Guanidine and guanidinium salt catalyzed enantioselective phosphorus carbon bond formation reactions 3

Chapter 3


56

















Chapter 3

Chiral Guanidinium Salt Catalyzed Phospha-Mannich
Reactions

Chapter 3


57
3.1 Hydrogen bond donors catalyzed asymmetric reactions.

Electrophilic activation by small-molecule hydrogen bond donors has provided an
important paradigam for design of enantioselective catalysts.
1
Salts of organic bases
were shown to be successful in the activation of imines and other anionic
intermediates through hydrogen bonds.
MeO
R
O
O
150a R=Me-70
o
C
150b
R=Et-22
o
C
+
Bis(amidinium) salt 148
tBu
H
N
NH
HN
H
N
Ph
PhPh
Ph
2BAr

F-
4
BAr
F-
4
=
B
F
3
C CF
3
F
3
C
F
3
C
F
3
C CF
3
CF
3
CF
3
MeO
O
OHH
H
R

152a
R=Me
152b R=Et
MeO
OHH
R
H
O
151a
R=Me
151bR=Et
a
80% yield
151a
15% ee
152a
47% ee
151a/152a
1:22
b
quant. yield
151b
48% ee
152b
7% ee
151b/152b
1:11
149
148
Scheme 3.1. Göbel’s chiral bis(amidinium) salt 148 catalyzed Diels-Alder reaction.

Göbel and co-workers
2
reported a chiral bis(amidinium) salt 148 catalyzed
Diels-Alder reaction which constituted a key step of the Quinkert-Dane Estrone
Synthesis. The hydrogen-bond-mediated association of dienophiles 149 with the
chiral salt 148 accelerated the Diels-Alder reaction with diene
7-methoxy-4-vinyl-1,2-dihydronaphthalene (149) by more than three orders of
magnitude. In addition, the chemo-selectivities of the adducts were excellent
(151a:152a = 1:22 and 151b:152b = 1:11,
respectively). However, only moderate
enantioselectivities were observed (Scheme 3.1).
Chapter 3


58
The drawback of this type of proton catalyst was that the bisamidine 148 cannot
bind a single carbonyl group by two hydrogen bonds simultaneously because of the
large distance between the amidinium groups. To expand the scope of
amidinium-catalyzed reaction, Göbel and co-workers
3
reported an easily synthesized
bisamidines 153 derived from malonodinitril. This proton catalyst 153 was found to
increase the reaction rate of a series of reactions like Diels-Alder reaction and
Friedel-Crafts reaction (Scheme 3.2). Enantioselectivities, however, remained
constantly low even at low temperature.
O
+
H
N

N
N
H
N
Ph
PhPh
Ph
H H
BAr
F-
4
bisamidine
153
1mol%
153
CDCl
3
O
O
+
~12% ee
N
NO
2
+
10 mol%
153
CDCl
3
N

NO
2
154
endo-
155
exo-
155
156
95a
157

Scheme 3.2. Göbel’s bisamidines 153 catalyzed asymmetric reactions.

Johnston and co-workers reported the use of a chiral proton catalyst 158 to
promote enantioselective direct aza-Herry reaction (Scheme 3.3).
4
The catalyst can
tolerate a range of substituents and substitution patterns on several aldimines 159 and
nitroalkanes. Nitroacetic acid easters can afford similar results in which anti-addition
products were preferred.
5
The catalysts can be easily removed from the final reaction
Chapter 3


59
mixture via a base wash.
R
1
C

6
H
4
H
N
Boc
NO
2
R
2
+
HQuin-BAM
.
HOTf 158
N N
H H
N NH
H H
-
OTf
158
R
1
C
6
H
4
HN
Boc
NO

2
R
2
-20
o
C
159
R
1
=H,p-NO
2
, m-NO
2
, o-NO
2
, p-CF
3
O, p-Cl, p-CF
3
R
2
=H,Me
160
50 - 69% yield
59 to 95% ee
7:1 - 19:1 dr (R
2
=Me)
N N
H H

N NH
H H
-
OTf
161
1. H, Quin(
6
(
9
Anth)
2
Pyr)-BAM
.
HOTf 161
toluene, -78
o
C
2. NaBH
4
,CoCl
2
R
1
C
6
H
4
H
N
Boc

159
+
CO
2
tBu
NO
2
R
1
C
6
H
4
HN
Boc
CO
2
tBu
NH
2
162
69 - 88% yield
78 - 95% ee
5:1 - 11:1 dr

Scheme 3.3. Johnston’s chiral proton catalyst catalyzed enantioselective direct
aza-Herry reaction.

3.2 Chiral guanidinium salt catalyzed phospha-Mannich reactions
The addition of phosphonates to imines (Pudovik reaction or phospha-Mannich

reaction) is a widely utilized method for the formation of P-C bonds. However, to best
of our knowledge, there were no reports on the use of phosphorus nucleophiles such
Chapter 3


60
as secondary phosphine oxides [R
2
P(O)H] and H-phosphinates [(RO)P(O)HR] for the
addition to imines. The only previous report on the preparation of P-chiral
phosphinate esters was through resolution using phosphotriesterase.
6
Yuan and
co-workers reported the synthesis of optically pure α-amino-H-phosphinic acids
employing chiral ketimines.
7
We aimed to develop an organocatalyst catalyzed
phospha-Mannich reaction using secondary phosphine oxides and H-phosphinates.
3.2.1 Synthesis of guanidinium salt 168.
2-Chloro-1,3-dimethylimidazolinium chloride 163 was found to form guanidines
easily with appropriate primary amines.
8
This type of reaction provided a simple
method to prepare guanidines/guanidinium salts (Scheme 3.4).
NMeMeN
Cl
Cl
-
H
2

N
Me
Et
3
N
DCM
N
Me
+
MeN NMe
163 164
165

Scheme 3.4. Synthesis of guanidines from DMC 163 and amine.

Ph Ph
H
2
N NH
2
N
Cl
N
+
N
PhPh
N
N
N
N

N H H
BF
4
BF
4
166 167
BF
4
-
168
.
2HBF
4
Et
3
N/DCM
quantitive yield
++

Scheme 3.5. Synthesis of guanidinium salts

Guanidinium 168
.
2HBF
4

was prepared from enantiopure diamine 166 and
pyrrolidinium salt 167 in one step with excellent yield (Scheme 3.5). The free base
guanidine 168 was obtained after basifying guanidinium salt 168
.

2HBF
4
with 6M
NaOH aqueous solution. The absence of
19
F signal detected in the
19
F NMR indicated
Chapter 3


61
the successful basification of 168
.
2HBF
4
.
3.2.2 Chiral guanidinium salt catalyzed phospha-Mannich reactions of
phosphine oxides
3.2.2.1 Optimization study of phospha-Mannich reactions of phosphine oxides
Table 3.1. Guanidine- and guanidinium-catalyzed phospha-Mannich reactions.
125f
5mol%catalyst
169a
+
Ph
P
R
RO
P

R
RO
H
Ph
NTs
0
o
C, THF
R=1-naphthyl
NHTs

entry catalyst time/h
a
ee/%
b

1
168 (base)
1.5 33
2
168
.
0.5HBF
4

1.5 63
3
168
.
HBF

4

2.5 80
4
168
.
1.5HBF
4

2.5 47
5
168
.
2HBF
4

4 5
a
Monitored by TLC.
b
Determined by HPLC.

In preliminary studies, it was found that both the guanidinium salt 168
.
2HBF
4
and
guanidine 168 could catalyze the phospha-Mannich reaction between secondary
phosphine oxides and imines (Table 3.1, entries 1 and 5). It was surprised that the
results in terms of enantioselectivities obtained in the presence of the catalysts

basified from K
2
CO
3
were inconsistent. It was proposed that this basification method
offered catalysts carrying uncertain numbers of protons and the number of protons on
the catalyst had a significant influence on the ees. This effect was evaluated by
Chapter 3


62
employing catalysts 168
.
xHBF
4
(x = 0.5, 1, 1.5) prepared purposely. These catalysts
168
.
xHBF
4
(x = 0.5, 1, 1.5) were obtained by mixing different ratio of the free base
168 and 168
.
2HBF
4
(ratio = 1:3, 1:1, 3:1, respectively). It was discovered the highest
ee was obtained with catalyst 168
.
HBF
4

, which carried one single proton (entry 3).
The results obtained with other catalysts dropped dramatically (entries 1, 2, 4 and 5).
N
PhPh
N
N
N
N
N
BF
4
-
170
.
HBF
4
171
.
HBF
4
172
.
HBF
4
N N
NN
N N
MeO OMe
H
H

BF
4
-
N N
N
N
N
N H
BF
4
-
N
PhPh
N
N
N
N
N
BF
4
-
H
iPr iPr
iPr
iPr
iPr
iPr
iPr
iPr
H

BF
4
-
N
PhPh
N
N
BF
4
-
H
iPr
iPr
iPr
iPr
NH
2
173
.
2HBF
4
174

Figure 3.1. A series of guanidinium salts synthesized as catalysts for
phospha-Mannich reactions.

Following the previous studies, a series of guanidinium salts carrying one proton
(Figure 3.1) were synthesized readily from commercially available chiral diamines
and corresponding salts under the same conditions. In the case of preparation of 173,
only guanidine salt 174 was obtained rather than 173

.
2HBF
4
even under hash
conditions (MeCN, reflux). It was likely that the steric effect prevented the formation
of the second guanidine.


Chapter 3


63
Table 3.2. The effect of catalyst structure on enantioselectivity.
125f
5 mol% catalyst
169a
+
Ph
P
R
RO
P
R
RO
H
Ph
NTs
THF
R = 1-naphthyl
NHTs

entry catalyst temp/
o
C time/h
a
ee/%
b

1
170
.
HBF
4
-20 16 5
2
171
.
HBF
4

-20 14 5
3
172
.
HBF
4

-20 24 75
4
168

.
HBF
4
-50 14 87
5
168
.
HPF
6

-50 14 80
6
168
.
HBAr
F
4
-50 14 92
a
100% conversion.
b
Determined by HPLC.

These guanidinium salts were also evaluated in the phospha-Mannich reaction of
phosphine oxides (Table 3.2). Both the guanidinium salt 170
.
HBF
4
bearing less
sterically hindred group (entry 1) and the guanidinium salt 171

.
HBF
4
derived from the
dicyclohexyl amine (entry 2) gave poor enantioselectivities. At -20
o
C, the
guanidinium salt 172
.
HBF
4
gave good enantiomeric excess but worse than 168
.
HBF
4
.
The reaction temperature was another factor which may be considered to increase the
optical purity significantly. Fortunately, decreasing the reaction temperature to -50
o
C
did not affect the reaction rate much; the reaction catalyzed by 168
.
HBF
4
at -50
o
C
could complete within 14 h and good result was observed (entry 4). It was reported
that different counterions of the chiral salt catalysts could affect the reaction rate and
Chapter 3

64
enantioselectivities.
3
In our current research, the guanidinium salts with different
weakly-coordinating anions were tested under -50
o
C (entries 5 and 6). It was found
that the ee increased to 92% when
-
BAr
F
4
(Figure 3.2), the less coordinating anion,
was employed.

3.2.2.2 Highly enantioselective phospha-Mannich reaction between phosphine
oxides and imines catalyzed by guanidinium salts.
Under the optimum conditions, the phospha-Mannich reaction was investigated
with phosphine oxide 125f and different imines (Table 3.3, entries 1-7). Imines
bearing electron-donating (entry 1) and electron-withdrawing substituents (entry 2)
provided adducts with high ees. The reaction time for completed conversion of the
bulky 2-naphthyl imine was also 14h and 92% ee was observed (entry 3).
Heterocyclic imine (entry 4) furnished slightly lower ee. Imines derived from
aliphatic aldehydes, such as cyclohexanecarbaldehyde, gave adduct with 70% ee
(entry 5) while imine derived from pivalaldehyde afforded adduct with 91% ee (entry
6). Imine derived from trans-cinnamyl aldehyde also provided 1,2–addition adduct
169h with high ee (entry 7). Diaryl phosphine oxides 125a and 125g carrying phenyl
and ortho-trifluoromethylphenyl groups respectively, afforded adducts with moderate

to good ees (entries 8 and 9). The racemic phosphine oxide 125h added to phenyl
imine to generate two diastereisomers with a diastereisomeric ratio (dr) of 1:1 and
high ees (entry 10).

Table 3.3. Guanidinium-catalyzed (168
.
HBAr
F
4
) phospha-Mannich reaction of
Chapter 3


65
di-1-naphthyl phosphine oxide 125 and various imines
xmol%168
.
HBAr
F
4
THF, -50 or - 60
o
C
125a R
1
=R
2
=Ph
125f R
1

=R
2
= 1-Naphthyl
125g
R
1
=R
2
=2-CF
3
Ph
125h R
1
=Ph,R
2
= 1-Naphthyl
169b-k
+
P
R
1
R
2
O
H
R
NTs
R
P
R

1
R
2
O
NHTs

entry
125
R
169
X time/h yield/%
a
ee/%
b

1
125f
4-MeC
6
H
5

169b
5 14 98 92
2
125f
4-FC
6
H
5

169c
c
5 14 97 90
3
125f
2-naphthyl
169d
5 14 98 92
4
125f
2-furyl
169e
5 14 92 87
5
d
125f
Cy
169f
10 16 95 70
6
125f
tBu
169g
10 40 89 91
7
125f
trans-PhCH=CH
169h
5 36 89 90

8
e
125a
Ph
169i
f
20 96 75 56
9
125g
Ph
169j
f

20 14 93 82
10
125h
Ph
169k
g
20 14 90 75;85
a
Isolated yield.
b
Determined by chiral HPLC analysis.
c
the absolute configuration of
169c was assigned using X-ray crystallographic analysis.
d
tBuOMe as solvent.
e

DCM:Et
2
O 1:1 as solvent.
f
PG (imine) = 4-phenylbenzenesulfonyl.
g
PG (imine) =
benezenesulfonyl.

3.2.3 Phospha-Mannich reaction of H-phosphinates
3.2.3.1 Optimization study of phospha-Mannich reaction of H-phosphinates and
imines
Chapter 3


66
The H-phosphinate such as benzyl benzylphosphinate 179a was another type of
phosphorus nucleophile. The H-phosphinates were prepared from the literature
reported protocol (Scheme 3.6). Following the reported reagents and conditions
9
, a
mixture of H-phosphinic acids 177 and phosphinic acid 178 were obtained. The
phosphinic acid 178 were undesired product and generated from the double attack of
the intermediate 176. The modified protocol employed 0.5 eq. of corresponding
benzyl bromides rather than 1 eq. of alkylation reagents. The slow dropwise addition
of benzyl bromide was the key to increase the selectivities and to improve the yields
of H-phosphinic acid 177. The reaction mixture was conducted the next step without
further purification after a simple acid-base work-up. H-phosphinate 179a were
finally obtained with high yields via Hewitt reaction.

10


H
2
PO
3
.
NH
3
i
P
OH
BnO
H
TMSO
P
OTMS
H
176
ii
P
OH
BnO
Bn
iii
P
OBn
BnO
H

177 178
179a
175

Scheme 3.6. Synthesis of benzyl benzylphosphinate. Reagents and conditions: (i)
1.05 eq. (TMS)
2
NH, 110
o
C, 1-2h; (ii) 0.5 eq. benzylbromide, DCM, 0
o
C to rt. (iii)
benzyl chloroformate, pyridine, DCM, rt to reflux, 15 min.

It was found that the addition of rac-benzyl benzylphosphinate 179a to imines can
be catalyzed by 168
.
HBF
4
(Scheme 3.7). However, the reaction was slow at room
temperature and low ee was observed (<5% ee). The products 180a contained two
chiral centers and the definition of relative configuration was shown in the Figure 3.2.
Chapter 3


67

179a
5mol%168
.

HBF
4
toluene, r.t.
syn-180a
+
Ph
NHTs
P
OBn
BnO
P
Bn
O OBn
H
Ph
NTs
anti-180a
Ph
NHTs
P
Bn
OBnO
+
24 h, <20%conv. < 5% ee

Scheme 3.7. Guandinium 168
.
HBF
4
catalyzed phospha-Mannich reaction of

rac-benzyl benzylphosphinate 179a to imine.

anti-
180a
Ph NHTs
P
OBn
BnO
syn-180a
Ph
NHTs
P
Bn
OBnO
Ph
NHTs
P
Bn
OBnO
Ph
NHTs
P
Bn
OBnO
H
C
H
C
H
P

H
P
Group of highest priority on carbon center (H
C
) and group of highest priority on phosphorus
center (H
P
) are the opposite side - anti configuration
Group of highest priority on carbon center (H
C
) and group of highest priority on phosphorus
center (H
P
)arethesameside-sy n configuration
Ph
NHTs
P
Bn
OBnO
H
C
H
P
Ph
NHTs
P
Bn
OBnO
H
C

H
P

Figure 3.2. The definition of the relative configuration of 180a

Table 3.4. Guanidinium-catalyzed phospha-Mannich reaction of benzyl
benzylphosphinate 179a
179a
5 mol% catalyst
toluene, temp
10 eq. K
2
CO
3
syn-180a
+
Ph
NHTs
P
OBn
BnO
P
Bn
O OBn
H
Ph
NTs
anti
-180b
Ph

NHTs
P
Bn
OBnO
+

Entry
a
catalyst temp/
o
C time/h
b

ee of
syn-180a/%
c
ee of
anti-180a/%
c
1
168
.
HBF
4

rt <1 20 23
2
168
.
HPF

6

rt <1 20 20
3
168
.
HCl
rt <1 10 5
4
168
.
HClO
4

rt <1 3 4
Chapter 3


68
5
168
.
HBAr
F
4
rt <1 30 50
6
168
.
HBAr

F
4
-20 48 42 70
a
donor : acceptor = 1:1.2.
b
Monitored by TLC, >99% conversion.
c
Determined By
HPLC.

K
2
CO
3
was used as an additive and significant acceleration of reaction rate was
observed without decreasing the ee (Table 3.4, entry 1). Guanidinium salts with
different counterions were investigated (entries 2-5). Catalyst 168
.
HPF
6
gave similar
results in terms of reaction rate and ee (entry 2). When the catalysts with the
counterions Cl
-
and ClO
4
-
were employed, the reaction can reach 100% conversion
less than one hour; but the ees decreased dramatically (entries 3 and 4). Catalyst

168
.
HBAr
F
4
gave the most promising result under the same condition (entry 5). Better
result was observed when reaction temperature was lowered to –20
o
C although long
reaction time was required (entry 6). After the reaction completed, the catalyst was
recovered and NMR characterization revealed that the guanidinium catalyst
168
.
HBAr
F
4
was unchanged; the catalyst was not converted to guanidine 168 during
the course of the reaction.
Different solvent systems were also tested in the phospha-Mannich reaction.
When DCM was used as the solvent, better ee was observed but the reaction rate was
much slower (Table 3.5, entry 2). Racemic 179a was used as limiting reagent (Table
3.4, entries 1-6 and Table 3.5 entries 1 and 2) in these experiments, resulting in a
diastereomeric ratio (dr) of 1:1. When the amount of imine increased to 1:2 (entry 3),
the ee of both diastereoisomers improved. Furthermore, more promising results were
demonstrated when the amount of racemic donor 179a was increased to 2:1 (entry 4);
Chapter 3


69
the ee of the major diastereoisomer (syn) was increased to 82%. In addition, the other

chlorinated solvent CHCl
3
was tested, but only about 40% conversion was observed
even after 4 days (entry 5). A compromised solvent mixture (DCM: toluene, 1:1) was
used to make a balance between reaction rate and ee (entry 6). When the amount of
179a was increased to 2:1 (entry 7), the ee of major diastereosiomer was improved to
89% and dr was also improved to 4:1.

Table 3.5. Guanidinium-catalyzed phospha-Mannich reaction of benzyl
benzylphosphinate 179a.
179a
5mol%
168
.
HBAr
F
4
-20
o
C
10eq. K
2
CO
3
syn-
180a
+
Ph
NHTs
P

OBn
BnO
P
Bn
O OBn
H
Ph
NTs
anti-180a
Ph
NHTs
P
Bn
OBnO
+

entry

solvent
donor :
acceptor
time/h
a
ee of
syn-180a/%
b
ee of
anti-180a/%
b

dr
c
1 THF 1:1.2 24 40 65 1:1
2 DCM 1:1.2 60 65 50 1:1
3 Toluene 1:2 20 44 73 1:1
4 Toluene 2:1 20 70 37 3:1
5
d
CHCl
3
2:1 96 n.d. n.d. n.d.
6
Toluene:DCM
1:1
2:1 20 82 25 3:1
7
Toluene:DCM
1:1
3:1 24 89 7 4:1
a
Determined by TLC, 100% conversion.
b
Determined by HPLC.
c
Approximated by
1
H NMR and confirmed by HPLC.
d
40% conversion (estimated by TLC).

Chapter 3


70
i
Cl
O
+
P
Bn
O OH
H
P
Bn
O OR
H
ROH
O
R
ii
182a R=2-MeOC
6
H
4
CH
2
182b R=2-NO
2
C

6
H
4
CH
2
182c
R = 2-NpCH
2
177
181

Scheme 3.8. Synthesis of phosphinates bearing different phosphinic acid easters.
Reagents and conditions: (i) triphosgen, DCM, sealed tube; (ii) DCM, 1eq. pyridine,
rt to reflux.

Table 3.6. The addition of benzyl phosphinates with different protecting groups to
imines.
5mol%168
.
HBAr
F
4
toluene, -20
o
C
10eq. K
2
CO
3
s

y
n
-
183
+
P
Bn
O OR
H
Ph
NTs
Ph NHTs
P
Bn
ORO
182
ant
i
-
183
Ph
NHTs
P
OR
BnO

entry
a
183 [R]
time/h

b

ee of 183/%
c
dr
d
1
183a[2-MeOC
6
H
4
CH
2
]
24 45; 67 2:1
2
183b[2-NO
2
C
6
H
4
CH
2
]
24 70; 30 2:1
3
183c[2-NpCH
2
]

24 65; 47 2:1
a
Donor : acceptor = 2:1.
b
Determined by TLC, 100% conversion.
c
Determined by
HPLC.
d
Approximated by
1
H NMR and confirmed by HPLC.

A series of benzyl phosphinates bearing different protecting groups were
synthesized from the corresponding benzyl alcohols 181 (Scheme 3.8). The protecting
groups of benzyl phosphinates can perform as auxiliary groups to provide the
potentially steric and electronic effect to increase optical purity. These phosphinates
were employed in the phospha-Mannich reaction (Table 3.6). The enantioselectivities
of major diasteroisomers of phosphinates with electron-donating and
electro-withdrawing substituents (182a and 182b respectively) decreased dramatically
(entries 1 and 2). The phosphinate with more sterically hindered 2-naphthyl group
Chapter 3


71
was expected to increase the ee; however, the ee dropped to 65% for major
diastereoisomer.
The effect of different protecting groups on imines was investigated in the
phospha-Mannich reactions (Table 3.7). The N-benzenesulfonyl and
N-p-nitrobezenesulfonyl imine both gave the similar level of enantioselectivity

(entries 1 and 2). The imine with more steric hindrance mesitylenesulfonyl group
could not afford decent conversion after 48 hours (entry 3). Other types of protecting
groups were also tested in the phospha-Mannich reactions. However, the reactions of
the tert-butyl carbonate (Boc) and benzyl protected imines were slow and the results
in terms of enantioselectivieties and dr were not determined (entries 4 and 5).

Table 3.7. The phospha-Mannich reaction of imines with different N-protecting
groups.
5mol%168
.
HBAr
F
4
toluene : DCM 1:1, -20
o
C
10eq. K
2
CO
3
syn-184
+
P
Bn
O OBn
H
Ph
NPG
Ph NHPG
P

Bn
OBnO
179a
Ph
NHPG
P
OBn
BnO
anti-184
+

entry
a
PG time/h
b

ee of 184/%
c
dr
d
1 Benzenesulfonyl

24 85; 11 3:1
2 Ns 24 81; 36 2:1
3 Mesitylenesulfonyl 48 n.d. n.d.
4 Boc 48 n.d. n.d.
5 Bn 48 n.d. n.d.
a
Donor : acceptor = 3:1.
b

Determined by TLC, 100% conversion.
c
Determined by
HPLC.
d
Approximated by
1
H NMR and confirmed by HPLC.

Chapter 3


72
3.2.3.2 Highly enantioselective phospha-Mannich reaction of H-phosphinates
The phospha-Mannich reaction of benzyl benzylphosphinate 179a can be further
optimized by decreasing the reaction temperature to –40
o
C under the optimum
condition (Table 3.8, entry 1). Good yield and high enantioselectivity of the major
diastereoisomer was observed.

Table 3.8. Guanidinium-catalyzed phospha-Mannich reaction of benzyl
benzylphosphinate 179a and various imines.
179a
10mol%
168
.
HBAr
F
4

DCM:toluene 1:1
10equiv.K
2
CO
3
,-40
o
C
syn
-180a-g
+
Ar
NHTs
P
Bn
OBnO
P
OBn
BnO
H
Ar
NTs

entry
a
Ar
syn-180
time/h yield/%
b

dr
c

ee of
syn-180/%
d
1 Ph
180a
39 83 6:1 94
2
e
4-FC
6
H
5

180b
35 90 6:1 90
3
e
4-ClC
6
H
5

180c
108 90 4:1 92
4
e
4-MeC

6
H
5

180d
100 85 4:1 90
5
f
2-naphthyl
180e
39 93 6:1 91
6
f
2-furyl
180f
40 71 7:1 94
7 trans-PhCH=CH
180g
65 92 3:1 90
8 Cy
180h
96 n.d. n.d. n.d.
a
donor : acceptor = 3:1.
b
Isolated yield of two isomers.
c
Approximated by
1
H NMR

and confirmed by HPLC.
d
Determined by HPLC.
e
PG (imine) = benzenesulfonyl.
f

15 mol% catalyst.

Several other aromatic N-benzenesulfonyl imines (Table 3.8, entries 2-4) were
employed rather than their corresponding N-tosyl imines because the products
Chapter 3


73
obtained from the corresponding N-tosyl imines could not be separated by chiral
HPLC. The para-substituted electron-withdrawing group F substituted at
para-position did not provide a significant accelerated reaction rate but high yield and
high enantioselectivity was observed (entry 2). When the para-substituent was Cl or
methyl group, the reaction rates were much slower reaction rate and long reaction
time was required to achieve full conversion with high ees (180c and 180d,
respectively). Other N-tosyl imines (entries 5-7) were also employed. The reaction
time for complete conversion of bulky 2-naphthyl imine was 39 h (entry 5) and good
result was observed. The imine derived from trans-cinnamyl aldehyde also provided
adducts with high ee (entry 7). On the other hand the imine derived from
cyclohexanecarbaldehyde gave a slow reaction and low conversion after 4 days (entry
8).
Different benzyl arylphosphinates 179b-179f were prepared to investigate the
scope of the reaction (Table 3.9). Adducts 180i-j were obtained with high ees (entries
1-2). H-phosphinate 179d bearing an electron-withdrawing group, 179e bearing an

electron-donating group and 179f bearing an alkenyl chain afforded modest ees
(entries 3-5). The best diastereoselectivity (16:1) was obtained when highly
electron-withdrawing H-phosphinate 179c was used (entry 2). The absolute and
relative stereochemistries were determined using the X-ray crystallographic analysis
of syn-180m.


Chapter 3


74
Table 3.9. Guanidinium-catalyzed phospha-Mannich reaction with benzyl
alkylphosphinates 179b-179e.
179b-e
10mol% 168
.
HBAr
F
4
DCM:toluene 1:1
10 equiv. K
2
CO
3
,-40
o
C
syn-180i-m
+
Ph

NHTs
P
Bn
OBnO
P
OBn
RO
H
Ph
NTs

entry

179 [R]
syn-180
time/h Yield/%
a
dr
b
ee of syn-180 [%]
c
1
179b[2-NpCH
2
] 180i
38 92 6.5:1 94
2
179c[4-CF
3
Ph CH

2
]
180j
36 92 16:1 94
3
179d[4-NO
2
PhCH
2
]
180k
36 90 5.5:1 89
4
179e[4-MePhCH
2
]
180l
43 83 5:1 88
5
d

179f[Trans-PhCH=CHCH
2
]
180m
168 82 7:1 82
a
Isolated yield of two isomers.
b
Determined with

1
H NMR and HPLC.
c
Determined
by HPLC.
d
20 mol% catalyst, −60
o
C, PG (imine) = benzensulfonyl.

3.2.3.3 Enantioselective phospha-Mannich reaction of other aryl H-phosphinates
Benzyl phenylphosphinate (136a) was also employed in the phospha-Mannich
reaction. However, only low enantioselectivity was observed under the previous
optimum condition. Re-optimization was conducted to increase the optical purity of
the phospha-Mannich reaction of benzyl phenylphosphinate.

Table 3.10. Effects of various protecting groups of phenyl phosphinates on the
phospha-Mannich reaction.

10mol% 168
.
HBAr
F
4
0
o
C, DCM
syn-181
+
Ph

NHTs
P
Ph
OBnO
P
OR
PhO
H
Ph
NTs
136a
Ph
NHTs
P
OR
PhO
anti-181

entry
a

136 [R]
181
yield/%
b
ee/%
c

Chapter 3

75
1
136a [Bn]
181a
56 30; 25
2
136b [2-NpCH
2
]
181b
37 35; 15
3
136c [3,5-MeOC
6
H
4
CH
2
]
181c
58 32; 20
4
136d [3-NO
2
C
6
H
4
CH

2
]
181d
58 36; 14
5
136e [Et]
181e
45 38; 18
6
136f [i-Bu]
181f
48 56; 32
a
donor : acceptor 1:1.2.
b
Isolated.
c
Determined by HPLC.

The phosphinates 136 bearing different groups on the phosphinic acid easters were
first investigated in the phospha-Mannich reaction (Table 3.10). Adducts with
substituted aromatic groups (entries 2-4) afforded higher ee than adduct without
substituent (entry 1). H-phosphinates bearing an electron withdrawing group (136d,
entry 4) and a bulky substituent (136b, entry 2) provided adduct with slightly higher
ee than electron donating group (136c, entry 3). Higher ee was observed when R is
aliphatic group (entries 5 and 6), and the highest ee (56%) was achieved with isobutyl
group (entry 6). The observation indicated that the steric hindrance may play an
essential role in order to increase the enantioselectivities. It was believed that the
introduction of much bulkier groups such as adamantyl might increase the
enantioselectivities. However, the synthesis of such compounds was unsuccessful.

Table 3.11. Solvent effects on the phospha-Mannich reaction of benzyl
phenylphosphinate 136a.
10mol% 168
.
HBAr
F
4
conditions
syn-181f
+
Ph
NHTs
P
Ph
Oi-BuO
P
O
i-Bu
PhO
H
Ph
NTs
136f
Ph
NHTs
P
Oi-Bu
PhO
anti-181f

Chapter 3


76
entry
a
solvent additives temp/
o
C time/h
b
dr
c
ee/%
d

1 DCM 10 eq. K
2
CO
3
-20 22 1:2 5; 56
2 Et
2
O 10 eq. K
2
CO
3
-20 16 1:2 50; 44
3 THF 10 eq. K
2

CO
3
-20 16 1:2 40; 37
4 toluene 10 eq. K
2
CO
3
-20 16 1:1.5 6; 23
a
donor : acceptor 3:1.
b
Detemined by TLC.
c
Determined by NMR and HPLC.
c

Determined by HPLC.

Solvent effects were evaluated by screening different types of solvent at -20
o
C
using 10 mol% guanidinium catalyst 168
.
HBAr
F
4
(Table 3.11). It was found that
chlorinated solvent such as DCM resulted in incomplete conversion after 22 hours of
reaction time (entry 1). However, the best ee (56%) was observed in DCM as solvent.
Reactions in other common solvents such as Et

2
O, THF and toluene were faster
(entries 2 to 4). Unfortunately, the major diastereoisomers gave lower ee than their
minor counterparts.
When the protecting group of imine was replaced by 4-phenylbenzene sulfonyl
group, the best result was observed (Scheme 3.9). The reaction was quenched after 17
h, and ee of the major diastereoisomer was increased to 60% and dr was also
improved to 3:1.

10 mol% 168
.
HBAr
F
4
toluene, -20
o
C
syn-182
+
Ph
NHPG
P
Ph
O
i
-BuO
P
O
i
-Bu

PhO
H
Ph
N
136f
Ph
NHPG
P
O
i
-Bu
PhO
anti-182
S
Ph
O
O
PG = 4-phenylbenzenesulfonyl
60% ee of syn-No, dr = 3:1

Chapter 3


77
Scheme 3.9. Phospha-Mannich reaction of phenylphosphinates 136f.

3.2.4 Kinetic resolution study of rac-H-phosphinates.
Chiral phosphine oxides and phosphines are typically prepared using enantiopure
starting materials, chiral auxiliaries or recrystallizations of the racemic phosphines.
11

This methodology can provide an alternative strategy to obtain enantiomerically pure
H-phosphinates via kinetic resolution. The phospha-Mannich reaction was
re-optimized and was conducted with rac-179c. The reaction was quenched at 63%
conversion and the unreacted H-phosphinate (S)-179c was found to have an ee of 87%
and was recovered in 85% of the theoretical yield (Scheme 3.10). It was found that
when enantiomerically enriched (S)-179c was re-subjected to the reaction condition in
the absence of imine for 24 h, no racemization was observed.

Chapter 3


78
20 mol% 168
.
HBAr
F
4
DCM:toluene 1:1
10 equiv. K
2
CO
3
,-50
o
C
syn-180j+
P
OBn
RO

H
Ph
NTs P
OBn
RO
H
+
(S)-179c
R=4-CF
3
PhCH
2
52% yield (syn + anti)
dr 1.6:1
1equiv.
1equiv.
rac-179c
63% conversion
S=8.2
anti-180j+
87% ee
50%ee
50% ee
32% yield
(85% of
theoretical
yield)
(2)
P
OO

H
P
O
O
H
CF
3
34.6%
[a]
ee of starting material 87% (ee
SM
)
ee of P chiral center on allproducts 50% (ee
Pdt
)
C =100xee
SM
/(ee
SM
+ ee
Pdt
)=63%
S =ln[(1-C)x(1-ee
SM
)]/ln[(1 - C)x(1+ee
SM
)] = 8.2
[a] based on HPLC analysis and conversion.
F
3

C
P
O
S
O
O
H
N
O
CF
3
P
O
O
S
O
O
H
N
CF
3
syn-180jA
28.7%
[a]
syn-180jB
9.6%
[a]
P
O
S

O
O
H
N
O
CF
3
anti-180jC
18.5%
[a]
P
O
O
S
O
O
H
N
CF
3
anti-180jD
6.3%
[a]
2.3%
[a]
syn-180jB
and
anti-180jD
are
generated from (

S
)
-179c
syn-180jA
and
anti-180jC a
re
generated from (
R
)
-179c

Scheme 3.10. Kinetic resolution of rac-179c.
Since the absolute and relative configuration of syn-180 adducts have been
determined, the absolute configuration of remaining 179c could be deduced. The ee of
Chapter 3


79
remaining 179c was 87%. In other words, the enantioselective ratio of remaining 179c
was 93.5:6.5. 34.6% of major enantiomer of remaining 179c and 2.3% of minor
enantiomer were observed based on the 63.1% conversion (39.1% x 93.5% = 34.6%,
39.1% x 6.5% = 2.3%). Syn-180jA was found to be the major product (28.7% base on
HPLC and conversion) and its absolute configuration was determined to be S isomer
on phosphorus chiral center (S
P
) and R isomer on carbon chiral center (R
C
). Syn-180jA
was obtained from (R)-179c so the remaining (R)-179c could not exceed 21.3% (50%

(R)-179c or (S)-179c in the rac-6c). The major enantiomer of remaininged starting
materials was determined to be (S)-179c. Similarly, the major enantiomer of anti-180j
was assigned to be S isomers on both phosphorus and carbon chiral center.
3.3 Conclusion and future study
In this chapter, we have disclosed a highly enantioselective phospha-Mannich
reaction catalyzed by a novel guanidinium catalyst, obtained from commercially
available diamine in one step with excellent yield. Using this catalyst, asymmetric
phospha-Mannich reaction has been developed using secondary phosphine oxides and
H-phosphinates as P-nucleophiles. Using this methodology, a series of
enantiomerically enriched α-amino phosphine oxides, α-amino phosphinates were
prepared. A kinetic resolution study of rac-H-phosphinate indicated a possible
synthetic route to obtain secondary H-phosphinate with high enantiopurity.
Although to my best knowledge, this is the first example of highly
enantioselective phospha-Mannich reaction using secondary phosphine oxides and
H-phosphineates, there is an obvious disadvantage of this reaction - the low atom
Chapter 3


80
efficiency of catalyst. The novel guanidinium salt 168
.
HBAr
F
4
is against the general
definition of small organic molecular catalysis in term of its large molecular weight
(M
w
). It was discussed that if the catalyst loading was 10 mol%, the M
w

should not
exceed 500.
12
However, M
w
of the guanidinium salts 168
.
HBAr
F
4
is 1376.9. In other
words, under the optimized condition, to obtain 40.0 milligrams of theoretical yield of
phospha-Mannich adduct 180a, 11.0 milligrams of 168
.
HBAr
F
4
was required.
The future study should be focused on the following points.
(1) First, the synthesis of chiral guanidinium salts demonstrated a readily method to
prepare guanidines/guanidinium salts catalysts. To synthesize guanidines and
guanidinium salts of structural and electronic diversity is a highly interesting
direction.
(2) Second, although the phospha-Mannich reaction of secondary phosphine oxides
and H-phosphinates was successfully developed in this chapter, the reaction scope
was uncompleted: (a) the ee of phospha-Mannich reaction using
phenylphosphinate was only 60%, (b) although imines derived from aliphatic
aldehyde were employed in the phospha-Mannich reaction with secondary
phosphine oxide, the reactions with H-phosphinates were not fully explored, (c)
ketimines are readily synthetic available and can be used in the phospha-Mannich

reaction.