Access to Aryl and Heteroaryl Trifluoromethyl Ketones from Aryl Bromides and Fluorosulfates with Stoichiometric CO

Article abstract of DOI:10.1021/acs.orglett.0c01117

We report a sequential one-pot preparation of aromatic trifluoromethyl ketones starting from readily accessible aryl bromides and fluorosulfates, the latter easily prepared from the corresponding phenols. The methodology utilizes low pressure carbon monoxide generated ex situ from COgen to generate Weinreb amides as reactive intermediates that undergo monotrifluoromethylation affording the corresponding aromatic trifluoromethyl ketones (TFMKs) in good yields. The stoichiometric use of CO enables the possibility for accessing ¹³C-isotopically labeled TFMK by switching to the use of ¹³COgen.

Full text of DOI:10.1021/acs.orglett.0c01117

pubs.acs.org/OrgLett
Letter
Access to Aryl and Heteroaryl Trifluoromethyl Ketones from Aryl
Bromides and Fluorosulfates with Stoichiometric CO
Martin B. Johansen, Oliver R. Gedde, Thea S. Mayer, and Troels Skrydstrup*
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ABSTRACT: We report a sequential one-pot preparation of aromatic
trifluoromethyl ketones starting from readily accessible aryl bromides
and fluorosulfates, the latter easily prepared from the corresponding
phenols. The methodology utilizes low pressure carbon monoxide
generated ex situ from COgen to generate Weinreb amides as reactive
intermediates that undergo monotrifluoromethylation affording the
corresponding aromatic trifluoromethyl ketones (TFMKs) in good
yields. The stoichiometric use of CO enables the possibility for
accessing 13C-isotopically labeled TFMK by switching to the use of
13COgen.
participation of a specific organocopper reagent (PPh3)3CuCF3
he incorporation of fluorine into bioactive molecules for
Tthe enhancement or alteration of their chemical and under 20 bar of pressure of carbon monoxide (CO).5
Bearing in mind the toxicity of CO, it would be
advantageous from a safety point of view to investigate
synthetic routes that circumvent the use of pressurized gas
cylinders, as well as reaction conditions requiring high CO
pressures. In this study, we wish to report on a two-step, one-
pot catalytic protocol for accessing aryl and heteroaryl
trifluoromethyl ketones from the corresponding aryl bromides
or phenols via their fluorosulfates,6 without the need for highly
reactive intermediates, specialized reagents, or pressurized
lecture bottles. This carbonylative methodology can be carried
out with just stoichiometric quantities of CO with respect to
the aryl electrophile using the commercially available CO
surrogate, COgen.7 Moreover, it is adaptable to the full
incorporation of 13CO to afford isotopically labeled TFMK
with carbon-13.
We have recently shown in a stoichiometric study that the
Pd-catalyzed carbonylative trifluoromethylation of aryl bro-
mides is not a viable route for accessing TFMK using common
CF3 reagents under low CO pressures.8 By combining these
results with the recent advances reported by the Buchwald
group and our own research group within low pressure
aminocarbonylations, a sequential one-pot method to prepare
aryl and heteroaryl TFMK was explored.9 We envisaged
preparation of a stable acyl species from the corresponding aryl
biological properties is a strategy commonly applied in the
pharmaceutical and agrochemical industry. About 60% of the
top-selling pharmaceuticals display at least one fluorine-
containing motif.1 Trifluoromethyl ketones (TFMKs) con-
nected to an aryl or heteroaryl ring possess an electron-poor
carbonyl group capable of forming stable hydrates, in addition
to displaying enhanced lipophilicity compared to the
corresponding methyl ketone. These properties render this
motif useful in drug design and in its utilization as enzyme
inhibitors (Scheme 1a).2,3 Efavirenz, a drug used for the
treatment of HIV, exhibits a reduced TFMK and can be found
on the World Health Organization’s model list of essential
medicines reported in 2019. The trifluoromethyl ketone
substructure has also been exploited as a starting point for
the synthesis of (i) fluorinated heterocycles by condensation
reactions, (ii) F-containing olefins with Wittig reagents, (iii) α-
fluoro amines by reductive amination, and (iv) fluorinated
alkanes through reductions or alkylations.2
Considering the importance of aryl and heteroaryl
trifluoromethyl ketones, it is somewhat surprising that only
few synthetic routes to these structures have been reported.
The traditional strategies rely on rather harsh conditions such
as the addition of either organolithium or organomagnesium
reagents to trifluoroacetyl electrophiles (Scheme 1b).4 These
methods have limited functional group tolerance and often
require cryogenic reaction temperatures. Because of the
trifluoromethyl ketone’s electrophilic nature, further addition
of the nucleophile to the carbonyl group is a common side
reaction. The group of Wu recently reported on the Pd-
catalyzed carbonylative trifluoromethylation of aromatic
iodides to yield the corresponding TFMKs, relying on the
Received: March 27, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01117
© XXXX American Chemical Society
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A

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Scheme 1. Synthesis of Aromatic Trifluormethyl Ketones
from Aryl Halides
Table 1. Optimization of Sequential One-Pot Synthesis of
Aromatic Trifluoromethyl Ketones
a
b
entry
deviation
yield
1
2
3
4
none
80%
59%
46%
62%
58%
3.0 equiv of TMSCF3
TMSCF3 added slowly over 1 h
0 °C in second step
5
40 °C in second step
c
6
7
8
9
10
11
12
13
14
15
TESCF3 instead of TMSCF3
1.4 equiv of TMAF
0.6 equiv of TMAF
CsF instead of TMAF
TBAF (1 M in THF) instead of TMAF
Na2CO3 instead of Et3N
K2CO3 instead of Et3N
Pd(OAc)2/Xantphos
48%
75%
49%
0%
0%
65%
72%
21%
37%
65%
dioxane as solvent
CPME as solvent
a
Reactions were performed using 0.50 mmol of 4-bromoanisole. CO
b
released ex situ from COgen premix using Cy2NMe in PhMe. 1H
NMR yield using 1,3,5-trimethoxybenzene as internal standard.
c
Mixture of TFMK and O-TES-hemiaminal. PhMe = toluene. Pd
precat. = Xantphos Pd G4. TMAF = tetramethylammonium fluoride.
TBAF = tetrabutylammonium fluoride. TMSCF3 = trimethyl-
(trifluoromethyl)silane.
°C followed by workup with TBAF led to the target product in
a sequential one-pot fashion. Performing the reaction with 3.0
equiv of TMSCF3, slow addition of TMSCF3, or addition of
TMSCF3 at 0 or 40 °C all led to deteriorated yields (entries
2−5). TESCF3 was less effective for promoting this trans-
formation (entry 6). Increasing the amount of the activator
resulted in a slightly decreased yield of 75% (entry 7), while
lowering the number of activator equivalents afforded a yield of
49% of the desired product (entry 8). Other fluoride-based
activators such as CsF or TBAF (1 M in THF) did not show
any activity at all illustrating the importance of TMAF (entries
9 and 10). Substituting Et3N with Na2CO3 or K2CO3 afforded
the product in a yield of 65% and 72%, respectively (entries 11
and 12). Replacing the precatalyst with Pd(OAc)2 and
Xantphos resulted in a large decrease in yield (entry 13).
Finally, dioxane and CPME were screened, but these efforts
only led to product yields of 37% and 65%, respectively
(entries 14 and 15).
Next, we proceeded to investigate the generality of this
transformation (Scheme 2). Isolation of trifluoroacetophenone
2a from the test system after column chromatography could be
achieved in a 72% yield. Similarly, the 3,5-di- and 3,4,5-
trimethoxy substituted bromobenzene gave 2b and 2c in yields
of 52% and 40%, respectively. Various O-functionalized 4-
bromophenol substrates were efficiently converted into the
corresponding TFMKs in yields ranging between 45% and 59%
(compounds 2d−2f). Compound 2g was isolated in a yield of
77%, and the corresponding carbon-13 labeled derivative 13C-
2g could be readily prepared with 13COgen. Trimethylsilyl
(TMS) substituted bromobenzenes were also converted into
the corresponding TFMK. The 4-TMS product 2h was
isolated in a 39% yield while the 3-TMS product zifrosilone
bromide or fluorosulfate and ex situ generated CO from
COgen in our two-chamber reactor, COware, that upon
treatment with TMSCF3 would afford the corresponding
TFMK.10,11 Previous work from the group of Leadbeater
revealed that Weinreb amides are viable candidates, and as
such we set out to investigate this possibility.12
Initial efforts were performed with 4-bromoanisole as the
test substrate. After careful optimization of the reaction
parameters, the corresponding TFMK was obtained in an
80% NMR yield with 14% unreacted Weinreb amide (Table 1,
entry 1). TFMK and the Weinreb amide were in general the
only two products observed in the crude reaction mixtures.
The optimal reaction conditions for the initial Pd-catalyzed
aminocarbonylation consisted of heating a reaction mixture of
the aryl bromide, the hydrochloride salt of N,O-dimethylhy-
droxylamine (1.5 equiv), triethylamine (Et3N, 1.5 equiv), and
the fourth generation Buchwald-type palladacycle precatalyst
(Xantphos Pd G4, 2 mol %) in toluene (PhMe, 0.5 M) at 80
°C overnight in the presence of CO (1.5 equiv). COgen
premix containing COgen, Pd(OAc)2 (0.5 mol %), and
HBF4P(t-Bu)3 (0.5 mol %) in conjunction with base
(Cy2NMe) was used to release CO ex situ in 20 mL COware.
Subsequent addition of the Ruppert-Prakash reagent, TMSCF3
(2.0 equiv), with an activator (TMAF, 1.0 equiv) for 2 h at 25
B
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a
(2i), a clinical candidate as acetylcholinesterase (ACE)
inhibitor,3b and its 13C-labeled analog 13C-2i could both be
prepared in identical yields. Heteroaryl bromides, such as
quinoline and benzothiophene, proved to be viable substrates
for this methodology (2j−2l and 13C-2j).
Scheme 2. Scope of Aromatic Trifluoromethyl Ketones
3′-Fluoro-4-bromobiphenyl was converted into the corre-
sponding TFMK 2m in a yield of 59%, and 61% for the 13C-
isotope labeled compound (13C-2m). Compound 2m
represents a two-step precursor to LP-533401 and a three-
step precursor to LP-615819 (Scheme 1), both reported to
display inhibitory activities toward the tryptophan hydroxylase
(TPH).3d No double addition of the trifluoromethyl anion to a
substrate bearing a carboxylate ester in the 4-position of an aryl
bromide was observed (compound 2n). 4-Bromobiphenyl was
converted efficiently to 2o in a 79% yield. As evident from 2p
and 2q, alkyl chloride substituents are well tolerated and
represent a useful handle for further modification of the
TFMK. The corresponding 13C-labeled compounds 13C-2p
and 13C-2q were likewise prepared. An alkynyl substituted
substrate was converted into the TFMK 2w in a 54% yield.
Lastly, aromatic TFMKs 2s, 2t, 13C-2t possessing fluoride and
chloride substituents were synthesized, which can serve as
electrophiles for SNAr or cross-coupling reactions. 2s and 2t
have been reported as interesting and convenient intermediates
for the synthesis of cyclopentene and spirocyclic compounds,
respectively, both investigated for their application as
pesticides and insecticides.13
We also investigated aryl fluorosulfates as potential electro-
philes in this transformation (Scheme 2 bottom). The
corresponding fluorosulfate obtained from 4-phenylphenol
proved worthwhile in this transformation providing the
TFMK 2o in an isolated yield of 79%, which is identical to
the yield of the corresponding aryl bromide transformation.
Slightly altered reaction conditions were used, such as the
catalyst loading was increased to 3 mol % of Xantphos Pd G4,
and Et3N was replaced with K2CO3.
4-Thiomethyl, 4-adamantyl, and 3-(N,N-diethylamino)
substituted phenylfluorosulfate substrates afforded the prod-
ucts 2u−2w in moderate yields. A substrate possessing the
bisphenol A core led to the TFMK 2x with a yield of 41%. A
second addition of CF3 was realized onto the internal ketone
affording the 2y in a 44% yield.
We next focused our efforts to scale up the reaction.
Conversion of 5 mmol of aryl bromide 1m into the
trifluoromethyl ketone 2m only led to a 39% isolated yield
along with the corresponding unreacted Weinreb amide (54%
isolated yield). Instead, the reaction mixture was filtered and
concentrated after the initial aminocarbonylation. NMR
analysis of the filter cake suggested that the insoluble
hydrochloride salt of triethylamine was selectively removed.
The concentrated filtrate was redissolved in toluene with
TMAF into which TMSCF3 was added dropwise. This
approach led to the isolation of 1.04 g (77%) of 2m (Scheme
2).14
Having established a methodology to access (hetero)aryl
trifluoromethyl ketones, we proceeded to investigate the
chemical use of 2m as a model substrate for TFMKs in
general (Scheme 3). The [1,2]-addition of cyclopropylacety-
lene onto the carbonyl functionality is important for the
synthesis of Efavirenz.3c Therefore, the copper-catalyzed
addition of cyclopropylacetylene was performed to furnish
the carbinol product 3m in an 84% yield.15 A NaBH4 reduction
of 2m followed by an SNAr reaction with 2-amino-4,6-
a
Reactions were performed on a 0.50 mmol scale, and isolated yields
for the nonlabeled products are based on the average of two runs.
Reactions leading to the 13C-labeled compounds were run only once,
b
and yields are based on isolated product. Reaction performed on 5
mmol scale; see Supporting Information for experimental details. 3
mol % of Xantphos Pd G4 instead of 2 mol %, and K2CO3 instead of
Et3N. 4.0 equiv of TMSCF3 were used instead of 2.0 equiv. See
c
d
Supporting Information for experimental details.
C
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Scheme 3. Post-modification Studies of 2m
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01117.
Experimental procedures, product characterization, and
spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Troels Skrydstrup − Carbon Dioxide Activation Center
(CADIAC), Interdisciplinary Nanoscience Center (iNANO),
and Department of Chemistry, Aarhus University, DK-8000
Aarhus C, Denmark; orcid.org/0000-0001-8090-5050;
Email: ts@chem.au.dk
a
b
c
[1,2]-Addition. Reduction and SNAr reaction. Johnson−Corey−
d
Chaykovsky oxetane formation. Wittig reaction. Ar = 3′-fluoro-
[1,1′-phenyl]-4-yl. See Supporting Information for experimental
details.
Authors
dichloropyrimidine yielded 52% of 4m over 2 steps.3d
Performing a Johnson−Corey−Chaykovsky reaction on 2m
afforded 63% of the corresponding trifluoromethyl oxetane
5m, which is an isostere to the tert-butyl group.16 A Wittig
reaction on the ketone functionality of 2m was conducted to
afford the trifluorocrotyl product 6m in an 85% yield.
Comparing the chemical shift of the CF3 group in the 19F
NMR spectrum with similar structures suggested that 6m has
been isolated almost exclusively as the E-isomer (E/Z >
99:1).17
Iloperidone is an antipsychotic pharmaceutical bearing an
aromatic methyl ketone functionality.18 We have demonstrated
that the CF3 analog of iloperidone 6q can be synthesized from
2q by simple SN2 displacement of the chloride with a
commercially available amine (Scheme 4). This approach
Martin B. Johansen − Carbon Dioxide Activation Center
(CADIAC), Interdisciplinary Nanoscience Center (iNANO),
and Department of Chemistry and Department of Engineering,
Aarhus University, DK-8000 Aarhus C, Denmark;
orcid.org/0000-0003-1638-6692
Oliver R. Gedde − Carbon Dioxide Activation Center
(CADIAC), Interdisciplinary Nanoscience Center (iNANO),
and Department of Chemistry, Aarhus University, DK-8000
Aarhus C, Denmark
Thea S. Mayer − Carbon Dioxide Activation Center
(CADIAC), Interdisciplinary Nanoscience Center (iNANO),
and Department of Chemistry, Aarhus University, DK-8000
Aarhus C, Denmark
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01117
a
Scheme 4. Synthesis of a CF3 Analog of Iloperidone
Notes
The authors declare the following competing financial
interest(s): Troels Skrydstrup is co-owner of SyTracks A/S,
which commercializes the two-chamber system (COware),
COgen premix, and 13COgen.
ACKNOWLEDGMENTS
■
We thank the Danish National Research Foundation (Grant
No. DNRF118), the Independent Research Fund Denmark −
Technology and Production (Grant No. 4148-00031),
NordForsk (Grant No. 85378), and Aarhus University for
financial support.
a
See Supporting Information for experimental details.
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