Palladium-catalyzed [3+2] annulation of allenyl carbinol acetates with C,N-cyclic azomethine imines

Article abstract of DOI:10.1039/c9cc06670e

In this paper, a palladium-catalyzed [3+2] annulation of allenyl carbinol acetates with azomethine imines has successfully been developed under mild reaction conditions, affording biologically interesting tetrahydropyrazoloisoquinoline derivatives in high to excellent yields and with excellent stereoselectivity. The reaction follows a tandem [3+2] cycloaddition/allylation/elimination of AcOH pathway. Allenyl carbinol acetates also reacted well with in situ generated azomethine imine under cocatalysis of Ag(i)/Pd(0) catalysts in a similar reaction pathway.

Full text of DOI:10.1039/c9cc06670e

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Palladium-catalyzed [3+2] annulation of allenyl
carbinol acetates with C,N-cyclic azomethine
imines†
Cite this: Chem. Commun., 2019,
55, 12841
Received 27th August 2019,
Accepted 2nd October 2019
Biming Mao,a Junya Zhang,a Yi Xu,a Zhengyang Yan,a Wei Wang,b Yongjun Wu,b
a
Changqing Sun,b Bing Zhenga and Hongchao Guo
*
DOI: 10.1039/c9cc06670e
rsc.li/chemcomm
In this paper, a palladium-catalyzed [3+2] annulation of allenyl have never been reported. As part of our previous work on the
carbinol acetates with azomethine imines has successfully been Pd-catalyzed cycloaddition reaction of methylene-TMM5 and
developed under mild reaction conditions, affording biologically our continuing efforts on cycloaddition reactions,6 herein, we
interesting tetrahydropyrazoloisoquinoline derivatives in high to present the first palladium-catalyzed [3+2] annulation of allenyl
excellent yields and with excellent stereoselectivity. The reaction carbinol acetates with azomethine imines to furnish biologically
follows a tandem [3+2] cycloaddition/allylation/elimination of AcOH interesting functionalized dihydropyrazolo[5,1-a]isoquinoline
pathway. Allenyl carbinol acetates also reacted well with in situ derivatives7 (Scheme 1c).
generated azomethine imine under cocatalysis of Ag(I)/Pd(0) catalysts
in a similar reaction pathway.
We commenced our exploration with allenyl carbinol acetate
(1a) and C,N-cyclic azomethine imine (2a) as model substrates
(Table 1). Employing Pd(dba)2 (5 mol%)/PPh3 (11 mol%) as the
Transition metal-catalyzed cycloadditions are extremely power- catalyst, the allenyl carbinol acetate 1a was reacted with azomethine
ful tools for the convergent synthesis of diverse carbo- and
heterocyclic compounds.1 Readily accessible and versatile allenes
are often employed as key reaction partners for the development
of various cycloaddition reactions.2 Among all types of allene
compounds, allenyl carbinol esters demonstrated distinctive
capability in palladium catalysis and thus have attracted consider-
able attention in recent years.2 In general, under palladium
catalysis conditions, allenyl carbinol esters generate palladium-
butadienyl species A having diverse reactivities. Plenty of reports
dealt with allenylic substitution reactions of allenyl carbinol esters
through reaction of intermediate A with a variety of nucleophiles
to construct novel allene molecules (Scheme 1a).3 In comparison,
the cycloaddition reaction via palladium-butadienyl intermediates
was rarely studied.2 Most recently, utilizing the palladium-butadienyl
species from allenyl carbinol esters as four-membered synthons,
Shao and coworkers developed Pd-catalyzed asymmetric [4+1]
cycloaddition and [4+3] cycloaddition/cross coupling reaction to
construct valuable spiro- and bicyclic compounds (Scheme 1b).4
To the best of our knowledge, allenyl carbinol acetates serving as
two-carbon synthons for palladium-catalyzed [3+2] annulation
a Department of Applied Chemistry, China Agricultural University, Beijing 100193,
China. E-mail: hchguo@cau.edu.cn
b College of Public Health, Zhengzhou University, Zhengzhou 450001, China
† Electronic supplementary information (ESI) available. CCDC 1923209. For ESI
Scheme 1 Pd-Catalyzed allenylic substitutions and cycloaddition reactions
of allenic esters.
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9cc06670e
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Table 1 Screening of the reaction conditionsa
Table 2 Scope of allenyl carbinol acetates 1a
Entry
Ar
t/h
3
Yieldb (%)
1
2
3
4
5
6
7
8
Ph (1a)
2-FC6H4 (1b)
3-FC6H4 (1c)
4-FC6H4 (1d)
12
16
18
14
16
16
14
16
19
19
18
18
18
18
17
17
12
18
14
16
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
99
94
98
99
98
99
99
93
99
97
82
99
92
99
98
99
91
97
85
98
2-ClC6H4 (1e)
3-ClC6H4 (1f)
4-ClC6H4 (1g)
2,4-Cl2C6H3 (1h)
3,4-Cl2C6H3 (1i)
3,5-Cl2C6H3 (1j)
2-BrC6H4 (1k)
3-BrC6H4 (1l)
4-BrC6H4 (1m)
2-MeC6H4 (1n)
3-MeC6H4 (1o)
4-MeC6H4 (1p)
2-MeOC6H4 (1q)
3-MeOC6H4 (1r)
4-MeOC6H4 (1s)
2-Naphthyl (1t)
Entry
L
Solvent
t/h
Yieldb (%)
1
2
3
4
5
6
7
8
PPh3
dppe
dppbz
DPEphos
Xantphos
L1
L1
L1
L1
L1
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
CH3CN
Toluene
AcOEt
AcOEt
12
16
16
16
16
12
12
24
12
24
12
12
88
89
52
79
90
91
90
77
76
87
94
99
9
10
11
12
13
14
15
16
17
18
19
20
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
3ra
3sa
3ta
9
10
11
12c
L1
L1
a
Unless otherwise indicated, all the reactions were carried out with 1a
(0.20 mmol) and 2a (0.10 mmol) in 1 mL of solvent at rt using Pd(dba)2
a
All the reactions were performed with 1 (0.20 mmol), 2a (0.1 mmol),
Pd(dba)2 (0.005 mmol) and L1 (0.011 mmol) in ethyl acetate (2 mL) at
b
(5 mol%)/L (11 mol%) as the catalyst under argon. Isolated yield.
c
b
2 mL of solvent was used.
25 1C under argon. Isolated yield.
imine 2a in 1,2-dichloroethane (DCE) at 25 1C (entry 1). reaction to give 98% yield of product 3ta (entry 20). The
The reaction completed in 12 h to give the [3+2] cycloadduct products’ structures were resolved using X-ray crystallographic
in 88% yield. According to this initial result, we next evaluated data of product 3aa.8 Only E-isomers were produced in all the
several diphosphine ligands and a phosphoramidite ligand (L1) cases (entries 1–20).
(entries 2–6). Most ligands resulted in high yields (entries 2
Next, diversified azomethine imines were synthesized and
and 4–6), except for dppbz (entry 3). Ligand L1 proved to be a evaluated in this [3+2] annulation (Table 3). Several halogenated
promising ligand, yielding the 2,3-dihydropyrazole derivative 3aa and methyl-substituted azomethine imines furnished the corres-
in 91% yield (entry 6). Using the L1 ligand, we then screened ponding products in high to excellent yields (entries 1–8).
several solvents such as dichloromethane (DCM), THF, CH3CN, A special tricyclic azomethine imine (2j) acted efficiently, producing
toluene, and ethyl acetate (AcOEt) (entries 7–11). The results 99% yield of the product (entry 9). Azomethine imines with
revealed that ethyl acetate was the optimal solvent, leading to a different benzoyl protecting groups performed the reaction
94% yield (entry 11). Additionally, when 2 mL of ethyl acetate was well (entries 10–16). The substrate bearing an acetyl protecting
used to increase the solubility of 2a under otherwise identical group also worked, delivering the corresponding product in
conditions, the yield was increased to 99% yield (entry 12). 65% yield (entry 17).
Consequently, we established the optimized reaction conditions
as follows: using Pd(dba)2 (5 mol%) and phosphoramidite L1 in situ generated azomethine imine (Scheme 2). In the presence
(11 mol%) as the catalyst in 2 mL of ethyl acetate at 25 1C. of AgOTf, hydrazide 2s could easily be transformed into azo-
In particular, allenyl carbinol acetate also reacted well with
Subsequently, under the best reaction conditions, we applied methine imine in situ, which then reacted with allenyl carbinol
this [3+2] annulation reaction to a variety of substituted allenyl acetate 1a under catalysis of Pd(PPh3)4 in one-pot to produce
carbinol acetates 1 for construction of 2,3-dihydropyrazole deriv- the desired product 3as in 72% yield.
atives (Table 2). In general, this protocol can be implemented for
An asymmetric version of the reaction was also investigated
a series of allenyl carbinol acetates 1 and the corresponding (Table 4). Several axially chiral phosphoramidite ligands were
products were obtained in good to excellent yields (82–99%) tried (entries 1–4). Using S3 as a chiral ligand, a moderate 51%
(entries 1–20). The halides including fluorine, chlorine, and bromine ee was obtained (entry 3). A screening of several solvents such
as well as electron-donating groups such as methyl and methoxyl as DCM, THF, CH3CN, toluene, Et2O and CF3Ph (entries 5–10)
and their substitution position on the benzene ring had no revealed that the reaction in toluene led to 87% yield and 80% ee
significant impact on reaction efficiency (entries 1–19). In addition, (entry 8). However, a further attempt to improve enantioselectivity
naphthyl-substituted allenyl carbinol acetate 1t executed the failed.
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Table 3 Scope of the C,N-cyclic azomethine imines 2a
Table 4 Investigation on asymmetric variantsa
Entry
R1/R2
t/h
3
Yieldb (%)
1
2
3
4
5
6
7
8
7-F/Ph (2b)
5-Cl/Ph (2c)
6-Cl/Ph (2d)
5-Br/Ph (2e)
6-Br/Ph (2f)
7-Br/Ph (2g)
5-Me/Ph (2h)
7-Me/Ph (2i)
26
26
23
26
20
24
17
17
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
70
76
95
80
91
75
85
92
Entry
Sx
Solvent
t/h
Yieldb (%)
eec (%)
9
24
3aj
99
1
2
3
4
5
6
7
8
9
S1
S2
S3
S4
S3
S3
S3
S3
S3
S3
DCE
DCE
DCE
DCE
DCM
THF
CH3CN
Toluene
Et2O
24
48
12
36
12
20
10
20
12
12
90
70
91
80
90
77
76
87
86
87
À7
À40
51
41
61
67
47
80
79
10
11
12
13
14
15
16
17
H/4-FC6H4 (2k)
H/4-ClC6H4 (2l)
H/4-BrC6H4 (2m)
H/4-MeC6H4 (2n)
H/4-MeOC6H4 (2o)
H/4-CF3C6H4 (2p)
H/4-NO2C6H4 (2q)
H/Me (2r)
16
12
12
12
16
16
19
16
3ak
3al
90
99
99
92
78
98
88
65
3am
3an
3ao
3ap
3aq
3ar
10
CF3Ph
77
a
All the reactions were performed with 1a (0.20 mmol), 2 (0.1 mmol),
Pd(dba)2 (0.005 mmol) and L1 (0.011 mmol) in ethyl acetate (2 mL) at
a
Unless otherwise indicated, all the reactions were performed with 1a
(0.20 mmol) and 2a (0.10 mmol) in the presence of Pd(dba)2 (5 mol%)
b
25 1C under argon. Isolated yield.
b
and a chiral ligand (11 mol%) in 1 mL of solvent. Isolated yield.
c
Determined by HPLC analysis using a chiral stationary phase.
Scheme 2 Ag(I)/Pd(0)-Catalyzed one-pot intramolecular cyclization/
[3+2] cycloaddition reaction.
As shown in Scheme 3, Pd-catalyzed [3+2] annulation operated
successfully on a 2 mmol scale (0.5 g) and completed in 12 h
under the standard reaction conditions to produce product 3aa in
97% yield. Product 3aa was subjected to hydrogenation promoted
by Pd/C, giving products 4a and 4b in 54% and 15% yield,
respectively. SmI2-Mediated ring-opening led to tetrahydroiso-
quinoline 5 in 58% yield.
To investigate the mechanism of this reaction, control experi-
ments were designed and performed (Scheme 4). Without the use of
palladium catalyst and ligand L1, no annulation product 3aa was
observed. When only phosphine ligand L1 was employed under
similar standard conditions without Pd(dba)2, the desired product
3aa could also not be observed. These results suggest that the
Scheme 3 Scale-up reaction and further transformations of the cycloadduct.
palladium catalyst formed from Pd(dba)2 and L1 did catalyze this acetate 1a undergoes [3+2] cycloaddition with azomethine imine 2a,
reaction and phosphine could not work as an organocatalyst to affording intermediate II. Subsequent allylation of the acetyloxy
promote this reaction. In fact, the successful asymmetric reaction in anion gave intermediate III and regenerated the Pd catalyst. Further
Table 4 has proved that the palladium complex formed from elimination of acetic acid generated product 3aa. Furthermore, we
Pd(dba)2 and phosphine worked as the catalyst in this reaction.
conducted a mass spectrometry analysis study on the reaction
According to our previous work,5 some related reports2,4 and mixture. As illustrated in Scheme 5, the key species II and III have
the results in Scheme 4, we described a logical mechanism in been successfully detected, further elucidating the rationalization of
Scheme 5. Pd-Butadienyl intermediate I from allenyl carbinol the proposed pathway.
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Conflicts of interest
There are no conflicts to declare.
Notes and references
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In conclusion, palladium-catalyzed [3+2] annulation has
been accomplished under mild reaction conditions to give
the functionalized tetrahydropyrazoloisoquinoline derivatives
in good to excellent yields. The reaction follows a tandem [3+2]
cycloaddition/allylation/elimination of AcOH pathway. This is
the first example of allenyl carbinol acetates acting as C2
synthons for annulation reactions.
This work was supported by the National Natural Science
Foundation of China (No. 21572264, 21871293) and the Chinese
Universities Scientific Fund (No. 2018TC052, 2018TC055 and
2019TC085).
8 Crystallographic data for 3aa have been deposited with the
Cambridge Crystallographic Data Centre as deposition number
CCDC 1923209†.
12844 | Chem. Commun., 2019, 55, 12841--12844
This journal is ©The Royal Society of Chemistry 2019