Chiral magnesium BINOL phosphate- catalyzed phosphination of imines: Access to enantioenriched r-amino phosphine oxides

Article abstract of DOI:10.1021/ol200456y

A new method to synthesize chiral R-amino phosphine oxides is reported. The reaction combines N-substituted imines and diphenylphosphine oxide and is catalyzed by a chiral magnesium phosphate salt. A wide variety of aliphatic and aromatic aldimines substituted by electron-neutral benzhydryl or dibenzocycloheptene groups were excellent substrates for the addition reaction. The dibenzocycloheptene protected imines afforded improved enantioselectivity in the resulting products. Substituted diphenylphosphine oxide nucleophiles also showed good reactivity.

Full text of DOI:10.1021/ol200456y

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2054–2057
Chiral Magnesium BINOL Phosphate-
Catalyzed Phosphination of Imines:
Access to Enantioenriched r-Amino
Phosphine Oxides
Gajendrasingh K. Ingle,† Yuxue Liang,† Michael G. Mormino,† Guilong Li,‡
Frank R. Fronczek,§ and Jon C. Antilla*,†
Department of Chemistry, University of South Florida, 4202 East Fowler Avenue,
Tampa, Florida 33620, United States, School of Chemistry and Chemical Engineering,
Sun Yat-Sen University, Guangzhou, 510275, China, and Department of Chemistry
X-ray Laboratory, Louisiana State University, Baton Rouge,
Louisiana 70803, United States
jantilla@usf.edu
Received February 19, 2011
ABSTRACT
A new method to synthesize chiral R-amino phosphine oxides is reported. The reaction combines N-substituted imines and diphenylphosphine
oxide and is catalyzed by a chiral magnesium phosphate salt. A wide variety of aliphatic and aromatic aldimines substituted by electron-neutral
benzhydryl or dibenzocycloheptene groups were excellent substrates for the addition reaction. The dibenzocycloheptene protected imines
afforded improved enantioselectivity in the resulting products. Substituted diphenylphosphine oxide nucleophiles also showed good reactivity.
Chiral phosphorus containing compounds such as R-
amino phosphonic acids and their derivatives have at-
tracted considerable attention due to their promising
biological properties.1 They have found applications as
antibacterials,2 antiviral agents,3 and enzyme inhibitors.4
The absolute configuration of phosphonyl compounds
strongly influences their biological properties;5 therefore
(5) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.; Charles, A. F.;
Rogers, W. L.; Smith, S. A.; Deforrest, J. M.; Oehl, R. S.; Petrillo, E. W.,
Jr. J. Med. Chem. 1995, 38, 4557–4569.
ꢀ
ꢀ
ꢀꢀ
(6) For review, see: (a) Merino, P.; Marques-Lopez, E.; Herrera, R. P.
† University of South Florida.
Adv. Synth. Catal. 2008, 350, 1195–1208. (b) Ordonez, M.; Rojas-cabrera,
‡ Sun Yat-Sen University.
H.; Cativiela, C. Tetrahedron 2009, 65, 17–49.
§ Louisiana State University.
(7) For organocatalytic hydrophosphonylation, see: (a) Joly, G. D.;
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102–4103. (b) Akiyama,
T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett. 2005, 7, 2583–2585. For
recent work on hydrophosphonylation, see:(c) Nakamura, S.; Nakashima,
H.; Yamamura, A.; Shibata, N.; Toru, T. Adv. Synth. Catal. 2008,
350, 1209–1212. (d) Cheng, X.; Goddard, R.; Buth, G.; List., B.
Angew. Chem., Int. Ed. 2008, 47, 5079–5081. (e) Zhao, D.; Wang, Y.;
Mao, L.; Wang, R. Chem.;Eur. J. 2009, 15, 10983–10987. For
hydrophosphoynlation of ketimines, see:(f) Nakamura, S.; Hayashi,
M.; Hiramatsu, Y.; Shibata, N.; Funahashi, Y.; Toru, T. J. Am.
Chem. Soc. 2009, 131, 18240–18241. Foratheoreticalstudyonthechiral
phosphoric acid catalyzed hydrophosphonylation, see:(g) Yamanaka, M.;
Hirata, T. J. Org. Chem. 2009, 74, 3266–3271. (h) Akiyama, T.; Morita, H.;
Bachu, P.; Mori, K.; Yamanaka, M.; Hirata, T. Tetrahedron 2009, 65,
4950–4956.
(1) For reviews on biological activity of R-amino phosphonic acids
and their derivatives, see: (a) Kafarski, P.; Lejczak, B. Phosphorus Sulfur
Silicon Relat. Elem. 1991, 63, 193–215. (b) Romanenko, V. D.; Kukhar,
V. P. Chem. Rev. 2006, 106, 3868–3965.
(2) (a) Atherton, F. R.; Hassall, R. W.; Lambert, R. W. J. Med.
Chem. 1986, 29, 29–40. (b) Huber, J. W.; Gilmore, W. F.; Robertson,
L. W. J. Med. Chem. 1975, 18, 106–108. (c) Pratt, R. F. Science1989, 246,
917–919.
(3) Huang, J.; Chen, R. Heteroat. Chem. 2000, 11, 480–492.
(4) (a) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M.
J. Med. Chem. 1989, 32, 1652–1661. (b) Bird, J.; De Mello, R. E.; Miles-
Williams, A. J.; Rahman, S. S.; Ward, R. W. J. Med. Chem. 1994, 37,
158–169. (c) Smith, W. W.; Bartlett, P. A. J. Am. Chem. Soc. 1998, 120,
4622–4628.
r
10.1021/ol200456y
Published on Web 03/17/2011
2011 American Chemical Society

numerous methods for the enantioselective synthesis of
chiral R-amino phosphoric acids by hydrophosphonyla-
tion of imines (aza-Pudovik reaction) are reported.6,7
However, other R-amino phosphorus derivatives such as
R-amino phosphine oxides have had much less attention
for their biological properties due to the lack of a direct
enantioselective synthetic route.
Table 1. Catalytic Reaction Condition Optimization for the
Enantioselective Addition of Diphenylphosphine Oxide to
N-Benzhydryl Imine
Recently, organocatalyzed hydrophosphination using
secondary phosphines8 has also been demonstrated. Ad-
9
10
ꢀ
ditionally, in 2007, Melchiorre and Cordova reported
enantioselective organocatalytic hydrophosphination of
R,β-unsaturated aldehydes with diphenylphosphine using
a chiral secondary amine catalyst to provide enantioen-
riched aldehydes with β-phosphine substitution. How-
ever, very few examples exist with phosphine oxides as
the nuclophile. In 1999, Shibasaki reported the first
catalytic asymmetric addition of diphenylphosphine oxide
to cyclic imines, catalyzed by a heterobimetallic lantha-
noid complex.11 The corresponding chiral amino phos-
phine oxide products were obtained in good yield and
enantioselectivity, but the substrate scope of this reaction
was limited to cyclic imines. In 2009, a chiral guanidinium
salt-catalyzed phospha-Mannich reaction of N-tosyl imi-
nes with di-1-naphthyl phosphine oxide was reported.12
The R-amino phosphine oxide products were obtained in
high yield and high ee. However, only a single example of a
diphenyl phosphine oxide as a nucleophile was reported,
and with moderate ee. Lastly the addition of dialkyl
phosphine oxides to N-acyl pyrroles was reported re-
cently, obtaining products with excellent yield and
enantioselectivity.13
yield
ee
entrya
catalyst (mol %)b
solvent
(%)c
(%)d
1
2
3
4
5
6
7
8
9
H(1b) Purified on silica gel (10) toluene
H(1c) Purified on silica gel (10) toluene
H(1a) Purified on silica gel (10) toluene
H(1a) Purified on silica gel (10) CH3CN
68
61
72
97
56
96
95
92
87
0
38
82
91
55
91
93
80
80
Na(1a) (10)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Ca(1a)2 (5)
Mg(1a)2 (5)
Mg(1a)2 (2.5)
H(1a) washed with HCl (10)
a General conditions: 1.2 equiv of imine and 1.0 equiv of diphenyl-
phosphine oxide. b See Supporting Information for details on the
synthesis of the catalysts and for the optimization table. c Isolated yields.
d Ee determined by chiral HPLC analysis.
catalyzed by chiral BINOL magnesium phosphate.17 Dur-
ing the screening process we soon realized an electron-
neutral, unactivated protecting group provided consider-
able enhancement in the yield and enantioselectivity, simi-
lar to that observed by Wulff and co-workers in an
aziridination reaction.18
We began by examining the catalytic asymmetric addi-
tion of diphenylphosphine oxide 3a to benzhydryl imine 2a
as a model reaction (Table 1). During optimization we
found that acetonitrile and ‘H(1a) purified on silica gel’
were found to be the best solvent and catalyst for this
reaction (entry 4). In the wake of the new results published
by Ishihara,15 we screened alkali, and alkaline earth metal
phosphate salts. Na(1a) allowed for only a 55% ee (entry 5),
while Ca(1a)2 resulted in a 91% ee (entry 6). Mg(1a)2
was found to be the best catalyst, providing 93% asym-
metric induction (entry 7). However, lowering the catalyst
loading of Mg(1a)2 to 2.5 mol % resulted in a decrease in ee
(entry 8). It was interesting to note that ‘H(1a) washed with
hydrochloric acid’ achieved only a 80% ee for the resulting
product (entry 9).
The use of chiral phosphoric acids to activate imine
substrates for nuclophilic addition is well studied.14 Re-
cently, Ishihara and co-workers reported that purification
of chiral phosphoric acids by silica gel chromatography
can result in mixtures of the free acid and the alkali or
alkaline earth metals, as their phosphate salts.15 These
phosphate salts were found to be active catalysts for new
transformations.16
Herein we report a highly enantioselective addition of
diphenylphosphine oxide to N-substituted imines
(8) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Mazzanti, A.;
Sambri, L.; Melchiorre, P. Chem. Commun. 2007, 722–724.
(9) Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre, P.
Angew. Chem., Int. Ed. 2007, 46, 4504–4506.
(10) Ibrahem, I.; Rios, R.; Vesely, J.; Hammar, P.; Eriksson, L.;
ꢀ
Himo, F.; Cordova, A. Angew. Chem., Int. Ed. 2007, 46, 4507–4510.
(11) Yamakoshi, K.; Harwood, S. J.; Kanai, M.; Shibasaki, M.
Tetrahedron Lett. 1999, 40, 2565–2568.
(12) Fu, X.; Loh, W.; Zhang, Y.; Chen, T.; Ma, T.; Liu, H.; Wang, J.;
Tan, C. Angew. Chem., Int. Ed. 2009, 48, 7387–7390.
(13) Zhao, D.; Mao, L.; Wang, Y.; Yang, D.; Zhang, Q.; Wang, R.
Org. Lett. 2010, 12, 1880–1882.
(14) For reviews on chiral phosphoric acid, see: (a) Akiyama, T.;
Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999–1010. (b)
Akiyama, T. Chem. Rev. 2007, 107, 5744–5758. (c) Terada, M. Chem.
Commum. 2008, 4097–4112.
A series of substitued imines were then investigated
for the asymmetric hydrophosphination reaction in the
(15) Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew.
Chem., Int. Ed. 2010, 49, 3823–3826.
(16) (a) Zhang, Z.; Zheng, W.; Antilla, J. C. Angew. Chem., Int. Ed.
2011, 50, 1135–1138. (b) Drouet, F.; Lalli, C.; Liu, H.; Masson, G.; Zhu,
J. Org. Lett. 2011, 13, 94–97. For reports on metal and Brønsted acid
catalysis, see:(c) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem.;
Eur. J. 2010, 16, 9350–9365.
(17) Lv, J.; Li, X.; Zhong, L.; Luo, S.; Cheng, J.-P. Org. Lett. 2010,
12, 1096–1099.
(18) Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D. Org. Lett. 2008, 10,
5429–5432.
Org. Lett., Vol. 13, No. 8, 2011
2055

Table 2. Catalytic Asymmetric Addition of Diphenylphosphine
Oxide to N-Benzhydryl Imines
Table 3. Catalytic Asymmetric Addition of Diphenylphosphine
Oxide to Imines 5
entrya
R
product
yield (%)b
ee (%)c
entrya
R
product
yield (%)b
ee (%)c
1
Ph (2a)
4a
4b
4c
4d
4e
4f
95
95
96
95
95
97
97
95
93
96
92
88
65
73
93
90d
89
92
90
92
95
96
91
91
86
62
52
48
2
4-MeOC6H4 (2b)
2-MeC6H4 (2c)
3-MeC6H4 (2d)
4-FC6H4 (2e)
4-BrC6H4 (2f)
4-NO2C6H4 (2g)
1-Naph (2h)
2-Furyl (2i)
c-C6H11 (2j)
isopropyl
1
Ph (5a)
6a
6b
6c
6d
6e
6f
90
92
92
95
98
72
73
84
86
99d
92
96
16
87
85
80
74
93
3
2
4-MeOC6H4 (5b)
2-MeC6H4 (5c)
4-FC6H4 (5d)
2-Furyl (5e)
isopropyl
4
3
5
4
6
5
7
4g
4h
4i
6e,f
7d
8d
9d
8
n-Propyl
6g
6h
6i
9
n-Butyl
10
11e
12e
13e
14e
4j
Ph-(CH2CH2)
4k
41
4m
4n
a General conditions: 2.0 equiv of imine and 1.0 equiv of the
phosphine oxide with 5 mol % Mg(1a)2. b Isolated yield. c Determined
by chiral HPLC analysis. d Using the optimized conditions, with Ca(1a)2
as the catalyst, a 95% yield and 90% ee of 6 were obtained, and with
‘H(1a) washed with HCl’, a 90% yield and 79% ee of 6 were found.
e Imine was generated in situ. f (S)-H(1a) was used to synthesize Mg(1a)2.
n-Propyl
n-Butyl
Ph-(CH2CH2)
a General conditions: 1.2 equiv of imine and 1.0 equiv of the
phopshine oxide with 5 mol % Mg(1a)2. b Isolated yields. c Ee deter-
mined by chiral HPLC analysis. d Using the optimized conditions, with
Ca(1a)2 as the catalyst, a 96% yield and 81% ee of 4 could be obtained.
e Imine was generated in situ (see Supporting Information).
conditions revealed the best selectivity when 2 equiv of
imine 5a were treated with 1 equiv of diphenylphosphine
oxide in CH2Cl2 at room temperature (Table 3). Inorder to
determine the utility of the new protecting group, we
synthesized four new imines (Table 3, 5b-e). We opted
to synthesize the imines which had induced a relatively
lower enantioselectivity with the benzhydryl protecting
group in our previous study (see Table 2). When we
subjected 5a to the optimized reaction conditions, we
found a 90% yield and 99% ee for the resulting product
6a. For the benzhydryl protecting group, product 4a was
obtained with a 96% yield and 93% asymmetric induction.
For imine 5b, a 92% ee was obtained for product 6b, while
in the case of the benzhydryl protected imine a 90% ee was
observed in product 4b. Imines 5c and 5d both underwent
diphenylphosphine oxide addition with excellent yield and
enantioselectivity. For the products6cand 6d, an increased
asymmetric induction was observed when compared to the
benzhydryl protected counterpart 4c and 4e respectively.
However, for the heteroaromatic (2-furyl) imine, the pro-
duct 6e was obtained in lower enantiomeric excess (87%)
than product 4i (91%). In the case of aliphatic aldimines,
imines derived from isobutyl aldehydes gave comparable
results in terms of yield and enantioselectivity (4k and 6f).
The products 6g, 6h showed better asymmetric induction
than products 4l, 4m. The dibenzocycloheptene protecting
group was critical for asymmetric induction in 6i; the
product was obtained in 93% ee, while product 4n gave
only a 48% ee. Overall 5H-dibenzo[a,d]cyclohepten-5-
amine derived imines gave better asymmetric inductions
in the resulting products than benhydryl imines, while
presence of catalyst Mg(1a)2 under the optimized reaction
conditions (Table 2). To our delight, all the imines under-
went addition of diphenylphosphine oxide to afford R-
amino phosphine oxide products in excellent yield and
enantioselectivity. Electron-donating substituents in the
para- (entry 2), ortho- (entry 3), and meta- (entry 4)
positions were all shown to be excellent substrates for the
phospha-Mannich reaction. Likewise, the use of electron-
withdrawing substituents (entries 5-7) in the para-posi-
tion also provided for high yields and excellent asymmetric
induction. A sterically hindered 1-napthyl substituted
imine was also an excellent substrate, allowing the pre-
paration of 4h in 95% yield with 96% ee (entry 8). A
heteroaromatic (2-furyl) substitution also proved to be a
good substrate with a high yield and ee for product 4i being
observed (entry 9). We also examined the aliphatic sub-
strate scope; cyclohexyl and isopropyl imines gave good
yields and enantioselectivities (entries 10 and 11). How-
ever, it was found that n-propyl, n-butyl, and 3-phenyl
propyl substituted imines afforded moderate yields and
enantioselectivities when chosen as a substrate for the
reaction (entries 12-14).
Next we chose to investigate the imine protecting group
on the nucleophilic addition. We began this study by
preparing 5a from benzaldehyde and 5H-dibenzo[a,
d]cyclohepten-5-amine.19 Optimization of the reaction
(19) Hjelmencrantz, A.; Friberg, A.; Berg, U. J. Chem. Soc., Perkin
Trans. 2 2000, 1293–1300.
2056
Org. Lett., Vol. 13, No. 8, 2011

Table 4. Catalytic Asymmetric Addition of Aromatic Phosphine
Oxides (3b-e) to N-Benzhydryl Imine
Scheme 1. Deprotection of 4a and Determination of Absolute
Configuration
yields for both protecting groups were comparable. We
hypothesized that the dibenzocycloheptene protected imi-
nes could have enhanced CH-π20 and π-π21 stacking
interactions with catalyst Mg(1a)2 in the transition state,
which leadto a better asymmetricinduction in the resulting
products.
entrya
R
product
yield (%)b
ee (%)c
1
2
3
4
4-ClC6H4 (3b)
4-FC6H4 (3c)
9b
9c
9d
9e
93
88
79
63
84d
84
4-MeOC6H4 (3d)
4-MeC6H4 (3e)
87
89
We have also shown that the benzhydryl group can be
removed with good yield to provide the R-amino phos-
phine oxide 7a, with preserved enantioselectivity
(Scheme 1). Protection of the amine with a Boc group
allowed for product 8a, which was used to deterimine
the absolute stereochemistry of the chiral phosphine
oxide through X-ray crystallographic analysis (see Support-
ing Information).
The reactivity of various aliphatic/aromatic phosphine
oxides22 was evaluated for a hydrophosphination reaction
(Table 4). To our satification, aromatic phosphine oxides
bearing either an electron-withdrawing (entries 1 and 2) or
electron-donating substituent (entries 3 and 4) underwent
nucleophilic addition to N-benzhydryl imine affording
products in good yield and excellent enantioselectivity.
However, aliphatic phosphine oxides such as benzyl, di-
tert-butyl, and diethyl phosphine oxide as well as sterically
demanding aromatic phosphine oxide (2,6-dimethyl phos-
phine oxide) did not undergo a phospha-Mannich reaction
under optimized conditions.
a General conditions: 1.2 equiv of imine and 1.0 equiv of oxide 3b-e
with 5 mol % Mg(1a)2. b Isolated yield. c Determined by chiral HPLC
analysis. d With CH2Cl2 as a the solvent, a 78% yield and 80% ee of 9b
were obtained, while using Ca(1a)2 as the catalyst resulted in a 77% yield
and 79% ee of 9b.
excellent yields and enantioselectivities catalyzed by a
chiral phosphate salt. This method provides a simple and
direct access to chiral R-amino phosphine oxides. In this
study, we have examined the addition of diphenylpho-
sphine oxide to two different N-substituted imines. The
imines synthesized from 5H-dibenzo[a,d]cyclohepten-5-
amine provided better enantioselectivity than those de-
rived from benzhydryl imines, while both imines gave
comparable yields. Also, the substituted diphenylpho-
sphine oxides were excellent nucleophiles obtaining
chiral R-amino phosphine oxides in good yield and
enantioselectivity.
Acknowledgment. We thank the National Institutes of
Health (NIH GM-082935) and the National Science
Foundation (NSF-0847108) for financial support.
In summary, we have developed a new method where
diphenylphosphine oxides can be added to imines with
Supporting Information Available. Characterization,
chiral HPLC conditions, experimental preparation, and
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) For a review, see: Nishio, M. Tetrahedron 2005, 61, 6923–6950.
(21) (a) Janiak, C. J. Chem. Soc., Dalton Trans. 2000, 3885–3896. (b)
Roesky, H. W.; Andruh, M. Coord. Chem. Rev. 2003, 236, 91–119.
(22) Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 10521–
10523.
Org. Lett., Vol. 13, No. 8, 2011
2057