Gold-catalyzed sequential alkyne activation for the synthesis of 4,6-disubstituted phosphorus 2-pyrones

Article abstract of DOI:10.1021/ol3029274

Tandem gold-catalyzed addition of alkynyl phosphonic acid monoethyl esters to terminal alkynes and cyclization were developed for the synthesis of 4,6-disubstituted phosphorus 2-pyrones in one reaction vessel based on the concept of sequential alkyne acti

Full text of DOI:10.1021/ol3029274

ORGANIC
LETTERS
2013
Vol. 15, No. 1
26–29
Gold-Catalyzed Sequential Alkyne
Activation for the Synthesis of
4,6-Disubstituted Phosphorus 2‑Pyrones
Juntae Mo,† Dongjin Kang,† Dahan Eom,† Sung Hong Kim,‡ and Phil Ho Lee*,†
Department of Chemistry, Kangwon National University, Chuncheon 200-701,
Republic of Korea and Analysis Research Division Daegu Center, Korea Basic Science Institute,
Daegu 702-701, Republic of Korea
phlee@kangwon.ac.kr
Received October 23, 2012
ABSTRACT
Tandem gold-catalyzed addition of alkynyl phosphonic acid monoethyl esters to terminal alkynes and cyclization were developed for the
synthesis of 4,6-disubstituted phosphorus 2-pyrones in one reaction vessel based on the concept of sequential alkyne activation. Alkynyl enol
phosphonates were selectively obtained through the gold-catalyzed addition reaction in the presence of a catalytic amount of triethylamine. Also,
gold-catalyzed cyclization of alkynyl enol phosphonates was successful in giving a variety of 4,6-disubstituted phosphorus 2-pyrones.
2-Pyrones are an important structural motif found not
only in valuable biologically active compounds1 but also in
diverse synthetic intermediates.2 Recently, the activity of
2-pyrones as potent HIV protease inhibitors led to further
investigations of 2-pyrone and its derivatives.3
Organophosphorus compounds continue to receive
widespread attention due to their ubiquity in biological
systems4 and their potential to serve as novel phar-
maceuticals.5 Since there is a remarkable similarity in
reactivity and bioactivity between the carbon species
† Kangwon National University.
‡ Korea Basic Science Institute.
(1) (a) Mori, T.; Ujihara, K.; Matsumoto, O.; Yanagi, K.; Matsuo,
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I. J. S. Nat. Prod. Rep. 2005, 22, 369. (c) Schlingmann, G.; Milne, L.;
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and their phosphorus counterparts,6 we imagined phos-
phorus 2-pyrones to have potential bioactivities similar to
r
10.1021/ol3029274
Published on Web 12/13/2012
2012 American Chemical Society

those of the 2-pyrones reported. However, so far, only
four synthetic methods of phosphorus 2-pyrones have
been described in the literature. In 1978, Razumov et al.
reported the synthesis of two phosphorus 2-pyrones
through intermolecular aldol condensation and sequen-
tial thermal cyclization reactions (eq 3).7 In the same year,
Sigal et al. prepared phosphorus 2-pyrone by addition of
bromine to mesityl-2-butenyl phostinate and successive
dehydrobromination (eq 2).8 In 2002, Cremer et al. pre-
pared two phosphorus 2-pyrones through a bromina-
tionÀdehydrobromination sequence (4 steps) from the
corresponding saturated phostone (eq 3).9 These methods
depend on the functionalization of a preformed cyclic
phostinate and phostone nucleus. Recently, Ding et al.
reported an efficient procedure to synthesize 6-substituted
phosphorus 2-pyrones through Ag-catalyzed cyclization
of (Z)-2-alken-4-ynylphosphonic acid monoethylesters
(eq 4).10 However, to the best of our knowledge, a synthetic
method for 4,6-disubstituted phosphorus 2-pyrones has
never been reported thus far. Based on the concept of
sequential alkyne activation,11 we herein describe gold-
catalyzed sequential intermolecular addition of 1-alkynyl-
phosphonic acid monoethyl esters to alkynes followed by
intramolecular cyclization of alkynyl enol phosphonates in
one reaction vessel, leading to the formation of the 4,6-
disubstituted phosphorus 2-pyrones (Scheme 1).
(1a) (Table 1). 1-Alkynyl phosphonic acid monoethyl
esters were readily prepared from the basic hydrolysis of
diethyl 1-alkynylphosphonates, which weresynthesizedby
the reaction of lithium alkynides with diethyl phosphoryl
chloride.12 AuCl and AuCl3 in the presence of AgOTf or
Table 1. Optimization of Tandem Addition and Cyclizationa
entry
cat. (mol %)
AuCl (5)
temp (°C) time (h) yield (%)b
1
2
80
40
80
40
40
60
40
40
30
80
12
24
12
24
24
24
9
0
AuCl (5)/AgOTf (5)
AuCl3 (5)
0
3
0
4
AuCl3 (5)/AgOTf (15)
Ph3PAuCl (5)/AgOTf (5)
Ph3PAuCl (5)/AgOTf (5)
Ph3PAuCl(5)/AgNTf2 (5)
Ph3PAuCl (5)/AgSbF6 (5)
JohnPhos-Aud (5)
AgOTf (5)
0
5
51
50 (13)c
6
7
62
55
68
0
8
16
14
12
9
10
a 1a (0.4 mmol) and 2a (0.2 mmol) were used in DCE (0.8 mL).
b Isolated yield of 3a. c 2-Ethoxy-6-methyl-4-phenyl-5-phenethyl-1,2-oxa-
phosphorin 2-oxide (4a). d JohnPhos-Au: (acetonitrile)[(2-biphenyl)-
di-tert-butylphosphine]gold(I) hexafluoroantimonate.
Scheme 1. Synthesis of 4,6-Disubstituted Phosphorus 2-Pyrones
not failed to catalyze the tandem reaction (entries 1À4).
Treatment of 1a and 2a with Ph3PAuCl and AgOTf
(5 mol % each) as a catalyst selectively gave the cyclized
tandem product 3a in 51% yield in DCE at 40 °C after 24 h
(entry 5). The reaction was sensitive to the temperature.
When this reaction was carried out in DCE at 60 °C for
24 h, 3a was obtained in 50% yield and, in addition,
2-ethoxy-6-methyl-5-phenethyl-4-phenyl-1,2-oxaphosphor-
in 2-oxide (4a) was isolated in 13% yield (entry 6). The
noncoordinating counterion of the cationic gold(I) catalyst
had a little effect on the product distribution. When AgNTf2
or AgSbF6 was used, we selectively isolated 3a in 62% and
55% yields, respectively (entries 7 and 8). The best result was
obtained by using the catalyst (acetonitrile)[(2-biphenyl)-di-
tert-butylphosphine]gold(I) hexafluoroantimonate (5 mol %)
in dichloroethane at 30 °C after 14 h, which gave rise to 3a in
68% yield through CÀOandsequentialCÀC bond formation
in one reaction vessel (entry 9). AgOTf alone failed to catalyze
the tandem reaction (entry 10). To check the possibility of
catalysis by a protic acid, we attempted the tandem reaction in
the presence of trifluoromethanesulfonic acid (5 mol %) in
dichloromethane at 30 °C. Under these conditions, the reac-
tion did not proceed.
Weinitiatedourinvestigationusingphenylethynyl phos-
phonic acid monoethyl ester 2a and 5-phenyl-1-pentyne
(5) (a) Ruda, G. F.; Wong, P. E.; Alibu, V. P.; Norval, S.; Read,
K. D.; Barrett, M. P.; Gilbert, I. H. J. Med. Chem. 2010, 53, 6071.
(b) Congiatu, C.; Brancale, A.; Mason, M. D.; Jiang, W. G.; McGuigan,
C. J. Med. Chem. 2006, 49, 452. (c) Kafarski, P.; LeJczak, B. Curr. Med.
Chem.: Anti-Cancer Agents 2001, 1, 301. (d) Colvin, O. M. Curr. Pharm.
Des. 1999, 5, 555. (e) Mader, M. M.; Bartlett, P. A. Chem. Rev. 1997, 97,
1281. (f) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem.
1991, 63, 193.
(6) (a) Dillon, K. B.; Mathey, F.; Nixon, 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.
(7) Razumov, A. I.; Liorber, B. G.; Sokolov, M. P.; Zykova, T. V.;
Salakhutdinov, R. A. Zh. Obshch. Khim. 1978, 48, 51.
(8) Sigal, I.; Loew, L. J. Am. Chem. Soc. 1978, 100, 6394.
(9) Polozov, A. M.; Cremer, S. E. J. Organomet. Chem. 2002, 646,
153.
(10) Peng, A.-Y.; Ding, Y.-X. Org. Lett. 2005, 7, 3299.
(11) (a) Luo, T.; Dai, M.; Zheng, S.-L.; Schreiber, S. L. Org. Lett.
2011, 13, 2834. (b) Sperger, C. A.; Fiksdahl, A. J. Org. Chem. 2010, 75,
4542. (c) Sperger, C.; Fiksdahl, A. Org. Lett. 2009, 11, 2449. (d) Liu,
X.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2008, 47, 3805. (e) Zhao, J.;
Hughes, C. O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 7436.
(f) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285.
The scope of the tandem reaction was examined with a
variety of alkynes 1 and 1-alkynyl phosphonic acid mono-
ethyl esters 2 (Table 2). Treatment of 2a with 1-hexyne (1b)
and 3-phenyl-1-propyne (1c) with a gold catalyst gave the
(12) Lahrache, H.; Robin, S.; Rousseau, G. Tetrahedron Lett. 2005,
46, 1635.
Org. Lett., Vol. 15, No. 1, 2013
27

cyclized 4,6-disubstituted phosphorus 2-pyrones 3b and 3c
in 71% and 70% yields, respectively, in DCE at 30 °C
within 16 h (entries 1 and 2). Reaction of 2a with enyne 1d
in the presence of the gold catalyst gave the desired 3d in
62% yield albeit with an excess amount (5 equiv) of 1d
(entry 3). Under the optimized reactionconditions, ethynyl
phosphonic acid monoethyl ester 2b having an electron-
donating 4-methylphenyl group was reacted with 1-hexyne
(1b) and 3-cyclohexyl-1-propyne (1e) to afford 3e and 3f in
good yields in one reaction vessel (entries 4 and 5). Certain
labile functional groups commonly employed in organic
synthesis such as chloro or ester moieties substituted on the
alkyne were tolerated under these reaction conditions
(entries 6 and 7). Phosphonic acid monoethyl ester 2c
having an electron-withdrawing 4-chlorophenyl group
underwent the Au-catalyzed tandem reaction with 1a
and 1f, producing the phosphorus 2-pyrones 3i (56%)
and 3j (50%) in slightly lower yields, presumably because
the capacity of the triple bond of 2c to coordinate gold and
the nucleophilicity of phosphonic acid monoethyl ester is
diminished by the existing chloride group (entries 8 and 9).
The chloride functionality provides a handle to introduce
other groups at the para position of phenyl group at the
C-4 position via transition-metal-catalyzed cross-coupling
reactions. Subjecting 1-hexynylphosphonic acid mono-
ethyl ester 2d to 1b and 1h produced the phosphorus
2-pyrones 3k and 3l in moderate to good yields (entries
10 and 11). When 4-phenyl-1-butyne (1i) and 5-phenyl-1-
pentyne (1a) were used, the corresponding desired phos-
phorus 2-pyrones 3m and 3n were obtained in 67% and
62% yields, respectively (entries 12 and 13). Exposure of
5-chloro-1-pentyne (1f) and2dtothe goldcatalyst afforded
3o in 64% yield through intermolecular CÀO followed by
intramolecular CÀC bond formation (entry 14).
Table 2. Au-Catalyzed Preparation of Phosphorus 2-Pyronesa
Although the mechanism of the present reaction has not
been fully established at the present stage, a possible
reaction pathway is shown in Scheme 2. Coordination of
a gold catalyst to the triple bond in alkyne 1 results in the
formation of the intermediate A which, upon nucleophilic
attack of the oxygen on the 1-alkynyl phosphonic acid
monoethyl ester 2, is converted to a σ-gold complex B.
Then, 1-alkynyl enol phosphonate 5 was produced after
deprotonation followed by protodeauration of B. The
triple bond in alkyne 1 rather than 2 was first activated
by a gold catalyst, presumably because the capacity of the
triple bond of 2 to coordinate gold is diminished by
conjugation. Coordination of a gold catalyst to a triple
bond in 5 results in the formation of the intermediate C
which, upon nucleophilic attack of the carbon on the enol
phosphonate, is cyclized leading to a σ-gold complex D.
Subsequent deprotonation and protodeauration of D
afforded the phosphorus 2-pyrone derivative 3 to release
the gold catalyst back into the catalytic cycle. In addi-
tion, gold-catalyzed isomerization of 5 may occur at a
higher temperature to produce the more substituted enol
a Reactions were carried out with 1 (0.4 mmol), 2 (0.2 mmol), and
(acetonitrile)[(2-biphenyl)-di-tert-butylphosphine]gold(I) hexafluoroanti-
monate (5 mol %) in DCE (0.8 mL) at 30 °C. b Isolated yield. c Alkyne
(5 equiv) was used.
(13) (a) Lee, P. H.; Kang, D.; Choi, S.; Kim, S. Org. Lett. 2011, 13,
3470. (b) Lee, P. H.; Kim, S.; Park, A.; Chary, B. C.; Kim, S. Angew.
Chem., Int. Ed. 2010, 49, 6806. (c) Chary, B. C.; Low, W. S.; Kim, S.;
Kim, H.; Lee, P. H. Chem.;Asian J. 2011, 6, 1970.
phosphonate E.13 The repeated activation of the triple
bond in E by the gold catalyst followed by cyclization,
28
Org. Lett., Vol. 15, No. 1, 2013

Scheme 2. Plausible Mechanism of Gold-Catalyzed Tandem
Reaction
Scheme 3. Au-Catalyzed Addition of 1-Alkynyl Phosphonic
Acid Monoethyl Esters to Alkynesa
a Conditions: 1 (0.4 mmol) and 2 (0.2 mmol) in the presence of
(acetonitrile)[(2-biphenyl)-di-tert-butylphosphine]gold(I) hexafluoroanti-
monate (5 mol %) and Et3N (10 mol %) were used in DCE (0.8 mL) at
30 °C.
Table 3. Au-Catalyzed Cyclization of 1-Alkynyl Enol Phosphonatea
deprotonation, and protodeauration would give 4,5,
6-trisubstituted phosphorus 2-pyrone 4, which is supported
by the formation of a side product (4a) in entry 6 (Table 1).
Next, we attempted to isolate the intermediate 5 toprove
the plausible mechanism of the present tandem reaction.
Gratifyingly, 1-alkynyl enol phosphonates were selectively
obtained with the gold catalyst in the presence of triethy-
lamine (Scheme 3).14 For example, treatment of 1a and 2a
with JohnPhos-Au (5 mol %) in the presence of triethyla-
mine (10 mol %) selectively gave phenylethynyl enol
phosphonate 5a in 69% yield in DCE at 30 °C after 14 h
without formation of the tandem product (3a). The addi-
tion of 2b to 1f proceeded smoothly to provide the desired
enol phosphonate 5c in 81% yield. Likewise, hexynyl
enol phosphonate 5d was synthesized in 73% yield from
5-chloro-1-pentyne (1f) and 2d.
Based on the above mechanistic considerations, gold-
catalyzed cyclization of 5 was examined (Table 3). We were
pleased to observe that treatment of 5c with John-Phos-Au
(5 mol %) selectively provided 3g in 83% yield in DCE at
30 °C after 3 h without formation of 4,5,6-trisubstituted
phosphorus 2-pyrone (entry 3). Similarly, 5b and 5d were
smoothly converted to the corresponding 4,6-disubstituted
phosphorus 2-pyrones (3c and 3o) in excellent yields
under the mild reaction conditions (DCE, 30 °C, 1À2 h)
catalyzed by gold (entries 2 and 5). Isolation of alkynyl
enol phosphonates (Scheme 3) and their cyclization to
phosphorus 2-pyrones (Table 3) indicate that the gold-
catalyzed sequential alkyne activation process is operated
as shown in Scheme 2.
entry
product
time (h)
yield (%)
1
2
3
4
5
3a
3c
3g
3i
2
2
3
6
1
84
86
83
72
94
3o
a 5 (0.2 mmol) and (acetonitrile)[(2-biphenyl)-di-tert-butylphosphine]
gold(I) hexafluoroantimonate (5 mol %) in DCE (0.8 mL) at 30 °C.
In conclusion, we have developed the tandem gold-
catalyzed addition of 1-alkynyl phosphonic acid mono-
ethyl esters to terminal alkynes and cyclization for the
synthesis of 4,6-disubstituted phosphorus 2-pyrones in one
reaction vessel based on the concept of sequential alkyne
activation. 1-Alkynyl enol phosphonates were selectively
obtained through the gold-catalyzed addition reaction in
the presence of a catalytic amount of triethylamine. Also,
gold-catalyzed cyclization of alkynyl enol phosphonates
was successful in giving phosphorus 2-pyrones.
Acknowledgment. Wethank the NCRL(2012-0001245)
program funded by the National Research Foundation of
Korea. P.H.L. thanks Prof. S. Chang (KAIST) for helpful
discussions.
Supporting Information Available. Experimental pro-
cedure and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) Additional studies of the role of Et3N in selectively giving
1-alkynyl enol phosphonates are currently underway. (a) Peng, A.;
Ding, Y. Synthesis 2003, 205. (b) Hua, R.; Tanaka, M. Chem. Lett. 1998,
431.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
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