Direct Activation of Unmodified Morita-Baylis-Hillman Alcohols through Phosphine Catalysis for Rapid Construction of Three-Dimensional Heterocyclic Compounds

Article abstract of DOI:10.1021/acs.orglett.9b01783

The phosphine-catalyzed tandem annulation reaction of Morita-Baylis-Hillman (MBH) alcohols with azomethine imines has been achieved for the synthesis of biologically important (epoxymethano)-pyrazolo[5,1-b]quinazoline derivatives. A variety of MBH alcohol

Full text of DOI:10.1021/acs.orglett.9b01783

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Direct Activation of Unmodified Morita−Baylis−Hillman Alcohols
through Phosphine Catalysis for Rapid Construction of Three-
Dimensional Heterocyclic Compounds
†
†
,†
†
†
†
†
‡
Leijie Zhou, Chunhao Yuan, Yuan Zeng, Qijun Wang, Chang Wang, Min Liu, Wei Wang,
‡
,†,‡
Yongjun Wu, Bing Zheng,* and Hongchao Guo*
†
Department of Applied Chemistry, China Agricultural University, Beijing 100193, P. R. China
College of Public Health, Zhengzhou University, Zhengzhou 450001, China
‡
*
S Supporting Information
ABSTRACT: The phosphine-catalyzed tandem annulation
reaction of Morita−Baylis−Hillman (MBH) alcohols with
azomethine imines has been achieved for the synthesis of
biologically important (epoxymethano)-pyrazolo[5,1-b]-
quinazoline derivatives. A variety of MBH alcohols and
azomethine imines were well-tolerated under the mild reaction
conditions, providing novel 3D heterocyclic compounds in
high yields with excellent diastereoselectivities. It is the first time the direct activation of unmodified MBH alcohols acting as
new oxa-synthons has been achieved.
1
he Morita−Baylis−Hillman (MBH) reaction has made
great progress since it was first found around 50 years
chemistry, diverse strategies focusing on transformations of the
T
electron-deficient double bond and the hydroxy or amino
2
,4
2
group in MBH adducts have been established. In conven-
tional strategies, these MBH adducts were generally trans-
ago. To date, its development has been nearly perfect. The
reaction has been an extremely convenient means for
converting a simple compound into densely functionalized
products in a catalytic and atom-economical way. As a result, a
large variety of MBH adducts could be easily accessed
5
6
formed into their derivatives such as acetates, carbonates,
7
and halides, which were usually activated by a Lewis base or a
metal catalyst to form a zwitterionic intermediate to pair with
various reaction partners. This strategy has made many
2
2,3
(
Scheme 1a). For their further application in synthetic
2
significant achievements; however, there is a fatal flaw because
of the extra modifications and the generation of a leaving
group, which are large wastes of atomic economy, efficiency,
and starting materials (Scheme 1b). Therefore, to make full use
of the MBH adducts, it is very important and indispensable to
discover a direct way to activate MBH adducts.
Scheme 1. Previous Works and Our Strategy
In the past two decades, phosphine catalysis has emerged as
a reliable and powerful tool for the construction of structurally
8
diverse carbo- and heterocycles. In the phosphine-promoted
reactions, the catalysis cycle is typically initiated by the
addition of the Lewis basic phosphine to the electron-deficient
alkenes, alkynes, or allenes, leading to the formation of
8
zwitterionic intermediates. In principle, in the presence of
phosphine, a nucleophilic attack to MBH alcohols will occur to
give a phosphorus ylide, which may perform a further 1,3-
hydrogen transfer between the hydroxy and the carbon anion
to form a new zwitterionic intermediate (Scheme 1b). This
ylide may act as a reactive species in new reactions, and thus
the direct activation of MBH alcohols is realized. This will
open a new road for the application of various MBH adducts.
Encouraged by this design, we began our attempts on the
Received: May 22, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01783
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
application of ylides from MBH alcohols in organic synthesis.
We herein report phosphine-catalyzed tandem annulation
reactions of Morita−Baylis−Hillman alcohols with azomethine
imines, giving 3D heterocyclic compounds, which are highly
valuable molecular scaffolds in the development of medicines
Table 2. Scope of MBH Alcohols
9
and agrochemicals (Scheme 1c).
Initially, we chose the azomethine imine 1a and the Morita−
Baylis−Hillman adduct 2a as the model substrates for
screening reaction conditions (Table 1). The reaction worked
entry
R1/R2
3
t (min)
yield (%)
b
1
2
3
4
5
6
7
8
9
C H /Me (2a)
2-FC H /n-Pr (2b)
3-FC H /n-Pr (2c)
4-FC H /Me (2d)
2-ClC H /n-Pr (2e)
3-ClC H /n-Pr (2f)
4-ClC H /n-Pr (2g)
2-BrC H /n-Pr (2h)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
6
5
5
5
4
3
4
5
6
6
5
7
9
9
6
6
5
96
89
98
97
96
97
98
84
87
91
98
94
95
96
95
98
89
95
93
80
70
65
68
6
5
a
Table 1. Optimization of the Reaction Conditions
6
4
6
4
6
4
6
4
6
4
6
4
6
4
3-BrC H /n-Pr (2i)
4-BrC H /n-Pr (2j)
b
6
4
entry
cat.
none
solvent
CH Cl
t (min)
3aa/4aa yield (%)
1
0
3aj
3ak
3al
6
4
c
1
2
3
4
5
6
7
240
120
8
6
6
60
4
20
90
0/94
2
2
11
12
13
14
15
16
17
18
19
20
2-MeC H /n-Pr (2k)
6
4
PPh3
CH Cl
2
2
2
2
2
2
2
2
2
49/trace
92/0
96/0
90/0
80/0
90/0
89/0
75/0
3-MeC H /n-Pr (2l)
6
4
PPh Me
CH Cl
2
2
4-MeC H /n-Pr (2m)
3am
3an
3ao
3ap
3aq
3ar
3as
3at
6
4
PPhMe2
CH Cl
2
2-MeOC H /n-Pr (2n)
6
4
PBu3
CH Cl
2
3-MeOC H /n-Pr (2o)
6
4
DABCO
DBU
CH Cl
2
4-MeOC H /n-Pr (2p)
6
4
CH Cl
2
2-naphthyl/Me (2q)
2-thiophenyl/Me (2r)
N-Boc-3-indole/n-Pr (2s)
styryl/n-Pr (2t)
Et/n-Pr (2u)
i-Pr/Me (2v)
d
8
PPhMe2
CH Cl
2
5
5
5
40
70
120
e
9
PPhMe2
CH Cl
2
a
Unless otherwise indicated, reactions of 1a (0.10 mmol) and 2a
(
0.12 mmol) were carried out at 25 °C in the presence of catalyst
21
22
23
3au
3av
3ax
(
0.02 mmol) in 1.5 mL of the solvent. The dr is >20:1, determined by
1
b
c
H NMR analysis. Isolated yield. dr is 2.8:1, determined by isolated
Cy/Me (2x)
d
e
yields. 10 mol % catalyst was used. 5 mol % catalyst was used.
a
Unless otherwise indicated, reactions of 1a (0.10 mmol) and 2 (0.12
mmol) were carried out at 25 °C in the presence of catalyst (0.02
1
mmol) in 1.5 mL of the solvent. The dr is >20:1, determined by H
NMR analysis. Isolated yield.
in CH Cl at room temperature without any catalyst, giving an
undesirable thermal [3 + 2] cycloadduct 4aa in 94% yield with
b
2
2
around 3:1 diastereomeric ratio (dr) (Table 1, entry 1). To our
delight, under the catalysis of PPh , the reaction afforded the
longer reaction times (entries 21−23). The relative config-
3
desired product 3aa in 49% yield with >20:1 dr (entry 2).
Next, we examined different phosphine catalysts, all of which
uration of the product was assigned through X-ray crystallo-
10
graphic analysis of 3ax.
efficiently promoted the reaction (entries 3−5). PPhMe
Subsequently, 6-fluoro-substituted quinazoline-derived
imine was tested for the reaction, and the cycloadduct 3ba
was obtained in 84% yield in 60 min (Table 3, entry 1),
whereas 6-methyl-substituted quinazoline-derived dipole pro-
vided 86% yield of the product 3cw (entry 2). Different
sulphonyl protecting groups for the quinazoline-based dipoles
were also carefully evaluated. No matter the position or the
electronic property of the substituents on the benzene ring of
the sulphonyl group, the corresponding products (3dw−3gw)
were furnished in high yields (entries 3−6).
Next, we explored the asymmetric version of this tandem
annulation by using chiral phosphine (Table 4). The results
showed that bifunctional phosphine C1 delivered 3aa at 0 °C
in high yield, albeit with low ee (entry 1). In contrast, C2
showed very low catalytic activity and enantioselectivity (entry
2). Spirophosphine C3 afforded 3aa in excellent 95% yield
with 15% ee (entry 3). Decreasing the reaction temperature to
−35 °C, an improved but still low enantioselectivity was
achieved as 21% ee (entry 4).
2
exhibited the highest catalytic activity, giving 96% yield of
product 3aa in 6 min (entry 4). Other Lewis bases such as
DABCO and DBU could also efficiently catalyze this reaction.
With the use of DABCO as the catalyst, an 80% yield of
product 3aa was obtained (entry 6), and DBU resulted in a
better 90% yield (entry 7). Decreasing the catalyst loading to
1
0 and 5%, a satisfactory 89 and 75% were still accomplished,
respectively (entries 8 and 9).
Under the optimized conditions, a variety of aryl-substituted
MBH adducts were explored for the reaction with azomethine
imine 1a. As indicated in Table 2, in general, MBH adducts
with different substituents on the benzene ring, regardless of
the electronic properties or position of the substituents, gave
high yields of the corresponding products within <10 min
(entries 1−16). The fused aromatic- or heteroaromatic-group-
substituted MBH adducts were also suitable substrates for the
reaction and produced the products with excellent yields
within 5 min (entries 17 and 18). To our delight, N-Boc-3-
indole-substituted and styryl-substituted MBH adducts deliv-
ered the heterocyclic products with 93 and 80% yields in 5
min, respectively (entries 19 and 20). In addition, the alkyl-
substituted MBH adducts worked well, too, albeit they cost
As indicated in Scheme 2a, this phosphine-catalyzed tandem
reaction is scalable, being able to accomplish the gram-scale
synthesis of the cycloadduct 3aa in 85% yield. The treatment
of product 3aa with Boc O and DMAP at rt for 12 h achieved
2
B
DOI: 10.1021/acs.orglett.9b01783
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Scope of Azomethine Imines
Scheme 2. Reaction on the Gram Scale, Further
Transformations, and Kinetic Resolution
1
2
3
b
entry
R /R /R
6-F/4-MeC H /Me
3
t (min)
yield (%)
1
2
3
4
5
6
3ba
3cw
3dw
3ew
3fw
3gw
60
15
5
6
6
84
86
92
92
90
85
6
4
6-Me/4-MeC H /n-Pr
6
4
H/C H /n-Pr
6
5
H/1-Nap/n-Pr
H/4-t-BuC H /n-Pr
H/2-MeC H /n-Pr
6
4
5
6
4
a
Unless otherwise indicated, reactions of 1 (0.10 mmol) and 2 (0.12
mmol) were carried out at 25 °C in the presence of catalyst (0.02
1
mmol) in 1.5 mL of the solvent. The dr is >20:1, determined by H
b
NMR analysis. Isolated yield.
a
Table 4. Optimization of Asymmetric Reaction Conditions
Scheme 3. Plausible Reaction Mechanism
b
c
,
d
philic substitution reaction resulted in the final product 3aa
with the simultaneous regeneration of phosphine catalyst.
In summary, we have developed a phosphine-catalyzed
tandem reaction of Morita−Baylis−Hillman alcohols with
azomethine imines. Under phosphine catalysis, the direct
activation of unmodified MBH alcohols has been achieved for
the first time. A variety of MBH alcohols functioned as a new
type of oxa-synthon to react with azomethine imines under
mild reaction conditions, providing a series of biologically
important functionalized (epoxymethano)-pyrazolo[5,1-b]-
quinazoline derivatives in high yields with excellent diaster-
eoselectivities. An asymmetric variant under the catalysis of
spirophosphine C3 afforded a chiral product in high yield with
excellent diastereoselectivities and up to 21% ee. The reaction
provides a very useful tool for the synthesis of pharmaceutically
important 3D heterocyclic compounds, indicating that the
unmodified MBH adducts have great potential in synthetic
chemistry through direct activation.
entry catalyst T (°C)
solvent
CH Cl
t (h) yield (%)
ee (%)
1
2
3
4
C1
C2
C3
C3
0
0
0
8
12
8
95
21
95
92
13
3
15
21
2
2
CH Cl
2
2
2
2
CH Cl
2
−35
CH Cl
24
2
a
Unless otherwise indicated, reactions of 1a (0.10 mmol) and 2a
0.25 mmol) were carried out in the presence of catalyst (0.02 mmol)
in 1.5 mL of the solvent. The dr is >20:1, determined by H NMR
(
1
b
c
analysis. Isolated yield. ee was determined by chiral HPLC analysis.
d
After recrystallization.
the protection of the amino group, giving the derivative 5 in
2% yield. Further treatment of 5 with LiAlH provided the
reduction product 6 in 65% yield, whereas the direct reduction
of 3aa failed (Scheme 2b). In the presence of compound 7 and
Na CO as a base, a 1,4-addition occurred to provide
functionalized product 8 in 86% yield (Scheme 2b).
As displayed in Scheme 3, a plausible stepwise mechanism
was proposed for this tandem reaction. Phosphine attacked
MBH alcohol 2a to form the zwitterionic intermediate I, which
isomerized to the zwitterionic intermediate II via a proton
transfer. The oxygen anion then underwent a nucleophilic
addition to the electron-deficient carbon−nitrogen double
bond of 1a to generate intermediate III. A subsequent proton
shift lead to the intermediate IV, which performed an
intramolecular Mannich-type reaction to give the intermediate
V. The consequent proton shift and intramolecular nucleo-
8
4
2
3
8
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.9b01783.
Experimental procedure, characterization data, HPLC
analysis data, NMR spectra, and X-ray crystallographic
data (PDF)
C
DOI: 10.1021/acs.orglett.9b01783
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
Cyclopenta [b] annulated Arenes and Heteroarenes. Angew. Chem.,
Int. Ed. 2016, 55, 1777.
4) For selected reviews, see: (a) Liu, T.-Y.; Xie, M.; Chen, Y.-C.
Organocatalytic Asymmetric Transformations of Modified Morita−
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Organocatalytic Enantioselective Methodologies using Morita−
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Derivatives (MBHADs): Versatile Reactivity in Lewis Base-Promoted
Annulation. Org. Biomol. Chem. 2015, 13, 8578.
CCDC 1882911 and 1914325 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(
AUTHOR INFORMATION
Corresponding Authors
■
(
5) For selected examples of MBH acetates, see: (a) Wang, X.;
Meng, F.; Wang, Y.; Han, Z.; Chen, Y.; Liu, L.; Wang, Z.; Ding, K.
Aromatic Spiroketal Bisphosphine Ligands: Palladium-Catalyzed
Asymmetric Allylic Amination of Racemic Morita−Baylis−Hillman
Adducts. Angew. Chem., Int. Ed. 2012, 51, 9276. (b) Wang, X.; Guo,
P.; Han, Z.; Wang, X.; Wang, Z.; Ding, K. Spiroketal-Based
Diphosphine Ligands in Pd-Catalyzed Asymmetric Allylic Amination
of Morita−Baylis−Hillman Adducts: Exceptionally High Efficiency
and New Mechanism. J. Am. Chem. Soc. 2014, 136, 405. (c) Han, X.;
Yao, W.; Wang, T.; Tan, Y. R.; Yan, Z.; Kwiatkowski, J.; Lu, Y.
Asymmetric Synthesis of Spiropyrazolones through Phosphine-
Catalyzed [4 + 1] Annulation. Angew. Chem., Int. Ed. 2014, 53,
643. (d) Wang, X.; Wang, X.; Han, Z.; Wang, Z.; Ding, K.
Palladium-Catalyzed Asymmetric Allylic Allylation of Racemic
Morita−Baylis−Hillman Adducts. Angew. Chem., Int. Ed. 2017, 56,
116. (e) Liu, J.; Han, Z.; Wang, X.; Meng, F.; Wang, Z.; Ding, K.
Palladium-Catalyzed Asymmetric Construction of Vicinal Tertiary
and All-Carbon Quaternary Stereocenters by Allylation of β-
Ketocarbonyls with Morita−Baylis−Hillman Adducts. Angew. Chem.,
Int. Ed. 2017, 56, 5050.
(6) For selected examples of MBH carbonates, see: (a) Jiang, Y.-Q.;
Shi, Y.-L.; Shi, M. Chiral Phosphine-Catalyzed Enantioselective
Construction of γ-Butenolides through Substitution of Morita−
Baylis−Hillman Acetates with 2-Trimethylsilyloxy Furan. J. Am. Chem.
Soc. 2008, 130, 7202. (b) Cui, H.-L.; Feng, X.; Peng, J.; Lei, J.; Jiang,
K.; Chen, Y.-C. Chemoselective Asymmetric N-Allylic Alkylation of
Indoles with Morita−Baylis−Hillman Carbonates. Angew. Chem., Int.
Ed. 2009, 48, 5737. (c) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Highly
Enantioselective [3 + 2] Annulation of Morita−Baylis−Hillman
Adducts Mediated by L-Threonine-Derived Phosphines: Synthesis of
*
E-mail: 2014026@cau.edu.cn (B.Z.).
E-mail: hchguo@cau.edu.cn (H.G.).
*
ORCID
Hongchao Guo: 0000-0002-7356-4283
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
5
This work is supported by the Natural Science Foundation of
China (nos. 21572264 and 21871293), the Program for
Changjiang Scholars, and the Innovative Research Team
Project (no. IRT1042).
1
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DOI: 10.1021/acs.orglett.9b01783
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Organic Letters
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DOI: 10.1021/acs.orglett.9b01783
Org. Lett. XXXX, XXX, XXX−XXX