Phosphine-catalyzed [3+2] annulation of electron-deficient alkynes with N-hydroxyphthalimide: Synthesis of 3a-hydroxyisoxazolo [3,2-a]isoindol-8 (3aH)-ones

Article abstract of DOI:10.1002/adsc.201300426

The phosphine-catalyzed [3+2] annulation of electron-deficient alkynes with N-hydroxyphthal-imide has been developed to give a variety of pharmaceutically attractive 3a-hydroxyisoxazolo [3,2-a]isoindol-8 (3aH)-ones in good to excellent yields.

Full text of DOI:10.1002/adsc.201300426

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DOI: 10.1002/adsc.201300426
Phosphine-Catalyzed [3+2]Annulation of Electron-Deficient
Alkynes with N-Hydroxyphthalimide: Synthesis of
3a-Hydroxyisoxazolo
N
U
Qing-Fa Zhou,a,b,* Xue-Ping Chu,a Fei-Fei Ge,a Yue Wang,a and Tao Lua,b,*
a
School of Basic Sciences, China Pharmaceutical University, Nanjing 210009, Peopleꢀs Republic of China
Fax : (+86)-025-8628-5179; phone: (+86)-025-8618-5160; e-mail: zhouqingfa@cpu.edu.cn
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Peopleꢀs Republic of
b
China
Fax : (+86)-025-8628-5179; e-mail: lut163@163.com
Received: May 11, 2013; Revised: July 2, 2013; Published online: October 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300426.
Abstract: The phosphine-catalyzed [3+2]annulation
of electron-deficient alkynes with N-hydroxyphthal-
ACHTUNGTRENNUNG
pounds. However, while the these reactions have
been widely explored,[11] the electrophiles mainly in-
clude aldehydes, imines or activated ketones and no
example of an amide was reported as an electrophile
so far. While numerous examples of N-
AHCTUNGTRENNUNG
a]isoindol-8ACHTUNGTRENNUNG
hydroxyphthalACTHNUTRGNEUNGimide (NHPI) being used as a catalyst
Keywords:
N
for the oxidation of certain types of hydrocarbons can
ficient alkynes; fused heterocycles; N-hydroxy-
phthalimide; nucleophilic phosphines
be found,[12] there are no examples of N-hydroxy-
G
ACHTUNGTRENpNGNU hthalimide being used in phosphine-catalyzed annu-
lation reactions with activated alkynes. Herein, we
wish to report novel examples of the phosphine-cata-
lyzed [3+2]annulation reactions of N-hydroxyphthal-
AHCTUNGTREGiNNUN mide (NHPI) with electron-deficient alkynes for the
The development of competent methodologies to con- construction of the pharmaceutically attractive nitro-
struct heterocyclic motifs is of great importance in gen-containing fused heterocycle derivatives – 3a-
(3aH)-ones[13] – and
both synthetic organic chemistry and medicinal hydroxyisoxazoloACTHNUTRGNENG[U 3,2-a]isoindol-8AHCTUNGTRENNGUN
chemistry due to their occurrence in a wide range of also showcase an example of the development for the
natural products and drugs.[1] Accordingly, a great Morita–Baylis–Hillman reactions with amides as elec-
deal of target-directed and diversity-oriented synthet- trophile partners of MBH reactions.
ic methods have been exploited for heterocycle syn-
At the outset of our study, we first chose ethyl pro-
thesis.[2] Thus far, while the synthesis of heterocycles piolate (1a) and N-hydroxyphthalimide (2) as the
has been the subject of a large body of literature, the standard substrates to search for suitable reaction
construction of highly functionalized nitrogen-con- conditions for the synthesis 3a-hydroxyisoxazolo
taining fused heterocycles remains highly desirable, a]isoindol-8(3aH)-one derivatives, and the results are
especially the synthesis of “drug-like” molecules.[3]
shown in Table 1. The reaction of 1a with 2 in the
ACHTUNGTRENNUNG[3,2-
AHCTUNGTRENNUNG
Nucleophilic phosphine-catalyzed reactions are presence of Ph3P (20 mol%) in CH2Cl2 at room tem-
among the most important methods available for ring perature for 6 h afforded 3a as a white solid in 51%
construction.[4] Some famous examples include inter- yield (entry 1, Table 1), and this compound was char-
1
molecular double-Michael reactions of dinucleophiles acterized by H and 13C NMR spectroscopy and HR-
with acetylenes or allenes,[5] annulation of Morita– MS analysis. Subsequently, Bu3P with relatively stron-
Baylis–Hillman adduct carbonates with activated ger nucleophilicity was tested in the reaction and it
alkene,[6] cycloadditions of allenes to a wide range of afforded the product 3a in comparable yield, but no
polarized C=X bonds (X=N, O, and C),[7] annulations product was obtained when the weaker nucleophilic
via the “Huisgen zwitterion”.[8] Recently, intramolecu- trimethyl phosphite was used as catalyst in place of
lar Morita–Baylis–Hillman reactions[9] and intramo- Ph3P in CH2Cl2 (entries 2 and 3, Table 1). The yield of
lecular Rauhut–Currier reactions[10] have also become 3a could be improved by heating CH2Cl2 at reflux,
an important tool for the synthesis of cyclic com- but it decreased sharply when the reaction was car-
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Qing-Fa Zhou et al.
COMMUNICATIONS
Table 1. Optimization of the reaction conditions for 3a.[a]
to a certain extent. Only a trace of product was found
in the absence of PPh3, which further showed the im-
portance of Ph3P for this transformation. Thus, we es-
tablished the optimal reaction conditions for the ef-
fective construction of 3a-hydroxyisoxazolo
ACHTUNGTRENUN[NG 3,2-a]iso-
indol-8(3aH)-one derivatives 3 as follows: use of
AHCTUNGTRENNUNG
20 mol% PPh3 as the catalyst and DMF as the solvent
to perform the reaction at room temperature.[14]
Following the above optimized conditions, we first
investigated a range of alkynoates As depicted in
Table 2 all tested terminal alkynoates were found to
be applicable to this reaction to give products 3 in
good to excellent yields under the optimized reaction
conditions. The nature of the substituent on the ben-
zene ring of the benzyl propiolate had a slight impact
on the yields. For example, for substrates with
a methyl or methoxy group attached on the benzene
ring, the corresponding products were obtained in
yields of 89% and 99%, respectively (entries 4 and 6,
Table 2). Substrates with a Cl or nitro group on the
benzene ring also gave the desired products in the ex-
Entry Catalyst
Solvent
T [oC] t [h] Yield [%][b]
1
2
Ph3P
Bu3P
CH2Cl2
CH2Cl2
r.t.[c]
r.t.
6
6
6
6
6
6
6
6
6
6
6
1
1
1
6
6
6
6
51
48
0
3
P
N
r.t.
4
5
6
7
8
9
10
11
12
13
14
15
16d)
17e)
18f)
Ph3P
Bu3P
Ph3P
Bu3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
acetone 60
THF
toluene
CH3CN 60
DMF
DMF
DMF
DMF
DMF
DMF
reflux
reflux
0
65
58
42
31
60
36
0
31
32
70
99
88
83
trace
80
0
reflux
60
60
60
r.t.
0
r.t.
r.t.
r.t.
Table 2. Synthesis of 3a-hydroxyisoxazolo
(3aH)-one derivatives 3 from alkynoates 1 and N-hydroxy-
AHCTUNGTRENNUNG
phthalimide 2.[a]
ACHTUNGTREN[NUNG 3,2-a]isoindol-8-
AHCTUNGTRENNUNG
[a]
Unless noted otherwise, the reaction of ethyl propiolate
1a (0.6 mmol), N-hydroxyphthalimide 2 (0.5 mmol) and
catalyst (20 mol%) was performed in 1 mL of solvent
under N2.
Isolated yield based on 2.
r.t.=room temperature.
10 mol% of Ph3P were used.
No catalyst was used.
5 mol% of Ph3P were used.
[b]
[c]
[d]
[e]
[f]
Entry
R1
R2
3
Yield [%][b]
1
2
3
4
5
6
7
H
H
H
H
H
H
H
H
H
H
H
Me
n-hexyl
Ph
Et
Me
PhCH2
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
99
99
95
89
92
99
99
96
ried out at 08C in the presence of either Ph3P or Bu3P
in CH2Cl2 (entries 4–7, Table 1). Solvent screening re-
vealed a significant solvent effect. Et2O also led to
the target product 3a in moderate yield, while its kin-
dred solvent-THF delivered no product at all (en-
tries 8 and 10, Table 1).
4-Me-C6H4-CH2
4-MeS-C6H4-CH2
4-MeO-C6H4-CH2
4-F-C6H4-CH2
4-Cl-C6H4-CH2
4-NO2-C6H4-CH2
1-naphthyl-CH2
2-furyl-CH2
Et
8[c]
9[c]
10
11[d]
12
13[e]
14
94
96
90
When shifting the solvent to acetone, toluene, or
CH3CN, 3a was obtained in 36, 31 or 32% yield, re-
spectively (entries 9, 11 and 12, Table 1). DMF gave
the best result for 3a with respect to the reaction time
as well as the yield (entry13, Table 1). Therefore, re-
action temperature and catalyst amount were further
examined in DMF (entries 14–18, Table 1). Lowering
the reaction temperature to room temperature led to
a better yield in DMF. However, on further decreas-
ing the temperature to 08C, the yield decreased slight-
ly, even with a prolonged reaction time of 6 h. De-
creasing the loading of the catalyst PPh3 to 10 mol%
or 5 mol% did affect the reaction rate and the yield
55 (99)[e]
trace (83)[e]
99
Et
Et
[a]
Unless noted otherwise, the reactions were performed on
a 0.5-mmol scale with 1.2 equiv. of 1, 1.0 equiv. of 2 and
20 mol% of Ph3P in 1 mL DMF at room temperature
under N2 for 1 h.
Isolated yield based on 2.
For 6 h.
[b]
[c]
[d]
[e]
For 0.75 h.
20 mol% of Bu3P were used
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Phosphine-Catalyzed [3+2]Annulation of Electron-Deficient Alkynes with N-Hydroxyphthalimide
Table 3. Synthesis of 3a-hydroxyisoxazolo
(3aH)-one derivatives 8 from alkynyl ketones 1 and N-hy-
droxyphthalimide 2.[a]
ACHTUNGTREN[NUNG 3,2-a]isoindol-8-
cellent yields, although the a longer reaction time was
needed. (entries 8 and 9, Table 2). To our delight,
naphthalen-1-ylmethyl propiolate as well as furan-2-
ylmethyl propiolate also reacted smoothly with 2 to
AHCTUNGTRENNUNG
give the desired 3a-hydroxyisoxazolo
ACHTUNGTREN[NUNG 3,2-a]isoindol-8-
ACHTUNGTRENNUNG(3aH)-one derivatives in excellent yields (entries 10
and 11, Table 2). It is worth mentioning here that,
under the above conditions, ethyl 2-butynoate and
ethyl 3-phenylpropiolate could also react with 2 to
furnish the corresponding 3a-hydroxyisoxazolo
a]isoindol-8(3aH)-one derivatives 3l and 3n in the
yields of 55% and 99%, respectively (entries 12 and
ACHTUNGTNER[NUNG 3,2-
ACHTUNGTRENNUNG
14, Table 2). To our disappointment, only a trace of Entry
R1
R2
8
Yield [%][b]
target product was formed when ethyl non-2-ynoate
1[c]
H
H
Me
Ph
Me
Ph
8a
57 (96)[d]
was applied in the reaction (entry 13, Table 2). Happi-
2
8b
8c
8d
8e
8f
8g
8h
8i
99
99
99
99
99
74
84
74
99
ly, ethyl non-2-ynoate could give the target product in
3
4
5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-Pr
good yield when Bu3P was used as catalyst in place of
Ph3P. And it was nice to see that ethyl 2-butynoate
could also give a better result in the presence of Bu3P
than that in the presence of Ph3P. It is highlighted
here that dimethyl acetylenedicarboxylate 4 gave the
corresponding product 5 in the yield of 99% under
our reaction conditions; while Yavari et al. reported
that dimethyl acetylenedicarboxylate 4 in the pres-
ence of a stoichiometric amount of triphenylphos-
phine at room temperature in CH2Cl2 yielded a pyrro-
loisoindole derivative 6,[15] which suggested that our
reaction conditions played an important role in the
present annulation reaction (Scheme 1).
4-F-C6H4
4-Cl-C6H4
4-MeO-C6H4
3,4-(MeO)2C6H3
3-pyridyl
Ph
6
7[e]
8
9[c]
10[c]
8j
[a]
Unless noted otherwise, the reactions were performed on
a 0.5-mmol scale with 1.2 equiv. of 7, 1.0 equiv. of 2 and
20 mol% of Ph3P in 1 mL of DMF at room temperature
under N2 for 1 h.
[b]
[c]
[d]
[e]
Isolated yield based on 2.
For 6 h.
3 equiv. of but-3-yn-2-one were used.
For 2 h.
ACHUTNGERN[NUG 3,2-a]isoindol-8ACHTUNTGREN(NUGN 3aH)-one derivatives 8b and 8c were
obtained in excellent yields, respectively (entries 2
and 3, Table 3). Screening revealed that several sub-
stituents, such as F, Cl, and MeO, on the aryl ring of
the internal alkyne were well tolerated, but the yields
decreased clearly when MeO was present on the aryl
ring of the internal alkyne (entries 4–8, Table 2). No-
tably, 3-phenyl-1-pyridin-4-ylpropynone was also com-
patible with the standard reaction conditions but gave
a decreased yield (entry 9, Table 3). An alkyl-substi-
tuted alkynyl ketone like 1-phenylhex-2-yn-1-one also
successfully underwent annulation to give 8j in an ex-
cellent yield.[16]
Scheme 1. Dimethyl acetylenedicarboxylate 4 as substrate.
To further broaden the scope of this phosphine-cat-
The structures of the products were undeniably
alyzed protocol, we also investigated a range of alkyn- confirmed by X-ray crystallographic analyses of the
yl ketones (Table 3). In the case of the reaction of compounds 8b[17] and 8c.[18] The ORTEP diagram of
but-3-yn-2-one with 2, under the standard conditions, 8b is shown in Figure 1.
the target product 8a was obtained in 57% yield and
Mechanistically, a suggested catalytic cycle for this
a large amount of 2 was not consumed. However, the unexpected [3+2] annulation of electron-deficient alk-
product 8a was obtained in an excellent yield of 96%
ACHTUNGTRENyNUNG nes with N-hydroxyphthalimide (NHPI) has been
after increasing the amount of but-3-yn-2-one to proposed (Scheme 2).[9b] The reaction could be trig-
3 equiv. (entry 1, Table 3). The standard conditions gered by the nucleophilic addition of Ph3P to the elec-
proved general for aromatic alkynyl ketones. For ex- tron-deficient carbon-carbon triple bond of 1a to pro-
ample, when 1-phenylpropynone and 4-phenylbut-3- duce zwitterion I, which can then deprotonate N-hy-
yn-2-one were treated with 2, 3a-hydroxyisoxazolo- droxyphthalimide (NHPI) 2 to generate intermediates
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Scheme 2. Proposed mechanism for PPh3-catalyzed [3+2]annulation of electron-deficient alkynes with N-hydroxyphthal-
imide.
ACHTUNGTRENNUNG
Experimental Section
General Experimental Procedure
To a solution of the electron-deficient alkyne (0.6 mmol)
and N-hydroxyphthalimide (81.5 mg, 0.5 mmol) in dry DMF
(1 mL) was added Ph3P (26.2 mg, 0.1 mmol) or Bu3P
(20.0 mg, 0.1 mmol). The resulting mixture was stirred at
room temperature under a nitrogen atmosphere for the re-
quired period of time. After completion of the reaction as
monitored by TLC, the reaction mixture was diluted with
CH2Cl2, and was washed with water and brine successively,
dried over MgSO4, filtered, and concentrated under vacuum.
Purification by flash chromatography (SiO2; ethyl acetate/
PE, 1:10~1:3) yielded the desired products.
Figure 1. X-ray crystal structure of 8b.
Ethyl 3a-hydroxy-8-oxo-3a,8-dihydroisoxazoloACTHNUTRGNE[NUG 3,2-a]isoin-
dole-3-carboxylate (3a): Yield: 129.2 mg (99%); white solid;
mp 74–758C; IR (KBr): v=3417, 3086, 2983, 1791, 1741,
1707, 1683, 1649, 1614, 1467, 1371, 1182, 1087, 1057, 879,
II and III. Intermediate II then undergoes Michael
addition to III to give IV.[19] Intermediate IV might
then undergo intramolecular nucleophilic attack to
form intermediate V, followed by proton transfer and
elimination of Ph3P to produce the desired product
3a.
In conclusion, a novel and efficient [3+2]annula-
tion of electron-deficient alkynes with N-hydroxyph-
thalimide (NHPI) has been developed by using Ph3P
as catalyst. With the application of this synthetic
696 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=8.01 (d, J=
7.7 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.72 (dd, J=7.6,
1.0 Hz, 1H), 7.61 (s, 1H), 7.54 (dd, J=7.6, 0.8 Hz, 1H), 4.53
(brs, 1H), 4.25–4.19 (m, 1H), 4.19–4.13 (m, 1H), 1.28 (t, J=
7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=173.94, 162.05,
159.13, 145.89, 135.69, 130.68, 128.31, 126.23, 125.01, 112.13,
95.80, 61.08, 14.28; HR-MS (ESI): m/z=262.0711, calcd. for
C13H12NO5 [M+H]+: 262.0710.
method, a series of 3a-hydroxyisoxazolo
ACHTUNGTREN[NUNG 3,2-a]isoin-
dol-8(3aH)-one derivatives was prepared in good to Acknowledgements
ACHTUNGTRENNUNG
excellent yields under mild reaction conditions. This
protocol is associated with readily available starting
materials, mild conditions, high yields and wide range
of synthetic potential of the product. Especially, the
structures of these products may be attractive for po-
tential drug discovery. The potential utilization and
extension of the scope of the methodology and the
examination of the biological activity of the products
are the subject of ongoing studies in our laboratory.
This work was financially supported by the National Natural
Science Foundation of China (Grant No.21102179) and Fun-
damental Research Funds for the Central Universities (No.
JKZ2011011).
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Phosphine-Catalyzed [3+2]Annulation of Electron-Deficient Alkynes with N-Hydroxyphthalimide
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