Synthesis of functionalized 2,5-dihydro-1,2-oxaphospholes via one-pot three-component reaction

Article abstract of DOI:10.1007/s13738-014-0460-4

An efficient one-pot synthesis of novel 2,5-dihydro-1,2-oxaphosphole derivatives via a three-component reaction of triphenyl phosphine, dialkyl acetylenedicarboxylates, and methyl (arylmethylidene) pyruvates has been reported. Carrying out the reaction in

Full text of DOI:10.1007/s13738-014-0460-4

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0460-4
ORIGINAL PAPER
Synthesis of functionalized 2,5-dihydro-1,2-oxaphospholes
via one-pot three-component reaction
•
Saeed Balalaie Leila Baoosi Fatemeh Tahoori
•
•
•
Frank Rominger Hamid Reza Bijanzadeh
Received: 13 November 2013 / Accepted: 29 April 2014
Ó Iranian Chemical Society 2014
Abstract An efficient one-pot synthesis of novel 2,5-
dihydro-1,2-oxaphosphole derivatives via a three-compo-
nent reaction of triphenyl phosphine, dialkyl acetylenedi-
carboxylates, and methyl (arylmethylidene) pyruvates has
been reported. Carrying out the reaction in mild reaction
conditions and synthesis of functionalized oxaphospholes
are advantages of this approach.
published describing novel syntheses of organophosphorus
compounds [12–15]. Yavari et al. [16–21] reported that the
reaction of triphenylphosphine with activated acetylenic
compounds in the presence of ketones to access the cor-
responding oxaphospholes. Esmaeili et al. [22] used isatin
for the synthesis of spirooxaphospholes. Recently, Zhu and
co-workers reported the preparation of fluorinated oxa-
phospholes using aryl or styryl trifluoromethyl ketones
[23]. The selection of the starting material has an essential
role in this reaction. Methyl (arylmethylidene) pyruvates
with three functional groups could be used as suitable
starting materials in organic synthesis. They play an
important role as an attractive starting material for the
following reasons: (a) They have higher reactivity in
comparison with usual b,c-unsaturated a-ketones; (b) they
contain active functional groups which can be used for
further synthesis; and (c) their preparation is easy [24, 25].
As a part of our current studies on the development of
new routes in synthesis of heterocycles via one-pot MCRs
based on methyl (arylmethylidene) pyruvates [26–28], we
report here a three-component reaction of triphenylphos-
phine 1, dialkyl acetylenedicarboxylates 2, and methyl
(arylmethylidene) pyruvates 3 for the synthesis of poly-
functionalized 2,5-dihydro-1,2-oxaphospholes 4 at room
temperature (Scheme 1).
Keywords 2,5-Dihydro-1,2-oxaphospholes Á Methyl
(arylmethylidene) pyruvate Á One-pot three-component
reaction Á Pseudorotation
Introduction
Organophosphorus compounds are very important class of
heterocyclic compounds widely used in organic synthesis
[1–4], and they exhibit diverse interesting biological
activities [5–10]. 1,2-Oxaphosphole derivatives are het-
erocyclic compounds which contain an O and a P atom in
their molecules, with a variety of biological, industrial, and
synthetic uses [11]. A large number of methods have been
Dedicated to Prof. M. Shamsipur on the occasion of his 65th birthday.
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-014-0460-4) contains supplementary
material, which is available to authorized users.
Results and discussions
S. Balalaie (&) Á L. Baoosi Á F. Tahoori Á H. R. Bijanzadeh
Peptide Chemistry Research Center, K. N. Toosi University of
Technology, P. O. Box 15875-4416, Tehran, Iran
e-mail: balalaie@yahoo.com
Recently, we have focused our research and development
efforts on the preparation of new compound libraries
containing biologically active heterocyclic skeletons. In
this way, methyl (arylmethylidene) pyruvates 3 have been
used as suitable starting materials. Existence of an active
alkene in the structure of methyl (arylmethylidene)
F. Rominger
Organisch-Chemisches Institut der Universitat Heidelberg,
¨
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
123

J IRAN CHEM SOC
Scheme 1 Synthesis of
polyfunctional 2,5-dihydro-1,2-
oxaphospholes via three-
component reaction
PPh3
1
MeOOC
COOMe
O
rt
MeOOC
Ar
COOMe
Ar
COOMe
PPh3
DCE
O
3
MeOOC
4a-d
2
mole ratios of the reactants are consistent with the 1.2:1.2:1
adducts of triphenylphosphine, dialkyl acetylenedicarbox-
ylate, and methyl (arylmethylidene) pyruvates. The model
reaction was checked in ethanol, methanol, dichlorometh-
ane, and THF. In all cases, the yields of product 4d were
between 45 and 55 %.
Table 1 Synthesis of 2,5-dihydro-1,2-oxaphosphole 4a–d via three-
component reaction
Entry
1
R
Ar
Product 4
Yielda
(%)
Me 4-MeO–
C6H4
67
77
72
82
Typically, the reaction of dialkyl acetylenedicarboxylate
with triphenylphosphine in the presence of methyl (aryl-
methylidene) pyruvates proceeded spontaneously at room
temperature in dichloroethane and was completed within
5 h at room temperature. The results are summarized in
Table 1. Our investigation showed that the existence of
bromine substituent on the aromatic ring in methyl (aryl-
methylidene) pyruvates increases the yield of product.
4a
4b
2
3
4
Me 4-Cl–
C6H4
Me 4-Me–
C6H4
MeOOC
COOMe
MeOOC
4c
Ar
PPh3
O
4
Me 4-Br–
C6H4
The structures of the products 4a–d were deduced from
their HRMS (ESI) spectra and NMR spectroscopic data.
The distinguished peak in the 1H-NMR spectra of the
products was indicated by two doublet signals at d
6.70–6.90 ppm for the olefinic trans H-atoms with
J = 15.9 Hz, and the methoxy groups resonated at d
3.81–4.29 ppm. The 13C-NMR spectra of 4d showed a
distinguished peak at d 83.4 ppm, and the C=O groups
appeared at d 161.3, 165.2, 167.0 ppm. In 31P-NMR data, a
distinguished peak was shown at d ?30.49 ppm. Mean-
while, the structure of 4d was confirmed by the X-ray
crystallographic data. (Fig. 1).
4d
Reaction conditions: 1.2 mmol 2, 1.2 mmol PPh3, 1 mmol methyl
(arylmethylidene) pyruvate, 10 ml C2H4Cl2, 5 h
a
Yield of isolated product
pyruvates could candidate them for the synthesis of com-
plex molecules. Meanwhile, the molecule has additional
ketone group which able to participate in further cycliza-
tion. They can be synthesized according to the known
procedure by the reaction of aromatic aldehydes and
pyruvic acid in an aqueous methanol solution in the pre-
sence of KOH [24].
Pseudorotation is a known property in some stable
oxyphosphoranes, and the contribution of the conforma-
tional transmission effect has essential role in the barrier of
pseudorotation in monocyclic oxyphosphoranes [29, 30]. In
the synthesized compounds 4a-d, existence of three phenyl
groups and also three methyl ester groups could affect the
pseudorotation in these compounds. In compounds 4a-d, it
is important to notice that the P atom is placed in the center
of a trigonal bipyramidal ring and three aromatic groups,
which are joined to it change their position frequently
because of the berry pseudorotation in pentacoordinated
phosphorus compounds, the aromatic picks are broad.
We began our investigation with methyl (4-bromophe-
nyl methylidene) pyruvate 3d; its reaction with triphenyl-
phosphine and dimethyl acetylenedicarboxylate in
dichloroethane at room temperature was selected as the
model reaction. The product was the desired oxaphosphole
4d with 82 % yield.
The reaction was checked at different temperatures,
increasing the temperature led to a mixture of products.
The best yield was obtained at room temperature. Mean-
while, the ratio of reactants was optimized. The optimized
123

J IRAN CHEM SOC
addition/cyclization reaction sequence. To the best of
our knowledge, this is the first report for the synthesis
of oxaphospholes using methyl (arylmethylidene)
pyruvates. The present procedure has the advantage
that the reaction is performed under neutral conditions
and at room temperature, and the products have other
active functional groups which could be used for fur-
ther reactions.
Conclusions
In conclusion, an efficient approach for the one-pot syn-
thesis of 2,5-dihydro-1,2-oxaphospholes via three-compo-
nent reaction of dialkyl acetylenedicarboxylate, methyl
(arylmethylidene) pyruvates and triphenylphosphine has
been developed. Notably, high bond-forming efficiency,
good to high yields, synthesis of polyfunctional com-
pounds, carrying out the reaction at room temperature, and
easy workup are advantages of this approach.
Fig. 1 ORTEP structure of compound 4d
Experimental section
Mechanistically, it is conceivable that the reaction
involves the initial formation of a 1,3-dipolar intermediate
A which could be formed through reaction of triphenyl-
phosphine and dialkyl acetylenedicarboxylate, and then it
reacts with carbonyl group of methyl (arylmethylidene)
pyruvates 3. Cyclization of the zwitterionic intermediate
B leads to the 2,5-dihydro-1,2-oxaphospholes. A tentative
mechanism for this transformation is proposed in
Scheme 2. Cyclization of this zwitterionic intermediate
B leads to the 2,5-dihydro-1,2-oxaphospholes tricarboxy-
late 4a-d.
All solvents were anhydrous grade, unless otherwise noted.
Starting materials were purchased from commercial sup-
pliers and used without further purification, unless other-
wise noted. Melting points were determined on an
Electrothermal 9100 apparatus. Infrared spectra were
1
recorded on an ABB FT-IR FTLA 2000 spectrometer. H-
NMR and 13C-NMR spectra were run on Bruker DRX-500
AVANCE and Bruker DRX-300 AVANCE spectrometer at
1
500 and 300 MHz for H-NMR, and 125 and 75 MHz for
13C-NMR, respectively. Chemical shifts are reported in
ppm, relative to internal solvent peaks. Coupling constants
J are reported in Hz. HR-ESI MS were obtained on a
Bruker APEX-Qe ESI FT-ICR instrument.
The formation of the products 4a-d could be cate-
gorized as domino reactions. The reaction could pro-
ceed via a domino zwitterion formation/nucleophilic
Scheme 2 Proposed
PPh3
e
M
OOC
mechanism for the synthesis
2,5-dihydro-1,2-oxaphosphole
e
M
O
COO
e
M
OOC
1
r
t
e
M
COO
r
A
e
M
COO
r
A
PPh3
O
D
E
C
3
4
e
M
OOC
2
PPh3
COO
e
M
COO
e
M
OOC
e
M
e
OOC
M
PPh3
A
O
COO
r
A
e
M
O
B
r
A
e
M
COO
3
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J IRAN CHEM SOC
General procedure for the synthesis of 2,5-dihydro-1,2-
3,4,Dimethyl(E)-5-(4-methylstyryl)-5-methyl-2,2,2-
oxaphospholes 4a–d
triphenyl-2,5-dihydro-1,2-oxaphosphole-
3,4,5tricarboxylate (4c)
To a stirred solution of dialkyl acetylenedicarboxylate
(1.2 mmol) and methyl (arylmethylidene) pyruvates
(1 mmol) in 1,2-dichloroethane (10 ml) was added drop-
wisely a solution of Ph3P (1.2 mmol) at room temperature
and the mixture was stirred for 5 h. The progress of reac-
tion was monitored by TLC (eluent hexane/ethyl acetate
3:1). The solvent was removed under reduced pressure, and
produced oil which was purified by prep TLC plates
(Eluent hexane/ethyl acetate 3:1). Further purification was
done by recrystallization in diethylether.
0.438 g, 72 %, as a yellow oil; Rf (20 % AcOEt/hexane)
0.50. IR(neat): 1,792, 1,751, 1,653. 1H-NMR(300 MHz,
CDCl3): 2.33 (3H, s, Me); 3.80 (3H, s, MeO); 3.84(3H, s,
MeO); 4.29 (3H, s, MeO); 6.71 (2H, s, =CH); 7.13 (2H, d,
J = 8.0, Ar); 7.27 (2H, d, J = 8.0, Ar); 7.13–7.32 (15H, m,
Ar). 13C-NMR(75 MHz, CDCl3): 21.3 (Me), 52.5 (MeO),
53.7(MeO), 60.1 (MeO), 83.7, 120.7, 122.8, 127.0, 128.5
(d, 2JCP = 20.1, Co of PPh3), 129.4, 132.0 (d, 3JCP = 16.2,
3
Cm of PPh3), 132.1, 132.3 (d, JCP = 12.5, Cm of PPh3),
132.6, 138.7, 147.7, 161.4 (O=C–O), 165.4 (O=C–O),
167.3 (O=C–O). 31P-NMR(121 MHz, CDCl3): ? 30.22.
HRMS (ESI): [M?H]? found 609.20364. C36H34O7P
requires 609.
3,4-Dimethyl(E)-5-(4-methoxystyryl)-5-methyl-2,2,2-
triphenyl-2,5-dihydro-1,2-oxaphosphole-3,4,5
tricarboxylate (4a)
3,4,Dimethyl(E)-5-(4-bromostyryl)-5-methyl-2,2,2-
triphenyl-2,5-dihydro-1,2-oxaphosphole-
3,4,5tricarboxylate (4d)
0.418 g, 67 %, as a yellow oil. Rf (20 %AcOEt/hexane)
0.55. IR(neat): 1,786, 1,653, 1,600.1H-NMR(500 MHz,
CDCl3): 3.80 (6H, s, MeO); 3.84 (3H, s, MeO); 4.29 (3H, s,
MeO); 6.60 (1H, d, J 16.1 Hz, = CH); 6.69 (1H, d,
J = 16.1, =CH); 6.86 (2H, d, J = 8.7, Ar); 7.35 (2H, d,
J = 8.7, Ar); 6.86–7.68 (15H, m, Ar); 13C-
NMR(125 MHz, CDCl3): 52.5 (MeO), 53.7 (MeO), 55.3
0.551 g, 82 %, as a colorless crystal.m.p 155–160 °C.
Rf(20 %AcOEt/hexane) 0.43. IR(neat): 1,791, 1,655. H-
1
NMR(300 MHz, CDCl3): 3.81 (3H, s, MeO); 3.85 (3H, s,
MeO); 4.29 (3H, s, MeO); 6.68 (1H, d, J = 15.9, = CH);
6.75 (1H, d, J = 15.9, =CH); 7.27 (2H, d, J = 7.2, Ar);
7.44 (2H, d, J = 7.2, Ar); 7.30–7.90 (15H, m, Ar). 13C-
NMR(75 MHz, CDCl3): 52.6 (MeO), 53.8 (MeO), 60.1
2
(MeO), 60.0 (MeO), 83.7, 114.0 (d, JCP = 26.7, Co of
Ph3P), 114.1, 119.4, 122.9, 125.3 (P–Ph), 127.8 (P–Ph),
4
128.1 (d, JCP = 6.3, CP of PPh3), 128.4, 128.5 (d,
3
3JCP = 14.4, Cm of Ph3P), 128.6 (d, JCP = 12.5, Cm of
2
3
Ph3P), 131.8, 132.0 (d, JCP = 10.1, Cm of Ph3P),132.1,
(MeO), 83.4, 122.5, 122.6, 122.7, 127.5 (d, JCP = 21.0,
3
Co of PPh3), 128.6, 130.8, 131.4 (d, JCP = 14.6, Cm of
4
132.2 (d, JCP = 2.5, CP of PPh3), 147.7, 160.6, 161.4
1
PPh3), 131.8, 132.0 (d, JCP = 71.6, Cipso of PPh3), 134.3,
(O=C–O), 165.4 (O=C–O), 167.3 (O=C–O); 31P–
NMR(121 MHz, CDCl3): ? 30.98. HRMS (ESI): [M?H]?
found 625.19969. C36H34O8P requires 625.19987.
147.7, 161.3 (O=C–O), 165.2 (O=C–O), 167.0 (O=C–O).
31P-NMR (121 MHz, CDCl3): ?30.49. HRMS (ESI):
[M?H]? found 673.09864. C35H BrO7P requires
79
31
673.09866, [M?H]? found 675.09704. C35H BrO7P
81
31
3,4-Dimethyl(E)-5-(4-chlorostyryl)-5-methyl-2,2,2-
triphenyl-2,5-dihydro-1,2-oxaphosphole-
3,4,5tricarboxylate (4b)
requires 675.09712.
Colorless
crystal
(polyhedron),
dimensions
0.34 9 0.11 9 0.04 mm3, crystal system triclinic, space
ꢀ
˚
group P1, Z = 4, a = 8.7881(7) A, b = 18.3827(15) A,
˚
0.478 g, 76.6 %, as a yellow oil. Rf (20 % AcOEt/hexane)
1
0.47. IR (neat): 1,789, 1,751, 1,655. H-NMR(500 MHz,
˚
c = 20.7030(17) A, a = 108.300(2) deg, b = 90.223(2)
3
˚
deg, c = 101.620(2) deg, V = 3,102.2(4) A , q = 1.442
CDCl3): 3.80 (6H, s, MeO); 3.84 (3H, s, MeO); 4.28 (3H, s,
MeO); 6.60 (1H, d, J = 16.1, =CH); 6.69 (1H, d, J = 16.1,
=CH); 7.28 (2H, d, J = 8.4, Ar); 7.33 (2H, d, J = 8.4, Ar);
7.28–7.67 (15H, m, Ar). 13C-NMR(125 MHz, CDCl3):
52.5 (MeO), 53.9 (MeO), 60.0 (MeO), 83.4, 122.6, 125.5,
g/cm3, T = 200(2) K, hmax = 24.01 deg, radiation Mo
˚
Kalpha, k = 0.71073 A, 0.5 deg MeOga-scans with CCD
area detector, covering the asymmetric unit in reciprocal
space with a mean redundancy of 4.5, and a completeness
˚
of 97.7 % to a resolution of 0.95 A, 37471 reflections
2
128.2, 128.3, 128.5 (d, JCP = 12.0, Co of Ph3P), 128.8,
3
128.9, 130.8, 132.1 (d, JCP = 9.8, Cm of Ph3P), 133.8 (d,
measured, 8,174 unique (R(int) = 0.0333), 6,451 observed
[I [ 2r(I)], intensities were corrected for Lorentz and
polarization effects, an empirical absorption correction was
applied using SADABS [31] based on the Laue symmetry
of the reciprocal space, l = 1.43 mm-1, Tmin = 0.65,
Tmax = 0.94, structure solved by direct methods and
1JCP = 53.9, Cipso of PPh3), 147.7, 161.3 (O=C–O), 165.2
(O=C–O),
167.0
(O=C–O).
31P-NMR(121 MHz,
CDCl3): ? 29.91. HRMS (ESI): [M?H]? found
629.15119. C35H ClO7P requires 629.15153, [M?H]?
35
31
37
found 631.14799. C35H ClO7P requires 631.14829.
31
123

J IRAN CHEM SOC
refined against F2 with a full-matrix least-squares algo-
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package [32], 815 parameters refined, hydrogen atoms
were treated using appropriate riding models, goodness of
fit 1.03 for observed reflections, final residual values
R1(F) = 0.042, wR(F2) = 0.094 for observed reflections,
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