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1

Asymmetric organocatalytic synthesis of quaternary -hydroxy phosphonates: En route

to -aryl phosphaisoserines

Inmaculada Serrano, David Monge,* Eleuterio lvarez, Rosario Fernndez,* and Jos M.

Lassaletta*

Instituto de Investigaciones Qumicas (CSIC-US), C/ Amrico Vespucio 49,

E-41092 Sevilla (Spain), and Departamento de Qumica Orgnica,

Universidad de Sevilla, C/ Prof. Garca Gonzlez, 1, 41012 Sevilla (Spain)

[email protected]; [email protected]

Contents

Page

1. General information 2

2. General procedure for the thermal reaction of tert-butyl hydrazone 2

with -keto phosphonate 3. 3

3. General procedure for the catalytic enantioselective reactions of

tert-butyl hydrazone 2 with -keto phosphonate 3. 3

4 General procedure for the enantioselective synthesis of

azoxy compounds 6. 3

5. Characterization of azoxy compounds 6 3-7

6. General procedure for the one-pot synthesis of

-amino--hydroxyphosphonates 5. 7

7. Characterization of -amino--hydroxyphosphonates 5 8-9

8. NMR Spectra 11-46

9. HPLC Chromatograms 47-64

Electronic Supplementary Material (ESI) for ChemComm.This journal is The Royal Society of Chemistry 2015

2

1. General Information. Spectra were recorded at [1H NMR (400 MHz); 13C NMR (100

MHz); 31P NMR (162 MHz)] with the solvent peak used as the internal reference (7.26 and

77.0 ppm for 1H and 13C respectively). Column chromatography was performed on silica gel

(Merck Kieselgel 60). Analytical TLC was performed on aluminum backed plates (1.5 5

cm) pre-coated (0.25 mm) with silica gel (Merck, Silica Gel 60 F254). Compounds were

visualized by exposure to UV light or by dipping the plates in solutions of KMnO4,

anisaldehyde or phosphomolibdic acid stains followed by heating. Melting points were

recorded in a metal block and are uncorrected. Optical rotations were measured on a Perkin-

Elmer 341 MC polarimeter. The enantiomeric excess (ee) of the products was determined by

chiral stationary phase HPLC (Daicel Chiralpak OJ/AD-H/IA/IB columns). Unless otherwise

noted, analytical grade solvents and commercially available reagents were used without

further purification. Formaldehyde tert-butyl hydrazone 2,[1] not commercially available -

keto phosphonates 3,[2] and catalysts I-IV[3] were synthesized according to literature

procedures.

Keto phosphonate 3g was prepared according to procedures reported in

the literature.[2] 1H NMR (400 MHz, CDCl3) 8.20 (d, J = 8.4 Hz, 1H),

7.51 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 3.91 (d, J = 10.8 Hz, 6H). 13C

NMR (125 MHz, CDCl3) 198.2 (d, J = 184.1 Hz), 139.8, 133.8, 133.0, 131.5, 131.0, 127.2,

126.9, 54.5 (d, J = 7.5 Hz). HRMS: calculated for [C9H10Cl2O4P]+ 282.9688; found:

282.9680.

[1] a) Y. Kamitori, M. Hojo, R. Masuda, T. Yoshida, S. Ohara, K. Yamada, N. Yoshikawa, J. Org. Chem. 1988, 53, 129; b) J. E. Baldwin, R. M. Adlington, J. C. Bottaro, J. N. Kolhe, M. Perry, A.U. Jain, Tetrahedron 1986, 42, 4223; c) J.-S. M. Lehn, S. Javed, D. M. Hoffman, Inorg. Chem. 2007, 46, 993. [2] Keto phosphonates 3 were prepared by the Michaelis-Arbuzov reaction: a) D. A. Nicholson, H. Vaughn J. Org. Chem. 1971, 36, 3843. For characterization of 3b, 3d, and 3e: b) Y. Huang, F. Berthiol, B. Stegink, M. M. Pollard, A. J. Minnaard, Adv. Synth. Catal. 2009, 351, 1423. For characterization of 3c, 3h and 3i: c) X. Chen, J. Wang, Y. Zhu, D. Shang, B. Gao, X. Liu, X. Feng, Z. Su, C. Hu, Chem. Eur. J. 2008, 14, 10896. For characterization of 3f and 3j: d) D. V. Griffiths, K. Karim, J. E. Harris, J. Chem. Soc., Perkin Trans. 1997, 1, 2539. For characterization of 3k and 3l: e) D. V. Griffiths, M. J. Al-Jeboori, Y.-K. Cheong, P. Duncanson, J. E. Harris, M. C. Salt, H. V. Taylor. Org. Biomol. Chem. 2008, 6, 577.

3

2. General procedure for the thermal reaction of tert-butyl hydrazone 2 with -keto

phosphonate 3.

Formaldehyde tert-butyl hydrazone 2 (94 L, 0.8 mmol) was added to a solution of -keto

phosphonate 3 (0.4 mmol) in toluene (0.5 mL) at room temperature. The mixture was stirred

until consumption of starting material (TLC monitoring).

3. General procedure for the catalytic enantioselective reactions of tert-butyl hydrazone

2 with -keto phosphonate 3.

Formaldehyde tert-butyl hydrazone 2 (134 L, 1.2 mmol) was added to a solution of -keto

phosphonate 3 (0.6 mmol) and catalyst I (0.06 mmol, 48 mg) in toluene (0.6 mL) at 78 C.

The mixture was stirred for the time as specified in Table 2 (TLC monitoring).

4. General procedure for the enantioselective synthesis of azoxy compounds 6.

Following the general procedure for the catalytic enantioselective reactions of hydrazone 2

with -keto phosphonates 3. After consumption of starting material, MeOH (2 mL) and

MMPP (742 mg, 3 equiv.) were subsequently added at 78 C. The reaction mixture was

allowed to warm up to room temperature for completion (2-3 h.). The mixture was then

diluted with H2O (5 mL), extracted with CH2Cl2 (3 x 10 mL), dried over Na2SO4 and

concentrated in vacuo. The resulting residue was purified by column chromatography (1:3

Hexane-AcOEt) to afford pure products 6. Enantiomeric excess (ee) was determined by

HPLC analysis.

5. Characterization of azoxy compounds 6

(6a): white solid (168 mg, 85%); M.p. = 72-74 C. 1H NMR (300 MHz,

CDCl3) 7.61 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 2H), 7.30 (t, J = 8.0

Hz, 1H), 4.23 (dd, J = 17.6, 5.9 Hz, 1H), 4.03 (t, J = 17.8 Hz, 1H), 3.85 (d, J

= 11.3 Hz, 1H), 3.76 (d, J = 10.4 Hz, 3H), 3.52 (d, J = 10.4 Hz, 3H), 1.47 (s,

9H). 13C NMR (125 MHz, CDCl3) 138.2, 128.2 (d, J = 2.6 Hz), 127.8 (d, J = 2.9 Hz), 125.9

(d, J = 4.3 Hz), 77.3, 77.0 (d, J = 162.7 Hz), 58.5 (d, J = 5.8 Hz), 54.3 (d, J = 7.4 Hz), 53.8 (d,

[3] X. G. Liu, J. J. Jiang, M. Shi, Tetrahedron Lett. 2007, 18, 2773.

4

J = 7.5 Hz), 28.1. 31P NMR (162 MHz, CDCl3) 23.3. HRMS: m/z calculated for

[C14H23N2O5P]+: 331.1423; found: 331.1422. The enantiomeric excess was determined by

HPLC using a Chiralpak OJ column [hexane/i-PrOH (90:10)]; flow rate 1 mL/min; major =

22.5 min, minor = 12.9 min (90% ee); []D20 = +23.0 (c 0.5, CHCl3).

(6b): White solid (173 mg, 81%), M.P. = 75-77 C. 1H NMR (400 MHz,

CDCl3) 7.60 (d, J = 7.4 Hz, 2H), 7.37-7.27 (m, 3H), 4.23 (dd, J = 17.7, 5.9

Hz, 1H), 4.19-4.04 (m, 3H), 4.02-3.86 (m, 2H), 3.84-3.70 (m, 1H), 1.46 (s,

9H), 1.27 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,

CDCl3) 138.6, 128.1 (d, J = 2.0 Hz), 127.8 (d, J = 3.0 Hz), 126.1 (d, J = 4.0 Hz), 77.3, 75.5

(d, J = 162.0 Hz), 63.8 (d, J = 7.0 Hz), 63.3 (d, J = 7.0 Hz), 58.7 (d, J = 6.0 Hz), 28.2, 16.5 (d,

J = 6.0 Hz), 16.4 (d, J = 6.0 Hz). 31P NMR (162 MHz, CDCl3) 21.3. HRMS: m/z calculated

for [C16H28N2O5P]+: 359.1736; found: 359.1732. The enantiomeric excess was determined by

HPLC using a Chiralpak OJ column [hexane/i-PrOH (98:2)]; flow rate 1 mL/min; major = 28.2

min, minor = 18.2 min (86% ee); []D20 = +17.6 (c 0.5, CHCl3).

(6c): White solid (196 mg, 95%); M.p. = 92-94 C. 1H NMR (300 MHz,

CDCl3) 7.48 (dd, J = 8.2, 1.9 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 4.22 (dd,

J = 17.6, 6.0 Hz, 1H), 3.99 (t, J = 17.9 Hz, 1H), 3.82 (d, J = 11.0 Hz, 1H),

3.75 (d, J = 10.4 Hz, 3H), 3.52 (d, J = 10.3 Hz, 3H), 2.34 (s, 3H), 1.48 (s,

9H). 13C NMR (75 MHz, CDCl3) 137.5 (d, J = 2.5 Hz), 135.3, 128.9 (d, J = 1.7 Hz), 125.8

(d, J = 4.2 Hz), 77.2, 75.6 (d, J = 163.1 Hz), 58.6 (d, J = 5.9 Hz), 54.3 (d, J = 7.2 Hz), 53.7 (d,

J = 7.4 Hz), 28.2, 21.1. 31P NMR (162 MHz, CDCl3) 23.5. HRMS: m/z calculated for

[C15H25N2O5P]+: 345.1579; found: 345.1582. The enantiomeric excess was determined by

HPLC using a Chiralpak IA column [hexane/i-PrOH (90:10)]; flow rate 1 mL/min; major =

19.5 min, minor = 14.2 min (97% ee); []D20 = +27.1 (c 0.5, CHCl3).

(6d): Yellow solid (130 mg, 60%); M.p. = 70-72 C. 1H NMR (300

MHz, CDCl3) 7.48 (d, J = 6.8 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 4.14

(dd, J = 17.6, 6.3 Hz, 1H), 3.98 (t, J = 17.3 Hz, 1H), 3.76 (s, 3H), 3.71

(d, J = 10.4 Hz, 3H), 3.51 (d, J = 10.3 Hz, 3H), 1.44 (s, 9H). 13C NMR

(75 MHz, CDCl3) 159.0 (d, J = 2.5 Hz), 130.1, 127.2 (d, J = 4.4 Hz), 113.4 (d, J = 2.0 Hz),

77.1, 75.3 (d, J = 163.9 Hz), 58.3 (d, J = 6.9 Hz), 55.1, 54.2 (d, J = 7.4 Hz), 53.7 (d, J = 7.4

Hz), 28.0. 31P NMR (162 MHz, CDCl3) 23.6. HRMS: m/z calculated for [C15H25N2O6P]+:

5

361.1529; found: 361.1523. The enantiomeric excess was determined by HPLC using a

Chiralpak IA column [hexane/i-PrOH (90:10)]; flow rate 1 mL/min; major = 30.3 min, minor =

20.2 min (84% ee); []D20 = +17.7 (c 0.5, CHCl3).

(6e): White solid (181 mg, 83%); M.p. = 86-88 C. 1H NMR (300 MHz,

CDCl3) 7.55 (d, J = 6.7 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 4.18 (dd, J =

17.5, 6.3 Hz, 1H), 4.02 (d, J = 8.6 Hz, 1H), 4.01 (t, J = 16.8 Hz, 1H), 3.76

(d, J = 10.4 Hz, 3H), 3.59 (d, J = 12.0 Hz, 3H), 1.46 (s, 9H). 13C NMR

(125 MHz, CD