Copper-Catalyzed Oxidative Benzylic C(sp3)?H Cyclization for the Synthesis of β-Lactams

Article abstract of DOI:10.1002/chem.201905777

β-Lactams are important structural motifs because of their ubiquity in natural products and pharmaceuticals. We report herein a Cu-catalyzed intramolecular oxidative C(sp³)?H amidation for the synthesis of β-lactams using tBuOOtBu. This method

Full text of DOI:10.1002/chem.201905777

A Journal of
Accepted Article
Title: Copper-Catalyzed Oxidative Benzylic C(sp3)–H Cyclization for
the Synthesis of β-Lactams
Authors: Kanako Nozawa-Kumada, Satoshi Saga, Yuta Matsuzawa,
Masahito Hayashi, Masanori Shigeno, and Yoshinori Kondo
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To be cited as: Chem. Eur. J. 10.1002/chem.201905777
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Copper-Catalyzed Oxidative Benzylic C(sp3)–H Cyclization for the
Synthesis of β-Lactams
Kanako Nozawa-Kumada,* Satoshi Saga, Yuta Matsuzawa, Masahito Hayashi, Masanori Shigeno, and
Yoshinori Kondo*
Abstract: β-Lactams are important structural motifs because of their
ubiquity in natural products and pharmaceuticals. We report herein a
Cu-catalyzed intramolecular oxidative C(sp3)–H amidation for the
synthesis of β-lactams using tBuOOtBu. This method is based on
features high atom economy and step economy. One of the
conventional C(sp3)–H functionalization reactions for β-lactam
syntheses involves transition-metal (Pd,[9a,b,f,h] Ni,[9e,i] Cu,[9c,d]
Co[9g])-catalyzed intramolecular oxidative coupling between N–H
and C(β)–H bonds (Scheme 1a).[9] Although this approach
avoids prefunctionalization of C(sp3)–H bonds of the substrates,
a pyridine- or quinoline-based directing group (DG) is typically
used, thus necessitating addition and removal steps. Thus, DG-
assisted synthesis offsets the synthetic efficiency provided by
the direct C(sp3)–H functionalization; for this reason, a DG-free
route is also desirable.
Kharasch–Sosnovsky
amidation
and
does
not
require
prefunctionalization of C(sp3)–H bonds or the installation of a
directing group, thereby allowing for the straightforward synthesis of
β-lactams. Our intramolecular functionalization protocol can be
extended to diverse benzylic C(sp3)–H bonds and shows excellent
functional group tolerance.
In 1957, the Kharasch–Sosnovsky reaction[10] was
introduced, namely the Cu-catalyzed transformation of an allylic
C(sp3)–H bond to an ester by using a peroxyester, which is
proposed to be initiated by abstraction of an allylic hydrogen
atom by an alkoxy radical derived from a copper-initiated
decomposition of peroxyester. Following this, significant efforts
have been invested to improve the efficiency of this
methodology.[11] One of the most notable strategies in this
regard is the construction of C(sp3)–N bonds by using amines or
amides with peroxides, as this strategy can be applied to not
only allylic C(sp3)–H bonds but also benzylic and aliphatic
The β-lactam motif is found in important natural and bioactive
compounds[1] such as penicillin, ezetimibe,[2] and aztreonam[3]
(Figure 1). Because of the structural significance of β-lactams,
much effort has been devoted to their synthesis.[4] The classical
methods for β-lactam synthesis include the Staudinger
reaction,[5] Kinugasa reaction,[6] and cyclization of amino acids.[7]
Recently, transition-metal-catalyzed C(sp3)–H functionalization[8]
has emerged as an attractive method in synthetic chemistry
because it does not involve prefunctionalization, and thus
Figure 1. Natural and bioactive β-lactam derivatives.
[*]
Dr. K. Nozawa-Kumada, S. Saga, M. Hayashi, Dr. M. Shigeno, Prof.
Dr. Y. Kondo
Graduate School of Pharmaceutical Sciences
Tohoku University
6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: kumada@m.tohoku.ac.jp
ykondo@m.tohoku.ac.jp
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Scheme 1. Transition-metal-catalyzed oxidative coupling between N–H and
C(β)–H bonds for the synthesis of β-lactams.
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C(sp3)–H bonds.[12] For example, Powell et al. have developed a
copper-catalyzed intermolecular amidation of allylic and benzylic
C−H bonds with sulfonamides using tBuOOAc.[12b] Compared to
such intermolecular C(sp3)–N bond formation, reports of
intramolecular C(sp3)–N bond formation to construct N-
heterocyclic compounds have been limited. In our previous work,
we have developed a copper-catalyzed oxidative isoindolinone
synthesis using tBuOOtBu via intramolecular benzylic C(sp3)–H
bond functionalization.[13a] However, there has been no report to
build β-lactams by this strategy. Thus inspired, we attempted the
Cu-catalyzed oxidative cyclization of linear alkanoic amides with
a peroxide for the synthesis of β-lactams. This reaction proceeds
via an intramolecular Kharasch–Sosnovsky-type C(sp3)–H
amidation in the presence of a first-row transition-metal, Cu
catalyst, and no DG installation is needed (Scheme 1b). This
reaction is assumed to be initiated by the abstraction of
hydrogen at the benzylic position by the alkoxy radical, similar to
the original Kharasch-Sosnovsky reaction. The radical species
would be rapidly trapped by a copper(II) amide complex for
efficient construction of the C(sp3)–N bond (Scheme 1c).[14]
We began our investigation using N,3-diphenylpropanamide
1a as the substrate to optimize the reaction conditions (Table 1).
The use of CuCl2/DMAP as the catalyst and tBuOOtBu
(peroxide) in 1,2-dichloroethane (DCE) at 130 °C was effective
for the cyclization (entry 1). The desired reaction did not proceed
in the absence of CuCl2, DMAP, or tBuOOtBu (entries 2–4).
Using other copper sources instead of CuCl2 decreased the yield
(entry 5). The use of a phosphine ligand or bidentate nitrogen
ligand Phen also led to lower yields (entry 6). Other oxidants
such as tBuOOAc or tBuOOH did not work for the reaction (entry
7). Screening of a variety of solvents revealed that DCE was the
Table 1. Effect of reaction parameters.
Isolated yields. [a] The ratio was determined by 1H-NMR. [b] 10 mol% of CuCl2
and 30 mol% of DMAP were used.
entry
variation from standard conditions
none
yield (%)[a]
Scheme 2. Scope and limitations of intramolecular C(sp3)–H amidation for β-
lactam synthesis.
1
2
3
4
5
72 (71)[b]
without CuCl2
0
without DMAP
0
without tBuOOtBu
0
CuCl,
CuI,
[(MeCN)4Cu]OTf,
CuBr2,
34–66
Cu(OAc)2, or Cu(OTf)2 instead of CuCl2
PPh3, Pyridine, or Phen, instead of DMAP
tBuOOAc or tBuOOH, instead of tBuOOtBu
benzene, PhCl, or MeCN, instead of DCE
10 mol% of CuCl2 and 30 mol% of DMAP
6
7
8
9
0–12
0
Scheme 3. CAN-mediated removal of aryl group on nitrogen atom of 2i.
trace
61
best solvent (entry 8). A higher catalyst loading led to increased
formation of a byproduct, thus reducing the yield slightly (entry
9).
With the optimized reaction conditions in hand, we next
investigated the substrate scope of C(sp3)–H functionalization
for the synthesis of β-lactams (Scheme 2). A wide range of
functional groups, including halogens, were tolerated under the
[a] Determined by 1H-NMR using 1,1,2-trichloroethane as an internal
standard. [b] Isolated yield in parentheses.
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reaction conditions. The reaction of substrates possessing
halogen atoms or electron-withdrawing groups at β-position on
the benzene ring gave the desired products in acceptable yields
(2b–f). The substrate with the electron-donating methoxy group
at the 4-position led to an undesired reaction, generating an
olefin.[15] Next, we investigated the effect of aryl groups on the
nitrogen atom. The reactions gave cyclized products 2g–p in low
to moderate yields, regardless of the electronic properties of the
aryl groups. This method could be applied to synthesize the 3-
substituted β-lactam 2q in good yield. Furthermore, we
investigated the reaction of 1r with different substituents at α-
lactam synthesis. First, the reaction was conducted using 1a-D
as
a substrate under the optimized conditions and the
intramolecular KIE value of 8.1 was observed (Scheme 5).
Furthermore, based on the reaction with 1a and 1a-2D as the
substrates under the standard conditions in a single vessel, the
magnitude of the intermolecular KIE was determined to be 9.0
(Scheme 6). These results indicated that C(sp3)–H abstraction
may be the rate-determining step in this reaction.
In conclusion, we have developed
a
Cu-catalyzed
intramolecular oxidative C(sp3)–H amidation for the synthesis of
β-lactams, which are the core structures of many natural and
bioactive compounds. Our protocol based on Kharasch–
Sosnovsky amidation provides straightforward access to β-
lactams, as prefunctionalization and DG installation are not
required. Our intramolecular functionalization is applicable to a
variety of benzylic C(sp3)–H bonds. Further studies to expand
the scope of the substrates and broaden the synthetic
application of our method to other heterocycles are in progress,
and the results will be reported in due course.
position of the amide and found to give
a mixture of
diastereomers 2r and 2r’ with almost the same ratio. Polycyclic
fused β-lactams, which are widespread in pharmaceutical
chemistry, could also be produced in an efficient manner (2s).
Subsequently, we treated β-lactam 2i with ceric ammonium
nitrate (CAN) under mild conditions and obtained an N-free β-
lactam
3
(Scheme 3).[16] This result indicated that the
synthesized β-lactams could be further transformed into useful
compounds, thus demonstrating their structural diversity.
We next performed some experiments to gain insight into the
reaction mechanism. Under the optimized conditions and in the
presence of 3.0 equiv of a radical scavenger such as TEMPO or
BHT (Scheme 4), the reaction was completely inhibited,
indicating that the reaction proceeded via a radical process.
Finally, we measured the kinetic isotope effect (KIE) of this β-
Acknowledgements
This work was financially supported by the Japan Society for the
Promotion of Science (JSPS) KAKENHI Grant no. 19K16309.
This work was also supported by Grand for Basic Science
Research Projects from The Sumitomo Foundation, the Platform
Project for Supporting Drug Discovery and Life Science
Research funded by Japan Agency for Medical Research and
Development (AMED), Tohoku University Center for Gender
Equality Promotion (TUMUG), and Morinomiyako Project for
Empowering Women in Research.
Keywords: β-lactam • C(sp3)–H functionalization • copper •
oxidation • Kharasch–Sosnovsky reaction
Scheme 4. Radical scavenger experiment.
[1]
a) The Organic Chemistry of β-Lactams (Eds.: G. I. Georg), VCH, New
York, 1993; b) Natural Lactones and Lactams: Synthesis, Occurrence
and Biological Activity (Eds.: T. Janecki), Wiley-VCH, Weinheim, 2014;
c) G. S. Singh, Mini-Reviews Med. Chem. 2004, 4, 93–109; d) E. Turos,
C. Coates, J.-Y. Shim, Y. Wang, J. M. Leslie, T. E. Long, G. S. K.
Reddy, A. Ortiz, M. Culbreath, S. Dickey, D. V. Lim, E. Alonso, J.
Gonzalez, Bioorganic Med. Chem. 2005, 13, 6289–6308; e) A.
MacGowan, Curr. Opin. Pharmacol. 2011, 11, 470–476; f) G. S. Singh,
M. D’hooghe, N. De Kimpe, Tetrahedron 2011, 67, 1989–2012; g) L.
Decuyper, K. Magdalenić, M. Verstraete, M. Jukič, I. Sosič, E. Sauvage,
A. M. Amoroso, O. Verlaine, B. Joris, S. Gobec, M. D’hooghe, Chem.
Eur. J. 2019, 25, 16128–16140.
Scheme 5. Intramolecular kinetic isotope effect.
[2]
a) S. D. Turley, J. M. Dietschy, Curr. Opin. Lipidol. 2003, 14, 233–240;
b) J. W. Clader, J. Med. Chem. 2004, 47, 1–9; c) M. A. Blazing, R. P.
Giugliano, C. P. Cannon, T. A. Musliner, A. M. Tershakovec, J. A.
White, C. Reist, A. McCagg, E. Braunwald, R. M. Califf, Am. Heart J.
2014, 168, 205–212; d) A. Tarui, A. Tanaka, M. Ueo, K. Sato, M.
Omote, A. Ando, New J. Chem. 2015, 39, 9325–9329.
[3]
[4]
a) R. N. Brogden, R. C. Heel, Drugs 1986, 31, 96–130; b) R. J. Duma,
Ann. Intern. Med. 1987, 106, 766–767.
a) S. France, A. Weatherwax, A. E. Taggi, T. Lectka, Acc. Chem. Res.
2004, 37, 592–600; b) B. Alcaide, P. Almendros, C. Aragoncillo, Chem.
Rev. 2007, 107, 4437–4492; c) B. Alcaide, P. Almendros, C.
Aragoncillo, Curr. Opin. Drug Disc. 2010, 13, 685–697; d) B. Alcaide, P.
Scheme 6. Intermolecular kinetic isotope effect.
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Almendros, Chem. Rec. 2011, 11, 311–330; e) A. Kamath, I. Ojima,
Tetrahedron 2012, 68, 10640–10664; f) T. Orbegozo, F. Burel, P.
Jubault, X. Pannecoucke, Tetrahedron 2013, 69, 4015–4039; g) B.
Alcaide, P. Almendros, A. Luna, RSC Adv. 2014, 4, 1689–1707; h) C. R.
Pitts, T. Lectka, Chem. Rev. 2014, 114, 7930–7953; i) S. Hosseyni, A.
Jarrahpour, Org. Biomol. Chem. 2018, 16, 6840–6852.
Mei, Y. Li, Y.-L. Ma, B. Wu, Org. Lett. 2014, 16, 480–483; g) X. Wu, K.
Yang, Y. Zhao, H. Sun, G. Li, H. Ge, Nat. Commun. 2015, 6, 6462; h)
S.-J. Zhang, W.-W. Sun, P. Cao, X.-P. Dong, J.-K. Liu, B. Wu, J. Org.
Chem. 2016, 81, 956–968; i) Y. Aihara, N. Chatani, ACS Catal. 2016, 6,
4323–4329; j) T. Zhou, M.-X. Jiang, X. Yang, Q. Yue, Y.-Q. Han, Y.
Ding, B.-F. Shi, Chin. J. Chem. 2020, 38, 242–246.
β-Lactam synthesis by other types of C(sp3)–H functionalization, see: k)
J. Pedroni, M. Boghi, T. Saget, N. Cramer, Angew. Chem. 2014, 126,
9210–9213; Angew. Chem. Int. Ed. 2014, 53, 9064–9067; l) A. McNally,
B. Haffemayer, B. S. L. Collins, M. J. Gaunt, Nature 2014, 510, 129–
133; m) D. Willcox, B. G. N. Chappell, K. F. Hogg, J. Calleja, A. P.
Smalley, M. J. Gaunt, Science 2016, 354, 851–857; n) D. Dailler, R.
Rocaboy, O. Baudoin, Angew. Chem. 2017, 129, 7324–7328; Angew.
Chem. Int. Ed. 2017, 56, 7218–7222.
[5]
a) H. Staudinger, Liebigs Ann. Chem. 1907, 356, 51–123; b) F. H. van
der Steen, G. van Koten, Tetrahedron 1991, 47, 7503–7524; c) C.
Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide, Eur. J. Org. Chem.
1999, 3223–3235; d) B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002,
124, 1578–1579; e) C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide,
Curr. Med. Chem. 2004, 11, 1837–1872; f) E. C. Lee, B. L. Hodous, E.
Bergin, C. Shih, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11586–11587;
g) Y.-R. Zhang, L. He, X. Wu, P.-L. Shao, S. Ye, Org. Lett. 2008, 10,
277–280.
[10] M. S. Kharasch, G. Sosnovsky, J. Am. Chem. Soc. 1958, 80, 756.
[11] Kharasch−Sosnovsly type C(sp3)–H functionalization (etherification or
methylation, etc.), see: a) J. Eames, M. Watkinson, Angew. Chem.
2001, 113, 3679–3683; Angew. Chem. Int. Ed. 2001, 40, 3567–3571; b)
M. B. Andrus, J. C. Lashley, Tetrahedron 2002, 58, 845–866; c) J. A.
Mayoral, S. Rodríguez-Rodríguez, L. Salvatella, Chem. Eur. J. 2008, 14,
9274–9285; d) R. T. Gephart, C. L. Mcmullin, N. G. Sapiezynski, E. S.
Jang, M. J. B. Aguila, T. R. Cundari, T. H. Warren, J. Am. Chem. Soc.
2012, 134, 17350–17353; e) S. K. Rout, S. Guin, K. K. Ghara, A.
Banerjee, B. K. Patel, Org. Lett. 2012, 14, 3982–3985; f) Q. Xia, X. Liu,
Y. Zhang, C. Chen, W. Chen, Org. Lett. 2013, 15, 3326–3329; g) J.
Zhao, H. Fang, J. Han, Y. Pan, Org. Lett. 2014, 16, 2530–2533; h) S. K.
Rout, S. Guin, W. Ali, A. Gogoi, B. K. Patel, Org. Lett. 2014, 16, 3086–
3089; i) B. L. Tran, M. Driess, J. F. Hartwig, J. Am. Chem. Soc. 2014,
136, 17292–17301; j) C.-Y. Wang, R.-J. Song, W.-T. Wei, J.-H. Fan, J.-
H. Li, Chem. Commun. 2015, 51, 2361–2363; k) T. K. Salvador, C. H.
Arnett, S. Kundu, N. G. Sapiezynski, J. A. Bertke, M. R. Boroujeni, T. H.
Warren, J. Am. Chem. Soc. 2016, 138, 16580–16583; l) W. Zhang, F.
Wang, S. D. McCann, D. Wang, P. Chen, S. S. Stahl, G. Liu, Science
2016, 353, 1014–1018; m) B. Lu, F. Zhu, H.-M. Sun, Q. Shen, Org. Lett.
2017, 19, 1132–1135; n) H. F. T. Klare, A. F. G. Goldberg, D. C.
Duquette, B. M. Stoltz, Org. Lett. 2017, 19, 988–991; o) A. Vasilopoulos,
S. L. Zultanski, S. S. Stahl, J. Am. Chem. Soc. 2017, 139, 7705–7708.
[12] Kharasch−Sosnovsly type C(sp3)–N bond formation, see: a) J. S. Clark,
C. Roche, Chem. Commun. 2005, 5175–5177; b) G. Pelletier, D. A.
Powell, Org. Lett. 2006, 8, 6031–6034; c) S. Wiese, Y. M. Badiei, R. T.
Gephart, S. Mossin, M. S. Varonka, M. M. Melzer, K. Meyer, T. R.
Cundari, T. H. Warren, Angew. Chem. 2010, 122, 9034–9039; Angew.
Chem. Int. Ed. 2010, 49, 8850–8855; d) D. A. Powell, H. Fan, J. Org.
Chem. 2010, 75, 2726–2729; e) Q. Xia, W. Chen, H. Qiu, J. Org. Chem.
2011, 76, 7577–7582; f) S. Santoro, R.-Z. Liao, F. Himo, J. Org. Chem.
2011, 76, 9246–9252; g) Q. Xia, W. Chen, J. Org. Chem. 2012, 77,
9366–9373; h) R. T. Gephart, D. L. Huang, M. J. B. Aguila, G. Schmidt,
A. Shahu, T. H. Warren, Angew. Chem. 2012, 124, 6594–6598; Angew.
Chem. Int. Ed. 2012, 51, 6488–6492; i) B. L. Tran, B. Li, M. Driess, J. F.
Hartwig, J. Am. Chem. Soc. 2014, 136, 2555–2563; j) P. K. Chikkade,
Y. Kuninobu, M. Kanai, Chem. Sci. 2015, 6, 3195–3200; k) F. Teng, S.
Sun, Y. Jiang, J.-T. Yu, J. Cheng, Chem. Commun. 2015, 51, 5902–
5905; l) H.-T. Zeng, J.-M. Huang, Org. Lett. 2015, 17, 4276–4279; m) X.
Qi, L. Zhu, R. Bai, Y. Lan, Sci. Rep. 2017, 7, 43579.
[6]
a) M. Kinugasa, S. Hashimoto, J. Chem. Soc., Chem. Commun. 1972,
466–467; b) M. Miura, M. Enna, K. Okuro, M. Nomura, J. Org. Chem.
1995, 60, 4999–5004; c) A. Basak, S. C. Ghosh, T. Bhowmich, A. K.
Das, V. Bertolasi, Tetrahedron Lett. 2002, 43, 5499–5501; d) M. M.-C.
Lo, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 4572–4573; e) R. Shintani,
G. C. Fu, Angew. Chem. 2003, 115, 4216–4219; Angew. Chem. Int. Ed.
2003, 42, 4082–4085; f) J. Marco-Contelles, Angew. Chem., 2004, 16,
2248–2250; Angew. Chem. Int. Ed. 2004, 43, 2198–2200; g) S. Stecko,
B. Furman, M. Chmielewski, Tetrahedron 2014, 70, 7817–7844; h) M.
Chigrinova, D. A. MacKenzie, A. R. Sherratt, L. L. W. Cheung, J. P.
Pezacki, Molecules 2015, 20, 6959–6969; i) Y. Takayama, T. Ishii, H.
Ohmiya, T. Iwai, M. C. Schwarzer, S. Mori, T. Taniguchi, K. Monde, M.
Sawamura, Chem. Eur. J. 2017, 23, 8400–8404; j) T. Shu, L. Zhao, S.
Li, X.-Y. Chen, C. von Essen, K. Rissanen, D. Enders, Angew. Chem.
2018, 130, 11151–11154; Angew. Chem. Int. Ed. 2018, 57, 10985–
10988.
[7]
a) T. Kunieda, T. Nagamatsu, T. Higuchi, M. Hirobe, Tetrahedron Lett.
1988, 29, 2203–2205; b) C. Palomo, J. M. Aizpurua, R. Urchegui, M.
Iturburu, A. O. de Retana, C. Cuevas, J. Org. Chem. 1991, 56, 2244–
2247; c) J. Escalante, M. A. González-Tototzin, J. Aviña, O. Muñoz-
Muñiz, E. Juaristi, Tetrahedron 2001, 57, 1883–1890; d) M. A. Bonache,
G. Gerona-Navarro, M. Martín-Martínez, M. T. García-López, P. López,
C. Cativiela, R. González-Muñiz, Synlett 2003, 1007–1011; e) S.
Kanwar, S. D. Sharma, Bull. Chem. Soc. Jpn. 2006, 79, 1748–1752.
For selected recent reviews, see: a) R. Jazzar, J. Hitce, A. Renaudat, J.
Sofack-Kreutzer, O. Baudoin, Chem. Eur. J. 2010, 16, 2654–2672; b) O.
Baudoin, Chem. Soc. Rev. 2011, 40, 4902–4911; c) C. Zhang, C. Tang,
N. Jiao, Chem. Soc. Rev. 2012, 41, 3464–3484; d) G. Rouquet, N.
Chatani, Angew. Chem. 2013, 125, 11942–11959; Angew. Chem. Int.
Ed. 2013, 52, 11726–11743; e) S. A. Girard, T. Knauber, C.-J. Li,
Angew. Chem. 2014, 126, 76–103; Angew. Chem. Int. Ed. 2014, 53,
74–100; f) C. Zheng, S.-L. You, RSC Adv. 2014, 4, 6173–6214; g) C.
Liu, J. Yuan, M. Gao, S. Tang, W. Li, R. Shi, A. Lei, Chem. Rev. 2015,
115, 12138–12204; h) A. Batra, P. Singh, K. N. Singh, Eur. J. Org.
Chem. 2016, 4927–4947; i) S.-R. Guo, P. S. Kumar, M. Yang, Adv.
Synth. Catal. 2017, 359, 2–25; j) M. K. Lakshman, P. K. Vuram, Chem.
Sci. 2017, 8, 5845–5888; k) B. V. Varun, J. Dhineshkumar, K. R.
Bettadapur, Y. Siddaraju, K. Alagiri, K. R. Prabhu, Tetrahedron Lett.
2017, 58, 803–824; l) H. Yi, G. Zhang, H. Wang, Z. Huang, J. Wang, A.
K. Singh, A. Lei, Chem. Rev. 2017, 117, 9016–9085; m) H. Sterckx, B.
Morel, B. U. W. Maes, Angew. Chem. 2019, 131, 8028–8055; Angew.
Chem. Int. Ed. 2019, 58, 7946–7970; n) Q. Zhang, B.-F. Shi, Chin. J.
Chem. 2019, 37, 647–656.
[8]
[13] a) K. Nozawa-Kumada, J. Kadokawa, T. Kameyama, Y. Kondo, Org.
Lett. 2015, 17, 4479–4481. Also see: b) K. Nozawa-Kumada, S. Kurosu,
M. Shigeno, Y. Kondo, Asian J. Org. Chem. 2019, 8, 1080–1083.
[14] In this reaction, the active Cu(I) species can be formed through the
disproportionation of Cu(II), see: a) A. E. King, L. M. Huffman, A.
Casitas, M. Costas, X. Ribas, S. S. Stahl, J. Am. Chem. Soc. 2010, 132,
12068–12073; b) B. Chen, X.-L. Hou, Y.-X. Li, Y.-D. Wu, J. Am. Chem.
Soc. 2011, 133, 7668–7671; c) W.-J. Yoo, T. Tsukamoto, S. Kobayashi,
Angew. Chem. Int. Ed. 2015, 54, 6587–6590; d) J. C. Vantourout, H. N.
Miras, A. Isidro-Llobet, S. Sproules, A. J. B. Watson, J. Am. Chem. Soc.
2017, 139, 4769–4779.
[9]
a) M. Wasa, J.-Q. Yu, J. Am. Chem. Soc. 2008, 130, 14058–14059; b)
Q. Zhang, K. Chen, W. Rao, Y. Zhang, F.-J. Chen, B.-F. Shi, Angew.
Chem. 2013, 125, 13833–13837; Angew. Chem. Int. Ed. 2013, 52,
13588–13592; c) Z. Wang, J. Ni, Y. Kuninobu, M. Kanai, Angew. Chem.
2014, 126, 3564–3567; Angew. Chem. Int. Ed. 2014, 53, 3496–3499; d)
X. Wu, Y. Zhao, G. Zhang, H. Ge, Angew. Chem. 2014, 126, 3780–
3784; Angew. Chem. Int. Ed. 2014, 53, 3706–3710; e) X. Wu, Y. Zhao,
H. Ge, Chem. Eur. J. 2014, 20, 9530–9533; f) W.-W. Sun, P. Cao, R.-Q.
[15] 29% of 3-(4-methoxyphenyl)-N-phenyl-2-propenamide was obtained.
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[16] a) L. S. Hegedus, M. A. McGuire, L. M. Schultze, C. Yijun, O. P.
Anderson, J. Am. Chem. Soc. 1984, 106, 2680–2687; b) B. Alcaide, M.
F. Alyt, M. A. Sierra, J. Org. Chem. 1996, 61, 8819–8825; c) L. Banfi, G.
Guanti, Eur. J. Org. Chem. 2002, 3745–3755.
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10.1002/chem.201905777
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Kanako Nozawa-Kumada,* Satoshi
Saga, Yuta Matsuzawa, Masahito
Hayashi, Masanori Shigeno, and
Yoshinori Kondo*
Page No. – Page No.
Copper-Catalyzed Oxidative Benzylic
C(sp3)–H Cyclization for the
Synthesis of β-Lactams
Straightforward β-lactam synthesis: Cu-catalyzed intramolecular oxidative C(sp3)–H
amidation for the synthesis of β-lactams has been developed. This reaction
proceeds via an intramolecular Kharasch–Sosnovsky-type C(sp3)–H amidation in
the presence of a first-row transition-metal, Cu catalyst, and no DG installation is
needed.
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