Me2Zn-mediated addition of acetylenes to aldehydes and ketones

Article abstract of DOI:10.1021/jo050115r

Contrary to expectations, commercially available 2 M Me₂Zn in toluene is able to promote the addition of phenylacetylene to aldehydes and ketones. This reactivity is determined by a new, unprecedented mechanism, which involves activation of the zinc reagent via coordination with carbonyl substrates that behave "ligand like". Broad scope, high tolerance to functional groups, and a simple procedure make this new method highly interesting for the synthetic chemist.

Full text of DOI:10.1021/jo050115r

Me2Zn-Mediated Addition of Acetylenes to
Aldehydes and Ketones
Pier Giorgio Cozzi,*,† Jens Rudolph,‡,§ Carsten Bolm,‡
Per-Ola Norrby,| and Claudia Tomasini†
Dipartimento di Chimica “G. Ciamician”,
Alma Mater Studiorum, Universita` di Bologna,
Via Selmi 2, 40126 Bologna, Italy, Institute of Organic
Chemistry, RWTH Aachen University, Landoltweg 1,
D-52056, Aachen, Germany, and Department of Chemistry,
Technical University of Denmark, Building 201,
Kemitorvet, DK-2800 Kgs. Lyngby, Denmark
FIGURE 1. Acetylenic alcohols as precursors of valuable
compounds.
SCHEME 1. Addition of Acetylenes 2a-d to
Carbonyl Compounds Promoted by Me2Zn
piergiorgio.cozzi@unibo.it
Received January 20, 2005
Traditionally, propargylic alcohols are synthesized by
addition of a metal acetylide to aldehydes or ketones with
a stoichiometric or catalytic amount of a base.3 However,
the reported methods possess some drawbacks and hence
a general, highly tolerable and simple procedure for the
selective alkynylation of enolizable aldehydes and ke-
tones, is desirable. We found that mixtures of Me2Zn and
acetylenes add to aldehydes and ketones affording the
desired products in good to excellent yields (Scheme 1).
Thus, when the commercially available 2 M solution
of Me2Zn in toluene was mixed with of phenylacetylene
(1.5 equiv each) at room temperature and reacted with
benzaldehyde (1 equiv) at 0 °C, the addition product 3a
was isolated in 45% yield after 24 h (entry 1, Table 1).
Performing the reaction at room temperature gave 3a in
89% yield (entry 2, Table 1). Consequently, this protocol
was used for all further reactions.
A substrate screening revealed that other acetylenes
were also applicable although they proved to be less
reactive than phenylacetylene (Table 1, entries 3-5).
Various aldehydes reacted smoothly giving the corre-
sponding propargylic alcohols in good to high yields at
room temperature. Table 2 shows that aromatic and
aliphatic ketones reacted as well.
Contrary to expectations, commercially available 2 M Me2Zn
in toluene is able to promote the addition of phenylacetylene
to aldehydes and ketones. This reactivity is determined by
a new, unprecedented mechanism, which involves activation
of the zinc reagent via coordination with carbonyl substrates
that behave “ligand like”. Broad scope, high tolerance to
functional groups, and a simple procedure make this new
method highly interesting for the synthetic chemist.
The addition of acetylides to carbonyl substrates gives
access to propargylic alcohols, which are valuable build-
ing blocks and useful intermediates for the synthesis of
complex natural products.1 Moreover, the addition of
alkynes to ketones is a practical strategy to create
tertiary alcohols with a new stereogenic center under
mild conditions (Figure 1).2
* To whom correspondence should be addressed. Fax: +39
0512099456.
† Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum,
Universita` di Bologna.
When a Me2Zn/phenylacetylene mixture was used (1.5
equiv each with respect to the carbonyl compound), only
aliphatic ketones furnished addition products in high
yields, while aromatic ketones were rather unreactive
substrates. The introduction of an electron-withdrawing
group enhanced the reactivity of the latter substrates.
The use of 3 equiv of the Me2Zn/phenylacetylene mixture
increased the yield in the addition to acetophenone and
chloroacetophenone (Table 2, entries 2 and 3), but the
‡ RWTH Aachen University.
§ New address: BASF AG, GCB/O - M313, 67056 Ludwigshafen,
Germany.
| Technical University of Denmark.
(1) (a) Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2003, 5, 3197. (b)
Cuzzupe, A. N.; Hutton, C., A.; Lilly, M. J.; Mann, R. K.; McRae, K. J.;
Zammit, S. C.; Rizzacasa, M. A. J. Org. Chem. 2001, 66, 2382. (c) Pilli,
R. A.; Victor, M. M.; de Meijere, A. J. Org. Chem. 2000, 65, 5910. (d)
Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed.
2000, 39, 2632.
(2) For reviews, see: (a) Pu, L. Tetrahedron 2003, 59, 9873. (b) Cozzi,
P. G.; Hilgraf, R.; Zimmermann, N, Eur. J. Org. Chem. 2004, 4095.
For recent papers about allkynylation, see: (a) Liu, L.; Wang, R.; Kang,
Y.-F.; Chen, C.; Xu, Z.-Q.; Zhou, Y.-F.; Ni, M.; Cai, H.-Q.; Gong, M.-Z.
J. Org. Chem. 2005, 70, 1084, and ref. therein. (b): Xu, Z.; Wang, R.;
Xu, Y.; Da, C.-s.; Yan, W.-j.; Chen, C. Angew. Chem., Int. Ed. 2003,
42, 5747. (c) Zhou, Y.-f.; Wang, R.; Xu, Z.-q; Yan, W.-j.; Liu, L.; Gao,
Y.-f.; Da, C.-s. Tetrahedron: Asymmetry 2004, 15, 589. (d) Li, M.; Zhu,
X.-Z.; Yuan, K.; Cao, B.-X.; Hou, X.-L. Tetrahedron: Asymmetry 2004,
15, 219.
(3) (a) Anad, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687. (b) Li, X.; Lu, G.; Kwok, W. H.; Chan, A. S. C. J. Am. Chem. Soc.
2002, 124, 12636. (c) Cozzi, P. G. Angew. Chem., Int. Ed. 2003, 42,
2895. (d) Lu, G.; Li, X.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew.
Chem., Int. Ed. 2003, 42, 5057. (e) Jiang, B.; Si, Y.-G. Tetrahedron
Lett. 2003, 44, 6767.(f) Liu, L.; Kang, Y.-f.; Wang, R.; Zhou, Y.-f.; Chen,
C.; Ni, M.; Gong, M.-z Tetrahedron: Asymmetry 2004, 15, 3757.
10.1021/jo050115r CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/07/2005
J. Org. Chem. 2005, 70, 5733-5736
5733

TABLE 1. Alkynylation of Aldehydes Using Me2Zn as
Promoter
to make it a more reactive base toward acetylenes. It is
well-known that amino alcohols activate alkyl-,6 aryl-,7
and alkynylzinc3 derivatives toward the attack of carbo-
nyl substrates. This activation is crucial to make reaction
with the carbonyl compound possible.8 Our results indi-
cate that the carbonyl oxygen might behave in a “ligand
like” fashion promoting the reaction of Me2Zn with an
alkyne by coordination of its lone pairs to the Me2Zn. To
elucidate the nature of the deprotonation and of the
subsequent addition step, we have undertaken a DFT
study of a small model system, consisting of Me2Zn,
acetone, and acetylene.
All calculations were performed at the B3LYP/LACVP*
level (Hay-Wadt double-ú valence + ECP for Zn,9 6-31G*
for other atoms) in Jaguar 4.2 from Schro¨dinger, Inc.10
Stationary points were verified by analytic normal-mode
analysis. All reaction barriers were calculated from the
lowest preceding point on the potential energy surface,
always a precomplex of all reactants. Initially, we inves-
tigated the deprotonation of acetylene by Me2Zn (Figure
1).
In the absence of activation, the barrier is calculated
to be 155 kJ/mol, too high to be expected to show
significant reactivity at room temperature. Coordinating
a molecule of acetone to the Zn atom lowers the barrier
to 138 kJ/mol, a value more in line with the observed
reactivity. Adding harmonic corrections to these figures
(ZPE or ∆∆G) changes the absolute numbers, but does
not affect the trend. Looking at the structures, we can
see that acetone coordination induces a bending in the
linear and nonpolar Me2Zn molecule, increasing the
basicity of the methyl group.
We also investigated the subsequent addition of
MeZnCCH to a ketone. In the simplest possible mecha-
nism, starting from the favored adduct in the preceding
deprotonation step, the acetylene is simply transferred
to the carbonyl carbon in a four-membered monocyclic
TS (Figure 2).
yieldb
product (%)
entrya
aldehyde
R3
1
benzaldehyde
Ph
3a
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
45c
30d
78
48
80
30
83
70
92
86
90
79
68
86
70
91
89
2
benzaldehyde
Ph
3
benzaldehyde
Ph
4
benzaldehyde
TMS
nBu
CO2Et
Ph
5
benzaldehyde
6
benzaldehyde
7
4′-chlorobenzaldehyde
4′-bromobenzaldehyde
3′-fluorobenzaldehyde
3′-bromobenzaldehyde
8
Ph
9
Ph
10
11
12
13
14
15
16
17
Ph
4′-trifluoromethylbenzaldehyde Ph
4′-nitrobenzaldehyde
4′-methylbenzaldehyde
1-naphthylaldehyde
trans-cinnamaldehyde
octanal
Ph
Ph
Ph
Ph
Ph
Ph
3m
3n
3o
cyclohexylaldehyde
a All reactions were carried out in anhydrous toluene at room
temperature, employing 1.5 equiv of a Me2Zn/phenylacetylene
mixture. b Yield after flash chromatography. c The reaction was
performed at 0 °C. d The reaction was performed using a 1.1 M
toluene solution of Et2Zn.
TABLE 2. Alkynylation of Ketones with Phenyl
Acetylene Using Me2Zn as Promoter
entrya
ketone
product yieldb (%)
1
acetophenone
acetophenone
4a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
14
36c
40c
31
44
94
41
66
80
85
86
59
77
75
40
55
80
2
3
4′-chloroacetophenone
4′-fluoroacetophenone
4′-bromoacetophenone
3′-trifuoromethylacetophenone
3′-cyanoacetophenone
4-phenylbut-3-en-2-one
oxo-phenylacetic acid methylester
2-pentanone
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1-hexen-5-one
4-methyl-2-pentanone
3-methyl-2-butanone
4-phenyl-2-butanone
methylcyclopropyl ketone
2,2-dimethyl-1-cyclopentanone
cyclohexanone
This reaction has an activation barrier of only 83 kJ/
mol, indicating that in the presence of ketone, the
alkynylzinc species is reacted as soon as it is formed.
In consideration of the accepted mechanism for ligand-
assisted addition of Et2Zn to aldehydes,6b we also inves-
tigated the possibility that a zinc ketone complex acts
as a bifunctional catalyst, bringing together an additional
1 equiv of ketone and zinc reagent in a bicyclic TS (Figure
3). This reaction has an even lower barrier, only 66 kJ/
mol, but at the cost of a higher molecularity and thus an
unknown entropic cost. The relative importance of the
two pathways will be determined by the propensity of
the zinc species to form higher order complexes, which
in turn will be strongly affected by the solvent. However,
a All reactions were carried out in anhydrous toluene at room
temperature, employing 1.5 equiv of Me2Zn/phenylacetylene mix-
ture. b Yield after flash chromatography. c The reactions were
performed using 3 equiv of Me2Zn/phenylacetylene mixture.
results were still not satisfactory. As demonstrated with
various substrates, the procedure is highly tolerant to a
broad range of functional groups.
These results are intriguing also from a theoretical
point of view, because they open the reaction mechanism
to questions. It was previously reported that the addition
of Me2Zn to a solution of phenylacetylene did not show
any change in the 1H and 13C spectra, indicating that no
reaction took place between the two compounds.4 More
recent studies revealed that the formation of MeZnCCPh
is promoted by the adventitious presence of moisture,
although the reaction is incomplete.5 Apparently, in both
studies it was necessary to activate the Me2Zn in order
(5) Pinet, S.; Pandya, S. U.; Chavant, P. Y.; Ayling, A.; Vallee, Y.
Org. Lett. 2002, 4, 1463.
(6) (a) Rasmussen, T.; Norrby, P.-O. J. Am. Chem. Soc. 2003, 125,
5130, and references therein. (b) Yamakawa, M.; Noyori, R. J. J. Am.
Chem. Soc. 1995, 117, 6327. For reviews, see: (c) Soai, K.; Niwa, S.
Chem. Rev. 1992, 92, 833. (d) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101,
757.
(7) (a) Rudolph, J.; Rasmussen, T.; Bolm C.; Norrby, P.-O. Angew.
Chem., Int. Ed. 2003, 42, 3002. (b) Rudolph, J.; Bolm C.; Norrby,
P.-O. J. Am. Chem. Soc. 2005, 127, 1548 and refs therein.
(8) (a) Frantz D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806. (b) Dahmen, S. Org. Lett. 2004, 6, 2113.
(9) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270.
(10) http://www.schrodinger.com.
(4) Li reported that a mixture of phenylacetylene and Me2Zn was
rather unreactive towards aldehydes: Li, Z.; Upadhyay, V.; DeCamp,
A. E.; DiMichele L.; Reider, P. J. Synthesis 1999, 1453.
5734 J. Org. Chem., Vol. 70, No. 14, 2005

FIGURE 2. TSs for the deprotonation of acetylene.
FIGURE 3. Transition states found for the addition of acetylene to acetone.
4-phenylethyl-2-butynoate (3d),14 1-(4-chlorophenyl)-3-phenylprop-
the relatively low barrier to reaction indicates that the
alkynyl zinc, already complexed to the ketone, may react
through the monocyclic TS before encountering other
activating species.
In conclusion, we have described the unexpected and
facile addition of phenylacetylene to aldehydes and
ketones promoted by Me2Zn without the employment of
specific ligands. This reaction has an interesting potential
for the direct synthesis of tertiary propargylic alcohols.
Furthermore, our study demonstrates that the substrate
itself can become a ligand and catalyze a background
reaction, which might result in lowering the enantiose-
lectivity in a desired asymmetric transformation.
2-yn-1-ol (3e),11 1-(4-bromophenyl)-3-phenylpropyn-1-ol (3f),15
1-(3-fluorophenyl)-3-phenylprop-2-yn-1-ol (3g),16 1-(3-bromophe-
nyl)-3-phenylprop-2-yn-1-ol (3h),17 3-phenyl-1-(4-trifluorometh-
ylphenyl)prop-2-yn-1-ol (3i),18 1-(4-nitrophenyl)-3-phenylprop-
2-yn-1-ol (3j),3b 3-phenyl-1-p-tolylprop-2-yn-1-o (3k),19 1-naphthyl-
3-phenylprop-2-yn-1-ol (3l),19 1,5-diphenylpent-1-en-4-yn-3-ol
(3m),20 1-phenyldec-1-yn-3-ol (3n),21 1-cyclohexyl-3-phenylprop-
2-yn-1-ol (3o),21 2,4-diphenylbut-3-yn-2-ol (4a),3d 2-(4-chlorophe-
(11) Li, Z.-B.; Pu, L. Org. Lett. 2004, 6, 1065.
(12) Nakamura, S.; Kusuda, S.; Kawamura, K.; Toru, T. J. Org.
Chem. 2002, 67, 640.
(13) Braga, A. L.; Appelt, H. R.; Silveira, C. C.; Wessjohann, L. A.;
Schneider, P. H. Tetrahedron 2002, 58, 10413.
(14) Krause, N.; Seebach, D. Chem. Ber. 1987, 120, 1845.
(15) Liu, L.; Pu, L. Tetrahedron 2004, 60, 7427.
(16) Kamble, R. M.; Singh, V. K. Tetrahedron Lett. 2003, 44, 5347.
(17) Xu, Z.; Chen, C.; Xu, J.; Miao, M.; Yan, W.; Wang, R. Org. Lett.
2004, 6, 1193.
Experimental Section
1,3-Diphenylprop-2-yn-1-ol (3a),11 1-phenyl-3-trimethylsilyl-
prop-2-yn-1-ol (3b),12 1-phenylhept-2-yn-1-ol (3c),13 4-hydroxy-
J. Org. Chem, Vol. 70, No. 14, 2005 5735

nyl)-4-phenylbut-3-yn-2-ol (4b),22 2-(4-fluorophenyl)-4-phenylbut-
3-yn-2-ol (4c),3c 2-(4-bromophenyl)-4-phenylbut-3-yn-2-ol (4d),3c
2-(3-trifluoromethylphenyl)-4-phenylbut-3-yn-1-ol (4e),3c 3-meth-
yl-1,5-diphenylpent-1-en-4-yn-3-ol (4g),23 2-hydroxy-2,4-diphe-
nylethyl-but-3-ynoate (4h),24 3methyl-1-phenylhex-1-yn-3-ol (4i),25
3,5-dimethyl-1-phenylhex-1-yn-3-ol (4k),26 3,4-dimethyl-1-phe-
nylpent-1-yn-3-ol (4l),27 3-methyl-1,5-diphenylpent-1-yn-3-ol (4m),3c
2-cyclopropyl-4-phenylbut-3-yn-2-ol (4n),3c 2,2-dimethyl-1-phe-
nylethynylcyclopentanol (4o),3c and 1-phenylethynyl-1-cyclohex-
anol (4p)27 are known compounds.
Typical Procedure for the Alkynylation of Carbonyl
Compounds. In an oven-dried flask connected to a nitrogen/
vacuum line was placed phenylacetylene (1.6 mmol) followed by
the slow addition of Me2Zn 2 M solution in toluene (1.5 mmol,
0.75 mL). The resulting solution was stirred at room tempera-
ture for 30 min. Then, the aldehyde or ketone (1 mmol) was
added dropwise to the reaction mixture. The resulting solution
was stirred at room temperature for 24 h, and then the reaction
mixture was diluted with diethyl ether (5 mL) and quenched
with water (10 mL). The mixture was stirred for 10 min and
then filtered over Celite. The aqueous phase was separated and
extracted with diethyl ether (2 × 5 mL). The combined organic
phases were dried over Na2SO4 and evaporated under reduced
pressure to give a crude oil which was purified by flash
chromatography (cyclohexane/diethyl ether 8:2-9:1 or cyclohex-
ane/acetone 8:1-9:1 as eluant).
4-(1-Hydroxy-1-methyl-3-phenylprop-2-yl-benzoni-
trile) (4f). 1H NMR (CDCl3, 300 MHz) δ: 1.87 (s, 3H); 7.37-
7.34 (m, 3H); 7.53-7.47 (m, 3H); 7.64 (m, 1H); 7.98 (m, 1H); 8.04
(t, 1H, J ) 1.2 Hz). 13C NMR (CDCl3, 75 MHz) δ: 33.6; 69.7;
85.7; 91.1; 112.4; 118.8; 121.9; 128.4; 128.9; 129.2; 129.6; 131.3;
131.7; 147.2; 176.4. Anal. Calcd: C, 88.13; H, 8.05; N, 5.71.
Found: C, 88,06; H, 8.18; N, 5.75.
3-Methyl-1-phenylhept-6-en-1-yn-3-ol (4j). 1H NMR (CDCl3,
300 MHz) δ: 1.64 (s, 3H); 1.88-1.97 (m, 3H); 2.35-2.47 (m, 2H);
5.03-5.18 (m, 2H); 5.89-6.00 (m, 1H); 7.22-7.30 (m, 3H); 7.36-
7.39 (m, 2H). 13C NMR (CDCl3, 75 MHz) δ: 29.3; 30.0; 42.7; 68.5;
83.7; 92.5; 114.9; 122.7; 128.2; 131.6; 138.4; 140.6. Analysis
calcd: C, 83.96; H, 8.05. Found: C, 84,00; H, 8.01.
Acknowledgment. P.G.C. thanks FIRB and MIUR
(Rome) “Progetto Stereoselezione in Chimica Organica.
Metodologie ed Applicazioni” and the University of
Bologna (funds for selected research topics) for financial
support of this research. C.T. thanks MURST Cofin
2002 (“Sintesi di peptidi ciclici o lineari contenenti
amminoacidi inusuali analoghi di arginina, glicina o
acido aspartico (RGD) come nuovi inbitori di integrine“),
FIRB 2001 (“Eterocicli azotati come potenziali inbitori
enzimatici”), and 60% (Ricerca Fondamentale Orien-
tata). C.B. and J.R. are grateful to the Fonds der
Chemischen Industrie and to the Deutsche Forschungs-
gemeinschaft (DFG) within the Collaborative Research
Center (SFB) 380 and the Graduiertenkolleg (GRK) 440
for financial support. P.-O.N. thanks the Carlsberg
Foundation and the Danish Natural Science Research
Council for providing computational resources.
(18) Praveen Rao, P. N.; Uddin, J. Md.; Knaus, E. E. J. Med. Chem.
2004, 47, 3972.
(19) Liu, Q.-Z.; Xie, N.-S.; Luo, Z.-B.; Cui, X.; Cun, L.-F.; Gong,
L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. J. Org. Chem. 2003, 68, 7921.
(20) Kang, Y.-F.; Liu, L.; Wang, R.; Yan, W.-J.; Zhou, Y.-F. Tetra-
hedron: Asymmetry 2004, 15, 3155.
(21) Gao, G.; Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002, 4, 4143.
(22) Saito, B.; Katsuki, T. Synlett 2004, 1557.
(23) Zhou, Y.; Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.; Han, Z.
Org. Lett. 2004, 6, 4147.
1
Supporting Information Available: Copies of H NMR
for compounds 3a-o and 4a-e,g-i,k-o and energies and
Cartesian coordinates, TS energies (Hartree), zero potential
energy (kJ/mol), and lowest frequencies (cm-1) for reactants
and complexes determined at the B3LYP/LACVP* level of
theory. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) Jiang, B.; Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451.
(25) Miyamoto, H.; Yasaka, S.; Tanaka, K. Bull. Chem. Soc. Jpn.
2001, 74, 185.
(26) Riddell, F. G.; Bremner, M.; Strange, J. H. Magn. Reson. Chem.
1994, 32, 118.
(27) Ishikawa, T.; Mizuta, T.; Hagiwara, K.; Aikawa, T.; Kudo, T.;
Saito, S. J. Org. Chem. 2003, 68, 3702.
JO050115R
5736 J. Org. Chem., Vol. 70, No. 14, 2005