N-Heterocyclic Carbene-Catalyzed Umpolung of β,?-Unsaturated 1,2-Diketones

Article abstract of DOI:10.1021/acs.orglett.7b03358

The umpolung of β,?-unsaturated diketones through N-heterocyclic carbene catalysis is described, which allows access to a variety of highly functionalized bicyclic cyclohexene-β-lactones and 1,3,4-triaryl benzenes. An unprecedented reaction pattern involv

Full text of DOI:10.1021/acs.orglett.7b03358

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
N‑Heterocyclic Carbene-Catalyzed Umpolung of β,γ-Unsaturated
1,2-Diketones
Jian Liu,†,§ Deb Kumar Das,‡,§ Guoxiang Zhang,‡ Shuang Yang,‡ Hao Zhang,‡ and Xinqiang Fang*,‡
†College of Chemistry, Fuzhou University, Fuzhou, 350116, China
‡State Key Laboratory of Structural Chemistry, Center for Excellence in Molecular Synthesis, Fujian Institute of Research on the
Structure of Matter, University of Chinese Academy of Sciences, Fuzhou, 350100, China
S
* Supporting Information
ABSTRACT: The umpolung of β,γ-unsaturated diketones through
N-heterocyclic carbene catalysis is described, which allows access to
a variety of highly functionalized bicyclic cyclohexene-β-lactones and
1,3,4-triaryl benzenes. An unprecedented reaction pattern involving
the catalytic formation of nucleophilic O-acylated homoenolate
intermediate is proposed. A diverse set of transformations on the
product further showed the synthetic potential of this protocol.
Scheme 1. Selected Umpolung Modes of Unsaturated
Substrates via NHC Organocatalysis
he unique and irreplaceable roles of umpolung (or polarity
Treversal) have attracted long-standing and global research
interest among the chemical community.1 Various approaches
have been developed to facilitate the umpolung of different types
of molecules. In this context, N-heterocyclic carbene (NHC)
organocatalysis has been one of the most versatile and powerful
methods to achieve this purpose.2 Widely studied trans-
formations are benzoin and Stetter reactions wherein the
polarity reversal of aldehydes is realized via the formation of the
Breslow intermediate, which have been well documented.3
Furthermore, NHC-mediated umpolung of the remote β-
position of an unsaturated substrate through conjugation has
significantly expanded the domain of this chemistry. For
instance, in 2004, Glorius and Bode independently reported
the a3−d3 umpolung of enals through a homoenolate
intermediate, which opened a new era for the whole field of
NHC catalysis (Scheme 1a).4 Furthermore, Fu, Scheidt,
Matsuoka, Glorius, and Lupton have developed the umpolung
of unsaturated esters/ketones/sulfones via a deoxy-Breslow
intermediate (Scheme 1b).5 Our group recently achieved the
umpolung of alkynyl diketones via the formation of O-acylated
allenolate, allowing rapid access to α-pyrones (Scheme 1c).6 A
noteworthy NHC-catalyzed reaction of cinnamils leading to
2,3,8-triaryl vinyl fulvenes was reported by the Nair group, but
the mechanism features an initial [3,3]-rearrangement pathway,
with no homoenolate type intermediate and umpolung of
substrates claimed by the authors.7 Considering the unique and
irreplaceable roles of the remote position activation, the
discovery of new unsaturated substrates that can participate in
NHC-catalyzed novel umpolung remains challenging and
necessary. In this report, we disclose the catalytic formation of
an O-acylated homoenolate intermediate via an NHC-catalyzed
umpolung of alkenyl 1,2-diketones, which could afford a series of
cyclohexenyl β-lactones and 1,2,4-triaryl benzenes under mild
conditions through an unprecedented pathway (Scheme 1d).
The investigation commenced by subjecting easily available
diketone 1a to the conditions involving a series of carbene
precursors A−G (Table 1). The initial test with imidazolium A
and K2CO3 resulted in a product that was finally identified as 2a
by analogy to the single-crystal X-ray structure of 2h (Scheme
2), a highly substituted bicyclic compound with a cyclohexene
and β-lactone unit (Table 1, entry 1). Efforts to further improve
the yield of 2a indicated that bases played a crucial role with
respect to the outcomes of the reaction. For instance, the organic
base, DBU, led to a yield of 45% (Table 1, entry 2), and weak
bases (Et3N or NaOAc) did not show any reactivities (Table 1,
entries 3 and 4). Strong inorganic bases such as KOH and
tBuOK afforded 2a in low to moderate yields (38% and 52%,
Received: October 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03358
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Reaction Conditions Optimization
Scheme 2. Substrate Scope for β-Lactone Formation
b
entry
catalyst (mol %)
base
solvent
yield (%)
1
2
3
4
5
6
7
A (20)
A (20)
A (20)
A (20)
A (20)
A (20)
A (20)
A (20)
A (10)
A (20)
A (20)
none
K2CO3
DBU
Et3N
NaOAc
KOH
tBuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
none
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
CH2Cl2
THF
THF
THF
THF
THF
74
45
0
0
38
52
86
82
69
48
36
0
c
8
9
10
11
12
13
14
15
16
A (20)
B (20)
C−G (20)
H (20)
0
26
0
Cs2CO3
Cs2CO3
Cs2CO3
13
a
All reactions were run on a 0.2 mmol scale; all yields were of isolated
products based on 1; ee values were determined via HPLC analysis on
a chiral stationary phase.
a
Reaction conditions: 1a (0.2 mmol), base (20 mol %), solvent (2
b
mL), argon protection, 4.5−24 h. Isolated yields based on 1a.
c
Cs2CO3 (1.0 equiv) was used.
respectively, Table 1, entries 5 and 6). To our delight, further
screening of bases indicated that the employment of Cs2CO3 can
promote the yield to an acceptable level (86%, Table 1, entry 7).
Moreover, increasing the amount of Cs2CO3 showed little
impact on the outcome (Table 1, entry 8), but a drop in the yield
was detected when the catalyst loading was decreased to 10 mol
% (Table 1, entry 9). Exchange of the solvent from THF to
toluene or CH2Cl2 significantly retarded the reaction (Table 1,
entries 10 and 11). The presence of catalyst A is necessary since
Cs2CO3 itself could not initiate the transformation (Table 1,
entry 13). Imidazolium B and triazolium H can also catalyze this
annulation, however, in a very low efficiency (Table 1, entries 14
and 16, respectively), and catalysts C−G proved inert to this
reaction (Table 1, entry 15).
Having established the optimal conditions, we focused on
evaluating the scope and limitations of this transformation.
Substrates with aliphatic ketone moieties were examined first.
Removal of the electron-withdrawing chlorine atom in 1a
showed no influence on the yield, releasing 2b in an excellent
yield of 92% (Scheme 2, 2b). Substrates with electron-donating
methyl or methoxy groups at the aryl rings were also well
tolerated (Scheme 2, 2c and 2d). Introduction of other electron-
withdrawing groups such as Br, F, or 3,4-Cl was also possible,
with very limited impact on the yields detected (Scheme 2, 2e,
2f, and 2g). Furthermore, the phenyl ring can be changed to a
heterocyclic furan group, and the product was determined
unambiguously via single-crystal X-ray structure analysis
(Scheme 2, 2h, CCDC 1487464). Replacement of the methyl
group at the ketone moiety with ethyl or n-propyl was also
amenable under the standard conditions, generating the
corresponding bicyclic products in high yields (Scheme 2, 2i,
2j, and 2k). Unfortunately, the introduction of a methyl group
into the alkene unit did not form the desired product, despite the
full conversion of the starting material (Scheme 2, 2l). The
evaluation of the substrate scope was subsequently performed
on aromatic 1,2-diketones. To our delight, phenyl diketone 1m
afforded the annulation product in 86% yield (Scheme 2, 2m),
and the variations of the substitution pattern on the Ar1 group
with additional electron-donating or -withdrawing groups were
feasible, providing the annulation products with diversely
substituted aromatic groups in 74−92% yields (Scheme 2,
2n−2s). A heteroaromatic ring substituted substrate was also
amenable under the standard conditions (Scheme 2, 2t).
Moreover, the introduction of electron-withdrawing groups
such as Cl or Br on the Ar2 ring did not encumber the reaction,
delivering 2u−2x in 78−85% yields (Scheme 2, 2u−2x).
Further examination of the substrates with electron-rich aryl
groups at the ketone units showed somewhat unexpected results
because 1,2,4-triarylbenzenes were obtained, probably through a
late-stage decarboxylation−release of the acyloxy group pathway
(Scheme 3). A similar electron-donating substituent-assisted
decarboxylation has also been observed in Scheidt’s report of
dynamic kinetic resolution of β-keto esters.8 Triaryl benzenes
have found wide applications in material sciences, including
liquid crystals, microporous organic solids, molecular rotors, and
molecular wires.9 NHC-mediated formation of benzene
derivatives has been reported by Chi, Lupton, Ye, and Wang,
respectively.10 In these reports, the substrates were usually enals
B
DOI: 10.1021/acs.orglett.7b03358
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope for Benzene Formation
Scheme 5. Enantioselective Transformation
The synthetic potential of the annulation products is
demonstrated in Scheme 6. For instance, reaction of 2a with
Scheme 6. Derivatizations of Product 4a
a
All reactions were run on a 0.2 mmol scale; all yields were of isolated
benzyl amine afforded amide 5a in 62% yield, and a global
reduction of 2a by DIBAL-H allowed access to the heavily
substituted cyclohexene 5b (CCDC 1487465). The β-lactone
unit of 2a can be selectively hydrolyzed under I2/NaHCO3
conditions to generate ester 5c in excellent yield. Oxidation of
the double bond resulted in epoxide 5d in excellent yield.14
Furthermore, highly substituted cyclohexenone 5f can be
obtained in an excellent yield through a two-step pathway.15
The possible mechanism of this unique transformation is
shown in Scheme 7. The nucleophilic attack of the α-carbonyl
products based on 3.
and the products were mainly 1,2,3,5-tetrasubstituted and 1,3,5-
trisubstituted benzenes; methods of using ketones in benzene
construction and reactions leading to 1,2,4-triarylbenzens are
still underdeveloped. Thus, we expanded the substrate scope
and a series of 4-OMe-C6H4 group substituted diketones were
surveyed; the reaction proved insensitive to the electronic
properties of the Ar3 ring (Scheme 3, 4a−4k). Besides the 4-
OMe group, the substrates with 4-tBu, 3,4-Me2, 3,4-(OMe)2,
3,4,5-(OMe)3, and even 4-Me substituents were all compatible
under the standard conditions (Scheme 3, 4l−4v). Further
study revealed that stable products obtained in Scheme 2 can
also be transferred to benzene derivatives via a simple operation,
thus affording 4w−4ac in good yields (Scheme 3, 4w−4ac).
Using equal amounts of 3b and 3e under standard conditions I,
cross-coupling products 4be and 4eb could be produced in
similar yields (Scheme 4).
Scheme 7. Proposed Reaction Mechanism
Scheme 4. Cross-coupling Reaction
group of 1a by a carbene catalyst leads to intermediate I, and an
intramolecular rearrangement happens to allow the formation of
O-acylated homoenolate III possibly via epoxy intermediate II.7
Then, a Michael addition of III to another molecule of substrate
1b is proposed to produce enolate IV, and the second acyl
transfer occurs to afford a new enolate V. Then, after the
Attempts to realize an enantioselective transformation in this
study revealed that triazolium catalyst H11 can afford product 2a
in moderate yield with 48% ee. A promising 80% ee was
perceived when imidazolium I12 was utilized, albeit in a low yield
(Scheme 5).13
C
DOI: 10.1021/acs.orglett.7b03358
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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intramolecular aldol reaction and the regeneration of carbene
catalyst, VII is formed. The final product 4b is obtained probably
through the double bond migration under the basic reaction
conditions. A series of acyl transfer and rearrangements feature
this process, and two C−C bonds and two C−O bonds are
newly constructed in this catalytic cycle.
In conclusion, the umpolung of β,γ-unsaturated diketones via
NHC catalysis was achieved, allowing access to a broad range of
highly substituted cyclcohexene-β-lactones and triaryl substi-
tuted benzene derivatives in a concise and efficient fashion. The
synthetic applications of the products were further demon-
strated by a series of highly selective transformations. Moreover,
an unprecedented catalytic cycle involving O-acylated homo-
enolate was proposed on the basis of experimental results.
Further studies on the mechanistic details of this transformation
and new applications of unsaturated diketones are in progress in
our group.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03358.
Experimental procedures, optimization details, data for all
new compounds, NMR and HPLC spectra (PDF)
Accession Codes
CCDC 1487464−1487465 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
(6) Kong, X.; Zhang, G.; Yang, S.; Liu, X.; Fang, X. Adv. Synth. Catal.
2017, 359, 2729.
(7) Sinu, C. R.; Suresh, E.; Nair, V. Org. Lett. 2013, 15, 6230.
(8) (a) Cohen, D. T.; Eichman, C. C.; Phillips, E. M.; Zarefsky, E. R.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 7309. (b) Cohen, D. T.;
Johnston, R. C.; Rosson, N. T.; Cheong, P. H.-Y.; Scheidt, K. A. Chem.
Commun. 2015, 51, 2690.
AUTHOR INFORMATION
̈
̈
(9) (a) Geng, Y.; Fechtenkotter, A.; Mullen, K. J. Mater. Chem. 2001,
11, 1634. (b) Kobayashi, K.; Sato, A.; Sakamoto, S.; Yamaguchi, K. J.
Am. Chem. Soc. 2003, 125, 3035. (c) Hiraoka, S.; Hisanaga, Y.; Shiro,
M.; Shionoya, M. Angew. Chem., Int. Ed. 2010, 49, 1669. (d) Tanaka, Y.;
Koike, T.; Akita, M. Chem. Commun. 2010, 46, 4529.
■
Corresponding Author
*E-mail: xqfang@fjirsm.ac.cn.
ORCID
(10) (a) Zhu, T.; Zheng, P.; Mou, C.; Yang, S.; Song, B.-A.; Chi, Y. R.
Nat. Commun. 2014, 5, 5027. (b) Zhu, T.; Mou, C.; Li, B.; Smetankova,
M.; Song, B.-A.; Chi, Y. R. J. Am. Chem. Soc. 2015, 137, 5658.
(c) Candish, L.; Levens, A.; Lupton, D. W. Chem. Sci. 2015, 6, 2366.
(d) Zhang, C.-L.; Ye, S. Org. Lett. 2016, 18, 6408. (e) Zhang, C.-L.;
Gao, Z.-H.; Liang, Z.-Q.; Ye, S. Adv. Synth. Catal. 2016, 358, 2826.
(f) Jia, Q.; Wang, J. Org. Lett. 2016, 18, 2212.
Xinqiang Fang: 0000-0001-8217-7106
Author Contributions
§J.L. and D.K.D. contributed equally.
Notes
The authors declare no competing financial interest.
(11) Wadamoto, M.; Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A. J.
Am. Chem. Soc. 2007, 129, 10098.
ACKNOWLEDGMENTS
■
̈
(12) Herrmann, W. A.; Goossen, L. J.; Kocher, C.; Artus, G. R. J.
Angew. Chem., Int. Ed. 1996, 35, 2805.
This work was supported by NSFC (21502192 and 21402199),
the Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB20000000), and the Chinese
Recruitment Program of Global Experts. We thank Professor
Daqiang Yuan, and Professor Qingfu Sun from Fujian Institute
of Research on the Structure of Matter (FJIRSM) for the help in
X-ray structure determination and data analysis.
(13) The absolute configuration of 2a was not determined.
(14) The relative configuration of the product was assigned by analogy
to a known report; see: Toselli, N.; Martin, D.; Achard, M.; Tenaglia,
A.; Buono, G. J. Org. Chem. 2009, 74, 3783.
(15) For selected reports, see: (a) Watanabe, M.; Murata, K.; Ikariya,
T. J. Am. Chem. Soc. 2003, 125, 7508. (b) Ma, Y.; Song, C.; Ma, C.; Sun,
Z.; Chai, Q.; Andrus, M. B. Angew. Chem., Int. Ed. 2003, 42, 5871.
(c) Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2008, 130,
6070.
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DOI: 10.1021/acs.orglett.7b03358
Org. Lett. XXXX, XXX, XXX−XXX