Direct Access to α-Oxoketene Aminals via Copper-Catalyzed Formal Oxyaminalization of Alkenes under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.9b00518

A copper-catalyzed four-component formal oxyaminalization of alkenes with Togni's reagent and amines using molecular oxygen as both the oxidant and oxygen source has been developed for the first time, offering a straightforward and efficient method for the synthesis of a range of structurally diverse α-oxoketene aminals. The use of cheap copper catalyst and readily available substrates, excellent functional group tolerance, broad substrate scope, mild conditions, and simple procedure are the attractive features of the strategy.

Full text of DOI:10.1021/acs.orglett.9b00518

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Access to α‑Oxoketene Aminals via Copper-Catalyzed Formal
Oxyaminalization of Alkenes under Mild Conditions
Lu Wang,† Chaorong Qi,*,†,‡ Tianzuo Guo,† and Huanfeng Jiang*,†
†Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510640, P.R. China
‡State Key Laboratory of Luminescent Materials and Devices, South China University of Technology, Guangzhou 510640, P.R.
China
S
* Supporting Information
ABSTRACT: A copper-catalyzed four-component formal oxy-
aminalization of alkenes with Togni’s reagent and amines using
molecular oxygen as both the oxidant and oxygen source has
been developed for the first time, offering a straightforward and
efficient method for the synthesis of a range of structurally
diverse α-oxoketene aminals. The use of cheap copper catalyst
and readily available substrates, excellent functional group tolerance, broad substrate scope, mild conditions, and simple
procedure are the attractive features of the strategy.
Scheme 1. Synthetic Strategies for α-Oxoketene Aminals
etene aminals constitute an important class of biologically
Kactive compounds which are frequently found in many
pharmaceuticals and agrochemicals.1 More importantly, due to
their unique structural characteristics, they have been widely
used as versatile building blocks for the construction of a range
of medicinally relevant heterocyclic compounds in the past
years.2,3 In addition, these molecules can serve as efficient
ligands in transition-metal catalysis.4
For the preparation of ketene aminal compounds, many
methods based on two-component reactions have been
developed.2a However, these methods generally suffer from
the use of not easily accessible starting materials and tedious
procedures. In particular, α-oxoketene aminals, one of the most
important kind of ketene aminals, are often prepared by the
condensation reaction between α-oxoketene dithioacetals and
amines (Scheme 1A, a), but the corresponding ketene
dithioacetals need to be synthesized from ketones in advance
via a two-step procedure involving the use of toxic and highly
volatile carbon disulfide and methyl iodide as the reagents.
Other methods based on C−C bond formation include the
acylation of 1,1-diaminoethenes with acyl chlorides (Scheme
1A, b)5a and the condensation between orthocarbonic acid
derivatives with ketones (Scheme 1A, c),5b,c both of which also
suffer from the drawback of using not easily obtained reagents
and rather narrow substrate scope. Therefore, the development
of a new strategy for the efficient synthesis of α-oxoketene
aminals, especially from readily available starting materials via a
simple one-step process, is highly desirable but remains a great
challenge.
which would enable the rapid assembly of ketene aminals with
great structural diversity, has not been reported yet.
As part our continuous interest in oxidative functionalization
of unsaturated hydrocarbons with molecular oxygen,7 herein,
we wish to report the first copper-catalyzed four-component
formal oxyaminalization of alkenes with amines, Togni’s
reagent, under aerobic conditions. The novel reaction proceeds
by transition-metal-catalyzed oxytrifluoromethylation of al-
kenes8 and subsequent C−F bond activation process,9,10 which
provides an unprecedented route to a variety of structurally
Alkenes are the most abundant and commonly used organic
building blocks in large-scale chemical synthesis. Recently,
difunctionalization of alkenes has emerged as a powerful tool
for making valuable products due to their step and atom-
economy.6 However, the oxyaminalization of simple alkenes,
Received: February 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00518
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
diverse and synthetically useful α-oxoketene aminals (Scheme
1B).
Scheme 2. Scope of Alkenes
We began our study with the synthesis of ketene aminal 4aa
by using styrene (1a), Togni’s reagent 2a, and diethylamine
(3a) as the model substrates. After scrupulous examination of
the reaction parameters, we were glad to find that combining
CuS (10 mol %) and 2-methyl-1,10-phenanthroline (L2, 20
mol %) as the ligand under an oxygen atmosphere provided
the best result, giving 4a in 72% yield upon isolation.11 It is
worth noting that the structure of the ligand has a great impact
on the activity of catalyst (Scheme S1, a). Among various
pyridine−base bidentate and tridentate ligands screened,
monosubstituted 1,10-phenanthroline derivative L2 proved to
be the most effective. Different CF3 reagents were also
screened for the transformation (Scheme S1, b). Using Togni’s
reagent 2b instead of 2a as the trifluoromethyl group source
gave lower yield, while other CF3 reagents including
Umemoto’s reagent (2c), TMSCF3, and CF3SO2Na failed to
provide the desired product. Several other copper salts (Table
S1, entries 2−5) and solvents (Table S1, entries 6−9) were
examined, but all of them gave 4aa in lower yields. Two
control experiments showed that both copper catalyst and
molecular oxygen are essential for the reaction to occur (Table
S1, entries 17 and 18).
With the optimized reaction conditions in hand, we then
examined the generality and limitations of the copper-catalyzed
process, and the representative results are summarized in
Scheme 2. To our delight, a wide range of styrene derivatives
could undergo smooth reaction with 2a and 3a to give the
corresponding products in moderate to high yields. Both
electron-donating and electron-withdrawing substituents at the
para positions of the benzene ring, including tert-butyl,
methoxyl, phenyl, halide (F, Cl and Br), trifluoromethyl,
nitrile, nitro, and ester groups, were well tolerated (4ba−ka),
which may be beneficial for further transformations. In general,
ortho-substituted substrates gave the corresponding products
(4na−qa) in slightly lower yields than their meta- or para-
substituted analogues, which may be due to the steric effect.
The multisubstituted substrates, 1,3-bis(trifluoromethyl)-5-
vinylbenzene (1r) and 1,2,3,4,5-pentafluoro-6-vinylbenzene
(1s), worked well to afford the expected products 4ra and
4sa in 71% and 52% yields, respectively. Notably, the reaction
of estrone-derived alkene 1u proceeded smoothly with high
efficiency. 4-Vinylpyridine and 4-methyl-5-vinylthiazole, which
are heteroaromatic alkenes, were also suitable substrates for the
reaction to give the products 4va and 4wa in satisfactory yields.
Internal alkenes, such as trans-stilbene and 1,2-dihydronaph-
thalene, could enter into the reaction to give products 4xa and
4ya without difficulty. Moreover, our protocol could be applied
to aliphatic alkenes, which are often challenging substrates for
difunctionalization reaction. For example, but-3-en-1-ylben-
zene could afford the product 4za, albeit in a low yield.
Then the scope of amines was studied. As can be seen from
Scheme 3, a variety of amines were viable partners for this
transformation. Both acyclic and cyclic secondary amines took
part in the reaction efficiently, giving the desired products
(4ab−rj) in good to high yields. Various primary amines,
including those with long or bulky alkyl substituents, also
reacted well with 1a and 2a to provide the corresponding
products 4ak−ap. The structures of the products 4rj and 4an
were unambiguously confirmed by means of X-ray crystallo-
graphic analysis. It is worth mentioning that heterocyclic
ketene aminals, such as 4aq and 4ar, could be obtained from
a
Reaction conditions: 1 (0.1 mmol), 2a (0.12 mmol), 3a (0.7 mmol),
CuS (10 mol %), L2 (20 mol %), MeCN (1 mL), 60 °C, 10 h, O2
(balloon). Yields of isolated products are given.
the corresponding diamines by the present protocol, but in
these cases Cu(OAc)2 was used as catalyst instead of CuS.
However, aromatic amines failed to undergo the reaction, and
the substrates could be recovered unchanged.
To demonstrate the synthetic benefit of our copper-
catalyzed protocol, the newly formed 4an was further
converted to several useful heterocyclic compounds. As
shown in Scheme 4, 4an could undergo Michael addition/
cyclization reaction with dimethyl acetylenedicarboxylate to
give the pyridine derivative 5 in 51% yield.12a Product 6
bearing a fused three-ring system could be synthesized with
high efficiency by the interaction of 4an with isatin in refluxing
toluene.3d The structure of 6 was also characterized by X-ray
diffraction analysis. Additionally, treating 4an with benzoyl
isothiocyanate or 1,4-benzoquinone could gave 2,5,6-trisub-
stituted 4-thioxopyrimidine 712b and benzofuran derivative
8,12c respectively, in good yields under metal-free conditions.
To gain more insight into the mechanism of the reaction, a
series of control experiments were performed. First, the
reaction of 1a, 2a, and 3a could be inhibited by the radical
scavengers 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO),
2,6-di-tert-butyl-4-methylphenol (BHT), and benzoquinone,
revealing the reaction might proceed through a radical pathway
(Scheme 5, a). Second, when the reaction was conducted in
the absence of air, no trace of 4aa was detected. Moreover, the
reaction under an 18O2 atmosphere gave the 18O-isotopologue
4aa′ in 71% yield and in 83% isotopic purity (Scheme 5, b).
B
DOI: 10.1021/acs.orglett.9b00518
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of Amines
Scheme 4. Versatile Transformations of the Ketene Aminal
Products
a
a
Reaction conditions: (a) 4an (0.2 mmol), dimethyl acetylenedi-
carboxylate (1.3 equiv), toluene (2 mL), room temperature, 30 min;
(b) 4an (0.5 mmol), isatin (1.1 equiv), toluene (3 mL), reflux, 4 h;
(c) 4an (0.2 mmol), benzoyl isothiocyanate (1.25 equiv), THF (2
mL), room temperature, 24 h, N2; (d) 4an (0.4 mmol), 1,4-
benzoquinone (1.2 equiv), AcOH (3 mL), reflux, 1 h.
Scheme 5. Mechanism Studies
a
Reaction conditions: 1 (0.1 mmol), 2a (0.12 mmol), 3 (0.7 mmol),
CuS (10 mol %), L2 (20 mol %), MeCN (1 mL), 60 °C, 10 h, O2
b
(balloon). Yields of isolated products are given. The reaction was
carried out with Cu(OAc)2 as the catalyst instead of CuS.
These results indicated that the carbonyl oxygen atom of
products 4 originated from molecular oxygen. Finally, it was
found that 1a could react with 2a in the presence of 1 equiv of
triethylamine to give 3,3,3-trifluoro-1-phenylpropan-1-one (9)
in 16% yield, and the treatment of compound 9 with 7 equiv of
3a in acetonitrile gave 4aa in almost quantitative yield
(Scheme 5, c), indicating compound 9 is the reaction
intermediate for the transformation.
On the basis of the above investigations and previous
reports,8,10e−g,13,14 a plausible mechanism for the reaction is
postulated in Scheme 6. Initially, the Cu(I) species, generated
in situ from Cu(II) via reduction by amine 3a as electron
donor,13 undergoes single-electron transfer with Togni’s
reagent 2a to give a CF3 radical. The addition of CF3 radical
to styrene 1a then yields benzylic radical 10,14 which can be
trapped by molecular oxygen to give α-trifluoromethyl-
substituted ketone 9 via intermediates 11 and 12. Sub-
sequently, ketone 9 undergoes dehydrofluorination in the
presence of 3a as the base to afford gem-difluoro-substituted
vinyl ketone 13.10e−g Nucleophilic substitution of 13 with 3a
finally furnishes the target product 4aa via intermediates 14−
16 through two similar addition−elimination processes. In this
mechanism, 3a plays triple roles: it serves not only as a
coupling partner but also as a reductant and base, which
explains why an excess amount of 3a is required to facilitate
significant product formation.
In conclusion, we have disclosed a copper-catalyzed four-
component formal oxyaminalization of alkenes, providing a
straightforward and efficient method for the synthesis of a
range of synthetically important α-oxoketene aminals. The
reaction employs Togni’s reagent as a one-carbon synthon and
molecular oxygen as both the oxidant and oxygen source. This
C
DOI: 10.1021/acs.orglett.9b00518
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Discenza, L.; Yanchunas, J., Jr.; Stein, P. D.; Atwal, K. S. J. Med. Chem.
2008, 51, 7541. (c) Chen, N.; Meng, X.; Zhu, F.; Cheng, J.; Shao, X.;
Li, Z. J. Agric. Food Chem. 2015, 63, 1360.
Scheme 6. Plausible Mechanistic Pathway
(2) For selective reviews, see: (a) Huang, Z.-T.; Wan, M.-X.
Heterocycles 1994, 37, 1233. (b) Wang, K.-M.; Yan, S.-J.; Lin, J. Eur. J.
Org. Chem. 2014, 2014, 1129.
(3) For some recent examples, see: (a) Chen, L.; Huang, R.; Du, X.-
X.; Yan, S.-J.; Lin, J. ACS Sustainable Chem. Eng. 2017, 5, 1899.
(b) Ma, Y.-L.; Wang, K.-M.; Huang, R.; Lin, J.; Yan, S.-J. Green Chem.
2017, 19, 3574. (c) Thirupathi, A.; Janni, M.; Peruncheralathan, S. J.
Org. Chem. 2018, 83, 8668. (d) Wang, B.-Q.; Zhang, C.-H.; Tian, X.-
X.; Lin, J.; Yan, S.-J. Org. Lett. 2018, 20, 660. (e) Zhao, M.; Li, X.;
Shao, J.; Chen, W.; Xie, N.; Yuan, H.; Sun, Q.; Zhang, W. Org. Lett.
2018, 20, 3057.
(4) Wen, L.-R.; Jin, X.-J.; Niu, X.-D.; Li, M. J. Org. Chem. 2015, 80,
90.
(5) (a) Armati, A.; De Ruggieri, P.; Rossi, E.; Stradi, R. Synthesis
1986, 1986, 573. (b) Kantlehner, W. Synthesis 1979, 1979, 343.
(c) Kantlehner, W.; Mergen, W. W.; Haug, E. Liebigs Ann. Chem.
1983, 1983, 290.
(6) For selective reviews, see: (a) Cardona, F.; Goti, A. Nat. Chem.
2009, 1, 269. (b) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev.
2011, 111, 2981. (c) Chemler, S. R.; Bovino, M. T. ACS Catal. 2013,
3, 1076. (d) Zhu, Y.; Cornwall, R. G.; Du, H.; Zhao, B.; Shi, Y. Acc.
Chem. Res. 2014, 47, 3665. (e) Yin, G.; Mu, X.; Liu, G. Acc. Chem. Res.
2016, 49, 2413. (f) Coombs, J. R.; Morken, J. P. Angew. Chem., Int.
Ed. 2016, 55, 2636. (g) Lan, X.-W.; Wang, N.-X.; Xing, Y. Eur. J. Org.
Chem. 2017, 2017, 5821. (h) Sauer, G. S.; Lin, S. ACS Catal. 2018, 8,
5175.
protocol features the use of cheap copper catalyst and readily
available starting materials, excellent functional group toler-
ance, broad substrate scope, mild conditions, and a simple
procedure. Further investigation on the mechanistic details and
synthetic applications are now underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00518.
Experimental procedures, condition screening table,
characterization data, and copies of NMR spectra for
all products (PDF)
(7) For our recent work on molecular oxygen as an oxidant, see:
(a) Wu, W.; Jiang, H. Acc. Chem. Res. 2012, 45, 1736. (b) Tang, X.;
Wu, W.; Zeng, W.; Jiang, H. Acc. Chem. Res. 2018, 51, 1092.
(8) (a) Pham, P. V.; Nagib, D. A.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2011, 50, 6119. (b) Zhang, C.-P.; Wang, Z.-L.; Chen,
Q.-Y.; Zhang, C.-T.; Gu, Y.-C.; Xiao, J.-C. Chem. Commun. 2011, 47,
6632. (c) Deb, A.; Manna, S.; Modak, A.; Patra, T.; Maity, S.; Maiti,
D. Angew. Chem., Int. Ed. 2013, 52, 9747. (d) He, Z.; Zhang, R.; Hu,
M.; Li, L.; Ni, C.; Hu, J. Chem. Sci. 2013, 4, 3478. (e) Tomita, R.;
Yasu, Y.; Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2014, 53, 7144.
(f) Kawamoto, T.; Sasaki, R.; Kamimura, A. Angew. Chem., Int. Ed.
2017, 56, 1342.
Accession Codes
CCDC 1882257, 1882261, and 1882263 contain 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 Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
(9) For selective reviews on C−F activation, see: (a) Amii, H.;
Uneyama, K. Chem. Rev. 2009, 109, 2119. (b) Zhang, X.; Cao, S.
Tetrahedron Lett. 2017, 58, 375.
AUTHOR INFORMATION
Corresponding Authors
■
(10) For some recent examples, see: (a) Lu, X.; Wang, Y.; Zhang, B.;
Pi, J.-J.; Wang, X.-X.; Gong, T.-J.; Xiao, B.; Fu, Y. J. Am. Chem. Soc.
2017, 139, 12632. (b) Yoshida, S.; Shimomori, K.; Kim, Y.; Hosoya,
T. Angew. Chem., Int. Ed. 2016, 55, 10406. (c) Wang, C.-Q.; Ye, L.;
Feng, C.; Loh, T.-P. J. Am. Chem. Soc. 2017, 139, 1762. (d) Fujita, T.;
Takazawa, M.; Sugiyama, K.; Suzuki, N.; Ichikawa, J. Org. Lett. 2017,
19, 588. (e) Song, P.; Yu, P.; Lin, J.-S.; Li, Y.; Yang, N.-Y.; Liu, X.-Y.
Org. Lett. 2017, 19, 1330. (f) Fuchibe, K.; Hatta, H.; Oh, K.; Oki, R.;
Ichikawa, J. Angew. Chem., Int. Ed. 2017, 56, 5890. (g) Xu, L.; Zhang,
Q.; Xie, Q.; Huang, B.; Dai, J.-J.; Xu, J.; Hu, H.-J. Chem. Commun.
2018, 54, 4406.
*E-mail: crqi@scut.edu.cn.
*E-mail: jianghf@scut.edu.cn.
ORCID
Chaorong Qi: 0000-0003-4776-2443
Huanfeng Jiang: 0000-0002-4355-0294
Notes
The authors declare no competing financial interest.
(11) For more details, see the Supporting Information.
(12) (a) Aggarwal, V.; Ila, H.; Junjappa, H. Synthesis 1983, 1983,
147. (b) Aggarwal, V.; Kumar, A.; Ila, H.; Junjappa, H. Synthesis 1981,
1981, 157. (c) Aggarwal, V.; Ila, H.; Junjappa, H. Synthesis 1982,
1982, 65.
(13) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322. (b) Reiser, O. Acc. Chem. Res. 2016, 49, 1990.
(c) Wang, C.; Guo, M.; Qi, R.; Shang, Q.; Liu, Q.; Wang, S.; Zhao, L.;
Wang, R.; Xu, Z. Angew. Chem., Int. Ed. 2018, 57, 15841. (d) Ye, J.;
Kalvet, I.; Schoenebeck, F.; Rovis, T. Nat. Chem. 2018, 10, 1037.
(14) (a) Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011,
50, 9120. (b) Lin, J.-S.; Dong, X.-Y.; Li, T.-T.; Jiang, N.-C.; Tan, B.;
Liu, X.-Y. J. Am. Chem. Soc. 2016, 138, 9357. (c) Wang, F.; Chen, P.;
Liu, G. Acc. Chem. Res. 2018, 51, 2036.
ACKNOWLEDGMENTS
■
The authors thank the Ministry of Science and Technology of
the People’s Republic of China (2016YFA0602900), the
National Natural Science Foundation of China (21572071),
and the Guangdong Natural Science Foundation
(2017A030313054) for financial support.
REFERENCES
■
(1) (a) Kondo, H.; Taguchi, M.; Inoue, Y.; Sakamoto, F.;
Tsukamoto, G. J. Med. Chem. 1990, 33, 2012. (b) Shi, Y.; Sitkoff,
D.; Zhang, J.; Klei, H. E.; Kish, K.; Liu, E. C.-K.; Hartl, K. S.; Seiler, S.
M.; Chang, M.; Huang, C.; Youssef, S.; Steinbacher, T. E.;
Schumacher, W. A.; Grazier, N.; Pudzianowski, A.; Apedo, A.;
D
DOI: 10.1021/acs.orglett.9b00518
Org. Lett. XXXX, XXX, XXX−XXX