Lewis Basic Salt-Promoted Organosilane Coupling Reactions with Aromatic Electrophiles

Article abstract of DOI:10.1021/jacs.1c05764

Lewis basic salts promote benzyltrimethylsilane coupling with (hetero)aryl nitriles, sulfones, and chlorides as a new route to 1,1-diarylalkanes. This method combines the substrate modularity and selectivity characteristic of cross-coupling with the practicality of a base-promoted protocol. In addition, a Lewis base strategy enables a complementary scope to existing methods, employs stable and easily prepared organosilanes, and achieves selective arylation in the presence of acidic functional groups. The utility of this method is demonstrated by the synthesis of pharmaceutical analogues and its use in multicomponent reactions.

Full text of DOI:10.1021/jacs.1c05764

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Lewis Basic Salt-Promoted Organosilane Coupling Reactions with
Aromatic Electrophiles
Tyler W. Reidl and Jeffrey S. Bandar*
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ABSTRACT: Lewis basic salts promote benzyltrimethylsilane coupling with (hetero)aryl nitriles, sulfones, and chlorides as a new
route to 1,1-diarylalkanes. This method combines the substrate modularity and selectivity characteristic of cross-coupling with the
practicality of a base-promoted protocol. In addition, a Lewis base strategy enables a complementary scope to existing methods,
employs stable and easily prepared organosilanes, and achieves selective arylation in the presence of acidic functional groups. The
utility of this method is demonstrated by the synthesis of pharmaceutical analogues and its use in multicomponent reactions.
1,1-Diarylalkanes are valuable compounds often prepared by
coupling functionalized benzylic reagents with aromatic
electrophiles.1 In practice, the benzylic coupling partner and
mechanism for achieving C−C bond formation define the
scope and suitability of a given method. A widely used strategy
is transition metal-catalyzed coupling of aryl (pseudo)halides
with benzyl magnesium, zinc, and boron compounds.2,3 This
approach enables robust and predictable reactivity often at the
expense of using reactive benzylic reagents prepared in situ.
Significant effort has therefore been focused on alternative
coupling partners and strategies to increase the efficiency and
scope of 1,1-diarylalkane synthesis.1,4−6
Benzylic deprotonation represents one such attractive
strategy that generates carbanion intermediates for metal-
catalyzed7 and catalyst-free8 reactions with aryl electrophiles
(Figure 1, left). Direct deprotonative arylation is perhaps ideal,
as no catalyst is needed and only inexpensive reagents are used.
However, this approach often leads to multiarylation side
products and typically requires acidic pronucleophiles such as
diarylmethanes.8 Deprotonative activation also limits the
coupling scope to relatively simple substrates in which the
most acidic proton is at the desired benzylic position.
We sought a new benzylic arylation method that blends the
modularity and selectivity of cross-coupling with the
Figure 1. Background and motivation for Lewis base-promoted aryl
coupling reactions of organotrimethylsilanes.
practicality of a base-promoted protocol. This drew our
attention toward Lewis base activation of Lewis acidic benzyl
compounds, an underdeveloped approach for aryl Csp2−Csp3
We herein report that Lewis basic salts promote the direct
coupling.9 In this regard, benzyltrimethylsilanes could be ideal
coupling of benzyltrimethylsilanes to a range of aromatic
electrophiles (Figure 1, bottom). Benzylic arylation out-
coupling partners as they are air stable, nonhygroscopic, and
easily accessed in great diversity.10 Furthermore, distinct
competes potential anionic side reactions to enable mono-
selective coupling in the presence of acidic and electrophilic
synthetic routes are available to complex benzyltrimethylsilanes
that cannot be used to access analogous organometallic
reagents.11 To date, the high stability of benzyltrimethylsilanes
Received: June 3, 2021
Published: July 27, 2021
has rendered them unreactive in metal-catalyzed cross-
coupling,12 and thus their use in arylation reactions is
limited.13 More specialized silanes are required to overcome
this challenge in conjunction with Pd- and metallaphotoredox-
catalyzed methodology (Figure 1, right).14
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a
functional groups. This strategy can be extended to other
organosilanes and reaction sequences, including the tandem
arylation/isomerization of allylsilanes as a new route to alkenyl
arenes. Thus, Lewis base-promoted arylation provides a
practical coupling protocol with a reaction scope that
complements established methods.
Table 1. Product Scope Using Cyanoarene Electrophiles
We recently reported the monoselective defluoroallylation of
trifluoromethylarenes enabled by fluoride activation of
allyltrimethylsilanes (Scheme 1a).15 This reaction is proposed
to operate through an anionic allyl intermediate that undergoes
single electron transfer (SET) to the trifluoromethylarene,
leading to C−F bond cleavage and allylation of the resulting
difluorobenzylic radical. This sequence has similarities to
photoinduced electron transfer (PET) allylation of 1,4-
dicyanoarenes using allyltrimethylsilane, namely SET prior to
C−C bond formation.16 Benzyltrimethylsilane has also been
examined in PET studies, although these reactions suffer from
low regioselectivity and side product formation while requiring
use of ultraviolet light (Scheme 1b).16a,17 On the basis of these
precedents, we hypothesized Lewis base activation of organo-
trimethylsilanes could promote their direct coupling with
aromatic electrophiles beyond trifluoromethylarenes.
Scheme 1. Organosilane Reactions with Aryl Electrophiles
a
and Development of Base-Promoted Arylation
a
Yields determined by 1H NMR spectroscopy; 18-crown-6 added as a
b
1 M solution in THF. 18 h time for salts other than CsF. Yields
improve to 57% and 84% at 100 °C without 18-crown-6 for Cs2CO3
and KF, respectively.
a
Isolated yields from reactions using 1.0 mmol of cyanoarene; 18-
b
c
crown-6 added as a 1 M solution in THF. 1.5 equiv of silane. 2.0
equiv of silane.
To test this hypothesis, we examined the reaction of 4-
cyanopyridine (1) with benzyltrimethylsilane (2) and found
18-crown-6-ligated cesium fluoride promotes monoselective
coupling in 3 h at room temperature (rt) in DMSO (95% yield,
Scheme 1c). Less basic anions, including carbonate, bifluoride,
and phosphate salts, promote arylation in moderate yields.
Conditions in the boxes of Scheme 1c show the ability to
adjust reaction parameters depending on priority, ranging from
the use of fluoride-free salts without 18-crown-6 to short
reaction times or large reaction scale.
Table 1 contains a product scope for benzyltrimethylsilane
coupling with cyanoarenes using CsF and 18-crown-6 in
DMSO. Primary, secondary, and tertiary benzylsilanes react
with 2- and 4-cyanopyridines and electron-deficient cyano-
benzenes (Table 1a,b). The products feature redox-active and
electrophilic aryl substituents such as alkynes (6), styrenes (9),
nitriles (7, 10, 12, 16), sulfones (8), trifluoromethyl groups
(11), and activated halides (17, 18, 20, 22, and 25−27).
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Acidic and electrophilic functional groups, including alkyl
benzoates (17), phthalimides (18), alkenes (19), alkylpyr-
idines (19−21, 28), and esters (22−24) are also tolerated.
Table 1c shows products of α-heteroatom benzylsilanes (25−
27) and with paroxetine (28) and bepotastine (29) drug
substructures. Product 27, derived from an α,α-difluorobenzyl-
trimethylsilane prepared via trifluoromethylarene defluorosily-
lation, illustrates a benzylic coupling partner unique to this
method.11a,18 In sum, the scope features substitution patterns
and functionalities that are difficult to access or not tolerated in
alternative arylation strategies.
This method can facilitate access to 1,1-diarylalkane
compound libraries from abundantly available cyano- and
chloroarenes. We selected the antihistamine chlorpheniramine
to demonstrate this concept, for which the corresponding
benzylsilane precursor 40 was readily prepared on 75 mmol
scale (Figure 2).21 Coupling of 40 with eight arene
electrophiles generated diverse chlorpheniramine analogues,
including trifluoromethyl- (41), methyl- (42), halo- (43, 44)
and aryl-substituted (46) variants. A 2-chloro-1,3-benzothia-
zole (45), a 4-cyanoquinazoline (47), and 4-chloroquinoline
(48) also reacted to access greater structural variety.
We next examined aryl electrophiles that do not generate
cyanide byproducts (Scheme 2a). 2-Chloro-1,3-azoles are
effective coupling partners (30−32), as are chlorides with
extended π-systems, such as 1,3-dichloroisoquinoline (33), 9-
chloroacridine (34), and the 2-chloroquinoline derivative of
the antitumor drug imiquimod (35). Although 4-halopyridines
do not react under these conditions, 4-sulfonylpyridines
provide good yields (Scheme 2b).19 To show the benefits of
this finding, 4-chloropyridine 37, for which the 4-cyano
congener is not commercially available, was converted to
sulfone 38 on a multigram scale without chromatography
(Scheme 2c).20 Benzylsilane coupling to 38 under the standard
conditions without crown ether yielded 5.9 g of diarylalkane
39. Thus, base-promoted benzylation is applicable to
heteroaryl halides either directly or after sulfonyl group
installation.
Figure 2. Synthesis of chlorpheniramine analogues. Yields shown are
of purified products. 18-Crown-6 added as a 1 M solution in THF.
aChloroarene substrate used.
a
Scheme 2. Expansion of Aryl Electrophile Scope
We next performed studies on the reaction selectivity for
arylation over other anionic processes. When the aryl
electrophile is removed from the standard conditions, toluene
forms in 80% yield after 2 h (Scheme 3a).22 This suggests
benzylic protonation is a competing pathway with arylation;
however, it is interesting to note that benzylation of 4-
cyanopyridine occurs in solvents significantly more acidic than
toluene (Scheme 3b).23,24 Furthermore, separate reactions of
two benzylsilane isomers (50 and 52) led to regiospecific
arylation for the original position of the −SiMe3 group
(Scheme 3c). These results demonstrate arylation occurs
preferentially over potential proton transfer events.25 An
important implication is that deprotonation of acidic diary-
lalkane products is minimized, thus preventing multiarylation
side reactions. These findings also illustrate critical advantages
of a Lewis base-promoted arylation method, as a Brønsted base
approach would not generate benzylic carbanions in the
presence of more acidic protons, and would likely lead to
multiarylation and poor selectivities in substrates with multiple
benzylic positions.26
To explain the high arylation selectivity, we propose an
anionic benzylic intermediate25 undergoes rapid aromatic
substitution via a polar or SET-based mechanism (Figure
3).27 The SET mechanism is the base-promoted analogous
pathway to PET reactions of organosilanes with 1,4-
dicyanoarenes.17,28,29 A polar process is also plausible as
cyano- and sulfonylarenes can participate in typical addition−
elimination substitution reactions.30 Distinguishing between
these processes is known to be challenging for addition of
anionic reagents to similar electrophiles,31,32 and we have made
observations explainable by both pathways.33 The coupling
mode may also be substrate dependent, although arylation
a
b
1
Isolated product yields. Yields determined by H NMR spectros-
copy of crude reaction mixtures. 18-Crown-6 added as a 1 M solution
in THF.
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a
a
Scheme 3. Investigation of Benzylic Arylation Selectivity
Scheme 4. Expanded Scope Using New Coupling Partners
a
Yields determined by 1H NMR spectroscopy of crude reaction
b
mixture. Isolated product yields. 18-Crown-6 added as 1 M solution
in THF.
a
Yields are of purified product; diastereoselectivities determined by
1H NMR spectroscopy; 18-crown-6 added as 1 M solution in THF.
b
c
>10:1 alkene E:Z ratios observed. Reaction performed at 60 °C.
d
e
Corresponding 4-phenylsulfonylpyridine used as substrate. ArCN
(1 equiv), organosilane (1.2 equiv) and acrylamide (1−2 equiv) used.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05764.
■
sı
Figure 3. Potential pathways and rationale for selective arylation.
Detailed experimental procedures, characterization data,
and NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
uniformly outcompetes other potential anionic side reac-
tions.34
■
Jeffrey S. Bandar − Department of Chemistry, Colorado State
University, Fort Collins, Colorado 80523, United States;
orcid.org/0000-0001-5418-3082; Email: jeff.bandar@
colostate.edu
From these studies, we realized organosilane arylation could
be incorporated into tandem base-promoted reaction sequen-
ces. First, we found allyltrimethylsilanes react to form allyl
arene intermediates that undergo stereoselective isomerization
to aryl alkenes 54, 55, and 56 (Scheme 4a).35,36 Next, we
targeted a three-component coupling process between organo-
silanes, aryl electrophiles, and Michael acceptors. We
hypothesized selective benzylic arylation would occur and
the remaining catalytic organosilane/fluoride combination
could initiate a Michael addition reaction (Scheme 4b).37
Thus, γ,γ-diaryl amides 57 and 58 can be prepared via this
strategy. Using methallyltrimethylsilane, tetrasubstituted alkene
59 forms through three selective base-promoted processes
(arylation, addition, and alkene isomerization).
In conclusion, Lewis basic salts provide a practical means of
engaging benzyl- and allyltrimethylsilanes in aryl coupling
reactions. This approach enables regio- and monoselective
access to 1,1-diarylalkane and aryl alkene products with
complementary scope to existing methods. The strategic
application of multiple base-promoted processes also facilitates
advanced coupling sequences, a prospect we continue to
explore.
Author
Tyler W. Reidl − Department of Chemistry, Colorado State
University, Fort Collins, Colorado 80523, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05764
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
National Institute of General Medical Sciences of the National
Institutes of Health under award no. R35GM138350. We
thank the National Institutes of Health for a postdoctoral
fellowship for T.W.R. (F32GM140567) and Colorado State
University for startup funding. The content is solely the
responsibility of the authors and does not necessarily reflect
the official views of the National Institutes of Health. We thank
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Arylation of Benzyl Alcohols by Nickel Catalysis. J. Am. Chem. Soc.
2021, 143, 513−523.
Shawn Wright (CSU) for initial studies on allyltrimethylsilane
arylation reactions and Professor Yiming Wang (University of
Pittsburgh) for input on this manuscript.
(6) For representative arylation reactions that proceed through
benzylic radicals, see (a) Vasilopoulos, A.; Zultanski, S. L.; Stahl, S. S.
Feedstocks to Pharmacophores: Cu-Catalyzed Oxidative Arylation of
Inexpensive Alkylarenes Enabling Direct Access to Diarylalkanes. J.
Am. Chem. Soc. 2017, 139, 7705−7708. (b) Zhang, W.; Chen, P.; Liu,
G. Copper-Catalyzed Arylation of Benzylic C−H bonds with
Alkylarenes as the Limiting Reagents. J. Am. Chem. Soc. 2017, 139,
7709−7712. (c) Hoshikawa, T.; Inoue, M. Photoinduced direct 4-
pyridination of C(sp3)−H Bonds. Chem. Sci. 2013, 4, 3118−3123.
(d) Qvortrup, K.; Rankic, D. A.; MacMillan, D. W. C. A General
Strategy for Organocatalytic Activation of C−H Bonds via Photo-
redox Catalysis: Direct Arylation of Benzylic Ethers. J. Am. Chem. Soc.
2014, 136, 626−629. (e) Gao, L.; Wang, G.; Cao, J.; Chen, H.; Gu,
Y.; Liu, X.; Cheng, X.; Ma, J.; Li, S. Lewis Acid-Catalyzed Selective
Reductive Decarboxylative Pyridylation of N-Hydroxyphthalimide
Esters: Synthesis of Congested Pyridine-Substituted Quaternary
Carbons. ACS Catal. 2019, 9, 10142−10151. (f) Tellis, J. C.;
Primer, D. N.; Molander, G. A. Single-electron transmetalation in
organoboron cross-coupling by photoredox/nickel dual catalysis.
Science 2014, 345, 433−436.
REFERENCES
■
(1) For reviews, see (a) Mondal, S.; Panda, G. Synthetic
methodologies of achiral diarylmethanols, diaryl and triarylmethanes
(TRAMs) and medicinal properties of diaryl and triarylmethanes-an
overview. RSC Adv. 2014, 4, 28317−28358. (b) Belal, Md.; Li, Z.; Lu,
X.; Yin, G. Recent advances in the synthesis of 1,1-diarylalkanes by
transition-metal catalysis. Sci. China: Chem. 2021, 64, 513−533.
(c) Nambo, M.; Crudden, C. M. Recent Advances in the Synthesis of
Triarylmethanes by Transition Metal Catalysis. ACS Catal. 2015, 5,
4734−4742. (d) Xu, J.; Bercher, O. P.; Talley, M. R.; Watson, M. P.
Nickel-Catalyzed, Stereospecific C−C and C−B Cross-Couplings via
C−N and C−O Bond Activation. ACS Catal. 2021, 11, 1604−1612.
(e) Kshatriya, R.; Jejurkar, V. P.; Saha, S. Advances in The Catalytic
Synthesis of Triarylmethanes (TRAMs). Eur. J. Org. Chem. 2019,
2019, 3818−3841. (f) Jia, T.; Cao, P.; Liao, J. Enantioselective
synthesis of gem-diarylalkanes by transition metal-catalyzed asym-
metric arylations (TMCAAr). Chem. Sci. 2018, 9, 546−559.
(g) Moon, P. J.; Lundgren, R. J. Metal-Catalyzed Ionic Decarbox-
ylative Cross-Coupling Reactions of C(sp3) Acids: Reaction Develop-
ment, Mechanisms, and Application. ACS Catal. 2020, 10, 1742−
1753.
(7) For examples, see (a) Sha, S.-C.; Tcyrulnikov, S.; Li, M.; Hu, B.;
Fu, Y.; Kozlowski, M. C.; Walsh, P. J. Cation-π Interactions in the
Benzylic Arylation of Toluenes with Bimetallic Catalysts. J. Am. Chem.
Soc. 2018, 140, 12415−12423. (b) Jiang, H.; Sha, S.-C.; Jeong, S. A.;
Manor, B. C.; Walsh, P. J. Ni(NIXANTPHOS)-Catalyzed Mono-
Arylation of Toluenes with Aryl Chlorides and Bromides. Org. Lett.
2019, 21, 1735−1739. (c) Burton, P. M.; Morris, J. A. Palladium-
Catalyzed Benzylic Arylation of 2-Methyl Azaarenes. Org. Lett. 2010,
12, 5359−5361. (d) Zhang, S.; Hu, B.; Zheng, Z.; Walsh, P. J.
Palladium-Catalyzed Triarylation of sp3 C−H Bonds in Heteroaryl-
methanes: Synthesis of Triaryl(heteroaryl)methanes. Adv. Synth.
Catal. 2018, 360, 1493−1498.
(8) For examples, see (a) Wei, X.; Qu, B.; Zeng, X.; Savoie, J.;
Fandrick, K. R.; Desrosiers, J.-N.; Tcyrulnikov, S.; Marsini, M. A.;
Buono, F. G.; Li, Z.; Yang, B.-S.; Tang, W.; Haddad, N.; Gutierrez,
O.; Wang, J.; Lee, H.; Ma, S.; Campbell, S.; Lorenz, J. C.; Eckhardt,
M.; Himmelsbach, F.; Peters, S.; Patel, N. D.; Tan, Z.; Yee, N. K.;
Song, J. J.; Roschangar, F.; Kozlowski, M. C.; Senanayake, C. H.
Sequential C−H Arylation and Enantioselective Hydrogenation
Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an
11β-HSD-1 Inhibitor. J. Am. Chem. Soc. 2016, 138, 15473−15481.
(b) Li, M.; Berritt, S.; Matuszewski, L.; Deng, G.; Pascual-Escudero,
A.; Panetti, G. B.; Poznik, M.; Yang, X.; Chruma, J. J.; Walsh, P. J.
Transition-Metal-Free Radical C(sp3)−C(sp2) and C(sp3)−C(sp3)
Coupling Enabled by 2-Azaallyls as Super-Electron-Donors and
Coupling-Partners. J. Am. Chem. Soc. 2017, 139, 16327−16333.
(c) Ji, X.; Huang, T.; Wu, W.; Liang, F.; Cao, S. LDA-Mediated
Synthesis of Triarylmethanes by Arylation of Diarylmethanes with
Fluoroarenes at Room Temperature. Org. Lett. 2015, 17, 5096−5099.
(d) Janin, Y. L.; Huel, C.; Legraverend, M.; Aubertin, A.-M.; Bisagni,
E. Syntheses of 4-Benzylpyridones via Nucleophilic Aromatic
Substitutions. Synthesis 2001, 2001, 1806−1811. (e) Dyker, G.;
Muth, O. Synthesis of Methylene- and Methine-Bridged Oligopyr-
idines. Eur. J. Org. Chem. 2004, 2004, 4319−4322.
(2) For examples, see (a) Negishi, E.; King, A. O.; Okukado, N.
Selective carbon-carbon bond formation via transition metal catalysis.
3. A highly selective synthesis of unsymmetrical biaryls and
diarylmethanes by the nickel- or palladium-catalyzed reaction of
aryl- and benzylzinc derivatives with aryl halides. J. Org. Chem. 1977,
42, 1821−1823. (b) Metzger, A.; Melzig, L.; Despotopoulou, C.;
Knochel, P. Pd-Catalyzed Cross-Coupling of Functionalized Organo-
zinc Reagents with Thiomethyl-Substituted Heterocycles. Org. Lett.
2009, 11, 4228−4231. (c) Ohmiya, H.; Yorimitsu, H.; Oshima, K.
Cobalt-catalyzed Cross-coupling Reaction of Chloropyridines with
Grignard Reagents. Chem. Lett. 2004, 33, 1240−1241. (d) Endo, K.;
Ishioka, T.; Ohkubo, T.; Shibata, T. One-Pot Synthesis of
Symmetrical and Unsymmetrical Diarylmethanes via Diborylmethane.
J. Org. Chem. 2012, 77, 7223−7231.
(3) Several reports describe the arylation of benzyl zinc reagents
without a transition metal catalyst. (a) Quinio, P.; Roman, D. S.;
León, T.; William, S.; Karaghiosoff, K.; Knochel, P. Transition-Metal-
Free Cross-Coupling of Aryl and N-Heteroaryl Cyanides with
Benzylic Zinc Reagents. Org. Lett. 2015, 17, 4396−4399. (b) Shiota,
T.; Yamamori, T. Regioselective Reactions of Organozinc Reagents
with 2,4-Dichloroquinoline and 5,7-Dichloropyrazolo[1,5-a]-
pyrimidine. J. Org. Chem. 1999, 64, 453−457.
(4) For example reactions of aryl halides with styrenes via benzylic
metal intermediates, see (a) Friis, S. D.; Pirnot, M. T.; Buchwald, S. L.
Asymmetric Hydroarylation of Vinylarenes Using a Synergistic
Combination of CuH and Pd Catalysis. J. Am. Chem. Soc. 2016,
138, 8372−8375. (b) Logan, K. M.; Smith, K. B.; Brown, M. K.
Copper/Palladium Synergistic Catalysis for the syn- and anti-Selective
Carboboration of Alkenes. Angew. Chem., Int. Ed. 2015, 54, 5228−
5231.
(5) For examples of cross-electrophile coupling, see (a) Ackerman,
L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix, D. J. Cobalt co-
catalysis for cross-electrophile coupling: diarylmethanes from benzyl
mesylates and aryl halides. Chem. Sci. 2015, 6, 1115−1119.
(b) Poremba, K. E.; Kadunce, N. T.; Suzuki, N.; Cherney, A. H.;
Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive Cross-
Coupling To Access 1,1-Diarylalkanes. J. Am. Chem. Soc. 2017, 139,
5684−5687. (c) Charboneau, D. J.; Barth, E. L.; Hazari, N.; Uehling,
M. R.; Zultanski, S. L. A Widely Applicable Dual Catalytic System for
Cross-Electrophile Coupling Enabled by Mechanistic Studies. ACS
Catal. 2020, 10, 12642−12656. (d) Guo, P.; Wang, K.; Jin, W.-J.; Xie,
H.; Qi, L.; Liu, X.-Y.; Shu, X.-Z. Dynamic Kinetic Cross-Electrophile
(9) For a recent report on alkoxide-promoted arylation of tertiary
benzylic boronates, see: Takeda, M.; Nagao, K.; Ohmiya, H.
Transition-Metal-Free Cross-Coupling by Using Tertiary Benzylic
Organoboronates. Angew. Chem., Int. Ed. 2020, 59, 22460−22464.
(10) For example routes to benzyltrimethylsilanes (a) Das, M.;
O’Shea, D. F. Synthesis and application of benzyl-TMS derivatives as
bench stable benzyl anion equivalents. Tetrahedron 2013, 69, 6448−
6460. (b) Li, W.; Gao, G.; Gao, Y.; Yang, C.; Xia, W. Direct oxidation
of the C(sp2)−C(sp3) bond from benzyltrimethylsilanes to phenols.
Chem. Commun. 2017, 53, 5291−5293. (c) Takahashi, H.; Hossain,
K. M.; Nishihara, Y.; Shibata, T.; Takagi, K. Synthesis of
Functionalized Benzylsilanes from Arylzinc Compounds and
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Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(Iodomethyl)trimethylsilane by Means of a Novel Rh Catalysis. J. Org.
Chem. 2006, 71, 671−675.
Mechanistic and Computational Details of the Persulfate-Initiated
Catalysis. ACS Catal. 2019, 9, 4015−4024.
(11) For examples, see (a) Utsumi, S.; Katagiri, T.; Uneyama, K. Cu-
deposits on Mg metal surfaces promote electron transfer reactions.
Tetrahedron 2012, 68, 1085−1091. (b) Kundu, P. K.; Ghosh, S. K.
Magnesium-induced regiospecific C-silylation of suitably substituted
enoates and dienoates. Tetrahedron 2010, 66, 8562−8568. (c) Zhang,
T.; Zhang, Z.; Nishiyama, Y.; Maekawa, H. Facile and highly selective
silylation of vinylpyridines at the β-olefinic carbon by magnesium-
promoted reduction. Tetrahedron 2016, 72, 2293−2299.
(21) For other routes to chlorpheniramine analogues, see (a) Deane,
K. J.; Summers, R. L.; Lehane, A. M.; Martin, R. E.; Barrow, R. A.
Chlorpheniramine Analogues Reverse Chloroquine Resistance in
Plasmodium falciparum by Inhibiting PfCRT. ACS Med. Chem. Lett.
2014, 5, 576−581. (b) Dong, C.; Wang, X.; Pei, Z.; Shen, R. Metal-
Free Denitrogenative C−C Couplings of Pyridotriazoles with Boronic
Acids To Afford α-Secondary and α-Tertiary Pyridines. Org. Lett.
2019, 21, 4148−4152.
(12) (a) Grimaud, L.; Jutand, A. Role of Fluoride Ions in Palladium-
Catalyzed Cross-Coupling Reactions. Synthesis 2017, 49, 1182−1189.
(b) Hiyama, T.; Minami, Y.; Mori, A. Transition-Metal-Catalyzed
Cross-coupling of Organosilicon Compounds. In Organosilicon
Chemistry: Novel Approaches and Reactions; Hiyama, T., Oestreich,
M., Eds.; Wiley-VCH, 2020; pp 271−332. See also ref 14a.
(13) For benzyltrimethylsilane arylation via aryl C−H substitution,
see (a) Wu, Y.; Bouvet, S.; Izquierdo, S.; Shafir, A. Synthesis of
Polysubstituted Iodoarenes Enabled by Iterative Iodine-Directed para
and ortho C−H Functionalization. Angew. Chem., Int. Ed. 2019, 58,
2617−2621. (b) Dong, J.; Wang, X.; Wang, Z.; Song, H.; Liu, Y.;
Wang, Q. Metal-, photocatalyst-, and light-free late-stage C−H
alkylation of N-heteroarenes with organotrimethylsilanes using
persulfate as a stoichiometric oxidant. Org. Chem. Front. 2019, 6,
2902−2906. (c) Puthanveedu, M.; Polychronidou, V.; Antonchick, A.
P. Catalytic Selective Metal-Free Cross-Coupling of Heteroaromatic
N-Oxides with Organosilanes. Org. Lett. 2019, 21, 3407−3411.
(14) (a) Itami, K.; Mineno, M.; Kamei, T.; Yoshida, J. A General and
Straightforward Route toward Diarylmethanes. Integrated Cross-
Coupling Reactions Using (2-Pyridyl)silylmethylstannane as an Air-
Stable, Storable, and Versatile Coupling Platform. Org. Lett. 2002, 4,
3635−3638. (b) Corcé, V.; Chamoreau, L.-M.; Derat, E.; Goddard, J.-
P.; Ollivier, C.; Fensterbank, L. Silicates as Latent Alkyl Radical
Precursors: Visible-Light Photocatalytic Oxidation of Hypervalent
Bis-Catecholato Silicon Compounds. Angew. Chem., Int. Ed. 2015, 54,
11414−11418. (c) Jouffroy, M.; Primer, D. N.; Molander, G. A. Base-
Free Photoredox/Nickel Dual-Catalytic Cross-Coupling of Ammo-
nium Alkylsilicates. J. Am. Chem. Soc. 2016, 138, 475−478.
(15) Luo, C.; Bandar, J. S. Selective Defluoroallylation of
Trifluoromethylarenes. J. Am. Chem. Soc. 2019, 141, 14120−14125.
(16) For representative studies, see (a) Mizuno, K.; Ikeda, M.;
Otsuji, Y. A novel photosubstitution of dicyanobenzenes by allylic and
benzylic silanes. Tetrahedron Lett. 1985, 26, 461−464. (b) Nakanishi,
K.; Mizuno, K.; Otsuji, Y. Photosubstitution of Dicyanobenzenes by
Allylic Silanes, Germanes, and Stannanes via Photoinduced Electron
Transfer. Bull. Chem. Soc. Jpn. 1993, 66, 2371−2379. (c) For a related
recent method: Liu, Y.; Li, H.; Chiba, S. Photoinduced Cross-
Coupling of Aryl Iodides with Alkenes. Org. Lett. 2021, 23, 427−432.
(17) For representative studies, see (a) Mizuno, K.; Terasaka, K.;
Yasueda, M.; Otsuji, Y. Photoarylmethylation of 1,4-Dicyanonaph-
thalene by Use of Group 14 Organometallic Compounds. Chem. Lett.
1988, 17, 145−148. (b) Tamai, T.; Mizuno, K.; Hashida, I.; Otsuji, Y.
Photoinduced Electron-Transfer Reactions of Arylmethyl-Substituted
14 Group Compounds: Photoarylmethylation and Photooxygenation.
Bull. Chem. Soc. Jpn. 1993, 66, 3747−3754. For a related photoredox-
catalyzed oxidative [1,2]-Brook rearrangement/arylation reaction, see
(c) Deng, Y.; Liu, Q.; Smith, A. B., III. Oxidative [1,2]-Brook
Rearrangements Exploiting Single-Electron Transfer: Photoredox-
Catalyzed Alkylations and Arylations. J. Am. Chem. Soc. 2017, 139,
9487−9490.
(22) For examples of Lewis base-promoted benzyltrimethylsilane
addition reactions, see refs 10a, 13c, and (a) Yao, W.; Li, R.; Jiang, H.;
Han, D. An Additive-Free, Base-Catalyzed Protodesilylation of
Organosilanes. J. Org. Chem. 2018, 83, 2250−2255. (b) Reich, H. J.
Mechanism of C−Si Bond Cleavage Using Lewis Bases (n → σ*). In
Lewis Base Catalysis in Organic Synthesis; Vedejs, E., Denmark, S. E.,
Eds.; Wiley-VCH: Weinheim, 2016; pp 233−280.
(23) As detailed in ref 22, benzyltrimethylsilane addition reactions
are typically performed in nonacidic solvents. These reactions
typically require a strong Lewis base, such as fluoride or alkoxide
salts, in contrast to reactivity observed in Scheme 1c.
(24) Bordwell, F. G. Equilibrium acidities in dimethyl sulfoxide
solution. Acc. Chem. Res. 1988, 21, 456−463.
(25) Lewis base-promoted reactions of benzyl and allylsilanes have
been proposed to react through penta- and hexacoordinate silicate as
well as carbanion intermediates. For a review, see ref 22b.
(26) To demonstrate this, deprotonative silylation of 1,2,3-
trimethylbenzene produces a 6:1 mixture of 52:50, with no obvious
way to favor 50 as the major product. Subjection of the 6:1 mixture of
52:50 to the arylation conditions results in an analogous 6:1 ratio of
products 53:51. See Supporting Information for full details.
(27) For reviews on SET in substitution reactions, see (a) Rossi, R.
A.; Pierini, A. B.; Penenory, A. B. Nucleophilic Substitution Reactions
̃ ̃
by Electron Transfer. Chem. Rev. 2003, 103, 71−167. (b) Zhang, N.;
Samanta, S. R.; Rosen, B. M.; Percec, V. Single Electron Transfer in
Radical Ion and Radical-Mediated Organic, Materials and Polymer
Synthesis. Chem. Rev. 2014, 114, 5848−5958.
(28) Measured reduction potentials of benzyl radicals and
cyanoarenes span a similar range that is sensitive to the substrate
identity, see (a) Sim, B. A.; Milne, P. H.; Griller, D.; Wayner, D. D. M.
Thermodynamic Significance of ρ+ and ρ- from Substituent Effects
on the Redox Potentials of Arylmethyl Radicals. J. Am. Chem. Soc.
1990, 112, 6635−6638. (b) McDevitt, P.; Vittimberga, B. M. The
electron transfer reactions of cyano substituted pyridines and
quinolines with thermally generated diphenyl ketyl. J. Heterocycl.
Chem. 1990, 27, 1903−1908. (c) Mori, Y.; Sakaguchi, Y.; Hayashi, H.
Magnetic Field Effects on Chemical Reactions of Biradical Radical Ion
Pairs in Homogeneous Fluid Solvents. J. Phys. Chem. A 2000, 104,
4896−4905.
(29) Cyanoarenes are commonly used in redox substitution
reactions; see refs 6c to 6e and Leifert, D.; Studer, A. The Persistent
Radical Effect in Organic Synthesis. Angew. Chem., Int. Ed. 2020, 59,
74−108.
(30) (a) Thompson, A. D.; Huestis, M. P. Cyanide Anion as a
Leaving Group in Nucleophilic Aromatic Substitution: Synthesis of
Quaternary Centers at Azine Heterocycles. J. Org. Chem. 2013, 78,
762−769. (b) Wei, X.; Zhang, C.; Wang, Y.; Zhan, Q.; Qiu, G.; Fan,
L.; Yin, G. Decyanative Cross-Coupling of Cyanopyrimidines with O-,
S-, and N-Nucleophiles: A Route to Alkoxylpyrimidines, Amino-
pyrimidines and Alkylthiopyrimidines. Eur. J. Org. Chem. 2019, 2019,
7142−7150. (c) Barlin, G. B.; Brown, W. V. Useful Reactions of
Nucleophiles with Some Methylsulphonyl Derivatives of Nitrogen
Heterocycles. J. Chem. Soc. C 1967, 2473−2476.
(18) Other products from benzyltrimethylsilanes prepared via
reductive trimethylsilylation are 17, 18, 21−24, 30, and those in
Figure 2.
(19) The observation that 4-halopyridines do not undergo
benzylation is consistent with a coupling process that is not metal-
catalyzed.
(20) Nguyen, V. D.; Nguyen, V. T.; Haug, G. C.; Dang, H. T.;
Arman, H. D.; Ermler, W. C.; Larionov, O. V. Rapid and
Chemodivergent Synthesis of N-Heterocyclic Sulfones and Sulfides:
(31) For examples of nucleophilic benzylation reactions of activated
cyano and sulfonylarenes that have been proposed to proceed via
either pathway, see refs 3a, 8a, 9, and Lei, Y.; Yang, J.; Qi, R.; Wang,
S.; Wang, R.; Xu, Z. Arylation of benzyl amines with aromatic nitriles.
Chem. Commun. 2018, 54, 11881−11884.
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pubs.acs.org/JACS
Communication
(32) For discussions on one and two electron modes of addition in
SNAr reactions, see (a) Terrier, F. Other SNAr Substitution Pathways.
In Modern Nucleophilic Aromatic Substitution; Wiley-VCH: Weinheim,
2013; pp 423−463. (b) Pross, A. The single electron shift as a
fundamental process in organic chemistry: the relationship between
polar and electron-transfer pathways. Acc. Chem. Res. 1985, 18, 212−
219. (c) Percec, V.; Clough, R. S.; Grigoras, M.; Rinaldi, P. L.;
Litman, V. E. Reductive dehalogenation versus substitution in the
polyetherification of 4,4′-dihalodiphenyl sulfones with bisphenolates.
Macromolecules 1993, 26, 3650−3662. (d) Bacaloglu, R.; Bunton, C.
A.; Ortega, F. Single-electron transfer in aromatic nucleophilic
addition and substitution in aqueous media. J. Am. Chem. Soc.
1988, 110, 3503−3512.
(33) A discussion of observations made that pertain to potential
mechanistic pathways are described in the Supporting Information.
(34) We note that a potential alternative pathway involves initial
addition to the nitrile followed by rearrangement; see (a) Miller, J. A.;
Dankwardt, J. W.; Penney, J. M. Nickel Catalyzed Cross-Coupling and
Amination Reactions of Aryl Nitriles. Synthesis 2003, 2003, 1643−
1648. (b) For a discussion of a related pathway for sulfur-based
̌
̌
electrophiles, see Dean, W. M.; Siauciulis, M.; Storr, T. E.; Lewis, W.;
Stockman, R. A. Versatile C(sp2)−C(sp3) Ligand Couplings of
Sulfoxides for the Enantioselective Synthesis of Diarylalkanes. Angew.
Chem., Int. Ed. 2016, 55, 10013−10016.
(35) For example allyltrimethylsilane coupling reactions, see
(a) Akram, M. O.; Mali, P. S.; Patil, N. T. Cross-Coupling Reactions
of Aryldiazonium Salts with Allylsilanes under Merged Gold/Visible-
Light Photoredox Catalysis. Org. Lett. 2017, 19, 3075−3078. (b) De
Carolis, M.; Protti, S.; Fagnoni, M.; Albini, A. Metal-Free Cross-
Coupling Reactions of Aryl Sulfonates and Phosphates through
Photoheterolysis of Aryl−Oxygen Bonds. Angew. Chem., Int. Ed. 2005,
44, 1232−1236.
(36) For related isomerization observed during allylsilane arylation
̈
reactions, see (a) Vorbruggen, H.; Krolikiewcz, K. Conversion of
heterocyclic N-oxides into α-alkylated heterocycles. Trimethylsilanol
as leaving group  IV. Tetrahedron Lett. 1983, 24, 889−890.
(b) Denmark, S. E.; Werner, N. S. Cross-Coupling of Aromatic
Bromides with Allylic Silanolate Salts. J. Am. Chem. Soc. 2008, 130,
16382−16393.
(37) Yamashita, Y.; Kobayashi, S. Catalytic Carbon−Carbon Bond-
Forming Reactions of Weakly Acidic Carbon Pronucleophiles Using
Strong Brønsted Bases as Catalysts. Chem. - Eur. J. 2018, 24, 10−17.
11945
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J. Am. Chem. Soc. 2021, 143, 11939−11945