A convenient synthesis of N-t-butyl-N′-aminocarbonyl-N-(substituted)benzoylhydrazine containing α-aminoalkylphosphonate groups in a one-pot procedure

Article abstract of DOI:10.1002/hc.3

A variety of novel N-t-butyl-N′-aminocarbonyl-N-(substituted)benzoylhydrazines containing α-aminoalkylphosphonate groups were synthesized. Treatment of α-aminoalkylphosphonates with triphosgene yielded α-isocyanatoalkylphosphonates, and subsequent addition with N-t-butyl-N-substituted benzoylhydrazines provided the title compounds in a one-pot procedure with good yields. The triphosgene-mediated reaction for the synthesis of α-isocyanatoalkylphosphonates enjoys a number of advantages: the reaction is carried out under mild condition in good yield, triphosgene is relatively safe to handle because of its low vapor pressure and high stability, and the experimental procedure is simple. This method can be applicable to the synthesis of other α-isocyanatoalkyl-phosphonates and urylenediphosphonates. The structures of all of the products and by-products were confirmed by ¹H NMR, ³¹P NMR, IR and mass spectroscopy, and elemental analysis. We also found that some of the compounds possess potential anti-tobacco mosaic virus (TMV) activities and anticancer activities.

Full text of DOI:10.1002/hc.3

Heteroatom Chemistry
Volume 12, Number 2, 2001
A Convenient Synthesis of N-t-Butyl-NЈ-
Aminocarbonyl-N-(Substituted)Benzoyl-
hydrazine Containing ␣-Aminoalkylphos-
phonate Groups in a One-Pot Procedure
Qingmin Wang, Zaiguo Li, Runqiu Huang, and Junran Cheng
Research Institute of Elemento-Organic Chemistry, State Key Laboratory of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
Received 10 October 2000; revised 29 November 2000
INTRODUCTION
ABSTRACT: A variety of novel N-t-butyl-NЈ-amino-
carbonyl-N-(substituted)benzoylhydrazines contain-
ing ␣-aminoalkylphosphonate groups were synthe-
sized. Treatment of ␣-aminoalkylphosphonates with
triphosgene yielded ␣-isocyanatoalkylphosphonates,
and subsequent addition with N-t-butyl-N-substituted
benzoylhydrazines provided the title compounds in a
one-pot procedure with good yields. The triphosgene-
mediated reaction for the synthesis of ␣-isocyanatoal-
kylphosphonates enjoys a number of advantages: the
reaction is carried out under mild condition in good
yield, triphosgene is relatively safe to handle because
of its low vapor pressure and high stability, and the
experimental procedure is simple. This method can be
applicable to the synthesis of other ␣-isocyanatoalkyl-
phosphonates and urylenediphosphonates. The struc-
tures of all of the products and by-products were con-
firmed by 1H NMR, 31P NMR, IR and mass
spectroscopy, and elemental analysis. We also found
that some of the compounds possess potential anti-
tobacco mosaic virus (TMV) activities and anticancer
activities. ᭧ 2001 John Wiley & Sons, Inc. Hetero-
atom Chem 12:68–72, 2001
Recently, a new class of insect growth regulators, the
1,2-diacyl-1-tert-butylhydrazines, have been found to
mimic the action of 20-hydroxyecdysone to activate
the ecdysone receptor, leading to lethal premature
molting [1–4]. In addition, ␣-aminophosphonic acid
derivatives are of considerable chemical and phar-
macological importance as isosteres of aminocar-
boxylic acids [5,6]. Various related compounds of
these types also can serve in agrochemistry as anti-
fungal agents, herbicides, plant regulators, and plant
virucides [7,8]. Considering the wide application of
these compounds and their potential to serve as in-
sect growth regulators, we decided to introduce the
␣-aminoalkylphosphonate groups into the structures
of acylhydrazines, and therefore, we designed and
synthesized a series of the title compounds.
RESULTS AND DISCUSSION
Synthesis of the Products and Reaction
Mechanism
We synthesized the title compounds as shown in
Scheme 1.
␣-Aminoalkylphosphonates 1 were treated with
triphosgene to give ␣-isocyanatoalkylphosphonates
2, and subsequent addition of N-t-butyl-N-substi-
tuted benzoylhydrazines provided the title com-
pounds 3 in a one-pot procedure with good yields.
Correspondence to: Runqiu Huang.
Contract Grant Sponsor: National Natural Science Foundation
of China
Contract Grant Number: 29832050.
᭧ 2001 John Wiley & Sons, Inc.
68

A Convenient Synthesis of N-t-Butyl-NЈ-Aminocarbonyl-N-(Substituted)Benzoylhydrazine 69
SCHEME 1
SCHEME 2
Medved and Kabachnik have reported the syn-
thesis of diethyl ␣-isocyanatoalkylphosphonates by
use of diethyl ␣-aminoalkylphosphonates and phos-
gene, but only in 36% yield [9]. This method has not
achieved much synthetic utility, in part due to the
high toxicity of phosgene gas and the necessary and
complicated experimental setup associated with use
of it.
We found that triphosgene can be used to con-
vert diphenyl ␣-aminoalkylphosphonates 1 to di-
phenyl ␣-isocyanatoalkylphosphonates 2 under mild
conditions in the presence of triethylamine through
the steps shown in Scheme 2. At first, the nucleo-
philic attack of triethylamine on triphosgene forms
phosgene, which is condensed with 1 to give ␣-chlo-
rocarbonylaminophosphonates 4. Then ␣-isocyana-
toalkylphosphonates 2 are obtained from 4 by elim-
ination of one molecule of hydrogen chloride.
The intermediate 2 shows a very strong IR band
at approximately 2240 cmמ1, indicating the presence
of the cumulative double bond of NסCסO. The in-
termediates 2 are highly moisture sensitive. No iso-
cyanates 2 were obtained by regular column chro-
matography probably because of reactions with
water and other nucleophilic species present in silica
gel. Reactions of 2 with nucleophiles were best car-
ried out in one pot without isolating the isocyanate
intermediate 2. The triphosgene-mediated reaction
for the synthesis of ␣-isocyanatoalkyl-phosphonates
outlined here enjoys a number of advantages over
the previous method [9] in that the reaction is car-
ried out under mild condition in good yield, and tri-
phosgene is safer to use than phosgene due to its
lower vapor pressure and higher stability. Also the
experimental procedure is very simple. Further-
more, this highly efficient method is expected to have
wide synthetic utility for other ␣-isocyanatoalkyl-
phosphonates.
SCHEME 3
zylphosphonate (2.68 mmol) and triethylamine in 10
mL of methylene dichloride was added dropwise to
a solution of triphosgene in 5 mL of methylene di-
chloride during 50 minutes at מ10ЊC. Finally, the
title compound 3a was obtained in 83.2% yield. At
the same time, the by-product 5a was obtained in
9.9% yield. If the rate of addition of 1 was carried
out during 2 hours at מ15ЊC, the title compound 3a
was obtained in higher yield, and the by-product 5a
was not detected.
It has been reported that urylenediphosphonates
5 can be prepared from urea, phosphite esters, and
aldehydes [10]. However, this method requires rigid
experimental conditions and provides low yields
(limited to 60% or less). We found that treatment of
triphosgene with 2 equivalents of ␣-aminoalkylphos-
phonates in the presence of triethylamine afforded
urylenediphosphonates in high yield (Ͼ80%). As a
consequence of its practical simplicity and high ef-
ficiency, this new method for synthesis of urylene-
diphosphonates is expected to have wide synthetic
utility for the preparation of symmetrical ureas of
type 5.
In some cases, small amounts of urylenediphos-
phonates 5 were isolated as by-products, as shown
in Scheme 3. They can be formed by the reaction of
␣-aminoalkylphosphonates 1 with the intermediates
2. The formation of 5 can be retarded by use of a
lower temperature and a slower rate of addition of
1. For example, a solution of ␣-amino-4-chloroben-
The Structures of the Products and By-Products
All the products and by-products were colorless crys-
talline solids, and their structures were confirmed by
1H NMR, 31P NMR, IR and mass spectroscopy, and
elemental analysis. The data are summarized in Ta-
bles 1–3.

70 Wang et al.
TABLE 1 Physical Constants of Products 3 and By-Products 5
Elemental
C
Analysis(%)
H
Found (Calcd)
N
No.
Xn
R
m.p. (ЊC)
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
4–Cl–C6H4
Ph
4–Cl–C6H4
Ph
4–Cl–C6H4
2–Cl–C6H4
2,4–Cl2–C6H3
3–NO2–C6H4
3–NO2–C6H4
4–NO2–C6H4
4–Me–C6H4
H
199–201
174–175
140–142
200–201
214–215
205–206
100–102
188–189
115–117
216–217
164–166
150–152
174–175
150–151
83.2
86.1
81.4
81.6
72.1
85.7
79.6
85.0
90.8
73.8
88.2
67.9
/
62.97(62.89)
66.56(66.78)
63.59(63.92)
64.62(64.69)
60.75(61.04)
62.77(62.89)
61.09(61.04)
61.71(61.79)
62.70(62.85)
62.77(62.85)
67.84(68.10)
63.61(63.64)
60.55(60.56)
55.18(55.60)
5.12(5.28)
5.56(5.78)
5.51(5.69)
5.19(5.43)
4.79(4.96)
5.01(5.28)
4.86(4.96)
4.81(5.19)
5.37(5.59)
5.52(5.59)
6.42(6.38)
6.37(6.32)
3.93(4.17)
3.77(3.59)
7.10(7.10)
7.55(7.54)
6.74(6.78)
7.41(7.30)
6.85(6.89)
7.26(7.10)
6.58(6.89)
9.10(9.30)
8.80(8.88)
8.80(8.88)
6.65(7.00)
7.99(8.24)
3.59(3.62)
3.68(3.33)
3,5-Me2
2-F
2-F
H
3,5-Me2
H
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
/
3j
3k
31
5a
5g
4–Cl–C6H4
2,4–Cl2–C6H3
/
/
TABLE 2 1HNMR Data of Products 3 and By-Products 5
Compound
d
3a
1.20(s), 1.28(s)(9H, But); 5.50(dq, 1H, CHPO, 2JPH ס 22.9 Hz, 3JHH ס 10.4 Hz, J ס 6.3 Hz); 6.57–7.40(m,
19H, Ph)
3b
3c
1.20(s), 1.27(s)(9H, But); 5.43–5.46(m, 1H, CHPO); 6.44(s), 6.47(s)(2H, NH); 6.60–7.30(m, 20H, Ph)
1.27(s, 9H, But); 1.80(s), 2.02(s)(6H, Me); 5.51(dd, 1H, CHPO, 2JPH ס 22.9 Hz, 3JHH ס 10.4 Hz); 6.50–
7.30(m, 17H, Ph)
3d
3e)
1.32(s), 1.39(s)(9H, But); 5.20–5.61(m, 1H, CHPO); 6.69–7.40(m, 19H, Ph); 8.58(s), 8.66(s)(2H, NH)
1.15(s), 1.24(s)(9H, But); 5.45(dd, 1H, CHPO, 2JPH ס 22.9 Hz, 3JHH ס 10.4 Hz); 6.66–7.28(m, 18H, Ph);
7.79(br., 1H, NH)
3f
3g
1.30(s), 1.34(s)(9H, But); 6.12–6.32(m, 1H, CHPO); 6.52–7.40(m, 19H, Ph); 7.80(br., 1H, NH)
1.27(s, 9H, But); 1.85(s), 2.02(s)(6H, Me); 6.11(dd, 1H, CHPO, 2JPH ס 22.9Hz, 3JHH ס 9.4Hz); 6.55–7.30(m,
16H, Ph); 7.64(br, 1H, NH)
3H
3i
1.27(s, 9H, But); 5.59(dd, 1H, CHPO, 2JPH ס 22.9Hz, 3JHH ס 9.4Hz); 6.65–8.21(m, 19H, Ph); 7.91(br, 1H, NH)
1.32(s), 1.39(s)(9H, But); 1.93(s), 2.12(s)(6H, Me); 5.73(dd, 1H, CHPO, 2JPH ס 23.2Hz, 3JHH ס 10.0Hz); 6.56–
8.36(m, 17H, Ph); 8.54(s, 1H, NH)
3i
1.42 (s, 9H, But); 1.98(s), 2.15(s)(6H, Me); 5.68(dd, 1H, CHPO, 2JPH ס 19.8 Hz, 3JHH ס 9.9 Hz); 6.64–8.36(m,
17H, Ph); 8.54(br., 1H, NH)
(100ЊC)
3j
1.29 (s, 9H, But); 1.61(s), 1.81(s)(6H, Me); 5.66(dd, 1H, CHPO, 2JPH ס 22.9 Hz, 3JHH ס 9.4 Hz); 6.60–8.07(m,
17H, Ph)
3k
3l
1.27 (s, 9H, But); 1.78(s), 2.00(s)(6H, C6H3-Me2); 2.35(s, 3H, C6H4-Me); 5.53(dd, 1H, CHPO, 2JPH ס 22.4Hz,
3JHH ס 9.9 Hz); 6.53–7.40(m, 17H, Ph)
1.37 (s, 9H, But); 2.12(s, 6H, Me); 3.76(dd, 2H, CH2PO, 2JPH ס 9.4 Hz, 3JHH ס 5.2Hz); 6.80–7.36(m, 18H,
Ph); 7.6(br., 1H, NH)
5a
5g
5.78(dd, 1H, CHPO, 2JPH ס 22.9 Hz, 3JHH ס 10.4 Hz); 6.80–7.30(m, 28H, Ph)
5.88–6.04(m, 1H, CHPO); 6.80–7.60(m, 26H, Ph)
The products may undergo enolization as shown
in Scheme 4.
The hydrazine A may be converted into the enol
form B at room temperature. The t-butyl groups in
A and B are magnetically nonequivalent, and there-
fore, the H atoms of the t-butyl groups of the prod-
ucts show two single peaks. Owing to the unstability
of the enol form B, it can be converted into the hy-
drazine A at higher temperature (100ЊC) and the H
atoms of the t-butyl groups of the products obtained
at 100ЊC exhibit a single peak (for example, 3i in Ta-
ble 2). These results are in full agreement with ex-
pected data of novel N-t-butyl-NЈ-alkoxyl-N-(substi-
tuted)-benzoylhydrazines [11]. The H atom at the
␣-C sometimes exhibits a dd peak due to the cou-
pling of the P atom and the (N-)H atom but some-
times exhibits this interaction as a multiplet.
The dp of the product 3a is 15.57, whereas the dp

A Convenient Synthesis of N-t-Butyl-NЈ-Aminocarbonyl-N-(Substituted)Benzoylhydrazine 71
TABLE 3 IR Data of Some Products
Compound
IR (cmמ1) (KBr)
3a
3i
3343.0, 3062.5, 3043.0, 2915.5, 1707.1, 1682.5, 1588.0, 1533.7, 1486.4, 1360.5, 1241.7, 1197.6, 1155.1,
955.8, 759.8, 721.7, 685.5, 655.2
3360.0, 3103.0, 2951.0, 1707.6, 1660.8, 1624.7, 1589.4, 1527.6, 1486.1, 1382.0, 1348.6, 1236.4, 1200.1,
948.5, 760.2, 731.4, 684.0
5a
3341.0, 3053.0, 1691.0, 1588.0, 1540.2, 1487.2, 1263.3, 1242.4, 1198.8, 1184.0, 1156.7, 1087.0, 1066.9,
1021.0, 937.7, 763.9, 721.7, 685.9
מ4
potential anticancer activities. For example, at 10
M, the inhibition rate of compound 3d to A-549 at-
tains 74.0%, and the inhibition rate of compound 3e
to BEL-7402 attains 66.7%.
EXPERIMENTAL
All the melting points were determined with a
Thomas-Hoover melting point apparatus and are un-
corrected. IR spectra were recorded with a Shimadu-
435 spectrometer. H NMR and 31P NMR spectra
1
SCHEME 4
were recorded with a Bruker AC-P200 instrument,
tetramethylsilane and 85% H3PO4 being used as in-
ternal and external standards, respectively. Elemen-
tal analyses were carried out with a Yanaco CHN
Corder MT-3 elemental analyzer. Mass spectra were
recorded with an HP5988A spectrometer using the
EI method.
of the corresponding intermediate diphenyl ␣-
amino-4-chlorobenzylphosphonate is 17.05. Owing
to the effect of steric hindrance, the P chemical shift
of the product 3a is found at a higher field.
The IR data of 3a, 3i, and 5a are listed in Table
3. We can see from Table 3 that all absorption bands
Synthesis of Intermediates
מ1
appear as expected. For 3a, 3343.0 cm (s) corre-
sponds to an N–H stretching absorption band,
␣-Aminoalkylphosphonates 1 were prepared accord-
ing to reported procedures [4,12]. Triphosgene was
synthesized by chlorination of dimethyl carbonate
[13]. N-t-butyl-N-substituted benzoylhydrazines
were obtained by a convenient procedure [14].
1707.1 cmמ1 (s) and 1682.5 cmמ1 (s) to CסO stretch-
מ1
ing absorption bands, 1588.0 cm (s) and 1486.4
מ1
cm (s) to phenyl ring stretching absorption bands
מ1
in the group OPh, 1241.7 cm
(s) to the PסO
מ1
stretching absorption bands, 1197.6 cm (s) and
1155.1 cm (s) to the C–O stretching absorption
bands in the Ph–O–P, and 955.8 cm (s) due to the
מ1
Synthesis of the Products 3: General Procedure
מ1
P–O stretching absorption band in the P–O–Ph
group.
The EI-MS (15 ev) of the product 3i gives the
molecular ion peaks (630.40, M) and those of the
main fragments.
A solution of ␣-aminoalkylphosphonate 1 (2.68
mmol) and triethylamine (8.04 mmol) in 10 mL of
methylene dichloride was added dropwise to a so-
lution of triphosgene (1.34 mmol) in 10 mL of meth-
ylene dichloride during 2 hours under magnetic stir-
ring at מ15ЊC, and then the resulting mixture was
stirred at room temperature for 1 hour. A solution
of N-t-butyl-N-substitutedbenzoylhydrazine (2.41
mmol) in 10 mL of methylene dichloride was added
to the mixture with stirring at room temperature.
After the addition, the reaction mixture was stirred
at room temperature for 8 hours. After the solvent
had been removed under vacuum, the residue was
dissolved in 20 mL of ethyl acetate and filtered. The
BIOLOGICAL ACTIVITY
The preliminary biological tests showed that insec-
ticidal activities of the products are low. However,
we found that some of the compounds possess po-
tential anti-TMV activities. For example, at 500 ppm,
the inhibitory rate of compound 3b to TMV is 20%,
and we found that some of the compounds possess

72 Wang et al.
bruggen, C.; Augustyns, K.; Haemers, A. Synthesis
1995, 1074.
[6] Wang, Q. M.; Chen, Z.; Zeng, Q.; Huang, R. Q. Het-
eroat Chem 1999, 10(3), 209.
[7] Gruszeeha, G.; Soroka, M. Pol J Chem 1979, 53, 2327.
[8] Dai, Q.; Chen, R. Y. Heteroat Chem 1997, 8(3), 203.
[9] Medved, T. Y.; Kabachnik, M. I. Izvest Akad Nauk
SSSR Otdel Khim Nauk 1956, 684.
[10] Birum, G. H. J Org Chem 1974, 39(2), 209.
[11] Wang, Q. M.; Li, Z. G.; Huang, R. Q. CCS Symposium
Series 2000, China Chemical Society, Beijing, 2000,
318.
filtrate was evaporated and the residue was purified
by vacuum column chromatography on silica gel us-
ing a mixture of petroleum ether (60–90ЊC) and ethyl
acetate as the eluent. Finally, colorless crystalline 3
was obtained.
REFERENCES
[1] Wing, K. D. Science 1988, 241(4864), 467–469.
[2] Wing, K. D.; Slawecki, R. A.; Carlson, G. R. Science
1988, 241(4864), 470–472.
[3] Hsu, A. C. T. ACS Symposium Series 443 (Synthesis
and Chemistry of Agrochemical II), American Chem-
ical Society, Washington 1991, 478–490.
[4] Wing, K. D. U.S. Patent 5,424,333, 1995, Chem Abstr
123(1995)313108e.
[12] Wang, Q. M.; Zeng, Q. Symposium Of Agrochemicals
IX Chinese Chemical Society, China Chemical Soci-
ety, Shanghai, 1998, 238.
[13] Eckert, H.; Forstor, B. Angew Chem Int Ed Engl 1987,
26(9), 894.
[5] Borloo, M.; Jiao, X. Y.; Wojtowicz, H.; Rajan, R.; Ver-
[14] Wang, Q. M.; Huang, R. Q. Phosphorus Sulfur Silicon
2000, 161, 173.