Zirconocene-Zinc Transmetalation and in Situ Cetalytic Asymmetric Addition to Aldehydes

Full text of DOI:10.1021/jo9811827

6454
J . Org. Chem. 1998, 63, 6454-6455
Sch em e 1
Zir con ocen e-Zin c Tr a n sm eta la tion a n d in
Situ Ca ta lytic Asym m etr ic Ad d ition to
Ald eh yd es
Peter Wipf* and Seth Ribe
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
Received J une 23, 1998
Ta ble 1. Asym m etr ic Ad d ition of 1-Hexen ylzir con ocen e
(2, R ) C4H9) to Ben za ld eh yd e in th e P r esen ce of
Ca ta lytic Liga n d s L* (6-10) To Give
The direct generation of organometallic reagents from
alkenes and alkynes is a useful strategy for efficient C,C
bond formation, since unsaturated substrates are readily
available. Hydrozirconation with Cp2ZrHCl (Schwartz re-
agent)1,2 provides organozirconocene reagents that can
readily be added to enones,3 aldehydes,4,5 epoxides,6 and
isocyanates,7 but enantioselective protocols have so far been
rare.8 We have recently reported5 a high-yielding protocol
for the in situ transmetalation of alkenylzirconocenes to
alkylzinc species and have now succeeded in developing a
catalytic asymmetric protocol for subsequent additions to
aldehydes.
(S)-1-P h en yl-2-h ep ten -1-ol
entry
L* (mol %)
yield (%)
ee (%)
15a
2
6 (8)
6 (10)
6 (2)
92
88
99
77
85
80
76
80
73
88
90
38
81
19
3
3
The alkenylzirconocene complex 2, obtained by treatment
of a solution of alkyne 1 in CH2Cl2 with Cp2ZrHCl, rapidly
undergoes transmetalation at -65 °C to generate the alk-
enylzinc intermediate 3 (Scheme 1). The resulting zir-
conocene byproducts are efficient promoters for the 1,2-
addition of organozinc derivatives to aldehydes.9 Accordingly,
even in the absence of the usual amino alcohol ligands,10
addition of aldehydes 4 results in rapid formation of racemic
allylic alcohols (()-5. We were interested to see if upon
addition of chiral zinc ligands pioneered by Noyori10,11 an
asymmetric pathway was capable of competing with the
achiral, zirconocene-induced aldehyde addition. Our initial
attempts with 1-hexyne, benzaldehyde, and 8 mol % of the
proline-derived amino alcohol 612 furnished 1-phenyl-2-
hepten-1-ol in a disappointing 38% ee (Table 1).5a We later
found that this reaction could be optimized by allowing for
1 h of equilibrating time at -65 to -30 °C before addition
of the aldehyde. Under these conditions, the desired product
was obtained in an improved 81% ee in the presence of 10
4
7 (10)
8 (10)
9 (10)
10 (10)
13 (10)
13 (5)
13 (2)
13 (10)
5
1
6
70
89
95
90
78
83
7
8
9
10
11a
a
This reaction was run at 0 °C; all other reactions were run at
-30 °C.
mol % of 6 (entry 2). However, a decrease in the catalyst
loading to 2 mol % reduced the enantioselectivity to 19% ee
(entry 3).13
Since addition of nucleophiles such as MeLi that were
envisioned to neutralize the achiral pathway mediated by
Cp2ZrMeCl formed in the transmetalation with dimethyl-
zinc14 did not improve enantioselectivity, we turned our
attention to chiral ligands 7,11 8,15 9,16 and 10.17 Surpris-
ingly, amino alcohols 7 and 8 gave very low or no asymmetric
induction (Table 1, entries 4 and 5). Ligand 7 ((+)-DAIB),
for example, has been successfully used in the catalytic 1,2-
addition of alkenylzinc reagents, prepared similarly by in
situ borane-zinc transmetalation.18 However, in the zir-
conocene-zinc manifold only 3% ee was obtained. Thioac-
etate 9 led to a considerable improvement (70% ee, entry
6), but the best results were achieved with van Koten’s thiol
amine 10 (89% ee, entry 7). Encouraged by the results
(1) Schwartz, J .; Labinger, J . A. Angew. Chem., Int. Ed. Engl. 1976, 15,
333.
(2) Wipf, P.; J ahn, H. Tetrahedron 1996, 52, 12853.
(3) (a) Hart, D. W.; Schwartz, J . J . Am. Chem. Soc. 1974, 96, 8115. (b)
Loots, M. J .; Schwartz, J . J . Am. Chem. Soc. 1977, 99, 8045. (c) Lipshutz,
B. H.; Ellsworth, E. L. J . Am. Chem. Soc. 1990, 112, 7440. (d) Wipf, P.;
Smitrovich, J . H. J . Org. Chem. 1991, 56, 6494. (e) Wipf, P.; Xu, W. J .;
Smitrovich, J . H.; Lehmann, R.; Venanzi, L. M. Tetrahedron 1994, 50, 1935.
(4) (a) Maeta, H.; Hashimoto, T.; Hasegawa, T.; Suzuki, K. Tetrahedron
Lett. 1992, 33, 5965. (b) Zheng, B.; Srebnik, M. J . Org. Chem. 1995, 60,
3278.
(5) (a) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197. (b) Wipf, P.;
Xu, W. Org. Synth. 1996, 74, 205.
(6) Wipf, P.; Xu, W. J . Org. Chem. 1993, 58, 825.
(7) Negishi, E.; Swanson, D. R.; Miller, S. R. Tetrahedron Lett. 1988, 29,
1631.
(8) For the Cu(I)-catalyzed asymmetric addition of organozirconocenes
to R,â-unsaturated acyloxazolidinones, see: Wipf, P.; Takahashi, H. Chem.
Commun. 1996, 2675.
(9) In fact, Cp2ZrCl2 is a catalyst for diethylzinc addition to aldehydes.
At 0 °C, the addition of Et2Zn to benzaldehyde proceeds in 4 h to 50% in
the presence of 10 mol % of zirconocene dichloride. In the absence of
zirconocene catalyst, only 0-5% conversion is observed.
(10) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49. (b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
(11) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J . Am. Chem. Soc.
1986, 108, 6071.
(13) Enantioselectivities in entries 1-7 in Table 1 were determined by
polarimetry; the % ee for entry 5 in Table 2 was determined via the Mosher
ester derivative; all other ee’s were obtained by chiral HPLC using a
Chiracel OD column. The absolute configurations of (S)-1-phenyl-2-hepten-
1-ol and (S)-4,4-dimethyl-1-phenylpent-2-en-1-ol were assigned on the basis
of comparison with the literature [R]18D; all other products were assigned
correspondingly.
(14) The use of diethylzinc in place of dimethylzinc provided essentially
identical yields and asymmetric inductions.
(15) Soai, K.; Yokoyama, S.; Hayasaka, T. J . Org. Chem. 1991, 56, 4264.
(16) J in, M. J .; Ahn, S. J .; Lee, K. S. Tetrahedron Lett. 1996, 37, 8767.
(17) Knotter, D. M.; van Maanen, H. L.; Grove, D. M.; Spek, A. L.; van
Koten, G. Inorg. Chem. 1991, 30, 3309.
(18) Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 170. The
preparation of secondary (E)-allylic alcohols by hydroboration of alkynes
and boron-zinc transmetalation is related in concept and scope to our
protocol but provides considerably lower yields for sterically hindered
aldehydes.
(12) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J . Am. Chem. Soc. 1987,
109, 7111.
S0022-3263(98)01182-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/02/1998

Communications
J . Org. Chem., Vol. 63, No. 19, 1998 6455
Sch em e 2
Ta ble 2. Ca ta lytic Asym m etr ic Ad d ition of Alk yn es 1
to Ald eh yd es 4 in th e P r esen ce of 10 m ol % of Ch ir a l
Liga n d 1322
entry
alkyne 1, R )
n-C4H9
aldehyde 4, R ) yield (%) ee (%)
1
2
3
4
5
6
7
8
9
(p-Cl)C6H4
(p-CF3)C6H4
(p-OMe)C6H4
(m-OMe)C6H4
c-C6H11
83
71
75
79
63
71
73
66
67
97
93
63
99
74
64
83
99
92
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
(CH3)3C
3-hexyne
PhCH2CH2
Ph
Ph
TIPSOC(O)CH2CH2 Ph
F igu r e 1. Kinetic studies (GC) for 1-phenyl-2-hepten-1-ol forma-
tion in a mixture of hexenylzirconocene/Me2Zn at -30 °C in the
absence of chiral ligand and in the presence of 10 mol % of 8 and
13. Rates for disappearance of benzaldehyde (not shown) were
analogous to the product formation kinetics. All measurements
were reproduced two to four times.
obtained with this amino thiol ligand,19 we sought to
enhance stereoselectivity by increasing the steric bulk at the
benzylic position of 10. Starting from (R)-ethylbenzylamine
11,20 Eschweiler-Clark methylation followed by ortho lithi-
ation and trapping with elemental sulfur yielded amino thiol
13 in 54% overall yield (Scheme 2).17 Addition of 10, 5, and
2 mol % of this catalyst to the test reaction provided chiral
benzylic alcohol in very satisfactory 95%, 90%, and 78% ee,
respectively (Table 1, entries 8-10). As expected, an
increase in the reaction temperature from -30 to 0 °C led
to a decrease in ee from 95% to 83% (entry 11).
The scope of the asymmetric aldehyde addition of zir-
conocene-derived organozinc reagents with 10 mol % of
catalyst 13 is illustrated in Table 2. Electron-withdrawing
substituents on aromatic aldehydes are well tolerated and,
in general, lead to increases in % ee’s up to 97% for
p-chlorobenzaldehyde (entry 1). Interestingly, the electron-
rich p-methoxybenzaldehyde provides a low ee of 63%,
whereas the m-methoxy substituent boosts selectivity to 99%
(entries 3 and 4). Aliphatic aldehydes are poorer substrates
in terms of enantioselectivity, and with cyclohexylcarbox-
aldehyde and hydrocinnamaldehyde the enantioselectivity
drops to 64-74% ee. Very promising preliminary results
were obtained with the internal alkyne 3-hexyne and a silyl
ester functionalized terminal alkyne that provided benzal-
dehyde addition products in 99 and 92% ee, respectively
(entries 8 and 9).
Initially, we rationalized the successful catalysis with
amino thiols 10 and, in particular, 13, vs amino alcohols such
as 7 and 8 with the greater oxophilicity of zirconium over
zinc species that would lead to an unfavorable complexation
equilibrium with amino alcohols. However, kinetic GC
experiments actually established that in the presence of
amino alcohol 8 the addition of zirconocene-derived hex-
enylzinc to benzaldehyde actually proceeded considerably
faster to 50% completion than the reaction catalyzed by
amino thiol 13 (Figure 1). Product formation in the presence
of 13 is comparable to the rate obtained in the absence of
chiral ligand, e.g., for the reaction entirely mediated by
achiral or racemic zirconocene byproducts. Therefore, the
high enantioselectivity observed with amino thiol 13 is not
based on faster kinetics for the asymmetric reaction,21 and
the significant increase in reaction rate observed with amino
alcohol 8 does not support the hypothesis that preferential
complex formation between 8 and zirconocene is mainly
responsible for the decrease in asymmetric induction. The
presence of both zirconium and zinc species in the reaction
mixture clearly complicates the interpretation of kinetic
data, and more mechanistic studies will be needed to
elucidate the role that the zirconocene byproducts play in
the catalytic cycle.
In conclusion, in situ hydrozirconation of alkynes, trans-
metalation to dimethylzinc, and chiral amino thiol-catalyzed
addition to aldehydes provides an efficient protocol for the
asymmetric preparation of (E)-allylic alcohols. Highlights
of this reaction are the excellent enantioselectivities ob-
served with the new chiral ligand 13 and aromatic aldehydes
as well as the efficiency of the reaction with the internal
alkyne 3-hexyne and the functionalized substrate 4-pen-
tynoate. Further structural modifications of 13 will be
explored in order to improve enantioselectivities with ali-
phatic aldehydes.
Ack n ow led gm en t . This work was supported by the
National Science Foundation and the Sloan and Camille
Dreyfus Foundations.
Su p p or tin g In for m a tion Ava ila ble: Experimental details
and characterization for all new compounds. Copies of 1H and
13C NMR spectra (10 pages).
J O9811827
(22) In
a typical protocol, a suspension of 0.21 g (0.81 mmol) of
zirconocene hydrochloride in 2 mL of dry CH2Cl2 under N2 was treated with
94 µL (0.81 mmol) of 1-hexyne at room temperature. The mixture was
allowed to stir for 5 min before the removal of all volatiles in vacuo. The
resulting light yellow solid was then dissolved in 2 mL of dry toluene, cooled
to -65 °C, and then treated with 0.41 mL (0.82 mmol) of Me2Zn (2.0 M in
toluene). To this mixture was added 16.6 mg (0.085 mmol) of ligand 13.
After a period of 1 h, accompanied by slow warming to -30 °C, a solution
of 115 mg (0.81 mmol) of 4-chlorobenzaldehyde in 2 mL of dry toluene was
added. The reaction mixture was stirred overnight (12 h) before being
quenched with saturated NaHCO3. The solution was extracted (3×) with
EtOAc, washed with brine, dried (MgSO4), filtered through a pad of SiO2,
and chromatographed on SiO2 (9:1 hexanes/EtOAc) to yield 151 mg (83%)
of (S)-1-(4-chlorophenyl)hept-2-en-1-ol as a colorless oil: [R]D +48.0 (c 1.51,
CHCl3). Chiral HPLC (Chiralcel OD column) analysis using 0.5% i-PrOH
in hexane as the eluent indicated 97% ee: 1H NMR δ 7.25-7.31 (m, 5 H),
5.72 (dt, 1 H, J ) 15.3, 6.5 Hz), 5.56 (dd, 1 H, J ) 15.3, 6.8 Hz), 5.09 (d, 1
H, J ) 6.8 Hz), 2.34 (bs, 1 H), 2.08-2.01 (m, 2 H), 1.41-1.25 (m, 4 H), 0.89
(t, 3 H, J ) 7.0 Hz); 13C NMR δ 142.0, 133.5, 133.2, 132.1, 128.7, 127.7,
74.7, 32.0, 31.4, 22.4, 14.1; HRMS (EI) calcd for C13H17OCl 224.0968, found
224.0971.
(19) For other applications of amino thiols as ligands in zinc-mediated
aldehyde additions, see ref 16 and: (a) Kang, J .; Lee, J .; Kim, J . J . Chem.
Soc., Chem. Commun. 1994, 2009. (b) van Koten, G.; Rijnberg, E.; J astr-
zebski, J .; J anssen, M.; Boersma, J . Tetrahedron Lett. 1994, 35, 6521.
(20) This compound was obtained in 98% ee from BASF. We thank Drs.
Dietrich and Ritter for a generous sample of 11.
(21) In the addition to hydrocinnamaldehyde (Table 2, entry 6), we also
analyzed the dependence of the % ee on conversion and found it to be
consistent at 65 ( 2% throughout the course of the reaction.