Computational and experimental studies on copper-mediated selective cascade C-H/N-H annulation of electron-deficient acrylamide with arynes

Article abstract of DOI:10.1039/C8CC08708C

An efficient and convenient copper-mediated method has been developed to achieve direct cascade C-H/N-H annulation to synthesize 2-quinolinones from electron-deficient acrylamides and arynes. This method highlights an emerging but simple strategy to transform inert C-H bonds into versatile functional groups in organic synthesis to provide a new method of synthesizing 2-quinolinones efficiently. Mechanistic investigations by experimental and density functional theory (DFT) studies suggest that an organometallic C-H activation via a Cu(iii) intermediate is likely to be involved in the reaction.

Full text of DOI:10.1039/C8CC08708C

Volume 55 Number 6 18 January 2019 Pages 719–872
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Abing Duan, Shu-Yu Zhang et al.
Computational and experimental studies on
copper-mediated selective cascade C–H/N–H
annulation of electron-deficient acrylamide with
arynes

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Computational and experimental studies on
copper-mediated selective cascade C–H/N–H
annulation of electron-deficient acrylamide with
Cite this: Chem. Commun., 2019,
55, 755
Received 31st October 2018,
Accepted 26th November 2018
arynes†
a
Chao Chen,a Yu Hao,a Ting-Yu Zhang,a Jin-Long Pan,
Jun Ding,a Heng-Ye Xiang,a
DOI: 10.1039/c8cc08708c
Man Wang,a Tong-Mei Ding,a Abing Duan*b and Shu-Yu Zhang
*
a
rsc.li/chemcomm
An efficient and convenient copper-mediated method has been
developed to achieve direct cascade C–H/N–H annulation to syn-
thesize 2-quinolinones from electron-deficient acrylamides and
arynes. This method highlights an emerging but simple strategy to
transform inert C–H bonds into versatile functional groups in
organic synthesis to provide
a new method of synthesizing
2-quinolinones efficiently. Mechanistic investigations by experi-
mental and density functional theory (DFT) studies suggest that
an organometallic C–H activation via a Cu(III) intermediate is likely
to be involved in the reaction.
Transition metal-catalyzed selective cascade C–H/N–H activation
and annulation is an arguably ideal approach for the direct one-pot
synthesis of nitrogen-containing heterocyclic molecules with great
atom and step economy.1 Among them, cascade cyclization of an
amide with an alkyne or aryne to form six-membered lactams,
which are partial structures of natural products and pharmaceu-
tical agents, has gained considerable attention in recent years.
While significant advances have been made in this field using Ru,2
Rh,3 Pd,4 etc.5 as catalysts (Scheme 1A), the development of an ideal
strategy that avoids the use of noble metal catalysts and oxidants
due to potential pharmaceutical chemical studies and highly
efficient, economical, and environmentally benign production
Scheme 1 Approaches for the synthesis of 2-quinolinones via cascade
C–H/N–H annulation.
methods in an intensively investigated field still focuses on recent years,7 the C–H activation of electron-deficient alkenes
synthetic chemistry. In particular, reactivity enabled by cheap or acrylamides has remained elusive because of the rate-limiting
and abundant copper catalysts6 has attracted our interest.
electrophilic metalation step. To date, the study by Loh and Feng
Despite the exploitation of Cu-catalyzed direct C(sp2)–H func- is the only one to report the Cu-catalyzed C–H trifluoromethyl-
tionalization of electron-rich alkenes and benzylamides in ation of acrylamides with Togni’s reagent (Scheme 1B).8 In our
continuous efforts and interest to develop efficient and selective
unactivated C–H functionalization and its application in the
a Sixth People’s Hospital South Campus, Shanghai Key Laboratory for Molecular
synthesis of natural products,9 herein, we describe the first non-
Engineering of Chiral Drugs, and School of Chemistry and Chemical Engineering,
noble metal copper-mediated bidentate carboxamide-directed
cascade C–H/N–H annulation of electron-deficient acrylamides
with arynes10 to synthesize 2-quinolinones. This method offers a
practical solution for the rapid synthesis of polycyclic 2-quinolinone
cores, which are widely found in a variety of natural products
and pharmaceutically active compounds, many of which pos-
sess remarkable biological activities (Scheme 1C).11 In addition,
Shanghai Jiao Tong University, Shanghai, 200240, China.
E-mail: zhangsy16@sjtu.edu.cn
b College of Environmental Science & Technology, Hunan University, Changsha,
410082, China. E-mail: duanabing@hnu.edu.cn
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data of all new compounds, DFT data and copies of
NMR spectra. CCDC 1858672 (7). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c8cc08708c
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the detailed mechanistic investigations by experimental and DFT which indicates that the N,N-bidentate DG is vital to the
studies provide a valuable understanding of the Cu-mediated reaction taking place.
cascade C–H/N–H annulation reaction.
With the optimal conditions in hand, we subsequently explored
Our strategy was inspired by transition metal-catalyzed the substrate scope of acrylamides to survey the general reactions.
C–H activation/functionalization via the assistance of the As shown in Scheme 3, a-substituted acrylamides bearing alkyl,
N,N-bidentate directing group (DG).12 First, coordination of aryl, and benzyl groups were readily annulated in 52–72% yields
electron-deficient acrylamides to a copper catalyst generated (5–9). The electron-withdrawing group-substituted a-fluoro-
complex I ligated by the N,N-bidentate DG (Scheme 2). The acrylamide 4a showed lower efficiency and gave the annulation
bidentate DG significantly improves the electron-deficient product 4 in 39% isolated yield. A variety of acrylamides with
acrylamides’ reactivity to undergo a dominant intramolecular different a-cyclic substituents, such as cyclopropyl, cyclopentyl,
acetate-assisted C–H metalation-deprotonation (CMD) process cyclohexyl, piperonyl, a-naphthyl, and 3-indolyl smoothly under-
to give a key five-membered complex II. We believe the rate- went the cascade reaction and provided the corresponding
limiting step of inert electron-deficient alkene C(sp2)–H activa- annulation products in good to excellent yields (10–15). In
tion would be crucial. Furthermore, the steric hindrance of addition, a,b-substituted acrylamides could be utilized to give
copper complex II can efficiently avoid the general competing the 2-quinolinone products (16 and 17) in moderate yields.
side reactions of arynes with copper as a catalyst, such as the Obviously, the conversion is sensitive to b-substituted groups
self-coupling,13a or polymerization.13b After the process of carbo-
cupration with arynes, reductive elimination of III yields the
desired multi-substituted 2-quinolinones, and the copper catalyst
can be regenerated by oxygen for the next cycle.
Based on the considerations mentioned above, we started to
evaluate our hypothesis with electron-deficient N-quinolyl
methacrylamide 1a and Kobayashi benzyne precursor14 2a as
the model substrates. After the exploration of the Cu-mediated
reaction system for our assumption (see the ESI†), the desired
2-quinolinone product 3 was obtained in a 68% yield by using
catalytic amounts of Cu(OAc)2 (50%), CsF (1.2 equiv.), and TBAI
(1.5 equiv.) at 80 1C in DMA/MeCN (1 : 1) under O2 as an oxidant
for 12 h. When Pd(OAc)2 (20 mol%) was used as the catalyst
instead of Cu(OAc)2, a substantially decreased yield of 3 was
obtained with oxidants such as O2, AgOAc and K2S2O8, demon-
strating that the Cu catalyst is superior to the Pd catalyst due to
its improved catalysis and wide availability in this reaction
system. In addition, the effect of the DG was investigated.
Trace products were detected when 8-quinolyl was replaced
by OMe, naphthalene and Ph. In contrast, the 2-oxazolinyl DG
exhibited a similar result (65% yield) to 8-quinolyl acrylamide,
Scheme 3 Substrate scope of acrylamide and arynes. Reaction condi-
tions: methacrylamide (0.2 mmol), 2a (0.4 mmol), Cu(OAc)2 (0.1 mmol),
Scheme 2 Our strategy: approaches for the synthesis of 2-quinolinones
via Cu-mediated cascade C–H/N–H annulation.
CsF (0.24 mmol), and TBAI (0.3 mmol) in DMA : MeCN (1 : 1, 2 mL) at 80 1C
under O2 for 12 h.
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since it is difficult for the stabilized intermediates to be formed electron-rich benzylamides utilizing bidentate chelation, the
with higher steric hindrance. We then examined the scope of theoretical efforts toward understanding the challenging
functionalized aryne precursors as the general annulation C(sp2)–H activation and Cu-catalyzed cascade C–H/N–H annu-
partner for this reaction. Moreover, various substituted acryl- lation of electron-deficient alkenes were still missing. Consis-
amide substrates were reacted with various aryne precursors. tent with our experiments, a series of DFT calculations were
These precursors were well-tolerated under the Cu(OAc)2/O2 performed and are shown in Fig. 1. The electron-deficient
system and easily provided the desired 2-quinolinone derivative acrylamide 1a reacts with the Cu(OAc)2 to form the most stable
C–H/N–H annulation products (18–25) in good to excellent complex Com. From the substrate coordinated complex Com, this
yields. To demonstrate the application of our copper-mediated step undergoes TS1 with a 7.2 kcal molÀ1 barrier to generate I
cascade C–H/N–H annulation method as an efficient and versa- ligated by the N,N-bidentate DG and releases HOAc. Subsequently,
tile synthetic strategy to form 2-quinolinones, the core polycyclic I undergoes an acetate-assisted metalation-deprotonation (CMD)
units of orixalone D (pyranoquinoline),15 meloscine,16 and to produce a five-membered II via TS2 with an overall barrier of
preskimmianine17 (26–28), which are partial structures of natural 21.2 kcal molÀ1. This step is the rate-determining step and is in
products and pharmaceutical agents, were one-step synthesized good agreement with the experiment results (a KIE value of 5.1
under these mild conditions.
was observed). Then, II reacts with arynes to generate a stable
To gain some preliminary understanding of the reaction intermediate INT1 and subsequently form a four-membered
mechanism, several experiments were performed under the intermediate INT2 (via TS3) with a 16.2 kcal molÀ1 free energy
standard conditions. The intermolecular kinetic isotope effect barrier. The disproportionation of Cu(OAc)2 gives a Cu(III) inter-
experiment was conducted, and a KIE value of 5.1 was observed mediate INT3. From INT3, the opening of the four-membered ring
(see the ESI†), as predicted in Scheme 2, indicating that the leads to the formation of a seven-membered intermediate III.
C–H activation of inert electron-deficient alkenes is clearly the An interesting conformational change takes place in this step.
rate-determining step of the copper-catalyzed catalytic cycle. Finally, reductive elimination of III (via TS5) yields the desired
Moreover, a radical trapping experiment was performed. The annulation product 3 and Cu(OAc)2, which can regenerate and
annulation was not inhibited by the addition of 1 equiv. of the undergo oxidation for the next cycle. Reviewing the whole
radical scavenger (TEMPO, BHT, or PhSSPh) and still yielded energy profile, we found that C–H activation is the key process
the corresponding annulation products. These experiments in the annulation reaction. The results are in accordance with
suggest that the SET mechanism is most likely not involved the mechanistic study.
in this reaction; rather, a plausible organometallic C–H activa-
In summary, we have developed the first copper-mediated
tion mechanism via a Cu(III)18 intermediate is proposed for this cascade C–H/N–H annulation of electron-deficient acrylamides
cascade C–H/N–H annulation.
with arynes to give an efficient and straightforward strategy for
Although the pioneer computational studies by Stahl19a the synthesis of 2-quinolinones. These reactions are operation-
and Chen19b established Cu-catalyzed C(sp2)–H activation of ally simple and robust, and the copper/O2 system avoids the use
Fig. 1 DFT-computed relative Gibbs free energy profiles of the annulation reaction with arynes. Energies are in kcal molÀ1 and key bond lengths are in Å.
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J. Selvakumar, S. Dana, U. Mukherjee and M. Baidya, Chem. – Eur. J.,
2018, 24, 3448. For recent Ni-catalyzed functionalization of alkenes,
see: ( f ) J.-W. Gu, Q.-Q. Min, L.-C. Yu and X. Zhang, Angew. Chem.,
Int. Ed., 2016, 55, 12270; (g) J. Derosa, V. T. Tran, M. N. Boulous,
J. S. Chen and K. M. Engle, J. Am. Chem. Soc., 2017, 139, 10657;
(h) W. Li, J. K. Boon and Y. Zhao, Chem. Sci., 2018, 9, 600.
of sensitive and expensive noble metals. In addition, experi-
mental and computational mechanistic investigations reveal
that the Cu-mediated cascade reaction possibly undergoes an
organometallic C–H activation/addition sequence via a Cu(III)
intermediate. Furthermore, the applications of this C–H annu-
lation methodology in the synthesis of more complex natural
alkaloids are currently under investigation.
This work was supported by the ‘‘Thousand Youth Talents
Plan’’, NSFC (21672145, 51733007), the Shuguang program
(16SG10) from SEDF&SMEC, the STCSM (17JC1403700), and
the Innovation Fund (IFPM016A002) from the Joint Research
Center for Precision Medicine of Shanghai Jiao Tong University.
8 C. Feng and T.-P. Loh, Angew. Chem., Int. Ed., 2013, 52, 12414.
9 (a) S.-Y. Zhang, Q. Li, G. He, W. A. Nack and G. Chen, J. Am. Chem.
Soc., 2015, 137, 531; (b) T.-Y. Zhang, J.-B. Lin, Q.-Z. Li, J.-C. Kang,
J.-L. Pan, S.-H. Hou, C. Chen and S.-Y. Zhang, Org. Lett., 2017,
19, 1764; (c) T.-Y. Zhang, C. Liu, C. Chen, J.-X. Liu, H.-Y. Xiang,
W. Jiang, T.-M. Ding and S.-Y. Zhang, Org. Lett., 2018, 20, 220.
10 For recent reviews on aryne chemistry, see: (a) S. S. Bhojgude and
A. T. Biju, Angew. Chem., Int. Ed., 2012, 51, 1520; (b) P. M. Tadross and
B. M. Stoltz, Chem. Rev., 2012, 112, 3550. For recent HDDA-trapping
reactions with benzynes of nature products, see: (c) T. R. Hoye,
B. Baire, D. Niu, P. H. Willoughby and B. P. Woods, Nature, 2012,
490, 208; (d) S. P. Ross and T. R. Hoye, Nat. Chem., 2017, 9, 523. For a
review of arynes in natural product total synthesis, see:
(e) P. M. Tadross and B. M. Stoltz, Chem. Rev., 2012, 112, 3550. For
elegant work regarding aryne insertion, see: ( f ) Z. Zuo, H. Wang,
Y. Diao, Y. Ge, J. Liu and X. Luan, ACS Catal., 2018, 8, 11029;
(g) M. Mesgar, J. Nguyen-Le and O. Daugulis, J. Am. Chem. Soc.,
2018, 140, 13703; (h) L. Zhou, H. Li, W. Zhang and L. Wang, Chem.
Commun., 2018, 54, 4822; (i) M. Thangaraj, S. S. Bhojgude, M. V.
Mane and A. T. Biju, Chem. Commun., 2016, 52, 1665.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 For recent selected reviews, see: (a) P. Ruiz-Castillo and S. L. Buchwald,
Chem. Rev., 2016, 116, 12564; (b) D. A. Petrone, J.-T. Ye and M. Lautens, 11 (a) G. Claassen, E. Brin, C. Crogan-Grundy, M. T. Vaillancourt,
Chem. Rev., 2016, 116, 8003; (c) R.-Y. Zhu, M. E. Farmer, Y.-Q. Chen and
J.-Q. Yu, Angew. Chem., Int. Ed., 2016, 55, 10578; (d) P. Koschker and
B. Breit, Acc. Chem. Res., 2016, 49, 1524.
2 For selected examples of Ru-catalyzed C–H/N–H annulations, see:
(a) L. Ackermann, A. V. Lygin and N. Hofmann, Angew. Chem.,
Int. Ed., 2011, 50, 6379; (b) D.-G. Yu, F. De Azambuja and F. Glorius,
H. Z. Zhang, S. X. Cai, J. Drewe, B. Tseng and S. Kasibhatla, Cancer
Lett., 2009, 274, 243; (b) A. Maiti, P. Reddy, M. Sturdy, L. Marler,
S. Pegan, A. Mesecar, J. Pezzuto and M. Cushman, J. Med.
Chem., 2009, 52, 1873; (c) J. Kraus, H. Tatipaka, S. McGuffin,
N. Chennamaneni, M. Karimi, J. Arif, C. Verlinde, F. Buckner and
M. Gelb, J. Med. Chem., 2010, 53, 3887.
Angew. Chem., Int. Ed., 2014, 53, 2754; (c) X. Shi, R. Wang, X. Zeng, 12 For the pioneering work using 8-aminoquinoline as an N,N-
Y. Zhang, H. Hu, C. Xie and M. Wang, Adv. Synth. Catal., 2018,
360, 4049.
3 For selected examples of Rh-catalyzed C–H/N–H annulations, see:
(a) T. K. Hyster and T. Rovis, J. Am. Chem. Soc., 2010, 132, 10565;
(b) J. Karthikeyan, R. Haridharan and C.-H. Cheng, Angew. Chem.,
Int. Ed., 2012, 51, 12343; (c) X. Li, X. Li and N. Jiao, J. Am. Chem. Soc.,
bidentate directing group, see: V. G. Zaitsev, D. Shabashov and O.
Daugulis, J. Am. Chem. Soc., 2005, 127, 13154. For recent reviews,
see: (a) G. Rouquet and N. Chatani, Angew. Chem., Int. Ed., 2013,
52, 11726; (b) O. Daugulis, J. Roane and L. D. Tran, Acc. Chem. Res.,
2015, 48, 1053; (c) G. He, B. Wang, W. A. Nack and G. Chen, Acc.
Chem. Res., 2016, 49, 635.
2015, 137, 9246; (d) Y. Xu, G. Zheng, X. Yang and X. Li, Chem. 13 (a) C. Xie, L. Liu, Y. Zhang and P. Xu, Org. Lett., 2008, 10, 2393;
Commun., 2018, 54, 670.
4 For selected examples of Pd-catalyzed C–H/N–H annulations, see:
(b) Y. Mizukoshi, K. Mikami and M. Uchiyama, J. Am. Chem. Soc.,
2015, 137, 74.
(a) G.-W. Wang, T.-T. Yuan and D.-D. Li, Angew. Chem., Int. Ed., 2011, 14 Y. Himeshima, T. Sonada and H. Kobayashi, Chem. Lett., 1983, 1211.
50, 1380; (b) J. Karthikeyan and C.-H. Cheng, Angew. Chem., Int. Ed., 15 (a) M. F. Grundon, The Alkaloids: Quinoline Alkaloids Related to
2011, 50, 9880; (c) X.-L. Peng, W.-G. Wang, C. Jiang, D. Sun, Z.-H. Xu
and C.-H. Tung, Org. Lett., 2014, 16, 5354; (d) J. Wu, S. Xiang, J. Zeng,
M. Leow and X.-W. Liu, Org. Lett., 2015, 17, 222.
Anthranilic Acid, Academic Press, London, 1988, vol. 32, p. 341;
(b) C. Ito, M. Itoigawa, A. Furukawa, T. Hirano, T. Murata,
N. Kaneda, Y. Hisada, K. Okuda and H. Furukawa, J. Nat. Prod.,
2004, 67, 1800.
5 (a) H. Shiota, Y. Ano, Y. Aihara, Y. Fukumoto and N. Chatani, J. Am.
Chem. Soc., 2011, 133, 14952; (b) L. Grigorjeva and O. Daugulis, 16 (a) W. E. Oberhaensli, Helv. Chim. Acta, 1969, 52, 1905;
Angew. Chem., Int. Ed., 2014, 53, 10209; (c) S. Zhai, S. Qiu, X. Chen,
J. Wu, H. Zhao, C. Tao, Y. Li, B. Cheng, H. Wang and H. Zhai, Chem.
Commun., 2018, 54, 98.
(b) M. Daudon, H. Mehri, M. M. Plat, E. W. Hagaman, F. M. Schell
and E. Wenkert, J. Org. Chem., 1975, 40, 2838.
17 A. Monira, I. G. Alexander, G. W. Peter and A. A. James, J. Nat. Prod.,
1994, 57, 670.
6 For the selected reviews of copper catalyzed C–H activation, see:
(a) S. E. Allen, R. R. Walvoord, R. Padilla-Salinas and M. C. Kozlowski, 18 For an excellent study on Cu(III)-mediated C–H fuctionalization, see:
Chem. Rev., 2013, 113, 6234; (b) X.-X. Guo, D.-W. Gu, Z. Wu and
W. Zhang, Chem. Rev., 2015, 115, 1622.
7 For recent selected references, see: (a) L. D. Tran, I. Popov and
O. Daugulis, J. Am. Chem. Soc., 2012, 134, 18237; (b) L. D. Tran,
J. Roane and O. Daugulis, Angew. Chem., Int. Ed., 2013, 52, 6043;
(a) A. E. King, L. M. Huffman, A. Casitas, M. Costas, X. Ribas and
S. S. Stahl, J. Am. Chem. Soc., 2010, 132, 12068. For an elegant study
on hypervalent iodine mediated Cu(III)-catalyzed reaction, see:
(b) R. J. Phipps, N. P. Grimster and M. J. Gaunt, J. Am. Chem. Soc.,
2008, 130, 8172.
(c) Z. Wang, J. Ni, Y. Kuninobu and M. Kanai, Angew. Chem., Int. Ed., 19 (a) A. M. Suess, M. Z. Ertem, C. J. Cramer and S. S. Stahl, J. Am.
2014, 53, 3496; (d) J. Liu, L. Yu, S. Zhuang, Q. Gui, X. Chen, W. Wang
and Z. Tan, Chem. Commun., 2015, 51, 6418; (e) A. Mandal,
Chem. Soc., 2013, 135, 9797; (b) H. Tang, B. Zhou, X.-R. Huang,
C. Wang, J. Yao and H. Chen, ACS Catal., 2014, 4, 649.
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