Asymmetric Formal [5 + 3] Cycloadditions with Unmodified Morita-Baylis-Hillman Alcohols via Double Activation Catalysis

Article abstract of DOI:10.1021/acscatal.8b04942

The discovery of a previously unreported activation mode and reaction pathway is important but challenging for the development of asymmetric organocatalysis. Here we disclosed a formal [5 + 3] cycloaddition reaction of unmodified Morita-Baylis-Hillman alcohols from 2-cyclopentenone and aldehydes with cyclic azomethine imines. A double catalytic system, combining chiral primary amine from cinchona alkaloid and achiral 2-mercaptobenzoic acid, has proved to be crucial for the chemoselectivity and enantioselectivity, through covalently dual activation of the sterically hindered enone substrates. A spectrum of tricyclic frameworks bearing substantial substitutions were produced in moderate to high yields with good stereoselectivity (up to 98% ee, >19:1 dr). Assisted by the experimental observations, a plausible catalytic mechanism is proposed; moreover, the key intermediates suggested have been detected and elucidated by high-resolution mass spectrometry analysis.

Full text of DOI:10.1021/acscatal.8b04942

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Letter
Asymmetric Formal [5 + 3] Cycloadditions with Unmodified
Morita-Baylis-Hillman Alcohols via Double Activation Catalysis
Qian-Qian Yang, Xiang Yin, Xiao-Long He, Wei Du, and Ying-Chun Chen
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04942 • Publication Date (Web): 10 Jan 2019
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ACS Catalysis
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Asymmetric Formal [5 + 3] Cycloadditions with Unmodified
MoritaBaylisHillman Alcohols via Double Activation
Catalysis
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Qian-Qian Yang,† Xiang Yin,† Xiao-Long He,† Wei Du,*† and Ying-Chun Chen*†,‡
† Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education and Sichuan Research Center
for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
‡ College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China
Supporting Information Placeholder
ABSTRACT: The discovery of previously unreported activation mode and reaction pathway is important but challenging for the
development of asymmetric organocatalysis. Here we disclosed a formal [5 + 3] cycloaddition reaction of unmodified
MoritaBaylisHillman alcohols from 2-cyclopentenone and aldehydes with cyclic azomethine imines. A double catalytic system,
combining chiral primary amine from cinchona alkaloid and achiral 2-mercaptobenzoic acid, has proved to be crucial for the
chemoselectivity and enantioselectivity, through covalently dual activation of the sterically hindered enone substrates. A spectrum of
tricyclic frameworks bearing substantial substitutions were produced in moderate to high yields with good stereoselectivity (up to
98% ee, >19:1 dr). Assisted by the experimental observations, a plausible catalytic mechanism is proposed; moreover, the key
intermediates suggested have been detected and elucidated by high-resolution mass spectrometry analysis.
KEYWORDS: [5 + 3] cycloaddition, unmodified MoritaBaylisHillman alcohol, cyclic azomethine imine, double activation
catalysis, asymmetric aminocatalysis, thiol catalysis
azomethine imines. Here we would like to report the discovery
The MoritaBaylisHillman (MBH) alcohols are densely
functionalized compounds, which have been extensively
investigated in the field of asymmetric catalysis.1 On the other
hand, much attention has also been paid on the asymmetric
transformations with MBH products.2 While fruitful results
have been presented under the catalysis of chiral Lewis basic
tertiary amines or phosphines,3 the direct application of
unmodified MBH alcohols, especially those derived from cyclic
enones, has been much less explored. As outlined in Scheme 1a,
MBH alcohols were successfully utilized as sterically hindered
activated alkenes in rhodium-catalyzed asymmetric -1,4-
addition/hydroxy elimination reactions, and kinetic resolution
of MBH alcohols also could be realized.4 On the other hand, Liu
and Chen pioneered the aminocatalytic asymmetric
functionalizations of MBH alcohols, and either - or -addition
could be accomplished by employing different nucleophiles
(Scheme 1b).5 Later, Albrecht and Jørgensen developed ,-
regioselective [4 + 2] formal cycloadditions of MBH alcohols
and 3-olefinic oxindoles, by generating H-bonding dienamine
species (Scheme 1c).6 Nevertheless, the development of
conceptually new regioselective reaction modes and pathways
with unmodified MBH alcohols still remains to be expanded.
Cyclic azomethine imines are commonly employed as 1,3-
dipoles in asymmetric [3 + 2] cycloaddition reactions with
diverse activated alkenes.7 They also have been utilized as
electrophilic zwitterionic counterparts in [3 + 3] or [4 + 3]
formal cycloaddition reactions via metal or organic catalysis.8
In our continuing efforts to develop diverse asymmetric
cycloaddition reactions with cyclic enone-type substrates via
aminocatalysis,9 we were interested in the potential
combination of unmodified MBH alcohols and cyclic
of an unexpected ,-regioselective formal [5
+ 3]
cycloaddition reaction10 via amine/thiol-based double
activation and cascade catalysis, providing an efficient protocol
to access the fused tricyclic heterocyclic products with high
enantioselectivity (Scheme 1d).
Scheme 1. Diverse Regioselective Asymmetric Reactions
with Unmodified Cyclic MBH Alcohols
a) Rhodium-catalyzed -1,4-additions

O
OH
O
O
OH


Rh(I)/L*
R1B(OH)2

n
R
R
+
*
R


*
n
n
R1
n = 1, 2
b) - or -additions via iminium ion catalysis


O
O
*
O
OH
NH2
NuH
R
or
R

*
R
*

Nu
Nu
c) ', -[4 + 2] cyclodditions via dienamine catalysis
 
EtO2C

EtO2C
O
*
O
OH
R
NH2
[4 + 2]
+

O
O
N
N
R
Boc
Boc
d) This work: ', -[5 + 3] cycloadditions via cascade catalysis
 
R1
O
*
O
O
OH
R

*
*
N
NH2
*
N
+
N
N
thiol
[5 + 3]

R1
R
O
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Table 1. Screening Conditions of Catalytic [5 + 3] Reaction
followed by a retro-aldol process (Table 1, entry 1).11 Replacing
TFA with weaker salicylic acid A2 resulted in very poor
conversion (entry 2). While extensive screenings by changing
various catalytic parameters failed to significantly prohibit the
undesired [3 + 2] pathway,11 we speculated that the presence of
another nucleophilic species might competently deliver the -
Michael addition intermediate, thus facilitating the expected
formal [5 + 3] cycloaddition reaction. Encouraged by our recent
success in amine/thiol-based double activation catalysis,12,13 it
was pleasing that adding catalytic amounts of 2-
mercaptobenzoic acid T1 significantly improved both yield and
enantiopurity of cycloadduct 4a (entry 3 vs entry 1); moreover,
dramatically increased reactivity was observed by using
salicylic acid A2 as the additive, and product 4a was apparently
generated (entry 4 vs entry 2). Therefore, the application of
amine/thiol double catalytic system successfully improved the
chemoselectivity, indicating that a different catalytic pathway
might be involved. The ortho-carboxylic group of T1 was
crucial for the reaction,13b as low reactivity was generally
observed when 3-mercaptobenzoic acid T2, 4-mercaptobenzoic
acid T3, methyl ester T4, or simple benzenethiol T5 was
applied with amine C1 and acid A2 (entries 58). A moderate
yield was obtained by using 2-mercaptophenol T6, albeit with
poor enantioselectivity (entry 9). Subsequently, more acid
additives were tested with amine C1 and thiol T1, and better
yield and enantiocontrol were achieved with a chiral phosphoric
acid A3 (entry 10), but acid A4 was a mismatched choice (entry
11). Inferior results were also obtained by using amines C2 and
C5 (entries 12 and 13); nevertheless, high enantioselectivity
was attained under the catalysis of 2-substituted amines C3 and
C4, and only trace amount of byproduct 3a was detected
(entries 14 and 15). Solvent had significant effect on the
enantioselectivity (entries 1618), and an excellent ee value
was gained in mesitylene (entry 17). We further compared the
reaction with amine C3 and acid A3 in the absence of thiol T1,
and much poorer results were produced, verifying the
superiority of the current double activation catalytic system
(entry 19). A lower yield was obtained when the reaction was
conducted at a larger scale, but high enantioselectivity was
retained (entry 20).
of MBH Alcohol 1a and Azomethine Imine 2aa
1
2
3
4
5
6
7
8
Ph
Ph
C
A
T
(20 mol %)
(20 mol %)
(20 mol %)
O
O
H
H
O
HO
Ph
O
N
N
N
N
+
+
N
N
solvent, 50 °C
24 h
H
H
4a
Ph
1a
2a
Ph
O
O
3a
OMe
R2
X
OH
CO2H
NH2
R3
R1
N
N
9
A2
SH
NH2
N
C5
1 = CO2H, R2 = R3 = H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
T1
T2
T3
T4
T5
T6
R
R
R
R
R
R
1 = R3 = H, R2 = CO2H
1 = R2 = H, R3 = CO2H
R
O
O
C1
C2
C3
C4
X = H, R = H
P
1 = CO2Me, R2 = R3 = H
1 = R2 = R3 = H
*
O
X = OCH3, R = H
X = H, R = tBu
X = H, R = Ph
OH
(R)
(S)
A3
A4
1 = OH, R2 = R3 = H
entry cat. acid thiol
solvent
toluene
yield (%)b ee (%)c
1d
2d
3d
4d
5
C1 TFA
C1 A2
C1 TFA
/
25 (72)
<10 (<5)
41 (55)
68 (28)
<10 (<5)
trace (<5)
25 (<5)
trace (<5)
55 (20)
70
52 (32)
/
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
/
72 (52)
63 (40)
/
T1
T1
T2
T3
T4
T5
T6
T1
T1
T1
T1
T1
T1
T1
C1
C1
C1
C1
C1
C1
C1
C1
C2
C5
C3
C4
C3
C3
C3
C3
C3
A2
A2
A2
A2
A2
A2
A3
A4
A3
A3
A3
A3
A3
A3
A3
A3
A3
6
/
7
60
8
/
9
21 (51)
79
10
11
12
13e
14
15
16
17
18
19
20 f
53
71
57
55
58
57
89
70
78
84
o-xylene
T1 mesitylene
73
80
78
92
Table 2. Substrate Scope and Limitations of MBH Alcohols
1 and Azomethine Imines 2a
T1
/
THF
82
55
R1
C3
A3
T1
mesitylene
(20 mol %)
(20 mol %)
(20 mol %)
37
66
O
H
O
O
HO
R
N
N
T1 mesitylene
53
89
N
+
aUnless noted otherwise, reactions were performed with 1a (0.075
mmol), 2a (0.05 mmol), amine C (20 mol %), acid A (20 mol %)
and thiol T (20 mol %) in solvent (0.5 mL) at 50 °C for 24 h. bYield
mesitylene
50 °C, 24 h
dr >19:1
N
H
R1
R
1
2
O
4
c
entry
R
R1
yield (%)b ee (%)c
of the isolated product 4a. Determined by HPLC analysis on a
1
d
chiral stationary phase; dr >19:1 by H NMR analysis; Data in
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a, 78
4b, 68
4c, 72
4d, 72
4e, 82
4f, 78
4g, 78
4h, 81
4i, 64
4j, 51
92
95
98d
95
97
88
94
91
81
94
parentheses referred to product 3a. eFor 48 h. fAt a 1.0 mmol scale.
2-ClC6H4
3-BrC6H4
4-BrC6H4
3
The initial reaction with MBH alcohol 1a and azomethine
imine 2a was conducted in the presence of cinchonidine-
derived amine C1 (20 mol %) and trifluoroacetic acid (TFA, 20
mol %) in toluene at 50 C. The above mentioned ,-
regioselective formal [5 + 3] cycloadduct 4a was isolated in a
low yield with fair enantioselectivity and exclusive
diastereoselectivity; unfortunately, a tricyclic product 3a was
dominantly produced with low enantiocontrol, probably
through an ,-regioselective [3 + 2] cycloaddition reaction7a
4
5
2-CH3OC6H4
3-CH3C6H4
4-CH3C6H4
1-naphthyl
2-thienyl
6
7
8
9
10e
2-styryl
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Nevertheless, slightly reduced yields and enantioselectivity
11
12
13
14
15
16
17
18
19
20
21
22
cHex
Ph(CH2)2-
Ph
Ph
4k, 68
4l, 60
90
84
98
95
92
87
84
89
97
84
85
89
1
2
3
4
5
6
7
8
were observed for the azomethine imine substrates 2 possessing
a heteroaryl group (entries 20 and 21). Notably, a cyclohexyl
group-substituted substrate also could be smoothly applied
(entry 22).14
Ph
2-ClC6H4
4-ClC6H4
3-BrC6H4
3-CH3C6H4
4-CH3C6H4
4m, 71
4n, 75
4o, 69
4p, 68
4q, 80
Ph
Ph
The multiple functionalities of the cycloadduct enable the
latent transformations to produce the architectures with higher
molecular complexity. As outlined in Scheme 2, the in situ
generated 1,3-dipole from substance 5 underwent highly
diastereoselective [3 + 2] cycloaddition with 4a, affording the
spirocyclic framework 6 in an excellent yield.15 In addition, the
enone moiety could be chemoselectively hydrogenated under
mild catalysis of Raney Ni and H2 (1 atm), giving product 7 in
a moderate yield. Notably, full hydrogenation of the enone
groups and simultaneously N-N bond cleavage could be
accomplished by simply increasing the H2 pressure, and a
bicyclic product 8 fusing a valuable eight-membered 1,5-
diazocane scaffold was constructed effectively.16
Ph
Ph
Ph
2-CH3OC6H4 4r, 70
Ph
1-naphthyl
3-furyl
4s, 78
4t, 57
4u, 63
4v, 62
9
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
2-thienyl
chexyl
Ph
aUnless noted otherwise, reactions were performed with MBH
alcohol 1 (0.15 mmol), azomethine imine 2 (0.1 mmol), amine C3
(20 mol %), acid A3 (20 mol %) and thiol T1 (20 mol %) in
mesitylene (1.0 mL) at 50 °C for 24 h. bYield of the isolated
c
product. Determined by HPLC analysis on a chiral stationary
phase; dr >19:1 by 1H NMR analysis. dThe absolute configuration
of enantiopure 4c was determined by X-ray analysis. The other
products were assigned by analogy. eFor 72 h.
Scheme 3. More Mechanism Studies and Proposed Catalytic
Cycle for Formal [5 + 3] Cycloaddition Reaction
Ph
C1
A2
T1
(20 mol %)
(20 mol %)
(20 mol %)
O
H
O
a)
Ph
O
N
N
Scheme 2. Synthetic Transformations of Product 4a
N
+
toluene, 50 °C
24 h
N
Ph
H
H
Ph
4a
Ph
9
2a
O
Cl
O
Ph
H
N
5
>19:1 dr
59%, 44% ee
N
N
Ph
N
Ph
Ph
56%
O
Ph
b)
C1
A2
T1
(20 mol %)
(20 mol %)
(20 mol %)
D
O
DIPEA, Ag2CO3
O
N
N
H
HO
O
N

Ph

toluene, 50 °C, 48 h
>19:1 dr
N
+

6
N
H
40%
96%, 98% ee
Ph

H
toluene, 50 °C
D2O (20 equiv)
24 h
N
Ph
Ph
H
H
Ph
D
Ph
O
2a
1a
H
O
O
4a
71%
Raney Ni
H2 (1 atm)
N
N
c)
O
O
Ph
N
HO
N
CO2H
H
O
H2O
EtOH, 12 h
>19:1 dr
H

S
I
H
Ph
Ph
N

N
H
O
O
Ph
+H2O

7
73%, 96% ee
4a
96% ee
1a
+
T1
Ph
Ph
R
Raney Ni
H2 (5 atm)
Ph
H
H
calcd. 347.0712 (M+Na+)
found 347.0713
H2O
O
N
4a
HO
R
NH2
EtOH, 12 h
>19:1 dr
H2O
C1
N
R
HN
Ph
H
Ph
H
O
NH
Ph
8
80%, 97% ee
N
N

*
N

S
With the optimized conditions in hand, the substrate scope
O
Ph
CO2H
and limitations of the formal [5 + 3] cycloadditions of
unmodified MBH alcohols and azomethine imines were
explored. The results are summarized in Table 2. An array of
MBH alcohols 1 derived from diverse aryl or heteroaryl
aldehydes exhibited similar reactivity with substrate 2a, and the
corresponding fused heterocycles were generally obtained in
moderate yields with high to excellent enantioselectivity (Table
2, entries 29). A slightly lower yield was attained for a MBH
alcohol with a 2-styryl group, but still with outstanding
enantiocontrol (entry 10). Importantly, the MBH alcohols
bearing either a branched or linear alkyl substitution could be
effectively applied, affording the cycloadducts 4k and 4l with
high ee values (entries 11 and 12). On the other hand, a
spectrum of cyclic azomethine imines 2 were investigated in
combination with MBH alcohol 1a. The aryl imines 2 with both
electron-withdrawing and -donating substitutions were well
tolerated (entries 1318), and a remarkable ee value was
produced for that with a 1-naphthyl group (entry 19).
VI
iminium ion
= R
N
II
calcd.622.2499 (M+Na+)
Ph
R
NH
found 622.2492
O
N
N
H
O

Ph
CO2H
SH
N
N
V
4-aminofulvene
calcd.642.3203 (M+Na+)
found 642.3206
R
Ph
NH
2a
Ph
T1
Ph
H
*
O
H


S
R
N
Ph
NH
O
H
N

N
H
O
III
N
Ph
calcd.774.3472 (M+H+)
found 774.3488
H
O
IV
iminium ion
In order to gain insights into the reaction mechanism, we
conducted more experiments. As outlined in Scheme 3a, the
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1,3-dipolar cycloaddition of -benzylidene-2-cyclopentenone
AUTHOR INFORMATION
Corresponding Author
1
2
3
4
5
6
7
8
9 and azomethine imine 2a provided the same product 4a but
with apparently reduced yield and enantioselectivity under the
catalysis of amine C1, acid A2 and thiol T1, in comparison with
those with MBH alcohol 1a (59% yield, 44% ee vs 68% yield,
63% ee; data in Table 1, entry 4), indicating that the current
formal [5 + 3] cycloaddition would not proceed via the possible
2,2-dienone intermediate 9.17 In addition, apparent deuteration
was observed for one -H in product 4a by adding D2O (20
equiv) into the standard catalytic reaction of 1a and 2a,
verifying that a protonation process at -position occurs in the
reaction (Scheme 3b). As a result, a plausible catalytic cycle is
proposed for the formal [5 + 3] cycloaddition of MBH alcohol
1a and azomethine imine 2a via double activation catalysis of
amine C1 and thiol T1. As illustrated in Scheme 3c, reversible
-addition of thiol T1 to enone 1a would give sulphide I after
elimination of H2O.18 Then the more stereoselectively matched
dienamine-type intermediate II would be generated between
amine C1 and I,12a and -regioselective Mannich-type reaction
would proceed with azomethine imine 2a to produce
intermediate III accordingly. Since the ortho-carboxylic group
of T1 is crucial for the formal [5 + 3] cycloaddition,13b it might
serve as an intramolecular H-bonding (or proton) donor to
generate the partially cationic sulfonium moiety, which would
facilitate the -deprotonation and sequential release of T1 to
deliver iminium ion IV.5a Isomerization of IV to 4-
aminofulvene intermediate V was followed, which could be -
protonated to giving iminium ion VI.19 Finally, intramolecular
aza-Michael addition at -position would construct the observed
formal [5 + 3] product 4a after releasing amine C1 via
hydrolysis. Notably, the key proposed intermediates I, II, III
and V have been successsfully detected by high-resolution mass
spectrometry analysis of the catalytic mixture, further
supporting the high feasibility of the current covalent double
activation catalysis.20
duweiyb@scu.edu.cn
ycchen@scu.edu.cn
Notes
The authors declare no competing financial interests.
Funding Sources
We are grateful for the financial support from the NSFC (21572135
and 21772126) and Sichuan University Distinguished Young
Scientist Program (2017SCU04A15).
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REFERENCES
(1) For selected reviews, see: (a) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Recent Advances in the Baylis−Hillman Reaction
and Applications. Chem. Rev. 2003, 103, 811–892. (b) Basavaiah, D.;
Rao, A. J.; Reddy, R. J. The Baylis–Hillman Reaction: A Novel
Source of Attraction, Opportunities and Challenges in Synthetic
Chemistry. Chem. Soc. Rev. 2007, 36, 1581–1588. (c) Masson, G.;
Housseman, C.; Zhu, J. The Enantioselective Morita–Baylis–Hillman
Reaction and Its Aza Counterpart. Angew. Chem., Int. Ed. 2007, 46,
4614–4628. (d) Wei, Y.; Shi, M. Recent Advances in Organocatalytic
Asymmetric Morita–Baylis–Hillman/Aza-Morita–Baylis–Hillman
Reactions. Chem. Rev. 2013, 113, 6659–6690.
(2) For selected reviews, see: (a) Singh, V.; Batra, S. Advances in the
Baylis–Hillman Reaction-Assisted Synthesis of Cyclic Frameworks.
Tetrahedron 2008, 64, 4511–4574. (b) Basavaiah, D.; Reddy, B. S.;
Badsara, S.S. Recent Contributions from the BaylisHillman
Reaction to Organic Chemistry. Chem. Rev. 2010, 110, 5447–5674.
(3) For selected reviews, see: (a) Liu, T.-Y.; Xie, M.; Chen, Y.-C.
Organocatalytic Asymmetric Transformations of Modified Morita–
Baylis–Hillman Adducts. Chem. Soc. Rev. 2012, 41, 4101–4112. (b)
Rios, R. Organocatalytic Enantioselective Methodologies Using
Morita–Baylis–Hillman Carbonates and Acetates. Catal. Sci.
Technol. 2012, 2, 267278. (c) Xie, P.; Huang, Y. Morita–Baylis–
Hillman Adduct Derivatives (MBHADs): Versatile Reactivity in
Lewis Base-Promoted Annulation. Org. Biomol. Chem. 2015, 13,
85788595.
(4) (a) Gendrineau, T.; Genet, J.-P.; Darses, S. Rhodium-Catalyzed
Functionalization of Sterically Hindered Alkenes. Org. Lett. 2010, 12,
308310. (b) Wang, F.; Li, S.; Qu, M.; Zhao, M.-X.; Liu, L.-J.; Shi,
M. A Highly Efficient Kinetic Resolution of MoritaBaylisHillman
Adducts Achieved by N-Ar Axially Chiral Pd-Complexes Catalyzed
Asymmetric Allylation. Chem. Commun. 2011, 47, 12813–12815. (c)
Wang, Y.; Feng, X.; Du, H. Kinetic Resolution of Hindered
MoritaBaylisHillman Adducts by Rh(I)-Catalyzed Asymmetric
1,4-Addition/-Hydroxy Elimination. Org. Lett. 2011, 13,
49544957. (d) Xuan, Q.; Wei, Y.; Chen, J.; Song, Q. An Expedient
E-Stereoselective Synthesis of Multi-Substituted Functionalized
Allylic Boronates from Morita–Baylis–Hillman Alcohols. Org.
Chem. Front. 2017, 4, 1220–1223.
In conclusion, we have investigated an unprecedented ,-
regioselective formal [5 + 3] cycloaddition reaction of
unmodified MoritaBaylisHillman alcohols from 2-
cyclopentenone with cyclic azomethine imines, which
significantly relied on the double activation catalysis of chiral
primary amine and achiral 2-mercaptobenzoic acid. The
substitution patterns for both types of substrates are substantial,
and a spectrum of highly functionalized tricyclic frameworks
were effectively produced in moderate to excellent
enantioselectivity, which could be further applied to construct
chiral architectures with higher molecular complexity.
Furthermore, mechanism studies demonstrated that the current
formal cycloaddition proceeded in a complicated cascade
process via regio- and chemoselective covalently double
activation of MoritaBaylisHillman alcohols with amine and
thiol catalysts, and the key intermediates have been potentially
verified through high-resolution mass spectrometry analysis.
Further studies will be reported in due course.
(5) (a) Qiao, Z.; Shafiq, Z.; Liu, L.; Yu, Z.-B.; Zheng, Q.-Y.; Wang,
D.; Chen, Y.-J. An Organocatalytic, -Regioselective, and Highly
Enantioselective
Nucleophilic
Substitution
of
Cyclic
MoritaBaylisHillman Alcohols with Indoles. Angew. Chem., Int.
Ed. 2010, 49, 72947298. (b) Qiao, Z.; Zhong, N.-J.; Zhang, T.; Liu,
L.; Wang, D.; Chen, Y.-J. An Organocatalytic, δ-Regioselective,
Diastereoselective, and Enantioselective Nucleophilic Substitution of
Cyclic Morita–Baylis–Hillman Alcohols with N-Boc-3-benzyl-2-
oxindoles. Eur. J. Org. Chem. 2013, 2013, 2140–2146. (c) Ren, C.;
Wei, F.; Xuan, Q.; Wang, D.; Liu, L. Organocatalytic
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the ACS
Publications website.
Complete experimental procedures and characterization of new
products; NMR spectra and HPLC chromatograms (PDF); cif files
of enantiopure 4c and 6.
Enantioselective
Reaction
of
Cyclopent-2-enone-Derived
MoritaBaylisHillman Alcohols with 4‐Hydroxycoumarins. Adv.
Synth. Catal. 2016, 358,132–137.
(6) Stiller, J.; Kowalczyk, D.; Jiang, H.; Jørgensen, K. A.; Albrecht, Ł.
Novel Organocatalytic Activation of Unmodified Morita–Baylis–
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Hillman Alcohols for the Synthesis of Bicyclic α-Alkylidene
Ketones. Chem. - Eur. J. 2014, 20, 13108–13112.
(b) Yuan, C.; Wu, Y.; Wang, D.; Zhang, Z.; Wang, C.; Zhou, L.;
Zhang, C.; Song, B.; Guo, H. Formal [5 + 3] Cycloaddition of
Zwitterionic Allylpalladium Intermediates with Azomethine Imines
for Construction of N,O-Containing Eight-Membered Heterocycles.
Adv. Synth. Catal. 2018, 360, 652658. (c) Krishna, U. M.; Deodhar,
K. D.; Trivedi, G. K.; Mobin, S. M. Novel Route to Functionalized
Cyclooctanoids via [5 + 3] Cycloaddition. J. Org. Chem. 2004, 69,
967969. (d) Arrayás, R. G.; Liebeskind, L. S. 3-Pyranyl and 3-
Pyridinyl Molybdenum -Complexes as Chiral Scaffolds for the
Enantioselective Construction of Substituted Oxa- and
Aza[3.3.1]bicyclics: First Enantio- and Regiocontrolled [5 + 3]
Cycloaddition Reactions. J. Am. Chem. Soc. 2003, 125, 90269027.
(11) For more details, see the Supporting Information.
(12) (a) Wang, Z.-X.; Zhou, Z.; Xiao, W.; Ouyang, Q.; Du, W.; Chen,
Y.-C. Double Activation Catalysis for α-Alkylidene Cyclic Enones
with Chiral Amines and Thiols. Chem. - Eur. J. 2017, 23, 10678–
10682. (b) Yang, Q.-Q.; Xiao, W.; Du, W.; Ouyang, Q.; Chen, Y.-C.
Asymmetric [4 + 2] Annulations to Construct Norcamphor Scaffolds
with 2-Cyclopentenone via Double Amine-Thiol Catalysis. Chem.
Commun. 2018, 54, 11291132. For reviews, see: (c) Skubi, K. L.;
Blum, T. R.; Yoon, T. P. Dual Catalysis Strategies in Photochemical
Synthesis. Chem. Rev. 2016, 116, 10035–10074. (d) Afewerki, S.;
Córdova, A. Combinations of Aminocatalysts and Metal Catalysts: A
Powerful Cooperative Approach in Selective Organic Synthesis.
Chem. Rev. 2016, 116, 13512–1357.
(13) For selected examples of thiol-mediated or catalyzed reactions,
see: (a) Aroyan, C. E.; Miller, S. J. Enantioselective Rauhut−Currier
Reactions Promoted by Protected Cysteine. J. Am. Chem. Soc. 2007,
129, 256–257. (b) The ortho-acidic group has been proved to be
crucial for the thiol catalysis, see: Selig, P. S.; Miller, S. J. Ortho-
Acidic Aromatic Thiols as Efficient Catalysts of Intramolecular
Morita–Baylis–Hillman and Rauhut–Currier Reactions. Tetrahedron
Lett. 2011, 52, 2148–2151. (c) Hashimoto, T.; Kawamata, Y.;
Maruoka, K. An Organic Thiyl Radical Catalyst for Enantioselective
Cyclization. Nat. Chem. 2014, 6, 702–705.
(14) C,N-Cyclic azomethine imines failed to participate in similar
formal [5 + 3] cycloadditions. For selected examples, see: (a)
Cheng, X.; Cao, X.; Xuan, J.; Xiao, W.-J. Silver(I)- and Base-
Mediated [3 + 3]-Cycloaddition of C,N-Cyclic Azomethine Imines
with Aza-Oxyallyl Cations. Org. Lett. 2018, 20, 52–55. (b) Zhu, C.-
Z.; Feng, J.-J.; Zhang, J. Rhodium-Catalyzed Intermolecular [3 + 3]
Cycloaddition of Vinyl Aziridines with C,N-Cyclic Azomethine
Imines: Stereospecific Synthesis of Chiral Fused Tricyclic 1,2,4-
Hexahydrotriazines. Chem. Commun. 2017, 53, 46884691. (c)
Yuan, C.; Zhou, L.; Xia, M.; Sun, Z.; Wang, D.; Guo, H. Phosphine-
Catalyzed Enantioselective [4 + 3] Annulation of Allenoates with
C,N-Cyclic Azomethine Imines: Synthesis of Quinazoline-Based
Tricyclic Heterocycles. Org. Lett. 2016, 18, 5644−5647. (d) Zhang,
L.; Liu, H.; Qiao, G.; Hou, Z.; Liu, Y.; Xiao, Y.; Guo, H. Phosphine-
1
2
3
4
5
6
7
8
(7) For selected examples, see: (a) Chen, W.; Du, W.; Duan, Y.-Z.; Wu,
Y.; Yang, S.-Y.; Chen, Y.-C. Enantioselective 1,3-Dipolar
Cycloaddition of Cyclic Enones Catalyzed by Multifunctional
Primary Amines: Beneficial Effects of Hydrogen Bonding. Angew.
Chem., Int. Ed. 2007, 46, 7667−7670. (b) Hong, L.; Kai, M.; Wu, C.;
Sun, W.; Zhu, G.; Li, G.; Yao, X.; Wang, R. Enantioselective 1,3-
Dipolar Cycloaddition of Methyleneindolinones and N,N′-Cyclic
Azomethine Imines. Chem. Commun. 2013, 49, 6713−6715. (c) Arai,
T.; Ogino, Y.; Sato, T. Development of
Bis(oxazolidine)pyridineMetal Catalyst for the [3
a
Tailor-Made
2]
9
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cycloaddition of Azomethine Imines with Propiolates. Chem.
Commun. 2013, 49, 77767778. (d) Li, J.; Lian, X.; Liu, X.; Lin, L.;
Feng, X. Nickel(II)-Catalyzed Enantioselective 1,3-Dipolar
Cycloaddition of Azomethine Imines with Alkylidene Malonates.
Chem. - Eur. J. 2013, 19, 51345140. (e) Hori, M.; Sakakura, A.;
Ishihara, K. Enantioselective 1,3-Dipolar Cycloaddition of
Azomethine Imines with Propioloylpyrazoles Induced by Chiral
−Cation Catalysts. J. Am. Chem. Soc. 2014, 136, 13198–13201. (f)
Yin, C.; Lin, L.; Zhang, D.; J.; Feng, Liu, X.; Feng, X. Asymmetric
[3 + 2] Cycloaddition of Methyleneindolinones with N,N‑Cyclic
Azomethine Imines Catalyzed by
a N,N‑Dioxide-Mg(OTf)2
Complex. J. Org. Chem. 2015, 80, 9691−9699. (g) Gong, J.; Wan,
Q.; Kang, Q. Asymmetric [3 + 2] Cycloaddition Employing N,N-
Cyclic Azomethine Imines Catalyzed by Chiral-at-Metal Rhodium
Complex. Org. Lett. 2018, 20, 3354−3357.
(8) For selected examples, see: (a) Chan, A.; Scheidt, K. A. Highly
Stereoselective Formal [3
+ 3] Cycloaddition of Enals and
Azomethine Imines Catalyzed by N-Heterocyclic Carbenes. J. Am.
Chem. Soc. 2007, 129, 5334−5335. (b) Na, R.; Jing, C.; Xu, Q.; Jiang,
H.; Wu, X.; Shi, J.; Zhong, J.; Wang, M.; Benitez, D.; Tkatchouk, E.;
Goddard, W. A.; Guo, H.; Kwon, O. Phosphine Catalyzed
Annulations of Azomethine Imines: Allene-Dependent [3 + 2], [3 +
3], [4 + 3], and [3 + 2 + 3] Pathways. J. Am. Chem. Soc. 2011, 133,
13337–13348. (c) Jin, Q.; Zhang, J.; Jiang, C.; Zhang, D.; Gao, M.;
Hu, S. Self [3 + 4] Cycloadditions of Isatin N,N′-Cyclic Azomethine
Imine 1,3-Dipole with N-(o-chloromethyl)aryl Amides. J. Org.
Chem. 2018, 83, 8410–8416. (d) (g) Wei, L.; Wang, Z.-F.; Yao, L.;
Qiu, G.; Tao, H.; Li, H.; Wang, C.-J.; Copper(II)-Catalyzed
Asymmetric 1,3-Dipolar [3
+ 4] Cycloaddition and Kinetic
Resolution of Azomethine Imines with Azoalkenes. Adv. Synth.
Catal. 2016, 358, 39553959. (e) Liang, L.; Huang, Y. Phosphine-
Catalyzed [3 + 3]-Domino Cycloaddition of Ynones and Azomethine
Imines to Construct Functionalized Hydropyridazine Derivatives.
Org. Lett. 2016, 18, 2604–2607.
(9) (a) Feng, X.; Zhou, Z.; Zhou, R.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-
C. Stereodivergence in Amine-Catalyzed Regioselective [4 + 2]
Cycloadditions of -Substituted Cyclic Enones and Polyconjugated
Malononitriles. J. Am. Chem. Soc. 2012, 134, 19942−19947. (b)
Feng, X.; Zhou, Z.; Ma, C.; Yin, X.; Li, R.; Dong, L.; Chen, Y.-C.
Trienamines Derived from Interrupted Cyclic 2,5-Dienones: Remote
δ,ɛ-C=C Bond Activation for Asymmetric Inverse-Electron-Demand
Aza-DielsAlder reaction. Angew. Chem., Int. Ed. 2013, 52,
1417314176. (c) Zhou, Z.; Wang, Z.-X.; Ouyang, Q.; Xiao, W.; Du,
W.; Chen, Y.-C. Cross-Conjugated Trienamine Catalysis with -
Alkylidene 2-Cyclohexenones: Application in ,-Regioselective
Aza-DielsAlder Reaction. Chem. - Eur. J. 2017, 23, 2945–2949. (d)
Zhou, Z.; Wang, Z.-X.; Zhou, Y.-C.; Xiao, W.; Ouyang, Q.; Du, W.;
Chen, Y.-C. Switchable Regioselectivity in Amine-Catalysed
Asymmetric Cycloadditions. Nat. Chem. 2017, 9, 590−594. (e) Xiao,
W.; Yang, Q.-Q.; Chen, Z.; Ouyang, Q.; Du, W.; Chen, Y.-C. Regio-
and Diastereodivergent [4 + 2] Cycloadditions with Cyclic 2,4-
Dienones. Org. Lett. 2018, 20, 236239.
Catalyzed Highly Enantioselective [3
+ 3] Cycloaddition of
Morita−Baylis−Hillman Carbonates with C,N-Cyclic Azomethine
Imines. J. Am. Chem. Soc. 2015, 137, 4316–4319. (e) Wang, D.; Lei,
Y.; Wei, Y.; Shi, M. A Phosphine-Catalyzed Novel Asymmetric [3 +
2] Cycloaddition of C,N-Cyclic Azomethine Imines with -
Substituted Allenoates. Chem. - Eur. J. 2014, 20, 1532515329.
(15) (a) Lee, K. J.; Choi, J.-K.; Yum, E. K.; Cho, S. Y. Novel 1,3-
Dipolar Cycloadditions of Fulvenes and Hydrazonyl Chlorides: A
Facile Synthesis of the Cyclopenta[d]pyridazines. Tetrahedron Lett.
2009, 50, 6698–6700. (b) Moeinpour, F.; Bakavoli, M.; Davoodnia,
A.; Morsali, A. Investigation into the Regiochemistry of Some
Pyrazoles Derived from 1,3-Dipolar Cycloaddition of Acrylonitrile
with Some Nitrilimines: Theoretical and Experimental Studies. J.
Chil. Chem. Soc. 2011, 56, 870874.
(16) Yamashita, Y.; Kobayashi, S. NO Cations as Highly Efficient
Catalysts for Carbon–Carbon Bond Forming Reactions. Chem. Lett.
2009, 38, 678–679.
(17) In comparison with the data (52% ee) in Table 1, entry 1,
apparently different enantioselectivity for cycloadduct 4a (33% ee)
(10) For limited examples, see: (a) Yin, X.; Zheng, Y.; Feng, X.; Jiang,
K.; Wei, X.-Z.; Gao, N.; Chen, Y.-C. Asymmetric [5 + 3] Formal
Cycloadditions with Cyclic Enones through Cascade Dienamine–
Dienamine Catalysis. Angew. Chem., Int. Ed. 2014, 53, 6245–6248.
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was observed for the reaction of 2,2-dienone 9 and 2a under the same
Catalyzed Difunctionalization of -Fluoroalkyl ,-Enones: A
Direct Approach to -Amino -Diazo Carbonyl Compounds. Angew.
Chem., Int. Ed. 2018, 57, 1578715791. (d) Jiang, G.; List, B. Direct
Asymmetric -Allylation of Aldehydes with Simple Allylic Alcohols
Enabled by the Concerted Action of Three Different Catalysts.
Angew. Chem., Int. Ed. 2011, 55, 94719474. (e) Tao, Z.-L.; Zhang,
W.-Q.; Chen, D.-F.; Adele, A.; Gong, L.-Z. Pd-Catalyzed
Asymmetric Allylic Alkylation of Pyrazol-5-ones with Allylic
Alcohols: The Role of the Chiral Phosphoric Acid in C−O Bond
Cleavage and Stereocontrol. J. Am. Chem. Soc. 2013, 135,
9255−9258. (g) Zheng, P.-F.; Ouyang, Q.; Niu, S.-L.; Shuai, L.; Yuan,
Y.; Jiang, K.; Liu, T.-Y.; Chen, Y.-C. Enantioselective [4 + 1]
Annulation Reactions of ‑Substituted Ammonium Ylides to
Construct Spirocyclic Oxindoles. J. Am. Chem. Soc. 2015, 137,
9390−9399.
catalysis of amine C1 and TFA, also suggesting that different reaction
pathways would be involved. See the Supporting Information for
more details.
(18) The in situ 1H NMR analysis supported the formation of
intermediate I. See the Supporting Information for more details.
(19) MBH alcohols derived from 2-cyclohexenone failed to participate
in such a reaction, which cannot undergo similar isomerization
processes.
(20) Mass spectrometry analysis has been widely applied for
mechanism studies, see: (a) Di Marco, V. B.; Bombi, G. G.
Electrospray Mass Spectrometry (ESI-MS) in the Study of Metal-
Ligand Solution Equilibria. Mass Spectrom. Rev. 2006, 25, 347379.
(b) Vikse, K. L.; Ahmadi, Z.; McIndoe, J. S. The Application of
Electrospray Ionization Mass Spectrometry to Homogeneous
Catalysis. Coord. Chem. Rev. 2014, 279, 96114. (c) Wang, H.;
Zhang, L.; Tu, Y.; Xiang, R.; Guo, Y.-L.; Zhang, J. Phosphine-
1
2
3
4
5
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SYNOPSIS TOC
1
2
3
4
5
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7
8
9
R1
O
O
amine
acid
(20 mol %)
(20 mol %)
HO
R
H
O

N
N
N
+
thiol
(20 mol %)

N
R1
H
R
O
amine/thiol double activation catalysis
formal [5 + 3] cycloadditions
>19:1 dr
8198% ee
10
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