Chiral N-phosphoryl imines: Design, synthesis and direct asymmetric addition reactions with diketones and diesters

Article abstract of DOI:10.1016/j.tetlet.2010.06.072

Chiral N-phosphoryl imines derived from (S)-BINOL have been designed and synthesized in good to excellent chemical yields. These N-phosphoryl imines were found to react with diketones smoothly without the use of any bases. They can also serve as electroph

Full text of DOI:10.1016/j.tetlet.2010.06.072

Tetrahedron Letters 51 (2010) 4403–4407
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Tetrahedron Letters
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Chiral N-phosphoryl imines: design, synthesis and direct asymmetric
addition reactions with diketones and diesters
b,
Hao Sun a, Trideep Rajale b, Yi Pan a, , Guigen Li
*
*
a School of Chemistry and Chemical Engineering, and the State Key Lab of Coordination Chemistry, Nanjing University, Nanjing 210093, PR China
b Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral N-phosphoryl imines derived from (S)-BINOL have been designed and synthesized in good to
excellent chemical yields. These N-phosphoryl imines were found to react with diketones smoothly with-
out the use of any bases. They can also serve as electrophiles for the reaction with diethyl malonate in the
presence of potassium carbonate. Good yields (62%—quant) and excellent diastereoselectivities (up to
99:1 dr) have been achieved for 10 examples.
Received 23 April 2010
Revised 7 June 2010
Accepted 14 June 2010
Available online 19 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Ph
H
N
N
N
O
N
O
Ph
Ph
Chiral imine chemistry has been playing an important role in
asymmetric synthesis because it can result in numerous amino
building blocks, such as a- and b-amino acids, amino alcohols, ami-
O
O
O
N
P
P
P
N
N
no ketones, etc.1,2 Chiral imines can be utilized as both electro-
philes and dienophiles for many asymmetric reactions.3 The
search for new efficient imines for general asymmetric synthesis
has become important, interesting, and challenging. In the past
several years, we have designed and synthesized chiral N-phospho-
nyl imines based on the use of commercial chemicals, vicinal
(1R,2R)-diaminocyclohexane, and (1R,2R)-1,2-diphenylethylene
diamine as chiral auxiliaries (Fig. 1A and B).4–9 The resulting N-
phosphonyl imines were proven to be effective in asymmetric
induction for various reactions, such as aza-Darzens reaction,4a
H
Ar
Ar
Ar
Ph
C
B
A
Figure 1. Structures of chiral N-phosphonyl and N-phosphoryl imines.
verted into its lithium enolate form prior to the 1,2-addition
reaction.7b In order to conduct the direct addition reaction, we
re-visited chiral N-phosphoryl imine chemistry and found that
the (S)-BINOL-derived chiral N-phosphoryl imines can be reacted
with diketones smoothly without the use of any bases. In this Let-
ter, we report our preliminary results on this study as represented
by Scheme 1.
aza-Henry reaction,5a addition of allylmagnesium bromides5b
,
and 1,2-asymmetric additions of ester- and ketone-derived
enolates.6 Very recently, they have also been utilized for the asym-
metric synthesis of N-phosphonyl b-amino Weinreb amides,7a
b-aminomalonates,7b b-amino esters,8a ,b-diamino esters,8b,c and
a
2. Results and discussion
terminal-functionalized chiral propargylamines.9
During the study of N-phosphonyl imines, we also attempted to
render chiral N-phosphoryl imine chemistry by using BINOL deriv-
atives (Fig. 1C), but the success was limited.4 However, these N-
phosphoryl imines are also useful chiral auxiliaries and would
potentially complement our N-phosphonyl imine chemistry in re-
gard to reactivity, asymmetric control, and substrate scope. For
example, when we directly subjected chiral N-phosphonyl imines
to the reaction with cyclohexane-1,3-dione, no 1,2-addition prod-
ucts were observed at all. Cyclohexane-1,3-dione had to be con-
The chiral phosphoramide 6 was synthesized by following the
synthetic route as shown in Scheme 2. (S)-BINOL 3 was first treated
with phosphorus oxychloride in the presence of triethylamine10 to
produce phosphoryl chloride 4 which was then converted to phos-
phoryl azide 5 by treating with sodium azide in acetone at room
temperature.11 The resulting phosphoryl amide 6 was obtained
via catalytic hydrogenation in a quantitative yield. This chiral
amide has been proven to be stable by storing it at rt for several
weeks with no indication of decomposition as revealed by 1H
NMR analysis.
For the synthesis of chiral N-phosphoryl imine, phosphoramide
6 was initially treated with benzaldehyde, TiCl4, and Et3N in
CH2Cl2, but very little product was observed as indicated by TLC
* Corresponding authors. Fax: +86 25 83314502 (Y.P.); tel.: +1 806 742 3015; fax:
+1 806 742 1289 (G.L.).
E-mail addresses: yipan@nju.edu.cn (Y. Pan), guigen.li@ttu.edu (G. Li).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.072

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H. Sun et al. / Tetrahedron Letters 51 (2010) 4403–4407
O
O
O
O
O
O
N
O
O
CH2Cl2, 4Å M.S.
rt. 6 h
P
P
+
NH OH
Ar
H
Ar
O
1
2
Up to 99:1 dr and 94% yield
Scheme 1. 1,2-Asymmetric addition of cyclohexane-1,3-dione onto N-phosphoryl imines.
POCl3, NEt3
OH
OH
O
O
O
Benzene, rt, 15 h
72 %
NaN3, rt, Acetone
quant.
P
Cl
3
5
4
10% Pd/C, H2 atm,
O
O
O
O
O
THF, rt, 5 h
quant.
P
P
N3
O
NH2
6
Scheme 2. Synthesis of (S)-BINOL-based N-phosphoramide.
monitoring. There are several reports on the synthesis and reac-
tions of the corresponding thio phosphoryl analogues of imines
1.12 The known condensation procedure was employed for their
synthesis.11–13 As shown in Table 1, good to excellent yields (71–
100%) were obtained for nine substrates that were examined.
Besides aldehydes for imine formations, acetophenone was also
proven to be a suitable substrate for this formation (entry 9). The
resulting chiral N-phosphoryl imines showed good stability and
solubility in most common organic solvents, such as DCM, CHCl3,
THF, toluene, etc. In fact, when chiral N-phosphoryl imine 1a was
stored in an oven at 60 °C for 2 h, there was no sign of decomposi-
tion; and only ꢀ10% decomposition was observed when it was kept
at 80 °C for 1 h as monitored by 1H NMR determinations.
We then carefully studied the addition reactions of chiral N-
phosphoryl imine 1a with cyclohexane-1,3-dione as the model
reaction. As shown in Table 2, all common solvents that were
examined showed their effectiveness without the use of any bases.
The imine 1a was consumed within 6 h in both DCM and toluene in
the presence of 4 Å molecular sieves. Excellent chemical yields,
90% and 92%, respectively, were obtained for these two cases (en-
tries 1 and 2). Furthermore, the product was confirmed to be a sin-
gle diastereoisomer as revealed by 1H and 31P NMR measurements.
The more polar solvent, CH3CN, led to a similar yield of 90%, but the
diastereoselectivity was slightly decreased to 97:3 (entry 5). Other
solvents, Et2O, THF, benzene, and EtOAc, resulted in not only lower
chemical yields (78–88%) but also decreased the diastereoselecivi-
Table 1
Synthesis of chiral phosphoryl iminesa
170 ºC
O
O
O
N
O
O
O
ArCR(OEt) 2
+
P
P
NH2
R
Ar
1a-i
6
Entry
Ar
R
Product
Time (min)
Mp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Ph
H
H
H
H
H
H
H
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
12
5
117–119
128–130
133–135
112–114
120–122
97–99
94–96
116–118
118–120
94
96
100
85
93
81
84
92
71
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
Ph
10
10
10
13
10
10
20
Me
a
Conditions: mixture of phosphoramide 6 (1.0 mmol) and ArCR(OEt)2 (1.3 mmol) at 170 °C.
Isolated yields after column chromatography.
b

H. Sun et al. / Tetrahedron Letters 51 (2010) 4403–4407
4405
Table 2
The reaction of imine 1a with 1,3-cyclohexanedione under different conditionsa
O
O
O
O
O
O
N
O
O
P
solvent
4Å M.S.
P
+
NH OH
Ar
H
Ph
O
1a
Solvent
2a
Entry
Time (h)
Temp (°C)
Yieldb
drc
1
2
3
4
5
6
7
8
CH2Cl2
Toluene
Benzene
Et2O
CH3CN
THF
6
6
6
6
6
6
6
6
25
25
25
25
25
25
25
25
92
90
85
87
90
88
78
92
>99:1
>99:1
95:5
87:13
97:3
94:6
98:2
>99:1
EtOAc
CH2Cl2
K2CO3
d
9
10
11
CH2Cl2
CH2Cl2
CH2Cl2
12
6
6
25
0
À78
92
>99:1
>99:1
—
53
NRe
a
b
c
Conditions: 1a (0.2 mmol) and 1,3-cyclohexanedione (0.24 mmol) in the presence of 4 Å molecular sieves (100 mg).
Isolated yields.
Determined by 1H NMR or 31P NMR after column chromatography.
0.2 mmol of K2CO3 was added.
d
e
No reaction was observed.
ty (98:2–87:13, entries 3, 4, 6 and 7). The addition of K2CO3 to the
reaction mixture did not give any improvement on both the yield
and diasteoselectivity (entry 8). The yield was substantially de-
creased to 53% when the reaction was performed at 0 °C (entry
10), and no reaction was observed at À78 °C (entry 11).
As shown in Table 3, nine substrates were examined under the
optimal conditions. Good to excellent chemical yields (62–92%)
and diastereoselectivities (dr = 90:10–99:1) have been achieved
except for the case of acetophenone-derived imine (entry 9) which
did not give any product. A slightly decreased yield was observed
when a methoxy substituent is present on the aromatic ring of
imine substrate, but excellent diastereoselectivity was still shown
(entry 3).
We then turned our attention to linear substrates, acetylacetone
and diethyl malonate. We found that these new N-phosphoryl
imines can react with acetylacetone even at À78 °C, the reaction
proceeded to completion within 5 h without the use of any bases
to afford good diastereoselectivity (87:13 dr) and an excellent yield
(96%) (Scheme 3). However, when diethyl malonate was used for
this reaction, K2CO3 was found to be necessary to give good diaste-
reoselectivity (83:17 dr) and an excellent yield (quant) (Scheme 4).
To determine the absolute configuration, product 8 was subject
to deprotection using HCl/MeOH at rt followed by the treatment
with (Boc)2O in the presence of NaHCO3 to afford (R)-diethyl 2-
[(N-t-Boc-amino)(phenyl)methyl]malonate 9 (Scheme 5). The R
absolute configuration was confirmed by comparing its optical
Table 3
Reaction of 1,3-cyclohexanedione with N-phosphoryl iminesa
O
O
O
O
O
O
O
O
N
P
CH2Cl2, 4Å M.S.
rt, 6 h
+
P
NH OH
Ar
H
Ar
O
1a-i
2a-h
Mp (°C)
Entry
Ar
R
Product
Yieldb (%)
drc
1
2
3
4
5
6
7
8
9
Ph
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
—
154–156
136–138
121–123
150–152
130–132
141–143
150–152
138–140
—
92
78
62
87
94
64
80
91
NRd
>99:1
94:6
>99:1
95:5
98:2
90:10
92:8
96:4
—
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
Ph
Me
a
b
c
Conditions: 1a (0.2 mmol) and 1,3-cyclohexanedione (0.24 mmol) in CH2Cl2 in the presence of 4 Å molecular sieves (100 mg) at rt for 6 h.
Isolated yields.
Determined by 1H NMR or 31P NMR after column chromatography.
No reaction was observed.
d

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H. Sun et al. / Tetrahedron Letters 51 (2010) 4403–4407
O
N
O
O
CH2Cl2, 4Å M.S.
O
O
O
O
O
P
P
-78 oC, 5h
NH
Ph
Ph
O
1a
O
7
87:13 dr, 96% yield
Scheme 3. Addition of acetylacetone onto chiral N-phosphoryl imine.
O
K2CO3 (1.0 equiv)
O
O
O
N
O
O
P
O
O
CH2Cl2, 4Å M.S.
OEt
rt, 8h
P
NH OEt
EtO
O
Ph
EtO
Ph
O
1a
8
83:17 dr, 100% yield
Scheme 4. K2CO3-assisted addition of diethyl malonate onto chiral N-phosphoryl imine.
O
O
O
O
P
1) HCl/MeOH, rt, 12 h
O
NH
OEt
NH
OEt
2) (Boc)2O, NaHCO3,
MeOH, 14 h
Ph
EtO
O
Ph
EtO
O
O
O
8
9
Scheme 5. Conversion of product 8 to an authentic sample.
rotation with that of an authentic sample as reported in the litera-
ture which showed the opposite sign.14
lely the responsibility of the authors and does not necessarily rep-
resent the official views of the National Institute on Drug Abuse or
the National Institutes of Health.
Since the polarity of BINOL is very weak, it can be recovered
near quantitatively simply by washing the crude cleavage mixture
with 15:85 ratio EtOAc/hexane through a silica gel column.
Finally, it is anticipated that the resulting bis-carbonyl products
can be further subjected to various reactions, such as NaBH4-based
reduction and RMgX- or RLi-based carbonyl additions to give other
useful synthetic building blocks, which will be conducted in our
laboratories in due course.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.06.072.
References and notes
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In summary, (S)-BINOL-based chiral N-phosphoryl imines have
been designed and synthesized. These N-phosphoryl imines have
been proven to be efficient for the direct 1,2-addition reaction with
both cyclic and linear diketones without the use of any bases. They
can also serve as electrophiles for the reaction with diethyl malon-
ate in the presence of potassium carbonate. The absolute configu-
ration has been unambiguously determined by converting the
product into an authentic sample.
Acknowledgments
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