A Cu-mediated one-pot Michael addition/α-arylation strategy using a diaryliodonium salt: A direct and efficient approach to α-aryl-β-substituted cyclic ketone scaffolds

Article abstract of DOI:10.1039/c5cc09837h

The direct and efficient construction of α-aryl-β-substituted cyclic ketone scaffolds has been achieved using a Cu-mediated one-pot Michael addition/α-arylation strategy. The reaction features easily available materials, broad substrate scope, moderate to good yield, and an excellent diastereoselectivity.

Full text of DOI:10.1039/c5cc09837h

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: J. Pan, T. Chen, Z.
Zhang, Y. Li, X. Zhang and F. Zhang, Chem. Commun., 2015, DOI: 10.1039/C5CC09837H.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Please do not adjust margins
Page 1 of 5
ChemComm
View Article Online
DOI: 10.1039/C5CC09837H
Journal Name
COMMUNICATION
Cu-mediated one-pot Michael addition/α-arylation strategy using
diaryliodonium salt: Direct and efficient approach to α-aryl-β-
substituted cyclic ketone scaffolds†
Received 00th January 20xx,
Accepted 00th January 20xx
Jin-Long Pan, Tao Chen, Zhi-Qiang Zhang, Yi-Fan Li, Xiao-Ming Zhang, and Fu-Min Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A direct and efficient construction of α-aryl-β-substituted cyclic
ketone scaffolds has been achieved using Cu-mediated one-pot
Michael addition/α-arylation strategy. The reaction features easily
available materials, broad substrate scope, moderate to good yield,
and excellent diastereoselectivity.
α-Aryl-β-substituted cyclic ketone scaffolds are widely found in
many natural products, bioactive compounds and drugs, such
as isoabietenin A,1a N-methylwelwitindolione C isonitrile,1b
tubingensin A,1c and 1-aza-4-methoxyl-5-phenyl [4.4.0]decane
(Figure 1).1d Such scaffolds also serve as key building blocks in
the total synthesis of biologically active molecules.2 Given the
important synthetic value of α-aryl-β-substituted cyclic ketone
scaffolds, various methods have been developed to construct
them, but most of methods have several drawbacks. Classical α-
arylation of sily enol ether with aryl halides was commonly used,
but this process usually requires noble metal like Pd and an
expensive ligand.3 Alternative procedures include Pd-catalyzed
intramolecular hydroalkylation,4 1,3-rearrangement,5 Rh-
catalyzed Michael addition,6 C‒H insertion,7 tandem olefin
Fig. 1 The selected bioactive molecules bearing α-aromatic-β-
substituted cyclic ketone scaffolds.
using an electrophilic aromatic reagent, which would afford
synthetically challenging α-aryl-β-substituted cyclic ketone
scaffolds in tandem or one-pot processes. Key to success would
be selecting a suitable arylating reagent, because arylating
enolates is usually more difficult than alkylating them.13 We
focused on the diaryliodonium salt as a candidate trapping
reagent based on the pioneering work by the groups of Sanford,
Stang, Gaunt, MacMillan, Olofsson and others.14,15 These
isomerization/Claisen
hydroacylation reactions,8 one-pot Cu-catalyzed reduction and
Pd-catalyzed transition metal-free
arylation,9
rearrangement/intramolecular
rearrangements,10 and organocatalytic tandem Michael
addition/aldol reaction/dehydration reactions11 (Scheme 1),
but they either require multi-step substrate preparation with
lower total yields or show narrow substrate scope. Therefore,
more direct and efficient methods for constructing α-aryl-β-
substituted cyclic ketone scaffolds are still in high demand.
Efficient construction of α,β-bis-substituted cyclic ketone
skeletons has been achieved using tandem Michael reactions,12
in which different electrophiles trap the enolated intermediate.
We speculated that the enolated intermediate could be trapped
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry,
Lanzhou University, Lanzhou, 730000, P.R. China. Email: zhangfm@lzu.edu.cn.
Fax: 86-931-8912582.
Electronic Supplementary Information (ESI) available: Experimental procedures
and spectroscopic data. See DOI: 10.1039/x0xx00000x
Scheme 1 Outline of the construction of α-aryl-β-substitued
cyclic ketone scaffolds.
†
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
COMMUNICATION
Journal Name
nontoxic, highly electrophilic diaryliodonium salts are easily solvents showed the best combination to be Et2O for Michael
prepared, insensitive to air and moisture, and reactive under addition and DMF for arylation (entries 12‒1V4ie)w. AWrticele Oanllsinoe
DOI: 10.1039/C5CC09837H
mild conditions in the presence or absence of metal mediators. screened various counterions in the diaryliodonium salt, and
Especially, when combined with Cu salt, the diaryliodonium salt found the OTf anion perform better than BF4, PF6, CF3CO2, or Br
can lead to synthetically challenging C‒C(Ar) bond formation.15i- anions (entries 15‒18). Screening other reaction conditions did
n Here we describe our efforts to use the diaryliodonium salt in not significantly improve the results.19 Therefore, we defined
Cu-mediated one-pot Michael addition/α-arylation strategy to the optimal reaction conditions as R2CuLi
generate α-aryl-β-substituted cyclic ketone scaffolds.
•
LiCN/Et2O/-
78 °C/Ph2IOTf, DMF/Cu(OAc)2/-20 °C, which we applied to
subsequent experiments.
First we selected 2-cyclohexen-1-one as a Michael acceptor,
and screened appropriate nucleophilic species as a Michael With the optimal reaction conditions in hand, we explored the
donor and various aromatic electrophilic reagents as the substrate scope of the one-pot transformation (Table 2).
resulting enolated intermediate trapping partner (Table 1). Symmetric diaryliodonium salts containing p-F, p-Cl, p-Br, p-Me,
After the attempts of short investigation,16 we were pleased to p-CF3, p-OMe, p-iPr, p-tBu, o-Me, m-Me or m-Br substituents
find Gilman reagent17 and diphenyliodonium triflate (2a) are worked well, giving the corresponding products 3b
-3l in
ideal choices. The desired product 3a was obtained in 21% yield moderate to good yield. The product 3m containing two
after using the diphenyliodonium triflate (2a) to capture the substitutents on the aromatic ring was also isolated when the
reaction intermediate at -78 °C, and the structure of 3a was corresponding diaryliodonium triflate was used. Next, we
further confirmed by X-ray crystallography (entry 1).18 examined the scope of asymmetric diaryliodonium salts,
Encouraged by this preliminary result, we conducted arylation obtaining the expected products 3n
at various temperatures from -78 °C to 25 °C, obtaining the best particular, we generated the heteroaromatic ring product 3p
-3p in moderate yield. In
.
results at -20 °C, which gave 3a in 46% yield (entries 2‒5). In an These results show that the one-pot transformation tolerates
effort to further improve the yield of this one-pot reaction, we various electron-withdrawing and -donating groups at the
added different Cu salts to the reaction system before injecting ortho-, meta- or para- positions of the aromatic ring, and the α-
diphenyliodonium triflate (entries 6‒11), obtaining the best aryl-β-substituted cyclic ketone was obtained in moderate to
results with Cu(OAc)2, which afforded 3a in 68% yield. Screening good yield with excellent diastereoselectivity.
Table 1 Selected optimization of one-pot reaction conditiona
Table 2 Scope of diaryliodioum salts
Entry Reagent
Additive Solventb
Temp.c Yieldd (%)
1
2
3
4
5
6
7
8
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IBF4
Ph2IPF6
-
-
-
-
Et2O/DMF -78 21
Et2O/DMF -40
41
46
35
33
61
38
59
49
54
68
34
47
26
66
63
59
21
Et2O/DMF -20
Et2O/DMF -10
-
Et2O/DMF 0
CuOAc
CuBr
CuI
CuTc
Et2O/DMF -20
Et2O/DMF -20
Et2O/DMF -20
Et2O/DMF -20
9
10
11
12
13
14
15
16
17
18
Cu(OTf)2 Et2O/DMF -20
Cu(OAc)2 Et2O/DMF -20
Cu(OAc)2 THF/DMF -20
Cu(OAc)2 Et2O/NMP -20
Cu(OAc)2 Et2O/DME -20
Cu(OAc)2 Et2O/DMF -20
Cu(OAc)2 Et2O/DMF -20
Ph2I(CF3CO2) Cu(OAc)2 Et2O/DMF -20
Ph2IBr Cu(OAc)2 Et2O/DMF -20
We then examined the scope of Michael acceptors under the optimal
reaction conditions (Table 3). Using 6-methyl-2-cyclohexen-1-one led
to the corresponding product 3q in 63% yield (dr approximate 3.5:1),
while acceptors with substituents at the 5-position afforded the
desired products 3r and 3s with moderate diastereoselectivity (dr
approximate 7:1), respectively. Using 4, 4-dimethyl-2-cyclohexen-1-
one led to the product 3t in 46% yield, and analogues of the dimethyl
a) Reaction was performed using enone (0.2 mmol) and Gilman reagent (0.2
mmol) in 1.5 mL solvent at -78 °C, then electrophile was added to reaction
mixture at the noted temperature; b) The Michael addition was performed
in the former, and the arylation in the latter; c) The arylation reaction
temperature; d) Isolated yield of product 3a
.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
acceptor worked well, providing only product 3u in 45% yield. intermediate. This key Cu(III)-arylating species reactsViwewitAhrtiMcleicOhnalineel
DOI: 10.1039/C5CC09837H
Additionally, 2-cyclohepten-1-one is an ideal acceptor, and the addition enolated intermediate through path a and/or path b, and a
corresponding product 3v was isolated in 34% yield.
subsequent phenyl group transfer and formation of a C‒C(Ar) bond
generate the product and concomitantly regenerate the Cu(I)
catalyst. As a first step towards verifying this mechanism and
excluding a radical pathway, we added the radical scavengers (2, 2,
Table 3 Scope of Michael acceptors
6,
6-tetramethylpiperidine-1-oxyl
(TEMPO)
and
1,
1-
diphenylethylene (DPE)) to the reaction mixture before injecting the
diphenyliodonium salt. The desired product 3a was isolated in a
slightly lower yield (58% and 51%, respectively.). These results
support the proposed mechanism in Scheme 2, but further studies
are needed to establish the mechanism conclusively.
Screening other lithium reagents as potential Michael donors
showed that commercially available methyl, propyl, hexyl, iso-propyl,
and iso-butyl reagents gave the expected products 3w-3aa in 45-52%
yield (Table 4). Particularly, sterically hindered tert-butyl lithium
worked well, generating the product 3ab in 43% yield and
demonstrating that our one-pot reaction can efficiently introduce a
tert-butyl group onto a cyclic ketone substrate. Using a phenyl
lithium led to the bisphenyl-substituted product 3ac in 32% yield. To
further demonstrate the synthetic utility of our approach, we
prepared several organic lithium reagents in situ and tested them in
our one-pot transformation, and the corresponding products 3ad-
3ag were obtained in moderate yield. It is notable that the OTBS
group in product 3ae and the allylic silyl group in 3ag could be
transformed into other synthetically valuable groups. Remarkably,
our one-pot approach was able to generate product 3af in 38% yield,
in contrast to the original four-step synthesis reported by Rétey,
which started from 2-chlorocyclohexanone to generate 3af in only
16% yield with poor cis/trans selectivity.2e
Scheme 2 The proposed reaction mechanism.
To investigate the synthetic applications of our one-pot reaction, we
investigated the derivatization of product 3a (Scheme 3). The
carbonyl group was reduced to the corresponding alcohol 4a in
excellent yield and diastereoselectivity. The ring in 3a was expanded
to give the Baeyer-Villiger oxidation product 4b in 88% yield, and
Beckmann rearrangement via the oxime 4c was achieved to generate
Table 4 Scope of Michael donors19
Based on our experimental results and precedents in the
literature15k,l, 20, we proposed a mechanism for the current one-pot
reaction (Scheme 2). Initially, a catalytic Cu(I) species, which is either
the copper enolated intermediate generated in situ or a species
derived from the Cu(II) additive by reduction or disproportionation,
reacts with diaryliodonium salt to provide an activated Cu(III)-Ar
Scheme 3 The diverse transformation of product 3a
.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
COMMUNICATION
Journal Name
10 (a) A. J. Sisti and G. M. Rusch, J. Org. Chem. 1974, 39, 1182; (b)
D. F. Taber, D. A. Gerstenhaber and J.DFO.IB: 1e0r.r1y0,3V9Ji./eCwO5ArCrgtCi.c0lCe9hO8en3lm7inHe.
2011, 76, 7614.
4d. Reduction of the oxime 4c led to cis 3-butyl-2- phenylcyclohexan-
1-amine (4e), while reductive amination generated the trans-amine
4f, which was further transformed to the hydroindole skeleton 4g via
11 S. Duce, M. Jorge, I. Alonso, J. L. G. Ruano and M. B. Cid, Org.
a
Pd-catalyzed intramolecular annulation. Horner–Wadsworth–
Biomol. Chem. 2011, 9, 8253.
Emmons reaction of 3a afforded the corresponding ester 4h in 80%
yield, and the Corey-Chaykovsky reaction generated epoxide 4i.
Notably, several cyclohexane derivatives bearing three continuous
stereocenters were generated in excellent diastereoselectivity and
good yield.
12 For selective reviews, see: (a) Z. Galeštoková and R. Šebasta,
Eur. J. Org. Chem. 2012, 6688; (b) H.-C. Guo and J.-A. Ma,
Angew. Chem. Int. Ed. 2006, 45, 354; Recently selective
examples: (c) N. Germain and A. Alexakis, Chem. Eur. J. 2015,
21, 8597; (d) C. Bleschke, M. Tissot, D. Müller and A. Alexakis,
Org. Lett. 2013, 15, 2152; (e) G. Chai, S. Wu, C. Fu and S. Ma,
J. Am. Chem. Soc. 2011, 133, 3740.
In summary, we have developed the first Cu-assisted, one-pot
method for preparing α-aryl-β-substituted cyclic ketone scaffolds.
The current transformation features the broad substrate scopes with
excellent diastereoselectivity, easily prepared starting material, and
cheap Cu species as irritant. Detailed mechanistic studies and
development of synthetic applications are underway in our
laboratory.
13 P. O. Norrby, T. B. Petersen, M. Bielawski and B. Olofsson,
Chem. Eur. J. 2010, 16, 8251.
14 For recently selected reviews, see: (a) M. Brown, U. Farid and
T. Wirth, Synlett 2013, 424; (b) Z. Xiao and C. Xia, Chin. J. Org.
Chem. 2013, 33, 2119; (c) E. A. Merritt and B. Olofsson, Angew.
Chem. Int. Ed. 2009, 48, 9052; (d) V. V. Zhdankin and P. J. Stang,
Chem. Rev. 2008, 108, 5299; (e) V. V. Zhdankin and P. J. Stang,
Chem. Rev. 2002, 102, 2523.
15 For recently selective examples, see: (a) S. G. Modha and M. F
Greaney, J. Am. Chem. Soc. 2015, 137, 1416; (b) E. Cahard, H.
P. J. Male, M. Tissot and M. J. Gaunt, J. Am. Chem. Soc. 2015,
137, 7986; (c) F. Tinnis, E. Stridfeldt, H. Lundberg, H. Adolfsson
and B. Olofsson, Org. Lett. 2015, 17, 2688; (d) M. Fañanás-
Mastral and B. L. Feringa, J. Am. Chem. Soc. 2014, 136, 9894;
(e) F. Zhang, S. Das, A. J. Walkinshaw, A. Casitas, M. Taylor, M.
G. Suero and M. J. Gaunt, J. Am. Chem. Soc. 2014, 136, 8851;
(f) C. Liu, W. Zhang, L.-X. Dai and S. L. You, Chem. Asian J. 2014,
Acknowledgements
We gratefully acknowledge financial support from the NSFC (Grant
Nos. 21272097, 21290181, and 21502080.).
Notes and references
1
(a) J.-H.Yang, X. Du, F. He, B. H. Zhang, X. N. Li, J. Su, Y. Li, J.-X.
Pu and H.-D. Sun, J. Nat. Prod. 2013, 76, 256; (b) K. Stratmann,
R. E. Moore, R. Bonjouklian, J. B. Deeter, G. M. L. Patterson, S.
Shaffer, C. D. Smith and T. A. Smitka, J. Am. Chem. Soc. 1994,
116, 9935; (c) M. R. TePaske, J. B. Gloer, D. T. Wicklow and P.
F. Dowd, J. Org. Chem. 1989, 54, 4743; (d) D.-I. Kim, H. M.
9
, 2113; (g) M. Iyanaga, Y. Aihara and N. Chatani, J. Org. Chem.
2014, 79, 11933; (h) R. Ghosh, E. Stridfeldt and B. Olofsson,
Chem. Eur. J. 2014, 20, 8888; (i) Q. Y. Toh, A. McNally, S. Vera,
N. Erdmann and M. J. Gaunt, J. Am. Chem. Soc. 2013, 135
,
3772; (j) J. Guo, S. Dong, Y. Zhang, Y. Kuang, X. Liu, L. Lin and
Deutsch, X. Ye and M. M. Schweri, J. Med. Chem. 2007, 50
,
2718.
X. Feng, Angew. Chem. Int. Ed. 2013, 52, 10245; (k) Y. Wang,
2
(a) D. Garayalde, K. Krüger and C. Nevado, Angew Chem. Int.
Ed. 2011, 50, 911; (b) D. F. Taber and W. Tian, J. Org. Chem.
2008, 73, 7560; (c) Q. Huang, Q. Wang, J. Zheng, J. Zhang, X.
Pan and X. She, Tetrahedron 2007, 63, 1014; (d) Q. Wang, Q.
Huang, B. Chen, J. Lu, H. Wang, X. She and X. Pan, Angew.
Chem. Int. Ed. 2006, 45, 3651; (e) M. Rettig, A. Sigrist and J.
C. Chen, J. Peng and M. Li, Angew. Chem. Int. Ed. 2013, 52,
5323; (l) B. Chen, X. L. Hou, Y. X. Li and Y. D. Wu, J. Am. Chem.
Soc. 2011, 133, 7668; (m) J. S. Harvey, S. P. Simonovich, C. R.
Jamison and D. W. C. MacMillan, J. Am. Chem. Soc. 2011, 133
13782; (n) R. J. Phipps and M. J. Gaunt, Science 2009, 323
1593.
,
,
Rétey, Helv. Chim. Acta. 2000, 83, 2246; (f) S. G. Mills, M. 16 The replacement of lithium reagent with magnesium or zinc
species only afforded the Michael addition product, and the
desired product 3a wasn’t isolated.
MacCoss, D. Underwood, S. K. Shah, P. E. Finke, D. J. Miller, R.
J. Budhu, M. A. Cascieri, S. Sadowski and C. D. Strader, Bioorg.
Med. Chem. Lett. 1995, 5, 1345; (g) D. L. J. Clive, P. L. Wickens 17 (a) H. Gilman, R. G. Jones and L. A. Woods, J. Org. Chem. 1952,
17, 1630; (b) B. H. Lipshutz, R. S. Wilhelm and J. A. Kozlowski,
J. Org. Chem. 1984, 49, 3938; (c) B. H. Lipshutz, S. Sharma and
E. L. Ellworth, J. Am. Chem. Soc. 1990, 112, 4032.
and G. V. J. da Silva, J. Org. Chem. 1995, 60, 5532.
3
(a) T. Iwama, V. B. Birman, S. A. Kozmin and V. H. Rawal, Org.
Lett. 1999,
2006,
1, 673; (b) T. Iwama and V. H. Rawal, Org. Lett.
18 CCDC 1429348 (compound 3a) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
19 For the details, see the Supporting Information.
8
, 5725; (c) W. Su, S. Raders, J. G. Verkade, X. Liao and
J. F. Hartwig, Angew. Chem. Int. Ed. 2006, 45, 5852.
4
5
(a) X. Wang, T. Pei, X. Han, X. Han and R. A. Widenhoefer, Org.
Lett. 2003, 5, 2699; (b) X. Han, X. Wang, T. Pei and R. A.
Widenhoefer, Chem. Eur. J. 2004, 10, 6333.
(a) J. C. R. Brioche, T. A. Barker, D. J. Whartrup, M. D. Barker 20 (a) A. Casitas and X. Ribas, Chem. Sci. 2013,
4, 2301; (b) R. J.
Phipps, N. P. Grimster and M. J. Gaunt, J. Am. Chem. Soc. 2008,
130, 8172.
and J. P. A. Harrity, Org. Lett. 2010, 12, 4832; (b) J.-O.
Zirimwabagabo and J. P. A. Harrity, Chem. Commun. 2014, 50
,
2735.
6
7
(a) G. Herrán, M. Mba, C. Murcia, J. Plumet and A. G. Csáky,
Org. Lett. 2005, 7, 1669; (b) G Herrán, J. Plumet, A. Segura, A.
Silverio and A. G. Csáky, ARKIVOC, 2008, 42; (c) A. G. Csáky, M.
Mba and J. Plumet, J. Org. Chem. 2001, 66, 9026.
(a) D. F. Taber, C. M. Paquette, P. Gu and W. Tian, J. Org. Chem.
2013, 78, 9772; (b) D. F. Taber and W. Tian, J. Org. Chem. 2007,
72, 3207.
8
9
R. Okamoto and K. Tanaka, Org. Lett. 2013, 15, 2112.
J. Chae, J. Yun and S. L. Buchwald, Org. Lett. 2004, 6, 4809.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
View Article Online
DOI: 10.1039/C5CC09837H
Graphic Abstract
The first Cu-mediated, one-pot Michael addition/α-arylation
method for preparing α-aryl-β-substituted cyclic ketone
scaffolds have been developed.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins