Cross-cyclotrimerization with two nitriles as a synthetic pathway to unsymmetrically 3,3'-disubstituted bis(tetrahydroisoquinolines)

Article abstract of DOI:10.3390/molecules14082918

Microwave assisted CpCo(CO)2 catalyzed cross-cyclotrimerizations of 1,7,9,15-hexadecatetrayne with two different nitriles to give unsymmetrically substituted bis(tetrahydroisoquinolines) was studied. The reaction proceeded with a range of alkyl and aryl n

Full text of DOI:10.3390/molecules14082918

Molecules 2009, 14, 2918-2926; doi:10.3390/molecules14082918
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Cross-Cyclotrimerization with Two Nitriles as a Synthetic
Pathway to Unsymmetrically 3,3’-Disubstituted
bis(Tetrahydroisoquinolines)
Aneta Kadlčíková 1 and Martin Kotora 1,2,
*
1
Department of Organic and Nuclear Chemistry, and Center for Structural and Synthetic Application
of Transition Metal Complexes, Faculty of Science, Charles University in Prague, Hlavova 8, 128
43 Praha 2, Czech Republic
2
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
Flemingovo nám. 2, 166 10 Praha 6, Czech Republic
* Author to whom correspondence should be addressed; E-mail: kotora@natur.cuni.cz
Received: 10 July 2009; in revised form: 31 July 2009 / Accepted: 3 August 2009 /
Published: 10 August 2009
Abstract: Microwave assisted CpCo(CO)2 catalyzed cross-cyclotrimerizations of 1,7,9,15-
hexadecatetrayne with two different nitriles to give unsymmetrically substituted
bis(tetrahydroisoquinolines) was studied. The reaction proceeded with a range of alkyl and
aryl nitriles with reasonable isolated yields.
Keywords: cyclotrimerization; cobalt; microwave heating; pyridines
1. Introduction
Lewis base catalyzed processes constitute a large group of reactions that has been extensively used
in organic synthesis and especially in asymmetric catalysis [1]. Among Lewis bases that have recently
attracted considerable attention are pyridine N-oxides and their congeners. For example, they are able
to strongly activate halosilanes via Lewis base-acid interaction to such an extent that halosilanes react
with various functional groups. In this respect, enantioselective catalytic allylation of aldehydes have
been intensively studied [2-8]. A number of various N-oxides [9-20], N,N-dioxides [21-27] and even
N,N,N-trioxides [28] based on heterocyclic compounds with pyridine ring have been synthesized for
this purpose.

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We have recently demonstrated that microwave irradiation-enhanced Co-complex catalyzed
[2+2+2]-cross-cyclotrimerization of diynes with nitriles can be conveniently used for simple and
expedient synthesis of various bipyridines. Their oxidation, usually by MPCBA, and resolution into
enantiomers yielded the corresponding chiral bipyridine N,N-dioxides [29-33]. The compounds
catalyzed asymmetric allylation of aldehydes in up to 87% ee. In our last report we showed that the
cyclotrimerization of 1,7,9,15-hexadecatetrayne with two different nitriles, benzonitrile and (R)-
tetrahydrofurancarbonitrile, furnished unsymmetrically substituted bis(tetrahydroisoquinoline) in 28%
isolated yield, along with the symmetric derivative (20% isolated yield). Its further oxidation afforded
two diastereoisomeric bis(tetrahydroisoquinoline) N,N’-dioxides that catalyzed enantioselective
allylation of aldehydes [34]. This result provided us with impetus to study potential application of
cobalt-complex catalyzed cross-cyclotrimerization of 1,7,9,15-hexadecatetrayne (1) with various
nitriles as a pathway to unsymmetrically substituted bis(tetrahydroisoquinolines).
2. Results and Discussion
The microwave assisted cyclotrimerization of alkynes with nitriles offers several advantages in
comparison with standard thermal conditions. Among these are, for example, reduced reaction times
from hours to minutes, reactants are thus exposed to high reaction temperatures for shorter periods of
time reducing possibility of thermal decomposition, and also the use of lower boiling point solvents
such as THF, which allows easier separation of products [35-40].
For the study of cross-cyclotrimerization of 1,7,9,15-hexadecatetrayne (1) with various nitriles the
previously used conditions were applied: CpCo(CO)2 (20 mol%), nitrile R1-CN (1 equiv.), nitrile R2-
CN (1-20 equiv.), THF as solvent. The reactions were carried out in microwave reactor (microwave
irradiation 300 W, reaction time 25 min). A series of cross-cyclotrimerization reactions between two
different nitriles with 1,7,9,15-hexadecatetrayne (1) in various molar ratios was carried out with varied
success (Scheme 1).
Scheme 1. Co-cyclotrimerization of tetrayne 1 with nitriles 2 and 3.
CpCo(CO)2
(20 mol%)
R1 CN
R2 CN
+
+
THF, MW
2
3
1
R1
R1
R2
N
N
N
N
N
N
R2
R1
R2
4
5
6

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In all cases the desired products of cross-cyclotrimerization of 1 with two different nitriles 2 and 3 –
unsymmetrically substituted bis(tetrahydroisoquinolines) 4 – were formed. The reaction was always
accompanied by the formation of varying amounts of symmetrically substituted bis(tetrahydr-
oisoquinolines) 5 and/or 6, the products of cyclotrimerization of 1 with 2 or 3. Some of the most
representative examples are given in Table 1.
Table 1. Cross-cyclotrimerization of tetrayne 1 with two nitriles 2 and 3.
Entry R1-CN R2-CN
R1/R2 a Yield (%)b 4 Yield (%)b 5 Yield (%)b 6
1
2
3
4
5
6
7
8
C6H5 CH3
3a
1/1
1/10
1/20
1/1
1/10
1/1
1/5
1/1
1/10
1/1
10/1
1/1
4a, 10
25
25
4b, 23
28
4c, 20
28
4d, 28
24
4e, 20
28
4f, 12
20
5a, 30
10
10
5a, 15
10
5a, 10
0
0
0
0
0
0
0
0
0
C6H5 4-MeOC6H4
C6H5 2-C5H4Ne
C6H5 THF*c
3b
3c
3d
2
5a, 10
10
traces
9
10
11
12
13
14
15
16
17
CH3 3,4,5-(MeO)3C6H4 3e
6e, 9
5
6f, 30
15
0
0
0
0
0
0
CH3 4-CF3C6H4
CH3 4-ClC6H4
3f
10/1
1/1
10/1
1/1
3g
4g, 22
27
6g, 10
5
CH3 THF*c
3d
4h, 16d
16d
6h, 16d
3d
10/1
5b, 16d
b
c
e
a Molar ratio. Isolated yields. (R)-tetrahydrofuran-2-yl. d 1H-NMR yields. 2-pyridyl.
Thus the cross-cyclotrimerization of benzonitrile (2) with acetonitrile (3a, 1/1 2/3a ratio) gave
preferentially symmetrical product 5a (Entry 1), the change of the nitrile ratio to 1/10 resulted in the
preferential formation of 4a (25% isolated yield) which was accompanied by a small amount of 5a
(10%) (Entry 2). The formation of 6a was not detected. Further change of the nitrile ratio did not
affect the reaction outcome (Entry 3). The analogical results were obtained also in other cases. Thus
cross-cyclotrimerization of benzonitrile (2) and 4-methoxybenzonitrile (3b, 1/10 2/3b ratio) gave 4b in
28% isolated yield along with 10% of 5a (Entry 5). The formation of 4c was achieved in 28% isolated
yield (1/5 2/3c ratio) and 5a was formed in just 2% yield (Entry 7). Finally benzonitrile (2) and (R)-
tetrahydrofurancarbonitrile (2d) were cross-cyclotrimerized to yield the corresponding 4d in 28%
isolated yield. Unlike in the previous cases, the best result was obtained when both nitriles were used
in 1/1 molar ratio (compare Entries 8 and 9). In none of the cases was the formation of 6a-6d detected.
Then combination of acetonitrile (3a) and other nitriles was also studied. The best results for
cyclotrimerization of 3a with nitriles 3e-3g giving the highest yields of the corresponding
bis(tetrahydroisoquinolines) 4e-4g (28, 20, and 27% yields, respectively) occurred when the molar
ratios of 3a/3e, 3a/3f, and 3a/3g were 10/1 (Entries 11, 13, and 15). On the other hand, for the

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reactions of 3a with nitrile 3d the optimal ratio of 3a/3d was 1/1 (Entry 16). The formation 5b was not
observed under these conditions.
It should be emphasized that the cross-cyclotrimerization proceeded only under microwave
irradiation. Carrying out the reaction under standard thermal condition (130 °C, 24-48 h) or attempts to
facilitate the cyclotrimerization by visible light irradiation gave rise to intractable reaction mixtures.
Attempts to carry out the cyclotrimerization sequentially, i.e. to cyclotrimerize tetrayne 1 with one
nitrile, isolate the expected intermediate (1-diynyltetrahydroisoquinoline), and then to carry out the
second cyclotrimerization with another nitrile, also failed. The first reaction under the above
mentioned conditions usually proceeded with low selectivity for the monocyclotrimerization (only up
to 30%) and low yields (~10%), regardless of the nitrile used, making the whole process
uneconomical. Carrying out the monocyclotrimerization under less forcing conditions by using another
catalytic system, e.g. CoCl2·6H2O, Zn, dppe [41,42], did not meet the expectations either. Although the
reaction proceeded exclusively to yield 1-diynyltetrahydroisoquinolines, the yields did not exceed in
10%. The use of catalysts based on other transition metals (Rh, Ru) did not promote the
cyclotrimerization.
Experimental
General
All solvents, unless otherwise stated, were used as obtained. THF was distilled from sodium and
13
benzophenone under Ar. All other reagents were obtained from commercial sources. 1H- and C-
NMR spectra were recorded on a Varian UNITY 300 (1H at 300 MHz, 13C at 75 MHz) as solutions in
C6D6. Chemical shifts are given in δ-scale, coupling constants J are given in Hz. Mass spectra were
recorded on a LTQ Orbitrap XL. Infrared spectra were recorded on a FTIR Nicolet avatar Drift KBr
and are reported in wave numbers (cm-1). Fluka 60 silica gel was used for flash chromatography. TLC
was performed on silica gel 60 F254-coated aluminum sheets (Merck). All reactions were carried out
under an argon atmosphere using flasks or in microwave reactor Biotage Initiator. Hexadeca-1,7,9,15-
tetrayne (1) was prepared according to the previously reported method [43].
General procedure for cross-cyclotrimerization
R1CN (0.48 mmol), R2CN (4.8 mmol) and CpCo(CO)2 (18 mg, 0.1 mmol) were added under
atmosphere of argon to a solution of hexadeca-1,7,9,15-tetrayne (1, 100 mg, 0.48 mmol) in dry and
degassed THF (3 mL) contained in a vial. Then the vial was placed into the microwave oven and
irradiated for 25 min (300 W) (during the process temperature and pressure reached 180 °C and 20
barr, respectively). Unreacted nitriles were then removed under reduced pressure and column
chromatography of the residue on silica gel using the indicated eluent systems yielded the products.
5,6,7,8-Tetrahydro-1-(5,6,7,8-tetrahydro-3-methylisoquinolin-1-yl)-3-phenylisoquinoline (4a). Eluent:
3/1 hexane/EtOAc; yield: 40 mg (25%) of the title compound as a viscous colorless liquid and 30 mg
1
(10%) of symmetrical benzonitrile substituted product 5a. Compound 4a: H-NMR: δ 1.44-1.49 (m,
8H), 2.44-2.48 (m, 4H), 2.51 (s, 3H), 2.61-2.66 (m, 4H), 6.59 (s, 1H), 7.19 (s, 1H), 7.24-7.29 (m, 3H),

Molecules 2009, 14
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8.17-8.20 (m, 2H); 13C-NMR: δ 23.2 (2C), 23.9, 24.0, 24.8, 26.8, 27.0, 30.2, 30.5, 120.4, 123.3, 127.9
(2C), 128.2, 128.5, 129.2, 129.4, 130.8, 141.0, 147.4, 148.0, 154.0, 154.7, 158.7, 159.3; IR (THF) ν
696, 1069, 1430, 1590, 1722, 2858, 2933, 3085 cm-1; ESI-MS m/z (% relative intensity) 355 (M+,
100), 377 (15); HR-ESI calculated for C25H26N2 355.2169 found 355.2169.
5,6,7,8-Tetrahydro-1-(5,6,7,8-tetrahydro-3-phenylisoquinolin-1-yl)-3-(4-methoxyphenyl)iso-quinoline
(4b). Eluent: 3/1 hexane/EtOAc; yield: 60 mg (28%) of the title compound as a viscous colorless
1
liquid and 20 mg (10%) of symmetrical benzonitrile substituted product 5a. Compound 4b: H-NMR:
δ 1.48-1.50 (m, 8H), 2.51-2.53 (m, 4H), 2.69-2.71 (m, 4H), 3.31 (s, 3H), 6.91-6.93 (m, 2H), 7.18-7.20
(m, 1H), 7.19-7.21 (m, 1H); 7.27-7.32 (m, 3H), 8.21-8.24 (m, 4H); 13C-NMR: δ 23.2, 23.3, 23.9, 24.0,
27.1 (2C), 30.5 (2C), 55.5, 115.0, 119.8, 120.5, 127.9 (2C), 129.2 (4C), 129.5 (2C), 130.3, 131.1,
133.6, 141.0, 148.1 (2C), 153.9, 154.0, 159.0, 159.2, 161.4; IR (THF) ν 694, 835, 1030, 1172, 1247,
1307, 1416, 1451, 1514, 1550, 1589, 1608, 2931 cm-1; ESI-MS m/z (% relative intensity) 447 (M+,
100), 448 (36), 469 (8), 893 (50), 915 (50), 916 (35), 917 (15); HR-ESI calculated for C30H30N2O
447.2431 found 447.2426.
5,6,7,8,-Tetrahydro-1-(5,6,7,8-tetrahydro-3-phenylisoquinolin-1-yl)-3-(pyridin-2-yl)isoquino-line (4c).
Eluent: 1/1 hexane/EtOAc; yield: 55 mg (28%) of the title compound as a viscous colorless liquid and
1
4 mg (2%) of symmetrical benzonitrile substituted product 5a. Compound 4c: H-NMR: δ 1.44-1.46
(m, 8H), 2.43-2.64 (m, 8H), 6.84-6.85 (m, 1H), 7.18-7.21, (m, 3H), 7.26-7.32 (m, 2H), 8.19-8.29 (m,
3H), 8.57-8.58 (m, 1H), 9.52 (s, 1H); 13C-NMR: δ 22.0, 22.2, 22.8, 22.9, 26.1, 29.3, 29.4, 30.0, 119.7,
123.1, 126.9 (2C), 128.3 (2C), 128.5, (2C), 130.0, 130.8, 133.7, 135.0, 139.8, 147.3, 147.5, 148.4,
149.6, 150.5, 153.1, 157.7, 158.4; IR (THF) ν 689, 751, 806, 1024, 1160, 1430, 1588, 2855, 2922,
3036 cm-1; ESI-MS m/z (% relative intensity) 418 (M+, 100), 440 (61); HR-ESI calculated for
C29H27N3 418.2269, found 418.2278.
3-[(R)-Tetrahydrofuran-2-yl]-3’-phenyl-(5,5’,6,6’,7,7’,8,8’-octahydro-l,l’-biisoquinoline)
(4d).
Eluent: 5/1 hexane/EtOAc; yield: 56 mg (28%) of the title compound as a viscous colorless liquid and
1
20 mg (20%) of symmetrical product 5a. Compound 4d: H-NMR: δ 1.36-1.68 (m, 11H), 2.08-2.14
(m, 1H), 2.19-2.26 (m, 1H), 2.46-2.68 (m, 7H), 3.74-3.80 (m, 1H), 3.95-4.0 (m, 1H), 5.23 (t, J= 7Hz;
13
1H), 7.15-7.19 (m, 1H), 7.25-7.29 (m, 3H), 7.4 (s, 1H), 8.16-8.19 (m, 2H); C-NMR: δ 23.2 (2C),
24.0 (2C), 26.7, 27.0, 27.1, 30.4, 30.5, 34.0, 69.5, 82.4, 120.3, 120.5, 128.2, 128.6 (2C), 129.2 (2C),
130.4, 131.0, 140.9, 148.0, 148.1, 153.9, 158.4, 159.1, 160.1; IR (THF) ν 699, 961, 1069, 1432, 1722,
2877, 2937, 3292 cm-1; ESI-MS m/z (% relative intensity) 411 (M+, 100), 412 (31), 433 (27); HR-ESI
calculated for C28H30N2O+H+ 411.2431, found 411.2421.
5,6,7,8-Tetrahydro-1-(5,6,7,8-tetrahydro-3-(3,4,5-trimethoxyphenyl)isoquinolin-1-yl)-3-methyl-iso-
quinolne (4e). Eluent: 3/1 hexane/EtOAc; yield: 60 mg (28%) of the titled compound as a viscous
colorless liquid and 2 mg (5%) of symmetrical 3,4,5-trimethoxybenzonitrile substituted product 6e.
1
Compound 4e: H-NMR: δ 1.46-1.51 (m, 8H), 2.42-2.65 (m, 11H), 3.42 (s, 6H), 3.88 (s, 3H), 6.56
(s, 1H), 7.42 (s, 1H), 7.53 (s, 2H); 13C-NMR: δ 23.3, 23.9, 24.0, 24.7, 26.8, 26.9, 30.2, 30.5, 56.6 (2C),
61.2, 106.1, 120.3, 123.4, 128.6 (2C), 129.0 (2C), 130.5, 136.4, 141,4, 147.4, 148.0, 154.3, 155.0,
155.1, 158.7, 159.3; IR (THF) ν 853, 1068, 1127, 1228, 1430, 1554, 2858, 2934, 1584, 1721 cm-1;

Molecules 2009, 14
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ESI-MS m/z (% relative intensity) 445 (M+, 100), 467 (33); HR-ESI calculated for
C28H32N2O3 445.2486 found 445.2476.
1-(3-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-1-yl)-5,6,7,8-tetrahydro-3-methyl-
isoquinoline (4f). Eluent: 3/1 hexane/EtOAc; yield: 40 mg (20%) of this product as a viscous colorless
liquid and 30 mg (15%) of symmetrical 4-(trifluoromethyl)benzonitrile substituted product 6f.
Compound 4f: 1H-NMR: δ 1.46-1.50 (m, 8H), 2.45-2.48 (m, 4H), 2.51 (s, 3H), 2.58-2.64 (m, 4H), 6.60
(s, 1H), 7.16 (s, 1H), 7.47 (m, 2H), 8.00 (m, 2H); 13C-NMR: δ 23.1, 23.2, 23.7, 23.8, 24.0, 24.7, 26.8,
27.0, 30.1, 30.4, 32.6, 120.8, 123.5, 126.3, 126.4, 127.7, 128.1, 129.2, 132.0, 144.1, 148.0, 148.3,
152.2, 154.8, 158.3, 159.6; IR (THF) ν 848, 1015, 1068, 1123, 1161, 1323, 1432, 1591, 2858,
2928 cm-1; ESI-MS m/z (% relative intensity) 423 (M+, 100), 445 (58); HR-ESI calculated for
C26H25N2F3 445.2486 found 445.2476.
1-(3-(4-Chlorophenyl)-5,6,7,8-tetrahydroisoquinolin-1-yl)-5,6,7,8-tetrahydro-3-methylisoquinoline
(4g). Eluent: 3/1 hexane/EtOAc; yield: 50 mg (27%) of this product as a viscous colorless liquid and 9
mg (5%) of symmetrical 4-chlorobenzonitrile substituted product 6g. Compound 4g: 1H-NMR: δ 1.43-
1.49 (m, 8H), 2.44-2.47 (m, 4H), 2.51 (s, 3H), 2.57-2.63 (m, 4H), 6.59 (s, 1H), 7.12 (s, 1H), 7.21-7.24
13
(m, 2H), 7.89-7.92 (m, 2H); C-NMR: δ 23.2, 23.3, 23.9, 24.0, 24.7, 26.8, 26.9, 30.1, 30.4, 120.2,
123.4, 128.8 (2C), 129.2 (2C), 129.6, 131.2, 135.3, 139.3, 147.5, 148.1, 152.6, 154.8, 158.5, 159.4; IR
(THF) ν 834, 1012, 1304, 1431, 1492, 1592, 2857, 2932 cm-1; ESI-MS m/z (% relative intensity) 389
(M+, 100), 391 (36); ESI-MS m/z (% relative intensity) 389 (M+, 100), 391 (36); HR-ESI calculated
for C25H25N2Cl 389.1779 found 389.1779.
5,6,7,8-Tetrahydro-1-(5,6,7,8-tetrahydro-3-methylisoquinolin-1-yl)-3-(tetrahydrofuran-2-yl)-
isoquinoline (4h). Eluent: EtOAc; yield: 52 mg (32%) of the mixture of this product and the
symmetrical (R)-tetrahydrofurancarbonitrile substituted product 6h in the ratio of 1:1. Compound 4h:
1H-NMR: δ 1.36-1.66 (m, 12H), 2.01-2.10 (m, 2H), 2.18-2.29 (m, 2H), 2.38-2.50 (m, 7H), 3.74-3.79
13
(m, 1H), 3.91-3.97 (m, 1H), 5.15-5.19 (m, 1H), 6.56 (s, 1H), 7.36 (s, 1H); C-NMR: δ 22.9, (2C),
23.7, 24.3, 26.3, 26.5, 26.6, 29.8, 30.1, 30.5, 33.6, 69.1, 82.0, 119.8, 199.9, 129.8, 130.0, 147.5, 147.6,
158.0, 158.3, 159.7, 159.8.
Conclusions
In conclusion, we have demonstrated that CpCo(CO)2 catalyzed cross-cyclotrimerization of
1,7,9,15-hexadecatetrayne with two different nitriles under microwave irradiation can be a convenient
method for synthesis of unsymmetrically substituted bis(tetrahydroisoquinolines). Although the
isolated yields of the unsymmetrical products did not exceed 30%, this shortcoming is counterweighed
by the simplicity and expeditiousness of the cross-cyclotrimerization method and also by the fact that
sequential two step cyclotrimerization cannot be applied due to low selectivity and thermal instability
of the starting tetrayne. Last but not least, it also should taken into the account that during two
catalytic cycles six new bonds are formed.

Molecules 2009, 14
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Acknowledgements
Authors gratefully acknowledge financial support from the Czech Science Foundation (Grant No.
203/08/0350) and Ministry of Education of the Czech Republic to the Center for Structural and
Synthetic Application of Transition Metal Complexes (Project Nos. LC06070, MSM0021620857, and
Z40550506).
References and Notes
1. For recent review, see: Denmark, S.E.; Beutner, G.L. Lewis Base Catalysis in Organic Synthesis.
Angew. Chem. Int. Ed. 2008, 47, 1560–1638.
2. Chelucci, G.; Thummel, R.P. Chiral 2,2‘-Bipyridines, 1,10-Phenanthrolines, and 2,2‘:6‘,2‘‘-
Terpyridines: Syntheses and Applications in Asymmetric Homogeneous Catalysis. Chem Rev.
2002, 102, 3129–3170.
3. Malkov, A.V.; Kočovský, P. Chiral Bipyridine Derivatives in Asymmetric Catalysis. Curr. Org.
Chem. 2003, 7, 1737–1757.
4. Chelucci, G.; Murineddu, G.; Pinna, G.A. Chiral pyridine N-oxides: useful ligands for asymmetric
catalysis. Tetrahedron Asymmetry 2004, 15, 1373–1389.
5. Kočovský, P.; Malkov, A.V. From Transition Metals To Organocatalysis, Russ. Chem. Bull. Int.
Ed. 2004, 53, 1806–1812.
6. Orito, Y.; Nakajima, M. Chiral Base-Catalyzed Aldol Reaction of Trimethoxysilyl Enol Ethers:
Effect of Water as an Additive on Stereoselectivities. Synthesis 2006, 1391–1401.
7. Malkov, A.V.; Kočovský, P.; Chiral N-Oxides In Asymmetric Catalysis. Eur. J. Org. Chem. 2007,
29–36.
8. For general review on allylation of the carbonyl group see: Denmark, S.; Catalytic
Enantioselective Addition of Allylic Organometallic Reagents to Aldehydes and Ketones. Chem.
Rev. 2003, 103, 2763–2793.
9. Malkov, A.V.; Orsini, M.; Pernazza, D.; Muir, K.W.; Langer, V.; Kočovský, P. Chiral 2,2‘-
Bipyridine-Type N-Monoxides as Organocatalysts in the Enantioselective Allylation of
Aldehydes with Allyltrichlorosilane. Org. Lett. 2002, 4, 1047–1049.
10. Malkov, A.V.; Bell, M.; Vassieu, M.; Bugatti, V.; Kočovský, P.; New pyridine-derived N-oxides
as chiral organocatalysts in asymmetric allylation of aldehydes. J. Mol. Catal. 2003, 196,
179–186.
11. Malkov; A.V.L.; Dufková, L.; Farrugia L.; Kočovský, P. Quinox, a Quinoline-Type N-Oxide, as
Organocatalyst in the Asymmetric Allylation of Aromatic Aldehydes with Allyltrichlorosilanes:
The Role of Arene-Arene Interactions. Angew. Chem., Int. Ed. 2003, 42, 3674–3676.
12. Malkov, A.V.; Bell, M.; Castelluzzo, F.; Kočovský, P. METHOX: A New Pyridine N-Oxide
Organocatalyst for the Asymmetric Allylation of Aldehydes with Allyltrichlorosilanes. Org. Lett.
2005, 7, 3219–3222.
13. Pignataro, L.; Benaglia, M.; Annunziata, R.;. Cinquini, M.; Cozzi, F. Structurally Simple Pyridine
N-Oxides as Efficient Organocatalysts for the Enantioselective Allylation of Aromatic Aldehydes.
J. Org. Chem. 2006, 71, 1458–1463.
14. García-Flores, F.; Flores-Michel, K. S.; Juristi, E. Asymmetric allylation of N-benzoylhydrazones
promoted by novel C2-symmetric bis-sulfoxide organocatalysts. Tetrahedron Lett. 2006, 47,
8235–8238.

Molecules 2009, 14
2925
15. Chelucci, G.; Baldino, S.; Pinna, G.A.; Benaglia, M.; Buffa, L.; Guizzetti, S. Chiral pyridine N-
oxides derived from monoterpenes as organocatalysts for stereoselective reactions with
allyltrichlorosilane and tetrachlorosilane. Tetrahedron 2008, 64, 7574–7582.
16. Muller, C.A.; Hoffart, T.; Holbach, M.; Reggelin, M. Pyridyl-N-oxide Substituted hellicaly Chiral
Poly(methacrylate)s in asymmetric Organocatalysis. Macromolecules 2005, 38, 5375–5380.
17 Pignataro, L.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Celentano, G. Readily available pyridine-
and quinoline-N-oxides as new organocatalysts for the enantioselective allylation of aromatic
aldehydes with allyl(trichloro)silane. Chirality 2005, 17, 396–403.
18. Chelucci, G.; Belmonte, N.; Benanglia, M.; Pignataro, L. Enantioselective allylation of aldehydes
with allyltrichlorosilane promoted by new chiral dipyridylmethane N-oxides. Tetrahedron Lett.
2007, 48, 4037–4041.
19. Simonini, S.; Benaglia, M.; Pignataro, L.; Guizzetti, S.; Celentano, G. A New Class of Chiral
Lewis Basic Metal-Free Catalysts for Stereoselective Allylations of Aldehydes. Synlett 2008,
1061–1065.
20 Chai, Q.; Sung, C.; Sun, Z.; Ma, Y.; Ma, C.; Dai, Y.; Andrus, M.B. Asymmetric allylation of
aldehydes with allyltrichlorosilane using aza-paracyclophane-oxazoline-N-oxide catalysts.
Tetrahedron Lett. 2006, 47, 8611–8615.
21. Nakajima, N.; Saito, M.; Shiro, M.; Hashimoto, S. (S)-3,3‘-Dimethyl-2,2‘-biquinoline N,N‘-
Dioxide as an Efficient Catalyst for Enantioselective Addition of Allyltrichlorosilanes to
Aldehydes. J. Am. Chem. Soc. 1998, 120, 6419–6420.
22. Nakajima, N.; Saito, M.; Hashimoto, S. One-pot Enantioselective Synthesis of optically Active
Homoallylic Alcohols from Allyl Halides. Chem. Pharm. Bull. 2000, 48, 306-307.
23. Nakajima, N.; Saito, M.; Hashimoto, S. Selective synthesis of optically active allenic and
homopropargylic alcohols from propargyl chloride.
2449–2452.
Tetrahedron Asymmetry 2002, 13,
24. Shimada, T.; Kina, A.; Ikeda, S.; Hayashi, T. A Novel Axially Chiral 2,2’-Bipyridine N,N’-
Dioxide. Its preparation and Use for Asymmetric Allylation of Aldehydes with
Allyl(trichloro)silane as a Highly Efficient Catalyst. Org. Lett. 2002, 4, 2799–2801.
26. Shimada, T.; Kina, A.; Hayashi, T. A Novel Axially Chiral 2,2‘-Bipyridine N,N‘-Dioxide. Its
Preparation and Use for Asymmetric Allylation of Aldehydes with Allyl(trichloro)silane as a
Highly Efficient Catalyst. J. Org. Chem. 2003, 68, 6329–6337.
27. Kina, A.; Shimada, T.; Hayashi, T. A New Approach to Axially Chiral Bipyridine N,N -Dioxides
Bearing Aromatic Substituents and their Use for Catalytic Asymmetric Allylation of Aldehydes
with Allyl(trichloro)silane. Adv. Synth. Catal. 2004, 346, 1169–1174.
28. Wong, W.L.; Lee, C.S.; Leung, H.K.; Kwong, H.L. The first series of chiral 2,2 :6 ,2 -terpyridine
tri-N-oxide ligands for Lewis base-catalyzed asymmetric allylation of aldehydes. Org. Biomol.
Chem. 2004, 2, 1967–1969.
29. Hrdina, R.; Stará, I.G.; Dufková, L.; Mitchel, S.; Císařová, I.; Kotora, M. Synthesis of
atropoisomeric pyridines via cobalt-catalyzed cocyclotrimerization of diynes with benzonitrile.
Tetrahedron 2006, 62, 968–976.
30 Hrdina, R.; Kadlčíková, A.; Valterová, I.; Hodačová, J.; Kotora, M. An easy route to
atropoisomeric bipyridine N,N′-dioxides and allylation of aldehydes. Tetrahedron Asymmetry
2006, 17, 3185–3191.

Molecules 2009, 14
2926
31. Hrdina, R.; Valterová, I.; Hodačová, J.; Kotora, M. A Simple Approach to Unsymmetric
Atropoisomeric Bipyridine N,N -Dioxides and Their Application in Enantioselective Allylation of
Aldehydes. Adv. Synth. Catal. 2007, 349, 822–826.
32. Hrdina, R.; Dračínský, M.; Valterová, I.; Hodačová, J.; Císařová, I.; Kotora, M. New Pathway to
C2-Symmetric Atropoisomeric Bipyridine N,N -Dioxides and Solvent Effect in Enantioselective
Allylation of Aldehyde. Adv. Synth. Catal. 2008, 350, 1449–1456.
33. For application of alkyne-nitrile cyclotrimerization in organic synthesis, see: Turek, P.; Kotora,
M. Synthesis of pyridines by [2+2+2]-cyclotrimerization of alyknes with nitriles. Targ.
Heterocyclic Syst. 2009, 13, in press.
34. Kadlčíková, A.; Hrdina, R.; Valterová, I.; Kotora, M. Simple and Fast Synthesis of New Axially
Chiral Bipyridine N,N’-Dioxide for Highly Enantioselective Allylation of Aldehydes. Adv. Synth.
Catal. 2009, 351, 1279–1283.
35. Zhou, Y.; Porco, J.A.; Snyder, J.K. Synthesis of 5,6,7,8-Tetrahydro-1,6-naphthyridines and
Related Heterocycles by Cobalt-Catalyzed [2 + 2 + 2] Cyclizations. Org. Lett. 2007, 9, 393–395.
36. Young, D.D.; Deiters, A. A General Approach to Chemo- and Regioselective Cyclotrimerization
Reactions. Angew. Chem. Int. Ed. 2007, 47, 5187–5190.
37. Zou, Y.; Young, D.D.; Cruz-Montanez, A.; Deiters, A. Synthesis of Anthracene and
Azaanthracene Fluorophores via [2+2+2] Cyclotrimerization Reactions Org. Lett. 2008, 10,
4661–4664.
38. McIver, A.; Young, D.D.; Deiters, A. A general approach to triphenylenes and azatriphenylenes:
total synthesis of dehydrotylophorine and tylophorine. Chem. Commun. 2008, 4750–4752.
39. Turek, P.; Hocek, M.; Pohl, R.; Klepetářová, B.; Kotora, M. Cobalt-Induced Synthesis of 6-
(Pyridin-2-yl)purines by Microwave-Enhanced [2+2+2] Cyclotrimerization. Eur. J. Org. Chem.
2008, 3335–3343.
40. Zhou, Y.; Beeler, A.B.; Cho, S.; Wang, Y.; Franzblau, S.G.; Snyder, J. K. Library Synthesis
Using 5,6,7,8-Tetrahydro-1,6-naphthyridines as Scaffolds. J. Comb. Chem. 2008, 10, 534–540.
41. Kase, K.; Goswami, A.; Ohtaki, K.; Tanabe, E.; Saino, N.; Okamoto, S.; On-Demand Generation
of an Efficient Catalyst for Pyridine Formation from Unactivated Nitriles and α,ω-Diynes Using
CoCl2-6H2O, dppe, and Zn. Org. Lett. 2007, 9, 931–934.
42. Goswami, A.; Ohtaki, K.; Kase, K.; Ito, T.; Okamoto, S. Synthesis of Substituted 2,2 -Bipyridines
and 2,2 :6 ,2 -Terpyridines by Cobalt-Catalyzed Cycloaddition Reactions of Nitriles and , -
Diynes with Exclusive Regioselectivity. Adv. Synth. Catal. 2008, 350, 143–152.
43. Sondheimer, F.; Amiel, Y. Unsaturated Macrocyclic Compounds. Synthesis of Cyclohexadeca-
1,3,9,11-tetrayne by a Novel Cyclization Reaction. J. Am. Chem. Soc. 1957, 79, 5817-5820.
Sample Availability: Samples of the compounds are available from the authors.
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