Steric influence of N-phosphorus-arylimines on the rhodium-catalyzed asymmetric arylation

Article abstract of DOI:10.1016/j.tet.2011.06.033

Examination of the rhodium-catalyzed asymmetric arylation of benzaldehyde-imines bearing ethoxy, isopropoxy, phenyl, cyclohexyl, 3,5-xylyl, and 2,4,6-mesityl N-phosphorus activating/protecting groups revealed that bulky N-phosphorus groups retarded the arylation and at the same time prevented the competitive hydrolysis of an imine. Although the level of enantioselectivity was dependent favorably on the bulkiness ranging from 88% ee to 53% ee, the reactivity was drastically decreased along with bulkiness ranging from 95% to 3%.

Full text of DOI:10.1016/j.tet.2011.06.033

Tetrahedron 67 (2011) 6469e6473
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Steric influence of N-phosphorus-arylimines on the rhodium-catalyzed
asymmetric arylation
,b,
Xinyu Hao a, Qian Chen a, Ken-ichi Yamada a, Yasutomo Yamamoto b, Kiyoshi Tomioka a
*
a Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo, Kyoto 606-8501, Japan
b Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe 610-0395, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2011
Received in revised form 9 June 2011
Accepted 13 June 2011
Available online 17 June 2011
Examination of the rhodium-catalyzed asymmetric arylation of benzaldehyde-imines bearing ethoxy,
isopropoxy, phenyl, cyclohexyl, 3,5-xylyl, and 2,4,6-mesityl N-phosphorus activating/protecting groups
revealed that bulky N-phosphorus groups retarded the arylation and at the same time prevented the
competitive hydrolysis of an imine. Although the level of enantioselectivity was dependent favorably on
the bulkiness ranging from 88% ee to 53% ee, the reactivity was drastically decreased along with bulk-
iness ranging from 95% to 3%.
Dedicated to Professor Satoshi Omura on
the celebration of Tetrahedron Prize 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Bulkiness
Hydrolysis
Enantioselectivity
Imine
Boroxine
1. Introduction
2a, tuned sterically by introducing 2-methyl substituent on
diphenyl-phosphane group as one of the keys, which was antici-
Diarylmethylamines are key building blocks and potential in-
termediates for some biologically significant pharmaceuticals.1 Our
studies directed toward the catalytic asymmetric addition reaction
of an N-PMP (4-methoxyphenyl)-imine were disclosed first in 1990
by using 5 mol % of chiral aminoether as a catalytic controller for
the reaction of organolithium reagents.2 This strategy3 was suc-
cessfully extended to the chiral diether4 or aminoether5-controlled
asymmetric Mannich-type addition of lithium ester enolate to
imines. Chiral amidophosphaneecopper(II) catalyst was the second
generation for asymmetric alkylation of N-sulfonylimine with
diorganozinc reagents.6,7 The continuing studies of catalytic car-
bonecarbon bond forming reaction resulted in the amidophos-
phaneerhodium(I) complex-catalyzed asymmetric arylation of
N-Ts (toluenesulfonyl)-arylimine with arylboronic acids as an aryl
group source in 2004,8 in which ortho-trimethylsilyl substituent of
arylimine was the key for high enantioselectivity.9 Then, the more
general asymmetric arylation of a N-Dpp (diphenylphosphonyl)-
arylimine 1 was developed by relying on chiral amidophosphane
pated by the stereochemical analysis of an imineeRh(I)eamido-
phosphane complex (Scheme 1).10 Produced N-Dpp-amide was
easily deprotected to the corresponding free amine by mild acidic
hydrolysis, being contrasting to the N-Ts protecting group, which
requires rather harsh conditions to remove off.9 On the contrary,
the major problem in the arylation of N-Dpp (diphenylphos-
phonyl)-arylimine was the competitive imine hydrolysis that was
overcome by using water-removing conditions10a or water-free
conditions.10b The present purpose is the study of steric in-
fluences of phosphorus N-activating/protecting group on the
reactivity, enantioselectivity, and competitive imine hydrolysis.
N
O
PPh2
P(Tol-2)2
O
O
2a
HN
PPh2
(Ar'BO)3
or
N
NHBoc
+
Ar'
Ar
Ar'3B
Ar
3
Rh(acac)(C2H4)2
1
up to 99% ee
* Corresponding author. Tel.: þ81 774 65 8676; fax: þ81 774 65 8658; e-mail
Scheme 1. Sterically tuned-up amidomonophosphane 2a-Rh(I)-catalyzed arylation
under water-removing or water-free conditions.
address: tomioka@pharm.kyoto-u.ac.jp (K. Tomioka).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.033

6470
X. Hao et al. / Tetrahedron 67 (2011) 6469e6473
In our hypothetical model the C]N double bond of N-Dpp-
in good 95% yield and 3b with higher 81% ee in 74% yield, re-
spectively, as has been described10a (entries 1 and 2). The enan-
tioselectivity was determined by chiral stationary phase HPLC (see
Experimental section). 1-Naphthaldimine 1c afforded 3c with 78%
ee in 93% yield (entry 3). 4-Methylbenzaldehyde-imine 1d was
converted to the corresponding product 3d with 69% ee in 91% yield
(entry 4).11 Such small reactivity and moderate enantioselectivity
dependencies on the bulkiness of aryl substituent indicated the
usefulness of the model A and B where steric interaction may be
critical at the N-protecting/activating site. Additional support to
this hypothetical model is the fact that benzaldehyde-imine bear-
ing a smaller N-Ts group was converted to the corresponding amide
with somewhat poorer 66% ee in 83% yield,9 indicating that N-Dpp
should be a little bit bulkier than N-Ts group.
imine 1 is expected to coordinate to rhodium(I) on the re-face as
shown in A to give the product with the observed S-configuration
(Fig. 1).10a Coordination on the si-face (B) is unfavorable due to
steric repulsion between the axial phenyl of the phosphorus (2b)
and the phenyl group of Dpp. This analysis indicated that the
bulkiness of the phenyl group on the phosphorus atom of a ligand
favors A over B, and therefore increased bulkiness around this li-
gand part is expected to improve the enantioselectivity of the
reaction.
The reaction of 1a was further examined at lower 40 ꢀC for
prolonged 9 h to give 3a with 59% ee in 36% yield. The reaction in
a different solvent, dioxane, at 100 ꢀC for 2 h gave 3a with 56% ee in
65% yield, indicating n-propanol at 60 ꢀC is the suitable conditions.
3. Preparation of N-phosphorus imines
Other benzaldehyde-imines
6 bearing ethoxy, isopropoxy,
cyclohexyl, 3,5-xylyl, and 2,4,6-mesityl N-phosphorus groups, 6a,12
6bee,13 were prepared by the condensation of benzaldehyde 4 or
its acetal 7 with the corresponding amides 5a,12 5b,14 5c,13 5d,15 and
5e16 (Scheme 2).
Fig. 1. ImineeRh(I)eamidophosphane 2b complexes A and B.
In order to experimentally confirm this hypothetical model the
steric modification of phosphane ligand as shown in 2a was found
to be one certain approach, and examination of the steric influence
of imine N-phosphorous part should be another possibility that is
also another purpose of the present study. We describe the steric
influence of N-phosphorus-arylimines on reactivity, competitive
hydrolysis, and enantioselectivity.
2. Influences of aryl substituents on reactivity, competitive
hydrolysis, and enantioselectivity
At first the influence of aryl substituent of the N-Dpp-arylimines
1 was examined on the reactivity and enantioselectivity under the
established conditions9 for N-Ts-imines by using 6.6 mol % of our
prototype diphenylphosphino-ligand 2b, 6 mol % of Rh(I), and
1.67 equiv of 4-phenylphenylboroxine as an aryl source in n-
propanol at 60 ꢀC for 2e5 h (Table 1). 4-Phenylphenylation of
benzaldehyde-imine 1a and bulkier 2-trimethylsilylbenzaldehyde-
imine 1b gave the corresponding addition product 3a with 70% ee
Scheme 2. Preparation of imines 6aee bearing N-phosphorus activating/protecting
groups.
4. Asymmetric 4-phenylphenylation of N-phosphorus imines
Diethoxyphosphorimide 6a and isopropoxy derivative 6b were
converted to the corresponding products 8a with 61% ee in 74%
yield and 8b with 53% ee in 76% yield, suggesting that alkoxy
substituents on the phosphorus is not bulky enough than a phenyl
group in 1a (Table 2, entries 1e3). It is important to note the
formation of benzaldehyde in each 15% yields by competitive
hydrolysis of imines 6a and 6b. Dicyclohexyl-phosphorimide 6c
was better than 1a with regards to enantioselectivity, 78% ee
versus 70% ee, however, the reactivity is rather poorer than that of
1a to give 8c in only 10% yield and recover 6c in 81% yield without
hydrolysis after 22 h heating at 100 ꢀC17 (entry 4). Although 3,5-
xylyl phosphorimide 6d was converted to 8d in 42% yield at
60 ꢀC for 20 h, the enantioselectivity was 67% ee and 6d was re-
covered in 40% yield without substantial detection of benzalde-
hyde (entry 5). Imine 6e bearing the bulkiest 2,4,6-
mesitylphosphorus group was converted to 8e with expectedly
high 88% ee. However, the yield was unsatisfactorily low of only
3% after 8 h at 100 ꢀC17 and starting imine 6e was recovered in
89% yield without hydrolysis (entry 6).18
Table 1
Rh(I)-2b-catalyzed asymmetric 4-phenylphenylation of imines 1
N
PPh2
O
O
PPh2
O
PPh2
2b
NHBoc
6.6 mol %
HN
6 mol % Rh(acac)(C2H4)2
N
Ar
+
(4-PhC6H4BO)3
1.67 eq
n-PrOH
60 °C
Ar
1
Ph
3
Entry
1
Ar
Ph
Time/h
3
Yield/%
ee/%
1a
2a
3
1a
2
3.5
5
3a
3b
3c
3d
95
74
93
91
70
81
78
69
1b
1c
1d
2-TMSC6H4
1-Naph
4-MeC6H4
4
3.5
a
The data was referred from Ref. 10a.

X. Hao et al. / Tetrahedron 67 (2011) 6469e6473
6471
621 cmꢁ1. EIMS m/z: 377 (Mþ). Anal. Calcd for C22H24NOPSi: C,
70.00; H, 6.41; N, 3.71. Found: C, 69.72; H, 6.65; N, 3.54.
Table 2
4-Phenylphenylation of benzaldehyde-imines 6 with various phosphorus N-acti-
vating/protecting groups
7.1.2. Diisopropyl benzylidenephosphoramidate (6b)13. Colorless oil.
1H NMR: 1.35 (6H, d, J¼6.1 Hz), 1.39 (6H, d, J¼6.1 Hz), 4.70e4.85
(2H, m), 7.45e7.55 (2H, m), 7.58 (1H, m), 7.90e8.00 (2H, m), 9.08
(1H, d, J¼32.4 Hz). 13C NMR: 23.7 (CH3), 23.9 (CH3), 72.0 (d,
J¼6.2 Hz, CH3), 128.9 (CH), 130.4 (CH), 133.8 (CH), 135.5 (d,
J¼29.9 Hz, C), 175.1 (d, J¼5.2 Hz, CH). IR (KBr): 1631, 995 cmꢁ1. EIMS
m/z: 269 (Mþ). HRMS-EI m/z: calcd for C13H20NO3P, 269.1181.
Found: 269.1178.
N
PPh2
O
P
O
O
P
R
R
NHBoc
2b
6.6 mol %
HN
N
R
R
6 mol % Rh(acac)(C2H4)2
+
(4-PhC6H4BO)3
1.67 eq
n-PrOH
60 °C or 100 °C
Ph
6
8
7.1.3. N-Benzylidene-P,P-dicyclohexylphosphinic amide (6c)13. Colorless
solid of mp 127e128 ꢀC. 1H NMR: 1.15e1.55 (10H, m), 1.60e1.71 (2H,
m), 1.72e1.88 (6H, m), 1.90e2.10 (4H, m), 7.45e7.55 (2H, m), 7.56 (1H,
m), 7.91 (2H, d, J¼7.6 Hz), 9.06 (1H, d, J¼29.3 Hz). 13C NMR: 24.8 (d,
J¼3.1 Hz, CH2), 25.3 (d, J¼4.1 Hz, CH2), 25.9 (CH2), 26.2 (CH2), 26.3
(CH2), 26.4 (CH2), 34.4 (CH), 35.0 (CH), 128.9 (CH), 129.8 (CH), 133.1
(CH), 136.0 (d, J¼22.6 Hz, C), 174.2 (d, J¼9.2 Hz, CH). 31P NMR: 47.3. IR
(KBr): 1627, 1180 cmꢁ1. EIMS m/z: 317 (Mþ). HRMS-EI m/z: calcd for
C19H28NOP, 317.1909. Found: 317.1914.
Entry
6
R
Temp/ꢀC
Time/h
8
Yield/%
ee/%
1
6a
6b
1a
6c
6d
6e
OEt
60
60
4
6
2
22
20
8
8a
8b
3a
8c
8d
8e
74 (15a)
76 (15a)
95
61
53
70
78
67
88
2
OiPr
3b
4
Ph
60
cHex
3,5-Xyl
2,4,6-Mes
100c
60
10 (81d)
42 (40d)
3 (89d)
5
6
100c
a
Recovery % of benzaldehyde.
The data is duplicated from entry 1, Table 1 for easy comparison.
No reaction took place at 60 ꢀC.
b
c
d
Recovery % of starting imine 6 without hydrolysis.
7.1.4. N-Benzylidene-P,P-bis(3,5-xylyl)phosphinic amide (6d)13. Colorless
solid of mp 75e76 ꢀC. 1H NMR: 2.33 (12H, s), 7.12 (2H, m), 7.45e7.65
(7H, m), 7.02 (2H, d, J¼7.3 Hz), 9.30 (1H, d, J¼31.8 Hz). 13C NMR: 21.2
(CH3), 129.1 (d, J¼25.7 Hz, CH), 129.2 (CH), 130.2 (CH), 132.7 (d,
J¼126 Hz, C), 133.5 (CH), 133.6 (d, J¼3.1 Hz, CH), 136.0 (d, J¼24.7 Hz, C),
5. Mechanistic insight
Substituents of phenyl group in N-Dpp-arylimines influenced
not so much on reactivity and enantioselectivity to give products
with 81e69% ee in reasonably high yields, indicating the plausi-
bility of hypothetical imineeRh(I)eamidophosphane complex
model. On the other hand, the bulkiness of N-phosphorus part
influenced much on the reactivity negatively and enantioselectivity
positively, implying also plausibility of the model. With bulky N-
phosphorus groups the competitive hydrolysis of imine was pre-
vented. The poor reactivity of imines bearing bulky N-phosphorus
part may indicate the difficulty in coordination of imine to Rh(I).
138.1 (C), 138.2 (C), 173.3 (d, J¼8.2 Hz, CH). IR (KBr): 1126, 694 cmꢁ1
.
EIMS m/z: 361 (Mþ). HRMS-EI m/z: calcd for C23H24NOP, 361.1596.
Found: 361.1601.
7.1.5. N-Benzylidene-P,P-bis(2,4,6-mesityl)phosphinic amide (6e)13
.
Colorless solid of mp 149e150 ꢀC. 1H NMR: 2.25 (6H, s), 2.42 (12H,
s), 6.82 (2H, s), 6.83 (2H, s), 7.48 (2H, m), 7.54 (1H, m), 7.93 (2H, d,
J¼7.9 Hz), 9.30 (1H, d, J¼33.0 Hz). 13C NMR: 20.9 (CH3), 23.0 (d,
J¼3.1 Hz, CH3), 128.9 (CH), 129.2 (d, J¼121 Hz, C), 130.2 (CH), 130.8
(d, J¼13.4 Hz, CH), 133.1 (CH), 136.6 (d, J¼24.7 Hz, C), 140.9 (d,
J¼3.1 Hz, C), 142.0 (d, J¼10.3 Hz, C), 171.4 (d, J¼7.2 Hz, CH). IR (KBr):
6. Conclusion
1454, 1377, 825 cmꢁ1 EIMS m/z: 389 (Mþ). Anal. Calcd for
.
C25H28NOP: C, 77.10; H, 7.25; N, 3.60. Found: C, 77.37; H, 7.27; N,
3.54.
Possibility in the control of reactivity, enantioselectivity, and
competitive hydrolysis of N-phosphorus arylimine was pursued by
examining the steric influences of N-phosphorus groups on aryla-
tion. Although the bulky cyclohexyl and 2,4,6-mesityl N-phospho-
rus groups retarded hydrolysis, but arylation was also blocked. As
has been expected from imineeRh(I)eamidophosphane complex
model, the bulkiest mesityl derivative gave the highest enantiose-
lectivity of 88% although the yield was poorest. These clearly in-
dicated the reality and utility of imineeRh(I)eamidophosphane
complex model as the fundamental of our further approach.
7.2. General procedure for the catalytic asymmetric 4-
phenylphenylation of an imine with boroxine
Under argon atmosphere, a reaction flask was charged with
Rh(acac)(C2H4)2 (15.5 mg, 0.06 mmol), 2b (31.0 mg, 0.066 mmol),
imine 1 (6) (1 mmol), and (4-PhC6H4BO)3 (902 mg, 1.67 mmol). To
the flask was added n-PrOH (2.5 mL). The reaction mixture was put
in a preheated oil bath (60 ꢀC or 100 ꢀC), and then stirred for
2e22 h at the same temperature. After dilution with AcOEt, the
mixture was washed with brine, dried over Na2SO4, and then
concentrated. The resulting residue was purified through silica gel
column chromatography to give 3 (8).
7. Experimental
7.1. General
All NMR was recorded at 500 MHz (1H), 125 MHz (13C), and
7.2.1. (ꢁ)-(S)-N-[Biphenyl-4-yl(phenyl)methyl]-P,P-diphenylphos-
202 MHz (31P) in CDCl3. Chemical shift was expressed in
d
parts per
phinic amide (3a). Chromatography (hexane/acetone¼5/1) gave 3a
25
million. Specific rotation was measured in CHCl3.
(438 mg, 95%) as colorless solid of mp 190e191 ꢀC. [
a]
ꢁ27.0 (c
D
0.56, CHCl3). 70% ee (HPLC, Daicel Chiralpak AD, hexane/i-PrOH¼4/
1, 1.0 mL/min, 254 nm, major 14.2 min and minor 17.4 min). 1H
NMR: 3.66 (1H, dd, J¼6.4, 9.8 Hz), 5.50 (1H, dd, J¼9.8, 11.6 Hz),
7.24e7.35 (8H, m), 7.36e7.40 (4H, m), 7.41e7.49 (4H, m), 7.52 (2H, d,
J¼8.2 Hz), 7.57 (2H, d, J¼8.2 Hz), 7.84e7.88 (4H, m). 13C NMR: 58.3
(CH), 127.1 (CH), 127.2 (CH), 127.3 (CH), 127.6 (CH), 128.1 (CH), 128.4
(d, J¼13.4 Hz, CH), 128.6 (CH), 128.8 (CH), 131.9 (CH), 132.3 (d,
J¼8.8 Hz, CH), 132.31 (d, J¼129 Hz, C), 132.39 (d, J¼8.8 Hz, CH),
7.1.1. P,P-Diphenyl-N-(2-(trimethylsilyl)benzylidene)phosphinic am-
ide (1b)19. Colorless oil. 1H NMR: 0.33 (9H, s), 7.40e7.55 (8H, m),
7.64 (1H, d, J¼6.1 Hz), 7.92 (4H, dd, J¼7.9, 11.7 Hz), 8.33 (1H, d,
J¼7.6 Hz), 9.59 (1H, d, J¼32.4 Hz). 13C NMR: 0.7 (CH3), 128.46 (CH),
128.51 (d, J¼12.4 Hz, CH), 129.4 (CH), 131.7 (d, J¼8.7 Hz, CH), 131.8
(d, J¼2.1 Hz, CH),132.2 (CH),132.8 (d, J¼126 Hz, C),135.0 (CH),140.9
(C), 144.8 (C), 174.7 (d, J¼7.2 Hz, CH). IR (KBr): 1585, 1123, 702,

6472
X. Hao et al. / Tetrahedron 67 (2011) 6469e6473
132.41 (d, J¼129 Hz, C), 140.1 (C), 140.8 (C), 142.4 (d, J¼4.1 Hz, C),
127.6 (CH), 128.6 (CH), 128.8 (CH), 140.2 (C), 140.7 (C), 142.3 (d,
J¼5.1 Hz, C), 143.2 (d, J¼5.1 Hz, C). 31P NMR: 4.55. IR (KBr): 1223,
763, 702 cmꢁ1. EIMS m/z: 395 (Mþ). Anal. Calcd for C23H26NO3P: C,
69.86; H, 6.63; N, 3.54. Found: C, 70.02; H, 6.73; N, 3.53.
143.3 (d, J¼4.1 Hz, C). 31P NMR: 22.3. IR (KBr): 1184, 725, 694 cmꢁ1
.
EIMS m/z: 459 (Mþ). Anal. Calcd for C31H26NOP: C, 81.03; H, 5.70; N,
3.05. Found: C, 80.75; H, 5.87; N, 3.08.
7.2.2. (ꢁ)-N-[Biphenyl-4-yl-(2-trimethylsilylphenyl)methyl]diphenyl-
phosphinic amide (3b). Chromatography (hexane/acetone¼5/1) gave
7.2.6. (ꢁ)-Diisopropyl [biphenyl-4-yl(phenyl)methyl]phosphoramidate
(8b). Chromatography (hexane/AcOEt¼4/1) gave 8b (320 mg,
3b (395 mg, 74%) as colorless solid of mp 211e212 ꢀC. [
a]
25 ꢁ27.6 (c
76%) as a white solid of mp 126e127 ꢀC. [
a
]
25 ꢁ9.8 (c 1.05, CHCl3).
D
D
1.00, CHCl3). 81% ee (HPLC, Daicel Chiralpak OD-H, hexane/i-PrOH¼
10/1, 1.0 mL/min, 254 nm, major 7.8 min and minor 14.9 min). 1H
NMR: ꢁ0.17 (9H, s), 3.74 (1H, dd, J¼6.1, 9.8 Hz), 5.83 (1H, dd, J¼9.8,
11.0 Hz), 7.25 (1H, m), 7.32e7.36 (5H, m), 7.39e7.44 (5H, m),
7.47e7.49 (4H, m), 7.53e7.57 (3H, m), 7.73e7.77 (3H, m), 7.91e7.95
(2H, m). 13C NMR: 0.04 (CH3), 56.7 (CH), 126.5 (CH), 127.0 (CH), 127.1
(CH), 127.3 (CH), 128.3 (d, J¼12.4 Hz, CH), 128.6 (d, J¼12.4 Hz, CH),
128.8 (CH), 129.3 (CH), 129.4 (CH), 131.7 (CH), 131.80 (CH), 131.83 (d,
J¼129 Hz, C), 131.9 (CH), 132.5 (d, J¼129 Hz, C), 133.1 (d, J¼10.3 Hz,
CH), 134.8 (CH), 138.4 (C), 140.0 (C), 140.7 (C), 143.6 (d, J¼3.1 Hz, C),
143.6 (d, J¼4.1 Hz, C). 31P NMR: 20.2. IR (KBr): 1126, 845 cmꢁ1. EIMS
m/z: 531 (Mþ). HRMS-EI m/z: calcd for C34H34NOPSi: 531.2147.
Found: 531.2153.
53% ee (HPLC, Daicel Chiralpak OD-H, hexane/i-PrOH¼15/1,
1.0 mL/min, 254 nm, major 4.6 min and minor 5.5 min). 1H NMR:
1.10 (3H, d, J¼6.1 Hz), 1.11 (3H, d, J¼6.1 Hz), 1.29 (6H, d, J¼6.1 Hz),
3.29 (1H, dd, J¼9.8, 9.8 Hz), 4.52e4.55 (2H, m), 5.47 (1H, dd, J¼9.8,
9.8 Hz), 7.26 (1H, m), 7.31e7.36 (7H, m), 7.41e7.44 (2H, m),
7.53e7.58 (4H, m). 13C NMR: 23.4 (d, J¼5.1 Hz), 23.5 (d, J¼5.1 Hz,
CH3), 23.7 (d, J¼4.1 Hz, CH3), 58.9 (CH), 71.0 (d, J¼5.1 Hz, CH), 127.1
(CH), 127.2 (CH), 127.3 (CH), 127.32 (CH), 127.7 (CH), 128.5 (CH),
128.8 (CH), 140.1 (C), 140.7 (C), 142.6 (d, J¼5.1 Hz, C), 143.4 (d,
J¼5.1 Hz, C). 31P NMR: 2.64. IR (KBr): 1254, 891, 759 cmꢁ1. EIMS m/
z: 423 (Mþ). Anal. Calcd for C25H30NO3P: C, 70.90; H, 7.14; N, 3.31.
Found: C, 70.70; H, 7.15; N, 3.25.
7.2.7. (e)-N-[Biphenyl-4-yl(phenyl)methyl] dicyclohexylphosphinic
7.2.3. (ꢁ)-N-[Biphenyl-4-yl(naphthylmethyl)diphenylphosphinic
amide (8c). Chromatography (hexane/acetone¼5/1) gave 8c
23
amide (3c). Chromatography (hexane/acetone¼5/1) gave 3c
(48 mg, 10%) as colorless solid of mp 245e246 ꢀC. [
a
]
ꢁ15.3 (c
D
25
(473 mg, 93%) as colorless solid of mp 228e229 ꢀC. [
a
]
ꢁ12.5 (c
0.30, CHCl3). 78% ee (HPLC, Daicel Chiralpak AD, hexane/i-PrOH¼
15/1, 1.0 mL/min, 254 nm, major 46.7 min and minor 42.2 min). 1H
NMR: 1.10e1.16 (6H, m), 1.20e1.50 (4H, m), 1.60e1.80 (10H, m),
1.85e1.99 (2H, m), 2.69 (1H, dd, J¼9.5, 9.5 Hz), 5.71(1H, dd, J¼9.5,
9.5 Hz), 7.32e7.39 (8H, m), 7.43 (2H, t, J¼7.9 Hz), 7.52e7.61 (4H, m).
13C NMR: 25.38 (CH2), 25.40 (CH2), 25.71 (CH2), 25.74 (CH2), 25.77
(CH2), 25.9 (CH2), 26.4 (d, J¼3.1 Hz, CH2), 26.5 (d, J¼4.1 Hz, CH2),
36.3 (d, J¼11.3 Hz, CH), 37.0 (d, J¼12.4 Hz, CH), 127.1 (CH), 127.2
(CH), 127.3 (CH), 127.6 (CH), 128.1 (CH), 128.5 (CH), 128.8 (CH), 139.9
(C), 140.8 (C), 143.4 (d, J¼3.1 Hz, C), 144.2 (d, J¼3.1 Hz, C). 31P NMR:
45.03. IR (KBr): 1164, 702 cmꢁ1. EIMS m/z: 471 (Mþ). HRMS-EI m/z:
calcd for C31H38NOP: 471.2691. Found: 471.2684.
D
1.04, CHCl3). 78% ee (HPLC, Daicel Chiralpak OD-H, hexane/i-PrOH¼
4/1, 1.0 mL/min, 254 nm, major 6.8 min and minor 10.4 min). 1H
NMR: 3.76 (1H, dd, J¼6.8, 9.5 Hz), 6.23 (1H, dd, J¼9.5, 12.5 Hz),
7.30e7.34 (2H, m), 7.37e7.43 (9H, m), 7.45e7.48 (3H, m), 7.50e7.55
(3H, m), 7.70 (1H, m), 7.72e7.91 (8H, m). 13C NMR: 55.6 (CH), 123.9
(CH), 125.3 (CH), 125.4 (CH), 125.6 (CH), 126.2 (CH), 127.0 (CH), 127.3
(CH), 128.3 (CH), 128.4 (d, J¼6.2 Hz, CH), 128.5 (d, J¼12.4 Hz, CH),
128.7 (CH), 128.8 (CH), 130.5 (C), 131.82 (d, J¼127 Hz, C), 131.84 (d,
J¼2.1 Hz, CH), 131.9 (d, J¼2.1 Hz, CH), 132.0 (d, J¼9.3 Hz, CH), 132.4
(d, J¼9.5 Hz, CH),132.7 (d, J¼127 Hz, C),134.0 (C),138.4 (d, J¼5.2 Hz,
C), 140.0 (C), 140.7 (C), 142.4 (d, J¼3.1 Hz, C). IR (KBr): 1184, 752,
698 cmꢁ1. EIMS m/z: 509 (Mþ). Anal. Calcd for C35H28NOP: C, 82.49;
H, 5.54; N, 2.75. Found: C, 82.23; H, 5.84; N, 2.63.
7.2.8. (ꢁ)-N-[Biphenyl-4-yl(phenyl)methyl] bis(3,5-xylyl)phosphinic
amide (8d). Chromatography (hexane/Et2O¼5/1) gave 8d (218 mg,
7.2.4. (ꢁ)-N-[Biphenyl-4-yl-(4-methylphenyl)methyl]diphenylphos-
42%) as colorless solid of mp 218e219 ꢀC. [
a]
23 ꢁ17.4 (c 1.00, CHCl3).
D
phinic amide (3d). Chromatography (hexane/acetone¼5/1) gave 3d
67% ee (HPLC, Daicel Chiralpak AD, hexane/i-PrOH¼15/1, 1.0 mL/
min, 254 nm, major 17.5 min and minor 20.2 min). 1H NMR: 2.249
(6H, s), 2.254 (6H, s), 3.60 (1H, dd, J¼6.7, 10.1 Hz), 5.49 (1H, dd,
J¼10.1, 11.9 Hz), 7.07 (2H, m), 7.25e7.35 (8H, m), 7.42e7.45 (6H, m),
7.52e7.58 (4H, m). 13C NMR: 21.1 (CH3), 58.2 (CH), 127.1 (d,
J¼10.3 Hz, CH), 127.3 (d, J¼8.2 Hz, CH), 127.7 (CH), 128.2 (CH), 128.5
(CH), 128.8 (CH), 129.9 (d, J¼5.1 Hz, CH), 130.0 (d, J¼5.1 Hz, CH),
133.56 (CH), 133.59 (CH), 138.1 (d, J¼11.3 Hz, C), 140.0 (C), 140.9 (C),
142.7 (d, J¼3.1 Hz, C),143.5 (d, J¼5.1 Hz, C). 31P NMR: 22.17. IR (KBr):
1195, 825, 652 cmꢁ1. EIMS m/z: 515 (Mþ). HRMS-EI m/z: calcd for
C35H34NOP: 515.2378. Found: 515.2374.
22
(429 mg, 91%) as colorless solid of mp 187e188 ꢀC. [
a
]
ꢁ16.3 (c
D
1.09, CHCl3). 69% ee (HPLC, Daicel Chiralpak AD, hexane/i-PrOH¼4/
1, 1.0 mL/min, 254 nm, major 17.0 min and minor 19.2 min). 1H
NMR: 2.33 (3H, s), 3.64 (1H, dd, J¼6.7, 10.1 Hz), 5.47 (1H, dd, J¼10.1,
11.3 Hz), 7.12 (2H, d, J¼7.9 Hz), 7.19 (2H, d, J¼7.9 Hz), 7.32e7.41 (7H,
m), 7.42e7.48 (4H, m), 7.49 (2H, d, J¼7.9 Hz), 7.56 (2H, d, J¼7.9 Hz),
7.84e7.88 (4H, m). 13C NMR: 21.0 (CH3), 58.1 (CH), 127.1 (CH), 127.2
(CH), 127.3 (CH), 127.5 (CH), 128.0 (CH), 128.4 (d, J¼12.4 Hz, CH),
128.8 (CH), 129.3 (CH), 131.9 (CH), 132.3 (d, J¼8.8 Hz, CH), 132.36 (d,
J¼8.8 Hz, CH), 132.39 (d, J¼129 Hz, C), 132.5 (d, J¼129 Hz, C), 136.9
(C), 140.0 (C), 140.4 (d, J¼5.2 Hz, C), 140.8 (C), 142.6 (d, J¼4.1 Hz, C).
31P NMR: 22.2. IR (KBr): 1184, 725, 694 cmꢁ1. EIMS m/z: 473 (Mþ).
Anal. Calcd for C32H28NOP: C, 81.16; H, 5.96; N, 2.96. Found: C,
80.99; H, 5.91; N, 2.88.
7.2.9. (ꢁ)-N-[Biphenyl-4-yl(phenyl)methyl] bis(2,4,6-mesityl)-phos-
phinic amide (8e). Chromatography (hexane/acetone¼5/1) gave 8e
(14 mg, 3%) as colorless solid of mp 122e123 ꢀC. [
a
]
D
23 ꢁ18.1 (c 0.35,
CHCl3). 88% ee (HPLC, Daicel Chiralpak AD, hexane/i-PrOH¼4/1,
1.0 mL/min, 254 nm, major 11.5 min and minor 27.4 min). 1H NMR:
2.23 (3H, s), 2.24 (3H, s), 2.27 (6H, s), 2.28 (6H, s), 3.68 (1H, dd, J¼5.2,
9.2 Hz), 5.34 (1H, dd, J¼9.2, 10.4 Hz), 6.74 (2H, s), 6.75 (2H, s),
7.19e7.27 (7H, m), 7.32 (1H, t, J¼7.6 Hz), 7.42 (2H, t, J¼7.6 Hz), 7.46
(2H, d, J¼8.3 Hz), 7.54 (2H, d, J¼7.3 Hz). 13C NMR: 20.9 (CH3), 22.92
(CH3), 22.96 (CH3), 22.99 (CH3), 59.9 (CH), 127.0 (CH), 127.1 (CH),
127.2 (CH), 127.5 (CH), 127.9 (CH), 128.4 (CH), 128.7 (CH), 129.9 (d,
J¼121 Hz, C), 131.0 (d, J¼122 Hz, C), 130.9 (d, J¼12.4 Hz, CH), 139.8
(C),140.45 (C),140.48 (C),140.51 (C),140.9 (C),141.4 (d, J¼10.3 Hz, C),
141.6 (d, J¼10.5 Hz, C),143.0 (d, J¼5.1 Hz, C),143.8 (d, J¼5.1 Hz, C). IR
7.2.5. (ꢁ)-Diethyl
[biphenyl-4-yl(phenyl)methyl]phosphoramidate
(8a). Chromatography (hexane/AcOEt¼4/1) gave 8a (294 mg, 74%)
as colorless solid of mp 124e125 ꢀC. [
a
]
24 ꢁ13.5 (c 0.48, CHCl3). 61%
D
ee (HPLC, Daicel Chiralpak OD-H, hexane/i-PrOH¼15/1, 1.0 mL/min,
254 nm, major 7.9 min and minor 10.2 min). 1H NMR: 1.19 (3H, dt,
J¼0.9, 7.0 Hz), 1.20 (3H, dt, J¼0.9, 7.0 Hz), 3.38 (1H, dd, J¼9.8,
9.8 Hz), 3.83e3.91 (2H, m), 3.98e4.06 (2H, m), 5.47 (1H, dd, J¼9.8,
9.8 Hz), 7.27e7.36 (8H, m), 7.43 (2H, m), 7.54e7.58 (4H, m). 13C
NMR: 15.9 (d, J¼3.1 Hz, CH3), 16.0 (d, J¼3.1 Hz, CH3), 59.0 (CH), 62.4
(d, J¼3.1 Hz, CH2), 127.1 (CH), 127.2 (CH), 127.3 (CH), 127.4 (CH),

X. Hao et al. / Tetrahedron 67 (2011) 6469e6473
6473
(KBr): 1161, 721, 648 cmꢁ1. EIMS m/z: 544 (Mþ1). Anal. Calcd for
T.; Maekawa, M.; Yamamoto, Y.; Nakano, M.; Tomioka, K. Chem. Pharm. Bull.
2010, 58, 265e269.
C37H38NOP: C, 81.74; H, 7.04; N, 2.58. Found: C, 81.91; H, 7.18; N, 2.53.
8. Select examples of Rh-catalyzed asymmetric additions of arylboron reagents to
imines: (a) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.;
Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584e13585; (b) Otomaru, Y.; Toku-
naga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307e310; (c) Weix, D. J.; Shi,
Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092e1093; (d) Duan, H.-F.; Jia, Y.-X.;
Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2006, 8, 2567e2569; (e) Jagt, R. B. C.; Toullec,
P. Y.; Geerdink, D.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J. Angew. Chem., Int.
Ed. 2006, 45, 2789e2791; (f) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am.
Chem. Soc. 2007, 129, 5336e5337; (g) Nakagawa, H.; Rech, J. C.; Sindelar, W. R.;
Ellman, J. A. Org. Lett. 2007, 9, 5155e5157; (h) Trincado, M.; Ellman, J. A. Angew.
Chem., Int. Ed. 2008, 47, 5623e5626; (i) Kurihara, K.; Yamamoto, Y.; Miyaura, N.
Adv. Synth. Catal. 2009, 351, 260e270.
Acknowledgements
This research was partially supported by a Grant-in-Aid for
Young Scientists (B) and a Grant-in-Aid for Scientific Research (A)
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
References and notes
9. Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.; Tomioka, K. J. Am. Chem. Soc. 2004,
126, 8128e8129.
10. (a) Hao, X.; Kuriyama, M.; Chen, Q.; Yamamoto, Y.; Yamada, K.; Tomioka, K. Org.
Lett. 2009, 11, 4470e4473; (b) Hao, X.; Chen, Q.; Yamamoto, Y.; Kuriyama, M.;
Yamada, K.; Tomioka, K. Catal.: Sci. Technol. 2011, 1, 62e64.
1. (a) Spencer, C. M.; Foulds, D.; Peters, D. H. Drugs 1993, 46, 1055e1080; (b)
Bishop, M. J.; McNutt, R. W. Bioorg. Med. Chem. Lett. 1995, 5, 1311e1314; (c)
Sakurai, S.; Ogawa, N.; Suzuki, T.; Kato, K.; Ohashi, T.; Yasuda, S.; Kato, H.; Ito, Y.
Chem. Pharm. Bull. 1996, 44, 765e777.
2. (a) Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron Lett. 1990, 31,
6681e6684.
11. 1-Naphthyl group 1c represents 2-substituted phenyl group, though smaller
than 2-trimethylsilyl group 1b that is far larger than 2-methyl group.
12. Zwierzak, A.; Napieraj, A. J. Tetrahedron 1996, 52, 8789e8794.
€
13. (a) Yamada, K.; Harwood, S. J.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed.
3. Tomioka, K. Synthesis 1990, 541e549.
1999, 38, 3504e3506; (b) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47,
5561e5568.
14. For amide: Sosnovsky, G.; Zaret, E. H. J. Org. Chem. 1969, 34, 968e9704.
15. For amide: Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki, K.; Ku-
mobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.; Takaya, H. J. Org.
Chem. 1994, 59, 3064e3076.
16. For amide; (a) Harger, M. J. P.; Shimmin, P. A. J. Chem. Soc., Perkin Trans. 1 1993,
227e232; (b) Harger, M. J. P. J. Chem. Soc., Perkin Trans. 2 1980, 154e160.
17. No reaction took place at 60 ꢀC.
18. The reaction under the established conditions described in Ref. 9 did not give
8e probably because of too much bulkiness.
4. (a) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am. Chem. Soc.
1997, 119, 2060e2061; (b) Kambara, T.; Tomioka, K. J. Org. Chem. 1999, 64,
9282e9285.
5. Tomioka, K.; Fujieda, H.; Hayashi, S.; Hussein, M. A.; Kambara, T.; Nomura, Y.;
Kanai, M.; Koga, K. Chem. Commun. 1999, 715e716.
6. (a) For review of copper-catalyzed reaction see: Yamada, K.; Tomioka, K. Chem.
Rev. 2008, 108, 2874e2886; (b) Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem.
Soc. 2000, 122, 12055e12056; (c) Soeta, T.; Nagai, K.; Fujihara, H.; Kuriyama, M.;
Tomioka, K. J. Org. Chem. 2003, 68, 9723e9727.
7. For dimethylzinc-mediated radical addition of acetal to enantiomerically pure
imine, see: (a) Akindele, T.; Yamada, K.; Tomioka, K. Acc. Chem. Res. 2009, 42,
345e355; (b) Akindele, T.; Yamamoto, Y.; Maekawa, M.; Umeki, H.; Yamada, K.;
Tomioka, K. Org. Lett. 2006, 8, 5729e5732; (c) Akindele, T.; Yamada, K.; Sejima,
19. Prepared according to the procedure reported in Lauzon, C.; Desrosiers, J.;
Charette, A. B. J. Org. Chem. 2005, 70, 10579e10580.