Direct Access to Aryl Bis(trifluoromethyl)carbinols from Aryl Bromides or Fluorosulfates: Palladium-Catalyzed Carbonylation

Article abstract of DOI:10.1002/anie.201802647

A palladium-catalyzed carbonylative approach for the direct conversion of (hetero)aryl bromides into their α,α-bis(trifluoromethyl)carbinols is described, and it employs only stoichiometric amounts of carbon monoxide and trifluoromethyltrimethylsilane. In addition, aryl fluorosulfates proved highly compatible with these reaction conditions. The method is tolerant of a diverse set of functional groups, and it is adaptable to late-stage carbon-isotope labeling.

Full text of DOI:10.1002/anie.201802647

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Direct Access to Aryl Bis(trifluoromethyl)carbinols from Aryl
Bromides or Fluorosulfates via a Pd-Catalyzed Carbonylation
Authors: Troels Skrydstrup, Katrine Domino, Cedrick Veryser,
Benjamin Wahlqvist, Cecilie Gaardbo, Karoline T. Neumann,
Kim Daasbjerg, and Wim De Borggraeve
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802647
Angew. Chem. 10.1002/ange.201802647
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10.1002/anie.201802647
Angewandte Chemie International Edition
COMMUNICATION
Direct Access to Aryl Bis(trifluoromethyl)carbinols from Aryl
Bromides or Fluorosulfates via a Pd-Catalyzed Carbonylation
Katrine Domino+, Cedrick Veryser+, Benjamin A. Wahlqvist, Cecilie Gaardbo, Karoline T.
Neumann, Kim Daasbjerg, Wim M. De Borggraeve and Troels Skrydstrup*
Abstract: A Pd-catalyzed carbonylative approach for the
direct conversion of (hetero)aryl bromides into their a,a-
bis(trifluoromethyl)carbinols is described, applying only
stoichiometric amounts of carbon monoxide and
trifluoromethyltrimethyl-silane. In addition, aryl fluorosulfates
proved highly compatible to these reaction conditions. The
method is tolerant of a diverse set of functional groups, and it
is adaptable to late-stage carbon isotope labeling.
in the presence of hexafluoroacetone.[8] Alternatively, a,a-
bis(trifluoromethyl)carbinols can be prepared from the
corresponding
trifluoroacetophenones using
carboxylic
acid
a
derivatives
nucleophilic CF3-source
or
from
(Scheme 1b).[9] Nevertheless, these methods are limited by
substrate biased regioselectivity, low functional group tolerance,
the use of toxic reagents[10] and/or the need of extra steps for
preliminary introduction or activation of the carbonyl functionality.
OH
CF3
a)
F3C CF3 F3C CF3
The introduction of a fluorine atom into bioactive molecules
can strategically alter their chemical and biological properties.[1] In
recent years, an increasing number of fluorine-containing drugs
have been launched, justifying the need for new synthetic
methodologies centered on the incorporation of fluorine-
containing motifs.[1a] One of these privileged motifs is the a,a-
bis(trifluoromethyl)carbinol group. Compounds containing this
substructure have shown biological activity against cancer,
diabetes, hepatitis C, dyslipidemia and inflammation (Scheme
1a).[2] An interesting feature of this motif is the presence of a large
number of fluorine atoms, which renders them as promising
contrast agents for 19F-MRI.[3] This technique allowed in vivo
CF3
O
O
O
S
O
O
O
Ph
F3C
N
O
CF2CF2CF3
O
N
Epoxy prepolymer (III)
S
Liver X-receptor
agonist (I)
OH
CF3
Tyrosine phosphatase inhibitor (II)
Contrast agent for 19F-MRI
OH CF3
b) Established Methods: SEAr and Nucleophilic Acyl Substitution and/or Addition
O
O
OH
CF3
Br
F3C
O
CF3
SEAr
F3C
CF3
CF3
R
R
R
R
Mg/Li
target identification of carbinol II,
a tyrosine phosphatase
OH
CF3
Substrate-controlled
regioselectivity
Low functional group
tolerance
Preinstallation of carboxylic
acid and subsequent activation
inhibitor.[3a] Furthermore, aryl a,a-bis-(trifluoromethyl)carbinol-
containing polymers display excellent material properties, as well
as high thermal stability and flame resistance.[4] The
hexafluoroisopropanol group can also be found in ligand design,
either by merit of its inductive electron withdrawing properties or
as a bulky substituent.[5] Other applications include their use for
the detection of nerve agents[6] and as precursors for the
synthesis of Martin’s spirosilanes.[7]
CF3-source
X
CF3
R
X = O(CO)Ar, OR, Cl, imidazole, CF3
CF3-source: TMSCF3, Bu3SnCF3, CHF3
c) This Work
OH
a) *CO, F
Pd catalysis
CF3
CF3
Direct approach
High yields
Broad scope
Late-stage
*
C
X
(Het)
Ar
(Het)
Ar
R
R
b) Ruppert's
Reagent
X = Br, OSO2F
30 examples
isotope labeling
Scheme 1. Examples of bis(trifluoromethyl)carbinol-containing bioactive
molecules and polymer materials, and previous strategies for the introduction of
this functional group.
Despite the multidisciplinary impact of this fluorinated motif,
only few synthetic strategies have been reported for its installation
(Scheme 1b). Most procedures rely on electrophilic aromatic
substitution or the use of organolithium or -magnesium reagents
Herein, we wish to report a general and mild protocol for the
direct conversion of aryl bromides or fluorosulfates into (hetero)-
aryl a,a-bis(trifluoromethyl)carbinols applying a Pd-catalyzed
carbonylative transformation. The latter class of starting materials
indirectly allows phenols as substrates for this transformation.
Furthermore, the developed methodology is suitable for direct and
late-stage carbon isotope labeling of the target compound.[11]
[ ]
*
K. Domino,[+] C. Veryser,[+] B. A. Wahlqvist, C. Gaardbo, Dr. K. T.
Neumann, Prof. Dr. T. Skrydstrup
Carbon Dioxide Activation Center (CADIAC), Department of
Chemistry and the Interdisciplinary Nanoscience Center (iNANO),
Aarhus University
Gustav Wieds Vej 14, 8000 Aarhus C (Denmark)
E-mail: ts@chem.au.dk
C. Veryser,[+] Prof. Dr. W. M. De Borggraeve
Molecular Design and Synthesis, Department of Chemistry
KU Leuven
We started our investigation by optimizing the carbonylation
of 4-bromoanisole 1a with a nucleophilic CF3-source, using a two-
chamber system and the ex situ generation of carbon monoxide
from COgen.[11a,12] After thorough evaluation of the reaction
parameters, the desired a,a-bis(trifluoromethyl)carbinol 2a was
successfully isolated in an 81% yield (Table 1, entry 1). The
Celestijnenlaan 200F, Box 2404, 3001 Leuven (Belgium)
[+]
These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) can be found under http://dx.doi.org/XXXX.
This article is protected by copyright. All rights reserved.

10.1002/anie.201802647
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of the reaction conditions.[a]
a) CO (1.2 equiv)
*
Pd(OAc)2 (3 mol%)
Xantphos (4.5 mol%)
KF (3.5 equiv)
a) CO (1.2 equiv)
OH
CF3
Pd(OAc)2 (3 mol%)
Xantphos (4.5 mol%)
KF (3.5 equiv)
*
C
Br
OH
CF3
DMF, 80 °C, 18 h
CF3
(Het)
Ar
(Het)
Ar
R
R
Br
C
b) TMSCF3 (2.2 equiv)
rt, 1 h
CF3
DMF, 80 °C, 18 h
1 - 0.6 mmol
2
MeO
1a - 0.6 mmol
MeO
b) TMSCF3 (2.2 equiv)
rt, 1 h
OH
CF3
OH
CF3
C
OH
OH
2a
CF3
CF3
MeO
O
C
CF3
C
CF3
C
Entry
1
Deviation from standard conditions
None
Yield of 2a [%][b]
CF3
CF3
Ph
MeO
Me
89 [81][c]
OMe
2d - 67%[a]
2a - 80%
2b - 76%
2c - 81%
Xantphos-Pd-G4 instead of Pd(OAc)2 and
Xantphos
2
89
OH
CF3
C
OH
CF3
OH
CF3
C
C
Me
CF3 Cl
3
4
Pd(dba)2 instead of Pd(OAc)2
Dppf instead of Xantphos
DPEPhos instead of Xantphos
MeCN instead of DMF
Dioxane instead of DMF
CsF instead of KF
0
CF3
CF3
N
76
83
38
0
MeO
NC
MeO
O
5
2e - 79%[a]
2f - 80%[a]
2g - 71%[a]
6
66%[a,b]
OH
OH
OH
OH
CF3
CF3
CF3
7
CF3
CF3
CF3
CF3
C
C
C
C
N
CF3
8
47
0
N
N
N
N
9
[Me4N]F instead of KF
KF (2.1 equiv)
Me
2h - 89%
2i - 79%[a]
2j - 72%[a]
2k - 81%[a]
10
11
12
13
14
83
0
OH
OH
CF3
C
No KF
CF3
CF3
C
OH
F
CF3
CF3
CF3
Me
N
Me
TESCF3 instead of TMSCF3
TMSCF3 (2.05 equiv)
TMSCF3 (1.0 equiv)
74
77
22
C
N
F
S
Me
2l - 74%[a,c]
(1.25 g)
Me
2m - 82%[a]
2n - 34%[a]
[a] All reactions were performed in a two-chamber setup. CO was released
from a solid precursor in one chamber; see Supporting Information for full
details. [b] Yields determined by 1H-NMR using 1,3,5-trimethoxybenzene as
internal standard. [c] Isolated yield. The carboxylic acid was observed as the
major side-product.
OH
CF3
OH
OH
CF3
C
CF3
CF3
OH
C
C
CF3
CF3
C
CF3
O
CF3
O
HO
CF3
2o - 55%[a,d]
2r - 82%[a]
2q - 73%[a,e]
Ph
2p - 74%[a]
optimized reaction conditions composed of the aryl bromide with
Pd(OAc)2 (3 mol%), Xantphos (4.5 mol%), CO (1.2 equiv), and KF
(3.5 equiv), heated in DMF for 18 h, followed by the addition of
Ruppert’s reagent at room temperature in a one-pot fashion. We
suspect the reaction initially generates an acyl halide
intermediate,[13] which subsequently reacts with TMSCF3.
41%[a,f]
OH
CF3
OH
CF3
*
C
*
C
OH
C
OH
CF3
O
O
N
O
CF3
F3C
F3C
CF3
CF3
C
S
Ph
Ph
N
Me
N
CF3
T0901317 (2u) - 70%[a]
13C-T0901317 (2u) - 74%[a]
Liver X-receptor agonist
2t - 77%[a]
13C-2t - 78%[a]
Hepatitis C virus inhibitor
2s - 50%[a,g]
Performing the carbonylative coupling with the Xantphos-Pd-
G4 precatalyst[14] instead of Pd(OAc)2 provided a similar reaction
outcome (entry 2). In contrast, no conversion was observed with
Pd(dba)2, and the starting material 1a was fully recovered (entry
3). Substituting Xantphos with other bidentate phosphine ligands
resulted in a slightly lower yield (entries 4 and 5). Next, several
other solvents were screened, however, they provided moderate
to no conversion of the model substrate 1a (entries 6 and 7).
Optimization of the fluoride source revealed that CsF and n-
Bu4NF were inferior to KF. When the amount of KF was lowered
to 2.1 equiv., a slight decrease in yield was observed. In the
absence of a fluoride source, no product was formed, and the
starting material was fully recovered (entries 8–11), whereas
replacement of Ruppert’s reagent with TESCF3 led to a drop in
yield (entry 12). Conducting the Pd-catalyzed carbonylative
coupling in the presence of TMSCF3 had a detrimental effect on
the reaction outcome, as only starting material could be recovered
(results not shown). The Marshall group has previously reported
that the CF3-anion can interchange with Xantphos on the metal
center possibly exerting a hampering effect in the catalytic
cycle.[15] Efforts to lower the amount of Ruppert’s reagent,
provided only lower conversions to 2a (entries 13 and 14).
Noteworthy, in the presence of one equivalent of TMSCF3, a
mixture of p-methoxy trifluoroacetophenone and a,a-
bis(trifluoromethyl)carbinol 2a was observed, indicating that
Scheme 2. Scope of aryl bromides. All reactions were performed in a two-
chamber setup. CO was released from a solid precursor in one chamber (see
Supporting Information for full details). Yields are isolated and are the average
of duplicates. [a] 1.5 equiv of KF were initially added, followed by 2.5 equiv of
KF after the carbonylation step. [b] Reaction performed on the corresponding
Ar-Cl at 120 oC. [c] Reaction performed on a 5.0 mmol scale. [d] Starting from
5-bromophthalide using 3.2 equiv of TMSCF3. [e] From an approx. 4:1 mixture
of (E)- and (Z)-bromostyrene. [f] From (Z)-bromostyrene. [g] The reaction was
performed with 0.3 mmol of the aryl dibromide and 4.4 equiv of TMSCF3.
selective formation of the trifluoroacetophenone could not be
achieved under the applied reaction conditions. Finally, we
observed that performing the reaction with a balloon of CO
instead only led to a 6% yield of 2a.16
With the optimized conditions in hand, we commenced an
investigation on the generality of this transformation (Scheme 2).
Initially, it was established that aryl bromides containing either
only electron rich (2a–2c) or electron poor (2e and 2f) substituents
could be efficiently transformed into the corresponding a,a-
bis(trifluoromethyl)carbinols in high yields. The effect of o-
substituents was not detrimental for the outcome of the reaction
as shown for 2c. At this point, a beneficial effect of splitting the
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10.1002/anie.201802647
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COMMUNICATION
addition of KF was observed. This ensured that fluoride is present
to activate Ruppert’s reagent upon its addition. As shown with
compounds 2g and 2m, halide substituents including chloride or
fluoride were well tolerated, with the former representing a useful
handle for possible post-functionalization of the carbinol product.
Heteroaromatic bromides including pyridine, indole, pyrimidine,
quinoline and benzothiophene were also applicable for the
synthesis of a,a-bis(trifluoromethyl)carbinols (2h–2k, 2n and 2s).
Even heterocycles as substituents or fused to the benzene ring
were tolerated as exemplified by compounds 2l, 2m, 2o and 2p.
Further adaptation to a gram scale synthesis was shown for the
pyrrole substituted compound 2l. Addition of a third trifluoromethyl
group was observed with 5-bromophthalide involving the lactone
carbonyl group to give 2o. Both cis- and trans-bromostyrene were
found to be viable substrates for this carbonylative coupling.
Interestingly, the two stereoisomers led to the same trans-product
2q in 73% and 41% isolated yields, resp.17 An internal alkyne was
tolerated under the applied reaction conditions as illustrated with
2r. Finally, an activated aryl chloride was attempted, providing the
corresponding bis(trifluoromethyl)carbinol 2e in a 66% yield,
though with a reaction temperature of 120 oC.
of two bioactive molecules, including late-stage 13C-isotopic
labeling.[12a] As such, the hepatitis C virus inhibitor 2t was
synthesized in two steps from 4-bromo-N-methylaniline with a
77% yield for the carbinol formation. Similarly, the liver X-receptor
agonist T0901317 (2u) could be prepared in only three steps from
4-bromoaniline under mild reaction conditions. Importantly, a 13C-
isotope label could be introduced in the last step in similar yields
as for their unlabeled counterparts applying 13C-COgen.[11a,12]
Aryl fluorosulfates are easily prepared from phenols and have
gained increased interest either as a robust connector in SuFEx
click chemistry or as
a
leaving group.[19–21] We therefore
investigated the possible application of these electrophilic
substrates for the synthesis of aryl a,a-bis(trifluoromethyl)-
carbinols. Initially, the aryl fluorosulfates were prepared from the
corresponding phenols according to a recent procedure relying on
the ex-situ generation of gaseous sulfuryl fluoride in the two-
chamber set-up, COware.[21a] As depicted in Scheme 3, these
electrophiles proved to be well-suited for the catalytic protocol
providing the bis(trifluoromethyl)carbinols in good yield as shown
for the introduction of one carbinol unit with products 2b, 2v–2z,
2ac and 2ad, and two units with 2aa and 2ab. Interestingly, some
double bond migration was observed for the allylic benzene 2x.17
Finally, the bis(trifluoromethyl)carbinol obtained from estrone
could easily be prepared with specific incorporation of a carbon-
13 label (13C-2z).
Our methodology could be adapted to the efficient preparation
OH
SO2F2 (1.5 equiv)
R
Et3N (2.0 equiv)
CH2Cl2, rt, 18 h
3
a) CO (1.2 equiv)
*
ref. [19a]
To conclude, additional experiments were performed to
examine the comparative reactivity of aryl bromides and the
fluorosulfates in the Pd-mediated carbonylation step. As can be
Pd(OAc)2 (3 mol%)
Xantphos (4.5 mol%)
KF (1.5 equiv)
OH
CF3
OSO2F
C
*
DMF, 80 °C, 18 h
CF3
R
R
b) TMSCF3 (2.2 equiv)
KF (2.5 equiv), rt, 1 h
a)
OH
a) CO (1.0 equiv)
KF (1.0 equiv)
Pd(OAc)2 (3 mol%)
Xantphos (4.5 mol%)
DMF, 80 °C, Rxn time
4 - 0.6 mmol
2
Br
CF3
C
CF3
OH
CF3
C
OH
CF3
OH
CF3
C
2b
CF3
CF3
C
1b (1 equiv)
4b (1 equiv)
CF3
O
S
Time: 1 h. 18 h.
1b[%][b]: 98. 86.
4b[%][b]: 26. 10.
2b[%][b]: 68. 79.
OSO2F
b) TMSCF3 (2.2 equiv)
KF (2.5 equiv)
rt, 1 h
Me
O
2b - 82%
OMe OH
2v - 59%
2w - 81%
OH
OMe OH
CF3
CF3
CF3
C
C
C
CF3
+
CF3
CF3
b)
Me
a) CO (1.2 equiv)
Pd(OAc)2 (3 mol%)
Xantphos (4.5 mol%)
KF (1.5 equiv)
OH
CF2CF3
Br
C
CF2CF3
Me
2x - 84% (1:1.5)
F3C
2y - 77%
OH
F3C
C
N
N
DMF, 80 °C, 18 h
OH
CF3
b) TMSCF2CF3 (2.2 equiv)
KF (2.5 equiv), rt, 1 h
OH
CF3
*
C
Me
1l - 0.6 mmol
Me
5 - 83%
CF3
H
C
H
CF3
H
c)
O
CsF (9 mol%)
(PhMe2Si)2 (0.9 mmol)
2z - 72%[a]
Me
O
13C-2z - 72%[a]
CO2
O
2aa - 52%[b]
DMSO, rt
ref. [20]
1.02 mmol
HO CF3
CF3
OH
CF3
HO CF3
CF3
a) CO
OH
C
C
C
C
CF3
CF3
Pd(OAc)2 (3 mol%)
Xantphos (4.5 mol%)
KF (1.5 equiv)
OSO2F
F3C
HO
CF3
H
H
H
O
H
HO
F3C
F3C
N
DMF, 80 °C, 18 h
H
nBu
2ad - 71%[a]
H
C
Cl
2ac - 46%
Me
Me
b) TMSCF3 (2.2 equiv)
KF (2.5 equiv), rt, 1 h
O
Me
O
Me
O
2ab - 67%[b]
1z
- 0.6 mmol
2z - 68%
F3C
Scheme 4. Additional experiments with aryl bromides and aryl fluorosulfates. a)
Competition experiments between aryl bromide 1b and aryl fluorosulfate 4b.[a,b]
b) An example with pentafluoroethyltrimethylsilane.[a] c) An application with CO2
as the CO source. [a] Reaction was performed in a two-chamber setup. CO was
released from a solid precursor in one chamber (see Supporting information for
full details). [b] Yields determined by GC using dodecane as internal standard.
Scheme 3. Scope of aryl fluorosulfates. All reactions were performed in a two-
chamber setup. CO was released from a solid precursor in one chamber (see
Supporting Information for full details). Yields are isolated and are the average
of duplicates. [a] 3.2 equiv of TMSCF3 was used. [b] The reaction was performed
with 0.3 mmol of the aryl fluorosulfate and 4.4 equiv of TMSCF3.
This article is protected by copyright. All rights reserved.

10.1002/anie.201802647
Angewandte Chemie International Edition
COMMUNICATION
[4]
[5]
a) P. E. Cassidy, T. M. Aminabhavi, V. S. Reddy, J. W. Fitch, Eur. Polym.
J. 1995, 31, 353. b) J. W. Fitch, E. Bucio, L. Martinez, J. Macossay, S. R.
Venumbaka, N. Dean, D. Stoakley, P. E. Cassidy, Polymer. 2003, 44,
6431. c) J. R. Griffith, J. G. O’rear, Highly fluorinated diglycidyl ethers,
1975, US3879430. M. Miyasaka, N. Koike, Y. Fujiwara, H. Kudo, T.
Nishikubo, Polym. J. 2011, 43, 325.
seen in Scheme 4a with 1b and 4b in equal amounts, the napthyl
fluorosulfate proved to be substantially more reactive in the
transformation to the bis(trifluoromethyl)carbinol 2b. In a second
experiment, we demonstrated that pentafluoroethyltrimethyl-
silane can be exploited for the generation of the
bis(pentafluoroethyl)carbinols as illustrated in the transformation
of 1l to 5 in a satisfactory yield of 83% (Scheme 4b). Lastly, this
protocol could be coupled up to the efficient disilane-mediated
reduction of CO2 to carbon monoxide for the conversion of the
estronyl fluorosulfate 1y to the corresponding bis(trifluoromethyl)-
carbinol 2z in a 68% yield (Scheme 4c).22
a) S. Morikawa, K. Michigami, H. Amii, Org. Lett. 2010, 12, 2520. b) M.
E. O’Reilly, I. Ghiviriga, K. A. Abboud, A. S. Veige, J. Am. Chem. Soc.
2012, 134, 11185. c) L. Ratjen, M. van Gemmeren, F. Pesciaioli, B. List,
Angew. Chem. Int. Ed. 2014, 53, 8765.
[6]
[7]
[8]
a) L. Kong, J. Wang, X. Fu, Y. Zhong, F. Meng, T. Luo, J. Liu, Carbon
2010, 48, 1262. b) L. Kong, J. Wang, T. Luo, F. Meng, X. Chen, M. Li, J.
Liu, Analyst 2010, 135, 368.
a) H. Lenormand, V. Corcé, G. Sorin, C. Chhun, L.-M. Chamoreau, L.
Krim, E.-L. Zins, J.-P. Goddard, L. Fensterbank, J. Org. Chem. 2015, 80,
3280. b) E. F. Perozzi, J. C. Martin, J. Am. Chem. Soc. 1979, 101, 1591.
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b) J. Sepio, R. L. Soulen, J. Fluorine Chem. 1984, 24, 61. c) T. J.
Barbarich, B. G. Nolan, S. Tsujioka, S. M. Miller, O. P. Anderson, S. H.
Strauss, J. Fluorine Chem. 2001, 112, 335.
In summary, an efficient procedure for the direct formation of
(hetero)aryl
a,a-bis(trifluoromethyl)carbinols
from
the
corresponding (hetero)aryl bromides and fluorosulfates has been
demonstrated relying on Pd-mediated carbonylation with
stoichiometric
amounts
of
carbon
monoxide
and
trifluoromethyltrimethylsilane. Particularly noteworthy with this
protocol is its ease in operation, but also its suitability even in the
presence of a wide range of other functional groups. This
chemistry will undoubtedly allow for the rapid introduction of the
[9]
a) L. A. Babadzhanova, N. V. Kirij, Y. L. Yagupolskii, W. Tyrra, D.
Naumann, Tetrahedron 2005, 61, 1813. Y. Chang, C. Cai, J. Fluorine
Chem. 2005, 126, 937. b) I. A. Sanhueza, K. J. Bonney, M. C. Nielsen,
F. Schoenebeck, J. Org. Chem. 2013, 78, 7749. c) Y. Zhang, M. Fujiu,
H. Serizawa, K. Mikami, J. Fluorine Chem. 2013, 156, 367. J. B. Geri, M.
M. Wade Wolfe, N. K. Szymczak, Angew. Chem. Int. Ed. 2018, 57, 1381.
bis(trifluoromethyl)carbinol unit into
pharmaceutically relevant molecules.
a
wide variety of
[10] The time-weighted average exposure limit for hexafluoroacetone has
been set to 0.1 ppm by the US National Institute for Occupational Safety
and Health. For CO, the time-weighted average exposure limit is 35 ppm.
[11] a) P. Hermange, A. T. Lindhardt, R. H. Taaning, K. Bjerglund, D. Lupp,
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Acknowledgments
We are deeply appreciative of generous financial support from the
Danish National Research Foundation (grant no. DNRF118), and
Aarhus University. C.V. thanks FWO Vlaanderen and the King
Baudouin Foundation acting on behalf of the Platform for
Education and Talent for fellowships received.
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Keywords: • carbonylation • aryl bromides • palladium •
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carbonylative cross couplings due to a lower CO partial pressure
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accounting for these isomerizations.
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10.1002/anie.201802647
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COMMUNICATION
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10.1002/anie.201802647
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COMMUNICATION
Katrine Domino+, Cedrick Veryser+,
Benjamin A. Wahlqvist, Cecilie Gaardbo,
Karoline T. Neumann, Kim Daasbjerg,
Wim M. De Borggraeve, Troels
Skrydstrup*
OH
CF3
OH
CF3
13C
OH
F
C
CF3
CF3
H
1) *CO, F
Pd cat.
CF
Me
3 H
*
C
CF3
(Het)
Ar
(Het)
Ar
R
R
N
H
2) Ruppert's
Reagent
= Br, OSO2F
F
30 examples
Me
Me
O
Page No. – Page No.
Direct approach
Good yields
Broad scope
Late-stage isotope labeling
Direct Access to Aryl
Bis(trifluoromethyl)carbinols from
Aryl Bromides or Fluorosulfates via a
Pd-Catalyzed Carbonylation
6 Fluorines are better than 3: The titled reaction allows for the direct synthesis
of aryl bis(trifluoromethyl)carbinols from aryl bromides and fluorosulfates with
stoichiometric carbon monoxide and two equivalents of trifluoromethyl-
trimethylsilane. The method exhibits good functional group tolerance and is
suitable for carbon isotope labeling.
This article is protected by copyright. All rights reserved.