Uncatalyzed One-pot diastereoselective synthesis of α-amino phosphonates under solvent-free conditions

Article abstract of DOI:10.1002/ejoc.201001096

Uncatalyzed one-pot, three-component reactions of aldehydes, chiral α-methylamines, and dimethyl phosphite under solvent-free conditions were used for the diastereoselective synthesis of α-amino phosphonates. The reactions proceeded with extremely high ef

Full text of DOI:10.1002/ejoc.201001096

FULL PAPER
DOI: 10.1002/ejoc.201001096
Uncatalyzed One-Pot Diastereoselective Synthesis of α-Amino Phosphonates
Under Solvent-Free Conditions
Gaurao D. Tibhe,[a] Selene Lagunas-Rivera,[a] Elena Vargas-Díaz,[b]
Oscar García-Barradas,[c] and Mario Ordoñez*[a]
Keywords: Diastereoselectivity / α-Amino phosphonates / Kabachnik–Fields reaction / α-Amino phosphonic acids /
Phosphorus / Multicomponent reactions
Uncatalyzed one-pot, three-component reactions of alde-
hydes, chiral α-methylamines, and dimethyl phosphite under
solvent-free conditions were used for the diastereoselective
synthesis of α-amino phosphonates. The reactions proceeded
with extremely high efficiency under mild conditions and
gave good yields and diastereoselectivities (70:30 to 93:7 dr).
This approach could be useful for the large-scale synthesis
of several α-amino phosphonates.
chemistry.[12] A number of procedures for the stereoselective
synthesis of α-amino phosphonates have been described,
but there are two main pathways: (1) hydrophosphonylation
of imines (Pudovik reaction),[13–15] and (2) three-component
reaction in which an aldehyde, an amine, and a di- or trial-
kyl phosphite react in a one-pot fashion (Kabachnik–Fields
reaction).[16–18]
Introduction
Optically active α-amino phosphonates and α-amino
phosphonic acids are analogues of α-amino acids in which
the planar carboxylic acid group (CO2H) is replaced by a
sterically more demanding tetrahedral phosphonic acid
group (–PO3H2). Compounds of this class are currently at-
tracting interest in organic and medicinal chemistry, as well
as in agriculture, due to their important biological and
pharmacological properties.[1] Thanks to the tetrahedral
configuration at the phosphorus atom, α-amino phos-
phonic acids act as stable analogues of the unstable tetrahe-
dral-carbon transition state in peptide hydrolysis and there-
fore act as enzyme inhibitors.[2] Many natural and synthetic
α-amino phosphonic acids, α-amino phosphonates, and
phosphonopeptides have potential applications as, for ex-
ample, anti-HIV,[3] antibacterial,[4] antibiotic,[5] antican-
cer,[6] antitumor,[7] and antiviral agents.[8] Furthermore, in
agrochemistry a number of α-amino phosphonic acids and
derivatives are used as fungicidal[9] and herbicidal agents.[10]
The biological activity of an α-amino phosphonic acid
or derivative depends on the absolute configuration of the
stereogenic center α to the phosphorus atom.[11] As a result,
routes to optically active α-aminophosphonic acids by ster-
eoselective synthesis have been widely studied in organic
These processes are both catalyzed either by acid or base
and are the most convenient methods for the synthesis of
α-amino phosphonic acids and derivatives in optically pure
form. However, in spite of their potential utility, these meth-
ods typically suffer from one or more disadvantages, such
as high cost, the need for a stoichiometric amount of cata-
lyst, moisture sensitivity, the need for specialized handling
techniques, tedious workup, and non-recyclability of the
catalyst. The use of harmful organic solvents is also unde-
sirable from an environmental point of view, and methods
that reduce solvent use are widely sought. We aimed to de-
velop an environmentally safe method, and here we report
a diastereoselective approach to α-amino phosphonates in-
volving one-pot, three-component reactions of alkane- and
arenecarbaldehydes, chiral amines, and dimethyl phosphite
[HP(O)(OMe)2] under solvent-free conditions (chromatog-
raphy was required for purification). This method is clean
and rapid and affords the corresponding α-amino phos-
phonates with good to excellent yields and moderate to
good diastereoselectivities, while avoiding any need for ad-
dition of any catalyst.
[a] Centro de Investigaciones Químicas, Universidad Autónoma
del Estado de Morelos,
Av. Universidad 1001, 61209 Cuernavaca, Morelos, México
Fax: +52-777-329-7997
E-mail: palacios@ciq.uaem.mx
[b] Escuela Nacional de Ciencias Biológicas del IPN,
11340, México, D. F., México
Results and Discussion
[c] Unidad de Servicios de Apoyo en Resolución Analítica,
Universidad Veracruzana,
Initially, we explored one-pot, three-component reac-
tions [the aldehydes 1, the well-known (S)-α-methylbenzyl-
amine (2a; R = Me, α-MBA) as the chiral source, and
HP(O)(OMe)2 (3)] under solvent-free conditions in the ab-
Luis Castelazo Ayala s/n, Col. Industrial Animas,
91190 Xalapa, Veracruz, México
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001096.
Eur. J. Org. Chem. 2010, 6573–6581
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6573

M. Ordoñez et al.
FULL PAPER
sence of a catalyst. The reaction mixtures were stirred at influenced by the size of the alkyl group in the α-position
80 °C for 5–8 h and gave the expected α-amino phosphon- of the chiral amine. The results are summarized in Table 1
ates 4a–f. The results are summarized in Table 1 (Entries 1– (Entries 7–12).
6).
α-MBA, phenylglycinol, and esters of phenylglycine in
optically pure form and in both configurations have been
used as the chiral sources for diastereoselective syntheses
of α-amino phosphonates under three-component catalyzed
conditions, but to the best of our knowledge (S)-1-(1Ј-
naphthyl)ethylamine (2c) had not been used in this pro-
cess.[22] In order to examine the diastereoselectivity in the
synthesis of α-amino phosphonates, it was of interest to
evaluate the amine 2c as a chiral source. We anticipated that
the diastereoselectivity might be increased as the size of the
aryl group increased from phenyl to 1-naphthyl; experimen-
tally, however, three-component reactions of aliphatic and
aromatic aldehydes, the amine 2c, and dimethyl phosphite
under solvent-free conditions and in the absence of catalyst
afforded mixtures of α-amino phosphonates 6a–f in excel-
lent yields but with diastereoselectivities identical to those
obtained with (S)-α-MBA as the chiral source. The results
are summarized in Table 2 (Entries 1–6).
Table 1. Diastereoselective three-component reactions with the chi-
ral amines 2a (RЈ = Me) and 2b (RЈ = Et).
Entry
R
RЈ
Product
Yield [%][a]
dr[b]
1
2
3
4
5
6
7
8
9
Ph
4-ClC6H4
4-MeOC6H4
iBu
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
91
80
89
87
79
86
80
83
82
86
83
83
75:25
72:28
76:24
73.27
71:29
75:25
74:26
76:24
78:22
73:27
72:28
77:23
iPr
tBu
Ph
4-ClC6H4
4-MeOC6H4
iBu
10
11
12
iPr
tBu
Table 2. Diastereoselective three-component reactions with the chi-
ral amines 2c (RЈ = 1-naphthyl) and 2d (RЈ = tBu).
Et
[a] Isolated yields. [b] Determined by 31P NMR (81 and 202 MHz)
examination of the crude reaction mixtures.
With both aliphatic and aromatic aldehydes the reactions
in all cases afforded mixtures of the diastereoisomeric α-
amino phosphonates, with predominance of the (R,S)-4a–f
diastereoisomers. The diastereoisomeric ratios were deter-
mined by 31P NMR spectroscopy at 81 and 202 MHz, and
the configurations of the major and minor diastereoiso-
meric products were determined by analogy with results re-
ported in the literature.[19]
Entry
R
RЈ
Product Yield [%][b]
dr[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
4-ClC6H4
4-MeOC6H4
iBu
Ar[a]
Ar[a]
Ar[a]
Ar[a]
Ar[a]
Ar[a]
tBu
tBu
tBu
tBu
6a
6b
6c
6d
6e
6f
85
79
90
84
91
88
91
90
91
92
92
92
52
86
91
93
71:29
71:29
78:22
69:31
64:36
72:28
93:07
91:09
90:10
90:10
90:10
84:16
89:11
82:18
80:20
91:09
iPr
tBu
Ph
In all cases the diastereoisomeric ratios were similar to
those obtained in the hydrophosphonylation of imines de-
rived from 1 (R = Ph)[20] as well as in the three-component
reactions [aldehyde, 2a, and HP(O)(OMe)2] in the presence
of a 5.0 m lithium perchlorate solution in diethyl ether
(LPDE).[19] In addition, steric congestion was not a prob-
lem under these conditions, because the reactions with iso-
butyraldehyde and pivalaldehyde (Table 1, Entries 5 and 6,
respectively) afforded the α-amino phosphonates in excel-
lent yields and with moderate diastereoselectivities.
7a
7b
7c
7d
7e
7f
4-ClC6H4
4-FC6H4
4-MeOC6H4
3,4-Me2OC6H4 tBu
Me
Bn
iBu
iPr
tBu
tBu
tBu
tBu
tBu
7g
7h
7i
tBu
7j
[a] Ar = 1-naphthyl. [b] Isolated yields. [c] Determined by 31P NMR
(81 and 202 MHz) examination of the crude reaction mixtures.
Trehan et al.[21] found that Schiff bases derived from (R)-
α-ethylbenzylamine show C=N π-facial selectivity superior
to that of Schiff bases derived from the commonly used (R)-
We next focused our attention on the evaluation of (S)-
α-MBA in the alkyllithium addition reaction. We therefore 3,3-dimethyl-2-butylamine (2d) as the chiral source with the
evaluated (S)-α-ethylbenzylamine as a chiral inductor in the goal of obtaining α-amino phosphonates with better dia-
diastereoselective synthesis of α-amino phosphonates under stereoselectivity. In this context, benzaldehyde was initially
these one-pot, three-component reaction conditions. The chosen, due to its high reactivity, and it was treated with
one-pot reactions of both aliphatic and aromatic aldehydes the chiral amine 2d and HP(O)(OMe)2 at 80 °C to afford
1, (S)-α-ethylbenzylamine (2b; RЈ = Et), and dimethyl phos- the α-aminophosphonates 7a in 91% yield and 93:7 dia-
phite under solvent-free conditions gave mixtures of the α- stereoisomeric ratio, as evidenced by 31P NMR spec-
amino phosphonates (R,S)-5a–f in excellent yields and with troscopy (Table 2, Entry 7). In order to explore the general
diastereoselectivities identical to those obtained with (S)-α- applicability of the amine 2d as a chiral auxiliary in the
MBA, so the diastereoselectivities in these reactions are not diastereoselective synthesis of α-amino phosphonates 7, a
6574
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Eur. J. Org. Chem. 2010, 6573–6581

Uncatalyzed One-Pot Diastereoselective Synthesis of α-Amino Phosphonates
variety of aldehydes were studied (Table 2). In most exam-
ples, the diastereoisomeric ratios were good to excellent. Al-
though the reactions appear to be relatively insensitive to
the structure of the aldehyde component, the reaction with
phenylacetaldehyde gave the phosphophenylalanine deriva-
tive in only 52% yield (Table 2, Entry 13), possibly due to
isomerization of the imine prior to (or during) the reaction.
The configuration of the new stereogenic center was as-
signed by comparison with the α-amino phosphonates con-
taining (S)-α-MBA moieties. The results are summarized in
Table 2 (Entries 7–16).
Figure 1. Optimized geometries for the most stable conformations
In an effort to explain the diastereoselectivities of these
one-pot, three-component reactions for the synthesis of the
α-amino phosphonates 4–7, we carried out ab initio MO
and DFT studies on the structures of the Schiff bases 8–15.
Complete optimizations were performed at the HF/3-21G
level, and single-point energies were calculated at the HF/6-
31+G*, MP2/6-31+G*, and B3LYP/6-31+G* levels.[21,23–25]
The B3LYP/6-31+G* energies of several minima are shown
in Table 3.
of the imines 8–15.
formations, in which the phenyl and 1-naphthyl groups are
oriented in a similar manner and do not lead to a difference
in steric hindrance.[27]
Table 3. Relative energies [kcalmol–1] for imines 8–15.
Figure 2. Proposed mechanism for nucleophilic attack of
HP(O)(OMe)2 onto imines.
Entry
R
RЈ
Imine Dihedral angle B3LYP/6-31+G*
The high diastereoselectivities obtained in the nucleo-
philic additions of dimethyl phosphite to imines 10 and 13
bearing the voluminous tBu group can be interpreted by
assuming that the tBu groups block the si faces of the corre-
sponding imines. In this case the nucleophilic attack pro-
ceeds stereoselectively at the re faces to afford the (R,S)
diastereoisomers preferentially.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
Ph
Ph
Ph
Ph
Ph
iBu
iBu
Ph
Ph
8
–3.4
109.6
–3.9
136.5
–10.7
–115.5
–6.2
108.7
–5.3
136.3
–11.1
–114.5
2.0
0.00
1.60
0.00
1.70
0.00
2.97
0.00
1.93
0.00
1.89
0.00
3.02
0.00
2.24
0.00
2.44
8
Ar[a]
Ar[a]
tBu
tBu
Ph
9
9
10
10
11
11
12
12
13
13
14
14
15
15
Ph
iBu Ar[a]
iBu Ar[a]
iBu
iBu
Ph
Ph
iBu
iBu
tBu
tBu
Ph
Ph
Ph
Conclusions
We have demonstrated highly diastereoselective one-pot,
three-component reactions of aldehydes, chiral amines, and
dimethyl phosphite under uncatalyzed and solvent-free con-
ditions. We also demonstrated that Schiff bases derived
from (S)-3,3-dimethyl-2-butylamine show C=N π-facial
selectivities superior to those of Schiff bases derived from
the commonly used (S)-α-methylbenzylamine. This pro-
cedure could be useful in the large-scale synthesis of α-
amino phosphonates.
104.0
0.74
102.9
Ph
[a] Ar = 1-naphthyl.
For all Schiff bases the C–H bond of the amine in the
most stable conformation was eclipsed with the N–C–H
fragment, as would be expected from the 1,3-allylic strain
model.[26] The conformations with C–Ph and C–Me
eclipsed with N–C–H were appreciably higher in energy at
all levels of calculation. The optimized geometries for the
most stable conformations of imines 8–15 are shown in Fig-
ure 1.
Experimental Section
General Information: All commercial materials were used as re-
ceived unless otherwise noted. Flash chromatography was per-
formed with 230–400 mesh Silica Flash 60® silica gel. Thin layer
chromatography was performed with pre-coated TLC sheets of sil-
ica gel (60 F254, Merck). NMR spectra were recorded with a Var-
ian System instrument (500 MHz for 1H, 202 MHz for 31P, and
125 MHz for 13C) and a Mercury instrument (200 MHz for 1H and
For the most stable conformation, nucleophilic attack of
HP(O)(OMe)2 on the imines should take place at the re face
(less hindered side) to afford the (R,S) diastereoisomers as
the main products (Figure 2). Additionally, the common
diastereoselectivity observed both with (S)-α-MBA (2a) and
with (S)-1-(1Ј-naphthyl)ethylamine (2c) as the chiral auxil-
iaries can be explained on the basis of the Schiff base con- 81 MHz for 31P) and calibrated with CDCl3 as solvent and TMS
Eur. J. Org. Chem. 2010, 6573–6581
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6575

M. Ordoñez et al.
FULL PAPER
as internal standard. High-resolution FAB+ mass spectra (HRMS)
were obtained with a JEOL MStation MS-700. Microanalyses were
determined with an Elemental VARIO EL III machine.
6.80 (AAЈBBЈ, J = 8.3 Hz, 2 H, Harom), 6.82* (AAЈBBЈ, J = 8.3 Hz,
2 H, Harom), 7.12–7.27 (m, 14 H, Harom) ppm. 13C NMR
(125 MHz, CDCl3): δ = 22.1 (CH3CH), 53.4 [d, J = 7.0 Hz, (CH3O)
2P], 53.7 [d, J = 7.0 Hz, (CH3O)2P], 53.8* [d, J = 7.1 Hz, (CH3O)
2P], 55.0* (CH3O), 55.2 (CH3O), 56.7* (d, J = 153.0 Hz, CH–P),
57.1 (d, J = 154.2 Hz, CH–P), 114.0 (d, J = 2.2 Hz), 114.1* (d, J
= 2.2 Hz), 126.7, 127.0*, 127.1, 127.2* 128.4, 128.5*, 129.5 (d, J =
6.5 Hz), 129.7* (d, J = 6.5 Hz), 159.4 (d, J = 2.8 Hz) ppm. 31P
NMR (202 MHz, CDCl3): δ = 27.50*, 27.79 ppm. HRMS [FA]+:
m/z (%) = 338 (100) [M + H]+, 228 (100) [M – 110]+.
General Procedure for the Synthesis of α-Amino Phosphonates: The
chiral amine (1.0 equiv.) was added to the aldehyde (1.0 equiv.), and
the mixture was stirred at room temperature for 15 min prior to
the addition of dimethyl phosphite (1.05 equiv.). The reaction mix-
ture was then stirred at 80 °C for 5–8 h. Progress of the reaction
was monitored by TLC. The crude product was analyzed by 31P
NMR spectroscopy and then purified by column chromatography.
Dimethyl (R,S)- and (S,S)-{3-Methyl-1-[(1-phenylethyl)amino]-
butyl}phosphonate (4d): Isovaleraldehyde (250 mg, 2.90 mmol), (S)-
MBA (350 mg, 2.90 mmol), and dimethyl phosphite (330 mg,
3.04 mmol) were stirred at 80 °C for 8 h. The product 4d was ob-
tained (750 mg, 87%) as a yellow oil. Asterisk denotes minor dia-
stereoisomer. 1H NMR (500 MHz, CDCl3): δ = 0.33 [d, J = 6.8 Hz,
3 H, (CH3)2CH], 0.73 [d, J = 6.8 Hz, 3 H, (CH3)2CH], 0.74* [d, J
= 6.8 Hz, 3 H, (CH3)2CH], 0.81* [d, J = 6.6 Hz, 3 H, (CH3)2CH],
1.24 (d, J = 6.3 Hz, 3 H, CH3CH), 1.32–1.44* (m, 2 H, CH2CH),
1.48–1.59* (m, 2 H, CH2CH), 1.64–1.73 [m, 1 H, CH(CH3)2], 1.76–
1.80* [m, 1 H, CH(CH3)2], 2.58–2.62 (m, 1 H, CH–P), 2.73–2.78*
(m, 1 H, CH–P), 3.57* [d, J = 10.2 Hz, 3 H, (CH3O)2P], 3.59* [d,
J = 10.2 Hz, 3 H, (CH3O)2P], 3.67 [d, J = 10.2 Hz, 3 H, (CH3O)
2P], 3.68 [d, J = 10.2 Hz, 3 H, (CH3O)2P], 3.95* (q, J = 6.5 Hz, 1
H, CH–N), 4.06 (dq, J = 6.6, 2.9 Hz, 1 H, 1 H, CH–N), 7.10–7.26,
(m, 10 H, Harom) ppm. 13C NMR (125 MHz, CDCl3): δ = 20.8
(CH3CH), 22.3*, (CH3CH), 22.8* [(CH3)2CH], 23.5 [(CH3)2CH],
23.7 [d, J = 12.4 Hz, CH2 CH(CH3)2], 24.0* [(CH3)2CH], 24.5
[(CH3)2CH], 24.8* [d, J = 8.5 Hz, CH2CH(CH3)2], 39.7* [d, J =
8.5 Hz, (CHCH3)], 40.1 [d, J = 2.4 Hz, (CHCH3)], 49.5* (d, J =
144.6 Hz, CH–P), 49.7* (d, J = 152.3 Hz, CH–P), 52.4* [d, J =
7.4 Hz, (CH3O)2P], 52.5 [d, J = 7.4 Hz, (CH3O)2P], 52.7 [d, J =
7.4 Hz, (CH3O)2P], 53.1* [d, J = 7.3 Hz, (CH3O)2P], 55.7* (d, J =
10.5 Hz, CH–N), 56.2 (CH–N), 126.9, 127.1*, 127.2*, 127.3, 128.2,
128.3*, 144.7, 145.0* ppm. 31P NMR (202 MHz, CDCl3): δ =
32.49*, 33.54 ppm. HRMS [FA]+: m/z (%) = 300 (44.61) [M +
H]+, 190 (100.0) [M – 110]+, 105 (45.46).
Dimethyl (R,S)- and (S,S)-{(Phenyl)[(1-phenylethyl)amino]methyl}-
phosphonate (4a): Benzaldehyde (250 mg, 2.35 mmol), (S)-α-meth-
ylbenzylamine (MBA, 280 mg, 2.35 mmol), and dimethyl phosphite
(250 mg, 2.46 mmol) were stirred at 80 °C for 5 h. The product 4a
was obtained (540 mg, 91%) as a white solid. M.p. 60 °C. Asterisk
1
denotes minor diastereoisomer. H NMR (500 MHz, CDCl3): δ =
1.26 (d, J = 6.5 Hz, 3 H, CH3CH), 3.37* [d, J = 10.7 Hz, 3 H,
(CH3O)2P], 3.43 [d, J = 10.7 Hz, 3 H, (CH3O)2P], 3.70* [d, J =
10.7 Hz, 3 H, (CH3O)2P], 3.73 [d, J = 10.7 Hz, 3 H, (CH3O)2P],
3.80 (m, 1 H, CH–N), 4.06 (d, J = 21.0 Hz, 1 H, CH–P), 7.12–7.30
(m, 20 H, Harom) ppm. 13C NMR (125 MHz, CDCl3): δ = 22.2
(CH3CH), 53.2* [d, J = 6.5 Hz, (CH3O)2P], 53.5 [d, J = 6.5 Hz,
(CH3O)2P], 53.8 [d, J = 7.4 Hz, (CH3O)2P], 53.9* [d, J = 7.4 Hz,
(CH3O)2P], 54.9* (d, J = 16.2 Hz, CH–N), 55.2 (d, J = 12.1 Hz,
CH–N), 57.5* (d, J = 156.9 Hz, CH–P), 58.2* (d, J = 135.9 Hz,
CH–P), 126.7, 127.0*, 127.1, 127.3*, 128.2*, 128.4, 128.4, 128.5,
128.6, 129.9, 132.7, 136.0, 144.9 ppm. 31P NMR (81 MHz, CDCl3):
δ = 27.21*, 27.54 ppm. HRMS [FA]+: m/z (%) = 320 (100) [M +
H]+, 210 (53.5), [M – 110]+. C17H22NO3P (319.34): calcd. C 63.94,
H 6.94, N 4.39; found C 63.55, H 6.94, N 4.33.
Dimethyl (R,S)- and (S,S)-{(4-Chlorophenyl)[(1-phenylethyl)amino]-
methyl}phosphonate (4b): 4-Chlorobenzaldehyde (250 mg, 1.78
mmol), (S)-MBA (210 mg, 1.78 mmol), and dimethyl phosphite
(200 mg, 1.87 mmol) were stirred at 80 °C for 6 h. The product 4b
was obtained (500 mg, 80%) as an oil. Asterisk denotes minor dia-
stereoisomer. 1H NMR (500 MHz, CDCl3): δ = 1.21* (d, J =
6.3 Hz, 3 H, CH3CH), 1.25 (d, J = 6.3 Hz, 3 H, CH3CH), 2.40–
2.76 (br. s, 1 H, NH), 3.41* [d, J = 10.2 Hz, 3 H, (CH3O)2P], 3.47
[d, J = 10.2 Hz, 3 H, (CH3O)2P], 3.70 [d, J = 10.2 Hz, 3 H, (CH3O)
2P], 3.75* [d, J = 10.2 Hz, 3 H, (CH3O)2P], 3.76 (q, J = 6.5 Hz, 1
H, CH–N), 4.05 (d, J = 21.0 Hz, 1 H, CH–P), 7.09–7.26 (m, 18 H,
Harom) ppm. 13C NMR (125 MHz, CDCl3): δ = 22.4 (CH3CH),
24.7* (CH3CH), 53.2* [d, J = 7.2 Hz, (CH3O)2P], 53.5 [d, J =
7.4 Hz, (CH3O)2P], 53.8 [d, J = 7.4 Hz, (CH3O)2P], 54.0* [d, J =
7.2 Hz, (CH3O)2P], 54.9* (d, J = 17.6 Hz, CH–N), 55.6 (d, J =
12.0 Hz, CH–N), 56.7* (d, J = 156.3 Hz, CH–P), 57.3 (d, J =
152.5 Hz, CH–P), 126.7, 126.9*, 127.2, 127.3*, 128.4, 128.6, 128.7
(J = 2.2 Hz), 128.8* (J = 2.3 Hz), 129.6 (J = 6.3 Hz), 129.8* (J =
6.4 Hz), 133.6 (J = 3.6 Hz), 133.7 (J = 3.6 Hz), 134.5*, 134.9,
143.5*, 144.7 ppm. 31P NMR (202 MHz, CDCl3): δ = 26.60*,
26.96 ppm. HRMS [FA]+: m/z (%) = 354 (25.56) [M + H]+, 294
(100) [M + H – 110]+, 105 (100).
Dimethyl (R,S)- and (S,S)-{2-Methyl-1-[(1-phenylethyl)amino]-
propyl}phosphonate (4e): Isobutyraldehyde (250 mg, 3.46 mmol),
(S)-MBA (410 mg, 3.46 mmol), and dimethyl phosphite (400 mg,
3.63 mmol) were stirred at 80 °C for 8 h. The product 4e was ob-
tained (780 mg, 79%) as a yellow oil. Asterisk denotes minor dia-
stereoisomer. 1H NMR (500 MHz, CDCl3): δ = 0.77* (d, J =
6.8 Hz, 3 H, CH3), 0.87 (d, J = 6.8 Hz, 3 H, CH3), 0.92* (d, J =
6.8 Hz, 3 H, CH3), 1.02* (d, J = 6.8 Hz, 3 H, CH3), 1.24* (d, J =
6.8 Hz, 3 H, CH3), 1.26 (d, J = 6.8 Hz, 3 H, CH3), 1.88–197 [m, 1
H, CH(CH3)2], 2.06–2.15* [m, 1 H, CH(CH3)2], 2.52 (dd, J = 12.8,
3.1 Hz, 1 H, CH–P), 2.71* (dd, J = 18.9, 3.2 Hz, 1 H, CH–P), 3.55*
[d, J = 10.5 Hz, 3 H, (CH3O)2P], 3.64* [d, J = 10.5 Hz, 3 H,
(CH3O)2P], 3.67 [d, J = 10.5 Hz, 3 H, (CH3O)2P], 3.69 [d, J =
10.5 Hz, 3 H, (CH3O)2P], 3.95* (q, J = 6.5 Hz, 1 H, CH–N), 4.03
(dq, J = 6.5, 3.4 Hz, 1 H, CH–N), 7.12–7.29 (m, 10 H, Harom) ppm.
13C NMR (125 MHz, CDCl3): δ = 17.4 (d, J = 2.6 Hz, CH3), 18.3*
(d, J = 2.6 Hz, CH3), 20.4* (d, J = 12.3 Hz, CH3), 20.6 (d, J =
14.3 Hz, CH3), 23.7* (CH3), 24.8 (CH3), 28.6* [d, J = 5.1 Hz,
(CHCH3)2], 29.8 [d, J = 5.8 Hz, (CHCH3)2], 52.1 [d, J = 7.5 Hz,
(CH3O)2P], 52.2* [d, J = 7.0 Hz, (CH3O)2P], 52.4 [d, J = 7.4 Hz,
(CH3O)2P], 52.6* [d, J = 7.3 Hz, (CH3O)2P], 56.2* (CH–N), 56.4
Dimethyl (R,S)- and (S,S)-{(4-Methoxyphenyl)[(1-phenylethyl)-
amino]methyl}phosphonate (4c): 4-Methoxybenzaldehyde (250 mg,
1.83 mmol), (S)-MBA (210 mg, 1.83 mmol), and dimethyl phos-
phite (200 mg, 1.92 mmol) were stirred at 80 °C for 6 h. The prod-
uct 4c was obtained (570 mg, 89%) as a yellow oil. Asterisk denotes
1
minor diastereoisomer. H NMR (500 MHz, CDCl3): δ = 1.24 (d, (CH–N), 56.8* (d, J = 141.2 Hz, CH–P), 57.9 (d, J = 135.0 Hz,
J = 6.5 Hz, 3 H, CH3CH), 3.38* [d, J = 10.4 Hz, 3 H, (CH3O)2P],
3.44 [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.70* [d, J = 10.5 Hz, 3 H,
(CH3O)2P], 3.73 [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.74 (s, 3 H,
CH–P), 127.0 (d, J = 15.2 Hz), 127.4, 128.1, 128.3*, 144.6,
145.0* ppm. 31P NMR (202 MHz, CDCl3): δ = 31.58*, 33.12 ppm.
HRMS [FA]+: m/z (%) = 286 (100) [M + H]+, 176 (44.3) [M –
CH3O), 3.75* (s, 3 H, CH3O), 4.00 (d, J = 20.5 Hz, 1 H, CH–P), 110]+.
6576
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6573–6581

Uncatalyzed One-Pot Diastereoselective Synthesis of α-Amino Phosphonates
Dimethyl (R,S)- and (S,S)-{2,2-Dimethyl-1-[(1-phenylethyl)amino]- 2.3 Hz), 129.5 (d, J = 6.3 Hz), 129.9* (d, J = 6.4 Hz), 133.4 (d, J =
propyl}phosphonate (4f): tert-Butylacetaldehyde (250 mg, 2.90
mmol), (S)-MBA (330 mg, 2.90 mmol), and dimethyl phosphite
(330 mg, 3.04 mmol) were stirred at 80 °C for 8 h. The product 4f
was obtained (740 mg, 86%) as an oil. Asterisk denotes minor dia-
stereoisomer. 1H NMR (500 MHz, CDCl3): δ = 0.91 [s, 9 H, (CH3)
3C], 1.11* [s, 9 H, (CH3)3C], 1.28* (d, J = 6.5 Hz, 3 H, CH3CH),
1.35 (d, J = 6.3 Hz, 3 H, CH3CH), 1.71 (br. s, 1 H, NH), 2.40 (d,
J = 13.1 Hz, CH–P), 2.65* (d, J = 16.9 Hz, CH–P), 3.62* [d, J =
10.6 Hz, 3 H, (CH3O)2P], 3.67* [d, J = 10.6 Hz, 3 H, (CH3O)2P],
3.75 [d, J = 10.6 Hz, 3 H, (CH3O)2P], 3.81 [d, J = 10.6 Hz, 3 H,
3.6 Hz), 133.6* (d, J = 3.7 Hz), 135.1, 142.1, 142.8 ppm. 31P NMR
(202 MHz, CDCl3): δ = 32.57, 32.65* ppm. HRMS [FA]+: m/z (%)
= 368 (34.67) [M + H]+, 258 (100.0) [M – 110]+.
Dimethyl (R,S)- and (S,S)-{(4-Methoxyphenyl)[(1-phenylpropyl)-
amino]methyl}phosphonate (5c): 4-Methoxybenzaldehyde (250 mg,
1.83 mmol), (S)-α-ethylbenzylamine (240 mg, 1.83 mmol), and di-
methyl phosphite (200 mg, 1.92 mmol) were stirred at 80 °C for 6 h.
The product 5c was obtained (500 mg, 82%) as an oil. Asterisk
1
denotes minor diastereoisomer. H NMR (500 MHz, CDCl3): δ =
0.67 (t, J = 7.4 Hz, 3 H, CH3CH2), 0.68* (t, J = 7.4 Hz, 3 H,
CH3CH2), 1.52–1.62 (m, 2 H, CH2CH3), 1.68–1.76* (m, 2 H,
CH2CH3), 3.39* [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.44 [d, J =
10.4 Hz, 1 H, (CH3O)2P], 3.59–362 (m, 1 H, CHCH2), 3.69* [d, J
= 10.5 Hz, 3 H, (CH3O)2P], 3.72 (s, 3 H, CH3O), 3.72 [d, J =
10.2 Hz, 3 H, (CH3O)2P], 3.75* (s, 3 H, CH3O), 3.94 (d, J =
19.3 Hz, 1 H, CH–P), 6.77 (AAЈBBЈ, J = 8.4 Hz, 2 H), 6.82*
(AAЈBBЈ, J = 8.3 Hz, 2 H), 7.10–7.21 (m, 10 H, Harom), 7.23
(AAЈBBЈ, J = 7.5 Hz, 2 H), 7.25 (AAЈBBЈ, J = 7.5 Hz, 2 H) ppm.
(CH3O)2P], 4.06–4.11* (m, 1 H, CH–N), 7.21–7.37 (m, 5 H, Harom
)
ppm. 13C NMR (125 MHz, CDCl3): δ = 22.5* (CH3), 24.4 (CH3),
27.7 {d, J = 6.2 Hz, [(CH3)3C]}, 27.8* {d, J = 6.4 Hz, [(CH3)3C]},
34.5 (d, J = 7.7 Hz, CHCH3), 35.1* [d, J = 8.1 Hz, (CHCH3)],
51.7* [d, J = 6.9 Hz, (CH3O)2P], 51.8 [d, J = 7.4 Hz, (CH3O)2P],
52.1 [d, J = 7.4 Hz, (CH3O)2P], 57.0 (CH–N), 61.0* (d, J =
140.0 Hz, CH–P), 61.5 (d, J = 132.0 Hz, CH–P), 126.9, 127.1,
127.8, 128.0, 128.2, 144.4, 145.9* ppm. 31P NMR (202 MHz,
CDCl3): δ = 31.42*, 32.25 ppm. HRMS [FA]+: m/z (%) = 300 (100)
[M + H]+, 190 (100) [M – 110]+.
13C NMR (125 MHz, CDCl3):
δ = 10.0 (CH3CH2), 10.8*
(CH3CH2), 28.9 (CH2CH3), 31.0* (CH2CH3), 53.4 [(CH3O)2P],
53.5 [(CH3O)2P], 55.2 (CH3O), 56.5* (d, J = 160.0 Hz, CH–P), 57.1
(d, J = 153.4 Hz, CH–P), 62.1 (d, J = 10.3 Hz, CH–N), 113.9 (d,
J = 2.0 Hz), 114.0* (d, J = 2.0 Hz), 127.0, 127.2*, 127.5, 127.7*,
128.2, 128.3*, 129.2 (d, J = 6.5 Hz), 129.8* (d, J = 6.8 Hz), 143.2,
159.1, 159.2* ppm. 31P NMR (202 MHz, CDCl3): δ = 27.61*,
27.96 ppm. HRMS [FA]+: m/z (%) = 364 (20.81) [M]+, 254 (100.0)
[M – 110]+.
Dimethyl (R,S)- and (S,S)-{Phenyl[(1-phenylpropyl)amino]methyl}-
phosphonate (5a): Benzaldehyde (250 mg, 2.35 mmol), (S)-α-ethyl-
benzylamine (310 mg, 2.35 mmol), and dimethyl phosphite
(250 mg, 2.46 mmol) were stirred at 80 °C for 6 h. The product 5a
was obtained (920 mg, 80%) as an oil. Asterisk denotes minor dia-
stereoisomer. 1H NMR (500 MHz, CDCl3): δ = 0.69 (t, J = 7.4 Hz,
3 H, CH3CH2), 0.70* (t, J = 7.4 Hz, 3 H, CH3CH2), 1.55–1.63 (m,
2 H, CH2), 1.72–1.78* (m, 2 H, CH2), 3.39* [d, J = 10.5 Hz, 3 H,
(CH3O)2P], 3.45 [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.60–3.66 (m, 1
H, CH–N), 3.71* [d, J = 10.6 Hz, 3 H, (CH3O)2P], 3.74 [d, J =
10.5 Hz, 3 H, (CH3O)2P], 4.01 (d, J = 19.8 Hz, 1 H, CH–P), 7.10–
7.31 (m, 20 H, Harom) ppm. 13C NMR (125 MHz, CDCl3): δ = 10.2
(CH3CH2), 10.7* (CH3CH2), 29.0 (CH2CH3), 31.1* (CH2CH3),
53.2* [d, J = 6.8 Hz, (CH3O)2P], 53.4 [d, J = 7.1 Hz, (CH3O)2P],
53.6 [d, J = 7.1 Hz, (CH3O)2P], 53.8* [d, J = 7.1 Hz, (CH3O)2P],
57.3* (d, J = 162.5 Hz, CH–P), 57.8 (d, J = 151.2 Hz, CH–P), 61.4*
(d, J = 17.4 Hz, CH–N), 62.3 (d, J = 10.7 Hz, CH–N), 127.1,
127.2*, 127.4, 127.6*, 127.7 (d, J = 2.9 Hz), 127.9* (d, J = 2.9 Hz),
128.1*, 128.2 (d, J = 6.4 Hz), 128.4*, 128.4 (d, J = 2.2 Hz), 128.5*
(d, J = 2.3 Hz), 128.6* (d, J = 6.4 Hz), 129.8, 132.6*, 135.6*, 136.4,
Dimethyl (R,S)- and (S,S)-{2-Methyl-1-[(1-phenylpropyl)amino]-
propyl}phosphonate (5e): Isobutyraldehyde (250 mg, 3.46 mmol),
(S)-α-ethylbenzylamine (410 mg, 3.46 mmol), and dimethyl phos-
phite (400 mg, 3.63 mmol) were stirred at 80 °C for 8 h. The prod-
uct 5e was obtained (780 mg, 79%) as an oil. Asterisk denotes
1
minor diastereoisomer. H NMR (500 MHz, CDCl3): δ = 0.69* (t,
J = 6.2 Hz, 3 H, CH3CH2), 0.70 (t, J = 7.2 Hz, 3 H, CH3CH2),
0.73 (d, J = 6.8 Hz, 3 H, CH3CH), 0.84 (d, J = 6.9 Hz, 3 H,
CH3CH), 0.92* (d, J = 7.0 Hz, 3 H, CH3CH), 1.01* (d, J = 7.0 Hz,
3 H, CH3CH), 1.45–1.70 (m, 2 H, CH2CH3), 1.84–2.16* (m, 2 H,
CH2CH3), 2.50 (dd, J = 12.4, 3.1 Hz, 1 H, CH–P), 2.68* (dd, J =
20.0, 3.0 Hz, 1 H, CH–P), 3.49* [d, J = 10.0 Hz, 3 H, (CH3O)2P],
3.61* [d, J = 10.0 Hz, 3 H, (CH3O)2P], 3.64 [d, J = 10.2 Hz, 3 H,
(CH3O)2P], 3.67 [d, J = 10.2 Hz, 3 H, (CH3O)2P], 3.70–3.75 (m, 1
142.4*, 143.1. 31P NMR (202 MHz, CDCl3):
δ = 27.26*,
27.70 ppm. HRMS [FA]+: m/z (%) = 334 (36.50) [M + H]+, 224
)
ppm. 13C NMR
(100.0) [M – 110]+.
H, CH–N), 7.11–7.25* (m, 10 H, Harom
(125 MHz, CDCl3): δ = 10.6* (CH3CH2), 10.7 (CH3CH2), 17.3 (d,
J = 2.5 Hz, CH3CH), 18.4* (d, J = 1.9 Hz, CH3CH), 20.1* (d, J =
12.0 Hz, CH3CH), 20.5 (d, J = 14.6 Hz, CH3CH), 28 ppm. 4* (d,
J = 4.9 Hz, CH2), 29.0 (d, J = 6.0 Hz, CH2), 30.6* [CH(CH3)2],
31.3 [CH(CH3)2], 51.8 [d, J = 7.5 Hz, (CH3O)2P], 52.1* [d, J =
7.4 Hz, (CH3O)2P], 52.3 [d, J = 7.2 Hz, (CH3O)2P], 52.7* [d, J =
7.4 Hz, (CH3O)2P], 56.4 (d, J = 133.7 Hz, CH–P), 56.5 (d, J =
147.5 Hz, CH–P), 63.0 (CH–N), 63.1* (CH–N), 127.0, 127.1*,
127.7*, 127.9, 128.0, 128.1*, 143.1, 143.2*. 31P NMR (202 MHz,
CDCl3): δ = 31.44*, 33.50 ppm. HRMS [FA]+: m/z (%) = 300
(34.16) [M + H]+, 254 (100.0) [M + H – 110]+.
Dimethyl (R,S)- and (S,S)-{(4-Chlorophenyl)[(1-phenylpropyl)-
amino]methyl}phosphonate (5b): 4-Chlorobenzaldehyde (250 mg,
1.78 mmol), (S)-α-ethylbenzylamine (240 mg, 1.78 mmol), and di-
methyl phosphite (200 mg, 1.87 mmol) were stirred at 80 °C for 6 h.
The product 5b was obtained (500 mg, 80%) as an oil. Asterisk
1
denotes minor diastereoisomer. H NMR (500 MHz, CDCl3): δ =
0.68 (t, J = 7.4 Hz, 3 H, CH3CH2), 0.69* (t, J = 7.4 Hz, 3 H,
CH3CH2), 1.53–1.61 (m, 2 H, CH2CH3), 1.69–1.75* (m, 2 H,
CH2CH3), 3.43* [d, J = 10.5 Hz, 3 H, (CH3O)2P], 3.48 [d, J =
10.5 Hz, 3 H, (CH3O)2P], 3.56–3.62 (m, 1 H, CH–N), 3.69* [d, J
= 10.5 Hz, 3 H, (CH3O)2P],3.72 [d, J = 10.5 Hz, 3 H, (CH3O)2P],
3.95 (d, J = 20.2 Hz, 1 H, CH–P), 7.03–7.29 (m, 18 H, Harom
)
Dimethyl (R,S)- and (S,S)-{2,2-Dimethyl-1-[(1-phenylpropyl)amino]-
ppm. 13C NMR (125 MHz, CDCl3): δ = 10.0 (CH3CH2), 10.7* propyl}phosphonate (5f): tert-Butylacetaldehyde (250 mg, 2.90
(CH3CH2), 29.1 (CH2CH3), 31.0* (CH2CH3), 53.3* [d, J = 6.9 Hz, mmol), (S)-α-ethylbenzylamine (390 mg, 2.90 mmol), and dimethyl
(CH3O)2P], 53.4 [d, J = 7.2 Hz, (CH3O)2P], 53.6 [d, J = 7.2 Hz,
phosphite (330 mg, 3.04 mmol) were stirred at 80 °C for 8 h. The
(CH3O)2P], 53.8* [d, J = 6.9 Hz, (CH3O)2P], 56.7* (d, J = product 5f was obtained (710 mg, 79%) as an oil. Asterisk denotes
1
153.7 Hz, CH–P), 57.3 (d, J = 151.5 Hz, CH–P), 61.4* (d, J =
16.5 Hz, CH–N), 62.4 (d, J = 10.5 Hz, CH–N), 127.1, 127.3*,
127.4, 127.5*, 128.1, 128.4*, 128.5 (d, J = 2.3 Hz), 128.7* (d, J =
minor diastereoisomer. H NMR (500 MHz, CDCl3): δ = 0.60* (t,
J = 7.4 Hz, 3 H, CH3CH2), 0.68 (t, J = 7.4 Hz, 3 H, CH3CH2),
0.69 [s, 9 H, (CH3)3C], 1.01* [s, 9 H, (CH3)3C], 1.49–161 (m, 2 H,
Eur. J. Org. Chem. 2010, 6573–6581
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6577

M. Ordoñez et al.
FULL PAPER
CH2CH3), 2.29 (d, J = 12.6 Hz, 1 H, CH–P), 2.54* (d, J = 17.8 Hz,
[d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.80 [d, J = 10.6 Hz, 3 H, (CH3O)
1 H, CH–P), 3.43* [d, J = 10.6 Hz, 3 H, (CH3O)2P], 3.53* [d, J = 2P], 3.81* [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.82 (s, 3 H, CH3O),
10.5 Hz, 3 H, (CH3O)2P], 3.63 [d, J = 10.6 Hz, 3 H, (CH3O)2P],
3.68 [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.70–3.72 (m, 1 H, CH–N),
7.11–7.22 (m, 10 H, Harom) ppm. 13C NMR (125 MHz, CDCl3): δ
4.17 (d, J = 20.2 Hz, 1 H, CH–P), 4.73 (d, J = 6.3 Hz, 1 H, CH–N),
6.78–7.90 (m, 11 H, Harom) ppm. 13C NMR (125 MHz, CDCl3): δ
= 21.7 (CH3CH), 53.4 [(CH3O)2P], 53.7 [(CH3O)2P], 55.2 (CH3O),
= 10.5* (CH3CH2), 10.7 (CH3CH2), 27.6 [d, J = 6.1 Hz, (CH3)3C], 57.0 (d, J = 154.4 Hz, CH–P), 114.0, 123.0, 123.3*, 125.3, 125.5,
27.8* [d, J = 6.6 Hz, (CH3)3C], 29.1* (CH2CH3), 30.9 (CH2CH3), 125.7, 127.5*, 128.8, 129.6 (d, J = 6.7 Hz), 130.9, 131.4*, 133.8,
34.4 [d, J = 7.8 Hz, C(CH3)3], 35.3* [d, J = 7.8 Hz, C(CH3)3], 51.6* 133.9*, 159.3 ppm. 31P NMR (202 MHz, CDCl3): δ = 27.14*,
[d, J = 7.2 Hz, (CH3O)2P], 51.7 [d, J = 7.3 Hz, (CH3O)2P], 51.9 [d,
J = 7.3 Hz, (CH3O)2P] 52.1* [d, J = 7.4 Hz, (CH3O)2P], 60.8* (d,
J = 135.0 Hz, CH–P), 61.1 (d, J = 130.0 Hz, CH–P), 63.5 (CH–N),
64.4* (d, J = 3.9 Hz, CH–N), 127.0*, 127.8, 128.0*, 128.4, 142.8,
143.7* ppm. 31P NMR (202 MHz, CDCl3): δ = 32.20*, 33.43 ppm.
HRMS [FA]+: m/z (%) = 314 (18.26) [M + H]+, 204 (100.0) [M +
H – 110]+.
27.37 ppm. HRMS [FA]+: m/z (%) = 400 (20.05) [M + H]+, 290
(77.85) [M – 110]+, 155 (100).
Dimethyl (R,S)- and (S,S)-(3-Methyl-1-{[1-(naphthalen-1-yl)ethyl]-
amino}butyl)phosphonate
(6d):
Isovaleraldehyde
(250 mg,
2.90 mmol), (S)-1-(1Ј-naphthyl)ethylamine (496 mg, 2.90 mmol),
and dimethyl phosphite (330 mg, 3.04 mmol) were stirred at 80 °C
for 8 h. The product 6d was obtained (850 mg, 84%) as an oil.
Asterisk denotes minor diastereoisomer. 1H NMR (500 MHz,
CDCl3): δ = 0.47 [d, J = 6.5 Hz, 6 H, (CH3CH)], 0.76 [d, J =
6.6 Hz, 3 H, (CH3)2CH], 0.84 [d, J = 6.7 Hz, 3 H, (CH3)2CH],
0.88* [d, J = 6.6 Hz, 6 H, (CH3)2CH], 1.44–1.50 (m, 2 H, CH2CH),
1.60–1.70* [m, 1 H, CH(CH3)2], 1.83–1.96 [m, 1 H, CH(CH3)2],
2.73–2.80 (m, 1 H, CH–P), 3.00 (ddd, J = 14.8, 7.9, 5.6 Hz, 1 H,
CH–P), 3.69* [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.70 [d, J = 10.5 Hz,
3 H, (CH3O)2P], 3.72 [d, J = 10.5 Hz, 3 H, (CH3O)2P], 3.75* [d, J
= 10.4 Hz, 3 H, (CH3O)2P], 4.97* (q, J = 6.5 Hz, 1 H, CH–N),
5.15* (m, 1 H, CH–N), 7.43–7.52 (m, 4 H, Harom), 7.69–7.75* (m,
4 H, Harom), 7.82–7.87 (m, 3 H, Harom), 8.28* (dd, J = 12.4, 8.6 Hz,
3 H, Harom) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.0
(CH3CH), 22.1* (CH3CH), 22.9 [(CH3)2CH], 23.1* [(CH3)2CH],
23.5 [(CH3)2CH], 23.9 (d, J = 12.1 Hz, CH2CH3), 24.5* [(CH3)2-
CH], 24.8* (d, J = 9.1 Hz, CH2CH3), 39.8* (d, J = 2.5 Hz, CH–
N), 40.4 (d, J = 2.5 Hz, CH–N), 50.0 (d, J = 142.1 Hz, CH–P),
52.5 [d, J = 7.5 Hz, (CH3O)2P], 52.7 [d, J = 7.4 Hz, (CH3O)2P],
53.0* [(CH3O)2P], 123.1, 123.2*, 123.5, 123.7*, 125.2, 125.3*,
125.5, 125.6*, 125.7, 125.8*, 127.3, 127.4*, 128.8, 128.9*, 131.1*,
131.6, 133.8, 133.9*, 140.8*, 140.9 ppm. 31P NMR (202 MHz,
CDCl3): δ = 32.60*, 33.52 ppm. HRMS [FA]+: m/z (%) = 350 (100)
[M + H]+, 240 (100) [M + H – 110]+, 155 (75.6). C19H28NO3P
(349.41): calcd. C 65.31, H 8.08, N 4.01; found C 65.09, H 8.87, N
4.40.
Dimethyl (R,S)- and (S,S)-[{[1-(Naphthalen-1-yl)ethyl]amino}-
(phenyl)methyl]phosphonate
(6a):
Benzaldehyde
(250 mg,
2.35 mmol), (S)-1-(1Ј-naphthyl)ethylamine (420 mg, 2.35 mmol),
and dimethyl phosphite (250 mg, 2.46 mmol) were stirred at 80 °C
for 8 h. The product 6a was obtained (730 mg, 85%) as an oil.
Asterisk denotes minor diastereoisomer. 1H NMR (500 MHz,
CDCl3): δ = 1.42* (d, J = 6.4 Hz, 3 H, CH3CH), 1.44 (d, J =
6.5 Hz, 3 H, CH3CH), 3.38* [d, J = 10.5 Hz, 3 H, (CH3O)2P], 3.43
[d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.75 [d, J = 10.5 Hz, 3 H, (CH3-
O)2P], 3.76* [d, J = 10.5 Hz, 3 H, (CH3O)2P], 3.80* (d, J = 22.7 Hz,
1 H, CH–P), 4.17 (d, J = 20.6 Hz, 1 H, CH–P), 4.40* (d, J =
6.5 Hz, 1 H, CH–N), 4.69 (dd, J = 12.7, 6.4 Hz, 1 H, CH–N), 7.17–
7.83 (m, 12 H, Harom) ppm. 13C NMR (125 MHz, CDCl3): δ =
21.8* (CH3), 24.8 (CH3), 50.6 [(CH3O)2P], 52.8 [(CH3O)2P], 57.6*
(d, J = 157.5 Hz, CH–P), 57.8 (d, J = 152.0 Hz, CH–P), 122.3,
123.3*, 125.3, 125.5*, 125.7, 127.5, 128.0, 128.4, 128.6, 128.8*,
128.9, 131.0, 131.4*, 133.8, 134.0* ppm. 31P NMR (202 MHz,
CDCl3): δ = 26.29*, 26.57 ppm. HRMS [FA]+: m/z (%) = 370 (100)
[M + H]+, 260 (100) [M – 110]+, 155 (73.46).
Dimethyl (R,S)- and (S,S)-[(4-Chlorophenyl){[1-(naphthalen-1-yl)-
ethyl]amino}methyl]phosphonate
(6b):
4-Chlorobenzaldehyde
(250 mg, 1.78 mmol), (S)-1-(1Ј-naphthyl)ethylamine (304 mg,
1.78 mmol), and dimethyl phosphite (200 mg, 1.87 mmol) were
stirred at 80 °C for 6 h. The product 6a was obtained (560 mg,
1
79%) as an oil. Asterisk denotes minor diastereoisomer. H NMR
Diethyl (R,S)- and (S,S)-(2-Methyl-1-{[1-(naphthalen-1-yl)ethyl]-
(500 MHz, CDCl3): δ = 1.46* (d, J = 6.6 Hz, 3 H, CH3CH), 1.49
(d, J = 6.5 Hz, 3 H, CH3CH), 3.48* [d, J = 10.5 Hz, 3 H, (CH3O)
2P], 3.53 [d, J = 10.5 Hz, 3 H, (CH3O)2P], 3.79 [d, J = 10.5 Hz, 3
H, (CH3O)2P], 3.81* [d, J = 10.5 Hz, 3 H, (CH3O)2P], 4.17 (d, J =
20.8 Hz, 1 H, CH–P), 4.41* (d, J = 6.3 Hz, 1 H, CH–N), 4.72 (q,
J = 6.5 Hz, 1 H, CH–N), 7.17–7.96 (m, 11 H, Harom) ppm. 13C
NMR (125 MHz, CDCl3): δ = 21.9 (CH3CH), 24.2* (CH3CH),
53.4 [(CH3O)2P], 53.9 [(CH3O)2P], 56.9* (d, J = 145.0 Hz, CH–P),
57.2 (d, J = 151.9 Hz, CH–P), 122.8, 123.3*, 125.3, 125.4*, 125.6*,
125.7, 127.5, 128.6, 128.7*, 128.8, 129.6 (d, J = 6.4 Hz), 129.8* (d,
J = 6.3 Hz), 130.8, 131.3*, 133.6 (d, J = 3.6 Hz), 133.7* (d, J =
3.6 Hz), 133.8, 133.9*, 134.5*, 134.8, 139.0*, 140.2 ppm. 31P NMR
(202 MHz, CDCl3): δ = 26.34*, 26.68 ppm. HRMS [FA]+: m/z (%)
= 404 (18.62) [M + H]+, 294 (34.94) [M – 110]+, 155 (100).
amino}propyl)phosphonate
(6e):
Isobutyraldehyde
(250 mg,
3.46 mmol), (S)-1-(1Ј-naphthyl)ethylamine (590 mg, 3.46 mmol),
and dimethyl phosphite (400 mg, 3.63 mmol) were stirred at 80 °C
for 8 h. The product 6e was obtained (950 mg, 82%) as an oil.
Asterisk denotes minor diastereoisomer. 1H NMR (500 MHz,
CDCl3): δ = 1.01 [d, J = 6.9 Hz, 6 H, (CH3)2CH], 1.13, (dd, J =
6.9, 0.8 Hz, 3 H, CH3CH), 1.50 (br. s, NH), 2.72 (d, J = 12.0 Hz,
1 H, CH3CH), 2.92 (dd, J = 18.0, 3.2 Hz, 1 H, CH–P), 3.65 [d, J
= 10.5 Hz, 3 H, (CH3O)2P], 3.68* [d, J = 10.5 Hz, 3 H, (CH3-
O)2P], 3.72* [d, J = 10.5 Hz, 3 H, (CH3O)2P], 3.73 [d, J = 10.5 Hz,
3 H, (CH3O)2P], 4.90–4.94 (m, 1 H, CH–N), 5.08–5.15 (m, 1 H,
CH–N), 7.41–7.53 (m, 6 H, Harom), 7.73–7.78 (m, 1 H, Harom),
7.83–7.89* (m, 5 H, Harom), 8.26 (d, J = 5.4 Hz, 2 H, Harom) ppm.
13C NMR (125 MHz, CDCl3): δ = 17.6 (CH3CH), 18.2* (CH3CH),
20.5* [d, J = 12.5 Hz, (CH3)2CH], 20.8 [d, J = 14.4 Hz, (CH3)2CH],
23.0* [(CH3)2CH], 24.5 [(CH3)2CH], 28.7* (d, J = 5.2 Hz), 29.2 (d,
Dimethyl (R,S)- and (S,S)-[(4-Methoxyphenyl){[1-(naphthalen-1-yl)-
ethyl]amino}methyl]phosphonate (6c): 4-Methoxybenzaldehyde (250
mg, 1.83 mmol), (S)-1-(1Ј-naphthyl)ethylamine (310 mg, 1.83 J = 5.7 Hz), 52.0 [(CH3O)2P], 52 ppm. 5 [(CH3O)2P], 56.8* (d, J =
mmol), and dimethyl phosphite (200 mg, 1.92 mmol) were stirred
140.2 Hz, CH–P), 57.0 (d, J = 133.3 Hz, CH–P), 123.1, 123.7,
124.1, 125.2, 125.3*, 125.5, 125.6*, 125.7*, 127.3, 127.4*, 128.8,
128.9*, 131.1*, 131.5, 134.0*, 140.5, 140.9*. 31P NMR (202 MHz,
CDCl3): δ = 30.96*, 32.27 ppm. HRMS [FA]+: m/z (%) = 336 (100)
at 80 °C for 6 h. The product 6c was obtained (560 mg, 76%) as an
1
oil. Asterisk denotes minor diastereoisomer. H NMR (500 MHz,
CDCl3): δ = 1.46* (d, J = 6.4 Hz, 3 H, CH3CH), 1.49 (d, J =
6.5 Hz, 3 H, CH3CH), 3.45* [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.50 [M + H]+, 226 (72.74) [M + H – 110]+, 155 (37.4).
6578
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6573–6581

Uncatalyzed One-Pot Diastereoselective Synthesis of α-Amino Phosphonates
Dimethyl (R,S)- and (S,S)-(2,2-Dimethyl-1-{[1-(naphthalen-1-yl)-
ethyl]amino}propyl)phosphonate (6f): tert-Butylacetaldehyde
2.01 mmol), (S)-1,2,2-trimethylpropylamine (200 mg, 2.01 mmol),
and dimethyl phosphite (230 mg, 2.11 mmol) were stirred at 80 °C
(250 mg, 2.90 mmol), (S)-1-(1Ј-naphthyl)ethylamine (490 mg, for 6 h. The product 7c was obtained (570 mg, 91%) as an oil.
2.90 mmol), and dimethyl phosphite (330 mg, 3.04 mmol) were
stirred at 80 °C for 8 h. The product 6f was obtained (890 mg, 88%)
as an oil. Asterisk denotes minor diastereoisomer. 1H NMR
Asterisk denotes minor diastereoisomer. 1H NMR (500 MHz,
CDCl3): δ = 0.85 [s, 9 H, (CH3)3C], 0.89* [s, 9 H, (CH3)3C], 0.92
(d, J = 6.4 Hz, 3 H, CH3CH), 2.08 (q, J = 6.4 Hz, 1 H, CH–N),
(500 MHz, CDCl3): δ = 0.97 [s, 9 H, (CH3)3C], 1.16* [s, 9 H, (CH3) 3.49* [d, J = 10.5 Hz, 3 H, (CH3O)2P], 3.59 [d, J = 10.4 Hz, 3 H,
3C], 1.42* (d, J = 6.5, Hz, 3 H, CH3CH), 1.48 (d, J = 6.6, Hz, 3 (CH3O)2P], 3.76 [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.83* [d, J =
H, CH3CH), 2.49 (d, J = 12.5 Hz, 1 H, CH–N), 2.79* (d, J = 10.5 Hz, 3 H, (CH3O)2P], 3.97* (d, J = 22.6 Hz, 1 H, CH–P), 4.16
16.0 Hz, 1 H, CH–N), 3.62* [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.68* (d, J = 21.0 Hz, 1 H, CH–P), 7.01–7.10 (m, 2 H, Harom), 7.34–
[d, J = 10.3 Hz, 3 H, (CH3O)2P], 3.69 [d, J = 10.6 Hz, 3 H, (CH3-
O)2P], 3.81 [d, J = 10.4 Hz, 3 H, (CH3O)2P], 4.95 (m, 1 H, CH– (CH3CH), 17.3* (CH3CH), 26.3* [(CH3)3C], 26.4 [(CH3)3C], 34.0
N), 5.05 (m, 1 H, CH–N), 7.43–7.50 (m, 5 H, Harom), 7.71–7.77 [C(CH3)3], 35.4* [C(CH3)3], 53.4 [d, J = 6.9 Hz, (CH3O)2P], 54.0
7.41 (m, 2 H, Harom) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.2
(m, 2 H, Harom), 7.84–7.87* (m, 5 H, Harom), 8.30* (d, J = 8.3 Hz, [d, J = 6.9 Hz, (CH3O)2P], 57.5 (d, J = 153.7 Hz, CH–P), 58.0 (d,
2 H, Harom) ppm. 13C NMR (125 MHz, CDCl3): δ = 22.0 J = 15.7 Hz, CH–N), 115.2 (dd, J = 21.5, 2.5 Hz), 130.3 (dd, J =
(CH3CH), 24.5* (CH3CH), 27.8 [(CH3)3C], 27.9* [(CH3)3C], 34.7 8.1, 6.4 Hz), 131.5* (dd, J = 4.4, 3.2 Hz), 161.4 (d, J = 3.4 Hz),
[d, J = 7.4 Hz, C(CH3)3], 35.0* 7 [d, J = 8.2 Hz, C(CH3)3], 52.0
[(CH3O)2P], 52.3 [(CH3O)2P], 61.2* (d, J = 132.4 Hz, CH–P), 62.4 26.00* (d, J = 4.8 Hz), 26.23 (d, J = 5.2 Hz) ppm. HRMS [FA]+:
(d, J = 131.2 Hz, CH–P), 123.3, 123.7*, 125.0, 125.1, 125.3*, 125.4,
m/z (%) = 318 (100) [M + H]+, 208 (100) [M + H – 110]+.
163.4 (d, J = 3.5 Hz) ppm. 31P NMR (202 MHz, CDCl3): δ =
125.5*, 125.6, 125.8*, 127.3, 127.4*, 128.8, 128.9*, 130.8*, 131.6, C15H25FNO3P (317.34): calcd. C 56.77, H 7.94, N 4.41; found C
133.8 (d, J = 2.5 Hz) ppm. 31P NMR (202 MHz, CDCl3): δ =
31.65*, 32.09 ppm. HRMS [FA]+: m/z (%) = 350 (100) [M + H]+,
240 (100) [M – 110]+, 155 (96.9).
57.01, H 7.80, N 4.52.
Dimethyl (R,S)- and (S,S)-{(4-Methoxyphenyl)[(1,2,2-trimethyl-
propyl)amino]methyl}phosphonate (7d): 4-Methoxybenzaldehyde
(250 mg, 1.83 mmol), (S)-1,2,2-trimethylpropylamine (180 mg,
1.83 mmol), and dimethyl phosphite (200 mg, 1.92 mmol) were
stirred at 80 °C for 6 h. The product 7d was obtained (500 mg,
Dimethyl (R,S)- and (S,S)-{(Phenyl)[(1,2,2-trimethylpropyl)amino]-
methyl}phosphonate (7a): Benzaldehyde (250 mg, 2.35 mmol), (S)-
1,2,2-trimethylpropylamine (237 mg, 2.35 mmol), and dimethyl
phosphite (250 mg, 2.46 mmol) were stirred at 80 °C for 8 h. The
product 7a was obtained (640 mg, 91%) as a solid. M.p. 66 °C.
Asterisk denotes minor diastereoisomer. 1H NMR (500 MHz,
CDCl3): δ = 0.79 [s, 9 H, (CH3)3C], 0.83* [s, 9 H, (CH3)3C], 0.86
(d, J = 6.4 Hz, 3 H, CH3CH), 2.09 (br, 1 H, CH–N), 3.50 [d, J =
10.4 Hz, 3 H, (CH3O)2P], 3.70 [d, J = 10.4 Hz, 3 H, (CH3O)2P],
3.77* [d, J = 10.5 Hz, 3 H, (CH3O)2P], 4.13 (d, J = 21.4 Hz, 1
H, CH–P), 7.29–7.39 (m, 5 H, Harom) ppm. 13C NMR (125 MHz,
CDCl3): δ = 13.2 (CH3CH), 17.4* (CH3CH), 26.3 [(CH3)3C], 34.0
[C(CH3)3], 35.5* [C(CH3)3], 53.4 [d, J = 6.9 Hz, (CH3O)2P], 54.0
[d, J = 6.9 Hz, (CH3O)2P], 57.8 (d, J = 15.9 Hz, CH–N), 57.9 (d,
J = 152.5 Hz, CH–P), 127.8 (d, J = 3.2 Hz), 128.3 (d, J = 2.5 Hz),
128.8 (d, J = 6.4 Hz), 135.7 (d, J = 4.1 Hz) ppm. 31P NMR
(202 MHz, CDCl3): δ = 27.26*, 27.54 ppm. HRMS [FA]+: m/z (%)
= 300 (100) [M + H]+, 190 (16.3) [M – 110]+.
1
92%) as an oil. Asterisk denotes minor diastereoisomer. H NMR
(500 MHz, CDCl3): δ = 0.82 [s, 9 H, (CH3)3C], 0.86* [s, 9 H, (CH3)
3C], 0.89 (d, J = 6.4 Hz, 3 H, CH3CH), 2.10 (q, J = 6.4, Hz, 1 H,
CH–N), 2.26* (q, J = 6.4, Hz, 1 H, CH–N), 3.44* [d, J = 10.4 Hz,
3 H, (CH3O)2P], 3.55 [d, J = 10.3 Hz, 3 H, (CH3O)2P], 3.74 [d, J
= 10.4 Hz, 3 H, (CH3O)2P], 3.78 (s, 3 H, CH3O), 3.81* [d, J =
10.3 Hz, 3 H, (CH3O)2P], 4.11 (d, J = 20.9 Hz, 1 H, CH–P), 6.87
(AAЈBBЈ, J = 8.8 Hz, 2 H, Harom), 7.29 (AAЈBBЈ, J = 8.8 Hz, 2 H,
Harom) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.1 (CH3CH),
17.3* (CH3CH), 26.3 (CH3)3C, 33.0 [C(CH3)3], 35.4* [C(CH3)3],
53.4 [(CH3O)2P], 53.9 [(CH3O)2P], 55.1 [(CH3O)], 57.3 (d, J =
152.5 Hz, CH–P), 57.5 (d, J = 16.0 Hz, CH–N), 113.6, 127.4 (d, J
= 4.3 Hz), 129.8 (d, J = 6.4 Hz), 159.1 (d, J = 3.0 Hz) ppm. 31P
NMR (202 MHz, CDCl3): δ = 26.49*, 26.84 ppm. HRMS [FA]+:
m/z (%) = 330 (100) [M + H]+, 272 (3.10) [M – 58]+, 220 (100) [M –
110]+.
Dimethyl (R,S)- and (S,S)-{(4-Chlorophenyl)[(1,2,2-trimethylprop-
yl)amino]methyl}phosphonate (7b): 4-Chlorobenzaldehyde (250 mg,
1.78 mmol), (S)-1,2,2-trimethylpropylamine (179 mg, 1.78 mmol),
and dimethyl phosphite (200 mg, 1.87 mmol) were stirred at 80 °C
for 6 h. The product 7b was obtained (530 mg, 90%) as an oil.
Asterisk denotes minor diastereoisomer. 1H NMR (500 MHz,
CDCl3): δ = 0.85 [s, 9 H, (CH3)3C], 0.89* [s, 9 H, (CH3)3C], 0.92
(d, J = 6.4 Hz, 3 H, CH3CH), 2.08 (q, J = 6.4 Hz, 1 H, CH–N),
2.23* (q, J = 6.4 Hz, 1 H, CH–N), 3.51* [d, J = 10.5 Hz, 3 H,
(CH3O)2P], 3.61 [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.76 [d, J =
10.4 Hz, 3 H, (CH3O)2P], 3.97* (d, J = 22.6 Hz, 1 H, CH–P), 4.16
(d, J = 21.0 Hz, 1 H, CH–P), 7.30–7.36 (m, 4 H, Harom) ppm. 13C
NMR (125 MHz, CDCl3): δ = 13.1 (CH3CH), 26.3 [(CH3)3C], 34.0
Dimethyl (R,S)- and (S,S)-{(3,4-Dimethoxyphenyl)[(1,2,2-trimeth-
ylpropyl)amino]methyl}phosphonate (7e): 3,4-Dimethoxybenzalde-
hyde
(250 mg,
1.50 mmol),
(S)-1,2,2-trimethylpropylamine
(150 mg, 1.50 mmol), and dimethyl phosphite (170 mg, 1.57 mmol)
were stirred at 80 °C for 6 h. The product 7e was obtained (500 mg,
1
91%) as an oil. Asterisk denotes minor diastereoisomer. H NMR
(500 MHz, CDCl3): δ = 0.83 [s, 9 H, (CH3)3C], 0.86* [s, 9 H, (CH3)
3C], 0.90 (d, J = 6.4 Hz, 3 H, CH3CH), 2.06–2.17 (m, 1 H, CH–
N), 3.55 [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.73 [d, J = 10.4 Hz, 3
H, (CH3O)2P], 3.85 (s, 6 H, CH3O), 4.10 (d, J = 20.7 Hz, 1 H, CH–
P), 6.80 (d, J = 8.2 Hz, 1 H, Harom), 6.87 (d, J = 5.2 Hz, 1 H,
Harom), 6.99 (s, 1 H, Harom) ppm. 13C NMR (125 MHz, CDCl3): δ
= 13.2 (CH3CH), 26.3* (CH3)3C, 26.4 (CH3)3C, 34.0 [C(CH3)3],
35.5* [C(CH3)3], 53.4 [d, J = 6.9 Hz, (CH3O)2P], 54.0 [d, J =
7.0 Hz, (CH3O)2P], 55.7 (CH3O), 55.8 (CH3O), 57.5 (d, J =
155.0 Hz, CH–P), 57.6 (d, J = 16.0 Hz, CH–N), 110.6 (d, J =
2.4 Hz), 111.5 (d, J = 5.3 Hz), 121.3 (d, J = 7.7 Hz), 128.0 (d, J =
4.7 Hz), 148.6 (d, J = 3.2 Hz), 148.8 (d, J = 2.6 Hz) ppm. 31P NMR
[C(CH3)3], 53.5 [(CH3O)2P], 53.9 [(CH3O)2P], 57.4 (d,
J =
158.7 Hz, CH–P), 57.8 (d, J = 15.6 Hz, CH–N), 128.4 (d, J =
2.4 Hz), 130.0 (d, J = 6.2 Hz), 133.5 (d, J = 4.0 Hz), 134.4 (d, J =
4.6 Hz) ppm. 31P NMR (202 MHz, CDCl3): δ = 25.65*, 25.90 ppm.
HRMS [FA]+: m/z (%) = 334 (100) [M + H]+, 244 (20.25) [M –
110]+.
Dimethyl (R,S)- and (S,S)-{(4-Fluorophenyl)[(1,2,2-trimethylprop- (202 MHz, CDCl3): δ = 26.42*, 26.72 ppm. HRMS [FA]+: m/z (%)
yl)amino]methyl}phosphonate (7c): 4-Fluorobenzaldehyde (250 mg,
= 360 (100) [M + H]+, 302 (1.17) [M – 58]+, 250 (100) [M – 110]+.
Eur. J. Org. Chem. 2010, 6573–6581
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6579

M. Ordoñez et al.
FULL PAPER
Dimethyl (R,S)- and (S,S)-{1-[(1,2,2-trimethylpropyl)amino]-
ethyl}phosphonate (7f): Acetaldehyde (250 mg, 5.68 mmol), (S)-
1,2,2-trimethylpropylamine (570 mg, 5.68 mmol), and dimethyl
phosphite (650 mg, 5.97 mmol) were stirred at 80 °C for 6 h. The
product 7f was obtained (1.30 g, 92%) as an oil. Asterisk denotes
J = 152.0 Hz, CH–P), 52.4 [d, J = 5.1 Hz, (CH3O)2P], 52.6* [d, J
= 6.9 Hz, (CH3O)2P], 53.7 [d, J = 7.3 Hz, (CH3O)2P], 59.8* (CH–
N), 60.4 (d, J = 9.6 Hz, CH–N) ppm. 31P NMR (202 MHz,
CDCl3): δ = 31.41, 31.84* ppm. HRMS [FA]+: m/z (%) = 280 (100)
[M + H]+; 222 (51.98) [M – 58]+, 170 (100) [M – 110]+.
1
minor diastereoisomer. H NMR (500 MHz, CDCl3): δ = 0.83 [s,
Dimethyl (R,S)- and (S,S)-{2-Methyl-1-[(1,2,2-trimethylpropyl)-
9 H, (CH3)3C], 0.83* [s, 9 H, (CH3)3C], 0.90 (d, J = 6.4 Hz, 3 H,
CH3CH), 0.94* (d, J = 6.6 Hz, 3 H, CH3CH), 1.20 (dd, J = 18.1,
7.0 Hz, 1 H, CH3CH–P), 1.27* (dd, J = 17.7, 7.1 Hz, 1 H, CH3CH–
P), 2.33–2.41 (m, 1 H, CH3CH–N), 2.95* (dq, J = 15.0, 7.0 Hz, 1
H, CH–P), 3.01 (dq, J = 15.0, 7.0 Hz, 1 H, CH–P), 3.72* [d, J =
10.4 Hz, 3 H, (CH3O)2P], 3.74 [d, J = 10.3 Hz, 3 H, (CH3O)2P],
3.76* [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.77 [d, J = 10.2 Hz, 3 H,
(CH3O)2P] ppm. 13C NMR (125 MHz, CDCl3): δ = 14.5 (CH3CH–
N), 14.7 (CH3CH–P), 16.4* (CH3CH–N), *16.8 (CH3CH–P), 26.2*
[(CH3)3C], 26.3 [(CH3)3C], 33.1* [C(CH3)3], 34.2 [C(CH3)3], 48.1
(d, J = 157.5 Hz, CH–P), 50.3* (d, J = 157.9 Hz, CH–P), 52.6*
[(CH3O)2P], 52.8 [d, J = 7.1 Hz, (CH3O)2P], 53.2* [(CH3O)2P], 53.6
[(CH3O)2P], 58.9 [d, J = 13.6 Hz, (CH–N)], 61.3* [d, J = 9.9 Hz,
amino]propyl}phosphonate
(7i):
Isobutyraldehyde
(250 mg,
3.46 mmol), (S)-1,2,2-trimethylpropylamine (350 mg, 3.46 mmol),
and dimethyl phosphite (400 mg, 3.53 mmol) were stirred at 80 °C
for 8 h. The product 7i was obtained (820 g, 91%) as an oil. Aster-
isk denotes minor diastereoisomer. 1H NMR (500 MHz, CDCl3):
δ = 0.89 [s, 9 H, (CH3)3C], 0.98 (d, J = 6.4 Hz, 6 H, CH3CH), 1.04
[d, J = 6.9 Hz, 3 H, (CH3)2CH], 1.07 [d, J = 6.9 Hz, 3 H, (CH3)2-
CH], 2.01–2.21 [m, 1 H, CH(CH3)2], 2.46 (q, J = 6.4 Hz, 1 H, CH–
N), 2.51–2.58* (m, 1 H, CH–N), 2.80* (d, J = 14.9 Hz, 1 H, CH–
P), 2.90 (d, J = 18.3 Hz, 1 H, CH–P), 3.75 [d, J = 10.5 Hz, 3 H,
(CH3O)2P], 3.76* [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.80 [d, J =
10.3 Hz, 3 H, (CH3O)2P] ppm. 13C NMR (125 MHz, CDCl3): δ =
14.8* (CH3CH), 15.0 (CH3CH), 17.7* [(CH3)2CH], 18.5 [(CH3)2-
CH], 20.2 [(CH3)2CH], 20.4* [(CH3)2CH], 26.3* [(CH3)3C], 26.4
[(CH3)3C], 29.3* [d, J = 6.2 Hz, CH(CH3)2], 29.4 [d, J = 5.3 Hz,
CH(CH3)2], 34.4* [C(CH3)3], 34.8 [C(CH3)3], 52.2 [d, J = 6.7 Hz,
(CH–N)] ppm. 31P NMR (202 MHz, CDCl3):
δ = 30.75*,
31.24 ppm. HRMS [FA]+: m/z (%) = 338 (100) [M + H]+, 180 (53.5)
[M – 58]+, 128 (23.81) [M – 110]+.
Dimethyl (R,S)- and (S,S)-{2-Phenyl-1-[(1,2,2-trimethylpropyl)amino]- (CH3O)2P], 53.3 [d, J = 6.2 Hz, (CH3O)2P], 57.4* (d, J = 138.4 Hz,
ethyl}phosphonate (7 g): Phenylacetaldehyde (250 mg, 2.08 mmol),
(S)-1,2,2-trimethylpropylamine (210 mg, 2.08 mmol), and dimethyl
phosphite (240 mg, 5.18 mmol) were stirred at 80 °C for 6 h. The
product 7g was obtained (330 g, 52%) as an oil. Asterisk denotes
minor diastereoisomer. 1H NMR (500 MHz, CDCl3): δ = 0.45* (d,
J = 6.4 Hz, 1 H, CH3CH), 0.69 [s, 9 H, (CH3)3C], 0.81* [s, 9 H,
(CH3)3C], 0.93 (d, J = 6.5, Hz, 3 H, CH3CH), 2.26 (q, J = 6.5, Hz,
1 H, CH–N), 2.80 (dt, J = 14.1, 8.2, Hz, 2 H, CH–P), 3.08–3.16
(m, 1 H, CH-CH2Ph), 3.23 (dd, J = 14.3, 8.2 Hz, 1 H, CH2Ph),
3.70 [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.75 [d, J = 10.3 Hz, 3 H,
(CH3O)2P], 7.18–7.32 (m, 5 H, Harom) ppm. 13C NMR (125 MHz,
CDCl3): δ = 14.3* (CH3CH), 15.1 (CH3CH), 25.8* [(CH3)3C], 26.1
[(CH3)3C], 34.4* (CH2Ph), 34.6 (CH2Ph), 37.1* [C(CH3)3], 37.2
[C(CH3)3], 52.5 [d, J = 7.5 Hz, (CH3O)2P], 53.6 [d, J = 7.3 Hz,
(CH3O)2P], 55.2* (d, J = 154.0 Hz, CH–P), 55.5 (d, J = 154.8 Hz,
CH–P), 60.1* (CH–N), 60.4 (d, J = 8.8 Hz, CH–N), 126.4, 126.6*,
128.1, 128.2*, 129.6, 129.8*, 138.2 (d, J = 11.3 Hz) ppm. 31P NMR
(202 MHz, CDCl3): δ = 29.71, 29.85* ppm. HRMS [FA]+: m/z (%)
= 314 (100) [M + H]+, 256 (40.85) [M – 58]+, 204 (87.17) [M –
110]+.
CH–P), 58.7 (d, J = 146.5 Hz, CH–P), 61.1 (d, J = 9.1 Hz, CH–N)
ppm. 31P NMR (202 MHz, CDCl3): δ = 30.45*, 31.95 ppm. HRMS
[FA]+: m/z (%) = 266 (100) [M + H]+, 208 (45.64) [M – 58]+, 156
(100) [M – 110]+.
Dimethyl (R,S)- and (S,S)-{2,2-Dimethyl-1-[(1,2,2-trimethylpropyl)-
amino]propyl}phosphonate (7j): tert-Butylacetaldehyde (250 mg,
2.90 mmol), (S)-1,2,2-trimethylpropylamine (490 mg, 2.90 mmol),
and dimethyl phosphite (330 mg, 3.04 mmol) were stirred at 80 °C
for 8 h. The product 7j was obtained (750 g, 93%) as an oil. Aster-
isk denotes minor diastereoisomer. 1H NMR (500 MHz, CDCl3):
δ = 0.89* [s, 9 H, (CH3)3C], 0.91 [s, 9 H, (CH3)3C], 0.97 (d, J =
6.4 Hz, 1 H, CH3CH), 1.05* [s, 9 H, (CH3)3C], 1.08 [s, 9 H, (CH3)3-
C], 2.53–2.60 (m, 1 H, CH–N), 2.70 (d, J = 18.1 Hz, CH–P), 3.71
[d, J = 10.6 Hz, 3 H, (CH3O)2P], 3.73* [d, J = 10.5 Hz, 3 H,
(CH3O)2P], 3.74* [d, J = 10.3 Hz, (CH3O)2P], 3.79 [d, J = 10.3 Hz,
(CH3O)2P] ppm. 13C NMR (125 MHz, CDCl3): δ = 14.4* (CH3),
14.6 (CH3), 26.2* [(CH3)3C], 26.6 [(CH3)3C], 27.7* [d, J = 6.1 Hz,
(CH3)3C], 28.0 [d, J = 7.0 Hz, (CH3)3C], 35.0 [d, J = 1.4 Hz,
C(CH3)3], 36.3 [d, J = 7.8 Hz, C(CH3)3], 51.8* [(CH3O)2P], 53.5 [d,
J = 7.4 Hz, (CH3O)2P], 62.3 (d, J = 7.6 Hz, CH–N), 62.4 (d, J =
145.0 Hz, CH–P) ppm. 31P NMR (202 MHz, CDCl3): δ = 30.16,
32.67* ppm. HRMS [FA]+: m/z (%) = 280 (100) [M + H]+, 222
(35.98) [M – 58]+, 170 (100) [M – 110]+.
Dimethyl (R,S)- and (S,S)-{3-Methyl-1-[(1,2,2-trimethylpropyl)amino]-
butyl}phosphonate (7h): Isovaleraldehyde (250 mg, 2.90 mmol), (S)-
1,2,2-trimethylpropylamine (290 mg, 2.90 mmol), and dimethyl
phosphite (330 mg, 3.04 mmol) were stirred at 80 °C for 8 h. The
product 7h was obtained (700 g, 86%) as an oil. Asterisk denotes
Supporting Information (see footnote on the first page of this arti-
cle): 31P NMR spectra of all diastereoisomeric mixtures.
1
minor diastereoisomer. H NMR (500 MHz, CDCl3): δ = 0.85 [s,
9 H, (CH3)3C], 0.87* [s, 9 H, (CH3)3C], 0.89 [d, J = 6.8 Hz, 3 H,
(CH3)2CH], 0.91* [d, J = 6.9 Hz, 3 H, (CH3)2CH], 0.92 [d, J =
6.7 Hz, 3 H, (CH3)2CH], 0.97 (d, J = 6.4 Hz, 3 H, CH3CH–N),
1.31–1.43 [m, 1 H, CH(CH3)2], 1.57–1.65* [m, 1 H, CH2(CH3)2],
1.89 (dt, J = 20.1, 6.7 Hz, 2 H, CH–P), 2.43 (q, J = 6.4 Hz, 1 H,
CH–NH), 2.62* (dq, J = 6.4, 2.2 Hz, 1 H, CH–N), 2.89–2.97 (m,
1 H, CH2CH), 3.74 [d, J = 10.3 Hz, 3 H, (CH3O)2P], 3.75* [d, J =
10.2 Hz, 3 H, (CH3O)2P], 3.76* [d, J = 10.3 Hz, 3 H, (CH3O)2P],
3.80 [d, J = 10.2 Hz, 3 H, (CH3O)2P] ppm. 13C NMR (125 MHz,
CDCl3): δ = 14.8* (CH3CH), 15.3 (CH3CH), 21.5* [(CH3)2CH],
22.5 [(CH3)2CH], 22.8 [(CH3)2CH], 23.4* [(CH3)2CH], 24.0* [d, J
= 11.6 Hz, CH(CH3)2], 24.6 [d, J = 8.7 Hz, CH(CH3)2], 26.3*
[(CH3)3C], 26.4 [(CH3)3C], 34.4 (CH2), 34.6* (CH2), 40.3*
[C(CH3)3], 40.8 [(CH3)3C], 50.6* (d, J = 152.0 Hz, CH–P), 51.6 (d,
Acknowledgments
We thank the Consejo Nacional de Ciencia
(CONACYT) of México (project 62271) for financial support. We
also thank Victoria Labastida for the HRMS analysis.
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Received: August 4, 2010
Published Online: October 20, 2010
Eur. J. Org. Chem. 2010, 6573–6581
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6581