Catalyst-Free and Selective C-N Bond Functionalization: Stereospecific Three-Component Coupling of Amines, Dichloromethane, and >P(O)H Species Affording α-Aminophosphorus Compounds

Article abstract of DOI:10.1021/jo501961h

Catalyst-free and selective C-N bond functionalization has been achieved through three-component coupling of amines, dihalomethane, and >P(O)H species. This reaction takes place stereospecifically with retention of configuration at phosphorus, which can produce various new optically active phosphorus analogues of α-amino acids.

Full text of DOI:10.1021/jo501961h

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Article
Catalyst-Free and Selective C-N Bond Functionalization: Stereospecific
Three-Component-Coupling of Amines, Dichloromethane and
>P(O)H Species Affording alpha-Aminophosphorus Compounds
Yalei Zhao, Xiuling Chen, Tieqiao Chen, Yongbo Zhou, Shuang-Feng Yin, and Li-Biao Han
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501961h • Publication Date (Web): 03 Dec 2014
Downloaded from http://pubs.acs.org on December 7, 2014
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CatalystꢀFree and Selective CꢀN Bond Functionalization: Stereospecific
ThreeꢀComponentꢀCoupling of Amines, Dichloromethane and >P(O)H Species
Affording αꢀAminophosphorus Compounds
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Yalei Zhao,§ Xiuling Chen,§ Tieqiao Chen, Yongbo Zhou,* ShuangꢀFeng Yin* and LiꢀBiao Han
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha, 410082, People’s Republic of China.
Eꢀmail: zhouyb@hnu.edu.cn; sf_yin@hnu.edu.cn
Abstract: The catalystꢀfree and selective CꢀN bond functionalization has been achieved through threeꢀcomponentꢀcoupling
of amines, dihalomethane and >P(O)H species. This reaction takes place stereospecifically with retention of configuration at
phosphorus which can produce various new optically active phosphorus analogues of αꢀamino acids.
O
O
R1R2N CH2
P
Z1
Z2
R1R2N
R3
+
CH2X
2 + H
P
Z1
Z2
1
Z1, Z2 = alkyl, alkoxy, aryl
Retention of P-chiral configuration
Selective C-N bond cleavage
INRODUCTION
Carbonꢀnitrogen (CꢀN) bonds are abundant in numerous organic compounds including natural products and fine chemicals.1 It would
therefore be important and useful to make CꢀN bond cleavage for constructing new compounds in organic synthesis.2 However, CꢀN
bonds are generally stable, which makes their functionalization difficult.3 Considerable efforts have been devoted to resolve the
challenge.2ꢀ3 However, among the reported systems, transition metal and their complexes are generally required as the catalysts to fulfill
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the cleavage and further functionalization of CꢀN bonds.2ꢀ3 The limited availability and difficult removal of transition metals from
products led to the development of alternative green metalꢀfree catalytic systems, but they remain scarce.4ꢀ5 Due to the interest in the CꢀN
activation and further functionalization, and combined with our previous work,6 we accidentally discovered a catalystꢀfree and selective
CꢀN cleavage, leading to an efficient alternative synthesis method to αꢀaminophosphorus compounds.
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αꢀAminophosphorus compounds are structural analogoues to natural αꢀamino acids, which have wide applications in the
research fields of physiological processes in living organisms, as well as diagnostic and therapeutic studies.7 Over the past half a
century, numerous methods for the preparation of such compounds have been developed with KabachnikꢀFields reaction and
Pudovik reaction being the most popular choices.8ꢀ9 However, in those systems, transition metals are generally required or the
scope of starting materials is limited to aldehydes (ketones) or imines. Especially, there is no precedent on the stereospecific
synthesis of Pꢀchiral αꢀaminophosphorus compounds. Herein we report that, without the aid of any catalysts, selective CꢀN bond
functionalization is achieved: by simply combining an amine, a >P(O)H compound (Hꢀphosphonate, Hꢀphosphinate or secondary
phosphine oxide) and dihalomethane, a oneꢀpot threeꢀcomponent coupling reaction takes place stereospecifically and selectively to
afford the αꢀaminophosphorus compounds 1 in high yields (eq 1).
RESULTS AND DISCUSSION
When a mixture of (EtO)2P(O)H (0.5 mmol), CH2Cl2 (0.5 mL) and Et3N (1.5 mmol) in DMF (0.5 mL) is heated at 100 °C for 12
h, the unsymmetrical substituted product, αꢀaminophosphonate 1a is selectively obtained in 92% yield through CꢀN bond cleavage
(eq 2). It is noted that the use of other methylene halides also produces the corresponding αꢀaminophosphonate 1a in good to
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excellent yields under the same reaction conditions (CH2Br2,, 91%; CH2I2, 86%; CH2BrCl, 75%), but no corresponding coupling
products can be obtained when dihalomethane is switched to other haloalkanes, such as CHCl3, CH3CHCl2,,ClCH2CH2Cl, or
CH3CCl2CH3. This reaction is highly solventꢀdependent. In addition to DMF, under similar reaction conditions, 1a can also be
obtained from DMSO and MeCN in excellent yields, respectively. However, the reaction hardly proceeds in EtOAc, hexane,
toluene, THF, dioxane and ethanol.
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As shown in Table 1, this reaction can be successfully applied to other substrates, indicating that this is a general method for the
preparation of a variety of αꢀaminophosphorus compounds. Besides (EtO)2P(O)H, (iꢀPrO)2P(O)H and (PhO)2P(O)H can also react
efficiently with Et3N to give the corresponding coupling products 1b and 1c in satisfactory yields (Entries 1 and 2). As to
symmetrical tertiary amines, in addition to Et3N, the use of triallylamine also produces the corresponding αꢀaminophosphonate in a
good yield (Entry 3). Moreover, both for triethylamine and triallylamine, only one of the three CꢀN bonds of the amine is cleaved
to give the corresponding coupling products. The reaction with polyamine is noteworthy. For example, the use of urotropine
produces a bisphosphorylamino compound selectively in high yields (Entry 4). For primary and secondary amines, the NꢀH bond
cleavage takes place predominantly to produce the corresponding coupling products (Entries 5ꢀ8). No coupling products from the
CꢀN bond cleavage can be detected from these reactions. In addition, such a high selectivity is also observed in the CꢀN bond
cleavage with tertiary amines. For example, with nꢀBuNMe2, regardless of the tiny electronic and steric difference between nꢀBu
and Me, an almost exclusive cleavage takes place on the NꢀMe bond to produce nꢀBuMeNCH2P(O)(OEt)2 in 95% yield (Entry 9).
Besides HP(O)(OEt)2, other >P(O)H species, such as a cyclic Hꢀphosphonate (Entry 10), a Hꢀphosphinate (Entry 11) and
secondary phosphine oxides (Entries 12ꢀ14) all react efficiently and selectively with nꢀBuNMe2 to give the corresponding
αꢀaminophosphorus compounds in high yields. As expected, high selectivity on CꢀN bond cleavage (NꢀMe cleavage) is gained for
dimethyloctylamine (Entry 15), and a good selectivity preferring the NꢀMe cleavage (85% selectivity) is also observed for
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diethylmethylamine MeNEt2 (Entry 16). Moreover, selective NꢀMe bond cleavages are achieved for amines bearing secondary
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alkyl groups (Entries 17ꢀ18), and cyclic amines such as 1ꢀmethylpiperidine and 4ꢀmethylmorpholine (Entries 19ꢀ20). However,
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Table 1. OneꢀPot ThreeꢀComponentꢀCoupling Reactions Forming αꢀAminophosphorus Compounds.a
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aA mixture of HP(O)Z1Z2 (0.5 mmol), amine (1.5 mmol) and CH2Cl2 (0.5 mL) in DMF (0.5 mL) was heated overnight in a sealed glass tube (75 °C for
primary and secondary amines, 100 °C for tertiary amines). bIsolated yield based on HP(O)Z1Z2 used. Selectivity was determined on the basis of the ratio
of the products calculated from 31P NMR and/or GC analysis results of the mixture.
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with tꢀBuNMe2 (Entry 21), the selective cleavage of NꢀtꢀBu rather than NꢀMe is observed. The selectivity is 96% preferring the
NꢀtꢀBu cleavage which is striking considering the nearly perfect selective NꢀMe bond cleavage for iꢀPrNMe2 (Entry 16). Similarly,
in the cases of Me2NCH2Ph and Me2NCH2CH=CH2, which simultaneously bear two NꢀMe bonds, preferred cleavages for
NꢀCH2Ph (85% selectivity) and Nꢀallyl bond (67% selectivity) proceeds (Entries 20 and 21). Therefore, the ease of NꢀR cleavage
in the coupling reactions follows the decreasing order of H, tꢀBu, allyl, benzyl > Me > primary and secondary alkyl groups.10
Importantly, this oneꢀpot threeꢀcomponent coupling reaction takes place highly stereospecifically to produce the corresponding
Pꢀchiral aminophosphorus compounds, a new class of phosphorus analogues of amino acids. They are difficult to be synthesized in
high yields through other methods by employing the easily accessible optically pure Pꢀchiral Hꢀphosphinates as substrates (Table
2).11a One can see that (RP)ꢀ2a and (RP)ꢀ2b reacts efficiently with a variety of amines to produce the corresponding optically pure
(SP)ꢀαꢀaminophosphinates selectively. The absolute configuration at the phosphorus atom of the product from
dimethylcyclohexylamine with (RP)ꢀ2b was determined unambiguously by Xꢀray analysis (Figure 1), showing that this
threeꢀcomponent coupling takes place with retention of the configuration at phosphorus. On the other hand, from the reaction of 2a
(RP/SP=60/40) with dimethylcyclohexylamine, the corresponding coupling product can be obtained with the same diastereomer’s
ratio, confirming that this coupling reaction proceeds stereospecifically. It is noted that this reaction also presents a rare example
for stereospecific substitution reactions of optically active hydrogen phosphorus compounds since epimerization usually occurs
during such reactions.11b, c This simple threeꢀcomponentꢀcoupling, taking place highly stereospecifically, has not been recognized
before.
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The reaction mechanism of the above threeꢀcomponentꢀcoupling reaction was investigated thoroughly. First, the stoichiometry
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Table 2. OneꢀPot ThreeꢀComponentꢀCoupling Reactions Forming PꢀChiral Aminophosphorus Compounds.a
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O
P
O
P
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DMF
R1R2N R3
Z
R1R2N
Z
+
+
H
CH2Cl2
OMen
OMen
(SP)-1
Men = (-) menthyl
(RP)-2a: Z = Ph, > 99% ee, (RP)-2b: Z = CH2Ph,> 99% ee
ee (%)c
> 99
% yield (selectivity)b
R1R2N R3
(SP)-1
(RP)-2
(SP)-1a
(SP)-1b
n-Bu N Me
(RP)-2a
95(98)
94(98)
96(99)
Me
> 99
> 99
(RP)-2b
(RP)-2a
N
Me
Me
(SP)-1c
(SP)-1d
Me
(RP)-2b
95(99)
93(95)
> 99
> 99
N
(SP)-1e
(SP)-1f
Me
90(96)
> 99
N
Me
H
Me
n-C8H17
N
H
(RP)-2a
(SP)-1g
> 99
> 99
75(99)
65(85)
Me N CH2Ph
(SP)-1h
(SP)-1i
Me
Et2N Et
> 99
> 99
98
72
(SP)-1j
2 N
aA mixture of (RP)ꢀ2 (0.2 mmol), amine (0.6 mmol) and CH2Cl2 (0.3 mL) in DMF (0.3 mL) was heated overnight in a sealed glass tube (75 °C for primary
and secondary amines, 100 °C for tertiary amines). bIsolated yield based on (RP)ꢀ2 used. Selectivity was determined on the bases of the ratio of the products
calculated from 31P NMR and /or GC of the mixture. cEantiomeric excess determined by 1H and 31P NMR.
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Figure 1. ORTEP Drawing of the (Sp)ꢀ1d. Hydrogen atoms are omitted for clarity; ellipsoids are drawn at 50% probability. Selected bond lengths (Å) and
angles (deg): C11ꢀP1 = 1.8134(13), C19ꢀP1 = 1.8033(12), O1ꢀP1 = 1.5933(10), O2ꢀP1 = 1.4812(9), C1ꢀO1ꢀP1 = 121.91(7), O2ꢀP1ꢀO1 = 115.56(5),
O2ꢀP1ꢀC19 = 112.44(6), O1ꢀP1ꢀC19 = 101.48(5), O2ꢀP1ꢀC11 = 114.82(6), O1ꢀP1ꢀC11 = 103.82(5), C19ꢀP1ꢀC11 = 107.47(6).
of the reaction was determined exactly by using 1,4ꢀdiazabicyclo[2.2.2]octane (DABCO) (eq 3). Heating a mixture of DABCO
(1.5 mmol), (EtO)2P(O)H (0.5 mmol) and CH2Cl2 (0.5 mL) in DMF (0.5 mL) at 100 °C overnight resulted in a halogenated
αꢀaminophosphorus compound in 81% yield based on (EtO)2P(O)H. This result indicates that one αꢀaminophosphonate is
produced accompanying with one chloroalkane in the present system.
N
DMF
+
+
CH2Cl2
N
HP(O)(OEt)2
100 o
C
(3)
P(O)(OEt)2
Cl
N
N
1u
81%
On the other hand, under the reaction conditions, CH2Cl2 reacts with Et3N to form the corresponding
1ꢀchloroꢀN,N,Nꢀtriethylmethaniminium chloride 3a in 89% yield (reaction conditions: 100 °C in DMF for 10 h) as colorless
crystals.12 Importantly, the αꢀaminophosphonate can be obtained quantitatively by heating 3a with an equal amount of diethyl
phosphite in DMF at 100 °C for 2 h (Scheme 1). Instead of CH2Cl2, an experiment using CD2Cl2 as the substrate confirms that the
two protons of the methylene group of dichloromethane are not affected during the reaction, showing that the proton for the
formation of the ammonium chloride comes from the hydrogen phosphonate. Moreover, the presence of the two chloro atoms in
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3a are essential for this reaction since the replacement of one chloro atom by BF4, without nucleophilicity, fails to produce the
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αꢀaminophosphonate with (EtO)2P(O)H under similar reaction conditions.
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Scheme 1. Reactions of triethylamine with dichloromethane forming 3.
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On the basis of these observations and literature,13 the reaction sequences for the stereospecific threeꢀcomponentꢀcoupling are
illustrated in (eq 4). First, the methaniminium chloride 3 formed by the reaction of R3N with CH2Cl2 is decomposed to produce
methyleneamonium chloride 4.10 Intermediate 4 is an electrophile14 which subsequently is attacked by the phosphorus of 2’, a
tautomer of 28e,k,15 to give the product with retention of configuration at phosphorus.
In summary, we have demonstrated a general and efficient threeꢀcomponentꢀcoupling of amines, dichloromethane and >P(O)H
species producing the important αꢀaminophosphorus compounds in high yields. This reaction takes place stereospecifically with
retention of configuration at phosphorus which can readily produce various new chiral optically active phosphorus analogues of
amino acids. This reaction also provides a novel CꢀN bond fuctionalization without the aid of any catalysts.
EXPERIMENTAL SECTION
General Information. Except where otherwise noted, all reactions were carried out in ovenꢀdried schlenk tubes under N2
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atmosphere with dry solvents under anhydrous conditions. Dry solvents were obtained by purification according to standard
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methods. Reagents were used as received unless otherwise noted. H, 13C and 31P NMR spectra were recorded on a 500 MHz
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spectrometer (500 MHz for 1H, 125 MHz for 13C, and 202 MHz for 31P NMR spectroscopy) or a 400 MHz spectrometer (400 MHz
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1
for H, 100 MHz for 13C, and 162 MHz for 31P NMR spectroscopy). CDCl3 or C6D6 was used as the solvent. Chemical shifts for
1H NMR are referred to internal Me4Si (0 ppm) and reported as follows: chemical shift (δ ppm), multiplicity, integration and
coupling constant (Hz). Data for 13C NMR are reported in ppm relative to the center line of a triplet at 77.0 ppm for chloroformꢀd,
and those for 31P NMR were relative to H3PO4 (85% solution in D2O, 0 ppm). The electron ionization (EI) and electrospray
ionization (ESI) method are used as the ionization method for the HRMS measurement, and the mass analyzer type is TOF for EI
and ion trap for ESI.
General Procedure for Synthesis of αꢀAminophosphorus Compounds
An ovenꢀdried schlenk tube containing an Teflonꢀcoated stir bar was charged with a mixture of R2P(O)ꢀH (0.5 mmol), amine
(1.5 mmol), and dichloromethane (0.5 mL) in 0.5 mL of DMF under N2 atmosphere and stirred at a selected temperature (75 °C for
primary and secondary amine, 100 °C for tertiary amine) for 12 h. After completion of the reaction, saturated solution of Na2CO3
(10 mL) was added to the reaction mixture, and extracted with ethyl acetate. The combined organic extracts were dried over
Na2SO4, concentrated in vacuum, and the resulting residue was passed through a short silica chromatography (particle size 40ꢀ50
ꢁm) or preparative GPC to afford the pure products.
General Procedure for Synthesis of pꢀChiral Aminophosphinates
An ovenꢀdried schlenk tube containing an Teflonꢀcoated stir bar was charged with a mixture of Pꢀchiral Hꢀphosphinates (0.2
mmol), amine (0.6 mmol), and dichloromethane (0.3 mL) in 0.3 mL of DMF under N2 atmosphere and stirred at a selected
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temperature (75 °C for primary amine, 100 °C for tertiary amine) for 12 h. After the reaction was finished, Na2CO3 saturated
solution (5 mL) was added to the reaction mixture, and extracted with ethyl acetate. The combined organic extracts were dried
over anhydrous Na2SO4, concentrated in vacuum, and the resulting residue was passed through a short silica chromatography
(particle size 40ꢀ50 ꢁm) or preparative GPC to afford the pure products.
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Synthesis of ammonium chloride and ammonium tetrafluoroborate
An ovenꢀdried schlenk tube containing an Teflonꢀcoated stir bar was charged with a mixture of Et3N (1.5 mmol), and
dichloromethane (0.5 mL) in 0.5 mL of DMF under N2 atmosphere stirred at 100 °C for 10 h. The mixture was then cooled to
room temperature and removal of the volatiles under vacuum afforded a white solid. Recrystallization of the crude product from
MeOH and Et2O gave 1ꢀchloroꢀN,N,Nꢀtriethylmethaniminium chloride 3a as a colorless crystal in 89% yield. Similarly, using
dichloromethaneꢀd2 as substrate resulted in 3aꢀd.
For the synthesis of ammonium tetrafluoroborate: in a glass tube, 3a (0.2 mmol) was dissolved in 0.5 mL DMSOꢀd6, and AgBF4
(0.2 mol) was added under N2 atmosphere. The mixture was stirred at room temperature for 1 h, and then removal of the solid by
filtration afforded the corresponding ammonium tetrafluoroborate 3b quantitatively.
1H, 13C, and 31P NMR spectra data of the products
Diethyl(N,Nꢀdiethylaminomethyl)phosphonate (1a).16 Following the general procedure, the crude product was purified by column
chromatography on silica gel and eluted with ethyl acetate/petroleum ether (3/1) to afford a pale yellow liquid.Yield: 102.6 mg,
92%. 1H NMR (CDCl3, 400 MHz): δ 4.11ꢀ4.19 (m, 4H ), 2.86 (d, 2H, J PꢀH = 10.8 Hz), 2.71 (q, 4H, J = 7.2 Hz), 1.32ꢀ1.35 (m, 6H),
1.05 (t, 6H, J = 7.2 Hz); 31P NMR (CDCl3, 162 MHz): δ 26.77; 13C NMR (CDCl3, 100 MHz): δ 61.8 (d, J pꢀc = 6.9 Hz) , 47.7 (d, J
1
pꢀc = 162.8 Hz), 48.2 (d, J = 8.6 Hz), 16.3 (d, J pꢀc = 5.8 Hz), 11.4. (1aꢀd). H NMR (CDCl3, 400 MHz): δ 4.10ꢀ4.15 (m, 4H ),
pꢀc
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2.66 (q, 4H, J = 5.7 Hz), 1.31 (t, 6H, J = 5.6 Hz), 1.01 (t, 6H, J = 5.6 Hz).
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Diisopropyl(N,Nꢀdiethylaminomethyl)phosphonate (1b).16 Following the general procedure, the crude product was purified by
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column chromatography on silica gel and eluted with ethyl acetate / petroleum ether (3/1) to afford a colorless liquid. Yield: 119.2
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mg, 95%. H NMR (400 MHz, CDCl3) δ 4.62ꢀ4.70 (m. 2H), 2.70 (d, 2H, J =10.8 Hz), 2.60 (q, 4H, J =7.0 Hz), 1.24 (d, 12H, J
=10.4 Hz), 0.94 (t, 6H, J = 7.0 Hz); 31P NMR (162 MHz, CDCl3) δ 24.17; 13C NMR (100 MHz, CDCl3) δ 70.1 (d, J PꢀC = 2.0 Hz),
49.8 (d, J PꢀC = 163.7 Hz), 48.2 (d, J PꢀC = 8.8 Hz), 24.1 (d, J PꢀC = 3.5Hz), 24.0 (d, J PꢀC =5.0 Hz), 11.6.
Diphenyl(N,Nꢀdiethylaminomethyl)phosphonate (1c). Following the general procedure, the crude product was purified by column
chromatography on silica gel and eluted with ethyl acetate / petroleum ether (3/1) to afford a colorless liquid. Yield: 110.1 mg,
69%. 1H NMR (400 MHz, CDCl3) δ 7.31 (t, 4H, J = 8.0 Hz), 7.20 (d, 4H, J = 8.4 Hz), 7.15 (t, 2H, J =7.2 Hz), 3.21 (d, 2H, J =9.2
Hz), 2.76 (q, 4H, J = 7.2 Hz), 1.05 (t, 6H, J = 8.4 Hz); 31P NMR (162 MHz, CDCl3) δ 18.87; 13C NMR (100 MHz, CDCl3) δ 150.6
(d, J PꢀC = 9.7 Hz), 129.6, 125.0, 120.6 (d, J PꢀC = 4.3 Hz), 49.2 (d, J PꢀC =163.0 Hz), 48.4 (d, J PꢀC = 8.9 Hz), 11.7. HRMS (EI) m/z:
[M] Calcd for C17H22NO3P 319.1337; Found 319.1335.
Diethyl(N,Nꢀdiallylaminomethyl)phosphonate (1d).17 Following the general procedure, the crude product was purified by
1
preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 90.2 mg, 73%. H NMR (400 MHz, C6D6) δ 5.75ꢀ5.86
(m, 2H), 5.13 (dd, 2H, J1 = 2.0 Hz, J2 = 17.2 Hz), 5.03 (dd, 2H, J1 = 2.0 Hz, J2 = 10.4 Hz), 3.96ꢀ4.06 (m, 4H), 3.25 (d, 4H, J = 6.4
Hz), 2.83 (d, 2H, J = 10.8 Hz), 1.07 (t, 6H, J = 7.6 Hz); 31P NMR (162 MHz, C6D6) δ 24.90; 13C NMR (100 MHz, C6D6) δ 135.8,
117.8, 61.7 (d, J PꢀC = 6.6 Hz), 58.3 (d, J PꢀC = 8.6 Hz), 49.1 (d, J PꢀC = 162.1 Hz), 16.7 (d, J PꢀC = 5.7 Hz).
N,Nꢀbis(diethoxyphosphinoylmethyl)ꢀNꢀmethylamine (1e).18 Following the general procedure, the crude product was purified by
1
preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 63.7 mg, 77%. H NMR (CDCl3, 400 MHz): δ
4.11ꢀ4.22 ( m, 8H ), 3.06 (d, 4H, J PꢀH =9.2 Hz), 2.63 (s, 3H), 1.34 (t, 12H, J = 7.0 Hz); 31P NMR (CDCl3, 162 MHz): δ 25.41; 13
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NMR (CDCl3, 100 MHz): δ 61.8 (t, Jpꢀc = 3.4 Hz), 53.4 (dd, J1 pꢀc = 10.0 Hz, J2 pꢀc = 156.7 Hz), 45.8 (t, Jpꢀc = 6.9 Hz), 16.4 (t, Jpꢀc
=
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2.9 Hz).
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Diethyl NꢀOctylaminomethylphosphonate (1f).19 Following the general procedure, the crude product was purified by preparative
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GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 113.1 mg, 81%. H NMR (400 MHz, C6D6) δ 3.96ꢀ4.10 (m, 4H),
2.87 (d, 2H, J PꢀH = 12.4 Hz), 2.45 (t, 2H, J = 6.8 Hz), 1.36 (br, 1H), 1.29 (br, 4H), 1.21 (br, 8H), 1.09 (t, 6H, J = 7.2 Hz), 0.90 (t,
3H, J = 6.4 Hz); 31P NMR (162 MHz, C6D6) δ 26.15; 13C NMR (100 MHz, C6D6) δ 61.8 (d, J PꢀC = 6.7 Hz), 51.7 (d, J PꢀC = 16.2 Hz),
46.2 (d, J PꢀC = 153.5 Hz), 32.3, 30.2, 29.9, 29.7, 27.5, 23.1, 16.7 (d, J PꢀC = 5.7 Hz), 14.4.
Diethyl(Nꢀbutylmethylaminomethyl)phosphonate (1g). Following the general procedure, the crude product was purified by
1
preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 113.8 mg, 96%. H NMR (400 MHz, C6D6) δ 3.98ꢀ4.08
(m, 4H), 2.67 (d, 2H, J PꢀH = 10.8 Hz), 2.32ꢀ2.37 (m, 5H), 1.21ꢀ1.36 (m, 4H), 1.09 (t, 6H, J = 6.8 Hz), 0.86 (t, 3H, J = 6.8 Hz); 31
P
NMR (162 MHz, C6D6) δ 24.69; 13C NMR (100 MHz, C6D6) δ 61.6 (d, J PꢀC = 5.7 Hz), 59.5 (d, J PꢀC = 13.4 Hz), 54.0 (d, J PꢀC
=
163.0 Hz), 44.2 (d, J PꢀC = 6.7 Hz), 29.9, 20.6, 16.7 (d, J PꢀC = 5.7 Hz), 14.2. HRMS (EI) m/z: [M] Calcd for C10H24NO3P 237.1494;
Found 237.1490.
Diethyl (4ꢀmethylpiperazinꢀ1ꢀyl)methylphosphonate (1h).20 Following the general procedure, the crude product was purified by
preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 116.3 mg, 93%. 1H NMR (400 MHz, CDCl3) δ 4.07ꢀ4.20
(m, 4H), 2.76 (d, 2H, J
= 11.2 Hz), 2.66 (br, 4H), 2.42 (br, 4H), 2.25 (s, 3H), 1.32 (t, 6H, J = 6.8 Hz); 31P NMR (162 MHz,
PꢀH
CDCl3) δ 24.37; 13C NMR (100 MHz, CDCl3) δ 62.1 (d, J PꢀC = 6.7 Hz), 55.1, 54.8, 54.0 (d, J PꢀC = 172.5 Hz), 45.9, 16.6 (d, J PꢀC
=
4.8 Hz).
Diethyl(N,Nꢀdibutylaminomethyl)phosphonate (1i).21 Following the general procedure, the crude product was purified by
preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 128.5 mg, 92%. 1H NMR (400 MHz, CDCl3) δ 4.06ꢀ4.15
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(m, 4H), 2.83 (d, 2H, J PꢀH = 10.0 Hz), 2.54 (t, 4H, J = 6.8 Hz), 1.36ꢀ1.43 (m, 4H), 1.24ꢀ1.33 (m, 10H), 0.88 (t, 6H, J = 7.6 Hz); 31
NMR (162 MHz, CDCl3) δ 26.10; 13C NMR (100 MHz, CDCl3) δ 61.8 (d, J PꢀC = 6.7 Hz), 55.2 (d, J PꢀC = 8.4 Hz), 50.0 (d, J PꢀC
161.1 Hz), 29.1, 20.41, 16.5 (d, J PꢀC = 5.7 Hz), 14.1.
P
=
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2ꢀNꢀbutylmethylaminomethylꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaphospholane 2ꢀoxide (1j). Following the general procedure, the
crude product was purified by preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 118.4 mg, 90%. 1H NMR
(400 MHz, CDCl3) δ 2.97 (d, 2H, J PꢀH = 9.6 Hz), 2.50 (t, 2H, J = 7.2 Hz), 2.39 (s, 3H), 1.49 (s, 6H), 1.39ꢀ1.48 (m, 2H), 1.37 (s,
6H), 1.26ꢀ1.35 (m, 2H), 0.90 (t, 3H, J = 7.2 Hz); 31P NMR (162 MHz, CDCl3) δ 39.09; 13C NMR (100 MHz, CDCl3) δ 88.0 (d, J
PꢀC = 1.9 Hz), 58.6 (d, J PꢀC = 12.4 Hz), 54.1 (d, J PꢀC = 147.7 Hz), 44.0 (d, J PꢀC = 5.7 Hz), 29.5, 25.0 (d, J PꢀC = 3.8 Hz), 24.2 (d, J
PꢀC = 4.7 Hz), 20.4, 14.1. HRMS (EI) m/z: [M] Calcd for C12H26NO3P 263.1650; Found 263.1656.
Isopropyl (Nꢀbutylmethylaminomethyl)phenylphosphinate (1k). Following the general procedure, the crude product was purified
1
by preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 128.9 mg, 91%. H NMR (400 MHz, C6D6) δ
7.91ꢀ7.98 (m, 2H), 7.10ꢀ7.16 (m, 3H), 4.53ꢀ4.64 (m, 1H), 2.71ꢀ2.84 (m, 2H), 2.34 (s, 3H), 2.17ꢀ2.32 (m, 2H), 1.28 (d, 3H, J = 6.4
Hz), 1.03ꢀ1.21 (m, 4H), 0.97 (d, 3H, J = 6.0 Hz), 0.76 (t, 3H, J = 7.6 Hz); 31P NMR (162 MHz, C6D6) δ 35.97; 13C NMR (100
MHz, C6D6) δ 133.3 (d, J PꢀC = 121.1 Hz), 132.5 (d, J PꢀC = 8.6 Hz), 131.7 (d, J PꢀC = 2.9 Hz), 127.9, 69.3 (d, J PꢀC = 6.7 Hz), 59.6 (d,
J PꢀC = 12.4 Hz), 57.4 (d, J PꢀC = 121.1 Hz), 44.4 (d, J PꢀC = 4.7 Hz), 29.8, 24.7 (d, J PꢀC = 2.8 Hz), 24.1 (d, J PꢀC = 4.7 Hz), 20.4, 14.2.
HRMS (EI) m/z: [M] Calcd for C15H26NO2P 283.1701; Found 283.1710.
diphenyl(Nꢀbutylmethylaminomethyl)phosphine oxide (1l). Following the general procedure, the crude product was purified by
preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 141.6 mg, 94%. 1H NMR (400 MHz, C6D6) δ 7.84ꢀ7.89
(m, 4H), 7.16 (br, 4H), 7.06ꢀ7.08 (m, 2H), 3.02 (d, 2H, J PꢀH = 6.4 Hz), 2.39 (s, 3H), 2.37 (t, 2H, J = 6.8 Hz), 1.18ꢀ1.25 (m, 2H),
1.07ꢀ1.16 (m, 2H), 0.78 (t, 3H, J = 7.2 Hz); 31P NMR (162 MHz, C6D6) δ 24.74; 13C NMR (100 MHz, C6D6) δ 134.5 (d, J
=
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94.3 Hz), 131.6 (d, J PꢀC = 8.6 Hz), 131.4 (d, J
= 1.9 Hz), 128.5 (d, J
= 10.4 Hz), 60.0 (d, J PꢀC = 10.5 Hz), 58.5 (d, J
=
PꢀC
PꢀC
PꢀC
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87.7 Hz), 44.6 (d, J PꢀC = 5.7 Hz), 29.7, 20.5, 14.2. HRMS (EI) m/z: [M] Calcd for C18H24NOP 301.1596; Found 301.1595.
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Dibutyl(Nꢀbutylmethylaminomethyl)phosphine oxide (1m). Following the general procedure, the crude product was purified by
preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 121.5 mg, 93%. 1H NMR (400 MHz, C6D6) δ 2.31ꢀ2.36
(m, 7H), 1.42ꢀ1.58 (m, 8H), 1.24ꢀ1.33 (m, 8H), 0.89 (t, 3H, J = 7.2 Hz), 0.83 (t, 6H, J = 7.2 Hz); 31P NMR (162 MHz, CDCl3) δ
43.22; 13C NMR (100 MHz, CDCl3) δ 60.4 (d, J PꢀC = 9.5 Hz), 56.6 (d, J PꢀC = 81.1 Hz), 44.7 (d, J PꢀC = 4.8 Hz), 30.0, 27.5 (d, J PꢀC
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= 64.8 Hz), 24.7 (d, J
= 13.4 Hz), 24.3 (d, J
= 3.8 Hz), 20.7, 14.3, 13.9. HRMS (ESI) m/z: [M+Na]+ Calcd for
PꢀC
PꢀC
C14H32NOPNa 284.2114; Found 284.2113.
bis(4ꢀphenylbutyl)(Nꢀbutylmethylaminomethyl)phosphine oxide (1n). Following the general procedure, the crude product was
purified by preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 188.1 mg, 91%. 1H NMR (400 MHz, C6D6) δ
7.11ꢀ7.16 (m, 6H), 7.01ꢀ7.05 (m, 4H), 2.38ꢀ2.45 (m, 4H), 2.56ꢀ2.29 (m, 7H), 1.36ꢀ1.50 (m, 12H), 1.21ꢀ1.27 (m, 4H), 0.834 (t, 3H,
J = 6.8 Hz); 31P NMR (162 MHz, C6D6) δ 42.78; 13C NMR (100 MHz, C6D6) δ 142.4, 128.7, 128.7, 126.2, 60.4 (d, J PꢀC = 10.5 Hz),
56.7 (d, J PꢀC = 80.0 Hz), 44.7 (d, J PꢀC = 4.8 Hz), 35.8, 33.3 (d, J PꢀC = 12.4 Hz), 29.9, 27.7 (d, J PꢀC = 63.8 Hz), 21.9 (d, J PꢀC = 2.8
Hz), 20.7, 14.3. HRMS (ESI) m/z: [M+Na]+ Calcd for C26H40NOPNa 436.2740; Found 436.2736.
Diethyl(NꢀOctylmethylaminomethyl)phosphonate (1o). Following the general procedure, the crude product was purified by
preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 127.6 mg, 87%. 1H NMR (400 MHz, C6D6) δ 3.97ꢀ4.09
(m, 4H), 2.70 (d, 2H, J PꢀH = 10.8 Hz), 2.36ꢀ2.39 (m, 5H), 1.25ꢀ1.40 (m, 12H), 1.10 (t, 6H, J = 6.8 Hz), 0.90 (t, 3H, J = 6.8 Hz); 31
P
NMR (162 MHz, C6D6) δ 24.67; 13C NMR (100 MHz, C6D6) δ 61.6 (d, J PꢀC = 6.7 Hz), 59.8 (d, J PꢀC = 13.3 Hz), 54.0 (d, J PꢀC
=
162.9 Hz), 44.2 (d, J PꢀC = 6.7 Hz), 32.3, 30.0, 29.8, 27.9, 27.6, 23.1, 16.7 (d, J PꢀC = 5.7 Hz), 14.4. HRMS (EI) m/z: [M] Calcd for
C14H32NO3P 293.2120; Found 293.2109.
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Diethyl(Nꢀcyclohexylmethylaminomethyl)phosphonate (1p). Following the general procedure, the crude product was purified by
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preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 121.1mg, 92%. H NMR (400 MHz, C6D6) δ 4.02ꢀ4.12
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(m, 4H), 2.74 (d, 2H, J PꢀH = 11.2 Hz), 2.44 (s, 3H) 2.23ꢀ2.30 (m, 1H), 1.45ꢀ1.67 (m, 6H), 1.11 (t, 6H, J = 6.8 Hz), 0.84ꢀ1.10 (m,
4H); 31P NMR (162 MHz, C6D6) δ 25.36; 13C NMR (100 MHz, C6D6) δ 64.4 (d, J PꢀC = 14.3 Hz), 61.7 (d, J PꢀC = 6.7 Hz), 50.4 (d, J
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= 167.8 Hz), 39.8 (d, J
= 3.8 Hz), 28.6, 26.5, 26.1, 16.7 (d, J
= 5.7 Hz). HRMS (EI) m/z: [M] Calcd for C12H26NO3P
PꢀC
PꢀC
PꢀC
263.1650; Found 263.1643.
Diethyl(Nꢀisopropylmethylaminomethyl)phosphonate (1q). Following the general procedure, the crude product was purified by
preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 89.3 mg, 80%. 1H NMR (400 MHz, CDCl3) δ 4.09ꢀ4.18
(m, 4H), 2.82ꢀ2.92 (m, 1H), 2.73 (d, 2H, J PꢀH = 10.8 Hz), 2.38 (s, 3H), 1.32 (t, 6H, J = 7.2 Hz), 0.97 (d, 6H, J = 6.8 Hz); 31P NMR
(162 MHz, CDCl3) δ 26.34; 13C NMR (100 MHz, CDCl3) δ 62.0 (d, J PꢀC = 6.7 Hz), 55.3 (d, J PꢀC = 14.3 Hz), 48.6 (d, J PꢀC = 168.7
Hz), 39.7 (d, J PꢀC = 2.8 Hz), 17.6, 16.5 (d, J PꢀC = 5.7 Hz). HRMS (EI) m/z: [M] Calcd for C9H22NO3P 223.1337; Found 223.1331.
Piperidinꢀ1ꢀylmethylꢀphosphonic acid diethyl ester (1r).22 Following the general procedure, the crude product was purified by
column chromatography on silica gel and eluted with ethyl acetate/petroleum ether (4/1) to afford a pale yellow liquid.Yield: 104.6
1
mg, 89%. H NMR (CDCl3, 400 MHz): δ 4.11ꢀ4.21 ( m, 4H ), 2.78 (d, 2H, J PꢀH = 11.2 Hz), 2.62 (br, 4H), 1.57ꢀ1.63 (m, 4H),
1.42ꢀ1.44 (m, 2H); 1.34 (t, 6H, J = 7.0 Hz,); 31P NMR (CDCl3, 162 MHz): δ 25.85; 13C NMR (CDCl3, 100 MHz): δ 62.0 (d, Jpꢀc
6.7 Hz), 56.2 (d, J pꢀc = 9.5 Hz), 53.8 (d, J pꢀc = 160.4 Hz), 25.9, 23.6, 16.5 (d, J pꢀc = 5.8Hz).
=
Diethyl (morpholinomethyl)phosphonate (1s).22 Following the general procedure, the crude product was purified by column
chromatography on silica gel and eluted with ethyl acetate/petroleum ether (4/1) to afford a pale yellow liquid. Yield: 105.5 mg,
89%. 1H NMR (CDCl3, 400 MHz): δ 4.11ꢀ4.21 ( m, 4H ), 3.71 (t, 4H, J = 4.8 Hz), 2.78 (d, 2H, J PꢀH = 12.0 Hz), 2.65 (t, 4H, J = 4.6
Hz), 1.34 (t, 6H, J = 7.2 Hz); 31P NMR (CDCl3, 162 MHz): δ 24.95; 13C NMR (CDCl3, 100 MHz): δ 66.6, 61.8 (d, J pꢀc = 6.7 Hz),
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55.0 (d, J pꢀc = 10.4 Hz), 54.1 (d, Jpꢀc = 163.0 Hz), 16.2 (d, J pꢀc = 5.6 Hz).
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Diethyl(N,Nꢀdimethylaminomethyl)phosphonate (1t).23 Following the general procedure, the crude product was purified by
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preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 79.9 mg, 82%. H NMR (400 MHz, C6D6) δ 3.96ꢀ4.07
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(m, 4H), 2.57 (d, 2H, J PꢀH = 11.6 Hz), 2.23 (s, 6H), 1.07 (t, 6H, J = 7.6 Hz); 31P NMR (162 MHz, C6D6) δ 24.16; 13C NMR (100
MHz, C6D6) δ 61.7 (d, J PꢀC = 6.6 Hz), 55.7 (d, J PꢀC = 162.9 Hz), 47.5 (d, J PꢀC = 11.5 Hz), 16.7 (d, J PꢀC = 5.7 Hz).
Diethyl [4ꢀ(2ꢀchloroethyl)ꢀ piperazinꢀ1ꢀyl]methylphosphonate (1u). Following the general procedure, the crude product was
purified by preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 120.9 mg, 81%. 1H NMR (400 MHz, C6D6) δ
3.95ꢀ4.10 (m, 4H), 3.14 (t, 2H, J = 6.8 Hz), 2.60 (d, 2H, J PꢀH = 11.6 Hz), 2.55 (br, 4H), 2.31 (t, 2H, J = 7.2 Hz), 2.17 (t, 4H, J = 4.8
Hz), 1.09 (t, 6H, J = 7.2 Hz); 31P NMR (162 MHz, C6D6) δ 23.61; 13C NMR (100 MHz, C6D6) δ 61.7 (d, J PꢀC = 6.7 Hz), 59.9, 54.7
(d, J
= 163.9 Hz), 55.3 (d, J PꢀC = 10.5 Hz), 53.4, 41.3, 16.7 (d, J PꢀC = 5.7 Hz). HRMS (EI) m/z: [M+H]+ Calcd for
PꢀC
C11H25ClN2O3P 299.1286; Found 299.1283.
(Sp)ꢀ(ꢀ)ꢀmenthyl phenyl(Nꢀbutylmethylaminomethyl)phosphinate (Sp)ꢀ1a. Following the general procedure, the crude product was
purified by preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 72.1 mg, 95%. 1H NMR (400 MHz, C6D6) δ
7.96ꢀ8.04 (m, 2H), 7.08ꢀ7.16 (m, 3H), 4.50ꢀ4.58 (m, 1H), 2.76ꢀ2.88 (m, 2H), 2.53ꢀ2.65 (m, 1H), 2.36 (s, 3H) 2.19ꢀ2.34 (m, 2H),
1.86ꢀ1.92 (m, 1H), 1.34ꢀ1.52 (m, 3H), 1.15ꢀ1.23 (m, 2H), 1.06ꢀ1.14 (m, 6H), 1.02 (d, 3H, J = 6.8 Hz), 0.80ꢀ0.99 (m, 2H), 0.77 (t,
3H, J = 7.2 Hz), 0.61ꢀ0.68 (m, 1H), 0.59 (d, 3H, J = 6.0 Hz); 31P NMR (162 MHz, C6D6) δ 35.21; 13C NMR (100 MHz, C6D6) δ
130.2 (d, J PꢀC = 121.0 Hz), 128.0 (d, J PꢀC = 9.5 Hz), 127.5 (d, J PꢀC = 2.8 Hz), 123.9, 71.6 (d, J PꢀC = 7.6 Hz), 55.6 (d, J PꢀC = 12.4
Hz), 53.5 (d, J PꢀC = 122.0 Hz), 45.2 (d, J PꢀC = 4.7 Hz), 40.2 (d, J PꢀC = 4.8 Hz), 39.5, 30.2, 27.3, 25.6, 21.9, 19.0, 17.9, 17.2, 16.2,
12.0, 10.0. HRMS (EI) m/z: [M] Calcd for C22H38NO2P 379.2640; Found 379.2628.
(Sp)ꢀ(ꢀ)ꢀmenthyl benzyl(Nꢀbutylmethylaminomethyl)phosphinate (Sp)ꢀ1b. Following the general procedure, the crude product was
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purified by preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 73.9 mg, 94%. 1H NMR (400 MHz, C6D6) δ
7.41ꢀ7.44 (m, 2H), 7.14ꢀ7.17 (m, 2H), 7.03ꢀ7.08 (m, 1H), 4.35ꢀ4.43 (m, 1H), 3.12ꢀ3.32 (m, 2H), 2.43ꢀ2.58 (m, 3H), 2.32 (s, 3H)
2.17ꢀ2.28 (m, 2H), 1.87ꢀ1.92 (m, 1H), 1.35ꢀ1.48 (m, 3H), 1.22ꢀ1.35 (m, 5H), 0.97ꢀ1.14 (m, 2H), 0.85ꢀ0.93 (m, 9H), 0.78ꢀ0.82 (m,
1H), 0.75 (d, 3H, J = 6.4 Hz); 31P NMR (162 MHz, C6D6) δ 46.36; 13C NMR (100 MHz, C6D6) δ 133.5 (d, J PꢀC = 7.6 Hz), 130.7 (d,
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J PꢀC = 5.7 Hz), 128.5 (d, J PꢀC = 1.9 Hz), 126.7 (d, J PꢀC = 2.8 Hz), 75.8 (d, J PꢀC = 6.7 Hz), 59.8 (d, J PꢀC = 11.4 Hz), 56.4 (d, J PꢀC
=
114.4 Hz), 49.1 (d, J PꢀC = 5.8 Hz), 44.2, 43.9 (d, J PꢀC = 6.6 Hz), 37.1 (d, J PꢀC = 83.9 Hz), 34.4, 31.6, 29.8, 26.0, 23.1, 22.2, 21.3,
20.8, 15.9, 14.3. HRMS (ESI) m/z: [M+H]+ Calcd for C23H41NO2P 394.2869; Found 394.2870.
(Sp)ꢀ(ꢀ)ꢀmenthyl phenyl(Nꢀcyclohexylmethylaminomethyl)phosphinate (Sp)ꢀ1c. Following the general procedure, the crude
1
product was purified by preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 75.1 mg, 96%. H NMR (400
MHz, CDCl3) δ 7.81ꢀ7.86 (m, 2H), 7.49ꢀ7.53 (m, 1H), 7.42ꢀ7.46 (m, 2H), 4.27ꢀ4.36 (m, 1H), 2.81ꢀ3.00 (m, 2H), 2.38 (s, 3H),
2.22ꢀ2.35 (m, 2H), 1.50ꢀ1.80 (m, 8H), 1.26ꢀ1.42 (m, 2H), 0.94ꢀ1.17 (m, 10H), 0.89 (d, 3H, J = 6.8 Hz), 0.79ꢀ0.85 (m, 1H), 0.76 (d,
3H, J = 7.2 Hz); 31P NMR (162 MHz, CDCl3) δ 37.61; 13C NMR (100 MHz, CDCl3) δ 132.8 (d, J PꢀC = 123.9 Hz), 131.9 (d, J PꢀC
=
8.6 Hz), 131.7, 127.9 (d, J PꢀC = 11.5 Hz), 76.2 (d, J PꢀC = 9.5 Hz), 64.3 (d, J PꢀC = 11.4 Hz), 53.4 (d, J PꢀC = 125.8 Hz), 48.9 (d, J PꢀC
= 5.7 Hz), 43.3, 39.8 (d, J PꢀC = 2.9 Hz), 34.1, 31.5, 28.7, 27.7, 25.8 (d, J PꢀC = 6.6 Hz), 25.7, 22.9, 22.0, 21.2, 15.8. HRMS (EI) m/z:
[M] Calcd for C24H40NO2P 405.2797; Found 405.2789.
(Sp)ꢀ(ꢀ)ꢀmenthyl benzyl(Nꢀcyclohexylmethylaminomethyl)phosphinate (Sp)ꢀ1d. Following the general procedure, the crude
product was purified by preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 77.1 mg, 95%. The purified
o
product was dissolved in hexane and let it stand in ꢀ30 C for overnight afforded a white solid. Crystal suitable for Xꢀray
o
1
crystallography was obtained from recrystallization of the solid from hexane at ꢀ30 °C (R.T slowly cooled to ꢀ30 C). H NMR
(400 MHz, CDCl3) δ 7.31ꢀ7.34 (m, 2H), 7.27ꢀ7.29 (m, 2H), 7.19ꢀ7.23 (m, 1H), 4.14ꢀ4.22 (m, 1H), 3.16ꢀ3.32 (m, 2H), 2.62 (d, 2H,
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PꢀH = 9.6 Hz), 2.38 (s, 3H), 2.26ꢀ2.34 (m, 1H), 1.96ꢀ2.04 (m, 1H), 1.67ꢀ1.80 (m, 6H), 1.61 (d, 3H, J = 12.8 Hz), 1.31ꢀ1.39 (m,
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1H), 1.22ꢀ1.29 (m, 2H), 1.13ꢀ1.18 (m, 3H), 1.00ꢀ1.05 (m, 1H), 0.91ꢀ0.97 (m, 2H), 0.87 (d, 3H, J = 6.8 Hz), 0.80 (d, 3H, J = 6.4
Hz), 0.77 (d, 3H, J = 6.8 Hz); 31P NMR (162 MHz, CDCl3) δ 49.97; 13C NMR (100 MHz, CDCl3) δ 132.6 (d, J PꢀC = 9.5 Hz), 130.2
(d, J PꢀC = 5.7 Hz), 128.3 (d, J PꢀC = 2.8 Hz), 126.5 (d, J PꢀC = 2.8 Hz), 76.2 (d, J PꢀC = 7.6 Hz), 64.5 (d, J PꢀC = 12.4 Hz), 52.6 (d, J PꢀC
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= 118.2 Hz), 48.7 (d, J PꢀC = 5.8 Hz), 43.7, 38.5, 36.1 (d, J PꢀC = 85.8 Hz), 34.1, 31.5, 28.2 (d, J PꢀC = 13.8 Hz), 26.3, 26.0 (d, J PꢀC
=
5.8 Hz), 25.6, 22.8, 22.0, 21.1, 15.6. HRMS (ESI) m/z: [M+Na]+ Calcd for C25H42NO2PNa 442.2845; Found 442.2839.
(Sp)ꢀ(ꢀ)ꢀmenthyl benzyl(((S)ꢀ3,3ꢀdimethylbutanꢀ2ꢀyl)(methyl)aminomethyl)phosphinate (Sp)ꢀ1e. Following the general procedure,
the crude product was purified by column chromatography on silica gel and eluted with ethyl acetate / petroleum ether (3/1) to
afford a colorless liquid. Yield: 78.3 mg, 93%. 1H NMR (400 MHz, CDCl3) δ 7.22ꢀ7.34 (m, 5H), 4.11ꢀ4.19 (m, 1H), 3.15ꢀ3.38 (m,
2H), 2.62ꢀ2.78 (m, 2H), 2.37ꢀ2.39 (m, 1H), 2.35 (s, 3H), 1.99ꢀ2.07 (m, 1H), 1.53ꢀ1.61 (m, 3H), 1.21ꢀ1.32 (m, 3H), 0.94 (s, 9H),
0.86ꢀ0.92 (m, 7H), 0.74ꢀ0.79 (m, 7H); 31P NMR (162 MHz, CDCl3) δ 49.77; 13C NMR (100 MHz, CDCl3) δ 132.4 (d, J
= 7.9
PꢀC
Hz), 130.2 (q, J PꢀC = 5.5 Hz), 128.3 (d, J PꢀC = 2.5 Hz), 126.5 (d, J PꢀC = 2.9 Hz), 76.1 (d, J PꢀC = 8.0 Hz), 68.8 (d, J PꢀC = 11.3 Hz),
56.2 (d, J PꢀC = 113.6 Hz), 48.6 (d, J PꢀC = 5.5 Hz), 43.5, 40.1 (d, J PꢀC = 3.9 Hz), 36.2, (d, J PꢀC = 83.2 Hz) , 35.8, 34.0, 31.4, 27.9,
25.6, 22.7, 21.9, 21.1, 15.5, 6.5. HRMS (EI) m/z: [M+H] Calcd for C25H45NO2P 422.3182; Found 422.3164.
(Sp)ꢀ(ꢀ)ꢀmenthyl benzyl(((S)ꢀ3ꢀmethylbutanꢀ2ꢀyl)(methyl)aminomethyl)phosphinate (Sp)ꢀ1f. Following the general procedure, the
crude product was purified by column chromatography on silica gel and eluted with ethyl acetate / petroleum ether (3/1) to afford a
1
colorless liquid. Yield: 73.2 mg, 90%. H NMR (400 MHz, CDCl3) δ 7.19ꢀ7.33 (m, 5H), 4.11ꢀ4.19 (m, 1H), 3.17ꢀ3.35 (m, 2H),
2.55ꢀ2.67 (m, 2H), 2.26(s, 3H), 2.16ꢀ2.22 (m, 1H), 1.94ꢀ1.99 (m, 1H), 1.69 (d, 1H, J = 12.4 Hz), 1.58 (d, 3H, J = 11.6 Hz),
1.20ꢀ1.37 (m, 3H), 1.05 (d, 3H, J = 6.4 Hz), 0.85ꢀ0.98 (m, 11H), 0.77 (t, 6H, J = 7.0 Hz); 31P NMR (162 MHz, CDCl3) δ 49.73; 13
C
NMR (100 MHz, CDCl3) δ 132.5 (d, J
= 7.9 Hz), 130.2 (q, J PꢀC = 5.5Hz), 128.3 (d, J PꢀC = 2.4 Hz), 126.5 (d, J PꢀC = 3.0 Hz),
PꢀC
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76.1 (d, J PꢀC = 7.0 Hz), 66.5 (d, J PꢀC = 11.8 Hz), 54.0 (d, J PꢀC = 116.1 Hz), 48.6 (d, J PꢀC = 5.6 Hz), 43.6, 36.0 (d, JPꢀC = 3.9 Hz),
35.9 (d, J PꢀC = 84.6 Hz), 34.0, 31.9, 31.4, 25.5, 22.7, 21.9, 21.1, 21.0, 20.4, 15.5, 9.2. HRMS (EI) m/z: [M] Calcd for C24H42NO2P
407.2953; Found 407.2939.
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(Sp)ꢀ(ꢀ)ꢀmenthyl phenyl(NꢀOctylaminomethyl)phosphinate (Sp)ꢀ1g. Following the general procedure, the crude product was
purified by preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 63.1 mg, 75%. 1H NMR (400 MHz, CDCl3)
δ 7.79ꢀ7.83 (m, 2H), 7.45ꢀ7.52 (m, 1H), 7.40ꢀ7.44 (m, 2H), 4.28ꢀ4.36 (m, 1H), 3.00ꢀ3.11 (m, 2H), 2.55ꢀ2.59 (m, 2H), 2.19ꢀ2.26 (m,
1H), 1.79ꢀ1.85 (m, 1H), 1.57ꢀ1.65 (m, 2H), 1.36 (t, 3H, J = 12.4 Hz), 1.20 (br, 12H), 0.96ꢀ1.04 (m, 2H), 0.92ꢀ0.94 (m, 3H),
0.83ꢀ0.87 (m, 6H), 0.69ꢀ0.80 (m, 4H); 31P NMR (162 MHz, CDCl3) δ 37.33; 13C NMR (100 MHz, CDCl3) δ 132.2 (d, J PꢀC = 121.1
Hz), 132.1(d, J PꢀC = 2.9 Hz), 131.6 (d, J PꢀC = 9.5 Hz), 128.3 (d, J PꢀC = 12.4 Hz), 76.9 (d, J PꢀC = 7.6 Hz), 51.5 (d, J PꢀC = 14.3 Hz),
49.3 (d, J PꢀC = 105.6 Hz), 48.9 (d, J PꢀC = 5.7 Hz), 43.4, 34.1, 31.9, 31.5, 29.8, 29.5, 29.3, 27.1, 25.8, 22.9, 22.7, 21.9, 21.2, 15.8,
14.1. HRMS (ESI) m/z: [M+H]+ Calcd for C25H45NO2P 422.3182; Found 422.3183.
(Sp)ꢀ(ꢀ)ꢀmenthyl phenyl(N,Nꢀdimethylaminomethyl)phosphinate (Sp)ꢀ1h. Following the general procedure, the crude product was
purified by preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 43.8 mg, 65%. 1H NMR (400 MHz, CDCl3)
δ 7.81ꢀ7.86 (m, 2H), 7.51ꢀ7.55 (m, 1H), 7.43ꢀ7.48 (m, 2H), 4.27ꢀ4.35 (m, 1H), 2.77ꢀ2.90 (m, 2H), 2.30 (s, 6H), 2.22ꢀ2.28 (m, 1H),
1.74ꢀ1.80 (m, 2H), 1.58ꢀ1.68 (m, 2H), 1.25ꢀ1.41 (m, 2H), 0.98ꢀ1.56 (m, 1H), 0.95 (d, 3H, J = 7.2 Hz), 0.88 (d, 3H, J = 6.8 Hz),
0.77ꢀ0.84 (m, 1H), 0.75 (d, 3H, J = 6.4 Hz); 31P NMR (162 MHz, CDCl3) δ 36.04; 13C NMR (100 MHz, CDCl3) δ 132.8 (d, J PꢀC
=
=
122.0 Hz), 131.9 (d, J
120.1 Hz), 48.9 (d, J
= 2.9 Hz), 131.6 (d, J
= 9.6 Hz), 128.3 (d, J PꢀC = 12.4 Hz), 76.6 (d, J
= 8.5 Hz), 59.6 (d, J PꢀC
PꢀC
PꢀC
PꢀC
= 5.7 Hz), 47.8 (d, J
= 10.4 Hz), 43.3, 34.1, 31.5, 25.7, 22.9, 22.0, 21.2, 15.9. HRMS (EI) m/z: [M]
PꢀC
PꢀC
Calcd for C19H32NO2P 337.2171; Found 337.2169.
(Sp)ꢀ(ꢀ)ꢀmenthyl phenyl(N,Nꢀdiethylaminomethyl)phosphinate (Sp)ꢀ1i. Following the general procedure, the crude product was
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purified by preparative GPC using CHCl3 as eluent to afford a pale yellow liquid. Yield: 71.6 mg, 98%. H NMR (400 MHz,
CDCl3) δ 7.80ꢀ7.85 (m, 2H), 7.48ꢀ7.52 (m, 1H), 7.40ꢀ7.44 (m, 2H), 4.25ꢀ4.34 (m, 1H), 2.84ꢀ2.95 (m, 2H), 2.53ꢀ2.62 (m, 4H),
2.26ꢀ2.33 (m, 1H), 1.75ꢀ1.80 (m, 1H), 1.57ꢀ1.67 (m, 2H), 1.26ꢀ1.39 (m, 2H), 0.94ꢀ1.05 (m, 2H), 0.944 (d, 3H, J = 6.8 Hz ),
0.83ꢀ0.88 (m, 9H), 0.77ꢀ0.81 (m, 1H), 0.74 (d, 3H, J = 6.4 Hz); 31P NMR (162 MHz, CDCl3) δ 37.26; 13C NMR (100 MHz, CDCl3)
δ 132.9 (d, J PꢀC = 121.0 Hz), 131.9 (d, J PꢀC = 9.5 Hz), 131.7 (d, J PꢀC = 2.9 Hz), 127.9 (d, J PꢀC = 12.4 Hz), 76.3 (d, J PꢀC = 7.6 Hz),
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53.3 (d, J
= 122.0 Hz), 48.9 (d, J
= 5.7 Hz), 48.5 (d, J
= 7.6 Hz), 43.3, 34.1, 31.5, 25.7, 22.9, 22.0, 21.2, 15.8, 11.6.
PꢀC
PꢀC
PꢀC
HRMS (EI) m/z: [M] Calcd for C21H36NO2P 365.2484; Found 365.2469.
(Sp)ꢀ(ꢀ)ꢀmenthyl phenyl(N,Nꢀdiallylaminomethyl)phosphinate (Sp)ꢀ1j. Following the general procedure, the crude product was
purified by preparative GPC using CHCl3 as eluent to afford a colorless liquid. Yield: 56.1 mg, 72%. 1H NMR (400 MHz, CDCl3)
δ 7.78ꢀ7.83 (m, 2H), 7.49ꢀ7.54 (m, 1H), 7.41ꢀ7.46 (m, 2H), 5.54ꢀ5.64 (m, 2H), 5.02ꢀ5.07 (m, 4H), 4.26ꢀ4.34 (m, 1H), 3.08ꢀ3.25 (m,
4H), 2.84ꢀ2.98 (m, 2H), 2.24ꢀ2.35 (m, 1H), 1.74ꢀ1.79 (m, 2H), 1.58ꢀ1.68 (m, 2H), 1.26ꢀ1.41 (m, 2H), 0.98ꢀ1.02 (m, 1H), 0.95 (d,
3H, J = 7.2 Hz), 0.87 (d, 3H, J = 6.8 Hz), 0.78ꢀ0.85 (m, 1H), 0.75 (d, 3H, J = 6.8 Hz); 31P NMR (162 MHz, CDCl3) δ 37.24; 13
NMR (100 MHz, CDCl3) δ 135.6, 133.1 (d, J PꢀC = 123.0 Hz), 132.3 (d, J PꢀC = 8.5 Hz), 132.2 (d, J PꢀC = 2.8 Hz), 128.4 (d, J PꢀC
C
=
12.3 Hz), 118.1, 76.7 (d, J PꢀC = 7.6 Hz), 58.6 (d, J PꢀC = 7.6 Hz), 52.7 (d, J PꢀC = 121.0 Hz), 49.3 (d, J PꢀC = 5.8 Hz), 43.7, 34.5, 31.8,
26.0, 23.3, 22.3, 21.6, 16.2. HRMS (EI) m/z: [M] Calcd for C23H36NO2P 389.2484; Found389.2468.
1ꢀchloroꢀN,N,Nꢀtriethylmethaniminium chloride (3a). 1H NMR (400 MHz, DMSOꢀd6 δ 5.41 (s, 2H), 3.42 (q, 6H, J = 7.3 Hz), 1.27
(t, 9H, J = 7.2 Hz). (3aꢀd). 1H NMR (400 MHz, DMSOꢀd6 δ3.42 (q, 6H, J = 7.3 Hz), 1.28 (t, 9H, J = 7.2 Hz).
1ꢀchloroꢀN,N,Nꢀtriethylmethaniminium tetrafluoroborate (3b). 1H NMR (400 MHz, DMSOꢀd6 δ 5.33 (s, 2H), 3.40 (q, 6H, J = 7.2
Hz), 1.27 (t, 9H, J = 7.2 Hz).
ASSOCIATED CONTENT
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Supporting Information. CIF files of chiral αꢀaminophosphonate., copies of H, 13C and 31P NMR spectra for products. This
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AUTHOR INFORMATION
Notes
The authors declare no competing financial interest.
AUTHOR CONTRIBUTIONS
Corresponding Author: Eꢀmail: zhouyb@hun.edu.cn; sf_yin@hnu.edu.cn. Fax: (+) 86ꢀ731ꢀ88821171.
§ These authors contributed equally.
ACKNOWLEDGMENT
This work is supported by the NSFC (21273066, 21273067, 21373080), the Doctoral Fund of Chinese Ministry of Education
(No.20110161120008), and the Fundamental Research Funds for the Central Universities (Hunan University).
REFERENCES
(1) Lawrence, S. A. Amines: Synthesis, Properties and Applications, 9th ed, United Kingdom at the university Press, Cambridge, 2004.
(2) a) Turner, N. J. Chem. Rev. 2011, 111, 4073ꢀ4087; b) Roglans, A.; PlaꢀQuintana, A.; MorenoꢀMañas, M. Chem. Rev. 2006, 106, 4622ꢀ4643; c) Ho Jun, C. Chem. Soc. Rev.
2004, 33, 610ꢀ618; d) Li, Y.; Ma, Li.; Li, Z.; Chin. J. Org. Chem. 2013, 33, 704ꢀ714 and references cited therein.
(3) a) Geng, W.; Zhang, W.; Hao, W.; Xi, Z. J. Am. Chem. Soc. 2012, 134, 20230ꢀ20233; b) Ling, Z.; Yun, L.; Liu, L.; Wu, B.; Fu, X. Chem. Commun. 2013, 49, 4214ꢀ4216.
(4) Mai, W.; Song, G.; Yuan, J.; Yang, L.; Sun, G.; Xiao, Y.; Mao, P.; Qu, L. RSC Adv. 2013, 3, 3869ꢀ3872.
(5)
Nguyen, T. B.; Ermolenko, L.; AlꢀMourabit, A. Green Chem. 2013, 15, 2713ꢀ2717.
(6) Chen, X.; Chen, T.; Zhou, Y.; Au, CꢀT.; Han, L.; Yin, S. Org. Biomol.Chem, 2014, 12, 247ꢀ250.
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(7)
For reviews on their preparation and applications, see: a) Aminophosphonic and Aminophosphinic Acids: Chemistry and Biological Activity, Kukhar, V. P.; Hudson, H. R.
Eds, John Wiley & Sons, Chichester, 2000; b) Ordóñez, M.; Sayago, F. J.; Cativiela, C. Tetrahedron. 2012, 68, 6369ꢀ6412; c) Kudzin, Z. H.; Kudzin, M. H.; Drabowics,
J.; Stevens, C. Curr. Org. Chem. 2011, 15, 2015ꢀ2071; d) Mucha, A.; Kafarski, P.; Berlicki, L.; J. Med. Chem. 2011, 54, 5955ꢀ5980; e) Olivier, B.; Laurent, G.; JeanꢀLuc,
M. Org. Lett. 2012, 14, 3404ꢀ3407; f) ösapay, G.; Szilagyi, I.; Deres, J. Tetrahedron, 1987, 43, 2977ꢀ2983; g) Queffelec, C.; Ribière, P.; Montchamp, J. L. J. Org. Chem,
2008, 73, 8987ꢀ8991; h) Jovic, F.; Louise, L.; Mioskowski, C.; Renard, P. Y. Tetrahedron. Lett, 2005, 46, 6809ꢀ6814.
10
11
12
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57
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(8)
Via KabachnikꢀFields reaction and Pudovik reaction to αꢀaminophosphonates see a) Fields, E. K. J. Am. Chem. Soc. 1952, 74, 1528ꢀ1531; b) Allen, J. G.; Atherton, F. R.;
Hall, M. J.; Hassall, C. H.; Holmes, S. W.; Lambert, R. W. Nisbet, L. J.; Ringrose, P. S. Nature, 1978, 272, 56ꢀ58; c) Pratt, R. F. Science, 1989, 246, 917ꢀ919; d) Bhagat, S.
Chakraborti, A.K. J. Org. Chem. 2007, 72, 1263ꢀ1270. e) Tibhe, G. D.; LagunasꢀRivera, S.; VargasꢀDíaz, E.; GarcíaꢀBarradas, O.; Ordoñez, M. Eur. J. Org. Chem. 2010,
6573. f) Bhattacharya, A. K.; Raut, D. S.; Rana, K. C.; Polanki, I. K.; Khan, M. S.; Iram, S. Eur. J. Med. Chem. 2013, 66, 146. g) Bhattacharya, A. K.; Rana, K. C.;
Pannecouque, C.; Clercq, E. D. ChemMedChem 2012, 7, 1601. h) Todorov, P. T.; Wesselinova, D. W.; Pavlov, N. D.; Martinez, J.; Calmes, M.; Naydenova, E. D. Amino
Acids 2012, 43, 1445. i) Todorov, P. T.; Pavlov, N. D.; Shivachev, B. L.; Petrova, R. N.; Martinez, J.; Naydenova, E. D.; Calmes, M. Heteroatom Chem. 2012, 23, 123. j)
Rossi, J.ꢀC.; Marull, M.; Larcher, N.; Taillades, J.; Pascal, R.; van der Lee, A.; Gerbier, P. Tetrahedron: Asymmetry 2008, 19, 876. k) Wang, Y.; Wang, Y.; Yu, J.; Miao,
Z.; Chen, R. Chem. Eur. J. 2009, 15, 9290
(9)
a) Han, W.; Mayer, P.; Ofial, A. R.; Adv. Synth. Catal. 2010, 352, 1667ꢀ1676; b) Han, W.; Ofial, A. R. Chem. Commun. 2009, 6023ꢀ6025; c) Balsé, O.; Li, C. Chem.
Commun. 2009, 4124ꢀ4126; d) Gao, Y.; Huang, Z.; Zhuang, R.; Xu, J.; Zhang, P.; Tang, G.; Zhao, Y. Org. Lett. 2013, 15, 4214ꢀ4217; e) McDonald, S. L.; Wang, Q.
Angew. Chem. Int. Ed. 2014, 53, 4667ꢀ4670; f) Ordóňez, M.; RojasꢀCabrera, H.; Cativiela, C. Tetrahedron. 2009, 65, 17ꢀ49.
(10) Other than SN2 mechanism for methyl, 1o alkyl and 2o alkyl, the cleavage of H, allyl, benzyl and tꢀBuꢀN bond probably occurs by a SN1 mechanism.
(11) a)Xu, Q.; Zhao, C.; Han, L. J. Am. Chem. Soc. 2008, 130, 12648ꢀ12655. (b) Emmick, T. L.; Letsinger, R. L. J. Am. Chem. Soc. 1968, 90, 3459. (c) Farnham,
W. B.; Murray, R. K.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 5808.
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2
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5
6
7
8
9
(12) a) Almarzoqi, B.; George, A. V.; Isaacs, N. S. Tetrahedron Lett. 1986, 42, 601ꢀ607; b) Park, K.; Jung, I.; Chung, Y.; Han, J. Adv. Synth. Catal. 2007, 349, 411ꢀ416; c)
Nevstad, G. O.; Songstad, J. Acta. Chem. Scand. B, 1984, 38, 469ꢀ477; d) Langlois, M.; Meyer, C.; Soulier, J. L. Synth. Commun 1992, 22, 1895ꢀ1911; e) Böhme, H.;
Lehners, W.; Keitzer, G. Chem. Ber, 1958, 91, 340ꢀ345, f) Böhme, H.; Mundlos, E.; Herboth, O. E. Chem. Ber, 1957, 90, 2003ꢀ2008.
(13) a) Chambers, R. A.; Pearson, D. E. J. Org. Chem. 1963, 28, 3144. b) Shamma, M.; Deno, N.; Remar, J. F. Tetrahedron Lett. 1966, 7, 1375. c) Schreiber, J.; Maag, H.;
Hashimoto, N.; Eschenmoser, A. Angew. Chem. Int. Ed. 1971, 10, 330. d) Bryson, T. A.; Bonitz, G. H.; Reichel, C. J.; Dardis, R. E. J. Org. Chem.
1980, 45, 524ꢀ525. e) Fletcher, M. O.; Zhang, L.; Vu, Q.; Dolbier, W. R.; Jr. J. Chem. Soc., Perkin Trans. 2, 1999, 1187ꢀ1192.
(14) a) Danishefsky, S.; Kitahara, T.; Mckee, R.; Schuda, P. F. J. Am. Chem. Soc., 1976, 98, 6715ꢀ6717; b) Wu, K.; Ahmed, M.; Chen, C.; Huang, G.; Hon, Y.; Chou, P. Chem.
Commun. 2003, 890ꢀ891.
10
11
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13
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16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15) Quin, L. D. A. Guide to Organophosphorus Chemistry; Wileyꢀ Interscience: New York, 2000. Chapter 2, pp 8ꢀ34.
(16) a) Sindt, M.; Stephan, B.; Schneider, M.; Mieloszynski, L. J. Phosphorus, Sulfur and Silicon and the Related Elements. 2001, 174, 163–176; b) Charandabi, D. M. R. M.
A.; Ettel, L. M.; Kaushik, P. M.; Huffman, H. J.; Morse, W. K. Phosphorus, Sulfur and Silicon and the Related Elements. 1989, 44, 223–234.
(17) Issleib, K.; Kuehne, U.; Krech, F. Phosphorus, Sulfur and Silicon and the Related Elements. 1983, 17, 73–80.
(18) Prishchenko, A. A.; Livantsov, M. V.; Novikova, O. P.; Livantsova, I. L.; Petrosyan, V. S. Heteroatom. Chem. 2010, 21, 71–77.
(19) Zomova, M. A.; Zh, V.; Molodykh.; Kudryavtseva, A. L.; Teplyakova, V. L.; Fedorov, B. S.; Ivanov, B. E. Pharm. Chem. J. 1986, 20, 774–777,
Khimiko-Farmatsevticheskii Zhurnal. 1986, 20, 1324–1327.
(20) Chaudhary, P.; Kumar, R.; Verma, A. K.; Singh, D.; Yadav, V.; Chhillar, A. K.; Sharma, G. L.; Chandra, R. Bioorg. & Med. Chem. 2006, 14, 1819–1826.
(21) Bel'skii, V. E.; Kudryavtseva, L. A.; Kurguzova, A. M.; Ivanov, B. E. Bull. Acad. Sci. USSR, Div. chem. Sci. (Engl. Transl.). 1975, 24, 958ꢀ960, Izvestiya Akademii Nauk
SSSR, Seriya Khimicheskaya. 1975, 24, 1047ꢀ1051.
(22) a) Prauda, I.; Greiner, I.; Ludanyi, K.; Keglevich, G. Synth. Commun. 2007, 37, 317–322. b) Bel'skii, V. E.; Bakeeva, R. F.; Kudryavtseva, L. A.; Kurguzova, A. M.;
Ivanov, B. E. Bull. Acad. Sci. USSR, Div. chem. Sci. (Engl. Transl.). 1975, 24, 1511ꢀ1512, Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya. 1975, 24, 1624ꢀ1625.
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1
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(23) a) Laurenco, C.; Burgada, R. Tetrahedron. 1976, 32, 2089–2098. b) Prishchenko, A. A.; Livantsov, M. V.; Boganova, N. V.; Lutsenko, I. F. J. Gen. Chem. USSR (Engl.
4
5
6
Transl.). 1989, 59, 2133–2134.
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