Stereodivergence in amine-catalyzed regioselective [4 + 2] cycloadditions of β-substituted cyclic enones and polyconjugated malononitriles

Article abstract of DOI:10.1021/ja3106219

Switchable reaction patterns of β-substituted cyclic enones via amine-based dienamine activation are reported. While γ-regioselective vinylogous Michael addition was observed with alkylidenemalononitriles, a completely different [4 + 2] cycloaddition was obtained with allylidene- or alkynylidenemalononitrile substrates, affording densely substituted bicyclo[2.2.2]octanes or analogous architectures with moderate to excellent diastereo- and enantioselectivity by the catalysis of primary amines from natural quinidine or quinine. Importantly, high diastereodivergence was achieved through unusual hydrogen-bonding interactions of multifunctional primary-amine catalytic systems. Endo cycloadducts were efficiently produced using a combination of 9-amino-9-deoxyepiquinidine and salicylic acid, while exo variants were obtained using 6′-hydroxy-9-amino-9-deoxyepiquinidine. Moreover, we successfully isolated the Michael addition intermediates in some cases, indicating that the above [4 + 2] reaction via dienamine catalysis may proceed by a stepwise Michael-Michael cascade rather than by a concerted Diels-Alder cycloaddition pathway.

Full text of DOI:10.1021/ja3106219

Article
pubs.acs.org/JACS
Stereodivergence in Amine-Catalyzed Regioselective [4 + 2]
Cycloadditions of β‑Substituted Cyclic Enones and Polyconjugated
Malononitriles
Xin Feng,† Zhi Zhou,† Rong Zhou,† Qing-Qing Zhou,† Lin Dong,† 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 of Medical University, Chongqing 400038, China
S
* Supporting Information
ABSTRACT: Switchable reaction patterns of β-substituted
cyclic enones via amine-based dienamine activation are
reported. While γ-regioselective vinylogous Michael addition
was observed with alkylidenemalononitriles, a completely
different [4 + 2] cycloaddition was obtained with allylidene-
or alkynylidenemalononitrile substrates, affording densely
substituted bicyclo[2.2.2]octanes or analogous architectures
with moderate to excellent diastereo- and enantioselectivity by
the catalysis of primary amines from natural quinidine or
quinine. Importantly, high diastereodivergence was achieved
through unusual hydrogen-bonding interactions of multifunctional primary-amine catalytic systems. Endo cycloadducts were
efficiently produced using a combination of 9-amino-9-deoxyepiquinidine and salicylic acid, while exo variants were obtained
using 6′-hydroxy-9-amino-9-deoxyepiquinidine. Moreover, we successfully isolated the Michael addition intermediates in some
cases, indicating that the above [4 + 2] reaction via dienamine catalysis may proceed by a stepwise Michael−Michael cascade
rather than by a concerted Diels−Alder cycloaddition pathway.
a pathway involving extended dienamine I (Scheme 1). The
similar vinylogous Michael addition of β-methylcyclohexenone
INTRODUCTION
■
2-Aminobutadienes, the dienamine species of α,β-unsaturated
ketones, are valuable intermediates in organic synthesis. In
1992, the Enders group developed a diastereoselective [4 + 2]
cycloaddition with nitroalkenes based on a chiral auxiliary
strategy.1 In 2002, Barbas and co-workers had reported the first
amine-catalyzed direct [4 + 2] cycloaddition of α,β-unsaturated
ketones and nitroalkenes.2 Since then, several highly stereo-
selective [4 + 2] cycloadditions of α,β-unsaturated ketones and
various electron-deficient dienophiles have been presented.3
Despite the diversity of these reactions, only a few of them3d,e
involve β,β-disubstituted enones,4 probably because these
compounds form a highly congested all-carbon quaternary
stereocenter.5 An even more important challenge to expanding
these catalytic reactions is to diversify the diastereochemical
outcomes of [4 + 2] cycloadditions of α,β-unsaturated ketones
using the dienamine pathway.6 To the best of our knowledge,
such diastereodivergent cycloadditions have not been reported
to date, although a variety of catalytic protocols have been
developed over the past years to achieve stereodivergence in
asymmetric synthesis.7,8
Scheme 1. Switchable Regioselective Reaction Pathways of
β-Methylcyclohexenone via Dienamine Catalysis
Dienamine catalysis can be used to expand the reaction
diversity based on β-substituted cyclic enones. In fact, the
Melchiorre group9 reported that such substrates can be added
to nitroalkenes by highly γ-regioselective Michael addition in
the presence of a cinchona alkaloid-derived primary amine10 via
Received: October 28, 2012
Published: November 15, 2012
© 2012 American Chemical Society
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Article
(2a) to benzylidenemalononitrile (3) was observed to give
product 4 under the catalytic action of the chiral primary amine
9-amino-9-deoxyepiquinidine (1a) and o-fluorobenzoic acid
(A1), albeit with low enantioselectivity. Unexpectedly, the
reaction pathway was switched completely when the electro-
phile was replaced with related substrate 3-phenylallylidene-
malononitrile (5a). The crowded bicyclo[2.2.2]octane deriva-
tives 6a and 6a′, whose skeleton is ubiquitous in natural
products and biologically important compounds,11 were
delivered via cross-dienamine II with good enantioselectivity
but a low endo/exo ratio.
Table 1. Screening of Conditions for the [4 + 2]
Cycloaddition Involving β-Methylcyclohexenone (2a) and 3-
a
Phenylallylidenemalononitrile (5a)
To expand the usefulness of [4 + 2] cycloadditions involving
β-substituted cyclic enones, we describe here a systematic study
of the stereoselective [4 + 2] reaction of these compounds with
polyconjugated malononitriles. Importantly, we achieved
significant stereodivergence through unusual hydrogen-bonding
interactions involving the identical multifunctional primary-
amine catalytic systems derived from quinidine or quinine.
b
c
entry
1
acid
A1
t (h) yield (%)
6a:6a′
ee (%)
1
2
1a
1b
1c
1d
1e
1f
17
18
16
15
21
47
43
26
26
43
24
23
19
41
18
19
19
24
93
94
90
94
88
88
83
91
88
80
−
85
83
82
83
87
90
91
2:1
1.2:1
1:2
92/23
89/35
A1
3
A1
−86/−64
−80/−67
97/63
−/76
−/−80
88/51
91/56
82/38
−
4
A1
1:1.5
2.5:1
1:9
5
A1
RESULTS AND DISCUSSION
■
6
A1
Endo-Selective [4 + 2] Cycloaddition Survey. A variety
of chiral primary amines 1a−g derived from natural cinchona
alkaloids (Scheme 1) were initially screened in the [4 + 2]
cycloaddition of 2a and 5a (Table 1, entries 1−7). An excellent
enantiomeric excess (ee) was obtained for the major endo
diastereomer 6a in the presence of catalyst 1e, a derivative of
1a,10k but the diastereomeric ratio (dr) was still disappointing
(entry 5). Surprisingly, the diastereocontrol was switched in the
presence of 6′-hydroxy-9-amino-9-deoxyepiquinidine (1f),10e
and good diastereoselectivity with a modest ee was attained for
the exo cycloadduct 6a′ (entry 6). The diastereoselectivity was
also better for 6′-hydroxy-9-amino-9-deoxyepiquinine (1g)
(entry 7). Thus, hydrogen bonding involving the 6′-OH
group appears to improve the exo diastereoselectivity.
7
1g
1e
1e
1e
1e
1e
1a
1a
1a
1a
1a
1c
A1
1:6
8
(S)-A2
(R)-A2
A3
2:1
9
2.1:1
2.5:1
−
10
11
12
13
d
TsOH
A4
8.2:1
97/−
99/−
98/−
90/−
A4
8:1
e
14
A4
7.6:1
3:1
15
16
17
18
A5
A6
4:1
95/−
A7
1:1.4
4:1
77/17
A4
−96/−
a
Unless noted otherwise, the reactions were performed with 0.12
mmol of 2a, 0.1 mmol of 5a, 20 mol % 1, and 40 mol % acid in 1 mL
of toluene at 35 °C. Combined isolated yields of separable 6a and
Some acid additives were also tested with amine 1e. Similarly
poor dr values were obtained for chiral N-Boc-phenylglycine
(A2) and phosphoric acid A3 (Table 1, entries 8−10), and
almost no reaction occurred in the presence of p-
toluenesulfonic acid (entry 11). To our gratification, using
salicylic acid (A4) dramatically improved the endo selectivity
and gave excellent enantioselectivity (entry 12). Similarly good
results were obtained for the combination of amine 1a and acid
A4 on both a small scale (entry 13) and a large scale (entry
14).12 The o-OH group of acid A4 appears to play a crucial role
in this catalytic system,13 since using o-methoxybenzoic acid
(A5) gave lower diastereoselectivity (entry 15). Introducing
another OH group at the meta position (A6) also decreased the
stereocontrol (entry 16), and using m-hydroxybenzoic acid
(A7) gave very poor results (entry 17). We were pleased to find
that for amine 1c, the diastereoselectivity could be switched
using A4, producing the endo adduct 6a having the
configuration opposite to that of amine 1a with excellent ee
and a good dr (entry 18 vs entry 3).
Reaction Scope of Endo [4 + 2] Cycloaddition. After
optimizing the catalytic conditions, we investigated the
reactions of a variety of β-substituted cyclic enones 2 and
polyconjugated malononitriles in the presence of amine 1a and
acid A4. The results are summarized in Table 2. Allylidenema-
lononitriles 5 bearing diverse aryl groups with either electron-
donating or -withdrawing groups were well-tolerated in
cycloadditions with 2a, and most produced the corresponding
products 6a−g with excellent diastereo- and enantioselectivities
(entries 1−7). A heteroaryl-substituted diene substrate also
b
c
6a′. ee for 6a/ee for 6a′, as determined by chiral HPLC analysis.
d
e
TsOH = p-toluenesulfonic acid. The reaction was run on a 1.0 mmol
scale.
gave noteworthy results (entry 8). Comparable stereocontrol
was observed in reactions between 5a and cyclohexenones with
larger β-alkyl or even alkenyl groups (entries 9−11). In fact, a
2-phenylethynyl-substituted cyclohexenone showed complete
diastereocontrol, albeit with lower reactivity (entry 12); this
compound also reacted with alkyl-substituted allylidenemalo-
nonitriles to give products 6m and 6n with good results
(entries 13 and 14). Simple 2-cyclohexenone also delivered
good data (entry 15). Using β-methylcyclopentenone provided
product 6p with exclusive diastereocontrol, though the ee value
was moderate (entry 16). In comparison, high enantioselectiv-
ity with modest diastereoselectivity was obtained for β-
methylcycloheptenone (entry 17).14 On the other hand,
additional substrates were used to explore the catalytic efficacy
of amine 1c. An array of cycloadducts were obtained with the
opposite configuration to that of catalyst 1a; the enantiose-
lectivities were excellent, although the dr values were modest
(entries 18−22).15
Notably, it was found that alkynylidenemalononitrile
substrates 7 also exhibited high reactivities in the [4 + 2]
cycloadditions with β-substituted cyclic enones under the same
catalytic conditions. As summarized in Table 3, an array of
chiral cycloadducts 8a−i with different alkynyl groups were
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a
Table 2. Substrate Scope of Endo Cycloadditions with Cyclic Enones and Allylidenemalononitriles
b
c
d
entry
n
R
R1
t (h)
6, yield (%)
dr
ee (%)
1
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
2
1
1
1
1
1
Me
Me
Me
Me
Me
Me
Me
Me
nBu
Ph
19
22
19
16
22
74
22
24
23
28
36
62
72
72
32
29
45
19
35
33
29
59
6a, 82
6b, 85
6c, 78
6d, 80
6e, 84
6f, 78
6g, 87
6h, 86
6i, 89
6j, 78
6k, 80
6l, 91
6m, 72
6n, 41
6o,76
8:1
11:1
9:1
99
99
p-MeC6H4
3
3,4-(MeO)2C6H3
98
4
m-ClC6H4
p-ClC6H4
o-BrC6H4
p-BrC6H4
2-furyl
Ph
10:1
12:1
12:1
12:1
11:1
13:1
10:1
9:1
99
e
5
99
6
98
7
99
8
99
9
98
10
11
12
13
14
15
16
17
vinyl
Ph
97
1-propenyl
PhCC
PhCC
PhCC
H
Ph
94
Ph
>19:1
>19:1
>19:1
7.5:1
>19:1
4:1
97
nPr
97
iPr
91
Ph
96
Me
Ph
6p, 94
6q, 66
6b, 65
6d, 70
6i, 66
6j, 67
6l,71
75
Me
Ph
92
f
18
Me
p-MeC6H4
m-ClC6H4
Ph
3.5:1
4:1
−96
−97
−95
−96
−94
f
19
Me
f
20
nBu
3:1
f
21
vinyl
Ph
4:1
f
22
PhCC
Ph
5:1
a
Unless noted otherwise, the reactions were performed with 0.12 mmol of 2, 0.1 mmol of 5, 20 mol % 1a, and 40 mol % A4 in 1 mL of toluene at 35
b
c
d
e
°C. Isolated yields of the pure endo isomers. Determined by 1H NMR analysis of the crude products. Determined by chiral HPLC analysis. The
f
absolute configuration of 6e was determined by X-ray analysis. Those of the other products were assigned by analogy. Catalyst 1c was used.
with a 6′-OH group, since these amines switch the
diastereoselectivity to the exo products, as illustrated in Table
1, entries 6 and 7. Therefore, we further optimized the
conditions to improve the results for the exo cycloadditions.
The data are summarized in Table 4. At first, more acidic
Table 3. Substrate Scope of Endo Cycloadditions with Cyclic
Enones and Alkynylidenemalononitriles
a
Table 4. Screening of Conditions for the Exo [4 + 2]
Cycloaddition
t
8, yield
b
ee
(%)
c
d
a
entry
n
R
R1
(h)
(%)
dr
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
2
1
1
Me
Ph
Ph
Ph
Ph
12
18
15
12
17
22
8a, 89
8b,72
>19:1
5.5:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
6:1
96
85
97
PhCC
8c, 91
8d, 86
8e, 82
8f, 73
8g, 83
8h, 78
8i, 56
8a, 71
8c, 74
Me
p-ClC6H4
p-BrC6H4
m-CNC6H4
94
Me
96
Me
96
b
c
entry
1
acid
solvent
t (h) yield (%)
6a′:6a ee (%)
Me
o-MeOC6H4 17
95
1
2
3
4
5
6
7
8
1f
1f
1f
1f
1f
1f
1f
1f
1f
(S)-A2
(R)-A2
A3
toluene
toluene
toluene
toluene
THF
46
46
46
46
59
48
52
48
46
84
86
56
78
78
67
88
72
79
>19:1
>19:1
>19:1
5:1
79
78
Me
2-thienyl
Ph
25
28
18
17
93
Me
85
61
e
10
Me
Ph
5:1
−95
−95
A4
74
e
11
PhCC
Ph
4.5:1
(S)-A2
(S)-A2
(S)-A2
(S)-A2
(S)-A2
8:1
30
a
Unless noted otherwise, the reactions were performed with 0.12
mmol of 2, 0.1 mmol of 7, 20 mol % 1a and 40 mol % A4 in 1 mL of
Et2O
8:1
56
DCM
9:1
63
b
toluene at 35 °C. Isolated yields of the pure endo isomers.
MeCN
toluene
9:1
−11
85
c
d
Determined by 1H NMR analysis of the crude products. Determined
d
e
9
>19:1
by chiral HPLC analysis. Catalyst 1c was used.
a
Unless noted otherwise, the reactions were performed with 0.12
mmol of 2a, 0.1 mmol of 5a, 20 mol % 1f, and 40 mol % acid in 1 mL
efficiently constructed with good stereoselectivity in the
presence of amine 1a (entries 1−9) or 1c (entries 10 and 11).
Exo-Selective [4 + 2] Cycloaddition Survey. We also
conducted further studies of reactions involving amines 1f or 1g
b
c
of toluene at 35 °C. Combined isolated yields of 6a and 6a′. ee of
d
6a′ as determined by chiral HPLC analysis. The reaction was run at
room temperature.
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additives were screened (entries 1−4). Exclusive exo control
was observed in the presence of amine 1f and chiral acid A2,
while the enantioselectivity was slightly improved (entries 1
and 2). It should be noted that the exo selectivity was decreased
when acid A4 was used (entry 4), indicating that the hydrogen-
bonding interaction of the OH group of A4 would affect that of
chiral amine 1f. A few solvents were investigated using the
combination of 1f and (S)-A2 but generally provided inferior
results (entries 5−8). Even the enantioselectivity was inverted
in MeCN (entry 8). Finally, it was found that the reaction still
proceeded smoothly in toluene at ambient temperature, leading
to the exo cycloadduct with better enantioselectivity (entry 9).
Reaction Scope of the Exo [4 + 2] Cycloaddition.
Consequently, a number of cyclic enones and allylidenemalo-
nonitriles 5 in toluene at ambient temperature were explored in
toluene at ambient temperature. The results are summarized in
Table 5. Good enantioselectivity with moderate to excellent
diastereoselectivity was obtained for the reactions of various
cyclohexenones and allylidenemalononitriles by the catalysis of
amine 1f and (S)-A2 (entries 1−7), and similar data were
obtained with β-methylcycloheptenone (entry 8). Nevertheless,
o-fluorobenzoic acid A1 was found to be a superior additive
when used in combination with amine 1g. Exo enantiomers
with the opposite configuration to that of amine 1f were
produced with comparable stereoselectivities (entries 9−14).
Preliminary Mechanism Studies with Experimental
Observations. Although the early investigations of amine-
catalyzed direct [4 + 2] cycloadditions of α,β-unsaturated
ketones with electron-deficient dienophiles involving the in situ
generation of 2-amino-1,3-butadienes suggested that such
reactions proceed via a concerted Diels−Alder reaction
pathway, no affirmative evidence has been provided by either
experimental or computational results to date.2,3,16 In addition,
a stepwise mechanism involving double Michael addition has
also been proposed for the amine-catalyzed [4 + 2] processes of
α,β-unsaturated ketones, but still without authoritative proof.17
In contrast, we fortunately isolated a low yield of the Michael
addition intermediate 9a′ in the reaction of β-phenyl-
cyclohexenone 2b and alkynylidenemalononitrile 7a in the
presence of amine 1f and acid (S)-A2, along with the expected
exo cycloadduct 8b′. Compound 9a′ could be converted to
cycloadduct 8b′ under the same catalytic conditions, verifying
that 9a′ is the reaction intermediate. Moreover, the Michael
addition product 9b was dominantly generated in the reaction
of enone 2b and alkynylidenemalononitrile 7b bearing an δ-
alkyl group by the catalysis of amine 1a and salicylic acid A4,
albeit in low yield (Scheme 2). Therefore, this amine-catalyzed
[4 + 2] cycloaddition reaction is more likely to occur by a
stepwise Michael−Michael addition pathway.18
On the other hand, in contrast to the vinylogous Michael
addition reported by Melchiorre,9 the same [4 + 2]
cycloaddition as for polyconjugated malononitriles also
occurred in the reaction of 1-nitrodiene 10 and β-
methylcyclohexenone 2a through the catalytic action of
amine 1a and acid A4. Product 11a was obtained with exclusive
endo selectivity in fair yield as a result of lower reactivity
(Scheme 3). Interestingly, the Michael addition intermediate 12
was isolated as a major product in the reaction of diene 10 and
simple cyclohexenone 2c under the same catalytic conditions,
which also supports a stepwise Michael−Michael addition
cascade. It should be noted that exo-11a and exo-11b were
produced for the same substrate combinations catalyzed by
supramolecular self-assemblies formed from chiral amines and
poly(alkene glycol)s, through a proposed Diels−Alder reaction
pathway.19
a
Table 5. Substrate Scope of the Exo Cycloaddition
6′,
t
yield
b
ee
(%)
c
d
entry
n
R
R1
(h)
(%)
dr
1
2
1
1
1
1
1
1
1
2
1
1
1
1
1
1
Me
Me
Me
Me
Ph
46 6a′, 76 >19:1
71 6b′, 65 >19:1
49 6e′, 66
85
82
p-MeC6H4
p-ClC6H4
2-furyl
Ph
e
3
8:1
84
4
48 6h′, 73 >19:1
81
5
nBu
72 6i′, 55
58 6l′, 53
58 6o′, 64
96 6q′, 63
61 6a′, 62
52 6b′, 55
56 6e′, 60
68 6h′, 62
70 6i′, 54
47 6l′, 55
6:1
4:1
68
6
PhCC
Ph
71
7
H
Ph
9:1
80
8
Me
Ph
8:1
82
9
Me
Ph
6:1
−82
−81
−82
−79
−65
−71
10
11
12
13
14
Me
p-MeC6H4
p-ClC6H4
2-furyl
Ph
8:1
Me
7:1
Me
9:1
nBu
6:1
PhCC
Ph
3.8:1
a
The reactions were performed with 0.12 mmol of 2 and 0.1 mmol of
5 in 1 mL of toluene at room temperature [entries 1−8, conditions (i);
b
entries 9−14, conditions (ii)]. Isolated yields of the pure exo isomers.
c
d
Determined by 1H NMR analysis of the crude products. Determined
e
by chiral HPLC analysis. The absolute configuration of 6e′ was
determined by X-ray analysis. Those of the other products were
assigned by analogy.
Scheme 2. Isolation of Michael Addition Intermediates
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Scheme 3. Reactions of 1-Nitrodiene Substrate 10 via Dienamine Catalysis
Synthetic Transformations of Cycloadduct 6a. The
multifunctionality of the cycloadducts allows certain highly
chemoselective transformations. We could diastereoselectively
reduce the carbonyl group of cycloadduct 6a using (−)-DIP-
chloride, giving separable alcohol 13 in good yield (Scheme 4).
ASSOCIATED CONTENT
■
S
* Supporting Information
Complete experimental procedures, characterization data, and
crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 4. Synthetic Transformations of Cycloadduct 6a
AUTHOR INFORMATION
■
Corresponding Author
ycchenhuaxi@yahoo.com.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from National Natural
Science Foundation of China (21122502 and 21021001) and
the National Basic Research Program of China (973 Program)
(2010CB833300).
REFERENCES
■
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Hoffman degradation reaction with the corresponding amide
14, affording complex caged carbamate product 15.
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CONCLUSION
■
We have developed aminocatalytic asymmetric and regiose-
lective [4 + 2] cycloadditions of β-substituted cyclic enones
with polyconjugated malononitriles. High stereodivergence has
been achieved by relying on different hydrogen-bonding
interactions. Endo cycloadducts were efficiently produced
using the combined catalytic system of 9-amino-9-deoxyepi-
quinidine and salicylic acid, while exo variants were produced
using 6′-hydroxy-9-amino-9-deoxyepiquinidine. Moreover, the
corresponding products with the opposite configuration could
be obtained using catalytic chiral amines derived from natural
quinine, further improving the stereodivergent outcomes with
the same substrates. A broad spectrum of densely substituted
bicyclo[2.2.2]octanes and related architectures have been
constructed with moderate to excellent enantioselectivities.
Moreover, we have provided direct experimental proofs that the
above [4 + 2] process via dienamine catalysis may occur in a
stepwise Michael−Michael cascade rather than via a concerted
Diels−Alder cycloaddition. We hope that such multifunctional
catalytic systems will be applicable to more stereodivergent
reactions involving dienamine or other types of amine catalysis.
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Journal of the American Chemical Society
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Supporting Information.
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