Pd(II)-catalyzed coupling-cyclization reaction of?o-ethylnylphenylphosphonamides monoesters with allyl halide

Article abstract of DOI:10.1016/j.tet.2008.08.091

4-Allyl-phosphaisoquinolin-1-ones were synthesized by palladium-catalyzed coupling-cyclization of o-ethynylphenylphosphonamide monoethyl esters with allyl halides with high regioselectivity and good yields. The synthesized 4-allyl-phosphaisoquinolin-1-one

Full text of DOI:10.1016/j.tet.2008.08.091

Tetrahedron 64 (2008) 10507–10511
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Tetrahedron
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Pd(II)-catalyzed coupling–cyclization reaction of o-ethylnylphenyl-
phosphonamides monoesters with allyl halide
,
Wei Tang a, Yi Ding b, Yi-Xiang Ding a
*
a Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
b College of Life and Environment Sciences, Shanghai Normal University, Shanghai 200234, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2008
Received in revised form 27 August 2008
Accepted 29 August 2008
Available online 4 September 2008
4-Allyl-phosphaisoquinolin-1-ones were synthesized by palladium-catalyzed coupling–cyclization of
o-ethynylphenylphosphonamide monoethyl esters with allyl halides with high regioselectivity and good
yields. The synthesized 4-allyl-phosphaisoquinolin-1-ones show bioactivity as inhibitor of MCH-1R.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
4-Allylic phosphaisoquinolin-1-ones
Pd(II)-catalyzed
Cyclized coupling reaction
Allyl halide
Heterocycle
MCH-1R
1. Introduction
coupling–cyclization with a carbon–carbon bond-forming reaction,
which would allow us to synthesize 3,4-disubstituted phos-
Isoquinolin-1-ones, a structural unit in many natural products,
are important intermediates in organic synthesis.1 For a long time,
isoquinolin-1-one compounds have gained considerable synthetic
and pharmacological interest because of their potential antitumor
activity, such as potential antitumor activity,2 cytotoxicity,3 cardio-
vascular activity,4 antineoplastic,5 antimicrobial,6 inhibition of hu-
man thymidylate synthase,7 inhibition of PARP activity,8 and
reduction of systolic blood pressure,9 etc. Phosphaisoquinolin-1-
ones are phosphorus analogues of isoquinolin-1-ones that can be
anticipated to have bioactivities.10 So, the synthesis of phosphaiso-
quinolin-1-one derivatives and the assessment of their biological
properties are very attractive. Here we would like to report the re-
search of 4-allyl-phosphaisoquinolin-1-one.
Transition metal-catalyzed methodology has been proven to be
one of the most powerful pathways for the formation of carbocycles
as well as nitrogen-containing heterocycles.11,12 Recently, we
reported13 an intramolecular cyclization reaction of o-ethynylphe-
nylphosphonamides monoethyl ester catalyzed by PdCl2(CH3CN)2,
which provides a convenient method of preparing 3-substituted
phosphaisoquinolin-1-ones. In continuation of the above in-
vestigation, we recently decided to search for a new procedure of
phaisoquinolin-1-ones and permit further elaboration of more
complex derivatives to study its bioactivity. On the other hand,
palladium-catalyzed allylation is a practical tool for introducing the
allyl group into the products.14 The coupling–cyclization of o-
ethynylphosphonamide with allyl halides may provide an efficient
pathway to the allyl-substituted cyclic compounds. In this paper,
we wish to present a full account of our observation on the cou-
pling–cyclization of o-ethynylphosphonamide 1 with allyl halides 2
(Scheme 1).
R4
R2
R4
R2
10mol%PdCl2(CH3CN)2
CH3CN, methyloxirane
+
X
NHR3
OEt
R3
OEt
R1
P
1
N
R1
P
3
O
O
2
X=Br, Cl
Scheme 1. Coupling–cyclization of o-ethynylphenylphosphonamides (1) with allyl
halides (2).
2. Results and discussion
The reaction of o-(2-phenylethynyl)phenylphosphonamides
monoethyl ester (1a) and allyl bromide 2a was used to optimize the
reaction conditions and some representative results are listed in
* Corresponding author. Tel.: þ86 21 54925334; fax: þ86 21 64166128.
E-mail address: dingyx@mail.sioc.ac.cn (Y.-X. Ding).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.091

10508
W. Tang et al. / Tetrahedron 64 (2008) 10507–10511
Table 1
Pd(II)-catalyzed coupling–cyclization of the o-(1-phenylethynyl)phenylphosphonamides monoethyl ester (1a) with allyl bromide 2aa
Ph
Ph
Ph
PdCl2(CH3CN)2
CH3CN.base
+
+
Br
N
N
NHCH2Ph
CH2Ph
CH2Ph
P
P
P
1a
O
OEt
O
OEt
O
OEt
4a
2a
3a
Entry
Equiv of 2a
Base
Equiv of base
Temperature (ꢀC)
Time (h)
3a (%)
4a (%)
1
2
3
4
5
6
2
2
2
2
5
10
K2CO3
Et3N
P(OEt)3
Methyloxirane
Methyloxirane
Methyloxirane
3
3
3
10
50
50
25–80
25–80
25–80
25–80
80
12
12
12
12
4
0
0
0
0
0
0
12
0
0
65b
85c
90
80
4
a
Reaction conditions: 1a (0.1 mmol), catalyst (0.01 mmol), anhydrous solvent (3 mL).
Compound 1a (25%) was recovered.
Compound 1a (11%) was recovered.
b
c
Table 1. Through control experiments, we found that the use of PdCl2
or PdCl2(CH3CN)2 as a catalyst, in the presence of a large excess of
methyloxirane,15 the reaction proceeds smoothly and product 3a
was isolated in 85% yield with 10% recovery of the reactant 1a (Table
1, entry 5). Other palladium catalysts (e.g., Pd(PPh3)4 and Pd(OAc)2)
were less effective and gave only unchanged starting materials. The
use of K2CO3, Et3N, or P(OEt)3 as a base proved to be ineffective and
none of the desired product was detected; while the reaction
employing proton scanvenger, such as methyloxirane, in place of
base, proceeded smoothly. Only use of 10 equiv methyloxirane
afforded the desired product 3a in 65% yield and the cyclized product
4a in 12% yield. Use of a large excess of methyloxirane (about
50 equiv), the cyclized product 4awas not detected. Moreover, use of
fewer equivalents of allyl bromide resulted in lower yields (Table 1,
entries 4 and 5). Subsequently, the effects of employing various
solvents were studied. We found that CH3CN or THF as the solvent
was effective, and the reaction couldn’t proceed in DMF, DMSO, or
DCM. The best result was obtained when 10 mol % of PdCl2(CH3CN)2
and 10 equiv of allyl bromide (2a) in the presence of 50 equiv
methyloxirane in CH3CN were used, leading to a 90% yield of 3a.
Based on the above optimization efforts, this method was ap-
plied to the synthesis of other 4-allylic phosphaisoquinolin-1-ones.
The results are summarized in Table 2. A variety of 4-allyl-
phosphaisoquinolin-1-ones were obtained in good to excellent
yields. Functionalities such as aryl, alkyl, ether on the alkyne moiety
and chloro, methoxy substituents on the benzene ring are tolerated.
In addition, the N-unsubstituted phosphamide compound
(Table 2, entry 2) can also afford the corresponding product in good
yield. Under the same reaction conditions, the reaction of o-ethy-
nylphenylphosphonamides monoethyl ester (1) with 3-chloro-1-
butene were also examined (Table 2, entries 8, 9, 10, 11, and 12), the
reaction afforded desired products (3) as an E and Z mixture (E/
Z¼77:23) in good combined yields. Under the above standard
conditions, product 3h was isolated in 85% yield. The result in-
dicated that vinylpalladium intermediate (B) firstly inserts the
carbon–carbon bond of allyl chloride to give a carbon–palladium
intermediate, which undergoes
b-chloride elimination to afford
desired product 3h (Scheme 2).
On the basis of the observed regioselectivity of the 3-chloro-1-
butene reaction and the related literature,16 proposed mechanism
is shown in Scheme 3. It presumably involves (i) the formation of
the complex through coordination of the ethynyl moiety of 1 with
PdCl2(CH3CN)2; (ii) regioselective nucleophilic attack of the acti-
vated triple bond by nitrogen in the endo mode would give the
Table 2
a
Coupling–cyclization of the o-ethynylphenylphosphonamides monoethyl esters 1 with allyl halide 2 employing PdCl2(CH3CN)2
R4
R2
R4
R2
10mol%PdCl2(CH3CN)2
CH3CN, methyloxirane
X
+
NHR3
OEt
R3
R1
P
1
N
R1
P
3
O
O
OEt
2
X=Br, Cl
Entry
R1
R2
R3
R4
X
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
H
H
Cl
Cl
Cl
Cl
MeO
H
H
Cl
Cl
Cl
H
Cl
OCH3
H
C6H5
C6H5
C6H5
C6H5
p-EtC6H5
n-Bu
C6H5
C6H5
n-Bu
C6H5
C6H5
p-EtC6H5
C6H5
C6H5
C6H5
C6H5CH2
H
C6H5CH2
n-Pr
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
n-Pr
n-Pr
C6H5
C6H5
C6H5
CH2CO2Et
CH2CO2Et
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
4
6
4
4
4
6
4
4
6
4
4
4
4
4
4
4
4
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
90
69
92
87
88
82
85
85
78
86
81
83
83
80
78
82
85
9
10
11
12
13
14
15
16
17
C6H5
C6H5
Cl
a
Reaction conditions: 1 (0.1 mmol), catalyst (0.01 mmol), anhydrous solvent (3 mL), methyloxirane (5 mmol) and allyl halide 2 (1 mmol) at 80 ꢀC in CH3CN.

W. Tang et al. / Tetrahedron 64 (2008) 10507–10511
10509
1-ones with high regioselectivity and good yields. These
compounds show some bioactivities as inhibitor of MCH-1R. This
reaction represents the first example of phosphonamides cou-
pling–cyclization reaction with allyl halides, the olefin moiety of
the resulting 4-allylic phosphaisoquinolin-1-ones provides possi-
bilities for further functionalization for more complex derivatives
to research its bioactivity. The synthesis of more derivatives and
further biochemical evaluations are underway.
Cl
Cl
Pd(II)
R2
NR3
OEt
3 h
+
R2
Pd(II)
R1
P
NR3
OEt
R2
R1
P
O
O
NR3
OEt
R1
P
Β
O
Path : insertion/β−Cl elimination
Scheme 2. Reaction of o-ethynylphenylphosphonamides monoester (1) with 3-chloro-
1-butene.
4. Experimental
4.1. General
vinylpalladium species B; (iii) in the presence of a large excess of
methyloxirane, followed by insertion of the carbon–carbon bond of
allylic halide to give a carbon–palladium intermediate C, which
NMR spectra were all recorded on a Varian Mercury 300 spec-
trometer using CDCl3 as the solvent. The 1H NMR spectra used
CDCl3 (with TMS) as the internal reference at 7.27 ppm. MS spectra
were determined using a HP5989A mass spectrometer. IR spectra
were measured on a Y-Zoom Cursor instrument. Starting materials
1 were prepared as described previously.13
subsequently undergoes b-elimination affording desired product 3
with regeneration of the Pd(II) catalyst. On the other hand, the
vinylpalladium species B could also undergo protonation and lead
to the cyclized product, which is competitive with the allylation.
4.2. General procedure for the preparation of 4-allyl-
phosphaisoquinolin-1-ones (3)
R2
R2
NR3
OEt
NHR3
OEt
A mixture of o-ethylnylphenylphosphonamide monoethyl es-
ters (1) (0.1 mmol), allyl bromide (1.0 mmol), methyloxirane
(5.0 mmol), and PdCl2(CH3CN)2 (0.01 mmol) in 3 ml CH3CN was
stirred at 80 ꢀC in a 25 ml flask for 4 h under nitrogen. The reaction
mixture was then diluted with EtOAc and washed with brine, dried
(Na2SO4), and evaporated in vacuo. Chromatography of the residue
on silica gel using hexane/EtOAc as eluent gave the corresponding
product 4-allyl-phosphaisoquinolin-1-ones (3).
R1
P
R1
P
O
3
Pd(II)
O
1
Br
Pd(II)
Pd(II)
R2
R2
NR3
OEt
NR3
OEt
R1
P
4.3. Characterization data for products 3
R1
P
B
O
O
H
C
4.3.1. Compound 3a
H+
Oily. Yield: 90%. 1H NMR:
d 8.06–7.98 (m, 1H), 7.59–7.27 (m, 6H),
7.08–7.02 (m, 5H), 6.67–6.65 (m, 2H), 5.83–5.72 (m, 1H), 5.07 (dd,
J¼9, 15.9 Hz, 1H), 4.92 (dd, J¼2.1, 10.5 Hz, 1H), 4.78 (dd, J¼2.1,
17.4 Hz, 1H), 4.13–4.06 (m, 2H), 3.97 (dd, J¼7.5, 15.9 Hz, 1H), 3.07 (d,
J¼2.4 Hz, 2H),1.29 (t, J¼7.2 Hz, 3H); MS (EI): m/z: 415 (Mþ,100), 361
(69), 304 (30), 291 (24), 165 (7), 105 (9), 91 (90), 77 (10), 65 (12); IR
(film, cmꢁ1): 3060, 2926, 1591, 1472, 1241, 1028, 950, 701. Anal.
Calcd for C26H26NO2P: C, 75.16; H, 6.31; N, 3.37. Found: C, 74.83; H,
6.39; N, 3.46.
R2
NR3
Br
R1
P
O
OEt
Scheme 3. A proposed mechanism of cyclized coupling reaction.
To probe whether the synthesized 4-allyl-phosphaisoquinolin-
1-ones are of biological activities, these compounds underwent
a preliminary screening. We firstly tested their inhibitory activity
against the enzyme SHP-1 (Src homology 2-containing phospha-
tase-1), one of the protein tyrosine phosphatases (PTPs). At a con-
4.3.2. Compound 3b
Oily. Yield: 69%. 1H NMR:
d 7.95–7.88 (m, 1H), 7.61–7.35 (m, 8H),
centration of 20 mg/mL, the SHP-1 inhibition ratios of 3c, 3d, 3e, 3g,
6.10 (s, 1H), 5.99–5.86 (m, 1H), 5.08–4.94 (m, 2H), 4.01–3.93 (m,
2H), 3.22–3.20 (m, 2H),1.25 (t, J¼6.9 Hz, 3H); MS (EI): m/z: 325 (Mþ,
100), 296 (43), 278 (27), 252 (43), 220 (14), 128 (18), 104 (14), 77
(27), 44 (50); IR (film, cmꢁ1): 3120, 2981, 1616, 1594, 1478, 1409,
1223, 1043, 958, 783, 697. Anal. Calcd for C19H20NO2P: C, 70.14; H,
6.20; N, 4.31. Found: C, 69.97; H, 6.37; N, 4.21.
3h, 3i, 3j, 3k, and 3l are 20.2%, 21.8%, 24.7%, 36.6%, 23.5%, 54.3%,
33.8%, 23.3%, and 39.6%, respectively. Then their inhibitory activity
against the MCH-1R (molanin-concentrating hormone receptor-1)
was also tested, with IC50 value of 3c, 3d, 3e 3n are 4.30, 3.78, 10.23,
and 7.6 mmol, respectively. In comparison, 4-allylphosphaisocou-
marins17 have no MCH-1R activities, and 4-unsubstituted phos-
phaisoquinolin-1-ones13 showed low MCH-1R activities. 4-Allyl
group and N atom may be the basic factor. This represents the first
example using the phosphorus analogues of heterocyclic natural
products as MCH-1R inhibitors.
4.3.3. Compound 3c
A pale yellow solid; mp: 88–89 ꢀC. Yield: 92%. 1H NMR:
d 8.01–
7.95 (m, 1H), 7.51–7.27 (m, 5H), 7.10–7.03 (m, 5H), 6.65 (d, J¼6.6 Hz,
2H), 5.81–5.67 (m, 1H), 5.05 (dd, J¼9.0, 15.6 Hz, 1H), 4.93 (dd, J¼1.8,
10.5 Hz, 1H), 4.75 (dd, J¼1.8, 17.4 Hz, 1H), 4.20–4.08 (m, 2H), 3.95
(dd, J¼8.1, 15.6 Hz, 1H), 3.05 (d, J¼3.6 Hz, 2H), 1.31 (t, J¼6.9 Hz, 3H);
MS (EI): m/z: 449 (Mþ, 58), 358 (4), 330 (7), 128 (7), 91 (100), 77 (4),
65 (11); IR (film, cmꢁ1): 3061, 2926, 1637, 1587, 1472, 1242, 1156,
1027, 953, 701. Anal. Calcd for C26H25ClNO2P: C, 69.41; H, 5.60; N,
3.11. Found: C, 69.79; H, 5.80; N, 2.95.
3. Conclusion
In summary, we have developed a novel PdCl2(CH3CN)2-cata-
lyzed coupling–cyclization of o-ethylnylphenylphosphonamide
monoethyl esters with allyl halides to 4-allyl-phosphaisoquinolin-

10510
W. Tang et al. / Tetrahedron 64 (2008) 10507–10511
4.3.4. Compound 3d
4.3.10. Compound 3j
Oily. Yield: 87%. 1H NMR:
d
7.93–7.88 (m, 1H), 7.51–7.36 (m, 7H),
Z/E¼77:23. Oily. Yield: 86%. 1H NMR:
d 8.01–7.96 (m, 1H), 7.56–
5.88–5.57 (m, 1H), 5.02 (dd, J¼1.8, 10.2 Hz, 1H), 4.92 (dd, J¼1.8,
17.4 Hz, 1H), 4.13–3.98 (m, 2H), 3.63–3.50 (m, 1H), 3.16–3.14 (m,
2H), 2.91–2.81 (m, 1H), 1.31–1.23 (m, 5H), 0.55 (t, J¼7.2 Hz, 3H);
MS (EI): m/z: 401 (Mþ, 100), 372 (28), 344 (35), 303 (26), 215 (10),
104 (15), 91 (7), 77 (18), 65 (6); IR (film, cmꢁ1): 3060, 2968, 1638,
1587, 1474, 1240, 1158, 1022, 954, 829, 703. Anal. Calcd for
7.30 (m, 5H), 7.08–7.02 (m, 5H), 6.66–6.61 (m, 2H), 5.36–5.00 (m,
3H), 4.19–4.04 (m, 2H), 3.95 (dd, J¼8.1, 15.6 Hz, 1H), 3.07–2.97 (m,
2H), 1.53–1.51 (m, 2.3H), 1.38 (d, J¼6.6 Hz, 0.7H), 1.29 (t, J¼6.9 Hz,
3H); MS (MALDI): m/z: 463 (Mþ, 100), 464 (Mþþ1, 28); IR (film,
cmꢁ1): 3063, 3029, 2982, 1715, 1588, 1473, 1243, 1157, 1028, 955,
701. Anal. Calcd for C27H27ClNO2P: C, 69.90; H, 5.87; N, 3.02. Found:
C, 69.55; H, 5.77; N, 3.01.
C
22H25ClNO2P: C, 65.75; H, 6.27; N, 3.49. Found: C, 66.08; H, 6.38;
N, 3.48.
4.3.11. Compound 3k
4.3.5. Compound 3e
Z/E¼77:23. A yellow solid; mp: 92–93 ꢀC. Yield: 81%. 1H NMR:
Oily. Yield: 88%. 1H NMR:
d
8.00–7.95 (m, 1H), 7.54–7.44 (m, 2H),
d 7.92–7.86 (m, 1H), 7.56–7.34 (m, 7H), 5.42–5.22 (m, 2H), 4.12–3.96
7.14–6.95 (m, 7H), 6.67–6.65 (m, 2H), 5.82–5.70 (m, 1H), 5.03 (dd,
J¼9.0, 15.9 Hz, 1H), 4.93 (dd, J¼1.8, 10.2 Hz, 1H), 4.75 (dd, J¼1.8,
17.1 Hz, 1H), 4.19–4.08 (m, 2H), 3.99 (dd, J¼8.1, 15.9 Hz, 1H), 3.07 (d,
J¼3.6 Hz, 2H), 2.69 (q, J¼7.8 Hz, 2H), 1.33–1.24 (m, 6H); MS
(MALDI): m/z: 477 (Mþ, 100), 478 (Mþþ1, 42); IR (film, cmꢁ1): 3030,
2968, 1715, 1589, 1473, 1245, 1157, 1027, 953, 697. Anal. Calcd for
(m, 2H), 3.61–3.48 (m, 1H), 3.15–3.06 (m, 2H), 2.92–2.79 (m, 1H),
1.58 (dd, J¼1.2, 6 Hz, 2.3H), 1.44–1.42 (m, 0.7H), 1.27–1.23 (m, 5H),
0.54 (t, J¼2.4 Hz, 3H); MS (MALDI): m/z: 415 (Mþ, 100), 416 (Mþþ1,
33); IR (film, cmꢁ1): 3018, 2968, 1587, 1476, 1237, 1162, 1025, 958,
705. Anal. Calcd for C23H27ClNO2P: C, 66.42; H, 6.54; N, 3.37. Found:
C, 66.58; H, 6.64; N, 3.31.
C
28H29ClNO2P: C, 70.36; H, 6.12; N, 2.93. Found: C, 70.38; H, 6.17; N,
2.83.
4.3.12. Compound 3l
Z/E¼77:23. Oily. Yield: 83%. 1H NMR:
d 7.91–7.86 (m, 1H), 7.56–
4.3.6. Compound 3f
7.45 (m, 2H), 7.27–7.23 (m, 4H), 5.43–5.24 (m, 2H), 4.12–3.94 (m,
2H), 3.61–3.49 (m, 1H), 3.16–3.09 (m, 2H), 2.91–2.75 (m, 1H), 2.71
(q, J¼7.5 Hz, 2H), 1.59 (d, J¼5.7 Hz, 2.3H), 1.45 (d, J¼6.6 Hz, 0.7H),
1.29–1.22 (m, 8H), 0.54 (t, J¼7.5 Hz, 3H); MS (MALDI): m/z: 443
(Mþ, 100), 444 (Mþþ1, 32); IR (film, cmꢁ1): 3024, 2967, 2876, 1587,
1472, 1243, 1157, 1025, 954, 830, 773. Anal. Calcd for C25H31ClNO2P:
C, 67.64; H, 7.04; N, 3.16. Found: C, 67.68; H, 7.07; N, 2.95.
A pale yellow solid; mp: 111–112 ꢀC. Yield: 82%. 1H NMR:
d 7.93–
7.87 (m, 1H), 7.50–7.46 (m, 1H), 7.35–7.30 (m, 1H), 7.16–7.14 (m, 3H),
6.91–6.89 (m, 2H), 5.97–5.84 (m, 1H), 5.30 (dd, J¼10.2, 15.9 Hz, 1H),
4.90 (d, J¼10.2 Hz, 1H), 4.63 (d, J¼17.7 Hz, 1H), 4.48 (dd, J¼6.9,
16.5 Hz, 1H), 4.05–3.95 (m, 2H), 3.32–3.15 (m, 2H), 2.32–2.13 (m,
2H), 1.63–1.60 (m, 2H), 1.52–1.30 (m, 2H), 1.23 (t, J¼6.9 Hz, 3H),
0.924 (t, J¼6.9 Hz, 3H); MS (MALDI): m/z: 429 (Mþ, 40), 430 (Mþþ1,
100); IR (film, cmꢁ1): 3030, 2927, 1596, 1475, 1245, 1029, 949, 821.
Anal. Calcd for C24H29ClNO2P: C, 67.05; H, 6.80; N, 3.26. Found: C,
67.09; H, 6.57; N, 2.98.
4.3.13. Compound 3m
A pale yellow solid; mp: 130–131 ꢀC. Yield: 83%. 1H NMR:
d 7.96–
7.89 (m, 1H), 7.72–7.59 (m, 2H), 7.35–7.32 (m, 3H), 7.19–6.95 (m,
8H), 5.99–5.87 (m, 1H), 5.10–5.05 (ddd, J¼1.9, 1.9, 1.4 Hz, 2H), 4.23–
4.13 (m, 2H), 3.36_3.35 (d, J¼2.1 Hz), 1.27 (t, J¼14.0 Hz, 3H); IR (film,
cmꢁ1): 3060, 2977, 1609, 1589, 1549, 1490, 1249, 1238, 1022, 946,
784, 695; MS (EI) m/z: 402 (Mþþ1, 26), 401 (Mþ, 100), 372 (28), 354
(17), 328 (19), 280 (17), 180 (20), 77 (47). Anal. Calcd for
4.3.7. Compound 3g
Oily. Yield: 85%. 1H NMR:
d 7.52–7.46 (m, 2H), 7.36–7.27 (m, 4H),
7.16–7.03 (m, 5H), 6.65 (d, J¼7.2 Hz, 2H), 5.82–5.70 (m, 1H), 5.07
(dd, J¼9.0, 16.2 Hz, 1H), 4.92 (d, J¼10.2 Hz, 1H), 4.76 (d, J¼17.4 Hz,
1H), 4.17–4.04 (m, 2H), 3.98–3.91 (m, 1H), 3.93 (s, 3H), 3.05 (d,
J¼4.2 Hz, 2H), 1.33 (t, J¼6.9 Hz, 3H); MS (EI): m/z: 445 (Mþ, 100),
354 (17), 326 (30), 308 (20),159 (7), 115 (11), 91 (56), 77 (4), 65 (14);
IR (film, cmꢁ1): 3030, 2980, 1737, 1604, 1490, 1233, 1029, 952, 701.
Anal. Calcd for C27H28NO3P: C, 72.79; H, 6.34; N, 3.14. Found: C,
72.59; H, 6.64; N, 2.91.
C25H24NO2P: C, 74.08; H, 6.03; N, 3.49. Found: C, 74.53; H, 6.14; N,
3.49.
4.3.14. Compound 3n
Oily. Yield: 80%. 1H NMR:
d 7.92–7.86 (m, 1H), 7.64–7.53 (m, 2H),
7.33–7.29 (m, 2H), 7.21–6.95 (m, 8H), 5.93–5.82 (m, 1H), 5.11–5.01
(ddd, J¼1.4, 1.4 Hz, 2.0 Hz, 2H), 4.22–4.14 (m, 2H), 3.31 (dd, J¼0.5,
1.4 Hz, 2H), 1.28 (t, J¼14.0 Hz, 3H); IR (film, cmꢁ1): 3060, 2929,
1639, 1492, 1256, 1025, 956, 785, 696; MS (EI) m/z: 437 (Mþþ2, 36),
436 (Mþþ1, 36), 435 (Mþ,100), 407 (12), 406 (17), 314 (10),180 (27),
77 (37). Anal. Calcd for C25H23ClNO2P: C, 68.89; H, 5.32; N, 3.21.
Found: C, 68.47; H, 5.46; N, 3.06.
4.3.8. Compound 3h
Z/E¼77:23. Oily. Yield: 85%. 1H NMR:
d 8.05–7.98 (m, 1H), 7.70–
7.27 (m, 6H), 7.08–7.00 (m, 5H), 6.66–6.62 (m, 2H), 5.37–5.27 (m,
1H), 5.19–5.12 (m, 1H), 5.06 (dd, J¼9.3, 15.3 Hz, 1H), 4.17–4.03 (m,
2H), 3.96 (dd, J¼8.1, 15.3 Hz, 1H), 3.09–3.00 (m, 2H), 1.63–1.37 (m,
3H), 1.28 (t, J¼7.2 Hz, 3H); MS (MALDI): m/z: 429 (Mþ, 100), 430
(Mþþ1, 40); IR (film, cmꢁ1): 3028, 2933, 1591, 1473, 1241, 1164,
1028, 950, 701. Anal. Calcd for C27H28NO2P: C, 75.51; H, 6.57; N,
3.26. Found: C, 75.69; H, 6.54; N, 3.17.
4.3.15. Compound 3o
Oily. Yield: 78%. 1H NMR:
d 7.65–7.60 (m, 1H), 7.43–7.33 (m, 3H),
7.19–6.90 (m, 9H), 5.98–5.84 (m, 1H), 5.10–5.04 (t, J¼18.5 Hz, 2H),
4.25–4.14 (m, 2H), 3.87 (s, 3H), 3.34 (s, 2H), 1.31 (t, J¼14.0 Hz, 3H);
4.3.9. Compound 3i
13C NMR (CDCl3, 125 MHz)
d: 16.3, 34.4, 55.6, 61.0, 111.3, 116.1, 118.9,
Z/E¼77:23. Oily. Yield: 78%. 1H NMR:
d
7.96–7.89 (m, 1H), 7.67–
119.6,123.8,125.3,126.1,127.5,127.6,127.8,128.1,130.2,132.3,136.3,
137.5, 138.3, 138.9, 158.4; IR (film, cmꢁ1): 3059, 2980, 1638, 1559,
1552, 1490, 1261, 1028, 957, 759, 696; MS (EI) m/z: M¼431, 354 (30),
233 (17), 221 (17), 205 (24), 197 (13), 191 (13), 105 (100), 91 (46);
HRMS (EI). Calcd for
431.1651.
7.35 (m, 3H), 7.13–7.12 (m, 3H), 6.92–6.89 (m, 1H), 5.61–5.44 (m,
1H), 5.30 (dd, J¼9.3, 16.5 Hz, 1H), 5.09–5.01 (m, 1H), 4.48 (dd, J¼6.9,
16.5 Hz, 1H), 4.01–3.90 (m, 2H), 3.27–3.14 (m, 2H), 2.33–2.11 (m,
2H), 1.74–1.49 (m, 3H), 1.66–1.55 (m, 1H), 1.47–1.29 (m, 3H), 1.22 (t,
J¼7.2 Hz, 3H), 0.94 (t, J¼7.2 Hz, 3H); MS (EI): m/z: 410 (Mþþ1, 14),
366 (9), 338 (3), 289 (3), 247 (5), 106 (6), 91 (100), 77 (4), 65 (12); IR
(film, cmꢁ1): 3063, 2931,1594,1473,1245,1094,1034, 954, 738, 697.
Anal. Calcd for C25H32NO2P: C, 73.33; H, 7.88; N, 3.42. Found: C,
73.17; H, 7.74; N, 3.21.
C
20H21ClNO4P (Mþ): 431.1650. Found:
4.3.16. Compound 3p
Oily. Yield: 82%. 1H NMR:
d
7.97–7.89 (m, 1H), 7.60–7.31 (m, 8H),
5.89–5.76 (m, 1H), 5.02–4.94 (ddd, J¼3.6, 1.4 Hz, 1.5 Hz, 2H), 4.20–

W. Tang et al. / Tetrahedron 64 (2008) 10507–10511
10511
5. Cho, W. J.; Kim, E. K.; Park, I. Y.; Jeong, E. Y.; Kim, T. S.; Le, T. N.; Kim, D. D.; Lee,
E. S. Bioorg. Med. Chem. 2002, 10, 2953.
6. Pettit, G. R.; Meng, Y. H.; Herald, D. L.; Graham, K. A. N.; Pettit, R. K.; Doubek,
D. L. J. Nat. Prod. 2003, 66, 1065.
7. Li, S. W.; Nair, M. G.; Edwards, D. M.; Kisliuk, R. L.; Gaumont, Y.; Dev, I. K.; Duch,
D. S.; Humphreys, J.; Smith, G. K.; Ferone, R. J. Med. Chem. 1991, 34, 2746.
8. Watson, C. Y.; Whish, W. J.; Threadgill, M. D. Bioorg. Med. Chem. 1998, 6, 721.
9. Yamada, Y.; Ando, K.; Komiyama, K.; Shibata, S.; Nakamura, I.; Hayashi, Y.;
Ikegami, K.; Uchida, I. Bioorg. Med. Chem. Lett. 1997, 7, 1863.
4.12 (m, 3H), 3.96–3.77 (m, 3H), 3.19–3.14 (m, 2H),1.30 (t, J¼14.1 Hz,
3H), 0.99 (t, J¼14.5 Hz, 3H); IR (film, cmꢁ1): 3078, 2982, 1819, 1753,
1638, 1553, 1246, 1186, 1030, 656, 705; MS (EI) m/z: 412 (Mþþ1, 28),
411 (Mþ, 100), 338 (24), 310 (26), 294 (19), 292 (14), 269 (21), 268
(17). Anal. Calcd for C23H26NO4P: C, 67.14; H, 6.37; N, 3.40. Found: C,
66.80; H, 6.56; N, 3.55.
10. (a) Scherrer, R. A. Antiinflammatory Agents; Academic: New York, NY, 1974; Vol.1,
p 79; (b) Almquist, R. G.; Chao, W.-R.; White, C. J. J. Med. Chem. 1985, 28, 1067.
11. For the intramolecular annulations of amines to a triple bond, see: (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. Organometallics 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.
4.3.17. Compound 3q
Oily. Yield: 85%. 1H NMR:
d
7.92–7.879 (d, J¼15.4 Hz, 1H), 7.53–
7.27 (m, 7H), 5.85–5.76 (m, 1H), 4.99 (ddd, J¼1.8, 3.1, 1.7 Hz, 2H),
4.23–4.12 (m, 3H), 3.95–3.73 (m, 3H), 3.14 (m, 2H), 1.31 (t,
J¼14.0 Hz, 3H), 1.01 (t, J¼14.3 Hz, 3H); IR (film, cmꢁ1): 3061, 2982,
1752, 1607, 1496, 1246, 1029, 958, 104; MS (EI) m/z: 447 (Mþþ2, 35),
446 (Mþþ1, 30), 445 (Mþ, 100), 372 (21), 344 (33), 328 (16), 303
(23), 302 (16). Anal. Calcd for C23H25ClNO4P: C, 61.96; H, 5.65; N,
3.14. Found: C, 61.74; H, 5.42; N, 2.92.
12. For the intramolecular annulations of amides to a triple bond, see: (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) Kobayashi, Y.; Fukuyama, T. J. Heterocycl. Chem. 1998, 35,
1043; (e) McDonald, F. E.; ChatterJee, A. K. Tetrahedron Lett. 1997, 38, 7687; (f)
Khan, M. W.; Kundu, N. G. Synlett 1997, 1435; (g) Ohe, K.; Ishihara, T.; Chatani,
N.; Kawasaki, Y.; Murai, S. J. Org. Chem. 1991, 56, 2267; (h) Sakamoto, T.; Kondo,
Y.; Iwashita, S.; Nagano, T.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 1305; (i)
Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H.; McKillop, A. Tetrahedron Lett. 1985,
26, 5963; (j) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86; (k) Zhang, H.;
Larock, R. C. Tetrahedron Lett. 2002, 43, 1359.
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant No.20572123) for financial support and The National Center
for Drug Screening for the primary test of bioactivity.
References and notes
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