Phosphane-Catalyzed [3+3] Annulation of C,N-Cyclic Azomethine Imines with Ynones: A Practical Method for Tricyclic Dinitrogen-Fused Heterocycles

Article abstract of DOI:10.1002/adsc.201600223

A phosphane-catalyzed [3+3] annulation of azomethine imines with ynones has been developed. Under mild reaction conditions, the reaction proceeds smoothly to afford tricyclic dinitrogen-fused heterocyclic compounds in moderate to excellent yields with moderate to excellent stereoselectivies. Using a chiral phosphine as the catalyst, the reaction could work to give the cycloadduct in moderate yield with moderate enantioselectivity. (Figure presented.) .

Full text of DOI:10.1002/adsc.201600223

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DOI: 10.1002/adsc.201600223
Phosphane-Catalyzed [3+3] Annulation of C,N-Cyclic Azome-
thine Imines with Ynones: A Practical Method for Tricyclic
Dinitrogen-Fused Heterocycles
Zhen Li,a Hao Yu,a Yang Liu,a Leijie Zhou,a Zhanhu Sun,a and Hongchao Guoa,*
a
Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan Road, Beijing 100193, Peopleꢀs
Republic of China
Fax: (+86)-10-6273-0784; e-mail: hchguo@cau.edu.cn
Received: February 24, 2016; Revised: March 21, 2016; Published online: May 24, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600223.
Abstract: A phosphane-catalyzed [3+3] annulation
of azomethine imines with ynones has been devel-
oped. Under mild reaction conditions, the reaction
proceeds smoothly to afford tricyclic dinitrogen-
fused heterocyclic compounds in moderate to excel-
lent yields with moderate to excellent stereoselecti-
vies. Using a chiral phosphine as the catalyst, the
reaction could work to give the cycloadduct in mod-
erate yield with moderate enantioselectivity.
struction of spirocyclopentanone skeletons.[5] In 2013,
Ramachary and co-workers achieved a phosphane-
catalyzed Tomiat–Zipper cyclization of methyleneox-
indoles with 4-phenylbut-3-yn-2-one, providing func-
tionalized five-membered spirooxindoles.[6] Most re-
cently, Du developed phosphane-promoted [4+2] an-
nulation reactions of unsaturated pyrazolones with
but-3-yn-2-one and [3+2] annulation reactions of un-
saturated pyrazolones with 4-phenylbut-3-yn-2-one,
providing pyrano[2,3-c]pyrazoles and spirocyclopent-
anonepyrazolones.[7] All these annulations have been
focused on the [3+2] or [4+2] annulation of the
ynone with electron-deficient alkenes or ketones; to
the best of our knowledge, the [3+3] annulation reac-
tion with the use of ynones as the phosphane acceptor
has never been reported.
Keywords: annulation; azomethine imines; hetero-
cycles; phosphanes; ynones
In the past two decades, nucleophilic phosphane-cata-
In the past five years, it has been demonstrated that
lyzed annulation reactions have intensely been ex- 1,3-dipoles formed in situ from the addition of a phos-
plored and have become a powerful tool for the syn- phane to a phosphane acceptor, could react with
thesis of synthetically useful or biologically important a stable 1,3-dipole to furnish a stepwise [3+X] annu-
carbocyclic and heterocyclic compounds,[1] and total lation reaction.[8] On the basis of this principle, when
syntheses of natural products.[2] These reactions gener- a stable 1,3-dipole meets with an ynone under phos-
ally proceed via zwitterionic intermediates formed in phane catalysis conditions, a [3+3] annulation might
situ from the addition of the Lewis basic phosphane be achieved. Among the various stable 1,3-dipoles,
to phosphane acceptors such as activated allenes, al- azomethine imines are highly valuable substrates and
kynes, MBH carbonates and acetates. Therefore, the have often served as three-membered synthons in
search for new phosphane acceptors and the explora- [3+2], [3+3] and [4+3] cycloaddition reactions for
tion of their reaction activities are among the key the synthesis of diverse biologically important dinitro-
tasks in the research on nucleophilic phosphane catal- gen-fused heterocyclic compounds,[9] which have dis-
ysis. In recent years, a new acceptor of phosphanes, played a wide range of bioactivities such as analgesic,
the ynone unit, has attracted attention. Under phos- antipyretic, anti-inflammatory, anorectic, antibacteri-
phane catalysis conditions, ynone acts as a C2 or C3 al, antitumor, anti-Alzheimer, herbicidal and pestici-
synthon to furnish various annulation reactions. In dal activities.[10] In consideration of these characteris-
2012, the Shi group and the Huang group explored tics, we chose an azomethine imine as the 1,3-dipole
the phosphane-catalyzed [3+2] annulation of ynones substrate and explored its annulation reaction with
with isatins, affording spiro[furan-2,3’-indoline]- ynones under phosphane catalysis conditions. Herein
2’,4(5H)-diones.[3,4] The Huang group presented we present the first example of a phosphane-catalyzed
a phosphane-catalyzed [3+2] annulation reaction of [3+3] annulation of azomethine imines with ynones
ynones and 2-arylideneindane-1,3-diones for the con- to deliver dinitrogen-fused heterocycles (Scheme 1).
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with PPh3 as the catalyst, a concise solvent screening
was performed. In several solvents such as CHCl3, tol-
uene, THF and CH3CN, no better results were ob-
tained (entries 4–7). In order to improve both yield
and selectivity of the reaction, we turned our atten-
tion to the use of different Brønsted acids as the addi-
tive, expecting that it would favour the reaction (en-
tries 8–12). To our delight, this strategy was found to
be effective in increasing the yield. In the presence of
Scheme 1. Phosphane-catalyzed [3+3] annulation of ynones
with azomethine imines.
In our initial study, the reaction of azomethine 20 mol% of benzoic acid, phenol, pivalic acid or
imine 1a with but-3-yn-2-one 2a was carried out in acetic acid, the yields were remarkably increased to
the presence of 20 mol% PPh3 in CH2Cl2 at room 86–92%. Particularly, when 20 mol% phenol was
temperature (Table 1, entry 1). The desired [3+3] an- used, the [3+3] annulation product 3aa was obtained
nulation product 3aa was obtained in 69% yield with in 91% yield, moreover the side-product 4 was not
>20:1 Z/E ratio. Unfortunately, the mixture of (Z)- observed (entry 9). In contrast, with the use of 2-
and (E)-isomers could not be separated by flash naphthol as the additive, the product was produced in
column. Furthermore, a trace amount of addition a relatively low yield (entry 12). Finally, the optimal
product 4 was observed. Using more nucleophilic reaction conditions were determined as 20 mol% of
phosphanes such as EtPPh2 and Me2PPh as the cata- Ph3P as the catalyst and 20 mol% phenol as the addi-
lyst, the yields deteriorated (entries 2 and 3). Next, tive in dichloromethane at room temperature.
Having established the optimal reaction conditions,
the scope of C,N-cyclic azomethine imines was first
Table 1. Optimization of the reaction conditions.[a]
explored. As shown in Table 2, various azomethine
imines with different substituents including electron-
neutral, electron-donating and electron-withdrawing
group were well tolerated, providing the desired prod-
ucts in high yields and good to excellent Z/E ratios
(entries 1–7). The substrates with electron-donating
groups on the phenyl ring gave better yields than
those bearing electron-withdrawing groups (entries 2–
4 vs. 5–7). The substrates with electron-withdrawing
groups seemed more active and were fully converted
in shorter times than those substrates with electron-
Table 2. Scope of the C,N-cyclic azomethine imines.[a]
Entry
Catalyst
Additive
Solvent
Yield [%][b]
[c]
1
2
3
4
5
6
7
8
PPh3
EtPPh2
Me2PPh
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
–
–
–
–
–
–
–
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
toluene
THF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
69
48
39
65
43
48
64
Entry
R in 1
Time [h]
3
Yield [%][b]
PhCO2H
phenol
PivOH
CH3CO2H
2-naphthol
92
9
91[d]
90
1
2
3
4
5
6
7
H (1a)
24
23
21
24
15
15
14
3aa
3ba
3ca
3da
3ea
3fa
3ga
91
79
88
84[c]
67
70
71
10
11
12
5-Me (1b)
7-Me (1c)
8-Me (1d)
7-Cl (1e)
5-Br (1f)
7-Br (1g)
86
58[d]
[a]
Unless noted otherwise, reactions were carried out in
2 mL of solvent using 0.1 mmol of 1a, 0.2 mmol of 2a and
20 mol% of phosphane.
Isolated yields, the Z/E ratio is >20:1, determined by
1H NMR analysis of the crude product. Unless noted oth-
erwise, a trace of the by-product 4, which could not be
separated out by flash column chromatography, was ob-
served.
[b]
[a]
Unless noted otherwise, reactions were carried out in
2 mL of CH2Cl2 using 0.1 mmol of 1, 0.2 mmol of 2a,
0.02 mmol of phenol in the presence of 20 mol% of Ph3P.
Isolated yields. Unless noted otherwise, the Z/E ratio is
>20:1, determined by 1H NMR analysis of the crude
product.
[b]
[c]
[c]
[d]
No additive.
No side product 4 was observed.
The Z/E ratio is 8:1.
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Table 3. Scope of the ynones.[a]
Z:E[b]
Figure 1. The X-ray crystallographic structure of (Z)-3ca.
Entry R in 2
R’ Time
3
Yield
[%][b]
[h]
1
2
3
4
5
6
7
8
3-MeC6H4 (2b)
H
H
H
H
H
H
H
H
H
H
H
H
22
36
22
22
22
20
11
18
11
14
10
14
3ab 78
3ac 80
3ad 73
3ae 71
3af 70
3ag 72
3ah 91
3ai 84
3aj 87
3ak 94
3al 88
3am 90
20:1
15:1
3:1
>20:1
>20:1
>20:1
5:1
6:1
3:1
12:1
4:1
3:1
donating groups, but a part of these substrates con-
verted into side products, leading to relatively lower
yields (entries 5–7). The major isomer of product 3
was unambiguously assigned to be Z-isomer according
to X-ray crystallographic data of the product 3ca
(Figure 1).[11] It is worth noting that using 1.25 g
(5 mmol) of azomethine imine 1a, the Ph3P-catalyzed
[3+3] annulation reaction of 1a with 2a still proceed-
ed smoothly in CH2Cl2 at room temperature for 24 h
to afford the product 3aa in 78% yield with >20:1 Z/
E. Compared with the yield of the reaction on the
milligram scale (Table 2, entry 1), the yield somewhat
dropped, but is acceptable. Thus this reaction could
be a practical method for the synthesis of dinitrogen-
fused heterocycles.
Next, a variety of ynones was synthesized and in-
vestigated in the [3+3] annulation reaction. As shown
in Table 3, the electronic properties of the substitu-
ents on the phenyl rings of the ynones 2 have a re-
markable influence on the activity of the reaction
(Table 3, entries 1–12). Compared with the substrates
(2b–2g) with electron-donating groups, the substrates
(2h–2m) bearing electron-withdrawing groups under-
went the [3+3] annulation to afford the products 3 in
higher yields (84–94% vs. 70–80%yields, entries 7–12
vs. 1–6). The substrates bearing electron-donating
groups or electron-withdrawing groups showed mod-
erate to good Z/E selectivity (entries 1–12). The pro-
tocol could also be applied to 4-biphenylyl and 2-
naphthyl ynones, providing [3+3] annulation products
4-MeC6H4 (2c)
4-EtC6H4 (2d)
4-n-PrC6H4 (2e)
4-nBuC6H4 (2f)
4-OMeC6H4 (2g)
3-FC6H4 (2h)
4-FC6H4 (2i)
9
3-ClC6H4 (2j)
4-ClC6H4 (2k)
4-BrC6H4 (2l)
4-CNC6H4 (2m)
10
11
12
13
H
22
3an 82
>20:1
14
H
H
Me 72
Et 72
17
22
3ao 76
5:1
15
16
17
18
19
2-thienyl (2p)
Ph (2q)
Ph (2r)
TMS (2s)
cyclohexyl (2t)
3ap 71
3aq 75
3ar 77
3:4[c]
1:1
>20:1
[d]
H
H
72
72
–
–
–
–
[d]
–
–
[a]
Reactions were performed in 2 mL of CH2Cl2 at room
temperature using 0.1 mmol of 1a, 0.2 mmol of 2,
0.02 mmol of phenol and 20 mol% of Ph3P.
Isolated yields. The Z/E ratio was determined by
1H NMR analysis of the crude product.
[b]
[c]
[d]
(Z)- and (E)-3ap were separated by flash column.
No reaction.
in high yields with good to excellent Z/E selectivities strates, the desired [3+3] annulation products could
(entries 13 and 14). The thienyl-substituted ynone not be obtained and only starting materials were re-
(2p) smoothly underwent the annulation reaction as covered (entries 18 and 19).
well, but the Z/E selectivity was very poor, moreover
An asymmetric variant of this phosphane-catalyzed
the (E)-isomer was produced as a major isomer [3+3] annulation of C,N-cyclic azomethine imines
(entry 15). Especially, the mixture of (Z)- and (E)-3ap with ynones was also investigated by employing sever-
could be separated by flash column. Both 1-phenyl- al chiral phosphanes (P1–P5) (Table 4). The [3+3] an-
pent-1-yn-3-one (2q) and 1-phenylhex-1-yn-3-one (2r) nulation of the C,N-cyclic azomethine imine 1a and
also worked under the standard reaction conditions to but-3-yn-2-one 2a was selected as a model reaction
give the cycloadducts in high yields, albeit requiring (Table 4). The thiourea and amino acid-based bifunc-
prolonged reaction time (entries 16 and 17). The rela- tional chiral phosphanes (P1–P3) demonstrated mod-
tive configurations of the compounds 3aq and 3ar had erate enantioselective catalytic capability, producing
not been determined because attempts to get their the desired product in 34–51% yield and 15–30% ee
single crystals and the analysis through 2D NMR data (Table 4, entries 1–4). In particular, the commercially
failed. Disappointedly, with trimethylsilylalkynyl available amino acid-based phosphane P3 gave an en-
ketone (2s) and cyclohexylalkynyl ketone (2t) as sub- couraging result (51% yield and 30% ee) (entry 3)
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Table 4. Screening of the reaction conditions for an asym-
metric variant.[a]
Entry Cat. Temp. [8C] Time [h] Yield [%][b] ee [%][c]
1
2
3
4
P1
P2
P3
P3
25
25
25
0
36
36
24
72
34
48
51
39
À15
À20
30
Scheme 2. A proposed mechanism of phosphane-catalyzed
[3+3] annulation.
20
[a]
proton shifts in phosphine-catalyzed annulations of al-
lenoates,[12] thus assisting the [1,2]- or [1,3]-hydrogen
shift. In this reaction, phenol might favor formation
of B from A and formation of E from D through as-
sisting [1,2]- and [1,3]-hydrogen shifts. In path b, the
Unless noted otherwise, reactions were carried out in
2 mL of CH2Cl2 using 0.1 mmol of 1a, 0.2 mmol of 2a,
0.02 mmol of phenol and 20 mol% of phosphane.
Isolated yields. The Z/E ratio is >20:1, determined by
1H NMR analysis of the crude product.
[b]
[c]
Determined by chiral HPLC analysis.
intermediate
C undergoes intramolecular proton
transfer and isomerization to give the intermediate J.
Subsequent elimination of phosphane produces Man-
(the absolute configuration of the product 3aa has not nich-type by-product 4.
been determined). However, with P3 as chiral cata-
In conclusion, the phosphane-catalyzed [3+3] annu-
lyst, the attempt to improve the enantioselectivity by lation of azomethine imines with ynones has been
decreasing the reaction temperature to 08C failed, achieved under mild reaction conditions, providing
only affording the cycloadditon product in 39% yield tricyclic heterocyclic compounds in high yields with
and 20% ee (entry 4). Unfortunately, the catalytic ac- moderate to excellent stereoselectivies. Using a com-
tivity of cyclic chiral phosphanes P4 and P5 was very mercially available amino acid-based phosphane as
weak, providing the cycloadduct in very low yield chiral catalyst, the reaction could work to give the cy-
with accompanying formation of side product 4.
cloadduct in moderate yield with moderate enantiose-
A plausible mechanism to account for the forma- lectivity. The present protocol provides a rapid, effi-
tion of the product 3 and side product 4 is proposed cient and practical method to construct valuable dini-
in Scheme 2. Ph3P acts as a nucleophilic promoter to trogen-fused heterocycles with potential biological ac-
initiate the reaction and undergoes an addition to tivity.
ynone 2a to produce zwitterionic intermediate A, fol-
lowed by proton transfer to give intermediate B,
which then undergoes conjugate addition to 1a to
afford intermediate C. In path a, the intermediate C
Experimental Section
performs intramolecular addition to give the inter-
mediate D. Subsequent proton transfer led to inter-
mediate E, which carries out elimination of Ph3P to
form the final product 3aa. Isotopic labeling experi-
General Procedure for Phosphane-Catalyzed [3+3]
Annulation Reactions of Azomethine Imines with
Ynones
ments and computation results had proved that water
or other protic sources can promote [1,2]- and [1,3]- (0.1 mmol) in 2 mL of CH2Cl2 was added but-3-yn-2-one
To
a stirred solution of C,N-cyclic azomethine imine
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(0.2 mmol) at room temperature. Phosphane (0.02 mmol)
was then added into the above solution. The resulting mix-
ture was stirred at room temperature for the specified time,
and was then concentrated. The residue was purified by
flash column (ethyl acetate/petroleum ether) to afford the
corresponding product.
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the
National
S&T
Pillar
Program
of
China
(2015BAK45B01), and Research Fund for the Doctoral Pro-
gram of Higher Education of China (No. 20120008110038).
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