Thorpe–Ingold Effect in Branch-Selective Alkylation of Unactivated Aryl Fluorides

Article abstract of DOI:10.1002/anie.201804479

Presented herein is a general protocol for the alkylation of simple aryl fluorides with unbiased secondary Grignard reagents by means of nickel catalysis. This study revealed a general Thorpe–Ingold effect in the ligand backbone which confers a high degree of selectivity for the secondary carbon center in the C?C coupling event. This protocol is characterized by mild reaction conditions, robustness, and simplicity. Both electron-rich and electron-deficient aryl fluorides are suitable candidates in this transformation. Equally amenable are a variety of heterocycles, permitting the coupling without over alkylation at the electrophilic sites.

Full text of DOI:10.1002/anie.201804479

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Accepted Article
Title: Catalytic Thorpe-Ingold Effect for Branch-Selective Alkylation of
Unactivated Aryl Fluorides
Authors: Matthew J O'Neill, Tim Riesebeck, and Josep Cornella
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804479
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10.1002/anie.201804479
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Catalytic Thorpe-Ingold Effect for Branch-Selective Alkylation of
Unactivated Aryl Fluorides
Matthew J. O’Neill§, Tim Riesebeck§ and Josep Cornella*
Abstract: Herein we present a general protocol for the alkylation of
simple aryl fluorides with unbiased secondary Grignard reagents by
means of Ni catalysis. This study revealed a general Thorpe-Ingold
effect in the ligand backbone which confers a high degree of
selectivity for the secondary position in the C‒C coupling event. This
protocol is characterized by mild conditions, robustness, and
simplicity. Both electron-rich and electron-deficient aryl fluorides are
suitable candidates in this transformation. Equally amenable are a
variety of heterocycles, permitting the coupling without over
alkylation at the electrophilic sites.
While C‒F bonds can indeed be privileged structures, conferring
distinct electronic profiles that modulate ADME (Absorption,
Distribution, Metabolism and Excretion) effects and other desirable
properties, such benefits are usually desired in the context of large,
complex molecules.[8] In contrast, simple, unactivated aryl fluorides
are largely available and in some cases, less expensive than the
corresponding chloride congeners.[9,10] In contrast to other respective
halides, C‒F bonds are extremely strong and unreactive (BDE: 127
kcal/mol), and only highly nucleophilic transition metals are capable
of functionalizing them.[11] This further complicates reaction
development, as highly electron rich metal complexes in conjunction
with nucleophilic organometallics favors the unproductive reaction
pathways (β-hydride elimination and isomerization). Hence, a fine
balance needs to be struck to accommodate a highly nucleophilic
catalyst which favors coupling in the absence of isomerization
events.
The formation of C(sp2)‒C(sp3) connections through cross-coupling
of aryl halides and alkyl nucleophiles are of increasing importance in
contemporary chemistry, as the proliferation of methods to form
C(sp2)‒C(sp2) bonds has led to an oversaturation of ‘flat’ molecular
modalities.[1] In order to facilitate an increase in obtainable, complex
chemical space, the development of effective C(sp2)‒C(sp3)
couplings is highly desirable. Whereas tremendous advances have
occurred when tertiary and secondary halides are used,[2] less
attention has been placed on the homologous reaction with
secondary and tertiary nucleophiles.[3] The primary confounding
factor in the development of these transformations is observed
clearly in the currently proposed mechanism (Figure 1). Depending
on the relative rates of β-hydride elimination and reductive
elimination from crucial intermediate II, two degenerate products can
arise from unproductive pathways. Despite these difficulties, efficient
and highly selective transition metal-catalyzed protocols have been
developed utilizing aryl (pseudo)halides and branched nucleophiles.
Generally, these protocols rely on the use of highly electron-rich and
sterically congested ligands around the metal center to promote
reductive elimination, thus enhancing selectivity.[4-6] Though classic
cross-coupling focused on the use of traditional electrophiles, recent
years have witnessed elegant expansions of viable candidates, with
much emphasis on the activation of C‒F bonds as a particularly
compelling area. This has challenged the notion of C‒F bonds as
elusive products rather than tractable starting materials[7]
Figure 2. (A) Kumada’s seminal work. (B) Thorpe-Ingold effect in octahedral
complexes. (C) Optimization of the ligand backbone. Anions in the Ni
complexes are omitted for clarity.a Angles measured from X-ray structures of
b
the corresponding NiCl2 complexes. See SI for details.
tetradecane as internal standard
GC yield using
In 1973 Kumada et al. united these concepts and reported high
levels of isomerization when iPrMgCl was reacted with
fluorobenzene (Scheme 1A).[12] Since then, this transformation
persists as a challenge in catalysis and a general solution remains
elusive.[13] Herein we present a catalytic strategy based on a unique
nickel system which circumvents some of the above limitations. This
Figure 1. Mechanism and challenges in Ni-catalyzed C‒F alkylation.
[*]
[§]
Matthew O’Neill, Tim Riesebeck, and Josep Cornella
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,
Mülheim an der Ruhr, 45470, Germany.
E-mail: cornella@mpg.de
These authors contributed equally to this work.
protocol permits the coupling
of
unbiased secondary
alkylmagnesium halides with unactivated aryl fluorides under very
mild conditions with minimal isomerization.
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Figure 3. Scope of the branch-selective alkylation of aryl fluorides under nickel catalysis. Reaction conditions: aryl fluoride (1 equiv), Grignard (1.1 – 2.0 equiv),
Ni(acac)2 (5 mol%), L4 (5 mol%), CsF (20 mol%) in toluene at 25 ºC. a At 0 ºC. b At 40 ºC. c At 60 ºC. d 10 mol% Ni(acac)2 and L4. e without CsF.
We initiated our investigations exploring the coupling of 4-
fluoroanisole (1) with Grignard 2. After a preliminary survey of
ligands, dppp (L1) was identified as the most promising ligand with
Ni(acac)2, obtaining rather moderate levels of selectivity (3:1, vide
infra).[14] At this point, we questioned if selectivity could be influenced
by judicious substitution on the backbone of the phosphine ligand.
Indeed, previous studies by Moloy and Goldberg[15] revealed that
gem-dialkyl substitution within the backbone of the bidentate ligand
caused a remarkable influence on the rates of reductive elimination
in Pt(IV) complexes. This effect arises as the desired reductive
elimination is dependent on a transient open coordination site
(Figure 2B). We hypothesized that, in contrast to octahedral
complexes, stronger chelation in a square planar Ni center would
induce a geometrically constrained environment, thus minimizing
vacant sites, speculated to lead to isomerization events (Figure 2B).
To test this hypothesis, we subjected L2 and L3 to the reaction
conditions, and to our delight an increase of the yield (61% and
85%) as well as the selectivity (95:5) was obtained (Figure 2C).
More importantly, when Me groups were replaced by Et groups (L4)
that exaggerate the magnitude of the Thorpe-Ingold effect,[16] a large
increase in selectivity (97:3) was observed with concomitant rise in
yield (91%).[14][17] We believe the gem-dialkyl effect posed by L4
additives, CsF was found to aid in preventing further isomerization.
Although still unclear at this point, F anions might serve as transient
ligands, thus binding to the metal and suppressing open coordination
sites for isomerization.[18] The Thorpe-Ingold effect has traditionally
been exploited in a stoichiometric fashion using substrate-designed
approaches.[16] However, this work constitutes an example of a
ligand gem-dialkyl effect, which translates regiochemical fidelity in a
catalytic synthetic application.[19]
As depicted in Figure 3, a variety of electronically unbiased
Grignard reagents were accommodated. In this regard, sBuMgCl,
iPrMgCl and (4-phenylbutan-2-yl)MgBr delivered the coupling
product with excellent selectivity for the secondary position.
Unfortunately, challenging tertiary Grignards are currently beyond
this scope, providing predominantly isomerized byproducts. A wide
range of heterocycle motifs commonly encountered in drug
discovery and material science applications were tolerated.
Variously substituted pyridines (5-13) can be accessed in good
yields with excellent selectivities. These include functionalized
pyridines bearing thiophenes (10 and 11), which have been studied
as scaffolds for inhibition of cytochrome P450 A26.[20]
A
phenylpyridine with CF3 accessory displayed excellent
a
chemoselectivity, with no observable cleavage of the C(sp3)‒F bond
to yield 6 and 7. Quinoline and pyrimidine both performed well under
these conditions (14-16). Indoles elaborated at the 5- and 6- position
were obtained in excellent yield with high selectivity (18 and 19), as
well as an indole coupled at a peripheral phenyl fluoride (30 and 31).
It is worth pointing out that such mild conditions allow for the
coupling of heterocyclic substrates without traces of the commonly
obtained Ziegler alkylation at more acidic α-position to the
heteroatom.[21] Furthermore, additional control experiments
translates into
a faster reductive elimination thus preventing
isomerization and increasing yield. It is important to mention that the
selectivity trend correlates perfectly with the angle compression at
the tetrahedral quaternary center in the backbone of the ligand. In
contrast, the P‒Ni‒P angle did not lead to a correlation on the
selectivity and yields, thus reinforcing the validity of the gem-dialkyl
effect. Control experiments indicated the requirement of all the
components in the catalytic system. Finally, in a screening for
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excluding the catalyst showed no competing SNAr with
electrondeficient heterocycles. Substituted benzene analogues with
diverse electronics participated in facile coupling. These electronic
perturbations include those induced by an extended aromatic system
(17), alkylated amines (21 and 22), protected alcohols (23) as well
as aryl ethers (24 and 25). Both pyrazoles and pyrroles are tolerated
under the current conditions and lead to secondary products in
suitable selectivities (26-29). In addition, Grignard nucleophiles
derived from cyclohexyl and cyclopropyl moieties readily underwent
the desired transformation (14 and 20).
discussions and generous support. We thank Pascal Ortsack and
Christoph Rustemeier for preparation of starting materials.
To showcase the robustness of our method, an intermediate en
route to fluvastatin could be scaled up to 5 mmol without an
appreciable decrease in selectivity or yield (30, Figure 4A). In
addition to being viable on increased scales, the applicability of the
method in more functionalized molecules was a further point of
interest. The richly nitrogenated antipsychotic drug blonanserin
provided an optimal template for this examination, and we
gratifyingly obtained the elaborated compound 34 in good yield
(Figure 4B).
We envisaged that the utility of the Thorpe-Ingold ligand effect,
combined with the distinct electronic properties of C-F electrophiles,
could be utilized to a practical effect in a host of interesting contexts.
One such application of interest was the divergent functionalization
of pyridines. We therefore sought to develop a coherent protocol
with which to yield complete complements of 3,4- and 2,3-dialkyl
isomers of pyridine, all commencing from the common precursor 35
(Figure 4C). Building upon the work of Schlosser,[22] regioselective
lithiation of 35 can be achieved by a sensible choice of the base.
Deprotonation proceeding with DABCO or DIPEA provides
compounds 36 and 39 respectively. Subsequent Fe-catalyzed
alkylation following Fürstner’s protocol provides material suitable for
the Ni-catalyzed reaction, with complete chemoselectivity observed
in both cases (37 and 40).[23] Thus, 2,3-dialkylpyridine 38 and 3,4-
dialkylpyridine 41 are obtained in 3 steps from 36. These results
collectively showcase the synthetic versatility of simple fluorinated
heterocycles, and point to the importance of wider method
development to realize their full potential. This underscores the need
for a broader shift in perceptions of C‒F functionalization, and the
need for complementary methods to functionalize, as well as
construct these moieties.
Figure 4. (A) Scale-up of the protocol. (B) Application to complex nitrogenated
bioactive molecule (C) Exhaustive substitution of pyridine. Reagents and
conditions: (a) Grignard (1.1 equiv), Ni(acac)2 (5-10 mol%), L4 (5-10 mol%),
CsF (20 mol%) in toluene; (b) DABCO (1 equiv), BuLi (1.0 equiv), THF -60 ºC;
then hexachloroethane (2 equiv), -70 ºC; (c) 5 mol% Fe(acac)3, Grignard (1.2
equiv), THF:NMP (10:1), 25 ºC, 20 min; (d) DIPEA (1.0 equiv), BuLi (1.0
equiv), - 75 ºC, 2 h; then hexachloroethane (2 equiv), -70 ºC.
Keywords: nickel, isomerization, Thorpe-Ingold, C‒F activation,
cross-coupling
[1]
[2]
a) F. Diederich, P. J. Stang. Metal-catalyzed Cross Coupling Reactions.
Wiley-VCH, New York, 1998. b) R. Jana, T. P. Pathak, M. S. Sigman,
Chem. Rev. 2011, 111, 1417.
For selected examples of transition-metal catalyzed couplings using
secondary and tertiary electrophiles, see: a) A. Rudolph, M. Lautens,
Angew. Chem. Int. Ed. 2009, 48, 2656; Angew. Chem. 2009, 121,
2694; b) S. L. Zultanski, G. C. Fu, J. Am. Chem. Soc. 2013, 135, 624;
c) Q. Zhou, K. M. Cobb, T. Tan, M. P. Watson, J. Am. Chem. Soc. 2016,
138, 12057; d) J. Wang, T. Qin, T. –G. Chen, L. Wimmer, J. T. Edwards,
J. Cornella, B. Vokits, S. A. Shaw, P. S. Baran, Angew. Chem. Int. Ed.
2016, 55, 9676; Angew. Chem. 2016, 128, 9828; e) Z. Zuo, D. T.
Ahneman, L. Chu, J. A. Terrett, A. G. Doyle, D. W. C. MacMillan,
Science, 2014, 345, 437; f) Z. Ariki, Z. Maekawa, M. Nambo, C. M.
Crudden, J. Am. Chem. Soc. 2018, 140, 78; g) S. E. Denmark, A. J.
Cresswell, J. Org. Chem. 2013, 78, 12593; h) A. Piontek, E. Bisz, M.
Szostak, Angew. Chem. Int. Ed. 10.1002/anie.201800364; Angew.
Chem. 10.1002/ange.201800364.
In summary, a method has been developed to achieve high levels
of selectivity in the coupling of secondary alkyl nucleophiles with
unactivated C‒F aryl electrophiles. Notably, the synthetic efficacy
was attributed to the effect of gem-dialkyl substitution on the ligand
backbone, after observing
a correlation between the angle
compression and respective selectivities. The resulting method
tolerates a wide variety of functional groups, and has been applied to
the modification of complex drug targets as well as scaled up without
erosion of the selectivity and yield. A more complete understanding
of this effect and its generality is being rigorously explored in our lab,
and will be reported in due course.
[3]
[4]
For examples of transition-metal catalyzed couplings using tertiary
nucleophiles and aryl halides, see: a) A. Joshi-Pangu, C. –Y. Wang, M.
R. Biscoe J. Am. Chem. Soc. 2011, 133, 8478; b) C. Lohre, T. Dröge, C.
Wang, F. Glorius, Chem. –Eur. J. 2011, 17, 6052; c) D. N. Primer, G. A.
Molander, J. Am. Chem. Soc. 2017, 139, 9847.
Acknowledgements
For selected examples of transition-metal catalyzed couplings using
secondary alkylstannanes and alkylzinc reagents, see: a) L. Li, C. –W.
Wang, R. Huang, M. R. Biscoe, Nat. Chem. 2013, 5, 607; b) D. A.
Powell, T. Maki, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 510; c) M.
Pompeo, R. D. J. Froese, N. Hadei, M. J. Organ, Angew. Chem. Int. Ed.
Financial support for this work was provided by Max-Planck-
Gesellschaft, Max-Planck-Institute für Kohlenforschung and Fulbright
Komission (M. J. O.). We thank Prof. A. Fürstner for helpful
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2012, 51, 11354; Angew. Chem. 2012, 124, 11516; d) T. Thaler, B.
Haag, A. Gavryushin, K. Schober, E. Hartmann, R. M. Gschwind, H.
Zipse, P. Mayer, P. Knochel, Nat. Chem. 2010, 2, 125; e) Y. Yang, K.
Niedermann, C. Han, S. L. Buchwald, Org. Lett. 2014, 16, 4638; f) C.
Han, S. L. Buchwald, J. Am. Chem. Soc. 2009, 131, 7532; g) A.
Krasovskiy, C. Duplais, B. H. Lipshutz, J. Am. Chem. Soc. 2009, 131,
15592; h) A. Joshi-Pangu, M. Ganesh, M. Biscoe, Org. Lett. 2011, 13,
1218; i) D. Hass, J. M. Hammann, R. Greiner, P. Knochel, ACS Catal.
2016, 6, 1540.
Kuniyasu, N. Kambe, Org. Lett. 2016, 18, 4868; n) H. Shi, W. Dai, B.
Wang, S. Cao, Organometallics, 2018, 37, 459; o) T. Iwasaki, K.
Okamoto, H. Kuniyasu, N. Kambe, Chem. Lett. 2017, 46, 1504; p) T.
Chu, Y. Boyko, I. Korobkov, G. I. Nikonov, Organometallics 2015, 34,
5363; q) H. Ogawa, Z. –K. Yang, H. Minami, K. Kojima, T. Saito, C.
Wang, M. Uchiyama, ACS Catal. 2017, 7, 3988.
[10] 4-chlorotoluene ($55/mol) vs 4-fluorotoluene ($39/mol). Price retrieved
from www.sigmaaldrich.com.
[11] For selected examples on catalytic C–F functionalization using
unactivated fluoroarenes, see: a) J. W. Dankwadrt, J. Organomet.
Chem. 2005, 690, 932; b) N. Yoshikai, H. Mashima, E. Nakamura, J.
Am. Chem. Soc. 2005, 127, 17978; c) L. Ackermann, R. Bom, J. H.
Spatz, D. Meyer, Angew. Chem. Int. Ed. 2005, 44, 7216; Angew. Chem.
2005, 117, 7382; d) M. Tobisu, T. Xu, T. Shimasaki, N. Chatani, J. Am.
Chem. Soc. 2011, 133, 19505; e) V. P. W. Böhm, C. W. K. Gstöttmayr,
T. Weskamp, W. A. Hermann, Angew. Chem. Int. Ed. 2001, 40, 3387;
Angew. Chem. 2001, 113, 3500; f) F. Mongin, L. Mojovic, B. Gillamet, F.
Trecourt, G. Queguiner, J. Org. Chem. 2002, 67, 8991; g) L. –G. Xie, Z.
–X. Wang, Chem. –Eur J. 2010, 16, 10332; h) F. Zhu, Z. –X. Wang, J.
Org. Chem 2014, 79, 4285; i) W. –J. Guo, Z. –X. Wang, J. Org. Chem.
2013, 78, 1054; j) T. Kom, M. A. Schade, S. Wirth, P. Knochel, Org Lett.
2006, 8, 726; k) T. Niwa, H. Ochiai, Y. Watanabe, T. Hosoya, J. Am.
Chem. Soc. 2015, 137, 14313; l) F. Zhu, Z. –X. Wang, Adv. Synth.
Catal. 2013, 355, 3694; m) X. –W. Liu, J. Echavarren, C. Zarate, R.
Martin, J. Am. Chem. Soc. 2015, 137, 12470.
[5]
For selected examples of transition-metal catalyzed couplings with
secondary Grignards, see: a) K. Tamao, Y. Kiso, K. Sumitami, M.
Kumada, J. Am. Chem. Soc. 1972, 94, 9268; b) T. Hayashi, M. Konishi,
Y. Kobori, M. Kumada, T. Higuchi, K. Hirotsu, J. Am. Chem. Soc. 1984,
106, 158; c) G. Consiglio, A. Indolese, J. Organometal. Chem. 1991,
417, C36; d) I. Kalvet, T. Sperger, T. Scattolin, G. Magnin, F.
Schoenebeck, Angew. Chem. Int. Ed. 2017, 56, 7078; Angew. Chem.
2017, 129, 7184; e) C. A. Busacca, M. C. Eriksson, R. Fiaschi,
Tetrahedron Lett. 1999, 40, 3101; f) S. Kanemura, A. Kondoh, H.
Yorimitsu, K. Oshima, Synthesis, 2008, 16, 2659; g) C. E. I. Knappke, A.
J. von Wangelin, Chem. Soc. Rev. 2011, 40, 4948; h) A. H. Cherney,
Kadunce, N. T.; S. E. Reisman, Chem. Rev. 2015, 115, 9587 and
references therein.
[6]
For examples of transition-metal catalyzed couplings with secondary
alkylboron nucleophiles, see: a) S. D. Dreher, P. G. Dormer, D. L.
Sandrock, G. A. Molander, J. Am. Chem. Soc. 2008, 130, 9257; b) L. Li,
S. Zhao, A. Joshi-Pangu, M. Diane, M. R. Biscoe, J. Am. Chem. Soc.
2014, 136, 14027 c) A. F. Littke, C. Dai, G. C. Fu, J. Am. Chem. Soc.
2000, 122, 4020; d) N. Kataoka, Q. Shelby, J. Stambuli, J. F. Hartwig, J.
Org. Chem. 2002, 67, 5553; e) A. van den Hoogenband, J. H. M. Lange,
J. W. Terpstra, M. Koch, G. M. Visser, M. Visser, T. J. Korstanje, J. T. B.
H. Jastrzebski, Tetrahedron. Lett. 2008, 49, 4122; f) D. Imao, B. W.
Glassspoole, V. S. Laberge, C. M. Crudden, J. Am. Chem. Soc. 2009,
131, 5024; g) M. Rubina, M. Rubin, V. Gevorgyan, J. Am. Chem. Soc.
2003, 125, 7198; h) H. Doucet, Eur. J. Org. Chem. 2008, 2013; i) J. P.
Hildebrand, S. P. Marsden, Synlett, 1996, 9, 893; j) J. P. G. Rygus, C.
M. Crudden, J. Am. Chem. Soc. 2017, 139, 18124; k) J. Li, M. D. Burke,
J. Am. Chem. Soc. 2011, 133, 13774; l) L. Chausset-Boissarie, K.
Ghozati, E. LaBine, J. L. –Y. Chen, V. Aggarwal, C. M. Crudden, Chem.
‒Eur. J. 2013, 19, 17698.
[12] Y. Kiso, K. Tamao, M. Kumada, J. Organomet. Chem. 1973, 50, C12.
[13] For a single specific example using iPrLi, see: D. Heijnen, J. –B.
Gualtierotti, V. Homillos, B. L. Feringa, Chem. –Eur. J. 2016, 22, 3991.
[14] See Supporting Information for details.
[15] a) J. E: Marcone, K. G. Moloy, J. Am. Chem. Soc. 1998, 120, 8527; b)
K. L. Arthur, Q. L. Wang, D. M. Bregel, N. A. Smythe, B. A. O’Neill, K. I.
Goldberg, K. G. Moloy, Organometallics 2005, 24, 4624; c) J. A. van
Rijn, M. A. Siegler, A. L. Spek, E. Bouwman, E. Drent, Organometallics,
2009, 28, 7006.
[16] For examples on the nature of gem-dialkyl compression effects, see: a)
M. S. Newman, R. J. Harper, J. Am. Chem. Soc. 1958, 80, 6350; b) R.
F. Brown, N. M. Van Gulick, J. Org. Chem 1956, 21, 1046; c) A. L.
Ringer, D. H. Maegers, J. Org. Chem. 2007, 72, 2533; d) S. M.
Bachrach, J. Org. Chem. 2008, 73, 2466.
[7]
For reviews on C‒F activation, see: a) J. L. Kiplinger, T. G. Richmond,
C. E. Osterberg, Chem. Rev. 1994, 94, 373; b) H. Amii, K. Uneyama,
Chem. Rev. 2009, 109, 2119; c) T. Ahrens, J. Kohlmann, M. Ahrens, T.
Braun, Chem. Rev. 2015, 115, 931; d) O. Eisenstein, J. Milani, R. N.
Perutz, Chem. Rev. 2017, 117, 8710.
[17] L2, L3 and L4 could be obtained in high yield in 2 steps from the
commercially available 1,3-diol. See Supporting Information.
[18] A similar effect had been observed by Cook et al., in which FeF3 H2O
was found to be a superior catalyst in preventing isomerization events
in the coupling of secondary Grignards with activated C–O electrophiles.
T. Agrawal, S. P. Cook, Org. Lett., 2013, 15, 96.
[8]
[9]
a) M. G. Campbell, T. Ritter, Chem. Rev. 2015, 115, 612; b) T. Liang, C.
N. Neumann, T. Ritter, Angew. Chem. Int. Ed. 2013, 52, 8214; Angew.
Chem. 2013, 125, 8372.
[19] For an exceptional case study in ligand optimization for Ni-catalyzed
cross-coupling to improve synthetic methodology, see: K. Wu, A. G.
Doyle, Nat. Chem. 2017, 9, 779.
For selected examples on catalytic C–F functionalization using
activated fluoroarenes or polyfluorinated compounds, see: a) T. Braun,
R. N. Perutz, M. I. Sladek, Chem. Commun. 2001, 2254; b) T. Schaub,
M. Backes, U. Radius, J. Am. Chem. Soc. 2006, 128, 15964; c) A. D.
Sun, J. A. Love, Org. Lett. 2011, 13, 2750; d) Y. Nakamura, N. Yoshikai,
E. Nakamura, Org. Lett. 2012, 14, 3316; e) D. Yu, C. –S. Wang, C. Yao,
Q. Shen, L. Lu, Org. Lett. 2014, 16, 5544; f) T. Wang, B. J. Alfonso, J.
A. Love, Org. Lett. 2007, 9, 5629; g) J. –R. Wang, K. Manabe, Org. Lett.
2009, 11, 741; h) T. Wang, J. Love, Organometallics, 2008, 27, 3290; i)
T. Saeki, Y, Takashima, K. Tamao, Synlett, 2005, 11, 1771; j) M.
Ohash, T. Kambara, T. Hatanaka, H. Saijo, R. Doi, S. Ogoshi, J. Am.
Chem. Soc. 2011, 133, 3256; k) K. Kikushima, M. Greillier, M. Ohashi,
S. Ogoshi, Angew. Chem. Int. Ed. 2017, 56, 16191; Angew. Chem.
2017, 129, 16409; l) J. D. Weaver, S. Senaweera, Tetrahedron 2014,
70, 7413; m) T. Iwasaki, A. Fukuoka, X. Min, W. Yokoyama, H.
[20] T. T. Denton, X Zhang, J. R. Cashman, J. Med. Chem. 2005, 48, 224.
[21] a) K. Ziegler, H. Zeiser, Chem. Ber. 1930, 1847; b) K. Ziegler, H. Zeiser,
Chem. Ber. 1931, 174; c) H. G. Richey Jr., J. Farkas Jr., Tetrahedron.
Lett. 1985, 26, 275; d) H. Vorbrüggen, M. Maas, Heterocycles, 1988, 27,
2659; for a recent example, see: F. –F. Zhuo, W. –W Xie, Z. –X. Yang,
L. Zhang, P. Wang, R. Yuan, C. –S. Da, J. Org. Chem. 2013, 78, 3243.
[22] a) G. –Q. Shi, S. Takagishi, M. Schlosser, Tetrahedron 1994, 50, 1129;
b) E. Marzi, C. Bobbio, F. Cottet, M. Schlosser, Eur. J. Org. Chem.
2005, 2116.
[23] A. Fürstner, A. Leitner, M. Mendez, H. Krause, J. Am. Chem. Soc. 2002,
124, 13856.
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10.1002/anie.201804479
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Matthew J. O’Neill, Tim Riesebeck, and
Josep Cornella*
Page No. – Page No.
Catalytic Thorpe-Ingold Effect for
Branch-Selective
Unactivated Aryl Fluorides
Alkylation
of
Cross-coupling of aromatic C-F bonds with secondary alkylmagnesium nucleophiles
has been accomplished by means of nickel catalysis. gem-Dialkyl substitution of the
ligand backbone revealed a chelation effect which translated to high yields and
selectivities for retention of the nucleophile configuration.
This article is protected by copyright. All rights reserved.