Cross-conjugated Trienamine Catalysis with α′-Alkylidene 2-Cyclohexenones: Application in β,γ-Regioselective Aza-Diels–Alder Reaction

Article abstract of DOI:10.1002/chem.201605606

Endo-type cross-conjugated trienamines between highly congested α′-alkylidene 2-cyclohexenones and a chiral primary amine catalyst serve as HOMO-raised dienophiles in inverse-electron-demand aza-Diels–Alder cycloadditions with a number of 1-azadiene substrates. The reactions exhibit exclusive β,γ-regioselectivity, and multifunctional products with high molecular complexity are efficiently constructed in excellent diastereo- and enantioselectivity (>19:1 d.r., up to 99 % ee).

Full text of DOI:10.1002/chem.201605606

A Journal of
Accepted Article
Title: Cross-conjugated Trienamine Catalysis with α´-Alkylidene 2-
Cyclohexenones: Application in β,γ-Regioselective Aza-Diels-
Alder Reaction
Authors: Ying-Chun Chen, Zhi Zhou, Zhou-Xiang Wang, Qin Ouyang,
Wei Xiao, and Wei Du
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To be cited as: Chem. Eur. J. 10.1002/chem.201605606
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Cross-conjugated Trienamine Catalysis with -Alkylidene 2-
Cyclohexenones: Application in ,-Regioselective Aza-
DielsAlder Reaction
Zhi Zhou,[a] Zhou-Xiang Wang,[a] Qin Ouyang,[b] Wei Xiao,[a] Wei Du,[a] and Ying-Chun Chen*[a,b]
Dedication ((optional))
Abstract: Endo-type cross-conjugated trienamines between highly
congested -alkylidene 2-cyclohexenones and a chiral primary amine
catalyst serve as HOMO-raised dienophiles in inverse-electron-
demand aza-DielsAlder cycloadditions with a number of 1-azadiene
substrates. The reactions exhibit exclusive ,-regioselectivity, and
multifunctional products with high molecular complexity are efficiently
constructed in excellent diastereo- and enantioselectivity (>19:1 dr,
up to 99% ee).
the application of structurally diverse polyunsaturated ketone
substrates may have high potentials to uncover new reaction
modes via amine-based catalysis.
To the best of our knowledge, the direct ,-regioselective
functionalization of cyclic enone substrates via aminocatalysis
has been less explored.[7] Recently, we successfully established
the diversified intermolecular asymmetric cycloaddition reactions
of -alkylidene 2-cyclopentenones catalyzed by cinchona-
derived primary amines. The ,-regioselective [6+2] and ,-
regioselective [2+2] cycloadditions were developed through the
in situ generation of formal 4-aminofulvene intermediates
(Scheme 1, d).[8] Inspired by this success, we envisaged that the
cross-trienamine intermediates generated from the analogous -
Introduction
Over the past years, asymmetric trienamine catalysis of
chiral amines has been established as a powerful protocol
for the remote functionalization of polyconjugated carbonyl
compounds in a highly stereoselective manner.[1] While
,-
regioselective cycloaddition reactions were commonly
observed for 2,4-dienal molecules,[2,3] the structural
complexity of the analogous dienone substrates enables
more versatile strategies for the development of a variety of
alkylidene 2-cyclohexenones and
a primary amine would
participate in different kinds of regioselective cycloaddition
reactions, either in an endo-I or an exo-II pattern. As a result, the
HOMO-raised ,- or ,-C=C bond might perform as an ideal
dienophile partner in an inverse-electron-demand DielsAlder-
type cycloaddition reaction with an electron-deficient diene,[9,10]
successfully furnishing a previously undisclosed reactive version
with cyclic enone substances (Scheme 1).
regioselective reactions. The similar
,-regioselective
normal-electron-demand Diels Alder cycloadditions as

those of 2,4-dienals have been furnished with linear 2,4- or
3,5-dienones through the formation of extended trienamine
species (Scheme 1, a).[4] In addition, the application of
interrupted
-regioselective inverse-electron-demand cycloadditions or
-regioselective bisvinylogous additions (Scheme 1, b).[5] In
-allylic cyclic enones could accomplish either
,

contrast, cross-conjugated trienamine intermediates would
be preferably generated with cyclic 2,4-dienone materials in
the presence of a primary amine catalyst, and ,-
regioselective formal [4+2] cycloadditions would occur with
electron-deficient dienophiles (Scheme 1, c).[6] As a result,
[a]
[b]
Z. Zhou, Z.-X. Wang, W. Xiao, Dr. W. Du, Prof. Dr. Y.-C. Chen
Department of Medicinal Chemistry
West China School of Pharmacy
Sichuan University
Chengdu, 610041 (China)
Fax: (+) 86 28 85502609
E-mail: ycchen@scu.edu.cn
Dr. Q. Ouyang, Prof. Dr. Y.-C. Chen
College of Pharmacy
Scheme 1. Diverse trienamine modes of various dienone substrates.
Results and Discussion
Third Military Medical University
Chongqing, 400038 (China)
Consequently, the initial screening studies were
conducted with readily available -propylidene cyclohexen-
2-one[11] 1a and a variety of electron-deficient dienes. It was
pleasing that 3-styryl-1,2-benzoisothiazole-1,1-dioxide[12] 2a
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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catalyst C3 could not catalyze the reaction (Table 1, entry
3).[15] Subsequently, an array of acid additives were tested in
Table 1. Screening studies of [4+2] cycloaddition of -propylidene
cyclohexen-2-one 1a and 1-azadiene 2a[a]
combination with amine C1 (Table 1, entries 48), and
salicylic acid A3 gave the best results (Table 1, entry 5).
Later, a few solvents were explored with amine C1 and acid
A3 (Table 1, entries 912), but inferior results were generally
obtained, and even no reaction happened in THF (Table 1,
entry 12). We further investigated the reaction with amine C2
and salicylic acid A3, and a better ee value was also obtained
(Table 1, entry 13). Finally, it was found that the reaction
proceeded smoothly at a larger scale catalyzed by C1 and
A3, and the similar good data were attained (Table 1, entry
14).
With the optimized catalytic conditions in hand, we then
investigated a variety of -alkylidene cyclic ketones and 3-
vinyl-1,2-benzoisothiazole-1,1-dioxides under the catalysis
of amine C1 and acid A3. The results are summarized in
Table 2. At first, a number of cyclohexen-2-ones bearing
variously structured -alkylidene substitutions were
explored in reactions with 1-azadiene 2a. It was pleasing that
Entry
1
1
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CHCl3
Acid
A1
A1
A1
A2
A3
A4
A5
A6
A3
A3
A3
A3
A3
A3
Yield (%)[b]
62
ee (%)[c]
86
2,2
could be well tolerated, and excellent enantioselectivity was
generally obtained (Table 2, entries 1 10). In addition, 2,2-
-dienones with either linear or branched -alkyl groups
C1
C2
C3
C1
C1
C1
C1
C1
C1
C1
C1
C1
C2
C1

2
65
73

dienones with -aryl or -heteroaryl substitutions also
exhibited comparable reactivity, and high to outstanding
3
Trace
63
enantiocontrol was observed (Table 2, entries 11
14). It was
4
85
noteworthy that a 2,2 -dienone bearing a -methyl group still


showed good reactivity, and product 3o with a quaternary
chiral center was smoothly produced (Table 2, entry 15).
Nevertheless, the analagous cyclopenten-2-ones generally
showed much lower reactivity probably due to the more
congested structures, and only a low yield with a moderate
ee value was obtained for an -isopropylidene substrate
(Table 2, entry 16). On the other hand, an array of 1-
azadienes with diverse aryl or heteroaryl groups were further
explored, and the corresponding cycloadducts were
produced in high to excellent enantioselectivity (Table 2,
5
76
93
6
74
92
7
73
90
8
59
78
9
71
86
10
11
12
13
14[d]
PhCF3
78
89
m-Xylene
THF
68
91
entries 1727). Unfortunately, 1-azadienes with alkyl
substitutions failed to participate in the cycloaddition
reactions. Moreover, a few substrates were studied by the
catalysis of amine C2 and acid A3, and the cycloadducts with
an opposite configuration were generally furnished with good
enantioselectivity (data in parentheses).
Trace
72

Toluene
Toluene
83
92
70
[a] Unless noted otherwise, reactions were performed with 2,2-dienone1a
(0.2 mmol), 1-azadiene 2a (0.1 mmol), amine C (20 mol%) and acid A (40
mol%) in solvent (1.0 mL) at 50 C for 72 h. [b] Isolated yield. [c] By HPLC
analysis on a chiral stationary phase; dr >19:1 by 1H NMR analysis. [d] At
0.5 mmol scale (for 2a).
Table 2. Substrate scope and limitations of [4+2] cycloadditions[a]
was a suitable partner, and the desired aza-DielsAlder
cycloaddition[13] occurred smoothly in toluene at 50 °C, using
9-amino-9-deoxyepiquinine C1 and benzoic acid A1 as the
catalysts.[14] In addition, the reaction exhibited exclusive
,-
Entry
R, R1
Et, H
Me, H
R2, R3
Ph, H
Ph, H
Yield (%)[b]
3a, 76 (72)
3b, 75
ee (%)[c]
93 (83)
81
regioselectivity and endo-selectivity, and cycloadduct 3a was
isolated in 62% yield after 72 h, along with a good ee value
(Table 1, entry 1). 9-Amino-9-deoxyepiquinidine C2 gave the
product with an opposite configuration in moderate
enantiocontrol (Table 1, entry 2). Nevertheless, bifunctional
1
2
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(Table 3, entries 1
analogue showed comparable reactivity, and an excellent ee
value was obtained for product 5h (Table 3, entry 8).

7). In addition, the benzo[d]thiazole
3
nPr, H
Ph, H
3c, 78 (73)
3d, 76
3e, 80
96 (85)
93
4
nPent, H
iBu, H
Ph, H
5
Ph, H
95
6
PhCH2CH2, H
iPr, H
Ph, H
3f, 83 (72)
3g, 82
3h, 81 (74)
3i, 78
91 (81)
97
Table 3. Asymmetric aza-DielsAlder reaction of benzo[d]oxazole- or
benzo[d]thiazole-based 1-azadienes 4[a]
7
Ph, H
8
3-Pent, H
cPent, H
cHex, H
Ph, H
Ph, H
98 (94)
93
9
Ph, H
10
11
12
13
14
15
16[f]
17
18
19
20
21
22
23
24
25
26
27
Ph, H
3j, 82 (78)
3k, 82
99 (91)
95[d,e]
86[e]
90[e]
86[e]
89
Ph, H
4-MeOC6H4, H
4-NO2C6H4, H
2-Thienyl, H
Ph, Me
Ph, H
3l, 78
Entry
X
O
O
O
O
O
O
O
S
R1
Yield (%)[b]
5a, 76
5b, 76
5c, 75
5d, 72
5e, 70
5f, 78
ee (%)[c]
92
Ph, H
3m, 76
3n, 72
3o, 72
3p, 36
3q, 81
3r, 76
1
2
3
4
5
6
7
8
Ph
Ph, H
4-FC6H4
3-BrC6H4
4-MeC6H4
2-MeOC6H4
2-Thienyl
iPr
92
Ph, H
91
iPr, H
Ph, H
77
91
iBu, H
3-ClC6H4, H
2-F-4-BrC6H3, H
4-BrC6H4, H
3-MeC6H4, H
2-MeOC6H4, H
4-MeOC6H4, H
2-Thienyl, H
4-BrC6H4, H
4-MeOC6H4, H
Ph, 5,7-Me2
Ph, 6-Cl
90
89
iBu, H
92
90
iBu, H
3s, 85
90
5g, 74
5h, 65
93
iBu, H
3t, 80
91
Ph
98
iBu, H
3u, 76
3v, 78
95
[a] Reactions were performed with 2,2-dienone 1 (0.2 mmol), 1-azadiene 4
(0.1 mmol), amine C1 (20 mol%) and acid A3 (40 mol%) in toluene (1.0 mL)
at 35 C for 48 h. [b] Isolated yield. [c] Determined by HPLC analysis on a
chiral stationary phase; dr >19:1 by 1H NMR analysis.
iBu, H
91
iBu, H
3w, 82
3x, 81
92
PhCH2CH2, H
PhCH2CH2, H
iBu, H
91
3y, 72
89
3z, 82
90
iBu, H
3aa, 78
93
[a] Unless noted otherwise, reactions were performed with cyclohexen-2-
one derivative 1 (0.2 mmol) and 1-azadiene 2 (0.1 mmol), amine C1 (20
mol%), acid A3 (40 mol%) in toluene (1.0 mL) at 50 C for 72 h. Data in
parentheses were obtained with amine C2. [b] Isolated yield. [c] Determined
by HPLC analysis on a chiral stationary phase; dr >19:1 by 1H NMR analysis.
[d] The absolute configuration of 3k was determined by X-ray analysis.[16]
The other products were assigned by analogy. [e] The ee value was
determined after derivation, see the SI. [f] Cyclopenten-2-one derivative was
used.
Apart from the 1-azadienes derived from saccharins, we
found
that
the
much
less
explored
2-vinyl-
benzo[d]oxazoles[17]
4
also demonstrated to be good
partners in cycloaddition reactions with -alkylidene cyclic
enones under the same catalytic conditions. As summarized
in Table 3, a spectrum of benzo[d]oxazole derivatives with
aryl, heteroaryl or even alkyl substitutions could be smoothly
Scheme 2. Synthetic transformations of cycloadduct 3k.
utilized, and the complex heterocyclic systems 5a
g were
produced in moderate yields with high enantioselectivity
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Interestingly, cycloadduct 3k could be isomerized to the Z-
diversely structured electron-deficient 1-azadienes. These
configured product 3k

in a high yield, simply by the
reactions also exhibited exclusive
endo-diastereoselectivity, and
heterocyclic systems were efficiently constructed with
moderate to excellent enantioselectivity (up to 99% ee),
which might be useful in medicinal chemistry. We believe that

,

-regioselectivity and
irradiation of a LED lamp, while the inverse conversion could
be realized by heating (Scheme 2). Additionally, the enone
functional group of 3k efficiently reacted with
a
number of fused
phenylhydrazine to furnish
a
pyrazole derivative
6.
Importantly, the full reduction of both enone and enamide
functionalities could be smoothly achieved with Et3SiH and
the new trienamine mode with congested 2,2-dienones
would have high potentials to design more asymmetric
reactions, and even accomplish some novel reaction
pathways. More results will be reported in due course.
BF3·Et2O, and the product
diastereocontrol.
7 was obtained in exclusive
In order to get some insight into the regioselectivity,
density functional theory (DFT) calculations were performed
to analyze the possibility and reactivity of the simplified
cross-conjugated trienamine intermediates, either in an
Experimental Section
endo-I or an exo-version II. The geometries of I and II were
General
optimized at b3lyp/6-31G(d) level. The energies were
calculated at b3lyp/6-31G++(d,p) level (toluene as solvent).
As shown in Scheme 3, the Gibbs free energy of intermediate
For the synthesis of starting materials, full characterization data, NMR
spectra, and HPLC traces, see the Supporting Information.
I
was 5.0 kcal/mol lower than that of intermediate II, which
General procedure for amine-catalyzed aza-DielsAlder reaction
suggested that the endo-version might be more stable than
I
the exo-version II in the balance of diverse trienamine modes.
Since the raise of the energy of the highest occupied
molecular orbital (ϵHOMO) of dienophile partner in the inverse-
electron-demand DielsAlder-type reaction would reduce
HOMO-LUMO energy gap, and further promote the reaction,
The reaction was carried out with -alkylidene cyclic enone 1 (0.2 mmol),
1-azadiene 2 (0.1 mmol), amine C1 (0.02 mmol) and salicylic acid A3 (0.04
mmol) in dry toluene (1.0 mL) at 50 ºC until consumption of 2, which was
monitored by TLC analysis. Purification by flash chromatography on silica
gel (EtOAc/petroleum ether) gave the endo-cycloadduct 3.
the ϵHOMO of both intermediates were also studied, showing
that ϵHOMO of
results implied that the intermediate
stability but also higher reactivity to promote the inverse-
electron-demand Diels Alder-type reaction, which were
I
was 0.19 eV higher than that of II. These
(4aR,5S,12aR,E)-5-Phenyl-3-propylidene-3,4,4a,5-tetrahydro-1H-
benzo[4,5]isothiazolo[2,3-a]quinolin-2(12aH)-one 11,11-dioxide (3a):
Obtained as a white solid in 76% yield after flash chromatography and the
enantiomeric excess was determined to be 93% by HPLC analysis on
Chiralpak AD-H column (30% 2-propanol/n-hexane, 1 mL/min), UV 254
nm, tmajor = 13.79 min, tminor = 18.40 min; [α]D20 = +28.6 (c = 1.60 in CHCl3);
1H NMR (600 MHz, CDCl3): δ (ppm) 7.82 (d, J = 8.4 Hz, 1H), 7.73 (d, J =
7.8 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.43-7.40 (m,
2H), 7.35-7.33 (m, 1H), 7.29-7.26 (m, 2H), 6.72 (t, J = 6.6 Hz, 1H), 5.82
(m, 1H), 4.45 (m, 1H), 4.26 (m, 1H), 3.66 (dd, J = 18.6 Hz, 1.8 Hz, 1H),
2.74 (dd, J = 18.6 Hz, 3.6 Hz, 1H), 2.60 (m, 1H), 2.30 (m, 1H), 2.02 (dd, J
= 16.8 Hz, 4.8 Hz, 1H), 1.80 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR
(150 MHz, CDCl3): δ (ppm) 195.3, 144.0, 140.4, 133.2, 133.1, 132.8, 131.6,
130.1, 129.5, 128.7, 127.9, 127.3, 121.2, 120.8, 112.5, 102.9, 53.8, 43.5,
41.6, 38.0, 23.2, 21.1, 12.5; ESI-HRMS: calcd. for C24H23NO3S+Na+
428.1296, found 428.1299.
I
had not only higher

consistent with our experimental results.
(4aR,5R,12aR,E)-3-(3-Methylbutylidene)-2-oxo-5-phenyl-
2,3,4,4a,5,12a-hexahydro-1H-benzo[4,5]oxazolo[3,2-a]quinoline-6-
carbonitrile (5a): Obtained as a white solid in 76% yield after flash
chromatography and the enantiomeric excess was determined to be 92%
by HPLC analysis on Chiralpak AD-H column (40% 2-propanol/n-hexane,
1 mL/min), UV 254 nm, tmajor = 6.83 min, tminor = 11.26 min; [α]D20 = 31.1
(c = 1.10 in CHCl3); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.41-7.31 (m, 3H),
7.26-7.23 (m, 3H), 7.17 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.92-
6.86 (m, 2H), 4.58 (m, 1H), 3.70 (d, J = 10.4 Hz, 1H), 2.99 (dd, J = 18.0
Hz, 5.6 Hz, 1H), 2.71 (dd, J = 18.0 Hz, 10.8 Hz, 1H), 2.63 (dd, J = 16.8 Hz,
2.4 Hz, 1H), 2.50 (m, 1H), 2.39 (m, 1H), 1.99-1.75 (m, 3H), 0.94 (d, J = 6.4
Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ (ppm)
195.6, 159.4, 146.8, 142.7, 140.2, 131.5, 130.6, 128.9, 128.4, 127.9, 124.4,
122.4, 119.7, 118.5, 112.5, 110.3, 106.8, 55.9, 50.7, 40.5, 40.3, 38.7, 37.0,
28.2, 26.6, 22.7, 22.3; ESI-HRMS: calcd. for C27H26N2O2+Na+ 433.1886,
found 433.1890.
Scheme 3. DFT calculation study on the trienamine intermediates.
Conclusions
We have investigated the reactions of -alkylidene 2-
cyclohexenone substrates under the catalysis of cinchona
alkaloid based primary amines. Endo-type cross-conjugated
trienamine intermediates were preferably generated, which
subsequently served as ideal dienophiles in inverse-
electron-demand aza-DielsAlder cycloadditions with
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Acknowledgements
[6] X. Feng, Z. Zhou, R. Zhou, Q.-Q. Zhou, L. Dong, Y.-C. Chen, J. Am. Chem.
Soc. 2012, 134, 19942.
[7]
For limited examples involving -functionalization of cyclic enone
compounds, see: a) X. Yin, Y. Zheng, X. Feng, K. Jiang, X.-Z. Wei, N.
Gao, Y.-C. Chen, Angew. Chem. 2014, 126, 6359; Angew. Chem. Int.
Ed. 2014, 53, 6245; b) X. Gu, T. Guo, Y. Dai, A. Franchino, J. Fei, C. Zou,
D. J. Dixon, J. Ye, Angew. Chem. 2015, 127, 10387; Angew. Chem. Int.
Ed. 2015, 54, 10249; c) C. Zou, C. Zeng, Z. Liu, M. Lu, X. Sun, J. Ye,
Angew. Chem. 2016, 128, 14469; Angew. Chem. Int. Ed. 2016, 55,
14257.
We are grateful for the financial support from the NSFC
(21372160, 21125206 and 21321061).
Keywords: organocatalysis • trienamine • regioselectivity •
cyclic enones • aza-DielsAlder cycloaddition
[1]
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10.1002/chem.201605606
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Cross-conjugated Trienamine
Catalysis with -Alkylidene 2-
Cyclohexenones: Application in ,-
Regioselective Aza-DielsAlder
Reaction
Endo-type cross-conjugated trienamines between -alkylidene 2-cyclohexenones
and a chiral primary amine catalyst serve as HOMO-raised dienophiles in inverse-
electron-demand aza-DielsAlder cycloadditions with a number of 1-azadiene
substrates. A diversity of chiral heterocyclic systems were efficiently constructed in
excellent stereoselectivity.
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