PhI(OCOCF3)2-mediated C-C bond formation concomitant with a 1,2-Aryl shift in a metal-free synthesis of 3-arylquinolin-2-ones

Article abstract of DOI:10.1021/ol400743r

The reaction of the readily available N-methyl-N-phenylcinnamamides with phenyliodine bis(trifluoroacetate) (PIFA) in the presence of Lewis acids provides a general and efficient assembly of a variety of 3-arylquinolin-2-one compounds. This novel approach features not only metal-free oxidative C(sp ²)-C(sp²) bond formation but also an exclusive 1,2-aryl migration.

Full text of DOI:10.1021/ol400743r

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
PhI(OCOCF3)2‑Mediated CꢀC Bond
Formation Concomitant with a
1,2-Aryl Shift in a Metal-Free
Synthesis of 3‑Arylquinolin-2-ones
Le Liu, Hang Lu, Hong Wang, Chao Yang, Xiang Zhang, Daisy Zhang-Negrerie,
Yunfei Du,* and Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of
Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
duyunfeier@tju.edu.cn; kangzhao@tju.edu.cn
Received March 19, 2013
ABSTRACT
The reaction of the readily available N-methyl-N-phenylcinnamamides with phenyliodine bis(trifluoroacetate) (PIFA) in the presence of Lewis acids
provides a general and efficient assembly of a variety of 3-arylquinolin-2-one compounds. This novel approach features not only metal-free
oxidative C(sp2)ꢀC(sp2) bond formation but also an exclusive 1,2-aryl migration.
The development of a transition-metal-free approach
for direct oxidative CꢀC bond formation is undoubtedly a
topic of great interest in organic synthesis since such
transformations represent an attractive alternative to
the traditional transition metal-catalyzed oxidative CꢀC
coupling reactions.1 In recent decades, hypervalent iodine
reagents2 have emerged as a class of efficient and envi-
ronmentally benign nonmetal oxidants that can realize the
constructions of CꢀC bonds3 without the involvement
of transition metals.4 Furthermore, the hypervalent iodine
reagents may also trigger a particular 1,2-aryl shift in
some I(III)-mediated rearrangement reactions5 of aryl-
substituted alkenes. To the best of our knowledge, the utili-
zation of hypervalent iodine reagent torealize a concurrent
(1) For selected reviews on transition-metal-catalyzed oxidative
CꢀC coupling reactions, see: (a) Ritleng, V.; Sirlin, C.; Pfeffer, M.
Chem. Rev. 2002, 102, 1731. (b) Liu, C.; Zhang, H.; Shi, W.; Lei, A.
Chem. Rev. 2011, 111, 1780. (c) Dyker, G. Angew. Chem., Int. Ed. 1999,
38, 1698. (d) Chen, X.; Engle, K. M.; Wang, D.; Yu, J. Angew. Chem.,
Int. Ed. 2009, 48, 5094. (e) Wencel-Delord, J.; Droge, T.; Liu, F.;
Glorius, F. Chem. Sco. Rev 2011, 40, 4740.
(2) For selected reviews, see: (a) Zhdankin, V. V.; Stang, P. J. Chem.
Rev. 2008, 108, 5299. (b) Richardson, R. D.; Wirth, T. Angew. Chem.,
Int. Ed. 2006, 45, 4402. (c) Zhdankin, V. V. J. Org. Chem. 2011, 76, 1185.
(d) Ding, Q.; Ye, Y.; Fan, R. Synthesis 2013, 45, 1.
(3) For selected examples, see: (a) Desjardins, S.; Andrez, J.; Canesi,
S. Org. Lett. 2011, 13, 3406. (b) Dohi, T.; Kato, D.; Hyodo, R.;
Yamashita, D.; Shiro, M.; Kita, Y. Angew. Chem., Int. Ed. 2011, 50,
3784. (c) Dohi, T.; Minamitsuji, Y.; Maruyama, A.; Hirose, S.; Kita, Y.
Org. Lett. 2008, 10, 3559. (d) Castro, S.; Fernandea, J. J.; Vicente, R.;
Fanans, F. J.; Rodriguez, F. Chem Commun. 2012, 48, 9089. (e)
Ackermann, L.; Dell’Acqua, M.; Fenner, S.; Vicente, R.; Sandmann,
R. Org. Lett. 2011, 13, 2358. (f) Yan, J.; Wu, J.; Jin, H. J. Organomet.
Chem. 2007, 692, 3636. (g) Zheng, C.; Fan, R. Chem. Commun. 2011, 47,
12221. (h) Matousek, V.; Togni, A.; Bizet, V.; Cahard, D. Org. Lett.
2011, 13, 5762. (i) Kita, Y.; Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.;
Dohi, T. J. Am. Chem. Soc. 2009, 131, 1668. (j) Huang, J.; Liang, Y.;
Pan, W.; Yang, Y.; Dong, D. Org. Lett. 2007, 9, 5345. (k) Matcha, K.;
Antonchick, A. P. Angew. Chem., Int. Ed. 2013, 52, 2082. (l) Sun, Y.;
Gan, J.; Fan, R. Adv. Synth. Catal. 2011, 353, 1735. (m) Liang, J.; Chen,
J.; Du, F.; Zeng, X.; Li, L.; Zhang, H. Org. Lett. 2009, 11, 2820.
(4) For selected examples describing the use of a transition metal
employing hypervalent iodine as oxidant, see: (a) Brand, J. P.;
Charpentier, J.; Waser, J. Angew. Chem., Int. Ed. 2009, 48, 9346. (b)
Muniz, K.; Streuff, J.; Hovelmann, C. H.; Nunez, A. Angew. Chem., Int.
Ed. 2007, 46, 7125. (c) Cho, S, H.; Yoon, J.; Chang, S. J. Am. Chem. Soc.
2011, 123, 5996. (d) Iglesias, A.; Perez, E. G.; Muniz, K. Angew. Chem.,
Int. Ed. 2010, 49, 8109. (e) Muniz, K. J. Am. Chem. Soc. 2007, 129, 14542.
(f) Alexanian, E.; Lee, C.; Sorensen, E. J. Am. Chem. Soc. 2005, 127,
7690. (g) Li, Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008, 130,
2962. (h) Steuff, J.; Hovelmann, C. H.; Nieger, M.; Muniz, K. J. Am.
Chem. Soc. 2005, 127, 14586. (i) Liu, G.; Stahl, S. S. J. Am. Chem. Soc.
2006, 128, 7179. (j) Brand, J. P.; Chevalley, C.; Scopelliti, R.; Waser, J.
Chem. ꢀEur. J. 2012, 18, 5655.
r
10.1021/ol400743r
XXXX American Chemical Society

Scheme 1. Proposed I(III)-Mediated C(sp2)ꢀC(sp2) Oxidative
Coupling of N-Phenylcinnamamides Based on the Previously
Reported Transition-Metal-Mediated Coupling Reaction
Table 1. Optimization of Iodine(III)-Mediated CꢀC Oxidative
Coupling and 1,2-Aryl Shifta
entry oxidant
additive
time (h) yieldb (%)
1
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIDA
PhIO
24
12
24
12
6
NR
20
43
60
68
55
67
72
88
65
NR
2
BF3 Et2O (1)
3
3
TFA (5)
4
BF3 Et2O (1)/TFA (5)
3
5
BF3 Et2O (1)/TFA (10)
3
6c
7d
8e
9f
10
11
BF3 Et2O (1)
0.5
3
BF3 Et2O (1)/TFA (10)
6
6
3
BF3 Et2O (1)/TFA (10)
3
BF3 Et2O (1)/TFA (10)
6
3
BF3 Et2O (1)/TFA (10)
8
3
BF3 Et2O (1)/TFA (10)
24
3
oxidative C(sp2)ꢀC(sp2) bond formation and 1,2-aryl shift
has never been reported. In this communication, we dis-
close thatN,N-disubstitutedarylcinnamamidecompounds
can be converted to the biologically important 3-arylqui-
nolin-2-ones through an unprecedented I(III)-mediated
oxidative C(sp2)ꢀC(sp2) bond formation, along with a
simultaneous aryl migration (see the graphical abstract).
As far as we know, this methodology represents a rare
application of hypervalent iodine reagents in which both
C(sp2)ꢀC(sp2) bond formation and aryl migration are
realized at the same time.
β-Unsubstituted N-arylacrylamide derivatives have
been well studied as a useful substrate for the construction
of heterocyclic framework through oxidative CꢀC bond
formation.6 Notably, starting from the readily available
N-phenylcinnamamidesubstrates, Nagasawa and co-workers6e
realized the synthesis of 3- alkylideneoxindoles through
palladium-catalyzed aromatic CꢀH functionalization/
intramolecular alkenylation (Scheme 1, a). Inspired by the
fact that the oxidative role played by hypervalent iodine
a All reactions were carried out with 1a (0.4 mmol) and oxidant
(1.5 equiv) in DCE (16 mL) unless otherwise stated. b Isolated yields. c TFA
was used as the solvent. d 2.0 equiv of oxidant was used. e The concentration
of the reaction was 0.05 M. f The concentration of the reaction was 0.025 M.
reagents in some C(sp2)ꢀC(sp2) coupling reactions con-
siderably resemble that of the transition-metal/oxidant
system,7 we envisaged that the same oxidative CꢀC bond
formation might also be achieved from the reaction between
a suitable iodine(III) reagent and an N-acryloylaniline
substrate. We postulate that the electrophilic addition of
the iodine(III) reagent to the double bond in the substrate
affords the intermediate A,8 which undergoes annulation
(and forms intermediate B) and the subsequent elimination
to give the expected alkylideneoxindoles (Scheme 1, b).
Initially, the readily available N-methyl-N-phenylcinna-
mamide 1a was selected as the model substrate to probe the
feasibility of the proposed conversion. To our surprise and
delight, the reaction of 1 equiv of 1a with 1.5 equiv of PIFA
in the presence of 1 equiv of BF3 Et2O in DCE did not give
3
the expectedfive-membered oxindole productbutafforded
20% yield of a six-membered N-methyl-3-phenylquinolin-
2(1H)-one 2a (the structure of which was unambiguously
confirmed through X-ray crystallographic analysis), the
process of which obviously involves an interesting oxi-
dative CꢀC bond formation and 1,2-aryl shift. Further
condition screening was carried out to formulate the most
optimal conditions for this extraordinary reaction.
(5) For selected examples, see: (a) Singh, F. V.; Rehbein, J.; Wirth, T.
ChemistryOpen 2012, 1, 245. (b) Justik, M. W.; Koser, G. F. Tetrahedron
Lett. 2004, 45, 6159. (c) Kawamura, Y.; Maruyama, M.; Tokuoka, T.;
Tsukayama, M. Synthesis 2002, 2490. (d) Prakash, O.; Tanwar, M. P.
Bull. Chem. Soc. Jpn. 1995, 68, 1168. (e) Prakash, O.; Pahuja, S.; Goyal,
S.; Sawhney, S. N.; Moriarty, R. M. Synlett 1990, 6, 337. (f) Guerard,
K. C.; Guerinot, A.; Bouchard-Aubin, C.; Menard, M.; Lepage, M.;
Beaulieu, M. A.; Canesi, S. J. Org. Chem. 2012, 77, 2121.
(6) For selected examples, see: (a) Piou, T.; Neuville, L.; Zhu, J. Org.
Lett. 2012, 14, 3760. (b) Wu, T.; Mu, X.; Liu, G. Angew. Chem., Int. Ed.
2011, 50, 12578. (c) Pinto, A.; Jia, Y.; Neuvile, L.; Zhu, J. Chem. ꢀEur. J
2007, 13, 961. (d) Wei, H.; Piou, T.; Dufour, J.; Neuvile, L.; Zhu, J. Org.
Lett. 2011, 13, 2247. (e) Ueada, S.; Okada, T.; Nagasawa, H. Chem.
Commun. 2010, 46, 2462. (f) Liu, X.; Xin, X.; Xiang, D.; Zhang, R.;
Kumar, S.; Zhou, F.; Dong, D. Org. Biomol. Chem. 2012, 10, 5643. (g)
Jaegil, S.; Dufour, J.; Wei, H.; Piou, T.; Duan, X.; Vors, J.; Neuville, L.;
Zhu, J. Org. Lett. 2010, 12, 4498. (h) Yip, K.; Yang, D. Org. Lett. 2011,
13, 2134. (i) Zeng, W.; Chemler, S. R. J. Am. Chem. Soc. 2007, 129,
12948. (j) Zhang, G.; Luo, Y.; Wang, Y.; Zhang, L. Angew. Chem., Int.
Ed. 2011, 50, 4450. (k) Lovick, H.; Michael, F. E. J. Am. Chem. Soc.
2010, 132, 1249. (l) Wei, W.; Zhou, M.; Fan, J.; Liu, W.; Song, R.; Liu,
Y.; Hu, M.; Xie, P.; Li, J. Angew. Chem., Int. Ed. 2013, 52, 1. (m) Li, Y.;
Sun, M.; Wang, H.; Tian, Q.; Yang, S. Angew. Chem., Int. Ed.
2012, 52, 1.
The results are summarized in Table 1. When BF3 Et2O
was used together with TFA as additive, the yield of 2a
3
(7) A notable fact is that the N-arylenamines can be converted to
indole products via either the Pd(OAc)2/Cu(OAc)2- or PhI(OAc)2-
mediated oxidative CꢀC coupling. For the transition-metal method
developed by Glorius, see: (a) Wurtz, S.; Rakshit, S.; Neumann, J. J.;
Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2008, 47, 7230. For the
I(III)-mediated approach developed by our group, see: (b) Yu, W.; Du,
Y.; Zhao, K. Org. Lett. 2009, 11, 2417.
(8) (a) Tu, D.; Ma, L.; Tong, X.; Deng, X.; Xia, C. Org. Lett. 2012, 14,
4830. (b) Fujita, M.; Yoshida, Y.; Miyata, K.; Wakisaka, A.; Sugimura,
T. Angew. Chem., Int. Ed. 2010, 49, 7068.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Synthesis of 4-Unsubstituted 3-Arylquinolin-2-one via PIFA-Mediated CꢀC Bond Formation and 1,2-Aryl Shifta
a All reactions were carried out at rt with 1a (0.4 mmol), PIFA (1.5 equiv), BF3 Et2O (1 equiv), and TFA (10 equiv) in DCE (16 mL) unless other
3
stated. b Isolated yield. c The ratio of 2h (7-F) and 2h0 (5-F) is 1.2:1. d The ratio of 2i (7-CF3) and 2i0 (5-CF3) is 1.3:1. e TFA was used as the solvent.
was dramatically increased to 60% (Table 1, entry 4). With
the increase of the dosage of TFA, the yield was raised to
68% and the reaction time was greatly shortened (Table 1,
entry 5). However, when TFA was used as the sole solvent,
the reaction produced moreunidentifiedbyproductswhich
resulted in a decreased yield of 2a (Table 1, entry 6). Fur-
ther screening shows that the concentration of substrate 1a
in the solvent can also influence the yield of the product
(Table 1, entries 8 and 9). Specifically, when the reac-
tion was carried out at a concentration of 0.025 M, the
reaction became much cleaner and the desired product 2a
could be isolated in an excellent yield of 88%. Solvent
study shows that none of the other solvents such as TFE,
toluene, EtOAc, CH3CN, or THF is superior to DCE
(not shown). The other hypervalent iodine reagents were also
tested under the optimized conditions, and it was found that
the less potent PhI(OAc)2 provided 2a in comparable lower
yield (Table 1, entry 10), while another iodine(III) reagent,
i.e., iodosobenzene, failed to afford the desired product under
the same conditions (Table 1, entry 11).
Upon optimal reaction conditions (Table 1, entry 9), we
proceeded to explore the generality of this newly developed
method. Cinnamamides bearing other substituents such
as benzyl (1b), isopropyl (1c), and cyclopropylmethyl (1d)
substituents on the nitrogen atom were all converted to
the desired cyclized/migrated products 29 in satisfactory to
excellent yields (Table 2, entries 2ꢀ4). However, for the cin-
namamide that bears no substitution on the nitrogen atom,
the reaction afforded a complex mixture (not shown). Our
results also show that both the electron-donating and the
electron-withdrawing group at the para-position of the ani-
lide moiety could be well tolerated (Table 2, entries 5ꢀ7).
However, the electron-rich amide 1f led to 2f in a lower yield
due to the formation of more unidentified byproducts.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Investigations of the Reactions Involved 3,3-Disub-
stituted Acrylic Acid Amides
Scheme 3. Plausible Mechanistic Pathway
In the case of meta-substituted substrates bearing
either an F or a CF3 group (Table 2, entries 8 and 9),
two separable regioisomeric 3-arylquinolin-2-one pro-
ducts 2h/2h0 and 2i/2i0 were formed in each case, with the
cyclization occurred preferentially at the less hindered
position. Ortho-substituted substrates were also toler-
able as demonstrated by the formation of 2j and 2k
(Table 2, entries 10 and 11).
Investigation on the substitution effect of the acrylic
motif shows that the reactants containing substituted
aryl groups all delivered the corresponding 3-arylquinoli-
nones in lower yields than the unsubstituted counter-
part 1a, regardless the electronic nature of the substituent
(Table 2, entries 12ꢀ15). It is also worth noting that
3-(2-bromophenyl)-1-methyl-1,2-dihydroquinoline (2o), a
key intermediate to access naturally occurring cryptotack-
ieine 1 and cryptosanguinolentine 2,10 can be successfully
obtained in acceptable yield by this method (Table 2,
entry 15). However, for an alkyl-substituted arylic amide,
i.e., N-methyl-N-phenylbut-2-enamide, we failed to get the
desired product under the described conditions (not shown).
To gain further insight into the scope of the method,
various 3,3-disubstituted acrylic acid amides were synthesized
and studied. To our delight, 3,3-diarylacrylic acid amides
that bear two aryl substrates (1qꢀs) underwent the same
CꢀC bond formation and 1,2-aryl shift process to give the
desired product 2qꢀs, respectively (Scheme 2). Yield values
show that the substrate bearing a p-methoxy group gave
a better yield (Scheme 2, 2s), but on the other hand, all
doubly substituted substrates give lower yields than the
singly substituted 1a.
A possible mechanistic pathway is outlined in Scheme 3.11
First, the nucleophilic attack on the iodine center by the
carbonyl oxygen of the amide moiety12 in 1a affords
3-azatriene C, which undergoes an electrocyclic ring
closure13 and the subsequent proton elimination to give
intermediate D. Assisted by the nitrogen lone-pair con-
jugation, a concerted process including the 1,2-aryl shift
and the breakage of the OꢀI bond occurs to convert D to
the iminium salt E, along with the release of phenyl iodide
and the trifluoroacetate. Finally, intermediate E gives
3-phenylquinolin-2-one 2a with the removal of one
proton.
In conclusion, we have discovered an I(III)-mediated
metal-free approach for the assembly of the biologically
important 3-arylquinolin-2-one skeleton. Compared with
that existing transition-metal-catalyzed CꢀC oxidative
coupling that affords the five-membered oxindole products,
this novel approach has realized the construction of the
six-membered quinolin-2-one skeleton through an unprece-
dented metal-free oxidative C(sp2)ꢀC(sp2) bond formation,
along with an exclusive 1,2-aryl migration. Further inves-
tigation on the reaction mechanism and the application of
the method are underway in our laboratory.
(9) The debenzylation of 2b could proceed smoothly with NBS in the
presence of AIBN under reflux in chlorobenzene to give the debenzy-
lated product 2b0 in 83% yield. For previous work describing this
reaction, see: Baker, S. R.; Parsons, A. F.; Wilson, M. Tetrahedron Lett.
1998, 39, 331.
(10) (a) Fresneda, P. M.; Molina, P.; Delgado, S. Tetrahedron Lett.
1999, 40, 7275. (b) Fresneda, P. M.; Molina, P.; Delgado, S. Tetra-
hedron 2001, 57, 6197. (c) Zhu, W.; Ma, D. Chem. Commun. 2004, 40,
888.
(11) The reaction may also adopt an alternative mechanistic pathway
involving the formation of an alkyl aryl iodane intermediate (see the
Supporting Information for details). For a recent publication describing
such a similar 1,2-aryl shift reaction, see ref 5a.
Acknowledgment. Y.D. acknowledges the National
Natural Science Foundation of China (No. 21072148)
for financial support. We also thank Professor Richard
P. Hsung (University of Wisconsin at Madison) for
valuable discussions and suggestions.
(12) For selected examples, see: (a) Wang, J.; Yuan, Y.; Xiong, R.;
Zhang-Negrerie, D.; Du, Y.; Zhao, K. Org. Lett. 2012, 14, 2210. (b)
Kajiyama, D.; Inoue, K.; Ishikawa, Y.; Nishiyama, S. Tetrahedron 2010,
66, 9779.
(13) For selected examples, see: (a) Sklenicka, H. M.; Hsung, R. P.;
McLaughlin, M. J.; Wei, L.; Gerasyuto, A. I.; Brennessel, W. B. J. Am.
Chem. Soc. 2002, 124, 10442. (b) Parker, K.; Mindt, T. L. Org. Lett.
2001, 3, 3875. (c) Clayden, J.; Purewal, S.; Helliwell, M.; Mantell, S. J.
Angew. Chem., Int. Ed. 2002, 41, 1049.
Supporting Information Available. Experimental pro-
cedures, spectral data for all new compounds, and X-ray
structural data of 2a. This material is available free of
charge via the Internet at http://pubs.acs.org
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX