A facile route to 1,5-Benzodiazepin-2-yl-phosphonates via ytterbium chloride-catalyzed three-component reaction

Article abstract of DOI:10.1002/hc.20573

1,5-Benzodiazepin-2-yl-phosphonates were facilely synthesized via a one-pot threecomponent condensation of o-diaminobenzene, 1,3-diketone and diethyl phosphite in the presence of a catalytic amount of ytterbium chloride under mild reaction conditions.

Full text of DOI:10.1002/hc.20573

Heteroatom Chemistry
Volume 21, Number 2, 2010
A Facile Route to
1,5-Benzodiazepin-2-yl-phosphonates via
Ytterbium Chloride-Catalyzed
Three-Component Reaction
Xiaofeng Ji, Lijian Cai, Zhigang Yao, Xu Fan, and Shen Qi
Key Laboratory of Organic Synthesis, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, People’s Republic of China
Received 14 September 2009; revised 12 December 2009, 11 January 2010
of this type of compounds have attracted and are
ABSTRACT: 1,5-Benzodiazepin-2-yl-phosphonates
still attracting special attention of organic synthetic
were facilely synthesized via
a one-pot three-
chemists. Many research groups dedicated their ef-
forts to this direction, which resulted in a vast di-
versity of synthetic pathways [15]. However, from
the viewpoint of the ring size of azaheterocycle,
there were very few papers describing the synthetic
routes toward the seven-membered or fused seven-
membered azaheterocyclic phosphonates [16–18].
In another respect, benzodiazepine and its deriva-
tives are well known to possess a number of use-
ful biological properties and proved to be of con-
siderable importance and interest to the medicinal
field [19–22]. Encouraged by the valuable proper-
ties of α-amino phosphonates and benzodiazepines
provided, we conceived the idea of developing effi-
cient methods for the synthesis of benzodiazepine-
based phosphonates, with a hope of finding novel
seven-membered azaheterocyclic phosphonates as
lead compounds in the further research on bioac-
tive materials.
The most straightforward and efficient way
of synthesizing α-amino phosphonate is the one-
pot condensation of carbonyl compound, amine
and phosphite, usually catalyzed by Lewis acid. In
continuation of our studies on lanthanide halide
catalyzed carbon–nitrogen bond-forming reactions
[23–26], we investigated the effectiveness of lan-
thanide chlorides, which are readily available and
economical, as Lewis acid-type catalysts for the
three-component reaction of o-diaminobenzene, 1,3-
diketone, and phosphite that would provide a novel,
component condensation of o-diaminobenzene, 1,3-
diketone and diethyl phosphite in the presence of a
catalytic amount of ytterbium chloride under mild
ꢀ
C
reaction conditions.
2010 Wiley Periodicals, Inc.
Heteroatom Chem 21:89–95, 2010; Published online in
Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20573
INTRODUCTION
α-Amino phosphonate and its derivatives are an im-
portant class of compounds widely used in the bio-
chemical field, the pharmaceutical field, and the field
of metal complexation as well [1–7]. Among these
compounds, the azaheterocyclic phosphonates oc-
cupy an important position because of the already
presented and well-promised biological activities of
them [8–14]. Thus, the methods for the synthesis
Correspondence to: Xu Fan; e-mail: jixiaofeng 163@126.com.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant numbers: 20872106, 20632040.
Contract grant sponsor: State Key Laboratory of
Organometallic Chemistry.
Contract grant sponsor: Shanghai Institute of Organic
Chemistry.
Contract grant sponsor: Chinese Academy of Sciences.
2010 Wiley Periodicals, Inc.
c
ꢀ
89

90 Ji et al.
TABLE 1 Conditions Screening for YbCl3-Catalyzed Con-
densation of o-Diaminobenzene, Pentane-2,4-dione, and Di-
ethyl Phosphitea
rapid, and efficient route toward 1,5-benzodiazepin-
2-yl-phosphonate. Herein, we wish to report our pre-
liminary results.
NH2
O
O
10 mol% YbCl3
HOP(OEt)2
+
+
RESULTS AND DISCUSSION
NH2
1a
2a
3
O
At the outset, the reaction of o-diaminobenzene
(1a), pentane-2,4-dione (2a), and diethyl phos-
phite (3) in a 1:1:2 mole ratio was attempted
in the presence of catalytic amount of yt-
terbium chloride (YbCl3) at room temperature
under solvent-free condition. As we predicted,
P(OEt)2
H
N
N
+
N
H
N
H
P(OEt)2
O
P(OEt)2
O
5a
4a
the product was obtained as
a mixture of
diethyl (2,4-dimethyl-2,3-dihydro-1H-benzo[b][1,4]
diazepin-2-yl)phosphonate (monophosphonate 4a)
and tetraethyl (2,4-dimethyl-2,3,4,5-tetrahydro-1H-
benzo[b][1,4]diazepine-2, 4-diyl)bis(phosphonate)
(diphosphonate 5a) with the yield of 56% and 8%,
respectively (Table 1, entry 6). Then, various condi-
tions including solvent, temperature, and the molar
ratio of the respective substrates were screened in
order to address their influence on the activity and
selectivity of the reaction. The results are listed in
Table 1. Obviously, the molar ratio of the three sub-
strates was the key factor affecting the ratio between
4a and 5a. When 1a, 2a, and 3 were mixed at an
1:1:1 mole ratio, the monophosphonate 4a was ob-
tained as the major product in 61% yield and only
trace of diphosphonate 5a was detected, whereas an
1:1:4 mole ratio afforded 5a as the major product
in 57% yield (entries 1 and 9). Bearing in mind that
solvent can affect the reactivity, several classical or-
ganic solvents were chosen as the medium for com-
parison to optimize the process and it was found that
solvent-free condition was the best choice (entries 1–
5). Reaction temperature was also investigated. Rais-
ing the temperature from room temperature to 60◦C
resulted in a decrease in the yield of 4a accompanied
by an increase of 5a at 1:1:2 mole ratio of the sub-
strates (entries 6–8). However, the reaction carried
Ratio of
Entry 1a/2a/3 Solvent
Temperature Yield of Yield of
(◦C)
4a (%) 5a (%)
1
2
3
4
5
6
7
8
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:2
1:1:2
1:1:2
1:1:4
1:1:4
1:1:4
–
22
22
22
22
22
22
40
60
22
40
50
61
42
41
35
18
56
34
14
Trace
14
Trace
Trace
Trace
Trace
Trace
8
24
25
57
65
CH3CN
THF
Toluene
CH2Cl2
–
–
–
–
–
–
9
10
11
22
55
a Typical reaction conditions: o-diaminobenzene, pentane-2,4-
dione,and YbCl3 (10 mol% relative to o-diaminobenzene) were mixed
and stirred for 1 h, and diethyl phosphite was then added, and the
mixture was stirred for another 24 h.
out at 1:1:4 mole ratio and 40◦C provided the highest
overall yield and selective formation of product 5a
(entry 10).
The syntheses of diphosphonates 5 using substi-
tuted o-diaminobenzene were then attempted under
the conditions described in Table 1, entry 10 (1: 2a:
3 = 1:1:4, 40◦C), and the corresponding products
were obtained as an inseparable mixture of cis- and
trans-stereoisomer in moderate yields (Scheme 1).
NH2
O
O
10 mol% YbCl3
40oC, 24 h, neat
O
+
+ HOP(OEt)2
R1
NH2
1b: R1 = CH3
1c: R1 = NO2
2a
3
P(OEt)2
H
N
N
R1
+
R1
N
H
N
H
P(OEt)2
O
P(OEt)2
O
4b trace
4c trace
5b 53%
5c 50%
SCHEME 1 Synthesis of diphosphonates.
Heteroatom Chemistry DOI 10.1002/hc

Facile Route to 1,5-Benzodiazepin-2-yl-phosphonates via Ytterbium Chloride-Catalyzed Three-Component Reaction 91
O
R2
P(OEt)2
H
R2
N
N
NH2
NH2
O
O
10 mol% YbCl3
40oC, 24 h, neat
+
+
HOP(OEt)2
R2
N
H
N
H
P(OEt)2
O
P(OEt)2
O
1a
2d: R2 = C2H5
2g: R2 = Ph
4d
47%
4g 53%
3
5d
5g
not detected
SCHEME 2 Synthesis of monophosphonates.
When benzoylacetone (2g) was used instead
of pentane-2,4-dione to generate the correspond-
ing diphosphonate 5g under the same conditions
mentioned above, no hoped-for product was de-
tected while monophosphonate 4g was obtained in
53% yield (Scheme 2). Similarly, hexane-2,4-dione
(2d) afforded monophosphonate 4d in 47% yield
without the formation of the corresponding
diphosphonate 5d. The results indicated that the
effect of the steric hindrance plays an important
role in the addition of the second portion of di-
ethyl phosphite to imine. Once the exocyclic alkyl
adjacent to the carbon–nitrogen double bond of the
monophosphonate 4 was larger than methyl, the nu-
cleophilic addition of diethyl phosphite to the imine,
that forms the diphosphonate 5, would not occur.
This gives us a chance to develop the methodology to
synthesis benzodiazepine-based monophosphonate
selectively.
is Yb > Gd > Sm > La, which is in contrast to the
order of their ionic radius. Further investigation on
the reaction temperature demonstrated that raising
the temperature to a certain extent led to an increase
in yield whereas overheating affected the yield in the
negative direction (Table 2, entries 4–6), and the best
yield was obtained at 40◦C. Increasing the catalyst
loading did not lead to an increase of yield (entry 7).
Samarium diiodide (SmI2), the representative com-
pound of divalent lanthanide, also showed moderate
activity (entry 8).
To demonstrate the generality of this method,
the process was extended to a serial of acyl ace-
tone with YbCl3 as the representative lanthanide
catalyst. The corresponding benzodiazepine-based
phosphonates were obtained in moderate yields,
and the results are summarized in Table 3. The
Then the attention was turned to establishing
the optimum conditions for the synthesis of 1,5-
benzodiazepin-2-yl-phosphonate and the reaction
of o-diaminobenzene, benzoylacetone, and diethyl
phosphite was investigated as the model. First, sev-
eral lanthanide halides were screened and the re-
sults listed in Table 2 showed the influence of central
metal on the catalytic activity. The active sequence
TABLE
3 YbCl3-Catalyzed One-Pot Synthesis of 1,5-
Benzodiazepin-2-yl-phosphonatesa
R2
N
NH2
O
O
10 mol% YbCl3
+
HOP(OEt)
+
2
R2
NH2
N
H
P(OEt)2
O
1a
2
3
4
Entry
R2
Product
Isolated Yield (%)
1
2
3
4
Me
Et
i-Bu
amyl
Ph
4-ClPh
4-BrPh
4-MePh
4-MeOPh
4a
4d
4e
4f
4g
4h
4i
61
51
60
52
58c
55
47
49
44
TABLE 2 Lanthanide Halide Catalyzed Condensation of
o-Diaminobenzene, Benzoylacetone, and Diethyl Phosphitea
Entry
Catalyst
Temperature (◦C)
Yield (%)
5b
6d
7d
8d
9e
1
2
3
4
5
6
7b
8
LaCl3
SmCl3
GdCl3
YbCl3
YbCl3
YbCl3
YbCl3
SmI2
40
40
40
40
22
50
40
40
29
31
36
58
43
50
53
45
4j
4k
a Typical reaction conditions: o-diaminobenzene/1,3-diketone/diethyl
phosphite
1:1:1, 22◦C. o-Diaminobenzene, 1,3-diketone and
=
10 mol% YbCl3 were mixed and stirred for 1 h, and diethyl phos-
phite was then added and the mixture was stirred for another 24 h.
b 40◦C, 3 h + 12 h.
a Typical reaction conditions: o-diaminobenzene/benzoylacetone/
diethyl phosphite = 1:1:1, catalyst loading 10 mol%.
b Catalyst loading 20 mol%.
c Along with 30% of 3-(2-aminophenylimino)-1-phenylbutan-1-one.
d 50◦C, 12 h + 12 h.
e 35◦C, 12 h + 12 h.
Heteroatom Chemistry DOI 10.1002/hc

92 Ji et al.
of B presumably resulted in the lower yield of the
product.
In conclusion, we described here a novel and
facile route for the synthesis of benzodiazepine-
based phosphonates via three-component condensa-
tion of o-diaminobenzene, 1,3-diketone and diethyl
phosphite with YbCl3 as an efficient catalyst un-
der mild conditions. The reaction is one-pot, atom-
economic, and can be handled easily. Further stud-
ies on the application of the present method to the
synthesis of azaheterocyclic phosphonates are under
investigation.
SCHEME 3 Plausible intermediates.
activity of 1-aryl substituted-1,3-butanediones is
somewhat lower than that of 1-alkyl substituted
ones, and heightened temperature are necessary
for the former to get the yields close to those of
the latter. For example, pentane-2,4-dione (2a) re-
acted with o-diaminobenzene (1a) and diethyl phos-
phite (3) at 22◦C leading to the corresponding prod-
uct 4a in 61% yield (Table 3, entry 1), whereas
1-(4-chlorophenyl)butane-1,3-dione (2h) generated
a 55% yield of product 4h despite the reaction was
carried out at temperature of 50◦C (entry 6).
The moderate yields of the reaction impelled us
to infer the plausible mechanism. It was consid-
ered that the required benzodiazepine-based phos-
phonate can be formed via a three-step sequence
involving (i) lanthanide-catalyzed condensation of
o-diaminobenzene with a less hindered carbonyl to
produce β-carbonyl imine A (Scheme 3), (ii) the
second condensation of carbonyl with amino group
leading to benzodiazepine B, followed by (iii) nu-
cleophilic addition of diethyl phosphite to B to gen-
erate the target molecule. The analyses of the crude
product of the reaction with o-diaminobenzene, ben-
zoylacetone, and diethyl phosphite indicated that
β-carbonyl imine 6g was obtained in 30% yield be-
sides the expected product 4g (Scheme 4). The result
suggested that benzodiazepine B is relatively diffi-
cult to be formed from A, probably due to the strong
cyclic tension caused by the two imino groups ex-
isting in the same seven-membered ring. However,
once B is generated, it is very reactive and trans-
form to 4g quickly. The hardness of the formation
EXPERIMENTAL
General Remarks
All the manipulations were conducted under dry
Ar atmosphere with flame-dried glassware. Lan-
thanide chlorides were synthesized according to the
method described by Taylor and Carter [27]. o-
Phenylenediamine was recrystallized from hot water
containing sodium hydrosulfite and treated with de-
colorizing charcoal. Diethyl phosphite was prepared
by the reported procedure [28].
IR spectra were obtained on a Nicolet FT-IR
1
1000 spectrophotometer. H and 13C NMR spectra
were obtained on Varian INOVA-400 and System-
300 spectrometers using tetramethylsilane (TMS) as
an internal reference. HRMS data were recorded on
a Micromass GCT instrument. Elemental analyses
were determined on a Carlo Erba EA1110-CHNS-O
analyzer.
General Procedure
A mixture of o-diaminobenzene (1 mmol), 1,3-
diketone (1 mmol), and ytterbium chloride (0.1
mmol) was stirred at room temperature for the given
time. Then, diethyl phosphite (1 mmol) was added
and the stirring was continued at an appropriate
temperature. After completion of the reaction (TLC),
NH2
O
O
10 mol% YbCl3
Ph
+
+ HOP(OEt)2
Ph
NH2
1a
2g
3
N
O
Ph
N
N
NH2
H
P(OEt)2
O
4g 58%
6g 30%
SCHEME 4 YbCl3-catalyzed reaction of o-diaminobenzene, benzoylacetone with diethyl phosphite.
Heteroatom Chemistry DOI 10.1002/hc

Facile Route to 1,5-Benzodiazepin-2-yl-phosphonates via Ytterbium Chloride-Catalyzed Three-Component Reaction 93
saturated NaHCO3 solution was added and the mix-
ture was extracted with ethyl acetate (10 mL × 3).
The organic layer was dried over anhydrous sodium
sulfate and evaporated under reduced pressure. The
crude product was purified by chromatography on
silica gel using acetone–petroleum ether (1:3) as elu-
ent to afford the product. All the products were new
Diethyl
(2-Methyl-4-pentyl-2,3-dihydro-1H-
benzo[b][1,4]diazepin-2-yl)phosphonate
(4f). mp
85−86◦C; IR (KBr) ν : 764, 964, 1049, 1234, 1643,
2931, 2962, 3279 cm−1; H NMR (400 MHz, CDCl3)
1
δ : 7.12–6.78 (m, 4H), 4.26–4.06 (m, 4H), 3.53 (s,
br, 1H), 2.69 (dd, J = 13.2, 10.0 Hz, 1H), 2.63–2.59
(m, 2H), 2.29 (dd, J = 16.4, 13.2 Hz, 1H), 1.71–1.68
(m, 2H), 1.54 (d, J = 14.8 Hz, 3H), 1.38–1.35 (m,
4H), 1.30 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz,
3H), 0.92 (t, J = 6.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ : 174.1, 140.7, 136.4, 127.0, 125.5, 122.5,
122.2, 70.1 (JCP = 151.4 Hz), 63.6, 62.3, 42.5, 37.2,
31.6, 26.1, 24.6, 22.5, 16.4, 14.0; HRMS Calcd for
C19H31N2O3P 366.2072, found 366.2081; Anal. Calcd
for C19H31N2O3P: C, 62.28; H, 8.53; N, 7.64. Found:
C, 62.53; H, 8.50; N, 7.69.
compounds and were identified by IR, 1H NMR, 13
NMR, HRMS, and elemental analyses.
C
Diethyl (2,4-Dimethyl-2,3-dihydro-1H-benzo[b]
[1,4]diazepin-2-yl)phosphonate (4a). mp 103-
105◦C; IR (KBr) ν : 771, 972, 1026, 1234, 1643,
2978, 3279 cm−1; 1H NMR (400 MHz, CDCl3)
δ: 7.13-6.79 (m, 4H), 4.26–4.07 (m, 4H), 3.51
(s, br, 1H), 2.75–2.69 (m, 1H), 2.40 (s, 3H),
2.32 (dd, J = 18.0, 13.6 Hz, 1H), 1.55 (d, J =
14.4 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 1.29 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 171.2,
Diethyl
(2-Methyl-4-phenyl-2,3-dihydro-1H-
benzo[b][1,4]diazepin-2-yl)phosphonate (4g). mp
137−138◦C; IR (KBr) ν : 694, 748, 964, 1227,
1605, 3263 cm−1; 1H NMR (400 MHz, CDCl3) δ:
8.06–6.85 (m, 9H), 4.19–4.02 (m, 4H), 3.68 (s,
br, 1H), 3.18 (dd, J = 13.2, 9.6 Hz, 1H), 2.93
(t, J = 13.2 Hz, 1H), 1.52 (d, J = 14.8 Hz, 3H),
1.25 (t, J = 6.8 Hz, 3H), 1.16 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ: 167.2, 141.0,
139.3, 136.5, 130.2, 128.2, 127.8, 127.1, 126.0, 122.6,
122.1, 70.7 (JCP = 147.6 Hz), 63.1, 62.3, 33.5, 24.6,
16.3; HRMS Calcd for C20H25N2O3P 372.1603, found
372.1589; Anal. Calcd for C20H25N2O3P: C, 64.50; H,
6.77; N, 7.52. Found: C, 64.57; H, 6.84; N, 7.38.
140.4, 136.4, 126.9, 125.5, 122.5, 122.2, 70.0 (JCP
=
153.4 Hz), 63.7, 62.2, 38.2, 29.6, 24.5, 16.3; HRMS
Calcd for C15H23N2O3P 310.1446, found 310.1446;
Anal. Calcd for C15H23N2O3P: C, 58.05; H, 7.47; N,
9.03. Found: C, 57.82; H, 7.33; N, 8.95.
Diethyl
(4-Ethyl-2-methyl-2,3-dihydro-1H-
benzo[b][1,4]diazepin-2-yl)phosphonate (4d). mp
141−142◦C; IR (KBr) ν : 772, 972, 1049, 1227, 1651,
2978, 3279 cm−1; 1H NMR (400 MHz, CDCl3) δ:
7.15–6.79 (m, 4H), 4.27–4.09 (m, 4H), 3.54 (s, br,
1H), 2.74–2.59 (m, 3H), 2.31 (dd, J = 16.8, 9.2 Hz,
1H), 1.54 (d, J = 14.8 Hz, 3H), 1.32–1.24 (m, 9H);
13C NMR (75 MHz, CDCl3) δ:174.5, 140.6, 136.3,
126.9, 125.4, 122.4, 122.1, 69.8 (JCP = 151.8 Hz),
63.5, 62.2, 37.1, 35.3, 24.5, 16.3, 10.3; HRMS Calcd
for C16H25N2O3P 324.1603, found 324.1602; Anal.
Calcd for C16H25N2O3P: C, 59.25; H, 7.77; N, 8.64.
Found: C, 59.18; H, 7.75; N, 8.49.
Diethyl
(4-(4-Chlorophenyl)-2-methyl-2,3-
dihydro-1H-benzo[b] [1,4]diazepin-2-yl) phosphonate
(4h). mp 141–142◦C; IR (KBr) ν : 748, 802, 949,
1057, 1088, 1227, 1605, 3271 cm−1; H NMR (400
1
MHz, CDCl3) δ: 8.03–6.85 (m, 8H), 4.19–4.02 (m,
4H), 3.65 (s, br, 1H), 3.17 (dd, J = 13.6, 9.6 Hz, 1H),
2.85 (t, J = 14.8 Hz, 1H), 1.52 (d, J = 14.8 Hz, 3H),
1.26 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H); 13
C
Diethyl
(4-Isobutyl-2-methyl-2,3-dihydro-1H-
NMR (75 MHz, CDCl3) δ: 165.9, 140.8, 137.8, 136.5,
136.4, 128.5, 128.4, 127.9, 126.3, 122.7, 122.2, 70.9
(JCP = 149.7 Hz), 63.3, 62.3, 33.6, 24.7, 16.3; HRMS
Calcd. for C20H24ClN2O3P 406.1213, found 406.1204;
Anal. Calcd for C20H24ClN2O3P: C, 59.04; H, 5.95; N,
6.89. Found: C, 59.18; H, 5.98; N, 6.74.
benzo[b][1,4]diazepin-2-yl)phosphonate (4e). mp
101−102◦C; IR (KBr) ν : 756, 964, 1049, 1227, 1643,
2978, 3287 cm−1; 1H NMR (400 MHz, CDCl3) δ :
7.13–6.79 (m, 4H), 4.25–4.06 (m, 4H), 3.55 (s, br,
1H), 2.69 (t, J = 11.6 Hz, 1H), 2.58−2.45 (m, 2H),
2.86 (t, J = 14.8 Hz, 1H), 2.15–2.08 (m, 1H), 1.55 (d,
J = 15.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.28 (t, J
= 7.2 Hz, 3H), 1.01 (d, J = 6.8 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ : 173.3, 140.5, 136.5, 126.9,
125.4, 122.3, 122.0, 70.0 (JCP = 150.7 Hz), 63.5, 62.2,
51.4, 37.2, 26.4, 24.5, 22.5, 16.3; HRMS Calcd for
C18H29N2O3P 352.1916, found 352.1904; Anal. Calcd
for C18H29N2O3P: C, 61.35; H, 8.29; N, 7.95. Found:
C, 61.17; H, 8.22; N, 7.89.
Diethyl
(4-(4-Bromophenyl)-2-methyl-2,3-
dihydro-1H-benzo[b] [1,4]diazepin-2-yl) phosphonate
(4i). mp 135–136◦C IR (KBr) ν : 772, 833, 949,
1018, 1064, 1227, 1605, 3271 cm−1; 1H NMR
(400 MHz, CDCl3) δ: 7.95–6.84 (m, 8H), 4.20–4.02
(m, 4H), 3.65 (s, br, 1H), 3.16 (dd, J = 13.6, 9.2 Hz,
1H), 2.85 (t, J = 14.4 Hz, 1H), 1.52 (d, J = 14.8 Hz,
3H), 1.26 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz,
Heteroatom Chemistry DOI 10.1002/hc

94 Ji et al.
3H); 13C NMR (75 MHz, CDCl3) δ : 166.1, 140.8,
138.2, 136.5, 131.4, 128.8, 127.9, 126.3, 125.0, 122.8,
122.3, 70.9 (JCP = 149.8 Hz), 63.3, 62.4, 33.6, 24.7,
16.4; HRMS Calcd for C20H24BrN2O3P 450.0708,
found 450.0703; Anal. Calcd for C20H24ClN2O3P: C,
53.23; H, 5.36; N, 6.21. Found: C, 53.43; H, 5.40; N,
6.21.
(m, 8H), 3.91 (s, br, 1H), 3.87 (s, br, 1H), 2.67–2.57
(m, 1H), 2.20 (s, 3H), 2.03–1.98 (m, 1H), 1.66−1.60
(m, 6H), 1.30–1.23 (m, 12H); HRMS Calcd for
C20H36N2O6P2 462.2049, found 462.2060; Anal.
Calcd for C20H36N2O6P2: C, 51.94; H, 7.85; N, 6.06.
Found: C, 52.05; H, 7.82; N, 5.92.
Tetraethyl
tetrahydro-1H-benzo[b]
(2,4-Dimethyl-7-nitro-2,3,4,5-
[1,4]diazepine-2,4-diyl)bis
Diethyl
(2-Methyl-4-(p-tolyl)-2,3-dihydro-1H-
(phosphonate) (5c). mp 176–177◦C; IR (KBr) ν:
833, 964, 1026, 1227, 2986, 3279 cm−1; 1H NMR
(400 MHz, CDCl3) δ: 7.69–7.58 (m, 2H), 6.62–6.60
(m, 1H), 4.56 (s, br, 1H), 4.24–4.16 (m, 8H),
4.01 (s, br, 1H), 2.45–2.23 (m, 2H), 1.74–1.60
(m, 6H), 1.37–1.33 (m, 12H); HRMS Calcd for
C19H33N3O8P2 493.1743, found 493.1758; Anal.
Calcd. for C19H33N3O8P2: C, 46.25; H, 6.74; N, 8.52.
Found: C, 45.94; H, 6.64; N, 8.19.
benzo[b] [1,4]diazepin-2-yl)phosphonate (4j). mp
144–146◦C; IR (KBr) ν : 748, 802, 964, 1034, 1234,
1605, 2978, 3287 cm−1; H NMR (400M Hz, CDCl3)
1
δ: 7.96–6.83 (m, 8H), 4.19–4.03 (m, 4H), 3.66 (s, br,
1H), 3.14 (dd, J = 13.6, 9.6 Hz, 1H), 2.93 (t, J =
12.8 Hz, 1H), 2.41 (s, 3H), 1.52 (d, J = 15.2 Hz, 3H),
1.26 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 6.8 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ: 167.1, 141.2, 140.5, 136.6,
128.9, 127.7, 127.1, 125.7, 122.6, 122.1, 70.6 (JCP
=
146.3 Hz), 63.0, 62.3, 33.3, 24.6, 21.2, 16.3; HRMS
Calcd for C21H27N2O3P 386.1759, found 386.1761;
Anal. Calcd for C21H27N2O3P: C, 65.27; H, 7.04; N,
7.25. Found: C, 65.36; H, 7.03; N, 7.52.
REFERENCES
[1] Hiratake, J.; Oda, J. Biosci Biotechnol Biochem 1997,
61, 211.
[2] Kafarski, P.; Lejczak, B. Phosphorus, Sulfur, Silicon
1991, 63, 193.
[3] Kaplan, A. P.; Bartlett, P. A. Biochemistry 1991, 30,
8165.
[4] Beers, S. A.; Schwender, C. F.; Loughney, D. A.;
Malloy, E.; Demarest, K.; Jordan, J. Bioorg Med
Chem 1996, 4, 1693.
[5] Maier, L.; Diel, P. J. Phosphorus, Sulfur, Silicon 1991,
57, 57.
[6] Hirschmann, R.; Smith, A. B., III; Taylor, C. M.,
Benkovic, P. A.; Taylor, S. D.; Yager, K. M.;
Sprengler, P. A.; Venkovic, S. J. Science 1994, 265,
234.
[7] Wieczorek, P.; Kaczanowska, M.; Lejczak, B.;
Kafarski, P. Pestic Sci 1990, 30, 43.
[8] Sakuri, H.; Okamoto, Y.; Fukuda, M. Jpn Patent
7912364, 1979; Chem Abstr 1979, 91, 20707.
[9] Hassan, J. PCT Int Appl, WO 2000004031, 2000;
Chem Abstr 2000, 132, 108102.
Diethyl
(4-(4-Methoxyphenyl)-2-methyl-2,3-
dihydro-1H-benzo[b] [1,4]diazepin-2-yl) phosphonate
(4k). mp 171−172◦C; IR (KBr) ν: 748, 810, 949,
1018, 1227, 1605, 2986, 3279 cm−1; H NMR (400
1
MHz, CDCl3) δ: 8.03–6.83 (m, 8H), 4.19–4.03 (m,
4H), 3.87 (s, 3H), 3.65 (s, br, 1H), 3.13 (dd, J = 13.2,
10.0 Hz, 1H), 2.90 (t, J = 13.2 Hz, 1H), 1.52 (d, J =
14.8 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.2
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ: 166.6, 161.5,
141.4, 136.6, 132.1, 128.9, 127.6, 125.6, 122.7, 122.2,
113.6, 70.6 (JCP = 146.3 Hz), 63.1, 62.4, 55.3, 33.3,
24.6, 16.3; HRMS Calcd for C21H27N2O4P 402.1708,
found 402.1709; Anal. Calcd for C21H27N2O4P: C,
62.68; H, 6.76; N, 6.96. Found: C, 62.41; H, 6.73; N,
6.97.
Tetraethyl (2,4-Dimethyl-2,3,4,5-tetrahydro-1H-
benzo[b] [1,4]diazepine-2,4-diyl)bis (phosphonate)
(5a). mp 112−113◦C; IR (KBr) ν: 748, 949, 1042,
[10] Boduszek, B.; Oleksyszyn, J.; Kam, C. M.; Selzler, J.;
Smith, R. E.; Powers, J. C. J Med Chem 1994, 37,
3969.
[11] Powers, J. C.; Boduszek, B.; Oleksyszyn, J. PCT Int
Appl, WO 9529691, 1995; Chem Abstr 1996, 124,
203102.
[12] Augustyns, K. J.; Vanhoof, G. C.; Borloo, M. J.;
De Meester, I. A.; Goossens, F. J.; Haemers, A.; Hen-
driks, D. F.; Lambeir, A. M.; Scharpe, S. L. PCT Int
Appl, WO 9534538, 1995; Chem Abstr 1996, 124,
261758.
[13] Scharpe, S. L.; De Meester, I. A.; Belyaev, A. A.;
Lambeir, A. M. V.; Augustyns, K. J.; Haemers, A.;
Goossens, F. J.; Hendriks, D. F. PCT Int Appl, WO
9946272, 1999; Chem Abstr 1999, 131, 223514.
[14] Jomaa, H. PCT Int Appl, WO 0004031, 2000; Chem
Abstr 2000, 132, 108102.
1
1226, 1597, 2978, 3279 cm−1; H NMR (400 MHz,
CDCl3) δ: 6.82–6.76 (m, 4H), 4.19–4.08 (m, 8H), 3.96
(s, br, 2H), 2.69–2.60 (m, 1H), 2.31−2.00 (m, 1H),
1.68–1.64 (m, 6H), 1.35–1.22 (m, 12H); HRMS Calcd
for C19H34N2O6P2 448.1892, found 448.1888; Anal.
Calcd for C19H34N2O6P2: C, 50.89; H, 7.64; N, 6.25.
Found: C, 51.00; H, 7.53; N, 6.26.
Tetraethyl
(2,4,7-Trimethyl-2,3,4,5-tetrahydro-
1H-benzo[b] [1,4]diazepine-2,4-diyl)bis (phospho-
nate) (5b). mp 130-131◦C; IR (KBr) ν: 802, 949,
1049, 1227, 1605, 2986, 3287 cm−1; 1H NMR
(400 MHz, CDCl3) δ: 6.67–6.59 (m, 3H), 4.18–4.08
[15] Moonen, K.; Laureyn, I.; Stevens, C. V. Chem Rev
2004, 104, 6177.
Heteroatom Chemistry DOI 10.1002/hc

Facile Route to 1,5-Benzodiazepin-2-yl-phosphonates via Ytterbium Chloride-Catalyzed Three-Component Reaction 95
[16] Osipov, S. N.; Artyushin, O. I.; Kolomiets, A.
[22] Randall, L. O.; Kappel, B. Benzodiazepines; Garat-
tini, S.; Mussini, E.; Randall, L. O. (Eds.); Raven
Press: New York, 1973; p. 27.
F.; Bruneau, C.; Dixneuf, P. H. Synlett 2000, 7,
1031.
[17] Yokomatsu, T.; Yoshida, Y.; Nakabayashi, N.;
Shibuya, S. J Org Chem 1994, 59, 7562.
[18] Gaffar, A. U.S. Patent 5753633, 1998; Chem Abstr
1998, 129, 8161.
[19] Schutz, H. Benzodiazepines; Springer: Heidelberg,
West Germany, 1982.
[23] Zhang, H. H.; Zhou, Z. Q.; Yao, Z. G.; Xu, F.; Shen,
Q. Tetrahedron Lett 2009, 50, 1622.
[24] Zhou, Z. Q.; Xu, F.; Han, X. Y.; Zhou, J.; Shen, Q. Eur
J Org Chem 2007, 5265.
[25] Xu, F.; Luo, Y. Q.; Wu, J. T.; Shen, Q.; Chen, H. Het-
eroatom Chem 2006, 17, 389.
[20] Smalley, R. K. Comprehensive Organic Chemistry;
Barton, D.; Ollis, W. D. (Eds.); Pergamon: Oxford,
UK, 1979; Vol. IV, p. 600.
[21] Landquist, J. K. Comprehensive Heterocyclic Chem-
istry; Katritzky, A. R.; Rees, C. W. (Eds.); Pergamon:
Oxford, UK, 1984; Vol. I, p. 166.
[26] Han, X. Y.; Xu, F.; Luo, Y. Q.; Shen, Q. Eur J Org
Chem 2005, 1500.
[27] Taylor, M. D.; Carter, C. P. J Inorg Nucl Chem 1962,
24, 387.
[28] McCombie, H.; Saunders, B. C.; Stacey, G. J. J Chem
Soc 1945, 380.
Heteroatom Chemistry DOI 10.1002/hc