Lewis acid-mediated nucleophilic addition of dialkylphosphite to C=N double bond of hydrazones

Article abstract of DOI:10.1080/10426500802466973

The synthesis of new phenyl substituted derivatives (2) of -hydrazino-alkylphosphonic acids by Lewis acid-mediated addition of dialkylphosphite to hydrazones, derived from benzoylhydrazines and benzaldehydes, is described. Reactions were successfully prom

Full text of DOI:10.1080/10426500802466973

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Phosphorus, Sulfur, and Silicon
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Lewis Acid–Mediated
Nucleophilic Addition of
Dialkylphosphite to C=N Double
Bond of Hydrazones
Chia-Ling Lien a , Shu-Hua Yeh a & Chi-Tung Hsu a
a Department of Applied Chemistry , Chaoyang
University of Technology , Taiwan, R.O.C.
Published online: 18 Feb 2009.
To cite this article: Chia-Ling Lien , Shu-Hua Yeh & Chi-Tung Hsu (2009) Lewis
Acid–Mediated Nucleophilic Addition of Dialkylphosphite to C=N Double Bond of
Hydrazones, Phosphorus, Sulfur, and Silicon and the Related Elements, 184:3,
543-549, DOI: 10.1080/10426500802466973
To link to this article: http://dx.doi.org/10.1080/10426500802466973
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Phosphorus, Sulfur, and Silicon, 184:543–549, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802466973
Lewis Acid–Mediated Nucleophilic Addition of
Dialkylphosphite to C=N Double Bond of Hydrazones
Chia-Ling Lien, Shu-Hua Yeh, and Chi-Tung Hsu
Department of Applied Chemistry, Chaoyang University of Technology,
Taiwan, R.O.C.
The synthesis of new phenyl substituted derivatives (2) of α-hydrazino-
alkylphosphonic acids by Lewis acid–mediated addition of dialkylphosphite to
hydrazones, derived from benzoylhydrazines and benzaldehydes, is described. Re-
actions were successfully promoted by boron trifluoride etherate under mild condi-
tions in methylene chloride at room temperature.
Keywords Dialkylphosphite; α-hydrazinoalkylphosphonic acids derivatives; hydra-
zones; Lewis acid; nucleophilic addition
INTRODUCTION
Hydrazinoalkylphosphonic acids and their derivatives, as analogs of
more renowned aminoalkylphosphonic acids and their derivatives,
have gradually gained some interest recently due to their poten-
tial biological activity.1 With a very few examples available in the
literature, the most efficient method to synthesize derivatives of α-
hydrazinoalkylphosphonic acids involves the addition of dialkylphos-
phite to compounds bearing a hydrozono group (C=N-N). However, the
reaction condition was either reported as a base-catalyzed nucleophilic
addition or at a high reaction temperature, which dramatically de-
creases its scope and utility in the preparation of different derivatives
of this class of compounds. Thus, Rachon and Wasielewski reported that
the preparation of α-hydrazinoalkylphosphonic acids was based on the
addition of diethyl phosphite on aliphatic aldazine catalyzed by a base.2
Received 3 August 2008; accepted 10 September 2008.
The authors gratefully acknowledge the financial support from the National Science
Council of Taiwan, R.O.C. We also thank the Regional Instruments Center at National
Chung-Hsing University for HRMS.
Address correspondence to Chi-Tung Hsu, Department of Applied Chemistry,
Chaoyang University of Technology, Wufong, Taichung County 41349, Taiwan, R.O.C.
E-mail: cthsu@cyut.edu.tw
543

544
C.-L. Lien et al.
A similar reaction condition, in which diethyl phosphite was added to
◦
a bis-imines at 80–110 C in the presence of triethylamine was re-
cently reportedby Ali.3 Diel and Maier described a method to prepare
α- hydrazinomethylphosphonic acid derivatives using the addition of
◦
dialkylphophite to hydrazone at 120–130 C, in which their hydazone
was prepared by the condensation of formaldehyde with a hydrazine.1
Unfortunately, this method does not apply to hydrazones that are de-
rived from carbonyl compounds other than formaldehyde. As a matter
of fact, it has been mentioned that other substituted hydrazones are
inert to nucleophilic addition of dialkylphosphite.4
SCHEME 1
Recently, we have reported the preparation of α-hydrazino-(disub-
stituted)methyl-phosphonic acid derivatives as depicted in Scheme 1,
in which the dialkylphosphite group was introduced, via a nucleophilic
addition mediated by boron trifluoride etherate, to hydrazones pre-
pared from benzoylhydrazine and various dialkyl ketones, represent-
ing a convenient method for the synthesis of new derivatives of α-
hydrazino-disubstitutedalkylphosphonic acids.5
RESULTS AND DISCUSSION
As an extension of the new method we developed, we want to report here
the synthesis of another series of new compounds, as shown in Scheme
2. As indicated in our previous report for the synthesis of derivatives
of α-hydrazino-disubstitutedalkyl-phosphonic acids, the preparation of
compounds (2) was also inspired by the work of Schlemminger et al.,
in which various phosphites were successfully added onto heterocyclic
imines mediated by Lewis acid, such as boron trifluoride etherate.6
SCHEME 2

Lewis Acid–Mediated Nucleophilic Addition of Dialkylphosphite
545
TABLE I Hydrazone Intermediates (1a)–(1g)
Entry
X
Y
Yield
mp(◦C)
(1a)
(1b)
(1c)
(1d)
(1e)
(1f)
4-Cl
H
4-Cl
4-NO2
H
H
90%a
96%a
96%a
96%a
95%a
96%a
90%b
231–2337
167–1688
219–2229
256–25710
159–16111
212–21312
209–21113
4-Cl
4-Cl
4-Cl
4-CH3
4-CH3
H
4-Cl
H
(1g)
aCompounds were prepared by Method A: refluxing in ethanol.
bCompound was prepared by Method B: reaction in hexane at room temperature.
All compounds were characterized by comparison of their spectroscopic and physical
data with those reported in the literature indicated.
Hence, the desired compounds (2) have been synthesized successfully
via BF3-mediated nucleophilic addition of dialkylphosphite to various
benzaldehyde hydrazones at room temperature in methylene chloride.
The required hydrazone intermediates (1a)–(1g) were prepared us-
ing the condensation of benzoylhydrazines and benzaldehydes either
in refluxing ethanol (Method A) or in hexane with or without the pres-
ence of a drying agent at room temperature (Method B). The known
compounds have been reported before, and yields are usually high as
shown in Table I.
The prepared hydrazones were initially reacted with dimethylphos-
phite without adding Lewis acid as a catalyst. As expected, the reaction
resulted in no reaction, either at room temperature or at refluxing tem-
perature of the solvent used. On the other hand, when one equivalent of
boron trifluoride etherate was added into the reaction mixture at room
temperature, the hydrazone was converted into the desired product as
anticipated. TLC indicated that all reactions showed only one major
product with moderate yields ranging from 53–89%. Pure products can
be obtained by column chromatography giving either a semisolid or a
crystallizing compound as shown in Table II. All final compounds were
1
demonstrated by IR, H NMR, and mass spectroscopy. Several com-
pounds, including (2a), (2e), and (2f), had also been identified by 31P
NMR spectroscopy.
EXPERIMENTAL
1H NMR spectra were obtained by a Varian Mercury 200 MHz in CDCl3
solvent (unless otherwise noted), and chemical shifts were reported in
δ ppm. 31P NMR spectra were determined on a Bruker Avance 500

546
C.-L. Lien et al.
TABLE II Hydrazinomethylphosphonates (2a)–(2g)
Entry
H
Y
Yielda
mp(◦C) or Physical appearance
(2a)
(2b)
(2c)
(2d)
(2e)
(2f)
4-Cl
H
4-Cl
-NO2
H
H
33%
21%
30%
18%
42%
23%
53%
116–120
semisolid
semisolid
semisolid
129–130
154–155
pink oil
4-Cl
4-Cl
4-Cl
4-CH3
4-CH3
H
4-Cl
H
(2g)
aAll pure compounds were obtained by column chromatography on silica gel.
MHz spectrometer using 85% phosphoric acid as external standard.
Melting points were uncorrected. IR spectra were obtained by a Perkin
Elmer Paragon 500 and reported in wave number. Mass spectral (ESI)
data were obtained from the Applied Chemistry Department, Chaoyang
University of Technology, and HRMS data were obtained from the In-
struments Center, National Chung Hsing University. All the reagents
were used as received from the commercial sources, unless otherwise
noted.
General Procedure for the Preparation of Hydrazones (1a)
to (1g): Method A
2-(Phenylmethylene)-(4-chloro)benzoic acid hydrazide (1a)
To a solution of 4-chlorobenzhydrazide (1.00 g, 5.80 mmol) in ethanol
(50 mL), benzaldehyde (0.62 g, 5.80 mmol) was added. The mixture was
refluxed for 2.5 h. The mixture was cooled down to room temperature,
and the solvent was evaporated by a rotary evaporator to give a residue.
The residue was triturated by hexane, and the resulting precipitate
was collected by suction-filtration and washed with a small amount of
hexane to give a white solid, 1.36 g (90%), mp 231–233◦C (Lit.7, mp
1
229◦C). H NMR(CDCl3): δ 8.29 (s, 1H), 7.86 (d, J = 8.2 Hz, 4H), 7.78
(br s, 1H), 7.33–7.47 (m, 5H, Ar-H). The syntheses of (1b) to (1f) were
conducted in a similar way as described in Method A. Their physical
data (melting points) have been recorded in Table I.
Method B
2-(Phenylmethylene)benzoic acid hydrazide (1g)
To a solution of benzohydrazide (0.50 g, 3.7 mmol) in hexane (10 mL),
benzaldehyde (1.16 g, 10.9 mmol) was added with magnetic stirring.
The mixture was stirred at room temperature for 14 h. A resultant

Lewis Acid–Mediated Nucleophilic Addition of Dialkylphosphite
547
precipitate was obtained by suction-filtration, and washed with hexane
to give a white solid, 0.72 g (88 %). mp 211–212◦C (Lit.13, mp 210–
212◦C).
General Procedures for the Syntheses of Dimethyl
Hydrazino-Phenylsubstituted-Methyl-Phosphonates
2-[(Dimethoxyphosphinyl)phenylmethyl]–(4-chloro)
benzoic acid hydrazide (2a)
To a solution of (1a) (0.50 g, 1.9 mmol) in THF (40 mL) at room
temperature, dimethylphosphite (0.21 g, 2.1 mmol) was added followed
by boron trifluoride diethyl etherate (0.68 g, 2.3 mmol). The mixture
was stirred at room temperature for 14 h. The solvent was evapo-
rated by a rotary evaporator, and the residue was dissolved in ethyl
acetate (30 mL) and washed with water (30 mL) three times and
with saturated NaCl solution one time. The organic layer was dried
over anhydrous sodium sulfate and filtered. The solvent was evapo-
rated to give a crude product, 0.63 g (89%). Pure product was obtained
by column silica gel chromatography eluted with acetone/methylene
chloride (1:3) giving 0.19 g (30%) as yellow solid, mp 116∼120 ◦C.
IR(film) cm−1: 3273, 2955, 2952, 2854, 1717, 1652, 1560, 1540; 1H NMR
(CDCl3): δ 8.53 (s, 1H), 7.65∼7.28 (m, 9H), 4.63 (d, J = 13.2 Hz, 1H),
3.69 (dd, J = 3.6, 10.6 Hz, 6H); 31P NMR: δp (CDCl3, 202.46 MHZ):
δ24.01 ppm; HRMS calculated for C16H18ClN2O4P : 368.0693, Found:
368.0690.
2-[(Dimethoxyphosphinyl)-4-chlorophenylmethyl]benzoic acid
hydrazide (2b)
A similar reaction as described in (2a) was conducted at room tem-
perature for 14 h to give a crude product, 0.63 g (89%), which was puri-
fied by column silica gel chromatography eluted with actone/methylene
chloride (1:3) giving a white solid, (yield 30%). Mp 116–120 ◦C; IR (film)
cm−1: 3274, 2925, 2854, 1717, 1653, 1560, 1540; 1H NMR(CDCl3): δ 8.24
(s, 1H), 7.69∼7.27 (m, 9H), 4.65 (d, J = 14.0 Hz, 1H), 3.73 (dd, J = 1.0,
10.6 Hz, 6H); HRMS calculated for C16H18ClN2O4P : 368.0693, Found:
368.0695.
2-[(Dimethoxyphosphinyl)-4-chlorophenylmethyl]-(4-chloro)
benzoic acid hydrazide (2c)
A similar reaction as described in (2a) was conducted at room tem-
perature for 12 h to give a crude product, 0.25 g (61%), which was pu-
rified by column silica gel chromatography eluted with ethyl acetate/

548
C.-L. Lien et al.
hexane (1:3), giving a pure semi-solid (yield 30%); IR (film) cm−1: 3260,
1
2925, 2850, 1717, 1653, 1558, 1540; H NMR (CDCl3): δ 8.37 (s, 1H),
7.75∼7.32 (m, 8H), 4.61 (d, J = 13.8 Hz, 1H), 3.70 (dd, J = 2.4, 10.6
Hz, 6H); HRMS calculated for C16H17Cl2N2O4P : 402.0303, Found:
402.0298.
2-[(Dimethoxyphosphinyl)-4-chlorophenylmethyl]-(4-nitro)
benzoic acid hydrazide (2d)
A similar reaction as described in (2a) was conducted at room temper-
ature for 12 h to give a crude product, 0.26 g (64%), which was purified
by column silica gel chromatography eluted with ethyl acetate/hexane
(1:1), giving a pure semi-solid (17 %); IR(film) cm−1: 3241, 2928, 2857,
1
1717, 1653, 1558, 1540; H NMR(CDCl3): δ 8.39∼7.34 (m, 9H), 4.66
(d, J = 14.2 Hz, 1H), 3.46 (s, 3H), 3.11 (s, 3H); HRMS calculated for
C16H17ClN3O6P : 413.0543, Found: 413.0540.
2-[(Dimethoxyphosphinyl)-4-methylphenylmethyl]benzoic
acid hydrazide (2e)
A similar reaction as described in (2a) was conducted at room tem-
perature for 24 h yielding a crude product 1.21 g (83%), which was
purified by column silica gel chromatography eluted first with 100%
ethyl acetate followed by methanol/methylene chloride (5:95). The col-
lected material was further crystallized from ethyl acetate to give a
white solid, 0.61 g (42%), mp 129–130 ◦C, 1H NMR (CDCl3): δ 7.98 (d, J
= 6.6 Hz, 1H), 7.69∼7.17 (m, 9H), 5.50 (dd, J = 5.4, 18.2 Hz, 1H), 4.58
(dd, J = 2.4, 12.6 Hz, 1H), 3.74 (dd, J = 3.8, 10.5 Hz, 6H), 2.36∼2.35
(s, 3H); 31P NMR: δp (CDCl3, 202.46 MHZ): δ24.30 ppm; MS(ESI) m/z
349.060 [M+H]+.
2-[(Dimethoxyphosphinyl)-4-methylphenylmethyl]-(4-chloro)
benzoic acid hydrazide (2f)
A similar reaction as described in (2a) was conducted at room temper-
ature for 50 h to give a crude product, 1.24 g (89%), which was purified
by column silica chromatography eluted with acetone/methylene chlo-
ride (1:3). The collected material was further crystallized from methy-
◦
1
lene chloride to give 0.32 g (23%), mp 154–155 C; H NMR (CDCl3):
δ 8.12 (d, J = 7.2 Hz, 1H), 7.65–7.16 (m, 8H), 5.48 (dd, J = 7.6, 18.4
Hz, 1H), 4.55 (dd, J = 2.6, 12.4 Hz, 1H), 3.73 (dd, J = 4.2, 11.6 Hz,
6H), 2.36–2.35 (s, 3H); 31P NMR: δp (CDCl3, 202.46 MHZ): δ24.24 ppm;
MS(ESI)m/z 383.036 [M+H]+.

Lewis Acid–Mediated Nucleophilic Addition of Dialkylphosphite
549
2-[(Dimethoxyphosphinyl)phenylmethyl]benzoic acid
hydrazide (2g)
A similar reaction as described in (2a) was conducted at room tem-
perature for 46 h to give a crude product. Pure product was obtained
by column silica gel chromatography eluted with 100% ethyl acetate to
1
give a pink oil, 0.79 g (53%); H NMR (CDCl3): δ 8.07 (d, 1H, J = 7.0
Hz, 1H), 7.68–7.28 (m, 10H), 5.52 (ddd, J = 2.2, 7.0, 17.6 Hz, 1H), 4.64
(dd, J = 2.2, 13.2 Hz, 1H), 3.73 (dd, J = 1.8, 10.6 Hz, 6H); MS(ESI) m/z
335.085 [M+H]+.
REFERENCES
[1] (a) P. J. Diel and L. Maier, Phosphorus, Sulfur, and Silicon, 36, 85 (1988); (b) P. J.
Diel and L. Maier, U.S. Pat. Appl. US 4,734,119 (1988).
[2] J. Rachon and C. Wasielewski, Roczniki Chemii., 50(3), 477 (1976).
[3] T. E. Ali, ARKIVOC, ii, 71 (2008).
[4] (a) C. Yuan, S. Chen, R. Xie, H. Feng, and L. Maier, Phosphorus, Sulfur, and Silicon,
106, 115 (1995); (b) K. Afarinkia, C. W. Rees, and J. I. G. Cadogan, Tetrahedron, 46,
7175 (1990).
[5] C.-L. Lien and C.-T. Hsu, Intern. J. Appl. Sci. and Eng., 6(1), 11 (2008).
[6] I. Schlemminger, A. Willecke, W. Maison, R. Koch, A. Lutzen, and J. Martens, J.
Chem. Soc. Perkin Trans. I, 2804 (2001).
[7] S. Rostamizadeh and S. A. G. Housaini, Tetrahedron Lett., 45, 8753 (2004).
[8] Y. A. Al-Farkh, F. H. Al-Hajjar, and H. S. Hamoud, J. Chem. Eng. Data, 23, 345
(1978).
[9] T. R. Vakula and V. R. Srinivasan, Indian J. Chem., 7, 580 (1969).
[10] K. G. Desai and K. R. Desai, Indian J. Chem., Sec. B, 44B(10), 2097 (2005).
[11] M. Dabiri, P. Salehi, M. Baghbanzadeh, and M. Bahramnejad, Tetrahedron Lett.,
47, 6983 (2006).
[12] W. T. Flowers, J. F. Robinson, D. R. Taylor, and A. E. Tipping, J. Chem. Soc., Perkin
Trans. 1, 349 (1981).
[13] J. B. Hendrickson and D. D. Sternbach, J. Org. Chem., 40, 3450 (1975).