Synthesis of azaheterocyclic vinylphosphonates by ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.201300375

The title compounds were synthesized by ruthenium-catalyzed ring-closing metathesis of N-tosyl-N-(ω-alkenyl)aminomethylvinyl phosphonates, which were obtained from N-(ω-alkenyl)-N-tosylamides. These compounds, in turn, were prepared from unsaturated alcohols through the Mitsunobu reaction. This methodology gives access to five- and six-membered ring compounds. Additionally, chiral phosphonates can be obtained easily. Organocatalysis and ring-closing metathesis enable a two-step synthesis of azaheterocyclic vinylphosphonates, giving access to five- and six-membered ring compounds. The required (ω-alkenyl) p-toluenesulfonamides were obtained through the Mitsunobu reaction, which allows the synthesis of chiral phosphonates. Copyright

Full text of DOI:10.1002/ejoc.201300375

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300375
Synthesis of Azaheterocyclic Vinylphosphonates by Ring-Closing Metathesis
Cécile Garzon,[a] Mireille Attolini,*[a] and Michel Maffei*[a]
Keywords: Nitrogen heterocycles / Organocatalysis / Metathesis / Phosphorus / Ruthenium
The title compounds were synthesized by ruthenium-cata-
lyzed ring-closing metathesis of N-tosyl-N-(ω-alkenyl)-
aminomethylvinyl phosphonates, which were obtained from
N-(ω-alkenyl)-N-tosylamides. These compounds, in turn,
were prepared from unsaturated alcohols through the Mitsu-
nobu reaction. This methodology gives access to five- and
six-membered ring compounds. Additionally, chiral phos-
phonates can be obtained easily.
phosphonates 2. These compounds, in turn, could be ob-
tained through the organocatalyzed substitution reaction of
diethyl α-(tert-butoxycarbonyloxymethyl)vinylphosphonate
(1)[8] by a N-p-toluenesulfonamide possessing a terminal
double bond, namely, N-(ω-alkenyl)-p-toluenesulfonamide
(Scheme 1).
Introduction
Aminophosphonic acids and their derivatives constitute
an important class of biologically active molecules.[1] Al-
though less studied, β-aminovinylphosphonates have re-
ceived attention as a result of their use in the preparation
of β-aminophosphonic acids derivatives, which display
interesting biological properties,[2] and because of their use
in the synthesis of 2,4-disubstituted tetrahydrothiophenes.[3]
Whereas several synthetic methods for acyclic β-amino-
vinylphosphonates have been reported,[4] only a few reports
on the preparation of their cyclic counterparts exist, that is,
by palladium-catalyzed Hirao coupling[5] or through organ-
ocatalyzed annulations of allenic phosphonates.[6] We be-
came interested in the synthesis of this class of compounds,
as some of them are reported to possess antiantagonist ac-
tivity at GABA (γ-aminobutyric acid) receptors,[7] or may
lead to phosphodiesterase inhibitors.[5] It occurred to us
that these cyclic phosphonates, namely, azaheterocyclic
vinylphosphonates, would result from the ring-closing me-
tathesis (RCM) of suitably protected (aminomethyl)vinyl-
Results and Discussion
However, the planned approach may be hampered by the
synthesis of such N-p-toluenesulfonamides, as the methods
available for their preparation are limited to direct tosyl-
ation of alkenylamines[9] or alkylation of p-toluenesulfon-
amide by ω-bromoalkenes.[10] These two methods cannot be
generalized because of the low availability of the starting
materials. Therefore, we turned towards the use of the Mit-
sunobu reaction. By starting with the work of Weinreb[11]
and Dobbs,[12] we devised the synthesis of several N-Boc,N-
(ω-alkenyl)-p-toluenesulfonamides by reaction of N-Boc-p-
toluenesulfonamide with ω-alkenyl alcohols.
After some experimentation, it appeared that the usual
Mitsunobu conditions, that is, diethyl azodicarboxylate
(DEAD)/triphenylphosphane (PPh3) in THF at room tem-
perature gave miscellaneous results, with formation of by-
products, whereas the use of DEAD/1,2-bis(diphenylphos-
phanyl)ethane (dppe) in THF at room temperature led to
much better yields. Thus, we could easily obtain several all-
ylic and homoallylic N-Boc,N-(ω-alkenyl)-p-toluenesulfon-
amides (Table 1), which afforded the required N-(ω-alk-
enyl)-p-toluenesulfonamides upon subsequent cleavage of
the Boc group with trifluoroacetic acid in dichloromethane
at room temperature. It is noteworthy that chiral alcohols
reacted without any racemization (Table 1, entries 2 and 4).
With those reagents in hand together with those already
described,[11,12] the synthesis of the required phosphonates
for the final RCM step was straightforward with the use of
our recently reported[8] 1,4-diazabicyclo[2.2.2]octane
(DABCO)-catalyzed substitution from 1. Thus, the reac-
Scheme 1. Retrosynthetic approach to azaheterocyclic vinylphos-
phonates.
[a] Aix Marseille Université, CNRS, iSm2 UMR 7313,
13397 Marseille, France
E-mail: michel.maffei@univ-amu.fr
mireille.attolini@univ-amu.fr
Homepage: www.ism2.univ-cezanne.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300375.
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C. Garzon, M. Attolini, M. Maffei
SHORT COMMUNICATION
Table 1. Synthesis of N-(ω-alkenyl)-p-toluenesulfonamides 7–10 by
Table 2. Synthesis of N-tosyl-N-(ω-alkenyl)aminomethylvinyl phos-
Mitsunobu reaction.[a]
phonates.[a]
[a] Isolated yields are given.
tions were carried out in THF at room temperature and
were usually complete after 1 h; the yields ranged from 77
to 98% (Table 2).
Finally, the RCM step was carried out by using these
phosphonates. A great number of catalysts have been re-
ported for the metathesis reaction,[13] and ruthenium carb-
ene complexes are the most widely used, particularly for the
synthesis of organophosphorus compounds.[14] We rapidly
found that the first-generation Grubbs catalyst (A, Fig-
ure 1) was ineffective in our case, which is not a surprising
result, as the starting vinylphosphonates belong to the
class III olefins, which are known to react with difficulty.[15]
Therefore, we used more-active catalysts such as the second-
generation Grubbs catalysts (B) and the Hoveyda–Grubbs
catalysts (C), which were much more satisfactory.
[a] Reactions conditions:
sulfonamide (1.1 mmol), and DABCO (0.2 mmol) were stirred in
anhydrous toluene (5 mL) at room temperature for 1 h. [b] Isolated
1 (1 mmol), N-(ω-alkenyl)-p-toluene-
Thus, a series of five-membered azaheterocyclic phos-
phonates (Table 3) could be easily obtained under rather
dilute conditions (substrate: 0.02 m) with low catalyst load- yield.
ing (5 mol-%) by using either B or C; both catalysts gave
essentially similar results. Also, chiral phosphonates were
obtained from enantiomerically pure p-toluenesulfonamides
without any racemization, as checked by careful chiral
HPLC analysis. Thus, the presence of an alkyl substituent
α to the nitrogen atom did not affect the yield.
From an experimental point of view, the products were
contaminated with black ruthenium byproducts that could
not be removed by flash chromatography. However, treat-
ment of the crude product with activated charcoal prior to
chromatography, as already described,[16] allowed clean and
efficient removal of these impurities.
Figure 1. Catalysts used for the RCM reaction of N-tosyl-N-(ω-
alkenyl)aminomethylvinyl phosphonates.
try 1 vs. 2). In contrast to five-membered ring phosphon-
The synthesis of the six-membered ring analogues is out- ates, the presence of a methyl substituent α to the nitrogen
lined in Table 4. Azaheterocyclic phosphonate 22 was ob- atom (Table 4, entries 3 and 4) led to a mixture of three
tained efficiently by using both catalysts, but this time the compounds (i.e., 19, 23, and 24), in which expected aza-
Grubbs II catalyst (B) gave the highest yield (Table 4, en- heterocyclic phosphonate 23 was formed in low amounts
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Azaheterocyclic Vinylphosphonates by Ring-Closing Metathesis
Table 3. Synthesis of five-membered ring azaheterocyclic vinylphos-
phonates by RCM.[a]
Table 4. Synthesis of six-membered ring azaheterocyclic vinylphos-
phonates by RCM.[a]
[a] Reactions were carried out with the catalyst (5 mol-%) in re-
fluxing dichloromethane for 24 h. [b] Isolated yield.
[a] Reactions were carried out with the catalyst (5 mol-%) in re-
fluxing dichloromethane for 24 h. [b] Isolated yield. [c] With 1,4-
benzoquinone (10 mol-%). [d] With titanium isopropoxide (30 mol-
%).
(23–24% yield), regardless of the catalyst. Byproduct 24
was formed from competitive homodimerization of the sub-
strate, and 19 resulted from RCM of 25, which was formed
by migration of the double bond in 15 prior to cyclisation five-membered ring series), the entropic factor that ac-
(Scheme 2). counts for cyclization is less pronounced in this case. The
This side reaction was reported several times, and dif- use of catalyst B instead of C gave essentially the same re-
ferent additives were used for its suppression.[17] Accord- sults.
ingly, we carried out the RCM reaction of 15 in the presence
Finally, we were interested in using substrate 13 to afford
of 1,4-benzoquinone (10 mol-%), which resulted in com- a seven-membered ring azaheterocyclic vinylphosphonate,
plete elimination of side product 19 (Table 4, entry 5). The which has never been formed. Instead, only products 26
same result was obtained in the presence of titanium iso- (arising from homodimerization) and 22 (formed by RCM
propoxide (30 mol-%; Table 4, entry 6), but the amount of of the isomerized substrate) were obtained in 60 and 31%
homodimerization product 24[18] remained identical in both yield, respectively, regardless of the catalyst and the condi-
reactions. This high amount of homodimerization product tions employed (Scheme 3). The presence of benzoquinone
reflects the fact that, although the vinylphosphonate moiety or titanium isopropoxide did not improve the reaction out-
is reactive towards the RCM reaction (as exemplified in the come.
Scheme 2. Different products obtained from metathesis of 15.
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C. Garzon, M. Attolini, M. Maffei
SHORT COMMUNICATION
was stirred at room temperature for 1 h. The solvent was removed
in vacuo, and the residue was purified by flash chromatography on
silica gel.
Synthesis of Diethyl Azaheterocyclic Vinylphosphonates by RCM:
A solution of N-tosyl-N-(ω-alkenyl)aminomethylvinyl phosphonate
(0.26 mmol, 1 equiv.) in dichloromethane (10 mL) was added to a
solution of catalyst B or C (0.013 mmol, 0.05 equiv.) in anhydrous
and degassed dichloromethane (3 mL) under an atmosphere of ar-
gon. The mixture was heated at reflux for 24 h, with TLC monitor-
ing. After total consumption of the reagent, the solvent was re-
moved in vacuo. The residue was dissolved in ethyl acetate (10 mL)
and charcoal (1 g) was added. The suspension was stirred at room
temperature for 48 h and filtered. Ethyl acetate was removed
in vacuo, and the residue was purified by flash chromatography.
Scheme 3. Different products obtained from metathesis of 13.
Conclusions
In summary, we have described the synthesis of aza-
heterocyclic vinylphosphonates through the RCM reaction
of
N-tosyl-N-(ω-alkenyl)aminomethylvinylphosphonates,
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR and 13C NMR assignments and copies of the 1H
NMR, 13C NMR, and 31P NMR spectra.
which are easily obtained by DABCO-catalyzed substitu-
tion of diethyl α-(tert-butoxycarbonylmethyl)vinylphos-
phonate (1) by N-(ω-alkenyl)-N-tosylamides. Whereas five-
membered ring azaheterocyclic vinylphosphonates were
easily obtained in good yields, their six-membered counter-
parts gave less satisfactory results, as side reactions such
as homodimerization and double-bond isomerization of the
substrate occurred to a large extent. Although the latter re-
action could be suppressed by the presence of additives in
the RCM reaction, homodimerization remains a competi-
tive side reaction. Nevertheless, the separation of this
homodimerization byproduct from the desired compound
by flash chromatography was a rapid and efficient task, and
as such, the reaction remains synthetically useful. Finally,
additional appeal of this methodology lies in the fact that
chiral compounds may be obtained easily.
Acknowledgments
Financial support by the French Ministère de la Recherche et de
la Technologie (grant to C. G.) and by the Centre National de la
Recherche Scientifique (CNRS) is gratefully acknowledged. Dr.
Herve Clavier is thanked for fruitful discussions.
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A
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Received: March 12, 2013
Published Online: May 5, 2013
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