Three-Component Coupling Reaction in Water: A One-Pot Protocol for the Construction of P–S–C(sp3) and P–Se–C(sp3) Bonds

Article abstract of DOI:10.1002/ejoc.201700344

A one-pot, three-component coupling reaction of primary alkyl halides (or tosylates), elemental sulfur/selenium, and P(O)–H compounds in water was developed. This procedure affords valuable phosphorothioates/phosphoroselenoates, including P-chiral compounds, with broad substrate scope and high efficiency. Moreover, this facile protocol can be applied to gram-scale preparations.

Full text of DOI:10.1002/ejoc.201700344

A Journal of
Accepted Article
Title: Three-Component Coupling Reaction in Water: A One-Pot
Protocol for the Construction of P-S-C(sp3) and P-Se-C(sp3)
Bonds
Authors: Xinghua Zhang, Zheng Shi, Changwei Shao, Jinlong Zhao,
Dungai Wang, Gaoqi Zhang, and Liang Li
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700344
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10.1002/ejoc.201700344
European Journal of Organic Chemistry
COMMUNICATION
Three-Component Coupling Reaction in Water: A One-Pot
Protocol for the Construction of P-S-C(sp3) and P-Se-C(sp3)
Bonds
Xinghua Zhang,*[a] Zheng Shi,[a] Changwei Shao,[a] Jinlong Zhao,[a] Dungai Wang,[a] Gaoqi Zhang,[a] and
Liang Li*[a]
ABSTRACT:
A one-pot three-component coupling reaction of
primary alkylhalides (or tosylates), elemental sulfur/selenium and
P(O)-H compounds in water is developed, affording the valuable
phosphorothioates or phosphoroselenoates including the P-chiral
compounds with broad substrate scope and high efficiency.
Moreover, this facile protocol also can be applicable for the gram-
scale preparation.
Introduction
The P-chalcogen derivatives are important and useful scaffolds
in medicines1, agricultural industry2 and organic synthesis3.
Among them, phosphorothioates have received considerable
attention in the past decades due to their unique properties. The
phosphorothioates were normally synthesized by coupling H-
phosphonates with disulfides4,5a
,
sulfonylhydrazides5b, aryl
sulfonyl chlorides5c,6 or thiols7,8, catalyzed by transition metals,
e.g., Cu5,7,9 and Pd10. However, these protocols have their own
limitations, including narrow scope of substrates, foul-smelling
materials and expensive metal catalysts. In addition,
conventional strategies for the construction of P-S-C(sp3) bond
often started with toxic and moisture sensitive phosphoryl
chloride11 [Scheme 1(a)], sodium reagents4 [Scheme 1(b)],
RSX8a [Scheme 1(c)] or phenylphosphinothioate salt12 [Scheme
1(d)], which required a two-step workup procedure, further
limiting their applications.
Scheme 1. Synthesis of P-Chalcogen Derivatives
Results and Discussion
At the outset, compound 1a, (2-(4-bromobutyl)isoindoline-1,3-
dione), 2a, sulfur powder, and 3a, diphenylphosphine oxide,
were chosen as model substrates to investigate the optimum
reaction condition. The influence of the base, reaction time and
reaction temperature were screened, which were summarized in
Table 1. The desired P-S-C coupling product, 4a, was obtained
in 31% yield when the reaction mixtures, 1a (0.5 mmol), 2a (0.5
mmol) and 3a (0.5 mmol), were stirred in neat water (0.75 mL) at
Even though some of the above reported procedures are
efficient, to the best of our knowledge, there are still no reports
on the synthesis of the P-chalcogen derivatives in aqueous
solutions, i.e. water. Furthermore, the increased environmental
requirements called for more efficient and organic solvent free
procedures for chemical syntheses13. As a part of our continued
activities in this area6,14, herein we report a facile one-pot three-
component coupling of P(O)-H compounds with elemental
sulfur/selenium and primary alkylhalides (or tosylates) under
relatively mild conditions in water [Scheme 1(e)].
o
50 C for 24 h (Table 1, entry 3). However, trace amount of 4a
were examined by reducing reaction temperature and time
(Table 1, entries 1 and 2). As expected, the yield of product 4a
dramatically increased to 82% when the organic base, 1.0 equiv.
of Et3N, was added (Table 1, entry 4). Unfortunately, the P-S-
C(sp3) bond transformation was not found to be accelerated by
elevating the reaction temperature to 80 oC (80% yield, Table 1,
entry 5). Moreover, an increase of the base amount results in a
reduced yield (72%, 69% yields, Table 1, entries 6-7). No
apparent improvement was observed when the usage amount of
2a, 3a was raised to 1.2 equiv. (84%, 78% yields, Table 1,
[a]
School of Chemical and Environmental Engineering, Shanghai
Institute of Technology, 100 Hai-Quan Road, Shanghai 201418,
China
E-mail: xhzhang@sit.edu.cn; lilianglcx@sit.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700344
European Journal of Organic Chemistry
COMMUNICATION
Table 2. Base-Promoted Synthesis of Phosphorothioates in Watera
Table 1. Optimization of Reaction Condition
T(oC)
25
25
50
50
80
50
50
50
50
50
50
50
50
50
50
50
50
50
Entry
1a
Base
t(h)
12
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
Yield (%)d
Trace
Trace
31
None
2a
None
3a
None
4a
Et3N(1.0eq.)
Et3N(1.0eq.)
Et3N(1.2eq.)
Et3N(1.5eq.)
Et3N(1.2eq.)
Et3N(1.5eq.)
Et3N(1.5eq.)
Na2CO3(1.5eq.)
K2CO3(1.5eq.)
DIPA(1.5eq.)
DIPEA(1.5eq.)
NaOH(1.5eq.)
t-BuOK(1.5eq.)
Et3N(2eq.)
Et3N(3eq.)
82
5a
80
6a
72
7a
69
8b
84
9b
78
10c
11c
12c
13c
14c
15c
16c
17c
91
54
73
61
89
54
31
65
18c
37
[a] The reactions were performed with (entries 1-7): 1a (0.5 mmol), 2a (0.5
mmol), 3a (0.5 mmol), Base (0-1.5 eq. based on 1a), H2O (0.75 mL) in air. [b]
Entries 8-9: 1a (0.5 mmol), 2a (0.6 mmol), 3a (0.6 mmol), Base (1.2-1.5 eq.
based on 1a), H2O (0.75 mL) in air. [c] Entries 10-18: 1a (0.5 mmol), 2a (0.75
mmol), 3a (0.75 mmol), Base (1.5-3 eq. based on 1a), H2O (0.75 mL) in air.
dIsolated yields based on 1a. (DIPA
= Diisopropylamine, DIPEA =
Diisopropylethylamine)
entries 8-9). The further study showed that this reaction was
carried out most efficiently as the amount of the Et3N, sulfur
powder (2a) and P(O)-H compound (3a) were all increased to
1.5 equiv (91% yield, Table 1, entry 10). We then also
investigated the influence of the base (Table 1, entries 10-16)
and Et3N was found to be superior to other bases, including
Na2CO3, K2CO3, NaOH, t-BuOK, DIPA and DIPEA. Notably,
increasing the amount of Et3N led to a drastic reduction in
reaction efficiency (Table 1, entries 17 and 18). Therefore, the
optimum reaction condition was set as 1a (0.5 mmol), 2a (0.75
mmol), 3a (0.75 mmol), and Et3N (0.75 mmol) in 0.75 mL water
at 50 oC for 24 h for the reaction scope investigations.
[a] Reaction conditions: 1 (0.5 mmol), 2a (0.75 mmol), 3 (0.75 mmol), Et3N
(0.75 mmol), H2O (0.75 mL) at 50°C for 24 h. Isolated yields based on 1. [b]
for 4h, 4i: 1 (0.75 mmol), 2a (0.75 mmol), 3 (0.5 mmol), Et3N (0.75 mmol), H2O
(0.75 mL) at 50°C for 24 h. Isolated yields based on 3.
examined under optimized reaction conditions. As illustrated in
Table 2, the substrates bearing different leaving groups (iodide,
bromide, chloride, tosylate) were readily reacted with sulfur
powder and P(O)-H compounds to afford the corresponding
phosphorothioates in moderate to excellent yields. Moreover,
the P-S-C(sp3) bond was unambiguously confirmed by the X- ray
crystallographic analysis of 4b (Figure 1). Bis-coupling products
can also be obtained from bis-substituted primary alkylbromides,
To explore the scope of the established protocol, a wide set of
primary
alkylhalides
(or
tosylates),
1,
and
four
organophosphorus compounds containing P(O)-H, 3, were
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10.1002/ejoc.201700344
European Journal of Organic Chemistry
COMMUNICATION
with yields in 71% and 49%, respectively (Table 2, 4l, 4m).
Moreover, functional groups including carboxylic ester, hydroxyl,
alkoxyl, bromide, chloride, alkynyl and alkenyl groups were
tolerable under the current protocol, and afforded the
corresponding products 4e-4k in 48-91% yields (Table 2, 4e-4k).
Substituted primary alkylbromides with methoxy, alkenyl, and
carboxylic ester groups could also react with DOPO (3b) and
Table 3. Base-Promoted Synthesis of Phosphoroselenoates in Watera
optically
pure
H-phosphinate
((RP)-(-)-menthyl
benzylphosphinate) (3c)15 to provide corresponding products in
65%, 56% and 59% yields (Table 2, 4r, 4s and 4x), respectively.
It is worth noting that the R configuration of enantiomerically
pure P-chiral phosphorothioates 4t-4x was confirmed by X-ray
diffraction of 4w (Figure 1)12. In contrasted to the classical
Atherton-Todd reaction, the configuration at the phosphorus
atom obtained by this approach is retentive, but not inversed16.
However, less-effective reactions were also observed for H-
phosphonates, 3d, which resulted in the corresponding products
4y and 4z in only 11% and 6% yields in water. To our delight,
this method was not only suitable for small quantity synthesis,
but also applicable for the gram-scale preparation. A gram scale
preparation of compound 4a, S-(4-(1,3-dioxoisoindolin-2-yl)butyl)
diphenylphosphinothioate, was obtained in 84% isolated yield
(Table 2, 4a, 3.66 g), further demonstrating the practicality of the
method.
[a] Unless otherwise mentioned, the reactions were performed with 1a (0.75
mmol), 2b (0.6 mmol), 3 (0.5 mmol), Et3N (0.75 mmol) at 50°C for 24 hours in
0.75 mL water. Isolated yields based on 3.
Figure 1. Single-crystal X-ray structure of compound 4b (left) and (Rp)-4w
(right) (ellipsoids at the 50% probability level). Some of the hydrogen atoms
are omitted for clarity. Selected bond lengths [Å] and angles [deg]: 4b: P(1)-
S(1) 2.0757(9), S(1)-C(23) 1.826(2), C(23)-S(1)-P(1) 99.68(7), C(22)-C(23)-
S(1) 110.29(14); 4w: P(1)-S(1) 2.0865(12), S(1)-C(25) 1.828(4), C(25)-S(1)-
P(1) 99.04(13), C(24)-C(25)-S(1) 111.0(2).
Figure 2 Single-crystal X-ray structure of compound 5b (left) and (Rp)-5j (right)
(ellipsoids at the 50% probability level). Some of the hydrogen atoms are
omitted for clarity. Selected bond lengths [Å] and angles [deg]: 5b: Se(1)-C(23)
1.968(2), Se(1)-P(1) 2.2278(9), C(23)-Se(1)-P(1) 98.39(6), C(22)-C(23)-Se(1)
110.06(15); 5j: Se(1)-C(25) 1.971(6), Se(1)-P(1) 2.2362(15), C(25)-Se(1)-P(1)
95.64 (18), C(24)-C(25)-Se(1) 111.0(4).
Encouraged by the successful and efficient construction of P-S-
C(sp3) bond, we further extended the optimized reaction
conditions to the construction of P-Se-C(sp3) bond. As collected
in Table 3, the established protocol could also be applied to the
synthesis of phosphoroselenoates by using selenium powder to
instead of sulfur powder, generating the corresponding products
5 in moderate to good yields. The presence of the P-Se-C(sp3)
was clearly identified by single-crystal X-ray diffraction (Figure 2,
5b). Different alkylhalides (or tosylates) were also examined
using the established reaction protocol with similar reaction
yields (Table 3, 5a, 5b, 5g and 5h), further corroborating the
efficiency of this synthetic strategy. In addition, functional groups
(Table 3, 5e, 5f) did not change the yields of the P-Se-C(sp3)
coupling products significantly. As an application of the current
63% yield. Similarly, retentive configurations at the phosphorus
atom were obtained from the P-chiral precursors 3c, which was
first confirmed by X-ray diffraction of 5j (Figure 2). This
observation further confirmed the formation of the chiral P-Se-
C(sp3) bond in this protocol (Table 3, 5g-5j).
Conclusions
In conclusion, a simple and efficient one-pot protocol for the
construction of P-S-C or P-Se-C bond from elemental sulfur or
selenium has been achieved under organic solvent-free and
metal-free conditions. This methodology provided an alternative
strategy to generate the valuable phosphorothioates or
method,
a gram-scale reaction was also conducted and
corresponding product 5d (Table 3, 5d, 2.41g) was obtained in
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10.1002/ejoc.201700344
European Journal of Organic Chemistry
COMMUNICATION
2005, 53, 2181-2184; f) A. P. Zhang, J. Q. Sun, C. M. Lin, X. Y. Hu and
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Experimental Section
Typical procedure for synthesis of phosphorothioates in
water (A). Compound 1 (0.5 mmol), 2a (0.75 mmol), 3 (0.75
mmol), Et3N (0.75 mmol) and H2O (0.75 mL) were charged into a
20 mL glass tube without exclusion of air, and the reaction
mixture was then stirred at 50 oC for 24 h. After completion of
the reaction, the mixture was extracted with ethyl acetate (5.0
mL x 3). Then the organic phases were combined and dried with
anhydrous MgSO4, purified by silica gel column chromatography
(ether/ethyl acetate as eluent) to afford the corresponding
product 4 in yields listed in Table 2. The identity and purity of
products were confirmed by 1H, 13C, 31P, HRMS, and X-ray
single crystal diffractometer spectroscopic analysis.
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Typical procedure for synthesis of phosphoroselenoates
in water (B). Compound 1 (0.75 mmol), 2b (0.6 mmol), 3 (0. 5
mmol), Et3N (0.75 mmol) and H2O (0.75 mL) were charged into a
20 mL glass tube without exclusion of air, and the reaction
mixture was then stirred at 50 oC for 24 h. After completion of the
reaction, the mixture was extracted with ethyl acetate (5.0 mL x
3). Then the organic phases were combined and dried with
anhydrous MgSO4, purified by silica gel column chromatography
(ether/ethyl acetate as eluent) to afford the corresponding
product 5 in yields listed in Table 3. The identity and purity of
products were confirmed by 1H, 13C, 31P, HRMS, and X-ray
single crystal diffractometer spectroscopic analysis.
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Acknowledgements
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We are grateful for the National Natural Science Foundation of
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funding of Shanghai Institute of Technology (XTCX2016-7) and
Start funding of Shanghai Institute of Technology (YJ2013-46)
for financial support.
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Keywords: three-component coupling • P-chalcogen derivative •
phosphorothioate • phosphoroselenoate
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European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Organophosphorous chemistry
Xinghua Zhang,* Zheng Shi, Changwei
Shao, Jinlong Zhao, Dungai Wang,
Gaoqi Zhang and Liang Li*
Page No. – Page No.
A convenient and efficient one-pot protocol for the construction of P-S-C or P-Se-C
bond from elemental sulfur or selenium has been developed in water, a series of
valuable phosphorothioates or phosphoroselenoates including the P-chiral
compounds were produced in good to excellent yields.
Three-Component Coupling Reaction
in Water: A One-Pot Protocol for the
Construction of P-S-C(sp3) and P-Se-
C(sp3) Bonds
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