Design and synthesis of a tridentate ligand inspired by the phenomenon of self-assembly catalysis and its application in the asymmetric alkynylation of N-(diphenylphosphinoyl) imines

Article abstract of DOI:10.1016/j.tetasy.2010.07.020

On the basis of the phenomenon of self-assembly catalysis, a tridentate ligand was designed and synthesized in two steps. The application in alkynylation of N-(diphenylphosphinoyl) imines gave the expected products. Aromatic, heteroaromatic N-(diphenylphosphinoyl) imines were employed and gave optically active propargylic amines in good yields (up to 89%) and excellent enantioselectivities (up to 96%) by a simple experimental procedure. The direct use of sulfone amides in the alkynylation of N-(diphenylphosphinoyl) aliphatic imines made this method very attractive.

Full text of DOI:10.1016/j.tetasy.2010.07.020

Tetrahedron: Asymmetry 21 (2010) 2037–2042
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Design and synthesis of a tridentate ligand inspired by the phenomenon
of self-assembly catalysis and its application in the asymmetric alkynylation
of N-(diphenylphosphinoyl) imines
Wenjin Yan a,b, Peng Li a, Jingchao Feng a, Dong Wang a, Shaoqun Zhu a, Xianxing Jiang a, Rui Wang a,b,
*
a Key Lab of Preclinical Study for New Drugs of Gansu Province, State Key Laboratory of Applied Organic Chemistry and Institute of Biochemistry and Molecular Biology
Lanzhou University, Lanzhou 730000, China
b China State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
On the basis of the phenomenon of self-assembly catalysis, a tridentate ligand was designed and synthe-
sized in two steps. The application in alkynylation of N-(diphenylphosphinoyl) imines gave the expected
products. Aromatic, heteroaromatic N-(diphenylphosphinoyl) imines were employed and gave optically
active propargylic amines in good yields (up to 89%) and excellent enantioselectivities (up to 96%) by a
simple experimental procedure. The direct use of sulfone amides in the alkynylation of N-(diphenylphos-
phinoyl) aliphatic imines made this method very attractive.
Received 5 June 2010
Accepted 9 July 2010
Available online 13 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The screening of efficient catalysts for asymmetric C–C bond
formation is one of the main goals for organic research. For this
purpose, the asymmetric construction of optically active propargyl
amines remains attractive, despite many excellent catalytic sys-
tems having been developed.1 Preliminary examples were mostly
focused on the addition of terminal alkynes to N-aryl or N-alkyl
imines,2 whereas a few examples in which N-activated imines
were employed as electrophilic reagents were also reported.3–6
N-Phosphinoylimines have drawn considerable attention
because the resulting phosphonamide products could be easily
deprotected under mild conditions (such as MeOH and HCl).7,8
Notably, while using amino alcohols as promoters and organozincs
as nucleophilic reagents, a stoichiometric amount of ligands
(0.5–1 equiv) and a long reaction time (over 24 h in general) were
necessary for high enantioselectivities.9
Recently, we have reported that stoichiometric amounts of pro-
line-derived b-amino alcohol ligands and diethylzinc could
promote the addition of terminal alkynes to N-(diphenylphos-
phinoyl) imines to afford N-(diphenylphosphinoyl)-protected
propargylic amines in excellent yields and ee.10 Herein we report
a highly enantioselective alkynylation of N-(diphenylphosphinoyl)
imines utilizing a new tridentate ligand inspired by the phenome-
non of self-assembly catalysis.
In our previous study, the alkynylation of N-(diphenylphosphi-
noyl) benzaldimine with various terminal alkynes could achieve
the corresponding product in excellent enantioselectivities by
using a stoichiometric amount of proline-derived b-amino alcohol
as catalysts. In general, a long reaction time was required. Surpris-
ingly, we found an exception that the addition of 2-ethynylthioph-
ene could be completed after 12 h. In view of this phenomenon, it
is possible that the Lewis base accelerated the alkynylation pro-
cess. Thus, the following studies were launched.
At first, a series of ligands derived from proline were employed
to investigate the difference between the addition of 2-ethynylthi-
ophene and phenylacetylene. The results (Table 1) showed that all
the reactions could be complete after 12 h with a 10% molar cata-
lyst loading. These results indicated that the ligand L1 gave the
highest ee (70%). In contrast, the addition of phenylacetylene pro-
moted by L1 was obtained in only 47% ee even with 20% molar cat-
alyst loading.10a The potential transition state is proposed in
Figure 1; the main difference between 1 and 2 is the heteroatom
S (State 2), which might be activated as a coordinating point.
To verify our hypothesis, the following experiment was de-
signed. First, a solution of 0.06 mmol L1, 0.06 mmol Et2Zn, and
0.06 mmol 2-ethynylthiophene was stirred in CH2Cl2 at room tem-
perature. Meanwhile, 0.4 mmol Et2Zn in CH2Cl2 was stirred with
phenylacetylene in the presence of N-methylimidazole11 to create
the zinc alkynylide. After 7 h the first flask was cooled to ꢀ10 °C,
the solution of second flask was transferred through a syringe,
and the substrate dissolving in CH2Cl2 was added dropwise after
0.5 h. The resulting mixture was quenched after stirring for 60 h
* Corresponding author. Tel.: +86 931 8912567; fax: +86 931 8911255.
E-mail address: wangrui@lzu.edu.cn (R. Wang).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.07.020

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W. Yan et al. / Tetrahedron: Asymmetry 21 (2010) 2037–2042
Table 1
The asymmetric addition of 2-ethynylthiophene to N-benzylidene-P,P-diphenylphosphinic amide catalyzed by L1–L6a
OH
OH
OH
OH
Et
OH
Ph
OH
Ph
N
N
N
N
N
N
Et
L6
L5
L4
L3
L1
L2
O
P
P
HN
Ph
Ph
P
S
N
Ph
L1-L6/Et2Zn
Ph
+
CH2Cl2, rt
S
1a
Ligandb
b
2ab
Entry
t (h)
Yield (%)
eec(%)
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
12
12
12
12
12
12
85
70
63
82
67
75
70
9
0
55
50
33
a
b
c
All reactions were carried out under argon at room temperature on a 0.2 mmol scale with aldimine/Et2Zn/2-ethynylthiophene = 1:4:4.
The proportion of the ligand is 10 mol %.
The enantiomeric excess was determined by HPLC analysis on a Chiralcel AD column.
Et
Znc
S
Et
Znb
Et
Znb
S
Zna
N
Zna
N
O
O
O
O
P
S
P
Ph
Ph
Ph
N
Ph
N
2
1
Figure 1. The potential transition states: (1) phenylacetylene addition to N-(diphenylphosphinoyl) benzaldimine; (2) 2-ethynylthiophene addition to N-(diphenylphos-
phinoyl) benzaldimine.
at ꢀ10 °C. The addition product N-(1,3-diphenylprop-2-ynyl)-P,P-
diphenylphosphinic amide was obtained in 79% yield and 88% ee.
Following the above results, a potential self-assembly catalysis
was proposed (see Fig. 2). State 3 was created by the reaction of L1
and Et2Zn. After the addition of 2-ethynylthiophene, the alkyne
was exchanged with ethyl due to the acidity of terminal acetylenic
C–H, then the ligand-linked State 4 was formed. State 5 was estab-
lished through the coordination after the addition of zinc alkyny-
lide, and the addition of phenylacetylene from zincb or zincc to
imine gave the product with an (S)-configuration.
A comparison with the addition reaction in our previous report
indicated that this self-assembly catalyst gave better results even
with lower catalyst loading.12 We suspected that the participation
of heteroatom S was the key to facilitate the alkynylation process.
However, since the manipulation was very complex, it inspired us
to design new ligands to match our conjecture; a tridentate ligand
which showed excellent catalytic performance in some reactions
due to the three coordinate points.13 The resulting tridentate li-
gand could accelerate the alkynylation of N-(diphenylphosphinoyl)
imine and provided the product with an (S)-configuration (see
Fig. 3).
Ligands L7–L9 were synthesized according to our hypothesis
(Scheme 1). It is very convenient to prepare such heteroatom-con-
tained ligands. At first, the heterocyclic aromatic aldehydes are
stirred with prolinol in CH3CN for 24 h at room temperature. After
the evaporation of CH3CN, the corresponding ligand can be ob-
tained via reduction with NaBH4 in CH3OH.
The investigation of the efficiency of L7, L8, and L9 was carried
out at room temperature with CH2Cl2 as solvent and aldimine/
Et2Zn/phenylacetylene = 1:3:3 with 20% catalyst loading; the best

W. Yan et al. / Tetrahedron: Asymmetry 21 (2010) 2037–2042
2039
Et
S
OH
O
O
EtZn
N
DCM
S
N
N
ZnEt2
3
4
Et
Znc
Et
S
Zn
S
O
N
P
Ph
Ph
O
Znb
Et
O
N
Et
N
O
P
Ph
N
Ph
6
Figure 2. The potential procedure for the addition of phenylacetylene to N-benzylidene-P,P-diphenylphosphinic amide catalyzed by the self-assembly of L1/ZnEt2/2-
ethynylthiophene.
Under the optimized conditions, various imines derived from
aromatic aldehydes were employed to react with aromatic and
heterocyclic aryl terminal alkynes and the results are shown in
Table 4.14
When phenylacetylene was employed as nucleophiles, the alk-
ynylation of N-benzylidene-P,P-diphenylphosphinic amide affor-
Et
ded the product with an (S)-configuration in good yield with 91%
ee (Table 4, entry 1). Other imines derived from aromatic alde-
hydes were employed and could be converted into the correspond-
ing products in good yields and with excellent ee. Furthermore, the
presence of an electron-donating group at the para-position of the
aromatic ring could give excellent enantioselectivities (up to 94%)
with good yields (Table 4, entries 2 and 3). As the data presented in
Table 4, with an electron-drawing group at the para-position the
corresponding product could also be accessed with good enanti-
oselectivity and in moderate yields (Table 4, entries 4–6). With
the electron-drawing group at the meta-position, a moderate ee
was obtained (Table 4, entry 7). When N-(naphthalen-2-ylmethyl-
ene)-P,P-diphenylphosphinic amide was employed, the corre-
sponding product was afforded in 77% yield and 90% ee. With
heterocyclic aryl imines as the substrate, the best enantioselectiv-
ity was obtained at 95% ee. Considering the similar structure of
substrates and mode of action of the chiral promoter, the absolute
configuration of all products (Table 4, entries 2–9) was tentatively
assigned to be an (S)-configuration.
Znb
O
P
N
Znc
X
O
Et
N
Ph
Ph
Figure 3. The design of a tridentate ligand based on the self-assembly ligand.
result was observed by employing L8 as the ligand (Table 2). Th re-
sult is better than our previous studies.
Further optimizations focused on the solvent, catalyst loading,
and temperature were performed. As indicated in Table 3, CH2Cl2
was the best solvent for this reaction (Table 3, entries 1–3). The
ee could be slightly improved upon when the ratio of Alkynylzinc
and substrate was 4: 1 (Table 3, entries 4–6). The ee could be im-
proved to 83% with 81% yield when the temperature was lowered
to ꢀ10 °C. Increasing the catalyst loading to 35% afforded the
resulting phosphinamide in 91% ee. Increasing the catalyst loading
further did not give better results.
N
N
N
OH
OH
a, b
OH
N
H
OH
N
S
L8
O
L7
L9
Scheme 1. Preparation of tridentate ligands L7–L9. Reagents and conditions: (a) 1-heterocyclic aldehyde (1 equiv), CH3CN, 24 h; (b) NaBH4, CH3OH.

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W. Yan et al. / Tetrahedron: Asymmetry 21 (2010) 2037–2042
Table 2
The asymmetric addition of phenylacetylene to N-benzylidene-P,P-diphenylphosphinic amide catalyzed by L7–L9a
O
P
O
HN
Ph
Ph
P
Ligand/Et2Zn
N
Ph
Ph
+
CH2Cl2, rt
2aa
1a
a
Entry
Ligandb
t (h)
Yield (%)
eec (%)
1
2
3
L7
L8
L9
30
12
24
63
73
86
40
71
59
a
b
c
All reactions were carried out under argon at room temperature on a 0.2 mmol scale with aldimine/Et2Zn/2-ethynylthiophene = 1:3:3.
The proportion of the ligand is 10 mol %.
The enantiomeric excess was determined by HPLC analysis on a Chiralcel AD column.
Table 3
The asymmetric addition of phenylacetylene to N-benzylidene-P,P-diphenylphosphinic amide catalyzed by L8a
O
N
P
OH
O
HN
Ph
Ph
P
N
Ph
S
Ph
+
Et2Zn
2aa
1a
a
Entry
Solvent
ZnEt2/1a
T (°C)
t (h)
Yield (%)
eee(%)
1b
2b
3b
4b
5b
6b
7b
8c
9d
Tol
DCM
Hex
DCM
DCM
DCM
DCM
DCM
DCM
3
3
3
4
5
6
4
4
4
rt
rt
rt
rt
rt
rt
ꢀ10
ꢀ10
ꢀ10
16
12
18
12
12
12
60
60
60
70
81
77
83
82
86
81
84
83
55
71
57
73
68
63
83
91
91
a
b
c
All reactions were carried out under argon at room temperature on a 0.2 mmol scale.
The proportion of the ligand is 20 mol %.
The proportion of the ligand is 35 mol %.
The proportion of the ligand is 50 mol %.
The enantiomeric excess was determined by HPLC analysis on a Chiralcel AD column.
d
e
Although the design of this ligand was based on 2-ethynylthi-
this imine was difficult. We noticed that the sulfone amides could
be used directly in the asymmetric alkylation of N-phos-
phinoylalkylimines,16 and we decided to preform this stable pre-
cursor in our system. Although the enantioselectivity was
decreased slightly, the yield of resulting product was clearly im-
proved (up to 92%). In view of simple experimental procedure,
the other aliphatic aldehyde-derived sulfone amides were em-
ployed to test the applicability of this three-chelate ligand, and
the results are listed in Table 5. In general, the corresponding prod-
ophene, the use of ethynylthiophene gave products, which could
be used as important intermediates in manufacturing dyes, aroma
compounds, and pharmaceuticals.15 The addition of 2-ethynylthi-
ophene to various imines gave the corresponding products in mod-
erate to high yields (Table 4, entries 10–16). Substitution at the
para-position with both electron-donating groups and electron-
drawing groups provided excellent enantioselectivities. The het-
erocyclic imine also gave the best result with 96% ee.
With 3-ethynylthiophene as nucleophiles, various imines de-
rived from aromatic aldehydes could be readily converted into
the corresponding products in moderate to high yields, but with
a slight decrease in enantioselectivity compared to the addition
of 2-ethynylthiophene.
The aliphatic aldehyde-derived N-phosphinoylimines could be
prepared by the reaction of the corresponding aldehydes and P,P-
diphenylphosphinic amide in the presence of p-toluenesulfinic acid
and then by the treatment of sulfone with a strong base.
ucts could be obtained in good yields with moderate ee, with a-
branched aliphatic aldehyde-derived sulfone amides affording
higher ee. Further increase of catalyst loading (up to 100%) and/
or decrease of temperature (down to ꢀ30 °C) did not improve
the enantiselectivity when butyraldehyde-derived sulfone amide
was treated as a substrate.
3. Conclusion
The aliphatic aldehyde-derived N-phosphinoylimines could be
achieved by the reaction of the corresponding aldehydes and P,P-
diphenylphosphinic amide in the presence of p-toluenesulfinic acid
and then treatment of sulfone with a strong base. The alkynylation
of N-(2-methylpropylidene)-P,P-diphenylphosphinic amide gave
the product in 78% yield and 79% ee, however the purification of
Self-assembly catalysis has been established through the com-
parison of addition of 2-ethynylthiophene with phenylacetylene
in the alkynylation of N-(diphenylphosphinoyl) imines. After a sys-
tematic investigation, a self-assembly catalyst was obtained. In
light of this phenomenon, a novel class of tridentate ligands were
designed and synthesized. These ligands were evaluated in the

W. Yan et al. / Tetrahedron: Asymmetry 21 (2010) 2037–2042
2041
Table 4
drous CH2Cl2 (0.5 mL). Then the solution of diethylzinc in CH2Cl2
(0.8 mL, 0.8 mmol, 4.0 equiv) was added. The reaction mixture
was stirred for 30 min, and an alkyne (0.8 mmol, 4.0 equiv) was
added. The resulting solution was stirred for an additional 7 h,
before adding the appropriate imine substrate. The reaction mix-
ture was stirred at ꢀ10 °C for 48–60 h. Saturated aqueous NH4Cl
(2 mL) was added slowly at 0 °C and the resulting mixture was
extracted with CH2Cl2 (3 ꢁ 5 mL). The combined organic layers
were dried over Na2SO4. After filtration and evaporation of the
solvents, the crude residue was purified by flash chromatography
(silica gel, hexane/ethyl acetate), giving the corresponding
compound.
The asymmetric addition of terminal alkynes to N,N-(diphenylphosphinoyl) imines
catalyzed by L8a
O
P
N
O
HN
Ph
OH
Ph
P
N
Ph
R2
+
Ar
Ph
35mol %
S
Ar
R2
DCM, Et2Zn, -10oC
2aa-2jc
1a-1j
a-c
R2
Entry
Ar
Product
t (h)
Yield (%)
eeb(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2aa
2ba
2ca
2da
2ea
2fa
2ga
2ha
2ia
2ab
2bb
2cb
2db
2eb
2fb
2ib
2ac
2cc
2dc
2jc
60
60
60
60
60
60
60
72
60
48
48
48
48
48
48
48
50
50
50
50
83
87
89
75
77
80
79
77
80
82
76
83
79
77
73
84
85
89
82
79
91
94
91
88
92
91
83
90
95
94
94
95
94
92
93
96
84
90
89
92
4-MeC6H5
4-MeOC6H5
4-FC6H5
4-ClC6H5
4-BrC6H5
3-ClC6H5
2-Naphthyl
3-Thienyl
C6H5
4-MeC6H5
4-MeOC6H5
4-FC6H5
4-ClC6H5
4-BrC6H5
3-Thienyl
C6H5
4.1.1. N-(1,3-Diphenylprop-2-ynyl)-P,P-diphenylphosphinic
amide 2aa
White solid, mp 178–180 °C, 93% yield. 91% ee determined by
HPLC analysis (Daicel Chiralcel AD column, hexane/2-propanol N-
(2-methylpropylidene)-P,P-diphenylphosphinic amide gave the
product in 78% yield and 79% ee, however the purification of this
imine was difficult. We noticed that the sulfone amides could be
used directly in the asymmetric alkylation of N-phosphinoylalkyli-
mines.16 We decided to perform this stable precursor in our sys-
tem. Although the enantioselectivity decreased slightly, the yield
of resulting product could be improved upon (up to 92%). In view
of a simple experimental procedure, the other aliphatic alde-
hyde-derived sulfone amides were employed to test the applicabil-
ity of this three-chelate ligand, and the results are listed in Table 5.
In general, the corresponding products could be obtained in good
C6H5
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
3-Thienyl
3-Thienyl
3-Thienyl
3-Thienyl
4-MeOC6H5
4-FC6H5
2-Thienyl
a
All reactions were carried out under argon at room temperature on a 0.2 mmol
scale with aldimine/Et2Zn/2-ethynylthiophene = 1:4:4.
b
The enantiomeric excess was determined by HPLC analysis on a Chiralcel AD
yields with moderate ee. It was observed that a-branched aliphatic
column.
aldehyde-derived sulfone amides afforded higher ee. Increasing the
catalyst loading further (up to 100%) or/and decreasing the tem-
perature (down to ꢀ30 °C) did not improve the enantioselectivity
when butyraldehyde-derived sulfone amide was treated as the
substrate.85:15, 1.0 mL/min). Retention time: tmajor = 12.40 and
enantioselective alkynylation of aromatic N-(diphenylphosphinoyl)
imines and provided the expected products in good yields and
excellent enantioselectivities. Although moderate enantioselectivi-
ties were obtained in the synthesis of
amines, the stable precursor imine adduct could be used directly.
tminor = 11.26 min. ½a D20
ꢂ
¼ ꢀ92 (c 1.0, CHCl3). 1H NMR (300 MHz,
a-aliphatic-a-propargylic
CDCl3): d 8.13–8.06 (m, 2H), 7.90–7.83 (m, 2H), 7.71–7.69 (m,
2H), 7.54–7.46 (m, 4H), 7.44–7.37 (m, 5H), 7.35–7.30 (m, 5H),
5.40 (t, J = 9.6 Hz, 1H), 3.55 (t, J = 9.3 Hz, 1H). 13C NMR (75 MHz,
CDCl3): d 140.4 (d, J(c–p) = 18 Hz), 133.4, 132.8 (d, J(c–p) = 39 Hz),
132.1 (d, J(c–p) = 27 Hz), 132.8 (d, J(c–p) = 39 Hz), 131.7, 131.5,
129.0, 128.7 (d, J(c–p) = 24 Hz), 128.4 (d, J(c–p) = 48 Hz), 128.0,
4. Experimental
4.1. General procedure for alkynylation of N-
(diphenylphosphinoyl) imines
127.4, 122.8, 89.0 (d, J(c–p) = 24 Hz), 85.6, 47.2. IR (neat):
m = 3160,
1489, 1437, 1186, 1125, 1060, 695, 544 cmꢀ1. HRMS for C27H22NOP
(M+H+): calcd 408.1512, found 408.1524.
In an oven-dried Schlenk flask under an inert atmosphere of
argon was placed L8 13.8 mg (0.07 mmol), followed by anhy-
Table 5
Catalytic asymmetric synthesis of
a
-aliphatic-propargylic aminesa
O
O
P
N
P
HN
Ph
OH
HN
Ph
Ph
Ph
R1
R2
+
R1
35mol %
S
S
O2
R2
DCM, Et2Zn, -10oC
1k-1p
2ka-2kc
a-c
Entry
R1
R2
Product
t (h)
Yield (%)
eeb(%)
1
2
3
4
5
6
7
8
i-Pr
C6H5
C6H5
C6H5
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
3-Thienyl
2ka
2ma
2na
2ob
2mb
2pb
2nb
2kc
32
32
32
24
24
24
24
32
92
93
91
94
92
92
91
92
78
82
63
85
83
53
52
69
c-C6H11
n-C6H13
i-Pr
c-C6H11
n-C3H7
n-C6H13
i-Pr
a
All reactions were carried out under argon at room temperature on a 0.2 mmol scale with aldimine/Et2Zn/2-ethynylthiophene = 1:4:4.
The enantiomeric excess was determined by HPLC analysis on a Chiralcel AD column.
b

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W. Yan et al. / Tetrahedron: Asymmetry 21 (2010) 2037–2042
4.2. General procedure for the synthesis of three-chelate ligands
L7–L9
References
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963.
Prolinol (2.02 g, 20 mmol) and 2-heterocyclic aldehyde
(20 mmol) were dissolved in 40 mL anhydrous CH3CN, and the
resulting mixture was stirred for 24 h at room temperature. Then
the solvent was removed under reduced pressure, and the result-
ing brown liquid was dissolved in 40 mL CH3OH. Solid NaBH4
(1.477 g, 39.05 mmol) was slowly added at 0 °C; the reaction mix-
ture was stirred at room temperature overnight. Then the solvent
was removed under reduced pressure, and 40 mL 30% aqueous
Na2CO3 was added and the resulting solvent was extracted with
CH2Cl2 (3 ꢁ 20 mL). The extract was dried over Na2SO4 and concen-
trated under reduced pressure to yield the crude product. The
crude product was then purified by flash chromatography with
hexane/acetate to give the corresponding compounds.
2. For selected examples see: (a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638;
(b) Colombo, F.; Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew.
Chem., Int. Ed. 2003, 42, 5763; (c) Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L.
Org. Lett. 2003, 5, 3273; (d) Wei, C.; Mague, J. T.; Li, C.-J. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5749; (e) Benaglia, M.; Negri, D.; DellMAnna, G. Tetrahedron
Lett. 2004, 45, 8705; (f) Gommermann, N.; Knochel, P. Chem. Commun. 2004,
2324; (g) KnNpfel, T.; Aschwanden, P. P.; Ichikawa, T.; Carreira, E. M. Angew.
Chem., Int. Ed. 2004, 43, 5971; (h) Orlandi, S.; Colombo, F.; Benaglia, M. Synthesis
2005, 1689; (i) Ji, J.-X.; Wu, J.; Chan, A. S. C. Proc. Natl. Acad. Sci. U.S.A. 2005, 102,
11196; (j) Gommermann, N.; Knochel, P. Chem. Eur. J. 2006, 12, 4380; (k) Taylor,
A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143; (l) Bisai, A.; Singh, V. K. Org. Lett.
2006, 8, 2405; (m) Benaglia, M.; Orlandi, S.; Usuelli, F.; Celentano, G. J. Org.
Chem. 2006, 71, 2064; (n) Aschwanden, P.; Stephenson, C. R. J. F.; Carreira, E. M.
Org. Lett. 2006, 8, 2437; (o) Zani, L.; Eichhorn, T.; Bolm, C. Chem. Eur. J. 2007, 13,
2587; (p) Rueping, M.; Antonchick, A. P.; Brinkmann, C. Angew. Chem., Int. Ed.
2007, 46, 6903; (q) Dodda, R.; Zhao, C.-G. Org. Lett. 2007, 9, 165; (r) Dodda, R.;
Zhao, C.-G. Tetrahedron Lett. 2007, 48, 4339; (s) Labonne, A.; Zani, L.;
Hintermann, L.; Bolm, C. J. Org. Chem. 2007, 72, 5704.
3. For addition to N-acyl imines see: (a) Jiang, B.; Si, Y.-G. Angew.Chem., Int. Ed.
2004, 43, 216; (b) Wu, T. R.; Chong, J. M. Org. Lett. 2006, 8, 15; (c) Gonzalez, A.
Z.; Canales, E.; Soderquist, J. A. Org. Lett. 2006, 8, 3331.
4. For addition to nitrones see: Wei, W.; Kobayashi, M.; Ukaji, Y.; Inomata, K.
Chem. Lett. 2006, 35, 176.
5. For addition to N-sulfonyl aldimines see: Blay, G.; Cardona, L.; Climent, E.;
Pedro, J. R. Angew. Chem., Int. Ed. 2008, 47, 5593.
6. For addition to N-sulfinylimines see: (a) Patterson, A. W.; Ellman, J. A. J. Org.
Chem. 2006, 71, 7110; (b) Turcaud, S.; Berhal, F.; Royer, J. J. Org. Chem. 2007, 72,
7893.
7. For a review see: Weinreb, S. M.; Orr, R. K. Synthesis 2005, 1205.
8. For selected examples see: (a) Morimoto, H.; Wiedemann, S. H.; Yamaguchi, A.;
Harada, S.; Chen, Z.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2006,
45, 3146; (b) Mattson, A. E.; Bharadwaj, A. R.; Zuhl, A. M.; Scheidt, K. A. J. Org.
Chem. 2006, 71, 5715; (c) Ong, W. W.; Beeler, A. B.; Kesavan, S.; Panek, J. S.;
Porco, J. A., Jr. Angew. Chem., Int. Ed. 2007, 46, 7470; (d) Saito, S.; Tsubogo, T.;
Kobayashi, S. Chem. Commun. 2007, 1236; (e) Fang, Y.-Q.; Jacobsen, E. N. J. Am.
Chem. Soc. 2008, 130, 5660; (f) Du, Y.; Xu, L.-W.; Shimizu, Y.; Oisaki, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 16146; (g) Lettan, R. B.;
Woodward, C. C.; Scheidt, K. A. Angew. Chem., Int. Ed. 2008, 47, 2294; (h)
Trincado, M.; Ellman, J. A. Angew. Chem., Int. Ed. 2008, 47, 5623.
9. For selected examples see: Yan, G.; Wu, Y.; Lin, W.; Zhang, X. Tetrahedron:
Asymmetry 2007, 18, 2643; Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron:
Asymmetry 2007, 18, 2828; (c) Xu, X.-H.; Qiu, X.-L.; Qing, F.-L. Tetrahedron 2008,
64, 7353.
4.2.1. (1-(Pyridin-2-ylmethyl)pyrrolidin-2-yl)methanol L7
Pale yellow oil, 2.8 g, 73% yield, ½a D20
ꢂ
¼ ꢀ83 (c 0.4, CHCl3). 1H
NMR (300 MHz, CDCl3) d = 7.35 (d, J = 0.8, 1H), 6.30 (dd, J = 1.7,
3.1, 1H), 6.22–6.14 (m, 1H), 3.84 (d, J = 14.3, 1H), 3.63–3.52 (m,
2H), 3.39 (dd, J = 2.9, 10.9, 1H), 3.12–2.99 (m, 1H), 2.72 (dd,
J = 2.9, 5.9, 2H), 2.53–2.39 (m, 1H), 1.93–1.65 (m, 4H). 13C NMR
(75 MHz, CDCl3): d = 159.2, 149.0, 148.5, 136.7, 122.8, 122.1, 65.3,
63.0, 60.1, 55.1, 27.6, 23.5. IR (neat):
m = 3340, 2951, 2872, 1593,
1435, 1047, 760, 630 cmꢀ1 HRMS for C11H16N2O (M+H+): calcd
193.1335, found 193.1331.
4.2.2. (1-(Thiophen-2-ylmethyl)pyrrolidin-2-yl)methanol L8
Pale yellow oil, 3.42 g, 87% yield, ½a D20
ꢂ
¼ ꢀ83 (c 0.5, CHCl3). 1H
NMR (300 MHz, CDCl3) d = 7.22 (dd, J = 1.2, 5.0, 1H), 6.93 (dt,
J = 3.2, 7.6, 2H), 4.08 (d, J = 14.1, 1H), 3.73 (d, J = 14.1, 1H), 3.63
(dd, J = 3.5, 10.9, 1H), 3.42 (dd, J = 2.6, 10.9, 1H), 3.09 (dt, J = 4.7,
9.4, 1H), 2.78 (ddt, J = 3.1, 6.0, 9.0, 1H), 2.60 (s, 1H), 2.41 (dd,
J = 8.3, 17.3, 1H), 1.97–1.65 (m, 4H). 13C NMR (75 MHz, CDCl3):
d = 142.6, 126.5, 125.4, 124.8, 63.7, 62.0, 54.3, 52.5, 27.8, 23.5. IR
(neat):
m = 3389, 2958, 2960, 2872, 2805, 1440, 1376, 1080, 1075,
1041, 851, 699, 477 cmꢀ1. HRMS for C10H15NOS (M+H+): calcd
198.0947, found 198.0952.
10. (a) Yan, W.; Mao, B.; Zhu, S.; Jiang, X.; Liu, Z.; Wang, R. Eur. J. Org. Chem. 2009,
19, 3790; (b) Zhu, S.; Yan, W.; Mao, B.; Jiang, X.; Wang, R. J. Org. Chem. 2009, 74,
6980.
11. Yang, F.; Xi, P.; Yang, L.; Lan, J.; Xie, R.; You, J. J. Org. Chem. 2007, 72,
5457.
4.2.3. (1-(Furan-2-ylmethyl)pyrrolidin-2-yl)methanol L9
Pale yellow oil, 2.9 g, 80% yield, ½a D20
ꢂ
¼ ꢀ88 (c 0.5, CHCl3). 1H
NMR (300 MHz, CDCl3) d = 7.35 (d, J = 0.8, 1H), 6.30 (dd, J = 1.7,
3.1, 1H), 6.22–6.14 (m, 1H), 3.84 (d, J = 14.3, 1H), 3.63–3.52 (m,
2H), 3.39 (dd, J = 2.9, 10.9, 1H), 3.12–2.99 (m, 1H), 2.72 (dd,
J = 2.9, 5.9, 2H), 2.53–2.39 (m, 1H), 1.93–1.65 (m, 4H). 13C NMR
(75 MHz, CDCl3): d = 159.2, 149.0, 148.5, 136.7, 122.8, 122.1, 65.3,
12. In our previous report if the temperature was lowered to ꢀ10 °C, the product
could be isolated in 23% yield even after 72 h.
13. For selected examples see: (a) Funabashi, K.; Jachmann, M.; Kanai, M.;
Shibasaki, M. Angew. Chem., Int. Ed. 2003, 42, 5489; (b) Yoshikai, N.; Miura,
K.; Nakamura, E. Adv. Synth. Catal. 2009, 351, 1014.
63.0, 60.1, 55.1, 27.6, 23.5. IR (neat):
m = 3387, 2958, 2874, 1738,
14. Other terminal alkynes such as trimethylsilylacetylene and 1-heptyne were
also used, but with trimethylsilylacetylene no corresponding products were
obtained while with 1-heptyne the corresponding products were obtained in
moderate yields (from 64% to 73%) and lower ee (from 33% to 50%).
15. For selected examples see: (a) Cho, W.-S.; Kim, H.-J.; Littler, B. J.; Miller, M. A.;
Lee, C.-H.; Lindsey, J. S. J. Org. Chem. 1999, 64, 7890; (b) Schneider, J. W.; Gao, Z.;
Li, S.; Farooqi, M.; Tang, T.-S.; Bezprozvanny, D.; Frantz, E.; Hsieh, J. Nat. Chem.
Biol. 2008, 4, 408.
1459, 1240, 1149, 1075, 1044, 1014, 921, 735, 600 cmꢀ1. HRMS
for C10H15NO2 (M+H+): calcd 182.1176, found 182.1172.
Acknowledgments
We are grateful for the Grants from the National Natural Sci-
ence Foundation of China (Nos. 20932003 and 90813012), the Na-
tional S & T Major Project of China (2009ZX09503-017).
16. (a) Côté, A.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 2771; (b) Côté,
A.; Boezio, A. A.; Charette, A. B. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5405.