Synthesis of phosphaisoquinolin-1-ones by Pd(II)-catalyzed cyclization of o-(1-alkynyl)phenylphosphonamide monoesters

Article abstract of DOI:10.1021/jo0614644

A Pd(II)-catalyzed intramolecular cyclization of o-(1-alkynyl) phenylphosphonamide monoethyl esters was examined, and a new class of six-membered phosphorus heterocycles (phosphaisoquinolin-1-ones) were formed with high regioselectivity and good yields. T

Full text of DOI:10.1021/jo0614644

Synthesis of Phosphaisoquinolin-1-ones by Pd(II)-Catalyzed
Cyclization of o-(1-Alkynyl)phenylphosphonamide Monoesters
Wei Tang 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 July 14, 2006
A Pd(II)-catalyzed intramolecular cyclization of o-(1-alkynyl)phenylphosphonamide monoethyl esters
was examined, and a new class of six-membered phosphorus heterocycles (phosphaisoquinolin-1-ones)
were formed with high regioselectivity and good yields. The present reaction is the first example of
intramolecular addition of P-NH to substituted alkynes, which provides a valuable way to synthesize
novel phosphorus heterocycles with potential bioactivities.
Introduction
phacoumarins showed good inhibitory activity against SHP-
1,11 and phosphaisocoumarins served as inhibitors of protein
tyrosine phosphatase 1B (PTP1B).12 Because there is a remark-
able similarity in reactivity and bioactivities between the carbon
species and their phosphorus counterparts,13 one can anticipate
that the phosphonamide analogues of isoquinolin-1-ones (i.e.,
phosphaisoquinolin-1-ones) would have potential bioactivities
similar to those of isoquinolin-1-ones (Figure 1). To the best
of our knowledge, phosphaisoquinolin-1-ones are a new type
of phosphorus heterocycles that have never been synthesized
thus far. So, the synthesis of phosphaisoquinolin-1-ones and the
assessment of their biological properties are very attractive.
The transition-metal-catalyzed cyclization of alkynes pos-
sessing a nucleophile in proximity to the triple bond is an
important process in organic synthesis, which can construct
various heterocycles in an efficient and atom-economic way.
Over the past few years, the intramolecular annulations of
amines,14 amides,15 imines,16 carboxylic acids,17 alcohols,18 and
phosphonic acid monoesters12 to a triple bond have been
Isoquinolin-1-ones have gained considerable synthetic and
pharmacological interest for a long time because of their diverse
bioactivities, such as antitumor activity,1 cytotoxicity,2 cardio-
vascular activity,3 antineoplastic property,4 antimicrobial prop-
erty,5 inhibition of human thymidylate synthase,6 inhibition of
PARP activity,7 and reduction of systolic blood pressure.8
Organophosphorus compounds continue to receive widespread
attention due to their ubiquity in biological systems9 and their
potential to serve as novel pharmaceuticals.10 Recent studies
have indicated that a lot of heterocycle analogues containing
phosphorus show the expected bioactivity. For example, phos-
(1) (a) Cho, W. J.; Park, M. J.; Chung, B. H.; Lee, C. O. Bioorg. Med.
Chem. Lett. 1998, 8, 41. (b) Sladkov, V. I.; Sazonova, N. M.; Grekova, G.
S.; Kalistratov, S. G.; Sokolova, A. S.; Chernov, V. S.; Suvorov, N. N.
Pharm. Chem. J. 1989, 23, 47.
(2) Cho, W. J.; Kim, E. K.; Park, M. J.; Choi, S. U.; Lee, C. O. Bioorg.
Med. Chem. 1998, 6, 2449.
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R. K.; Doubek, D. L. J. Nat. Prod. 2003, 66, 1065.
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Y.; Dev, I. K.; Duch, D. S.; Humphreys, J.; Smith, G. K.; Ferone, R. J.
Med. Chem. 1991, 34, 2746.
(10) For examples of phosphorus compounds as pharmaceuticals, see:
(a) Kafarski, P.; LeJczak, B. Curr. Med. Chem.: Anti-Cancer Agents 2001,
1, 301. (b) Colvin, O. M. Curr. Pharm. Des. 1999, 5, 555. (c) Zon, G.
Prog. Med. Chem. 1982, 19, 205. (d) Stec, W. J. Organophosphorus Chem.
1982, 13, 145. (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.
(7) Watson, C. Y.; Whish, W. J.; Threadgill, M. D. Bioorg. Med. Chem.
1998, 6, 721.
(11) Li, X. S.; Zhang, D. W.; Pang, H.; Shen, F.; Fu, H.; Jiang, Y. Y.;
Zhao, Y. F. Org. Lett. 2005, 7, 4919.
(8) Yamada, Y.; Ando, K.; Komiyama, K.; Shibata, S.; Nakamura, I.;
Hayashi, Y.; Ikegami, K.; Uchida, I. Bioorg. Med. Chem. Lett. 1997, 7,
1863.
(9) (a) Westheimer, F. H. Science 1987, 235, 1173. (b) Seto, H.;
Kuzuyama, T. Nat. Prod. Rep. 1999, 16, 589.
(12) Peng, A. Y.; Ding, Y. X. J. Am. Chem. Soc. 2003, 125, 15006.
(13) (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.
10.1021/jo0614644 CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/05/2006
J. Org. Chem. 2006, 71, 8489-8492
8489

Tang and Ding
SCHEME 2. Synthesis of
o-(1-Alkynyl)phenylphosphonamide Monoesters
FIGURE 1. Isoquinolin-1-one (A) and the designed phosphaisoquino-
lin-1-ones (B).
TABLE 1. Transition-Metal-Catalyzed Cyclization of the
SCHEME 1. Approach to Synthesize 2
o-(1-Alkynyl)phenylphosphonamide Monoethyl Ester (1a)a
extensively investigated using transition-metal reagents as
effective catalysts. However, analogous intramolecular cycliza-
tion of P-NH to alkynes has never been reported thus far. In
this paper, we report a mild and efficient palladium-catalyzed
intramolecular cyclization of o-(1-alkynyl)phenylphosphonamide
monoethyl esters 1, leading to the formation of the phospha-
isoquinolin-1-ones 2 (Scheme 1).
entry
catalyst (10 mol %)
time (h)
temp (°C)
yield (2a) (%)b
1
2
3
4
5
6
7
8
9
none
PdCl2
24
24
4
reflux
25-80
25-80
80
80
80
reflux
reflux
reflux
60
0
65
80
trace
0
0
0
0
0
trace
0
PdCl2(CH3CN)2
PdCl2(PPh3)2
Pd(PPh3)4
Pd(OAc)2
AgI
AgNO3
CuI
CuCl2
24
12
12
12
12
12
24
72
Results and Discussion
10
11
AcOH
reflux
A two-step approach to phosphaisoquinolin-1-ones has been
examined involving (i) preparation of the key starting materials
1 by the amination of phosphonyl chloride and (ii) the Pd(II)-
catalyzed cyclization of the starting materials 1.
a Reaction conditions: 1a (0.1 mmol), catalyst (0.01 mmol), anhydrous
solvent (1 mL). b Isolated yield.
The o-(1-alkynyl)phenylphosphonamide monoethyl esters 1
of 3 with thionyl chloride and subsequent amination of
phosphonyl chloride with an amine such as benzylamine or
n-propylamine in CH2Cl2 at 0 °C (Scheme 2). The o-(1-alkynyl)-
phenylphosphonic acid monoethyl esters 3 were prepared as
described previously.12
were prepared according to the known method19 by treatment
(14) (a) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J.
M. J. Org. Chem. 2001, 66, 4525. (b) Kondo, T.; Okada, T.; Suzuki, T.;
Mitusudi, T.-a. J. Organomet. Chem. 2001, 622, 149. (c) Mu¨ller, T. E.;
Berger, M.; Grosche, M.; Herdtweck, E.; Schmidtchen, F. P. Organome-
tallics 2001, 20, 4384. (d) Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers,
J. B. Tetrahedron Lett. 1998, 39, 5159. (e) Yu, M. S.; de Leon, L. L.;
McGuire, M. A.; Botha, G. Tetrahedron Lett. 1998, 39, 9347. (f) Mahanty,
J. S.; De, M.; Das, P.; Kundu, N. G. Tetrahedron 1997, 53, 13397. (g)
Cacchi, S.; Carnicelli, V.; Marinelli, F. J. Organomet. Chem. 1994, 475,
289. (h) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989, 30,
2581. (i) Utimoto, K.; Miwa, H.; Nozaki, H. Tetrahedron Lett. 1981, 22,
4277.
(15) (a) Van Esseveldt, B. C. J.; van Delft, F. L.; de Gelder, R.; Rutjes,
F. P. J. T. Org. Lett. 2003, 5, 1717. (b) Kozawa, Y.; Mori, M. Tetrahedron
Lett. 2002, 43, 1499. (c) Torres, J. C.; Pilli, R. A.; Vargas, M. D.; Violante,
F. A.; Garden, S. J.; Pinto, A. C. Tetrahedron 2002, 58, 4487. (d) Sashida,
H.; Kawamukai, A. Synthesis 1999, 1145. (e) Kobayashi, Y.; Fukuyama,
T. J. Heterocycl. Chem. 1998, 35, 1043. (f) McDonald, F. E.; ChatterJee,
A. K. Tetrahedron Lett. 1997, 38, 7687. (g) Khan, M. W.; Kundu, N. G.
Synlett 1997, 12, 1435. (h) Ohe, K.; Ishihara, T.; Chatani, N.; Kawasaki,
Y.; Murai, S. J. Org. Chem. 1991, 56, 2267. (i) NagaraJan, A.; Balasubra-
manian, T. R. Indian J. Chem., Sect. B. 1989, 28, 67. (j) Sakamoto, T.;
Kondo, Y.; Iwashita, S.; Nagano, T.; Yamanaka, H. Chem. Pharm. Bull.
1988, 36, 1305. (k) Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H.;
McKillop, A. Tetrahedron Lett. 1985, 26, 5963.
The intramolecular cyclization of the o-(1-alkynyl)phe-
nylphosphonamide monoethyl ester (1a) was first examined
(Table 1). Through control experiments, we found that the use
of PdCl2 as a catalyst gave the product 2a in only 65% yield,
and PdCl2(CH3CN)2 improved the yield to 80%; other palladium
catalysts (e.g., PdCl2(PPh3)2, Pd(PPh3)4, and Pd(OAc)2) gave
only unchanged starting materials. Next, silver salts (AgI,
AgNO3) and copper salts (CuI, CuCl2) were tested, and no
improvement was observed. PdCl2(CH3CN)2 was an excellent
catalyst for the current reaction, but the catalyst CuI showed
less activities for this reaction. Although CuI was an excellent
catalyst for intramolecular cyclization of 2-alkynylphenylphos-
phonic acid monoesters,12 the catalyst PdCl2(CH3CN)2 was less
effective for intramolecular cyclization of 2-alkynylphenylphos-
phonic acid monoesters. All facts showed that the palladium
catalyst PdCl2(CH3CN)2 was crucial for this reaction. We also
examined the reaction of 1a to 2a in the presence of AcOH
without Pd catalysts; however, none of the desired product was
detected, and only salt was formed for a long time.
(16) (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86. (b)
Zhang, H.; Larock, R. C. Tetrahedron Lett. 2002, 43, 1359.
(17) (a) Melis, K.; Opstal, T.; Verpoort, F. Eur. J. Org. Chem. 2002,
22, 3779. (b) Anastasia, L.; Xu, C.; Negishi, E.-i. Tetrahedron Lett. 2002,
43, 5673. (c) Bellina, F.; Ciucci, D.; Vergamini, P.; Rossi, R. Tetrahedron
2000, 56, 2533. (d) Qing, F. L.; Gao, W. Z. Tetrahedron Lett. 2000, 41,
7727. (e) Kundu, N. G.; Pal, M.; Nandi, B. J. Chem. Soc., Perkin Trans.
1998, 1, 561. (f) Liao, H. Y.; Cheng, C. H. J. Org. Chem. 1995, 60, 3711.
(g) Ogawa, Y.; Maruno, M.; Wakamatsu, T. Heterocycles 1995, 41, 2587.
(18) (a) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 2528.
(b) Bates, C. G.; SaeJueng, P.; Murphy, J. M.; Venkataraman, D. Org. Lett.
2002, 4, 4727. (c) Cutchins, W. W.; McDonald, F. E. Org. Lett. 2002, 4,
749. (d) Aschwanden, P.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2000, 2,
2331. (e) McDonald, F. E.; Reddy, K. S.; Diaz, Y. J. Am. Chem. Soc. 2000,
122, 4304.
In the presence of PdCl2(CH3CN)2 (10 mol %), the reaction
of 1a was performed at room temperature for 24 h in CH3CN,
and product 2a was isolated in 55% yield with 36% recovery
of the reactant 1a. While the reaction was run at 80 °C for 4 h,
the reactant 1a disappeared completely and gave product 2a in
80% good isolated yield.
(19) Hirschmann, R.; Yager, K. M.; Talor, C. M.; Witherrington, J.;
Sprengeler, P. A.; Phillips, B. W.; Moore, W.; Smith, A. B. J. Am. Chem.
Soc. 1997, 119, 8177.
8490 J. Org. Chem., Vol. 71, No. 22, 2006

Synthesis of Phosphaisoquinolin-1-ones
TABLE 2. PdCl2(CH3CN)2-Catalyzed Cyclization of the o-(1-Alkynyl)phenylphosphonamide Monoethyl Esters 1a
entry
substrate
R1
R2
C6H5
C6H5
C6H5
n-Bu
C6H5
C6H5
n-Bu
p-EtC6H5
p-EtC6H5
cyclopropyl
CH3OCH2
C6H5
R3
time (h)
product
yield (%)c
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OMe
C6H5CH2
H
n-Pr
C6H5CH2
C6H5CH2
n-Pr
C6H5CH2
C6H5CH2
n-Pr
4
8
4
6
4
4
4
4
4
4
6
6
2a
2b
2c
2d
2e
2f
2g
2h
2i
80
68
72
87
85
67
85
72
70
90
65
79
10
11b
12
1j
1k
1l
C6H5CH2
n-Pr
C6H5CH2
2j
2k
2l
a The reaction of 1 was carried out in the presence of 10 mol % of PdCl2(CH3CN)2 at 80 °C in CH3CN for 4 h. b The addition of a few drops of CH3CO2H
was essential for the reactant 1k. c Isolated yield.
SCHEME 3
The reaction solvents were next studied. The use of DMF,
DMSO, toluene, and DCM as the solvent proved to be
ineffective, and none of the desired product was detected; only
with CH3CN or THF as the solvent did the cyclization reaction
proceed smoothly, and CH3CN proved to be the most suitable
solvent. Moreover, it is particularly noteworthy that the reaction
proceeded well without rigorously anhydrous or oxygen-free
conditions, which will be a great advantage for practical use.
On the basis of the above optimization efforts, this method
was applied to the synthesis of a variety of 2-, 3-, and
7-substituted phosphaisoquinolin-1-ones, and results are sum-
marized in Table 2. In the presence of catalytic amounts of
PdCl2(CH3CN)2, o-(1-alkynyl)phenylphosphonamide monoethyl
esters 1 with a variety of substituents (R1, R2, and R3) could be
cyclized to form phosphaisoquinolin-1-ones 2 in CH3CN with
moderate heating in good to excellent yields.
The chemical properties of substituents (R2) on the acetylene
monitored by TLC and 1H NMR spectra indicated that no other
regioisomers had been observed during the reaction progress.
Factors affecting the above regioselectivity are not yet very clear.
A possible explanation is that the longer C-P and P-N bond
lengths would be less favorable for the transition state leading
to five-membered ring products than that leading to six-
membered ring products. The structures of 2 were assigned on
the basis of 1H NMR and 13C NMR spectra and X-ray
crystallographic analysis (see Supporting Information).
terminal did not affect the yields of the phosphaisoquinolin-1-
ones. Both aryl-substituted (entries 1-3, 5, 6, 8, 9, and 12) and
alkyl-substituted (entries 4, 7, and 10) alkynes were able to
tolerate the reaction conditions. However, the methoxymethyl-
substituted alkyne (entry 11) has a significant effect on the yield
of the phosphaisoquinolin-1-one. The reactant 1k only gave 15%
of product 2k under the typical reaction conditions. However,
with a few drops of CH3CO2H added, the reaction could give
2k in 65% yield. In this instance, an external proton source
presumably facilitated the cleavage of vinylpalladium species
D to afford 2k and to regenerate a reactive Pd(II) species (see
proposed reaction mechanism in Scheme 3).
Functionalities such as chloro and methoxy on the aromatic
ring also did not affect the reaction efficiency. In addition, the
unsubstituted phosphonamide compound (entry 2) can also
afford the cyclization product in good yields. The current
reaction is extremely versatile and provides a convenient method
for the synthesis of various phosphaisoquinolin-1-ones.
In contrast with the cyclization of o-(1-alkynyl)benzamides,
which gave a 5-exo-dig cyclization predominantly in the
presence of transition-metal catalysts, the current reaction shows
very high regioselectivity to give the 6-endo-dig20 cyclization
product. In each case, only the six-membered endocyclic
phosphaisoquinolin-1-ones were obtained, and the reaction
On the basis of the above results and the related literature,21
a plausible reaction mechanism is shown in Scheme 3. It
presumably involves (i) the formation of the complex C through
coordination of the alkynyl moiety of 1 with PdCl2(CH3CN)2;
(ii) regioselective nucleophilic attack of the activation triple bond
by nitrogen in the endo mode to give the vinylpalladium species
D (iii) which subsequently undergoes in situ protonation with
regeneration of the Pd(II) catalyst to product 2.
To probe whether the synthesized phosphaisoquinolin-1-ones
possessed biological activities, their in vitro antitumor properties
(20) (a) Baldwin, J. E. J. Chem. Soc. Chem. Commun. 1976, 734. (b)
Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas,
R. C. J. Chem. Soc., Chem. Commun. 1976, 736.
(21) (a) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54, 5856. (b)
Iritani, K.; Matsubara, S.; Utimoto, K. Tetrahedron Lett. 1988, 15, 1799.
J. Org. Chem, Vol. 71, No. 22, 2006 8491

Tang and Ding
The resulting residue was purified by column chromatography using
hexane/EtOAc as eluent to give the corresponding 2. The isolated
yield and the physical data for 2 are as follows.
were evaluated in an A-549 lung cell line by the SRB assay.
At a concentration of 10-4 mol/L, the A-549 lung cell growth
inhibition ratios of 2a, 2c, 2d, 2e, 2f, 2h, 2j, and 2l are 97.2%,
74.7%, 83.2%, 97.0%, 97.2%, 97.2%, 97.5%, and 97.2%,
respectively, but their biological activities drop obviously with
the decrease of concentration. So, further studies are needed to
confirm this possibility.
2-Benzyl-1-ethoxy-3-phenyl-benzo[c][1,2] Azaphosphinine 1-Ox-
ide (2a). Purification by flash chromatography (4:1 hexane/EtOAc)
afforded 300 mg of the product as a pale yellow solid. Mp: 95-
96 °C. Yield: 80%. 1H NMR (300 MHz, CDCl3): δ 7.97 (dd, J )
13.2 Hz, J ) 7.5 Hz, 1H), 7.57-7.27 (m, 8H), 7.07-6.96 (m, 3H),
6.67(d, J ) 6.9 Hz, 2H), 6.20 (d, J ) 2.1 Hz, 1H), 5.17 (dd, J )
15 Hz, J ) 8.1 Hz, 1H), 4.42 (dd, J ) 15.3 Hz, J ) 9.6 Hz, 1H),
4.17-4.07 (m, 2H), 1.30 (t, J ) 6.9 Hz, 3H). 13C NMR (75.4 MHz,
CDCl3): δ 144.1, 138.2 (d, J ) 6.9 Hz), 137.8 (d, J ) 1.8 Hz),
136.4 (d, J ) 5.1 Hz), 131.9 (d, J ) 2.6 Hz), 128.7, 128.4 (d, J )
8.4 Hz), 128.3 (2 C), 128.2 (2 C), 127.9 (2 C), 127.7 (2 C), 126.9
(d, J ) 11.6 Hz), 126.8, 126.5 (d, J ) 15.5 Hz), 122.0 (d, J )
171.0 Hz), 112.6 (d, J ) 10.2 Hz), 60.4 (d, J ) 6.3 Hz), 48.7 (d,
J ) 3.4 Hz), 16.4 (d, J ) 6.8 Hz). 31P NMR (121 MHz, CDCl3):
δ 17.83. MS (EI): m/z 375 (M+, 90), 91 (100). HRMS (EI): Calcd
for C23H22NO2P (M+ + 1), 376.1458; found, 376.1460.
Conclusion
In summary, we have developed a novel PdCl2(CH3CN)2-
catalyzed cyclization reaction of o-(1-alkynyl)phenylphospho-
namide monoethyl esters to phosphaisoquinolin-1-ones with high
regioselectivity and good yields. The present reaction represents
the first example of intramolecular addition of P-NH to alkynes,
which provides a new approach to synthesize phosphorus
heterocycles. The further biochemical evaluation of them and
the extension of this reaction are underway.
2-Benzyl-7-chloro-1-ethoxy-3-phenyl-benzo[c][1,2] Azaphos-
phinine 1-Oxide (2e). Purification by flash chromatography (4:1
hexane/EtOAc) afforded 347 mg of the product as a yellow solid.
Experimental Section
1
Mp: 126-127 °C. Yield: 85%. H NMR (300 MHz, CDCl3): δ
General Procedure for the Preparation of o-(1-Alkynyl)-
phenylphosphonamide Monoethyl Esters 1. At ambient temper-
ature, a solution of o-(1-alkynyl)phenylphosphonic acid monoethyl
ester 3 (2 mmol) in CH2Cl2 (5 mL) was treated with thionyl chloride
(6 mmol). After 2 h, the mixture was concentrated and the resultant
opaque oil was exposed to a high vacuum (1 mmHg) for 3 h. The
crude phosphonyl chloride was dissolved in CH2Cl2 (5 mL), and
then Et3N (2.2 mmol) and amine (10 mmol) were added at 0 °C;
the solution was stirred for 4 h at ambient temperature. Concentra-
tion afforded a residue that was purified by column chromatography
using hexane/EtOAc as eluent to give the corresponding 1. The
isolated yield and the physical data for 1 are as follows.
7.92 (dd, J ) 14.1 Hz, J ) 2.1 Hz, 1H), 7.50-7.46 (m, 1H), 7.38-
7.28 (m, 5H), 7.27-7.19 (m, 1H), 7.05-6.97 (m, 3H), 6.67-6.64
(m, 2H), 6.17 (d, J ) 1.5 Hz, 1H), 5.15 (dd, J ) 15.3 Hz, J ) 8.1
Hz, 1H), 4.40 (dd, J ) 15.6 Hz, J ) 9.9 Hz, 1H), 4.16-4.10 (m,
2H), 1.28 (t, J ) 3.9 Hz, 3H). 13C NMR (75.4 MHz, CDCl3): δ
144.5, 137.5, 136.5 (d, J ) 5.7 Hz), 136.1 (d, J ) 5.1 Hz), 132.2
(d, J ) 17.2 Hz), 132.1, 129.0, 128.5 (d, J ) 15.4 Hz), 128.4 (2
C), 128.3 (d, J ) 4.2 Hz), 128.2 (2 C), 128.0 (2 C), 127.7 (2 C),
127.0, 123.6 (d, J ) 170.4 Hz), 111.9 (d, J ) 8.9 Hz), 60.8 (d, J
) 6.1 Hz), 48.9 (d, J ) 3.5 Hz), 16.4 (d, J ) 6.8 Hz). 31P NMR
(121 MHz, CDCl3): δ 16.07. MS (EI): m/z 409 (M+, 36), 380
(3), 91 (100), 77 (6), 43 (9). IR (film, cm-1): 2926, 1714, 1609,
1472, 1248, 1123, 1028, 955. HRMS (EI): Calcd for C23H21ClNO2P
(M+ + 1), 410.1086; found, 410.1071.
N-Benzyl (2-Phenylethynylphenyl)phosphonamide Monoethyl
Ester (1a). Purification by flash chromatography (1:1 hexane/
EtOAc) afforded 375 mg of the product as a yellow solid. Mp:
1
96-97 °C. Yield: 50%. H NMR (300 MHz, CDCl3): δ 8.14-
7-Chloro-1-ethoxy-3-methoxylmethyl-2-propyl-benzo[c]-
[1,2] Azaphosphinine 1-Oxide (2k). A few drops of CH3CO2H
were added, and purification by flash chromatography (4:1 hexane/
8.05 (m, 1H), 7.66-7.32 (m, 8H), 7.26-7.20 (m, 5H), 4.31-4.02
(m, 4H), 3.53 (q, J ) 8.4 Hz, 1H), 1.31 (t, J ) 7.2 Hz, 3H). MS
(EI): m/z 375 (M+, 100). Anal. Calcd for C23H22NO2P: C, 73.59;
H, 5.91; N, 3.73. Found: C, 73.29; H, 6.02; N, 3.63.
1
EtOAc) afforded 213 mg of the product as oil. Yield: 65%. H
NMR (300 MHz, CDCl3): δ 7.84-7.82 (m, 1H), 7.47-7.44 (m,
1H), 7.26-7.17 (m, 1H), 6.07 (d, J ) 1.8 Hz, 1H), 4.47 (d, J )
12.9 Hz, 1H), 4.01-3.87 (m, 3H), 3.82-3.73 (m, 1H), 3.71-3.40
(m, 1H), 3.39 (s, 3H), 1.63-1.53 (m, 2H), 1.25 (t, J ) 6.6 Hz,
3H), 0.87-0.82 (t, J ) 7.8 Hz, 3H). 13C NMR (75.4 MHz,
CDCl3): δ 140.0, 136.1 (d, J ) 4.6 Hz), 132.1 (d, J ) 15.0 Hz),
132.0, 128.1 (d, J ) 7.2 Hz), 127.9 (d, J ) 9.1 Hz), 123.0 (d, J )
127.3 Hz), 108.5 (d, J ) 7.6 Hz), 72.2 (d, J ) 3.4 Hz), 60.9 (d, J
) 4.7 Hz), 57.6, 44.8 (d, J ) 1.4 Hz), 24.9, 16.2 (d, J ) 5.0 Hz),
11.1. 31P NMR (121 MHz, CDCl3): δ 17.47. MS (EI): m/z 329
(M+, 100), 314 (4), 300 (29), 256 (28), 229 (28), 97 (5), 57 (11),
41 (22). IR (film, cm-1): 2964, 1621, 1471, 1245, 1158, 1029,
959, 843, 788. HRMS (EI): Calcd for C15H21ClNO3P (M+ + 1),
330.1029; found, 330.1020.
(2-Phenylethynylphenyl)phosphonamide Monoethyl Ester
(1b). Purification by flash chromatography (1:1 hexane/EtOAc)
afforded 273 mg of the product as a yellow solid. Mp: 115-116
1
°C. Yield: 48%. H NMR (300 MHz, CDCl3): δ 8.13-8.06 (m,
1H), 7.65-7.31 (m, 8H), 4.20-3.95 (m, 2H), 3.50 (d, J ) 2.7 Hz,
2H), 1.31 (t, J ) 7.2 Hz, 3H). MS (EI): m/z 285 (M+, 100). Anal.
Calcd for C16H16NO2P: C, 67.36; H, 5.65; N, 4.91. Found: C,
67.15; H, 5.68; N, 4.72.
N-Propyl (2-Phenylethynylphenyl)phosphonamide Monoethyl
Ester (1c). Purification by flash chromatography (2:1 hexane/
1
EtOAc) afforded 294 mg of the product as oil. Yield: 45%. H
NMR (300 MHz, CDCl3): δ 8.12-8.05 (m, 1H), 7.65-7.38 (m,
8H), 4.17-4.00 (m, 2H), 3.24 (q, J ) 7.5 Hz, 1H), 3.01-2.89 (m,
2H), 1.47-1.40 (m, 2H), 1.33 (t, J ) 9.6 Hz, 3H), 0.81 (t, J ) 7.5
Hz, 3H). MS (EI): m/z 327 (M+, 1). Anal. Calcd for C19H22NO2P:
C, 69.71; H, 6.77; N, 4.28. Found: C, 69.35; H, 6.70; N, 4.05.
General Procedure for the Preparation of Phosphaisoquino-
lin-1-ones 2. To a solution of o-(1-alkynyl)phenylphosphonamide
monoethyl esters 1 (1 mmol) and acetonitrile (5 mL) was added
PdCl2(CH3CN)2 (0.1 mmol), and the mixture was heated at 80 °C
for 4 h. The reaction mixture was diluted with EtOAc and washed
with brine, dried over Na2SO4, filtered, and evaporated in vacuo.
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant No. 20572123) for financial support.
Supporting Information Available: Typical experimental
procedures and spectral data for 1 and 2 and the CIF for 2e. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO0614644
8492 J. Org. Chem., Vol. 71, No. 22, 2006