Asymmetric dearomatic diels-alder reactions of diverse heteroarenes via π-system activation

Article abstract of DOI:10.1021/ol501217u

An asymmetric dearomatic Diels-Alder protocol for various heteroarenes, such as benzofuran, benzothiophene, or even furan, has been developed via π-system activation. This method involves in situ generation of formal trienamine species embedding a heteroa

Full text of DOI:10.1021/ol501217u

Letter
pubs.acs.org/OrgLett
Asymmetric Dearomatic Diels−Alder Reactions of Diverse
Heteroarenes via π‑System Activation
You-Cai Xiao,† Cai-Zhen Yue,† Peng-Qiao Chen,† and Ying-Chun Chen*,†,‡
†Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education, West China School of Pharmacy, and
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
‡College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China
S
* Supporting Information
ABSTRACT: An asymmetric dearomatic Diels−Alder proto-
col for various heteroarenes, such as benzofuran, benzothio-
phene, or even furan, has been developed via π-system
activation. This method involves in situ generation of formal
trienamine species embedding a heteroaromatic moiety, and
an array of chiral fused frameworks with high molecular
complexity and skeletal diversity were efficiently constructed in
good to excellent stereoselectivity by the catalysis of a
cinchona-based primary amine.
ith their occurrence in many natural products and
bioactive compounds as illustrated in Figure 1,1
Scheme 1. π-System Activation of Hetero Ring via Formal
Trienamine Catalysis
W
Figure 1. Representative benzofuran- or furan-based natural products.
polycyclic benzofuan- or furan-based architectures have
attracted great attention in synthetic organic chemistry.
Although there are many methods concerning the synthesis
of such fused heterocycles, most of them are generally related
to nonasymmetric examples.2 One of the most common and
straightforward ways to construct these frameworks is the
dearomatic Diels−Alder reaction between vinylbenzofurans or
vinylfurans and olefinic dienophiles, which was first reported by
Kamthong and Robertson in 1939.3 However, most of the
previous presentations suffer from harsh conditions due to the
relatively low reactivity of the diene moiety and high energy
barrier encountered in the dearomatization process (Scheme
1).4 In contrast to the extensive research in stereoselective
cycloadditions of the analogous vinylindoles to access chiral
hydrocarbazoles,5 to the best of our knowledge, only a single
example was reported with more reactive 3-siloxyvinylbenzo-
furan as the diene partner by the catalysis of a chiral Holmium
complex to date.6 Therefore, a general and efficient asymmetric
protocol to construct these privileged structures is in high
demand.
Recently, a number of reactions have been developed
through the HOMO-activation of the remote CC bond of
unsaturated carbonyl compounds via either dienamine7 or
trienamine catalysis.8 Such a strategy has been utilized to
activate aromatic compounds. Melchiorre reported an asym-
Received: April 28, 2014
© XXXX American Chemical Society
A
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Letter
metric Diels−Alder reaction of β-indolyl enals through in situ
dearomatic formation of indole-2,3-quinodimethanes.9
Jørgensen et al. disclosed that the polycyclic core of
anthracenes could be activated by a conjugated enamine
intermediate, and highly stereoselective dearomatic Diels−
Alder reactions have been developed with electron-deficient
dienophiles.10 Inspired by our recent studies on the asymmetric
Friedel−Crafts reaction of furans11 and diverse asymmetric
cycloadditions via HOMO-activation of amine catalysts,12 we
envisaged that the relatively inert 2- or 3-vinyl heteroarenes
could be HOMO-raised through generating formal trienamine
species as outlined in Scheme 1; thus, the subsequent
dearomatic Diels−Alder reaction for the synthesis of diverse
chiral fused heterocycles, including benzofuran or furan-based
frameworks, could be facilitated under mild and metal-free
catalytic conditions (Scheme 1).
other maleimides with an N-aryl group, good yields and high
enantioselectivity were generally obtained (entries 2−4).
Nevertheless, maleimide 3e with an N-benzyl group gave a
decreased yield and enantiocontrol (entry 5). On the other
hand, β-(2-benzofuryl)methyl enones 2 bearing diverse α′-aryl
groups could be well tolerated (entries 6−8), while a 2-thienyl-
substituted substrate produced a slightly lower yield and ee
value (entry 9). In addition, similar good results were obtained
for enone partners with various substituents on the benzofuran
ring (entries 10−12). Importantly, the enone substrate
containing a 2-benzothiophenyl moiety was also compatible
with this type of asymmetric Diels−Alder reaction, and a chiral
tetrahydrodibenzo[b,d]thiophene framework was efficiently
constructed with high enantioselectivity (entry 13). Moreover,
the highly enantioenriched cycloadducts with an opposite
configuration could be produced by the catalysis of 9-amino-9-
deoxyepiquinidine 1b under similar catalytic conditions (Table
1, data in parentheses).
Initially, we designed substrate (E)-4-(benzofuran-2-yl)-1-
phenylbut-2-en-1-one 2a (Table 1, X = O, R1 = H, Ar = Ph),
It was pleasing that both enones 5a and 5b substituted by the
3-benzofuryl and 3-benzothiophenyl group, respectively,
exhibited comparable reactivity with maleimide 3a under the
same catalytic conditions, and dearomatic cycloadducts 6a and
6b were obtained as stable substances in good yields and with
high enantioselectivity. A tetrahydrocarbazole 6c was directly
formed in a moderate yield through a 1,3-H shift of the
cycloadduct, but only a moderate ee value was obtained
(Scheme 2).16
Table 1. Asymmetric Diels−Alder Reactions of Enones 2 and
a
Maleimides 3
Scheme 2. Asymmetric Diels−Alder Reactions of 3-
Heteroaryl Enones
b
c
entry
Ar
R1
3
yield (%)
ee (%)
1
Ph
Ph
Ph
Ph
Ph
H
3a
3b
3c
3d
3e
3a
3a
3a
3a
3a
3a
3a
3a
4a, 82 (60)
4b, 85
92 (−82)
91
2
H
3
H
4c, 76
90
4
H
4d, 73 (70)
4e, 68
89 (−80)
73
5
H
6
p-MeOC6H4
p-ClOC6H4
2-naphthyl
2-thienyl
Ph
H
4f, 81
86
7
H
4g, 80
88
8
H
4h, 76 (74)
4i, 68
83 (−97)
9
H
80
82
84
85
92
10
11
12
5-Me
7-Me
5-F
H
4j, 84
Ph
4k, 73
Unfortunately, 2,5-dienone-type substrate 2b bearing an α′-
enolizable methyl group exhibited no reactivity with dienophile
3a catalyzed by amine 1a, probably due to the preferable
generation of an undesired dienamine intermediate as outlined
in Scheme 3. As a result, we envisioned that deconjugated
formal 3,5-dienone-type substrate 7 might be more likely to
Ph
4l, 81
d
13
Ph
4m, 72
a
Unless noted otherwise, the reaction was conducted with enone 2 (X
= O, 0.12 mmol), maleimide 3 (0.1 mmol), catalyst 1a (20 mol %),
and salicylic acid (40 mol %) in toluene (1.0 mL) at 70 °C for 36 h.
Then the cycloadduct was treated with p-TsOH in CHCl3 at rt for 2 h.
b
c
Isolated yield for two steps. By chiral HPLC analysis; dr >19:1 by 1H
Scheme 3. A Deconjugation Strategy To Realize the Formal
Trienamine Catalysis for Enones with Enolizable α′-Alkyl
Group
d
NMR analysis. X = S.
which could be considered as a 2,5-dienone-type substance,13
and tested the potential Diels−Alder reaction with maleimide
3a under the catalysis of 9-amino-9-deoxyepiquinine 1a and
salicylic acid (SA) in toluene.14 Encouragingly, the desired
regioselective dearomatic cycloaddition occurred smoothly at
70 °C, and a more stable aromatic product 4a was obtained in
good yield with high stereoselectivity after treatment with p-
TsOH in chloroform (Table 1, entry 1, >19:1 dr, 92% ee).15
Subsequently, we explored the scope of both types of
substrates. The more stable fused heteroarenes were generated
and analyzed after the asymmetric cycloaddition reactions. For
B
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Letter
generate the required formal trienamine intermediate with the
amine catalyst.17
Scheme 5. More Exploration of Dearomatic Diels−Alder
Reactions
Thus, ketone 7a was prepared and tested, but it was unstable
under the catalytic conditions, and the desired cycloadduct 8a
was not detected. Gratifyingly, the analogous 7b with a
benzothiophene skeleton successfully participated in the Diels−
Alder cycloaddition with dienophile 3a, and product 8b was
isolated in a moderate yield and with excellent stereoselectivity.
Ketone 7c with an α′-ethyl group smoothly afforded the
cycloadduct 8c, albeit in a lower yield and enantioselectivity. It
is interesting that 3-benzofuryl enones 9 with α′-enolizable
alkyl groups showed better stability and reactivity and efficiently
produced the expected cycloadducts 6d−6f even at rt, though
only a modest ee value could be attained for 9c with a branched
cyclohexyl group (Scheme 4).
Scheme 4. Asymmetric Diels−Alder Cycloadditions of
Deconjugated Enones
To further explore the generality of this method, more
dienophiles were investigated with substrate 9a. As illustrated in
Scheme 5, 3-olefinic oxindoles18 10 could smoothly react with
9a to deliver the spirocyclic19 cycloaddition products 11a and
11b with high molecular complexity in excellent yields and ee’s.
Besides, benzylidenecyanoacetate 12 also showed good
reactivity with enone 9a. The diastereoselectivity was poor,
while the major cycloadduct 13 could be isolated in a low yield
but with excellent enantioselectivity. Nevertheless, β-nitro-
styrene did not react in a cycloaddition manner but gave an α-
regioselective Michael addition product (see the Supporting
Information (SI)).20 Importantly, even enone 14 derived from
3-furaldehyde could be utilized in the asymmetric dearomatic
Diels−Alder reactions with dienophiles 10 at rt, and chiral
tetrahydrobenzofurans 15a and 15b incorporating a spiroox-
indole skeleton were constructed in high yields and with
excellent stereoselectivity. The absolute configuration of
cycloadduct 15b was determined by X-ray analysis after
conversion to furan derivative 16, as outlined in Scheme 5.21
It should be noted that the analogous enones derived from 2-
furaldehyde, thiophene-2- or 3-aldehydes have not been
successfully used through the same dearomatic cycloaddition
strategy (see the SI).
and chemoselectively obtained under the mild catalytic
hydrogenation with Raney Ni (Scheme 6).
Scheme 6. Hydrogenation of Diels−Alder Product 6d
In summary, a simple and highly stereoselective dearomatic
Diels−Alder cycloaddition reaction with diverse five-membered
heteroarenes has been developed. This method relies on in situ
generation of formal trienamine species from a variety of enone
substrates properly tethered to a benzofuran, benzothiophene,
or even furan ring, which raises the HOMO-energy of the
relatively inert heteroaromatic diene moiety and promotes the
subsequent pericyclic reactions with electron-deficient dien-
ophiles. A spectrum of fused or spiro hydrodibenzofuran,
Finally, the Diels−Alder cycloadduct 6d was submitted to
further transformation. The multifunctional hexahydrodibenzo-
furan 17 with five continuous stereogenic centers was smoothly
C
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Ricci, A. Angew. Chem., Int. Ed. 2008, 47, 9236. (b) Wang, X.-F.; Chen,
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(c) Zheng, C.; Li, Y.; Zhang, J.; Chen, X.; Chai, Z.; Ma, W.; Zhao, G.
hydrodibenzothiophene, and tetrahydrobenzofurans with highly
structural complexity were efficiently constructed in good yields
and with moderate to excellent enantioselectivity, which might
find further application in medicinal chemistry and biological
studies. We also hope that the HOMO-activation strategy
presented in this work would provide more opportunities to
develop new asymmetric reactions with diverse heteroarenes.
Chem.Eur. J. 2010, 16, 5853. (d) Tan, B.; Hernan
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ASSOCIATED CONTENT
* Supporting Information
Complete experimental procedures and characterization of new
products, CIF file of enantiopure product 16, NMR spectra,
and HPLC chromatograms. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
(9) (a) Liu, Y.; Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am.
Chem. Soc. 2011, 133, 15212. (b) Liu, Y.; Nappi, M.; Escudero-Adan
E. C.; Melchiorre, P. Org. Lett. 2012, 14, 1310.
́
,
AUTHOR INFORMATION
■
(10) (a) Jiang, H.; Rodríguez-Escrich, C.; Johansen, T. K.; Davis, R.
L.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2012, 51, 10271.
(b) Rodríguez-Escrich, C.; Davis, R. L.; Jiang, H.; Stiller, J.;
Johansen, T. K.; Jørgensen, K. A. Chem.Eur. J. 2013, 19, 2932.
(11) Li, J.-L.; Yue, C.-Z.; Chen, P.-Q.; Xiao, Y.-C.; Chen, Y.-C. Angew.
Chem., Int. Ed. 2014, 53, 5449.
Corresponding Author
*E-mail: ycchen@scu.edu.cn.
Notes
The authors declare no competing financial interest.
(12) For a review, see: Li, J.-L.; Liu, T.-Y.; Chen, Y.-C. Acc. Chem. Res.
2012, 45, 1491.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the NSFC
(21122056, 21372160, and 21321061), 973 Program
(2010CB833300), and Program for Changjiang Scholars and
Innovative Research Team in University (IRT13031).
(13) (a) For trienamine catalysis with 2,4-dienones, see: Xiong, X.-
F.; Zhou, Q.; Gu, J.; Dong, L.; Liu, T.-Y.; Chen, Y.-C. Angew. Chem.,
Int. Ed. 2012, 51, 4401. (b) With cyclic 2,5-dienones, see: Feng, X.;
Zhou, Z.; Ma, C.; Yin, X.; Li, R.; Dong, L.; Chen, Y.-C. Angew. Chem.,
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J. 2014, 20, 2145.
(14) For reviews of cinchona-based primary aminocatalysis, see:
(a) Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 9748. (b) Jiang, L.;
Chen, Y.-C. Catal. Sci. Technol. 2011, 1, 354.
(15) For more screening conditions, see the Supporting Information.
(16) The cycloaddition of 5c and 3a also occurred by using DABCO
as the catalyst, probably via a trienol intermediate after deprotonation.
Changing the N-protecting group to Bn or Boc has no benefit for the
Diels−Alder reaction.
(17) Chen, P.-Q.; Xiao, Y.-C.; Yue, C.-Z.; Chen, Y.-C. Org. Chem.
Front. 2014, 1, 490.
(18) (a) Jia, Z.-J.; Jiang, H.; Li, J.-L.; Gschwend, B.; Li, Q.-Z.; Yin, X.;
Grouleff, J.; Chen, Y.-C.; Jørgensen, K. A. J. Am. Chem. Soc. 2011, 133,
5053. (b) Zhou, Q.-Q.; Yuan, X.; Xiao, Y.-C.; Dong, L.; Chen, Y.-C.
Tetrahedron 2013, 69, 10369.
(19) For a review on the catalytic synthesis of chiral spirocyclic
compounds, see: Rios, R. Chem. Soc. Rev. 2012, 41, 1060.
(20) (a) Jia, Z.-J.; Zhou, Q.; Zhou, Q.-Q.; Chen, P.-Q.; Chen, Y.-C.
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(21) The absolute configuration of other cycloadducts was assigned
on the basis of a presumed common catalytic mechanism similar to
that of cycloadduct 15b. See the Supporting Information.
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