An easy route to atropoisomeric bipyridine N,N′-dioxides and allylation of aldehydes

Article abstract of DOI:10.1016/j.tetasy.2006.11.025

Axially chiral bipyridine N,N′-dioxides (Lewis basic organocatalysts) are easily accessible in three steps from commercially available material. The key step of this reaction sequence is cobalt-catalyzed heterocyclotrimerization of 1-pyridyl-1,7-octadiyne

Full text of DOI:10.1016/j.tetasy.2006.11.025

Tetrahedron: Asymmetry 17 (2006) 3185–3191
An easy route to atropoisomeric bipyridine
N,N0-dioxides and allylation of aldehydes
a
a
b
´
´
´
Radim Hrdina, Aneta Kadlcˇıkova, Irena Valterova,
b
a,b,
*
´
Jana Hodacˇova and Martin Kotora
aDepartment of Organic and Nuclear Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 43 Prague 2, Czech Republic
bInstitute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo na´meˇstı´ 2, 166 10 Prague 6, Czech Republic
Received 7 November 2006; accepted 13 November 2006
Available online 12 December 2006
Abstract—Axially chiral bipyridine N,N0-dioxides (Lewis basic organocatalysts) are easily accessible in three steps from commercially
available material. The key step of this reaction sequence is cobalt-catalyzed heterocyclotrimerization of 1-pyridyl-1,7-octadiynes with
nitriles. Our effort was focused on the synthesis of unsymmetrically substituted bipyridines. The scope of the cyclotrimerization reaction
was tested under thermal and microwave conditions. Two of the synthesized bipyridine N,N0-dioxides were successfully resolved into
enantiomers and tested in enantioselective allylation of aldehydes.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Organocatalysis is one of the rapidly developing fields of
organic synthesis and involves the acceleration of chemical
reactions with a catalytic or a substoichiometric amount of
an organic compound, which does not contain a metal
atom. Recently, the scope of organocatalytic reactions
has been expanded upon considerably from aldol conden-
sation to Ullmann coupling, which is usually considered
to be a transition-metal-mediated reaction.1 Nevertheless,
there is still demand for developing new inexpensive and
more efficient organocatalysts. Our attention was focused
on the activation of Lewis acids by Lewis bases. Typical
representatives of Lewis bases are bipyridine N,N0-diox-
ides, which are able to activate trichlorosilanes and catalyze
a number of various reactions (allylation, propargylation,
aldol condensation, ring opening of epoxides, etc.).2 The
allylation of aldehydes is usually a first choice reaction to
test the catalytic properties and enantioselectivity of a
new organocatalyst.3–9 Herein, we report a new and simple
route to a variety of axially chiral bipyridine N,N0-dioxides
using a sequence of three steps: (i) [2+2+2]-cocyclotrimer-
ization of 2-pyridyl-octadiynes with benzonitrile to provide
unsymmetrical bipyridines, (ii) oxidation, and finally (iii)
resolution into enantiomers.
The starting ortho-substituted 1-pyridyl-1,7-octadiynes
were prepared by Krause modification of the Sonogashira
coupling of 1,7-octadiyne with halopyridines 1 (Scheme
1).10 The coupling proceeded smoothly to afford the desired
pyridyldiynes 2 in moderate to good isolated yields (22–
73%) (Scheme 1). [2+2+2]-Cyclotrimerization of nitriles
with alkynes (diynes) catalyzed by CpCo(L)n (L = CO, eth-
ane, etc.) under thermal conditions11 is known to be one of
the most straightforward methods for the synthesis of
bipyridines.12 Thus, this protocol was used for assembling
the desired bipyridine framework.
At the outset, the reaction of pyridyldiynes 2 with benzo-
nitrile was carried out under standard conditions:
X
R
Ph
N
1
N
N
Pd/Cu cat
Ph CN
+
R
(i
-Pr)2NH
conditions
A or B
(Table 1)
R
N
THF
3
2
*
Scheme 1. Preparation of diynes 2 and their cocyclotrimerization with
benzonitrile to bipyridines 3.
Corresponding author. Tel.: +42 221951334; fax: +42 221951326;
e-mail: kotora@natur.cuni.cz
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.025

3186
R. Hrdina et al. / Tetrahedron: Asymmetry 17 (2006) 3185–3191
20 mol % of CpCo(CO)2, 140 ꢁC, 24 h (Scheme 1). Typical
examples of thermal cyclotrimerizations are presented in
Table 1 (conditions A). The reaction with unsubstituted
2-pyridyl-1,7-octadiyne 2a gave the corresponding product
3a in a rather mediocre isolated yield of 30% (entry 1). The
cyclotrimerizations of diynes bearing various substituents
in position 3 2b–2e afforded bipyridines in even lower yields
(9–27%) (entries 2–5). Surprisingly, the reaction of benzo-
nitrile with diyne 2f did not yield any product (entry 6).
Moreover, in all cases we observed the formation of tar-
like products that indicated polymerization of the starting
material.
To overcome the side reactions caused by the prolonged
heating of the reactants and to attempt to increase the
yields of the desired reaction, we decided to carry out the
cyclotrimerization under microwave irradiation. The posi-
tive effect of microwave irradiation on the course of
the reaction has been noticed for a number of various
processes.13
Thus, cyclotrimerizations were run in closed vessels in a
microwave reactor and irradiated for 20 min (during this
time, the internal temperature and pressure rose to
200 ꢁC and 5 bar, respectively) (Table 1, conditions B).
Gratifyingly, in all cases the bipyridines were isolated in
improved yields. Unsubstituted bipyridine 3a was formed
in 43% yield. Methyl-substituted bipyridine 3b was ob-
tained in high 84% yield. Bipyridines 3c–3e bearing elec-
tron-accepting groups such as F, CF3, and CN were
isolated in 35%, 65%, and 30% yields, respectively. Micro-
wave irradiation also proved to be very effective for the
cyclotrimerization of 3-methoxypyridyl-diyne 2f that
yielded the corresponding bipyridine 3f in very good yield
(72%) (entry 6).
Table 1. Cyclotrimerization of diynes 2 with benzonitrile to bipyridines 3
Entry Diyne
Product
R.C.a Yieldb
(%)
Ph
N
N
1
A
B
30
43
N
3a
2a
2b
2c
2d
2e
Ph
Ph
Ph
Ph
N
2
A
B
27
84
H3C
F3C
F
Out of the series of the bipyridines prepared, compounds 3b
and 3c bearing CH3 and CF3 groups at the 3-position were
chosen for further transformations. Their oxidation with m-
chloroperbenzoic acid (m-CPBA) proceeded smoothly to
give the corresponding bipyridine N,N0-dioxides 4b and 4c
in 25% and 23% isolated yields, respectively (Scheme 2).
These racemic compounds 4b and 4c were resolved into
enantiomers by using semipreparative chiral HPLC (Chira-
cel OD-H column) in 90% and 85% combined yields. The
absolute configuration was estimated from absolute config-
uration of the allylation products obtained.14
CH3
CF3
F
N
N
3b
N
N
3
A
B
24
35
N
3c
The axially chiral bipyridine N,N0-dioxides (S)-(ꢀ)-4b and
(S)-(+)-4c obtained here were examined for their catalytic
activity and enantioselectivity in the asymmetric addition
of allyltrichlorosilane to benzaldehyde 5a, 4-trifluorometh-
ylbenzaldehyde 5b, and 4-methoxybenzaldehyde 5c in
dichloromethane (Table 2). The allylation catalyzed by
methyl-substituted bipyridine (S)-(ꢀ)-4b proceeded in all
cases with very good yields of the corresponding (R)-homo-
allylic alcohols 6 within 6 h with rather average ees. The
highest ee was obtained in the reaction with benzaldehyde
(74%). The reaction with 5c gave product 6c with lower
enantioselectivity then expected. This observation is sur-
prising, because it has previously been observed that the
N
N
4
A
B
9
65
N
3d
N
N
5
A
B
18
30
NC
CN
N
3e
Ph
Ph
Ph
(
S
)-4
and
)-4
HPLC
resolution
N
N
N
N
MCPBA
O
O
N
X
X
6
A
B
0
72
H3CO
(R
OCH3
N
N
3
4
3f
2f
4b, X = CH3, 25%
4c, X = CF3, 23%
a Reaction conditions: A = CpCo(CO)2 (20 mol %), 140 ꢁC, 24 h;
B = CpCo(CO)2 (20 mol %), MW irradiation, 20 min.
b Isolated yields.
Scheme 2. Oxidation of the bipyridines 3b and 3c to their resolution.

R. Hrdina et al. / Tetrahedron: Asymmetry 17 (2006) 3185–3191
3187
Table 2. Enantioselective allylation of para-substituted benzaldehydes
cat. ( )-4
tions in C6D6 or CDCl3 with Me4Si as an internal standard
referenced to the residual solvent signal. Chemical shifts
are given in d-scale, coupling constants J are given in
Hertz. Melting points (uncorrected) were determined using
a Kofler apparatus. Mass spectra were recorded on a ZAB-
SEQ (VG-Analytical) instrument. Infrared spectra were re-
corded on a Bruker IFS 55 spectrometer as CHCl3 solu-
tions and are reported in wave numbers (cmꢀ1). Fluka 60
silica gel was used for flash chromatography. TLC was per-
formed on silica gel 60 F254-coated aluminum sheets
(Merck). All reactions were carried out under an argon
atmosphere using the Schlenk-tube technique or in a
microwave reactor Biotage Initiator.
S
(5 mol%)
O
OH
i
-Pr2NEt
SiCl3
+
H
CH2Cl2
6h, -78 ºC
R
R
5
(R)-6
4-CH OC H
6 4
a, R = C6H5; b, R = 4-CF3C6H4 ; c, R =
3
Entry
Aldehyde 5
Alcohol 6
Yield,a eeb (%)
(S)-(ꢀ) 4b
(S)-(+) 4c
1
2
4
5a
5b
5c
6a
6b
6c
87 (74)
82 (63)
79 (41)
53 (72)
36 (27)
30 (68)
a GC yields.
4.2. Preparation of diynes 2
b Ee was determined by GC (HP-Chiral b, details are given in Experi-
4.2.1. General procedure for preparation of pyridyl-substi-
tuted 1,7-octadiynes. CuI (0.5 mmol), PdCl2(MeCN)2
(0.25 mmol), PPh3 (0.5 mmol) were suspended in dry, de-
gassed THF (10 mL) under an argon atmosphere. Aryl-
iodide (10 mmol), 1,7-octadiyne (10 mmol), and (iPr)2NH
(10 mL) were added to the suspension and the reaction
was left stirring at 50 ꢁC temperature overnight. The solu-
tion was extracted with water (20 mL) and diethylether
(2 · 15 mL) and the organic layer dried over MgSO4 before
being evaporated under reduced pressure. Purification of
the residue on silica gel provided the corresponding
compounds.
mental Section).
introduction of electron-donating groups (Me, OMe, etc.)
onto the aromatic ring of benzaldehyde usually leads to
increase in enantioselectivity. On the other hand, the
observed decrease in asymmetric induction in the reaction
with 5b is not surprising and it has been observed with ben-
zaldehydes bearing electron-withdrawing groups.3a,4 Allyl-
ations of benzaldehydes 5a–5c catalyzed by trifluoromethyl-
substituted bipyridine N,N0-dioxides (S)-(+)-4c under the
same conditions gave the corresponding (R)-homoallylic
alcohols 6 in lower yields (30–53%). However, the enantio-
selectivity trend was quite different. Thus the enantioselec-
tivity of the allylation was similar for benzaldehyde 5a
(72%), but a lower ee of 27% was observed for 4-trifluoro-
methylbenzaldehyde 5b, while 68% was observed in the
reaction with 4-methoxybenzaldehyde.
4.2.2. 2-(Octa-1,7-diynyl)pyridine 2a. 2-Iodopyridine (1 g,
4.9 mmol), PPh3 (127 mg, 0.48 mmol), CuI (46 mg,
0.24 mmol), PdCl2(MeCN)2 (31 mg, 0.12 mmol), THF
(5 mL), 1,7-octadiyne (1.3 mL, 9.7 mmol), i-Pr2NH
(5 mL). Column chromatography on silica gel (3/1 hex-
ane/EtOAc) afforded 600 mg (67%) of a viscous liquid.
1H NMR (400 MHz, C6D6) d 1.38–1.42 (m, 4H), 1.75 (t,
J = 2.3 Hz, 1H), 1.80–1.92 (m, 2H), 2.03–2.07 (m, 2H),
6.49–6.52 (m, 1H), 6.86–6.90 (m, 1H), 7.12–7.16 (m, 1H),
8.40 (d, J = 4.0 Hz, 1H); 13C NMR (100 MHz, C6D6) d
18.7, 19.6, 28.2, 28.4, 69.7, 82.7, 84.6, 90.7, 122.7, 127.5,
136.1, 145.5, 150.9; IR (CHCl3) m 3307, 2949, 2867, 2231,
2116, 1585, 1563, 1465, 1429, 1329, 1271, 1150, 1048,
992 cmꢀ1; EI-MS m/z (% relative intensity) 183 (M+, 41),
182 (100), 167 (39), 154 (42), 143 (7), 130 (25), 117 (19),
89 (17), 78 (11), 63 (11), 51 (10), 39 (11); HR-MS calcd
for C13H13N 183.10480, found 183.10396.
3. Conclusion
In conclusion, this work has shown that cobalt-catalyzed
[2+2+2]-cocyclotrimerization of pyridyl-diynes with
benzonitrile under microwave irradiation is a convenient
and straightforward method for the preparation of axially
chiral unsymmetric bipyridines. Comparison of catalytic
activity and enantioselectivity of methyl- and trifluoro-
methyl-substituted N,N0-oxides clearly indicates that the
control of the catalyst properties is likely more complicated
than it has been so far assumed. These results may thus
provide impetus for further development of more selective
catalysts.
4.2.3. 3-Methyl-2-(octa-1,7-diynyl)pyridine 2b. 2-Bromo-
3-methyl-pyridine (1 g, 5.8 mmol), PPh3 (87 mg, 0.3 mmol),
CuI (63 mg, 0.3 mmol), PdCl2(MeCN)2 (43 mg, 0.16
mmol), THF (6.5 mL), 1,7-octadiyne (1.5 mL, 11.6 mmol),
i-Pr2NH (6.5 mL). Column chromatography on silica gel
(1.5/1 hexane/EtOAc) afforded 837 mg (73%) of a viscous
4. Experimental
1
4.1. General methods
liquid. H NMR (400 MHz, C6D6) d 1.40–1.44 (m, 4H),
1.76 (t, J = 2.8 Hz, 1H), 1.85–1.89 (m, 2H), 2.09–2.12 (m,
2H), 2.19 (s, 3H), 6.54–6.57 (m, 1H), 6.89 (dd, J = 7.8,
1.0 Hz, 1H), 8.34 (dd, J = 4.7, 1.1 Hz, 1H); 13C NMR
(100 MHz, C6D6) d 18.7, 19.7, 20.2, 28.3, 28.4, 69.8, 81.5,
84.6, 94.5, 122.7, 135.8, 137.0, 145.2, 148.3; IR (CHCl3) m
3307, 3056, 3015, 2949, 2867, 2227, 2115, 1581, 1426,
1386, 1327, 1289, 1226, 1137, 1114, 1079 cmꢀ1; EI-MS
m/z (% relative intensity) 196 (M+, 100), 182 (40), 168
All solvents, unless otherwise stated, were used as obtained.
THF was distilled from sodium and benzophenone, and
dichloromethane from CaH2 under Ar. All other reagents
were obtained from commercial sources.
1H and 13C NMR spectra were recorded on a Varian
AVANCE 400 (1H at 400 MHz, 13C at 100.6 MHz) as solu-

3188
R. Hrdina et al. / Tetrahedron: Asymmetry 17 (2006) 3185–3191
1
(94), 154 (20), 144 (36), 130 (41), 117 (23), 103 (16), 89 (7);
HR-MS calcd for C14H15N 197.12045, found 197.12105.
(53%) of a viscous liquid. H NMR (400 MHz, C6D6) d
1.43–1.46 (m, 4H), 1.80 (t, J = 2.4 Hz, 1H), 1.86–1.90 (m,
2H), 2.14–2.17 (m, 2H), 6.45 (d, J = 9.0 Hz, 1H), 6.62–
6.65 (m, 1H), 8.12 (d, J = 4.6 Hz, 1H), 3.22 (s, 3H); 13C
NMR (100 MHz, C6D6) d 18.8, 20.1, 28.4, 28.6, 55.9,
70.0, 79.8, 85.3, 95.9, 118.3, 124.2, 136.5, 143.3, 158.6; IR
(CHCl3) m 3672, 3308, 3063, 3013, 2943, 2866, 2838,
2231, 2117, 1929, 1871, 1818, 1727, 1579, 1567, 1285,
1254, 1193, 1124, 1070, 1018 cmꢀ1; EI-MS m/z (% relative
intensity) 212 (MꢀH+, 100), 198 (77), 184 (73), 170 (26),
160 (22), 146 (22), 133 (21), 117 (22), 104 (10), 89 (27);
HR-MS calcd for C14H15NO 213.11536, found 213.11571.
4.2.4. 3-(Trifluoromethy)-2-(octa-1,7-diynyl)pyridine 2c. 2-
Chloro-3-(trifluoromethyl)pyridine
(10 g,
55 mmol),
PPh3(1.44 g, 5.5 mmol), CuI (524 mg, 2.8 mmol),
PdCl2(MeCN)2 (358 mg, 1.39 mmol), 1,7-octadiyne
(14.6 mL, 112 mmol), THF (60 mL), i-Pr2NH (60 mL).
Column chromatography on silica gel (3/1 hexane/EtOAc)
afforded 4 g (30%) of a viscous liquid. 1H NMR (400 MHz,
C6D6) d 1.38–1.43 (m, 4H), 1.78 (t, J = 2.75 Hz, 1H), 1.85–
1.89 (m, 2H), 2.04–2.07 (m, 2H), 6.34–6.38 (m, 1H), 7.23–
7.25 (m, 1H), 8.26 (d, J = 4.9 Hz, 1H); 13C NMR
(100 MHz, C6D6) d 18.7, 19.7, 27.9, 28.4, 70.2, 79.5, 85.0,
98.2, 122.7, 123.9, 126.6, 134.6, 143.6, 154.0; IR (CHCl3)
m 3308, 2996, 2950, 2867, 2236, 2117, 1588, 1568, 1440,
1279, 1166, 1147, 1077, 1030, 1021, 984, 810 cm1; EI-MS
m/z (% relative intensity) 250 (M+, 100), 236 (52), 222
(43), 212 (9), 198 (34), 185 (19), 154 (12), 105 (9); HR-
MS calcd for C14H11F3N 250.09218, found 250.08413.
4.3. Preparation of bipyridines 3
4.3.1. General procedure for catalytic cyclotrimerization of
pyridyl-substituted 1,7-octadiynes with benzonitrile under
thermal conditions. Pyridyloctadiyne (0.4 mmol) was dis-
solved in dry benzonitrile (16 mmol) under an argon atmo-
sphere. Then the cobalt catalyst CpCo(CO)2 (11.3 lL,
0.08 mmol) was added and the reaction mixture was heated
at 140 ꢁC for 24 h. Then the reaction was quenched with
water (1 mL) and benzonitrile was evaporated under re-
duced pressure. Purification of the residue on silica gel pro-
vided the corresponding compounds.
4.2.5. 3-Fluoro-2-(octa-1,7-diynyl)pyridine 2d. 3-Fluoro-2-
chloro-pyridine (1 g, 7.6 mmol), PPh3 (119 mg, 0.4 mmol),
CuI (72 mg, 0.4 mmol), PdCl2(MeCN)2 (50 mg, 0.2 mmol),
1,7-octadiyne (2 mL, 15.2 mmol), THF (8 mL), i-Pr2NH
(8 mL). Column chromatography on silica gel (2/1 hex-
ane/EtOAc) afforded 962 mg (62%) of a viscous liquid.
1H NMR (400 MHz, C6D6) d 1.36–1.40 (m, 4H), 1.75 (t,
J = 2.8 Hz, 1H), 1.82–1.86 (m, 2H), 2.04–2.07 (m, 2H),
6.30–6.34 (m, 1H), 6.58–6.63 (m, 1H), 8.06–8.08 (m, 1H);
13C NMR (100 MHz, C6D6) d 18.8, 19.8, 28.2, 28.5, 70.1,
77.0, 85.0, 98.0, 123.6, 124.7, 147.2, 160.7, 163.3; IR
(CHCl3) m 3308, 2991, 2950, 2866, 2837, 2236, 2117,
1594, 1563, 1449, 1329, 1264, 1236, 1182, 1101 cmꢀ1; EI-
MS m/z (% relative intensity) 200 (MꢀH+, 100), 185
(41), 172 (42), 159 (8), 148 (28), 135 (22), 122 (6); HR-
MS calcd for C13H12FN 201.09538, found 201.09638.
4.3.2. General procedure for catalytic cyclotrimerization of
pyridyl-substituted 1,7-octadiynes with benzonitrile under
microwave conditions. Pyridyloctadiyne (0.4 mmol) was
put to a vial filled with argon. Then benzonitrile (16 mmol)
and the cobalt catalyst CpCo(CO)2 (11.3 lL, 0.08 mmol)
were added to a starting material under an argon atmo-
sphere. The vial was then placed into the microwave reac-
tor and irradiated for 20 min. (Internal temperature and
pressure in the vial rose to 200 ꢁC and 5 bar within 5 min
and they stayed constant.) The reaction mixture was
quenched with water (1 mL) and benzonitrile was evapo-
rated under reduced pressure. Purification of the residue
on silica gel provided the corresponding compounds.
4.2.6. 2-(Octa-1,7-diynyl)pyridine-3-carbonitrile 2e. 2-
Chloro-3-pyridinecarbonitrile (1 g, 7.2 mmol), PPh3
(108 mg, 0.4 mmol), CuI (78 mg, 0.4 mmol), PdCl2(MeCN)2
(54 mg, 0.2 mmol), 1,7-octadiyne (1.87 mL, 14.4 mmol),
THF (8 mL), i-Pr2NH (8 mL). Column chromatography
on silica gel (dichloromethane) afforded 330 mg (22%) of a
4.3.3. 5,6,7,8-Tetrahydro-3-phenyl-1-(pyridin-2-yl)isoquino-
line 3a. Diyne 2a (62 mg, 0.3 mmol), benzonitrile
(1.6 mL, 16 mmol), CpCo(CO)2 (11.3 lL, 0.08 mmol). Col-
umn chromatography on silica gel (3/1 hexane/EtOAc)
afforded 49 mg (43%) of a viscous liquid. 1H NMR
(400 MHz, C6D6) d 1.47–1.54 (m, 4H), 2.44–2.47 (m,
2H), 3.20–3.25 (m, 2H), 6.73–6.76 (m, 1H), 7.20–7.34 (m,
5H), 8.07–8.10 (m, 1H), 8.19–8.22 (m, 2H), 8.58 (d,
J = 4.9 Hz, 1H); 13C NMR (100 MHz, C6D6) d 23.2,
24.2, 28.3, 30.8, 121.9, 123.7, 126.6, 128.6 (2C), 130.1,
130.2 (2C), 132.9, 137.5, 141.6, 149.3, 149.4, 154.6, 157.6,
162.2; IR (CHCl3) m 3724, 3688, 3305, 3063, 3020, 2947,
2883, 2851, 2223, 1595, 1562, 1460, 1423, 1389, 1327,
1219, 1168, 1139, 1080, 851 cmꢀ1; EI-MS m/z (% relative
intensity) 286 (M+, 100), 271 (16), 258 (36), 250 (16), 236
(7), 198 (7), 167 (6), 142 (10); HR-MS calcd for
C20H18N2 286.14700, found 286.14671.
1
viscous liquid. H NMR (400 MHz, C6D6) d 1.40–1.43 (m,
4H), 1.75 (t, J = 2.7 Hz, 1H), 1.86–1.88 (m, 2H), 2.00–2.03
(m, 2H), 6.04 (dd, J = 7.9, 4.9 Hz, 1H), 6.72 (dd, J = 7.9,
1.8 Hz, 1H), 8.07 (dd, J = 4.9, 1.8 Hz, 1H); 13C NMR
(100 MHz, C6D6) d 18.7, 19.7, 27.9, 28.5, 70.2, 80.2, 84.9,
99.1, 114.3, 117.9, 122.5, 130.0, 140.5, 153.9; IR (CHCl3) m
3308, 3013, 2950, 2234, 2116, 1558, 1430, 1329, 1227,
1178, 1101 cmꢀ1, EI-MS m/z (% relative intensity) 207
(MꢀH+, 100), 193 (38), 179 (28), 168 (8), 155 (17), 142
(13), 129 (6), 114 (15); HR-MS calcd for C14H12N2
208.10005, found 208.10000.
4.2.7. 3-Methoxy-2-(octa-1,7-diynyl)pyridine 2f. 2-Bromo-
3-methoxypyridine (1 g, 5.32 mmol), PPh3 (86 mg,
0.3 mmol), CuI (52 mg, 0.3 mmol), PdCl2(MeCN)2
(35 mg, 0.1 mmol), 1,7-octadiyne (1.4 mL, 11 mmol),
THF (5.6 mL), i-Pr2NH (5.6 mL). Column chromatogra-
phy on silica gel (2/1 hexane/EtOAc) afforded 600 mg
4.3.4. 5,6,7,8,-Tetrahydro-1-(3-methylpyridin-2-yl)-3-phenyl-
isoquinoline 3b. Diyne 2b (79 mg, 0.4 mmol), benzonitrile
(1.6 mL, 16 mmol), CpCo(CO)2 (11.3 lL, 0.08 mmol).
Column chromatography on silica gel (3/1 hexane/EtOAc)

R. Hrdina et al. / Tetrahedron: Asymmetry 17 (2006) 3185–3191
3189
afforded 103 mg (86%) of a viscous liquid. 1H NMR
(400 MHz, C6D6) d 1.44–1.47 (m, 4H), 2.45 (s, 3H), 2.42–
2.48 (m, 2H), 2.62–2.66 (m, 2H), 6.75–6.78 (m, 1H),
7.13–7.20 (m, 2H), 7.25–7.29 (m, 3H), 8.14–8.16 (m, 2H),
8.51 (d, J = 4.1 Hz, 1H); 13C NMR (100 MHz, C6D6) d
19.8, 23.2, 23.9, 27.0, 30.4, 120.6, 123.3, 127.8 (2C),
129.3, 129.4 (2C), 131.1, 132.8, 138.7, 140.8, 147.2, 148.2,
153.7, 158.6, 159.6; IR (CHCl3) m 3062, 2942, 2864, 2837,
1589, 1555, 1498, 1450, 1432, 1420, 1384, 1348, 1313,
155.2, 163.5; IR (CHCl3) m 2938, 2865, 2234, 1593, 1580,
1563, 1498, 1457, 1429, 1422, 1386, 1359, 1315, 1233,
1095 cmꢀ1; EI-MS m/z (% relative intensity) 310 (MꢀH+,
100), 296 (12), 283 (46), 250 (10), 235 (7), 147 (8); HR-MS
calcd for C21H17N3 311.14224, found 311.14349.
4.3.8. 5,6,7,8-Tetrahydro-1-(3-methoxypyridin-2-yl)-3-phen-
ylisoquinoline 3f. Diyne 2f (85 mg, 0.4 mmol), benzonit-
rile (1.6 mL, 16 mmol), CpCo(CO)2 (11.3 lL, 0.08 mmol).
Column chromatography on silica gel (3/1 hexane/EtOAc)
afforded 91 mg (72%) of a white solid. Mp 121 ꢁC (hep-
1249, 1208, 1163, 1110, 1026, 956, 911, 871, 825 cmꢀ1
;
EI-MS m/z (% relative intensity) 300 (M+, 100), 285 (55),
272 (75), 258 (17); HR-MS calcd for C21H20N2
300.16264, found 300.16187.
1
tane); H NMR (400 MHz, C6D6) d 1.44–1.46 (m, 4H),
2.41–2.43 (m, 2H), 2.58–2.60 (m, 2H), 3.10 (s, 3H), 6.65
(d, J = 8.4 Hz, 1H), 6.82–6.85 (m, 1H), 7.15–7.17 (m,
1H), 7.22–7.26 (m, 3H), 8.17–8.19 (m, 2H), 8.37 (d,
J = 4.8 Hz, 1H); 13C NMR (100 MHz, C6D6) d 23.3,
23.9, 26.7, 30.4, 56.2, 119.7, 121.6, 124.8, 128.7 (2C),
129.8 (2C), 130.0, 131.9, 141.8, 142.7, 148.4, 151.8, 155.1,
155.6, 158.1; IR (CHCl3) m 3623, 3060, 3012, 2936, 2860,
2832, 1711, 1587, 1448, 1420, 1280, 1207, 1112, 1014,
774, 701, 574 cmꢀ1; EI-MS m/z (% relative intensity) 316
(M+, 100), 301 (55), 288 (45), 273 (15) 158 (10), 149 (12);
HR-MS calcd for C21H20N2O 316.15756, found 316.15756.
4.3.5.
1-(3-(Trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahy-
dro-3-phenylisoquinoline 3c. Diyne 2c (1.67 g, 6.6 mmol),
benzonitrile (26 mL, 262 mmol), CpCo(CO)2 (138 lL,
0.98 mmol). Column chromatography on silica gel (3/1
hexane/EtOAc) afforded 830 mg (35%) of a white solid.
1
Mp 112 ꢁC (heptane); H NMR (400 MHz, C6D6) d 1.40–
1.46 (m, 4H), 2.37–2.38 (m, 2H), 2.50–2.54 (m, 2H),
6.50–6.54 (m, 1H), 7.14–7.18 (m, 2H), 7.24–7.27 (m, 2H),
7.50 (dd, J = 7.9, 1.2 Hz, 1H), 8.17–8.19 (m, 2H), 8.40 (d,
J = 3.8 Hz, 1H); 13C NMR (100 MHz, C6D6) d 23.2,
23.7, 26.9, 30.3, 122.1, 123.5, 126.7, 127.1, 128.5 (2C),
130.1, 130.2 (2C), 131.4, 136.1, 141.2, 148.9, 153.1, 154.6,
157.7, 159.7; IR (CHCl3) m 3308, 2926, 2855, 2236, 1600,
1569, 1440, 1321, 1147, 1121, 1030, 811 cmꢀ1; EI-MS m/z
(% relative intensity) 354 (M+, 100), 333 (20), 326 (74),
306 (16), 285 (41), 177 (6), 153 (6); HR-MS calcd for
C21H17N2F3 354.13438, found 354.13296.
4.4. Preparation of bipyridine N,N0-dioxides
4.4.1. General procedure for oxidation of bipyridines.
A
solution of bipyridine (1.66 mmol) in dichloromethane
(11 mL) was cooled to 0 ꢁC. Then MCPBA (630 mg,
3.65 mmol) was added, the reaction mixture was allowed
to reach room temperature and stirred for 1 h. Then the
reaction mixture was quenched with brine (10 mL), ex-
tracted with dichloromethane (10 mL), the organic layer
was dried over MgSO4, and the volatiles were removed un-
der reduced pressure. Purification of the residue on silica
gel provided the corresponding bis-N-oxides.
4.3.6. 1-(3-Fluoropyridin-2yl)-5,6,7,8-tetrahydro-3-phenyl-
isoquinoline 3d. Diyne 2d (120 mg, 0.6 mmol), benzonit-
rile (1.6 mL, 16 mmol), CpCo(CO)2 (11.3 lL, 0.08 mmol).
Column chromatography on silica gel (3/1 hexane/EtOAc)
afforded 79 mg (65%) of a white solid. Mp 126 ꢁC (hep-
1
tane); H NMR (400 MHz, C6D6) d 1.39–1.43 (m, 4H),
4.4.2. 5,6,7,8,-Tetrahydro-1-(3-methylpyridin-2-yl)-3-phen-
ylisoquinoline N,N-dioxide 4b. Bipyridine 3b (500 mg,
1.66 mmol), dichloromethane (11 mL), m-chloroperoxy-
benzoic acid (630 mg, 3.65 mmol). Column chromatogra-
phy on silica gel (9/1 MeOH/CHCl3) afforded 160 mg
2.38–2.39 (m, 2H), 2.63–2.66 (m, 2H), 6.57–6.60 (m, 1H),
7.17–7.19 (m, 3H), 7.23–7.28 (m, 2H), 8.17–8.19 (m, 2H),
8.28 (d, J = 4.5 Hz, 1H); 13C NMR (100 MHz, C6D6) d
23.1, 23.8, 26.8, 30.4, 122.2, 124.7, 124.9, 125.4 (d,
J = 3.4 Hz), 128.7 (2C), 130.1, 130.2 (2C), 132.4, 141.4,
146.2 (d, J = 5.3 Hz), 149.1, 155.2, 158.2, 160.8; IR
(CHCl3) m 3605, 2931, 2859, 1724, 1690, 1592, 1553,
1449, 1433, 1384, 1350, 1312, 1237, 1180, 1161, 1136,
1101, 1028, 1001, 870, 802 cmꢀ1; EI-MS m/z (% relative
intensity) 304 (M+, 100), 285 (38), 276 (65), 250 (6), 152
(8); HR-MS calcd for C20H17N2F304.13757 found
304.13883.
1
(25%) of a white solid. Mp decomposition >100 ꢁC; H
NMR (400 MHz, CDCl3) d 1.72–1.88 (m, 4H), 2.15
(s, 1H), 2.19–2.27 (m, 1H), 2.60–2.68 (m, 1H), 2.80–2.83
(m, 2H), 7.16–7.28 (m, 5H), 7.38–7.43 (m, 3H), 7.84–7.87
(m, 2H), 8.2 (d, J = 6.1 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 17.7, 21.6, 21.7, 24.5, 28.3, 125.1, 126.9, 127.4,
127.8 (2C), 129.1, 129.4 (2C), 132.5, 134.7, 136.4, 137.3,
137.3, 141.5, 142.8, 146.1; IR (CHCl3) m 3663, 3383, 3062,
2988, 2946, 2866, 1596, 1473, 1456, 1449, 1425, 1394,
1355, 1343, 1278, 1262, 1249, 1135, 1086, 1044, 964, 914,
885, 851, 817 cmꢀ1; EI-MS m/z (% relative intensity) 332
(M+, 6), 315 (42), 299 (34), 285 (17), 272 (18), 259 (16),
236 (7), 212 (7), 185 (7), 157 (7), 141 (8), 129 (16); HR-
MS calcd for C21H20N2O2 332.15240, found 332.15309.
4.3.7. 2-(5,6,7,8-Tetrahydro-3-phenylisoquinolin-1-yl)pyr-
idine-3-carbonitrile 3e. Diyne 2e (247 mg, 1.2 mmol),
benzonitrile (4.6 mL, 48 mmol), CpCo(CO)2 (83.5 lL,
0.59 mmol). Column chromatography on silica gel (3/1 hex-
ane/EtOAc) afforded 109 mg (30%) of a white solid. Mp
1
129 ꢁC (heptane); H NMR (400 MHz, C6D6) d 1.41–1.44
(m, 4H), 2.35–2.38 (m, 2H), 2.78–2.81 (m, 2H), 7.17–7.21
(m, 4H), 7.31–7.35 (m, 2H), 8.23 (dd, J = 4.8, 1.6 Hz, 1H),
8.33–8.36 (m, 2H); 13C NMR (100 MHz, C6D6) d 23.0,
23.8, 27.3, 30.5, 111.9, 119.0, 123.2, 123.3, 128.8 (2C),
129.9, 130.3 (2C), 132.5, 141.2, 142.7, 149.9, 152.0, 155.1,
4.4.3. 1-(3-(Trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-
3-phenylisoquinoline N,N-dioxide 4c. Bipyridine 3c
(957 mg, 2.5 mmol), dichloromethane (16 mL), m-chloro-
peroxybenzoic acid (695 mg, 5.5 mmol). Column chromato-
graphy on silica gel (9/1 MeOH/CHCl3), afforded 220 mg

3190
R. Hrdina et al. / Tetrahedron: Asymmetry 17 (2006) 3185–3191
1
(23%) of a white solid. Mp decomposition >100 ꢁC; H
NMR (300 MHz, CDCl3) d 1.74–1.90 (m, 4H), 2.38–2.43
(m, 2H), 2.82–2.86 (m, 2H), 7.30–7.48 (m, 5H), 7.6 (d,
J = 7.8 Hz, 1H), 7.79–7.83 (m, 2H), 8.47 (d, J = 6.6 Hz,
1H); 13C NMR d (75 MHz, CDCl3) d 21.5, 21.8, 24.9,
28.3, 122.4, 125.7, 128.0 (2C), 128.1, 129.3, 129.4 (2C),
129.9, 131.9, 132.7, 135.3, 136.8, 139.3, 142.4, 142.5,
146.3; IR (CHCl3) m 3085, 3061, 3033, 2931, 2858, 1599,
1477, 1451, 1420, 1392, 1321, 1257, 1217, 1203, 1175,
1140, 1118, 1081, 1033, 1015, 964, 911, 884, 870, 823, 779,
758, 738, 699, 672, 619, 562 cmꢀ1; EI-MS m/z (% relative
intensity) 386 (M+, 9), 369 (50), 354 (65), 341 (35), 326
(45), 314 (30), 301 (100), 285 (30), 273 (10); HR-MS calcd
for C21H17N2F3 386.12421, found 386.12537.
Acknowledgments
We gratefully acknowledge financial support from the
Czech Science Foundation (Grant No. 203/05/0102) and
Ministry of Education of the Czech Republic to the Center
for Structural and Synthetic Application of Transition
Metal Complexes (Project No. LC06070).
References
1. For a general concept of organocatalysis and typical exam-
ples, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem. 2001,
113, 3840–3864; Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2001, 40, 3726–3748; (b) Malkov, A.; Kocˇovsky´, P. Curr.
Org. Chem. 2003, 7, 1737–1757; (c) Palomo, C.; Oiarbide, M.;
Garcia, J. M. Chem. Soc. Rev. 2004, 33, 65–75; (d) Dalko, P.
I.; Moisan, L. Angew. Chem. 2004, 116, 5248–5286; Dalko, P.
I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5135–5175; (e)
Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719–724; (f)
Berkessel, R.; Gro¨ger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim, 2005.
2. For review on usage of pyridine-N-oxides, see: Chelucci, G.;
Murineddu, G.; Pinna, G. A. Tetrahedron: Asymmetry 2004,
15, 1373–1389.
3. (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am.
Chem. Soc. 1998, 120, 6419–6420; (b) Nakajima, M.; Saito,
M.; Hashimoto, S. Chem. Pharm. Bull. 2000, 48, 306–307; (c)
Nakajima, M.; Saito, M.; Hashimoto, S. Tetrahedron:
Asymmetry 2002, 13, 2449–2452.
4.5. Resolution of bipyridine N,N0-dioxides into enantiomers
4.5.1. (S)-(ꢀ)-5,6,7,8,-Tetrahydro-1-(3-methylpyridin-2-yl)-
3-phenylisoquinoline N,N-dioxide (S)-4b. Separation of
racemic 4b carried out on HPLC with a column with a
chiral phase (Chiralcel OD-H, 0.46 · 25 cm, 3/1 heptane/
2-propanol, 0.7 mL/min), afforded (S)-(ꢀ)-4b and (R)-
(+)-4b. Each enantiomer was obtained in >98% ee (tS =
20 min, tR = 37 min). The separated enantiomers were
purified by column chromatography on silica gel (9/1
CHCl3/2-propanol) prior to the use. [a]D = ꢀ350 (c 0.01,
CHCl3).
4.5.2.
(S)-(+)-1-(3-(Trifluoromethyl)pyridin-2-yl)-5,6,7,8-
4. (a) Shimada, T.; Kina, A.; Ikeda, S.; Hayashi, T. Org. Lett.
2002, 4, 2799–2801; (b) Shimada, T.; Kina, A.; Hayashi, T. J.
Org. Chem. 2003, 68, 6329–6337; (c) Kina, A.; Shimada, T.;
Hayashi, T. Adv. Synth. Catal. 2004, 346, 1169–1174.
5. (a) Malkov, A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.;
Langer, V.; Meghani, P.; Kocˇovsky´, P. Org. Lett. 2002, 2,
tetrahydro-3-phenylisoquinoline N,N-dioxide (S)-(+)-4c.
Separation of racemic 4c carried out by HPLC with a col-
umn with a chiral phase (Chiralcel OD-H, 0.46 · 25 cm, 3/
1 heptane/2-propanol, 0.7 mL/min), afforded (S)-(+)-4b
and (R)-(ꢀ)-4b. Each enantiomer was obtained in >98%
ee (tS = 24 min, tR = 35 min). The separated enantiomers
were purified by column chromatography on silica gel (9/
1 CHCl3/2-propanol) prior to the use. [a]D = +39 (c 0.01,
CHCl3).
´
1047–1049; (b) Malkov, A.; Dufkova, L.; Farrugia, L.;
Kocˇovsky´, P. Angew. Chem., Int. Ed. 2003, 42, 3674–3677;
(c) Malkov, A. V.; Bell, M.; Vassieu, M.; Bugatti, V.;
Kocˇovsky´, P. J. Mol. Catal. A: Chem. 2003, 196, 179–186; (d)
Malkov, A. V.; Bell, M.; Castelluzzo, F.; Kocˇovsky´, P. Org.
Lett. 2005, 7, 3219–3222.
4.6. Enantioselective allylation
6. Wong, W. L.; Lee, C. S.; Leung, H. K.; Kwong, H. L. Org.
Bio. Chem. 2004, 2, 1967–1969.
4.6.1. General procedure for the enantioselective allylation of
benzaldehydes with allyltrichlorosilane catalyzed by 4. To
a solution of 4b (4c) (0.0125 mmol) in dichloromethane
(0.8 mL), aldehyde (0.25 mmol), diisopropylethylamine
(54 lL, 0.31 mmol), and allyltrichlorosilane (46 lL,
0.31 mmol) were added at ꢀ78 ꢁC and the reaction mixture
was stirred for 3 h. The reaction was quenched with satu-
rated aqueous NaHCO3 (1 mL), the organic layer was sep-
arated and dried over MgSO4. Yields and ees were
determined by GC (HP-Chiral b, 30 m · 0.25 mm, oven:
80 ꢁC for 15 min, then 1 ꢁC/min to 150 ꢁC, 5 min at that
temperature).
7. (a) Pignataro, L.; Benaglia, M.; Cinquini, M.; Cozzi, F.;
Celentano, G. Chirality 2005, 17, 396–403; (b) Pignataro, L.;
Benaglia, M.; Annunziata, R.; Cinquini, M.; Cozzi, F. J. Org.
Chem. 2006, 71, 1458–1463.
8. Muller, C. A.; Hoffart, T.; Holbach, M.; Reggelin, M.
Macromolecules 2005, 38, 5375–5380.
´
´
´
ˇ
´
9. Hrdina, R.; Stara, I. G.; Dufkova, L.; Mitchel, S.; Cısarova,
I.; Kotora, M. Tetrahedron 2006, 62, 968–976.
10. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467–4470; (b) Takahashi, S.; Kuroyama, Y.;
Sonogashira, K.; Hagihara, N. Synthesis 1980, 627–630; (c)
Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551–8553.
11. For reviews see: (a) Bo¨nnemann, H.; Brijoux, W. Adv.
Heterocycl. Chem. 1990, 48, 177–222; (b) Shore, N. E.
[2+2+2] Cycloadditions. In Comprehensive Synthesis; Trost,
B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon: Oxford,
1991; Vol. 5, pp 1129–1162; (c) Grotjahn, D. B. Transition
Metal Alkyne Complexes: Transition Metal-Catalyzed Cyclo-
trimerization. In Comprehensive Organometallic Chemistry II;
Abel, E. W., Stone, F. G. A., Wilkinson, G., Hegedus, L. S.,
Eds.; Pergamon: Oxford, 1995; Vol. 12, pp 741–770; (d)
Bo¨nnemann, H.; Brijoux, W. Cyclomerization of Alkynes. In
Transition Metals for Organic Synthesis; Beller, M., Bolm, C.,
4.6.1.1. (R)-(+)-1-(4-Trifluoromethylphenyl)-but-3-en-1-
ol 6b. (tR = 59.58 min, tS = 61.09 min).
4.6.1.2. (R)-(+)-1-Phenyl-but-3-en-1-ol 6a. (tR = 57.90
min, tS = 58.33 min).
4.6.1.3.
(R)-(+)-1-(4-Methoxyphenyl)-but-3-en-1-ol
6c. (tR = 83.64 min, tS = 84.26 min).

R. Hrdina et al. / Tetrahedron: Asymmetry 17 (2006) 3185–3191
3191
´
Eds.; Wiley: Weinheim, Germany, 1998; Vol. 1, pp 114–135; 12148; (e) Varela, J. A.; Castedo, L.; Maestro, M.; Mahıa, J.;
´
´
(e) Varela, J. A.; Saa, C. Chem. Rev. 2003, 103, 3787–3801.
Saa, C. Chem. Eur. J. 2001, 7, 5203–5213; (f) Uhm, J.; An, H.
12. For leading references on 2,20-bipyridine synthesis, see: (a)
Bo¨nnemann, H.; Brinkmann, R. Synthesis 1975, 600–602; (b)
Botteghi, C.; Caccia, G.; Chelucci, G.; Soccolini, F. J. Org.
Chem. 1984, 49, 4290–4293; (c) Varela, J. A.; Castedo, L.;
W. J. Korean Chem. Soc. 2001, 45, 268–272.
13. Kappe, O. C.; Stadler, A. Microwaves in Organic and
Medicinal Chemistry; Wiley-VCH: Weinheim, 2005.
14. It is known that catalysis by (S)-bipyridine-N,N-dioxides
provide (R)-products and vice versa, for details see Ref. 3a
and 4.
´
Saa, C. J. Org. Chem. 1997, 62, 4189–4192; (d) Varela, J. A.;
Castedo, L.; Saa, C. J. Am. Chem. Soc. 1998, 120, 12147–
´