Synthesis of 2-phosphonoheterocycles via base-promoted 5-endo cyclization

Article abstract of DOI:10.1016/j.tetlet.2020.152742

Herein, a synthesis of 2-phosphonodihydrofurans and 2-phosphonodihydropyrroles via 5-endo cyclization of O-and N-propargylated compounds is described. The reaction is promoted by potassium tert-butoxide and allows a fast access to interesting heterocycles which were easily converted into 2-arylated pyrroles under acidic conditions.

Full text of DOI:10.1016/j.tetlet.2020.152742

Tetrahedron Letters 64 (2021) 152742
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2-phosphonoheterocycles via base-promoted 5-endo
cyclization
Ameni Bousbia a, Mohamed Lamine Benkhoud a, Laurent El-Kaïm b, Sébastien Prévost b,
⇑
a Laboratory of Physico-chemistry of Microstructures and Microsystems, Preparatory Institute for Scientific and Technical Studies, University of Carthage, BP51, 2078 La Marsa, Tunisia
b Laboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA, UMR 7652, Institut Polytechnique de Paris, 91128 Palaiseau, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, a synthesis of 2-phosphonodihydrofurans and 2-phosphonodihydropyrroles via 5-endo cycliza-
tion of O-and N-propargylated compounds is described. The reaction is promoted by potassium tert-
butoxide and allows a fast access to interesting heterocycles which were easily converted into 2-arylated
pyrroles under acidic conditions.
Received 7 October 2020
Revised 30 November 2020
Accepted 4 December 2020
Available online 29 December 2020
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
5-Endo cyclization
Dihydrofurans
Dihydropyrroles
Phopshonates
Alkynes
Introduction
phono-2,5-dihydrofurans (Scheme 1.b) [8]. Another method to
obtain phosphonodihydropyrroles was based on a metal-catalyzed
Heterocyclic phosphonates have attracted considerable atten-
tion for many years, especially due to their remarkable activities
[1]. For instance, phosphonopyrrolidine 1 (Fig. 1) is known to exhi-
bit bactericidal, fungicidal and herbicidal activities whereas phos-
cycloisomerization of (hydroxy)allenes (Scheme 1.c) [9]. By exam-
ining the literature examples, no easy and general method has
been reported. The starting material synthesis often required sev-
eral steps whereas the scope of the reaction is relatively limited.
Concerning the formation of dihydrofurans or dihydropyrroles,
we and other groups have explored the potential of alkyne in var-
ious 5-endo-dig cyclization strategies [10]. Indeed, in 2012, the
group of Miranda first reported a synthesis of 2,3-dihydropyrroles
from N-propargyl Ugi adducts whereas we recently developed a
phonotetrahydrofuran
2 has shown important HCMV and
antitumor activities [2]. In addition, the phosphonate group can
mimic the carboxylic moiety found in some biologically active sug-
ars such as the sialic acids [3]. On the other hand, heterocyclic
phosphonates could be important synthetic intermediates as
shown by isoindolinone 3 which may be used for the synthesis
of important biologically active alkaloids (Fig. 1) [4].
For all these reasons, several research groups turned their atten-
tion to the development of new synthesis of heterocyclic phospho-
nates. Concerning dihydropyrroles and dihydrofurans, several
approaches were developed [5]. Ring-closure metathesis, which
is a classical method to obtain this kind of heterocycles [6], was
applied to the synthesis of 2-phosphono-2,5-dihydropyrroles
(Scheme 1.a) as well as dihydrofurans [7]. Except this ruthe-
nium-catalyzed transformation, only few methods were developed
for the synthesis of 2-phosphonodihydropyrroles or dihydrofurans.
Recently, the group of Touil developed a base-promoted reaction
between 1,4-diones and dialkyl phosphites to obtain 2-phos-
2,5-dihydrofuran synthesis via
a 5-endo-dig cyclization of
O-propargyl mandelic acid amides induced by potassium
tert-butoxide (Scheme 1.d). Based on these results, we were keen
to develop a 5-endo-dig cyclization reaction to get a direct access
to 2-phosphonodihydropyrroles and 2-phosphonodihydrofurans
(Scheme 1.e).
Results and discussion
At the outset, we focused our attention on the synthesis of 2-
phosphonodihydrofurans. For that, several O-propargylated start-
ing materials 7a-e were synthesized through an alcohol insertion
into diazo group strategy (Scheme 2) [11]. Starting from acyl chlo-
rides 4a-e, different a-keto phosphonates 5a-e were obtained and
directly transformed into corresponding diazo phosphonates 6a-e.
Finally, an acid-catalyzed insertion of propargylic alcohol delivered
⇑
Corresponding author.
E-mail address: sebastien.prevost@ensta-paris.fr (S. Prévost).
https://doi.org/10.1016/j.tetlet.2020.152742
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

A. Bousbia, Mohamed Lamine Benkhoud, L. El-Kaïm et al.
Tetrahedron Letters 64 (2021) 152742
Table 1
O
HN
N
Scope of the dihydrofuran synthesis.a
HO2C
P(OH)2
O
N
HOHN
P(OH)2
O
N
H
O
N
O
P(OMe)2
O
N
O
H2N
Bn
1
2
3
bactericidal, fungicidal
and herbicidal activities
HCMV and antitumor
activities
Entry
1
Ar (SM)
Me
8a-eb
80a-eb
Fig. 1. Selected valuable 2-phosphonoheterocycles.
49%
8%
(
7a)
2
3
4
5
50%
57%
15%
36%
–
F
(
7b)
a) Synthesis of 2-phosphono-2,5-dihydropyrroles via RCM:
–
(7c)
7d)
MeO
[Ru] cat
45%
–
BnN
BnN
R2
Ph
(
R2
P(OMe)2
R1
P(OMe)2
O
Me
O
R1 = Me or Ph
(7e)
R
2 = H, Ph or alkyl
b) Base-promoted synthesis of 2-phosphono-2,5-dihydrofurans
a
Reactions were carried out with substrate 7 (0.5 mmol) and tBuOK (1.5 mmol,
1.5 eq.) in CH3CN (2 mL).
Ph
b
HO
O
Isolated yields.
Ph
O
Ph
K2CO3
O
Ph
P(OR1)2
Ar
H
O
Ar
P
O
R1 = Me or Et
When alkyne 7a, with a para-methylbenzene substituent, was sub-
mitted to the conditions, a mixture of 2,3-dihydrofuran 8a (49%
yield) and 2,5-dihydrofuran 80a (8% yield) was obtained (Table 1,
entry 1). Different para substituted compounds were tested under
the reaction conditions and, when the aromatic moiety was func-
tionalized with a fluorine or a methoxy group, 2,3-dihydrofurans
8b (50% yield) and 8c (57% yield) were isolated as the only product
(Table 1, entry 2 and 3). However, alkyne 7d with a phenyl group in
para position delivered a mixture of regioisomers in favor of 2,5-
dihydrofuran 80d (Table 1, entry 4). Finally, meta-methylsubsti-
tuted 2,3-dihydrofuran 8e was synthesized despite a slightly lower
yield (Table 1, entry 5, 36% yield).
In order to explain the formation of the two observed dihydro-
furan regioisomers, two possible pathways are proposed in scheme
3. 2,5-Dihydrofuran 80 may result on the direct attack of the depro-
tonated form of 7 onto the alkyne moiety. Indeed, after deprotona-
tion, A may cyclize in a 5-endo-dig fashion to form anion B which,
after reprotonation, delivers the 2,5-dihydrofuran scaffold. How-
ever, the alkyne moiety may first isomerize into allene C which
would be then deprotonated. A 5-endo-trig cyclization of D, fol-
lowed by reprotonation, would explain the formation of 2,3-dihy-
drofuran 8.
(OR1)2
c) Synthesis of 2-phosphono-2,5-dihydrofurans via cycloisomerization
R1
Ph
R
R
AgNO3
O
P
R1
(MeO)2P
O
O
HO
Ph
(OMe)2
R = Me or Ph
R1 = H, Me or Ph
d) Previous works on 5-endo-dig cyclization:
X
X
tBuOK
X = NP (Miranda's work)
X = O (our work)
NHR
Ar
Ar
O
NHR
O
e) This work:
X
X
X
base
or
Ar
P(OR)2
O
Ar
O
Ar
P(OR)2
P(OR)2
O
X = O, NPg
Scheme 1. Synthesis of 2-phosphonodihydropyrroles and dihydrofurans.
After having synthesized 2-phosphonodihydrofurans, we were
keen to extend the reaction to nitrogenated substrates. In this
objective in mind, N-propargylated imines 11a-f were synthesized
from several aldehydes 9a-f via
(scheme 4). After a benzyl protection, desired nitrogenated starting
materials 12a-f were obtained in good overall yields.
For the cyclization, the former conditions were applied to
propargyl 12a but 2,5-dihydropyrrole 13a was isolated in a poor
a Kabachnik-Fields reaction
OH
a) TsNHNH2, HCl
THF, r.t.
O
N2
O
P(OiPr)3
BF3.OEt2
Et2O, r.t.
OiPr
OiPr
O
OiPr
P
OiPr
O
O
Ar
P
Ar
OiPr
P
OiPr
O
r.t.
b) Na2CO3
iPrOH/EtO2
50 °C
Ar
Cl
Ar
4a-e
5a-e
6a-e
7a-e
4
Yields from = 23-58%
Scheme 2. Synthesis of O-propargylated starting materials.
expected O-propargylated starting materials 7a-e in good overall
yields [12].
Then, based on our former results on 5-endo-dig cyclization
[10c], phosphonoalkynes 7 were treated with 1.5 equivalent of
potassium tert-butoxide in acetonitrile (Table 1). Reactions were
carried out on diisopropyl phosphonate compounds which are
more tolerant of basic conditions than less hindered phosphonates.
Scheme 3. Involved mechanism for the synthesis of the two regioisomers.
2

A. Bousbia, Mohamed Lamine Benkhoud, L. El-Kaïm et al.
Tetrahedron Letters 64 (2021) 152742
Scheme 4. Synthesis of N-propargylated starting materials.
9% yield (Table 2, entry 1). Moreover, a significant amount of
depropargylation of starting material 12a was observed during
the reaction. Taking into account literature precedents [10a], THF
was used as solvent and, with 2.5 equivalents of potassium tert-
butoxide, a 12% yield of 13a was observed at room temperature
(Table 2, entry 3) and a 32% yield was obtained at 50 °C whereas
no depropargylation was observed at this temperature (Table 2,
entry 4). Finally, more polar solvents were tested and dihydropy-
rrole 13a was isolated in 42% yield when DMSO was used as sol-
vent (Table 2, entry 6).
We next investigated the scope of the reaction using these new
conditions (Scheme 5). Different propargyl 12 were engaged in the
cyclization reaction and, in all cases, 2,5-dihydropyrroles 13 were
obtained as only regioisomers. 2,5-Dihydropyrroles 13a and 13b,
bearing a para-halogenated aromatic group, were isolated in mod-
erate yields (42% and 13% respectively). Then, when the aromatic
moiety was substituted with a phenyl or methyl group in para
position, the cyclization reaction was carried out with DMF as sol-
vent and desired dihydropyrroles 13c-d were obtained in low to
moderate yields (54% and 16% respectively). Contrary to dihydrofu-
ran synthesis, no desired cyclized product was observed with a
methoxy group in para position. Very interestingly, 2,5-dihydropy-
rrole 13f, bearing a meta-substituted aromatic group, was isolated
in a good 62% yield.
Scheme 5. Scope of the dihydropyrrole synthesis[a,b]. aReactions were run on
0.5 mmol scale. bIsolated yields. cDMF was used as solvent.
With this straightforward approach to dihydropyrroles in hand,
we envisioned that the interest of the method could be raised by
allowing reaching pyrroles from the same starting materials. Pyr-
role is a very important heteroaromatic scaffold in chemistry due
to its interesting properties in biology and material chemistry
[13]. Its aromatic nature together with the leaving group ability
of the phosphonyl moiety were in strong support for this potential
transformation. Indeed, under acidic conditions (1 equivalent of
pTSA in dichloromethane) 2-phosphonodihydropyrroles 13a-f
underwent phosphorus elimination at room temperature to deliver
corresponding pyrroles 14a-f in very good yields (Scheme 6, 65 to
94% yields).
Scheme 6. 2-Arylated pyrrole synthesis[a]. aIsolated yields.
Conclusion
In summary, we have developed a short synthesis of 2-phos-
phonodihydrofurans and pyrroles via a base-promoted 5-endo
cyclization. Despite moderate yields, this method offers an easy
access to a wide range of phosphono heterocycles which, in the
case of dihydrofurans, represent very important sugar analogues.
In addition, the phosphonate group could be easily eliminated
under acidic conditions to deliver 2-arylated pyrroles. Further
explorations of 5-endo-dig cyclizations are currently in progress
in our group.
Table 2
Optimization of the 5-endo-dig cyclization on the nitrogenated propargyl compound.a
BnN
NBn
tBuOK (eq.)
OiPr
OiPr
OiPr
OiPr
P
O
P
O
solvent
T °C, 20 h
Cl
Cl
12a
13a
Declaration of Competing Interest
Entry
tBuOK (eq.)
solvent
T (°C)
Yieldb (%)
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
1
2
3
4
5
6
1.5
1.5
2.5
2.5
2.5
2.5
CH3CN
THF
THF
THF
DMF
DMSO
50
r.t.
r.t.
50
50
50
9[c]
0
12c
32
28
42
Acknowledgments
a
b
c
Ms Vanessa Chen and Ms Farah Taieb-Tamacha are thanked for
their assistance. The authors gratefully acknowledge the Ministry
of Higher Education and Scientific Research of Tunisia (MHESR)
Reactions were carried out with substrate 12a (0.5 mmol) in 2 mL of solvent.
Isolated yields.
Formation of a depropargylated side-product.
3

A. Bousbia, Mohamed Lamine Benkhoud, L. El-Kaïm et al.
Tetrahedron Letters 64 (2021) 152742
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