Nickel-Catalyzed N-Arylation of Fluoroalkylamines

Article abstract of DOI:10.1002/anie.202014340

The Ni-catalyzed N-arylation of β-fluoroalkylamines with broad scope is reported for the first time. Use of the air-stable pre-catalyst (PAd2-DalPhos)Ni(o-tol)Cl allows for reactions to be conducted at room temperature (25 °C, NaOtBu), or by use of a comm

Full text of DOI:10.1002/anie.202014340

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Accepted Article
Title: Nickel-Catalyzed N-Arylation of Fluoroalkylamines
Authors: Ryan McGuire, Arun Yadav, and Mark Stradiotto
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Nickel-Catalyzed N-Arylation of Fluoroalkylamines
Ryan T. McGuire,[a] Arun A. Yadav,[b] and Mark Stradiotto*,[a]
Abstract: The Ni-catalyzed N-arylation of -fluoroalkylamines with
broad scope is reported for the first time. Use of the air-stable pre-
catalyst (PAd2-DalPhos)Ni(o-tol)Cl allows for reactions to be
conducted at room temperature (25 ºC, NaOtBu), or by use of a
commercially available dual-base system (100 ºC, DBU/NaOTf), to
circumvent decomposition of the N-(-fluoroalkyl)aniline product.
The mild protocols disclosed herein feature broad (hetero)aryl
(pseudo)halide scope (X = Cl, Br, I, and for the first time phenol
derived electrophiles), encompassing base sensitive substrates and
enantioretentive transformations, in a manner that is unmatched by
any previously reported catalyst system.
The introduction of fluorinated substituents is an effective
strategy for controlling the adsorption, distribution, metabolism,
and excretion of active pharmaceutical ingredients (APIs), as
Figure 1. Metal-catalyzed N-arylation of fluoroalkylamines with (hetero)aryl
well as engendering desirable performance profiles in
agrochemicals.[1] In the case of -fluoroalkylamino groups, the
altered conformational preferences, acid-base properties, and
hydrogen-bonding abilities arising from the included fluorine
atoms allows such fragments to serve as bioisosteres for
biologically important amide, sulfonamide, and related
(pseudo)halides.
transformations involving -fluoroalkylamine nucleophiles have
proven challenging, in some cases leading to catalyst inhibition.[9]
The first cross-coupling of this type demonstrating useful scope
was reported in 2015 by Brusoe and Hartwig (Figure 1),[10] in
which an optimized Pd catalyst system allowed for the cross-
coupling of -fluoroalkylamines with (hetero)aryl chlorides and
bromides. The use of KOPh, while non-ideal as this reagent is
unavailable from common chemical suppliers and generated
HOPh as a difficult-to-remove by-product, proved critical to the
success of this chemistry; stronger bases including LiHMDS or
MOtBu (M = Na or K) were shown to decompose the desired N-
(-fluoroalkyl)aniline product under the conditions (100 ºC)
required to effect catalytic turnover. The first copper-catalyzed C-
N cross-coupling of -fluoroalkylamines was disclosed by Hu and
co-workers in 2019 (Figure 1).[11] Although the use of an
inexpensive and Earth-abundant base-metal Cu catalyst and
K2CO3 in this chemistry is attractive,[12] forcing reaction conditions
(110-120 ºC and 5-20 mol% Cu2O) were required, and only
transformations of (hetero)aryl bromides were described.
Notwithstanding these and other[13],[14],[15] isolated reports
detailing the synthesis of N-(-fluoroalkyl)anilines by various
means, important challenges remain with regard to reaction
development. Particularly attractive would be the discovery of a
base-metal catalyst system that could enable C-N cross-
couplings of -fluoroalkylamines with (hetero)aryl chlorides and
phenol derivatives – the two most inexpensive and widely
available[16] (hetero)aryl electrophile classes. Notably, such
reactions of phenol-derived electrophiles involving any catalyst
system are unknown. Given the sensitivity of the targeted N-(-
fluoroalkyl)anilines toward strong base upon heating,[10] and the
low boiling points of many -fluoroalkylamine reagents (e.g.,
CF3CH2NH2, 37 ºC), an optimal catalyst system would operate at
room temperature and/or in combination with mild, commercially
available bases. Herein we report on the establishment of such a
system, which makes use of a simple, bisphosphine-ligated Ni
pre-catalyst (Figure 1).
functionalities,
properties.[2]
while
offering
distinct
physicochemical
A
recently disclosed small molecule (Gilead
Sciences, GS-6207) that functions as a long-acting therapy for the
treatment of HIV highlights the benefits of incorporating the -
fluoroalkylamino motif in API design.[3]
In this context, and given the prevalence of substituted
anilines in top-selling pharmaceuticals and agrochemicals,[1] it is
surprising that such commercial bioactive molecules featuring the
N-(-fluoroalkyl)aniline substructure are uncommon. One
contributing factor is that the assembly of N-(-fluoroalkyl)anilines
by convenient disconnection strategies, such as exploiting
(hetero)aryl (pseudo)halide and -fluoroalkylamine substrates, is
challenging in comparison to analogous reactions involving
simple alkylamines.[4] For example, in a report from Francotte and
co-workers,[5] SNAr chemistry involving CF3CH2NH2 is shown to
require the combination of an electron-poor chloroarene, as well
as forcing conditions (160 ºC, 50 h), to afford the desired N-(-
fluoroalkyl)aniline, in keeping with established reactivity trends.[6]
Despite the broad utility of metal-catalyzed Ullmann-Goldberg
(Cu[7]) and Buchwald-Hartwig (Pd[8]) C-N cross-couplings, such
[a]
[b]
R. T. McGuire, Prof. Dr. M. Stradiotto
Department of Chemistry
Dalhousie University
Halifax, Nova Scotia B3H 4R2 (Canada)
E-mail: mark.stradiotto@dal.ca
Dr. A. A. Yadav
Paraza Pharma, Inc.
2525 Avenue Marie-Curie
Montreal, Quebec, H4S 2E1 (Canada)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.202YXXXXX.
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In the quest to identify a base-metal catalyst system that
could facilitate the room temperature N-arylation of -
fluoroalkylamines, we initiated a screening campaign employing
air-stable (DalPhos)Ni(o-tol)Cl[17] pre-catalysts, with a focus
initially on reactions employing (hetero)aryl chlorides (Figure 2).
These pre-catalysts were chosen on the basis of their established
utility in enabling otherwise challenging C-N cross-couplings of
electronically diverse nucleophile/electrophile pairings, including
in many cases at room temperature with performance that meets
or exceeds that of other superlative catalyst systems (e.g., Pd,
Cu, Ni, and other). In positing that reactions conducted at room
temperature might allow for the use of NaOtBu without inducing
decomposition of the N-(-fluoroalkyl)aniline product,[18] we
examined C-N cross-couplings of 2,2-difluoroethylamine with
electron-rich, heteroaryl, and sterically hindered aryl chlorides,
leading to 1a-1c (Figure 2). Most of these pre-catalysts performed
poorly, as did (DPPF)Ni(o-tol)Cl,[19] which is used widely in Ni-
catalyzed C-N cross-coupling.[17f, 20] While pre-catalysts based on
PAd-DalPhos and Phen-DalPhos performed well with selected
electrophiles, only (PAd2-DalPhos)Ni(o-tol)Cl[17g],[21] afforded
>75% conversion to each of 1a-1c under the conditions
employed. In turn, these products were obtained in synthetically
useful isolated yields.[22] Throughout, no competing C-O cross-
Figure 3. Scope of Ni-catalyzed N-arylation of fluoroalkylamines using
NaOtBu at room temperature. Unless indicated otherwise, isolated yields are
reported from reactions conducted on 0.48 mmol scale (aryl halide, 0.24 M in
toluene), with NaOtBu (1.1 equiv; 2.3 equiv when using the HCl salt shown)
and fluoroalkylamine (1.2 equiv) for 18 h (unoptimized). [a] Yield determined
on the basis of response-factor calibrated GC data using authentic material.
[b] Using 3.0 equiv amine. [c] Amine delivered as the HCl salt, and 2.3 equiv
NaOtBu used. [d] Conducted at 65 ºC. [e] Using (DPPF)Ni(o-tol)Cl. [f] For 2d
we were unable to obtain sufficient resolution of the racemate under a range
of HPLC conditions so as to allow unequivocal determination of
enantioretentivity when using enantioenriched amine.
Figure 2. Pre-catalyst screen for the Ni-catalyzed N-arylation of fluoroal-
kylamines. Reactions were conducted at 0.12 mmol scale (aryl halide, 0.24
M in toluene), with NaOtBu (1.1 equiv), and 2,2-difluoroethylamine (1.2
equiv) for 18 h (unoptimized). Reported GC yields determined on the basis
of response-factor calibrated GC data using authentic material, with the
mass balance corresponding to unreacted starting material. [a] Isolated
yield. [b] Using 3 mol% Ni. [c] Volatile product.
optimized on a per-substrate basis, and the amount needed to
conveniently achieve high conversion to product is indicated in
Figure 3 (typically 1-3 mol% Ni). While such loadings are higher
than those employed with the AdBippyPhos/Pd system,[10] use of
the base-metal Ni herein rather than Pd, under room temperature
conditions employing commercially available NaOtBu offers
distinct reactivity advantages, including enabling the use of
sulfonate electrophiles (leading to 1d and 1s-1u) not described
previously in the literature for -fluoroalkylamine C-N cross-
coupling products arising from NaOtBu were observed.[23]
The success of (PAd2-DalPhos)Ni(o-tol)Cl in enabling
these room temperature reactions provided motivation for a more
detailed exploration of substrate scope (Figure 3). The successful
cross-coupling of 2,2-difluoroethylamine with 1-X-naphthalene
electrophiles (X = Cl, Br, I, OTs, OTf) leading to 1d established
that a range of halide and sulfonate coupling partners can be used
under these conditions. Catalyst loading was not exhaustively
couplings.
When
examining
transformations
of
1-
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chloronaphthalene in detail, high isolated yields of 1d were
obtained when using 0.5 mol% Ni (0.48 mmol ArCl, 86%),
including in reactions where the scale was increased ten-fold (4.8
mmol ArCl, 90%). Moreover, while for convenience 18 h reaction
times were employed generally, careful monitoring of such
reactions revealed that >95% conversion to 1d was achieved after
only 0.5 h (0.5 mol% Ni). Synthetically useful conversion to 1d
was also achieved at both 0.25 mol% (89%) and 0.1 mol% (54%)
Ni loading levels. Taken together, these observations suggest
that the use of < 0.5 mol% Ni loadings and short reaction times
can be employed with some substrate pairings in this room
temperature chemistry.
reactive phenol-derived electrophiles), we selected the ‘dual-
base’
DBU/NaOTf
system[24a]
(DBU
=
1,8-
diazabicyclo(5.4.0)undec-7-ene) to test in C-N cross-couplings of
2,2-difluoroethylamine using (PAd2-DalPhos)Ni(o-tol)Cl as a
pre-catalyst (Figure 4A). We were pleased to find that at elevated
temperature (100 ºC) this protocol allowed for such cross-
couplings to be achieved with otherwise base-sensitive aryl
chloride or phenol-derived electrophiles bearing aldehyde,
ketone, or ester functionality, leading to the desired N-(-
fluoroalkyl)anilines (1d, 3a-3e).[26] The reported cross-couplings
in Figure 4A embody new and useful features that are worthy of
mention with regard to the use of an amine base, including: the
first examples of thermally promoted Ni-catalyzed C-N cross-
couplings of non-triflate electrophiles; and the first C-N cross-
couplings of aryl mesylate and sulfamate electrophiles by use of
any metal catalyst.
The entries presented in Figures 2 and 3 demonstrate that
a range of linear primary -fluoroalkylamines can be efficiently
cross-coupled with (hetero)aryl (pseudo)halides at room
temperature
using
(PAd2-DalPhos)Ni(o-tol)Cl,
including
electron-rich and electron-poor electrophiles, and those featuring
ortho-substitution (1c, 1e, 1o, 2d). Heterocyclic electrophiles
based on pyridine (1b, 1e, 2a), quinoline (1f), benzothiophene
(1i), benzothiazole (1j), quinaldine (1k, 1r), and quinoxaline (1p)
core structures also proved to be suitable substrates under these
room temperature conditions. Conversely, five-membered
heteroaryl electrophiles were not employed with success in this
chemistry. The chemoselective cross-coupling of N-methyl-3-
chloroaniline with a cyclobutane-derived -fluoroalkylamine to
give 1q, as well as the successful cross-coupling of 3,3,3-
trifluoropropylamine leading to 1r, establishes the viability of using
such -fluoroalkylamines in this chemistry.
Cross-couplings
using
1,1,1-trifluoro-2-propanamine
established the ability of (PAd2-DalPhos)Ni(o-tol)Cl to effect
reactions involving branched primary -fluoroalkylamines (Figure
3). Such reactions proceeded successfully with electron-rich,
electron-poor, ortho-substituted, and heterocyclic aryl chlorides,
leading to 2a-2d, in a manner that did not lead to detectable
racemization when using the enantioenriched nucleophile (er
>99:1). While efforts to extend such reactions to 2-
(trifluoromethyl)pyrrolidine were unsuccessful with (PAd2-
DalPhos)Ni(o-tol)Cl, a test cross-coupling of this type using
(DPPF)Ni(o-tol)Cl at 65 ºC proceeded efficiently (2e).
Although methoxy (1a, 1m, 1o, 1t, 2b), nitrile (1l, 2c), fluoro
(1m), boronic acid (1n), and secondary amine (1q) substitution on
the aryl electrophile did not prove problematic in this chemistry,
some limitations were encountered when we attempted to employ
electrophiles featuring base-sensitive functionalities (including
aldehydes, ketones, and esters) in Ni-catalyzed cross-couplings
of 2,2-difluoroethylamine with NaOtBu, even under room
temperature conditions. In all such cases, complex reaction
mixtures were obtained, which we attribute in part to degradation
of the electrophile. To circumvent such issues, we sought to
identify a complementary protocol that makes use of a more mild
organic amine base, as has been developed lately for use in Pd-
Figure 4. Ni-catalyzed cross-coupling of base-sensitive electrophiles
employing the DBU/NaOTf dual-base mixture, and competition studies.
Unless indicated otherwise, isolated yields are reported from reactions
conducted on 0.48 mmol scale (aryl halide, 0.24 M in toluene), with DBU and
catalyzed C-N cross-coupling, including with (hetero)aryl
24]
chlorides.[18a,
While Buchwald and co-workers recently
NaOTf (2.0 equiv each) and fluoroalkylamine (2.0 equiv) for 18
h
disclosed the first Ni-catalyzed C-N cross-couplings that make
use of such a base (NEt3) without recourse to microwave,
photoredox, or electrochemical protocols and/or use of
exogenous reductants, the reported transformations are restricted
to reactions of (hetero)aryl triflates and anilines.[25] Given our
interest in cross-couplings of aryl chlorides (as well as less
(unoptimized). [a] Yield determined on the basis of response-factor calibrated
GC data using authentic material.
To gain insights into the reactivity preferences of the (PAd2-
DalPhos)Ni(o-tol)Cl pre-catalyst in room temperature cross-
couplings of -fluoroalkylamines employing NaOtBu, a selection
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[1]
(a) K. Muller, C. Faeh, F. Diederich, Science 2007, 317, 1881-1886; (b)
T. Fujiwara, D. O'Hagan, J. Fluorine Chem. 2014, 167, 16-29; (c) Y. Zhou,
J. Wang, Z. N. Gu, S. N. Wang, W. Zhu, J. L. Acena, V. A. Soloshonok,
K. Izawa, H. Liu, Chem. Rev. 2016, 116, 422-518; (d) H. B. Mei, J. L.
Han, S. Fustero, M. Medio-Simon, D. M. Sedgwick, C. Santi, R.
Ruzziconi, V. A. Soloshonok, Chem. Eur. J. 2019, 25, 11797-11819.
N. A. Meanwell, J. Med. Chem. 2018, 61, 5822-5880.
of competition studies were conducted. While (hetero)aryl
chlorides, bromides, and phenol derivatives such as tosylates
each independently proved to be viable electrophiles in this
chemistry (Figure 3), the competition results presented in Figure
4B establish the Cl > Br > OTs reactivity trend in sterically and
electronically similar substrates. In a complementary competition
employing the heteroatom-containing nucleophiles 2,2-
difluoroethylamine, furfurylamine, and 2-aminopyridine with 1-
chloronaphthalene, preferential formation of the pyridine-derived
aniline product (B) over both the alkylamine (A) and the -
fluoroalkylamine (1d) derivatives was noted. The 1d:A ratio
(1.3:1) indicated a modest preference for the fluorinated versus
the non-fluorinated alkylamine nucleophile (Figure 4C), in
contrast to competition studies reported by Hu and co-workers
focusing on Cu-catalyzed C-N cross-coupling of an aryl bromide,
whereby the alkylamine was preferred (3.1:1) over the -
fluoroalkylamine.[11] The competitive formation of 1d and A herein
also contrasts the results of studies focusing on the
AdBippyPhos/Pd system, in which p-toluidine and n-butylamine
nucleophiles were cross-coupled preferentially, with no
conversion of the contending pentafluoropropylamine.[10] While
many factors are likely to contribute to our observed selectivity,
the favorable nature of 2-aminopyridine as a nucleophile in C-N
cross-couplings employing (PAd2-DalPhos)Ni(o-tol)Cl was noted
in our previous studies.[17g]
[2]
[3]
J. O. Link, M. S. Rhee, W. C. Tse, J. Zheng, J. R. Somoza, W. Rowe, R.
Begley, A. Chiu, A. Mulato, D. Hansen, E. Singer, L. K. Tsai, R. A. Bam,
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Chem. Int. Ed. 2017, 56, 16136-16179.
In
summary,
the
Ni-catalyzed
N-arylation
of
fluoroalkylamines is reported, spanning an unprecedented range
of coupling partners including (hetero)aryl halides (X = Cl, Br, I),
and for the first time by use of any catalyst system, phenol-derived
(hetero)aryl electrophiles. Use of air-stable (PAd2-DalPhos)Ni(o-
[8]
(a) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534-1544; (b) P. Ruiz-
Castillo, S. L. Buchwald, Chem. Rev. 2016, 116, 12564-12649; (c) R.
Dorel, C. P. Grugel, A. M. Haydl, Angew. Chem. Int. Ed. 2019, 58, 17118-
17129.
tol)Cl as
a pre-catalyst in this chemistry allows for the
[9]
J. L. Henderson, S. L. Buchwald, Org. Lett. 2010, 12, 4442-4445.
implementation of mild reaction conditions (i.e., room temperature
or use of an organic amine base), so as to avoid both degradation
of the N-(-fluoroalkyl)aniline product and/or base-sensitive
substituents, as well as substrate/product racemization. Ongoing
work is focused on expanding our mechanistic understanding of
how the DalPhos ligand family engenders desirable reactivity in
this and related chemistry.[27]
[10] (a) A. T. Brusoe, J. F. Hartwig, J. Am. Chem. Soc. 2015, 137, 8460-8468.
(b) A. T. Brusoe, J. F. Hartwig, PCT Int. Appl. US (2016),
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[11] S. Chen, H. Wang, W. Jiang, P. X. Rui, X. G. Hu, Org. Biomol. Chem.
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[12] J. D. Hayler, D. K. Leahy, E. M. Simmons, Organometallics 2019, 38, 36-
46.
[13] For the Cu-catalyzed N-arylation of -fluoroalkylamines with arylboronic
acids, see: H. Wang, Y.-H. Tu, D.-Y. Liu, X.-G. Hu, Org. Biomol. Chem.
2018, 16, 6634-6637.
[14] For the Cu- or Ag-catalyzed N-trifluoroethylation of anilines and related
substrates with trifluorodiazoalkanes, see: (a) H. Q. Luo, G. J. Wu, Y.
Zhang, J. B. Wang, Angew. Chem. Int. Ed. 2015, 54, 14503-14507; (b)
S. Hyde, J. Veliks, B. Liegault, D. Grassi, M. Taillefer, V. Gouverneur,
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Acknowledgements
We are grateful to the NSERC of Canada (Discovery Grant
RGPIN-2019-04288 and Engage Grant NSERC EGP 542827-19
for M.S.; CGS-D Scholarship for R. T. M.), Paraza Pharma Inc.
(in particular Claudio Sturino and Arshad Siddiqui), the Province
of Nova Scotia (Graduate Scholarship for R. T. M.), and Dalhousie
University for their support of this work. We thank Prof. Alex
Speed, Mr. Xiao Feng, and Ms. Erin Welsh (Dalhousie) for
technical assistance in obtaining HPLC data, as well as Dr.
Michael Lumsden and Mr. Xiao Feng (Dalhousie) for technical
assistance in the acquisition of NMR and MS data.
[15] For mechanistically varied reports appearing since 2015, each featuring
isolated entries involving the formation of N-(-fluoroalkyl)anilines, see:
(a) E. B. Corcoran, M. T. Pirnot, S. S. Lin, S. D. Dreher, D. A. DiRocco,
I. W. Davies, S. L. Buchwald, D. W. C. MacMillan, Science 2016, 353,
279-283; (b) C. A. Malapit, M. Borrell, M. W. Milbauer, C. E. Brigham, M.
S. Sanford, J. Am. Chem. Soc. 2020, 142, 5918-5923; (c) S. U. Dighe, F.
Julia, A. Luridiana, J. J. Douglas, D. Leonori, Nature 2020, 584, 75-81.
[16] For a quantitative analysis regarding the commercial availability of
substituted aryl reagents, see: L. B. Huang, L. K. G. Ackerman, K. Kang,
A. M. Parsons, D. J. Weix, J. Am. Chem. Soc. 2019, 141, 10978-10983.
[17] (a) C. M. Lavoie, P. M. MacQueen, N. L. Rotta-Loria, R. S. Sawatzky, A.
Borzenko, A. J. Chisholm, B. K. V. Hargreaves, R. McDonald, M. J.
Ferguson, M. Stradiotto, Nat. Commun. 2016, 7, 11073; (b) C. M. Lavoie,
P. M. MacQueen, M. Stradiotto, Chem. Eur. J. 2016, 22, 18752-18755;
(c) C. M. Lavoie, R. McDonald, E. R. Johnson, M. Stradiotto, Adv. Synth.
Catal. 2017, 359, 2972-2980; (d) J. P. Tassone, P. M. MacQueen, C. M.
Keywords: amination • cross-coupling • fluoroalkylamine •
ligand design • nickel
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Lavoie, M. J. Ferguson, R. McDonald, M. Stradiotto, ACS Catal. 2017, 7,
6048-6059; (e) A. V. Gatien, C. M. Lavoie, R. N. Bennett, M. J. Ferguson,
R. McDonald, E. R. Johnson, A. W. H. Speed, M. Stradiotto, ACS Catal.
2018, 8, 5328-5339; (f) C. M. Lavoie, M. Stradiotto, ACS Catal. 2018, 8,
7228-7250; (g) J. S. K. Clark, M. J. Ferguson, R. McDonald, M. Stradiotto,
Angew. Chem. Int. Ed. 2019, 58, 6391-6395; (h) R. T. McGuire, J. F. J.
Paffile, Y. Q. Zhou, M. Stradiotto, ACS Catal. 2019, 9, 9292-9297; (i) J.
P. Tassone, E. V. England, P. M. MacQueen, M. J. Ferguson, M.
Stradiotto, Angew. Chem. Int. Ed. 2019, 58, 2485-2489; (j) R. T. McGuire,
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Int. Ed. 2020, 59, 8952-8956.
[18] Single examples of the Pd-catalyzed C-N cross-coupling of 2,2,2-
trifluoroethylamine with activated (hetero)aryl bromides at room
temperature are featured in each of the following reports: (a) J. M. Dennis,
N. A. White, R. Y. Liu, S. L. Buchwald, J. Am. Chem. Soc. 2018, 140,
4721-4725; (b) S. D. McCann, E. C. Reichert, P. L. Arrechea, S. L.
Buchwald, J. Am. Chem. Soc. 2020, 142, 15027-15037.
[19] N. H. Park, G. Teverovskiy, S. L. Buchwald, Org. Lett. 2014, 16, 220-223.
[20] J. S. K. Clark, C. M. Lavoie, P. M. MacQueen, M. J. Ferguson, M.
Stradiotto, Organometallics 2016, 35, 3248-3254.
[21] Both PAd2-DalPhos and (PAd2-DalPhos)Ni(o-tol)Cl are in the process
of being commercialized by MilliporeSigma (product numbers 919551
and 919578, respectively).
[22] In some cases, product volatility resulted in a moderate isolated yield,
despite high conversion to product as determined on the basis of
response factor-calibrated GC data (>85% for all transformations
reported herein), in keeping with observations of Brusoe and Hartwig (ref.
10).
[23] P. M. MacQueen, J. P. Tassone, C. Diaz, M. Stradiotto, J. Am. Chem.
Soc. 2018, 140, 5023-5027.
[24] (a) G. L. Beutner, J. R. Coombs, R. A. Green, B. Inankur, D. Lin, J. Qiu,
F. Roberts, E. M. Simmons, S. R. Wisniewski, Org. Process Res. Dev.
2019, 23, 1529-1537; (b) S. K. Kashani, J. E. Jessiman, S. G. Newman,
Org. Process Res. Dev. 2020, 24, 1948-1954.
[25] R. Y. Liu, J. M. Dennis, S. L. Buchwald, J. Am. Chem. Soc. 2020, 142,
4500-4507.
[26] Efforts to use less expensive sodium trifluoroacetate in place of sodium
triflate resulted in inferior catalytic performance.
[27] The authors declare the following competing financial interests:
Dalhousie University has filed patents on some of the DalPhos ancillary
ligands and derived nickel pre-catalysts used in this work, from which
royalty payments may be derived.
This article is protected by copyright. All rights reserved.

10.1002/anie.202014340
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Ryan T. McGuire, Arun A. Yadav, and
Mark Stradiotto*
Page No. – Page No.
Nickel-Catalyzed N-Arylation of
Fluoroalkylamines
Ni-cely mild: The Ni-catalyzed N-arylation of -fluoroalkylamines is reported. The
mild protocols and broad (hetero)aryl (pseudo)halide scope, encompassing base
sensitive substrates and enantioretentive transformations, is unmatched by any
previously reported catalyst system.
This article is protected by copyright. All rights reserved.