Stereospecific Preparations of P-Stereogenic Phosphonothioates and Phosphonoselenoates

Article abstract of DOI:10.1021/acs.joc.6b01192

P-Stereogenic phosphonothioates and phosphonoselenoates were readily prepared utilizing R_P-menthyl phenylphosphite 1 by two methods. The first method used elemental sulfur or selenium to react with 1, followed by alkylation of the intermediates

Full text of DOI:10.1021/acs.joc.6b01192

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Note
Stereospecific Preparations of P-Stereogenic
Phosphonothioates and Phosphonoselenoates
Wei-Min Wang, Li-Juan Liu, Lan Yao, Fan-Jie Meng, Yong-
Ming Sun, Chang-Qiu Zhao, Qing Xu, and Li-Biao Han
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01192 • Publication Date (Web): 13 Jul 2016
Downloaded from http://pubs.acs.org on July 21, 2016
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The Journal of Organic Chemistry
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Stereospecific Preparations of P-Stereogenic Phosphonothioates and
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Phosphonoselenoates
WeiꢀMin Wang,a LiꢀJuan Liu,a Lan Yao,a FanꢀJie Meng,a YongꢀMing Sun,a ChangꢀQiu Zhao,a* Qing
Xub and LiꢀBiao Hanc*.
a College of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, Shandong 252059, China
b College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, China
c National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan
ABSTRACT: PꢀStereogenic phosphonothioates and phosphonoselenoates were readily prepared utilizing RPꢀmenthyl pheꢀ
nylphosphite 1 by means of two methods. The first method used elemental sulfur or selenium to react with 1, followed by alkylaꢀ
tion of the intermediates with alkyl halides. The second used 1 to react with disulfide or diselenide. Both methods stereospecifically
produced the title compounds in nearly quantitative yields under mild conditions. Stereospecific chalcogenation of the phosphoryl
was proposed as the key step in these reactions.
Phosphonothioates and related compounds are widely used as agricultural pesticides due to their important biological activity
such as acetylcholine esterase inhibitors.1,2 These compounds are also famous neurotoxins, herbicides and insecticides. For the purꢀ
pose to explore the metabolism and degradation of these substances in the organism or the nature, phosphonothioates and phosꢀ
phinithioates, especially the Pꢀstereogenic ones, are usually used as substrates.3 Apart from the traditional agricultural, pharmacoꢀ
logical and toxicological applications, Pꢀstereogenic PꢀS species also are widely used as chemicalꢀshift solvating reagent in the
analysis of chiral substances. For example, (RP)ꢀt-BuPhP(S)OH was an efficient chemical shift reagent used to distinguish the enanꢀ
tiomers of chiral amines, alcohols and others with NMR spectroscopy.4 In addition, PꢀS compounds can be used as precursors for
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the preparation of Pꢀstereogenic compounds via nucleophlic substitution, in inverting or retaining configuration on phosphorus,
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with alkoxide or alkyl anions as attacking reagents, respectively.5
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Although the Pꢀstereogenic phosphonothioates and their analogues have versatile applications, the preparation methods were
quite limited, due to the difficulty to acquire Pꢀstereogenic starting materials. On the other hand, HꢀP(O) compounds could be conꢀ
veniently converted to PꢀS compounds by literature methods. For example, Mislow and coworker obtained diastereomerically enꢀ
riched phosphonothioates from a mixture of two stereoisomers of chiral HꢀP(O) compounds.6 The early preparation of (RP)ꢀt-
BuPhP(S)OH was involved in the sulfurization of racemic HꢀP species and kinetic resolution of the products.7 Recently, Kuo obꢀ
tained two enantiomers of optically pure phosphonothioates by means of kinetic resolution.3b An effective preparation of the comꢀ
pounds was realized from the conversion of PꢀH bonds to the PꢀCl bonds, followed by the reaction with thiols, affording phosphonꢀ
othioates in high optical purity, as reported by Han.8 However, to the best of our knowledge, a straightforward preparation of phosꢀ
phonothioates from Pꢀstereogenic HꢀP species has not been realized.
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Recently, we reported a convenient synthesis of RPꢀ(ꢀ)ꢀmenthyl phenylphosphinate 1.9 Considering the usefulness of the PꢀS
compounds and the deficiency of the effective method to acquire them, we pursued the steroeoselective formation of PꢀS bonds
utilizing 1. As discussed below, when 1 reacted with a dialkyldisulfides or elemental sulfur, the title compounds were stereospecifiꢀ
cally produced in nearly quantitative yields under mild conditions.
The study was first carried out by treating a diastereomeric mixture of RPꢀ1/SP-1’ (46/54) with elemental sulfur in the presence of
triethylamine. Two single peaks at 66.8 and 66.5 ppm, in the same ratio of 46/54, were observed in 31PꢀNMR spectroscpy, which
were assigned as the two stereoisomers of phenylphosphinothioate salt 2 and 2’ (Scheme 1). Subsequent addition of ethyl bromide
to the mixture, the alkylation at sulfur took place, affording Sꢀethyl phenylphosphonothioate, also in a mixture of two stereoisomers.
The two peaks at 43.4 and 43.3 ppm on 31P NMR spectroscpy, in the same ratio to the original 1/1’, were assigned as 3b and 3b’. In
proton NMR spectroscpy, the multiplet at 4.43 ppm was assigned as the hydrogen on the αꢀcarbon of menthoxy, and the signals of
3b and 3b’ were coincided together.
Scheme 1. Reaction of 1 or 1/1’ with sulfur followed by alkylation with EtBr and the 31P-NMR spectroscopy.
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Table 1. Preparation of P-chalcogen derivatives 3 (Method A).
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Entry
Y
S
S
S
S
S
S
S
R’
temp./time Solvent Yield % a
1
2
3
4
5
6
7
8
Me
Et
rt/2h
ether
ether
3a, 99 b
3b, 99
3c, 93
3d, 89
3e, 88
3f, 83
3g, 95
3k, 99
3l, 99
rt/72h
9
iPr
50oC/120h neat
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sBu
55oC/72h
neat
neat
cHex 50oC/72h
tBu
60oC/72h
neat
Bn
rt/3h
ether
ether
ether
Se Me
Se Et
rt/2h
9
rt/72h
a
Typicaly procedure of Method A: Reaction of 1 with sulfur or selenium powder in the presence of triethylamine, followed by alkylaꢀ
tion with alkyl halides. The yields were calculated on 31P{H}NMR spectroscopy. b Methyl iodide was used in entry 1, and the alkyl broꢀ
mide were used in other entries.
When optically pure (RP)ꢀ1 was used in the above reactions, only one stereoisomer was detected during the both steps (Scheme 1).
At the first step, only the single peak at 66.5 ppm on 31PꢀNMR spectroscpy was observed. After addition of ethyl bromide, another
signal was observed at 43.4 ppm. The two peaks were assigned as 2 and 3b, respectively, with an R configuration on phosphorus
based on the results of singleꢀcrystal Xꢀray diffraction (vide infra). On the proton NMR spectroscpy, one ddt peak for 3b was obꢀ
served at 4.43 ppm. The formation of a sole stereoisomer for 2 and 3b indicated the reaction of 1 with sulfur proceed in stereospeꢀ
cific manner. Therefore the alkylation on sulfur took place to afford 3b as the sole product.
Various alkyl halides could be used for the Sꢀalkylation of 2, affording the sole RPꢀstereoisomers. As observed in Table 1, aliꢀ
phatic alkyl groups, as well as benzyl, were introduced into the molecules of 3 in excellent yields. The primary alkyl halides such as
methyl iodide and ethyl bromide gave quantitatively 3a and 3b, respectively, at room temperature. The reactions of secondary and
tertiary alkyl halides were performed at a slightly elevated temperature, affording 3c to 3f in good yields.
For 2ꢀbromobutane (R = sꢀBu), two stereoisomers of 3f based on the racꢀ2ꢀcarbon were obtained in ca. 1:1 ratio, which was conꢀ
firmed by the two groups of qt peaks of secꢀhydrogen in 2ꢀbutyl, as observed at 3.26 and 3.19 ppm on proton NMR spectroscpy. No
Cꢀstereoselectivity was detected during the formation of the two isomers. The Seꢀalkyl Oꢀmenthyl phosphonoselenoate 3k and 3l
were similarly prepared, also in quantitative yields, by reaction of 1 with elemental selenium, followed by alkylation. The similar
configurationꢀretention mechanism was deducted for the formation of 3k and 3l.
The R configuration of 3 was unambiguously confirmed by Xꢀray diffraction of 3a. The crystallographic information and cif file
of 3a can be found in the Supporting Information. Because alkylation of 2 took place at sulfur atom, the sulfurization of 1 or inserꢀ
tion of sulfur into PꢀH bond was thence conformed to proceed via Pꢀretention mechanism.6 As observed in Scheme 2, it was proꢀ
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posed that the phosphorus atom attacked at sulfur with its lone pair electron, to form configurationꢀretention intermediate 2A that
was converted to 2B and then to 3.
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Scheme 2. A proposed mechanism for the formation of 3.
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On the other hand, Xu and Huang reported a reaction of (RO)2P(O)ꢀH with disulfides or diselenides, forming Sꢀalkyl phosphonoꢀ
thioates or Seꢀalkyl phosphonoselenoates, respectively.10 When this method was applied to RPꢀ1, as observed in Scheme 3 and Taꢀ
ble 2), we found that the chirality on phosphorus was totally kept intact, also stereospecifically affording one stereoisomer of 3.
Both proton and 31PꢀNMR spectroscopies confirmed that the compounds obtained herein were the same compounds to that obtained
from Method A. Thus the same Pꢀretaining products were obtained from the reaction.
Table 2. Preparation of P-chalcogen derivatives 3 (Method B).
Entry
Y
S
S
S
S
S
S
S
R’
temp./time Solvent Yield % a
1
2
3
4
5
6
7
8
Me
rt/16h
rt/16h
rt/24h
rt/24h
rt/20h
rt/20h
neat
neat
3a, 99
3e, 98
cHex
tBu
Bn
neat
3f, 91
neat
3g, 98
3h, 93 b
3i, 83 b
3j, 89 b
3m, 99 b
Ph
ether
ether
ether
ether
pꢀTol
2,4,5ꢀCl3C6H2 rt/20h
rt/48h
Se Ph
a Typical procedure for Method B: Dimethyl disulfide (0.225 g, 2.4 mmole) and 1 (0.560 g, 2 mmole) was heated at 80°C with stirring
for 16 hours in the presence of AIBN (32.8 mg, 0.2 mmole). The yield was calculated on 31P{H}NMR spectroscopy. b The reactions were
carried out in ether in the absence of AIBN.
Noteworthy, with aromatic disulfides or diselenides, the above reactions of 1 efficiently took place under air, via simple stirring
at room temperature (Scheme 3). Half an equivalent of the disulfide or diselenide 4 was enough to convert 1 to 3 because the genꢀ
erated benzenethiol or benzeneselenol could be oxidized back to 4 by air. The reaction of aliphatic disulfides did not readily proꢀ
ceed under similar conditions. However, in the presence of free radical initiator such as AIBN (2,2’ꢀazobisisobutyronitrile) and at
elevated temperature, they also reacted with 1 affording 3 as single stereoisomers in excellent yields.
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The Journal of Organic Chemistry
It was assumed that aliphatic groups might have stronger electronꢀdonating ability. The increased electron density on sulfur of alꢀ
iphatic disulfides might raise the difficult approaching of phosphorus. On the other hand, the presence of AIBN was helpful to the
cleavage of PꢀH bond by means of formation of free radical on phosphorus, which was less influenced by the electronꢀenrichment
on sulfur atom, leading to an easy occurring reaction (Scheme 4).
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Scheme 3. Preparation of 3 from disulfide or diselenide.
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Scheme 4. A proposed free radical mechanism for the reaction of 1 with aliphatic disulfide.
In summary, the Pꢀchalcogen derivatives, Sꢀalkyl phosphonothioates and Seꢀalkyl phosphonoselenoates were prepared stereospeꢀ
cifically from two methods. The S or Seꢀalkylation with aliphatic alkyl groups was completed by the reaction of 1 with elemental
sulfur or selenium, followed by reactions with alkyl halides. The reaction was confirmed to proceed in Pꢀretaining mechanism by
Xꢀray crystallography. When 1 directly reacted with disulfide or diselenide, the S or Seꢀalkylation products were also afforded steꢀ
reoꢀspecifically, via the same Pꢀretaining mechanism. The present study provides a convenient method for the generation of Pꢀ
chalcogen derivatives, which have extensive applications in both organic synthesis as precursors or auxiliaries, and in pharmacoloꢀ
gy as substrates to explore the metabolism.
Experimental section
All solvents when needed were freshly distilled prior to use. Except 1 that was prepared according to a literature,9 all starting maꢀ
terials and catalysts are commercially available. The purity of the products was checked by TLC on preꢀcoated plates of Silica gel
GF254 using as mobile phase a 3:1 mixture of petroleum ether and ethyl acetate. Melting points were determined on a digital melting
1
point apparatus and temperatures were uncorrected. H NMR spectroscpies were recorded on a 400ꢀMHz spectrometer. Chemical
1
shift for H NMR spectroscpy (in parts per million) relative to internal tetramethylsilane (Me4Si, δ= 0.00 ppm) with CDCl3 or
DMSO. 13C NMR spectroscpies were recorded at 101 mHz Chemical shifts for 13C NMR spectroscpies are reported (in parts per
million) relative to CDCl3 (δ = 77.0 ppm). 31P NMR spectroscpies were recorded at 162 MHz, and chemical shifts reported (in parts
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per million) relative to external 85% phosphoric acid (δ= 0.0 ppm). TLC plates were visualized by UV. The ionization method of
the highꢀresolution mass spectrum (HRMS) is electron impact (EI). The type of the mass analyzer is quadrupole.
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Preparation of (RP)-S-ethyl O-menthyl phenylphosphonothioate (3b) (Typical procedure for preparation of Sꢀalkyl Oꢀmenthyl
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phenylphosphonothioates, Method A)
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A mixture of 1 (1.01 g, 3.6 mmole), triethylamine (0.5 ml, 3.6 mmole) and sulfur powder ( 0.178 g, 5.4 mmole) in diethyl ether
(5 ml) was stirred at room temperature for 24 h. The excess sulfur powder was filtered away and washed with ether (5 ml). The
combined filtrate was evaporated in vacuo to afford 2 as a yellow solid (1.49 g) quantitatively which was used directly without furꢀ
ther purification.
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To the solution of 2 (0.413 g, 1 mmole) in ether (5 ml), ethyl bromide (0.150 ml, 2 mmole) was added. The mixture was stirred
for 72 h at room temperature. The solid was filtered off and washed with ether for three times. The combined filtrated was evapoꢀ
rated in vacuo and the residue was purified with preparative TLC (silica gel, chloroform/methanol 20:1 as eluent) to afford the
1
product as pale yellow oil (306 mg, 90% yield). H NMR (400 MHz, CDCl3) δ = 7.98 – 7.81 (m, 2H), 7.63 – 7.40 (m, 3H), 4.47
(ddd, JPꢀH=19.4, J=10.6, J=4.5, 1H), 2.79 (dq, J=12.4, 7.4, 2H), 2.35 (d, J=12.3, 1H), 2.20 (dtd, J=13.8, 6.9, 2.2, 1H), 1.77 – 1.61
(m, 2H), 1.57 – 1.37 (m, 2H), 1.26 (dd, J=13.8, 6.3, 5H), 1.21 – 1.01 (m, 1H), 0.97 (d, J=7.0, 3H), 0.91 (t, J=6.7, 6H). 31P NMR
(162 MHz, CDCl3) δ 40.97. 13C NMR (101 MHz, CDCl3) δ = 134.3 (d, J=150.5), 132.1 (d, J=3.1), 131.1 (d, J=10.8), 128.3 (d,
J=14.7), 48.67 (d, J=7.3), 43.5, 34.0, 31.6, 29.6, 29.6, 25.6, 24.8 (d, J=2.5), 22.9, 21.8, 21.1, 16.1 (d, J=5.8), 16.0. HRMS (ESI+)
calculated for C18H29O2PS: 340.1626, found: 340.1517.
(RP)-S-methyl O-menthyl phenylphosphonothioate (3a)
The compound was prepared by reaction of 2 with methyl iodide in ether for 2 h, isolated as a pale yellow solid (301 mg, 92%
yield). Mp 75ꢀ76°C. 1H NMR (400 MHz, CDCl3) δ = 7.93 – 7.77 (m, 2H), 7.60 – 7.38 (m, 3H), 4.45 (ddd, JPꢀH=19.3, J=10.6, J=4.5,
1H), 2.31 (d, J=12.2, 1H), 2.24 – 2.06 (m, 3H), 2.06 – 1.82 (m, 1H), 1.67 (dd, J=21.0, 8.1, 2H), 1.42 (t, J=11.1, 2H), 1.30 – 1.13 (m,
2H), 1.04 (dd, J=13.0, 2.6, 1H), 0.95 (d, J=7.0, 3H), 0.87 (t, J=6.7, 6H). 31P NMR (162 MHz, CDCl3) δ 44.62. 13C NMR (101 MHz,
CDCl3) δ = 133.3 (d, J=150.4), 132.2 (d, J=2.9), 131.1 (d, J=10.7), 128.4 (d, J=14.8), 48.7 (d, J=7.2, 2.8), 43.5, 34.0, 31.6, 25.7,
22.9, 22.9, 21.8, 21.1, 15.9, 11.9. HRMS (ESI+) calculated for C17H28O2PS [M + H]+: 327.1531, found: 327.1542.
(RP)-S-isopropyl O-menthyl phenylphosphonothioate (3c)
The compound was prepared by reaction of 2 with isopropyl bromide at 50°C for 120 h, isolated as a pale yellow solid from reꢀ
crystallization with etherꢀhexane (262 mg, 74% yield). Mp 117ꢀ118°C. 1H NMR (400 MHz, CDCl3) δ = 7.91 (dd, J=13.8, 7.1, 2H),
7.53 (dd, J=23.0, 5.5, 3H), 4.61 – 4.31 (m, 1H), 3.57 – 3.29 (m, 1H), 2.35 (d, J=11.5, 1H), 2.21 (s, 1H), 1.81 – 1.55 (m, 3H), 1.53 –
1.36 (m, 4H), 1.34 – 1.16 (m, 5H), 1.15 – 1.02 (m, 1H), 0.98 (d, J=7.0, 3H), 0.92 (dd, J=6.5, 4.2, 6H). 31P NMR (162 MHz, CDCl3)
δ 42.41. 13C NMR (101 MHz, CDCl3) δ 135.7, 132.0, 131.1 (d, J=10.8), 128.3 (d, J=14.7), 48.7 (d, J=7.3), 43.5, 37.4, 34.05, 31.6,
29.7, 25.5 (d, J=6.5), 22.9, 21.9, 21.1, 16.1, ꢀ0.1. HRMS (ESI+) calculated for C19H32O2PS[M + H]+: 355.1861, found: 355.1855
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(RP)-S-secbutyl O-menthyl phenylphosphonothioate (3d)
The compound was prepared by reaction of 2 with secbutyl bromide at 55°C for 72 h, isolated as pale yellow oil (279 mg, 76%
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2
3
4
5
6
7
8
9
yield. 1H NMR (400 MHz, CDCl3) δ = 7.91 (dd, J=13.8, 7.1, 2H), 7.53 (dd, J=23.0, 5.5, 3H), 4.61 – 4.31 (m, 1H), 3.57 – 3.29 (m,
1H), 2.35 (d, J=11.5, 1H), 2.21 (s, 1H), 1.81 – 1.55 (m, 3H), 1.53 – 1.36 (m, 4H), 1.34 – 1.16 (m, 5H), 1.15 – 1.02 (m, 1H), 0.98 (d,
J=7.0, 3H), 0.92 (dd, J=6.5, 4.2, 6H). 31P NMR (162 MHz, CDCl3) δ 42.71. 13C NMR (101 MHz, CDCl3) δ 135.9 (J=33.8), 134.4
(J=33.7), 131.9 (J=3.0), 131.0 (J=5.4), 128.2 (J=11.5), 78.9 (J=3.8), 77.0 (J=32.2), 48.7 (J=7.7), 43.8, 43.5, 34.0, 31.5 (J=6.9), 25.4
(J=16.9), 23.0 (J= 4.5), 22.9, 22.8 (J=3.8), 21.9, 21.0 (J=16.9), 16.1, 11.2, 11.0. HRMS (ESI+) calculated for C20H33O2PS:
368.1939, found: 368.1836.
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(RP)-S-cyclohexyl O-menthyl phenylphosphonothioate (3e)
The compound was prepared by reaction of 2 with cyclohexyl bromide at 55°C for 72 h, isolated as pale yellow oil (295 mg, 75%
1
yield). H NMR (500 MHz, CDCl3): δ 7.89ꢀ7.85 (m, 2H), 7.54ꢀ7.50 (m, 1H), 7.48ꢀ7.44 (m, 2H), 4.46ꢀ4.40 (m, 1H), 3.28ꢀ3.23 (m,
1H), 2.34ꢀ2.29 (m, 1H), 2.21ꢀ2.14 (m, 1H), 2.08ꢀ2.05 (m, 1H), 1.80ꢀ1.15 (m, 14H), 1.09ꢀ1.00 (qd, J = 13.1 Hz, J = 4.6 Hz, 1H),
0.94 (d, J = 7.3 Hz, 3H), 0.90ꢀ0.80 (m, 7H). 13C NMR (125.4 MHz, CDCl3): δ 135.2 (JCP = 149.7 Hz), 132.0 (JCP = 3.1 Hz), 131.0
(JCP = 10.3 Hz), 128.3 (JCP = 14.5 Hz), 78.9 (JCP = 8.3 Hz), 48.7 (JCP = 7.1 Hz), 45.1 (JCP = 2.1 Hz), 43.5, 35.5 (JCP = 4.1 Hz), 35.4
(JCP = 4.1 Hz), 34.1, 31.6, 25.9 (JCP = 15.5 Hz), 25.5, 25.3, 22.9, 21.9, 21.2, 16.1. 31P NMR (201.9 MHz, CDCl3): δ 42.2. HRMS for
C22H35O2PS, calcd: 394.2095, found: 394.2073.
(RP)-S-tertbutyl O-menthyl phenylphosphonothioate (3f)
The compound was prepared by reaction of 2 with tertbutyl bromide at 60°C for 72 h, isolated as pale yellow oil (262 mg, 71%
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yield). H NMR (400 MHz, CDCl3) δ = 8.07 – 7.67 (m, 2H), 7.65 – 7.31 (m, 2H), 4.58 – 4.21 (m, 1H), 2.34 (d, J=12.3, 1H), 2.17
(dtd, J=13.9, 6.9, 2.3, 1H), 1.74 – 1.57 (m, 1H), 1.45 (s, 9H), 1.39 – 1.24 (m, 2H), 1.15 (dd, J=23.3, 12.2, 2H), 1.09 – 0.97 (m, 1H),
0.93 (d, J=7.0, 3H), 0.88 (dd, J=6.6, 5.1, 6H). 31P NMR (162 MHz, CDCl3) δ 40.20. 13C NMR (101 MHz, CDCl3) δ = 136.2 (d,
J=150.0), 131.8 (d, J=3.1), 131.1 (d, J=10.8), 128.2 (d, J=14.7), 50.2 (d, J=3.4), 48.7 (d, J=7.4), 43.6, 34.1, 32.9 (d, J=5.1), 31.6,
25.4, 22.9, 21.9, 21.2, 16.1. HRMS (ESI+) calculated for C20H34O2PS[M + H]+: 369.2009, found: 369.2012.
(RP)-S-benzyl O-menthyl phenylphosphonothioate (3g)
The compound was prepared by reaction of 2 with benzyl chloride at rt for 3 h, isolated as pale yellow solid (326 mg, 81% yield).
Mp 62ꢀ63 °C. 1H NMR (400 MHz, CDCl3) δ = 7.89 – 7.74 (m, 2H), 7.58 – 7.38 (m, 3H), 7.26 – 7.13 (m, 5H), 4.42 (ddd, JPꢀH=19.6,
J=10.6, J=4.5, 1H), 4.20 – 3.86 (m, 2H), 2.35 (d, J=12.2, 1H), 2.17 (dq, J=6.8, 4.8, 1H), 1.68 (dd, J=17.7, 7.2, 2H), 1.42 (dd,
J=15.6, 6.8, 2H), 1.22 (dd, J=23.3, 12.1, 2H), 1.03 (ddd, JPꢀH=26.5, J=13.4, J=3.6, 1H), 0.94 (d, J=7.0, 3H), 0.88 (dd, J=10.8, 6.7,
6H). 31P NMR (162 MHz, CDCl3) δ 42.36. 13C NMR (101 MHz, CDCl3) δ = 137.4 (d, J=2.3), 137.3 (d, J=2.3), 134.7 (d, J=6.4),
133.2 (d, J=6.5), 132.1 (d, J=3.0), 131.0 (d, J=10.9), 128.4 (d, J=0.9), 128.4 (d, J=1.5), 128.2 (d, J=1.5), 127.3 (d, J=1.5), 48.7,
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48.6, 43.5, 34.6, 34.0, 31.6, 25.6, 22.9, 21.9, 21.2, 16.0. HRMS (ESI+) calculated for C23H32O2PS[M + H]+: 403.1844, found:
403.1855
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Preparation of (RP)-Se-ethyl O-menthyl phenylphosphonoselenoate (3l) (Typical procedure for preparation of Seꢀalkyl Oꢀ
menthyl phenylphosphonoselenoates 3kꢀ3l, Method A)
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Triethylamine (0.263 ml, 1.892 mmole) was added to the mixture of 1 (0.265 g, 0.946 mmole) and selenium powder (82.2 mg,
1.04 mmole, 1.1 eq.) with stirring. Ether (5 ml) was added to the mixture and the resulted suspension was stirred at room temperaꢀ
ture for 24 h. Ethyl bromide (0.141 ml, 1.892 mmole, 2 eq.) was added and the mixture was stirred at room temperature for 72 h.
Ether (10 ml) was added to the mixture and the solid was filtered away, washed with ether. The combined ether solution was
washed with water, dried over magnesium sulfate. After evaporation of solvent, the residue was purified with preparative TLC (siliꢀ
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ca gel, chloroform/methanol 20:1 as eluent) to afford yellow oil as product (308 mg, 84% yield). H NMR (400 MHz, CDCl3) δ =
7.89 – 7.75 (m, 2H), 7.57 – 7.38 (m, 3H), 4.43 (ddd, J=20.2, 10.3, 4.5, 1H), 2.87 – 2.61 (m, 3H), 2.34 (d, J=12.2, 1H), 2.15 (dt,
J=13.7, 6.9, 1H), 1.67 (dd, J=20.4, 8.0, 2H), 1.53 – 1.38 (m, 2H), 1.33 (q, J=7.3, 2H), 1.28 – 1.13 (m, 2H), 1.05 (ddd, J=16.7, 13.7,
3.6, 1H), 0.94 (d, J=7.0, 3H), 0.87 (t, J=6.2, 6H). 31P NMR (162 MHz, CDCl3) δ 38.24. 13C NMR (101 MHz, CDCl3) δ 136.4, 135.0,
132.0 (d, J=3.1), 130.7 (d, J=11.2), 128.3 (d, J=14.7), 48.7 (d, J=7.5), 43.5, 34.0, 31.6, 25.6, 22.9, 21.8, 21.2, 20.0 (d, J=3.1), 16.6
(d, J=4.7), 16.2. MS (ESI+) calculated for C18H29O2PSe: 388.107, found: 388.1. Elemental analysis: calculated for C18H29O2PSe: C,
55.81; H, 7.55; found: C, 55.75; H, 7.66.
(RP)-Se-methyl O-menthyl phenylphosphonoselenoate (3k)
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The product was isolated as yellow oil (286 mg, 84% yield). H NMR (400 MHz, CDCl3) δ = 7.83 (ddd, J=13.8, 8.2, 1.3, 2H),
7.58 – 7.40 (m, 3H), 4.44 (ddd, JPꢀH=19.9, J=10.6, J=4.5, 1H), 2.34 (d, J=12.3, 1H), 2.17 (ddd, J=18.6, 9.3, 4.6, 1H), 2.07 – 2.02 (m,
3H), 1.68 (dd, J=20.7, 8.5, 2H), 1.43 (dd, J=16.7, 6.8, 2H), 1.22 (dd, JPꢀH=23.3, J=12.1, 2H), 1.05 (ddd, J=16.7, 13.8, 3.8, 1H), 0.95
(d, J=7.0, 3H), 0.88 (t, J=7.2, 6H). 31P NMR (162 MHz, CDCl3) δ 38.74. 13C NMR (101 MHz, CDCl3) δ 135.4, 134.1, 132.2 (d,
J=3.1), 130.8 (d, J=11.2), 128.4 (d, J=14.7), 48.7 (d, J=7.5), 43.5, 34.0, 31.6, 25.7, 22.9, 21.8, 21.2, 16.1, 4.5. Elemental analysis:
calculated for C17H27O2PSe: C, 54.69; H, 7.29; found: C, 54.75; H, 7.38.
Preparation of (RP)-S-methyl O-menthyl phenylphosphonothioate (3a) (Typical procedure for preparation of Sꢀalkyl Oꢀ
menthyl phenylphosphonothioate; Method B).
Dimethyl disulfide (0.225 g, 2.4 mmole) and 1 (0.560 g, 2 mmole) was heated at 80°C with stirring for 16 hours in the presence
of AIBN (32.8 mg, 0.2 mmole). After removing low boiling point substances, the residue was purified as above (for 3a) and gave
the same spectroscpy data to Method A in 85% isolated yield.
(RP)-S-cyclohexyl O-menthyl phenylphosphonothioate (3e)
The compound was prepared from 2 and dicyclohexyl disulfide in 98% yield, giving the same spectroscpy data to the compound
obtained from method A.
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(RP)-S-tertbutyl O-menthyl phenylphosphonothioate (3f)
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The compound was prepared from 2 and ditertbutyl disulfide in 91% yield, giving the same spectroscpy data to the compound
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(RP)-S-benzyl O-menthyl phenylphosphonothioate (3g)
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The compound was prepared from 2 and dibenzyl disulfide in 98% yield, giving the same spectroscpy data to the compound obꢀ
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tained from method A.
(RP)-S-phenyl O-menthyl phenylphosphonothioate (3h) (Typical procedure for preparation of S or Seꢀaryl Oꢀmenthyl pheꢀ
nylphosphonothioate, Method B).
To the solution of 1 (0.276 g, 0.984 mmole) in ether (1 ml), diphenyl diselenide (0.214 g, 0.984 mmole) was added, and the reꢀ
sulted solution was stirred open to air at room temperature for 24 h. the crude product was purified with preparative TLC (silica gel,
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chloroform/methanol 20:1 as eluent) to afford a pale yellow oil as product (324 mg, 85% yield). H NMR (500 MHz, CDCl3): δ
7.74ꢀ7.69 (m, 2H), 7.53ꢀ7.49 (m, 1H), 7.41ꢀ7.38 (m, 4H), 7.31ꢀ7.27 (m, 1H), 7.24ꢀ7.21 (m, 2H), 4.58ꢀ4.51 (m, 1H), 2.27ꢀ2.17 (m,
2H), 1.74ꢀ1.68 (m, 2H), 1.50ꢀ1.43 (m, 2H), 1.23ꢀ1.16 (q, J = 11.9 Hz, 1H), 1.13ꢀ1.04 (qd, J = 11.3 Hz, J = 4.9 Hz, 1H), 0.97 (d, J =
6.1 Hz, 3H), 0.90 (d, J = 7.3 Hz, 3H), 0.87 (d, J = 8.6 Hz, 3H). 13C NMR (125.4 MHz, CDCl3): δ 135.4 (JCP = 4.1 Hz), 133.2 (JCP
=
149.9 Hz), 132.2 (JCP = 3.1 Hz), 131.4 (JCP = 10.3 Hz), 129.0 (JCP = 2.1 Hz), 128.7 (JCP = 2.1 Hz), 128.1 (JCP = 14.4 Hz), 126.7 (JCP
= 5.1 Hz), 79.8 (JCP = 8.3 Hz), 48.7 (JCP = 7.1 Hz), 43.4, 34.0, 31.6, 25.6, 22.9, 21.9, 21.2, 16.0. 31P NMR (201.9 MHz, CDCl3): δ
39.8. HRMS for C22H29O2PS, calcd: 388.1626, found: 388.1604.
(RP)-S-p-methylphenyl O-menthyl phenylphosphonothioate (3i)
The compound was prepared from 2 and ditolyl disulfide, isolated as pale yellow oil (265 mg, 67% yield). 1H NMR (500 MHz,
CDCl3): δ 7.74ꢀ7.70 (m, 2H), 7.51ꢀ7.47 (m, 1H), 7.41ꢀ7.37 (m, 2H), 7.27ꢀ7.25 (m, 2H), 7.02 (d, J = 7.6 Hz, 2H), 4.55ꢀ4.50 (m, 1H),
2.29 (s, 3H), 2.26ꢀ2.15 (m, 2H), 1.72ꢀ1.65 (m, 2H), 1.46ꢀ1.42 (m, 2H), 1.22ꢀ14 (q, J = 12.1 Hz, 1H), 1.11 (dq, J = 13.1 Hz, J = 3.4
Hz, 1H), 0.96 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H). 13C NMR (125.4 MHz, CDCl3): δ 138.9 (JCP
=
3.1 Hz), 135.3 (JCP = 4.1 Hz), 133.4 (JCP = 149.9 Hz), 132.1 (JCP = 3.1 Hz), 131.4 (JCP = 11.3 Hz), 129.8 (JCP = 2.0 Hz), 128.1 (JCP
= 14.4 Hz), 122.8 (JCP = 5.0 Hz), 79.7 (JCP = 8.3 Hz), 48.7 (JCP = 6.1 Hz), 43.4, 34.0, 31.6, 25.6, 22.9, 21.9, 21.2, 21.1, 16.0. 31P
NMR (201.9 MHz, CDCl3): δ 39.9. HRMS for C23H31O2PS, calcd: 402.1782, found: 402.1792.
(RP)-S-(2,4,5-trichlorophenyl) O-menthyl phenylphosphonothioate (3j)
The compound was prepared from 2 and ditolyl disulfide, isolated as pale yellow oil (366 mg, 76% yield). 1H NMR (500 MHz,
CDCl3): δ 7.81ꢀ7.75 (m, 3H), 7.58ꢀ7.55 (m, 1H), 7.48ꢀ7.44 (m, 3H), 4.62ꢀ4.55 (m, 1H), 2.25ꢀ2.14 (m, 2H), 1.75ꢀ1.67 (m, 2H), 1.51ꢀ
1.46 (m, 2H), 1.25ꢀ1.18 (q, J = 11.5 Hz, 1H), 1.13ꢀ1.05 (qd, J = 13.4 Hz, J = 3.4 Hz, 1H), 0.99 (d, J = 7.4 Hz, 3H), 0.91 (d, J = 9.2
Hz, 3H), 0.88 (d, J = 7.4 Hz, 3H). 13C NMR (125.4 MHz, CDCl3): 132.2, 132.1, 131.4, 131.3, 131.2, 130.8, 130.7, 130.2, 129.1,
128.9, 128.4, 128.3, 48.6 (JCP = 2.3), 43.1, 34.2, 31.7, 25.6, 23.0, 22.1, 21.1, 15.6, 0.1. 31P NMR (201.9 MHz, CDCl3): δ 38.0.
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HRMS for C22H26Cl3O2PS, calcd: 490.0457, found: 490.0380. Elemental analysis: calculated for C22H26Cl3O2PS: C, 53.72; H, 5.33;
found: C, 53.89; H, 5.41.
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(RP)-Se-phenyl O-menthyl phenylphosphonoselenoate (3m)
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To the solution of 1a (0.276 g, 0.984 mmole) in ether (1 ml), diphenyl diselenide (0.309 g, 0.984 mmole) was added, and the reꢀ
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sulted solution was stirred open to air at room temperature for 24 h. the crude product was purified with preparative TLC (silica gel,
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chloroform/methanol 20:1 as eluent) to afford a pale yellow solid as product (369 mg, 86% yield). Mp 34ꢀ35°C. H NMR (500
MHz, CDCl3): δ 7.70ꢀ7.65 (m, 2H), 7.51ꢀ7.45 (m, 3H), 7.41ꢀ7.37 (m, 2H), 7.31ꢀ7.28 (m, 1H), 7.21ꢀ7.18 (m, 2H), 4.55ꢀ4.50 (m, 1H),
2.29ꢀ2.15 (m, 2H), 1.74ꢀ1.66 (m, 2H), 1.50ꢀ1.44 (m, 2H), 1.25ꢀ1.18 (q, J = 11.6 Hz, 1H), 1.12ꢀ1.04 (qd, J = 12.8 Hz, J = 4.0 Hz,
1H), 0.98 (d, J = 5.2 Hz, 3H), 0.92ꢀ0.83 (m, 7H). 13C NMR (125.4 MHz, CDCl3): δ 136.3 (JCP = 4.1 Hz), 135.5 (JCP = 136.4 Hz),
132.2 (JCP = 3.1 Hz), 131.0 (JCP = 11.4 Hz), 129.1 (JCP = 2.1 Hz), 128.5 (JCP = 2.0 Hz), 128.1 (JCP = 15.5 Hz), 124.2 (JCP = 5.1 Hz),
80.1 (JCP = 9.3 Hz), 48.7 (JCP = 7.3 Hz), 43.4, 34.0, 31.6, 25.7, 23.0, 21.9, 21.2, 16.1. 31P NMR (201.9 MHz, CDCl3): δ 36.3. HRMS
for C22H29O2PSe, calcd: 436.1070, found: 436.1089.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: literabc@hotmail.com, libiaoꢀhan@aist.go.jp
Notes
The authors declare no competing financial interest..
ACKNOWLEDGMENT
The authors acknowledge the financial support of the Natural Science Foundation of China (grant no. 20772055)
ASSOCIATED CONTENT
Supporting Information
The Supporting Information, including crystallographic information and cif file of 3a, photocopies of 1H, 31P, and 13C NMR spectroscpies,
is available free of charge on the ACS Publications website.
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(5) Methylthio of 3a could be displaced by alkyloxy with inversion of configuration, however displaced by RM with retention of configuration.
(a) Farnham, W. B.; Mislow, K. Chem. Commun. 1972, 120. (b) Kawashima, T.; Kojima, S.; Inamoto, N. Chem. Lett. 1989, 849ꢀ852. (c) Debruin,
K. E.; Tang, C. W.; Johnson, D. M.; Wilde, R. L. J. Am. Chem. Soc. 1989, 111, 5871ꢀ5879
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of 1/1’ and fiveꢀfold molar excess of dimethyl disulphide in nꢀheptane afforded 60:40 mixture of 3a/3a’, and the reaction was complicated by epiꢀ
merization. They did not distinguish the two diastereomers and discuss the stereochemistry of sulfurization, as seen Ref. 5a and: Farnham, W. B.;
Mislow, K. Chem. Commun., 1971, 605.
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