Phosphine-initiated domino reaction: A convenient method for the preparation of spirocyclopentanones

Article abstract of DOI:10.1002/asia.201301641

An efficient synthetic approach has been developed for the construction of the spirocyclopentanone skeleton via a phosphine-catalyzed [3+2] annulation reaction. With this novel and economical protocol, various quaternary carbon-centered spirocyclopentanones could be readily obtained. New domino reaction: An efficient synthetic approach has been developed for the construction of spirocyclopentanone skeletons via a phosphine catalyzed [3+2] annulation reaction of ynones and 2-arylideneindane-1,3-diones. With this novel and economical protocol, various quaternary carbon-centered spirocyclopentanones could be obtained readily under mild conditions in excellent yields.

Full text of DOI:10.1002/asia.201301641

COMMUNICATION
DOI: 10.1002/asia.201301641
Phosphine-Initiated Domino Reaction: A Convenient Method for the
Preparation of Spirocyclopentanones
Ling Liang, Erqing Li, Peizhong Xie, and You Huang*[a]
Abstract: An efficient synthetic approach has been devel-
oped for the construction of the spirocyclopentanone skele-
ton via a phosphine-catalyzed [3+2] annulation reaction.
With this novel and economical protocol, various quaternary
carbon-centered spirocyclopentanones could be readily ob-
tained.
been paid to ynone derivatives in organocatalytic domino
reactions.[9] Recently, Tomita and Fu reported elegant intra-
molecular cycloaddition reactions.[10] Later on, Shi et al.[11]
and Huang et al.,[12] respectively, reported on phosphine-cat-
alyzed intermolecular [3+2] cycloaddition reactions of
ynones with N-substituted isatins. Recently, asymmetric var-
iants of the intermolecular [3+2] cycloaddition reactions of
ynones have also been reported by other groups.[13] Based
on these pioneering studies and our own work on phos-
phine-catalyzed domino reactions,[14] herein we report
a phosphine-catalyzed intermolecular domino annulation re-
action of ynones with 2-arylideneindane-1,3-diones that de-
livers efficiently spirocyclopentanones. In this reaction, air-
and water-stable, inexpensive phosphine instead of sensitive
metals was used as catalyst, and environmentally benign eth-
anol was used as solvent. The domino reaction could pro-
ceed smoothly to produce the desired adducts in excellent
yields under mild conditions.
Carbocyclic spiro motifs are the structural centerpieces of
biologically active products, chiral ligands, and new materi-
als (Figure 1). For example, fredericamycin A[1], which was
isolated from a new strain of Streptomyces griseus, exhibits
antitumor activity, and dimethyl gloiosiphone A exhibits an-
Initially, we carried out the reaction of ynone 1a with 2-
arylideneindane-1,3-dione 2a in CHCl3 in the presence of
benzoic acid (30 mol%) by using 10 mol% phosphine as
catalyst. Encouragingly, the annulation product 3a was iso-
lated in 74% yield (Table 1, entry 1). The yield could be im-
proved to 93% by increasing the catalyst loading to
30 mol% (Table 1, entry 2). To optimize the performance of
Figure 1. Representative spirocyclic compounds.
timicrobial activity against several Staphylcoccus, Bacillus,
and Salmonella species.[2] Furthermore, their rigid structures
make them ideal candidates for the development of chiral li-
gands, which have been applied successfully to various reac-
tions (Figure 1).[3] Thus, great attention has been drawn to
the development of efficient methods to build these spirocy-
clic systems.[4]
Table 1. Optimization of reaction conditions for the domino reaction.[a]
In the past decades, phosphine-catalyzed domino reac-
tions[5] have become a powerful tool in the construction of
carbo- and heterocycles.[6] While electron-deficient alkenes[7]
and alkynes[8] have been well studied, little attention has
Entry
Solvent
Cat. [%]
t
Yield[b]
1
2
3
4
CHCl3
CHCl3
CHCl3
CHCl3
THF
PPh3 (10)
PPh3 (30)
PPh2Et (30)
24 h
20 h
20 h
18 h
5 d
7 d
7 d
24 h
24 h
15 h
2 d
74
93
83
81
NR
84
60
82
85
90
80
PACHTNGUTER(NNUG p-OMePh)3 (30)
5[b]
6
DABCO (30)
PPh3 (30)
PPh3 (30)
PPh3 (30)
PPh3 (30)
PPh3 (30)
PPh3 (30)
[a] L. Liang, E. Li, P. Xie, Prof. Dr. Y. Huang
State Key Laboratory and Institute of Elemento-organic chemistry
Collaborative Innovation Center of Science and Engineering (Tian-
jin)
THF
7
8
9
toluene
CH2Cl2
CH3CN
EtOH
EtOH
Nankai University
Tianjin 30071 (China)
Fax : (+86)22-23503627
10
11[c]
E-mail: hyou@nankai.edu.cn
[a] Reaction conditions: 1a (0.75 mmol), 2a (0.5 mmol), 30 mol%
PhCOOH, 3.0 mL solvent, room temperature. [b] Isolated yields. [c] The
reaction was carried out without PhCOOH.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201301641.
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You Huang et al.
Table 2. Investigation of the substrate scope.[a]
the reaction, various catalysts and solvents were investigated
(Table 1, entries 3–11). However, other phosphine catalysts
did not lead to better results, and no reaction occurred
when 1,4-diazabicycloACTHUNGTRENNG[U 2.2.2]octane (DABCO) was used as
a catalyst (Table 1, entries 3–5). Solvent screening revealed
that the solvent significantly affected the reaction perfor-
mance (Table 1, entries 6–10). EtOH was identified as the
optimal reaction medium for this reaction. In the absence of
benzoic acid, a lower yield of product was obtained, even at
a prolonged reaction time (Table 1, entry 11). In addition,
the structure and stereochemistry of 3a was determined by
a combination of NMR spectroscopy, high-resolution mass
spectrometry (HRMS), and single-crystal X-ray analysis
(Figure 2).[15]
Entry
R1
R2
R3
t [h]
Yield[b]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
15
10
10
10
10
10
10
12
12
3
24
12
48
53
20
35
18
18
21
21
22
14
90 (3a)
93 (3b)
96 (3c)
90 (3d)
91 (3e)
95 (3 f)
94 (3g)
88 (3h)
87 (3i)
90 (3j)
73 (3k)
62 (3l)
87 (3m)
84 (3n)
96 (3o)
89 (3p)
95 (3q)
97 (3r)
83 (3s)
84 (3t)
NR (3u)
86 (3d)
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
4-Cl-C6H4
4-F-C6H4
4-OMe-C6H4
4-NO2-C6H4
2,4-Cl-C6H3
2-furyl
2-thienyl
1-naphthyl
styryl
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
9
10[c]
11
12
13
14
15
16
17
18
19
20
21
22[d]
Ph
Ph
Me
di-Me
H
H
Me
H
4-F-C6H4
4-Me-C6H4
nBu
Ph
[a] Unless otherwise noted, reaction conditions were: 1a (0.75 mmol), 2a
(0.5 mmol), 30 mol% PhCOOH, 30 mol% PPh3, 3.0 mL solvent, room
temperature. [b] Isolated yields. [c] The reaction was carried out at 708C
at a 2:1 ratio of 1:2. [d] The reaction was carried out with 3.0 mmol 2d.
Figure 2. X-ray crystal structure of 3a.
butyl, no reaction occurred. Furthermore, for one represen-
tative example, we showed that the reaction could be car-
ried out on a gram scale to afford the desired product 3d
without loss of reactivity (entry 22).
In further studies, we were delighted to find that the reac-
tion of ynone 1a, indane-1,3-dione, and p-Br-benzaldehyde
Next, the reaction of various ynones and 2-arylidenein-
dane-1,3-diones 2 was evaluated under the optimized reac-
tion conditions (Table 1, entry 10), and the results are shown
in Table 2. In all cases, the reactions proceeded smoothly to
produce the desired products in good to excellent yields
(73–97%).
in the presence of
a catalytic amount of l-proline
Various substrates 2 bearing diverse aromatic groups on
R3 could participate in the domino reactions to afford the
corresponding products with excellent yields (Table 2, en-
tries 2–9). In the presence of a strong electron-donating
(10 mol%) and PPh3 (30 mol%) at room temperature in
EtOH furnished the desired product 3d in 44% yield
(Scheme 1). In this multicomponent reaction, multiple ste-
reocenters were generated in a single step.
À
group ( OMe), an increase in temperature was required
To demonstrate the practicality of our method, the asym-
metric variant of this domino reaction was also investigated
in a basic manner, with l-valine-derived phosphine[16] as
a catalyst (Scheme 2). In this reaction, 3b was obtained with
(Table 2, entry 10). It is worth noting that 2-arylidenein-
dane-1,3-diones bearing strong electron-withdrawing groups
on R3 resulted in somewhat lower yields (Table 2, en-
tries 11–12).2-Arylideneindane-1,3-diones bearing 2-furyl, 2-
thiophenyl, and 2-naphthyl also gave rise to the desired
products in high yields, albeit at prolonged reaction times
(Table 2, entries 13–15). Pleasingly, a substrate with a vinylic
group could participate in the reaction efficiently (Table 2,
entry 16). Different ynones were also probed, and products
were obtained with excellent yields (Table 2, entries 17–20).
When 1-phenylpent-1-yn-3-one was used, 3q was obtained
as a single isomer (Table 2, entry 17). The steric hindrance
at the a position of the ynone only slightly influenced the
reaction (Table 2, entry 18). Unfortunately, when R1 was n-
Scheme 1. One-pot reaction.
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You Huang et al.
Scheme 2. Reaction catalyzed by l-valine-derived phosphine.
Scheme 4. The proposed reaction mechanism.
and ethanol) and elimination of the catalyst yield the final
product 3a. An analogous mechanistic proposal pertaining
to the synthesis of spirocyclic oxindoles has been postulated
by other groups during the preparation of this manuscript.[19]
In theory, there are three possible structures for the inter-
mediate II generated from ynones and phosphine (Figure 2).
On the basis of the results obtained by DFT calculations, we
found that the thermodynamically most stable structure is II
Scheme 3. Control experiments.
a promising enantiomeric excess of 16% and a yield of
53%.
Next, control experiments were carried out to investigate
the reaction mechanism (Scheme 3). As previously men-
tioned, the additive accelerates the reaction (Table 1, en-
tries 10 and 11). We speculated that the proton migration
process might be accelerated by PhCOOH. To examine this
possibility, 1a-D3 was synthesized, and the reaction was car-
ried out in dry CHCl3. In this reaction, deuterated product
3a’ was obtained in 88% yield, and deuterium was found
not only at the a carbon but also at the d carbon. This result
indicated that the deuterium atom at the d position came
from the a position. Furthermore, when the reaction was
carried out in the presence of 20 equivalents of D2O, deuter-
ated product 3a’’ was obtained in 89% yield, and 89% deu-
terium was incorporated in the product 3a’’ both at the
a and d positions, respectively. This result shows that the re-
action first undergoes a rapid H/D exchange at the a posi-
tion of the ynone to produce 1a-D3;[17] accordingly, a similar
result was obtained for the two different control experi-
ments.
On the basis of the above experimental results and previ-
ous studies,[10–13] we propose a plausible reaction mechanism
for the domino reaction (Scheme 4). The reaction was ra-
tionalized to proceed in a tandem manner. First, the nucleo-
philic attack of the phosphine catalyst on ynone 1a gener-
ates the intermediate I, which subsequently undergoes
a proton shift (mediated by benzoic acid and ethanol)[18] and
produces the enolate II. Subsequently, enolate II nucleophil-
ically adds to 2-arylideneindane-1,3-dione 2a to furnish in-
termediate III. Intramolecular nucleophilic addition of the
carbanion to the double bond then delivers cyclic intermedi-
ate IV. Finally, proton migration (assisted by benzoic acid
À
because a significant intramolecular P O interaction stabil-
À
izes this intermediate (Figure 3). The short P O distance be-
Figure 3. DFT-computed relative enthalpies and free energies of three
possible structures of intermediate II.
tween the phosphorus and carbonyl oxygen atoms is
2.000 ꢁ.[20] The excellent stereoselectivity in the [3+2] pro-
À
cess might thus be attributed to the P O interaction, which
exists in the reaction steps (intermediates II–V).
In summary, we have successfully developed an environ-
mentally friendly synthetic strategy for preparing highly
functionalized spiro-cyclopentanones in good to excellent
yields; this transformation constructed two new bonds and
one ring with both reactants being completely used. The re-
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You Huang et al.
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action can be performed in the environmentally benign sol-
vent ethanol and showed good functional group tolerance.
Readily available starting materials, mild reaction condition,
and an inexpensive catalyst make this reaction valuable in
synthetic chemistry. We expect that this protocol could be
potentially applied to the synthesis of carbocyclic spiro
motifs present in natural products.
Experimental Section
Ynones 1 (0.75 mmol), 2-arylideneindane-1,3-diones 2 (0.5 mmol), and
benzoic acid (30 mol%) were dissolved in EtOH (3.0 mL). Subsequently,
PPh3 (30 mol%) was added, and the reaction mixture was stirred at
room temperature. After complete conversion, as indicated by thin-layer
chromatography (TCL), all volatiles were removed in vacuo, and the resi-
due was purified by column chromatography (petroleum ether/ethyl ace-
tate=10:1).
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Acknowledgements
This work was supported financially by the National Natural Science
Foundation of China (21172115, 20972076) and the Research Fund for
the Doctoral Program of Higher Education of China (20120031110002).
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Keywords: annulation · domino reaction · phosphine · spiro
compounds · ynone
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Received: December 10, 2013
Published online: February 23, 2014
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