New pathway to C2-symmetric atropoisomeric bipyridine N,N′-dioxides and solvent effect in enantioselective allylation of aldehydes

Article abstract of DOI:10.1002/adsc.200800141

The [2+2+2] cyclotrimerization of 1,7,9,15-hexadecatetrayne with nitriles catalyzed by dicarbonylcyclopentadienylcobalt(I) opened a new pathway for the synthesis of C₂-symmetrical bis(tetrahydroisoquinolines) that were used as starting material

Full text of DOI:10.1002/adsc.200800141

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DOI: 10.1002/adsc.200800141
New Pathway to C2-Symmetric Atropoisomeric Bipyridine
N,N’-Dioxides and Solvent Effect in Enantioselective Allylation
of Aldehydes
a
b
b
b
ˇ
ˇ
´
Radim Hrdina, Martin Dracínsky, Irena Valterovµ, Jana Hodacovµ,
c
a,b,
ˇ
Ivana Císarovµ, and Martin Kotora *
a
Department of Organic and Nuclear Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 43 Praha 2, Czech
Republic
Fax : (+420)-220-951-326; e-mail: kotora@natur.cuni.cz
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10
Praha 6, Czech Republic
b
c
Department of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 43 Praha 2, Czech Republic
Received: March 7, 2008; Published online: June 9, 2008
Dedicated to Milan Hµjek on the occasion of his 65th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
[5]
sky, Dennmark,[6] and others,[7] who prepared vari-
ous catalysts and showed that they can catalyze a
number of reactions, there are still issues that have
not yet been clarified and are awaiting further explo-
ration such as: i) the relationshipbetween the struc-
ture of bipyridine N,N’-dioxides and degree of enan-
tioselectivity, ii) the course of the reaction mecha-
nism(s), and also iii) the development of simple syn-
thetic approaches to new potential catalysts.
´
Abstract: The [2 +2+2]cyclotrimerization of
1,7,9,15-hexadecatetrayne with nitriles catalyzed by
dicarbonylcyclopentadienylcobalt(I) opened a new
pathway for the synthesis of C2-symmetrical bis(te-
trahydroisoquinolines) that were used as starting
material for the preparation of axially chiral bipyri-
dine N,N’-dioxides. The N,N’-dioxides (1 mol%)
were found to be highly catalytically active and
enantioselective (upto 83% ee) for the asymmetric
allylation of aldehydes with allyl(trichloro)silane in
various solvents. In addition, a dramatic solvent
effect was observed where the use of different sol-
vents induced opposite chiralities of the product
with the same enantiomer of the catalyst, e.g., 65%
ee (S) in acetonitrile (MeCN) vs. 82% ee (R) in
chlorobenzene.
Since the bipyridine framework is accessible by [2+
2+2]cyclotrimerization of alkynes with nitriles,[8,9] in
our previous reports the effort was focused on the de-
velopment of new synthetic procedures for the syn-
thesis of unsymmetrically substituted bipyridine N,N’-
dioxides via the cyclotrimerization pathway.[10] During
the course of our study we found that a convenient
method for the preparation of the bipyridine precur-
sors of the bipyridine N,N’-dioxides is the
CpCo(CO)2-catalyzed cyclotrimerization under micro-
wave irradition.[10,11] The prepared bipyridine N,N’-di-
oxides showed interesting enantioselectivity in the al-
lylation of benzaldehydes.[12] In this communication
we report: i) a new simple methodology for the syn-
thesis of C2-symmetric substituted bipyridines with
Keywords: asymmetric catalysis; cobalt; cyclotrime-
rization; microwave heating; organocatalysis; sol-
vent effect
Enantioselective organocatalysis is one of the fast the bis(tetrahydroisoquinoline) framework, ii) the
growing areas in organic synthesis.[1] The main reason synthesis of the corresponding chiral bipyridine N,N’-
for its success lies in the high level of enantioselectivi- dioxides, and iii) a hitherto unreported solvent effect
ty that can usually be achieved by the use of rather on the enantioselectivity of the benzaldehyde allyla-
simple substances. One such class of compounds are tion.
bipyridine N,N’-dioxides[2] that activate various sub-
Initially, it was conceived that the partially hydro-
strates through a Lewis base reaction mechanism. Al- genated isoquinoline units in a bipyridine compound
though a great deal of work has been done in this would result in the following effects: i) by analogy
area by the groups of Nakajima,[3] Hayashi,[4] Kocov- with Binol and H8-Binol,[13] the tetrahydroisoquino-
ˇ
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Radim Hrdina et al.
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has not yet been reported. We envisioned that the
synthesis of the C2-symmetrical bis(tetrahydroisoqui-
nolines) could be accomplished by a cobalt complex-
catalyzed co-cyclotrimerization of 1,7,9,15-hexadeca-
tetrayne 1 with nitriles 2 (Scheme 1). The tetrayne 1
was prepared from the commercially available 1,7-oc-
tadiyne by Pd-catalyzed oxidative dimerization[15] in
15% isolated yield (the major side reaction was oligo-
merization of the starting material). Initial attempts
to affect the catalytic cyclotrimerization of tetrayne 1
with nitriles 2 in the presence of CpCo(CO)2 under
thermal conditions (1408C) did not meet with success
and only complex reaction mixtures were obtained.
Gratifyingly, the cyclotrimerization with an excess of
Scheme 1. Oxidation of 3 to 4.
line moiety should be sterically bulkier than the iso- nitriles 2 in the presence of a catalytic amount of
quinoline unit, and the combination with itself should CpCo(CO)2 proceeded under microwave irradiation
result in a larger dihedral angle,[14] ii) the presence of affording regioselectively the corresponding bipyri-
hydrogenated rings should increase its solubility in or- dines 3 in reasonable isolated yields (Table 1). Thus
ganic solvents. Although the cyclotrimerization of a the reaction with acetonitrile 2a afforded bipyridine
tetrayne with nitriles can be envisioned as a simple 3a in 36% yield (entry 1). Also the reaction with ben-
approach to C2-symmetrical bipyridines, only three zonitrile 2b gave the corresponding products in 51%
syntheses of bipyridines with the 6,6’,7,7’-tetrahydro- yield (entry 2). Similarly, the cyclotrimerizations with
1,1’-bis-5H-cyclopenta[c]pyridine framework were re- substituted benzonitriles, 4-trifluoromethylbenzoni-
ported.[9] Interestingly, the use of this methodology trile 2c, 4-methoxybenzonitrile 2d, and 3,4,5-trime-
for the preparation of bis(tetrahydroisoquinolines) thoxybenzonitrile 2e afforded bipyridines 3c–e in 47,
Table 1. Cocyclotrimerization of tetrayne 1 with nitriles 2 to symmetrical bipyridines 3.
Entry
1
Nitrile 2
Bipyridine 3
Yield[a]
36%
2a
2b
2c
3a
3b
3c
2
51%
47%
3
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New Pathway to C2-Symmetric Atropoisomeric Bipyridine N,N’-Dioxides
Table 1. (Continued)
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Entry
Nitrile 2
Bipyridine 3
Yield[a]
4
2d
2e
3d
3e
50%
5
6
46%
48%
2f
3f
7
8
2g
2h
3g
3h
34%
21%
9
2i
3i
9%
[a]
Isolated yields.
50, and 46% yields (entries 3–5). Furthermore the cy- recently reported catalytic system CoCl2·6H2O/dppe/
clotrimerization with (R)-tetrahydrofuran-2-carboni- Zn[9c,16] for the cyclotrimerization of alkynes with ni-
trile 2f proceeded uneventfully to give bipyridine 3f triles was met with only partial success. After the re-
in good 48% isolated yield (entry 6). The reactions action time of 24 h, an 8:1 mixture of 1-(1’,7’-octa-
with alkyl nitriles such as benzyl cyanide 2g, cyclohex- diyn-1’-yl)-3-phenyl-5,6,7,8-tetrahydroisoquinoline
anecarbonitrile 2h and cyclopropanecarbonitrile 2i and bipyridine 3b was isolated in 50% combined
proceeded as well, albeit in lower yields of 34, 21 and yield, indicating that this procedure is not convenient
9%, respectively (entries 6–9). The lower yields of the for the straightforward synthesis of bis(tetrahydroiso-
products in the latter entries could be attributed to a quinolines).
greater steric hindrance of the nitrile grouplocated
Out of the prepared compounds, bipyridines 3b, 3e,
on the secondary carbon atom. In addition, using the and 3f were selected for further oxidation by
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Radim Hrdina et al.
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were resolved into enantiomers by using HPLC with
a chiral stationary phase (assignment of absolute con-
figuration was similar as previously reported).[10b] Oxi-
dation of 3f afforded a mixture of diastereoisomers
(R,R,R)-4c and (S,R,R)-4c that were isolated by using
a simple column chromatography on alumina in 48
and 28% yields, respectively. The configuration and
structure of (R,R,R)-4c was unequivocally assigned by
X-ray crystallographic analysis (Figure 1).
The next target was to check the catalytic and
enantioselective properties of the prepared chiral bi-
pyridine N,N’-dioxides 4 in the addition of allyl(tri-
chloro)silane to benzaldehydes (Sakurai–Hosomi re-
action). Allylation of model compounds such as 4-tri-
fluoromethylbenzaldehyde 5a, benzaldehyde 5b, and
4-methoxybenzaldehyde 5c with 1 mol% of the cata-
lyst was used as a standard procedure at À78 or
À408C depending on the melting point of the solvent
used. Although the allylation of benzaldehydes has
usually been run only in acetonitrile, dichlorome-
thane, and chloroform, we assumed that it would also
be useful to study the course of the reaction in other
solvents (Table 2). To the best of our knowledge, such
a study has not been done yet, presumably because of
the low solubility of the hitherto prepared catalysts in
various solvents. At the outset we studied the allyla-
tion of benzaldehyde 5b in commonly used solvents
such as dichloromethane (entry 1) and acetonitrile
(entry 2) with (S)-4a. It proceeded with full conver-
sion to give product (R)-6b with average ee of 55 and
Figure 1. View on the molecule of (R,R,R)-4c with atom
numbering schema. The displacement ellipsoids are drawn
on 50% probability level. The second part of the molecule is
generated via rotation of the two-fold axis passing perpen-
i
À
dicularly on the C1 C1 bond, symmetry code: (i) 1Àx, Ày,z.
MPCBA to the corresponding bipyridine N,N’-diox- 65%, respectively. The asymmetric induction proceed-
ides 4 (Scheme 1). Bipyridine N,N’-dioxides 4a and 4b ed as was previously observed: the (S)-catalysts gave
were obtained in 41 and 22% yield, respectively, and (R)-products (and vice versa). As for diastereoisomer-
Table 2. Allylation of benzaldehyde 5b in various organic solvents.
Entry
T [8C]
Solvent
Catalyst – ee [%][a] – (Yield [%][b])
(R,R,R)-4c ACHTER(UNG S,R,R)-4c
(S)-4a
A
1
2
3
4
5
6
7
8
À78
À40
À40
À78
À78
À40
À40
À40
À78
À78
À78
À78
À78
À78
À78
CH2Cl2
MeCN
CHCl3
EtNO2
PhMe
PhF
PhCl
m-C6H4F2
C7F8
CFCl3
n-pentane
THF
EtOAc
MeOC6F5/PhMe[c]
MeCN/THF[d]
55 (100), R
65 (100), R
36 (100), R
53 (71), R
83 (45), S
78 (100), S
79 (100), S
73 (100), S
50 (14), S
40 (14), S
44 (1), S
59 (50), S
48 (100), S
37 (44), R
63 (82), R
0 (0)
75 (10), S
9
10
11
12
13
14
15
70 (100), S
74 (100), S
66 (10), S
34 (100), R
[a]
Determined by GC.
GC yields.
[b]
[c]
[d]
3/1 mixture.
1/1 mixture.
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New Pathway to C2-Symmetric Atropoisomeric Bipyridine N,N’-Dioxides
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ic catalysts (R,R,R)-4c and (S,R,R)-4c, in dichlorome-
thane the former afforded (S)-6b (59% ee) and the
latter (R)-6b (37% ee) (entry 1), and in acetonitrile
the former afforded (S)-6b (48% ee) and the latter
one (R)-6b (63% ee) (entry 2). This clearly indicated
that asymmetric induction was controlled by the axial
chirality of the biaryl moiety.[17] Next, the allylation of
benzaldehyde catalyzed by (S)-4a was carried out in
chloroform (entry 3) and nitroethane (entry 4) to give
the corresponding product (R)-6b with lower enantio-
Scheme 2. Enantioselective allylation of benzaldehydes 5.
selectivity (36 and 53% ee). The allylation catalyzed higher than that of the catalysts prepared by
by (S)-4a in toluene (entry 5) proceeded to give the Hayashi.[4c]
opposite enantiomer (S)-6b with good enantioselectiv-
To assess the effect of the substituent on the aro-
ity (83%) and reasonable conversion (45%). Surpris- matic ring of benzaldehyde on enantioselectivity, the
ingly, (R,R,R)-4c did not catalyze the allylation, but in allylation of benzaldehydes 5a, 5b, and 5c was carried
the presence of (S,R,R)-4c was formed (S)-6b (75% out in acetonitrile at À408C (Scheme 2, Table 3) (the
ee), albeit in low yield (10%). Then the allylation cat- reaction with benzaldehyde is presented for compari-
alyzed by (S)-4a was run in a number of other sol- son). The allylation catalyzed by (R)-4a in MeCN of
vents (entries 6–15) and in all cases the product with 5a, 5b, and 5c gave the corresponding products (S)-6a,
the opposite stereochemistry (S)-6b was obtained in (S)-6b, and (S)-6c in good yields with 30, 65, and 80%
variable enantioselectivities and yields. Good enantio- ees, respectively (entries 1–3). This trend is in accord-
selectivity was obtained in fluorobenzene (entry 6, ance with previously published data showing an in-
78% ee), chlorobenzene (entry 7, 79% ee), and m-di- crease of enantioselectivity in the allylation of substi-
fluorobenzene (entry 8, 73% ee). Similar values were tuted benzaldehydes, when the substituents gradually
achieved also in polar aprotic solvents such as THF change from electron-withdrawing to -donating
(entry 12, 70% ee) and ethyl acetate (entry 13, 74% ones.[3a,4,9b] A similar trend was also observed in the
ee). A combination of pentafluoroanisole with toluene case of catalyst (R)-4b bearing trimethoxyphenyl sub-
did not have a positive effect either on enantioselec- stituents during the allylation in acetonitrile, albeit
tivity (66% ee) or on catalytic activity (10% yield) with lower enantioselectivity. This observation was
(entry 14). Finally, the allylation was carried out in a rather surprising, because it was previously shown
1/1 mixture of MeCN and THF (entry 15), because in that the presence of electron-rich aromatic rings had
pure solvents (entries 2 and 12) it proceeded with sim- a beneficial effect on enantioselectivity.[4c] The reac-
ilar ees, but with the opposite enantioselectivity. In tions catalyzed with (R,R,R)-4c in acetonitrile (en-
this instance (R)-6b was formed (34% ee), clearly tries 1–3) proceeded with a similar trend in enantiose-
showing that the effect of MeCN prevailed over that lectivity; however, the reaction with 5a gave (R)-6a
of THF.
(15% ee) and those with 5b and 5c afforded (S)-6b
Furthermore, the high catalytic activity of 4a was (48% ee) and (S)-6c (60% ee). As for (S,R,R)-4c a dif-
reflected by the fact that the allylation of benzalde- ferent picture was observed: the reaction with 5a and
hyde 5b (chlorobenzene, À408C) with 0.1 mol% of 5b gave (R)-6a (16% ee) and (R)-6b (46% ee) (en-
(S)-4a proceeded with full conversion within 1 h tries 1 and 2) but with 5c chiral induction was not ob-
(TOF of >1000) and without loss of enantioselectivity served (entry 3).
(80% ee). The turnover frequency of (S)-4a was thus
Table 3. Allylation of benzaldehydes 5 to alcohols 6 in acetonitrile and chlorobenzene.
Entry
5
Solvent
Catalyst[a] – ee [%][b] – (Yield [%][c])
(R)-4a
(R)-4b
A
ACHTRE(UGN S,R,R)4c
1
2
3
4
5
6
5a
5b
5c
5a
5b
5c
MeCN
MeCN
MeCN
PhCl
PhCl
PhCl
30 (100), S
65 (100), S
80 (100), S
61 (83), R
82 (100), R
60 (78), R
7 (32), S
15 (82), R
48 (100), S
60 (100), S
0 (0)
0 (0)
0 (0)
16 (100), R
46 (100), R
0 (100)
75 (40), S
62 (100), S
56 (47), S
52 (61), S
68 (24), S
73 (90), R
70 (100), R
33 (96), R
[a]
Reactions were run at À408C.
Determined by GC.
GC yields.
[b]
[c]
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The allylations were then carried out in chloroben- 1H NMR spectroscopy in various solvents. Spectra of
zene under the same reaction conditions for compari- solutions containing various molar ratios of allyl(tri-
son. As expected, catalysis by (R)-4a provided (R)- chloro)silane and N,N’-dioxide 4a ranging from ~1:10
6a–c. The best enantioselectivity (82% ee) was ob- to ~20:1 were recorded in CD2Cl2 at À738C and in
served in the reaction with simple benzaldehyde 5b C6D5Cl at À408C. The results of these measurements
(entry 5). In the case of trifluoromethylbenzaldehyde clearly indicated that in both solvents three types of
5a and methoxybenzaldehyde 5c the ees were just 61 allyl(trichloro)silane/4a complexes are generally
and 60% , respectively (entries 4 and 6). The reaction formed depending on the N-oxide:bound silane ratio
catalyzed by (R)-4b proceeded with a reversed enan- (only part of the added silane is bound). In low allyl-
tioselectivity trend (entries 4–6); enantioselectivity
A
decreased as the substituents changed from electron- formed. Comparison of the obtained H NMR spectra
withdrawing to electron-donating: 6a (CF3, 73% ee), indicated that the structures of the two complexes
6b (H, 70% ee), 6c (OMe, 33% ee). Surprisingly, the were different. When the amount of allyl(trichloro)si-
reactions in the presence of (R,R,R)-4c did not pro- lane was increased to a 1:1 ratio with respect to 4a,
ceed at all (entries 4–6). On the other hand, catalysis the formation of a 1:1 complex was observed. At high
by (S,R,R)-4c provided the expected products with ratios (>10:1) formation of 2:1 complexes took place.
the stereochemistry and enantioselectivity trends re- (Detailed discussion and spectra supporting these as-
versed: 75% ee [(S)-6a], 62% ee [(S)-6b] and 56% ee sumptions can be found in the Supporting Informa-
[(S)-6c] (entries 4–6). It should be noted that the tion). Although it is difficult at the moment to deter-
same solvent effect was observed also in the allyla- mine the exact structure of these complexes and their
tions of benzaldehydes catalyzed by the previously relative reactivity with respect to aldehydes, it may be
prepared N,N’-dioxides bearing one tetrahydroisoqui- concluded that the change in enantioselectivity could
noline unit.[18]
be the result of the participation of complexes with
Although the enantioselectivities realized are aver- different N-oxide:allyl(trichloro)silane stoichiometry.
age, there are several issues worthy of mention. First- Obviously, in such cases an aldehyde could approach
ly, it is the origin of the profound solvent effect. Al- each species from a different side resulting in the for-
though a similar phenomenon has been observed in mation of different enantiomers. Another issue is the
several transition metal-catalyzed reactions,[19] its reversal of the enantioselectivity trend observed in
extent in organocatalysis, to the best of our knowl- the case of catalysis by (R)-4b and (S,R,R)-4c in
edge, is rather unexpected. Not only could it effect chlorobenzene (Table 2, entries 4–6), that is, reversal
stereochemistry reversion at the newly formed center of enantioselectivity in allylation of the electron-rich
of chirality, but it could also change the influence of and electron-poor substrate aldehydes (usually in the
electron-donating and electron-withdrawing groups presence of bipyridine N,N’-dioxides higher enantio-
attached to the aromatic ring of benzaldehydes on selectivity is observed in the allylation of electron-
asymmetric induction. Secondly, in the case of diaste- rich than electron-poor substrate aldehydes). This
reoisomeric catalysts 4c, the change of solvent could effect might be related to the presence of additional
completely hinder the transfer of chiral information interactions prior to or during the reaction of the al-
[Table 2, (S,R,R)-4c, entry 3] or even totally inhibit dehyde with the complex. A similar trend was ob-
the reaction [Table 2, (R,R,R)-4c, entries 4–6). Theo- served before in the allylation of benzaldehydes by
retically, the above mentioned effects are not impossi- pyridine mono-N-oxides.[5c] In view of the foregoing,
ble if the key enantiodifferentiating steps are influ- it cannot be excluded that the allylation catalyzed by
enced significantly by modified transition states or if our bipyridine N,N’-dioxides could also proceed
entirely different mechanisms are involved. It can be through the monooxide reaction mechanism in some
reasoned that the solvent may have participated in solvents (chlorobenzene, etc.).
enantiodifferentiating steps that are critical to the ste-
In conclusion, the presented results show that i) the
reochemical outcome of the product, instead of serv- CpCo(CO)2 catalyzed cyclotrimerization of 1,7,9,15-
ing merely as spectator molecules. Although, it has hexadecatetrayne with nitriles under microwave irra-
been shown that the allylation should proceed diation represents the first general synthetic proce-
through a six-membered transition state,[20] and two dure for an efficient preparation of C2-symmetrical bi-
reaction mechanisms have been proposed with respect pyridines having the bis(5,6,7,8-tetrahydroisoquino-
to the catalyst used (dioxide[3a,5b] and monooxide[5c] line) framework,[21,22] ii) these can serve as the starting
mechanism), the true nature of the transition com- material for the synthesis of chiral bis(5,6,7,8-tetrahy-
plex, its spatial arrangement and stoichiometry, is not droisoquinoline) N,N’-dioxides, iii) the N,N’-dioxides
exactly known.
can serve as highly active organocatalysts for allyla-
In order to shed light on the above mentioned phe- tion of aldehydes with good enantioselectivity and, iv)
nomena, we decided to study the interaction of allyl- the appropriate choice of the solvent can control con-
ACHTREUNG(trichloro)silane with an N,N’-dioxide catalyst by figuration at the newly created center of chirality by
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New Pathway to C2-Symmetric Atropoisomeric Bipyridine N,N’-Dioxides
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1.2 mmol), and allyl(trichloro)silane (210 mg, 170 mL,
1.2 mmol) were added at À40 or À788C and the reaction
mixture was stirred for 1 h. Then it was quenched with satu-
rated aqueous NaHCO3 (1 mL), the organic layer was sepa-
rated and dried over MgSO4. Yields and ees of homoallyl al-
cohols 6 were determined by GC (HP-Chiral b, 30 m”
0.25 mm, oven: 808C for 15 min, then 18CminÀ1 to 1508C,
5 min at that temperature).
changing the character of the catalytically active spe-
cies. Further experiments to assess the scope of the
bipyridine formation, clarify the reaction mechanism
of allylation, as well as to increase enantioselectivity
are under way and will be reported in due time.
Experimental Section
Allylationof beznaldehyde 5b catalyzed by
(S)-4a: In
MeCN at À408C to afford (R)-(+)-1-phenyl-but-3-en-1-ol
(6b); tR =57.90 min, tS =58.33 min, 65% ee (100% yield). In
PhCl at À408C to afford (S)-(À)-6b, 79% ee (100% yield).
Experimental details of all procedures and compound
charaterization data can be found in Supporting Informa-
tion.
General Procedure for Cyclotrimerization of Hexa-
deca-1,7,9,15-tetrayne (1) with Nitriles
To
a solution of hexadeca-1,7,9,15-tetrayne 1 (200 mg,
0.95 mmol) in a dry nitrile (15 mL) or a solution of a nitrile
(20 mmol) in dry and degassed THF in a vial was added
CpCo(CO)2 (34 mg, 0.16 mmol) under an atmosphere of
argon. Then the vial was placed into the microwave oven
and irradiated for 30 min (300 W) (during the process tem-
perature and pressure reached 2008C and 20 barr). Then the
nitrile was removed under reduced pressure and column
chromatography of the residue on silica gel (solvent) afford-
ed the respective product.
Acknowledgements
We gratefully acknowledge financial support from the Czech
Science Foundation (Grant No. 203/05/0102 and 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).
Bis-1,1’-(5,6,7,8-tetrahydro-3-phenylisoquinoline)
(3b):
Starting from benzonitrile (15 mL); column chromatography
(3/1 hexane/Et2O) afforded the title compound as a pale
yellow solid; yield: 202 mg (51%); mp193 8C (EtOAc);
1H NMR (400 MHz, C6D6): d=1.44–1.48 (m, 8H), 2.48–2.52
(m, 4H), 2.64–2.72 (m, 4H), 7.16- 7.20 (m, 2H), 7.27–7.32
(m, 6H), 8.20–8.22 (m, 4H); 13C NMR (100 MHz, C6D6):
d=23.3 (2C), 24.1 (2C), 27.3 (2C), 30.6 (2C), 121.3 (2C),
128.6 (4C), 130.0 (2C), 130.2 (4C), 131.8 (2C), 141.8 (2C),
149.0 (2C), 154.8 (2C), 160.0 (2C); IR (CHCl3): n=3059,
2939, 2917, 2856, 2828, 1587, 1552, 1413, 1305, 1216, 1159,
1023, 859, 770, 688, 672, 612 cmÀ1 ; EI-MS: m/z (% relative
intensity)=416 (M+, 100), 388 (20), 208 (22), 180 (7); HR-
MS: m/z=416.22416, calcd. for C30H28N2: 416.22525.
References
[1] a) R. Berkessel, H. Grçger, Asymmetric Organocataly-
sis, Wiley-VCH, Weinheim 2005; b) Enantioslective Or-
ganocatalysis, (Ed.: P. I. Dalko), Wiley-VCH, Wein-
heim 2007.
[2] G. Chelucci, G. Murineddu, G. A. Pinna, Tetrahedron:
Asymmetry 2004, 15, 1373–1389.
Bis-1,1’-[5,6,7,8-tetrahydro-3-(tetrahydrofuran-2-yl)isoqui-
noline] (3f): Starting from hexadeca-1,7,9,15-tetrayne 1
[3] a) N. Nakajima, M. Saito, M. Shiro, S. Hashimoto, J.
Am. Chem. Soc. 1998, 120, 6419–6420; b) M. Nakaji-
ma, M. Saito, M. Uemura, S. Hashimoto, Tetrahedron
Lett. 2002, 43, 8827–8829; c) N. Nakajima, M. Saito, S.
Hashimoto, Chem. Pharm. Bull. 2000, 48, 306–307;
d) N. Nakajima, M. Saito, S. Hashimoto, Tetrahedron:
Asymmetry 2002, 13, 2449–2452; e) N. Nakajima, T.
Yokota, M. Saito, S. Hashimoto, Tetrahedron Lett.
2004, 45, 61–64.
[4] a) T. Shimada, A. Kina, S. Ikeda, T. Hayashi, T. Org.
Lett. 2002, 4, 2799–2801; b) T. Shimada, A. Kina, T.
Hayashi, J. Org. Chem. 2003, 68, 6329–6337; c) A.
Kina, T. Shimada, T. Hayashi, Adv. Synth. Catal. 2004,
346, 1169–1174.
(90 mg,
0.42 mmol),
(R)-tetrahydrofuran-2-carbonitrile
(1.0 g, 10.3 mmol), THF (3 mL), and CpCo(CO)2 (16 mg,
0.08 mmol). Column chromatography (EtOAc) afforded the
title compound as a pale yellow viscous liquid; yield: 90 mg
1
(48%); H NMR (400 MHz, C6D6): d=1.44–1.64 (m, 12H),
2.04–2.08 (m, 2H), 2.17–2.22 (m, 2H), 2.48- 2.50 (m, 6H),
2.51–2.66 (m, 2H), 3.72–3.78 (m, 2H), 3.92–3.98 m (2H)
5.18 (t, J=7.0 Hz, 2H), 7.36 (s, 2H); 13C NMR (100 MHz,
C6D6): d=23.2 (2C), 24.0 (2C), 26.6 (2C), 26.9 (2C), 30.4
(2C), 33.9 (2C), 69.5 (2C), 82.4 (2C), 120.2 (2C), 130.3 (2C),
147.8 (2C), 158.5 (2C), 160.0 (2C); IR (CHCl3): n=2970,
2936, 2860, 1590, 1555, 1448, 1432, 1394, 1324, 1299, 1220,
1159, 1061, 1001, 916, 871, 748 cmÀ1 ; EI-MS: m/z (% rela-
tive intensity)=404 (M+, 100), 376 (18), 359 (78), 348 (18),
292 (16), 256 (22), 213 (10), 185 (14), 167 (14), 149 (22), 129
(20), 111 (18), 97 (30); HR-MS: m/z=404.24527, calcd. for
C26H32N2O2: 404.24638.
[5] a) A. V. Malkov, M. Orsini, D. Pernazza, K. W. Muir,
ˇ
´
V. Langer, P. Meghani, P. Kocovsky, Org. Lett. 2002, 4,
1047–1049; b) A. V. Malkov, M. Bell, M. Vassieu, V.
ˇ
´
Bugatti, P. Kocovsky, J. Mol. Catal. A 2003, 196, 179–
186; c) A. V. Malkov, L. Dufkovµ, L. Farrugia, P. Ko-
ˇ
´
covsky, Angew. Chem. 2003, 115, 3802–3805; Angew.
Chem. Int. Ed. 2003, 42, 3674–3677; d) A. V. Malkov,
General Procedure for Catalytic Enantioselective
Allylationof Benzaldehydes with Allyl(trichloro)-
silane
ˇ
´
M. Bell, F. Castelluzzo, P. Kocovsky, Org. Lett. 2005, 7,
3219–3222.
[6] a) S. E. Denmark, Y. Fan, J. Am. Chem. Soc. 2002, 124,
4233–4235; b) S. E. Denmark, Y. Fan, M. D. Eastgate,
J. Org. Chem. 2005, 70, 5235–5248.
To a solution of 4 (0.01 mmol) in a solvent (1 mL) aldehyde
(1 mmol),
diisopropyl
A
(155 mg,
208 mL,
Adv. Synth. Catal. 2008, 350, 1449 – 1456
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[7] For epoxide cleavage, see: a) B. Tao, M. M. C. Lo, G. C.
Fu, J. Am. Chem. Soc. 2001, 123, 353–354; for allyla-
tion, see: b) W.-L. Wong, C.-S. Lee, H.-K. Leung, H.-L.
Kwong, Org. Biomol. Chem. 2004, 2, 1967–1969;
c) C. A. Müller, T. Hoffart, M. Holbach, M. Reggelin,
Macromolecules 2005, 38, 5375–5380; L. Pignataro, M.
Benaglia, R. Annunziata, M. Cinquini, F. Cozzi, J. Org.
Chem. 2006, 71, 1458–1463; d) G. Chelucci, N. Bel-
monte, M. Benanglia, L. Pignataro, Tetrahedron Lett.
2007, 48, 4037–4041.
[16] K. Kase; A. Goswami, K. Ohtaki; E. Tanabe, N. Saino,
S. Okamoto, Org. Lett. 2007, 9, 931–934.
[17] A similar result was also obtained with diastereoiso-
meric unsymmetrical bipyridine N,N’-dioxides 7. Thus
allylation of benzaldehyde in CH2Cl2 catalyzed by
(S,R)-7 affforded (R)-6b alcohol (48% ee, 48%) where-
as (R,R)-7 gave (S)-6b (49% ee, 86%).
[8] For previous reports on bipyridine formation see: Co
catalysis a) H. Bçnnemann, R. Brinkmann, Synthesis
1975, 600–602; b) C. Botteghi, G. Caccia, G. Chelucci,
F. Soccolini, J. Org. Chem. 1984, 49, 4290–4293; c) J. A.
Varela, L. Castedo, C. Saµ, J. Org. Chem. 1997, 62,
4189–4192; d) J. A. Varela, L. Castedo, C. Saµ, J. Am.
Chem. Soc. 1998, 120, 12147–12148; e) J. A. Varela, L.
Castedo, M. Maestro, J. Mahía, C. Saµ, Chem. Eur. J.
2001, 7, 5203–5213; f) J. Uhm, H. W. An, J. Korean
Chem. Soc. 2001, 45, 268–272; for Rh catalysis: g) A.
Wada, K. Noguchi, M. Hirano, K. Tanaka, Org. Lett.
2007, 9, 1295–1298.
[18] Thus allylation of benzaldehyde catalyzed by (S,R)-7,
(R,R)-7 and (S)-8 run in toluene (À788C) gave (S)-6b
(20% ee), (R)-6b (36% ee), and (S)-6b (34% ee), re-
spectively. For catalysis in CH2Cl2 by (S,R)-7, (R,R)-7
see ref.[17]; catalysis by (S)-8 gave (R)-6b (80% ee).
[9] a) Y. Yamamoto, R. Ogawa, K. Itoh, J. Am. Chem. Soc.
2001, 123, 6189–6190; b) Y. Yamamoto, K. Kinpara, R.
Ogawa, H. Nishiyama, K. Itoh, Chem. Eur. J. 2006, 12,
5618–5631; c) A. Goswami, K. Ohtaki; K. Kase; T. Ito,
S. Okamoto, Adv. Synth. Catal. 2008, 350, 143–152.
ˇ
ˇ
[10] a) R. Hrdina, A. Kadlcíkovµ, I. Valterovµ, J. Hodacovµ,
[19] a) An Rh/bisphosphinite complex gave 73% ee (S) in
ethanol but 6% ee (R) in benzene during the hydroge-
nation of dehydroamino esters, see: R. Selke, J. Prakt.
Chem. 1987, 329, 717–724; b) an Rh/phosphoramidite
complex gave 90% ee (R) in CH2Cl2 but 26% ee (S) in
MeOH during the hydrogenation of an enol acetate,
see: L. Panella, B. L. Feringa, J. G. De Vries, A. J. Min-
naard, Org. Lett. 2005, 7, 4177–4180; c) an Rh/phos-
phine-phosphoramidite complex gave 99.6% ee (R) in
trifluoroethanol but 71.2% ee (S) in methyl ethyl
ketone during the hydrogenation of an itaconate, see:
W. Zhang, X. Zhang, J. Org. Chem. 2007, 72, 1020–
1023; d) a Cr-salen complex gave 52% ee (R,R) in
MeCN and 65% ee (S,S) in toluene during the epoxida-
tion of conjugated alkenes, see: H. Imanishi, T. Katsu-
ki, Tetrahedron Lett. 1997, 38, 251–254.
[20] a) K. Kitayama, H. Tsuji, Y. Uozumi, T. Hayashi, Tetra-
hedron Lett. 1996, 37, 4169–4172; b) T. Hayashi, J. W.
Han, A. Takeda, J. Tang, K. Nohmi, K. Mukaide, H.
Tsuji, Y. Uozumi, Adv. Synth. Catal. 2001, 343, 279–
283.
[21] So far only the synthesis of bis(tetrahydroisoquinoline)
has been reported: A. T. Nielsen, J. Org. Chem. 1970,
35, 2498–2503.
M. Kotora, Tetrahedron: Asymmetry 2006, 17, 3185–
3191; b) R. Hrdina, I. Valterovµ, J. Hodacovµ, M.
ˇ
Kotora, Adv. Synth. Catal. 2007, 349, 822–826.
[11] Microwave induced cyclotrimerizations of alkynes with
nitriles, see also: a) Y. Zhou, J. A. Porco, Jr., J. K.
Snyder, Org. Lett. 2007, 9, 393–395; b) D. D. Young, A.
Deiters, Angew. Chem. 2007, 119, 5279–5282; Angew.
Chem. Int. Ed. 2007, 46, 5187–5190.
[12] For a review on allylation reactions, see: S. Denmark,
Chem. Rev. 2003, 103, 2763–2793.
[13] T. T. L. Au-Yeng, S.-S. Chan, A. S. C. Chan, Adv. Synth.
Catal. 2003, 345, 537–555.
[14] The larger dihederal angle leads to higher enantioselec-
tivity, see: a) H. Guo, K. Ding, Tetrahedron Lett. 2000,
41, 1061–1064; b) Y. Wang, H. Guo, K. Ding, Tetrahe-
dron: Asymmetry 2000, 11, 4153–4162; c) Y. Wang, X.
Li, J. Sun, K. Ding, K. Organometallics 2003, 22, 1856–
1862; d) K. E. Torraca, X. Huang, C. A. Parrish, S. L.
Buchwald, J. Am. Chem. Soc. 2001, 123, 10770–10771;
e) Y. Wang, K. Ding, J. Org. Chem. 2001, 66, 3238–
3241; f) K. H. Lam, L. Xu, L. Feng, Q.-H. Fan, F. L.
Lam, W.-H. Lo, A. S. C. Chan, Adv. Synth. Catal. 2005,
347, 1755–1758.
[15] a) F. Sondheimer, Y. Amiel, J. Am. Chem. Soc. 1957,
79, 5817–5820; b) Q. Liu, D. J. Burton, Tetrahedron
Lett. 1997, 38, 4371–4374.
[22] For application of chiral bipyridines, see: G. Chelucci,
R. P. Thummel, Chem. Rev. 2002, 102, 3129–3170.
1456
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