N-Phosphinyl Imine Chemistry (I): Design and Synthesis of Novel N-Phosphinyl Imines and their Application to Asymmetric aza-Henry Reaction

Article abstract of DOI:10.1111/j.1747-0285.2010.01047.x

Novel chiral N-phosphinamide and N-phosphinyl imines have been designed, synthesized and applied to asymmetric aza-Henry reaction to give excellent chemical yields (92%- quant.) and diastereoselectivity (91% to >99%de). The reaction showed a great substra

Full text of DOI:10.1111/j.1747-0285.2010.01047.x

ª 2010 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2010.01047.x
Chem Biol Drug Des 2011; 77: 20–29
Research Article
N-Phosphinyl Imine Chemistry (I): Design and
Synthesis of Novel N-Phosphinyl Imines and their
Application to Asymmetric aza-Henry Reaction
Received 19 August 2010, revised 15 September 2010 and accepted for
publication 19 September 2010
Suresh Pindi, Parminder Kaur,
Gaurav Shakya and Guigen Li*
Department of Chemistry and Biochemistry, Texas Tech University,
Lubbock, TX 79409-1061, USA
*Corresponding author: Guigen Li, guigen.li@ttu.edu
Imine chemistry has been playing a crucial role for drug develop-
ment and discovery because most drugs and their precursors con-
tain amino functionality; this places imine chemistry among the
most important and active research areas in modern organic, bioor-
ganic, and medicinal chemistry (1–12). b-Nitroamines are particu-
larly important synthetic precursors because of their easy
conversion into many other useful building blocks, such as vicinal
diamines and a-amino acids (13–17). The vicinal diamine motif has
been proven to play crucial roles in many biological systems. For
example, the diamine functionality of some opioid ligands is
responsible for their selective binding onto their receptors of l, d,
and j types for pharmacological studies in central and peripheral
nervous systems (18–20). The diamine functionality was also found
to exist in chemotherapeutical bleomycin A2 and B2 (21), glycopep-
tides (21) and edeine A1 and B1 of antibiotics (22). The evidence
indicates that chirality of diamine ligands also plays critical roles
in biological processes (20). In this work, we have shown a simple
and facile methodology for the formation of the S-enantiomer of
b-nitroamines in high enantioselectivity. There are many
approaches to chiral diamine compounds (23,24), particularly those
involving N-protected imine starting materials with various protect-
ing groups, such as Ar2CH- ⁄ Bn- (4,25–27), alkoxycarbonyl (7,28,29),
Ar2PO- (30,31), Aryl- (32–34), and ArSO2, (35–38) can be employed
Novel chiral N-phosphinamide and N-phosphinyl
imines have been designed, synthesized and
applied to asymmetric aza-Henry reaction to give
excellent chemical yields (92%
– quant.) and
diastereoselectivity (91% to >99%de). The reac-
tion showed a great substrate scope in which
aromatic ⁄ aliphatic aldehyde- and ketone-derived
N-phosphinyl imines can be employed as electro-
philes. The chiral N-phosphinamide can be stored
at room temperature for more than 2 months with-
out inert gas protection, and chiral N-phosphinyl
imines were also proven to be highly stable at
room temperature for a long period under inert
gas protection. The N-phosphinyl group enabled
the product purification to be performed simply by
washing crude product with EtOAc and hexane.
This reaction joined other eight GAP (Group-Assis-
tant-Purification) chemistry processes that were
developed in our laboratories. The absolute config-
uration has been unambiguously determined by
converting a b-nitroamine product into a known N-
Boc sample.
Ph
Ph
N
R
N
R
R
R
P
P
O
N
N
O
R1
R1
P
P
LiHMDS, THF
–78 °C, 6 – 8 h
NH
H(CH3)
O
O
N
H3C NO2
+
NO2
R
R
H(CH3)
92% - quant. yields and
91% to >99% de
Key words: aza-Henry reaction, chiral N-phosphinamide, GAP
(Group-Assistant-Purification) chemistry, N-phosphinyl imines
as both electrophiles and dienophiles for asymmetric reactions (4–
14). These protecting groups were often found to be crucial during
20

N-Phosphinyl Imine Chemistry (I)
I
Ph
Ph
N
R1
R1
R
N
R
R
R
II R2
N
N
N
R2
III
P
P
P
O
N
N
O
X
R1
R1
R1
Figure 1: Design of novel chiral N-phosphinyl imines.
Table 1: Synthetic results of chiral N-phosphinyl imines
O
P
TiCl4, Et3N
DCM, 0 oC - r.t.
O
N
P
+
R
H(CH3)
O
NH2
R
H(CH3)
4a-4l
16 h
3
a-l
Entry
R
Product
Yielda
1
2
3
4
5
6
7
8
9
Phenyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
94
75
86
92
92
88
90
91
85
82
Ndb
Ndb
p-nitrophenyl
o-fluorophenyl
p-fluorophenyl
o-bromophenyl
p-bromophenyl
o-furanyl
o-methylphenyl
p-methylphenyl
p-methoxyphenyl
t-butyl
10
11
12
4j
4k
4l
phenyl (methyl)
aIsolated yields after column chromatography.
bTi(iOPr)4 was used in place of TiCl4 for the reaction; yields are not determined as they are unstable inside silica gel column; 1H-NMR showed crude products
are nearly pure.
the control of regio-, enantio-, and chemoselectivity for asymmetric
reactions (4,7,25–38). Even though a great progress has been made
in this field, the continuous search of new imines with superior
properties for general use and for asymmetric synthesis still
remains challenging (1–12).
recovery of auxiliary for reuse; More importantly, it showed concise
purification of crude product simply by washing with common
organic solvents without the need for column chromatography or
recrystallization, which has been defined as GAP (Group-Assistant-
Purification) chemistry (40).
In the past several years, we and others have established chiral N-
phosphonyl and N-phosphoryl imine chemistry (39–50) and sub-
sequently applied this chemistry to a series of asymmetric C-C bond
formations via carbonyl-type additions including asymmetric catalytic
Strecker reaction of achiral N-phosphonyl imines (39,40). These
reactions have resulted in versatile chiral amino building blocks in
good to excellent chemical yields and diastereo- and enantioselec-
tivities. During continuing study of this chemistry, we encountered
difficulty preparing aliphatic aldehyde- and ketone-derived N-phos-
phonyl imines; this prompted us to continue the search for new imi-
nes to overcome this problem. In this communication, we are
pleased to present the design and synthesis of novel chiral N-phos-
phinyl imines of C2 symmetry and their application to asymmetric
aza-Henry reaction (Figure 1 and Tables 1 and 2). This special
N-phosphinyl group showed efficient and easy deprotection and
As shown in Figure 1, these novel imines are anticipated to serve
as a new family of C=N electrophiles and dienophiles for advanced
synthesis and asymmetric catalysis. The design of new imines is
mainly divided into three regions: I, II, and III. Region I has been
conducted by using 1,2-cyclohexyl and 1,2-diphenyl groups; X can
be oxygen or sulfur atom. For region II, both primary and secondary
alkyl groups have been employed for attaching onto nitrogens so
far. The two amino centers become chiral after they are forced by
their neighboring chiral carbon centers in region I (39–46). It is
envisioned that directly introducing carbons to replace correspond-
ing pro-chiral nitrogens would lead to efficient asymmetric induction
for many reactions (51,52). At the same time, this design generates
N-phosphinyl imines instead of N-posphonyl or N-posphoryl ones so
as to lead to the successful preparation of aliphatic aldehyde- and
ketone-derived imines.
Chem Biol Drug Des 2011; 77: 20–29
21

Pindi et al.
Table 2: Results of asymmetric aza-Henry reaction using N-phosphinyl imines
P
P
LiHMDS, THF
-78 oC, 6 - 8 h
O
NH
H(CH3)
O
N
H3C NO2
+
NO2
R
R
H(CH3)
4a-4k, 4l
5
6a-6k, 6l
Entry
Substrate
R
Product
Yielda,b
dec
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
Phenyl
6a
6b
6c
6d
6e
6f
6g
6h
6i
96
Quant
96
94
p-nitrophenyl
o-fluorophenyl
p-fluorophenyl
o-bromophenyl
p-bromophenyl
o-furanyl
o-mehtylphenyl
p-mehtylphenyl
p-mehtoxyphenyl
t-butyl
>99
>99
98
>99
94
91
97
>99
94
96
92
Quant
Quant
Quant
96
98
94
10
11
12
4j
4k
4l
6j
6k
6l
96
94
phenyl (methyl)
>99
aIsolated yields after washing with ethylacetate.
bCombined yields of the two diastereomers.
cGreater than 99%de means only single isomer was observed based on 31P-NMR analysis of crude samples.
(COCl)2, DCM
0°C -RT, 10h
Ph
Ph
NH3, DCM
Ph
Ph
Ph
P
Ph
P
P
O
Cl
O
OH
O
NH2
–78°C-RT, 12h
2
1
3
Scheme 1: Synthesis of (2S,5S )-diphenyl N-phosphinamide.
Asymmetric aza-Henry reaction was chosen as the model reaction
for this initial study because this reaction has become a highly
active topic in asymmetric synthesis recently (53–56). The corre-
sponding b-nitroamines can be converted into a series of amino
compounds, such as vicinal diamines and a-amino acids, that are
common structural motifs present in biologically active compounds
and natural products (55,56). This reaction also serves as the model
reaction for asymmetric catalytic systems using organometallic and
organocatalysts (57–60).
obtained from Aldrich and used as obtained from commercial
sources without any further purification. Flash chromatographic col-
umns were carried out on silica gel 60, (230–400 mesh).
Preparation of chiral phosphinamide
Chiral phosphinamide (3) was prepared starting from phosphinic
chloride (2), which required the synthesis of phosphinic acid (1).
Phosphinic acid was synthesized using the known procedure (61).
Initially, phosphinic chloride was synthesized as shown in
Scheme 1.
Experimental Section
In a 100-mL oven-dried round-bottomed flask, phosphinic acid (1)
(6.0 g, 22.08 mmol) was loaded. This was purged with nitrogen and
then anhydrous dichloromethane (60 mL) was added. The suspen-
sion was brought to 0 ꢀC, and oxalyl chloride (7.7 mL, 88.32 mmol)
was added with syringe pump for 30 min. Then, reaction mixture
was slowly brought to room temperature and stirred for 10 h. Sol-
vent was evaporated, and trituration with hexane afforded phosphi-
nic chloride (2) as a white solid.
General remarks
All commercially available solvents, unless otherwise mentioned,
were used without purification. THF was distilled from sodium ⁄ ben-
zophenone ketyl. All the glasswares used were dried overnight at
100 ꢀC. All melting points are uncorrected. The NMR spectra were
recorded at 500, 125, and 202 MHz for H, 13C, and 31P, respectively.
1
Shifts are reported in ppm based on an internal TMS standard (for
1H ⁄ CDCl3) or on residual solvent peaks (for 13C ⁄ CDCl3). 31P NMR
spectra were referenced to external H3PO4 (0.00 ppm). LiHMDS,
KHMDS, LDA, and n-BuLi were obtained from Acros. Nitromethane
and titanium (IV) chloride (1.0 M solution in dichloromethane) were
A 250-mL round-bottomed flask was loaded with phosphinic chlo-
ride (2) (5.0 g, 18.4 mmol) and anhydrous dichloromethane (60 mL).
Then, the flask was equipped with dewar condenser. The solution
22
Chem Biol Drug Des 2011; 77: 20–29

N-Phosphinyl Imine Chemistry (I)
was cooled to )78 ꢀC, and ammonia gas was condensed using
dewar and approximately 6 mL was added. Then, reaction mixture
was stirred at )78 ꢀC for 5 h and allowed to warm slowly to room
temperature and stirred for another 7 h. The solution was diluted
with dichloromethane and filtered through celite pad and solvent
evaporated under vacuum. A pale yellow solid was obtained, and
recrystallization with ethylacetate afforded phosphinamide (3) as
white cottony crystals.
129.8, 128.9 (d, J = 5.4 Hz), 128.7, 128.6 (d, J = 2.0 Hz), 128.3,
126.7 (d, J = 2.4 Hz), 126.6 (d, J = 2.5 Hz), 49.3, 48.6, 45.3, 44.9,
32.4 (d, J = 9.4 Hz), 28.7 (d, J = 8.9 Hz). 31P NMR (202 MHz, CDCl3)
d 57.1.
HRMS (ESI): m ⁄ z calcd for C23H23NOP, 360.1512 [M+Na]+, found:
360.1524.
Compound 4b sticky liquid; yield (0.167 g, 75%);
1
Compound 3 White crystals; yield (4.57 g, 98%); mp 190–
[a]D = )53.60 (c 0.5, CHCl3); H NMR (500 MHz, CDCl3) d 8.77 (d,
24
1
192 ꢀC,[a]D = )101.00 (c 0.6, CHCl3); H NMR (500 MHz, CDCl3) d
J = 31.5 Hz, 1H), 8.24-8.22 (m, 2H), 7.82-7.80 (m, 2H), 7.35-7.33 (m,
4H), 7.32-7.30 (m, 2H), 7.27-7.19 (m, 3H), 7.11-7.08 (m, 1H), 3.71-
3.58 (m, 2H), 2.79-2.69 (m, 1H), 2.61-2.38 (m, 3H); 13C NMR
24
7.38-7.31 (m, 8H), 7.29-7.23 (m, 2H), 3.53-3.45 (m, 1H), 3.09-3.02
(m, 1H), 2.55-2.32 (m, 4H), 2.25-2.16 (m, 1H), 2.12-2.03 (m, 1H); 13C
NMR (125 MHz, CDCl3)
d
136.8 (d, J = 5.0 Hz), 136.6 (d,
(125 MHz, CDCl3) d 172.1 (d, J = 9.0 Hz), 150.2, 140.3 (d,
J = 5.6 Hz), 128.8 (d, J = 2.5 Hz), 128.8 (d, J = 5.4 Hz), 128.5
(d, J = 1.5 Hz), 127.7 (d, J = 4.4 Hz), 126.9 (d, J = 3.0 Hz), 126.8 (d,
J = 2.5), 47.9, 47.3, 46.5, 45.8, 31.1 (d, J = 10.4 Hz), 27.3 (d,
J = 10.4 Hz). 31P NMR (202 MHz, CDCl3) d 54.9.
J = 24.7Hz), 136.1 (d, J = 4.5Hz), 135.1 (d, J = 6.0), 130.2, 128.9 (d,
J = 5.4 Hz), 128.6 (d, J = 1.5 Hz), 128.3 (d, J = 2.0 Hz), 127.9 (d,
J = 4.5Hz), 127.0 (d, J = 2.5 Hz), 126.8 (d, J = 3.0 Hz), 123.8, 49.1,
48.5, 45.3, 44.6, 32.4 (d, J = 9.9 Hz), 28.1 (d, J = 9.4 Hz). 31P NMR
(202 MHz, CDCl3) d 58.0.
HRMS (ESI): m ⁄ z calcd for C16H18NNaOP, 294.1018 [M+Na]+, found:
294.1019.
Compound 4c white solid; yield (0.179 g, 86%); mp 118–
120 ꢀC, [a]D = )54.60 (c 0.6, CHCl3); 1H NMR: d 9.07 (d,
24
J = 32.5 Hz, 1H), 7.82 (t, J = 2.0 Hz, 1H), 7.49-7.02 (m, 13H), 3.82-
3.55 (m, 2H), 2.78-2.37 (m, 4H). 13C NMR: d 168.2 (d, J = 11.8 Hz),
164.6, 162.5, 136.6 (d, J = 9.8 Hz), 135.6 (d, J = 10.0 Hz), 135.18,
135.11, 128.9, 128.6 (d, J = 8.0 Hz), 129.4 (d, J = 10.0 Hz), 128.25,
128.24, 128.14, 128.10, 126.9 (d, J = 8.4 Hz), 126.6 (d, J = 9.0 Hz),
124.2 (d, J = 7.5 Hz), 116.2, 116.1, 49.2 (d, J = 23.0 Hz), 45.5 (d,
J = 21.8 Hz), 32.4 (d, J = 9.5 Hz), 28.5 (d, J = 6.0 Hz). 31P NMR: d
56.83.
General procedure for the synthesis of chiral
N-phosphinyl imine (4a-4j)
In a dry vial, under inert gas protection, phosphinamide (3) (1.0
equiv.) was taken and dissolved in dry dichloromethane. To the
solution, corresponding aldehyde (1.5equiv.) was added followed by
the addition of triethylamine (3.0 equiv.). The reaction was cooled
to 0 ꢀC and titanium (IV) chloride (1.0 M solution in DCM, 0.5
equiv.) was added to the reaction (Scheme 2). The reaction was
stirred at room temperature for 16–20 h and after that the mixture
was loaded directly to silica gel. The reaction mixture was purified
through column chromatography (ethyl acetate ⁄ hexane ⁄ 1% Et3N).
Pure product was obtained by eluting the reaction mixture with
ethyl acetate ⁄ hexane ⁄ triethylamine (60:40:1 mL) as white or pale
yellow solid in all of the cases reported.
Compound 4d sticky solid; yield (0.192 g, 94%); [a]D = )48.20
24
(c 0.6, CHCl3); 1H NMR: d 8.71 (d, J = 33.0 Hz, 1H), 7.70 (t,
J = 1.5 Hz, 1H), 7.34-7.07 (m, 13H), 3.61-3.55 (m, 2H), 2.74-2.32 (m,
4H). 13C NMR: d 165.2 (d, J = 11.8 Hz), 162.4, 136.8, 135.8 (d,
J = 9.8 Hz), 135.6 (d, J = 10.0 Hz), 135.2, 135.0, 127.8, 127.4 (d,
J = 8.0 Hz), 127.0 (d, J = 10.0 Hz), 126.5, 126.4, 126.1, 126.0, 125.8
(d, J = 8.0 Hz), 125.7 (d, J = 9.5 Hz), 125.2 (d, J = 6.5 Hz), 116.8,
116.3, 47.2 (d, J = 20.0 Hz), 43.5 (d, J = 21.0 Hz), 33.4 (d,
J = 9.0 Hz), 28.1 (d, J = 6.0 Hz). 31P NMR: d 56.63.
Preparation of aliphatic and ketimines 4k, 4l
In a round-bottomed flask, the chiral phosphinamide (1.0 equiv.)
was taken and Ti(OiPr)4 (1.5 equiv.) was then added to it. The flask
was evacuated and protected with N2 atmosphere. The dry toluene
(6 mL) was added to the flask followed by the addition of triethyl-
amine (3.0 equiv.). Finally, the corresponding aliphatic aldehyde or
ketone (1.3 equiv.) was added to the mixture and the reaction mix-
ture was refluxed overnight. The reaction completion was monitored
by crude NMR. Upon completion of the reaction, the solvent was
dried under vacuum and crude imine was used for the final aza-
Henry reaction.
Compound 4e pale yellow solid; yield (0.220 g, 92%); mp 105–
1
107 ꢀC, [a]D = )36.00 (c 0.6, CHCl3); H NMR (500 MHz, CDCl3) d
24
9.05 (d, J = 32.0 Hz, 1H), 7.82-7.79 (m, 1H), 7.56-7.52 (m, 1H), 7.37-
7.35 (m, 4H), 7.34-7.31 (m, 4H), 7.28-7.21 (m, 3H), 7.13-7.09 (m, 1H),
3.70-3.55 (m, 2H), 2.76-2.65 (m, 1H), 2.59-2.35 (m, 3H); 13C NMR
(125 MHz, CDCl3) d 173.6 (d, J = 8.4 Hz), 136.6 (d, J = 4.0 Hz), 135.6
(d, J = 6.0 Hz), 134.1, 133.5, 129.4, 128.9 (d, J = 5.4 Hz), 128.7
(d, J = 2.0 Hz), 128.3 (d, J = 2.0 Hz), 128.0 (d, J = 5.0 Hz), 127.4,
127.0 (d, J = 2.5 Hz), 126.7 (d, J = 2.4 Hz), 49.1, 48.5, 45.5, 44.9,
32.4 (d, J = 9.9 Hz), 28.3 (d, J = 8.9 Hz). 31P NMR (202 MHz, CDCl3)
d 56.9.
Compound 4a White solid; yield (0.186 g, 94%); mp 102–
1
104 ꢀC, [a]D = )44.66 (c 0.6, CHCl3); H NMR (500 MHz, CDCl3) d
24
8.74 (d, J = 33.0 Hz, 1H), 7.71-7.69 (m, 2H), 7.52-7.49 (m, 1H), 7.43-
7.38 (m, 2H), 7.38-7.29 (m, 6H), 7.29-7.23 (m, 1H), 7.23-7.19, (m,
2H), 7.11-7.07 (m, 1H), 3.66-3.53 (m, 2H), 2.76-2.66 (m, 1H), 2.58-
2.34 (m, 3H); 13C NMR (125 MHz, CDCl3) d 174.5 (d, J = 9.4 Hz),
136.7 (d, J = 4.4 Hz), 135.7 (d, J = 6.0 Hz), 135.6, 135.4, 133.3,
HRMS (ESI): m ⁄ z calcd for C23H22BrNOP, 438.0617, found: 438.0625.
Compound 4f pale yellow solid; yield (0.213 g, 88%); mp 138–
1
140 ꢀC, [a]D = )46.00 (c 0.6, CHCl3); H NMR (500 MHz, CDCl3) d
24
8.67 (d, J = 32.0 Hz, 1H), 7.55 (s, 4H), 7.36-7.33 (m, 4H), 7.32-7.26
Chem Biol Drug Des 2011; 77: 20–29
23

Pindi et al.
(m, 3H), 7.25-7.22 (m, 1H), 7.22-7.19 (m, 2H), 7.11-7.08 (m, 1H),
3.66-3.49 (m, 2H), 2.76-2.66 (m, 1H), 2.58-2.35 (m, 3H); 13C NMR
(125 MHz, CDCl3) d 173.2 (d, J = 9.4 Hz), 136.5 (d, J = 4.0 Hz),
135.6 (d, J = 6.0 Hz), 134.2 (2C), 132.1, 130.9, 128.9 (d, J = 5.4 Hz),
128.6 (d, J = 1.9 Hz), 128.3, 128.2 (d, J = 2.5 Hz), 128.1 (d,
J = 4.5 Hz), 126.9 (d, J = 2.5 Hz), 126.7 (d, J = 2.5 Hz), 49.2, 48.6,
45.5, 44.8, 32.4 (d, J = 9.4 Hz), 28.5 (d, J = 9.4 Hz). 31P NMR
(202 MHz, CDCl3) d 57.3.
J = 3.4 Hz), 136.1 (d, J = 6.0 Hz), 131.9, 128.9 (d, J = 5.4 Hz), 128.6
(d, J = 2.0 Hz), 128.3 (d, J = 4.4 Hz), 128.1 (d, J = 2.0 Hz), 126.8 (d,
J = 2.0 Hz), 126.5 (d, J = 2.5 Hz), 114.1, 55.5, 49.3, 48.7, 45.7,
45.0, 32.3 (d, J = 9.4 Hz), 28.9 (d, J = 8.9 Hz). 31P NMR (202 MHz,
CDCl3) d 56.8.
Typical procedure for aza-Henry reaction with
chiral N-phosphinyl imines
HRMS (ESI): m ⁄ z calcd for C23H22BrNOP, 438.0617, found: 438.0619.
A oven-dried reaction vial was purged with nitrogen and loaded
with nitromethane (0.03 mL, 0.556 mmol) and 3 mL of dry THF. The
reaction vial was cooled to )78 ꢀC, and 1 M solution of LiHMDS
(0.278 mL, 0.278 mmol) was added slowly. The reaction mixture
was stirred at the same temperature for 45 min. Then, predissolved
solution of imine in dry THF (3 mL) was added slowly. Stirring was
continued at )78 ꢀC for 8 h. At this temperature, reaction was
quenched with 2 mL of NH4Cl followed by 10 mL of water. Then
the aqueous layer was extracted with 2 · 10 mL of ethylacetate.
After extraction, the organic layer was washed with brine and dried
over Na2SO4. The solvent was evaporated to obtain pale yellow
solid, which was washed with minimum amount of ethylacetate fol-
lowed by hexanes to afford the pure product as a white solid with-
out any further purification.
Compound 4g sticky liquid; yield (0.174 g, 90%);
1
[a]D = )54.62 (c 0.5, CHCl3); H NMR (500 MHz, CDCl3) d 8.43 (d,
24
J = 33.5 Hz, 1H), 7.61-7.60 (m, 1H), 7.36-7.30 (m, 7H), 7.29-7.21 (m,
3H), 7.14-7.10 (m, 1H), 6.91 (d, J = 3.5 Hz, 1H), 6.50 -6.49 (m, 1H),
3.68-3.56 (m, 2H), 2.73-2.63 (m, 1H), 2.53-2.31 (m, 4H); 13C NMR
(125 MHz, CDCl3) d 160.2 (d, J = 8.0 Hz), 151.9 (d, J = 28.6 Hz),
147.6, 136.7 (d, J = 3.9 Hz), 135.6 (d, J = 5.9 Hz), 128.9 (d,
J = 5.5 Hz), 128.5, 128.2 (2C), 126.8 (d, J = 2.4 Hz), 126.6
(d, J = 2.5 Hz), 121.4, 112.6, 49.3, 48.7, 45.5, 44.8, 32.4 (d,
J = 9.4 Hz), 28.3 (d, J = 9.4 Hz). 31P NMR (202 MHz, CDCl3) d 58.3.
HRMS (ESI): m ⁄ z calcd for C21H20NNaO2P, 372.1123 [M+Na]+, found:
372.1128.
Compound 6a White solid; yield (0.056 g, 96%); mp 195–
1
Compound 4h white solid; yield (0.187 g, 91%); mp 163–
197 ꢀC,[a]D = )77.00 (c 0.6, CHCl3); H NMR (500 MHz, CDCl3) d
24
1
165 ꢀC, [a]D = )56.00 (c 0.6, CHCl3); H NMR (500 MHz, CDCl3) d
7.34-7.31 (m, 2H), 7.29-7.14 (m, 11H), 6.79-6.78 (m, 2H), 4.50-4.44 (m,
1H), 4.35-4.28 (m, 2H), 3.61-3.53 (m, 1H), 3.32 (t, J = 10.0 Hz, 1H)
3.01-2.95 (m, 1H), 2.53-2.39 (m, 2H), 2.26-2.17 (m, 1H), 2.12-2.03 (m,
1H); 13C NMR (125 MHz, CDCl3) d 137.7 (d, J = 4.0 Hz), 136.1 (d,
J = 5.9 Hz), 135.9 (d, J = 5.0 Hz), 129.0 (d, J = 2.4 Hz), 128.8 (d,
J = 5.4 Hz), 128.7, 128.6 (d, J = 1.5 Hz), 128.1, 127.5 (d, J = 5.0 Hz),
127.1 (d, J = 3.0 Hz), 127.0 (d, J = 2.5 Hz), 126.1, 80.8 (d,
J = 3.4 Hz), 52.4 (d, J = 1.0 Hz), 47.9, 47.3, 47.0, 46.4, 30.6 (d,
J = 11.4 Hz), 27.2 (d, J = 9.9 Hz),. 31P NMR (202 MHz, CDCl3) d 56.3.
24
9.54 (d, J = 33.3 Hz, 1H), 7.80-7.77 (m, 1H), 7.42-7.11 (m, 13H),
3.72-3.56 (m, 2H), 2.79-2.38 (m, 7H); 13C NMR (125 MHz, CDCl3) d
173.9 (d, J = 9.4 Hz), 141.1, 137.2, 136.4 (d, J = 6.0 Hz), 133.1,
133.7, 133.3, 131.6, 129.7, 129.4 (d, J = 5.4 Hz), 129.1, 128.7 (d,
J = 2.2 Hz), 128.6 (d, J = 4.5 Hz), 127.3, 127.0, 126.5, 49.8, 48.7,
46.4, 45.4, 32.9 (d, J = 9.1 Hz), 28.9 (d, J = 8.9 Hz), 19.9. 31P NMR
(202 MHz, CDCl3) d 57.2.
HRMS (ESI): m ⁄ z calcd for C24H24NNaOP, 396.1488 [M+Na]+, found:
396.1490.
HRMS (ESI): m ⁄ z calcd for C24H25N2NaO3P, 443.1490 [M+Na]+,
found: 443.1492.
Compound 4i white solid; yield (0.175 g, 85%); mp 145–147 ꢀC,
1
[a]D = )62.40 (c 0.6, CHCl3); H NMR (500 MHz, CDCl3) d 8.70 (d,
Compound 6b White solid; yield (0.057 g, quantitative); mp
24
1
J = 33.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.38-7.32 (m, 6H), 7.27-7.19
(m, 5H), 7.11-7.07 (m, 1H), 3.65-3.55 (m, 2H), 2.75-2.64 (m, 1H), 2.57-
2.42 (m, 2H), 2.41-2.34 (m, 4H); 13C NMR (125 MHz, CDCl3) d 174.1 (d,
J = 9.4 Hz), 144.2, 136.8 (d, J = 4.0 Hz), 135.9 (d, J = 5.9 Hz), 133.2,
132.9, 129.9, 129.4, 128.9 (d, J = 5.4 Hz), 128.6 (d, J = 1.5 Hz), 128.3
(d, J = 5.0 Hz), 128.2 (d, J = 2.0 Hz), 126.8 (d, J = 2.4 Hz), 126.6 (d,
J = 2.5 Hz), 49.3, 48.7, 45.6, 44.9, 32.3 (d, J = 9.4 Hz), 28.8 (d,
J = 8.9 Hz), 21.8. 31P NMR (202 MHz, CDCl3) d 56.9.
208–210 ꢀC,[a]D = )57.8 (c 0.8, CHCl3); H NMR (500 MHz, CDCl3)
24
d 7.97-7.96 (m, 2H), 7.38-7.21 (m, 10H), 6.89 (d, J = 9.0 Hz, 2H),
4.74-4.68 (m, 1H), 4.52-4.42 (m, 2H), 3.62-3.53 (m, 1H), 3.36 (t,
J = 11.0 Hz, 1H) 3.04-2.97 (m, 1H), 2.58-2.43 (m, 2H), 2.29-2.20 (m,
1H), 2.14-2.05 (m, 1H); 13C NMR (125 MHz, CDCl3) d 147.4, 144.7
(d, J = 3.9 Hz), 136.2 (d, J = 5.9 Hz), 135.4 (d, J = 5.4 Hz), 129.2 (d,
J = 2.5 Hz), 128.8 (d, J = 1.5 Hz), 128.7 (d, J = 5.4 Hz), 127.5 (d,
J = 4.5 Hz), 127.3 (d, J = 2.4 Hz), 127.3 (d, J = 3.0 Hz), 127.1,
123.7, 80.5 (d, J = 2.9 Hz), 51.5, 48.0 (d, J = 7.4 Hz), 47.4 (d,
J = 7.9 Hz), 30.5 (d, J = 11.9 Hz), 27.3 (d, J = 10.4 Hz),. 31P NMR
(202 MHz, CDCl3) d 56.9.
HRMS (ESI): m ⁄ z calcd for C24H25NOP, 374.1674 [M+H]+, found:
374.1660.
Compound 4j pale yellow solid; yield (0.176 g, 82%); mp 136–
HRMS (ESI): m ⁄ z calcd for C24H24N3NaO5P, 488.1351 [M+Na]+,
found: 488.1344.
1
138 ꢀC, [a]D = )106.00 (c 0.25 CHCl3); H NMR (500 MHz, CDCl3)
24
d 8.65 (d, J = 33.0 Hz, 1H), 7.68-7.65 (m, 2H), 7.36-7.33 (m, 6H),
7.26-7.19 (m, 3H), 7.10-7.07 (m, 1H), 6.92-6.89 (m, 2H), 3.85 (s, 3H),
3.62-3.54 (m, 2H), 2.73-2.62 (m, 1H), 2.57-2.31 (m, 3H); 13C NMR
Compound 6c White solid; yield (0.056 g, 96%); mp 178–
180 ꢀC; [a]D = )60.52 (c 0.6, CHCl3) 1H NMR: d 7.37-7.17 (m,
24
(125 MHz, CDCl3)
d
173.2 (d, J = 8.9 Hz), 163.8, 136.9 (d,
12H), 6.946-6.944 (m, 2H), 6.75 (t, J = 4.5 Hz, 1H), 4.74-4.68 (m,
24
Chem Biol Drug Des 2011; 77: 20–29

N-Phosphinyl Imine Chemistry (I)
1H), 4.43-4.34 (m, 2H), 3.59-3.50 (m, 1H), 3.34 (t, J = 11.0 Hz, 1H),
3.05-2.98 (m, 1H), 2.56-2.38 (m, 2H), 2.38-2.18 (m, 1H), 2.12-2.03
(m, 1H). 13C NMR: d 160.9, 158.9, 135.8, 129.9 (d, J = 10.8 Hz),
128.9 (d, J = 9.8 Hz), 128.86 (d, J = 7.8 Hz), 128.80 (d, J = 6.5 Hz),
128.7 (d, J = 10.5 Hz), 127.3 (d, J = 10.3 Hz, 2C), 127.1 (d,
J = 8.0 Hz), 127.0 (d, J = 7.0 Hz), 124.5 (d, J = 11.0 Hz), 115.6,
115.5, 79.8, 48.7, 47.2, 46.6, 30.7 (d, J = 8.0 Hz), 27.2 (d,
J = 4.9 Hz), 127.1 (d, J = 1.9 Hz), 110.5, 107.6, 78.6 (d, J = 3.5 Hz),
77.2, 77.0, 76.7, 47.9, 47.3, 47.1, 46.9, 30.6 (d, J = 11.9 Hz), 27.2.
31P NMR (202 MHz, CDCl3) d 56.0.
HRMS (ESI): m ⁄ z calcd for C22H24N2O4P, 411.1474 [M+H]+, found:
411.1490.
J = 6.0 Hz), 27.6 (d, J = 9.8 Hz), 27.3, 27.2. 31P NMR:
d
Compound 6h White solid; yield (0.055 g, 96%); mp 174–
55.70.HRMS (ESI): m ⁄ z calcd for C24H25FN2O3P 439.1587 [M+H]+,
176 ꢀC,[a]D = )83.01 (c 0.5, CHCl3); H NMR (500 MHz, CDCl3) d
1
24
found: 439.1563.
7.40-7.01 (m, 13H), 6.82-6.79 (m, 1H), 4.89-4.78 (m, 1H), 4.37-4.25
(m, 2H), 3.60-3.38 (m, 2H), 3.10-2.99 (m, 1H), 2.58-2.35 (m, 2H),
Compound 6d White solid; yield (0.053 g, 92%); mp 198–
2.29-2.05 (m, 5H); 13C NMR (125 MHz, CDCl3)
d 136.1 (d,
200 ꢀC, [a]D = )68.40 (c 0.6, CHCl3); 1H NMR: d 7.34-7.26 (m,
J = 5.4 Hz), 135.9 (2C), 134.6, 130.7, 128.8 (d, J = 2.5 Hz), 128.8 (d,
J = 5.5 Hz), 128.5 (d, J = 2.0 Hz), 127.9, 127.4 (d, J = 5.0 Hz), 127.0
(d, J = 2.5 Hz), 126.9 (d, J = 2.5 Hz), 126.5, 125.2, 80.3 (d,
J = 5.0 Hz), 48.9, 47.9, 47.3, 46.9, 46.2, 30.7 (d, J = 11.4 Hz), 27.4
(d, J = 9.9 Hz), 18.9. 31P NMR (202 MHz, CDCl3) d 55.7.
24
10H), 6.83-6.78 (m, 2H), 6.68-6.59 (m, 2H), 4.78-464 (m, 1H), 4.39-
4.26 (m, 2H), 3.63-3.52 (m, 1H), 3.36 (t, J = 10.0 Hz, 1H), 3.29-3.12
(m, 1H), 2.62-2.14 (m, 4H). 13C NMR: d 163.2, 161.3, 136.1, 135.7
(d, J = 4.8 Hz), 133.4, 129.0 (d, J = 9.8 Hz, 2C), 128.7 (d,
J = 10.5 Hz), 128.6 (d, J = 11.5 Hz, 2C), 127.9 (d, J = 12.3 Hz, 2C),
127.5 (d, J = 10.0 Hz, 2C), 127.1 (d, J = 12.0 Hz), 80.8, 51.7, 47.9,
47.3, 46.7, 30.5 (d, J = 11.0 Hz), 29.6 (2C), 27.3 (d, J = 9.8 Hz). 31P
NMR: d 56.43. HRMS (ESI): m ⁄ z calcd for C24H24FN2NaO3P
461.1406 [M+Na]+, found: 461.1402.
Compound 6i White solid; yield (0.057 g, 98%); mp 188–
1
190 ꢀC,[a]D = )79.00 (c 0.6, CHCl3); H NMR (500 MHz, CDCl3) d
24
7.36-7.25 (m, 10H), 6.97 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 8.0 Hz,
2H), 4.48-4.37 (m, 2H), 4.34-4.29 (m, 1H), 3.61-3.53 (m, 1H), 3.08 (t,
J = 10.0 Hz, 1H), 3.01-2.94 (m, 1H), 2.53-2.38 (m, 2H), 2.27 (s, 3H),
2.25-2.18 (m, 1H), 2.11-2.02 (m, 1H); 13C NMR (125 MHz, CDCl3) d
137.9, 136.2 (d, J = 5.9 Hz), 136.0 (d, J = 5.5 Hz), 134.6 (d,
J = 3.4 Hz), 129.4, 129.1 (d, J = 2.5 Hz), 128.8 (d, J = 5.4 Hz), 128.6
(d, J = 2.0 Hz), 127.5 (d, J = 4.5 Hz), 127.1 (d, J = 3.0 Hz), 127.0 (d,
J = 2.4 Hz), 125.9, 80.8 (d, J = 4.0 Hz), 55.2 (d, J = 1.5 Hz), 48.0,
47.4, 47.1, 46.5, 30.7 (d, J = 11.4 Hz), 27.3 (d, J = 10.4 Hz), 21.0.
31P NMR (202 MHz, CDCl3) d 55.7.
Compound 6e White solid; yield (0.057 g, quantitative); mp
210–212 ꢀC,[a]D = )83.00 (c 0.6, CHCl3); 1H NMR (500 MHz,
24
CDCl3) d 7.48-7.43 (m, 1H), 7.35-7.15 (m, 12H), 6.99-6.94 (m, 1H),
4.92-4.81 (m, 1H), 4.38 (dd, J1 = 6.0 Hz, J2 = 12.9 Hz 1H), 4.32 (dd,
J1 = 4.5 Hz, J2 = 12.6 Hz 1H), 3.96-3.89 (m, 1H), 3.69-3.55 (m, 1H),
3.05-2.94 (m, 1H), 2.61-2.40 (m, 2H), 2.32-2.13 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 136.4 (d, J = 2.4 Hz), 135.8, 135.7, 133.0,
129.8, 128.9 (d, J = 2.4 Hz), 128.8 (d, J = 3.4 Hz), 128.6 (d,
J = 1.9 Hz), 127.9, 127.3 (d, J = 4.4 Hz), 127.1 (d, J = 3.0 Hz), 126.9
(d, J = 2.0 Hz), 121.9, 79.2 (d, J = 5.0 Hz), 52.0, 47.7, 47.1, 46.5,
45.9, 30.7 (d, J = 11.4 Hz), 27.1 (d, J = 9.9 Hz). 31P NMR (202 MHz,
CDCl3) d 56.4.
HRMS (ESI): m ⁄ z calcd for C25H27N2NaO3P, 457.1657 [M+Na]+,
found: 457.1667.
Compound 6j White solid; yield (0.054 g, 94%); mp 210–
1
212 ꢀC,[a]D = )82.00 (c 0.6, CHCl3); H NMR (500 MHz, CDCl3) d
24
HRMS (ESI): m ⁄ z calcd for C24H25BrN2O3P, 499.0786 [M+H]+, found:
499.0778.
7.37-7.26 (m, 10H), 6.74-6.89 (m, 4H), 4.48-4.43 (m, 2H), 4.35-4.31
(m, 1H), 3.76 (s, 3H), 3.63-3.54 (m, 1H), 3.02-2.95 (m, 2H), 2.55-2.39
(m, 2H), 2.27-2.19 (m, 1H), 2.12-2.03 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 159.4, 136.2 (d, J = 6.0 Hz), 136.0 (d, J = 4.9 Hz), 129.6
(d, J = 4.0 Hz), 129.1 (d, J = 2.5 Hz), 128.8 (d, J = 5.5 Hz), 128.6 (d,
J = 2.0 Hz), 127.6 (d, J = 5.0 Hz), 127.3, 127.1 (d, J = 3.0 Hz), 127.0
(d, J = 2.5 Hz), 114.1, 80.8 (d, J = 3.4 Hz), 55.2, 52.1, 48.1, 47.5,
47.2, 46.6, 30.8 (d, J = 11.3 Hz), 27.3 (d, J = 10.4 Hz). 31P NMR
(202 MHz, CDCl3) d 55.8.
Compound 6f White solid; yield (0.057 g, quantitative); mp 194–
1
196 ꢀC,[a]D = )79.00 (c 0.6, CHCl3); H NMR (500 MHz, CDCl3) d
24
7.39-7.27 (m, 12H), 6.67 (d, J = 8.1, 2H), 4.53-4.45 (m, 1H), 4.34 (d,
J = 5.7Hz, 2H), 3.66-3.45 (m, 2H), 3.06-2.95 (m, 1H), 2.58-2.41 (m, 2H),
2.31-2.06 (m, 2H); 13C NMR (125 MHz, CDCl3) d 136.8 (d, J = 3.9 Hz)
136.1 (d, J = 5.5 Hz), 136.7 (d, J = 4.9 Hz), 131.8, 129.1 (d,
J = 2.5 Hz), 128.7 (d, J = 5.4 Hz), 128.6 (d, J = 2.0 Hz), 127.9, 127.5
(d, J = 4.4 Hz), 127.1 (d, J = 2.0 Hz), 122.1, 80.5 (d, J = 4.0 Hz), 51.8,
47.9, 47.3 (d, J = 10.4 Hz), 46.6, 30.4 (d, J = 11.4 Hz), 27.2 (d,
J = 10.4 Hz). 31P NMR (202 MHz, CDCl3) d 56.7.
HRMS (ESI): m ⁄ z calcd for C25H27N2NaO4P, 473.1606 [M+Na]+,
found: 473.1624.
Compound 6k Sticky off white solid; yield (0.072 g, 96%);
1
Compound 6g White solid; yield (0.070 g, 96%); mp 192–
[a]D = )64.52 (c 0.6, CHCl3); H NMR: d 7.33-7.26 (m, 10H), 4.14-
24
1
194 ꢀC,[a]D = )87.00 (c 0.6, CHCl3); H NMR (500 MHz, CDCl3) d
4.06 (m, 2H), 3.54-3.45 (m, 2H), 2.62-2.56 (m, 1H), 2.52-2.48 (m, 1H),
2.45-2.31 (m, 4H), 2.54 (t, J = 8.5 Hz, 1H), 1.18 (s, 9H). 13C NMR: d
136.7 (d, J = 10,0 Hz), 135.8 (d, J = 9.0 Hz, 2C), 128.9 (d,
J = 10.0 Hz), 128.5, 128.4, 128.1, 127.8 (d, J = 8.8 Hz), 127.7, 126.8
(d, J = 2.4 Hz), 126.5 (d, J = 8.8 Hz), 127.7 (d, J = 10.3 Hz), 73.4,
60.3, 45.1, 44.5, 32.3 (d, J = 9.5 Hz), 26.0, 25.9, 25.4 (3C). 31P
NMR: d 55.18.
24
7.38-7.24 (m, 10H), 7.19-7.18 (m, 1H), 6.16-6.15 (m, 1H), 5.71 (d,
J = 3.5 Hz, 1H), 4.61-4.55 (m, 1H), 4.45-4.35 (m, 2H), 3.62-3.53 (m,
1H), 3.11-3.01 (m, 2H), 2.56-2.39 (m, 2H), 2.28-2.18 (m, 1H), 2.13-
2.03 (m, 1H); 13C NMR (125 MHz, CDCl3) d 150.3 (d, J = 5.4 Hz),
142, 136.0 (d, J = 3.4 Hz), 134.6 (d, J = 5.4 Hz), 129.4 (d,
J = 2.4 Hz), 128.8 (d, J = 5.4 Hz), 128.7 (d, J = 1.5 Hz), 127.5 (d,
Chem Biol Drug Des 2011; 77: 20–29
25

Pindi et al.
Ph
Ph
NH2 HBr
NO2
P
O
NH
Ph
Ph
48% aq. HBr
MeOH, 10 h
NO2
P
+
O
OH
NH
6a
7
Boc
Et3N, (Boc)2O
DCM, 12 h
NO2
Scheme 2: Absolute configura-
tion determination and recovery of
auxiliary.
8
Compound 6l White solid; yield (0.082 g, 76%); mp 158–
phosphinic chloride (2) that was treated with ammonia at )78 ꢀC
to produce 3 in quantitative yield. In fact, the synthesis of 3 has
been readily conducted on a 20.0 g-scale to consistently give a
quantitative overall yield. N-Phosphinamide (3) was obtained as a
white solid and can be stored at room temperature in the air for
more than 2 months without any decomposition as monitored by
1H-NMR determination.
160 ꢀC, [a]D = )60.52 (c 0.6, CHCl3); 1H NMR: d 7.48-7.10 (m,
24
15H), 4.65 (q, J = 10.5 Hz, 2H), 3.78-3.42 (m, 1H), 3.24-3.05 (m, 1H),
2.65-2.22 (m, 4H), 1.77 (bs, 1H, NH), 1.41 (s, 3H). 13C NMR: d 142.9
(d, J = 11.8 Hz), 137.1 (d, J = 9.8 Hz), 136.3 (d, J = 10.0 Hz),
129.46, 129.41, 128.9 (d, J = 8.8 Hz), 128.7 (2C), 128.6 (d,
J = 2.4 Hz), 128.4 (d, J = 8.8 Hz), 127.7 (d, J = 10.3 Hz), 127.6,
126.8, 124.3 (2C), 84.0, 49.5, 49.3, 48.9, 48.6, 33.5 (d, J = 9.5 Hz),
31.2 (d, J = 8.0 Hz), 27.6 (d, J = 9.8 Hz), 27.3, 27.2. 31P NMR: d
53.51.
Chiral N-phosphinyl imines were then prepared by following a simi-
lar procedure for the previous chiral N-phosphonamides synthesis
(Table 1) (39–46). In this synthesis, aldehydes were reacted with
chiral N-phosphonamide (3) in the presence of triethylamine and
TiCl4 in DCM solution. When compared with the previous synthesis
of chiral N-phosphonyl imines where chemical yields ranged from
62% to 74%, in the present synthesis of N-phosphinyl imines, much
higher yields were obtained (up to 94%); only in one difficult case
(p-NO2-Ph, entry 2, Table 1), yield of 75% was observed. The result-
ing N-phosphinyl imines were found to be stable at room tempera-
ture for a long time under inert gas atmosphere. For preparation of
the aliphatic imine and ketimine, the use of TiCl4 led to predomi-
nant formation of enamines. We found that the use of Ti(i-OPr)4
instead of TiCl4 for this synthesis led to efficient formation of imi-
nes (entry 11 and 12, Table 1, respectively), but these two imines
were found unstable to column chromatographic. Therefore, they
were directly subjected to aza-Henry reaction without special purifi-
cation.
HRMS (ESI): m ⁄ z calcd for C25H28N2O3P 435.1838 [M+H]+, found:
435.1833.
Determination of absolute configuration
Removal of N-phosphinyl group followed by
in situ t-Boc protection
In a 50-mL round-bottomed flask, 0.200 g of aza-Henry product (1.0
equiv.) and 5 mL of methanol were taken. To this solution, 0.8 mL
of 48% aq. HBr (1.0 equiv.) was added and the reaction mixture
was stirred at room temperature for 10 h. Disappearance of starting
material was observed by TLC, then volatiles were evaporated and
crude product was dried overnight under vacuum. To the above
crude mixture, 10 mL of dichloromethane was added, and this sus-
pension was cooled to 0 ꢀC. At this temperature, 0.42 mL of trieth-
ylamine was added slowly. To this resulting mixture, 0.436 g of
di-tert-butyl dicarbonate was added and stirred at room temperature
for 12 h (Scheme 2). After aqueous workup, the crude product was
The asymmetric aza-Henry reaction using 4a as the electrophile
was studied under a condition similar to the chiral N-phosphonyl
imine-based system. The reaction of 4a with lithium nitronate,
which was generated by treating nitromethane with LiHMDS, was
smoothly finished at )78 ꢀC in 8 h (45). Excellent yield of 96% and
diastereoselectivity of 94%de were achieved. Other strong bases,
such as n-BuLi, LDA and KHMDS, resulted in either low yields or
poor diastereoselectivity. Also, similar to the previous aza-Henry
reaction (45), THF was proven to be the best solvent while diethyl
ether gave slightly lower diastereoselectivity, but DCM led to no
product formation at all. The present chiral N-phosphinyl imines
showed higher reactivity toward lithium nitronate when compared
with their N-phosphonyl imine counterparts that required the reac-
tion temperature to be raised to )10 ꢀC to reach complete con-
sumption of imine starting materials.
purified by column chromatography to obtain compound (8). [a]24
D
+13.27 (c = 0.8, CHCl3) {Literature value [a]24 )20.1 (c = 0.48,
D
CHCl3) for R isomer}.
Results and Discussion
The present study was started from the synthesis of chiral N-phos-
phinamide (3) as shown in Scheme 1. The starting material, phos-
phinoic acid (1), was prepared via an addition reaction of
1,4-biphenyl-1,3-butadiene according to a known procedure (61).
Phosphinoic acid (1) was next reacted with oxalylchloride to give
26
Chem Biol Drug Des 2011; 77: 20–29

N-Phosphinyl Imine Chemistry (I)
Results of asymmetric aza-Henry reaction were summarized in
Table 2. The reaction showed wide substrate scope in which aro-
matic and aliphatic aldehyde-derived imines and ketimines all
worked well. For five cases, 2, 3, 5, 9, and 12 in Table 2, complete
diastereoselectivities and almost quantitative yields were achieved.
Even in the cases of aliphatic imine and ketimine (entries 11 and
12, Table 2), excellent yields (96% and 94%, respectively) and dia-
stereoselectivities (96%de and >99%de, respectively) were
obtained. The reaction of 4b with lithium nitronate was completed
at )78 ꢀC within 4 h, which is because of the electron withdrawing
effect of p-NO2-Ph group (entry 2, Table 2). In contrast, p-methoxy-
substituted aromatic imine, 4j, was reacted with lithium nitronate
at a slower rate, and the reaction took 9 h to completion (entry 10,
Table 2).
Ph
O-
Li
N
H
N
O
Ph
P
O
Re face
Ph
Figure 2: Proposed transition state involved in aza-Henry reaction.
belongs to GAP chemistry (Group-Assistant-Purification chemistry)
that enables easy workup simply by washing the crude products
with common organic solvents. The auxiliary can be cleaved easily
under mild condition to regenerate the free amines and phosphinoic
acid precursor for reuse. More applications of this new chiral
reagents will be applied for other asymmetric reactions in the near
future.
Another attractive characteristic of the present aza-Henry reaction
was shown by the fact that the product purification was conducted
simply by washing the crude product with ethylacetate and hexane.
This reaction joined a family of asymmetric reactions in that achiral
and chiral N-phosphonyl groups as well as the present chiral N-
phosphinyl group enabled the product purification to be achieved by
washing (39–46). The recovery of auxiliary for reuse can be per-
formed easily in high yields. The flexibility of these auxiliaries by
changing their C2-substituents would be anticipated to give greener
synthesis and reactions. In fact, as mentioned earlier, we have
defined this phenomenon as the GAP synthesis or GAP chemistry
(40), which would encourage the synthetic community to search for
more environmentally friendly syntheses and reactions to shorten
preparation period and to minimize the use of manpower and
energy.
Acknowledgments
We thank the Robert A. Welch Foundation (D-1361), NIH
(R03DA026960) and NSFC (20928001) for their generous support.
We thank our coworkers Teng Ai, Walter Wever, Trideep Rajale,
Venkatesh Kattamuri, and Jianbin Wu for their valuable suggestions
and assistance.
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