Synthesis of phosphaisocoumarins via iodocyclization

Article abstract of DOI:10.1021/ol0499506

4-Iodophosphaisocoumarins can be prepared in good yield and with high regioselectivity under mild conditions by the reaction of o-(1-alkynyl) phenylphosphonates with I₂ or ICI. The present reaction represents the first example of a phosphonate

Full text of DOI:10.1021/ol0499506

ORGANIC
LETTERS
2004
Vol. 6, No. 7
1119-1121
Synthesis of Phosphaisocoumarins via
Iodocyclization
Ai-Yun Peng and Yi-Xiang Ding*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
dingyx@mail.sioc.ac.cn
Received January 8, 2004
ABSTRACT
4-Iodophosphaisocoumarins can be prepared in good yield and with high regioselectivity under mild conditions by the reaction of o-(1-
alkynyl)phenylphosphonates with I2 or ICl. The present reaction represents the first example of a phosphonate iodocyclization onto a C−C
triple bond. The resulting iodides can be further elaborated using palladium-catalyzed coupling reactions.
Isocoumarins are a class of naturally occurring lactones that
display diverse bioactivities.1 Phosphaisocoumarins are
phosphorus isocoumarin analogues that also could have
bioactivities.2 Recently, we reported3 a synthesis of 3-sub-
stituted phosphaisocoumarins having no substituent at the
4-position that exploited the Cu(I)-catalyzed cyclization of
o-(1-alkynyl)phenylphosphonic acid monoesters. In continu-
ation of the above investigation, we recently decided to
search for a new procedure that would allow us to synthesize
3,4-disubstituted phosphaisocoumarins.
example, iodocyclization of o-(1-alkynyl)benzoic acids or
esters5 is an important way of synthesizing isocoumarins.
By way of contrast, only a few examples of the electrophilic
cyclization of alkenyl phosphates6 and alkenylphosphonates7
are reported in the literature, and to the best of our
knowledge, the analogous reaction of phosphates or phos-
phonates onto a C-C triple bond has never been described
thus far. In this paper, we describe the iodocyclization of
o-(1-alkynyl)phenylphosphonates 1 using I2 or ICl as the
electrophile; this leads to 4-iodophosphaisocoumarins 2 in
moderate to excellent yield (Scheme 1). Moreover, not only
Iodocyclization of an unsaturated C-C bond with a wide
variety of nucleophiles, including N, O, and S nucleophiles,
has been extensively studied4 and has become a powerful
method for the construction of various heterocycles. For
Scheme 1
(1) (a) Powers, J. C.; Asgian, J. L.; Ekici, O¨ . D.; James, K. E. Chem.
ReV. 2002, 102, 4639 and references therein. (b) Nozawa, K.; Yamada,
M.; Tsuda, Y.; Kawai, K. I.; Nakajima, S. Chem. Pharm. Bull. 1981, 29,
2491. (c) Hussain, M. T.; Rama, N. H.; Malik, A. Indian J. Chem. 2001,
40B, 372. (d) Lee, J. H.; Park, Y. J.; Kim, H. S.; Hong, Y. S.; Kim, K. W.;
Lee, J. J. J. Antibiot. 2001, 54, 463. (e) Whyte, A. C.; Gloer, J. B.; Mallock,
D. J. Nat. Prod. 1996, 59, 765. (f) Shimoda, H.; Matsuda, H.; Yamahara,
J.; Yoshikawa, M. Biol. Pharm. Bull. 1998, 21, 809. (g) Umehara, K.;
Matsumoto, M.; Nakamura, M.; Miyase, T.; Kuronagi, M.; Noguchi, H.
Chem. Pharm. Bull. 2000, 48, 566.
(2) (a) Engel, R., Ed. Handbook of Orgnophosphorus Chemistry; Marcel
Dekker: New York, 1992; Chapter 11. (b) Quin, L. D., Ed. A Guide to
Organophosphorus Chemistry; John Wiley & Sons: New York, 2000;
Chapter 11.
does our iodocyclization reaction open up a new path for
the synthesis of phosphaisocoumarins, but the presence of
iodine at the 4-position also permits further elaboration to
more complex derivatives.
The starting alkynes 1 for our approach were readily
prepared by the Pd-catalyzed cross-coupling reaction8 of the
(3) Peng, A.-Y.; Ding, Y.-X. J. Am. Chem. Soc. 2003, 125, 15006.
(4) See the review: Frederickson, M.; Grigg, R. Org. Prep. Proced. Int.
1997, 29, 33.
10.1021/ol0499506 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/03/2004

Scheme 2
Table 1. Synthesis of Phosphaisocoumarins via
Iodocyclizationa
entry
R1
R2
C6H5
n-C4H9
H
product
yield (%)b
1
2
3
4c
5
6
H
H
H
H
2a
2b
2c + 3c
2c
2d + 4d
2e + 4e
83
70
4 + 65
35
64 + 30
67 + 25
corresponding aryl perfluoroalkanesulfonates with terminal
acetylenes (Scheme 2).
H
First, we examined the reaction of 2-(phenylethynyl)-
phenylphosphonic acid diethyl ester (1a) with 2.0 equiv of
iodine in several different organic solvents at room temper-
ature. We found that the reaction was highly dependent on
the type of solvent used. In CH3CN and DMF, we did not
obtain the desired phosphaisocoumarin 2a but rather the
diiodide 3a (Figure 1, R1 ) H, R2 ) Ph) from diiodination
Cl
Cl
p-EtC6H4
C6H5
7
8
9
10
11c
12
Cl
Cl
Cl
Cl
Cl
CH3O
n-C4H9
cyclopropyl
CH2OCH3
SiMe3
SiMe3
C6H5
2f
2g
2h
2i
2i
2j
64
76
46
0
82
93
a All reactions were conducted at room temperature with 2.0 equiv of I2
in CHCl3 for 12 h unless otherwise specified.
conditions. Aryl-substituted (entries 1, 5, 6, and 12) and
alkyl-substituted (entries 2 and 7-9) alkynes were also well
accommodated. However, 1c (entry 3) gave diiodide 3c as
the major product with very little of the desired product 2c
being formed. A bulky SiMe3 group (1i, entry 10) totally
halted the reaction, and starting material was completely
recovered under these conditions. Use of the strong electro-
phile ICl instead of I2 afforded the desired products 2c and
2i in moderate yields for 1c and 1i (entries 4 and 11). It is
also worth mentioning that for the reactions of 1d and 1e
(entries 5 and 6), the ketone byproducts 4d and 4e were
isolated in 30 and 25% yields, respectively, which contrasted
with the other cases where only small amounts of such
byproducts were formed.
Figure 1.
of the triple bond. However, when the reaction was run in
CHCl3 or CH2Cl2, the product 2a was produced in good
isolated yield (83 and 80%, respectively) with trace byprod-
ucts 3a and 4a (as monitored by TLC). When the same
reaction was carried out in benzene, 2a was isolated in 35%
yield with 40% recovery of 1a and 15% of 4a. Rossi et al.5a
have isolated a similar ketone byproduct 4 during the
iodocyclization of o-(arylethynyl)benzoates. The structures
of 3a and 4a were confirmed by their IR, 1H NMR, and MS
spectra. There was no five-membered-ring product 5a
detected in each case.
On the basis of the above results, the iodocyclization of
other alkynes 1 with 2.0 equiv of iodine was conducted in
CHCl3 at room temperature, and the results are summarized
in Table 1. I2 was efficient in most cases, and a variety of
4-iodophosphaisocoumarins were obtained in good to excel-
lent yields. Functionalities such as chloro and methoxy on
the benzene ring were able to withstand the reaction
The reaction shows high regioselectivity for six-membered-
ring phosphaisocoumarins 2. Five-membered-ring products
5 were never detected under the reaction conditions. The
structures of 2 were confirmed by spectroscopic methods
(see Supporting Information) and chemically. Thus, the
palladium-catalyzed triethylammonium formate reduction9
of these iodides did not provide 7 but rather compounds of
structure 6 (Table 2). It was relatively easy to distinguish
1
the isomers 6 and 7 by H NMR spectral analysis of their
olefinic proton signal. For example, the olefinic proton of
7b should couple with the neighboring methylene protons,
but this coupling was absent for 6b. Compound 6c has two
olefinic protons at the 3- and 4-positions resonating at δ 6.76
and 6.09 ppm, respectively, with different coupling constants
to phosphorus, which was consistent with the proposed
structure. In addition, the structure of 6j was determined
unambiguously by X-ray crystallographic analysis.3
(5) (a) Rossi, R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L.
Tetrahedron 2003, 59, 2067. (b) Yao, T.; Larock, R. C. J. Org. Chem.
2003, 68, 5936. (c) Biagetti, M.; Bellina, F.; Carpita, A.; Stabile, P.; Rossi,
R. Tetrahedron 2002, 58, 5023.
(6) Bartlett, P. A.; Jernstedt, K. K. J. Am. Chem. Soc. 1977, 99, 4829.
(7) (a) Zhao, Y.-F.; Yan, S.-J.; Zhai, C. J. Org. Chem. 1985, 50, 2136.
(b) Yokomatsu, T.; Shioya, Y.; Iwasawa, H.; Shibuya, S. Heterocycles 1997,
46, 463.
(9) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1986, 27, 5541.
(8) Chen, Q.-Y.; Yang, Z.-Y. Tetrahedron Lett. 1986, 27, 1171.
1120
Org. Lett., Vol. 6, No. 7, 2004

Table 2. 1H NMR Spectral Properties of the Deiodide Products
Scheme 4
6
R1
R2
δ olefinic proton
6.69 (d, J H-P ) 2.1 Hz)
6a
6b
6c
H
H
H
C6H5
n-C4H9 5.80 (s)
triple bond activated by coordination to I+ followed by
elimination of ethyl iodide.5b On the other hand, the iodonium
intermediate A could also undergo intermolecular attack by
I-, which would lead to compound 3, or attack by water,
which would provide R-iodoketone 7 and HI.5a Deiodination
of 8 by HI10 should then produce ketone 4.
H
6.76 (dd, J H-P ) 18.3 Hz, J H-H ) 6.0 Hz, 3-H),
6.09 (dd, J H-H ) 6.0 Hz, J H-P ) 2.4 Hz, 4-H)
6.66 (d, J H-P ) 1.8 Hz)
6j CH3O C6H5
Plausible mechanisms for the formation of compounds
2-4 are shown in Scheme 3. The desired reaction to form
2 should involve intramolecular nucleophilic attack by the
oxygen of the phosphonyl group in an endo mode on the
The presence of iodine at the 4-position of phosphaiso-
coumarins allows further structural elaboration, most notably
using palladium-catalyzed coupling reactions. For example,
when compound 2a was exposed to Sonogashira coupling
conditions11 with phenylacetylene, the corresponding cou-
pling product 9 was isolated in excellent yield (Scheme 4).
In summary, we have devised a novel strategy for the
synthesis of phosphaisocoumarins that proceeds with high
regioselectivity; our approach uses the iodocyclization of
o-(1-alkynyl)phenylphosphonates with I2 or ICl under mild
conditions. The present reaction is the first example of the
iodocyclization of phosphonates to a C-C triple bond. The
resulting 4-iodophosphaisocoumarins have considerable po-
tential for further elaboration, especially using palladium-
catalyzed methods. Further investigation into the scope and
limitations of this novel electrophilic cyclization is underway.
Scheme 3
Supporting Information Available: Details of experi-
mental procedures as well as compound characterizations for
2 and 9. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0499506
(10) Gemal, A. L.; Luche, J. L. Tetrahedron Lett. 1980, 27, 3195.
(11) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
23, 4467. (b) Sonogashira, K. ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, p 521.
Org. Lett., Vol. 6, No. 7, 2004
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