M. E. Dmitriev, V. V. Ragulin / Tetrahedron Letters 53 (2012) 1634–1636
1635
phosphorus–carbon bond immediately following attack of anion A
PIII-OC(O)CF3 phosphonite 6 with the acylimine cation 7, and there-
fore the molecule of 8 contains a mixed anhydride PIV-OC(O)CF3
fragment. 31P NMR data of the reaction mixture confirmed the
structures of esters 8.
on the electrophilic carbon atom of the acylic fragment of the PIII-
OAc derivative 2 with subsequent formation of the N-protected a-
aminoalkylphosphorylic compound 3 and isolation of AcA accord-
ing to an Arbuzov-type reaction11(Scheme 1).
Usually the 31P NMR spectrum of the reaction mixture, when
complete, demonstrated a singlet due to phosphinic acid 3 and
two signals for the diastereomers of the corresponding ester 8.
The appearance of diastereomeric forms for the ester 8 can be ex-
Golderman and Soroka have described the addition of PIII-OAlk
esters to N-alkylalkanimines in the presence of dry HCl via an
Arbuzov-type reaction of N-alkylalkaniminium salts generated
in situ from N-alkylalkanimines.15 These data confirm our opinion
on the reaction mechanism for amidoalkylation of hydrophosph-
orylic compounds in acetic anhydride with acid catalysis.11
plained by the asymmetry at the phosphorus and a-carbon atoms
in phosphinate 8 (Scheme 3). Moreover, the signals of both diaste-
reomers of 8 in the 31P NMR spectrum were complicated by the
spin-spin interaction between the 31P and 19F atoms (see examples
of the 31P NMR spectra of reaction mixtures in the Supplementary
data, part III).
We also propose the existence of an equilibrium between
poorly-stable CF3(O)CO-PIV esters 8 and the corresponding N-alkyl-
oxycarbonylphosphinic acids 3 in the reaction medium (Scheme 3).
Following aqueous treatment of the reaction mixture the equilib-
rium shifts toward the stable acids 3, which were isolated as white
powders or solids.
In this Letter, we report the synthesis of N-protected
a-amin-
oalkylphosphinic acids 3 by the reaction of alkylphosphonous acids
4, trifluoroacetic anhydride (TFAA) and N,N0-alkylidenebiscarba-
mates 5 in toluene or dichloromethane at room temperature fol-
lowed by aqueous treatment of the reaction mixture (Scheme 2).
Our route consisted of the in situ generation of both the PIII-
OC(O)CF3 derivative of trivalent phosphorus and the N-alkoxycar-
bonylimine cation for the Arbuzov-type reaction by the addition
of TFAA (1 equiv) to a mixture of phosphonous acid 4 and N,N0-
alkylidenebiscarbamate 5 (Scheme 3).
We propose that the starting alkylphosphonous acid 4 can react
with TFAA to give the reactive phosphonite, X-P{OC(O)CF3}2 6 and
trifluoroacetic acid (TFA) (Scheme 3). The latter can protonate the
oxygen (C@O) or nitrogen atoms of biscarbamate 5 followed by
The isolated N-protected phosphinic acids 3 are low-ionizing
acids in aprotic solvents. Typically, the 31P NMR spectra of 3, con-
taining one chiral a-carbon atom, in chloroform-D solution, show
two signals due to the diastereomers, which can be explained by
the asymmetry at the phosphorus atom also. The slow proton ex-
change in the P(O)OH fragment of acid 3 permits the observation
of both diastereomers of phosphinic acids 3 in CDCl3 or anhydrous
DMSO-d6 solutions. The 31P NMR spectrum of N-protected phos-
phinic acid 3 in CD3OD was usually a singlet. We also observed a
singlet in the 31P NMR spectrum of this N-protected phosphinic
acid 3 in CDCl3 after the addition of CD3OD or TFA, which can accel-
erate proton exchange in the P(O)OH fragment of acid 3 with re-
spect to the 31P NMR time scale.
In conclusion, we have presented new data confirming the ear-
lier proposed mechanism for amidoalkylation of hydrophosphory-
lic compounds involving an Arbuzov-type reaction step. Moreover,
we have described a new and milder procedure for the synthesis of
N-protected a-aminophosphinic acids in organic solvents. The use
of biscarbamates as stable synthetic equivalents of unstable alde-
formation of the N-alkoxycarbonylimine cation (and salt)
7
(Scheme 3).11 The highly reactive N-alkoxycarbonylimine salts 7
generated in situ from N,N0-alkylidenebiscarbamates 5 react with
phosphonites
6 to give N-protected a-aminophosphinates 8
according to an Arbuzov-type reaction (Scheme 3).
Nucleophilic attack of the phosphorus atom of the intermediate
PIII-OC(O)CF3 compound 6 on the positively charged carbon atom
of the N-alkoxycarbonylimine cation 7 occurs followed by forma-
tion of the phosphorus–carbon bond and immediately following
attack of CF3COOꢀ on the electrophilic carbon of the acylic frag-
ment of the PIII-OC(O)CF3 phosphonite 6 with subsequent forma-
tion of the PIV-OC(O)CF3 ester of desired phosphinic acid 8 and
trifluoroacetic anhydride (TFAA) (Scheme 3). The latter can again
react with the starting phosphonous acid 4 to give intermediate
PIII-OC(O)CF3 phosphonite 6 and a molecule of TFAA, which cata-
lyzes the formation of the intermediate N-alkoxycarbonylimine
cation 7 and the process is repeated (Scheme 3).
hydes should be of interest for the synthesis of difficult to access
N-protected phosphinic
General procedure for the synthesis of
a,
a0-pseudo-dipeptides.
a-amidoalkylphosphory-
We have found that alkylphosphonous acids 4 react with TFAA
lic compounds 3a–o by reaction of alkylphosphonous acids 4, tri-
fluoroacetic anhydride and N,N0-alkylidenebiscarbamates 5.
TFAA (3 mmol) was added slowly at room temperature to a stir-
red mixture of the corresponding phosphonous acid of type 4
(3 mmol) and alkylidene-N,N0-biscarbamate 5 (3 mmol) in toluene
or CH2Cl2 (3–5 mL). Stirring was continued at room temperature
for 3–45 h, and the reaction progress was monitored by 31P NMR
spectroscopy. After evaporation of the solvents the residue was
partitioned between sodium hydrogencarbonate solution (10 ml)
and Et2O (10 ml) or hexane/toluene (10/1 ml). The precipitated
alkylcarbamate was filtered and the aqueous part of the filtrate
and N,N0-benzylidene- and N,N0-alkylidenebiscarbamates 5 in tolu-
ene or dichloromethane to give the desired N-protected
a-amin-
oalkylphosphinic acids 3 (Table 1) in good to moderate yields
after aqueous treatment of the reaction mixture.
Also, we found that the optimum ratio of components
(4:5:TFAA) was 1:1:1 (see Table 1 and Supplementary data, part II).
The reaction progress was monitored by 31P NMR spectroscopy
and we found that esters of N-alkyloxycarbonylphosphinic acids 8
were formed successfully in the reaction medium. We propose that
these esters 8 are products of in situ Arbuzov-type reaction of
1) r.t., CH2Cl2
O
AlkO
CF3
O
H
N
or MePh;
2) H2O
O
P
R
HN
O
O
O
O
O
+
H
X
+
N
H
OAlk
X
P
OH
4
R
OH
OAlk
CF3
5
3
X = Me, EtOC(O)CH2CH2, EtOC(O)CH(Me)CH2
R = Me, Et, i-Pr, i-Bu, CH(Me)CH2Me, Ph Alk = Et, CH2Ph
Scheme 2. Synthesis of N-protected a-aminoalkylphosphinic acids 3.