Catalytic enantioselective addition of terminal alkynes to aromatic aldehydes using zinc-hydroxyamide complexes

Article abstract of DOI:10.1039/b911592g

A mandelamide ligand, derived from (S)-mandelic acid and (S)-phenylethanamine, catalyzes the addition of aryl-, alkyl- and silyl-alkynylzinc reagents to aromatic and heteroaromatic aldehydes with good yields and good to high enantioselectivities.

Full text of DOI:10.1039/b911592g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Catalytic enantioselective addition of terminal alkynes to aromatic aldehydes
using zinc-hydroxyamide complexes†
Gonzalo Blay,a Luz Cardona,a Isabel Ferna´ndez,a Al´ıcia Marco-Aleixandre,a M. Carmen Mun˜ozb and
Jose´ R. Pedro*a
Received 12th June 2009, Accepted 17th July 2009
First published as an Advance Article on the web 17th August 2009
DOI: 10.1039/b911592g
A mandelamide ligand, derived from (S)-mandelic acid and (S)-phenylethanamine, catalyzes the
addition of aryl-, alkyl- and silyl-alkynylzinc reagents to aromatic and heteroaromatic aldehydes with
good yields and good to high enantioselectivities.
amide chiral ligands that are conveniently synthesized in simple,
Introduction
short sequences and from cheap, easily available chiral resources.12
The enantioselective alkynylation of aldehydes is one of the
Recently we disclosed that simple (S)-mandelamides (Fig. 1) in
combination with Ti(OiPr)4 could be used to effectively catalyze
the addition of dialkylzinc reagents to aldehydes with moderate
to good enantioselectivity.13 In absence of Ti(OiPr)4, these ligands
also catalyze the addition of dimethylzinc to a-ketoesters,14 and
we have advanced the alkynylation of heteroaromatic aldehydes,15
with good yields and enantioselectivities for both reactions.
most convenient methods for the synthesis of chiral nonracemic
secondary propargylic alcohols, as a new C-C bond is formed
concomitantly with the creation of a stereogenic center in a single
transformation.1 These kinds of compounds serve as precursors
for a variety of chiral materials since the heteroatom and alkyne are
handles for further transformations. For this reason, propargylic
alcohols have been used as intermediates in the efficient synthesis
of many natural products and pharmaceuticals.2
A number of catalytic protocols for this enantioselective re-
action have been developed in the last years. In most of them,
bisalkynylzinc or alkylakynylzinc species are used as nucleophiles
because these reagents feature a high functional group tolerance
and a slow rate of addition to carbonyl groups in the absence
of a Lewis basic ligand.3 After the pioneering work by Carreira
et al.4 on the alkynylation of aldehydes with zinc acetylides
generated in situ from terminal alkynes and Zn(OTf)2 using
ephedrine as chiral inductor, a number of N,O ligands have been
employed as catalysts or pre-catalysts in these reactions. Examples
include amino alcohols,5 imino alcohols,6 oxazolidines,7 hydroxy
sulfonamides8 and hydroxy carboxyamides.9 Furthermore, some
catalysts based on the axially chiral 1,1¢-bi-2-naphthol ligand and
Ti(IV) have been developed.10 Based on the same kinds of ligands,
Shibasaki has described the asymmetric alkynylation of aldehydes
promoted by the In(III)/BINOL complex and Cy2NMe.11
Fig. 1 Mandelamide ligands used in this study.
The design of new chiral ligands to be used in catalytic
enantioselective reactions is an area of permanent interest. Easy
preparation by short pathways from readily available non expen-
sive starting materials, modularity and structural variation, low
molecular weight, availability in both enantiomeric forms and
stability are desirable features in any ligand of practical use. Ac-
cording to these premises, our group has been developing hydroxy
In this paper, we report the enantioselective addition of a variety
of terminal alkynes to aromatic and heteroaromatic aldehydes
using simple mandelamide ligands and dimethylzinc, with high
yields and good to high enantioselectivities.
Results and discussion
Addition of phenylacetylene
aDepartament de Qu´ımica Orga`nica, Facultat de Qu´ımica, Universitat
de Vale`ncia, Dr. Moliner 50, E-46100-Burjassot (Vale`ncia), Spain.
E-mail: jose.r.pedro@uv.es; Fax: +34 963544328
The reaction between benzaldehyde and phenylacetylene in the
presence of Me2Zn and mandelamides 1-5 in toluene was used for
the optimization process (Scheme 1, Table 1). Ti(OiPr)4 was not
used to avoid addition of dimethlyzinc to the aldehyde.13 The study
of this reaction revealed the following results:15
bDepartamento de F´ısica Aplicada, Universidad Polite´cnica de Valencia,
E-46071, Vale`ncia, Spain
† Electronic supplementary information (ESI) available: NMR spectra and
HPLC chromatograms for compounds 8be, 8cd, 8ce, 8de, 8ds, 8dt, 8du and
9. CCDC reference numbers 734711. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/b911592g
a) Mandelamides (S)-1 and (S,S)-3 gave the best results in terms
of enantioselectivity.
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Scheme 1 Addition of phenylacetylene to benzaldehyde.
Table 1 Alkynylation of benzaldehyde (7a) with phenylacetylene (6a) in
the presence of dimethylzinc and mandelamides as chiral ligandsa
Entry
L
T/◦C
8aa Yieldb (%)
Eec(%)
1
2
3
4
5
6
7
8
9
1
2
3
4
5
1
3
1
3
3
3
3
3
3
0
0
0
0
0
50
50
70
65
80
85
85
87
90
86
84
90
81
95
87
68
90
51
29
50
4
31
42
65
40
70
3
89
79
64
79
70
10d
11e
12ef
13eg
14eh
70/0
70/0
70/0
70/0
70/0
Scheme 2 Pre-formation of the alkynylzinc species and effect on the
enantioseletivity of the reaction.
a All the reactions were carried out in toluene under nitrogen, 7a (1 mmol),
L (0.2 mmol), Me2Zn (6 mmol), 6a (7.2 mmol). b Isolated product after
column chromatography. c Determined by HPLC on a Chiralcel OD-H
column. d Reaction according Scheme 2, equation 2. e Reaction according
Scheme 2, equation 1. f Me2Zn (5 mmol). g Me2Zn (4 mmol). h Et2Zn
(6 mmol)
Scheme 3 Enantioselective addition of phenylacetylene to aldehydes.
withdrawing (NO2) or electron-releasing (MeO) groups in ortho
brought about a decrease in the enantioselectivity of the reaction.
Remarkably, bulky naphthyl-aldehydes (entries 14 and 15) and,
especially, heteroaromatic aldehydes bearing electron-rich five
membered heterocycles provided the corresponding propargylic
alcohols with high yields and enantioselectivities (entries 16–19).
Aliphatic aldehydes reacted fast under the reaction conditions,
b) The enantioselectivity of the reaction was dependent on the
temperature of reaction between the alkyne and dimethylzinc.
c) The enantioselectivity of the reaction was dependent on the
order of addition of the mandelamide ligand.
d) The enantioselectivity of the reaction was dependent on the
number of equivalents of Me2Zn
Table 2 Enantioselective addition of phenylacetylene (6a) to aldehydes
The optimal reaction conditions required pre-formation of the
alkynylzinc reagent by heating the alkyne and Me2Zn at 70 ◦C
in the presence of the mandelamide ligand (until the formation
of an abundant white precipitate), followed by addition of the
aldehyde at 0 ◦C (Scheme 2, equation 1). Pre-formation of the
alkynylzinc reagent in the absence of the ligand followed by the
addition of ligand and aldehyde at 0 ◦C resulted in a racemic
product (Scheme 2, equation 2). Although we do not have a
clear explanation for this fact, we believe that the formation of
the catalytic complex involves deprotonation of the mandelamide,
which can be achieved by Me2Zn at high temperature but not by the
according to Scheme 3a
Entry
7
R2
t (h)
8
Yieldb (%) Eec(%) Config.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
7a Ph
1
2
2
1
1
8aa
8ab
8ac
8ad
8ae
8af
8ag
8ah
8ai
93
70
90
96
70
80
91
90
96
93
87
90
89
63
82
88
79
76
76
80
83
64
32
81
59
80
89
83
89
90
88
34
47
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
S
7b 4-BrC6H4
7c 4-ClC6H4
7d 4-FC6H4
7e 4-MeC6H4
7f 4-MeOC6H4 1.5
7g 3-ClC6H4
7h 3-MeC6H4
7i 3-MeOC6H4
7j 2-ClC6H4
2
2
2
2
◦
8aj
less basic pre-formed alkynylzinc reagent at 0 C. The reduction
7k 2-NO2C6H4 2.5
8ak
8al
8am 89
in the number of equivalents of Me2Zn (entries 12 and 13), as
well as the use of Et2Zn (entry 14) gave rise to a reduction in the
enantioselectivity.
7l 2-MeC6H4 1.5
7m 2-MeOC6H4 3.5
7p 1-naphthyl
7q 2-naphthyl
7r 2-furyl
7s 3-furyl
7t 2-thienyl
7u 3-thienyl
1
1
1
1
1.5
2
8ap
8aq
8ar
8as
8at
8au
8an
8ao
86
91
88
94
91
86
99
64
The optimized conditions were applied to a number of aromatic
and aliphatic aldehydes (Scheme 3). The results are gathered in
Table 2. In general, the reaction took place with high yields and
enantiomeric excesses from good to high for most aromatic aldehy-
des (Table 2, entries 1–15). There is not a clear relationship between
enantioselectivity and the electronic features of the substituents
on the aromatic ring, although for p-halobenzaldehydes it can
be observed an increase of the ee with the electronegativity of
the halogen atom (entries 2–4). The presence of strong electron-
S
S
S
R
R
7n PhCH2CH2 0.5
7o cyclohexyl
1
a All the reactions were carried out in toluene under nitrogen, 7 (1 mmol),
3 (0.2 mmol), Me2Zn (6 mmol), 6a (7.2 mmol). b Isolated product after
column chromatography. c Determined by HPLC.
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Table 4 Enantioselective addition of tert-butylacetylene (6c) to aldehydes
although with variable yields and low enantioselectivities (entries
20 and 21).
according to Scheme 5a
The absolute stereochemistry of the products was assigned by
comparison of the optical rotation signs and HPLC retention times
with values described in the literature for known compounds,
and for the rest of the compounds it was assigned on the
assumption of a uniform mechanistic pathway. According to this,
the configuration of the stereogenic center was R in aromatic
and aliphatic propargylic alcohols 8aa–8aq and 8an–ao, and S
in heteroaromatic propargylic alcohols 8ar–8au.16
Entry
7
R2
t (h)
8
Yieldb (%) Eec(%) Config.
1
2
3
4
5
6
7
7a Ph
3
3
3
1.5
2.5
3.5
1.7
8ca
8cd
8ce
8cr
8cs
8ct
8cu
93
91
93
79
98
95
90
67
65
66
85
90
90
77
R
R
R
S
S
S
S
7d 4-FC6H4
7e 4-MeC6H4
7r 2-furyl
7s 3-furyl
7t 2-thienyl
7u 3-thienyl
a All the reactions were carried out in toluene under nitrogen, 7 (1 mmol),
3 (0.2 mmol), Me2Zn (6 mmol), 6c (7.2 mmol). b Isolated product after
column chromatography. c Determined by HPLC.
Addition of aliphatic alkynes
Although a relatively large number of catalysts have been described
for the alkynylation of aldehydes with phenylacetylene, the addi-
tion of other aliphatic alkynes has been less studied. For instance,
only four examples of catalytic alkynylations of benzaldehyde with
4-phenyl-1-butyne (6b) have been reported so far.4b,5h,6c,11
We studied the addition of this alkyne to aldehydes under our
catalytic conditions (Scheme 4). In this case, the pre-formation of
the alkynylzinc reagent required a little bit longer time until the
formation of the white precipitate (30 min). Several aromatic and
heteroaromatic aldehydes were alkynylated with good yields and
enantiomeric excesses (Table 3). Again the absolute configuration
of the stereogenic center was assigned to be R in aromatic
propargylic alcohols and S in heteroaromatic propargylic alcohols
after comparison.
heating the alkyne and ligand 3 with dimethylzinc for 1 h until
the apparition of the white precipitate (Scheme 5). In general the
reaction required short times to completion (from 1 to 2.5 h)
and the corresponding propargylic alcohols were obtained in very
high yields and enantiomeric excesses from good to excellent,
especially with heteroaromatic aldehydes (Table 4). These are the
highest enantioselectivities described so far for the addition of
tert-butylacetylene to aromatic aldehydes.
Scheme 5 Enantioselective addition of tert-butylacetylene to aldehydes.
In this case, an assignment of the absolute stereochemistry of
the products with literature data was not possible. To determine
the absolute stereochemistry of compound 8ca (67% ee) we pre-
pared a carbamate derivative. Upon reaction with (S)-phenylethyl
isocyanate, a mixture of two diastereomeric carbamates was
obtained (Scheme 6).17 The major diastereomer (R,S)-9 could
be separated by crystallization and its relative stereochemistry
was determined by X-ray analysis‡ of the crystals. Knowing the
absolute stereochemistry at C9 was S from the method of synthesis,
the R absolute stereochemistry at the propargylic carbon C2
then follows (Fig. 2). This result shows that tert-butylacetylene
follows the same stereochemical pathway as phenylacetylene and
4-phenyl-1-butyne.
Scheme 4 Enantioselective addition of 4-phenyl-1-butyne to aldehydes.
Then, we studied the addition of the highly sterically hindered
tert-butylacetylene (6c). This is a very challenging substrate on
account of its bulkiness and lower reactivity. The addition of
t-butylacetylene (6c) to benzaldehyde with an 80% yield and
53% ee reported by Jiang5i is the only successful example in the
literature with aromatic aldehydes so far. Besides, Dahmen has
reported the addition of 6c to cyclohexanecarbaldehyde in the
presence of a paracyclophane-based imino phenol with 52% yield
and 82% ee,5f while Jiang reported 93% yield and 96% ee for
the same reaction using an amino alcohol as ligand.5h In our
conditions, the pre-formation of the alkynylzinc species required
Addition of trimethylsilylacetylene
Finally we studied the addition of trimethylsilylacetylene (6d) to
aldehydes. This alkyne is a synthetic equivalent of acetylene and
allows obtaining terminal propargylic alcohols after removal of
the trimethylsilyl group. A few examples on the enantioselective
addition of trimethylsilylacetylene to some aromatic5b,f,g,j,8f,10l and
aliphatic4c,5g,h aldehydes has been described.
Table 3 Enantioselective addition of 4-phenyl-1-butyne (6b) to aldehydes
according to Scheme 4a
Entry
7
R2
t (h)
8
Yieldb (%) Eec(%) Config.
1
2
3
4
5
6
7
7a Ph
3
3
3
1.5
2.5
3.5
1.7
8ba
8bd
8be
8br
8bs
8bt
8bu
96
95
94
96
93
90
94
88
90
87
90
92
91
89
R
R
R
S
S
S
S
The addition of 6d was carried out by following the described
procedure. Formation of the white precipitate required heating
7d 4-FC6H4
7e 4-MeC6H4
7r 2-furyl
7s 3-furyl
7t 2-thienyl
7u 3-thienyl
‡ Crystal data: C22H25NO2, M = 335.43, monoclinic, a = 9.9740(3), b =
˚
8.8110(3), c = 12.1490(5) A, b = 108.2480(10), V = 1013.97(6), Z = 2,
8581 reflections measured, 4178 reflections independent (Rint = 0.0957, R =
0.0683, Rall = 0.1258), Flack parameter = -1(2). CCDC 734711 contains
the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
a All the reactions were carried out in toluene under nitrogen, 7 (1 mmol),
3 (0.2 mmol), Me2Zn (6 mmol), 6b (7.2 mmol). b Isolated product after
column chromatography. c Determined by HPLC.
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Table 5 Enantioselective addition of trimethylsilylacetylene (6d) to
aldehydes according to Scheme 7a
Entry
7
R2
t (h)
8
Yieldb(%)
Eec(%) Config.
1
2
3
4
5
6
7
7a Ph
23
23
8da
8dd
8de
8dr
67
79
72
87
84
81
90
52
57
51
78
74
72
69
R
R
R
S
S
S
S
7d 4-FC6H4
7e 4-MeC6H4 23
7r 2-furyl
7s 3-furyl
7t 2-thienyl
7u 3-thienyl
2
6.5 8ds
21
7
8dt
8du
a All the reactions were carried out in toluene under nitrogen, 7 (1 mmol),
3 (0.2 mmol), Me2Zn (6 mmol), 6d (7.2 mmol). b Isolated product after
column chromatography. c Determined by HPLC.
groups can be used as nucleophilic partners in the reaction. An
advantage of our catalytic system is that mandelamide ligands are
easily prepared in a one step procedure, and a modular design
of the catalyst is possible by varying the starting hydroxy acid
and amine; also, both enantiomers of the catalyst are available
from the corresponding mandelic acid and a-methylbenzylamine
enantiomers. Furthermore, the reaction times are short and, unlike
most other described procedures, the use of additional Lewis acid
such as Ti(OiPr)4 is not required.
Scheme 6 Synthesis of carbamate derivatives of compound 8ca.
Experimental
General experimental
Glassware was oven-dried overnight at 120 ◦C. Reactions were
monitored by TLC analysis using Merck Silica Gel 60 F-254
thin layer plates. Flash column chromatography was performed
on Merck silica gel 60, 0.040–0.063 mm. Specific optical rotations
were recorded on a Perkin-Elmer 241 polarimeter using sodium
light (D line 589 nm), values are given in 10-1 deg cm2 g-1. IR
spectra were recorded in a Nicolet Avatar 320 FT-IR spectrometer.
NMR spectra were recorded on Bruker Advance spectrometers in
the deuterated solvents as stated, using residual non-deuterated
solvent as internal standard and CFCl3 as internal standard
for 19F NMR. J values are given in Hz. The carbon type was
determined by DEPT experiments. Mass spectra were recorded
on a Fisons Instruments VG Autospec GC 8000 series. Mass
spectra (EI) were run at 70 eV. Mass spectra (FAB) were carried
out at 30 kV in a MNBA matrix. Chiral HPLC analyses were
performed in an Agilent 1100 series instrument equipped with
a refraction index detector using chiral stationary columns from
Daicel. Retention times are given in min. All alkynes and aldehydes
were commercially available and used as purchased without
further purification. Toluene was distilled from CaH2 and stored
Fig. 2 ORTEP diagram for (R,S)-9 with ellipsoids drawn at 40%
probability.
with Me2Zn at 70 ◦C for 45 min. The resulting alkynylzinc reagent
was less reactive and the reaction with the aldehydes was carried
out at rt (Scheme 7). Yields between 67–90% were obtained with
all tested aldehydes (Table 5). Again, heterocyclic aldehydes gave
higher enantiomeric excesses, from 80 to 90% ee (entries 4–7),
than benzaldehyde derivatives (entries 1–3), which provided the
expected products with ee in the range of 50%.
˚
on 4 A molecular sieves. Mandelamides were prepared according
Scheme
aldehydes.
7
Enantioselective addition of trimethylsilylacetylene to
to procedures described in the literature.13,15
General Procedure for the catalytic asymmetric alkynylation of
aldehydes
Conclusions
In conclusion, simple mandelamides and dimethylzinc catalyze
the enantioselective addition of terminal alkynes to aromatic and
heteroaromatic aldehydes affording high yields and enantiose-
lectivities of the corresponding propargylic alcohols. Terminal
alkynes substituted with aromatic, aliphatic or trimethylsiyl
A 2 M solution of Me2Zn in toluene (3 mL, 6 mmol) was added to a
solution of alkyne 6 (7.2 mmol) in dry toluene (5 mL), under argon
at room temperature. After 15 min, a solution of ligand 3 (83 mg,
0.2 mmol) in dry toluene (2 mL) was added and, after 15 min
◦
at room temperature, the solution was heated at 70 C until the
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25
formation of an abundant white precipitate in the solution (20 min
for alkyne 6a, 30 min for alkyne 6b, 60 min for alkyne 6c and 45 min
for alkyne 6d). Then, the reaction mixture was cooled to 0 ◦C and
aldehyde 7 (1 mmol) was added. After the reaction was complete
(TLC), 1M HCl (20 mL) was added (CAUTION! Gas evolution)
and the reaction extracted with diethyl ether (3 ¥ 15 mL). The
organic layer was washed with brine, dried, concentrated and
chromatographed on silica gel to give compound 8.
enantiomer (S) tr = 23.5 min, to be 80%; [a]D +3.1 (c 0.54 in
CHCl3).
(R)-1-(3-Methoxhyphenyl)-3-phenyl-2-propyn-1-ol (8ai)6b
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 18.0 min, minor
25
enantiomer (S) tr =26.7 min, to be 83%; [a]D +5.4 (c 0.51 in
CHCl3).
(R)-1,3-Diphenyl-2-propyn-1-ol (8aa)4a,10j,15
(R)-1-(2-Chlorophenyl)-3-phenyl-2-propyn-1-ol (8aj)7c
Ee was determined by HPLC (Chiralcel OD-H), hexane:i-PrOH
90:10, 1 mL/min, major enantiomer (R) tr = 13.1 min, minor
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 10.5 min, minor
25
enantiomer (S) tr = 21.7 min, to be 89%; [a]D +6.7 (c 0.54 in
25
enantiomer (S) tr = 11.5 min, to be 64%; [a]D -37.9 (c 0.51 in
CHCl3).
CHCl3).
(R)-1-(4-Bromophenyl)-3-phenyl-2-propyn-1-ol (8ab)8b
(R)-1-(2-Nitrophenyl)-3-phenyl-2-propyn-1-ol (8ak)5g
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 10.1 min, minor
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 14.6 min, minor
25
enantiomer (S) tr = 33.3 min, to be 62% ee; [a]D +8.8 (c 0.54 in
25
enantiomer (S) tr = 17.0 min, to be 32%; [a]D -12.4 (c 0.53 in
CHCl3).
CHCl3).
(R)-1-(4-Chlorophenyl)-3-phenyl-2-propyn-1-ol (8ac)8b
(R)-1-(2-Methylphenyl)-3-phenyl-2-propyn-1-ol (8al)10h
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 9.6 min, minor
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 9.9 min, minor
25
enantiomer (S) tr = 27.2 min, to be 82%; [a]D +6.2 (c 0.53 in
25
enantiomer (S) tr = 22.2 min, to be 81%; [a]D -12.4 (c 0.53 in
CHCl3).
CHCl3).
(R)-1-(4-Fluorophenyl)-3-phenyl-2-propyn-1-ol (8ad)8b
(R)-1-(2-Methoxyphenyl)-3-phenyl-2-propyn-1-ol (8am)8b
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 9.5 min, minor
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 16.1 min, minor
25
enantiomer (S) tr = 27.4 min, to be 88%; [a]D +5.2 (c 0.51 in
25
enantiomer (S) tr =18.1 min, to be 59%; [a]D -5.8 (c 0.55 in
CHCl3).
CHCl3).
(R)-1-(4-Methylphenyl)-3-phenyl-2-propyn-1-ol (8ae)7c
(R)-1,5-Diphenyl-2-pentyn-3-ol (8an)5d
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 9,9 min, minor
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 15.6 min, minor
25
25
enantiomer (S) tr = 20.6 min, to be 79%; [a]D +2.8 (c 0.47 in
enantiomer (S) tr = 28.9 min, to be 34%; [a]D -22.3 (c 0.53 in
CHCl3).
CHCl3).
(R)-1-(4-Methoxylphenyl)-3-phenyl-2-propyn-1-ol (8af)8b
(R)-1-Cyclohexyl-3-phenyl-2-propyn-1-ol (8ao)18
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 15.0 min, minor
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 6.2 min, minor
25
25
enantiomer (S) tr = 31.1 min, to be 76%; [a]D +24.1 (c 0.31 in
enantiomer (S) tr = 12.8 min, to be 49%; [a]D -4.0 (c 0.54 in
CHCl3).
CHCl3).
(R)-1-(3-Chlorophenyl)-3-phenyl-2-propyn-1-ol (8ag)6b
(R)-3-Phenyl-1-(naphth-1-yl)-2-propyn-1-ol (8ap)10h
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 9.8 min, minor
Ee was determined by HPLC (Chiralpack AD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 22.9 min, minor
25
25
enantiomer (S) tr = 30.1 min, to be 76%; [a]D +12.6 (c 0.54 in
enantiomer (S) tr = 17.1 min, to be 80%; [a]D -19.8 (c 0.48 in
CHCl3).
CHCl3).
(R)-1-(3-Methylphenyl)-3-phenyl-2-propyn-1-ol (8ah)6b
(R)-3-Phenyl-1-(naphth-2-yl)-2-propyn-1-ol (8aq)5g
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 11.5 min, minor
Ee was determined by HPLC (Chiralpack AD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 22.9 min, minor
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25
enantiomer (S) tr = 17.1 min, to be 80%; [a]D -19.8 (c 0.48 in
(S)-1-(Furan-3-yl)-5-phenyl-2-pentyn-1-ol (8bs)15
CHCl3).
Ee was determined by HPLC (Chiralcel OD-H), hexane:i-PrOH
90:10, 1 mL/min, major enantiomer tr = 11.9 min, minor
enantiomer tr = 22.6 min, to be 92%; [a]D25 +12.3 (c 0.52 in CHCl3).
(S)-1-(Furan-2-yl)-3-phenyl-2-propyn-1-ol (8ar)10j,15
Ee was determined by HPLC (Chiralcel OD-H), hexane:i-PrOH
90:10, 1 mL/min, major enantiomer tr = 10.3 min, minor
enantiomer tr = 21.1 min, to be 83%; [a]D25 +34.0 (c 0.58 in CHCl3).
(S)-5-Phenyl-1-(thiophen-2-yl)-2-pentyn-1-ol (3bt)15
Ee was determined by HPLC (Chiralcel OD-H), hexane:i-PrOH
90:10, 1 mL/min, major enantiomer tr = 14.7 min, minor
enantiomer tr = 30.6 min, to be 91%; [a]D25 +27.5 (c 0.57 in CHCl3).
(S)-1-(Furan-3-yl)-3-phenyl-2-propyn-1-ol (8as)11,15
Ee was determined by HPLC (Chiralcel OD-H), hexane:i-PrOH
90:10, 1 mL/min, major enantiomer tr = 9.6 min, minor enan-
(S)-5-Phenyl-1-(thiophen-3-yl)-2-pentyn-1-ol (3bu)15
25
tiomer tr = 24.7 min, to be 89%; [a]D +3.0 (c 0.53 in CHCl3).
Ee was determined by HPLC (Chiralcel OD-H), hexane:i-PrOH
90:10, 1 mL/min, major enantiomer tr = 14.7 min, minor
enantiomer tr = 29.9 min, to be 89%; [a]D25 +15.4 (c 0.51 in CHCl3).
(S)-3-Phenyl-1-(thiophen-2-yl)-2-propyn-1-ol (8at)15
Ee was determined by HPLC (Chiralcel OD-H), hexane:i-PrOH
90:10, 1 mL/min, major enantiomer tr = 11.2 min, minor
enantiomer tr = 23.2 min, to be 90%; [a]D25 +20 (c 0.53 in CHCl3).
(R)-4,4-Dimethyl-1-phenyl-2-pentyn-1-ol (3ca)15
Ee was determined by HPLC (Chiralcel OD-H), hexane:i-PrOH
90:10, 1 mL/min, major enantiomer tr = 5.8 min, minor enan-
(S)-3-Phenyl-1-(thiophen-3-yl)-2-propyn-1-ol (8au)11,15
25
tiomer tr = 4.7 min, to be 67%; [a]D +18.8 (c 0.51 in CHCl3).
Ee was determined by HPLC (Chiralcel OD-H), hexane:i-PrOH
90:10, 1 mL/min, major enantiomer tr = 11.5 min, minor
enantiomer tr = 30.8 min, to be 88%; [a]D25 +20 (c 0.53 in CHCl3).
(R)-4,4-Dimethyl-1-(4-fluorophenyl)-2-pentyn-1-ol (8cd)
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 5.0 min, minor
(R)-1,5-Diphenyl-2-pentyn-1-ol (8ba)11,15
25
enantiomer (S) tr = 4.6 min, to be 65%; [a]D +20.3 (c 0.57 in
CHCl3); nmax(film)/cm-1 3358, 2970, 2231, 1606, 1508, 1262, 1157,
1067, 985, 860, 836 and 771; dH(300 MHz; CDCl3) 7.51 (dd, J 8.4
and 5.4, 2H), 7.05 (t, J 8.4, 2H), 5.42 (s, 1H), 2.14 (br s, 1H), 1.26
(s, 9H); dC(75 MHz; CDCl3) 162.5 (C, JC-F (d) 244.4), 137.1 (C, JC-F
(d) 2.8), 128.5 (2CH, JC-F (d) 7.8), 115.3 (2CH, JC-F (d) 21.1), 96.1
(C), 78.2 (C), 64.0 (CH), 30.9 (3CH3), 27.5 (C); m/z (EI) 206.1115
(M+, 100%, C13H15FO requires 206.1107), 123 (42) and 69 (36).
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 15.7 min, minor
25
enantiomer (S) tr = 27.4 min, to be 88%; [a]D +13.0 (c 0.52 in
CHCl3).
(R)-1-(4-Fluorophenyl)-5-phenyl-2-pentyn-1-ol (8bd)11
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 12.3 min, minor
(R)-4,4-Dimethyl-1-(4-methylphenyl)-2-pentyn-1-ol (8ce)
25
enantiomer (S) tr = 34.8 min, to be 90%; [a]D +17.6 (c 0.54 in
Ee was determined by HPLC (Chiralpack AD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 5.9 min, minor
CHCl3).
25
enantiomer (S) tr = 5.2 min, to be 66%; [a]D +20.1 (c 0.56 in
(R)-1-(4-Methylphenyl)-5-phenyl-2-pentyn-1-ol (8be)
CHCl3); nmax(film)/cm-1 3374, 2969, 2231, 1512, 1363, 1262, 1066,
982, 817 and 759; dH(300 MHz; CDCl3) 7.43 (d, J 8.4, 2H), 7.18
(d, J 8.4, 2H), 5.41 (s, 1H), 2.36 (s, 3H), 2.08 (br s, 1H) and 1.27
(s, 9H); dC(75 MHz; CDCl3) 138.5 (C), 137.9 (C), 129.1 (2CH),
126.7 (2CH), 95.5 (C), 78.5 (C), 64.5 (CH), 30.9 (3CH3), 27.5 (C)
and 21.1 (CH3); m/z (EI) 202.1539 (M+, 91%, C14H18O requires
202.1358), 187 (100), 172 (27) and 145 (58).
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (R) tr = 11.4 min, minor
25
enantiomer (S) tr = 22.2 min, to be 87%; [a]D +16.3 (c 0.56 in
CHCl3); nmax(film)/cm-1 3373, 2970, 2222, 1225, 1013, 814 and
762; dH(300 MHz; CDCl3) 7.28 (d, J 7.8, 2H), 7.25–7.10 (m, 5H),
7.08 (d, J 7.8, 2H), 5.31 (s, 1H), 2.78 (t, J 7.5, 2H), 2.49 (td, J 7.5
and 1.8, 2H), 2.28 (s, 3H) and 2.00 (br s, 1H); dC (75 MHz; CDCl3)
140.5 (C), 138.2 (C), 138.0 (C), 129.2 (2CH), 128.5 (2CH), 128.4
(2CH), 126.6 (2CH), 126.3 (CH), 86.5 (C), 80.9 (C), 64.6 (CH),
34.9 (CH2), 21.1 (CH3) and 21.0 (CH2); m/z (EI) 250.1353 (M+,
27%, C18H18O requires 250.1358), 235 (17), 217 (5), 119 (33) and
91 (100).
(S)-1-(Furan-2-yl)-4,4-dimethyl-2-pentyn-1-ol (8cr)15
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (S) tr = 5.6 min, minor
25
enantiomer (R) tr = 5.3 min, to be 85%; [a]D +16.8 (c 0.53 in
CHCl3).
(S)-1-(Furan-2-yl)-5-phenyl-2-pentyn-1-ol (8br)15
(S)-1-(Furan-3-yl)-4,4-dimethyl-2-pentyn-1-ol (8cs)15
Ee was determined by HPLC (Chiralcel OD-H), hexane:i-PrOH
90:10, 1 mL/min, major enantiomer tr = 13.9 min, minor
enantiomer tr = 21.7 min, to be 90%; [a]D25 +14.2 (c 0.54 in CHCl3).
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 0.5 mL/min), major enantiomer (S) tr = 9.5 min, minor
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25
enantiomer (R) tr = 9.1 min, to be 90%; [a]D +16.2 (c 0.56 in
(S)-3-Trimethylsilyl-1-(tiophen-2-yl)-2-propyn-1-ol (8dt)
CHCl3).
Ee determined by HPLC (Chiralpack AD-H, hexane:i-PrOH
95:5, 0,5 mL/min), major enantiomer (S) tr = 14.8 min, minor
(S)-4,4-Dimethyl-1-(tiophen-2-yl)-2-pentyn-1-ol (8ct)15
25
enantiomer (R) tr = 13.0 min, to be 63%; [a]D +28.7 (c 0.57 in
CHCl3); nmax(film)/cm-1 3394, 2960, 2899, 2174, 1410, 1251, 1041,
844, 794 and 761; dH(300 MHz; CDCl3) 7.30 (dd, J 5.0, 0.9, 1H),
7.18 (unresolved dt, J 3.5, 1H), 6.98 (dd, J 5.0 and 3.5, 1H), 5.64
(s, 1H), 2.40 (br s, 1H) and 0.22 (s, 9H); dC(75 MHz; CDCl3) 144.3
(C), 126.7 (CH), 126.2 (CH), 125.7 (CH), 104.0 (C), 91.2 (C), 60.6
(CH) and -0.3 (3CH3); m/z (EI) 210.0532 (M+, 100%, C10H14OSiS
requires 210.0535), 195 (9), 167 (97) and 120 (91).
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (S) tr = 5.7 min, minor
25
enantiomer (R) tr = 5.1 min, to be 90%; [a]D +38.4 (c 0.51 in
CHCl3).
(S)-4,4-Dimethyl-1-(tiophen-3-yl)-2-pentyn-1-ol (8cu)15
Ee was determined by HPLC (Chiralcel OD-H, hexane:i-PrOH
90:10, 1 mL/min), major enantiomer (S) tr = 5.5 min, minor
25
(S)-3-Trimethylsilyl-1-(tiophen-3-yl)-2-propyn-1-ol (8du)
enantiomer (R) tr = 5.0 min, to be 77%; [a]D +17.7 (c 0.57 in
CHCl3).
Ee determined by HPLC (Chiralpack AD-H, hexane:i-PrOH 95:5,
1 mL/min), major enantiomer (S) tr = 8.0 min, minor enantiomer
(R)-3-(Trimethylsilyl)-1-phenyl-2-propyn-1-ol (8da)6b,10l
25
(R) tr = 6.8 min, to be 69%; [a]D +13.9 (c 0.56 in CHCl3);
n
max(film)/cm-1 3363, 3105, 2959, 2173, 1419, 1251, 1041, 844,
Ee was determined by HPLC (Chiralpack AD-H, hexane:i-PrOH
95:5, 1 mL/min), major enantiomer (R) tr = 7.4 min, minor
794 and 761; dH(300 MHz; CDCl3) 7.40 (m, 1H), 7.32 (dd, J 5.1
and 3.0, 1H), 7.18 (dd, J 5.1 and 1.2, 1H), 5.48 (s, 1H), 2.25 (br s,
1H), 0.21 (s, 9H); dC(75 MHz; CDCl3) 141.7 (C), 126.5 (CH), 126.4
(CH), 122.8 (CH), 104.7 (C), 90.7 (C), 60.9 (CH) and -0.2 (3CH3);
m/z (EI) 210.0535 (M+, 100%, C10H14OSiS requires 210.0535), 195
(3), 167 (36), 120 (13).
25
enantiomer (S) tr = 6.5, to be 52%;[a]D +11.2 (c 0.58, CHCl3).
(R)-1-Fluorophenyl-3-(trimethylsilyl)-2-propyn-1-ol (8dd)10l
Ee determined by HPLC (Chiralpack AD-H, hexane:i-PrOH 95:5,
1 mL/min), major enantiomer (R) tr = 6.8 min, minor enantiomer
25
(S) tr = 6.1 min, to be 57%; [a]D +13.7 (c 0.54 in CHCl3).
Synthesis of carbamates 9 and 10
(R)-1-Methylphenyl-3-(trimethylsilyl)-2-propyn-1-ol (8de)
A
solution of (R)-4,4-dimethyl-1-phenyl-2-pentyn-1-ol (8ca,
83.4 mg, 0.44 mmol, Table 5, entry 1, 67% ee), (S)-phenylethyl
isocyante (113 mL, 0.72 mmol) and a catalytic amount of 4-
dimethylaminopyridine (DMAP) in toluene (1.7 mL) was stirred
at 80 ◦C under nitrogen atmosphere for 24 h. The solvent
was removed under reduced pressure and the concentrated was
dissolved in dichloromethane and washed with saturated aqueous
NaHCO3 and brine. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. Column chromatography
eluting with hexane-EtOAc gave a mixture of two diastereomeric
carbamates (121.5 mg, 85%). The major diastereomer (43 mg)
could be obtained pure after crystallization from toluene (0.4 mL).
A second crystallization allowed to obtain suitable crystals for
X-ray analysis.
Ee determined by HPLC (Chiralpack AD-H, hexane:i-PrOH 95:5,
1 mL/min), major enantiomer (R) tr = 8.2 min, minor enantiomer
25
(S) tr = 6.7 min, to be 51%; [a]D +13.3 (c 0.52 in CHCl3);
n
max(film)/cm-1 3375, 2960, 2899, 2173, 1513, 1411, 1250, 1043,
983, 843 and 761; dH(300 MHz; CDCl3) 7.43 (d, J 8.4, 2H), 7.19
(d, J 8.4, 2H), 5.42 (s, 1H), 2.36 (s, 3H), 2.15 (br s, 1H) and 0.20 (s,
9H); dC(75 MHz; CDCl3) 138.2 (C), 137.5 (C), 129.3 (2CH), 126.7
(2CH), 105.1 (C), 91.3 (C), 64.8 (CH), 21.2 (CH3) and -0.2 (3CH3);
MS (EI) 218.1130 (M+, 100%, C13H18OSi requires 218.1127), 203
(86) and 175 (43).
(S)-1-(Furan-2-yl)-3-(trimethylsilyl)-2-propyn-1-ol (8dr)5g
Major diastereomer (R,S)-9: mp128–129 ◦C (toluene), [a]D
25
Ee determined by HPLC (Chiralpack AD-H, hexane:i-PrOH
95:5, 0.5 mL/min), major enantiomer (S) tr = 13.2 min, minor
-13.2 (c 0.55 in CHCl3); nmax(KBr)/cm-1 3038, 2969, 2241, 1690,
1541, 1224, 1053, 914, 698; dH(300 MHz; CDCl3) 7.54 (unresolved
d, 2H), 7.40–7.20 (m, 8H), 6.42 (s, 1H), 5.03 (br d, J 6.6, 1H), 4.84
(qd, J 7.2 and 6.6), 1.44 (d, J 7.2, 3H) and 1.23 (s, 9H); dC(75 MHz;
CDCl3) 154.5 (C), 143.4 (C), 138.2 (C), 128.6 (CH), 128.5 (CH),
128.4 (CH), 127.7 (CH), 127.3 (CH), 125.9 (CH), 96.2 (C), 75.4
(C), 66.6 (CH), 50.8 (CH), 30.7 (CH3), 27.5 (CH3) and 22.4 (C);
dH(300 MHz; dmso-d6) 7.98 (d, J 8.1, 1H), 7.50–7.20 (m, 10H),
6.28 (s, 1H), 4.63 (dq, J 8.1 and 6.9, 1H), 1.29 (d, J 6.9, 3H) and
1.17 (s, 9H); dC(75 MHz; dmso-d6) d 154.2 (C), 144.8 (C), 138.3
(C), 128.5 (CH), 128.2 (CH), 127.2 (CH), 126.6 (CH), 125.7 (CH),
95.3 (C), 76.3 (C), 64.9 (CH), 50.1 (CH), 30.4 (CH3), 27.0 (CH3)
and 22.6 (C); m/z (FAB) 335.1889 (M+, 0.5%, C22H25NO2 requires
335.1885) and 171 (100).
25
enantiomer (R) tr = 12.8 min, to be 74%; [a]D +16.2 (c 0.52 in
CHCl3).
(S)-1-(Furan-3-yl)-3-(trimethylsilyl)-2-propyn-1-ol (8ds)
Ee determined by HPLC (Chiralpack AD-H, hexane:i-PrOH 93:7,
1 mL/min), major enantiomer (S) tr = 5.9 min, minor enantiomer
25
(R) tr = 5.4 min, to be 73%; [a]D +11.3 (c 0.59 in CHCl3);
n
max(film)/cm-1 3363, 2960, 2173, 1503, 1410, 1251, 1160, 1204,
943, 845 and 760; dH(300 MHz; CDCl3) 7.52 (m, 1H), 7.40 (t, J
1.6, 1H), 6.50 (m, 1H), 5.38 (s, 1H), 2.12 (br s, 1H), 0.20 (s, 9H);
dC(75 MHz; CDCl3) 143.6 (CH), 140.3 (CH), 126.1 (C), 109.2
(CH), 104.4 (C), 90.0 (C), 57.7 (CH) and -0.2 (3CH3); MS (EI)
194.0773 (M+, 100%, C10H14O2Si requires 194.0763), 179 (58), 161
(30), 104 (86) and 73 (54).
Minor diastereomer (S,S)-10, significative peaks taken from the
diastereomeric mixture: dH(300 MHz; dmso-d6) 7.98 (d, J 8.1,
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1H), 7.50–7.20 (m, 10H), 6.30 (s, 1H), 4.67 (dq, J = 8.1 and 6.9,
1H), 1.33 (d, J = 6.9, 3H), 1.21 (s, 9H).
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222; (c) S. Dahmen, Org. Lett., 2004, 6, 2113–2116.
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Tetrahedron Lett., 2005, 46, 863–865; (c) A. L. Braga, H. R. Appelt,
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2002, 58, 10413–10416.
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Acknowledgements
Financial support from the Ministerio de Ciencia e Innovacio´n
and FEDER (CTQ 2006–14199/BQU) is gratefully acknowl-
edged.
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