wittig{horner reagents: powerful tools in the synthesis of
TRANSCRIPT
Turk J Chem
(2016) 40: 225 – 247
c⃝ TUBITAK
doi:10.3906/kim-1502-56
Turkish Journal of Chemistry
http :// journa l s . tub i tak .gov . t r/chem/
Review Article
Wittig–Horner reagents: powerful tools in the synthesis of 5-and 6-heterocyclic
compounds; shedding light on their application in pharmaceutical chemistry
Rizk Elsayed KHIDRE1,2,∗, Wafaa Mahmoud ABDOU1
1Chemical Industries Division, National Research Centre, Dokki, Giza, Egypt2Department of Chemistry, Faculty of Science, Jazan University, Jazan, Saudi Arabia
Received: 09.02.2015 • Accepted/Published Online: 22.06.2015 • Final Version: 02.03.2016
Abstract: This paper reviews literature over 25 years’ activity on phosphoryl carbanion reagents and shows that these
compounds are powerful tools in organic chemistry. The main target of this review is to outline some of the reactive
peculiarities that make this class of compounds powerful tools in the synthesis of 5- and 6-heterocyclic compounds and/or
substituted heterocycle phosphor esters. The importance of these latter compounds in pharmacology is also discussed.
Key words: Phosphonyl carbanions reagents, phospha-Michael (P-Michael) addition, Perkin-type reaction, five-
membered heterocycles, six-membered heterocycles, nucleophiles
1. Introduction
Organophosphorus compounds, in parallel, are noteworthy for their biological activity,1−4 especially when they
are associated with various heterocycles.5 One of the most important of these bioactive heterocycles are the
substituted heterocycle phosphor esters and/or heterocycles containing phosphorus groups.6 In spite of their
importance, methods for the direct synthesis of these types of heterocycles are quite limited.7,8 With this
aim, our group and others investigated for over 25 years the usefulness of phosphoryl carbanions (also known
as Wittig–Horner (WH) or Wadsworth–Horner–Emmons (WHE) reagents) in the construction of several five-
and six-membered heteroring systems. Related substituted heterocycle phosphor esters and/or heterocycles
containing phosphorus groups were reported.
This review article describes the progress over last three decades in the chemistry of phosphoryl carban-
ions, showing their synthetic usefulness as versatile building blocks in the construction of five- or six-membered
heterocycles (Scheme 1) and in connection to our previous review articles.9−14 The classification is based upon
the size of the heterocyclic rings (five-membered and six-membered rings) and the number of heteroatoms in the
given molecule regardless of the site of attack by the reagent. There are, however, some exceptions to this clas-
sification, some of which will emerge in the subsequent discourse. Heterocyclic derivatives, on the other hand,
are of great importance in pharmaceutical chemistry. The main purpose of this review is to represent a survey
of the utility of phosphonyl carbanions in the synthesis of 5- and 6-heterocyclic compounds and provide useful
and up-to-date data for chemists. Furthermore, pharmacological applications of the produced heterocycles are
discussed.
∗Correspondence: [email protected]
225
KHIDRE and ABDOU/Turk J Chem
(RO)2P RO
HN P
O
OROR
NH
P
O
OROR
N P
OOR
OR
O
P
O
RO
RO
NN
O
O
O
R
P
OOROR
O
O
P
NN
CNORO
NNPh
P ORORO
HN
O
P OR
OR
O
N
SS
ONH2
P
O
OROR
P
NHN
OHO
HN
P
O
OR
OROO
P OROR
O
O
O
NHP
O
OR
OR
S
O P
NN
NNH
S POROR
O
H
OOR
OR
1
2 3
4
5
6
7
8
9
1011
12
13
14
15
16
Scheme 1.
2. Synthesis of five-membered heterocycles
2.1. Five-membered heterocycles with one heteroatom
2.1.1. Pyrroles and their fused systems
Phosphonyl carbanions 17 were reacted with amine 18 in refluxed toluene containing p -toluenesulfonic acid
(PTSA) to give phosphorylpyrrolidin-2-ones 21 in high yields via formation of intermediates imines 19 and
enamines 20 followed by lactamization (Scheme 2).15
δ -Amino-β -keto-phosphonates 22 were treated with 4-acetamidobenzenesulfonyl azide (4-ABSA) in the
presence of NaH to afford δ -amino-α -diazo-β -ketophosphonates 23. Stereoselective intramolecular cyclization
of the latter compounds gives pyrrolidine-2-phosphonates 24. Olefination reaction of 24 gives 2-ethylidene
pyrrolidine 25 in good yields (Scheme 3).16
Hydroxypyrroles 29 were obtained, in excellent yields, by reaction of oxime 26a,b with α -phosphoryl-
vinyl-p -tolylsulfoxide 27 in DMF containing NaH via intermediates 28 (Scheme 4).17
226
KHIDRE and ABDOU/Turk J Chem
P CO2Et
O
R1
OEtOEtO
+ R2NH2
PTSAP CO2Et
N
R1
OEtO
EtO
R2
P CO2EtHN
R1
OEtO
EtO
R2N
P
O
R2
R1
O OEt
OEt
1719
2021
18
-EtOH
R1 = Me, n-Bu, Ph, 3,4-(OMe)2C6H3R2 = n-hexyl, benzyl
Scheme 2.
Boc = t-buty carboxylate
R1
NHBoc
O
P(OMe)2
O
R1
NHBoc
O
P(OMe)2
O
N2
N
O
Boc
P(OMe)2R1O i) base
ii) R2CHO
i) NaHii) 4-ABSA
2223
5242
R1 = n-Bu, t-Bu, Ph ; R2 = Me, n-Pr, n-C6H13
N
O
Boc
R1R2
CH2Cl2
Rh2(OAc)4
Scheme 3.
R
N
O
Me
O
PEtO
EtO CH2
S
O
R1
NOH
R
Me SO
R1
+
OH
26a, R = Meb, R = Ph
27, R1 = 4-MeC6H4 29
NO
R
MeS
OR1
P(OEt)2ONaH
28
O
Scheme 4.
Indol-2-yl methylphosphonate 33 and 1,4-dihydroquinolin-2-ylphosphonate 34 were synthesized by reac-
tion of 3-phenyl-[2,4]-benzoxazine-1-one 30 with diethyl vinylphosphonate 31a (Scheme 5).18
227
KHIDRE and ABDOU/Turk J Chem
P
O
EtOEtO
N
COPh
OEtPO
OEtOEt
N
O
PO
OEt
OEt+
33, 41% 34, 27%
31a
PhOCLiH/DMF N
COPh
O
P OEt
OEt
O
N
O
Ph
O
30 32
Scheme 5.
N -aryl-α -phosphonylglycine derivatives 37 were formed by reaction of ethyl 2-diazophosphonylacetate
35 and substituted aromatic aniline 36 in toluene in the presence of catalytic Rh2 (OAc)4 at reflux temperature,
while the Wittig–Horner reaction of 37 with o -iodobenzaldehydes 38 in CH2Cl2 gave Z−olefinic adducts 39
in high yields. Intramolecular cyclization of 39 in DMF in the presence of PdCl2 and KOAc gave 2-ethyl indole
carboxylates 40 in good yields (Scheme 6).19,20
EtO2C P(OEt)2
N2+
NH2
YNH
P(OEt)2
EtO2C
Y35 36
37
BaseNHEtO2C
Y
X
NEtO2C
Y39 40
X
O
CHO
XI
37 +
38
PdCl2
CH2Cl2 KOAc, DMF
O
X = H, 6-NO2, 5-OMe; Y = 4-CO2Et, 4-CH2CO2Et, 3,4-OCH2O-, 2-Br
Rh2(OAc)4
toluene
r.t.
I
Scheme 6.
Intramolecular cyclization of N -((diphenylphosphoryl)methyl)aniline 41 in THF containing either BuLi
at –78 ◦C 17 or LDA21 afforded indole-2-diphenylphosphine oxides 42 in high yields (Scheme 7).
NR2
P
Ph
O
PhN
X
R2
P
O
PhPh
n-BuLi/THF
or LDA
41 42
R1 = CONEt2, R2 = i-Pr, propynyl; X = OH
R1 = CN, R2 = Me, i-Pr, PhCH2; X =NH2
R1
Scheme 7.
3-Formyl pyrrolidine 43 was treated with triethyl phosphonoacetate 31a in THF to yield pyrrolidine
228
KHIDRE and ABDOU/Turk J Chem
acrylate 44. Hydrogenation, and hydrolysis followed by intramolecular cyclization of 44 gave aminopyrrolizidine
45 (Scheme 8).22
NAc
N
CHO
Bn
Ac
N CO2Me
NBnAc
Ac
N
O
N
Bn
H
43 44
P
O
45, 61%
THF, base+
31b
EtO
EtO
i) H2-Pd/C
ii) H3Oiii) cyclization
CO2Me
Scheme 8.
In the same fashion, (1,2-bis(benzyloxy)-5-methylhexahydro-1H -pyrrolizin-3-yl)methyl benzoate 48 was
synthesized from the reaction of pyrrolidine-2-carbaldehyde 46 with diethyl acetyl methylenephosphonate 31d
to yield adduct 47, followed by hydrogenation and intramolecular cyclization (Scheme 9).23−25
N
OBnBnO
CBz
CHOBzOH2CN
OBnBnO
CBz46
31d 47
48
BzOP
O
Pd-C/H2
cyclization
+ EtO
EtO
N
Me
BzO
BnO
BnO
OMe
COMe
Scheme 9.
2.1.2. Furans and thiophenes and their fused systems
Cyclopropane phosphonate 50a,b and 3-(thiophen-2-yl)pent-2-enedinitrile 51a,b were prepared from the re-
action of 3(2-thienyl)acrylonitrile 49a,b with cyano methylene phosphonate 31e in THF containing NaH at
reflux. In addition, phosphono-substituted furan 52c was also isolated from 49a (Scheme 10).26
229
KHIDRE and ABDOU/Turk J Chem
R
NC PO
OEt
OEt
CN
R
CH2CN
+
50a (23%)b (46%)
51a (22%)b (28%)
49a, R = CO2Etb, R = CN
52c (26%)
+
OP
CNEtO
EtO
31e
S
CN
R O
CN
NC
P
O
EtOEtO
S S
NaH, THF, ref lux
S
Scheme 10.
Similarly, treatment of 49a with phosphonoacetate 31c afforded phosphono-substituted furans 173 and
174 (Scheme 11).26
S
CN
CO2Et O
CN
EtO2C
EtO2C
O
CN
CO2Et
P
O
EtOEtO
53 (41%) 54 ( 23%)
+31c
OP
CO2EtEtOEtO S
(EtO)2P
O
S
THF, NaH,ref lux49a
Scheme 11.
Diethyl (1,7-dioxaspiro-[4.4]nona-3,8-dien-9-yl)phosphonate 57 was recently obtained from reaction of
2-acetylfuran 55 with diethyl vinylphosphonate 31a in DMF containing lithium hydride (Scheme 12).27
O
Me
OMe
55
+P(OEt)2
31a
OMe
OMe
+CH
56
P(OEt)2
O O
MeMe
P(OEt)2O57, 67%
-
O
O
LiH/DMF
Scheme 12.
Knoevenagel condensation reaction of oxathiolone 58 with α -phosphonyl carbanions 31b,c,e in refluxed
ethanol in the presence of EtONa followed by sequential alkylation gave benzothien-3-ylphosphonates 60 in 66%
yield (Scheme 13). Benzothienylphosphonate esters 60a–c showed significant antimicrobial activity against a
panel of representative gram-positive pathogenic microorganisms, gram-negative microorganisms, and fungi.28
230
KHIDRE and ABDOU/Turk J Chem
S
O
O
+P(OEt)2
R
HO
58 31b,c,e
60
R = CO2Me; b, R = CO2Et; c, R = CN
EtONa
S O
EtOR
P(OEt)2
O
O
S O
HO R
P(OEt)2
OO
Na
SO
HO R
P(OEt)2
OOH
- H2O
Alkylation
59A59B
Scheme 13.
2.2. Synthesis of five-membered heterocycles with more than one heteroatom
2.2.1. Pyrazoles and their fused systems
[3+2] Cycloaddition reaction of diazomethane with vinyl-1,2-butadienylphosphonates 61a,b yielded pyrazole-
3-phosphonates 63a,b (Scheme 14).29
C C CMe
MePO
RO
RO HNN
P
O
RO
RO
Me
Me
61a, R = Meb, R = Et
63a,b
CH2N2+
H
H
NN
62
C
C
C
Me
Me
P ORORO
Scheme 14.
Pyrazolinyl-3-phosphonate 66 and diazaphosphole 67 were prepared in 27% and 44% yields, respectively,
from the reaction of 2-diazo-1,3-indandione 64 with phosphonoacetate 31b,c in a mixture of LiOH/H2O/CHCl3
at reflux. On the other hand, spiroindene-2,3‘-pyrazolyl phosphonate 69 and spiro diazaphosphole 70 were
yielded from the reaction of 64 with cyanomethylphosphonate 31e (Scheme 15).30
Similarly, spiro[indene-2,3‘-pyrazol]-5‘-yl)phosphonate 72 was synthesized in 72% yield by treatment of
diazoketone 64 with diethyl vinylphosphonate 31a under phase-transfer catalysis conditions (Scheme 16).30
Spiroindene-2,3‘-pyrazolinyl phosphonates (66, 69, and 72) and spiro diazaphospholes (67, 70) showed
more significant antimicrobial activity towards tested organisms (bacteria and fungi). Furthermore, the phosp-
hole derivatives (67 and 70) are more active than the phosphonate derivatives (66, 69, and 72).30
231
KHIDRE and ABDOU/Turk J Chem
AlkylationN N
O
O NN
O
O
O
Et
PO
OEtOEt+
P
NN
O
O Et
CO2ROOEt
P
CO2R
O
OEtEtO
LiOH/H2O/CHCl3
PCNO
EtOEtO
+
70, 33%69, 38%O
O
NN
P(OEt)2NH2OO
O
P
NN
CN
Et
OEtO
LiOH/H2O/CHCl3
64 31b, R = Mec, R = Et
66, 27%
67, 44%
31e
CH
CN
P(OEt)2
OLi OH-N N
O
O
CH
CO2R
P(OEt)2
O
Li
N N
O
O
OH-
Alkylation
65
68
Scheme 15.
NNHO
OP(OEt)2
O+LiOH/H2O/CHCl3
Alkylation
P(OEt)2
O
O
O
NNEt
P(OEt)2
O
N N
O
O
6431a
71
72
Scheme 16.
Vilsmeier–Haack reaction of phosphonyl ethylene hydrazones 73 gave 1-phenyl-4-diethoxyphosphonylpyrazoles
74 in 46%–81% yields (Scheme 17).31
PEtO
EtO R
NNHPh
O DMF/POCl3N
N
Ph
RPO
EtOEtO
R = H, Me, Ph
46-81%
73 74
Scheme 17.
Cyclization of β -hydrazonophosphonates 75 into their corresponding 4-phosphonopyrazoles 76 was
achieved via their reaction with triethyl orthoformate in xylene containing a few drops of glacial acetic acid
(Scheme 18).32,33
232
KHIDRE and ABDOU/Turk J Chem
PRRR2
N
NHR1
O
HC(OEt)3
NN
R1
R2PO
R
R
R = Ph, OEt; R1 = Me, Ph, CH2CF3; R2 = Me, CH(Me)2, Ph
AcOH/xylene68-94%
75 76
Scheme 18.
2.2.2. Oxazole and its fused systems
In a recent report, 2-azido-4,6-di-tert-butylphenol 77 was reacted with diethyl vinylphosphonate 31a in sodium
ethanolate solution under reflux to give 2-benzoxazole phosphonate 78 in 74% yield via a coupling cyclization
reaction of 77 with 31a in one step with tandem NH alkylation and extrusion of nitrogen. Similarly, benzoxazole
phosphonates 79 (72%) were formed from the reaction of the azide 77 with saturated WHE reagents 31 (Scheme
19).34
N3
OH
N
OEtONa-N2
Et
P OEtOEt
O
O
P (OEt)2
R1
77
O
P (OEt)2
EtONa-N2
N
O
Et
P
R1
OEtOEt
O
R1 = SMe, -C(S)NH2, C(O)Me, Ph, 4-ClC6H4, CN, CO2Me, CO2Et
31a
31
78
79
Scheme 19.
Stereoselective 1,3-dipolar cycloaddition of allyldiphenylphosphine oxides 80 with nitrile oxides 81 af-
forded ∆2 -isoxazolines 82 (Scheme 20).35,36
O
PPh
Ph R1R2 C N O
NO
R2POPh
Ph
R1
281808
R1 = H, Me, Et, n-Pr, i-Pr
R2 = Me, Et, n-Pr, hexyl, Ph, CO2Et, (CH2)nCO2Me (n = 2,3)
+
Scheme 20.
233
KHIDRE and ABDOU/Turk J Chem
Treatment of diethyl phosphonoacetates 31b,c with triketoindane-2-oxime 83 in EtOH/EtONa at re-
flux temperature yielded spiroindene-2,3’-isoxazolidinylphosphonate 85 and adduct 86. Compound 83 was
treated with (methylthio)methylphosphonate 31f,g in EtOH/EtONa at reflux to give diethyl(3-ethoxy 4-oxo-
4-hydroindeno[2,1-d ][1,3]oxazol-2yl)phosphonate 88 (Scheme 21). Compounds 85, 86, and 88 were screened
against some gram-positive bacteria, gram-negative bacteria, and fungi. Compound 85 showed feeble activity
against gram-positive bacteria. Compounds 86 and 88 displayed no activity against the tested bacteria. Com-
pound 86 is moderately active against D. specifera at 780 µg/cm3 while compounds 85 and 88 are more active
against D. specifera at 780 µg/cm3 . Compounds 85 and 88 registered 100% spore germination inhibition of
F. oxysporum at 320 µg/cm3 .37
O
O
NOH
O
O
O
NO
Et
OP
O
OEtOEt
RO2C
NO
O
Et
POEtOEt
O
EtOH/EtONa
83
O
P (OEt)2
CO2R
O
O
NH
O
P(OEt)2
O
O
OR
-ROH
Alkylation
85, 36% 86, 35%
EtOH/EtONa
O
P (OEt)2
SR 31f ,g
O
N
O
OEt
O
O
N
O
P(OEt)2
O
88, 72%
AlkylationSR
P
O
OEt
OEt
-RSH
R = Me, Et
R = Me, Et
31b,c
84
87
Scheme 21.
Oxazolophosphonate 91 and the diolefin 90 were obtained from the reaction of 2-(hydroxyimino)-1,3-
diphenylpropane-1,3-dione 89 with phosphoacetonitrile 31c (Scheme 22).38
NOHPh
CHCN
PhCHCN
90, (19%)
31e
91, (41%)
OHN
PhPhOC
NC PO
OEt
OEt
+(EtO)2PCH2CN
O
NOHPh
O
PhO
89
Scheme 22.
The reaction between alloxan-5-oxime derivatives 92 with thiomethylphosphonates 44f,g to give the cor-
responding fused substituted [1,3]oxazolo[4,5-d ]2-pyrimidinylphosphonate 93 was reported. Triazaspiro[4,5]dec-
3-en-4-ylphosphonate 94 and [1,3]oxazolo[4,5-d ]pyrimdin-2-ylidene ethylphosphonate 95 were obtained from the
reaction of 92 with allyl phosphonates 31h (Scheme 23).39
234
KHIDRE and ABDOU/Turk J Chem
O
P SR
EtO
EtO
N
N O
N
O
O
R1
R1
H
PO
OEt
OEt
N
NO
R1
R1
O
O
O
PEtO
EtO
O
HN
Me
P OEtOOEt
N
N O
N
O
O
R1
R1
Et
P OEtOEtO
R = Me, Et
+
94 95
93
31h
H
31f ,g
R1 = H, Me
92
N
N
O
O
NOHO
R1
R1
Scheme 23.
2.2.3. Thiazole and oxaphosphole and their fused systems
5-Benzylidene-4-thiazolidines 96 was reacted with phosphonoacetates 31b,c in EtOH/EtONa at room temper-
ature to yield diethyl 6-benzylidene-3,5-dioxotetrahydro-2H -thiazolo[2,3-b ]thiazol-2-ylphosphonate 97. Fused
phosphonopyranones 99 together with olefins 98 were regioselectivity synthesized when the above reaction
occurred at reflux temperature (Scheme 24).40
NH
SPh
O
S
P CO2R
O
EtO
EtO
N
SS
O
P
O
OEt
OEt
Ph
O
N
SPh
O
CO2R
CO2RO
S
NEt
SO
Ph
P
O
EtOOEt
+
96
97 (58%)
98, 30%99, 30%
EtONa/EtOH
r.t
ref lux
Scheme 24.
On the other hand, compound 96 was reacted with phosphonoacetonitrile 31f in DMF containing LiH
at reflux temperature to afford Michael addition product 100 along with thiazolo[2,3-b ]thiazolo-phosphonate
101 (Scheme 25).40
235
KHIDRE and ABDOU/Turk J Chem
NH
S
O
S
CN
Ph
P
O
EtOEtO
101, 40%100, 25%
N
SS
Ph
ONH2
P
O
OEtOEt
+(EtO)2PCH2CN
O
31f
NH
SPh
O
S
96
Scheme 25.
Treatment of phosphonyl carbanions 31b,c,f with 1-(5-methylfuran-2-yl)ethanone 102, in DMF contain-
ing LiH under reflux, afforded oxaphospholes 104 (55%–48.2% yield) along with phosphonate 103 (17%–22.6%
yield) (Scheme 26).28
102
+P(OEt)2
31b,c,f
104
O
Me
Me
R/- H2O
103
O
Me
Me
OH
RPOEt
+OP
Me
Me R
O
OEt
R = CN, CO2Me, CO2Et
O
OO
MeMe
OOEt
P(OEt)2
O
R
O- EtOH
LiH/DMF
A
Scheme 26.
2.2.4. Triazoles and diazaphosphole and their fused systems
One pot reaction of methoxyimine 105, phosphonyl acetohydrazide 106, and aromatic or/and heterocycles
aldehyde gave 1,2,4-triazoles 107 in moderate to excellent yields (Scheme 27).41
N OMeP
O
NH
NH2
OEtO
EtO
N
NN
n n
105106 107
+
R(n = 0,1,2)
R = Ph, 4-MeOC6H4, 4-NCC6H4, 4-ClC6H4, thiazol-2-yl, pyrid-2-yl, thien-2-yl
RCHO+
EtONa
toluene
Scheme 27.
Hydrazonyl halides 108 were reacted with WH reagents 31c,f in NaOEt at room temperature to yield
diazaphospholes 109 via cyclization followed by hydrolysis of intermediates B and C, respectively (Scheme
28).42
236
KHIDRE and ABDOU/Turk J Chem
NR1
ClNPh
OP
EtO
EtOR
R
R1
P
O
OEtOEt
NNHPh
PN
N
R
R1 Ph
OOEt
P
NN
R
R1 Ph
OHO
108 109
31c,f
B C
HHH
H
R1 = CO2Et, Ph, COPh; R = CO2Et, CN
NaOEt
-EtOH Hydrolysis
Scheme 28.
Diazoketone 64 was reacted with diethyl (methylthio)methylphosphonate 31g to yield spiro[1,2,4-diazaphosphole-
3,2‘-indene]-1‘,3‘-dione-4-oxide 110 along with indeno-[2,1-e ][4,1,2]oxadiazin-9(1H)-one 111 (Scheme 29).30
Compound 110 showed more significant antimicrobial activity than the unphosphorylated oxadiazine 111.
N N
O
O
+ LiOH/H2O/CHCl3P(OEt)2
O
a) -EtOH or - (EtO)2POHP
NN
SMe
Et
OEtO
O
O
SMeb) Alkylation
O
NN
SMe
EtO
+
111, 17%110, 49%64 31g
Scheme 29.
Nucleophilic addition of HWE reagents 31b,c,f to 1,2,4-triazole-3-thiol-4-aminoarylidenes 112 in DMF
containing LiH yielded β -amino-phosphonates 113 (≈55% yield) and thiadiazoles 114. On the other hand, thia-
diazoles 114 were, however, exclusively obtained in 75%–80% yield when the reaction (112 and the same WHE
reagents) proceeded in MeOH/MeONa containing a catalytic amount of 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ) (Scheme 30).43
Compounds 114 showed more significant antimicrobial activity, with minimal inhibitory concentration
(MIC) of 54–140 and 22–143 mmol L−1 and minimal bactericidal concentration (MBC) values of 70–439 and
44–268 mmol L−1 compared with MIC/MBC for ciprofloxacin of 48–386 (MIC, mmol L−1) and 55–396 for
(MBC mmol L−1) and MIC/MBC for chloramphenicol of 70–439 (MIC, mmol L−1) and 65–619 (MBC mmol
L−1) against a panel of gram-positive and gram-negative bacterial pathogens: Klebsiella pneumoniae 2011E,
Pseudomonas aeruginosa 6065 Y, Escherichia coli BW54, Escherichia coli BW55, Acinetobacter haemolyticus
BW62, Stenotrophomonas maltophilia D457R, Staphylococcus epidermis 887E, Bacillus cereus ATCC 11778,
Staphylococcus aureus ATCC 29213, and Sarcina lutea.43
3. Synthesis of six-membered heterocycles
3.1. Synthesis of six-membered heterocycles with one heteroatom
3.1.1. Pyridines and pyrans and their fused systems
Diethyl 1-cyano-2-ethoxyvinylphosphonate 117 was reacted with cyclobutenyl amine 115 in a mixture of DMF
and THF (1:1) containing sodium hydride to afford pyridine-3-carbonitriles 119 (Scheme 31).44
237
KHIDRE and ABDOU/Turk J Chem
+ R2PEtO
OEt
O
DMF/LiH
R1= 4-Me2NC6H4, 4-ClC6H4; R2 = CO2Me, CO2Et, CN
NN N
N R1
SH
N
NN
NH R1
HS
R2
P OEtOEt
O
MeOH/MeONa/DDQ
� /-H2
NN N NH
R1SR2
P OEtOEtO
NN N NH
R1SR2
P OEtOEtO
+
112113 114
114
31
Scheme 30.
COCF3
NH2
R1 NaH
20 oC
COCF3
NH
R1
- EtONa
P(OEt)2
CN
O
EtO 117
COCF3
NH
R1
P(OEt)2
O
CN
N
CN
CF3R1
R1 = C4H7, C6H11
115 116 118
119 (48-60%)
Scheme 31.
Reaction of β -fluoroamidinium salt 120 with acetyl methylene phosphonate 31e in DMF containing
t -BuOK gave the 1,3-butadienylphosphonates 121 in good yields. The latter compound was treated with
ammonia to afford pyridin-3-ylphosphonate 122 in 60% yield (Scheme 32).45
F
NEt2N
OP
COMe
EtO
EtO F
Et2NCOMe
P
O
OEt
OEt N
F P
O
OEt
OEt
Me
122
Et
Et I-
t-BuOK, DMF
121120
31e NH3
- Et2NH
Scheme 32.
2-(hydroxyimino)-1,3-Diphenylpropane-1,3-dione 89 was reacted with diethyl phosphonoacetates 31b,c
to yield oxazolophosphonate 123a,b (20%) and phosphono-1-ethoxypyridinone 126a,b (32%) (Scheme 33).38
238
KHIDRE and ABDOU/Turk J Chem
OP
CO2R
EtO
EtONOH
PhO
PhO
OHN
PhPhOC
RO2C P
O
OEtOEt
N
OEt
O
PRO2CPh
PhOC
O
OEt
OEt
89
31b,c123a,b ( 20%)
126a,b (32%)
-H2O
NOHPh
O
PhCO2R
+ 31b,c NOHPhO
Ph
RO2C
CO2R
POEtOEt
O
-ROH
124125
LiOEt
Scheme 33.
Quinolinyl phosphonate 129 and 2-aminoquinolin-3-ylphosphonate 132 along with 1H -indol-2-ylphosphonate
133 were synthesized from the reaction of 3-phenyl-2,4-benzoxazine-1-one 30 with phosphonoacetate 31b,c and
phosphonoacetonitrile 31e, respectively (Scheme 34).18
N
O
Ph
O
P CO2R
O
EtOEtO
N O
OEt
COPh
P
O
OEt
OEt
31b,c
P CN
O
EtOEtO
N NH2
O
COPh
P
O
OEt
OEt
N
COPh
OEt
P
OOEt
OEt
30
129, 64%
132, 37%
133, 24%
31e
LiH/DMF N
O
Ph
OP
CO2R
OEtOEt
O
Li
NH
COPh
O P
CO2R
OEtOEt
O
Li
-ROH
LiH/DMF N
O
Ph
OP
CN
OEtOEt
O
Li
NH
COPh
O P
CN
OEtOEt
O
Li -HCN
127 128
130 131
Scheme 34.
4-(p -tolyl)-2,3-Benzoxazine-1-one 134 was treated with phosphonyl carbanion 31a–c,e to give the sub-
stituted isoquinoline derivative 136 and 138, via intermediates 135 and 138, respectively (Scheme 35).18
239
KHIDRE and ABDOU/Turk J Chem
N
O
O
R
N
O
R
R
P
O
OEt
OEt
N
R
O
P
O
OEt
OEt
31b,c,e
31a
138
134, R = 4-MeC6H4 136, R = CO2Me, CO2Et, CN
NOH
O
R
R PO
OEt
OEt
- H2O
NOH
O
R
P
O
OEtOEt - H2O
135
137
O
PEtOOEt
O
P REtO
OEt
Scheme 35.
2-(phenylmethylene)-1,3-Diphenylpropanedione 139 was reacted with phosphonyl carbanion 140 in the
presence of NaH and/or NaOEt to afford substituted pyran-3-ylphosphonate 142 via intermolecular 1:4 addition
followed by intramolecular cyclization 141 (Scheme 36).46
PEtOEtO
O
PhO
PhO
Ph
+Toluene/NaH
or EtONa/EtOH
Ph O
Ph
OH Ph
P
OEt
OEtOO
O
Me
MeMe
O
OBu-t
O O
POEt
OEt
O
Ph
Ph
Ph
O
- (CH3)3COH
139 140 141
142
Scheme 36.
3.2. Synthesis of six-membered heterocycles with more than one heteroatom
3.2.1. Pyridazines, oxazines, and oxathiines and their fused systems
2-Diazotrifluoroacetoacetate 143 was allowed to react with phosphonyl carbanion reagents 31c,e in acetonitrile
to give olefinic adduct 144a,b. Reductive cyclization of 144a using triphenylphosphine yielded pyridazines
146 (Scheme 37).47
240
KHIDRE and ABDOU/Turk J Chem
O
F3C
CO2Et
N2O
PEtO
EtO
CH2R1F3C
CO2Et
N2
R2H
F3C
OEt
ON
CO2Et
NPPh3 N
N
F3C
OEt
CO2Et
PPh3
143
145 146
+
31c,e
- Ph3PO
144a, R = CO2Etb, R = CN
only 144a
i) LiCl
ii) EtN(i-Pr)2
Scheme 37.
When compound 83 was reacted with diethyl cyanomethylphosphonate 31e, indeno-[1,2-b ][1,4]oxazin-
3yl)phosphonate 148 together with indeno[2,1-d ][1,3]-oxazole-2-carbonitrile 150 was obtained (Scheme 38).
Compound 148 showed more significant antifungal activity against D. specifera and F. oxysporum.37
EtOH/EtONa
O
P (OEt)2
CN
O
OH
CP(OEt)2
CN
O
148, 48%
150, 21%
NOH
O
O
NHP
O
N
O
CN
O
OEt
OEtNH2
31e
-H2O
-(EtO)2P(O)O
O
NH
O
CN
-H2
O
O
NOH
83
147
149
Scheme 38.
In a systematic study, the behavior of indandione oxime 83 towards diethyl vinylphosphonate 31a was
reported and indeno[1,2-b ][1,4]oxazin-3-yl)phosphonate 153 along with indeno[a ]pyrrole 150 was obtained
(Scheme 39).37
Barbituric acid-5-oximes 92 were reacted with phosphonyl carbanion reagents 31b,c to afford the
pyrimidino[4,5-b ][1,4]oxazin-3yl)phosphonate 156 and spiro[pyrimidine[5,3‘][1,2]oxazole]-4‘yl)phosphonate 158
via intermediates 155 and 157, respectively. Moreover, [1,4]oxazino[3,2-d ]pyrimidin-2,4-dione phosphonates
160 were obtained via Perkin-type condensation of 92 with phosphonoacetonitrile 31f (Scheme 40).39
241
KHIDRE and ABDOU/Turk J Chem
83
EtOH/EtONa
O
P (OEt)2
153, 46%
-H2O
O
O
NHP
O
OEt
OEt
31a
-(EtO)2P(O)O
O
N
O
P
O
EtO OEt
O
N
O
OEt
O
O
N
O
P(OEt)2
O
154, 14%
Alkylation
+
O
O
NOH
151 152
Scheme 39.
N
N
O
O
NOHO
R1
R1
N
N O
N
OO
O
R1
R1 PO
OEt
OEt
N
N ONO
OP O
OEtEtO
OH
EtR1
R1
O
N
N
O
OH
NO
R1
R1
P
CN
OEt
OEt
160, 74%
31f
92
158, 28%
155
31b,c
159
P CO2RO
EtO
EtO
P CNO
EtO
EtO
O
R1 = H, Me
EtONa/EtOH-H2O
N
NOR
N
OO
O
R1
R1 PO
OEt
OEt
OH
156, 35%
N
N
O
O
NHO
R1
R1 P
CO2R
O
OEtOEt
O
-ROH
Alkylation
N
N O
HN
NH2O
O
R1
R1 PO
OEt
OEt
157
Scheme 40.
Similarly, pyrimido[4,5-b ][1,4]oxazin-6-ylphosphonate 162 via intermediate 161, and pyrrolo-[3,2-d ]pyri-
midine-2,4-dione 165 were obtained from the reaction between compound 92 and vinylphosphonate 31a
(Scheme 41).39
242
KHIDRE and ABDOU/Turk J Chem
+
R1 = H, Me
O
PEtOEtO
N
N O
N
O
O
R1
R1
Et
PO
OEt
OEt
N
N
N
O
O
R1
R1
OEt
92
165, 21%
162, 43%31aN
N
O
O
NOHO
R1
R1
N
N O
N
O
O
R1
R1
O
PO
OEt
OEt -H2O
Alkylation
N
N
N
O
O
R1
R1
O
O P
O
OEtOEt
N
N
N
O
O
R1
R1
O
-(EtO)2PO
O
Alkylation
161
163
164
Scheme 41.
Diethyl vinylphosphonate 31a was reacted with oxime 89 to give [1,4]oxazinephosphonate 167 via
intermediate 166 (Scheme 42).38
O
PEtOOEt
N
O
PhOC
Ph P
O
OEtOEt
89 167, 70%
31a
NOHPh
O
PhO
CH2
N(O)
O
PhOC
Ph P
O
OEtOEtLiH
-H2O
166
Scheme 42.
6-Hydroxybenzo[d ][1,3]oxathiol-2-one 58 was reacted with diethyl vinylphosphonate 31a in EtONa so-
lution to furnish 1,4-benzoxathiin-2-ylphosphonate 168 in 64% yield via a cycloaddition reaction and tandem
OH-alkylation as displayed in Scheme 43.28
P(OEt)2
O
S
O
O+
HO
58 31a
EtONa/
S O
EtO
168, 64%
OMe
P(OEt)2
O
Alkylation
Scheme 43.
243
KHIDRE and ABDOU/Turk J Chem
In the same fashion, 1,4-benzoxathiin-2yl-methylphosphonate 169 was obtained from the reaction be-
tween 58 and allylphosphonate 31h (Scheme 44).28
EtONa/
AlkylationS
O
O
+
HO
58
S O
EtO
169, 66%
OMe
CH2P(OEt)2
OP(OEt)2
CH=CH2
O
P(OEt)2
CH Me
O
A B31h
Scheme 44.
Benzoxathiinphosphonates 168 and 169 showed more significant antimicrobial activity than some known
drugs ciprofloxacin and ketoconazole (standards) against a panel of representative gram-positive pathogenic
microorganisms, gram-negative microorganisms, and fungi.28
3.2.2. Oxaphosphinine, diazaphosphinine, and thiadiazine and their fused systems
Phosphonates 171 and oxaphosphinine oxides 173 were synthesized, in almost equal yields, by reaction of
5-bromo-2-acetylthiophene 170 with phosphonyl carbanion 31b,c,e in dry DMF containing LiH under reflux
temperature (Scheme 45).27 The antiinflammatory activity in vivo of compound 173 was examined at 50 mg/kg
body weight and displayed inhibitory activities, which were equivalent to that of the standard indomethacin at
100 mg/kg.27
S
Me
OBr
172 173
S
R
(EtO)2P
171
R = CO2Me, CO2Et, CN
Me
O
OHSBr
Me
R
P OEt
OEtO
SBr
Me
OEtO
P
RO
170
O
- EtOH
- HBr
31b,c,e
P RO
EtO
EtO
Scheme 45.
Enamine phosphonates 174 was reacted with nitriles to afford 1,5,2-diazaphosphine-2-oxides 175. While
highly stable hydrogen-bonded amine-dihydrodiazaphosphinine adducts 176 were synthesized either by addition
of diisopropyl amine to diazaphosphine oxide 175 or by the reaction of phosphonate 174 with nitriles in the
presence of lithium diisopropylamine (LDA) (Scheme 46).48
244
KHIDRE and ABDOU/Turk J Chem
R1
R2
PO OEt
OEt
NH2
NP
N R3R2
R1O OEt
(i-Pr)2HN
NP
N R3R2
R1O OEt
i) LDA
ii) R3CN
i) BuLiii) R3CN N
H(i- Pr) 2
671471
175
R1 = H, Me, Ph
R2 = C2F5, CF3, Ph, 2-furyl, 2-pyridyl
R3 = CF3, C2F5, C7H5, 2-furyl, 2-pyridyl
H
H
Scheme 46.
Reactions between 1,2,4-triazole-3-thiol-4-aminoarylidenes 115 and diethyl [methyl(thioalkyl)]phosphonates
methanolic sodium methoxide in the presence catalytic amount of DDQ yielded thiadiazine-2-phosphonates 177
(≈72% yield). As displayed in Scheme 47, compounds 177 were formed via elimination of the alkylthiol motif
from intermediate 176, followed by intramolecular cyclization (Scheme 47).43
+SR2P
EtOOEt
O
R1 = 4-Me2NC6H4, 4-ClC6H4; R2 = Me, Et
NN N
N R1
SHN
NN
NH R1
SH
R2S
P OEtOEt
OMeOH/MeONa
DDQ
-R2SH
-H2
NN
NNH
R1
S POEt
OEt
O
115 176 177
Scheme 47.
1,2,4-Triazole-3-thiol-4-aminoarylidenes 115 were reacted with diethyl(2-methylallyl)phosphonate 178
in MeOH/MeONa/DDQ solution to give the fused thiadiazine-5-methylphosphonates 180a,b in ≈75% yield.
According to the mechanism outlined in Scheme 48, Michael addition by imine 115 onto the isomerized ylide
form of the phosphonate reagent resulted in the formation of final products 180 via tandem loss of the H2
molecule from the initially formed intermediate 179.43
4. Conclusion
Phosphoryl carbanions (WHE) are versatile and convenient intermediates for construction of many types of
five- and six-membered heterocycles. This survey attempted to summarize the synthetic potential of phosphoryl
carbanions, as starting precursors, in the synthesis of 5- and 6-membered heterocycles since 1985.
245
KHIDRE and ABDOU/Turk J Chem
+ PEtO
OEt
O
NN N
N R1
SH
N
NN
NH R1
SH
P OEtOEt
O
MeOH/MeONa
DDQ
-2H NN
NN R1
SP
OEt
OEtO
PEtO
OEt
O
MeMe
Me
Me
115178
179180
Scheme 48.
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