Cl catalyzed one-pot synthesis of α-aminophosphonate derivatives containing a 4-phenoxyquinazoline moiety under microwave irradiation

Article abstract of DOI:10.1002/cjoc.201190035

[BMIM]Cl catalyzed three component Mannich-type reaction of 4-(quinazolin-4-yloxy)benzenamine and aldehyde with dialkyl phosphite under microwave irradiation has been described. The salient features of the reaction leading to new α-aminophosphonates include shorter reaction time and good yields. The method is environmentally friendly and does not require toxic catalysts or solvents. To the best of our knowledge, this is the first report for [BMIM]Cl induced one-pot synthesis of α-aminophosphonate derivatives. [BMIM]Cl catalyzed three component Mannich-type reaction of 4-(quinazolin-4- yloxy)- benzenamine and aldehyde with dialkyl phosphite under microwave irradiation has been described. The salient features of the reaction leading to new α-aminophosphonates include shorter reaction time and good yields. The method is environmentally friendly and does not require toxic catalysts or solvents. To the best of our knowledge, this is the first report for [BMIM]Cl induced one-pot synthesis of α-aminophosphonate derivatives. Copyright

Full text of DOI:10.1002/cjoc.201190035

FULL PAPER
[BMIM]Cl Catalyzed One-Pot Synthesis of α-Aminophospho-
nate Derivatives Containing a 4-Phenoxyquinazoline
Moiety under Microwave Irradiation
Bai, Song(柏松)
Song, Baoan*(宋宝安)
Hu, Deyu(胡德禹)
Bhadury, Pinaki S.
Yang, Song*(杨松)
Xue, Wei(薛伟)
Research and Development Center for Fine Chemicals, Education Ministry Key Laboratory of Green Pesticide and
Bioengineering, Guizhou University, Guiyang, Guizhou 550025, China
[BMIM]Cl catalyzed three component Mannich-type reaction of 4-(quinazolin-4-yloxy)benzenamine and alde-
hyde with dialkyl phosphite under microwave irradiation has been described. The salient features of the reaction
leading to new α-aminophosphonates include shorter reaction time and good yields. The method is environmentally
friendly and does not require toxic catalysts or solvents. To the best of our knowledge, this is the first report for
[BMIM]Cl induced one-pot synthesis of α-aminophosphonate derivatives.
Keywords quinazoline, α-aminophosphonates, [BMIM]Cl, microwave chemistry, multicomponent reaction
Introduction
tion on exposure to air/moisture. With the advent of
precise microwave reactors in 1986, microwave-induced
reactions have gained popularity in the synthetic appli-
cations. The advantages of using microwave-assisted
synthesis over conventional methods in the preparation
of α-aminophosphonates with potent anti-viral activity
were first realized by our group in 2006.11 On the other
hand, certain environment-friendly, recyclable ionic
liquids (ILS) are known to catalyze effectively many
organic reactions without the requirement of any or-
ganic solvent.12 Based on these reports, we thought to
explore the possibility of executing a three-component
hydrophosphonylation reaction for the preparation of
novel α-aminophosphonates from 4-(quinazolin-4-
yloxy)benzenamine, aromatic or heterocyclic aldehyde
and dialkyl phosphite in presence of an ionic liquid
[BMIM]Cl under microwave conditions (Scheme 1).
Many natural and synthetic aminophosphonic acids,
their phosphonate esters and short peptides incorporat-
ing this unit are well known for their pharmacological
and medicinal activities.1 Besides being routinely em-
ployed as pharmacological agents,2 peptide mimetics,3
enzyme inhibitors,4 herbicides,5 fungicides,6 and
anti-TMV agents,7 α-aminophosphonates play signifi-
cant role in hapten design for antibody generation.8 In
view of different biological and chemical applications
of α-aminophosphonates, the development of suitable
synthetic methodologies for their generation has been a
topic of great interest in recent times. The general
method involves hydrophosphonylation of pregenerated
imines by nucleophilic phosphites in the presence of
Lewis acid catalysts such as SnCl4, BF3•Et2O, or TiCl2.9
Previously generated imines, in selected cases, have
also been reacted with phosphites in presence of lantha-
nide triflate, InCl3, In(OTf)3, GaI3, BiCl3, LiClO4,
Mg(ClO4)2, Yttria-zircona Lewis acid, ZrOCl2•8H2O
and KAl(SO4)2•12H2O.10 Unfortunately, these ap-
proaches afford favorable results only with imines de-
rived from aromatic or aliphatic amines and cannot be
successfully extended to those derived from polynuclear
heteroaromatic amines. Moreover, the catalytic methods
are unsuitable for three component reactions involving
carbonyl compound, amine and dialkyl phosphite due to
the possibility of deactivation of the catalyst by amine.
In addition, these catalysts are often toxic, difficult to
separate from reaction mixture and prone to deactiva-
Results and discussion
In order to establish the optimum condition for the
reaction, the results of model reaction involving
4-(quinazolin-4-yloxy)benzenamine, benzaldehyde and
diethyl phosphite in conventional solvents (Table 1)
were compared with those obtained in presence of ionic
liquids [BMIM]X (Table 2). The best result was
achieved by using [BMIM]Cl under MW heating at 90
℃ for 30 min (yield 74%, Entry 2, Table 2). It is worth
noting that the yields were significantly lower (0—15%)
in conventional solvents such as THF, MeCN,
*
E-mail: basong@gzu.edu.cn, yangsdqj@gmail.com
Received May 20, 2010; revised September 26, 2010; accepted Sepetmber 29, 2010.
Project supported by the National Key Program for Basic Research (Nos. 2010CB126105, 2010CB134504) and the National Natural Science Foun-
dation of China (No. 20872021).
Chin. J. Chem. 2011, 29, 109— 117
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
109

Bai et al.
FULL PAPER
Scheme 1 Synthesis route to α-aminophosphonate derivative
containing a 4-phenoxyquinazoline moiety
Table 2 Synthesis of α-aminophosphonates by the reaction of
4-(quinazolin-4-yloxy)benzenamine, benzaldehyde and diethyl
phosphite in ionic liquids as catalystsa
Entry
Catalyst
[BMIM]Cl
Temperature
Time Yieldc/%
1
2
3
4
5
6
7
8
9
90 ℃
5 h
64
74
32
35
42
44
51
56
nrd
35
nrd
31
46
14
30
nrd
[BMIM]Cl
90 ℃, MWb (40 W) 30 minb
[BMIM]PF6
[BMIM]PF6
[BMIM]PF6
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]HSO4
r.t.
10 h
5h
90 ℃
90 ℃, MWb (40 W) 35 min
r.t.
10 h
5 h
90 ℃
90 ℃, MWb (40 W) 30 min
90 ℃
90 ℃
70 ℃
90 ℃
6 h
5 h
5 h
6 h
10 [BMIM]DBP
11 [BMIM]OTM
12 [BMIM]SbF6
13 [BMIM]SbF6
90 ℃, MWb (40 W) 40 min
14
[BMIM]NO3
90 ℃
90 ℃
90 ℃
20 h
15 h
24 h
15 [BMIM]DCN
16 [BMIM]MBS
a 4-(Quinazolin-4-yloxy)benzenamine (1 mmol), benzaldehyde (1
mmol) and diethyl phosphite (1.5 mmol) in presence of IL (1 g).
b Microwave heating. c Isolated yield. d No reaction.
chloroform, xylene, alcohol, DMF or DMSO (Table 1)
in the absence of ionic liquid under classical mode al-
though a marginal improvement (yield 31%, Entry 3,
Table 1) was noted with MW assisted heating.
Having established the ideal reaction condition, the
synthetic scope of the reaction was further evaluated
with different aldehydes and dialkyl phosphites, and the
results of our studies are summarized in Table 3. It may
be observed that reaction of benzaldehyde and hetero-
cyclic aldehyde furfural with diethyl phosphite afforded
good to moderate yield of the product respectively (En-
tries 2 and 17, Table 3). As expected, presence of an
electron withdrawing group in the aldehyde improved
the rate and yield of the reaction due to enhanced
Table 3 Synthesis of α-aminophosphonates by the reaction of
various aldehydes, dialkyl phosphites and 4-(quinazolin-4-yloxy)-
bezenamine in IL [BMIM]Cl under microwave irradiation
EntryCompd.
Phosphite
Time/minYielda/%
1
2
3
4
7a
7b
7c
7d
Z＝2-F
Z＝H
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OPr-n)2
HP(O)(OPr-n)2
30
30
30
30
69
74
68
70
Z＝2-F
Z＝H
Z＝
Table 1 Synthesis of α-aminophosphonates by the reaction of
4-(quinazolin-4-yloxy)benzenamine, benzaldehyde and diethyl
phosphite in conventional solvents
5
6
7e
7f
HP(O)(OEt)2
30
30
63
60
3,4,5-(OMe)3
Z＝
HP(O)(OPr-n)2
3,4,5-(OMe)3
Entry
Solvent
Xylene
Xylene
Xylene
Temperature
r.t.
Time Yieldb/%
24 h 10
13 h 15
31
7
7g
7h
7i
7j
7k
Z＝2-F
HP(O)(OPr-i)2
HP(O)(OPr-i)2
HP(O)(OEt)2
HP(O)(OPr-n)2
HP(O)(OPr-i)2
HP(O)(OEt)2
30
30
30
30
30
67
70
73
72
70
1
8
Z＝H
2
90 ℃
9
Z＝4-CF3
3
90 ℃, MWa ( 40 W) 50 min
10
11
Z＝4-CF3
4
5
THF
MeCN
Reflux
12 h
13 h
24 h
13 h
12h
nrc
nrc
nrc
nrc
nrc
nrc
nrc
nrc
nrc
nrc
Z＝4-CF3
Reflux
12
13
14
15
16
7l
7m
7n
Z＝2,3-Cl2
30
30
30
40
40
67
64
67
63
55
6
CH2CH3OH
CH2CH3OH
CH3OH
CHCl3
r.t.
Reflux
Z＝2,3-Cl2 HP(O)(OEtOMe)2
Z＝2,3-Cl2
HP(O)(OPr-i)2
7
7o Z＝4-N(CH3)2 HP(O)(OPr-n)2
8
Reflux
7p Z＝4-N(CH3)2 HP(O)(OPr-i)2
9
r.t.
12h
10
11
12
13
DMF
90 ℃
7 h
17
18
7q
7r
HP(O)(OEt)2
HP(O)(OEt)2
40
30
65
68
DMF
90 ℃, MWa (40 W)
50 min
7 h
Z＝3-CF3
DMSO
90 ℃
a
Isolated and unoptimized yields after purification; all products
DMSO
90 ℃, MWa (40 W)
50 min
were characterized by IR, 1H, 13C , 31P NMR, elemental analysis,
and MS.
a Microwave heating. b Isolated yield. c No reaction.
110
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 109— 117

One-Pot Synthesis of α-Aminophosphonate Derivatives
electrophilic reactivity of the carbonyl group (Entries 1,
3, 7, 9—11, and 18, Table 3), whereas aldehydes pos-
sessing electron-donating groups afforded the corre-
sponding α-aminophosphonates in slightly lower yields
(Entries 5, 6, 15 and 16, Table 3).
α-aminophosphonates containing 4-phenoxyquinazoline
moieties offers several advantages including high yield,
fast reaction rate and reusability of the ionic liquid.
Table
4
Recycling of [BMIM]Cl in the reaction of
The proposed mechanism of the reaction involving
4-(quinazolin-4-yloxy)benzenamine, aldehyde and
dialkyl phosphite is depicted in Scheme 2. The
phosphite can exist in phosphonate-phosphite tautomer-
ism13 with the phosphite form serving as the active nu-
cleophilic form. The in situ generated electrophilic
imine (confirmed by spectral data) is supposedly at-
tacked by the nucleophilic phosphite tautomer at the
electrophilic imine carbon (path B) before leading to the
final product. At the same time, possibility of attack at
the imine functionality through the phosphonate form
via a four membered cyclic transition state (path A)
cannot be completely ruled out. This is due to that the
phosphonate tautomer is associated with more dipolar
character and perhaps is the more favored form under
the influence of ion-pair generated from the ionic liquid
[BMIM]Cl in presence of microwave irradiation.
4-(quinazolin-4-yloxy)benzenamine, benzaldehyde and dipropyl
phosphite
Entry
Recycle number
Yield/%
70
1
2
3
4
5
1
2
3
4
5
67
71
67
65
Experimental
The melting points of the products were determined
on a XT-4 binocular microscope (Beijing Tech Instru-
ment Co., China) and were uncorrected. IR spectra (KBr
disks) were recorded on a Bruker Vector 22 spectrome-
1
ter. H and 13C NMR spectra were recorded at room
In comparison with traditional solvents and catalysts,
easy recycling and reusability of [BMIM]Cl make this
method more attractive and economic. The catalytic
activity of recycled [BMIM]Cl in the reaction of
4-(quinazolin-4-yloxy)benzenamine, benzaldehyde and
dipropyl phosphite was investigated. As shown in Table
4, [BMIM]Cl could be reused for at least five times
without showing any significant loss of activity.
temperature on a JEOL-ECX 500 NMR spectrometer
operating at 500 and 125 MHz, respectively, using TMS
as an internal standard. Mass spectral studies were con-
ducted on an Agilent 5973 organic mass spectrometer.
Elemental analysis was performed on an Elementar
Vario-III CHN analyzer. Analytical TLC was performed
on silica gel GF254. Column chromatographic purifica-
tion was carried out using silica gel. All reagents were
of analytical reagent grade or chemically pure. All sol-
vents were dried, deoxygenated, and redistilled before
use.
Catalytic efficacy of the ionic liquid mostly depends
upon the nature of the counter anion. The [BMIM]Cl
catalyzed MW assisted synthesis of novel
Scheme 2 Plausible mechanism for the formation of α-aminophosphonate from 4-(quinazolin-4-yloxy)benzenamine, aldehyde and
dialkyl phosphite catalyzed by [BMIM]Cl under microwave irradiation
Chin. J. Chem. 2011, 29, 109— 117
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
111

Bai et al.
FULL PAPER
X-ray diffraction
quinazoline 2-H), 8.38 (d, J＝7.5 Hz, 1H, quinazoline
8-H), 8.00 (d, J＝8.0 Hz, 1H, quinazoline 5-H), 7.91—
7.88 (m, 1H, quinazoline 7-H), 7.66 (t, J＝8.0 Hz, 1H,
quinazoline 6-H), 7.05—7.03 (m, 2H, ArH), 6.77—6.76
(m, 2H, Ar-H), 3.73 (s, 2H, NH2); 13C NMR (CDCl3,
125 MHz ) δ: 167.6, 154.5, 151.6, 144.5, 144.3, 134.1,
127.8, 127.5, 123.8, 123.7, 122.5, 116.6; IR (KBr) ν:
3417, 3327, 3041, 1610, 1570, 1510, 148＋7, 1203, 1072,
For the structure determination of a single crystal of
7o (Figure 1), X-ray intensity data were recorded on a
Rigaku Raxis-IV diffraction meter using graphite
monochromated Mo Kα radiation (λ＝0.71073 Å). In
the range of 1.79°≤θ≤25.00°, 4846 independent re-
flections were obtained. Intensities were corrected for
Lorentz and polarization effects and empirical absorp-
tion, and all data were corrected using SADABS pro-
gram. The structure was solved by direct methods
SHELXS-97 program. All the non-hydrogen atoms
were refined on F2 anisotropically by full-matrix least
squares method. The hydrogen atoms were located from
the difference Fourier map, but their positions were not
refined. The contributions of these hydrogen atoms were
included in structure-factor calculations. The final
least-square cycle gave wR＝0.2788, R＝0.093 for 3738
－1
837＋cm . MS (ESI) m/z: 238 ([M＋H] ), 260 ([M＋
Na] ). Anal. calcd for C14H11N3O: C 70.87, H 4.67, N
17.71; found C, 70.61, H, 4.78, N, 17.82.
General experimental procedure for the preparation
of title compounds 7a— 7r
4-(Quinazolin-4-yloxy)benzenamine (1 mmol), al-
dehyde (1 mmol) and dialkyl phosphite (1.5 mmol)
were successively added to 1 g of [BMIM]Cl placed in a
round bottomed flask. The mixture was heated with stir-
ring in a DiscoveryTM LabMate instrument at 90 ℃ and
40 W power for 30—40 min. After the completion of
the reaction as indicated by TLC, the reaction mixture
was diluted with water and extracted with ethyl acetate
(10 mL×4). The combined ethyl acetate extracts were
dried over anhydrous Na2SO4, filtered, concentrated in
vacuo, and the crude product was purified by column
chromatography on silica gel (100 — 200 mesh,
EtOAc-hexane, V ∶ V ＝ 1 ∶ 2) to afford pure
α-aminophosphonates.
reflection with I＞2σ(I); the weighting scheme, w＝
2
2
2
1/[σ (Fo )＋(0.1459P)2＋4.3334P], where P＝[(Fo )＋
2
2(FC )]/3. The max and min difference peaks and holes
－3
were 1.07 and －0.82 e•A , respectively, s＝1.11, and
(∆/σ)max＝0.190. The scattering factors were taken from
SHELXL-97. Crystallographic data for the structure
have been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publication No.
CCDC-757481.
Diethyl(2-fluorophenyl)[4-(quinazolin-4-yloxy)-
phenylamino]methylphosphonate (7a)
Colorless
1
solid, m.p. 179—181 ℃; H NMR (D3CCOCD3, 500
MHz) δ: 8.56 (s, 1H, quinazoline 2-H), 8.31 (d, J＝7.5
Hz, 1H, quinazoline 8-H), 7.95 — 7.92 (m, 2H,
quinazoline 5-H and 7-H), 7.71 — 7.68 (m, 2H,
quinazoline 7-H and ArH), 7.33—7.30 (m, 1H, ArH),
7.19—7.13 (m, 2H, ArH), 7.06—7.04 (m, 2H, ArH),
6.88—6.86 (m, 2H, ArH), 5.84—5.82 (m, 1H, NH),
5.19 (dd, J＝9.8, 9.8 Hz, 1H, N-CH-P), 4.20—4.17 (m,
2H, CH2), 3.95—3.78 (m, 2H, CH2), 1.28 (t, J＝7.4 Hz,
3H, CH3), 1.06 (t, J＝7.5 Hz, 3H, CH3); 13C NMR
(D3CCOCD3, 125 MHz) δ: 167.1, 162.2, 160.0, 154.1,
151.7, 144.8, 144.6, 144.5, 134.0, 129.4, 127.8, 127.6,
124.5, 123.4, 122.5, 114.0, 62.9, 62.7, 48.8, 47.6, 15.9,
15.6; 31P NMR (D3CCOCD3, 200 MHz) δ: 21.9; 19F
NMR (D3CCOCD3, 200 MHz) δ: －119.2; IR (KBr) ν:
3298, 3049, 2974, 2926, 1622, 1573, 1508, 1489, 1373,
1271, 1232, 1203, 1074, 1055, 1031, 842, 765, 678, 5＋84
Figure 1 The molecular structure of compound 7o.
Synthetic procedures
Intermediates 2, 3 were prepared according to the
reported methods34,35 and a detailed procedure can be
found in the supporting information.
General procedure for the preparation of intermedi-
ates 4
＋
－1
cm ; MS (ESI) m/z: 482 ([M＋H] ), 504 ([M＋Na] ),
520 ([M＋K]＋). Anal. calcd for C25H25FN3O4P: C 62.37,
H 5.23, N 8.73; found C 62.27, H 5.15, N 8.59.
To a 50 mL single-necked round bottomed flask
were added 4-aminophenol 3 g (0.0275 mol) and K2CO3
7 g (0.0507 mol) followed by acetonitrile (20 mL). The
solution was stirred for 20 min at room temperature, and
then 4.51 g (0.0275 mol) of solid 4-chloroquinazoline
was added into the flask. The mixture was refluxed for 2
h. Purification by column chromatography on silica gel
(petroleum ether-EtOAc, V∶V＝1∶2) afforded a yel-
low solid, m.p. 184—186 ℃, yield 49%.
Diethyl
phenyl[4-(quinazolin-4-yloxy)phenyl-
amino]methylphosphonate (7b) Colorless solid; m.p.
1
159—161 ℃; H NMR (CDCl3, 500 MHz) δ: 8.74 (s,
1H, quinazoline 2-H), 8.32 (d, J ＝ 7.5 Hz, 1H,
quinazoline 8-H), 7.98 (d, J＝8.6 Hz, 1H, quinazoline
5-H), 7.89—7.88 (m, 1H, quinazoline 7-H), 7.62 (t, J＝
8.1 Hz, 1H, quinazoline 6-H), 7.51—7.49 (m, 1H, ArH),
7.37—7.26 (m, 4H, ArH), 7.01—6.99 (m, 2H, ArH),
1H NMR (CDCl3, 500 MHz) δ: 8.78 (s, 1H,
112
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 109— 117

One-Pot Synthesis of α-Aminophosphonate Derivatives
6.68—6.66 (m, 2H, ArH), 4.96—4.92 (m, 1H, NH),
4.72 (dd, J＝7.5, 7.5 Hz, 1H, N-CH-P), 4.16—4.10 (m,
2H, CH2), 3.96—3.64 (m, 2H, CH2), 1.33 (t, J＝7.5 Hz,
3H, CH3), 1.12 (t, J＝7.5 Hz, 3H, CH3); 13C NMR
(CDCl3, 125 MHz) δ: 167.4, 154.4, 151.6, 144.5, 144.4,
144.2, 128.7, 128.7, 127.9, 127.8, 127.5, 123.7, 122.4,
114.5, 63.5, 63.4, 63.3, 63.3, 57.0, 55.8, 16.5, 16.5, 16.3;
31P NMR (CDCl3, 200 MHz) δ: 23.0; IR (KBr) ν: 3286,
3043, 2981, 2931, 1620, 1575, 1508, 1489, 1375, 1271,
found C 66.11, H 6.27, N 8.62.
Diethyl [4-(quinazolin-4-yloxy)phenylamino]-
(3,4,5-trimethoxyphenyl)methylphosphonate
(7e)
1
Colorless solid; m.p. 153—154.5 ℃; H NMR (CDCl3,
500 MHz) δ: 8.75 (s, 1H, quinazoline 2-H), 8.34 (d, J＝
8.1 Hz, 1H, quinazoline 8-H), 7.99 (d, J＝8.6 Hz, 1H,
quinazoline 5-H), 7.91—7.88 (m, 1H, quinazoline 7-H),
7.64 (t, J＝7.5 Hz, 1H, quinazoline 6-H), 7.04—7.03 (m,
2H, ArH), 6.74—6.68 (m, 4H, ArH), 4.89—4.86 (m, 1H,
NH), 4.62 (dd, J＝6.9, 6.9 Hz, 1H, N-CH-P), 4.16—
4.11 (m, 2H, CH2), 4.00—3.73 (m, 11H, 3OCH3 and
CH2), 1.34 (t, J＝7.5 Hz, 3H, CH3), 1.17 (t, J＝7.5 Hz,
3H, CH3); 13C NMR (CDCl3, 125 MHz) δ: 167.4, 154.4,
153.4, 151.6, 114.6, 114.5, 144.3, 134.1, 131.4, 127.9,
127.5, 123.7, 122.4, 116.5, 114.6, 104.8, 104.7, 63.5,
63.5, 63.4, 63.3, 60.9, 57.4, 56.2, 16.6, 16.4; 31P NMR
(CDCl3, 200 MHz) δ: 22.9; IR (KBr) ν: 3309, 3043,
2976, 2931, 1618, 1570, 1506, 1489, 1373, 1278－, 1242,
－1
1222, 1201, 1070, 1055, 1024, 827, 775, 702, 584 cm ;
MS (ESI＋) m/z: 464 ([M＋H]＋), 486 ([M＋Na]＋), 502
([M＋K] ). Anal. calcd for C25H26N3O4P: C 64.79, H
5.65, N 9.07; found C 64.62, H 5.78, N 8.92.
Dipropyl (2-fluorophenyl)[4-(quinazolin-4-yloxy)-
phenylamino]methylphosphonate (7c)
Colorless
solid; m.p. 119—120 ℃; 1H NMR (CDCl3, 500 MHz) δ:
8.74 (s, 1H, quinazoline 2-H), 8.32 (d, J＝8.0 Hz, 1H,
quinazoline 8-H), 7.98 (d, J＝8.6 Hz, 1H, quinazoline
5-H), 7.89—7.86 (m, 1H, quinazoline 7-H), 7.64—7.55
(m, 2H, quinazoline 6-H and ArH), 7.27—7.25 (m, 1H,
ArH), 7.15—7.06 (m, 2H, ArH), 7.03 (d, J＝9.2 Hz, 2H,
ArH), 6.71 (d, J＝8.6 Hz, 2H, ArH), 5.20 (dd, J＝8.6,
8.6 Hz, 1H, N-CH-P), 5.03—4.99 (m, 1H, NH), 4.14—
4.10 (m, 2H, CH2), 3.88—3.60 (m, 2H, CH2), 1.74—
1.70 (m, 2H, CH2), 1.49—1.44 (m, 2H, CH2), 0.96 (t,
J＝7.5 Hz, 3H, CH3), 0.78 (t, J＝7.5 Hz, 3H, CH3); 13C
NMR (CDCl3, 125 MHz) δ: 167.4, 161.8, 161.8, 159.9,
154.4, 151.5, 144.3, 144.0, 134.1, 127.8 127.5, 124.7,
123.7, 122.5, 116.5, 114.3, 69.1, 69.0, 48.9, 47.6, 24.0,
23.9, 23.7, 23.7, 10.1, 9.85; 31P NMR (CDCl3, 200 MHz)
δ: 22.3; 19F NMR (CDCl3, 200 MHz) δ: －118.2; IR
(KBr) ν: 3317, 3066, 2968, 2935, 1620, 1570, 1508,
1489, 1373, 1273, 1226, 1205, 1070, 1058, 1010, 844,
1
1199, 1053, 1031, 1002＋, 833, 777, 678, 570 cm ; MS
(ESI) m/z: 554 ([M＋H] ), 576 ([M＋Na]＋), 592 ([M＋
K]＋). Anal. calcd for C28H32N3O7P: C 60.75, H 5.83, N
7.59; found C 60.86, H 5.69, N 7.75.
Dipropyl [4-(quinazolin-4-yloxy)phenylamino]-
(3,4,5-trimethoxyphenyl)methylphosphonate
(7f)
1
Colorless solid, m.p. 170—171 ℃; H NMR (CDCl3,
500 MHz ) δ: 8.76 (s, 1H, quinazoline 2-H), 8.34 (d, J＝
8.0 Hz, 1H, quinazoline 8-H), 7.99 (d, J＝8.1 Hz, 1H,
quinazoline 5-H), 7.91—7.88 (m, 1H, quinazoline 7-H),
7.65 (t, J＝7.5 Hz, 1H, quinazoline 6-H), 7.04—7.02 (m,
2H, ArH), 6.74—6.68 (m, 4H, ArH), 4.88—4.85 (m, 1H,
NH), 4.63 (dd, J＝6.9, 6.9 Hz, 1H, N-CH-P), 4.05—
4.02 (m, 2H, CH2), 3.89—3.60 (m, 11H, 3OCH3 and
CH2), 1.71—1.67 (m, 2H, CH2), 1.54—1.51 (m, 2H,
CH2), 0.96 (t, J＝7.5 Hz, 3H, CH3), 0.84 (t, J＝7.5 Hz,
3H, CH3); 13C NMR (CDCl3, 125 MHz) δ: 167.4, 154.4,
153.4, 151.6, 114.7, 114.5, 144.3, 134.1, 131.6, 127.9,
127.5, 123.7, 122.4, 116.5, 114.6, 104.7, 68.8, 60.9,
57.4, 56.2, 24.0, 23.8, 10.1, 10.0; 31P NMR (CDCl3, 200
MHz) δ: 22.8; IR (KBr) ν: 3311, 3043, 2986, 2935,
1620, 1570, 1506, 1489, 1373, －1282, 1234, 1203, 1068,
＋
－1
773, 680, 572 cm ; MS (ESI) m/z: 510 ([M＋H] ), 532
([M ＋ Na] ＋ ), 548 ([M ＋ K] ＋ ). Anal. calcd for
C27H29FN3O4P: C 63.65, H 5.74, N 8.25; found C 63.80,
H 5.57, N 8.11.
Dipropyl
phenyl[4-(quinazolin-4-yloxy)phenyl-
amino]methylphosphonate (7d) Colorless solid; m.p.
1
110—111 ℃; H NMR (CDCl3, 500 MHz) δ: 8.74 (s,
1
1H, quinazoline 2-H), 8.33 (d, J ＝ 8.0 Hz, 1H,
quinazoline 8-H), 7.98 (d, J＝8.6 Hz, 1H, quinazoline
5-H), 7.89—7.86 (m, 1H, quinazoline 7-H), 7.64 (t, J＝
8.1 Hz, 1H, quinazoline 6-H), 7.50—7.49 (m, 2H, ArH),
7.37—7.26 (m, 3H, ArH), 7.01—6.99 (m, 2H, ArH),
6.67—6.65 (m, 2H, ArH), 4.93—4.89 (m, 1H, NH),
4.76 (dd, J＝7.5, 7.5 Hz, 1H, N-CH-P), 4.05—3.98 (m,
2H, CH2), 3.85—3.52 (m, 2H, CH2), 1.71—1.67 (m, 2H,
CH2), 1.54—1.51 (m, 2H, CH2), 0.95 (t, J＝7.5 Hz, 3H,
CH3), 0.80 (t, J＝7.5 Hz, 3H, CH3); 13C NMR (CDCl3,
125 MHz) δ: 167.4, 154.4, 151.6, 144.5, 144.2, 134.0,
128.7, 128.1, 127.9, 127.9, 123.7, 122.4, 114.5, 68.8,
68.7, 57.0, 55.8, 24.0, 23.9, 23.8, 23.7, 10.0, 9.9; 31P
NMR (CDCl3, 200 MHz) δ: 22.9; IR (KBr) ν: 3294,
3039, 2966, 2893, 1620, 1575, 1506, 1489－, 1373, 1273,
1004, 83＋3, 773, 678, 578 cm ; MS (ESI) m/z: 582
([M＋H] ), 604 ([M＋Na]＋), 620 ([M＋K]＋). Anal.
calcd for C30H36N3O7P: C 61.95, H 6.24, N 7.22; found
C 61.99, H 6.05, N 6.99.
Diisopropyl(2-fluorophenyl)[4-(quinazolin-4-yl-
oxy)phenylamino]methylphosphonate
(7g)
1
Colorless solid; m.p. 155—156 ℃; H NMR (CDCl3,
500 MHz) δ: 8.74 (s, 1H, quinazoline 2-H), 8.31 (d, J＝
8.1 Hz, 1H, quinazoline 8-H), 7.96 (d, J＝8.6 Hz, 1H,
quinazoline 5-H), 7.90—7.87 (m, 1H, quinazoline 7-H),
7.64—7.53 (m, 2H, quinazoline 6-H and ArH), 7.26—
7.25 (m, 1H, Ar-H), 7.14—7.06 (m, 2H, ArH), 7.02 (d,
J＝8.6 Hz, 2H, ArH), 6.70 (d, J＝8.6 Hz, 2H, ArH),
5.07 (dd, J＝8.6, 9.2 Hz, 1H, N-CH-P), 4.94—4.90 (m,
1H, NH), 4.83—4.79 (m, 1H, OCH), 4.47—4.43 (m, 1H,
OCH), 1.37 (d, J＝6.3 Hz, 3H, CH3), 1.34 (d, J＝6.3 Hz,
3H, CH3), 1.26 (d, J＝6.3 Hz, 3H, CH3), 0.88 (d, J＝6.3
Hz, 3H, CH3); 13C NMR (CDCl3, 125 MHz) δ: 167.4,
1
1230, 1201, 1070,＋827, 775, 700, 580 cm ; MS (ESI)
m/z: 492 ([M＋H] ), 514 ([M＋Na]＋), 530 ([M＋K]＋).
Anal. calcd for C27H30N3O4P: C 65.98, H 6.15, N 8.55;
Chin. J. Chem. 2011, 29, 109— 117
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
113

Bai et al.
FULL PAPER
161.9, 159.8, 154.4, 151.6, 144.2, 144.2, 144.0, 134.0,
129.0, 127.9, 127.5, 123.7, 122.4, 116.6, 114.2, 72.4,
72.2, 49.4, 48.1, 24.2, 23.9, 23.0; 31P NMR (CDCl3, 200
MHz) δ: 20.6; 19F NMR (CDCl3, 200 MHz) δ: －118.0;
IR (KBr) ν: 3298, 3290, 2974 , 2935, 1620, 1575, 1508,
1489, 1373,－1265, 1234, 1203, 1072, 1022＋, 842, 775,
7.5 Hz, 1H, quinazoline 8-H), 7.98 (d, J＝8.6 Hz, 1H,
quinazoline 5-H), 7.89—7.87 (m, 1H, quinazoline 7-H),
7.65—7.63 (m, 5H, quinazoline 6-H and ArH), 7.03 (d,
J＝8.6 Hz, 2H, ArH), 6.64 (d, J＝8.6 Hz, 2H, ArH),
4.93—4.90 (m, 1H, NH), 4.82 (dd, J＝6.9, 6.9 Hz, 1H,
N-CH-P), 4.07—4.00 (m, 2H, CH2), 3.92—3.66 (m, 2H,
CH2), 1.71—1.66 (m, 2H, CH2), 1.55—1.51 (m, 2H,
CH2), 0.94 (t, J＝7.5 Hz, 3H, CH3), 0.82 (t, J＝7.5 Hz,
3H, CH3); 13C NMR (CDCl3, 125 MHz) δ: 167.4, 154.4,
151.6, 144.5, 144.0, 140.3, 134.1, 128.2, 128.2, 127.9,
127.5, 125.6, 123.7, 122.5, 116.5, 114.6, 69.1, 69.0,
50.6, 55.7, 23.9, 23.8, 10.0, 9.9; 31P NMR (CDCl3, 200
MHz) δ: 21.8; 19F NMR (CDCl3, 200 MHz) δ: －62.4;
IR (KBr) ν: 3302, 3041, 2970, 2937 , 1618, 1570, 1508,
1489, 1375, 1274, 1222, 1207, 1068, 1033, 1004, 839,
1
678, 584 cm ; MS (ESI) m/z: 5＋10 ([M＋H] ), 532 ([M
＋
＋ Na] ), 548 ([M ＋ K] ). Anal. calcd for
C27H29FN3O4P: C 63.65, H 5.74, N 8.25; found C 63.75,
H 5.87, N 8.02.
Diisopropyl phenyl[4-(quinazolin-4-yloxy)phenyl-
amino]methylphosphonate (7h) Colorless solid, m.p.
1
136—138 ℃; H NMR (CDCl3, 500 MHz) δ: 8.74 (s,
1H, quinazoline 2-H), 8.31 (d, J ＝ 8.0 Hz, 1H,
quinazoline 8-H), 7.98 (d, J＝8.6 Hz, 1H, quinazoline
5-H), 7.89—7.86 (m, 1H, quinazoline 7-H), 7.64 (t, J＝
8.1 Hz, 1H, quinazoline 6-H), 7.50—7.48 (m, 2H, ArH),
7.35—7.26 (m, 3H, ArH), 6.98 (d, J＝8.6 Hz, 2H, ArH),
6.65 (d, J＝8.6 Hz, 2H, ArH), 4.90 (dd, J＝7.5, 10.3 Hz,
1H, N-CH-P), 4.72—4.68 (m, 1H, NH), 4.66—4.64 (m,
1H, OCH), 4.47—4.43 (m, 1H, OCH), 1.33 (d, J＝6.3
Hz, 3H, CH3), 1.27—1.25 (m, 6H, 2-CH3), 0.93 (d, J＝
5.8 Hz, 3H, CH3); 13C NMR (CDCl3, 125 MHz) δ:
167.4, 154.4, 151.6, 114.7, 144.6, 144.0, 128.6, 128.1,
128.1, 127.9, 127.5, 123.7, 122.3, 114.5, 72.3, 72.2,
72.0, 71.9, 57.5, 56.3, 24.3, 23.9, 23.9, 23.3, 23.2; 31P
NMR (CDCl3, 200 MHz) δ: 21.3; IR (KBr) ν: 3290,
3032, 2978, 2933, 1620, 1573, 1506, 1489－, 1373, 1271,
＋
－1
775, 680, 574 cm ; MS (ESI) m/z: 582 ([M＋H] ), 560
([M ＋ Na] ＋ ), 598 ([M ＋ K] ＋ ). Anal. calcd for
C28H29F3N3O4P: C 60.11, H 5.22, N 7.51; found C
59.98, H 5.09, N 7.36.
Diisopropyl[4-(quinazolin-4-yloxy)phenylamino]-
[4-(trifluoromethyl)phenyl]methylphosphonate (7k)
1
Colorless solid, m.p. 134—136 ℃; H NMR (CDCl3,
500 MHz) δ: 8.74 (s, 1H, quinazoline 2-H), 8.33 (d, J＝
8.0 Hz, 1H, quinazoline 8-H), 7.97 (d, J＝8.6 Hz, 1H,
quinazoline 5-H), 7.89—7.87 (m, 1H, quinazoline 7-H),
7.63—7.61 (m, 5H, quinazoline 6-H and ArH), 7.02 (d,
J＝9.2 Hz, 2H, ArH), 6.63 (d, J＝9.2 Hz, 2H, ArH),
4.88—4.84 (m, 1H, NH), 4.76—4.74 (m, 1H, OCH),
4.70 (dd, J＝7.5, 7.5 Hz, 1H, N-CH-P), 4.58—4.51 (m,
1H, OCH), 1.35 (d, J＝6.3 Hz, 3H, CH3), 1.29 (d, J＝
6.3 Hz, 3H, CH3), 1.25 (d, J＝6.3 Hz, 3H, CH3), 1.01 (d,
J＝6.3 Hz, 3H, CH3); 13C NMR (CDCl3, 125 MHz) δ:
167.4, 154.4, 151.6, 144.4, 144.3, 144.2, 134.1, 128.4,
128.3, 127.9, 127.5, 125.5, 123.7, 122.5, 116.5, 114.5,
72.4, 72.4, 57.4, 56.2, 24.2, 24.2, 23.9; 31P NMR
(CDCl3, 200 MHz) δ: 20.1; 19F NMR (CDCl3, 200 MHz)
δ: －62.3; IR (KBr) ν: 3311, 3041, 2978, 2935, 1618,
1575, 1508, 1489, 1373, 1273, 1230, 1207, 1066, 98＋9,
1
1232, 1201, 1070,＋827, 771, 700, 582 cm ; MS (ESI)
m/z: 492 ([M＋H] ), 514 ([M＋Na]＋), 530 ([M＋K]＋).
Anal. calcd for C27H30N3O4P: C 65.98, H 6.15, N 8.55;
found C 65.84, H 6.29, N 8.41.
Diethyl [4-(quinazolin-4-yloxy)phenylamino][4-
(trifluoromethyl)phenyl]methylphosphonate
(7i)
1
Colorless solid, m.p. 157—159 ℃; H NMR (CDCl3,
500 MHz) δ: 8.74 (s, 1H, quinazoline 2-H), 8.33 (d, J＝
8.1 Hz, 1H, quinazoline 8-H), 7.98 (d, J＝8.6 Hz, 1H,
quinazoline 5-H), 7.90—7.87 (m, 1H, quinazoline 7-H),
7.63—7.59 (m, 5H, quinazoline 6-H and ArH), 7.03 (d,
J＝8.6 Hz, 2H, ArH), 6.64 (d, J＝8.6 Hz, 2H, ArH),
4.96—4.92 (m, 1H, NH), 4.81 (dd, J＝6.9, 6.9 Hz, 1H,
N-CH-P), 4.17—4.10 (m, 2H, CH2), 4.04—3.79 (m, 2H,
CH2), 1.32 (t, J＝6.9 Hz, 3H, CH3), 1.17 (t, J＝6.9 Hz,
3H, CH3); 13C NMR (CDCl3, 125 MHz) δ: 167.4, 154.4,
151.6, 144.5, 144.1, 144.0, 140.2, 134.1, 128.2, 128.2,
127.9, 127.5, 125.6, 123.7, 122.6, 116.5, 114.5, 63.7,
63.6, 63.5, 56.9, 55.7, 16.5, 16.3; 31P NMR (CDCl3, 200
MHz) δ: 21.9; 19F NMR (CDCl3, 200 MHz) δ: －62.4;
IR (KBr) ν: 3313, 3043, 2983, 2931, 1620, 1570, 1508,
1490, 1375, 1271, 1228, 1207, 1070, 1049, 1018, 844,
－1
837, 773, 680, 5＋78 cm ; MS (ESI)＋m/z: 560 ([M＋H] ),
582 ([M＋Na] ), 598 ([M＋K] ). Anal. calcd for
C28H29F3N3O4P: C 60.11, H 5.22, N 7.51; found: C
59.99, H 5.16, N 7.41.
Diethyl[2,3-dichlorophenyl][4-(quinazolin-4-yl-
oxy)phenylamino]methylphosphonate (7l) Colorless
solid; m.p. 209—211 ℃; 1H NMR (CDCl3, 500 MHz) δ:
8.74 (s, 1H, quinazoline 2-H), 8.33 (d, J＝8.0 Hz, 1H,
quinazoline 8-H), 7.98 (d, J＝8.6 Hz, 1H, quinazoline
5-H), 7.89—7.87 (m, 1H, quinazoline 7-H), 7.63 (t, J＝
7.4 Hz, 1H, quinazoline 6-H), 7.55—7.41 (m, 2H, ArH),
7.21 (d, J＝8.1 Hz, 1H, ArH), 7.03 (d, J＝8.6 Hz, 2H,
ArH), 6.64 (d, J＝8.6 Hz, 2H, ArH), 5.40 (dd, J＝8.6,
8.1 Hz, 1H, N-CH-P), 5.14—5.10 (m, 1H, NH), 4.27—
4.21 (m, 2H, CH2), 3.96—3.66 (m, 2H, CH2), 1.38 (t,
J＝6.6 Hz, 3H, CH3), 1.08 (t, J＝7.4 Hz, 3H, CH3); 13C
NMR (CDCl3, 125 MHz) δ: 167.4, 154.4, 151.6, 144.4,
134.1, 130.1, 127.9, 127.5, 127.1, 123.7, 122.6, 116.5,
114.2, 63.7, 63.7, 53.3, 52.1, 16.5, 16.1, 16.1; IR (KBr)
ν: 3296, 3059, 2989, 2929, 1622, 1570, 1506, 1489,
＋
－1
783, 680, 570 cm ; MS (ESI) m/z: 532 ([M＋H] ), 554
([M ＋ Na] ＋ ), 570 ([M ＋ K] ＋ ). Anal. calcd for
C26H25F3N3O4P: C 58.76, H 4.74, N 7.91; found C
58.94, H 4.87, N 8.06.
Dipropyl[4-(quinazolin-4-yloxy)phenylamino][4-
(trifluoromethyl)phenyl]methylphosphonate
(7j)
1
Colorless solid, m.p. 112—114 ℃; H NMR (CDCl3,
500 MHz) δ: 8.74 (s, 1H, quinazoline 2-H), 8.33 (d, J＝
114
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 109— 117

One-Pot Synthesis of α-Aminophosphonate Derivatives
1373, 1273, 1230, 1197, 1053, 1024,＋835, 765, 677, 5＋86
Anal. calcd for C25H24Cl2N3O4P: C 56.40, H 4.54, N
7.89; found: C 56.23, H 4.51, N 7.76.
(m, 1H, NH), 4.62 (dd, J＝7.5, 7.5 Hz, 1H, N-CH-P),
4.02—3.97 (m, 2H, CH2), 3.85—3.56 (m, 2H, CH2),
2.92 (s, 6H, CH3-N-CH3) 1.70—1.63 (m, 2H, CH2),
1.54—1.47 (m, 2H, CH2), 0.93 (t, J＝7.5 Hz, 3H, CH3),
0.82 (t, J＝7.5 Hz, 3H, CH3); 13C NMR (CDCl3, 125
MHz ) δ: 167.5, 154.5, 151.6, 150.4, 144.8, 144.7, 144.0,
134.0, 128.7, 128.7, 127.8, 127.4, 123.7, 122.3, 116.6,
114.6, 112.6, 68.6, 68.6, 56.3, 55.1, 40.6, 23.9, 23.8,
10.1, 10.0; 31P NMR (CDCl3, 200 MHz) δ: 23.6; IR
(KBr) ν: 3277, 3068, 2962, 2893, 1616, 1575, 1506,
1487, 1373, 1273,－1232, 1201, 1060, 1029, 829, 777,
－1
cm ; MS (ESI) m/z: 532 ([M＋Na] ), 554 ([M＋H] ).
Bis(2-methoxyethyl)(2,3-dichlorophenyl)[4-(quin-
azolin-4-yloxy)phenylamino]methylphosphonate (7m)
1
Colorless solid; m.p. 146—148 ℃; H NMR (CDCl3,
500 MHz) δ: 8.73 (s, 1H, quinazoline 2-H), 8.33 (d, J＝
8.0 Hz, 1H, quinazoline 8-H), 7.98 (d, J＝8.6 Hz, 1H,
quinazoline 5-H), 7.90—7.87 (m, 1H, quinazoline 7-H),
7.63 (t, J＝8.0 Hz, 1H, quinazoline 6-H), 7.54—7.41 (m,
2H, Ar-H), 7.21 (t, J＝8.1 Hz, 1H, ArH), 7.03 (d, J＝
9.2 Hz, 2H, ArH), 6.63 (d, J＝9.2 Hz, 2H, ArH), 5.51
(dd, J＝8.2, 8.1 Hz, 1H, N-CH-P), 5.36—5.32 (m, 1H,
NH), 4.29—4.26 (m, 2H, CH2), 4.08—3.99 (m, 2H,
CH2), 3.61—3.59 (m, 2H, CH2), 3.50—3.40 (m, 2H,
CH2), 3.38 (s, 3H, CH3), 3.33 (s, 3H, CH3); 13C NMR
(CDCl3, 125 MHz) δ: 167.4, 154.4, 151.6, 144.4, 143.7,
134.0, 130.0, 127.9, 127.5, 127.2, 123.7, 122.5, 116.5,
114.2, 71.5, 71.4, 71.3, 66.2, 66.2, 59.0, 58.9, 53.6, 52.4;
31P NMR (CDCl3, 200 MHz) δ: 22.1; IR (KBr) ν: 3296,
3062, 2985 , 2929, 1623, 1570, 1516, 1489, 1373, 1269,
＋
1
680, 590, 576 cm ; MS (ESI) m/z: 557 ([M＋Na] ),
573 ([M＋K]＋). Anal. calcd for C29H35N4O4P: C 65.16,
H 6.60, N 10.48; found C 65.10, H 6.43, N 10.57.
Diisopropyl[4-(dimethylamino)phenyl][4-(quina-
zolin-4-yloxy)phenylamino]methylphosphonate (7p)
1
Colorless solid, m.p. 177—179 ℃; H NMR (CDCl3,
500 MHz) δ: 8.73 (s, 1H, quinazoline 2-H), 8.31 (d, J＝
8.1 Hz, 1H, quinazoline 8-H), 7.96 (d, J＝8.0 Hz, 1H,
quinazoline 5-H), 7.88—7.85 (m, 1H, quinazoline 7-H),
7.61 (t, J＝8.0 Hz, 1H, quinazoline 6-H), 7.32—7.30 (m,
2H, ArH), 6.98 (d, J＝8.6 Hz, 1H, ArH), 6.67 (t, J＝8.6
Hz, 4H, ArH), 4.80—4.77 (m, 1H, NH), 4.74—4.64 (m,
1H, OCH), 4.58 (dd, J＝7.5, 7.5 Hz, 1H, N-CH-P),
4.46—4.40 (m, 1H, OCH), 2.91 (s, 6H, CH3-N-CH3),
1.33 (d, J＝6.3 Hz, 3H, CH3), 1.27 (d, J＝4.5 Hz, 3H,
CH3), 1.25 (d, J＝4.0 Hz, 3H, CH3), 0.96 (d, J＝5.7 Hz,
3H, CH3); 13C NMR (CDCl3, 125 MHz) δ: 167.5, 154.5,
151.6, 150.3, 145.0, 144.9, 143.9, 134.0, 128.9, 128.8,
127.8, 127.4, 123.7, 122.2, 116.6, 114.6, 112.6, 72.1,
71.7, 56.8, 55.6, 40.6, 24.4, 24.4, 24.3; 31P NMR
(CDCl3, 200 MHz) δ: 22.0; IR (KBr) ν: 3292, 3068,
2968, 2920, 1616, 1575, 1508, 1489, 1373, 1273, 1228,
－1
1232, 1199, 1070, 1051, 1026,＋835, 783, 677, 5＋84 cm ;
MS (ESI) m/z: 592 ([M＋Na] ), 614 ([M＋H] ). Anal.
calcd for C27H28Cl2N3O6P: C 54.74, H 4.76, N 7.09;
found C 54.75, H 4.86, N 7.24.
Diisopropyl(2,3-dichlorophenyl)[4-(quinazolin-4-
yloxy)phenylamino]methylphosphonate
(7n)
Colorless solid, m.p. 159—161 ℃; 1H NMR (DMSO-d6,
500 MHz) δ: 8.66 (s, 1H, quinazoline 2-H), 8.31 (d, J＝
8.0 Hz, 1H, quinazoline 8-H), 8.01 (d, J＝8.6 Hz, 1H,
quinazoline 5-H), 7.97 (t, J＝8.6 Hz, 1H, quinazoline
7-H), 7.74 (t, J＝7.4 Hz, 1H, quinazoline 6-H), 7.70 (d,
J＝7.4 Hz, 1H, A-H), 7.61 (d, J＝7.5 Hz, 1H, ArH),
7.41 (d, J＝8.0 Hz, 1H, ArH), 7.04 (d, J＝9.2 Hz, 2H,
ArH), 6.77 (d, J＝9.2 Hz, 2H, ArH), 5.23 (dd, J＝10.3,
10.3 Hz, 1H, N-CH-P), 4.93—4.90 (m, 1H, NH), 4.77—
4.74 (m, 1H, OCH), 4.35—4.33 (m, 1H, OCH), 1.31 (d,
J＝6.3 Hz, 3H, CH3), 1.28 (d, J＝6.3 Hz, 3H, CH3),
1.20 (d, J＝6.3 Hz, 3H, CH3), 0.80 (d, J＝5.8 Hz, 3H,
－1
1203, 1070, 997, 821, 773＋, 678, 594, 580 c＋m ; MS
(ESI) m/z: 557 ([M＋Na] ), 573 ([M＋K] ). Anal.
calcd for C29H35N4O4P: C 65.16, H 6.60, N 10.48; found
C 65.04, H 6.48, N 10.29.
Diethyl furan-2-yl[4-(quinazolin-4-yloxy)phenyl-
amino]methylphosphonate (7q) Colorless solid, m.p.
1
154—156 ℃; H NMR (CDCl3, 500 MHz) δ: 8.76 (s,
13
CH3); C NMR (DMSO-d6, 125 MHz) δ: 167.2, 154.5,
1H, quinazoline 2-H), 8.35 (d, J ＝ 8.6 Hz, 1H,
quinazoline 8-H), 7.99 (d, J＝8.6 Hz, 1H, quinazoline
5-H), 7.88 (t, J＝6.9 Hz, 1H, quinazoline 7-H), 7.64 (t,
J＝6.9 Hz, 1H, quinazoline 6-H), 7.41 (s, 1H, furan-H),
7.07 (d, J＝8.6 Hz, 2H, ArH), 6.75 (d, J＝8.6 Hz, 2H,
ArH), 6.43 (t, J＝3.5 Hz, 1H, furan-H), 6.36 (s, 1H,
furan-H), 4.88 (dd, J＝8.6, 8.6 Hz, 1H, N-CH-P), 4.66
—4.63 (m, 1H, NH), 4.24—4.21 (m, 2H, CH2), 4.08—
3.85 (m, 2H, CH2), 1.35 (t, J＝6.9 Hz, 3H, CH3), 1.22 (t,
J＝6.9 Hz, 3H, CH3); 13C NMR (CDCl3, 125 MHz) δ:
167.4, 154.4, 151.6, 149.3, 144.6, 144.1, 142.6, 134.0,
127.9, 127.5, 123.7, 122.5, 116.6, 114.7, 110.5, 109.0,
109.0, 63.6, 63.4, 51.2, 549.9, 16.4, 16.3; 31P NMR
(CDCl3, 200 MHz) δ: 20.6; IR (KBr) ν: 3288, 3043,
2978, 2926, 1620, 1570, 1508, 1489, 1375, 1271－, 1242,
151.5, 145.0, 144.0, 138.2, 135.0, 130.3, 128.7, 128.4,
128.0, 123.9, 123.0, 116.1, 114.1, 72.1, 72.0, 71.8, 53.5,
52.2, 24.4, 24.1, 24.0; 31P NMR (DMSO-d6, 200 MHz)
δ: 20.0; IR (KBr) ν: 3300, 3062, 2980 , 2931, 1622,
1570, 1506, 1489, 1373, 1269, 1232, 1205, 1070, 99＋5,
－1
833, 771, 677, 592 cm ; MS (ESI) m/z: 560 ([M＋H] ),
582 ([M＋Na]＋). Anal. calcd for C27H28Cl2N3O6P: C
57.87, H 5.04, N 7.50; found C 57.72, H 5.10, N 7.37.
Dipropyl[4-(dimethylamino)phenyl][4-(quinazo-
lin-4-yloxy)phenylamino]methylphosphonate
(7o)
1
Colorless solid, m.p. 179—181 ℃; H NMR (CDCl3,
500 MHz) δ: 8.73 (s, 1H, quinazoline 2-H), 8.32 (d, J＝
8.0 Hz, 1H, quinazoline 8-H), 7.97 (d, J＝8.6 Hz, 1H,
quinazoline 5-H), 7.88—7.87 (m, 1H, quinazoline 7-H),
7.61 (t, J＝8.6 Hz, 1H, quinazoline 6-H), 7.33—7.30 (m,
2H, ArH), 7.31 (d, J＝1.7 Hz, 2H, ArH), 6.99 (d, J＝9.2
Hz, 2H, ArH), 6.68 (t, J＝9.2 Hz, 4H, ArH), 4.82—4.79
1
1201, 1070, 1056, 1028＋, 842, 771, 680, 580 cm ; MS
(ESI) m/z: 454 ([M＋H] ), 476 ([M＋Na]＋), 492 ([M＋
K]＋). Anal. calcd for C23H24N3O5P: C 60.92, H 5.34, N
Chin. J. Chem. 2011, 29, 109— 117
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
115

Bai et al.
FULL PAPER
9.27; found C 61.00, H 5.30, N 9.09.
Diethyl[4-(quinazolin-4-yloxy)phenylamino][3-
(trifluoromethyl)phenyl]methylphosphonate
reaction mixture was diluted with water and extracted
with ethyl acetate (10 mL×4). The combined ethyl
acetate extracts were dried over anhydrous Na2SO4, fil-
tered, concentrated in vacuo, and the crude product was
purified by column chromatography on silica gel (100—
200 mesh, EtOAc-hexane, V∶V＝1∶2) to afford pure
α-aminophosphonates. The water-soluble ionic liquid
that went into the aqueous layer of the filtrate was sepa-
rated from the unreacted starting materials by extracting
the filtrate with ethyl acetate. The water layer was fur-
ther dried at 80 ℃ under vacuum to regenerate the ionic
liquid for reuse.
(7r)
1
Colorless solid, m.p. 154—156 ℃; H NMR (CDCl3,
500 MHz) δ: 8.73 (s, 1H, quinazoline 2-H), 8.32 (d, J＝
8.0 Hz, 1H, quinazoline 8-H), 7.97 (d, J＝8.0 Hz, 1H,
quinazoline 5-H), 7.88—7.87 (m, 1H, quinazoline 7-H),
7.75 (s, 1H, ArH), 7.71 (d, J＝7.5 Hz, 1H, ArH), 7.64—
7.61 (m, 1H, quinazoline 6-H), 7.57 (d, J＝8.0 Hz, 1H,
ArH), 7.48 (t, J＝7.5 Hz, 1H, ArH), 7.02 (d, J＝8.6 Hz,
2H, ArH), 6.64 (d, J＝9.2 Hz, 2H, Ar-H), 4.94—4.90
(m, 1H, NH), 4.79 (dd, J＝6.9, 6.9 Hz, 1H, N-CH-P),
4.17—4.11 (m, 2H, CH2), 3.99—3.75 (m, 2H, CH2),
1.32 (t, J＝7.5 Hz, 3H, CH3), 1.14 (t, J＝7.5 Hz, 3H,
CH3); 13C NMR (CDCl3, 125 MHz) δ: 167.4, 154.4,
151.6, 144.5, 144.1, 134.1, 131.1, 129.3, 127.9, 127.5,
125.0, 123.7, 122.6, 116.5, 114.5, 63.6, 63.6, 56.9, 55.7,
16.5, 16.2, 16.1; 31P NMR (CDCl3, 200 MHz) δ: 21.9;
19F NMR (CDCl3, 200 MHz) δ: －62.4; IR (KBr) ν:
3292, 3049, 2978, 2926, 1618, 1570, 1508, 1489 , 1373,
1271, 1238, 1209, 1070, 1045, 1016, 837, 771, 680, 5＋76
References
1
Balsara, N. P.; Fetters, L. J.; Hadjichristidis, N.; Lohse, D. J.;
Han, C. C.; Graessley, W. W.; Krishnamoorti, R. Bull.
Chem. Soc. Jpn. 1999, 32, 6137.
2
3
Baylis, E. K.; Campbell, C. D.; Dingwall, J. G. J. Chem.
Soc., Perkin. Trans. 1 1984, 2845.
Kafarski, P.; Lejczak, B.; Forlani, G.; Chuiko, A. L.; Loz-
insky, M. O.; Jasicka-Misiak, L.; Czekaza, K.; Lipok, J.
Phosphorus, Sulfur Sillcon Relat. Elem. 1999, 144, 621.
Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M.
J. Med. Chem. 1989. 32, 1652.
＋
－1
cm ; MS (ESI) m/z: 532 ([M＋H] ), 554 ([M＋Na] ),
570 ([M＋K]＋). Anal. calcd for C26H25F3N3O4P: C
58.76, H 4.74, N 7.91; found C 58.65, H 4.70, N 7.78.
4
Synthesis of N-[4-(trifluoromethyl)benzylidene]-4-
5
6
Natchev, I. A. Liebigs Ann. Chem. 1988, 861.
Maier, L.; Spörri, H. Phosphorus, Sulfur Sillcon Relat. Elem.
1991, 61, 69.
(a) Hu, D. Y.; Wan, Q. Q.; Yang, S.; Song, B. A.; Bhadury,
P. S.; Jin, L. H.; Yan, K.; Liu, F.; Chen, Z.; Xue, W. J. Ag-
ric. Food Chem. 2008, 56, 998.
(b) Long, N.; Cai, X. J.; Song, B. A.; Yang, S.; Chen, Z.;
Bhadury, P. S.; Hu, D. Y.; Jin, L. H.; Xue, W. J. Agric.
Food Chem. 2008, 56, 5242.
(c) Chen, M. H.; Chen, Z.; Song, B. A.; Bhadury, P. S.;
Yang, S.; Cai, X. J.; Hu, D. Y.; Xue, W.; Zeng, S. J. Agric.
Food Chem. 2009, 57, 1383.
Hirschmann, R.; Smith III, A. B.; Taylor, C. M.; Benkovic,
P. A.; Taylor, S. D.; Yager, K. M.; Spengler, P. A.; Venk-
ovic, S. J. Sciences 1994, 265, 234.
(a) Petov, K. A.; Chauzov, V. A.; Erkhina, T. S. Usp. Khim.
1974, 43, 984.
(b) Laschat, S.; Kunz, H. Synthesis 1992, 90.
(c) Yokomatsu, T.; Yoshida, Y.; Shibuya, S. J. Org. Chem.
1994, 59, 7930.
(quinazolin-4-yloxy)benzenamine
In the reaction of 4-(quinazolin-4-yloxy)benzen-
amine, 4-(trifluoromethyl)benzaldehyde and diethyl
phosphite catalyzed by [BMIM]Cl at 90 ℃ for 10 min,
generation of imine was confirmed by spectral data both
in conventional and microwave assisted heating.
Yellow solid, m.p. 186—188 ℃; 1H NMR (CDCl3, 500
MHz) δ: 8.80 (s, 1H, N＝CH), 8.56 (s, 1H, quinazoline
2-H), 8.40 (d, J＝7.5 Hz, 1H, quinazoline 8-H), 8.04—
8.01 (m, 3H, quinazoline 5-H and Ar-H), 7.94—7.91 (m,
1H, quinazoline 7-H), 7.75 (d, J＝8.0 Hz, 2H, ArH),
7.70—7.66 (m, 1H, quinazoline 6-H), 7.38 (d, J＝9.2
7
8
9
13
Hz, 2H, ArH), 7.34 (d, J＝8.6 Hz, 2H, ArH); C NMR
(CDCl3, 125 MHz) δ: 167.4, 154.4, 151.6, 144.5, 144.1,
144.0, 134.1, 128.2, 128.2, 127.9, 127.5, 125.6, 123.7,
122.6, 116.5, 114.5, 63.7, 63.6, 63.5, 56.9, 55.7; 19F
NMR (CDCl3, 200 MHz) δ: －62.6; IR (KBr) ν: 3057,
－1
1620, 1566, 1＋490, 1209, 1066, 839 cm ; MS (ESI) m/z:
394 ([M＋H] ), 416 ([M＋Na]＋), 434 ([M＋K]＋). Anal.
calcd for C22H14F3N3O: C 67.17, H 3.59, N 10.68; found
C 67.45, H 3.84, N 10.38.
10 (a) Qian, C.; Huang, T. J. Org. Chem. 1998, 63, 4125.
(b) Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141.
(c) Ghosh, R.; Maiti, S.; Chakraborty, A.; Maiti, D. J. Mol.
Catal A: Chem. 2004, 210, 53.
Representative procedure for recycling of [BMIM]Cl
in the reaction of 4-(quinazolin-4-yloxy)benzenamine,
benzaldehyde and dipropyl phosphite
(d) Sun, P. P.; Hu, Z. X.; Huang, Z. H. Synth. Commun.
2004, 34, 4293.
4-(Quinazolin-4-yloxy)bezenamine (0.237 g,
1
(e) Zhan, Z. P.; Li, J. P. Synth. Commun. 2005, 35, 2501.
(f) Heydari, A.; Karimian, A.; Ipaktschi, J. Tetrahedron Lett.
1998, 39, 6729.
(g) Bhagat, S.; Chakraborti, A. K. J. Org. Chem. 2007, 72,
1263.
mmol), benzaldehyde (0.106 g, 1 mmol) and dipropyl
phosphite (0.249 g, 1.5 mmol) were added successively
to 1 g of [BMIM]Cl placed in a round bottomed flask.
The mixture was stirred and heated at 90 ℃ for 30 min
at 40 W in a DiscoveryTM LabMate instrument. After
the completion of the reaction as indicated by TLC, the
(h) Ramalingam, S.; Kumar, P. Catal Lett. 2008, 125, 315.
(i) Bhagat, S.; Chakraborti, A. K. J. Org. Chem. 2008, 73,
116
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 109— 117

One-Pot Synthesis of α-Aminophosphonate Derivatives
6029.
2002, 4, 436.
(j) Sonar, S. S.; Shelke, K. F.; Kakade, G. K.; Shingate, B.
B.; Shingare, M. S. Chin. Chem. Lett. 2009, 20, 1042.
11 Xu, Y. S.; Yan, K.; Song, B. A.; Xu, G. F.; Yang, S.; Xue,
W.; Hu, D. Y.; Lu, P.; Ouyang, G. P.; Jin, L. H.; Chen, Z.
Molecules 2006, 11, 666.
(c) Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Huang, J.; Sun, D.
Green Chem. 2004, 6, 75.
(d) Sahoo, S.; Joseph, T.; Halligudi, S. B. J. Mol. Catal. A:
Chem. 2006, 244, 179.
(e) Ranu, B. C.; Jana, R. Eur. J. Org. Chem. 2006, 3767.
13 Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett.
2005, 7, 2583.
12 (a) Lee, S. G.; Park, J. H.; Kang, J.; Lee, J. K. Chem.
Commun. 2001, 17, 1698.
(b) Yadav, J. S.; Reddy, B. V.; Sreedhar, P. Green Chem.
(E1005201 Zaho, C.)
Chin. J. Chem. 2011, 29, 109— 117
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
117