One-pot fluorination and organocatalytic Robinson annulation for asymmetric synthesis of mono- and difluorinated cyclohexenones

Article abstract of DOI:10.3390/molecules23092251

A one-pot fluorination and organocatalytic Robinson annulation sequence has been developed for asymmetric synthesis of 6-fluoroyclohex-2-en-1-ones and 4,6-difluorocyclohex-2-en-1-ones. The reactions promoted by cinchona alkaloid amine afforded products bearing two or three stereocenters in good to excellent yields with up to 99% ee and 20:1 dr.

Full text of DOI:10.3390/molecules23092251

molecules
Communication
One-pot Fluorination and Organocatalytic Robinson
Annulation for Asymmetric Synthesis of Mono- and
Difluorinated Cyclohexenones
1
,
1
2
2
3
Xin Huang *, Weizhao Zhao , Xiaofeng Zhang , Miao Liu , Stanley N. S. Vasconcelos
2
,
and Wei Zhang *
1
College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China;
zhao792129582@163.com
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard,
Boston, MA 02125, USA; Xiaofeng.Zhang002@umb.edu (X.Z.); liumiaomarcus@gmail.com (M.L.)
Departamento de Farmácia, Universidade de São Paulo, Av. Prof. Lineu Prestes, 580 São Paulo,
SP 05508-000, Brazil; stanleynsv@gmail.com
2
3
*
Correspondence: xin.huang@zjnu.cn (X.H.); wei2.zhang@umb.edu (W.Z.);
Tel.: +1-617-287-6147 (W.Z.); Fax: +1-617-287-6030 (W.Z.)
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 4 August 2018; Accepted: 31 August 2018; Published: 4 September 2018
Abstract: A one-pot fluorination and organocatalytic Robinson annulation sequence has been
developed for asymmetric synthesis of 6-fluoroyclohex-2-en-1-ones and 4,6-difluorocyclohex-2-en-
1
-ones. The reactions promoted by cinchona alkaloid amine afforded products bearing two or three
stereocenters in good to excellent yields with up to 99% ee and 20:1 dr.
Keywords: organocatalysis; fluorination;
α-fluoro-β-keto ester; Michael addition; Robinson
annulation; cyclohexenone
1
. Introduction
The development of new synthetic methods for organofluorine compounds is an active topic
in organic and medicinal chemistry. Introduction of fluorine atom(s) could have significant
impact on molecules’ biological activity, bioavailability, and metabolic property [ ]. Shown in
Figure 1 are bioactive fluorinated cyclohexenones [ ] including intermediate for antitumor agent
COTC (Figure 1A) [ ], aromatase inhibitor (Figure 1B) [ ], and retinal protein bacteriorhodopsin
Figure 1C) [8].
1–4
5
6
7
(
Figure 1. Bio-active fluorinated cyclohexenones.
The
sites [ ]. The asymmetric Michael addition reactions of
monofluorinated nucleophiles [16 19] is an attractive topic. These nucleophiles have been used to react
with nitroolefins [10 11 13 14 16 17], N-alkyl maleimides [12 15], chalcones [18], and -unsaturated
β-ketoester scaffold is a versatile synthon for being both electrophilic and nucleophilic
9
α
-fluoro- -keto esters [10 15] and other
β
–
–
,
,
,
,
,
,
α,β
Molecules 2018, 23, 2251; doi:10.3390/molecules23092251
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2251
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aldehydes [19]. Beside the Michael addition reactions, some Michael addition-initiated reactions
involving -fluoro- -keto esters have also been reported [20 22]. Those reactions include
α
β
–
Michael/aldol (Robinson) [20], Michael/Michael/aldol [21], and Michael/aza-Henry/lactamization
sequences [22] for the construction of cyclohexenones, cyclohexanones, and 2-piperidinones bearing
multiple stereocenters.
As part of our recent effort on the synthesis of organofluorine compounds using
α-fluoro-β-keto
esters [23 25], we have reported a one-pot fluorination/Robinson annulation sequence for fluorinated
–
cyclohexenones 1 (Scheme 1A) [23], Robinson annulation/dehydrofluorination/aromatization
sequence for phenols 2 (Scheme 1B) [24], and pyridines [25]. We envisioned that in the presence
of an organocatalyst, such as cinchona alkaloid primary amine cat-1, the one-pot asymmetric synthesis
could be developed for the preparation of monofluorocyclohexenones 3 and difluorocyclohexenones 4
(Scheme 1C).
Scheme 1. Robinson annulation-based one-pot synthesis.
2
. Results and Discussions
A number of six organocatalysts were screened for the asymmetric Robinson annulation reaction
of chalcone 6a and -fluoro- -ketoester 5a (Table 1, entries 1–6). It was found that the reaction with
0 mol% of cat-1 gave the desired product 3a in 79% yield with 5:1 dr and 99% ee (entry 1), while other
α
β
2
catalysts did not give good results. Acidity of the reaction system plays an important role in amine
catalysis for lowering the LUMO energy of iminium ions [26]. Thus, an investigation of the reactions in
the presence of different acids was carried out. The best result was achieved by adding CF C H CO H
3
6
4
2
to afford 3a in 89% yield with 9:1 dr and 99% ee (entry 10). We lowered the reaction temperature to
◦
−
20 C which slightly increased the dr to 12:1, but significantly decreased the yield to 51% (entry 13).
Because we failed to get the crystal of
3 for X-ray structure analysis, the absolute configuration of 3a
was deduced based on the information reported in the literature [27]. The S-amine catalyst promoted a

Molecules 2018, 23, 2251
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highly selective Re-face attack at the Michael acceptor. We believed that our reactions also catalyzed
by the S-amine cat-1 could have the same stereochemistry outcome.
Table 1. Screening of catalysts for the Robinson annulation a.
Yield (%) b
dr c
ee (%) d
Entry
Cat
Additive
C H CO H
1
2
3
4
5
6
7
8
9
cat-1
cat-2
cat-3
cat-4
cat-5
cat-6
cat-1
cat-1
cat-1
cat-1
cat-1
cat-1
cat-1
79
NR
NR
NR
trace
27
42
52
45
89
5:1
-
-
-
-
3:1
5:1
6:1
5:1
9:1
8:1
8:1
12:1
99
-
-
-
-
85
92
92
95
99
90
90
99
1
6
5
2
C H CO H
6
5
2
C H CO H
6
5
2
C H CO H
6
5
2
C H CO H
6
5
2
C H CO H
6
5
2
None
AcOH
TsOH
1
1
1
0
1
2
CF C H CO H
3
6
4
2
CCl CO H
75
77
51
3
2
CF CO H
3
2
e
1
3
CF C H CO H
3
6
4
2
a
Reaction of 0.1 mmol of 5a and 0.15 mmol of 6a in 0.5 mL of MeCN. b Isolated yield. c Determined by H-NMR of
crude reaction mixture. d Determined by chiral HPLC. Reaction was carried out at −20 C.
e
◦
The combination of fluorination and the Robinson annulation as a one-pot reaction for fluorinated
cyclohexenone 3a was then attempted (Table 2). The fluorination step does not need to be asymmetric
because both stereocenters were generated during the subsequential Michael addition. The fluorination
◦
reaction of
β-ketoester
8
with SelectFluor
™
was conducted under microwave heating at 120 C for 20
min without using a catalyst. After the completion of the fluorination, chalcone 6a, CF C H CO H
3
6
4
2
◦
and catalyst cat-1 were added to the reaction mixture at 25 C for the Robinson annulation. But this
one-pot fluorination/Robinson annulation only gave 3a in <10% yield probably due to the effect of the
acidic SelectFluor
K CO , and Cs CO were used for the reaction. It was found that addition of 1.5 equiv. of Na CO
3
™ derivative in the reaction mixture. To address this issue, bases including Na CO ,
2 3
2
3
2
3
2
gave 3a in 82% yield with a good ee and dr (Table 2, entry 6).

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Table 2. One-pot synthesis of 6-fluorocyclohex-2-en-1-ones 3 a.
Yield (%) b
dr c
ee (%) d
Entry
Base (equiv)
1
2
3
4
5
6
7
None
<10
42
67
85
57
82
83
-
-
Na CO (0.5)
9:1
3:1
1.5:1
9:1
9:1
9:1
99
85
52
99
99
99
2
3
K CO (0.5)
2 3
Cs CO (0.5)
2 3
Na CO (1.0)
2 3
Na CO (1.5)
2 3
Na CO (2.0)
2 3
a
, 0.15 mmol of 6a in 0.5 mL of MeCN. b Yield of isolated
Determined by H-NMR. d Determined by HPLC on Venusil Chiral OD-H column with 90:10
hexane/i-PrOH.
Reaction of 0.1 mmol of 8, 0.15 mmol of SelectFluor™
c
1
product 3a
.
With the optimized conditions in hand, the scope of the one-pot synthesis of
6
-fluorocyclohexenones 3a
Substrates
products 3b
–
j
using different Michael acceptor
6
was investigated (Scheme 2).
1
6
with electron-donating (SMe, Ph) and electron-withdrawing (Br, CF ) groups on Ar gave
in 82–90% yields with >96% ee and >9:1 dr. Reaction of a chalcone bearing a thiophene
3
–f
2
ring also gave product 3h in a good yield and ee. The introduction of substituents on Ar of
products 3i and 3j with decreased ee, probably due to an unfavorable stereoelectronic effect.
6 gave
Scheme 2. One-pot synthesis of 6-fluorocyclohex-2-en-1-ones 3.
We have recently reported a one-pot Robinson annulation/dehydrofluorination/aromtization
sequence for fluorinated phenols using -fluoro- -ketoesters and -fluoro- -unsaturated ketones
as substrates [24]. We envisioned that -fluoro- -unsaturated ketones could be used for asymmetric
synthesis of 4,6-difluorocyclohexanones under organocatalytic conditions. Indeed, one-pot reactions
of -ketoester went smoothly to afford 4a in 53–65% yields with 5:1-8:1 dr and 89–93% ee (Scheme 3).
2
α
β
α
α,β
α
α
,
β
6
4
β
8
–c

Molecules 2018, 23, 2251
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However, all of these reactions afforded 4a
–
c
as decarboxylated products, even at low reaction
◦
temperatures (
−
30–0 C). No aromatization products were observed under the reaction temperature
without heating [24]. The products 4a–c were found not to be stable during the workup and rotary
vapor concentration of the crude product.
Scheme 3. One-pot synthesis of 4,6-difluorocyclohexanones 4.
3
. Conclusions
In summary, a one-pot fluorination and cinchona alkaloid amine-promoted organocatalytic
Robinson sequence for asymmetric synthesis of fluorocyclohexenones bearing two stereocenters has
been developed. Both stereocenters were established during the step of Michael addition to afford
fluorinated cyclohexanones with up to 99% ee and 20:1 dr. Using fluorinated chalcones as Michael
acceptors, 4,6-diflorocyclohexanones bearing three stereocenters were also synthesized stereoselectively
and in good yields.
Supplementary Materials: Supplementary Materials are available online, General procedure; characterization of
1
13
H and C NMR spectra of products, HPLC spectra of racemic and enantioenriched products.
Author Contributions: X.H. developed above reactions. W.Z., X.Z., M.L., and S.N.S.V. expanded the substrate
scope. W.Z. conceived and supervised the project.
Funding: Joseph P. Healey Research Grant from UMass Boston.
Acknowledgments: We would like to thank the Centre for Green Chemistry at the University of Massachusetts
Boston, Zhejiang Normal University to support this work.
Conflicts of Interest: The authors declare no conflicts of interest
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Sample Availability: Samples of the compounds are available from the authors.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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