One-step synthesis of diazaspiro[4.5]decane scaffolds with exocyclic double bonds

Article abstract of DOI:10.1039/c4ob00516c

Unactivated yne-en-ynes reacted with a range of substituted aryl halides in the presence of Pd(OAc)₂-PPh₃ to afford diazaspiro[4.5]decane with exocyclic double bonds. Three carbon-carbon bonds are formed in this domino reaction, which involves highly regioselective C-C coupling and spiro scaffold steps. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00516c

Organic &
Biomolecular Chemistry
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One-step synthesis of diazaspiro[4.5]decane
scaffolds with exocyclic double bonds†
Cite this: Org. Biomol. Chem., 2014,
12, 5356
Lidong Li, Qiong Hu, Pingping Zhou, Haifeng Xie, Xiaorong Zhang, Hao Zhang,
Yadong Hu, Fei Yin and Yimin Hu*
Received 7th March 2014,
Accepted 11th June 2014
DOI: 10.1039/c4ob00516c
www.rsc.org/obc
Unactivated yne-en-ynes reacted with a range of substituted aryl
Waldmann reported a highly enantioselective Lewis acid-
halides in the presence of Pd(OAc)2–PPh3 to afford diazaspiro[4.5]- catalyzed 1,3-dipolar cycloaddition for the synthesis of biologi-
decane with exocyclic double bonds. Three carbon–carbon bonds cal 3,3′-pyrrolidinyl-spirooxindoles.6
are formed in this domino reaction, which involves highly regio-
Domino reaction strategies for the preparation of spiro
scaffolds have found significant applications in synthetic
design.7,8 In the current study, novel domino methods9 have
been developed to synthesize 4,9-dimethylene-2,7-diazaspiro-
[4.5]decane compounds through intermolecular and sub-
sequent coupling reduction that led directly to spiro ring
scaffolds through the treatment of the linear yne-en-yne. This
study focuses on the development of a palladium-catalyzed
strategy10 for the design of spiro scaffolds. Thus, we used the
palladium-catalyzed reactions of a to g (Table 2) with aryl
halides, providing a direct, efficient, and economical methodo-
logy for the construction of the naturally occurring and bio-
logically active azaspirodecane core.11
selective C–C coupling and spiro scaffold steps.
Natural-product-inspired scaffolds are a rich source of com-
pounds with diverse bioactivities.1 The challenging molecular
architecture and potential biological activities were developed
by a synthesis based on a rational synthetic design both
efficiently and economically.2 Ding and co-workers developed
an efficient synthesis of chiral aromatic spiroketals and rele-
vant diphosphine ligands.3 Methods for the synthesis of four
spiro [4.5], [5.5], and [5.6] system scaffolds were reported for
drug discovery (Scheme 1).4 Barbas reported on a highly
efficient organocatalytic domino Michael–aldol approach for
the direct construction of quaternary bispirocyclic oxindole
derivatives.5
A survey of the reaction conditions using yne-en-yne (a) and
4-bromobezonitrile as
a test experiment was performed
(Table 1). The efficiency of the domino reaction can be con-
siderably enhanced by increasing the reaction temperature to
130 °C. By contrast, higher reaction temperatures (>145 °C)
lead to the decomposition of aa, as shown by TLC. The addi-
tive bases played an important role in the efficiency of this
domino reaction by simply varying the bases from caesium
carbonate to tributylamine under otherwise identical con-
ditions, as well as furnishing the unexpected 4,9-dimethylene-
2,7-diazaspiro[4.5]decane aa in 86% yield. Among the catalysts,
{Pd(PPh3)4, Pd(dba)2–PPh3, PdCl2–PPh3, Pd(OAc)2–PPh3, and
[AuCl(PPh3)–AgSbF6], [Rh(COD)2]+SbF6−}, Pd(OAc)2–PPh3 have
been found to be most effective. DMF has been proven to be a
better solvent than toluene. Thus, the following standard reac-
tion conditions have been selected to conduct substrate inves-
tigations: yne-en-yne (1 equiv.) reacted with different aryl
halides (1.1 equiv.) in the presence of 2 mol% of Pd(OAc)2 and
4 mol% of Ph3P with nBu3N (2 equiv.) as an additive in DMF
at 130 °C.
Scheme 1 Representative examples of diazaspiro ring scaffolds.
Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Key
Laboratory of Molecular-Based Materials, School of Chemistry and Materials
Science, Anhui Normal University, Wuhu, Anhui 241000, China.
E-mail: yiminhu@mail.ahnu.edu.cn; Fax: +86 553 388 3517; Tel: +86 553 386 9310
†Electronic supplementary information (ESI) available: Experimental procedures
Illustrative examples of the novel spiro scaffolds scope are
shown in Table 2. Interestingly, various yne-en-ynes and substi-
tuted aryl halides are compatible with this palladium-catalyzed
and characterization of all new compounds. CCDC 965252, 965254 and 965256.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ob00516c
5356 | Org. Biomol. Chem., 2014, 12, 5356–5359
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Table 1 Palladium-catalyzed domino reactions for the formation of diazaspiro[4.5]decanea
Entry
[Pd] [mol%]
Base [equiv.]
Solvent
t [h]
T [°C]
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2–PPh3 (1 : 2)
Pd(OAc)2–PPh3 (2 : 4)
Pd(OAc)2–PPh3 (2 : 4)
Pd(OAc)2–PPh3 (2 : 4)
Pd(OAc)2–PPh3 (2 : 4)
Pd(OAc)2–PPh3 (2 : 4)
Pd(OAc)2–PPh3 (2 : 4)
Pd(OAc)2–PPh3 (2 : 4)
Pd(OAc)2–PPh3 (2 : 4)
Pd(OAc)2–PPh3 (2 : 4)
Pd(PPh3)4 (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
Cs2CO3 (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Toluene
DMF
DMF
DMF
DMF
DMF
20
16
20
24
20
20
20
20
20
20
20
20
20
20
20
130
130
130
130
145
120
110
130
130
130
130
130
130
130
130
22
79
86
86
53
73
19
13
30
41
11
50
14
38
59
9
10
11
12
13
14
15
Pd(dba)2–PPh3 (2 : 4)
PdCl2–PPh3 (2 : 4)
AuCl(PPh3)–AgSbF6 (2)
[Rh(COD)2]+SbF6− (2)
a General conditions: all reactions were carried out under argon. b Isolated yield after flash column chromatography. dba = dibenzylidene acetone.
Table 2 Palladium-catalyzed domino reaction for the formation of fused spiro scaffoldsa
Entry
S
Y/R1
R2C6H4X
Product
Yieldb (%)
1
2
3
4
5
6
7
8
a
a
a
a
a
b
b
b
c
c
c
c
d
d
d
d
e
e
e
f
PG = Ts; R1 = H
p-NCC6H4Br
aa
ab
ac
ad
ae
ba
bb
bc
ca
cb
cc
cd
da
db
dc
dd
ea
eb
ec
fa
86
76
78
77
71
76
74
78
85
83
76
78
83
84
68
66
61
62
51
74
67
69
PG = Ts; R1 = H
p-CH3OCC6H4Br
p-OHCC6H4Br
m-NCC6H4Br
m-CH3OCC6H4Br
p-NCC6H4Br
p-CH3OCC6H4Br
m-NCC6H4Br
p-NCC6H4Br
p-CH3OCC6H4Br
p-CHO
m-NCC6H4Br
p-NCC6H4Br
p-CH3OCC6H4Br
m-NCC6H4Br
m-CH3OCC6H4Br
p-NCC6H4Br
p-CH3OCC6H4Br
m-CH3OCC6H4Br
p-NCC6H4Br
PG = Ts; R1 = H
PG = Ts; R1 = H
PG = Ts; R1 = H
PG = Ts; R1 = p-CH3
PG = Ts; R1 = p-CH3
PG = Ts; R1 = p-CH3
PG = Ts; R1 = p-F
9
10
11
12
13
14
15
16
17
18
19
20
21
22
PG = Ts; R1 = p-F
PG = Ts; R1 = p-F
PG = Ts; R1 = p-F
PG = Ts; R1 = o-F
PG = Ts; R1 = o-F
PG = Ts; R1 = o-F
PG = Ts; R1 = o-F
PG = Benzenesulfonyl; R1 = H
PG = Benzenesulfonyl; R1 = H
PG = Benzenesulfonyl; R1 = H
PG = Benzenesulfonyl; R1 = p-CH3
PG = Benzenesulfonyl; R1 = p-CH3
PG = Benzenesulfonyl; R1 = p-CH3
f
f
p-CH3OCC6H4Br
m-NCC6H4Br
fb
fc
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Table 2 (Contd.)
Entry
S
Y/R1
R2C6H4X
Product
Yieldb (%)
23
24
25
26
27
g
g
g
g
a
PG = Benzenesulfonyl; R1 = p-F
PG = Benzenesulfonyl; R1 = p-F
PG = Benzenesulfonyl; R1 = p-F
PG = Benzenesulfonyl; R1 = p-F
PG = Ts; R1 = H
p-NCC6H4Br
ga
gb
gc
gd
aa
77
72
75
67
76
p-CH3OCC6H4Br
m-NCC6H4Br
m-CH3OCC6H4Br
p-NCC6H4I
a General conditions: a–g (1.0 equiv.), R2C6H4X (X = Br; I) (1.1 equiv.), Pd(OAc)2 (2 mol%), PPh3 (4 mol%), nBu3N (2 equiv.), DMF 10 mL, 130 °C,
20 h. b Isolated yield after flash column chromatography.
one-pot domino reaction. Diazaspiro[4.5]decane compounds
with exocyclic double bonds were readily isolated in good to
excellent yields when aryl halides with electron-withdrawing
groups, including ketyl or cyano, were employed. Additionally,
2-methylene-N1,N3-bis(3-phenylprop-2-yn-1-yl)propane-1,3-
diamine was employed with various substituted groups includ-
ing para- or ortho-substituted groups on the benzene ring (i.e.,
methyl and fluoro). Using aryl halides with yn-en-ynes sub-
strates, the reaction yielded 9-benzylidene-4-(diphenylmethy-
lene)-2,7-diazaspiro[4.5]decanes aa, ca, cb, da, and db, with
yields above 80%. The yield of compound aa was the highest at
86%. Simultaneously, the desired 4,9-dimethylene-2,7-diaza-
spiro[4.5]decanes were obtained in good yields ranging from
Fig. 1 The molecular structure of compound ga. Thermal ellipsoids are
66% to 78% when a number of yn-en-ynes were used in the drawn at the 30% probability level.
reaction with aryl bromides (ab–ae, ba–bc, cc, cd, dc, dd, fa–fc,
ga–gd). The comparison of the substrates f and g revealed that
including both yne-en-ynes and aryl halides, and the generality
the electronic properties of the substrates also influenced the
regioselectivity of both yne-en-ynes and aryl bromides. The
results indicated that fc and gc exhibited good yields at 69%
and 75%, respectively. However, the yield of the desired
product was slightly reduced when iodobenzene was
employed.
of this process make the reaction highly valuable because of
the synthetic and medicinal importance of these spiro hetero-
cycles. The mechanism is still not clear. Further investigations
that aim to better understand this catalytic transformation,
evaluate the process with a broader scope of substrates, syn-
thesize more complex products, and explore their biological
activity tests are in progress in our laboratory.
The authors thank the National Natural Science Foundation
of China (21272005 and 21072003) and the Department of
Human Resources of Anhui Province for financial support.
The authors also thank Dr Yun Wei and Prof. Xiaolong Mu for
X-ray crystallography.
All the resulting spiro scaffolds were confirmed by one- (1H,
13C) and two-dimensional (COSY) NMR spectral analyses, and
elemental or HR-MS analyses, respectively. The molecular
structures of fa, ga (Fig. 1), and gb were confirmed using
single-crystal X-ray analyses (see the ESI† for details).12
In summary, we have developed a palladium-catalyzed
domino reaction for the synthesis of spiro scaffold dicycles
through multistep C–C bond formation by treatment of the
yne-en-ynes with a range of substituted aryl halides that afford
diazaspiro[4.5]decane with exocyclic double bond derivatives
in moderate to very good yields and excellent regioselectivity.
This process provides a new methodology for the synthesis of
the spiro heterocyclic ring system. The ready accessibility of
the starting materials, a wide range of compatible substrates
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