One-Pot Two-Step Synthesis of Optically Active α-Amino Phosphonates by Palladium-Catalyzed Hydrogenation/Hydrogenolysis of α-Hydrazono Phosphonates

Article abstract of DOI:10.1002/adsc.201600945

An efficient and convenient one-pot procedure for the stereoselective catalytic synthesis of ring-substituted [amino(phenyl)methyl]phosphonates has been developed. The enantioselective hydrogenation of easily available diisopropyl (Z)-[aryl(phenylhydrazono)methyl]phosphonates using palladium(II) acetate as a precatalyst, (R)-2,2′-bis(diphenylphosphino)-5,5′-dichloro-6,6′-dimethoxy-1,1′-biphenyl [(R)-Cl–MeO-BIPHEP] as a ligand, and (1S)-(+)-10-camphorsulfonic acid as an activator in a mixture of 2,2,2-trifluoroethanol and methylene chloride at ambient temperature results in the formation of corresponding [aryl(2-phenylhydrazino)methyl]phosphonates. The subsequent cleavage of the N?N bond has been accomplished with molecular hydrogen after the addition of palladium on carbon and methanol into crude reaction mixture to afford the optically active [amino(aryl)methyl]phosphonates. The method is operationally simple and provides an appreciable enantioselectivity up to 98 % ee. (Figure presented.).

Full text of DOI:10.1002/adsc.201600945

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DOI: 10.1002/adsc.201600945
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One-Pot Two-Step Synthesis of Optically Active
a-Amino Phosphonates by Palladium-Catalyzed
Hydrogenation/Hydrogenolysis of a-Hydrazono Phosphonates
Nataliya S. Goulioukina,a, b,* Ilya A. Shergold,a Victor B. Rybakov,a and Irina
P. Beletskayaa, b,*
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a
Department of Chemistry, Moscow State University, Leninskie Gory, GSP-1, Moscow 119991, Russia
Fax: (+7)-495-939-1854; e-mail: goulioukina@org.chem.msu.ru beletska@org.chem.msu.ru
Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, 31 Leninsky prosp., Moscow
b
119071, Russia
17 Received: August 25, 2016; Accepted: October 20, 2016; Published online: && &&, 0000
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Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600945
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aldimines and ketimines and asymmetric reduction of
a,b-dehydroaminophosphonates.[2] Several years ago
we reported on the feasibility of Rh-catalyzed asym-
metric hydrogenation of a-imino phosphonates as a
straightforward access to optically active a-amino
phosphonates containing the quaternary b-carbon
atom.[3] Subsequently, this approach was extended on
oxazaborolidine catalyzed reduction of (2,2,2-tri-
fluoro-1-iminoethyl)phosphonates with catecholebor-
ane.[4] Along with all apparent advantages, some
pitfalls of this method should be mentioned. First, a-
imino phosphonates are actually an equilibrium
mixture of Z/E-isomers, which may have an adverse
effect on the overall stereoselectivity of the process. In
addition, these starting substrates are slowly hydro-
lyzed on storage. Finally, the common synthesis of a-
imino phosphonates via the Michaelis-Arbuzov rear-
rangement requires the usage of labile imidoyl
chlorides under harsh reaction conditions.[5] When the
present paper was in preparation, Zhou et al. commu-
nicated on excellent results in Pd-catalyzed asymmet-
ric hydrogenation of a-tosylimino phosphonates.[6]
However, the latter precursors cannot be considered
the best choice, because they are synthesized from the
same racemic a-tosylamino phosphonates by N-chlori-
nation/dehydrochlorination procedure.[7]
Abstract: An efficient and convenient one-pot
procedure for the stereoselective catalytic synthesis
of ring-substituted [amino(phenyl)methyl]phospho-
nates has been developed. The enantioselective
hydrogenation of easily available diisopropyl (Z)-
[aryl(phenylhydrazono)methyl]phosphonates using
palladium(II) acetate as a precatalyst, (R)-2,2’-bis
(diphenylphosphino)-5,5’-dichloro-6,6’-dimethoxy-
1,1’-biphenyl [(R)-Cl–MeO-BIPHEP] as a ligand,
and (1S)-(+)-10-camphorsulfonic acid as an activa-
tor in a mixture of 2,2,2-trifluoroethanol and
methylene chloride at ambient temperature results
in the formation of corresponding [aryl(2-phenyl-
hydrazino)methyl]phosphonates. The subsequent
cleavage of the NÀN bond has been accomplished
with molecular hydrogen after the addition of
palladium on carbon and methanol into crude
reaction mixture to afford the optically active
[amino(aryl)methyl]phosphonates. The method is
operationally simple and provides an appreciable
enantioselectivity up to 98% ee.
Keywords: a-amino phosphonates; asymmetric cat-
alysis; a-hydrazono phosphonates; hydrogenation;
palladium
Readily accessible a-oxo phosphonates[8] are im-
portant reagents for the preparation of elaborate
50 a-Amino phosphonates, particularly nonracemic ones, phosphonates. Unfortunately, they cannot be used for
51 have been a topic for decades due to a wide spectrum the synthesis of the corresponding a-imino phospho-
52 of their possible applications.[1] Nevertheless, the nates since the interaction of simple nucleophiles like
53 stereocontrolled formation of a-amino phosphonates ammonia and amines as well as water, alcohols and
54 remains a challenge in chemical synthesis. Among thiols with a-oxo phosphonates leads to CÀP bond
55 catalytic concepts for the enantioselective synthesis of cleavage.[9] On the contrary, nucleophiles with an a-
56 a-amino phosphonates, two methodologies are lead- heteroatom, such as hydroxylamine and substituted
57 ing, namely, asymmetric hydrophosphonylation of hydrazines, smoothly react with a-oxo phosphonates
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to yield the corresponding oximes and hydrazones. a-
Hydrazono phosphonates are quite stable, easy to
handle, and can be isolated as individual Z- or E-
isomers. In general terms, hydrazones (in particular N-
acylhydrazones) are recognized as stable imine surro-
gates and versatile electrophiles for the synthesis of
various nitrogen-containing compounds.[10] As for the
chemistry of organophosphorus compounds, the use of
a-C=N unsaturated precursors in the synthesis of
10 racemic a-amino phosphonates originated from reduc-
11 tion of a-hydrazono phosphonates.[11]
12
Over the recent fifteen years, palladium complexes
13 have been successfully applied in asymmetric hydro-
14 genation of various prochiral substrates bearing C=N
15 double bond,[6,12] including hydrazones.[12e,13] Consider-
16 able advances in this field and our previous experi-
17 ence[14] prompted us to study an application of
18 palladium catalysis for the synthesis of optically active
19 a-amino phosphonates using a-hydrazono phospho-
20 nates as convenient precursors. Herein we report our
21 results.
22
We prepared three model precursors (Z)-1, (Z)-2a,
23 and (E)-2a distinguished by substituent at the nitro-
24 gen atom and by the configuration of the C=N double
25 bond (Figure 1). N-Benzoylated a-hydrazono phos-
Figure 2. The molecular structure[16] of hydrazone (Z)-1, with
atom labels. Displacement ellipsoids are drawn at 30%
probability level. The H atoms are presented as small spheres
of arbitrary radius.
26 phonate was synthesized according to a known
27 procedure[15] and was isolated by column chromatog-
28 raphy as an individual Z-isomer [(Z)-1]. We unambig-
29 uously proved the conformation across the C=N bond
30 by the X-ray diffraction data (Figure 2).[16]
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32
33
34
35
36
a-Hydrazono phosphonate 2a was synthesized
using a modified literature procedure[19] by the con-
densation of diethyl benzoylphosphonate with phenyl-
hydrazine hydrochloride in ethanol in the presence of
pyridine[20] as a mixture of Z- and E-isomers in a ratio
of 75:25. Individual isomer (Z)-2a was obtained by
simple crystallization from ethanol. The second isomer
(E)-2a was isolated in a pure state by chromatogra-
phy. The stabilization of isomer (Z)-2a by intra-
molecular hydrogen bond had previously been as-
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38
39
40
41
Figure 1. Model substrates screened in palladium-catalyzed
asymmetric hydrogenation.
We strongly hoped to use (Z)-1 as a prochiral sumed in the literature on the basis of comparative
42 precursor, this compound being the only a-hydrazono analysis of the spectral data[19,21] and the chromato-
43 phosphonate for which the possibility of stereoselec- graphic mobility[19] of isomers 2a. This assumption was
44 tive catalytic hydrogenation had been mentioned in unambiguously confirmed by the X-ray diffraction
45 the literature with the Rh(I) catalyst derived from 1,2- data (Figure 3).[22]
46 bis[(2R,5R)-2,5-diethylphospholano]benzene [(R,R)-
Preliminary experiments on the homogeneous
47 Et-DUPHOS].[15,17] The concept of substrate chelation enantioselective hydrogenation of isomers 2a were
48 in highly enantioselective rhodium catalyzed hydro- carried out using 5 mol% palladium acetate as a
49 genation is well known,[18] and phosphonate (Z)-1, precatalyst, 5 mol% ligand (S)-2,2’-bis(diphenyl-
50 containing an additional carbonyl group capable of phosphino)-1,1’-binaphthyl [(S)-BINAP] in 2,2,2-tri-
51 capturing the catalytic center fits in this concept. fluoroethanol (TFE) in the presence of 10 mol% (1S)-
52 Unfortunately, all our attempts to reduce (Z)-1 under (+)-10-camphorsulfonic acid (CSA) as an activator,
53 the palladium catalysis conditions (including those and hydrogen pressure of 50 atm. We found these
54 listed below in Table 1) were unsuccessful: the reac- conditions to be optimal for the enantioselective
55 tion either did not occur at all or resulted in hydrogenation of a-oxyimino phosphonates.[14] The
56 unidentified products.
reaction course was monitored by the 31P NMR
57
method. It turned out that under these conditions a-
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Table 1. Screening of reaction conditions for the asymmetric hydrogenation of hydrazones 2a.[a]
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2
3
4
5
6
7
8
9
Entry Pressure
[atm]
T
[8C]
Solvent
Conversion of (Z)-2a
Yield of 3a
Yield of (E)-2a
ee
[%][b]
[%][b]
[%][b]
[%][c]
1[d]
2
50
50
50
50
50
50
50
50
50
50
50
20
30
40
60
70
60
20
20
20
20
20
20
20
20
40
60
20
20
20
20
20
TFE
TFE
TFE
TFE
–
100
25
37
99
0
93
0
95
6
18
4
20
6
4
n.a.
78
n.a.
n.a.
n.a.
89
90
91
89
80
71
82
88
90
84
82
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
3[e]
4[f]
5
33
71
90
96
98
95
90
86
80
90
92
88
88
TFE/PhMe (1:1)
TFE/CH2Cl2 (1:1)
TFE/CH2Cl2 (1:2)
TFE/CH2Cl2 (1:3)
TFE/CH2Cl2 (1:4)
TFE/CH2Cl2 (1:3)
TFE/CH2Cl2 (1:3)
TFE/CH2Cl2 (1:3)
TFE/CH2Cl2 (1:3)
TFE/CH2Cl2 (1:3)
TFE/CH2Cl2 (1:3)
TFE/CH2Cl2 (1:3)
6
7
8
9
10
11
12
13
14
15
16
96
100
100
99
100
100
98
100
100
100
100
2
4
10
14
18
10
8
12
12
[a] Unless otherwise stated, reactions were carried out with (Z)-2a (0.14 mmol), Pd(OAc)2 (7 mmol, 5 mol%), (S)-BINAP (7
mmol, 5 mol%), CSA (14 mmol, 10 mol%), and 4 mL of solvent under directed conditions for 1.5 h.
[b] Determined by 31P NMR analysis of the crude reaction mixture.
[c] Determined by H NMR analysis of the crude reaction mixture after addition of CSA (1 equiv.); n.a. – not analysed.
1
[d] (E)-2a was used as a substrate; 5% of (Z)-2a was detected in the crude reaction mixture by 31P NMR analysis.
[e] 1 equiv. of CSA was used.
[f] 5 mol% CSA was used.
33 hydrazono phosphonate (E)-2a (dP =11.1 ppm) did 4.82 ppm (2JPH =13.0 Hz)) corresponding to two dia-
34 not undergo hydrogenation either at room temper- stereomeric salts formed after the reaction mixture
35 ature or at 608C (Table 1, entry 1). On the contrary, in was treated with 1 equiv. of CSA.[24] The stereo-
36 the case of substrate (Z)-2a (dP =11.8 ppm), the selectivity of the process in entry 2 was 78% ee. It
37 reaction completed within 1.5 h and afforded diethyl must be noted that the same ee value was obtained
38 [phenyl(2-phenylhydrazino)methyl]phosphonate (3a) when antipodal ligand (R)-BINAP was applied. The
39 as the major product in 93% yield.[23] Besides, the usage of (Æ)-BINAP afforded the racemic product 3a.
40 formation of a minor amount (6%) of (E)-2a was These results indicate that the chirality of CSA plays
41 detected (entry 2). This is not surprising because the no role in stereodifferentiation which is controlled
42 mutual transformation of Z/E-isomers of a-hydrazono solely by the chiral ligand.
43 phosphonate 2a is known to be catalyzed by acid, and
It is known that TFE[25] serves as a “magic” solvent
44 the more polar and sterically less hindered E-isomer in homogeneous enantioselective Pd-catalyzed hydro-
45 becomes predominant in a polar protonic solvent.[19,21b] genation.[12a–e,13,14,26] However, it has been shown that
46 The yield of (E)-2a increased and hence the yield of its dilution with such low-polarity solvents as
47 3a decreased with an increase in the amount of CSA toluene[27] or dichloromethane[6,12g,28] have had a good
48 used. In the presence of 1 equiv. of CSA, the reaction effect in some cases. As applied to substrate (Z)-2a,
49 was mainly reduced to the isomerization of the the use of a TFE/PhMe (1:1) mixture as solvent led to
50 substrate (Z)-2a to the E-form (entry 3). An attempt a noticeable decrease in the chemiselectivity of the
51 to decrease the amount of the Brønsted acid to process (entry 5). On the contrary, the dilution of TFE
52 5 mol% resulted in a drastic decrease in conversion with dichloromethane exerted almost no effect on the
53 (entry 4).
yield of target product 3a, but the stereoselectivity of
54
The enantiomeric excess of product 3a was hydrogenation increased substantially (entries 6–9).
1
55 estimated by the H NMR method from the ratio of When using a TFE/CH2Cl2 (1:3) mixture, the enantio-
56 integral intensities of doublets of the methinic a-CH meric excess of a-hydrazino phosphonate 3a was 91%
57 protons (dH =4.77 ppm (2JPH =13.1 Hz) and dH = (entry 8). An increase in the reaction temperature to
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mixture. Under the optimal hydrogenolysis conditions
found (10 mol% Pd/C and 3 equiv. of CSA in a TFE/
CH2Cl2/MeOH (1:3:2) mixture of solvents (substrate
concentration 0.023 M) at 608C and at hydrogen
pressure of 5 atm for 5 h), we succeeded in achieving
an 86% yield of amino phosphonate 4a (entry 1,
Table 2).
6
7
8
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Table 2. Ligand screening for the asymmetric hydrogenation
of hydrazone (Z)-2b.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Figure 3. The molecular structure[22] of hydrazone (Z)-2a,
with atom labels. Displacement ellipsoids are drawn at 30%
probability level. The H atoms are presented as small spheres
of arbitrary radius.
32 40 or 608C induced a sharp drop in ee to 80 and 71%,
33 respectively (entries 10 and 11). Both the yield and
34 the enantiomeric excess of product 3a exhibit pro-
35 nounced bell-shaped dependence on the hydrogen
36 pressure in a range of 20–70 atm (entries 8 and 12–16)
37 attaining the maximum at 50 atm.
[a] Determined by 31P NMR analysis of the crude reaction
mixture.
38
At the next stage we had to find conditions for the
39 reduction of a-hydrazino phosphonate 3a in order to
40 obtain target optically active diethyl [amino(phenyl)-
41 methyl]phosphonate (4a). Palladium on carbon (Pd/
42 C) is a common catalyst of NÀN bond hydrogenol-
43 ysis,[29] and the reaction is carried out, as a rule, in
44 acidic medium by adding hydrochloric or acetic acid
[b] Determined by 31P NMR analysis of the corresponding
(S)-naproxen amides.
The enantiomeric excess of product 4a was deter-
45 to prevent catalyst inactivation by the amines mined by 31P NMR from the ratio of integral inten-
46 formed.[30] We preferred to use Pd/C in combination sities of well resolved signals at dP =21.26 and
47 with CSA.[31] The optimization of conditions of this 21.53 ppm of two diastereomeric amides 5a formed
48 step included the variation of solvent (TFE, CH2Cl2, after the reaction mixture treatment with (S)-naprox-
49 MeOH), substrate concentration (0.014–0.035 M), en chloride in pyridine.[33] The stereoselectivity of the
50 hydrogen pressure (5–40 atm), temperature (20– process in entry 1 was 89% ee, which is lower than the
51 808C), and amount of the catalyst (5–30 mol%) and expected value of 91% ee (entry 8, Table 1). The
52 CSA (0–3 equiv.). a-Hydrazino phosphonate 3a is decrease in the optical purity of a-amino phosphonate
53 easily oxidized in air to form a-hydrazono phospho- 4a compared to a-hydrazino phosphonate 3a is likely
54 nates 2a,[11d,32] and hence the hydrogenation (under caused by the hydrogenation of trace amounts of (E)-
55 the conditions of entry 8, Table 1) and hydrogenolysis 2a (formed in the first step of the process) in the
56 were carried out one-pot by adding the necessary presence of Pd/C and is not related to the racemiza-
57 amounts of Pd/C, CSA, and solvent to the reaction tion of 3a or 4a in the course of hydrogenolysis.[30b,c,34]
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Table 3. Two-step palladium-catalyzed asymmetric hydrogenation of hydrazones 2b–i.[a]
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2
3
4
5
6
Entry Substrate Ar
Yield of (R)-4 [%][b] ee [%][c] dP of (S)-naproxen deriv. of 4 [ppm][d] Optical rotation sign[e]
7
8
9
1
2
3
4
5
6
7
8
(Z)-2b
(Z)-2c
(Z)-2d
(Z)-2e
(Z)-2f
(Z)-2g
(Z)-2h
(Z)-2i
Ph
96(82)
92(82)
80(72)
82(72)
72(69)
62(57)
60(55)
57(52)
92
95
91
90
93
92
97
98
20.16, 20.42
19.14 (JPF =4.1 Hz), 19.36 (JPF =4.0 Hz) (+)
(+), (R)[f]
4-FC6H4
4-ClC6H4
4-MeC6H4
4-PhC6H4
3-FC6H4
2-MeC6H4
1-naphthyl
18.95, 19.16
19.61, 19.84
19.34, 19.59
18.70, 18.90
20.49, 20.70
19.88, 20.10
(+)
(+)
(+)
(+)
(+)
(+)
10
11
12
13
14
15
16
17
18
19
[a] Reactions were performed on a 0.56-mmol scale: 1) (R)-Cl–MeO-BIPHEP (28 mmol, 5 mol%), Pd(OAc)2 (28 mmol,
5 mol%), CSA (56 mmol, 10 mol%), CH2Cl2 (12 mL), TFE (4 mL); 2) 10% Pd/C (56 mmol, 10 mol%), CSA (1.68 mmol,
3 equiv.), MeOH (8 mL).
[b] Determined by 31P NMR analysis of the crude reaction mixture; isolated yields are given in parentheses.
[c] Determined by 31P NMR analysis of the corresponding (S)-naproxen amides.
20 [d] The signals of major diastereomers are given in bold.
[e] Solvent CHCl3.
21
22
23
24
25
26
[f] The absolute configuration was determined by single-crystal X-ray diffraction of the corresponding (S)-naproxen amide
(R,S)-5b.
Previously it had been shown that in the homoge- phosphonate 4b (96%) were obtained using (R)-Cl–
27 neous palladium-catalyzed hydrogenation of a-oxo, a- MeO-BIPHEP (entry 7). These conditions were chos-
28 oxyimino, and a-tosylimino phosphonates the enantio- en as optimal. Note that the yield of a-hydrazino
29 selectivity of the process increased substantially on phosphonate 3b in the first step did not exceed 20%
30 going from ethyl to isopropyl esters[6,14,35] (although in the case of bidentate phosphines (2S,3S)-2,3-bis
31 opposite examples are also known).[36] We synthesized (diphenylphosphino)butane [(S,S)-CHIRAPHOS] and
32 diisopropyl
(Z)-[phenyl(phenylhydrazono)methyl]- 1,2-bis[(2S,5S)-2,5-dimethylphospholano]benzene
33 phosphonate [(Z)-2b], however, this replacement led [(S,S)-Me–DUPHOS] forming rigid five-membered
34 only to a slight increase in the degree of stereo- chelates.
35 differentiation, but noticeably increased the yield of the
36 corresponding product 4b (entries 1 and 2, Table 2).
Under the optimal reaction conditions, a series of
diisopropyl (Z)-[aryl(phenylhydrazono)methyl]-
37
We also screened a series of ligands which showed phosphonates (Z)-2c–i was explored to examine the
38 the best results in homogeneous Pd-catalyzed hydro- reaction scope. The obtained results presented in
39 genation.[26,28,35,37] Among atropoisomeric C2-symmet- Table 3 show that the electronic effect of the sub-
40 ric bidentate ligands of the triarylphosphine type only stituent in the para-position of the benzene ring exerts
41 (S)-2,2’-bis(diphenylphospino)-5,5’,6,6’,7,7’,8,8’-octahy- only a slight effect on both the stereoselectivity of the
42 dro-1,1’-binaphthyl [(S)-H8-BINAP] (entry 4) showed process and the yield of the product (entries 1–5). The
43 an unsatisfactory result. It is worth mentioning that a corresponding para-substituted a-amino phosphonates
44 characteristic feature of (S)-H8-BINAP is an appreci- 4c–f were isolated with an optical purity of 90–95%
45 ably increased dihedral angle between the planes of and a 69–82% yield. The yield of the product
46 the aromatic fragments.[38] On the whole, the ligands substantially decreased for meta- and ortho-substituted
47 of the biphenyl type, namely, (S)-5,5’-bis(diphenyl- substrates (Z)-2g,h (entries 6 and 7) or their 1-
48 phosphino)-4,4’-bi-1,3-benzodioxole [(S)-SEGPHOS] naphthyl analog (Z)-2i (entry 8). It can be asserted on
49 (entry 5), (S)-2,2’-bis(diphenylphosphino)-6,6’-dime- the basis of the 31PNMR monitoring data that the
50 thoxy-1,1’-biphenyl [(S)-MeO-BIPHEP] (entry 6), and reactivity decreases in these cases in the hydrogenol-
51 (R)-2,2’-bis(diphenylphosphino)-5,5’-dichloro-6,6’-di-
ysis step. For highly sterically hindered substrates (Z)-
52 methoxy-1,1’-biphenyl [(R)-Cl–MeO-BIPHEP] (en- 2h,i, the degree of stereodifferentiation simultane-
53 try 7) turned out to be more efficient than the ligands ously increases in the step of asymmetric hydro-
54 of the binaphthyl type (S)-BINAP (entry 2) and (R)- genation: the enantiomeric excess of products 4h,i
55 2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl
56 BINAP] (entry 3). Both the highest enantiomeric
57 excess (92% ee) and the best yield of a-amino amino phosphonates by enantiopure naproxen
[(R)-T- attains 97–98% ee (entries 7 and 8).
It is known that on the derivatization of chiral a-
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chloride the resonance of phosphorus in the 31PNMR
spectrum of the corresponding diastereomeric amide
with opposite configurations of the C*ÀP and
C*ÀC(O) stereocenters shifted upfield in relation to
the signal corresponding to the diastereomer with the
coinciding configurations of two asymmetric carbon
atoms.[39] In the 31PNMR spectra of (S)-naproxen
derivatives of products 4b–i, the signal of the major
diastereomer is always shifted upfield (Table 3). This
10 means that for the hydrogenation of a-hydrazono
11 phosphonates (Z)-2b–i in the presence of (R)-Cl–
12 MeO-BIPHEP the arising stereogenic center adopts
13 the (R)-configuration and, as a consequence, products
14 (R)-4b–i are formed. It is worth noting that all ligands
15 with the (R)-configuration listed in Table 2 led to the
16 formation of product (R)-4b and, on the contrary, (S)-
17 4a,b were formed when (S)-ligands were used.
18
The validity of the spectral correlations presented
19 above was also confirmed by the X-ray diffraction
20 data. With this aim in view, a racemic sample of a-
21 amino phosphonate (Æ)-4b obtained by the modified
22 KabachnikÀFields reaction[40] was acylated by (S)-
23 naproxen chloride. The chromatographically less mo-
24 bile diastereomer of a-amido phosphonate (S,S)-5b
25 (dP =20.42 ppm) was isolated as an oil using column
26 chromatography, while the chromatographically more
27 mobile diastereomer (R,S)-5b (dP =20.16 ppm) was
28 acquired in crystalline form. The absolute configura-
29 tion of the C*ÀP stereocenter was established as (R)
30 by anomalous dispersion effects in diffraction meas-
31 urements on a single crystal (Figure 4).[41]
32
Speaking of regularities observed, we can sum up
Figure 4. The molecular structure[41] of (S)-naproxen amide
(R,S)-5b, with atom labels. Displacement ellipsoids are
drawn at 30% probability level. The H atoms are presented
as small spheres of arbitrary radius.
33 that the homogeneous palladium-catalyzed hydroge-
34 nation of a-oxo phosphonates[35] and E-isomers of the
35 corresponding oximes[14] and tosylimines[6] using (R)-
36 ligands of the binaphthyl and biphenyl types provides
37 (S)-enantiomers of the products, but the hydrogena-
38 tion of Z-oximes and Z-phenylhydrazones affords (R)- complete kinetic analysis, it allows for the interpreta-
39 enantiomers. A tentative mechanism for homogeneous tion of the above mentioned stereoselectivity of the
40 Pd(II)-catalyzed asymmetric hydrogenation can be process in terms of the quadrant model (Scheme 2).
41 outlined on the basis of previous investigations of
The substituent on the imine nitrogen atom seems
42 Zhou et al.,[12c] which include isotope-labeling to be the most important factor determining the Re-
43 tests,[26,28,42] NMR experiments, and DFT calcula- face coordination of E-substrates (leading to (S)-
44 tions[28] and taking into account general mechanistic products) and Si-face coordination of Z-substrates
45 aspects.[43] Initially, the heterolytic activation of molec- (leading to (R)-products). In the case of E-isomers
46 ular hydrogen results in the production of monohy- like E-oximes[14] and E-tosylimines,[6] the impacts of
47 dride palladium complex A (Scheme 1). Then, dissoci- the dialkoxyphosphoryl group and N-substituent are
48 ation equilibriums in solution[28] would enable the matched, so the change of diethyl phosphonates to
49 formation of metalÀsubstrate complex B. The next diisopropyl phosphonates improves the enantioselec-
50 stage of the inner-sphere migratory insertion of the tivity of the process. On the contrary, in the case of a-
51 bound substrate into the metal hydride bond (PdÀH) hydrazono phosphonates (Z)-2 a similar effect was not
52 leads to Pd amide (or alkoxide) intermediate C. observed because the influences of the phosphonate
53 Finally, the reaction with a proton donor (for instance, group and N-substituent are mismatched. Without a
54 HX) furnishes the final product and re-forms the substituent at a heteroatom, a poor stereocontrol can
55 (diphosphine)PdX2 complex. The postulated catalytic be expected because the preference of Re-face coordi-
56 cycle involved exclusively Pd(II) species. Although nation of the prochiral substrate depends only on the
57 this scheme requires further systematic study and bulkiness of the dialkoxyphosphoryl group. Indeed,
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In summary, we have developed a convenient,
highly efficient, general method for a direct catalytic
synthesis of optically active a-amino phosphonates
bearing an aryl substituent in the a-position employ-
ing Z-isomers of a-phenylhydrazono phosphonates as
the prochiral precursors. The usability of these starting
substrates and the fact that they are readily available
make the present approach particularly attractive and
practical. The proposed two-step one-pot procedure
combines advantages of both homogeneous and heter-
ogeneous palladium catalysis and includes asymmetric
hydrogenation in the TFE/CH2Cl2 medium using Pd
(OAc)2/(R)-Cl–MeO-BIPHEP as a catalyst and CSA
as an activator, followed by hydrogenolysis over Pd/C.
This protocol provides a rapid access to a-amino
phosphonates in high yields and enantioselectivity up
to 98% ee. It appeared that configuration of the C=N
double bond in substrate and the substituent at the
nitrogen atom played a remarkable role in the origin
of enantioselectivity in asymmetric palladium-cata-
lyzed hydrogenation. Further mechanistic studies are
underway and will be reported in due course.
Experimental Section
Synthesis of diisopropyl (R)-[amino(phenyl)methyl]phos-
phonate [(R)-(4b)] as a representative example for the
syntheses of a-amino phosphonates (R)-4b–i:
Scheme 1. A plausible catalytic cycle for homogeneous
hydrogenation of a-oxo phosphonates (Q=O) and corre-
27 sponding oximes (Q=NOH), tosylimines (Q=NTs), and
phenylhydrazones (Q=NNHPh), catalyzed by (diphosphine)
PdX2 complexes (X=OAc or OC(O)CF3).
28
29
30
31
A Schlenk tube dried at 1208C for 1 h, equipped with a
stirring bar and a septum cap, was charged with (R)-Cl–
MeO-BIPHEP (18.2 mg, 28 mmol, 5 mol%), Pd(OAc)2
32 we have observed that the enantioselectivity in (6.3 mg, 28 mmol, 5 mol%) and anhydrous CH2Cl2 (12 mL).
The mixture was stirred under argon until (R)-Cl–MeO-
BIPHEP completely dissolved. Then (Z)-2b (201.8 mg,
0.56 mmol), CSA (13.0 mg, 56 mmol, 10 mol%) and anhy-
drous TFE (4 mL) were added. The mixture was stirred
under argon until complete homogenization and transferred
33 palladium catalyzed hydrogenation of a-oxo phospho-
34 nates appreciably increased on going from diethyl to
35 diisopropyl esters, nevertheless, enantiomeric excess
36 did not exceed 55%.[35]
37
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46
47
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49
50
51
52
53
54
55
Scheme 2. Origin of enantioselectivity in asymmetric hydrogenation of E-isomers of a-oxyimino phosphonates[14] (a) and a-
hydrazono phosphonates (Z)-2 (b) catalyzed by palladium complexes with (R)-ligands of biaryl diphosphine type.
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with a syringe into a stainless-steel autoclave with a glass
liner, equipped with a stirring bar and filled with dry argon.
The autoclave was sealed, pressurized with H2 to 50 atm and
the reaction mixture was stirred at ambient temperature for
1.5 h. After the end of the hydrogenation the pressure was
reduced to atmospheric and the autoclave was flushed with
argon. 10% Pd/C (59.6 mg, 56 mmol, 10 mol%), CSA
(390.3 mg, 1.68 mmol, 3 equiv.) and anhydrous MeOH
(8 mL) were added to the reaction mixture under an argon
flux. The autoclave was sealed, pressurized with H2 to 5 atm
and the reaction mixture was stirred at 608C for 5 h. After
the end of hydrogenolysis, the autoclave was cooled to the
ambient temperature and the solid components of the
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11
12
13 reaction mixture were filtered off and washed with anhy-
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naphthyl)propanoyl chloride (15 mg, 60 mmol, 1.5 equiv.) and
analyzed by 31P NMR to determine the enantiomeric excess.
IR (film): n=3380, 3297, 2979, 2935, 1454, 1386, 1375, 1237,
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
1105, 1008, 990, 699, 560 cmÀ1
;
31P NMR (162 MHz, CDCl3):
1
d=23.2 ppm; H NMR (400 MHz, CDCl3): d=1.01 (d, J=
6.2 Hz, 3H, CH3), 1.22 (d, J=6.2 Hz, 3H, CH3), 1.23 (d, J=
6.2 Hz, 3H, CH3), 1.26 (d, J=6.2 Hz, 3H, CH3), 2.10 (br. s,
2H, NH2), 4.15 (d, J=17.1 Hz, 1H, PCH), 4.49 (m, 1H, CH(i-
Pr)), 4.60 (m, 1H, CH(i-Pr)), 7.25 (m, 1H, CH(Ph)), 7.31 (m,
2H, CH(Ph)), 7.43 (m, 2H, CH(Ph)) ppm; 13C NMR (101
MHz, CDCl3): d=23.4 (J=5.5 Hz, CH3), 23.8 (J=5.2 Hz,
CH3), 24.0 (J=3.5 Hz, CH3), 24.1 (J=3.2 Hz, CH3), 54.4 (J=
150.4 Hz, CP), 71.0 (J=7.5 Hz, CH(i-Pr)), 71.3 (J=7.3 Hz,
CH(i-Pr)), 127.6 (J=3.1 Hz, CH(Ph)), 127.9 (J=6.2 Hz,
2CH(Ph)), 128.2 (J=2.4 Hz, 2CH(Ph)), 137.8 (J=3.3 Hz, C
(Ph)) ppm; HR-MS: m/z=294.1230, calcd. for [M+Na]+
(C13H22NO3PNa): 294.1230; [a]D25: +12.38 (c 1.54, CHCl3) for
an enantiomerically enriched sample of 92% ee.
Acknowledgements
We thank the Russian Foundation for Basic Research (Grant
No. 15-03-04594-a) for financially supporting this work.
I.P.B. is grateful to the Russian Science Foundation (Grant
No. 14-23-00186). The research work was carried out using
NMR spectrometer Agilent 400-MR and diffractometer STOE
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