Four-component reaction for the preparation of α-amino phosphonates from methyleneaziridines

Article abstract of DOI:10.1021/jo9004958

α-Amino phosphonates can be rapidly assembled in moderate to good yields (42-65%) via a "one-pot" process that brings together four components through the construction of three new intermolecular bonds.

Full text of DOI:10.1021/jo9004958

SCHEME 1. MCR Approach to r-Amino Phosphonates
Four-Component Reaction for the Preparation of
r-Amino Phosphonates from Methyleneaziridines
Peter M. Mumford,† Gary J. Tarver,‡ and Michael Shipman*
Department of Chemistry, UniVersity of Warwick, Gibbet
Hill Road, CoVentry, CV4 7AL, United Kingdom, and
Schering Plough Corporation, Newhouse, Scotland,
ML1 5SH, United Kingdom
m.shipman@warwick.ac.uk
with the hydrophosphonylation step. In this way, the preparation
of R-amino phosphonates can be realized through a more direct
multicomponent reaction (MCR). As four-component reactions
(4CRs) are generally more useful in diversity-oriented synthesis
and library generation than 3-CRs,10 we thought that the
development of a 4-CR for the synthesis of R-amino phospho-
nates would be of considerable value to medicinal chemists. In
this Note, we describe what we believe is the first 4-CR for the
synthesis of R-amino phosphonates and outline its scope and
limitations.
In previous studies, we have devised a 3-CR for the synthesis
of ketimines from 2-methyleneaziridines both in solution11 and
on solid phase.12 The reaction involves opening of methylenea-
ziridine at C-3 by using a Grignard reagent under Cu(I) catalysis,
and capture of the resulting metalloenamine with a carbon-based
electrophile (R2-X). By further manipulation of the resulting
ketimines, a range of compound classes including ketones,11,12
amines,13 R-amino nitriles,14 hydantoins,15 and ꢀ-lactams16 can
be made in “one-pot”. By combining this approach to ketimines
with hydrophosphonylation,6 we reasoned that it should be
possible to develop a flexible approach to R-amino phosphonates
(Scheme 1). Notably, this 4-CR would create three new
intermolecular bonds and generate up to four points of chemical
diversity in a single transformation.
ReceiVed March 5, 2009
R-Amino phosphonates can be rapidly assembled in moderate
to good yields (42-65%) via a “one-pot” process that brings
together four components through the construction of three
new intermolecular bonds.
R-Amino phosphonic acids and their derivatives act as
analogues of R-amino acids, and as such they constitute
important motifs in medicinal chemistry.1,2 They display a range
of biological activities including use as antibiotics,3 herbicides,4
and fungicides.5 The most general and straightforward prepara-
tive route to these compounds involves hydrophosphonylation
of imines (Pudovic reaction).6 This transformation has broad
substrate scope and has been successfully extended to the
synthesis of enantiopure derivatives through the application of
asymmetric catalysis.7
Methyleneaziridines 1a-c used in this study were prepared
according to published methods.17 Treatment of 1a in THF with
EtMgCl (2.5 equiv) and CuI (20 mol %) induced ring-opening
of the aziridine at C-3 to generate the metalloenamine, which
was alkylated with BnBr (1.5 equiv). Subsequent addition of
diethylphosphite (2.5 equiv) yielded R-amino phosphonate 2a
in 65% yield after silica gel column chromatography (Scheme
The Kabachnik-Fields reaction8,9 combines imine formation,
through condensation of an amine with an aldehyde (or ketone),
† University of Warwick.
‡ Schering Plough.
(1) For a monograph, see: Aminophosphonic and Aminophosphinic Acids:
Chemistry and Biological ActiVity; Kukhar, V. P., Hudson, H. R., Eds.; John
Wiley & Sons: New York, 2000.
(2) Huang, J.; Chen, R. Heteroat. Chem. 2000, 11, 480–492.
(3) Wu, Z.; Walsh, C. T. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 11603–
11607.
(4) For recent examples, see: (a) Forlani, G.; Occhipinti, A.; Berlicki, L.;
Dzieziola, G.; Wieczorek, A.; Kafarski, P. J. Agric. Food Chem. 2008, 56, 3193–
3199. (b) Xiao, L.-X.; Li, K.; Shi, D.-Q. Phosphorus, Sulfur Silicon Relat. Elem.
2008, 183, 3156–3165.
(5) Yang, S.; Gao, X.-W.; Diao, C.-L.; Song, B.-A.; Jin, L.-H.; Xu, G.-F.;
Zhang, G.-P.; Wang, W.; Hu, D.-Y.; Xue, W.; Zhou, X.; Lu, P. Chin. J. Chem.
2006, 24, 1581–1588.
(6) Pudovik, A. N.; Konovalova, I. V. Synthesis 1979, 81–96.
(7) (a) Gro¨ger, H.; Hammer, B. Chem.sEur. J. 2000, 6, 943–948. (b) Ma,
J.-A. Chem. Soc. ReV. 2006, 35, 630–636. (c) Merino, P.; Marque´s-Lo´pez, E.;
Herrera, R. P. AdV. Synth. Catal. 2008, 350, 1195–1208.
(8) (a) Fields, E. K. J. Am. Chem. Soc. 1952, 74, 1528–1531. (b) Kabachnik,
M. I.; Medved, T. Y. Dokl. Akad. Nauk SSSR 1952, 83, 689–692. (c) Kabachnik,
M. I.; Medved, T. Y. IzV. Akad. Nauk SSSR, Ser. Khim. 1953, 1126–1128.
(9) For a review, see: Zefirov, N. S.; Matveeva, E. D. ARKIVOC 2008, 1–
17.
(10) For a monograph, see: Multicomponent Reactions; Zhu, J., Bienayme´,
H., Eds.; Wiley-VCH: Weinhein, Germany, 2005.
(11) (a) Hayes, J. F.; Shipman, M.; Twin, H. Chem. Commun. 2000, 1791–
1792. (b) Hayes, J. F.; Shipman, M.; Twin, H. J. Org. Chem. 2002, 67, 935–
942.
(12) Margathe, J. F.; Shipman, M.; Smith, S. C. Org. Lett. 2005, 7, 4987–
4990.
(13) (a) Hayes, J. F.; Shipman, M.; Twin, H. Chem. Commun. 2001, 1784–
1785. (b) Hayes, J. F.; Shipman, M.; Slawin, A. M. Z.; Twin, H. Heterocycles
2002, 58, 243–250.
(14) Shiers, J. J.; Clarkson, G. J.; Shipman, M.; Hayes, J. F. Chem. Commun.
2006, 649–651.
(15) Montagne, C.; Shiers, J. J.; Shipman, M. Tetrahedron Lett. 2006, 47,
9207–9209.
(16) Cariou, C. C. A.; Clarkson, G. J.; Shipman, M. J. Org. Chem. 2008,
73, 9762–9764.
(17) (a) Ennis, D. S.; Ince, J.; Rahman, S.; Shipman, M. J. Chem. Soc., Perkin
Trans. 1 2000, 2047–2053. (b) Shipman, M. Synlett 2006, 3205–3217. (c) Ince,
J.; Ross, T. M.; Shipman, M.; Slawin, A. M. Z.; Ennis, D. S. Tetrahedron 1996,
52, 7037–7044.
10.1021/jo9004958 CCC: $40.75
Published on Web 04/07/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3573–3575 3573

SCHEME 2. r-Amino Phosphonate Synthesis by 4-CR
SCHEME 5.
Deprotection to r-Amino Phosphonic Acids
consistent with this reaction proceeding through a cyclic
iminium ion.13,14
TABLE 1. 4-Component r-Aminophosphonate Synthesis
entry
SM
R1
R2-X
product
yielda (%)
To establish if the resulting R-amino phosphonates could be
converted into the corresponding R-amino phosphonic acids,
deprotection of one of the products was investigated. Hydro-
genolysis of 2 yielded primary amine 5, which upon further
treatment with HCl then propylene oxide gave R-amino phos-
phonic acid 6 in 90% overall yield (Scheme 5).
To conclude, a versatile 4-CR for the rapid synthesis of
R-amino phosphonates from methyleneaziridines has been
developed by the sequential formation of three new intermo-
lecular bonds through a sequence that involves aziridine opening,
C-alkylation, and hydrophosphonylation of the resulting imine.
Work to produce other important classes of compounds by use
of methyleneazidine MCRs is ongoing in our laboratory.
1
2
3
4
5
6
7
8
9
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
1a
Et
Et
Et
Et
Et
Et
Et
Et
BnBr
BnBr
BnBr
THPO(CH2)3Br
CH2dCHCH2Br
p-MeOC6H4CH2Br
CH3CtCCH2Br
p-BrC6H4CH2Br
BnBr
2a
2b
2c
2d
2e
2f
2g
2h
2i
65
57
54b
60
61
62
57
52
63
62
42
61
iBu
Bn
c-Hex
Allyl
10
11
12
BnBr
BnBr
BnBr
2j
2k
2l
a Isolated yield after aqueous workup and column chromatography.
Detailed experimental procedures and full characterization data are
provided in the Supporting Information. b Isolated as ca. 1:1 mixture of
1
diastereomers as judged by H NMR spectroscopy.
Experimental Section
Synthesis of r-Amino Phosphonates: General Procedure.
Copper(I) iodide (20 mol %) in a round-bottomed flask was flame-
dried under vacuum and then purged with nitrogen (three cycles
performed). THF (2 mL) was added and the mixture was cooled to
-30 °C, whereupon the Grignard reagent (2.5 equiv) was added.
After 10 min, methyleneaziridine 1 in THF (1 mL) was added and
the reaction mixture was stirred at room temperature for 3 h. Upon
cooling to 0 °C, the electrophile (1.5 equiv) was added dropwise,
and the mixture was heated at 45 °C. After 3 h, the phosphite (2.5
equiv) was added dropwise and heating was continued at 45 °C
overnight. Upon cooling to room temperature, the mixture was
diluted with Et2O (20 mL) and washed with a saturated aqueous
solution of NH4Cl (2 × 20 mL), 50% NaOH solution (2 × 20 mL),
and brine (2 × 20 mL). The organic phase was dried over MgSO4,
filtered, and concentrated in vacuo. Purification of the R-amino-
phosphonate was achieved by column chromatography with silica
pretreated with Et3N.
SCHEME 3.
SCHEME 4.
Use of Ethyl Phenylphosphinate in 4-CR
Use of Difunctionalized Electrophiles in 4-CR
2 and Table 1, entry 1). Interestingly, no additives were required
to effect the final phosphite addition step, which was complete
after stirring overnight at 45 °C. As Lewis acids are known to
accelerate Pudovic reactions,6,18 we speculate that the magne-
sium and copper salts produced in this MCR assist in the
addition of the P-H bond across the imine. Good variation in
the structure of the methyleneaziridine, Grignard, and electro-
phile component is achieved in this 4-CR (Table 1). While the
chemical yields are modest (42-65%), this limitation is offset
by the significant increases in molecular complexity achieved
in this “one-pot” procedure. Changes in the nature of the
phosphorus-containing component are also possible. For ex-
ample, ethyl phenylphosphinate can be used to make 3 by use
of the same general protocol (Scheme 3).
Diethyl [3-(Benzylamino)-1-phenylhexan-3-yl]phosphonate
(2a). R-Amino phosphonate 2a was prepared from CuI (26 mg,
0.14 mmol), ethylmagnesium chloride (2 M in THF, 880 µL, 1.76
mmol), 1a (102 mg, 0.70 mmol), benzyl bromide (130 µL, 1.09
mmol), and diethyl phosphite (230 µL, 1.79 mmol) according to
the general procedure. Workup followed by column chromatography
(30% ethyl acetate in petroleum ether) afforded 2a (185 mg, 65%)
as a pale yellow oil. IR (film) 2958, 1603, 1453, 1230, 1049 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.44-7.23 (10H, m), 4.24 (4H, dt,
J ) 7.6, 14.6 Hz), 3.97 (2H, s), 2.91-2.76 (2H, m), 2.13-1.99
(2H, m), 1.93-1.75 (2H, m), 1.62-1.55 (3H, m), 1.41 (6H, t, J )
6.9 Hz), 1.01 (3H, t, J ) 7.3 Hz) ppm; 13C NMR (100 MHz, CDCl3)
δ 142.6 (C), 141.1 (C), 128.43 (CH), 128.41 (CH), 128.40 (CH),
128.2 (CH), 126.9 (CH), 125.8 (CH), 61.7 (CH2, d, JCP ) 7.6 Hz),
59.7 (C, d, JCP ) 135.7 Hz), 47.6 (CH2, d, JCP ) 2.8 Hz), 35.9
(CH2, d, JCP ) 4.0 Hz), 35.8 (CH2, d, JCP ) 4.4 Hz), 29.7 (CH2, d,
By using 1,3-diiodopropane as electrophile, the chemistry can
be further extended to the synthesis of piperidines. For example,
methyleneaziridine 1a can be transformed into piperidine 4 in
49% yield (Scheme 4). In this case, higher yields were observed
with use of LiP(O)(OEt)2 in the addition step,19 a finding
JCP ) 5.4 Hz), 16.7 (CH3, d, JCP ) 5.6 Hz), 16.5 (CH2, d, JCP
)
7.6 Hz), 14.7 (CH3) ppm; 31P NMR (161 MHz, CDCl3) δ 30.6
ppm; MS (ES+) m/z 404 ([M + H]+, 100); HRMS (ES+) calcd for
C23H35NO3P (M + H)+ 404.2349, found 404.2345.
(18) Bhattacharya, A. K.; Rana, K. C. Tetrahedron Lett. 2008, 49, 2598–
2601, and references cited therein.
(19) LiP(O)(OEt)2 has been used previously in additions to ketimines. See,
for example: Davis, F. A.; Lee, S.; Yan, H.; Titus, D. D. Org. Lett. 2001, 3,
1757–1760.
Diethyl [3-(Benzylamino)-1,5-diphenylpentan-3-yl]phospho-
nate (2j). R-Amino phosphonate 2j was prepared from CuI (26
mg, 0.14 mmol), benzylmagnesium chloride (2 M in THF, 890 µL,
1.78 mmol), 1a (103 mg, 0.71 mmol), benzyl bromide (130 µL,
3574 J. Org. Chem. Vol. 74, No. 9, 2009

1.09 mmol), and diethyl phosphite (230 µL, 1.79 mmol) according
to the general procedure. Workup followed by column chromatog-
raphy (30% ethyl acetate in petroleum ether) afforded 2j (205 mg,
62%) as a white solid. Mp 69-70 °C; IR (film) 2923, 1601, 1451,
1221, 1022 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.41-7.17 (15H,
m), 4.22 (4H, dt, J ) 7.3 Hz, 14.5 Hz), 3.96 (2H, s), 2.92-2.76
(4H, m), 2.21-2.03 (4H, m), 1.70 (1H, br s), 1.37 (6H, t, J ) 7.1
Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 142.5 (C), 141.0 (C),
128.6 (CH), 128.5 (CH) 128.3 (CH), 127.1 (CH), 126.0 (CH), 62.0
(CH2, d, JCP ) 7.4 Hz), 59.7 (C, d, JCP ) 136.4 Hz), 47.4 (CH2, d,
16.9 (CH3, d, JCP ) 5.4 Hz), 15.1 (CH3) ppm; 31P NMR (161 MHz,
d4-MeOD) δ 31.1 ppm; MS (ES+) m/z 314 ([M + H]+, 100); HRMS
(ES+) calcd for C16H29NO3P (M + H)+ 314.1880, found 314.1890.
(3-Amino-1-phenylhexan-3-yl)phosphonic Acid (6). R-Amino
phosphonate 5 (203 mg, 0.65 mmol) in concentrated hydrochloric
acid (20 mL) was refluxed for 14 h. On cooling to room
temperature, the solvent was removed in vacuo. The residue was
dissolved in the minimum amount of hot ethanol (ca. 1 mL) and
cooled to room temperature, then excess propylene oxide (20 mL)
added. After the mixture was stirred for 3 h, the precipitated
phosphonic acid 6 (152 mg, 91%) was isolated by filtration as a
white solid. Mp 204-206 °C; IR (film) 2961, 2872, 1603, 1525,
JCP ) 3.2 Hz), 35.9 (CH2, d, JCP ) 4.6 Hz), 29.8 (CH2, d, JCP
)
5.4 Hz), 16.8 (CH3, d, JCP ) 8.6 Hz) ppm; 31P NMR (161 MHz,
CDCl3) 30.2 ppm; MS (ES+) m/z 466 ([M + H]+, 100); HRMS
(ES+) calcd for C28H37NO3P (M + H)+ 466.2506, found 466.2519.
Anal. Calcd for C28H36NO3P: C, 72.23; H, 7.79; N, 3.01. Found:
C, 72.56; H, 7.78; N, 2.95.
1496, 1454, 1147 cm-1 1H NMR (400 MHz, d4-AcOD) δ
;
7.32-7.19 (5H, m), 2.91-2.77 (2H, m), 2.36-1.99 (4H, m),
1.67-1.52 (2H, m), 1.00 (3H, t, J ) 7.1 Hz) ppm; 13C NMR (100
MHz, d4-AcOD) δ 141.1 (C), 128.4 (CH), 128.1 (CH), 126.0 (CH),
58.5 (C, d, JCP ) 145.0 Hz), 35.1 (CH2), 34.8 (CH2), 29.3 (CH2),
16.1 (CH2, d, JCP ) 4.5 Hz), 13.5 (CH3) ppm; 31P NMR (161 MHz,
d4-AcOD) δ 17.1 ppm; MS (ES+) m/z 258.0 ([M + H]+, 100);
HRMS (ES+) calcd for C12H21NO3P (M + H)+ 258.1254, found
258.1255.
Diethyl (3-Amino-1-phenylhexan-3-yl)phosphonate (5). Pal-
ladium (10 wt % on activated carbon; 52 mg), was added to
R-amino phosphonate 2a (346 mg, 0.86 mmol) in methanol (10
mL), water (10 mL) and concentrated hydrochloric acid (5 mL).
The resulting mixture was stirred at room temperature under a
hydrogen atmosphere for 14 h. After filtration through Celite, the
mixture was concentrated in vacuo. Purification by column chro-
matography (10% methanol in dichloromethane) afforded 5 (267
mg, 99%) as a clear colorless oil. IR (film) 2959, 1603, 1454, 1224,
1020 cm-1; 1H NMR (400 MHz, d4-MeOD) δ 7.31-7.16 (5H, m),
4.21 (4H, dt, J ) 7.3, 14.6 Hz), 2.82-2.69 (2H, m), 2.00-1.84
(2H, m), 1.80-1.62 (2H, m), 1.60-1.46 (2H, m), 1.39 (6H, t, J )
7.1 Hz), 0.99 (3H, t, J ) 7.3 Hz) ppm; 13C NMR (100 MHz, d4-
MeOD) 143.6 (C), 129.5 (CH), 129.3 (CH), 127.0 (CH), 64.0 (CH2,
Acknowledgement. This work was financially supported by
the Biotechnology and Biological Sciences Research Council
(BBSRC) and Schering Plough. We also acknowledge EPSRC
for the provision of mass spectrometers (EP/C007999/1).
Supporting Information Available: Characterization data
1
and H and 13C NMR spectra for compounds 2a-l, and 3-6,
and experimental procedures for their preparation. This material
is available free of charge via the Internet at http://pubs.acs.org.
d, JCP ) 7.8 Hz), 63.9 (CH2, d, JCP ) 8.0 Hz), 56.1 (C, d, JCP
)
145.7 Hz), 39.3 (CH2, d, JCP ) 3.1 Hz), 39.1 (CH2, d, JCP ) 2.6
Hz), 30.8 (CH2, d, JCP ) 5.2 Hz), 17.6 (CH2, d, JCP ) 5.4 Hz),
JO9004958
J. Org. Chem. Vol. 74, No. 9, 2009 3575