Hydrophosphonylation of alkenes or nitriles by double radical transfer mediated by titanocene/propylene oxide

Article abstract of DOI:10.1016/j.tetlet.2011.09.096

Hydrophosphonylation reactions have emerged as efficient processes for the functionalization of alkenes or alkynes. Synthesis of alkylphosphonates was achieved by an original double radical transfer mediated by titanocene and propylene oxide. By the same way, nitriles which are considered as inert functions in radical process lead to aminobisphosphonates.

Full text of DOI:10.1016/j.tetlet.2011.09.096

Tetrahedron Letters 52 (2011) 6693–6696
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Hydrophosphonylation of alkenes or nitriles by double radical transfer
mediated by titanocene/propylene oxide
Camille Midrier a, Mathias Lantsoght b, Jean-Noël Volle a, Jean-Luc Pirat a, David Virieux a,
,
⇑
Christian V. Stevens b
a Institut Charles Gerhardt – UMR 5253, Architecture Moléculaire et Matériaux Nanostructurés, Ecole Nationale Supérieure de Chimie de Montpellier, 8, rue de l’Ecole Normale,
34296 Montpellier Cedex 5, France
b Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Gent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2011
Revised 14 September 2011
Accepted 20 September 2011
Available online 2 October 2011
Hydrophosphonylation reactions have emerged as efficient processes for the functionalization of alkenes
or alkynes. Synthesis of alkylphosphonates was achieved by an original double radical transfer mediated
by titanocene and propylene oxide. By the same way, nitriles which are considered as inert functions in
radical process lead to aminobisphosphonates.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Radical
Titanocene
Hydrophosphonylation
Alkenes
Nitriles
Considerable efforts have been directed toward the develop-
ment of radical procedures due to their high selectivity and com-
patibility with densely functionalized substrates.1 Beside catalytic
transformations, radical-induced chain reactions are generally con-
sidered as efficient processes. The most notable aspect of such
reactions is supported by the concept of atom economy particu-
larly when only the additions to unsaturated compounds are
involved.2
leading to the anti-Markovnikov products.7 The mildness of the rad-
ical reaction and the drawback generally associated to the use of tri-
butyltin hydride prompted several research groups to develop
alternative radical initiators. In this context, titane-centered radicals
are easily formed in the presence of activated zinc and are then usu-
ally used to induce homolytical bond cleavage in substituted oxir-
anes. Subsequently, the newly formed radical adds to various
unsaturated functions such as C@O or C@C bonds.8
Hydroamination reactions and hydrophosphonylations emerged
recently as new methodologies for the P–C bond formation from
simple and available precursors. Along with metal-catalyzed reac-
tions using complexes of palladium,3 rhodium,4 nickel,5 or even cop-
per,6 the radical method gained a lot of attention. Due to the nature
of the weak P–H bond, P-centered radicals are easily formed in the
presenceof radical initiatorswhichreadily add toalkenes or alkynes.
Another feature of P–H phosphorus reagents is related to the fast
transfer of hydrogen to a carbon radical thus limiting the polymeri-
zation often observed when radical reactions are performed. In pio-
neering work, the addition of secondary phosphine oxides to
terminal alkynes initiated by catalytic amount of benzoyl peroxide
was reported. More recently triethylborane/oxygen was used suc-
cessfully for the radical addition of P–H reagents to terminal alkenes
Bisphosphonates are an important family of compounds which
are used in the treatment of various bone diseases such as Paget’s
disease, metastatic bone disease, and osteoporosis because of their
effect on the metabolism of calcium.9 They are analogous to the nat-
urally occurring pyrophosphate,10 are able to inhibit the action of
osteoclasts, thereby reducing the resorption of bone tissue.11 Bis-
phosphonates are a well-established class of drugs12 with important
properties and several of these compounds are on the market (Etidr-
onate 1 is used to treat osteoporosis and Pamidronate 2 to treat bone
metastases in breast cancer, Fig. 1).10 The b-aminobisphosphonate
Zoledronate 3 and Risedronate 4 sodium salt are among the most
O
O
R = Me, Etidronate 1
R = (CH2)2NH2, Pamidronate 2
R = CH2-1-imidazolyl, Zoledronate 3
R = CH2-3-pyridyl, Risedronate 4
(HO)2P
P(OH)2
⇑
Corresponding author.
E-mail addresses: david.virieux@enscm.fr (D. Virieux), Chris.Stevens@UGent.be
R
OH
Figure 1. Structures of established bisphosphonate drugs.
(C.V. Stevens).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.096

6694
C. Midrier et al. / Tetrahedron Letters 52 (2011) 6693–6696
potent bisphosphonates used in therapy.13 In the context of chemo-
therapy, recent development on the binding mode opened the way
to the design of novel, potent enzyme and cell growth inhibitors that
have weak bone-binding affinity.14 To date little research has been
O
Zn
Cp2TiCl2
Cp2TiCl
8
9
O(Cl)TiCp2
H
conducted on
a-aminobisphosphonates due to the lack of synthetic
O
methods.15
(EtO)2P
H
With this in mind, the synthesis of new aminobisphosphonates
represents a clear interest for the pharmaceutical industry. Herein,
we report a new, mild, and atom economic phosphonylation of al-
kenes and a double phosphonylation of nitriles to form amin-
obisphosphonates, using induced phosphorus-centered radicals
mediated by titanocene dichloride (Cp2TiCl2).
6
O(Cl)TiCp2
O
O
(EtO)2P
(EtO)2P
R
10
R
7
5
Initial experiments were carried out on the phosphonylation of
alkenes as model reaction using bis(cyclopentadienyl)titanium
dichloride (Cp2TiCl2) in the presence of butene (R = n-butyl) 5
and diethyl phosphite 6 (Scheme 1). The results of the optimization
are listed in Table 1. Initial conversions were rather low (15–66%),
however, these conditions allowed to set-up the influence of each
reagent. Entries 1–4 (Table 1) confirmed the necessity of zinc and
the titanocene reagent. Interestingly, the hydrophosphonylation
was only effective in the presence of propylene oxide. The best sol-
vent proved to be THF with the formation of 66% of 7 while in tol-
uene or dioxane the conversion did not exceed 24%.
In a second set of reactions, the quantities of diethyl phosphite 6
(entries 4–6, Table 1) were lowered, leading to a reduced conver-
sion of the substrate. To insure a high yield and to limit the oligo-
merization of the alkene 5, 3 equiv of 6 were used which is notably
less than generally employed in radical hydrophosphorylation
reactions where 10 equiv are often needed.7b Titanocene
(5 mol %) resulted in a slight decrease of conversion (60%, entry
8). In optimized conditions, a quantitative yield of diethyl hex-
ylphosphonate was obtained (entry 9).
Further, this titanocene-mediated hydrophosphonylation reac-
tion was confirmed using different alkenes. Using the optimized
conditions, the reaction was applied to styrene giving the anti-
Markovnikov product in 37% yield. For internal alkenes such as
cyclohexene, the hydrophosphonylation took place in only 35%
yield. Therefore, the reaction was launched for 4 h at 120 °C in
the MW leading to a quantitative conversion on 31P NMR.
A plausible mechanism for the addition of diethyl phosphite 6
to alkene 5 is given in Scheme 2. Taking into account the required
O
O
(EtO)2P
H
(EtO)2P
R
Scheme 2. Radical mechanism of alkene phosphonylation mediated by titanocene.
O
O
O
Cp2TiCl2, Zn,
O
(EtO)2P
P(OEt)2
R
CN + (EtO)2P
H
11
6
R
NH2
12a-n
THF, reflux
Scheme 3. Double phosphonylation of nitriles
– synthesis of a-aminobis
phosphonates.
Table 2
Optimization of the Ti-catalyzed phosphonylation of cyclopropylnitrile
(R = cyclopropyl)
Entry Reaction conditions
31P-NMR yield (%)
1
2
3
4
5
6
7
8
2 equiv propylene oxide, 2 h, 120 °C (MW)
0 equiv propylene oxide, 2 + 2 h, 120 °C (MW)
35a
29 + 29a
0 equiv propylene oxide, 2 h, 140 °C (MW), THF 10b
[RCN] = 0.1 M
[RCN] = 0.2 M
[RCN] = 0.4 M
[RCN] = 2.0 M
[RCN] = 4.0 M
54b
70b
90b
59b
70b
a
Entries 1–3: [RCN] = 0.2 M, 10 mol % Cp2TiCl2, THF.
2 equiv propylene oxide, 10 mol % Cp2TiCl2, 17 h, reflux, THF.
b
O
O
Cp2TiCl2, Zn,
O
R
(EtO)2P
+ (EtO)2P
H
R
5
6
7
Table 3
THF, reflux
Double phosphonylation of nitriles – synthesis of aminobisphosphonates
or MW (120 °C)
R-CN
Reaction
time
Isolated yield (31P NMR yield)
Scheme 1. Radical addition of diethyl phosphite to alkenes.
12a Me-CN
12b c-Pr-CN
12c i-Pr-CN
4 days
20 h
43 (77)
94 (Quant.)
0 (2)
25 (53)
34 (83)
48 (63)
0 (10)
69 (78)
20 (20)
0 (8)
Table 1
4 days
3 days
18.5 h
4 days
3 days
23.5 h
3 days
4 days
40.5 h
Optimization of the hydrophosphonylation reaction conditions under microwave
(R = n-butyl)
12d Ph(CH2)2-CN
12e p-Cl-C6H4CH2-CN
12f FCH2-CNa
12g BrCH2CH2-CN
12h Cl(CH2)3-CN
12i p-Me-C6H4-CN
12j 2-pyridyl-CN
12k PhCH2NH(CH2)2-CN
Entry Diethyl
phosphite
Zn
Cp2TiCl2 Propylene
Time 31P NMR
(equiv) (equiv)
oxide
(h)
yield (%)
(equiv)
(equiv)
1
2
3
4
5
6
7
8
9
3
3
3
3
2
1
2
3
3
0
4
4
4
4
4
4
4
4
0.1
0
2
2
0
2
2
2
2
2
2
1
1
1
1
2
2
3
2
2
0
0
0
0 (32)
0.1
0.1
0.1
0.1
0.1
0.05
0.1
Ph
66
37
32
28
60
Quant.
N
CN
12l
4 days
34 (98)
Ph
12m HO2CCH2-CN
12n MeO(CH2)2-CN
18.5 h
18.5 h
41 (88)
À(74)
a
Fluorine was reduced from the end product.

C. Midrier et al. / Tetrahedron Letters 52 (2011) 6693–6696
6695
O
O
O
R
CN
[TiIII]
(EtO)2P
H
Cp2TiCl
(EtO)2P
O(Cl)TiCp2
-
9
10
O(Cl)TiCp2
R
O
O
O
O
O
(EtO)2P
H
(EtO)2P
R
(EtO)2P
(EtO)2P
P(OEt)2
13
N
14
R
NH2
12
N
[TiIII]
[TiIV
]
Scheme 4. Radical mechanism of nitrile phosphonylation mediated by titanocene.
presence of epoxypropane, the formation of the diethyl
alkylphosphonate 7 can be seen as the result of a double radical
transfer reaction. Cp2TiCl radical 9 was generated from the reaction
of titanocene dichloride 8 and zinc dust and then transferred to the
epoxide leading to the homolytic cleavage of the C–O bond. A sec-
ond radical transfer to diethyl phosphite 6 occurred to afford the
phosphorus-centered radical 10. In the final stage, hydrophospho-
nylation of the alkene afforded the desired alkylphosphonate.
Generally nitriles are relatively insensitive to radical conditions
and are often used as solvent. In order to determine the influence
of the titanocene reagent in such a process, we attempted the reac-
tion using cyclopropanenitrile 11 (R = c-propyl) and diethyl phos-
phite 6 (Scheme 3) in the conditions used for alkenes (3 equiv of
7, 4 equiv of Zn, 0.1 equiv of titanocene and 2 equiv of propylene
oxide). Interestingly, a double phosphonylation on the rather inert
Generally, the reaction did not work for aromatic nitriles. When
it was effective the resulting yields remained quite low (com-
pounds 12i and 12j). Stabilisation due to conjugation might be
the reason for this low reactivity. For
a-aminomethylnitrile, the
reaction did not proceed. When a nitrogen atom occupied the beta
position, only low yields were obtained for the secondary amines.
By contrast, the tertiary amino nitrile gave a good yield (12n).
The main difficulty encountered in this reaction was the purifi-
cation due to the presence of residual diethyl phosphite 6.
Although it would be possible to isolate most of the amin-
obisphosphonates 12 using column chromatography, a significant
amount was lost during this process as such derivatives were
highly polar.16
From a mechanistic point of view, the formation of bisphosph-
onate 12 clearly suggests that radical reaction on the cyano group
occurs in such a process. The Cp2TiCl reagent 9 has unambiguously
an influence on the behavior of the reaction as no reaction was ob-
served when acetonitrile was reacted with diethyl phosphite with
AIBN or with triethyl borane/air. It has been recently proposed that
complexation of the nitrile to titanium might occur thus enhancing
the radical acceptor character of the cyano group by lowering its
LUMO.17 According to these results, we could propose the mecha-
nism depicted in the Scheme 4. Then, the diethyl phosphonyl rad-
ical 10 could add to the titane (III)-activated nitrile leading to the
formation of the coordinated iminyl radical 13 which further
evolved to afford the N–Ti bond intermediate 14. The addition
mechanism of the second diethyl phosphite remains unclear as
both radical and nucleophilic additions to the imino intermediate
are possible leading to the bisphosphonate 12.
nitrile function was observed affording the
a-aminobisphospho-
nate 12b. The reaction conditions were therefore varied to try to
increase the conversion (Table 2).
Unlike the reaction with alkenes, it can be noted that phospho-
nylation of nitriles can be realized in the absence of propylene
oxide under microwaves (entries 1–3). However, the formation of
side products was remarkably diminished when using epoxypro-
pane. Reducing the amount of titanocene resulted in lower yield,
as changing the temperature of the reaction did. Adding catalyst
in two stages did not improve the conversion significantly.
Since microwave conditions are not strictly required, we also
used thermal activation. In such conditions, the rate of the reaction
is lower and overnight heating is required. A set of experiments
was realized under thermal activation to find the optimum nitrile
concentration. Optimizations were conducted using cyclopropyl-
nitrile because it gave a better yield. It was found that a cyclopro-
pylnitrile concentration of 0.4 M (entry 6) gave the best
conversion. The amount of side-products generally tended to in-
crease with the concentration, but remained at fairly low level
for most of the reactions. Formation of by-products only became
significant for the high concentrations (2.0 and 4.0 M, entries 7
and 8).
In conclusion, titanocene dichloride/zinc reagent has proven for
the first time to generate phosphorus radicals. It was successfully
employed in the hydrophosphonylation of alkenes by a double rad-
ical transfer offering an alternative method to the existing ones.
This procedure also proved to be particularly effective in the reac-
tion of nitriles which generally exhibit low or no reactivity under
radical conditions. In this way, alkyl aminobisphosphonates can
be synthesized in moderate yields.
Then, the reaction was run using the best conditions (entry 6,
Table 2) with a variety of different nitriles as substrates to deter-
mine the scope. The results are summarized in Table 3. It seems
that generally the reaction works for alkyl nitriles (compounds
12a–d). However, the steric hindrance induced by the isopropyl
group of isobutyronitrile prevented the reaction and this nitrile
did not react as well (12c). Surprisingly, some halogenated nitriles
appeared to be compatible with these reaction conditions (12f–h),
although the reactivity was mainly depending on the position of
the halogen atom. When it is directly bounded to the alpha or gam-
ma position, relatively high 31P NMR conversions were observed.
However, when the halogen is in the beta position, only small
amounts of the desired product were obtained.
Acknowledgments
We thank the French Ministry of Education for financial sup-
port. We also would like to thank Miss Laura Totterdell and Mar-
lene Nogier for their participation to this work.
References and notes
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mixture of Cp2TiCl2 (1.2 mmol) and activated Zn powder (48 mmol), under a
nitrogen atmosphere, is added deoxygenated THF (30 mL). To this mixture,
nitrile (12 mmol, 0.4 mol mLÀ1); diethyl phosphite (48 mmol); and propylene
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filtered through filter paper and concentrated in vacuo. The residue was
dissolved in CH2Cl2 or AcOEt (30 mL) and aqueous HCl (1 M) was added. The
organic layer was removed and the aqueous layer was washed once more
CH2Cl2 or AcOEt (30 mL). The aqueous phase was basified to pH = XX with
NaHCO3 (1 M) and was extracted three times with CH2Cl2 or AcOEt. The
combined organic phases are dried over MgSO4 and concentrated in vacuo.
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Purification
protocol
by
column
chromatography:
Purification
by
chromatography on silica gel using a gradient of solvents: CH2Cl2 to [CH2Cl2/
EtOH, 9/1]. Purification protocol by oxidation of the residual diethyl phosphite and
extraction: The reaction mixture is filtered through filter paper and
concentrated in vacuo. The oil is redissolved in HCl (30 mL, 1 M). Hydrogen
peroxide is added to the mixture (40 mL) and left to stir for 30 min. A color
change from yellow, to orange, to red is observed. The mixture is basified using
NaOH (25 mL, 4 M). The product is extracted with CH2Cl2 (3 Â 150 mL). The
combined organic phases were dried over MgSO4 and concentrated in vacuo.
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