Direct Regio- and Diastereoselective Diphosphonylation of Cyclic Enamines: One-Pot Synthesis of α,α'-Bis(diphenylphosphoryl)- and α,α'-Bis(diphenylphosphorothioyl)cycloalkanones

Article abstract of DOI:10.1055/s-0036-1588970

A straightforward regio- and diastereoselective process has been developed for the synthesis of unprecedented symmetrical trans -α,α'-bis(diphenylphosphoryl)- and α,α'-bis(diphenylphosphorothioyl)-cycloalkanones, through the reaction of cyclic enamines with excess P -chlorodiphenylphosphine in the presence of triethylamine, followed by oxidation or sulfurization and hydrolytic workup.

Full text of DOI:10.1055/s-0036-1588970

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
N. Jebli et al.
Letter
Synlett
Direct Regio- and Diastereoselective Diphosphonylation of Cyclic
Enamines: One-Pot Synthesis of α,α′-Bis(diphenylphosphoryl)-
and α,α′-Bis(diphenylphosphorothioyl)cycloalkanones
Nejib Jebli*a
Wouter Debrouwerb
O
1) Ph2PCl (6 equiv), Et3N (6.6 equiv)
MeCN, 0 °C to reflux, 2 h
X
P
O
X
P
Jan K. E. T. Bertonb
Kristof Van Heckec
Christian V. Stevensb
Soufiane Touila
Ph
Ph
Ph
Ph
N
one-pot
2) [X]
3) HCl (2 N), 0–25 °C, 12 h
X = O, S
•
•
•
One-pot synthesis
High regio- and diastereoselectivity
Catalyst-free process
a Laboratory of Heteroatom Organic Chemistry, University
of Carthage, Faculty of Sciences of Bizerte, 7021 Jarzouna,
Tunisia
nejib.jebli@yahoo.com
b SynBioC Research Group, Department of Sustainable
Organic Chemistry and Technology, Ghent University,
Coupure Links 653, 9000 Ghent, Belgium
c XStruct, Department of Inorganic and Physical Chemistry,
Krijgslaan 281-S3, 9000 Ghent, Belgium
Received: 21.01.2017
Accepted after revision: 20.02.2017
Published online: 08.03.2017
P-chlorodiphenylphosphine, followed by oxidation or sul-
furization and hydrolytic workup, would allow a straight-
forward approach to unprecedented symmetrical α,α′-
bis(diphenylphosphoryl)- and α,α′-bis(diphenylphosphoro-
thioyl)cycloalkanones. Being tridentate ligands, these com-
pounds might show enhanced complexing properties with
regard to their α-phosphonylketone homologues.6,24–26
To the best of our knowledge, symmetrical α,α′-bis(di-
DOI: 10.1055/s-0036-1588970; Art ID: st-2017-b0058-l
Abstract A straightforward regio- and diastereoselective process has
been developed for the synthesis of unprecedented symmetrical trans-
α,α′-bis(diphenylphosphoryl)- and α,α′-bis(diphenylphosphorothioyl)-
cycloalkanones, through the reaction of cyclic enamines with excess P-
chlorodiphenylphosphine in the presence of triethylamine, followed by
oxidation or sulfurization and hydrolytic workup.
phenylphosphoryl)-
and
α,α′-bis(diphenylphosphoro-
thioyl)cycloalkanones have never been synthesized, but
there are only two reports concerning the synthesis of acy-
clic analogues of α,α′-bis(diphenylphosphoryl)cycloal-
kanones. This includes (i) the TFAA/TfOH-mediated self-ac-
ylation of diphenylphosphorylacetic acid27 and (ii) the bro-
mination of 3-(diphenylphosphoryl)-3-methylbutanone
followed by a Michaelis–Arbuzov phosphonylation.28 The
scope of these reactions is, however, limited and only two
acyclic α,α′-bis(diphenylphosphoryl)ketones have been
synthesized from these strategies, in lower than 40% overall
yield.
By comparison with these existing strategies, our meth-
od, which uses easily prepared enamines and commercially
available P-chlorodiphenylphosphine as starting materials,
has the advantages of brevity (one-pot protocol), generality,
satisfactory yields, and mild reaction conditions. Further-
more, it is applicable for the production of both bisphos-
phine oxide and bisphosphine sulfide derivatives.
Key words enamines, P-chlorodiphenylphosphine, α,α′-bis(diphenyl-
phosphoryl)cycloalkanones, α,α′-bis(diphenylphosphorothioyl)cycloal-
kanones, P-ligands
An important area in the chemistry of organophospho-
rus compounds is the design of new types of P-ligands con-
taining, along with the phosphoryl or thiophosphoryl moi-
eties, one or more other functional groups (keto, amino, hy-
droxy, etc.). The interest for these compounds is due to their
well-known useful applications, such as in the high-perfor-
mance extraction of various metals including uranium (VI),
thorium (IV), and rare earths (III),1–7 in the preparation of
ion-selective electrodes,8–10 or as ligands for transition-
metal-catalyzed cross-coupling reactions and asymmetric
synthesis.11–16 Some of their fluorescent complexes with
lanthanum-group metals are also used as light-emitting
components in organic light-emitting diodes.17
Within our ongoing studies on the reactivity and poten-
tial synthetic applications of imines and enamines18–21 and
inspired by the reaction of enamines with chlorophos-
phines which leads to α-phosphonylcycloalkanones,22,23 we
anticipated that treatment of cyclic enamines with excess
In order to establish the optimum reaction conditions
for the formation of the target compounds, we used 1-mor-
pholinocyclohexene (1a) and P-chlorodiphenylphosphine
as model substrates, in the presence of triethylamine. The
reaction was studied by varying several conditions (sol-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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N. Jebli et al.
Letter
Synlett
Table 1 Optimization of the Reaction Conditions
O
1) Ph2PCl, Et3N, solvent,
0 to T (°C), time
O
O
P
O
P
O
O
P
Ph
Ph
Ph
Ph
Ph
Ph
N
and/or
2) [O]: DMSO, reflux, 2 h
3) HCl (2 N), 0–25 °C, 12 h
1a
2a
3a
Entry
Ph2PCl (equiv)a
Solvent
Temp (°C)
Time (h)
Yield of 2a (%)b
Yield of 3a (%)b
1
2
1
1
1
1
1
1
2
2
2
3
3
3
4
5
6
7
Et2O
25
2
2
2
3
64
63
61
58
75
67
72
63
57
49
40
36
28
21
13
15
Et2O
reflux
25
3
THF
2
2
4
THF
reflux
25
2
3
5
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
2
6
6
reflux
25
2
5
7
2
10
15
13
28
35
33
39
43
51
51
8
reflux
reflux
25
2
9
12
2
10
11
12
13
14
15
16
reflux
reflux
reflux
reflux
reflux
reflux
2
12
2
2
2
2
a 1.1 equiv of Et3N for each equiv of Ph2PCl.
b Isolated yield.
vents, molar equivalents of Ph2PCl, temperature, reaction
time). The results of these comparative experiments are
summarized in Table 1.
two equivalents of the phosphorus electrophile in MeCN at
room temperature, the desired product 2a was isolated in
only 10% yield (Table 1, entry 7). The yield in 2a was en-
hanced to 15% by heating in refluxing MeCN, for two hours
(Table 1, entry 8). Further improvement of the yield to 35%
was observed when using three equivalents of Ph2PCl in re-
fluxing MeCN (Table 1, entry 11). Under the same reaction
conditions, it was gratifying to observe that 51% yield of the
desired product 2a was obtained when the amount of
Ph2PCl was increased to six molar equivalents (Table 1, en-
try 15). Switching to seven equivalents of Ph2PCl brought no
improvement to the yield of 2a (Table 1, entry 16).
Based on these results, the optimized conditions were
established as follows: The enamine reacts in the presence
of six equivalents of Ph2PCl and 6.6 equivalents of Et3N in
MeCN at 0 °C to reflux temperature for two hours. The oxi-
dation or sulfurization of the obtained bisphosphine inter-
mediate was performed in a one-pot protocol by treating,
respectively, with dimethyl sulfoxide (DMSO) under reflux
for two hours or with elemental sulfur at room tempera-
ture, for the same time. Finally, the acidic hydrolysis leading
Initially, the reaction was tested with one equivalent
Ph2PCl and 1.1 equivalents Et3N in different solvents, in or-
der to improve the experimental protocol for the formation
of the monophosphonylated products22,23 and to ascertain if
the desired diphosphonylated compounds could be detect-
ed in these conditions. The reaction provided mainly the
monophosphonylated product 3a with trace amounts of
the α,α′-bis(diphenylphosphoryl)cyclohexanone (2a, Table
1, entries 1–6). The best results were recorded with MeCN
as solvent, which gave 75% and 6% yields of 3a and 2a, re-
spectively (Table 1, entry 5). On the basis of these observa-
tions, it could be concluded that the formation of the first
C–P bond seems to be quite faster than that of the second,
which explains the sufficiency of one equivalent of Ph2PCl
for the completion of the monophosphonylation step.
With these preliminary results in hand, we next focused
on how to enhance the yield of the desired diphosphonylat-
ed product 2a by increasing the molar ratio of Ph2PCl. As
shown in Table 1, when the reaction was conducted with
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
N. Jebli et al.
Letter
Synlett
to the desired diphosphonylketone was accomplished by
treatment with HCl (2N) at 0 °C to room temperature for 12
hours.
Table 2 Substrate-Scope Studies
O
1) Ph2PCl (6 equiv), Et3N (6.6 equiv)
MeCN, 0 °C to reflux, 2 h
X
P
O
X
P
With the optimized conditions in hand,29 we next stud-
ied the scope of this methodology. A variety of structurally
diverse enamines derived from cyclic ketones and morpho-
line were investigated and a series of α,α′-bis(diphenyl-
phosphoryl)- and α,α′-bis(diphenylphosphorothioyl)cy-
cloalkanones of type 2 were obtained in satisfactory yields
(Table 2). One can notice that the yield slightly increased
when enamines derived from substituted cyclohexanones
were used as starting materials. The method also proved to
work for 1-morpholinocyclopentene.
Ph
Ph
Ph
Ph
N
2) [X]
3) HCl (2 N), 0–25 °C, 12 h
(with its enantiomer)
2
1
Entry Enamine [X]a Product
trans/cis (%)b Yield (%)c
O
O
O
O
P
Ph
Ph
Ph
P
N
1
2
[O]
[O]
100/0
100/0
51
60
Ph
The reaction was found to be highly diastereoselective.
Although, for compounds 2, a mixture of cis and trans iso-
mers is possible, the trans configuration is obtained exclu-
sively, except for the five-membered cyclic compounds 2d
and 2g (cis isomer present in 30% and 13% ratio, respective-
ly, see Table 2). The trans configuration was assigned on the
basis of the single-crystal X-ray diffraction data of com-
pounds 2a, 2b and 2g which indicated that the relative ste-
reochemistry of the two phosphonyl groups is trans (Figure
1). It should be noted that in case of compound 2b, the 4-
methylcyclohexan-1-one ring is mainly observed in the
chair conformation. However, a small fraction was observed
adopting a boat conformation. The ratio was properly de-
fined in two parts with final occupancy factors of 0.94 and
0.06, for the chair and boat conformations, respectively
(Figure 1, b).
A mechanistic rationalization for the formation of the
target compounds 2a–g is provided in Scheme 1. This pro-
posed mechanism involves, first of all, a nucleophilic attack
by enamine on the phosphorus electrophile, giving rise to a
(diphenylphosphinyl)enamine intermediate I1 in equilibri-
um with its regioisomer I2. The less-substituted (less-hin-
dered) and less-conjugated enamine I2 was assumed to be
more reactive than I1, what explains the regioselectivity in
the second phosphinylation step and the formation of the
second C–P bond from the less-hindered side, giving rise to
the α,α′-bis(diphenylphosphinyl)enamine intermediate I3,
rather than its α,α-regioisomer. The I3 intermediates were
not stable enough to be isolated or hydrolyzed directly to
obtain the corresponding α,α′-bis(diphenylphosphinyl)ke-
tones. They were thus subjected, in situ, to oxidation or sul-
furization followed by acid hydrolysis, to give the final α,α′-
bis(diphenylphosphoryl)- or α,α′-bis(diphenylphosphoro-
thioyl)cycloalkanones 2, predominately in their trans form.
The observed diastereoselectivity is actually only set in
the final hydrolysis step. The obtained results indicate that
C-protonation of the C=C double bond in intermediate I4 oc-
curs predominately from the side of the Ph2P=X group on
the sp3 carbon, giving rise to the trans isomer. This strongly
suggests that the diphenylphosphoryl, or diphenylthio-
phosphoryl group Ph2P=X on the sp3 carbon, specifically di-
2a
O
N
O
P
O
O
P
Ph
Ph
Ph
Ph
2b
O
N
O
P
O
O
P
Ph
Ph
Ph
Ph
3
[O]
100/0
65
2c
O
N
O
O
O
P
Ph
Ph
P
4
5
[O]
[S]
70/30
100/0
58
53
Ph
Ph
2d
O
N
S
O
S
P
Ph
Ph
Ph
P
Ph
2e
O
N
S
P
O
S
P
Ph
Ph
Ph
Ph
6
7
[S]
[S]
100/0
87/13
61
55
2f
O
N
O
S
S
P
Ph
Ph
P
Ph
Ph
2g
a [X], [O]: DMSO, reflux, 2 h; [S]: 1/8 S8, 25 °C, 2 h.
b Determined from the 31P NMR spectra.
c Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
N. Jebli et al.
Letter
Synlett
In summary, we have successfully developed a straight-
forward regio- and diastereoselective approach to unprece-
dented symmetrical trans-α,α′-bis(diphenylphosphoryl)-
and
α,α′-bis(diphenylphosphorothioyl)cycloalkanones,
through the reaction of cyclic enamines with excess P-chlo-
rodiphenylphosphine in the presence of triethylamine, fol-
lowed by oxidation or sulfurization and hydrolytic workup.
The synthesized compounds could have promising applica-
tions as tridentate ligands for the complexation of various
metals including rare earths (III). These studies are ongoing
in our laboratory and will be reported in due course.
Acknowledgment
We gratefully acknowledge the Tunisian Ministry of Higher Education
and Scientific Research and the Belgium Research Foundation Flan-
ders (FWO) for financial support. K. V. Hecke thanks the Hercules
Foundation (project AUGE/11/029 ‘3D-SPACE: 3D Structural Platform
Aiming for Chemical Excellence’) for funding.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588970.
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References and Notes
Figure 1 (a) X-ray molecular structure of compound 2a. (b) X-ray mo-
lecular structure of compound 2b showing both chair and boat (in yel-
low) conformations. Thermal displacements ellipsoids are drawn at the
50% probability level.
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rects the C-protonation of the double bond in I4, but wheth-
er it is only sterically mediated to obtain the less hindered
trans isomer, whether the Ph2P=X group induces a strong
stereoelectronic control or whether this group is first pro-
tonated and then, in a specific conformation, transfers the
proton to the C=C double bond, is not clear at this time; fur-
ther work will be undertaken to clarify this situation.
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O
N
O
N
O
N
O
N
O
–
N
Cl
PPh2
Et3N
Cl
Ph2P-Cl
Ph2PCl
PPh2
Ph2P
PPh2
PPh2
– Et3N
– HCl
I2
I1
1
O
N
O
N
X
O
X
HCl (2 N)
Et3N
[x]
X
Ph2P
X
PPh2
– Et3N
– HCl
Ph2P
Ph2P
PPh2
PPh2
2
I3
I4
Scheme 1 Proposed mechanism for the formation of compounds 2
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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N. Jebli et al.
Letter
Synlett
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sphere (N2) and cooled at 0 °C, P-chlorodiphenylphosphine (1
mmol) in dry MeCN (3 mL) was added dropwise within 15 min.
The resulting solution was warmed up to r.t. and stirred for 1 h.
The reaction mixture was cooled again at 0 °C, and the second
portion of P-chlorodiphenylphosphine (5 mmol) in dry MeCN
(15 mL) was added in the same manner as before. The mixture
was allowed to warm up to r.t. and then refluxed for an extra 2
h. The reaction mixture was then cooled and treated with
DMSO or sulfur as follows.
Oxidation
DMSO (6 mmol) was added, and the mixture was heated under
reflux for 2 h. After cooling, 2 N aq HCl solution (30 mL) was
added dropwise at 0 °C and stirring was continued at r.t. for 12
h. The mixture was then extracted with CH2Cl2 (3 × 10 mL). The
organic phase was dried over MgSO4 and concentrated under
vacuum. The residue obtained was chromatographed on a silica
gel column using CH2Cl2 as eluent or recrystallized from toluene
(in the case of compounds 2a and 2c).
Sulfurization
Ground sulfur (6 mmol) was added, and the reaction mixture
was stirred at r.t. until complete dissolution of the sulfur in 2 h.
2 N aq HCl solution (30 mL) was then added dropwise at 0 °C
and stirring was continued at r.t. for 12 h. The mixture was then
extracted with CH2Cl2 (3 × 10 mL). The organic phase was dried
over MgSO4 and concentrated under vacuum. The residue
obtained was chromatographed on a silica gel column using
CH2Cl2 as eluent.
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(29) General Procedure for the Synthesis of α,α′-Bis(diphenyl-
phosphoryl)- and α,α′-Bis(diphenylphosphorothioyl)cycloal-
kanones 2
The compounds obtained were characterized by various spec-
troscopic tools including IR, NMR (1H, 31P, 13C) spectroscopy,
mass spectrometry, and single-crystal X-ray diffraction (see the
Supporting Information).
trans-2,6-Bis(diphenylphosphoryl)cyclohexanone (2a)
Yield 51%; white solid; mp 249–250 °C. IR (neat): νP=O = 1245
cm–1; νC=O = 1706 cm–1 31P NMR (161.97 MHz, CD3OD): δ = 33.3
.
(s, 2 P). 1H NMR (400.13 MHz, CD3OD): δ = 2.01–2.22 (m, 6 H, 3
CH2), 4.15–4.20 (m, 2 H, 2 CHP), 7.38–7.83 (m, 20 H, ArH). 13C
NMR (100.61 MHz, CD3OD): δ = 21.7 (t, CH2, 3JC–P = 6.0 Hz), 27.1
(s, 2 CH2), 51.7 (d, 2 CHP, 1JC–P = 66.4 Hz), 201.7 (s, C=O); ArC: δ =
128.3, 128.4, 128.7, 128.8, 130.4, 129.9, 130.4, 130.5, 130.6,
130.9, 131.4, 131.8, 131.9,132.2. ESI-HRMS: m/z calcd for
To a well-stirred solution of enamine 1 (1 mmol) and Et3N (6.6
mmol) in dry MeCN (15 mL), maintained under an inert atmo-
C
30H28O3P2 [M + H]+: 499.15864; found: 499.15796.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E