Catalytic Asymmetric Addition of Alkyl and Aryl Alkynes to N-(Diphenylphosphinoyl)imines

Article abstract of DOI:10.1021/acs.joc.6b01599

A 3,3′-di(1-diphenylmethylpiperazinyl)methyl H₈BINOL compound, (S)-11, was prepared from the Mannich-type reaction of (S)-H₈BINOL with paraformaldehyde and 1-(diphenylmethyl)piperazine. This compound can catalyze the asymmetric react

Full text of DOI:10.1021/acs.joc.6b01599

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Article
Catalytic Asymmetric Addition of Both Alkyl and
Aryl Alkynes to N-(Diphenylphosphinoyl)imines
Jun Ying, Xue-Dan Wu, Danny Wang, and Lin Pu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01599 • Publication Date (Web): 30 Aug 2016
Downloaded from http://pubs.acs.org on September 1, 2016
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Catalytic Asymmetric Addition of Alkyl and Aryl
Alkynes to Nꢀ(Diphenylphosphinoyl)imines
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Jun Ying, Xue-Dan Wu, Danny Wang and Lin Pu*
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904ꢀ4319.
Email Address: lp6n@virginia.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
TOC Graphic
O
PPh2
O
Ph
Ph
HN
PPh2
N
N
N
(S)-11, Et2Zn
imidazole
N
R2
+
OH
OH
R1
H
Ti(OiPr)4
R2 = alkyl, aryl toluene, 0 oC
R1
R2
Ph
Ph
52-85% ee
40-80% yield
N
i
alkyne/Et Zn/(S)-11/imidazole/Ti(O Pr )/aldimine = 4:4:0.3:0.3:1:1
2
4
(S)-11
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Abstract
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A 3,3’ꢀdi(1ꢀdiphenylmethylpiperazinyl)methyl H8BINOL compound (S)ꢀ11 was prepared
from the Mannichꢀtype reaction of (S)ꢀH8BINOL with paraformaldehyde and 1ꢀ(diphenyl)methyl
piperazine. This compound can catalyze the asymmetric reaction of alkyl and aryl alkynes with
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Nꢀ(diphenylphosphinoyl)imines in the presence of Et2Zn and Ti(OiPr)4.
It exhibits
unprecedented high enantioselectivity (up to 85% ee) for a simple alkyl alkyne addition to the Nꢀ
(diphenylphosphinoyl)imines. The easy removal of the Nꢀ(dipehenylphosphinoyl) protecting
groups makes this method practically useful for the asymmetric synthesis of chiral propargyl
amines.
1. Introduction
Chiral propargyl amines are important building blocks for the synthesis of numerous
pharmaceuticals, biologically active compounds and natural products.1 The enantioselective
alkyne addition to imines represents a very efficient process to produce chiral propargyl amines
and a number of highly enantioselective catalytic systems have been developed.1ꢀ3 For example,
extensive work has been conducted by using the Cu(I)ꢀcatalyzed reaction of terminal alkynes
with Nꢀarylimines that could be generated in situ from an aldehyde and an arylamine, and
excellent enantioselectivity has been achieved for a number of substrates in the presence of
various nitrogenꢀcontaining chiral ligands.2 In many of these reactions, however, the Nꢀ
protecting groups of the propargyl amine products, such as the aryl groups, are not easily
removable for further transformation.
Among the imine substrates studied in the asymmetric alkyne additions to generate
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propargyl amines, the use of Nꢀ(diphenylphosphinoyl)imines is particularly interesting because
the Nꢀdiphenylphosphinoyl activating/protecting group can be easily removed under very mild
conditions after the reaction.4ꢀ6 For example, when a methanol solution of an optically active Nꢀ
(diphenylphosphinoyl) propargyl amine was treated with aqueous HCl at room temperature for 2
h, the resulting propargyl amine was obtained in 92% yield with retention of the enantiomeric
purity.6 Several reports have appeared for the catalytic asymmetric alkyne addition to the Nꢀ
(diphenylphosphinoyl)imines and high enantioselectivity has been observed for certain
substrates, but there are still limitations in these methods.5,6 For example, no highly
enantioselective reaction of Nꢀ(diphenylphosphinoyl)imines with simple alkyl alkynes was
reported, although good reults have been obtained for the additions of alkynes with aryl,
TMSOCH2, TMS or 2ꢀpropenyl groups.5,6 As shown in Scheme 1, although the 1,1’ꢀbiꢀ2ꢀ
napthol (BINOL) compound (R)ꢀ1 showed high enantioselectivity for the reaction of aryl
alkynes with Nꢀ(diphenylphosphinoyl)imines, it gave only 14% ee and 22% yield for the reaction
of 1ꢀhexyne with Nꢀ(diphenylphosphinoyl)benzaldimine (2).6
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Scheme 1. An aliphatic alkyne addition to the Nꢀ(diphenylphosphinoyl)imine 2.
O
PPh2
O
PPh2
Br
HN
N
(R)-1 (20 mol %)
OH
OH
ZnMe2 (6 equiv)
toluene, 0 oC
H
+
Br
(7.2 equiv)
2
22%, 14% ee
(R)-1
In our laboratory, we have discovered that the 3,3’ꢀdi(aminomethyl) substituted partially
hydrogenated BINOL (H8BINOL) derivatives exhibit high enantioselectivity for the asymmetric
alkyne, aryl and vinyl additions to aldehydes.7,8 This class of compounds can be synthesized in
oneꢀstep from the Mannichꢀtype reaction of H8BINOL with paraformaldehyde and a secondary
amine (Scheme 2). We have also explored the use of these compounds in combination with
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Et2Zn and Ti(OiPr)4 to catalyze the alkyne addition to Nꢀ(diphenylphosphinoyl)imines and have
achieved high enantioselectivity for the reactions of both alkyl and aryl alkynes. Herein these
results are reported.
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Scheme 2. Synthesis of 3,3’ꢀdi(aminomethyl)H8BINOLs
NR2
∆
OH
OH
OH
OH
+
(CH2O)n
+ NHR2
NR2
(S)-H8BINOL
2. Results and Discussion
Previously, we reported the use of the 3,3’ꢀdi(morpholinylmethyl) H8BINOL (S)ꢀ3 (Figure
1) in combination with Et2Zn and Ti(OiPr)4 to catalyze the phenylacetylene addition to aldehydes
with high enantioselectivity.7a Therefore, we first tested the use of this compound to catalyze the
reaction of phenylacetylene with 2 in the presence of Et2Zn and Ti(OiPr)4 and the results are
given in Table 1. As shown in entry 1 of Table 1, in the presence of 30 mol % (S)ꢀ3, the Nꢀ
(diphenylphosphinoyl) propargyl amine product was obtained with 58% yield and 50% ee. We
found that addition of pyridine (30 mol %) as an additive improved both the yield and ee of the
product (entry 2). We have prepared the monomorpholinylmethyl substituted H8BINOL
derivatives (S)ꢀ4 and (S)ꢀ5, but these compounds gave much lower enantioselectivity (entries
3,4). Especially, compound (S)ꢀ5 with a bulky TBS group gave almost no enantioselectivity at
all (entry 4). These results demonstrate that both the 3,3’ꢀaminomethyl groups are important for
the chiral induction. Compound (S)ꢀ6 is a sulfurꢀsubstituted analog of (S)ꢀ3 and it gave the same
enantioselectivity as (S)ꢀ3 (entry 5). However, when (S)ꢀ7, an analog of (S)ꢀ3 without the
oxygen atom in the morpholinyl ring, was used, the enantioselectivity was significantly
decreased (entry 6).
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Figure 1. Chiral H8BINOL derivatives containing 3ꢀaminomethyl substitutents.
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6
N
O
N
O
N
O
7
8
9
OH
OH
OH
OTBS
OH
OMe
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N
O
(S)-5
(S)-3
(S)-4
N
N
N
N
S
OH
OH
OH
OH
S
(S)-6
(S)-7
Table 1. Results for the reaction of phenylacetylene with 2 catalyzed by (S)ꢀ3 – (S)ꢀ7.a
O
O
PPh2
HN
PPh2
chiral ligand
Et2Zn
N
+
H
Ti(OiPr)4
toluene, 0 oC, 48 h
2
Entry Chiral ligand
Additive
none
Yield (%) ee (%)
1
2
3
4
5
6
(S)ꢀ3
(S)ꢀ3
(S)ꢀ4
(S)ꢀ5
(S)ꢀ6
(S)ꢀ7
58
70
62
60
58
62
50
pyridine
pyridine
pyridine
pyridine
pyridine
58 (S)
43
3
59
49
a. Alkyne/Et2Zn/Ligand/Ti(OiPr4)/imine = 4:4:0.3:1:1. Pyridine (30 mol%) was added in entries
2ꢀ6. The reactions were conducted at 0 oC in toluene for 48 h. All the yields are isolated.
The study of (S)ꢀ3, (S)ꢀ6 and (S)ꢀ7 indicates that the additional hetero atoms in the cyclic
amine groups of these compounds should play a role in the asymmetric induction. The
intermediate A is proposed to guide our exploration of this catalytic system. In A, the zinc
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acetylide is coordinated to the Lewis base additive (B) and the heterocyclic substituent of the
H8BINOL ligand. On the basis of this hypothesis, changing the hetero atom X and the additive
B should allow us to tune the catalytic properties of this system.
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X
B
N
Zn
Ph
Ph
Et
O
P
H
A
O
N
R' Ph
Ti
O
OR
OR
N
X
We thus designed a new type of catalyst for this reaction by incorporating an additional
nitrogen atom into the cyclic amine substituents to give (S)ꢀ8 (Figure 2). This compound was
prepared from the condensation of 1ꢀmethyl piperazine with H8BINOL and paraformaldehyde.
This compound represents an interesting class of H8BINOL derivatives in which the terminal
nitrogen atom could be easily modified by using various Nꢀsubstituents. This should allow us to
systematically modify the steric and electronic properties of the heteroatom X coordinated to the
zinc acetylide as shown in the proposed intermediate A.
Figure 2. Chiral H8BINOL derivatives containing 3,3’ꢀpiperazinyl substituents.
N
N
Me
N
N
Ph
OH
OH
OH
OH
N
N Me
N
N
Ph
(S)-8
(S)-9
Ph
Ph
N
N
N
N
N
N
Ph
OH
OH
OH
OH
Ph
Ph
N
N
Ph
(S)-10
(S)-11
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When (S)ꢀ8 was used to catalyze the reaction of phenylacetylene with 2 under the same
conditions as the use of (S)ꢀ3, it gave 47% ee for the addition product as shown in entry 1 of
Table 2. In order to improve the enantioselectivity of this reaction, we have used various Nꢀ
substituted piperazines to prepare compounds (S)ꢀ9 – (S)ꢀ11 and examined their catalytic
properties. As shown in entries 2 – 4 of Table 2, among these compounds, (S)ꢀ11 with a bulky 1ꢀ
(diphenyl)methyl substituent on each piperazine ring gave the best enantioselectivity (64% ee,
entry 4). When the solvent of the reaction was changed from toluene to CH2Cl2, THF and Et2O,
the yield and/or ee decreased (entries 5 – 7).
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Table 2. Results for the reaction of phenylacetylene with 2 catalyzed by the piperazine
derivatives (S)ꢀ8 – (S)ꢀ11.a
O
O
PPh2
PPh2
HN
chiral ligand
Et2Zn
Ti(OiPr)4, pyridine
solvent, 0 oC, 48 h
N
+
H
2
Entry Chiral ligand
Solvent
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
Yield (%)
ee (%)
47
1
2
3
4
5
6
7
(S)ꢀ8
67
42
48
63
low
45
60
(S)ꢀ9
56
(S)ꢀ10
(S)ꢀ11
(S)ꢀ11
(S)ꢀ11
(S)ꢀ11
50
64
ꢀ
35
Et2O
51
a. Alkyne/Et2Zn/Ligand/pyridine/Ti(OiPr4)/imine = 4:4:0.3: 0.3:1:1. The reactions were
conducted at 0 oC in toluene for 48 h. All the yields are isolated.
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Since (S)ꢀ11 shows improved enantioselectivity than the other H8BINOL compounds, we
further explored the reaction conditions for the use of this compound. The results are
summarized in Table 3. As shown in entry 2, without the additive, the enantioselectivity
significantly decreased for the reaction of phenylacetylene with 2. We tested the use of
imidazole in place of pyridine as the additive, the enantioselectivity was improved to 72% ee
(entry 3). Increasing the concentration of the reaction by reducing the solvent volume, the
enantioselectivty was further increased to 77% ee (entry 4). Lowering the reaction temperature
to ꢀ20 oC greatly decreased the reaction yield and also with small reduction in enantioselectivity
(entry 5). Increasing the reaction temperature to room temperature increased the yield but
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o
greatly reduced the enantioselectivity (entry 6). At 0 C, when the amount of Et2Zn was
increased to 6 equiv, the enantioselectivity was further enhanced to 81% ee (entry 7). In the
absence of Ti(OiPr)4, there was significant reduction of ee (entry 8). When Et2Zn was replaced
with Me2Zn, lower enantioselectivity was observed (entry 9). The configuration of the product
was determined to be S by comparing the HPLC retention time with those in the literature.5a,6
Besides imidazole, we also screened the use of a broad range of nitrogenꢀcontaining acyclic and
cyclic bases as the additive, but they all gave lower enantioselectivity (52 – 70% ee) under the
same conditions of entry 7.
Table 3. Results for the reaction of phenylacetylene with 2 catalyzed by (S)ꢀ11.a
O
PPh2
O
PPh2
HN
N
(S)-11, Et2Zn
+
R
H
Ti(OiPr)4
R
R = Ph, nBu toluene
2
R = Ph, nBu
Entry RC≡CH Additive
R2Zn
Yield (%)
ee (%)
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9
1
2
Ph
Ph
pyridine
none
Et2Zn (4 equiv)
Et2Zn (4 equiv)
Et2Zn (4 equiv)
Et2Zn (4 equiv)
Et2Zn (4 equiv)
Et2Zn (4 equiv)
Et2Zn (6 equiv)
Et2Zn (4 equiv)
Me2Zn (4 equiv)
Et2Zn (4 equiv)
Et2Zn (6 equiv)
63
60
72
75
24
82
80
67
70
52
55
64
47(S)
72
3
Ph
imidazole
imidazole
imidazole
imidazole
imidazole
imidazole
imidazole
imidazole
imidazole
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4
Ph
77
5b
6c
7d
8e
9f
10
11
Ph
74
Ph
37
Ph
Ph
81
60
Ph
68
nBu
nBu
85
74
a. Unless noted otherwise, the following reagent ratio was used: Alkyne/Et2Zn/(S)ꢀ
11/additive/Ti(OiPr4)/2 = 4:4:0.3:0.3:1:1, 2 (0.1 mmol) and toluene (1.0 mL for entries 1ꢀ3. 0.7
mL for entries 4ꢀ11). The reaction was allowed to proceed at 0 oC for 48 h. b. at ꢀ20 oC. c. at rt.
d. Alkyne/Et2Zn/(S)ꢀ11/additive/Ti(OiPr4)/2 = 7.2:6:0.3:0.3:1:1. e. Ti(OiPr4) was not added. f.
Me2Zn was used in place of Et2Zn. All the yields are isolated.
When the reaction conditions of entry 7 in Table 3 were applied to the reaction of 1ꢀhexyne
with 2, we were pleased to observe a high enantioselectivity (85% ee) for this aliphatic alkyne
addition (entry 10, Table 3). As described earlier in Scheme 1, the previous catalytic system
gave very low enantioselectivity for such an aliphatic alkyne addition. Increasing the amount of
Et2Zn from 4 equiv to 6 equiv reduced the enantioselectivity (entry 11, Table 3). We have
conducted the background reaction in the absence of the chiral catalyst. After 48 h at 0 oC, there
was only less than 20% conversion of the starting material to the product. That is, the chiral
catalyst (S)ꢀ11 promoted the reaction with good stereocontrol. The high enantioselectivity
observed for the reaction of 1ꢀhexyne with 2 catalyzed by (S)ꢀ11 in entry 10 prompted us to
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apply these conditions for the reaction of various alkyl alkynes with various Nꢀ
(diphenylphosphinoyl)imines. As the results summarized in Figure 3 show, when 1ꢀhexyne was
reacted with the aldimines containing electron donating Me group or the electronꢀwithdrawing
Br, the corresponding products 13 and 14 were obtained with good yields and ee’s. The addition
of other aliphatic alkynes to 2 also gave good enantioselectivities in the synthesis of compounds
15 – 18. The lower yields in the isolation of compounds 15, 16 and 18 could be attributed to the
sensitivity of the functional groups on the alkyl alkynes under the reaction conditions. The
reaction of the conjugated enynes with 2 was also studied which gave the products 19 and 20
with good results. We have treated an aliphatic imine with 1ꢀhexyne under the same conditions,
but no reaction was observed.
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Figure 3. Products for the reaction of aliphatic alkynes with Nꢀ(diphenylphosphinoyl)imines
catalyzed by (S)ꢀ11.
O
P
O
P
O
P
Ph
Ph
Ph
Ph
Ph
Ph
HN
HN
HN
Br
13
14
12
68%, 80% ee
61%, 81% ee
52%, 85% ee
O
O
O
Ph
P
Ph
P
Ph
P
Ph
HN
Ph
Ph
HN
HN
OTBS
15
16
17
50%, 85% ee
42%, 84% ee
65%, 77% ee
O
P
O
O
Ph
Ph
Ph
P
Ph
P
Ph
Ph
HN
HN
HN
Cl
18
19
64%, 81% ee
20
46%, 77% ee
71%, 78% ee
Reagents: Alkyne/ Et2Zn/(S)ꢀ11/additive/ Ti(OiPr4)/imidazole = 4:4:0.3:0.3:1:1, imine (0.1
mmol). All the yields are isolated.
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We applied the conditions of entry 7 in Table 3 for the asymmetric addition of aryl alkynes
to Nꢀ(diphenylphosphinoyl)imines. The results are summarized in Figure 4. Similar
enantioselectivity was observed for the phenylacetylene addition to Nꢀ(diphenylphosphinoyl)
benzaldimines containing an electronꢀdonating Me group or an electronꢀwithdrawing Br for the
formation of compounds 22 and 23. Addition of other aryl alkynes to 2 was studied. It was
found that the more electron rich aryl alkynes gave higher enantioselectivity for the formation of
products 24 – 26 than the more electron deficient aryl alkynes which gave the products 27 and
28. The lower yields of 27 and 28 could be attributed to their corresponding less nucleophilic
zinc acetylides.
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Figure 4. Products for the reaction of aromatic alkynes with Nꢀ(diphenylphosphinoyl)imines
catalyzed by (S)ꢀ11.
O
P
O
P
O
P
Ph
Ph
Ph
Ph
Ph
Ph
HN
HN
HN
Br
21
22
23
72%, 80% ee
80%, 81% ee
66%, 74% ee
O
O
O
Ph
P
Ph
P
Ph
P
Ph
Ph
HN
Ph
HN
HN
OMe
24
OMe
26
25
76%, 80% ee
72%, 75% ee
75%, 74% ee
O
P
O
P
Ph
Ph
Ph
Ph
HN
HN
Br
F
28
40%, 52% ee
27
56%, 67% ee
Reagents: Alkyne/Et2Zn//(S)ꢀ11/additive/Ti(OiPr4)/imine = 7.2:6:0.3: 0.3:1:1, imine (0.1 mmol).
All the yields are isolated.
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3. Conclusion
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We have discovered that a 3,3’ꢀdi(1ꢀdiphenylmethylpiperazinyl)methyl H8BINOL
compound can catalyze the asymmetric reaction of various alkynes with Nꢀ
(diphenylphosphinoyl)imines in the presence of Et2Zn and Ti(OiPr)4. It exhibits unprecedented
high enantioselectivity for the reaction of Nꢀ(diphenylphosphinoyl)imines with simple and
functional alkyl alkynes. The easy removal of the Nꢀ(diphenylphosphinoyl) protecting groups of
the propargylic amine products makes this method useful for the synthesis of this class of
important chiral compounds. Because this catalyst system utilizes two metallic reagents in
combination with a multifunctional chiral ligand, more detailed study of the reaction mechanism
is necessary in order to gain better understanding of this reaction and further improve the
catalytic efficiency. Work along this line will be conducted.
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4. Experimental
General Data
Reactions were carried out under nitrogen in vials. All commercial chemicals were used without
further purification unless otherwise noted. Zinc reagents were purchased and stored in dry
nitrogen atmosphere. Toluene was distilled over sodium and benzophenone under nitrogen. All
the NMR spectra were obtained in CDCl3 unless indicated otherwise. Compounds (S)ꢀ3,7d (S)ꢀ
67e and (S)ꢀ77e were known compounds and their NMR spectra match those reported (See SI).
Synthesis and Characterization of (S)-4. (a) To a solution of (S)ꢀH8BINOL (2.04 mmol, 600
mg, 1 equiv) and K2CO3 (10.2 mmol, 1.4 g, 5 equiv) in 20 mL THF was added MeI (2.04 mmol,
o
127.1 µL, 1 equiv) at room temperature under nitrogen. Then the reaction was heated to 50 C
and stirred for 24 h. After cooled to room temperature, the mixture was quenched with water (10
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mL) and extracted with CH2Cl2 (3 x 15 mL). The organic layer was then dried over anhydrous
Na2SO4 and concentrated by rotary evaporation. The crude mixture was purified by flash
column chromatography on silica gel eluted with hexanes/CH2Cl2 (5/1) to give OꢀMeꢀ(S)ꢀ
H8BINOL as a white powder in 70% yield (440 mg). The NMR spectra match those reported.8a
(b) Paraformaldehyde (5.0 mmol, 150 mg, 5 equiv) was added to a 2ꢀneck round bottom flask
fitted with condenser under nitrogen. The flask was then charged with dioxane (10 mL,
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o
degassed), and the mixture was cooled to 0 C. Morpholine (5.0 mmol, 431 uL, 5 equiv) was
added dropwise into the mixture over 20 min. After the addition was completed, the ice bath was
removed and the mixture was warmed to room temperature for 2 h. It was then heated at 65 oC
for 18 h. After the solution was cooled to room temperature, OꢀMeꢀ(S)ꢀH8BINOL (1.0 mmol,
308 mg, 1 equiv) dissolved in dioxane (5 mL) was added, and the resulting solution was reheated
to 95 oC for 20 h. Upon completion of the reaction, the mixture was diluted with ethyl acetate
(15 mL) and washed with saturated NaHCO3 (3 x 15 mL) and H2O (3 x 15 mL). The organic
layer was then dried over anhydrous Na2SO4 and concentrated by rotary evaporation. The crude
mixture was purified by flash column chromatography on silica gel eluted with hexanes/ethyl
acetate (20/1 to 10/1) to give pure (S)ꢀ4 as a white powder in 65% yield (265 mg). m.p. 80 ꢀ 82
1
oC. H NMR (600 MHz, CDCl3) δ 10.31 (s, 1H), 7.12 (d, 1H, J = 8.4 Hz), 6.87 (d, 1H, J = 8.4
Hz), 6.81 (s, 1H), 3.83 (d, 1H, J = 13.8 Hz), 3.76 (m, 7H), 3.70 (d, 1H, J = 13.8 Hz), 2.83 (m,
4H), 2.62 (s, 4H), 2.38 (m, 2H), 2.20 (m, 2H), 1.76 (m, 8H). 13C {1H} NMR (150 MHz, CDCl3)
δ 154.8, 152.0, 136.5, 136.2, 129.6, 129.0, 128.6, 127.5, 125.7, 124.3, 117.7, 109.2, 66.7, 61.9,
56.1, 53.0, 29.5, 29.3, 27.2, 27.1, 23.4, 23.35, 23.32, 23.2. HRMS [ESI(TOF)] for C26H34NO3
[M+H+]: m/z: calcd for: 408.2539; found: 408.2536.
Synthesis and Characterization of (S)-5. (a) To a solution of (S)ꢀH8BINOL (1.7 mmol, 500
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mg, 1 equiv) in 10 mL THF was added nBuLi (2.0 mmol, 2.5 M in hexanes, 0.8 mL, 1.2 equiv)
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6
o
at 0 C under nitrogen. The reaction was stirred for 20 min. Then TBSCl (2.0 mmol, 306 mg,
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1.2 equiv) in 5 mL THF was added and the resulting solution was warmed to room temperature.
After 20 h, the reaction was quenched with saturated NH4Cl solution (10 mL) and extracted with
CH2Cl2 (3 x 15 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated
by rotary evaporation. The crude mixture was purified by flash column chromatography on
silica gel eluted with hexanes/CH2Cl2 (8/1 to 5/1) to give OꢀTBSꢀ(S)ꢀH8BINOL as a white
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powder in 74% yield (512 mg).
The NMR spectra match those reported.8b
(b)
Paraformaldehyde (6.25 mmol, 188 mg, 5 equiv) was added to a 2ꢀneck round bottom flask fitted
with condenser under nitrogen. The flask was then charged with dioxane (10 mL, degassed), and
o
the mixture was cooled to 0 C. Morpholine (6.25 mmol, 548 uL, 5 equiv) was added dropwise
into the mixture over 20 min. After the addition was completed, the ice bath was removed and
the mixture was warmed to room temperature for 2 h. It was then heated at 65 oC for 18 h. After
the solution was cooled to room temperature, OꢀTBSꢀ(S)ꢀH8BINOL (1.25 mmol, 512 mg, 1
equiv) dissolved in dioxane (5 mL) was added, and the resulting solution was reheated to 95 oC
for 20 h. Upon completion of the reaction, the mixture was diluted with ethyl acetate (15 mL)
and washed with saturated NaHCO3 (3 x 15 mL) and H2O (3 x 15 mL). The organic layer was
then dried over anhydrous Na2SO4 and concentrated by rotary evaporation. The crude mixture
was purified by flash column chromatography on silica gel with hexanes/ethyl acetate (25/1 to
1
15/1) to give pure (S)ꢀ5 as a white powder in 59% yield (374 mg). m.p. 70 ꢀ 73 oC. H NMR
(600 MHz, CDCl3) δ 10.21 (s, 1H), 6.97 (d, 1H, J = 8.4 Hz), 6.71 (m, 2H), 3.79 (d, 1H, J = 13.2
Hz), 3.70 (s, 4H), 3.54 (d, 1H, J=13.8 Hz), 2.78 (m, 2H), 2.71 (m, 2H), 2.60 (m, 4H), 2.48 (m,
2H), 2.16 (m, 2H), 1.70 (m, 8H), 0.70 (s, 9H), 0.16 (s, 3H), ꢀ0.01 (s, 3H). 13C {1H} NMR (150
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MHz, CDCl3) δ 152.1, 150.1, 137.0, 136.4, 129.6, 128.8, 128.08, 128.06, 127.5, 124.7, 117.6,
116.0, 66.7, 61.9, 52.9, 29.5, 29.4, 27.3, 27.0, 25.3, 23.4, 23.33, 23.30, 23.2, 17.7, ꢀ4.1, ꢀ4.8.
HRMS [ESI(TOF)] for C31H46NO3Si [M+H+]: m/z: calcd for: 508.3247; found: 508.3253.
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Synthesis and Characterization of (S)-11. Paraformaldehyde (23.8 mmol, 714.3 mg, 4 equiv)
was added to a 2ꢀneck round bottom flask fitted with condenser under nitrogen. The flask was
o
then charged with dioxane (20 mL, degassed), and the mixture was cooled to 0 C. 1ꢀ
(Diphenylmethyl)piperazine (23.8 mmol, 6.0 g, 4 equiv) was added dropwise into the mixture
over 20 min. After the addition was completed, the ice bath was removed and the mixture was
warmed to room temperature for 2 h. It was then heated at 65 oC for 18 h. After the solution was
cooled to room temperature, (S)ꢀH8BINOL (6.0 mmol, 1.76 g, 1 equiv) dissolved in dioxane (10
mL) was added, and the resulting solution was reheated to 65 oC for 18 h. Upon completion of
the reaction, the mixture was diluted with ethyl acetate (20 mL) and washed with saturated
NaHCO3 (3 x 20 mL) and H2O (3 x 20 mL). The organic layer was then dried over anhydrous
Na2SO4 and concentrated by rotary evaporation. The crude solid was washed with EtOH to give
pure (S)ꢀ11 as a white powder in 90% yield (4.44 g). m.p. 182ꢀ185 oC. 1H NMR (600 MHz,
CDCl3) δ 10.46 (s, 2H), 7.42 (m, 8H), 7.28 (m, 8H), 7.20 (m, 4H), 6.74 (s, 2H), 4.27 (m, 2H),
3.87 (d, 2H, J = 13.8 Hz), 3.58 (d, 2H, J = 13.8 Hz), 2.76ꢀ2.33 (m, 22H), 2.17 (m, 2H), 1.72 (m,
8H). 13C {1H} NMR (150 MHz, CDCl3) δ 152.4, 142.6, 142.5, 135.6, 128.6, 128.5, 128.4, 127.9,
127.3, 127.1, 127.0, 124.0, 118.2, 76.0, 61.6, 52.8, 51.5, 29.3, 27.0, 23.4, 23.3, [α]24D = +16.5 (c
= 1.10, CHCl3). HRMS [ESI(TOF)] for C56H63N4O2 [M+H+]: m/z: calcd for: 823.4951; found:
823.4950.
Compounds (S)-8, (S)-9 and (S)-10 were prepared in the same way as (S)-11 by using the
corresponding commercially available 1-substituted piperazine as the starting material.
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Characterization of (S)-8. Prepared from (S)ꢀH8BINOL (3.4 mmol), white solid, 1.36g, 77%
5
6
1
yield. m.p. 180 ꢀ 182 oC. H NMR (600 MHz, CDCl3) δ 6.69 (s, 2H), 3.77 (d, 2H, J = 13.2 Hz),
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3.58 (d, 2H, J = 13.8 Hz), 2.70 (m, 4H), 2.59ꢀ2.43 (m, 16H), 2.36 (m, 2H), 2.25 (s, 6H), 2.15 (m,
2H), 1.69 (m, 8H). 13C {1H} NMR (150 MHz, CDCl3) δ 152.2, 135.7, 128.5, 127.3, 124.0, 118.2,
61.4, 54.7, 52.4, 45.8, 29.2, 27.0, 23.3, 23.2. HRMS [ESI(TOF)] for C32H47N4O2 [M+H+]: m/z:
calcd for: 519.3699; found: 519.3701.
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Characterization of (S)-9. Prepared from (S)ꢀH8BINOL (2.2 mmol), white solid, 1.13g, 80%
1
yield. m.p. 240 ꢀ 243 oC. H NMR (600 MHz, CDCl3) δ 10.45 (s, 2H), 7.25 (m, 4H), 6.89 (m,
6H), 6.76 (s, 2H), 3.87 (d, 2H, J = 13.8 Hz), 3.66 (d, 2H, J = 13.8 Hz), 3.19 (s, 8H), 2.74 (m,
12H), 2.38 (m, 2H), 2.19 (m, 2H), 1.72 (m, 8H). 13C {1H} NMR (150 MHz, CDCl3) δ 152.2,
151.0, 135.9, 129.1, 128.6, 127.5, 124.0, 120.0, 118.1, 116.4, 61.5, 52.5, 49.1, 29.2, 27.0, 23.3,
23.2. HRMS [ESI(TOF)] for C42H51N4O2 [M+H+]: m/z: calcd for: 643.4012; found: 643.4015.
Characterization of (S)-10. Prepared from (S)ꢀH8BINOL (3.4 mmol), white solid, 1.94 g, 85%
1
yield. m.p. 193 ꢀ 195 oC. H NMR (600 MHz, CDCl3) δ 10.67 (s, 2H), 7.30 (m, 10H), 6.73 (s,
2H), 3.83 (d, 2H, J = 13.8 Hz), 3.59 (d, 2H, J = 13.8 Hz), 3.48 (s, 4H), 2.74ꢀ2.16 (m, 28H), 1.72
(m, 8H). 13C {1H} NMR (150 MHz, CDCl3) δ 152.3, 138.0, 135.6, 129.0, 128.4, 128.2, 127.2,
127.1, 124.0, 118.2, 62.8, 61.5, 52.7, 52.5, 29.2, 27.0, 23.3, 23.2. HRMS [ESI(TOF)] for
C44H55N4O2 [M+H+]: m/z: calcd for: 671.4325; found: 671.4324.
General procedure for the alkyne addition to N-(diphenylphosphinoyl)imines catalyzed by
(S)-11
Under nitrogen, (S)ꢀ11 (30 mol %, 24.8 mg) and imidazole (30 mol %, 2 mg) were added
into a vial and dissolved in toluene (0.3 mL). An alkyne (4 equiv or 7.2 equiv) and Et2Zn (4
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equiv or 6 equiv) were then added and the mixture was stirred at room temperature for 5 h. Then,
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Ti(OiPr)4 (1 equiv) was added and the stirring continued at room temperature for 3 h. A Nꢀ
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(diphenylphosphinoyl)imine (0.1 mmol, 1 equiv) was added and the mixture was cooled to 0 C
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and stirred for 48 h. The reaction was quenched with the addition of water (2 mL) and extracted
with ethyl acetate (3 x 4 mL). The organic layer was dried with anhydrous Na2SO4, filtered and
then concentrated by rotary evaporation. The crude mixture was purified by flash column
chromatography on silica gel with hexanes/ethyl acetate (1/1) to give the propargyl
phosphonamide products with 40 ꢀ 80% yield and 52 ꢀ 85% ee.
We have also conducted a larger scale for the reaction of 2 (1.15 mmol) with 1ꢀhexyne
which gave the product 12 in 45% yield and 85% ee.
Characterization of the propargyl phosphonamides prepared from the asymmetric alkyne
addition to N-(diphenylphosphinoyl)imines.
Compounds 12,6 15,6 16,5a 19,5a 21,6 22,6 23,5a 26,6 and 276 are known compounds and their
NMR spectra match those reported (See SI).
(S)-P,P-Diphenyl-N-(1-(p-tolyl)hept-2-yn-1-yl)phosphinic amide, 13. White solid, 27.2 mg,
68% yield. m.p. 138 ꢀ 140 oC. 80% ee determined by HPLC analysis: CHIRALPAK ADꢀH
i
column, 90:10 hexanes: PrOH, flow rate = 1.0 mL/min, λ = 225 nm, retention time: tminor = 16.6
1
min, tmajor = 20.0 min. [α]25D = ꢀ13.7 (c = 0.96, CHCl3). H NMR (600 MHz, CDCl3) δ 8.02 (m,
2H), 7.82 (m, 2H), 7.52 (m, 1H), 7.47 (m, 5H), 7.38 (m, 2H), 7.12 (d, 2H, J = 7.8 Hz), 5.09 (t,
1H, J = 9.6 Hz), 3.37 (t, 1H, J = 9 Hz), 2.31 (s, 3H), 2.19 (t, 2H, J = 7.2 Hz), 1.47 (m, 2H), 1.40
(m, 2H), 0.91 (t, 3H, J = 7.2 Hz). 13C {1H} NMR (150 MHz, CDCl3) δ 138.2 (d, J = 4.7 Hz),
137.4, 132.7 (d, J = 9.8 Hz), 131.9, 131.8, 129.1, 128.4 (d, J = 12.6 Hz), 127.1, 86.0, 79.8 (d, J =
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6 Hz), 46.6, 30.7, 22.0, 21.1, 18.5, 13.6. 31P {1H} NMR (243 MHz, CDCl3) δ 23.1. HRMS
[ESI(TOF)] for C26H29NOP [M+H+]: m/z: calcd for: 402.1987; found: 402.1985.
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(S)-N-(1-(4-Bromophenyl)hept-2-yn-1-yl)-P,P-diphenylphosphinic amide, 14. White solid,
28.5 mg, 61% yield. m.p. 140 ꢀ 143 oC. 81% ee determined by HPLC analysis: CHIRALPAK
ADꢀH column, 90:10 hexanes: iPrOH, flow rate = 1.0 mL/min, λ = 225 nm, retention time: tminor
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1
= 14.9 min, tmajor = 20.2 min. [α]23D = ꢀ10.9 (c = 1.18, CHCl3). H NMR (600 MHz, CDCl3) δ
8.01 (m, 2H), 7.79 (m, 2H), 7.53 (m, 1H), 7.48 (m, 5H), 7.43 (m, 2H), 7.38 (m, 2H), 5.08 (t, 1H,
J = 9 Hz), 3.44 (t, 1H, J = 7.8 Hz), 2.21 (m, 2H), 1.48 (m, 2H), 1.40 (m, 2H), 0.91 (t, 3H, J = 7.2
Hz). 13C {1H} NMR (150 MHz, CDCl3) δ 140.1 (d, J = 3.8 Hz), 132.6 (d, J = 9.9 Hz), 132.0 (d, J
= 10.5 Hz), 131.7 (d, J = 9.8 Hz), 131.5, 129.1, 128.4 (d, J = 12.9 Hz), 121.7, 86.6, 79.1 (d, J =
6.9 Hz), 46.4, 30.6, 22.0, 18.4, 13.6. 31P {1H} NMR (243 MHz, CDCl3) δ 23.5. HRMS
[ESI(TOF)] for C25H26NOPBr [M+H+]: m/z: calcd for: 466.0935; found: 466.0932.
(S)-P,P-diphenyl-N-(1-phenylnon-2-yn-1-yl)phosphinic amide, 17. White solid, 27.0 mg,
o
65% yield. m.p. 110ꢀ112 C. 77% ee determined by HPLC analysis: CHIRALPAK ADꢀH
i
column, 90:10 hexanes: PrOH, flow rate = 1.0 mL/min, λ = 225 nm, retention time: tminor = 10.4
1
min, tmajor = 11.5 min. [α]24D = ꢀ13.4 (c = 0.95, CHCl3). H NMR (600 MHz, CDCl3) δ 8.03 (m,
2H), 7.82 (m, 2H), 7.60 (d, 2H, J=8.4 Hz), 7.52 (m, 1H), 7.46 (m, 3H), 7.37 (m, 2H), 7.32 (t, 2H,
J=7.2 Hz), 7.25 (m, 1H), 5.13 (t, 1H, J = 9.6 Hz), 3.41 (t, 1H, J = 9 Hz), 2.20 (m, 2H), 1.49 (m,
2H), 1.38 (m, 2H), 1.29 (m, 4H), 0.88 (t, 3H, J = 7.2 Hz). 13C {1H} NMR (150 MHz, CDCl3) δ
141.0 (d, J = 4.7 Hz), 132.7 (d, J = 9.9 Hz), 131.9 (d, J = 7.4 Hz), 131.8 (d, J = 9.6 Hz), 128.5,
128.4 (d, J = 12.8 Hz), 127.7, 127.2, 86.3, 79.7 (d, J = 6.2 Hz), 46.8, 31.3, 28.6, 28.5, 22.5, 18.8,
14.0. 31P {1H} NMR (243 MHz, CDCl3) δ 23.2. HRMS [ESI(TOF)] for C27H31NOP [M+H+]:
m/z: calcd for: 416.2143; found: 416.2141.
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(S)-N-(6-Chloro-1-phenylhex-2-yn-1-yl)-P,P-diphenylphosphinic amide, 18. White solid,
18.7 mg, 46% yield. m.p. 107ꢀ109 oC. 77% ee determined by HPLC analysis: CHIRALPAK
ADꢀH column, 90:10 hexanes: iPrOH, flow rate = 1.0 mL/min, λ = 225 nm, retention time: tminor
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= 21.6 min, tmajor = 25.2 min. [α]24D = ꢀ11.5 (c = 0.61, CHCl3). H NMR (600 MHz, CDCl3) δ
8.00 (m, 2H), 7.82 (m, 2H), 7.56 (d, 2H, J = 7.8 Hz), 7.52 (m, 1H), 7.47 (m, 3H), 7.39 (m, 2H),
7.33 (t, 2H, J = 7.8 Hz), 7.26 (t, 1H, J = 7.2 Hz), 5.14 (t, 1H, J = 9.6 Hz), 3.61 (t, 2H, J = 6.6 Hz),
3.42 (t, 1H, J = 8.4 Hz), 2.39 (m, 2H), 1.92 (m, 2H). 13C {1H} NMR (150 MHz, CDCl3) δ 140.7
(d, J = 4.8 Hz), 132.5 (d, J = 9.8 Hz), 132.0 (d, J = 6.9 Hz), 131.8 (d, J = 9.8 Hz), 128.6, 128.4 (d,
J = 12.6 Hz), 127.9, 127.1, 84.1, 80.8 (d, J = 5.6 Hz), 46.7, 43.7, 31.2, 16.2. 31P {1H} NMR (243
MHz, CDCl3) δ 23.2. HRMS [ESI(TOF)] for C24H24NOPCl [M+H+]: m/z: calcd for: 408.1284;
found: 408.1280.
(S)-N-(3-(Cyclohex-1-en-1-yl)-1-phenylprop-2-yn-1-yl)-P,P-diphenylphosphinic amide, 20.
o
White solid, 29.2 mg, 71% yield. m.p. 154ꢀ156 C. 78% ee determined by HPLC analysis:
i
CHIRALCEL ODꢀH column, 93:7 hexanes: PrOH, flow rate = 1.0 mL/min, λ = 225 nm,
retention time: tminor = 10.7 min, tmajor = 8.3 min. [α]24D = ꢀ26.7 (c = 1.21, CHCl3). H NMR (600
1
MHz, CDCl3) δ 8.04 (m, 2H), 7.81 (m, 2H), 7.61 (d, 2H, J=7.2 Hz), 7.52 (m, 1H), 7.46 (m, 3H),
7.37 (m, 2H), 7.32 (d, 2H, J=7.8 Hz), 7.25 (m, 1H), 6.09 (s, 1H), 5.26 (t, 1H, J=9.6 Hz), 3.46 (t,
1H, J = 9 Hz), 2.09 (d, 4H, J = 6 Hz), 1.62 (m, 4H). 13C {1H} NMR (150 MHz, CDCl3) δ 140.7
(d, J = 4.4 Hz), 135.1, 132.8 (d, J = 9.8 Hz), 131.9 (d, J = 7.8 Hz), 131.8 (d, J = 9.8 Hz), 128.5,
128.4 (d, J=12.8 Hz), 127.8, 127.3, 120.2, 87.4, 86.0 (d, J = 6.3 Hz), 47.1, 29.1, 25.6, 22.2, 21.5.
31P {1H} NMR (243 MHz, CDCl3) δ 23.3. HRMS [ESI(TOF)] for C27H27NOP [M+H+]: m/z:
calcd for: 412.1830; found: 412.1829.
(S)-P,P-Diphenyl-N-(1-phenyl-3-(p-tolyl)prop-2-yn-1-yl)phosphinic amide, 24. White solid,
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Mp 172ꢀ174 oC, 32.0 mg, 76% yield. 80% ee determined by HPLC analysis: CHIRALPAK ADꢀ
H column, 93:7 hexanes: iPrOH, flow rate = 1.0 mL/min, λ = 254 nm, retention time: tminor = 28.6
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min, tmajor = 32.7 min. [α]23D = ꢀ46.8 (c = 1.10, CHCl3). H NMR (600 MHz, CDCl3) δ 8.08 (m,
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2H), 7.84 (m, 2H), 7.68 (d, 2H, J = 7.8 Hz), 7.52 (m, 1H), 7.46 (m, 3H), 7.40ꢀ7.34 (m, 4H), 7.29
(m, 3H), 7.11 (d, 2H, J=7.8 Hz), 5.38 (t, 1H, J = 9.6 Hz), 3.53 (t, 1H, J = 8.4 Hz), 2.35 (s, 3H).
13C {1H} NMR (150 MHz, CDCl3) δ 140.4 (d, J = 4.2 Hz), 138.5, 132.8 (d, J = 9.9 Hz), 132.0 (d,
J = 8.9 Hz), 131.8 (d, J = 9.8 Hz), 131.5, 129.0, 128.6, 128.5 (d, J = 12.9 Hz), 127.9, 127.3, 119.6,
88.1 (d, J=6 Hz), 85.7, 47.2, 21.5. 31P {1H} NMR (243 MHz, CDCl3) δ 23.4. HRMS [ESI(TOF)]
for C28H25NOP [M+H+]: m/z: calcd for: 422.1674; found: 422.1660.
(S)-N-(3-(3-Methoxyphenyl)-1-phenylprop-2-yn-1-yl)-P,P-diphenylphosphinic amide, 25.
Colorless oil, 32.8 mg, 75% yield. 74% ee determined by HPLC analysis: CHIRALPAK ADꢀH
i
column, 90:10 hexanes: PrOH, flow rate = 1.0 mL/min, λ = 254 nm, retention time: tminor = 22.2
1
min, tmajor = 26.3 min. [α]23D = ꢀ38.9 (c = 0.65, CHCl3). H NMR (600 MHz, CDCl3) δ 8.07 (m,
2H), 7.84 (m, 2H), 7.67 (d, 2H, J = 7.8 Hz), 7.51 (m, 1H), 7.47 (m, 3H), 7.39ꢀ7.35 (m, 4H), 7.29
(t, 1H, J = 7.8 Hz), 7.21 (t, 1H, J = 7.8 Hz), 7.00 (d, 1H, J = 7.2 Hz), 6.92 (s, 1H), 6.87 (d, 1H, J
= 8.4 Hz), 5.39 (t, 1H, J = 9.6 Hz), 3.79 (s, 3H), 3.54 (t, 1H, J = 9 Hz). 13C {1H} NMR (150
MHz, CDCl3) δ 159.2, 140.3 (d, J = 4.4 Hz), 132.8 (d, J = 9.9 Hz), 132.0 (d, J = 6.9 Hz), 131.8 (d,
J = 9.8 Hz), 129.3, 128.7, 128.5 (d, J = 12.8 Hz), 128.0, 127.3, 124.2, 123.7, 116.6, 114.9, 88.6 (d,
J = 6.2 Hz), 85.4, 55.3, 47.1. 31P {1H} NMR (243 MHz, CDCl3) δ 23.4. HRMS [ESI(TOF)] for
C28H25NO2P [M+H+]: m/z: calcd for: 438.1623; found: 438.1631.
(S)-N-(3-(4-Bromophenyl)-1-phenylprop-2-yn-1-yl)-P,P-diphenylphosphinic amide, 28.
o
White solid, Mp 175ꢀ178 C, 19.5 mg, 40% yield. 52% ee determined by HPLC analysis:
i
CHIRALPAK ADꢀH column, 90:10 hexanes: PrOH, flow rate = 1.0 mL/min, λ = 254 nm,
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retention time: tminor = 26.2 min, tmajor = 29.0 min. [α]25D = ꢀ12.2 (c = 0.48, CHCl3). H NMR
(600 MHz, CDCl3) δ 8.04 (m, 2H), 7.84 (m, 2H), 7.64 (d, 2H, J = 7.2 Hz), 7.52 (m, 1H), 7.46ꢀ
7.35 (m, 9H), 7.29 (m, 1H), 7.22 (d, 2H, J = 7.8 Hz), 5.38 (t, 1H, J = 9 Hz), 3.56 (t, 1H, J = 8.4
Hz). 13C NMR (150 MHz, CDCl3) δ 140.1 (d, J = 4.4 Hz), 133.1, 132.7 (d, J = 9.6 Hz), 132.0,
131.8 (d, J = 9.5 Hz), 131.5, 128.7, 128.5 (d, J = 12.5 Hz), 128.1, 127.2, 122.6, 121.6, 90.0 (d, J
= 5.0 Hz), 84.5, 47.1. 31P {1H} NMR (243 MHz, CDCl3) δ 23.4. HRMS [ESI(TOF)] for
C27H22NOPBr [M+H+]: m/z: calcd for: 486.0622; found: 486.0636.
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Acknowledgements
Partial supports of this work from the donors of the Petroleum Research Fund—administered by
the American Chemical Society and the US National Science Foundation (CHEꢀ1565627) are
gratefully acknowledged.
Supplementary Materials Available: NMR spectra and HPLC plots of the propargylic amine
products. This information is available free of charge via the Internet at http://pubs.acs.org/.
References
1. Reviews: (a) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2004, 4095ꢀ4105.
(b) Zani, L.; Bolm, C. Chem. Commun. 2006, 4263ꢀ4275. (c) Trost, B. M.; Weiss, A. H. Adv.
Synth. Catal. 2009, 351, 963ꢀ983.
2. (a) Wei, C.; Li, C. J. J. Am. Chem. Soc. 2002, 124, 5638ꢀ5639. (b) Ji, J. X.; Wu, J.; Chan, A.
S. C. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 11196ꢀ11200. (c) Bisai, A.; Singh, V. K. Org.
Lett. 2006, 8, 2405ꢀ2408. (d) Colombo, F.; Benaglia, M.; Orlandi, S.; Usuelli, F.; Celentano,
G. J. Org. Chem. 2006, 71, 2064ꢀ2070. (e) Gommermann, N.; Koradin, C.; Polborn, K.;
Knochel, P. Angew. Chem. Int. Ed. 2003, 42, 5763ꢀ5766. (f) Knӧpfel, T. P.; Aschwanden, P.;
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Page 22 of 23
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2
3
4
5
6
7
8
9
Ichikawa, T.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971ꢀ5973. (g) Aschwanden,
P.; Stephenson, C. R. J.; Carreira, E. M. Org. Lett. 2006, 8, 2437ꢀ2440. (h) Lu, Y.; Johnstone,
T. C.; Arndtsen, B. A. J. Am. Chem. Soc. 2009, 131, 11284ꢀ11285.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
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35
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38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. Other work on the asymmetric alkyne addition to imines: (a) Traverse, J. F.; Hoveyda, A. H.;
Snapper, M. L. Org. Lett. 2003, 5, 3273ꢀ3275. (b) Jiang, B.; Si, Y. G. Angew. Chem., Int. Ed.
2004, 43, 216ꢀ218. (c) Gonzalez, A. Z.; Canales, E.; Soderquist, J. A. Org. Lett. 2006, 8,
3331ꢀ3334. (d) Zani, L.; Eichhorn, T.; Bolm, C. Chem. Eur. J. 2007, 13, 2587ꢀ2600. (e)
Rueping, M.; Antonchick, A. P.; Brinkmann, C. Angew. Chem., Int. Ed. 2007, 46, 6903ꢀ6906.
(f) Blay, G.; Cardona, L.; Climent, E.; Pedro, J. R. Angew. Chem., Int. Ed. 2008, 47, 5593ꢀ
5596. (g) De Armas, P.; Tejedor, D.; GarcíaꢀTellado, F. Angew. Chem., Int. Ed. 2010, 49,
1013ꢀ1016.
4. A review on using Nꢀdiphenylphosphinoylimines in stereoselective synthesis: Weinreb, S.
M.; Orr, R. K. Synthesis 2005, 8, 1205ꢀ1227.
5. (a) Yan, W.; Mao, B.; Zhu, S.; Jiang, X.; Liu, Z.; Wang, R. Eur. J. Org. Chem. 2009, 3790ꢀ
3794; (b) Zhu, S.; Yan, W.; Mao, B.; Jiang, X.; Wang, R. J. Org. Chem. 2009, 74, 6980ꢀ6985.
(c) Yan, W.; Li, P.; Feng, J.; Wang, D.; Zhu, S.; Jiang, X.; Wang, R. Tetrahedron: Asymmetry
2010, 21, 2037ꢀ2042
6. Blay, G.; Ceballos, E.; Monleón, A.; Pedro, J. R. Tetrahedron 2012, 68, 2128ꢀ2134.
7. (a) Liu, L.; Pu, L. Tetrahedron 2004, 60, 7427–7430. (b) Qin, Y. –C.; Pu, L. Angew. Chem.
Int. Ed. 2006, 45, 273ꢀ277. (c) Qin, Y. –C.; Liu, L.; Sabat, M.; Pu, L. Tetrahedron 2006,
62, 9335–9348. (d) Turlington, M.; Pu, L. Org. Synth. 2010, 87, 59ꢀ67. (e) DeBerardinis, A.
M.; Turlington, M.; Ko, J.; Sole, L.; Pu, L. J. Org. Chem. 2010, 75, 2836–2850. (f)
DeBerardinis, A. M.; Turlington, M.; Pu, L. Angew. Chem. Int. Ed. 2011, 123, 2416–2418.
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(g) Gu, S. –X.; Huang, W. –C.; Wu, X. –D.; Ying, J.; Pu, L. Syn. Comm. 2015, 45, 1541ꢀ
1545. (h) Pu, L. Acc. Chem. Res. 2014, 47, 1523–1535.
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8
9
8. (a) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 12094ꢀ12095. (b) Sattely,
E. S.; Meek, S. J., Malcolmson, S. J.; Schrock, R. R. Hoveyda, A. H. J. Am. Chem. Soc. 2009,
131, 943ꢀ953.
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