A concise assembly of electron-deficient 2,4-dienes and 2,4-dienals: Regio- and stereoselective exo-Diels-Alder and redox reactions through sequential amine and carbene catalysis

Article abstract of DOI:10.1002/anie.201208349

Ideal relay catalysis: A γ,δ-regioselective anomalous exo-Diels-Alder reaction with electron-deficient β-substituted 2,4-dienes and 2,4-dienals has been developed by using trienamine activation. The resulting multifunctional cycloadducts contain perfectly positioned functional groups, thereby facilitating a 1,5-hydride transfer from the C-H group of an aldehyde to an activated alkene under sequential catalysis of a carbene (see scheme). Copyright

Full text of DOI:10.1002/anie.201208349

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Angewandte
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DOI: 10.1002/anie.201208349
Asymmetric Synthesis
A Concise Assembly of Electron-Deficient 2,4-Dienes and 2,4-Dienals:
Regio- and Stereoselective exo-Diels–Alder and Redox Reactions
through Sequential Amine and Carbene Catalysis**
Chao Ma, Zhi-Jun Jia, Jing-Xin Liu, Qing-Qing Zhou, Lin Dong, and Ying-Chun Chen*
The use of a hydride donor for transfer hydrogenation of
electrophilic carbonyl, imine, or activated alkene groups has
been established as one of the most powerful tools in organic
synthesis. A number of hydride donors, such as alcohols,
formic acid, or Hantzsch esters, have been successfully
applied under either metal- or organocatalysis.[1] Interestingly,
the inherent electrophilic aldehyde group that contains a
À
C H bond, has been also elegantly used in rhodium-catalyzed
hydroacylation reactions through C–H activation.[2] More
importantly, in 2006, Scheidt and co-workers firstly reported
that organic N-heterocyclic carbenes (NHCs) could mediate
the hydroacylation of activated ketones with aldehydes
Scheme 1. Proposed Diels–Alder and redox reactions through sequen-
tial amine and carbene catalysis. EWG=electron-withdrawing group.
through hydride transfer,[3] rather than the traditional acyl
anion transfer pathway (benzoin reaction).[4] This protocol
was compatible to a variety of aldehydes and activated
ketones;[5] nevertheless, to our knowledge, there is still no
report on the conjugate reduction of activated alkenes
through hydride transfer from aldehyde compounds under
the catalysis of NHCs, probably because the acyl anion
transfer version (Stetter reaction) is more competitive.[4]
Recently, we and other groups disclosed a new trienamine
reactive mode of 2,4-dienal substrates, which demonstrated to
be successful in asymmetric Diels–Alder reactions with
diverse electron-deficient dienophiles through HOMO acti-
vation.[6] Such a catalytic tool is tolerant to a broad spectrum
of functional groups, thus giving versatile synthetic oppor-
tunities to construct chiral compounds with high molecular
complexity. We envisaged that a g,d-regioselective Diels–
Alder cycloaddition of electron-deficient 2,4-dienes with 2,4-
dienals might be developed by using trienamine activation, as
proposed in Scheme 1. Thus, the obtained multifunctional
cycloadducts could serve as ideal substrates for the study of
a carbene-catalyzed conjugate reduction through 1,5-hydride
transfer from an aldehyde group.[7] Nevertheless, such an
unprecedented sequence might be highly challenging,
because the perfect control on regio-, chemo-, and stereose-
lectivity must be achieved in both amine- and carbene-
catalyzed steps.[8]
The initial reaction of electron-deficient 2,4-diene 2a from
cinnamaldehyde and malononitrile and 2,4-dienal 3a in the
presence of chiral amine 1a[9] (Scheme 2) was complicated
owing to poor regioselectivity and other reaction patterns,[10]
[*] C. Ma, Z.-J. Jia, J.-X. Liu, Q.-Q. Zhou, Dr. L. Dong, Prof. Dr. Y.-C. 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)
E-mail: ycchenhuaxi@yahoo.com.cn
Prof. Dr. Y.-C. Chen
College of Pharmacy, Third Military Medical University
Chongqing, 400038 (China)
[**] We are grateful for financial support from the NSFC (20972101,
21125206 and 21021001), and the National Basic Research Program
of China (973 Program, 2010CB833300).
Scheme 2. Rational design of electron-deficient 2,4-diene substrates to
realize g,d-regioselective Diels–Alder (DA) and redox reactions.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; OFBA=o-fluorobenzoic
acid; TMS=trimethylsilyl; TBS=tert-butyldimethylsilyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208349.
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Table 1: Substrate scope and limitations.[a]
and product 4 was mainly isolated but still in a very low yield.
We reasoned that g,d-regioselectivity might be facilitated by
introducing a substituent at the b-position to increase steric
hindrance. In fact, the expected cycloaddition took place
smoothly with 2,4-diene 2b, but a domino intramolecular
vinylogous[11] aldol reaction occurred to give the bicyclic
product 5 as a diastereomeric mixture.[12] Consequently, the b-
phenyl-substituted 2,4-diene 2c without an active g-C–H
group was employed, and the g,d-regioselective cycloadduct
6a was pleasingly produced in a high yield in 1,4-dioxane, with
exclusive anomalous exo control even at higher temperature.
As a result, the bulky benzylidenemalononitrile motif would
not only act as a highly electron-withdrawing group, but also
significantly contribute to abnormal exo selectivity, probably
because of steric reason.[13] More importantly, it was found
that Scheidtꢀs triazolium salt 7 was a good carbene precursor
for the designed 1,5-hydride transfer reaction.[12] The diaste-
reoselective conjugate reduction of activated alkene 6a took
place efficiently in methanol, and ester product 8a was
obtained as a single diastereomer. It should be noted that the
Stetter reaction product was not detected under the current
catalytic conditions. Therefore, the presence of another b-
substituent on the skeleton of the 2,4-diene is crucial for the
success of both g,d-regioselective Diels–Alder and redox
reactions, probably because the generation of an all-carbon
quaternary center is unfavorable in the other reaction pattern.
After having established the Diels–Alder and intramo-
lecular 1,5-hydride transfer pathways of 2,4-diene 2c and 2,4-
dienal 3a, we turned our attention to develop a one-pot
asymmetric version. We found that the reaction failed when
simultaneously combining amine and carbene catalysis
together; however, the later redox reaction could proceed
smoothly by directly adding triazolium salt 7 (20 mol%),
DBU (50 mol%), and methanol to the finished Diels–Alder
solution without further workup.[12] Salicylic acid was found to
be a superior additive in the Diels–Alder reaction step, and
a remarkable ee value (98%) was obtained for product 8a by
employing the bulky amine 1b (Scheme 2) developed in our
group (Table 1).[14]
Consequently, we explored the reactions of a variety of
2,4-dienes 2 and 2,4-dienals 3 in the presence of amine 1b in
combination with salicylic acid. Then the intramolecular
redox reaction was directly carried out to give the ester
products 8. The results are summarized in Table 1. The one-
pot Diels–Alder/redox sequence exhibited excellent diaste-
reoselectivity, and a single diastereomer was generally
produced. 2,4-Dienes 2 bearing diverse d-aryl groups with
either electron-donating or -withdrawing substitutions or
heteroaryl groups were well-tolerated in reactions with 2,4-
dienal 3a, and the corresponding products 8a–8k were
produced with outstanding ee values and moderate to good
yields (Table 1, entries 1–11). Notably, 2,4-dienes bearing
branched alkyl groups at d-position were also compatible,
giving the expected products 8l and 8m with good data
(Table 1, entries 12 and 13).[15] Furthermore, diverse aryl or
heteroaryl groups were tolerated at the b-position of 2,4-
dienes 2, and products 8n–8q were obtained in similar good
results (Table 1, entries 14–17). Notably, the domino vinyl-
ogous aldol reaction as that of 2b (Scheme 2) did not happen
Entry Product 8
t
Yield ee
[h][b] [%][c] [%][d]
1
8a R=4-BrC6H4
12 72
15 73
24 75
12 72
98
98[e]
99
96
98
99
97
97
96
96
96
96
92
2
3
4
8b R=2-ClC6H4
8c R=3-ClC6H4
8d R=4-CF3C6H4
5
6
7
8e R=4-Br-2-FC6H3 12 66
8 f R=Ph 20 78
8g R=4-MeOC6H4 40 61
8
9
10
11
12
13
8h R=1-naphthyl
8i R=2-furyl
8j R=2-thienyl
8k R=2-pyridyl
8l R=iPr
40 59
60 76
60 69
60 69
17 59
48 52
8m R=cHex
14
15
16
17
18
19
8n R1 =4-ClC6H4
40 59
97
93
98
99
99
99
8o R1 =3,4-Cl2C6H3 22 55
8p R1 =4-MeC6H4 40 72
8q R1 =2-furyl
8r R1 =iPr
40 56
40 61
48 58
8s R1 =cHex
20
21
22
8t R2 =R3 =H
24 65
94
88
98
8u R2 =H, R3 =Me 20 62
8v R2 =Et, R3 =H
60 61
98/
99
23
8w (d.r.=2:1)
24 67
[a] Reactions were performed with diene 2 (0.12 mmol), 2,4-dienal 3
(0.1 mmol), amine 1b (20 mol%), and salicylic acid (SA; 20 mol%) in
dioxane (0.5 mL) at 508C. After completion, salt 7 (20 mol%), DBU
(50 mol%), 4 ꢀ MS (30 mg), and MeOH (0.5 mL) were added at 08C and
stirred for 30 min. [b] For DA reaction step. [c] Yield of isolated product
for two steps. [d] Determined by HPLC analysis using a chiral stationary
phase. [e] The absolute configuration of 8b was determined by X-ray
analysis, see the Supporting Information.[16] The other products were
assigned by analogy.
for 2,4-dienes with a branched alkyl group at the b-position.
Thus, the following carbene-mediated redox reaction could be
conducted to provide products 8r and 8s, also in exclusive
diastereocontrol (Table 1, entries 18 and 19). Moreover, a few
2,4-dienals were further tested in reactions with 2,4-diene 2c.
Good data were afforded for products 8t–8v (Table 1,
entries 20–22), but a low d.r. value was observed for product
8w from 4-phenyl-2,4-heptadienal in the redox step, probably
because of the steric effect of the additional methyl substitu-
ent; nevertheless, the ee values were excellent for both
separable diastereomers (Table 1, entry 23).
The g,d-regioselective Diels–Alder reaction of a 2,4-diene
9 from chalcone and Meldrumꢀs acid with 2,4-dienal 3a also
proceeded smoothly catalyzed by amine 1b and salicylic acid,
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thereby leading to cycloadduct 10 in excellent diastereo- and
enantioselectivity and with good yield. The carbene-mediated
intramolecular redox reaction also took place efficiently,
giving two separable diastereomers 11a and 11b in almost the
same ratio. In comparison with the former substrates, such
a low diastereoselectivity may be ascribed to the different
structure of the Meldrumꢀs acid motif. As a result, more
stereodivergency could be introduced with this type of 2,4-
dienes (Scheme 3).[17]
dented 1,5-hydride transfer from the C–H group of an
aldehyde to an activated alkene under sequential catalysis
of a carbene. A spectrum of diversely structured chiral
products have been efficiently produced, thus allowing the
concise constructions of polycyclic frameworks with high
chemical and stereogenic complexity. Currently the develop-
ment of an asymmetric version of hydride transfer with
aldehydes is under investigation.
Received: October 17, 2012
Published online: November 29, 2012
Keywords: asymmetric synthesis · carbene catalysis ·
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cycloaddition · redox reactions · trienamine
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Scheme 4. Constructions of complex polycyclic structures.
mCPBA=m-chloroperbenzoic acid.
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=
intermediate 12 could be hydrogenated to give a diastereo-
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cycloaddition with electron-deficient b-substituted 2,4-dienes
and 2,4-dienals by using a trienamine activation strategy. The
resulting multifunctional cycloadducts contain perfectly posi-
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[15] 2,4-Dienes with a linear alkyl group at the d-position have not
been produced yet.
[16] CCDC 909394 (8b) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[17] For exploration on more electron-deficient 2,4-diene substrates,
see the Supporting Information.
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