METHOX: A new pyridine N-oxide organocatalyst for the asymmetric allylation of aldehydes with allyltrichlorosilanes

Article abstract of DOI:10.1021/ol050972h

(Chemical Equation Presented) Allylation of aromatic aldehydes with allyltrichlorosilane is catalyzed by the new terpene-derived pyridine N-oxide (+)-METHOX (≤5 mol %) in MeCN with high enantioselectivities (≤96% ee) and conversion rates; this catalyst re

Full text of DOI:10.1021/ol050972h

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3219-3222
METHOX: A New Pyridine N-Oxide
Organocatalyst for the Asymmetric
Allylation of Aldehydes with
Allyltrichlorosilanes†
Andrei V. Malkov,* Mark Bell,‡ Fabiomassimo Castelluzzo, and Pavel Kocˇovsky´*
Department of Chemistry, Joseph Black Building, WestChem, UniVersity of Glasgow,
Glasgow G12 8QQ, Scotland, UK
amalkoV@chem.gla.ac.uk; paVelk@chem.gla.ac.uk
Received April 29, 2005
ABSTRACT
Allylation of aromatic aldehydes with allyltrichlorosilane is catalyzed by the new terpene-derived pyridine N-oxide (+)-METHOX (e5 mol %)
in MeCN with high enantioselectivities (e96% ee) and conversion rates; this catalyst retains high selectivity even at room temperature.
Allyltrichlorosilane (2) and related reagents can be activated
by chiral Lewis-basic catalysts1 to effect asymmetric allyla-
tion of aromatic and heteroaromatic aldehydes 1 (Scheme
1).1-7 Among the most successful catalysts reported to date1-7
our pyridine-type N-monoxides PINDOX (4),4 iso-PINDOX
(5),7 and QUINOX (6)6 (Figure 1), which give e96% ee
Scheme 1
are Denmark’s phosphoramides;1 axially chiral bipyridine
N,N-bisoxides, developed by Nakajima2 and Hayashi;3 and
† Dedicated to Dr. Jiˇr´ı Za´vada on the occasion of his 70th birthday.
‡ Current address: Kemisk Institut, Aarhus Universitet, 8000 Aarhus C,
Denmark.
(1) For leading reviews, see: (a) Denmark, S. E.; Stavenger, R. A. Acc.
Chem. Res. 2000, 33, 432. (b) Denmark, S. E.; Fu, J. Chem. Commun. 2003,
167. (c) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763.
(2) Nakajima, N.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem.
Soc. 1998, 120, 6419.
(3) (a) Shimada, T.; Kina, A.; Ikeda, S.; Hayashi, T. Org. Lett. 2002, 4,
2799. (b) Shimada, T.; Kina, A.; Hayashi, T. J. Org. Chem. 2003, 68, 6329.
Figure 1.
(Table 1, entries 1-6). For the reactions catalyzed by 4 and
5, we proposed the silicon chelation between the oxygen of
10.1021/ol050972h CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/28/2005

Table 1. Allylation of Aldehydes 1 with 2 Catalyzed by Chiral Lewis Bases (Scheme 1)a
entry
aldehyde
R
catalyst (mol %)
solvent
temp (°C)
time (h)
yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(+)-4 (10)
(+)-4 (10)
(-)-5 (10)
(-)-5 (10)
(+)-6 (10)
(+)-6 (10)
(-)-7 (10)
(+)-8 (10)
(+)-9 (10)
(-)-10 (10)
(-)-11 (10)
(-)-11 (10)
(-)-11 (10)
(+)-12 (10)
(+)-12 (10)
(+)-12 (10)
(+)-12 (10)
(+)-12 (5)
(+)-12 (1)
(+)-12 (10)
(+)-12 (5)
(+)-12 (2)
(+)-12 (10)
(+)-12 (10)
(+)-12 (10)
(+)-12 (10)
(+)-12 (10)
(+)-12 (5)
(+)-12 (5)
(+)-12 (5)
(+)-12 (5)
CH2Cl2
MeCN
CH2Cl2
MeCN
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CHCl3
CHCl3
CHCl3
MeCN
MeCN
MeCN
MeCN
-60
-20
-20
-40
-40
-40
-60
-60
-60
-60
-60
-40
-60
-40
-20
0
-40
-40
-40
-20
-20
-20
0
24
24
18
18
2
78
95
90f
84g
93g
96g
87h,i
70h,i
41j,k
68j,k
16j,k
58j,k
80j
80j
82j,l
96
94
90
96
96
95
96
93
93
23e
75
60
60
66
55
15e
35e
44e
46e
52
12
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
74
63
49
g95
g95
68
g95
g95
90
g95
g95
73m
45e
26e
86
g95
g95
0
91
87
94
94
89
93
96
89
rt
-40
-20
0
-40
-40
-40
-40
4-CF3-C6H4
4-MeO-C6H4
2-MeO-C6H4
2,6-Me2-C6H4
a Reaction was carried out at 0.4 mmol scale with 1.1 equiv of 2 in the presence of the catalyst (10 mol %, unless stated otherwise) and (i-Pr)2NEt (1
1
equiv) as a base. b Isolated yield (product pure by H NMR). c Determined by chiral HPLC or GC. d All products 3 were of (S)-(-)-configuration (unless
otherwise stated), as revealed by the comparison of their optical rotations (measured in CHCl3) and their GC and HPLC retention times with the literature
data and with the behavior of authentic samples.2-7 e Incomplete conversion. f Ref 4. g Ref 7. h Ref 6. i (R)-(+)-3a was formed. Ref 6. j Catalyst was of
87% ee. k Ref 5. l With the catalyst that was of 96% ee, the asymmetric induction was enhanced to 90% ee (at -40 °C). m Yield was 41% with 2 mol % of
the catalysts; yield was 85% with 20 mol %. The catalyst loading did not alter the enantioselectivity (94-95% ee).
the pyridine N-oxide and the nitrogen of the remaining
pyridine ring.4,7,8 However, the monodentate catalyst 7,
lacking the second nitrogen, proved to catalyze the allylation
of benzaldehyde with 41% ee (entry 7), showing that
bidentate chelation is not strictly required.5 Its ortho-methoxy
analogue 8, where a weak coordination of MeO to silicon
might be anticipated, exhibited higher enantioselectivity (68%
ee; entry 8),5 whereas the ortho-fluoro derivative 9 was
ineffective (entry 9).5
The latter results raised a question as to the role of the
MeO group in 8: does it affect the reaction via a silicon
coordination or via some unidentified electronic effect (such
as arene-arene interaction)? To address this issue, we have
now synthesized the para isomer 10 and found it also to be
fairly effective (58% ee, entry 10), which indicates that the
MeO effect is likely to be of electronic origin, namely, via
increasing the electron density of the phenyl moiety of the
catalyst. By contrast, decreasing the electron density, as in
the fluoro derivative 9, is detrimental to the reaction (entry
9). Therefore, we set out to synthesize even more electron-
rich dimethoxy and trimethoxy derivatives 11 and 12,
respectively; for the latter compound, we propose the
acronym METHOX.
(4) Malkov, A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.; Langer, V.;
Meghani, P.; Kocˇovsky´, P. Org. Lett. 2002, 4, 1047.
(5) Malkov, A. V.; Bell, M.; Vassieu, M.; Bugatti, V.; Kocˇovsky´, P. J.
Mol. Catal. A 2003, 196, 179.
(6) Malkov, A. V.; Dufkova´, L.; Farrugia, L.; Kocˇovsky´, P. Angew.
Chem., Int. Ed. 2003, 42, 3674.
(7) Malkov, A. V.; Bell, M.; Orsini, M.; Pernazza, D.; Massa, A.;
Herrmann, P.; Meghani, P.; Kocˇovsky´, P. J. Org. Chem. 2003, 68, 9659.
(8) Similarly, both Nakajima2 and Hayashi3 proposed a chelation of
silicon by the two oxygens of their N,N-bisoxides. For a related chelation
of trifluorosilanes by phenanthroline, featuring hexacoordinate silicon,
see: Nakash, M.; Gut, D.; Goldvaser, M. Inorg. Chem. 2005, 44, 1023.
The synthesis of 10-12 relied on Kro¨hnke annulation9
(Scheme 2) and commenced with the preparation of the
Kro¨hnke salts 14a-c by iodination of the corresponding
acetophenones 13a-c in pyridine. Pinocarvone (-)-15,
obtained in a quantitative yield by the ene reaction of (+)-
3220
Org. Lett., Vol. 7, No. 15, 2005

were also observed with ortho-substituted aldehyde 1d (entry
30). On the other hand, increasing the steric hindrance about
the carbonyl group, as in 2,6-dimethyl-benzaldehyde (1e),
entirely prevented the reaction (entry 31).
Scheme 2a
Finally, allylation of benzaldehyde 1a was also carried out
with crotyltrichlorosilanes 18 (E/Z 87:13)13 and 1914 in
MeCN (Scheme 3), in the presence of 12 as a catalyst (5
Scheme 3
a a, Ar ) 4-MeO-C6H4; b, Ar ) 2,6-(MeO)2C6H3; c, Ar ) 2,4,6-
(MeO)3C6H2.
R-pinene with singlet oxygen,10,11 was then heated with the
respective salts 14a-c in the presence of AcONH4 to produce
the pyridine derivatives 16a-c, whose methylation in the
benzylic position, mediated by LDA,11,12 afforded 17a-c,
respectively, with excellent diastereoselectivity. Oxidation
of the pyridine nitrogen in 17a-c provided the required
N-oxides 10-12, respectively.
Indeed, the dimethoxy derivative (-)-11 proved to be a
more efficient catalyst than 8 or 10, exhibiting 80% ee
(compare entries 8 and 10 with 11). Switching from CH2Cl2
to MeCN or CHCl3 had little effect (entries 12 and 13).
mol %). The trans isomer 18 (1.2 mol excess) reacted
uneventfully, affording pure anti product (-)-20 (anti/syn
g99:1) of high enantiopurity (95% ee), which indicates a
kinetic preference for the (E)-isomer. Accordingly, the
reaction with pure (Z)-isomer 19 proved to be sluggish (26%
conversion), affording a 1:6 mixture of (-)-20 and (-)-21
of low enantioselectivity (26% ee).
In conclusion, the enantiopure, terpene-derived pyridine
N-oxide METHOX (+)-12 has been synthesized in three
steps from the inexpensive chiral pool and shown to catalyze
the asymmetric allylation of aromatic aldehydes 1 with
allyltrichlorosilane 2 and crotyltrichlorosilane 18 (e96% ee).
The efficacy of 12 also demonstrates that neither the
bidentate chelation of silicon to the catalyst nor the presence
of a chiral axis2-4,6,7 is a prerequisite for attaining high
enantioselectivity in these reactions. METHOX 12 has been
found to exhibit best activity in MeCN, and the reactions
are characterized by low catalyst loading (e5 mol %) and
high tolerance to aldehyde electronics.15 In this respect, the
behavior of 12 differs dramatically from that of 6, where a
huge dependence on the aldehyde electronics has been
observed.6,16,17 Furthermore, 12 retains high enantioselectivity
A real improvement was attained with the trimethoxy
derivative METHOX (+)-12 (entries 14-16), especially for
the reactions run in MeCN (entries 17-19), where the
conversion was essentially quantitative and the enantio-
selectivities were at the 96% ee level. It is notable that
lowering the catalyst loading proved to have no effect on
the enantioselectivity, though the reaction slowed to some
extent (entries 17-19). Furthermore, increasing the temper-
ature from the original -40 °C to room temperature resulted
in only a marginal deterioration of enantioselectivity (entries
20-24 and 25-27).
The electronic effects in the aldehyde were briefly
elucidated with the aid of substituted benzaldehydes 1b-e
and the champion catalyst METHOX (+)-12 (entries 28-
31). Both para-substituted aldehydes 1b and 1c proved to
react with a similar level of efficiency as 1a (entries 28 and
29), showing little dependence of the reaction on the
electronics of the electrophile. High reactivity and selectivity
(13) Prepared as an 87:13 trans/cis mixture via the CuCl-catalyzed
reaction of crotyl chloride with HSiCl3: Iseki, K.; Kuroki, Y.; Takahashi,
M.; Kishimoto, S.; Kobayashi, Y. Tetrahedron 1997, 53, 3513.
(14) Prepared as a practically pure isomer on Pd-catalyzed 1,4-addition
of HSiCl3 to butadiene: Tsuji, J.; Hara, M.; Ohno, K. Tetrahedron 1974,
30, 2143.
(9) For a review on Kro¨hnke annulation, see: Kro¨hnke, F. Synthesis 1976,
1. For recent overviews of the Kro¨hnke application in the synthesis of
terpenoid bipyridines, see ref 7 and the following: (a) Knof, U.; von
Zelewsky, A. Angew. Chem., Int. Ed. 1999, 38, 303. (b) Chelucci, G.;
Thummel, R. P. Chem. ReV. 2002, 102, 3129. (c) Fletcher, N. C. J. Chem.
Soc., Perkin Trans. 1 2002, 1831. (d) Malkov, A. V.; Kocˇovsky´, P. Curr.
Org. Chem. 2003, 7, 1737.
(10) Mihelich, E. D.; Eickhoff, D. J. J. Org. Chem. 1983, 48, 4135.
(11) Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.; Teply´,
F.; Meghani, P.; Kocˇovsky´, P. J. Org. Chem. 2003, 68, 4727.
(12) (a) Lo¨tscher, D.; Rupprecht, S.; Stoeckli-Evans, H.; von Zelewsky,
A. Tetrahedron: Asymmetry 2000, 11, 4341. (b) Kolp, B.; Abeln, D.;
Stoeckli-Evans, H.; von Zelewsky, A. Eur. J. Inorg. Chem. 2001, 1207.
(c) Lo¨tscher, D.; Rupprecht, S.; Collomb, P.; Belser, P.; Viebrock, H.; von
Zelewsky, A.; Burger, P. Inorg. Chem. 2001, 40, 5675.
(15) Note that the reactivity of METHOX 12 resembles that of the
bipyridine N,N-bisoxide recently reported by Hayashi.3
(16) Arene-arene interactions between the electron-rich catalyst 12 and
the substrate aldehyde can be proposed as a rationale for these observations.
However, the latter interactions differ from those observed previously for
QUINOX 6.6,17 High-level quantum chemical calculations are currently
being used on in our laboratory to shed more light on this issue: Malkov,
A. V.; Bendova´, L.; Hobza, P.; Kocˇovsky´, P. Unpublished results.
(17) For recent reviews on arene-arene interactions, see: (a) Hobza,
P.; Havlas, Z. Chem. ReV. 2000, 100, 4253. (b) Hunter, C. A.; Lawson, K.
R.; Perkins, J.; Urch, C. J. J. Chem. Soc., Perkin Trans. 1 2001, 651. (c)
Cozzi, F.; Annunziata, R.; Benaglia, M.; Cinquini, M.; Raimondi, L.;
Baldridge, K. K.; Siegel, J. S. Org. Biomol. Chem. 2003, 1, 157. (d) Meyer,
E. A.; Castellano, R. K.; Diederich, F. Angew. Chem., Int. Ed. 2003, 42,
1210.
Org. Lett., Vol. 7, No. 15, 2005
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at -20 and 0 °C, and even at room temperature (entries 20-
24), which has industrial implications.
Supporting Information Available: Experimental meth-
1
ods and H and 13C NMR spectra for key compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the University of Glasgow
for a studentship to M.B. and the University of Rome “La
Sapienza” for a fellowship to F.C.
OL050972H
3222
Org. Lett., Vol. 7, No. 15, 2005