Facile and practical enantioselective synthesis of propargylic alcohols by direct addition of alkynes to aldehydes catalyzed by chiral disulfide-oxazolidine ligands

Article abstract of DOI:10.1016/S0040-4020(02)01420-5

The enantioselective alkynylation reaction of aldehydes with alkynes and diethylzinc, catalyzed by chiral disulfide-oxazolidine ligands, provides a simple, practical and inexpensive method to access chiral propargylic alcohols in good yields and satisfact

Full text of DOI:10.1016/S0040-4020(02)01420-5

Tetrahedron 58 (2002) 10413–10416
Facile and practical enantioselective synthesis of propargylic
alcohols by direct addition of alkynes to aldehydes catalyzed
by chiral disulfide–oxazolidine ligands
a
a
b
Antonio L. Braga,a Helmoz R. Appelt, Claudio C. Silveira, Ludger A. Wessjohann
,
*
and Paulo H. Schneidera
a
´
Departamento de Quımica, Universidade Federal de Santa Maria, CEP-97105-900 Santa Maria, RS, Brazil
bLeibniz-Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany
Received 22 July 2002; accepted 30 October 2002
Abstract—The enantioselective alkynylation reaction of aldehydes with alkynes and diethylzinc, catalyzed by chiral disulfide–oxazolidine
ligands, provides a simple, practical and inexpensive method to access chiral propargylic alcohols in good yields and satisfactory ee’s. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
metric catalysis especially ligands binding via sulfur or
selenium, we describe in this article our studies on the
alkynylation of aldehydes. We have demonstrated pre-
viously that oxazolidine disulfides are appropriate ligands
for an enantioselective diethylzinc addition to aldehydes7
(Scheme 1).
A survey of the recent chemical literature reveals an
explosion of interest in the development and design of chiral
auxiliaries and catalysts to access pure or enriched chiral
compounds.1 Development of new or improved methods for
the asymmetric preparation of chiral propargylic alcohols
has gained considerable significance during the past years
because they are useful building blocks for the synthesis of
various biologically active and structurally interesting
compounds.2 Compounds of this important class had
been prepared by stoichiometric,3 enzymatic or catalytic4
reduction of acetylenic ketones or by enantioselective
alkynylation of aldehydes using stoichiometric5 or catalytic
amounts of ligands.6
Now, we wish to communicate that this kind of catalyst
promotes the direct enantioselective reaction of terminal
alkynes with aldehydes to afford propargylic alcohols in
good yields and satisfactory enantioselectivity (Scheme 2,
Tables 1 and 2).
Alkynyl zinc reagents are generated in situ by reaction of
terminal alkynes and diethylzinc, thus avoiding separate
preparative metalation steps. Thus, treatment of a solution
of an alkyne at 220 to 2308C in THF with diethylzinc and
5–10 mol% of a catalyst (1–3), followed by the aldehyde,
As part of our broader program to explore the preparation
and use of chiral organochalcogen compounds in asym-
Scheme 1.
Keywords: sulfide; asymmetric alkynylation; amino alcohol; diethylzinc; propargylic alcohol.
*
Corresponding author. Fax: þ55-55-220-8031; e-mail: albraga@quimica.ufsm.br
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01420-5

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A. L. Braga et al. / Tetrahedron 58 (2002) 10413–10416
Table 2. Asymmetric alkynylation of aldehydes catalyzed by chiral
disulfide (R,R)-2
Entry
Aldehyde
Acetylene Reaction
t Yield
(h) (%)
ee
(%)a
Scheme 2.
1
2
3
4
5
4a
4a
4b
4b
4c
24
48
24
48
24
50
67
51
55
54
60(2)(S)b
56(2)(S)
41(2)(S)
36(2)(S)
60(2)(S)
furnishes the desired adducts in moderate to satisfactory
yields and up to 60% ee, after 48 h of reaction. For each of
the propargylic adducts, GC analysis permitted the enantio-
meric purity of the products to be determined.
A preliminary study was conducted with the aim of
determining the best of the available chiral ligands and
solvent conditions (Table 1). We explored the catalyzed
alkynylation of benzaldehyde with phenylacetylene at 220
to 2308C for 48 h. The best results were obtained with the
ligand (R,R)-2. With this ligand, the corresponding
propargylic alcohol was obtained in 67% yield and 56% ee.
6
7
4c
4d
48
24
76
61
58(2)(S)
53(þ)(S)
In all cases studied, the desired propargylic alcohols were
slightly contaminated by the corresponding alkyl alcohols,
a-ethylaryl alcohol, resulting from the transfer of the ethyl
group of diethyl zinc to aldehydes, as previously reported.6a,8
It was observed also that the decrease of the catalyst
concentration from 10 to 5 mol% does not result in a
decrease of enantiomeric excess of the product, but the yield
was reduced (Table 1; entry 4). In this case, the by-product,
a-ethylaryl alcohol, was obtained in 41%. When the ligand
R,R-1 was used as catalyst, an average yield was obtained,
but racemic product was formed.
8
9
4d
4e
48
48
80
81
50(þ)(S)
52(2)(S)
10
4f
48
72
58(þ)(S)
With the ligand (R,R)-3 as catalyst, the best yield was
obtained, but the ee was very low. Interestingly, variation of
the solvent has a profound influence on the yields of
this reaction. The use of toluene or different mixtures
of toluene/THF resulted in the same level of optical purity
of the propargylic alcohols, but the yields were diminished,
specially by using toluene only, which resulted in a 7% yield
(Table 1; entry 5). This observation is in contrast to that of
Carreira5 who obtained the best result in pure toluene. Also
in contrast to this method, no amine base is required and the
reaction conditions can be considered almost neutral.
11
12
4g
4h
48
48
73
82
43(2)(S)
51(þ)(S)
Reactions were carried out at 220 to 2308C with 10 mol% ligand 2
following the general procedure.
a
The enantioselectivities was determined by GC analysis using chiral
columns.
The absolute configuration of the products was established by correlation
with known compounds or by analogy.3d,e,4a,6
b
Table 1. Ligand study: alkynylation of benzaldehyde with phenylacetylene in the presence of Ligands 1–3
Entry
Catalyst
Catalyst (mol%)
Solvent
Yield (%)
ee (%)a
1
2
3
4
5
6
7
(R,R)-1
(R,R)-2
(R,R)-3
(R,R)-2
(R,R)-2
(R,R)-2
(R,R)-2
10
10
10
5
10
10
10
PhCH3/THF 2.75:1
PhCH3/THF 2.75:1
PhCH3/THF 2.75:1
PhCH3/THF 2.75:1
PhCH3
65
67
69
23
7
–
56b
18
60
61
60
55
PhCH3/THF 5.5:1
PhCH3/THF 1:1
45
60
Reactions were carried out at 220 to 2308C with 5 or 10 mol% ligand following the general procedure described in Section 3.
Determined by GC analysis of crude reaction mixture using 2,6-Me,3-Pe-b-CD column (1558C).
With (S,S)-2 the opposite enantiomer was isolated in comparable yield and ee.
a
b

A. L. Braga et al. / Tetrahedron 58 (2002) 10413–10416
10415
In a second set of experiments, the influence of various
aldehydes, alkynes and the reaction time, on yield and
enantioselectivity were tested, using the best catalyst
(R,R-2). Most of the substituted aryl aldehydes underwent
the addition reaction with similar levels of enantioselec-
tivity compared with the parent benzaldehyde. Comparison
of several examples suggests that this chemistry is
applicable to both aromatic and aliphatic acetylenes.
layers were separated. The aqueous layer was extracted with
EtOAc (2£20 mL). The combined organic phase was
washed with brine and dried (MgSO4). After filtration, the
solvent was removed under reduced pressure. The crude
product was purified by column chromatography (silica gel,
10/1 hexane/EtOAc) to afford pure product. The enantio-
meric excess was determined by GC analysis of reaction
mixture on a 2,6-Me-3-Pe,b-CD column.
Increased reaction times (24–48 h) have only a small
influence on the reaction, giving slightly improved yields
but decreased ee’s (Table 2; entries 1–8).
3.1.1. (2)-1,3-Diphenylprop-2-yn-1-ol (4a).6 The typical
procedure was followed. The compound was purified by
flash chromatography (silica gel) by elution with 10%
EtOAc/hexane. The enantiomeric excess was determined by
1
GC analysis on a 2,6-Me-3-Pe,b-CD column (1558C). H
NMR (CDCl3, 200 MHz): d¼7.66–7.58 (m, 2H, ArH),
7.52–7.48 (m, 2H, ArH), 7.46–7.32 (m, 6H, ArH), 5.71 (m,
1H), 2.50 (d, J¼6.2 Hz, 1H). 13C NMR (CDCl3, 50 MHz):
d¼140.7, 131.8, 128.6, 128.5, 128.4, 126.8, 122.5, 88.8,
86.7, 65.2.
2. Conclusions
In summary, the chiral oxazolidine disulfide derived from
commercial (R)-cysteine was found to promote the
enantioselective alkynylation of aldehydes to afford the
chiral propargylic alcohols in good yields and satisfactory
enantiomeric excess under non-basic conditions. Although
this first generation of new, sulfur based catalyst is not yet as
optimized as the more traditional aminoalcohols,5 we are
confident that they will prove to be a useful alternative to
existing methods as was already shown in other organozinc
reactions,7,9 especially the case of preparation from cheap
cysteine is intriguing. Further studies dealing with their
improvement and application in organic synthesis are in
progress.
3.1.2. (2) 1-Phenylhept-2-yn-1-ol (4b). The typical
procedure was followed. The compound was purified by
flash chromatography (silica gel) by elution with 9%
EtOAc/hexane. The enantiomeric excess was determined
by GC on a 2,6-Me-3-Pe, b-CD column (50–1558C,
1
38C/min). H NMR (CDCl3, 200 MHz): d¼7.22–7.18 (m,
2H), 7.09–6.97 (m, 3H), 5.05 (m, 1H), 2.33 (s, 1H), 2.04–
1.96 (m, 2H), 1.36–1.19 (m, 4H), 0.70 (t, J¼6.94 Hz, 3H).
13C NMR (CDCl3, 50 MHz): d¼142.5, 129.4, 128.5, 127.9,
127.4, 87.4, 81.8, 65.1, 31.6, 22.9, 19.4, 14.6.
3.1.3. (2)-1-(4-Methylphenyl)-3-phenylprop-2-yn-1-ol
(4c). The typical procedure was followed. The compound
was purified by flash chromatography (silica gel) by elution
with 9% EtOAc/hexane. The enantiomeric excess was
determined by GC on a 2,6-Me-3-Pe,b-CD column (1558C).
1H NMR (CDCl3, 200 MHz): d¼7.48–7.42 (m, 4H, ArH),
7.28–7.26 (m, 3H, ArH), 7.18–7.14 (m, 2H, ArH), 5.60 (m,
1H), 2.64 (s, 1H), 2.33 (s, 3H). 13C NMR (CDCl3, 50 MHz):
d¼138.0, 137.7, 131.6, 129.2, 128.4, 128.1, 126.6, 122.4,
88.9, 86.3, 64.7, 21.0.
3. Experimental
Reagents were used as received unless otherwise stated. All
manipulations were carried out under an inert atmosphere of
Ar. The glassware was oven dried prior to use for the
alkynylation reactions. Optical rotations were measured on
a Perkin–Elmer 341 polarimeter. The H and 13C NMR
1
spectra were register on a Bruker DPX 200 spectrometer
using TMS as an internal standard. Elemental analyses (C,
H, N) were performed on a Vario El and Perkin–Elmer
CHN 2400 analyzer. Gas chromatography (GC) was
performed using a Varian 3400 gas chromatograph with
(2,6-Me-3-Pe)-b-cyclodextrin column as chiral stationary
phase for ee determination of the propargylic alcohols
obtained.
3.1.4. (1)-1-(2-Chlorophenyl)-3-phenylprop-2-yn-1-ol
(4d).6 The typical procedure was followed. The compound
was purified by flash chromatography (silica gel) by elution
with 9% EtOAc/hexane. The enantiomeric excess was
determined by GC analysis of his (methyl) ether derivate on
a 2,6-Me-3-Pe,b-CD column (50–1558C, 48C/min). 1H
NMR (CDCl3, 200 MHz): d¼7.85 (d, J¼7.3 Hz, 1H, ArH),
7.48 (m, 2H, ArH), 7.43–7.27 (m, 6H, ArH), 6.06 (m, 1H),
2.70 (s, 1H). 13C NMR (CDCl3, 50 MHz): d¼137.9, 132.9,
131.8, 129.8, 129.7, 128.7, 128.5, 128.4, 127.3, 122.3, 87.6,
86.7, 63.5.
3.1. Asymmetric alkynylation reactions. Typical
procedure
Acetylene (2.6 mmol) was added into a 15 mL two-neck
round bottom flask containing 0,85 mL dry THF at rt under
N2. The stirred mixture was then cooled to 2208C for 5 min,
followed by the addition of a 1.1 M solution of diethylzinc
in toluene (2.4 mmol). The resulting solution was stirred at
2208C for 15 min, and ligand (0.2 mmol, 10 mol%) was
added. The homogenous solution was stirred at 2208C for
15 min, and then aldehyde (2.0 mmol) was added via
syringe. The resulting mixture was stirred at 220 to 2308C
for 48 h. When the reaction was complete, it was quenched
by the addition of MeOH (1 mL) at 2208C, and as it
warmed to 08C, sat. NH4Cl (2 mL) was added. EtOAc
(50 mL) and sat. NH4Cl (10 mL) were then added and the
3.1.5. (2)-1-(4-Methoxyphenyl)hept-2-yn-1-ol (4e). The
typical procedure was followed. The compound was
purified by flash chromatography (silica gel) by elution
with 7% EtOAc/hexane. The enantiomeric excess was
determined by GC on a 2,6-Me-3-Pe,b-CD column (50–
1
1558C, 28C/min). H NMR (CDCl3, 200 MHz): d¼7.48–
7.39 (m, 2H), 6.95–6.81 (m, 2H), 5.35 (m, 1H), 3.72 (s, 3H),
3.04 (s, 1H), 2.29–2.20 (m, 2H), 1.51–1.41 (m, 4H), 0.89 (t,
J¼6.84 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d¼159.0,

10416
A. L. Braga et al. / Tetrahedron 58 (2002) 10413–10416
Construction of Chiral Molecules Using Aminoacids, Wiley:
New York, 1987.
133.6, 128.8, 128.6, 113.4, 113.3, 76.7, 80.1, 63.8, 54.8,
30.4, 21.6, 13.2.
2. (a) Overman, L. E.; Bell, K. L. J. Am. Chem. Soc. 1981, 103,
1851. (b) Cheon, S. H.; Christ, W. J.; Hawkins, L. D.; Jin, H.;
Kishi, Y.; Tanigushi, M. Tetrahedron Lett. 1986, 27, 4759.
(c) Cohen, N.; Lopresti, R. J.; Neukom, C.; Saucy, G. J. Org.
Chem. 1980, 45, 582. (d) Stork, G.; Nakamura, E. J. Am. Chem.
Soc. 1983, 105, 5510. (e) Zhu, G.; Lu, X. J. Org. Chem. 1995,
60, 1087.
3.1.6. (1)-1-(2-Chlorophenyl)-hept-2-yn-1-ol (4f). The
typical procedure was followed. The compound was
purified by flash chromatography (silica gel) by elution
with 10% EtOAc/hexane. The enantiomeric excess was
determined by GC on a 2,6-Me-3-Pe,b-CD column (50–
1558C, 38C/min). 1H NMR (CDCl3, 200 MHz): d¼7.73 (d,
J¼7.3 Hz, 1H, ArH), 7.33–7.14 (m, 4H, ArH), 5.76 (m,
1H), 3.05 (s, 1H), 2.25–2.18 (m, 2H), 1.55–1.28 (m, 4H),
0.88 (t, J¼6.9 Hz, 3H). 13C NMR (CDCl3, 50 MHz):
d¼138.4, 132.4, 129.3, 129.0, 128.0, 126.8, 87.2, 78.8,
61.6, 30.3, 21.7, 18.2, 13.3.
3. (a) Binkmeyer, R. S.; Kapoor, V. M. J. Am. Chem. Soc. 1977,
95, 8339. (b) Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa,
M. J. Am. Chem. Soc. 1984, 106, 6717. (c) Midland, M. M.;
Tramonato, A.; Kazubski, A.; Graham, R. S.; Tsai, D. J. S.;
Cardin, D. B. Tetrahedron 1984, 40, 1371. (d) Ramachandran,
P. V.; Teodorovic, A. V.; Rangaishenvi, M. V.; Brown, H. C.
J. Org. Chem. 1992, 57, 2379. (e) Bach, J.; Berenguer, R.;
Garcia, J.; Loscertales, T.; Vilarrasa, J. J. Org. Chem. 1996, 61,
9021.
3.1.7. (2)-Dodec-7-yn-6-ol (4g). The typical procedure was
followed. The compound was purified by flash chroma-
tography (silica gel) by elution with 8% EtOAc/hexane. The
enantiomeric excess was determined by GC on a 2,6-Me-3-
4. (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738. (b) Corey, E. J.; Helal, C. J.
Tetrahedon Lett. 1995, 36, 9153. (c) Helal, C. J.; Magriotis,
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(d) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61,
3214.
1
Pe,b-CD column (50–1558C, 38C/min). H NMR (CDCl3,
200 MHz): d¼4.45 (m, 1H), 2.15–2.12 (m, 2H), 1.58–1.40
(m, 4H), 1.36–1.23 (m, 8H), 0.86–0.80 (m, 6H). 13C NMR
(CDCl3, 50 MHz): d¼85.1, 81.3, 62.5, 38.0, 33.9, 30.6,
25.9, 22.9, 22.8, 18.2, 14.7, 13.8.
¨
5. (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem Soc.
´
2000, 122, 1806. (b) Boyall, D.; Lopez, F.; Sasaki, H.; Frantz,
3.1.8. (1)-1-Phenylnon-1-yn-3-ol (4h). The typical pro-
cedure was followed. The compound was purified by flash
chromatography (silica gel) by elution with 10% EtOAc/
hexane. The enantiomeric excess was determined by GC on
a 2,6-Me-3-Pe,b-CD column (50–1558C, 38C/min). 1H
NMR (CDCl3, 200 MHz): d¼7.33–7.31 (m, 2H), 7.15–
7.14 (m, 2H), 4.48 (m, 1H), 2.93 (s, 1H), 1.66–1.63 (m, 4H),
1.38–1.17 (m, 6H), 0.77 (t, J¼6.89 Hz, 3H). 13C NMR
(CDCl3, 50 MHz): d¼131.5, 128.7, 128.0, 122.7, 90.3, 84.5,
62.6, 37.7, 32.0, 28.8, 25.1, 22.4, 13.8.
D.; Carreira, E. M. Org. Lett. 2000, 26, 4233. (c) Anand, N. K.;
Carreira, E. M. J. Am. Chem Soc. 2001, 123, 9687. (d) Boyall,
D.; Frantz, D.; Carreira, E. M. Org. Lett. 2002, 15, 2605.
(e) El-Sayed, E.; Anand, N. K.; Carreira, E. M. Org. Lett. 2001,
19, 3017.
6. (a) Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.;
Reider, P. J. Synthesis 1999, 1453. (b) Corey, E. J.; Cimprich,
K. A. J. Am. Chem Soc. 1994, 166, 3151. (c) Anand, N. K.;
Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
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