Enantio and diastereoselective addition of phenylacetylene to racemic α-chloroketones.
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.
Molecules 2011, 16, 5298-5314; doi:10.3390/molecules16065298
Enantio and Diastereoselective Addition of Phenylacetylene to
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: firstname.lastname@example.org;
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
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 . We have also developed an enantioselective addition of
Molecules 2011, 16
phenylacetylene to ketones based on this concept . 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 . 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.
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 . 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 , 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 . 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.
7 c -- 6 94
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
crude reaction mixture by 1H-NMR. b The reaction was performed in the presence of Me2Zn
without ligands. c 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
THF at –20 °C. The 13C- and 1H-NMR data of the mixture of isolated epoxides were compared with
literature data . 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
Me2Zn,Ligand 20 mol%
Molecules 2011, 16
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.
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 . 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
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
(y mol %)
dr b T (h) ee anti c ee syn c Yield d
a All the reactions were performed at −20 °C under nitrogen and stopped after the time indicated.
b The diastereoisomeric ratio was 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.
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 , illustrated in Scheme 3.
Scheme 3. Preparation of chloroketones.
Me2Zn, x equiv.
8 (R,R)-Salen, y mol%
toluene, -20 °C, time
reflux, 4 h
1b, R = CH2Ph
1c, R = CH2CH2CH(CH3)2
1d, R = CH2(CH2)4CH3
1e, R = CH2CH3
1f, R = CH2(CH2)2CH3