Phosphane- and amine-catalyzed ring-opening reactions of cyclopropenones with isatin derivatives: Synthesis of carboxylated 1H-indoles and multisubstituted 2H-pyran-2-ones

Article abstract of DOI:10.1002/ejoc.201400077

The phosphane- and amine-catalyzed ring-opening reactions of cyclopropenones with isatin derivatives give different reaction outcomes. Under phosphane catalysis, carboxylated 1H-indoles are afforded in good yields, and under amine catalysis, multisubstituted 2H-pyran-2-ones are provided in moderate yields. The mechanistic aspects of these reactions are discussed on the basis of control experiments. Phosphane- and amine-catalyzed ring-opening reactions of cyclopropenones with isatin derivatives are developed. These reactions offer a facile synthetic method to construct carboxylated 1H-indoles and multisubstituted 2H-pyran-2-ones; Boc = tert-butoxycarbonyl, DABCO = 1,4-diazabicyclo[2.2.2]octane. Copyright

Full text of DOI:10.1002/ejoc.201400077

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201400077
Phosphane- and Amine-Catalyzed Ring-Opening Reactions of Cyclopropenones
with Isatin Derivatives: Synthesis of Carboxylated 1H-Indoles and
Multisubstituted 2H-Pyran-2-ones
Wen-Tao Zhao,[a] Xiang-Ying Tang,*[b] and Min Shi*[a,b]
Keywords: Small ring systems / Organocatalysis / Ring opening reactions / Phosphanes / Amines
The phosphane- and amine-catalyzed ring-opening reac-
tions of cyclopropenones with isatin derivatives give dif-
ferent reaction outcomes. Under phosphane catalysis, carb-
oxylated 1H-indoles are afforded in good yields, and under
amine catalysis, multisubstituted 2H-pyran-2-ones are pro-
vided in moderate yields. The mechanistic aspects of these
reactions are discussed on the basis of control experiments.
difficulty of such reactions relies on the high reactivity of
cyclopropenones, which causes either dimerization or fur-
ther undesired transformations with other reagents during
the process of the reaction.
Introduction
In 1959, the chemistry of cyclopropenone started as first
reported independently by Breslow and Volpin.[1] Since
then, cyclopropenones have drawn great attention from or-
ganic chemists as a result of their unique structure and reac-
tivity.[2] According to the Hückel rule, cyclopropenones
have a resonance form (aromatic cation) in which a negative
charge lies on the oxygen atom, and the aromatic nature of
the species makes the oxygen atom even more nucleophilic
than other ordinary carbonyl compounds (Figure 1). Con-
sequently, cyclopropenones are widely used as trapping
agents for electrophiles;[3] moreover, they have also emerged
as a powerful means to activate alcohols, aldoximes, and
primary amides by acting as organocatalysts.[4] As α,β-un-
saturated ketones, cyclopropenones are also treated as elec-
trophiles in 1,2- and 1,4-nucleophilic addition reactions.[5]
Moreover, the strain on cyclopropenones allows them to
easily take part in cycloaddition reactions owing to their
high activity.[6] Similar to other strained small ring mol-
ecules such as cyclopropenes, large ring strain[7] is another
factor attributing to the high reactivity of cyclopropenones,
and their transformations such as ring opening[8] and ring
enlargement[9] are frequently found in the literature. How-
ever, though intensively investigated, the reaction of cyclo-
propenones catalyzed by organocatalysts is quite challeng-
ing, and only very few examples have been reported.[10] The
Figure 1. Aromatic stabilization of cyclopropenes.
In the context of our ongoing efforts to investigate the
organocatalysis of diverse transformations of electron-
deficient alkenes such as the Morita–Baylis–Hillman reac-
tion[11] and other related reactions,[12] we attempted to find
a new representative instead of acrylate derivatives, ketenes,
or allenic esters. We envisaged that cyclopropenones would
be a good alternative in such transformations. Herein, we
wish to report the phosphane- and amine-catalyzed ring-
opening reactions of cyclopropenones with isatin deriva-
tives, which provides a facile synthetic method to construct
carboxylated 1H-indoles and multisubstituted 2H-pyran-2-
ones under mild conditions.
Results and Discussion
[a] Key Laboratory for Advanced Materials and Institute of Fine
Chemicals
We started our investigation by optimizing the PPh3-cat-
alyzed nucleophilic addition of isatin derivative 2a (Boc =
tert-butoxycarbonyl) to cyclopropenone 1a, and the results
are shown in Table 1. Upon adding a solution of cyclo-
propenone 1a (2 equiv.) to a mixture of 2a and PPh3
(20 mol-%) by using a syringe pump, all reactions pro-
ceeded smoothly in THF, CH2Cl2, MeCN, and toluene at
25 °C to deliver carboxylated 1H-indole 3a in 82–93% yield
School of Chemistry & Molecular Engineering, East China
University of Science and Technology,
130 Mei Long Road, Shanghai 200237 China
[b] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032 China
E-mail: Mshi@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400077.
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Ring-Opening Reactions of Cyclopropenones with Isatin Derivatives
(Table 1, entries 1–4). MeCN proved to be the best solvent
in this reaction, as it gave corresponding product 3a in 93%
yield (Table 1, entry 3). The structure of analogue 3c was
unambiguously determined by X-ray diffraction (Fig-
ure 2).[13] Next, we studied the ratio of 1a/2a by varying the
loading of 1a. Increasing the ratio of 1a/2a to 2.5 or
decreasing it to 1.5 or 1.0 impaired the production of 3a
dramatically (Table 1, entries 5–7). The optimal ratio was
2:1. Examination of the temperature revealed that 3a was
obtained in slightly lower yield at both 0 and 40 °C than at
25 °C (Table 1, entries 8 and 9). Upon adding 10 mol-%
PPh3, the yield of 3a decreased to 80% (Table 1, entry 10).
Moreover, if all the starting materials and catalyst were
mixed together in one portion, the reaction became sluggish
and 3a was delivered in only 24% yield; this suggests that
cyclopropenone is very reactive to undergo a self-reaction
or polymerization with the formation of complex product
mixtures (Table 1, entry 11).
Figure 2. ORTEP drawing of 3c.
Table 1. Screening of the reaction conditions catalyzed by PPh3.[a]
ployed as substrates, such as 1b (Ar1 = 4-MeC6H4) and 1c
(Ar1 = 4-FC6H4), which led to products 3k and 3l in 88%
and 86% yield, respectively (Table 2, entries 11 and 12).
Table 2. Scope of the reaction catalyzed by PPh3.[a]
Entry
1a/2a
Solvent
t [°C]
3a, yield [%][b]
1
2
3
4
5
6
7
8
2:1
2:1
2:1
2:1
1.5:1
1:1
2.5:1
2:1
2:1
2:1
2:1
THF
25
25
25
25
25
25
25
0
91
82
93
91
77
21
43
87
80
80
24
CH2Cl2
MeCN
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Entry
1, Ar1
2, R/Ar2
3, yield [%][b]
9
40
25
25
1
2
3
4
5
6
7
8
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
2a, H/C6H5
3a, 93
3b, 97
3c, 83
3d, 93
3e, 98
3f, 98
3g, 96
3h, 79
3i, 97
3j, 85
3k, 88
3l, 86
10[c]
11[d]
2b, H/2-MeC6H4
2c, H/3-MeC6H4
2d, H/4-MeC6H4
2e, H/3,5-Me2C6H3
2f, H/4-FC6H4
2g, H/3-FC6H4
2h, 5-F/4-FC6H4
2i, C10H7
[a] Conditions (unless otherwise specified): 2a (0.2 mmol), PPh3
(20 mol-%), solvent (1.5 mL), molecular sieves (4 Å, 50 mg); 1a
(0.4 mmol in 1.5 mL solvent) was added by syringe pump over
30 min. [b] Yield of isolated product. [c] Loading of PPh3: 10 mol-
%. [d] 1a, 1b, and PPh3 were added in one pot.
9
10
11
12
2j, 5-MeO/C6H5
1b, 4-MeC6H4 2a, H/C6H5
1c, 4-FC6H4 2a, H/C6H5
With the best reaction conditions in hand, we next
turned our efforts to study the scope and limitations of this
phosphane-catalyzed nucleophilic addition reaction (Table 2).
By using 1a as the model substrate, isatins 2 with different
aryl substituents at the C3 position (R = H) were tested,
and the corresponding carboxylated 1H-indoles 3a–g were
obtained in excellent yields without the observation of a
[a] Conditions (unless otherwise specified): 2a (0.2 mmol), PPh3
(20 mol-%), solvent (1.5 mL), molecular sieves (4 Å, 50 mg); 1a
(0.4 mmol in 1.5 mL solvent) was added by syringe pump over
30 min. [b] Yield of isolated product.
An explanation for the reaction sequence is depicted in
significant electronic impact (Table 2, entries 1–7). As for Scheme 1 by using 1a and 2a as models. The 1,4-addition
substrates 2h (5-F, Ar2 = 4-FC6H4) and 2j (5-MeO, Ar2 = of PPh3 with 1a gives zwitterionic intermediate A, which
C6H5), the reactions also proceeded smoothly and delivered abstracts a proton from the enolate resonance structure of
corresponding products 3h and 3j in 79 and 85% yield, 2a to deliver enolate B and cationic intermediate C. Inter-
respectively (Table 2, entries 8 and 10). Treatment of 3- molecular nucleophilic addition of B and C produces zwit-
naphthyl-substituted substrate 2i under the standard reac- terionic intermediate D, which undergoes elimination to
tion conditions gave desired product 3i in 97% yield give the corresponding carboxylated 1H-indole 3a together
(Table 2, entry 9). Other cyclopropenones were also em- with the regenerated PPh3 catalyst.
Eur. J. Org. Chem. 2014, 2672–2676
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W.-T. Zhao, X.-Y. Tang, M. Shi
SHORT COMMUNICATION
Table 3. Screening of the reaction conditions catalyzed by amines.[a]
Entry 1a/2a Catalyst Solvent
Yield [%]
isolated after recrystalli-
product
zation
1
2
3
4
5
6
7
8
2.5:1 DIPEA
2.5:1 Et3N
2.5:1 DBU
2.5:1 DMAP
2.5:1 DABCO THF
2:1 DABCO THF
1.5:1 DABCO THF
1:1 DABCO THF
1:1.5 DABCO THF
1:2 DABCO THF
1.5:1 DABCO CH2Cl2
1.5:1 DABCO toluene
1.5:1 DABCO 1,4-dioxane
1.5:1 DABCO MeCN
1.5:1 DABCO DMF
1.5:1 DABCO MeCN
1.5:1 DABCO MeCN
THF
THF
THF
THF
57
82
85
79
86
82
90
88
80
74
53
60
52
91
73
61
29
10
19
19
17
20
23
25
15
15
7
10
15
10
35
9
9
Scheme 1. Plausible mechanism for the reaction catalyzed by PPh3.
10
11
12
13
In general, the nitrogen atom is more electronegative and 14
more basic than the phosphorus atom. These two factors
15
16[b]
20
8
can majorly account for the differences between nitrogen-
and phosphane-containing organocatalysts. With respect to
this aspect, we also attempted to investigate the catalytic
behavior of nitrogen-containing catalysts (tertiary amines
and pyridine) in the reaction of 1 with 2. To our delight,
upon treating 1a and 2a in the presence of N,N-diisopropyl-
ethylamine (DIPEA, 20 mol-%) in THF for 1 h, new prod-
uct 4a was obtained in 57% yield (Table 3, entry 1). Its
structure was identified by X-ray diffraction of analogue
4d (Figure 3).[14] The structure contains a 2H-pyran-2-one
moiety, which is built at the 3-carbon of the indoline back-
bone. Other nitrogen-containing catalysts such as Et3N,
1,8-diazabicyclo[5,4,0]-7-undecene (DBU), 4-N,N-dimeth-
ylpyridine (DMAP), and 1,4-diazabicyclo[2,2,2]octane
(DABCO) all showed good catalytic activity in this reac-
tion, but DABCO gave the best result and furnished 4a in
86% yield (Table 3, entries 2–5). Next, with the use of
DABCO as the catalyst, a survey aimed at finding the opti-
mal ratio of 1a/2a was conducted (Table 3, entries 6–10).
The results indicated that the addition of 1.5 equiv. 1a by
syringe pump to a mixture of 2a and DABCO in THF re-
sulted in the highest yield (90%) of 4a (Table 3, entry 7).
Solvent effects were then investigated. Changing the solvent
to CH2Cl2, toluene, 1,4-dioxane, and DMF significantly re-
duced the yield of 4a (Table 3, entries 11–13 and 15). No-
tably, the use of MeCN produced 4a in 91% yield (Table 3,
entry 14). However, the addition of 1a or 2a by syringe
17[c]
[a] The reaction was performed on a 0.2 mmol scale (for 2a) in
solvent (2 mL) at room temperature (25 °C). [b] 1a was added by
syringe pump over 30 min. [c] 2a was added by syringe pump over
30 min.
Figure 3. ORTEP drawing of 4d.
To examine the substrate scope of this reaction, several
pump over 30 min decreased the yield of 4a significantly isatin derivatives 2 with different aryl substituents Ar2 were
(Table 3, entries 16 and 17). Noteworthy is that a trace first investigated by using 1a as a model substrate (Table 4).
amount of byproduct 5a (an analogue of 5g shown in Fig- The Ar2 substituents did not have a significant electronic
ure 4), which could not be completely separated from 4a, or steric impact on this reaction, and corresponding prod-
was observed on the basis of the NMR spectroscopic data. ucts 4a–h were afforded in good yields (Table 4, entries 1–
Fortunately, after recrystallization, 4a was obtained in pure 8). As for substrates 2i (R = 6-Br, Ar2 = C6H5), 2j (R = 5-
form, and the recrystallization yields are all indicated in MeO, Ar2 = C6H5), and 2k (R = 5-F, Ar2 = 4-FC6H4),
Table 3.
corresponding products 4i, 4j, and 4k were also obtained in
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Eur. J. Org. Chem. 2014, 2672–2676

Ring-Opening Reactions of Cyclopropenones with Isatin Derivatives
cyclopropenone were incorporated into the structure (Fig-
ure 4, also see the Supporting Information).
A plausible mechanism for the formation of 4 is pro-
posed in Scheme 2 by using 1a as a model. First, DABCO
abstracts one proton from 2 to generate anionic species A
(Nu–), which then initiates a 1,4-addition to the C=C bond
of 1a on the less sterically hindered side to furnish enolate
intermediate B. Subsequent intermolecular nucleophilic ad-
dition of intermediate B to another molecule of 1a takes
place to give intermediate C. After a ring-opening process
and intramolecular nucleophilic addition, intermediate C is
transformed into cyclopropane-containing anionic interme-
diate D through a concerted manner, and it then undergoes
another ring-opening process to generate intermediate E.
After protonation, final product 4 is formed together with
the regenerated catalyst.
Figure 4. The X-ray structure of 5g.
46, 80, and 67% yield, respectively (Table 4, entries 9–11).
Next, by using 2a as the model substrate, a variety of cyclo-
propenones 1 were investigated. Similar to the phosphane-
catalyzed reaction, substituents with different electronic
properties did not significantly affect the reaction outcome,
and 2H-pyran-2-ones 4l–n were furnished in 70–85% yield
(Table 4, entries 12–14). In all cases, the yield of 4 after
recrystallization is indicated in Table 4.
Table 4. Scope of the reaction catalyzed by DABCO.[a]
Scheme 2. Plausible mechanism for the reaction catalyzed by
amines.
Entry 1, Ar1
2, R/Ar2
Product
Yield [%]
isolated after
product recryst.
Conclusions
In summary, we developed phosphane- and amine-cata-
lyzed ring-opening reactions of cyclopropenones with isatin
derivatives to afford carboxylated 1H-indoles and multisub-
stituted 2H-pyran-2-ones in moderate to excellent yields.
These two products are the key intermediates in the synthe-
sis of biologically active compounds.[16] The methodology
displayed broad substrate scope and functional group com-
patibility, and the desired products were obtained under
very mild conditions. The unique activity of the cyclopro-
penones under the organocatalysis conditions was expli-
cated by proposed mechanisms. Further investigations to
examine the mechanistic details more extensively are un-
derway in our laboratory.
1
2
3
4
5
6
7
8
1a, C6H5
2a, H/C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
91
69
70
74
92
81
90
72
46
80
67
70
85
77
35
42
25
15
44
30
13
23
15
12
11
15
18
20
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1c, 4-FC6H4
2b, H/2-MeC6H4
2c, H/3-MeC6H4
2d, H/4-MeC6H4
2e, H/3,5-Me2C6H3
2f, H/4-FC6H4
2g, H/3-FC6H4
2h, H/C10H7
9
2i, 6-Br/C6H5
10
11
12
13
14
2j, 5-MeO/C6H5
2k, 5-F/4-FC6H4
2a, H/C6H5
1d, 3-ClC6H4 2a, H/C6H5
1e, 3-MeC6H4 2a, H/C6H5
[a] Conditions: 1 (0.75 mmol), 2 (0.5 mmol), DABCO (20 mol-%),
molecular sieves (4 Å, 100 mg), MeCN (5 mL), 25 °C, 1 h.
Experimental Section
Upon using 2g and 1a as substrates, the structure of by-
product 5g was identified by X-ray diffraction,[15] which
General Procedure for the Preparation of 3: A flame-dried Schlenk
indicated that two molecules of isatin and one molecule of flask was charged with substrate 2 (0.2 mmol), PPh3 (11 mg,
Eur. J. Org. Chem. 2014, 2672–2676
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W.-T. Zhao, X.-Y. Tang, M. Shi
SHORT COMMUNICATION
react with 1,3-dipoles and activated dienes to afford [3+2] and
[4+2] cycloadducts, see: b) A. Kascheres, J. A. R. Rodrigues, R.
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0.04 mmol), and molecular sieves (4 Å, 50 mg). Then, dry MeCN
(1.5 mL) was added. Compound 1 (0.4 mmol) in MeCN (1.5 mL)
was added by syringe over 30 min. The reaction mixture was stirred
at room temperature under an atmosphere of argon. Upon comple-
tion of the reaction, the mixture was evaporated under reduced
pressure, and the residue was purified by silica gel flash column
chromatography (petroleum/ethyl acetate, 20:1 v/v) to afford 3.
[9] a) K. Hemming, M. N. Khan, V. V. R. Kondakal, A. Pitard,
M. I. Qamar, C. R. Rice, Org. Lett. 2012, 14, 126; cyclopro-
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General Procedure for the Preparation of 4: A flame-dried Schlenk
flask was charged with substrate 1 (0.75 mmol), substrate 2
(0.5 mmol), DABCO (9 mg, 0.15 mmol), and molecular sieves (4 Å,
100 mg). Then, dry MeCN (1.5 mL) was added. The reaction mix-
ture was stirred at room temperature under an atmosphere of ar-
gon. Upon completion of the reaction, the mixture was evaporated
under reduced pressure, and the residue was purified by silica gel
flash column chromatography (petroleum/ethyl acetate, 4:1 v/v) to
afford a light yellow solid that was further purified by recrystalli-
zation (petroleum ether, with a few drops of dichloromethane).
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures; 13C NMR and 1H NMR
spectroscopic data and analytic data for 3 and 4; and crystallo-
graphic details of 3c, 4d, and 5g.
[11] a) M. Shi, Y.-M. Xu, Angew. Chem. Int. Ed. 2002, 41, 4507;
Angew. Chem. 2002, 114, 4689; b) Y. Wei, M. Shi, Chem. Rev.
2013, 113, 6659; c) Y. Wei, M. Shi, Acc. Chem. Res. 2010, 43,
1005.
[12] a) G.-L. Zhao, J.-W. Huang, M. Shi, Org. Lett. 2003, 5, 4737;
b) Y.-L. Shi, M. Shi, Org. Lett. 2005, 7, 3057.
Acknowledgments
[13] CCDC-969494 (for 3c) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. See also the Supporting
Information.
The authors thank the Shanghai Municipal Committee of Science
and Technology (grant number 11JC1402600), the National Basic
Research Program of China [grant number (973)-2010CB833302],
the Fundamental Research Funds for the Central Universities, and
the National Natural Science Foundation of China (NSFC) (grant
numbers 21072206, 20472096, 21372241, 20672127, 21361140350,
21102166, 21121062, 21302203, and 20732008) for financial sup-
port.
[14] CCDC-914709 (for 4d) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. See also the Supporting
Information.
[15] CCDC-931360 (for 5g) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. See also the Supporting
Information.
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Received: January 16, 2014
Published Online: March 12, 2014
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