New Lewis-Basic N-Oxides as Chiral Organocatalysts in Asymmetric Allylation of Aldehydes

Article abstract of DOI:10.1021/jo035074i

Allylation of aromatic and heteroaromatic aldehydes 1a-k with allyltrichlorosilane 2 can be catalyzed by the new heterobidentate, terpene-derived bipyridine N-monoxides 4, 6a,b, and 8-11 (≤10 mol %) to afford (S)-(-)-3 with high enantioselectivities (≤99% ee). The stereochemical outcome has been found to be controlled by the axial chirality of the catalyst, which in turn is determined by the central chirality of the annulated terpene units. Solvent effects on the conversion and the level of asymmetric induction have been elucidated, and MeCN has been identified as the optimal solvent for these catalysts.

Full text of DOI:10.1021/jo035074i

New Lew is-Ba sic N-Oxid es a s Ch ir a l Or ga n oca ta lysts in
Asym m etr ic Allyla tion of Ald eh yd es
Andrei V. Malkov,*,† Mark Bell,† Monica Orsini,†,‡ Daniele Pernazza,†,§ Antonio Massa,†,|
Pavel Herrmann,†, Premji Meghani,# and Pavel Kocˇovsky´*,†
Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, U.K., and AstraZeneca R&D,
Loughborough, Leics. LE11 5RH, U.K.
amalkov@chem.gla.ac.uk; p.kocovsky@chem.gla.ac.uk
Received J uly 24, 2003
Allylation of aromatic and heteroaromatic aldehydes 1a -k with allyltrichlorosilane 2 can be
catalyzed by the new heterobidentate, terpene-derived bipyridine N-monoxides 4, 6a ,b, and 8-11
(e10 mol %) to afford (S)-(-)-3 with high enantioselectivities (e99% ee). The stereochemical outcome
has been found to be controlled by the axial chirality of the catalyst, which in turn is determined
by the central chirality of the annulated terpene units. Solvent effects on the conversion and the
level of asymmetric induction have been elucidated, and MeCN has been identified as the optimal
solvent for these catalysts.
SCHEME 1 a
In tr od u ction
The Lewis-basic catalysis in the asymmetric Sakurai-
Hosomi-Denmark allylation1,2 of aldehydes 1 with al-
lyltrichlorosilanes, such as 2 (Scheme 1), has now been
firmly established.2-5 Particularly good enantioselectivi-
ties (e90% ee) and conversions have been attained with
2,2′-bipyridine-type N,N-dioxides as catalysts.3,4,6,7
a
For R, see Table 1.
In a preliminary communication, we have recently
reported on the synthesis of new terpene-derived bipy-
ridine monoxides 4 (PINDOX) and 6a (Me2PINDOX,
Chart 1), which exhibited enhanced enantioselectivity in
the latter reaction.7 Herein, we present an orchestration
of this theme, extended by the synthesis and application
of the iso-PINDOX series 8-11.
† University of Glasgow.
‡ Current address: Department of Chemistry, University of Rome
“La Sapienza”, P. A. Moro 5, 00185 Rome, Italy.
§ Current address: Department of Chemistry, University of Cardiff,
P.O. Box 912, Cardiff CF10 3TB, U.K.
| On leave from Department of Chemistry, University of Salerno,
Via S. Allende, 84081 Baronissi (Salerno), Italy.
Current address: Department of Organic Chemistry, Charles
University, Albertov 2030, 12840 Prague 2, Czech Republic.
#
AstraZeneca.
Resu lts a n d Discu ssion
* Corresponding author.
(1) (a) Hosomi, A.; Sakurai, H. J . Am. Chem. Soc. 1977, 99, 1673.
For overviews, see: (b) Hosomi, A. Acc. Chem. Res. 1988, 21, 200. (c)
Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432. (d)
Denmark, S. E.; Fu, J . Chem. Commun. 2003, 167. (e) Denmark, S.
E.; Fu, J . Chem. Rev. 2003, 103, 2763.
(2) (a) Denmark, S. E.; Coe, D. M.; Pratt, N. E.; Griedel, B. D. J .
Org. Chem. 1994, 59, 6161. (b) Denmark, S. E.; Stavenger, R. A.; Wong,
K.-T.; Su, X. J . Am. Chem. Soc. 1999, 121, 4982. (c) Denmark, S. E.;
Su, X.; Nishigaichi, Y. J . Am. Chem. Soc. 1998, 120, 12990. (d)
Denmark, S. E.; Pham, S. M. Helv. Chim. Acta 2000, 83, 1846. (e)
Denmark, S. E.; Fu, J . J . Am. Chem. Soc. 2000, 122, 12021. (f)
Denmark, S. E.; Fu, J . J . Am. Chem. Soc. 2001, 123, 9488. (g)
Denmark, S. E.; Fan, Y. J . Am. Chem. Soc. 2002, 124, 4233. See also
the reference section in ref 7.
(3) (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J . Am.
Chem. Soc. 1998, 120, 6419. (b) Nakajima, M.; Saito, M.; Hashimoto,
S. Chem. Pharm. Bull. 2000, 48, 306. See also: (c) Nakajima, M.; Saito,
M.; Uemura, M.; Hashimoto, S. Tetrahedron Lett. 2002, 43, 8827.
(4) (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.
Ca ta lyst Design a n d Syn th esis. The synthesis of
PINDY, the core bipyridine precursor to PINDOX (+)-4,
was described by us earlier in detail (Scheme 2; R )
H).7-10 Thus, (+)-nopinone (+)-13,8 prepared on a 20 g
scale from (-)-â-pinene (-)-12 either by NaIO4/OsO4
(6) For the use of other types of chiral Lewis bases, see ref 2 and
the following. Phosphoramides: (a) Iseki, K.; Kuroki, Y.; Takahashi,
M.; Kobayashi, Y. Tetrahedron Lett. 1996, 37, 5149. (b) Iseki, K.;
Kuroki, Y.; Takahashi, M.; Kishimoto, S.; Kobayashi, Y. Tetrahedron
1997, 53, 3513. Tartrates: (c) Wang, Z.; Wang, D.; Sui, X. Chem.
Commun 1996, 2261. (d) Wang, D.; Wang, Z. G.; Wang, M. W.; Chen,
Y. J .; Liu, L.; Zhu, Y. Tetrahedron: Asymmetry 1999, 10, 327.
(2-Pyridinyl)oxazolines (stoichiometric): (e) Angell, R. M.; Barrett, A.
G. M.; Braddock, D. C.; Swallow, S.; Vickery, B. D. Chem. Commun.
1997, 919.
(7) Malkov, A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.; Langer,
V.; Meghani, P.; Kocˇovsky´, P. Org. Lett. 2002, 4, 1047.
(5) For a complementary approach, relying on chiral Lewis acids,
see e.g.: (a) Mikami, K.; Matsukawa, S. Tetrahedron Lett. 1994, 35,
3133. (b) Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993, 34, 3453.
(c) Kobayashi, S.; Nishio, K. J . Org. Chem. 1994, 59, 6620. (d)
Kobayashi, S.; Nishio, K. Chem. Lett. 1994, 1773. (e) Short, J . D.;
Attenoux, S.; Berrisford, D. J . Tetrahedron Lett. 1997, 38, 2351.
(8) For our syntheses of the core bipyridines, see: (a) Malkov, A.
V.; Bella, M.; Langer, V. Kocˇovsky´, P. Org. Lett. 2000, 2, 3047. (b)
Malkov, A. V.; Baxendale, I. R.; Fawcett, J .; Russel, D. R.; Langer, V.;
Mansfield, D. J .; Valko, M.; Kocˇovsky´, P. Organometallics 2001, 20,
673. (c) Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.;
Teply´, F.; Meghani, P.; Kocˇovsky´, P. J . Org. Chem. 2003, 68, 4727.
10.1021/jo035074i CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/11/2003
J . Org. Chem. 2003, 68, 9659-9668
9659

Malkov et al.
CHART 1
SCHEME 2
plane (or near to), so that the two aromatic systems are
conjugated.13 Oxidation of one of the nitrogens automati-
cally lowers the electron density of that pyridine ring,
and this effect is conveyed through conjugation to the
other pyridine ring, whose nitrogen becomes less prone
to oxidation. Although this effect can hardly be expected
to be strong, it appears to be sufficient to allow selective
N-mono-oxidation under controlled conditions.
oxidation8b or by ozonolysis,8c was first converted into
oxime 14. Reductive acetylation of the latter oxime (Fe,
Ac2O, AcOH, rt, 10 min, 90%),8a,b,11 afforded enamide (-)-
15, which was converted into chloropyridine derivative
(-)-17 on Vilsmeier-Haack reaction (DMF, POCl3, 0 °C,
2 h; 70%).8a,b,12 Finally, the Ni(0)-mediated coupling of
the latter chloride (NiCl2, Ph3P, Zn, DMF, 60 °C, 18 h)
produced the bipyridine PINDY (+)-21 (50%), contami-
nated by the reduction product 19 (32%), which was
removed from the desired bipyridine by evaporation in
high vacuum.8 Oxidation of PINDY (+)-21 with MCPBA
(1 equiv) in CH2Cl2 at 0 °C for 45 min afforded selectively
the desired N-monoxide (+)-4 (96%); only traces of the
corresponding N,N-dioxide (-)-5 could be detected by
TLC in the crude reaction mixture. By contrast, oxidation
with 2 equiv of MCPBA, carried out at room temperature
for 24 h, produced N,N-dioxide (-)-5 (62%). The selectiv-
ity in the former case can be understood as follows: since
PINDY (+)-21 has an unrestricted rotation about the py-
py axis, the molecule can assume the conformation in
which the two pyridine rings are positioned in the same
We envisaged that the free rotation about the py-py
axis in 4 could be restricted by introducing two methyl
groups, as in 6a ,b. To this end, we set out to synthesize
the parent bipyridine 22, which we planned to oxidize in
a similar manner as in the case of 4.7 Oxime 14 was
submitted to the same strategy, this time employing
propionic (instead of acetic) anhydride in the reductive
acylation [Fe, (EtCO)2O, DMF, rt, 4 h], to obtain enamide
16 (80%). Owing to the increased steric bulk, the Vils-
meier-Haack reaction 16 f 18 required rather harsher
conditions (DMF, POCl3, 75 °C for 18 h, then 100 °C for
10 h; 63%), and so did the final coupling 18 f 22 [(Ph3P)2-
NiCl2, Zn, Me4NI, THF, 50 °C, 72 h]. The desired
bipyridine 22 (65%) thus formed was accompanied by a
small amount of the reduction product 20 (as revealed
1
by the H NMR spectrum of the crude product), which
was again removed by evaporation in high vacuum
followed by crystallization.
Unlike with PINDY (+)-21, N-oxidation of Me2PINDY
(+)-22 (Scheme 3) could not be controlled in favor of
N-monoxide; with 1 equiv of MCPBA at 0 °C for 2 h, the
reaction produced two atropoisomeric pairs of N-monox-
ides and N,N-dioxides (+)-6a (17%), (-)-6b (30%), (+)-
7a (14%), and (-)-7b (27%), accompanied by unreacted
bipyridine 22 (∼10%). While the N-monoxides 6a and 6b
were readily separated from the N,N-dioxides 7a and 7b
(9) For similar or alternative syntheses of the core bipyridines, see:
(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.
(10) For recent overviews on the synthesis of terpenoid bipyridines,
see: (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.
(11) For the method, see: Burk, M. J .; Casy, G.; J ohnson, N. B. J .
Org. Chem. 1998, 63, 6084.
(13) Crystallographic analysis of several terpene-derived bipyridines8b
revealed the s-trans disposition of the nitrogen atoms of the pyridine
rings. PINDOX (+)-4 showed bending from planarity by ∼25° in the
crystal.7
(12) An alternative, more robust synthesis of the triflate analogue
of 17 was developed by us recently.8c
9660 J . Org. Chem., Vol. 68, No. 25, 2003

Lewis-Basic N-Oxides as Chiral Organocatalysts
SCHEME 3
SCHEME 5
Kro¨hnke annulation16 (-)-24 + 25 f (+)-26 (43%).8c
Triflate 27, obtained from pyridone (+)-26 (99%), was
then dimerized via the Ni-mediated coupling8c,17 to give
iso-PINDY (+)-28 (51%).18 Although this route represents
a substantial short-cut with respect to the procedure
developed by von Zelewsky,9b it has been found to work
well only on a relatively small scale.8c For large-scale
syntheses, the von Zelewsky protocol9b is more robust and
reliable.
SCHEME 4
Deprotonation of (+)-289 with LDA, followed by the
reaction with MeI, BuI, and i-PrI, respectively, afforded
the bis-alkylated derivatives Me2-iso-PINDY (-)-29 (99%),
Bu2-iso-PINDY (-)-30 (93%), and i-Pr2-iso-PINDY (-)-
31 (56%), respectively.9,19 Controlled oxidation of the
latter bipyridines with ∼0.8 equiv of MCPBA (CH2Cl2, 0
°C, 45 min; 4 h for 31) afforded the corresponding
monoxides (+)-8, (-)-9, (-)-10, and (-)-11 (43%, 67%,
66%, and 61%, respectively) along with the unreacted
28-31 (48%, 21%, 18%, and 25%, respectively) and traces
of the corresponding N,N-dioxides (<5%).
Finally, to further probe the impact of the architecture
of the terpene moiety on the catalyst reactivity, we
utilized CANDY (-)-32, available from (+)-2-carene in
several steps,8c as a precursor of CANDOX (+)-33 (Scheme
5). Oxidation of (-)-32 with MCPBA (CH2Cl2, 0 °C, 2 h)
proved less selective than that in the PINDY and iso-
PINDY series and afforded a mixture of N-monoxide (+)-
33 (53%) and the corresponding N,N-dioxide (+)-34
(39%), which were separated by chromatography.
Allyla tion of Ald eh yd es w ith Allyltr ich lor osi-
la n es Ca ta lyzed by Ch ir a l Bip yr id in e N-Mon oxid es.
Addition of allyltrichlorosilane (2) to benzaldehyde (1a )
(Scheme 1), carried out in the presence of PINDOX (+)-4
by chromatography, separation of individual atropoiso-
mers required more careful chromatographic technique.14
This lack of sensitivity in the N-oxidation of (+)-22 can
be rationalized as follows: while in PINDY 21, the two
pyridine rings are conjugated, which is the prerequisite
for selective N-mono-oxidation (vide supra), and this
effect cannot be attained with Me2PINDY 22. Here, the
two pyridine rings cannot assume a planar conformation
about the py-py axis, so that they cannot be conjugated
and therefore behave as independent units, which leads
to the formation of a mono- and bisoxide mixture.
The configuration at the chiral axis of (-)-6b was found
to be (S) by single-crystal X-ray analysis,7 so that (+)-6a
must have (R)-configuration. The axial configuration of
dioxides (+)-7a and (-)-7b has not been rigorously
established and is only assumed by analogy with the
configuration of related N,N′-dioxides, e.g., (S)-(-)-1,1′-
bisisoquinoline N,N′-dioxide3a and (R)-(+)-3,3′-bis-
(methoxymethyl)-6,6′-diphenyl-2,2′-bipyridine N,N′-di-
oxide.4
(16) For the Kro¨hnke annulation, see: (a) Kro¨hnke, F. Chem. Ber.
1937, 70, 864. For a review, see: (b) Kro¨hnke, F. Synthesis 1976, 1.
For recent overviews of its application in the synthesis of terpenoid
bipyridines, see refs 8-10.
(17) For the method of an analogous dimerization of R-chloropy-
ridines, see refs 8 and the following: (a) Hayoz, P.; von Zelewsky, A.
Tetrahedron Lett. 1992, 33, 5165. (b) Dehmlow, E. V.; Sleegers, A.
Liebigs Ann. Chem. 1992, 9, 953. (c) Brenner, E.; Schneider, R.; Fort,
Y. Tetrahedron Lett. 2000, 41, 2881.
(18) Since the starting (+)-R-pinene was only of ∼90% ee, the
dimerization can potentially lead to the formation of diastereoisomers.
The crude product was purified by chromatography and the 1H NMR
spectrum of the bipyridine (+)-8 thus obtained showed no peaks
corresponding to the minor meso-diastereoisomer.8c
The synthesis of the iso-PINDY series 8-11 (Scheme
4) commenced with the ene-reaction of (+)-R-pinene with
singlet oxygen15 (+)-23 f (-)-24 (99%),8c,15 followed by
(14) The synthetic impracticality of 6a and 6b is further enhanced
(19) (a) Slightly lower yields have previously been reported for these
alkylations.9b (b) The alkylations are remarkably stereoselective (the
alkylating reagent approaches from the less hindered face). The minor
epimers formed (usually no more than 2%, as detected by NMR) were
removed during the chromatographic purification.8c
by the slow isomerization of the two atropoisomers to reach
a
thermodynamic equilibrium (6a :6b ∼1:2) at room temperature within
ca. 3 weeks in CDCl3.
(15) Mihelich, E. D.; Eickhoff, D. J . J . Org. Chem. 1983, 48, 4135.
J . Org. Chem, Vol. 68, No. 25, 2003 9661

Malkov et al.
TABLE 1. Allyla tion of Ald eh yd es 1 w ith Tr ich lor oa llylsila n e 2 (Sch em e 1)a
entry
catalyst
aldehyde
R
solvent
temp (°C)
time (h)
yield (%)b
% eec
configuration of 3d
1
2
3
4
5
6
7
8
(+)-4
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
1f
1g
1g
1h
1i
Ph
Ph
Ph
Ph
Ph
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
-90
-60
-40
-20
-20
-60
-60
-60
-60
-90
-20
-60
-40
-60
-60
-40
-20
-40
-20
-90
-60
-60
-60
-60
-60
-60
-20l
-60
-60
-20l
-60
-60
-20
-20l
-40
-40
-40
-40
-60
-40
-60
24
24
6
67f
78g
65g
95g
47f
71g
68f
62f
58f
52f
96g
23f
44f
63g
40f
45f
40f
50f
57f
18f
72g
67f
52f
57f
72g
75g
73g
75g
72g
84g
73g
15f
23g
75g
75g
41f
88g
73g
25f
78g
90g
92
90
87
84
80
87
87
89
65
83
53
56j
49j
85
83
81
78
83
82
41
98
82
14
10
46
88
80
83
84
80
84
97
93
85
96
91
96
95
96
92
22
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)h
(S)-(-)h
(R)-(+)
(R)-(+)
(S)-(-)
(S)-(-)k
(S)-(-)k
(S)-(-)k
(S)-(-)k
(S)-(-)k
(R)-(+)
(S)-(-)
(R)-(+)
(R)-(+)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(S)-(-)
(+)-4
(+)-4
(+)-4e
(+)-4e
(+)-4
24
18
24
24
24
24
48
24
48
48
48
18
18
24
58
18
48
12
24
24
24
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
p-Me-C6H4
p-MeO-C6H4
p-Cl-C6H4
p-NO2-C6H4
PhCHdCH2
PhCHdCH2
PhCH2CH2
PhCH2CH2
2-furyl
2-thiopheneyl
2-thiopheneyl
2-thiopheneyl
2-thiopheneyl
2-thiopheneyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(+)-4
(+)-4
9
(+)-4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
(+)-4
(+)-4e
(+)-4i
(+)-4i
(+)-4
(+)-4e
(+)-4e
(+)-4e
(+)-4e
(+)-4e
(-)-5
1i
1i
1i
1i
MeCN
1a
1a
1a
1a
1a
1a
1a
1a
1f
1a
1a
1f
1a
1a
1a
1a
1c
1j
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CH2Cl2
CH2Cl2
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
MeCN
(+)-6a
(-)-6b
(+)-7a
(-)-7b
(+)-8i
(-)-9i
(-)-9
(-)-9i
(-)-10i
(-)-10
(-)-10i
(-)-11
(-)-11
(-)-11e
(-)-11e
(-)-11e
(-)-11e
(-)-11e
(-)-11
(-)-11e
(+)-33e
PhCHdCH2
Ph
Ph
PhCHdCH2
Ph
Ph
Ph
Ph
p-MeO-C6H4
p-CF3-C6H4
2-naphth
PhCHdCH2
PhCHdCH2
Ph
MeCN
MeCN
MeCN
CH2Cl2
MeCN
1k
1f
1f
1a
CH2Cl2
a
The reaction was carried out at 1.0 mmol scale in CH2Cl2 with 1.1 equiv of 2, in the presence of the catalyst (10 mol %) and Bu4NI
(1 equiv). Isolated yield (note that some of the products are fairly volatile). c Determined by chiral HPLC or GC. Established from the
b
d
optical rotation (measured in CHCl3) by comparison with the literature data.3 e Carried out in the absence of Bu4NI. f Incomplete conversion.
Complete conversion. 3f is dextrorotatory in Et2O3 and levorotatory in CHCl3. With 20 mol % of the catalyst. The reaction is too
g
h
i
j
slow at lower temperatures. The configuration was assigned by Brown32 and Cozzi33 by analogy with their other results. The components
k
l
were mixed at ca. -60 °C and then allowed to warm to -20 °C, and the reaction was run for the specified period.
(7 mol %) as organocatalyst and Bu4NI20 at -90 °C,
produced (S)-(-)-3a (92% ee; Table 1, entry 1). In the
absence of Bu4NI, the reaction was slower and marginally
less selective.7 Raising the temperature led to accelera-
tion, accompanied by a very minor decrease of enantio-
selectivity (entries 2 and 3). Changing the solvent from
CH2Cl2 to MeCN led to a quantitative conversion and had
little effect on the enantioselectivity (entry 4). On the
other hand, in chloroform, both enantioselectivity and
conversion were reduced (entry 5), whereas practically
no reaction was observed in THF or acetone. Marginal
difference in selectivity was observed for p-substituted
benzaldehydes 1b-d , except for the p-nitro derivative 1e
(entries 6-9). 1- and 2-Naphthaldehydes exhibited high
asymmetric induction (88% and 79% ee, respectively, at
-60 °C),7 and so did cinnamaldehyde 1f (entries 10 and
11). However, saturated aldehydes, such as dihydrocin-
namaldehyde 1g, gave low enantioselectivities and reac-
tion rates (entries 12 and 13), demonstrating the ben-
eficial effect of the π-conjugation. High enantioselectivity
was also attained for furan and thiophene derivatives
1h ,i (entries 14-19), showing the compatibility of this
asymmetric reaction with a heteroaromatic system. Here
again, switching from CH2Cl2 to MeCN as the solvent
resulted in increasing the yields, whereas the enantiose-
lectivities remained practically identical (compare entries
16 with 18, and 17 with 19).
Whereas PINDOX (+)-4 proved to be a fairly efficient
catalyst for allylation of benzaldehyde and its congeners
1a -i, as shown above, the reaction catalyzed by N,N-
dioxide (-)-5 (7 mol %) at -90 °C, was found to be
considerably less selective, producing the opposite enan-
tiomer, i.e., (R)-(+)-3a , in only 41% ee (entry 20). The
latter result contrasts with the report by Nakajima, who
showed that when (S)-3,3-dimethyl-2,2′-biquinoline N,N′-
dioxide was employed as catalyst, (R)-(+)-3a was ob-
tained in 88% ee.3a,21
(21) Since both our and Nakajima N,N-dioxides produced the same
enantiomer of alcohol 3a , it can be assumed that the configuration at
the chiral axis in the intermediate arising from (-)-5 is the same as
that in Nakajima’s catalyst, i.e., (S).
(20) For the accelerating effect of Bu4NI, see ref 5e.
9662 J . Org. Chem., Vol. 68, No. 25, 2003

Lewis-Basic N-Oxides as Chiral Organocatalysts
CHART 2
SCHEME 6
was observed (80% ee; entry 30). A dramatic improve-
ment in asymmetric induction was attained with the
more congested i-Pr2-iso-PINDOX (-)-11: 97% ee at -60
°C in CH2Cl2 (entry 32), which puts this catalyst in the
league of Me2PINDOX (+)-6. However, the reaction rate
and conversion was rather low in this case (entries 32
and 33). To amend this flaw, we explored the effect of
the solvent and temperature. Thus, in chloroform at -20
°C the reaction proved to occur much faster and afforded
the product in good yield, although at some expense of
the enantioselectivity (85% ee; entry 34). An optimum
was found in acetonitrile, where high asymmetric induc-
tion was restored at -40 °C (96% ee) and the product
was obtained in good yield (entry 35). Both electron-rich
p-methoxybenzaldehyde (1c) and electron-poor p-trifluo-
romethylbenzaldehyde (1j) exhibited high enantioselec-
tivity (91% and 96% ee, respectively; entries 36 and 37),
showing that electronic effects are unimportant in this
system. 2-Naphthaldehyde (1k ) was found to be in the
same range (95% ee; entry 38). The power of the solvent
effect can again be seen in the case of cinnamaldehyde
(1f): although the reaction was slow in dichloromethane
(entry 39), a much faster process was observed in
acetonitrile (entry 40), both with high yield and high
asymmetric induction (92% ee). Hence, the combination
of i-Pr2-iso-PINDOX (-)-11 as catalyst and acetonitrile
as solvent appears to be a well-balanced choice, charac-
terized by good conversion rates, very high enantioselec-
tivities (e96% ee), and acceptable catalyst loading (7-
10 mol %).23,24 In contrast to most of these catalysts,
CANDOX (+)-33 exhibited substantially lower enantio-
selectivity (22% ee, entry 41).
To extend the scope of the reaction and shed further
light on the mechanism, allylation of benzaldehyde with
trans-crotyltrichlorosilane (E)-36 (prepared as an 87:13
trans/cis mixture via the CuCl-catalyzed reaction of crotyl
chloride with HSiCl3)6b was briefly explored (Scheme 6
and Table 2). With PINDOX (+)-4 as catalyst, the
reaction in CH2Cl2 produced mainly anti-37 (Table 2,
entries 1 and 2). i-Pr2-iso-PINDOX (-)-11 behaved in a
similar way, producing the anti-isomer practically enan-
tiopure (entry 3) but with low conversion. Changing the
solvent to acetonitrile resulted in considerable improve-
ment of the conversion rate and diastereoselectivity (98:
2) with barely any loss of the level of asymmetric
induction (98% ee; entry 4). The cis-crotyl derivative (Z)-
36 (prepared as a practically pure isomer on Pd-catalyzed
addition of HSiCl3 to butadiene)25 reacted much more
slowly than its trans-isomer even in acetonitrile and
afforded mainly syn-37 (87% ee; entry 5).
Assuming a bidentate coordination of the Lewis-basic
catalyst to the allyl silane, two atropoisomeric intermedi-
ates (aR)-35 and (aS)-35 (Chart 2) can be considered.22
Obviously, the configuration at the chiral axis should be
controlled by the chiral centers of the terpene framework.
To shed more light on the mechanism and, in particular,
to establish the sense of the axial chirality in the reactive
intermediate, we employed atropoisomeric Me2PINDOX
catalysts (+)-6a and (-)-6b, where the rotation about the
py-py bond is restricted.
Allylation of benzaldehyde (1a ) with allyltrichlorosi-
lane (2), catalyzed by Me2PINDOX (aR)-(+)-6a , resulted
in the formation of (S)-(-)-3a , which exhibited the same
configuration as that observed for the PINDOX-catalyzed
reaction but with increased enantioselectivity (98% ee;
entry 21). 2-Naphthaldehyde reacted similarly (91% ee).7
By contrast, the atropoisomeric catalyst (aS)-(-)-6b
induced the formation of the opposite enantiomer, i.e.,
(R)-(+)-3a , though with a slightly lower enantioselectivity
(82% ee; entry 22). These results clearly demonstrate the
decisive role of the chiral axis on the sense of the
asymmetric induction. Furthermore, since (+)-6a , where
the axial configuration is known to be (aR) (vide supra),
gave rise to the same enantiomer of the product as that
formed with (+)-4, the twist about the py-py axis
assumed by (+)-4 during the reaction must be the same,
i.e., (aR). Whereas the N-monoxides 6a and 6b gave very
high asymmetric induction, the corresponding atropoi-
someric N,N-dioxides 7a and 7b proved inefficient, af-
fording almost racemic products (entries 23 and 24).
Me2PINDOX (+)-6a was found to be the most enantio-
selective catalyst to date. However, its preparation was
not easy (vide supra) and it was configurationally un-
stable,14 and thus it could hardly become a popular, shelf-
type catalyst. Therefore, we endeavored to find an
alternative that would exhibit similar efficiency but
would be easier to synthesize and store. To this end, we
focused on the iso-PINDOX series 8-11 (Chart 1), whose
parent bipyridines 28-31 proved effective in other
catalytic reactions.8c
The basic iso-PINDOX (+)-8 did catalyze the allylation
reaction but with only modest enantioselectivity (46% ee;
entry 25), which was not unexpected since the chiral
centers had been moved further away from the pyridine
rings. By contrast, the methylated analogue (-)-9, where
the chirality was brought closer again to the reaction
center, improved the enantioselectivity considerably (up
to 88% ee; entries 26-28). The dibutyl congener (-)-10
exhibited similar efficiency, both for benzaldehyde (84%
ee; entry 29) and cinnamaldehyde (84% ee; entry 31). At
-20 °C in chloroform, marginal loss of enantioselectivity
(23) Note that, unlike with transition metal catalysts, the organo-
catalytic reactions currently require higher catalyst loading, with 10-
20 mol % being more the rule than an exception. Reactions that work
in the presence of 1 mol % or less of the catalyst are rare.4,24
(24) Malkov, A. V.; Dufkova´, L.; Farrugia, L.; Kocˇovsky´, P. Angew.
Chem., Int. Ed. 2003, 42, 3674.
(22) Note that chelation of Si by an N-monoxide catalyst, such as
PINDOX, would generate a six-membered ring [as in (aR)-35/(aS)-35],
which is in contrast to the N,N-dioxides, such as 5 and those reported
by Nakajima3 and Hayashi,4 where chelation leads to a seven-
membered ring.
(25) Tsuji, J .; Hara, M.; Ohno, K. Tetrahedron 1974, 30, 2143.
J . Org. Chem, Vol. 68, No. 25, 2003 9663

Malkov et al.
TABLE 2. Rea ction of Ben za ld eh yd e (1a ) w ith (E)- a n d (Z)-Cr otyltr ich lor osila n e 36 (Sch em e 6)a
entry
catalyst
crotyl
solvent
temp (°C)
time (h)
yield (%)b
anti-37 (% ee)c:syn-37 (% ee)c
configuration of 37d
1
2
3
4
5
(+)-4
(E)-36f
(E)-36f
(E)-36f
(E)-36f
(Z)-36g
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeCN
-60
-60
-60
-40
-40
24
15
18
18
18
54h
44h
27i
88i
37h
93 (87):7
96 (87):4
93 (g99):7
98 (98):2
(1S)-(-)
(1S)-(-)
(1S)-(-)
(1S)-(-)
(1S)-(-)
(+)-4e
(-)-11
(-)-11e
(-)-11e
10:90 (87)
a
The reaction was carried out at 1.0 mmol scale in CH2Cl2 with 1.1 equiv of 36, in the presence of the catalyst (10 mol %) and Bu4NI
(1 equiv). Isolated yield. c The anti/syn ratio was determined by GC. The enantiopurity was determined by chiral GC. Established
b
d
from the optical rotation (measured in CHCl3) by comparison with the literature data.3 e Carried out in the absence of Bu4NI. f The E/ Z
g
h
i
ratio was 87:13. Pure (Z)-isomer. Incomplete conversion. Complete conversion.
SCHEME 7
CHART 3
pyridine-type N-oxides lacking another pyridine ring
(Chart 3) exhibited high enantioselectivity in the allyla-
tion of benzaldehyde with 2 (87% ee with 43 and 68% ee
with 44), which was attributed to arene-arene interac-
tions as the key factor.24,27 However, the solvent effect
observed there was different from the trend shown here:
in the present study, MeCN was identified as the favored
solvent (higher reaction rates and excellent asymmetric
induction). In our previous work, CH2Cl2 and CHCl3 were
found to be the solvents of choice, whereas MeCN proved
inferior. Furthermore, the insensitivity of the present
catalysts to the electronic properties of the aldehyde
(Table 1, entries 36 and 37) sharply contrasts with the
behavior of 43, where the differences in enantioselectivity
were dramatic (12% ee for 1c and 96% ee for 1j).24 These
findings show that the key factors operating in the
reaction vary with the catalyst structure, and it would
be premature to try to further hypothesize before more
data are available.
In the crotylation, noteworthy is the discrepancy
between the composition of the starting crotyl derivative
and the anti/syn ratio of the product. Thus, with (E)-36,
which was an 87:13 mixture of geometrical isomers, the
product 37 was obtained as a 93:7 to 98:2 anti/syn
mixture (compare entries 1-4). Hence, the reaction of
(E)-36 must be kinetically preferred over that of (Z)-36,
which is confirmed by the observation of a much slower
reaction of pure (Z)-36 (entry 5).
The high preference for the formation of anti-37 from
(E)-36 (and syn-37 from (Z)-36) is compatible with the
generally accepted mechanism that involves a cyclic
transition state, where the incoming aldehyde is coordi-
nated to the Lewis-acidic site of Si (Scheme 7).2,3,22 On
the other hand, participation of the open-chain mecha-
nism would deteriorate the homogeneity of the process,
which would be manifested by a greater proportion of the
opposite diastereoisomer.24 The transition states 38-42,
proposed in Scheme 7, respect the stereoelectronic ef-
fect,2,7 which dictates that the Lewis-basic N-oxide oxygen
be positioned trans to the allylic group to enhance its
nucleophilicity. Assuming chelation to the nitrogen of the
second pyridine ring,26 the structures 38-42 represent
transition states that are compatible with both absolute
and relative stereochemistry of the allylation.
Con clu sion s
Whereas allylation of benzaldehyde 1a with allytrichlo-
rosilane 2, catalyzed by PINDOX (+)-4, produced (S)-
(-)-3a of 92% ee at -90 °C (Scheme 1), Me2PINDOX (+)-
6a gave 98% ee at -60 °C (Table 1, entries 1 and 21).
The synthesis of (+)-4 was straightforward (Scheme 2),
but (+)-6a presented several problems, mainly associated
with the poor selectivity of the final N-oxidation of the
bipyridine precursor (Scheme 3). In this instance, bisoxi-
dation was the main process and the N-monoxide was
formed as a 2:1 mixture of atropoisomers, of which the
minor one, (+)-6a , gave the highest enantioselectivities.
This catalyst is further tainted by its configurational
(26) Pyridine is certainly known to be capable of coordinating Si.
The propensity of various reagents to coordinate to Si and thus
accelerate nucleophilic substitution decreases in the following order:
F- > N-methylimidazole > DMAP > HMPA > N-methyl-2-pyridone
> pyridine N-oxide > Ph3PO > 2,4-dimethylpyridine > N-methyl-4-
pyridone > DMF > pyridine > Me3N: (a) Bassindale, A. R.; Stout, T.
Tetrahedron Lett. 1985, 26, 3403. (b) Brook, M. A. Silicon in Organic,
Organometallic, and Polymer Chemistry; J . Wiley: New York, 2000; p
135.
We have shown recently that chelation to the second
pyridine ring is not an absolute prerequisite to attain
high enantioselectivity and good reaction rates. Thus,
(27) Malkov, A. V.; Bell, M.; Vassieu, M.; Bugatti, V.; Kocˇovsky´, P.
J . Mol. Catal. A 2003, 196, 179.
9664 J . Org. Chem., Vol. 68, No. 25, 2003

Lewis-Basic N-Oxides as Chiral Organocatalysts
lability (at the chiral axis).14 With the isomeric N-
monoxides 8-11 (iso-PINDOX), the latter synthetic
problems have been eliminated and the N-monoxides
were formed with good selectivity (Scheme 4). The bis-
iso-propyl derivative (-)-11 was found to match the
enantioselectivity of (+)-6, but the conversion rates were
lower. Changing the solvent from CH2Cl2 to MeCN
resulted in a dramatic improvement of the reaction rates,
while the enantioselectivities remained high (96% ee)
both for the electron-rich and electron-poor benzalde-
hydes (Table 1, entries 32, 35-37). Only marginal loss
of enantioselectivity was observed when the reactions
were carried out at the industrially acceptable temper-
ature of -20 °C, rather than at the most common -90
or -60 °C. Stereoelectronically controlled O,N-chelation
of the silicon by the catalyst and cyclic transitions states
(Scheme 7) have been proposed to rationalize both
absolute and relative stereochemistry of allylation and
crotylation. A cyclic transition state is compatible with
the stereochemical outcome.
(s, 6 H), 1.31 (d, J ) 9.9 Hz, 2 H), 1.44 (s, 6 H), 2.29-2.33 (m,
2 H), 2.71-2.76 (m, 2 H), 3.01 (m, 4 H), 4.08 (t, J ) 5.6 Hz, 1
H), 7.08 (d, J ) 7.9 Hz, 1 H), 7.28 (d, J ) 7.9 Hz, 1 H); 13C
NMR (62.9 MHz) δ 21.3 (Me), 25.7 (Me), 30.2 (CH2), 31.6 (CH2),
39.1 (C), 39.8 (CH), 40.1 (CH), 124.4 (CH), 124.5 (CH), 134.1
(C), 140.8(C), 156.0 (C); HRMS (EI) 376.2154 (C24H28N2O2
requires 376.2151).
Oxid a t ion of (6R,6′R,8R,8′R)-(+)-5,5′,6,6′,7,7′,8,8′-Oc-
t a h yd r o-3,3′,7,7,7′,7′-h exa m et h ylb i(6,8-m et h a n oq u in o-
lin e) (+)-(22) w ith MCP BA. m-Chloroperoxybenzoic acid
(70%, 93 mg, 0.38 mmol) was added portion-wise to a stirred
solution of (+)-22 (141 mg, 0.38 mmol) in dichloromethane (5
mL) at 0 °C, and the stirring was continued at this tempera-
ture for a further 2 h. Then the mixture was poured into
saturated aqueous NaHCO3 (15 mL) and extracted with
dichloromethane (2 × 15 mL), and the organic layer was
washed with NaHCO3 (2 × 15 mL), dried with Na2SO4, and
concentrated in vacuo. Flash chromatography of the residue
on silica gel (15 g) with a petroleum ether/ethyl acetate
mixture (1:1), followed by ethyl acetate/methanol (20:1),
furnished the unreacted starting material (20 mg) and the
diastereoisomeric mixtures of, respectively, the N-monoxides
and the N,N′-dioxides as colorless oils (50 mg). The latter
mixture was then placed on a preparative silica gel plate
(Merck, 60 F254) and eluted using a mixture of petroleum ether,
diethyl ether, and acetone (8:1:1) to afford, in the following
order, monoxide (+)-6a (25 mg, 17%), monoxide (-)-6b (44 mg,
30%), bisoxide (-)-7b (40 mg, 27%), and bisoxide (+)-7a (21
mg, 14%) as white, crystalline solids.
Exp er im en ta l Section
Sta r tin g Ma ter ia ls. (-)-Pinocarvone (-)-24 was obtained
on a 40 g scale from (+)-R-pinene (+)-23 via the photochemical
oxidation (99%) according to the Mihelich procedure.15 The
Kro¨hnke salt 25 was prepared from tert-butyl R-bromoacetate
and pyridine by refluxing in ethyl acetate in the same manner
as the corresponding ethyl ester.8c,16 The trichlorosilyl enol
ethers were prepared according to the literature procedures.28
(6R, 6′R, 8R, 8′R)-(+)-5, 5′, 6, 6′, 7, 7′, 8, 8′- Oct a h yd r o-
6,6′,7,7′-tetr a m eth ylbis(6,8-m eth a n oqu in olin e) N-Mon -
oxid e (+)-(4). m-Chloroperoxybenzoic acid (70%, 167 mg, 0.68
mmol) was added portion-wise to a solution of (+)-PINDY8,9a,c
(+)-21 (233 mg, 0.68 mmol) in dichloromethane (5 mL) at 0
°C, and the mixture was stirred at this temperature for 45
min The reaction mixture was washed successively with
saturated NaHCO3 (3 × 10 mL) and brine (10 mL). After
drying over Na2SO4, the solvent was evaporated in vacuo. The
resulting solid was purified by column chromatography on
silica gel (10 × 2.5 cm; ethyl acetate/methanol, 25:1) to give
pure (+)-4 as a pale yellow solid (235 mg, 96%): mp 202-204
(R ,6R ,6′R ,8R ,8′R )-(+)-5,5′,6,6′,7,7′,8,8′-O c t a h y d r o -
3,3′,7,7,7′,7′-h exa m et h ylb i(6,8-m et h a n oq u in olin e)-1-ox-
id e (a R)-(+)-(6a ): mp 207-209 °C (ethyl acetate-methanol);
1
[R]D +28.4 (c 0.3, CHCl3); H NMR δ 0.66 (s, 3 H), 0.67 (s, 3
H), 1.1-1.2 (m, 2 H), 1.32 (s, 3 H), 1.35 (s, 3 H), 2.23 (m, 2 H),
2.66 (m, 2H), 2.90 (m, 5 H), 3.92 (t, J ) 5.6 Hz, 1 H), 6.89 (s,
1 H), 7.28 (s, 1 H); HRMS (EI) 388.5529 (C26H32ON2 requires
388.5518).
(S ,6R ,6′R ,8R ,8′R )-(-)-5,5′,6,6′,7,7′,8,8′-O c t a h y d r o -
3,3′,7,7,7′,7′-h exa m et h ylb i(6,8-m et h a n oq u in olin e)-1-ox-
id e (a S)-(-)-(6b): mp 223-225 °C (ethyl acetate/methanol;
this material spontaneously recrystallizes at 150-180 °C
before reaching the mp); [R]D -44.6 (c 1.0, CHCl3); 1H NMR δ
0.67 (s, 3 H), 0.78 (s, 3 H), 1.24 (d, J ) 9.9 Hz, 1 H), 1.42 (s, 3
H), 1.44 (d, J ) 9.9 Hz, 1 H), 1.47 (s, 3 H), 2.32 (m, 2 H), 2.71
(m, 2 H), 2.98 (m, 5 H), 4.01 (t, J ) 5.6 Hz, 1 H), 6.97 (s, 1H),
7.36 (s, 1 H); 13C NMR δ 17.65 (CH3), 18.64 (CH3), 21.47 (CH3),
21.53 (CH3), 26.12 (CH3), 26.45 (CH3), 30.88 (CH2), 31.06 (CH2),
31.57 (CH2), 31.74 (CH2), 39.50 (C), 39.62 (C), 40.39 (CH), 40.48
(CH), 40.53 (CH), 50.21 (CH), 127.61 (CH), 130.31 (C), 130.83
(C), 132.34 (2 × C), 137.47 (CH), 147.38 (C), 153.35 (2 × C),
164.15 (C); HRMS (EI) 388.5529 (C26H32ON2 requires 388.5518).
(ê,6R ,6′R ,8R ,8′R )-(+)-5,5′,6,6′,7,7′,8,8′-O c t a h y d r o -
3,3′,7,7,7′,7′-h exa m et h ylb i(6,8-m et h a n oq u in olin e)-1,1′-
d ioxid e (+)-(7a ): mp 229-231 °C (ethyl acetate/methanol);
[R]D +7.4 (c 0.2, CHCl3); 1H NMR δ 0.64 (s, 6 H), 1.28 (d, J )
9.9 Hz, 4 H), 1.37 (s, 6 H), 1.95 (s, 6 H), 2.21 (m, 2 H), 2.6-2.7
(m, 2 H), 2.8-2.9 (m, 4 H), 3.86-3.92 (q, J ) 5.6 Hz, 2 H),
6.90 (s, 2 H); 13C NMR δ 17.85 (2 × CH3), 18.45 (2 × CH),
21.46 (2 × CH3), 26.09 (2 × CH3), 30.59 (2 × CH2), 31.82 (2 ×
CH2), 40.22 (2 × CH), 40.29 (2 × CH), 40.44 (2 × CH), 127.05
(2 × CH), 133.33 (2 × C), 136.85 (2 × C), 139.07 (2 × C), 153.43
(2 × C); HRMS (EI) 404.5523 (C26H32O2N2 requires 404.5508).
(ê,6R ,6′R ,8R ,8′R )-(-)-5,5′,6,6′,7,7′,8,8′-O c t a h y d r o -
3,3′,7,7,7′,7′-h exa m et h ylb i(6,8-m et h a n oq u in olin e)-1,1′-
d ioxid e (-)-(7b): mp 233-235 °C (ethyl acetate/methanol);
1
°C (toluene); [R]D +56.0 (c 0.78, CHCl3); H NMR δ 0.69 (s, 3
H), 0.72 (s, 3H), 1.30 (d, J ) 9.9 Hz, 1 H), 1.33 (d, J ) 9.7 Hz,
1 H), 1.43 (s, 3 H), 1.47 (s, 3 H), 2.31-2.36 (m, 2 H), 2.99 (m,
4 H), 3.04 (t, J ) 5.6 Hz, 1 H), 4.14 (t, J ) 5.6 Hz, 1 H), 7.13
(d, J ) 8.0 Hz, 1 H), 7.52 (d, J ) 8.0 Hz, 1 H), 7.92 (d, J ) 8.0
Hz, 1 H), 8.63 (d, J ) 8.0 Hz, 1 H); 13C NMR (62.9 MHz) δ
21.30 (Me), 21.33 (Me), 25.8 (Me), 26.0 (Me), 30.4 (CH2), 30.9
(CH2), 31.1 (CH2), 31.5 (CH2), 39.1 (C), 39.2 (C), 39.8 (CH),
40.1 (CH), 40.3 (CH), 50.4 (CH), 123.3 (CH), 124.4 (CH), 125.5
(CH), 130.7 (C), 132.7 (C), 135.0 (CH), 145.1 (C), 146.6 (C),
157.1 (C), 166.5 (C); HRMS (EI) 360.2198 (C24H28N2O requires
360.2202).
(6R, 6′R, 8R, 8′R)-(-)-5, 5′, 6, 6′, 7, 7′, 8, 8′- Oct a h yd r o-
6,6′,7,7′-tetr a m eth ylbis(6,8-m eth a n oqu in olin e) N,N′-Di-
oxid e (-)-(5). m-Chloroperoxybenzoic acid (70%, 160 mg, 0.64
mmol) was added portion-wise to a solution of (+)-PINDY8,9a,c
(+)-21 (100 mg, 0.29 mmol) in dichloromethane (3 mL) at 0
°C, and the mixture was stirred at room temperature for 24
h. The reaction mixture was washed successively with satu-
rated NaHCO3 (3 × 10 mL) and brine (10 mL). After drying
over Na2SO4, the solvent was evaporated in vacuo. The
resulting solid was purified by column chromatography on
silica gel (10 × 2.5 cm; ethyl acetate/methanol, 5:1) to give
pure (-)-5 as a pale yellow solid (68 mg, 62%): mp 232-234
°C (ethyl acetate); [R]D -22.4 (c 0.78, CHCl3); 1H NMR δ 0.77
1
[R]D -15.7 (c 0.6, CHCl3); H NMR δ 0.78 (s, 6 H), 1.25 (m, 4
H), 1.37 (s, 6 H), 1.91 (m, 2 H), 2.05 (s, 6 H), 2.29 (m, 2 H),
2.73 (m, 2 H), 2.97 (m, 4 H), 3.98 (t, J ) 5.6 Hz, 2 H), 6.96 (s,
2 H); 13C NMR δ 14.58 (2 × CH), 18.25 (2 × CH3), 21.71 (2 ×
CH3), 26.12 (2 × CH3), 30.89 (2 × CH2), 31.84 (2 × CH2), 40.33
(2 × CH), 40.45 (2 × CH), 62.23 (2 × C), 126.99 (2 × CH),
133.09 (2 × C), 133.24 (2 × C), 140.08 (2 × C), 153.87 (2 × C);
HRMS (EI) 404.5501 (C26H32O2N2 requires 404.5508).
(28) Denmark, S. E.; Stavenger, R. A.; Winter, S. B. D.; Wong, K.-
T.; Barsanti, P. A. J . Org. Chem. 1998, 63, 9517.
J . Org. Chem, Vol. 68, No. 25, 2003 9665

Malkov et al.
N-Oxid a tion of iso-P INDY Der iva tives 28-31. m-Chlo-
roperoxybenzoic acid (70%, 167 mg, 0.68 mmol) was added
portion-wise to a solution of the respective iso-PINDY deriva-
tive 28-318c,9,29,30 (0.68 mmol) in dichloromethane (5 mL) at 0
°C, and the mixture was stirred at this temperature for 45
min (28-30) or for 4 h (31). The reaction mixture was then
diluted with ether and washed successively with saturated
NaHCO3 (3 × 10 mL) and brine (10 mL). After drying over
Na2SO4, the solvent was evaporated in vacuo. The resulting
solid was purified by column chromatography on silica gel (10
× 2.5 cm) with a mixture of petroleum ether and ethyl acetate
(10:1) to elute the unreacted starting material, followed by
ethyl acetate, to give pure 8-11, respectively as pale yellow
solids.
iso-P INDOX (+)-8 (43%): mp 171-172 °C (ethyl acetate/
hexane); [R]D +102.3 (c 1.03, CH2Cl2); 1H NMR δ (CDCl3, 400
MHz) 0.69 (s, 3H), 0.71 (s, 3H), 1.31 (d, J ) 9.6 Hz, 2H), 1.43
(s, 6H), 2.37-2.42 (m, 1H) 2.44-2.48 (m, 1H) 2.71 (dt, J ) 9.6
and 5.8 Hz, 2 H), 2.82 (dt, J ) 9.6 and 5.8 Hz, 2 H), 3.15-3.22
(m, 4 H), 6.98 (d, J ) 7.9 Hz, 1H), 7.32 (d, J ) 7.9 Hz, 1H),
7.90 (d, J ) 7.8 Hz, 1H), 8.53 (d, J ) 7.8 Hz, 1H); 13C NM δ
(CDCl3, 100 MHz) 21.4 (CH3), 21.7 (CH3), 26.2 (CH3), 26.4
(CH3), 31.5 (CH2), 31.9 (CH2), 32.2 (CH2), 37.0 (CH2), 39.7 (CH),
39.9 (C), 40.6 (CH), 46.5 (CH), 46.8 (CH), 122.6 (CH), 123.7
(CH) 124.7 (CH), 133.1 (CH), 142.6 (C), 144.9 (C), 146.1 (C),
147.0 (C), 147.8 (C), 156.8 (C); MS (EI) m/z 360 (M, 100%),
344 (M•+ - CH3 61%); HRMS (EI) 360.2203 (C24H28ON2
requires 360.2202).
Me-iso-P INDOX (-)-9 (66%): mp 166-169 °C (ethyl ac-
etate-hexane); [R]D -4.4 (c 1.05, CH2Cl2); 1H NMR δ (CDCl3,
400 MHz) 0.53 (d, J ) 9.8 Hz, 6H), 0.85 (m, 1H), 1.13 (m, 1H)
1.29 (d, J ) 6.6 Hz, 3H), 1.36 (s, 6H), 1.48 (d, J ) 6.6 Hz, 3H),
2.07-2.11 (m, 2H) 2.45 (dt, J ) 9.6 and 5.8 Hz, 2 H), 2.71 (t,
J ) 5.8 Hz, 2 H), 3.15 (dq, J ) 7.2 and 2.4 Hz, 1 H), 3.39 (dq,
J ) 7.2 and 2.4 Hz, 1 H), 6.90 (d, J ) 7.9 Hz, 1H), 7.21 (d, J
) 7.9 Hz, 1H), 7.85 (d, J ) 7.8 Hz, 1H), 8.43 (d, J ) 7.8 Hz,
1H); 13C NMR δ (CDCl3, 100 MHz) 15.3 (CH3), 18.7 (CH3), 20.9
(CH3), 21.3 (CH3), 26.3 (CH3), 26.7 (CH3), 28.6 (CH2), 28.9
(CH2), 35.3 (CH), 39.2 (CH), 41.8 (C), 42.0 (C), 47.2 (CH), 47.3
(CH), 47.5 (CH), 47.9 (CH), 122.7 (CH), 123.5 (CH), 124.9 (CH),
132.8 (CH), 142.4 (C), 144.9 (C), 146.9 (C), 147.8 (C), 150.5
(C), 160.6 (C); MS (EI) m/z 388 (M•+, 15%), 372 [M•+ - O, 20%],
357 [M•+ - (O + Me), 32%]; HRMS (EI) 388.2514 (C26H32ON2
requires 388.2515).
Hz, 3H), 1.33 (s, 3H), 1.35 (s, 3H), 1.54-1.57 (m, 2H) 2.28-
2.33 (m, 2H) 2.44-2.54 (m, 2H) 2.67-2.71 (m, 2H), 2.75-2.81
(m, 1H), 2.89-2.90 (m, 1H), 3.07-3.15 (m, 1H), 3.19 (t, J )
1.6 Hz, 1 H), 6.86 (d, J ) 8.1 Hz, 1H), 7.21 (d, J ) 8.3 Hz, 1H),
7.91 (d, J ) 7.6 Hz, 1H), 8.58 (d, J ) 7.6 Hz, 1H);
13C NMR δ
(CDCl3, 100 MHz) 20.4 (CH3), 21.0 (CH3), 21.3 (CH3), 21.4
(CH3), 22.1 (CH3), 22.6 (CH3), 26.2 (CH3), 26.7 (CH3), 28.6
(CH3), 28.8 (CH2), 29.7 (CH2), 30.7 (CH3), 41.5 (CH), 42.3 (C),
42.8 (C), 43.7 (CH), 45.9 (CH), 46.9 (C), 47.1 (CH), 49.5 (CH),
122.5 (CH), 123.4 (CH) 124.8 (CH), 132.9 (CH), 142.9 (C), 145.3
(C), 147.0 (C), 147.7 (C), 149.6 (C), 159.0 (C); MS (EI) m/z 444
(M•+, 8%), 429 (M+• - CH3, 19%); HRMS (EI) 467.3041 (C30H40
ON2Na requires 467.3038).
-
(4S,6R)-(-)-5,5-Dim eth yl-4,6-m eth an o-1-pr opion am ido-
cycloh exen e (-)-(16). Iron powder (12.5 g, 224 mmol) was
added to a stirred solution of nopinone oxime 148 (3.8 g, 25
mmol) and propionic anhydride (25 mL, 195 mmol) in DMF
(60 mL). Then, a few drops of chlorotrimethylsilane were added
under nitrogen to initiate the reaction, and the mixture was
stirred at room temperature for 4 h (until TLC showed that
the reaction was complete). The reaction mixture was diluted
with ether, and the solid was filtered off through a short
column of Celite. The filtrate was washed with NaOH (20%
aqueous solution), dried with NaSO4, and concentrated in
vacuo to afford sufficiently pure (-)-16, as a yellow oil (3.9 g,
80%): [R]D -40.7 (c 1.0, CHCl3); 1H NMR δ 0.91 (s, 3 H), 1.18
(t, J ) 7.8 Hz, 3 H), 1.29 (s, 3 H), 1.36 (d, J ) 8.7 Hz, 1 H),
2.02 (dt, J ) 6.3 Hz, J ) 1.6 Hz, 1 H), 2.10 (m, 1 H), 2.24 (q,
J ) 7.8 Hz, 2 H), 2.27-2.44 (m, 2 H), 5.93 (s, 1 H), 6.45 (br s,
1 H); HRMS (EI) 193.2890 (C12H19ON requires 193.2881).
(6R,8R)-(-)-2-Ch lor o-5,6,7,8-tetr ah ydr o-3,7,7-tr im eth yl-
[6,8-m eth a n oqu in olin e] (-)-(18). Dimethylformamide (4.9
g, 80 mmol) was added dropwise to stirred phosphoryl chloride
(27.5 g, 180 mmol) at 0 °C, followed by a solution of the
enamide (-)-16 (5.0 g, 25.9 mmol) in dimethylformamide (5
mL). After being stirred for 2 h at room temperature, the
mixture was heated at 75 °C for 18 h and at 100 °C for a
further 10 h. The resulting dark brown solution was poured
into ice-water (500 mL) to give a clear orange solution, which
was basified with aqueous 40% NaOH and extracted with
dichloromethane (3 × 200 mL), and the extract was dried (Na2-
SO4) and evaporated. The residue was purified by chromatog-
raphy on silica gel (120 g), using hexane and then a hexanes/
ethyl acetate mixture (9:1), to give (-)-18 as a yellowish oil:
1
Bu -iso-P INDOX (-)-10 (67%): mp 51-53 °C (ethyl acetate-
3.6 g (63%): [R]D -17.0 (c 1.0, CHCl3); H NMR δ 0.65 (s, 3
1
hexane); [R]D -22.6 (c 1.02, CH2Cl2); H NMR δ (CDCl3, 400
H), 1.20 (d, J ) 9.6 Hz, 1 H), 1.39 (s, 3 H), 2.04 (m, 1 H), 2.30
(s, 3 H), 2.62 (dt, J ) 8.4 Hz, J ) 8.0 Hz, 1 H), 2.87 (s, 2 H),
2.94 (t, J ) 6.0 Hz, 1H), 7.23 (s, 2 H); HRMS (EI) 221.7297
(C13H16NCl requires 221.7294).
MHz) 0.53 (s, 3H), 0.57 (s, 3H), 0.81-0.88 (m, 6H), 1.15 (m,
2H), 1.36-1.39 (m, 12H), 1.49 (s, 6H), 2.20 (m, 1H), 2.25-2.28
(m, 1H), 2.30-2.32 (m, 1H), 2.47 (dt, J ) 9.5 and 5.0 Hz, 2H),
2.65 (m, 1H) 2.72 (t, J ) 5.0 Hz, 2 H), 2.95 (d, J ) 9.5 Hz, 1H)
3.10 (m, 1H), 6.87 (d, J ) 7.9 Hz, 1H), 7.21 (d, J ) 8.0 Hz,
1H), 7.84 (d, J ) 7.8 Hz, 1H), 8.49 (d, J ) 7.9 Hz, 1H); 13C
NMR δ (CDCl3, 100 MHz) 14.6 (CH3), 21.0 (CH3), 21.3 (CH3),
21.4 (CH3), 23.2 (CH2), 23.4 (CH2), 26.4 (CH3), 26.8 (CH3), 28.0
(CH2), 28.8 (CH2), 28.9 (CH2), 30.4 (CH2), 30.6 (CH2), 32.7
(CH2), 40.8 (CH), 41.3 (C), 41.4 (C), 43.7 (CH), 44.3 (CH), 44.6
(CH), 47.1 (CH), 47.2 (CH), 122.5 (CH), 122.7 (CH) 124.8 (CH),
132.8 (CH), 142.3 (C), 144.7 (C), 147.0 (C), 147.7 (C), 150.0
(C), 160.2 (C); MS (EI) m/z 472 (M•+, 16%), 415 (M - Bu, 72%);
HRMS (EI) 472.3454 (C32H44ON2 requires 472.3454).
(6R ,6′R ,8R ,8′R )-(+)-5,5′,6,6′,7,7′,8,8′-Oct a h yd r o-3,3′,
7,7,7′,7′-h exa m et h ylb i(6,8-m et h a n oq u in olin e) (+)-(22).
A 50-mL, round-bottomed, two-necked flask containing a
magnetic stirring bar was charged with NiCl2(PPh3)2 (1.077
g, 1.65 mmol), zinc dust (0.54 g, 8.25 mmol), and Me4NI (1.658
g, 8.25 mmol). A rubber septum was placed over one neck of
the flask, and the other neck was connected to a Schlenk line.
The flask was evacuated and filled with nitrogen several times.
Dry THF (15 mL) was added via syringe through the septum,
and the mixture was stirred at room temperature. After the
dark green catalyst had formed (30 min), a nitrogen-purged
solution of (-)-18 (1.215 g, 5.5 mmol) in THF (5 mL) was added
via syringe. After stirring at 50 °C for 72 h, the mixture was
poured into 2 M aqueous ammonia (30 mL). Chloroform (100
mL) was added, and the precipitate was removed by filtration.
The aqueous layer was extracted with chloroform (2 × 50 mL).
The combined organic layers were washed with water and a
saturated aqueous NaCl solution, dried with Na2SO4, and
evaporated in vacuo. The residue was purified by chromatog-
raphy on silica gel (60 g), using a hexanes/ethyl acetate
mixture (9:1) and then ethyl acetate, to give (+)-22 as a
colorless viscous oil (0.69 g, 65%) that crystallized on stand-
ing: mp 127-129 °C (hexanes/ethyl acetate); [R]D +72.3 (c 0.7,
i-P r -iso-P INDOX (-)-11 (61%): mp 69-71 °C (ethyl acetate/
1
hexane); [R]D -21.9 (c 1.00, CH2Cl2); H NMR δ (CDCl3, 400
MHz) 0.51 (s, 3H), 0.55 (s, 3H), 0.77 (d, J ) 6.8 Hz, 3H), 0.96
(d, J ) 7.2 Hz, 3H), 1.00 (d, J ) 6.8 Hz, 3H), 1.11 (d, J ) 7.2
(29) A synthesis of the enantiomer of 28 was first described by us;8
it relied on the conversion of pyridone (-)-26 into the corresponding
chloride (40%), followed by Ni(0)-catalyzed coupling (90%). An alterna-
tive and rather lengthy procedure has been mentioned several times
in the literature,9 but the experimental procedures have not been
revealed.
(30) Enantiomers of 29-31 have been reported earlier but no optical
rotations had been given.9c
9666 J . Org. Chem., Vol. 68, No. 25, 2003

Lewis-Basic N-Oxides as Chiral Organocatalysts
1
CHCl3); H NMR, δ 0.61 (s, 6 H), 1.20 (d, J ) 9.6 Hz, 2 H),
(S)-(-)-1-P h en yl-bu t-3-en -1-ol (S)-(-)-(3a ): [R]D -61.2 (c
1
1.05, CHCl3); H NMR δ 2.06 (br s, 1 H), 2.48-2.56 (m, 2 H),
1.31 (s, 6 H), 2.01 (s, 6 H), 2.23 (m, 2 H), 2.60 (dt, J ) 9.6 Hz,
J ) 5.8 Hz, 2H), 2.85 (m, 4 H), 2.93 (t, J ) 5.5 Hz, 2 H), 7.24
(s, 2 H); 13C NMR δ 18.62 (2 × CH3), 21.67 (2 × CH3), 26.45 (2
× CH3), 31.40 (4 × CH2), 40.56 (2 × CH), 50.18 (2 × CH), 60.73
(2 × C), 129.19 (2 × C), 129.31 (2 × C), 137.95 (2 × CH), 153.50
(2 × C), 163.2 (2 × C); HRMS (EI) 372.5535 (C26H32N2 requires
372.5528).
4.77 (dd, J ) 7.7, 5.2 Hz, 1 H), 5.15-5.22 (m, 2 H), 5.79-5.89
(m, 1 H), 7.28-7.39 (m, 5 H); chiral GC (Supelco â-DEX 120
column, oven 100 °C for 5 min, then 1 deg/min to 200 °C, 10
min at that temperature) showed 92% ee (tR ) 31.06 min, tS
) 31.49 min).
(S)-(-)-1-(4-Met h yl-p h en yl)-b u t -3-en -1-ol (S)-(-)-(3b ):
1
[R]D -31.1 (c 0.9, CHCl3); H NMR δ 1.62 (br s, 1 H), 2.34 (s,
(7R,7′R,8R,8′R)-(+)-5,5′,6,6′,7,7′,8,8′-Octa h yd r o-6,6′,7,7′-
tetr am eth ylbi(7,8-m eth an oqu in olin e)-N-oxide (+)-33 (CAN-
DOX). m-Chloroperoxybenzoic acid (170 mg, 0.70 mmol) was
added portion-wise to a stirred solution of CANDY (-)-328c
(135 mg, 0.39 mmol) in dichloromethane (15 mL) at 0 °C, and
the stirring was continued at this temperature for a further 2
h. The mixture was then poured into a saturated aqueous
NaHCO3 (15 mL), and the product was extracted into dichlo-
romethane (2 × 15 mL). The organic layer was washed with
NaHCO3 (2 × 15 mL), dried with Na2SO4, and concentrated
in vacuo. Flash chromatography of the residue on silica gel
(15 g) with a petroleum ether/ethyl acetate mixture (1:1)
furnished N-mono-oxide (+)-33 (74 mg, 53%) as a white,
crystalline solid. Continued elution with an ethyl acetate/
methanol mixture (20:1) furnished N,N′-dioxide (+)-34 (57 mg,
39%), also as a white crystalline solid. Data for (+)-33: mp
3 H), 2.45-2.54 (m, 2 H), 4.70 (t, J ) 7.0, 1 H), 5.11-5.18 (m,
2 H), 5.75-5.86 (m, 1 H), 7.16 (d, J ) 7.4, 2 H), 7.25 (d, J )
7.4, 2 H); chiral GC (Supelco â-DEX 120 column, oven 100 °C
for 5 min, then 1 deg/min to 200 °C, 10 min at that temper-
ature) showed 87% ee (tR ) 37.53 min, tS ) 38.26 min).
(S)-(-)-1-(4-Meth oxy-p h en yl)-bu t-3-en -1-ol (S)-(-)-(3c):
1
[R]D -48.0 (c 1.0, CHCl3); H NMR δ 2.01 (br s, 1 H), 2.49 (t,
J ) 8.0, 2 H), 3.80 (s, 3 H), 4.68 (t, J ) 6.5, 1 H), 5.10-5.17
(m, 2 H), 5.74-5.84 (m, 1 H), 6.88 (d, J ) 8.7, 2 H), 7.27 (d, J
) 8.7, 2 H); chiral HPLC (Chiralcel OD-H, hexane/2-propanol
97:3, 1.0 mL/min) showed 87% ee (tR ) 14.73 min, tS ) 17.19
min).
(S)-(-)-1-(4-Ch lor o-p h en yl)-bu t-3-en -1-ol (S)-(-)-(3d ):
1
[R]D -60.6 (c 1. 5, CHCl3); H NMR δ 1.59 (br s, 1 H), 2.41-
2.54 (m, 2 H), 4.72 (dd, J ) 7.8, 5.0 Hz, 1 H), 5.14-5.19 (m, 2
H), 5.73-5.83 (m, 1 H), 7.28-7.33 (m, 4 H); chiral GC (Supelco
â-DEX 120 column, oven 100 °C for 5 min, then 1 deg/min to
200 °C, 10 min at that temperature) showed 89% ee (tR ) 51.70
min, tS ) 52.43 min).
1
118-120 °C (petroleum ether); [R]D +25.9 (c 1.0, CHCl3); H
NMR (CDCl3, 400 MHz) δ 0.71 (s, 3 H), 0.82 (s, 3 H), 1.17 (s,
3 H), 1.28 (s, 3 H), 1.39 (dt, J ) 8.7 and 5.4 Hz, 1 H), 1.49-
1.56 (m, 1 H), 1.81-1.87 (m, 1 H), 1.91-2.01 (m, 2 H), 1.95 (d,
J ) 8.4 Hz, 1 H), 2.00 (d, J ) 8.3 Hz, 1 H), 2.11-2.18 (m, 1
H), 2.44-2.54 (m, 2 H), 2.69-2.79 (m, 2 H), 6.98 (d, J ) 8.1
Hz, 1 H), 7.33 (d, J ) 8.0 Hz, 1 H), 7.76 (d, J ) 8.1 Hz, 1 H),
8.43 (d, J ) 8.0 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 15.89
(CH3), 16.8 (CH3), 18.8 (CH2), 20.21 (CH2), 23.28 (CH3), 24.43
(CH), 25.56 (CH), 25.70 (C), 26.17 (C), 28.17 (CH), 28.36 (CH2),
29.06 (CH), 29.54 (CH2), 29.62 (CH3), 122.66 (CH), 124.28 (CH),
125.14 (CH), 132.26 (C), 135.95 (CH), 136.87 (C), 138.66 (C),
147.53 (C), 148.59 (C), 156.86 (C); IR (CHCl3) ν 3027, 2965,
1528, 1486, 1452, 1321, 1257, 718 cm-1; HRMS (EI) 360.2196
(C24H28N2O requires 360.2202).
(S)-(-)-1-(4-Nitr o-p h en yl)-bu t-3-en -1-ol (S)-(-)-(3e): [R]D
1
-33.2 (c 0. 5, CHCl3); H NMR δ 2.19 (br s, 1 H), 2.42-2.49
(m, 1 H), 2.54-2.60 (m, 1 H), 4.86 (dd, J ) 8.0, 4.6 Hz, 1 H),
5.17-5.22 (m, 2 H), 5.74-5.84 (m, 1 H), 7.54 (d, J ) 8.6, 2 H),
8.21 (d, J ) 8.6, 2 H); chiral GC (Supelco â-DEX 120 column,
oven 100 °C for 5 min, then 1 deg/min to 200 °C, 10 min at
that temperature) showed 65% ee (tR ) 85.21 min, tS ) 85.77
min).
(S)-(-)-1-P h en yl-h exa-1,5-dien -3-ol (S)-(-)-(3f): [R]D -36.9
(c 1.06, CHCl3) and +10.3 (c 1.31, Et2O); 1H NMR δ 1.74 (br s,
1 H), 2.28-2.40 (m, 2H), 4.27-4.32 (m, 1 H), 5.09-5.15 (m, 2
H), 5.74-5.84 (m, 1 H), 6.18 (dd, J ) 15.9, 6.3 Hz, 1 H), 6.55
(d, J ) 15.8 hz, 1 H), 7.15-7.33 (m, 5 H); chiral HPLC
(Chiralcel OD-H, hexane/2-propanol 9:1, 0.75 mL/min) showed
83% ee (tR ) 10.2 min, tS ) 14.9 min).
(7R,7′R,8R,8′R)-(+)-5,5′,6,6′,7,7′,8,8′-Octa h yd r o-6,6′,7,7′-
tetr am eth ylbi(7,8-m eth an oqu in olin e)-(+)-N,N′-dioxide (+)-
(34). Obtained by continued elution after the isolation of (+)-
33 (CANDOX). Data for (+)-34: mp 210-212 °C (petroleum
(R)-(+)-1-P h en yl-h ex-5-en -3-ol (R)-(+)-(3g): [R]D +1.8 (c
1
ether); [R]D +13.6 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz)
1
0.9, CHCl3) [lit.31 [R]D +11.1 (c 3.14, CHCl3)]; H NMR δ 1.56
δ 0.74 (s, 6 H), 1.22 (s, 6 H), 1.37 (dt, J ) 5.4 and 5.3 Hz, 2 H),
1.50-1.60 (m, 2 H), 2.08 (d, J ) 8.3 Hz, 2 H), 2.11-2.17 (m, 2
H), 2.47 (dt, J ) 8.5 and 5.0 Hz, 2 H), 2.73 (m, 2 H), 7.08 (d,
J ) 7.9 Hz, 2 H), 7.28 (d, J ) 7.9 Hz, 2 H); 13C NMR (CDCl3,
100.6 MHz) δ 16.07 (2 × CH3), 20.05 (2 × CH2), 22.98 (2 ×
CH), 24.46 (2 × CH), 26.43 (2 × C), 28.12 (2 × CH3), 29.41 (2
× CH2), 124.01 (2 × CH), 124.36 (2 × CH), 138.04 (2 × C),
142.08 (2 × C), 148.85 (2 × C); IR (CHCl3) ν 3028, 2934, 1427,
1221, 727, 668 cm-1; HRMS (EI) 376.2144 (C24H28N2O2 re-
quires 376.2151).
(br s, 1 H), 1.73-1.85 (m, 2 H), 2.15-2.22 (m, 1 H), 2.29-2.36
(m, 1 H), 2.65-2.73 (m, 1 H), 2.78-2.85 (m, 1 H), 3.65-3.71
(m, 1 H), 5.14 (J ) 15.2 Hz, 2 H), 5.77-5.87 (m, 1 H), 7,17-
7.21 (m, 3 H), 7.26-7.30 (m, 2 H); chiral HPLC (Chiralcel OD-
H, hexane/2-propanol 95:5, 1 mL/min) showed 49% ee (tS
8.1 min, tR ) 10.9 min).
)
(S)-(-)-1-(2-F u r yl)-bu t-3-en e-1-ol (S)-(-)-(3h ): [R]D -4.9
(c 1.4, EtOH); 1H NMR δ 1.99 (br s, 1 H), 2.61-2.65 (m, 2 H),
4.65-4.85 (m, 1 H), 5.14-5.21(m, 2 H), 5.76-5.86 (m, 1 H),
5.74-5.84 (m, 1 H), 6.21-6.34 (m, 2 H), 7.38 (m, 1 H); chiral
HPLC (Chiralcel OD-H, hexane/2-propanol 97.5:2.5, 0.75 mL/
min) showed 85% ee (tR ) 15.3 min, tS ) 16.8 min).
Gen er a l P r oced u r e for Rea ction of Allyltr ich lor osi-
la n e w ith Ald eh yd es. Allyltrichlorosilane (75 µL, 0.47 mmol)
was added to a solution of the catalyst (4, 6a , or 8-11) (0.04
mmol), diisopropylethylamine (0.35 mL, 2 mmol), tetra-n-
butylammonium iodide (175.4 mg, 0.47 mmol), and aldehyde
(0.4 mmol) in dichloromethane (2 mL) under nitrogen at -60
°C (or -90 or -40 °C). The mixture was stirred at the same
temperature until completion (TLC monitoring; see Table 1
for the reaction time) and then quenched with aqueous
saturated NaHCO3 (1 mL). The aqueous layer was extracted
with ethyl acetate (3 × 10 mL). The combined organic layers
were washed with brine and dried over Na2SO4, and the
solvent was removed in vacuo. The residue was purified by
flash chromatography on silica gel [15 × 2 cm; petroleum ether/
ethyl acetate, 95:5]. Products 3 were either identical with the
authentic samples7 or their NMR data corresponded to those
published.3
(S)-(-)-(2-Th iop h en eyl)-bu t-3-en e-1-ol (S)-(-)-(3i): [R]D
1
-19 (c 1.0, CHCl3) [lit.32 -5.2 (c 1.1, EtOH); H NMR δ 2.62
(br t, J ) 6.8 Hz, 2H), 4.98 (t, J ) 6.8 Hz, 1H), 5.19 (m, 2H),
5.85 (m, 1H),; 6.99 (m, 2H), 7.26 (m, 1H); 13C NMR δ 42.7
(CH2), 68.3 (CH), 117.7 (CH2), 122.7 (CH), 123.5 (CH), 125.6
(CH), 132.8 (CH), 146.8 (C). chiral GC (Supelco â-DEX 120
column, oven 80 °C for 2 min, then 1 deg/min, showed 83% ee
(tminor ) 49.6 min, tmajor ) 49.8 min). The absolute configuration
was assigned by Brown32 and Cozzi33 by analogy with their
other results.
(31) Minova, N.; Mukaiyama, T. Bull. Chem. Soc. J pn. 1987, 60,
3697.
(32) Racherla, U. S.; Liao, Y.; Brown, H. C. J . Org. Chem. 1992, 57,
6614.
J . Org. Chem, Vol. 68, No. 25, 2003 9667

Malkov et al.
(S)-(-)-1-[(4-Tr iflu or om eth yl)-ph en yl]-bu t-3-en -1-ol (S)-
UV detection at 220 nm]; chiral GC [Supelco γ-CD 120, t1
35.23 min (minor), t2 ) 35.58 min (major)].
)
1
(-)-(3j):34 [R]D -33.6 (c 0.25, CH2Cl2); H NMR δ 2.07 (br s,
1H), 2.33-2.51 (m, 2H), 4.72 (dd, J ) 7.8, 3.1 Hz, 1H), 5.09-
5.14 (m, 2H), 5.67-5.78 (m, 1H), 7.41(d, J ) 8.4, 2H), 7.54 (d,
J ) 8.4, 2H); chiral GC (Supelco â-DEX 120 column, oven: 100
°C for 2 min, then 0.5 deg/min showed 91% ee (tS ) 30.9 min,
tR ) 31.9 min).
(1S,2R)-(-)-2-Met h yl-1-p h en yl-b u t -3-en -1-ol (1S,2R)-
(-)-(37): [R]D -15.7 (c 0.29, CH2Cl2) [lit. [R]D -23.55 (c 1.15,
CHCl3)2f or +17.1 (c 1.0, CHCl3) for the opposite enantiomer
of 60% ee2a]; 1H NMR (400 MHz, CDCl3) δ 0.96 (d, J ) 7.2 Hz,
3H), 1.87 (br s, 1 H), 2.51-2.54 (m, 1H), 4.55 (d, J ) 5.2 Hz,
1H), 5.13-5.16 (m, 2H), 5.65-5.74 (m, 1H), 7.19-7.27 (m, 5H);
chiral GC (Supelco â-DEX 120 column, oven 100 °C for 2 min,
(S)-(-)-1-(Na p h th a len -2-yl)-bu t-3-en -1-ol (S)-(-)-(3k ):
1
[R]D -55.0 (c 1.16, CHCl3); H NMR δ 2.09 (br s, 1 H), 2.47-
2.58 (m, 2 H), 4.84 (dd, J ) 7.6, 5.3 Hz, 1 H), 5.07-5.14 (m, 2
H), 5.71-5.82 (m, 1 H), 7.37-7.43 (m, 3 H), 7.74-7.78 (m, 4
H); chiral HPLC (Chiralcel OD-H, hexane/2-propanol, 9:1, 0.75
mL/min) showed 90% ee (tS ) 12.6 min, tR ) 14.4 min).
(1S,2S)-(-)-2-Met h yl-1-p h en yl-b u t -3-en -1-ol (1S,2S)-
(-)-(37): [R]D -34.7 (c 1.7, CHCl3) [lit. [R]D -97.0 (c 1.11,
CHCl3)2f or +75.0 (c 1.0, CHCl3)2a for the opposite enantiomer
then 0.5 deg/min showed 87% ee for the major product (t1
)
42.7 min (anti), t2 ) 43.9 min (minor syn), t3 ) 45.0 min (major
syn).
Ack n ow led gm en t. We thank the University of
Glasgow for a studentship to M.B., AstraZeneca for a
fully funded studentship to D.P., University of Rome for
a fellowship to M.O., University of Salerno for a fellow-
ship to A.M., the Socrates exchange program for a
fellowship to P.H., Degussa for a research grant, and
Dr. Alfred Bader for additional support.
1
of 66% ee]; H NMR (400 MHz, CDCl3) δ 0.87 (d, J ) 6.8 Hz,
3H), 2.14 (d, J ) 2.5 Hz, 1H), 2.44-2.53 (m, 1H), 4.36 (dd, J
) 7.9 and 2.4 Hz, 1H), 5.17-5.22 (m, 2H) 5.74-5.86 (m, 1H),
7.27-7.37 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 16.93, 40.71,
78.27, 117.24, 127.23, 128.05, 128.63, 141.04, 142.80; chiral
HPLC [Chiralpak OD-H, hexane/2-propanol, 95:5, flow rate
0.5 mL/min, t1 ) 14.57 min (major), t2 ) 15.98 min (minor),
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal methods and H and 13C NMR spectra for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(33) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A.
Angew. Chem., Int. Ed. 1999, 38, 3357.
(34) Doucet, H.; Santelli, M. Tetrahedron: Asymmetry 2000, 11,
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