DDQ-promoted C(sp3)[sbnd]H phosphorylation of cycloheptatriene

Article abstract of DOI:10.1016/j.tetlet.2019.04.021

An efficient and convenient C(sp³)[sbnd]H phosphorylation has been achieved via the DDQ-promoted cross-dehydrogenative coupling between cycloheptatriene and P(O)H compounds at room temperature. This transformation provides a direct synthetic route to the construction of C(sp³)[sbnd]P bonds with good functional group compatibility, leading to the formation of cyclohepta-2,4,6-trien-1-ylphosphonates in up to 99% yield.

Full text of DOI:10.1016/j.tetlet.2019.04.021

Accepted Manuscript
DDQ-promoted C(sp3)−H phosphorylation of cycloheptatriene
Chunxiao Wen, Guodian Yu, Yingcong Ou, Xiaofeng Wang, Kun Zhang, Qian
Chen
PII:
S0040-4039(19)30343-0
https://doi.org/10.1016/j.tetlet.2019.04.021
TETL 50736
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
14 March 2019
4 April 2019
9 April 2019
Please cite this article as: Wen, C., Yu, G., Ou, Y., Wang, X., Zhang, K., Chen, Q., DDQ-promoted C(sp3)−H
phosphorylation of cycloheptatriene, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.04.021
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cycloheptatriene
Chunxiao Wen, Guodian Yu, Yingcong Ou, Xiaofeng Wang, Kun Zhang, Qian Chen

1
Tetrahedron Letters
DDQ-promoted C(sp3)−H phosphorylation of cycloheptatriene
Chunxiao Wen, Guodian Yu, Yingcong Ou, Xiaofeng Wang, Kun Zhang*, Qian Chen
School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and convenient C(sp3)−H phosphorylation has been achieved via the DDQ-
promoted cross-dehydrogenative coupling between cycloheptatriene and P(O)H compounds at
room temperature. This transformation provides a direct synthetic route to the construction of
C(sp3)−P bonds with good functional group compatibility, leading to the formation of
cyclohepta-2,4,6-trien-1-ylphosphonates in up to 99% yield.
Available online
© 2019 Elsevier Ltd. All rights reserved.
Keywords:
Phosphorylation
Cycloheptatriene
Tropylium
C(sp3)−H
Organophosphorus compounds are widely used in organic
synthesis,1 materials,2 bioorganic and medical chemistry,3
coordination chemistry and catalysis,4 and flame retardants.5
As the most important class of ligands in metal-catalyzed
reactions, phosphine ligands have attracted much attention
because the phosphorous is an effective donor atom with
strong σ-donor properties.6 Compared to arylphosphines,
have received much attention because this strategy
represents more straightforward, efficient, and atom-
economic to achieve C(sp3) H phosphorylation.13 Base on
−
our recent studies on the construction of P
and P
S bonds,14 we became interested in exploring a direct
phosphorylation of various C(sp3)
H bonds. Most recently,
our group developed an efficient C(sp3)
H phosphorylation
of 1,3-diarylpropenes and xanthenes via CDC reactions
promoted by DDQ (2,3-dichloro-5,6-dicyano-1,4-
benzoquinone).15 To our knowledge, the C(sp3)
phosphorylation of cycloheptatriene has never been reported.
Herein, we report a DDQ-promoted direct C(sp3)
−aryl, P−F, P−O
−
−
−
+
phosphine ligands containing tropylium (C7H7 ) such as
sandwich complexes of the type [(η7-C7H7)M(η5-C5H5)] (M
= group 4−6 metals) are less well-documented7 probably due
to the difficulty in their synthesis, although tropyliums are
effective ligands for coordination to transition metals.8 The
phosphane-functionalization of the tropylium moiety mainly
relies on the lithiation at the cycloheptatrienyl ring (Scheme
1, eqn (1)).7 However, this method is somewhat limited
because alkyllithium reagents and phosphorus chlorides are
moisture sensitive and/or environmentally unfriendly. On
the other hand, the tropylation of phosphines can be realized
by the reactions of tropylium tetrafluoroborate with P(III)
compounds to afford cycloheptatriene-phosphonium
derivatives (Scheme 1, eqn (2)), while the products such as
[C7H7PPh3]-[BF4]+ are organic salts.9 Therefore, the
development of a direct and convenient protocol for the
preparation of P-tropylated compounds is still a significant
issue.
−
H
−
H
phosphorylation of cycloheptatriene, leading to the
formation of cyclohepta-2,4,6-trien-1-ylphosphonates at
room temperature (Scheme 1, eqn (3))
.
Cycloheptatriene and its related derivatives, which are
important moieties in various biologically active
compounds,10 have also been particularly utilized in organic
synthesis.11 Thus, the synthesis of 7-substituted
cycloheptatriene derivatives via the reactions of the
tropylium ion with various nucleophiles is of importance
and interest. Recently, the direct cross-dehydrogenative
coupling (CDC) reactions12 involving P(O)H compounds
Scheme 1. Tropylation of organophosphorus compounds.
———
 Corresponding authors.
E-mail addresses: qianchen@gdut.edu.cn (Q. Chen), kzhang@gdut.edu.cn (K. Zhang).

2
Tetrahedron
Table 1
Optimization of reaction conditions.a,b
Table 2
Scope of P(O)H compounds.a,b
Entry
2a (equiv)
Oxidant
Solvent
Yield of 3a (%)
1
2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.0
1.5
1.5
1.5
1.5
1.5
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
PIFA
DTBP
NQ
CH3NO2
DCM
THF
91
70
3
93
4
CH3CN
DMF
DMSO
DCE
96
5
42
6
45
7
99
8
DCE
99
9
DCE
77
10
11
12
13
14c
DCE
80
DCE
0
DCE
0
BQ
DCE
0
DDQ
DCE
quantitative
a
Reaction conditions: 1 (0.2 mmol), 2a, oxidant (0.3 mmol),
anhydrous solvent (2 mL), N2 atmosphere.
b
1
Yield based on 1 was determined by H NMR analysis of crude
products using an internal standard.
c DDQ (0.22 mmol) was employed.
The reaction conditions were tested by using a model
reaction of cycloheptatriene
2a, and the results were shown in Table 1. First, we carried
out the reaction of with 2a (2.0 equiv) using DDQ (1.5
equiv) as the oxidant in CH3NO2 at room temperature under
N2 atmosphere according to our previous work.15a To our
delight, the reaction proceeded smoothly to afford the
desired cyclohepta-2,4,6-trien-1-yldiphenylphosphine oxide
3a in 91% yield (entry 1). A screen of solvents was then
1 with diphenylphosphine oxide
1
a
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), DDQ (0.22
mmol), anhydrous DCE (2 mL), room temperature, N2 atmosphere,
9 h.
b Isolated yield based on 1.
We then set out to explore the generality of the CDC of
cycloheptatriene with P(O)H compounds. We first applied
the optimized conditions to the coupling of cycloheptatriene
carried out (entries 2−7). DCE (1,2-dichloroethane) was
proved to be the optimum solvent, leading to the formation
of 3a in 99% yield (entry 7). When 1.5 equiv of 2a were
employed, 3a was still obtained in excellent yield (entry 8),
while the employment of 1.0 equiv of 2a significantly
decreased the product yield (entry 9). We then turned to
1
with a variety of P(O)H compounds 2, and the results were
illustrated in Table 2. Diarylphosphine oxides bearing
different groups such as electron-donating groups (Me, OMe
and Ph) and weakly electron-withdrawing groups (Cl and F)
at para, meta, or ortho position of aromatic rings, as well as
heterocyclic di(thiophen-2-yl)phosphine oxide and sterically
hindered di(naphthalen-1-yl)phosphine oxide, were all
screen other synthetically common oxidants (entries 10−13).
The use of phenyliodine bis(trifluoroacetate) (PIFA) gave 3a
in 80% yield, while no reaction occurred when using di-t-
butyl peroxide (DTBP), 1,4-naphthoquinone (NQ) or 1,4-
benzoquinone (BQ) as the oxidant. Pleasingly, 3a was
obtained in quantitative yield when near-stoichiometric
amounts of DDQ (1.1 equiv) were added (entry 14). Finally,
we concluded that the optimized combination for the
phosphorylation of cycloheptatriene was to use 1.5 equiv of
P(O)H compounds as the phosphorus source, 1.1 equiv of
DDQ as the oxidant, DCE as the solvent, and the reaction
was set at room temperature under N2 atmosphere (entry 14).
applicable to the coupling with 73−99% yields (3a−3n).
When dibenzylphosphine oxide was employed, the desired
3o was isolated in 87% yield, while the reaction of
dibutylphosphine oxide or dicyclohexylphosphine oxide
with
1 afforded 3p or 3q in poor yield probably due to the
relatively weak nucleophilicity. We then turned our attention
to the reactions of dialkyl/diaryl phosphites. Unfortunately,
the coupling of dialkyl phosphites with
1 gave the
corresponding 3r 3u in low yields. However, the
−
employment of dibenzyl phosphite and diphenyl phosphite
gave the desired 3v and 3w in good yields probably owing
to the p-π-conjugated system, which may enhance the
nucleophilicity. In addition, the scale-up reaction was
attempted (Scheme 2). When we increased the scale of the
reaction of
1 with 2a from 0.2 to 4 mmol, 3a was isolated in
72% yield (0.84 g).

3
In consideration of significant applications of dialkyl
alkylphosphonates in organic synthesis,1 we then carried out
the Michaelis-Arbuzov-type reaction16 of
with the more
nucleophilic P(III) compounds (Table 3). Notably, the
reactions of trialkyl phosphites or triaryl phosphites with
afforded the desired 3r 3u or 3w 3y in excellent yields
(entries 1 7). In addition, the cross-coupling of P(III)
compounds bearing one or two alkoxy substituents with
1
1
−
−
−
Scheme 2. Scale-up of the phosphorylation reaction.
1
was attempted. When PhP(OMe)2, Ph2POMe, or Ph2POEt
was used as the phosphorus nucleophile, the corresponding
3z and 3a were isolated in moderate yields (entries 8−10).
Table 3
Scope of P(III) compounds.a,b
Entry
1
P(III) compound
Product
Yield (%)
98
3r
2
3
4
5
3s
3t
97
96
98
99
3u
3w
Scheme 3. Proposed mechanism.
Based on the above experimental results and our previous
work,15 a plausible reaction mechanism is outlined in
Scheme 3. Initially, cycloheptatriene
to generate a tropylium cation and a DDQH-anion. Then, the
less stable P(III) form, which exists with the P(V) form via
the tautomerization,17 attacks the tropylium cation to
produce an unstable phosphonium cation . The subsequent
deprotonation of generates the cross-coupling product
and DDQH2. Similarly, the reaction of tropylium cation
with P(III) compound
and the subsequent transformation via a pathway of the
Michaelis-Arbuzov reaction16 affords
. Notably, DDQ is
1 interacts with DDQ
2
6
7
8
98
98
45
5
5
3
4
2
produces a phosphonium cation 5',
3
used not only as the oxidant, but also as the hydrogen
acceptor in this reaction.
In summary, we have developed the DDQ-promoted
cross-dehydrogenative coupling between cycloheptatriene
and P(O)H compounds, providing a convenient protocol for
the synthesis of tropyl diarylphosphine oxides. Furthermore,
the Michaelis-Arbuzov-type reaction of P(III) compounds
affords a facile access to dialkyl/diaryl tropylphosphonates.
To the best of our knowledge, this finding is the first
example of C(sp3)
−H phosphorylation of cycloheptatriene.
9
3a
3a
42
57
The good functional group compatibility, high yields, and
mild reaction conditions showcase the potential of this
approach in chemical synthesis.
10
a
Acknowledgments
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), DDQ (0.22
mmol), anhydrous DCE (2 mL), room temperature, N2 atmosphere,
9 h.
We thank the Science and Technology Planning Project of
Guangdong Province (No. 2017A010103044) and 100 Young
Talents Programme of Guangdong University of Technology
(No. 220413506) for financial support.
b Isolated yield based on 1.

4
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associated with this article can be found, in the online version, at
http://...
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5
Highlights
1. The DDQ-promoted C(sp3)−H phosphoryl tion
has been achieved.
2. The reactions afford cyclohepta-2,4,6-trien-1-
ylphosphonates under mild conditions.
3. The protocol is halogen-, metal-, and strong
base-free.