Selective, Catalytic, and Metal-Free Coupling of Electron-Rich Phenols and Anilides Using Molecular Oxygen as Terminal Oxidant

Article abstract of DOI:10.1021/acs.orglett.8b01631

Selective oxidative homo- and cross-coupling of electron-rich phenols and anilides was developed using nitrosonium tetrafluoroborate as a catalyst. Oxidative coupling of phenols revealed unusual selectivities, which translated into the unprecedented synthesis of inverse Pummerer-type ketones. Mechanistic studies suggest that oxidative coupling of phenols and anilides shares a common pathway via homolytical heteroatom-hydrogen bond cleavage. Nitrosonium salt catalysis was applied for cross-dehydrogenative coupling initiated by generation of heteroatom-centered radicals.

Full text of DOI:10.1021/acs.orglett.8b01631

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selective, Catalytic, and Metal-Free Coupling of Electron-Rich
Phenols and Anilides Using Molecular Oxygen as Terminal Oxidant
Luis Bering,†,‡ Melina Vogt,‡ Felix M. Paulussen,‡ and Andrey P. Antonchick*,†,‡
†Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, 44227 Dortmund, Germany
‡Faculty of Chemistry and Chemical Biology, TU Dortmund, 44227 Dortmund, Germany
S
* Supporting Information
ABSTRACT: Selective oxidative homo- and cross-coupling
of electron-rich phenols and anilides was developed using
nitrosonium tetrafluoroborate as a catalyst. Oxidative coupling
of phenols revealed unusual selectivities, which translated into
the unprecedented synthesis of inverse Pummerer-type
ketones. Mechanistic studies suggest that oxidative coupling
of phenols and anilides shares a common pathway via homolytical heteroatom−hydrogen bond cleavage. Nitrosonium salt
catalysis was applied for cross-dehydrogenative coupling initiated by generation of heteroatom-centered radicals.
irect oxidativecoupling represents the ideal strategy for the
coupling has remained almost untouched within the last two
DconstructionofthebiarylskeletonasC−Cbondsareforged decades.12,14 Importantly, biaryl dimerization was exclusively
by two-fold C−H bond functionalization.1 Biphenols and
bisanilides are of particular importance, due to their frequent
reported based on the formation of radical cation intermediates
from highly electron-rich compounds.12,15 Initiation of oxidative
coupling by heteroatom−hydrogen bond cleavage using nitro-
sonium salts has never been reported before. Generation of
heteroatom-centeredradicalsoffersanentranceintodehydrogen-
ative cross-coupling, which remains unprecedented for nitro-
sonium salt catalysis. Driven by the ongoing interest of our group
in metal-free reaction methodologies, we aimed to explore novel
applications of nitrosonium salts as catalysts in oxidative
coupling.16 Herein, we report the catalytic, aerobic, and metal-
free selective oxidative coupling of electron-rich phenols and
anilides (Figure 1).
Weinitiatedourinvestigationwiththeoxidativehomocoupling
of phenol 1a. Multiparameter optimization for the synthesis of
biphenol 2a was performed (Tables S1 and S2). Under the
optimizedcondition, 2awasisolatedin84%yieldusing2.5mol%
of nitrosonium tetrafluoroborate in 4:1 DCM / TFA with fast
reactionrates(Scheme1).Homocouplingproduct2arevealedan
unusual C2−C5 connectivity with excellent regioselectivity,
mediatedbythedirectingeffectofthemethoxygroup. Formation
of the radical−radical recombination product 2a′ was not
detected.
With optimized conditions in hand, we explored the scope of
the catalytic and metal-free oxidative coupling methodology
(Scheme 2). Homocoupling of 2,4-substituted phenols was
accomplished in good yields. Although the oxidative coupling of
1aproceededwellusingalowloadingofNOBF4,wefoundtheuse
of borate salts as additives to be a potential alternative for the
oxidative coupling of highly reactive starting materials. Using
KB(C6F5)5 proved to be beneficial for the synthesis of 2b and 2c,
which were smoothly obtained with fast reaction rate. Exclusive
occurrence in natural products, organic synthesis, and materials
science.2 Selective homo- and cross-coupling of phenols has
received tremendous attention within the past decade and has
been described in a metal-catalyzed3 and metal-free4 fashion.
Selective oxidative coupling of phenols represents a great
challenge, due to the formation of regioisomers and the tendency
to undergo uncontrolled overoxidation.3c,5 Compared to
phenols, catalytic oxidative coupling of anilides is less explored.6
Increased oxidation potential and intrinsic nucleophilicity often
lead to undesired polymerization of anilides or formation of
diazenes.7 Most notably, the field of synthetic organic electro-
chemistry represents a powerful and clean approach for oxidative
coupling reactions.8 However, the lack of standardized
instrumentation with improved reproducibility and reduced
pricingremainsamajorobstacle.9 Further,additionofsupporting
electrolytes in high concentrations is often required to avoid
current gradients in batch reactors.10 Consequently, a metal-free
and catalytic methodology covering the selective oxidative
coupling of phenols and anilides using inexpensive and readily
available reagents without the requirement for specialized
equipment and production of stoichiometric amounts of waste
would be a highly valuable and a sustainable addition to the
portfolio of oxidative coupling reactions.
Nitrosonium salts are strong single-electron oxidants with a
redoxpotentialcomparabletothatofotherhighmolecularweight
two-electron oxidants, such as hypervalent iodine(III) reagents
and DDQ.11 In contrast to the use of stoichiometric oxidants,
nitrosonium salts employ ambient oxygen as a terminal oxidant
while producing water as a byproduct.12 Molecular oxygen is
considered to be the ideal oxidant due to its natural occurrence,
inexpensive character, and safe properties.13 Despite the unique
potential of nitrosonium salts, their application in oxidative
Received: May 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01631
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a
Scheme 2. Scope of the Catalytic Phenol Coupling
Figure 1. Nitrosonium ion-catalyzed oxidative coupling of phenols and
anilidesemploying ambientoxygen asterminal oxidant. PG= protecting
group.
Scheme 1. Catalytic Oxidative Phenol Coupling under
Optimized Reaction Conditions
selectivityforortho−orthocouplingwasobserved,underliningthe
remarkableshiftofselectivitycontrolledbythemostnucleophilic
position of the phenol. Note that 2c is highly prone to
overoxidation, which was avoided under the developed reaction
conditions.17 2,6-Substituted phenols yielded the corresponding
diketones2d−2fbymeansofpara−paracouplingandcontrolled
overoxidation in good to excellent yields. Product 2g revealed
para−meta selectivity as a single regioisomer in a comparable
manner to 2a, directedby the methoxy groups. Homocoupling of
naphthols was achieved in good yields (2h, 2i) and short reaction
times.Electron-deficient2jwassmoothlyformedusingtriflicacid
instead of TFA. Based on the remarkable work by Pappo and co-
workers, we aimed to achieve selective cross-coupling of phenols
and arenes using the developed reaction conditions.3d,18 Cross-
coupling required only a slight increase of catalyst loading,
yielding the desired products in high yields, perfect regioselec-
tivity, and fast reaction rate (2k, 2m−2p). Notably, phenol−
phenol heterocoupling was successfully performed (2l).
Systematic optimization of the reaction conditions provided a
controllable formation of overoxidation product such as
Pummerer-type ketone 2q (Scheme 3). Inverse connectivity is
in contrast to the known formation of Pummerer ketones, which
usually proceeds by means of ortho−para coupling and
subsequent 1,4-addition.19 Changing the solvent to DCM/
HFIP allowed the conversion of 2a to 2q in good yields and
revealed the course of the reaction. Additionally, phenol 1a was
converted to 2q in a one-potreaction. This annulation represents
anunprecedentedexampleofoxidativecouplingforthesynthesis
of novel inverse Pummerer-type ketones controlled by the
connectivity achieved within the first coupling step. Next, we
pointed our attention to the oxidative coupling of anilides.
Dehydrogenative coupling of phenols is well-known to proceed
via homolytical O−H bond cleavage and generation of phenoxy
a
Reaction conditions: 1 (0.5 mmol, 1 equiv), NOBF4 (12.5 μmol, 2.5
mol %) in 4:1 DCM/TFA (0.05 M), −15 °C, 1 h under air
b
atmosphere. 1 (0.2 mmol, 1 equiv), NOBF4 (0.02 mmol, 10 mol %),
KB(C6F5)4 (0.04 mmol, 20 mol %) in HFIP (0.05 M), 0 °C, 1 h
under air atmosphere. Using NaNO2 (0.06 mmol, 30 mol %), TfOH
c
d
(2 equiv) in MeCN. Reaction conditions for cross-coupling: 1 (0.25
mmol, 1 equiv), arene (0.75 mmol, 3 equiv, in red), NOBF4 (18.5
μmol, 7.5 mol %) in 4:1 DCM/TFA (0.1 M), 0 °C, 1 h under air
atmosphere.
Scheme 3. Synthesis of Inverse Pummerer-Type Ketone via
Stepwise and One-Pot Oxidative Annulation
radicals.Basedonthestructuralsimilarityofphenolsandanilides,
we expected anilides to be a suitable substrate for the developed
B
DOI: 10.1021/acs.orglett.8b01631
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methodology. Consequently, we assumed that coupling might
proceed by an initial N−H bond cleavage. We found that N-
phenylacetamide (3a) efficiently dimerized using 20 mol % of
nitrosonium salt (Scheme 4). We observed a stronger tendency
demanding adamantyl group did not alter the outcome of the
reaction, yielding 4i in 75% yield. 4j was obtained as a single
regioisomer, and the naphthyl substituent remained untouched
under the developed reaction conditions. Based on the observed
difference in reactivity between phenols and anilides, we
conducted a set of selective phenol−anilide cross-coupling
reactions. Unprecedented cross-coupling products 4k−4n were
obtainedingoodyield,excellentselectivity,andfastreactionrates.
Chemical differentiation between redox-active phenols and
anilides is potentially a unique feature of nitrosonium salt
catalysis. Tostresstheutilityofthe developedoxidativecoupling,
coupling of anilide 3a was repeated on 1 g scale. The product was
formed unaffectedly in short reaction time and only slightly
reduced yield.
a
Scheme 4. Scope of the Catalytic Anilide Coupling
Afterwedisclosedthescopeofthiscatalyticoxidativecoupling,
the reaction mechanism was studied (see the Supporting
Information for the details, Schemes S1−S5). When the reaction
was conducted under argon atmosphere and residual oxygen
removed from the solvent, no product was formed for both
phenols and anilides (Schemes S2a and S5a). According to our
hypothesis,oxidativecouplingisinitiatedbyhomolyticalO−Hor
N−H bond cleavage. This pathway was blocked through
functionalization of the heteroatom via methylation. For both
substrates, no conversion was observed (Schemes S2b and S5b),
whichexcludestheformationofaradicalcationspeciesthrougha
direct single-electron transfer. Finally, oxidative coupling was
repeatedinthepresenceofradicaltrapbutylatedhydroxytoluene.
Although no homocoupling product was detected, formation of
scavenging adducts was observed (Schemes S2c and S5c). These
results support the proposed homology between phenol and
anilide coupling under the reaction conditions.
Based on the control experiments, a mechanism is outlined in
Figure 2. Initially, the substrates are oxidized by homolytical
a
Reaction conditions: 3 (0.2 mmol, 1 equiv), NOBF4 (0.04 mmol, 20
mol %) in 2:1 DCM/TFA (0.1 M), 0 °C under air atmosphere.
b
c
NOBF4 (0.10 μmol, 5 mol %). Reaction conditions for cross-
coupling: 1 (0.2 mmol, 1 equiv, in red), 3 (0.6 mmol, 3 equiv),
NOBF4 (15 μmol, 7.5 mol %) in 3:1 DCM/TFA (0.1 M), 0 °C, 1 h
under air atmosphere.
for electrophilic nitration of the starting material, due to higher
nucleophilicity, which could be easily bypassed by increasing the
acid−solvent ratio (Table S3). We began our scope of
investigation for the coupling of different anilides. Products 4b
and 4c were obtained in good yields. However, anilides with
electron-withdrawing substituents were not reactive under the
developed reaction conditions, due to higher redox potentials.
Afterward, we tested various groups on the nitrogen atom.
Coupling of N-phenylbenzene-sulfonamide led to 4d in 53%
yield. Anilides equipped with different benzoyl groups were also
suitable for the aerobic coupling (4e−4h). Notably, even
functional groups with a strong electron-withdrawing effect
suchasanitrogroupwerewelltolerated(4f).Thehighlysterically
Figure 2. Proposed reaction mechanism. PG = protecting group.
heteroatom−hydrogen bond cleavage to form A. Intermediate A
reacts with a second equivalent of the substrate, or a nucleophilic
arene in the case of heterocoupling, by radical SEAr, and
subsequent rearomatization generates intermediate B. A second
oxidation by nitrosonium tetrafluoroborate leads to aromatiza-
tion andformationofproducts 2or4. Nitrogen monoxide, which
is formed upon oxidation of the starting material, is oxidized by
molecular oxygen generating nitrogen dioxide. Nitrogen dioxide
dimerizes to form dinitrogen tetroxide, which is in equilibrium
C
DOI: 10.1021/acs.orglett.8b01631
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P. V. G.; Dey, S.; Allen, S. E.; Niederer, K. A.; Sung, P.; Hewitt, K.;
Torruellas,C.;Herling,M.R.;Kozlowski,M.C.Org.Lett.2017,19,5505.
(4)(a)Constantin,M.-A.;Conrad,J.;Beifuss,U.GreenChem.2012,14,
2375. (b) Morimoto, K.; Sakamoto, K.; Ohnishi, Y.; Miyamoto, T.; Ito,
M.; Dohi, T.; Kita, Y. Chem. - Eur. J. 2013, 19, 8726. (c) Kita, Y.; Dohi, T.
Chem. Rec. 2015, 15, 886. (d) Morimoto, K.; Sakamoto, K.; Ohshika, T.;
Dohi, T.; Kita, Y. Angew. Chem., Int. Ed. 2016, 55, 3652. (e) Sharma, S.;
Parumala, S. K. R.;Peddinti,R. K. J. Org.Chem. 2017, 82, 9367.(f)More,
N. Y.;Jeganmohan, M. Eur. J. Org. Chem. 2017, 2017, 4305. (g)More, N.
Y.; Jeganmohan, M. Chem. Commun. 2017, 53, 9616.
(5) (a) Kirste, A.; Hayashi, S.; Schnakenburg, G.; Malkowsky, I. M.;
Stecker, F.; Fischer, A.; Fuchigami, T.; Waldvogel, S. R. Chem. - Eur. J.
2011,17,14164.(b)Jiang,Q.;Sheng,W.;Tian,M.;Tang,J.;Guo,C.Eur.
J. Org. Chem. 2013, 2013, 1861.
(6)(a)Ito,M.;Kubo,H.;Itani,I.;Morimoto,K.;Dohi,T.;Kita,Y.J.Am.
Chem. Soc. 2013, 135, 14078. (b) Jacquemot, G.; Menard, M.-A.;
L’Homme, C.; Canesi, S. Chem. Sci. 2013, 4, 1287. (c) Fujimoto, S.;
Matsumoto, K.; Iwata, T.; Shindo, M. Tetrahedron Lett. 2017, 58, 973.
(7)(a)Matsumoto,K.;Dougomori,K.;Tachikawa,S.;Ishii,T.;Shindo,
M.Org.Lett.2014,16,4754.(b)Matsumoto,K.;Yoshida,M.;Shindo,M.
Angew. Chem., Int. Ed. 2016, 55, 5272. (c) Morimoto, K.; Koseki, D.;
Dohi, T.; Kita, Y. Synlett 2017, 28, 2941.
(8)(a)Waldvogel,S. R.PureAppl. Chem.2010,82,1055.(b)Kirste,A.;
Schnakenburg,G.;Stecker,F.;Fischer,A.;Waldvogel,S.R.Angew.Chem.,
Int. Ed. 2010, 49, 971. (c) Kirste, A.; Elsler, B.; Schnakenburg, G.;
Waldvogel, S. R. J. Am. Chem. Soc. 2012, 134, 3571. (d) Elsler, B.;
Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. Angew.
Chem., Int. Ed. 2014, 53, 5210. (e) Schulz, L.; Enders, M.; Elsler, B.;
Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. Angew.
Chem., Int. Ed. 2017, 56, 4877. (f) Wiebe, A.; Lips, S.; Schollmeyer, D.;
Franke, R.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2017, 56, 14727.
(g) Waldvogel, S. R.; Dahms, B.; Franke, R. ChemElectroChem 2018, 5,
1249.
with NONO3 by means of disproportionation. Under acidic
conditions, a nitrosonium and a nitronium ion are released upon
protonation. Finally, the nitronium ion can oxidize nitrogen
monoxide instead of molecular oxygen, maintaining the catalytic
cycle.
Insummary,wedevelopedthecatalytic,aerobic,andmetal-free
dehydrogenative coupling of electron-rich phenols and anilides
using nitrosonium salts as the catalyst and ambient oxygen as the
sole oxidant. Phenols were efficiently homocoupled, revealing
unusual selectivity for biaryl formation. Unusual connectivity
translated into the synthesis of an unprecedented inverse
Pummerer-type ketone in good yields. Further, phenol−arene
heterocoupling was disclosed in excellent yield and selectivity.
Finally, we found evidence that phenols and anilides share a
similar pathway in oxidative coupling by synthesizing a set of
dimerized anilides and successfully performing the phenol−
anilide cross-coupling. Application of nitrosonium salts repre-
sents a sustainable and unprecedented entry into oxidative
coupling methodology. We believe that the presented method-
ology will accelerate development in the field of sustainable,
metal-free, andcatalyticdehydrogenativecouplingreactions, due
to the accessibility and low costs of nitrosonium salts and
exclusion of the requirement for any specialized equipment or
reagents.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.8b01631.
Details on the optimization, experimental procedures, and
compound characterization data (PDF)
(9) Yan, M.; Kawamata, Y.; Baran, P. S. Angew. Chem., Int. Ed. 2018, 57,
4149.
(10)Folgueiras-Amador,A. A.;Philipps,K.;Guilbaud,S.;Poelakker, J.;
Wirth, T. Angew. Chem., Int. Ed. 2017, 56, 15446.
AUTHOR INFORMATION
Corresponding Author
■
(11) (a) Lee, K. Y.; Kuchynka, D. J.; Kochi, J. K. Inorg. Chem. 1990, 29,
4196. (b) Zhai, L.; Shukla, R.; Wadumethrige, S. H.; Rathore, R. J. Org.
Chem.2010,75,4748.(c)Colomer,I.;Batchelor-McAuley,C.;Odell,B.;
Donohoe, T. J.; Compton, R. G. J. Am. Chem. Soc. 2016, 138, 8855.
(12)(a)Radner, F. J. Org. Chem. 1988, 53, 702. (b)Kim, E. K.;Kochi,J.
K.J.Org.Chem.1989,54,1692.(c)Tanaka,M.;Nakashima,H.;Fujiwara,
M.; Ando, H.; Souma, Y. J. Org. Chem. 1996, 61, 788.
*E-mail: andrey.antonchick@mpi-dortmund.mpg.de.
ORCID
Andrey P. Antonchick: 0000-0003-0435-9443
Notes
(13) (a) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41,
3381. (b)Allen, S. E.;Walvoord, R. R.;Padilla-Salinas, R.;Kozlowski, M.
C. Chem. Rev. 2013, 113, 6234.
(14) (a) Su, B.; Li, L.; Hu, Y.; Liu, Y.; Wang, Q. Adv. Synth. Catal. 2012,
354, 383. (b) Bering, L.; Paulussen, F. M.; Antonchick, A. P. Org. Lett.
2018, 20, 1978.
(15) Bandlish, B. K.; Shine, H. J. J. Org. Chem. 1977, 42, 561.
(16) (a) Bering, L.; Antonchick, A. P. Org. Lett. 2015, 17, 3134.
(b)Manna,S.;Antonchick,A.P.Chem.-Eur.J.2017,23,7825.(c)Bering,
L.; Antonchick, A. P. Chem. Sci. 2017, 8, 452.
(17) Barjau, J.; Schnakenburg, G.; Waldvogel, S. R. Angew. Chem., Int.
Ed. 2011, 50, 1415.
(18) (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 8754. (b) Stuart, D. R.; Fagnou, K. Science 2007,
316, 1172. (c)Gaster, E.;Vainer, Y.;Regev, A.;Narute, S.;Sudheendran,
K.; Werbeloff, A.; Shalit, H.; Pappo, D. Angew. Chem., Int. Ed. 2015, 54,
4198. (d) Dyadyuk, A.; Sudheendran, K.; Vainer, Y.; Vershinin, V.;
Shames, A. I.; Pappo, D. Org. Lett. 2016, 18, 4324.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.P.A. acknowledges the support of the DFG (Heisenberg
scholarship AN 1064/4-1) and the Boehringer Ingelheim
Foundation (Plus 3). L.B. is supported by the Verband der
Chemischen Industrie e.V.
REFERENCES
■
(1)(a)Yamaguchi,J.;Yamaguchi,A.D.;Itami,K.Angew.Chem.,Int.Ed.
2012, 51, 8960. (b)Girard,S. A.;Knauber, T.;Li, C.-J. Angew. Chem.,Int.
Ed. 2014, 53, 74. (c) Sun, C.-L.; Shi, Z.-J. Chem. Rev. 2014, 114, 9219.
(2) (a) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc. Rev.
2009,38,3193.(b)Grimsdale,A.C.;LeokChan,K.;Martin,R.E.;Jokisz,
P. G.; Holmes, A. B. Chem. Rev. 2009, 109, 897. (c) Bringmann, G.;
Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011, 111, 563.
(3) (a) Dewar, M. J. S.; Nakaya, T. J. Am. Chem. Soc. 1968, 90, 7134.
(b) Smrcina, M.; Vyskocil, S.; Maca, B.; Polasek, M.; Claxton, T. A.;
Abbott, A. P.; Kocovsky, P. J. Org. Chem. 1994, 59, 2156. (c) Lee, Y. E.;
Cao, T.; Torruellas, C.; Kozlowski, M. C. J. Am. Chem. Soc. 2014, 136,
6782. (d) Libman, A.; Shalit, H.; Vainer, Y.; Narute, S.; Kozuch, S.;
Pappo, D. J. Am. Chem. Soc. 2015, 137, 11453. (e)Shalit, H.; Libman, A.;
Pappo,D.J.Am.Chem.Soc.2017,139,13404.(f)Vershinin,V.;Dyadyuk,
A.;Pappo,D.Tetrahedron2017,73,3660.(g)Kang,H.;Lee,Y.E.;Reddy,
(19) Blakemore, P. R.; White, J. D. Chem. Commun. 2002, 1159.
D
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