Tandem addition of trialkyl phosphites to α,β-unsaturated imines: A comparison with silylated phosphites

Article abstract of DOI:10.1021/jo061256b

(Chemical Equation Presented) Trialkyl phosphites were evaluated for addition reactions to α,β-unsaturated imines. An acidic medium is required to allow consecutive 1,4- and 1,2-addition to occur. In this manner, 3-phosphonyl-1-aminophosphonates, phosphon

Full text of DOI:10.1021/jo061256b

Recently, we reported for the first time a tandem 1,4-1,2-
addition of dialkyl trimethylsilyl phosphite to R,â-unsaturated
imines 4 derived from cinnamaldehyde.4 As a consequence of
the fast but reversible 1,2-addition of dialkyl trimethylsilyl
phosphite to aldimines, this reaction was erroneously reported
earlier to proceed with complete 1,2-regioselectivity.5 Because
of the double addition of dialkyl trimethylsilyl phosphite under
acid catalysis, we were able to obtain 3-phosphonyl-1-amino-
phosphonates 6,4 which can be considered as glutamate ana-
logues and may therefore be of interest as selective Glu agonists
or antagonists.3
Tandem Addition of Trialkyl Phosphites to
r,â-Unsaturated Imines: A Comparison with
Silylated Phosphites
Ellen Van Meenen, Kristof Moonen,† Annelies Verwe´e, and
Christian V. Stevens*
Research Group SynBioC, Department of Organic Chemistry,
Faculty of Bioscience Engineering, Ghent UniVersity, Coupure
Links 653, B-9000 Ghent, Belgium
The unique reactivity of dialkyl trimethylsilyl phosphite
toward R,â-unsaturated imines 4 has prompted us to evaluate
the reactivity of other phosphorus nucleophiles. In particular,
the resemblance of trialkyl phosphites to dialkyl trimethylsilyl
phosphites, suggests these nucleophiles as potential tandem
addition candidates. Both phosphite reagents occur in the highly
nucleophilic σ3λ3 form.
chris.steVens@UGent.be
ReceiVed June 19, 2006
Addition of trialkyl phosphite to R,â-unsaturated imines 4
was reported to proceed with complete 1,4-regioselectivity when
a steric nitrogen substituent (t-Bu) was used as described by
Teulade and Savignac.6 In this case, imine 4a was treated with
0.96 equiv of triethyl phosphite in ethanol. A slight excess of
formic acid (1.04 equiv) was added to dealkylate the intermedi-
ate phosphonium ion. However, when the reaction was repeated
with 1 equiv of triethyl phosphite and i-Pr imine 4b, a small
amount of 3-phosphonyl-1-aminophosphonate 6b could be
detected in the crude reaction mixture after standard aqueous
workup and 31P NMR analysis.7 With an N-phenyl substituent,
the 3-phosphonyl-1-aminophosphonate 6c even becomes the
major product next to a considerable amount of unreacted
starting material 4c since only 1 equiv of triethyl phosphite is
added (Scheme 1).
Trialkyl phosphites were evaluated for addition reactions to
R,â-unsaturated imines. An acidic medium is required to
allow consecutive 1,4- and 1,2-addition to occur. In this
manner, 3-phosphonyl-1-aminophosphonates, phosphonic
acid analogues of glutamate, are obtained in good yields
(32-90%). The reaction is mainly influenced by the steric
bulk of the nitrogen substituent: less steric N-substituents
lead to better yields of the tandem adducts.
These results prompted us to search for appropriate reaction
conditions to achieve complete conversion of the imines 4 to
the 3-phosphonyl-1-aminophosphonates 6. The reaction pro-
ceeded vigorously upon addition of 2 equiv of formic acid to a
mixture of 2 equiv triethyl phosphite and the substrate 4 in
ethanol. Complete conversion to the 3-phosphonyl-1-amino-
phosphonates 6 was obtained in typically 30 min at room
temperature. The more sterically demanding i-Pr derivative 4b
required 24 h to achieve complete conversion, and the t-Bu-
Glu agonists or antagonists are not only important for the
characterization of different Glu receptor subtypes, but also for
the treatment of central nervous system diseases, such as
epilepsy, Huntington’s disease, Parkinson’s disease, dementia,
and chronic pain. Substitution of the carboxylate group by a
bioisosteric phosphonic acid is known to increase receptor
selectivity. Several phosphonic acid analogues of glutamate have
shown important activities in this area such as (S)-AP4 1, (S)-
AP5 2, and (R)-AP5 3. Where 1 and 2 are group III metabotropic
Glu Receptor (mGluR) agonists,1 phosphonic acid analogue 3
is a potent and selective competitive N-methyl D-aspartate
(NMDA, ionotropic GluR) antagonist.2 Further research into
new bioisosters has been indicated as a fruitful path to new
subtype-selective mGluR ligands.3
(1) (a) Tanabe, Y.; Nomura, A.; Masu, M.; Shigemoto, R.; Mizuno, N.;
Nakanishi, S. J. Neurosci. 1993, 13, 1372; (b) Nakajima, Y.; Iwakabe, H.;
Akazawa, C.; Nawa, H.; Shigemoto, R.; Mizuno, N.; Nakanishi, S. J. Biol.
Chem. 1993, 268, 11868; (c) Okamoto, N.; Hori, S.; Akazawa, C.; Hayashi,
Y.; Shigemoto, R.; Mizuno, N.; Nakanishi, S. J. Biol. Chem. 1994, 269,
1231.
(2) (a) Bra¨uner-Osborne, H.; Krogsgaard-Larsen, P. Br. J. Pharmacol.
1998, 123, 269; (b) Johansen, P. A.; Chase, L. A.; Sinor, A. D.; Koerner,
J. F.; Johnson, R. L.; Robinson, M. B. Mol. Pharmacol. 1995, 48, 140.
(3) For excellent reviews on ligands for glutamic receptors, see: Danbolt,
N. C. Prog. Neurobiol. 2001, 65, 1. Bra¨uner-Osborne, H.; Egebjerg, J.;
Nielsen, E. Ø.; Madsen, U.; Krogsgaard-Larsen, P. J. Med. Chem. 2000,
43, 2609.
(4) Moonen, K.; Van Meenen, E.; Verwe´e, A.; Stevens, C. V. Angew.
Chem., Int. Ed. 2005, 44, 7407.
(5) Afarinkia, K.; Cadogan, J. I. G.; Rees C. W. Synlett 1992, 123.
(6) Teulade, M.; Savignac, P. Synthesis 1987, 1037.
(7) Phosphonyl-1-aminophosphonates 6 are generally formed as a mixture
of two diastereomeric pairs. One pair can generally be recognized in the
31P spectrum as two doublets (JPP ≈ 10 Hz), while the other one usually
gives two singlets.
† K. Moonen is aspirant of the Fund for Scientific Research (FWO Vlaan-
deren).
* To whom correspondence should be addressed. URL: http://www.synbioc.-
ugent.be.
10.1021/jo061256b CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/02/2006
J. Org. Chem. 2006, 71, 7903-7906
7903

SCHEME 1. Addition of 1 equiv of Triethyl Phosphite to r,â-Unsaturated Imines 4
SCHEME 2. Proposed Reaction Mechanism of the Tandem 1,4-1,2-Addition of Trialkyl Phosphite to r,â-Unsaturated
Imines 4
SCHEME 3. Push-Pull Mechanism9
TABLE 1. Addition of 2 equiv of Trialkyl Phosphite to
r,â-Unsaturated Imines 4
time yielda diast
imine
R1
R2
R3
t-Bu
i-Pr
Ph
Ph
Bn
R
prod
at rt
(%)
ratio
4a
4b Ph
4c
4c
4d Ph
4e
4f
4g
4h Me
4i
4i
Ph
H
H
H
H
H
H
H
Et
Et
Et
6a
exclusiVe 1,4-addition
6b 24 h
6c 30 min 86
Me 6d 30 min 86
90
38/62
21/79
34/66
33/67
72/28
36/64
Ph
Ph
mechanism (Scheme 2), which is also indicated by the occur-
rence of 1,4-adducts as intermediates (especially with highly
steric demanding nitrogen substituents) and the similar diaster-
eomeric ratios of the final products.4
Et
Et
6e 30 min 78
6f 30 min 70
6g 3 h 72
6h 30 min 54b
Ph
Ph
Me
allyl
p-OMeBn Et
Me Ph
Me Bn
H
H
Et
Et
Et
6i
6j
55 h
30 min 65b 22/78
32c 25/7
59
In the case of trialkyl phosphite, the 1,4-addition is clearly
favored, causing no 1,2-adduct to appear in the reaction mixture.
The 1,4-adduct is the sole reaction intermediate or end product
in case the subsequent 1,2-addition is blocked (e.g., due to steric
hindrance). Previous research showed that the mechanism is
more complicated for the dialkyl trimethylsilyl phosphite
addition.4 In that case, the 1,2-addition is favored kinetically
over the 1,4-addition, causing the 1,2-adducts to appear very
fast in the reaction mixture. Therefore, it should be concluded
that trialkyl phosphite is more sterically demanding in this type
of reactions than dialkyl trimethylsilyl phosphite, which is quite
surprising at first sight comparing the OEt to the OTMS group.
A possible explanation for this unexpected behavior of dialkyl
trimethylsilyl phosphite can be found in the reaction mechanism
of dialkyl trimethylsilyl phosphite additions described in the
literature.8 In this mechanism, coordination of the nitrogen lone
pair with the silicon atom is suggested, which brings the (bulky)
nucleophile in close proximity of the electrophilic center.
Because of the presence of both a nucleophilic and an electro-
philic center in the silylated phosphite 13, the subsequent
transformation then occurs via a classical “push-pull” mech-
anism (Scheme 3).9
furan-2-yl
furan-2-yl
Ph
Ph
Me 6k 2 h
a Yield after acid-base extraction; b Yield after column chromatography
of the evaporated reaction mixture since the product decomposed during
acidic aqueous workup; c Yield after acid-base extraction and additional
column chromatography.
imine 4a even only reacted in a 1,4-fashion (Table 1). This
reactivity is opposite to the results obtained using dialkyl
trimethylsilyl phosphite as a nucleophile. Using dialkyl tri-
methylsilyl phosphite, the highly steric t-Bu group is the best
N-substituent to obtain double adducts, while phenyl, a less
sterically demanding nitrogen substituent, resulted only in the
1,2-adducts.4
As was the case for the dialkyl trimethylsilyl phosphite
tandem addition,4 the acid also plays a crucial role in the trialkyl
phosphite addition. Next to the imine activation and enamine
tautomerization, the acid (or its conjugated base) is required
for dealkylation of the phosphonium intermediates (Scheme 2).
From these experimental results, it was clear that both addition
reactions of trialkyl phosphite or dialkyl trimethylsilyl phosphite
to R,â-unsaturated imines 4 proceed very fast in acidic media,
yielding the corresponding diphosphonates 6 in high yields and
purity. Both reactions proceed via the tandem 1,4-1,2-addition
(8) Evans, D. A.; Hurst, K. M.; Takacs, J. M. J. Am. Chem. Soc. 1978,
100, 3467.
7904 J. Org. Chem., Vol. 71, No. 20, 2006

The 1,4-addition of dialkyl trimethylsilyl phosphite, on the
other hand, probably proceeds similarly to that of trialkyl
phosphite, i.e., without prior coordination with nitrogen. Fur-
thermore, the fast 1,2-addition of dialkyl trimethylsilyl phosphite
has proven to be a reversible reaction, which makes the 1,2-
adduct only a transient intermediate. Therefore, only limited
amounts of substrate (imine) are available for the 1,4-addition,
causing it to be the rate-determining step, which nevertheless
is favored by sterically demanding nitrogen substituents. The
final 1,2-addition proceeds again smoothly through nitrogen-
silicon coordination.
When trialkyl phosphite is used, no 1,2-adduct formation is
observed because of the lack of coordination. 1,4-Addition
proceeds through a classical nucleophilic attack. The final 1,2-
addition is now the rate-determining step, which is disfavored
by the sterically demanding nitrogen substituents. This is the
reason Teulade and Savignac only reported 1,4-addition to the
steric t-Bu-imines.6 These exceptional reaction kinetics, rather
than simply steric differences, explain the opposite reactivity
order for both reagents.
The generality of this method has been proven by selecting
different nitrogen substituents, both aromatic and aliphatic R,â-
unsaturated aldimines and different phosphorus nucleophiles
(Table 1). When trimethyl phosphite (R ) Me) was used, instead
of triethyl phosphite, methanol was chosen as a solvent (in stead
of ethanol) to prevent transesterification; however, the reaction
appeared to slow and more impurities were formed. Therefore,
the solvent is probably an important factor influencing the
reactivity of both nucleophiles.
during the reaction using preformed aldimines again led to the
formation of 3-phosphonyl-1-aminophosphonate 6 (in small
amounts). Dealkylation of the phosphonium intermediates by
water was confirmed by the detection of methanol or ethanol
in the reaction mixture.
In conclusion, the tandem 1,4-1,2-addition of trialkyl phos-
phites to R,â-unsaturated imines was studied and was found to
be perfectly supplementary to the method previously reported
using dialkyl trimethylsilyl phosphites.4 While the latter method
only allowed the preparation of 3-phosphonyl-1-aminophos-
phonates with considerably sterically demanding nitrogen sub-
stituents (e.g., i-Pr, t-Bu), addition of trialkyl phosphites
proceeded smoothly with little sterically demanding nitrogen
substituents due to the different reactivity of trialkyl phosphite
(higher tendency toward 1,4-addition than 1,2-addition). The
results presented here, together with our previous research,4,12
lead to a better understanding of the special reactivity and
regioselectivity of three different phosphorus nucleophiles
toward R,â-unsaturated nucleophiles: dialkyl phosphites,12
dialkyl trimethylsilyl phosphites4 and trialkyl phosphites. By
selecting the appropriate phosphorus reagent and reaction
conditions, it is now possible to obtain 1,2-, 1,4-, and 1,2-1,4-
adducts in high yields and purity. Furthermore, the spectroscopic
characteristics of 3-phosphonyl-1-aminophosphonates 6 have
been properly assessed, which allows their identification as
potential minor impurities in so-called exclusive R-aminophos-
phonylation protocols in the future.
Experimental Section
In addition, Kabachnik-Fields-type three-component reac-
tions are often employed for the preparation of R-aminoalkyl
phosphonates.10 To investigate the possibility that the above-
described tandem 1,4-1,2-addition also operates under these
conditions, the method reported by Kudrimoto and Bommena
was selected as a model.11 This method involves a solvent-free
three-component reaction between an aldehyde, an amine, and
a trialkyl phosphite, which was reported to yield exclusively
R-aminoalkyl phosphonates under the action of (bromodimeth-
yl)sulfonium bromide (Me2S‚Br2), even when an R,â-unsatur-
ated aldehyde was used. However, when cinnamaldehyde was
reacted with i-Pr-amine or aniline in the presence of 2 equiv of
trimethyl phosphite and 0.1 equiv of Me2S‚Br2, small amounts
of 3-phosphonyl-1-aminophosphonates 6b,d could be detected
by 31P NMR7 in the crude reaction mixture after standard
aqueous workup. Evaluating different time-temperature com-
binations, however, never resulted in complete conversion to
the 3-phosphonyl-1-aminophosphonates 6b,d (maximum up to
60% in the reaction mixture). The catalysis of this reaction by
(bromodimethyl)sulfonium bromide seems to be less efficient
than the acid catalysis discussed in the previous paragraph.
Furthermore, the water that is liberated during the condensation
reaction is required for the dealkylation of the intermediate
phosphonium ions as the reaction did not proceed when
aldimines were used directly in the reaction. Addition of water
General Procedure for the Synthesis of 3-Phosphonyl-
1-aminoalkyl Phosphonates 6. R,â-Unsaturated imine 4 (5 mmol)
was dissolved in 15 mL of absolute ethanol (or methanol in case
of trimethyl phosphite) in an oven-dried flask. Under a nitro-
gen atmosphere, 10 mmol of triethyl phosphite (or trimethyl
phosphite) and 10 mmol of formic acid were added consecu-
tively. When complete conversion was obtained (see Table 1), the
solvent was evaporated under reduced pressure. The crude product
was dissolved in 25 mL of diethyl ether and poured into 25 mL of
1 M aqueous HCl. The aqueous phase was washed twice with 15
mL of diethyl ether and made basic by addition of 1 N NaOH and
extracted three times with 20 mL of dichloromethane. The
3-phosphonyl-1-aminophosphonate 6 was obtained in satisfactory
purity after drying (MgSO4) and evaporation of the solvent. To
obtain the 3-phosphonyl-1-aminophosphonate perfectly pure, col-
umn chromatography with silica gel as a stationary phase and a
mixture of CH3CN, CH2Cl2, and MeOH (80/18/2) as a mobile phase
was appropriate.
Product Characterization of One Representative Example:
[3-(Dimethoxyphosphonyl)-3-phenylamino-1-phenylpropyl]phos-
phonic Acid Dimethyl Ester (6d). The product was obtained as a
mixture of two diastereomeric pairs (ratio: 34/66). 1H NMR δ (300
MHz, ppm): 2.29 (2H, multiplet), 2.52-2.71 (2H, multiplet), 3.38-
3.83 (4H, multiplet), 3.48 (3H, d, JHP ) 10.5 Hz), 3.49 (3H, d, JHP
) 10.5 Hz), 3.54 (3H, d, JHP ) 10.2 Hz), 3.65 (3H, d, JHP ) 11.0
Hz), 3.68 (3H, d, JHP ) 10.5 Hz), 3.69 (3H, d, JHP ) 10.5 Hz),
3.71 (3H, d, JHP ) 9.1 Hz), 3.78 (3H, d, JHP ) 10.2 Hz), 6.34 (2H,
d, J ) 8.3 Hz), 6.43 (2H, d, J ) 8.3 Hz), 6.46-6.61 (2H, multiplet),
6.78-7.15 (4H, multiplet), 7.16-7.37 (10H, multiplet). 13C NMR
δ (75 MHz, ppm): 31.1 (d, J ) 8.1 Hz, CH2), 32.1 (CH2), 39.9
(dd, JCP ) 139.6 Hz, JCP ) 13.8 Hz, CH), 40.2 (dd, JCP ) 137.3
Hz, JCP ) 8.1 Hz, CH), 48.1 (dd, JCP ) 154.6 Hz, JCP ) 16.2 Hz,
CH), 48.6 (dd, JCP ) 155.9 Hz, JCP ) 11.5 Hz, CH), 52.6 (d, JCP
(9) Wozniak, L.; Chojnowski, J. Tetrahedron 1989, 45, 2465.
(10) (a) Chandrasekhar, S.; Narsihmulu, C.; Shameem Sultana, S.;
Saritha, B.; Jaya Prakash, S. Synlett 2003, 505. (b) Heydari, A.; Karimian,
A.; Ipaktschi, J. Tetrahedron Lett. 1998, 39, 6729. (c) Chandrasekhar, S.;
Prakash, S. J.; Jagadeshwar; V., Narsihmulu, C. Tetrahedron Lett. 2001,
42, 5561. (d) Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141. (e)
Kaboudin, B.; Rahmani, A. Synthesis 2003, 2705. (f) Kaboudin, B.; Nazari,
R. Tetrahedron Lett. 2001, 42, 8211.
(12) Van Meenen, E.; Moonen, K.; Acke, D.; Stevens, C. V. ArkiVoc
2006, i, 31.
(11) Kudrimoto, S.; Bommena, V. R. Tetrahedron Lett. 2005, 46, 1209.
J. Org. Chem, Vol. 71, No. 20, 2006 7905

) 6.9 Hz, CH3), 52.8 (d, JCP ) 6.9 Hz, CH3), 53.4 (d, JCP ) 5.8
Hz, CH3), 53.5 (d, JCP ) 5.8 Hz, CH3), 113.6 (CH), 113.9 (d, JCP
) 10.4 Hz, CH), 118.1 (CH), 118.5 (CH), 127.6 (CH), 127.69 (CH),
127.74 (CH), 128.56 (CH), 128.59 (CH), 128.7 (CH), 128.8 (CH),
129.0 (CH), 129.2 (CH), 129.25 (CH), 129.28 (CH), 129.33 (CH),
129.4 (CH), 129.5 (CH), 129.57 (CH), 129.63 (CH), 129.7 (CH),
Acknowledgment. We thank the Fund for Scientific Re-
search Flanders and the Ghent University Research Fund for
financial support of this research.
Supporting Information Available: General experimental
methods, experimental procedures, and characterization data (1H
NMR, 13C NMR, 31P NMR, MS, IR) and 13C NMR spectra of the
compounds 6b-k. This material is available free of charge via the
Internet at http://pubs.acs.org.
134.17 (d, J ) 6.9 Hz, C), 135.88 (C), 146.12 (C), 146.63 (C). 31
P
NMR δ (121 MHz, ppm): 28.47, 28.74 (d, JPP ) 9.7 Hz), 30.76,
31.30 (d, JPP ) 9.7 Hz). IR ν (cm-1): 3301 (N-H), 1243 (br, Pd
O), 1043 (br, P-O). MS m/z: 428 ([M + H]+, 100), 318 ([M + H
- PO(OMe)2]+, 10).
JO061256B
7906 J. Org. Chem., Vol. 71, No. 20, 2006