Enantioselective alkynylation of aromatic aldehydes: Pyridyl phenylene terpeneol catalysts with flexible biaryl axes

Article abstract of DOI:10.1055/s-0030-1260325

Free rotating biaryl axes of pyridyl phenylene terpenols are fixed by zinc cations to give conformationally pure zinc complexes. These zinc alkoxide catalysts provide yields up to 99% and ee values up to 86% in the enantioselective addition of phenylacety

Full text of DOI:10.1055/s-0030-1260325

LETTER
2505
Enantioselective Alkynylation of Aromatic Aldehydes: Pyridyl Phenylene
Terpeneol Catalysts with Flexible Biaryl Axes
E
nantioselective Alkyn
a
ylation of
A
romatic Alde
h
hydes ias Leven, David Müller, Bernd Goldfuss*
Department of Organic Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, Germany
Fax +49(221)4705057; E-mail: goldfuss@uni-koeln.de
Received 15 April 2011
Dedicated to Prof. Dr. Dieter Enders on the occasion of his 65th birthday
give yields up to 99% and up to 95% ee when employed
as ligands in the addition of dialkylzincs (i.e., ZnMe2,
ZnEt2) to benzaldehyde.9
Abstract: Free rotating biaryl axes of pyridyl phenylene terpenols
are fixed by zinc cations to give conformationally pure zinc com-
plexes. These zinc alkoxide catalysts provide yields up to 99% and
ee values up to 86% in the enantioselective addition of phenylacet-
ylene to aromatic aldehydes.
Key words: enantioselectivity, biaryls, organometallic reagents,
zinc, alkynes
HO
N
HO
N
HO
N
The enantioselective addition of terminal alkynes to alde-
hydes is of great preparative interest for the generation of
enantiomerically enriched propargylic alcohols.1 Optical-
ly active secondary propargylic alcohols are valuable
building blocks in many pharmaceutical and natural prod-
uct syntheses.1 Addition reactions with organozinc re-
agents are useful for the synthesis of various propargylic
alcohols because the reactions can be carried out under
mild conditions and many functional groups are tolerated
without inconvenient side reactions.2
1
2
3
Figure 1 Diphenylpyridine-based terpenols 1–3 (the flexible chiral
biaryl axes are marked by arrows)
These pyridylacohols contain flexible phenylpyridyl moi-
eties with fast (P)/(M) biaryl equilibrium.9 This conforma-
tional equilibrium is found to be eliminated by
complexation of zinc cations (Scheme 2) and complexes
with conformationally pure biaryl axes are formed.9 The
conformations of the biaryl axes were identified as being
the origin of enantioselectivity in catalyzed additions of
zinc dialkyls to benzaldehyde.9
H
R
OH
*
1) L*, ZnMe2
2) aq work-up
RCHO
H
Ph
+
Ph
Scheme 1 Zinc-catalyzed addition of terminal alkynes to aldehydes
with organozinc reagents (L* are pyridyl phenylene terpenols)
*
*
There are many chiral catalysts that enable the asymmet-
ric alkynylation of carbonylic components, for example,
ephedrines,3 BINOLs,4 terpene-derived amino and py-
ridyl alcohols,5 and bisprolinols developed by Trost,6 and
other catalysts have been used for the asymmetric alkyny-
lation of aldehydes.7 Enantiopure atropisomeric biaryl
systems with flexible chiral axes such as BINOL or
BINAP are known to provide excellent results in various
types of catalytic asymmetric reactions.8
*
free
rotation
OH
ZnMe2
OH
N
O
N
N
ZnMe
(P)
(M)
pure conformation
catalyst
We report herein the use of catalysts with flexible biaryl
axes that are only fixed by a metal ion, to control enantio-
selectivity. Enantiopure pyridylterpenols with axial
chirality of this type (Figure 1) are accessible through a
single synthetic step from commercially available terpen-
ones and 2,6-diphenyl pyridine. These pyridylterpenols
Scheme 2 Observed elimination of the conformational equilibrium
during the formation of the catalytically active zinc alkoxide
The precatalysts 1–3 were employed for the asymmetric
alkynylation of aromatic aldehydes with phenylacetylene
as a model system for acetylenes of further synthetic inter-
est.
SYNLETT 2011, No. 17, pp 2505–2508
Advanced online publication: 22.09.2011
DOI: 10.1055/s-0030-1260325; Art ID: B07611ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1
Because the flexible biaryl systems were found to depend
strongly on the reaction conditions, four procedures were
tested to determine the most promising menthyl ligand in

2506
M. Leven et al.
LETTER
order to find an optimum for a general procedure B and C were carried out analogously except that the re-
(Table 1). The most important parameter affecting the action time for the preformation of the phenylacetylide
yield and ee was found to be the in situ preformation of the was 5 minutes; Procedure C employed a 1:1 mixture of
alkynylzinc species. The test catalytic reactions were all toluene and n-hexane as solvent. Procedure D avoided di-
carried out with 5 mol% precatalyst and all yields were rect reactions of the preformed catalysts with phenylacet-
isolated (Table 1).
ylene; thus, alkynylzinc and zinc alkoxide were generated
separately and combined before aldehydes were added.
R
A comparison of the procedures shown in Table 1 reveals
that the yields depend strongly on the duration of the pre-
formation of the alkynylzinc. The longer phenylacetylene
is allowed to react with dimethyl zinc and the precatalyst,
the higher the yields. The ee value decreases from 86 to
66% with longer equilibration of phenylacetylene among
the zinc species before the aldehydes are added (see pro-
cedures B and A). The type of aldehyde employed was
also significant. 1-Naphthaldehyde gave the highest ee
and yield (up to 99% yield and 82% ee) whereas the pro-
pargylic alcohol formed from trimethylacetaldehyde was
almost completely racemic (8% ee). Because the best re-
sults were achieved by applying procedure A, precatalysts
2 and 3 were tested according to procedure A.
H
Ph
1) RCHO
L* (5 mol%)
ZnMe2
Ph
H
equilibration
2) aq work-up
preformation
of acetylides
OH
Scheme 3 Stages of the zinc-catalyzed addition of phenylacetylene
to aldehydes with organozinc reagents (L* are pyridyl phenylene ter-
penols 1–3)
Table 1 Alkynylation of Aromatic Aldehydes with Phenyl-acety-
lene in the Presence of Dimethyl Zinc and the Precatalyst 1
(Scheme 1)
Aldehyde
Yield (%)a ee (%)a Enantiomer Procedureb
CHO
61
88
99
66
53
52
R
A
A
A
Table 2 Alkynylation of Aromatic Aldehydes with Phenylacety-
lene in the Presence of Dimethyl Zinc and Precatalyst 2 (Scheme 1)a
F
CHO
n.d.
R
Aldehyde
Yield (%)b ee (%)b
Enantiomer
CHO
54
88
87
57
55
16
S
CHO
99
82
R
A
F
CHO
n.d.
CHO
86
31
8
R
R
A
B
CHO
CHO
S
CHO
86
99
99
19
0
S
CHO
CHO
CHO
39
49
83
69
R
R
C
D
CHO
a Procedure A was used in all cases (Table 1).
b All Yields are isolated and the ee values were determined by chiral
HPLC.
a All Yields are isolated and the ee was determined by chiral HPLC.
b Procedure A: Precatalyst and dimethyl zinc were stirred at r.t. for
30 min in toluene. Phenylacetylene was added subsequently and the
mixture was stirred at 0 °C for 45 min before aldehyde was added.
Procedure B: See procedure A with stirring catalyst, dimethyl zinc
and phenylacetylene for 5 min. Procedure C: See procedure B with
toluene–n-Hexane (1:1) as solvent. Procedure D: See procedure A,
precatalyst (0.5 mmol) was stirred with dimethyl zinc (0.6 mmol) in
toluene for 45 min and, separately, a mixture of dimethyl zinc and
phenylacetylene was stirred in toluene for 30 min then added at 0 °C
to the catalyst complex.
These results presented in Table 2 suggest that the men-
thone-based ligand 1 performs much better in this type of
reaction than the fenchol ligand 2. The results for benzal-
dehyde and 3-fluorobenzaldehyde are similar (cf. Table 1
and Table 2), but 1-naphthaldehyde, cinnamic aldehyde
and trimethylacetaldehyde gave poor ee values (up to
52%), although the yields were high (up to 99%). The ver-
benone based ligand 3 also gave moderate ee values (up to
42%) and yields up to 99% (Table 3).
In procedure A, the precatalyst and dimethyl zinc were
combined and equilibrated. Phenylacetylene was added
and allowed to react with the zinc species for 45 minutes,
before the aldehydes were added (Scheme 3). Procedures
A surprising result of this study was the strong influence
of the applied reaction times. The significant effect of the
reaction protocol on the yields can be explained by the
Synlett 2011, No. 17, 2505–2508 © Thieme Stuttgart · New York

LETTER
Enantioselective Alkynylation of Aromatic Aldehydes
2507
(GO-930/9-1) as well as the Bayer AG, the BASF AG, the Wacker
AG, the Evonic AG, the Raschig GmbH, the Symrise GmbH, the
Solvay GmbH, and the OMG group for generous support.
Table 3 Alkynylation of Aromatic Aldehydes with Phenylacety-
lene in the Pesence of Dimethyl Zinc and Precatalyst 3 (Scheme 1)a
Aldehyde
Yield(%)b
ee (%)
22
Enantiomer
S
References and Notes
CHO
51
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F
CHO
99
91
25
9
n.d.
S
CHO
65
83
42
3
S
S
CHO
CHO
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a Procedure A was used in all cases (Table 1).
b All Yields are isolated and the ee values were determined by chiral
HPLC.
(4) (a) Wang, Q.; Chen, S. Y.; Yua, X. Q.; Pu, L. Tetrahedron
2007, 63, 4422. (b) Ramón, D. J.; Yus, M. Chem. Rev. 2006,
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A. S. C. Tetrahedron: Asymmetry 2003, 14, 449.
formation of aryl or alkyl ethanols as side products by re-
action with residual dimethyl zinc.5a
The enantioselectivities of the employed catalysts depend
on the duration of zinc acetylide preformation. When the
catalyst reacted with phenyl acetylene over a period of 45
minutes prior to addition of the aldehyde (benzaldehyde,
procedure A, Table 1) 69% ee was found. However, the
enantiomeric excess was increased to 86% when the reac-
tion with phenyl acetylene was restricted to only 5 min-
utes in an equivalent procedure (Table 1).
(5) (a) Liebehentschel, S.; Cvengroš, J.; Jacobi von Wangelin,
A. Synlett 2007, 2574. (b) Emmerson, D. P. G.; Hems, W.
P.; Davis, B. J. Org. Lett. 2006, 8, 207. (c) Watts, C. C.;
Thoniyot, P.; Hirayama, L. C.; Romano, T.; Singaram, B.
Tetrahedron: Asymmetry 2005, 16, 1829. For amino- and
pyridyl-terpenols for the addition of zinc dialkyls to
aldehydes, see also: (d) Steigelmann, M.; Nisar, Y.;
Rominger, F.; Goldfuss, B. Chem. Eur. J. 2002, 8, 5211.
(e) Goldfuss, B.; Steigelmann, M.; Khan, S. I.; Houk, K. N.
J. Org. Chem. 2000, 65, 77. (f) Goldfuss, B.; Steigelmann,
M.; Romiger, F. Eur. J. Org. Chem. 2000, 1785. For
ligands also containing aryl terpenol moieties, see:
(g) Goldfuss, B.; Steigelmann, M.; Löschmann, T.;
Schilling, G.; Rominger, F. Chem. Eur. J. 2005, 11, 4019.
(h) Gliga, A.; Schumacher, M.; Klare, H.; Soki, F.; Neudörfl,
J. M.; Goldfuss, B. Chem. Eur. J. 2011, 2, 256.
Therefore, it is clear that the catalytically active zinc
alkoxide is modified in the presence of phenyl acetylene
or the corresponding alkynyl zinc species. According to
NMR experiments, the catalytically active methyl zinc
alkoxide, based on ligand 1, was almost completely trans-
formed into species without methyl zinc groups under the
catalytic conditions.
(i) Goldfuss, B.; Löschmann, T.; Rominger, F. Chem. Eur. J.
2004, 10, 5422.
According to NOE experiments, the conformation of the
chiral biaryl axis is not retained for longer reaction times.
The conformational purity of the chiral biaryl axis could
only be determined for the initial unimpaired methyl zinc
complex. Enantioselectivities, however, are known to de-
pend nearly entirely on the conformations of the chiral bi-
aryl axes.9 Hence, the substitution of alkyl for alkynyl
groups at the zinc, and a conformational equilibration in
the employed catalyst system, explain why longer reac-
tion times result in decreased enantioselectivities in alde-
hyde alkynylations.10
(6) (a) Trost, B. M. J. Am. Chem. Soc. 2000, 122, 12003.
(b) Trost, B. M.; Mino, T. J. Am. Chem. Soc. 2003, 125,
2410. (c) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem.
Soc. 2001, 123, 3367. (d) Trost, B. M.; Shin, S.; Sclafani, J.
J. Am. Chem. Soc. 2005, 127, 8602.
(7) Other catalysts for the asymmetric alkynylation of
aldehydes: Sulfonamides: (a) Forrat, V. J.; Prieto, O.;
Ramón, D. J.; Yus, M. Chem. Eur. J. 2006, 12, 4431.
(b) Fang, T.; Du, D. M.; Lu, S. F.; Xu, J. Org. Lett. 2005, 7,
2081. (c) Xu, Z.; Lin, L.; Xu, J.; Yan, W.; Wang, R. Adv.
Synth. Catal. 2006, 348, 506. (d) Knochel, P.; Millot, N.;
Rodriguez, L. A.; Tucker, C. E. Org. React. 2004, 417.
Mandelamides: (e) Blay, G.; Fernandez, J.; Marco-
Alexandre, A.; Pedro, J. R. J. Org. Chem. 2006, 71, 6674.
Carbohydrate-derived catalysts: (f) Emmerson, D. P. G.;
Hems, W. P.; Davis, B. G. Org. Lett. 2006, 8, 207.
Cinchona alkaloids: (g) Anand, N. K.; Carreira, E. M. J. Am.
Chem. Soc. 2001, 123, 9687. (h) Ekström, J.; Zaitsev, A. B.;
Adolfsson, H. Synlett 2006, 885. Other alkaloid derived
catalysts: (i) Scarpi, D.; Galbo, F. L.; Guarna, A.
Acknowledgment
We are grateful to Dr. Nils E. Schloerer for carrying out elaborate
1D and 2D NMR studies supporting this work. We especially thank
the Fonds der Chemischen Industrie for financial support. We also
thank the Deutsche Forschungsgemeinschaft (DFG) for funding
Synlett 2011, No. 17, 2505–2508 © Thieme Stuttgart · New York

2508
M. Leven et al.
LETTER
Tetrahedron: Asymmetry 2006, 17, 1409.
at a temperature of 295 K.
(8) (a) Hayashi, T.; Yamamoto, A.; Hagihara, T.; Ito, Y.
Tetrahedron Lett. 1986, 27, 191. (b) Brunel, J. M. Chem.
Rev. 2005, 105, 857. (c) Shibasaki, M.; Sasai, H.; Arai, T.
Angew. Chem. Int. Ed. Engl. 1997, 36, 1871; Angew. Chem.
1997, 109, 1290. (d) Sasai, H.; Arai, T.; Satow, Y.; Houk, K.
N. J. Am. Chem. Soc. 1995, 117, 6194. (e) Grant, G. J.;
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(f) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102,
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Johnsen, W. L. Org. Lett. 2007, 9, 3969. (h) Brune, J. M.
Chem. Rev. 2005, 105, 857. (i) Matteoli, U.; Beghetto, V.;
Schiavon, C.; Scrivanti, A.; Menchi, G. Tetrahedron:
Asymmetry 1997, 8, 1403.
(9) (a) Leven, M.; Schlörer, N. E.; Neudörfl, J. M.; Goldfuss, B.
Chem. Eur. J. 2010, 13443. For biaryls containing terpene
moieties, see also: (b) Alpagut, Y.; Goldfuss, B.; Neudörfl,
J. Beilstein J. Org. Chem. 2008, 4, 25. (c) Lange, D. A.;
Neudörfl, J.-M.; Goldfuss, B. Tetrahedron 2006, 62, 3704.
(d) Kop-Weiershausen, T.; Lex, J.; Neudörfl, J.-M.;
Goldfuss, B. Beilstein J. Org. Chem. 2005, 1, 6. (e) Soki,
F.; Neudörfl, J.-M.; Goldfuss, B. Tetrahedron 2005, 61,
10449.
Procedure A: Pyridyl phenylene terpenol (0.074 mmol;
5 mol%; 1: 28 mg; 2: 29 mg; 3: 28 mg) was degassed in
vacuum for 10 min, then dissolved in toluene (6 mL) and a
solution of dimethyl zinc (2.0 M in toluene, 1.80 mL 3.6
mmol) was added at 0 °C. The ice bath was removed and the
catalyst was equilibrated for 30 min at r.t. Phenylacetylene
(3 mmol, 0.33 mL) was added at r.t. and the mixture was
further stirred for 45 min. The mixture was cooled on the ice
bath again and aldehyde (1.0 mmol) was added. The
colorless solution was kept at 0 °C for 3 days and the
reaction was subsequently quenched with saturated NaHSO4
(5 mL). The organic phase was separated, the aqueous phase
was extracted with MTBE (3 × 5 mL), and the combined
organic phases were evaporated. The resulting oil was
purified by column chromatography (n-hexanes–ethyl
acetate, 4:1; 70 g SiO2) to give the pure product.
Procedure B: See procedure A, with 5 min reaction time
after adding phenylacetylene.
Procedure C: See procedure A, with 5 min reaction time
after adding phenylacetylene and the solvent was replaced
by a mixture of toluene and n-hexanes (1:1).
Procedure D: See procedure A, the precatalyst was stirred
with dimethyl zinc (0.6 mmol) in toluene (3 mL) for 45 min
and, separately, a mixture of dimethyl zinc (3.0 mmol) and
phenylacetylene (3.0 mmol) in toluene (3 mL) was stirred
for 30 min, then added to the catalyst complex at 0 °C.
1,3-Diphenylprop-2-yn-1-ol:11b 1H NMR (300 MHz,
CDCl3): d = 2.36 (s, 1 H), 5.72 (s, 1 H), 7.34–7.64 (m, 10 H).
13C NMR (75.5 MHz, CDCl3): d = 42.0, 118.1, 123.0, 128.9,
140.0. HPLC [Daicel Chiracel OD-H; l = 254 nm; hexane–
IPA = 90:10; 0.8 mL/min]: tR = 10.7 (R), 17.4 (S) min.
1-(3-Fluorophenyl)-3-phenylprop-2-yn-1-ol:11c 1H NMR
(300 MHz, CDCl3): d = 1.28 (s, 1 H), 5.71 (s, 1 H), 7.28–
7.50 (m, 9 H). 13C NMR (75.5 MHz, CDCl3): d = 64.3, 86.6,
88.2, 113.7, 115.3, 122.0, 122.0, 122.3, 128.4, 128.8, 130.2,
131.8, 143.2, 164.5. HPLC [Daicel Chiracel OD-H; l = 254
nm; hexane–IPA = 90:10; 0.8 mL/min]: tR = 9.4, 21.8 min.
(E)-1,5-Diphenylpent-1-en-4-yn-3-ol:11a 1H NMR (300
MHz, CDCl3): d = 5.31 (t, J = 6.0 Hz, 1 H), 6.38 (m, 1 H),
6.90 (d, 1 H), 7.28–7.49 (m, 10 H). 13C NMR (75.5 MHz,
CDCl3): d = 63.5, 86.5, 87.9, 122.4, 126.8, 128.1, 128.2,
128.4, 128.7, 131.9, 132.1, 136.0. HPLC [Daicel Chiracel
OD-H; l = 254 nm; hexane–IPA = 90:10; 0.8 mL/min]:
tR = 14.1 (R), 39.8 (S) min.
(10) All reactions were carried out under an argon atmosphere
using Schlenk techniques. Solvents used in chemical
conversions were dried by standard methods and distilled
under argon prior to use. The enantiomeric excesses of the
chiral propargylic alcohols were determined by chiral
HPLC. A La Chrome elite unit from Hitachi was employed
together with a 25 cm Chiracel OD-H chiral column (flow:
0.8 mL/min; pressure: 32 bar; detection l = 240 nm; eluent:
90% n-hexanes and 10% i-propanol). The enantiomers of the
alcohols were identified by comparison to reference
spectra.11
NMR spectroscopy. Deuterated solvents where purchased
from Acros Organics. Toluene-d8 was stored over sodium-
lead alloy. NMR spectra for characterization of compounds
where recorded with a Bruker DPX 300 spectrometer (1H
frequency 300.13 MHz). 2D NMR and one-dimensional
high resolution spectra for analysis of the catalytically active
system were recorded with a Bruker AVANCE II 600
spectrometer (1H frequency 600.20 MHz) using a triple
resonance Z gradient probe and processed using TopSpin 2.1
software (Bruker inc.). The temperature was calibrated with
a 100% MeOH sample. 600 MHz 1D and 2D NMR
experiments were carried out according to the following
procedures.
Characterization of the methyl zinc alkoxide based on
ligand 1: Ligand 1 (0.026 mmol, 10 mg) was charged into
a NMR tube and degassed in vacuo for 10 min. absolute
toluene-d8 (0.30 mL) was added prior to addition of dimethyl
zinc (2 M in toluene, 0.8 mL, 0.156 mmol). The constitution
of the formed methyl zinc complex was confirmed by H,C-
HMQC, H,N-HMQC and H,H-NOESY spectroscopic
analysis at a temperature of 295 K. The conformation of the
chiral biaryl axis was determined by characteristic NOE
contacts.
1-(Naphthalen-1-yl)-3-phenylprop-2-yn-1-ol:11a 1H NMR
(300 MHz, CDCl3): d = 2.40 (d, J = 6.0 Hz, 1 H), 6.38 (d,
J = 5.9 Hz, 1 H), 7.40–7.80 (m, 8 H), 7.95 (d, J = 10.1 Hz,
1 H), 8.12 (d, J = 8.2 Hz, 1 H), 8.43 (d, J = 8.4 Hz, 1 H),
9.27 (d, J = 8.5 Hz, 1 H). 13C NMR (75.5 MHz, CDCl3): d =
63.3, 87.2, 89.0, 122.4, 124.9, 127.0, 128.4, 128.8, 130.7,
131.3, 131.8, 134.1, 135.4, 135.5, 138.0. HPLC [Daicel
Chiracel OD-H; l = 254 nm; hexane–IPA = 90:10; 0.8 mL/
min]: tR = 15.2 (R), 28.6 (S) min.
4,4-Dimethyl-1-phenylpent-1-yn-3-ol:11d 1H NMR (300
MHz, CDCl3): d = 1.09 (s, 9 H), 1.95 (1 H), 4.26 (d, J = 5.9
Hz, 1 H), 7.28–7.46 (m, 5 H). 13C NMR (75.5 MHz, CDCl3):
d = 25.4, 36.0, 71.9, 85.7, 89.0, 122.8, 128.3, 128.6, 131.7.
HPLC [Daicel Chiracel OD-H; l = 254 nm; hexane–
IPA = 90:10; 0.8 mL/min]: tR = 8.0 (R), 10.7 (S) min.
(11) (a) Gou, S.; Ye, Z.; Huang, Z.; Ma, X. Appl. Organomet.
Chem. 2010, 24, 374. (b) Geoghegan, P.; O’Leary, P.
Tetrahedron: Asymmetry 2010, 21, 867. (c) No HPLC
reference data available in the literature; (d) Frantz, D. E.;
Fässler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
1806.
In situ study of the reaction of the methyl zinc alkoxide
based on 1 with phenylacetylene: A sample was prepared
as described above. The mixture was equilibrated over a
period of 30 min and phenylacetylene (0.02 mL, 0.156
mmol) was added. The mixture was equilibrated for 1 h
prior to use for measurements. The methylzinc alkoxide
derivative of 1 was shown to be almost completely converted
into a new species, which was analyzed by H,C-HMQC,
H,C-HMBC, H,N-HMQC, and H,H-NOESY spectroscopy
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