Enantio and diastereoselective addition of phenylacetylene to racemic α-chloroketones

Article abstract of DOI:10.3390/molecules16065298

In this report, we have presented the first diastereoselective addition of phenylacetylene to chiral racemic chloroketones. The addition is controlled by the reactivity of the chloroketones that allowed the stereoselective reaction to be performed at -20

Full text of DOI:10.3390/molecules16065298

Molecules 2011, 16, 5298-5314; doi:10.3390/molecules16065298
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Enantio and Diastereoselective Addition of Phenylacetylene to
Racemic α-chloroketones
Silvia Alesi, Enrico Emer, Montse Guiteras Capdevila, Diego Petruzziello, Andrea Gualandi and
Pier Giorgio Cozzi *
Alma Mater Studiorum, Dipartimento di Chimica “G: Ciamician”, Università di Bologna, Via Selmi 2,
40126 Bologna, Italy
* Author to whom correspondence should be addressed; E-Mail: piergiorgio.cozzi@unibo.it;
Tel.: +39-051-209-9511; Fax: +39-051-209-9456.
Received: 26 May 2011; in revised form: 17 June 2011 / Accepted: 22 June 2011 /
Published: 23 June 2011
Abstract: In this report, we have presented the first diastereoselective addition of
phenylacetylene to chiral racemic chloroketones. The addition is controlled by the
reactivity of the chloroketones that allowed the stereoselective reaction to be performed at
–20 °C. Chiral racemic chloroketones are used in the reaction. By carefully controlling the
temperature and the reaction time we were able to isolate the corresponding products in
moderate yields and with good, simple and predictable facial stereoselection. Our reaction
is a rare example of the use of chiral ketones in an enantioselective alkynylation reaction
and opens new perspectives for the formation of chiral quaternary stereocenters.
Keywords: alkynylation; (R,R)-salen; chloroketones; Me2Zn; phenylacetylene
1. Introduction
The addition of carbon nucleophiles to reactive electrophilic functions, such as C=O and C=N
double bonds, is a process of fundamental importance in the development of chemical synthesis [1,2].
Among the various nucleophilic species available, alkynes are excellent reagents for mild and selective
C-C bond forming reactions [3-5]. In 2005, we found that mixtures of Me2Zn and acetylenes are able
to promote the room temperature alkynylation of aldehydes, ketones and imines to furnish propargylic
alcohols in good to excellent yields [6]. We have also developed an enantioselective addition of

Molecules 2011, 16
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phenylacetylene to ketones based on this concept [7]. Since our report, the enantioselective
alkynylation of ketones using R2Zn as deprotonating agent in the presence of chiral ligands has
been the subject of a number of interesting studies [8-13]. However, the diastereoselective and
enantioselective addition of acetylides has never been investigated in the case of ketones. Recently,
organocatalytic reactions have made possible the simple preparation of optically active α-chloro- or
α-bromoketones, useful starting materials for the preparation of densely functionalized building
blocks [14]. However, these useful starting material are difficult to isolate and the subsequent reaction
needs to be performed in situ. On the other hand, racemic α-haloketones are inexpensive and readily
accessible reagents. If the addition of a nucleophile to a racemic haloketone is realized in the presence
of a chiral catalyst in a stereoselective manner, highly densely functionalized building blocks
containing a quaternary stereocenter could be prepared (Scheme 1).
Scheme 1. Addition of a phenylacetylene to racemic chloroketones.
R1 OH
O
HO R1
Me2Zn
R
R
R
+
R1
2a
Ph
Cl
4 anti
Cl
Ph
Ph
Cl
1
3 syn
Herein, we report a successful realization of this concept using the Zn(Salen) promoted addition of
acetylene to racemic α-chloroketones.
2. Results and Discussion
During our studies in the addition of phenylacetylene promoted by Me2Zn performed in the absence
of air we found that α-chloroketones were particularly reactive substrates, and the reaction of 3-chloro-
2-butanone with phenylacetylene in the presence of Me2Zn furnished the corresponding alcohol
quantitatively, albeit as a mixture of diastereomers in 52:48 ratio (Scheme 1). In order to improve the
diastereoselection we have investigated the reaction in the presence of different ligands 5-9. We have
found that a good dr was obtained when the reaction was performed in the presence of the racemic
Salen ligand 8. On the other hand, other Schiff bases were also able to increase the dr of the reaction.
The possibility to use α-chloroketones as substrates for the addition of nucleophiles takes advantage of
their enhanced reactivity, and this opens new possibility for stereoselective addition of nucleophiles in
organic synthesis [15]. As the reactivity of the chloroketones, compared to other ketones, is remarkable
(even in the presence of the Salen ligands), we decided to investigate the reaction performing the
addition of phenylacetylene in the presence of enantiopure Salen ligands. We have disclosed the first
addition of phenylacetylene to ketones controlled by the Salen ligand [7], and other ligands able to
promote the addition of alkyne to ketones were introduced by other groups [8-13]. The addition of
phenylacetylene to silylketones promoted by Salen ligands was reported by Chan and Lu [16]. In all
these reports it is clearly shown that the reactivity of the ketones is quite different compared to
aldehydes and in all the systems reported, long reaction times and a high catalyst loading are required
for good stereoselection. The simple stereoselection of the reaction was assigned as anti by chemical
correlation with the diastereoisomeric epoxides 10 (Scheme 2).

Molecules 2011, 16
Table 1. Diastereoselective addition of phenylacetylene in the presence of ligands.
5300
O
Me OH
HO Me
+
Me2Zn,Ligand 20 mol%
Toluene
+
Ph
Cl
Ph
Cl
Ph
Cl
1a
2a
3aa syn
4aa anti
Entry a
ligand
syn%
anti%
1 b
--
48
52
2
23
77
OH
N
5
6
3
4
29
23
71
77
OH
N
Ph
Ph
Ph
N
N
7
Ph
N
N
OH
OH
5
22
78
+
_
8
Ph
Ph
N
6
29
6
71
94
N
+
_
9
7 c
--
a
All the reactions were performed at rt under nitrogen atmosphere Me2Zn (3 equiv.) and
phenylacetylene (3 equiv.) were added to toluene in a flask under strictly anhydrous conditions, and
stirred 10 min, then the ligand (20 mol%) was added and the reaction mixture and stirred for
5–10 min. Finally, the chloroketone (1 equiv.) was added. The reaction was stirred under
completion (monitored by TLC, 16–24 h) and quenched with water. The dr was determined on the
1
b
crude reaction mixture by H-NMR. The reaction was performed in the presence of Me2Zn
c
without ligands. The reaction was performed with lithium phenylacetylide, prepared by the
addition of 1 equiv. of n-BuLi to 1.1 equiv. of phenylacetylene at 0 °C.
The mixture of the diasteroisomers was transformed to the epoxides by treatment with tBuOK in
13
1
THF at –20 °C. The C- and H-NMR data of the mixture of isolated epoxides were compared with
literature data [17]. It is worth adding that the reaction of the lithium acetylide to the chloroketone
furnished the desired product with high stereoselectivity (Table 1, entry 7). The major diastereoisomer
derived by the attack of the alkyne to the chiral chloroketone can be rationalized by invoking the
Felkin-Anh model [18-22]. While the reaction with Me2Zn afforded the desired products with low

Molecules 2011, 16
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stereoselectivity (Table 1, entry 1), the the Zn(Salen) formed in situ controls the stereoselection
through the complexation of the chloroketone to the zinc Lewis acidic center. The simple anti
diastereoselection obtained in the case lithium phenylacetylene and with ligand mediated addition of
zinc phenylacetylide can be rationalized by a Felkin-Anh transition state in which the nucleophilic
alkyne attaches the carbonyl group in a conformation in which the chlorine is the larger group
(Scheme 2, Figure A).
Scheme 2. Assignment of the relative configuration of the diastereoisomers obtained by
addition of phenylacetylene to a racemic chloroketone.
Ph
HO Me
Cl
O
O
tBuOK
Me
minor diasteroisomer
Me
Me
Me
Me
10
Ph
Ph
3aa
syn
Ph
HO Me
Me
tBuOK
major diastereoisomer
11
Cl
anti
4aa
Nu:
H
Me
A
Me
O
Cl
The preliminary results obtained with 1a gave us the indication that the reactivity of the
chloroketone was very high, and that it was possible to reduce the temperature for the stereoselective
reaction. It is noteworthy that the Salen catalyzed addition of phenylacetylene to ketone is performed
at rt and no addition occurs with aliphatic or aromatic ketones at lower temperatures (0 °C or below).
The increased reactivity of chloroketone thus allowed the investigation of the reaction at reduced
temperature. Using commercially available racemic 3-chlorobutanone (1a) as a model substrate, we
have performed the reaction at low temperature, in the presence of the (R,R)-Salen 8 and in Table 2 we
report the results of this investigation. The reaction is stereoselective and the corresponding adducts
can be isolated in high enantiomeric and good diastereoisomeric excesses, albeit in low to moderate
yield. The enantiomeric excess obtained in the reaction is a function of the conversion. In fact, in order
to keep the stereoselection very high it is important to stop the reaction after 60 hours at –20 °C; if the
reaction is conducted at 0 °C, the adduct is isolated with a dr of 4:1 in favor of the anti diastereoisomer
in good yield (60–70%) but in very low ee. If the reaction is not stopped at –20 °C after 60 h, the
conversion is increased and the yield can be higher than 50%, but the facial stereoselection of the
isolated diastereoisomers was quite low. Performing the reaction at increased temperature (>0 °C) the
syn and anti stereoisomers are again isolated with good yield but in very low enantiomeric excess. This
is straightforwardly explained by considering the reactivity of the chloroketone and the background
reaction. At room temperature the Me2Zn promoted addition of phenylacetylene to ketone is occurring
without the catalysis of the Zn(Salen) complexes [6]. The conversion and the isolated yield of the
products can be improved at the expense of the enantiomeric excess. In order to increase the reaction

Molecules 2011, 16
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rate of the reaction the excess of Me2Zn, and phenylacetylene was adjusted, and a compromise
between reactivity and stereoselectivity was finally obtained. Similar reaction with aliphatic or
aromatic ketones do not give any traces of product if they are conducted at −20 °C, even in the
presence of the Salen ligand. The best conditions in the optimization were found when 4.5 equivalent
of Me2Zn and 30 mol % of Salen were employed in the reaction. The Salen and the Me2Zn were mixed
at rt for 1 hour before being to add the chloroketone at low temperature. The quantity of solvent was
also important in order to enhance the enantiomeric excess. The reaction was performed without
stirring, at −20 °C for 60 hours.
Table 2. Stereoselective addition of phenylacetylene to 3-chlorobutanone promoted by
(R,R)-Salen ligand.
O
Me2Zn, x equiv.
Me OH
HO Me
8
,
(R,R)-Salen y mol%
+
+
Ph
2a
3 equiv.
toluene, -20 °C, time
Cl
Cl
Ph
anti
Ph
Cl
1 equiv.
1a
3aa syn
4aa
Me2Zn
Salen
solvent
Entry a
dr b T (h) ee anti c ee syn c Yield d
(x equiv.) (y mol %) (mL)
1
2
3
4
5
3
5
6
4.5
4.5
20
20
20
30
10
1
1
1
1.5
1
78:22
77:23
76:24
82:18
83:17
72
72
60
60
60
70
79
50
90
50
40
45
50
82
67
25
45
53
25
69
a
All the reactions were performed at −20 °C under nitrogen and stopped after the time indicated.
The diastereoisomeric ratio was evaluated on the crude reaction mixture by H-NMR. The
b
1
c
enantiomeric excess was evaluated by chiral HPLC analysis (see experimental part for the
conditions) d Isolated yield (syn + anti) after chromatographic purification.
Delighted by the results obtained with 3-chlorobutanone, we decided to investigate the generality of
our reaction, studying other different chloroketones. The substrates were prepared using a methodology
developed by De Kimpe [23], illustrated in Scheme 3.
Scheme 3. Preparation of chloroketones.
O
O
O
O
NaOH, Bu4NHSO4
CHCl3, RX
O
O
R
O
O
O
O
SO2Cl2
O
O
R
O
Cl
R
R
O
O
H2SO4, H2O
reflux, 4 h
O
R
Cl
Cl
1b
, R = CH2Ph
1c
, R = CH2CH2CH(CH3)2
1d, R = CH2(CH2)4CH3
1e
, R = CH2CH3
1f
, R = CH2(CH2)2CH3

Molecules 2011, 16
5303
The corresponding ketones were prepared without difficulties in large scale, and were purified by
distillation. The ketones 1b-f was used in the reaction with phenylacetylene promoted by Me2Zn, by
using the conditions optimized for the substrate 1a and the results are reported in Table 3.
Table 3. Stereoselective addition of phenylacetylene to a series of α-chloroketones
promoted by (R,R)-Salen ligand.
Me2Zn, 4.5 equiv.
8 (R,R)-Salen, 30 mol%
O
Me OH
HO Me
R
R
R
Ph
+
+
toluene, -20 °C, time
2a
Cl
Ph
4ba-4fa
Cl
Ph
Cl
1 equiv.
3ba-3fa
3 equiv.
1b, R = CH2Ph
1c, R = CH2CH2CH(CH3)2
1d, R = CH2(CH2)4CH3
1e, R = CH2CH3
1f, R = CH2(CH2)2CH3
Entry a Ketone dr b
T (h)
60
120
60
60
140
60
ee anti c
90
ee syn c
82
Yield d (syn + anti)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
82:18
73:27
77:23
78:22
75:25
80:20
26
35
25
18
40
17
85
81
82
62
65
58
55
42
83
57
a
All the reactions were performed at −20 °C under nitrogen and stopped after the time indicated.
The diastereoisomeric ratios were evaluated on the crude reaction mixture by H-NMR. The
b
1
c
enantiomeric excess was evaluated by chiral HPLC analysis (see experimental part for the
conditions) d Isolated yield (syn + anti) after chromatographic purification.
Generally, the yields of the reaction are quite moderate, because the reaction was stopped in order
to obtain the highest enantiomeric excesses for the isolated adducts. The steric hindrance of the
ketones does not seem significant in the controlling the enantiomeric excess. The reaction also works
in the case of other haloketones, e.g. α.-fluoroketones, Scheme 4 Although was possible to perform the
reaction with other haloketones, generally the results were inferior compared to the chloroketones.
Scheme 4. Stereoselective addition of phenylacetylene to the fluoroketone 1g.
O
Me OH
Bn
Me2Zn, 4.5 equiv.
8 (R,R)-Salen, 30 mol%
HO Me
Bn
+
Ph
+
Ph
toluene, -20 °C, time
F
4ga
F
3ga
Ph
Ph
F
1g
2a
3 equiv
anti
syn
1 equiv
time: 60 h
yield: 24%
dr 52:48
ee anti 56%; ee sy n 35%
Concerning the possibility of using different substituted acetylenes in our reactions, we have briefly
investigated the reaction employing alkyl and silyl substituted acetylenes under the general conditions
developed for 3-chlorobutanone, and the data obtained are reported in Table 4. As is possible to evince

Molecules 2011, 16
5304
by the data, the reactivity of the acetylenes 2b-d was quite lower compared to phenylacetylene, and
products were isolated in low yield and with minor levels of stereoselectivity.
Table 4. Stereoselective addition of substituted acetylenes to 3-chlorobutanone promoted
by (R,R)-Salen ligand.
O
Me OH
Me2Zn, 4.5 equiv.
HO Me
+
8
(R,R)-Salen, 30 mol%
+ R
3 equiv.
2b, R = CH2Br
toluene, -20 °C, 80 h
Cl
1a
Cl
R
R
Cl
1 equiv.
4ab-4ad
3ab-3ad
2c
, R = SiMe3
2d
, R = (CH2)3CH3
Entry a
Alkyne
dr b
ee anti c ee syn c Yield d (syn + anti)
1
2
3
HCCCH2Br, 2b
HCCSiMe3, 2c
HCC(CH2)3CH3, 2d 83:17
64:36
75:25
66
75
68
53
62
41
25
15
20
a
All the reactions were performed at −20 °C under nitrogen atmosphere, by adding Me2Zn
(4 equiv) to Salen (30 mol%) at rt. Then the alkyne was added and the mixture was cooled to
b
−25 °C. The ketone 1a was added and the reaction kept without stirring for 80 h at −20 °C. The
diastereoisomeric ratios (anti: syn) were evaluated on the crude reaction mixture by 1H-NMR. c The
enantiomeric excess was evaluated by chiral HPLC analysis (see experimental part for the
conditions) d Isolated yield (syn + anti) after chromatographic purification.
We have established the absolute configuration of the products as indicated in Scheme 5.
Enantiopure 4-phenyl-3-chloro-butan-2-one was prepared from the corresponding (S)-3-phenyl-2-
chloropropanal following the procedure published by De Kimpe [24].
Scheme 5. Assignment of absolute configuration of the syn and anti stereoisomers on the
basis of diastereoselective addition to the enantioenriched (S)-1b.
O
1) 1.6 equiv. NaNO2
6 M HCl, 0 °C, 4h
1) MeMgBr, 3 equiv,
Et2O, 0°C, 1h
COOH
CHO
Ph
12
Ph
Ph
2) 2 equiv. LiAlH4
Et2O, 15 min
2) 3 equiv. PCC
CH2Cl2, rt, 15 h
NH2
Cl
Cl
13
1b
(S) , 20% ee
3) 3 equiv. PCC
CH2Cl2, rt, 15 h
O
HO
Me
Me
OH
(R,R) + (S,S) Salen
+
+
Ph
Ph
Ph
Ph
Me2Zn, toluene
Cl
(S) 1b, 20% ee
Cl
Ph
3ba syn
2a
Cl
Ph
4ba anti
The (S)-chloroaldehyde 13 was obtained in moderate yield from the aminoacid 12, and used without
purification in the subsequent steps. (S)-chloroaldehyde 11 was treated with MeMgBr at 0 °C, to give
the corresponding secondary alcohol that was directly oxidized with PCC to the ketone 1b. HPLC
analysis performed on the chloroketone established that the (S)-chloroketone was obtained with poor

Molecules 2011, 16
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enantiomeric excess of 20%, due to the racemization. Optically active chloroaldehydes have been used
in the diastereoselective addition of organometallic reagents [25-29]. The addition of Grignard
reagents to chloroaldehyde was reported to give good yield and moderate diastereoisomeric excess
both in Et2O or in THF, and racemization of the aldehydes seems not to occur [30]. Perhaps, the
racemization of our substrate is occurring during the oxidation step. Nevertheless, the enantiomeric
excess obtained for the chloroketone 1b was sufficient to assign the absolute configuration of the
products obtained in the alkynylation reactions. The reaction with the chloroketone 1b was performed
in the presence of 20 mol% of a racemic mixture of (R,R) and (S,S)-Salen ligand (Scheme 5). AS in the
case of the ketone 1a, the diastereoisomeric ratio of products 3ba and 4ba obtained was 4:1 in favor of
the anti diastereoisomer. The configuration of the stereogenic centers for all the diastereoisomers was
assigned by comparison of the HPLC traces obtained for the racemic and for the (S)-chloroketone. The
absolute configuration of the major diastereoisomer obtained in the reaction with (R,R)-Salen and
racemic 1b was 3S,4R. The absolute configuration for all the products was assigned by analogy, taking
in consideration that for all the chloroketones the anti and syn products have similar HPLC retention
times. Is worth adding that the absolute configuration obtained in the case of the chloroketone is
opposite to that in the Salen mediated addition of phenylacetylene to aliphatic and aromatic ketones.
In the case of aliphatic and aromatic ketones the (R,R)-Salen is inducing the formation of a new
stereogenic tertiary alcohol of (S) configuration [31]. However, the reaction conditions for the
alkynylation reactions in the case of the chloroketones are completely different from those of the
alkynylations of aromatic and aliphatic ketones. In addition, the presence of the stereogenic center of
the chiral chloroketone can induce a preferential coordination of one enantiomer of the chloroketone
as depicted in the model of Figure 1. In order to study the possibility of kinetic resolution, two
enantiomeric chloroketones 1b were separated by chiral HPLC analysis. When the reaction was
performed using 2 or more equivalents of chloroketone 1b, the excess of chloroketone was isolated
after the reaction performed in the presence of (R,R)-Salen ligand and it was analyzed by chiral HPLC.
The ketone 1b was isolated with no traces of enantioenrichment. In addition, when the optically active
(S)-1b (20% ee) was treated with 2 equivalent of Me2Zn in toluene and the solution obtained was
stirred at rt for two days, after quenching no reaction of Me2Zn with the choroketones took place.
According to the HPLC analysis of the crude reaction mixture the (S) chloroketone undergoes no
racemization in the presence of Me2Zn, as the enantiomeric excess of the chloroketones was
unchanged. Therefore, the result obtained in the reaction of racemic chloroketones is not determined
by a racemization of the chloroketones and the selective reaction of one enantiomer. The observed
facial stereoselection could result from a preferential coordination of one enantiomer of the
chloroketone to the Zn(Salen) complex, with this preferential stereoisomer reacting at a faster rate. It is
worth adding that the analysis of the reaction is complicated by the fast background reaction, which
has hampered any attempt to prove that the reaction was taking place via a kinetic resolution with
preferential coordination of the (R) chloroketones. The fast background reaction is favored by excess
of ketones, an excess that is necessary to investigate the kinetic resolution. For example, when the
reaction was performed using 3 equiv of 1a in the presence 1 equiv of phenylacetylene and 1.4 equiv.
of Me2Zn, the corresponding adducts were isolated with 15% ee for the anti stereoisomer. Performing
careful analysis and selecting different reaction times and concentrations, we were not able to measure
any enrichment of the starting chloroketones 1b. However, further studies are still necessary in order to

Molecules 2011, 16
5306
explain and understand the results obtained in the stereoselective addition of phenylacetylene to
haloketones, and work is in progress towards this objective.
Figure 1. Stereoselective addition of phenylacetylene on the chloroketone.
R
Cl
H
Ph
O
Me
N
O
Zn
H
N
Zn
Me
O
3. Experimental
3.1. General
1H-NMR spectra were recorded on Varian Gemini 200 and Varian Mercury 400 spectrometers.
Chemical shifts are reported in ppm from TMS with the solvent resonance as the internal standard
(deuterochloroform: δ = 7.27 ppm). Data are reported as follows: chemical shift, multiplicity
(s = singlet, d = duplet, t = triplet, q = quartet, bs = broad singlet, m = multiplet), coupling constants
13
(Hz). C-NMR spectra were recorded on Varian Gemini 200 and Varian Mercury 400 spectrometers.
Chemical shifts are reported in ppm from TMS with the solvent as the internal standard
(deuterochloroform: δ = 77.0 ppm). GC-MS spectra were taken by EI ionization at 70 eV on a
Hewlett-Packard 5971 with GC injection. They are reported as: m/z (rel. intense). LC-electrospray
ionization mass spectra were obtained with Agilent Technologies MSD1100 single-quadrupole mass
spectrometer. Chromatographic purification was done with 240–400 mesh silica gel. Determination of
enantiomeric excesses were performed on an Agilent Technologies 1200 instrument equipped with a
variable wave-length UV detector, using Daicel Chiralpak columns (0.46 cm I.D. × 25 cm) and HPLC
grade isopropanol and n-hexane were used as the eluting solvents. Melting points were determined
with a Bibby Stuart Scientific SMP 3 Melting Point Apparatus and are not corrected. All reactions
were carried out under inert gas and anhydrous conditions. Anhydrous solvents were supplied by
Aldrich in Sureseal® bottles and used avoiding purification. Me2Zn 2M in toluene was supplied in
Aldrich Sureseal® bottles and used as received. (R,R)-Salen is commercially available from Aldrich.
Phenyacetylene was purchased by Aldrich and used as received. 3-Chlorobutanone is commercially
available and was used after distillation. The chloroketones 1b-1f were prepared according to the
literature procedure described by De Kimpe [23], and were obtained in 16–20% yield (three reactions).
The fluoroketone 1g was obtained as reported in literature [32].

Molecules 2011, 16
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1
3-Chloro-4-phenylbutan-2-one (1b). C10H11ClO MW = 182.65. H-NMR (CDCl3, 300 MHz) δ: 2.35
(s, 3H); 3.11 (dd, 1H, J = 8.1, 14.4 Hz); 3.37 (dd, 1H, J = 6.3, 14.4 Hz); 4.44 (dd, 1H, J = 6.3, 8.1 Hz).
7.4–7.2 (m, 5H). 13C-NMR (CDCl3, 75 MHz) δ: 26.8; 39.8; 63.8; 127.2; 128.2; 128.6; 129.3.
O
Cl
1
3-Chloro-6-methyleptan-2-one (1c). C8H15ClO MW = 162.08. H-NMR (CDCl3, 300 MHz) δ: 0.92
(d, 3H, J = 6.6 Hz); 0.97 (d, 3H, J = 6.6 Hz); 1.8–1.71 (m, 5H); 2.32 (s, 3H); 4.22 (dd, 1H, J = 6.0,
9.0 Hz). 13C-NMR (CDCl3, 75 MHz) δ: 21.2; 22.7, 25.0, 25.6; 62.7, 203.5.
O
Cl
1
3-Chlorononan-2-one (1d). C9H17ClO MW = 148.63. H-NMR (CDCl3, 300 MHz) δ: 0.88 (m, 3H);
13
2.0–1.20 (m, 10H); 2.31, (s, 3H); 4.17 (dd, 1H, J = 5.4, 8.1 Hz). C-NMR (CDCl3, 75 MHz) δ: 13.9;
22.4; 25.8; 25.9; 28.5; 28.9; 31.4; 33.7; 64.3; 203.4.
O
Cl
1
3-Chloropentan-2-one (1e). C5H9ClO MW = 120.58. H-NMR (CDCl3, 300 MHz) δ: 1.02 (t, 3H,
J = 7.8 Hz); 2.1–1.8 (m, 2H); 2.31 (s, 3H); 4.12 (dd, 1H, J = 5.4, 7.8 Hz). 13C-NMR (CDCl3, 75 MHz)
δ: 10.5; 25.9; 27.2; 65.7; 203.3.
O
Cl
1
3-Chloroheptan-2-one (1f). C7H13ClO MW = 148.63. H-NMR (CDCl3, 300 MHz) δ: 0.92 (t, 3H,
J = 6.6 Hz); 1.40–1.31 (m, 4H); 2.0–1.80 (m, 2H); 2.31 (s, 3H); 4.16 (dd, 1H, J = 5.7, 8.1 Hz).
13C-NMR (CDCl3, 75 MHz) δ: 13.8; 22.0; 25.8; 28.1; 33.5; 64.3; 203.5.
O
Cl
3.2. Addition of Alkynes to Chloroketones
General procedure: In a flask under nitrogen containing a solution of (R,R)Salen (0.075 mg,
0.135 mmol) in toluene (1 mL), a 2 M solution of Me2Zn is added under stirring (1 mL, 2.025 mmol).
The mixture is stirred 10 min at rt, then phenylacetylene (0.15 mL, 1.35 mmol) was added. The
mixture was stirred 1 h at rt, then the solution was cooled to –25 °C. Chloroketone (0.45 mmol) was

Molecules 2011, 16
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added, and the mixture was kept at –20 °C without stirring for 60 h. The reaction was quenched with
water at –20 °C, then the reaction was diluted with Et2O. The organic phase (yellow) was separated
and the aqueous phase was extracted with Et2O. The organic phases were reunited, evaporated under
reduce pressure and purified by chromatography.
1
4-Chloro-3-methyl-1-phenylpent-1-yn-3-ol (3aa/4aa). C12H13ClO MW= 208.68. H-NMR (CDCl3,
200 MHz) δ: 1.67 (maj, s, 3H); 1.68 (min, s, 3H); 1.72 (d, 3H, J = 6.6 Hz); 1.61 (min, brs, 1H); 2.86
(maj, brs, 1H); 4.16 (maj, q, 1H, J = 6.6 Hz); 4.23 (min, q, 1H, J = 7.0 Hz); 7.35–7.30 (m, 3H);
7.50–7.46 (m, 2H). 13C-NMR (CDCl3, 50 MHz) δ: 20.0 (min); 20.7 (maj); 25.5 (min); 26.7 (maj); 65.2
(min); 68.8 (maj); 71.3 (min); 71.6 (maj); 84.8 (min); 85.1 (maj); 88.7 (maj); 89.7 (min); 122.2; 128.2;
128.6; 131.7. The ee was determined by HPLC analysis (Daicel Chiralcel OD column: hexane/i-PrOH
98.5:1.5, flow rate 0.50 mL/min, 27 °C, λ = 214, 250 nm: anti diasteroisomer (4aa) τmajor = 23.13 min,
τminor = 41.21 min; syn diasteroisomer (3aa) τmajor = 28.58 min., τminor = 45.83 min. anti:syn 82:18. ee
anti 85%. ee syn 65%. GCMS: 15.07 (maj); 15.16 (min). HMRS calcd for C12H13ClO: 208.0655; found
208.0659.
HO
Cl
2,3-Dimethyl-2-phenylethynyloxirane (10/11). C12H13ClO MW = 172.22. 1H-NMR (CDCl3, 200 MHz)
δ: 1.38 (maj, d, 3H, J = 5.6 Hz); 1.52 (min, d, 3H, J = 5.2 Hz); 1.61 (maj, s, 3H); 1.65 (min, s, 3H);
3.08 (min, q, J = 5.2 Hz); 3.39 (maj, q, 1H, J = 5.4 Hz); 7.35–7.30 (m, 3H); 7.50–7.46 (m, 2H).
13C-NMR (CDCl3, 50 MHz) δ: 13.7 (maj); 15.6 (min); 18.3 (maj); 23.3 (min); 51.2 (maj); 53.2 (min);
60.9 (maj); 61.4 (min); 81.6; 89.9; 122.2; 128.2; 128.5; 131.8.
O
4-Chloro-3-methyl-1,5-diphenylpent-1-yn-3-ol (3ba/4ba). C18H17ClO MW = 284.78. 1H-NMR
(CDCl3, 300 MHz) δ: 1.68 (s, 3H); 2.85 (min, dd, 1H, J = 11.1, 14.4 Hz); 2.99 (maj, dd, 1H, J = 10.8,
14.4 Hz); 3.55-3.41 (m, 1H); 4.09 (min, dd, 1H, J = 2.4, 11.1 Hz); 4.19 (maj, dd, 1H, J = 2.7, 10.8 Hz);
7.60–7.20 (m, 10H). 13C-NMR (CDCl3, 75 MHz) δ: 26.2 (maj); 26.8 (min); 27.3; 39.8 (min); 40.1
(maj); 71.2 (min); 71.3 (maj); 71.4 (min); 72.7 (maj); 85.5 (min); 85.6 (maj); 89.1 (maj); 89.4 (min);
122.1; 126.8; 128.3; 128.4; 128.7; 129.3; 131.8; 137.9 (maj); 138.0 (min). The ee was determined by
HPLC analysis Daicel Chiralcel OD column: hexane/i-PrOH 97.5:2.5, flow rate 0.50 mL/min, 27 °C,
λ = 214, 250 nm: anti diasteroisomer (4ba) τmajor = 21.97 min, τminor = 30.96 min; syn diasteroisomer
(3ba) τmajor = 23.48 min., τminor = 32.14 min. anti:syn 73:27. ee anti 85%. ee syn 65%. HMRS calcd for
C18H17ClO: 284.0978; found 284.0982. Daicel Chiralcel ODH column: hexane/i-PrOH 97.5:2.5, flow

Molecules 2011, 16
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rate 0.50 mL/min, 27 °C, λ = 214, 250 nm: anti diasteroisomer τmajor = 31.79 min, τminor = 43.47 min;
syn diasteroisomer τmajor = 35.61 min, τminor = 50.09 min.
HO
Cl
1
4-Chloro-3,7-dimethyl-1-phenyloct-1-yn-3-ol (3ca/4ca). C15H19ClO MW = 264.13. H-NMR (CDCl3,
300 MHz) δ: 0.88 (d, 3H, J = 6.6 Hz); 0.93 (d, 3H, J = 6.6 Hz); 1.59 (min, s, 3H); 1.6 (maj, s, 3H);
2.0–1.40 (m, 5H); 2.43 (min, brs, 1H); 2.8 (maj, brs, 1H); 3.95 (maj, dd, 1H, J = 2.1, 11.4 Hz); 4.06
13
(min, dd, 1H, J = 4.8, 7.5 Hz); 7.30–7.20 (m, 3H); 7.41–7.35 (m, 2H). C-NMR (CDCl3, 75 MHz)
δ: 20.6; 23.6 (maj); 25.3 (maj); 25.6 (min); 27.0 (min); 41.9 (maj); 42.4 (min); 69.2 (maj); 70.8 (maj);
71.3 (min); 71.4 (min); 85.3 (maj); 86.1 (min); 89.3 (min); 89.9 (maj); 122.2; 128.2; 128.6; 131.8. The
ee was determined by HPLC analysis Daicel Chiralcel OD column: hexane/i-PrOH 99:1, flow rate
0.50 mL/min, 27 °C, λ = 214, 250 nm: anti diasteroisomer (4ca) τmajor = 17.58 min, τminor = 47.78 min;
syn diasteroisomer (3ca) τmajor = 21.29 min, τminor = 50.02 min. anti:syn 77:23. ee anti 81%. ee syn
58%. HMRS calcd for C15H19ClO: 264.1281; found 264.1290.
HO
Cl
4-Chloro-3-methyl-1-phenyldec-1-yn-3-ol (3da/4da). C17H23ClO MW = 278.82. 1H-NMR (CDCl3, 300
MHz) δ: 0.82 (t, 3H, J = 7.2 Hz); 1.4–1.20 (m, 8H); 1.60 (s, 3H); 2.20–2.0 (m, 2H); 2.42 (maj, brs,
1H); 2.8 (min, brs, 1H); 3.88 (min, dd, 1H, J = 2.1, 11.1 Hz); 3.98 (maj, dd, 1H, J = 2.4, 10.8 Hz);
13
7.30–7.20 (m, 3H); 7.41–7.35 (m, 2H). C-NMR (CDCl3, 75 MHz) δ: 14.0 (maj); 15.2 (min); 22.5;
25.7; 27.0; 28.6; 31.6; 30.6 (maj); 33.5 (min); 71.2 (maj); 71.3 (min); 84.6 (maj); 84.8 (min); 89.3
(min); 89.9 (maj); 122.2; 128.2; 128.6; 131.7. The ee was determined by HPLC analysis Daicel
Chiralcel OD column: hexane/i-PrOH 99.5:0.5, flow rate 0.50 mL/min, 27 °C, λ = 214, 250 nm: anti
diasteroisomer (4da) τmajor = 23.20 min, τminor = 65.06 min; syn diasteroisomer (3da) τmajor = 30.40
min, τminor = 75.63 min. anti:syn 78:22. ee anti 82%. ee syn 55%. HMRS calcd for C17H23ClO:
278.1437; found 278.1441.
HO
Cl
1
4-Chloro-3-methyl-1-phenylhex-1-yn-3-ol (3ea/4ea). C13H15ClO MW = 222.71. H-NMR (CDCl3,
300 MHz) δ: 1.16 (min, t, 3H, J = 6.9 Hz); 1.51 (min, t, 2H, J = 6.9 Hz); 1.59 (min, s, 3H); 1.68 (maj,

Molecules 2011, 16
5310
s, 3H); 2.26–2.08 (m, 2H); 3.88 (min, dd, 1H, J = 2.1, 11.1 Hz); 3.97 (maj, dd, 1H, J = 2.1, 11.4 Hz);
13
7.35–7.22 (m, 3H); 7.45–7.30 (m, 2H). C-NMR (CDCl3, 75 MHz) δ: 12.0; 25.8 (maj); 26.4 (maj);
26.9 (min); 27.0 (min); 71.3 (min); 73.1; 74.3 (maj); 84.9; 89.3 (min); 89.8 (maj); 122.2; 128.2; 128.5;
131.7. GC: 16.40 (min); 16.52 (maj). The ee was determined by HPLC analysis Daicel Chiralcel OD
column: hexane/i-PrOH 98:2, flow rate 0.50 mL/min, 27 °C, λ = 214, 250 nm: anti diasteroisomer
(4ea) τmajor = 25.53 min, τminor = 51.00 min; syn diasteroisomer (3ea) τmajor = 34.73 min, τminor = 62.74 min.
anti:syn 75:25. ee anti 62%. ee syn 42%. GCMS: 15.07 (maj); 15.16 (min). HMRS calcd for
C13H15ClO: 208.0811; found 208.0815.
HO
Cl
1
4-Chloro-3-methyl-1-phenyloct-1-yn-3-ol (3fa/4fa). C15H19ClO MW = 250.76. H-NMR (CDCl3,
300 MHz) δ: 0.98 (t, 3H, J = 7.2 Hz); 2.0–1.20 (m, 6H); 1.70 (s, 3H); 2.50 (min, brs, 1H); 2.87 (maj,
brs, 1H); 3.85 (maj, dd, 1H, J = 2.4, 11.1 Hz); 3.98 (min, m, 1H); 7.35–7.22 (m, 3H); 7.45–7.30
(m, 2H).13C-NMR (CDCl3, 75 MHz) δ: 13.9; 22.0; 25.7 (min); 27.0 (maj); 29.2; 32.7 (min); 33.3
(maj); 71.1 (min); 72.7 (maj); 85.0; 89.3 (maj); 89.6 (min); 122.3; 128.3; 128.5; 131.7. GC: 18.9 (maj);
19.0 (min). The ee was determined by HPLC analysis Daicel Chiralcel OD column: hexane/i-PrOH
98:2, flow rate 0.50 mL/min, 27 °C, λ = 214, 250 nm: anti diasteroisomer (4fa) τmajor = 15.77 min,
τminor = 26.90 min; syn diasteroisomer (3fa) τmajor = 18.16 min, τminor = 28.48 min. anti:syn 80:20. ee
anti 83%. ee syn 57%. GCMS: 15.07 (maj); 15.16 (min). HMRS calcd for C13H15ClO: 208.0811; found
208.0815.
HO
Cl
1
2-Fluoro-3-methyl-1,5-diphenylpent-4-yn-3-ol (3ga/4ga). C18H17FO MW = 268.33. H-NMR (CDCl3,
300 MHz) δ: 1.62 (d, 3H, J = 9.0 Hz); 3.25–2.96 (m, 2H); 4.67–4.45 (m, 1H); 7.28–7.20 (m, 8H);
7.45–7.38 (m, 2H); 13C-NMR (CDCl3, 75 MHz) δ: 25.9 (d, J = 123 Hz); 36.7 (min, d, J = 85 Hz); 36.9
(maj, d, J = 85 Hz); 70.2 (maj, d, J = 83 Hz); 70.0 (min, d, J = 83 Hz); 97.9 (min, J = 725 Hz); 98.5
(maj, d, J = 725 Hz): 122.0; 128.2; 128.5; 128.7; 129.2; 131.7; 137.34; The ee was determined by
HPLC analysis Daicel Chiralcel OD column: hexane/i-PrOH 97:3, flow rate 0.50 mL/min, 27 °C,
λ = 214, 250 nm: anti diasteroisomer (4ga) τmajor = 30.23 min, τminor = 39.07 min; syn diasteroisomer
(3ga) τmajor = 33.45 min, τminor = 40.72 min. anti:syn 52:48. ee anti 56%. ee syn 35%. HMRS calcd for
C18H17FO: 268.1273; found 268.1268.
HO
F

Molecules 2011, 16
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1
6-Bromo-2-chloro-3-methyl-1-phenylhex-4-yn-3-ol (3ab/4ab). C13H14BrClO MW= 301.61. H-NMR
(CDCl3, 300 MHz) δ: 1.59 (min, s, 3H); 1.69 (maj, s, 3H); 2.6 (brs, 1H); 3.60–2.75 (m, 1H); 3.55–3.44
(m, 1H); 4.01 (s, 2H); 4.13 (t, 1H, J = 11.1 Hz); 7.40–7.20 (m, 5H).13C-NMR (CDCl3, 75 MHz)
δ: 13.7; 25.9 (maj); 27.0 (min); 36.6 (maj); 37.0 (min); 71.0 (maj); 71.1 (min); 72.4; 80.8 (maj); 80.5
(min); 86.8 (min); 87.0 (maj); 126.8; 128.5; 129.3; 137.7 (min); 137.8 (maj). The ee was determined
by HPLC analysis Daicel Chiralcel OD column: hexane/i-PrOH 98:2, flow rate 0.60 mL/min, 27 °C,
λ = 214, 250 nm: anti diasteroisomer (4ab) τmajor = 38.36 min, τminor = 56.42 min; syn diasteroisomer
(3ab) τmajor = 44.62 min, τminor = 65.56 min. anti:syn 64:36. ee anti 66%. ee syn 53%. HMRS calcd for
C13H14BrClO: 299.9917; found 299.9923.
Br
HO
Cl
4-Chloro-3-methyl-5-phenyl-1-(trimethylsilyl)pent-1-yn-3-ol (3ac/4ac). C15H21ClOSi MW = 280.87.
1H-NMR (CDCl3, 300 MHz) δ: 0.24 (s, 9H); 1.68 (s, 3H); 3.01 (dd, 1H, J = 10.8, 14.1 Hz); 3.52 (d,
1H, J = 14.1 Hz); 4.08 (maj, 1H, dd, J = 2.4, 10.8 Hz); 4.18 (min, m, 1H); 7.40–7.20 (m, 5H).
13C-NMR (CDCl3, 75 MHz) δ: −0.38 (min); −0.18 (maj); 27.4, 40.1; 70.9 (maj); 71.4 (min); 72.4;
90.5; 105.5; 126.8; 128.4; 129.3; 138.0. The ee was determined by HPLC analysis Daicel Chiralcel
OD column: hexane/i-PrOH 99.6:0.4, flow rate 0.50 mL/min, 27 °C, λ = 214, 250 nm: anti
diasteroisomer (4ac) τmajor = 28.53 min, τminor = 27.34 min; syn diasteroisomer (3ac) τmajor = 34.77 min,
τminor = 38.21 min. anti:syn 75:25. ee anti 75%. ee syn 62%. HMRS calcd for C15H21ClOSi: 280.1050;
found 280.1054.
Si
HO
Cl
1
2-Chloro-3-methyl-1-phenylnon-4-yn-3-ol (3ad/4ad). C16H21ClO MW = 301.61. H-NMR (CDCl3,
300 MHz) δ: 0.94 (t, 3H, J = 7.2 Hz); 1.60–1.40 (m, 4H); 1.63 (min, s, 3H); 1.65 (maj, s, 3H); 2.28
(t, 2H, J = 6.9 Hz); 2.43 (min, brs, 1H); 2.60 (maj, brs, 1H); 2.85 (min, dd, 1H, J = 11.1, 14.4 Hz); 2.98
(maj, dd, J = 10.8, 14.7 Hz); 3.56–3.46 (m, 1H); 4.07 (maj, dd, 1H, J = 2.7, 11.1 Hz); 4.12 (min, dd,
J = 2.4, 10.8 Hz); 7.40–7.20(m, 5H). 13C-NMR (CDCl3, 75 MHz) δ: 13.5; 18.3; 21.9; 26.2 (min); 26.9
(maj); 30.6; 39.9 (min); 40.1 (maj); 70.8 (maj); 71.0 (min); 80.4 (maj); 80.7 (min); 126.7; 128.4;
129.2; 138.2. The ee was determined by HPLC analysis Daicel Chiralcel OD column: hexane/i-PrOH
99.6:0.4, flow rate 0.50 mL/min, 27 °C, λ = 214, 250 nm: anti diasteroisomer (4ad) τmajor = 45.71 min,
τminor = 49.73 min; syn diasteroisomer (3ad) τmajor = 59.01 min, τminor = 75.52 min. anti:syn 83:17. ee
anti 68%. ee syn 41%. HMRS calcd for C13H14BrClO: 299.9917; found 299.9923.
HO
Cl

Molecules 2011, 16
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4. Conclusions
In conclusion, we have presented the first diastereoselective and enantioselective addition of
phenylacetylene to chiral racemic chloroketones. The reaction provides access to highly functionalized
products and the adducts were obtained in low yield and good stereoselection. The reactivity of
chloroketones in the presence of chiral zinc catalyst can be explored with other zinc reagents taking
advantage of the enhanced reactivity. Formation of quaternary and tertiary stereogenic centers from
racemic chloroketones will be the subject of other studies from our laboratory.
Acknowledgments
PRIN (Progetto Nazionale Stereoselezioni in Chimica Organica: Metodologie ed Applicazioni),
Bologna University, Fondazione Del Monte, and the European Commission through the project
FP7-201431 (CATAFLU.OR) are acknowledged for financial support.
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