Asymmetric Coupling of Carbon-Centered Radicals Adjacent to Nitrogen: Copper-Catalyzed Cyanation and Etherification of Enamides

Article abstract of DOI:10.1002/anie.202008338

The first copper-catalyzed asymmetric cyanation and etherification reactions of enamides have been established, where a carbon-centered radical adjacent to a nitrogen atom (CRAN) is enantioselectively trapped by a chiral copper(II) species. Moreover, the asymmetric cyanation of vinyl esters was disclosed as well. These reactions feature very mild reaction conditions and high functional group tolerance, and give a series of chiral α-cyano amides, α-cyano esters and α-hemiaminals in good yields with excellent enantioselectivity. The chiral α-cyano amides can be easily converted into enantioenriched 1,2-diamines and amino acids.

Full text of DOI:10.1002/anie.202008338

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Accepted Article
Title: Asymmetric Coupling of Carbon-Centered Radical Adjacent
to Nitrogen: Copper-Catalyzed Cyanation and Etherification of
Enamides
Authors: Guosheng Liu, Guoyu Zhang, Song Zhou, Liang Fu, Jianping
Zou, Pinhong Chen, and Yibiao Li
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10.1002/anie.202008338
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COMMUNICATION
Asymmetric Coupling of Carbon-Centered Radical Adjacent to
Nitrogen: Copper-Catalyzed Cyanation and Etherification of
Enamides
Guoyu Zhang,a† Song Zhou,b† Liang Fu,c Pinhong Chen,c Yibiao Li,*b Jianping Zou,*a and Guosheng
Liu*c
Dedication to the celebration of 70th anniversary of SIOC
Abstract: The first copper-catalyzed asymmetric cyanation and
etherification of enamides have been established, where a carbon-
centered radical adjacent to
a
nitrogen atom (CRAN) is
enantioselectively trapped by a chiral copper (II) species. Moreover,
the asymmetric cyanation of vinyl esters was disclosed as well.
These reactions featuring very mild reaction conditions and high
functional group tolerance give a series of chiral α-cyano amides, α-
cyano esters and α-hemiaminals in good yields with excellent
enantioselectivities, in which chiral α-cyano amides can be easily
converted into enantio-enriched 1,2-diamines and amino acids.
Optically pure amines and amides represent not only one of most
privileged moieties frequently found in natural products and drugs, but
also act as useful synthons in organic synthesis.[1] Therefore, much
effort has been devoted to their synthesis and many well-established
methods have been documented,[2] such as asymmetric
hydrogenation,[3] hydroboration,[4] Michael addition,[5] and so on.
Owing to highly reactive radical species, difunctionalization of alkenes
via radical pathways recently serves as a powerful tool in organic
synthesis.[6] Among them, reactions of enamides present an attractive
method for the concise and efficient synthesis of amides, where a
carbon radical adjacent to a nitrogen atom (CRAN) is considered as a
key intermediate.[7] To survey the possible asymmetric reaction, the
enantioseletive capture of CRAN becomes an inevitable problem.[8]
Recently, Phipps developed the first CPA-catalyzed asymmetric
decarboxylative Minisci-type reaction, where a chiral phosphoric acid
(CPA) catalyst could promote highly enenatioselective radical addition
of CRAN to pyridines via a hydrogen-bonding process.[9] Later on,
Studer and coworkers untilized this strategy to disclose the elegant
asymmetric radical difunctionation of enamides (Scheme 1a).[10]
Scheme 1. Asymmetric radical difunctionalization of enamides.
aliphatic alkenes were employed as substrate, these reactions involving
a
non-benzylic radical intermediate furnished the corresponding
products with low enantioselectivities. Although benzylic,[12a-b,13]
allylic[14] and propargylic radicals[15] could be efficiently and
enantioselectively trapped by chiral (Box)Cu(CN)2 species to deliver
enantioenriched organonitriles, the asymmetric cyanation of alkyl-
substituted carbon-centered radicals yielding the dialkyl-substituted
organonitriles with low levels of enantioselective induction still
remains a big challenging issue, presumably due to the less stabilities
of the transiently generated alkyl-substituted carbon-centered radical. It
is well known that a carbon-centered radical can be stablized by
heteroatoms adjacent to the radical such as nitrogen,[16] thus promoting
us to survey the enantioselective enantioselective cyanation of CRAN
generated by radical addition to enamides; in addition, a coordination
of the carbonyl group in the enamide to a copper center woud be
highly beneficial to the enantioselective induction (Scheme 1b, ii).
Moreover, Stahl and coworkers recently reported a copper-catalyzed
etherification of benzylic C-H bonds.[17] However, employing chiral
Box ligand failed to achieve an enantioselective reaction, yielding
racemic oxygenation products. The significantly different properties
between CRAN and benzylic radicals also intrigued us to investigate
the asymmetric coupling of CRAN to alcohols (Scheme 1b, iii).
However, it is noteworthy that CRAN can be easily over oxidized to
an iminium cation,[18] making the enantioselective coupling reaction
more challenging. Herein, we communicate the first copper-catalyzed
asymmetric cyanation of enamides, involving highly enantioselective
capture of CRAN by chiral L*Cu(CN)2 species. Moreover, the
enantioselective coupling of enamides to alcohols is also realized by
the same strategy (Scheme 1b). In addition, our method features
excellent functional group compatibility and provides an easy and
As our ongoing research interest in asymmetric radical
transformations (ATRs),[11] our group has developed a series of copper-
catalyzed asymmetric difunctionalizations of styrenes, such as
cyanation, arylation and alkynylation reactions, where a benzylic
radical intermedaite generated by radical addition across styrenes could
be efficiently and enantioselectively trapped by the corresponding
chiral (Box)Cu(II) species (Box = bisoxazoline), leading to the
formation of a chiral C-C bond (Scheme 1b, i).[11a, 12] However, when
[*]
G.-Y. Zhang, Prof. Dr. J.-P. Zou
Key Laboratory of Organic Synthesis of Jiangsu Province, College
of Chemistry and Chemical Engineering, Soochow University,
Jiangsu 215123, China
S. Zhou, Prof. Y. Li
School of Biotechnology and Health Science, Wuyi University,
Jiangmen, 529020, China.
Dr. L. Fu, Dr. P. Chen, Prof. Dr. G. Liu
State Key Laboratory of Organometallic Chemistry
Center for Excellence in Molecular Synthesis
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai, 200032 (China)
E-mail: gliu@mail.sioc.ac.cn
Home page: http://guoshengliu.sioc.ac.cn
These authors contributed equal to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
[†]
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10.1002/anie.202008338
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efficient access to a wide array of enantiomerically enriched CF3-
containing amides.
in 93% yield (92% ee), respectively. Moreover, substrates derived from
alkyl carboxylic acids were also suitable, and the reactions provided 2k
and 2l in 92-97% yields with 93-94% ee. Interestingly, reactions of N-
vinyl Boc-amides also worked nicely to furnish 2m in 72% yield with
98% ee, which is considered as a valuable synthon in organic synthesis.
Notably, N-vinyl benzamides, in which the N-H bond was protected by
phenyl or Boc groups, also proved amenable to the reaction, yielding
products 2n-2o in good yields with excellent enantioselectivities (86-
93% ee). N-vinyl phthalimde and N-vinly lactams could also be
employed as substrate to afford the corresponding products 2p-2r in
excellent yields with 87-90% ee. More importantly, the compatiblity of
various heteroarenes (furan, thiophene and pyridine) was examined
under the current reaction conditions, and the corresponding products
2s-2u were furnished in 70-94% yields with 93-96% ee. Unfortunately,
-substitued N-vinyl amides as substrate failed to deliver tetra-
substituted product (2v). Notably, the reaction of 1a could be
performed on a 10 mmol scale without loss of reaction efficiency and
enantioselectivity. The absolute structure of (S)-2a was unambiguously
To test the above hypothesis, we initially focused on the
asymmetric cyanation of enamides as the mode reaction. First, the
reaction of N-vinyl benzamide 1a with Togni-I reagent was surveyed,
using 5 mol% Cu(CH3CN)4PF6 and 6 mol% privileged Box ligand in
our previous reports.[12a] As shown in Table 1, the Box ligand L1 with
the indane moiety yielded the desired product 2a in 53% yield with
poor enantioselectivity (19% ee, entry 1). To our delight, the
enantioselectivity of 2a could be significantly improved by introducing
substituents into the Box ligands at the gem-carbon position (L2-L3),
but a yield of 2a was dramatically decreased (entries 2-3); for instance,
the reaction with ligand L3 provided 2a in 18% yield with 76% ee. The
Box ligands L4-L6 with benzyl groups on the oxazoline rings were
also investigated, and L4 exhibited a slightly lower enantioselectivity;
using L6 led to similar results as using L3 (entries 4-6). In the presence
of L3, copper catalyst screening revealed that CuOAc exhibited the
best reactivity to provide 2a in 64% yield, albelt with 69% ee (entry 7,
for details, see SI). Moreover, solvents also played a key role in the
reaction, and methyl tert-butyl ether (MTBE) proved to be the best to
afford 2a in 98% yield with 87% ee (entry 9). Notably, 1,2,4,5-
tetrafluorobenzene gave 2a with a better enantioselectivity but in a
moderate yield (entry 8). Decreasing the reaction temperature resulted
in better enantioselectivities without loss of the reaction efficiency. The
reaction performed at -20 oC and using L3 as ligand in MTBE provided
2a in 98% yield with 96% ee as the best results (entries 10-12). Again,
L6 and L3 exhibited similar reactivities under the optimized reaction
conditions (entries 12-13).
determined by the X-ray crystallography.[19]
.
A carbon-centered radical adjacent to oxygen has been extensively
studied, and its properties were similar to CRAN. We then turned our
attention to testing the asymmetric cyanation of the carbon-centered
radicals adjacent to an oxygen atom. To our delight, the asymmetric
trifluoromethylcyanation reaction of 3a indeed worked, in the presence
of L6 (Table 2B, for the optimization of the reaction conditions, see SI),
giving the product 4a with excellent enantioselectivity (90% ee), and a
series of enantioenriched α-cyano esters were successfully synthesized.
Both vinyl aryl esters and vinyl alkyl esters yielded the corresponding
products 4a-4e in good to excellent yields (70-99%) with excellent
enantioselectivities (87-91% ee). Notably, the reaction displays high
functional group tolerance, such as methoxyl, chloro and
trifluoromethyl moieties were compatible with the current reaction
conditions. More importantly, substrates bearing heterocycles such as
indole and thiophene, were suitable for the reaction to delivere the
desired product 4f-4g in good to excellent yields (70-90%) with
excellent enantioselectivities (89-90% ee). When chiral vinyl amino
acid ester 3h was employed as substrate, to our delight, the desired
product 4h was obtained in good yields with excellent
diastereoselectivities (d.r. = 10:1). Lastly, other various vinyl esters as
substrate were tested, vinyl phosphinate 3i gave product 4i in 86%
yield with 92% ee, while the reaction of vinyl-OTs 3j just afforded 4j
in 65% yield with moderate enantioselectivity (60% ee).
Table 1. Condition Screening[a]
Above results demonstrated that the generated CRAN could be
enantioselectively trapped by chiral copper(II) cyanide. Inspired by
these results, then we turned our attention to testing the asymmetric
coupling of CRAN with alcohols. Under the cyanation reaction
conditions, (MeO)4Si instead of TMSCN was initially employed as a
methoxide source, the reaction of enamide 1a with (MeO)4Si afforded
the desired trifluoromethoxylation product 6a in 37% yield with 53%
ee, in the presence of 10 mol% Cu(CH3CN)4PF6/12 mol% L3, and 51%
yield and 67% ee were obtained when 10 mol% Cu(CH3CN)4PF6/12
mol% L6 were used. After systematic screening, 10 mol%
Cu(CH3)4PF6/12 mol% L7 as catalyst provided a better performance to
give 6a in 59% yield with 89% ee. Gratifyingly, simple MeOH could
be directly applied to the reaction, providing 6a in 84% yield with 94%
ee as the best results (for details, see SI).
[a] Reaction condtions: 1a (0.1 mmol), Cu salt (5 mol%), ligand (6
mol%), Togni-I (0.2 mmol) and TMSCN (0.2 mmol) in solvent (1 mL)
under a nitrogen atmosphere at room temperature; [b] Yields were
determined by crude 1H NMR with CH2Br2 as an internal standard, and
enantiomeric excess (ee) value was determined by HPLC on a chiral
stationary phase; [c] At 0 oC. [d] At -10 oC. [e] At -20 oC.
After having established the optimal reaction conditions, the
substrate scope of the oxygenation of enamides was also explored
under the optimized reaction conditions, and the results were
summarized in Table 3. The reaction showed excellent functional
group tolerance, N-vinyl benzamides with various substituents on the
aromatic ring such as electron-donating groups (methyl, methoxyl) and
electron-deficient groups (halogen, phenyl, cyano, trifluoromethyl)
were suitable for the reaction to provide the corresponding products
6a-6j in moderate to excellent yield (55-91%) with excellent enantio-
selectivities (84%-96% ee). Notably, the ortho-substituted substrate
exhibited slightly lower enantioselectivity (6i, 86% ee). In addition, N-
vinyl-amides bearing 1- or 2-naphthalenyl groups could also give
products 6k in 65% yield (98% ee) and 6l in 74% yield (84% ee),
respectively. Enamide substrates derived from alkyl carboxylic acids
With the optimized reaction conditions in hand, the substrate scope
with respect to enamides was then explored, and these results were
summarized in Table 2A. N-Vinyl benzamides with various
substituents on the aromatic ring were suitable for the reaction to
provide the corresponding products 2a-2h in excellent yields (85%-
98%) with excellent enantioselectivities (92%-98% ee). In addition,
reactions of N-vinyl-amides with 1- or 2-naphthalenyl groups also
proceeded very well to give products 2i in 90% yield (93% ee) and 2j
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Table 2. Scope of enamides and vinyl esters.[a,b]
[a] All reactions were run on a 0.2 mmol scale in MTBE (2 mL) under a nitrogen atmosphere. [b] Isolated yields, and enantiomeric excess (ee)
values were determined by HPLC on a chiral stationary phase. [c] On a 10 mmol scale. [d] Using L6.
Table 3. Scope of enamides and alcohols.[a,b]
[a] All reactions were run on 0.2 mmol scale in DMAc (1 mL) under a nitrogen atmosphere. [b] Isolated yields, and enantiomeric excess (ee)
values determined by HPLC on a chiral stationary phase. [c] Reaction at -20 ºC.
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compared to the CRAN generated from substrate 1p (90% ee),
when two more carbon atoms were added to the carbon-centered
radical connecting to a nitrogen atom, the cyanation product 11
was produced with lower enantioselectivity (70% ee), and
increasing the carbon atoms resulted in even worse
enantioselectivity (<5% ee, 12) (Scheme 3b, ii). Based on these
studies, we concluded that the carbonyl group coordinating to
chiral Cu(II) species played an essential role in the asymmetric
radical coupling step.
were also suitable for reaction to give 6m in 55% yield with 86% ee.
Moreover, enamides bearing heterocycles, such as pyrridine and
furan, were also compatible with the reaction conditions to deliver
products 6n and 6o in good yields (80-87%) with excellent
enantioselectivities (95% ee).
Lastly,
a series of alcohols as coupling partners were
investigated. Reactions of simple alcohols, such as ethanol,
propanol, pentanol and benzyl alcohol, proceeded smoothyl to
yield corresponding products 6p-6s with excellent results. Notably,
the oxygenation reaction of CRAN also featured high functional
group tolerance, a series of alcohols containing various functional
groups such as cyclopropanyl (6t), diol (6u), sulfonyl (6v), alkynyl
(6w), aniline (6x) and methylenedioxybenzene (6y) were subjected
to the reaction conditions, giving the desired products in 60-86%
yields with 80-97% ee. Moreover, reactions of alcohols bearing
heteroarenes including furan and thiophene also proceeded very
well to afford 6z-7a in good yields with excellent
enantioselectivities, except that the reaction of alcohol with
benzoxazoline gave product 7b with moderate enantioselectivity
(60% ee). In addition, reactions of enamides with chiral alcohols
also furnished the products 7c-7e in good yields with high levels of
diastereoselective induction (94-97% de). Alcohols with a long
chain (7f) also proved amenable to the asymmetric etherification.
In order to showcase the synthetic utility of the method, further
transformations of the trifluoromethylcyanation products were
investigated (Scheme 2). Optically pure 1,2-diamine 8 could be
readily prepared through the hydrogenation of 2a using Raney
nickel catalyst in 90% yield with 99% ee. Moreover, 2q could be
transformed into amide 9 in 86% yield with 86% ee, the core
structure of which is similar to that of antiepileptic drug
Levetiracetam;[20] Interestingly, further recrystallization of product
9 in isopropanol yielded a small amount of precipitate only, and we
were delighted to find that the enantioselectivity of 9 in solution
was accumulated to 95% ee in 75% yield.
Scheme 3. Preliminary mechanistic studies.
In conclusion, we have developed the first copper-catalyzed
asymmetric cyanation and oxygenation of enamides proceeding
through a highly enantioselective capture of CRAN by a chiral
copper complex; and the asymmetric cyanation of vinyl esters was
illustrated as well. These methods allow for the straightforward and
efficient synthesis of various α-cyano amides, α-cyano ethers and
hemiaminals in good yields with excellent enantioselectivities
under very mild conditions. Preliminary mechanistic studies reveal
that the carbonyl group in the enamides plays a crucial role in
achieving high levels of enantioselectivities in the asymmetric
cyanation and etherification of the carbon-centered radicals
adjacent to a heteroatom.
Scheme 2. Synthetic applications.
Some control experiments revealed that the reactions involves
a radical pathway (for details, see SI). In addition, compared to
vinyl enolate 3a, the reaction of vinyl benzyl ethers yielded the
desired product with low enantioselectivity (10, 16% ee, Scheme 3,
i), indicating that the carbonyl groups in vinyl substrates were
essential for the asymmetric coupling. There are two possible roles
for the carbonyls: (1) decreasing the electron density of a carbon-
Acknowledgements
We are grateful for financial support from the National Nature
Science Foundation of China (Nos. 21532009, 21728201,
21790330 and 21821002), the Science and Technology
Commission of Shanghai Municipality (Nos. 17XD1404500,
17QA1405200 and 17JC1401200), and the strategic Priority
Research Program (No. XDB20000000) and the Key Research
Program of Frontier Science (QYZDJSSWSLH055) of the Chinese
Academy of Sciences.
centered radical and thus avoiding its overoxidation to
a
carbocation; and (2) acting as a coordinating site for chiral
copper(II) species to facilitate the asymmetric coupling of the
chiral copper(II) species with carbon-centered radicals. For vinyl
phosphite (3i) and sulfonate (3j) bearing a stronger electron-
withdrawing group than the carbonyl group in 3a, the reaction of 3i
led to slightly higher enantioselectivity than 3a, while the reaction
of 3j gave product 4j with much lower ee value (Scheme 3, i). We
reasoned that these outcomes might be attributed to the order of the
chelating ability of groups: phosphinyl > acyl > sulfonyl. Moreover,
Keywords: asymmetric radical reaction • copper catalysis •
cyanation • etherification • enamides
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10.1002/anie.202008338
Angewandte Chemie International Edition
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G. Zhang, S. Zhou, L. Fu, P. Chen, Y. Li,
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Asymmetric Coupling of Carbon-
Centered
Nitrogen:
Radical
Adjacent
Copper-Catalyzed
to
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Cyanation and Etherification of
Enamides
The first copper-catalyzed asymmetric cyanation and etherification of enamides have
been established, where a carbon-centered radical adjacent to a nitrogen atom
(CRAN) is enantioselectively trapped by a chiral copper (II) species. The asymmetric
cyanation of vinyl esters was illustrated as well. The reactions featuring very mild
reaction conditions and high functional group tolerance give a series of chiral α-cyano
amides, α-cyano esters and hemiaminals in good yields with excellent
enantioselectivities.
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