Selective synthesis of 2,3-disubstituted-2H-isoindol-1-ylphosphonate and 2,3-disubstituted-1,2-dihydroisoquinolin-1-ylphosphonate via metal-tuned reaction of α-amino (2-alkynylphenyl)methylphosphonate

Article abstract of DOI:10.1021/jo070716d

(Chemical Equation Presented) Palladium(II)-catalyzed reaction of α-amino (2-alkynylphenyl)methylphosphonate provides a novel and efficient route to 2,3-disubstituted-2H-isoindol-1-ylphosphonate via 5-exo-cyclization and [1,5]-H shift; while 2,3-disubstituted-1,2-dihydroisoquinolin-1-ylphosphonate is afforded through 6-endo-cyclization utilizing silver triflate as catalyst.

Full text of DOI:10.1021/jo070716d

SCHEME 1
Selective Synthesis of
2,3-Disubstituted-2H-isoindol-1-ylphosphonate
and 2,3-Disubstituted-1,2-dihydroiso-
quinolin-1-ylphosphonate via Metal-Tuned
Reaction of r-Amino
(2-Alkynylphenyl)methylphosphonate
Qiuping Ding,† Yang Ye,† Renhua Fan,*,† and Jie Wu*,†,‡
Department of Chemistry, Fudan UniVersity, 220 Handan Road,
Shanghai, 200433, People’s Republic of China, and State Key
Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Road, Shanghai 200032, People’s Republic of China
jie_wu@fudan.edu.cn
of phosphatase activity.6 On the other hand, recent studies have
indicated that a number of heterocycle analogues containing
phosphorus showed excellent bioactivities. For example, phos-
phacoumarins showed good inhibitory activity against SHP-1.7
In light of our interest in R-amino phosphonates and natural
product-like compounds, we required an efficient method to
generate R-amino phosphonate based scaffolds and its focused
library, with a hope of finding more active hits or leads for our
particular biological assays.8 Herein, we would like to disclose
our preliminary results for the synthesis of 2,3-disubstituted-
2H-isoindol-1-ylphosphonate 2 or 2,3-disubstituted-1,2-dihy-
droisoquinolin-1-ylphosphonate 3 from R-amino (2-alkynylphe-
nyl)methylphosphonate 1 under metal-tuned conditions (Scheme
1)
ReceiVed April 5, 2007
Palladium(II)-catalyzed reaction of R-amino (2-alkynylphe-
nyl)methylphosphonate provides a novel and efficient route
to 2,3-disubstituted-2H-isoindol-1-ylphosphonate via 5-exo-
cyclization and [1,5]-H shift; while 2,3-disubstituted-1,2-
dihydroisoquinolin-1-ylphosphonate is afforded through 6-en-
do-cyclization utilizing silver triflate as catalyst.
It is well-known that the transition metal- or Lewis acid-
catalyzed cyclization of alkynes possessing 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.9-15 Over the past few years,
(6) Beers, S. A.; Schwender, C. F.; Loughney, D. A.; Malloy, E.;
Demarest, K.; Jordan, J. Bioorg. Med. Chem. 1996, 4, 1693.
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6,703,514. (b) Wu, J.; Yang, Z.; Fathi, R.; Zhu, Q. U.S. Pat. Appl. Publ.
2004, 43 pp.
Organophosphorus compounds continue to receive wide-
spread attention due to their ubiquity in biological systems.1,2
Among these, in particular, R-amino phosphonic acids, their
phosphonate esters, and short peptides incorporating this unit
have attracted considerable focus since they are excellent
inhibitors of a wide range of proteolytic enzymes.3 In addition,
R-amino phosphonate derivatives have broad application due
to their antibacterial4 and antifungal5 activity, and as inhibitors
(9) (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) Muller, T. E.;
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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,
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† Fudan University.
‡ Chinese Academy of Sciences.
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10.1021/jo070716d CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/09/2007
J. Org. Chem. 2007, 72, 5439-5442
5439

TABLE 1. Screening of the Reaction of r-Amino (2-alkynylphenyl)methylphosphonate 1a by Different Catalysts
entry
metal catalyst
solvent
product
yield (%)a
1
2
AgOTf (5 mol %)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
3a
88
Sc(OTf)3 (5 mol %)
In(OTf)3 (5 mol %)
NR
3
NR
4
FeCl3 (5 mol %)
NR
5
Dy(OTf)3 (5 mol %)
Zn(OTf)2 (5 mol %)
CuI (5 mol %)
NR
6
NR
7
3a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
14
8
PdCl2 (5 mol %)
86
9
Pd(PhCN)2Cl2 (5 mol %)
Pd(OAc)2 (5 mol %)
Pd(PPh3)2Cl2 (5 mol %)
Pd(PhCN)2Cl2 (5 mol %)
Pd(PhCN)2Cl2 (5 mol %)
Pd(PhCN)2Cl2 (5 mol %)
Pd(PhCN)2Cl2 (5 mol %)
Pd(PhCN)2Cl2 (5 mol %)
Pd(PhCN)2Cl2 (1 mol %)
Pd(PhCN)2Cl2 (10 mol %)
92
10
11
12
13
14
15
16
17
18
82
57
47
THF
35
DCE
toluene
DMF
MeCN
MeCN
77
62
complicated
55
93
a Isolated yield based on substrate 1a.
the intramolecular annulations of amines,9 amides,10 imines,11
carboxylic acids,12 alcohols,13 and phosphonic acid derivatives14
to a triple bond have been extensively investigated by using
transition metal reagents as effective catalysts. In some cases,
Lewis acids were also found effective for this kind of trans-
formation.15 Recently, we have described three-component
reactions of aldehydes, amines, and diethyl phosphite catalyzed
by Lewis acid affording the corresponding R-amino phospho-
nates in excellent yields.16 Prompted by these results, we
envisaged that, in the presence of suitable metal catalyst, the
resulting R-amino phosphonate 1 could serve as a nucleophile
if a triple bond is available in the molecule. On the basis of
this consideration, we synthesized the key starting material 1
from amine, diethyl phosphite, and 2-alkynyl benzaldehyde,11a
which could be regarded as a good candidate for R-amino
phosphonate based heterocycle formation.
at 60-70 °C. To our delight, we observed the formation of a
product in 88% yield (Table 1, entry 1). Structure elucidation
1
by H, 13C, 31P NMR and mass spectroscopy revealed this
compound to be 1,2-dihydroisoquinolin-1-ylphosphonate 3a. In
this case, only the six-membered endocyclic 1,2-dihydroiso-
quinolin-1-ylphosphonate from 6-endo-dig12 cyclization was
obtained, and no five-membered exocyclic products were
detected by TLC monitoring. Further screening of Lewis acids
revealed that Sc(OTf)3, In(OTf)3, FeCl3, Dy(OTf)3, or Zn(OTf)2
was ineffective for this transformation and only starting material
1a was recovered (Table 1, entries 2-6). When CuI was utilized
as catalyst in the reaction, a 14% yield of compound 3a was
isolated (Table 1, entry 7). Different palladium(II) catalysts were
also employed in the reaction of 1a in acetonitrile (Table 1,
entries 8-11). To our surprise, the observations were in contrast
to those of the cyclization catalyzed by silver(I) or copper(I),
which proceeded by 5-exo-dig cyclization, and product 2a was
generated in good to excellent yields after 36 h. For instance,
Pd(PhCN)2Cl2 (5 mol %) was proved to be the most efficient
and the corresponding product 2a was afforded in 92% yield.
However, there few reports have appeared in the literature
concerning the preparation of phosphonylated isoindoles and
related compounds.17 The structure of 2a was verified by 1D
NMR (1H NMR, 13C NMR, DEPT135, 31P NMR) and 2D NMR
(H-H COSY, HSQC, HMBC), as well as mass spectroscopy.
Solvent screening of the Pd(PhCN)2Cl2 catalyzed reaction of
1a demonstrated acetonitrile was the best choice of solvent.
Increasing the catalyst amount to 10 mol % gave a similar result
(93% yield, entry 18). However, only a 55% yield of compound
2a was obtained after 48 h when 1 mol % of catalyst was
employed (entry 17). The reaction was retarded when it was
performed at room temperature.
To test this idea, our studies commenced with the reaction
of 1a in the presence of silver triflate (5 mol %) in acetonitrile
(11) (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86. (b)
Zhang, H.; Larock, R. C. Tetrahedron Lett. 2002, 43, 1359.
(12) (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.
(13) (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.
(14) (a) Peng, A. Y.; Ding, Y. X. J. Am. Chem. Soc. 2003, 125, 15006.
(b) Tang, W.; Ding, Y. X. J. Org. Chem. 2006, 71, 8489. (c) Peng, A. Y.;
Ding, Y. X. Org. Lett. 2005, 7, 3299.
With this promising result in hand, we started to investigate
the scope of this reaction under optimized conditions [Pd-
(15) For examples, see: (a) Asao, N.; Yudha, S. S.; Nogami, T.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 5526. (b) Yanada, R.;
Obika, S.; Kono, H.; Takemoto, Y. Angew. Chem., Int. Ed. 2006, 45, 3822.
(16) (a) Wu, J.; Sun, W.; Sun, X.; Xia, H.-G. Green Chem. 2006, 8,
365. (b) Wu, J.; Sun, W.; Xia, H.-G.; Sun, X. Org. Biomol. Chem. 2006, 4,
1663.
(17) Dieltiens, N.; Stevens, C. V. Org. Lett. 2007, 9, 465 and references
cited therein.
5440 J. Org. Chem., Vol. 72, No. 14, 2007

TABLE 2. AgOTf or Pd(PhCN)2Cl2 Catalyzed Reaction of r-Amino (2-alkynylphenyl)methylphosphonate 1 in MeCN
entry
R1/R2
method
product
yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
C6H5/4-MeOC6H4 (1a)
C6H5/4-MeC6H4 (1b)
C6H5/C6H5 (1c)
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
2a
2b
2c
2d
2e
2f
2g
2h
2i
92
87
95
80
97
92
90
96
64
76
88
55
C6H5/4-FC6H4 (1d)
C6H5/4-ClC6H4 (1e)
C6H5 /3-NO2C6H4 (1f)
C6H5/3-CF3C6H4 (1g)
n-Bu/4-MeOC6H4 (1h)
n-Bu/4-FC6H4 (1i)
n-Bu/3-NO2C6H4 (1j)
C6H5/4-MeOC6H4 (1a)
C6H5/C6H5 (1c)
2j
3a
3b
3c
3d
3e
3f
C6H5/4-FC6H4 (1d)
n-Bu/4-MeOC6H4 (1h)
n-Bu/C6H5 (1k)
73
52 (40)b
25 (68)b
60 (36)b
n-Bu/4-FC6H4 (1i)
a Isolated yield based on R-amino (2-alkynylphenyl)methylphosphonate 1. b The yield in parentheses is the recovery of compound 1.
(PhCN)2Cl2 (5 mol %), CH3CN, 60-70 °C; or AgOTf (5 mol
%), CH3CN, 60-70 °C]. The application of this methodology
to the synthesis of a variety of 2,3-disubstituted-2H-isoindol-
1-ylphosphonate 2 or 2,3-disubstituted-1,2-dihydroisoquinolin-
1-ylphosphonate 3 is summarized in Table 2. Synthetically, all
these cyclization reactions illustrated in Table 2 went to
completion at 60-70 °C within 36 h. In the presence of catalytic
amounts of Pd(PhCN)2Cl2, R-amino (2-alkynylphenyl)meth-
ylphosphonate 1 with a variety of substituted R1 and R2 groups
could be cyclized to form 2,3-disubstituted-2H-isoindol-1-
ylphosphonate 2 in CH3CN in good to excellent yields. When
R1 was phenyl, the reaction tolerated a range of R2 groups with
different electronic demands on aromatic rings involving
electron-donating and electron-withdrawing groups (Table 2,
entries 1-7). These reactions were very clean and the desired
products were afforded in good yields. For example, when
substrate 1e was employed in the reaction, the corresponding
product 2e was obtained in 97% yield (Table 2, entry 5). When
R1 was n-butyl, better results were generated when R2 has
electron-donating groups attached to the aromatic ring in the
palladium(II)-catalyzed reactions. We also utilized AgOTf as
catalyst in the reaction of R-amino (2-alkynylphenyl)meth-
ylphosphonate 1. As mentioned above, cyclization of substrate
1a provided the desired product 3a in 88% yield (Table 2, entry
11). Compounds 1c and 1d also reacted smoothly under similar
conditions leading to the 2,3-disubstituted-1,2-dihydroisoquino-
lin-1-ylphosphonate 3b or 3c in 55% and 73% yield, respectively
(Table 2, entries 12 and 13). However, when R1 was n-butyl,
the reactions could not go to completion and some starting
materials were recovered (Table 2, entries 14-16). From the
results shown in Tables 1 and 2, the reactions showed very high
regioselectivity. We reasoned that in the reaction process, it may
presumably involve the formation of π-complex via coordination
of the alkynyl moiety of 1 to Pd(II) or Ag(I), thus activating
the triple bond for regioselective nucleophilic attack by the
amino group in the endo or exo mode. However, factors
affecting the above regioselectivity are not yet very clear.
It is well-known that silver(I) salts have mild Lewis acidity
and have been used as catalysts in organic synthesis. Among
these salts, AgOTf is one of the most popular reagents for
inducing transformations, which take advantage of its affinity
for halogen and sulfur functional groups, and carbon-carbon
unsaturated bonds rather than oxygen functional groups.18 As
described by Asao,15a o-alkynylaryl aldimine reacted with
AgOTf leading to isoquinolinium in good yield. The observation
indicated that, in the presence of silver salt, at the beginning
the triple bond coordinated to the silver salt, and subsequently,
the nitrogen atom attacked on the triple bond via 6-endo-
cyclization afforded isoquinolinium intermediate. On the basis
of this result, we conceive that reaction of R-amino (2-
alkynylphenyl)methylphosphonate 1a catalyzed by AgOTf may
undergo a similar process, which leads to compound 3a via
6-endo-cyclization (Scheme 2, eq 1). However, in the presence
of palladium, 5-exo-cyclization is favorable.19 The intermediate
then undergoes [1,5]-H shift to afford the more stable compound
3a (Scheme 2, eq 2).
In summary, we have described palladium(II)- or silver(I)-
catalyzed reactions of R-amino (2-alkynylphenyl)methylphos-
phonate, which provides a novel and efficient route to 2,3-
disubstituted-2H-isoindol-1-ylphosphonate or 2,3-disubstituted-
1,2-dihydroisoquinolin-1-ylphosphonate. Mechanism studies, a
focused library generation, and screening for biological activity
of these small molecules are under investigation in our labora-
tory.
Experiment Section
General Procedure for Method A. R-Amino (2-alkynylphenyl)-
methylphosphonate 1 (0.25 mmol), Pd(PhCN)2Cl2 (0.0125 mmol,
5 mol %), and CH3CN (1.0 mL) were stirred at 60-70 °C under
(18) Black, T. H. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley & Sons: Chichester, UK, 1995; Vol. 6, p
4476.
(19) Zeni, R. G.; Larock, R. C. Chem. ReV. 2006, 106, 4644.
J. Org. Chem, Vol. 72, No. 14, 2007 5441

SCHEME 2
nitrogen atmosphere. After completion of the reaction, as indicated
by TLC, the reaction mixture was quenched with water (10 mL)
and extracted with EtOAc (2 × 10 mL). The extracts were
evaporated in vacuo, followed by purification on silica gel, affording
the product 2,3-disubstituted-2H-isoindol-1-ylphosphonate 2. Se-
lected examplesdiethyl 3-benzyl-2-(4-methoxyphenyl)-2H-isoin-
dol-1-ylphosphonate 2a: 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J
) 7.0 Hz, 6H), 3.80-3.98 (m, 7H), 4.13 (s, 2 H), 6.84-6.88 (m,
4H), 7.03-7.08 (m, 3H), 7.12-7.22 (m, 4H), 7.56 (dd, J ) 8.3,
1.0 Hz, 1H), 8.14 (d, J ) 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 15.9, 30.9, 55.2, 61.2, 106.5, 108.9, 113.1, 119.4, 120.4, 121.3,
122.9, 124.4, 126.0, 128.0, 128.1, 129.1, 130.6, 131.4, 132.4, 138.5,
159.6; 31P NMR (161 MHz, CDCl3) δ 10.34. m/z 449 (M+); HRMS
calcd for C26H28NO4P 449.1756, found 449.1752.
General Procedure for Method B. A mixture of R-amino (2-
alkynylphenyl)methylphosphonate 1 (0.5 mmol), AgOTf (0.025
mmol, 5 mol %), and CH3CN (2.0 mL) was stirred at 60-70 °C
under nitrogen atmosphere overnight. After completion of the
reaction as indicated by TLC, the reaction mixture was quenched
with water (10 mL) and extracted with EtOAc (2 × 10 mL). The
extracts were evaporated in vacuo, followed by purification on silica
gel, affording the product 2,3-disubstituted-1,2-dihydroisoquinolin-
1-ylphosphonate 3. Selected examplesdiethyl 3-butyl-2-(4-meth-
oxyphenyl)-1,2-dihydroisoquinolin-1-ylphosphonate 3d: 1H NMR
(400 MHz, CDCl3) δ 0.83 (t, J ) 7.2 Hz, 3H), 1.20-1.38 (m, 8H),
1.50 (m, 2H), 2.09 (m, 1H), 2.26 (m, 1H), 3.77 (s, 3H), 4.01-3.87
(m, 4H), 5.03 (d, J ) 18.6 Hz, 1H), 5.93 (s, 1H), 6.79 (d, J ) 8.0
Hz, 2H), 6.99 (d, J ) 8.0 Hz, 2H), 7.05 (t, J ) 7.6 Hz, 1H), 7.15
(m, 1H), 7.18 (d, J ) 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 13.8, 16.4, 22.3, 30.2, 33.0, 55.4, 62.2, 62.6, 65.03, 107.8, 113.9,
123.0, 125.4, 126.0, 127.0, 128.0, 129.7, 133.4, 140.6, 144.7, 156.3;
31P NMR (161 MHz, CDCl3) δ 21.02; MS (ESI) m/z 428.30 (M+
- 1); HRMS calcd for C24H32NO4P 429.2069, found 429.2065.
(For details, please see the Supporting Information.)
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20502004, 20642006)
and the Science & Technology Commission of Shanghai
Municipality (05ZR14013) is gratefully acknowledged.
Supporting Information Available: General experimental
information, characterization data, and copies of 1H and 13C NMR
spectra of compounds 1, 2, and 3. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO070716D
5442 J. Org. Chem., Vol. 72, No. 14, 2007