Synthesis of an optically active al(salalen) complex and its application to catalytic hydrophosphonylation of aldehydes and aldimines

Article abstract of DOI:10.1021/ja0651005

Optically active aluminum(salalen) complex 2 was newly synthesized in a modular synthetic manner, and it was found to serve as an efficient catalyst for hydrophosphonylation of aldehydes and aldimines, giving the corresponding α-hydroxy and α-amino phosph

Full text of DOI:10.1021/ja0651005

Published on Web 01/30/2007
Synthesis of an Optically Active Al(salalen) Complex and Its
Application to Catalytic Hydrophosphonylation of Aldehydes
and Aldimines
†
Bunnai Saito, Hiromichi Egami, and Tsutomu Katsuki*
Contribution from the Department of Chemistry, Faculty of Science, Graduate School,
Kyushu UniVersity, CREST, Japan Science and Technology Agency (JST), Hakozaki,
Higashi-ku, Fukuoka 812-8581, Japan
Received July 17, 2006; E-mail: katsuscc@mbox.nc.kyushu-u.ac.jp
Abstract: Optically active aluminum(salalen) complex 2 was newly synthesized in a modular synthetic
manner, and it was found to serve as an efficient catalyst for hydrophosphonylation of aldehydes and
aldimines, giving the corresponding R-hydroxy and R-amino phosphonates with high enantioselectivity,
respectively. The scope of the hydrophosphonylation was wide, and both aliphatic and aromatic aldehydes
and aldimines were successfully used as substrates for the reaction. The potent catalysis of the complex
is attributed to its unique structure: it adopts a distorted trigonal bipyramidal configuration which allows
the salalen ligand to take a cis-â-like structure wherein the chiral amino group is located close to the metal
center.
used as catalysts for the reaction of various aldehydes.2d,f
Recently, Kee et al. reported that chiral Al(salen) complexes
served as the catalyst for asymmetric hydrophosphonylation;
1
. Introduction
Optically active R-hydroxy and R-amino phosphonic acids
and their derivatives are biologically active compounds which
are widely used in pharmaceutical applications, and much effort
has been directed toward the development of asymmetric
hydrophosphonylation of carbonyl and imine compounds. To
our knowledge, heterobimetallic complexes (LLB and ALB)
reported by Shibasaki et al. are the most efficient catalysts for
asymmetric hydrophosphonylation of carbonyl compounds
however, the enantioselectivities obtained were modest (up to
6
4
9% ee). Shibasaki et al. also reported a competent catalytic
1-5
enantioselective hydrophosphonylation of aliphatic and cyclic
imines by using various heterobimetallic complexes suitably as
7,8
catalysts. Use of dimethyl phosphite of small molecular weight
is another advantage of this procedure. In 2004, Jacobsen et al.
reported a unique approach to R-amino phosphonates using
chiral thioureas as organocatalysts and for the first time achieved
high to excellent enantioselectivity in hydrophosphonylation of
(Pudovik reaction): LLB and ALB have been complementarily
†
Current address: Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts.
(
(
9
both aromatic and branched aliphatic imines. Still, introduction
1) Wiemer, D. F. Tetrahedron 1997, 53, 16609-16444.
2) (a) Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry
of a novel catalyst that can show wide applicability for
1
993, 4, 1779-1782. (b) Yokomatsu, T.; Yamagishi, T.; Shibuya, S.
Tetrahedron: Asymmetry 1993, 4, 1783-1784. (c) Rath, N. P.; Spilling,
C. D. Tetrahedron Lett. 1994, 35, 227-230. (d) Arai, T.; Bougauchi, M.;
Sasai, H.; Shibasaki, M. J. Org. Chem. 1996, 61, 2926-2927. (e)
Yokomatsu, T.; Yamagishi, T.; Matsumoto, K.; Shibuya, S. Tetrahedron
(6) (a) Duxbury, J. P.; Cawley, A.; Thornton-Pett, M.; Wantz, L.; Warne,
J. N. D.; Greatrex, R.; Brown, D.; Kee, T. P. Tetrahedron Lett. 1999, 40,
4403-4406. (b) Ward, C. V.; Jiang, M.; Kee, T. P. Tetrahedron Lett. 2000,
41, 6181-6184. (c) Duxbury, J. P.; Warne, J. N. D.; Mushtaq, R.; Ward,
C.; Thornton-Pett, M.; Jiang, M.; Greatrex, R.; Kee, T. P. Organometallics
2000, 19, 4445-4457.
(7) (a) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J. Org. Chem. 1995, 60,
6656-6657. (b) Gr o¨ ger, H.; Saida, Y.; Arai, S.; Martens, J.; Sasai, H.;
Shibasaki, M. Tetradedron. Lett. 1996, 37, 9291-9292. (c) Gr o¨ ger, H.;
Saida, Y.; Sasai, H.; Yamaguchi, K.; Martens, J.; Shibasaki, M. J. Am.
Chem. Soc. 1998, 120, 3089-3103. (d) Schlemminger, I.; Saida, Y.; Gr o¨ ger,
H.; Maison, W.; Durot, N.; Sasai, H.; Shibasaki, M.; Martens, J. J. Org.
Chem. 2000, 65, 4818-4825.
1
996, 52, 11725-11738. (f) Sasai, H.; Bougauchi, M.; Arai, T.; Shibasaki,
M. Tetrahedron Lett. 1997, 38, 2717-2720. (g) Yokomatsu, T.; Yamagishi,
T.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1 1997, 1527-1533. (h)
Groaning, M. D.; Rowe, B. J.; Spilling, C. D. Tetrahedron Lett. 1998, 39,
5
1
485-5488. (i) Cermak, D. M.; Du, Y.; Wiemer, D. F. J. Org. Chem.
999, 64, 388-393. (j) Yamagishi, T.; Yokomatsu, T.; Suemune, K.;
Shibuya, S. Tetrahedron 1999, 55, 12125-12136. (k) Skropeta, D.;
Schmidt, R. R. Tetrahedron: Asymmetry 2003, 14, 265-273.
(
3) For reviews of biological activity of amino phosphonic acids, see: (a)
Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem. 1991,
6
3, 193-215. (b) Kukhar, V. P., Hudson, H. R., Eds. Aminophosphonic
and aminophosphinic acids: chemistry and biological actiVity; John Wiley
Sons: Chichester, 2000.
(8) For other reports on synthesis of enantiomerically enriched R-amino
phosphonates using a catalytic asymmetric reaction as the key step, see:
(a) Sch o¨ llkopf, U.; Hoppe, I.; Thiele, A. Liebigs. Ann. Chem. 1985, 555-
559. (b) Sawamura, M.; Ito, Y.; Hayashi, T. Tetrahedron Lett. 1989, 30,
2247-2250. (c) Kitamura, M.; Tokunaga, M.; Pham, T.; Lubell, W. D.;
Noyori, R. Tetrahedron Lett. 1995, 36, 5769-5772. (d) Schmit, U.; Oehme,
G.; Krause, H. W. Synth. Commun. 1996, 26, 777-781. (e) Schmit, U.;
Krause, H. W.; Oehme, G.; Michalik, M.; Fischer, C. Chirality 1998, 10,
564-572. (f) Burk, M. J.; Stammers, T. A.; Straub, J. A. Org. Lett. 1999,
1, 387-390. (g) Kobayashi, S.; Kiyohara, H.; Nakamura, Y.; Matsubara,
R. J. Am. Chem. Soc. 2004, 126, 6558-6559. (h) Pawar, V. D.; Bettigeri,
S.; Weng, S.-S.; Kao, J.-Q.; Chen, C.-T. J. Am. Chem. Soc. 2006, 128,
6308-6309.
&
(
4) For a review of catalytic enantioselective preparation of R-hydroxy and
R-amino phosphonates, see: Gr o¨ ger, H.; Hammer, B. Chem.sEur. J. 2000,
6
, 943-948.
(
5) (a) Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett. 2005, 7, 2583-
2
585. (b) D e´ jugnat, C.; Etemad-Moghadam, G.; Rico-Lattes, I. Chem.
Commun. 2003, 1858-1859. (c) Yager, K. M.; Taylor, C. M.; Smith,
A. B., III J. Am. Chem. Soc. 1994, 116, 9377-9378. (d) Smith, A. B., III;
Yager, K. M.; Taylor, C. M. J. Am. Chem. Soc. 1995, 117, 10879-10880.
(
e) Lefebvre, I, M.; Evans, S. A., Jr. J. Org. Chem. 1997, 62, 7532-7533.
f) Davis, F. A.; Lee, S.; Yan, H.; Titus, D. D. Org. Lett. 2001, 4, 1757-
(
1
760.
(9) Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102-4103.
1978
9
J. AM. CHEM. SOC. 2007, 129, 1978-1986
10.1021/ja0651005 CCC: $37.00 © 2007 American Chemical Society

Catalytic Hydrophosphonylation of Aldehydes and Aldimines
A R T I C L E S
Scheme 1
Figure 1. The structure of salalen ligand 1 and its aluminum complex 2.
hydrophosphonylation of various aldehydes and aldimines has
been strongly required.
Some of these previous studies have disclosed that a function
active R-hydroxy and R-amino phosphonates. In this paper, we
describe the synthesis of a chiral aluminum salalen complex
and the full scope of asymmetric hydrophosphonylation using
7
1
4
which holds two different substrates [aldehyde (or aldimine)
and phosphite] simultaneously in a highly asymmetric atmo-
sphere is very important for constructing a new catalyst for
asymmetric hydrophosphonylation. For the past two decades,
chiral salen ligands have received a great deal of attention due
to their high asymmetry-inducing ability and ready availability.
To date, they have been successfully applied to a wide range
of enantioselective reactions including epoxidation, aziridination,
the complex as catalyst.
2. Results and Discussion
2.1. Preparation of Optically Active Aluminum(salalen)
Complex 2. A new optically active salalen ligand 1 was
prepared from cyclohexane-1,2-diamine in a stepwise manner
and converted into the desired aluminum complex 2 by its
14
treatment with Et AlCl. The X-ray analysis demonstrated that
2
10
sulfoxidation, Michael reaction, epoxide-opening reaction, etc.
complex 2 possessed a distorted trigonal bipyramidal configu-
These salen complexes adopt a mostly octahedral configuration
in which two ancillary ligands are trans-oriented. However,
recent studies have disclosed that cis-â isomers that provide
ration, and the absolute configuration of the coordinated tertiary
amine was determined to be S (Figure 1). The N-methyl group
was oriented syn to the chloro ligand that should be replaced
by a substrate, when the complex is used as a Lewis acid
1
0c
two vicinal coordination sites show unique catalysis. For
example, a di-µ-oxo Ti(salen) complex that bears chiral cis-â
salen ligands catalyzes asymmetric cyanation with high enan-
1
5
catalyst.
2.2. Asymmetric Hydrophosphonylation of Aldehydes.
With complex 2 in hand, we examined asymmetric hydrophos-
phonylation of benzaldehyde and found that the best result was
obtained when the reaction was carried out in tetrahydrofuran
(THF) at -15 °C with dimethyl phosphite (Scheme 1). Use of
bulky dialkyl or diaryl phosphite such as diphenyl phosphite
diminished enantioselectivity. Under the optimized conditions,
we examined the hydrophosphonylation of both aromatic and
aliphatic aldehyde. Fortunately, high enantioselectivity was
observed in both of the reactions. To our knowledge, this is the
first example that a molecular catalyst can be applied to the
reactions of both aromatic and aliphatic aldehydes with enan-
1
1
tioselectivity. Furthermore, a di-µ-oxo Ti(salen) complex has
been found to be an excellent precatalyst for asymmetric
sulfoxidation, in which a monomeric cis-â peroxo complex has
been proven to be the active species.12 Despite the potentiality
of cis-â isomers for asymmetric catalysis, metallosalen com-
plexes intrinsically adopt the trans conformer in preference to
the cis-â isomer. On the other hand, Kol et al. quite recently
reported that treatment of an achiral hybrid salan/salen tetraden-
tate [ONN(Me)O]-type ligand (hereafter referred to as salalen
ligand) with titanium and zirconium tetraethoxides yielded the
corresponding octahedral Ti- and Zr(salalen)(OEt)2 complexes,
respectively, in which the two diastereotopic ethoxy groups are
cis-oriented and the coordinated amino-nitrogen atom that is
closer to the metal ion by one C-C bond than the ethylene
carbon is chiral.13 Thus, we were intrigued by the catalysis of
the salalen complexes for hydrophosphonation. However, it was
considered that the presence of two diastereomeric alkoxides
that might be substituted equally easily with substrates would
lead to formation of a mixture of diastereomeric intermediates,
and therefore, the salalen complexes would not be very suitable
for the hydrophosphonylation. To take an advantage of the
salalen ligand, we synthesized the corresponding optically active
Al(salalen) complex instead and examined asymmetric hydro-
phosphonylation of aldehydes and aldimines to give optically
1
4
tioselectivities greater than 80% ee.
2.3. Asymmetric Hydrophosphonylation of Aldimines. In
Lewis acid promoted aldehyde reactions, the Lewis acid is
generally coordinated to the lone pair electrons trans to the
carbonyl substituent. In contrast, the imino nitrogen atom carries
an N-substituent, and its coordination requires a wider reaction
space than that of an aldehyde carbonyl group. Due to the
1
5
following unique structural features, however, we expected
that complex 2 could also be applied to hydrophosphonylation
of imines: (i) the cis-â-like ligand structure provides a wide
reaction site allowing coordination of imines, since the coor-
dination should occur from the open convex side of the salalen
ligand; (ii) nonetheless, the stereochemistry of the reaction there
should be efficiently controlled by the substituent on the chiral
nitrogen atom next to the metal ion.
(
10) (a) Canali, L.; Sherrington, D. C. Chem. Soc. ReV. 1999, 28, 85-93. (b)
Katsuki, T. Synlett 2003, 281-297. (c) Katsuki, T. Chem. Soc. ReV. 2004,
3
3, 437-444. (d) Larrow, J. F.; Jacobsen, E. N. Top. Organomet. Chem.
Since the N-protecting group of aldimines was considered to
affect the stereochemistry and rate of the hydrophosphonylation,
the reaction of dimethyl phosphite with aldimines derived from
2
004, 6, 123-152.
(
11) Belokon’, Y.; Caveda-Cepas, S.; Green, B.; Ikonnikov, N.; Khrustalev, V.;
Larichev, V.; Moskalenko, M.; North, M.; Orizu, C.; Tararov, V.; Tasinazzo,
M.; Timofeeva, G.; Yashkina, L. J. Am. Chem. Soc. 1999, 121, 3968-
3
973.
(
12) (a) Saito, B.; Katsuki, T. Tetrahedron Lett. 2001, 42, 3873-3876. (b) Saito,
B.; Katsuki, T. Tetrahedron Lett. 2001, 42, 8333-8336.
13) Yeori, A.; Gendler, S.; Groysman, S.; Goldberg, I.; Kol, M. Inorg. Chem.
Commun. 2004, 7, 280-282.
(14) A part of the study on asymmetric hydrophosphonylation has been
communicated: Saito, B.; Katsuki, T. Angew. Chem., Int. Ed. 2005, 44,
4600-4602.
(
(15) For the X-ray structure of 2, see the Supporting Information.
J. AM. CHEM. SOC.
9
VOL. 129, NO. 7, 2007 1979

A R T I C L E S
Saito et al.
Table 1. Asymmetric Hydrophosphonylation of Various
Benzaldimine Derivatives
Table 2. Asymmetric Hydrophosphonylation of
N-Aryl-benzaldimine Derivatives 5a
a
entry
PG
yield/%b
% ee
c
1
2
3
4
5
6
7
8
MeO-
a
b
c
d
e
N.D.
N.D.
<10
35
80
80
<10
91
c
Me2N-
t
d
BuO(O)C-
42
17
60
56
16
60
75
e
Ts
f
Bn
yield/%b
entry
Ar
% ee
f
p-MeOC6H4CH2-
Ph2CH-
Ph
f
c,d
d,f
f
1
2
3
4
5
a
b
c
d
e
f
91
91
89
95
93
90
78 (R)
g
h
h
e
f
80
69f
g
f
9
Ph
96
c
31
82
c
a
Reactions were carried out with imine (0.1 mmol) and dimethyl
g
b
6
87 (R)
phosphite (0.15 mmol) in the presence of 2 (10 mol %). Isolated yield.
Not determined. Determined by HPLC analysis using a chiral stationary
phase column (Daicel Chiralpak AS-H; hexane/i-PrOH ) 24:1). Deter-
mined by HPLC analysis using a chiral stationary phase column (Daicel
Chiralpak IA; hexane/AcOEt ) 3:2). Determined by HPLC analysis using
a chiral stationary phase column (Daicel Chiralpak AS-H; hexane/i-PrOH
4:1). The reaction was carried out at -15 °C.
c
d
e
a
Reactions were carried out with imine (0.1 mmol) and dimethyl
phosphite (0.15 mmol) in the presence of 2 (10 mol %). Isolated yields.
Determined by HPLC analysis using a chiral stationary phase column
b
f
c
d
(Daicel Chiralpak AS-H; hexane/i-PrOH ) 4:1). Absolute configuration
g
)
was determined by chiroptical comparison of the amino phosphonate
obtained by deprotection of the product (ref 22). e Determined by HPLC
analysis using a chiral stationary phase column (Daicel Chiralpak IA;
f
hexane/i-PrOH ) 9:1). Determined by HPLC analysis using a chiral
benzaldehyde and various amines was initially examined at room
temperature in THF by using complex 2 as catalyst (Table 1).
N-Methoxy- and N-(dimethylamino)-aldimines (3a and 3b) did
not show any reactivity (entries 1 and 2). N-tert-Butoxycarbonyl-
and N-p-toluenesufonyl-aldimines (3c and 3d) were poorly
reactive, and the enantioselectivities of their reactions were
modest (entries 3 and 4). Thus, we next examined the reactions
of the aldimines (3e and 3f) bearing a simple and noncoordi-
nating group such as benzyl and p-methoxybenzyl groups and
found that their reactions proceeded with good chemical yields
and moderate enantioselectivities (entries 5 and 6). Introduction
of a more bulky diphenylmethyl group badly diminished the
reaction rate and enantioselectivity (entry 7). Finally, a phenyl
group gave a promising result: the reaction of the N-phenyla-
ldimine 3h gave the best chemical yield with the same
enantioselectivity as that of the reaction of N-benzylaldimine
e (entry 8), and it proceeded almost quantitatively even at
15 °C with a better enantioselectivity of 75% ee.
Encouraged by these results, we next examined the reactions
of benzaldimines bearing a substituted phenyl group as the
N-protecting group (Table 2).16 Introduction of a p-methoxy
substituent improved enantioselectivity to 78% ee (entry 1),
while that of a p-bromo substituent largely reduced enantiose-
lectivity (entry 4). We also examined the effect of some other
substituted phenyl groups and found that the reaction of N-(3,4-
ethylenedioxyphenyl)imine 5e showed good enantioselectivity
of 82% ee together with good chemical yield (entry 5). Since it
had been reported that a 4-methoxyphenyl group can be cleaved
by treatment with cerium ammonium nitrate (CAN),
expected that a 3,4-ethylenedioxyphenyl group could also be
deprotected by the same procedure but it gave messy products.
stationary phase column (Daicel Chiralpak AD-H; hexane/i-PrOH ) 9:1).
g
The reaction was carried out with imine (0.5 mmol) and dimethyl phosphite
(0.75 mmol) in the presence of 2 (10 mol %).
Scheme 2
With the thought that an m-alkoxy group may exert not an
electronic but a steric effect on enantioselectivity, we further
examined the reaction of N-(4-methoxy-3-methylphenyl)aldi-
mine 5f instead and attained the best enantioselectivity of 87%
ee (entry 6). Fortunately, use of 5f as aldimine gave another
successfully deprotected the
4-methoxy-3-methylphenyl group to give the corresponding
amine in a good yield of 72% without loss of enantiopurity
3
-
1
9,20
advantage: anodic oxidation
(
Scheme 2), though its deprotection with CAN gave the amine
in a moderate yield (<40%). It is noteworthy to mention that
asymmetric induction observed in this reaction is opposite to
that observed in the hydrophsphonylation of benzaldehyde (cf.
Scheme 1 and Table 2). This might suggest that 5f was
2
1
coordinated in its stable (E)-form to complex 2.
5
a,17,18
we
(
17) For examples, see: (a) Kronenthal, D. R.; Han, V. Y.; Taylor, M. K.
J. Org. Chem. 1982, 47, 2765-2768. (b) Hasegawa, M.; Taniyama, D.;
Tomioka, K. Tetrahedron 2000, 56, 10153-10158. (c) Saito, S.; Hatanaka,
K.; Yamamoto, H. Tetrahedron 2001, 57, 875-887. (d) Haak, E.;
Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2002, 457-463.
(18) It has been reported that a 4-methoxyphenyl group can be deprotected by
means of CAN to give the corresponding R-aminophosphonate in moderate
yields; see: refs 5a, 17d.
(19) Marin, S. D. L.; Martens, T.; Mioskowski, C.; Royer, J. J. Org. Chem.
2005, 70, 10592-10595.
(20) The deprotection was carried out according to the reported procedure in
ref 19 with a slight modification.
(
16) For the recent studies of asymmetric reactions of imines and the effect of
the N-protecting group, see: (a) Enders, S.; Reinhold, U. Tetrahedron:
Asymmetry 1997, 8, 1895-1946. (b) Bloch, R. Chem. ReV. 1998, 98, 1407-
1
438. (c) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069-1094.
(
d) Gr o¨ ger, H. Chem. ReV. 2003, 103, 2795-2827. (e) C o´ rdova, A. Acc.
Chem. Res. 2004, 37, 102-112. (f) Vilaivan, T.; Bhanthumnavin, W.;
Sritana-Anant, Y. Curr. Org. Chem. 2005, 9, 1315-1392.
1980 J. AM. CHEM. SOC.
9
VOL. 129, NO. 7, 2007

Catalytic Hydrophosphonylation of Aldehydes and Aldimines
A R T I C L E S
Table 3. aAsymmetric Hydrophosphonylation of Various Aromatic
Table 4. Oane-Pot Hydrophosphonylation of Various Aldimine
Aldimines
Derivatives
entry
R
yield/%b
% ee
95c
entry
R
amine
yield/%b
% ee
1
2
3
4
5
6
7
p-BrC6H4
p-ClC6H4
p-MeOC6H4
p-CH3C6H4
o-CH3C6H4
2-C4H3S
a
b
c
d
e
f
>99
c
c
c
c
c
95
95
85
90
87
84
c
1
2
3
4
5
6
t-Bu
a
b
c
d
e
f
A
A
B
B
B
B
28
84
80
83
92
51
88
94
91
84
92
95
93
91
>99 (94)
92
c
cyclohexyl
(CH3)2CHCH2
octyl
PhCtC
(E)-PhCHdCH
d
d
c
86
d
d,e
2-C4H3O
2-[5-PhC4H2O]
g
h
63 (69)
d
15
d
e
8
79
a
Reactions were carried out with aldehyde (0.2 mmol), amine (0.2
mmol), and dimethyl phosphite (0.3 mmol) in the presence of 2 (10 mol
%) and MS 4 Å (ca. 100 mg). b Isolated yields. c Determined by HPLC
analysis using a chiral stationary phase column (Daicel Chiralpak AD-H;
hexane/i-PrOH ) 17:3). Determined by HPLC analysis using a chiral
stationary phase column (Daicel Chiralpak AD-H; hexane/i-PrOH ) 9:1).
a
Reactions were carried out with imine (0.2 mmol) and dimethyl
b
phosphite (0.3 mmol) in the presence of 2 (10 mol %). Isolated yields.
Determined by HPLC analysis using a chiral stationary phase column
Daicel Chiralpak AD-H; hexane/i-PrOH ) 7:3). The reaction was carried
out in tetrahydropyran. Determined by HPLC analysis using a chiral
stationary phase column (Daicel Chiralpak AD-H; hexane/i-PrOH )
7:3).
c
d
d
(
e
1
aliphatic aldimines also proceeded with high enantioselectivity
Under the optimized conditions, we examined asymmetric
(entries 1 and 2), although the reaction of pivalaldimine was
hydrophosphonylation of aromatic aldimines bearing a 4-meth-
oxy-3-methylphenyl group as an N-protecting group (Table 3).
All the reactions proceeded with good enantioselectivity. When
the substrate carried an electron-withdrawing p-substituent,
enantioselectivity was improved up to 95% ee (entries 1 and
slow. On the other hand, condensation of nonbranched aliphatic
aldehyde and 4-methoxy-3-methylphenylaniline gave not the
24
desired aldimine but unidentified polymeric materials. To
7
avoid this problem, we used bulky diphenylmethylamine instead
of 4-methoxy-3-methylphenylaniline. Fortunately, in situ hy-
drophosphonylation of the aldimines prepared from nonbranched
aliphatic aldehydes proceeded with high enantioselectivities
2
); however, the presence of an electron-donating p-substituent
somewhat decreased enantioselectivity to 85% ee (entry 3). The
presence of a methyl substituent at the o- or p-position had little
effect on enantioselectivity (entries 4 and 5). We also examined
the reactions of heteroaromatic aldimines. The reaction of
25
together with good chemical yields (entries 3 and 4). In situ
hydrophosphonylation of aldimines prepared from branched
aliphatic aldehydes and diphenylmethylamine was slow. It has
been reported that a diphenylmethyl group can be cleaved under
2
8
-thienyl aldimine proceeded with high enantioselectivity of
4% ee (entry 6). However, that of 2-furyl aldimine was
7,25
mild conditions. We also examined the reactions of alkynyl
moderately enantioselective (63% ee, entry 7). Although the
reason for this diminished enantioselectivity was not completely
clear, the presence of a hard base, furan ring, seemed to be
responsible. Thus, the reaction was examined in tetrahydropyran,
a more polar solvent, and a slight enantioselectivity enhancement
was observed. Thus, we further examined the reaction of 2-(5-
phenylfuryl) aldimine with the expectation that the phenyl group
would reduce the coordinating ability of the furan ring. Indeed,
the reaction in tetrahydropyran showed a significantly improved
enantioselectivity of 79% ee (entry 8).
and alkenyl aldimines in one pot. The reaction of the aldimine
prepared from phenylpropargyl aldehyde and diphenylmethyl-
amine also proceeded with high enantioselectivity (entry 5).
However, the reactions of cinnamaldimines prepared from
diphenylmethylamine or 4-methoxy-3-methylphenylaniline were
low enantioselectively and slow, though the reason is unclear
23
(entry 6).
2
.4. Mechanistic Consideration. In order to shed light on
the mechanism of the present reactions, we examined the relation
between the enantiomeric excesses (ee’s) of the product and
the catalyst in the hydrophosphonylation of benzaldehyde and
We also examined the reaction of aliphatic aldimines (Table
4). Different from aromatic N-aryl aldimines that are mostly
26
found that the ee’s correlated linearly to each other. This
crystalline, most aliphatic N-aryl aldimines are not crystalline
and are difficult to be purified chromatographically due to their
poor stability. Therefore, we examined the condensation of an
aliphatic aldehyde with an amine and subsequent hydrophos-
phonylation in one pot. To our delight, the reactions of branched
suggested that dimeric aluminum species do not participate in
this reaction and all the events occur in a monomeric cis-â
aluminum species. From this consideration and the X-ray
structure of 2, we propose a possible mechanism for this reaction
(Scheme 3). When complex 2 is exposed to a mixture of
aldehyde and dimethyl phosphite, the chloro ligand is replaced
(
21) We cannot completely rule out the possibility that stable (E)-5f is isomerized
to (Z)-5f in the presence of complex 2, but it is unlikely because no
formation of a minor isomer was detected under the conditions.
22) Tongcharoensirikul, P.; Suarez, A. I.; Voelker, T.; Thompson, C. M.
J. Org. Chem. 2004, 69, 2322-2326.
(24) Layer, R. W. Chem. ReV. 1963, 63, 489-510.
(25) It has been reported that compound 10c can be converted to optically active
phospholeucine which is a potent inhibitor of leucine aminopeptidase:
Shibasaki, M.; Sasai, H.; Tahara, Y. PCT Int. Appl. 1997, WO 9711954
A1 19970403.
(
(
23) The enantioselectivity of the reaction of benzaldimine that bears no hard
base unit did not depend on the solvent. The reactions both in THF and in
tetrahydropyran showed the identical enantioselectivity.
(26) For the data, see Supporting Information.
J. AM. CHEM. SOC.
9
VOL. 129, NO. 7, 2007 1981

A R T I C L E S
Scheme 3
Saito et al.
by the phosphite to give species A, to which the aldehyde
directing its carbonyl substituent (R) outward is coordinated.
The resultant species B undergoes intramolecular addition to
give an (S)-R-hydroxy phosphonate that is replaced by dimethyl
phosphite and completes the catalytic cycle. On the other hand,
when the substrate is an aldimine, it is coordinated to the species
A with the R group cis to the ion and the resultant D undergoes
the subsequent intramolecular addition to give an (R)-R-amino
phosphonate. This proposal agrees with the observed stereo-
chemistry.
In conclusion, we were able to synthesize chiral trigonal
bipyramidal aluminum(salalen) complex 2 providing a unique
asymmetric reaction site, in which the nitrogen atom is bound
to the metal ion and the N-methyl group on the resulting chiral
nitrogen atom is cis to the chloro ligand. Moreover, complex 2
was demonstrated to be an efficient catalyst for enantioselective
hydrophosphonylation of various aldehydes and aldimines with
dimethyl phosphite. The present study will open a new entry to
a general method for preparing optically active R-hydroxy and
R-amino phosphonic acids.
3.2. Synthesis of Salalen Ligand 1 and Its Aluminum Complex
. 3.2.1. Synthesis of Salalen Ligand 1. To a solution of (1R,2R)-
,2-cyclohexanediamine monohydrochloride (3.40 g, 22.56 mmol) in
2
1
dry methanol (ca. 100 mL) was added 3,5-di-tert-butyl salicylaldehyde
5.03 g, 21.48 mmol), and the resulting mixture was stirred for 3 h at
room temperature. After cooling to 0 °C, sodium borohydride (2.03 g,
3.7 mmol) was added to the solution and stirred for another 2 h at
room temperature. The reaction was quenched with H O, and the
mixture was extracted with Et O three times. The combined organic
phases were washed with brine and dried over Na SO . After filtration,
(
5
2
2
2
4
the filtrate was concentrated in vacuo and redissolved in dry ethanol
(100 mL). To the solution was added di-tert-butyl dicarbonate (5.45
mL, 23.6 mmol) at room temperature and stirred for 1.5 h. The mixture
was concentrated under reduced pressure and chromatographed on silica
gel (hexane/ethyl acetate ) 9/1-4/1) to give N-(tert-butoxycarbonyl)-
N′-(3,5-di-tert-butyl-2-hydroxyphenylmethyl)cyclohexanediamine (6.24
g, 67%).27
2
D
2
Colorless solid (hygroscopic). [R] +8.85 (c 1.33, CHCl
3
); IR
(
KBr): 3317, 2955, 2862, 1701, 1510, 1481, 1454, 1391, 1363, 1236,
-1
1
1
3
171, 1107, 1016, 872 cm ; H NMR (CDCl ): δ 7.21 (d, J ) 2.4
Hz, 1H), 6.85 (d, J ) 2.4 Hz, 1H), 4.42 (br d, J ) 10.3 Hz, 1H), 4.08
d, J ) 13.43 Hz, 1H), 3.87 (d, J ) 13.43 Hz, 1H), 3.40 (m, 1H),
(
2
1
.32-2.23 (m, 2H), 2.00 (m, 1H), 1.76-1.69 (m, 2H), 1.46 (s, 9H),
3. Experimental Section
.42 (s, 9H), 1.28 (s, 9H), 1.40-1.12 (m, 4H); 13C NMR (CDCl
3
): δ
3
.1. General. All reagents and solvents were used as supplied
155.7, 154.5, 140.1, 135.7, 123.0, 122.7, 122.1, 79.5, 60.4, 54.1, 50.4,
commercially, except for THF that was distilled from Na/Ph CO, before
2
35.0, 34.2, 33.5, 31.8, 31.4, 29.8, 28.5, 25.1, 24.7; HRFABMS. Calcd
1
13
+
use. H and C NMR spectra were measured on a JEOL GX-400
spectrometer at 400 and 100 MHz, respectively. All chemical shifts
were recorded in δ (ppm) relative to tetramethylsilane (TMS). Melting
points were measured with a B U¨ CHI Melting Point B-545 apparatus
and uncorrected. Infrared spectra were measured as a KBr disc or as a
thin film using a NaCl plate on a SHIMADZU FTIR-8600 spectro-
photometer, and only diagnostic absorptions are listed below. Optical
rotation was measured with a JASCO P-1020 polarimeter. High-
resolution FAB mass spectra were obtained from a JEOL JMX-SX/
SX 102A spectrometer. Enantiomeric excesses were determined by
HPLC analysis using a SHIMADZU LC-10AT-VP equipped with an
appropriate optically active column, as described in the footnotes to
the corresponding tables. TLC analysis was performed on Silica gel
for [C26
H
44
N
2
O
3
] : m/z ) 432.3352. Found: m/z ) 432.3349.
To a methanolic solution (ca. 80 mL) of the cyclohexanediamine
derivative (5.63 g, 13.01 mmol) in a 300 mL round-bottomed flask
were added aq. CH
(1.03 g) at room temperature. The flask was purged with H
installed with a rubber balloon filled with H . After stirring for about
2
O (ca. 37%, 1.21 mL, 16.27 mmol) and 10% Pd/C
2
and
2
5 h at room temperature, the mixture was filtered through a pad of
Celite that was subsequently washed with MeOH. The filtrate was
concentrated in vacuo and redissolved in MeOH (30 mL). To the
solution was added 3 M HCl (30 mL), and the whole mixture was
stirred for 36 h at room temperature. The reaction was quenched with
3 M NaOH (35 mL), and the resulting mixture was extracted with Et
three times. The combined organic phases were washed with brine and
dried over Na SO . After filtration, the filtrate was concentrated in vacuo
2
O
6
0 F254-coated glass plates (Merck). Visualization was accomplished
2
4
with irradiation of 254 nm UV light or a spray of a 12-molybdo(VI)-
phosphoric acid ethanol solution as the developing agent. Preparations
of catalysts and all the reactions were carried out under inert atmosphere,
unless otherwise specified.
and redissolved in methanol (ca. 100 mL). To the solution was added
3,5-di-tert-butylsalicylaldehyde (3.04 g, 13.0 mmol) and stirred for 3.5
(27) Campbell, E. J.; Nguyen, S. T. Tetrahedron Lett. 2001, 42, 1221-1225.
1982 J. AM. CHEM. SOC.
9
VOL. 129, NO. 7, 2007

Catalytic Hydrophosphonylation of Aldehydes and Aldimines
A R T I C L E S
h at room temperature. The precipitate was filtered off and washed
(S)-Dimethyl Hydroxy(4-chlorophenyl)methylphosphonate. Col-
2
2
with methanol to give the ligand 1 (5.54 g, 76%).
orless solid. Yield 88% (88% ee); Mp 70.1-70.7 °C; [R] -50.4
D
2
D
2
2d
Yellow solid. [R] -100.4 (c 1.00, CHCl
3
); IR (KBr): 2955, 2864,
3
(c 1.64, CHCl ), [lit. (S)-isomer (83% ee); (c 1.0, CHCl
3
)]; IR
1
8
628, 1601, 1477, 1447, 1393, 1362, 1244, 1204, 1171, 1030, 876,
(KBr): 3256, 2959, 2855, 1489, 1447, 1402, 1259, 1213, 1177, 1063,
-
1
1
-1 1
26 cm ; H NMR (CDCl
3
): δ 13.56 (s, 1H), 10.58 (br s, 1H), 8.37
1022, 880, 835, 799, 723, 561 cm ; H NMR (CDCl
3
): δ 7.43 (dd, J
(
s, 1H), 7.38 (d, J ) 2.4 Hz, 1H), 7.10 (d, J ) 2.4 Hz, 1H), 7.02 (d,
) 2.2, 8.3 Hz, 2H), 7.36 (d, J ) 8.6 Hz 2H), 5.04 (dd, J ) 4.8, 10.9
1
3
J ) 2.4 Hz, 1H), 6.79 (d, J ) 2.4 Hz, 1H), 3.79 (br ABq, 2H), 3.29
(
(
NMR (CDCl
1
3
Hz, 1H), 3.72 (d, J ) 10.5 Hz, 3H), 3.71 (d, J ) 10.5 Hz, 3H);
NMR (CDCl ): δ 134.7, 133.9 (d, J ) 3.3 Hz), 128.4 (d, J ) 2.5 Hz),
128.2 (d, J ) 5.8 Hz), 70.0 (d, J ) 159.3 Hz), 54.1 (d, J ) 6.8 Hz),
C
m, 1H), 2.96 (m, 1H), 2.22 (s, 3H), 2.00-1.63 (m, 5H), 1.43-1.29
m, 3H), 1.47 (s, 9H), 1.29 (s, 9H), 1.25 (s, 9H), 1.12 (s, 9H); 13
): δ 165.5, 157.9, 154.5, 139.6, 139.6, 136.4, 135.2, 126.7,
25.6, 123.1, 122.3, 120.8, 117.9, 70.2, 66.6, 35.3, 35.1, 34.8, 34.2,
1.8, 31.6, 29.7, 29.5, 25.3, 24.8; Anal. Calcd for C37 : C, 78.95;
3
C
9 4
53.7 (d, J ) 7.5 Hz); Anal. Calcd for C H12ClO P: C, 43.13; H, 4.83%.
Found: C, 43.02; H, 4.71%.
3
H N O
58 2 2
(S)-Dimethyl Hydroxy(4-methoxyphenyl)methylphosphonate. Col-
2
4
H, 10.39; N, 4.98%. Found: C, 78.94; H, 10.40; N, 4.92%.
.2.2. Synthesis of Aluminum Salalen Complex 2. To a solution
orless solid. Yield 87% (81% ee); Mp 71.2-71.3 °C; [R] -39.6 (c
D
d
2
3
3 3
1.59, CHCl ), [lit. (S)-isomer (78% ee); (c 1.0, CHCl )]; IR (KBr):
of salalen ligand 1 (453 mg, 0.806 mmol) in dry toluene (10 mL) was
added diethylaluminum chloride (0.92 M in hexane, 876 µL) at 0 °C,
and the solution was stirred overnight at room temperature. The yellow
suspension was concentrated in vacuo and resuspended in hexane. The
yellow precipitate was filtered off and washed with hexane to give
complex 2 (468 mg, 93%).
3225, 2955, 2851, 1612, 1512, 1464, 1250, 1205, 1063, 1032, 843,
-
1 1
800, 762, 685, 554 cm ; H NMR (CDCl
3
): δ 7.42 (dd, J ) 2.2, 8.8
Hz, 2H), 6.92 (d, J ) 8.8 Hz 2H), 4.99 (dd, J ) 4.9, 10.0 Hz, 1H),
1
3
3.73 (d, J ) 10.5 Hz, 3H), 3.67 (d, J ) 10.5 Hz, 3H); C NMR
(CDCl ): δ 159.4 (d, J ) 3.3 Hz), 128.3 (d, J ) 5.4 Hz), 128.1 (d,
J ) 1.7 Hz), 113.7, 69.8 (d, J ) 160.9 Hz), 55.4, 54.0 (d, J ) 7.5 Hz),
3
Yellow solid. IR (KBr): 2951, 2909, 2864, 1620, 1543, 1483, 1441,
15 5
53.7 (d, J ) 6.7 Hz); Anal. Calcd for C10H O P: C, 48.78; H, 6.14%.
1
6
2
420, 1389, 1360, 1304, 1256, 1204, 1177, 1130, 1011, 962, 851, 761,
Found: C, 48.72; H, 6.11%.
Dimethyl Hydroxy(2-chlorophenyl)methylphosphonate. Colorless
-
1 1
35, 600, 577 cm ; H NMR (CDCl
3
): δ 8.44 (s, 1H), 7.57 (d, J )
23
.4 Hz, 1H), 7.30 (d, J ) 2.4 Hz, 1H), 7.00 (d, J ) 2.4 Hz, 1H), 6.82
solid. Yield 96% (91% ee); Mp 112.9-113.2 °C; [R]D -65.7 (c 2.26,
CHCl ); IR (KBr): 3288, 3066, 3015, 2959, 1572, 1472, 1443, 1188,
1045, 839, 781, 754, 698, 626, 571, 536 cm ; H NMR (CDCl
7.72 (m, 1H), 7.39-7.26 (m, 4H), 5.58 (dd, J ) 5.7, 11.8 Hz, 1H),
(d, J ) 2.4 Hz, 1H), 4.57 (d, J ) 13.2 Hz, 1H), 3.40 (m, 1H), 3.37 (d,
3
-
1 1
J ) 13.2 Hz, 1H), 2.54 (m, 1H), 2.45 (s, 3H), 2.36-2.27 (m, 1H),
3
): δ
1
9
.77-1.84 (m, 3H), 1.52 (s, 9H), 1.38 (s, 9H), 1.29 (s, 9H), 1.27 (s,
H), 1.57-1.12 (m, 3H), 1.00-0.94 (m, 1H); Anal. Calcd for
1
3
3.82 (d, J ) 10.6 Hz, 3H), 3.65 (d, J ) 10.6 Hz, 3H); C NMR
(CDCl ): δ 134.5, 132.7 (d, J ) 7.5 Hz), 129.22, (d, J ) 3.3 Hz)
C
9
37
H N O
56 2 2
AlCl: C, 71.30; H, 9.06; N, 4.49%. Found: C, 71.35; H,
.03; N, 4.53%.
.3. Asymmetric Hydrophosphonylation of Aldehydes. 3.3.1.
3
129.16 (d, J ) 2.5 Hz), 129.0 (d, J ) 4.2 Hz), 126.9 (d, J ) 2.5 Hz),
66.9 (d, J ) 160.9 Hz), 54.1 (d, J ) 7.5 Hz), 53.8 (d, J ) 7.5 Hz);
3
General Procedure for Asymmetric Hydrophosphonylation of
Aldehydes with Dimethyl Phosphite. Complex 2 (12.5 mg, 0.02 mol)
and dimethyl phosphite (10.1 µL, 0.21 mmol) were dissolved in THF
Anal. Calcd for C
H, 4.85%.
(S)-Dimethyl 1-Hydroxy-3-phenyl-2-propenylphosphonate. Color-
less solid. Yield 77% (83% ee); Mp 82.6-83.3 °C; [R] -22.1 (c
9 4
H12ClO P: C, 43.13; H, 4.83%. Found: C, 43.22;
2
4
(1.0 mL) under a nitrogen atmosphere and stirred for 10 min at 0 °C.
D
2
d
After cooling to -15 °C, aldehyde (0.20 mmol) was added to the
solution and stirred for 48 h. The reaction mixture was quenched with
3 3
1.45, CHCl ), [lit. (S)-isomer (82% ee); (c 1.0, CHCl )]; IR (KBr):
3238, 3020, 2957, 2831, 1442, 1221, 1200, 1097, 1051, 976, 843, 795,
-
1 1
1
M HCl and extracted with AcOEt (ca. 1 mL × 3). The combined
3
764, 694, 569 cm ; H NMR (CDCl ): δ 7.41-7.23 (m, 5H), 6.80
organic phases were passed through a pad of Celite and Na SO . After
2
4
(dt, J ) 5.7, 15.9 Hz, 1H), 6.34 (dd, J ) 4.7, 15.9 Hz, 1H), 4.73 (ddd,
J ) 1.5, 6.4, 15.9 Hz, 1H), 3.84 (d, J ) 10.4 Hz, 3H), 3.82 (d, J )
removal of the solvent under reduced pressure, the residue was
chromatographed on silica gel (hexane/acetone ) 7:3-3:7) to give the
corresponding R-hydroxy phosphonate. The ee values were determined
by HPLC on a chiral stationary phase under the conditions described
in ref 14.
10.4 Hz, 3H); 13C NMR (CDCl
): δ 136.0 (d, J ) 2.5 Hz), 132.5 (d,
3
J ) 3.3 Hz), 128.4, 127.8, 126.5 (d, J ) 1.7 Hz), 123.3 (d, J ) 4.2
Hz), 69.3 (d, J ) 161.8 Hz), 54.0 (d, J ) 6.7 Hz), 53.7 (d, J ) 7.5
Hz); Anal. Calcd for C11
15 4
H O P: C, 54.55; H, 6.24%. Found: C, 54.70;
(
S)-Dimethyl Phenyl(hydroxy)methylphosphonate. Colorless solid.
H, 6.11%.
2
5
Yield 87% (90% ee); Mp 95.4-95.9 °C; [R] -44.7 (c 1.50, CHCl
3
),
)]; IR (KBr): 3242, 3011,
957, 2851, 1601, 1493, 1458, 1337, 1205, 1028, 862, 839, 779, 700,
Dimethyl 1-Hydroxy-3-phenyl-2-propylphosphonate. Colorless
oil. Yield 94% (91% ee); [R] +19.4 (c 0.74, CHCl
3302, 3024, 2953, 2855, 1736, 1603, 1495, 1452, 1234, 1033, 930,
3
829, 795, 843, 748, 702 cm ; H NMR (CDCl ): δ 7.31-7.18 (m,
5H), 3.90 (m, 1H), 3.82 (d, J ) 3.7 Hz, 3H), 3.79 (d, J ) 3.7 Hz, 3H),
2.98-2.91 (m, 1H), 2.78-2.71 (m, 1H), 2.10-2.00 (m, 2H); C NMR
D
d
2
D
5
2
[
2
6
lit. (S)-isomer (85% ee); (c 1.0, CHCl
3
3
); IR (neat):
-
1
1
-1 1
73, 554 cm ; H NMR (CDCl
m, 3H), 5.05 (dd, J ) 5.4, 11.0 Hz, 1H), 4.24 (br s, 1H), 3.70 (d, J )
0.4 Hz, 3H), 3.67 (d, J ) 10.4 Hz, 3H); C NMR (CDCl
28.2 (d, J ) 2.5 Hz), 128.1(d, J ) 3.3 Hz), 126.9 (d, J ) 5.8 Hz),
0.6 (d, J ) 158.4 Hz), 54.0 (d, J ) 6.7 Hz), 53.7 (d, J ) 7.5 Hz);
3
): δ 7.50-7.48 (m, 2H), 7.39-7.30
(
1
3
13
1
1
7
3
): δ 136.2,
3
(CDCl ): δ 140.9, 128.4, 128.3, 125.9, 66.8 (d, J ) 160.1 Hz), 53.4
(d, J ) 7.5 Hz), 53.3 (d, J ) 7.5 Hz), 33.0, 31.7(d, J ) 13.4 Hz);
Anal. Calcd for C11
6.98%.
Anal. Calcd for C
.06%.
S)-Dimethyl Hydroxy(4-nitrophenyl)methylphosphonate. Color-
H O
9 13 4
P: C, 50.01; H, 6.06%. Found: C, 49.91; H,
17 4
H O P: C, 54.10; H, 7.02%. Found: C, 53.97; H,
6
(
Dimethyl 1-Hydroxy-2-methylpropylphosphonate. Colorless oil.
24
24
D
less solid. Yield 95% (94% ee); Mp 132.8-133.3 °C; [R] -57.4
c 1.20, CHCl
KBr): 3220, 2959, 2856, 1605, 1524, 1416, 1354, 1227, 1186, 1065,
3
020, 866, 826, 779, 731, 696, 563 cm ; H NMR (CDCl ): δ 8.24
Yield 89% (89% ee); [R]
2959, 1466, 2855, 1387, 1219, 1130, 1040, 829, 787 cm ; H NMR
(CDCl ): δ 3.83 (d, J ) 4.4 Hz, 3H), 3.80 (d, J ) 4.4 Hz, 3H), 3.70
(dd, J ) 6.8, 12.5 Hz, 1H), 2.57 (br s, 1H), 2.15-2.05 (m, 1H), 1.08
(d, J ) 10.5 Hz, 3H), 1.06 (d, J ) 10.5 Hz, 3H); 13C NMR (CDCl
):
+4.29 (c 0.80, CHCl
3
); IR (neat): 3312,
D
2d
-1 1
(
(
1
(
3 3
), [lit. (S)-isomer (71% ee); (c 1.0, CHCl )]; IR
3
-
1 1
d, J ) 8.5 Hz, 2H), 7.68 (dd, J ) 2.1, 8.5 Hz, 2H), 5.21 (d, J ) 5.1,
3
1
9
2.2 Hz, 1H), 4.46 (br s, 1H), 3.78 (d, J ) 9.9 Hz, 3H), 3.67 (d, J )
δ 72.9 (d, J ) 155.1 Hz), 53.2 (d, J ) 6.8 Hz), 53.0 (d, J ) 6.8 Hz),
30.2 (d, J ) 2.5 Hz), 19.9 (d, J ) 9.0 Hz), 17.8 (d, J ) 7.5 Hz); Anal.
1
3
.9 Hz, 3H); C NMR (CDCl ): δ 147.5, 143.5, 127.4 (d, J ) 5.0
3
Hz), 123.4, 70.0 (d, J ) 157.6 Hz), 54.4 (d, J ) 6.7 Hz), 53.8 (d, J )
.5 Hz); Anal. Calcd for C P: C, 41.39; H, 4.63; N, 5.36%.
Found: C, 41.37; H, 4.58; N, 5.25%.
6 15 4
Calcd for C H O P: C, 39.56; H, 8.30%. Found: C, 39.42; H, 8.28%.
7
9 6
H12NO
(S)-Dimethyl 1-Hydroxypropylphosphonate. Colorless oil. Yield
2
D
3
61% (89% ee); [R] +12.0 (c 0.94, CHCl
3
), [lit. (S)-isomer (50.8%
J. AM. CHEM. SOC.
9
VOL. 129, NO. 7, 2007 1983

A R T I C L E S
Saito et al.
2
D
5
)];28 IR (neat): 3314, 2961, 2856, 1460,
ee); [R] -4.3 (c 0.5, CHCl
2
3
Dimethyl [N-(4-Methoxy-3-methylphenyl)amino](4-methoxyphe-
nyl)methylphosphonate (8c, Table 3, Entry 3). Viscous yellowish
855, 1217, 1119, 1034, 980, 837, 779 cm- ; H NMR (CDCl
.81 (pseudo d, J ) 10.5 Hz, 6H), 3.35 (br s, 1H), 1.79 (m, 2H), 1.08
t, J ) 7.4 Hz, 3H); C NMR (CDCl
3.3 (d, J ) 5.0 Hz), 53.2 (d, J ) 5.0 Hz), 24.8, 10.4 (d, J ) 13.3 Hz);
Anal. Calcd for C P: C, 35.72; H, 7.79%. Found: C, 35.64; H,
.81%.
.4. Asymmetric Hydrophosphonylation of Imines. 3.4.1. General
1
1
3
): δ
26
3
(
oil. Yield 92% (85% ee); [R]
D
3
+43.3 (c 0.98, CHCl ); IR (neat):
1
3
3308, 2997, 2951, 2835, 1611, 1508, 1462, 1302, 1236, 1180, 1032,
3
): δ 69.2 (d, J ) 159.3 Hz),
-
1 1
8
2
2
3
3
35, 791, 754 cm ; H NMR (CDCl ): δ 7.37 (dd, J ) 2.4, 8.6 Hz,
5
H), 6.87 (d, J ) 8.6 Hz, 2H), 6.59 (d, J ) 8.5 Hz, 1H), 6.49 (d, J )
.9 Hz, 1H), 6.35 (dd, J ) 2.9, 8.5 Hz, 2H), 4.67 (d, 23.7 Hz, 1H),
.78 (s, 3H), 3.76 (d, J ) 11.0 Hz, 3H), 3.70 (s, 3H), 3.50 (d, J ) 10.5
5 13 4
H O
7
3
13
Hz, 3H), 2.11 (s, 3H); C NMR (CDCl
3
): δ 159.4, 151.3, 139.9 (d,
Procedure for Asymmetric Hydrophosphonylation of Aromatic
N-(4-Methoxy-3-methylphenyl)aldimine Derivatives with Dimethyl
Phosphite (Tables 2 and 3). Complex 2 (12.5 mg, 0.020 mmol) and
aromatic N-(4-methoxy-3-methylphenyl)aldimine (0.20 mmol) were
dissolved in THF (1 mL) at -15 °C under nitrogen. To the solution
was added dimethyl phosphite (0.30 mmol, 27.5 µL), and the mixture
J ) 15.8 Hz), 129.1 (d, J ) 5.8 Hz), 127.86, 118.0, 114.4 (d, J ) 2.5
Hz), 111.8, 111.5, 56.3 (d, J ) 153.4 Hz), 56.28, 55.6, 54.2 (d, J )
6.7 Hz), 54.1 (d, J ) 6.7 Hz), 16.9; HRFABMS. Calcd for [C18
24
H -
+
5
NO P] : m/z ) 365.1392. Found: m/z ) 365.1394.
Dimethyl [N-(4-Methoxy-3-methylphenyl)amino](4-methylphe-
nyl)methylphosphonate (8d, Table 3, Entry 4). Viscous yellowish
2
D
4
oil. Yield 95% (90% ee); [R] +44.2 (c 1.03, CHCl
3
); IR (neat):
was stirred for 24 h. The reaction was quenched with H
was extracted with AcOEt (3× ca. 1 mL), and the combined organic
phases were passed through a pad of Celite and Na SO . After
2
O, the mixture
3
1
310, 2951, 2853, 1616, 1506, 1462, 1414, 1298, 1234, 1184, 1120,
-
1 1
032, 835, 791, 756 cm ; H NMR (CDCl ): δ 7.33 (dd, J ) 2.1, 8.1
3
2
4
Hz, 2H), 7.14 (d, J ) 8.1 Hz, 2H), 6.59 (d, J ) 8.6 Hz, 1H), 6.49 (d,
J ) 2.9 Hz, 1H), 6.35 (dd, J ) 2.9, 8.6 Hz, 1H), 4.69 (dd, J ) 8.1,
concentrating the filtrate under reduced pressure, the residue was
chromatographed on silica gel (hexane/AcOEt ) 7:3-3:7) to give the
corresponding R-aminophosphonate. The ee values were determined
by HPLC on a chiral stationary phase under the conditions described
in the footnotes to Tables 2 and 3.
2
3.8 Hz, 1H), 4.41 (m, 1H), 3.76 (d, J ) 10.6 Hz, 3H), 3.69 (s, 3H),
1
3
3
.49 (d, J ) 10.6 Hz, 3H), 2.31 (s, 3H), 2.11 (s, 3H); C NMR
): δ 150.9, 139.6 (d, J ) 15.0 Hz), 137.5 (d, J ) 3.3 Hz),
32.6, 129.3 (d, J ) 2.5 Hz), 127.56, 127.47 (d, J ) 3.3 Hz), 117.6,
(CDCl
3
1
(
R)-Dimethyl [N-(4-Methoxy-3-methylphenyl)amino]phenyl-
111.4, 111.2, 56.3 (d, J ) 151.8 Hz), 55.9, 53.9 (d, J ) 6.7 Hz), 53.7
+
methylphosphonate (6f, Table 2, Entry 6). Viscous yellowish oil.
(d, J ) 6.7 Hz), 21.3, 16.5; HRFABMS. Calcd for [C18
H24NO
4
P] :
2
4
m/z ) 349.1443. Found: m/z ) 349.1409.
3
Yield 90% (87% ee); [R] +29.0 (c 1.89, CHCl ); IR (neat): 3310,
999, 2952, 2851, 1616, 1504, 1458, 1234, 1184, 1034, 835, 756, 700
cm-1; 1H NMR (CDCl
D
Dimethyl [N-(4-Methoxy-3-methylphenyl)amino](2-methylphe-
nyl)methylphosphonate (8e, Table 3, Entry 5). Viscous yellowish
2
3
): δ 7.47-7.45 (m, 2H), 7.34 (m, 2H), 7.29-
2
D
5
oil. Yield 93% (87% ee); [R] +22.7 (c 1.73, CHCl
3
); IR (neat):
7
(
1
(
1
6
6
.25 (m, 1H), 6.64 (d, J ) 8.6 Hz, 1H), 6.49 (d, J ) 2.7 Hz, 1H), 6.35
dd, J ) 2.7, 8.6 Hz, 2H), 4.73 (d, 24.2 Hz, 1H), 3.76 (d, J ) 10.7 Hz,
H), 3.49 (s, 3H), 3.48 (d, J ) 10.5 Hz, 3H), 2.11 (s, 3H); 13C NMR
CDCl ): δ 150.9, 139.5 (d, J ) 15.8 Hz), 135.7, 128.5, 127.8, 127.6,
27.5, 117.6, 111.4, 111.2, 55.6 (d, J ) 150.9 Hz), 55.9, 53.9 (d, J )
.8 Hz), 53.7 (d, J ) 6.8 Hz), 16.5; Anal. Calcd for C17 P: C,
0.89; H, 6.61; N, 4.18. Found: C, 60.81; H, 6.63; N, 4.16.
Dimethyl [N-(4-Methoxy-3-methylphenyl)amino](4-bromophe-
nyl)methylphosphonate (8a, Table 3, Entry 1). Viscous yellowish
oil. Yield quant. (95% ee); [R] +48.0 (c 1.43, CHCl
306, 2995, 2951, 1616, 1591, 1506, 1462, 1234, 1184, 1032, 839,
54 cm-1; H NMR (CDCl
J ) 2.4, 8.5 Hz, 2H), 6.64 (d, J ) 8.6 Hz, 1H), 6.59 (d, J ) 8.4 Hz,
H), 6.31 (dd, J ) 2.9, 8.4 Hz, 2H), 4.68 (d, 24.4 Hz, 1H), 3.76 (d,
J ) 10.7 Hz, 3H), 3.70 (s, 3H), 3.55 (d, J ) 10.8 Hz, 3H), 2.11 (s,
H); C NMR (CDCl
d, J ) 2.5 Hz), 129.3 (d, J ) 5.8 Hz), 127.6, 121.8 (d, J ) 4.2 Hz),
17.6, 111.4, 111.1, 56.1 (d, J ) 150.9 Hz), 55.9, 54.1 (d, J ) 6.7
3
7
312, 2951, 2831, 1616, 1506, 1443, 1234, 1182, 1124, 1032, 833,
-
1 1
93, 756 cm ; H NMR (CDCl ): δ 7.52-7.50 (m, 1H), 7.20-7.15
3
(
m, 3H), 6.58 (d, J ) 8.5 Hz, 1H), 6.45 (d, J ) 2.8 Hz, 1H), 6.28 (dd,
J ) 2.8, 8.5 Hz, 1H), 3.78 (d, J ) 10.7 Hz, 3H), 3.68 (s, 3H), 3.49 (d,
J ) 10.5 Hz, 3H), 2.49 (s, 3H), 2.10 (s, 3H); 13C NMR (CDCl
): δ
50.8, 139.5 (d, J ) 15.0 Hz), 136.1 (d, J ) 6.7 Hz), 134.0 (d, J ) 1.7
3
3
H22NO
4
1
Hz), 130.4 (d, J ) 1.7 Hz), 127.6 (d, J ) 3.3 Hz), 127.5, 126.9 (d,
J ) 4.2 Hz), 126.4 (d, J ) 3.3 Hz), 117.4, 112.2, 111.0, 55.9, 53.8 (d,
J ) 7.5 Hz), 53.7 (d, J ) 6.8 Hz), 52.6 (d, J ) 152.6 Hz), 19.8, 16.5;
2
D
5
+
HRFABMS. Calcd for [C18
H
24NO
4
P] : m/z ) 349.1443. Found:
3
); IR (neat):
m/z ) 349.1416.
3
7
1
Dimethyl [N-(4-Methoxy-3-methylphenyl)amino](2-thienyl)meth-
ylphosphonate (8f, Table 3, Entry 6). Viscous yellowish oil. Yield
3
): δ 7.46 (d, J ) 8.3 Hz, 2H), 7.34 (dd,
2
D
6
9
2
7
6
1% (84% ee); [R] +43.7 (c 1.08, CHCl
3
); IR (neat): 3312, 2951,
1
853, 1616, 1501, 1464, 1296, 1242, 1188, 1119, 1022, 826, 795, 754,
02 cm ; H NMR (CDCl
.97 (t, J ) 4.3, 4.3 Hz, 1H), 6.64 (d, 8.3 Hz, 1H), 6.55 (d, J ) 2.7
-
1 1
3
): 7.23 (d, J ) 4.4 Hz, 1H), 7.15 (m, 1H),
13
3
(
1
3
): δ 151.1, 139.1 (d, J ) 15.8 Hz), 135.0, 131.7
Hz, 1H), 6.46 (dd, J ) 2.7, 8.8 Hz, 1H), 4.99 (dd, 7.3, 23.6 Hz, 1H),
4
.26 (m, 1H), 3.79 (d, J ) 10.3 Hz, 3H), 4.26 (s, 3H), 3.63 (d, J )
Hz), 53.8 (d, J ) 7.5 Hz), 16.5; HRFABMS. Calcd for [C17
PBr] : m/z ) 413.0392. Found: m/z ) 413.0392.
H21NO
4
-
13
1
0.5 Hz, 3H), 2.13 (s, 3H); C NMR (CDCl ): δ 151.3, 139.7, 139.3
3
+
(d, J ) 13.3 Hz), 127.5, 127.0 (d J ) 2.5 Hz), 126.0 (d, J ) 7.5 Hz),
1
5
25.2 (d, J ) 4.2 Hz), 117.8, 111.7, 111.1, 55.8, 54.2 (d, J ) 6.7 Hz),
3.8 (d, J ) 7.5 Hz), 52.8 (d, J ) 159.3 Hz), 16.5; Anal. Calcd for
Dimethyl [N-(4-Methoxy-3-methylphenyl)amino](4-chlorophe-
nyl)methylphosphonate (8b, Table 3, Entry 2). Viscous yellowish
2
4
15 4
C H20NO PS: C, 52.78; H, 5.91; N, 4.10. Found: C, 53.06; H, 5.96;
N, 3.97.
3
oil. Yield 95% (95% ee); [R] +44.5 (c 1.47, CHCl ); IR (neat):
D
3
1
306, 2995, 2953, 2849, 1734, 1616, 1504, 1462, 1410, 1234, 1184,
038, 839, 777, 754 cm-1; 1H NMR (CDCl
Dimethyl [N-(4-Methoxy-3-methylphenyl)amino](2-furyl)meth-
ylphosphonate (8g, Table 3, Entry 7). Viscous yellowish oil. Yield
3
): δ 7.40 (dd, J ) 2.3, 8.3
Hz, 2H), 7.31 (d, J ) 8.3 Hz, 2H), 6.59 (d, J ) 8.6 Hz, 1H), 6.46 (d,
J ) 2.9 Hz, 1H), 6.31 (dd, J ) 2.9, 8.6 Hz, 2H), 4.70 (d, 24.2 Hz,
2
D
6
9
4% (69% ee); [R] +72.2 (c 1.21, CHCl
3
); IR (neat): 3305, 2976,
2
851, 1738, 1616, 1502, 1445, 1296, 1234, 1115, 1024, 833, 793, 746
1
H), 3.70 (s, 3H), 3.68 (d, J ) 10.7 Hz, 3H), 3.55 (d, J ) 10.5 Hz,
-
1 1
cm ; H NMR (CDCl
3
): δ 7.39 (s, 1H), 6.65 (d, J ) 8.5 Hz, 1H),
.54 (d, J ) 2.7 Hz, 1H), 6.46 (dd, J ) 2.8, 8.7 Hz, 1H), 6.37 (t, J )
.2, 3.2 Hz, 1H), 6.33 (m, 1H), 4.83 (dd, J ) 8.4, 23.8 Hz, 1H), 4.19
1
3
3
H), 2.11 (s, 3H); C NMR (CDCl ): δ 151.1, 139.2 (d, J ) 15.0
3
6
3
(
Hz), 134.4 (d, J ) 2.5 Hz), 133.6 (d, J ) 4.2 Hz), 128.9 (d, J ) 5.0
Hz), 128.8 (d, J ) 3.3 Hz), 127.6, 117.6, 111.4, 111.1, 56.1 (d, J )
br s, 1H), 3.82 (d, J ) 10.5 Hz, 3H), 3.73 (s, 3H), 3.64 (d, J ) 10.7
1
50.9 Hz), 55.9, 54.1 (d, J ) 7.5 Hz), 53.8 (d, J ) 6.8 Hz), 16.5;
Hz, 3H), 2.14 (s, 3H); 13C NMR (CDCl ): δ 151.3, 149.1 (d, J ) 1.7
3
+
HRFABMS. Calcd for [C17
H
21NO
4
PCl] : m/z ) 369.0897. Found:
m/z ) 369.0904.
(28) Zhang, Y.; Yuan, C.; Li, Z. Tetrahedron 2002, 58, 2973-2978.
1984 J. AM. CHEM. SOC.
9
VOL. 129, NO. 7, 2007

Catalytic Hydrophosphonylation of Aldehydes and Aldimines
A R T I C L E S
Hz), 142.3 (d, J ) 3.3 Hz), 139.2 (d, J ) 14.2 Hz), 127.5, 117.9, 111.8,
1H NMR (CDCl
3
): δ 7.44-7.41 (m, 4H), 7.31-7.26 (m, 4H), 7.23-
1
6
11.1, 110.7 (d, J ) 2.5 Hz), 108.7 (d, J ) 7.5 Hz), 55.8, 54.1 (d, J )
.7 Hz), 53.6 (d, J ) 6.7 Hz), 51.0 (d, J ) 160.1 Hz), 16.5; Anal.
7.17 (m, 2H), 5.28 (d, J ) 2.7 Hz, 1H), 3.78 (d, J ) 10.5 Hz, 3H),
3.75 (d, J ) 10.5 Hz, 3H), 2.86 (m, 1H), 1.96 (septet, J ) 6.6 Hz,
1H), 1.80 (br s, 1H), 1.56-1.45 (m, 2H), 0.87 (d, J ) 6.6 Hz, 3H),
5
Calcd for C15H20NO P: C, 55.38; H, 6.20; N, 4.31. Found: C, 55.14;
H, 6.22; N, 4.21.
0.63 (d, J ) 6.6 Hz, 3H); 13C NMR (CDCl
): δ 143.8, 142.8, 128.3,
3
Dimethyl [N-(4-Methoxy-3-methylphenyl)amino][2-(5-phenylfu-
ryl)]methylphosphonate (8h, Table 3, Entry 8). Viscous yellowish
127.8, 127.12, 127.07, 126.9, 64.7 (d, J ) 3.3 Hz), 52.7 (d, J ) 7.5
Hz), 52.7 (d, J ) 7.5 Hz), 49.7 (d, J ) 143.4 Hz), 24.4 (d, J ) 10.8
2
6
+
oil. Yield 95% (79% ee); [R] +74.7 (c 1.38, CHCl
3
); IR (neat):
Hz), 23.5, 21.6; HRFABMS. Calcd for [C20
H29NO
3
P] : m/z )
D
3
8
7
6
3
306, 2976, 2853, 1614, 1504, 1445, 1296, 1234, 1184, 1109, 1020,
362.1885. Found: m/z ) 362.1886.
-
1 1
35, 793, 748 cm ; H NMR (CDCl
3
): δ 7.65 (d, J ) 7.3 Hz, 2H),
Dimethyl 1-[N-(Diphenylmethyl)amino]octylphosphonate (10d,
2
D
4
.37 (t, J ) 7.7, 7.7 Hz, 2H), 7.26 (m, 1H), 6.65 (d, J ) 8.5 Hz, 1H),
.58 (d, J ) 3.2 Hz, 2H), 6.50 (dd, J ) 2.9, 8.5 Hz, 1H), 6.45 (t, J )
.3, 3.3 Hz, 1H), 4.89 (dd, J ) 6.3, 24.1 Hz, 1H), 4.23 (br s, 1H), 3.85
Table 4, Entry 4). Viscous colorless oil. Yield 83% (84% ee); [R]
-23.1 (c 1.81, CHCl
1599, 1491, 1456, 1244, 1182, 1055, 1028, 818, 746, 702 cm ; H
NMR (CDCl ): δ 7.44-7.41 (m, 4H), 7.29 (m, 4H), 7.23-7.18 (m,
3
); IR (neat): 3472, 3308, 3061, 3026, 2926, 2853,
-
1
1
(
3
)
1
d, J ) 10.7 Hz, 3H), 3.72 (s, 3H), 3.66 (d, J ) 10.7 Hz, 3H), 2.14 (s,
3
1
3
H); C NMR (CDCl
1.7 Hz), 139.2 (d, J ) 14.2 Hz), 130.4, 128.5, 127.5, 127.3, 123.5,
17.9, 111.9, 111.1, 110.8 (d, 7.5 Hz), 106.1 (d, 2.5 Hz), 55.9, 54.2
3
): δ 153.7 (d, J ) 3.3 Hz), 151.4, 148.8 (d, J
2H), 5.22 (d, J ) 1.7 Hz, 1H), 3.79 (d, J ) 10.5 Hz, 3H), 3.74 (d,
J ) 10.5 Hz, 3H), 2.85 (m, 1H), 1.83-1.72 (m, 2H), 1.63-1.50 (m,
2H), 1.37-1.17 (m, 9H), 0.88 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl
3
):
(
d, J ) 6.7 Hz), 53.8 (d, J ) 6.7 Hz), 51.3 (d, J ) 160.9 Hz), 16.5;
δ 143.5, 143.0, 128.32, 128.29, 127.6, 127.2, 127.1, 127.0, 64.7 (d,
J ) 5.8 Hz), 52.8 (d, J ) 6.7 Hz), 52.7 (d, J ) 6.7 Hz), 51.5 (d, J )
+
HRFABMS. Calcd for [C21
H
24NO
5
P] : m/z ) 401.1392. Found:
m/z ) 401.1390.
145.1 Hz), 31.9, 30.3 (d, J ) 2.5 Hz), 29.6, 29.2, 26.0 (d, J ) 10.0
+
3
.4.2. General Procedure for in Situ Asymmetric Hydrophos-
Hz), 22.8, 14.3; HRFABMS. Calcd for [C23
H35NO
3
P] : m/z )
phonylation of N-(4-Methoxy-3-methylphenyl)aldimine and N-
404.2355 Found: m/z ) 404.2328.
Diphenylmethylimine Derivatives with Dimethyl Phosphite (Table
Dimethyl 1-[N-(Diphenylmethyl)amino]-3-phenylpropargylphos-
phonate (10e, Table 4, Entry 5). Viscous colorless oil. Yield 92%
4
). To a suspension of activated MS4 Å (ca. 100 mg) in THF (1 mL)
26
were added aldehyde (0.20 mmol) and amine (0.20 mmol), and the
suspension was stirred for 3-4 h at room temperature under a nitrogen
atmosphere. To the suspension were added complex 2 (12.5 mg, 20
µmol) and dimethyl phosphite (0.30 mmol, 27.5 µL) at -15 °C, and
the mixture was stirred for 24 h at -15 °C. The reaction was quenched
(86% ee); [R]D -133.5 (c 1.36, CHCl
3
); IR (neat): 3306, 3059, 3026,
2974, 2847, 1599, 1491, 1448, 1261, 1184, 1115, 1022, 837, 812, 747,
-
1
1
696 cm ; H NMR (CDCl
3
): δ 7.48 (d, J ) 7.8 Hz, 4H), 7.42 (d,
J ) 7.8 Hz, 2H), 7.35-7.19 (m, 9H), 5.30 (s, 1H), 3.96 (d, J ) 10.7
1
3
Hz, 3H), 3.93 (br s, 1H), 3.88 (d, J ) 10.7 Hz, 3H); C NMR
(CDCl ): δ 143.2, 141.3, 131.8 (d, J ) 2.5 Hz), 128.6, 128.4, 128.2,
with H
the combined organic phases were passed through a pad of Celite and
Na SO . After concentrating the filtrate under reduced pressure, the
residue was chromatographed on silica gel (hexane/AcOEt ) 7:3-3:7
or CH Cl /AcOEt ) 19:1-9:1) to give the corresponding R-amino-
2
O, the mixture was extracted with AcOEt (3 × ca. 1 mL), and
3
127.6, 127.4, 127.2, 127.1, 122.3 (d, J ) 3.3 Hz), 86.1, 83.2 (d, J )
2
4
4.2 Hz), 64.9 (d, J ) 16.7 Hz), 54.6 (d, J ) 7.5 Hz), 54.4 (d, J ) 7.5
+
Hz), 46.9; HRFABMS. Calcd for [C24
H25NO
3
P] : m/z ) 406.1572.
2
2
Found: m/z ) 406.1563.
phosphonate. The ee values were determined by HPLC on a chiral
stationary phase under the conditions described in the footnotes to
Table 4.
Dimethyl 1-[N-(Diphenylmethyl)amino]-3-phenyl-2-propenylphos-
phonate (10f, Table 4, Entry 6). Colorless solid. Yield 51% (15%
26
ee); Mp 97.9-98.0 °C; [R] +12.0 (c 0.00, CHCl ); IR (KBr): 3275,
3
D
Dimethyl 1-[N-(4-Methoxy-3-methylphenyl)amino]-2,2-dimeth-
ylpropylphosphonate (10a, Table 4, Entry 1). Colorless solid. Yield
3059, 3026, 2951, 2847, 1597, 1489, 1450, 1240, 1180, 1074, 1034,
-
1 1
804, 766, 746, 702 cm ; H NMR (CDCl ): δ 7.45-7.16 (m, 15H),
3
2
3
2
8% (88% ee); Mp 54.0-54.1 °C; [R]D -60.5 (c 0.53, CHCl
3
); IR
6.50 (dd, J ) 4.3, 16.0 Hz, 1H), 6.15 (ddd, J ) 5.6, 8.5, 15.9 Hz, 1H),
(
KBr): 3342, 2951, 1616, 1514, 1306, 1225, 1182, 1063, 1022, 826,
5.03 (s, 1H), 3.89 (d, J ) 10.5 Hz, 3H), 3.76 (d, J ) 10.5 Hz, 3H),
-
1
1
13
7
54 cm ; H NMR (CDCl
2.9 Hz, 1H), 6.44 (dd, J ) 2.9, 8.5 Hz, 1H), 3.75 (s, 3H), 3.68 (d,
J ) 10.7 Hz, 3H), 3.66 (d, J ) 10.0 Hz, 3H), 2.17 (s, 3H), 1.10 (s,
3
): δ 6.68 (d, J ) 8.5 Hz, 1H), 6.48 (d, J
3.64 (dd, J ) 8.8, 21.7 Hz, 1H); C NMR (CDCl
3
): δ 143.4, 142.0,
)
136.1 (d, J ) 2.5 Hz), 134.6 (d, J ) 13.3 Hz), 128.6, 128.5, 128.3,
127.9, 127.5, 127.2, 127.1, 127.0, 126.9 (d, J ) 4.2 Hz), 126.4 (d, J )
2.5 Hz), 123.5 (d, J ) 5.0 Hz), 63.9 (d, J ) 15.8 Hz), 56.0 (d, J )
157.6 Hz), 53.9 (d, J ) 7.5 Hz), 53.2 (d, J ) 7.5 Hz); Anal. Calcd for
1
3
9
1
H); C NMR (CDCl
3
): δ 150.3, 141.4 (d, J ) 4.2 Hz), 127.5, 116.4,
11.4, 111.4, 61.1 (d, J ) 147.6 Hz), 56.0, 53.5 (d, J ) 7.5 Hz), 52.1
(d, J ) 7.5 Hz), 35.7 (d, J ) 7.5 Hz), 27.7 (d, J ) 6.8 Hz), 16.6; Anal.
24 3
C H26NO P: C, 70.75; H, 6.43; N, 3.44. Found: C, 70.65; H, 6.35;
Calcd for C15 P: C, 57.13; H, 8.31; N, 4.44. Found: C, 57.13;
H
26NO
4
N, 3.37.
H, 8.16; N, 4.36.
3.4.3. Deprotection of N-Protecting 4-Methoxy-3-methylphenyl
Group through Anodic Oxidation (Scheme 2). The deprotection was
carried out according to the reported procedure19 with a slight
modification; the reaction was carried out without a reference electrode.
N-Protected R-amino phosphonate 6f (144.3 mg, 0.430 mmol) was
dissolved in a mixture of CH CN (18 mL) and H O (2 mL), which
Dimethyl
[N-(4-Methoxy-3-methylphenyl)amino]cyclohexyl-
methylphosphonate (10b, Table 4, Entry 2). Colorless oil. Yield 84%
2
D
3
(
3
94% ee); [R] -14.1 (c 0.85, CHCl ); IR (neat): 3319, 2926, 2853,
-
1 1
1
616, 1506, 1448, 1414, 1232, 1184, 1124, 1032, 826, 752 cm ; H
NMR (CDCl ): δ 6.68 (d, J ) 8.6 Hz, 1H), 6.49 (d, J ) 2.9 Hz, 1H),
3
3
2
6
3
1
.45 (dd, J ) 2.9, 8.6 Hz, 1H), 3.75 (s, 3H), 3.72 (d, J ) 10.5 Hz,
4 4
contained NaClO (1 mmol) and HClO (0.859 mmol). The electrolysis
H), 3.68 (d, J ) 10.0 Hz, 3H), 3.54 (m, 2H) 1.96-1.62 (m, 6H),
was conducted at 0 °C in a divided glass cell equipped with two
platinum electrodes. The reaction was monitored by TLC analysis at
intervals of ca. 15 min until the starting material was consumed (ca. 5
h). The voltage gradually ramped up by rotating a voltage knob and
was maintained at a constant voltage after the formation of the product
was detected. After 5 h, NaHCO and anhydrous Na SO were added
1
3
.36-1.06 (m, 5H); C NMR (CDCl ): δ 150.4, 141.2 (d, J ) 5.8
3
Hz), 127.6, 116.7, 111.4, 110.7, 57.2 (d, J ) 150.1 Hz), 56.0, 53.4 (d,
J ) 6.8 Hz), 52.4 (d, J ) 7.5 Hz), 40.0 (d, J ) 5.0 Hz), 31.0 (d, J )
1
1.7 Hz), 28.5 (d, J ) 5.0 Hz), 26.4, 26.3, 26.1, 16.6; Anal. Calcd for
P: C, 59.81; H, 8.27; N, 4.10. Found: C, 59.81; H, 8.27;
17 4
C H28NO
3
2
4
N, 4.08%.
to the solution, and the mixture was stirred and evaporated carefully
under reduced pressure. The concentrate was diluted with AcOEt and
Dimethyl 1-[N-(Diphenylmethyl)amino]-3-methylbutylphospho-
nate (10c, Table 4, Entry 3). Viscous colorless oil. Yield 80% (91%
filtrated through a pad of Celite and anhydrous Na
was concentrated under reduced pressure, the residue was chromato-
graphed on silica gel (CH Cl /MeOH ) 49/1-19/1) to give the
2 4
SO . After the filtrate
2
4
3
ee); [R] -73.1 (c 1.96, CHCl ); IR (neat): 3302, 3059, 3026, 2953,
D
-
1
2
866, 1597, 1491, 1456, 1242, 1182, 1055, 1028, 812, 742, 702 cm
;
2
2
J. AM. CHEM. SOC.
9
VOL. 129, NO. 7, 2007 1985

A R T I C L E S
Saito et al.
corresponding R-amino phosphonate (66.5 mg, 72%). Its spectroscopic
data were identical to those of the reported product.
Showa Denko K.K. for the generous donation of anhydrous
tetrahydropyran.
2
2
Acknowledgment. We are grateful to Emeritus Professor
Shigeru Torii for helpful suggestions in regard to the ex-
perimental conditions for anodic oxidation of the N-(4-
methoxy-3-methylphenyl) group. B.S. and H.E. acknowledge
Research Fellowships of the Japan Society for the Promotion
of Science for Young Scientists. We thank Dr. H. Yasuda,
Supporting Information Available: Experimental data and
X-ray crystallographic data files in CIF format for complex 2.
These materials are available free of charge via the Internet at
http://pubs.acs.org.
JA0651005
1986 J. AM. CHEM. SOC.
9
VOL. 129, NO. 7, 2007