Interesting by-products in the synthesis of chiral α- aminophosphinates from enantiopure sulfinimines

Article abstract of DOI:10.1016/j.tetlet.2003.12.151

A new reaction of enantiopure sulfinimines and ethyl phenylphosphinate is given. Several unexpected products were isolated and identified, their mechanism of formation is proposed.

Full text of DOI:10.1016/j.tetlet.2003.12.151

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1991–1994
Interesting by-products in the synthesis of chiral
a-aminophosphinates from enantiopure sulfinimines
b
Andrea Szabo, Zsuzsa M. Jaszay, Laszlo Toke and Imre Petnehazy
a
a,
ꢀ a
ꢀ
ꢀ ꢀ €
ꢀ
*
aDepartment of Organic Chemical Technology, Budapest University of Technology and Economics, H-1521 Budapest, Hungary
bOrganic Chemical Technology Research Group of the Hungarian Academy of Sciences, H-1521 Budapest, Hungary
Received 23 September 2003; revised 8 December 2003; accepted 18 December 2003
Abstract—A new reaction of enantiopure sulfinimines and ethyl phenylphosphinate is given. Several unexpected products were
isolated and identified, their mechanism of formation is proposed.
Ó 2004 Elsevier Ltd. All rights reserved.
a-Aminophosphonic and phosphinic acids are phos-
phorus analogues of a-aminocarboxylic acids, and
therefore have biological importance.1 Recently, we
published a method for the enantioselective synthesis of
substituted a-aminophosphinic acids 4 by the addition
of ethyl phenylphosphinate 1 to imines 2 (Scheme 1).2
The latter were prepared from an aldehyde and (S)-
phenylethylamine or (S)-phenylglycinol methyl ether.
These two simple chiral auxiliaries proved to be good to
excellent in inducing asymmetry on the imine carbon
atom resulting in enantiopure a-aminophosphinic acids
4 after deprotection of a-aminophosphinates 3. It has to
be pointed out that neither lithium as chelating metal,
nor a Lewis acid catalyst are required for induction of
the enantioselectivity in the phosphorylation reaction.
Continuing our work on the reactivity of phosphinate 1,
we decided to test sulfinamides as the chiral auxiliary,
therefore several sulfinimine derivatives were synthesized
in order to react them with ethyl phenylphosphinate.
Davis and co-workers successfully used enantiopure
p-toluenesulfinimines as versatile chiral imine building
blocks in the enantioselective synthesis of a- and b-
aminoacids,3;4 while others have used them in the syn-
thesis of chiral primary amines.5 This type of auxiliary
was also used in the enantioselective synthesis of b- and
a-amino-phosphonates6 providing excellent enantio-
meric excess using the lithium metal salt of methyl
phosphonic acid diethyl ester and that of diethyl phos-
phite, respectively.
We chose (S)-sulfinimines 5 as the aminophosphinate
precursors and prepared them by condensation of (S)-p-
toluenesulfinamide with an aldehyde in dichlorome-
R1
H
O
Ph
O
H
Ph
*
N
P
1
P
NH
+
Ph
*
*
EtO
*
Ph
ꢁ
EtO
thane with 4 A molecular sieves at reflux temperature,
R2
according to a method in the literature.7 After flash
chromatography (hexane–ethyl acetate 9:1) the imines
were isolated in moderate yields.8 The imines 5a–e and
2 equiv of ethyl phenylphosphinate 1 were kept at 70 °C
in toluene and the reaction was run until the imine was
consumed (50–100 h) (Scheme 2).
R1
R2
2
3
O
Ph
HO
1. concd. HCl or
R1: alkyl or aryl
R2: Me, CH2OMe
P
4
NH2
HBr in glacial acetic acid
*
2. H2, 10 % Pd/C
R1
Scheme 1.
In the 31P NMR spectra of the reaction mixtures several
phosphorus containing products were always observed
including thiophosphonic acid ester 6,9 phenylphos-
phonic acid monoethyl ester 8, phosphonyl p-tolylsulf-
oxide 9,10 and the unprotected aminophosphinic acid
ester 1011 besides the desired a-aminophosphinate 7.12
Keywords: a-Aminophosphinic acids; Ethyl phenylphosphonic acid;
Side reaction of p-tolylsulfinimines.
* Corresponding author. Fax: +36-1-463-3648; e-mail: ipetnehazy@
mail.bme.hu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.151

1992
A. Szabꢀo et al. / Tetrahedron Letters 45 (2004) 1991–1994
O
O
O
H
Ph
Ph
H
P
1
P
1
+
..
EtO
H
S
O
H
EtO
N
R
p
-
Tol
S
5
5
p-Tol
N
R
O
Ph
EtO
R: a=Ph, b=m-MeO-Ph
c=o-Cl-Ph, d=c-C6H11
*
toluene,
70 0
P
p-Tol
NH
*
C
S
O
e=CH2CH(CH3)2
Ph
P
1
R
O
EtO
H
7
..
O
O
Ph
Ph
*
Deprotection
P
Tol
O
-p
+
NH
P
Tol-p
*
+
R
O
EtO
S
Ph
HO
EtO
HO
N
S
C
P
NH2
11
H
R
S
6
7
..
*
OEt
p-
Tol
P
Ph
R
12
O
O
O
O
Ph
Ph
EtO
Ph
O
*
Ph
P
NH2
P
9
P
8
Tol-p
*
*
P
NH2
O
EtO
Ph
OH
EtO
S
+
+
*
Deprotection
P
EtO
EtO
H
R
1
10
O
O
10
R
Ph
P
Scheme 2.
OEt
HO
NH
CH
S
OEt
Ph
R
After separation of the products by column chroma-
tography (on silica gel, eluent: toluene–acetone 17:3) we
could isolate 6, 7, and 10 in pure form.
p-
Tol
P
13
O
According to expectations, a-aminophosphinates 7 were
obtained as four diastereomers although their yields
were modest using imine derivatives 5a–c prepared
from aromatic aldehydes. We could not observe the
formation of 7 at all for the aliphatic or alicyclic alde-
hydes 5d–e. In all cases, thiophosphonic acid ester 6 was
the main product. The phenylphosphonic acid mono-
ethyl ester 8, as well as 9 and 10, was also detected in the
reaction mixture, which indicated that the sulfur in 6
had been reduced; correspondingly the phosphorus in 8
had been oxidized.
O
Ph
EtO
P
p
-
Tol
S
9
O
O
Ph
P
EtO
H
1
O
OH
O
O
Ph
Ph
OEt
P
8
P
6
p-Tol
+
HO
P
EtO
EtO
S
Ph
OEt
S
p-Tol
Removal of the N-sulfinyl auxiliary and hydrolysis of
the ethyl esters from the diastereomers of 7 were
achieved in one step using concentrated hydrochloric
acid under reflux (Scheme 3) to give the a-aminophos-
phinic acids13 11 with ())-optical rotations (R).14 The
deprotection reactions occurred without racemization of
the a-carbon,2 still only modest enantiomeric excesses
were observed (Table 2).
P
14
Ph
O
O
OEt
Ph
H
P
O
S
OEt
Ph
p-Tol
P
15
O
O
Scheme 4.
Ph
*
O
P
Tol
O
-p
NH
Ph
HO
*
P
NH2
11
EtO
S
conc. HCl
*
Table 1. Ratio (%) of compounds detected from 31P NMR spectra
R
..
R
6a
7b
8c;d
9c
10e
R
7
a
b
c
d
e
41
37
35
55
83
19
35
22
––
––
15
3
11
7
14
18
30
––
––
Scheme 3.
6
7
31
13
14
4
We assume, that the formation of 6, 8, 9, and 10 can be
explained by attack of the phosphorus nucleophile 1 on
the sulfoxide moiety of 5 by a 1,2 addition causing loss
of chirality and producing 12 as an intermediate in the
first step of the reaction sequence (Scheme 4). In the
cases of the aliphatic imines (5d, 5e), this is the exclusive
direction of the reaction due to the weaker electrophi-
licity of the carbon atom compared to that of the aro-
matic substituents (Table 1).
a Yield after column chromatography (%): 6a: 34, 6b: 23, 6c: 20, 6d: 35,
6e: 60.
b Mixture of four diastereomers.
c
31P NMR (CDCl3, 500 MHz) 8: d ¼ 20:7, 9: d ¼ 1:1 ppm.
d The ratio of 6/9 is not reliable because part of 9 separated in solid
form from the NMR solution.
e
31P NMR (CDCl3, 500 MHz) 10a: d ¼ 40:0, 39.9; 10b: d ¼ 39:8, 39.7;
10c: d ¼ 38:7, 38.5 ppm.

A. Szabꢀo et al. / Tetrahedron Letters 45 (2004) 1991–1994
1993
Table 2. Enantiomeric excess (ee), yield, and chemical shifts of
a-aminophosphinic acids 11
5. (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc.
ꢀ
1997, 119, 9913; (b) Moreau, P.; Essiz, M.; Merour, J.-Y.;
Bouzard, D. Tetrahedron: Asymmetry 1997, 8, 591.
R
11
_
6. (a) Mikolajczyk, M.; Łyzwa, P.; Drabowicz, J. Tetra-
hedron: Asymmetry 1997, 8, 3991; (b) Mikolajczyk, M.;
Eea
Yield (%)
d
31P
_
a
b
c
20
40
30
52
48
58
30.3
31.6
37.9
Łyzwa, P.; Drabowicz, J.; Wieczorek, M. W.; Błaszcyk, J.
Chem. Commun. 1996, 1503; (c) Lefebvre, I. M.; Evans, S.
A. J. Org. Chem. 1997, 62, 7532.
7. Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.;
Fanelli, D. L.; Zhang, H. J. Org. Chem. 1999, 64, 1403.
8. Compound 5c is new, while the other sulfinimines are
a The enantiomeric ratio was determined by 31P NMR after methyl-
ation of the phosphinic acid 5 by diazomethane.
1
known. 5c: H NMR (CDCl3, 250 MHz) d ¼ 2:40 (s, 3H,
CH3), 7.33–7.67 (m, 4H, ArH), 7.71–7.87 (m, 4H, ArH),
9.08 (s, 1H, CH@N).
A subsequent 1,2-addition of the phosphinate 1 to the
C@N moiety in intermediate 12 results in the formation
of 13. Intermediate 13 can lose an aminophosphinate
moiety 10 (in racemic form) and at the same time the
side-product 9 is formed. Further transformation of 9 to
side-products 6 and 8 needs another 1,2-addition of the
phosphorus starting material to 9 supplying 14. The
latter intermediate––by an S–O phosphoryl migration––
gives 15, which splits into 6 and 8 by a redox process. A
possible radical mechanism can be ruled out, because
the same products were observed in the phosphorylation
reaction carried out in the presence of the 2,2,6,6-tetra-
methylpiperidine-1-oxyl radical trapping agent.15
9. Compound 6: 1H NMR (CDCl3, 250 MHz) d ¼ 1:38 (t,
JHH ¼ 6:9 Hz, 3H, CH3CH2O), 2.28 (s, 3H, CH3Ar), 4.34
(dq, JHH ¼ 6:9 Hz, JPH ¼ 14:1 Hz, 2H, CH3CH2O), 6.99–
7.14 (dd, 4H, ArH), 7.17–7.50 (m, 3H, ArH). 7.61–7.69
(m, 2H, ArH). 13C NMR (CDCl3) d ¼ 15:90 (d,
JPC ¼ 6:6 Hz, CH3CH2O), 20.69 (s, CH3Ar), 61.88 (d,
JPC ¼ 6:6 Hz, CH3CH2O), 122.31 (d, JPC ¼ 5:5 Hz),
127.63, 127.86, 129.52 (s, 2CAr), 130.86, 131.02, 131.10
(d, JPC ¼ 150 Hz, PCAr), 132.06 (d, JPC ¼ 2:6 Hz, CAr),
134.92 (d, JPC ¼ 3:8 Hz, 2CAr), 138.72 (d, JPC ¼ 2:3 Hz)
CAr
.
31P NMR (CDCl3) d ¼ 43:8. FAB-MS: m=z 293
[M+1]þ (calcd 292.3).
10. To give a chemical proof for the structure of 9, 6 was
oxidized by m-chloroperbenzoic acid. The product was
monitored by FAB-MS, the fragmentation was identical
with that of 9.
This side reaction sequence is interesting because,
according to our knowledge, there is only one example
in the literature when the sulfur atom of a p-toluene-
sulfinimine, and not the carbon, was attacked. Moreau
et al.5b aiming at the preparation of chiral amines also
isolated an S-substituted product, that is tolyl methyl-
sulfoxide, in a side reaction in the reaction of sulfinimine
5a and methylmagnesium bromide.
11. Compound 10a: 31P NMR (CDCl3) d ¼ 40:0, 39.9 ppm.
Compound 10b: 31P NMR (CDCl3) d ¼ 39:8, 39.7 ppm.
Compound 10c: 31P NMR (CDCl3) d ¼ 38:7, 38.5 ppm.
12. Compound 7a: oil. Yield: 15%. 1H NMR (CDCl3,
250 MHz) d ¼ 1:13 (t, JHH ¼ 7:1 Hz), 1.24 (t,
JHH ¼ 7:1 Hz), 3H, CH3CH2O, 2.15 (s, 3H, CH3Ar), 4.14
(dq, JHH ¼ 7:1 Hz, JPH ¼ 11:8 Hz, 2H, CH3CH2O), 5.58
(d, JPH ¼ 19:3 Hz), 5.62 (d, JHH ¼ 19:3 Hz) 1H, PCH, 6.35
(b, 1H, NH), 6.98–7.32 (m, 11H, ArH), 7.40–7.84 (m, 2H,
ArH). 13C NMR (CDCl3) d ¼ 16:35 (d, JPC ¼ 5:8 Hz,
CH3CH2O), 21.58 (s, CH3Ar), 62.85 (d, JPC ¼ 19:7 Hz,
CH3CH2O), 69.23 (d, JPC ¼ 110:0 Hz, PCH), 122.47,
123.54, 125.02, 125.94, 126.57, 126.67, 127.02, 127.20,
127.57, 128.07, 128.60 (d, JPC ¼ 93:6 Hz, PCAr), 130.70,
Work to improve the regioselectivity and examination of
the scope and limitation of these side-reactions is in
progress.
131.40, 131.90, 132.30, 132.70, 133.70, 137.90 CAr.
31P
NMR (CDCl3) d ¼ 41:3, 40.8, 40.0, 38.9. Compound 7b:
1
Acknowledgements
oil. Yield: 31%. H NMR (CDCl3, 250 MHz) d ¼ 1:15 (t,
JHH ¼ 7:1 Hz), 1.20 (t, JHH ¼ 7:1 Hz), 3H, CH3CH2O, 2.26
(s, 3H, CH3Ar), 3.53 (s), 3.56 (s), 3H, OCH3, 3.93 (dq,
JHH ¼ 7:1 Hz, JPH ¼ 11:7 Hz, 2H, CH3CH2O), 4.87 (b, 1H,
NH), 5.03 (d, JPH ¼ 19:6 Hz), 5.07 (d, JHH ¼ 19:6 Hz) 1H,
PCH, 6.64–6.72 (m, 2H, ArH), 7.05–7.50 (m, 11H, ArH).
13C NMR (CDCl3) d ¼ 16:65 (d, JPC ¼ 5:7 Hz,
CH3CH2O), 21.58 (s, CH3Ar), 55.24 (s, OCH3), 62.10 (d,
JPC ¼ 20:0 Hz, CH3CH2O), 73.21 (d, JPC ¼ 111:0 Hz,
PCH), 111.95, 112.29, 114.27, 114.42, 119.63, 119.91,
125.20 (d, JPC ¼ 107:0 Hz, PCAr), 125.44, 128.03, 128.24,
128.45, 128.93, 129.16, 132.67, 133.04, 133.19, 137.90,
Financial support by the Hungarian Scientific Research
Fund (OTKA No. T 038108) is gratefully acknowl-
edged. A.S. is grateful to Richter Gedeon Rt. for a
scholarship.
References and notes
1. Kuhkar, V. P.; Hudson, H. R. Aminophosphonic and
Aminophosphinic Acids; John Wiley & Sons: Chichester,
2000.
138.17 CAr
.
31P NMR (CDCl3) d ¼ 40:8, 40.6, 39.8, 39.7.
Compound 7c: oil. Yield: 19%. 1H NMR (CDCl3,
250 MHz) d ¼ 1:14 (t, JHH ¼ 7:1 Hz), 1.23 (t,
JHH ¼ 7:1 Hz), 3H, CH3CH2O, 2.14 (s, 3H, CH3Ar), 4.16
(dq, JHH ¼ 7:1 Hz, JPH ¼ 12:0 Hz, 2H, CH3CH2O), 5.68
(d, JPH ¼ 19:2 Hz), 5.72 (d, JHH ¼ 19:2 Hz) 1H, PCH, 6.42
(b, 1H, NH), 6.97–7.34 (m, 11H, ArH), 7.39–7.81 (m, 2H,
ArH). 13C NMR (CDCl3) d ¼ 16:40 (d, JPC ¼ 5:6 Hz,
CH3CH2O), 21.56 (s, CH3Ar), 62.80 (d, JPC ¼ 20:0 Hz,
CH3CH2O), 69.21 (d, JPC ¼ 109:0 Hz, PCH), 125.47,
126.54, 127.02, 127.94, 128.57, 128.67, 129.02, 129.20,
ꢀ
ꢀ
€
€
2. Szabo, A.; Jaszay, M. Z.; Hegedus, L.; Toke, L.;
ꢀ
Petnehazy, I. Tetrahedron Lett. 2003, 44, 4603.
3. (a) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu,
Y.-H. J. Org. Chem. 1996, 61, 440; (b) Davis, F. A.;
Fanelli, D. L. J. Org. Chem. 1998, 63, 1981.
4. (a) Davis, F. A.; Reddy, T. R.; Reddy, R. E. J. Org. Chem.
1992, 57, 6387; (b) Liu, G.; Cogan, D. A.; Ellman, J. A. J.
Am. Chem. Soc. 1997, 119, 9913.

1994
A. Szabꢀo et al. / Tetrahedron Letters 45 (2004) 1991–1994
129.57, 131.07, 131.60 (d, JPC ¼ 93:6 Hz, PCAr), 131.70,
JPH ¼ 17:6 Hz, 1H, PCH), 3.74 (b, 2H, NH2), 7.07–7.64
132.40, 132.90, 133.30, 133.70, 134.70, 138.00 CAr
NMR (CDCl3) d ¼ 40:3, 39.4, 38.8, 38.5.
.
31P
(m, 9H, ArH). 13C NMR (d6-DMSO) d: 37.96 (d,
JPC ¼ 92:6 Hz, PCH), 125.87, 126.03, 127.86, 127.90,
127.96, 129.00 (d, JPC ¼ 102:0 Hz, PCAr), 129.87, 130.98,
131.14, 131.46, 132.8 (d, JPC ¼ 16:5 Hz, CAr–Cl), 133.10
13. General procedure for a-aminophosphinic-acid 11:
a-Aminophosphinate 7 (1.5 Mmol) and 10 mL concen-
trated hydrochloric acid were refluxed for 8 h, then cooled
and evaporated in vacuum. Ethanol (10 mL) and 0.5 mL
propylene oxide were added to the residue, 11a–c were
isolated as crystals. Compound 11a: mp: 166 °C. 1H NMR
(d6-DMSO, 250 MHz) d ¼ 2:82 (d, JPH ¼ 16:9 Hz, 1H,
PCH), 3.39 (b, 3H, OH, NH2), 6.99–7.24 (m, 4H, ArH),
7.27–7.38 (m, 4H, ArH), 7.47–7.53 (m, 2H, ArH). Com-
pound 11b: mp: 186 °C. 1H NMR (D2O, 250 MHz)
d ¼ 2:46 (b, 2H, NH2), 3.09 (s, 3H, CArOCH3), 3.42 (d,
JPH ¼ 20:6 Hz, 1H, PCH), 6.58–7.20 (m, 9H, ArH). FAB-
MS: m=z 278 [M+1]þ (calcd 277.3). Compound 11c: mp:
178 °C 1H NMR d: (d6-DMSO, 250 MHz) 3.23 (d,
CAr.
31P NMR (d6-DMSO) d: 34.69.
14. The (R)-enantiomer of ethyl a-benzylamino-phenylphos-
phinic acid is known from the literature, and has been
isolated by resolution and by repeated crystallization from
the diastereomeric mixture of its ester. The absolute
configuration was then determined by X-ray crystallogra-
phy. See: Belov, Yu. P.; Rakhnovich, G. B.; Davankov, V.
A.; Godovikov, N. N.; Aleksandrov, G. G.; Struchkov,
Yu. T. Izv. Akad. Nauk. 1980, 5, 1125.
15. 2,2,6,6-Tetramethylpiperidine-1-oxyl (0.1 equiv), 1 equiv
of imine 5a or 5e and 2 equiv of ethyl phenylphosphinate
1 were kept at 70 °C in toluene.