Asymmetric addition of terminal alkynes to n-(Diphenylphosphinoyl)imines promoted by stoichiometric amounts of a proline-derlved ss-amino alcohol

Article abstract of DOI:10.1002/ejoc.200900342

A new synthetic methodology for the preparation of optically active propargylamines is described. The alkynylation of aromatic, heteroaromatic, aliphatic and α,β-unsaturated N-(di-phenylphosphinoyl)imines was investigated by using dieth-ylzinc and a proline-derived β-amino alcohol, N-(Diphenylphosphinoyl)-protected propargylic amines can be synthesized in high yields and with good to excellent: enantio-selectivities.

Full text of DOI:10.1002/ejoc.200900342

FULL PAPER
DOI: 10.1002/ejoc.200900342
Asymmetric Addition of Terminal Alkynes to N-(Diphenylphosphinoyl)imines
Promoted by Stoichiometric Amounts of a Proline-Derived β-Amino Alcohol
Wenjin Yan,[a,b] Bin Mao,[a] Shaoqun Zhu,[a] Xianxing Jiang,[a,b] Zhongli Liu,[a] and
Rui Wang*[a,b]
Keywords: Enantioslectivity / Asymmetric synthesis / Alkynylation / β-Amino alcohol / Propargylamines
A new synthetic methodology for the preparation of optically
active propargylamines is described. The alkynylation of aro-
matic, heteroaromatic, aliphatic and α,β-unsaturated N-(di-
phenylphosphinoyl)imines was investigated by using dieth-
ylzinc and a proline-derived β-amino alcohol. N-(Diphenyl-
phosphinoyl)-protected propargylic amines can be synthe-
sized in high yields and with good to excellent enantio-
selectivities.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
thesis and in the pharmaceutical industry remains a chal-
lenging task due to the harsh conditions of protecting
group removal.
Introduction
Optically active propargylamines are valuable chiral in-
termediates for the synthesis of various drugs and biolo-
gically active compounds.[1] Therefore, it is not surprising
that many excellent catalytic systems have been developed
for the construction of α-chiral propargylamines.[2] Most of
the examples focused on the use of CuI salts in combination
with nitrogen-containing ligands to catalyze the enantiose-
lective alkynylation of N-arylimines.[3] Chan et al. devel-
oped the addition processes by using N-tosylated amino-
By contrast, N-phosphinoylimines have drawn consider-
able attention because the resulting phosphonamide prod-
ucts can be easily deprotected under mild conditions (e.g.
HCl/MeOH).[14] For this reason, they were widely used in
catalytic asymmetric nitro-Mannich,[15] Mannich[16] and
Strecker[17] processes besides the addition of organometal-
lics.[18] Nevertheless, the enantioselective alkynylation of N-
phosphinoylimines has not yet been reported. Herein, we
report the first asymmetric addition of terminal alkynes to
N-(diphenylphosphinoyl)imines promoted by a proline-de-
rived β-amino alcohol.
[4]
imine ligands/CuI/Zn(Me)2 and N-tosylated amino-imine
ligands/CuII/Zn(Me)2 systems.[5] Some other methods in-
clude Hoveyda’s peptide-Zr-(OiPr)4·HOiPr system,[6]
Bolm’s amino alcohol catalysis system[7] and Rueping’s dual
catalysis system.[8] Jiang et al.[9] used stoichiometric
amounts of a chiral amino alcohol ligand to mediate the
addition of alkynes to trifluoromethyl-activated cyclic im-
ine. Chonget al.[10] and Soderquist et al.[11] carried out the
alkynylation of N-acylimines by using chiral alkynylbo-
ronates or alkynylboranes as nucleophilic reagents, respec-
tively. Recently, Pedro et al.[12] accomplished the alk-
ynylation of N-sulfonylaldimines by using a zinc/Binol ca-
talysis system. Hou et al.[13] provided N-(tert-butylsulfinyl)-
propargylamines by the addition of alkynes to optically
pure tert-butylsulfinimines. Unfortunately, the further ap-
plication of these α-chiral propargylamines in organic syn-
Results and Discussion
In the past few years, a great effort in our group has been
devoted to the investigation of the enantioselective catalytic
alkynylation of aldehydes and ketones[19] by using the li-
gands derived from natural amino acids. Gratifyingly, β-
amino alcohols have proved to be efficient in the alkylation
of ketones.
Thus, we initially decided to employ L1 (Figure 1) as a
promoter in the addition of phenylacetylene to N-(diphenyl-
phosphinoyl)benzaldimine. In view of the solubility of the
substrate imine, we chose CH2Cl2 as the solvent. The sub-
strate was consumed after 24 h, but we found no enantio-
selectivity (Table 1). We supposed that the steric bulk at the
α-position of the chiral amino alcohol was crucial for the
coordination of the ligand-zinc complex with the imine.
Hence, we prepared ligand L2 (Figure 1) to optimize the
reaction. Unfortunately, we obtained only racemic product.
We examined ligands L3–L5 next. We note that our hypoth-
esis, as described above, was further supported by the inves-
[a] State Key Laboratory of Applied Organic Chemistry, Lanzhou
University,
Lanzhou 730000, P. R. China
Fax: +86-931-8912567
E-mail: wangrui@lzu.edu.cn
[b] State Key Laboratory for Oxo Synthesis and Selective Oxi-
dation, Lanzhou Institute of Chemical Physics, Chinese Acad-
emy of Sciences,
Lanzhou 730000, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900342.
3790
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3790–3794

Enantioselective Alkynylation of N-(Diphenylphosphinoyl)imines
tigation of L3–L5. These results revealed that the enantio- Further increases to the steric hindrance of the substituents
selectivity increased in the order of L5 Ͻ L4 Ͻ L3, which on nitrogen led to a decrease in enantioselectivities (Table 1,
corresponds to the α-position of the chiral amino alcohols Entries 8 and 9), perhaps due to the rigidity of the pyrrol-
bearing a dihydrogen, diehthyl and two phenyl substituents, idine ring in these ligands.
respectively. Encouraged by these results, we designed li-
Further reaction optimization focused on the solvent,
gands L6–L10 (Figure 1) to test the effect of nitrogen sub- catalyst loading and temperature. After screening the sol-
stituent. We found that the size of the substituents bonded vent, we found that satisfactory yield and enantioselectivity
to the nitrogen had a significant effect on achieving high were achieved when we employed CH2Cl2 (Table 1, Entries
enantioselectivity and yield in the reaction.
1–3). When we employed 0.4 equiv. of L7, the standard ad-
dition of phenylacetylene to the N-(diphenylphosphinoyl)-
imine derived from benzaldehyde required 24 h at room
temperature, and the ee of the resulting phosphinamide
(isolated in 69% yield) increased to 68%. Therefore, we
used stoichiometric amounts of ligand to further enhance
the ee of the product, which we obtained in 85% ee and
73% yield (Table 2, Entry 5). In the above experiments, we
added 3 equiv. of diethylzinc and alkyne. To our delight, the
enantioselectivity slightly improved to 87% (79% yield) in
the presence of 4 equiv. of diethylzinc and alkyne (Table 2,
Entry 6). Further increasing the amount of diethylzinc and
alkyne did not improve enantioselectivity, although the
yield improved slightly (Table 2, Entry 7). We next probed
the effect of temperature on the reaction. As expected, we
obtained the addition product in 79% yield and 91% ee
after 36 h at 10 °C and in 78% yield and 95% ee after 48 h
Figure 1. The various catalysts in the alkynylation of N-phosphino- at 0 °C (Table 2, Entries 8 and 9, respectively). When we
ylimines.
lowered the temperature to –10 °C, the substrate could not
be converted completely even after 72 h (Table 2, Entry 10).
Table 2. Alkynylation of N-phosphinoylimines using L7.[a]
Table 1. Alkynylation of N-phosphinoylimines using L1–L10 as
catalysts.[a]
Entry Solvent Cat. [mol-%] T [°C]
t [h]
Yield [%][e] ee [%][f]
1[b]
2[b]
3[b]
4[b]
5[b]
6[c]
7[d]
8[c]
9[c]
10[c]
Et2O
Tol
20
20
20
Rt
Rt
Rt
Rt
Rt
Rt
Rt
10
0
24
24
12
24
24
24
24
36
48
72
63
59
83
69
73
79
81
79
78
23
42
46
0
68
85
87
84
91
95
97
Entry Ligand Cat. [mol-%]
t [h]
Yield [%][b]
ee [%][c]
THF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
1
2
3
4
5
6
7
8
9
10
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
20
20
20
20
20
20
20
20
20
20
24
24
24
24
24
24
24
24
24
24
37
42
55
52
45
57
63
54
50
53
0
0
47
4
40
100
100
100
100
100
100
0
53
57
20
40
11
–10
[a] Reaction conditions: reactions were carried out on a 0.2 mmol
scale; all reactions were processed under argon. [b] Aldimine/
Et2Zn/phenylacetylene = 1:3:3. [c] Aldimine/Et2Zn/phenylacetylene
= 1:4:4. [d] Aldimine/Et2Zn/phenylacetylene = 1:5:5. [e] Isolated
yields. [f] The ee was determined by HPLC analysis on a Chiralcel
AD column.
[a] Reaction conditions: reactions were carried out in CH2Cl2 at
room temperature on a 0.2 mmol scale with aldimine/Et2Zn/phen-
ylacetylene = 1:3:3; all reactions were processed under argon. [b]
Isolated yields. [c] The ee was determined by HPLC analysis on a
Chiralcel AD column.
Under the above-optimized conditions, we examined
various substituted imines (Table 3). All imines derived
Ligand L10, with the smallest substituent, gave the low- from aromatic aldehydes could be readily converted into the
est enantioselectivity and a moderate yield, while [1-(naph- corresponding products in moderate to high yields. The
thalene-2-ylmethyl)pyrrolidin-2-yl]methanol (L7) gave the presence of an electron-donating group on the para position
best result of 57% enantiomeric excess (ee) and 63% yield. of the aromatic ring gave excellent enantioselectivity (up to
Eur. J. Org. Chem. 2009, 3790–3794
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3791

W. Yan, B. Mao, S. Zhu, X. Jiang, Z. Liu, R. Wang
FULL PAPER
96% ee), but in moderate yields (Table 3, Entries 2 and 3). Table 4. Addition of various alkynes to N-(diphenylphosphinoyl)-
benzaldimine.[a]
The reaction proceeded not only with an electron-drawing
group on the para position but also on the meta position to
give high enantioselectivities and yields (Table 3, Entries 4–
6 and 10). When we used N-(diphenylphosphinoyl)-2-meth-
ylbenzaldimine, we obtained low enantioselectivity (Table 3,
Entry 11). We observed a large difference in enantio-
selectivity between the 1-naphthyl and 2-naphthyl cases
(16% ee for 1-naphthyl and 90% ee for 2-naphthyl). As ex-
pected, both α,β-unsaturated imine (Table 3, Entry 8) and
heteroarylimines (Table 3, Entries 12–15) also exhibited
high reactivities, providing good to excellent enantio-
selectivities (78–96% ee) and moderate to good yields. We
employed the aliphatic imines as substrates for the process
next. We also obtained the desirable products in satisfactory
yields (72% and 60%, Table 3, Entries 16 and 17) despite
the low enantioselectivity for the product from tBu-imine
(Table 3, Entry 17).
Entry R2
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
2-thienyl
12
36
48
72
72
74
85
75
70
53
94
91
85
90
84
3-thienyl
2-propenyl
TBSOCH2
TMS
[a] Reaction conditions: reactions were carried out in CH2Cl2 at
0 °C on a 0.2 mmol scale with aldimine/ligand/Et2Zn/alkyne =
1:1:4:4; all reactions were processed under argon. [b] Isolated yields.
[c] The ee was determined by HPLC analysis on a Chiralcel AD
column.
Importantly, this reaction could be carried out on gram
scale (2 mmol) to demonstrate the synthetic utility of the
present system. We found no obvious reduction of enantio-
selectivity and yield on a 0.2 mmol scale. The catalyst was
conveniently recovered over 90% through flash column
chromatography. The enantioselectivity of the product
could be upgraded to 99% by a simple recrystallization in
57% yield from hexane/ethyl acetate. Importantly, our re-
sults indicated that the free amine may easily be accessed.
N-(Diphenylphosphinoyl)propargylamine underwent a de-
protection with HCl/MeOH to the free amine in 94% yield.
We determined the absolute configuration of N-(1,3-di-
phenylprop-2-ynyl)-P,P-diphenylphosphinic amide to be
(S)-configured by chemical correlation with (S)-N-(1,3-
Table 3. Addition of phenylacetylene to various N-phosphinoyl-
imines.[a]
Entry
R1
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
48
36
48
48
48
48
48
48
48
48
48
48
36
48
36
24
24
78
70
74
83
87
86
72
75
84
77
72
72
62
70
79
72
60
95 (s)
95
96
93
92
87
90
78
16
84
33
78
96
95
90
88
21
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2-naphthyl
cinnamyl
1-naphthyl
3-ClC6H4
2-MeC6H4
2-furyl
diphenylprop-2-ynyl)-4-methylbenzenesulfonamide
(Fig-
ure 2).[12]
9
10
11
12
13
14
15
16
17
3-furyl
2-thienyl
3-thienyl
iPr
tBu
Figure 2. Determination of the absolute stereochemistry of N-(1,3-
diphenylprop-2-ynyl)-P,P-diphenylphosphinic amide. The literature
value is from ref.[12]
[a] Reaction conditions: reactions were carried out in CH2Cl2 and
0 °C on a 0.2 mmol scale with aldimine/ligand/Et2Zn/phenylacetyl-
ene = 1:1:4:4; all reactions were processed under argon. [b] Isolated
yields. [c] The ee was determined by HPLC analysis on a Chiralcel
AD column.
Conclusions
Furthermore, the optimized conditions were also appli-
We have developed a procedure for the enantioselective
cable to some quite challenging alkynes, and the results are alkynylation of N-(diphenylphosphinoyl)benzaldimine to
summarized in Table 4. Gratifyingly, the reactions of 2-eth- give N-(diphenylphosphinoyl)-protected propargylic amines
ynylthiophene, 3-ethynylthiophene, 2-methylbut-1-en-3-yne, by using diethylzinc and stoichiometric amounts of a pro-
prop-2-yn-1-ol protected by TBS and (trimethylsilyl)acetyl- line-derived β-amine alcohol. A variety of N-phosphinoyl-
ene with N-(diphenylphosphinoyl)benzaldimine afforded imines derived from aromatic, heteroaromatic, aliphatic and
the corresponding products in high to excellent enantio- α,β-unsaturated aldehydes were tested with different alk-
selectivities (83–94% ee).
ynes, providing the expected products in generally good
3792
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Eur. J. Org. Chem. 2009, 3790–3794

Enantioselective Alkynylation of N-(Diphenylphosphinoyl)imines
(S)-N-(1,3-Diphenylprop-2-ynyl)-4-methylbenzenesulfonamide: Com-
pound 3a (20.7 mg, 99% ee, 0.1 mmol) was dissolved in CH2Cl2
(15 mL) in a 50 mL round-bottomed flask, and Et3N (21 µL,
0.15 mmol) was added. The mixture was then cooled to 0 °C, and
Tos-Cl (19 mg, 0.1 mmol) was added in one portion. The resulting
mixture was stirred overnight and then washed successively with
aqueous HCl (1 , 5 mL) and H2O (5 mL). The organic layer was
separated and dried with Na2SO4. After filtration and evaporation
of the solvents, the crude residue was purified by flash chromatog-
raphy (silica gel, hexane/CH2Cl2), giving the product as a white
solid, m.p. 213–216 °C, 85% yield. [α]2D0 = –94 (c = 1.2, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.82 (dd, J = 5.1, 1.5 Hz, 2 H), 7.56
(dd, J = 5.7, 1.8 Hz, 2 H), 7.36–7.23 (m, 8 H), 7.12 (dd, J = 6.6,
1.8 Hz, 2 H), 5.57 (d, J = 9 Hz, 1 H), 4.89 (d, J = 9.3 Hz, 2 H),
2.32 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.6, 137.3,
131.5, 129.6, 128.7, 128.6, 128.5, 128.1, 127.5, 127.3, 121.9, 86.7,
yields and high to excellent enantioselectivities. The prod-
ucts could be conveniently converted into the correspond-
ing propargylic amines by treatment with HCl/MeOH. Al-
though the reaction required stoichiometric amounts of the
amino alcohols, the ligands could be recovered in 90% yield
by column chromatography, and the reaction conditions
were quite mild.
Experimental Section
N-(1,3-Diphenylprop-2-ynyl)-P,P-diphenylphosphinic Amide: In an
oven-dried Schlenk flask, under an inert atmosphere of argon, were
placed L7 (48.2 mg, 0.2 mmol), followed by anhydrous CH2Cl2
(2 mL). A solution of diethylzinc in CH2Cl2 (0.8 mL, 0.8 mmol,
4.0 equiv.) was then added. The reaction mixture was stirred for
30 min, and phenylacetylene (88 µL, 0.8 mmol, 4 equiv.) was
added. The resulting solution was stirred for an additional 7 h, and
N-benzylidene-P,P-diphenylphosphinic amide was then added. The
reaction mixture was stirred at 0 °C for 48 h. Subsequently, satu-
rated aqueous NH4Cl (2 mL) was added slowly at 0 °C, and the
resulting mixture was extracted with CH2Cl2 (3ϫ10 mL). The
combined organic layers were dried with Na2SO4. After filtration
and evaporation of the solvents, the crude residue was purified by
flash chromatography (silica gel, hexane/ethyl acetate) to give the
product as a white solid; m.p. 178–180 °C, 78% yield, 95% ee, as
determined by HPLC analysis (Daicel Chiralcel AD column, hex-
ane/2-propanol, 85:15, 1.0 mL/min, 254 nm). Retention times:
tmajor = 11.86 and tminor = 10.70 min. [α]2D0 = –92 (c = 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.13–8.06 (m, 2 H), 7.90–7.83
(m, 2 H), 7.71–7.69 (m, 2 H), 7.54–7.46 (m, 4 H), 7.44–7.37 (m, 5
H), 7.35–7.30 (m, 5 H), 5.40 (t, J = 9.6 Hz, 1 H), 3.55 (t, J =
9.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.4 [d, JC,P
= 4.5 Hz], 133.4, 132.8 [d, JC,P = 9.8 Hz], 132.1 [d, JC,P = 6.8 Hz],
132.8 [d, JC,P = 9.8 Hz], 131.7, 131.5, 129.0, 128.7 [d, JC,P = 6 Hz],
128.4 [d, JC,P = 12 Hz], 128.0, 127.4, 122.8, 89.0 [d, JC,P = 6 Hz],
85.4, 49.8, 21.4 ppm. IR (KBr): ν = 3265, 2920, 2221, 1595, 1488,
˜
1326, 1153, 1088, 1047, 814, 752, 673, 556 cm–1. HRMS for
C22H19NO2S [M + Na+]: calculated 384.1029; found 384.1034.
Supporting Information (see also the footnote on the first page of
this article): Preparative details and NMR spectra.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (20525206, 20772052, 90813012, and 20621091) and the
Chang Jiang Program of the Ministry of Education of China for
financial support.
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85.6, 47.2 ppm. IR (neat): ν = 3160, 1489, 1437, 1186, 1125, 1060,
˜
695, 544 cm–1. HRMS for C27H22NOP [M + H+]: calculated
408.1512; found 408.1524.
(1,3-Diphenylprop-2-ynyl)amine: N-(1,3-Diphenylprop-2-ynyl)-P,P-
diphenylphosphinic amide (40.7 mg, 99% ee, 0.1 mmol) was added
to a 50 mL round-bottomed flask. A mixture of MeOH (10 mL)
and concentrated aqueous HCl (1 mL) was added. The resulting
mixture was capped and stirred at room temperature for 2 h. The
reaction mixture was then concentrated by rotary evaporation, the
residue was dissolved in aqueous HCl (1 , 5 mL), and the precipi-
tate was removed by filtration. The filtrate was basified (pH Ͼ 12)
by the addition of NaOH (2 ), and the resulting mixture was ex-
tracted with CH2Cl2 (4ϫ20 mL). The combined organic layers
were dried with Na2SO4. After filtration and evaporation of the
solvents, the crude residue was purified by flash chromatography
(silica gel, hexane/ethyl acetate), giving the product as a colorless
oil, 94.2% yield, 99% ee, as determined by HPLC analysis (Daicel
Chiralcel AD column, hexane/2-propanol, 85:15, 1.0 mL/min,
254 nm). Retention times: tmajor = 8.30 and tminor = 9.08 min.
[α]2D0 = –27 (c = 0.6, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
7.10 (d, J = 7.2 Hz, 2 H), 7.48–7.45 (m, 2 H), 7.39 (t, J = 7.2 Hz,
2 H), 7.33–7.30 (m, 4 H), 5.03 (s, 1 H), 2.31 (t, J = 7.5 Hz, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 142.2, 131.6, 128.7, 128.3,
128.2, 127.9, 127.7, 126.8, 123.0, 91.3, 84.2, 48.1 ppm. IR (neat): ν
˜
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hedron: Asymmetry 2007, 18, 2901–2904.
= 3384, 2924, 2855, 2517, 1737, 1654, 1456, 1441, 1381, 1071, 1025,
727, 696, 527 cm–1. HRMS for C15H13N [M + H+]: calculated
208.1121; found 208.1129.
Eur. J. Org. Chem. 2009, 3790–3794
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: March 30, 2009
Published Online: June 19, 2009
3794
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Eur. J. Org. Chem. 2009, 3790–3794