Catalytic Efficient Nazarov Reaction of Unactivated Aryl Vinyl Ketones via a Bidentate Diiron Lewis Acid Activation Strategy

Article abstract of DOI:10.1002/adsc.201700820

A catalytic highly efficient Nazarov reaction of unactivated aryl vinyl ketones has been accomplished by employing aryl boric acid/Fe(OTf)₃. Significant progress was obtained in utilizing an extremely broad substrate scope, giving indanones in high yields with high regioselectivities and diastereoselectivities. The mechanistic investigation supports a bidentate diiron Lewis acid catalysis, and the strong double electrophilic activation of aryl vinyl ketones via simultaneous coordination plays a key role in achieving a high reaction efficiency. (Figure presented.).

Full text of DOI:10.1002/adsc.201700820

Title: Catalytic Efficient Nazarov Reaction of Unactivated Aryl Vinyl
Ketones via a Bidentate Diiron Lewis Acid Activation Strategy
Authors: Xin Zhou, Yukun Zhao, Yang Cao, and Lirong He
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700820
Link to VoR: http://dx.doi.org/10.1002/adsc.201700820

10.1002/adsc.201700820
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Catalytic Efficient Nazarov Reaction of Unactivated Aryl Vinyl
Ketones via a Bidentate Diiron Lewis Acid Activation Strategy
Xin Zhou,* Yukun Zhao,‡ Yang Cao,‡ and Lirong He
School of Chemsitry and Chemical Engineering, Southwest University, Chongqing 400715, China.
Fax: (+086)-023-6825-3157; e-mail: xinzhou@swu.edu.cn
‡
These authors contributed equally.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
potentially valuable since it promises to demonstrate
unactivated aryl vinyl ketones has been accomplished by an even higher catalytic efficiency than the respective
Abstract. A catalytic highly efficient Nazarov reaction of
employing aryl boric acid/Fe(OTf)3. Significant progress
was obtained in utilizing an extremely broad substrate
scope, giving indanones in high yields with high
monofunctional Lewis acid, concequently expanding
the substrate scope.[10] Nevertheless, to date,
relatively few examples of bidentate Lewis acid
catalysis have been reported,[11] which may be caused
by the difficulty of synthesis and the highly favored
regioselectivities
and
diastereoselectivities.
The
mechanistic investigation supports a bidentate diiron Lewis
acid catalysis, and the strong double electrophilic activation
of aryl vinyl ketones via simultaneous coordination plays a
key role in achieving a high reaction efficiency.
double
coordination
leading
to
catalyst
deactivation.[10a,12] Herein, we report the bidentate
diiron Lewis acid catalyzed Nazarov reaction of
unactivated aryl vinyl ketones by using aryl boric
acid/Fe(OTf)3 (Figure 1, C). The process delivered a
wide substrate scope, giving indanones in high yields
with high regioselectivities and diastereoselectivities.
Keywords: Nazarov reaction; Lewis acid catalysis;
Indanone; 4π electrocyclization; aryl vinyl ketone
Indane frameworks are widely found in natural
products and drug candidates possessing intriguing
bioactivities (Figure 1, A).[1] Intense efforts have been
devoted to their synthesis.[2] However, as theoretically
one of the most efficient strategies for the synthesis
of indanones, the catalytic Nazarov reaction of aryl
vinyl ketones has been rarely explored due to the
sluggish reactivity caused by the breaking of the
aromaticity during the reaction.[3-6] Stoichiometric or
superstoichiometric amounts of strong Brønsted or
Lewis acids are generally required.[7] Thus far, only
limited catalysts, such as Cu(II), Ir(III), Au(III) and
Al(III) have been developed for the activation of aryl
vinyl ketones based on the “polarizing strategy”,[8] or
the steric effect (Figure 1, B).[9] Coorperative
catalysis for the polarizing aryl vinyl ketones was
also developed by professor Luo by using
In(OTf)3/phosphoric acid as the catalyst.[8d] Moreover,
the effect on the aryl moiety of aryl vinyl ketones was
investigated, but electron deficient moieties have
been scarcely explored. These limited the utilization
of Nazarov reaction of aryl vinyl ketones for the
synthesis of indanones.
Lewis acids play a major role as catalysts in the
contemporary organic synthesis. Bidentate Lewis
acid catalysis, based on the simultaneous double
coordination and activation of a single substrate, is
Figure 1. Nazarov strategy for the synthesis of indanones.
1
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10.1002/adsc.201700820
Advanced Synthesis & Catalysis
Table 1. Optimization of the Reaction Conditions.
Entry[a]
1
2
3
4
5
6
7
8
Lewis Acid
Cu(OTf)2
Ni(OTf)2
Fe(OTf)2
Sc(OTf)3
Al(OTf)3
In(OTf)3
Fe(OTf)3
BF3.OEt2
None
Al(OTf)3
In(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Boric Acid
None
None
None
None
None
None
None
Time [h]
6
6
6
6
1.5
6
6
6
6
1.5
4
4
4
4
4
4
1.5
Yield [%][b]
0
0
0
0
22
37
50
43
0
33
52
47
56
72
77
92
None
9[c]
10
11
12
13
14
15
16
3,5-(CF3)2C6H3B(OH)2
3,5-(CF3)2C6H3B(OH)2
3,5-(CF3)2C6H3B(OH)2
PhB(OH)2
3,5-C6H3F2B(OH)2
C6F5B(OH)2
3,5-(CF3)2C6H3B(OH)2
BF3.OEt2
17[d]
3,5-(CF3)2C6H3B(OH)2
95
[a]
[b]
Reaction conditions: 1a (0.1 mmol), Fe(OTf)3 (10 mol%), boric acid (10 mol%) in DCM under N2.
Yield of the
Catalyst 3,5-
[c]
[d]
isolated product.
Other aryl boric acids listed in table 1 were also tested, no reaction occurred.
(CF3)2PhB(OH)2/Fe(OTf)3 (1:2, 5 mol%) was used.
Since various Lewis acids were effective activators
for boric acids,[13] it is surmised that such a complex
may act as a bidentate Lewis acid, thus effectively
activating the aryl vinyl ketones. Indeed, the catalytic
efficiency of the reaction was improved using aryl
boric acid/Al(OTf)3, In(OTf)3 and Fe(OTf)3 (Table 1,
entries 10-15 vs 5-7).[14a,15] By increasing the Lewis
acidity of boric acids, the reactivity of the reaction
was improved as anticipated (entries 12-15).
Indanone 2a was obtained with a 77% yield using
3,5-(CF3)2PhB(OH)2/Fe(OTf)3 as the catalyst (entry
15). BF3·OEt2/Fe(OTf)3 catalyzed the reaction more
efficiently,[14b] giving the corresponding 2a in a 92%
yield (entry 16). Further investigation revealed that
the ratio of aryl boric acid/Fe(OTf)3 has a significant
effect on the reactivity of the reaction. 3,5-
(CF3)2PhB(OH)2/Fe(OTf)3 (1:2, 5 mol%) catalyzed
the reaction smoothly, and delivered indanone 2a in
95% yield with 10:1 d.r. favoring the trans
stereoisomer within 1.5 hours (entry 17).[14c]
With the optimized reaction conditions in hand, we
first investigated the effect of the aryl fragment of
unactivated aryl vinyl ketones (Table 2, 2a-2p). The
electron rich aryl vinyl ketones underwent the
reaction smoothly, giving the corresponding
indanones in excellent yields with good
diastereoselectivities (Table 2, 2a-2e). It is
noteworthy that aryl vinyl ketones bearing a p-
methoxyl group on the aryl moiety also worked very
well (Table 2, 2f), which sharply contrasted with
previous reports.[7e,8d] The Nazarov reaction of
electron deficient aryl vinyl ketones represented a
significant challenge for the synthesis of indanones,
and has been scarcely investigated.[3] To our delight,
3,5-(CF3)2PhB(OH)2/Fe(OTf)3 (1:2) catalyzed the
reaction smoothly, giving the corresponding
indanones in good yields with good to excellent
diastereoselectivities (Table 2, 2h-2n). To the best of
our knowledge, this was the first example of the
catalytic Nazarov reaction of electron deficient aryl
vinyl ketones. To further expand the substrate scope,
heteroaryl vinyl ketones were tested, and excellent
results were obtained (2o-2p).
Subsequently, the influence of the vinyl fragment
of aryl vinyl ketones was investigated (Table 2, 2q-
2zc). Various β-aryl (1q-1t), heteroaryl (1u) and alkyl
substituted aryl vinyl ketones (1w) as well as aryl
dienyl ketone (1v) underwent the reaction smoothly,
providing the corresponding indanones in high yields
with high diastereoselectivities (Table 2, 2q-2w). The
α-alkyl aryl vinyl ketones were also suitable
substrates for the Nazarov reaction, and indanones
2x-2za were obtained in high yields with excellent
diastereoselectivities. With respect to α-aryl vinyl
ketone 1zb, however, the reaction did not proceed,
which may be caused by the steric interactions.
Fortunately, BF3·OEt2 /Fe(OTf)3 (1:1, 5 mol%) could
efficiently catalyze the reaction (Table 2, 2zb).[14d]
The synthetic utility of the methodology was further
demonstrated by the formal synthesis of (±)-
isopauciflorel F. The Nazarov reaction of 1zc
proceeded smoothly, giving indanone 2zc in a 94%
yield within 4 hours (Table 2, 2zc). The formal
synthesis of (±)-isopauciflorel F was then completed
following the previous report of Professor Snyder.[2d]
2
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10.1002/adsc.201700820
Advanced Synthesis & Catalysis
Table 2. Effect of the aryl fragment of unactivated aryl vinyl ketones for the Nazarov reaction.[a]
[a] Reaction conditions: 3,5-(CF3)2PhB(OH)2/Fe(OTf)3 (1:2, 5 mol%), 1 (0.2 mmol), in DCM (1.0 mL) under N2 at 40 °C. [b]
Catalyst loading: 10 mol%. [c] Reaction proceeded in DCE (1.0 mL) at 70 °C. [d] Catalyst BF3·OEt2/Fe(OTf)3 (1:1, 5 mol%)
was used.
3
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10.1002/adsc.201700820
Advanced Synthesis & Catalysis
Scheme 1. Nazarov reaction of α-unsubstituted chalcone.
The α-unsubstituted chalcones represent
a
significant challenge for the catalytic Nazarov
reaction, not only because of the inherent sluggish
reactivity of aryl vinyl ketones but also because of the
much favored nonproductive s-cis conformation.[9] To
our delight, the first catalytic Nazarov reaction of α-
unsubstituted chalcones was realized using our
catalyst, giving indanone 2zd in an 87% yield
(Scheme 1).[14e]
Our catalyst system exhibited a unique activation
capacity for the Nazarov reaction,[14f] and realized
unprecedented catalytic reactions of electron deficient
aryl vinyl ketones and α-unsubstituted chalcones.
High resolution mass spectrometer (HRMS) analysis
of the catalyst indicated that diiron species were
formed in situ.[14g] Attempts to characterize the
solution phase complex by a NMR experiment were
prevented due to broadening associated with
Scheme 2. Nazarov reaction of polarized aryl vinyl ketone.
paramagnetic Fe3+ species.[14g] However,
a
preliminary investigation provided pieces of
meaningful information at the current stage. The
probable TfOH catalysis for the reaction was
precluded, since it is catalytically inactive for the
challenging electron deficient aryl vinyl ketones and
α-unsubstituted chalcones.[14h] The approximate high
efficiency of the catalysts ArB(OH)2/Fe(OTf)3 (1:2)
with different aryl boric acids,[14f] combined with the
significant effect of the ratio of 3,5-
(CF3)2PhB(OH)2/Fe(OTf)3 (Table 1, entry 17 vs. 15),
is highly suggestive of a diiron catalytic active
species for the catalytic Nazarov reaction.
Compared with the unactivated aryl vinyl ketone
1a (Table 1, entries 7 and 17), the Nazarov reaction
of the corresponding polarized aryl vinyl ketone 1ze
proceeded much more efficiently (Scheme 2). The
Lewis acid activation and the substrate preactivation
played a key role for the Nazarov reaction of
polarized aryl vinyl ketones.[3,5,6] In addition, it is
more accessible for the activation of aryl vinyl
ketones via a chelating approach. Since the diiron
species catalyzed unactivated aryl vinyl ketones more
efficiently than the Fe(OTf)3 catalyzed polarized aryl
vinyl ketones, we thought the diiron species may
activate the unactivated aryl vinyl ketones via a
simultaneous double coordination approach.
Scheme 3. Control experiments.
To probe the origination of the unique catalytic
activity of our catalyst, substrates 1zf-1zh were
subjected to the Nazarov reaction (Scheme 3). The
control experiments highlight the significant steric
effect and that the o-methyl and α-phenyl groups of
aryl vinyl ketones prevent the coordination and
activation of ketones by catalysts on their sides;[14i]
the catalytic efficiency of diiron species is sharply
reduced and close to that of Fe(OTf)3 which highly
prefers to activate ketones in a single coordination
4
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10.1002/adsc.201700820
Advanced Synthesis & Catalysis
model even in the presence of excess Fe(OTf)3. In
principle, the single complexation leaves one sp2 lone
pair free and available for binding a second Lewis
acid. In view of this, a bidentate Lewis acid diiron
activation via the efficient simultaneous coordination
toward carbonyls, which promises to be even more
efficient than the single coordination activation mode,
was proposed to account for the unique catalytic
activity of our catalyst.[10] This was further supported
by the IR experiments (Figure 2). The carbonyl
region of the spectrum showed a peak at 1641 cm-1
corresponding to aryl vinyl ketone 1f (Figure 2, A).
With the treatment of Lewis acids, the carbonyl
stretch of the coordinated ketone 1f showed a large
shift (Figure 2, A vs. B and C). The characteristic
bands appeared at 1637 cm-1 for ketone 1f bound by
Fe(OTf)3 (Figure 2, B), while the carbonyl single
disappeared for ketone 1f coordinated by
(CF3)2PhB(OH)2/Fe(OTf)3 (1:2) (Figure 2, C).[14j] The
diiron species caused a significantly larger shift to
free ketone 1f, suggesting a more substantial
weakening of the carbonyl bond than with
Fe(OTf)3.[16] This was a strong signal that the diiron
species acted as a bidentate Lewis acid and activated
the carbonyls via simultaneous double coordination,
which is much stronger than the single coordination
of Fe(OTf)3.
catalytic efficiencies than the metal salts itself for the
Nazarov reaction of aryl vinyl ketones (Scheme 4 vs.
Table 1 entries 1, 5 and7).
Scheme 4. Bidentate Lewis acids catalyzed Nazarov
reaction of unactivated aryl vinyl ketones.
Based on the control experiments, HRMS analysis,
IR analysis and the previous reports,[3] a probable
mechanism of the reaction was proposed (Scheme 5).
A bidentate Lewis acid diiron species was facilely
generated in situ. The catalyst would then double
coordinate and activate the aryl vinyl ketones forming
a highly active intermediate A, which facilely
undergoes the 4π-electrocyclizations. The enolate C,
formed by the deprotonation of oxoallylic cation B,
then underwent a kinetic protonation, producing cis-
favored indanones. Thermodynamically stable trans-
indanones were finally obtained under the influence
of the Lewis acids via reversible enolization of the
ketones.[14f]
Scheme 5. Proposed reaction mechanism.
Figure 2. IR analysis for the mechanistic investigation.
In conclusion, we have developed a catalytic
highly efficient Nazarov reaction of unactivated aryl
vinyl ketones by using 3,5-(CF3)2PhB(OH)2/Fe(OTf)3.
The methodology demonstrated an extremely broad
substrate scope, giving the corresponding indanones
in high yields as well as high rigioselectivity and
diastereoselectivity. Notably, the challenging electron
deficient aryl vinyl ketones and α-unsubstituted
chalcones have been successfully explored for the
first time. Mechanistic investigation supports a
The bidentate activation was further strengthened
by the application of other bidentate Lewis acids in
the Nazarov reactions (Scheme 4). Bidentate Lewis
acids could be facilely synthesized via the
coordination of binucleating ligands, and have been
successfully applied in many reactions.[10,11]
Following
this
strategy,
bidentate
diiron,
bis(aluminium) and dicopper complexes were
synthesized,[14f] and demonstrated much higher
5
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10.1002/adsc.201700820
Advanced Synthesis & Catalysis
bidentate diiron Lewis acid catalysis, and the strong
double coordination and activation towards aryl vinyl
ketones play key roles for the high catalytic
efficiency of the reaction. Further application of the
bidentate diiron Lewis acid are currently underway.
[4] For selected examples of total synthesis using the
Nazarov reaction of aryl vinyl ketones, see: a) G. Liang,
Y. Xu, I. B. Seiple, D. Trauner, J. Am. Chem. Soc. 2006,
128, 11022; b) W. He, J. Huang, X. Sun, A. J. Frontier,
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d) J. A. Malona, K. Cariou, A. J. Frontier, J. Am. Chem.
Soc. 2009, 131, 7560; e) W. Z. Li, W. Duo, C. Zhuang,
Org. Lett. 2011, 13, 3538; f) P. Magnus, W. A. Freund,
E. J. Moorhead, T. Rainey, J. Am. Chem. Soc. 2012,
134, 6140; g) S. Cai, Z. Xiao, Y. Shi, S. Gao, Chem.
Eur. J. 2014, 20, 8677; h) Y. Shi, B. Yang, S. Cai, S.
Gao, Angew. Chem. 2014, 126, 9693; Angew. Chem.
Int. Ed. 2014, 53, 9539; i) Z. Zhou, M. A. Tius, Angew.
Chem. 2015, 127, 6135; Angew. Chem. Int. Ed. 2015,
54, 6037.
Experimental Section
To the solution of 3,5-(CF3)2C6H3B(OH)2 (0.01mmol, 5
mol%) in 1.0 mL CH2Cl2, Fe(OTf)3 (0.02mmol, 10 mol%)
was added under nitrogen atmosphere, the resulting
o
mixture was stirred at 40 C for 30 min. Aryl vinyl ketone
(0.2 mmol) was then added, the reaction mixture was
stirred at 40oC for indicated time. The product was then
directly purified by column chromatography on silica gel.
Acknowledgements
[5] For selected examples of the Nazarov reaction of
polarizing divinyl ketones, see: a) W. He, X. Sun, A. J.
Frontier, J. Am. Chem. Soc. 2003, 125, 14278; b) M.
Rueping, W. Ieawsuwan, A. P. Antonchick, B. J.
Nachtsheim, Angew. Chem. 2007, 119, 2143; Angew.
Chem. Int. Ed. 2007, 46, 2097; c) P. Cao, C. Deng, Y.
Y. Zhou, X. L. Sun, J. C. Zheng, Z. Xie, Y. Tang,
Angew. Chem. 2010, 122, 4565; Angew. Chem. Int. Ed.
2010, 49, 4463; d) M. Kawatsura, K. Kajita, S. Hayase,
T. Itoh, Synlett 2010, 1243; e) D. Leboeuf, V. Gandon,
J. Ciesielski, A. J. Frontier, J. Am. Chem. Soc. 2012,
134, 6296; f) G. E. Hutson, Y. E. Terkmen, V. H.
Rawal, J. Am. Chem. Soc. 2013, 135, 4988; g) K.
Kitamura, N. Shimada, C. Stewart, A. C. Atesin, T. A.
Atesin, M. A. Tius, Angew. Chem. 2015, 127, 6386;
Angew. Chem. Int. Ed. 2015, 54, 6288; h) Z. Xu, H.
Ren, L. Wang, Y. Tang, Org. Chem. Front. 2015, 2,
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Wong, Z. Zhou, M. A. Tius, Chem. 2015, 124, 5825;
Angew. Chem. Int. Ed. 2012, 51, 5727; And references
therein.
We appreciate the National Natural Science Foundation of China
(Grant No. 21302154), the Doctoral Foundation of Southwest
Univ. (SWU113046), and the Fundamental Research Funds for
the Central Universities (XDJK2013C111) for financial support.
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10.1002/adsc.201700820
Advanced Synthesis & Catalysis
3435; Angew. Chem. Int. Ed. 2010, 49, 3363; c) T.
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effect prevented the simultaneous double coordination
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bond (Figure 2, C).
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conditions, for details see the
supporting information (SI); b)
BF3 and Fe(OTf)3 were thought
to complex via a fluorine atom; c)
The syn and anti determination
were made on the basis of
coupling constants and NOESY analysis; d) The steric
7
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