New monoterpene-derived phosphinopyridine ligands and their application in the enantioselective iridium-catalyzed hydrogenation

Article abstract of DOI:10.1016/j.tet.2011.05.075

Pyridine derivatives with a phosphine or phosphinite pendant (1-11) have been synthesized from (+)-α-pinene, (-)-isopinocampheol, and/or (+)-camphor via Kro?hnke annulation or another annulation method as the key step for the construction of the pyridine nucleus. The iridium complex of 6 proved to catalyze hydrogenation of the prochiral unfunctionalized alkene 44 with 94% ee, whereas the complex of 2 was most efficient in the hydrogenation of the cinnamyl-type ester 45 (83% ee).

Full text of DOI:10.1016/j.tet.2011.05.075

Tetrahedron 67 (2011) 5421e5431
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New monoterpene-derived phosphinopyridine ligands and their application in
the enantioselective iridium-catalyzed hydrogenation
,
b
c
, ,
y
c,
Giorgio Chelucci a , Mauro Marchetti , Andrei V. Malkov
, Frederic Friscourt z, Martin E. Swarbrick d,
*
*
ꢀ ꢀ
,
ꢁ
ꢀ c
*
Pavel Kocovsky
a
ꢂ
Dipartimento di Chimica, Universita di Sassari, Via Vienna 2, I-07100 Sassari, Italy
b Istituto di Chimica Biomolecolare-CNR, Traversa La Crucca 3-Baldinca, I-07040 Sassari, Italy
c Department of Chemistry, WestChem, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
d Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow CM19 5AW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyridine derivatives with a phosphine or phosphinite pendant (1e11) have been synthesized from (þ)-
a-
Received 22 February 2011
Received in revised form 26 April 2011
Accepted 16 May 2011
€
pinene, (ꢀ)-isopinocampheol, and/or (þ)-camphor via Krohnke annulation or another annulation
method as the key step for the construction of the pyridine nucleus. The iridium complex of 6 proved to
catalyze hydrogenation of the prochiral unfunctionalized alkene 44 with 94% ee, whereas the complex of
2 was most efficient in the hydrogenation of the cinnamyl-type ester 45 (83% ee).
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 25 May 2011
Dedicated to Professor Joe D. Connolly on
the occasion of his 75th birthday and in
appreciation of his contribution to terpene
chemistry
1. Introduction
reduction of ketones with polymethylhydrosilane,21 Rh-catalyzed
hydroformylation22 and hydrosilylation,23 and the Pd-catalyzed
Chiral P,N-ligands play an important role in asymmetric tran-
sition metal-catalyzed reactions.1 Thus, for example, phosphino-
oxazolines have been developed for the highly enantioselective
Pd-catalyzed allylic substitution,2 Heck addition, hydrogenation,
and other reactions.3 The binaphthyl-type P,N-ligands, such as MAP
and its congeners,4 aside from also being employed in the Pd-
catalyzed allylic substitution,4ꢀ6 have revolutionized the Pd-
catalyzed Hartwig-Buchwald amination of aromatic halides,5,7,8
and enabled asymmetric Suzuki-Miyaura coupling.9 Furthermore,
the latter class has been shown to exhibit a unique way of co-
ordination of Pd5,6 and has contributed to a better understanding of
the memory effect in the Pd-catalyzed allylic substitution.6
In recent years we have developed pyridine-type ligands with
a chiral scaffold based on amino acids7b,10,11,12 and/or mono-
terpenes,13ꢀ17 and have demonstrated their application in the
enantioselective Mo-catalyzed allylic substitution,10 Pd-catalyzed
allylic substitution16b,18 Heck addition,15 Cu-catalyzed conjugate ad-
dition,11 allylic oxidation,13,14,19 cyclopropanation,14,20 Sn-catalyzed
Baeyer-Villiger oxidation.24
The N-oxides, prepared from some of our terpene-derived pyr-
idines, became organocatalysts of choice for the asymmetric al-
kylation of aldehydes with allyl and crotyl trichlorosilane.25,26
Rhodium- and ruthenium-catalyzed asymmetric hydrogenation
of functionalized olefins is one of the most powerful catalytic
methods for the asymmetric synthesis of chiral molecules.27 High
enantioselectivity and low catalyst loadings are usually observed
when the olefin substrate bears a coordinating group next to the
C]C bond. Therefore, unfunctionalized olefins had remained for
many years difficult substrates for asymmetric hydrogenation.
During the last decade, inspired by the Crabtree catalyst,28 Pfaltz,29
and others30 have developed various cationic iridium complexes,
containing chiral P,N-ligands and weakly coordinating counterions,
such as BArF (tetrakis[bis-3,5-(trifluoromethyl)phenyl]borate),
which have shown to be particularly effective for the enantiose-
lective hydrogenation of non-functionalized olefins.
Herein, we report on the synthesis of the terpene-derived phos-
phino-pyridine-typeligands1e11 andtheirapplicationintheiridium-
catalyzed asymmetric hydrogenation of alkenes30 and imines.31
* Corresponding authors. E-mail addresses: chelucci@uniss.it (G. Chelucci),
ꢁ
ꢀ
A.Malkov@lboro.ac.uk (A.V. Malkov), pavelk@chem.gla.ac.uk (P. Kocovsky).
2. Results and discussion
y
Present address: Department of Chemistry, Loughborough, University
Loughborough LE11 3TU, UK.
Present address: Complex Carbohydrate Research Center, University of Georgia,
Athens, GA 30602-4712, USA.
z
The monoterpene-derived phosphinopyridines 1, 2, and 4
(Chart 1) have been developed by us as efficient chiral ligands for
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.075

5422
G. Chelucci et al. / Tetrahedron 67 (2011) 5421e5431
N+
I−
ref 15,
16g, 24
R
AcONH4
−
1
3
+
N
O
R
N
N
N
O
PPh2
PPh2
PPh2
R
−
( )-14
15, R = 2-F-C6H4
16, R = Ph
17, R = 2-F-C6H4
18
(+)-4
(−)-5
, R = Ph
1, R = H
2, R = Me
3, R = i-Pr
1
ν
O2, h
Ac2O
m-CPBA
(R = Ph)
α
(+)- -pinene
1. Ac2O, reflux
2. HCl, reflux
R
N
+
N
N
N
PPh2
N
O−
3. Jones reagent
Me2CO, rt
Ph2P
PPh2
6
O
7, R = Ph
8, R = H
(−)-9
19
20
NaBH4, EtOH
1. 4-NO2-C6H4CO2H
DIAD, PPh3,
THF, rt
N
N
N
N
O
PPh2
O
PPh2
2. K2CO3, MeOH
OH
OH
11
10
21
22
−
1. n-BuLi, THF, 40 °C
2. PPh2Cl, 0 °C
3. BH3, THF, rt
N
N
ref 30j
PPh2
PPh2
Et2NH, 50 o
C
12
13
N
10
11
Chart 1.
O
PPh2
BH3
the Pd-catalyzed Heck addition15 and allylic substitution.16b,18 More
recently, we have introduced the isopropyl derivative 3 as one of the
mostefficientligandsin thePd-catalyzedBaeyer-Villigeroxidation.24
Aiming at an extension of the portfolio of this library of ligands, we
embarked on the synthesis of the pyridine-type ligands 5e9 and the
diastereoisomeric phosphinites 10 and 11, with a view of their po-
tentialutilizationtogenerate chelatesof transition metals. Whilethis
work was in progress, Andersson added diastereoisomeric phos-
phines 12 and 13 and also synthesized phosphinites 10 and 11.30j
23
Scheme 1.
by the Boekelheide rearrangement34 of the N-oxide (þ)-19, whose
preparation from (þ)-18 was straightforward (m-CPBA, CH2Cl2; 75%).
The key rearrangement gave rise to a 1:3 mixture of epimeric alco-
hols 21 and 22 (70%), which were oxidized with Jones’ reagent to
afford ketone (þ)-20 (84%). As expected, reduction of the latter ke-
tone with NaBH4 gave alcohol (þ)-21 (91%), whose epimerization
under Mitsunobu conditions, followed by hydrolysis, furnished al-
cohol 22 (50%). Deprotonation of alcohol 21, followed by treatment
with Ph2PCl, generated the corresponding phosphinite, which was
isolated and purified in its stable, protected form of the borane
complex (þ)-23 (41%).35 The free phosphinite 10 could then be re-
leased from the latter complex in situ by treatment with Et2NH. Al-
cohol 22 was then converted into phosphinite 11 in the same way.
While this work was in progress, Andersson reported on the syn-
thesisofboth10 and11 byusingasimilarstrategybutwitha different
way of obtaining the pure diastereoisomeric alcohols 21 and 22.30j
The synthesis of phosphine 7 (Scheme 2) required the usual
‘benzylic’ deprotonation of (þ)-18,14def,25b followed by reaction with
a complex of Ph2PCl and BH3, which provided (ꢀ)-24 (35%) with ex-
cellent diastereoselectivity. The release of the desired phosphine 7
from its protected form (ꢀ)-24 was effected by treatment with Et2NH
(99%) immediately before use.36 The analogous phosphine oxide
(ꢀ)-25 was obtained from (þ)-1825bviathesequenceofdeprotonation
and reaction with Ph2P(O)Cl (34%); again, the reaction proved highly
diastereoselective. However, reduction of (ꢀ)-25, expected to afford 7,
turned out to be sluggish and produced an intractable mixture.
The truncated phosphine 8, lacking the phenyl substituent in
2.1. Ligand synthesis
32
€
Krohnke annulation was employed as the key step in the
construction of the terpene/pyridine scaffold (Scheme 1): thus,
pinocarvone (ꢀ)-14, obtained from (þ)-
a
-pinene,33 was heated
with the readily enolizable -pyridinio ketones 15 and 16, re-
a
spectively (generated from the corresponding methyl aryl ketones
on iodination in pyridine), in the presence of ammonium acetate, to
produce the respective pyridine derivatives (þ)-1715,24 and
(þ)-18.25b Deprotonation of 17 in the ‘benzylic’ position with
n-BuLi, followed by alkylation with MeI and i-PrI, respectively, and
subsequent replacement of the fluoride with Ph2PK, produced
phosphines 1e3, as described by us previously.15,24 The enantio-
meric (ꢀ)-2 was prepared in the same way from (þ)-pinocarvone,
which in turn was obtained from (ꢀ)-
a
-pinene.15,16g
Ligand (þ)-4 was synthesized from (ꢀ)-b-pinene via (þ)-nopi-
none, again by the Krohnke annulation,15,16g and the same approach
was employed for the synthesis of (ꢀ)-5 from (þ)-camphor.16g The
quinoline-type ligand (þ)-6 was synthesized from (þ)-camphor
usinga sequenceinvolving functionalizationof the methyl groupand
construction of the pyridine moiety of the quinoline nucleus.18t
The synthesis of phosphinites 10 and 11 (Scheme 1) required
oxygenation of the ‘benzylic’ position in (þ)-18, which was attained
€
the
a
-position of the pyridine nucleus, was synthesized as follows
(Scheme 3): the Krohnke salt 26, readily available from ethyl
€

G. Chelucci et al. / Tetrahedron 67 (2011) 5421e5431
5423
reaction of the pure fluoride 34 with Ph2PLi40 afforded the desired
phosphine derivative but again as a 4:1 mixture of epimers, from
which the predominant (1R,3R,4S)-stereoisomer 9 (63%) was
obtained by chromatography, showing that purification of the
fluoride 34 was actually redundant.
1. n-BuLi, THF, -40 o
2. Ph2PCl.BH3, rt
C
N
N
18
Ph2P BH3
1. n-BuLi, THF, -40 o
C
24
2.2. Preparation of iridium complexes with ligands 1e10
2. Ph2P(O)Cl, rt
Et2NH, 50 o
C
The P,N-ligands 1e10 were converted into the corresponding
iridium complexes 35e42 on reaction with [(COD)IrCl]2 in boiling
CH2Cl2, followed by an anion exchange with NaBArF (Scheme 5).
All these complexes were air- and moisture-stable and were easily
purified by flash chromatography in moderate yields [35 (58%), 36
(52%), 37 (44%), 38 (63%), 39 (51%), 40 (75%), 41 (72%), and 42
(41%)]. Similarly, Andersson prepared the corresponding complexes
from ligands 10e13.30j Our complex 42, which is identical to his,30j
is shown here for comparison of its activity under slightly different
conditions; for further comparison we also show one of the results
he has attained with 4330j (vide infra).
N
7
Ph2P
O
25
Scheme 2.
bromoacetate via an SN2 substitution with pyridine,32 was reacted
with pinocarvone (ꢀ)-14 in the presence of ammonium acetate to
produce pyridone (þ)-27 (43%)14b that was converted into triflate
(þ)-28 (99%).14b Reduction of the latter derivative with formic acid,
catalyzed by palladium,37 afforded the deoxygenated pyridine de-
rivative (þ)-30 (65%), which was then converted into the phos-
phine/borane complex (þ)-31 (42%) as in the case of 24. Again, free
phosphine 8 was liberated from (þ)-31 on treatment with dieth-
ylamine. An alternative, two-step reduction of (þ)-28 included its
1 − 3
4
5
N
N
N
conversion into the a-chloropyridine 29 (pyridinium chloride, mi-
+
+
+
PPh2
BArF
PPh2
BArF
PPh2
BArF
Ir
Ir
Ir
R
crowave heating; 36%),38 followed by a Pd(0)-catalyzed reduction
with formic acid, which afforded (þ)-30 (95%); however, the overall
yield was rather low compared to that of the direct reduction.
−
−
−
35, R = H
38
39
36, R = Me
37, R = i-Pr
−
(
)-14
Br− N+
AcONH4
AcOH
Tf2O
Et3N
6
9
10
11
O
OTf
OEt
26
NH
N
BuOH
reflux
24 h
CH2Cl2
O
27
28
Ph
Ph
N
P
N
P
C5H5N+Cl−
NMP, MW
8
HCO2H, (AcO)2Pd, dppf
Et3N, DMF, 60 o
N
Ir
N
PPh2
Ir
+
+
+
+
Ir
Ir
C
P
O
O
R
−Ph2
Et2NH
Ph2
Ph2
−
−
−
BArF
BArF
BArF
BArF
1. n-BuLi, THF
−
HCO2H
Pd/C (10%)
40 oC
Cl
N
40
41
42
43
N
N
DMF
Scheme 5.
2. Ph2PCl.BH3
rt
Ph2P BH3
31
30
29
2.3. Hydrogenation of olefins 44e47 and imine 48 catalyzed
by iridium complexes 35e43
Scheme 3.
The synthesis of phosphine (ꢀ)-9 (Scheme 4) commenced with
the annulation reaction39 of tert-butyl N-(2-formyl-6-fluorophenyl)
carbamate 33 and the chiral ketone 32, which in turn was obtained
as a 4:1 mixture of epimers by oxidation of (ꢀ)-isopinocampheol.
The 5-fluorotetrahydroacridine derivative, resulting from the an-
nulation (70%), turned out to be a 4:1 mixture of epimers, from
which the more abundant (1R,3R,4S)-diastereoisomer 34 (61%
overall) was isolated by careful chromatography. The subsequent
Iridium complexes 35e43 were first evaluated as catalysts for the
asymmetric hydrogenation of (E)-a-methylstilbene 44 (Chart 2 and
Table 1, entries 1e15). The reactions were carried out at room tem-
perature with 1e2 mol % catalyst loading and at various hydrogen
Me
Me
CO2Et
1. t-BuOK, dioxane
rt, 2 h
44
45
OHC
+
OMe
2. 3M HCl, reflux 1 h
BocHN
N
O
F
F
OR
N
32
33
34
Me
Ph2PLi, THF
-10 oC, 30 min
46, R = H
, R = Ac
then 60 oC, 1 h
−
(
−
)-9
(
)-Isopinocampheol
47
48
Scheme 4.
Chart 2.

5424
G. Chelucci et al. / Tetrahedron 67 (2011) 5421e5431
Table 1
Hydrogenation of olefins 44e47 and imine 48 catalyzed by iridium complexes 35e43a
Entry
Substrate
Catalyst (mol %)
Ligand
Pressure (atm)
Time (h)
Temp (ꢂC)
Conversionb (%)
% eec,d (configuration)
1
2
3
4
5
6
7
8
44
44
44
44
44
44
44
44
44
44
44
44
44
44
44
45
45
45
45
45
45
45
45
45
45
45
46
46
46
46
46
47
48
48
48
48
35 (2)
36 (2)
ent-36 (1)
37 (2)
38 (1)
39 (1)
39 (1)
39 (1)
39 (1)
40 (1)
40 (2)
41 (1)
42 (0.5)
42 (2)
43 (0.5)
35 (2)
36 (2)
ent-36 (1)
37 (2)
38 (1)
39 (1)
40 (1)
40 (2)
42 (2)
42 (0.5)
43 (0.5)
ent-36 (1)
38 (1)
39 (1)
40 (1)
40 (2)
41 (2)
35 (2)
36 (2)
37 (2)
42 (2)
1
2
10
10
50
10
50
50
50
50
50
50
10
50
30
10
30
10
10
50
10
50
50
50
10
10
30
30
50
50
50
50
10
10
10
10
10
10
48
48
24
48
72
24
24
72
456
24
24
72
48
48
48
48
48
72
48
72
72
72
48
48
48
48
72
72
72
72
72
48
48
48
48
48
rt
rt
96
7
13
n.r.
34
10
56
17
29
69
97
n.r.
30
50
21 (R)e
n.d.
17 (R)
n.d.
29 (R)
29 (R)
33 (R)
18 (R)
4 (R)
62 (S)
94 (S)
n.d.
ent-2
3
4
5
5
5
5
6
6
25
25
25
25
50
25
25
25
25
25
rt
rt
rt
rt
rt
25
rt
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
9
10
10
11
1
12 (S)f
80 (S)e
41 (R)f
20 (S)g
83 (S)g
55 (R)
57 (S)g
17 (S)
38 (R)
69 (S)
77 (S)
n.d.
11
>99
>99
48
>99
>99
>99
90
97
15
15
10
n.r.
20
68
n.r.
n.r.
>99
>99
31
2
ent-2
3
4
5
6
25
25
25
25
rt
6
10
10
11
ent-2
4
5
6
6
9
1
2
3
10
rt
rt
9 (S)f
16 (S)f
n.d.
25
25
25
25
25
25
rt
rt
rt
rt
56h
2h
n.d.
n.d.
12h
0h
32 (S)i
n.d.
6
>99
48 (S)i
a
The reaction was carried out at a 0.2 mmol scale in CH2Cl2 (n.r.¼no reaction; n.d.¼not determined). The most significant results are highlighted by bold fonts in the last two
columns.
b
c
d
e
f
Determined by 1H NMR of the crude mixture.
Determined by chiral HPLC (see the Experimental section for details).
The absolute configuration was established by comparison of the HPLC retention times with the literature values (see the Experimental section).
The absolute configuration was assigned by comparison of the HPLC retention times with literature values (Ref. 41).
Results reported by Andersson (Ref. 30j).
The absolute configuration was assigned by comparison of the optical rotation and with the literature data (Ref. 42).
The absolute configuration was not determined.
g
h
i
The absolute configuration was assigned by comparison of the HPLC retention times with the literature values (Ref. 43).
pressures (10e50 bar). Steric parameters turned out to have a great
influence on the reactivity of this class of substrate. Thus, catalysts
35e39 and 41 seem to be too encumbered to accommodate the
rather bulky substrate, resulting in poor conversions. On the other
hand, the more flexible catalysts 40 and 42 exhibited good conver-
sions with moderate to good enantioselectivities (ꢁ94%; entries 10,
11, and 14). Interestingly, lower hydrogen pressure seems to induce
higher selectivity (entries 10 and 11).
the ligand (entry 33). Complexes 36 and 37 proved to be mediocre
catalysts (entries 34 and 35), whereas complex 42 catalyzed the
reaction efficiently, affording the product of modest enantiopurity
(48% ee, entry 36).
3. Conclusions
Pyridine-type ligands with a phosphine or phosphinite pendant
Ethyl (E)-b-methylcinnamate 45 was found to be very sensitive
(1e11) have been synthesized from (þ)-
a
-pinene or (ꢀ)-
b-pinene via
€
to the type of ligand used (Table 1, entries 16e26). Iridium catalysts
based on the chiral pyridine/phosphinite (42 and 43) showed very
low reactivity (entries 24e26), whereas the catalysts based on the
chiral phosphines (35e40; entries 16e23) promoted full conver-
sion with moderate to good enantioselectivities, clearly controlled
by the steric hindrance generated by the alkyl groups in the ‘ben-
zylic’ position of the ligand (entries 16e21). The enantiomeric ex-
cess varied from 20% (ligand with no substituent 35) to 83%
(methyl-substituted ligand 36).
Other olefinic substrates, such as 46 and 47, showed rather poor
reactivity and selectivity (Table 1, entries 27e32). Substantial dif-
ferences were observed in the hydrogenation of imine 48: thus, in
the presence of complex 35, the reaction, proceeded to completion
but the product turned out to be racemic, suggesting dissociation of
Krohnke annulation as the key step for the construction of the pyr-
idine nucleus step (1e4, 7, 8, 10, and 11), from (ꢀ)-isopinocampheol,
using another annulation method (9), and from (þ)-camphor (5 and
6). Their iridium complexes 35e42 were examined as chiral catalysts
in the hydrogenation of representative olefins. The complex 40
derived from ligand 6, has been found to catalyze hydrogenation
of the prochiral unfunctionalized alkene 44 with 94% ee, whereas
the complex 36, derived from ligand 2 was most efficient in the
hydrogenation of the cinnamyl-type ester 45 (83% ee). Hydrogena-
tion of imine 48 was less successful (48% ee with the complex of li-
gand 10). In general, hydrogenation carried out at lower pressure
(10 atm) and with higher catalyst loading (1e2 mol %) has been
shown to result in a significant increase in enantioselectivity
(compare entries 10 with 11 and 13 with 14 in Table 1).

G. Chelucci et al. / Tetrahedron 67 (2011) 5421e5431
5425
4. Experimental
evaporated. The residue was purified by flash chromatography on
a column of silica gel (1.5ꢄ50 cm) under nitrogen using a mixture of
4.1. General methods
petroleum ether and ethyl acetate (9:1) to give (ꢀ)-9 as a white
26
solid (328 mg, 63%): mp 96e97 ꢂC; [
a]
ꢀ48.7 (c 0.015, CHCl3); IR
D
All reactions were carried out under an inert atmosphere in
oven-dried glassware unless otherwise stated. Room temperature
refers to ambient room temperature (20e22 ꢂC); 0 ꢂC refers to an
ice slush bath. Heated experiments were conducted using ther-
mostatically controlled oil baths. Reactions were monitored by Thin
Layer Chromatography (TLC) using aluminum backed silica gel 60
(F254) plates, visualized using UV254nm and potassium permanga-
nate, PMA, Drangendorf and ninhydrin dips as appropriate. Flash
(KBr) cmꢀ1
1434 (s, arom C]C), 1412 (s, arom C]C), 1257, 1179, 119, 1027, 784
(m, arom CeH), 659 cmꢀ1; 1H NMR (400 MHz, CDCl3)
0.62 (s, 3H,
; n 2957 (s, CeH), 2927(s, CeH), 1478 (s, arom C]C),
d
16-H), 0.92 (d, 3H, J¼6.9 Hz, 17-H), 1.21 (d, 1H, J¼10.2 Hz, 10-H), 1.39
(s, 3H, 15-H), 2.07 (dt, 1H, J¼6.0, 2.4 Hz, 3-H), 2.50e2.11 (m, 1H, 3-
H), 2.89 (t, 1H, J¼5.4 Hz, 1-H), 2.23 (dt, 1H, J¼6.0, 2.4 Hz, 3-H),
6.91e6.99 (m, 1H), 7.16e7.44 (m, 11H), 7.52 (s, 1H, 9-H), 7.68 (d, 1H,
J¼7.8 Hz, 8-H); 13C NMR (100 MHz, CDCl3)
d 17.8 (CH3-17), 21.1
ꢃ
chromatography was carried out routinely using 60 A silica gel
(CH3-16), 26.3 (CH3-15), 28.7 (CH2-10), 39.1 (CH-4), 41.4 (C-2), 46.4
(CH-3), 47.6 (CH-1), 125.6 (CH-7), 126.2 (C-14), 127.6 (CH-8),
127.8e128.4 (6ꢄ aromCH), 130.0 (CH-6), 131.9 (CH-9), 133.9 (d,
J¼20.7 Hz, C0PAr2), 134.7 (d, J¼20.7 Hz, C0PAr2), 137.8e138.1 (C-5,
(Fischer) as the stationary phase unless otherwise stated. Melting
points were determined on a Kofler block and are uncorrected.
Optical rotations were recorded in CHCl3 at 20 ꢂC unless otherwise
indicated with an error of <ꢃ0.1. The [
10ꢀ1 deg cm2 ꢀ1. The NMR spectra were recorded on a Bruker
Spectrospin 400 (400 MHz) spectrometer. Chemical shifts are
reported in units, parts per million (ppm) downfield from TMS.
a
]
D
values are given in
2ꢄ CPAr2), 140.0 (C-11), 147.9 (d, J¼15.6 Hz, C-13), 162.0 (C-14); 31
P
g
NMR (162.0 MHz, CDCl3)
82.63; H, 6.70; N, 3.32. Found: C, 82.55; H, 6.73; N, 3.30.
d
ꢀ11.6 (s). Anal. Calcd for C29H28NP: C,
d
Coupling constants (J) are measured in Hertz (Hz) and are un-
adjusted; therefore, due to limits in resolution, in some cases there
are small differences (<1 Hz) in the measured J value of the same
coupling constant determined from different signals. Splitting
patterns are designed as follows: sdsinglet, dddoublet, tdtriplet,
ddddoublet of doublets, dtddoublet of triplets, tddtriplet of
doublets, dddddoublet of doublet of doublets, ttdtriplet of trip-
lets, sp.dseptet, mdmultiplet, brdbroad. Various 2D techniques
and DEPT experiments were used to establish the structures and to
assign the signals. The IR spectra were recorded on a JASCO FT-IR
spectrophotometer for a thin film between NaCl plates, or as
a KBr disc. The mass spectra (EI and/or CI) were measured on a Joel
JMS700 spectrometer. Enantiomeric excess was determined by
chiral HPLC analysis (using a Hewlett Packard Agilent 1100 Series
quaternary pump, vacuum degasser, diode array detector, manual
injector and Hewlett Packard ChemStation and a Diacel Chiracel IB
or OJ-H 0.46 cmꢄ25 cm column) as stated. The chiral GC and HPLC
methods were calibrated with the corresponding racemic mixtures.
Autoclave reactions were accomplished in a stainless steel auto-
clave manufactured by HEL Ltd.
4.2.2. (8S,10S)-(þ)-2-Phenyl-11,11-dimethyl-1-azatricyclo[7.1.1.05,6
]
undeca-2,4,6-triene 1-oxide (þ)-(19). m-Chloroperoxybenzoic acid
(70%, 0.70 g, 4 mmol, 2.0 equiv) was added portion-wise to a cooled
(0 ꢂC) solution of (þ)-1825b (0.50 g, 2 mmol, 1.0 equiv) in CH2Cl2
(20 mL). The mixture was then allowed to warm up to room tem-
perature and stirred overnight. The mixture was washed with an
aqueous solution of NaHCO3 (10%; 1ꢄ20 mL) and dried over MgSO4.
The solvent was removed under vacuum and the residue was pu-
rified by chromatography on silica gel (25 g) using ethyl acetate to
remove the unreacted starting material and some by-products,
followed by methanol to afford pure (þ)-19 as a white solid
20
(394 mg, 75%): mp 128e130 ꢂC (hexane); [
a
]
þ100.2 (c 0.6,
D
CHCl3); IR (KBr)
C), 1477 (s, arom C]C), 1447 (m, arom C]C), 1265 (s, NeO), 770 (s,
arom CeH) cmꢀ1 1H NMR (400 MHz, CDCl3)
0.73 (s, 3H, 12-H),
n 3051 (m, CeH), 2938 (s, CeH), 1662 (m, arom C]
;
d
1.32 (d, J¼9.8 Hz, 1H, 9-H), 1.42 (s, 3H, 13-H), 2.45 (m, 1H, 8-H), 2.69
(dt, J¼9.8, 5.7 Hz, 1H, 9-H0), 2.81 (t, J¼5.7 Hz, 1H, 10-H), 3.05e3.24
(m, 2H, 7-H), 6.92 (d, J¼7.8 Hz, 1H, 3-H), 7.19 (d, J¼7.8 Hz, 1H, 4-H),
7.42 (t, J¼6.9 Hz, 1H, 40-H), 7.45 (t, J¼6.9 Hz, 2H, 30-H, 50-H), 7.79 (d,
J¼6.9 Hz, 2H, 20-H, 60-H); 13C NMR (100 MHz, CDCl3)
d 21.1 (CH3-12),
25.8 (CH3-13), 31.2 (CH2-7), 31.5 (CH2-9), 39.31 (CH-8), 39.32 (C-11),
46.1 (CH-10), 122.9 (CH-3), 123.7 (CH-4), 128.0 (2ꢄ CH-30,50), 128.9
(CH-40), 129.5 (2ꢄ CH-20,60), 133.3 (C-10), 144.2 (C-5), 146.8 (C-2),
4.2. Materials
þ
All solvents were of reagent grade and were dried and distilled
under argon or nitrogen immediately before use as follows: tetra-
hydrofuran, diethyl ether, and toluene from sodium/benzophe-
none, dichloromethane from calcium hydride. Petroleum ether
refers to the fraction boiling in the range 40e60 ꢂC. Methanol and
ethanol were distilled over magnesium turnings and stored over
molecular sieves. Triethylamine was distilled immediately before
147.1 (C-6); MS (EI) m/z (%) 265 (Mꢅ , 50), 248 (MꢅþꢀOH, 65), 206
(MꢅþꢀOHꢀC3H6, 100), 83 (62); HRMS (EI) 265.1466 (C18H19NO re-
quires 265.1467).
4.2.3. (8R,10S)-(þ)-2-Phenyl-11,11-dimethyl-1-azatricyclo[7.1.1.05,6
]
undeca-2,4,6-trien-7-one (þ)-(20). A mixture of the N-oxide de-
rivative (þ)-19 (105.2 mg, 0.40 mmol) and acetic anhydride (5 mL)
was stirred at 110 ꢂC for 2 h under argon. The reaction mixture was
then cooled to room temperature and acetic anhydride was re-
moved under vacuum. An aqueous solution of hydrochloric acid
(3 M, 10 mL) was added to the residue and the resulting mixture
was refluxed for 1.5 h, then cooled to room temperature and chilled
with an ice bath. The solution was made alkaline (pHz12e13) by
a slow addition of an aqueous solution of sodium hydroxide (2 M).
The aqueous layer was extracted with CH2Cl2 (3ꢄ15 mL) and the
combined organic solutions were dried over MgSO4 and concen-
trated under vacuum to obtain a diastereoisomeric mixture of
benzylic alcohol derivatives (ratio 3:1) (74.2 mg, 70%). The latter
mixture of alcohols (74.2 mg, 0.28 mmol,1.0 equiv) was dissolved in
use from calcium hydride. (R)-(þ)-
a-Pinene was purchased from
Aldrich with a 98% ee. The synthesis of ligands 1, 2, and 3 was
reported previously.24
4.2.1. (1R,3R,4S)-(ꢀ)-1,3-Methano-2,2,4-trimethyl-5-(diphenylphos-
phino)-1,2,3,4-tetrahydroacridine (ꢀ)-(9). A solution of n-butyl-
lithium in hexane (2.5 M, 0.541 mL, 1.35 mmol) was added
dropwise to a cooled (ꢀ78 ꢂC) solution of diphenylphosphine
(252 mg, 1.35 mmol) in anhydrous THF (12 mL) under argon. The
solution was stirred at that temperature for 10 min and then
warmed to 0 ꢂC. A solution of (þ)-34 (315 mg, 1.23 mmol) in an-
hydrous THF (3 mL) was added dropwise and the mixture was
slowly warmed to room temperature and then heated at 60 ꢂC for
1 h. The mixture was then cooled to room temperature and a pu-
rified and degassed Et2O (30 mL) and water were added in se-
quence. The organic phase was separated, dried over Na2SO4, and
acetone (2 mL) and Jones’ reagent (70 mL, 0.28 mmol, 1.0 equiv) was
added and the mixture was stirred at room temperature for 30 min.
The reaction was then quenched by addition of propan-2-ol (10
drops) and the mixture was filtered over a silica pad. The filtrate

5426
G. Chelucci et al. / Tetrahedron 67 (2011) 5421e5431
was then made alkaline by addition of an aqueous solution of so-
dium hydroxide (2M). CH2Cl2 (10 mL) was then added, the two
layers were separated, the aqueous phase was extracted with
CH2Cl2 (3ꢄ15 mL). The combined organic solutions were dried over
2.83 (t, J¼5.8 Hz, 1H, 10-H), 3.51 (br s, 1H, OH), 4.97 (d, J¼3.2 Hz, 1H,
7-H), 7.35 (d, J¼7.8 Hz, 1H, 3-H), 7.38 (t, J¼7.4 Hz, 1H, 40-H), 7.45 (t,
J¼7.4 Hz, 2H, 30-H, 50-H), 7.52 (d, J¼7.8 Hz, 1H, 4-H), 8.00 (d,
J¼7.4 Hz, 2H, 20-H, 60-H); 13C NMR (100 MHz, CDCl3)
d 21.0 (CH3-12),
MgSO4 and concentrated under vacuum to give pure (þ)-20 as
26.6 (CH3-13), 29.6 (CH2-9), 44.9 (C-11), 45.5 (CH-8), 46.6 (CH-10),
71.5 (CH-7), 118.9 (CH-4), 126.7 (2ꢄ CH-20,60), 128.5 (CH-40), 128.6
(2ꢄ CH-30,50), 133.8 (CH-3), 139.2 (C-10), 139.8 (C-5), 155.0 (C-2),
157.2 (C-6); HRMS (EI) 265.1469 (C18H19NO requires 265.1467).
20
a white solid (62 mg, 84%): mp 155e157 ꢂC; [
a]
þ163.7 (c 0.6,
D
CHCl3); IR (KBr)
C), 1558 (s, arom C]C), 1455 (m, arom C]C), 779 (m, arom
CeH) cmꢀ1; 1H NMR (400 MHz, CDCl3)
0.83 (s, 3H, 12-H), 1.62 (s,
n 2975 (m, CeH), 1705 (s, C]O), 1585 (m, arom C]
d
3H, 13-H), 2.18 (dt, J¼8.2, 5.0 Hz, 1H, 9-H), 3.09e3.13 (m, 3H, 8-H, 9-
H0, 10-H), 7.41 (tt, J¼7.2, 1.3 Hz, 1H, 40-H), 7.47 (t, J¼7.2 Hz, 2H, 30-H,
50-H), 7.64 (d, J¼7.9 Hz, 1H, 3-H), 7.78 (d, J¼7.9 Hz, 1H, 4-H), 8.08
4.2.6. Borane-protected (7S,8R,10S)-(þ)-2-phenyl-11,11-dimethyl-
1-azatricyclo[7.1.1.05,6]undeca-2,4,6-trien-7-yl diphenylphosphinite
(þ)-(23). A solution of n-butyllithium in hexane (2.5M; 0.38 mL,
0.94 mmol, 1.0 equiv) was added dropwise to a solution of (þ)-21
(250 mg, 0.94 mmol, 1.0 equiv) in anhydrous THF (2 mL) under
argon at ꢀ40 ꢂC. The solution was stirred at that temperature for
30 min and then allowed to gradually warm to 0 ꢂC. Diphenyl-
phosphine chloride (0.20 mL,1.04 mmol,1.1 equiv) was then added
dropwise and the reaction mixture was warmed up to room tem-
perature and stirred for 3 h. A solution of borane in THF (1 M,
0.94 mL, 0.94 mmol, 1.0 equiv) was added dropwise to the latter
solution and the reaction mixture was stirred overnight. The re-
action was then quenched by addition of water (15 mL), the aque-
ous phase was extracted with CH2Cl2 (3ꢄ20 mL), and the combined
organic extracts were washed with brine (20 mL) and dried over
MgSO4. The solvent was removed under vacuum and the residue
was purified by chromatography on a column of silica gel (13 g)
using a mixture of petroleum ether and AcOEt (95:5) to give pure
(d, J¼7.2 Hz, 2H, 20-H, 60-H); 13C NMR (100 MHz, CDCl3)
d 22.7
(CH3-12), 26.7 (CH3-13), 39.3 (CH2-9), 47.1 (CH-10), 52.7 (C-11), 58.2
(CH-8), 123.2 (CH-4), 127.1 (2ꢄ CH-20,60), 128.7 (2ꢄ CH-30,50), 129.1
(CH-40),134.9 (CH-3),138.5 (C-20),144.8 (C-5),147.9(C-2),156.6 (C-6),
199.9 (C]O); MS (CI-isobutane) m/z (%) 264 ((MþH)þ, 100); HRMS
(CI-isobutane) 264.1389 (C18H18NO (MþH)þ requires 264.1388).
4.2.4. (7S,8R,10S)-(þ)-2-Phenyl-11,11-dimethyl-1-azatricyclo
[7.1.1.05,6]undeca-2,4,6-trien-7-ol (þ)-(21). Sodium borohydride
(4 mg, 0.103 mmol, 1.0 equiv) was added portion-wise to a solution
of ketone (þ)-20 (27 mg, 0.103 mmol, 1.0 equiv) in ethanol (1 mL)
and the reaction mixture was stirred at room temperature for
20 min. Water (2 mL) was then added to quench the remaining
sodium borohydride and the aqueous layer was extracted with
CH2Cl2 (3ꢄ5 mL). The combined organic layers were dried over
MgSO4 and concentrated under vacuum to afford pure (þ)-21 as
(þ)-23 (176 mg, 41%) as a white solid: mp 117e120 ꢂC (hexane);
20
19
a white solid (25 mg, 91%): mp 85e87 ꢂC; [
a
]
D
þ86.9 (c 1.5, CHCl3);
[
a
]
þ170.5 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d 0.82 (s, 3H,
D
IR (KBr)
(m, arom C]C), 1441 (m, arom C]C), 772 (m, arom CeH) cmꢀ1; 1H
NMR (400 MHz, CDCl3) 0.61 (s, 3H, 12-H), 1.39 (s, 3H, 13-H), 1.50
n
3430 (s, OH), 2933 (s, CeH), 1586 (m, arom C]C), 1568
12-H), 1.42 (s, 3H, 13-H), 1.48 (d, J¼9.7 Hz, 1H, 9-H), 1.54 (br s, 3H,
BH3), 2.73e2.79 (m, 2H,10-H, 9-H0), 2.84 (td, J¼6.4, 3.3 Hz,1H, 8-H),
5.78 (dd, JH,P2¼10.0 Hz, J¼3.3 Hz, 1H, 7-H), 7.33 (d, J¼7.8 Hz, 1H, 4-
H), 7.35e7.49 (m, 9H, 30-H, 50-H, 40-H, 6ꢄ aromH), 7.55 (d,
J¼7.8 Hz, 1H, 3-H), 7.72e7.77 (m, 2H, aromH), 7.90 (dd, J¼8.0,1.6 Hz,
2H, 20-H, 60-H), 8.02e8.07 (m, 2H, aromH); 13C NMR (100 MHz,
d
(d, J¼9.9 Hz, 1H, 9-H), 2.44 (td, J¼5.8, 3.3 Hz, 1H, 8-H), 2.50e2.60
(m, 1H, 9-H0), 2.74 (t, J¼5.8 Hz,1H, 10-H), 3.42 (br s, 1H, OH), 4.88 (d,
J¼3.3 Hz, 1H, 7-H), 7.29 (d, J¼7.8 Hz, 1H, 4-H), 7.33 (t, J¼7.0 Hz, 1H,
40-H), 7.39 (t, J¼7.0 Hz, 2H, 30-H, 50-H), 7.47 (d, J¼7.8 Hz, 1H, 3-H),
CDCl3) d 23.5 (CH3-12), 26.6 (CH3-13), 35.1 (CH2-9), 40.6 (C-11), 46.6
7.95 (d, J¼7.0 Hz, 2H, 20-H, 60-H); 13C NMR (100 MHz, CDCl3)
d
22.0
(CH-10), 47.0 (CH-8), 80.1 (CH-7), 118.6 (CH-3), 126.6 (2ꢄ CH-20,60),
128.3 (d, J¼10 Hz, 2ꢄ aromCH), 128.4 (d, J¼10 Hz, 2ꢄ aromCH),
128.49 (CH-40),128.51 (2ꢄ CH-30,50),131.2 (d, J¼11 Hz, 2ꢄ aromCH),
131.37 (d, J¼2 Hz, aromCH), 131.46 (d, J¼2 Hz, aromCH), 132.1 (d,
J¼11 Hz, 2ꢄ aromCH), 133.0 (d, J¼65 Hz, C), 133.7 (CH-4), 133.9 (d,
J¼65 Hz, C),139.1 (C-10),140.2 (C-5),154.0 (d, J¼6 Hz, C-6),155.0 (C-
(CH3-12), 25.7 (CH3-13), 33.0 (CH2-9), 39.5 (C-11), 45.1 (CH-8), 45.9
(CH-10), 73.2 (CH-7), 117.8 (CH-3), 125.64 (2ꢄ CH-20,60), 125.69 (CH-
40), 127.7 (2ꢄ CH-30,50), 132.9 (CH-4), 137.9 (C-10), 138.4 (C-5), 153.9
þ
(C-2), 156.9 (C-6); MS (EI) m/z (%) 265 (Mꢅ , 50), 248 (MꢅþꢀOH, 26),
206 (MꢅþꢀOHꢀC3H6, 50), 196 (100), 28 (39); HRMS (EI) 265.1469
(C18H19NO requires 265.1467).
2); 31P NMR (162.0 MHz, CDCl3)
d 105.9 (m). Anal. Calcd for
C30H31BNOP: C, 77.76; H, 6.74; N, 3.02. Found: C, 77.30; H, 6.69; N,
3.22.
4.2.5. (7R,8R,10S)-2-phenyl-11,11-dimethyl-1-azatricyclo[7.1.1.05,6
undeca-2,4,6-trien-7-ol (22). Diisopropyl azodicarboxylate
]
(0.62 mL, 3.12 mmol, 4 equiv) was added dropwise to a cold (0 ꢂC)
solution of alcohol (þ)-21 (200 mg, 0.78 mmol, 1 equiv), p-nitro-
benzoic acid (520 mg, 3.12 mmol, 4 equiv), and triphenylphosphine
(820 mg, 3.12 mmol, 4 equiv) in dry THF (6 mL). After completion of
the addition, the reaction mixture was allowed to warm to room
temperature and was stirred overnight at that temperature. The
mixture was then diluted with ether (10 mL) and the organic layer
was washed with a saturated aqueous solution of sodium carbonate
(2ꢄ15 mL), dried over MgSO4, and concentrated under vacuum. The
crude material was dissolved in methanol (3 mL) and potassium
carbonate (570 mg, 4.1 mmol, 10 equiv) was added portion-wise
and the reaction mixture was stirred at room temperature for
2 h. The solvent was evaporated under reduced pressure, the resi-
due was diluted with water (5 mL) and made alkaline by addition of
an aqueous solution of 2 M sodium hydroxide. The aqueous layer
was extracted with CH2Cl2 (3ꢄ20 mL) and the organic extract was
dried over MgSO4, and concentrated under vacuum to provide pure
alcohol 22 as a colorless oil (100.3 mg, 50%): 1H NMR (400 MHz,
4.2.7. Borane-protected (7R,8R,10S)-(ꢀ)-2-phenyl-7-(diphenylphos-
phino)-11,11-dimethyl-1-azatricyclo[7.1.1.05,6]undeca-2,4,6-triene
(ꢀ)-(24). A solution of n-butyllithium in hexane (2.5 M; 0.4 mL,
1.0 mmol, 1.0 equiv) was added dropwise to a solution of (þ)-18
(0.25 g,1.0 mmol,1.0 equiv) inTHF (2 mL) at ꢀ40 ꢂC. The solutionwas
stirred at that temperature for 1 h and then a solution of Ph2PCl$BH3
(3.0 mmol, 3.0 equiv)wasadded dropwise at ꢀ40 ꢂC [the Ph2PCl$BH3
solution was prepared by stirring for 30 min a mixture of borane in
THF (1 M, 3 mL, 3 mmol, 1.0 equiv) and chlorodiphenylphosphine
(0.54 mL, 3 mmol, 1.0 equiv) in diethyl ether (2 mL) at room tem-
perature]. The resulting solution was then gradually warmed up to
room temperature and stirred overnight. A saturated aqueous so-
lution of NH4Cl (2 mL) was then added to quench the reaction, the
mixture was extracted with CH2Cl2 (3ꢄ20 mL) and the combined
organic extracts were washed with brine (20 mL) and dried over
MgSO4. Thesolvent wasremoved under vacuumand the residuewas
purified by chromatography on silica gel (20 g) using a mixture of
hexane and diethyl ether (20:1) to give pure (ꢀ)-24 as a white solid
25
D
CDCl3)
d
0.70 (s, 3H,12-H),1.48 (s, 3H,13-H), 1.59 (d, J¼9.9 Hz,1H, 9-
(154 mg, 35%): mp 190e192 ꢂC (MeOH); [
a
]
ꢀ112.4 (c 1.0, CHCl3);
H), 2.53 (td, J¼5.8, 3.2 Hz, 1H, 8-H), 2.64 (dt, J¼9.9, 5.8 Hz, 1H, 9-H0),
IR (KBr) n 3050e2950 (s, CeH), 2397 (m, BeH),1560 (m, arom C]C),

G. Chelucci et al. / Tetrahedron 67 (2011) 5421e5431
5427
1425 (m, arom C]C), 771 (s, arom CeH) cmꢀ1; 1H NMR (400 MHz,
CDCl3)
a mixture of hexane and ethyl acetate (1:1) to give pure 29 (32 mg,
36%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
0.63 (s, 3H, 12-
d
0.74 (s, 3H,12-H),1.21 (d, J¼10.3 Hz,1H, 9-H),1.41 (s, 3H,13-
d
H), 1.54 (s, 3H, BH3), 2.45 (dt, J¼10.3, 5.8 Hz, 1H, 9-H0), 2.66 (t,
J¼5.8 Hz, 1H, 10-H), 2.77 (qd, J¼6.2, 2.0 Hz, 1H, 8-H), 4.43 (dd,
JH,P2¼13.4 Hz, J¼2.0 Hz, 1H, 7-H), 7.19e7.23 (m, 3H, 4-H, 30-H, 50-H),
7.25e7.29 (m, 3H, 40-H, 2ꢄ aromH), 7.35e7.43 (m, 3H, 20-H, 60-H,
aromH), 7.47e7.57 (m, 4H, 3-H, 3ꢄ aromH), 7.68e7.73 (m, 2H,
H), 1.27 (d, J¼9.8 Hz, 1H, 9-H), 1.40 (s, 3H, 13-H), 2.38 (m, 1H, 8-H),
2.69 (dt, J¼9.8, 5.7 Hz, 1H, 9-H0), 2.75 (t, J¼5.7 Hz, 1H, 10-H), 3.08 (d,
J¼2.1 Hz, 2H, 7-H), 7.01 (d, J¼8.9 Hz, 1H, 3-H), 7.17 (d, J¼8.9 Hz, 1H,
4-H); 13C NMR (100 MHz, CDCl3)
d 21.0 (CH3-12), 25.9 (CH3-13), 31.9
(CH2-7), 36.2 (CH2-9), 39.3 (C-11), 39.9 (CH-8), 45.8 (CH-10), 120.5
(CH-3), 135.7 (CH-4), 140.7 (C-5), 147.8 (C-6), 157.8 (C-2); LCMS
(GSK-gold) 3.31 mindmass 208.1.
aromH), 7.83e7.88 (m, 2H, aromH); 13C NMR (100 MHz, CDCl3)
d 20.9
(CH3-12), 25.9 (CH3-13), 28.3 (CH2-9), 42.4 (CH-8), 42.5 (C-11), 42.7
(d, J¼29 Hz, CH-7), 45.8 (CH-10), 117.1 (CH-3), 126.1 (2ꢄ CH-20,60),
128.2 (d, J¼10 Hz, 2ꢄ aromCH),128.33 (2ꢄ CH-30,50),128.39 (CH-40),
128.45 (d, J¼55 Hz, C), 128.5 (d, J¼10 Hz, 2ꢄ aromCH), 130.1 (d,
J¼2 Hz, aromCH), 131.0 (d, J¼2 Hz, aromCH), 131.7 (d, J¼55 Hz, C),
132.5 (d, J¼9 Hz, 2ꢄ aromCH), 134.2 (CH-4), 134.4 (d, J¼9 Hz, 2ꢄ
aromCH), 138.5 (C-10), 140.8 (d, J¼4 Hz, C-5), 153.1 (d, J¼7 Hz, C-6),
4.2.10. (8S,10S)-(þ)-11,11-Dimethyl-1-azatricyclo[7.1.1.05,6]undeca-
2,4,6-triene (þ)-(30). Method A. A mixture of 10% Pd/C (10 mg,
0.0077 mmol, 0.05 equiv) and 2-chloropyridine derivative 29
(32 mg, 0.155 mmol, 1.00 equiv) in formic acid 99% (0.25 mL) and
DMF (1.25 mL) was heated at 60 ꢂC for 5 h. The mixture was then
cooled to room temperature, diluted with CH2Cl2 (4 mL), and fil-
tered through a plug of Celite. The filtrate was made alkaline by
addition of an aqueous solution of sodium hydroxide (2 M). The
mixture was then extracted with CH2Cl2 (3ꢄ20 mL), dried over
MgSO4, and concentrated under vacuum to afford the pure pyridine
(þ)-30 (25.4 mg, 95%).
153.3 (C-2); 31P NMR (162.0 MHz, CDCl3)
d 25.8 (m); MS (EI) m/z (%)
þ
þ
447 (Mꢅ , 14), 433 (Mꢅ ꢀBH3, 58), 248 (MꢅþꢀPPh2$BH3, 57), 206
(MꢅþꢀPPh2$BH3ꢀC3H6, 100), 91 (73); HRMS (EI) 447.2286
(C30H31BNP requires 447.2293).
4.2.8. (7R,8R,10S)-(ꢀ)-2-Phenyl-11,11-dimethyl-1-azatricyclo[7.1.1.05,6
]
undeca-2,4,6-trien-7-yl(diphenyl)phosphine oxide (ꢀ)-(25). A 2.5 M
solution of n-butyllithium in hexane (0.8 mL, 2.0 mmol,1.0 equiv) was
added dropwise to a solution of (þ)-18 (0.50 g, 2.0 mmol, 1.0 equiv) in
anhydrous THF (5 mL) under an argon atmosphere at ꢀ40 ꢂC. The red
colorof the mixture turneddarkerand darker. The solutionwasstirred
at that temperature for 1 h and then a solution of diphenylphosphinic
chloride (0.40 mL, 2.0 mmol, 1.0 equiv) in THF (2 mL) was added
dropwise at ꢀ40 ꢂC. The solution was then gradually warmed up to
room temperature and stirred overnight. The reaction was then
quenched by addition of water (20 mL), the mixture was extracted
with CH2Cl2 (3ꢄ20 mL), the organic solution was washed with brine
(20 mL) and dried over MgSO4. The solvent was removed under vac-
uum and the residue was purified by chromatography on silica gel
(30g) using a mixture of petroleum etherand ethyl acetate (1:1)atthe
beginning, followed by a regular increase of the ethyl acetate ratio to
Method B. Formic acid 99% (38 mL, 1.00 mmol, 2.00 equiv) was
added dropwise to a solution of triflate (þ)-2814b (160 mg,
0.50 mmol, 1.00 equiv), triethylamine (0.21 mL, 1.50 mmol,
3.00 equiv), palladium(II) acetate (2.3 mg, 0.01 mmol, 0.02 equiv),
and 1,10-bis(diphenylphosphino)ferrocene (12 mg, 0.02 mmol,
0.04 equiv) in DMF (1 mL). The reaction mixture was stirred at 60 ꢂC
for 2 h under argon, then cooled to room temperature and diluted
with water (4 mL). The resulting mixture was extracted with ether
(3ꢄ10 mL) and the combined organic layers were washed succes-
sively with a saturated aqueous solution of NaHCO3 (30 mL) and
brine (30 mL), dried over Na2SO4, and evaporated. The brown res-
idue was then purified by column chromatography on silica gel
(4 g) using a mixture of hexane and ethyl acetate (9:1), to afford
20
pure (þ)-30 (55.6 mg, 65%) as a colorless oil: [
CHCl3); IR (KBr)
arom C]C), 1430 (m, arom C]C), 758 (s, arom CeH) cmꢀ1; 1H NMR
(400 MHz, CDCl3)
a
]
þ51.8 (c 1.0,
D
n
3020 (m, CeH), 1573 (m, arom C]C), 1524 (m,
pure ethyl acetate to give pure (ꢀ)-25 as a white solid (307 mg, 34%):
25
D
mp 104e106 ꢂC (hexane); [
a]
ꢀ54.0 (c 1.0, CHCl3); IR (KBr)
n
3016 (s,
d
0.61 (s, 3H, 12-H), 1.24 (d, J¼9.5 Hz, 1H, 9-H),
CeH),1596(m, aromC]C),1525(m, aromC]C),1432(m, aromC]C),
1.37 (s, 3H, 13-H), 2.33 (tt, J¼5.8, 2.8 Hz, 1H, 8-H), 2.64 (dt, J¼9.5,
5.8 Hz, 1H, 9-H0), 2.71 (t, J¼5.8 Hz, 1H, 10-H), 3.08 (d, J¼2.8 Hz, 2H,
7-H), 6.93 (dd, J¼7.4, 5.0 Hz, 1H, 3-H), 7.15 (dd, J¼7.4, 1.3 Hz, 1H, 4-
H), 8.31 (dd, J¼5.0, 1.4 Hz, 1H, 2-H); 13C NMR (100 MHz, CDCl3)
1216 (s, P]O), 771 (s, arom CeH) cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
0.63 (s, 3H,12-H),1.32 (s, 3H,13-H),1.54 (d, J¼10.2 Hz,1H, 9-H), 2.45
(dt, J¼10.2, 5.8 Hz, 1H, 9-H0), 2.60e2.65 (m, 2H, 8-H, 10-H), 4.32 (dd,
JH,P2¼13.9 Hz, J¼1.0 Hz, 1H, 7-H), 7.10 (td, J¼7.2, 1.5 Hz, 2H, 30-H, 50-H),
7.14e7.20 (m, 4H, 4-H, 40-H, 20-H, 40-H), 7.30 (td, J¼7.4, 3.0 Hz, 2H,
aromH), 7.35e7.51 (m, 5H, 3-H, aromH), 7.69e7.75 (m, 2H, aromH),
d
21.1 (CH3-12), 26.0 (CH3-13), 31.8 (CH2-9), 36.4 (CH2-7), 39.3 (C-
11), 40.1 (CH-8), 46.4 (CH-10), 120.2 (CH-3), 132.8 (CH-4), 141.7 (C-
5), 146.6 (CH-2), 156.8 (C-6); MS (CI-isobutane) m/z (%) 174
((MþH)þ, 100), 95 (11), 69 (61); HRMS (CI-isobutane) 174.1284
(C12H16N (MþH)þ requires 174.1283).
7.82e7.89 (m, 2H, aromH); 13C NMR (100 MHz, CDCl3)
d 20.8 (CH3-12),
25.7 (CH3-13), 28.4 (CH2-9), 41.1 (CH-8), 41.9 (C-11), 45.3 (d, J¼21 Hz,
CH-7), 45.9 (CH-10), 116.9 (CH-3), 126.0 (2ꢄ CH-20,60), 128.1 (d,
J¼12 Hz, 2ꢄ aromCH), 128.2 (2ꢄ CH-30,50), 128.22 (CH-40), 128.5 (d,
J¼12 Hz, 2ꢄ aromCH), 130.9 (d, J¼3 Hz, aromCH), 131.0 (d, J¼3 Hz,
aromCH), 131.15 (d, J¼9 Hz, 2ꢄ aromCH), 131.85 (d, J¼9 Hz, 2ꢄ
aromCH),133.0(d,J¼97 Hz, C),134.2 (CH-4),134.6 (d, J¼97Hz, C),138.4
(C-10),141.0 (d, J¼5Hz,C-5),152.0(d,J¼7Hz,C-6),153.3(C-2);31PNMR
4.2.11. Borane-protected
(7R,8S,10S)-(þ)-7-(diphenylphosphino)-
11,11-dimethyl-1-azatricyclo[7.1.1.05,6]undeca-2,4,6-triene
(þ)-(31). A solution of n-butyllithium in hexane (1.6 M; 0.42 mL,
0.67 mmol, 1.0 equiv) was added dropwise to a solution of (þ)-30
(120 mg, 0.67 mmol,1.0 equiv) in THF (2 mL) at ꢀ40 ꢂC. The solution
was stirred at that temperature for 1 h and then a solution of
Ph2PCl$BH3 (1.0 mmol, 1.5 equiv) was added dropwise at ꢀ40 ꢂC
[the Ph2PCl$BH3 solution was prepared by stirring for 30 min
a mixture of borane in THF (1 M, 1 mL, 1.0 mmol, 1.0 equiv) and
chlorodiphenylphosphine (0.18 mL, 1.0 mmol, 1.0 equiv) in diethyl
ether (2 mL) at room temperature]. The resulting solution was then
gradually warmed up to room temperature and stirred overnight. A
saturated aqueous solution of NH4Cl (2 mL) was then added to
quench the reaction, the mixture was extracted with CH2Cl2
(3ꢄ20 mL), and the combined organic extracts were washed with
brine (20 mL) and dried over MgSO4. The solvent was removed
under vacuum and the residue was purified by chromatography on
silica gel (20 g) using a mixture of hexane and ether (20:1) to give
(162.0 MHz, CDCl3)
d
33.4 (P]O); MS (EI) m/z (%) 449 (Mꢅþ, 15), 248
þ
(Mꢅ ꢀP(O)Ph2, 100), 206 (MꢅþꢀP(O)Ph2ꢀC3H6, 18); HRMS (EI)
449.1906 (C30H28NOP requires 449.1909).
4.2.9. (8S,10S)-2-Chloro-11,11-dimethyl-1-azatricyclo[7.1.1.05,6]un-
deca-2,4,6-triene (29). Pyridinium chloride (100 mg, 0.864 mmol,
2 equiv) was added to a solution of triflate (þ)-2814b (139 mg,
0.431 mmol, 1 equiv) in N-methyl-2-pyrrolidone (2.6 mL) and the
mixture was stirred under microwave irradiation (250 ꢂC) for
15 min. The resulting mixture was diluted with ethyl acetate (4 mL),
the organic layer was washed with water (2ꢄ10 mL), dried over
MgSO4, and concentrated under vacuum. The resulting brownish
oil was purified by column chromatography on silica gel (4 g) using

5428
G. Chelucci et al. / Tetrahedron 67 (2011) 5421e5431
26
D
pure (D)-31 as a white solid (103 mg, 42%): [
a
]
þ45.7 (c 1.0,
4.4. General procedure for the preparation of iridium(I)
catalysts 35e43
CHCl3); IR (KBr)
C), 1525 (m, arom C]C), 1432 (m, arom C]C), 1213 (s, PeBH3), 758
(s, arom CeH) cmꢀ1; 1H NMR (400 MHz, CDCl3)
0.69 (s, 3H, 12-H),
n
3018 (m, CeH), 2389 (m, BeH), 1576 (m, arom C]
d
[Ir(COD)Cl]2 (33.58 mg, 0.05 mmol, 0.5 equiv) and the respective
P,N-ligand (0.10 mmol, 1.0 equiv) were dissolved in CH2Cl2 (2 mL).
The resulting red solution was heated at 50 ꢂC until disappearance
of the starting P,N-ligand (TLC monitoring). The solution was then
cooled to room temperature and Na[BArF]46 (133 mg, 0.15 mmol,
1.5 equiv) was added, followed by water (2 mL), and the resulting
mixture was stirred vigorously for 30 min. The two layers were
separated and the aqueous layer was extracted with CH2Cl2
(2ꢄ3 mL). The combined organic layers were dried with MgSO4 and
concentrated in vacuo. The residue was then purified by flash
chromatography on silica gel (15 g) using a mixture of hexane and
CH2Cl2 (1:1) to give 35e43 as orange solids.
1.40 (s, 3H, 13-H), 1.50 (d, J¼10.3 Hz, 1H, 9-H), 2.53 (dt, J¼10.3,
5.8 Hz, 1H, 9-H0), 2.67 (t, J¼5.8 Hz, 1H, 10-H), 2.70 (qd, J¼6.2, 2.1 Hz,
1H, 8-H), 4.33 (dd, JH,P2¼13.8 Hz, J¼2.0 Hz, 1H, 7-H), 7.91e6.96 (m,
1H, 3-H), 7.15 (dd, J¼7.5, 1.5 Hz, 1H, 4-H), 7.29 (td, J¼7.6, 2.0 Hz, 2H,
aromH), 7.38 (td, J¼7.6, 1.4 Hz, 1H, aromH), 7.45e7.52 (m, 3H, 3ꢄ
aromH), 7.74 (ddd, J¼10.7, 8.0, 1.2 Hz, 2H, 2ꢄ aromH), 7.92 (ddd,
J¼10.3, 7.7, 1.8 Hz, 2H, 2ꢄ aromH), 8.23 (dd, J¼4.9, 1.7 Hz, 1H, 2-H);
13C NMR (100 MHz, CDCl3)
d 20.7 (CH3-12), 25.8 (CH3-13), 28.4
(CH2-9), 42.0 (d, J¼10 Hz, C-11), 42.4 (d, J¼29 Hz, CH-7), 42.7 (CH-
8), 45.8 (d, J¼2 Hz, CH-10), 121.1 (CH-3), 127.8 (d, J¼10 Hz, 2ꢄ
aromCH), 128.3 (d, J¼10 Hz, 2ꢄ aromCH), 129.3 (d, J¼53 Hz, C),
130.5 (d, J¼2 Hz, aromCH), 130.6 (d, J¼2 Hz, aromCH), 130.9 (d,
J¼55 Hz, C), 133.2 (CH-4), 133.21 (d, J¼9 Hz, 2ꢄ aromCH), 134.2 (d,
J¼9 Hz, 2ꢄ aromCH), 141.8 (d, J¼4 Hz, C-5), 146.4 (d, J¼2 Hz, CH-2),
4.4.1. (8S,10S)-(þ)-2-[20-(Diphenylphosphino)phenyl]-11,11-
dimethyl-1-azatricyclo[7.1.1.05,6]undeca-2,4,6-triene- 4-(1,5-
h
153.6 (d, J¼6 Hz, C-6); 31P NMR (162.0 MHz, CDCl3)
d
26.7 (m); MS
cyclooctadiene) iridium(I) tetrakis-[3,5-bis(trifluoromethyl)phenyl]
(EI) m/z (%) 371 (Mꢅ , 22), 357 (Mꢅ ꢀBH3,100),172 (MꢅþꢀPPh2$BH3,
86), 130 (MꢅþꢀPPh2$BH3ꢀC3H6, 100); HRMS (EI) 371.1653
(C24H27BNP requires 371.1646). Anal. Calcd for C24H27BNP: C, 77.64;
H, 7.33; N, 3.77. Found: C, 77.74; H, 7.44; N, 3.71.
borate (þ)-(35). Obtained from 1 (92.6 mg, 58%): mp 65e67 ꢂC
þ
þ
26
D
(hexane/Et2O 1:1); [
a
]
þ7.8 (c 1.0, CHCl3); IR (KBr)
n 3022 (s,
CeH), 1424 (m, arom C]C), 1353 (m, arom C]C), 1277 (m, arom
C]C), 772 (s, arom CeH) cmꢀ1 1H NMR (400 MHz, CDCl3)
0.29 (d, J¼10.0 Hz, 1H, 9-H), 0.52 (s, 3H, 12-H), 0.95e1.00 (m,
;
d
4.2.12. (1R,3R,4S)-(þ)-5-Fluoro-1,3-methano-2,2,4-trimethyl-
1,2,3,4-tetrahydroacridine (þ)-(34). (1R,5S)-2,6,6-Trimethylbicyclo
[3.1.1]heptan-3-one 3239,44 (365 mg, 2.40 mmol) was added to
a suspension of t-BuOK (539 mg, 4.80 mmol) in dry 1,4-dioxane
(15 mL) and the solution was stirred at room temperature for
10 min. tert-Butyl N-(2-formylphenyl)carbamate 3345 (478 mg,
2.00 mmol) was then added and the reaction mixture was stirred at
room temperature for 7 h. A 3.0 M solution of HCl (6 mL) was added
and the resulting mixture was heated under reflux from 4 h. Most
part of the solvent was then evaporated under reduced pressure
and the residue was taken up with a 5% NaOH solution and
extracted with Et2O. The organic phase was dried over anhydrous
Na2SO4, the solvent was evaporated, and the residue was purified
by flash chromatography on a column of silica gel (2ꢄ16 cm) using
a mixture of petroleum ether and ethyl acetate (4:1) to give 34 as
a 4:1 mixture of epimers at C4 (539.3 mg). This epimeric mixture
was submitted to further flash chromatography on a column of
silica gel (2ꢄ32 cm) using a mixture of CH2Cl2 and Et2O (9:1) to give
1H, CH2(COD)), 1.17e1.22 (m, 1H, CH2(COD)), 1.24 (s, 3H, 13-H),
1.27e1.34 (m, 1H, CH2(COD)), 1.58e1.70 (m, 2H, CH2(COD)),
1.93e2.03 (m, 1H, CH2(COD)), 2.25e2.34 (m, 1H, CH2(COD)),
2.36e2.61 (m, 4H, CH2(COD), 8-H, 9-H0, 10-H), 3.25 (dd, J¼18.0,
2.7 Hz, 1H, 7-H), 3.32 (dd, J¼18.0, 2.7 Hz, 1H, 7-H0), 3.44e3.62
(m, 1H, CH(COD)), 3.85e3.95 (m, 1H, CH(COD)), 4.32e4.51 (m,
1H, CH(COD)), 5.11e5.17 (m, 1H, CH(COD)), 7.02e7.14 (m, 7H,
aromH), 7.17e7.30 (m, 3H, aromH), 7.34e7.53 (m, 9H, aromH),
7.57e7.65 (m, 9H, aromH); 31PþNMR (162.0 MHz, CDCl3)
d 19.2
(s); MS (FAB) m/z (%) 734 (Mꢅ , 100), 626 (MꢅþꢀCOD, 16), 450
(42); HRMS (FAB) 734.2529 (C38H40NPIr requires 734.2530).
Anal. Calcd for C70H52BF24NPIr: C, 52.64; H, 3.28; N, 0.88. Found:
C, 52.38; H, 3.23; N, 1.01.
4.4.2. (7R,8S,10S)-(þ)-2-[20-(Diphenylphosphino)phenyl]-7,11,11-
trimethyl-1-azatricyclo[7.1.1.05,6]undeca-2,4,6-triene- 4-(1,5-
h
cyclooctadiene) iridium(I) tetrakis-[3,5-bis(trifluoromethyl)phenyl]
borate (þ)-(36). Obtained from 2 (83.8 mg, 52%): mp 61e63 ꢂC
25
the most abundant isomer (1R,3R,4S)-34 as a white solid (329 mg,
(hexane/CH2Cl2 1:1); [
a]
þ2.8 (c 0.25, CHCl3); IR (KBr)
n 3020 (s,
D
25
61%): mp 96e97 ꢂC; [
a
]
D
þ45.8 (c 4.59, CHCl3); IR (KBr)
n
2927 (s,
CeH), 1428 (m, arom C]C), 1354 (m, arom C]C), 1279 (m, arom
CeH), 1561 (s, arom C]C), 1465 (s, arom C]C), 1379 (s, arom C]C),
C]C), 770 (s, arom CeH) cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
0.51 (s,
1271, 1174, 862, 801 (m, arom CeH), 735 cmꢀ1; 1H NMR (300 MHz,
3H, 12-H), 0.55 (d, J¼10.2 Hz, 1H, 9-H), 0.80e0.85 (m, 1H,
CH2(COD)), 1.00e1.10 (m, 2H, CH2(COD)), 1.34 (s, 3H, 13-H),
1.36e1.44 (m, 1H, CH2(COD)), 1.60e1.70 (m, 1H, CH2(COD)), 1.85 (d,
J¼7.1 Hz, 3H, CH3C(7)), 2.02e2.04 (m, 1H, CH2(COD)), 2.08e2.12 (m,
1H, CH2(COD)), 2.40 (m, 1H, 9-H0), 2.52e2.62 (m, 2H, CH2(COD), 8-
H), 2.67 (t, J¼5.9 Hz, 1H, 10-H), 3.33e3.41 (m, 2H, CH(COD), 7-H),
4.10e4.15 (m, 1H, CH(COD)), 4.24e4.29 (m, 1H, CH(COD)),
5.27e5.33 (m, 1H, CH(COD)), 6.98e7.09 (m, 3H, aromH), 7.15e7.25
(m, 2H, aromH), 7.31e7.53 (m, 10H, aromH), 7.54e7.63 (m, 3H,
aromH), 7.66e7.74 (m, 10H, aromH); 31P NMR (162.0 MHz, CDCl3)
CDCl3)
d
0.66 (s, 3H, 16-H), 1.38 (d, 1H, J¼10.2, 10-H), 1.46 (s, 3H, 15-
H), 1.51 (d, 3H, J¼6.9 Hz, 17-H), 2.23 (dt, 1H, J¼6.0, 2.4 Hz, 3-H),
2.62e2.71 (m, 1H, 10-H0), 2.96 (t, 1H, J¼5.4 Hz, 1-H), 3.45 (dq, 1H,
J¼6.9, 1.5 Hz, 4-H), 7.24e7.4 (m, 2H, 6,7-H), 7.48 (d, 1H, J¼8.1 Hz, 8-
H), 7.59 (d, 1H, J¼1.8 Hz, 4-H); 13C NMR (100 MHz, CDCl3)
d 18.8
(CH3-17), 21.0 (CH3-16), 26.2 (CH3-15), 28.8 (CH2-10), 39.5 (CH-4),
41.3 (C-2), 46.6 (CH-3), 47.7 (CH-1), 112.2 (d, J¼19.1 Hz, CH-6), 122.5
(d, J¼4.5 Hz, CH-8), 125.4 (d, J¼19.1 Hz, CH-7), 128.7 (d, J¼19.1 Hz,
CH-11), 130.0 (d, J¼130.0 Hz, C-5), 137.1 (d, J¼11.4 Hz, C-4), 141.0 (s,
CH-9), 157.8 (d, J¼253.1 Hz, C-12), 163.7 (s, C-13). Anal. Calcd for
C17H18FN: C, 79.97; H, 7.11; N, 5.49. Found: C, 79.78; H, 7.23; N, 5.45.
d
11.1 (s); MS (FAB) m/z (%) 748 (Mꢅþ, 100), 636 (48), 558 (22); HRMS
(FAB) 748.2685 (C39H42NPIr requires 748.2687). Anal. Calcd for
C71H54BF24NPIr: C, 52.93; H, 3.38; N, 0.87. Found: C, 52.88; H, 3.26;
N, 0.98.
4.3. General procedure for the borane adduct deprotection
Borane-protected phosphine or phosphinite was dissolved in
diethylamine (1e2 mL) and stirred for 6 h. The conversion was
monitored by TLC. After completion of the reaction all volatiles
were removed under high-vacuum at 60 ꢂC to afford the free
phosphine/phosphinite. The free phosphine/phosphinite was then
immediately used for complexation with iridium.
4.4.3. (7R,8S,10S)-(þ)-2-[20-(Diphenylphosphino)phenyl]-7-
isopropyl-11,11-dimethyl-1-azatricyclo[7.1.1.05,6]undeca-2,4,6-triene-
h
4-(1,5-cyclooctadiene) iridium(I) tetrakis-[3,5-bis(trifluoromethyl)
phenyl] borate (þ)-(37). Obtained from 3 (71 mg, 44%): mp
22
64e66 ꢂC (hexane/Et2O 2:1); [
a]
þ28.8 (c 0.5, CHCl3); IR (KBr)
n
D
3020 (s, CeH), 1426 (m, arom C]C), 1353 (m, arom C]C), 1272 (m,

G. Chelucci et al. / Tetrahedron 67 (2011) 5421e5431
5429
arom C]C), 770 (s, arom CeH) cmꢀ1
;
1H NMR (400 MHz, CDCl3)
31P NMR (162.0 MHz, CDCl3)
d
12.1. Anal. Calcd for C71H54BF24IrNP:
d
0.35 (d, J¼6.6 Hz, 3H, CH3CH), 0.38 (s, 3H, 12-H), 0.66e0.76 (m,1H,
C, 52.93; H, 3.38; N, 0.87. Found: C, 52.62; H, 3.33; N, 0.88.
CH2(COD)), 0.83 (d, J¼10.2 Hz, 1H, 9-H), 0.96e1.09 (m, 2H,
CH2(COD)), 1.18e1.22 (m, 1H, CH2(COD)), 1.26 (s, 3H, 13-H), 1.35 (d,
4.4.6. (1S,4S)-(ꢀ)-1,4-Methano-11,11-dimethyl-4-(diphenylphospha-
J¼6.6 Hz, 3H, CH3 CH), 1.45e1.51 (m, 1H, CH2(COD)), 1.90e2.00 (m,
nylmethyl)-1,2,3,4-tetrahydroacridine-h
4-(1,5-cyclooctadiene) iridium(I)
0
1H, CH2(COD)), 2.22 (td, J¼6.1, 1.8 Hz, 1H, 8-H), 2.30e2.38 (m, 2H,
CH2(COD), 9-H0), 2.57 (t, J¼6.1 Hz, 1H, 10-H), 2.58e2.66 (m, 1H,
CH2(COD)), 3.06 (br s, 1H, 7-H), 3.16 (td, J¼6.6, 3.5 Hz, 1H,
CH3CHCH3), 3.55e3.43 (m, 1H, CH(COD)), 3.90e3.96 (m, 1H,
CH(COD)), 3.97e4.04 (m, 1H, CH(COD)), 5.05e5.11 (m, 1H,
CH(COD)), 6.84e6.90 (m, 2H, aromH), 6.91e6.97 (m, 2H, aromH),
7.04 (tq, J¼7.1, 1.5 Hz, 1H, aromH), 7.20e7.28 (m, 3H, aromH),
7.30e7.50 (m, 10H, aromH), 7.52e7.66 (m, 10H, aromH); 31P NMR
tetrakis-[3,5-bis(trifluoromethyl)phenyl]borate
(ꢀ)-(40). Obtained
25
D
from 6 (113.4 mg, 75%): mp 87 ꢂC (hexane/CH2Cl2 1:1); [
a]
ꢀ37.1 (c
0.35 CHCl3); IR (KBr)
1457 (m, arom C]C),1354 (arom C]C), 1277 (m, arom C]C), 744 (m,
arom CeH); 1H NMR (400 MHz, CDCl3) 0.15 (s, 6H, 12-H, 12H0),
n 2965 (s, CeH), 2926 (s, CeH), 2891 (s, CeH),
d
0.80e0.85 (m, 1H, CH2(COD)), 0.93e1.00 (m, 2H, CH2(COD)), 1.15 (s,
2H, 13-H), 1.30e1.40 (m, 1H, CH2(COD)), 1.55e1.64 (m, 2H, CH2(COD),
3-H), 1.67e1.71 (m, 2H, 2-H), 1.88e1.91 (m, 1H, 3-H0), 1.93e1.98 (m,
1H, CH2(COD)), 2.01e2.03 (m, 1H, CH2(COD)), 2.73 (t, J¼5.9 Hz, 1H, 1-
H), 3.29e3.37 (m, 2H, CH2(COD)), 4.10e4.15 (m, 1H, CH(COD)),
4.20e4.27 (m, 1H, CH(COD)), 4.51e4.60 (m, 1H, CH(COD)), 7.18e7.32
(m, 10H, aromH), 7.35e7.57 (m, 4H, aromH), 7.70e7.83 (m, 10H,
aromH), 7.91e8.04 (m, 3H, 8-H, 9-H, 5-H); 13C NMR (100 MHz, CDCl3)
(162.0 MHz, CDCl3)
d
8.9 (s); MS (FAB) m/z (%) 776 (Mꢅþ, 100), 668
(MꢅþꢀCOD, 5), 262 (58); HRMS (FAB) 776.3004 (C41H46NPIr re-
quires 776.3000). Anal. Calcd for C73H58BF24NPIr: C, 53.49; H, 3.57;
N, 0.85. Found: C, 53.12; H, 3.38; N, 0.97.
4. 4. 4. (6R,8R)-(þ)-5,7-Methano-6,6,8-trimethyl-2-(2-
d
19.25 (CH3-12), 19.27 (CH3-120), 27.0 (CH2-2), 28.0 (CH2(COD)), 30.1
diphenylphosphinophenyl)-5,6,7,8-tetrahydroquinoline-
h
4-(1,5-
(CH2-3), 35.0 (CH2-13), 50.1 (C-1), 51.2 (C-11), 58.6 (C-4), 124.5 (q,
J¼540 Hz, CF3), 126.0 (CH-7), 127.2 (C-10, C-80), 127.9 (C-5, C-8), 128.5
(C-6), 128.7 (CH(COD)), 128.9 (CH-arom), 129.3 (CH-arom), 131.3 (C-
arom), 131.8 (C-arom), 132.7 (CH-arom), 135.4 (CH-9), 139.2 (C-arom),
cyclooctadiene) iridium(I) tetrakis-[3,5-bis(trifluoromethyl)phenyl]
borate (þ)-(38). Obtained from 4 (100.6 mg, 63%): mp 74 ꢂC
25
D
(hexane/CH2Cl2 1:1); [
a
]
þ14.7 (c 1.0 CHCl3); IR (KBr)
n 2927 (s,
CeH), 1436 (m, arom C]C), 1354 (arom C]C), 1277 (m, arom C]
146.2 (C-50), 192 (C-100); 31P NMR (162.0 MHz, CDCl3)
d 28.1. Anal.
C), 748 (m, arom CeH); 1H NMR (400 MHz, CDCl3)
d
0.60 (d,
Calcd for C69H52BF24IrNP: C, 52.28; H, 3.31; N, 0.88. Found: C, 52.56;
H, 3.34; N, 0.85.
J¼10 Hz, 1H, 10-H), 0.63 (d, J¼10 Hz, 1H, 10-H), 0.73 (s, 3H, 9-H),
0.95e1.02 (m, 1H, CH2(COD)), 1.20e1.22 (m, 1H, CH2(COD)), 1.25 (s,
3H, 90-H), 1.31e1.34 (m, 1H, CH2(COD)), 1.59e1.71 (m, 1H,
CH2(COD)), 1.98e2.13 (m, 2H, CH2(COD)), 2.35e2.47 (m, 1H,
CH2(COD)), 2.53e2.57 (m, 3H, CH2(COD), 8-H, 10-H), 2.62 (dd,
J¼18.0, 2.5 Hz, 1H, 5-H), 2.81 (dd, J¼18.0, 2.5 Hz, 1H, 5-H0),
3.58e3.70 (m, 1H, CH(COD)), 3.72e3.85 (m, 1H, CH(COD)),
4.45e4.48 (m, 1H, CH(COD)), 4.84e4.91 (m, 1H, CH(COD)),
7.14e7.17 (m, 7H, aromH), 7.22e7.27 (m, 3H, aromH), 7.32e7.54 (m,
9H aromH), 7.61e7.73 (m, 9H, aromH); 13C NMR (100 MHz, CDCl3)
4.4.7. (1R,3R,4S)-(ꢀ)-5-Fluoro-1,3-methano-2,2,4-trimethyl-5-(di-
phenylphosphino)-1,2,3,4-tetrahydroacridine-h
4-(1,5-cyclooctadiene)
iridium(I) tetrakis-[3,5-bis(trifluoromethyl)phenyl]borate (ꢀ)-(41).
Obtained from 9 (108.9 mg, 72%): mp 86e88 ꢂC (hexane/CH2Cl2
1:1); [
CeH), 2889 (s, CeH), 1456 (m, arom C]C), 1348 (arom C]C), 741
(m, arom C-H); 1H NMR (400 MHz, CDCl3)
0.71 (s, 3H, 15-H),
a
]
D25
ꢀ35.5 (c 0.35 CHCl3); IR (KBr)
n 2974 (s, CeH), 2932 (s,
d
0.80e0.83 (m, 1H, CH2(COD)), 0.93e1.00 (m, 2H, CH2(COD)),
1.24e1.29 (m,1H, CH2(COD)),1.33 (d,1H, J¼9.8 Hz,10-H),1.43 (s, 3H,
16-H), 1.49 (d, J¼6.7 Hz, 3H, 17-H), 1.54e1.63 (m, 1H, CH2(COD)),
1.93e1.97 (m, 1H, CH2(COD)), 2.01e2.03 (m, 1H,CH2(COD)), 2.28 (dt,
J¼6.0, 2.3 Hz, 1H, 3-H), 2.57e2.65 (m, 1H, 10-H0), 2.93 (t, J¼5.6 Hz,
1H, 1-H), 3.29e3.32 (m, 2H, CH2(COD)), 3.42 (dq, J¼6.9, 1.5 Hz, 1H,
4-H), 4.05e4.12 (m, 1H, CH(COD)), 4.20e4.25 (m, 1H, CH(COD)),
4.54e4.61 (m,1H, CH(COD)), 7.20e7.38 (m, 2H, 6-H, 7-H), 7.40e7.47
(m, 10H, aromH), 7.51 (d, J¼8.1 Hz, 1H, 8-H), 7.55e7.65 (m, 4H,
aromH), 7.67 (s, 1H, 9-H), 7.72e7.85 (m, 8H, aromH); 13C NMR
d
21.7 (CH3-9), 25.5 (CH3-90), 28.5 (CH2-10), 30.8 (CH2(COD)), 33.1
(CH2-5), 39.4 (d, J¼10 Hz, C-7), 43.3 (CH-6), 45.6 (CH-8), 117.4 (C-3),
124.7 (q, J¼540 Hz, CF3), 127.3 (CH-40), 127.6 (CH-60), 128.7
(CH(COD)), 128.9 (C-12), 129.1 (CH-50), 129.3 (CH-arom), 129.5 (CH-
arom), 131.3 (C-arom), 131.8(C-arom), 137.9 (CH-4), 144.9 (C-10),
161.4 (C-2), 166.9 (C-11); 31P NMR (162.0 MHz, CDCl3)
d 20.0. Anal.
Calcd for C70H52BF24IrNP: C, 52.64; H, 3.28; N, 0.88. Found: C,
52.31; H, 3.24; N, 0.86.
4. 4. 5. (5S, 8R)-(þ)-5,7-Methano-8,9, 9-trimethyl-2-(2-
(100 MHz, CDCl3) d 18.9 (CH3-17), 22.4 (CH3-10), 22.5 (CH3-16), 24.4
diphenylphosphinophenyl)-5,6,7,8-tetrahydroquinoline-
h
4-(1,5-
(CH2-10), 28.1 (CH2(COD)), 34.8 (CH-4), 42.7 (C-2), 51.3 (CH-1), 55.6
(CH-3), 124.5 (q, J¼540 Hz, CF3), 125.6 (CH-7), 126.4 (C-14), 128.3
(CH(COD)),128.9 (CH-arom), 129.3 (CH-arom), 131.3 (C-arom), 131.8
(C-arom), 132.1 (C-11), 133.1 (CH-6), 133.4 (CH-arom), 133.9 (CH-9),
136.5 (C-5), 137.1 (C-arom), 151.7 (C-13), 162.0 (C-12); 31P NMR
cyclooctadiene) iridium(I) tetrakis-[3,5-bis(trifluoromethyl)phenyl]
borate (þ)-(39). Obtained from 5 (82.2 mg, 51%): mp 72 ꢂC (hex-
25
ane/CH2Cl2 1:1); [
a]
þ4.2 (c 0.75 CHCl3); IR (KBr)
n 2920 (s, CeH),
D
1420 (m, arom C]C), 1354 (arom C]C), 1277 (m, arom C]C), 744
(m, arom CeH); 1H NMR (400 MHz, CDCl3)
d
0.53 (s, 3H, 10-H), 0.59
(162.0 MHz, CDCl3) d 24.0. Anal. Calcd for C69H52BF24IrNP: C, 52.28;
(s, 3H, 10-H), 1.00e1.08 (m, 1H, CH2(COD)), 1.15 (s, 3H, 11-H),
1.33e1.45 (m, 1H, CH2(COD)), 1.59e1.65 (m, 2H, CH2(COD), 7-H),
1.68e174 (m, 1H, 6-H), 1.89e1.93 (m, 2H, CH(COD), 7-H0), 1.95e1.98
(m, 1H, 6-H0), 2.00e2.04 (m, 1H, CH2(COD)), 2.08e2.11 (m, 1H,
CH2(COD)), 2.50e2.59 (m,1H, CH2(COD)), 2.77 (t, J¼6.1 Hz,1H, 5-H),
3.30e3.39 (m, 2H, CH2(COD)), 4.09e4.15 (m, 1H, CH(COD)),
4.24e4.30 (m, 1H, CH(COD)), 5.61e5.69 (m, 1H, CH(COD)),
7.15e7.25 (m, 6H, aromH), 7.52e7.67 (m, 4H, aromH), 7.68e7.75 (m,
9H, aromH), 7.77e7.86 (m, 9H, aromH); 13C NMR (100 MHz, CDCl3)
H, 3.31; N, 0.88. Found: C, 51.583; H, 3.36; N, 0.91.
4.4.8. (7S,8R,10S)-(þ)-2-Phenyl-11,11-dimethyl-1-azatricyclo
[7.1.1.05,6]undeca-2,4,6-trien-7-yl diphenylphosphinite- 4-(1,5-
h
cyclooctadiene) iridium(I) tetrakis-[3,5-bis(trifluoromethyl)phenyl]
borate (þ)-(42). Obtained from 10 (66.2 mg, 41%): mp 69e71 ꢂC
25
(Et2O/CH2Cl2 1:1); [
a
]
D
þ32.3 (c 0.25, CHCl3); IR (KBr)
n 3020 (s,
CeH), 1638 (br m, arom C]C), 1279 (m), 1215 (s, PeO), 770 (s, arom
CeH) cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
0.68 (s, 3H, 12-H), 1.46 (m,
d
15.2 (CH3-11), 18.5 (CH3-10), 19.2 (CH2-10), 25.1 (CH2-7), 25.5
4H, 9-H, 13-H), 1.50e1.52 (m, 2H, CH2(COD)), 1.66e1.76 (m, 1H,
CH2(COD)), 1.80e1.90 (m, 2H, CH2(COD)), 1.91e2.12 (m, 3H,
CH2(COD)), 2.72e2.80 (m, 1H, CH(COD)), 2.82e2.94 (m, 3H, 8-H, 9-
H0,10-H), 3.00e3.60 (m,1H, CH(COD)), 4.27e4.35 (m, 2H, CH(COD)),
6.30 (dd, J¼8.6, 3.7 Hz, 1H, 7-H), 7.16e7.20 (m, 2H, aromH),
7.31e7.39 (m, 5H, aromH), 7.40e7.42 (m, 7H, aromH), 7.43e7.50 (m,
(CH2-6), 28.1 (CH2(COD)), 50.7 (CH2-5), 57.1 (C-9), 59.1 (C-8), 117.4
(C-3), 123.2 (CH-40), 124.7 (q, J¼540 Hz, CF3), 125.2 (CH-60), 125.9
(CH-50), 128.4 (CH(COD)), 129.1 (C-13), 129.5 (CH-arom), 129.3 (CH-
arom), 131.3 (C-arom), 131.8 (C-arom), 134.1 (C-30), 136.2 (C-20),
137.4 (C-arom), 137.6 (CH-4), 144.0 (C-10), 161.9 (C-2), 172.8 (C-12);

5430
G. Chelucci et al. / Tetrahedron 67 (2011) 5421e5431
5H, aromH), 7.56e7.70 (m, 10H, aromH);þ31P NMR (162.0 MHz,
(Chiracel OD, 1.0 mL minꢀ1, hexane/2-propanol, 95:5) t1¼9.5 min,
t2¼11.9 min.
CDCl3)
d
99.2 (s); MS (FAB) m/z (%) 750 (Mꢅ , 100), 642 (MꢅþꢀCOD,
28), 462 (48); HRMS (FAB) 750.2498 (C38H40NOPIr requires
750.2479). Anal. Calcd for C70H52BF24NOPIr: C, 52.12; H, 3.25; N,
0.87. Found: C, 52.21; H, 3.32; N, 0.81.
4.5.5. 4-Methoxy-N-(10-phenylethyl)aniline. Obtained from 48 on
hydrogenation (Table 1): 1H NMR (400 MHz, CDCl3)
d 1.42 (d,
J¼6.7 Hz, 3H, CH3), 3.61 (s, 3H, OCH3), 4.34 (q, J¼6.7 Hz, 1H, 1-H),
6.40 (d, J¼8.9 Hz, 2H, 20-H, 60-H), 6.61 (d, J¼8.9 Hz, 2H, 30-H, 50-H),
7.13 (tt, J¼7.3, 1.5 Hz, 1H, 400-H), 7.23 (td, J¼7.3, 2.0 Hz, 2H, 300-H, 500-
H), 7.29 (dd, J¼7.3, 1.5 Hz, 2H, 200-H, 600-H) in agreement with the
literature data;43 chiral HPLC (Chiralpak IB, 0.75 mL minꢀ1, hexane/
2-propanol, 99:1) tR¼13.2 min, tS¼19.3 min.
4.5. General procedure for the hydrogenation of alkenes
44e47 and imine 48
A solution of the alkene 44e47 (0.2 mmol, 1 equiv), or imine 48
(45 g, 0.2 mmol, 1 equiv) and the respective iridium catalyst
(4.0 mmol, 2 mol %) in CH2Cl2 (2 mL) was sealed in an autoclave and
the hydrogenation was performed at room temperature under
hydrogen gas; for the pressure, temperature, and duration, see
Table 1. The hydrogen was then released, the autoclave was purged
with nitrogen, and the reaction mixture was directly passed
through a short silica gel plug and flashed with a mixture of pe-
troleum ether and ethyl acetate (4:1). The filtrate was evaporated
and the residue was analyzed by 1H NMR to obtain the conversion
of the reaction; chiral HPLC was used to determine the enantio-
meric excess.
References and notes
1. (a) Morrison, J. D. Asymmetric Synthesis; Academic: New York, NY, 1983e1985;
Vols. 1e5; (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, NY, 1994; (c) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; John Wiley:
New York, NY, 2000; (d) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive
Asymmetric Catalysis; Springer: 1999; Vol. IeIII; (e) Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; John Wiley: New York, NY, 2002.
2. Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336.
3. McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151.
ꢁ
ꢁ
ꢁ
ꢁ
ꢀꢁ
ꢁ
ꢁ
ꢀ
ꢁ
4. (a) Vyskocil, S; Smrcina, M.; Hanus, V.; Polasek, M.; Kocovsky, P. J. Org. Chem.
ꢁ
ꢀ
ꢁ
1998, 63, 7738 For an overview, see: (b) Kocovsky, P.; Vyskocil, S; Smrcina, M.
Chem. Rev. 2003, 103, 3213.
4.5.1. 1,2-Diphenylpropane. Obtained from 44 on hydrogenation
ꢁ
ꢁ
ꢀ
ꢁ
ꢁ
ꢀ
ꢁ
ꢀ
ꢁ
5. Kocovsky, P.; Vyskocil, S; Císarova, I.; Sejbal, J.; Tislerova, I.; Smrcina, M.; Lloyd-
Jones, G. C.; Stephen, S. C.; Butts, C. P.; Murray, M.; Langer, V. J. Am. Chem. Soc.
1999, 121, 7714.
(Table 1): 1H NMR (400 MHz, CDCl3)
d
1.18 (d, J¼6.8 Hz, 3H, CH3CH),
2.71 (dd, J¼12.9, 8.0 Hz, 1H, 2-H), 2.86e3.00 (m, 2H, 1-H, 2-H0), 7.02
ꢁ
ꢁ
6. (a) Lloyd-Jones, G. C.; Stephen, S. C.; Murray, M.; Butts, C. P.; Vyskocil, S;
(d, J¼7.0 Hz, 2H, aromH), 7.10e7.25 (m, 8H, aromH); 13C NMR
ꢁ
ꢀ
Kocovsky, P. Chem.dEur. J. 2000, 6, 4348; (b) Fairlamb, I. J. S.; Lloyd-Jones, G. C.;
ꢁ
(100 MHz, CDCl3) d 21.1 (CH3), 41.8 (CH-1), 45.0 (CH2-2), 125.8 (CH-
ꢁ
ꢁ
ꢀ
Vyskocil, S; Kocovsky, P. Chem.dEur. J. 2002, 8, 4443; (c) Gouriou, L.; Lloyd-
Jones, G. C.; Vyskocil, S; Kocovsky, P. J. Organomet. Chem. 2003, 687, 525.
7. (a) Vyskocil, S; Smrcina, M.; Kocovsky, P. Tetrahedron Lett. 1998, 39, 9289 For
overviews, see: (b) Kocovsky, P.; Malkov, A. V.; Vyskocil, S; Lloyd-Jones, G. C.
ꢁ
40), 126.0 (CH-400), 127.0 (2ꢄ aromCH), 128.0 (2ꢄ aromCH), 128.3
(2ꢄ aromCH), 129.1 (2ꢄ aromCH), 140.8 (C-10), 146.9 (C-100) in
agreement with the literature data;41 chiral HPLC (Chiracel OJ-H,
0.5 mL minꢀ1, hexane/2-propanol, 99:1), tR¼13.2 min, tS¼19.3 min.
ꢁ
ꢁ
ꢀ
ꢁ
ꢁ
ꢁ
ꢁ
ꢀ
ꢁ
ꢁ
ꢀ
ꢁ
ꢁ
ꢀ
Pure Appl. Chem. 1999, 71, 1425; (c) Kocovsky, P. J. Organomet. Chem. 2003, 687,
256.
8. (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722; (b)
Aranyos, A.; Old, D. W.; Kiymori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J.
Am. Chem. Soc. 1999, 121, 4369; (c) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int.
Ed. 1999, 38, 2413; (d) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550. For an overview of MAP-type ligands applied to
HartwigeBuchwald amination, see Ref. 4b.
9. (a) Cammidge, A. N.; Crepy, K. V. L. Chem. Commun. 2000, 1723; (b) Yin, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051.
10. (a) Malkov, A. V.; Spoor, P.; Vinader, V.; Kocovsky, P. Tetrahedron Lett. 2001, 42,
4.5.2. Ethyl 3-phenylbutanoate. Obtained from 45 on hydrogena-
26
tion (Table 1): [
CDCl3)
a]
þ6.4 (c 1.4, CHCl3, 83% ee); 1H NMR (400 MHz,
D
d
1.11 (t, J¼7.1 Hz, 3H, CH3CH2), 1.23 (d, J¼7.2 Hz, 3H, 4-H),
2.46 (dd, J¼15.0, 7.2 Hz, 1H, 2-H), 2.54 (dd, J¼15.0, 7.2 Hz, 1H, 2-H0),
3.20 (q, J¼7.2 Hz, 1H, 3-H), 4.00 (q, J¼7.2 Hz, 2H, CH3CH2), 7.13 (t,
J¼7.1 Hz,1H, 40-H), 7.15 (d, J¼6.9 Hz, 2H, 20-H, 60-H), 7.22 (t, J¼7.1 Hz,
ꢁ
ꢀ
ꢀ
509; (b) Malkov, A. V.; Stary, I.; Gouriou, L.; Lloyd-Jones, G. C.; Langer, V.; Spoor,
2H, 30-H, 50-H); 13C NMR (100 MHz, CDCl3)
d 14.1 (CH3CH2), 21.8
ꢁ
ꢀ
P.; Vinader, V.; Kocovsky, P. Chem.dEur. J. 2006, 12, 6910.
(CH3-4), 36.5 (CH-3), 43.0 (CH2CH3), 60.2 (CH2-2), 126.3 (CH-40),
126.7 (2ꢄ CH-20,60), 128.4 (2ꢄ CH-30,50), 145.7 (C-10), 172.4 (C]O-1)
in agreement with the literature data;47 chiral HPLC (Chiralpak IB,
0.75 mL minꢀ1, hexane/2-propanol, 99:1), tR¼6.8 min, tS¼9.8 min.
ꢁ
ꢀ
11. Malkov, A. V.; Hand, J. B.; Kocovsky, P. Chem. Commun. 2003, 1948.
ꢀ
ꢀ
12. Malkov, A. V.; Stewart Liddon, A. J. P.; Ramírez-Lopez, P.; Bendova, L.; Haigh, D.;
ꢁ
ꢀ
Kocovsky, P. Angew. Chem., Int. Ed. 2006, 45, 1432.
ꢁ
ꢀ
13. Malkov, A. V.; Bella, M.; Langer, V.; Kocovsky, P. Org. Lett. 2000, 2, 3047.
14. (a) Malkov, A. V.; Baxendale, I. R.; Bella, M.; Langer, V.; Fawcett, J.; Russell, D. R.;
ꢁ
ꢀ
Mansfield, D. J.; Valko, M.; Kocovsky, P. Organometallics 2001, 20, 673; (b)
Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.; Teply, F.; Meghani, P.;
ꢀ
4.5.3. 2-Methyl-3-phenylpropan-1-ol. Obtained from 46 on hydro-
ꢁ
ꢀ
ꢀ
Kocovsky, P. J. Org. Chem. 2003, 68, 4727; (c) Malkov, A. V.; Stewart-Liddon, A. J.
genation (Table 1): 1H NMR (400 MHz, CDCl3)
d
0.85 (d, J¼6.8 Hz,
ꢁ
ꢀ
P.; Teply, F.; Kobr, L.; Muir, K. W.; Haigh, D.; Kocovsky, P. Tetrahedron 2008, 64,
4011. For overviews, see: (d) Knof, U.; von Zelewsky, A. Angew. Chem., Int. Ed.
Engl. 1999, 38, 303; (e) Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129;
3H, 4-H), 1.31 (br s, 1H, OH), 1.92e1.82 (m, 1H, 2-H), 2.35 (dd, J¼8.0,
13.4 Hz, 1H, 3-H), 2.68 (dd, J¼6.3, 13.4 Hz, 1H, 3-H0), 3.40 (dd, J¼5.9,
10.6 Hz, 1H, 1-H), 3.46 (dd, J¼5.9, 10.6 Hz, 1H, 1-H0), 7.12 (t, J¼7.1 Hz,
1H, 40-H), 7.14 (d, J¼6.9 Hz, 2H, 20-H, 60-H), 7.23 (t, J¼7.1 Hz, 2H, 30-
ꢁ
ꢀ
(f) Malkov, A. V.; Kocovsky, P. Curr. Org. Chem. 2003, 7, 1737.
ꢀ
ꢁ
ꢀ
15. Malkov, A. V.; Bella, M.; Stara, I. G.; Kocovsky, P. Tetrahedron Lett. 2001, 42, 3045.
16. (a) Gladiali, S.; Chelucci, G.; Soccolini, F.; Delogu, G.; Chiessa, G. J. Organomet.
Chem. 1989, 370, 285; (b) Chelucci, G.; Pinna, G. A.; Saba, A. Tetrahedron:
Asymmetry 1997, 8, 2571; (c) Chelucci, G. Tetrahedron: Asymmetry 1997, 8, 2667;
(d) Chelucci, G.; Berta, D.; Saba, A. Tetrahedron 1997, 53, 3843; (e) Chelucci, G.;
Thummel, R. P. Synth. Commun. 1999, 29, 1665; (f) Chelucci, G.; Saba, A.; Soc-
colini, F. Tetrahedron 2001, 57, 9989; (g) Chelucci, G.; Saba, A. Synth. Commun.
2001, 31, 3161; (h) Gladiali, S.; Chelucci, G.; Salvatora Mudadu, M.; Gastaut, M.-
A.; Thummel, R. P. J. Org. Chem. 2001, 66, 400; (i) Chelucci, G.; Loriga, G.;
Murineddu, G.; Pinna, G. A. Synthesis 2003, 73; (j) Chelucci, G.; Orru, G.; Soc-
colini, F. AKRIVOC 2004, 14, 44 For overviews, see: (k) Chelucci, G.; Orru, G.;
Pinna, G. A. Tetrahedron 2003, 59, 9471; (l) Chelucci, G. Chem. Soc. Rev. 2006, 35,
1230.
H, 50-H); 13C NMR (100 MHz, CDCl3)
d 16.9 (CH3-4), 38.2 (CH-2), 40.1
(CH2-3), 68.1 (CH2-1), 126.3 (CH-40), 128.7 (2ꢄ CH-20,60), 129.5 (2ꢄ
CH-30,50), 141.0 (C-10) in agreement with the literature data;48 chiral
HPLC (Chiracel OD, 1.0 mL minꢀ1
, hexane/2-propanol, 95:5)
t1¼8.5 min, t2¼10.0 min.
4.5.4. 2-Methyl-3-phenylpropyl ethanoate. Obtained from 47 on
hydrogenation (Table 1): 1H NMR (400 MHz, CDCl3)
(CDCl3
500 MHz):
d
d
¼0.94 (d, J¼6.7 Hz, 3H, 4-H), 2.07 (s, 3H, COCH3), 2.13
€
17. For other pyridine-type ligands, see: (a) Nordstrom, K.; Macedo, E.; Moberg, C. J.
Org. Chem. 1997, 62, 1604; (b) Bremberg, U.; Rahm, F.; Moberg, C. Tetrahedron:
(m, 1H, 2-H), 2.47 (dd, J¼7.8, 13.4 Hz, 1H, 3-H), 2.75 (dd, J¼6.4,
13.4 Hz, 1H, 3-H0), 3.93 (dd, J¼6.4, 10.8 Hz, 1H, 1-H), 3.98 (dd, J¼6.2,
10.8 Hz, 1H, 1-H0), 7.09 (t, J¼7.0 Hz, 1H, 40-H), 7.11 (d, J¼6.9 Hz, 2H,
€
Asymmetry 1998, 9, 3437; (c) Warnmark, K.; Stranne, R.; Cernerud, M.; Terrien,
€
I.; Rahm, F.; Nordstrom, K.; Moberg, C. Acta Chem. Scand. 1998, 52, 961. For an
€
ꢀ
overview of chiral pyridines, see: (d) Moberg, C.; Adolfsson, H.; Warnmark, K.
Acta Chem. Scand. 1996, 50, 195; (e) Canal, J. M.; Gomez, M.; Jimenez, F.; Ro-
camora, M.; Muller, G.; Dunach, E.; Franco, D.; Jimenez, A.; Cano, F. H. Organ-
20-H, 60-H), 7.20 (t, J¼7.0, 2H, 30-H, 50-H); 13C NMR (CDCl3)
d
14.4
ꢀ
~
ꢀ
(CH3-4), 16.8 (CH3eCO), 34.6 (CH-2), 40.1 (CH2-3), 68.7 (CH2-1),
126.1 (CH-40), 128.4 (2ꢄ CH-20,60),129.2 (2ꢄ CH-30,50),141.6 (C-10),
171.1 (C]O), in agreement with the literature data;49 chiral HPLC
ometallics 2000, 19, 966 For examples of bipyridine ligands with planar
€
€
€
chirality, see: (f) Worsdorfor, U.; Vogtle, F.; Nieger, M.; Waletzke, M.; Grimme,
S.; Glorius, F.; Pfaltz, A. Synthesis 1999, 597; (g) Rios, R.; Liang, J.; Mo, MM.-C.;

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Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
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€
dEur. J. 2000, 6, 1064. For examples of chiral terpyridines and their use in
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~
Wong, W.-T. Tetrahedron: Asymmetry 2001, 12, 2683; (k) Pena-Cabrera, E.;
€
Norrby, P.-O.; Sjogren, M.; Vitagliano, A.; De Felice, V.; Oslob, J.; Ishii, S.; O’Neill,
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ꢃ
D.; Akermark, B.; Helquist, P. J. Am. Chem. Soc. 1996, 118, 4299. Related nonchiral
ꢃ
phenanthrolines: (l) Oslob, J. D.; Akermark, B.; Helquist, P.; Norrby, P.-O. Or-
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€
ganometallics 1997, 16, 3015; (m) Hansson, S.; Norrby, P.-O.; Sjogren, M. P. T.;
ꢃ
€
Akermark, B. Organometallics 1993, 12, 4940; (n) Sjogren, M. P. T.; Hansson, S.;
ꢃ
ꢃ
Akermark, B. Organometallics 1994, 13, 1963; (o) Frisell, H.; Akermark, B. Or-
ꢃ
€
ganometallics 1995, 14, 561; (p) Sjogren, M. P. T.; Frisell, H.; Akermark, B. Or-
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ꢃ
Organometallics 1999, 18, 2884.
18. (a) Chelucci, G.; Medici, S.; Saba, A. Tetrahedron: Asymmetry 1998, 9, 3183; (b)
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lucci, G.; Caria, V.; Saba, A. J. Mol. Cat. A.1998,130, 51; (d) Chelucci, G.; Pinna, G. A.;
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Tetrahedron: Asymmetry 1999, 10, 543; (h) Chelucci, G.; Gladiali, S.; Saba, A. Tet-
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R. Tetrahedron: Asymmetry 1999, 10, 1457; (j) Chelucci, G.; Culeddu, N.; Saba, A.;
Valenti, R. Tetrahedron: Asymmetry 1999, 10, 3537; (k) Chelucci, G.; Deriu, S.;
Pinna, G. A.; Saba, A.; Valenti, R. Tetrahedron: Asymmetry 1999, 10, 3803; (l)
Chelucci, G.; Saba, A.; Sanna, G.; Soccolini, F. Tetrahedron: Asymmetry 2000, 11,
3427; (m) Chelucci, G.; Pinna, G. A.; Saba, A.; Sanna, G. J. Mol. Cat. A 2000,159, 423;
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P.; Bergquist, J.; Volker, S. F.; Andersson, P. G. Adv. Synth. Catal. 2009, 351, 375;
€
(i) Zalubovskis, R.; Hormann, E.; Pfaltz, A.; Moberg, C. ARKIVOC 2008, xiv, 58; (j)
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€
32. For the original publication, see: (a) Krohnke, F. Chem. Ber. 1937, 70, 864. For
€
a review, see: (b) Krohnke, F. Synthesis 1976, 1.
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€
with borane, see: (a) Ohff, M.; Holz, J.; Quirmbach, M.; Borner, A. Synthesis
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Onozawa, T.; Kusumoto, T.; Sato, K. J. Am. Chem. Soc. 1990, 112, 5244 For an in
situ liberation of phosphines, see: (c) Williams, D. B. G.; Lombard, H.; van
Niekerk, M.; Coetzee, P. P. Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 2115;
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observed at
deprotection the signal was shifted to
37. For a related method of dehalogenation of chloropyridine with a mixture of KF
and polymethylhydrosiloxane (PMHS), catalyzed by (AcO)2Pd, see: Rahaim, R.;
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d
P¼26.11, which is typical for phosphine/borane adducts; after
d
P¼ꢀ5.28, typical for free phosphines.
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