Enantioselective synthesis of tripodal cyclophanes and pyridinophanes by intramolecular [2+2+2] cycloaddition

Article abstract of DOI:10.1016/j.tet.2012.01.046

An enantioselective intramolecular [2+2+2] cycloaddition of 2-aminophenol-tethered triynes and diyne-nitriles proceeded using the chiral Rh catalysts, and tripodal cyclophanes and pyridinophanes with a long ansa chain (up to [16]pyridinophane) were obtained in acceptable yield with high to almost perfect ee. In the reaction of triynes, we elucidated that the oxygen atom at the alkyne terminus is essential for the excellent enantioselectivity. For the construction of cage-type molecule, the choice of rigid tether, which connects 1,6-diyne moiety with a side carbon chain having alkyne or cyano group on its terminus, was important, and 8-amino-2-naphthol moiety was also a preferable tether.

Full text of DOI:10.1016/j.tet.2012.01.046

Tetrahedron 68 (2012) 2679e2686
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Tetrahedron
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Enantioselective synthesis of tripodal cyclophanes and pyridinophanes by
intramolecular [2þ2þ2] cycloaddition
,
a
a
b
c
c
Takanori Shibata a , Mayu Miyoshi , Toshifumi Uchiyama , Kohei Endo , Nobuaki Miura , Kenji Monde
*
a Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku, Tokyo 169-8555, Japan
b Waseda Institute for Advanced Study, Nishiwaseda, Shinjuku, Tokyo 169-8050, Japan
c Faculty of Advanced Life Science, Frontier Research Center for the Post-genome Science and Technology, Hokkaido University, Sapporo 001-0021, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective intramolecular [2þ2þ2] cycloaddition of 2-aminophenol-tethered triynes and
diyne-nitriles proceeded using the chiral Rh catalysts, and tripodal cyclophanes and pyridinophanes with
a long ansa chain (up to [16]pyridinophane) were obtained in acceptable yield with high to almost
perfect ee. In the reaction of triynes, we elucidated that the oxygen atom at the alkyne terminus is es-
sential for the excellent enantioselectivity. For the construction of cage-type molecule, the choice of rigid
tether, which connects 1,6-diyne moiety with a side carbon chain having alkyne or cyano group on its
terminus, was important, and 8-amino-2-naphthol moiety was also a preferable tether.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 14 December 2011
Received in revised form 16 January 2012
Accepted 17 January 2012
Available online 21 January 2012
Keywords:
Enantioselective
Cyclophane
Planar chirality
Cycloaddition
1. Introduction
relatively high regioselectivity (7:1) in the reaction of silicon-
tethered triynes, but the yield was low (ca. 30%).10 Mascal ach-
Cyclophane is a cage-type molecule, where non-adjacent multi-
substituents on benzene ring are connected with ansa chain(s).1
When the ansa chain cannot flip around the benzene ring, planar
chirality is created. The use of chiral dipodal cyclophanes was al-
ready reported, and chiral discriminator,2 chiral polymers,3 and
chiral ligand4 are the representative examples. The major protocol
for the preparation of these planar-chiral cyclophanes had been
resolution of racemic compounds or diastereomers, however, cat-
alytic and enantioselective synthesis was reported in these years:
Tanaka reported a Rh- or Pd-catalyzed coupling of dithiol with
dibromide for the synthesis of paracyclophanes.5 He further dis-
closed a Rh-catalyzed [2þ2þ2] cycloaddition for the synthesis of
meta- and paracyclophanes.6 We also developed two strategies for
the enantioselective construction of chiral paracyclophane skele-
tons: consecutive Sonogashira coupling using a chiral Pd catalyst7
and ortho-lithiation using sparteine.8 In contrast to these achieve-
ments of dipodal cyclophane chemistry, tripodal cyclophane re-
mains unexplored. A simple approach to the tripodal cyclophane
synthesis is an intramolecular [2þ2þ2] cycloaddition of branched
triynes, and Huber disclosed the first report using Ziegler catalyst in
1966.9 But the mixture of symmetrical 1,3,5- and unsymmetrical
1,2,4-isomers were obtained in low yield. Damrauer realized
ieved the improved yield of 50% by using a stoichiometric amount
of [CoCp(CO)2] under the highly diluted condition at high tem-
perature, but the regioselectivity was low.11,12
Against these backgrounds, we focused on the development of
the first enantioselective synthesis of tripodal cyclophanes by
intramolecular [2þ2þ2] cycloaddition of branched triynes. We
designed triyne 1 as a preferable substrate: the oxidative coupling
proceeds selectively at nitrogen-tethered 1,6-diyne moiety. The
rigid tether of 2-aminophenol controls the orientation of the alkyl
side chain, and intramolecular alkyne insertion smoothly proceeds
prior to intermolecular one. Further, methoxymethyl group at the
alkyne terminus activates the alkyne moiety and facilitates the
reaction. Subsequent reductive elimination gives planar-chiral tri-
podal cyclophane 2 (Scheme 1).
In the precedent communication,13 we reported that Rh-
MeDUPHOS catalyst realized the high yield and excellent enantio-
selectivity, and that chiral tripodal compounds with various lengths
of ansa chains were obtained. In this manuscript, we scrutinized the
role of methoxymethyl group for the enantioselective induction.
Then, we further examined the hetero-[2þ2þ2] cycloaddition of
1,6-diyne-nitriles for the enantioselective synthesis of tripodal
pyridinophanes, where the three substituents at 2, 4, and 5-
positions of pyridine ring were connected together. Transition
metal-catalyzed hetero-[2þ2þ2] cycloaddition of two alkynes and
a cyano compound is an atom-economical and reliable protocol for
* Corresponding author. E-mail address: tshibata@waseda.jp (T. Shibata).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.046

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T. Shibata et al. / Tetrahedron 68 (2012) 2679e2686
Table 1
Effect of oxygen atom on the enantioselectivity
Entry
X
R
Triyne
Time/ha
Yield/%
ee/%
1
2
3
4
CH2CH2
OCH2
CH2
CH2OMe
Me
Me
1b
1c
1d
1e
2
0.5
1
88 (2b)
55 (2c)
81 (2d)
78 (2e)
98
88
88
94
Scheme 1. Design of an appropriate triyne for the synthesis of tripodal cyclophane.
CH2
H
2
a
Reaction time after completion of dropwise addition of triynes 1.
the synthesis of multi-substituted pyridine since the first report of
Co-catalyzed reaction by Yamazaki in 1973.14,15 Ru, Ni, and Fe-
catalyzed reactions were also reported.16 Maryanoff used the Co-
catalyzed reaction for the synthesis of dipodal pyrdinophanes:
the cycloaddition of yne-nitriles with alkynes selectively provided
2,4-pyridinophanes,17a and the cycloaddition of diynes with cyano
compounds did 2,5-pyridinophanes.17b But there is no example of
catalytic and enantioselective synthesis of pyridinophanes. In
contrast, the planar chirality of pyridinophane is a promising chiral
motif, and their applications as a coenzyme NADH model18a,b and
chiral ligands18c were already reported. Therefore, efficient asym-
metric synthesis of chiral pyridinophanes is strongly desired.
As a result, the corresponding cycloadduct 2c was obtained, and its
ee was still high, but significantly lower than entry 1. When triyne
1d with no oxygen atom at both propargylic positions was sub-
jected, the reaction smoothly proceeded to give cycloadduct 2d in
good yield with the same ee as entry 2 (entry 3). Triyne 1e with
unsubstituted alkyne terminus was also a good substrate, and the
ee of the corresponding tripodal product 2e was higher ee than
entries 2 and 3, but lower than entry 1 (entry 4).19
In the present catalysis, planar chirality is induced by the di-
rection of the alkyne insertion to the metallacyclopentadiene in-
termediate. The results of Table 1 indicate that the carbon side
chain without oxygen atom can control the enantioselectivity by
the aid of the chiral Rh catalyst, and the ee of about 90% was ach-
ieved. The coordination of oxygen atom at the appropriate prop-
argylic position to metal center improved it up to 98% (Fig. 1).
2. Results and discussion
2.1. Effect of side chain structure on the enantioselectivity
We achieved the extremely high enantioselectivity in the
intramolecular reaction of triynes, which have 3-methoxypropyn-
1-yl group at the end of alkyl side chain derived from the phenolic
oxygen atom.13 The side chain with paraphenylene moiety could be
also installed, and the reaction of triyne 1a proceeded to give
macrocyclic tripodal cyclophane 2a with excellent ee (Scheme 2).
Fig. 1. Effective asymmetric induction by the coordination of oxygen to the metal
center.
2.2. Screening of chiral ligands for the hetero-[2D2D2]
cycloaddition of a diyne-nitrile
As an extension of our work, we examined a hetero-[2þ2þ2]
cycloaddition of diyne-nitriles. There is no example of planar-
chirality induction along with the construction of pyridine ring.20
We chose diyne-nitrile 3a with five-carbon chain between phe-
nolic oxygen and a cyano group as a model substrate, and subjected
it to the optimal conditions for the reaction of triynes, but the de-
sired cycloadduct 4a could not be detected (entry 1 in Table 2).
When we switched MeDUPHOS to BINAP, tripodal 4a was obtained
in moderate yield with high ee (entry 2). Counter anion of Rh did
not affect the enantioselectivity but BARF gave the best yield in
shorter reaction time (entries 2e4). After screening several BINAP
derivatives (entries 5e8), we were pleased to find that Cy-BINAP
achieved the excellent enantioselectivity (entry 8). Among BINAP
derivatives, only Cy-BINAP showed the opposite enantioinduction.
When BARF was used in place of OTf, triyne 3a was completely
consumed right after dropwise addition of 3a over 10 min
(entry 9).19
Scheme 2. Reaction of triyne 1a possessing a paraphenylene-containing tether.
We scrutinized the effect of side chain structure on the enan-
tioselectivity (Table 1). In the precedent communication,13 we in-
stalled an oxygen atom to the propargylic position in the carbon
side chain of all triynes, and the result of triyne 1b having phenyl-
substituted diyne termini was listed as a selected example at entry
1. The absolute configuration of bromophenyl-substituted cyclo-
adduct was determined by X-ray diffraction analysis.13 We next
examined triyne 1c, where the oxygen atom was located at another
propargylic position, under the same reaction conditions (entry 2).

T. Shibata et al. / Tetrahedron 68 (2012) 2679e2686
2681
Table 2
Screening of chiral catalysts for the hetero-[2þ2þ2] cycloaddition
2.4. Rigid tether other than 2-aminophenol moiety
ortho-Phenylene moiety as a rigid tether is probably important
for the efficient intramolecular cycloaddition of diyne-nitriles
possessing very long ansa chains. We next subjected 3-
aminophenol-tethered diyne-nitriles 5a, 5b under the same re-
action conditions (Scheme 3). They were immediately consumed,
but the desired cycloadducts could not be detected in the complex
mixture. To suppress the flexibility of the side chain, we installed
a methyl group at its ortho position, but the reaction of 5c, 5d also
Entry
X
Chiral ligand
Time/ha
Yield/%
NDb
52
66
77
62
57
Trace
57
79
ee/%
gave
a complex mixture without the formation of desired
1
2
3
4
5
6
7
8
9
OTf
OTf
(S,S)-MeDUPHOS
(S)-BINAP
(S)-BINAP
4
2
2
0.5
2
2
3
2
0
d
cycloadducts (Scheme 3).
94 (R)
95 (R)
94 (R)
92 (R)
92 (R)
BF4
BARFc
OTf
(S)-BINAP
(S)-tolBINAP
(S)-H8-BINAP
(S)-SEGPHOSd
(S)-Cy-BINAP
(R)-Cy-BINAP
OTf
OTf
OTf
95 (S)
97 (R)
BARFc
a
Reaction time after completion of dropwise addition of diyne-nitrile 3a.
Not detected.
Tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.
5,50-Bis(diphenylphosphino)-4,40-bi-1,3-benzodi-oxole.
b
c
d
Scheme 3. Reaction of 3-aminophenol-tethered diyne-nitriles.
2.3. Scope of diyne-nitriles in the hetero-[2D2D2]
cycloaddition for the synthesis of pyridinophanes
We next used 8-amino-2-naphthol as a rigid tether, because
the orientation of two substituents at the 1 and 7 positions of
naphthalene ring are the same as that of 1 and 2 positions of
benzene ring (Scheme 4). As a result, an intramolecular reaction of
diyne-nitriles 6a, 6b efficiently proceeded to give the corre-
sponding tripodal pyridinophane 7a, 7b in high yield with excel-
lent ee.
The optimal reaction conditions were in hand, and we exam-
ined the substrate scope (Table 3). Diyne-nitrile 3b with phenyl-
substituted diyne termini was also transformed into tripodal
pyridinophane 4b with almost perfect ee, but there was a lack of
reproducibility in yield (14e78% for four-time experiments) (entry
1).21 Regarding the length of carbon chain (from n¼3e6), the re-
action of diyne-nitriles 3cee smoothly proceeded to give the
cycloadducts 4cee in high yield with excellent ee (entries 2e4).
Even diyne-nitrile 3f with further longer carbon chain (n¼11)
underwent an intramolecular reaction to give [16]pyridinophane
4f in high yield, but its value of specific rotation was almost zero,
and racemic isomers could not be resolved by HPLC analysis using
several chiral columns, which means that the enantiomers prob-
ably interconvert each other at room temperature (entry 5). To
stop the flipping of the long ansa chain, we used diyne-nitrile 3g
with phenyl-substituted diyne termini and ascertained the
asymmetric induction, but it was moderate (66% ee) (entry 6). The
high enantioselectivity was achieved by using BINAP in this case
(entry 7).
Scheme 4. Reaction of 8-amino-2-naphthol-tethered diyne-nitriles.
The same tether also worked well in the alkyne trimerization,
and triyne 8 underwent an intramolecular reaction to give tripodal
cyclophane 9 in high yield with excellent ee (Scheme 5).
Table 3
Substrate scope of diyne-nitriles in the hetero-[2þ2þ2] cycloaddition
Entry
n
R
Time/ha
Yield/%
ee/%b
1
2
3
4
5
6
7c
5
3
4
6
11
11
11
Ph
3b
3c
3d
3e
3f
0
0
0
0
0
2.5
1
Up to 78(4b)
79 (4c)
85 (4d)
89 (4e)
84 (4f)
81 (4g)
99
98
97
97
d
Me
Me
Me
Me
Ph
Scheme 5. Reaction of 8-amino-2-naphthol-tethered triyne.
3g
3g
66
91
3. Conclusions
Ph
84 (4g)
a
Reaction time after completion of dropwise addition of diyne-nitriles 3.
The absolute configuration is not determined.
BINAP was used in place of Cy-BINAP.
b
c
We have comprehensively studied the enantioselective intra-
molecular [2þ2þ2] cycloaddition of branched triynes and diyne-

2682
T. Shibata et al. / Tetrahedron 68 (2012) 2679e2686
nitriles for the synthesis of planar-chiral tripodal compounds. In the
reaction of triynes, methoxymethyl group played an important role
for the induction of the extremely high enantioselectivity. The re-
action of diyne-nitriles also proceeded with excellent enantiose-
lectivity, and even a [16]pyridinophane could be obtained. This is
the first example of catalytic and enantioselective synthesis of
pyridinophanes. The rigid tether in substrate, such as ortho-phe-
nylene and 1,7-naphthylene moiety, was found to be very impor-
tant for the efficient construction of cage-type macrocyclic
molecules.
4.3. Physical properties of substrates and cycloadducts
4.3.1. 2-(3-(4-(6-Methoxyhex-4-ynyl)phenyl)propyloxy)-N,N-bis(3-
phenylprop-2-ynyl)benzenamine (1a). Brown solid. Mp 53e54 ꢀC;
IR (CH2Cl2) 3055, 2312, 1599, 1363, 1244, 1093 cmꢁ1 1H NMR
;
d
1.76e1.85 (m, 2H), 2.17e2.26 (m, 4H), 2.67 (dd, J¼6.3, 8.0 Hz, 2H),
2.87 (dd, J¼6.5, 8.8 Hz, 2H), 3.38 (s, 3H), 4.06 (t, J¼6.3 Hz, 2H), 4.10
(t, J¼2.2 Hz, 2H), 4.38 (s, 4H), 6.87 (ddd, J¼1.7, 7.8, 7.8 Hz, 1H), 6.94
(ddd, J¼1.7, 7.8, 7.8 Hz, 1H), 7.01 (ddd, J¼1.7, 7.8, 7.8 Hz, 1H),
7.04e7.17 (m, 4H), 7.26e7.32 (m, 7H), 7.38e7.42 (m, 4H); 13C NMR
d
18.1, 30.1, 31.0, 32.0, 34.3, 41.7, 57.3, 60.1, 67.4, 76.2, 84.9, 85.5, 86.6,
112.3, 120.4, 120.6, 123.2, 123.4, 127.9, 128.1, 128.5, 131.7, 138.5,
139.0, 151.7 (two pairs of aromatic peaks are overlapped); HRMS
(FAB, positive) m/z calcd for C40H40NO2, 566.3059 ([Mþ1]þ); found,
566.3058 ([Mþ1]þ).
4. Experimental section
4.1. General
Anhydrous 1,2-dichloroethane (DCE) was purchased and dried
over activated molecular sieves 4 A. All solvents were degassed by
argon bubbling prior to use. All reactions were carried out under an
atmosphere of argon in oven-dried glassware with a magnetic
stirring bar.
IR spectra were recorded with a JASCO FT/IR-4100 spectrometer.
NMR spectra were recorded with a JEOL AL-400 (400 MHz),
Lambda-500 (500 MHz), or Bruker Avance-600 (600 MHz) spec-
trometer using tetramethylsilane as an internal standard and CDCl3
as a solvent. High-resolution mass spectra (HRMS) were measured
on a JEOL JMS-SX102A with FAB (Fast Atomic Bombardment)
method. Optical rotations were measured with Jasco DIP-1000 or
DIP-2000 polarimeter.
4.3.2. 2-(4-Oxa-6-octynyloxy)-N,N-bis(3-phenylprop-2-ynyl)ben-
ꢀ
zenamine (1c). Yellow oil. IR (CH2Cl2) 3059, 2227, 1595, 1500, 1362,
1242, 1138, 1092 cmꢁ1
;
1H NMR
d
1.81 (t, J¼2.2 Hz, 3H), 2.19 (tt,
J¼6.1, 6.1 Hz, 2H), 3.76 (t, J¼6.1 Hz, 2H), 4.11 (q, J¼2.2 Hz, 2H), 4.16
(t, J¼6.1 Hz, 2H), 4.34 (s, 4H), 6.90e6.97 (m, 2H), 7.02 (ddd, J¼1.7,
7.7, 7.7 Hz,1H), 7.26e7.30 (m, 7H), 7.39e7.44 (m, 4H); 13C NMR
d 3.5,
29.6, 41.6, 58.7, 65.1, 66.6, 75.2, 82.3, 84.9, 85.5, 112.4, 120.5, 120.6,
123.1, 123.5, 128.0, 128.1, 131.7, 138.5, 151.7; HRMS (FAB, positive) m/
z calcd for C31H30NO2, 448.2277 ([Mþ1]þ); found, 448.2282
([Mþ1]þ).
4.3.3. 2-(5-Heptynyloxy)-N,N-bis(3-phenylprop-2-ynyl)benzen-
amine (1d). Yellow oil. IR (CH2Cl2) 3059, 2235, 1595, 1500, 1365,
1240, 1140, 1107 cmꢁ1
;
1H NMR
d
1.74 (t, J¼2.5 Hz, 3H), 1.71e1.78
(m, 2H), 1.97e2.05 (m, 2H), 2.22 (tq, Jt¼2.5 Hz, Jq¼2.5 Hz, 2H), 4.07
(t, J¼6.3 Hz, 2H), 4.35 (s, 4H), 6.89 (dd, J¼1.5, 7.7 Hz, 1H), 6.93 (ddd,
J¼1.5, 7.7, 7.7 Hz, 1H), 7.02 (ddd, J¼1.5, 7.7, 7.7 Hz, 1H), 7.26e7.30 (m,
4.2. Typical experimental procedure for the [2D2D2]
cycloaddition
7H), 7.38e7.43 (m, 4H); 13C NMR
d 3.4, 18.5, 25.7, 28.5, 41.7, 67.8,
4.2.1. [2þ2þ2] Cycloaddition of the triynes. [Rh(cod)((S,S)-MeDU-
PHOS)]OTf (6.7 mg, 0.010 mmol) was placed in a Schlenk tube,
which was then evacuated and backfilled with argon. To the re-
action vessel was added dichloromethane (1.0 mL). While stirring
the solution at room temperature for 5 min, hydrogen gas was in-
troduced, and the solution was further stirred for 30 min at room
temperature. After removal of the solvent and hydrogen gas under
reduced pressure, argon gas was introduced. DCE (0.5 mL) was
added and the reaction vessel was immersed in an oil bath at 80 ꢀC
for 5 min. Then, triyne (0.10 mmol) in DCE (2.1 mL) was added
dropwise via syringe pump over 10 min. After the reaction mixture
was stirred at the temperature, the solvent was removed under
reduced pressure, and the crude products were purified by thin-
layer chromatography to give pure cycloadduct. The ee was de-
termined by HPLC analysis using a chiral column.
75.9, 78.7, 84.9, 85.5, 112.3, 120.5, 120.6, 123.2, 123.5, 127.9, 128.1,
131.7, 138.5, 151.8; HRMS (FAB, positive) m/z calcd for C31H29NO,
431.2249 (M); found, 431.2230 (M).
4.3.4. 2-(5-Hexynyloxy)-N,N-bis(3-phenylprop-2-ynyl)benzenamine
(1e). Yellow oil. IR (CH2Cl2) 3059, 2227, 1595, 1500, 1365, 1240,
1138, 1107 cmꢁ1; 1H NMR
d
1.76e1.85 (m, 2H), 1.94 (t, J¼2.7 Hz, 1H),
1.99e2.08 (m, 2H), 2.29 (dt, J¼2.7, 7.1 Hz, 2H), 4.07 (t, J¼6.3 Hz, 2H),
4.34 (s, 4H), 6.89 (dd, J¼1.5, 7.7 Hz, 1H), 6.94 (ddd, J¼1.5, 7.7, 7.7 Hz,
1H), 7.02 (ddd, J¼1.5, 7.7, 7.7 Hz, 1H), 7.25e7.30 (m, 7H), 7.38e7.43
(m, 4H); 13C NMR
d 18.2, 25.2, 28.4, 41.7, 67.7, 68.7, 84.1, 84.9, 85.5,
112.4, 120.6, 120.7, 123.2, 123.5, 128.0, 128.2, 131.7, 138.6, 151.8;
HRMS (FAB, positive) m/z calcd for C30H27NO, 417.2093 (M); found,
417.2091 (M).
4.3.5. 2,6-(1,2-o-Benzo-3-oxa-7-o-phenylenedecano)-4,7-diphenyl-
4.2.2. Hetero-[2þ2þ2] cycloaddition of the diyne-nitriles. [Rh(cod)2]
BARF (5.7 mg, 0.010 mmol) and Cy-BINAP (6.8 mg, 0.010 mmol)
were placed in a Schlenk tube, which was then evacuated and
backfilled with argon. To the reaction vessel was added dichloro-
methane (1.0 mL). While stirring the solution at room temperature
for 5 min, hydrogen gas was introduced, and the solution was further
stirred for 30 min at room temperature. After removal of the solvent
and hydrogen gas under reduced pressure, argon gas was in-
troduced. DCE (0.5 mL) was added and the reaction vessel was im-
mersed in an oil bath at 80 ꢀC for 5 min. Then, diyne-nitrile
(0.10 mmol) in DCE (2.1 mL) was added dropwise via syringe pump
over 10 min. After the reaction mixture was stirred at the tempera-
ture, the solvent was removed under reduced pressure, and the
crude products were purified by thin-layer chromatography to give
pure cycloadduct. The ee was determined by HPLC analysis using
a chiral column.
5-(methoxymethyl)isoindoline (2a). Brown solid. Mp 61e62 ꢀC; IR
(CH2Cl2) 3055, 2866, 2819, 1599, 1211 cmꢁ1 1H NMR
; d 1.42e1.56
(m, 1H), 1.85e2.03 (m, 2H), 2.42e2.71 (m, 4H), 2.96e3.11 (m, 2H),
3.28 (s, 3H), 3.56e3.63 (m, 1H), 3.75e3.85 (m, 1H), 4.01e4.18 (m,
3H), 4.27 (d, J¼10.0 Hz, 1H), 4.29 (dd, J¼1.7, 13.2 Hz, 1H), 4.43 (dd,
J¼1.7, 13.2 Hz, 1H), 4.52 (d, J¼10.0 Hz, 1H), 6.42 (d, J¼6.6 Hz, 1H),
6.57e6.68 (m, 2H), 6.74e6.85 (m, 2H), 6.86e6.94 (m, 4H),
7.13e7.19 (m, 1H), 7.26e7.47 (m, 6H), 7.47e7.57 (m, 2H); 13C NMR
d
27.5, 28.7, 31.4, 31.7, 32.9, 54.1, 54.1, 58.0, 68.9, 69.9, 119.3, 120.7,
121.4, 123.4, 126.7, 127.1, 127.7, 127.9, 128.0, 128.0, 128.1, 128.8,
129.0, 129.1, 129.2, 129.5, 133.1, 136.8, 137.0, 137.6, 138.7, 138.8,
139.7, 139.9, 140.6, 151.7; HRMS (EI, positive) m/z calcd for
C40H40NO2, 566.3059 ([Mþ1]þ); found, 566.3080 ([Mþ1]þ); ½a 2D1
ꢂ
41.5 (c 0.40, CHCl3, 98% ee). ee was determined by HPLC analysis
using a chiral column (Daicel Chiralpak IC-H(double): 4ꢃ250 mm,
254 nm UV detector, rt, eluent: 10% 2-propanol in hexane, flow

T. Shibata et al. / Tetrahedron 68 (2012) 2679e2686
2683
rate: 0.5 mL/min, retention time: 16 min for major isomer and
16.5 min for minor isomer).
1H), 6.78 (dd, J¼1.5, 8.3 Hz, 1H), 6.82 (ddd, J¼1.5, 7.6, 7.6 Hz, 1H), 7.32
(ddd, J¼2.0 7.6, 8.3 Hz,1H), 7.17e7.26 (m, 3H), 7.29e7.44 (m, 8H); 13C
NMR d 16.4, 30.1, 60.4, 62.1, 64.3, 64.9, 67.4, 113.2, 120.4, 126.9, 127.0,
4.3.6. (S)-2,6-(1,2-o-Benzo-3-oxaoctano)-4,7-diphenyl-5-(methox-
127.1, 128.4, 128.4, 132.5, 132.7, 135.7, 136.3, 137.7, 139.5, 140.2, 141.7,
ymethyl)isoindoline (2b).13
143.2, 157.5; HRMS (EI, positive) m/z calcd for C31H30NO2, 448.2277
([Mþ1]þ); found, 448.2279 ([Mþ1]þ); ½a 2D7
ꢂ
97.3 (c 1.415, CHCl3, 88%
ee). ee was determined by HPLC analysis using a chiral column
(Daicel Chiralpak OD-H(double): 4ꢃ250 mm, 254 nm UV detector, rt,
eluent: 10% 2-propanol in hexane, flow rate: 0.5 mL/min, retention
time: 10 min for major isomer and 12 min for minor isomer).
O
Ph
1
3
2
OMe
N
Ph
2b
4.3.8. 2,6-(1,2-o-Benzo-3-oxaheptano)-4,7-diphenyl-5-
methylisoindoline (2d). White solid. Mp 114 ꢀC; IR (CH2Cl2) 3055,
2927, 1599, 1496 cmꢁ1; 1H NMR
d 0.93e1.06 (m, 1H), 1.29e1.38 (m,
The pilot atom is the nitrogen (dotted circle) of pyrrolidine ring,
and we determined the above enantiomer as R isomer.
1H), 1.51e1.61 (m, 1H), 1.69e1.80 (m, 1H), 1.83e1.96 (m, 1H), 2.21
(s, 3H), 2.76 (ddd, J¼4.6, 11.8, 13.2 Hz, 1H), 2.97 (ddd, J¼3.7, 3.7,
13.2 Hz, 1H), 3.43 (ddd, J¼6.6, 8.5, 10.5 Hz, 1H), 3.69 (d, J¼14.6 Hz,
1H), 4.21 (dd, J¼2.2, 14.6 Hz, 1H), 4.47 (dd, J¼2.2, 14.6 Hz, 1H), 5.18
(d, J¼14.6 Hz, 1H), 6.87 (dd, J¼1.7, 7.7 Hz, 1H), 6.92 (ddd, J¼1.7, 7.7,
7.7 Hz, 1H), 6.98 (d, J¼2.0, 7.7, 7.7 Hz, 1H), 7.10 (dd, J¼2.0, 7.7 Hz,
1H), 7.12 (d, J¼7.7 Hz, 2H), 7.27e7.40 (m, 4H), 7.44 (dd, J¼7.7,
The observed VCD and IR spectra of (þ)-2b showed good
agreements with the calculated IR and VCD ones of (R)-2b.
7.7 Hz, 2H), 7.71 (s, br, 2H); 13C NMR
d 16.4, 26.0, 26.8, 31.3, 57.6,
63.9, 77.2, 124.0, 125.4, 126.5, 126.8, 128.2, 128.3, 129.3, 131.0, 131.3,
131.8, 136.9, 137.0, 137.2, 137.7, 140.3, 141.6, 142.1, 145.7, 154.5 (a
pair of aromatic peaks is overlapped); HRMS (EI, positive) m/z
calcd for C31H30NO, 432.23274 ([Mþ1]þ); found, 432.23116
([Mþ1]þ); ½a 2D4
ꢂ
174.1 (c 1.21, CHCl3, 88% ee). ee was determined by
HPLC analysis using a chiral column (Daicel Chiralpak AD-H:
4ꢃ250 mm, 254 nm UV detector, rt, eluent: 10% 2-propanol in
hexane, flow rate: 0.5 mL/min, retention time: 7 min for minor
isomer and 8 min for major isomer).
4.3.9. (R)-2,6-(1,2-o-Benzo-3-heptano)-4,7-diphenylisoindoline
(2e).
The pilot atom is the nitrogen (dotted circle) of pyrrolidine ring,
and we determined the above enantiomer as R isomer.
Pale yellow solid. Mp 153e154 ꢀC; IR (CH2Cl2) 3057, 2927, 1599,
1500 cmꢁ1
;
1H NMR
d
0.95e1.09 (m, 1H), 1.46 (t, J¼8.3 Hz, 1H),
1.58e1.74 (m, 2H), 1.75e1.89 (m, 1H), 2.70e2.83 (m, 2H), 3.36 (ddd,
J¼6.3, 9.0, 10.5 Hz, 1H), 4.01 (d, J¼14.5 Hz, 1H), 4.29 (dd, J¼2.0,
14.5 Hz, 1H), 4.91 (dd, J¼2.0, 14.5 Hz, 1H), 5.17 (d, J¼14.5 Hz, 1H),
6.82 (dd, J¼2.0, 7.6 Hz, 1H), 6.90 (ddd, J¼2.0, 7.6, 7.6 Hz, 1H), 6.95
(ddd, J¼2.0, 7.6, 7.6 Hz, 1H), 7.16 (dd, J¼2.0, 7.6 Hz, 1H), 7.28e7.51
4.3.7. (S)-2,6-(1,2-o-Benzo-3,7-dioxaoctano)-4,7-diphenyl-5-
methylisoindoline (2c).
(m, 9H), 7.69 (d, J¼7.6 Hz, 2H); 13C NMR
d 25.7, 30.0, 33.9, 57.6, 64.1,
76.7, 123.3, 123.8, 125.7, 126.6, 126.8, 127.4, 128.1, 128.4, 128.7, 131.0,
131.5,136.1,137.2,137.4,138.7,139.9,140.7,145.1,146.3,154.7; HRMS
(FAB, positive) m/z calcd for C30H27NO, 417.2093 (M); found,
417.2093 (M); ½a D
ꢂ
20 136.7 (c 0.82, CHCl3, 94% ee). ee was determined
by HPLC analysis using a chiral column (Daicel Chiralpak OD-
H(double): 4ꢃ250 mm, 254 nm UV detector, rt, eluent: 10% 2-
propanol in hexane, flow rate: 0.5 mL/min, retention time: 16 min
for minor isomer and 18 min for major isomer).
The pilot atom is the oxygen (dotted circle) at the benzylic po-
sition on the tether, and we determined the above enantiomer as S
isomer.
White solid. Decomp. 184 ꢀC; IR (CH2Cl2) 2929, 1595, 1487, 1228,
1093 cmꢁ1; 1H NMR
d 0.59e0.71 (m, 1H), 1.66e1.79 (m, 1H), 2.37 (s,
4.3.10. 6-{2-[Bis(but-2-ynyl)amino]phenoxy}hexanenitrile
3H), 3.34 (ddd, J¼2.7, 12.0, 12.0 Hz, 1H), 3.43 (ddd, J¼8.3, 10.5,
12.0 Hz, 1H), 3.49e3.56 (m, 1H), 3.60 (t, J¼10.5 Hz, 1H), 3.74
(d, J¼15.7 Hz, 1H), 4.36 (d, J¼12.0 Hz, 1H), 4.36e4.43 (m, 1H), 4.53
(dd, J¼2.7, 15.7 Hz, 1H), 4.63 (d, J¼15.7 Hz, 1H), 4.87 (d, J¼12.0 Hz,
(3a). Yellow oil. IR (neat) 3060, 2245, 1593, 1500, 1367, 1240,
1130 cmꢁ1
;
1H NMR
d
1.66e1.80 (m, 4H), 1.82 (t, J¼2.0 Hz, 3Hꢃ2),
1.91 (tt, J¼6.2, 6.2 Hz, 2H), 2.40 (t, J¼6.8 Hz, 2H), 3.99 (q, J¼2.0 Hz,
2Hꢃ2), 4.01 (t, J¼6.2 Hz, 2H), 6.83 (dd, J¼1.6, 7.6 Hz, 1H), 6.90 (ddd,

2684
T. Shibata et al. / Tetrahedron 68 (2012) 2679e2686
J¼1.6, 7.6, 7.6 Hz,1H), 6.98 (ddd, J¼1.6, 7.6, 7.6 Hz,1H), 7.16 (dd, J¼1.6,
7.6 Hz, 1H); 13C NMR
3.7, 17.1, 25.3, 25.5, 28.5, 40.8, 67.6, 75.0, 80.3,
112.3,119.6,120.2,120.8,123.0,139.0,151.5; HRMS (FAB, positive) m/z
29.4, 29.5, 41.7, 68.2, 84.9, 85.6, 112.2, 119.8, 120.5, 123.2, 123.5,
128.0, 128.1, 131.7, 138.5, 151.9 (two pairs of aliphatic peaks and
aromatic peaks are overlapped); HRMS (FAB, positive) m/z calcd for
d
calcd for C20H24N2O, 309.1967 (M); found, 309.1963 (M).
C
36H41N2O, 517.3219 ([Mþ1]þ); found, 517.3226 ([Mþ1]þ).
4.3.11. 6-{2-[Bis(3-phenylprop-2-ynyl)amino]phenoxy}hexanenitrile
4.3.17. (R)-2,6-(1,2-o-Benzo-3-oxaoctano)-2,3-dihydro-4,7-
(3b). Yellow oil. IR (CH2Cl2) 3059, 2245, 1595, 1500, 1365, 1240,
dimethyl-1H-pyrrolo[3,4-c]pyridine (4a).
1107 cmꢁ1 1H NMR
; d 1.71e1.73 (m, 4H), 1.91e1.94 (m, 2H),
2.28e2.33 (m, 2H), 4.05 (t, J¼6.2 Hz, 2H), 4.34 (s, 2Hꢃ2), 6.88 (d,
J¼7.5 Hz, 1H), 6.95 (dd, J¼7.1, 7.2 Hz, 1H), 7.03 (dd, J¼7.1, 7.5 Hz,
1H), 7.25e7.30 (m, 7H), 7.40e7.42 (m, 4H); 13C NMR
d 14.6, 22.9,
23.2, 26.2, 39.3, 65.4, 82.5, 83.1, 110.1, 117.2, 118.2, 118.5, 120.7,
121.1, 125.7, 125.8, 129.2, 136.3, 149.3; HRMS (FAB, positive) m/z
calcd for C30H29N2O, 433.2280 ([Mþ1]þ); found, 433.2243
([Mþ1]þ).
4.3.12. 4-{2-[Bis(but-2-ynyl)amino]phenoxy}butanenitrile
The pilot atom is the nitrogen (dotted circle) of pyrrolidine ring,
(3c). Yellow oil. IR (CH2Cl2) 3062, 2247, 1595, 1500, 1369, 1240,
and we determined the above enantiomer as R isomer.
1130 cmꢁ1
;
1H NMR
d
1.83 (t, J¼2.2 Hz, 3Hꢃ2), 2.15e2.21 (m, 2H),
Colorless oil. IR (CH2Cl2) 2924, 1593, 1487, 1227 cmꢁ1 1H NMR
;
2.72 (t, J¼7.4 Hz, 2H), 3.94 (q, J¼2.2 Hz, 2Hꢃ2), 4.09 (t, J¼5.6 Hz,
d 0.02e0.10 (m, 1H), 0.81e0.89 (m, 1H), 1.03e1.13 (m, 1H), 1.21e1.31
2H), 6.84 (dd, J¼1.6, 7.6 Hz, 1H), 6.90e6.94 (m, 2H), 7.19 (dd, J¼2.0,
(m, 1H), 1.44e1.54 (m, 1H), 1.87e1.95 (m, 1H), 2.24 (s, 3H), 2.37 (s,
3H), 2.93 (dd, J¼7.6, 12.8 Hz, 1H), 3.02e3.10 (m, 1H), 3.41e3.48 (m,
2H), 3.98 (d, J¼15.6 Hz, 1H), 4.18 (d, J¼15.6 Hz, 1H), 4.54 (d,
J¼15.6 Hz, 1H), 4.72 (d, J¼15.6 Hz, 1H), 6.68 (d, J¼7.7 Hz, 1H), 6.84
(ddd, J¼1.6, 7.7, 7.7 Hz, 1H), 7.09 (ddd, J¼1.6, 7.7, 7.7 Hz, 1H), 7.29
7.2 Hz, 1H); 13C NMR
d 3.4, 14.0, 25.5, 40.8, 65.9, 74.9, 80.3, 112.9,
119.3, 120.0, 121.3, 122.9, 139.3, 150.9; HRMS (FAB, positive) m/z
calcd for C18H20N2O, 280.1576 (M); found, 280.1564 (M).
4.3.13. 5-{2-[Bis(but-2-ynyl)amino]phenoxy}pentanenitrile
(dd, J¼1.6, 7.7 Hz, 1H); 13C NMR
d 16.3, 21.5, 23.2, 26.5, 29.5, 30.7,
60.7, 60.9, 68.4, 112.8, 120.1, 123.8, 127.0, 131.9, 133.1, 142.8, 147.1,
(3d). Yellow oil. IR (CH2Cl2) 3062, 2245, 1593, 1500, 1367, 1240,
1130 cmꢁ1
;
1H NMR
d
1.82 (t, J¼2.0 Hz, 3Hꢃ2), 1.92e2.04 (m,
152.4, 156.8, 157.1; HRMS (FAB, positive) m/z calcd for C20H24N2O,
4H), 2.49 (t, J¼6.8 Hz, 2H), 3.96 (q, J¼2.0 Hz, 2Hꢃ2), 4.03 (t,
J¼5.6 Hz, 2H), 6.83 (dd, J¼1.7, 7.7 Hz, 1H), 6.91 (ddd, J¼1.7, 7.6,
7.7 Hz, 1H), 6.97 (ddd, J¼1.7, 7.6, 7.7 Hz, 1H), 7.16 (dd, J¼1.7,
309.1967 (M); found, 309.1951 (M); ½a D28
ꢂ
40.2 (c 0.40, CHCl3, 94%
ee). ee was determined by HPLC analysis using a chiral column
(Daicel Chiralpak AD-H: 4ꢃ250 mm, 254 nm UV detector, rt, elu-
ent: 10% 2-propanol in hexane, flow rate: 0.5 mL/min, retention
time: 9 min for major isomer and 12 min for minor isomer).
7.7 Hz, 1H); 13C NMR
d 3.5, 17.0, 22.6, 28.3, 40.8, 67.2, 74.8, 80.3,
112.5, 119.5, 120.3, 121.0, 123.0, 139.1, 151.4; HRMS (FAB, posi-
tive) m/z calcd for C19H23N2O, 295.1810 ([Mþ1]þ); found,
295.1812 ([Mþ1]þ).
4.3.18. 2,6-(1,2-o-Benzo-3-oxaoctano)-2,3-dihydro-4,7-diphenyl-
1H-pyrrolo[3,4-c]pyridine (4b). Yellow solid. Decomp. 209 ꢀC; IR
4.3.14. 7-{2-[Bis(but-2-ynyl)amino]phenoxy}heptanenitrile
(CH2Cl2) 2931, 1595, 1489, 1230 cmꢁ1; 1H NMR
d 0.27e0.34 (m, 1H),
(3e). Yellow oil. IR (CH2Cl2) 3060, 2245, 1593, 1500, 1367, 1240,
0.87e0.90 (m, 1H), 1.08e1.11 (m, 2H), 1.36e1.45 (m, 1H), 1.70e1.74
(m, 1H), 2.74e2.82 (m, 1H), 3.02e3.06 (m, 1H), 3.46 (dd, J¼7.8,
7.8 Hz, 1H), 3.66 (dd, J¼8.6, 8.6 Hz, 1H), 4.11 (d, J¼15.2 Hz, 1H), 4.37
(d, J¼16.0 Hz, 1H), 4.65 (d, J¼16.0 Hz, 1H), 5.12 (d, J¼15.2 Hz, 1H),
6.72 (d, J¼8.1 Hz, 1H), 6.82 (dd, J¼7.6, 7.7 Hz, 1H), 7.08 (ddd, J¼1.6,
7.7, 8.1 Hz, 1H), 7.26e7.47 (m, 9H), 7.88 (d, J¼7.8 Hz, 2H); 13C NMR
1130 cmꢁ1; 1H NMR
d 1.50e1.61 (m, 4H), 1.67e1.74 (m, 2H), 1.82 (t,
J¼2.0 Hz, 3Hꢃ2), 1.85e1.93 (m, 2H), 2.36 (t, J¼7.0 Hz, 2H),
3.99e4.01 (m, 6H), 6.83 (d, J¼7.5 Hz, 1H), 6.89 (dd, J¼7.3, 7.8 Hz,
1H), 6.97 (dd, J¼7.3, 7.5 Hz,1H), 7.15 (d, J¼7.8 Hz,1H); 13C NMR
d 3.5,
16.9, 25.2, 25.4, 28.3, 28.9, 40.6, 67.7, 74.9, 80.2, 112.1, 119.6, 120.1,
120.5, 122.9, 138.8, 151.5; HRMS (FAB, positive) m/z calcd for
C21H27N2O, 323.2123 ([Mþ1]þ); found, 323.2122 ([Mþ1]þ).
d
23.6, 27.4, 29.2, 32.5, 59.6, 61.8, 69.0, 112.9, 120.2, 127.1, 127.2,
128.1, 128.5, 129.9, 131.3, 132.3, 132.6, 138.9, 139.7, 142.2, 149.6,
153.5, 156.6, 157.2 (two pairs of aromatic peaks are overlapped);
HRMS (FAB, positive) m/z calcd for C30H29N2O, 433.2280 ([Mþ1]þ);
4.3.15. 12-{2-[Bis(but-2-ynyl)amino]phenoxy}dodecanenitrile
(3f). Yellow oil. IR (CH2Cl2) 3060, 2245, 1593, 1500, 1367, 1240,
found, 433.2277 ([Mþ1]þ); ½a D16
ꢂ
8.4 (c 0.3, CHCl3, 98% ee). ee was
1130 cmꢁ1
;
1H NMR
d
1.30e1.36 (m, 10H), 1.40e1.45 (m, 2H),
determined by HPLC analysis using a chiral column (Daicel Chir-
alpak AD-H: 4ꢃ250 mm, 254 nm UV detector, rt, eluent: 2% 2-
propanol in hexane, flow rate: 1.0 mL/min, retention time: 8 min
for minor isomer and 9 min for major isomer).
1.47e1.53 (m, 2H), 1.61e1.67 (m, 2H), 1.80 (t, J¼2.3 Hz, 3Hꢃ2),
1.83e1.89 (m, 2H), 2.31 (t, J¼7.4 Hz, 2H), 3.96e4.00 (m, 6H),
6.83 (dd, J¼1.4, 8.0 Hz, 1H), 6.87 (ddd, J¼1.4, 7.6, 7.7 Hz, 1H),
6.96 (ddd, J¼1.5, 7.7, 8.0 Hz, 1H), 7.13 (dd, J¼1.5, 7.6 Hz, 1H); 13C
NMR
d
3.7, 17.1, 25.4, 26.2, 28.6, 28.7, 29.3, 29.3, 29.4, 29.4, 29.5,
4.3.19. 2,6-(1,2-o-Benzo-3-oxahexano)-2,3-dihydro-4,7-dimethyl-
40.8, 68.1, 75.0, 80.2, 112.0, 120.2, 120.4, 123.0, 138.9, 151.8 (a
pair of aromatic peaks is overlapped); HRMS (FAB, positive) m/z
calcd for C26H37N2O, 393.2906 ([Mþ1]þ); found, 393.2887
([Mþ1]þ).
1H-pyrrolo[3,4-c]pyridine (4c). Pale yellow oil. IR (CH2Cl2) 2937,
1591, 1479, 1217 cmꢁ1; 1H NMR
d 1.77e1.85 (m, 1H), 2.12e2.22 (m,
1H), 2.31 (s, 3H), 2.37 (s, 3H), 2.69e2.76 (m, 1H), 2.99 (dd, J¼9.6
9.6 Hz, 1H), 3.43e3.48 (m, 1H), 3.72 (d, J¼13.4 Hz, 1H), 3.81 (dd,
J¼7.8, 7.8 Hz, 1H), 4.02 (d, J¼14.6 Hz, 1H), 4.39 (d, J¼14.6 Hz, 1H),
4.58 (d, J¼13.4 Hz,1H), 6.68 (d, J¼8.1 Hz, 1H), 6.81 (dd, J¼7.6, 7.7 Hz,
1H), 6.97 (ddd, J¼1.8, 7.7, 8.1 Hz, 1H), 7.20 (dd, J¼1.8, 7.6 Hz, 1H); 13C
4.3.16. 12-{2-[Bis(3-phenylprop-2-ynyl)amino]phenoxy}dodecaneni-
trile (3g). Yellow oil. IR (CH2Cl2) 3059, 2245, 1595, 1500, 1367, 1242,
1107 cmꢁ1
;
1H NMR
d
1.26e1.42 (m, 12H), 1.49e1.55 (m, 2H),
NMR d 16.1, 21.3, 27.6, 33.8, 58.7, 62.4, 67.5, 114.8, 121.4, 126.3, 129.0,
1.58e1.65 (m, 2H), 1.90 (tt, J¼7.2, 7.6 Hz, 2H), 2.15 (t, J¼7.2 Hz, 2H),
4.04 (t, J¼6.4 Hz, 2H), 4.35 (s, 2Hꢃ2), 6.89 (d, J¼7.7 Hz, 1H), 6.93
(dd, J¼7.4, 7.6 Hz,1H), 7.02 (dd, J¼7.6, 7.7 Hz,1H), 7.23e7.33 (m, 7H),
131.9, 132.5, 141.5, 148.1, 155.3, 155.9, 157.7; HRMS (FAB, positive) m/
z
calcd for C18H21N2O, 281.1654 ([Mþ1]þ); found, 281.1642
([Mþ1]þ); ½a 3D3
ꢂ
43.9 (c 0.79, CHCl3, 98% ee). ee was determined by
HPLC analysis using a chiral column (Daicel Chiralpak AD-H:
7.39e7.42 (m, 4H); 13C NMR
d
17.1, 25.3, 26.3, 28.6, 28.7, 29.2, 29.3,

T. Shibata et al. / Tetrahedron 68 (2012) 2679e2686
2685
4ꢃ250 mm, 254 nm UV detector, rt, eluent: 2% 2-propanol in
hexaneþ0.1 vol % diethylamine, flow rate: 1.0 mL/min, retention
time: 20 min for minor isomer and 24 min for major isomer).
0.5 mL/min, retention time: 9 min for major isomer and 11 min for
minor isomer).
4.3.24. 6-{8-[Bis(but-2-ynyl)amino]-2-naphthoxy}hexanenitrile
4.3.20. 2,6-(1,2-o-Benzo-3-oxaheptano)-2,3-dihydro-4,7-dimethyl-
(6a). Brown solid. Mp 103e104 ꢀC; IR (CH2Cl2) 3060, 2247, 1599,
1H-pyrrolo[3,4-c]pyridine (4d). Pale yellow oil. IR (CH2Cl2) 2941,
1512, 1358, 1254, 1134 cmꢁ1 1H NMR
; d 1.69e1.83 (m, 4H), 1.86 (t,
1591, 1481, 1217 cmꢁ1
;
1H NMR
d
1.20e1.39 (m, 3H), 1.70e1.83 (m,
J¼2.1 Hz, 3Hꢃ2), 1.88e1.93 (m, 2H), 2.41 (t, J¼6.8 Hz, 2H), 4.01 (q,
J¼2.1 Hz, 2Hꢃ2), 4.16 (t, J¼6.2 Hz, 2H), 7.11 (dd, J¼2.4, 9.0 Hz, 1H),
7.24e7.34 (m, 2H), 7.50 (d, J¼8.0 Hz, 1H), 7.53 (d, J¼2.4 Hz, 1H), 7.72
2H), 2.36 (s, 3H), 2.40 (s, 3H), 2.81e2.85 (m, 1H), 3.19e3.23 (m, 1H),
3.26e3.31 (m, 1H), 3.98 (d, J¼14.4 Hz, 1H), 4.34 (d, J¼15.1 Hz, 1H),
4.47 (d, J¼15.1 Hz, 1H), 4.67 (d, J¼14.4 Hz, 1H), 6.75 (dd, J¼1.2,
8.0 Hz, 1H), 6.92e7.00 (m, 2H), 7.21 (dd, J¼2.0, 7.6 Hz, 1H); 13C NMR
(d, J¼9.0 Hz, 1H); 13C NMR
d 3.8, 17.2, 25.3, 25.6, 28.6, 42.6, 67.4,
75.2, 80.7, 103.1, 117.6, 118.7, 119.8, 123.2, 123.8, 130.0, 130.2, 130.4,
146.1, 157.0; HRMS (FAB, positive) m/z calcd for C24H26N2O,
358.2045 (M); found, 358.2029 (M).
d
16.6, 21.4, 25.4, 27.3, 33.5, 58.5, 62.0, 75.2, 121.9, 123.4, 125.4,
126.0, 131.3, 132.0, 144.6, 148.1, 154.7, 154.9, 156.9; HRMS (FAB,
positive) m/z calcd for C19H23N2O, 295.1810 ([Mþ1]þ); found,
295.1812 ([Mþ1]þ); ½a D35
ꢂ
17.7 (c 1.07, CHCl3, 97% ee). ee was de-
4.3.25. 7-{8-[Bis(but-2-ynyl)amino]-2-naphthoxy}heptanenitrile
termined by HPLC analysis using a chiral column (Daicel Chiralpak
AS-Hꢃ2: 4ꢃ250 mm, 254 nm UV detector, rt, eluent: 2% 2-propanol
in hexane, flow rate: 0.5 mL/min, retention time: 30 min for minor
isomer and 34 min for major isomer).
(6b). Brown solid. Mp 78e79 ꢀC; IR (CH2Cl2) 3066, 2249, 1597, 1508,
1360, 1252, 1134 cmꢁ1 1H NMR
; d 1.54e1.61 (m, 4H), 1.69e1.74 (m,
2H),1.85 (t, J¼2.1 Hz, 3Hꢃ2),1.88e1.91 (m, 2H), 2.37 (t, J¼7.0 Hz, 2H),
4.01 (q, J¼2.1 Hz, 2Hꢃ2), 4.15 (t, J¼6.2 Hz, 2H), 7.11 (dd, J¼2.6, 9.0 Hz,
1H), 7.25 (dd, J¼7.5, 7.9 Hz, 1H), 7.32 (d, J¼7.5 Hz, 1H), 7.50 (d,
J¼7.9 Hz, 1H), 7.53 (d, J¼2.6 Hz, 1H), 7.72 (d, J¼9.0 Hz, 1H); 13C NMR
4.3.21. 2,6-(1,2-o-Benzo-3-oxanonano)-2,3-dihydro-4,7-dimethyl-
1H-pyrrolo[3,4-c]pyridine (4e). Pale yellow oil. IR (CH2Cl2) 2927,
d 3.6,17.0, 25.2, 25.4, 28.4, 28.9, 42.4, 67.5, 75.0, 80.5,102.9,117.3,118.5,
1550,1488, 1226 cmꢁ1; 1H NMR
d
ꢁ0.16 to ꢁ0.07 (m, 1H), 0.51e0.60
119.7, 123.0, 123.6, 129.8, 129.9, 130.2, 145.8, 156.9; HRMS (FAB, pos-
itive) m/z calcd for C25H28N2O, 372.2202 (M); found, 372.2191 (M).
(m, 1H), 1.00e1.07 (m, 1H), 1.28e1.38 (m, 2H), 1.41e1.47 (m, 1H),
1.69e1.78 (m, 2H), 2.27 (s, 3H), 2.36 (s, 3H), 2.79e2.85 (m, 1H),
3.19e3.24 (m, 1H), 3.54e3.58 (m, 1H), 3.69e3.73 (m, 1H), 4.08 (d,
J¼14.8 Hz, 1H), 4.32 (d, J¼15.8 Hz, 1H), 4.52 (d, J¼15.8 Hz, 1H), 4.70
(d, J¼14.8 Hz, 1H), 6.75 (d, J¼7.9 Hz, 1H), 6.86 (dd, J¼7.7, 7.7 Hz, 1H),
7.11 (ddd, J¼1.7, 7.7, 7.9 Hz, 1H), 7.29 (dd, J¼1.7, 7.7 Hz, 1H); 13C NMR
4.3.26. 2,6-[1,4-(1,7-Naphthylene)-5-oxadecano]-2,3-dihydro-4,7-
dimethyl-1H-pyrrolo[3,4-c]pyridine (7a). Pale yellow solid. Mp
135 ꢀC; IR (CH2Cl2) 2945,1595,1508,1221 cmꢁ1; 1H NMR
d 1.35e1.47
(m, 3H),1.51e1.57 (m, 1H),1.74e1.80 (m, 1H), 2.06e2.12 (m, 1H), 2.24
(s, 3H), 2.42 (s, 3H), 2.62e2.67 (m, 1H), 2.70e2.76 (m,1H), 2.94e2.99
(m,1H), 3.21e3.25 (m,1H), 4.40 (d, J¼14.9 Hz, 1H), 4.50 (d, J¼16.2 Hz,
1H), 4.79 (d, J¼16.2 Hz, 1H), 4.90 (d, J¼14.9 Hz, 1H), 6.25 (d, J¼2.4 Hz,
1H), 6.99 (dd, J¼2.4, 8.9 Hz, 1H), 7.24 (dd, J¼7.2, 8.1 Hz, 1H), 7.49 (d,
J¼7.2 Hz, 1H), 7.63 (d, J¼8.1 Hz, 1H), 7.74 (d, J¼8.9 Hz, 1H); 13C NMR
d
15.1, 21.4, 24.9, 25.2, 27.6, 29.3, 35.2, 60.1, 61.3, 68.0, 112.0, 120.1,
122.7, 126.9, 131.7, 133.2, 142.1, 147.2, 151.4, 156.5, 157.9; HRMS (FAB,
positive) m/z calcd for C21H27N2O, 323.2123 ([Mþ1]þ); found,
27
323.2081 ([Mþ1]þ); ½
a
ꢂ
29.0 (c 1.25, CHCl3, 97% ee). ee was de-
436
termined by HPLC analysis using a chiral column (Daicel Chiralpak
AD-H: 4ꢃ250 mm, 254 nm UV detector, rt, eluent: 10% 2-propanol
in hexane, flow rate: 1.0 mL/min, retention time: 5 min for major
isomer and 8 min for minor isomer).
d
14.8, 20.9, 21.9, 25.9, 28.8, 35.5, 60.7, 61.1, 67.7, 101.8, 118.7, 123.3,
123.4, 126.8, 129.4, 130.9, 131.1, 131.5, 133.9, 148.3, 148.7, 151.3, 157.5,
158.6; HRMS (FAB, positive) m/z calcd for C24H26N2O, 358.2045 (M);
found, 358.2058 (M); ½a D22
ꢁ32.7 (c 1.63, CHCl3, 97% ee). ee was
ꢂ
4.3.22. 2,6-(1,2-o-Benzo-3-oxatetradecano)-2,3-dihydro-4,7-
determined by HPLC analysis using a chiral column (Daicel Chiralpak
AD-H: 4ꢃ250 mm, 254 nm UV detector, rt, eluent: 2% 2-propanol in
hexane, flow rate: 1.0 mL/min, retention time: 10 min for minor
isomer and 12 min for major isomer).
dimethyl-1H-pyrrolo[3,4-c]pyridine
(4f). White
solid.
;
Mp
105e106 ꢀC; IR (CH2Cl2) 2925, 1549, 1452, 1230 cmꢁ1
1H NMR
d
0.94e1.16 (m, 10H), 1.26e1.28 (m, 2H), 1.39e1.41 (m, 1H),
1.50e1.52 (m, 1H), 1.70e1.83 (m, 4H), 2.26 (s, 3H), 2.46 (s, 3H),
2.76e2.79 (m, 1H), 3.00e3.05 (m,1H), 3.95e3.97 (m,1H), 4.06e4.14
(m, 2H), 4.49 (d, J¼12.2 Hz, 1H), 4.61 (d, J¼12.2 Hz, 1H), 5.24 (d,
4.3.27. 2,6-[1,4-(1,7-Naphthylene)-5-oxaundecano]-2,3-dihydro-4,7-
dimethyl-1H-pyrrolo[3,4-c]pyridine (7b). White solid. Mp 60e61 ꢀC;
J¼14.4 Hz, 1H), 6.93e7.03 (m, 4H); 13C NMR
d
15.1, 21.6, 26.4, 26.6,
IR (CH2Cl2) 2941,1595,1508,1227 cmꢁ1; 1H NMR
d 1.01e1.06 (m,1H),
27.7, 28.2, 28.3, 28.5, 29.2, 29.9, 30.0, 33.7, 53.8, 55.4, 70.1, 114.8,
118.3, 121.5, 121.6, 122.8, 130.4, 138.7, 147.9, 148.6, 151.9, 158.3;
HRMS (FAB, positive) m/z calcd for C26H37N2O, 393.2906 ([Mþ1]þ);
found, 393.2943 ([Mþ1]þ).
1.14e1.32 (m, 3H), 1.53e1.60 (m, 2H), 1.76e1.82 (m, 1H), 1.89e1.96
(m, 1H), 2.22 (s, 3H), 2.42 (s, 3H), 2.80e2.85 (m, 1H), 3.08e3.23 (m,
3H), 4.55 (d, J¼14.5 Hz, 1H), 4.63 (d, J¼16.4 Hz, 1H), 4.77 (d,
J¼16.4 Hz, 1H), 4.89 (d, J¼14.5 Hz, 1H), 6.63 (d, J¼2.4 Hz, 1H), 7.04
(dd, J¼2.4, 8.7 Hz, 1H), 7.26 (dd, J¼7.6, 8.0 Hz, 1H), 7.51 (d, J¼7.6 Hz,
4.3.23. 2,6-(1,2-o-Benzo-3-oxatetradecano)-2,3-dihydro-4,7-
1H), 7.65 (d, J¼8.0 Hz, 1H), 7.78 (d, J¼8.7 Hz, 1H); 13C NMR
d 15.2,
diphenyl-1H-pyrrolo[3,4-c]pyridine (4g). White solid. Mp 64e65 ꢀC;
21.8, 24.3, 24.5, 26.7, 26.8, 32.1, 60.4, 61.0, 68.1, 101.6, 118.9, 123.4,
123.4, 126.7, 129.3, 131.0, 131.1, 131.2, 132.2, 147.4, 148.8, 149.7, 157.5,
158.3; HRMS (FAB, positive) m/z calcd for C25H28N2O, 372.2202 (M);
IR (CH2Cl2) 2929, 1597, 1502, 1228 cmꢁ1 1H NMR
; d 0.94e1.03 (m,
6H), 1.05e1.33 (m, 7H), 1.35e1.42 (m, 1H), 1.50e1.58 (m, 1H),
1.59e1.66 (m, 2H), 1.89e2.01 (m, 1H), 2.86 (t, J¼4.8 Hz, 2H),
3.95e4.03 (m, 3H), 4.67 (d, J¼13.2 Hz, 1H), 4.85 (d, J¼13.2 Hz, 1H),
5.05 (d, J¼12.8 Hz, 1H), 6.88e6.99 (m, 4H), 7.33e7.51 (m, 8H), 7.87
found, 372.2203 (M); ½a D24
ꢁ3.6 (c 1.365, CHCl3, >99% ee). ee was
ꢂ
determined by HPLC analysis using a chiral column (Daicel Chiralpak
AD-H: 4ꢃ250 mm, 254 nm UV detector, rt, eluent: 2% 2-propanol in
hexane, flow rate: 0.5 mL/min, retention time: 17 min for minor
isomer and 20 min for major isomer).
(d, J¼7.2 Hz, 2H); 13C NMR
d26.6, 26.7, 27.3, 28.1, 28.2, 28.3, 29.1,
29.7, 30.0, 34.1, 55.1, 55.7, 70.4, 115.1, 120.1, 121.6, 122.6, 127.4, 128.1,
128.4, 128.5, 129.3, 130.4, 130.7, 138.0, 138.5, 139.7, 149.7, 150.1,
153.0, 157.8 (a pair of aromatic peaks is overlapped); HRMS (FAB,
positive) m/z calcd for C36H40N2O, 516.3141 (M); found, 516.3118
4.3.28. N,N-Bis(but-2-ynyl)-2-(11-methoxyundec-9-ynyloxy)ben-
zenamine (8). Yellow oil. IR (CH2Cl2) 3050, 2931, 1458, 1211 cmꢁ1
;
(M); ½a 2D8
ꢂ
ꢁ6.4 (c 1.60, CHCl3, 65% ee). ee was determined by HPLC
1H NMR
d 1.37e1.43 (m, 6H), 1.50e1.57 (m, 4H), 1.84e1.88 (m, 8H),
analysis using a chiral column (Daicel Chiralpak AD-H: 4ꢃ250 mm,
254 nm UV detector, rt, eluent: 2% 2-propanol in hexane, flow rate:
2.21e2.25 (m, 2H), 3.37 (s, 3H), 4.02 (q, J¼2.0 Hz, 4H), 4.08 (t,
J¼1.8 Hz, 2H), 4.14 (t, J¼6.6 Hz, 2H), 7.12 (dd, J¼2.2, 8.8 Hz, 1H),

2686
T. Shibata et al. / Tetrahedron 68 (2012) 2679e2686
3. (a) Fiesel, R.; Huber, J.; Scherf, U. Angew. Chem., Int. Ed. 1996, 35, 2111e2113; (b)
Fiesel, R.; Huber, J.; Apel, U.; Enkelmann, V.; Hentschke, R.; Scherf, U.; Cabrera,
K. Macromol. Chem. Phys. 1997, 198, 2623e2650.
4. (a) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante, R. P.; Reider, P. J. J.
Am. Chem. Soc. 1997, 119, 6207e6208 For a review of [2.2]paracyclophane de-
rivatives for asymmetric syntheses, see: (b) Gibson, S. E.; Knight, J. D. Org. Bi-
omol. Chem. 2003, 1, 1256e1269.
5. (a) Tanaka, K.; Hori, T.; Osaka, T.; Noguchi, K.; Hirano, M. Org. Lett. 2007, 9,
4881e4884; (b) Hori, T.; Shibata, Y.; Tanaka, K. Tetrahedron: Asymmetry 2010,
21, 1303e1306.
6. (a) Tanaka, K.; Sagae, H.; Toyoda, K.; Noguchi, K.; Hirano, M. J. Am. Chem. Soc.
2007, 129, 1522e1523; (b) Tanaka, K.; Sagae, H.; Toyoda, K.; Hirano, M. Tetra-
hedron 2008, 64, 831e846; (c) Araki, T.; Hojo, D.; Noguchi, K.; Tanaka, K. Synlett
2011, 539e542.
7. Kanda, K.; Koike, T.; Endo, K.; Shibata, T. Chem. Commun. 2009, 1870e1872.
8. Kanda, K.; Endo, K.; Shibata, T. Org. Lett. 2010, 12, 1980e1983.
9. (a) Hubert, A. J.; Hubert, M. Tetrahedron Lett. 1966, 7, 5779e5782; (b) Hubert, A.
J. J. Chem. Soc. C 1967, 6e10.
10. Damrauer, R.; Hankin, J. A.; Haltiwanger, R. C. Organometallics 1991, 10,
3962e3964.
7.23e7.33 (m, 2H), 7.50 (d, J¼8.0 Hz, 1H), 7.53 (d, J¼2.2 Hz, 1H), 7.71
(d, J¼8.8 Hz,1H); 13C NMR
d 3.7,18.7, 26.1, 28.6, 28.8, 29.1, 29.3, 42.5,
57.4, 60.2, 68.0, 75.1, 75.7, 80.5, 87.1, 103.0, 117.3, 118.7, 122.9, 123.6,
129.8, 130.0, 130.3, 145.9, 157.1 (a pair of aliphatic peaks is over-
lapped); HRMS (FAB, positive) m/z calcd for C30H37N2O, 443.2824
(M); found, 443.2842 (M).
4.3.29. 2,6-[1,4-(1,7-Naphthylene)-5-oxatridecano]-4,7-dimethyl-5-
(methoxymethyl)isoindoline (9). White solid. Mp 46e47 ꢀC; IR
(CH2Cl2) 2929, 1599, 1506, 1227 cmꢁ1; 1H NMR
d 0.95e1.34 (m, 8H),
1.59e1.75 (m, 4H), 2.20(s, 3H), 2.29 (s, 3H), 2.86e2.96(m, 2H), 3.43 (s,
3H), 3.55e3.67 (m, 2H), 4.51e4.53 (m, 2H), 4.58 (d, J¼10.2 Hz, 1H),
4.65 (d, J¼13.0 Hz, 1H), 4.79e4.85 (m, 2H), 6.88 (d, J¼2.3 Hz,1H), 7.07
(dd, J¼2.3, 8.8 Hz,1H), 7.28 (d, J¼6.9, 8.1 Hz,1H), 7.46 (d, J¼6.9 Hz,1H),
7.61 (d, J¼8.1 Hz,1H), 7.78 (d, J¼8.8 Hz,1H); 13C NMR
d 16.0,16.6, 24.3,
25.7, 27.2, 27.9, 28.0, 28.2, 29.1, 58.3, 59.2, 60.8, 68.3, 69.1,102.4,118.8,
123.5, 125.4, 125.5, 128.1, 129.8, 130.8, 130.8, 131.3, 133.5, 137.1, 139.5,
139.5, 146.1, 157.1; HRMS (FAB, positive) m/z calcd for C30H37NO2,
11. Hansen, J.; Blake, A. J.; Li, W.-S.; Mascal, M. J. Chem. Soc., Perkin Trans. 1 1998,
3371e3376.
12. The reaction of 1,3,5-trisubstituted benzenes with branched compounds pos-
sessing three reaction sites is a regioselective approach for the tripodal cy-
clophane, but the yield was generally low: (a) Pascal, J. R. A.; Carter, M. L.;
Johnson, M. R.; Ho, D. M. Tetrahedron Lett. 1996, 37, 8125e8128; (b) Pascal, J. R.
A.; Winans, C. G.; Engen, D. V. J. Am. Chem. Soc. 1989, 111, 3007e3010; (c)
L’Esperance, R. P.; West, J. A. P.; Engen, D. V.; Pascal, J. R. A. J. Am. Chem. Soc.
1991, 113, 2672e2676; (d) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Faggi, C.;
Papalia, T. J. Org. Chem. 2007, 72, 4486e4496.
443.2824 (M); found, 443.2812 (M); ½a D24
ꢁ12.3 (c 1.40, CHCl3, 96%
ꢂ
ee). eewasdetermined by HPLC analysis using a chiralcolumn (Daicel
Chiralpak AD-H: 4ꢃ250 mm, 254 nm UV detector, rt, eluent: 10% 2-
propanol in hexane, flow rate: 0.5 mL/min, retention time: 11 min
for major isomer and 12 min for minor isomer).
13. The preliminary communication of this work: Shibata, T.; Uchiyama, T.; Endo,
K. Org. Lett. 2009, 11, 3906e3908.
Acknowledgements
14. Wakatsuki, Y.; Yamazaki, H. Tetrahedron Lett. 1973, 14, 3383e3384.
15. Other Co-catalyzed hetero-[2þ2þ2] cycloadditions for the construction of
pyridine ring: (a) Naiman, A.; Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1977,
16, 708e709; (b) Chang, H.-T.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2007, 9,
505e508.
16. Ru: (a) Yamamoto, Y.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2001, 123, 6189e6190
Ni: (b) McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie, J. J. Am. Chem. Soc. 2005,
127, 5030e5031 Fe: (c) D’Souza, B. R.; Lane, T. K.; Louie, J. Org. Lett. 2011, 13,
2936e2939.
This work was supported by Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Tech-
nology, Japan (No. 22350046) and the Global COE program ‘Center
for Practice Chemical Wisdom’ by MEXT. We also thank Takasago
International Corp. for the gift of Cy-BINAP and H8-BINAP.
17. (a) Moretto, A. F.; Zhang, H.-C.; Maryanoff, B. E. J. Am. Chem. Soc. 2001, 123,
~
3157e3158; (b) Bonaga, L. V. R.; Zhang, H.-C.; Moretto, A. F.; Ye, H.; Gauthier, D.
Supplementary material
A.; Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am. Chem. Soc. 2005, 127, 3473e3485.
18. (a) Kanomata, N.; Nakata, T. Angew. Chem., Int. Ed. 1997, 36, 1207e1211; (b)
Kanomata, N.; Nakata, T. J. Am. Chem. Soc. 2000, 122, 4563e4568; (c) Kanomata,
N.; Sakaguchi, R.; Sekine, K.; Yamashita, S.; Tanaka, H. Adv. Synth. Catal. 2010,
352, 2966e2978.
19. We checked the accordance of the structure observed by X-ray analysis (Ref. 13)
with the most stable structure by calculation (Gaussian03, CONFLEX). Then, we
determined the absolute configuration of cycloadducts 2b, 2c, 2e, and 4a using
chiroptical analysis by vibrational circular dichroism (VCD). See the
Supplementary data.
20. Enantioselective hetero-[2þ2þ2] cycloaddition of two alkynes and a cyano
compound for the generation of axial chirality: (a) Gutnov, A.; Heller, B.;
Fischer, C.; Drexler, H.-J.; Spannenberg, A.; Sundermann, B.; Sundermann, C.
Angew. Chem., Int. Ed. 2004, 43, 3795e3797; (b) Nishida, G.; Suzuki, N.; No-
guchi, K.; Tanaka, K. Org. Lett. 2006, 8, 3489e3492.
Synthetic scheme of diyne-nitriles, amino-2-naphthol-tethered
diyne-nitriles, and triyne, and the IR and VCD spectra of 2c, 2e, and
4a. Supplementary data related to this article can be found in the
online version, at doi:10.1016/j.tet.2012.01.046.
References and notes
€
1. For reviews, see: (a) Cyclophane Chemistry; Vogtle, F., Ed.; Wiley: Chichester, UK,
1993; (b) Modern Cyclophane Chemistry; Gleither, R., Hopf, H., Eds.; Wiley:
Chichester, UK, 2004.
2. (a) Oi, S.; Miyano, S. Chem. Lett. 1992, 987e990; (b) Hattori, T.; Harada, N.; Oi, S.;
Abe, H.; Miyano, S. Tetrahedron: Asymmetry 1995, 6, 1043e1046.
21. Isolated 4b was sufficiently stable for characterization.