P-C cross-coupling onto enamides: Versatile synthesis of α-enamido phosphane derivatives

Article abstract of DOI:10.1002/ejoc.201101293

We report herein the Pd-catalyzed P-C cross-coupling reaction between enol phosphates and secondary phosphane-borane complexes or phosphane oxides. The reaction was performed under mild conditions, owing to Pd activation of the P-H bonds of the phosphane-

Full text of DOI:10.1002/ejoc.201101293

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101293
P–C Cross-Coupling Onto Enamides: Versatile Synthesis of α-Enamido
Phosphane Derivatives
Monika Cieslikiewicz,[a,b] Alexis Bouet,[a] Sylvain Jugé,[c] Martial Toffano,[d]
Jérôme Bayardon,[c] Caroline West,[a] Krzystof Lewinski,[b] and Isabelle Gillaizeau*[a]
Keywords: Cross-coupling / Phosphaalkenes / Enols / Phosphanes / Boranes
We report herein the Pd-catalyzed P–C cross-coupling reac-
tion between enol phosphates and secondary phosphane–bor-
and to the powerful enol phosphate coupling reagents. New
useful chiral and achiral α-β-alkenylphosphane derivatives
ane complexes or phosphane oxides. The reaction was per- bearing an amido group in the α-position to the P center were
formed under mild conditions, owing to Pd activation of the
P–H bonds of the phosphane–boranes (or phosphane oxides)
obtained in yields up to 70%.
cursor reagent such as 2 has been investigated in the present
study for the Pd-catalyzed coupling with phosphane deriva-
tives.
In this communication, we wish to report the use of α-
amido enol phosphate 2, which is easily accessible from
amides, lactams, or imides,[8] in Pd-catalyzed coupling reac-
tions with chiral or achiral secondary phosphane–boranes
(or phosphane oxides) to afford their enamido derivatives.
These compounds are potentially interesting to yield hybrid
heterocyclic phosphane derivatives.[8]
Introduction
To date, a great deal of attention has been paid to the
development of new functionalized phosphane derivatives
as a result of their use in catalysis[1] or organocatalysis.[2]
However, methods available for their preparation that are
both easy and modular are still scarce, thus hindering the
design of hybrid ligands or organocatalysts and, conse-
quently, their applications. This is particularly true for the
synthesis of P-stereogenic phosphorus compounds bearing
a functional group.[1,3,4] Thus, the demand for innovative
synthetic routes to functionalized phosphorus compounds
led us to investigate a versatile P–C bond-forming reaction
starting from secondary phosphane derivatives by using a
Pd-catalyzed cross-coupling reaction.[5] Although hydro-
phosphination of alkynes provides an economical and toler-
ant method to produce α,β-unsaturated phosphorus com-
pounds, this methodology is not applicable to the prepara-
tion of cycloalkenylphosphorus compounds because of the
absence of small ring alkynes.[6] To overcome this problem,
a metal-catalyzed coupling procedure from vinyl halides or
triflates has been recently described.[7] However, as the syn-
thesis of functionalized phosphanes by a heterocyclic sub-
stituent remains challenging, the use of a heterocyclic pre-
Results and Discussion
Access to alkenylphosphane–borane complexes by Pd-
catalyzed P–C cross-coupling of vinyl halides or triflates
with secondary phosphane–borane complexes or phos-
phane oxides has already been disclosed.[7] However to the
best of our knowledge, there are no literature examples of
this coupling with non-aromatic heterocyclic scaffolds. The
major advantage of our strategy lies in the fact that a direct
precursor of the free phosphane function (such as a borane
complex or phosphane oxide) can be easily introduced at
the α position to the nitrogen-containing heterocycle. This
method would allow the synthesis of a range of original α-
enamido phosphane derivatives (Scheme 1).
To this end, the synthesis of requisite starting enol phos-
phates 2a–e was achieved in accordance with our previously
reported results.[8] The use of α-amido enol phosphate 2
presents several advantages over triflate reagents, particu-
larly because of its easy preparation and stability. Prelimi-
nary studies to focus the reaction were performed by using
seven-membered α-amido enol phosphate 2c and secondary
diphenylphosphane–borane complex 3a (Scheme 2). The
use of secondary phosphane–boranes has led to significant
progress in P–C bond formation,[9] and their products can
[a] Institut de Chimie Organique et Analytique,
UMR CNRS 6005, Université dЈOrléans,
rue de Chartres, 45100 Orléans, France
E-mail: isabelle.gillaizeau@univ-orleans.fr
[b] Department of Organic Chemistry, Jagiellonian University,
R. Ingardena 3, 30060 Krakow, Poland
[c] Institut de Chimie Moléculaire de lЈUniversité de Bourgogne,
UMR CNRS 5260,
9. av. A. Savary, BP 47870, 21078 Dijon cedex, France
[d] Laboratoire de Catalyse Moléculaire,
UMR 8182 CNRS, ICMMO,
Université Paris-Sud 11, 91405 Orsay cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101293.
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I. Gillaizeau et al.
SHORT COMMUNICATION
Scheme 1. P–C cross-coupling of secondary phosphane–boranes or phosphane oxides 3a–d with enol phosphates 2a–e.
be directly used in organic synthesis or in coordination An excess amount of phosphane substrate 3a was required
chemistry for the preparation of derivatives that cannot be
easily prepared by alternative approaches or obtained in
their trivalent form.[1f,4] The results are reported in Table 1.
for complete conversion of the starting enol phosphate.
Using (IMes)Pd(η-3–2-methylallyl)Cl, developed by Nol-
an’s group,[10] as a coupling catalyst was also successful and
afforded expected phosphane–borane 4c in similar yield
(Table 1, Entry 7). It is noteworthy that lower yields were
observed in the presence of K2CO3 as a base (Table 1, En-
tries 1 and 5). Performing the reaction in a polar coordinat-
ing solvent such as DMSO (Table 1, Entries 1–4) and/or un-
der microwave irradiation (MWI) to ensure a shorter reac-
tion time (Table 1, Entries 2 and 3) was ineffective due to
significant decomposition.
Scheme 2. Starting secondary phosphane–boranes 3a–c and phos-
phane oxide 3d.
In light of the optimized conditions (Table 1, Entry 6),
we envisaged performing the P–C cross-coupling reaction
of enol phosphates 2a–e with secondary phosphane deriva-
tives 3a–d (Scheme 2, diphenylphosphane–borane 3a, chiral
enantiopure phosphane–boranes 3b[11] and 3c,[12a] and chi-
ral phosphane oxide 3d).[12b] The results are summarized in
Table 2. The Pd-catalyzed coupling of enol phosphates 2a,
2c, and 2d with diphenylphosphane–borane 3a allowed us
to isolate desired tetrahydropyridinyl- and azepinylphos-
phane derivatives 4a, 4c, and 4d in low to good yields
(Table 2, Entries 1, 3, and 4). A noticeable exception was
observed with N-Boc six-membered enol phosphate 2b
(Table 2, Entry 2), from which expected phosphane 4b
could not be isolated, presumably because of its weak sta-
bility arising from internal steric hindrance.[13] Unfortu-
nately, only starting material was recovered. Increasing the
reaction temperature or using microwave activation was in-
effective, as an increase in the amount of decomposition
products was observed. Moreover, as borane decomplex-
ation could occur during the coupling reaction,[6b] an ad-
ditional amount of BH3·Me2S was also added at the end of
each previous experiment in an attempt to increase the
amount of phosphane–boranes 4a–d. Unfortunately, in
these cases, only unsubstituted enecarbamates resulting
from the reduction of the enol phosphate moiety and degra-
dation products were recovered.
Table 1. Optimization of the P–C coupling reaction between enol
phosphate 2c and Ph2PH·BH3 (3a).[a]
Entry
Base
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Solvent
Catalyst
Time Yield
[h]
[%][b]
1
DMSO
DMSO
DMSO
DMSO
CH3CN
CH3CN
CH3CN
dppfPdCl2
dppfPdCl2
dppfPdCl2
dppfPdCl2
dppfPdCl2
3
0.25
0.5
24
24
2
38
11
0
60
51
95
90
2[c]
3[c]
4
5
6
7
dppfPdCl2
(IMes)Pd(η3-
1
2-methylallyl)Cl[10]
[a] Conditions: Ph2PH(BH3) (3a, 2 equiv.), base (2 equiv.), and Pd
catalyst (5 mol-%) at 60 °C. [b] Isolated yield after purification by
column chromatography in air. [c] Reaction performed under mi-
crowave irradiation.
Using conditions similar to those reported for triflate
reagents,[7a] the P–C Pd-catalyzed cross-coupling reaction
was best performed by mixing phosphane 3a (2 equiv.) and
enol phosphate 2c (1 equiv.) in acetonitrile at 60 °C for 2 h
in the presence of a weak base (2 equiv. of Cs2CO3), and
(dppf)PdCl2 (5 mol-%) as catalyst (Table 1, Entry 6). Ex-
pected N-acetamido tetrahydroazepinylphosphane 4c was
thus isolated in 95% yield after purification by chromatog-
raphy on silica gel. The 31P NMR spectrum of phosphane–
borane 4c displays a significant signal at δ = +24.1 ppm.
The investigation was then conducted with enantiomer-
ically pure (S)-(o-anisyl)phenylphosphane–borane 3b pre-
pared by metal–halide exchange starting from the corre-
sponding chlorophosphane–borane (Table 2, Entries 5–
8).[4,11,14] We anticipated that the borane protecting group
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P–C Cross-Coupling Onto Enamides
Table 2. Pd-catalyzed P–C bond formation from enol phosphates 2a–e.
[a] Conducted with 3a (2 equiv.), Cs2CO3 (2 equiv.), and (dppf)PdCl2 (5 mol-%) in CH3CN. [b] Conducted with (S)-3b (2 equiv.), Cs2CO3
(2 equiv.), and (dppf)PdCl2 (5 mol-%) in CH3CN. [c] Conducted with (S,S)-3c (2 equiv.), Cs2CO3 (2 equiv.), and (dppf)PdCl2 (10 mol-%)
in CH3CN. [d] Conducted with (S,S)-3d (2 equiv.), DIPEA (4 equiv.), and (dppf)PdCl2 (10 mol-%) in DMSO. [e] Conducted with (S,S)-
3d (4 equiv.), DIPEA (8 equiv.), and (dppf)PdCl2 (10 mol-%) in DMSO. [f] Isolated yield after purification by column chromatography
in air. [g] Compounds were characterized by 1H NMR, 13C NMR, and 31P NMR spectroscopy. [h] Determined by using chiral SFC-
DAD.[15]
of 3b would prevent undesirable inversion at the phos- Table 2, Entries 1–4) probably due to the lower reactivity of
phorus atom. Notably, the yields recorded for 4e–h were phosphane 3b as a result of the inductive donor effect of
significantly lower than those previously obtained (see the methoxy group. Degradation products were also ob-
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I. Gillaizeau et al.
SHORT COMMUNICATION
served and no starting material was recovered. However, it
should be pointed out that, unfortunately, complete racemi-
zation of products 4e–h occurred during the P–C cross-cou-
pling reactions with 3b. Racemization at the P center was
established by chiral supercritical fluid chromatography
(SFC);[15] it may be explained by an inversion, under basic
conditions, of the phosphide–borane anion before ligand
exchange in the coordination sphere of the Pd.[3a,16] No im-
provement in the stereoselectivity of the reaction was ob-
served by changing the nature of the solvent (DMF,
CH3CN) or the temperature (40–60 °C). Nevertheless, the
stereoselective synthesis of chiral tetrahydropyridinyl- or
azepinylphosphane derivatives was alternatively achieved by
a Pd-catalyzed P–C bond-forming reaction by using enan-
tiomerically pure (S,S)-2,5-diphenylphospholane-borane
(3c).[5a] As chirality is borne by the phospholane skeleton,
no racemization was observed. Expected phosphanes 4i–l
(Table 2, Entries 9–12) were thus isolated enantiomerically
pure (Ͼ99.5%ee) in moderate yields. As reported by Tof-
fano et al.,[5] the observed low yield could be explained by
a lack of reactivity of secondary phosphane 3c and the pos-
sible decomplexation of the borane group. Enantiomeric ex-
cesses were determined by chiral SFC analysis: diode-array
detection ensured identification of the minor enantiomer.
In most cases, its concentration was so small that it was not
detected.[15] For the six-membered ring (Table 2, Entry 10),
we assume that the steric hindrance of the Boc group is
accountable for the failure to obtain derivative 4j.
Nevertheless, encouraged by these promising results, we
then turned our attention toward the use of enantiomer-
ically pure (S,S)-2,5-diphenylphospholane oxide (3d).[12]
Applying conditions previously reported,[5] the reaction was
carried out in the presence of (dppf)PdCl2 (10 mol-%) as a
catalyst and iPr2NEt as a base in DMSO. Desired phos-
phane oxides 4m–p were thus isolated in fair to good yields
in an enantiomerically pure form (Table 2, Entry 13–16). In
light of prior studies,[5] we were also pleased to observe that
the higher reactivity of phospholane oxide 3d ensured the
accomplishment of the P–C coupling with hindered six-
membered ring 2b, albeit in low yield (Table 2, Entry 14).
The good solubility of the base (iPr2NEt) in the reaction
solvent also appeared to be a positive factor for this P–C
coupling. The structures of 4h and 4o were unambiguously
determined by X-ray analyses (Figure 1, see also the Sup-
porting Information).[17] In the case of compound 4o, X-
ray diffraction analysis revealed that no epimerization at the
benzylic carbon atoms of the phospholane ring, which
would have led to diastereomeric or enantiomeric com-
pounds, was observed.
Figure 1. X-ray structures of α-enamido phosphane derivatives 4h
and 4o.
crease their biological activity.[19] To date, only a few papers
have reported the synthesis of pyrazinylphosphane deriva-
tives.[20] We therefore investigated the Pd-catalyzed P–C
bond construction between symmetrical bis-enol phosphate
2e[8c] and enantiopure phosphane oxide 3d (Table 2, En-
try 17). Dihydropyraninyl derivative 4q bearing two phos-
phane oxide groups in the 2- and 5-positions was isolated
in good yield in an enantiomerically pure form. Extensive
exploration to exploit the usefulness of the P–C cross-cou-
pling reaction and to obtain more mechanistic details will
be reported in due course.
Conclusions
In summary, we have described a useful Pd-catalyzed P–
C cross-coupling reaction that has been successfully applied
To study the scope of our methodology, we then focused to a range of chiral or achiral secondary phosphane–bor-
on the double P–C cross-coupling reaction. Given our pre- anes (or phosphane oxides) and α-amido enol phosphate
viously reported results that describe the easy functionaliza- reagents. This coupling was achieved under rather mild con-
tion of the dihydropyrazine ring and its possible aromatiza- ditions and in a very short time, leading stereoselectively to
tion into pyrazine,[8c] we anticipated obtaining a diphos- hindered tertiary α-enamido phosphane derivatives with up
phane with a dihydropyrazine moiety as a bridge. Pyrazines to 99.4%ee when the chirality is borne by the phospholane
are widely used intermediates in medicinal chemistry and ring. A large variety of phosphane derivatives as well as
for functional transformations.[8c,18] Furthermore, the in- different enol phosphates were coupled, showing the effi-
corporation of phosphorus into organic molecules could in- ciency of this cross-coupling reaction. It is worth noting
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P–C Cross-Coupling Onto Enamides
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Experimental Section
General Procedure for the Pd-Catalyzed P–C Cross-Coupling: Un-
der an atmosphere of argon, enol phosphate 2 (120 mg, 0.30 mmol)
was dissolved in distilled acetonitrile (2.5 mL) and secondary phos-
phane–borane 3a, 3b, or 3c (0.60 mmol) was added. Then, the con-
tents of the flask were evacuated and backfilled with argon three
times. After that, dppfPdCl2 (0.014 mmol) and Cs2CO3
(0.60 mmol) were introduced, and the degassing procedure was re-
peated. The reaction was carried out in an oil bath (65–70 °C) for
the appropriate time. The reaction mixture was filtered through
Celite, and the filtrate was evaporated. The crude product was puri-
fied by flash column chromatography to yield expected alkenyl-
phosphanes 4a–l.
[8]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and crystallographic data.
Acknowledgments
This work and the postdoctoral grant for A. B. were funded by the
Agence Nationale de la Recherche (grant ANR-07-blan-0292–04),
which is gratefully acknowledged. The French Embassy in Poland
is acknowledged for providing a cotutelle PhD grant to M. C.
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SHORT COMMUNICATION
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[17] CCDC-840881 (for 4h) and -840882 (for 4o) contain the sup-
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Received: September 5, 2011
Published Online: January 13, 2012
1106
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