New pinene-derived pyridines as bidentate chiral ligands

Article abstract of DOI:10.1016/j.tet.2008.02.045

A synthesis of new bidentate pyridines 8a-d, 9, and 10 has been developed, starting from triflate 14, readily available from β-pinene 11. A copper complex of the pyridine-oxazoline ligands 8a has been found to catalyze asymmetric allylic oxidation of cyclic olefins 36a-c with good conversion rates and acceptable enantioselectivity (≤67% ee). The imidazolium salt 10 has been identified as a precursor of the corresponding N,N′-unsymmetrical N-heterocyclic carbene ligand, whose complex with palladium catalyzed the intramolecular amide enolate α-arylation leading to oxindole 45 in excellent yield but with low enantioselectivity.

Full text of DOI:10.1016/j.tet.2008.02.045

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4011e4025
www.elsevier.com/locate/tet
New pinene-derived pyridines as bidentate chiral ligands
a,y
a,z
a,x
Andrei V. Malkov a, , Angus J.P. Stewart-Liddon , Filip Teply , Lukas Kobr ,
*
Kenneth W. Muir , David Haigh , Pavel Kocovsky
´ˇ
´
a
b
a,
*
´
ꢀ
a Department of Chemistry, WestChem, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, Scotland, UK
b Department of Medicinal Chemistry, Metabolic and Viral Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals,
Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, UK
Received 8 November 2007; received in revised form 24 January 2008; accepted 14 February 2008
Available online 7 March 2008
Dedicated to Professor Miloslav Ferles on the occasion of his 86th birthday and in recognition of his life-long contribution to pyridine chemistry
Abstract
A synthesis of new bidentate pyridines 8aed, 9, and 10 has been developed, starting from triflate 14, readily available from b-pinene 11. A
copper complex of the pyridineeoxazoline ligands 8a has been found to catalyze asymmetric allylic oxidation of cyclic olefins 36aec with good
conversion rates and acceptable enantioselectivity (ꢀ67% ee). The imidazolium salt 10 has been identified as a precursor of the corresponding
N,N0-unsymmetrical N-heterocyclic carbene ligand, whose complex with palladium catalyzed the intramolecular amide enolate a-arylation lead-
ing to oxindole 45 in excellent yield but with low enantioselectivity.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Chiral ligands; Transition metal catalysis; Asymmetric catalysis; Pyridine ligands; Oxazoline ligands; N,N0-Heterocyclic carbene ligands
1. Introduction
iso-PINDOX (6) for the enantioselective allylation of alde-
hydes with allyltrichlorosilane,5 oxazolines 3 and 4 as organo-
catalysts for reduction of ketones and imines,6 and phosphines,
such as 7, that proved to be efficient in asymmetric Heck
addition7 and Pd-catalyzed allylic substitution.8
Among the chiral bidentate N,N-ligands, bisoxazolines
have played a key role in transition metal-catalyzed enantio-
selective reactions in the last 15 years, where selectivities
attained for several reaction types have reached or even sur-
passed those typical for enzymatic processes.9 On the other
hand, pyridineeoxazoline hybrids (e.g., 3 and 4) have been
less well studied and the existing examples mostly contain
the chiral element in the oxazoline unit, whereas the pyridine
moiety is usually flat.6,9
The pyridine nucleus is a ubiquitous structural motif in
catalysis,1 supramolecular science,2 and medicinal chemistry.3
The search for efficient routes toward pyridine-containing
non-racemic structures is the key to the development of new
catalysts for a wide range of important enantioselective trans-
formations.1 We have previously developed bidentate pyri-
dines (Chart 1), such as PINDY (1) and CANDY (2) for the
copper-catalyzed asymmetric allylic oxidation and cyclopro-
panation,4 related N-oxide organocatalysts PINDOX (5) and
* Corresponding authors. Tel.: þ44 141 330 5943/4199; fax: þ44 141 330
4888.
E-mail addresses: amalkov@chem.gla.ac.uk (A.V. Malkov), pavelk@
The phosphineeoxazolines, chiral in the oxazoline unit,
represent another important class of ligands.9,10 Again, their
pyridine analogues, such 7, have only been reported occa-
sionally7e9 and the scope of their applications has not been
thoroughly studied.
ꢀ
´
chem.gla.ac.uk (P. Kocovsky).
y
Present address: Reaxa Ltd, Hexagon Tower, Blackley, Manchester M9
8ZS, UK.
z
Permanent address: Institute of Organic Chemistry and Biochemistry,
ꢀ
AVCR, 16610 Prague 6, Czech Republic.
x
The pioneering work on metal coordinated N-heterocyclic
carbenes (NHCs)11,12 has opened a new fertile field and these
Present address: Department of Chemistry and Biochemistry, University of
Colorado, Boulder, Colorado 80309-0215, USA.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.045

4012
A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
R2
R1
O
N
N
N
N
N
N
(–)-3, R1 = Ph, R2 = H
(+)-4, R1 = H, R2 = Ph
(+)-1
(–)-2
+
+
N
N
N
N
N
O-
O-
PPh2
(+)-5
(–)-6
(–)-7
Chart 1. Pyridine-derived ligands and organocatalysts.
enantioselectivity are not well understood.14 The combination
of the heterocarbene unit with a pyridine nucleus can be ex-
pected to mimic the phosphineepyridine ligands, possibly
with new applications.
Herein, we report on straightforward syntheses of three new
types of bidentate pyridines: the pinene-derived pyridyl oxazo-
lines 8aed, with chiral elements in both the oxazoline and
pyridine units, pyridyl phosphine 9, chiral in the pyridine
part, and the N,N-heterocyclic carbene precursor 10, again
chiral in the pyridine half (Chart 2).
O
N
O
N
N
N
R
Ph
(–)-8a, R = i-Pr
(–)-8b, R = t-Bu
(–)-8c, R = Ph
(+)-8d
N
N
+
N
Ph
P
N
–
BF4
Ph
(–)-9
Chart 2. New pyridine-derived ligands.
2. Results and discussion
(+)-10
2.1. Synthesis of 2-pyridyl oxazolines 8aed
ligands now spearhead numerous advances in both metal
catalysis and organocatalysis.13 However, efficient enantiose-
lective examples13 are limited and the variables governing
The synthetic route to the chiral 2-pyridyl oxazolines 8aed
commenced with ozonolysis of b-pinene (ꢁ)-11 (Scheme 1).
The resulting nopinone (þ)-12 (89%)4c was treated with
CO2Me
OH
O
OTf
*
Tf2O
H2N
+
NH3, MeOH
140 °C, 7 h
X
NH
N
R
(S)-(+)-15a, R = i-Pr
(S)-(+)-15b, R = t-Bu
(S)-(+)-15c, R = Ph
(R)-(–)-15c, R = Ph
(–)-11, X = CH2
(+)-12, R = O
(+)-13
(–)-14
(AcO)2Pd, CO
dppp, Et3N
O
O
OH
OH
Ph
*
*
N
N
HN
HN
R
(–)-16a, R = i-Pr
(–)-16b, R = t-Bu
(–)-16c, R = Ph
(+)-16d
MsCl, Et3N, CH2Cl2, 0 °C
O
N
O
N
*
*
N
N
R
Ph
(–)-8a, R = i-Pr
(–)-8b, R = t-Bu
(–)-8c, R = Ph
(+)-8d
Scheme 1. Synthesis of pyridyl oxazoline ligands from b-pinene.

A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
4013
methyl propiolate in a methanolic 7 M ammonia solution in an
2.2. Synthesis of 2-pyridyl phosphine 9
autoclave at 140 ꢂC to furnish pyridone (þ)-134c (71%) as a re-
sult of Michael addition, imine formation, and ring closure.4c
The latter intermediate was converted into triflate (ꢁ)-14
(ꢃ99%) on reaction with triflic anhydride.4c Triflate (ꢁ)-14
was then submitted to the palladium-catalyzed carbonylation15
in the presence of the respective amino alcohols 15aec to pro-
duce amides (ꢁ)-16a (82%), (ꢁ)-16b (52%), (ꢁ)-16c (68%),
and (þ)-16d (73%). In the end game, activation of the hydroxy
group in the latter amides by mesylation with methanesulfonyl
chloride resulted in a ring closure to produce oxazolines (ꢁ)-
8a (71%), (ꢁ)-8b (49%), (ꢁ)-8c (74%), and (þ)-8d (81%),
respectively.16
Palladium-catalyzed carbonylation of triflate (ꢁ)-14 in
methanol17 (Scheme 2) afforded the methyl ester (ꢁ)-17
(73%), whose reduction with LiAlH4 furnished the primary
alcohol (ꢁ)-18 (67%), which was then converted into chloride
(ꢁ)-19 (w100%) by treatment with SOCl2. The sodium phos-
phide 21, generated in situ from phospholane 2018 on reduc-
tion with metallic sodium,18 was then alkylated with chloride
19 to produce phosphine (ꢁ)-9 (65%).
2.3. Synthesis of the heterocyclic carbene precursor 10
We envisioned that the ultimate precursor (ꢁ)-24 could be
obtained from triflate (ꢁ)-144c (Scheme 3) using a strategy
similar to that employed for the synthesis of the oxazolines
(vide supra). Indeed, palladium-catalyzed carbonylation15 of
(ꢁ)-14 in the presence diamine 22 proceeded readily to
furnish amide (þ)-23 (70%). However, its reduction with
LiAlH4 gave the required amine (ꢁ)-24 in only 20% yield.19
Therefore, a different approach was adopted, first with a-pico-
linic aldehyde 25 as a model compound. Reductive amina-
tion20 of 25 with 22 using catalytic hydrogenation proceeded
readily to afford amine 26 (75%), which was then transformed
into the carbene precursor 27 (41%)21 by using the estab-
lished22 heating with HC(OEt)3 and NH4BF4.
CO, MeOH
(AcO)2Pd
Ph
P
OTf
CO2Me
N
N
Ph
Ph
(–)-14
(–)-17
20
1. LiAlH4
2. SOCl2
Na, THF
rt
Na+
P-
21
THF, rt
Ph
N
N
X
Ph
Ph
P
Ph
(–)-9
(–)-18, X = OH
(–)-19, X = Cl
21
The latter protocol was then applied to the synthesis of car-
bene precursor 10. The starting aldehyde (ꢁ)-28 was prepared
Scheme 2. Synthesis of pyridine phosphine ligand.
O
H2N
NHPh
OTf
22
LiAlH4
N
N
N
HN
HN
CO, (AcO)2Pd
dppf
NHPh
NHPh
(–)-14
(+)-23
(–)-24
HC(OEt)3
H2N
NHPh
22
NH4BF4
N
N
CHO
N
HN
H2, Pd/C
MeOH
120 °C
+
-
N
BF4
NHPh
N
Ph
25
26
27
H2, Pd/C
MeOH
CHO
DIBAH
CH2Cl2
-78 °C
(–)-17
+
H2N
22, Ar = Ph
NHAr
N
N
HN
NHAr
29, Ar = 2,4,6(Me)3C6H2
(–)-28
(–)-24, Ar = Ph
(–)-30, Ar = 2,4,6(Me)3C6H2
CO, MeOH
(AcO)2Pd
(Scheme 2)
HC(OEt)3
NH4BF4
120 °C
29
(–)-14
N2H4, EtOH
reflux
Br
N
N
O
O
N
H2N
+
N
HN
O
N
O
-
BF4
neat, melt
(+)-10
31
32
Scheme 3. Synthesis of pyridine heterocarbene ligand precursors.

4014
A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
To prepare the imidazolium analogues of 10, we attempted
the synthesis of the intermediates 34aec via the procedure
published by Njar,27 using the reaction of phenols 33aec
with carbonyldiimidazole (Scheme 4). However, rather than
obtaining the desired imidazoles 34aec, the carbonyl deriva-
tives 35aec were obtained and the structures of 35a,b were
confirmed by X-ray crystallography. While this work was in
progress, similar observations were made independently by
Fischer28 and Vennerstrom,29 clearly showing that the original
structural assignment by Njar27 was incorrect.
2.4. Asymmetric allylic oxidation catalyzed by copper
complexes
A number of chiral ligands have been designed to modify
the original KharasheSosnovsky reaction30,31 into an enantio-
selective process; these protocols include ethyl camphorate
(ꢀ10% ee),32 proline and its congeners (ꢀ65% ee),33 and
our terpene-derived bipyridines, such as 1 and 2 (ꢀ82%
ee).4,34 Bisoxazolines, introduced by Pfaltz, Evans, and And-
rus,35 and trisoxazolines developed by Katsuki,36 represented
a substantial improvement in the enantioselectivity (from 85
to 95% and finally to 99% ee)35,36 but the reactions tend to
be slow, which reduces their practicality. By contrast, Cu-com-
plexes of our terpene-derived bipyridines proved to react much
faster, which suggested that a hybrid containing both pyridine
and oxazoline units 8aed could be the ligands of choice. This
view is certainly supported by Singh’s report on a hybrid
ligand containing two oxazoline units appended to a pyridine
nucleus in 2,6-positions, which substantially accelerated
the oxidation, though at the expense of enantioselectivity
(ꢀ66% ee).37
Figure 1. A view of one of the two independent cations in solid imidazolium
fluoroborate (þ)-10 (the anion is omitted for clarity).
by reduction of ester (ꢁ)-17 with DIBAH23 at ꢁ78 ꢂC (75%).
Subsequent reductive amination with diamine 22 proceeded as
expected to give rise to diamine (ꢁ)-24 (80%), which repre-
sents a considerable improvement over the amide reduction
(23/24). The overall yield of this three-step sequence, start-
ing with the triflate carbonylation (14/17) and involving
reductive amination (28þ22/24) was 49%, which compares
favorably with the overall 14% yield of the original two-step
route that relied on carbonylation, followed by amide reduc-
tion (14/23/24).
In order to apply this methodology to the synthesis of (þ)-
10, we first prepared diamine 29 in two steps by melting the
commercially available N-(2-bromoethyl)phthalimide (31)
with mesidine,24 which afforded the amino phthalimide 32
(59%), whose deprotection with hydrazine hydrate in refluxing
ethanol25 furnished diamine 29 (90%).26 Reductive amination
of aldehyde (ꢁ)-28 with the latter diamine afforded (ꢁ)-30
(68%), which was then converted into the imidazolium fluoro-
borate (þ)-10 (39%) on heating with ethyl orthoformate and
NH4BF4 at 120 ꢂC in a sealed tube.22 Crystallographic analy-
sis of (þ)-10 confirmed the structure (vide infra): one of the
two crystallographically distinct but chemically identical
cations is shown in Figure 1.
The Cu(II) complexes of terpene-derived 2-pyridyl oxazo-
lines 8aed were employed as catalysts for the copper-catalyzed
allylic oxidation of cyclic alkenes, using the previously estab-
lished protocol.4,37 The Cu(II) complexes were generated
from (TfO)2Cu and the respective ligands, and reduced in situ
with phenylhydrazine to the corresponding Cu(I) species.
A clear color change from green to deep red was observed on ad-
dition of phenylhydrazine, indicating the change in the oxida-
tion state of copper. In order to investigate the catalytic
capability of the latter complexes, the allylic oxidation of five-
to seven-membered cycloalkenes 36aec were studied (Scheme
5), employing tert-butyl peroxybenzoate as the stoichiometric
oxidant (Table 1).
The copper complexes of all the pinene-derived pyridyl ox-
azolines 8aed were found to be active catalysts for the allylic
oxidation reaction but with varying degrees of reactivity and
R1
R1
R1
Im2CO
Im2CO
N
R2
HO
R2
O
O
R2
N
CH2Cl2
reflux, 24 h
N
N
R1
R1
R1
34a, R1 = Me, R2 = H
34b, R1 = Me, R2 = Me
34c, R1 = i-Pr, R2 = H
33a, R1 = Me, R2 = H
33b, R1 = Me, R2 = Me
33c, R1 = i-Pr, R2 = H
35a, R1 = Me, R2 = H
35b, R1 = Me, R2 = Me
35c, R1 = i-Pr, R2 = H
Scheme 4.

A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
4015
(TfO)2Cu, 8a–d
PhNHNH2,
[(COD)RhCl]2
OBz
(–)- 8c
MeOH
TsOH
O
OSiHPh2
+
OSiHPh2
OH
PhCO3(t-Bu)
Ph2SiH2
*
+ 38
Ph
Ph
Ph
Br
Ph
Ph
Me2CO
rt
CCl4
( )n
( )n
38
39
40
41
36a, n = 0
36b, n = 1
36c, n = 2
(S )-(–)-37a, n = 0
(S )-(–)-37b, n = 1
(S )-(–)-37c, n = 2
CrCl3, Mn
(+)-1
O
OH
+
H
Ph
THF
Scheme 5. Copper-catalyzed allylic oxidation; see Table 1.
42
43
Scheme 6. Rhodium-catalyzed hydrosilylation and NozakieHiyamaeKishi
allylation.
selectivity. The highest enantioselectivities were achieved by
employing the iso-propyl ligand (ꢁ)-8a (Table 1, entries 1e
5). The copper complex of (ꢁ)-8a exhibited similar reactivity
and enantioselectivity to those attained with the copper com-
plex of PINDY (1).4 Reducing the reaction temperature
resulted in a decrease in reactivity without any significant
increase in enantioselectivity (compare entries 1 and 4). Enan-
tioselectivity was improved in acetonitrile but the reactivity di-
minished considerably (entry 2). The reactivity was found to
be highly dependent on solvent, with reactions carried out in
acetone proceeding considerably faster than those in acetoni-
trile, chloroform, or ethyl acetate. Higher enantioselectivity
was observed for the transformation of cycloheptene com-
pared to cyclohexene, a trend also observed4 for bipyridine
chiral ligands 1 and 2. The increased steric bulk of tert-butyl
and phenyl substituted oxazolines (ꢁ)-8b and (ꢁ)-8c resulted
in considerably lower enantioselectivities (entries 6e11), pre-
sumably originating from the chiral cavity being too sterically
demanding to give effective enantiodiscrimination.
configuration of the product was opposite to that obtained
with diastereoisomeric (ꢁ)-8c (compare entries 9e11 with
12e14). This finding indicates that it is the chirality of the ox-
azoline moiety, rather than the terpene unit, which mainly dic-
tates the enantiodiscrimination.
2.5. Other applications of the pyridineeoxazoline ligands
Asymmetric, Rh-catalyzed hydrosilylation with diphenylsi-
lane as the stoichiometric reagent is a useful alternative to
asymmetric hydrogenation, as it avoids the use of high-pressure
hydrogen.9,38 To further assess the potential of our pyridinee
oxazolines, hydrosilylation of acetophenone (38) was investi-
gated, using ligands 8a,c (Scheme 6). The reaction proceeded
under standard conditions and the mixture of silylated primary
products 39/40 was hydrolyzed to produce alcohol 41 and the
recycled acetophenone. The conversion attained with (ꢁ)-8a
was 58% but an almost racemic alcohol 41 was obtained (4%
ee). Ligand (ꢁ)-8c induced 79% conversion but with only
a marginal improvement in the enantioselectivity (8% ee),
showing that this type of ligands is not suitable for the Rh-
catalyzed hydrosilylation. This behavior sharply contrasts
with that of pyridineeoxazoline 3 and of its congeners that
have been shown to exhibit high enantioselectivities (ꢀ95%
ee).39,40 It is pertinent to note that (þ)-4 and its analogues
have been developed by us as organocatalysts for asymmetric
hydrosilylation of both ketones and imines with trichlorosilane
and exhibited high enantioselectivities (ꢀ94% ee).41,42
Ligands 8aec can be regarded as pseudo C2-symmetric.
The sense of asymmetric induction observed for the allylic ox-
idation of cycloalkenes is indeed similar to that observed for
C2-symmetric terpene-derived bipyridine 1.4 Although rather
low enantioselectivity was observed for the phenyl substituted
ligand (þ)-8d (entries 12e14), interestingly, the absolute
Table 1
Asymmetric allylic oxidation of cycloalkenes catalyzed by Cu-complexes of
chiral ligands 8aed (Scheme 5)a
Entry Ligand Substrate
Solvent Time (h) Yield (%) ee (%)b
1
(ꢁ)-8a Cyclohexene
(ꢁ)-8a Cyclohexene
(ꢁ)-8a Cyclohexene
Me2CO
MeCN
0.5
72
67
15
15
45
62
39
62
50
43
62
48
76
43
72
44 (S)
60 (S)
20 (S)
45 (S)
67 (S)
0
The NozakieHiyamaeKishi allylation of aldehydes with
allyl halides is another reaction, in which chiral bipyridine,
oxazolines, salen derivatives, and other chiral ligands were
2
3
AcOEt 72
(ꢁ)-8a Cyclohexenec Me2CO 72
4
5
(ꢁ)-8a Cycloheptene Me2CO
6
employed (typically with ꢀ90% ee).43e49 Using the Furstner
¨
6
(ꢁ)-8b Cyclopentene Me2CO 16
(ꢁ)-8b Cyclohexene Me2CO 16
conditions46 and ligand (ꢁ)-8a and PINDY (þ)-1, respectively
(Scheme 6), the reaction of benzaldehyde 42 proceeded read-
ily to give 67% conversion with 8a and ꢃ99% with 1 but the
product 43 was practically racemic (4% ee with 8a and 8% ee
with 1).
7
22 (S)
23 (S)
14 (S)
7 (S)
8
(ꢁ)-8b Cycloheptene Me2CO 16
9
(ꢁ)-8c Cyclopentene Me2CO
(ꢁ)-8c Cyclohexene Me2CO
(ꢁ)-8c Cycloheptene Me2CO
3
10
11
12
13
14
a
0.5
1.5
0.5
42 (S)
19 (R)
14 (R)
30 (R)
(þ)-8d Cyclohexene
Me2CO
(þ)-8d Cyclohexenec CHCl3
72
5
(þ)-8d Cycloheptene Me2CO
2.6. Intramolecular a-arylation catalyzed by palladium
complexes
The reactions were carried out in the presence of the catalysts (5 mol %),
generated in situ by reduction of a mixture of (TfO)2CuII and the ligand with
PhNHNH2 at room temperature (unless stated otherwise).
Hartwig has developed an enantioselective version of the
Pd-catalyzed intramolecular amide enolate a-arylation leading
to biologically interesting oxindole50 bearing a benzylic
all-carbon stereocenter.51 Several chiral N-heterocyclic carbene
b
Determined by chiral HPLC; the absolute configuration was established by
optical rotation and the chiral HPLC mobility with reference to the authentic
sample.
c
The reaction was carried out at 0 ꢂC.

4016
A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
[Pd] (5 mol%)
(+)-10 (5 mol%)
t-BuONa
All solvents for the reactions were of reagent grade and were
Ph
Br
Ph
O
dried and distilled under argon or nitrogen immediately before
use as follows: tetrahydrofuran, diethyl ether, and toluene from
sodium/benzophenone under nitrogen, dichloromethane and
N,N-dimethyl formamide from calcium hydride. Methanol
and ethanol were distilled with sodium under argon and stored
O
dioxane
100 °C
N
N
Me
Me
44
45
Scheme 7. Palladium-catalyzed intramolecular a-arylation.
˚
over 4 A molecular sieves. Triethylamine and diisopropylethyl-
˚
amine were distilled from calcium hydride and stored over 4 A
molecular sieves. N,N-Dimethyl formamide and methanol were
degassed by three freeze-pump-thaw cycles before use in
methoxycarbonylation reaction. Petroleum ether refers to the
fraction boiling in the range of 40e60 ꢂC. Yields are given
for isolated products showing one spot on a TLC plate and no
impurities detectable in the NMR spectrum. The identity of
the products prepared by different methods was checked by
comparison of their NMR spectra. 2-Bromo-N-methylaniline
was prepared according to a published procedure.55 The chiral
GC and HPLC methods were calibrated with the corresponding
racemic mixtures; the absolute configuration of the allylic ben-
zoates (products of allylic oxidation) has been established by
comparison with authentic samples.4 Crystallographic analysis
of (þ)-10: [C25H32N3][BF4], M¼461.35, triclinic, space group
ligands were developed for this process but the enantioselec-
tivities attained to date are rather modest (ꢀ69% ee).50e53
Screening of various palladium complexes resulted in identifi-
cation of (AcO)2Pd and [(C3H5)PdCl]2 as suitable catalyst
precursors, which produced sufficiently reactive catalysts on
coordination to the pyridine-carbene ligand generated from
the imidazolium salt (þ)-10. Both complexes were found to
catalyze the cyclization of 44,54 giving rise to 45 at 100 ꢂC
(84% and 94% isolated yields, respectively), which compares
favorably with several other systems53 (Scheme 7). On the
other hand, little conversion was observed at 50 ꢂC (4% and
14%, respectively). Nevertheless, the product 45 was practi-
cally racemic in both cases (1e3% ee).
˚
P1 (No. 1), a¼8.7845(2), b¼9.7552(2), c¼15.3974(3) A, a¼
3
ꢂ
˚
3. Conclusion
106.688(1), b¼93.408(1), g¼104.149(1) , V¼1213.56(4) A ,
Z¼2, r¼1.263 g cmꢁ3. All measurements were made at
100 K on a Nonius Kappa CCD diffractometer with Mo Ka ra-
A straightforward synthesis of new pinene-derived biden-
tate pyridines 8aed, 9, and 10 has been described, starting
from the readily available common triflate 14. A copper com-
plex of the pyridineeoxazoline ligands 8a has been found to
catalyze asymmetric allylic oxidation of simple cyclic olefins
36aec with good conversion rates and modest enantioselec-
tivity (ꢀ67% ee). The imidazolium salt 10 has been identified
as a precursor of the corresponding N,N0-unsymmetrical
N-heterocyclic carbene ligand, whose complex with palla-
dium catalyzed the intramolecular amide enolate a-arylation
leading to oxindole 45 in excellent yield but with poor
enantioselectivity.
˚
diation (l¼0.71073 A). The WINGX package and SHELXL97
were used for all calculations;56 24378 intensities with q (Mo
Ka)<30.1ꢂ gave 7071 unique observations (Rint¼0.031) after
merging symmetry equivalents (including Friedel pairs). Re-
finement of 633 parameters finally gave R1¼0.059, wR2¼
0.13 over all 7071 observations and jDrj<0.42 e Aꢁ3. Only
˚
space group P1 is possible since the compound was made
from a natural terpene of known absolute configuration, which
could not be changed during our chemical transformations. The
unit cell contains two independent cation/anion pairs. The abso-
lute configurations of the cations could not be determined from
the crystallographic experiment and were assigned on the basis
of the known chemical history. The two cations display virtu-
4. Experimental section
˚
ally identical bond lengths (rms D¼0.006 A) and angles, which
4.1. General methods
are consistent with the proposed structure. However, the unit
cell contents are close to centrosymmetric; only the Cn17e
Cn25 rings (n¼1,2), especially the gem-dimethyl groups, seri-
ously break the pseudo-symmetry. Crystallographic data for
(þ)-10 have been deposited in the Cambridge Crystallographic
Data Centre (deposition number: CCDC 638212).
Melting points were determined on a Kofler block and are
uncorrected. Optical rotations were recorded in CH2Cl2 at
25 ꢂC unless otherwise indicated. The [a]D values are given
in 10ꢁ1 deg cm2 gꢁ1. The NMR spectra were recorded in
1
CDCl3, H at 400 MHz and 13C at 100 MHz with CDCl3 (d
7.26, 1H; d 77.0, 13C) and tetramethylsilane (d 0.0, 1H) as an in-
ternal standard; chemical shifts are given in d scale. Coupling
patterns are designated as follows: s, singlet; d, doublet; t, trip-
let; dd, doublet of doublets; ddd, doublet of doublet of doublets;
m, multiplet; br, broad. Various 2D techniques and DEPTexper-
iments were used to establish the structures and to assign the
signals. The mass spectra were measured on a high resolution,
dual-sector mass spectrometer using direct inlet and the lowest
temperature enabling evaporation. Flash column chromatogra-
phy was performed with Fischer Scientific Matrex 60 Silica gel.
4.1.1. (1R,9R,40S)-(ꢁ)-4-[40-Isopropyl-40,50-dihydro-oxazol-
20-yl]-10,10-dimethyl-3-aza-tricyclo-[7.1.1.02,7]-undeca-
2(7),3,5-triene (ꢁ)-8a16
Mesyl chloride (76 mL, 0.98 mmol, 2.0 equiv) in CH2Cl2
(1 mL) was slowly added dropwise to a stirred solution of hy-
droxyamide (ꢁ)-16a (146 mg, 0.48 mmol, 1.0 equiv) and anhy-
drous triethylamine (340 mL, 2.44 mmol, 5.0 equiv) in CH2Cl2
(10 mL) at 0 ꢂC. The reaction mixture was then allowed to
reach room temperature and stirred for a further 24 h. The sol-
vent was removed under reduced pressure and the resultant

A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
4017
residue was purified by flash chromatography on silica gel (pe-
troleum ethereethereacetone 80:10:10) to give oxazoline (ꢁ)-
8a (98 mg, 71%) as white solid: mp 55e57 ꢂC (CH2Cl2). [a]D
ꢁ45.2 (c 0.17, CH2Cl2); IR (cmꢁ1) n 1647 s (C]N), 1588 m,
1572 m, 1523 w, 1469 m, 1451 s, 1429 w, 1417 m, 1386 m,
CH2Cl2 (10 mL) at 0 ꢂC. The reaction mixture was then al-
lowed to reach room temperature and stirred for a further
48 h. The solvent was removed under reduced pressure and
the resultant residue was purified by flash chromatography
on silica gel (petroleum ethereethyl acetateetriethylamine
1:1:0.1) to give oxazoline (ꢁ)-8c (206 mg, 74%) as a clear
oil. [a]D ꢁ43.3 (c 0.6, CHCl3); IR (KBr, cmꢁ1) n 1636
(C]N), 2918 (CH/CH2/CH3), 3029 (AreH); 1H NMR
(400 MHz, CDCl3) d 0.61 (s, 3H), 1.22 (d, J¼9.9 Hz, 1H),
1.34 (s, 3H), 2.26e2.29 (m, 1H), 2.63e2.69 (m, 1H), 2.93
(d, J¼2.6 Hz, 2H), 3.12 (t, J¼5.6 Hz, 1H), 4.30 (t,
J¼8.5 Hz, 1H), 4.79 (dd, J¼10.2, 8.6 Hz, 1H), 5.35 (dd,
J¼10.2, 8.5 Hz, 1H), 7.15e7.36 (m, 5H), 7.43 (d, J¼7.8 Hz,
1H), 7.89 (d, J¼7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 21.6 (CH3), 26.3 (CH3), 31.0 (CH2), 31.9 (CH2), 39.5 (C),
40.3 (CH), 50.5 (CH), 70.7 (CH), 75.6 (CH2), 122.6 (CH),
127.3 (2ꢅCH), 128.0 (CH), 129.1 (2ꢅCH), 133.9 (C), 136.5
(CH), 142.5 (C), 142.7 (C), 164.6 (C), 167.1 (C); EIMS m/z
1
1370 s, 1262 s, 999 w, 971 m; H NMR (400 MHz, CDCl3)
d 0.65 (s, 3H), 0.94 (d, J¼6.5 Hz, 3H), 1.06 (d, J¼7.1 Hz,
3H), 1.28 (d, J¼9.5 Hz, 1H), 1.40 (s, 3H), 1.83e1.95 (m,
1H), 2.30e2.35 (m, 1H), 2.69e2.74 (m, 1H), 2.98 (d,
J¼2.5 Hz, 2H), 3.19 (t, J¼6.1 Hz, 1H), 4.10e4.22 (m, 2H),
4.46e4.50 (m, 1H), 7.48 (d, J¼7.7 Hz, 1H), 7.87 (d,
J¼7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 18.2 (CH3),
19.3 (CH3), 21.2 (CH3), 25.9 (CH3), 30.7 (CH2), 31.51 (CH2),
32.84 (CH), 39.03 (C), 39.87 (CH), 50.32 (CH), 70.64 (CH2),
72.91 (CH), 121.9 (CH), 133.2 (C), 135.5 (CH), 142.5 (C),
ꢄ
162.9 (C), 166.6 (C); EIMS m/z (%) 284 (Mþ , 11), 269 (4),
243 (4), 242 (37), 241 (100), 214 (4), 213 (23), 198 (5), 197
(8), 183 (6), 171 (6), 170 (9), 169 (9), 157 (5), 156 (7), 155
(15), 143 (4), 142 (5), 130 (6), 129 (5), 128 (10), 69 (6), 43
(4), 41 (8); HRMS (EI): 284.1889 (C18H24N2O requires:
284.1889).
ꢄ
(%) 318 (Mþ , 100), 275 (40), 245 (18), 244 (16), 200 (7),
172 (12), 155 (30), 128 (38), 91 (20), 89 (12), 77 (8), 41
(5); HRMS (EI): 318.1733 (C21H22N2O requires: 318.1732).
4.1.2. (1R,9R,40S)-(ꢁ)-4-(40-tert-Butyl-40,50-dihydro-oxazol-
20-yl)-10,10-dimethyl-3-aza-tricyclo[7.1.1.02,7]undeca-
2(7),3,5-triene (ꢁ)-8b16
4.1.4. (1R,9R,40R)-(þ)-10,10-Dimethyl-4-[40-phenyl-40,50-
dihydro-oxazol-20-yl]-3-aza-tricyclo[7.1.1.02,7]-undeca-
2(7),3,5-triene (þ)-8d16
Mesyl chloride (90 mL, 1.17 mmol, 2.3 equiv) in CH2Cl2
(1 mL) was slowly added dropwise to a stirred solution of
hydroxyamide (ꢁ)-16b (160 mg, 0.51 mmol, 1.0 equiv) and
anhydrous triethylamine (300 mL, 2.13 mmol, 4.18 equiv) in
CH2Cl2 (10 mL) at 0 ꢂC. The reaction mixture was then al-
lowed to reach room temperature and stirred for a further
16 h. The solvent was removed under reduced pressure and
the resultant residue was purified by flash chromatography
on silica gel (petroleum ethereethyl acetateetriethylamine
1:1:0.05) to give oxazoline (ꢁ)-8b (74 mg, 49%) as a white
solid: mp 105e107 ꢂC (CH2Cl2). [a]D ꢁ70.0 (c 0.1, CHCl3);
IR (KBr, cmꢁ1) n 1647 (C]N), 2868, 2916, 2958 (CH/CH2/
Mesyl chloride (185 mL, 2.04 mmol, 2.3 equiv) in CH2Cl2
(1 mL) was slowly added dropwise to a stirred solution of
hydroxyamide (þ)-16d (300 mg, 0.89 mmol, 1.0 equiv) and
anhydrous triethylamine (640 mL, 4.59 mmol, 5.2 equiv) in
CH2Cl2 (10 mL) at 0 ꢂC. The reaction mixture was then al-
lowed to reach room temperature and stirred for a further
48 h. The solvent was removed under reduced pressure and
the resultant residue was purified by flash chromatography on
silica gel (petroleum ethereethyl acetateetriethylamine
1:1:0.1) to give oxazoline (þ)-8d (227 mg, 81%) as a white
solid: mp 116e118 ꢂC (ethyl acetateehexane). [a]D þ45.2 (c
0.67, CHCl3); IR (KBr, cmꢁ1) n 1681 (C]O), 2978, 2954,
2925 (CH/CH2/CH3), 3059 (AreH); 1H NMR (400 MHz,
CDCl3) d 0.61 (s, 3H), 1.23 (d, J¼9.6 Hz, 1H), 1.35 (s, 3H),
2.26e2.30 (m, 1H), 2.67 (dt, J¼9.6, 5.6 Hz, 1H), 2.93 (d,
J¼2.4 Hz, 2H), 3.13 (t, J¼5.6 Hz, 1H), 4.30 (t, J¼8.4 Hz,
1H), 4.80 (dd, J¼10.4, 8.8 Hz, 1H), 5.35 (dd, J¼10.4, 8.8 Hz,
1H), 7.19e7.31 (m, 5H), 7.44 (d, J¼8.0 Hz, 1H), 7.92 (d,
J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 16.4 (CH3),
21.0 (CH3), 25.8 (CH2), 26.7 (CH2), 34.2 (C), 35.0 (CH),
45.5 (CH), 65.4 (CH), 70.4 (CH2), 117.4 (CH), 122.0
(2ꢅCH), 122.8 (CH), 123.9 (2ꢅCH), 128.9 (C), 130.7 (CH),
137.2 (C), 137.4 (C), 159.4 (C), 161.8 (C); EIMS m/z (%)
1
CH3); H NMR (400 MHz, CDCl3) d 0.59 (s, 3H), 0.90 (s,
9H), 1.21 (d, J¼9.6 Hz, 1H), 1.33 (s, 3H), 2.24e2.28 (m,
1H), 2.62e2.67 (m, 1H), 2.91 (d, J¼2.4 Hz, 2H), 3.11 (t,
J¼5.6 Hz, 1H), 4.03 (dd, J¼10.4, 8.4 Hz, 1H), 4.23 (t,
J¼8.4 Hz, 1H), 4.35 (dd, J¼10.4, 8.8 Hz, 1H), 7.41 (d,
J¼7.6 Hz, 1H), 7.84 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 21.2 (CH3), 25.9 (CH3), 26.0 (3ꢅCH3), 30.7 (CH2),
31.5 (CH2), 34.0 (C), 39.1 (C), 39.9 (CH), 50.3 (CH), 69.2
(CH2), 76.4 (CH), 122.0 (CH), 133.1 (C), 135.5 (CH), 142.6
ꢄ
(C), 162.8 (C), 166.5 (C); EIMS m/z (%) 298 (Mþ , 3) 241
(100), 213 (30), 197 (10), 170 (10), 155 (8), 128 (7), 83 (12);
HRMS (EI): 298.2044 (C19H26N2O requires: 298.2045).
ꢄ
318 (Mþ , 100), 276 (15), 275 (40), 245 (14), 200 (7), 214
(4), 172 (14), 155 (28), 128 (40), 118 (19), 85 (34), 83 (65),
47 (9); HRMS (EI): 318.1731 (C21H22N2O requires: 318.1732).
4.1.3. (1R,9R,40S)-(ꢁ)-10,10-Dimethyl-4-[40-phenyl-40,50-
dihydro-oxazol-20-yl]-3-aza-tricyclo[7.1.1.02,7]-undeca-
2(7),3,5-triene (ꢁ)-8c16
4.1.5. Pyridyl phosphine (ꢁ)-9
Mesyl chloride (152 mL, 1.67 mmol, 2.3 equiv) in CH2Cl2
(1 mL) was slowly added dropwise to a stirred solution of
hydroxyamide (ꢁ)-16c (246 mg, 0.73 mmol, 1.0 equiv) and
anhydrous triethylamine (530 mL, 3.80 mmol, 5.2 equiv) in
A thin sodium foil (126 mg, 5.492 mmol, 2.10 equiv) was
added to a stirred solution of phosphine 20 (857 mg,
2.746 mmol, 1.05 equiv) in dry THF (60 mL) and the mixture
was stirred under argon, until all sodium had dissolved

4018
A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
(4e6 h).
A
solution of chloro derivate 19 (580 mg,
1.0 equiv), (S)-(þ)-valinol (1.52 g, 14.7 mmol, 2.0 equiv), pal-
ladium acetate (55.5 mg, 0.25 mmol, 3 mol %), and dppp
(93.9 mg, 0.23 mmol, 3 mol %) under an argon atmosphere
at room temperature in a Schlenk flask. The flask was con-
nected with a balloon and flushed with carbon monoxide (car-
bon monoxide gas was bubbled through the solution) and the
reaction mixture was heated under a carbon monoxide atmo-
sphere at 70 ꢂC for 21 h. The solvent was then evaporated
under reduced pressure. Flash chromatography on silica gel
(petroleum ethereethereacetone 80:10:10, 150 mL, followed
by ethyl acetate) yielded hydroxyamide (ꢁ)-16a (1.81 g,
82%) as a white crystalline solid: mp 123e125 ꢂC (ethyl acet-
ateehexane). [a]D ꢁ13.5 (c 0.32, CH2Cl2); IR (cmꢁ1) n 3626
w, 3372 m, 1660 vs, 1588 s, 1523 vs, 1467 s, 1443 s, 1427 m,
1416 m, 1393 m, sh, 1387 m, 1370 m, 1242 m, 1084 w, 1053
w; 1H NMR (400 MHz, CDCl3) d 0.66 (s, 3H), 1.03 (d,
J¼7.1 Hz, 3H), 1.05 (d, J¼7.1 Hz, 3H), 1.28 (d, J¼9.9 Hz,
1H), 1.45 (s, 3H), 2.01e2.13 (m, 1H), 2.33e2.38 (m, 1H),
2.71e2.77 (m, 1H), 2.98e3.01 (m, 3H), 3.75e3.90 (m, 3H),
7.55 (d, J¼7.7 Hz, 1H), 7.97 (d, J¼8.1 Hz, 1H), 8.29 (br d,
J¼7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 18.9 (CH3),
19.6 (CH3), 21.3 (CH3), 25.9 (CH3), 29.2 (CH), 30.7 (CH2),
31.4 (CH2), 39.1 (C), 39.9 (CH), 50.2 (CH), 58.0 (CH), 64.7
(CH2), 120.1 (CH), 133.8 (C), 136.1 (CH), 145.4 (C), 165.1
2.615 mmol, 1.00 equiv) in THF (12 mL) was added dropwise
to the resulting dark red mixture under argon, whilst vigor-
ously stirring, and the mixture was stirred under argon over-
night. The solvent was then removed in vacuo and the solid
brown residue was purified by chromatography on a column
of silica gel (30ꢅ2.5 cm) with a mixture of petroleum ether
and ethyl acetate (6:1) [Rf (product)¼0.72, Rf (phosphine
20)¼0.9, Rf (chloro derivate 19)¼0.92] to give (ꢁ)-9
(717 mg, 65%) as yellow crystals: mp 132e134 ꢂC (petroleum
ethereethyl acetate). [a]D ꢁ5.0 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) d 0.49 (s, 3H), 1.07 (d, J¼8.70 Hz, 1H),
1.28 (s, 3H), 2.14e2.18 (m, 1H), 2.49e2.56 (m, 2H), 2.67 (s,
2H), 3.21 (s, 2H), 6.15 (d, J¼6.45 Hz, 1H), 6.85 (d,
J¼7.64 Hz, 1H), 6.92e6.98 (m, 2H), 7.13e7.17 (m, 2H),
7.21e7.25 (m, 4H), 7.36 (d, J¼7.70 Hz, 2H), 7.41 (d,
J¼7.70 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 21.50 (CH3),
26.39 (CH3), 31.20 (d, J¼13.3 Hz, CH2), 34.88 (CH2), 35.07
(CH2), 39.41 (C), 40.51 (CH), 50.37 (CH), 120.48 (CH),
120.82 (CH), 126.87 (CH), 126.92 (CH), 126.96 (CH), 127.08
(CH), 127.35 (CH), 127.41 (CH), 129.06 (CH), 129.39 (CH),
132.60 (CH), 132.67 (CH), 134.73 (CH), 136.39 (CH), 137.45
(C), 137.61 (C), 138.51 (CH), 151.54 (C), 151.71 (C), 151.92
(C), 165.20 (C); 31P NMR (162 MHz, CDCl3) d 0.48 (s); MS
ꢄ
ꢄ
(EI), m/z (%) 421.2 (Mþ , 71), 378.2 (7), 186.1 (8), 143.1 (10),
(C), 166.1 (C); EIMS m/z (%) 302 (Mþ , 3), 272 (34), 271
82.9 (100); HRMS (EI): 421.1959 (C29H28NP requires:
421.1959).
(100), 259 (31), 200 (13), 173 (18), 172 (45), 157 (11), 156
(8), 130 (12), 129 (11), 128 (10), 86 (31), 84 (48), 78 (8),
69 (18), 63 (9), 51 (18), 49 (56), 47 (10), 41 (9); HRMS
(EI): 302.1994 (C18H26N2O2 requires: 302.1994).
4.1.6. Pinene-derived N1-2-picolyl-N2-mesitylimidazol-
idinium tetrafluoroborate (þ)-10
A mixture of diamine (ꢁ)-30 (180 mg, 0.495 mmol), am-
monium tetrafluoroborate (65 mg, 0.620 mmol, 1.25 equiv),
and triethyl orthoformate (1.5 mL, 9.02 mmol, 18.2 equiv)
was heated under argon at 120 ꢂC for 5 h 40 min. The product
crystallized from the reaction mixture upon standing at room
temperature for 5 days. Filtration through sintered glass and
washing with ether yielded pure tetrafluroborate salt (þ)-10
(88 mg, 39%) as beige crystals: mp 167e170 ꢂC. [a]D
þ18.3 (c 0.19, CH2Cl2); 1H NMR (DMSO-d6) d 0.60 (s,
3H), 1.20 (d, J¼9.5 Hz, 1H), 1.41 (s, 3H), 2.27 (s, 6H), 2.28
(s, 3H), 2.31e2.35 (m, 1H), 2.69e2.75 (m, 1H), 2.84 (t,
J¼5.5 Hz, 1H), 2.89e3.01 (m, 2H), 3.91e4.06 (m, 2H),
4.18 (t, J¼10.5 Hz, 2H), 4.80 (s, 2H), 7.07 (s, 2H), 7.28 (d,
J¼8.0 Hz, 1H), 7.63 (d, J¼7.6 Hz, 1H), 8.95 (s, 1H); 13C
NMR d 17.46 (CH3), 20.90 (CH3), 21.40 (CH3), 26.15
(CH3), 30.47 (CH2), 30.80 (CH2), 49.08 (CH2), 50.08
(CH), 50.98 (CH2), 51.98 (CH2), 120.82 (CH), 129.73
(CH), 129.91 (C), 131.49 (C), 135.76 (C), 136.56 (CH),
139.71 (C), 148.48 (C), 160.70 (CH), 166.16 (C); HRMS
(FAB): 374.2596 (C25H32N3, i.e., MꢁBF4, required:
374.2596).
4.1.8. (ꢁ)-(6R,8R)-N-[(2S)-1-Hydroxy-3-methylbutan-2-yl]-
7,7-dimethyl-5,6,7,8-tetrahydro-6,8-methanoquinoline-2-
carboxamide (ꢁ)-16b15
Anhydrous triethylamine (630 mL, 4.5 mmol, 2.8 equiv) was
added to a mixture of triflate (ꢁ)-14 (500 mg, 1.6 mmol,
1.0 equiv), (S)-(þ)-tert-leucinol (375 mg, 3.2 mmol, 2.0 equiv),
palladium acetate (12 mg, 0.05 mmol, 3 mol %), and dppp
(20 mg, 0.05 mmol, 3 mol %) under an argon atmosphere at
room temperature in a Schlenk flask. The flask was connected
with a balloon and flushed with carbon monoxide (CO gas
was bubbled through the solution) and the reaction mixture
was heated under a carbon monoxide atmosphere at 70 ꢂC for
21 h. The solvent was then evaporated under reduced pressure.
Flash chromatography on silica gel (petroleum ethereethyl
acetate 1:1) yielded hydroxyamide (ꢁ)-16b (265 mg, 52%) as
a white solid: mp 157e159 ꢂC (CH2Cl2). [a]D ꢁ2.0 (c 0.5,
CHCl3); IR (KBr, cmꢁ1) n 1525, 1660 (amide C]O), 2868,
2924, 2968 (CH/CH2/CH3), 3371, 3415 (amide NH); 1H
NMR (400 MHz, CDCl3) d 0.60 (s, 3H), 0.98 (s, 9H), 1.21 (d,
J¼9.6 Hz, 1H), 1.38 (s, 3H), 2.27e2.31 (m, 1H), 2.65e2.2.75
(m, 2H), 2.91e2.93 (m, 3H), 3.57e3.64 (m, 1H), 3.86e3.93
(m, 2H), 7.48 (d, J¼7.6 Hz, 1H), 7.90 (d, J¼7.6 Hz, 1H), 8.29
(br s, 1H); 13C NMR (100 MHz, CDCl3) d 21.3 (CH3), 25.9
(CH3), 27.0 (3ꢅCH3), 30.7 (CH2), 31.3 (CH2), 33.7 (C), 39.1
(C), 39.9 (CH), 50.2 (CH), 60.6 (CH), 66.5 (CH2), 120.2
(CH), 133.8 (C), 136.1 (CH), 145.3 (C), 165.1 (C), 166.3 (C);
CIMS m/z (%) 317 ([MþH]þ, 100), 285 (40), 259 (30),
4.1.7. (ꢁ)-(6R,8R)-N-[(2S)-1-Hydroxy-3,3-dimethylbutan-2-
yl]-7,7-dimethyl-5,6,7,8-tetrahydro-6,8-methanoquinoline-
2-carboxamide (ꢁ)-16a15
Anhydrous triethylamine (3.9 mL, 27.8 mmol, 3.7 equiv)
was added to a mixture of triflate (ꢁ)-14 (2.38 g, 7.4 mmol,

A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
4019
241(2), 200 (4), 172 (5); HRMS (CI): 317.2226 (C19H29N2O2
requires: 317.2229).
26.3 (CH3), 31.0 (CH2), 31.8 (CH2), 39.5 (C), 40.3 (CH),
50.5 (CH), 56.9 (CH), 67.6 (CH2), 120.6 (CH), 127.3
(2ꢅCH), 128.3 (CH), 129.3 (2ꢅCH), 134.4 (C), 136.5 (CH),
139.4 (C), 145.6 (C), 165.6 (C), 166.0 (C); EIMS m/z (%)
4.1.9. (ꢁ)-(6R,8R)-N-[(1S)-2-Hydroxy-1-phenylethyl]-7,7-
dimethyl-5,6,7,8-tetrahydro-6,8-methanoquinoline-2-
carboxamide (ꢁ)-16c15
ꢄ
336 (Mþ , 1), 318 (2), 305 (100), 263 (10), 262 (5), 200
(20), 172 (65), 130 (15), 129 (14), 128 (10), 69 (18), 41 (7);
HRMS (EI): 336.1838 (C21H24N2O2 requires: 336.1838).
Anhydrous triethylamine (0.47 mL, 3.37 mmol, 3.1 equiv)
was added to a mixture of triflate (ꢁ)-14 (350 mg, 1.09 mmol,
1.0 equiv), (S)-(þ)-phenyl glycinol (298 mg, 2.18 mmol,
2.0 equiv), palladium acetate (10 mg, 3 mol %), and dppp
(16 mg, 3 mol %) under an argon atmosphere at room tempera-
ture in a Schlenk flask. The flask was connected with a balloon
and flushed with carbon monoxide (carbon monoxide gas was
bubbled through the solution) and the reaction mixture was
heated under a carbon monoxide atmosphere at 70 ꢂC for
21 h. The solvent was then evaporated under reduced pressure.
Flash chromatography on silica gel (petroleum ethereethyl
acetate 1:1) yielded hydroxyamide (ꢁ)-16c (247 mg, 68%) as
a white crystalline solid: mp 130e132 ꢂC (ethyl acetateehex-
ane). [a]D ꢁ31.3 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d 0.57 (s, 3H), 1.21 (d, J¼10.0 Hz, 1H), 1.51 (s, 3H), 2.25e
2.30 (m, 1H), 2.67 (dt, J¼10.0, 5.6 Hz, 1H), 2.92 (d,
J¼2.8 Hz, 3H), 3.03 (dd, J¼7.2, 5.2 Hz, 1H), 3.88e4.00 (m,
2H), 5.16 (td, J¼6.8, 4.0 Hz, 1H), 7.23e7.36 (m, 5H), 7.48
(d, J¼7.6 Hz, 1H), 7.91 (d, J¼7.6 Hz, 1H), 8.58 (br d,
J¼6.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 21.7 (CH3),
26.3 (CH3), 31.0 (CH2), 31.8 (CH2), 39.5 (C), 40.3 (CH), 50.5
(CH), 57.2 (CH), 67.7 (CH2), 120.7 (CH), 127.4 (2ꢅCH),
128.3 (CH), 129.3 (2ꢅCH), 134.4 (C), 136.5 (CH), 139.4 (C),
145.6 (C), 165.6 (C), 166.1 (C); CIMS m/z (%) 337
([MþH]þ,100), 319 (5), 305 (6), 217 (7), 202 (1), 174 (3),
164 (4), 138 (2), 113 (4), 73 (7); HRMS (CI): 337.1916
(C21H25N2O2 requires: 337.1838).
4.1.11. Methyl ester (ꢁ)-17
A Schlenk flask was charged with triflate (ꢁ)-14 (1.679 g,
5.225 mmol), palladium acetate (34 mg, 0.151 mmol,
3 mol %), and dppf (185 mg, 0.334 mmol, 6 mol %) and put
under argon via three vacuum/argon cycles. Triethylamine
(1.5 mL, 10.762 mmol, 2.06 equiv), dimethyl formamide
(20 mL), and methanol (11 mL) were added via septum and
syringe, the Schlenk flask was connected to a balloon, and
flushed with carbon monoxide. The mixture was heated under
a carbon monoxide atmosphere at 80 ꢂC for 24 h and the prog-
ress of the reaction was monitored by TLC (petroleum ethere
ethereacetone 80:10:10, Rf¼0.3). The solvent was evaporated
in vacuo and the crude ester was chromatographed on a silica
gel column (1ꢅ15 cm) with a petroleum ethereethereacetone
mixture (80:10:10, 400 mL) to obtain the product (ꢁ)-17
(884 mg, 73%) as an oil. [a]D ꢁ9.5 (c 0.16, CH2Cl2); IR
(cmꢁ1) n 1724 vs, 1590 w, 1578 w, 1469 m, 1436 m, 1427
1
m, 1417 m, 1387 w, 1370 w, 1260 vs, 1127 s, 1001 w; H
NMR d 0.59 (s, 3H), 1.21 (d, J¼10.1 Hz, 1H), 1.35 (s, 3H),
2.25e2.30 (m, 1H), 2.65e2.70 (m, 1H), 2.94 (d, J¼2.4 Hz,
2H), 3.12 (t, J¼5.6 Hz, 1H), 3.91 (s, 3H), 7.48 (d, J¼7.6 Hz,
1H), 7.89 (d, J¼7.5 Hz, 1H); 13C NMR d 20.20 (CH3),
24.81 (CH3), 29.61 (CH2), 30.59 (CH2), 38.03 (C), 38.76
(CH), 49.31 (CH3), 51.77 (CH), 122.38 (CH), 134.15 (C),
134.79 (CH), 142.67 (C), 165.23 (C), 165.80 (C); MS (EI)
ꢄ
231 (Mþ , 3), 188 (9), 128 (14), 88 (10), 86 (66), 84 (100),
4.1.10. (þ)-(6R,8R)-N-[(1R)-2-Hydroxy-1-phenylethyl]-7,7-
dimethyl-5,6,7,8-tetrahydro-6,8-methanoquinoline-2-
51 (33), 49 (100), 47 (17); HRMS (EI): 231.1259
(C14H17NO2 requires: 231.1259).
carboxamide (þ)-16d15
Anhydrous triethylamine (3.34 mL, 24.0 mmol, 3.1 equiv)
was added to a mixture of triflate (ꢁ)-14 (2.51 g, 7.8 mmol,
1.0 equiv), (R)-(ꢁ)-phenylglycinol (2.14 g, 15.6 mmol,
2.0 equiv), palladium acetate (59 mg, 0.24 mmol, 3 mol %),
and dppp (101 mg, 0.24 mmol, 3 mol %) under an argon atmo-
sphere at room temperature in a Schlenk flask. The flask was
connected with a balloon and flushed with carbon monoxide
(carbon monoxide gas was bubbled through the solution)
and the reaction mixture was heated under a carbon monoxide
atmosphere at 70 ꢂC for 21 h. The solvent was then evaporated
under reduced pressure. Flash chromatography on silica gel
(petroleum ethereethyl acetate 1:1) yielded hydroxyamide
(þ)-16d (1.908 g, 73%) as a white crystalline solid: mp
180e182 ꢂC (ethyl acetateehexane). [a]D þ61.8 (c 1.0,
4.1.12. Alcohol (ꢁ)-18
LiAlH4 (310 mg, 8.153 mmol, 2 equiv) was added into a so-
lution of ester (ꢁ)-17 (943 mg, 4.076 mmol) in dry ether
(38 mL) under argon. The resulting mixture was stirred at
25 ꢂC for 48 h. The reaction was then quenched with MeOH
(10 mL) and filtered through silica gel (2.5ꢅ5 cm). The col-
umn was washed with ethyl acetate (150 mL). The resulting
solution was evaporated in vacuo and the residue was purified
by silica gel chromatography in ethyl acetate [2.5ꢅ28 cm; Rf
(product)¼0.53, Rf (starting material) w0.9] to give white
crystals (ꢁ)-18 (553 mg, 67%): mp 111e112 ꢂC (petroleum
1
ethereethyl acetate). [a]D ꢁ21.0 (c 1.0, CHCl3); H NMR
(400 MHz, CDCl3) d 0.58 (s, 3H), 1.99 (d, J¼9.72 Hz, 1H),
1.34 (s, 3H), 2.23e2.28 (m, 1H), 2.61e2.66 (m, 1H), 2.86
(s, 2H), 2.90 (t, J¼5.56 Hz, 1H), 3.89 (br s, 1H), 4.61 (s,
2H), 9.96 (d, J¼7.64 Hz, 1H), 7.32 (d, J¼7.64 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 21.61 (CH3), 26.41 (CH3), 31.12
(CH2), 31.38 (CH2), 39.49 (C), 40.52 (CH), 50.48 (CH),
64.54 (CH2), 118.38 (CH), 129.02 (C), 136.19 (CH), 154.90
1
CHCl3); H NMR (400 MHz, CDCl3) d 0.69 (s, 3H), 1.28
(d, J¼9.8 Hz, 1H), 1.46 (s, 3H), 2.34e2.39 (m, 1H), 2.75
(dt, J¼9.8, 5.9 Hz, 1H), 2.99e3.03 (m, 4H), 3.98e4.07 (m,
2H), 5.25e5.30 (m, 1H), 7.13e7.42 (m, 5H), 7.47 (d,
J¼7.6 Hz, 1H), 7.91 (d, J¼7.6 Hz, 1H), 8.59 (br d,
J¼6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 21.7 (CH3),
ꢄ
(C), 165.81 (C); MS (EI) m/z (%) 203.15 (Mþ , 12), 202.13

4020
A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
(7), 170.11 (7), 160.08 (20), 142.07 (25), 130.07 (14), 85.00
(55), 82.94 (100); HRMS (EI): 203.1310 (C13H17NO requires:
203.1310).
acetateemethanol 95:5, Rf¼0.9). The solvent was evaporated
in vacuo and the crude product was purified by flash chroma-
tography on a silica gel column (1ꢅ15 cm) with ethyl acetate
to afford product (þ)-23 (83 mg, 70%) as an oil. [a]D þ2.2 (c
0.09, CH2Cl2); IR (cmꢁ1) n 3388 w, 3055 w, 1665 vs, 1604 s,
1589 m, 1525 vs, 1508 vs, 1468 m, 1442 m, 1428 w, 1416 w,
1386 w, 1370 w, 1317 w, 1254 m, 1180 w, 1155 w, 1071 w,
4.1.13. Chloride (ꢁ)-19
A solution of thionyl chloride (0.52 mL, 7 mmol, 2.6 equiv)
in dry CH2Cl2 (6.7 mL) was added dropwise to a stirred mix-
ture of alcohol (ꢁ)-18 (540 mg, 2.669 mmol) in dry CH2Cl2
(6.7 mL) at 0 ꢂC under argon. The mixture was allowed to
warm to room temperature for 4e5 h and stirred at room
temperature for another 24 h. The solvent and the excess of
thionyl chloride were removed in vacuo and the residue was
extracted with CH2Cl2 (75 mL) and saturated aqueous solution
of sodium bicarbonate (40 mL). The organic layer was sepa-
rated and aqueous layer was washed with another portion of
CH2Cl2 (30 mL). The combined DCM extracts were dried
over anhydrous MgSO4 and the solvent was removed in vacuo
to give pure product as yellow amorphous solid (ꢁ)-19
(591 mg, 99%). [a]D ꢁ18.9 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) d 0.58 (s, 3H), 1.22 (d, J¼4.68 Hz, 1H),
1.34 (s, 3H), 2.23e2.28 (m, 1H), 2.62e2.67 (m, 1H), 2.87
(s, 2H), 2.91 (m, 1H), 4.54 (s, 2H), 7.17 (d, J¼7.68 Hz, 1H),
7.36 (d, J¼7.76 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 21.59 (CH3), 26.35 (CH3), 31.09 (CH2), 31.49 (CH2),
39.47 (C), 40.40 (CH), 47.40 (CH2), 50.63 (CH), 120.78
(CH), 130.18 (C), 136.36 (CH), 152.37 (C), 166.61 (C); MS
1
1031 vw, sh, 993 w, 872 w, 694 m, 510 w; H NMR d 0.57
(s, 3H), 1.20 (d, J¼9.6 Hz, 1H), 1.36 (s, 3H), 2.25e2.30 (m,
1H), 2.63e2.69 (m, 1H), 2.88e2.92 (m, 3H), 3.33 (t,
J¼6.0 Hz, 2H), 3.63e3.69 (m, 2H), 4.02e4.08 (m, 1H),
6.58 (d, J¼7.4 Hz, 2H), 6.63 (t, J¼7.0 Hz, 1H), 7.08e7.13
(m, 2H), 7.48 (d, J¼7.6 Hz, 1H), 7.91 (d, J¼7.4 Hz, 1H),
8.22 (br s, 1H); 13C NMR d 21.69 (CH3), 26.34 (CH3),
31.02 (CH2), 31.76 (CH2), 39.30 (CH2), 39.52 (C), 40.29
(CH), 44.63 (CH2), 50.50 (CH), 113.10 (CH), 117.79 (CH),
120.51 (CH), 129.68 (CH), 134.26 (C), 136.55 (CH), 145.80
(C), 148.39 (C), 165.55 (C), 166.15 (C); MS (EI) m/z (%)
ꢄ
335 (Mþ , 19), 230 (31), 229 (8), 218 (12), 217 (80), 201
(8), 200 (7), 174 (15), 173 (100), 172 (18), 157 (7), 130
(13), 129 (8), 128 (8), 119 (26), 118 (9), 106 (35), 86 (32),
84 (50), 77 (16), 69 (10), 51 (16), 49 (46), 47 (10); HRMS
(EI): 335.1997 (C21H25N3O requires: 335.1998).
4.1.16. Phenyldiamine (ꢁ)-24
Method A: Lithium aluminum hydride (32 mg, 0.843 mmol,
3.5 equiv) was added to a solution of aminoamide (þ)-23
(80 mg, 0.238 mmol) in tetrahydrofuran (7 mL) under argon
at 0 ꢂC. The flask was fitted with a condenser, the mixture
was allowed to heat up, stirred at room temperature for 5 h,
and then heated to reflux for 23 h under argon. The excess
of the reducing agent was quenched by addition of sodium
sulfate decahydrate (5 g). The mixture was filtered through
Celite (washed with ethyl acetate). Flash chromatography of
the crude product on silica gel (1ꢅ15 cm; ethyl acetateemeth-
anol 95:5, Rf¼0.1, and then ethyl acetateemethanol 80:20,
Rf¼0.3) afforded aminoaniline (ꢁ)-24 (15 mg, 20%) as an oil.
Method B: Methanol (20 mL) and 5% palladium on carbon
(140 mg) were added to a flask containing aldehyde (ꢁ)-28
(254 mg, 1.262 mmol) and N1-phenyl-1,2-ethylenediamine
22 (174 mg, 1.278 mmol, 1.01 equiv) under argon. The system
was put scrupulously under argon via three vacuum/argon cy-
cles. The fourth evacuation was followed by filling with hy-
drogen gas from a fitted balloon. The mixture was stirred
vigorously for 6 h under a hydrogen atmosphere at room tem-
perature and the progress of the reaction was monitored by
TLC (ethyl acetateemethanol 80:20, Rf¼0.3). The solvent
was then evaporated in vacuo and the residue was chromato-
graphed on silica gel [2ꢅ10 cm; ethyl acetateemethanol
95:5, Rf¼0.1 (150 mL), followed by ethyl acetateemethanol
80:20, Rf¼0.3 (200 mL)] to obtain aminoaniline (ꢁ)-24
(324 mg, 80%) as an oil. [a]D ꢁ3.5 (c 0.23, CH2Cl2); IR
(cmꢁ1) n 3392 w, br, 3448 w, sh, 3312 w, br, sh, 3055 w,
1604 vs, 1591 m, 1584 m, sh, 1506 vs, 1469 m, 1450 m,
1431 m, 1416 m, 1386 w, 1369 w, 1322 m, 1260 m, br,
1180 w, 1155 w, 1114 w, br, 1070 w, 1030 w, sh, 993 w,
ꢄ
(EI), m/z (%) 221.1 (Mþ , 5), 186.1 (16), 142.1 (14), 82.9
(100); HRMS (EI): 221.0971 (C13H16ClN requires: 221.0971).
4.1.14. 1,2,5-Triphenyl-1H-phosphole (20)
A 50 mL round bottom flask equipped with air condenser
and stirring bar was charged with 1,4-diphenyl-1,3-butadiene
(2.00 g, 9.7 mmol) and phenylphosphonous acid dichloride
(7 mL). The mixture was heated at 225 ꢂC under argon for
3 h. The cooled yellow solid was transferred into ice-cold
15% aqueous KOH (100 mL) and pulverized by vigorous stir-
ring. The yellow precipitate was filtered off, washed with 15%
potassium hydroxide (50 mL) and with water (2ꢅ100 mL).
The precipitate was dried in vacuo using an oil pump and crys-
tallized from chloroform. The mother liquor was concentrated
to half of original volume and crystallized again to give yellow
crystals 20 (2.00 g, 66%). The identity of the product was con-
firmed by comparison of the 1H NMR spectrum of the product
with the analytical data in Ref. 57.
4.1.15. Anilinoamide (þ)-23
A Schlenk flask was charged with triflate (ꢁ)-14 (114 mg,
0.355 mmol), palladium acetate (3 mg, 0.013 mmol, 4 mol %),
and dppp (5 mg, 0.012 mmol, 3 mol %) and placed under
argon via three vacuum/argon cycles. N1-Phenyl-1,2-ethylene-
diamine (90 mL, 0.688 mmol, 1.9 equiv) and triethylamine
(150 mL, 1.08 mmol, 3.0 equiv) were added via septum and
syringe. The Schlenk flask was connected to a balloon and
flushed with carbon monoxide. The mixture was heated neat
under a carbon monoxide atmosphere at 70 ꢂC for 24 h. The
progress of the reaction was monitored by TLC (petroleum
ethereethereacetoneemethanol 50:30:17:3, Rf¼0.6, or ethyl
1
871 w, 694 m, 511 w, 409 w; H NMR d 0.57 (s, 3H), 1.20

A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
4021
(d, J¼9.7 Hz, 1H), 1.34 (s, 3H), 2.22e2.26 (m, 1H), 2.60e
2.65 (m, 1H), 2.84 (br s, 2H), 2.88 (t, J¼5.5 Hz, 2H), 3.18
(t, J¼5.5 Hz, 2H), 3.79 (s, 2H), 6.56 (d, J¼7.8 Hz, 2H), 6.62
(t, J¼7.7 Hz, 1H), 6.98 (d, J¼8.1 Hz, 1H), 7.07e7.12 (m,
2H), 7.29 (d, J¼7.6 Hz, 1H); 13C NMR d 21.61 (CH3),
26.41 (CH3), 31.15 (CH2), 31.39 (CH2), 39.49 (C), 40.45
(CH), 43.60 (CH2), 48.52 (CH2), 50.61 (CH), 54.78 (CH2),
113.28 (CH), 117.66 (CH), 120.26 (CH), 128.95 (C), 129.60
(CH), 136.10 (CH), 148.79 (C), 154.49 (C), 166.43 (C); MS
from chloroform to afford the tetrafluroborate salt, which was
filtered off and washed with ether. The product 27 (122 mg,
1
41%) was obtained as brownish crystals: mp 98e100 ꢂC; H
NMR d 4.17 (t, J¼9.5 Hz, 2H), 4.36 (t, J¼11.0 Hz, 2H), 4.94
(s, 2H), 7.19e7.26 (m, 4H), 7.35 (t, J¼8.6 Hz, 2H), 7.42 (d,
J¼7.0 Hz, 1H), 7.65e7.69 (m, 1H), 8.49e8.50 (m, 1H), 8.85
(s, 1H); 13C NMR d 47.79, 48.11, 52.28, 117.17, 122.68,
122.74, 126.43, 129.16, 136.68, 148.73, 154.14; HRMS
(FAB): 238.1344 (C15H16N3, i.e., MꢁBF4, requires: 238.1344).
ꢄ
(EI) m/z (%) 321 (Mþ , 3), 216 (37), 215 (100), 204 (25),
203 (100), 188 (10), 187 (64), 186 (35), 171 (13), 170 (9),
157 (9), 145 (17), 144 (27), 143 (22), 133 (24), 131 (10),
130 (16), 119 (21), 106 (32), 105 (12), 91 (10), 86 (19), 84
(29), 77 (20), 51 (12), 49 (35); HRMS (EI): 321.2206
(C21H27N3 requires: 321.2205).
4.1.19. Aldehyde (ꢁ)-28
Diisobutylaluminum hydride (1.75 mL, neat, 9.819 mmol,
2.7 equiv) was added dropwise to a solution of ester (ꢁ)-17
(846 mg, 3.658 mmol) in dichloromethane (90 mL) under ar-
gon at ꢁ78 ꢂC and the mixture was stirred at ꢁ78 ꢂC for
1 h. The progress of the reaction was monitored by TLC (pe-
troleum ethereethereacetone 80:10:10, Rf¼0.8). Upon com-
pletion, saturated aqueous solution of ammonium chloride
(35 mL) was added at ꢁ78 ꢂC under argon, the organic phase
was separated, and the aqueous layer was extracted with
dichloromethane (5ꢅ10 mL). The combined organic extracts
were dried over anhydrous MgSO4 and filtered, the solvent
was removed in vacuo, and the residue was chromatographed
on silica gel (4ꢅ10 cm; petroleum ethereethereacetone
80:10:10) to furnish aldehyde (ꢁ)-28 (553 mg, 75%) as an
oil that solidified upon refrigerating: mp 47e49 ꢂC. [a]D
ꢁ30.2 (c 0.21, CH2Cl2); IR (cmꢁ1) n 2833 m, 1704 vs, 1584
m, 1572 s, 1471 m, 1444 m, 1432 w, 1420 m, 1387 m, 1371
m, 1361 w, 1004 w; 1H NMR d 0.60 (s, 3H), 1.24 (d,
J¼10.1 Hz, 1H), 1.39 (s, 3H), 2.28e2.33 (m, 1H), 2.69e
2.75 (m, 1H), 2.96e2.97 (m, 2H), 3.04 (t, J¼6.1 Hz, 1H),
7.52 (d, J¼7.5 Hz, 1H), 7.71 (d, J¼7.6 Hz, 1H), 9.95 (s,
1H); 13C NMR d 20.22 (CH3), 24.86 (CH3), 29.62 (CH2),
30.80 (CH2), 38.13 (C), 38.80 (CH), 49.20 (CH), 119.37
(CH), 134.79 (CH), 135.27 (C), 148.16 (C), 166.19 (C),
4.1.17. N1-Phenyl-N2-(2-pyridinylmethyl)-1,2-ethane-
diamine (26)
Methanol (35 mL) and 5% palladium on carbon (492 mg)
were added to a flask containing 2-pyridinecarboxaldehyde
(529 mg, 4.939 mmol) and N1-phenyl-1,2-ethylenediamine
22 (673 mg, 4.941 mmol, 1.0 equiv) under argon. The system
was put scrupulously under argon via three vacuum/argon
cycles. The fourth evacuation was followed by filling with
hydrogen gas from a fitted balloon. The mixture was stirred
vigorously under a hydrogen atmosphere at room temperature
for 2 h. The progress of the reaction was monitored by TLC
(petroleum ethereethereacetone 80:10:10, Rf¼0.3). The
solvent was evaporated in vacuo and the residue was chroma-
tographed on silica gel (2ꢅ15 cm; ethyl acetateemethanol
80:20, 200 mL) to yield the product 26 (844 mg, 75%) as an
oil that solidified upon freezing: mp 32e34 ꢂC. IR (cmꢁ1) n
3445 w, sh, 3396 w, br, 3353 w, br, sh, 3315 w, br, sh, 3055
w, 1604 vs, 1594 s, sh, 1572 m, 1506 vs, 1477 s, 1433 s,
1321 m, 1259 m, 1180 m, 1156 m, sh, 1120 m, br, 1073 w,
1029 w, 996 m, 871 w, 694 s, 511 m, 404 m; 1H NMR
d 2.87 (t, J¼5.5 Hz, 2H), 3.18 (t, J¼5.5 Hz, 2H), 3.87 (s,
2H), 6.57 (d, J¼8.4 Hz, 2H), 6.63 (t, J¼7.6 Hz, 1H), 7.08e
7.12 (m, 3H), 7.21 (d, J¼7.4 Hz, 1H), 7.57 (dt, J¼1.5,
7.5 Hz, 1H), 8.49 (d, J¼4.8 Hz, 1H); 13C NMR d 43.88
(CH2), 48.68 (CH2), 55.16 (CH2), 113.33 (CH), 117.71
(CH), 122.42 (CH), 122.69 (CH), 129.59 (CH), 136.89
(CH), 148.85 (C), 149.73 (CH), 159.93 (C); MS (EI) m/z
ꢄ
192.43 (CO); MS (EI) m/z (%) 201 (Mþ , 21), 186 (21), 159
(34), 158 (100), 157 (19), 130 (32), 129 (20), 128 (20), 117
(10), 86 (19), 85 (17), 84 (30), 83 (26), 77 (11), 51 (12), 49
(31), 47 (11); HRMS (EI): 201.1153 (C13H15NO requires:
201.1154).
4.1.20. N1-Mesityl-1,2-ethanediamine (29)
Hydrazinemonohydrate(0.290 mL,5.950 mmol,2.03 equiv)
was added to a solution of phthalimide 32 (905 mg, 2.935 mmol)
inethanol(30 mL)under argonat room temperatureandthemix-
ture was refluxed for 2.5 h under argon. The progress of the reac-
tion was monitored by TLC (ethyl acetateemethanol 80:20).
Upon completion, the mixture was cooled and the white precip-
itate was filtered off and washed with ethanol (20 mL). The
filtrate was evaporated in vacuo, the residue was dissolved in
dichloromethane (15 ml) and water was added (10 mL). The
organic phase was separated and the aqueous was extracted
with dichloromethane (2ꢅ15 mL). Combined extracts were
dried over anhydrous MgSO4, filtered, and the solvent was re-
moved in vacuo to afford diamine 29 (469 mg, 90%) as a CO2-
sensitive oil (stored under Ar in the freezer). IR (cmꢁ1) n 3383
w, 1485 vs, 1444 m, 1375 m, 1304 m, 1232 m, 1155 m, 1102
ꢄ
(%) 227 (Mþ , 4), 122 (33), 121 (100), 120 (8), 119 (33),
118 (10), 110 (10), 109 (100), 107 (38), 106 (59), 94 (17),
93 (100), 92 (100), 88 (10), 86 (59), 84 (90), 79 (14), 78
(14), 77 (42), 66 (11), 65 (34), 51 (39), 49 (99), 48 (9), 47
(18); HRMS (EI): 227.1422 (C14H17N3 requires: 227.1422).
4.1.18. 2-Picolylphenylimidazolidinium tetrafluoro-
borate (27)
Triethyl orthoformate (1.25 mL, 7.515 mmol, 8.2 equiv) was
added to a mixture of diamine 26 (209 mg, 0.919 mmol) and
ammonium tetrafluoroborate (117 mg, 1.116 mmol, 1.2 equiv)
under argon and the mixture was heated under argon at
120 ꢂC for 5 h. The volatiles were evaporated on a rotavap (wa-
ter bath was heated up to 90 ꢂC) and the residue was crystallized

4022
A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
w, 1078 w, 1030 w, 960 w, 941 w, 858 s, 583 w, 567 w, 505 w; 1H
NMR d 1.98 (br s, 3H), 2.23 (s, 3H), 2.27 (s, 6H), 2.88e2.91 (m,
2H), 2.96e2.99 (m, 2H), 6.82 (s, 2H); 13C NMR d 18.35 (CH3),
20.55 (CH3), 42.60 (CH2), 51.30 (CH2), 129.43 (CH), 129.55
MgSO4, filtered, the solvent was removed in vacuo, and the
residue was chromatographed on silica gel (4ꢅ15 cm; petro-
leum ethereethyl acetate 90:10, 1 L, followed by petroleum
ethereethereacetone 80:10:10, 300 mL) to afford the product
32 (868 mg, 59%) as an oil. IR (cmꢁ1) n 3397 vw, br, 1774 m,
1712 vs, 1616 w, 1486 m, 1469 w, 1397 s, 1376 w, 1306 w,
1172 w, 1152 w, 1088 w, 1029 w, sh, 959 vw, 937 vw, 874
ꢄ
(C), 131.28 (C), 143.54 (C); MS (EI) m/z (%) 178 (Mþ , 14),
149 (12), 148 (100), 119 (10), 91 (11), 86 (22), 84 (34), 71 (9),
51 (13), 49 (37), 47 (8); HRMS (EI): 178.1470 (C11H18N2
requires: 178.1470).
1
w, 858 w, 798 m, 719 m, 717 m, 583 vw, 530 w; H NMR
d 2.17 (s, 3H), 2.20 (s, 6H), 3.26 (t, J¼6.6 Hz, 2H), 3.91 (t,
J¼6.6 Hz, 2H), 6.76 (s, 2H), 7.70e7.72 (m, 2H), 7.84e7.86
(m, 2H); 13C NMR d 18.31 (CH3), 20.50 (CH3), 38.69
(CH2), 46.69 (CH2), 123.29 (CH), 129.47 (CH), 129.58 (C),
131.41 (C), 132.06 (C), 133.99 (CH), 142.65 (C), 168.55
4.1.21. Pinene-derived N1-2-picolyl-N2-mesityl-1,2-ethane-
diamine (ꢁ)-30
Methanol (25 mL) and 5% palladium on carbon
(113 mg) were added to a flask containing aldehyde (ꢁ)-28
(200 mg, 0.994 mmol) and N1-mesityl-1,2-ethylenediamine
29 (179 mg, 1.004 mmol, 1.01 equiv) under argon. The system
was put under argon via three vacuum/argon cycles. The fourth
evacuation was followed by filling with hydrogen gas from
a fitted balloon. The reaction mixture was stirred vigorously
under a hydrogen atmosphere at room temperature for 3 h.
The disappearance of the aldehyde and development of the
product was monitored by TLC (petroleum ethereethereace-
tone 80:10:10, and ethyl acetateemethanol 80:20, Rf¼0.3).
The solvent was then evaporated in vacuo and the residue
was chromatographed on silica gel (2ꢅ15 cm; ethyl acetatee
methanol 80:20) to obtain the product (ꢁ)-30 (244 mg, 68%)
as an oil. [a]D ꢁ4.1 (c 0.19, CH2Cl2); IR (cmꢁ1) n 3349 w,
br, 1590 m, 1584 m, 1485 s, 1469 s, 1450 s, 1434 m, sh,
1416 s, 1386 w, 1375 w, sh, 1370 w, 1304 w, 1234 m, 1156
w, 1113 m, 1030 w, 1000 w, sh, 959 w, 858 m, 663 m, 584 w,
568 w, 505 w; 1H NMR d 0.65 (s, 3H), 1.29 (d, J¼9.5 Hz, 1H),
1.41 (s, 3H), 2.22 (s, 3H), 2.26 (s, 6H), 2.30e2.34 (m, 1H),
2.67e2.73 (m, 3H), 2.86 (t, J¼6.1 Hz, 2H), 2.92 (br s, 2H),
2.95 (t, J¼5.0 Hz, 1H), 3.07 (t, J¼5.0 Hz, 2H), 3.87 (s, 2H),
6.80 (s, 2H), 7.08 (d, J¼7.6 Hz, 1H), 7.36 (d, J¼7.5 Hz,
1H); 13C NMR d 18.44 (CH3), 20.54 (CH3), 21.21 (CH3),
26.05 (CH3), 30.79 (CH2), 31.04 (CH2), 39.13 (C), 40.17
(CH), 48.25 (CH2), 49.60 (CH2), 50.33 (CH), 54.90 (CH2),
119.64 (CH), 128.29 (C), 129.39 (CH), 129.63 (C), 131.02
(C), 135.58 (CH), 143.76 (C), 154.95 (C), 165.94 (C); MS
ꢄ
(CO); MS (EI) m/z (%) 308 (Mþ , 28), 149 (14), 148 (100),
119 (8), 86 (28), 84 (43), 51 (14), 49 (42); HRMS (EI):
308.1525 (C19H20N2O2 requires: 308.1525).
4.1.23. 2,6-Dimethylphenyl 1H-imidazole-1-carb-
oxylate (35a)
A solution of 2,6-dimethylphenol 33a (233 mg, 1.907 mmol)
and 1,10-carbonyldiimidazole (402 mg, 2.479 mmol, 1.3 equiv)
in dichloromethane (10 mL) was refluxed for 24 h under argon;
the progress of the reaction was monitored by TLC (petroleum
ethereethereacetone 80:10:10, Rf¼0.2). The solvent was then
removed in vacuo and the crude product was chromatographed
on a silica gel column (2ꢅ7 cm) with a petroleum ethereethere
acetoneemethanol mixture (50:30:17:3) to furnish pure product
35a (429 mg, 99%) as a white crystalline solid: mp 114e117 ꢂC
(petroleum ethereether 4:1); 1H NMR d 2.23 (s, 6H), 7.11e7.15
(m, 3H), 7.18 (br s, 1H), 7.60 (br s, 1H), 8.34 (s, 1H); 13C NMR
d 16.17 (CH3), 117.47 (CH), 127.04 (CH), 129.08 (CH), 130.06
(C), 131.20 (CH), 137.46 (CH), 146.46 (C), 147.25 (C); MS (EI)
ꢄ
216 (Mþ , 40), 144 (8), 123 (9), 122 (100), 121 (13), 107 (20),
105 (33), 103 (8), 95 (17), 91 (25), 84 (9), 79 (15), 78 (11), 77
(36), 68 (14), 65 (10), 49 (14); HRMS (EI): 216.0899
(C12H12N2O2 requires: 216.0899).
4.1.24. Mesityl 1H-imidazole-1-carboxylate (35b)
A solution of 2,4,6-trimethylphenol 33b (269 mg, 1.975 mmol)
and 1,10-carbonyldiimidazole (416 mg, 2.566 mmol, 1.3 equiv) in
dichloromethane (10 mL) was refluxed for 22.5 h under argon; the
progress of the reaction was monitored by TLC (petroleum ethere
ethereacetone 80:10:10, Rf¼0.3). The solvent was then removed
in vacuo and the crude product was chromatographed on a silica
gel column (2ꢅ15 cm) with a petroleum ethereethereacetonee
methanol mixture (50:30:17:3) to afford pure 35b (446 mg,
98%) as a white crystalline solid: mp 103e105 ꢂC (petroleum
ethereether 4:1); IR (cmꢁ1) n 3165 w, 3140 w, 2987 w, 2960 w,
sh, 2926 w, 2864 w, 1771 s, 1607 w, 1525 w, 1484 m, 1471 m,
1453 w, 1442 w, 1409 w, 1386 s, 1315 m, 1293 s, 1282 s, 1242
s, 1191 vs, 1184 s, 1163 m, 1124 m, 1095 m, 1058 m, 1036 w,
1019 w, 996 s, 900 w, 865 w, 833 w, 648 w; 1H NMR d 2.18 (s,
6H), 2.30 (s, 3H), 6.93 (s, 2H), 7.17 (br s, 1H), 7.59 (br s, 1H),
8.33 (br s, 1H); 13C NMR d 16.09 (CH3), 20.80 (CH3), 117.47
(CH), 129.57 (C), 129.67 (CH), 131.12 (CH), 136.68 (C),
ꢄ
(EI) m/z (%) 363 (Mþ , 1), 216 (18), 215 (100), 204 (17), 203
(100), 187 (39), 186 (12), 161 (20), 149 (8), 148 (21), 146
(15), 144 (10), 143 (8), 133 (9), 119 (9); HRMS (EI):
363.2674 (C24H33N3 requires: 363.2674).
4.1.22. 2-[20-(Mesitylamino)ethyl]-1H-isoindole-1,3(2H)-
dione (32)
Mesidine (0.670 mL, 4.772 mmol, 1 equiv) was added to N-
(2-bromoethyl)phthalimide 31 (1.214 g, 4.778 mmol) under
argon and the mixture was heated under argon at 160e
200 ꢂC for 45 min while stirring; the progress of the reaction
was checked by TLC (petroleum ethereethyl acetate 90:10
and petroleum ethereethereacetone 80:10:10). The mixture
solidified upon cooling, the solid material was dissolved in
dichloromethane (10 mL) and washed with 10% aqueous
solution of NaOH (30 mL). The organic phase was separated
and the aqueous layer was extracted with dichloromethane
(5ꢅ20 mL). The combined extracts were dried over anhydrous
ꢄ
137.46 (CH), 145.08 (C), 146.66 (C); MS (EI) 230 (Mþ , 38),
137 (10), 136 (100), 135 (15), 121 (23), 119 (26), 97 (9), 95

A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
4023
(12), 91 (34), 79 (9), 77 (13), 68 (11), 65 (9), 41 (11). HRMS (EI):
230.1055 (C13H14N2O2 requires: 230.1055).
4.1.27. General procedure for the reduction of allylic
benzoates 37b,c to allylic alcohols
A solution of allylic benzoate 37b,c (1.0 equiv) in THF
(10 mL) was added via cannula to a solution of LiAlH4
(2.0 equiv) in THF (5 mL) at 0 ꢂC under an argon atmosphere.
The mixturewas stirred at room temperature for 4 h, the reaction
was then quenched with aqueous NH4Cl (5 mL), product was
extracted into dichloromethane, and the organic solution was
dried over MgSO4. Concentration invacuo gave the crude allylic
alcohol, an aliquot of which was passed through a plug column
of silica gel, eluting with AcOEt to provide a GC sample. The
GC analysis was carried out using a Supelco b-DEXTM 120
fused capillary column (30 mꢅ0.25 mmꢅ0.25 mm film thick-
ness), carrier gas, He (flow 2 mL minꢁ1), injection temperature,
200 ꢂC; column temperature: initial temperature, 80 ꢂC
for 2 min; rate, 0.5 ꢂC/min; final temperature, 160 ꢂC
(tS¼15.86 min; tR¼16.46 min for the alcohol derived from
37b; tS¼30.89 min; tR¼31.89 min for the alcohol derived
from 37c).
4.1.25. 2,6-Diisopropylphenyl 1H-imidazole-1-
carboxylate (35c)
A solution of 2,6-diisopropylphenol 33c (278 mg, 1.559 mmol)
and 1,10-carbonyldiimidazole (333 mg, 2.054 mmol, 1.3 equiv) in
dichloromethane (10 mL) was refluxed for 24 h under argon; the
progress of the reaction was monitored by TLC (petroleum
ethereethereacetone 80:10:10, Rf¼0.4). The solvent was then re-
moved in vacuo and the crude product was chromatographed on
a silica gel column (2ꢅ7 cm) with a petroleum ethereethereace-
toneemethanol mixture (50:30:17:3) to give pure 35c (424 mg,
99%) as a white crystalline solid: mp 74e76 ꢂC (petroleum
ethereether 9:1); IR (cmꢁ1) n 3165 w, 3140 w, 3070 w, 3036 w,
2970 s, 2933 w, 2873 w, 1772 vs, 1609 vw, 1584 w, 1530 w,
1469 s, 1443 w, 1388 vs, 1366 w, 1314 s, 1291 vs, 1281 vs,
1258 m, 1241 vs, 1176 vs, 1148 w, 1110 w, sh, 1092 m, 1057 m,
1
1047 w, 994 s, 900 w, 831 w, 648 m; H NMR d 1.23 (d,
J¼6.7 Hz, 12H), 2.96 (septet, J¼6.7 Hz, 2H), 7.19e7.26 (m,
3H), 7.29e7.33 (m, 1H), 7.60 (br s, 1H), 8.34 (br s, 1H); 13C
NMR d 22.68 (CH3), 23.83 (CH3), 27.67 (CH), 117.51 (CH),
124.48 (CH), 127.72 (CH), 131.24 (CH), 137.46 (CH), 140.33
4.1.28. (ꢆ)-N-(2-Bromophenyl)-N-methyl-2-phenylpropan-
amide (ꢆ)-44
A
mixture of (ꢆ)-2-phenylpropionic acid (1.374 g,
9.15 mmol, 1.13 equiv) and thionyl chloride (1.4 mL,
19.181 mmol, 2.4 equiv) was refluxed for 3 h under argon.
Toluene was added (5 mL) and the excess of thionyl chloride
was distilled off on a rotary evaporator in vacuo; this proce-
dure was carried out twice. Crude 2-phenylpropanoyl chloride
was dissolved in toluene (8 mL) and added to a solution of 2-
bromo-N-methylaniline55 (1.509 g, 8.11 mmol), DMAP
(64 mg, 0.524 mmol, 6.5 mol %), and triethylamine (1.3 mL,
9.33 mmol, 1.15 equiv) in toluene (5 mL) under argon. The
reaction mixture was refluxed 13 h under argon, while the
reaction progress was monitored by TLC (petroleum ethere
ethereacetone 80:10:10, Rf¼0.6). The white precipitate was
filtered off and washed with toluene (30 mL). The filtrate
was evaporated in vacuo and the residue was purified via flash
chromatography on a column of silica gel (2ꢅ10 cm) with a
petroleum ethereether (95:5) mixture to elute impurities,
followed by a petroleum ethereethereacetone (80:10:10)
mixture to afford amide (ꢆ)-44 (2.276 g, 88%) as a yellow
oil.50 IR (cmꢁ1) n 3087 w, 3065 w, 3029 m, 3011 s, 1661 vs,
br, 1651 vs, br, sh, 1602 m, 1585 m, 1478 vs, 1454 s, 1435
m, 1422 m, 1382 s, 1283 s, 1248 m, 1182 w, 1160 w, 1133
m, 1120 m, 1068 w, 1048 s, 1032 s, 1005 w, 989 w, 947 w,
913 w, 700 s, 667 vvs; NMR corresponds to that reported in
the literature;50 MS (EI) 239 (51), 238 (MꢁBr, 100), 214
(64), 212 (66), 187 (37), 186 (16), 185 (39), 184 (16), 132
(9), 106 (15), 105 (100), 104 (23), 103 (18), 87 (12), 86
(22), 85 (71), 84 (34), 83 (94), 79 (21), 78 (14), 77 (43), 51
(12), 49 (30), 48 (10), 47 (22); HRMS (EI): 238.1232
(C16H16NO requires: 238.1232).
ꢄ
(C), 144.64 (C), 147.33 (C); MS (EI) m/z (%) 272 (Mþ , 6), 205
(48), 204 (55), 189 (7), 178 (7), 177 (15), 176 (27), 164 (8), 163
(62), 162 (14), 161 (100), 147 (11), 145 (10), 135 (8), 133 (21),
128 (8), 119 (8), 117 (17), 115 (10), 105 (11), 95 (16), 91 (38),
77 (9), 69 (10), 68 (12), 43 (18), 41 (13); HRMS (EI): 272.1523
(C16H20N2O2 requires: 272.1525).
4.1.26. General procedure for asymmetric allylic oxidation
catalyzed by Cu(I) complexes58
Ligand 8 (0.06 mmol, 6 mol %) and (TfO)2Cu (18 mg,
0.05 mmol, 5 mol %) were dissolved in acetone (4 mL) and
the green solution was stirred under an argon atmosphere
at room temperature for 1 h. Phenylhydrazine (7 mL,
0.07 mmol) was then added and the color of the solution
changed to red. After 10 min, olefin 36aec (5.0 mmol,
5.0 equiv) was added at the temperature indicated in Table 1,
followed by a dropwise addition of tert-butyl peroxybenzoate
(0.2 mL, 1.0 mmol, 1.0 equiv). The progress of the reaction
was monitored by TLC (hexaneeethyl acetate 9:1). Disappear-
ance of the peroxy ester indicated the completion of the reac-
tion. The solvent was then removed under reduced pressure,
the residue was dissolved in CH2Cl2 (15 mL), and the solution
was washed successively with saturated NaHCO3 (aq) solution,
brine, and water, and dried over MgSO4. Concentration and
chromatography on silica gel (hexaneeethyl acetate 10:1) af-
forded pure allylic benzoates 37aec. The yields and ee are
given in Table 1. Enantiomeric purity was determined by chiral
HPLC, as described by us earlier (for 37a),4 or via reduction
of the allylic benzoate to the corresponding allylic alcohol
(for 37b,c), as described below, followed by chiral GC
analysis. HPLC analysis of 37a: Chiracel OD-H, hexanee
2-propanol 99.8:0.2, 1.0 mL minꢁ1 (tS¼17.75 min, tR¼
20.31 min).
4.1.29. 1,3-Dimethyl-3-phenylindolin-2-one (45)
Amixtureofthecarbeneprecursor(þ)-10(5 mg,0.011 mmol,
5 mol %), palladium(II) acetate (3 mg, 0.013 mmol, 5 mol %),
and t-BuONa (45 mg, 0.468 mmol, 2 equiv) under argon was

4024
A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
ꢀ
´
4. (a) Malkov, A. V.; Bella, M.; Langer, V.; Kocovsky, P. Org. Lett. 2000, 2,
3047; (b) Malkov, A. V.; Baxendale, I. R.; Bella, M.; Langer, V.; Fawcett,
suspended in freshly distilled 1,4-dioxane (0.5 mL) at room tem-
perature. A solution of amide 44 (75 mg, 0.236 mmol, 1 equiv) in
dry 1,4-dioxane (1.5 mL) was then added and the resulting mix-
ture was stirred at 100 ꢂC for 5 h. Formation of the product and
consumption of the starting material was detected by TLC (petro-
leum ethereethyl acetate 85:15; product 45 had Rf¼0.2, starting
material 44 had Rf¼0.3). The reaction mixture was quenched
with saturated aqueous NH4Cl (10 ml) and extracted with diethyl
ether (3ꢅ10 mL), the combined extracts were dried over anhy-
drous MgSO4, and the filtered solution was evaporated in vacuo.
The residue was purified by flash chromatography on a column of
silica gel (15ꢅ1 cm) with a petroleum ethereethyl acetate mix-
ture (85:15) to afford 45 (47 mg, 0.198 mmol, 84%) as a colorless
oil, whose NMR data corresponded to those published.50 IR
(cmꢁ1) n 1716; MS (EI) m/z 237 [Mþ] (34), 222 (39), 195 (9),
86 (56), 84 (89), 51 (34), 49 (100), 47 (17); HRMS (EI):
237.1154 (C16H15NO requires: 237.1155). The enantiomeric
composition of 45 was determined by chiral HPLC using Chiral-
cel OD-H, hexanee2-propanol 98:2, flow rate 1.0 mL minꢁ1
(t1¼11.82 min, t2¼13.65 min).
ꢀ
J.; Russell, D. R.; Mansfield, D. J.; Valko, M.; Kocovsky, P. Organometallics
2001, 20, 673; (c) Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa,
´
´
ꢀ
´
A.; Teply, F.; Meghani, P.; Kocovsky, P. J. Org. Chem. 2003, 68, 4727.
5. (a) Malkov, A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.; Langer, V.;
ꢀ
´
Meghani, P.; Kocovsky, P. Org. Lett. 2002, 4, 1047; (b) Malkov, A. V.;
´
ꢀ
Bell, M.; Vassieu, M.; Bugatti, V.; Kocovsky, P. J. Mol. Catal. A: Chem.
´
ꢀ
´
2003, 196, 179; (c) Malkov, A. V.; Dufkova, L.; Farrugia, L.; Kocovsky,
P. Angew. Chem., Int. Ed. 2003, 42, 3674; (d) Malkov, A. V.; Bell, M.;
Orsini, M.; Pernazza, D.; Massa, A.; Herrmann, P.; Meghani, P.;
ꢀ
´
Kocovsky, P. J. Org. Chem. 2003, 68, 9659; (e) Malkov, A. V.; Bell,
M.; Castelluzzo, F.; Kocovsky, P. Org. Lett. 2005, 7, 3219; For recent
ꢀ
´
ꢀ
overviews, see: (f) Kocovsky, P.; Malkov, A. V. Izv. Akad. Nauk, Ser.
Khim. 2004, 1733; Russ. Chem. Bull. Int. Ed. 2004, 59, 1806; (g) Malkov,
´
ꢀ
´
A. V.; Kocovsky, P. Eur. J. Org. Chem. 2007, 29.
´
´
´
6. Malkov, A. V.; Stewart-Liddon, A. J. P.; Ramırez-Lopez, P.; Bendova, L.;
ꢀ
´
Haigh, D. Z.; Kocovsky, P. Angew. Chem., Int. Ed. 2006, 45, 1432.
´
7. Malkov, A. V.; Bella, M.; Stara, I. G.; Kocovsky, P. Tetrahedron Lett.
ꢀ
´
2001, 42, 3045.
8. (a) Chelucci, G.; Saba, A.; Soccolini, F. Tetrahedron Lett. 2001, 57, 9989;
ꢀ
´
(b) Kocovsky, P. J. Organomet. Chem. 2003, 687, 256.
9. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric
Catalysis; Springer: Heidelberg, 1999; Vols. IeIII.
ˇ
10. For an overview, see also the reference section in: Vyskocil, S.; Smrcina,
ꢀ
M.; Hanus, V.; Polasek, M.; Kocovsky, P. J. Org. Chem. 1998, 63, 7738.
ꢀ
ˇ
´ˇ
ꢀ
´
11. (a) Ofele, K. J. Organomet. Chem. 1968, 12, P42; (b) Wanzlink, H.-W.;
Acknowledgements
¨
Schonherr, H.-J. Angew. Chem., Int. Ed. Engl. 1968, 7, 141; (c) Arduengo,
¨
A. J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361.
We thank EPSRC for grant No. GR/T27051/01 and EPSRC
and GlaxoSmithKline for an industrial CASE award. We are
also grateful to Dr. Alfred Bader, the Socrates Exchange pro-
gram, and the University of Glasgow for an additional support.
We thank Dr. Pavel Fiedler of the Institute of Organic Chem-
istry and Biochemistry, Academy of Sciences of the Czech
Republic, for measuring some of the IR spectra.
12. For reviews on stable carbenes, see: (a) Bourissou, D.; Guerret, O.;
€
Gabbaı, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39; (b) Arduengo,
A. J. Acc. Chem. Res. 1999, 32, 913; For recent highlights on heterocyclic
carbenes, see: (c) Hahn, F. E. Angew. Chem., Int. Ed. 2006, 45, 1348; (d)
Kirmse, W. Angew. Chem., Int. Ed. 2004, 43, 1767 and references therein.
13. For reviews on N-heterocyclic carbenes: (a) Herrmann, W. A. Angew.
Chem., Int. Ed. 2002, 41, 1291; (b) Perry, M. C.; Burgess, K. Tetrahe-
´
dron: Asymmetry 2003, 14, 951; (c) Cesar, V.; Bellemin-Laponnaz, S.;
Gade, L. H. Chem. Soc. Rev. 2004, 33, 619; (d) Kantchev, E. A. B.;
O’Brien, C. J.; Organ, M. G. Angew. Chem., Int. Ed. 2007, 46, 2768;
Supplementary data
´
(e) Marion, N.; Dıez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int.
´
Ed. 2007, 46, 2988.
Crystallographic data (excluding structure factors) for the
structures 10, 35a, and 35b have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publi-
cation nos. CCDC 638212, 676789, and 676790. Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
þ44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk). Sup-
plementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.02.045.
14. For selected examples of chiral N-heterocyclic carbenes: (a) Ma, Y.; Song,
C.; Ma, C.; Sun, Z.; Chai, Q.; Andrus, M. B. Angew. Chem., Int. Ed. 2003,
42, 5871; (b) Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.; Reibens-
pies, J. H.; Burgess, K. J. Am. Chem. Soc. 2003, 125, 113; (c) Duan,
W.-L.; Shi, M.; Rong, G.-B. Chem. Commun. 2003, 2916; (d) Bonnet,
L. G.; Douthwaite, R. E.; Kariuki, B. M. Organometallics 2003, 22,
4187; (e) Gischig, S.; Togni, A. Organometallics 2004, 23, 2479; (f)
Arnold, P. L.; Rodden, M.; Davis, K. M.; Scarisbrick, A. C.; Blake,
A. J.; Wilson, C. Chem. Commun. 2004, 1612; (g) Catalano, V. J.;
Malwitz, M. A.; Etogo, A. O. Inorg. Chem. 2004, 43, 5714; (h) Tominaga,
S.; Oi, Y.; Kato, T.; An, D. K.; Okamoto, S. Tetrahedron Lett. 2004, 45,
5585; (i) Focken, T.; Rudolph, J.; Bolm, C. Synthesis 2005, 429; (j)
References and notes
Kremzow, D.; Seidel, G.; Lehmann, C. W.; Furstner, A. Chem.dEur. J.
¨
2005, 11, 1833; (k) Clavier, H.; Coutable, L.; Guillemin, J.-C.; Mauduit,
M. Tetrahedron: Asymmetry 2005, 16, 921; (l) Van Veldhuizen, J. J.;
Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc.
2005, 127, 6877; (m) Song, C.; Ma, C.; Ma, Y.; Feng, W.; Ma, S.;
1. For leading references, see: (a) Chelucci, G.; Thummel, R. P. Chem. Rev.
ꢀ
´
2002, 102, 3129; (b) Malkov, A. V.; Kocovsky, P. Curr. Org. Chem. 2003,
7, 1737; (c) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; Wiley-
VCH: New York, NY, 2000; For recent examples from our laboratory,
´
Chai, Q.; Andrus, M. B. Tetrahedron Lett. 2005, 46, 3241; (n) Cesar,
ꢀ
´
see, e.g.: (d) Malkov, A. V.; Hand, J. B.; Kocovsky, P. Chem. Commun.
V.; Bellemin-Laponnaz, S.; Wadepohl, H.; Gade, L. H. Chem.dEur. J.
2005, 11, 2862; (o) Chianese, A. R.; Crabtree, R. H. Organometallics
2005, 24, 4432; (p) Ma, M.; Peng, L.; Li, C.; Zhang, X.; Wang, J.
J. Am. Chem. Soc. 2005, 127, 15016; (q) For asymmetric cross- and
ring-opening cross-metathesis, see: Berlin, J. M.; Goldberg, S. D.; Grubbs,
R. H. Angew. Chem., Int. Ed. 2006, 45, 7591 and references therein.
15. For the method, see: (a) Meyers, A. I.; Robichaud, A. J.; McKennon, M. J.
´
2003, 1948; (e) Malkov, A. V.; Gouriou, L.; Lloyd-Jones, G. C.; Stary,
´
ꢀ
I.; Langer, V.; Spoor, P.; Vinader, V.; Kocovsky, P. Chem.dEur. J.
2006, 12, 6910.
2. (a) Cragg, P. A Practical Guide to Supramolecular Chemistry; J. Wiley &
Sons: New York, NY, 2005; (b) Steed, J. W.; Atwood, J. L. Supramole-
cular Chemistry; J. Wiley & Sons: New York, NY, 2000.
3. For the importance of a pyridine motif in drug discovery, see, e.g.: Laird,
T. Org. Process Res. Dev. 2006, 10, 851 and references therein.
Tetrahedron Lett. 1992, 33, 1181; (b) Brunner, H.; Storiko, R.; Nuber, B.
Tetrahedron: Asymmetry 1998, 9, 407.
¨

A.V. Malkov et al. / Tetrahedron 64 (2008) 4011e4025
4025
16. For the method, see: (a) Denmark, S. E.; Nakajima, N.; Nicaise, O. J.;
Faucher, A.; Edwards, J. P. J. Org. Chem. 1995, 60, 4884; (b) Gibertson,
S. R.; Xie, D.; Fu, Z. J. Org. Chem. 2001, 66, 7240.
116, 2742; (e) Andrus, M. B.; Zhou, Z. J. Am. Chem. Soc. 2002, 124,
8806.
36. (a) Kawasaki, K.; Tsumura, S.; Katsuki, T. Synlett 1995, 1245; (b)
Kawasaki, K.; Katsuki, T. Tetrahedron 1997, 53, 6337.
17. For the procedure, see: (a) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G.
Tetrahedron Lett. 1986, 27, 3931; (b) Choshi, T.; Yamada, S.; Sugino, E.;
Kuwada, T.; Hibino, S. J. Org. Chem. 1995, 60, 5899.
37. (a) DattaGupta, A.; Singh, V. K. Tetrahedron Lett. 1996, 37, 2633; (b)
Sekar, G.; DattaGupta, A.; Singh, V. K. J. Org. Chem. 1998, 63, 2961.
38. For a review of recent advances in the asymmetric hydrosilylation of
18. Phosphane 20 was obtained by heating a mixture of (E,E)-1,4-diphenyl-
butadiene with PhPCl2 at 220 ꢂC for 3 h: Thoumazet, C.; Melaimi, M.;
Ricard, L.; Mathey, F.; Le Floch, P. Organometallics 2003, 22,
1580.
€
ketones and imines see: Riant, O.; Mostefaı, N.; Courmacel, J. Synthesis
2004, 18, 2943.
39. (a) Brunner, H.; Obermann, U. Chem. Ber. 1989, 122, 499; (b) Brunner,
H.; Brandl, P. J. Organomet. Chem. 1990, 390, C81; (c) Brunner, H.;
Brandl, P. Tetrahedron: Asymmetry 1991, 2, 919; (d) Nishiyama, H.;
Sakaguchi, H.; Nakamura, T.; Horihata, M.; Kondo, M.; Itoh, K. Organo-
metallics 1989, 8, 846; (e) Nishiyama, H.; Kondo, M.; Nakamura, T.;
Itoh, K. Organometallics 1991, 10, 500.
19. For the procedure, see: Zhang, Y.; Du, D.; Chen, X.; Lu, S.; Hua, W.
Tetrahedron: Asymmetry 2004, 15, 177.
20. Deroche, A.; Morgenstern-Badarau, I.; Cesario, M.; Guilhem, J.; Keita,
´
B.; Nadjo, L.; Houee-Levin, C. J. Am. Chem. Soc. 1996, 118, 4567.
21. For recent strategies towards unsymmetric carbene precursors, see: (a)
´
Furstner, A.; Alcarazo, M.; Cesar, V.; Lehmann, C. W. Chem. Commun.
2006, 2176; (b) Paczal, A.; Benyei, A. C.; Kotschy, A. J. Org. Chem.
40. See Ref. 15b.
41. See Ref. 6.
¨
´
2006, 71, 5969 and references therein.
42. For other organocatalytic hydrosilylation reactions, see: (a) Malkov, A. V.;
ꢀ
´
Mariani, A.; MacDougall, K. N.; Kocovsky, P. Org. Lett. 2004, 6, 2253;
22. For the method, see: (a) Seiders, T. J.; Ward, W. D.; Grubbs, R. H. Org.
Lett. 2001, 3, 3225; (b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168.
ꢀ
(b) Malkov, A. V.; Stoncius, S.; MacDougall, K. N.; Mariani, A.;
ꢀ
´
McGeoch, G. D.; Kocovsky, P. Tetrahedron 2006, 62, 264; (c) Malkov,
ꢀ ꢀ ´
A. V.; Figlus, M.; Stoncius, S.; Kocovsky, P. J. Org. Chem. 2007, 72,
23. For the procedure, see: Choshi, T.; Kuwada, T.; Fukui, M.; Matsuya, Y.;
Sugino, E.; Hibino, S. Chem. Pharm. Bull. 2000, 48, 108.
ꢀ
ꢀ
´
1315; (d) Malkov, A. V.; Stoncius, S.; Kocovsky, P. Angew. Chem., Int.
24. For the procedure, see: McMaster, P. D.; Byrnes, E. W.; Block, A. J.;
Tenthorey, P. A. J. Med. Chem. 1981, 24, 53.
Ed. 2007, 46, 3722.
43. (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977,
99, 3179; (b) For a review of this area see: Denmark, S. E.; Fu, J. Chem.
Rev. 2003, 103, 2763.
44. Chen, C.; Tagami, K.; Kishi, Y. J. Org. Chem. 1995, 60, 5386.
45. (a) Sugimoto, K.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1997, 62, 2322;
(b) Wan, Z.-K.; Choi, H.-W.; Kang, F.-A.; Nakajima, K.; Demeke, D.;
Kishi, Y. Org. Lett. 2002, 4, 4431; (c) Choi, H.-W.; Nakajima, K.;
Demeke, D.; Kang, F.-A.; Jun, H.-S.; Wan, Z.-K.; Kishi, Y. Org. Lett.
2002, 4, 4435.
25. For the procedure, see: Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.;
Sawada, Y.; Inamura, N.; Asano, M.; Aramori, I.; Hatori, C.; Sawai, H.;
Oku, T.; Tanaka, H. J. Med. Chem. 1998, 41, 4062.
26. For alternative approaches to diamine 29, see: (a) Perillo, I.; Caterina,
M. C.; Lopez, J.; Salerno, A. Synthesis 2004, 851; (b) Tonzetich, Z. J.;
Lu, C. C.; Schrock, R. R.; Hock, A. S.; Bonitatebus, P. J., Jr. Organome-
tallics 2004, 23, 4362; (c) Han, X.; Michne, J. A.; Pin, S. S.; Burris, K. D.;
Balanda, L. A.; Fung, L. K.; Fiedler, T.; Browman, K. E.; Taber, M. T.;
Zhang, J.; Dubowchik, G. M. Bioorg. Med. Chem. Lett. 2005, 15, 3870;
(d) Marshall, C.; Ward, M. F.; Skakle, J. M. S. Synthesis 2006, 1040.
27. Njar, V. C. O. Synthesis 2000, 2019.
46. (a) Furstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349; (b) Furstner,
¨
¨
A.; Brunner, H. Tetrahedron Lett. 1996, 37, 7009.
47. Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A. Angew.
Chem., Int. Ed. 1999, 38, 3357.
28. Fischer, W. Synthesis 2002, 29.
29. Tang, Y.; Dong, Y.; Vennerstrom, J. L. Synthesis 2004, 2540.
30. (a) Kharash, M. S.; Sosnovsky, J. J. Am. Chem. Soc. 1958, 80, 756; (b)
Kharash, M. S.; Chang, N. C.; Sosnovsky, J. J. Am. Chem. Soc. 1959,
81, 5819; For mechanistic studies, see: (c) Pearson, A. J.; Chen, Y.-S.;
Han, G. R.; Hsu, S.-Y.; Ray, T. J. Chem. Soc., Perkin Trans. 1 1985,
267; (d) Kochi, J. K.; Bemis, A. Tetrahedron 1968, 24, 5099; (e) Walling,
C.; Zavitsas, A. A. J. Am. Chem. Soc. 1963, 85, 2084.
48. (a) Berkessel, A.; Menche, D.; Sklorz, C. A.; Schroder, M.; Paterson, I.
¨
Angew. Chem., Int. Ed. 2003, 42, 1032; (b) Inoue, M.; Suzuki, T.; Nakada,
M. J. Am. Chem. Soc. 2003, 125, 1140.
49. McManus, H. A.; Cozzi, P. G.; Guiry, P. J. Adv. Synth. Catal. 2006, 348,
551e558.
50. Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
51. Construction of all-carbon quaternary stereocenters in an enantioselec-
tive manner is a long-standing challenge to organic synthesis. For a
recent review, see the following: Trost, B. M.; Chunhui, J. Synthesis
2006, 369.
31. (a) Le Bras, J. E.; Muzart, J. J. Mol. Catal. A: Chem. 2002, 185, 113; (b)
Le Bras, J.; Muzart, J. Tetrahedron Lett. 2002, 43, 431.
32. Cammarata, A.; Napier, R.; Denney, D. B. J. Org. Chem. 1965, 30, 3151.
33. (a) Muzart, J. J. Mol. Catal. 1991, 64, 381; (b) Levina, A.; Muzart, F. Tet-
rahedron: Asymmetry 1995, 6, 147; (c) Levina, A.; Muzart, J. Synth. Com-
mun. 1995, 25, 1789; (d) Levina, A.; Henin, J.; Muzart, J. J. Organomet.
Chem. 1995, 494, 165; (e) Rispens, M. T.; Zondervan, C.; Feringa, B. L.
52. Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem. Commun.
2002, 2704.
53. (a) Arao, T.; Kondo, K.; Aoyama, T. Tetrahedron Lett. 2006, 47, 1417; (b)
Arao, T.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 1743; (c)
Chiral biscarbene Pd chelate has been reported as a catalyst for asymmet-
ric amide enolate a-arylation (90% yield, 11% ee): Bonnet, L. G.;
Douthwaite, R. E.; Hodgson, R. Organometallics 2003, 22, 4384.
54. Substrate 44 was prepared according to a literature procedure (Ref. 50),
which was modified; see Section 4.
Tetrahedron: Asymmetry 1995, 6, 661; (f) Soderdren, M. J.; Andersson,
P. G. Tetrahedron Lett. 1996, 37, 7577.
¨
34. For other bipyridines (with ꢀ71% ee in allylic oxidation), see, e.g.: (a)
Chelucci, G.; Loriga, G.; Murineddu, G.; Pinna, G. A. Tetrahedron
Lett. 2002, 43, 3601; (b) Lee, W.-S.; Kwon, H.-L.; Chan, H.-L.; Choi,
W.-W.; Ng, L.-Y. Tetrahedron: Asymmetry 2001, 12, 1007; (c) Bolm,
C.; Frison, J.-C.; Le Paih, J.; Moessner, C. Tetrahedron Lett. 2004, 45,
5019.
~
´
55. Fananas, F. J.; Granados, A.; Sanz, R.; Ignacio, J. M.; Barluenga, J.
Chem.dEur. J. 2001, 7, 2896.
56. (a) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565 and; J. Appl. Crys-
tallogr. 1999, 32, 837; (b) Sheldrick, G. M. SHELXS97 & SHELXL97;
35. (a) Gokhale, A. S.; Minidis, A. B.; Pfaltz, A. Tetrahedron Lett. 1995, 36,
1831; (b) Andrus, M. B.; Argade, A. B.; Chen, X.; Pamment, M. G.
Tetrahedron Lett. 1995, 36, 2945; (c) Evans, D. A.; Woerpel, K. A.;
Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726; (d)
Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994,
University of Gottingen: Gottingen, Germany, 1997.
¨
¨
57. Lukas, B.; Roberts, R. M. G.; Silver, J.; Wells, A. S. J. Organomet. Chem.
1983, 256, 103.
58. For the method, see Refs. 4 and 37.