Reactions of 1,1′-(azodicarbonyl)dipiperidine with organophosphorus reagents

Article abstract of DOI:10.1080/10426507.2011.586386

1,1′carbonyl)dipiperidine reacts with tris(dimethylamino)phosphine, trialkyl phosphites, phosphorus ylides, and Lawesson's reagents to give the phosphorodihydrazidic amide, oxadiazole, dihydropyridazine, ethylenic, and thicarbonyl products, respectively. The antibacterial and antifungal activities for the new compounds are reported. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental resource: Biological Evaluation.

Full text of DOI:10.1080/10426507.2011.586386

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Reactions of 1,1′-
(Azodicarbonyl)Dipiperidine with
Organophosphorus Reagents
Leila S. Boulos a , Hoda A. Abdel-Malek a , Naglaa F. El-Sayed a &
Maysa E. Moharam b
a Department of Organometallic and Organometalloid Chemistry ,
National Research Centre , Dokki , Cairo , Egypt
b Department of Microbial Chemistry , National Research Centre ,
Dokki , Cairo , Egypt
Published online: 05 Jan 2012.
To cite this article: Leila S. Boulos , Hoda A. Abdel-Malek , Naglaa F. El-Sayed & Maysa E. Moharam
(2012) Reactions of 1,1′-(Azodicarbonyl)Dipiperidine with Organophosphorus Reagents, Phosphorus,
Sulfur, and Silicon and the Related Elements, 187:2, 225-237, DOI: 10.1080/10426507.2011.586386
To link to this article: http://dx.doi.org/10.1080/10426507.2011.586386
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Phosphorus, Sulfur, and Silicon, 187:225–237, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.586386
REACTIONS OF 1,1ꢀ-(AZODICARBONYL)DIPIPERIDINE
WITH ORGANOPHOSPHORUS REAGENTS
Leila S. Boulos,1 Hoda A. Abdel-Malek,1 Naglaa F. El-Sayed,1
and Maysa E. Moharam2
1Department of Organometallic and Organometalloid Chemistry,
National Research Centre, Dokki, Cairo, Egypt
2Department of Microbial Chemistry, National Research Centre,
Dokki, Cairo, Egypt
GRAPHICAL ABSTRACT
O
N
N
N
H
N
N
N
O
N
O
O
N(R)2
P
N
N
O
7
N
N
N
O
OH
6
R3
R3
N
COOC2H5
N
O
C2H5O
N
N
O
N
H
N
OR
OR
O
10
O
P
O
9a, R = CH3
b, R = C2H5
c, R = CH(CH3)2
Abstract 1,1ꢁ-(Azodicarbonyl)dipiperidine reacts with tris(dimethylamino)phosphine, trialkyl
phosphites, phosphorus ylides, and Lawesson’s reagents to give the phosphorodihydrazidic
amide, oxadiazole, dihydropyridazine, ethylenic, and thicarbonyl products, respectively. The
antibacterial and antifungal activities for the new compounds are reported.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
resource: Biological Evaluation.
Keywords
tris(dialkylamino)phosphines; ylides
Alkyl phosphites; 1,1ꢁ-(azodicarbonyl)dipiperidine; Lawesson’s reagents;
INTRODUCTION
Our previous work reported that the new bioactive heterocyclic phosphorus sub-
stances synthesized from oxazolones possessed antischistosomal activity.1 In addition, we
Received 29 March 2011; accepted 1 May 2011.
Address correspondence to Leila S. Boulos, Department of Organometallic and Organometalloid Chemistry,
National Research Centre, El-Behoos St., Dokki, Cairo 12622, Egypt. E-mail: leilagoubran@yahoo.com
225

226
L. S. BOULOS ET AL.
have found that some of our newly prepared heterocyclic oxaphospholes exhibit antibac-
terial and antifungal activities.2 Moreover, it has been reported that different biological
and pharmacological activities are well known for substituted diazines and related com-
pounds.3–8 In continuation of our previous work in organophosphorus chemistry,1,2,9–11 we
have now synthesized new heterocyclic phosphorus compounds incorporating important
nuclei in the search for possible bactericidal and fungicidal activities.
RESULTS AND DISCUSSION
Chemistry
In connection with a previous communication,12 we report now on the reactions
of 1,1ꢁ-(azodicarbonyl)dipiperidine (1) with tris(dialkylamino)phosphines 2a,2b, trialkyl
phosphites 3a–c, phosphorus ylides 4a,4b, and Lawesson’s reagents 5a,5b (Scheme 1).
R
N
R
N
O
R
P
R
N
N
N
N
N
R
R
O
1
2a, R = CH3
b, R = C2H5
O
RO
OR
S
S
CHCR1
P
R2
Ph3P
R2
P
P
S
S
OR
3a, R = CH3
b, R = C2H5
c, R = CH(CH3)2
4a, R1 = OC2H5
b, R1 = OC(CH3)3
5a, R2 = C6H4-OCH3-p
b, R2 = S-C6H5
Scheme 1
We have found that when one mole equivalent of tris(dialkylamino)phosphine 2a
reacted with two mole equivalents of 1,1ꢁ-(azadicarbonyl)dipiperidine (1), in reflux-
ing toluene, compound 6 was isolated in a 68% yield (Scheme 2). Product 6 as a
pure compound exhibited a sharp melting point. Structure elucidation of Nꢁ,Nꢁꢁ,Nꢁꢁꢁ,Nꢁꢁꢁꢁ-
tetrapiperidinylcarbonyl-Nꢁꢁꢁ-hydroxy-N,N-dimethylphosphorodihydrazidic amide (6) was
substantiated on the basis of its elemental analyses, IR, 1H, 13C, 31P NMR, and mass spectral
data (cf. Experimental section).
We propose the reaction course depicted in Scheme 2 for the formation of 6. Thus,
initial attack of aminophosphine 2a on the most reactive center in 1 leads to the formation of
the dipolar adduct (A), which collapses to the most stable form 6 through rapid hydrolysis
of (A) (by the presence of unavoidable moisture) to give intermediate (B), which undergoes
further decomposition together with addition of another molecule of 1 to yield product
6.2,13

REAGENTS OF 1,1ꢀ-(AZODICARBONYL)DIPIPERIDINE WITH ORGANOPHOSPHORUS 227
+
P(N(R)2)3
R
N
R
N
O
O
N
N
+
N
N
R
P
R
N
N
N
N
O
N
O
A
1
R
R
2a, R = CH3
+ HOH
− HNR2
N(R)2
N(R)2
(R)2N
O
O
H
− HN(R)2
+
P
O
P
O
N
N
N
N
N
N
N
N
O
O
B
+ 1
+ HOH
O
O
N
N
O
N
H
N
N
O
N(R)2
P
N
N
O
N
OH
6
Scheme 2
On the other hand, when 1,1ꢁ-(azadicarbonyl)dipiperidine (1) was allowed to re-
act with tris(dialkylamino)phosphine 2a in the absence of solvent at room tempera-
ture for 15 min, colourless product 7 was obtained in an 85% yield together with
tris(dialkylamino)phosphine oxide 8a (Scheme 3). It is worth mentioning that when 1,1ꢁ-
(azodicarbonyl)dipiperidine (1) was allowed to react with tris(dialkylamino)phosphine (2b)
in the absence of solvent at room temperature for 10 min, the same product 7 was obtained
in an 80% yield. Compound 7 was chromatographically pure and possessed a sharp melting
point. Structural support for 2,5-di(piperidin-1-yl)-1,3,4-oxadiazole (7) was based on its
1
analysis, IR, H, 13C NMR, and mass spectral data (cf. Experimental section). In order
to identify unambiguously the structure of the reaction product (7), an X-ray structure
determination14–18 of crystalline 7 (Table 1) was performed (Figure 1).
Oxadiazole derivative 7 was probably obtained through a new competitive side re-
action pathway, in which the betaine structure produced in the first step of the reaction is
cyclized intramolecularlyunder drastic conditions as showninScheme3.19 2,5-di(piperidin-
1-yl)-1,3,4-oxadiazole was previously obtained from the reaction of azo compounds with
tributyl phosphine (TBP).19

228
L. S. BOULOS ET AL.
R3
O
C
O
R3
O
C
O
R3
R3
N
N
N
N
P(N(R)2)3
P(N(R)2)3
(A)
R3
R3
O
R3
O
R3
O
O
P(N(R)2)3
+
N
N
RN
N
N
P
8a, R = CH3
b, R = C2H5
NR
7
NR
R3
=
N
Scheme 3
Furthermore, this study was extended to include the behavior of 1,1ꢁ-(azodicarbonyl)
dipiperidine (1) toward trialkyl phosphites 3. Thus, we found that the reaction of 1 with
trimethyl phosphite (3a) in dry toluene proceeded at the reflux temperature to give a
chromatographically pure 1:1 adduct formulated as dimethyl (piperidin-1-yl)(piperidine-
1-carboylimino)methyl phosphate 9a. The structure of 9a was deduced from its elemental
Table 1 Compound 7: Selected bond length (Å) and angles (o)
Selected
bond
Bond length
(bond angle)
Selected
bond
Bond length
(bond angle)
O1 C6
O1 C8
N2 C8
N2 C9
N2 C12
N3 N4
N3 C6
N4 C8
N5 C6
◦N5 C13
C7 C10
C7 C11
C9 C14
1.377(5)
1.365(6)
1.370(6)
1.514(8)
1.470(7)
1.427(6)
1.273(6)
1.288(6)
1.368(6)
1.467(6)
1.509(7)
1.504(7)
1.506(7)
C11 C16
C12 C15
C13 C16
C14 C17
1.471(6)
1.502(7)
1.511(8)
1.506(9)
1.520(8)
101.6(3)
112.9(4)
115.0(4)
106.1(4)
105.5(4)
117.6(4)
114.5(4)
113.4(4)
C15 C17
C6 O1 C8
C8 N2 C9
C9 N2 C12
N4 N3 C6
N3 N4 C8
C6 N5 C10
C6 N5 C13
O1 C6 N3

REAGENTS OF 1,1ꢀ-(AZODICARBONYL)DIPIPERIDINE WITH ORGANOPHOSPHORUS 229
Figure 1 X-ray structure of compound 7.
analysis, IR, 1H, 13C, 31P NMR, and mass spectral data (cf. Experimental section). Similarly,
3b and 3c react with 1 to give the dialkyl phosphates 9b and 9c, respectively, in good yields
(Scheme 4). Structure assignments for 9b and 9c were substantiated on the basis of their
elemental analysis, IR, 1H, 13C, 31P NMR, and mass spectral data (cf. Experimental section).
O
O
N
N
RO
OR
N
−
N
+
N
N
P
N
N
O
OR
OR
O
+
P
1
OR
3a, R = CH3
b, R = C2H5
A
RO
c, R = CH(CH3)2
HOH
unavoidable moisture
O
N
N
O
N
N
−ROH
N
N
OR
OR
H
O
N
N
OR
H
P
O
H
P
O
OR
OR
O
9a, R = CH3
b, R = C2H5
c, R = CH(CH3)2
Scheme 4
A possible explanation for the course of the reaction of trialkylphosphites 3a–c with
1 is shown in Scheme 4. The reaction was assigned to proceed through an initial attack of
the phosphorus reagents 3a–c at the most reactive center in 1 and led to the formation of
dipolar adduct (A). The reaction was accompanied with rapid hydrolysis by the presence

230
L. S. BOULOS ET AL.
of unavoidable moisture and elimination of one molecule of alcohol under the applied
reaction conditions to afford the dialkylphosphate products 9a–c.
The reactions of 1 with phosphonium ylides 4a and 4b were also investigated.
We found that 1,1ꢁ-(azodicarbonyl)dipiperidine (1) reacted with three mole equivalents
of 4a in refluxing toluene in the presence of a few drops of DMF to give product 10 in
a 65% yield. Triphenylphosphine and triphenylphosphine oxide were also isolated from
1
the reaction media. The structure of product 10 was assigned on the basis of IR, H,
13C NMR, and mass spectral data (cf. Experimental section). A possible explanation of
the course of the reaction of phosphonium ylide 4a with 1 is shown in Scheme 5. The
reaction is assumed to proceed through olefination of the two carbonyl groups in 1 by
the Wittig reagent 4a, followed by addition of another molecule of phosphonium ylide 4a
CHCOR1
O
R3
N
−TPPO
R3
R3
N
N
2
Ph3P
CHCOOC2H5
R3
CHCOR1
N
+
4a
O
1
4a
PPh3
R1OCHC
CHCOR1
R1OCHC
H
−TPP
CHCOR1
R3
N
R3
N
R3
N
CHCOR1
R3
N
CHCOR1
−C2H5OH
N
R3
=
R1 = OC2H5
R3
R3
N
COOC2H5
N
C2H5O
O
10
O
Scheme 5
CHCOR1
N
R3
CHCOR1
N
R3
11
N
R3 =
,
R1 = OC(CH3)3
Compound 11

REAGENTS OF 1,1ꢀ-(AZODICARBONYL)DIPIPERIDINE WITH ORGANOPHOSPHORUS 231
and elimination of one molecule of alcohol under the applied reaction conditions to afford
10 (Scheme 5). On the other hand, when 1 was treated with two mole equivalents of 4b in
refluxing toluene in the presence of a few drops of DMF, the stable olefinic product 11 was
isolated together with triphenylphosphine oxide. The compound Tert-butyl-3,3ꢁ(diazene-
1,2-diyl)bis(3-piperidin-1-yl)acrylate (11) was chromatographically pure and exhibited a
sharp melting point. Structure elucidation of product 11 was confirmed by analytical results
and spectral data (see the Experimental section).
This study was further extended to include the reaction of Lawesson’s reagents 5a,b
with 1,1ꢁ-(azodicarbonyl)dipiperidine (1). We have found that, when one mole of 1 was
allowed to react with half an equivalent of 5a in dry tetrahydrofuran under warming for 1
h, product 12a was isolated in an 80% yield. Moreover, when one mole of 1 reacted with
one equivalent of 5a in refluxing acetonitrile for 1 h, 12b was isolated in an 85% yield. On
the other hand, 1,1ꢁ-(azodicarbonyl)dipiperidine 1 reacted with one equivalent of Japanese
reagent (JP) 5b in dry toluene at room temperature, to yield 12b that was isolated in an
80% yield (Scheme 6).
S
THF
H
N
R3
R3
N
H
under warming
O
12a
O
N
R3
R3
N
+
5a
O
S
H
+5b
R3
N
Acetonitrile
reflux
R3
N
H
S
12b
12b
R3 =
N
Scheme 6
Previously, it has been reported that when Nꢁ-(piperidine-1-carbonyl)piperidine-1-
carbohydrazide 1 was allowed to react with 5a in refluxing xylene for 1 h, a complex
mixture of products was produced.20
CONCLUSION
From the results of the present investigation, it can be concluded that the reac-
tion of 1,1ꢁ-(azodicarbonyl)dipiperidine (1) with tris(dialkylamino)phosphines 2, trialkyl
phosphites 3, phosphonium ylides 4, and Lawesson’s reagents 5 led to different products,
depending on the nature of the phosphorus reagents as well as on the stability of the ad-
dition products. The significance of these findings lies in the discovery of a new pattern
of attack by tris(dialkylamino)phosphines and in the establishment of a new method for

232
L. S. BOULOS ET AL.
the synthesis of tetrapiperdinylcarbonyl-Nꢁꢁꢁ-hydroxy-N,N-dimethylphosphorodihydrazidic
amide, piperidine carboylimino phosphate, and dihydropyridazine derivatives.
EXPERIMENTAL
Melting points were determined in open glass capillaries using an Electrothermal
IA 9000 series digital melting point apparatus (Electrothermal, Essex, UK) and were
uncorrected. The IR spectra were measured in KBr pellets with a Perkin-Elmer Infracord
1
Spectrophotometer model 157(Grating). The H and 13C NMR spectra were recorded in
CDCl3 and DMSO as solvents on a Joel-500 MHz spectrometer, and the chemical shifts
were recorded in δ values relative to TMS. The 31P NMR (125 MHz) spectra were taken with
a Varian CFT-20 (vs. external 85% H3PO4 standard). The mass spectra were performed
at 70 eV on a Shimadzu GCS-OP 1000 Ex spectrometer provided with a data system.
Elemental analyses were performed using an Elmenter Varu EL Germany Instrument.
Reaction of Tris(Dimethylamino)Phosphine (2a) with
1,1ꢀ-(Azodicarbonyl)Dipiperidine (1)
Tris(dimethylamino)phosphine 2a, 0.24 g (1 mmol) was added dropwise to a so-
lution of compound 1 0.5 g (2 mmol) in dry toluene (30 mL), and the reaction mixture
was refluxed for 4 h. After evaporation of the volatile material under reduced pressure,
◦
◦
the residue was washed several times with petroleum ether (b.r. 60 C–80 C) and crys-
tallized from ethyl acetate to give 6 Nꢁ,Nꢁꢁ,Nꢁꢁꢁ,Nꢁꢁꢁꢁ-tetrapiperdinylcarbonyl-Nꢁꢁꢁ-hydroxy-
N,Ndimethylphosphorodihydrazidic amide (6, C26H48N9O6P).
(6): Yield 68%, mp 175 ◦C–176 ◦C (ethyl acetate). IR [v, cm−1, KBr]: 3318 (NH),
3320 (OH), 1650 (C O), 1655 (C O), 1320, 860 (P N(CH3)2),21 1240 (P O).22 1
H
NMR (500 MHz, δ ppm, CDCl3): 1.56 (d, 24H, CH2 Pip.), 2.67 (d, 6H, 3JHP = 10.05 Hz,
P N(CH3)2), 3.38 (d, 16H, CH2 Pip.), 6.76 and 6.79 (2s, 2H, 1NH, 1OH, exchangeable
with D2O). 13C NMR (125 MHz, δ ppm, CDCl3): 24.4 (s, 4CH2 Pip.) 25.6 (s, 8CH2 Pip.),
37.8 (d, 2JCP = 25.50, O P N(CH3)2), 45.0 (s, CH2 Pip.), 158.4 (d, 3JCP = 12 Hz, C O),
3
2
158.0 (d, JCP = 12 Hz, C O), 159.5 (d, JCP = 35.50 Hz, O C N P). 31P NMR (δ
ppm, CDCl3): 26.24.23 MS m/z (%): 614 [M+] (Field Ionization Method). Anal. Calcd for
C26H48N9O6P (613.69): C, 50.89; H, 7.88; N, 20.54; P, 5.05. Found: C, 51.27; H, 8.12; N,
21.03; P, 5.20.
Reaction of Tris(Dialkylamino)Phosphine (2a) and/or (2b) with
1,1ꢀ-(Azodicarbonyl)Dipiperidine (1)
A mixture of 1 (0.25 g, 1 mmol) and excess of tris(dialkylamino)phosphine 2a and/or
2b was stirred at room temperature for 10–15 min. The reaction mixture was evaporated
under reduced pressure. The residue was washed several times with petroleum ether (b.r.
◦
◦
60 C–80 C) to give 2,5-di(piperidin-1-yl)-1,3,4-oxadiazole (7, C12H20N4O). The com-
◦
◦
pound was crystallized from petroleum ether (b.r. 60 C–80 C) and was separated as
colorless crystals, yield 80% and mp 75 C–76 C. IR [v, cm−1, KBr]: 1645 (C N). H
◦
◦
1
NMR (500 MHz, δ ppm, CDCl3): 1.62 (m, 12H, CH2 Pip.), 3.30 (m, 8H, CH2 Pip.). 13
C
NMR (125 MHz, δ ppm, CDCl3): 24.2 (s, 4CH2, pip.), 24.8 (s, 2CH2, pip.), 47.3 (CH2,
pip.), 160.6 (C N). MS m/z (%) 236 [M+] (80). Anal. Calcd for C12H20N4O (236.31):

REAGENTS OF 1,1ꢀ-(AZODICARBONYL)DIPIPERIDINE WITH ORGANOPHOSPHORUS 233
Table 2 Crystal data and experimental parameters used for the intensity data
Compound
7
Empirical formula
Formula weight
Crystal system/space group
C12H20N4O
236.319
Triclinic
6.3488(5)
8.7559(8)
12.1159(14)
101.085(3)
90.657(4)
105.527(4)
635.42(11)
2
a/Å
b/Å
c/Å
α/Å
β/Å
γ /Å
V/Å3
Z
Dx (Mg/cm−3
µ (mm−1
)
1.235
0.08
)
Color/Shape
Temp (K)
Colorless/prismatic
298
Theta range for collection
Reflection collected
Independent reflections
Data/restraints/parameters
R (gt)
2.910–28.283
3432
2949
154
0.066
Final R indices[1<3 (I)]
Rint 0.098
C, 60.99; H, 8.53; N, 23.71. Found:C, 60.97; H, 8.55;N, 23.79.Tris(dialkylamino)phosphine
oxide 8a and/or 8b were also isolated from the reaction mixture and identified.
X-Ray Crystallographic Study14–18
A single crystal of (7) was grown by crystallization from petroleum ether (b.r.
◦
◦
40 C–60 C). The crystal structure was solved and refined, using maxus (Nonius, De-
flt and Mac Science, Japan). MoKα (λ = 0.71073 Å) and a graphite monochromator were
used for data collection. A summary of the crystal analysis parameters is given in the
Table 2. CCDC 780686 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.com.ac.uk/data request/cif.
Reaction of Trimethyl Phosphite (3a) with
1,1ꢀ-(Azodicarbonyl)Dipiperidine (1)
Trimethyl phosphite (3a) (0.12 g, 1 mmol) was added dropwise to a solution of
compound 1 (0.25 g, 1 mmol) in dry toluene (30 mL), and the reaction mixture was refluxed
for 1 h. After evaporation of the volatile material under ◦reduced pressure, the residue was
◦
washed several times with petroleum ether (40 C–60 C) to give product 9a [dimethyl
(piperidin-1-yl)(piperidine-1-caboylimino)methyl phosphate] (9a, C14H27N4O5P).
Crystallized ◦from eth◦yl acetate, product 9a was separated as colorless crystals, yield
65% and mp 126 C–127 C. IR [v, cm−1, KBr]: 1260 (P O), 1628 (C O), and 3315
1
(NH). H NMR (500 MHz, δ ppm, CDCl3): 1.57 (m, 12H, CH2 Pip.), 3.40 (m, 8H,
3
CH2 Pip.), 3.83 (d, 6H JHP = 11.50 Hz, P(OCH3)2, 6.60 (s, NH, exchangeable with

234
L. S. BOULOS ET AL.
D2O). 13C NMR (125 MHz, δ ppm, CDCl3): 24.6 (s, 4CH2 Pip.), 25.4 (s, 2CH2 Pip.),
44.6 (s, 2CH2 Pip.), 47.2 (s, 2CH2 Pip.), 53.7 (d, 2JCP = 29.30, O P (OCH3)2), 158.4
(C N), 160.0 (C O). 31P NMR (δ ppm, CDCl3): 2.8. MS m/z (%) 362 [M+] (75). Anal.
Calcd for C14H27N4O5P (362.63): C, 46.40; H, 7.51; N, 15.46; P, 8.55. Found: C, 46.47;
H, 7.55; N, 15.45; P, 8.54.
Reaction of Triethyl Phosphite (3b) with
1,1ꢀ-(Azodicarbonyl)Dipiperidine (1)
Triethyl phosphite (3b) (0.16 g, 1 mmol) was added dropwise to a solution of com-
pound 1 (0.25 g, 1 mmol) in dry toluene (30 mL), and the reaction mixture was refluxed
for 4 h. After evaporation of the volatile materials under reduced pressure, the residue was
washed several times with Petroleum ether (b.r. 40 ◦C–60 ◦C) to give product 9b, [diethyl
(piperidin-1-yl)(piperidine-1-caboylimino)methyl phosphate] (9b, C16H31N4O5P).
Crystallized from ethyl acetate, 9b was separated as colorless crystals, yield 60% and
mp 139 ◦C–140 ◦C. IR [v, cm−1, KBr]: 1250 (P O), 1620 (C O), 3308 (NH). 1H NMR
(500 MHz, δ ppm, CDCl3): 1.38 (t, 6H, (O)P(OCH2 CH3)2), 1.57 (m, 12H, CH2 Pip.),
3.30 (m, 8H CH2 Pip.), 3.90 (m, 4H, (O)P(OCH2 CH3)2), 6.80 (s, NH, exchangeable with
3
D2O). 13C NMR (125 MHz, δ ppm, CDCl3): 21.9 (d, Jcp = 6.1 Hz, P O CH2 CH3),
24.8 (s, 4CH2 pip.), 25.5 (s, 2CH2 pip.), 47.3 (CH2 pip.), 51.3 (d, 2Jcp = 8.5 Hz P O CH2),
158.1 (C N), 160.6 (C O). 31P NMR (δ ppm, CDCl3): −0.21. MS m/z (%) 390 [M+]
(60). Anal Calcd for C16H31N4O5P (390.41): C, 49.22; H, 8.00; N, 14.35; P, 7.93. Found:
C, 49.23; H, 8.03; N, 14.53; P, 7.96.
Reaction of Triisopropyl Phosphite (3c) with
1,1ꢀ-(Azodicarbonyl)Dipiperidine (1)
Triisopropyl phosphite (3c) (0.2 g, 1 mmol) was added dropwise to a solution of
compound 1 (0.25 g, 1 mmol) in dry toluene (30 mL), and the reaction mixture was refluxed
for 4 h. After evaporation of the volatile materials under reduced pressure, the residue was
washed several times with petroleum ether (b.r. 40 ◦C–60 ◦C) to give product 9c [diisopropyl
(piperidin-1-yl)(piperidine-1-caboylimino)methyl phosphate] (9c, C18H35N4O5P).
Crystallized from ethyl acetate, 9c was separated as colorless crystals, yield 65% and
mp 143 ◦C–144 ◦C. IR [v, cm−1, KBr]: 1233 (P O), 1628 (C O), 997 (P(O iPr)2), 3314
(NH). 1H NMR (500 MHz, δ ppm, CDCl3): 1.25 (m, 12H, (O)P(O iPr)2), 1.59 (m, 12H,
CH2 Pip.), 3.30 (m, 8H CH2 Pip.), 4.74, 4.35 (2m, 2H, iPr), 6.60 (s, NH, exchangeable
with D2O). 13C NMR (125 MHz, δ ppm, CDCl3): 22.8 (O CH(CH3)2); 23.9 (4CH2,
2
pip.), 24.8 (2CH2, pip.), 45.0 (2CH2, pip.), 47.40 (2CH2, pip.), 51.2 (d, JCP = 7.6 Hz,
P(OCH(CH3)2), 158.1 (C N), 160.5 (C O). 31P NMR (δ ppm, CDCl3): −2.15. MS m/z
(%) 418 [M+] (30). Anal. Calcd. for C18H35N4O5P (418.47): C, 51.66; H, 8.43; N, 13.39;
P, 7.40. Found: C, 51.68; H, 8.47; N, 13.40; P, 7.42.
Reaction of Phosphonium Ylide 4a with
1,1ꢀ-(Azodicarbonyl)Dipiperidine 1
To a mixture of 1.05 g 4a (3 mmol) and 0.25 g (1 mmol) of 1 in dry toluene (40 mL),
a few drops of DMF were added. The reaction mixture was refluxed for 15 h. The volatile
material was evaporated under reduced pressure. The residue was subjected to silica gel

REAGENTS OF 1,1ꢀ-(AZODICARBONYL)DIPIPERIDINE WITH ORGANOPHOSPHORUS 235
column chromatography to give ethyl 1-(3-ethoxy-3-oxo-1-(piperidin-1-yl)prop-1-enyl)-6-
oxo-3-(piperidin-1-yl)-1,6-dihydropyridazine-4-carboxylate (10, C22H32N4O5).
Eluent: petroleum ether/ethyl acetate (90/10, v/v), 10 was separated as colorless
crystals, yield 55% and mp 29 ◦C–30 ◦C (petroleum ether/ethyl acetate). IR [v, cm−1, KBr]:
1624 (C O cyclic), 1707 (C O ester). 1H NMR (500 MHz, δ ppm, CDCl3): 1.22 (2t, 16H,
CH3 ethyl), 1.28 (m, 12H, CH2 Pip.), 3.05 (m, 8H, CH2 Pip.), 4.18 (m, 4H, CH2 ethyl),
5.30 (s, CHCOOC2H5), 7.60 (s, CH cyclic). 13C NMR (125 MHz, δ ppm, CDCl3): 14.3
(CH3), 22.7 (4CH2, pip.), 27.7 (2CH2, pip.), 47.5 (C5H10), 60.2 (CH2 ethyl), 77.2 (C C),
128.7 (C C cyclic), 143.4 (C O cyclic), 150.0 (C N), 163.1 (C O, cyclic), 166.4 (C O
ester); 167.5 (C O). MS m/z (%) 432 [M+] (50). Anal. Calcd for C22H32N4O5 (432.51):
C, 61.09; H, 7.46; N, 12.95. Found: C, 61.12; H, 7.49; N, 12.93. Triphenylphosphine and
triphenylphosphine oxide were also isolated and identified.
Reaction of Phosphonium Ylide 4b with
1,1ꢀ-(Azodicarbonyl)Dipiperidine (1)
To a mixture of 0.76 g of 4b (2 mmol) and 0.25 g (1 mmol) of 1 in dry toluene
(40 mL), a few drops of DMF were added. The reaction mixture was refluxed for 2 h.
The volatile material was evaporated under reduced pressure. The residue was subjected
to silica gel column chromatography to give product 11 [tert-butyl-3, 3ꢁ-(diazene-1,2-
diyl)bis(3-(piperidin-1-yl)acrylate] (11, C24H40N4O4).
Eluent: petroleum ether/ethyl acetate (90/10, v/v), 11 was separated as colorless
crystals, yield 60% and mp 35 ◦C–36 ◦C. IR [v, cm−1, KBr]: 1575 (N N), 1628 (C C),
1710 (C O ester). 1H NMR (500 MHz, δ ppm, CDCl3): 1.24 (m, 18H, 2–C(CH3)3), 1.55
(m, 12H, CH2 Pip.), 3.10 (m, 8H,CH2 Pip.), 5.37, 5.34 (2s, 2H, two = CH). 13C NMR
(125 MHz, δ ppm, CDCl3): 14.2 (CH3)3); 28.3 (4CH2, pip.), 29.7 (2CH2, pip.), 45.0 (2CH2,
pip.), 49.1 (2CH2, pip.), 102.0 (CH), 143.6 (C CH), 163.1 (C O ester). MS m/z (%) 448
[M+] (65). Anal. Calcd for C24H40N4O4 (448.6): C, 64.26; H, 8.99; N, 12.49. Found: C,
64.29; H, 9.27; N, 12.85. Triphenylphosphine oxide was also isolated.
Reaction of Lawesson’s Reagent (5a) with
1,1ꢀ-(Azodicarbonyl)Dipiperidine (1) in Tetrahydrofuran
A mixture of 0.2 g (0.5 mmol) of 5a and 0.2 g (1 mmol) of 1 was gently heated
for 1 h in rigorously dried tetrahydrofuran. The volatile material was evaporated under
reduced pressure. The residue was washed several times with petroleum ether (b.r. 40 ◦C–
◦
60 C) to give product 12a [Nꢁ-(piperidine-1-carbothioyl) piperidine-1-carbohydrazide]
(12a, C12H22N4OS).
Crystallized from n-hexane to ◦give 12a which was separated as colorless crys-
◦
tals, yield 80% and mp 180 C–181 C. IR [v, cm−1, KBr]: 1255 (C S), 1632 (C O),
1
3236 (NHC S), 3434 (NHC O). H NMR (500 MHz, δ ppm, CDCl3): 1.58 (m, 12H,
CH2 Pip.), 3.38 (m, 8H, CH2 Pip.), 6.6 (s, 2H, NH, exchangeable with D2O). 13C NMR
(125 MHz, δ ppm, CDCl3): 24.4 (4CH2, pip.), 25.5 (2CH2, pip.), 47.0 (2CH2, pip.), 49.1
(2CH2, pip.), 158.1 (C O), 182.0 (C S). MS m/z (%): 270 [M+] (75). Anal. Calcd for
C12H22N4OS (270.39): C, 53.30; H, 8.20; N, 20.72; S, 11.86. Found: C, 53.35; H, 8.28; N,
20.75; S, 11.88.

236
L. S. BOULOS ET AL.
Reaction of Lawesson’s Reagent (5a) with
1,1ꢀ-(Azodicarbonyl)Dipiperidine (1) in Acetonitrile
A mixture of 0.4 g (1 mmol) of 5a and 0.25 g (1mmol) of compound 1 was refluxed
in dry acetonitrile for 1 h. The volatile material was evaporated under reduced pressure. The
residue was washed several times with petroleum ether (b.r. 60 ◦C–80 ◦C) to give product
[12b Nꢁ-(piperidine-1-carbothioyl) piperidine-1-carbothiohydrazide] (12b, C12H22N4S2).
◦
◦ Crystallized from ethyl acetate 12b as colorless crystals, yield 85%, mp 167 C–
168 C. IR [v, cm−1, KBr]: 1200 (C S), 3201 (NHC S). H NMR (500 MHz, δ ppm,
1
CDCl3): 1.80 (m, 12H, CH2 Pip.), 3.34 (m, 8H, CH2 Pip.), 7.3 (s, 2H, NH, exchangeable
with D2O). 13C NMR (125 MHz, δ ppm, CDCl3): 24.3 (4CH2, pip.), 25.4 (2CH2, pip.),
44.9 (CH2, pip.), 188.1 (C S). MS m/z (%): 286 [M+] (45). Anal Calcd for C12H22N4S2
(286.46): C, 50.31; H, 7.74; N, 19.56; S, 22.39. Found: C, 50.34; H, 7.76; N, 19.53; S,
22.37.
Nꢀ-(Piperidine-1-Carbothioyl) Piperidine-1-Carbothiohydrazide
(12b, C12H22N4S2)
A mixture of 0.4 g (1 mmol) of 5b and 0.25 g (1 mmol) of compound 1 was stirred
in dry toluene for 1 h at room temperature. The volatile materials were evaporated under
reduced pressure. The residue was washed several times with petroleum ether (b.r. 60 ◦C–
80 ◦C) to give the same product 12b (mixed mp and comparative IR spectra).
Biological Screening
The antibacterial and antifungal activities were carried out in the Microbial Chemistry
Department, National Research Centre, using the diffusion plate method.24–27 The Supple-
mental Materials contain a summary of the results. The obtained results were compared
with reference antibiotics24–27 that were purchased from Egyptian markets.
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