Practical way for the synthesis of 3,3′-bis-substituted benzo[d][1,2]oxaphosphole 2-oxides by phosphonylation of in situ generated o-quinone methides

Article abstract of DOI:10.1016/j.tetlet.2018.01.093

Phosphonylation of the pretreated 2-(hydroxymethyl)phenol derivatives with acetic anhydride using trialkylphosphites as the nucleophilic reagents was reported, providing a practical way to the synthesis of novel highly steric 3,3′-bis-substituted benzo[d][1,2]oxaphosphole 2-oxides.

Full text of DOI:10.1016/j.tetlet.2018.01.093

Accepted Manuscript
Practical Way for the Synthesis of 3,3’-Bis-substituted Benzo[d][1,2]oxaphosp-
hole 2-Oxides by Phosphonylation of in situ Generated o-Quinone Methides
Xinchun He, Wenwen Lv, Xiaomeng Shi, Hao Wei, Min Shi, Feijun Wang
PII:
S0040-4039(18)30138-2
https://doi.org/10.1016/j.tetlet.2018.01.093
TETL 49680
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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28 December 2017
26 January 2018
29 January 2018
Please cite this article as: He, X., Lv, W., Shi, X., Wei, H., Shi, M., Wang, F., Practical Way for the Synthesis of
3,3’-Bis-substituted Benzo[d][1,2]oxaphosphole 2-Oxides by Phosphonylation of in situ Generated o-Quinone
Methides, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.01.093
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Tetrahedron Letters
Practical Way for the Synthesis of 3,3’-Bis-substituted Benzo[d][1,2]oxaphosphole 2-
Oxides by Phosphonylation of in situ Generated o-Quinone Methides
Xinchun Hea, Wenwen Lva, Xiaomeng Shia, Hao Wei b, , Min Shia,c and Feijun Wanga, 
a Key Laboratory for Advanced Materials, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237 (P. R. China)
b School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240 (P. R. China)
c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai
200032 (P. R. China)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Phosphonylation of the pretreated 2-(hydroxymethyl)phenol derivatives with
acetic anhydride using trialkylphosphites as the nucleophilic reagents was
reported, providing a practical way to the synthesis of novel highly steric 3,3’-bis-
substituted benzo[d][1,2]oxaphosphole 2-oxides.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Benzo[d][1,2]oxaphosphole 2-oxide
Orthoquinone methide
Michael addition reaction
Phosphonylation
Phosphoric acid
Introduction
Benzo[d][1,2]oxaphosphole 2-oxides are a type of cyclic
organophosphorus compounds, which are used as precursors of
stabilized carbon-centered radicals,1 photoluminescent
complexes,2 extractants,3 as well as the intermediates to the
synthesis of phosphoric acid catalysts4 and the ligands for metal
catlysis5. Especially, if benzo[d][1,2]oxaphosphole 2-oxide
derivatives have a rigid chiral carbon center at the 3-site of
benzo[d][1,2]oxaphosphole ring, just like the chiral oxazoline
coordinating group which have played a significant role in the
advancement of transition metal-based asymmetric catalysis,6
they could be potentially versatile precursors for the development
of chiral phosphoric acid catalysts and phosphine ligands
(Scheme 1a).
Scheme 1. Synthesis of 3,3’-bis-substituted benzo[d][1,2]
oxaphosphole 2-oxide and its potential application
under aerobic conditions8. However, the synthetic strategies to
the synthesis of 3,3’-bis-substituted benzo[d][1,2]oxaphosphole
2-oxides with highly steric hindrance received less attention.
Orthoquinone methides (o-QMs) generated in situ from 2-
(hydroxymethyl)phenols have received much attention in organic
synthesis due to their rich synthetic transformations such as
Michael addition reaction with carbon, nitrogen,9 sulfur, and
oxygen nucleophiles10. We envisioned that trialkylphosphite used
as nucleophile could react with acylated 2-
Given their high importance, there is ongoing interest in the
development of convenient and general protocols for the
synthesis of benzo[d][1,2]oxaphosphole 2-oxides. Julia Pérez-
Prieto and co-workers respectively reported the synthesis of 3-
mono-substituted benzo[d][1,2]oxaphosphole 2-oxides via the
reaction of hydroxyalkylphenols 2 with PBr3/HBr and then with
phosphite1c or the reaction of hydroxyalkylphenols with triethyl
phosphite7. Phil Ho Lee and co-workers reported an efficient
synthetic method of benzoxaphosphole 1- and 2-oxides through a
(hydroxy(aryl)methyl)phenol,11 a good type of o-quinone
methides precursors,12 to give the Michael addition product
which was further converted to benzo[d][1,2]oxaphosphole 2-
Pd-catalyzed C(sp2 and sp3)-H activation/C-O bond formation
———
 Corresponding author.
E-mail addresses: haowei@sjtu.edu.cn (H. Wei), feijunwang@ecust.edu.cn (F. Wang).

2
Tetrahedron Letters
oxide via subsequent cyclization and the transformation of P(III)
of base such as organic and inorganic bases was investigated
(Table 1, entries 10-13). As the base, the addition of NEt3 (1
equiv.) could remarkably raise the diastereoselectivity, affording
the 3aa in 85% of total yield and 1:6.75 of the ratio of cis-3aa to
trans-3aa. However, the stronger bases such as DMAP and
DABCO than NEt3 delivered lower diastereoselectivities.
Moreover, thiourea often used as the activator to promote the
transformation of α,β-unsaturated ketone was tested in this
reaction,15 and showed that the addition of thiourea could slightly
improve the diastereoselectivity (Table 1, entry 9). Along with
the decrease reaction temperature, the diastereoselectivity could
slightly increase, but the total yield of 3aa was remarkably
reduced (Table 1, entries 14-17).
to P(V) (Scheme 1b).13 Comparing with the recent report of
phosphorodiamidic acids catalyzed phosphonylation of in situ
formed o-quinone methides to generate uncyclized diaryl
phosphonates,14 herein, we wish to report the synthesis of 3,3’-
bis-substituted benzo[d][1,2]oxaphosphole 2-oxides from 2-
(hydroxymethyl)phenols.
Results and discussion
At the beginning of our studies upon this phosphonylation
process, reactions of 2-(hydroxy(phenyl)(o-tolyl)methyl)phenol
(1a) with P(OEt)3 (2a) were investigated as our model reaction
under different conditions (Table 1). We are glad to see that
when the mixture of starting materials 1a and Ac2O stirred in
CH2Cl2 for 2 h at room temperature were further treated with 2a
at room temperature for 12 h, the desired 2-ethoxy-3-phenyl-3-
(o-tolyl)-3H-benzo[d][1,2]oxaphosphole 2-oxide (3aa) with cis-
and trans- configurations were obtained in 17% and 64%,
respectively (Table 1, entry1). The diastereoselectivity of cis-3aa
to trans-3aa is 1:3.72, which was determined by crude 1H NMR.
However, in the reaction of 2-(hydroxymethyl)phenol 1a with 2a,
early reported methods1c,7 only gave trace of desired product 3aa.
Other acylation reagents such as AcCl (Table 1, entry 2) and
(Boc)2 (Table 1, entry 3) instead of Ac2O were used, delivering
the lower total yields of 3aa with lower dr-values. From the
screen of solvents (Table 1, entries 1 and 4-8), it was found that
CH2Cl2 was the best solvent and using DMF as the solvent
couldn’t give the corresponding products. In order to improve the
diastereoselectivity of this phosphonylation process, the addition
Table 1
With this optimized result in hand, we explored the substrate
scope of this phosphonylation process (Table 2). A series of 2-
(hydroxymethyl)phenols (1b-m) with different substituents were
tested. It is important to note that more steric phenols such as 1d
(Table 2, entry 3), 1f (Table 2, entry 5) and 1j (Table 2, entry 9)
couldn’t give the corresponding desired products 3. Moreover,
substrates 1k-m containing a halogen substituent on the phenol
ring only afford the acyclic Michael addition products 4ka-ma,
respectively (Table 2, entries 10-12). It is maybe due to the
electron-withdrawing property of halogen-atom that led to the
decrease of nucleophilicity of phenolic hydroxyl group, that can’t
promote the formation of benzo[d][1,2]oxaphosphole 2-oxides.
Other trialkylphosphites such as 2b and 2c can also give the
desired benzo[d][1,2]oxaphosphole 2-oxides in good yields
(Table 2, entries 13 and 14).
Optimizations of the conditions.a
Entry
Solvent
T (oC)
Base
Yield (%) of
Yield (%) of
Total yield (%)
drc
cis-3aab
trans-3aab
of 3aa
81
1
CH2Cl2
CH2Cl2
CH2Cl2
THF
rt
no
17
64
33
1: 3.72
1: 1.81
1: 2.35
1: 2.91
1: 2.18
1: 3.11
1: 2.71
2d
3e
4
rt
NEt3
no
20
53
67
78
65
74
34
trace
70
85
88
72
58
65
38
19
7
rt
20
20
21
18
9
47
58
44
56
25
trace
56
74
61
50
45
56
33
16
7
rt
no
5
PhMe
rt
no
6
CH3CN
(Et)2O
DMF
rt
no
7
rt
no
8
rt
no
trace
14
11
27
22
13
9
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
Thiourea
NEt3
DMAP
DABCO
EtN(i-Pr)2
NEt3
NEt3
NEt3
NEt3
NEt3
1: 4.08
1: 6.75
1: 1.87
1: 1.25
1: 3.42
1: 6.82
1: 6.91
1: 7.01
1: 7.08
-
10
11
12
13
14
15
16f
17g
18g
rt
rt
rt
rt
20
10
0
5
3
-10
-20
trace
-
-
-
a 1a (0.4 mmol) and Ac2O (0.48 mmol, 1.2 eq.) were stirred in solvent (2 mL) for 2 h at room temperature, then P(OEt)3 (0.48 mmol, 1.2 eq.) and base (0.4 mmol,
1 eq.) were added and further stirred for 12 h.
b Isolated yield.
c The dr-value was monitored by crude 1H NMR.
d AcCl (0.5 mmol, 1.2 eq.) instead of Ac2O was used.
e Boc2O (0.5 mmol, 1.2 eq.) instead of Ac2O was used.
f Reaction for 12 h.
g Reaction for 36 h.

acylated product 5o was obtained in 60% yield. While for 1p, as
reported in recent literature, acyclic product 4pa was obtained in
54% yield.
Table 2
Scope of the substrates.a
Entry Substrate 1
P(OR3)3
Product
Yield (%)b
70
1
2a
(dr = 1:2.40)
Scheme 2. Test of simple 2-(hydroxymethyl)phenols.
76
2a
2a
2a
2a
In order to develop its organocatalytic enantioselective β-
phosphonylation of orthoquinone methides, organocatalysts C1-3
were tested in this reaction (Figure 1). Regretfully, these catalysts
could not give any enantioselectivities, and 3aa with moderate
diastereoselectivities were obtained.
2
3
4
5
(dr = 1:2.57)
-
-
85
-
-
2a
2a
6
7
70
71
Figure 1. Using of chiral catalyst in this phosphonylation process.
To demonstrate the synthetic utility of the
benzo[d][1,2]oxaphosphole 2-oxides, ethylphosphonate 3ea
was treated with trimethylsilyl bromide (TMSBr),16 affording
cyclic phosphoric acid 6ea in 95% yield (Scheme 3a).
Furthermore, 6ea as a Brønsted acid catalyst was used in the
allylation of benzaldehyde with allylboronic acid pinacol ester,
showing good catalytic activity to give the addition product 7
in 83% yield (Scheme 3b).
2a
2a
8
9
54
-
-
2a
2a
2a
10
11
12
57
51
35
Scheme 3. Application of benzo[d][1,2]oxaphosphole 2-oxide
3ea.
Conclusion
In summary, we have developed a green and mild phospha-
Michael reaction of o-QMs with trialkylphosphites to afford 3,3’-
bis-substituted benzo[d][1,2]oxaphosphole 2-oxides in one pot
from easily available starting materials, 2-
(hydroxymethyl)phenols, phosphite esters, acetic anhydride and
NEt3. Moreover, the hydrolysis product 6ea showed its acid
catalytic property in the promotion of allylation of benzaldehyde.
The further application of benzo[d][1,2]oxaphosphole 2-oxides,
especially in the development of chiral phosphoric acid catalysts
and phosphine ligands, is currently undergoing in our group.
P(OMe)3
13
14
83
77
1e
1e
2b
P(OiPr)3
2c
a 1 (0.4 mmol) and Ac2O (0.48 mmol, 1.2 eq.) were stirred in CH2Cl2 (2 mL)
for 2 h at room temperature, then 2 (0.48 mmol, 1.2 eq.) and NEt3 (0.4 mmol,
1 eq.) were added and further stirred for 12 h.
b Isolated yield.
Acknowledgments
References and notes
Other 2-(hydroxymethyl)phenols 1o and 1p were also
investigated in this phosphonylation process (Scheme 2). For 1o,
We are grateful for financial support from the National
Natural Science Foundation of China (21372075, 81670958 and
81371178), the Shanghai Pujiang Program (16PJD017 and
16PJD027), and the Medical-Engineering Crossover Fund of
Shanghai Jiao Tong University (YG2015MS23 and
YG2016MS71).
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Highlights
•A convenient one pot procedure to generate 3,3’-
Bis-substituted Benzo[d][1,2]oxaphosphole 2-
Oxides.
• A green and mild phospha-Michael reaction of o-
QMs with trialkylphosphites was illustrated.
• Application of benzo[d][1,2]oxaphosphole 2-
oxide was illustrated.

6
Tetrahedron
Graphical Abstract
Practical Way for the Synthesis of 3,3’-Bis-
Leave this area blank for abstract info.
substituted Benzo[d][1,2]oxaphosphole 2-
Oxides by Phosphonylation of in Situ
Generated o-Quinone Methides
Xinchun He, Wenwen Lv, Xiaomeng Shi, Hao Wei, Min Shi and Feijun Wang