Acid/base-catalyzed cyclization of O-alkynylphenylphosphonic acid monoesters and (O-hydroxyphenyl)ethynylphosphinates

Article abstract of DOI:10.1002/hc.20728

In this work, we found that acids (i.e., HCl and NaHSO₃) rather than bases could catalyze the cyclization of o-alkynylphenylphosphonic acid monoesters at slow rates and give phosphaisocoumarins in low to medium yields, whereas the cyclization o

Full text of DOI:10.1002/hc.20728

Heteroatom Chemistry
Volume 22, Number 5, 2011
A
cid/Base-Catalyzed Cyclization of
O-Alkynylphenylphosphonic Acid Monoesters
and (O-Hydroxyphenyl)ethynylphosphinates
1
1
1
2
Ai-Yun Peng, Yidan Du, Yingling Wei, Liang Xie,
2
and Yi-Xiang Ding
1
School of Chemistry & Chemical Engineering, Sun Yat-sen University, 135 Xingangxi Lu,
Guangzhou, 510275, People’s Republic of China
2
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai, 200032, People’s Republic of China
Received 8 January 2011; revised 19 March 2011
erocycles in current organic synthesis, in which an
ABSTRACT: In this work, we found that acids
electrophile or a transition-metal catalyst is usu-
(
i.e., HCl and NaHSO ) rather than bases could cat-
3
ally used to activate the triple bond [1]. In recent
years, we have successfully applied this strategy to
the synthesis of a series of novel phosphorus hete-
rocycles, including phosphaisocoumarins [2], 2H-1,
alyze the cyclization of o-alkynylphenylphosphonic
acid monoesters at slow rates and give phosphaiso-
coumarins in low to medium yields, whereas the
cyclization of (o-hydroxyphenyl)ethynylphosphinates
proceeded very smoothly under basic conditions
rather than acidic conditions, and a series of phos-
phachromones could be prepared in excellent yields
2
1
-oxaphosphorin 2-oxides [3], phosphaisoquinolin-
-ones [4], and phosphachromones [5] via Pd(II),
Ag(I), and Cu(I)-catalyzed cyclization or halocycliza-
tion reactions. In the present study, we decided
to investigate whether cheap and easily available
acid/base alone could catalyze the formation of the
phosphorus heterocycles mentioned above.
at room temperature using K
2
CO as catalyst. This is
3
the first example of the synthesis of phosphorus het-
erocycles via acid/base-catalyzed intramolecular cy-
clization of alkynes. Possible mechanisms were dis-
cussed. ꢀC 2011 Wiley Periodicals, Inc. Heteroatom Chem
In recent years, acid- or base-catalyzed in-
tramolecular cyclization of o-substituted alkynes has
attracted much attention as an ecofriendly, metal-
free, and practical procedure to synthesize var-
ious heterocycles. Terada and Kanazaw [6] and
Uchiyama et al. [7] have reported that acid/base
catalysts can control the regioselectivity of the cy-
clization of o-alkynylbenzoic acid, selectively giving
six-member-ring isocoumarins or five-member-ring
phthalides. Alami and co-workers [8] have success-
fully prepared a series of isocoumarins, benzofu-
rans, and benzothiophenes via p-toluenesulfonic
acid (PTSA)-catalyzed cyclization of the correspond-
ing alkynes under microwave irradiation condi-
tions. Bihel et al. [9] found that trifluoroacetic acid
2
2:649–652, 2011; View this article online at wileyonlineli-
brary.com. DOI 10.1002/hc.20728
INTRODUCTION
The intramolecular cyclization of alkynes is one of
the most efficient methods to construct various het-
Correspondence to: Ai-Yun Peng; e-mail: cespay@mail.sysu
.edu.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 20602043.
Contract grant sponsor: Fundamental Research Funds for the
Central Universities.
ꢀ
c 2011 Wiley Periodicals, Inc.
(TFA) could mediate the 6-endo-dig cyclization of
o-alkynylbenzoates giving isocoumarins in high
649

650 Peng et al.
yields. Chromones have also been prepared effi-
ciently via the cyclization of o-hydroxy arylalkynones
in the presence of acids [10] such as PTSA, or base
TABLE 1 Acid-Catalyzed Cyclization of 1
R2
R2
aq. HCl in EtOAc
or
[11] such as Et
2
NH and K
2
CO . However, to the best
3
O
R1
P
OH
of our knowledge, such transition metal-free process
has not been applied to the synthesis of phospho-
R1
P
NaHSO3 in CH3CN
O
OEt
O
OEt
1
2
rus heterocycles. On the other hand, NaHSO has
3
ever been used as an efficient and inexpensive cat-
alyst for the synthesis of imidazoles [12], reducing
reagent [13], and dehalogenation reagent for polyflu-
oroalkyl halides [14], but its use as a catalyst in the
intramolecular cyclization reactions has never been
reported prior to this work.
Time
(h)
Yield Yield
a
b
Entry
R1
R2
n-Bu
Product
(%)
(%)
1
2
3
4
5
6
7
Cl
Cl
Cl
60
60
120
60
120
60
120
2a
2b
2c
2d
2e
2f
56
21
19
10
25
30
18
60
56
26
50
33
25
20
c-C H5
3
Ph
3
Ph
n-Bu
Ph
OMe c-C H5
OMe
H
RESULTS AND DISCUSSION
H
2g
We first examined the cyclization of 5-chloro-2-
a
b
Isolated yield under HCl-catalyzed conditions.
Isolated yield under NaHSO -catalyzed conditions.
(1-hexynyl)phenylphosphonic acid monoethyl ester
3
(
1a) under acid/base-catalyzed conditions. The reac-
tion of 1a with 1 equiv of Et
3
N or pyridine in MeCN
◦
at 80 C for 12 h did not give any cyclization prod-
uct. However, the analogues of 1a, o-ethynylbenzoic
acid derivatives, could cyclize under weak basic con-
ditions to give phthalides in good yields [6,7]. One
possible explanation for such phenomenon is that
the carbonyl group of isocoumarins or phthalides
is in a big conjugate system, whereas the phospho-
nyl group of phosphoisocoumrins is not conjugated
with the linked arene [2d], which may largely re-
duce the driving force of the cyclization of 1. In
addition, under weak basic conditions, the hinder
P(O)(OH)(OEt) might show lower nucleophilicity,
which would make it difficult to attack the inacti-
vated C C triple bond. Under acid-catalyzed con-
ditions, the reaction of 1a with PTSA in EtOH, or
with neat TFA, or with 37% aq. HCl in dimethyl-
sulfoxide (DMSO), dimethylformamide (DMF), cy-
then allowed to react with 37% aq. HCl in EtOAc
at room temperature and with NaHSO
80 C, respectively. As shown in Table 1, all substrates
3
in MeCN at
◦
examined could be cyclized in 6-endo model [15] to
phosphaisocoumrins 2 exclusively, and NaHSO was
3
more effective than HCl for most of the cases. How-
ever, compared with our previous Cu(I)-catalyzed
cyclization reactions of these substrates, the present
acid-catalyzed reactions were generally slow and the
+
yields were relatively low, indicating that H (pro-
ton acid) is not so effective as transition metal in
catalyzing the present cyclization reactions. In addi-
tion, whether under HCl- or NaHSO
3
-catalyzed con-
ditions, the yields of 2 were all much more depen-
2
1
dent on the nature of R rather than R . In cases
2
where R is an aryl group, the reactions proceeded
very slowly and gave the products in low yields after
5 days (120 h), and some of the starting materials
were still recovered unchanged.
We then turned our attention to examine
whether acid/base could catalyze the cycliza-
clohexane, CH
2
2
Cl , or toluene, also gave only trace
amounts of the desired phosphaisocoumarin 2a.
Fortunately, when 1a was treated with 37% aq. HCl
in EtOAc and MeCN at room temperature for 60 h,
2
a was isolated in 56% and 35% yield, respectively
tion
3.
of
When
(o-hydroxyphenyl)ethynylphosphinates
ethyl 5-chloro-2-hydroxyphenyl(1-
(entry 1, Table 1); heating could speed up the cy-
clization process to some extent, but had no appar-
ent effect on the yield of 2a. To our surprise, further
hexynyl)phosphinate (3a) was treated with the
addition of a catalytic amount of PTSA in CH Cl
or with BF O in toluene under refluxed condi-
tions, no cyclization product was observed even if
increasing the amount of the acid and extending
the reaction time. To our delight, in the presence of
2
2
studies showed that sodium bisulfite (NaHSO
3
), a
3
·Et
2
weak solid acid,was even more effective. The treat-
◦
ment of 1a with NaHSO
3
in MeCN at 80 C for 60 h
led to 2a in 60% yield (entry 1, Table 1). It has been
found by thin-layer chromatography (TLC) monitor-
10 mol% of K
2
CO , 3a was converted completely to
3
ing that when NaHSO
3
is used as catalyst, heating
the desired phosphachromone 4a within 2 h at room
and 1.0 equiv of the catalyst were necessary, and
MeCN was the best solvent.
A series of 2-(1-alkynyl)phenylphosphonic acid
monoesters 1 with a variety of substituents were
temperature in MeCN and DMF. When a nonpolar
solvent such as CH
reaction was slower but could be accelerated by
the addition of quantitative amount of K CO or
2
Cl
2
or toluene was used, the
2
3
Heteroatom Chemistry DOI 10.1002/hc

Acid/Base-Catalyzed Cyclization of Alkynes Containing Phosphorus 651
triple bond of 1 is activated by the coordination
TABLE 2 Base-Catalyzed Cyclization of 3
+
of H [16], which is then attacked by the adjacent
O
O
P
OEt
10% K2CO3
o
phosphonyl oxygen leading to the formation of 2.
OEt
R
P
R
+
In this course, as H exhibits weaker affinity to the
CH CN, 25 C
3
R'
R'
triple bond than the transition-metal catalyst, the
OH
O
3
4
acid, whether HCl or NaHSO , is not as effective as
3
+
CuI in catalyzing the cyclization. H showed espe-
Time
(h)
Isolated
Yield (%)
2
cially worse catalytic activity for the cases whereR
Entry
R
R
Product
+
is an aryl group, probably because H is difficult to
coordinate with the triple bond in a larger conjugate
system. Thus, the present acid-catalyzed process is
not a very practical way to synthesize phosphaiso-
coumarins. For the substrates 3, the cyclization reac-
tion can occur under base-catalyzed conditions since
the base can deprotonate or partially deprotonate
the hydroxyl so as to enhance the nucleophilicity of
the oxygen, and the triple bond may be activated by
the conjugate acid of the base. The intramolecular
1
2
3
4
5
Cl
Cl
Cl
Ph
Ph
n-Bu
Ph
2
6
6
2
2
4a
4b
4c
4d
4e
94
90
88
86
84
4-EtC H4
6
n-Bu
Ph
by heating. NaHCO , a weak inorganic base, was
less effective since the completion of the reaction
required longer time while using it as a catalyst. In
addition, Et N could also catalyze the cyclization re-
action efficiently, whereas other weak organic bases
such as pyridine and imidazole proved ineffective.
3
−
Michael addition of ArO onto the activated C C
triple bond followed by proton transfer leads to the
desired products 4 [6,7,11c].
3
However, when 5 mol% of PdCl was added to the
2
above reaction in pyridine or imidazole, the yield
of 4a was increased apparently as found by TLC
monitoring.
CONCLUSIONS
With these optimized conditions in hand, the re-
In summary, we have shown that the cyclization of o-
alkynylphenylphosphonic acid monoesters 1 can be
actions of 3a–3e with 10 mol% of K
2
CO were car-
3
ried out in MeCN at room temperature and the re-
sults are summarized in Table 2. As the results show,
all substrates tested could be converted to the cor-
responding phosphachomones in high yields. The
nature of the substituents seems not to influence the
yields but affect the reaction rate. In cases where R
catalyzed by acid (HCl or NaHSO
tion of (o-hydroxyphenyl)ethynylphosphinates 3 can
be catalyzed by base (K CO ). The results demon-
strated that the acid is mainly used to activate the
triple bond, whereas the base is usually used to
increase the nucleophilicity of the nucleophile. Al-
though the acid-catalyzed cyclization is not very ef-
fective for the synthesis of phosphaisocoumrins, the
3
), and the cycliza-
2
3
ꢁ
is chloro and R is an aryl group, the disappearance
of the substrates needed about 6 h, whereas for those
ꢁ
cases where R is a phenyl group and R is an alkyl
present work has shown that NaHSO has the poten-
3
group, the reactions could complete within 2 h.
Based on the above results and related lit-
eratures, plausible mechanisms are proposed in
Scheme 1. In the presence of an acid catalyst, the
tial to catalyze the cyclization reactions and provides
an ecofriendly, economical, and practical access to
phosphachromones via K
2
CO -catalyzed cyclization
3
of 3 under mild conditions.
R2
+H
R2
R2
+
H+
O
R1
P
O
OH
R1
R1
O
OEt
P
P
O
OEt
HO OEt
2
1
3
A
O
O
O
OEt
BH+
OEt
OEt
R
P
R
P
R
P
Base
R'
O-
R'
O
R'
OH
4
B
SCHEME 1 Plausible mechanisms of the acid-catalyzed cyclization of 1 and base-catalyzed cyclization of 3.
Heteroatom Chemistry DOI 10.1002/hc

652 Peng et al.
EXPERIMENTAL
umn chromatography on silica gel with petroleum
ether/EtOAc (2:1–1:1) as eluent to give the corre-
sponding product 4.
NMR spectra were all recorded on a Varian Mer-
cury300 spectrometer (Varian, Inc., Palo Alto, CA)
using CDCl
3
1
as the solvent unless stated other-
13
wise. The H NMRspectra and C NMR spectra
used CDCl (with tetramethylsilane) as the inter-
nal reference at 7.27 and 77.0 ppm, respectively.
REFERENCES
3
[
1] See recent reviews: (a) Heravi, M. M.; Sadjadi,
S. Tetrahedron 2009, 65, 7761; (b) Yamamoto, Y.;
Gridnev, I. D.; Patil, N. T.; Jin, T. Chem Commun
31
P NMR spectra used 85% H
3
PO as the external
4
reference. All reagents and solvents were used as
received. The starting materials 1 [2e] and 3 [5a]
were prepared according to our previous procedures.
The products 2 [2e] and 4 [5a] were confirmed
by the results of the NMR spectra data compared
with the literature values.
2
009, 5075.
[
2] (a) Peng, A.-Y.; Hao, F.; Li, B.; Wang, Z.; Du, Y. J Org
Chem 2008, 73, 9012; (b) Wei, P.; Ding, Y.-X. Synlett
2
005, 599; (c) Peng, A.-Y.; Ding, Y.-X. Tetrahedron
2005, 61, 10303; (d) Peng, A.-Y.; Ding, Y.-X. Org Lett
2004, 6, 1119; (e) Peng, A. Y.; Ding, Y. X. J Am Chem
Soc 2003, 125, 15006.
[
3] Peng, A.-Y.; Ding, Y.-X. Org Lett 2005, 7, 3299.
General Procedure for HCl-Catalyzed
Synthesis of 2
[4] (a) Tang, W.; Ding, Y.-X. Tetrahedron 2008, 64,
1
7
0807; (b) Tang, W.; Ding, Y.-X. J Org Chem 2006,
1, 8489.
To a stirred solution of 1 (0.5 mmol) in EtOAc
[5] (a) Xie, L.; Ma, J.; Ding, Y.-X. Tetrahedron Lett 2008,
4
2
9, 847; (b). Xie, L.; Ma, J.; Ding, Y.-X. Chin J Chem
008, 26, 1295.
(15 mL), 37% aq. HCl (1.5 mL) was added dropwise.
After stirring at room temperature for an appropri-
ate period of time as shown in Table 1, the reac-
tion mixture was diluted with EtOAc and washed
[
6] Kanazawa, C.; Terada, M. Tetrahedron Lett 2007, 48,
9
33.
[7] Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto,
Y.; Yonehara, M.; Hiroya, K.; Sakamoto, T. Org Lett
with 5% (w/v) K
dried over anhydrous Na
2
CO
3
, brine, and water, and then
SO . After removal of the
2
006, 8, 5517.
2
4
[
8] (a) Jacubert, M.; Provot, O.; Peyrat, J.-F.; Hamze,
A.; Brion, J.-D.; Alami, M. Tetrahedron 2010, 66,
solvent in vacuo, the residue was purified by col-
umn chromatography on silica gel with petroleum
ether/EtOAc (4:1–2:1) as eluent to give the corre-
sponding product 2.
3
775; (b) Jacubert, M.; Hamze, A.; Provot, O.; Peyrat,
J.-F.; Brion, J.-D.; Alami, M. Tetrahedron Lett 2009,
50, 3588; (c) Le Bras, G.; Hamze, A.; Messaoudi, S.;
Provot, O.; Le Calvez, P.-B.; Brion, J.-D.; Alami, M.
Synthesis 2008, 1607.
General Procedure for NaHSO -Catalyzed
Synthesis of 2
[9] Hellal, M.; Bourguignon, J.-J.; Bihel, F. J.-J. Tetrahe-
dron Lett 2008, 49, 62.
10] Alvaro, M.; Garcia, H.; Iborra, S.; Miranda, M. A.;
3
[
The mixture of 1 (0.5 mmol) and NaHSO
3
(0.5 mmol)
Primo, J. Tetrahedron 1987, 43, 143.
◦
[11] (a) Bhat, A. S.; Whetstone, J. L.; Brueggemeier, R. W.
Tetrahedron Lett 1999, 40, 2469; (b) McGarry, L. W.;
Detty, M. R. J Org Chem 1990, 55, 4349; (c) Brennan,
C. M.; Johnson, C. D.; McDonnell, P. D. J Chem Soc,
Perkin Trans II 1989, 957.
[12] (a) Sangshetti, J. N.; Kokare, N. D.; Kotharkar, S.
A.; Shinde, D. B. Monatsh Chem 2008, 139, 125; (b)
Han, X.; Ma, H.; Wang, Y. Russ J Org Chem 2008, 44,
in CH
3
CN (10 mL) was stirred at 80 C for an appro-
priate period of time as shown in Table 1. The reac-
tion mixture was then filtered and evaporated. The
residue was purified by column chromatography on
silica gel with petroleum ether/EtOAc (4:1–2:1) as
eluent to give the corresponding product 2.
8
63.
13] Huang, Z.-Z.; Ye, S.; Xia, W.; Tang, Y. Chem Commun
001, 1384.
[
[
[
General Procedure for K CO -Catalyzed
2
3
2
Synthesis of 4
The mixture of 3 (0.5 mmol) and K
in CH CN (5 mL) was stirred at room tempera-
14] Wu, F.; Yang, X.; Wang, Z.; Huang, W. J Fluorine
Chem 2007, 128, 84.
15] Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.;
Silberman, L.; Thomas, R. C. J Chem Soc, Chem
Commun 1976, 736.
2
CO (0.05 mmol)
3
3
ture for an appropriate period of time as shown
in Table 2. The reaction mixture was then filtered
and evaporated. The residue was purified by col-
[16] Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T.
Chem Commun 2009, 5075.
Heteroatom Chemistry DOI 10.1002/hc