Highly selective 1,4- and 1,6-addition of P(O)-H compounds to p-quinones: A divergent method for the synthesis of C- and O-phosphoryl hydroquinone derivatives

Article abstract of DOI:10.1002/chem.201202074

The reaction of P(O)-H compounds with p-quinones could proceed through either 1,4- or 1,6-addition pathways by employing different additives to selectively give the corresponding C- and O-phosphoryl hydroquinone derivatives in good yields. Oxidative doubl

Full text of DOI:10.1002/chem.201202074

DOI: 10.1002/chem.201202074
À
Highly Selective 1,4- and 1,6-Addition of P(O) H Compounds to
p-Quinones: A Divergent Method for the Synthesis of C- and O-Phosphoryl
Hydroquinone Derivatives
Biquan Xiong,[a, b] Ruwei Shen,[c] Midori Goto,[b] Shuang-Feng Yin,*[a] and
Li-Biao Han*[a, b]
À
Abstract: The reaction of P(O) H
compounds with p-quinones could pro-
ceed through either 1,4- or 1,6-addition
pathways by employing different addi-
tives to selectively give the correspond-
ing C- and O-phosphoryl hydroquinone
derivatives in good yields. Oxidative
ieved by tuning the solvent, affording a
facile synthesis of bis-substituted hy-
droquinones with phosphorus function-
ality. Further studies on these reactions
by using optically active H-phosphi-
nates showed that all addition reactions
took place stereospecifically with re-
tention of configuration at the phos-
phorus center. The findings lead to the
establishment of a divergent method
for the synthesis of C- and O-phos-
phoryl hydroquinone derivatives from
Keywords: nucleophilic addition ·
enantioselectivity
quinones
· phosphorus ·
À
double 1,4-addition of P(O) H com-
pounds to p-quinones was also ach-
À
easily available P(O) H compounds.
Introduction
and selective synthesis of these compounds is of importance
and is highly desired.
À
Hydroquinone compounds bearing heteroatom functionali-
ties form a class of valuable compounds with wide applica-
tions.[1–8] Many of them serve as important intermediates
from which to access molecules with advanced structures by
further manipulating the heteroatomic group through syn-
thetic chemistry.[2,3] Some hydroquinones with heteroatom
functionalities are used as reagents in medical research,
showing a variety of biological activities in aspects related
to antitumor,[4] HIV transcriptase inhibition, and immuno-
modulation.[5] Furthermore, they are also applied in material
science and the petroleum industry.[6–8] Thus, an efficient
As depicted in Scheme 1, the addition reaction of H E
(E=N, O, S, P etc.) to p-benzoquinone may represent one
of the most facile and efficient ways to prepare hydroqui-
[a] B. Xiong, S.-F. Yin, L.-B. Han
Department of Chemistry
Scheme 1. Traditional 1,4-addition of nucleophiles to p-quinones.
College of Chemistry and Chemical Engineering
Hunan University
Changsha, 410082 (P. R. China)
Fax : (+86)731-88821310
E-mail: sf_yin@hnu.edu.cn
nones substituted with a heteroatomic group.[9–11] Thus, the
reaction of a heteroatomic nucleophile with p-benzoquinone
gives 2-monosubstituted hydroquinone 3 through normal nu-
[b] B. Xiong, M. Goto, L.-B. Han
National Institute of Advanced Industrial Science
and Technology (AIST)
À
cleophilic 1,4-addition. Depending on the properties of E
H, the redox potential of 3, as well as the reaction condi-
tions, the initially formed hydroquinone 3 could be oxidized
and undergo further nucleophilic addition to give multisub-
stituted hydroquinones.[11i] Theoretically, this addition may
allow the introduction of up to four heteroatom functionali-
ties to p-benzoquinone, affording a fully substituted hydro-
quinone that is not easily fabricated by other methods.
Tsukuba, Ibaraki 305-8565 (Japan)
E-mail: libiao-han@aist.go.jp
[c] R. Shen
State Key Laboratory of Materials-Oriented
Chemical Engineering
College of Chemistry and Chemical Engineering
Nanjing University of Technology
Nanjing 210009 (P. R. China)
À
The reactions of p-quinones with E H (E=O, S, N) com-
pounds were investigated in considerable detail. The reac-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202074.
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Chem. Eur. J. 2012, 18, 16902 – 16910

FULL PAPER
À
tion of p-quinones with alcohols resulted in the formation of
the corresponding 4-alkoxy phenols, as reported by Mitsuno-
bu in 1968.[9b] Yamaoka initiated a study on the reaction of
p-quinone with amine in 1971 and found that mono- and
bis-substituted hydroquinones could be produced from the
reactions of p-quinone with primary and secondary amines
in alcohol solvents.[10m] The addition of thiols to p-benzoqui-
none has been discussed in detail by Snell and Weissberger;
they found that by using an excess of p-quinone, the mono-
substituted product could be formed with satisfactory yields
in alcohol solvent without addition of a catalyst.[11k] Yasuo
P(O) H compounds to p-quinones proceeded through a si-
multaneous double 1,4-addition and subsequent oxidation
process, rather than the generally accepted stepwise 1,4-ad-
dition/oxidation sequence (see below). Furthermore, when
À
Et3N was used as an additive, the reaction of P(O) H com-
pounds with p-quinones proceeded through a 1,6-addition
route, affording the O-phosphoryl-substituted hydroquinone
derivatives (Scheme 2, path 2). The disclosed reactions can
all be used for the preparation of optically active organo-
phosphorus hydroquinones from chiral H-phosphinates with
retention of configuration at the phosphorus center.
À
Abe further found that the adducts of S H type compounds
could be further oxidized by p-quinones, thus obtaining mul-
tisubstituted hydroquinones.[11j] Compared with O, N, and S
nucleophiles, the number of investigations on the addition
Results and Discussion
À
À
reaction of P(O) H compounds to p-quinones is rather lim-
Water-promoted selective 1,4-addition of P(O) H com-
ited. A brief study on the use of dialkylphosphites was re-
ported by Levin and Davydochkina, but the procedure used
for the preparation of hydroquinone derivatives bearing or-
ganophosphorus functionality is tedious and the selectivity
and yield were rather low.[12] Consequently, although hydro-
quinones with organophosphorus functionality are important
targets in organic synthesis, medicinal chemistry, and materi-
al science, the most frequently employed method for their
preparation is still achieved through treatment of
(RO)2P(O)Cl with phenols,[13] and then rearrangement by
reaction with organometallic reagents, for example, nBuLi
or lithium diisoprpylamine (LDA).[14] It is apparent that the
approach is time-consuming, limited in terms of generality,
and suffers from a lack of tolerance towards functional
groups.
pounds to p-quinones; selective synthesis of C-phosphoryl
hydroquinone derivatives: At the outset, we examined the
reaction of p-benzoquinone (1a) and diethyl phosphonate
(2a) conducted in toluene with a concentration of 0.5m at
808C; the outcome was the formation of diethyl 2,5-dihy-
droxyphenylphosphonate (3a) in 46% yield together with
bis-substituted product, tetraethyl 2,5-dihydroxy-1,4-phenyl-
enediphosphonate (4a) in 11.5% yield. Thus, besides the
1,4-addition to give 3a as major product, a double 1,4-addi-
tion and oxidation sequence occurred to produce the by-
product 4a. We next concentrated our efforts on optimizing
the reaction. As shown in Table 1, a change in the concen-
tration of substrates did not lead to any improvement. Al-
though a higher yield was obtained when the reaction was
conducted at a concentration of 1.0m, the product selectivity
declined. The reaction became rather sluggish and the yield
of 3a was poor after 24 h when the reaction was conducted
at low substrate concentration.
In this paper, we disclose the details of our findings on
the reaction of P(O) H compounds with p-quinones, provid-
ing a divergent method for the synthesis of both C- and O-
À
phosphoryl-substituted
hydroquinone
derivatives
(Scheme 2). During our ongoing project on the preparation
Table 1. Effects of additives on the 1,4-addition reaction of diethyl phos-
phonate to 1,4-benzoquinone.[a]
of organophosphorus compounds by employing relatively
[12]
À
easily accessible P(O) H compounds, we observed water-
promoted 1,4-addition and oxidative double 1,4-addition of
À
P(O) H compounds to p-quinones, affording a facile synthe-
sis of mono- and bis-substituted hydroquinones with phos-
phorus functionality (Scheme 2, path 1).
A mechanistic
study showed that this oxidative double 1,4-addition of
Entry
Conc.
[m]
Additive
[equiv]
Yield of 3a
Ratio of 3a/4a[b]
N
[%][b]
1
2
3
4
5
6
7
8
9
0.1
0.3
0.5
1.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
–
–
–
–
13
28
46
59
68
64
61
70
80
85
84
86:14
83:17
80:20
77:23
85:15
87:13
88:12
88:12
91:9
AcOH (0.2)
AcOH (0.5)
AcOH (1.0)
HCOOH (0.2)
H2O (0.2)
H2O (0.5)
H2O (1.0)
10
11
94:6
91:9
[a] Reaction conditions: 1,4-benzoquinone (0.5 mmol), diethyl phospho-
nate (0.5 mmol), additive, toluene, N2, 808C, 24 h. [b] Yields and selectivi-
ty were determined by GC analysis.
Scheme 2. Outline of our present work.
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S.-F. Yin, L.-B. Han et al.
À
Interestingly, both product yield and selectivity were im-
proved when a trace amount of protic solvent was added to
the reaction system. In the presence of 0.5 equivalent of
HOAc, the reaction of 1a with 2a gave 3a in 64% yield and
the selectivity of 3a/4a was improved to 87:13. The presence
of formic acid also gave good results, and the 1,4-addition
product 3a was formed in 70% yield with 3a/4a selectivity
of 88:12. Surprisingly, we observed that the addition of a
small amount of water improved the outcome of the reac-
tion; thus, the addition of 0.2 equivalent of water led to
80% yield and 91% selectivity for 3a. When the reaction
was performed in toluene at 808C in the presence of 0.5
equivalent of water, 3a was formed in 85% yield and the
byproduct 4a was produced in only 5% yield (Selectivity:
3a/4a=94:6). Adjusting the amount of water to 1.0 equiva-
lent caused a slight decrease in both the yield of 3a and the
selectivity.
0.5 mmol of P(O) H compounds, 0.5 equivalent of water as
additive, and 1 mL of toluene as the solvent at 808C under
N2 atmosphere as the optimized conditions.
As shown in Table 3, the selective 1,4-addition could be
applied to a variety of P(O) H substrates and p-quinones.
À
H-phosphonates bearing ethyl and isopropyl groups could
be efficiently added to p-benzoquinone to afford monosub-
stituted hydroquinones in high yields. Only a moderate yield
was observed when dimethyl phosphonate 2b was employed
in the reaction. On the other hand, diphenyl phosphonate
did not give the expected product, possibly due to the ten-
dency of this kind of substrate to undergo hydrolysis.[12d,e]
Secondary phosphine oxides such as diphenyl phosphine
oxide and bis(4-phenbutyl)phosphine oxide exhibited high
reactivity in the reaction and produced the corresponding
adducts in 98 and 77% yield, respectively. The reaction of
H-phosphinate 2 f also gave the desired product in high
yield. A variety of p-quinones including 2,5-dimethyl-1,4-
benzoquinone, 2,6-dimethyl-1,4-benzoquinone, 2,5-diphenyl-
1,4-benzoquinone, and naphthoquinone, were also exam-
ined. Whereas the reaction of 2,5-dimethyl-1,4-benzoqui-
none with 2a produced the corresponding product in 45%
yield, the use of 2,6-dimethyl-1,4-benzoquinone showed an
excellent adduct yield. In contrast, only 15% yield of 3j was
obtained from 2,6-di-tert-butyl-1,4-benzoquinone due to the
high steric hindrance. The reaction of naphthoquinone with
2a proceeded smoothly to give the desired adduct 3l in
good yield. However, 2-methylnaphthalene-1,4-dione 1g was
inert to this addition and no reaction was observed when 2a
and 1g were subjected to the reaction under the optimized
conditions.
The solvents used also had a significant influence on the
yield of 3a and the selectivity in the water-promoted 1,4-ad-
À
dition reaction of P(O) H compounds to p-quinones. As
demonstrated in Table 2, reactions conducted in solvents in-
Table 2. Effects of solvents on diethyl phosphonate 1,4-addition to p-
benzoquinone.[a]
Entry
Solvent
Yield of 3a [%][b]
Ratio of 3a/4a[b]
1
2
3
4
5
6
7
8
9
toluene
benzene
EtOAc
acetone
dioxane
hexane
DMF
DMSO
85
83
45
19
21
71
5
10
75
53
56
94:6
92:8
À
Et3N-promoted 1,6-addition of P(O) H compounds to p-
82:18
80:20
79:21
78:22
33:67
20:80
90:10
64:36
63:37
quinones; selective synthesis of O-phosphoryl hydroquinone
derivatives: To our surprise, when we switched the additive
from acid (or H2O) to an organic base (i.e., Et3N) the reac-
tion took place preferentially through 1,6-addition to give
diethyl 4-hydroxyphenyl phosphate (5a) as the major prod-
uct (Table 4). Thus, when the reaction of p-benzoquinone
(1a) with diethyl phosphonate (2a) was conducted following
a similar procedure in the presence of 10 mol% Et3N at
808C in toluene, 5a was detected (based on GC analysis) in
87% yield with 89% selectivity instead of the expected C-
phosphoryl 3a and 4a products. Decreasing the reaction
temperature led to an increase in both the yield of 5a and
the selectivity. When the reaction was carried out at room
temperature (258C), 5a was produced in 92% yield with a
selectivity of up to 95% after 24 h. We observed that a re-
duction in the amount of Et3N from 10 to 1 mol% resulted
in a sharp decrease in yield and selectivity of the expected
product; further increases in the amount of Et3N did not
lead to any significant improvement. Accordingly, the reac-
tion was further studied in toluene at 258C using 10 mol%
Et3N as catalyst.
diphenyl ether
methyl phenyl ether
no solvent
10
11
[a] Reaction conditions: 1,4-benzoquinone (0.5 mmol), diethyl phospho-
nate (0.5 mmol), H2O (0.25 mmol), solvent (1 mL), N2 atmosphere, 808C,
16 h. [b] Yields and selectivity were determined by GC analysis.
cluding toluene, benzene, hexane, diphenyl ether, and
methyl phenyl ether all showed a preference towards the
formation of 1,4-addition product 3a. The use of polar sol-
vents such as N,N-dimethylformamide (DMF) and dimethyl
sulfoxide (DMSO), however, gave a reverse selectivity.
Thus, the reactions in toluene, benzene, and hexane pro-
duced 3a in good to moderate yield, showing a selectivity of
94, 92, and 78%, respectively, whereas the employment of
DMF and DMSO gave 4a as the main product. Such a phe-
nomenon led to the establishment of a simple and direct
way to access bisphosphoryl-substituted hydroquinones (see
below). Accordingly, we chose 0.5 mmol of p-quinone,
Summarized in Table 5 are the results of the Et3N-pro-
moted 1,6-addition reaction with p-quinones across a variety
of P(O)H compounds. The reaction of H-phosphonates 2a–
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Phosphoryl Hydroquinone Derivatives
FULL PAPER
À
Table 3. Water-promoted selective 1,4-addition of P(O) H compounds to
p-quinones.[a]
Table 4. Optimization of the 1,6-addition reaction of diethyl phosphonate
to 1,4-benzoquinone.[a]
Entry p-Quinone 1
P(O) H 2
Product 3
Yield [%][c]
À
1
85
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
51
81
Entry
Et3N
[mol%]
Temp.
[8C]
Yield of 5a
Selectivity
G
[%][c]
of 5a [%][c]
1
10
10
10
10
1
25
40
80
100
25
25
92 (91[d]
91
)
97
91
89
88
78
96
94
2[b]
3[b]
4[b]
5
87
81
49
88
6
7
20
50
n.d.
98
25
87
[a] Reaction conditions: 1,4-benzoquinone (1 mmol), diethyl phospho-
nate (1 mmol), Et3N, toluene (1 mL), N2 atmosphere, RT, overnight.
[b] Reaction time: 14 h. [c] Yields and selectivity were determined by GC
analysis. [d] Isolated yield.
84
d with p-benzoquinone (1a) produced the expected O-phos-
phoryl hydroquinones in good to excellent yields. When H-
phosphinate 2 f was employed, the reaction gave the desired
product 5 f in 62% yield. The corresponding adduct 5g was
also obtained from an alkyl secondary phosphine oxide,
albeit in a slightly low yield. Nevertheless, the use of diphen-
yl phosphine oxide unfortunately did not generate the ex-
pected product because it was not acidic enough to allow
deprotonation and hence this substrate predominantly un-
derwent 1,4-addition, yielding 3e as the major product. In
addition to 1a, other p-quinones including 2,6-bis-substitut-
ed and 2,5-bis-substituted 1,4-benzoquinones and 1,4-naph-
thalenediones could also be employed to produce the O-
phosphoryl hydroquinones in good to high yields. Further-
more, the reaction of 2,5-dimethyl-1,4-benzoquinone (1c)
with 1a under the optimized conditions produced the ex-
pected diethyl 4-hydroxy-2,5-dimethylphenyl phosphate (5i)
in 93% yield. On the other hand, a mixture of regioisomers
5h and 5h’ were produced in 91% yield when 2,6-dimethyl-
1,4-benzoquinone was employed. It is noteworthy that, in
this reaction, the sterically hindered substrate 2,6-di-tert-
butyl-1,4-benzoquinone (1d) regioselectively furnished 5j in
82% yield. In addition, the reactions of 1,4-naphthalene-
dione (1 f) and 2-methylnaphthalene-1,4-dione (1g) with 2a
gave the corresponding products in 51 and 77% yield, re-
spectively.
77
8
9
2a
2a
2a
91
45
15
10
11
12
13
2a
2a
2a
87[b]
55
According to previous reports,[12c,f] we propose a mecha-
nism involving a single electron transfer (SET) radical proc-
ess on the selective 1,6-addition of P(O)H compounds to p-
quinones (Scheme 3). A catalytic amount of Et3N is needed
to deprotonate the P(O)H compounds to generate the cor-
responding anion, which are known to be good electron
donors. The anion can then react with p-quinone through a
SET process to give the semiquinone radical anion and a P-
centered radical. The anion of the 1,6-addition product is
n.d.
À
[a] Reaction conditions: 1,4-benzoquinone (1 mmol), P(O) H (1 mmol),
H2O (0.5 mmol), toluene (2 mL), N2 atmosphere, 808C, overnight. [b] Re-
action performed at 1108C. [c] Isolated yield. n.d.=not determined.
Chem. Eur. J. 2012, 18, 16902 – 16910
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S.-F. Yin, L.-B. Han et al.
[a]
À
Table 5. Et3N-promoted 1,6-addition of P(O) H compounds to p-quinones.
À
Entry
p-Quinone 1
P(O) H 2
Product 3
Yield
[%][c]
subsequently formed, followed by abstraction of a
proton from the protonated Et3N (or the P(O)H
compounds) to afford the 1,6-addition product and
regeneration of Et3N.[12c,f]
1
91
À
Oxidative double 1,4-addition of P(O) H com-
pounds to p-quinones; simultaneous double 1,4-ad-
dition and subsequent oxidation process: As descri-
bed above, bis-substituted hydroquinone 4a is
always generated as a byproduct in the 1,4-addition
2
3
4
1a
1a
1a
90
84
71
À
reaction of P(O) H compounds to p-quinones. This
phenomenon was also observed by others.[12,13] Sur-
prisingly, we found that 4a could also be formed
preferentially by adjusting the reaction conditions.
During the optimization of the 1,4-addition reaction
of diethyl phosphonate (2a) to p-benzoquinone, we
found that solvent had a significant impact on the
selectivity and formation of 3a and 4a. Whereas
the use of nonpolar solvents such as toluene and
benzene gave an excellent selectivity to produce 3a,
reactions run in polar solvent such as DMSO and
DMF favored the formation of bis-substituted prod-
uct 4a. When the reaction was conducted in DMSO
at 808C, 4a was isolated in a yield up to 72%
(based on diethyl phosphonate 2a; GC yield:
80%). Clearly, these findings allow a simple and
direct method for the preparation of 2,5-bis-substi-
tuted hydroquinones (Table 6).
5
6
1a
1a
n.d.
62
7
8
1a
55
The formation of product 4 was generally ex-
plained by a stepwise pathway involving 1,4-addi-
tion and oxidation as shown in Scheme 4.[13b] Ac-
cordingly, H-phosphonate 2 first adds to p-benzo-
quinone to produce monosubstituted hydroquinone
3, which is subsequently oxidized by another equiv-
alent of p-benzoquinone to give 2-substituted p-
benzoquinone A. Then, another 1,4-addition of H-
phosphonate 2 to A takes place, yielding the bis-
substituted product 4. In the whole transformation,
p-benzoquinone has dual functionality, serving both
as substrate and oxidant. Although such a stepwise
mechanism can explain the observed experimental
results, further study on the mechanism of this reac-
tion by us showed that this might not be the real
path. We conducted the reaction of diethyl-2,5-dihy-
droxyphenyl phosphonate (3a) with one equivalent
of p-benzoquinone (1a) under the same reaction
conditions. As monitored by GC and 31P NMR
analyses, no reaction was observed after heating the
mixture for 18 h at 808C, hence excluding the possi-
bility of the stepwise mechanism involving an inter-
mediate A. Indeed, this result is also consistent
with the expectation that 3, bearing an electron-
withdrawing group on the aromatic ring, should
2a
91 (65:35)
9
10
11
12
2a
2a
2a
2a
93
82
69
51
13
2a
77 (32:68) have a lower redox potential than hydroquinone,[11i]
suggesting that 2-substituted hydroquinone 3 cannot
be oxidized by p-benzoquinone. Accordingly, we
proposed an alternative pathway involving a simul-
[a] Reaction conditions: 1,4-benzoquinone (1 mmol), P(O)-H (1 mmol), Et3N (0.1 mmol),
toluene (1 mL), N2 atmosphere, RT, overnight. [b] Isolated yield. n.d.=not determined.
16906
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Phosphoryl Hydroquinone Derivatives
FULL PAPER
Scheme 3. A proposed SET mechanism for 1,6-addition of P(O)H com-
pounds to p-quinones.
Scheme 5. Our proposed mechanism: simultaneous double 1,4-addition
and subsequent oxidation.
À
Table 6. Oxidative double 1,4-addition of P(O) H compounds to p-qui-
nones to produce bisphosphoryl-substituted hydroquinones.[a]
H-phosphonate 2 to p-benzoquinone at the 2- and 5-position
simultaneously to produce a 2,5-disubstituted cyclohexa-
diene intermediate B followed by its oxidative aromatiza-
tion by another equivalent of p-benzoquinone to give the
final product 4. Similarly, p-benzoquinone also acts as both
substrate and oxidant.
À
Entry p-Quinone 1 P(O) H 2 Product 4
Yield [%][b]
1
72
Stereospecific 1,4- and 1,6-addition of optically active H-
phosphinates to quinones; synthesis of hydroquinones bear-
ing chiral P-stereogenic phosphorus functionality: It is
worth noting that the current 1,4- and 1,6-addition reactions
all proceed highly stereospecifically with retention of config-
uration at the phosphorus center, thus they can be applied
in the preparation of enantiomerically pure P-chiral com-
pounds by employing easily accessible optically pure H-
phosphinates such as (À)-menthyl phenylphosphinate (RP)-
2h (d.r.>99:1), (À)-menthyl benzylphosphinate (RP)-2i
(d.r.>99:1), and (À)-menthyl-4-vinylbenzylphosphinate
(RP)-2j (d.r.>99:1).[15]
2
3
4
1a
1a
1a
22
65
34
As shown in Table 7, a variety of optically pure monosub-
stituted hydroquinones with P-chiral phosphoryl functionali-
ty were readily generated in moderate to excellent yield by
simply heating a mixture of chiral H-phosphinate with p-
quinone in the presence of 0.5 equivalent of water. p-Benzo-
quinone (1a), 2,5-dimethyl-1,4-benzoquinone (1c), 2,5-di-
phenyl-1,4-benzoquinone (1e), and naphthoquinone (1 f)
could all be used to react with chiral H-phosphinate (RP)-
2h, yielding the corresponding products stereospecifically.
Compared with p-benzoquinone (1a), the reaction of 1c
and 1e was rather slow under the present reaction condi-
tions. Nevertheless, the expected products were obtained
stereospecifically in good yields. The reaction of naphtho-
quinone with (RP)-2h could afford the corresponding prod-
uct in yields up to 91% (d.r.>99:1). In addition to (RP)-2h,
(RP)-(À)-menthyl benzylphosphinate [(RP)-2i] and (RP)-(À)-
menthyl-4-vinylbenzylphosphinate [(RP)-2j] also served as
good substrates to produce the corresponding optically
active phosphoryl-substituted hydroquinones in good yields
(Table 7, entries 5–7). The stereochemistry at phosphorus
À
[a] Reaction conditions: 1,4-benzoquinone (1 mmol), P(O) H (1 mmol),
DMSO (1 mL), N2 atmosphere, 808C, overnight. [b] Isolated yield.
Scheme 4. Generally accepted mechanism: a stepwise pathway involving
1,4-addition and oxidation.[12a–b]
taneous double 1,4-addition and subsequent oxidation proc-
ess to rationalize the reaction. As depicted in Scheme 5, the
reaction takes place by the 1,4-addition of two molecules of
Chem. Eur. J. 2012, 18, 16902 – 16910
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16907

S.-F. Yin, L.-B. Han et al.
Table 7. Stereospecific 1,4-addition of optically active H-phosphinate to
p-quinones.[a]
À
Entry
P*(O) H 2
p-Quinone Product 6
Yield
[%][d]
1
1
95
2
3
2h
2h
2h
81
Figure 1. ORTEP drawing of compound (SP)-6a. Hydrogen atoms are
omitted for clarity; ellipsoids are drawn at 50% probability. Selected
À
À
À
bond lengths [ꢁ] and angles [8]: P1 O1 1.575 (19), P1 O2 1.496 (2), P1
À
À
C11 1.790 (3), P1 C17 1.784 (3), C1 O1 1.481 (3), O1-P1-O2 116.11
(11); O2-P1-C17 109.64 (13), O1-P1-C17 109.64 (13), O2-P1-C11 111.70
(13), O1-P1-C11 102.14 (12), C17-P1-C11 109.07 (13), C1-O1-P1 123.87
(17).
97[b]
4
5
6
91[c]
1a
1e
82
Scheme 6. Oxidative double 1,4-addition of optically active H-phosphi-
nate to p-quinones to produce bis-P-stereogenic-phosphoryl-substituted
hydroquinones.
2i
64
derivatives with retention of configuration at the phospho-
rus center. As exemplified in Scheme 7, the reaction of (À)-
menthyl phenylphosphinate [(RP)-2h] with 1,4-benzoqui-
7
1a
79
[a] Reaction conditions: 1,4-benzoquinone (0.5 mmol), optically active H-
phosphinate (0.5 mmol), H2O (0.25 mmol), toluene (1 mL), N2 atmos-
phere, 1008C, overnight. [b] Reaction performed at 1108C. [c] Naphtho-
quinone/H-phosphinate ratio 2:1. [b] Isolated yield.
Scheme 7. Et3N-promoted 1,6-addition of optically active phosphinate to
p-quinones.
was confirmed by X-ray analysis of compound 6a, which un-
ambiguously showed that the reaction proceeded with reten-
tion of configuration at the phosphorus center (Figure 1).
Furthermore, phosphoryl-substituted hydroquinone
7
none (1a) and 2,6-di-tert-butyl 1,4-benzoquinone (1d) in the
presence of 10 mol% Et3N took place smoothly at room
temperature and yielded the corresponding enantiomerically
pure P-chiral compounds (SP)-8a (d.r.>99:1) and (SP)-8b
(d.r.=95:5) in 67 and 84% yield, respectively. The X-ray
structure of (SP)-8b is shown in Figure 2.
(d.r.>99:1), bearing two P-stereogenic centers, was also suc-
cessfully obtained in 45% isolated yield from the reaction
of optically active (À)-menthyl phenylphosphinate [(RP)-2h]
with p-benzoquinone (1a) in DMSO through the oxidative
double 1,4-addition process (Scheme 6).
Finally, the Et3N promoted 1,6-addition of optically pure
H-phosphinate to p-quinones was also found to proceed
stereospecifically to afford the O-phosphoryl hydroquinone
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Chem. Eur. J. 2012, 18, 16902 – 16910

Phosphoryl Hydroquinone Derivatives
FULL PAPER
(0.5 mmol) in toluene (1 mL) under a nitrogen atmosphere, and the re-
sulting mixture was stirred at 808C for 16 h. GC analysis was used to
monitor the reaction, until the signal of p-benzoquinone disappeared (in-
dicating the end of the reaction). Removal of the solvent under reduced
pressure gave the crude product; pure 3a was obtained by passing the
crude product through a short silica gel column (n-hexane/EtOAc).
Yield: 0.2092 g (85%); yellow oil; 1H NMR (400 MHz, CDCl3, 258C,
TMS): d=9.35 (s, 1H; OH), 7.26 (br, 1H; OH), 6.98–7.26 (m, 1H; Ar),
6.69–6.88 (m, 2H; Ar), 3.97–4.17 (m, 4H; CH2), 1.28 ppm (t, 3J
ACHTUNGTRENNUNG(H,P)=
7.2 Hz, 6H; CH3); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=155.1 (d,
1
1J
G
N
N
3.8 Hz; Ar), 118.6 (d, 1J
Ar), 108.4 (d, 1J
16.1 ppm (d, 1J
d=21.9 ppm.
Typical procedure for the synthesis of 4a: p-Benzoquinone (1 mmol) and
diethyl phosphonate (1 mmol) were dissolved in DMSO (1 mL) under a
nitrogen atmosphere and the resulting mixture was stirred at 808C for
18 h (31P NMR spectroscopic analysis was used to monitor the reaction).
With the disappearance of the 31P signal of diethyl phosphite (indicating
the end of the reaction), water was added. Extraction with ethyl acetate
and removal of the solvent under reduced pressure gave the crude prod-
uct; pure 4a was obtained by passing the crude product through a short
silica gel column (n-hexane/EtOAc). Yield: 0.1375 g (72%); yellow oil;
1H NMR (400 MHz, CDCl3, 258C, TMS): d=11.62 (s, 2H; OH), 7.10 (t,
Figure 2. ORTEP drawing of compound (SP)-8b. Hydrogen atoms are
omitted for clarity; ellipsoids are drawn at 50% probability. Selected
À
À
bond lengths [ꢁ] and angles [8]: P1 O1 1.571 (11), P1 O2 1.470 (12),
3J
7.2 Hz, 12H; CH3); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=158.0
(t, 1J(C,P)=11.4 Hz; Ar), 127.2 (t, 1J (C,P)=5.7 Hz; Ar), 105.9 (dd, 1J-
(C,P1)=7.6 Hz, 1J(C,P2)=173.5 Hz; CP), 62.9 (dd, 1J(C,P1)=1.9 Hz, 1J-
(C,P2)=0.9 Hz; CH2), 16.2 ppm (dd, 1J(C,P1)=2.8 Hz, 1J
(C,P2)=1 Hz;
CH3); 31P NMR (160 MHz, CDCl3, 258C): d=22.32 ppm.
Typical procedure for the synthesis of 5a: Diethyl phosphonate (1 mmol)
was added to mixture of p-benzoquinone (1 mmol) and Et3N
ACHUTNGRENNUG ACHTUNGTRENNUNG(P,H)=
(H,H)=4 Hz, 2H; Ar), 4.03–4.22 (m, 8H; CH2), 1.35 ppm (t, 3J
À
À
À
P1 O3 1.589 (11), P1 C11 1.788 (15), C1 O1 1.473 (18); O1-P1-O2
114.95 (6), O1-P1-O3 102.26 (6), O1-P1-C11 108.86 (7), O2-P1-O3 115.67
(7), O2-P1-C11 112.86 (7), C1-O1-P1 112.36 (9), O3-P1-C11 100.84 (7).
AHCTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
Conclusion
a
We have developed a divergent method for the preparation
of C- and O-phosphoryl hydroquinone derivatives from
(0.1 mmol) in toluene under a nitrogen atmosphere, and the resulting
mixture was stirred at RT for 12 h (GC analysis was used to monitor the
reaction). When the reaction was complete, removal of the solvent under
reduced pressure gave the crude product; pure 5a was obtained by pass-
ing the crude product through a short silica gel column (n-hexane/
EtOAc). Yield: 0.2239 g (91%); yellow oil; 1H NMR (400 MHz, CDCl3,
258C, TMS): d=6.93 (d, 3J (H,H)=8 Hz, 2H; Ar), 6.65 (d, 3J (H,P)=
8.8 Hz, 2H; Ar), 4.17–4.24 (m, 4H; CH2), 1.33–1.37 (m, 6H; CH3),
0.07 ppm (s, 1H; OH); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=
154.1 (s; Ar), 143.2 (d, 1J (C,P)=7.7 Hz; Ar), 120.8 (d, 1J (C,P)=4.8 Hz;
Ar), 116.4 (s; Ar), 64.8 (d, 1J (C,P)=6.7 Hz; CH2), 16.1 ppm (d, 1J
(C,P)=6.7 Hz; CH3); 31P NMR (160 MHz, CDCl3, 258C): d=À5.82 ppm.
À
P(O) H compounds and p-quinones through selective 1,4-
and 1,6-addition reactions. The method avoids the use of
air-sensitive reagents, rendering a simple experimental pro-
cedure. It is noteworthy that all the reactions proceed in a
highly stereospecific fashion with retention of the configura-
tion at the phosphorus atom, allowing facile access to a vari-
ety of optically active organophosphorus compounds from
easily available optically active P(O)H compounds. Consid-
ering the utility of the resulting compounds, this protocol
will have wide application in the construction of biologically
active molecules, catalysis ligands, and organophosphorus
materials.
Crystallographic data: CCDC-902258 ((SP)-8b) and 902259 ((SP)-6a) con-
tain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Experimental Section
Acknowledgements
Solvents used for extraction and chromatography were of technical
grade. All solvents used in reactions were freshly distilled. All other re-
agents were recrystallized or distilled as necessary. All reactions were
performed under an atmosphere of dry nitrogen. 1H (400, 500 MHz), 13C
(100, 125 MHz), and 31P (160, 200 MHz) NMR spectra were recorded
with a JEOL LA-400 instrument or a JEOL LA-500 instrument, respec-
tively, in CDCl3 or [D6]DMSO, as specified below. 1H NMR chemical
shifts (d) are reported in parts per million (ppm), relative to TMS as in-
ternal standard; 13C NMR chemical shifts are reported relative to CDCl3
as internal standard, in broad-band decoupled mode. The abbreviations
used are as follows: singlet (s), doublet (d), double-doublet (dd), triplet
(t), quartet (q), multiplet (m).
This work was supported by the NSF of Hunan Province (10JJ1003), the
NSFC (20973056), and the program for New Century Excellent Talents
in Universities (NCET-10–0371), and the Canon Foundation. B. Xiong
and Dr. R. Shen contributed equally to this work.
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Received: June 12, 2012
Published online: November 9, 2012
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Chem. Eur. J. 2012, 18, 16902 – 16910