Mandelamide-zinc-catalyzed enantioselective alkyne addition to heteroaromatic aldehydes

Article abstract of DOI:10.1021/jo0610255

The (S,S)-mandelamide III catalyzes the additions of both aryl- and alkylalkynylzinc reagents to heteroaromatic aldehydes with good yields and enantioselectivities up to 92%. This catalyst is easily prepared in a one-step procedure, and both enantiomers a

Full text of DOI:10.1021/jo0610255

(OiPr)4 generates a highly enantioselective catalyst which
catalyzes the addition of alkynylzinc, produced in situ from the
reaction of phenylacetylene and dimethylzinc, to aromatic
aldehydes. Pu and co-workers developed a more convenient
procedure, using the BINOL/Ti(OiPr)4/Et2Zn combination, to
produce highly optically active secondary propargylic alcohols,
in which aliphatic and aromatic aldehydes are both suitable
substrates.4 Wang and co-workers recently found that complexes
of sulfonamide alcohols and Ti(OiPr)4 also catalyze the highly
enantioselective addition of phenylacetylene to both alkyl and
aromatic aldehydes.5 Other chiral ligands, including Cinchona
alkaloids,6 terpene- and carbohydrate-derived amino alcohols,7
ferrocenyl oxazoline alcohols,8 paracyclophane-based imine
phenols,9 oxazolidines,10 N-substituted proline,11 and â-hydroxy
amides,12 have also been reported to catalyze this asymmetric
addition reaction. Very recent developments have been re-
ported: Shibasaki and co-workers13 have described a catalytic
asymmetric alkynylation of aldehydes promoted by the In(III)/
BINOL complex and Cy2NMe, based in a dual activation of
both substrates due to the “bifunctional character” of In(III),
and Trost and co-workers14 have reported a practical alkynyl-
ation of aromatic and R,â-unsaturated aldehydes using their
proline-derived dinuclear zinc catalyst system, with high
reactivity and enantioselectivity.
Mandelamide-Zinc-Catalyzed Enantioselective
Alkyne Addition to Heteroaromatic Aldehydes#
Gonzalo Blay, Isabel Ferna´ndez,
Al´ıcia Marco-Aleixandre, and Jose´ R. Pedro*
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica,
UniVersitat de Vale`ncia, Dr. Moliner, 50, E-46100-Burjassot
(Vale`ncia), Spain
jose.r.pedro@uV.es
ReceiVed May 19, 2006
The (S,S)-mandelamide III catalyzes the additions of both
aryl- and alkylalkynylzinc reagents to heteroaromatic alde-
hydes with good yields and enantioselectivities up to 92%.
This catalyst is easily prepared in a one-step procedure, and
both enantiomers are available. Unlike most other described
methods, using this catalyst does not require the addition of
Ti(OiPr)4.
Despite the significant results achieved in this area, efforts
to develop new types of efficient chiral catalysts for this
(2) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806-1807. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc.
2001, 123, 9687-9688. (c) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org.
Lett. 2002, 4, 2605-2606. (d) Boyall, D.; Lopez, F.; Sasaki, H.; Frantz, D.
E.; Carreira, E. M. Org. Lett. 2000, 2, 4233-4236. (e) El-Sayed, E.; Anand,
N. K. Carreira, E. M. Org. Lett. 2001, 3, 3017-3020.
(3) (a) Lu, G.; Li, X.; Chan, W. L.; Chan, A. S. C. Chem. Commun.
2002, 172-174. (b) Li, X.; Lu, G.; Kwok, W. H.; Chan, A. S. C. J. Am.
Chem. Soc. 2002, 124, 12636-12637.
The asymmetric addition of metalated terminal alkynes to
aldehydes is one of the most important methods for producing
chiral secondary propargylic alcohols because it forms a new
C-C bond with concomitant creation of a stereogenic center
in a single transformation. The resulting optically active
propargylic alcohols are versatile building blocks for the
synthesis of a wide range of natural products and pharmaceu-
ticals, and besides, its acetylene and hydroxyl functions can be
used to construct very diverse molecular structures. Among
many organometallic nucleophiles, organozinc reagents tolerate
the presence of many functional groups that are reactive toward
organolithium and Grignard reagents. This property renders the
organozinc species attractive useful alternatives to these highly
active reagents.1
In their pioneering work, Carreira and co-workers discovered
that zinc acetylides, generated in situ from the reaction of
terminal alkynes and Zn(OTf)2 in the presence of triethylamine,
could enantioselectively add to aliphatic aldehydes when
promoted by the chiral ligand N-methylephedrine, and a high
enantiomeric excess up to 99% was achieved.2 However,
aromatic aldehydes cannot be used in this catalytic system due
to Cannizzaro reaction.2b Chan and co-workers3 have disclosed
that a combination of chiral BINOL and sulfonamide with Ti-
(4) (a) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855-1857. (b) Gao, G.;
Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002, 4, 4143-4146. (c) Xu, M.-
H; Pu, L. Org. Lett. 2002, 4, 4555-4557. (d) Moore, D.; Huang, W.-S.;
Xu, M.-H.; Pu, L. Tetrahedron Lett. 2002, 43, 8831-8834. (e) Li, Z.-B.;
Pu, L. Org. Lett. 2004, 6, 1065-1068. (f) Gao, G.; Xie, R.-G.; Pu, L. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5417-5420. (g) Gao, G.; Wang, Q.;
Yu, X.-Q.; Xie, R.-G.; Pu, L. Angew. Chem., Int. Ed. 2006, 45, 122-125.
(5) (a) Xu, Z.; Wang, R.; Xu, J.; Da, C.-S.; Yan, W.-J.; Chen, C. Angew.
Chem., Int. Ed. 2003, 2, 5747-5749. (b) Xu, Z.; Chen, C.; Xu, J.; Miao,
M.; Yan, W.; Wang, R. Org. Lett. 2004, 6, 1193-1195. (c) Ni, M.; Wang,
R.; Han, Z.; Mao, B.; Da, C.-S.; Liu, L.; Chen, C. AdV. Synth. Catal. 2005,
37, 1659-1665. (d) Xu, Z.; Lin, L.; Xu, J.; Yan, W.; Wang, R. AdV. Synth.
Catal. 2006, 348, 506-514.
(6) Kamble, M. J.; Singh, V. K. Tetrahedron Lett. 2003, 44, 5347-
5349.
(7) (a) Watts, C. C.; Thoniyot, P.; Hirayama, L. C.; Romano, T.;
Singaram, B. Tetrahedron: Asymmetry 2005, 16, 1829-1835. (b) Ya-
mashita, M.; Yamadam, K.; Omioka, K. AdV. Synth. Catal. 2005, 347,
1649-1652. (c) Emmerson, D. P. G.; Hems, W. P.; Davis, B. J. Org. Lett.
2006, 8, 207-210.
(8) Li, M.; Zhu, X.-Z.; Yuan, K.; Cao, B.-X.; Hou, X.-L. Tetrahedron:
Asymmetry 2004, 15, 219-222.
(9) Dahmen, S. Org. Lett. 2004, 6, 2113-2116.
(10) (a) Braga, A. L.; Appelt, H. R.; Silveria, C. C.; Wessjohann, L. A.;
Schneider, P. H. Tetrahedron 2002, 58, 10413-10416. (b) Kang, Y.; Wang,
R.; Liu, L.; Da, C.; Yan, W.; Xu, Z. Tetrahedron Lett. 2005, 46, 863-865.
(11) Han, Z.; Wang, R.; Zhou, Y.; Liu, L. Eur. J. Org. Chem. 2005,
934-938.
(12) Fang, T.; Du, D.-M.; Lu, S.-F.; Xu, J. Org. Lett. 2005, 7, 2081-
2084.
(13) (a) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohsima, T.; Shibasaki, M. Org.
Lett. 2005, 7, 1363-1366. (b) Takita, R.; Yakura, K.; Ohsima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2005, 127, 13760-13761.
* To whom correspondence should be addressed. Tel: +34 963544329.
FAX: +34 963544328.
# This work is dedicated to the memory of Professor Marcial Moreno-Man˜as.
(1) For reviews, see: (a) Pu, L.; Yu, H. B. Chem. ReV. 2001, 101, 757-
824. (b) Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc.
Chem. Res. 2000, 33, 373-381. (c) Pu, L. Tetrahedron 2003, 59, 9873-
9886. (d) Lu, G.; Li, Y.-M.; Li, X.-S.; Chan, A. S. C. Coord. Chem. ReV.
2005, 249, 1736-1744.
10.1021/jo0610255 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/18/2006
6674
J. Org. Chem. 2006, 71, 6674-6677

SCHEME 1. Alkynylation of Aldehydes in the Presence of
Dimethylzinc and Mandelamides as Chiral Ligands
FIGURE 1. Modification of heteroaromatic propargylic alcohols.
mandelamide I ligand in combination with Ti(OiPr)4 (1.4 equiv),
2 M Me2Zn in toluene (6 equiv), and phenylacetylene (7.2 equiv)
in dichloromethane solution (5 mL) at 0 °C. These reaction
conditions are very similar to those reported by Chan3 and Pu4a,b
for this same reaction using BINOL as chiral ligand. However,
with mandelamide I as ligand, 1-phenylethanol, which results
after methyl addition to benzaldehyde, was the main reaction
product (55%), the desired propargylic alcohol 3aa being
obtained in only 40% yield (entry 1). Using toluene as the
solvent and in absence of Ti(OiPr)4, the formation of the methyl
addition product could be avoided and the propargylic alcohol
3aa was obtained with moderate yield (65%) although with low
enantioselectivity (51% ee) (entry 2).
important asymmetric reaction are still in great need to probe
the relation between the ligand structure and catalytic activity.
Our group has been developing hydroxy amide chiral ligands
that are synthesized conveniently in simple, short sequences and
from cheap, available chiral resources.15 Recently, we disclosed
that simple (S)-mandelamides could be used to effectively
catalyze the addition of dimethylzinc to R-ketoesters with good
yield and enantioselectivity,16 as well as, in combination with
Ti(OiPr)4, to aromatic aldehydes with moderate to good enan-
tioselectivity.17 Herein, we wish to report the use of (S)-
mandelamides as chiral ligands in the alkynylation of benzal-
dehyde and heteroaromatic aldehydes, particularly 2- and
3-furanecarbaldehyde and 2- and 3-thiophenecarbaldehyde, with
several terminal alkynes (Scheme 1).
The reaction with these heteroaromatic aldehydes is particu-
larly interesting because of the possibility of manipulation on
the heterocyclic ring. Thus, 2-furyl alcohols can be transformed
into 6-hydroxy-2H-pyran-3(6H)-ones, important building blocks
for the synthesis of biologically active natural products, through
an oxidative rearrangement (Figure 1).18 On the other hand, the
thiophene ring in the resulting thienyl alcohols can be desulfu-
rized with Raney nickel acting as a masked four-carbon
synthon.19 However, despite the synthetic utility of these
products, the alkynylation of furane- and thiophenecarbalde-
hydes has been little explored and remains an interesting
challenging reaction.
The effect of the N-substituent of the ligand was studied with
mandelamides II-V. Thus, ligands II and III introduce an
additional stereogenic center on the amide substituent, while
ligands IV and V introduce an additional potentially coordinat-
ing atom. In the presence of ligands II-V, the reaction took
place with good yields but with variable enantioselectivity. Thus,
ligands I and III gave the reaction product with similar
enantiomeric excesses (51 and 50% ee, respectively, entries 2
and 4), ligands II and V lead to lower enantioselectivities (29
and 31% ee, respectively, entries 3 and 6), and the reaction
yielded almost racemic product with ligand IV (entry 5). Some
interesting results were obtained, however, when the reaction
was carried out at higher temperatures: at 50 °C, the enantio-
selectivity observed with ligand I decreased to 42% ee, while
with ligands II and III, it increased to 34 and 65% ee,
respectively. A further increase of the temperature to 70 °C
brought about a new decrease in the enantioselectivity with
ligand I (40% ee) and a new enantiomeric excess increase with
ligands II and III (48 and 70% ee, respectively).
To improve the enantioselectivity of the reaction, we decide
to preform the alkynylzinc reagent prior to the addition of the
aldehyde. According to the procedure described by Pu,4a
phenylacetylene was treated with Me2Zn at 70 °C for 30 min
until the formation of a white precipitate in the reaction mixture
appeared. The reaction temperature was lowered to 0 °C, and
then mandelamide III was added followed by benzaldehyde
(Scheme 2, eq 1). However, under these reaction conditions,
the desired propargylic alcohol 3aa was obtained in practically
racemic form (3% ee, entry 13). This result indicated that the
simultaneous presence of Me2Zn and mandelamide III was
essential for the formation of the catalyst.20 Effectively, to obtain
a good enantioselectivity, it was necessary to heat at 70 °C
phenylacetylene with dimethylzinc in toluene in the presence
of mandelamide III and then to add benzaldehyde at 0 °C (entry
To optimize the reaction conditions, we first studied the
asymmetric reaction of phenylacetylene (1a) with benzaldehyde
(2a). Initially, the reaction was carried out using 0.2 equiv of
(14) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem. Soc.
2006, 128, 8-9.
(15) Blay, G.; Ferna´ndez, I.; Marco-Aleixandre, A.; Pedro, J. R.
Tetrahedron: Asymmetry 2005, 16, 1207-1213.
(16) Blay, G.; Ferna´ndez, I.; Marco-Aleixandre, A.; Pedro, J. R. Org.
Lett. 2006, 8, 1287-1290.
(17) Blay, G.; Ferna´ndez, I.; Herna´ndez-Olmos, V.; Marco-Aleixandre,
A.; Pedro, J. R. Tetrahedron: Asymmetry 2005, 16, 1953-1958.
(18) (a) Chan, K.-F.; Wong, H. N. C. Org. Lett. 2001, 3, 3991-3994.
(b) Chan, K.-F.; Wong, H. N. C. Eur. J. Org. Chem. 2003, 82-91.
(19) (a) Yan, S.-M.; Nandy, S. K.; Selvakumar, A. R.; Fang, J.-M. Org.
Lett. 2000, 2, 3719-3721. (b) Krishna, P. R.; Lavanya, B.; Ilangovan, A.;
Sharma, G. V. M. Tetrahedron: Asymmetry 2000, 11, 4463-4472. (c)
Mohr, J. T.; Gribble, G. W.; Lin, S. S.; Eckenhoff, R. G.; Cantor, R. S. J.
Med. Chem. 2005, 48, 4172-4176.
J. Org. Chem, Vol. 71, No. 17, 2006 6675

TABLE 2. Alkynylation of Benzaldehyde and Heteroaromatic
Aldehydes in the Presence of Dimethylzinc and Mandelamide III,
According to Scheme 2, Equation 2
SCHEME 2. Procedures for the Alkynylation of Aldehydes
with Me2Zn and Mandelamides
t1
t2
yield
ee
entry alkyne 1 (R1) aldehyde 2 (R2) (min) (h) (%)a (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a, Ph
a, Ph
a, Ph
a, Ph
a, Ph
20
20
20
20
20
30
30
30
30
30
60
60
60
60
60
1
1
1
1.5
2
95
88
94
91
86
96
96
93
90
94
93
79
98
95
90
89
83
89
90
88
88
90
92
91
89
67
85
90
90
77
b, 2-furyl
c, 3-furyl
d, 2-thienyl
e, 3-thienyl
a, Ph
b, 2-furyl
c, 3-furyl
d, 2-thienyl
e, 3-thienyl
a, Ph
a, Ph
b, PhCH2CH2
b, PhCH2CH2
b, PhCH2CH2
b, PhCH2CH2
b, PhCH2CH2
c, t-Bu
c, t-Bu
c, t-Bu
c, t-Bu
c, t-Bu
3
1.5
2.5
3.5
1.7
2
b, 2-furyl
c, 3-furyl
d, 2-thienyl
e, 3-thienyl
1
1.5
1.5
1.5
a Yields refer to isolated product after column chromatography. b De-
termined by HPLC using chiral stationary phases.
TABLE 1. Results from the Addition of Phenylacetylene to
Benzaldehyde (Scheme 1, R1 ) R2 ) Ph) in the Presence of
Dimethylzinc and Mandelamides I-Va
entry
ligand
solvent
T (°C)
yield (%)b
ee (%)c
studied the highly sterically hindered tert-butylacetylene (1c),
obtaining again very good yields and enantioselectivities. This
acetylene is a very challenging substrate, and in fact, the
enantioselective addition of tert-butylacetylene to benzaldehyde
with an 80% yield and 53% ee reported by Jiang22 is the only
successful example reported so far. It is worth remarking that
with our catalytic system this reaction gave improved 93% yield
and 67% ee of the corresponding propargylic alcohol (entry 11).
More interesting, the results are still better with heteroaromatic
aldehydes 2b-e, specially with regards to the enantioselectivity
of the reaction (77-90% ee; entries 12-15).
The stereochemistry of the propargylic alcohols resulting from
the addition of phenylacetylene (1a) and 4-phenyl-1-butyne (1b)
was assigned by comparison of the optical rotations and retention
times in HPLC with values reported in the literature for 3aa,
3ac, and 3ba.23 According to that, the configuration of the
stereogenic center in 3aa and 3ba derived from benzaldehyde
must be R. If we assume that the sense of the enantioselectivity
with the heteroaromatic aldehydes is the same as with benzal-
dehyde, the configuration of the stereogenic center in compounds
3ab-3ae and 3bb-3be should be S because of the change in
the priority order when applying the CIP rules.24
In summary, we have developed a new procedure for the
enantioselective addition of terminal alkynes to heteroaromatic
aldehydes, affording high yields and enantioselectivities of
heterocyclic propargylic alcohols. An advantage of our system
is that the catalysts 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
R-methylbenzylamine enantiomers. Furthermore, the reaction
times are short, and unlike most other described procedures,
using mandelamide III does not require the addition of Ti(Oi-
Pr)4.
1d
2
3
4
5
6
7
8
9
10
11
12
13e
14f
I
I
II
III
IV
V
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
0
0
0
0
0
40
65
80
85
85
87
90
88
86
84
91
90
81
95
18
51
29
50
4
31
42
34
65
40
48
70
3
0
I
50
50
50
70
70
70
70/0
70/0
II
III
I
II
III
III
III
89
a Benzaldehyde (1 mmol), ligand (0.2 mmol), Me2Zn (6 mmol),
phenylacetylene (7.2 mmol). b Yields refer to isolated product after column
chromatography. c Enantiomeric excesses were determined by HPLC on a
Chiralcel OD-H column. d The reaction was carried out in the presence of
Ti(OiPr)4. 1-Phenylethanol was also obtained in 55% yield. e Reaction
according Scheme 2, eq 1. f Reaction according Scheme 2, eq 2.
14). Under these conditions (Scheme 2, eq 2), very good yield
(95%) and enantioselectivity (89% ee) were obtained.
We also checked the addition of the substrate at different
temperatures. However, no improvement was observed at either
higher (room temperature) or lower temperatures (-10 or -20
°C). Under the above optimized reaction conditions, ligand III
was employed to induce the enantioselective addition of
phenylacetylene to 2- and 3-furanecarbaldehyde and 2- and
3-thiophenecarbaldehyde.21 As the results summarized in Table
2 show, good yields (86-95%) and enantioselectivities (83-
90% ee) were obtained (entries 2-4), similar to those obtained
in the addition to benzaldehyde.
The generality of this catalytic system was examined using
two other terminal alkynes. Using the less reactive alkylacetyl-
ene (1b) instead of phenylacetylene (1a), excellent yields were
obtained (90-96%) with high enantioselectivities (88-92% ee)
in short reaction times (1.5-3.5 h; entries 6-10). We also
(22) Jiang, B.; Feng, Y. Tetrahedron Lett. 2002, 43, 2975-2977.
(23) A comparison with the tert-butylacetylene addition products 3ca-
3ce was not possible.
(24) The optical rotation signs and HPLC retention times of compounds
3aa, 3ac, and 3ba synthesized here coincide with those reported by
Shibashaki in ref 13. In that article, the stereochemistry of 3ac is reported
as being R, probably because of a distraction in the application of the CIP
rules. However, Shibashaki’s product is described as being S in Scifinder.
(20) We assume that the formation of the mandelamide-Zn complex
involves deprotonation of the mandelamide, which is carried out by Me2-
Zn (see ref 16). The preformed alkynylzinc reagent may be not basic enough
to achieve this deprotonation.
(21) Attempts of addition to N-methyl-2-pyrrolecarbaldehyde gave
complex reaction mixtures.
6676 J. Org. Chem., Vol. 71, No. 17, 2006

Experimental Section25
Gas evolution) and the reaction extracted with diethyl ether (3 ×
15 mL). The organic layer was washed with brine, dried, concen-
trated, and chromatographed on silica gel to give compound 3.
General Procedure for the Catalytic Asymmetric Alkynyl-
ation of Aldehydes. A 2 M solution of Me2Zn in toluene (3 mL,
6 mmol) was added to a solution of alkyne 1 (7.2 mmol) in dry
toluene (5 mL), under argon at room temperature. After 15 min, a
solution of ligand III (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 formation of a white precipitate in the
solution was formed (20 min for alkyne 1a, 30 min for alkyne 1b,
and 60 min for alkyne 1c). Then, the reaction mixture was cooled
to 0 °C, and aldehyde 2 (1 mmol) was added. After the reaction
was complete (TLC), 1 M HCl (20 mL) was added (CAUTION!
Acknowledgment. Financial support from the Spanish
Government (MEC, project BQU2001-3017) and from Gener-
alitat Valenciana (Grupos 03/168 and Project GV 05/10) is
acknowledged. A.M.-A. thanks the MEC for a predoctoral grant
(FPU program).
Supporting Information Available: Experimental general
methods, characterization data, 1H NMR and 13C NMR spectra for
compounds 3 and ligand V. This material is available free of charge
via the Internet at http://pubs.acs.org.
(25) For a description of the general experimental methods, see the
Supporting Information.
JO0610255
J. Org. Chem, Vol. 71, No. 17, 2006 6677