Rh(II)-Catalyzed C-H Alkylation of Benzylamines with Unactivated Alkenes: The Influence of Acid on Linear and Branch Selectivity

Article abstract of DOI:10.1021/acs.orglett.1c01224

The Rh-catalyzed C-H alkylation of benzylamine derivatives with unactivated 1-alkenes that proceeds via a picolinamide directing group is reported. The crucial role of an acid additive in this transformation is confirmed. Aromatic acids showed high linear selectivity, and aliphatic acids provided branched alkylation products as the major product. The reaction has a broad scope for benzylamines and alkenes. Deuterium labeling experiments suggest that a Rh-carbene intermediate is involved in the case of linear product formation. A different reaction pathway, however, appears to be involved in the case of branched alkylation products, and this pathway also appeared to be a minor pathway in linear-selective reactions.

Full text of DOI:10.1021/acs.orglett.1c01224

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Letter
Rh(II)-Catalyzed C−H Alkylation of Benzylamines with Unactivated
Alkenes: The Influence of Acid on Linear and Branch Selectivity
Amrita Das and Naoto Chatani*
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ABSTRACT: The Rh-catalyzed C−H alkylation of benzylamine derivatives with unactivated 1-alkenes that proceeds via a
picolinamide directing group is reported. The crucial role of an acid additive in this transformation is confirmed. Aromatic acids
showed high linear selectivity, and aliphatic acids provided branched alkylation products as the major product. The reaction has a
broad scope for benzylamines and alkenes. Deuterium labeling experiments suggest that a Rh-carbene intermediate is involved in the
case of linear product formation. A different reaction pathway, however, appears to be involved in the case of branched alkylation
products, and this pathway also appeared to be a minor pathway in linear-selective reactions.
Scheme 1. ortho-Alkylation of Benzylamines
he formation of C−C bonds via reactions using
Tunactivated alkenes is a subject of current interest in
the field of C−H bond activation.1 A pioneering example of
C−H alkylation with alkenes was reported by Murai in 1993
who used ruthenium catalysts in conjunction with a ketone as a
directing group to achieve ortho-C−H selective alkylation.2
Since then, many reports on this subject have appeared but the
scope of alkenes in C−H alkylation is still limited to activated
alkenes, such as α,β-unsaturated carbonyl compounds, styrene
derivatives, and norbornene.1 Furthermore, only a few cases of
branch-selective C−H alkylation using unactivated alkenes
have been reported.3
Given the fact that benzylamine skeletons are widely found
in various pharmaceutical and synthetic molecules,4 its C−H
functionalization with unactivated alkenes is a subject of
interest. The reported method for the C−H alkylation of
benzylamines involves the use of alkyl halides as coupling
partners with the use of stoichiometric amounts of a base,5
which results in the generation of hazardous products as waste
materials (Scheme 1a).6 On the other hand, C−H alkylation
with alkenes offers a much more environmentally friendly
reaction because all the molecules of the substrates and alkenes
are fully utilized in forming the desired products. Given our
ongoing interest in C−H alkylation reactions,7 we investigated
the ortho-alkylation of benzylamines with unactivated alkenes.
In our previous work, we reported the Rh-catalyzed linear-
selective, picolinamide chelation assisted C−H alkylation of
benzylamine derivatives with activated alkenes, such as
Received: April 10, 2021
Published: May 14, 2021
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Org. Lett. 2021, 23, 4273−4278
© 2021 American Chemical Society
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acrylates, styrenes, and maleimides.7l Our objective in this
study was to pursue the C−H alkylation of benzylamine
derivatives with unactivated 1-alkenes. The results of our
investigation highlight the crucial role of acid additives in
achieving a high linear selectivity as well as methods for tuning
the regioselectivity between linear and branch products
(Scheme 1b). The results of deuterium labeling experiments
suggest that two different reaction pathways are operative, one
for linear and another for branch products.
a
Scheme 2. Scope of Alkenes and Amines (Linear Selective)
The reaction was optimized by using the N-pyridinecarbonyl
protected 2-methylbenzylamine 1a and 1-heptene as model
substrates. We screened a series of acid additives8 for this
reaction using 5 mol % of Rh2(OAc)4 as a catalyst and 5 equiv
of 1-heptene at 170 °C under neat conditions for 16 h (Table
1). We initially examined aromatic acids as additives, and
Table 1. Effect of an Additive in the C−H Alkylation of 1a
a
with 1-Heptene
a
a
Reaction conditions: 1a (0.2 mmol), 1-heptene (1.0 mmol),
Reaction conditions: 1 (0.2 mmol), 1-alkene (1.0 mmol),
Rh2(OAc)4 (0.01 mmol), 2,6-difluorobenzoic acid (0.4 mmol) at
Rh2(OAc)4 (0.01 mmol), acid additive (0.4 mmol) at 170 °C for
16 h. Yields and linear/branch (l/b) ratios were determined by H
NMR analysis of the crude mixture. n.d. = not detected.
1
1
170 °C for 16 h. Linear/branch (l/b) ratio was determined by H
NMR analysis of the crude mixture. Isolated yields are shown. Gram
b
scale (5 mmol scale) reaction was performed where 2 mL toluene was
c
additionally used as solvent. 0.5 mL of toluene was additionally used
d
as solvent. Due to the complexity of the NMR spectrum of the crude
among them, 2-trifluoromethylbenzoic acid provided 64%
linear selectivity. Finally, to our delight, the use of 2,6-
difluorobenzoic acid gave excellent yields (96% NMR yield) of
2a and 2a′ with a linear/branch ratio of 85/15. In the absence
of an acid additive, only a 30% yield of product was observed
with a nearly 1:1 ratio of linear and branch products. After
screening several aliphatic acids, we found that the formation
of the branched product was slightly favored over the linear
product. Finally, phenylpropiolic acid provided the desired
product in high yield with the ratio 60/40 in favor of the
branched product 2a′. We were not able to improve the ratio
for branch selectivity further. However, it is noteworthy that
the acid used in the reaction plays a crucial role in tuning the
material, the linear/branch (l/b) ratio was determined after isolation.
ratio of linear and branched alkylation products and the
reaction involves a rare example of branch-selective C−H
alkylation with unactivated alkenes.
With the optimized reaction conditions in hand, we next
examined the substrate scope for this linear-selective alkylation
reaction by using 2 equiv of 2,6-difluorobenzoic acid as an
additive (Scheme 2). The reaction of 1a with 1-heptene gave
the desired product 2a in 84% isolated yield with an 85/15 = l/
b (linear/branch) ratio. The use of 5-methyl-1-hexene gave 2c
in good yield and high selectivity (71%, l/b = 91/9). Some
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functional groups were suitable for use in this reaction, such as
acetate (2d), ketone (2f), and cyano (2h), and all provided the
desired products in good to high yields. This alkylation
reaction was selective for monosubstituted alkenes over
disubstituted alkene moieties; thus, 2e was exclusively obtained
and the disubstituted alkene moiety remained intact. 4,4-
Disubstituted and allyl substituted alkenes (2i−2l) generally
showed an increased ratio of linear/branch products
containing an ester (2j) and other functionalities with
satisfactory yield and up to 95% linear selectivity (2i).
Biologically active substrates9 also reacted to afford the
corresponding alkylation products (2m and 2n). Vinyl-
cyclohexene was one of the more suitable alkenes for this
reaction, providing 2o in high yield and with high selectivity.
Next, the scope of benzylamines for this reaction was
examined. The 2-methoxybenzylamine derivative was reacted
with vinylhexane to obtain 2p in good yield with high
selectivity. The electron-deficient 2-trifluoromethyl substituent
also provided the desired product 2q in high yield and
excellent regioselectivity (l/b = 97/3). A naphthylmethylamine
(2r) derived substrate was well tolerated for this reaction.
The scope for branch-selective reaction was then inves-
tigated using phenylpropiolic acid as the additive (Scheme 3).
Scheme 4. Deprotection of Directing Group
Deuterium labeling experiments were conducted in order to
elucidate the reaction mechanism for this alkylation reaction
(Scheme 5). When the substrate 1a-D was reacted in the
Scheme 5. Deuterium Labelling Experiments
a
Scheme 3. Scope of Alkenes (Branch Selective)
absence of the alkene coupling partner in both systems, H/D
scrambling at the ortho-position was observed in the recovered
starting material in both cases (Scheme 5a and b), indicating
that the ortho-C−H bond cleavage is reversible. When the
deuterated substrate 1a-D was reacted with 1-heptene under
the optimized catalytic conditions using 2,6-difluorobenzoic
acid as the additive for a shorter reaction time, 0.40 D was
incorporated at the x position (Scheme 5c). However,
deuterium incorporation was also observed at the y position
although to a lesser extent (0.19 D). These data imply that the
deuterium atom of the ortho C−D bond in 1a-D is transferred
to both the x and y positions. It therefore appears that the
reaction proceeds via two different mechanisms for the
formation of linear-selective product. On the other hand,
when the branch-selective reaction was carried out using 1a-D
in the presence of phenylpropiolic acid as the additive,
deuterium incorporation was only observed at the x position
(0.37 D) and no deuterium incorporation was detected at the y
position (0.00 D) (Scheme 5d). This result suggests that the
branch-selective reaction proceeds via one major pathway
a
Reaction conditions: 1 (0.2 mmol), 1-alkene (1.0 mmol),
Rh2(OAc)4 (0.01 mmol), phenylpropiolic acid (0.4 mmol) at 170
°C for 16 h. Branch/linear (b/l) ratio was determined by H NMR
analysis of the crude mixture. Isolated yields were shown.
1
It was found that 1-hexadecene (2b′) also gave the desired
products with up to 65% branch selectivity and 2c′ was
obtained from 5-methyl-1-hexene in high yield with a 62/38
ratio. Some functional groups such as ester (2d′) and ketone
(2f′)-containing alkenes successfully led to the formation of
branch products as major products. These results are only
preliminary results, indicating that the reaction was branch-
selective, but that further optimization would still be needed.
After the successful removal of the picolinamide directing
group,10 an excellent yield was achieved with the complete
retention of linear/branch (l/b) selectivity (Scheme 4).
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where the deuterium atom from ortho C−D bond is transferred
only to the x position.
A reaction mechanism is proposed based on the results of
deuterium labeling experiments (Scheme 6). Throughout the
transferred to the x position (Scheme 5c). Finally, reductive
elimination occurs in the presence of the carboxylic acid to
give the desired linear product 2a and regeneration of the Rh-
species continues the catalytic cycle. The other mechanism for
the formation of branched products involves the elimination of
the carboxylic acid from A to generate the intermediate E.
Oxidative addition of the ortho C−H bond in E leads to the
formation of F via a reversible pathway. As a result, H/D
scrambling occurs at the ortho C−D bond (Scheme 5a and b).
An alkene insertion generates both intermediate G (as
evidenced by the incorporation of 0.37 D at the x position
of 5′, Scheme 5d) or H (as evidenced by the incorporation of
0.19 D at the y position of 5, Scheme 5c). Subsequent
reductive elimination in the presence of a carboxylic acid takes
place from G to furnish the branch product 2a′ and from H to
give the linear product 2a. In this pathway, the ortho C−H
bond is transferred to the y position in the branch product 2a′.
This path also appears to be the minor pathway for the linear
alkylation reaction 2a.
Scheme 6. Proposed Catalytic Cycle
In summary, we report herein the Rh(II)-catalyzed C−H
alkylation of benzylamine derivatives with unactivated alkenes
by utilizing a picolinamide directing group. The crucial role of
acid additives for producing high yields as well as a high linear/
branch ratio was realized. Though there is still room for
improving the branch selectivity, it is noteworthy that this
preliminary investigation reports a rare example of the
production of branch-selective alkylation products with
unactivated alkenes. Mechanistic investigations indicate that
two different reaction pathways are operative for product
formation. A carbene mechanism is proposed as a major
pathway for the formation of a linear product, and a reversible
hydrometalation pathway is operative in the case of the
formation of the branch product as well as the minor pathway
for linear alkylation. Further studies directed to improving
branch selectivity and a detailed understanding of the role of
the acid additive in tuning the branch/linear ratio are currently
underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01224.
Experimental procedures and characterization data of all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
proposed catalytic cycle, we used the term [Rh] as a rhodium
center because no clear evidence was obtained to confirm that
the structure of the actual catalytic species of rhodium was
either monometallic or bimetallic.3h,11 The oxidative addition
of a N−H bond to a Rh-center gives the Rh(IV) species A.12
Two different catalytic cycles from the rhodium intermediate A
are proposed to explain the formation of linear and branch
products. Alkene insertion into the Rh−H bond in A gives the
intermediate B.7l In the next step, α-elimination of the
carboxylic acid in B results in the formation of a carbene
intermediate C which appears to be the major pathway for
producing the linear alkylation product.7e,j,l From C, C−H
insertion into the carbene occurs to give intermediate D.13
This is consistent with the deuterium labeling experiment in
which a deuterium atom of the ortho C−D bond is largely
Naoto Chatani − Department of Applied Chemistry, Faculty of
Engineering, Osaka University, Suita, Osaka 565-0871,
Japan; orcid.org/0000-0001-8330-7478;
Email: chatani@chem.eng.osaka-u.ac.jp
Author
Amrita Das − Department of Applied Chemistry, Faculty of
Engineering, Osaka University, Suita, Osaka 565-0871,
Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01224
Notes
The authors declare no competing financial interest.
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(5) Zhao, Y.; Chen, G. Palladium-Catalyzed Alkylation of ortho-
C(sp2)−H Bonds of Benzylamide Substrates with Alkyl Halides. Org.
Lett. 2011, 13, 4850−4853.
(6) For a recent review on alkylation with unactivated alkyl halides,
see: Ankade, S. B.; Shabade, A. B.; Soni, V.; Punji, B. Unactivated
Alkyl Halides in Transition-Metal-Catalyzed C-H Bond Alkylation.
ACS Catal. 2021, 11, 3268−3292.
ACKNOWLEDGMENTS
■
This work was supported by Grant in Aid for Specially
Promoted Research by MEXT (No. 17H06091).
REFERENCES
■
(1) For selected recent reviews on C−H functionalization reactions
with alkenes, see: (a) Dong, Z.; Ren, Z.; Thompson, S. J.; Xu, Y.;
Dong, G. Transition-Metal-Catalyzed C−H Alkylation Using Alkenes.
Chem. Rev. 2017, 117, 9333−9403. (b) Chatani, N. The Use of a
Rhodium Catalyst/8-Aminoquinoline Direct Group in the C−H
Alkylation of Aromatic Amides with Alkenes: Possible Generation of a
Carbene Intermediate from an Alkene. Bull. Chem. Soc. Jpn. 2018, 91,
(7) For selected examples on C-H alkylation with alkenes from our
group, see: (a) Shibata, K.; Chatani, N. Rhodium-Catalyzed
Alkylation of C−H Bonds in Aromatic Amides with α,β -Unsaturated
Esters. Org. Lett. 2014, 16, 5148−5151. (b) Shibata, K.; Yamaguchi,
T.; Chatani, N. Rhodium-Catalyzed Alkylation of C−H Bonds in
Aromatic Amides with Styrenes via Bidentate − Chelation Assistance.
Org. Lett. 2015, 17, 3584−3587. (c) Shibata, K.; Chatani, N.
Rhodium-Catalyzed Regioselective Addition of the ortho C-H Bond in
Aromatic Amides to the C-C Double Bond in α,β-Unsaturated γ-
Lactones and Dihydrofurans. Chem. Sci. 2016, 7, 240−245. (d) He,
Q.; Yamaguchi, T.; Chatani, N. Rh(I)-Catalyzed Alkylation of ortho-
C−H Bonds in Aromatic Amides with Maleimides. Org. Lett. 2017,
19, 4544−4547. (e) Shibata, K.; Natsui, S.; Tobisu, M.; Fukumoto, Y.;
Chatani, N. An Unusual Endo-Selective C-H Hydroarylation of
Norbornene by the Rh(I)-Catalyzed Reaction of Benzamides. Nat.
Commun. 2017, 8, 1−8. (f) He, Q.; Chatani, N. A Synthesis of 3,4-
Dihydroisoquinolin-1(2H)-One via the Rhodium- Catalyzed Alkyla-
tion of Aromatic Amides with N-Vinylphthalimide. J. Org. Chem.
2018, 83, 13587−13594. (g) Rej, S.; Chatani, N. Rhodium(I)-
Catalyzed C8-Alkylation of 1-Naphthylamide Derivatives with
Alkenes through a Bidentate Picolinamide Chelation System. ACS
Catal. 2018, 8, 6699−6706. (h) Rej, S.; Chatani, N. Rhodium(I)-
Catalyzed Mono-Selective C−H Alkylation of Benzenesulfonamides
with Terminal Alkenes. Chem. Commun. 2019, 55, 10503−10506.
(i) Wang, C.; Rej, S.; Chatani, N. Ruthenium(II)-Catalyzed
Alkylation of C-H Bonds in Aromatic Amides with Vinylsilanes.
Chem. Lett. 2019, 48, 1185−1187. (j) Yamaguchi, T.; Natsui, S.;
Shibata, K.; Yamazaki, K.; Rej, S.; Ano, Y. Rhodium-Catalyzed
Alkylation of C−H Bonds in Aromatic Amides with Non-Activated 1-
Alkenes: The Possible Generation of Carbene Intermediates from
Alkenes. Chem. - Eur. J. 2019, 25, 6915−6919. (k) Ohara, N.; Rej, S.;
Chatani, N. Rh(I)-Catalyzed Addition of the Ortho C-H Bond in Aryl
Sulfonamides to Maleimides. Chem. Lett. 2020, 49, 1053−1057.
(l) Das, A.; Chatani, N. Rh(I)- and Rh(II)-Catalyzed C−H Alkylation
of Benzylamines with Alkenes and Its Application in Flow Chemistry.
Chem. Sci. 2021, 12, 3202−3209.
211−222. (c) Fernández, D. F.; Mascarenas, F.; López, F. Catalytic
̃
Addition of C−H Bonds across C−C Unsaturated Systems Promoted
by Iridium (I) and Its Group IX Congeners. Chem. Soc. Rev. 2020, 49,
7378−7405. (d) Rej, S.; Das, A.; Chatani, N. Strategic Evolution in
Transition Metal-Catalyzed Directed C−H Bond Activation and
Future Directions. Coord. Chem. Rev. 2021, 431, 213683.
(2) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Efficient Catalytic Addition of Aromatic
Carbon-Hydrogen Bonds to Olefins. Nature 1993, 366, 529−531.
(3) For a review on branch-selective C−H alkylation with alkenes,
see: (a) Crisenza, G. E. M.; Bower, J. F. Branch Selective Murai-Type
Alkene Hydroarylation Reactions. Chem. Lett. 2016, 45, 2−9. For
selected examples of branch-selective C−H alkylation with alkenes,
see: (b) Kuninobu, Y.; Matsuki, T.; Takai, K. Rhenium-Catalyzed
Regioselective Alkylation of Phenols. J. Am. Chem. Soc. 2009, 131,
9914−9915. (c) Crisenza, G. E. M.; McCreanor, N. G.; Bower, J. F.
Branch-Selective, Iridium-Catalyzed Hydroarylation of Monosubsti-
tuted Alkenes via a Cooperative Destabilization Strategy. J. Am. Chem.
Soc. 2014, 136, 10258−10261. (d) Crisenza, G. E. M.; Sokolova, O.
O.; Bower, J. F. Branch-Selective Alkene Hydroarylation by
Cooperative Destabilization : Iridium-Catalyzed Ortho-Alkylation of
Acetanilides. Angew. Chem., Int. Ed. 2015, 54, 14866−14870. (e) Ebe,
Y.; Nishimura, T. Iridium-Catalyzed Branch-Selective Hydroarylation
of Vinyl Ethers via C−H Bond Activation. J. Am. Chem. Soc. 2015,
137, 5899−5902. (f) Zell, D.; Bursch, M.; Muller, V.; Grimme, S.;
̈
Ackermann, L. Full Selectivity Control in Cobalt(III)-Catalyzed C−H
Alkylations by Switching of the C−H Activation Mechanism. Angew.
Chem., Int. Ed. 2017, 56, 10378−10382. (g) Xing, D.; Dong, G.
Branched-Selective Intermolecular Ketone α-Alkylation with Unac-
tivated Alkenes via an Enamide Directing Strategy. J. Am. Chem. Soc.
2017, 139, 13664−13667. (h) Rej, S.; Chatani, N. Rh(II)-Catalyzed
Branch-Selective C−H Alkylation of Aryl Sulfonamides with Vinyl-
silanes. Chem. Sci. 2020, 11, 389−395. For a recent report on branch-
selective alkenylation from our group, see: (i) Khake, S. M.; Yamazaki,
K.; Ano, Y.; Chatani, N. Iridium(III)-Catalyzed Branch-Selective C−
H Alkenylation of Aniline Derivatives with Alkenes. ACS Catal. 2021,
11, 5463−5471.
(8) For selected reviews on the role of acid additives in C-H
functionalizations, see: (a) Ackermann, L. Carboxylate-Assisted
Transition-Metal-Catalyzed C−H Bond Functionalizations: Mecha-
nism and Scope. Chem. Rev. 2011, 111, 1315−1345. (b) Arockiam, P.
B.; Bruneau, C.; Dixneuf, P. H. Ruthenium(II)-Catalyzed C−H Bond
Activation and Functionalization. Chem. Rev. 2012, 112, 5879−5918.
See also: (c) Feng, Y.; Wang, Y.; Landgraf, B.; Liu, S.; Chen, G. Facile
Benzo-Ring Construction via Palladium-Catalyzed Functionalization
of Unactivated sp3 C-H Bonds under Mild Reaction Conditions. Org.
Lett. 2010, 12, 3414−3417.
(4) (a) Kolhatkar, R.; Cook, C. D.; Ghorai, S. K.; Deschamps, J.;
Beardsley, P. M.; Reith, M. E. A.; Dutta, A. K. Further Structurally
Constrained Analogues of Cis-(6-Benzhydrylpiperidin-3-Yl) Benzyl-
amine with Elucidation of Bioactive Conformation: Discovery of 1,4-
Diazabicyclo[3.3.1]nonane Derivatives and Evaluation of Their
Biological Properties for the Monoamine Transporters. J. Med.
Chem. 2004, 47, 5101−−5113. (b) Xiao, K.; Chu, L.; Chen, G.;
Yu, J. Kinetic Resolution of Benzylamines via Palladium(II)-Catalyzed
C−H Cross-Coupling. J. Am. Chem. Soc. 2016, 138, 7796−7800.
(c) Mibu, N.; Yokomizo, K.; Sano, M.; Kawaguchi, Y.; Morimoto, K.;
Shimomura, S.; Sato, R.; Hiraga, N.; Matsunaga, A.; Zhou, J.-R.;
Ohata, T.; Aki, H.; Sumoto, K. Preparation and Antiviral Activity of
Some New C3- and CS-Symmetrical Tri-Substituted Triazine
Derivatives Having Benzylamine Substituents. Chem. Pharm. Bull.
2018, 66, 830−838. (d) Li, Y.; Yao, W.; Lin, J.; Li, F.; Wu, Y.; Xu, J.
Design, Synthesis, and Biological Activity of Novel Triazole
Sulfonamide Derivatives Containing a Benzylamine Moiety. J.
Heterocycl. Chem. 2019, 56, 2170−2178.
(9) For selected examples on bioacitivity of thymol and estrone, see:
́
́
̌
́
̌
́
(a) Mastelic, J.; Jerkovic, I.; Blazevic, I.; Poljak-Blazi, M.; Borovic, S.;
̌
̌
́
́
̌
́
̌
́
́
Ivancic-Bace, I.; Smrecki, V.; Zarkovic, N.; Brcic-Kostic, K.; Vikic-
́
Topic, D.; Muller, N. Comparative Study on the Antioxidant and
̈
Biological Activities of Carvacrol, Thymol, and Eugenol Derivatives. J.
Agric. Food Chem. 2008, 56, 3989−3996. (b) Pemp, D.; Esch, H. L.;
Hauptstein, R.; Möller, F. J.; Zierau, O.; Bosland, M. C.; Geppert, L.
N.; Kleider, C.; Schlereth, K.; Vollmer, G.; Lehmann, L. Novel Insight
in Estrogen Homeostasis and Bioactivity in the ACI Rat Model of
Estrogen-Induced Mammary Gland Carcinogenesis. Arch. Toxicol.
2019, 93, 1979−1992.
(10) O’Donovan, D. H.; De Fusco, C.; Spring, D. R. The Reductive
Cleavage of Picolinic Amides. Tetrahedron Lett. 2016, 57, 2962−2964.
(11) For a recent report on C-H oxygenation involving bimetallic
rhodium-electrocatalyst, see: Tan, X.; Massignan, L.; Hou, X.; Frey, J.;
Oliveira, J. C. A.; Hussain, M. N.; Ackermann, L. Rhoda-Electro-
4277
https://doi.org/10.1021/acs.orglett.1c01224
Org. Lett. 2021, 23, 4273−4278

Organic Letters
pubs.acs.org/OrgLett
Letter
catalyzed Bimetallic C-H Oxygenation by Weak O-Coordination.
Angew. Chem., Int. Ed. 2021, DOI: 10.1002/anie.202017359. See also
ref 3h.
(12) For selected examples on Rh(IV) species and N−H oxidative
addition, see: (a) Macgregor, S. A. Theoretical Study of the Oxidative
Addition of Ammonia to Various Unsaturated Low-Valent Transition
Metal Species. Organometallics 2001, 20, 1860−1874. (b) Mena, I.;
Casado, M. A.; García-orduna, P.; Polo, V.; Lahoz, F. J.; Fazal, A.;
̃
Oro, L. A. Direct Access to Parent Amido Complexes of Rhodium and
Iridium through N−H Activation of Ammonia. Angew. Chem., Int. Ed.
2011, 50, 11735−11738. (c) Veléz, E.; Betoré, M. P.; Casado, M. A.;
Polo, V. N−H Activation of Ammonia by [{M(μ -OMe)(Cod)}2] (M
= Ir, Rh) Complexes: A DFT Study. Organometallics 2015, 34, 3959−
3966. (d) Sinha, S. B.; Shopov, D. Y.; Sharninghausen, L. S.; Vinyard,
D. J.; Mercado, B. Q.; Brudvig, G. W.; Crabtree, R. H. A Stable
Coordination Complex of Rh(IV) in an N,O-Donor Environment. J.
Am. Chem. Soc. 2015, 137, 15692−15695.
(13) (a) Jones, N. D.; Lin, G.; Gossage, R. A.; McDonald, R.; Cavell,
R. G. Synthesis, Structure, and Reactivity of an Unusual Platinum
Olefin Carbene Complex, [(η4-cod)Pt{C(Ph2PNSiMe3)2-
κC,κN}]. Organometallics 2003, 22, 2832−2841. (b) Cantat, T.;
Demange, M.; Mézailles, N.; Ricard, L.; Jean, Y. Floch, P. Le. A
Bis(Thiophosphinoyl)Methylene Ruthenium Carbene Complex: Syn-
thesis, X-Ray Crystal Structure, and DFT Calculations of Its
Thermally Promoted Reverse α-Hydride Migration Process. Organo-
metallics 2005, 24, 4838−4841. (c) Heuclin, H.; Le Goff, X. F.;
Mézailles, N. Mixed (PS/PO)-Stabilized Geminal Dianion:
Facile Diastereoselective Intramolecular C-H Activations by a Related
Ruthenium-Carbene Complex. Chem. - Eur. J. 2012, 18, 16136−
16144. (d) Hu, F.; Xia, Y.; Ma, C.; Zhang, Y.; Wang, J. C−H Bond
Functionalization Based on Metal Carbene Migratory Insertion.
Chem. Commun. 2015, 51, 7986−7995.
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Org. Lett. 2021, 23, 4273−4278