Lewis base catalyzed enantioselective allylation of α,β- unsaturated aldehydes

Article abstract of DOI:10.1002/chem.201001523

Being selective: The catalytic allylation of, α,β-unsaturated aldehydes with allyltrichlorosilane in the presence of chiral 3,3′-unsymmetrically substituted bis(tetrahydroisoquinoline) N,N-dioxides was explored. The allylation of various aldehydes proceeded under mild reaction conditions (-78□ °C) with high yields and enantioselectivity (see scheme). This allylation was applied in the synthesis of (S)-(-)-goniothalamin.

Full text of DOI:10.1002/chem.201001523

DOI: 10.1002/chem.201001523
Lewis Base Catalyzed Enantioselective Allylation of a,b-Unsaturated
AHCTUNGTREUNNNG ldehydes
Aneta Kadlcˇꢀkovꢁ,[a] Irena Valterovꢁ,[b] Lucie Duchꢁcˇkovꢁ,[a] Jana Roithovꢁ,*[a] and
Martin Kotora*[a, b]
The invention and development of highly enantioselective
catalytic reactions with a low catalyst loading is one of the
current challenges in organic chemistry. One such area is the
activation of reactants by Lewis base/acid pairing.[1] Espe-
cially attractive in this regard is the enantioselective allyla-
tion of carbonyl compounds (Sakurai–Hosomi reaction)
with allylmetals to give chiral homoallylic alcohols that can
be used as building blocks in the synthesis of complex mole-
cules.[2]
tion[8] of hexadecatetrayne with benzonitrile and (R)-tetra-
hydrofurannitrile followed by oxidation with MCPBA.
In the last decade, considerable attention has been paid to
a possible variant of this reaction based on the activation of
allyltrichlorosilane or its derivatives by chiral Lewis bases,
such as pyridine N-oxides. A variety of bi- or monoden-
tate[2–6] catalysts have been synthesized and applied in the
catalytic allylation of aromatic aldehydes, which is used as a
benchmark reaction to assess the catalytic activity and the
scope of asymmetric induction. Although in some cases high
enantioselectivity was observed, this trend was not general
and the asymmetric induction was often highly dependent
on the presence of electron-accepting or -donating groups.
Another problem is the synthesis of the catalyst being often
complicated.
The presence of the additional center of chirality within
the molecular framework allowed easy separation of both
diastereoisomers by using simple column chromatography
on silica gel. The correct configuration was unequivocally
confirmed by a single-crystal X-ray analysis (Figure 1).
Second, the allylation of various benzaldehydes catalyzed by
1 (1 mol%, À788C, 1 h) in THF proceeded with high enan-
tioselectivity (up to 96%) and high yields regardless of elec-
tronic properties of the substituents on the aromatic ring.[7a]
Although the N-oxide-catalyzed allylation of benzalde-
hydes has been extensively studied, the reaction with a,b-
unsaturated aldehydes has been rather neglected. There
have been reported allylations of three aldehydes: cinnamal-
dehyde,[3,4b,c,5b–d,9–11] a-methylcinnamaldehyde,[5c,9] and 2-de-
cenal[3] with maximum enantioselectivities of 83, 76, and
81% ee, respectively. The lack of data in this area provided
the necessary impetus to study enantioselective allylation by
using 1.
Initially, the allylation of cinnamaldehyde 2a with allyltri-
chlorosilane in the presence of (R,R)-1 (1 mol%, 1 h) was
carried out in various solvents and gave 3a with the follow-
ing results: 92% yield, 97% ee in THF; 40% yield, 88% ee
in dichloromethane; 43% yield, 88% ee in toluene; 84%
yield, 96% ee in methoxycyclopentane; and 52% yield,
96% ee in 2-methylTHF[12]. Interestingly, the reaction in
MeCN did not proceed at all. The reaction catalyzed by
(S,R)-1 in THF gave 3a in 95% yield and 93% ee. The ally-
lation of other cinnamaldehydes 2b–g to homoallyl alcohols
We showed that the above-mentioned problems could be
overcome by the use of unsymmetrical diastereoisomeric
bis(tetrahydroisoquinoline) N,N’-dioxides 1 and appropriate
choice of solvent.[7] Lewis bases 1 were prepared in three
steps by a one-pot microwave-induced cross-cyclotrimeriza-
ˇ
ˇ
[a] A. Kadlcꢀkovꢁ, L. Duchꢁckovꢁ, Dr. J. Roithovꢁ, Prof. M. Kotora
Department or Organic and Nuclear Chemistry, Faculty of Science
Charles University in Prague
Hlavova 8, 128 43 Praha 2 (Czech Republic)
Fax : (+42)221951326
E-mail: kotora@natur.cuni.cz
roithova@natur.cuni.cz
[b] Prof. I. Valterovꢁ, Prof. M. Kotora
Institute of Organic Chemistry and Biochemistry
Academy of Sciences of the Czech Republic
Flemingovo nꢁm. 2, 166 10 Praha 6 (Czech Republic)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001523.
9442
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Chem. Eur. J. 2010, 16, 9442 – 9445

COMMUNICATION
allyl alcohols with nitro (3 f) or, surprisingly, methoxy
groups (3g) were formed with diminished enantioselectivity
(Table 1, entries 6 and 7).
We then studied the allylation of aliphatic a,b-unsaturated
aldehydes 4. Because of the slower reaction rate, the reac-
tions were run with 5 mol% of catalyst to ensure higher
yields. In general, the reactions proceeded in all cases; how-
ever, a strong dependence of the asymmetric induction on
the chiral backbone of the catalyst was observed (Table 1).
The allylation of crotylaldehyde 4a to 5a proceeded with an
average enantioselectivity of 85% ee for both catalysts
(Table 1, entry 8). Aldehydes with longer aliphatic chains
(Et and nBu) gave homoallylic alcohols 5b and 5c with ex-
cellent enantioselectivities of up to 99% ee (Table 1, en-
tries 9 and 10). The allylation of b,b-disubstituted aldehyde
4d gave 5d also with high asymmetric induction (Table 1,
entry 11). However, in the case of a-methylacrolein 4e high
enantioselectivity was achieved with the (S,R)-1 catalyst,
whereas its stereoisomer (R,R)-1 resulted in a diminished
selectivity (Table 1, entry 12). The same effect was also ob-
served in the allylation of a,b-disubstituted aldehydes 4 f
and 4g: the reaction catalyzed by (R,R)-1 proceeded with
low enantioselectivity, whereas the use of (S,R)-1 gave excel-
lent asymmetric induction (Table 1, entries 13 and 14).
To rationalize the high selectivity of the title reaction, the
reaction mechanism has been approached by means of den-
sity functional theory calculations.[13,20] The (S,R)-1 base is
considered here. The interaction between (S,R)-1 and allyl-
trichlorosilane leads to two types of complexes, and the
most stable isomers, 6a and 6b, are shown in Figure 2. The
interaction between the reactant and the catalyst can either
be due to the coordination of the oxygen atom of (S,R)-1 to
the silicon atom (6a) or be mediated by the interaction be-
tween the oxygen atoms of
Figure 1. ORTEP drawing of (R,R)-1 with the atom numbering scheme.
Thermal ellipsoids are drawn at the 50% probability level.
3 was performed with chiral N,N’-dioxides (R,R)-1 and
(S,R)-1. In general, both N,Nꢃ-dioxides catalyzed the highly
enantioselective allylation of most of the aldehydic sub-
strates (see Table 1). The enantioselectivity is not influenced
by substitution of Me (3b) or Cl (3c) at the a-position of
the double bond (Table 1, entries 2 and 3). Similarly, the
presence of electron-withdrawing halide groups (F and Br)
attached to the aromatic ring gave 3d and 3e with high
asymmetric induction (Table 1, entries 4 and 5). Only homo-
(S,R)-1 and hydrogen atoms of
the allyl group (6b). Both inter-
Table 1. Allylation of a,b-unsaturated 2 and 4 to homoallylic alcohols 3 and 5 catalyzed by (R,R)-1 or (R,S)-1.
mediates are further stabilized
by weak interactions between
the backbones of the catalyst
and the substrate.[14,15] Accord-
ingly, it is necessary to account
for the dispersion interactions
in the calculations. To this end,
we used the B97D functional,
which contains a semiempirical
correction for the dispersion in-
teractions.[16]
Starting with the formation
of intermediate 6a, several
transition structures for the
coupling with crotylaldehyde
have been found (all structures
can be found in the Supporting
Information). The most stable
arrangement corresponds to the
structure that is stabilized by p-
p stacking between crotylalde-
Entry
Aldehyde
R1
R2
R3
Alcohol
Catalyst (R,R)-1
Catalyst (S,R)-1
e.r. (R:S)[b]
Yield [%][a] e.r. (R:S)[b] Yield [%][a]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2 f
2g
4a
4b
4c
4d
4e
4 f
4g
H
H
H
F
H
–
–
–
–
–
–
–
H
H
H
H
3a
3b
3c
3d
3e
3 f
3g
5a
5b
5c
5d
92
90
35
74
80
60
80
40
85
90
30
20
35
70
98.7:1.3
94.3:5.7
96:4
95
99
35
75
85
60
80
90
90
95
35
25
80
90
3.5:96.5
1.4:98.6
3.2:96.8
4.5:95.5
2.6:97.4
30.4:69.6
18.5:81.5
7.4:92.6
2:98
1.9:98.1
7:93
2.7:97.3
1.8:98.2
1.9:98.1
Me
Cl
H
H
H
H
H
H
H
97.7:2.3
99.3:0.7
93.3:6.7
85.3:14.7
92.9:7.1
99.1:0.9
99.1:0.9
95.6:4.1
69.3:30.7
59.7:40.3
59.6:40.4
Br
NO2
MeO
Me
Et
nBu
Me
H
9
10
11
12
13
14
Me
H
H
Me 5e
Me
Me
Me
Et
5 f
5g
H
[a] Yield determined by 1H NMR spectroscopy. [b] Determined by GC; the values are average of three meas-
urements.
Chem. Eur. J. 2010, 16, 9442 – 9445
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9443

J. Roithovꢁ, M. Kotora et al.
Figure 2. B97D/cc-pVTZ//B97D/6-31g* potential energy diagram for the coupling of allyltrichlorosilane (C3H5SiCl3) with crotylaldehyde (C3H5CHO) cat-
alyzed by (S,R)-1 in THF. Structures 6a and 6b show the optimized geometries of complexes between (S,R)-1 and C3H5SiCl3. Structures (S)-TS1, (R)-
TS1, (S)-TS2, and (R)-TS2 show the optimized geometries of the transition structures. Energies are given relative to the sum of the enthalpies of the re-
actants (C3H5SiCl3 +C3H5CHO+(S,R)-1) at 298 K in THF (for details see the Supporting Information).
hyde and the phenyl substituent of (S,R)-1. In agreement
with the experimental results, the formation of the (S) prod-
uct is favored (via (S)-TS1) in that the corresponding energy
barrier is 3 kJmolÀ1 lower than that for the formation of the
(R) product (the grey reaction pathway in Figure 2,
Table 2).
substituent with the reactants plays an important role. The
transition structures in which the reactants are placed in the
vicinity of the THF substituent lie higher in energy that
those in which the reactants are more stabilized by the inter-
action with phenyl (for all structures, see the Supporting In-
formation). This effect is most evident for transition struc-
À
tures with the O Si bond because the THF group is com-
pletely remote.
Table 2. B97D/cc-pVTZ energetics[13] of the coupling between crotylalde-
hyde and allyltrichlorosilane.
Finally, the efficiency of the above-mentioned asymmetric
allylation was demonstrated by a short enantioselective syn-
thesis of (S)-(À)-goniothalamin (Scheme 1). The allylation
B97D/cc-pVTZ//B97D/6-31G*[12]
DE0K[a]
Gas phase
DH298K[b]
DG298K[c]
THF
THF
THF
(S)-TS1
(R)-TS1
(S)-TS2
(R)-TS2
6a
54
55
17
20
10
45
48
26
42
45
24
168
170
140
146
56
29
27
À6
À5
6b
À35
À29
À26
17
[a] Energies are given relative to the sum of energies of the reactants at
0 K (for details see the Supporting Information). [b] Energies are given
relative to the sum of enthalpies of the reactants (for details see the Sup-
porting Information). [c] Energies are given relative to the sum of Gibbs
energies of the reactants (for details see the Supporting Information).
Scheme 1. Synthesis of (S)-(À)-goniothalamin 8.
of cinnamaldehyde 2a (3.78 mmol) catalyzed by (S,R)-1
(1 mol%) in THF (À788C, 1 h) gave desired homoallyl alco-
hol (S)-(À)-3a in 97% isolated yield (97% ee). Esterifica-
tion of 3a with acryloyl chloride gave ester (S)-(À)-7 in
86% yield without loss of chirality (95% ee, GC). Ring-clos-
ing metathesis of 7 catalyzed by Grubbs 1st generation com-
An alternative mechanism can be found if intermediate
6b is considered (the black reaction pathway in Figure 2).
This transition structure is stabilized by a number of weak
interactions.[14] Besides the interaction between the oxygen
atoms of the catalyst and the hydrogen atoms of allyltri-
chlorosilane and crotylaldehyde, p–p interactions and the in-
teraction between the hydrogen atoms of the saturated rings
of the catalyst and the chlorine atoms should be considered.
Formation of the (S) product again proceeds via an energy
barrier that is 3 kJmolÀ1 lower than the formation of the (R)
product.
plex [RuCHPhCl2ACHTUNRGTNEG(UN PCy3)2] (10 mol%) was carried out.
Metathesis in dichlormethane (reflux, 15 h) gave (S)-(À)-go-
niothalamin 8 in 70% isolated yield (95% ee, HPLC). The
reaction in toluene gave only 30% of (S)-(À)-8 with identi-
cal enantioselectivity. It is important to stress that it was
necessary to keep the concentration of the reactants low
(0.01m) to maintain a high yield of 8. When the metathesis
was carried out at higher concentrations (ꢀ0.1m), the yields
did not exceed 20%. These results are in agreement with
previously reported results[17] and a recent study regarding
The calculations also clearly show why the chirality of the
THF substituent of (S,R)-1 plays a minor role. In all types of
transition structures found, the interaction of the phenyl
9444
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Chem. Eur. J. 2010, 16, 9442 – 9445

Enantioselective Allylation of a,b-Unsaturated Aldehydes
COMMUNICATION
ˇ
[7] a) A. Kadlcꢀkovꢁ, R. Hrdina, I. Valterovꢁ, M. Kotora, Adv. Synth.
concentration effect on the ring-closing metathesis of acrylic
esters.[18]
ˇ
Catal. 2009, 351, 1279–1283; b) A. Kadlcꢀkovꢁ, M. Kotora, Mole-
cules 2009, 14, 2918–2926; c) R. Hrdina, F. Opekar, J. Roithovꢁ, M.
Kotora, Chem. Commun. 2009, 2314–2316.
In conclusion, the easy preparation of (R,R)-1 and (R,S)-1
and their high catalytic activity enables the efficient allyla-
tion of a,b-unsaturated aldehydes to the corresponding ho-
moallyl alcohols to be carried out with high enantioselectivi-
ties of up to 99% ee. This method could serve as an alterna-
tive to the Keck allylation.[19]
[8] For previous results, see: a) R. Hrdina, I. G. Starꢁ, L. Dufkovꢁ, S.
ˇ
Mitchel, I. Cꢀsarovꢁ, M. Kotora, Tetrahedron 2006, 62, 968–976;
b) R. Hrdina, A. Kadlcꢀkovꢁ, I. Valterovꢁ, J. Hodacovꢁ, M. Kotora,
Tetrahedron: Asymmetry 2006, 17, 3185–3191; c) R. Hrdina, I. Val-
terovꢁ, J. Hodacovꢁ, M. Kotora, Adv. Synth. Catal. 2007, 349, 822–
ˇ
ˇ
ˇ
ˇ
826; d) R. Hrdina, T. Boyd, I. Valterovꢁ, J. Hodacovꢁ, M. Kotora,
ˇ
´
Synlett 2008, 3141–3144; e) R. Hrdina, M. Dracꢀnsky, I. Valterovꢁ, J.
ˇ
ˇ
Hodacovꢁ, I. Cꢀsarovꢁ, M. Kotora, Adv. Synth. Catal. 2008, 350,
1449–1456.
Experimental Section
[9] J. F. Traverse, Y. Zhao, A. H. Hoveyda, M. L. Snapper, Org. Lett.
2005, 7, 3151–3154.
[10] Q. Chai, C. Song, Z. Sun, Y. Ma, C. Ma, Y. Dai, M. B. Andrus, Tetra-
hedron Lett. 2006, 47, 8611–8615.
[11] a) G. Chelucci, N. Belmonte, M. Benaglia, L. Pignataro, Tetrahedron
Lett. 2007, 48, 4037–4041; b) G. Chelucci, S. Baldino, G. A. Pinna,
M. Benaglia, L. Buffa, S. Guizzetti, Tetrahedron 2008, 64, 7574–
7582.
[12] T. Robert, J. Velder, H.-G. Schmalz, Angew. Chem. 2008, 120, 7832–
7835; Angew. Chem. Int. Ed. 2008, 47, 7718–7721.
[13] The calculations were performed by using the B97D method with 6-
31G* basis sets as implemented in Gaussian 09. All intermediates
and transition structures were characterized by using frequency
analysis. The solvation effect of tetrahydrofuran was approximated
by using a SCRF single-point calculation at the B97D/cc-pVTZ
level of theory for the optimized geometries in the gas phase by
using a simple polarizable continuum model calculation. The final
energy was corrected for the basis-set superposition error at the
B97D/cc-pVTZ level of theory.
Cinnamaldehyde (0.4 mmol, 53 mg), diisopropylethylamine (0.6 mmol,
104 mL, 77 mg), and allyltrichlorsilane (0.6 mmol, 85 mL, 51 mg) were
added to
a solution of bipyridine-N,N’-dioxide (R,R)-1 (0.004 mmol,
2 mg) in THF (1 mL) at À788C. The mixture was stirred for 1 h, then
quenched with brine (4 mL), and the organic layer was separated, dried
over MgSO4, and filtered on silica gel. The ee was determined by using
GC (HP-Chiral ß column, 30 mꢄ0.25 mm; oven: 808C for 1 min, then
18CminÀ1 to 1608C, 5 min): tR =71.09 min, tS =71.78 min; e.r.: 98.7:1.3
(97% ee).
Characterization data for 3a: 90% yield as determined by 1H NMR.
1H NMR (CDCl3, 300 MHz, 258C): d=7.25–7.42 (m, 5H; Ar), 6.64 (d, J-
3
ACHTUNGTRENNUNG
(H,H)=16 Hz, 1H; CH), 6.27 (dd, 3J=16, 6.3 Hz, 1H; CH), 5.84–5.92
(m, 1H; CH), 5.19–5.26 (m, 2H; CH2), 4.37–4.42 (m, 1H; CHO), 2.38–
2.50 (m, 2H; CH2), 2.05 (s, 1H; OH). The spectral characteristics of 3a
are in agreement with previously reported data.[17b]
[14] P. Hobza, K. Mꢆller-Dethlefs, Non-Covalent Interactions: Theory
and Experiments, RSC, London, 2010.
Acknowledgements
ˇ
[15] E. C. Lee, D. Kim, P. Jurecka, P. Tarakeshwar, P. Hobza, K. S. Kim,
J. Phys. Chem. A 2007, 111, 3446-.
[16] S. Grimme, J. Comput. Chem. 2006, 27, 1787–1799.
The authors acknowledge financial support from grants 203/08/0350,
LC06070, MSM0021620857, Z40550506, and SVV 261205/2010. The au-
[17] a) A. de Fatima, R. A. Pilli, Tetrahedron Lett. 2003, 44, 8721–8724;
b) E. Sundby, L. Perk, T. Anthonsen, A. J. Aasen, T. V. Hansen, Tet-
rahedron 2004, 60, 521–524; c) P. Harsh, G. A. OꢃDoherty, Tetrahe-
dron 2009, 65, 5051–5055.
[18] B. Schmidt, D. Geißler, ChemCatChem 2010, 2, 423–429.
[19] G. E. Keck, K. H. Tarbet, L. S. Geraci, J. Am. Chem. Soc. 1993, 115,
8467–8468.
ˇ
thors would like to thank Dr. Ivana Cꢀsarovꢁ for the X-ray analysis.
Keywords: allylation · asymmetric synthesis · lewis bases ·
organocatalysis · nitrogen oxides
[20] Gaussian 09, Revision A.02, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V.
Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L.
Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasega-
wa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T.
Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bear-
park, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Ko-
bayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S.
S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J.
E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gom-
perts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Po-
melli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzew-
ski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D.
Daniels, ꢇ. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D.
J. Fox, Gaussian, Inc., Wallingford CT, 2009..
[1] S. E. Denmark, G. L. Beutner, Angew. Chem. 2008, 120, 1584–1663;
Angew. Chem. Int. Ed. 2008, 47, 1560–1638.
[2] S. E. Denmark, J. Fu, Chem. Rev. 2003, 103, 2763–2794.
[3] a) N. Nakajima, M. Saito, M. Shiro, H. Hashimoto, J. Am. Chem.
Soc. 1998, 120, 6419–6420; b) Y. Orito, M. Nakajima, Synthesis
2006, 1391–1401, and references therein.
[4] a) T. Shimada, A. Kina, S. Ikeda, T. Hayashi, Org. Lett. 2002, 4,
2799–2801; b) T. Shimada, A. Kina, T. Hayashi, J. Org. Chem. 2003,
68, 6329–6337; c) A. Kina, T. Shimada, T. Hayashi, Adv. Synth.
Catal. 2004, 346, 1169–1174.
[5] a) A. V. Malkov, M. Orsini, D. Pernazza, K. W. Muir, V. Langer, P.
ˇ
´
Meghani, P. Kocovsky, Org. Lett. 2002, 4, 1047–1049; b) A. V.
ˇ
´
Malkov, L. Dufkovꢁ, L. Farrugia, P. Kocovsky, Angew. Chem. 2003,
115, 3802–3805; Angew. Chem. Int. Ed. 2003, 42, 3674–3676;
ˇ
c) A. V. Malkov, P. Ramꢀrez-Lꢅpez, L. Biedermannovꢁ, L. Rulꢀsek,
ˇ
´
L. Dufkovꢁ, M. Kotora, F. Zhu, P. Kocovsky, J. Am. Chem. Soc.
2008, 130, 5441–5448.
ˇ
´
[6] For reviews, see: a) A. V. Malkov, P. Kocovsky, Eur. J. Org. Chem.
2007, 29–36; b) G. Chelucci, G. Murineddu, G. A. Pinna, Tetrahe-
dron: Asymmetry 2004, 15, 1373–1389.
Received: June 1, 2010
Published online: July 20, 2010
Chem. Eur. J. 2010, 16, 9442 – 9445
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9445