Synthesis of Chiral Phosphorus Reagents and Their Catalytic Activity in Asymmetric Borane Reduction of N-Phenyl Imine of Acetophenone

Article abstract of DOI:10.1002/hc.10190

Eleven chiral trivalent or quatrivalent phosphorus reagents were synthesized starting from L-proline, D-camphor, (+)- or (-)-1,1'-binaphthalene-2,2'-diol, (-)-α-phenylethylamine, etc. and their application as catalysts in asymmetric borane reduction of N-

Full text of DOI:10.1002/hc.10190

Heteroatom Chemistry
Volume 14, Number 6, 2003
Synthesis of Chiral Phosphorus Reagents and
Their Catalytic Activity in Asymmetric Borane
Reduction of N-Phenyl Imine of Acetophenone
Li Kangying, Zhou Zhenghong, Zhao Guofeng, and Tang Chuchi
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, People’s Republic of China
Received 4 April 2003; revised 23 April 2003
imines, there is still a challenge for other reduction
ABSTRACT: Eleven chiral trivalent or quatrivalent
methods in this important research area [3]. Dur-
phosphorus reagents were synthesized starting from
ing the past decade significant progress has been
L-proline, D-camphor, (+)- or (−)-1,1ꢀ-binaphthalene-
achieved in the preparation of chiral secondary al-
2,2ꢀ-diol, (−)-α-phenylethylamine, etc. and their appli-
cohols through asymmetric borane reduction of the
cation as catalysts in asymmetric borane reduction
corresponding prochiral ketones [4]. However, lit-
of N-phenyl imine of acetophenone was preliminar-
tle attention has been focused on the preparation
ily investigated. N-Phenyl α-phenylethylamine was ob-
of chiral secondary amines via asymmetric borane
tained in good yield with low to moderate enantiose-
reduction of imines, especially, asymmetric borane
ꢁ
C
lectivity. 2003 Wiley Periodicals, Inc. Heteroatom Chem
reduction of imines catalyzed by chiral phosphorus
reagents. To the best of our knowledge, the only re-
port was in 1996 by Brunel and Buono [5]. In their
14:546–550, 2003; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.10190
investigation, moderate enantioselectivity was ob-
tained in asymmetric borane reduction of imines cat-
alyzed by chiral reagent 1.
INTRODUCTION
Optically active secondary amines are important ver-
satile intermediates in the preparation of many bi-
ologically active compounds. They have also been
widely used as chiral auxiliary in the asymmetric
catalysis. During the past two decades much at-
tention of the organic chemists has been drawn to
their synthesis. The most challenging method is the
enantioselective reduction of the corresponding ke-
timines. Although some good results were obtained
via the asymmetric hydrogenation [1] and hydrosi-
lylation [2] in enantioselective reduction of acyclic
Herein, we report the synthesis of a series of
chiral trivalent and quadrivalent phosphorus com-
pounds starting from L-proline, D-camphor, (−)-1,
1ꢀ-binaphthalene-2,2ꢀ-diol, (−)-ꢀ-phenylethylamine,
etc. and the preliminary investigation of their cat-
alytic activity in asymmetric borane reduction of
ketimine.
Correspondence to: Tang Chuchi; e-mail: c.c.tang@eyou.com.
Contract grant sponsor: National Nature Science Foundation of
China.
RESULTS AND DISCUSSION
Synthesis of Chiral Phosphorus Reagents
Contract grant number: 20272025.
Contract grant sponsor: PhD Programs Foundation of Ministry
of Education of China.
2003 Wiley Periodicals, Inc.
L-prolinol is conveniently available through the re-
duction of L-prolinol. According to our previous
c
ꢁ
546

Synthesis of Chiral Phosphorus Reagents and Their Catalytic Activity 547
work [6], chiral phosphoramidates 2 and 3 were
obtained by the cyclization of L-prolinol with O-
phenyl phosphorodichloridate or O-phenyl phos-
phorodichloridothioate in the presence of triethy-
lamine. Two orientations existed in the reaction of
L-prolinol with O-phenyl N,N-diethyl phosphorami-
dochloridate, namely, N-phosphorylation and O-
phosphorylation. N-phosphorylation product 4 was
obtained as the major one with low isolated yield at
room temperature [7].
FIGURE 1 Molecular structure of compound 9.
Borane complex 5 was prepared via the cy-
clization of N,N,Nꢀ,Nꢀ-tetrathyl phenylphosphonous
diamide with (+)-cis-1,2,2-trimethylcyclopentane-
1,3-diamine, which was derived from D-camphor
through oxidation and amination [5].
hydroxyl phosphorylated.
The reaction of (−)-ꢀ-phenylethylamine with 1,
2-dibromoethane provided (−)-N,Nꢀ-bis(ꢀ-phenyle-
thyl)ethane-1,2-diamine [9]. Further cyclization
with phenyl phosphorodichloridate gave cyclophos-
phorodiamide 11.
The reaction of (−)-(S)-binaphthol with hex-
aalkyl phosphorous triamide afforded cyclic phos-
phoramidates 6 and 7. Further reaction of 6 and 7
with BH3·THF gave the corresponding borane com-
plexes 8 and 9, respectively.
Compound 12 was prepared by the reaction of L-
(−)-diisopropyl tartrate with hexaethyl phosphorous
triamide according to the literature [10].
To understand the structure of this type of bo-
rane complex, crystallographic study of 9 was con-
ducted via X-ray refraction. The molecular structure
of compound 9 is shown in Fig. 1.
As shown in Table 1, the bonds between the cen-
tral phosphorus atom and the four groups connected
to it are of single bond length. The six bond an-
gles at the central phosphorus atom deviated little
from the normal tetrahedral angle. The bond an-
gles O(1) P N, O(1) P O(2), and O(2) P B are
slightly smaller, N P O(2), N P B, and O(1) P B
are slightly larger.
◦
˚
TABLE 1 Selected Bond Lengths (A) and Bond Angles ( )
of 9
P(1) O(1)
P(1) O(2)
P(1) N(1)
P(1) B(1)
O(1) C(1)
O(2) O(20)
1.608
1.616
1.608
1.884
1.412
1.410
O(1) P(1) N(1)
N(1) P(1) O(2)
N(1) P(1) B(1)
O(1) P(1) O(2)
O(1) P(1) B(1)
O(2) P(1) B(1)
100.2
112.4
117.0
101.6
117.9
106.8
According to our reported method [7], the re-
action of (−)-(S)-binaphthol with diethyl phospho-
rochloridate led to product 10, with one phenolic

548 Kangying et al.
11, derived from (−)-α-phenylethylamine. For exam-
ple, better enantioselectivity and higher yield were
obtained when 4 was used as catalyst, which was also
much higher than that of phosphate 10, which con-
tained a proximal phenolic hydroxyl group. Better re-
sult was obtained with borane complex 9 rather than
trivalent phosphorus reagent 7. Additionally, it was
found that the carbon backbone has an important
role on their catalytic effect. For example, moderate
enantioselectivity was observed for borane complex
8 derived from (−)-(S)-binaphthol, while quite lower
enantioselectivity was obtained for the borane com-
plexes 5 and 12, which were derived from (+)-cis-
1,2,2-trimethylcyclopentane-1,3-diamine and L-(−)-
tartrate, respectively.
In conclusion, acyclic phosphoramidates con-
taining a proximal hydroxyl group (for example,
catalyst 4) and the cyclic phosphoranidite–borane
complexes containing sterically hindered and rigid
backbone (for example, catalyst 8) had good catalytic
activity in asymmetric borane reduction of imines.
These findings will play an important role on the
further design and synthesis of these types of new
catalysts.
Catalytic Asymmetric Borane Reduction
of Imine
Preliminary investigation of the catalytic effect of
chiral phosphorus reagents 2–12 in asymmetric bo-
rane reduction of imine was carried out using N-
phenyl imine of acetophenone as substrate and
BH3·THF as reductant. The experimental results are
listed in Table 2.
Preliminary tests showed that solvents, such as
toluene, THF, chloroform, and methylene chloride,
had no significant influence on enantioselectivity.
Hence, toluene was chosen as the solvent. It was
found that the reaction temperature (20–50◦C) was
not an essential factor to the catalytic activity to
most of the catalysts. However, the reaction ran very
slowly, even no reaction occurred below 20◦C. The
optimal reaction temperature was 20–30◦C. Further-
more, no obvious difference on chemical yield and
enantioselectivity was observed when the amount
of the catalyst ranged from 6 to 30 mol%. Thus,
10 mol% of catalyst was used.
As shown in Table 2, the structure of the chiral
phosphorus reagent had a marked influence on the
catalytic effect. Enantioselectivity was obviously en-
hanced with a slight drop in yield when P O bond
(2) was changed into P S bond (3) in the cyclophos-
phoramidates derived from L-prolinol. Furthermore,
acyclic phosphoramidate 4 with a proximal hydroxyl
group derived from L-prolinol had better catalytic ac-
tivity than those of cyclic phosphoramidates 2, 3, and
EXPERIMENTAL
1H and 31P NMR were recorded in CDCl3 on a Bruker
AC-P200 instrument using TMS as an internal stan-
1
dard for H and 85% H3PO4 as an external stan-
dard for 31P. Specific rotations were measured on a
Perkin-Elmer 241MC polarimeter. Elemental analy-
ses were conducted on a Yanaco CHN Corder MT-3
automatic analyzer. Melting points were determined
on a Yanaco MP-500 melting point apparatus. All
temperatures are uncorrected. All of the solvent was
used after drying and redistillation.
TABLE 2 10 mol% Chiral Phosphorus Reagents Cat-
alyzed Asymmetric Borane Reduction of N-phenyl imine of
Acetophenone in Toluene at 20–30◦C
Synthesis of 2
To a stirred mixture of L-(+)-prolinol (1.01 g,
10 mmol), triethylamine (2.02 g, 22 mmol), and 20 ml
of chloroform was added dropwise a solution of O-
phenyl phosphorodichloridate (2.11 g, 10 mmol) in
10 ml of chloroform at 60◦C. The resulting mixture
was refluxed for 3 h, then cooled to room temper-
ature. The reaction mixture was washed with wa-
ter (30 ml) and dried over anhydrous magnesium
sulfate. After removal of solvent the crude prod-
uct (3.20 g) was purified by column chromatogra-
phy on silica gel (300–400 mesh, gradient eluted
with petroleum ether/ethyl acetate) to give 2.00 g
Yielda
(%)
[α]25
(c, EtOH)
eeb
(%)
D
Catalyst
Configuration
2
51
35
73
53
58
48
48
45
89
63
+2.0 (1.9)
+5.8 (0.4)
+15.3 (0.8)
+2.1 (2.1)
+1.0 (1.2)
+12.6 (0.8)
+6.5 (1.6)
+2.6 (1.1)
−7.2 (2.5)
+4.0 (3.2)
8
32
59
9
S
S
S
S
S
S
S
S
R
S
3
4
5
7
4
8
48
25
10
28
15
9
10
11
12
aIsolated yield.
of 2. Yield, 83%, n25 1.5338. 31P NMR (δ, ppm):
D
bDetermined by comparison of maximum sepecific rotation value of
1
21.67, 16.42; H NMR (δ, ppm): 1.48–2.20 (m, 4H),
25
(+)-(S)-N-phenyl-α-phenylethylamine, [α]D + 26.1 (c 2.15, EtOH)
2.78–3.26 (m, 1H), 3.32–4.62 (m, 4H), 7.16 (m, 5H).
[9].

Synthesis of Chiral Phosphorus Reagents and Their Catalytic Activity 549
Anal. Calcd for C11H14NO3P: C, 55.23%; H, 5.90%; N,
5.86%; Found: C, 54.94%; H, 5.85%; N, 5.69%.
Synthesis of 6
A mixture of (−)-(S)-binaphthol (1.14 g, 4 mmol),
hexamethyl phosphorous triamide (0.90 g, 5.5
mmol), and 25 ml of dry toluene was refluxed un-
der nitrogen atmosphere until (−)-(S)-binaphthol
disappeared (monitored by TLC, about 8–9 h). Af-
ter cooling to room temperature, the reaction mix-
ture was concentrated under reduced pressure. The
crude product was purified by column chromatog-
raphy on silica gel (200–300 mesh, gradient eluted
with petroleum ether/ethyl acetate) to afford 1.39 g
Synthesis of 3
Similarly, 2.02 g of 3 was obtained through
the reaction of L-(+)-prolinol (1.01 g, 10 mmol)
with O-phenyl phosphorodichloridothioate (2.27 g,
10 mmol). Yield, 79%, m.p. 78–79◦C, [ꢀ]25D–26.7 (c 1,
1
CHCl3). 31P NMR (δ, ppm): 74.85, 83.33; H NMR
(δ, ppm): 1.48–2.24 (m, 4H), 2.84–3.28 (m, 1H),
3.34–4.68 (m, 4H), 7.14 (m, 5H). Anal. Calcd for
C11H14NO2PS: C, 51.95%; H, 5.46%; N, 5.50%; Found:
C, 51.82%; H, 5.46%; N, 5.30%.
of 6. Yield, 96%, m.p. 190–192◦C, [ꢀ]25 +580.8 (c
D
1
0.3, CHCl3). 31P NMR (δ, ppm): 149.09; H NMR (δ,
ppm): 2.53 (d, 6H), 7.39–7.92 (m, 12H). Anal. Calcd
for C14H24BN2P: C, 64.14%; H, 9.13%; N, 10.69%;
Found: C, 64.20%; H, 9.18%; N, 10.27%.
Synthesis of 4
To a stirred mixture of L-(+)-prolinol (1.01 g,
10 mmol), triethylamine (1.01 g, 10 mmol), and 15 ml
of toluene was added a solution of O-phenyl di-
ethylphosphoramidochloridate (2.48 g, 10 mmol) in
15 ml of toluene at room temperature. The resulting
mixture was stirred for 48 h and then filtered. After
removal of solvent the residue was purified by col-
umn chromatography on silica gel (200–300 mesh,
eluted with petroleum ether/ethyl acetate) to afford
1.29 g of 4. Yield, 41%, n25 1.4536, [ꢀ]25 +31.0 (c
Synthesis of 7
Similarly, the reaction of (−)-(S)-binaphthol (1.14 g,
4 mmol) with hexacthyl phosphorous triamide
(1.21 g, 5.5 mmol) gave 1.36 g of 7. Yield, 8.8%,
m.p. 204–207◦C, [ꢀ]25 +473.8 (c 0.3, CHCl3). 31P
D
NMR (δ, ppm): 150.10; 1H NMR (δ, ppm): 1.04 (t, 6H),
2.80–3.12 (m, 4H), 7.32–7.96 (m, 12H). Anal. Calcd
for C24H22NO2P: C, 74.41%; H, 5.69%; N, 3.62%;
Found: C, 74.24%; H, 5.87%; N, 3.62%.
D
D
0.4, CHCl3). 31P NMR (δ, ppm): 13.82; H NMR (δ,
ppm): 0.99 (t, 6H), 1.82 (m, 4H), 3.24 (m, 9H), 3.54
(s, 1H), 7.17 (m, 5H). Anal. Calcd for C15H25N2O3P:
C, 57.69%; H, 8.01%; N, 8.97%; Found: C, 57.76%; H,
8.07%; N, 8.79%.
1
Synthesis of 8
To a solution of 6 (0.43 g, 1.2 mmol) in 10 ml of
THF was added 2 M solution of BH3·THF in THF
(2 ml) under nitrogen atmosphere at room temper-
ature. The resulting mixture was stirred for 2 h at
the same temperature. After removal of solvent the
crude product was purified by column chromatog-
raphy on silica gel (200–300 mesh, gradient eluted
with petroleum ether/ethyl acetate) to give 0.40 g of
Synthesis of 5
A mixture of (+)-cis-1,2,2-trimethylcyclopentane-
1,3-diamine (0.83 g, 5.8 mmol), N,N,Nꢀ,Nꢀ-tetraethyl
phenylphosphonous diamide (1.47 g, 5.8 mmol),
and 50 ml of anhydrous toluene was refluxed un-
der nitrogen atmosphere until the reactant was com-
pletely consumed (monitored by TLC). After colling
to room temperature, 2 M solution of BH3TFH in
THF (2.9 ml) was added and the resulting mixture
was stirred overnight at room temperature. After
removal of solvent the crude product was purified
by column chromatography on silica gel (200–300
mesh, gradient eluted with petroleum ether/ethyl ac-
etate) to give 0.55 g of 5. Yield, 36%, m.p. 145–147◦C,
[ꢀ]25D +22.0 (c 0.1, CHCl3). 31P NMR (δ, ppm): 64.63;
1H NMR(δ, ppm): 0.81 (s, 3H), 1.17 (s, 6H), 1.23–
1.69 (m, 7H), 2.60 (s, 2H), 3.30 (dd, 1H), 7.38–7.86
(m, 5H). Anal. Calcd for C14H24BN2P: C, 64.14%;
H, 9.13%; N, 10.69%; Found: C, 64.20%; H, 9.18%;
N, 10.27%.
8. Yield, 90%, m.p. 201–204◦C, [ꢀ]25 +597.7 (c 0.6,
D
CHCl3). 31P NMR (δ, ppm): 131.99; 1H NMR (δ, ppm):
1.20–1.60 (m, 3H), 2.61 (d, 6H), 7.27–7.95 (m, 12H).
Anal. Calcd for C22H21BNO2P: C, 70.81%; H, 5.63%;
N, 3.76%; Found: C, 70.58%; H, 5.69%; N, 4.02%.
Synthesis of 9
Similarly, the reaction of 7 (0.46 g, 1.2 mmol) and 2 M
solution of BH3·THF in THF (2 ml) afforded 0.47 g of
9. Yield, 98%, m.p. 144–146◦C, [ꢀ]25 +470.0 (c 0.4,
D
CHCl3). 31P NMR (δ, ppm): 131.88; 1H NMR(δ, ppm):
1.21–1.60 (m, 3H), 1.67 (t, 6H), 2.80–3.12 (m, 4H),
7.26–7.98 (m, 12H). Anal. Calcd for C24H25BNO2P:
C, 72.39%; H, 6.28%; N, 3.52%; Found: C, 71.97%;
H, 6.37%; N, 3.48%. The crystal of 9 suitable for

550 Kangying et al.
X-ray analysis was obtained by slow evaporation of
the solvent (methylene chloride) for a couple of days.
10 h under a nitrogen atmosphere. After removal of
solvent the crude product was purified by distilla-
tion under reduced pressure to give 1.34 g of 12. b.p.
120–122◦C/66 Pa. yield 33%, n25 1.4538 (Lit. [10]:
D
Synthesis of 10
b.p. 138–139◦C/1 mmHg, n20 1.4572).
D
To a stirred mixture of (−)-(S)-binaphthol (0.72 g,
2.5 mmol), O,O-diethyl phosphorochloridate (0.43 g,
2.5 mmol), and 20 ml of methylene chloride was
added dropwise a solution of triethylamine (0.25 g,
2.5 mmol) in 5 ml of methylene chloride at 0◦C. The
reaction mixture was stirred for 24 h at room temper-
ature and washed successively with distilled water
and saturated aqueous NaCl. The organic layer was
dried over anhydrous magnesium sulfate. After re-
moval of solvent the crude product was recrystallized
from ethyl acetate to give 0.86 g of 10. Yield, 82%,
m.p. 178–180◦C, [ꢀ]25D −5.1 (c 1, CHCl3). 31P NMR (δ,
ppm): −4.91; 1H NMR (δ, ppm): 0.83 (t, 3H), 1.16 (t,
3H), 3.43 (dq, 2H), 3.80 (dg, 2H), 4.90 (br, 1H). Anal.
Calcd for C24H23O5P: C, 68.24%; H, 5.45%; Found: C,
68.05%; H, 5.35%.
General Procedure for Asymmetric Borane
Reduction of Imine
To a solution of N-phenyl imine of acetophenone
(prepared according to Ref. [11]) (0.78 g, 4 mmol),
catalyst (0.4 mmol), and 10 ml of dry toluene was
added 2 M solution of BH3·THF in THF (2 ml) at
room temperature. The reaction mixture was stirred
at 20–30◦C until TLC showed complete consumption
of the starting material. Ten milliliters of 1 M H Cl
was introduced and stirred for several minutes. The
organic layer was separated and washed with water
(2 × 10 ml). The combined aqueous phase was made
basic with saturated aqueous NaOH and extracted
with ether (3 × 10 ml). The combined organic lay-
ers were dried over anhydrous magnesium sulfate.
After removal of solvent the crude product was puri-
fied by distillation under reduced pressure, b.p. 178–
180◦C/1.3 k Pa (Ref. [12]: b.p. 142◦C/1.5 mmHg).
Synthesis of 11
To a stirred mixture of (−)-N,Nꢀ-di-(ꢀ-phenylethyl)
ethane-1,2-diamine (2.68 g, 10 mmol), triethylamine
(2.42 g, 24 mmol), and 40 ml of methylene chloride
was added dropwise O-phenyl phosphorodichlori-
date (2.11 g, 10 mmol) at 0◦C. The resulting mix-
ture was stirred for 24 h at room temperature, then
adjusted to pH = 7 with 2 N aqueous NaOH, and
washed with distilled water and saturated aque-
ous NaCl. The organic layer was dried over anhy-
drous magnesium sulfate. After removal of solvent
the residue was purified by column chromatography
on silica gel (200–300 mesh, eluted with petroleum
ether/ethyl acetate) to afford 3.25 g of 11 as a thick
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D
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A mixture of L-(−)-diisopropyl tartrate (0.43 g,
10 mmol), hexaethyl phosphorous triamide (3.71 g,
15 mmol), and 30 ml of dry toluene was refluxed for