Efficient syntheses of phosphonylated isochromenes by regioselective 6-endo-dig addition to carbon-carbon triple bond catalyzed by Pd(OAc) 2

Article abstract of DOI:10.1039/b908313h

Palladium(II)-catalyzed cycloisomerization of [(2-alkynylphenyl) hydroxymethyl]phosphonates 6 provides an efficient route to phosphonylated isochromenes 7 in THF at room temperature and the reaction proceeded in a regioselective manner leading to the 6-endo-dig products 7 in moderate to excellent yields.

Full text of DOI:10.1039/b908313h

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Efficient syntheses of phosphonylated isochromenes by regioselective
6-endo-dig addition to carbon-carbon triple bond catalyzed by Pd(OAc)2†‡
Fei Wang,a Zhiwei Miao*a,b and Ruyu Chen*a
Received 27th April 2009, Accepted 19th May 2009
First published as an Advance Article on the web 28th May 2009
DOI: 10.1039/b908313h
Palladium(II)-catalyzed cycloisomerization of [(2-alkynyl-
phenyl)hydroxymethyl]phosphonates 6 provides an efficient
route to phosphonylated isochromenes 7 in THF at room
temperature and the reaction proceeded in a regioselective
manner leading to the 6-endo-dig products 7 in moderate to
excellent yields.
Scheme 1
Organophosphorus compounds continue to receive widespread
attention due to their ubiquity in biological systems and their
potential to serve as novel pharmaceuticals.1 Moreover, recent
studies have indicated that heterocyclic analogues containing
phosphorus showed interesting bioactivities.2 Isochromenes are
interesting heterocyclic compounds and useful precursors of
important heterocyclic derivatives. Some isochromene derivatives
have showed interesting pharmacological activity;3 isochromenes
have found application as synthetic intermediates4 and are po-
tential precursors of isochromanes, whose biological activity is
well-known.5 The cyclization of alkynes containing proximate
nucleophilic centers, promoted by organopalladium complexes,
is developing into a highly effective strategy for heterocyclic ring
construction.6 Wu has reported the tandem cyclization-addition
reaction of 2-alkynylbenzaldehyde with diethyl phosphate cat-
alyzed by AgOTf to afford 1H-isochromen-1-ylphosphonates at
room temperature in moderate yields. With respect to substrate
scope, when a 4-fluorophenyl or butyl group was attached on the
triple bond of 2-alkynylbenzaldehyde, the reaction was compli-
cated and no desired product was isolated.7 Gabriele has already
reported several approaches to the Pd(II)-catalyzed synthesis of
heterocyclic derivatives starting from acetylenic substrates, by a
simple cycloisomerization approach8 as well as by carbonylative
cyclization reactions.9 Pd(II) can indeed catalyze cycloisomeriza-
tion methodology with readily available 2-alkynylbenzyl alcohols
1 for the synthesis of (Z)-1-alkylidene-1,3-dihydroisobenzofurans
and 1H-isochromenes (2 and 3, respectively, Scheme 1) under
neutral conditions.10
isochromenes by regioselective 6-endo-dig addition to a carbon-
carbon triple bond catalyzed by Pd(OAc)2.
We started our investigation with dimethyl (2-(2-ethynyl)-
phenyl)(hydroxyl)methylphosphonate 6a, readily available using
dimethyl phosphite 4 reacted with o-alkynyl benzaldehyde 5 in the
presence of triethyl amine in THF at room temperature.11 This step
generally gives yields of the product above 90%. After treatment
of this compound with a catalytic amount of palladium(II)
acetate (10 mol%) in THF at room temperature, we observed
the formation of a product in 90% yield (Table 1, entry 1).
Structure elucidation by 1H, 13C, 31P NMR and mass spectroscopy
revealed this compound to be 1H-isochromen-1-ylphosphonate
7a. In this case, only the six-membered endocyclic phosphonylated
Table 1 Screening of the reactions of {[2-(phenylethynyl)phenyl]hydroxy-
methyl}phosphonate 6a under different conditionsa
Entrya
Catalyst
Solvent
Yield (7a)d
1
Pd(OAc)2
CuI
CuBr
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
DMF
Toluene
THF
THF
THF
THF
90
—
—
—
—
—
92
78
80
70
—
—
—
(8) 94
2
3
We recently reported the efficient syntheses of (thio)phospho-
nylated isobenzofurans by tandem nucleophilic addition and
regioselective 5-exo-dig addition to a carbon-carbon triple bond
with a cooperative effect from DBU (1,8-diazabicyclo[5.4.0]undec-
7-ene).11 Herein we report the synthesis of phosphonylated
4
Cu(OAc)2
Pd(PPh3)2Cl2
AlCl3
5
6
7b
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DMAP
Pyridine
AcOK
9
10
11c
12c
13c
14c
aState Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai
University, Tianjin, 300071, China. E-mail: miaozhiwei@nankai.edu.cn;
Fax: +86 2350 2351; Tel: +86 2350 4783
DBU
bKey Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology
(Ministry of Education), Tsinghua University, Beijing, 100084, China
a Unless otherwise noted all the reactions were performed with 0.5 mmol
of 6a and 10 mol% catalyst in 5 ml solvent for 5 h at room temperature.
b 20 mol% of Pd(OAc)2 was used. c The amount of base was 2 equiv. of
substrate 6a. d Isolated yields.
† Dedicated to Professor Ruyu Chen on the occasion of her 90th birthday.
‡ Electronic supplementary information (ESI) available: Detailed descrip-
tion of experimental procedures, full characterization of new compounds
7a-j shown in Table 2. See DOI: 10.1039/b908313h
2848 | Org. Biomol. Chem., 2009, 7, 2848–2850
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isochromenes from 6-endo-dig12 cyclization were obtained, and
no five-membered exocyclic products were detected by TLC
monitoring. The transition-metal-catalyzed synthesis of various
heterocycles via cyclization of alkynes possessing a nucleophile
in proximity to the triple bond is one of the most important
processes in organic synthesis.13 Further screening the reaction of
substrates in the presence of a variety of metal catalysts revealed
that cyclizations were not observed in the presence of other kinds
of catalysts, such as CuI, CuBr, Cu(OAc)2, Pd(PPh3)2Cl2 and AlCl3
(Table 1, entry 2–6) and only starting material 6a was recovered.
Increasing the catalyst amount to 20 mol% gave a similar result
(92% yield, Table 1, entry 7). Solvent screening showed that THF
led to better results than with the other solvents tested, i.e. CH2Cl2,
DMF, and toluene (Table 1, entries 8–10). Thus, the selective
synthesis of 6-endo-dig 1H-isochromen-1- ylphosphonate 7a from
dimethyl (2-(2-ethynyl)phenyl)(hydroxyl)methylphosphonate 6a
was achieved through the use of Pd(OAc)2 and THF as solvent.
In an extension of this work, we also examined the base-
induced reaction in order to compare the selectivity of this
reaction with that obtained in the Pd-catalyzed process. We
found that, using DBU as the base, the reaction of 6a selectively
afforded the isobenzofuran derivative 8, arising from a 5-exo-
dig cyclization mode, in 94% yield (Table 1, entry 14).11 The
other nitrogen-containing basic catalysts, such as 4-(N,N -dimethyl
amino)pyridine (DMAP), pyridine, or AcOK, proved to be
ineffective under similar conditions (Table 1, entries 11–12).
Based on the above optimization efforts, we next examined
the scope and limitations of the present Pd(OAc)2 catalyzed 6-
endo-dig cyclization with a series of dialkyl (2-(2-ethynyl)phenyl)-
(hydroxyl)methylphosphonate 6. The application of this
methodology to the synthesis of a variety of 1H-isochromen-
1-ylphosphonates 7 is summarized in Table 2. The reaction
of o-alkynyl benzaldehyde 5 proceeded smoothly with dialkyl
phosphite 4 in the present of Et3N in THF at room temperature,
and gave nearly quantitative yields of dialkyl (2-(2-ethynyl)-
phenyl)(hydroxyl)methylphosphonate 6. As can be seen all the
reactions of substrates bearing no further substituent at the
benzylic position (R2 = H) went to completion in the presence
of catalytic amounts of Pd(OAc)2 in THF at room tempera-
ture within five hours and the six-membered 1H-isochromen-
1-ylphosphonates 7 were obtained in good to excellent yields
(Table 2, entries 2–10). When R1 was replaced by 4-methylphenyl
6f-g or 4-fluorophenyl 6h-i, the reaction was still going very
well and the desired products were isolated (Table 2, entries
6–9). The results indicated that an electron-donor group or
electron-withdrawing group attached on the aromatic ring of
dialkyl (2-(2-ethynyl)phenyl)(hydroxyl)methylphosphonate 6 had
no great influence on this cyclization reaction. The reaction
of 6j, bearing a butyl group as R1, proceeded smoothly to
give 7j in 72% yield (Table 2, entry 10). When o-alkynyl
acetophenone 5 was employed as the starting material and
reacted with dimethyl phosphate 4 to synthesise dimethyl (2-(2-
ethynyl)phenyl)(hydroxyl)ethylphosphonate 6k, no reaction oc-
curred (Table 2, entry 11). Compared with the AgOTf-catalyzed
reaction of 2-alkynylbenzaldehyde with diethyl phosphate,7 our
method has the advantage of wider substrate scope (Table 2,
entries 8–10). But just as Wu et al. mentioned in their work,7 the
corresponding product 1H-isochromen-1-ylphosphonate 7 were
unstable and easily decomposed at room temperature.
Formation of 7a was traced by 31P NMR spectroscopy
as shown in Fig. 1. The starting material dimethyl (2-(2-
ethynyl)phenyl)(hydroxyl)methylphosphonate 6a in THF showed
a
31P NMR resonance at 23.70 ppm. After Pd(OAc)2 (0.011 g,
10% mol) was added to the solution of 6a, two new single
peaks at 19.73 ppm and 17.72 ppm appeared and assigned as
two intermediates of Pd(OAc)2 upon coordination of the triple-
bond of 6a (intermediate 9) and the intermediate palladium ate
complex 11 (Scheme 2). Over time, 31P NMR signals of the starting
material gradually disappeared and the signals of 7a (single peak
at 16.60 ppm) increased. Pd(OAc)2 catalyzed the reaction via
formation of the intermediate 9, with an active carbon-carbon
triple bond. The reaction was almost complete after five hours
according to the 31P NMR spectra (Fig. 1).
Table 2 Reactions of dialkyl (2-(2-ethynyl)phenyl)(hydroxyl)methyl-
phosphonate 6
Fig. 1 31P-NMR stack spectra for the synthesis of 7a (ppm).
Entrya Substrate 4
6
R1
R2
Yield of 7 (%)b
Based on 31P NMR stack spectra (Fig. 1), a plausible mechanism
for Pd(OAc)2 catalyzed cyclization reaction of 6 to 7 is outlined
in Scheme 2. The process consists of the following key steps:
(1) coordination of Pd(OAc)2 to the triple bond of dialkyl (2-(2-
ethynyl)phenyl)(hydroxyl)methylphosphonate 6 forming complex
9,13 which activates the triple bond toward nucleophilic attack,14
(2) intramolecular nucleophilic attack of the oxygen atom of the
hydroxyl group on the activated carbon-carbon triple bond to
afford intermediate 10, (3) elimination of proton occurs to give
complex 11 and AcOH, (4) protonolysis of 11 by AcOH gives the
6-endo-dig product 7 with regeneration of Pd(OAc)2.
1
H(O)P(OCH3)2
H(O)P(OC2H5)2
H(O)P(OC3H7-n)2 6c
H(O)P(OC3H7-i)2 6d
H(O)P(OC4H9-n)2 6e
H(O)P(OCH3)2
H(O)P(OC2H5)2
H(O)P(OCH3)2
H(O)P(OC2H5)2
H(O)P(OCH3)2
H(O)P(OCH3)2
6a
6b
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
7a
7b
7c
7d
7e
7f
7g
7h
7i
90
86
85
80
82
85
81
83
82
72
—
2
3
4
5
Ph
6
6f
6g
6h
6i
p-CH3C6H4
p-CH3C6H4
p-FC6H4
p-FC6H4
n-C4H9
7
8
9
H
H
CH3
10
11
6j
7j
—
6k Ph
a Unless otherwise noted all the reactions were performed with 0.5 mmol
of 5 and 10 mol% Pd(OAc)2 in 5 ml solvent at room temperature. b Isolated
yields.
In conclusion, we have described a general method for
the efficient synthesis of phosphonylated isochromenes via
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6 (a) J. J. Li, and G. W. Gribble, Palladium in Heterocyclic Chemistry,
Pergamon, Oxford, 2000; (b) In Handbook of Organopalladium Chem-
istry for Organic Sythesis, E. Negishi, Ed., Wiley, New York, 2002;
(c) S. Cacchi, G. Fabrizi and L. Moro, J. Org. Chem., 1997, 62, 5327;
(d) G. X. Dai and R. C. Larock, J. Org. Chem., 2003, 68, 920 and
references therein.
7 X. X. Yu, Q. P. Ding, W. Z. Wang and J. Wu, Tetrahedron Lett., 2008,
49, 4390.
8 (a) B. Gabriele, G. Salerno, A. Fazio and M. R. Bossio, Tetrahedron
Lett., 2001, 42, 1339; (b) B. Gabriele, G. Salerno and A. Fazio, Org.
Lett., 2000, 2, 351; (c) B. Gabriele, G. Salerno and E. Lauria, J. Org.
Chem., 1999, 64, 7687; (d) B. Gabriele and G. Salerno, Chem. Commun.,
1997, 1083; (e) B. Gabriele, R. Mancuso and G. Salerno, J. Org. Chem.,
2008, 73, 7336; (f) B. Gabriele, R. Mancuso, G. Salerno, G. Ruffolo and
P. Plastina, J. Org. Chem., 2007, 72, 6873; (g) B. Gabriele, G. Salerno
and A. Fazio, J. Org. Chem., 2003, 68, 7853; (h) B. Gabriele, G. Salerno
and M. Costa, Synlett, 2004, 2468.
9 (a) B. Gabriele, G. Salerno, A. Fazio and F. B. Campana, Chem.
Commun., 2002, 1408; (b) A. Bacchi, M. Costa, B. Gabriele, G. Pelizzi
and G. Salerno, J. Org. Chem., 2002, 67, 4450; (c) B. Gabriele, G.
Salerno, L. Veltri, M. Costa and C. Massera, Eur. J. Org. Chem., 2001,
4607; (d) G. P. Chiusoli, M. Costa, B. Gabriele and G. Salerno, J. Mol.
Catal. A: Chem., 1999, 143, 297; (e) A. Bacchi, G. P. Chiusoli, M. Costa,
C. Sani, B. Gabriele and G. Salerno, J. Organomet. Chem., 1998, 562, 35;
(f) B. Gabriele, R. Mancuso, G Salerno, E. Lupinacci, G. Ruffolo and
M. Costa, J. Org. Chem., 2008, 73, 4971; (g) B. Gabriele, R. Mancuso,
G Salerno and P. Plastina, J. Org. Chem., 2008, 73, 756; (h) B. Gabriele,
R. Mancuso, G Salerno and M. Costa, J. Org. Chem., 2007, 72, 9278;
(i) B. Gabriele, P. Plastina, G Salerno, R. Mancuso and M. Costa, Org.
Lett., 2007, 9, 3319; (j) B. Gabriele, G Salerno, A. Fazio and L. Veltri,
Adv. Synth. Catal., 2006, 348, 2212; (k) B. Gabriele, G Salerno, L. Veltri,
R. Mancuso, Z. Y. Li, A. Crispini and A. Bellusci, J. Org. Chem., 2006,
71, 7895; (l) B. Gabriele, R. Mancuso, G Salerno and M. Costa, Adv.
Synth. Catal., 2006, 348, 1101; (m) A. Bacchi, M. Costa, N. Della Ca`,
B. Gabriele, G Salerno and S. Cassoni, J. Org. Chem., 2005, 70, 4971;
(n) M. Costa, N. Della Ca`, B. Gabriele, C. Massera, G Salerno and
M. Soliani, J. Org. Chem., 2004, 69, 2469; (o) B. Gabriele, G Salerno,
P. Plastina, M. Costa and A. Crispini, Adv. Synth. Catal., 2004, 346,
351; (p) B. Gabriele, P. Plastina, G. Salerno and R. Mancuso, Synthesis,
2006, 4247.
Scheme 2
intramolecular 6-endo-dig cyclization of dialkyl (2-(2-ethynyl)-
phenyl)(hydroxyl)methylphosphonate 6 catalyzed by Pd(OAc)2 in
THF at room temperature. The yields obtained were good to
excellent in most cases, even though the reaction did not take
place in the presence of an alkyl substituent at the benzylic
position and the regioselectivity was always 100% favoring
6-endo-dig cyclization. The process holds promise as a useful
tool for the construction of complex heterocycles phosphonylated
isochromenes. Further studies on the mechanistic details and
synthetic potential of these cyclizations are in progress.
10 B. Gabriele, G. Salerno, A. Fazio and R. Pittelli, Tetrahedron, 2003, 59,
6251.
11 F. Wang, Y. D. Wang, L. C. Cai, Z. W. Miao and R. Y. Chen, Adv.
Synth. Catal., 2008, 350, 2733.
Acknowledgements
12 (a) K. Melis, T. Opstal and F. Verpoort, Eur. J. Org. Chem., 2002, 3779;
(b) L. Anastasia, C. Xu and E.-I. Negishi, Tetrahedron Lett., 2002, 43,
5673; (c) F. Bellina, D. Ciucci, P. Vergamini and R. Rossi, Tetrahedron,
2000, 56, 2533; (d) F. L. Qing and W. Z. Gao, Tetrahedron Lett., 2000,
41, 7727; (e) N. G. Kundu, M. Pal and B. Nandi, J. Chem. Soc., Perkin
Trans. 1, 1998, 561; (f) H. Y. Liao and C. H. Cheng, J. Org. Chem., 1995,
60, 3711; (g) Y. Ogawa, M. Maruno and T. Wakamatsu, Heterocycles,
1995, 41, 2587.
We thank the Committee of Science and Technology of Tianjin
(07JCZDJC04800), the Research Foundation for the Doctoral
Program of Higher Education of China (20070055042) and
Project 973 of the Ministry of Science and Technology of China
(2007CB914800) for financial support.
13 (a) S. Obika, H. Kono, Y. Yasui, R. Yanada and Y. Takemoto, J. Org.
Chem., 2007, 72, 4462; (b) R. Yanada, S. Obika, H. Kono and Y.
Takemoto, Angew. Chem., Int. Ed., 2006, 45, 3822; (c) G. Zeni and R. C.
Larock, Chem. Rev., 2004, 104, 2285; (d) F. Alonso, I. P. Beletskaya and
M. Yus, Chem. Rev., 2004, 104, 3079; (e) S. Cacchi and G. Fabrizi, Chem.
Rev., 2005, 105, 2873; (f) I. Nakamura and Y. Yamamoto, Chem. Rev.,
2004, 104, 2127; (g) D. Conreaux, D. Bouyssi, N. Monteiro and G.
Balme, Curr. Org. Chem., 2006, 10, 1325; (h) G. Varchi and I. Ojima,
Curr. Org. Chem., 2006, 10, 1341; (i) B. Schmidt and J. Hermanns, Curr.
Org. Chem., 2006, 10, 1363; (j) G. Vasapollo and G. Mele, Curr. Org.
Chem., 2006, 10, 1397; (k) S. Cacchi, G. Fabrizi and A. Goggiamani,
Curr. Org. Chem., 2006, 10, 1423; (l) Z. Zhang, G. Zhu, X. Tong, F.
Wang, X. Xie, J. Wang and L. Jiang, Curr. Org. Chem., 2006, 10, 1457;
(m) F. Ragaini, S. Cenini, E. Gallo and A. Caselli, Curr. Org. Chem.,
2006, 10, 1479.
Notes and references
1 (a) For examples of phosphorus compounds as pharmaceuticals, see:
P. Kafarski and B. LeJczak, Curr. Med. Chem.: Anti-Cancer Agents,
2001, 1, 301; (b) O. M. Colvin, Curr. Pharm. Des., 1999, 5, 555; (c) G.
Zon, Prog. Med. Chem., 1982, 19, 205; (d) M. M. Mader and P. A.
Bartlett, Chem. Rev., 1997, 97, 1281; (e) P. Kafarski and B. Lejczak,
Phosphorus, Sulfur Silicon Relat. Elem., 1991, 63, 193.
2 X. S. Li, D. W. Zhang, H. Pang, F. Shen, H. Fu, Y. Y. Jiang and Y. F.
Zhao, Org. Lett., 2005, 7, 4919.
3 (a) For representative examples, see: M. R. Michaelides, R. Schoenleber,
S. Thomas, D. M. Yamamoto, D. R. Britton, R. MacKenzie and J. W.
Kebabian, J. Med. Chem., 1991, 34, 2946; (b) M. P. DeNinno, R.
Schoenleber, R. J. Perner, L. Lijewski, K. E. Asin, D. R. Britton, R.
MacKenzie and J. W. Kebabian, J. Med. Chem., 1991, 34, 2561.
4 See, for example: K. Kobayashi, A. Konishi, Y. Kanno and H.
Suginome, J. Chem. Soc., Perkin Trans. 1, 1993, 111.
14 (a) A. Arcadi, S. Cacchi, M. Del Rosario, G. Fabrizi and F. Marinelli,
J. Org. Chem., 1996, 61, 9280; (b) G. X. Dai and R. C. Larock, J. Org.
Chem., 2003, 68, 920; (c) N. Asao, T. Nogami, K. Takahashi and Y.
Yamamoto, J. Am. Chem. Soc., 2002, 124, 764.
5 See, for example: Y. C. Xu, E. Lebeau, J. W. Gillard and G. Attardo,
Tetrahedron Lett., 1993, 34, 3841, and references cited therein.
2850 | Org. Biomol. Chem., 2009, 7, 2848–2850
This journal is
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©