Highly regio-and stereoselective nickel-catalyzed addition of dialkyl phosphites to ynamides: An efficient synthesis of β-aminovinylphosphonates

Article abstract of DOI:10.1002/adsc.201000792

A highly regio-and stereoselective, nickel(II)-catalyzed procedure for the hydrophosphonylation of ynamides has been developed. This protocol provides a straightforward and efficient entry to a series of β-aminovinylphosphonates that can easily be prepared in good yields from a wide range of ynamides and dialkyl phosphites as well as useful insights into the reactivity of ynamides under nickel catalysis.

Full text of DOI:10.1002/adsc.201000792

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DOI: 10.1002/adsc.201000792
Highly Regio- and Stereoselective Nickel-Catalyzed Addition
of Dialkyl Phosphites to Ynamides: an Efficient Synthesis of
b-Aminovinylphosphonates
Antoine Fadel,a Frꢀdꢀric Legrand,b Gwilherm Evano,b,* and Nicolas Rabassoa,*
a
Laboratoire de Synthꢁse Organique et Mꢀthodologie, ICMMO, UMR CNRS 8182, Bꢂt. 420, Universitꢀ Paris-Sud 11,
15 rue Georges Clemenceau, 91405 Orsay Cedex, France
Fax : (+33)-1-6915-6278; e-mail: nicolas.rabasso@u-psud.fr
Institut Lavoisier de Versailles, UMR CNRS 8180, Universitꢀ de Versailles Saint-Quentin en Yvelines, 45 avenue des
b
Etats-Unis, 78035 Versailles Cedex, France
Fax : (+33)-1-3925-4452; e-mail: evano@chimie.uvsq.fr
Received: October 20, 2010; Published online: February 4, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000792.
Abstract: A highly regio- and stereoselective, nick-
el(II)-catalyzed procedure for the hydrophosphony-
lation of ynamides has been developed. This proto-
col provides a straightforward and efficient entry to
a series of b-aminovinylphosphonates that can
easily be prepared in good yields from a wide range
of ynamides and dialkyl phosphites as well as useful
insights into the reactivity of ynamides under nickel
catalysis.
Scheme 1. Regio- and stereoselective addition of dialkyl
phosphites to ynamides.
Herein, we describe the successful nickel-catalyzed
hydrophosphonylation of ynamides, which yields
densely functionalized b-phophoryloxy-enamines with
high levels of regio- and stereoselectivities.
Keywords: aminophosphonates; hydrophosphonyla-
tion; nickel catalysis; ynamides
To test our hypothesis, ynamide 4, readily prepared
by our alkynylation procedure with vinyl dibro-
AHCTUNGTRENNUNG
mides,[3a,b] was reacted with diethyl phosphite in the
presence of various activators or transition metal cat-
Functionalized vinylphosphonates are especially alysts: results from these studies are shown in Table 1.
useful small organic molecules and have received con- After checking that the reaction could not be mediat-
siderable attention over the past decade.[1] Among all ed by simple Brønsted acids (entry 1) or radical initia-
the methods available for their preparation, the tran- tors (entry 2), the activity of a set of representative
sition metal-catalyzed hydrophosphonylation of al- catalysts with potential for activating the triple bond
kynes is certainly one of the most efficient to date of the starting ynamide was evaluated. Quite surpris-
and has been widely studied recently.[2] However, ex- ingly, most catalysts with high affinities for p-elec-
amples of addition to internal alkynes are still limited, trons such as silver, gold, copper or platinum com-
suffer from low regioselectivity and have not been ap- plexes (entries 3–8) failed to promote the reaction
plied to heteroatom-substituted alkynes. Our interest and the starting ynamide was completely recovered,
in the chemistry of ynamides[3,4] and aminophospho- which might be due to a too strong complexation of
nates[5] led us to consider the possibility of a metal- the metal center with diethyl phosphite. While palla-
catalyzed addition of dialkyl phosphites 2 to ynamides dium tetrakistriphenylphosphine, which has been
1 (Scheme 1), which would provide an efficient access demonstrated to be a quite efficient catalyst for the
to b-aminovinylphosphonates 3,[6] molecules that have hydrophosphonylation of alkynes,[2] only gave minor
not received much attention and for which there is no amounts of the a-isomer 6, the use of nickel(II) bro-
general synthesis to date despite their synthetic use- mide turned out to be a lot more efficient since the
fulness[7] and their potential in medicinal chemistry.[8] expected b-aminovinylphosphonate 5 could be isolat-
ed in 71% yield with complete regio- and stereocon-
Adv. Synth. Catal. 2011, 353, 263 – 267
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263

Antoine Fadel et al.
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Table 1. Screening of catalysts for the hydrophosphonyla-
Table 2. Solvent optimization.
tion.
Entry Activator or Catalyst 5:6[a]
E-5:Z-5[a] Yield[g]
Entry
Solvent
5:6[a]
E-5:Z-5[a]
Yield[c]
1
2
3
4
5
6
DMSO
DMF
ethanol
acetonitrile
THF
NR[b]
NR[b]
NR[b]
NR[b]
>95:5
>95:5
–
–
–
–
–
–
–
–
1
2
3
4
5
6
7
8
TfOH[b,c]
NR[f]
NR[f]
NR[f]
NR[f]
NR[f]
NR[f]
NR[f]
NR[f]
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
AIBN[d,e]
[b,e]
AgPF6
AgOTf[d,e]
AuCl[b,e]
>95:5
>95:5
45%
75%
[b,e]
toluene
Cu
G
CuI[d,e]
[a]
Measured by 31P NMR analysis of crude reaction mix-
PtCl2
[Rh(OAc)2]2
Pd(PPh3)4
NiBr2
tures.
[d,e]
[d,e]
f
9
10
11
U
NR
–
[b]
[c]
No reaction.
Yield of pure, isolated product.
A
>5:95 >5:95
>95:5 >95:5
10%
71%
[d,e]
[a]
Measured by 31P NMR analysis of crude reaction mix-
tures.
Reaction performed in DCM at room temperature.
1 equiv. of activator used.
Reaction performed in refluxing toluene.
10 mol%.
No reaction.
all cases.[5a,9] The reaction was found to be compatible
with a variety of aromatic groups, including heteroar-
omatics (Table 3, entries 7 and 8), and the presence of
electron-withdrawing (Table 3, entries 3–5) or donat-
ing (Table 3, entry 2) groups had virtually no effect on
the reaction. The lower yields observed with sub-
strates possessing an ester in the ortho position, an ar-
omatic chloride or a pyridine ring might be due to
[b]
[c]
[d]
[e]
[f]
[g]
Yield of pure, isolated product.
trol.[5a,9] Interestingly, the selectivity observed in competitive addition of the ester to the activated
À
favour of the b-isomer is complementary to the one triple bond, insertion into the C Cl bond/competitive
observed in the thermal addition of diethyl phosphite Tavsꢄ reaction[11] or catalyst poisoning, respectively.
to ynamines where the a-isomer is formed predomi-
Notably, the presence of an additional double bond
nantly.[10] Attempts at lowering the catalyst loading was tolerated (Table 3, entry 10) and the correspond-
resulted in a more sluggish reaction and lower yields ing aminodienylphosphonate was isolated in good
(57% yield with 5 mol% NiBr2, 6% yield with yield as a single regio- and stereoisomer.
2 mol% NiBr2).
The hydrophosphonylation of alkyl-subtituted yn-
ACHTUNGTRENaNGNU mides (Table 3, entries 11–13) was, however, found
In an effort to further improve the yield of the hy-
drophosphonylation reaction and to check whether to be more difficult, even though the reaction was
the selectivity could be modified, we briefly examined still highly selective. In these cases, the corresponding
the used of various solvents (Table 2). While the use aminovinylphosphonates could be isolated in modest
of highly polar solvents such as DMF, DMSO, ethanol yields, which might be due to the unstability of the
or acetonitrile completely inhibited the reaction, THF starting materials.
and toluene were found to be the most efficient ones,
The scope of the reaction was also investigated
the last one being superior in terms of yield of isolat- with respect to the nature of the electron-withdrawing
ed product, which might simply be due to a combina- group of the ynamide (Table 4). The reaction was
tion of its higher boiling point and its poor ability to found to be compatible with all classes of ynamides
chelate the nickel(II) catalyst.
including yne-sulfonamides, yne-amides, yne-carb-
ACHTUNGTRENaNGNU mates and yne-oxazolidinones. In addition, the pres-
With these optimized conditions in hand, the scope
of the reaction was next investigated with regard to ence of bulky substituents on the ynamide (Table 4,
the substituent on the triple bond of the ynamide: re- entries 4 and 7) did not inhibit the reaction or affect
sults from these studies are shown in Table 3. A varie- its selectivity and the corresponding densely substitut-
ty of aminovinylphosphonates could be obtained in ed aminovinylphosphonates could still be obtained in
reasonable to good yields, even on a multigram scale synthetically useful yields. Besides the fact that no
(Table 3, entry 1), with complete regio- and stereo- traces of the regio- or stereoisomers could be detect-
control, the E-b-isomer being exclusively formed in ed in all these reactions, this hydrophosphonylation
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Adv. Synth. Catal. 2011, 353, 263 – 267

Highly Regio- and Stereoselective Nickel-Catalyzed Addition of Dialkyl Phosphites to Ynamides
Table 3. Scope and limitations: substitution of the ynamide.
Table 3. (Continued)
Entry Ynamide
2-Amino-1-alken- Yield[a]
ylphosphonate
12
24%
32%
Entry Ynamide
2-Amino-1-alken- Yield[a]
ylphosphonate
13
[a]
Yield of pure, isolated product.
Reaction performed on a 4-gram scale.
No reaction.
71%,
[b]
[c]
1
75%[b]
Table 4. Scope and limitations: hydrophosphonylation of repre-
sentative ynamides.
2
3
4
61%
74%
35%
Entry Ynamide
2-Amino-1-alkenyl-
phosphonate
Yield[a]
71%
1
2
3
5
61%
27%
61%
53%
6
7
4
48%
86%
69%
5
6
73%
94%
87%
8
9
–
NR[c]
64%
7
10
[a]
Yield of pure, isolated product.
procedure also seems to be highly selective for the
ynamide and no over-hydrophosphonylation, which
would yield to the formation of amino-bisphospho-
nates, could be evidenced.
11
20%
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Antoine Fadel et al.
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elimination. This reaction pathway would mostly
afford the a-isomer, due to chelation of the metal
center to the electron-withdrawing group after the hy-
drometallation step, as shown in related hydrostanny-
lation reactions.[13] In our case, the nickel(II)[14] cata-
lyst most probably simply acts as a strong Lewis acid:
coordination to the electron-rich triple bond of the
ynamide 1 would facilitate an inner-sphere addition of
dialkyl phosphite (Scheme 3). This would account for
both the observed stereoselectivity and the strong sol-
vent effect since a polar, coordinating solvent proba-
bly prohibits chelation of the ynamide. The complete
regioselectivity of this step would finally be due chela-
tion of the nickel catalyst to the electron-withdrawing
group, a phenomenon that has been involved in a
number of processes with ynamides.[15] Proton transfer
from the resulting vinyl-nickel complex would finally
produce the b-aminovinylphosphonate 3 and regener-
Scheme 2. Scope and limitations with representative dialkyl ate the nickel catalyst.
phosphites.
In conclusion, we have developed a highly efficient
nickel(II)-catalyzed hydrophosphonylation of yna-
mides. This procedure affords b-aminovinylphospho-
Finally, the hydrophosphonylation of ynamide 4 nates with complete regio- and stereocontrol and pro-
with other dialkyl phosphites 2 was also evaluated to vides useful insights into both the reactivity of yn-
further test our procedure (Scheme 2). Other dialkyl
ACHTUNGTRENaNUGN mides in transition metal-catalyzed processes and hy-
phosphites such as dimethyl or diisopropyl phosphite drophosphonylation of alkynes. Applications of this
were found to perform well under our hydrophospho- reaction to other heteroatom compounds and selec-
nylation conditions, the former being a little superior tive preparation of a-aminovinylphosphonates from
in terms of yield. Only diphenyl phosphite did not ynamides are under way and will be reported in due
participate in the reaction since starting ynamide was course.
completely recovered from the crude reaction mix-
ture. The use of deutero-diethyl phosphite 8[12] was
equally efficient, yielding the deuterated aminovinyl-
phosphonate 9 in good yield and selectivities.
Experimental Section
The mechanism of this novel nickel(II)-catalyzed
General Procedure for the Nickel-Catalyzed
Hydrophosphonylation
hydrophosphonylation reaction is unlikely to proceed
similarly to that of the palladium(0)[2a] or nickel(0)[2c]
À
version which involve oxidative addition into the P H
To a solution of ynamide (11.90 mmol) and dialkyl phos-
bond followed by hydrometallation and reductive phite (35.70 mmol) in toluene (40 mL) was added nickel(II)
Scheme 3. Possible mechanism for the nickel(II)-catalyzed hydrophosphonylation reaction.
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Adv. Synth. Catal. 2011, 353, 263 – 267

Highly Regio- and Stereoselective Nickel-Catalyzed Addition of Dialkyl Phosphites to Ynamides
bromide (1.19 mmol). The reaction mixture was refluxed for
2–6 h, cooled to room temperature, diluted with ethyl ace-
tate and hydrolyzed with 1M HCl. Purification by flash
chromatography on silica gel afforded the desired aminovi-
nylphosphonates.
[6] For recent reviews on aminophosphonates, see: a) F.
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Acknowledgements
We thank the CNRS, the University Paris-Sud 11 and Univer-
sity of Versailles Saint-Quentin en Yvelines for financial sup-
port. GE and FL acknowledge the ANR (project DYNA-
MITE) for financial support.
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