Asymmetric alkynyl additions to aldehydes catalyzed by tunable oxovanadium(V) complexes of Schiff bases of β-amino alcohols

Article abstract of DOI:10.1055/s-2006-948195

The first example of asymmetric alkynyl additions to aldehydes catalyzed by oxovanadium(V) catalysts of tridentate Schiff bases of β-amino alcohols 3a-h is reported. Catalytic reactions employing the best-performing catalyst 3g furnish chiral propargyl alcohols in good to excellent enantioselectivities from 73% to 99% ee. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-948195

LETTER
1871
Asymmetric Alkynyl Additions to Aldehydes Catalyzed by Tunable
Oxovanadium(V) Complexes of Schiff Bases of b-Amino Alcohols
Asymmetric
A
h
lkynyl
A
ddi
e
tions to
A
ld
n
ehyde
s
g-Hsiang Hsieh, Han-Mou Gau*
Department of Chemistry, National Chung-Hsing University, Taichung 402, Taiwan
Fax +886(4)22862547; E-mail: hmgau@dragon.nchu.edu.tw
Received 16 March 2006
alkynylzinc reagent from ZnEt2 and terminal alkynes at
room temperature.12
Abstract: The first example of asymmetric alkynyl additions to
aldehydes catalyzed by oxovanadium(V) catalysts of tridentate
Schiff bases of b-amino alcohols 3a–h is reported. Catalytic reac-
tions employing the best-performing catalyst 3g furnish chiral
propargyl alcohols in good to excellent enantioselectivities from
73% to 99% ee.
To our knowledge, there are only a couple examples of
asymmetric alkynyl additions to aldehydes catalyzed by
systems other than zinc and titanium metals. One is the
above-mentioned boron system by Corey and coworker
and another one is an In/BINOLate system by Shibasaki
and coworkers.13 Yet, there is no report of vanadium
catalysts for asymmetric alkynylation reactions. We here
report the first example of asymmetric alkynylation reac-
tions employing chiral oxovanadium(V) complexes of
tridentate Schiff bases of b-amino alcohols. Like the tita-
nium(IV) metal center, the vanadium(V) metal behaves as
a Lewis acidic center. In this study, a series of amino al-
cohols 1a–d with one or two stereogenic centers were pre-
pared starting from L-phenylalanine according to standard
procedures. Treatment of 1a–d with 2-hydroxy benzalde-
hyde or 2-hydroxy-3,5-di-tert-butylbenzaldehyde afford-
ed quantitative yields of Schiff bases 2a–e (Equation 1).
These Schiff bases reacted with 1 mol equivalent VO(Oi-
Pr)3 in absolute ethanol at room temperature for one hour
to give quantitative yields of oxovanadium(V) complexes
3a–e (Equation 2).14 Those complexes were confirmed by
Key words: oxovanadium complex, alkynylation, Schiff bases,
b-amino alcohols, aromatic aldehydes, aliphatic aldehydes, propar-
gyl alcohols
Chiral secondary propargyl alcohols are important build-
ing blocks for many important biological compounds1 and
considerable efforts were devoted in recent years to devel-
oping catalytic systems for synthesis of chiral propargyl
alcohols. The first effective asymmetric alkynyl addition
to aldehydes for the synthesis of chiral propargyl alcohols
was demonstrated by Corey and coworker using chiral
oxazaborolidines.2 Recent studies of asymmetric alkynyl-
ations to aldehydes employed zinc reagents1,3 exclusively,
and both aromatic and aliphatic aldedydes were reported
to furnish chiral propargyl alcohols in high yields and
high enantioselectivities with the use of either zinc or
titanium catalysts. For zinc systems, catalytic alkynyl
additions to aliphatic aldehydes were first developed by
Carreira and coworkers using Zn(OTf)2 and an ephedrine
ligand.4 Following the paper, BINOLs5 and chiral nitro-
gen-containing alcohols6 were reported as ligands to in-
duce high stereoselectivities, and in a recent paper,
alkynyl additions to unsaturated aldehydes were reported
by Trost and coworkers.7 For titanium-catalyzed alkyny-
lation reactions, BINOLs or H8-BINOLs were demon-
strated to be excellent ligands by Chan et al.,8 Pu et al.,9
and Gong and coworkers.10 For those catalytic systems,
alkynylzinc reagents were generated from reactions of di-
ethylzinc with terminal alkynes in general at elevated tem-
peratures or from dimethylzinc with alkynes. Wang and
coworkers developed a titanium-sulfonamide alcohol sys-
tem to achieve excellent enantioselectivities of chiral pro-
pargyl alcohols with alkynylzinc reagents prepared at
room temperature from diethylzinc.11 Recently, Pu and
coworkers found that an addition of hexamethylphos-
phoramide (HMPA) greatly accelerates the formation of
1
elemental analyses and by H NMR and 13C NMR spec-
troscopy and square pyramidal structures are suggested
for the complexes based on the known related structures.15
R2
Bn
R1
R2
CHO
OH
Bn
R1
N
OH
R3
+
R3
OH
H2N
OH
R3
R3
1a: R1 = R2 = H
2a: R1 = R2 = H, R3 = H
2b: R1 = R2 = Ph, R3 = H
2c: R1 = Ph, R2 = H, R3 = H
2d: R1 = t-Bu, R2 = H, R3 = H
2e: R1 = t-Bu, R2 = H, R3 = t-Bu
R
3 = H or t-Bu
1b: R1 = R2 = Ph
1c: R1 = Ph, R2 = H
1d: R1 = t-Bu, R2 = H
Equation 1
The asymmetric alkynylation was first examined on benz-
aldehyde employing 10 mol% catalysts 3a–e at –20 °C
for 24 hours (Equation 3) and results are listed in Table 1.
For catalyst 3a of R1 = R2 = R3 = H, the propargyl alcohol
was obtained in 100% yield with a low enantioselectivity
of 12% ee in R-configuration (entry 1). When 3b of
R1 = R2 = Ph was used, the propargyl alcohol was ob-
SYNLETT 2006, No. 12, pp 1871–1874
0
1
.0
8
.2
0
0
6
Advanced online publication: 24.07.2006
DOI: 10.1055/s-2006-948195; Art ID: W05606ST
© Georg Thieme Verlag Stuttgart · New York

1872
S.-H. Hsieh, H.-M. Gau
LETTER
R2
Bn
Table 1 Alkynylation of Benzaldehyde Catalyzed by Oxo-
vanadium(V) Complexes of Schiff Bases of Amino Alcoholsa,b
R1
R2
Bn
R1
Entry Catalyst R1
R2
H
Ph
H
H
H
H
H
H
R3
H
H
H
H
R4
Et
Et
Et
Et
Yield (%)c ee (%)d
N
OH
R4OH, r.t., 1 h
O
V
N
O
+ VO(O-i-Pr)3
O
R3
OH
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
H
100
100
100
95
12
rac
43
75
32
84
96
69
– i-PrOH
R3
OR4
R3
Ph
R3
Ph
2a–e
3a: R1 = R2 = H, R3 = H, R4 = Et
3b: R1 = R2 = Ph, R3 = H, R4 = Et
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
3c: R1 = Ph, R2 = H, R3 = H, R4 = Et
3d: R1 = t-Bu, R2 = H, R3 = H, R4 = Et
3e: R1 = t-Bu, R2 = H, R3 = t-Bu, R4 = Et
3f: R1 = t-Bu, R2 = H, R3 = H, R4 = i-Pr
3g: R1 = t-Bu, R2 = H, R3 = H, R4 = i-Bu
3h: R1 = t-Bu, R2 = H, R3 = H, R4 = t-Bu
t-Bu Et
78
H
H
H
i-Pr
i-Bu
100
98
3g
3h
t-Bu 100
Equation 2
a Benzaldehyde:ZnEt2:phenylacetylene:catalyst = 0.5:1.5:1.5:0.05
mmol; toluene, 5 mL; CH2Cl2, 2.5 mL.
tained as a racemic mixture in 100% yield (entry 2). When
the reaction was conducted using catalyst 3c having a
Schiff base containing two stereogenic centers with
R1 = Ph and R2 = H, the enantioselectivity of the product
increases to 43% ee (entry 3). When R1 of Ph is replaced
with a bulkier t-Bu group as in catalyst 3d, the reaction
furnished the product in a dramatic increase of the enan-
tioselectivity up to 75% ee (entry 4). The steric effect of
R3 group on the phenolate ring was then examined. For 3e
with R3 of bulky t-Bu groups, the yield of the product
decreases to 78% and the enantioselectivity drops sub-
stantially to 32% ee (entry 5).
b ZnEt2 and phenylacetylene were refluxed in toluene for 6 h and the
resulted solution cooled to r.t. The resulted mixture was transferred to
the solution of the catalyst in CH2Cl2 at –20 °C followed by the
addition of benzaldehyde.
c Yields were calculated based on 1H NMR spectra.
d The ee values were determined by HPLC using an OD column from
Daicel.
Alkynyl additions to various aldehydes were then con-
ducted employing the best performed oxovanadium(V)
catalyst 3g. The desired chiral propargyl alcohols were
obtained in excellent isolated yields (Table 2). It is found
that positions of the substituted group on aromatic alde-
hydes play a key role in stereoselectivities with higher
enantioselectivities obtained for substrates having an
ortho-substituted group. For example, the enantioselectiv-
ity of the propargyl alcohol obtained from 1-naphthalde-
hyde at 96% ee (entry 2) is much higher than the
enantioselectivity for 2-naphthaldehyde at 78% ee (entry
3). Similarly, a higher enantioselectivity was observed for
2-chlorobenzaldehyde at 90% ee (entry 4) than the enan-
tioselectivity at 75% ee for 4-chlorobenzaldehyde (entry
5). For 2-bromobenzaldehyde, the product was obtained
in a superb 99% ee (entry 6). For 2-iodobenzaldehyde, the
propargyl alcohol was obtained in an excellent enantiose-
lectivity of 92% ee (entry 7). For the aromatic aldehyde
containing a strong electron-withdrawing CF3 at the para-
position, the product in a slightly lower enantioselectivity
of 85% ee was obtained (entry 8). In this study, two exam-
ples of 1-hexynyl additions to aromatic aldehydes were
examined and a reaction time of 48 hours is required to af-
ford products in satisfactory yields. For 1-naphthalde-
hyde, the addition reaction gave the product in a moderate
66% yield but with an excellent enantioselectivity of 93%
ee (entry 9). For 2-bromobenzaldehyde, the product was
obtained in 84% yield with 80% ee (entry 10). For ali-
phatic aldehydes, the product in a moderate 73% ee was
obtained for the phenylacetylenyl addition to benzylalde-
hyde (entry 11) and a good 88% ee was obtained for
cyclohexylaldehyde as the substrate (entry 12).
H
HO
O
3 (10 mol%)
H
Ph
toluene–CH2Cl2 (2:1),
–20 °C, 24 h
(R)
+
H
Ph
/ZnEt2
Equation 3
The above results demonstrate that catalysts with Schiff
bases containing two stereogenic centers are superior in
stereocontrol to catalysts having Schiff bases with one ste-
reogenic center. In catalytic reactions, the benzaldehyde
accesses the vanadium metal center from the open site
trans to the strong oxo ligand and, thus, the size of the
OR4 alkoxide group on the vanadium metal is expected to
affect the stereoselectivity of chiral propargyl alcohols as
well. To study the steric effect of the R4 group, the Schiff
base 2d was reacted with 1 mol equivalent VO(Oi-Pr)3 in
2-propanol, isobutanol, or tert-butanol to furnish quantita-
tive yields of complexes 3f–h in one hour after removing
volatile materials completely (Equation 2). Asymmetric
alkynylation reactions using catalysts 3f–h were then con-
ducted and enantioselectivities improve to 84% ee for cat-
alyst 3f having a bulkier 2-propoxide ligand (entry 6) and
to 96% for 3g with the isobutoxide ligand (entry 7). How-
ever, the enantioselectivity of the chiral propargyl alcohol
drops significantly to 69% ee with the catalyst 3h having
OR4 of the bulkiest tert-butoxide ligand (entry 8).
Synlett 2006, No. 12, 1871–1874 © Thieme Stuttgart · New York

LETTER
Asymmetric Alkynyl Additions to Aldehydes
1873
in this study. First, isolated oxovanadium(V) complexes
of Schiff bases are used as effective catalysts. Second, the
catalysts are stable and can be easily prepared from reac-
tions of VO(Oi-Pr)3 with Schiff bases of amino alcohols
in alcohol. Third, stereoselectivities of propargyl alcohols
are tunable through adjustments of steric sizes of substit-
uents on Schiff base ligands and of the alkoxide ligand on
the vanadium metal. Further investigations of oxovanadi-
um(V) complexes in asymmetric catalysis are currently
underway.
Table 2 Asymmetric Alkynylation of Aldehydes Catalyzed by
Oxovanadium Catalyst 3ga,b
Entry Substrate
Alkyne
Isolated ee
yield (%) (%)
1
2
CHO
95
96
Ph
Ph
C
C
CH
CH
94
96
CHO
Acknowledgment
3
4
92
96
78
90
CHO
Ph
Ph
C
C
CH
CH
Financial support from National Science Council of Taiwan,
Republic of China (Grant Number NSC-93-2113-M-005-021) is
appreciated.
Cl
CHO
References and Notes
(1) For references, please see: Pu, L. Tetrahedron 2003, 59,
9873.
(2) Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116,
3151.
5
6
91
95
75
99
CHO
Ph
Ph
C
C
CH
CH
Cl
(3) (a) Frantz, D. E.; Fässler, R.; Carreira, E. M. J. Am. Chem.
Soc. 2000, 122, 1806. (b) Jiang, B.; Chen, Z.; Xiong, W.
Chem. Commun. 2002, 1524. (c) Braga, A. L.; Appelt, H.
R.; Silveira, C. C.; Wessjohann, L. A.; Schneider, P. H.
Tetrahedron 2002, 58, 10413. (d) Kamble, R. M.; Singh, V.
K. Tetrahedron Lett. 2003, 44, 5347. (e) Makita, N.;
Hoshino, Y.; Yamamoto, H. Org. Biomol. Chem. 2004, 2,
3312. (f) Xu, Z.; Chen, C.; Xu, J.; Miao, M.; Yan, W.; Wang,
R. Org. Lett. 2004, 6, 1193. (g) Fang, T.; Du, D.-M.; Lu, S.-
F.; Xu, J. Org. Lett. 2005, 7, 2081. (h) Emmerson, D. P. G.;
Hems, W. P.; Davis, B. G. Org. Lett. 2006, 8, 207.
(4) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687.
(5) Xu, M.-H.; Pu, L. Org. Lett. 2002, 4, 4555.
(6) (a) Lu, G.; Li, X.; Zhou, Z.; Chan, W. L.; Chan, A. S. C.
Tetrahedron: Asymmetry 2001, 12, 2147. (b) Dahmen, S.
Org. Lett. 2004, 6, 2113. (c) Zhu, M.; Li, X.-Z.; Yuan, K.;
Cao, B.-X.; Hou, X.-L. Tetrahedron: Asymmetry 2004, 15,
219. (d) Kang, Y.-F.; Liu, L.; Wang, R.; Yan, W.-J.; Zhou,
Y.-F. Tetrahedron: Asymmetry 2004, 15, 3155.
(e) Yamashita, M.; Yamada, K.-I.; Tomioka, K. Adv. Synth.
Catal. 2005, 347, 1649. (f) Mao, J.; Wan, B.; Wu, F.; Lu, S.
Chirality 2005, 17, 243. (g) Thoniyot, C. C. P.; Hirayama,
L. C.; Romano, T.; Singaram, B. Tetrahedron: Asymmetry
2005, 16, 1829. (h) Pizzuti, M. G.; Superchi, S.
Tetrahedron: Asymmetry 2005, 16, 2263.
Br
CHO
CHO
7
96
92
I
Ph
C
C
CH
CH
8
96
66
85
93
CHO
Ph
F3C
9c
nBu
C
CH
CHO
10c
84
80
nBu
C
CH
Br
CHO
11
12
85
96
73
88
Ph
Ph
C
CH
CHO
CHO
(7) Trost, B. M.; Weiss, A. H.; Wangelin, A. J. J. Am. Chem.
Soc. 2006, 128, 8.
C
CH
(8) (a) Liu, G.; Li, X.; Chan, W. L.; Chan, A. S. C. Chem.
Commun. 2002, 172. (b) Li, X.; Lu, G.; Kwok, W. H.; Chan,
A. S. C. J. Am. Chem. Soc. 2002, 124, 12636.
(9) (a) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855. (b) Gao, G.;
Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002, 4, 4143.
(c) Liu, L.; Pu, L. Tetrahedron 2004, 60, 7427.
(10) Liu, Q.-Z.; Xie, N.-S.; Luo, Z.-B.; Cui, X.; Cun, L.-F.; Gong,
L.-Z.; Mi, A.-Q.; Jiang, Y.-C. J. Org. Chem. 2003, 68, 7921.
(11) Xu, Z.; Wang, R.; Xu, J.; Da, C.-S.; Yan, W.-J.; Chen, C.
Angew. Chem. Int. Ed. 2003, 42, 5747.
a Reaction conditions are the same as those described in footnote of
Table 1.
b The ee values were determined by HPLC using an OD column from
Daicel and compared with literature values.
c 48 h.
In summary, the first example of oxovanadium(V) cata-
lysts catalyzed asymmetric alkynylation reactions is re-
ported. The chiral propargyl alcohols are obtained in high
isolated yields with good to excellent enantioselectivities
up to 99% ee. Several important features are demonstrated
(12) Gao, G.; Wang, Q.; Yu, X.-Q.; Xie, R.-G.; Pu, L. Angew.
Chem. Int. Ed. 2006, 45, 122.
(13) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 13760.
Synlett 2006, No. 12, 1871–1874 © Thieme Stuttgart · New York

1874
S.-H. Hsieh, H.-M. Gau
LETTER
127.43, 127.01, 126.77, 126.67, 126.05, 125.95, 124.98,
119.78, 119.51, 118.84, 93.35, 90.92, 87.19, 86.39, 84.50,
79.54, 79.07, 78.62, 42.02, 36.23, 36.11, 25.58, 19.13,
17.97, 17.74. Anal. Calcd for C24H24NO4V (%): C, 65.31; H,
5.48; N, 3.17. Found: C, 65.66; H, 5.08; N, 3.57.
(14) General Procedures for Synthesis of Oxovanadium(V)
Complexes 3a–h.
To a solution of a Schiff base (1.00 mmol) in 10 mL
appropriate alcohol, VO(Oi-Pr)3 (0.24 mL, 1.0 mmol) was
added at r.t. The mixture was stirred for 1 h and the solvent
was removed under reduced pressure to give a quantitative
yield of the product. All compounds were characterized by
1H NMR and 13C NMR spectroscopy and by elemental
analyses. Two sets of NMR resonances are observed for
each complex due to the presence of two isomers in solution.
Spectroscopic data of complexes 3c and 3g as examples are
listed in the following. The two isomers are designated as
major and minor based on relative intensities of resonances.
1H NMR spectra for the two isomers in the phenyl region are
overlapped and resonances of the minor are included in data
of the major.
Complex 3g: brown solid. 1H NMR (400 MHz, CDCl3): d
(major, 71%) = 7.45–6.77 (m, CH=N, Ph), 4.89 (d, J = 4.0
Hz, 1 H, CHN), 4.85 (ddd, J = 6.8, 11.4, 28.0 Hz, 2 H,
OCH2), 4.05 (d, J = 12.0 Hz, 1 H, CHO), 3.83 (dd, J = 12.4,
12.4 Hz, 1 H, CHAHBPh), 3.43 (d, J = 13.2 Hz, 1 H,
CHAHBPh), 2.16–2.06 (m, 1 H, CH2CH), 1.18 (s, 9 H, t-Bu),
1.03 [d, J = 6.8 Hz, 6H, CH(CH3)2] ppm; d (minor, 29%) =
5.24 (d, J = 4.0 Hz, 1 H, CHN), 5.05 (ddd, J = 6.8, 11.0, 30.8
Hz, 2 H, OCH2), 4.32 (d, J = 11.6 Hz, 1 H, CHO), 3.28 (d,
J = 14.0 Hz, 1 H, CHAHBPh), 2.62 (dd, J = 12.4, 12.4 Hz, 1
H, CHAHBPh), 2.40–2.22 (m, 1 H, CH2CH), 1.21 (s, 9 H, t-
Bu), 1.12 [d, J = 6.8 Hz, 6 H, CH(CH3)2] ppm. 13C{1H}
NMR (100 MHz, CDCl3): d = 165.18, 163.73, 161.93,
161.78, 137.98, 137.17, 135.37, 135.08, 132.25, 132.15,
130.20, 130.03, 128.44, 128.38, 126.67, 126.60, 120.01,
119.34, 119.04, 118.97, 118.64, 118.57, 98.05, 94.60, 89.84,
88.71, 83.31, 78.13, 36.77, 36.31, 35.81, 31.91, 31.60,
27.55, 27.12, 19.47, 19.41, 18.79. Anal. Calcd for
C24H32NO4V (%): C, 64.13; H, 7.18; N, 3.12. Found: C,
63.72; H, 7.42; N, 3.59.
Complex 3c: dark green solid. 1H NMR (400 MHz, CDCl3):
d (major, 69%) = 7.56 (s, 1 H, CH=N), 7.50–6.76 (m, Ph),
6.43 (d, J = 3.2 Hz, 1 H, CHO), 5.34–5.26 (m, 2 H, OCH2),
4.20 (d, J = 6.0 Hz, 1 H, CHN), 3.61 (dd, J = 7.6, 9.2 Hz, 1
H, CHAHBPh), 2.62 (dd, J = 2.0, 9.0 Hz, 1 H, CHAHBPh),
1.59 (t, J = 5.2 Hz, 3 H, CH3) ppm; d (minor, 31%) = 7.57 (s,
1 H, CH=N), 6.65 (d, J = 3.6 Hz, 1 H, CHO), 5.40–5.36 (m,
2 H, OCH2), 4.53 (d, J = 7.2 Hz, 1 H, CHN), 2.57 (dd,
J = 2.4, 9.2 Hz, 1 H, CHAHBPh), 2.47 (dd, J = 7.6, 9.2 Hz, 1
H, CHAHBPh), 1.69 (t, J = 4.8 Hz, 3 H, CH3) ppm. 13C{1H}
NMR (100 MHz, CDCl3): d = 163.26, 162.86, 162.71,
140.50, 137.86, 137.11, 135.82, 135.57, 132.45, 132.35,
130.19, 130.14, 128.70, 128.60, 128.55, 128.47, 127.62,
(15) (a) Hartung, J.; Drees, S.; Greb, M.; Schimdt, P.; Svoboda,
I.; Fuess, B.; Murso, A.; Stalke, D. Eur. J. Org. Chem. 2003,
2388. (b) Blum, S. A.; Bergman, R. C.; Ellman, J. A. J. Org.
Chem. 2003, 68, 150.
Synlett 2006, No. 12, 1871–1874 © Thieme Stuttgart · New York