The Synthesis of Phosphaisocoumarins by Cu(I)-Catalyzed Intramolecular Cyclization of o-Ethynylphenylphosphonic Acid Monoesters

Article abstract of DOI:10.1021/ja038627f

Cu(I)-catalyzed intramolecular cyclization of o-ethynylphenylphosphonic acid monoethyl esters was examined, and a new class of six-membered phosphorus heterocycles was formed with high regioselectivity and good yields. The present reaction is the first ex

Full text of DOI:10.1021/ja038627f

Published on Web 11/15/2003
The Synthesis of Phosphaisocoumarins by Cu(I)-Catalyzed Intramolecular
Cyclization of o-Ethynylphenylphosphonic Acid Monoesters
Ai-Yun Peng and Yi-Xiang Ding*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received September 20, 2003; E-mail: dingyx@mail.sioc.ac.cn
Scheme 1
Isocoumarins have gained considerable synthetic and pharma-
cological interest for a long time because of their diverse biological
activities, such as inhibition of serine proteases,1 antifungal,2
antibacterial,3 antiangiogenic,4 cytoxic,5 immunomodulatory,6 and
differentiation inducing activity against leukemic cells.7 Because
phosphonates are an important bioactive compound and phosphonic
acid analogues of naturally occurring carboxylic acids might inhibit
similar biochemical work of the carboxylic acids,8 one can anticipate
Scheme 2 a
that the phosphonic acid analogues of isocoumarins (i.e., phos-
phaisocoumarins) would have potential bioactivities similar to those
of isocoumarins. However, phosphaisocoumarins are a new type
of phosphorus heterocycles that have never been synthesized thus
far.8c,9 To enrich the phosphorus chemistry and find new bioactive
compounds, we decided to study the syntheses and bioactivities of
a (a) RfSO2F, Et3N, room temperature; (b) R2CtCH, 5 mol %
PdCl2(PPh3)2, Et3N, DMF, 90 °C; (c) NaOH, H2O, reflux 2-3 h, then HCl.
them.
The transition-metal-catalyzed cyclization of alkynes possessing
a nucleophile in proximity to the triple bond is one of the most
important processes in organic synthesis, which can construct
various heterocycles in an efficient and atom economic way. Over
the past few years, the intramolecular annulations of carboxylic
acids,10 alcohols,11 amines,12 amides,13 and imines14 to a triple bond
have been extensively investigated using Pd, Cu, Ag, Zn, Hg, W,
Ru, or Rh reagents as effective catalysts. However, to the best of
our knowledge, analogue intramolecular cyclization of P-OH to
alkynes has never been reported thus far, and there were only a
few examples of the intermolecular addition of P-OH to alkynes.15
In this study, we first report a mild and efficient copper-catalyzed
intramolecular cyclization of o-ethynylphenylphosphonic acid mo-
noethyl esters 1, leading to the formation of the phosphaisocou-
marins 2 (Scheme 1).
Table 1. CuI-Catalyzed Cyclization of the
o-Ethynylphenylphosphonic Acid Monoethyl Esters 1a
isolated yield
of 2 (%)
1
2
entry
1
R
R
2
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
C6H5
n-Bu
n-Bu
C6H5
p-CH3CH2C6H4
p-NO2C6H4
CH2OH
CH2OCH3
H
cyclopropyl
C6H5
2a
2b
2c
2d
2e
2f
2g
2h
2i
80
79
75
83
92
63
62
74
55
71
88
60
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
10
11
12
1j
1k
1l
2j
2k
2l
OMe
NO2
p-CH3CH2C6H4
The key starting materials 1 were readily prepared from the basic
hydrolysis of compounds 5, which were synthesized by the Pd-
catalyzed cross-coupling reaction16 of the corresponding phenyl
perfluoroalkanesulfonates 417 with alkynes (Scheme 2, see Sup-
porting Information).
a The reaction of 1 was carried out in the presence of 10 mol % CuI at
90 °C in DMF for 4 h.
reaction in toluene, the isolated yield of 2a increased to 78%. It is
also worth noting that this reaction does not need anhydrous and
oxygen-free conditions.
Cyclization of the 2-(phenylethynyl)phenylphosphonic acid mo-
noethyl ester (1a) was first examined. In the presence of 10 mol %
CuI, the reaction of 1a proceeded smoothly at 90 °C in DMF to
give 2a in 80% isolated yield (entry 1, Table 1). Both the metal
catalyst and thermal conditions were necessary for this reaction.
When the reaction of 1a was performed in the absence of CuI or
at room temperature, the reactant 1a was recovered completely.
Through control experiments, we found that silver salts (e.g., AgI,
AgNO3) did not promote the reaction, and palladium complexes
(e.g., PdCl2(PPh3)2, PdCl2, PdCl2(MeCN)2) were less effective to
this reaction. Moreover, just like the cyclization of alkynoic acids,10
this reaction also needs a solvent with Lewis basicity or a general
base. For example, the use of DMF or DMSO as the solvent could
lead to the formation of 2a in good yield, whereas very little desired
product was detected by TLC in toluene, 1,4-dioxane, and CH3CN
without a base. When 2 equiv of Et3N was added to the above
The application of this methodology to the synthesis of a variety
of 3- and 7-substituted phosphaisocoumarins is summarized in Table
1. In the presence of catalytic amounts of CuI, o-ethynylphe-
nylphosphonic acid monoethyl esters 1 with a variety of substituted
R1 and R2 groups can be cyclized to form phosphaisocoumarins 2
in DMF with moderate heating in good to excellent yields. The
current reaction is extremely versatile and provides a convenient
method for the synthesis of various phosphaisocoumarins. For
example, alkyne can bear alkyl, aryl, and free hydroxyl (entry 7);
chloro, methoxy, and nitro substituents on the benzene ring are
tolerated.
This reaction shows very high regioselectivity. In each case, only
the six-membered endocyclic phosphaisocoumarins from 6-endo-
dig18 cyclization were obtained, and no five-membered exocyclic
9
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J. AM. CHEM. SOC. 2003, 125, 15006-15007
10.1021/ja038627f CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
concentration of 50 µM, the PTP1B inhibition ratios of 2d, 2k, 2l
are 41%, 52.8%, 45.8%, respectively. The further biochemical
evaluation of them and the extension of this reaction are underway.
Supporting Information Available: Typical experimental proce-
dures and spectra data for previously undisclosed compounds and
crystallographic data of 2k (PDF and CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
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products were detected by TLC monitoring. Our observations are
in contrast to those of the cyclization of the alkynoic acids, which
proceeded 5-exo-dig cyclization predominantly in the presence of
AgI or CuI.10 Factors affecting the above regioselectivity are not
yet very clear. A possible explanation is that the longer C-P and
P-O bond lengths would make less geometric constraint for an
endo ring closure19 and lower the stability of the exocyclic products.
The structures of 2 were assigned on the basis of 1H NMR and 13
C
NMR spectra and X-ray crystallographic analysis (see Supporting
Information). The structure of 2k was shown as in Figure 1.
On the basis of the above observations and the nucleophilicity
to strong electrophiles of phosphonyl,20 a plausible mechanism may
be proposed in Scheme 3. It presumably involves the formation of
the π-complex A. In this step, a general base can deprotonate P-OH
of compound 1, and DMF, a Lewis base, can form a P-O-H‚‚‚
OdC hydrogen bond, both of which can enhance the nucleophilicity
of phosphonyl. The coordination of the alkynyl moiety of 1 to Cu-
(I) activates the triple bond. Regioselective nucleophilic attack of
the triple bond by phosphonyl in the endo mode would give the
vinylcopper species B, which subsequently undergoes in situ
protonation with regeneration of the Cu(I) catalyst to produce the
product 2.
In summary, we have developed a novel CuI-catalyzed cycliza-
tion reaction of o-ethynylphenylphosphonic acid monoesters to
phosphaisocoumarins with high regioselectivity and good yields.
The present reaction represents the first example of intramolecular
addition of P-OH to alkynes, which provides a new approach to
synthesize phosphorus heterocycles. Phosphaisocoumarins may have
potential bioactivities, and we have tested them preliminarily as
inhibitors of Protein Tyrosine Phoshatase 1B (PTP1B). At a
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