Asymmetric synthesis of α-aminophosphonates using the inexpensive chiral catalyst 1,1'-binaphthol phosphate

Article abstract of DOI:10.3390/molecules15085782

Asymmetric addition under mild conditions of dialkyl phosphites on aldimines derived from cinnamaldehyde catalyzed by the inexpensive chiral organocatalyst (R)-3,3'- [4-fluorophenyl]₂-1,1'-binaphthol phosphate has been found effective to give n

Full text of DOI:10.3390/molecules15085782

Molecules 2010, 15, 5782-5796; doi:10.3390/molecules15085782
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Asymmetric Synthesis of α-Aminophosphonates Using the
Inexpensive Chiral Catalyst 1,1’-Binaphthol Phosphate
Weiming Xu, Sha Zhang, Song Yang *, Lin-Hong Jin, Pinaki S. Bhadury, De-Yu Hu and
Yuping Zhang
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key
Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou
University, Guiyang 550025, China; E-Mails: xuweiming2009@163.com (W.X.); lisarik@126.com
(S.Z.); fcc.jinlh@gzu.edu.cn (L.-H.J.); bhadury@gzu.edu.cn (P.-S.B.); fcc.dyhu@gzu.edu.cn (D.-
Y.H.); zhangyupinggz@163.com (Y.Z.)
* Author to whom correspondence should be addressed; E-Mail: gdjhzx@gmail.com;
Tel.: (+86) 851 829 2170; Fax: (+86) 851 362 2211.
Received: 19 June 2010; in revised form: 18 August 2010 / Accepted: 20 August 2010 /
Published: 24 August 2010
Abstract: Asymmetric addition under mild conditions of dialkyl phosphites on aldimines
derived from cinnamaldehyde catalyzed by the inexpensive chiral organocatalyst (R)-3,3’-
[4-fluorophenyl]2-1,1’-binaphthol phosphate has been found effective to give new α-
amino-phosphonates 9 in moderate yields (30–65%) and enantiomeric excess
(8.4%–61.9%).
Keywords: α-aminophosphonate derivatives; aldimines; cinnamaldehyde; chiral organo-
catalyst; asymmetric addition
1. Introduction
α-Aminophosphonic acids, structural analogues of amino acids, are known for their diversity in
agricultural and biological applications. A large number of α-aminophosphonic acids and their
phosphonate esters and a few short peptides of natural and synthetic origin bearing similar structural
features exhibit enzyme inhibitory [1-11], antibiotic [12], antibacterial [13-15], antiviral [16],
antifungal [17], and herbicidal activities [18]. As the biological activity of α-aminophosphonates is
markedly influenced by the absolute configuration of the α-carbon atom directly linked to the

Molecules 2010, 15
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phosphorous center [19], the synthesis of optically pure enantiomers of α-aminophosphonates and their
derivatives with desired property constitutes an important task in organic synthesis [20]. The strategy
for this challenging asymmetric transformation mostly relies upon catalytic hydrophosphonylation of
either a preformed or in situ generated imine with dialkyl phosphates [21-26]. Since these reactions
typically involve Mannich type nucleophilic attack of a phosphite at the electrophilic imine, both the
components of the reaction can be simultaneously activated, at least in principle, by a bifunctional
organocatalyst. Based on this concept, Akiyama et al. [27] have designed an enantioselective
hydrophosphonylation of preformed aromatic and unsaturated imines catalyzed by the axially chiral
binaphthyl phosphoric acid derivative 6b affording α-aminophosphonates with an enantiomeric excess
of up to 90%. The same catalyst was subsequently utilized by our group [28] in a highly
enantioselective preparation of a series of fluorine containing asymmetric α-aminophosphonates
through hydrophosphonylation of aldimines mostly derived from cinnamaldehyde. Due to the growing
concern for the influence of the nature of the substrate and the catalyst structure on the
enantiomerically pure final asymmetric hydrophosphonylation of aldehydes and imines, organic
reactions with use of conventional organic chiral catalyst have attracted the attention of synthetic
organic chemists. A number of chiral binaphthyl phosphoric acid derivative catalysts such as 6b, with
varying substituents at the 3- and 3′-positions of the binaphthyl scaffold have been extensively studied
recently [29,30]. With this information in hand, we proceeded to synthesize enantiopure α-
aminophosphonates with heterocycle moieties to investigate their biological activities. We found
however that the enantioselectivity of chiral Brønsted acid 6b- catalyzed enantioselective
hydrophosphonylations of imines with benzothiazoles moieties was very poor [31]. This indicates that
the structures of imine and catalyst play an important role in affecting the reaction’s enantioselectivity.
Herein we studied the effect of a relatively simple and inexpensive catalyst (R)-3,3’-[4-fluorophenyl]2-
1,1’-binaphthol phosphate (6a) which was obtained from easily accessible 4-bromofluorobenzene. The
bulky 3,3’ aryl substituents of catalyst 6b has been replaced in this catalyst by a less sterically
demanding 4-fluorophenyl group. The synthetic route to the asymmetric α-aminophosphonates in
presence of chiral catalyst is depicted in Scheme 1. The structures of the target compounds were firmly
established by IR, 1H-, 13C-, 31P- and 19F-NMR spectra and elemental analysis.
Scheme 1. Synthetic route to title chiral compounds 9.
R1
NH2
CHO
Et3N
N
+
CH2Cl2
reflux
R1
7
F
F
O
H
O
P
OR2
R1
O
R1
OR2
O
P
*
O
OR2
OR2
(10 mol%)
N
+
N
H
H P
Xylene r.t.
7
8
9a-p
30%-65% yields, 8.4%-61.9% ee
R1=H, 2-F,2-CH3,4-CH3; R2=Et, n-Pr,
i-Pr , n-Bu,

Molecules 2010, 15
5784
2. Results and Discussion
The catalysts 6a and 6b were prepared from starting material R-BINOL through a five step
synthetic sequence [32] involving etherification, boronation, Suzuki coupling, demethylation, and
phosphorylation under a strictly inert atmosphere, as is shown in Scheme 2.
Scheme 2. Synthetic route to chiral catalysts 6a and 6b.
B(OH)2
OH
OH
OCH3
OCH3
CH3I
OMe
OMe
1.TMEDA, n-BuLi, Et2O
2.B(OEt)3 -78 oC
3.HCl 0 oC
K2CO3 reflux
B(OH)2
1
2
3
Ar
Ar
Ar
O
1.POCl3,
Pyridine
2.H2O, 0o C
Ar-Br,Pd(PPh3)4,
Ba(OH)2 8H2O,
OCH3
OCH3
OH
OH
1.CH2Cl2, BBr3
2.H2O, 0oC
O
P
dioxane /H2O
70 oC, 5h
H
O
Ar
Ar
Ar
4
5
6
6a: Ar=4-fluorophenyl
6b: Ar=3,5-bis(trifluoro-methyl)phenyl
The suitability of the imine structure for enantioselective catalytic synthesis of chiral α-amino-
phosphonates was studied first and the results are shown in Table 1. In line with our earlier
observation [28] that catalyst 6b was more suited to cinnamaldehyde-derived imines (entry 4)
compared to the one derived from benzaldehyde and heterocyclic amine (entry 2), the catalyst 6a
showed too a similar trend with cinnamaldehyde in enhancing the enantioselectivity (entry 1 vs. entry 3).
Table 1. Effect of Imine Structure on Enantioselectivity. a
OEt
10 mol% Chrial
Bronsted acid
OEt
O
O
P
*
OEt
OEt
R4
+
H P
R4
R3
N
Xylene r.t.
R3
N
H
Entry
Catalyst
R3
R4
CH3
Yield (%)
e.e. (%)b
1
6a
20
0
N
F
F
S
CH3
N
S
2
6b
56
10.2
3
4
6a
6b
51
45
31.9
89.5
CH3
CH3
a Reaction conditions: aldimine (1 mmol), catalyst 6a or 6b (0.1 mmol), xylene (15 mL), diethyl
phosphite (2 mmol), room temp. for 24 h; b Determined by chiral HPLC.

Molecules 2010, 15
5785
Having established cinnamaldehyde as the ideal substrate for the reaction, it was reacted with
different aromatic amines (Table 2) to generate aldimines for further conversion into α-amino-
phosphonates. The formation of these imines is generally accompanied by side products due to the
possibility of a 1,4-Michael attack on cinnamaldehyde by a nucleophile/base. The product 7 was
obtained in relatively low yield in protic solvent, while at elevated reaction temperature Michael
adducts started to appear. Under optimized conditions, the new cinnamaldehyde imines were prepared
by refluxing the aldehyde and amine components in methylene chloride followed by recrystallization
from ethanol. Whilst the low boiling methylene chloride restricts the formation of Michael addition
product, the use of inert atmosphere prevents undesired oxidation of aldehyde into the acid. Activation
of the amine by a weak organic base e.g. triethylamine and addition of molecular sieves were found
advantageous to improve the yield of the imine. The desired aldimines 7 from different amines were
obtained in 65–85 % yield, as shown in Table 2.
Table 2. Synthesis of imine 7.
Entry
7
R
H
2-F
2-CH3
4-CH3
Time (h)
Yield (%)
1
2
3
4
7a
7b
7c
7d
3
5
8
8
85
89
77
65
a
Reaction conditions: aniline (5 mmol), aldehyde (5 mmol), triethylamine (0.2 mL), CH2Cl2
(15 mL), 40 ºC; b Yields refer to isolated pure compounds.
Addition of dialkyl phosphite 8 via its nucleophilic phosphite tautomer bearing the Bronsted acidic
OH group to cinnamaldehyde imine 7 in presence of catalyst 6a then leads to the generation of title
chiral α-aminophosphonates 9 as listed in Table 3. The imine and the phosphite are presumed to be
simultaneously activated by the phosphoric acid hydrogen and phosphoryl oxygen of the catalyst
respectively through a nine membered transition state [28]. The stereochemical course of the attack is
controlled by the aryl groups at the 3,3’-positions of the catalyst. The scope of various dialkyl
phosphites in the asymmetric hydrophosphonylation reaction was investigated first. As evident from
the data presented in Table 3, similar to the observation made by Akiyama et al. [27], diisopropyl
phosphite afforded the highest enantioselectivity (61.9%). This is expected because as per the
proposed model, the OH moiety of dialkyl phosphite should play a significant role in conferring
enantioselectivity. Irrespective of the nature of amine, the trend in enantioselectivity generally
followed the order i-Pr > n-Bu > Et > n-Pr. As for different aromatic amines, electron donating
substituent such as methyl group on the aryl ring seems to have a positive influence on ee of the target
compounds to a certain degree. We reasoned that the hydrogen bond activation of imine induced by
phosphoric acid catalyst should be more favorable in presence of electron donating groups. It was also
found that imine obtained from o-methyl aniline displayed greater enantioselectivity compared to the
one derived from p-methyl aniline. The results shown in Table 3 afforded only moderate yield, and the
outcome depended on, to some extent, the substrate and the nucleophilic phosphite structures. A
representative chiral HPLC chromatogram of 9k is shown in Figure 1.

Molecules 2010, 15
Table 3. Organocatalytic enantioselective reaction with chiral phosphoric acid 6a.
5786
Entry
1
2
3
4
Compound R1
R2
Et
Pr
i-Pr
Bu
Et
Yield (%)
41
52
33
65
e.e. (%)
16.5
17.3
36.9
16.7
18.8
8.4
9a
9b
9c
9d
9e
9f
H
H
H
H
2-F
2-F
5
6
60
54
Pr
7
8
9
10
11
12
13
14
15
16
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
2-F
2-F
i-Pr
Bu
Et
31
47
51
48
32
48
50
45
44.2
27.5
31.9
16.9
61.9
30.1
28.3
15.3
51.5
22.7
2-CH3
2-CH3
2-CH3
2-CH3
4- CH3
4- CH3
4- CH3
4- CH3
Pr
i-Pr
Bu
Et
Pr
i-Pr
Bu
30
39
a Reaction conditions:. aldimine (10 mmol), catalyst 6a (56 mg, 0.1 mmol), xylene (15 mL), dialkyl
b
c
phosphite 8 (1 mmol), room.temp; Determined by chiral HPLC; Yields refer to isolated pure
compounds.
Figure 1. Representative chiral HPLC chromatogram of enantioenriched α-aminophosphonate 9k.
In order to optimize the reaction parameters for the preparation of 9k, its enantioselective synthesis
was carried out under different conditions, as shown in Table 4. Amongst the various solvents selected
for the study (acetonitrile, methylene chloride, toluene and xylene, entries 1–4), xylene afforded the
highest enantioselectivity under identical condition of temperature and catalyst loading. When the
reaction was executed at room temperature with reduced catalyst amount (entries 6 and 7),
enantioselectivity dropped significantly whereas on enhancing the loading (entry 5), no significant
improvement was noticed compared to 10% loading (61.9% ee, entry 4). As expected for this type of

Molecules 2010, 15
5787
catalytic reaction, enantioselectivity was lowered when the temperature was raised to 50 °C (entry 10)
and at lower temperatures (entries 8 and 9) ee was enhanced, but only marginally. Therefore, the
enantioselective synthesis of 9k was best conducted in xylene at room temperature with 10 mol%
loading of catalyst 6a (entry 4).
Further, based on the sign of optical rotation of 9k, its absolute configuration in the presence of
catalyst (R)-6a was proposed as (R) by comparison with literature data [20,28]. The proposed
stereochemical model of the transition state was discussed in earlier work [23,27,28].
Table 4. Optimization of reaction parameters for enantioselective synthesis of 9k using
chiral catalyst 6a.
Entry
1
2
3
4
5
6
7
Solvent
acetonitrile
methylene chloride
toluene
xylene
xylene
xylene
xylene
xylene
xylene
Temp (°C)
Cat 6a (mol%) ee (%)
r.t
r.t
r.t
r.t
r.t
r.t
r.t
0
10
10
10
10
20
5
30.1
48.0
52.8
61.9
65.1
49.9
20.9
64.9
68.3
57.9
2
8
9
10
10
10
10
-40
50
xylene
3. Experimental
3.1. General
The melting points of the products were determined on a XT-4 binocular microscope (Beijing Tech
Instrument Co., China) and were not corrected. The IR spectra were recorded on a Bruker VECTOR22
spectrometer in KBr disks. Elemental analysis was performed on an Elementar Vario-III CHN
analyzer. The reagents were all of analytical grade or chemically pure. Analytical TLC was performed
1
13
on silica gel GF254. H-NMR and C-NMR spectra were recorded on a JEOL-ECX 500 instrument
1
13
31
19
(500 MHz for H, 125 MHz for C, 200 MHz for P, 470 MHz for F) using CDCl3, acetone d6,
1
DMSO d6 as solvent. TMS (δ = 0) served as an internal standard for H-NMR, CDCl3 (δ = 77.0) was
13
31
used as an internal standard for C-NMR, H3PO4 (δ = 0) was used as an internal standard for P-
NMR, CF3COOD was used as an external standard (δ = −76.5) for 19F-NMR. IR spectra were recorded
on a Bruker VECTOR32 spectrometer and are reported in terms of frequency of absorption. Elemental
analysis was performed on an Elementar Vario-III CHN analyzer. The HPLC was carried out on an
Agilent 1100 series apparatus equipped with DAD detector using Chiralpak AD-H-amylose tri(3,5-
dimethylphenylcarbamate) coated on 5 μm silica-gel and Chiralpak IA-amylose tri(3,5-
dimethylphenylcarbamate) immobilized on silica-gel columns (each of 250 × 4.6 mm i.d., Daicel
Chemical Industries Ltd). All solvents were purified and dried according to standard procedure.
Organic solutions were concentrated under reduced pressure on a Buchi rotary evaporator. Molecular
sieves (5Ǻ) were flame activated and the reactions were monitored by TLC with Huanghai GF254

Molecules 2010, 15
5788
silica-gel coated plates. The intermediates 6a-b and 7 were prepared according to the literature
methods as described [25,27].
3.2. Preparation of chiral catalysts 6a-b
(R)-3,3’-[4-fluorophenyl]2-1,1’-binaphthyl phosphate (6a): This compound was obtained as a white
solid, m.p. > 290 °C; [α]D20 = -291.2 (c = 0.04, CHCl3); IR (KBr cm-1): ν 3419 (OH), 2968 (C-H), 1382
1
(C-F), 1249 (P=O). H-NMR (DMSO-d6,): δ 8.11(q, J = 4.70 Hz, 2H, Ar-H ), 8.03–8.06(m, 2H, Ar-
H), 7.41(t, J = 7.20 Hz, 1H, Ar-H), 7.24–7.31(m, 3H, Ar-H), 7.02 (d, J = 8.60 Hz, 1H, Ar-H); 13C-
NMR (CDCl3): δ 163.2, 161.2, 148.0, 134.9, 133.8, 132.9, 132.3, 130.5, 128.9, 126.4, 125.2, 123.1,
115.0; 31P-NMR (CDCl3): δ 4.64; 19F-NMR (CDCl3) : δ -115.6.
(R)-3,3’-[3,5-bis(trifluoromethyl)phenyl]2-1,1’-binaphthyl phosphate (6b): This compound was
obtained as a white solid, m.p > 250 °C, [α]D20 = -195.1 (c= 0.9, CHCl3). 1H-NMR (DMSO-d6,): δ 8.24
(s, 4H), 7.94–7.98 (m, 4H), 7.81 (s, 2H), 7.47 (t, J = 7.15 HZ, 2H), 7.26–7.33 (m, 4H);
13C-NMR (CDCl3): δ 145.5, 140.2, 132.8, 131.5, 131.2, 130.9, 130.7, 130.3, 128.5, 127.2, 126.9,
126.7, 125.9, 124.5, 123.3, 122.4, 120.8, 120.2; 31P-NMR (CDCl3): δ 5.77; 19F-NMR (CDCl3): δ -62.7.
3.3. Preparation of intermediate imines 7
To a 50 mL three necked round-bottomed flask equipped with a stirring bar, were placed
cinnamaldehyde (5 mmol), aniline (5 mmol ) and methylene chloride (15 mL). Once a clear solution
was obtained, freshly distilled dry triethylamine (2 mL) and molecular sieves (5Å) were added. The
reaction mixture was first stirred for 5 min at room temperature and then refluxed for the indicated
time shown in Table 2. The reaction mixture was filtered and the solvent was removed under reduced
pressure. The crude product obtained was recrystallized from ethanol to afford a yellow solid.
1
3-Phenylallylideneaminobenzene (7a): Yield 85%, m.p. 105–107 °C; IR (KBr cm-1): ν 1620 (C=N); H-
NMR (CDCl3): δ 8.26 (d, J = 8.00 Hz, 1H, Ar-H), 7.53 (d, J = 6.85 Hz, 2H, Ar-H), 7.34–7.41(m, 5H, Ar-
H), 7.09–7.25(m, 5H, Ar-H + -CH=);13C-NMR (CDCl3): δ 161.7, 151.8, 144.1, 135.6, 129.7, 129.2, 129.0,
128.6, 127.6, 126.2, 121.0.
2-(3-Phenyl-allylideneamino)fluorobenzene (7b): Yield 89%, m.p. 72–73 °C; IR (KBr cm-1): ν 1629
(C=N); 1H-NMR (CDCl3): δ 8.13–8.20 (m, 1H, Ar-H), 7.54 (d, J = 6.90 Hz, 2H, Ar-H), 7.34–7.41 (m, 3H,
Ar-H), 7.10–7.21(m, 4H, Ar-H + -CH=), 6.86(d, J = 7.45 Hz, 1H, -CH=), 2.30(s, 3H, CH3); 13C-NMR
(CDCl3): δ 161.5, 151.3, 143.6, 135.7, 131.7, 130.3, 129.6, 129.0, 128.8, 127.5, 126.7, 125.7, 117.8, 17.9.
2-(3-Phenylallylideneamino)-methylbenzene (7c): Yield 77%, m.p. 71–73 °C; IR (KBr cm-1): ν 1627
(C=N); 1H-NMR (CDCl3): δ 8.13–8.20 (m, 1H, Ar-H), 7.54 (d, J = 6.90 Hz, 2H, Ar-H), 7.34-7.41 (m, 3H,
13
Ar-H), 7.10–7.21 (m, 4H, Ar-H + -CH=), 6.86 (d, J = 7.45 Hz, 1H, -CH=), 2.30 (s, 3H, CH3); C-NMR
(CDCl3): δ 161.5, 151.3, 143.6, 135.7, 131.7, 130.3, 129.6, 129.0, 128.8, 127.5, 126.7, 125.7, 117.8, 17.9.

Molecules 2010, 15
5789
4-(3-Phenylallylideneamino)-methylbenzene (7d): Yield 65%; m.p. 76–77 °C; IR (KBr cm-1): ν 1625
1
(C=N); H-NMR (CDCl3): δ 8.27–8.29 (m, 1H, Ar-H), 7.52–7.54 (m, 2H, Ar-H), 7.33–7.40 (m, 3H,
Ar-H), 7.08–7.19 (m, 6H, Ar-H + -CH=), 2.36 (s, 3H, CH3); 13C-NMR (CDCl3): δ 160.8, 149.1, 143.6,
136.1, 135.7, 129.9, 129.5, 129.0, 128.8, 127.5, 120.9, 21.1.
3.4. Preparation of title chiral compounds 9a-p
The mixture of aldimine (1 mmol) and the catalyst 6a (0.1 mmol, 0.056 g) in xylene (15 mL) was
stirred for 15 min at room temperature. When a yellow suspension resulted, dialkyl phosphite was
added and the reaction mixture was further stirred at room temperature for 24 h. The reaction was
stopped by the addition of aqueous NaHCO3 and the solution was extracted with ethyl acetate. The
combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by preparative chromatography (eluent: petroleum ether/
ethyl acetate = 3/1) to provide the product in 30~65% yield, which was further subjected to chiral
HPLC analysis on a Daicel Chiralpak IA column. Considering the effect of enatiomer self-
disproportionation [33], we loaded a smple of compound 9k of 61.9% ee on a regular gel column and
subjected the sample to chromatography with petroleum ether-ethyl acetate = 3/1, v/v, then the ee
value of sample 9k purified by preparative chromatography was determined on a chiral stationary
phase (IA column), which was as the same as the original compound 9k. Also, using literature method
[34] to make it, no sublimation was found for the title compound 9k over the temperature range from
R.T to 50 °C.
Diethyl 1-[N-(phenyl)amino]-3-phenyl-2-propenylphosphonate (9a): White solid, yield 41%; m.p.
80.0–81.5 °C; IR (KBr cm-1): ν 3292 (N-H), 2985 (C-H), 1600 (C=C), 1496 (C=C), 1222 (P=O), 1020
(P-O-C); 1H-NMR (CDCl3): δ 7.16–7.36(m, 6H, Ar-H), 6.68–6.76 (m, 4H, Ar-H), 6.24 (tt, J = 5.72,
5.42 Hz, 1H, CH-P), 4.43 (tt, J = 6.85, 6.87 Hz, 1H, -CH=), 4.28 (t, J = 8.02 Hz, 1H, -CH=),
13
4.15–4.20 (m, 4H, CH2O), 1.29 (t, J = 7.4Hz, 6H, CH3); C-NMR (CDCl3): δ 146.6, 136.2, 132.9,
129.3, 128.6, 127.9, 126.6, 123.5,118.6, 113.8, 63.5, 54.7, 53.8, 16.6; 31P-NMR (CDCl3): δ 22.3; Anal.
Calcd for C19H24NO3P: C 66.07, H 7.00, N 4.06; Found: C 65.99, H 7.18, N 4.19; Analysis: Daicel
Chiralpak IA (hexane-EtOH = 90:10 / v/v), Flow rate = 1.0 mL/min, UV = 254 nm,
tR (minor) = 8.45 min (R), tR (major) = 10.25 min (S). e.e. 16.5%.
Di-n-propyl 1-[N-(phenyl)amino]-3-phenyl-2-propenylphosphonate (9b): White solid, yield 52%; m.p.
59.6–61.1 °C; IR (KBr cm-1): ν 3317 (N-H), 2966 (C-H), 1602 (C=C), 1498 (C=C), 1230 (P=O), 1015
1
(P-O-C); H-NMR (CDCl3): δ 7.15–7.36(m, 6H, Ar-H), 6.68–6.76(m, 4H, Ar-H), 6.24(tt,
J = 5.45, 5.42 Hz, 1H, CH-P), 4.40 (br, 1H, -CH=), 4.30 (br, 1H, -CH=), 4.02–4.09 (m, 4H, CH2O),
13
1.65 (t, J = 6.85 Hz, 4H, CH2), 0.91 (t, J = 7.45 Hz, 6H, CH3); C-NMR (CDCl3): δ 146.5, 136.3,
132.9, 129.3, 128.6, 127.9, 126.6, 126.6, 118.6, 113.8, 68.4, 54.7, 53.5, 23.9, 10.1; 31P-NMR (CDCl3):
δ 22.8; Anal. Calcd for C21H28NO3P: C 67.54, H 7.56, N 3.75; Found: C 67.31, H 7.56, N 3.63;
Analysis: Daicel Chiralpak IA (hexane-EtOH = 90:10 / v/v), Flow rate = 1.0 mL/min, UV = 250 nm,
tR (minor) = 7.38 min (R), tR (major) = 8.31 min (S). e.e. 17.3%.

Molecules 2010, 15
5790
Diisopropyl 1-[N-(phenyl)amino]-3-phenyl-2-propenylphosphonate (9c): White solid, yield 33%; m.p.
81.4–82.5 °C; IR (KBr cm-1): ν 3294 (N-H), 2976 (C-H), 1600 (C=C), 1498 (C=C), 1224 (P=O), 981
(P-O-C); 1H-NMR (CDCl3): δ 7.15–7.35 (m, 4H, Ar-H), 6.67–6.75 (m, 4H, Ar-H), 6.24 (tt, J = 5.70,
5.45 Hz, 1H, CH-P), 4.74–4.77 (m, 2H, CH-O), 4.37 (br, 1H, -CH=), 4.26 (br, 1H, -CH=), 1.33–1.35
13
(m, 6H, CH3); C-NMR (CDCl3): δ 146.7, 136.5, 132.3, 129.3, 128.6, 127.7, 126.6, 123.9, 118.4,
113.8, 71.7, 55.1, 53.9, 24.0; 31P-NMR (CDCl3): δ 21.0; Anal. Calcd for C21H28NO3P: C 67.54, H 7.56,
N 3.75; Found: C 67.79, H 7.93, N 3.79; Analysis: Daicel Chiralpak IA (hexane-EtOH = 90:10 / v/v),
Flow rate = 1.0 mL/min, UV = 254 nm, tR (minor) = 6.56 min (R), tR (major) = 7.26 min (S). e.e.
36.9%.
Di-n-butyl 1-[N-(phenyl)amino]-3-phenyl-2-propenylphosphonate (9d): White solid, yield 65%; m.p.
53.1–54.7 °C; IR (KBr cm-1): ν 3290 (N-H), 2956 (C-H), 1602 (C=C), 1498 (C=C), 1219 (P=O), 1024
1
(P-O-C); H-NMR (CDCl3): δ 7.15–7.35 (m, 6H, Ar-H), 6.68–6.76 (m, 4H, Ar-H), 6.24
(tt, J = 5.45, 5.45 Hz, 1H, CH-P), 4.43 (tt, J = 7.15, 7.15 Hz, 1H, -CH=), 4.27 (t, J = 8.30 Hz, 1H, -
CH=), 4.07–4.13 (m, 4H, CH2O),1.61–1.62 (m, 4H, CH2), 1.34 (t, J = 7.45 Hz, 4H, CH2), 0.87 (d,
J = 7.45 Hz, 6H, CH3); 13C-NMR (CDCl3): δ 146.5, 136.4, 132.9, 129.3, 128.6, 127.8, 126.6, 123.6,
118.5, 113.8, 66.7, 54.7, 53.5, 32.6, 18.7, 13.6; 31P-NMR (CDCl3): δ 22.9; Anal. Calcd for
C23H32NO2P: C 71.66, H 8.37, N 3.63; Found: C 71.51, H 8.47, N 3.55; Analysis: Daicel Chiralpak IA
(hexane-EtOH = 90:10 / v/v), Flow rate = 1.0 mL/min, UV = 254 nm, tR (minor) = 7.01 min (R), tR
(major) = 7.72 min (S). e.e. 16.7%.
Diethyl 1-[N-(2-fluorophenyl)amino]-3-phenyl-2-propenylphosphonate (9e): White solid, yield 60%;
m.p. 60.6–60.9 °C; IR (KBr cm-1): ν 3280 (N-H), 2985 (C-H), 1616 (C=C), 1525 (C=C), 1325 (C-F),
1236 (P=O), 1018 (P-O-C) ; 1H-NMR (CDCl3): δ 7.21–7.37 (m, 4H, Ar-H), 6.94–7.02 (m, 2H, Ar-H),
6.65–6.73 (m, 3H, Ar-H), 6.26 (tt, J = 5.42, 5.45 Hz, 1H, CH-P), 4.16–4.24 (m, 2H, -CH=), 4.12–4.14
(m, 4H, CH2O), 1.30 (t, J = 8.05 Hz, 6H, CH3); 13C-NMR (CDCl3): δ 152.9, 151.0, 136.2, 135.0,
132.9, 128.6, 128.0, 126.7, 124.6, 123.1, 118.1, 114.7, 113.5, 63.1, 54.5, 53.3, 16.5; 31P-NMR
(CDCl3): δ 22.2; Anal. Calcd for C19H23FNO3P: C 62.80, H 6.38, N 3.85; Found: C 62.74, H 6.44, N
3.67; Analysis: Daicel Chiralpak IA (hexane-EtOH = 95:5 / v/v), Flow rate = 1.0 mL/min,
UV = 250 nm, tR (minor) = 6.99 min (R), tR (major) = 9.01 min (S). e.e. 18.8%.
Di-n-propyl 1-[N-(2-fluorophenyl)amino]-3-phenyl-2-propenylphosphonate (9f): Yellow oil; yield
54%; IR (KBr cm-1): ν 3421 (N-H), 2968 (C-H), 1618 (C=C), 1510 (C=C), 1332 (C-F), 1246 (P=O),
997 (P-O-C); 1H-NMR (CDCl3): δ 7.21–7.37 (m, 4H, Ar-H), 6.93–7.02 (m, 2H, Ar-H), 6.67–6.73 (m,
3H, Ar-H), 6.27–6.32 (m, 1H, CH-P), 4.50 (br, 2H, -CH=), 4.02–4.09 (m, 4H, CH2O), 1.63–1.70 (m,
4H, CH2), 0.90 (t, J = 14.9 Hz, 6H, CH3); 13C-NMR (CDCl3): δ 152.9, 151.0, 136.2, 135.0, 132.9,
128.6, 128.0, 126.6, 124.6, 123.2, 118.1, 114.7, 113.4, 68.5, 54.5, 53.3, 24.0, 10.0; 31P-NMR (CDCl3):
δ 22.1; Anal. Calcd for C21H27FNO3P: C 64.45, H 6.90, N 3.58; Found: C 64.50, H 6.79, N 3.40;
Analysis: Daicel Chiralpak IA (hexane-EtOH = 95:5 / v/v), Flow rate = 1.0 mL/min, UV = 250 nm,
tR (minor) = 6.38 min (R), tR (major) = 7.88 min (S). e.e. 8.4%.

Molecules 2010, 15
5791
Diisopropyl 1-[N-(2-fluorophenyl)amino]-3-phenyl-2-propenylphosphonate (9g): Yellow oil; yield
31%; IR (KBr cm-1): ν 3421(N-H), 2980(C-H), 1618 (C=C), 1514 (C=C), 1386 (C-F), 1246 (P=O),
989 (P-O-C); 1H-NMR (CDCl3): δ 7.21–7.36 (m, 4H, Ar-H), 6.94–7.02 (m, 2H, Ar-H), 6.64–6.72 (m,
3H, Ar-H), 6.26 (tt, J = 5.42, 5.45 Hz, 1H, CH-P), 4.73–4.81 (m, 2H, CH-O), 4.37 (br, 1H, -CH=),
1.33–1.39 (m, 6H, CH3), 1.25–1.28 (m, 6H, CH3); 13C-NMR (CDCl3): δ 152.8, 150.9, 136.3, 135.2,
31
128.6, 127.9, 126.6, 124.6, 123.4, 117.9, 114.7, 113.4, 71.8, 54.9, 53.7, 24.2; P- NMR (CDCl3): δ
20.3; Anal. Calcd for C21H27FNO3P: C 64.45, H 6.90, N 3.58; Found: C 64.34, H 6.84, N 3.60;
Analysis: Daicel Chiralpak IA (hexane-EtOH = 95:5 / v/v), Flow rate = 1.0 mL/min, UV = 250 nm,
tR (minor) = 5.66 min (R), tR (major) = 7.12 min (S). e.e. 44.2%.
Di-n-butyl 1-[N-(2-fluorophenyl)amino]-3-phenyl-2-propenylphosphonate (9h): Yellow oil; yield
47%; IR (KBr cm-1): ν 3419 (N-H), 2960 (C-H), 1618 (C=C), 1514 (C=C), 1332 (C-F), 1247 (P=O),
1022 (P-O-C); 1H-NMR (CDCl3): δ 7.21–7.36 (m, 4H, Ar-H), 6.93–7.01 (m, 2H, Ar-H), 6.65–6.73 (m,
3H, Ar-H), 6.27–6.31 (m, 1H, CH-P), 4.44 (br, 2H, -CH=), 4.07–4.15 (m, 4H, CH2O), 1.60–1.62 (m,
4H, CH2), 1.35–1.36 (m, 4H, CH2), 0.87–0.88 (m, 6H, CH3); 13C-NMR (CDCl3): δ 152.9, 151.0, 136.2,
135.0, 132.9, 128.6, 128.0, 126.6, 124.6, 123.2, 118.1, 114.7, 113.4, 66.7, 54.5, 53.3, 32.6, 18.7, 13.6;
31P-NMR (CDCl3): δ 22.1; Calcd for C23H31FNO3P: C 65.87, H 7.40, N 3.34; Found: C 65.77, H 7.40,
N 3.47; Analysis: Daicel Chiralpak IA (hexane-EtOH = 95:5 / v/v), Flow rate = 1.0 mL/min,
UV = 250 nm, tR (minor) = 6.20 min (R), tR (major) = 7.45 min (S). e.e. 27.5%.
Diethyl 1-[N-(2-methylphenyl)amino]-3-phenyl-2-propenylphosphonate (9i): White solid, yield 51%;
m.p. 58.5–59.4 °C; IR (KBr cm-1): ν 3334 (N-H), 2978 (C-H), 1653(C=C), 1521 (C=C), 1230 (P=O),
1
1018 (P-O-C); H-NMR (CDCl3): δ 7.05–7.37 (m, 6H, Ar-H), 6.62–6.71 (m, 3H, Ar-H), 6.27 (tt,
J = 5.61, 5.72 Hz, 1H, CH-P), 4.52 (br, 1H, -CH=), 4.47 (br, 1H, -CH=), 4.14–4.17 (m, 4H, CH2O),
2.25 (s, 3H, CH3); 13C-NMR (CDCl3): δ 144.6, 136.3, 132.8, 130.3, 128.6, 127.9, 127.1, 126.7, 123.8,
122.9, 118.2, 111.2, 63.0, 54.8, 53.6, 17.6, 16.5; 31P-NMR (CDCl3): δ 23.0; Anal. Calcd for
C20H26NO3P: C 66.84, H 7.29, N 3.90; Found: C 67.04, H 7.45, N 3.74; Analysis: Daicel Chiralpak IA
(hexane-EtOH = 90:10 / v/v), Flow rate = 1.0 mL/min, UV = 250 nm, tR (minor) = 5.95 min (R), tR
(major) = 7.29 min (S). e.e. 31.9%.
Dipropyl 1-[N-(2-methylphenyl)amino]-3-phenyl-2-propenylphosphonate (9j): White solid, yield 48%;
m.p. 60.0–62.4 °C; IR (KBr cm-1): ν 3442 (N-H), 2966 (C-H), 1604 (C=C), 1512 (C=C), 1240 (P=O),
1
999 (P-O-C); H-NMR (CDCl3): δ 7.05–7.36 (m, 6H, Ar-H), 6.62–6.70 (m, 3H, Ar-H), 6.26–6.32
(tt, J = 5.45, 5.42 Hz, 1H, CH-P), 4.54 (br, 1H, -CH=), 4.02–4.11 (m, 4H, CH2O), 2.25(s, 3H, CH3),
1.66–1.68 (m, 4H, CH2), 0.90–0.93 (m, 6H, CH3); 13C-NMR (CDCl3): δ 144.3, 136.2, 132.8, 130.3,
31
128.6, 127.8, 127.1, 126.6, 123.9, 122.9, 118.2, 111.2, 68.4, 54.8, 53.5, 24.0, 17.6, 10.1; P-NMR
(CDCl3): δ 22.9; Anal. Calcd for C22H30NO3P: C 68.20, H 7.80, N 3.62; Found: C 68.11, H 8.05, N
3.40; Analysis: Daicel Chiralpak IA (hexane-EtOH = 90:10 / v/v), Flow rate = 1.0 mL/min,
UV = 250 nm, tR (minor) = 6.35 min (R), tR (major) = 6.33 min (S). e.e. 16.9%.
Diisopropyl 1-[N-(2-methylphenyl)amino]-3-phenyl-2-propenylphosphonate (9k): White solid, yield
20
32%; m.p. 61.8–63.1 °C; [α]D -59.1(c 0.9, CHCl3); IR (KBr cm-1): ν 3387 (N-H), 2974 (C-H), 1604

Molecules 2010, 15
5792
1
(C=C), 1510 (C=C), 1230(P=O), 1020 (P-O-C); H-NMR (CDCl3): δ 7.04–7.36 (m, 6H, Ar-H),
6.60–6.69 (m, 3H, Ar-H), 6.27 (tt, J = 5.42, 5.45 Hz, 1H, CH-P), 4.73–4.78 (m, 2H, CH-O), 4.40 (br,
1H, -CH=), 4.17 (br, 1H, -CH=), 2.25 (s, 3H, CH3), 1.33–1.35 (m, 3H, CH3), 1.25–1.27 (m, 3H, CH3);
13C-NMR (CDCl3): δ 144.8, 136.5, 132.4, 130.3, 128.6, 127.7, 127.2, 126.6, 124.2, 122.7, 118.0,
31
111.1, 72.1, 55.2, 54.0, 23.9, 17.6; P-NMR (CDCl3): δ 21.1; Anal. Calcd for C22H30NO3P: C 68.20,
H 7.80, N 3.62; Found: C 68.50, H 7.75, N 3.51; Analysis: Daicel Chiralpak IA
(hexane-EtOH = 90:10 / v/v), Flow rate = 1.0 mL/min, UV = 250 nm, tR (minor) = 4.74 min (R), tR
(major) = 5.29 min (S). e.e. 61.9%.
Dibutyl 1-[N-(2-methylphenyl)amino]-3-phenyl-2-propenylphosphonate (9l): White solid, yield 48%;
m.p. 62.2–64.1 °C; IR (KBr cm-1): ν 3400 (N-H), 2958 (C-H), 1604 (C=C), 1510 (C=C), 1244 (P=O),
1
1022 (P-O-C) ; H-NMR (CDCl3): δ 7.05–7.36 (m, 6H, Ar-H), 6.61–6.70 (m, 3H, Ar-H), 6.26 (tt,
J = 5.45, 5.70 Hz, 1H, CH-P), 4.53 (br, 1H, -CH=), 4.03–4.13 (m, 5H, -CH= + CH2O), 2.24 (s, 3H,
CH3), 1.59–1.64 (m, 4H, CH2), 1.32-1.39 (m, 4H, CH2), 0.86–0.91 (m, 6H, CH3); 13C-NMR (CDCl3): δ
144.7, 136.4, 132.7, 130.3, 128.6, 127.8, 127.1, 126.6, 123.9, 122.9, 118.2, 111.2, 66.7, 54.7, 53.5,
31
32.6, 18.7, 17.6, 13.6; P-NMR (CDCl3): δ 22.9; Anal. Calcd for C24H34NO3P: C 69.37, H 8.25, N
3.37; Found: C 69.16, H 8.04, N 3.03; Analysis: Daicel Chiralpak IA (hexane-EtOH = 90:10 / v/v),
Flow rate = 1.0 mL/min, UV = 250 nm, tR(minor) = 5.17 min (R), tR (major) = 5.94 min (S). e.e.
30.1%.
Diethyl 1-[N-(4-methylphenyl)amino]-3-phenyl-2-propenylphosphonate (9m): Yellow oil; yield 51%;
IR (KBr cm-1): ν 3304 (N-H), 2981 (C-H), 1614 (C=C), 1517 (C=C), 1236 (P=O), 1024 (P-O-C); 1H-
NMR (CDCl3): δ 7.19–7.33 (m, 5H, Ar-H), 6.96 (d, J = 9.20 Hz, 2H, Ar-H), 6.67 (dd, J = 5.20,
5.20 Hz, 1H, -CH=), 6.61 (d, J = 8.60 Hz, 2H, Ar-H), 6.24 (tt, J = 5.70, 5.40 Hz, 1H, CH-P), 4.42 (dd,
J = 6.31, 5.70 Hz, 1H, -CH=), 4.03–4.08 (m, 4H, CH2O), 2.21 (s, 3H, CH3),1.65-1.68 (m, 6H, CH3);
13C- NMR (CDCl3): δ 144.2, 136.4, 132.9, 129.7, 128.6, 127.8, 126.6, 123.7, 114.0, 63.1, 55.0, 53.8,
31
20.4, 16.5; P-NMR (CDCl3): δ 23.1; Anal. Calcd for C20H26NO3P: C 66.84, H 7.29, N 3.90; Found:
C 66.69, H 7.15, N 3.80; Analysis: Daicel Chiralpak IA (hexane-EtOH = 90:10 / v/v), Flow
rate = 1.0 mL/min, UV = 254 nm, tR (minor) = 8.08 min (R), tR (major) = 8.79 min (S). e.e. 28.3%.
Dipropyl1-[N-(4-methylphenyl)amino]-3-phenyl-2-propenylphosphonate (9n): Yellow oil; yield 45%;
IR (KBr cm-1): ν 3304 (N-H), 2968 (C-H), 1616(C=C), 1519 (C=C), 1236 (P=O), 1001 (P-O-C);
1H-NMR (CDCl3): δ 7.19–7.34 (m, 5H, Ar-H), 6.96 (d, J = 8.60 Hz, 2H, Ar-H), 6.65 (dd,
J = 4.62, 4.62 Hz, 1H, -CH=), 6.59 (d, J = 8.10 Hz, 2H, Ar-H), 6.23 (tt, J = 5.20, 5.40 Hz, 1H, CH-P),
4.73–4.77 (m, 4H, CH2O), 2.22 (s, 3H, CH3), 4.38 (dd, J = 5.70, 5.70 Hz, 1H, -CH=), 1.33–1.36 (m,
4H, CH2), 1.24–1.26 (m, 6H, CH3); 13C-NMR (CDCl3): δ144.3, 136.4, 133.0, 129.8, 128.6, 127.8,
126.5, 123.8, 68.4, 55.0, 53.8, 24.0, 20.4, 10.0; 31P-NMR (CDCl3): δ 23.0; Anal. Calcd for
C22H30NO3P: C 68.20, H 7.80, N 3.62; Found: C 68.01, H 7.85, N 3.53; Analysis: Daicel Chiralpak IA
(hexane-EtOH = 95:5 / v/v), Flow rate = 1.0 mL/min, UV = 254 nm, tR (minor) = 7.70 min (R),
tR (major) = 8.40 min (S). e.e. 15.3%.

Molecules 2010, 15
5793
Diisopropyl 1-[N-(4-methylphenyl)amino]-3-phenyl-2-propenylphosphonate (9o): Yellow oil; yield
30%; (KBr cm-1): ν 3300 (N-H), 2978 (C-H), 1616 (C=C), 1519 (C=C), 1250 (P=O), 989 (P-O-C);
1H-NMR (CDCl3): δ 7.19–7.34 (m, 5H, Ar-H), 6.96 (d, J = 8.00 Hz, 2H, Ar-H), 6.67 (dd,
J = 5.20, 5.20 Hz, 1H, -CH=), 6.23 (tt, J = 5.20, 5.40 Hz, 1H, CH-P), 4.14-4.47 (m, 2H, CH-O), 4.32
(dd, J = 6.30, 6.30 Hz, 1H, -CH=), 2.21 (s, 3H, CH3), 1.28–1.31 (m, 12H, CH3),1.27 (t, J = 7.60 Hz,
12H, CH3); 13C-NMR (CDCl3): δ 144.4, 136.5, 132.6, 129.8, 128.5, 127.7, 126.6, 124.2, 113.9, 71.6,
55.5, 54.2, 24.3, 23.9, 20.4; 31P-NMR (CDCl3): δ 21.1; Anal. Calcd for C22H30NO3P: C 68.20, H 7.80,
N 3.62; Found: C 68.11, H 7.65, N 3.44; Analysis: Daicel Chiralpak IA (hexane-EtOH = 90:10 / v/v),
Flow rate = 1.0 mL/min, UV = 254 nm, tR (minor) = 6.12 min (R), tR (major) = 6.57 min (S). e.e.
51.5%.
Di-n-butyl 1-[N-(4-methylphenyl)amino]-3-phenyl-2-propenylphosphonate (9p): Yellow oil; yield
39%; IR (KBr cm-1): ν 3444 (N-H), 2958 (C-H), 1683 (C=C), 1521 (C=C), 1234 (P=O), 1022 (P-O-C);
1H-NMR (CDCl3): δ 7.19–7.34 (m, 5H, Ar-H), 6.96 (d, J = 8.00 Hz, 2H, Ar-H), 6.67 (dd, J = 3.50,
6.30 Hz, 1H, -CH=), 6.60 (d, J = 8.00 Hz, 2H, Ar-H), 6.23 (tt, J = 5.20, 5.70 Hz, 1H, CH-P), 4.41 (dd,
J = 6.30, 6.30 Hz, 1H, -CH=), 4.05–4.15 (m, 8H, 4CH2O), 2.22 (s, 3H, CH3), 1.56–1.64 (m, 4H, CH2),
1.33–1.39 (m, 4H, CH2), 0.86–0.90 (m, 6H, CH3); 13C-NMR (CDCl3): δ 144.2, 136.4, 132.9, 129.8,
31
128.5, 127.8, 126.6, 123.8, 114.0, 66.7, 55.0, 53.8, 32.6, 20.4, 18.7, 13.6; P-NMR (CDCl3): δ 22.9;
Anal. Calcd for C24H34NO3P: C 69.37, H 8.25, N 3.37; Found: C 69.26, H 8.09, N 3.22; Analysis:
Daicel Chiralpak IA (hexane-EtOH = 90:10 / v/v), Flow rate = 1.0 mL/min, UV = 254 nm,
tR (minor) = 6.55 min (R), tR (major) = 7.05 min (S). e.e. 22.7%.
4. Conclusions
In summary, we have employed and studied the role of axially chiral binaphthyl phosphoric acid 6a
in the asymmetric hydrophosphonylation of different aldimines with dialkyl phosphites. The desired α-
aminophosphonates 9a-9p could be obtained in moderate yields and enantioselectivity. Although the
presence of bulky substituents at the 3, 3’ positions of the catalyst appears to influence the outcome of
the reaction, the enantioselectivity is still largely governed by the combined nature of the substrate and
the catalyst structure. Further application of similar organocatalysts obtained by making subtle
structural variation in the parent moiety is currently underway.
Acknowledgements
The authors wish to thank the National Key Project for Basic Research (2010CB126105) and the
National Natural Science Foundation of China (20872002) for the financial support.
References and Notes
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Sample Availability: Samples of the compounds are available from the authors.
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