β-lactam synthesis via copper-catalyzed directed aminoalkylation of unactivated alkenes with cyclobutanone O-benzoyloximes

Article abstract of DOI:10.1021/acs.orglett.1c01007

A new protocol for amide-directed Cu-catalyzed aminoalkylation of unactivated alkenes using cyclobutanone oxime esters as alkyl radical donors is developed. Both primary and secondary alkyl groups can be selectively installed at the C4 position of termina

Full text of DOI:10.1021/acs.orglett.1c01007

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Letter
β‑Lactam Synthesis via Copper-Catalyzed Directed Aminoalkylation
of Unactivated Alkenes with Cyclobutanone O‑Benzoyloximes
Heng Zhang, Xiaoyan Lv, Hanrui Yu, Zibo Bai, Gong Chen,* and Gang He*
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ABSTRACT: A new protocol for amide-directed Cu-catalyzed amino-
alkylation of unactivated alkenes using cyclobutanone oxime esters as alkyl
radical donors is developed. Both primary and secondary alkyl groups can be
selectively installed at the C4 position of terminal or cis-internal 3-
alkenamides in moderate to good yield. This reaction offers a useful method
for the diastereoselective synthesis of β-lactams bearing 4-cyanoalkyl β-
substituents. The use of a weakly coordinating counteranion as the Cu catalyst is critical for the formation of β-lactam products.
Scheme 1. Synthesis of β-Lactam via Copper-Catalyzed
Directed Aminoalkylation of Unactivated Alkenes
he field of metal-catalyzed functionalization of alkenes
has greatly advanced over the past few decades, offering
T
streamlined access to various synthetically useful carbon
frameworks.1 In comparison to activated alkenes, functional-
ization of unactivated alkenes remains challenging.2 Recently,
substrate-directed approaches have emerged as an effective
strategy for facilitating metal-catalyzed functionalization of
unactivated alkenes.3−9 While the installation of aryl groups on
alkenes has been achieved under various metal catalyses, the
installation of alkyl groups on alkenes is much less developed.
Notably, the Zhao group reported a novel radical-mediated
amino-benzylation reaction of alkenes with benzyl radicals
generated from methylarene solvents under Cu catalysis using
an aminoquinoline (AQ) auxiliary (Scheme 1A).8 It was
proposed that the addition of benzyl radicals to the alkene
forms an AQ-chelated CuIII-metallacycle intermediate, which
then gives the β-lactam product following the intramolecular
C−N reductive elimination.10,11 Recently, we reported an
enantioselective version of this reaction using 4-alkyl Hantzsch
esters as the donor of alkyl radicals, a biaryl diphosphine oxide
ligand as the chiral ligand, and peroxycarbonate as the oxidant
(Scheme 1B).12 The reaction worked well for benzyl and
normal secondary and tertiary alkyl groups, whereas the
primary alkyl groups gave a low yield. Herein, we report a new
protocol for this auxiliary-directed Cu-catalyzed aminoalkyla-
tion of unactivated alkenes using cyclobutanone oxime esters
as the donor of alkyl radicals (Scheme 1C). Both primary and
secondary alkyl groups can be installed. This reaction offers a
useful method for diastereoselective synthesis of β-lactams
bearing various 4-cyanoalkyl β-substituents.13
While the 4-alkyl Hantzsch esters serve as an excellent alkyl
radical precursor in our previous enantioselective reaction
system, the need for an external oxidant and the poor
performance of primary alkyl groups prompted us to explore
other types of alkyl donors. Recently, cycloketone oxime esters
have emerged as very effective alkyl donors that can be readily
formed by the cleavage of the N−O bond by single-electron
Received: March 23, 2021
Published: April 14, 2021
https://doi.org/10.1021/acs.orglett.1c01007
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3620−3625
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transfer and the subsequent β C−C scission.14−16 These alkyl
groups have been successfully utilized in the additions to
alkenes and arenes and in the other C−C and C−heteroatom
coupling reactions. In particular, the Fu group reported that
the 3-cyanoalkyl groups can be selectively added at the γ
position of AQ-coupled 3-butenamides to give Heck-type
trans-substituted alkene products using a Cu(OAc)2·H2O
catalyst in a 2-butanol solvent (Scheme 1C).9 Unlike Zhao’s
system, an unusual benzoate ligand-facilitated β elimination of
a CuIII intermediate was proposed for the formation of the
alkylated alkene product.
respectively). In contrast, the use of a Cu catalyst bearing
strongly coordinating anions such as OAc and iodide gave a
small amount of lactam product 3, instead, forming a mixture
of 5, 4, and 6 along with recovered 1. Other solvents such as
dichloroethane (DCE), THF, and 2-BuOH gave lower yields
of 3 (entries 7−10). The addition of the (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl oroxidanyl (TEMPO) reagent
abolished the formation of 3, primarily generating the O-
alkylation product of TEMPO (entry 14). Addition of chiral
BINAP oxide (BINAPO) gave 3 in lower yield with low
enantioselectivity (entry 15). As seen in our previous system,
the incorporation of an iodo group at position 5 of
aminoquinoline increases the β-lactam selectivity (entries 16
and 17).17 The ester group of cyclobutanone oximes also had a
significant impact on the reaction. The p-CF3-benzoyl group
showed the best yield and chemoselectivity (entry 18, and see
the results for other analogues in the Supporting Information).
The trans-alkene substrate gave little β-lactam product (entry
20).
Intrigued by Fu’s study, we wondered whether the
cycloketone oxime esters can be employed in our system to
form the β-lactam product under modified conditions. As
shown in Table 1, the model reaction of cis-3-hexenamide 1
a
Table 1. Optimization of the Reaction of 1 with 2
With the optimized conditions in hand, we next examined
the scope of cyclobutanone oxime esters and alkenes (Scheme
2). Cyclobutanone oxime esters bearing equivalent substitu-
ents at C2 worked well, giving the desired β-lactam products
(7−10) in moderate to good yields with exclusive anti-
Scheme 2. Scope of cis-Alkenes and Cyclobutanone Oxime
a
Esters
entry
deviation from standard conditions
none
yield (%) (3/5/4+6/1)
b
1
67 (60 )/28/0/0
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Cu(OAc)2 as the catalyst
CuOAc as the catalyst
CuI as the catalyst
CuOTf as the catalyst
Cu(MeCN)4BF4 as the catalyst
dichloromethane as the solvent
THF as the solvent
2-BuOH as the solvent
DCE as the solvent
rt
50 °C
under air
with TEMPO
with the BINAPO ligand
IQ replaced with AQ
trace/22/46/25
trace/19/56/19
trace/7/37/43
60/32/0/0
60/24/0/10
47/31/0/20
45/26/0/18
42/26/0/14
40/25/0/15
20/10/0/57
58/28/0/10
54/30/0/0
0/0/0/95
32 (14% ee)/35/0/16
52/43/0/0
IQ replaced with 5-chloro-8-
aminoquinoline
66/29/0/0
18
19
20
4-CF3-C6H4CO replaced with Bz
with 10 mol % Cu
trans-alkene isomer of 1
49/15/0/15
60/30/0/0
trace/47/0/45
a
Yields were based on 1H NMR analysis of the crude reaction mixture
using 1,1,2,2-tetrachloroethane as an internal standard on a 0.1 mmol
b
scale. Isolated yield. Reaction on a 1 mmol scale gave 3 in 52%
isolated yield. See the Supporting Information for additional
optimization results.
bearing a 5-iodoquinoline auxiliary with cyclobutanone oxime
ester 2 bearing a p-CF3-benzoyl group gave the desired β-
lactam product 3 in 60% isolated yield with exclusive anti-
diastereoselectivity along with 28% of N-alkylation product 5
using the Cu(MeCN)4PF6 catalyst in dioxane at 80 °C (entry
1). Notably, little Heck-type product 6 was formed. The use of
Cu catalysts bearing other weakly coordinating counteranions
such as OTf and BF4 gave similar results (entries 5 and 6,
a
Isolated yields on a 0.1 mmol scale. cis-Alkene substrates were used
unless otherwise specified.
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Letter
diastereoselectivity. Reactions of cyclobutanone oxime esters
bearing non-equivalent substituents at C2 gave products as a
mixture of diastereoisomers in moderate yields (11−13).
Reactions of oxime esters bearing one substituent at C1 also
gave products as a roughly 1:1 diastereomeric mixture (14 and
15). As shown by 14−19, alkyl, phenyl, and cyclopropyl
substituents at the γ position of cis-3-alkenamides are tolerated.
As shown in Scheme 3, terminal alkenes also worked well
under the standard conditions. Reaction of plain 3-butenamide
Scheme 5. Mechanistic Considerations
a
Scheme 3. Reactions of Terminal Alkenes
elimination (RE) of III gives β-lactam product IV in anti-
diastereoselectivity and regenerates CuI. As a competing
pathway, alkyl radical VIII can react with IQ-chelated CuII
to form an alkyl-CuIII intermediate IX, which gives the N-
alkylation side product X upon C−N RE. The ligand (L) on
Cu complexes II and III could strongly influence their
reactivity. Our control experiments showed that strong
coordinating ligands such as OAc and iodide suppress the
formation of the β-lactam product. Notably, it was proposed
that OBz-facilitated concerted β-elimination of CuIII complex
XI affords alkylated alkene product XII in Fu’s system.9
Interestingly, benzoate anion VII is also generated in our
system but does not cause β-elimination. We suspect that the
OAc or iodide ligand might play a more relevant role in the β-
elimination of III.
a
Isolated yields on a 0.1 mmol scale.
with oxime esters bearing one substituent at C1 gave products
as a roughly 1:1 diastereomeric mixture (22 and 25). Reaction
of α-substituted 3-butenamide with unsubstituted cyclo-
butanone oxime esters gave α,β-trans-substituted β-lactams in
moderated yields (23 and 24) with moderate diastereoselec-
tivity.
As shown in Scheme 4, treatment of compound 3 with
NaOMe in MeOH at 90 °C gave acyclic β-amino ester 26 in
Scheme 4. Representative Transformations of β-Lactam 3
In summary, we have developed a Cu-catalyzed amino-
alkylation reaction of unactivated alkenes using cyclobutanone
oxime esters as the donor of alkyl radicals and 5-iodo-8-
aminoquinoline as the directing auxiliary. Both primary and
secondary alkyl groups can be selectively installed at the C4
position of terminal or cis-internal 3-alkenamides in moderate
to good yield. This reaction offers a useful method for the
diastereoselective synthesis of β-lactams bearing various 4-
cyanoalkyl β-substituents. Further studies are needed to better
understand and improve the chemoselectivity of this Cu-
catalyzed radical-mediated reaction.
good yield. The IQ group of 3 can be removed via a three-step
sequence to give 27: photoredox-mediated dehalogenation
followed by AQ cleavage by ozonolysis.18
This reaction likely follows a reaction pathway similar to that
of the previous Cu-catalyzed enantioselective aminoalkylation
of alkene with 4-alkyl Hantzsch esters, a Cu(MeCN)4PF6
catalyst, and a biaryl phosphine oxide ligand (Scheme 5).12,19
A CuI catalyst might first be oxidized by oxime ester V via
single-electron transfer (SET) to form CuII and iminyl radical
VI. VI then rearranges to generate alkyl radical VIII, which
attacks IQ-chelated CuII alkene complex II to form five-
membered CuIII-metallacycle III. Intramolecular reductive
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01007.
Detailed synthetic procedures, compound character-
ization, NMR spectra, X-ray crystallographic data, and
computational details (PDF)
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Accession Codes
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Letter
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of unactivated alkene: (a) Smith, S. M.; Takacs, J. M. Amide-Directed
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CCDC 2071976 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Gong Chen − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China; orcid.org/0000-0002-5067-
9889; Email: gongchen@nankai.edu.cn
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Dicarbofunctionalization of Alkenyl Carbonyl Compounds via
Directed Nucleopalladation. J. Am. Chem. Soc. 2016, 138, 15122−
15125. (c) Basnet, P.; Dhungana, R. K.; Thapa, S.; Shrestha, B.; Kc,
S.; Sears, J. M.; Giri, R. Ni-Catalyzed Regioselective β,δ-Diarylation of
Unactivated Olefins in Ketimines via Ligand-Enabled Contraction of
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in Situ Generation of Cationic Ni(II) Catalysts. J. Am. Chem. Soc.
2018, 140, 15586−15590.
Gang He − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China; orcid.org/0000-0002-9064-
3418; Email: hegang@nankai.edu.cn
Authors
Heng Zhang − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Xiaoyan Lv − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Hanrui Yu − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Zibo Bai − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
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(6) AQ-directed enantioselective functionalization of unactivated
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Chiral Monodentate Oxazoline Ligand. J. Am. Chem. Soc. 2018, 140,
3542−3546. (b) Liu, Z.; Li, X.; Zeng, T.; Engle, K. M. Directed,
Palladium(II)-Catalyzed Enantioselective anti-Carboboration of
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(c) Bai, Z.; Zheng, S.; Bai, Z.; Song, F.; Wang, H.; Peng, Q.; Chen, G.;
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yl Compounds via Conjunctive Cross-Coupling. J. Am. Chem. Soc.
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01007
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (21725204), the “111” project (B06005) of MOE
China, and NCC2020FH02 for financial support of this work.
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15547−15550. (e) Mou, X.-Q.; Rong, F.-M.; Zhang, H.; Chen, G.;
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trifluoromethylation of O-homoallyl Benzimidates. Org. Lett. 2019,
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(12) Bai, Z.; Zhang, H.; Wang, H.; Yu, H.; Chen, G.; He, G.
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model reaction, the 5-iodo group can be removed under photoredox-
mediated dehalogenation conditions, thus enabling cleavage of the
auxiliary.
(18) (a) Nguyen, J. D.; D’Amato, E. M.; Narayanam, J. M. R.;
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iodides in visible-light-mediated free radical reactions. Nat. Chem.
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(19) Recent research on interaction of Cu(II) with unsaturated
species using an 8-aminoquinoline directing group: Wootton, T. L.;
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Organic Letters
pubs.acs.org/OrgLett
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Porter, J. A.; Grewal, K. S.; Chirila, P. G.; Forbes, S.; Coles, S. J.;
Horton, P. N.; Hamilton, A.; Whiteoak, C. J. Merging Cu-catalysed
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tional and experimental studies on an expedient construction of
complex fused heterocycles. Org. Chem. Front. 2020, 7, 1235−1242.
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