One-pot tandem 1,4-1,2-addition of phosphites to α,β-unsaturated imines for the synthesis of glutamic acid analogues

Article abstract of DOI:10.1002/anie.200501830

(Chemical Equation Presented) Evidently so: New mechanistic findings indicate that addition of dialkyl trimethylsilyl phosphites to α,β-unsaturated imines has been incorrectly reported as an exclusive 1,2-addition. When α,β-unsaturated imines are used as

Full text of DOI:10.1002/anie.200501830

Angewandte
Chemie
Synthetic Methods
DOI: 10.1002/anie.200501830
One-Pot Tandem 1,4–1,2-Addition of Phosphites
to a,b-Unsaturated Imines for the Synthesis of
Glutamic Acid Analogues**
Kristof Moonen, Ellen Van Meenen, Annelies VerwØe,
and Christian V. Stevens*
Amino phosphonates and their corresponding amino phos-
phonic acids are known as amino acid mimetics and, there-
fore, affect the physiological activity of the cell.[1] The
synthesis of 1-alkylamino phosphonates by a reaction of a
dialkyl phosphite and an imine under thermal conditions had
been described in the early 1950s.[2] However, dialkyl
phosphites are generally considered to be poor nucleophiles
because they exist predominantly in a s4l5 configuration.[3]
Dialkyl trimethylsilyl phosphites were presented by Afarinkia
et al. as excellent mild phosphonylation agents because the
more nucleophilic s3l3 form of the dialkyl phosphite reagent
could be obtained by O-silylation with trimethylsilyl chloride
(TMSCl) in dichloromethane and triethylamine as the base.[4]
Furthermore, exclusive 1,2-addition to a,b-unsaturated
imines containing a phenyl group was reported by the same
authors using diethyl trimethylsilyl phosphite.[5] During our
research into azaheterocyclic phosphonates,[6] we planned to
use this phosphonylation reaction with a,b-unsaturated
imines 5a–d derived from cinnamaldehyde. The diethyl
trimethylsilyl phosphite was prepared in situ, as described
previously.[4] The reaction mixture consisted mainly of the 1,2-
adduct 9a (31P NMR: d = 24.44 ppm) and residual starting
material after 24 h of reaction with the imine 5a. However,
several small 31P NMR signals were present and became more
abundant upon prolonged reaction times. The minor peaks
appeared as two doublets (J = 9.7 Hz) next to two singlets and
could be assigned to be the double-addition product 6a (two
diastereomers, ratio: 27:73) after its isolation in very low yield
by column chromatography. The same type of product was
obtained using imines 5b–d in increasing amounts propor-
tional to the steric bulk of the N-substituent, which also
explains the decreasing yields of 1,2-adducts when more
sterically demanding N-substituents were used in the original
[*] K. Moonen,[+] E. Van Meenen, A. VerwØe, Prof. Dr. C. V. Stevens
Research Group SynBioC
Department ofOrganic Chemistry
Faculty ofBioscience Engineering
Ghent University, Coupure links 653, 9000 Ghent (Belgium)
Fax: (+32)9-264-6243
E-mail: chris.stevens@ugent.be
[+] K.M. is aspirant of the Fund for Scientific Research (FWO
Vlaanderen).
[**] We thank the Fund for Scientific Research Flanders and Ghent
University for financial support of this research.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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report.[5] With a N-phenyl substituent, however, only 1,2-
addition was observed.
though the latter was said to act as a catalyst in the reaction
mechanism proposed by Afarinkia et al.[4] Addition of NH4Cl
led to approximately the same result as obtained before
(complete conversion in 72 h) and acidification of the
reaction medium was observed. Therefore, (NH4)2SO4 was
selected as a more acidic salt to replace the triethylammo-
nium salts after filtration, thus leading to a remarkable
acceleration of the reaction rate (complete conversion after
3 h of reflux). Moreover, when diethyl trimethylsilyl phos-
phite was mixed with an imine in dry dichloromethane, the
reaction proceeded violently upon addition of one equivalent
of concentrated sulfuric acid to yield 6c as a single product in
30 minutes at room temperature. Also with other a,b-
unsaturated imines, complete conversion into the correspond-
ing PAP was observed.[11] Diastereomeric ratios were deter-
The obtained diphosphonates can be of major importance
because of their high similarity to glutamic acid. (S)-Glutamic
acid (Glu) is the main excitatory neurotransmitter in the
central nervous system (CNS) and operates through two main
heterogeneous classes of receptors: ionotropic and metabo-
tropic Glu receptors (iGluRs and mGluRs, respectively).
Both classes are further subdivided into several subclasses,
but the number of functional receptors in the CNS is not
known. Selective Glu agonists and antagonists are not only
important for the characterization of different Glu receptor
subtypes, but also for the treatment of CNS diseases, such as
epilepsy, Huntingtonꢀs disease, Parkinsonꢀs disease, dementia,
chronic pain, and so forth. Therefore, the Glu receptor field
has been, and continues to be, in a state of almost explosive
development.[7] A number of phosphonic acid Glu analogues
are known as potent selective Glu antagonists or agonists
(Scheme 1). Substitution of the carboxylate group by a
1
mined from 31P and H NMR integration measurements (see
Table 1).
As the reaction of imine 5b with diethyl trimethylsilyl
phosphite catalyzed by sulfuric acid proceeds too rapidly to
detect any reaction intermediates, triethylammonium chlo-
ride was selected as a less potent catalyst to monitor the
reaction as a function of time. Rapid disappearance of 5b was
observed, whereas the amount of the 1,2-adduct grew
accordingly to a maximum. The PAP 6c was formed more
slowly, however, finally becoming the only end product of the
reaction (see Figure 1). This kind of behavior suggests that the
imine is protonated first by the acid and becomes activated
towards nucleophilic attack of the dialkyl trimethylsilyl
phosphite (Scheme 2). 1,2-Addition is clearly the fastest
reaction pathway and the N-trimethylsilyl 1-alkylamino-
phosphonate 9 is formed after nucleophilic attack of the
nitrogen atom at the trimethylsilyl group of phosphonium salt
8. These three steps all occur in an equilibrium which was
demonstrated in a separate experiment (Scheme 3). When
dimethyl (1-amino-1-phenylmethyl)phosphonate (14) was N-
silylated using TMSCl and subsequently treated with a large
excess of diethyl trimethylsilyl phosphite, diethyl phospho-
nate 15 was mainly recovered along with small amounts of 14.
When the same experiment was repeated without silylation
and using diethyl phosphite, no exchange at all occurred. This
clearly demonstrated the reversibility (8Ð9) of the reaction
and the leaving-group capacity of the intermediate positively
charged phosphonium group.
The initial equilibrium allows two possible routes to the
PAP 6 (Scheme 2). The first (pathway A) is complete
reversion into the iminium salt 7 followed by a slow 1,4-
addition, whereas the second (pathway B) starts with an SN’-
like substitution of the phosphonium group. Both routes yield
the same intermediate enamine 10, which subsequently
isomerizes to the imine 11. A final 1,2-addition then yields
PAP 6, which only shows phosphonyl exchange at the
1 position.
However, enamine 10 or imine 11, the suggested inter-
mediates in this reaction mechanism (Scheme 2), were never
observed. Furthermore, the proposed reaction mechanisms
require an external proton source, as one equivalent of
protons is incorporated in the final product 6. Therefore, an
experiment was performed using only 0.1 equivalents of
sulfuric acid together with 2.0 equivalents of P(OEt)2OTMS.
Scheme 1. Selected examples ofphosphonic acid Glu analogues with
GluR-agonist or -antagonist activity.
bioisosteric phosphonic acid group is known to increase
receptor selectivity. For example, (S)-AP4 (1) is shown as a
group III mGluR agonist, some tenfold more potent than
Glu.[9] (S)-AP5( 3) activates the same group III receptors, but
with markedly lower potency and selectivity. (R)-AP5( 4) on
the other hand can not be shown to interact with mGluRs, but
is a potent and selective competitive N-methyl d-aspartate
(NMDA; iGluR) antagonist.[8] The diphosphonic acid deriv-
ative of AP4 has been tested several times as a Glu analogue
without any activity so far.[10] However, further research into
new bioisosteres has been indicated as a fruitful path to new
subtype-selective mGluR ligands.[7]
The previous results prompted us to look for appropriate
reaction conditions to achieve higher yields of the desired Glu
bioisosteres. When the imine 5b was added to two equivalents
of diethyl trimethylsilyl phosphite, prepared in situ, complete
conversion of the imine into the 3-phosphonyl 1-alkylamino
phosphonate (PAP) 6c was achieved after 72 h at reflux.
However, when the diethyl trimethylsilyl phosphite was
filtered first to remove the triethylammonium salts, no
reaction occurred at all when the imine was added. Also no
reaction was observed on addition of LiCl or TMSCl, even
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Table 1: Conversion ofimines 5 to PAP 6 using P(OR)2OTMS (2 equiv) and H2SO4 (1 equiv).
Imine Product
Yield[a] [%]
82
d.r. [%]
29:71
5a
5b
6a (R=Et)
6b (R=Me)
6c (R=Et)
70
80
19:81
29:71
5c
5d
6d (R=Me)
6e (R=Et)
77
78
32:68
33:67
6 f (R=Me)
6g (R=Et)
82
85
49:51
36:64
5e
5 f
6h (R=Me)
6i (R=Me)
46
20
22:78
12:88
5g
5h
6j (R=Me)
6k (R=Me)
74
60
36:64
–
[a] Yield after column chromatography or acid–base extraction.
1,2-adduct using the remaining phosphite in the reaction
mixture. This result shows that water can also act as a proton
source for this reaction. The structure of intermediate imine
11 was confirmed in a separate experiment (Scheme 4) using
subequivalent amounts of sulfuric acid or the non-protic
Lewis acid AlCl3 as an activator, together with a limiting
amount of diethyl trimethylsilyl phosphite (0.9 equivalents).
Under these conditions, there was no free phosphite in the
work-up and the intermediate 1,4-adduct 16 was obtained in a
mixture of 6 and starting material 5. The structure of 16 was
confirmed after hydrolysis to the corresponding aldehyde 17
and comparison with literature data.[12]
Figure 1. Composition (c) ofthe reaction mixture during the reaction
^
of 5b ( ) with P(OEt)2OTMS in the presence ofHNEt 3Cl, measured
by NMR spectroscopy. 1,2-Adduct 9 (&) appears as an intermediate in
From the evolution of the reaction intermediates as a
function of the reaction time (Figure 2), it is clear that the 1,2-
adduct 9 is not a real intermediate of the PAP formation.
After the initial 1,2-adduct formation (which can also be
noticed in Figure 1), the 1,2-addition is also blocked by the
absence of protons. Furthermore, the observation that a
considerably higher reaction rate results for imines bearing
more sterically demanding N-substituents (tBu > iPr> Bn @
Ph) is in favor of the tandem addition, as the 1,2-addition
should be slowed down by the steric bulk. One case of a
~
the reaction, whereas PAP 6c ( ) seems to be the final product.
The reaction proceeded very sluggishly under these condi-
tions, and the formation of 6 was stopped completely after 3–
4 h as expected. From that point, the concentration of 10
started to increase (31P NMR: d = ꢀ 27 ppm in the reaction
medium), while the rest of the imine 7 was slowly consumed
(Figure 2). However, addition of water for the work-up led to
the conversion of 10 into 6 and some of the imine 7 into the
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Scheme 4. Isolation and identification of the intermediate 1,4-adduct.
double addition of ketene silyl acetals to a,b-unsaturated
imines has been reported, which also proceeded in a 1,4–1,2-
tandem fashion.[14]
In summary, our observations in this field lead to a new
insight regarding the use of dialkyl trimethylsilyl phosphite
which contradicts earlier research:[5] when this reagent is
present in its apparently most nucleophilic form, dialkyl
trimethylsilyl phosphite fails to react either in a 1,2- or a 1,4-
addition in the absence of a protic acid. Furthermore, it has
been demonstrated that dialkyl phosphite itself is able to
convert imines into the corresponding 1-aminoalkyl phos-
phonates with complete 1,2-regioselectivity.[2,13] However, in a
sufficiently acidic medium, dialkyl trimethylsilyl phosphite is
able to convert a,b-unsaturated imines 5 into diphosphonates
6 in one step through a sequential tandem 1,4–1,2-addition
(pathway A of Scheme 2).[15] As the free phosphonic acids of
diphosphonates[16] are potential Glu agonists or antagonists,
our future research will be directed towards the synthesis of
enantiopure PAP derivatives.[17]
Scheme 2. Suggested reaction mechanisms.
Received: May 26, 2005
Published online: October 20, 2005
Scheme 3. Phosphonyl exchange reactions.
Keywords: amino acids · Michael addition · phosphorylation ·
.
reaction mechanisms · regioselectivity
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Figure 2. Composition (c) ofthe reaction mixture during the reaction
of 5c (ꢀ) with P(OEt)2OTMS in the presence of0.1 equivalents of
H2SO4, measured by NMR spectroscopy. Only a small amount of1,2-
~
^
adduct 9 ( ) is formed, whereas PAP 6c ( ) is formed initially very
quickly. When the reaction stops because ofa lack ofprotons, the
concentration ofintermediate enamine 10 (&) starts to increase.
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[11] A typical procedure and spectral data of all products are
available in the Supporting Information.
[12] M.-P. Teulade, P. Savignac, Synthesis 1987, 1037.
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known; all consist of multiple reaction steps: a) E. ꢁhler, S.
Kanzler, Liebigs Ann. Chem. 1994, 867; b) Z. Kudzin, A.
Kotynski, G. Andrijewski, J. Organomet. Chem. 1994, 479, 199;
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-P. Dꢂpfer, A. Balszuweit, Phosphorus Sulfur Relat. Elem. 1983,
14, 171.
[16] PAPs 6 can be dealkylated using TMSBr, see: C. E. McKenna,
M. T. Higa, N. H. Cheung, M. C. McKenna, Tetrahedron Lett.
1977, 155; an example with a general experimental procedure is
included in the Supporting Information.
[17] Spectral data, general procedures, sample spectra, and addi-
tional mechanistic evidence are available in the Supporting
Information.
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