Efficient synthesis of 4-phosphinoyl-4,5,6,7-tetrahydro-2H-indazol-3- ylamines

Article abstract of DOI:10.1016/j.tet.2011.09.093

We described in this paper an efficient synthesis of variously substituted 4-phosphinoyl-4,5,6,7-tetrahydro-2H-indazol-3-ylamines involving nucleophilic addition of hydrazine on β-ketothioamides as key-step.

Full text of DOI:10.1016/j.tet.2011.09.093

Tetrahedron 67 (2011) 9440e9445
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of 4-phosphinoyl-4,5,6,7-tetrahydro-2H-indazol-3-ylamines
,
,
a,
Nourchaine Jelaiel a b, Corinne Comoy a, Brigitte Fernette a, Mohamed Lofti Efrit b , Yves Fort
*
*
a
ꢀ
ꢀ
ꢁ
ꢀ
ꢀ
ꢀ
ꢀ
Laboratoire Structures et Reactivite des Systemes Moleculaires Complexes (SRSMC) UMR CNRS 7565, Faculte des Sciences, Universite Henri Poincare,
ꢁ
F-54506 Vandoeuvre-les-Nancy, France
b
ꢁ
ꢀ ꢀ
ꢀ
ꢀ
Laboratoire de Synthese Organique et Heterocyclique, Departement de chimie, Faculte des Sciences de Tunis, El Manar, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 May 2011
Received in revised form 16 September 2011
Accepted 20 September 2011
Available online 25 September 2011
We described in this paper an efficient synthesis of variously substituted 4-phosphinoyl-4,5,6,7-
tetrahydro-2H-indazol-3-ylamines involving nucleophilic addition of hydrazine on
b-ketothioamides
as key-step.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
3-Phosphorylcyclohexanones
4-Phosphinoyl-4,5,6,7-tetrahydro-2H-
indazol-3-ylamines
b-Phosphorylthioamides
Alternative deacetylation and
debenzoylation
1. Introduction
synthesizing azaheterocyclic derivatives,6,7 we then investigated
the preparation of various phosphinoyltetrahydroindazolyl amines.
Because of their chemical and/or biological significance, nitro-
gen containing heterocycles represent an important and attractive
area of organic chemistry. Among various series of heterocycles, we
focused our attention on indazolyl moieties. As mentioned in lit-
erature, numerous examples of indazolyl heterocycles exhibit bi-
ological properties as well as anticoagulating agent,1 topoisomerase
bacterium II inhibitor,2 or for treatment of hypercholesterol,3 tu-
berculosis,4 . (Fig. 1).
2. Results and discussion
In our knowledge, the most current strategy for the preparation
of tetrahydroindazolyl or pyrazolyl rings consists in a cyclo-
condensation of hydrazines with 1,3-dicarbonyl compounds, un-
saturated ketones, b
-ketoesters or thioamides.8e12 Consequently,
we envisioned to build 1,2-diazole cycle using a such cyclo-
condensation step between N-substituted hydrazines and desired
phosphinoyl b-ketothiamides to success in the preparation of the
expected amino tetrahydroindazoles (Scheme 1).
N
NH
O
N
N
N
H
N
N
O
O
O
S
N
N
N
H
O
H
1
4
II
O
I
R7
N
N
O
S
O
O
Fig. 1. Examples of imidazolyl heterocycles with inhibiting biological properties.
NHR6
NHR6
P(Ph)2
R
R
R
R
Given that phosphonate-containing azaderivatives are of bi-
ological interest,5 it seems interesting to combine indazolyl ring
and phosphinoyl group in the same skeleton to enhance the po-
tential biological properties. In connection with our interest in
P(Ph)2
P(Ph)2
O
4
3
O
2
O
1
Scheme 1. Retrosynthetic analysis for the elaboration of indazolylamines 4.
The expected 3-phosphinoylcyclohexanones 2aeg were pre-
pared in good yields (58e81%) by reaction between cyclohex-2-
enones 1aeg and P-chlorodiphenylphosphine (1 equiv) (Table 1),
at room temperature. A mechanism proposal might envision in-
troduction of phosphinoyl group according to Michael addition of
* Corresponding authors. Tel.: þ0 33 (0)3 83 68 47 81; e-mail addresses: mo-
hamedlotfi.efrit@fst.rnu.tn (M.L. Efrit), Yves.Fort@srsmc.uhp-nancy.fr (Y. Fort).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.093

N. Jelaiel et al. / Tetrahedron 67 (2011) 9440e9445
9441
Table 3
the in situ prepared diphenylphosphinyl acetate, followed by [1,2]
Preparation of the 4-phosphinoyl-4,5,6,7-tetrahydro-2H-indazol-3-ylamines 4aei
oxaphospholane formation and then ring opening by acidic hy-
drolysis to give 2aeg.
O
S
R
N
N
H N-NHR (1.1eq), CHCl ,
rt, 24h
NHR
P(Ph)
NHR
Table 1
Preparation of the 3-phosphinoylcyclohexanones 2aeh and mechanism proposal
P(Ph)
3a-c
O
4a-i
O
O
R
OH
R
O
R
R
R
R
i) Ph PCl (1eq), AcOH, rt
ii) H O, reflux, 2-6h
R
Compound
R6
R7
Yieldsa (%)
R
R
R
R
R
P(Ph)
O
P(Ph)
O
R
R
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
Ph
Ph
H
CH3
CH2CH2CN
74
51b,c
68
76
68
74
60
61
70
R
1a-g
2a-g
H O, H
CH2Ph
CH2Ph
CH2Ph
c-Hex
c-Hex
c-Hex
H
CH3
CH2CH2CN
H
CH3
CH
OH
R
R
O
Ph
Ph
O
R
R
R
R
P
P
R
R
Ph
Ph
+
O
R
R
OAc
CH2CH2CN
a
Isolated yield after silica gel chromatography.
Isomer 4b was obtained in mixture with 5b.
Yield of 4b after purification by silica gel chromatography, 23% of 5b were also
Compound
R1
R2
R3
R4
R5
Yieldsa (%)
b
c
2a
2b
2c
2d
H
H
H
H
H
H
H
H
H
H
CH3
H
H
CH3
H
81
79
76
72
CH3
CH3
H
obtained as by-product.
H
CH3
H3C
H3C
O
S
2e
H
H
H
H
H
58
NHR6
P(Ph)2
2f
Me
H
H
64
R7NH-NH2
then -H2O
R7NH-NH2
then -H2O
O
3a-c
NR7
NR7
NH2
S
R7
H
N
S
N
S
N
2g
Me
H
H
H
62
NHR6
P(Ph)2
NHR6
P(Ph)2
NHR6
P(Ph)2
a
Isolated yield after silica gel chromatography.
O
O
O
In a second step, isothiocyanates were used to introduce the
expected thioamide units (Table 2). The sequence was realized
within THF by action of potassium tert-butoxide (1 equiv) on
3-phosphinoylcyclohexanones 2a,b, for 2 h, followed by the addi-
tion of isothiocyanate (1 equiv). The reaction was performed at
room temperature overnight. The expected 2-phosphinoyl-6-
oxocyclohexanecarbothioamides 3aed were then isolated in good
yields (66e81%).
-H2S
-H2S
R7
R7
N
N
N
N
NHR6
NHR6
P(Ph)2
P(Ph)2
O
O
5a-i
4a-i
Scheme 2. Proposed mechanism for the reaction of 3aec with hydrazine.
Table 2
Preparation of the 2-phosphinoyl-6-oxocyclohexanecarbothioamides 3aed
O
O
S
Surprisingly, in the case of the addition of methylhydrazine on
-ketothioamide 3a, a mixture of isomers 4b and 5b was isolated.
b
i) tBuOK (1eq), THF, rt, 2h
NHR
R
R
R
R
Isomers 4b and 5b were able to be separated by chromatography on
silica gel (respectively, 51 and 23% yields). Structures of 4b and 5b
were determined after a detailed two-dimensional NMR study (see
Supplementary data). Potential explanations for these results in-
volve electronic considerations. General behavior could be
explained by a nucleophilic addition of the most reactive nitrogen
atom present in hydrazine reagents. Due to the overall electron-
withdrawing effect of the cyano group, only primary amino group
of the propionitrileehydrazine could react as nucleophile center
conducting to the formation of derivatives 4c, 4f, and 4i. In contrast
with methylhydrazine, the methyl group slightly increased the
electron-density on the central nitrogen atom, and consequently its
nucleophile character compared to the terminal one. However,
starting from thioamides 3b and c, only isomers 4e and 4h were
afforded in 68 and 61% yields, respectively, no trace of isomers 5e
and 5h was detected, electronic effect induced by the methyl group
did not affect the reactivity. On the other hand, starting from
N-phenylthioamide 3a, mixture of isomers 4b and 5b was obtained,
nucleophile character of methylamino group was displayed in this
case. Considering the proposed mechanism (Scheme 3), the for-
mation of the indazolyl ring may be realized by nucleophilic
ii) R N=C=S (1eq), THF, rt, 16h
iii) Hydrolysis
P(Ph)
O
P(Ph)
R
R
O
2a-b
3a-d
Compound
R2
R4
R5
R6
Yieldsa (%)
3a
3b
3c
3d
H
H
H
H
H
Ph
81
77
72
66
H
H
CH2Ph
c-Hex
Ph
H
H
CH3
CH3
CH3
a
Isolated yield after silica gel chromatography.
The following stage consisted in adding hydrazines (1.1 equiv)
-ketothioamides 3aed to lead to ring closure of the targeted
4-phosphinoyl-4,5,6,7-tetrahydro-2H-indazol-3-ylamines
on
b
4aei
(Table 3).
By considering the possible mechanism (Scheme 2), such a cyc-
lisation can lead to the formation of the two isomers 4 and 5,
according to the nucleophilic attack of the primary or the secondary
amino site in hydrazine.
In a general way, it is to be noted that only isomers 4a and 4cei
were generated in the reaction mixture in good yields (60e76%).

9442
N. Jelaiel et al. / Tetrahedron 67 (2011) 9440e9445
addition of the amino group of [I] on thioamide substituent; as the
result various intermediates [I-5b] to [III-5b] might be envisioned.
[III-5b], which presents a strong density of charge on nitrogen atom
of the amine, might be favored only in the presence of phenyl as an
electronic stabilizing effect substituent. Subsequent H2S elimina-
tion allowed the formation of the compound 5b.
a cleavage of the carbonyl moieties occurred easily and led to the
interesting phosphinoylthioamides 9b, c, and e in 77, 72, and 76%
yields, respectively.
This deacetylation (or debenzoylation for 7a) sequence, using
hydrazine as reagent and at room temperature as condition, turns
out an interesting alternative leading to an efficient and versatile
preparation of
substrates.
b-phosphorylthioamides from easily accessible
H3C
N
O
S
N
NHPh
3. Conclusion
NHPh
CH3NH-NH2
We succeeded in the synthesis of various 4-phosphinoyl-
4,5,6,7-tetrahydro-2H-indazol-3-ylamines with moderate to good
over yields (33e47%); an extension of this reaction sequence can be
envisioned to allow the preparation of compounds bearing ap-
propriate substituents, which can confer a potential biological ac-
tivity to these heterocycles.
P(Ph)2
P(Ph)2
3a
5b
O
O
CH3NH-NH2
then -H2O
- H2S
H
S+
NH2
H3C
H
H3C
N
N
S
N
H
-
N
4. Experimental section
4.1. General
NHPh
Ph
P(Ph)2
P(Ph)2
O
[III-5b]
[I]
O
1H, 13C, and 31P NMR spectra were recorded at 400 or 250 or 200,
100 or 63 or 50 and 300 Mhz, respectively, with CDCl3 as solvent
and TMS (for 1H NMR) or H3PO4 31P NMR) as internal standards.
(
HRMS spectra were recorded on a BRUKER micrOTOF-Q spec-
trometer. MS were recorded on an SHIMADZU GCMS-QP2010
spectrometer. Melting temperatures are uncorrected.
H
H
H
N
H3C
H3C
N
+
-
N
N
S
SH
N
H
H
N
Cyclohex-2-enones 1aeg were commercially available or pre-
Ph
P(Ph)2
Ph
P(Ph)2
pared according to the procedure described in literature.16e18
[I-5b]
[II-5b]
O
O
4.2. General procedure for the preparation of 3-
(diphenylphosphinoyl)cyclohexanones (2aeh)
Scheme 3. Proposed mechanism for the formation of 4-phosphinoyl-4,5,6,7-
tetrahydro-1H-indazol-3-ylamine 5b.
In the second part of our work, we tried to apply the strategy
To a solution of cyclohexenones 1aeg (5.0 mmol, 1.0 equiv) in
glacial acetic acid (50 mL) was added dropwise P-chlor-
odiphenylphosphine (5.0 mmol, 1.0 equiv) at room temperature,
under nitrogen atmosphere. After addition of H2O (1.5 mL), the
reactional mixture was refluxed during a reaction time (tR). After
extraction with chloroforme (CHCl3), the combined organic layers
were washed with an aqueous saturated NaCl solution, then with
an aqueous saturated NaHCO3 solution. After drying (MgSO4), fil-
tration, and solvent evaporation, the crude product was purified by
recrystallisation in diethyl ether (Et2O).
described above for 4aei to reach pyrazoles 8 starting from acyclic
b
-ketophosphonates 6a,b13e16 (Table 4). The expected ketothioa-
mides 7aed were easily prepared by addition of potassium enolates
derived from 6a,b on phenyl-, benzyl- or c-hexylisothiocyanates
(77e87% yields). Nevertheless, concerning the second step, in spite
of numerous realized experiments, no trace of the expected aza-
heterocyclic derivatives 8 was observed. Due to the nearness of
phosphoryl unit in
a-position as electron-withdrawing group,
Table 4
Aliphatic series: preparation of compounds 7aed and 9b,c,e
4.2.1. 3-(Diphenylphosphinoyl)cyclohexanone (2a). Compound 2a
tR: 2 h; solid; yield¼81%; mp 144e146 ꢀC; 1H NMR dH (ppm)
1.70e2.50 (m, 9H, CH, CH2), 7.40e7.90 (m, 10H, CHar); 13C NMR dC
(ppm) 22.6, 25.5 (JCP 15.9 Hz), 37.1 (JCP 75.7 Hz), 38.6, 40.3,
128.0e132.0, 208.6 (JCP 14.6 Hz); 31P NMR dP (ppm) 31.46; HRMS
calcd for C18H19NaO2P (MþNa)þ: 321.1015; found: 321.1014.
R
N
R
N
O
O
X P
O
P
O
X P
i) tBuOK (1eq),
R
X
X
HN-NHR (1.1eq),
rt, 24h
O
THF, rt, 2h
NHR
8
R
ii) R N=C=S (1eq), R HN
S
THF, rt, 16h
O
P
S
6a-b
7a-d
X
X
NHR
9b,c,e
4.2.2. 3-(Diphenylphosphinoyl)-3,5,5-trimethylcyclo hexanone (2b).
Compound 2b tR: 5 h; solid; yield¼79%; mp 116e118 ꢀC; 1H NMR dH
(ppm) 1.20e3.10 (m, 6H, CH2), 1.01 (s, 3H, CH3), 1.04 (s, 3H, CH3),
1.42 (d, 3H, 3JPH 17.9 Hz, CH3), 7.20e8.10 (m, 10H, CHar); 13C NMR dC
(ppm) 22.1, 28.8, 33.9, 37.0 (JCP 13.7 Hz), 41.3, 42.1 (JCP 68.9 Hz),
45.0, 53.5, 128.0e133.0, 210.0; 31P NMR dP (ppm) 36.74.
Compound
X
R1
R2
Yieldsa (%)
7a
7b
7c
7d
Ph
Ph
Ph
Ph
CH2Ph
c-Hex
87
86
77
81
EtO
EtO
EtO
CH3
CH3
CH3
9b
9c
9e
Ph
EtO
EtO
Ph
CH2Ph
Ph
77
72
76
4.2.3. 3-(Diphenylphosphinoyl)-3-methylcyclohexanone
(2c). Compound 2c tR: 2 h; solid; yield¼76%; mp 131e133 ꢀC; 1H
3
NMR dH (ppm) 1.32 (s, 3H, JPH 18.0 Hz, CH3), 1.00e2.90 (m, 8H,
a
Isolated yield after silica gel chromatography.
CH2), 7.30e7.80 (m, 10H, CHar); 13C NMR dC (ppm) 25.1 (JCP 13.9 Hz),

N. Jelaiel et al. / Tetrahedron 67 (2011) 9440e9445
9443
27.8, 29.6, 32.5 (JCP 69.6 Hz), 44.2, 44.9, 127.0e135.0, 211.5 (JCP
13.2 Hz); 31P NMR dP (ppm) 31.56.
4.61e4.66 (m, 1H, CHC(S)), 7.03e7.78 (m, 15H, CHar), 9.67 (s, 1H,
NH); 13C NMR dC (ppm) 21.9 (JCP 12.8 Hz), 22.2, 38.7, 39.3 (JCP
56.5 Hz), 39.6, 60.4, 127.5e135.7, 197.9 (JCP 3.0 Hz), 205.9 (JCP
7.5 Hz); 31P NMR dP (ppm) 35.1; HRMS calcd for C26H26NNaO2PS
(MþNa)þ: 470.1314; found: 470.1337.
4.2.4. 3-(Diphenylphosphinoyl)-5-methylcyclohexanone
(2d). Mixture of diastereoisomers: tR: 3 h; solid; yield¼72%; mp
3
104e106C; 1H NMR dH (ppm) 1.02 (d, 3H, JHH 6.4 Hz, CH3),
1.10e2.80 (m, 8H, CH, CH2), 7.20e8.00 (m, 10H, CHar); 13C NMR dC
(ppm) 21.7, 21.7, 26.5, 29.8 (JCP 13.2 Hz), 37.4 (JCP 75.6 Hz), 41.9, 42.1,
128.0e132.0, 199.2 and 208.2 (JCP 11.7 Hz); 31P NMR dP (ppm) 32.13
(63%) and 34.47 (38%).
4.3.3. 2-(Diphenylphosphinoyl)-6-oxocyclohexane carbothioic acid
cyclohexylamide (3c). Solid; yield¼72%; mp 213e215 ꢀC; 1H NMR
dH (ppm) 1.29e1.77 (m, 12H, CH2), 2.02e2.44 (m, 4H, CH2),
3.63e3.65 (m, 1H, CHN), 3.81e3.89 (m, 1H, CHP(O)), 4.06e4.11 (m,
1H, CHC(S)), 7.14e7.61 (m, 10H, CHar), 8.93 (s, 1H, NH); 13C NMR dC
(ppm) 21.7, 22.1, 23.3, 24.6, 30.6, 37.7 (JCP 59.6 Hz), 41.0, 54.7, 60.4,
128.1e132.4, 195.4 (JCP 4.5 Hz), 205.6 (JCP 13.3 Hz); 31P NMR dP
(ppm) 35.4; HRMS calcd for C25H31NO2PS (MþH)þ: 440.1808;
found: 440.1812.
4.2.5. 3-(Diphenylphosphinoyl)-4-isopropylcyclo
hexanone
(2e). Mixture of diastereoisomers: tR: 6 h; solid; yield¼58%; mp
3
178e180 ꢀC; 1H NMR dH (ppm) 0.44 (d, 3H, JHH 6.7 Hz, CH3), 0.75
(d, 3H, 3JHH 6.7 Hz, CH3), 1.40e2.80 (m, 9H, CH, CH2), 7.20e8.00 (m,
10H, CHar); 13C NMR dC (ppm) 15.9,16.3, 28.8, 32.4 (JCP 15.4 Hz), 33.2
(JCP 73.1 Hz), 42.3, 43.6, 44.2, 129.0e134.0, 210.3 (JCP 11.2 Hz); 31P
NMR dP (ppm) 33.60 (51%) and 31.92 (49%).
4 . 3 . 4 . 2 - ( D i p h e n y l p h o s p h i n o y l ) - 2 , 4 , 4 - t r i m e t h y l - 6 -
oxocyclohexanecarbothioic
acid
phenylamide
(3d). Solid;
yield¼66%; mp 198e200 ꢀC; 1H NMR dH (ppm) 1.29e3.14 (m, 4H,
3
4.2.6. (5R)-3-(Diphenylphosphinoyl)-5-isopropenyl-2-
methylcyclohexanone (2f). Mixture of diastereoisomers: tR: 6 h;
solid; yield¼64%; mp 167e169 ꢀC; 1H NMR dH (ppm) 0.97 (m, 3H,
3JHH 6.6 Hz, CH3), 1.05 (s, 3H, CH3), 1.20e3.10 (m, 7H, CH, CH2),
4.76e4.79 (m, 2H, CH2]C), 7.30e8.00 (m, 10H, CHar); 13C NMR dC
(ppm) 15.6 and 16.3 and 17.9 and 14.0, 19.8, 26.8, 35.2, 39.2 (JCP
71.9 Hz), 40.4, 44.4, 128.0e135.0, 199.6 (JCP 9.2 Hz); 31P NMR dP
(ppm) 31.45 (66%) and 30.15 (19%) and 34.79 (8%) and 33.39 (7%).
CH2), 1.11 (s, 3H, CH3), 1.16 (s, 3H, CH3), 1.49 (d, 3H, JPH 18.0 Hz,
CH3), 4.31e4.35 (m, 1H, CHC(S)), 7.29e7.96 (m, 15H, CHar), 10.28 (s,
1H, NH); 13C NMR dC (ppm) 22.1, 27.2, 34.0, 37.1 (JCP 13.6 Hz), 41.2,
42.1 (JCP 68.7 Hz), 45.1, 65.8, 128.4e132.6, 194.2 (JCP 3.0 Hz), 210.4
(JCP 13.6 Hz); 31P NMR dP (ppm) 38.7.
4.4. General procedure for the preparation of 4-phosphinoyl-
4,5,6,7-tetrahydro-2H-indazol-3-ylamines (4aei)
4.2.7. (5S)-3-(Diphenylphosphinoyl)-5-isopropenyl-2-
methylcyclohexanone (2g). Mixture of diastereoisomers: tR: 6 h;
solid; yield¼62%; mp 167e168 ꢀC; 1H NMR dH (ppm) 1.00 (m, 3H,
3JHH 6.9 Hz, CH3), 1.08 (s, 3H, CH3), 1.20e3.20 (m, 7H, CH, CH2),
4.78e4.81 (m, 2H, CH2]C), 7.50e8.00 (m, 10H, CHar); 13C NMR dC
(ppm) 15.7 and 12.5, 20.3, 26.8, 35.2, 39.2 (JCP 71.7 Hz), 40.5, 40.6,
120.0e135.0, 199.5 and 210.1 (JCP 9.3 Hz); 31P NMR dP (ppm) 31.44
(41%), 33.43 (26%), 34.76 (23%), 31.53 (10%).
Hydrazine (0.0011 mol, 1.1 equiv) was added to a solution of b-
ketothioamides 3aec (0.001 mol, 1.0 equiv) in CHCl3. After 24 h of
stirring at room temperature, the residue was dried (MgSO4), sol-
vent was evaporated and the crude product was purified by column
chromatography on silica gel (0.063e0.200 mm, eluent: 90/10
Et2O/EtOH).
4.4.1. [4-(Diphenylphosphinoyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]
phenylamine (4a). Solid; yield¼74%; mp 216e218 ꢀC; 1H NMR dH
(ppm) 1.66e1.73 (m, 2H, CH2), 1.86e1.98 (m, 2H, CH2), 2.26e2.40
(m, 2H, CH2), 3.49e3.55 (m, 1H, CHP(O)), 6.59 (s, 1H, HNeN),
7.07e7.70 (m, 15H, CHar), 7.74 (s, 1H, NHPh); 13C NMR dC (ppm) 24.1,
25.6, 26.3, 34.8 (JCP 78.1 Hz), 99.8 (JCP 6.8 Hz), 128.4e132.1, 144.8;
31P NMR dP (ppm) 39.4.
4.3. General procedure for the preparation of 2-phosphinoyl-
6-oxocyclohexanecarbothioamides (3aed)
To a solution of potassium tert-butoxide (0.01 mol, 1.0 equiv) in
anhydrous THF (10 mL) was added dropwise 3-phosphinoylc-
yclohexanones 2 (0.01 mol, 1.0 equiv) in solution in anhydrous
THF (20 mL) at room temperature, under nitrogen atmosphere.
After 2 h of stirring, isothiocyanate (0.01 mol, 1.0 equiv) in solution
in anhydrous THF (5 mL) was added to the reactional mixture. After
16 h of stirring at room temperature, the hydrolysis was performed
with an aqueous saturated NH4Cl solution. The aqueous layer was
then extracted twice with CHCl3 (2ꢁ50 mL). After drying (MgSO4),
filtration and solvent evaporation, the crude product was purified
by column chromatography on silica gel (0.063e0.200 mm, eluent:
95/5 Et2O/EtOH).
4.4.2. [4-(Diphenylphosphinoyl)-2-methyl-4,5,6,7-tetrahydro-2H-in-
dazol-3-yl]phenylamine (4b). Solid; yield¼51%; mp 223e225 ꢀC; 1H
NMR dH (ppm) 1.50e1.79 (m, 2H, CH2), 1.85e2.00 (m, 2H, CH2),
2.30e2.55 (m, 2H, CH2), 3.65 (s, 3H, CH3), 3.78e3.90 (m, 1H,
CHP(O)), 6.70e7.87 (m, 15H, CHar), 8.62 (s, 1H, NHPh); 13C NMR dC
(ppm) 21.5, 21.6, 25.1, 35.0, 35.8 (JCP 64.1 Hz), 97.3 (JCP 5.3 Hz),
116.2e144.1, 149.2; 31P NMR dP (ppm) 38.6; HRMS calcd for
C26H26N3NaOP (MþNa)þ: 450.1706; found: 450.1703.
4.4.3. [4-(Diphenylphosphinoyl)-1-methyl-4,5,6,7-tetrahydro-1H-in-
dazol-3-yl]phenylamine (5b). Solid; yield¼23%; mp 222e224 ꢀC; 1H
NMR dH (ppm) 1.41e1.57 (m, 2H, CH2), 1.78e2.04 (m, 2H, CH2),
2.30e2.65 (m, 2H, CH2), 3.63 (s, 3H, CH3), 3.71e3.85 (m, 1H,
CHP(O)), 6.52e7.86 (m, 15H, CHar), 8.08 (s, 1H, NHPh); 13C NMR dC
(ppm) 20.2, 22.2, 23.3, 31.5 (JCP 48.3 Hz), 34.7, 99.9 (JCP 6.8 Hz),
113.9e144.0, 147.8; 31P NMR dP (ppm) 40.1; HRMS calcd for
C26H27N3OP (MþH)þ: 428.1886; found: 428.1896.
4.3.1. 2-(Diphenylphosphinoyl)-6-oxocyclohexane carbothioic acid
phenylamide (3a). Solid; yield¼81%; mp 202e204 ꢀC; 1H NMR dH
(ppm) 1.87e1.95 (m, 2H, CH2), 2.18e2.25 (m, 2H, CH2), 2.62e2.69
(m, 2H, CH2), 4.22e4.29 (m,1H, CHP(O)), 4.53e4.61 (m,1H, CHC(S)),
7.02e7.83 (m, 15H, CHar), 11.58 (s, 1H, NH); 13C NMR dC (ppm) 21.9
(JCP 13.6 Hz), 22.5, 38.8, 39.6 (JCP 68.6 Hz), 61.8, 123.0e139.0, 196.8
(JCP 2.3 Hz), 205.9 (JCP 8.3 Hz); 31P NMR dP (ppm) 35.0; HRMS calcd
for C25H25NO2PS (MþH)þ: 434.1338; found: 434.1366.
4.4.4. 3-[4-(Diphenylphosphinoyl)-3-phenylamino-4,5,6,7-
tetrahydro-2H-indazol-2-yl]propionitrile (4c). Solid; yield¼68%; mp
228e230 ꢀC; 1H NMR dH (ppm) 1.45e1.49 (m, 2H, CH2), 1.81e1.93
(m, 2H, CH2), 2.23e2.52 (m, 2H, CH2), 2.76e2.88 (m, 2H, CH2),
3.67e3.76 (m, 1H, CHP(O)), 4.03e4.09 (m, 2H, CH2CN), 6.51e7.74
4.3.2. 2-(Diphenylphosphinoyl)-6-oxocyclohexane carbothioic acid
benzylamide (3b). Solid; yield¼77%; mp 195e197 ꢀC; 1H NMR dH
(ppm) 1.71e1.77 (m, 2H, CH2), 1.92e1.96 (m, 2H, CH2), 2.14e2.22
(m, 2H, CH2), 3.92e3.99 (m, 1H, CHP(O)), 4.15e4.19 (m, 2H, CH2N),

9444
N. Jelaiel et al. / Tetrahedron 67 (2011) 9440e9445
(m, 15H, CHar), 7.89 (s, 1H, NHPh); 13C NMR dC (ppm) 15.2, 18.1, 20.9,
24.1, 33.1 (JCP 70.1 Hz), 43.6, 102.0 (JCP 6.8 Hz), 114.7, 119.9e144.9,
150.5; 31P NMR dP (ppm) 40.3.
at room temperature, under nitrogen atmosphere. After 2 h of
stirring, isothiocyanate (0.01 mol, 1.0 equiv) in solution in anhy-
drous THF (5 mL) was added to the reactional mixture. After 16 h of
stirring at room temperature, the hydrolysis was performed with
an aqueous saturated NH4Cl solution. The aqueous layer was then
extracted twice with CHCl3 (2 x 50 mL). After drying (MgSO4), fil-
tration and solvent evaporation, the crude product was purified by
column chromatography on silica gel (0.063e0.200 mm, eluent:
98/2 Et2O/EtOH).
4.4.5. Benzyl-[4-(diphenylphosphinoyl)-4,5,6,7,-tetrahydro-2H-in-
dazol-3-yl]amine (4d). Solid; yield¼76%; mp 219e211 ꢀC; 1H NMR
dH (ppm) 1.33e1.41 (m, 2H, CH2), 1.61e1.68 (m, 2H, CH2), 2.43e2.49
(m, 2H, CH2), 3.60e3.97 (m, 3H, CHP(O), CH2N), 5.13 (s, 1H, HNeN),
6.33 (s,1H, NHBn), 7.25e7.52 (m,15H, CHar); 13C NMR dC (ppm) 21.0,
23.5, 25.1, 34.1 (JCP 115.5 Hz), 52.8, 100.4 (JCP 6.9 Hz), 128.0e143.8,
146.8; 31P NMR dP (ppm) 39.6; HRMS calcd for C26H27N3OP
(MþH)þ: 428.1886; found: 428.1876.
4.5.1. 2-(Diphenylphosphinoyl)-3-oxo-3, N-diphenyl thiopropionamide
(7a). Solid; yield¼87%; mp 184e186 ꢀC; 1H NMR dH (ppm) 6.45 (d,
1H, 2JPH 21.0 Hz, CHP(O)), 7.22e8.02 (m, 20H, CHar),11.35 (s, 1H, NH);
13C NMR dC (ppm) 67.3 (JCP 44.5 Hz), 125.1e139.0, 186.4 (JCP 6.0 Hz),
190.6 (JCP 4.5 Hz); 31P NMR dP (ppm) 28.3; HRMS calcd for
C27H22NNaO2PS (MþNa)þ: 478.1001; found: 478.0994.
4.4.6. Benzyl-[4-(diphenylphosphinoyl)-2-methyl-4,5,6,7-
tetrahydro-2H-indazol-3-yl]amine (4e). Solid; yield¼68%; mp
227e229 ꢀC; 1H NMR dH (ppm) 1.26e1.39 (m, 2H, CH2), 1.51e1.64
(m, 2H, CH2), 2.36e2.43 (m, 2H, CH2), 3.66 (s, 3H, CH3), 3.70e4.00
(m, 3H, CHP(O), CH2N), 6.13 (s, 1H, NHBn), 7.15e7.42 (m, 15H, CHar);
13C NMR dC (ppm) 21.6, 23.5, 24.7, 34.2, 35.1 (JCP 145.5 Hz), 52.7,
100.0 (JCP 6.8 Hz), 127.0e145.8, 147.8; 31P NMR dP (ppm) 39.1; HRMS
calcd for C27H29N3OP (MþH)þ: 442.2043; found: 442.2039.
4.5.2. (2-Oxo-1-phenylthiocarbamoylpropyl) phosphonic acid diethyl
ester (7b). Solid; yield¼86%; mp 170e172 ꢀC; 1H NMR dH (ppm)
3
1.35 (t, 6H, JHH 6.0 Hz, CH3CH2O), 2.48 (s, 3H, CH3), 4.22 (qp, 4H,
3
2
3JHH 6.0 Hz, JPH 6.0 Hz, CH2O), 5.24 (d, 1H, JPH 24.0 Hz, CHP(O)),
7.23e7.42 (m, 5H, CHar), 10.65 (s, 1H, NH); 13C NMR dC (ppm) 16.2,
32.2, 63.3, 71.6 (JCP 113.9 Hz), 123.0e139.1, 186.0 (JCP 8.3 Hz), 198.9
(JCP 5.3 Hz); 31P NMR dP (ppm) 14.1.
4.4.7. 3-[3-Benzylamino-4-(diphenylphosphinoyl)-4,5,6,7-
tetrahydro-2H-indazol-2-yl]propionitrile (4f). Solid; yield¼74%; mp
233e235 ꢀC; 1H NMR dH (ppm) 1.29e1.38 (m, 2H, CH2), 1.50e1.59
(m, 2H, CH2), 2.34e2.41 (m, 2H, CH2), 2.75e2.81 (m, 2H, CH2),
3.72e4.00 (m, 3H, CHP(O), CH2N), 4.06e4.10 (m, 2H, CH2CN), 7.01
(s, 1H, NHBn), 7.15e7.52 (m, 15H, CHar); 13C NMR dC (ppm) 18.1, 21.6,
22.7, 24.3, 35.1 (JCP 90.5 Hz), 42.9, 52.7, 102.1 (JCP 6.3 Hz),
128.3e144.6, 148.9; 31P NMR dP (ppm) 39.8; HRMS calcd for
C29H29N4NaOP (MþNa)þ: 503.1971; found: 503.1986.
4.5.3. 1-(Benzylthiocarbamoyl-2-oxopropyl) phosphonic acid diethyl
ester (7c). Solid; yield¼77%; mp 175e177 ꢀC; 1H NMR dH (ppm)
3
1.28 (t, 6H, JHH 6.0 Hz, CH3CH2O), 2.43 (s, 3H, CH3), 4.17 (qp, 4H,
3JHH 6.0 Hz, 3JPH 6.0 Hz, CH2O), 4.73e4.79 (m, 2H, CH2N), 5.20 (d,1H,
2JPH 24.0 Hz, CHP(O)), 7.33e7.36 (m, 5H, CHar), 9.29 (s, 1H, NH); 13
C
NMR dC (ppm) 16.1, 32.2, 50.7, 62.2, 68.4 (JCP 86.7 Hz), 127.6e135.8,
188.0, 198.4 (JCP 5.3 Hz); 31P NMR dP (ppm) 14.4.
4.4.8. Cyclohexyl-[4-(diphenylphosphinoyl)-4,5,6,7-tetrahydro-2H-
indazol-3-yl]amine (4g). Solid; yield¼60%; mp 218e220 ꢀC; 1H NMR
dH (ppm) 1.09e1.25 (m, 6H, CH2), 1.45e1.88 (m, 8H, CH2), 2.22e2.43
(m, 2H, CH2), 3.18e3.26 (m, 1H, CHN), 3.58e3.67 (m, 1H, CHP(O)),
4.90 (s, 1H, HNeN), 6.10 (s, 1H, NHecHex), 7.34e7.72 (m, 10H, CHar);
13C NMR dC (ppm) 18.4, 20.9, 21.8, 24.9, 25.4, 32.2 (JCP 113.1 Hz), 35.3,
51.9, 94.1 (JCP 5.9 Hz), 128.3e132.1, 152.2; 31P NMR dP (ppm) 37.3;
HRMS calcd for C25H31N3OP (MþH)þ: 420.2199; found: 420.2197.
4.5.4. 1-(Cyclohexylthiocarbamoyl-2-oxopropyl) phosphonic acid di-
ethyl ester (7d). Solid; yield¼81%; mp 172e174 ꢀC; 1H NMR dH
3
(ppm) 1.37 (t, 6H, JHH 6.0 Hz, CH3CH2O), 1.60e2.01 (m, 10H, CH2),
3
3
2.43 (s, 3H, CH3), 4.17 (qp, 4H, JHH 6.0 Hz, JPH 6.0 Hz, CH2O),
4.30e4.36 (m,1H, CHN), 5.11 (d,1H, 2JPH 24.0 Hz, CHP(O)), 9.02 (s,1H,
NH); 13C NMR dC (ppm) 16.2, 24.1, 25.4, 30.7, 32.1, 54.7, 63.7, 69.0 (JCP
114.3 Hz),185.9 (JCP 7.5 Hz),198.4(JCP 5.3 Hz); 31PNMR dP (ppm) 14.2.
4.4.9. Cyclohexyl-[4-(diphenylphosphinoyl)-2-methyl-4,5,6,7-
tetrahydro-2H-indazol-3-yl]amine (4h). Solid; yield¼61%; mp
220e222 ꢀC; 1H NMR dH (ppm) 1.09e1.28 (m, 6H, CH2), 1.42e1.78
(m, 8H, CH2), 2.26e2.39 (m, 2H, CH2), 3.23e3.31 (m, 1H, CHN), 3.56
(s, 3H, CH3), 3.53e3.62 (m, 1H, CHP(O)), 6.23 (s, 1H, NHecHex),
7.31e7.70 (m, 10H, CHar); 13C NMR dC (ppm) 18.9, 20.2, 21.8, 23.9,
25.7, 32.8 (JCP 113.1 Hz), 34.7, 35.3, 52.6, 97.4 (JCP 7.0 Hz),
127.3e135.4, 151.2; 31P NMR dP (ppm) 38.3; HRMS calcd for
C26H33N3OP (MþH)þ: 434.2356; found: 434.2347.
4.6. General procedure for the preparation of the derivatives
9b, c and e
Hydrazine (0.0011 mol, 1.1 equiv) was added to a solution of b-
ketothioamides 7aed (0.001 mol,1.0 equiv) in ethanol. After 24 h of
stirring at room temperature, the residue was dried (MgSO4), sol-
vent was evaporated and the crude product was purified by column
chromatography on silica gel (0.063e0.200 mm, eluent: AcOEt).
4.6.1. 2-(Diphenylphosphinoyl)-N-phenylthio acetamide (9b). Gummy
liquid; yield¼77%; 1H NMR dH (ppm) 4.09 (d, 2H, 2JPH 12.0 Hz, CH2P),
7.12e7.81 (m, 15H, CHar), 11.47 (s, 1H, NH); 13C NMR dC (ppm) 49.2 (JCP
55.0 Hz), 123.2e139.2, 191.4 (JCP 7.4 Hz); 31P NMR dP (ppm) 33.1;
HRMS calcd for C20H18NNaOPS (MþNa)þ: 374.0739; found: 374.0742.
4.4.10. 3-[3-Cyclohexylamino-4-(diphenylphosphinoyl)-4,5,6,7-
tetrahydro-2H-indazol-2-yl] propionitrile (4i). Solid; yield¼70%; mp
224e226 ꢀC; 1H NMR dH (ppm) 1.14e1.28 (m, 6H, CH2),1.39e1.93 (m,
8H, CH2), 2.30e2.41 (m, 2H, CH2), 2.79e2.85 (m, 2H, CH2), 3.22e3.31
(m,1H, CHN), 3.58e3.69 (m,1H, CHP(O)), 4.07e4.12 (m, 2H, CH2CN),
6.80 (s, 1H, NHecHex), 7.24e7.78 (m, 10H, CHar); 13C NMR dC (ppm)
16.9, 18.4, 20.7, 21.8, 24.7, 26.0, 32.2 (JCP 103.2 Hz), 35.7, 44.6, 51.8,
98.3 (JCP 7.2 Hz), 127.3e137.1, 150.4; 31P NMR dP (ppm) 37.3.
4.6.2. (Benzylthiocarbamoylmethyl)phosphonic acid diethyl ester
(9c). Gummy liquid; yield¼72%; 1H NMR dH (ppm) 1.18 (t, 6H, 3JHH
6.0 Hz, CH3CH2O), 3.36 (d, 2H, 2JPH 24.0 Hz, CH2P), 3.96 (qp, 4H, 3JHH
3
6.0 Hz, JPH 6.0 Hz, CH2O), 4.72e4.74 (m, 2H, CH2N), 7.17e7.27 (m,
4.5. General procedure for the preparation of the derivatives
7aed
5H, CHar), 9.39 (s,1H, NH); 13C NMR dC (ppm) 15.3, 43.0 (JCP 126.7 Hz),
49.3, 62.0, 124.4e135.2, 191.3 (JCP 6.0 Hz); 31P NMR dP (ppm) 21.1.
To a solution of potassium tert-butoxide (0.01 mol, 1.0 equiv) in
4.6.3. Phenylthiocarbamoylmethylphosphonic acid diethyl ester
(9e). Gummy liquid; yield¼76%; 1H NMR dH (ppm) 1.34 (t, 6H, 3JHH
6.0 Hz, CH3CH2O), 3.65 (d, 2H, 2JPH 24.0 Hz, CH2P), 4.19 (qp, 4H, 3JHH
anhydrous THF (10 mL) was added dropwise
b-phosphorylketones
6a,b13e16 (0.01 mol, 1.0 equiv) in solution in anhydrous THF (20 mL)

N. Jelaiel et al. / Tetrahedron 67 (2011) 9440e9445
9445
6.0 Hz, 3JPH 6.0 Hz, CH2O), 7.11e7.72 (m, 5H, CHar), 11.09 (s, 1H, NH);
13C NMR dC (ppm) 16.3, 46.3 (JCP 126.7 Hz), 63.4, 122.8e139.2, 190.5
(JCP 6.8 Hz); 31P NMR dP (ppm) 21.2.
4. Guo, S.; Song, Y.; Huang, Q.; Yuan, H.; Wan, B.; Wang, Y.; He, R.; Beconi,
M. G.; Franzblau, S. G.; Kozikowski, A. P. J. Med. Chem. 2010, 53,
649e659.
5. Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev. 2004, 104, 6177e6215.
6. See for examples: (a) Jelaiel, N.; Said, N.; Touil, S.; Efrit, M. L. Phosphorus, Sulfur
Silicon Relat. Elem. 2010, 185, 2382e2392; (b) Besbes, N.; Jellali, H.; Pale, P.;
Srasra, E.; Efrit, M. L. C. R. Chimie 2010, 13, 358e364; (c) Ouerfelli, I.; Gatri, R.;
Efrit, M. L.; Dua, N.; Perruchon, J.; Golhen, S.; Toupet, L.; Fillaut, J. L. J. Orga-
nomet. Chem. 2011, 696, 670e675; (d) Zarguil, A.; Boukhris, S.; El Efrit, M. L.;
Souizi, A.; Essassi, E. M. Tetrahedron Lett. 2008, 49, 5883e5886.
7. See for examples: (a) Comoy, C.; Banaszak, E.; Fort, Y. Tetrahedron 2006, 62,
6036e6041; (b) Banaszak, E.; Comoy, C.; Fort, Y. Tetrahedron Lett. 2006, 47,
6235e6238; (c) Chartoire, A.; Comoy, C.; Fort, Y. Tetrahedron 2008, 64,
10867e10873; (d) Chartoire, A.; Comoy, C.; Fort, Y. Org. Biomol. Chem. 2011, 9,
1839e1845.
Acknowledgements
ꢀ
We gratefully acknowledge financial support from Faculte des
ꢀ
Sciences, Universite de Tunis. We thank Sandrine Adach for re-
ꢀ
cording mass spectra (UMR CNRS SRSMC e Universite Henri
ꢀ
Poincare, Nancy I).
Supplementary data
8. (a) The Chemistry of Heterocycles: Structures, Reactions and Applications; Theo-
phil Eicher, T., Hauptmann, S., Eds.; Wiley: 2003; (b) Claramunt, R. M.; Lopez,
C.; Perez-Medina, C.; Pinilla, E.; Torres, M. R.; Elguero, J. Tetrahedron 2006, 62,
11704e11713.
9. Nakhai, A.; Bergman, J. Tetrahedron 2009, 65, 2298e2306.
10. Amirthaganesan, S.; Aridoss, G.; Park, K. S.; Lim, K. T.; Jeon, Y. T. Bull. Korean
Chem. Soc. 2010, 31, 1135e1142.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.09.093.
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