Chiral pyridine N-oxides derived from monoterpenes as organocatalysts for stereoselective reactions with allyltrichlorosilane and tetrachlorosilane

Article abstract of DOI:10.1016/j.tet.2008.05.105

The synthesis of enantiomerically pure C₂-symmetric dipyridylmethane ligands and related N,N′-dioxides is reported. A procedure for the synthesis of a few new enantiomerically pure C₂-symmetric pyridine N-oxides and the preparation of four pyridine N-oxides with oxygen and nitrogen atoms as further coordinating elements in the heterocycle framework is described. All compounds were prepared from naturally occurring monoterpenes. These new compounds were assessed as organocatalysts in two different reactions, namely the allylation of aldehydes with allyltrichlorosilane that afforded homoallylic alcohols in good yields and up to 85% ee and the stilbene oxide opening by the addition of tetrachlorosilane that gave chlorohydrin in quantitative yield and up to 70% ee.

Full text of DOI:10.1016/j.tet.2008.05.105

Tetrahedron 64 (2008) 7574–7582
Contents lists available at ScienceDirect
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Chiral pyridine N-oxides derived from monoterpenes as organocatalysts for
stereoselective reactions with allyltrichlorosilane and tetrachlorosilane
,
a
b
c
,
c
Giorgio Chelucci a , Salvatore Baldino , Gerard A. Pinna , Maurizio Benaglia , Laura Buffa ,
*
*
Stefania Guizzetti c
a
`
Dipartimento di Chimica, Universita di Sassari, via Vienna 2, I-07100 Sassari, Italy
Dipartimento Farmaco Chimico Tossicologico, Universita di Sassari, Via Muroni 23, I-07100 Sassari, Italy
c Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano, Via Golgi, 19-20133 Milano, Italy
b
`
a r t i c l e i n f o
a b s t r a c t
The synthesis of enantiomerically pure C2-symmetric dipyridylmethane ligands and related N,N0-di-
oxides is reported. A procedure for the synthesis of a few new enantiomerically pure C2-symmetric
pyridine N-oxides and the preparation of four pyridine N-oxides with oxygen and nitrogen atoms as
further coordinating elements in the heterocycle framework is described. All compounds were prepared
from naturally occurring monoterpenes. These new compounds were assessed as organocatalysts in two
different reactions, namely the allylation of aldehydes with allyltrichlorosilane that afforded homoallylic
alcohols in good yields and up to 85% ee and the stilbene oxide opening by the addition of tetra-
chlorosilane that gave chlorohydrin in quantitative yield and up to 70% ee.
Article history:
Received 4 February 2008
Received in revised form 8 May 2008
Accepted 22 May 2008
Available online 27 May 2008
Keywords:
Pyridine N-oxides
Organocatalysis
Monoterpenes
Allyltrichlorosilane
Epoxide opening
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
derived from tertiary amines.5 The high nucleophilicity of the ox-
ygen in N-oxides, coupled with a high affinity of silicon for oxygen
The replacement or the co-existence of metal-based catalysts
with equally efficient metal-free counterparts is a very attractive
field of research. In addition, there are possible future applications
of non-toxic, lowcost and more environmentally friendly promoters
on industrial scale with obvious benefits from the environmental
and economic point of view.1 In this context, the chemistry of penta
and/or hexavalent silicon compounds has recently attracted much
attention because of the possibility to develop organocatalyzed
enantioselective reactions.2
The coordination of a Lewis base to a tetracoordinated silicon
atom leads to hypervalent silicate species of increased Lewis acidity
at the silicon centre. As a consequence, such extracoordinated
organosilicon compounds become very reactive carbon nucleo-
philes or hydride donors with a strong electrophilic character at
silicon and an enhanced capability to transfer a formally negatively
charged group to an acceptor.3 Among Lewis basic catalysts,4 a class
of compounds that deserve special attention are chiral N-oxides
represent ideal properties for the development of synthetic
methodology based on nucleophilic activation of organosilicon
reagents. The most popular examples in chiral N-oxide derivatives
are those with a pyridine (or quinoline-type) scaffold that are able
to activate trichlorosilanes and catalyze a number of reactions such
as allylation of aldehydes, aldol condensations and ring opening of
epoxides.5
Although a variety of chiral pyridine N-oxide derivatives are able
to perform these transformations with a high level of stereocontrol,
they were often synthesized according to long and tedious pro-
cedures, sometimes also involving a resolution step. Furthermore,
a difficult-to-control stereogenic element such as a stereogenic axis
in the catalyst is often required to achieve high levels of stereo-
control. Therefore, the search for new, readily available and efficient
chiral organocatalysts for the reaction of trichlorosilyl compounds
is still very active.
On this basis, we have undertaken the preparation of chiral
organocatalysts, from naturally occurring and easily available
monoterpenes, containing two pyridine rings connected by
a proper tunable spacer. In this context, we have recently reported
the synthesis of chiral dipyridines with an isopropylidene backbone
between two pyridine rings.6,7 The preliminary results obtained by
the C2-symmetric dipyridylmethane ligands 1–4 (Fig. 1) and their
* Corresponding authors. Tel.: þ39 079 229539; fax: þ39 079 229559 (G.C.); tel.:
þ39 0250314171; fax: þ39 0250314159 (M.B.).
E-mail addresses: chelucci@ssmain.uniss.it (G. Chelucci), maurizio.benaglia@
unimi.it (M. Benaglia).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.105

G. Chelucci et al. / Tetrahedron 64 (2008) 7574–7582
7575
3,3-dimethylpentane-2,4-dione 5 to an
a
-methylene ketone, fol-
lowed by pyrido-anellation of the formed unisolated 1,5-dicarbonyl
intermediates. This strategy has been firstly examined in order to
prepare the dipyridylmethane 1.
N
N
N
N
N
N
N
N
Thus, the lithium dienolate of the diketone 5, generated in THF
by treatment with lithium diisopropylamide (LDA) at ꢀ78 ꢁC for
2 h, was treated at ꢀ78 ꢁC with the Michael acceptor (ꢀ)-pino-
1
2
carvone (6),8 obtained in turn from (þ)-
a-pinene, and the resulting
reaction mixture was allowed to slowly reach room temperature.
Ammonium acetate and acetic acid were added, THF was then
distilled off over a 3 h period and finally, the mixture was heated at
120 ꢁC for 3 h. This one-pot process afforded the dipyridylmethane
1 in 28% yield.
3
4
Figure 1. C2-symmetric dipyridylmethane ligands 1–4.
With the desired dipyridylmethane 1 in hand, this protocol was
extended to other more sterically hindered
a
-methylene ketones
-methylene
derivatives in the enantioselective palladium-catalyzed allylic al-
kylation of 1,3-diphenylprop-2-enyl acetate with dimethyl-malo-
nate,6a copper-catalyzed cyclopropanation of styrene with ethyl
diazoacetate6b and enantioselective addition of allyltrichlorosilane
to aldehydes have also been described.7
Herein, we wish to report full experimental details for the
preparation of the ligands 1–4 and related N,N0-dioxides (Scheme 1).
A procedure for the synthesis of a few new enantiomerically pure
C2-symmetric pyridine N-oxides (Schemes 2–4) and the preparation
of four pyridine N-oxides with oxygen and nitrogen atoms as further
coordinating elements in the heterocycle framework is also
described (Schemes 5 and 6). All these new compounds have been
assessed as organocatalysts in two reactions involving trichlorosilyl
compounds: the allylation of aldehydes with allyltrichlorosilane and
the opening of meso-epoxides by addition of tetrachlorosilane.
(Scheme 1). Thus, the application of this protocol to
a
ketones 7,9 810 and 9,11 obtained from (þ)-3-carene, (ꢀ)-iso-pino-
campheol and (þ)-
a-pinene, afforded the related dipyridyl-
methanes 2, 3 and 4 in 8, 10 and 21% yield, respectively (Scheme 1).
The overall yield of 1 and 4 was comparable, but it was much lower
for the other two ligands 2 and 3, probably due to the instability of
the cyclopropane ring and the steric hindrance of carbonyl groups
that determines a reduction of their ability to undergo the aza-
anellation step.
It is worth mentioning that although the overall yield of the
process is low, this procedure represents a straightforward way to
obtain C2-symmetric dipyridylmethane ligands. Oxidation of 1–4
with 3-chloroperbenzoic acid (2.6 equiv) in CH2Cl2 at room tem-
perature for 24 h afforded the corresponding N,N0-dioxides 10–13
(24–79% yield) (Scheme 1).
Then, we considered that the synthesis of enantiomerically pure
C2-symmetric pyridine N-oxides was worthy of investigation. In
fact, although some examples of pyridine N-oxides without addi-
tional coordinating elements have been reported in organo-
catalyzed reactions based on trichorosilane reagents, none of them
possess C2-symmetry.5 Thus, pyridine N-oxides 14, 15 and 16 were
prepared (Fig. 2).
2. Results and discussion
In considering possible synthetic pathways to dipyridylmethane
ligands of type 1–4, we decided that the most direct approach to
these ligands could have been the tandem one-pot synthesis of the
two pyridine rings by a double Michael addition of the dianion of
O
6
b
+N
-O O-
10
N
N
N
N+
28%
79%
1
O
7
N
b
+N
O-
N+
-O
8%
24%
a
2
11
O
O
5
O
8
b
N
N
N
N
N+
+N
10%
60%
-O O-
12
3
O
b
9
N+
+N
76%
21%
-O O-
13
4
Scheme 1. Synthesis of dipyridylmethane ligands 1–4 and N-oxides 10–13. Reactions: (a) (i) LDA, THF, ꢀ78 ꢁC, 2 h, then
a
-methylene ketone (2–5), ꢀ78 ꢁC to slowly rt, (ii) NH4OAc,
AcOH, THF, reflux, 5 h; (b) MCPBA (2.3 equiv), CH2Cl2, rt, 24 h.

7576
G. Chelucci et al. / Tetrahedron 64 (2008) 7574–7582
Ref. 13
Ref.12
O O
O
N
N
OH
18
17
26
MCPBA
CH2Cl2,
a
r.t., 24 h,
86%.
N+
O-
14
19
+
N
N
OH
OH
Scheme 2. Synthesis of pyridine N-oxide 14.
27
28
b
93%
b
95%
a
+
O
O
O
21
O
N
N
20
9
OMe
OMe
c
29
30
b
c
55%
60%
N+
O-
15
N
22
N+
N+
Scheme 3. Synthesis of pyridine N-oxide 15. Reactions: (a) (i) 20, LDA, THF, ꢀ40 ꢁ
C
OMe O-
32
OMe O-
31
then 9, ꢀ40 ꢁC to rt, (ii) NH4OAc, AcOH, 70 ꢁC, 3 h, then 120 ꢁC, 3 h, 31% overall; (b)
MCPBA, CH2Cl2, rt, 24 h, 89%.
Scheme 5. Synthesis of pyridine N-oxides 31 and 32. Reactions: (a) chromatographic
separation; (b) NaH, THF, rt, then MeI; (c) MCPBA, CH2Cl2, rt, 24 h.
The preparation of the C2-symmetric pyridine N-oxide 14 has
previously been reported by Kotsuki (Scheme 2).12 Their synthesis
is hinged upon the pyrido-anellation with NH4OAc and Cu(OAc)2 in
propionic acid of the diketone 18 that was in turn obtained by re-
action of (þ)-camphor 17 with potassium metal in DMF13 (37%
overall yield). The N-oxide 14 was finally prepared in 86% yield by
oxidation of 19 with MCPBA in CH2Cl2.
a
N
N
N
N
N
N
N
N
69%
O
33
1
This procedure represents an interesting way to obtain C2-
symmetric pyridines such as 14, but is restricted to ketones such as
camphor 17 with only an
limitations, we have developed a one-pot process that is based on
the Michael addition of the enolate of a ketone to an -methylene
a-enolizable position. To overcome these
a
79%
O
a
ketone, followed by pyrido-anellation of the formed unisolated 1,5-
dicarbonyl intermediate. This strategy has firstly been pursued to
obtain the pyridine 22 (Scheme 3).
34
4
Scheme 6. Synthesis of pyridine N-oxides 33 and 34. Reactions: (a) MCPBA (0.2 equiv),
CH2Cl2, rt, 24 h.
Thus, conjugate addition of the lithium enolate of (þ)-nopinone
20, generated by treatment with LDA at ꢀ40 ꢁC for 2 h, with the
a-
Then, deciding to investigate the catalytic activity of pyridine N-
oxides bearing an additional coordinating element in the hetero-
cycle framework, the new enantiomerically pure pyridine N-oxides
31,32 and 33,34 with potentially coordinating ethereal oxygen and
pyridine nitrogen, respectively, were prepared.
The synthesis of 31 and 32 starts from a 3:1 mixture of the
epimeric alcohols 26, differing in the configuration at C8, that was
previously prepared by von Zelewsky14 (Scheme 5). Careful flash
chromatography of 26 gave pure diastereomers 27 and 28, which
were then treated separately with the sodium hydride/methyl io-
dide system to afford the 8-methoxytetrahydroquinolines 29 and
30 in quantitative yields. Finally, the oxidation of these quinolines
methylene ketone 9 (from ꢀ40 ꢁC to room temperature) gave the
1,5-dicarbonyl intermediate 21 that was not isolated, but directly
converted into the pyridine 22 (31% overall yield) by treatment
with the ammonium acetate/acetic acid system (120 ꢁC, 3 h).
According to this protocol, the pyridine 25 was prepared by
reaction of the ketone 23 with the unsaturated ketone 8 (Scheme
4). Unfortunately in this case the yield of 25 was very low (8%).
From the pyridines 22 and 25, the related N-oxides 15 and 16, re-
spectively, were obtained in high yields (89 and 97%) by oxidation
with an excess of MCPBA in CH2Cl2 (Schemes 3 and 4).
a
+
O
O
O
O
N+
O-
N+
O-
14
24
23
8
15
b
N+
O-
16
N
N+
25
O-
16
Scheme 4. Synthesis of pyridine N-oxide 16. Reaction: (a) (i) 23, LDA, THF, ꢀ40 ꢁC,
then 8, ꢀ40 ꢁC to rt, (ii) NH4AcO, AcOH, 70 ꢁC, 3 h, then 120 ꢁC, 3 h, 8%; (b) MCPBA,
CH2Cl2, rt, 24 h, 97%.
Figure 2. C2-symmetric pyridine N-oxides 14–16.

G. Chelucci et al. / Tetrahedron 64 (2008) 7574–7582
7577
Table 2
with an excess of MCPBA in CH2Cl2 produced the pyridine N-oxides
Allylation reaction promoted by N,N0-dioxides 10–13a
31 and 32 in 55 and 60% yield, respectively (Scheme 5).
The N-monoxide 33 (69% yield) and 34 (79% yield) were also
prepared from the parent dipyridylmethane 1 and 4 by oxidation
with MCPBA (Scheme 6). However, in this case, in order to increase
the selective N-monoxide formation, a large excess of dipyridyl-
methane (5 equiv) with respect to MCPBA (1 equiv) was used and
the unconverted starting material and the product were separated
by flash chromatography.
Entry Catalyst Temp (ꢁC) Time (h) Yieldb (%) Eec (%)c Configurationd
1
2
3
4
5
6
7e
10
11
12
13
13
13
13
0
0
0
72
72
72
67
67
67
67
30
24
22
37
58
97
98
4
30
35
85
83
77
64
S
S
S
S
S
S
S
ꢀ40
0
25
0
The catalytic activity and stereodifferentiating ability of the new
pyridine N-oxide derivatives were then examined in the allylation
of aldehydes15 and opening of meso-epoxides.16
a
The reaction was carried out at 0.3 mmol scale in CH3CN (2 ml) with allyl(tri-
chloro)silane (1.2 equiv), catalyst (10 mol %), DIPEA (3 equiv) for 60 h.
b
Isolated yields after flash chromatography.
Determinated by HPLC on a Chiracel OD column (hexane/isopropanol 95:5; flow
c
Initially, the asymmetric addition of allyltrichlorosilane to
benzaldehyde, which is used as a testing ground for new chiral
nucleophilic catalysts, was examined (Scheme 7). In a typical pro-
cedure, 0.1 mol equiv of catalyst,1.2 mol equiv of allyltrichlorosilane
and 3 mol equiv of DIPEA in acetonitrile were reacted for 48 h at
different temperatures. Isolated yields and ees, as determined by
HPLC, are collected in Tables 1 and 2. The absolute configuration was
assigned to the predominant isomer of the obtained homoallylic
alcohol on the basis of its optical rotation.
rate 0.8 ml/min;
l
220 nm): tR¼10.4 min, tS¼11.3 min.
d
Assigned by comparison of optical rotation.
Reaction run in CH2Cl2.
e
element for the silicon atom (entries 8 and 9). Still more worse
results were found with N-oxides 33 and 34 bearing a pyridine
nitrogen as further coordinating element (entries 10 and 11).
More interesting results were obtained with dipyridylmethane
N,N0-dioxides 10–13. The data related to the catalytic ability of these
catalysts to promote the addition of allyltrichlorosilane to benzal-
dehyde are collected in Table 2.7
Among the C2-symmetric dipyridylmethane N,N0-dioxides 10–
13, compound 13 performed the reaction much better than its
congeners. In fact, already at 0 ꢁC it was able to produce in 58% yield
and 83% ee the homoallylic alcohol, the enantiomeric excess of
which was increased to 85% by running the allylation at ꢀ40 ꢁC.
Interestingly, raising the temperature to 25 ꢁC brought about
a higher yield (98%) with only a slight decrease of the enantiose-
lectivity (77% ee, entry 6). A solvent change from MeCN to CH2Cl2
led to a quantitative yield, but with a negative effect on the enan-
tioselectivity (entry 7 vs 5). Finally, the use of other solvents (tol-
uene, DME and THF) led to lower yields and enantiomeric excesses.
Having identified catalyst 13 as the most efficient one, its use
was extended to the addition of allyltrichlorosilane to other aro-
matic aldehydes (Table 3). The reported data show that ees equal to
or greater than 70% and yields constantly higher than 58% could be
obtained (entries 1–5).
OH
*
O
SiCl3
H
catalyst, DIPEA
Scheme 7. Addition of allyltrichlorosilane to benzaldehyde promoted by pyridine
N-oxides.
First, the catalytic efficiency of pyridine N-oxides was in-
vestigated and the results are reported in Table 1. The data show
clearly that the related pyridine N-oxides 14, 15 and 16 are not good
promoters of the addition of allyltrichlorosilane to benzaldehyde at
low temperature. The sterically hindered N-oxide 14 catalyzed the
reaction only at room temperature in fair yield, but no enantiose-
lectivity was observed (entries 1 and 2). Also compound 16 was
quite ineffective in promoting the reactions, whereas best results
were obtained with catalyst 15 that was able to afford the homo-
allylic alcohol with 42% ee at ꢀ40 ꢁC, albeit low yielding (entry 3).
The product was isolated in improved yield and slightly increased
enantioselectivity by employing tetrabutylammonium iodide as
additive (31% yield and 48% ee), whereas a decrease of the enan-
tioselectivity was produced by running the reaction at 0 ꢁC (entries
4 and 5).
Table 3
Allylation of aldehydes with allyltrichlorosilane using 13a
O
OH
Cat. 13, DIPEA,
SiCl3
+
R
H
R
CH3CN, 0 °C
Modest results were also obtained with pyridine N-oxides 31
and 32 bearing the methoxy group as a potentially chelating
Entry
R
Yieldb (%)
eec(%)
Configurationd
1
2
3
4
5
6
7
Ph
58
68
65
60
61
41
46
83
70
80
75
73
18
4
S
S
S
S
S
S
S
Table 1
p-O2NC6H4
Allylation reaction promoted by N-oxides 14–16, and 31–34
p-MeOC6H4
2-Thiophenyl
3-Thiophenyl
Ph–CH]CH
Ph–CH2CH2
Entrya
Catalyst
Temp (ꢁC)
Yieldb (%)
eec (%)
Configurationd
1
14
14
15
15
15
16
16
31
32
33
34
0
25
ꢀ40
ꢀ40
0
ꢀ40
ꢀ40
0
n.r.
65
23
31
51
n.r
11
21
17
n.r
21
d
<5
42
48
37
d
15
35
12
d
7
d
n.d.
S
S
S
d
R
S
R
d
S
2d
3
4e
5d
6
a
The reaction was carried out at 0.3 mmol scale in CH3CN (2 ml) with allyl(tri-
chloro)silane (1.2 equiv), catalyst (10 mol %), DIPEA (3 equiv) at 0 ꢁC for 60 h.
b
Isolated yields after flash chromatography.
Determinated by HPLC on a chiral column.
Assigned by comparison of optical rotation.
7e
8
c
d
9
10
11
0
0
0
These results show that an electron-withdrawing group at the
para-position of benzaldehyde exhibits a negative impact on the
enantioselectivity (entry 2), whereas the substrate bearing an
electron-donating group at the para-position does not seem to af-
fect the stereoselectivity (entry 3). Marginal difference in selectivity
and yield was observed for the two isomeric thiophene-carbox-
aldehydes (entries 4 and 5) showing the compatibility of the new
a
Typical experimental conditions: 0.1 mol equiv of catalyst, 1.2 mol equiv of
allyltrichlorosilane, 3 mol equiv of DIPEA, CH3CN, 67 h.
b
Yields of isolated products.
As determined by HPLC on a chiral stationary phase; yields and ee are average of
c
duplicate experiments.
d
Reaction time: 40 h.
e
Reaction runs in the presence of 1 mol/equiv of Bu4NþIꢀ as additive.

7578
G. Chelucci et al. / Tetrahedron 64 (2008) 7574–7582
catalyst in the reaction with heteroaromatic systems. Finally, both
-unsaturated and saturated aldehydes such as cinnamaldehyde
and dihydrocinnamaldehyde, respectively, afforded the corre-
sponding homoallylic alcohols with low enantiomeric excesses
(entries 6 and 7).
Me
Me
a,b
N+
N+
N+
O-
OMe
O-
O-
N+
O-
N+
O-
37
The results point out, once again, that in the asymmetric ally-
lation of aldehydes with allyltrichlorosilanes the efficiency of the
process, for N-oxide based catalysts, depends both on the possi-
bility to have a bis-chelation to the silicon centre and on the chelate
ring size of silicon in the hypothesized transition state. These
considerations stand out comparing a homogeneous series of N-
monoxides and N,N0-dioxides derived from bipyridine and dipyr-
idylmethane ligands. Thus, bipyridine N-monoxide 35a17 (Fig. 3)
(87% ee at ꢀ40 ꢁC) is more stereoselective than bipyridine N,N0-
dioxide 35b17 (41% ee at ꢀ90 ꢁC), which is in turn a better catalyst
than dipyridylmethane N-monoxide 34 (no activity at ꢀ40 ꢁC), but
less selective than dipyridylmethane N,N0-dioxide 13 (85% ee at
ꢀ40 ꢁC) that shows similar selectivity of 35a. In other words, in the
case of bidentate Lewis bases, in the dipyridine series it seems that
ligands forming an even-membered chelate ring (35a and 13) are
more stereoselective than those generating an odd-membered ring
(35b and 34).
39
38
+
N+
N+
O-
N
O-
O-
Fe
R
R
R
N
Me
40
R
R
42: R = 3,5-Me2C6H3
41
Figure 5. Pyridine N-oxide derivatives used in opening of meso-epoxides.
by addition of tetrachlorosilane in CH2Cl2. In particular, as a model
for the evaluation of catalytic activity of all new N-oxides, the
opening of cis-stilbene oxide was examined (Scheme 8). The re-
action was performed at ꢀ78 ꢁC in the presence of DIPEA, to give
the corresponding chlorohydrin 4420 in yields and enantiose-
lectivities, which are reported in Table 4.
HO
Cl
O
catalyst, SiCl4,
DIPEA, CH2Cl2
N
N
N
O X
35a,b
O
36
44
43
a: X= no atom, b: X= O
Scheme 8. Enantioselective opening of cis-stilbene oxide.
Figure 3. Dipyridine N-monoxide 35a, N,N0-dioxide 35b and pyridine N-oxide 36.
Pyridine N-oxides 14–16 gave 44 in high yield, but with poor
enantioselectivity (entries 1–3). Also for this transformation com-
pound 17 gave better results than its congeners, affording the
product with the modest asymmetric induction of 37% ee (entry 2).
Concerning catalysts 31 and 32, it should be noted these epi-
mers, which differ in the C8 configuration, behave as pseudoe-
nantiomers. In fact, they give opposite configuration of the allylic
alcohol, indicating that the steric control of the reaction depends
chiefly on the stereogenic centre bonded to the oxygen, though in
the catalyst 32 the other stereocentres are in a mismatching re-
lation with the one in the C8. Moreover, since catalyst 31 affords the
product with the same (S)-configuration and similar level of ster-
eodifferentiation (41% ee) of the related N-oxide 3618 (Fig. 3) in
which a methyl group replaces a methoxy group in the C8, it is likely
to exclude with 31 and 32 the involvement of silicon coordination
by the methoxy group in the reaction course.
On the basis of these observations and previous studies from
other groups on O-based bidentate ligands,15 a possible transition
state model C compatible with the stereoselection observed for the
new organocatalysts such as 13 is proposed in Figure 4, as a work-
ing hypothesis for future studies.
Table 4
Ring opening of cis-stilbene oxide by addition of tetrachlorosilane
Entrya
Catalyst
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
14
15
16
33
34
10
11
12
13
12
12
77
83
95
50
47
100
71
100
91
100
91
<5
37
<5
<5
<5
<5
7
70
38
67
37
9
10d
11e
While the enantioselective allylation of aldehydes with allyl-
chlorosilanes is the reaction that has most exploited pyridine
N-oxide derivatives as chiral catalysts, the ring opening of meso-
epoxides has received much less attention.5 In fact only a few
catalysts, shown in Figure 5, have been used in this process.19
On this basis, the new pyridine and dipyridine N-oxides were
tested as metal-free catalysts in the ring opening of meso-epoxides
a
Typical experimental conditions: 0.1 mol equiv of catalyst, 1 mol equiv of tetra-
chlorosilane, and 3 mol equiv of DIPEA, CH2Cl2, ꢀ78 ꢁC, 18 h.
b
Yields of isolated products.
As determined by HPLC on a chiral stationary phase; yields and ee are average of
c
duplicate experiments.
d
Reaction runs with 20% mol/equiv of catalyst.
Reaction runs in the presence of proton sponge as a base.
e
Catalysts 33 and 34 gave acceptable yields of the chlorohydrin
44 (47–50%), which however showed to be in both cases a racemic
compound (entries 4 and 5). These results were very disappointing,
considering that the pyridine N-oxide 40, differing from 34 by
a carbon spacer between the two pyridine rings, produced the
opening of cyclooctene epoxide 45 to the corresponding chloro-
hydrin 46 in 85% ee (Scheme 9), although this catalyst was con-
siderably less efficient with other substrate types.21 Once again it
appears that the chelate ring size of silicon plays a basic role in
determining the efficiency of the process.
+
Cl-
N+
Cl
Si
Cl
O
R2
Ph
R1
+
O
O
N
H
C
Figure 4. Proposed transition state for allylation catalyzed by 13.

G. Chelucci et al. / Tetrahedron 64 (2008) 7574–7582
7579
Trimethyl-3-methylenebicyclo[2.2.1]heptan-2-one7,(1R,4S,5R)-4,6,6-
trimethyl-2-methylenebicyclo[3.1.1]heptan-3-one 8 and (1R,5R)-6,6-
dimethyl-3-methylenebicyclo[3.1.1]heptan-2-one 9 were prepared
from (þ)-3-carene,9 (ꢀ)-iso-pinocampheol (98% pure, 95% ee by GLC,
O
HO
Cl
catalyst, SiCl4,
DIPEA, CH2Cl2
b
Aldrich),10 and (ꢀ)- -pinene (99% pure, Aldrich),11 respectively.
45
46
(5S,7R,8R)- and (5S,7R,8S)-2-Phenyl-8-hydroxy-5,7-methano-
6,6-dimethyl-5,6,7,8-tetrahydroquinoline (27 and 28, respectively)
were prepared as a mixture of epimers at C812 and then obtained as
pure diastereomers by flash chromatography (petroleum ether/
ethyl acetate¼85/15).
Scheme 9. Enantioselective opening of cyclooctene epoxide.
Contrasting results were obtained with dipyridine N,N0-dioxides
10–13. In fact, while all catalysts effected the transformation with
excellent yields, only compound 12 showed to be a moderately ef-
fective stereodifferentiating catalyst, affording the chlorohydrin 44
in quantitative yield and 70% ee after 18 h at ꢀ78 ꢁC in CH2Cl2 (en-
tries 8). Unfortunately, any attempt to improve the stereochemical
efficiency of 12 by increasing the catalyst loading or by changing the
base did not lead to any positive effect (entries 10 and 11).
Having determined that compound 12 was the best catalyst in
the opening of cis-stilbene oxide, its ability to promote the cleavage
of cyclooctene epoxide with SiCl4 was also examined. The related
chlorohydrin was obtained in 52% yield and 40% ee after 20 h at
ꢀ20 ꢁC.
4.2. Synthesis of the pyridine ligands
4.2.1. 2-Bis[(5R,5R)-5,7-methano-7,7-dimethyl-5,6,7,8-
tetrahydroquinolin-2-yl]propane 1
A solution of 3,3-dimethylpentan-2,4-dione (1.410 g, 11.0 mmol)
in anhydrous THF (6 ml) was added dropwise at a cooled (ꢀ78 ꢁC)
solution of lithium diisopropylamide (22.0 mmol) in anhydrous
THF (44 ml). The resulting solution was stirred at ꢀ78 ꢁC for 2 h and
then a solution of (ꢀ)-pinocarvone 6 (0.71 g, 0.01 mol) in THF (3 ml)
was added dropwise at ꢀ78 ꢁC. After 15 min at ꢀ78 ꢁC, the solution
was allowed to reach slowly room temperature (overnight) and
then poured into a mixture of ammonium acetate (8.5 g, 0.11 mol)
and acetic acid (33 ml). The flask was connected with a distillation
head and the THF was distilled off over a 3 h period and then the
mixture was heated at 120 ꢁC for 3 h. Most part of the acetic acid
was removed under reduced pressure and the residue was taken up
with H2O (500 ml) and extracted with ethyl ether (3ꢂ50 ml). The
organic phase was separated and extracted with 10% HCl
(3ꢂ20 ml). The acid phase was basified with 10% NaOH solution and
then extracted with ethyl ether (3ꢂ50 ml). The organic phase was
dried on anhydrous Na2SO4, the solvent was evaporated and the
3. Conclusion
In conclusion, a successful approach to the synthesis of enan-
tiomerically pure C2-symmetric dipyridylmethane ligands is de-
scribed. Full experimental details for their preparation and that of
the related N,N0-dioxides are reported. A procedure for the syn-
thesis of a few new enantiomerically pure C2-symmetric pyridine
N-oxides and the preparation of four pyridine N-oxides with oxy-
gen and nitrogen atoms as further coordinating elements in the
heterocycle framework are also described. All compounds were
prepared from naturally occurring monoterpenes.
These new compounds have been assessed as organocatalysts in
two different reactions involving trichlorosilyl compounds. In the
allylation of benzaldehyde with allyltrichlorosilane the corre-
sponding homoallylic alcohol has been obtained in modest to good
yields and up to 85% ee. In the ring opening of cis-stilbene oxide by
addition of tetrachlorosilane at ꢀ78 ꢁC, the corresponding chloro-
hydrin has been obtained in generally very high yield and enan-
tioselectivity up to 70%. It has been demonstrated that in both
reactions, N,N0-dioxide derivatives act, without a doubt, better than
the corresponding mono N-oxide or other prepared pyridine N-
oxide derivatives.
residue was purified by flash chromatography (petroleum ether/
20
ethyl acetate¼98/2) to give 1: 1.08 g (28%); mp 161 ꢁC; [
a
]
D
þ63.2
(c 1.1, CHCl3); 1H NMR:
d
7.04 (d, 2H, J¼7.8 Hz), 6.73 (d, 2H,
J¼7.8 Hz), 3.07 (d, 4H, J¼2.7 Hz), 2.72–2.60 (m, 4H), 2.40–2.30 (m,
2H), 1.77 (s, 6H), 1.38 (s, 6H), 1.27 (d, 2H, J¼8.8 Hz), 0.63 (s, 6H). 13
C
NMR:
d 165.1, 155.1, 138.1, 132.7, 117.7, 47.4, 46.0, 40.3, 39.4, 36.6,
31.9, 28.9, 26.0, 21.3. Anal. Calcd for C27H34N2: C, 83.89; H, 8.87; N,
7.75. Found: C, 83.99; H, 8.84; N, 7.77.
4.2.2. 2-Bis[(5R,7R,8S)-7,8-methano-5,9,9-trimethyl-5,6,7,8-
tetrahydroquinolin-2-yl]propane 2
Following the above procedure using (1R,4R,6S)-4,7,7-tri-
methyl-3-methylenebicyclo[4.1.0]heptan-2-one, compound 2 was
4. Experimental
obtained and purified by flash chromatography (petroleum ether/
ꢀ26.5 (c 0.61, CHCl3); 1H
20
ethyl acetate¼8/2) oil; 0.45 (8%); [
a
]
D
4.1. General methods
NMR:
d
7.26 (d, 2H, J¼6 Hz), 6.78 (d, 2H, J¼6 Hz), 2.92–2.81 (m, 2H),
2.21–2.13 (m, 2H), 1.80 (d, 2H, J¼6.3 Hz), 1.77 (s, 6H), 1.36–1.22 (m,
TLC was performed on Merck silica gel 60 TLC plates F254 and
visualized using UV or phosphomolibdic acid. Flash chromatogra-
phy was carried out on silica gel (230–400 mesh).
4H),1.23 (s, 6H),1.19 (d, 6H, J¼5.4 Hz), 0.62 (s, 6H). 13C NMR:
d 164.7,
155.4, 134.8, 131.3, 118.4, 47.2, 32.3, 30.3, 28.7, 28.1, 27.0, 23.7, 23.0,
18.1, 16.3. Anal. Calcd for C29H38N2: C, 84.01; H, 9.24; N, 6.76. Found:
C, 84.00; H, 9.26; N, 6.75.
All reagents and solvents were purchased from Aldrich and used
as-received. Low boiling petroleum ether was the fraction collected
between 40 and 60 ꢁC. THF was distilled from sodium-benzophe-
none ketyl and degassed thoroughly with dry nitrogen directly be-
fore use. Melting points were determined on a Bu¨chi 510 capillary
apparatus and are uncorrected. The NMR spectra were obtained
with a Varian VXR-300 spectrometer at 300 for 1H and 75.4 MHz for
13C. Chemical shifts are reported in parts per million downfield from
internal Me4Si in CDCl3. Optical rotations were measured with
a Perkin–Elmer 241 polarimeter in a 1 dm tube. Elemental analyses
were performed on a Perkin–Elmer 240B analyser.
4.2.3. 2-Bis[(5R,7R,8S)-5,7-methano-6,6,8-trimethyl-5,6,7,8-
tetrahydroquinolin-2-yl]propane 3
Following the above procedure using (1R,2S,5R)-2,6,6-tri-
methyl-4-methylenebicyclo[3.1.1]heptan-3-one, compound 3 was
obtained and purified by flash chromatography (petroleum ether/
20
ethyl acetate¼98/2) oil; 0.80 g (10%); [
a]
ꢀ11.9 (c 1.2, CHCl3); 1H
D
NMR:
d
7.00 (d, 2H, J¼7.8 Hz), 6.73 (d, 2H, J¼7.8 Hz), 3.18–3.08 (m,
2H), 2.70–2.63 (m, 2H), 2.54–2.44 (m, 2H), 2.14–2.07 (m, 2H), 1.79
(s, 6H), 1.39 (s, 6H), 1.33 (d, 6H, J¼7.2 Hz), 1.27 (d, 2H, J¼9.6 Hz), 0.64
3,3-Dimethylpentane-2,4-dione 5 was prepared from pentane-
(s, 6H). 13C NMR:
d 165.0, 158.8, 137.9, 132.3, 117.7, 47.6, 46.8, 46.7,
2,4-dione.22 (ꢀ)-Pinocarvone 6 was obtained by oxidation of
41.3, 38.8, 28.7, 26.3, 20.9,18.2. Anal. Calcd for C29H38N2: C, 84.01; H,
9.24; N, 6.76. Found: C, 84.12; H, 9.21; N, 6.73.
(þ)-
a
-pinene (98% pure, 91% ee by GLC, Aldrich).8 (1R,4S)-1,7,7-

7580
G. Chelucci et al. / Tetrahedron 64 (2008) 7574–7582
4.2.4. 2-Bis[(6R,8R)-6,8-methano-7,7-dimethyl-5,6,7,8-
tetrahydroquinolin-2-yl]propane 4
Following the above procedure using (1R,5R)-6,6-dimethyl-3-
methylenebicyclo[3.1.1]heptan-2-one, compound 4 was obtained
1H), 2.83 (t, 1H), 2.68–2.61 (m, 1H), 2.56–2.51 (m, 1H), 1.58 (d, 1H,
J¼9.9 Hz), 1.44 (s, 3H), 0.70 (s,3H). 13C NMR:
d 158.1, 154.9, 139.3,
154.9, 139.3, 139.1, 133.5, 126.4, 128.3, 126.6, 118.6, 74.0, 46.8, 46.2,
40.3, 33.9, 26.6, 23.0. Anal. Calcd for C18H19NO: C, 81.47; H, 7.22; N,
5.28. Found: C, 81.53; H, 7.21; N, 5.24.
after flash chromatography (petroleum ether/ethyl acetate¼98/2),
20
0.89 (21%), mp 136–137 ꢁC; [
d
a
]
ꢀ44.4 (c 1.2, CHCl3); 1H NMR:
D
7.23 (d, 2H, J¼7.8 Hz), 6.80 (d, 2H, J¼7.8 Hz), 2.96 (t, 2H, J¼5.7 Hz),
4.2.9. (5S,7R,8R)-2-Phenyl-8-methoxy-5,7-methano-6,6-dimethyl-
5,6,7,8-tetrahydroquinoline 29
Sodium hydride (0.022 g, 0.91 mmol) was cautiously added to
a cooled (0 ꢁC) solution of (5S,7R,8R)-2-phenyl-8-hydroxy-5,7-
2.87 (d, 4H, J¼2.4 Hz), 2.72–2.62 (m, 2H), 2.32–2.24 (m, 2H), 1.75 (s,
6H), 1.40 (s, 6H), 1.28 (d, 2H, J¼6.9 Hz), 0.65 (s, 6H). 13C NMR:
d
164.6, 163.7, 134.8, 126.4, 118.8, 50.3, 47.3, 40.2, 39.0, 30.9, 28.8,
26.0, 21.1. Anal. Calcd for C27H34N2: C, 83.89; H, 8.87; N, 7.75. Found:
C, 83.75; H, 8.85; N, 7.73.
methano-6,6-dimethyl-5,6,7,8-tetrahydroquinoline
(0.133 g,
0.5 mmol) in THF (12 ml). After 1 h was added CH3I (0.063 ml,
0.143 g, 1.0 mmol) at 0 ꢁC and the resulting mixture was stirred at
0 ꢁC for 2 h. Water was added and the organic phase was separated
and the aqueous was extracted with Et2O (3ꢂ10 ml). The combined
organic phase was dried on anhydrous Na2SO4, the solvent was
4.2.5. (2R,4R,5R,7R)-Bis(2,4,5,7-methano)-3,3,6,6-tetramethyl-
1,2,3,4,5,6,7,8-octahydroacridine 22
A solution of (þ)-nopinone (1,38 g, 0.01 mol) in anhydrous THF
(3 ml) was added dropwise at a cooled (ꢀ40 ꢁC) solution of lithium
diisopropylamide (10.0 mmol) in anhydrous THF (50 ml). The
resulting solution was stirred at ꢀ40 ꢁC for 2 h and then a solution
of (1R,5R)-6,6-dimethyl-3-methylenebicyclo[3.1.1]heptan-2-one 9
(0.01 mol) in THF (3 ml) was added dropwise at ꢀ40 ꢁC. After
15 min at ꢀ40 ꢁC, the solution was allowed to reach slowly room
temperature (overnight) and then poured into a mixture of am-
monium acetate (7.71 g, 0.10 mol) and acetic acid (30 ml). The flask
was connected with a distillation head and THF was distilled off
over a 3 h period and then the mixture was heated at 120 ꢁC for 3 h.
Most part of the acetic acid was removed under reduced pressure
and the residue was taken up with H2O (500 ml) and extracted with
ethyl ether (3ꢂ50 ml). The organic phase was separated and
extracted with 10% HCl (3ꢂ20 ml). The acid phase was basified with
10% NaOH solution and then extracted with ethyl ether (3ꢂ50 ml).
The organic phase was dried on anhydrous Na2SO4, the solvent was
evaporated and the residue was purified by flash chromatography
evaporated and the residue was purified by flash chromatography
25
(petroleum ether/ethyl acetate¼8/2) to give 29: 113 mg (93%); [
a]
D
þ96.2 (c 0.11, CHCl3); 1H NMR:
d
8.03 (d, 2H, J¼6.9 Hz), 7.51 (d, 1H,
J¼7.8 Hz) 7.48–7.33 (m, 3H), 7.30 (d, 1H, J¼7.8 Hz), 4.62 (d, 1H,
J¼3.0 Hz) 2.79–2.60 (m, 4H), 1.46 (s, 3H), 0.82 (s, 3H). 13C NMR:
d
156.70, 155.0, 139.7, 139.6, 133.5, 128.5, 128.3, 126.7, 118.4, 83.4,
59.3, 47.0, 44.8, 40.3, 34.4, 26.7, 23.2. Anal. Calcd for C19H21NO: C,
81.68; H, 7.58; N, 5.01. Found: C, 81.70; H, 9.38; N, 4.55.
4.2.10. (5S,7R,8S)-2-Phenyl-8-methoxy-5,7-methano-6,6-dimethyl-
5,6,7,8-tetrahydroquinoline 30
Starting from (5S,7R,8S)-2-phenyl-8-hydroxy-5,7-methano-6,6-
dimethyl-5,6,7,8-tetrahydroquinoline and following the above
procedure, the tetrahydroquinoline 30 was obtained: 132 mg
25
(95%); [
a
]
þ26.8 (c 0.13, CHCl3); 1H NMR:
8.02 (d, 2H, J¼7.2 Hz),
d
D
7.51 (d, 1H, J¼7.8 Hz), 7.48–7.32 (m, 3H), 7.29 (d, 1H, J¼8.1 Hz), 4.52
(d, 1H, J¼2.7 Hz), 3.84 (s, 3H), 2.77 (t, 1H, 6 Hz), 2.63–2.54 (m, 2H),
(petroleum ether/ethyl acetate¼9/1) to give 22: 0.80 g (31%); mp
1.70–1.65 (m, 1H), 1.45 (s, 3H), 0.64 (s, 3H). 13C NMR:
d 156.0, 155.0,
25
197–198 ꢁC; [
a
]
ꢀ52.7 (c 0.11, CHCl3); 1H NMR:
d
7.16 (s, 1H), 2.93–
139.7, 139.5, 128.5, 128.3, 126.7, 118.6, 80.6, 58.8, 46.5, 45.2, 44.3,
29.5, 26.5, 20.9. Anal. Calcd for C19H21NO: C, 81.68; H, 7.58; N, 5.01.
Found: C, 81.70; H, 9.38; N, 4.55.
D
2.84 (m, 6H), 2.72–2.61 (m, 2H), 2.33–2.25 (m, 2H), 1.39 (s, 6H), 1.29
(d, 2H, J¼9.6 Hz), 0.68 (s, 6H). 13C NMR:
d 161.5, 134.8, 126.9, 49.9,
40.2, 39.2, 31.0, 31.0, 26.1, 21.2. Anal. Calcd for C19H25N: C, 85.34; H,
9.42; N, 5.24. Found: C, 85.30; H, 9.44; N, 5.26.
4.3. General procedure for the preparation of N-oxides
4.2.6. (1R,3S,4R,5R,6S,8R)-Bis(1,3,6,8-methano)-2,2,4,5,7,7-
hexamethyl-1,2,3,4,5,6,7,8-octahydroacridine 25
Following the above procedure and using (1R,2S,5S)-2,6,6-tri-
methylbicyclo[3.1.1]heptan-3-one and (1R,2S,5R)-2,6,6-trimethyl-
3-Chloroperbenzoic acid (0.61 mmol) was added portion-wise
to a solution of the proper pyridine derivative (0.47 mmol) in
CH2Cl2 (10 ml). After 24 h stirring at room temperature, the re-
action mixture was washed successively with saturated NaHCO3
(3ꢂ8 ml) and brine (10 ml). The aqueous phase was extracted with
CH2Cl2 (3ꢂ10 ml) and the combined organic phase was dried on
anhydrous Na2SO4, the solvent was evaporated and the residue was
purified by flash chromatography (ethyl acetate) to give N-oxides.
4-methylenebicyclo[3.1.1]heptan-3-one, the tetrahydroquinoline
25
25 was obtained: 140 mg (8%); mp 85–86 ꢁC; [
a]
þ13.5 (c 0.72,
D
CHCl3); 1H NMR:
d 6.66 (s, 1H), 3.13–3.03 (m, 2H), 2.64–2.58 (t, 2H,
J¼5.4 Hz), 2.52–2.40 (m, 2H), 2.13–2.06 (m, 2H), 1.38 (s, 6H), 1.35 (s,
6H), 1.29 (d, 2H, J¼9.6 Hz), 0.62 (s, 6H). 13C NMR:
d 157.0, 137.6,
130.0, 47.1, 46.9, 41.3, 38.3, 28.8, 26.4, 21.1, 18.5. Anal. Calcd for
4.3.1. (1S,4R,5R,8S)-Bis(1,4,5,8-methano)-4,5,11,11,12,12-
hexamethyl-1,2,3,4,5,6,7,8-octahydroacridine N-oxide 14
Compound 14 was obtained from octahydroacridine 19 and
C
21H29N: C, 85.37; H, 9.89; N, 4.74. Found: C, 85.33; H, 9.90; N, 4.77.
4.2.7. (5S,7R,8R)-2-Phenyl-8-hydroxy-5,7-methano-6,6-dimethyl-
5,6,7,8-tetrahydroquinoline 27
purified by flash chromatography using ethyl acetate: 126 mg
25
(86%); mp 190–191 ꢁC; [
a
]
D
ꢀ2.9 (c 0.69, MeOH); 1H NMR:
d 0.67 (s,
20
Mp 122–123 ꢁC; [
a
]
D
þ5.15 (c 0.93, CHCl3); 1H NMR:
d
8.00 (d,
6H), 0.91 (s, 6H), 1.09 (ddd, 2H, J¼12.7, 9.0, 3.9 Hz), 1.55 (ddd, 2H,
J¼12.9, 9.0, 3.9 Hz), 1.66 (s, 6H), 1.83 (ddd, 2H, J¼12.9, 9.8, 3.9 Hz),
2.08 (ddt, 2H, J¼12.7, 9.8, 3.9 Hz), 2.76 (d, 2H, J¼3.9 Hz), 6.89 (s, 1H).
Anal. Calcd for C21H29NO: C, 80.98; H, 9.38; N, 4.50. Found: C, 80.96;
H, 9.40; N, 4.54.
2H, J¼7.2 Hz), 7.54–7.34 (m, 5H), 5.03 (d, 1H, J¼3.3 Hz), 3.19 (broad,
1H), 2.83 (t, 1H), 2.68–2.61 (m, 1H), 2.56–2.51 (m, 1H), 1.58 (d, 1H,
J¼9.9 Hz), 1.44 (s, 3H), 0.76 (s, 3H). 13C NMR:
d 157.2, 154.9, 139.6,
139.2, 133.6, 128.4, 128.3, 126.6, 118.8, 71.3, 46.5, 45.5, 44.7, 29.5,
26.4, 20.8. Anal. Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28.
Found: C, 81.55; H, 7.24; N, 5.27.
4.3.2. (2R,4R,5R,7R)-Bis(2,4,5,7-methano)-3,3,6,6-tetramethyl-
1,2,3,4,5,6,7,8-octahydroacridine N-oxide 15
4.2.8. (5S,7R,8S)-2-Phenyl-8-hydroxy-5,7-methano-6,6-dimethyl-
Compound 15 was obtained from octahydroacridine 22 and
5,6,7,8-tetrahydroquinoline 28
purified by flash chromatography using ethyl acetate: 65 mg (89%);
20
25
Mp 109–110 ꢁC; [
a
]
D
þ135.9 (c 0.72, CHCl3); 1H NMR:
d
8.00 (d,
mp 234–235 ꢁC; [
a]
ꢀ14.4 (c 0.62, CHCl3); 1H NMR:
d 6.84 (s, 1H),
D
2H, J¼7.2 Hz), 7.54–7.34 (m, 5H), 4.96 (d, 1H, J¼3.3 Hz), 3.19 (broad,
4.02 (t, 2H, J¼5.4 Hz), 2.91 (s, 4H), 2.76–2.65 (m, 2H), 2.31–2.24 (m,

G. Chelucci et al. / Tetrahedron 64 (2008) 7574–7582
7581
2H),1.44 (s, 6H),1.25 (d, 2H, J¼9.9 Hz), 0.72 (s, 6H).13C NMR:
d
152.4,
154.4, 135.1, 131.0, 125.9, 124.5, 120.7, 116.1, 50.0, 45.3, 40.2, 40.0,
39.7, 39.0, 38.9, 31.2, 30.9, 30.6, 30.2, 28.1, 26.0, 25.7, 25.3, 21.0, 21.0.
Anal. Calcd for C27H34N2O: C, 80.55; H, 8.51; N, 6.96. Found: C,
80.50; H, 8.52; N, 6.98.
129.4, 125.4, 40.1, 39.8, 39.1, 31.3, 30.4, 25.8, 21.3. Anal. Calcd for
C
19H25NO: C, 80.52; H, 8.89; N, 4.94. Found: C, 80.55; H, 8.84; N, 4.95.
4.3.3. (1R,3S,4R,5R,6S,8R)-Bis(1,3,6,8-methano)-2,2,4,5,7,7-
hexamethyl-1,2,3,4,5,6,7,8-octahydroacridine N-oxide 16
Compound 16 was obtained from octahydroacridine 25 and
4.4. General procedure for the preparation of N,N0-dioxides
purified by flash chromatography using ethyl acetate: 142 mg
3-Chloroperbenzoic acid (0.13 mmol) was added portion-wise
to a solution of the proper dipyridylmethane (0.5 mmol) in CH2Cl2
(10 ml). After 24 h stirring at room temperature, the reaction
mixture was washed successively with saturated NaHCO3 (3ꢂ8 ml)
and brine (10 ml). The aqueous phase was extracted with CH2Cl2
(3ꢂ10 ml) and the combined organic phase was dried on anhydrous
Na2SO4, the solvent was evaporated and the residue was purified by
flash chromatography (ethyl acetate) to give N,N0-dioxides.
25
(97%); foam solid; [
a
]
D
þ25.9 (c 0.14, CHCl3); 1H NMR:
d 6.51 (s,1H),
3.35–3.38 (dd, 2H, J¼6.6, 3.0 Hz), 2.65–2.70 (t, 2H, J¼5.7 Hz), 2.47–
2.54 (m, 2H), 2.11–2.18 (m, 2H), 1.53 (d, 6H, J¼6.6 Hz), 1.44 (s, 2H),
1.39 (s, 6H), 0.61 (s, 6H). 13C NMR:
d 147.0, 141.7, 121.6, 47.6, 46.5,
41.5, 34.5, 28.2, 25.8, 20.5, 15.7. Anal. Calcd for C21H29NO: C, 80.98;
H, 9.38; N, 4.50. Found: C, 80.92; H, 9.39; N, 4.56.
4.3.4. (5S,7R,8S)-2-Phenyl-8-methoxy-5,7-methano-6,6-dimethyl-
5,6,7,8-tetrahydroquinoline N-oxide 31
4.4.1. 2-Bis[(5S,7S)-5,7-methano-6,6-dimethyl-5,6,7,8-
tetrahydroquinolin-2-yl]propane N,N0-dioxide 10
Compound 31 was obtained from octahydroacridine 29 and
purified by flash chromatography using petroleum ether/ethyl
Compound 10 was obtained starting from 1: 0.165 g (79%); mp
25
25
acetate¼4/6: 77 mg (55%); foam solid; [
1H NMR:
1H, J¼7.8 Hz), 4.68 (d, 1H, J¼2.4 Hz), 3.71 (s, 3H), 2.81 (t, 1H, J¼5.7),
2.64–2.54 (m, 2H), 1.47 (s, 3H), 1.80–1.72 (m, 1H), 0.67 (s, 3H). 13
NMR: 148.1, 145.2, 144.3, 133.2, 129.5, 128.9, 120.0, 125.5, 122.5,
76.6, 59.0, 46.3, 45.8, 43.5, 29.4, 26.2, 20.7. Anal. Calcd for
19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C, 77.25; H, 7.18; N, 4.74.
a
]
þ161.3 (c 0.23, CHCl3);
202–205 ꢁC; [
a]
ꢀ7.28 (c 0.11, CHCl3); 1H NMR:
d 7.31 (d, 2H,
D
D
d
7.78 (dd, 2H, J¼8.1, 1.8 Hz), 7.24 (d, 1H, J¼7.8 Hz), 6.91 (d,
J¼8.1 Hz), 6.89 (d, 2H, J¼8.1 Hz), 2.89 (dq, 4H, J¼18.9, 2.7 Hz), 2.73
(t, 2H, J¼5.4 Hz), 2.63–2.53 (m, 2H), 2.36–2.28 (m, 2H), 1.89 (s, 6H),
C
1.37 (s, 6H), 1.36–1.18 (m, 2H), 0.62 (s, 6H). 13C NMR:
d 153.9, 145.2,
d
141.6, 123.2, 119.5, 45.6, 41.9, 39.3, 39.2, 31.1, 30.7, 25.7, 24.4, 20.8.
Anal. Calcd for C27H34N2O2: C, 77.48; H, 8.19; N, 6.69. Found: C,
77.51; H, 8.16; N, 6.66.
C
4.3.5. (5S,7R,8R)-2-Phenyl-8-methoxy-5,7-methano-6,6-dimethyl-
5,6,7,8-tetrahydroquinoline N-oxide 32
4.4.2. 2-Bis[(5R,7R,8S)-7,8-methano-5,9,9-trimethyl-5,6,7,8-
tetrahydroquinolin-2-yl]propane N,N0-dioxide 11
Compound 32 was obtained from octahydroacridine 30 and
purified by flash chromatography using petroleum/ethyl
Compound 11 was obtained starting from 2: 53.5 mg (24%); mp
25
94–97 ꢁC; [
a
]
þ151.2 (c 0.36, CHCl3); 1H NMR:
d 7.34 (d, 2H,
D
25
acetate¼4/6: 83 mg (60%); mp 167–169 ꢁC; [
a
]
þ98.5 (c 0.61,
J¼8.4 Hz), 7.11 (d, 2H, J¼8.4 Hz), 2.89–2.74 (m, 2H), 2.28–2.08 (m,
4H), 1.80 (s, 6H), 1.39–1.26 (m, 4H), 1.25 (d, 6H, J¼6.6 Hz), 1.22 (s,
D
CHCl3); 1H NMR:
d
7.78 (dd, 2H, J¼8.1,1.8 Hz), 7.50–7.38 (m, 3H),
7.23 (d, 1H, J¼7.8 Hz), 6.92 (d, 1H, J¼7.8 Hz), 4.75 (d, 1H, J¼3 Hz),
3.69 (s, 3H), 2.80–2.65 (m, 3H), 1.47 (s, 3H), 1.33 (d, 1H, J¼8.7 Hz),
6H), 0.62 (s, 6H). 13C NMR:
d 153.8, 147.5, 138.4, 121.7, 118.9, 89.0,
41.8, 32.2, 29.8, 27.5, 24.7, 24.0, 23.2, 22.4, 18.0, 15.1. Anal. Calcd for
C29H38N2O2: C, 77.99; H, 8.58; N, 6.27. Found: C, 77.82; H, 8.57; N,
1.80–1.72 (m, 1H), 0.95 (s, 3H). 13C NMR:
d
144.2, 145.7, 144.7, 133.3,
129.6,128.9, 128.0, 125.3,122.3, 79.4, 59.1, 47.1, 44.0, 40.6, 34.5, 26.7,
23.4. Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C,
77.25; H, 7.18; N, 4.74.
6.25.
4.4.3. 2-Bis[(5R,7R,8S)-5,7-methano-6,6,8-trimethyl-
tetrahydroquinolin-2-yl]propane N,N0-dioxide 12
4.3.6. 2-Bis[(5S,7S)-5,7-methano-6,6-dimethyl-5,6,7,8-
tetrahydroquinolin-2-yl]propane N-oxide 33
The above procedure was followed starting from 1, but using
a large excess of 1 (5 equiv) with respect to MCPBA was used. The
Compound 12 was obtained starting from 3: 0.134 g (60%); mp
25
185–188 ꢁC; [
a
]
D
þ91.9 (c 0.43, CHCl3); 1H NMR:
d 7.23 (d, 2H,
J¼8.1 Hz), 6.86 (d, 2H, J¼8.1 Hz), 3.23–3.09 (m, 2H), 2.71 (t, 2H,
J¼5.7), 2.52–2.40 (m, 2H), 2.10–2.01 (m, 2H), 1.84 (s, 6H), 1.41 (m,
unconverted starting material 1 and 33 were recovered by flash
2H),1.37 (s, 6H),1.22 (d, 6H, J¼6.6 Hz), 0.58 (s, 6H). 13C NMR:
d 155.1,
25
chromatography: 130 mg (69%); foam solid; [
a]
ꢀ37.5 (c 0.52,
148.2, 141.1, 123.1, 118.5, 47.1, 46.4, 41.8, 41.4, 34.3, 28.1, 25.8, 25.0,
20.4, 14.1. Anal. Calcd for C29H38N2O2: C, 77.99; H, 8.58; N, 6.27.
Found: C, 77.98; H, 8.58; N, 6.28.
D
CHCl3); 1H NMR:
d
7.28 (d, 1H, J¼7.5 Hz), 7.09 (d, 1H, J¼7.8 Hz), 6.88
(d,1H, J¼7.5 Hz), 6.86 (d,1H, J¼7.8 Hz), 3.16–2.56 (m, 6H), 2.39–2.30
(m, 2H), 2.30–2.22 (m, 2H), 1.86 (s, 3H), 1.77 (s, 3H), 1.38 (s, 3H), 1.35
(s, 3H), 1.34–1.18 (m, 2H), 0.63 (s, 3H), 0.59 (s, 3H). 13C NMR:
d
163.2,
4.4.4. 2-Bis[(6R,8R)-6,8-methano-7,7-dimethyl-5,6,7,8-
tetrahydroquinolin-2-yl]propane N,N0-dioxide 13
154.9, 154.8, 146.5, 142.6, 137.6, 132.9, 121.8, 120.7, 115.2, 65.7, 45.9,
45.7, 45.2, 39.4, 39.2, 39.1, 36.4, 31.7, 31.2, 30.8, 27.6, 25.9, 25.7, 25.5,
21.1, 20.8. Anal. Calcd for C27H34N2O: C, 80.55; H, 8.51; N, 6.96.
Found: C, 80.50; H, 8.53; N, 6.97.
Compound 13 was obtained starting from 4: 159 mg (76%); mp
25
82–84 ꢁC; [
a
]
ꢀ35.9 (c 0.22, CHCl3); 1H NMR:
d 7.33 (d, 2H,
D
J¼8.1 Hz), 7.06 (d, 2H, J¼8.1 Hz), 3.83 (t, 2H, J¼2.7 Hz), 2.90 (dq, 4H,
J¼17.1, 2.7 Hz), 2.66–2.54 (m, 2H), 2.27–2.18 (m, 2H), 1.88 (s, 6H),
4.3.7. 2-Bis[(6R,8R)-6,8-methano-7,7-dimethyl-5,6,7,8-
tetrahydroquinolin-2-yl]propane N-oxide 34
The above procedure was followed starting from 9, but using
a large excess of 4 (5 equiv) with respect to MCPBA was used. The
1.36 (s, 6H), 1.80 (s, 2H), 0.63 (s, 6H). 13C NMR:
d 158.1, 154.9, 153.5,
130.0, 125.7, 120.0, 42.5, 40.1, 39.9, 39.0, 31.2, 29.9, 25.7, 24.3, 21.0.
Anal. Calcd for C27H34N2O2: C, 77.48; H, 8.19; N, 6.69. Found: C,
77.50; H, 8.15; N, 6.68.
unconverted starting material 4 and 34 were recovered by flash
25
chromatography: 149 mg (79%); mp 85–90 ꢁC; [
a
]
D
þ35.7 (c 0.83,
4.5. General procedure for the allylation reaction
CHCl3); 1H NMR:
d
7.31 (d, 1H, J¼3.9 Hz), 7.28 (d, 1H, J¼3.3 Hz), 7.05
(d, 1H, J¼8.1 Hz), 6.98 (d, 1H, J¼7.8 Hz), 3.90 (t, 1H, J¼5.4 Hz), 2.94
(s, 2H), 2.85 (s, 2H), 2.73 (t, 1H, J¼11.1 Hz), 2.61–2.52 (m, 2H), 2.28–
2.21 (m, 2H), 1.84 (s, 3H), 1.72 (s, 3H), 1.37 (s, 3H), 1.33 (s, 3H), 1.18–
To a stirred solution of catalyst (0.03 mmol) in acetonitrile
(2 ml) kept under nitrogen, an aldehyde (0.3 mmol) and diisopro-
pylethylamine (0.154 ml, 0.9 mmol) were added in this order. The
mixture was then cooled to 0 ꢁC and allyl(trichloro)silane
1.31 (m, 2H), 0.63 (s, 3H), 0.58 (s, 3H). 13C NMR:
d 164.4, 161.8, 156.1,

7582
G. Chelucci et al. / Tetrahedron 64 (2008) 7574–7582
(0.054 ml, 0.36 mmol) was added dropwise by means of a syringe.
After 48 h stirring at 0 ꢁC the reaction was quenched by the addi-
tion of a saturated aqueous solution of NaHCO3 (1 ml). The mixture
was allowed to warm-up to room temperature and water (2 ml)
and AcOEt (5 ml) were added. The organic phase was separated and
dried over Na2SO4, filtered, and concentrated under vacuum at
room temperature to afford the crude products. These were puri-
fied by flash chromatography with different hexanes/AcOEt mix-
tures as eluants. Yield and ee are indicated in the tables.
hexanes/AcOEt mixtures as eluants. Yield and ee are indicated in
the tables.
4.6.1. Chlorohydrin 44
This product was purified with a hexanes/AcOEt 90:10 mixture
as eluant. The enantiomeric excess was determined by HPLC on
a Chiralpak AD column (hexane/isopropanol 97:3; flow rate 0.8 ml/
min;
l
220 nm): tminor¼24.8 min, tmajor¼26.1 min.
4.6.2. Chlorohydrin 46
4.5.1. 1-Phenyl-3-buten-1-ol
This product was purified with a hexanes/AcOEt 90:10 mixture
as eluant. The enantiomeric excess was determined on the tri-
fluoroacetate derivative by GC on chiral stationary phase (Agilent
HP-chiral) tminor¼31.0 min, tmajor¼32.2 min.
This product was purified with a hexanes/AcOEt 90:10 mixture
as eluant. The enantiomeric excess was determined by HPLC on
a Chiracel OD column (hexane/isopropanol 95:5; flow rate 0.8 ml/
min;
l
220 nm): tR¼10.4 min, tS¼11.3 min.
Acknowledgements
4.5.2. 1-(4-Methylphenyl)-3-buten-1-ol
This product was purified with a hexanes/AcOEt 90:10 mixture
as eluant. The enantiomeric excess was determined by HPLC on
a Chiracel OD column (hexane/isopropanol 99:1; flow rate 0.8 ml/
Financial support from MIUR (PRIN 2005035123, Regio- and
enantioselective reactions mediated by transition metal catalysts
for innovative processes in fine chemicals synthesis) and from the
University of Sassari is gratefully acknowledged by G.C. Financial
support from MIUR (Rome) within the national project ‘Nuovi
metodi catalitici stereoselettivi e sintesi stereoselettiva di molecole
funzionali’ is gratefully acknowledged by M.B.
min;
l
220 nm): tR¼26.3 min, tS¼25.0 min.
4.5.3. 1-(4-Nitrophenyl)-3-buten-1-ol
This product was purified with a hexanes/AcOEt 80:20 mixture
as eluant. The enantiomeric excess was determined by HPLC on
a Chiralpak AD column (hexane/isopropanol 97:3; flow rate 0.8 ml/
References and notes
min;
l
220 nm): tR¼31.9 min, tS¼34.7 min.
1. For a general overview on organic catalysis, see: (a) Berkessel, A.; Groger, H.
Asymmetric Organic Catalysis; Wiley VCH: Weinheim, 2005; For recent reviews
on organocatalysis, see: (b) Enantioselective Organocatalysis. Reactions and Ex-
perimental Procedures; Dalko, P. I., Ed.; Wiley VCH: Weinheim, 2007; (c) Sym-
posium-in-print on Orgnocatalysis Tetrahedron 2006, 62 issues 2 and 3; (d) List,
B. Chem. Commun. 2006, 819; (e) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2004, 35, 5138; See also: (f) Acc. Chem. Res. 2004, 37 tematic issue 8; (g) Adv.
Synth. Catal. 2004, 346 tematic issues 8 and 9.
2. Review: Benaglia, M.; Guizzetti, S.; Pignataro, L. Coord. Chem. Rev. 2008, 252,
492.
3. Review: (a) Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. Rev. 1993, 93,
1371; (b) Furin, G. G.; Vyazankina, O. A.; Gostevsky, B. A.; Vyazankin, N. S.
Tetrahedron 1988, 44, 2675.
4.5.4. 1-(2-Thienyl)-3-buten-1-ol
This product was purified with DCM as eluant. The enantiomeric
excess was determined by HPLC on a Chiracel OD column (hexane/
isopropanol 90:10; flow rate 0.8 ml/min;
tS¼7.7 min.
l
230 nm): tR¼7.1 min,
4.5.5. 1-(3-Thienyl)-3-buten-1-ol
This product was purified with a hexanes/AcOEt 60:40 mixture
as eluant. The enantiomeric excess was determined by HPLC on
a Chiracel OD column (hexane/isopropanol 95:5; flow rate 0.8 ml/
4. Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560.
ˇ
´
5. Reviews: (a) Malkov, A. V.; Kocovsky, P. Eur. J. Org. Chem. 2007, 29; (b) Chelucci,
G.; Marineddu, G.; Pinna, G. A. Tetrahedron: Asymmetry 2004, 15, 1373.
6. (a) Chelucci, G.; Loriga, G.; Murineddu, G.; Pinna, G. A. Tetrahedron Lett. 2002,
43, 8599; (b) Chelucci, G.; Chessa, S.; Orru` , G. J. Mol. Catal. A 2004, 220, 145.
7. Chelucci, G.; Belmonte, N.; Benaglia, M.; Pignataro, L. Tetrahedron Lett. 2007, 48,
4037.
min;
l
220 nm): tR¼11.1 min, tS¼14.1 min.
4.5.6. (E)-1-Phenyl-1,5-hexadien-3-ol
This product was purified with a hexanes/AcOEt 90:10 mixture
as eluant. The ee was determined by HPLC on a Chiracel OD column
8. Mihelich, E. D.; Eickhoff, D. J. J. Org. Chem. 1983, 48, 4135.
9. Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.; Teply, F.; Meghani, P.;
Kocovsky, P. J. Org. Chem. 2003, 68, 4727.
10. Bessie`re-Chre´tien, Y.; Grison, C. Bull. Soc. Chim. Fr. 1970, 3103.
11. Gianini, M.; von Zelewsky, A. Synthesis 1996, 702.
(hexane/isopropanol 99:1; flow rate 0.8 ml/min;
l 220 nm):
tR¼10.3 min, tS¼16.1 min.
12. Kotsuki, H.; Sakai, H.; Jun, J.-G.; Shiro, M. Heterocycles 2000, 52, 661.
13. Kiyooka, S.-I.; Yamashita, T.; Tashiro, J.; Takano, K.; Uchio, Y. Tetrahedron Lett.
1986, 27, 5629.
4.5.7. 1-Phenyl-5-hexen-3-ol
This product was purified with a hexanes/AcOEt 80:20 mixture
as eluant. The enantiomeric excess was determined by HPLC on
a Chiracel OD column (hexane/isopropanol 95:5; flow rate 0.8 ml/
14. Collomb, P.; von Zelewsky, A. Tetrahedron: Asymmetry 1995, 6, 2903.
15. For a general review on the catalytic asymmetric allylation, see: Denmark, S. E.;
Fu, J. Chem. Rev. 2003, 103, 2763; For general reviews on chiral Lewis base-pro-
moted asymmetric allylation of aldehydes with allyltrichorosilanes, see: (a) Or-
ito, Y.; Nakajima, M. Synthesis 2006, 1391; (b) Oestreich, M.; Rendler, S. Synthesis
2005, 1727; (c) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
16. Denmark, S. E.; Barsanti, P. A.; Beutner, G. L.; Wilson, T. W. Adv. Synth. Catal.
2007, 349, 567 and references cited there.
min;
l
210 nm): tR¼10.7 min, tS¼15.8 min.
4.6. General procedure for the epoxide opening reaction
To a stirred solution of catalyst (0.03 mmol) in CH2Cl2 (2 ml)
kept under nitrogen, stilbene epoxide or cyclooctene epoxide
(0.3 mmol) and diisopropylethylamine (0.154 ml, 0.9 mmol) were
added in this order. The mixture was then cooled to ꢀ78 ꢁC and
tetrachlorosilane (0.3 mmol) was added dropwise by means of
a syringe. After 12 h stirring at ꢀ78 ꢁC the reaction was quenched
by the addition of a saturated aqueous solution of NaHCO3 (1 ml).
The mixture was allowed to warm-up to room temperature and
water (2 ml) and AcOEt (5 ml) were added. The organic phase was
separated and dried over Na2SO4, filtered, and concentrated under
vacuum at room temperature to afford the crude chlorohydrin that
was finally purified by flash chromatography with different
17. Malkov, A. V.; Bell, M.; Orsini, M.; Pernazza, D.; Massa, A.; Herrmann, P.; Me-
ghani, P.; Kocovsky, P. J. Org. Chem. 2003, 68, 9659.
18. Malkov, A. V.; Bell, M.; Vassieu, M.; Bugatti, V.; Kocovsky, P. J. Mol. Catal. A 2003,
196, 179.
19. Ligand 37: Nakajima, M.; Sasaki, Y.; Shiro, S.; Hashimoto, S. Tetrahedron:
Asymmetry 1997, 8, 341; Ligand 38: Fuji, M.; Honda, A. J. Heterocycl. Chem. 1992,
29, 931; Ligand 39: Malkov, A. V.; Dufkova´, L.; Farrugia, L.; Kocovsky, P. Angew.
Chem., Int. Ed. 2003, 42, 3674; Ligands 40 and 41: Malkov, A. V.; Orsini, M.;
Pernazza, D.; Muir, K. W.; Langer, V.; Meghani, P.; Kocovsky, P. Org. Lett. 2002,
1047; Ligand 42: Tao, B.; Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 353.
20. Tokuoka, E.; Totani, S.; Matsunaga, H.; Ishizuka, T.; Hashimoto, S.; Nakajima, M.
Tetrahedron: Asymmetry 2005, 16, 2391.
21. Malkov, A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.; Larger, V.; Meghani, P.;
Kocovsky, P. Org. Lett. 2005, 7, 3219.
22. Adam, W.; Heidenfelder, T.; Sahin, C. Synthesis 1995, 1163.