Double axially chiral bisphosphorylimides as novel Bronsted acids in asymmetric three-component Mannich reaction

Article abstract of DOI:10.1016/j.tetasy.2012.06.008

A double axially chiral bisphosphorylimide has been demonstrated to be an efficient and highly sterically hindered Bronsted acid in asymmetric three-component Mannich reactions. Optically active syn-β-amino ketones were obtained in high yields (up to 99%)

Full text of DOI:10.1016/j.tetasy.2012.06.008

Tetrahedron: Asymmetry 23 (2012) 904–909
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Double axially chiral bisphosphorylimides as novel Brønsted acids
in asymmetric three-component Mannich reaction
Ying-Ying Chen a, Yi-Jun Jiang a, Yan-Sen Fan a, Di Sha a, Qifeng Wang a, Guangliang Zhang a,
a,
Liangyu Zheng b, , Suoqin Zhang
⇑
⇑
a College of Chemistry, Jilin University, Changchun 130012, PR China
b Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun 130012, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 May 2012
Accepted 13 June 2012
A double axially chiral bisphosphorylimide has been demonstrated to be an efficient and highly sterically
hindered Brønsted acid in asymmetric three-component Mannich reactions. Optically active syn-b-amino
ketones were obtained in high yields (up to 99%) with excellent diastereoselectivity (99:1) and enantiose-
lectivity (up to 99% ee). A gram-scale reaction was also performed to prove the synthetic application
value of this reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
cooperation of two axially chiral structures with the same config-
uration. Inspired by these structures, we envisioned that a phos-
The catalytic asymmetric Mannich reaction is one of the most
efficient methods for preparing enantioenriched b-amino carbonyl
compounds, which are highly useful chiral building blocks and
intermediates in organic synthesis.1 Compared to indirect asym-
metric two-component Mannich reactions, direct three-compo-
nent Mannich reactions do not need the tedious preparation of
enolates or imines; as a result they have received increasing
interest. Although great progress has been made in controlling
stereoselectivity by using chiral organometallic-2 and organo-
catalysts3 in direct three-component Mannich reactions, there is
still room for further improvement, especially with regard to
diastereoselectivity.
BINOL-derived phosphoramides have emerged as new chiral
Brønsted acids since the utilization of N-triflyl phosphoramides
by Yamamoto in asymmetric Diels–Alder reaction in 2006 (Fig. 1,
A).4 Impressive results have also been reported by List et al. who
introduced pyridinyl and phosphinyl groups onto the phosphora-
mides for desymmetrization of meso anhydrides and intramolecu-
lar asymmetric N,O-acetalization (Fig. 1, B and C).5 Phosphoramide
D, the key scaffold of these catalysts, is more structurally tunable
than BINOL-derived phosphoric acids, since the amino group can
be further modified with various functional groups. On the other
hand, phosphoric acids possessing two C2-symmetrical backbones
(Fig. 1, E and F) have been reported as efficient catalysts in asym-
metric hydrogenation6 and 1,3-dipolar cycloaddition7 reactions,
indicating the unique enantioselective control ability from the
phoramide catalyst bearing two BINOL-derived phosphoryl
backbones might be an excellent chiral Brønsted acid catalyst with
more steric hindrance than that with mono-axially chiral back-
bones in catalytic asymmetric reactions.8 Herein we report our
preliminary results in the design and synthesis of bisphosphoryli-
mides 1 (Fig. 1), and their application in highly diastereo- (syn/anti
>99/1) and enantioselective (up to 99% ee) direct three-component
Mannich reactions.
2. Results and discussion
The synthesis of bisphosphorylimides 1 was started from (R)-BI-
NOL 2. As shown in Scheme 1, the protection of BINOL with a MOM
group was conducted in saturated NaOH aq on a 50 g scale with
high yield (92%). Phosphoryl chlorides 4 were synthesized accord-
ing to the literature.9a Compounds 4 were converted into phos-
phoryl azides and then treated with catalytic hydrogenation to
generate phosphorylamides 5.9b,c Condensation of 4 and 5 in
DMF generated the final bisphosphorylimides 1a–f with good
yields (71–84%).
The catalytic activity and stereoselectivity of catalysts 1a–f
were examined in a three-component Mannich reaction of cyclo-
hexanone 6, aniline 7 and p-nitrobenzaldehyde 8a in the presence
of 2 mol % catalyst 1 (Table 1). In entry 1 of Table 1, racemic prod-
uct 9a was obtained with high syn-diastereoselectivity by using 1a
as the catalyst. When (R,R)-3,30-bis-phenyl-BINOL bisphosphoryli-
mide 1b was employed, syn-9a was formed with good enantiose-
lectivity (92% ee) (Table 1, entry 2). Catalysts 1c and 1d were
further screened and the enantioselectivity was improved when
increasing the size of 3,30-substituents on both or individual BINOL
⇑
Corresponding authors. Tel.: +86 431 85155252 (L.Z.); +86 431 85168468; fax:
+86 431 85168420 (S.Z.).
E-mail addresses: lyzheng@jlu.edu.cn (L. Zheng), suoqin@jlu.edu.cn (S. Zhang).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.008

Y.-Y. Chen et al. / Tetrahedron: Asymmetry 23 (2012) 904–909
905
Figure 1. Design of double axially chiral bisphosphorylimides.
Ar
MOMCl
O
NaOH aq.
ref. 9a
O
O
OH
OH
OMOM
OMOM
1) NaN3
P
Cl
92%
2) 10% Pd/C, H2
82-90%
Ar
(R)-4
(R)-2
(R)-3
Ar
Ar
Ar'
O
(R,R)-1a: Ar, Ar' = H, H
(R,R)-1b: Ar, Ar' = phenyl, phenyl
(R,R)-1c: Ar, Ar' = phenyl, 1-naphthyl
(R,R)-1d: Ar, Ar' = 1-naphthyl, 1-naphthyl
(R,R)-1e: Ar, Ar' = phenyl, 3,5-(CF3)2C6H3
(R,R)-1f: Ar, Ar' = phenyl, 3,5-(CH3)2C6H3
O
P
O
NaH, (R)-4
71-84%
O
O
O
O
O
P
P
NH2
O
N
H
Ar
Ar
Ar'
1a-f
(R)-5
(R,R)-
Scheme 1. Synthesis of BINOL-derived bisphosphorylimides 1.
Table 1
relatively lower yields and stereoselectivities (Table 1, entries 5
and 6). It should be noticed that excellent syn-diastereoselectivities
were observed in all cases in Table 1. Compared with the reversed
results (the anti-isomer of 9a with lower diastereoselectivity) re-
ported by Gong et al. by using BINOL-derived phosphoric acid cat-
alysts,3i our results revealed the unique and remarkable steric
effects of these double axially chiral backbones of bisphosphoryli-
mides 1. Although the syn-isomers could be obtained in proline
with moderate to high enantioselectivity,3f,m,n proline-derived tet-
razole,3j amino acids,3k,l ionic liquid,11 and chiral tin dibromide3c
catalyzed asymmetric three-component Mannich reactions, gener-
ally gave lower diastereoselectivities and/or high catalyst loading
(10–30%) was necessary for complete transformation. Therefore,
our process provides a highly efficient approach to prepare enan-
tiopure syn-b-amino carbonyl compounds by using bisphospho-
rylimide 1d (Table 1, entry 4).
With the optimized conditions in hand, aryl aldehydes 8a–m
were investigated for asymmetric three-component Mannich reac-
tions (Table 2). In entries 1–9, benzaldehyde and its derivatives
containing electron withdrawing groups at the ortho-, meta-, and
para-positions were examined and syn-selective Mannich adducts
were obtained exclusively in high yields and with excellent enanti-
oselectivity. Generally, benzaldehydes bearing electron donating
groups afford their corresponding products with relatively low ste-
reoselectivity in three-component Mannich reactions.1a,f However,
by using bisphosphorylimide 1d, benzaldehydes 8j–m with elec-
tron donating groups were converted into the corresponding syn-
b-amino carbonyl ketones with excellent diastereoselectivity and
enantioselectivity (Table 2, entries 10–13).
Bisphosphorylimides 1 catalyzed three-component Mannich reactionsa
CHO
O
NH2
O
HN
Cat. 1, 5Å MS
+
+
toluene, r.t., 12 h
NO2
NO2
6
7
8a
9a
Entry
Catalyst
Yieldb (%)
drc (syn/anti)
eed (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
53
85
98
>99
90
81
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
5
92
96
99
93
97
a
The reaction was performed with 8 mmol of 6, 0.2 mmol of 7, 0.22 mmol of 8a,
90 mg of 5 Å molecular sieves, and 2 mol % of catalysts 1 in 1.5 mL of toluene at
room temperature for 12 h.
b
Isolated yield.
c
Determined by 1H NMR spectroscopy.
d
The enantiomeric excess of the syn-product was determined by chiral analysis
(Chiralpak AD-H) on HPLC; the relative and absolute configuration was determined
by comparing the characteristic peak of 1H NMR shifts and retention time of HPLC of
products with those of the literature data.
backbones (Table 1, entries 3 and 4). Compound (R,R)-3,30-bis
(1-naphthyl)-BINOL bisphosphorylimide 1d gave the best result
in 99% yield with 99% enantioselectivity and >99/1 diastereoselec-
tivity.10 Bisphosphorylimides bearing electron withdrawing sub-
stituents 1e and electron donating substituents 1f on one of the
BINOL backbones were further examined and 9a was obtained in

906
Y.-Y. Chen et al. / Tetrahedron: Asymmetry 23 (2012) 904–909
Table 2
toluene (Na). All other reagents were used without purification.
All reactions were monitored by thin layer chromatography. Puri-
fication of the reaction products was carried out by flash chroma-
tography on silica gel. Chemical yields refer to pure isolated
substances. The melting points were recorded on a melting point
apparatus (MPA100, Stanford Research Systems, Inc.). Optical rota-
tions were measured using a 0.8 mL cell with a 1 cm path length on
Jasco-P-2000 digital polarimeter and concentrations (c) were re-
Bisphosphorylimide 1d catalyzed syn-selective three-component Mannich reactionsa
O
NH2
O
NHPh
O
1d,
2 mol%
5Å MS
+
+
H
R
R
toluene, r.t., 12 h
6
7
8
9
Entry
R
Product
Yieldb (%)
drc (syn/anti)
eed (%)
1
2
3
4
5
6
7
8
4-NO2C6H4
C6H5
2-FC6H4
3-FC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-CF3C6H4
3-MeC6H4
4-MeC6H4
9a
9b
9c
9d
9e
9f
9g
9h
9i
>99
>99
87
90
98
92
92
>99
90
96
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
99e
98f
99f
99f
96e
97f
97e
99f
98f
>99f
95f
90f
96f
ported in g ꢀ (100 mL)ꢁ1
.
1H NMR, 13C NMR, and 31P NMR spectra
were recorded on Bruker 300 MHz or 400 MHz spectrometers
(300 MHz for 1H NMR, 75 MHz for 13C NMR, and 162 MHz for 31P
NMR). Chemical shifts of 1H and 13C signals are given in d relative
to the signal of tetramethylsilane (TMS). IR spectra were recorded
on Nicolet Avatar 360 FT-IR spectrometer. High-resolution mass
spectroscopic analysis (HRMS) data were measured on a Bruker
ApexII mass spectrometer by means of the ESI technique. Analyti-
cal HPLC was recorded on a HPLC machine equipped with Agilent
1100 series quaternary pump with a UV diode array detector.
The chiral stationary phase was Daicel Chiralcel AD-H, AS-H, OD-
H, and OJ-H column.
9
10
11
12
13
9j
9k
9l
83
84
>99
4-(CH3)2CHC6H4
3-MeOC6H4
9m
a
The reaction was performed with 8 mmol of 6, 0.2 mmol of 7, 0.22 mmol of 8,
90 mg of 5 Å molecular sieves, and 2 mol % of catalyst 1d in 1.5 mL of toluene at
room temperature for 12 h.
b
4.2. General experimental procedures and characterization data
for catalysts 1a–f
Isolated yield.
c
Determined by 1H NMR.
d
The enantiomeric excess of the syn-product was determined by chiral analysis
(Chiralpak AD-H, AS-H, OD-H, and OJ-H) on HPLC.
4.2.1. (R)-2,20-Bis(methoxymethoxy)-1,10-binaphthyl 2
e
The relative and absolute configuration was determined by comparing the
(R)-2,20-Dihydroxy-1,10-binaphthyl (40 g, 0.14 mol) was dis-
solved in THF (120 mL) after which saturated NaOH solution
(50 mL) was added to the solution in one portion. After cooling
the temperature of the mixture to 15 °C, chloromethyl methyl
ether (56 mL, 0.7 mol) was slowly added from a dropping funnel
and the reaction temperature was kept below 20 °C. The reaction
mixture was stirred for 5 h at 20 °C and 50 mL water was added.
The complex was then extracted with CH2Cl2 (100 mL ꢀ 4). The or-
ganic layers were combined, washed with brine (200 mL), dried
over Na2SO4, and concentrated under reduced pressure. The crude
product was crystallized from ethanol twice to give the product as
white crystals (44 g, 0.12 mol, 92%).
characteristic peak of the 1H NMR shifts and retention time of HPLC of products
with those of the literature data.
f
Relative and absolute configuration was assigned according to entries 1, 5, and
7 of Table 2.
CHO
O
NH2
O
HN
1 mol% Cat. 1d, 5Å MS
+
+
toluene, r.t. , 24 h
CN
CN
8h
9h
94% yield, > 99: 1 dr, 99% ee
Scheme 2. Gram scale reactions of 9h.
4.2.2. (R)-3,30-Diaryl-1,10-binaphthyl-2,20-diyl phosphoramide
59b,c
A gram scale reaction was also performed to test the scalability of
this asymmetric Mannich reaction. As shown in Scheme 2, by using
1 mol % catalyst 1d, syn-9h was isolated in comparable yield (94%)
without any loss of stereoselectivity (>99:1 dr, 99% ee) in 24 h.
Sodium azide (5.5 mmol) was added to a stirred solution of (R)-
6 (5.0 mmol) in acetone (30 mL). The resulting mixture was stirred
for 6 h at room temperature and the white precipitate was col-
lected through a funnel under nitrogen. The filtrate was concen-
trated in vacuo to give (R)-3,30-diphenyl-1,10-binaphthyl-2,20-diyl
phosphoroazidate as a white solid. (R)-3,30-Diphenyl-1,10-binaph-
thyl-2,20-diyl phosphoroazidate was then dissolved in dry THF
(10 mL) and 10% Pd/C (0.15 g) was added. The complex was placed
in an autoclave under 3 atm of hydrogen and stirred overnight.
After the reaction was complete, Pd/C was filtered through filter
paper and the filtrate was concentrated under reduced pressure.
The crude product was purified with silica gel column chromatog-
raphy (CH2Cl2/CH3OH = 50:1) to give the product.
3. Conclusion
In conclusion, a series of double axially chiral bisphosphoryli-
mides 1 were synthesized and have been successfully used in
asymmetric three-component Mannich reactions. (R,R)-3,30-Bis(1-
naphthyl)-BINOL bisphosphorylimide 1d showed the best diaste-
reo-control ability compared with other Brønsted acid catalysts.
The syn-b-amino ketones were obtained exclusively in high yields
and with excellent enantioselectivities based on a wide scope of
benzaldehydes. The gram scale reaction showed the feasibility of
this methodology for potential application in preparing useful syn-
thetic intermediates. Further applications of double axially chiral
bisphosphorylimides in other enantioselective reactions are cur-
rently in progress.
4.2.2.1. (R)-3,30-Diphenyl-1,10-binaphthyl-2,20-diyl phosphora-
mide 5b.
White solid, 85% yield; mp 198–199 °C;
½
a 2D0
ꢂ
¼ ꢁ342:0 (c 1, THF); 1H NMR (300 MHz, DMSO-d6) d 8.22 (s,
2H), 8.16 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 7.1 Hz, 2H), 7.72 (d,
J = 7.1 Hz, 2H), 7.62–7.31 (m, 10H), 7.21 (dd, J = 17.5, 8.5 Hz, 2H);
13C NMR (75 MHz, DMSO-d6) d 144.9, 144.7, 144.1, 144.0, 137.3,
137.0, 134.0, 134.0, 133.7, 131.5, 131.4, 131.3, 131.1, 130.9,
129.9, 129.9, 128.8, 128.7, 128.2, 127.7, 127.6, 126.9, 126.7,
4. Experimental
4.1. General information
126.2, 126.1, 126.0, 125.8, 122.4, 122.1; FT-IR (KBr)
m 3229, 3052,
2922, 1540, 1500, 1291, 1245, 1140, 977, 957, 878, 754 cmꢁ1
;
HRMS(ESI+) m/z calcd for C32H23NO3P ([M+H]+): 500.1410, found:
500.1413.
The solvents used were purified by distillation over the drying
agents indicated and were transferred under argon: THF (Na),

Y.-Y. Chen et al. / Tetrahedron: Asymmetry 23 (2012) 904–909
907
4.2.2.2. (R)-3,30-Dinaphthyl-1,10-Binaphthyl-2,20-diyl phospho-
4.2.3.4. (R,R)-1d.
White solid, 71% yield; mp 283–284 °C;
ramide 5d.
White solid, 90% yield; mp 245–246 °C;
½
a 2D0
ꢂ
¼ ꢁ94:2 (c 1, THF) ; 1H NMR (300 MHz, DMSO-d6) d 8.23–
½
a 2D0
ꢂ
¼ ꢁ180:8 (c 1, THF); 1H NMR (300 MHz, DMSO-d6) d 8.23–
6.92 (m, 46H), 6.68–6.60 (m, 1H), 5.99 (d, J = 7.0 Hz, 1H); 13C
NMR (75 MHz, DMSO-d6) d 146.9, 146.7, 146.2, 134.7, 134.6,
134.2, 134.0, 133.4, 133.2, 133.1, 132.9, 132.7, 132.5, 132.4,
132.3, 132.2, 132.1, 131.9, 131.8, 131.7, 131.4, 131.3, 131.0,
130.8, 130.7, 130.6, 130.0, 128.8, 128.6, 128.4, 128.1, 127.7,
127.3, 127.2, 126.9, 126.7, 126.5, 126.3, 126.2, 125.8, 125.5,
124.9, 123.0, 122.3, 122.1; 31P NMR (162 MHz, DMSO-d6) d ꢁ0.8;
8.08 (m, 4H), 8.06–7.91 (m, 4H), 7.80–7.30 (m, 16H); 13C NMR
(75 MHz, DMSO-d6) d 145.6, 145.4, 144.7, 144.6, 135.3, 134.5,
133.1, 132.8, 132.7, 132.7, 132.6, 132.5, 132.5, 132.3, 132.0,
131.9, 131.8, 131.7, 131.6, 131.0, 130.8, 128.7, 128.6, 128.5,
128.2, 128.0, 127.8, 127.1, 126.9, 126.4, 126.2, 126.0, 125.7,
125.6, 125.6, 125.5, 125.3, 125.2, 121.9, 121.3; FT-IR (KBr)
m
3059, 2928, 1540, 1514, 1461, 1291, 970, 859, 773 cmꢁ1; HRMS(E-
FT-IR (KBr)
891, 776, 750 cmꢁ1
([M+H]+): 1182.3108, found: 1182.3108.
m
3051, 2956, 2860, 1509, 1445, 1388, 1203, 954,
SI+) m/z calcd for
C
40H27NO3P ([M+H]+): 600.1723, found:
;
HRMS(ESI+) m/z calcd for C80H50NO6P2
600.1719.
4.2.3. Double axially chiral catalysts (R,R)-1
4.2.3.5. (R,R)-1e.
Synthesized by using (R)-1,10-binaphthyl-
To a stirred solution of (R)-1,10-binaphthyl-3,30-diaryl phos-
phoryl chloride (1.3 mmol) in dry DMF (10 mL) was added NaH
(80% in oil, 4 mmol) under a nitrogen atmosphere at room temper-
ature. After stirring for 5 min, (R)-1,10-binaphthyl-3,30-diaryl phos-
phoramide (1 mmol) was added in one portion and the mixture
was stirred for another 1 h. After the reaction was complete,
30 mL of CH2Cl2 was added to the flask and the mixture was
washed with saturated brine (50 mL ꢀ 5). The organic layer was
dried over Na2SO4 and concentrated under reduced pressure. The
crude product was purified with silica gel column chromatography
(CH2Cl2/CH3OH = 20:1). The product was then successively dis-
solved in CH2Cl2, acidified with 4 M HCl (10 mL), washed with
brine (20 mL ꢀ 2), dried over Na2SO4, and concentrated in vacuo
to give catalyst (R,R)-1.
3,30-diphenyl phosphoryl chloride and (R)-1,10-binaphthyl-3,30-di-
[3,5-bis(trifluoromethyl)]phenyl phosphoramide. White solid,
74% yield; mp 294–295 °C; ½a D20
ꢂ
¼ ꢁ307:0 (c 1, THF) ; 1H NMR
(300 MHz, DMSO-d6)
d 8.45 (s, 2H), 8.35 (s, 1H), 8.17 (d,
J = 8.3 Hz, 1H), 8.13–7.91 (m, 4H), 7.91–7.72 (m, 5H), 7.72–6.92
(m, 20H), 6.92–6.69 (m, 3H); 13C NMR (75 MHz, DMSO-d6) d
146.5, 146.5, 146.4, 146.4, 146.3, 146.1, 146.0, 145.9, 145.9,
140.1, 139.9, 137.4, 136.9, 133.9, 133.5, 132.3, 132.1, 131.5,
131.1, 131.1, 131.0, 130.8, 130.7, 130.2, 130.1, 130.0, 129.8,
129.8, 129.7, 129.6, 129.2, 129.1, 129.1, 128.7, 128.3, 128.2,
127.3, 126.7, 126.6, 126.1, 125.8, 125.5, 125.2, 125.0, 124.6,
124.5, 122.8, 122.6, 122.3, 121.6, 121.3, 120.5, 119.9, 118.0,
117.7; 31P NMR (162 MHz, DMSO-d6) d 0.4, ꢁ3.0; FT-IR (KBr)
m
3059, 2928, 2843, 1507, 1382, 1376, 1278, 1180, 1134, 997, 892,
747, 682 cmꢁ1
([M+H]+): 1254.1977, found: 1254.1974.
; HRMS(ESI+) m/z calcd for C68H38F12NO6P2
4.2.3.1. (R,R)-1a.
White solid, 79% yield; mp 260–261 °C;
½
a 2D0
ꢂ
¼ ꢁ99:6 (c 1, THF) ; 1H NMR (300 MHz, DMSO-d6) d 8.22–
8.10 (m, 2H), 8.10–8.02 (m, 2H), 8.02–7.94 (m, 2H), 7.94–7.84
(m, 2H), 7.65–7.54 (m, 2H), 7.54–7.38 (m, 6H), 7.38–7.16 (m,
8H); 13C NMR (75 MHz, DMSO-d6) d 148.7, 148.6, 148.6, 148.1,
131.7, 131.6, 130.7, 130.6, 130.4, 130.2, 130.2, 128.4, 126.4,
126.2, 126.0, 126.0, 125.0, 124.9, 121.9, 121.6, 121.1; FT-IR (KBr)
4.2.3.6. (R,R)-1f.
Synthesized by using (R)-1,10-binaphthyl-
3,30-diphenyl phosphoryl chloride and (R)-1,10-binaphthyl-,30-di-
(3,5-dimethylphenyl) phosphoramide. White solid, 72% yield; mp
321–322 °C;
½
a 2D0
ꢂ
¼ ꢁ258:0 (c 1, THF)
;
1H NMR (300 MHz,
DMSO-d6) d 8.17–8.05 (m, 6H), 8.02–7.86 (m, 3H), 7.56–7.41 (m,
7H), 7.41–7.31 (m, 5H), 7.31–7.21 (m, 4H), 7.21–6.98 (m, 7H),
6.66 (t, J = 7.4 Hz, 1H), 6.52–6.41 (m, 3H), 2.34 (s, 6H), 1.68 (s,
6H); 13C NMR (75 MHz, DMSO-d6) d 146.8, 146.7, 146.6, 137.4,
137.0, 136.9, 136.7, 135.7, 134.0, 131.8, 131.7, 131.6, 131.5,
130.4, 130.3, 130.2, 130.1, 130.1, 129.7, 129.6, 129.4, 128.3,
128.2, 128.0, 127.8, 127.5, 126.9, 126.7, 126.1, 126.0, 125.9,
124.8, 124.5, 21.0, 20.3; 31P NMR (162 MHz, DMSO-d6) d 3.7, 1.2;
m
2923, 1505, 1591, 1621, 1451, 1213, 1146, 975, 988, 885 cmꢁ1
;
HRMS(ESI+) m/z calcd for C40H26NO6P2 ([M+H]+): 678.1230, found:
678.1227.
4.2.3.2. (R,R)-1b.
White solid, 84% yield; mp 253–254 °C.
½
a 2D0
ꢂ
¼ ꢁ175:6 (c 1, THF); 1H NMR (300 MHz, DMSO-d6) d 8.27–
7.89 (m, 10H), 7.61–6.97 (m, 24H), 6.82 (t, J = 7.5 Hz, 2H), 6.63 (t,
J = 7.6 Hz, 4H); 13C NMR (75 MHz, DMSO-d6) d 146.5, 146.4,
146.3, 137.3, 137.0, 134.2, 133.9, 131.7, 131.6, 130.2, 129.8,
129.5, 128.3, 128.2, 127.7, 126.9, 126.7, 126.0, 125.9, 125.8,
124.8, 124.7, 122.6, 122.2; 31P NMR (162 MHz, DMSO-d6) d 2.2;
FT-IR (KBr)
m
3049, 2916, 1600, 1502, 1359, 1209, 971, 891, 842,
751 cmꢁ1
;
HRMS(ESI+) m/z calcd for C68H50NO6P2 ([M+H]+):
1038.3108, found: 1038.3110.
FT-IR (KBr)
m
3066, 2966, 2930, 1646, 1571, 1422, 1136, 994,
4.3. General experimental procedures for the asymmetric Man-
nich reaction and characterization data for compounds 9a–m
957, 858 cmꢁ1; HRMS(ESI+) m/z calcd for C64H42NO6P2 ([M+H]+):
982.2482, found: 982.2485.
To
a
suspension of aniline (0.2 mmol), benzaldehyde
4.2.3.3. (R,R)-1c.
Synthesized by using (R)-1,10-binaphthyl-
(0.22 mmol) and 5 Å molecular sieves (90 mg) in 1.5 mL of dry tol-
uene in a vial were added 1d (0.004 mmol). After stirring at room
temperature for 0.5 h, cyclohexanone (8 mmol) was added to the
mixture. The reaction was completed in 12 h and the resulting
mixture was concentrated under reduced pressure. The residue
was purified with silica gel column chromatography (petroleum
ether/ethyl acetate = 8:1) to give pure product 7.
3,30-diphenyl phosphoryl chloride and (R)-1,10-binaphthyl-3,30-
dinaphthyl phosphoramide 5d. White solid, 75% yield; mp 233–
234 °C; ½a 2D0
ꢂ
¼ ꢁ204:6 (c 1, THF); 1H NMR (300 MHz, DMSO-d6) d
8.25–7.66 (m, 14H), 7.66–7.02 (m, 25H), 6.99–6.89 (m, 2H), 6.59–
6.38 (m, 2H), 6.38–6.19 (m, 1H); 13C NMR (75 MHz, DMSO-d6) d
147.3, 147.2, 146.7, 146.4, 137.6, 136.7, 134.7, 134.6, 134.5,
133.3, 132.5, 132.3, 132.2, 132.1, 131.9, 131.8, 131.6, 131.0,
130.7, 130.4, 130.3, 130.0, 129.8, 129.7, 129.5, 129.1, 128.5,
128.4, 128.3, 128.2, 128.0, 127.9, 127.4, 127.1, 126.8, 126.5,
126.2, 126.1, 125.7, 125.6, 125.4, 125.2, 125.0, 124.7, 122.7,
4.3.1. (R)-2-((R)-(4-
Nitrophenyl)(phenylamino)methyl)cyclohexanone 9a3i,11
Yield: 99%; syn/anti: >99/1; 99% ee (Daicel Chirapak AD-H, hex-
ane/isopropanol = 70/30, flow rate 1.0 mL/min, tR (major) = 7.666 -
122.0; 31P NMR (162 MHz, DMSO-d6) d 1.2, ꢁ0.3; FT-IR (KBr)
m
;
3054, 2923, 2851, 1594, 1502, 1201, 959, 887, 776, 749 cmꢁ1
min, tR (minor) = 10.600 min); ½a D20
ꢂ
¼ þ37:4 (c 1, CHCl3); 1H NMR
HRMS(ESI+) m/z calcd for
found: 1082.2799.
C
72H46NO6P2 ([M+H]+):1082.2795,
(300 MHz, DMSO-d6) d 8.14 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.7 Hz,
2H), 7.06–6.91 (m, 2H), 6.62–6.41 (m, 3H), 4.94 (t, J = 6.5 Hz, 1H),

908
Y.-Y. Chen et al. / Tetrahedron: Asymmetry 23 (2012) 904–909
2.93–2.79 (m, 1H), 2.41–2.23 (m, 2H), 1.96–1.48 (m, 6H); 13C NMR
(75 MHz, DMSO-d6) d 209.3, 151.8, 147.7, 146.3, 128.7, 128.5,
123.2, 116.2, 113.0, 56.1, 54.7, 41.4, 27.5, 26.7, 23.7.
jor) = 14.983 min, tR (minor) = 20.766 min); ½a D20
¼ þ22:2 (c 1,
ꢂ
CHCl3); 1H NMR (300 MHz, DMSO-d6) d 7.44 (d, J = 8.2 Hz, 2H),
7.32 (d, J = 8.2 Hz, 2H), 6.98 (t, J = 7.7 Hz, 2H), 6.77–6.30 (m,
3H), 4.80 (d, J = 6.1 Hz, 1H), 2.84–2.67 (m, 1H), 2.43–2.16 (m,
2H), 1.96–1.46 (m, 6H); 13C NMR (75 MHz, DMSO-d6) d 209.7,
147.9, 142.6, 130.8, 129.4, 128.6, 119.5, 115.9, 113.0, 56.3,
54.2, 41.3, 27.4, 26.8, 23.5.
4.3.2. (R)-2-((R)-Phenyl(phenylamino)methyl)cyclohexanone 9b
Yield: 99%; syn/anti: >99/1; 98% ee (Daicel Chirapak OJ-H, hex-
ane/isopropanol = 80/20, flow rate 0.75 mL/min, tR (ma-
jor) = 20.500 min, tR (minor) = 29.233 min); ½a D20
¼ þ37:6 (c 1,
ꢂ
CHCl3); 1H NMR (300 MHz, DMSO-d6) d 8.14 (d, J = 8.7 Hz, 2H),
7.65 (d, J = 8.6 Hz, 2H), 6.98 (t, J = 7.9 Hz, 2H), 6.63–6.38 (m, 3H),
4.94 (t, J = 6.5 Hz, 1H), 2.94–2.79 (m, 1H), 2.41–2.21 (m, 2H),
1.99–1.46 (m, 6H); 13C NMR (75 MHz, DMSO-d6) d 214.9, 153.4,
148.2, 133.7, 133.1, 132.2, 131.6, 120.8, 118.1, 61.8, 59.9, 46.5,
32.3, 31.9, 28.7.
4.3.8. 4-((R)-((R)-2-Oxocyclohexyl)(phenylamino)methyl)
benzonitrile 9h
Yield: 99%; syn/anti: >99/1; 99% ee (Daicel Chirapak AS-H, hex-
ane/isopropanol = 80/20, flow rate 0.8 mL/min, tR (ma-
jor) = 22.650 min, tR (minor) = 34.816 min); ½a D20
¼ þ46:6 (c 1,
ꢂ
CHCl3); 1H NMR (300 MHz, DMSO-d6) d 7.73 (d, J = 8.0 Hz, 2H),
7.57 (d, J = 7.9 Hz, 2H), 6.98 (t, J = 7.7 Hz, 2H), 6.67–6.35 (m, 3H),
4.89 (d, J = 6.1 Hz, 1H), 2.94–2.70 (m, 1H), 2.43–2.15 (m, 2H),
2.01–1.40 (m, 6H); 13C NMR (75 MHz, DMSO-d6) d 209.5, 149.4,
147.8, 147.7, 131.9, 128.7, 128.3, 118.9, 116.1, 113.0, 109.3, 56.1,
54.7, 54.7, 41.4, 27.4, 26.7, 23.6.
4.3.3. (R)-2-((R)-(2-Fluorophenyl)(phenylamino)methyl)
cyclohexanone 9c
Yield: 87%; syn/anti: >99/1; 99% ee (Daicel Chirapak OJ-H, hex-
ane/isopropanol = 95/5, flow rate 1.0 mL/min, tR (major) = 18.500 -
min, tR (minor) = 27.766 min); ½a D20
ꢂ
¼ þ65:6 (c 1, CHCl3); 1H NMR
(300 MHz, DMSO-d6) d 7.40 (t, J = 7.7 Hz, 1H), 7.28–6.92 (m, 5H),
6.59–6.42 (m, 3H), 5.08 (d, J = 6.2 Hz, 1H), 2.90–2.74 (m, 1H),
2.42–2.21 (m, 2H), 2.03–1.51 (m, 6H); 13C NMR (75 MHz, DMSO-
d6) d 209.5, 161.5, 158.3, 147.9, 147.8, 129.8, 129.7, 128.8, 128.7,
128.4, 128.3, 124.2, 124.1, 116.1, 115.2, 114.9, 112.7, 54.9, 48.3,
41.3, 27.7, 26.6, 23.6.
4.3.9. (R)-2-((R)-(Phenylamino)(4-(trifluoromethyl)phenyl)-
methyl)cyclohexanone 9i
Yield: 90%; syn/anti: >99/1; 98% ee (Daicel Chirapak AS-H, hex-
ane/isopropanol = 95/5, flow rate 1.0 mL/min, tR (major) = 12.333 -
min, tR (minor) = 17.333 min); ½a D20
ꢂ
¼ þ9:6 (c 1, CHCl3); 1H NMR
(300 MHz, DMSO-d6) d 7.84–7.47 (m, 4H), 6.98 (t, J = 7.7 Hz, 2H),
6.65–6.37 (m, 3H), 4.91 (d, J = 6.2 Hz, 1H), 2.96–2.75 (m, 1H),
2.42–2.20 (m, 2H), 1.99–1.46 (m, 6H); 13C NMR (75 MHz, DMSO-
d6) d 209.6, 148.3, 147.9, 128.7, 128.0, 124.9, 124.9, 116.1, 113.0,
56.2, 54.5, 41.4, 27.4, 26.8, 23.6.
4.3.4. (R)-2-((R)-(3-Fluorophenyl)(phenylamino)methyl)
cyclohexanone 9d
Yield: 90%; syn/anti: >99/1; 99% ee (Daicel Chirapak OJ-H, hex-
ane/isopropanol = 85/15, flow rate 1.0 mL/min, tR (ma-
jor) = 15.816 min, tR (minor) = 23.883 min); ½a D20
ꢂ
¼ þ16:6 (c 1,
4.3.10. (R)-2-((R)-(Phenylamino)(m-tolyl)methyl)cyclohexanone
9j
Yield: 96%; syn/anti: >99/1; 99% ee (Daicel Chirapak OJ-H, hex-
ane/isopropanol = 90/10, flow rate 0.5 mL/min, tR (ma-
CHCl3); 1H NMR (300 MHz, DMSO-d6) d 7.41–7.09 (m, 3H), 7.08–
6.86 (m, 3H), 6.65–6.38 (m, 3H), 4.86 (d, J = 6.1 Hz, 1H), 2.87–
2.69 (m, 1H), 2.45–2.18 (m, 2H), 2.03–1.37 (m, 6H); 13C NMR
(75 MHz, DMSO-d6) d 209.7, 163.9, 160.6, 148.1, 148.0, 146.6,
146.5, 130.0, 129.9, 128.7, 123.3, 116.1, 114.0, 113.7, 113.5,
113.2, 113.1, 56.4, 54.4, 41.4, 27.3, 26.8, 23.6.
jor) = 31.350 min, tR (minor) = 34.400 min);
½
a 2D0
ꢂ
¼ þ33:0 (c 1,
CHCl3); 1H NMR (300 MHz, DMSO-d6) d 7.25–7.06 (m, 3H), 6.96
(t, J = 7.5 Hz, 3H), 6.53 (d, J = 8.0 Hz, 2H), 6.45 (t, J = 7.3 Hz, 1H),
4.80 (t, J = 6.4 Hz, 1H), 2.79–2.67 (m, 1H), 2.43–2.17 (m, 5H),
1.95–1.45 (m, 6H); 13C NMR (75 MHz, DMSO-d6) d 209.7, 148.4,
143.1, 137.0, 128.5, 127.9, 127.5, 127.2, 124.2, 115.6, 113.0, 56.6,
54.7, 41.3, 27.0, 26.7, 23.6, 21.2.
4.3.5. (R)-2-((R)-(4-Fluorophenyl)(phenylamino)methyl)
cyclohexanone 9e3i,11
Yield: 98%; syn/anti: >99/1; 96% ee (Daicel Chirapak AD-H, hex-
ane/isopropanol = 80/20, flow rate 0.5 mL/min, tR (ma-
jor) = 11.833 min, tR (minor) = 15.466 min); ½a D20
ꢂ
¼ þ16:6 (c 1,
4.3.11. (R)-2-((R)-(Phenylamino)(p-tolyl)methyl)cyclohexanone
9k
CHCl3); 1H NMR (300 MHz, DMSO-d6) d 7.51–7.22 (m, 2H), 7.13–
7.00 (m, 2H), 7.00–6.88 (m, 2H), 6.52 (d, J = 7.7 Hz, 2H), 6.44 (t,
J = 7.2 Hz, 1H), 4.81 (d, J = 6.2 Hz, 1H), 2.85–2.62 (m, 1H), 2.43–
2.10 (m, 2H), 1.96–1.42 (m, 6H); 13C NMR (75 MHz, DMSO-d6) d
209.9, 162.5, 159.3, 148.1, 148.1, 139.2, 129.0, 128.9, 128.6,
115.9, 114.8, 114.6, 113.0, 56.6, 54.1, 41.3, 27.5, 26.9, 23.5.
Yield: 83%; syn/anti: >99/1; 95% ee (Daicel Chirapak OJ-H, hex-
ane/isopropanol = 90/10, flow rate 0.5 mL/min, tR (ma-
jor) = 29.316 min, tR (minor) = 33.133 min); ½a D20
¼ þ20:2 (c 1,
ꢂ
CHCl3); 1H NMR (300 MHz, DMSO-d6) d 7.21 (d, J = 7.6 Hz, 2H),
7.03 (d, J = 7.8 Hz, 2H), 6.94 (t, J = 7.8 Hz, 2H), 6.52 (d, J = 8.0 Hz,
2H), 6.43 (t, J = 7.2 Hz, 1H), 4.77 (d, J = 5.8 Hz, 1H), 2.81–2.64 (m,
2H), 2.44–2.14 (m, 5H), 1.95–1.41 (m, 6H); 13C NMR (75 MHz,
DMSO-d6) d 209.9, 148.3, 140.0, 135.4, 128.6, 128.6, 127.0, 115.7,
113.0, 56.7, 54.4, 41.3, 27.3, 26.8, 23.5, 20.6.
4.3.6. (R)-2-((R)-(4-Chlorophenyl)(phenylamino)methyl)
cyclohexanone 9f
Yield: 92%; syn/anti: >99/1; 97% ee (Daicel Chirapak AD-H, hex-
ane/isopropanol = 97/3, flow rate 1.0 mL/min, tR (major) = 14.316 -
min, tR (minor) = 19.933 min); ½a D20
ꢂ
¼ þ30:0 (c 1, CHCl3); 1H NMR
4.3.12. (R)-2-((R)-(4-isopropylphenyl)(phenylamino)methyl)
cyclohexanone 9l
Yield: 84%; syn/anti: >99/1; 90% ee (Daicel Chirapak AD-H, hex-
ane/isopropanol = 98/2, flow rate 0.5 mL/min, tR (major) = 20.200 -
(300 MHz, DMSO-d6) d 7.38 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.2 Hz,
2H), 6.98 (t, J = 7.6 Hz, 2H), 6.59–6.40 (m, 3H), 4.82 (d, J = 6.2 Hz,
1H), 2.76 (q, J = 7.1 Hz, 1H), 2.43–2.11 (m, 2H), 1.95–1.44 (m, 6H);
13C NMR (75 MHz, DMSO-d6) d 209.7, 148.0, 147.9, 142.2, 130.9,
129.0, 128.6, 127.9, 115.9, 113.0, 56.4, 54.2, 41.3, 27.4, 26.8, 23.5.
min, tR (minor) = 25.583 min); ½a D20
ꢂ
¼ þ8:4 (c 1, CHCl3); 1H NMR
(300 MHz, DMSO-d6) d 7.26 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 7.9 Hz,
2H), 6.96 (t, J = 7.6 Hz, 2H), 6.54 (d, J = 7.9 Hz, 2H), 6.44 (t,
J = 7.3 Hz, 1H), 4.82 (t, J = 6.5 Hz, 1H), 2.93–2.63 (m, 2H), 2.42–
2.19 (m, 2H), 2.02–1.36 (m, 6H), 1.16 (d, J = 6.6 Hz, 6H); 13C NMR
(75 MHz, DMSO-d6) d 210.0, 148.3, 146.2, 140.4, 128.6, 127.0,
125.9, 115.6, 112.9, 56.6, 54.2, 41.3, 33.0, 27.3, 26.8, 23.9, 23.5;
4.3.7. (R)-2-((R)-(4-Bromophenyl)(phenylamino)methyl)
cyclohexanone 9g3i,11
Yield: 92%; syn/anti: >99/1; 97% ee (Daicel Chirapak AD-H,
hexane/isopropanol = 97/3, flow rate 1.0 mL/min, tR (ma-

Y.-Y. Chen et al. / Tetrahedron: Asymmetry 23 (2012) 904–909
909
HRMS(ESI+) m/z calcd for C22H28NO ([M+H]+): 322.2165, found:
322.2166.
Chem. Soc. Rev. 2008, 37, 29–41; (c) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007,
5797–5815; (d) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541–2569;
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Angew. Chem., Int. Ed. 1998, 37, 1044–1070; (h) Tramontini, M.; Angiolini, L.
Tetrahedron 1990, 46, 1791–1837.
4.3.13. (R)-2-((R)-(3-
Methoxyphenyl)(phenylamino)methyl)cyclohexanone 9m
Yield: 99%; syn/anti: >99/1; 96% ee (Daicel Chirapak OD-H, hex-
ane/isopropanol = 95/5, flow rate 1.0 mL/min, tR (minor) = 15.150 -
2. (a) Kobayashi, S.; Kobayashi, J.; Yazaki, R.; Ueno, M. Chem. Asian J. 2007, 2, 135–
144; (b) Kobayashi, S.; Yazaki, R.; Seki, K.; Ueno, M. Tetrahedron 2007, 63, 8425–
8429; (c) Salter, M. M.; Kobayashi, J.; Shimizu, Y.; Kobayashi, S. Org. Lett. 2006,
8, 3533–3536; (d) Kobayashi, S.; Kobayashi, J.; Ishitani, H.; Ueno, M. Chem. Eur.
J. 2002, 8, 4185–4190; (e) Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron 1999,
55, 8857–8867.
min, tR (major) = 17.700 min); ½a D20
ꢂ
¼ þ34:0 (c 1, CHCl3); 1H NMR
(300 MHz, DMSO-d6) d 7.16 (t, J = 8.1 Hz, 1H), 7.05–6.85 (m, 4H),
6.72 (dd, J = 8.1, 2.4 Hz, 1H), 6.54 (d, J = 7.8 Hz, 2H), 6.46 (t,
J = 7.2 Hz, 1H), 4.82 (t, J = 6.4 Hz, 1H), 3.69 (s, 3H), 2.81–2.67 (m,
1H), 2.42–2.21 (m, 2H), 1.94–1.42 (m, 6H); 13C NMR (75 MHz,
DMSO-d6) d 209.7, 159.1, 148.3, 144.8, 129.0, 128.5, 119.3, 115.7,
113.0, 113.0, 111.4, 56.5, 54.8, 54.6,41.2, 27.0, 26.7, 23.4.
3. (a) Wu, C.; Fu, X.; Li, S. Tetrahedron: Asymmetry 2011, 22, 1063–1073; (b) Wu,
C.; Fu, X.; Ma, X.; Li, S.; Li, C. Tetrahedron Lett. 2010, 51, 5775–5777; (c)
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Cheng, X.; Goddard, R.; Buth, G.; List, B. Angew. Chem., Int. Ed. 2008, 47, 5079–
5081; (f) Yang, J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed. 2007, 46, 609–
611; (g) Ramasastry, S. S.; Zhang, H.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc.
2007, 129, 288–289; (h) Cheng, L.; Wu, X.; Lu, Y. Org. Biomol. Chem. 2007, 5,
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9336–9337.
4.4. Experimental procedures for gram scale asymmetric
Mannich reactions
To a solution of aniline (1 g, 0.011 mol), 4-cyanobenzaldehyde
(1.55 g, 0.012 mol), 5 Å molecular sieves (4.80 g) in 80 mL of dry
toluene in
a 250 mL round-bottomed flask was added 1d
(0.127 g, 0.107 mmol). After stirring at room temperature for
0.5 h, cyclohexanone (44.38 mL, 0.43 mol) was added to the mix-
ture. The reaction was completed in 24 h and the resulting mixture
was concentrated under reduced pressure. The residue was puri-
fied using silica gel column chromatography (petroleum ether/
ethyl acetate = 5:1) to give pure product 9h (3.07 g, 94%).
4. Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356–5357.
5. (a) Wakchaure, V. N.; List, B. Angew. Chem., Int. Ed. 2010, 49, 4136–4139; (b)
ˇ
´
Vellalath, S.; Coric, I.; List, B. Angew. Chem., Int. Ed. 2010, 49, 9749–9752.
6. Guo, Q. S.; Du, D. M.; Xu, J. Angew. Chem., Int. Ed. 2008, 47, 759–762.
7. (a) Chen, X. H.; Zhang, W. Q.; Gong, L. Z. J. Am. Chem. Soc. 2008, 130, 5652–5653;
(b) Yu, J.; He, L.; Chen, X. H.; Song, J.; Chen, W. J.; Gong, L. Z. Org. Lett. 2009, 11,
4946–4949; (c) Yu, J.; Chen, W. J.; Gong, L. Z. Org. Lett. 2010, 12, 4050–4053.
8. During the preparation of this manuscript, List et al. reported the design and
synthesis of C2-symmetric imidodiphosphoric acids catalysts and their elegant
ˇ
Acknowledgments
´
application to asymmetric spiroacetalization reactions: Coric, I.; List, B. Nature
2012, 483, 315–319.
9. (a) Wu, T. R.; Shen, L.; Chong, J. M. Org. Lett. 2004, 6, 2701–2704; (b) Cox, P. J.;
Wang, W.; Snieckus, V. Tetrahedron Lett. 1992, 33, 2253–2256; (c) Kim, S. H.;
Jung, D. Y.; Chang, S. J. Org. Chem. 2007, 72, 9769–9771; (d) Sun, H.; Rajale, T.;
Pan, Y.; Li, G. Tetrahedron Lett. 2010, 51, 4403–4407.
10. Reducing the amount of cyclohexanone 6 led to the incomplete conversion of
in situ generated imine even with a prolonged reaction time.
11. Zheng, X.; Qian, Y.-B.; Wang, Y. Eur. J. Org. Chem. 2010, 515–522.
We are grateful for the financial support from the National Nat-
ural Science Foundation of China (No. 20802025) and the Jilin
Province Science
& Technology Development Program (Nos.
20100538, 20110436, 201215033).
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