One-Pot Benzo[b]phosphole Synthesis through Sequential Alkyne Arylmagnesiation, Electrophilic Trapping, and Intramolecular Phospha-Friedel-Crafts Cyclization

Article abstract of DOI:10.1021/acs.orglett.5b02950

A one-pot multicomponent synthesis of a benzo[b]phosphole derivative has been achieved by a sequence of transition-metal-catalyzed arylmagnesiation of an internal alkyne, electrophilic trapping of the resulting alkenylmagnesium species with a dichloroorganophosphine, and an intramolecular phospha-Friedel-Crafts reaction. With appropriate arylmagnesiation and P-C bond formation conditions, the present method allows for the modular and expedient preparation of benzophospholes bearing a variety of substituents on the phosphorus atom, the C2 and C3 atoms, and the benzo moiety.

Full text of DOI:10.1021/acs.orglett.5b02950

Letter
pubs.acs.org/OrgLett
One-Pot Benzo[b]phosphole Synthesis through Sequential Alkyne
Arylmagnesiation, Electrophilic Trapping, and Intramolecular
Phospha-Friedel−Crafts Cyclization
Bin Wu, Rena Chopra, and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: A one-pot multicomponent synthesis of a
benzo[b]phosphole derivative has been achieved by a
sequence of transition-metal-catalyzed arylmagnesiation of an
internal alkyne, electrophilic trapping of the resulting
alkenylmagnesium species with a dichloroorganophosphine,
and an intramolecular phospha-Friedel−Crafts reaction. With
appropriate arylmagnesiation and P−C bond formation
conditions, the present method allows for the modular and
expedient preparation of benzophospholes bearing a variety of substituents on the phosphorus atom, the C2 and C3 atoms, and
the “benzo” moiety.
Scheme 1. Multicomponent Benzophosphole Synthesis
Initiated by (Migratory) Arylmetalation of Alkyne
enzo[b]phosphole derivatives have garnered considerable
interest for their semiconducting, fluorescent, and
B
coordinating properties, which hold promise for application
in various areas such as organic electronics, bioimaging,
coordination chemistry, and catalysis.1 While the synthesis of
this class of compounds has been occasionally reported since
the late 1960s,2 recent years have witnessed the development of
new efficient synthetic approaches. For example, approaches
based on the intramolecular cyclization of alkynylarenes bearing
o-phosphorus substituents have been developed,3 and the thus-
synthesized benzophosphole derivatives have been demon-
strated to serve as n-type semiconducting materials for organic
light-emitting devices4 or environment-sensitive fluorescent
bioimaging probes.5 These and other studies illustrate the
importance of the ability to flexibly modify peripheral
substituents of the benzophosphole core and thus to tune its
structural and electronic properties for desired applications.6−8
Besides the intramolecular cyclization approaches, a highly
atom-economical benzophosphole synthesis involving oxidative
annulation of secondary phosphine oxides and internal alkynes
has been developed.9 More recently, our group has developed
the one-pot construction of benzophospholes from arylzinc
reagents, alkynes, and chlorophosphines,10 capitalizing on
cobalt-catalyzed migratory arylzincation as the key step
(Scheme 1a).11
unsymmetrical diarylphosphine oxide is used as the starting
material. Our multicomponent approach is limited with respect
to the scope of alkynes.10 Because of the intrinsic limitation of
the migratory arylzincation,11 the method does not allow access
to valuable 2,3-diarylbenzophosphole motifs.4,5
Each of the above-mentioned approaches, however, has a
significant limitation. The intramolecular cyclization approaches
require multistep preparation of the cyclization precursors and
thus are not suitable for the rapid generation of various
substituted benzophospholes.3 The oxidative annulation suffers
from randomization of the regiochemistry of the “benzo”
moiety due to a mechanism involving a spirocyclic
intermediate.9 The problem becomes even worse when an
Herein we report that a transition-metal-catalyzed arylmag-
nesiation reaction of an alkyne12,13 can be integrated into a
Received: October 12, 2015
© XXXX American Chemical Society
A
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Letter
modular multicomponent protocol for benzophosphole syn-
thesis. The arylmagnesiation is followed by electrophilic
trapping of the resulting cis-β-styrylmagnesium species with a
dichloroorganophosphine and a subsequent intramolecular
phospha-Friedel−Crafts (PFC) reaction,14 thereby affording a
benzophosphole derivative in a one-pot operation (Scheme
1b). The new method has resolved some of the above
limitations and significantly broadens the scope of accessible
benzophospholes. The migratory arylzincation and the present
arylmagnesiation approaches enable the preparation of alkoxy-
substituted benzophospholes with complementary positional
selectivities. The utility of the present benzophosphole
synthesis is also demonstrated by the facile preparation of a
precursor to 5,6-benzophospholyne and exploration of its
reactivity.
Scheme 2. Benzophosphole Synthesis Initiated by Ni-
Catalyzed Alkyne Arylmagnesiation
a
To achieve the present benzophosphole synthesis, we
employed the Ni-catalyzed alkyne arylmagnesiation reaction
developed by Xue, Zhao, and Hor13d as the first step because it
presents several advantages, including broad applicability to
diarylalkynes, simplicity of the catalytic system, and near
stoichiometric ratio of the arylmagnesium reagent and the
alkyne. With careful optimization of the arylmagnesiation and
C−P bond formation steps, we were able to establish a protocol
for the desired multicomponent coupling (Scheme 2; see the
Supporting Information for the optimization study). The
addition of 4-methoxyphenylmagnesium bromide (1a) (1.2
equiv) to diphenylacetylene (2a) (1 equiv) in the presence of
NiCl2 (5 mol %) at 60 °C was followed by the reaction of the
resulting alkenylmagnesium species with CuCN·2LiCl (30 mol
%) and dichlorophenylphosphine (2.5 equiv) to afford, upon
oxidation with H2O2, the desired benzophosphole oxide 3aaa in
a respectable isolated yield of 61% (protocol A). Unlike
literature precedents on intramolecular PFC reactions,14c−e the
addition of a Lewis acid such as AlCl3 or ZnCl2 was not
necessary, presumably because the magnesium salt derived
from the Grignard reagent itself served as a Lewis acid.
A variety of para-substituted aryl Grignard reagents
participated in the coupling reaction with diphenylacetylene
and PhPCl2 to afford the corresponding 6-substituted
benzophosphole derivatives 3aaa−3gaa in 38−68% yield. The
reaction of m-tolylmagnesium bromide afforded a mixture of 5-
methyl- and 7-methylbenzophosphole derivatives 3haa and
3haa′ in a ca. 1:1 ratio as a result of non-regioselective PFC
cyclization. By contrast, the PFC step in the reaction of 3,4-
methylenedioxyphenylmagnesium bromide took place with
exclusive regioselectivity, furnishing the 5,6-disubstituted
product 3iaa in 41% yield. o-Methoxyphenylmagnesium
bromide was also amenable to the present method, affording
the desired 4-methoxybenzophosphole 3jaa, albeit in a modest
yield. As expected from the scope of the Ni-catalyzed
arylmagnesiation,13d a series of diarylalkynes participated in
the coupling with 4-methoxyphenyl or 4-trimethylsilylphenyl
Grignard reagent to afford the corresponding benzophosphole
oxides 3aba−3aha in ca. 50−60% yield. Besides the diary-
lalkynes, a bis(2-thienyl)alkyne could also be incorporated into
a benzophosphole product (see 3aia). The reaction of
aryl(alkyl)alkynes regioselectively afforded 2-aryl-3-alkylbenzo-
phosphole derivatives 3aja−3ala, albeit in somewhat lower
yields.
a
The reactions were performed using 0.6 mmol of 1 and 0.5 mmol of
b
2. The benzophosphole product was oxidized using sulfur powder
instead of H2O2.
exclusive regioselectivity (Scheme 3). This regioselectivity is
particularly notable in comparison with the complementary
regioselectivity achieved with our previous protocol based on
the migratory arylzincation (Scheme 1a).10 With that protocol,
the reaction of the 3,4-methylenedioxyphenylzinc reagent and
2j resulted in exclusive formation of 6,7-methylenedioxybenzo-
phosphole 3ija′ as a result of regioselective 1,4-cobalt migration
to the proximity of the ether moiety.
A modification of protocol A allows variation of the P
substituent of the benzophosphole. Thus, using the dichlor-
oorganophosphine generated in situ from PCl3 and an
organozinc reagent instead of PhPCl2 enabled the synthesis
of benzophospholes bearing different P-aryl and -alkyl
substituents in moderate yields (Table 1).
As expected from the regiochemistry of 3iaa, the reaction of
3,4-methylenedioxyphenyl Grignard reagent 1i and 1-phenyl-1-
butyne (2j) with protocol A afforded the 5,6-methylenediox-
ybenzophosphole derivative 3ija in a modest yield with
B
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Scheme 3. Complementary Regioselectivities of
Benzophosphole Syntheses from 3,4-
Methylenedioxyphenylmetal Reagents
Scheme 5. Generation of and Nucleophilic Additions to 5,6-
Benzophospholyne
a
Table 1. Variation of the P Substituent
a
B3LYP/6-31G(d)-optimized structure (phenyl groups at the 1-, 2-,
and 3-positions have been omitted for clarity).
entry
R
product
yield (%)
1
2
3
4
4-MeOC6H4
4-Me2NC6H4
4-FC6H4
i-Pr
3aab
3aac
3aad
3aae
47
51
47
54
structure and reactivity of indolynes and other arynes,15 we
examined the structure of the 5,6-benzophospholyne species 5
to be generated from precursor 4 by a DFT calculation
(B3LYP/6-31G(d)). The internal angles of the CC termini
of 5 are very similar (θCCC = 128 and 127°), and there is only a
small difference in the NPA charges at C5 (+0.04) and C6
(+0.03). These features suggest similar electrophilicities of the
C5 and C6 positions. In line with this prediction, the addition
of a nucleophile such as p-cresol or p-anisidine to 4 in the
presence of CsF resulted in the formation of a nearly equimolar
mixture of regioisomeric adducts 6 and 7 (Scheme 5b).
5,6-Benzophospholyne 5 was amenable to a series of
cycloaddition reactions (Scheme 6). The Diels−Alder reaction
with furan proceeded efficiently to afford cycloadduct 8 in 81%
yield (Scheme 6). Likewise, the reaction with anthracene
furnished phosphole-embedded triptycene 9 in 63% yield.
a
The reactions were performed using 0.6 mmol of 1a and 0.5 mmol of
2a.
Besides the Ni-catalyzed reaction, other transition-metal-
catalyzed arylmagnesiations can also be integrated into the
present approach for benzophosphole synthesis. For example,
the Cr-catalyzed arylmagnesation using p-tolyl Grignard reagent
1c and 5-decyne (2m) developed by Yorimitsu and Oshima13c
enabled the one-pot preparation of 2,3-dibutylbenzophosphole
derivative 3cma, albeit in a modest yield (Scheme 4). Such an
alternative protocol would complement the Ni-catalyzed
protocols because the Ni-catalyzed arylmagnesiation is not
applicable to dialkylalkynes.13d
Scheme 6. Cycloaddition Reactions of 5,6-
Benzophospholyne
Scheme 4. Benzophosphole Synthesis Employing Cr-
Catalyzed Arylmagnesiation
In comparison with existing approaches such as intra-
molecular cyclization,3 the present benzophosphole synthesis
enables facile preparation of benzophospholes variously
substituted on the “benzo” moiety. We exploited this advantage
to explore the reactivity of hitherto unknown 5,6-benzophos-
pholyne species (Scheme 5). The silyl triflate precursor 4 was
prepared by assembly of 3-trimethylsilyl-4-benzyloxyphenyl
Grignard reagent 1k and diphenylacetylene (2a) according to
protocol A followed by deprotection of the benzyl group and
triflation. Guided by the studies of Garg and Houk on the
C
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Letter
(h) Cordaro, J. G.; Stein, D.; Grutzmacher, H. J. Am. Chem. Soc.
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Furthermore, Pd-catalyzed annulation of 5 and 2-iodobiphen-
yl16 afforded phosphole-embedded triphenylene 10, the planar
structure of which was confirmed by X-ray crystallographic
analysis.
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In conclusion, we have developed a one-pot multicomponent
method for the construction of benzophosphole derivatives
through the integration of transition-metal-catalyzed arylmag-
nesiation of an alkyne, trapping of the resulting alkenylmagne-
sium species with dichloroorganophosphine, and intramolecular
phospha-Friedel−Crafts cyclization. The method allows for the
streamlined and expeditious preparation of benzophospholes
with various substituents on the P atom, the C2 and C3 atoms,
and the benzo moiety, complementing the scope of our
previous method based on the cobalt-catalyzed migratory
arylzincation reaction. The flexibility of the present method
with respect to the substitution pattern of the benzo moiety
enabled facile access to 5,6-benzophospholyne. We anticipate
that the present method will also pave the way for the
investigation of hitherto unknown 4,5- and 6,7-benzophospho-
lynes and thus allow for the synthesis of various polycyclic
aromatic systems featuring benzophosphole moieties.7c,8
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02950.
(9) (a) Unoh, Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int.
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2013, 135, 16754.
(10) Wu, B.; Santra, M.; Yoshikai, N. Angew. Chem., Int. Ed. 2014, 53,
7543.
Experimental procedures and characterization data for
new compounds (PDF)
Crystallographic data for 10 (CIF)
(11) Tan, B.-H.; Dong, J.; Yoshikai, N. Angew. Chem., Int. Ed. 2012,
51, 9610.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nyoshikai@ntu.edu.sg.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Nanyang Technological
University. We thank Drs. Yongxin Li and Rakesh Ganguly
(Nanyang Technological University) for assistance with the X-
ray crystallographic analysis.
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DOI: 10.1021/acs.orglett.5b02950
Org. Lett. XXXX, XXX, XXX−XXX