Synthesis of 2H-1,2-oxaphosphorin 2-oxides via Ag2CO 3-catalyzed cyclization of (Z)-2-alken-4-ynylphosphonic monoesters

Article abstract of DOI:10.1021/ol051126+

(Chemical Equation Presented) Six new 2-ethoxy-2H-1,2-oxaphosphorin 2-oxides were synthesized with high regioselectivity in good yields via Ag ₂CO₃-catalyzed cyclization of (Z)-2-alken-4-ynylphosphonic monoesters in CH₂Cl<

Full text of DOI:10.1021/ol051126+

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3299-3301
Synthesis of 2H-1,2-Oxaphosphorin
2-Oxides via Ag2CO3-Catalyzed
Cyclization of
(Z)-2-Alken-4-ynylphosphonic
Monoesters
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 May 15, 2005
ABSTRACT
Six new 2-ethoxy-2H-1,2-oxaphosphorin 2-oxides were synthesized with high regioselectivity in good yields via Ag2CO3-catalyzed cyclization
of (Z)-2-alken-4-ynylphosphonic monoesters in CH2Cl2 at room temperature. This cyclization of P-OH to substituted alkynes is reported for the
first time. The products are a class of phosphorus heterocycles with potential use and are heretofore prepared with difficulty.
2-Pyrones are important structural subunits in a wide variety
of biologically active natural products,1 as well as useful
versatile synthetic intermediates.2 Recently, the activity of
2-pyrones as potent HIV protease inhibitors1c invoked
additional interest in the investigation of 2-pyrones and their
analogues. Since there is a remarkable similarity in reactivity
and bioactivities between the carbon species and their
phosphorus counterparts,3 one would anticipate that phos-
phorus 2-pyrone analogues might have potential bioactivities
similar to those of the 2-pyrones reported herein.
However, so far, only five phosphorus 2-pyrone analogues
have been reported in the literature (compounds 1-5, Figure
1). In 1978, Razumov et al. reported the synthesis of 1 and
2 via intermolecular aldol condensation followed by thermal
cyclization reactions.4 In the same year, Sigal et al. prepared
3 by addition of bromine to mesityl-2-butenylphostinate
followed by dehydrobromination.5 In 2002, Cremer et al.6
prepared a mixture of 4 and 5 through a bromination-
dehydrobromination sequence (4 steps) from the correspond-
ing saturated phostone. Unfortunately, the scope of the above
methods has not been examined, and they usually suffer from
low yields and lengthy procedures. Thus, new and improved
methodologies for synthesis of phosphorus 2-pyrone ana-
logues are merited.
(1) (a) Claydon, N.; Asllan, M.; Hanson, J. R.; Avent, A. G. Trans. Br.
Mycol. Soc. 1987, 88, 503. (b) Barrero, A. F.; Oltra, J. E.; Herrador, M.
M.; Sanchez, J. F.; Quilez, J. F.; Rojas, F. J.; Reyes, J. F. Tetrahedron
1993, 49, 141. (c) Vara Prasad, J. V. N.; Para, K. S.; Lunney, E. A.; Ortwine,
D. F.; Dunbar, J. B., Jr.; Fergunson, D.; Tummino, P. J.; Hupe, D.; Tait, B.
D.; Domagala, J. M.; Humblet, C.; Bhat, T. N.; Liu, B.; Guerin, D. A. M.;
Baldwin, E. T.; Erickson, J. W.; Sawyer, T. K. J. Am. Chem. Soc. 1994,
116, 6989. (d) Shi, X.; Leal, W. S.; Liu, Z.; Schrader, E.; Meinwald, J.
Tetrahedron Lett. 1995, 36, 71. (e) Gehrt, A.; Erkel, G.; Anke, T.; Sterner,
O. Z. Naturforsch. 1998, 53c, 89. (f) Schlingmann, G.; Milne, L.; Carter,
G. T. Tetrahedron 1998, 54, 13013.
(2) (a) Okamura, H.; Shimizu, H.; Iwagawa, T.; Nakatani, M. Tetrahedron
Lett. 2000, 41, 4147. (b) Posner, G. H.; Lee, J. K.; White, M. W.; Hutchings,
R. H.; Dai, H.; Kachinski, J. L.; Kensler, T. W. J. Org. Chem. 1997, 62,
3299. (c) Posner, G. H.; Cho, C.-G.; Anjeh, T. E. N.; Johnson, N.; Horst,
R. L.; Kobayashi, T.; Okano, T.; Tsugawa, N. J. Org. Chem. 1995, 60,
4617.
Building on methodology that has recently been developed
in our group to synthesize phosphaisocoumarins by Cu(I)-
catalyzed cyclization of 2-(1-alkynyl)phenylphosphonic mono-
(3) (a) Dillon, K. B.; Mathey, F.; Nixon FRS, J. F. Phosphorus: The
Carbon Copy; John Wiley & Sons: Chichester, 1998. (b) Quin, L. D. A
Guide to Organophosphorus Chemistry; John Wiley & Sons: New York,
2000; Chapter 11.
(4) Razumov, A. I.; Liorber, B. G.; Sokolov, M. P.; Zykova, T. V.;
Salakhutdinov, R. A. Zh. Obshch. Khim. 1978, 48, 51.
(5) Sigal, I.; Loew, L. J. Am. Chem. Soc. 1978, 100, 6394.
(6) Polozov, A. M.; Cremer, S. E. J. Organomet. Chem. 2002, 646, 153.
10.1021/ol051126+ CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/24/2005

Table 1. Transition-Metal-Catalyzed Cyclization of
(Z)-2-Alken-4-phenylethynyl-phosphonic Monoesters 6aa
Figure 1. Known phosphorus 2-pyrone analogues.
Scheme 1. Approach To Synthesize 7
entry
catalyst
CuI
AgI
AgNO3
Ag2CO3
solvent temp (°C) time (h) yield (%)b
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
20-100
20-100
20-100
20-100
20-100
20
8
8
8
8
8
24
24
24
24
0
0
0
0
0
52
56
0
CuI + Et3N DMF
AgNO3
Ag2CO3
CuI
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
20
20
20
AgI
0
a Reaction conditions: 6a (0.05 mmol), catalyst (0.005 mmol), anhydrous
solvent (0.50 mL). b Isolated yield.
Scheme 2. Synthesis of Monoesters 6
Table 2. Ag2CO3-Catalyzed Cyclization of
(Z)-2-Alken-4-ynyl-phosphonic Monoesters 6a
esters,7 we envisaged that 2H-1,2-oxaphosphorin 2-oxides
7 will be accessible starting from (Z)-2-alken-4-ynylphos-
phonic monoesters 6 (Scheme 1). 2-Pyrones,8 alkylidene
lactones,9 and other oxygenated heterocycles10 have been
prepared by cyclization of the corresponding substituted
alkynes, but such methodology has never been used to
synthesize 2H-1,2-oxaphosphorin 2-oxides. In this com-
munication, we wish to report a new and efficient procedure
to synthesize 2H-1,2-oxaphosphorin 2-oxides by transition-
metal-catalyzed cyclization of (Z)-2-alken-4-ynylphosphonic
monoesters.
The key starting materials 6 were readily prepared from
basic hydrolysis of compounds 8, which were synthesized
by the Pd-catalyzed cross-coupling reaction of (Z)-2-iodovi-
nylphosphonates with terminal alkynes11 (Scheme 2).
We first examined the cyclization of (Z)-2-alken-4-
phenylethynylphosphonic monoester 6a (Table 1). Although
2-(1-alkynyl)phenylphosphonic monoesters were converted
to phosphaisocoumarins in good yields in the presence of
CuI, AgI, or AgNO3 in DMF, or in toluene by addition of a
general base, no cyclization product 7a was observed under
similar conditions even at 100 °C and adding Et3N (Table
1, entries 1-5). We found that this reaction was very
sensitive to the solvent and the catalyst. When using CH2-
entry
R
time (h)
product
yield (%)b
1
2
3
4
5
6
Ph
24
24
6
6
6
7a
7b
7c
7d
7e
7f
56
50
84
92
77
54
p-EtC6H4
n-Bu
n-C6H13
cyclopropyl
CH2OCH3
12
a General reaction conditions: 6 (0.20 mmol), catalyst (0.02 mmol),
anhydrous CH2Cl2 (2.0 mL). b Isolated yield.
Cl2 as the solvent, AgNO3 or Ag2CO3 could catalyze the
reaction at room temperature to give 7a in 52% and 56%
yields, respectively (Table 1, entries 6, 7), whereas CuI and
AgI were still ineffective for this reaction (Table 1, entries
8, 9).
To explore the scope of this reaction, the variation of
substituent R was investigated in the presence of catalytic
amounts of Ag2CO3 in CH2Cl2 (see Table 2). For those cases
where R is aryl, the presence of Ag2CO3 is essential and the
yields of 7 are only moderate (Table 2, entries 1 and 2).
However, in cases where R is n-Hex, n-Bu, and cyclopropyl,
Ag2CO3 is very effective (Table 2, entries 3-5); these
substrates were found to proceed in the desired cyclization
reaction at slow rates even in the absence of a silver salt.
When R is an electron-withdrawing methoxymethyl group,
the reaction gave the desired product 7f in only 54% yield
(Table 2, entry 6). Thus, the nature of R groups has much
effect on this reaction.
(7) Peng, A.-Y.; Ding, Y.-X. J. Am. Chem. Soc. 2003, 125, 15006.
(8) (a) Anastasia, L.; Xu, C.; Negishi, E.-i. Tetrahedron Lett. 2002, 43,
5673. (b) Biagetti, M.; Bellina, F.; Carpita, A.; Viel, S.; Mannina, L.; Rossi,
R. Eur. J. Org. Chem. 2002, 1063. (c) Ogawa, Y.; Marun, M.; Wakamatsu,
T. Heterocycles 1995, 42, 2587. (d) Wiley, R. H.; Jarboe, C. H.; Hayes, F.
N. J. Am. Chem. Soc. 1957, 79, 2602. (e) Jacobs, T. L.; Dankner, D.;
Dankner, A. R. J. Am. Chem. Soc. 1958, 80, 864.
(9) (a) Dalla, V.; Pale, P. New J. Chem. 1999, 23, 803. (b) Rossi, R.;
Bellina, F.; Biagetti, M.; Catanese, A.; Mannina, L. Tetrahedron Lett. 2000,
41, 5281. (c) Belil, C.; Pascual, J.; Serratosa, F. Tetrahedron 1964, 20,
2701.
Unlike the cyclization of (Z)-2-en-4-ynoic acids, which
often leads to five- and six-membered ring products,8,9 this
(10) Pale, P.; Chuche, J. Eur. J. Org. Chem. 2000, 1019.
(11) Huang, X.; Zhang, C.; Lu, X. Synthesis 1995, 769.
3300
Org. Lett., Vol. 7, No. 15, 2005

reaction shows high 6-endo-dig12 regioselectivity for six-
membered ring products, and no five-membered ring prod-
ucts were detected by TLC monitoring in each case. The
structure of 7 was confirmed by spectroscopic methods
Scheme 3. Plausible Mechanism that Leads to Formation of 7
1
(especially by H NMR spectral analysis; see Supporting
Information). For example, the vinylic proton at the C5
position of 7c resonates at 5.48 ppm as a double doublet
3
4
with coupling constants of JH,H ) 6.3 Hz and JH,P ) 1.5
Hz, which was similar to that of 4 in the literature6 and
consistent with the proposed structure.
All of the obtained products (7a-f) were stable upon
chromatography with silica gel and amenable to full char-
acterization. However, if left at room temperature for
extended periods, they began to decompose to strongly polar
compounds, which have not been fully characterized; 7c-f
were relatively more stable than the aryl-substituted 7a and
7b. The decomposition processes were much slower when
they were stored in a refrigerator in sealed anhydrous flasks
and accelerated under basic conditions. This might account
for the result that cyclization of 6a did not give 7a under
basic conditions (in DMF or addition of Et3N). Compared
to 7, phosphaisocoumarins exhibit greater stability and are
not prone to decomposition even under thermal and basic
conditions.7
attack of the triple bond by the phosphonyl oxygen in the
endo mode would give the vinyl silver species A, which
subsequently undergoes proton transfer with regeneration of
the silver catalyst to produce 7.
In conclusion, we have developed a novel and effective
Ag2CO3-catalyzed cyclization of (Z)-2-alken-4-ynylphos-
phonic monoesters to 2-ethoxy-2H-1,2-oxaphosphorin 2-ox-
ides under mild conditions. This cyclization of P-OH to
substituted alkynes is reported for the first time and is of
synthetic interest because the products are a class of
phosphorus heterocycles with potential use and are heretofore
prepared with difficulty. Further investigations of this process
are underway.
On the basis of the above results and the related litera-
ture,9,10 a plausible mechanism is proposed in Scheme 3. The
coordination of the alkynyl moiety of 6 with Ag2CO3 or
AgNO3 activates the triple bond. Regioselective nucleophilic
Supporting Information Available: Typical experimen-
tal procedures and spectral data for 6, 7, and 8. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
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