Hydroxymethylpyridine catalysts for the enantioselective alkynylation of aldehydes

Article abstract of DOI:10.1055/s-2007-986630

Chiral 2-hydroxymethylpyridines based on fenchol and menthol were evaluated as catalysts for the enantioselective addition of terminal alkynes to aldehydes. With one of the fenchol-based ligands, the operationally simple protocol gave propargylic alcohols

Full text of DOI:10.1055/s-2007-986630

2
574
LETTER
Hydroxymethylpyridine Catalysts for the Enantioselective Alkynylation
of Aldehydes
H
S
ydroxymethy
a
lpyridine-C
b
atalyzed Al
r
kynylatio
i
ns na Liebehentschel, Ján Cvengroš, Axel Jacobi von Wangelin*
Department of Organic Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, Germany
Fax +49(221)4705057; E-mail: axel.jacobi@uni-koeln.de
Received 20 March 2007
O
Abstract: Chiral 2-hydroxymethylpyridines based on fenchol and
menthol were evaluated as catalysts for the enantioselective addi-
tion of terminal alkynes to aldehydes. With one of the fenchol-based
ligands, the operationally simple protocol gave propargylic alcohols
with excellent yields and up to 85% ee for various aldehyde and
alkyne derivatives.
BuLi, THF,
–78 °C
R
R'
R
R'
Br
N
Li
N
N
OH
Scheme 1 One-pot synthesis of hydroxymethylpyridines
Keywords: alkynes, propargylic alcohols, pyridines, asymmetric
catalysis, zinc
This work utilizes a set of 12 chiral hydroxymethylpyr-
idines derived from (–)-fenchone (1a–d), (–)-menthone
(
2a–d), and (–)-8-phenylmenthone (3a–d), respectively,
The enantioselective addition of metalated terminal
alkynes to aldehydes is one of the most important methods
1
9,20
provided by Schmalz and co-workers (Figure 1).
for the synthesis of chiral secondary propargylic alcohols In an initial screening, we investigated the catalytic activ-
1
exhibiting high atom economy. The resultant optically ity of hydroxymethylpyridines 1a–3d in a model system,
active propargylic alcohols are versatile building blocks the enantioselective addition of phenylacetylene to 2-bro-
for the synthesis of a wide range of natural products and mobenzaldehyde (Table 1). The catalytically active spe-
2
pharmaceuticals, and besides, its alkyne and hydroxy cies was preformed by slowly adding a solution of Me
Zn
2
functions can be further manipulated. Organozinc re- in toluene to a mixture of alkyne and ligand in diglyme at
agents constitute versatile and useful organometallics by room temperature. After stirring for 90 minutes, the alde-
virtue of their compatibility with many functional groups, hyde was added and the resulting solution stirred at room
which renders them highly attractive alternatives to their temperature. In all cases, conversion of 2-bromobenzalde-
3
lithium and magnesium counterparts.
hyde was >90% with quantitative yield of the propargylic
alcohol in most cases. Gratifyingly, the sometimes-
Among the many chiral catalysts for asymmetric alkynyl-
ations of aldehydes reported to date, e.g. ephedrines,
cinchona alkaloids, terpene- and carbohydrate-derived
amino alcohols, ferrocenyl oxazoline alcohols, para-
cyclophane-based imine phenols, oxazolidines, substi-
tuted prolines, b-hydroxyamides and sulfonamides,
mandelamides, BINOLs, and Trost’s bisprolinols,
4
5
pyridylfenchols
pyridylmenthols
6
7
8
9
N
H
1
0
11
14
N
H
N
H
OH
OH
1
2
13
OH
1a
2a
3a
chiral ligands possessing a pyridine donor have, to the
best of our knowledge, appeared to be not very effective.
Precedents include Bolm’s work on the asymmetric
alkylation of aldehydes and enones using catalytic
N
Br
N
Br
N
Br
OH
OH
OH
amounts of optically active pyridines and C -symmetric
2
1
b
2b
3b
1
5
2
,2¢-bipyridines. Herein, we report on the application of
novel pyridine ligands containing chiral fenchol and
menthol moieties to the enantioselective alkynylation of
1
6,17
benzaldehydes.
N
Me
N
Me
Ph
N
Me
OH
OH
OH
Hydroxymethylpyridines can be easily synthesized by a
mild and efficient one-pot procedure from 2-bromo-
pyridines, a chiral ketone, and BuLi via bromine–lithium
OH
3c
1c
2c
1
5,17b,18,19
exchange in high yields (Scheme 1).
N
N
Ph
OH
3d
1d
SYNLETT 2007, No. 16, pp 2574–2578
0
1
.1
0
.2
0
0
7
Advanced online publication: 28.08.2007
DOI: 10.1055/s-2007-986630; Art ID: G09207ST
Georg Thieme Verlag Stuttgart · New York
Figure 1 Series of chiral hydroxymethylpyridines19c
©

LETTER
Hydroxymethylpyridine-Catalyzed Alkynylations
2575
Table 1 Catalyst Screening in the Model Reaction
Br
OH
*
Br
L* (20 mol%)
Br
OH
*
O
Me2Zn (3 equiv)
+
Ph
+
Me
diglyme, 20 h, r.t.
Ph
4
5
6
7
Entry
Ligand
(R)-1a
(R)-1b
(R)-1c
(R)-1d
(S)-2a
(S)-2b
(S)-2c
(S)-3a
(S)-3b
(S)-3c
(S)-3d
6:7a
ee of 6 (%)
Config of 6b
(–)-R
(–)-R
(–)-R
(–)-R
(+)-S
1
2
3
4
5
6
7
8
9
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
49
77
66
50
2
13
12
17
34
24
25
(+)-S
(+)-S
(+)-S
(–)-R
(+)-S
1
1
0
1
(+)-S
a
By GC-MS.
b
By comparison of optical rotation with literature precedents.
competitive methyl addition toward 7 was completely This might be due to chelating coordination of the alde-
suppressed under the reaction conditions. Pyridylfenchols hyde to zinc(II), as 4-nitrobenzaldehyde gave a signifi-
1
a–d induced the highest enantioselectivities (49–77% ee, cantly lower ee (entry 7). As a representative for aliphatic
entries 1–4), while 8-phenylmenthols 3a–d and menthols aldehydes, cyclohexane carbaldehyde was reacted but
a–c gave poor ee. However, the employment of bromo- afforded only moderate enantioselectivity (entry 8). a,b-
2
pyridine 3b effected an abnormal reversal of enantio- Unsaturated aldehydes also gave moderate to good ee
selectivity within the menthol series favouring the R- (entries 11–14). As a representative of aliphatic alkynes,
enantiomer (entry 9). The best results were obtained with 1-octyne was employed in identical reactions with
1
5b,19b
fenchone-derived ligand 1b
giving quantitative yield cinnamaldehyde and 2-bromobenzaldehyde, albeit with
moderate ee (entries 14, 15).
of propargylic alcohol 6 with 77% ee (entry 2).
After having established the optimal catalyst system, we Figure 2 illustrates a simple mechanistic explanation of
focused our attention on the optimization of reaction the observed stereoselectivity in the presence of fenchol
parameters such as solvent, temperature, and duration of ligand 1b which is based upon steric repulsion in the
alkynylzinc preformation. Unlike most literature proto- transition state of the si attack thus favoring re facial
22
cols that use toluene as solvent, Table 2 documents the addition. With a-bromo cinnamaldehyde (entry 13), one
superiority of hexane (entry 10). This resulted in en- might invoke an alternative transition state involving
hanced enantioselectivity and allowed for rapid preforma- additional Br–Zn coordination.
tion of the alkynylzinc species within five minutes. To the
In summary, we have demonstrated the usefulness of
best of our knowledge, this accounts for the fastest
chiral hydroxymethylpyridines as catalysts for the enan-
quantitative preformation of the desired alkynylzinc spe-
tioselective alkynylation of aldehydes. With pyridyl-
2
1
cies without residual methyl addition toward 7.
fenchol 1b, very good enantioselectivities have been
We then extended the scope of the general methodology obtained. Optimizations of the reaction parameters result-
to other substrates. Various substituted benzaldehydes ed in an extremely rapid preformation of the intermediate
were reacted with phenylacetylene, ethyl propiolate, or alkynylzinc species within five minutes at room tempera-
trimethylsilylacetylene under identical conditions. In all ture. No residual methyl addition to the aldehyde has been
cases, conversions were >90% with virtually no formation detected under the reaction conditions. Applications of
of methyl addition product (<1%). 2-Nitrobenzaldehyde this easily accessible class of ligands to other asymmetric
gave the best enantioselectivities (82–85% ee) indepen- reactions are currently being investigated.
dent on the nature of the alkyne (entries 6, 9, 10, Table 3).
Synlett 2007, No. 16, 2574–2578 © Thieme Stuttgart · New York

2
576
S. Liebehentschel et al.
LETTER
Table 2 Optimization of the Model Reactiona
a
Table 3 Substrate Scope (continued)
Br
O
1b (20 mol%)
Me2Zn (3 equiv)
Br
OH
1b (20 mol%)
Me2Zn (3 equiv)
OH
O
+
Ph
+
R
Ar
solvent, 20 h
Ar
hexane, 20 h, r.t.
R
4
5
6
Entry
Aldehyde
R
ee (%)b
Configc
Entry Solvent
Temp (°C)b Protocolc ee (%)d
Me
O
513a
Ph
Ph
59
85
(–)-R
(–)-R
1
2
3
4
5
6
7
8
9
0
1
diglyme
toluene
20
20
20
20
20
20
20
20
10
5
A
A
A
A
A
A
A
B
B
B
B
72 (R)
65 (R)
73 (R)
41 (R)
76 (R)
79 (R)
79 (R)
78 (R)
84 (R)
85 (R)
81 (R)
NO2
O
diglyme–toluene (1:1)
614g
THF
PhCl
O
714g
Ph
Ph
63
(+)-R
hexane–toluene (1:1)
hexane
O N
2
O
O
O
hexane
813b
47d
85
(–)-R
Re
hexane
1
1
hexane
NO2
NO2
hexane
0
9
CO Et
2
a
b
c
Conversions always >90%.
Reaction temperature. Preformation always at r.t.
A: ligand, solvent, phenylacetylene, Me Zn, 1.5 h, r.t., then 2-bro-
mobenzaldehyde, 20 h, r.t. B: like protocol A, but mixture was stirred
for 5 min at r.t. before addition of 2-bromobenzaldehyde.
2
10
TMS
TMS
Ph
82
Re
d
Determined by HPLC; absolute configuration determined by
comparison of optical rotation with literature precedents.
O
1
1
1
114g
213a
314g
53
81
77
31
69
(–)-R
(–)-R
(–)-S
Re
Table 3 Substrate Scopea
Ph
1
b (20 mol%)
Me2Zn (3 equiv)
OH
O
O
O
O
+
R
Ar
Ar
hexane, 20 h, r.t.
R
Ph
Br
Entry
114g
Aldehyde
R
ee (%)b
Configc
TMS
n-Hex
n-Hex
O
Ph
76
78
64
53
(+)-R
(–)-R
(–)-R
R
Ph
1414g
Br
O
28
Ph
Ph
Ph
Ph
Br
O
1523
Re
OMe O
313a
a
Conversions always >90%. Preformation time of active alkynylzinc
species: 5 min.
Determined by HPLC.
O
b
414g
c
Determined by comparison of optical rotation with literature
precedents.
MeO
d
Reaction performed at 5 °C.
e
Tentatively assigned by analogy to similar compounds.
Synlett 2007, No. 16, 2574–2578 © Thieme Stuttgart · New York

LETTER
Hydroxymethylpyridine-Catalyzed Alkynylations
2577
Acknowledgment
I.
Br
O
Me
O
Y-e
Ph
N
R
R
H
We thank Prof. H.-G. Schmalz (University of Cologne) for the
donation of ligands and excellent technical support. A.J.v.W. is an
Emmy-Noether fellow of the DFG and a recipient of the 2007
Thieme Journal Award.
Zn
R
Zn
Me
H
*
HO
re facial attack
Ph
II.
References
Me
Br
H
H
R
(1) For reviews on alkyne additions to carbonyl compounds,
see: (a) Frantz, D. E.; Fässler, R.; Tomooka, C. S.; Carreira,
E. M. Acc. Chem. Res. 2000, 33, 373. (b) Pu, L.
Zn
Y-e
Ph
N
R
O
S
O
*
HO
Zn
si facial attack
Ph
Tetrahedron 2003, 59, 9873. (c) Cozzi, P. G.; Hilgraf, R.;
Zimmermann, N. Eur. J. Org. Chem. 2004, 4095.
Me
(d) Aschwanden, P. A.; Carreira, E. M. In Acetylene
Figure 2 Facial selectivity in the model reaction with ligand 1b
Chemistry: Chemistry, Biology, and Material Science;
Diederich, F.; Stang, P. J.; Tykwinski, R. R., Eds.; Wiley-
VCH: Weinheim, 2005, 101.
(
2) (a) Modern Acetylene Chemistry; Stang, P. J.; Diederich, F.,
Eds.; VCH: Weinheim, 1995. (b) Marshall, J. A.; Wang, X.
J. J. Org. Chem. 1992, 57, 1242. (c) Corey, E. J.; Cimprich,
K. A. J. Am. Chem. Soc. 1994, 116, 3151. (d) Roush, W. R.;
Sciotti, R. J. J. Am. Chem. Soc. 1994, 116, 6457. (e) Myers,
A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492.
General Procedure for the Asymmetric Alkynylation of Alde-
hydes
To a solution of phenylacetylene (100 mL, 0.9 mmol, 3 equiv) and
1
b (18.6 mg, 60 mmol, 0.2 equiv) in dry hexane (1 mL) was added
a solution of Me Zn in toluene (450 mL, 2.0 M in toluene, 0.9 mmol,
3
2
(
6
f) Trost, B. M.; Krische, M. J. J. Am. Chem. Soc. 1999, 121,
131.
equiv) at r.t. under argon. The clear solution was stirred for 5 min
at r.t., then aldehyde (0.3 mmol, 1 equiv) was added through a sy-
ringe and the resulting reaction mixture stirred for 20 h at r.t. The
(
3) For reviews on organozinc chemistry, see: (a) Knochel, P.;
Calaza, M. I.; Hupe, E. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A.; Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004, 619. (b) Knochel, P.; Millot,
N.; Rodriguez, A.; Tucker, C. E. Org. React. 2001, 58, 417.
reaction was quenched with sat. aq NaHSO solution (2 mL) and
3
stirred vigorously for 15 min. The organic phase was separated and
the aqueous phase extracted with MTBE (3 × 5 mL). The combined
organic layers were washed with brine, dried over MgSO , concen-
4
(
c) Jacobi von Wangelin, A.; Frederiksen, M. U. In
trated and purified by silica gel chromatography (cyclohexane–
EtOAc, 3:1). The enantioselectivities of the propargyl alcohols
were determined by HPLC on a Chiralcel OD-H column.
Transition Metals for Organic Synthesis, 2nd ed.; Beller, M.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004, 519.
(
(
4) Kamble, M. J.; Singh, V. K. Tetrahedron Lett. 2003, 44,
5347.
Characterization of the New Compounds
5) (a) Frantz, D. E.; Fässler, R.; Carreira, E. M. J. Am. Chem.
Soc. 2000, 122, 1806. (b) Anand, N. K.; Carreira, E. M.
J. Am. Chem. Soc. 2001, 123, 9687.
6) (a) Watts, C. C.; Thoniyot, P.; Hirayama, L. C.; Romano, T.;
Singaram, B. Tetrahedron: Asymmetry 2005, 16, 1829.
Ethyl 4-Hydroxy-4-(2-nitrophenyl)but-2-ynoate
1
H NMR (300 MHz, CDCl ): d = 7.93–7.53 (m, 4 H), 6.20 (s, 1 H),
3
1
3
4
.26 (q, 2 H), 3.63 (s, 1 H), 1.32 (t, 3 H). C NMR (75 MHz,
(
CDCl ): d = 153.1, 147.5, 134.2, 133.7, 129.9, 129.4, 125.3, 84.1,
3
7
1
7.7, 62.5, 61.0, 13.9. IR (ATR): 3360, 2972, 2237, 1712, 1609,
528, 1447, 1347, 1248, 1093, 1029, 948, 856, 813, 789, 751, 705
(b) Yamashita, M.; Yamadam, K.; Omioka, K. Adv. Synth.
–
1
Catal. 2005, 347, 1649. (c) Emmerson, D. P. G.; Hems, W.
P.; Davis, B. J. Org. Lett. 2006, 8, 207.
cm . MS (EI, 70 eV): m/z = 281, 237, 217, 207, 187, 171, 170, 159,
1
8
50, 148, 143, 135, 134, 132, 130, 121, 115, 105, 104, 93, 92, 87,
1, 80, 79, 78, 77, 69, 65, 56, 54, 53. Determination of ee by HPLC
(
7) Li, M.; Zhu, X.-Z.; Yuan, K.; Cao, B.-X.; Hou, X.-L.
Tetrahedron: Asymmetry 2004, 15, 219.
[
Daicel Chiralcel OD-H, l = 254 nm, hexane–i-PrOH (90:10); 1.0
(8) Dahmen, S. Org. Lett. 2004, 6, 2113.
mL/min; 85% ee]: t = 8.0 min (minor) and t = 8.7 min (major).
R
R
(
9) (a) Braga, A. L.; Appelt, H. R.; Silveria, C. C.; Wessjohann,
L. A.; Schneider, P. H. Tetrahedron 2002, 58, 10413.
[
4
a] +1.2 (c 0.5, CH Cl ). Anal. Calcd for C H NO : C, 57.83; H,
D 2 2 12 11 5
.45; N, 5.62. Found: C, 57.94; H, 4.47; N, 5.54.
(b) Kang, Y.; Wang, R.; Liu, L.; Da, C.; Yan, W.; Xu, Z.
Tetrahedron Lett. 2005, 46, 863.
(10) Han, Z.; Wang, R.; Zhou, Y.; Liu, L. Eur. J. Org. Chem.
2005, 934.
11) (a) Fang, T.; Du, D.-M.; Lu, S. F.; Xu, J. Org. Lett. 2005, 7,
2081. (b) Li, X.; Lu, G.; Kwok, W. H.; Chan, A. S. C. J. Am.
Chem. Soc. 2002, 124, 12636.
12) Blay, G.; Fernández, I.; Marco-Aleixandre, A.; Pedro, J. R.
J. Org. Chem. 2006, 71, 6674.
1
-(2-Nitrophenyl)-3-trimethylsilylprop-2-yn-1-ol
1
H NMR (300 MHz, CDCl ): d = 7.71–7.52 (m, 4 H), 5.98 (s, 1 H),
0
3
.27 (s, 9 H). 13C NMR (75 MHz, CDCl ): d = 133.7, 129.6, 129.3,
3
(
1
6
2
1
7
25.0, 61.8, –0.3. IR (ATR): 2961, 1529, 1351, 1250, 1038, 983,
–1
81, 663 cm . MS (EI, 70 eV): m/z = 248, 235, 232, 216, 214, 203,
02, 190, 189, 187, 173, 172, 164, 161, 160, 148, 147, 146, 145,
43, 135, 132, 130, 121, 119, 115, 107, 105, 104, 103, 93, 91, 83,
9, 75, 73, 67, 59, 55, 53. Determination of ee by HPLC [Daicel
(
(
13) (a) Wang, Q.; Chen, S.-Y.; Yua, X.-Q.; Pu, L. Tetrahedron
Chiralcel OD-H, l = 254 nm, hexane–i-PrOH (99:1); 0.5 mL/min;
8
2007, 63, 4422. (b) Lu, G.; Li, X.; Chen, G.; Chan, W. L.;
2% ee]: t = 17.1 min (minor) and t = 19.3 min (major). [a] –0.6
R R D
Chan, A. S. C. Tetrahedron: Asymmetry 2003, 14, 449.
14) (a) Trost, B. M. J. Am. Chem. Soc. 2000, 122, 12003.
(
c 0.4, CH Cl ). Anal. Calcd for C H NO Si: C, 57.80; H, 6.06; N,
2 2 12 15 3
(
5
.62. Found: C, 57.91; H, 6.12; N, 5.58.
(
2
b) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc.
001, 123, 3367. (c) Trost, B. M.; Mino, T. J. Am. Chem.
Soc. 2003, 125, 2410. (d) Trost, B. M.; Fettes, A.; Shireman,
B. T. J. Am. Chem. Soc. 2004, 126, 2660. (e) Trost, B. M.;
Synlett 2007, No. 16, 2574–2578 © Thieme Stuttgart · New York

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S. Liebehentschel et al.
LETTER
Shin, S.; Sclafani, J. A. J. Am. Chem. Soc. 2005, 127, 8602.
(18) Herrmann, W. A.; Haider, J. J.; Fridgen, J.; Lobmaier, G. M.;
Spiegler, M. J. Organomet. Chem. 2000, 603, 69.
(19) (a) El Sheikh, S.; Schmalz, H.-G. Curr. Opin. Drug
Discovery Dev. 2004, 7, 882. (b) Elmas, S. Schmalz, H.-G.
Diploma Thesis; Universität zu Köln: Germany, 2005. (c)
Goto, S.; Velder, J.; El Sheikh, S.; Sakamoto, Y.; Mitani, M.;
Elmas, S.; Adler, A.; Becker, A.; Neudörfl, J.-M.; Schmalz,
H.-G.; manuscript in preparation.
(
4
f) Trost, B. M.; Yeh, V. S. C. Angew. Chem. Int. Ed. 2002,
1, 861; Angew. Chem. 2002, 114, 889. (g) Trost, B. M.;
Weiss, A. H.; Jacobi von Wangelin, A. J. Am. Chem. Soc.
2006, 128, 8.
(
15) (a) Bolm, C.; Schlingloff, G.; Harms, K. Chem. Ber. 1992,
125, 1191. (b) Kwong, H.-L.; Lee, W.-S. Tetrahedron:
Asymmetry 1999, 10, 3791. (c) Bolm, C.; Ewald, M.;
Zehnder, M.; Neuburger, M. A. Chem. Ber. 1992, 125, 453.
(20) For a concise review on chiral camphor-based pyridines, see:
Chelucci, G. Chem. Soc. Rev. 2006, 35, 1230.
(d) For the preparation of related chiral hydroxymethyl-
pyridines, see: Bolm, C.; Ewald, M.; Felder, M.; Schlingloff,
G. Chem. Ber. 1992, 125, 1169.
16) For precedent reference regarding SAR calculations of
chiral fenchone-based organozinc catalysts, see: Goldfuss,
B.; Steigelmann, M. J. Mol. Model. 2000, 6, 166.
17) For precedents on the asymmetric addition to aldehydes
using chiral fenchone-based ligands, see: (a) Goldfuss, B.;
Steigelmann, M.; Khan, S. I.; Houk, K. N. J. Org. Chem.
(21) Cozzi and coworkers reported on the ligand-free
preformation of alkynylzinc species within 30 min: Cozzi, P.
G.; Rudolph, J.; Bolm, C.; Norrby, P.-O.; Tomasini, C.
J. Org. Chem. 2005, 70, 5733.
(22) Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. 2002, 30,
49; Angew. Chem. 1991, 103, 34.
(
(
(23) Buckle, D. R.; Fenwick, A. E. J. Chem. Soc., Perkin Trans. 1
1989, 3, 477.
2000, 65, 77. (b) Genov, M.; Kostova, K.; Dimitrov, V.
Tetrahedron: Asymmetry 1997, 8, 1869.
Synlett 2007, No. 16, 2574–2578 © Thieme Stuttgart · New York