B(C6F5)3: A New Class of Strong and Bulky Lewis Acid for Exo-Selective Intermolecular Diels-Alder Reactions of Unreactive Acyclic Dienes with α,β-Enals

Article abstract of DOI:10.1021/acs.orglett.5b02066

Lewis acid B(C₆F₅)₃ catalyzed the Diels-Alder reactions of multisubstituted open-chain dienes and α,β-enals to afford the desired products with high exo-selectivities are reported. The substituent effect of the dienes and dienophiles on the products stereoselectivity was thoroughly investigated, and it was found that most of the desired exo-Diels-Alder products could be obtained in good yields and with high exo-stereoselectivities.

Full text of DOI:10.1021/acs.orglett.5b02066

Letter
pubs.acs.org/OrgLett
B(C6F5)3: A New Class of Strong and Bulky Lewis Acid for Exo-
Selective Intermolecular Diels−Alder Reactions of Unreactive Acyclic
Dienes with α,β-Enals
Jia-Hui Zhou,† Bing Jiang,† Fei-Fan Meng,† Yun-He Xu,*,† and Teck-Peng Loh*,†,‡
†Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
S
* Supporting Information
ABSTRACT: Lewis acid B(C6F5)3 catalyzed the Diels−Alder
reactions of multisubstituted open-chain dienes and α,β-enals to
afford the desired products with high exo-selectivities are reported.
The substituent effect of the dienes and dienophiles on the product’s
stereoselectivity was thoroughly investigated, and it was found that
most of the desired exo-Diels−Alder products could be obtained in
good yields and with high exo-stereoselectivities.
he Lewis acid catalyzed intermolecular Diels−Alder (DA)
amino-3-siloxy dienes,7 Danishefsky dienes,8 silyloxy dienes,9
silylated dienes,10 or bulky dienes11 with dienophiles such as
carbene complexes,12 highly substituted dienophiles,13 to the
best of our knowledge, the intermolecular exo-selective DA
reactions of unreactive simple open-chain dienes with α,β-
unsaturated enals have rarely been reported.9,14 The need to
use special substrates such as reactive dienes as well as poor
selectivities observed in some of these cases highlight the huge
potential for further development in this field.
Therefore, there is a need to discover a new and more
reactive catalyst that can catalyze the exo-DA reaction of less
reactive open-chain dienes and dienophiles. We envisage that a
bulky Lewis acid will steer the reaction to the exo pathway
instead of the usual endo pathway due to unfavorable steric
repulsion between the Lewis acid and the diene. On the basis of
this thinking, we embarked on the search for highly exo-
selective intermolecular Diels−Alder reaction using open-chain
dienes and simple α,β-unsaturated enals as dienophiles.
T
reaction is one of the most important organic trans-
formations in organic synthesis as it provides one of the most
efficient entries to six-membered ring-containing compounds.1
Due to the many methods available for the control of relative
and absolute stereochemistries, this method is now widely used
for the construction of complex natural products and
pharmaceuticals.2 Despite the fact that it is often employed in
organic synthesis, there are still reactivity and selectivity
problems associated with the less reactive multisubstituted
open-chain dienes.3 In most cases, the endo-selective products
were obtained as the major products due to favorable secondary
orbital interactions.4 Therefore, a major challenge in this area is
the design of a general method to obtain the highly exo-
selective DA reaction for this type of system that can lead to
different stereochemical control in the resulting products
(Scheme 1).5
Except for a few special cases of Diels−Alder reactions that
employed highly reactive dienes such as cyclopentadienes,6 1-
Initial screening of the reaction using diene 1a with the easily
accessible E-isomer of dienophile 2a (Table 1) revealed that
when a variety of common Lewis acids such as In(OTf)3, InBr3,
FeCl3, Sc(OTf)3, and Yb(OTf)3 were employed (Table 1,
entries 1−5), no reaction was observed. On the other hand,
using the more reactive Lewis acids such as BF3·OEt2, SnCl4,15
and AlCl3 led to the formation of the desired products in low to
moderate to good yields. As expected, the endo-selective [4 + 2]
Diels−Alder product was obtained as the major product. To
test our hypothesis using bulky Lewis acid, we first explored the
use of bulky aluminum tris(2,6-diphenylphenoxide) (ATPH) as
catalyst as previously reported by Yamamoto. While this
catalyst works with reactive dienes, no reaction was observed in
Scheme 1. Diels−Alder Reaction of Open-Chain Dienes and
Enals
Received: July 19, 2015
© XXXX American Chemical Society
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a,b
Table 1. Diels−Alder Studies Using Different Lewis Acids
Table 2. Substituent Effect of Diene in Diels−Alder Reaction
a
Catalyzed by B(C6F5)3
c
entry
Lewis cid
yield (%) (3aa:3aa′:3aa″)
1
2
3
4
5
6
7
8
9
10
ln(OTf)3
ln Br3
FeCl3
Yb(OTf)3
Sc(OTf)3
ATPH6b
SnCl4
65 (29:57:14)
23 (30:70:0)
99 (0:24:76)
AlCl3
BF3 OEt2
B(C6F5)3
d
e
f
80 (88:12:0) ; 73 ; 55
a
Diels−Alder reactions were run with 0.5 equiv of Lewis acid, 1 equiv
of dienophile (0.2 mmol), and 2.0 equiv of diene (0.4 mmol) under N2
b
atmosphere at −78 °C. Isolated yield of exo and endo isomers.
c
Diastereomeric ratios were based on 1H and 13C NMR analysis.
d
1
88:12 dr ratio of 3aa and 3aa′ was determined from the crude H
e,f
NMR spectra of the reaction. Conversion yield determined
according to H NMR spectra analysis (0.2 equiv and 0.1 equiv of
1
B(C6F5)3 was used, respectively).
this DA reaction with open-chain dienes even when a
stoichiometric amount of the Lewis acid was used. Therefore,
a more reactive bulky Lewis acid is needed to effect this
transformation. We decided to explore the use of B(C6F5)3, a
bulky Lewis acid used widely in the synthesis of frustrated
Lewis pairs (FLP).16 To our delight, exo-selective compound
3aa could be obtained as the major product in high yield when
50 mol % of B(C6F5)3 was used in this reaction (Table 1, entry
10).
With this exciting discovery, we then turned our attention to
investigate the substituent effect of the dienophiles and
dienes.17 It was found that no desired product could be
detected when the bulky silyl-protected enal 2b was applied in
the reaction (Table 2, entry 2). In addition, in the case of diene
1b, with a linear alkyl-substituted diene, a good yield with a
dominant exo-selective isomer could be obtained under the
standard reaction conditions (Table 2, entry 3). The diene with
an acetal protecting group resulted in a mixture of exo- and
endo-selective products in 37% yield and with a 60/40 ratio
(Table 2, entry 4). Further screening showed that when the
diene’s protecting group was changed to a triisopropylsilyl
group, the product of 3da was obtained in high yield and with
good exo stereoselectivity (Table 2, entry 5). To our delight,
excellent yield and exo/endo stereoselectivity of the DA product
could be observed when the tert-butyldiphenylsilyl was applied
as the protecting group (Table 2, entry 6). It was also noted
that the removal of the methyl group at the C-1 position of the
diene would slightly decrease the product’s exo/endo stereo-
selectivity (Table 2, entry 7).
Further exploration of the substrate scopes using various
dienes and dienophiles were carried out (Figure 1). We are
pleased to find that all of the reactive β-substituted enals and
multisubstituted dienes worked well to afford the desired
products in moderate to good yields. First, different substituted
enals were tested as the dienophiles. Comparing the results, it
was found that the enals with electron-deficient substituents at
the β-position (Figure 1, 3ea) could react easily in the DA
a
Diels−Alder reactions were run with 0.1 equiv of B(C6F5)3, 1 equiv
of dienophile (0.2 mmol), and 2.0 equiv of diene (0.4 mmol) in DCM
b
under N2 atmosphere at −78 °C for 48 h. Isolated yield of exo and
c
endo isomers. Diastereomeric ratios were based on 1H NMR analyses.
d
Conversion yield was determined according to 1H NMR spectral
analysis.
reaction. However, only moderate yields but high exo-
selectivities of the desired products could be obtained by
using enals with an electron-rich group (Figure 1, 3ed).
Moreover, the α,α,β-trisubstituted enal with a more bulky
protecting group also can be used in the DA cycloaddition
reaction to give the corresponding product 3ag (the relative
configuration was determined by X-ray crystallographic
analysis) in an acceptable yield. Next, various dienes were
also synthesized and examined in this reaction. It was observed
that the dienes with linear alkyl or alkenyl substituents all could
afford the products in high yields with high selectivities when
reacted with enal 2a (Figure 1, 3ga, 3ha, 3ia, 3ja, and 3ka).
Furthermore, the replacement of the 2-Me on the diene with
phenyl group (Figure 1, 3ma and 3na) led to significantly
decreased yields but without damaging the exo-selectivities of
the products (the relative configuration of 3ma was determined
by X-ray crystallographic analysis).
B
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Lewis acid to effect abnormal selectivity in other organic
transformations as well as application of this exo-Diels−Alder
reactions for the synthesis of complex molecules are in
progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02066.
Experimental procedures and spectral data for all new
compounds (1H NMR, 13C NMR, HRMS) (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xyh0709@ustc.edu.cn.
*E-mail: teckpeng@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the funding support of National
Science Foundation for Young Scientists of China (21202156),
the National Natural Science Foundation of China (21372210),
and the State Key Program of National Natural Science
Foundation of China (21432009). We also thank Nanyang
Technology University for financial support of this research.
The authors are grateful to Mr. Koh Peng Fei Jackson
(Nanyang Technological University, Singapore) for his careful
proofreading of the final manuscript.
Figure 1. Multisubstituted open-chain dienes and dienophiles in
Diels−Alder reactions catalyzed by B(C6F5)3. (a) Diels−Alder
reactions were run with 0.1 equiv of B(C6F5)3, 1 equiv of dienophile
(0.2 mmol), and 2.0 equiv of diene (0.4 mmol) under N2 atmosphere
for 48 h. (b) Isolated yield of exo and endo isomers. (c) Diastereomeric
1
ratios were based on H NMR analysis. (d) Diels−Alder reactions
were run with 0.5 equiv of Lewis acid.
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Diels−Alder Reaction
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