First application of amino-TADDOL derivatives in enantioselective addition of diethylzinc to aryl aldehydes: Effect of substituents on the nitrogen atom

Article abstract of DOI:10.1016/S0957-4166(00)00090-2

Five amino-TADDOL derivatives have been used as catalysts for the enantioselective addition of diethylzinc to aromatic aldehydes. Moderate to good enantioselectivities were obtained (up to 88% ee). The substituents on the nitrogen atom play an important role in the stereochemistry, even reversing the enantioselectivity. The effects of Li salts of aminoalcohols on the reaction were explored. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00090-2

Tetrahedron: Asymmetry 11 (2000) 1733±1740
First application of amino-TADDOL derivatives in
enantioselective addition of diethylzinc to aryl aldehydes:
e€ect of substituents on the nitrogen atom
Chang-Tao Qian,* Fei-Feng Gao and Jie Sun
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
3
54 Fenglin Lu, Shanghai 200032, China
Received 11 January 2000; accepted 21 February 2000
Abstract
Five amino-TADDOL derivatives have been used as catalysts for the enantioselective addition of diethylzinc
to aromatic aldehydes. Moderate to good enantioselectivities were obtained (up to 88% ee). The sub-
stituents on the nitrogen atom play an important role in the stereochemistry, even reversing the enantio-
selectivity. The e€ects of Li salts of aminoalcohols on the reaction were explored. # 2000 Elsevier Science
Ltd. All rights reserved.
1
. Introduction
In recent years, a variety of aminoalcohols, namely exclusively 1,2-aminoalcohols, have been
1
used as catalysts in the enantioselective addition of diethylzinc to aldehydes. Applications of
2
3
1
1
,3 - and 1,4 -aminoalcohols have been occasionally reported. There are also a few examples of
0
4
0
5
,2-substituted ferrocenyl aminoalcohols and 2-amino-2 -hydroxy-1,1 -binaphtyl (NOBIN).
However, inspection of the impressively long lists of these ligands revealed an almost total
absence of the representatives of the amino-TADDOL series.
It has been known that, in metal complexes, (P)-BINOL and (R,R)-TADDOL provide similar
6
ligand spheres with l-shape of axially disposed aromatic groups. Therefore, we thought that
amino-TADDOLs could also be applicable to the enantioselective reaction. We ®rst used amino-
TADDOL derivatives 1, 2, 3, 4 and 5 (Fig. 1) as catalysts for the addition of Et Zn to aromatic
2
aldehydes.
We found that the substituents on the nitrogen atom strongly a€ected both the chemical yield
and the enantioselectivity, and in some cases showed a reverse stereochemistry.1 The lithium
0b
*
Corresponding author. Fax: 0086-21-64166128; e-mail: qianct@pub.sioc.ac.cn
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00090-2

1
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C.-T. Qian et al. / Tetrahedron: Asymmetry 11 (2000) 1733±1740
Figure 1.
salts of ligands were also studied which showed di€erent e€ects compared to their parent ligands.
Herein we wish to report the results of this study.
2
. Results and discussion
Compounds 1±4 were directly prepared according to the literature. Compound 5 was prepared
8a
by direct ethylation instead of by the literature method.8 Attempts to modify the amino group
with n-Bu and i-Pr all failed by direct alkylation, reductive alkylation with aldehyde or reduction
of ketoamide derivative.
b
Since benzaldehyde has been most extensively studied in other systems, we focused our e€orts
on the diethylzinc addition to benzaldehyde in our initial study so that the results could be easily
ꢀ
compared with those from previous studies. It was reacted for 24 h at 0 C in hexane and 5% mol
ligand was used as a catalyst. The results from these experiments are tabulated in Table 1.
An interesting trend emerges with changing the substituent on the nitrogen atom (entries 1±4,
Table 1). The primary aminoalcohol 1 without additive was inecient in terms of both chemical
yield and enantioselectivity (entry 1, Table 1). In addition, it gave a condensation by-product 6
7
(Fig. 2), which was identi®ed by NMR, MS, IR and X-ray di€raction analysis. The molecular
structure of 6 is shown in Fig. 3.
Compound 6 was also tested as a catalyst for the addition reaction according to standard
procedures; it turned out to be an inecient catalyst with 38% yield and 0% ee.
Substituting one hydrogen atom with a methyl on the nitrogen in 2 led to a much improved
enantioselectivity with 80% ee (R) as well as chemical yield (99%). The benzyl derivative 4 gave
the same e€ect with 81% ee (S). However, the sense of stereoinduction is opposite between 2 and
4
2
(cf. entries 2 and 4, Table 1). Using 3, where another methyl is introduced onto the nitrogen in
, again caused the reversal of the con®guration with 85% ee (S) (entry 3, Table 1).
Some other representative aldehydes have been investigated under the same reaction conditions
entries 5±28, Table 1)
(
Ligand 2 always gave products of (R)-con®guration while 3 and 4 favored the opposite con-
guration. In all cases, 4 a€orded excellent yields (85±100% yield) and good enantioselectivity
79±88% ee), which shows that 4 is not sensitive to steric or electronic e€ects of aldehydes. Ligand
®
(
2
4
(
is strongly a€ected by the steric hindrance. When the 2-MeO substitutent was changed to a
-MeO, the enantiomeric excess rose from 57 to 71% and the yield decreased from 100 to 60%
cf. entries 5 and 8, Table 1). On the other hand, the electronic e€ect had a great in¯uence on 3;
substitution of 4-CF with 4-MeO led to an increase in ee and yield from 43 to 88% and from
3
7
0 to 94%, respectively. It is very interesting to note that such a small change in the substituent
on the nitrogen atom can lead to such a big di€erence. Extensive studies have been made previously
concerning the enantioselective addition of diethylzinc to aldehydes by experimental and theo-
retical methods. In general, it is thought bulky alkyl groups on the nitrogen atom tend to increase

C.-T. Qian et al. / Tetrahedron: Asymmetry 11 (2000) 1733±1740
1735
Table 1
Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed by amino-TADDOLa
Figure 2.

1
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C.-T. Qian et al. / Tetrahedron: Asymmetry 11 (2000) 1733±1740
Figure 3. The molecular structure of 6
9
the enantioselectivity for 1,2-aminoalcohols. However, sometimes a simple change of the back-
bone substituents in ligands leads to reversal of stereochemistry. In this case, we assume that the
crowded fabric of the 1,4-aminoalcohol has caused our experiment results.
10
We postulate the reactive intermediates like 7 and 8 (Fig. 4). The syn tricyclic structures are less
favored because of the electrostatic repulsion between the two non-reacting Zn±Et groups in the
Figure 4.

C.-T. Qian et al. / Tetrahedron: Asymmetry 11 (2000) 1733±1740
1737
central four-membered ring,11a so alkylation of benzaldehyde occurs from the mixed-ligand
complexes 7 and 8 mainly via anti-con®gured 7/4/4 tricyclic transition states.11
When R =R =H or R =Me, R =H, it reacts via 7 and gives R-enriched products. When
1
2
1
2
R =R =Me, the repulsion between R and adjacent Ph reinforces that between R and the ethyl
1
2
1
2
on the bridged zinc atom, and the transition state is forced to reverse to avoid the repulsion. It gives
S-enriched products. In the case of 4, it also gives S-enriched ones for the same reason as with 3,
because of the repulsion between Bn on the nitrogen and the ethyl on the bridged zinc atom. The
results from 5 (shown in Table 2) supported this assumption. In the case of R =Et and R =H,
1
2
since ethyl is larger than methyl and smaller than benzyl, the energy di€erence between 7 and 8
was so small that there must be a rapid equilibrium between them and the reaction can take place
via both 7 and 8 equally. Therefore, in all cases, 5 gave low ee values (entries 1±4, Table 2).
Table 2
Enantioselective addition of diethylzinc to aldehydes catalyzed by 5a
It has been noted previously that use of the lithium salt of a ligand usually leads to enhance-
ment in selectivity,12 and decrease in enantiomeric excess or reverse of the sense of chirality
compared to the parent alcohol.13 Under our conditions, when the lithium salts of the ligands
were used as catalysts, there was a sharp decrease in enantioselectivity for 2 and 3 (cf. entries 2, 3,
6
and 7, Table 3). For ligand 4, it also led to a slight decrease (cf. entries 10 and 11, Table 3). On
the contrary, for 1 the selectivity and yield increased from 40 to 56% and from 38 to 72%,
respectively, and no by-product was detected when the lithium salt was used. We propose that the
presence of an additional labile hydrogen on the nitrogen may cause the reaction to proceed
+
through a di€erent intermediate. For 5, it did not matter much. Obviously, Li plays an impor-
tant role in reaction mechanism. We could elucidate these e€ects by following 7/4/4 tricylic
complexes 9 and 10 (Fig. 5). Because the Li atom takes the place of Zn±Et in the seven-membered
ring, the loss of electrostatic repulsion between the two non-reacting Zn±Et groups in central
four-membered ring caused the decrease of ee values (entries 1±4 and 6±8, Table 3) or reversal of
the con®guration (entry 7, Table 3).
In order to probe the assumed model 9 and 10, we changed the order of addition of BuLi. After
.1 equiv. of diethylzinc was ®rst added to a solution of the ligand in hexane and stirred for 30
2
min, 1 equiv. of BuLi was added. After 10 min, 1 equiv. of aromatic aldehyde was syringed into
ꢀ
the reaction mixture at 0 C and stirred for 24 h. The results turned out to be completely di€erent
(shown in Table 4); it just caused relatively lower decrease of ee values than Li salts. We assumed
it was due to metal exchange between Zn and Li.
Experiments are underway to apply the present ligands to other asymmetric reactions.

1
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C.-T. Qian et al. / Tetrahedron: Asymmetry 11 (2000) 1733±1740
Table 3
E€ect of lithium salts of 1, 2, 3, 4 and 5 on the yield and enantioselectivitya
Figure 5.
Table 4
E€ect of addition order of n-BuLi on the reactiona
3
. Experimental
All experiments were carried out under an Ar atmosphere. Aromatic aldehydes were distilled
with calcium hydride and hexane was dried using standard methods and was distilled before use.
Et Zn (1 M in hexane solution) was purchased from Fluka.
2

C.-T. Qian et al. / Tetrahedron: Asymmetry 11 (2000) 1733±1740
1739
3.1. General procedure for the enantioselective addition of Et Zn to aromatic aldehydes using 1±5
2
as catalyst
To a suspension of 3 (27 mg, 0.05 mmol) in hexane (2.0 ml) was added diethylzinc (2.1 ml, 2.1
ꢀ
mmol) at 0 C. After stirring the mixture for 30 min, 4-methoxybenzaldehyde (136.0 mg, 1.0
ꢀ
mmol) was added and the reaction mixture was stirred for 24 h at 0 C. The reaction was
quenched by 10% HCl and the product was extracted with ethyl acetate. The extract was dried
over MgSO and then evaporated under reduced pressure. The residue was puri®ed by ¯ash
4
chromatography (pentane:AcOEt 5:1) to give 100% yield and 87% ee of alcohol.
3.2. General procedure for the enantioselective addition of Et Zn to aromatic aldehydes using
2
lithium salt of 1±5 as catalyst
To a suspension of 3 (27 mg, 0.05 mmol) in hexane (2.0 ml) was added equivalent of n-BuLi,
ꢀ
stirred for 20 min, and diethylzinc (2.1 ml, 2.1 mmol) was then added at 0 C. After stirring of the
mixture for 30 min, 4-methoxybenzaldehyde (136.0 mg, 1.0 mmol) was added and the reaction
ꢀ
mixture was stirred for 24 h at 0 C. The reaction was quenched by 10% HCl and the product was
extracted with ethyl acetate. The extract was dried over MgSO , and then evaporated under
4
reduced pressure. The residue was puri®ed by ¯ash chromatography (pentane:AcOEt 5:1) to give
9
1% yield and 65% ee of alcohol.
3
.3. Preparation of 5
The mixture of 1 (0.98 g, 2.1 mmol), K CO (500 mg, 25 mmol), 18-crown-6 (70 mg, 0.2 mmol)
2
3
and EtI (2.5 ml, 25 mmol) was dissolved in 20 ml CH CN, then re¯uxed for 5 days. Et O (50 ml)
3
2
was added to the solution, then ®ltered and directly evaporated. The residue was puri®ed by ¯ash
chromatography (pentane:AcOEt 8:1) to give 1.02 g (2.0 mmol, 98% yield) of 5. The spectral data
are in accord with those reported.8
3
.4. Preparation of 6
In the general procedure of 1 as catalyst, it gave 6 as a by-product (25 mg, 0.045 mmol). Yield
0
2
ꢀ
1
9
0%. ‰ꢀŠ =^39.0 (c=1.10, CHCl ). Mp 230±232 C. H NMR (300 MHz, CDCl , ppm): ꢁ 8.51
D
s, 1H, OH), 7.81±7.78 (m, 2H, arom. H), 7.65±7.63 (m, 2H, arom. H), 7.52±7.02 (m, 22H, arom.
3
3
(
H), 4.47 (d, J=8.33, 1H, CH), 4.27 (d, J=8.34, 1H, CH), 1.17 (s, 6H, CH ). MS (EI): m/z 554
3
+
(
2
M , 14), 271 (100), 105 (38), 165 (19), 77(15). Anal. calcd for C H NO : C, 82.42; H, 6.37; N,
38 35 3
^1
.53. Found: C, 81.97; H, 6.33; N, 2.41. IR (KBr, cm ): ꢂ=3430, 3057, 1636, 1599, 1491, 1446,
1
371, 1172, 1080, 1054, 943, 886, 704.
Crystal structure analysis of 6: X-ray di€raction data were collected on a Rigaku AFC7R
Ê
di€ractometer with graphite monochromated Mo-Ka radiation, l=0.71069 A, and a 12 Kw
rotating anode generator, at room temperature using the !±2ꢃ scan technique to a maximum 2ꢃ
ꢀ
value of 55.0 . Compound 6, colorless cube, C H NO , Mr=553.69, crystal size 0.2Â0.2Â0.3
38
35
3
Ê
mm, orthorhombic, space group P2 2 2 (#19), a=16.792(4) A, b=18.484(2) A, c=9.874(2) A,
Ê
Ê
1
1
Ê
3
^1
^1
V=3064.7(10) A , Z=4, ꢄ=0.75 cm , F000=1176.00, ꢅcalc=1.20 g cm , R=0.040, Rw=0.046.
The intensities of representative re¯ections were measured after every 200; of 3967 collected
re¯ections, 3013 were independent. A linear correction factor was applied to account for this. The

1
740
C.-T. Qian et al. / Tetrahedron: Asymmetry 11 (2000) 1733±1740
data were corrected for Lorentzian-polarization e€ects. The structure were solved by heavy atom
Patterson methods and expanded using Fourier techniques. The non-hydrogen atoms were
14
re®ned anisotropically. All calculations were performed using Texsan.
Acknowledgements
Financial support from the National Natural Sciences Foundation of China and the Chinese
Academy of Sciences is gratefully acknowledged.
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(