Phosphorus-Containing Bis-allenes: Synthesis and Heterocyclization Reactions Mediated by Iodine or Copper Dibromide

Article abstract of DOI:10.1021/acs.orglett.7b00648

Bisphosphorylallenes were easily obtained in multigram scale from the Wittig-type rearrangement of bispropargyl alcohols. Unlike other conjugated bis-allenes, these reagents underwent a double cyclization mediated by iodine or copper dibromide leading to the formation of bis-1,2-oxaphospholenes.

Full text of DOI:10.1021/acs.orglett.7b00648

Letter
pubs.acs.org/OrgLett
Phosphorus-Containing Bis-allenes: Synthesis and Heterocyclization
Reactions Mediated by Iodine or Copper Dibromide
I. Essid,†,‡ C. Laborde,† F. Legros,† N. Sevrain,† S. Touil,‡ M. Rolland,§ T. Ayad,†,∥ J.-N. Volle,†
J.-L. Pirat,*,† and D. Virieux*,†
†Institut Charles Gerhardt, CNRS UMR 5253, Ecole Nationale Super
́
ieure de Chimie de Montpellier, 8 Rue de l’Ecole Normale, 34
de Carthage, Faculte des Sciences de Bizerte, 7021 Jarzouna,
§Institut Europee
́ ́
n des Membranes - CC047, Universite de Montpellier, 34095 Montpellier, France
296 Montpellier, France
‡Laboratoire de Chimie Organique des Het
Tunisie
́
er
́
oel
́
em
́
ents, Universite
́
́
∥PSL Research University, Chimie ParisTech-CNRS, Institut de Recherche de Chimie Paris, 11 Rue Pierre et Marie Curie, 75 005
Paris, France
S
* Supporting Information
ABSTRACT: Bisphosphorylallenes were easily obtained in
multigram scale from the Wittig-type rearrangement of
bispropargyl alcohols. Unlike other conjugated bis-allenes,
these reagents underwent a double cyclization mediated by
iodine or copper dibromide leading to the formation of bis-1,2-
oxaphospholenes.
rearrangement.7 Typical reactions of conjugated bis-
umulenes, and more specifically allenes, are versatile
Cbuilding blocks in organic synthesis, and their unique
(phosphinylallenes) obtained from the thermal rearrangement
of benzene-1,2-bis(propargyl alcohols) and chlorodiphenyl
phosphines underwent intramolecular [2 + 2] cycloaddition
leading to naphtho[b]cyclobutenes.8
The present work relates the synthesis of conjugated 1,2-
bis-phosphorylallenes9 and explores their reactivity in a double
heterocyclization process (Figure 1).
reactivity makes them particularly attractive reagents.
Although their high reactivity may have impeded the
development of efficient organic transformations, recent
years have seen the emergence of mild processes allowing
the selective modifications of allenes into valuable functional
and/or cyclic derivatives.1 These new methodologies have
thus considerably extended the synthetic organic tool box, and
allenes are even increasingly involved in cascade or tandem
reactions, metal catalyzed organic transformations, and
enantioselective reactions for the synthesis of natural product.2
Similar to Janus, allenyl derivatives bearing an electron-
withdrawing group have two faces and typically behave as
ambivalent reagents. For instance, allenyl phosphonates,
-phosphinates, or -phoshine oxides that belong to this
category present alkene functions having electrophilic and
nucleophilic character.3
Figure 1. Double heterocyclization of bisphosphonylallenes.
In contrast with monoallenes, bis-allenes remain more
rarely used. They can be divided into conjugated and
nonconjugated allenes.4 Recently, their synthesis and reactivity
have been reviewed by Hopf et al.,5 and Alcaide et al.
reported cyclization reactions of these atypical structures
specifically for the synthesis of a fused heterocyclic pattern.6
Although conjugated bis-allenes are not common, some
studies based on their reactivity have already been explored.
Most of the studies involved the intramolecular reactions
between the two unsaturated allenyl systems. For example, the
thermal cyclization of conjugated bis-allenes gave straightfor-
wardly bismethylene cyclobutenes through a Cope-type
1,2-Bisphosphorylallenes 2 were readily obtained in two
steps from terminal propargyl alcohols. The first step involved
the synthesis of diyne-diols 1 from Glaser−Hay coupling
mediated by copper and nickel salts in the presence of air
(Scheme 1).10 The reactions proceeded smoothly and
furnished both symmetrical and unsymmetrical diyne-diols 1
in 62−88% yields comparable with those of the literature. In
Received: March 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00648
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Letter
react independently are quite scarce in literature, particularly
for conjugated bis(allenes).4−6 Bisphosphonylallenes 2a−h
were subjected to electrophilic cyclization mediated by the
addition of iodine in chloroform at 110 °C in a sealed tube.12
It appeared that a double reaction occurred and two products
were observed by 31P NMR in almost equal proportions (two
singlets in 31P NMR). At this stage, the main hypothesis was
that the reaction proceeded through the possible formation of
bis(iodooxaphospholenes) 3 and oxaphosphinine dioxides 4
(Scheme 2). Nevertheless, the ambiguity was easily resolved
Scheme 1. Synthesis of Bisphosphonylallenes 2a−j from
Diyne-diols 1a−h
Scheme 2. Cyclization of Bis-allenylphosphonates 2
Promoted by Iodine, and C2-Symmetric and Meso
Representation of Bisoxaphospholenes 3 (R1 = R2)
the second step, diyne-diols 1a−1h were reacted with either
diethyl chlorophosphite or chlorodiphenylphosphine to give
the bis-allenylphosphonates 2a−2h and bis-allenylphosphine
oxides 2i−j in multigram scales in yields up to 99% (Table
1).11
Table 1. Yields of Diynes 1a−h and Bis-allenes 2a−j
by deprotection of the ethyl phosphonic ester functions.
Indeed, the cleavage of the ethyl group using trimethylsilyl
bromide resulted in the formation of only one product,
thereby confirming the presence of one type of heterocyclic
linkage.13 In terms of mechanism, the formation of bis(oxa-
phospholenes) 3 was suspected rather than oxaphosphinines
4. Although both types of compounds could be formed, the
formation of the six-membered ring compound 4 and the
a
Isolated yields.
2
attack of the phosphoryl directly on the Csp carbon of the
The reactions readily proceeded at low temperature in the
presence of triethylamine as a base to give first the trivalent
phosphorus ester. The latter spontaneously rearranged as the
temperature rose to room temperature. It can be noted that
cyclopropyl diyne 1c failed to give the desired bis-allene 2c
core cleanly. A complex mixture of phosphorus compounds
was observed as the probable result of cyclopropyl ring
opening. By contrast, the reaction worked well with
cyclopentyl- and cyclohexyl diynes 1d and 1e. Even
dibenzosuberenyl substituted diyne 1h afforded the expected
bis-allene 2h in 61% isolated yield.
The reaction proceeded efficiently from dichlorophenyl-
phosphine giving the bis-allenyl diphosphine dioxides 2i−j in
80% to 71% yields.
With the bis-allenylphosphonates 2a−h in hand, their
behavior in electrophilic cyclization was studied. To the best
of our knowledge, the reactions where two allenyl systems
iodonium intermediate 5 (red arrows) are clearly less
favorable (Scheme 2). Therefore, the two singlets observed
by 31P NMR can readily be explained by the presence of two
stereogenic phosphorus atoms illustrated by the C2-symmetric
and meso-bisoxaphospholenes 3 (Scheme 2).
The cyclization reaction was then extended to other bis-
allenes 2a−h, thus affording bisoxaphospholenes 3a, 3d, and
3e in 37% to 68% isolated yields. Unfortunately, the reaction
of dibenzosuberenyl allene 2h failed to give cleanly the
bisoxaphospholene core. In this case, it is plausible that a
concurrent addition of iodine to the alkene moiety of the
dibenzosuberenyl group preferentially took place during the
reaction (Table 2).
Similarly, a cyclization mediated by cupric bromide
originally developed by Ma et al. for the synthesis of
bromo-oxaphospholenes has been studied.14 These reactions
were conducted in ethanol at 50 °C in the presence of an
B
DOI: 10.1021/acs.orglett.7b00648
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
orientations of oxaphospholene rings. Steric or electronic
repulsions appeared sufficient to ensure configurational
stability in solid form. By contrast, in solution, no apparent
Table 2. Diiodo- and Dibromobisoxaphospholenes 3 and 6
a
b
compd
R1
Me
R2
Me
X
diastereomeric ratio
yield (%)
1
diastereotopicity was observed in the 13C or H NMR of
3a
3d
3e
6a
6b
6d
6e
6f
I
62/38
53/47
53/47
64/36
92/8
68
37
60
78
63
53
58
49
42
(CH2)4
(CH2)5
Me
(CH2)4
(CH2)5
Me
I
potential diastereotopic groups or for the other bisoxaphos-
pholenes 3 and 6.
Electrophilic cyclization was also attempted from bis-allenyl
phosphine oxide 2i (Scheme 4). The purpose of this reaction
I
Br
Br
Br
Br
Br
Br
Et
Et
(CH2)4
(CH2)5
Ph
(CH2)4
(CH2)5
Ph
64/36
69/31
100/0
Scheme 4. Proposed Mechanism for the Reaction of Bis-
allene 2i with PTSA
6g
Ph
Me
93/7
a
b
Determined by 31P NMR experiments. Isolated yields.
excess of CuBr2, and the formation of dibromo-bisoxa-
phospholenes 6a−b and 6d−g were observed and isolated
in a range of 42−78% yield (Scheme 3 and Table 2).
Scheme 3. Cyclization of Bis-allenylphosphonates 2
Promoted by CuBr2
The nature of the substituents R1 or R2 had a decisive
influence on the diastereoselectivity of the reaction mediated
by CuBr2. When R1 and R2 were methyl, cyclopentyl, or
cyclohexyl groups, the reaction produced the bis 4-bromo-
oxaphospholenes 6 with moderate diastereoselectivities,
whereas phenyl or ethyl substituents furnished high
diastereomeric ratios of 100/0 and 92/8, respectively. In the
case of a phenyl group, a unique diastereoisomer 6f was
confirmed by the presence of one singlet in 31P NMR and by
the explicit 1H and 13C NMR spectra. Similarly, mixed
derivative 6g (Ph and Me substituents) was obtained in 93/7
diastereomeric ratio.
The presence of the oxaphospholene core was definitively
confirmed by an X-ray diffraction experiment on dibromo-
oxaphospholene 6f-OH (Figure 3).15 The compound 6f-OH
crystallized in an orthorhombic Pcca centro-symmetric space
group. The packing diagram indicated that, at solid state,
bisoxaphospholene 6f-OH presented fixed conformational
was the synthesis of bis(benzophosphinene) dioxide 7
through an intramolecular SEAr trapping of the tertiary
carbocation 9. Both Lewis and Bronsted acid activations were
̈
attempted. However, no reaction was observed with Lewis
acids such as boron trifluoride etherate, silver nitrate, bismuth
trichloride, mercury acetate, or iron trifluoromethylsulfonate at
temperatures ranging from room temperature to 100 °C. Even
dry para-toluene sulfonic acid (PTSA) gave no reaction. By
contrast, the presence of water drastically changed the nature
of the expected product when PTSA was used in dichloro-
methane in a sealed tube, giving diphosphine dioxide 8 in
52% isolated yield.
In light of the structure of the final product 8, a plausible
mechanism was proposed (Scheme 4). As expected, the first
step is consistent with the formation of the tertiary
carbocation 9. The lack of reactivity observed for the phenyl
moiety prevented the Friedel−Crafts cyclization. Surprisingly,
no reaction was observed with the second allenyl group. The
carbocation is then trapped by water giving the alcohol 10. An
oxa-Michael addition occurred through a Bronsted acid
̈
activation of the phosphoryl group leading to the diphosphine
dioxide 8 after isomerization of the exocyclic alkene bond.
In conclusion, bisphosphonylallenes 2 were easily synthe-
sized from diyne diols 1. The behavior of such reagents when
they were engaged in polar cyclization using iodine or cupric
bromide proved to be original compared to other conjugated
bis-allenes. Specifically, the two allenyl systems reacted
independently creating four bonds in a single step and giving
bis(oxaphospholene) halides 3 and 6. Further, these original
structures could be investigated for their reactivity and their
unusual features, particularly for the formation of atropochiral
bis(phosphonic acids).
Figure 3. X-ray representation of dibromo-bisoxaphospholene 6f-
OH.
C
DOI: 10.1021/acs.orglett.7b00648
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00648.
■
S
Crystallographic data for 6f-OH (CIF)
Experimental details; NMR data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jean-luc.pirat@enscm.fr.
*E-mail: david.virieux@enscm.fr.
ORCID
D. Virieux: 0000-0002-6495-9478
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the French Ministry of Higher Education
and Scientific Research and the Tunisian Ministry of Higher
Education and Scientific Research for funding of this work.
́
Iwasawa, H.; Shibuya, S. Heterocycles 1997, 46, 463. (g) Andre, V.;
Lahrache, H.; Robin, S.; Rousseau, G. Tetrahedron 2007, 63, 10059.
(h) Huang, J.; Wang, H.; Peng, A.-Y. Eur. J. Org. Chem. 2014, 2014,
8126.
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