Synthesis of Dibenzophospholes by Tf2O-Mediated Intramolecular Phospha-Friedel-Crafts-Type Reaction

Article abstract of DOI:10.1021/acs.orglett.9b00219

A Tf₂O-mediated intramolecular phospha-Friedel-Crafts-type reaction of secondary biarylphosphine oxides has been developed. The reaction is promoted simply by Tf₂O to form the corresponding dibenzophospholes under metal-free conditio

Full text of DOI:10.1021/acs.orglett.9b00219

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Dibenzophospholes by Tf2O‑Mediated Intramolecular
Phospha-Friedel−Crafts-Type Reaction
Kazutoshi Nishimura, Koji Hirano,* and Masahiro Miura*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: A Tf2O-mediated intramolecular phospha-
Friedel−Crafts-type reaction of secondary biarylphosphine
oxides has been developed. The reaction is promoted simply
by Tf2O to form the corresponding dibenzophospholes under
metal-free conditions. The starting substrates are readily
available and easy-to-handle phosphine oxides, and the
regioselectivity is controlled by the innate electronic nature.
Thus, this newly developed protocol can provide concise and complementary approach to the highly π-conjugated
dibenzophospholes of potent interest in material chemistry.
direct couplings. However, its synthetic potential has not been
dibenzophosphole is a key motif in the design of
1
Aphosphorus-containing functional organic materials. studied well: only a few examples were reported by using
biarylphosphinic acid substrates and excess PCl5 under harsh
conditions (refluxed PhNO2 solvent), and the regioselectivity
in the reaction was also not mentioned.8 Thus, there still
remains a large demand for development of the dibenzophosp-
hole synthesis via intramolecular PFC reaction.
Accordingly, considerable attention has been focusing on the
rapid and concise synthesis of the dibenzophosphole frame-
work. Although the conventional synthetic procedures required
tedious and multistep sequences with complicated and
unstable starting substrates and/or reagents,2 recent advances
in the transition-metal-catalyzed C−H functionalization
provide a potentially more efficient approach to the above
target structure, as exemplified by the palladium-catalyzed
intramolecular C−H/P−H3 and C−H/P−C4 couplings of
biarylphosphine derivatives (Scheme 1a and b).5 Although
somewhat specific, the Et3B/O2-initiated radical phosphination
of biarylphosphine oxide also provides the corresponding
dibenzophoshole efficiently (Scheme 1c).6 On the other hand,
the intramolecular phospha-Friedel−Crafts reaction (PFC)7 is
traditional but can be a good alternative to the aforementioned
Meanwhile, our research group recently developed a metal-
free, Tf2O-promoted protocol for the generation of highly
electrophilic and reactive phosphenium cation equivalents
from readily available and stable secondary phosphine oxides
and successfully applied it to phosphinative cyclization9 and
formal [3 + 2] cycloaddition10 with alkynes. During our
continuing interest in this chemistry,11 we envisioned our
blueprint for the synthesis of dibenzophospholes via the
phosphenium cation intermediate. Herein, we report a Tf2O-
mediated intramolecular PFC reaction of biarylphosphine
oxides (Scheme 1d). The reaction proceeds under metal-free
conditions, and the regioselectivity is controlled by the innate
electronic nature of substrates. Additionally, several hetero-
arene-fused dibenzophospholes are also readily prepared.
Thus, the present protocol can provide useful and comple-
mentary access to various dibenzophosphole derivatives.
Our initial working scenario is shown in Scheme 2. The
secondary biarylphosphine oxide 1 undergoes the tautomeriza-
tion to the corresponding hydroxylphosphine 1′. If its OH
group is activated with Tf2O, a highly electrophilic
phosphenium cation equivalent A could be formed.12 The
highly reactive and electrophilic phosphorus center can be
readily trapped with the proximal aromatic ring, and
subsequent rearomatization with the concomitant removal of
proton delivers the desired dibenzophosphole 2 (intra-
molecular PFC reaction).13 On the basis of the above
Scheme 1. Direct C−H Phosphination Approaches to
Dibenzophospholes
Received: January 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00219
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
mmol) with good reaction efficiency, thus indicating
reproducibility and reliability of the present protocol (entry 7).
With conditions in entry 7 in Table 1, the intramolecular
PFC reaction of several biarylphosphine oxides 2 was
performed (Scheme 3). The standard reaction conditions
Scheme 2. Working Hypothesis
Scheme 3. Tf2O-Promoted Intramolecular PFC Reaction of
a
Various Biarylphosphine Oxides 1
hypothesis, we started optimization studies with biphenylphos-
phine oxide 1a as the model substrate (Table 1). In an initial
Table 1. Optimization for Metal-Free Intramolecular PFC
Reaction of Biphenylphosphine Oxide 1a for Synthesis of
a
Dibenzophosphole Oxide 2a
b
entry
activator
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
(CF3CO)2O
Ts2O
TfOH
base
solvent
DCE
DCE
DCE
DCE
yield (%)
1
2
3
4
5
6
DMAP
pyridine
2,6-lutidine
Et3N
K2CO3
none
none
none
none
none
81
84
67
84
73
84
DCE
DCE
a
Reaction conditions: 1 (0.10 mmol), Tf2O (0.12 mmol), toluene
c
d
7
toluene
PhCF3
1,4-dioxane
DMF
toluene
toluene
toluene
(90), (66)
(1.5 mL), 90 °C, 8 h, N2. Isolated yields are shown. The formed P−C
8
9
10
11
12
13
64
41
22
9
13
20
b
c
bonds are indicated with bold lines. 24 h. 120 °C.
were equally compatible with electron-neutral (Me, t-Bu, Ph),
-donating (OMe), and -withdrawing (Cl and CF3) groups, and
the corresponding dibenzophospholes 2b−g were obtained in
good yields (66−82%). The Me substituent at the ortho
position was also tolerated (2h). Additionally, the higher π-
conjugated system 2i and dibenzophosphole 2j bearing
functional groups on both benzene rings were readily prepared
from the corresponding biarylphosphine oxides without any
difficulties. On the other hand, the meta-substituted substrate
gave an almost 1:1 regiomixture of 2k and 2k′, which is
reflected by the electronically controlled ring closing process as
shown in Scheme 2: in contrast, under the reported palladium-
catalyzed conditions, the more sterically accessible 2k was
preferably formed (ca. 9:1−10:1).3,4
The more salient unique and positive regioselectivity was
observed in the reaction with the 2-naphthyl-substituted
substrate 1l (Scheme 4). Under the palladium catalysis, 1l
was known to be cyclized exclusively at the less sterically
congested position to form 2l′ (left).15 On the other hand, in
the Tf2O-mediated protocol, the regioselectivity was mainly
pyridine
pyridine
none
a
Reaction conditions: 1a (0.10 mmol), activator (0.12 mmol), base
(0.12 mmol), solvent (1.5 mL), 90 °C, 20 h, N2 then H2O2 aq (30%,
ca. 5 drops). GC yield. Isolated yield in parentheses. Reaction time
was 8 h. Without H2O2 aq workup. 1.0 mmol scale.
b
c
d
experiment, treatment of 1a (0.10 mmol) with Tf2O (1.2
equiv) in the presence of DMAP (1.2 equiv) in DCE at 90 °C
(almost same conditions as those in our previous work)10 was
followed by quenching with H2O2 aq to afford the desired
dibenzophosphole oxide 2a in 81% GC yield (entry 1).
Subsequently, we screened several organic and inorganic bases
(entries 2−6), but surprisingly the reaction proceeded
smoothly even in the absence of any bases (entry 6), which
prompted us to reconsider our initial working hypothesis (vide
infra). The solvent evaluation (entries 7−10) revealed that less
polar toluene gave a better result, leading to 2a in 90% isolated
yield (entry 7). Notably, under conditions in entry 7 the
initially formed P(III) dibenzophosphole can be spontaneously
oxidized with residual Tf2O and/or its derivatives in situ, and
thus the corresponding dibenzophosphole oxide 2a was
observed as the sole product even without any additional
oxidative workup with H2O2 aq.14 Although we also tested
other activating reagents including (CF3CO)2O, Ts2O, and
TfOH, Tf2O still proved to be optimal (entries 11−13). The
reaction could also be conducted on a 10-fold larger scale (1.0
Scheme 4. Reaction of 2-Naphthyl Substrate 1l
B
DOI: 10.1021/acs.orglett.9b00219
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Letter
dominated by the electronic factors to deliver the opposite
regioisomer 2l selectively (right). Such a complementary
regioselectivity can provide divergent access to the dibenzo-
phosphole from the same starting substrate.
An additional feature of the present strategy is accom-
modation of heteroaromatic rings (Figure 1). The furan- and
by NMR to reconsider the reaction mechanism. While
preliminary, a five-coordinated, Tf2O adduct is believed to be
a more plausible intermediate than the initially proposed low
coordinated phosphenium cation species. Thus, an alternative
P(V)-mediated pathway may be operative in the C−P bond
forming step. However, additional mechanistic studies are
necessary for the conclusive statement (see the Supporting
Information for details).
In conclusion, we have revisited the classical phospha-
Friedel−Crafts-type reaction of the biarylphosphine derivatives
and developed metal-free, Tf2O-mediated conditions for the
synthesis of dibenzophospholes. The newly developed protocol
is simple, practical, and compatible with several functional
groups and heteroaromatic rings, and the observed regiose-
lectivity is apparently controlled by the innate electronic
nature, thus providing a good alternative to the reported
transition-metal-catalyzed C−H phosphination strategies.3,4
Additional mechanistic investigation and further application
of related electrophilic phosphination reaction to other
phosphorus-containing organic molecule synthesis are ongoing
in our laboratory and will be reported in due course.
Figure 1. Structure and isolated yields of heteroarene-fused
dibenzophosphole derivatives. The formed P−C bonds are indicated
with bold lines. See Scheme 1 for reaction conditions.
ASSOCIATED CONTENT
* Supporting Information
■
S
thiophene-fused bent-type dibenzophosphole derivatives 2m
and 2n were successfully prepared in good yields under
identical conditions. The structure of 2n was also confirmed by
X-ray crystallography (CCDC 1889358). In these cases, the
reaction occurred exclusively at the more electron-rich α-
position of heterocycles, which is consistent with the
electronically controlled PFC reaction mechanism. The more
π-conjugated benzothiophene-condensed 2o was readily
synthesized. Moreover, the ladder-type analogue 2p was also
accessible. In the reaction of indole-containing substrate, the
regioselectivity was moderate (2q:2q′ = 5:1), but a syntheti-
cally acceptable combined yield (51%) was observed.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00219.
1H, 13C{1H}, and 31P{1H} NMR spectra, ORTEP
drawing, and NMR studies (PDF)
Accession Codes
CCDC 1889358 and 1891190 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Finally, we carried out the double cyclization reaction of 1r
(Scheme 5). Pleasingly, the reaction proceeded well under the
Scheme 5. Double Cyclization of 1r to Form
Dibenzophospholothiophene 2r
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: k_hirano@chem.eng.osaka-u.ac.jp.
*E-mail: miura@chem.eng.osaka-u.ac.jp.
ORCID
Koji Hirano: 0000-0001-9752-1985
Masahiro Miura: 0000-0001-8288-6439
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Nos. JP
15H05485 (Grant-in-Aid for Young Scientists (A)) and
18K19078 (Grant-in-Aid for Challenging Research (Explor-
atory)) to K.H. and JP 17H06092 (Grant-in-Aid for Specially
Promoted Research) to M.M. We thank Dr. Yuji Nishii (Osaka
University) for his assistance in obtaining X-ray diffraction
data.
standard conditions to form the structurally novel dibenzo-
phospholothiophene 2r in 67% yield with ca. 1:1 syn/anti
ratio.16 The syn-isomer of 2r was successfully crystallized and
analyzed by single crystal X-ray diffraction (CCDC 1891190).
The result demonstrates the high synthetic potential of Tf2O-
promoted, metal-free protocol for the synthesis of other highly
condensed phosphole derivatives.
Given the unexpected result that the reaction proceeded
smoothly in the absence of any bases (entry 6 in Table 1), we
monitored the reaction mixture of 1a with Tf2O in toluene-d8
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Letter
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DOI: 10.1021/acs.orglett.9b00219
Org. Lett. XXXX, XXX, XXX−XXX