
R
2,2,2-trifluoroethyl-
Over the past few decades, the use of hypervalent iodine(III)
(HVI) reagents in organic chemistry has undergone tremendous
growth, owing to the advantages of mild reaction conditions and
broad reactivity, and of recyclable, environmentally-benign by-
products.[17] The synthesis of (2,2,2-trifluoroethyl)arenes has
recently been accomplished with mesityl (2,2,2-trifluoroethyl)-
arene (1)
CF3
N2
iv)
G
v)
F3C
“Cu, Ni, Co, Zn, Ir, Pd”
G = H, Cl, I, B(OR)2, MgBr
X
R
(HO)2B
R
b) HVI-mediated strategies for the synthesis of 1:
OTf
i)
ii)
I
[a]
[b]
Dr. Z. Zhao, K.C.Y. Ma and Dr. Prof. G.K. Murphy
Department of Chemistry
University of Waterloo, 200 University Ave W., Waterloo, ON,
Canada, N2L3G1
H
H3C
CF3
2
1
“Pd”
CuI or hν
R
R
E-mail: graham.murphy@uwaterloo.ca
c) This work: denitrogenative hydrotrifluoromethylation:
Dr. Prof. C.Y. Legault
Department of Chemistry
Université de Sherbrooke, Sherbrooke, Québec,
Canada, J1K2R1
E-mail: claude.legault@usherbrooke.ca
CF3
I
NH2
1.5 equiv 2
N
H CF3
O
H
H
KOH, CsF
CH3CN/H2O
rt, 10 min
2
O
3
1
R
R
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Various syntheses of 2,2,2-trifluoroethylarenes (1).
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desired product 1a was observed by quantitative 19F NMR (Table
1, entry 1). Conducting the reaction solely in water failed, but
when a 1:1 mixture of acetonitrile and water (by volume) was
employed, product 1a was observed in 33% yield (Table 1, entries
2 and 3; also, see Supporting Information for complete details on
univariate screening of reaction conditions). Various other
solvents such as THF, 1,4-dioxane and MeOH all gave 1a, albeit
in lower yield than acetonitrile (entries 4-6). Substituting the water
co-solvent with alcohols (eg. MeOH, i-PrOH, etc) caused the
reactions to fail, except for t-amyl alcohol which led to 1a in a
decreased yield of 15% (entry 7). Many other inorganic and
organic bases were tested, and we found that t-BuOK, NaH,
NaOH, KOH and DBU (among many others) were all viable,
giving 1a in increased yield (entries 8-12). We adopted KOH as
our base, and found that while increasing its loading had little
effect, decreasing its loading gave a decreased yield of 1a (entry
13). The effect of temperature was investigated, and while the
reaction performed equally well with cooling (down to -10 °C),
heating to 40 °C or beyond proved detrimental (entry 14). No
improvement was observed when testing dropwise or reverse
addition of reagents, and when additives were tested,[22, 25] we
found that including 30 mol% of CsF resulted in an increased yield
of 1a of 72% (entry 15, also see Supporting Information). Further
optimization involved testing the loading of 2, in which decreasing
the loading proved detrimental, and increasing its loading had no
effect (entries 16 and 17). We retested the effect of base on the
protocol using CsF, and found that when 3 equiv KOH was added,
1a was observed in 80% NMR yield, and was recovered in 70%
isolated yield (entry 18). Finally, we tested Togni’s CF3-
benziodoxole reagent[19] in the reaction, but it failed to generate
any desired product (entry 19.) These results show that an
electrophilic trifluoromethylation can interrupt a typical Wolff-
Kishner reduction, giving (2,2,2-trifluoroethyl)arene 1a in high
yield. Remarkably, the reaction was also operative in a variety of
alcohol- and ether-derived organic solvents, it worked equally well
using either strong inorganic or weaker organic bases, it required
no stringent reagent addition techniques, and it was complete in
10 min at room temperature.
4
5
K2CO3 (2.2)
K2CO3 (2.2)
K2CO3 (2.2)
K2CO3 (2.2)
t-BuOK (2.2)
NaH (2.2)
THF
1,4-dioxane
MeOH
–
24%
18%
21%
15%
54%
52%
55%
61%
54%
42%
49%
72%
70%
70%
80%(70%)
–
–
6
–
7
CH3CN[e]
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
–
8
–
9
–
10
11
12
13
14[f]
15
16[g]
17[h]
18[g]
19[i]
NaOH (2.2)
KOH (2.2)
DBU (2.2)
KOH (1.5)
KOH (2.2)
KOH (2.2)
KOH (2.2)
KOH (2.2)
KOH (3.0)
KOH (3.0)
–
–
–
–
–
CsF (30)
CsF (30)
CsF (30)
CsF (30)
CsF (30)
[a] 19F NMR yield using 4-fluorotoluene as internal standard. [b] Isolated
yield. [c] No H2O added. [d] Only H2O; no CH3CN. [e] t-amyl alcohol used
instead of H2O. [f] Performed at 40 °C. [g] Using 1.5 equiv 2. [h] Using 2.0
equiv 2. [i] Using Togni’s benziodoxole reagent (CAS: 887144-97-0) instead
of 2.
We then prepared a series of differently-substituted aryl
aldehyde hydrazones (3a-3an) and subjected them to the
trifluoromethylation reaction. First, a series of p-substituted
derivatives (3a-3l) were tested, and they are arranged in Scheme
2 according to their Hammett substituent constants (sp).[26]
Substrates possessing strongly electron-withdrawing substituents
such as -nitro (3b), -cyano (3c), -CF3 (3d) or -CO2Me (3e) were
all feasible, giving the products 1b-1e in good to excellent yield.
Substrates
possessing
inductively
electron-withdrawing
substituents were also viable, with the -tosylate (1f), -bromo (1g)
and -chloro (1h) products being recovered in 56-66% yield. The
hydrazones of benzaldehyde (3i) and p-tolualdehyde (3j) were
moderately effective, giving 1i and 1j in 47 and 52% NMR yield,
respectively. The reaction performed less optimally when the
substrates possessed strongly electron-donating substituents at
the para- position, with the p-anisyl- derivative 3k giving 1k in 34%
yield, and the p-dimethylamino derivative 3l giving 1l in 14% yield.
Substituents at the ortho- position were less well tolerated, as the
nitro- (3m) and bromo- (3n) derivatives were converted to 1m and
1n in 68% and 51% yield, respectively, a significant decrease over
that observed for para- substitution. Likewise, ortho-fluoro
derivative 3o was converted to 1o in only 16% NMR yield. The
reactivity was restored upon meta- substitution, with the nitro- and
cyano- products 1p and 1q being recovered in 86% and 84% yield,
respectively. Substrate 3r, possessing an inductively electron-
withdrawing benzyloxy- group was converted to 3r in 28% yield.
Table 1. Optimization of the reaction conditions.
CF3
I
O
NH2
H
N
H CF3
H
2
1.2 equiv
O
base, additive
1a
3a
solvent:H2O (1:1)
rt, 10 min
Ph
Ph
Base
(equiv)
additive
(mol%)
yield[a]
entry
solvent
(yield)[b]
1
2
3
K2CO3 (2.2)
K2CO3 (2.2)
K2CO3 (2.2)
CH3CN[c]
–
–
–
trace
0%
[d]
–
CH3CN
33%
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NH2
H
CF3
I
O
H
CF3
H
3 equiv KOH
30 mol% CsF
N
+
CH3CN : H2O (1 : 1)
rt, 10 min
R
1a - 1an
2
1.5 equiv
O
R
3a - 3an
R
O2N
MeO
CF3
CF3
CF3
NO2
CF3
CF3
CF3
R
Cl
R
R
Br
1ak, 58%[a]
CF3
Cl
1a, R = 4-Ph, 70%
1b, R = NO2, 95%
1c, R = CN, 91%
1d, R = CF3, 75%[a]
1e, R = CO2Me, 79%
1f, R = OTs, 58%
1g, R = Br, 66%
1u, R = F, 83%
1v, R = Br, 91%
1w, R = OMe, 80%
1x, R = OBn, 76%
1y, R = O-allyl, 46%
1ad, R = Br, 86%
1m, R = NO2, 68%
1n, R = Br, 51%
1o, R = F, 16%[a]
1s, 88%
CF3
CF3
Br
R
N
R
R
CF3
1am, 66% (87%[a]
)
CF3
CF3
NO2
1al, 36%
1h, R = Cl, 56%
1i, R = H, 47%[a]
1j, R = Me, 52%[a]
1k, R = OMe, 34%
1l, R = N(Me)2, 14%[a]
1ae, R = Cl, 90%
1af, R = Br, 90%
1ag, R = Me, 75%
1ah, R = OMe, 64%
1ai, R = OBn, 71%
1aj, R = O-allyl, 29%
NO2
CF3
1z, R = F, 71%
1p, R = NO2, 86%
1q, R = CN, 84%,
1r, R = OBn, 28%[a]
Cl
1t, 76%
1aa, R = OMe, 82%
1ab, R = OBn, 72%
1ac, R = O-allyl, 40%
O
1an, 15%[a]
Scheme 2. Synthesis of 2,2,2-(trifluoroethyl)arenes 1. [a] 19F NMR yields.
A number of disubstituted derivatives were also tested, with
dihalohydrazones 3s and 3t being converted to 1s and 1t in 88%
and 76% yield, respectively. We tested a series of hydrazones
possessing a nitro group and an additional substituent at various
positions about the arene. First tested were the 5-nitro derivatives,
and found 2-halo (-F, 3u; -Br, 3v), 2-methoxy- (3w) or 2-
benzyloxy- (3x) substituents to all give the products 1u-x in high
yield. Only the 2-allyloxy derivative 3y was less effective, where
complete consumption of the hydrazone gave 1y in only 46% yield.
Reversing the substitution pattern (2-nitro, 5-R) was equally well
tolerated, which was unexpected given the decreased yield
observed previously with ortho-nitro substrate 1m. The 5-fluoro-
(3z), 5-methoxy- (3aa) and 5-benzyloxy- (3ab) variants were
converted to the products 1z-1ab in 71-82% yield, with the 5-
allyloxy-derived hydrazone 3ac progressing to 1ac in lower (40%)
yield. Relocating the second substituent to the 4- position was
also feasible, from which the bromo-substituted product (1ad)
was recovered in 86% yield. Lastly, a series of 3-nitro derivatives
bearing an additional group at the 4-position were tested, and we
found the chloro- (3ae) bromo- (3af), methyl- (3ag), methoxy-
(3ah) and benzyloxy-substituted (3ai) hydrazones to give
products 1ae-1ai in 64-90% yield. Again, the allyloxy- derivative
3aj reacted poorly, giving 1aj in 29% yield, suggesting a general
incompatibility of the reaction conditions with aryl allyl ethers. We
reacted disubstituted hydrazone derivative 3ak, which possessed
methoxy and bromine substituents (no nitro group) in the reaction,
and generated 1ak in 58% yield. Finally, we tested other arene
scaffolds, starting with 2-naphthyl derivative 3al, which gave 1al
in 36% yield. Two heteroaromatic derivatives were also tested,
and while the 3-pyridyl derivative 3am gave 1am in 66% yield
(87% by NMR), the 2-furyl substrate 3an was only converted to
1an in 15% yield by NMR. These results demonstrate the
versatility of the reaction, in that a wide scope of functional groups
can be distributed about the arene, generating products readily
available for further functionalization. Electron-rich arenes (3k, 3l,
3an) that presumably destabilize the putative carbanionic
intermediate were less effective, even though full conversions
were observed; however, if also appended with an electron-
withdrawing group, even at a position precluding it from stabilizing
the anionic intermediate through resonance (3w/3x vs 3aa/3ab),
the reactivity was generally restored.
We carried out various control experiments to gain insight into
the scope and mechanism of the reaction. Subjecting diazo
compound 4 to the reaction conditions failed to give 1b, as did p-
toluenesulfonyl hydrazone 5 and phenylhydrazone 6 (Scheme 3a).
Based on these results, we reasoned that the hydrazones are not
initially oxidized to diazo compounds in this process.[24d, 27] We
anticipated that 6 would not lead to 1b, given its inability to expel
nitrogen gas, but we were surprised that 5 also failed, as
CF3
R
3 equiv KOH
30 mol% CsF
H
CF3
H
I
O
H
(a)
+
CH3CN : H2O
rt, 10 min
O2N
O2N
O
2
1b, 0%
4 R = N2
5 R = N-NHTs
6 R = N-NHPh
1.5 equiv
ND2
CF3
I
O
3 equiv KOH
30 mol% CsF
H/D CF3
H
N
(b)
+
H
rt, 10 min
O2N
O2N
O
2
i) CH3CN : H2O
ii) CD3CN : H2O
iii) CD3CN : D2O
1b, 85%, H:D = 100 : 0
1b, 83%, H:D = 100 : 0
1b, 48%, H:D = 1 : 4
[D2]-3b
1.5 equiv
NH2
N
3 equiv KOH
30 mol% CsF
H
H
CF3
(c)
CF3
CH3CN : H2O
rt, 10 min
O2N
O2N
7
1b, trace
Scheme 3. Control experiments testing hydrazone and diazo derivatives.
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p-tosylhydrazones were previously found to be interchangeable
shell by water co-solvent. A summary of the results is illustrated
in Figure 1. The calculations suggest the deprotonation of
hydrazone 1b to be fast and slightly exergonic. The resulting
anion (Int-A1) would then form N-bonded intermediate Int-A2 by
association with 2. The latter will isomerize to Int-A4 through
dissociation of the carboxylate (Int-A3). The rate-determining
step (RDS) is suggested to be the reductive elimination TS[A4-
A5], leading to the formation of the key C-C bond. We could not
converge the alternative [1,2]-reductive elimination transition
structure (not shown), which would result in the N-CF3
hydrazone.[37] Considering the numerous simplifications of the
computational model, and our inability to computationally identify
the beneficial role played by CsF, the computed barrier of the
RDS (ΔG‡ = 20.9 kcal/mol) is in good agreement with the
estimated experimental barrier of 19 kcal/mol for this bimolecular
process. This highly exergonic, irreversible RDS furnishes azo
intermediate Int-A5, which undergoes fast (ΔG‡ = +4.1 kcal/mol)
and irreversible N-deprotonation/nitrogen extrusion, giving
product anion (Int-A6). The calculations suggest that C-
deprotonation of Int-A5 would not kinetically compete with N-
deprotonation, hence the absence of formation of 7. In addition,
the calculations are consistent with the control experiment
described in Scheme 3c; the chemoselective conversion of 7 to
1b would not readily occur at room temperature (ΔG‡ = 27.7
kcal/mol). The results also suggest that 1b would be in equilibrium
with its anion (Int-A6) under the described basic conditions; this
with hydrazones (eg 5 vs 3b) in HVI-mediated denitrogenation
24e, 28]
reactions.[24d,
The differing reactivity observed here is
attributed to the decreased nucleophilicity of the hydrazone
possessing the p-Ts group. We next used deuterium labelling to
elucidate the source of the proton in the products. Using [D2]-3b
failed to induce any observable deuterium incorporation (by NMR
analysis), as did employing CD3CN (Scheme 3b, i and ii).
Replacing water with D2O led to significant deuterium
incorporation in the product (~80% by NMR), albeit with a large
decrease in overall yield. These results strongly suggest that the
water co-solvent is being deprotonated in the reaction,
presumably from a penultimate a-CF3 benzyl anion intermediate,
consistent with a Wolff-Kishner-type mechanism.
We turned to quantum chemical calculations to gain insights
into the most plausible mechanism. The geometry optimizations
were performed with the M062X density functional,[29] in
combination with the 6-31+G(d,p) basis set[30] for all atoms except
iodine, for which LANL2DZdp + ECP was used.[31] In accord with
the recent benchmarking study of Nakajima, Nemoto, and co-
workers,[32] single points calculations were performed using the
MN15 density functional,[33] in combination with the aug-cc-
pVTZ[34] basis set for all atoms except iodine, for which SDD[35]
was used. The complex nature of the reaction conditions,
involving multiple solvents and salts, makes modelling
challenging. To account for the organic co-solvent, we performed
the calculations using SMD implicit solvation model for acetonitrile. prediction is consistent with the observation of the deuteration of
We used the recently corrected radius for iodine for SMD
calculations.[36] The potassium and cesium counterions were
omitted, as they were expected to be fully dissociated in water
solvation shells. Finally, free anionic species were treated as
adducts with a water molecule to represent their explicit solvation
1b when treated under the classical reactions conditions in the
presence of D2O. The proposed pathway is also comparatively
lower than possible competing pathways. For example, the
calculations suggest that the activation barrier of C-protonation of
Int-A1 to afford Int-B (red path, Wolff-Kishner pathway) is 7.7
Figure 1. Calculated mechanism of the reaction, or mechanistic proposal guided by computational analysis (explicit water molecules omitted for clarity).
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Román, J. F. Sanz-Cervera, A. Simón-Fuentes, J. Bueno, S. Villanova,
J. Org. Chem. 2008, 73, 8545-8552.
kcal/mol higher in energy. Anion Int-A1 is ambident and C-
bonding to iodane 2 was also investigated; the RDS (TS-
CBonded, in green) of this pathway, which would lead to a N-CF3
hydrazone, was found to be disfavored by 3.5 kcal/mol over the
proposed mechanism. In analogy to Int-A4, we could not find the
alternative [1,2]-reductive elimination transition structure from the
C-bonded intermediate, which would lead to Int-A5. Overall, the
calculations are in good agreement with the control experiments
and support the illustrated mechanism.
[4]
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In conclusion, the first denitrogenative hydrotrifluoro-
methylation of benzaldehyde hydrazones has been successfully
developed using Togni’s widely available benziodoxolone reagent.
Using this method, substrates possessing a wide range of
functional groups and substitution patterns were efficiently
converted into the desired (trifluoroethyl)arenes. Computational
analysis of this novel reaction led to a mechanistic proposal in
which the key trifluoromethylation step occurs in concert with
reductive elimination of the iodoarene. This operationally simple
process relies on a safe and reliable hypervalent iodine reagent,
and consists of a new, rapid and highly efficient strategy to
synthesize these valuable motifs. Given the prevalence of these
motifs in biologically active compounds, and the easy access to
the requisite hydrazone precursors, this synthetic strategy holds
significant potential.
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Acknowledgements
This work was supported by the Natural Sciences and
Engineering Research Council (NSERC) of Canada, the
University of Waterloo and l’Université de Sherbrooke. Additional
financial support was provided by the Early Researcher Award
from the Province of Ontario (GKM). This research was enabled
in part by support provided by Compute Canada
(www.computecanada.ca).
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Zhensheng Zhao, Kevin C.Y. Ma,
Claude Y. Legault* and Graham K.
Murphy*
Page No. – Page No.
Denitrogenative Hydrotrifluoro-
methylation of Benzaldehyde
Hydrazones: Synthesis of (2,2,2-
Trifluoroethyl)arenes
Combining benzaldehyde hydrazones with Togni’s benziodoxolone reagent under
basic conditions results in a rapid and chemoselective synthesis of (2,2,2-
trifluoroethyl)arenes. Computational analysis suggests reductive elimination of
iodoarene to occur in concert with the key C-C bond forming step.
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