Enantioselective zinc/BINOL-catalysed alkynylation of aldimines generated in situ from α-amido sulfones

Article abstract of DOI:10.1002/chem.201102909

Chiral nonracemic N-Cbz-protected propargylic amines have been prepared by the addition of terminal alkynes to imines generated in situ from α-amido sulfones in the presence of diethylzinc and BINOL-type ligands as catalysts. The reactions give good yields and high enantioselectivities (ee values up to 95 %) for a good number of aromatic and heteroaromatic α-amido sulfones and alkynes. Copyright

Full text of DOI:10.1002/chem.201102909

DOI: 10.1002/chem.201102909
Enantioselective Zinc/BINOL-Catalysed Alkynylation of Aldimines
Generated in Situ from a-Amido Sulfones
Gonzalo Blay, Ana Brines, Alicia Monleꢀn, and Josꢁ R. Pedro*[a]
Abstract: Chiral nonracemic N-Cbz-protected propargylic amines have been pre-
pared by the addition of terminal alkynes to imines generated in situ from a-
amido sulfones in the presence of diethylzinc and BINOL-type ligands as catalysts.
The reactions give good yields and high enantioselectivities (ee values up to 95%)
for a good number of aromatic and heteroaromatic a-amido sulfones and alkynes.
Keywords: alkynylation · asymmet-
ric catalysis · enantioselectivity · nu-
cleophilic addition
amines
· propargylic
Introduction
Optically active propargylic amines are useful building
blocks for organic synthesis and important skeletons in bio-
logically active compounds and natural products.[1] Conse-
quently, considerable efforts have been made to develop
methodologies for generating compounds of this kind in op-
tically active form.[2] In this context, most of the studies re-
ported so far have involved catalytic enantioselective al-
ACHTUNGTRENNUNG
kynylation of N-arylimines in the presence of CuI salts in
combination with nitrogen-containing ligands.[3] Other meth-
ods involve the enhancement of the electrophilic aptitude of
the carbon-nitrogen double bond through the binding of
electron-withdrawing groups to the nitrogen atom, leading
to N-protected propargylic amines.[4]
A possible alternative to these methods is the generation
of the imine in situ through the use of a precursor with a
good leaving group at the carbon a to the nitrogen atom.
a-Amido sulfones 1 (Scheme 1) are suitable precursors of
imines because they react with basic reagents by de
ACHUTGTNRNEUGpN roCAHTUNGTRNEtNUGN on-
ACHTUNGTRENNUNGation of the carbamate and elimination of the sulfinate
Scheme 1. Alkynylation of a-amido sulfones, together with the BINOL-
group to give N-carbamoyl imines.[5] Advantageously, a-
amido sulfones are stable solids that can be readily obtained
in one-step fashion by condensation of carbamates and
sodium aryl sulfinates with the desired aldehydes.[6] In fact,
several authors have described the non-asymmetric alkyny-
lation of a-amido sulfones[7] and Moloney has reported ex-
amples of diastereoselective alkynylations of an a-amido
sulfone derived from ethyl pyroglutamate with Grignard re-
agents and zinc bromide.[8] In addition, a-amido sulfones
have been used as reactive precursors of imines for the
type ligands used in this study.
asymmetric addition of organometallic reagents, in Mannich,
aza-Henry, Strecker and other asymmetric nucleophilic addi-
tion reactions.[5] In particular, enantioselective addition of
dialkylzinc and diarylzinc reagents to imines generated in
situ from a-amido sulfones has been described by Brꢀse,[9]
Charette,[10] Gong,[11] and Minnaard and Feringa,[12] with dif-
ferent metal complexes. To the best of our knowledge, how-
ever, there has been only one example of enantioselective
alkynylation of a-amido sulfones, recently reported by
Wang, which uses a prolinol-derived tridentate ligand.[13]
Herein, we describe the enantioselective alkynylation of
a-amido sulfones 1 with terminal alkynes 2 catalysed by a
chiral BINOL-type zinc complex as a new and convenient
method to synthesise N-carbamoyl-protected propargylic
amines 3 (Scheme 1).
[a] Dr. G. Blay, A. Brines, A. Monleꢁn, Prof. Dr. J. R. Pedro
Departament de Quꢂmica Orgꢃnica, Facultat de Quꢂmica
Universitat de Valꢄncia, C/Dr. Moliner 50, 46100 Burjassot (Spain)
Fax : (+34)963544328
E-mail: jose.r.pedro@uv.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102909.
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FULL PAPER
Results and Discussion
(Table 1, footnote [a], Procedure B, entries 17–19).[14] In this
way, the alkynylation product 3aa was obtained with the
same enantioselectivity (85% ee) but with a better yield
(69% yield, Entry 17). The use of more concentrated reac-
tion mixtures[4c,15] resulted in lower yields and enantioselec-
tivities (Entry 18), whereas the use of only 3 equiv of Et2Zn
in hexane (1m) gave the best results (87% ee, 70% yield,
Entry 19). Other a-amido sulfones bearing different N-pro-
tecting groups (Boc, COOEt) were also tested, but led to
worse results.
Our initial studies were performed with use of the N-benzyl-
ACHTUNGTRENNUNGoxyACHTUNGTRENNUNG
carbonyl-para-toluenesulfone 1a (R1 =Ph), derived from
benzaldehyde, and phenylacetylene (2a, R2 =Ph). Firstly,
the reaction was conducted under reaction conditions simi-
lar to those reported by our group for the enantioselective
alkynylation of N-tosylaldimines (Table 1, footnote [a], Pro-
Table 1. Enantioselective addition of phenylacetylene (2a, R2 =Ph) to
a-amido sulfone 1a (R1 =Ph): screening of ligands and conditions.[a]
The optimised conditions (Table 1, Entry 19) were used
for the addition of phenylacetylene (2a) to several N-ben-
Entry
L
Solvent
T
[8C]
t
Yield
[%][b]
ee
[h]
[%][c]
AHCTUNGTREUNGzNN ylACHTNUTRGEGoNNUN xyCAHTNUGTRENcGUNN arbonyl-para-toluenesulfones 1 derived from substi-
tuted benzaldehydes with good results (Table 2, entries 1–9).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16[d]
17
18[e]
19[f]
L1
L2
L3
L4
L5
L6
L7
L8
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
hexane
CH2Cl2
ClCH2CH2Cl
CHCl3
RT
RT
RT
RT
RT
RT
RT
RT
0
3
4
2
2
2
2
21
3
2
24
5
5
5
7
17
4
4
4
4
35
64
64
26
32
35
24
18
50
7
20
52
45
24
16
54
69
63
70
11
13
33
18
43
81
51
5
Table 2. Enantioselective addition of phenylacetylene (2a, R2 =Ph) to
a-amido sulfones 1.[a]
83
–
À25
0
81
84
83
80
5
85
85
80
87
0
0
0
0
0
0
0
0
THF
R1
t
3
Yield
[%][b]
ee
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Entry
1
[h]
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
Ph
3
3
5
3
3
3
2
2
3
2
3
2
3
2
3
2
3
3aa
3ba
3ca
3da
3ea
3 fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
70
61
60
73
61
42
61
62
63
58
63
66
41
33
33
52
72
87
88
83[d]
90
91
83
86
90
90
78
88
74
76
2
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
3-MeC6H4
2-MeC6H4
2-ClC6H4
2-thienyl
2-furanyl
3-thienyl
3-furanyl
1-naphthyl
2-naphthyl
C6H4CH2CH2
cyclohexyl
[a] Procedure A (entries 1–16): a solution of L (0.0025 mmol, 0.2 equiv)
in the indicated solvent (0.4 mL) was added to a pre-formed mixture of
2a (0.9 mmol, 7.2 equiv) and Me2Zn in toluene (2m, 0.375 mL,
0.75 mmol, 6 equiv), followed by addition of 1a (0.125 mmol). Pro
ACHTUNGERTNcNUNG e-
ACHTUNGTRENNUNG
0.75 mmol, 6 equiv) was added to a pre-formed mixture of 2a (0.9 mmol,
7.2 equiv) and L (0.025 mmol, 0.2 equiv) in CH2Cl2 (0.4 mL), followed by
addition of a solution of 1a (0.125 mmol) in CH2Cl2 (1 mL). [b] Yields of
3aa after column chromatography. [c] Determined by HPLC. [d] Proce-
dure A was followed, but Et2Zn in hexane (1m, 0.75 mmol, 0.75 mmol,
6 equiv) was used instead of Me2Zn in toluene (2m). [e] Solvent volumes
reduced to 50%. [f] Reaction was carried out with Et2Zn in hexane (1m,
0.375 mL, 0.375 mmol, 3 equiv).
88
60
54
cedure A, entries 1–16).[4c] In this way, after 3 h, product 3aa
was obtained, although with low yield (35%), and low enan-
tiomeric excess (11%) (Table 1, Entry 1). Other BINOL-
type ligands (L2–L8) were also tested with variable results
(Table 1, entries 2–8).
[a] A solution of Et2Zn in hexane (1m, 0.375 mL, 0.375 mmol, 3 equiv)
was added to a pre-formed mixture of 2a (0.9 mmol, 7.2 equiv) and L6
(0.025 mmol, 0.2 equiv) in CH2Cl2 (0.4 mL), followed by addition of a so-
lution of 1 (0.125 mmol) in CH2Cl2 (1 mL). [b] Yields of 3 after column
chromatography. [c] Determined by HPLC. [d] Determined after deriva-
tisation (see Scheme 2).
In view of reports published by Wang[4e] during the course
of our research, we decided to test the use of diethylzinc as
a substitutive for dimethylzinc. Although the results of the
reaction (Entry 16) were practically identical (85% ee and
54% yield) to those obtained with Me2Zn (Entry 12,
84% ee, 52% yield) we were able to isolate a secondary
product (5% yield) resulting from the addition of Et2Zn to
the a-amido sulfone 1a from the reaction mixture. This
seemed to indicate incomplete formation of the alkynylating
reagent. Consequently, we decided to modify the procedure
for the formation of the alkynylzinc reagent by adding the
Et2Zn to a pre-formed solution of the alkyne and the ligand
Both electron-donating (Me, OMe) and electron-with-
drawing (F, Cl, Br) substituents in ortho, meta and para posi-
tions were tolerated well, providing the expected products
with good yields and enantioselectivities ranging from 83 to
91% ee. A number of a-amido sulfones (1j–m) derived
from heteroaromatic aldehydes were also suitable substrates,
giving the corresponding propargylic Cbz-amides with good
yields and with ee values from 74% to 88% (Table 2, en-
tries 10–13). The bulky a-amido sulfones 1n and 1o, derived
from 1- and 2-naphthylcarbaldehyde, respectively, gave
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J. R. Pedro et al.
Table 3. Enantioselective addition of terminal alkynes 2 to a-amido sulfones 1.[a]
lower yields (33%) and very different enantioselec-
tivities. Whereas a-amido sulfone 1n, derived from
1-naphthylcarbaldehyde, gave the corresponding
propargylic Cbz-amide practically as a racemate
(2% ee), its isomer 1o, derived from 2-naphthyl-
ACHTUNGTRENNUNGcarbACHTUNGTRENNUNGaldehyde, gave the reaction product with an in-
teresting 88% ee (Table 2, entries 14 and 15). This
different behaviour of two such naphthyl deriva-
tives has been observed in other reactions.[4d] Al-
though the cause is not completely clear, we believe
that a peri interaction between the reacting species
and the proton at C(8) of the naphthalene ring
might account for the low ee observed with 1n. Fi-
nally, the aliphatic a-amido sulfones 1p and 1q re-
acted with phenylacetylene to give the correspond-
ing products 3pa and 3qa with moderate yields and
enantioselectivities (Table 2, entries 16 and 17).
We next studied additions of other alkynes
(Table 3). para-Methoxyphenylacetylene (2b) react-
ed with a number of representative a-amido sul-
fones giving good yields of products 3 with high
enantiomeric excesses, ranging from 86 to 92%
(Table 3, entries 1–5). Similarly, addition of 2- and
3-ethynylthiophenes (entries 6–15) to various a-
amido sulfones gave the corresponding products in
moderate to high yields and with high enantioselec-
tivities (88–95% ee).
Entry
1
R1
2
R2
t
3
Yield
[%][b]
ee
[h]
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1b
1d
1h
1j
1a
1b
1d
1h
1j
1a
1b
1d
1h
1j
Ph
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
2d
2d
2d
2d
2d
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2-thienyl
2-thienyl
2-thienyl
2-thienyl
2-thienyl
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
3ab
3bb
3db
3hb
3jb
3ac
3bc
3dc
3hc
3jc
3ad
3bd
3dd
3hd
3jd
84
72
72
89
74
81
83
72
74
94
66
57
80
56
56
88
89
92
91
86
90
90
92
95
88
90
89
92
94
89
4-MeC6H4
4-ClC6H4
2-MeC6H4
2-thienyl
Ph
4-MeC6H4
4-ClC6H4
2-MeC6H4
2-thienyl
Ph
3-thienyl
3-thienyl
3-thienyl
3-thienyl
4-MeC6H4
4-ClC6H4
2-MeC6H4
2-thienyl
3-thienyl
[a] A solution of Et2Zn in hexane (1m, 0.375 mL, 0.375 mmol, 3 equiv) was added to a
pre-formed mixture of 2 (0.9 mmol, 7.2 equiv) and L6 (0.025 mmol, 0.2 equiv) in
CH2Cl2 (0.4 mL), followed by addition of a solution of 1 (0.125 mmol) in CH2Cl2
(1 mL). [b] Yields of 3 after column chromatography. [c] Determined by HPLC.
The absolute configuration of the stereogenic
centre in compound 3ca was determined to be S by
chemical correlation with the known (S)-(+)-N-
benzyloxycarbamoyl-para-methoxyphenylglycine
methyl
ester (4, Scheme 2).[16] For the rest of the propargylic Cbz-
amides 3 it was assigned by analogy.
Scheme 2. Determination of the absolute stereochemistry of compound
A plausible simplified catalytic cycle for the reaction is
outlined in Figure 1. Deprotonation of the BINOL ligand
and the acetylene by diethylzinc would give a BINOL zin-
cate–ethylalkynylzinc complex catalyst I. On the other hand,
reaction between the a-amido sulfone and another diethyl-
zinc would provide a N-Cbz-protected imine, which would
coordinate to the catalyst to give intermediate II. Transfer
of the alkynylide from the ethylalkynylzinc molecule to the
imine would release the reaction product and a BINOL-
3ca. i) O3, MeOH, À408C, 1 h, followed by BF3·Et2O, reflux, 3.5 h, 47%.
zincACHTUNGTRENNUNGate III, which after coordination with another ethylalky-
nylzinc molecule would regenerate the complex catalyst, re-
initiating the cycle.
Alkynylide transfer from the alkynylethylzinc molecule
coordinated to one of the BINOL oxygen in state II would
be assisted by coordination of the carbamate carbonyl
oxygen atom through a six-membered ring leading to the
propargyl amide with the S configuration (Figure 2).
The propargylic amines 3 prepared by this methodology
can be used to synthesise other Cbz-protected amines by se-
ꢀ
lective chemical reduction of the C C triple bond
(Scheme 3). Treatment of 3aa with lithium aluminium hy-
dride yielded the E allylic amine 5 (64% yield), whereas
catalytic hydrogenation with the Lindlar catalyst gave the Z
isomer 6 (99% yield). On the other hand, on complete hy-
Figure 1. Simplified catalytic cycle for the alkynylation of a-amido sul-
fones in the presence of Zn–BINOL complexes.
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Chem. Eur. J. 2012, 18, 2440 – 2444

Enantioselective Alkynylation of a-Amido Sulfones
FULL PAPER
formed into the corresponding N-Cbz-protected E and Z al-
lylic amines and aliphatic amines by reductive treatments.
Experimental Section
General: Reactions were carried out under nitrogen in round-bottomed
flasks oven-dried overnight at 1208C. Commercial reagents were used as
purchased. a-Amido sulfones 1 were each prepared from the correspond-
ing aldehyde, carbamate and sodium para-toluenesulfinate as described
in the literature.[6] Solvents were dried when necessary; toluene was dis-
tilled from CaH2. Dichloromethane was distilled from CaH2 and stored
over molecular sieves (4 ꢆ). Reactions were monitored by TLC analysis
(silica gel 60 F-254 thin layer plates). Flash column chromatography was
performed on silica gel 60 (0.040–0.063 mm). Melting points were deter-
mined in capillary tubes. 1H NMR spectra were run at 300 MHz for 1H
and at 75 MHz for 13C NMR. 1H NMR spectra and 13C NMR spectra
were internally referenced to CHCl3 (d=7.26 and 77.0 ppm, respective-
ly). Chemical shifts are reported in ppm. The carbon type was deter-
mined by DEPT experiments. Electrospray ionisation mass spectra (ESI)
were recorded with a Q-TOF premier mass spectrometer and an electro-
spray source. The drying gas and also the nebulising gas was nitrogen.
Specific optical rotations were measured with use of sodium light (D line
589 nm). Chiral HPLC analyses were performed with a chromatograph
and UV diode-array detector on chiral stationary phase columns.
Figure 2. Stereochemical model for the alkynylation of N-Cbz aldimines
generated in situ from a-amido sulfones in the presence of Zn–BINOL
complexes (one of the aromatic substituents at C(3) of the ligand has
been omitted for clarity).
General procedure for the enantioselective alkynylation of compounds 1
(Tables 2 and 3):
A solution of Et2Zn in hexane (1m, 0.375 mL,
0.375 mmol) was added dropwise at RT under nitrogen to a solution of
ligand L6 (17.7 mg, 0.025 mmol) and an alkyne 2 (0.9 mmol) in CH2Cl2
(0.4 mL). After stirring for 1.5 h, the reaction mixture was cooled to 08C.
After 15 min, a solution of an a-amido sulfone 1 (0.125 mmol) in CH2Cl2
(1.0 mL) was added by syringe. The solution was stirred until the reaction
was complete (TLC). The reaction mixture was quenched with water
(1.0 mL), extracted with CH2Cl2 (3ꢇ15 mL), dried over MgSO4 and con-
centrated under reduced pressure. Purification by flash chromatography
on silica gel afforded the compound 3 (for characterisation of com-
pounds 3 see the Supporting Information).
Scheme 3. Selective reduction of the triple bond. i) LiAlH4, THF, 08C to
RT, 3 h, 64%; ii) H2, Lindlar catalyst, C6H6, RT, 1.5 h, 99%; iii) H2, Pd/
CaCO3, EtOH, RT, 1 h, 99%. Reactions took place without appreciable
loss of ee.
drogenation of the triple bond in the presence of Pd/CaCO3
(5%) the Cbz-protected saturated amine 7 was obtained
almost quantitatively. In all of these synthetic transforma-
tions the reaction products were obtained without any ap-
preciable loss of stereochemical integrity. Interestingly, these
alkynylation/reduction procedures are an alternative to the
alkenylation and alkylation of N-Cbz imines with organome-
tallic reagents. Although several syntheses of chiral allylic
amines by alkenylation of imines have been described,[17]
our method constitutes an interesting alternative because of
the high enantioselectivity of the alkynylation reaction and
the complete diastereoselectivity in the partial reduction of
the triple bond.
(+)-Methyl
2-benzyloxycarbonylamino-2-(4-methoxyphenyl)ethanoate
(4): Ozone-enriched oxygen was bubbled through a solution of product
3ca (18.6 mg, 0.050 mmol) in MeOH (15 mL) at À408C for 1 h. The
excess ozone was removed by bubbling nitrogen for 5 min. The resulting
solution was allowed to reach RT, BF3·Et2O (0.19 mL) was added, and
the mixture was heated at reflux temperature for 3.5 h. After the system
had cooled to RT, saturated aqueous NaHCO3 (10 mL) was added, the
organic solvent was removed under reduced pressure, and the resulting
aqueous solution was extracted with dichloromethane (3ꢇ15 mL),
washed with brine (10 mL) and dried over MgSO4. Removal of the sol-
vent under reduced pressure followed by flash chromatography gave 4
(47%): m.p. 66–688C; [a]2D0 = +45.1 (c=0.7, CHCl3, 83% ee) {lit.[16]
[a]2D5 = +106.9 (c=0.58)}; 1H NMR (300 MHz, CDCl3): d=7.35–7.28 (m,
7H), 6.86 (d, JH,H =8.7 Hz, 2H), 5.75 (d, JH,H =7.1 Hz, 1H), 5.29 (d,
J
H,H =6.6 Hz, 1H), 5.10 (d, JH,H =12.4 Hz, 1H), 5.04 (d, JH,H =12.4 Hz,
Conclusion
1H), 3.78 (s, 3H), 3.70 ppm (s, 3H); 13C NMR (75.5 MHz, CDCl3): d=
171.5 (C), 159.8 (C), 155.3 (C), 136.1 (C), 128.6 (CH), 128.5 (CH), 128.4
(CH), 128.20 (C), 128.16 (CH), 114.3 (CH), 67.1 (CH2), 57.3 (CH), 55.3
(CH3), 52.8 ppm (CH3); HRMS (ESI): m/z calcd for C18H19NO5Na
[M+Na]+: 352.1161; found: 352.1583; the ee value (83%) was deter-
We report a new procedure for the catalytic enantioselective
alkynylation of N-benzyloxycarbonyl-para-toluenesulfones
derived from aldehydes to give N-Cbz-protected propargylic
amines based on the use of terminal alkynes, diethylzinc and
BINOL-type ligands. The steric effect of the 3,3’-substitu-
ents in the ligand plays a crucial role for obtaining high
enantioselectivities. The reactions work with a variety of ar-
omatic and heteroaromatic starting materials, and with dif-
ferent alkynes, providing the expected products with good
yields and high enantiomeric excesses (74–95%). The N-
Cbz-protected propargylic amines can be efficiently trans-
mined by chiral HPLC (Chiralpak IC), hexane/iPrOH 97:3, 1 mLminÀ1
major enantiomer tr =76.6 min, minor enantiomer tr =100.5 min.
,
(+)-(E)-N-Benzyloxycarbonyl-1,3-diphenylprop-2-en-1-amine (5): A so-
lution of LiAlH4 in THF (1m, 0.050 mmol, 50 mL) was added dropwise at
08C under nitrogen to a solution of 3aa (0.050 mmol) in THF (0.4 mL).
The reaction mixture was allowed to reach RT. After 3 h, the reaction
was quenched with water (1 mL). The aqueous layer was extracted with
CH2Cl2 (3ꢇ15 mL). The organic layer was washed with brine (10 mL)
and dried over MgSO4. Removal of the solvent under reduced pressure
followed by flash chromatography gave 5 (64%). m.p. 110–1118C; [a]D20
=
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J. R. Pedro et al.
+29.4 (c=0.68, CHCl3, 87% ee); 1H NMR (300 MHz, CDCl3): d=7.33–
7.22 (m, 15H), 6.54 (d, JH,H =16.6 Hz, 1H), 6.31 (dd, JH,H =15.9, 6.0 Hz,
1H), 5.52 (s, 1H), 5.18 (s, 1H), 5.14 (d, JH,H =12.2 Hz, 1H), 5.10 ppm (q,
Org. Chem. 2007, 11, 127–157; f) G. Blay, A. Monleꢁn, J. R. Pedro,
Curr. Org. Chem. 2009, 13, 1498–1539.
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H,H =12.2 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=155.5 (C), 144.8
(C), 136.34 (C), 136.30 (C), 131.2 (C), 129.0 (CH), 128.8 (CH), 128.6
(CH), 128.5 (CH), 128.2 (CH), 127.81 (CH), 127.76 (CH), 127.0 (CH),
126.5 (CH), 67.0 (CH2), 56.8 ppm (CH); HRMS (ESI): m/z calcd for
C23H21NO2Na [M+Na]+: 366.1470; found: 366.1920; the ee value (87%)
was determined by chiral HPLC (Chiralcel OD-H), hexane/iPrOH 90:10,
1 mLminÀ1
19.3 min.
, major enantiomer tr =28.4 min, minor enantiomer tr =
(+)-(Z)-N-Benzyloxycarbonyl-1,3-diphenylprop-2-en-1-amine (6): A so-
lution of 3aa (0.056 mmol) in benzene (0.56 mL) was stirred under hy-
drogen in the presence of Lindlarꢈs catalyst (3.6 mg) for 1.5 h. The reac-
tion mixture was then filtered through a pad of Celiteꢉ with EtOAc. The
solvent was removed under reduced pressure to give 6 (99%). M.p. 67–
698C; [a]2D0 = +13.8 (c=1.04, CHCl3, 87% ee); 1H NMR (300 MHz,
CDCl3): d=7.34–7.23 (m, 13H), 7.16 (d, JH,H =8.8 Hz, 2H), 6.67 (d,
J
H,H =10.3 Hz, 1H), 5.78–5.75 (m, 2H), 5.17 (s, 1H), 5.09 ppm (s, 2H);
13C NMR (75.5 MHz, CDCl3): d=155.4 (C), 141.5 (C), 136.1 (C), 131.4
(C), 128.8 (CH), 128.6 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.1
(CH), 127.9 (CH), 127.6 (CH), 127.5 (CH), 126.6 (CH), 120.3 (CH), 66.8
(CH2), 42.5 ppm (CH); HRMS (ESI): m/z calcd for C23H21NO2Na
[M+Na]+: 366.1470; found: 366.1920; the ee value (87%) was deter-
mined by chiral HPLC (Chiralcel OD-H), hexane/iPrOH 95:5,
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1 mLminÀ1
26.0 min.
, major enantiomer tr =22.9 min, minor enantiomer tr =
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(+)-N-Benzyloxycarbonyl-1,3-diphenylpropan-1-amine (7): A solution of
3aa (27.5 mg, 0.081 mmol) in absolute EtOH (7.5 mL) was stirred under
hydrogen in the presence of Pd/CaCO3 (5%, 10.5 mg) for 1 h. The reac-
tion mixture was then filtered through silica gel with elution with EtOAc.
The solvent was removed under reduced pressure to give compound 7
(99%). M.p. 65–678C; [a]D20 = +18.1 (c=1.29, CHCl3, 87% ee); 1H NMR
(300 MHz, CDCl3): d=7.33–7.24 (m, 12H), 7.19 (d, JH,H =7.2 Hz, 1H),
7.13 (d, JH,H =7.7 Hz, 2H), 5.110 (s, 1H), 5.113 (d, JH,H =12.3 Hz, 1H),
5.04 (d, JH,H =12.2 Hz, 1H), 4.73 (q, JH,H =7.2 Hz, 1H), 2.70–2.52 (m,
2H), 2.17–2.02 ppm (m, 2H); 13C NMR (75.5 MHz, CDCl3): d=155.6
(C), 142.2 (C), 141.2 (C), 136.4 (C), 128.7 (CH), 128.5 (CH), 128.4 (CH),
128.3 (CH), 128.1 (CH), 127.5 (CH), 126.4 (CH), 126.0 (CH), 66.8 (CH2),
55.2 (CH2), 38.3 (CH), 32.5 (CH2) ppm; HRMS (ESI): m/z calcd for
C23H23NO2Na [M+Na]+: 368.1626; found: 368.2292; the ee value (87%)
was determined by chiral HPLC (Chiralcel OD-H), hexane/iPrOH 90:10,
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1 mLminÀ1
27.0 min.
,
major enantiomer tr =22.9 min, minor enantiomer tr =
[14] We believe that the formation of the catalytic species requires the si-
multaneous deprotonation of the BINOL ligand and the alkyne by
the strongly basic diethylzinc. We have observed similar results
during our research on the enantioselective alkynylation of alde-
hydes catalysed by Zn-mandelamide complexes. See: a) G. Blay, I.
Fernꢌndez, A. Marco-Aleixandre, J. R. Pedro, J. Org. Chem. 2006,
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Acknowledgements
Financial support from the Ministerio de Ciencia e Innovaciꢁn and
FEDER (CTQ2009–13083) and from the Generalitat Valenciana
(ACOMP/2011/267) is gratefully acknowledged. A.M. thanks the Gener-
alitat Valenciana for a predoctoral grant.
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Received: September 16, 2011
Published online: January 19, 2012
2444
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