Atropisomeric (R,R)-2,2′-Bi([2]paracyclo[2](5,8)quinolinophane) and (R,R)-1,1′-Bi([2]paracyclo[2](5,8)isoquinolinophane): Synthesis, structural analysis, and chiroptical properties

Article abstract of DOI:10.1021/jo048147m

(Chemical Equation Presented) Atropisomeric (R,R)-2,2′-bi([2] paracyclo[2](5,8)quinolinophane) [(R,R)-1] and (R,R)-1,1′-bi([2]- paracyclo[2](5,8)isoquinolinophane) [(R,R)-2] have been prepared in moderate overall yield (17 and 9%, respectively) by a four-step sequence starting from (R)-(-)-4-amino[2.2]paracyclophane and (R)-(-)-4-carboxy[2.2]paracyclophane, respectively. The structures have been determined on the basis of NOE ¹H NMR analysis and molecular mechanics (MM) calculations performed with a Spartan02 program, using the MMF94s force field. A preliminary, qualitative analysis of the chiroptical properties of these two compounds has also been attempted. The main spectral data can be interpreted in terms of an almost planar 2,2′-bisquinoline chromophore inserted in a paracyclophane structure in the case of (R,R)-1, while in the case of (R,R)-2, the main role is played by a distorted 1,1′-bisisoquinoline chromophore. On the basis of the above structural results, a hypothesis about the enantioselection capability of these two molecules has also been formulated.

Full text of DOI:10.1021/jo048147m

Atropisomeric (R,R)-2,2′-Bi([2]paracyclo[2](5,8)quinolinophane)
and (R,R)-1,1′-Bi([2]paracyclo[2](5,8)isoquinolinophane):
Synthesis, Structural Analysis, and Chiroptical Properties
Giacomo Ricci,† Renzo Ruzziconi,*,† and Egidio Giorgio‡
Dipartimento di Chimica, Universita` di Perugia, via Elce di Sotto, 8 06123 Perugia, Italy, and
Dipartimento di Chimica, Universita` della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
ruzzchor@unipg.it
Received October 20, 2004
Atropisomeric (R,R)-2,2′-bi([2]paracyclo[2](5,8)quinolinophane) [(R,R)-1] and (R,R)-1,1′-bi([2]-
paracyclo[2](5,8)isoquinolinophane) [(R,R)-2] have been prepared in moderate overall yield (17 and
9%, respectively) by a four-step sequence starting from (R)-(-)-4-amino[2.2]paracyclophane and
(R)-(-)-4-carboxy[2.2]paracyclophane, respectively. The structures have been determined on the
1
basis of NOE H NMR analysis and molecular mechanics (MM) calculations performed with a
Spartan02 program, using the MMF94s force field. A preliminary, qualitative analysis of the
chiroptical properties of these two compounds has also been attempted. The main spectral data
can be interpreted in terms of an almost planar 2,2′-bisquinoline chromophore inserted in a
paracyclophane structure in the case of (R,R)-1, while in the case of (R,R)-2, the main role is
played by a distorted 1,1′-bisisoquinoline chromophore. On the basis of the above structural results,
a hypothesis about the enantioselection capability of these two molecules has also been formulated.
Chiral C2-symmetric N,N-donor ligands have recently
received renewed attention as valuable ligands of transi-
tion metals in homogeneous stereoselective catalysis.1
Among these, bisoxazolines,2 semicorrines,3 and salen-
positions, of the heterocyclic ring.5 However, applications
to stereoselective syntheses of atropisomeric diazabiaryl
derivatives exhibiting only axial chirality are little
known. The reason for such scarce consideration rests
in the poor conformational stability of the chiral atro-
pisomers due to the low rotational barrier.6 Conforma-
tional stability can be substantially increased by dialkyl
substitution or anellation at 3,3′-position of the hetero-
cyclic rings. In this case, it depends on the size of the
4
type chelating ligands are the most widely used in
transition-metal-catalyzed asymmetric reactions. Par-
ticular interest has been devoted to bipyridine-based
ligands whose chirality is often due to the presence of
stereogenic centers as substituents, mostly in the 6,6′
† Universita` di Perugia.
‡ Universita` della Basilicata.
(5) (a) Fletcher, N. J. Chem. Soc., Perkin Trans. 1 2002, 1831-1842.
(b) Lotscher, D.; Rupprecht, S.; Collomb P.; Viebrock, M.; von Zelewsky,
A.; Burger P. Inorg. Chem. 2001, 40, 5675-5681. (c) Lotscher, D.;
Rupprecht, S.; Stoeckli-Evans, H. von Zelewsky, A. Tetrahedron:
Asymmetry 2000, 11, 4341-4357. (d) Von Zelewsky, A. Coord. Chem.
Rev. 1999, 190-191, 811-825. (e) Kwong, M.-L.; Lee, W.-S.; Ng, H.-
F.; Chiu, W.-H.; Wong, W.-T. J. Chem. Soc., Dalton Trans. 1998, 1043-
1046. (f) Ito, K.; Katsuki, T. Chem. Lett. 1994, 1857-1860. (g) Bolm,
C.; Zehnder, M.; Bur, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 205-
207, (h) Gladiali, S.; Pinna, L.; Delogu, G.; Graf, E.; Brunner, H.
Tetrahedron: Asymmetry 1990, 1, 937-942.
(1) (a) Ojima, I. Catalytic Asymmetric Synthesis; Wiley VCH: New
York, 2000. (b) Fache, F.; Schhulz, E.; Tommasino, M. L.; Lemaire,
M. Chem. Rev. 2000, 100, 2159-2232. (c) Togni, A.; Venanzi, L. M.
Angew. Chem., Int. Ed. Engl. 1994, 33, 497-526.
(2) (a) Braunstein, P.; Naud, F. Angew. Chem., Int. Ed. Engl. 2001,
40, 680-699. (b) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000,
33, 325-335. (c) Pfaltz, A. J. Heterocycl. Chem. 1999, 36, 1437-1451.
(d) Ghosh, A. K. Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry
1998, 9, 1-45.
(3) (a) Pfaltz, A. Synlett 1999, 835-842. (b) Pfaltz, A. Acta Chem.
Scand. 1996, 50, 189-194. (c) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339-
345.
(4) For a review, see: Canali, L.; Sherrington, D. C. Chem. Soc. Rev.
1999, 28, 85-93.
(6) (a) Goller, A. H.; Grummt, U.-W. Chem. Phys. Lett. 2002, 354,
233-242, 2000, 321, 399-405. (b) Jaime, C.; Font, J. J. Mol. Strucuture
1989, 195, 103-110. (c) Fabian, W. M. F. J. Comput. Chem. 1988, 9,
369-377.
10.1021/jo048147m CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/11/2005
J. Org. Chem. 2005, 70, 1011-1018
1011

Ricci et al.
CHART 1
bridge. For instance, 3,3′ dimethylene- and trimethylene-
bridged in 2,2′-pyridine and 2,2′-diquinoline undergo
rapid conformational inversion, whereas the 3,3′-tetram-
ethylene-bridged systems are conformationally so stable
that the racemic mixture can be resolved.7
Conformationally very stable 2,2′-diazabiaryl ligands
can also be obtained by alkyl substitution, or anellation,
at the 3,3′position of the corresponding N-oxides. Accord-
ingly, racemic mixtures of 3,3′-disubstituted 2,2′-bipy-
ridine and 2,2′-biquinoline N,N′-dioxides have been easily
resolved and the enantiomers successfully employed as
ligands in several transition-metal-catalyzed enantio-
selective reactions.8
SCHEME 1a
The low barrier to the rotation around the bond linking
the heterocyclic moieties, created by the repulsion of the
nitrogen lone pairs, is also responsible for the rapid one-
step atropisomerization at the anti configuration of
axially chiral 1,1′-biisoquinolines, especially when bulky
alkyl groups are present in the 8,8′-positions.9 Only N,N′-
dioxide exhibits a substantial conformational stability
allowing the racemic mixture to be easily resolved.10
The presence of chiral substituents of the same con-
figuration at the n,n′-positions of C2-symmetric diaz-
abiaryl ligands inevitably induces diastereoisomerism.
How the presence of stereogenic centers or other types
of chirality affects the atropisomerism of this class of
compounds and eventually the diastereomeric ratio (for
instance, the (R,P,R)/(R,M,R)11 ratio) of chiral diazabiaryl
derivatives is still an intriguing question. Our interest
in the chemistry of chiral [2.2]paracyclophane-based
a Key: (a) (1) BuLi, (2) MeOCHdCHCO2Me, THF, rt; (b) conced
HCl;( c) POBr3, 120 °C, 1.5 h; (d) NiCl2‚6H2O, PPh3, Zn, DMF, 50
°C, 1 h.
12
ligands spurred us to investigate the contribution of
the planar chirality to the conformational stability of
some chiral biquinolinophanes. In this paper we report
the synthesis, the structural analysis (by 1H NMR
spectroscopy and molecular mechanics calculations), and
an unprecedented first qualitative investigation about
the chiroptical properties of the (R,R)-2,2′-bi([2]paracyclo-
[2](5,8)quinolinophane) [(R,R)-1] and (R,R)-1,1′-bi([2]-
paracyclo[2](5,8)isoquinolinophane) [(R,R)-2] (Chart 1).
Results and Discussion
(R,R)-2,2′-Bi([2]paracyclo[2](5,8)quinolino-
phane) [(R,R)-1]. (R)-(-)-4-Carboxy[2.2]paracyclophane
[(R)-3] was the selected precursor of both biquino-
linophane (R,R)-1 and biisoquinolinophane (R,R)-2.
From the acid 3, (R)-(-)-4-amino[2.2]paracyclophane
[(R)-4] was prepared in four steps in excellent overall
yield (>95%) and on a multigram scale through a slightly
modified Curtius rearrangement of the acylzide, followed
by the alkaline hydrolysis of the resulting isocyanate. The
lithium amide, obtained by the reaction of (R)-4 with
butyllithium, was made to react with ethyl 3-methoxy-
acrylate to obtain the corresponding amide (R)-5 in 40%
yield (Scheme 1). Acid-catalyzed cyclization converted
(R)-5 into the 2-quinolone (R)-6 from which the expected
2-bromoquinolinophane (R)-7 was obtained in fairly good
(7) (a) Rashidi-Ranjbar, P.; Sandstrom, J.; Wong, H. N. C.; Wang,
X. C. J. Chem Soc., Perkin Trans. 2 1992, 1625-1628. (b) Wang, X.
C.; Wong, H. N. C. Tetrahedron 1995, 51, 6941-6960.
(8) (a) Jiao, Z.; Feng, X.; Liu, B.; Chen, F.; Zhang, G.; Jiang, Y. Eur.
J. Org. Chem. 2003, 3818-3826. (b) Denmark, S. E.; Fan, Y. J. Am.
Chem. Soc. 2002, 124, 4233-4235. (c) Liu, B.; Feng, X.; Chen, F.;
Zhang, G.; Cui, X.; Jiang, Y Synlett 2001, 1551-1554. (d) Malkov, A.
V.; Orsini, M.; Pernazza, D.; Muir, K. W.; Langer, V.; Meghani, P.;
Kocˇovsky´ Org. Lett. 2002, 4, 1047-1049. (e) Shimada, T.; Kina, A.;
Ikeda, S.; Hayashi, T. Org. Lett. 2002, 4, 2799-2801. (f) Nakajima,
M.; Yamaguchi, Y.; Hashimoto, S. J. Chem. Soc., Chem. Commun.
2001, 1596-1597. (g) Nakajima, M.; Yamaguchi, Y.; Hashimoto, S. J.
Chem. Soc. Chem. Commun. 2001, 1596-1597. (h) Saito, M.; Nakajima,
M.; Hashimoto, S. Tetrahedron 2000, 56, 9589-9594. (i) Saito, M.;
Nakajima, M.; Hashimoto, S. J. Chem. Soc., Chem. Commun. 2000,
1851-1852. (j) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J.
Am. Chem. Soc. 1998, 120, 6419-6420.
yield by treatment with POBr3. Finally, Ni(0)-catalyzed
homocoupling of (R)-7 in DMF
14
allowed the biquino-
linophane (R,R)-1 to be obtained in satisfactory yield
(72%).
1H NMR Analysis and Theoretical Calculations.
1H NMR analysis turned out to be a valuable tool for
drawing the structure of (R,R)-1 in solution in its more
stable conformation. Four AB systems can be identified
in the range of aromatic protons which are attributable
(9) (a) Tsue, H.; Fujinami, H.; Itakura, T.; Tsukiya, R.; Kobayashi,
K.; Takahashi, H.; Hirao, K. J. Chem. Soc., Perkin Trans. 1 1999,
3677-3683. (b) Hirao, K.; Tsukiya, R.; Yano, Y.; Tsue, H. Heterocycles
1996, 42, 415-422; c) Chelucci, G.; Cabras, M. A.; Saba, A.; Sechi, A.
Tetrahedron: Asymmetry 1996, 7, 1027-1032.
(10) Fujii, M.; Honda, A. J. Heterocycl. Chem. 1992, 29, 931-933.
(11) For the designations R, S, P, and M, see: Eliel E. L.; Wilen, S.
H. Stereochemistry of Organic Compounds; Wiley Interscience: New
York, 1994; Chapter 14.
(12) (a) Cipiciani, A.; Fringuelli, F.; Mancini, V.; Piermatti, O.; Pizzo,
F.; Ruzziconi, R. J. Org. Chem. 1997, 62, 3744-3747. (b) Ruzziconi,
R.; Piermatti, O.; Ricci, G.; Vinci, D. Synlett 2002, 747-750.
(13) (a) Waters, J. F.; Sutter, J. K.; Meador, M. A. B.; Baldwin, L.
J.; Meador, M. A. J. Pol. Science: Part A: Polymer Chem. 1991, 29,
1917-1924. (b) Falk, H.; Reich-Rohrwig; Schlogl, K. Tetrahedron 1970,
26, 511-527.
(14) Tiecco, M.; Testaferri, L.; Marco, T.; Chianelli, D.; Montanucci,
M. Synthesis 1984, 736-738.
1012 J. Org. Chem., Vol. 70, No. 3, 2005

Atropisomeric (R,R)-2,2′-Bi([2]paracyclo[2](5,8)quinolinophane)
FIGURE 1. NOE in the most stable conformation of
(R,R)-1.
FIGURE 3. UV and CD spectra of (R,R)-1.
effect is located at ca. 360 nm (∆ꢀ -10), followed by a
sequence of positive/negative CD bands (∆ꢀ +20, -25,
+5, and -15 at 310, 290, 270, and 250 nm, respectively).
The complex shape of the CD spectrum of (R,R)-1
explains why its [R]D is so low: notice that a series of
positive/negative Cotton effects, having similar intensi-
ties, is present down to 240 nm. If one considers that the
OR at the sodium D line can be calculated by the Kronig-
Kramers transform, which can assume the following
approximate form16
FIGURE 2. Most stable conformation of (R,R)-1.
to the four pair of protons of the quinolinophane moieties.
The highest field AB system centered at δ 5.74 can
certainly be attributed to the two protons (H-15 and
H-16) of the phenyl ring overlooking the quinoline moiety
and falling into the shielding cone of the heterocyclic ring.
[R]D ) (9151/MW)Σi(Riλi2/(5892 - λi2)
(1)
1
In this respect, the most significant H NMR signals
fall at δ 8.17 and 8.86 ppm, assigned to H-4 and H-3,
respectively, and at δ 4.54 and 3.83 assigned to the two
protons H-9s and H-18s which are almost coplanar with
the quinoline moiety and turned toward the heterocyclic
ring (Figure 1).
The presence of a substantial NOE between H-3′ and
H-9s is consistent with a stable conformation where the
two 2,2′-bonded quinolinophane moieties are nearly
coplanar, the nitrogen atoms being placed anti each
other.
Furthermore, a weak NOE between protons H-3 and
H-10′ suggests that the two quinoline moieties are
slightly rotated around the C-2-C-2′ bond so that C-3-
H-3 bond points to the middle of the C-9′-C-10′ bridge.
A theoretical conformational analysis, performed with the
Spartan02 program, using the MMFF94s force field,15
seems to confirm the above conclusions. According to the
calculations, (R,R)-1 would exist in only one conforma-
tion (Figure 2) with the nitrogen atoms anti each other
and a dihedral angle N-C-C-N of -173°.
[R]D, Absorption and Circular Dichroism (CD)
Spectra. Biquinolinophane (R,R)-1 shows low values of
optical rotation ([R]D +36 (c 0.027, THF) or -10 (c 0.11,
CHCl3)), which are also strongly solvent-dependent. The
absorption and circular dichroism (CD) spectra of (R,R)-
1, measured in THF, are reported in Figure 3.
where MW is the molecular weight and Ri is the
rotational strength corresponding to the electronic tran-
sitions occurring at λi, it results that the contributions
coming from the sequence of CD bands at wavelengths
longer than 240 nm tend to cancel each other and in
practice only the 220 nm positive Cotton effect will
provide a contribution to the [R]D. However, its absolute
value would not be large, taking into account the dis-
tance, on the wavelength scale, from the sodium D line;
i.e., the denominator of eq 1 will be large. Accordingly, a
small value of the optical rotation at 589 nm would be
expected. To formulate some spectrum/structure relation-
ships, following an established procedure17 based on the
exciton coupling optical activity,18 (R,R)-1 could be
considered, from the optical properties point of view, as
an aggregate of the transoid-2,2′-bi(quinoline) chro-
mophore and two, suitably disposed, p-xylene chro-
mophores. Such a procedure requires knowledge of the
spectroscopic properties of the two chromophores. Whereas
the spectroscopic characteristics of p-xylene are well-
known,17 those of 2,2′-bis(quinoline) have not been re-
ported. However it is reasonable to invoke the presence
of such a chromophore because the absorptions at 360
and 300 nm in the UV spectrum of (R,R)-1 cannot be
ascribed to the simple quinoline chromophore (which
absorbs below 300 nm 19). By contrast, the NMR and
Four main absorption regions can be easily identified
in the UV spectrum: a first maximum is observed at
about 360 nm (ꢀ ca. 20 000), a second one is centered at
about 300 nm (ꢀ ca. 30 000) with a definite shoulder at
250 nm (ꢀ ca. 20 000), followed by an intense absorption
at 200 nm (ꢀ ∼60 000, THF cutoff). The CD spectrum
looks quite complex: in fact, the lowest-energy Cotton
(16) To this end, the simple Kronig-Kramers transforms formulas
(eq 10) of Moscowitz have been used: Moscowitz, A. Theory and
analysis of rotatory dispersion curves. In Optical Rotatory Dispersion:
Application to Organic Chemistry; Djerassi, C., Ed.; McGraw-Hill
Publ.: New York, 1960; Chapter 12.
(17) (a) Rosini, C.; Ruzziconi, R.; Superchi, S.; Fringuelli, F.;
Piermatti, O. Tetrahedron: Asymmetry 1998, 9, 55. (b) Lanari, D.;
Marrocchi, A.; Minuti, L.; Rosini, C.; Superchi, S.; Taticchi, A.
Tetrahedron: Asymmetry 2002, 13, 1257.
(15) Spartan02; Wavefunction Inc., Irvine, CA, 2002.
J. Org. Chem, Vol. 70, No. 3, 2005 1013

Ricci et al.
SCHEME 2a
computational results discussed previously, point out that
the most stable conformer of (R,R)-1 contains an almost
planar transoid-2,2′-bis(quinoline) group. Such a largely
conjugate system could show absorption bands at much
longer wavelengths than quinoline. Therefore, the analy-
sis of the chiroptical properties of (R,R)-1 in terms of
exciton coupling optical activity requires the complete
characterization of the above transoid-2,2′-bis(quinoline)
chromophore followed by some coupled-oscillator calcula-
tions using, for instance, the DeVoe model.20 Alternately,
a quantum-chemical treatment of the CD spectrum (at
a semiempirical or ab initio level)21 could be carried out,
but these kinds of analyses are well beyond the scope of
the present paper and will be the object of a future study.
(R,R)-1,1′-Bi[2]paracyclo[2](5,8)isoquinolino-
phane [(R,R)-2]. In the synthesis of (R,R)-2, the acid
(R)-3 was treated with SOCl2 and the resulting acyl
chloride was made to react with aminoacetaldehyde
diethyl acetal to give the amidoacetal (R)-8 in 99% yield
(Scheme 2). Cyclization of (R)-8 in polyphosphoric acid
at 100 °C gave the expected 1-isoquinolone (R)-9 (47%
yield) which was transformed into the 1-bromoisoquino-
linophane 10 (45%) by treatment with POBr3. Again, the
Ni(0)-catalyzed homocoupling of 10 in DMF allowed the
desired biisoquinolinophane (R,R)-2 to be obtained in
42% yield.
a Key: (a) (1) SOCl2, rt, 12 h, (2) H2NCH2CH(OEt)2, Et2O, 25
°C; (b) polyphosphoric acid, 110 °C, 30 min; (c) POBr3, 100 °C, 7
h; (d) NiCl2‚6H2O, PPh3, Zn, DMF, 50 °C, 1 h.
1H NMR Analysis and Theoretical Calculations.
1
In the frequency range of the aromatic protons the H
NMR spectrum of 1,1′-biisoquinolinophane (R,R)-2 is
substantially different from that observed for 2,2′-quino-
linophane (R,R)-1 and some considerations may be useful
for drawing the conformational structure. In this case too,
four AB systems can be identified which are attributable
to the four pairs of protons of the quinolinophane
moieties.
FIGURE 4. NOE of the most stable conformation of (R,R)-2.
The two doublets at δ 8.84 and 7.70 can be assigned
to proton H-3 and H-4, respectively, whereas the AB
system at δ 5.93-5.80 is certainly attributable to the two
protons of the phenyl ring overlooking the quinoline
moiety. Significantly, the signals of H-3 and H-3′ are
shifted at upper field compared with the corresponding
proton of (R,R)-1 (Figure 4).
With respect to (R,R)-1, the chemical shift values of
the corresponding protons H-15 and H-16 in biisoquino-
linophane (R,R)-2 are significantly higher (∆δ, +0.1 and
0.2 ppm, respectively). This is consistent with an almost
perpendicular arrangement of the two C-1-C-1′-bonded
isoquinoline moieties, with the protons H-15 and H-16
of one quinolinophane moiety falling into the deshielding
cone of the other.
(18) Treatments of the exciton (coupled-oscillator) model and its
application to organic stereochemistry: (a) Mason, S. F. Quart. Rev.
1963, 17, 20. (b) Mason, S. F. Theory. In Optical Rotatory Dispersion
and Circular Dichroism in Organic Chemistry; Snatzke, G., Ed.; Wiley
and Sons: London, 1967; Chapter 4, p 71. (c) Gottarelli, G.; Mason, S.
F.; Torre, G. J. Chem. Soc. B 1971, 1349. (d) Charney, E. The Molecular
Basis of Optical Activity - Optical Rotatory Dispersion and Circular
Dichroism; Wiley and Sons: New York, 1979. (e) Mason, S. F.
Molecular Optical Activity and Chiral Discrimination; Cambridge
University Press: Cambridge, 1982. Qualitative exciton treatments
leading to simple chirality rules can be found in: (f) Harada, N.;
Nakanishi, K. Acc. Chem. Res. 1972, 5, 257. (g) Harada, N.; Nakanishi,
K. Circular Dichroic Spectroscopy: Exciton Coupling in Organic
Stereochemistry; University Science Books: Mill Valley, CA, 1983. (h)
Nakanishi, K.; Berova, N. In Circular Dichroism: Principles and
Applications; Nakanishi, K., Berova, N., Woody R. W., Eds.; VCH
Publishers: New York, 1994; Chapter 13, p 361. (i) Nakanishi, K.;
Berova, N. In Circular Dichroism: Principles and Applications;
Nakanishi, K., Berova, N., Woody, R. W., Eds.; Wiley-VCH Publish-
ers: New York, 2000; Chapter 12, p 337.
Moreover, the two protons of the ethylenic bridges
turned toward the heterocyclic ring (H-9s and H-10s)
resonate at abnormally high field (δ 0.88 and 1.96,
respectively) compared with the corresponding proton in
biquinolinophane (R,R)-1 (δ 4.55 and 3.2, respectively).
The most plausible explanation is that the two isoquino-
line moieties are rotated around the C-1-C-1′ bond
defining a substantial dihedral angle θ. In such way, H-9s
and H-10s protons of one quinolinophane moiety fall into
the shielding cone of the other. Thus, H-9, the proton of
the bridge resonating at the lowest field in 2,2′-biquino-
linophane (R,R)-1 becomes the highest field resonating
proton in 1,1′-biisoquinolinophane (R,R)-2. NOE experi-
ments also confirm this conformational hypothesis. Ac-
cordingly, a substantial interaction is observed between
the protons H-3 and H-10′ and to a lesser extent between
the proton H-4-and H-9′. Therefore, the conformation
pR,aS,pR (chiral axis nomenclature) or R,P,R (helix
nomenclature) can be unequivocally assigned to the
biisoquinolinophane (R,R)-2.
(19) Baba, H.; Yamazaki, I. J. Mol. Spectrosc. 1972, 44, 118.
(20) (a) DeVoe, H. J. Chem. Phys. 1964, 41, 393; (b) 1965, 43, 3199.
(c) Rosini, C. Salvadori, P.; Zandomeneghi, M. Tetrahedron: Asymmetry
1993, 4, 545. (d) Superchi, S.; Giorgio, E.; Rosini, C. Chirality 2004,
16, 422.
(21) Grimme, S.; Harren, J.; Sobanski, A.; Voegtle, F., Eur. J. Org.
Chem. 1998, 1491.
1014 J. Org. Chem., Vol. 70, No. 3, 2005

Atropisomeric (R,R)-2,2′-Bi([2]paracyclo[2](5,8)quinolinophane)
and 235 nm) positive Cotton effects dominate (they are
near 589 nm and provide an OR value at the sodium D
line of +811, i.e., a value which is larger than the
experimental one!). The contributions coming from the
higher energy and negative CD bands (below 220 nm,
far away from 589 nm) are certainly smaller and can only
reduce the 811 value, and therefore, a large OR value is
expected.
It is noteworthy that the UV spectrum of (R,R)-2
closely resembles that of 8,8′-dimethyl-1,1′-biisoquinoline
[(R)-11],9a which exhibits an almost constant absorption
(ꢀ about 10 000) in the region down to 250 nm, followed
by a broad high intensity (ꢀ ca. 70 000) band in the 250-
200 nm region, with a maximum at ca. 220 nm. These
absorption features are related to a distorted 1,1′-
biisoquinoline chromophore: the dihedral angle θ be-
tween the aryl planes 9a being 102° (when evaluated from
the crystal structure) or 90.2° (by AM1 calculations). The
CD spectrum of this derivative is quite simple: for the
(R) absolute configuration we have a positive Cotton
effect (∆ꢀ + 10 ca.) at ca. 320 nm, followed by a strong
negative couplet (-160, +240 ca.) centered at 230 nm. It
FIGURE 5. Conformations of (R,R)-2: (a) more stable; (b) less
stable.
is well-known, since the seminal paper of Mason and co-
23a
workers
on the analysis of CD spectra of biaryl
derivatives, that the strong couplet effect is due to the
exciton coupling of the intense electronic transitions of
the aryl chromophores, polarized along the axis. Fur-
thermore, the shapes of both the UV and CD spectra
depend on the value of the dihedral angle θ. In particular,
for large angles (θ in the range of 80-100°) the absorption
band is broad in the 220 nm spectral range and a
negative couplet corresponds to the R configuration of
the biaryl. With this information it is now possible to
return to the spectra of (R,R)-2, by attempting a qualita-
tive interpretation. First of all, as noticed above, the
comparison of the absorption spectra shows that both
(R,R)-2 and (R)-8,8′-dimethyl-1,1′-biisoquinoline [(R)-11]
strongly contain the same distorted 1,1′-biisoquinoline
chromophore, the difference in shape occurring in the
250-200 nm range could be due to the fact that while
the dihedral angle of (R)-11 is of the order of 90-100°,9a
the present MM calculation gives a much smaller dihe-
dral angle (72°) in (R,R)-2. This is in keeping with the
UV spectrum of (R,R)-2, where a sequence of less intense
(longer wavelength)/more intense (shorter wavelength)
absorption bands is observed between 250 and 200 nm,
characteristic of a biaryl possessing a small θ angle.23 In
addition, our MM calculations show that the (R,R) planar
chirality of (R,R)-2 induces a positive twist of the 1,1′-
biisoquinoline moiety. Thus, according to the Mason
analysis, a positive couplet should be expected in the
250-200 nm spectral region, i.e., where the coupling of
the allowed, long-axis polarized electronic transition of
the biaryl chromophore occurs, as experimentally ob-
served (Figure 6). In summary, even a simple, qualitative
FIGURE 6. UV and CD spectra of (R,R)-2.
The above NMR conclusions are in keeping with the
results of molecular mechanics calculations, similar to
those carried out previously.15 In fact, two conformers
have been identified for (R,R)-2: the conformer (R,R)-
2-A having the (R,P,R) configuration, where the two
isoquinoline rings define a dihedral angle θ of about 72°
(Figure 5a), and the conformer (R,R)-2-B has a (R,M,R)
configuration, where the same angle is -134° (Figure 5b).
According to the energy values provided by these
calculations, conformer (R,R)-2-A is largely prevalent
(91%).
[R]D, Absorption ,and Circular Dichroism (CD)
Spectra. Biisoquinolinophane (R,R)-2 shows [R]D +468
(c 0.5, CHCl3), +556 (c 0.05, MeOH), +437 (c 0.027, CH3-
CN), which are very strong positive values that are
slightly solvent-dependent.22 The UV and CD spectra of
(R,R)-2, measured in CH3CN, are reported in Figure 6.
In the electronic spectrum four main regions of absorp-
tion can be easily identified: a long absorption tail occurs
from 360 nm down to 290 nm (ꢀ ca. 10 000), a maximum
is centered at about 270 nm (ꢀ ca. 20 000) with a definite
shoulder at 240 nm (ꢀ ca. 25 000), followed by an intense
absorption maximum (ꢀ ca. 90 000) at about 205 nm. The
CD spectrum shows a very broad, intense Cotton effect
located between 340 and 260 nm (∆ꢀmax +30, and +40 at
290 and 275 nm, respectively), followed by a sequence of
positive/negative CD bands (∆ꢀ +50 and ∆ꢀ -35 at 220
and 235 nm, respectively). Below 220 nm, at least one
other negative CD band can be observed at 205 nm (∆ꢀ
-80). The high value of optical rotation measured for
(R,R)-2 can be explained following the same reasoning
as for (R,R)-1. Now the two lowest energy (at 280-300
(23) (a) Mason, S. F.; Seal, R. H.; Roberts, D. R. Tetrahedron 1974,
30, 1671. (b) Rosini. C.; Rosati, I.; Spada, G. P. Chirality 1995, 7, 353.;
(c) Di Bari, L.; Pescitelli, G.; Salvadori, P. J. Am. Chem. Soc. 1999,
121, 7988. (d) Rosini, C.; Superchi, S.; Peerlings, H. W. I.; Meijer, E.
W. Eur. J. Org. Chem. 2000, 61. (e) Di Bari, L.; Pescitelli, G.; Marchetti,
F.; Salvadori, P. J. Am. Chem. Soc. 2000, 122, 6395. (f) Bandin, M.;
Casolari, S.; Cozzi, P. G.; Proni, G.; Schmohel, E.; Spada, G. P.;
Tagliavini, E.; Umani-Ronchi, A. Eur. J. Org. Chem. 2000, 491. (g)
Proni, G.; Spada, G. P.; Lustenberger, P.; Welti, R.; Diederich, F. J.
Org. Chem. 2000, 65, 5522.
(22) These OR values are also obtained at different concentrations,
and it is well-known that this experimental parameter may also affect
the OR measurement. Eliel, E. L.; Wilen, S. H. Stereochemistry of
organic compounds; J. Wiley and Sons: New York, 1994; Chapter 13,
p 1076. Polavarapu, P. L. Chirality 2002, 14, 768.
J. Org. Chem, Vol. 70, No. 3, 2005 1015

Ricci et al.
the main source of optical activity can be found in the
presence of the paracyclophane moiety, i.e., the molecular
chirality is only due to insertion of the (almost planar)
2,2′-biquinolino chromophore in a paracyclophane struc-
ture. By contrast, in (R,R)-2 the paracyclophane struc-
tural motif only constitutes a (relatively small) pertur-
bation which only slightly modifies the main source of
optical activity, i.e., the presence of a distorted 1,1′-
biisoquinoline chromophore. These results can be useful
to (at least preliminary) predict the ability of these
ligands to induce steroselectivity in asymmetric catalysis.
Biquinolinophane (R,R)-1, where the nitrogen atoms are
in an anti spatial relationship, should coordinate metal
ions poorly, while (R,R)-2 has the same atoms in a
relative disposition which is suitable for efficient coor-
dination. As a result, if a direct correlation between
coordination capability and induced enantioselectivity
exists, we can expect that the former compound will
provide low enantioselection values in asymmetric reac-
tions while better results should be obtained in reactions
employing the latter ligand. Further studies are needed
to fully understand the spectrum/structure correlations
in these molecules and to verify the reliability of the
present prediction of the enantioselection capability of
these two ligands.
FIGURE 7. Dihedral angles of the two quinoline moieties in
the more stable conformer (R,R)-2-A and in the less stable
conformer (R,R)-2-B.
analysis of the UV/CD spectra of (R,R)-2 can reveal some
interesting spectrum/structure correlations. Unfortu-
nately, the distorted 1,1′-biisoquinoline moiety cannot be
considered responsible for all the spectral features of
(R,R)-2; in fact, the shape of its CD spectrum is more
complex than that of (R)-11. In particular, in the case of
(R,R)-2, the 350-250 nm range possesses a positive,
broad, and very intense Cotton effect, while a negative,
well-defined, and less intense CD band is observed for
(R)-11. In addition, the intensity of the couplet at 220-
230 nm in the spectrum of (R,R)-2 is much smaller than
that of a model compound (R)-11 (note that θ in (R)-11
is 90-100° and shows a couplet with ∆ꢀ -200, +200, a
distortion of 72° should induce an even more intense
couplet).23 These observations suggest that a “perturbed”,
distorted 1,1′-biisoquinoline chromophore, is really re-
sponsible for the spectroscopic properties of (R,R)-2 is
where by “perturbation” we intend the effect of the
paracyclophane moieties which cannot be neglected in
order to completely explain the optical activity of this
molecule.
Experimental Section
(R)-(-)-4-Amino[2.2]paracyclophane [(R)-4]. (R)-(-)-4-
Carboxy[2.2]paracyclophane [(R)-3] (10.0 g, 40 mmol) was
made to react 12 h with SOCl2 (20 mL) at 20 °C under stirring.
Excess chlorinating reagent was evaporated at reduced pres-
sure, toluene (20 mL) was added to the residue, and the
mixture was evaporated again at reduced pressure to remove
any trace of SOCl2. Acetone (100 mL) was added to the
resulting gray solid, and the solution was poured into a
previously prepared solution of NaN3 (10 g, 0.15 mol) in H2O
(50 mL) and acetone (35 mL). The mixture was made to react
at 20 °C for 1 h, and then it was poured into ice-water (300
mL) and extracted with diethyl ether (3 × 100 mL). The
collected extracts were dried with Na2SO4, and the solvent was
evaporated at reduced pressure. Toluene (125 mL) was added
to the resulting white solid, and the solution was refluxed until
the starting acyl azide disappeared (TLC, SiO2, eluent light
petroleum/diethyl ether 9:1). Usually 2 h are enough to
complete the conversion of the acyl azide into the correspond-
ing isocyanate. Toluene was evaporated at reduced pressure,
the residue was dissolved in THF (100 mL), and 40% aqueous
tetrabutylammonium hydroxide (30 mL) was added in portions
while stirring. After the addition was completed, the mixture
was refluxed for 5 min before it was poured into iced water
(600 mL). The white solid was filtered and washed with water
until neutrality, and dried in the presence of P2O5 until
Conclusions
Atropisomeric (R,R)-2,2′-bi[2]paracyclo[2](5,8)quino-
linophane [(R,R)-1] and (R,R)-1,1′-bi[2]paracyclo-[2](5,8)-
isoquinolinophane [(R,R)-2] can be prepared in moderate
overall yield (17 and 9%, respectively) by a four-step
sequence starting from (R)-(-)-4-amino[2.2]paracyclophane
and (R)-(-)-4-carboxy[2.2]paracyclophane, respectively.
1H NMR experiments and theoretical calculations are
in excellent accordance in drawing the structure of both
2,2′-biquinolinophane (R,R)-1 and 1,1′-biisoquinolinophane
(R,R)-2 exhibiting both planar and axial chirality. The
low rotational barrier around the C-2-C-2′ bond allows
(R,R)-1 to exist as a mixture of (R,P,R) and (R,M,R)
conformational diastereoisomers both having the nitro-
gen atoms anti each other. According to our MM calcula-
tions 1,1′-biisoquinolinophane (R,R)-2 seems to strongly
prefer the (R,P,R) conformation (91%) with a dihedral
angle between the two quinoline moieties of about 72°.
The minor conformer exhibits opposite axial chirality
(R,M,R) with a dihedral angle of -134°. The energy
difference between the two conformers (ca. 1.3 kcal/mol)
has to be ascribed most probably to the steric repulsion
between the two phenyl groups overlapping the quinoline
moieties in the minor conformer (Figure 7).
constant weight (7.7 g, 95% from the acid). Mp: 241-243 °C
1
dec. [R]20 ) -71 (c 0.58, CHCl3). H NMR δ: 7.16 (dd, J )
D
7.6 and 1.9 Hz, 1 H), 6.58 (dd, J ) 7.7 and 1.9 Hz, 1 H), 6.38
(dd, J ) 7.7 and 1.9 Hz, 2H), 6.25 (d, J ) 7.5 Hz, 1 H), 6.12
(dd, J ) 7.5 and 1.7 Hz, 1 H), 5.37 (d, J ) 1.7 Hz, 1 H), 3.46
(broad s, 2 H), 3.14-2.91 (m, 6 H), 2.85-2.78 (m, 1 H), 2.70-
2.60 (m, 1 H). 13C NMR δ: 144.9, 141.0, 138.9, 138.8, 135.2,
133.4, 132.4, 131.4, 126.7, 124.1, 122.8, 122.2, 35.3, 34.9, 32.9,
32.2. IR (KBr) 3472, 3385 cm-1. MS m/z: 223 (M+, 26), 119
(100), 104 (5), 91 (16). Anal. Calcd for C16H17N: C, 86.05; H,
7.67; N, 6.27. Found: C, 85.92; H, 7.81; N, 6.38.
The structural information obtained by a theoretical
conformational analysis is fully confirmed by the analysis
(although preliminary and very qualitative) of the chi-
roptical properties of these molecules. In fact, for (R,R)-1
(R)-[2]Paracyclo[2](5,8)quinolinophan-2(1H)-one [(R)-
6]. Butyllithium (19.0 mL 1.59 M in hexane, 30 mmol) was
added to a solution of (R)-(-)-4-amino[2.2]paracyclophane [(R)-
4] (6.8 g, 30 mmol) in THF (100 mL) at -30 °C. The
1016 J. Org. Chem., Vol. 70, No. 3, 2005

Atropisomeric (R,R)-2,2′-Bi([2]paracyclo[2](5,8)quinolinophane)
temperature was raised to 20 °C, ethyl 3-ethoxyacrylate (2.2
g, 15 mmol) was added, and the mixture was allowed to react
for 2 h before it was poured into water and extracted with
diethyl ether (3 × 50 mL). The collected organic phases were
dried with Na2SO4, and the solvent was evaporated at reduced
pressure. Aqueous HCl (36% w/w) was added to the resulting
brown solid, and the mixture was vigorously stirred for 24 h.
The yellow solid, identified as (R)-N-([2.2]paracyclophan-
4-yl)-3-methoxyacrylamide [(R)-5] by its 1H NMR spectrum,
was filtered, washed with water, and dissolved in CHCl3. The
organic solution was dried with Na2SO4 before the solvent was
evaporated at reduced pressure leaving a sticky brown mate-
rial. Chromatography on silica gel (eluent, ethyl acetate/light
petroleum 8:2) allowed pure (R)-6 (3.3 g, 40%) to be isolated.
(R)-5. 1H NMR δ: 8.31 (broad s, 1 H), 7.02 (s, 1 H), 6.76 (d,
J ) 7.6 Hz, 1 H), 6.56-6.42 (AB system, JAB ) 7.6 Hz, 2 H),
6.45-6.39 (m, 5 H), 4.13 (s, 3 H), 3.22 (dd, J ) 14.3 and 9.7
Hz, 1 H), 3.16-2.97 (m, 5 H), 2.87-2.76 (m, 2 H).
(R)-6. Mp: 251-256 dec. 1H NMR (DMSO-d6) δ 10.99 (s, 1
H), 7.66 (d, J ) 9.7 Hz, 1 H), 6.68-6.50 (AB system, JAB ) 7.5
Hz, 2 H), 6.41 (d, J ) 9.7 Hz, 1 H), 6.47-6.35 (AB system, JAB
) 7.8 Hz, 2 H), 6.16 (dd, J ) 7.6 and 1.3 Hz, 1 H), 5.97 (dd, J
) 7.6 and 1.3 Hz, 1 H), 3.78 (dd, J ) 13.2 and 10.0 Hz, 1 H),
3.51 (t, J ) 11.5 Hz, 1 H), 3.03-2.61 (m, 6 H). 13C NMR
(DMSO-d6) δ 162.5, 139.2, 139.1, 138.8, 138.6, 137.9, 136.3,
133.0, 132.9, 128.6, 127.6, 126.4, 125.8, 121.4, 120.4, 34.3, 33.3,
31.8, 30.9. IR (KBr) νmax: 3688 cm-1. Anal. Calcd for C19H17-
NO: C, 82.88; H, 6.22; N, 5.09. Found: C, 82.78; H, 6.29; 5.16.
(R)-(-)-N-(2,2-Dimethoxyethyl)[2.2]paracyclophane4-
carboxyamide [(R)-8]. (R)-4-Chlorocarbonyl[2]paracyclo[2]-
(5,8)paracyclophane (5.5 g, 20 mmol), prepared as above, was
added to a solution of aminoacetaldehyde dimethyl acetal (4.8
g, 46 mmol) in diethyl ether (75 mL) at 0 °C while stirring.
After 1 h at 20 °C, H2O (150 mL) was added, the organic phase
was separated, and the aqueous phase was further extracted
with CH2Cl2 (3 × 50 mL). The collected organic phases were
washed with brine and dried with Na2SO4. After the solvent
was evaporated at reduced pressure, a white solid was
recovered that was identified as (R)-(-)-N-(2,2-dimethoxy-
ethyl)-4-carboxyamido[2.2]paracyclophane (6.9 g, 99%) on the
basis of their spectroscopic and analytical properties. Mp:
1
132-134 °C. [R]20 ) -89 (c ) 0.5, CHCl3). H NMR δ: 6.78
(broad d, J ) 7.9 Hz, 1 H), 6.68 (d, J ) 1.9 Hz, 1 H), 6.59 (dd,
J ) 7.8 e 1.8 Hz, 1 H), 6.54 (tight m, 2 H), 6.49 (d, J ) 7.8 Hz,
1 H), 6.42 (broad d, J ) 8.0 Hz, 1 H), 5.79 (broad s, 1 H), 4.50
(t, J ) 5.2 Hz, 1 H), 3.69 (ddd, J ) 12.8, 10.1 and 2.5 Hz, 1 H),
3.64-3.52 (m, 2 H), 3.45 (s, 3 H), 3.44 (s, 3 H), 3.23-2.85 (m,
7 H). 13C NMR δ: 159.2, 150.2, 140.1, 139.7, 139.2, 139.1,
135.9, 135.0, 132.6, 132.5, 132.4, 131.7, 131.6, 102.7, 54.4, 41.1,
35.3, 35.2, 35.1, 34.8. IR νmax: 3441, 3009, 2931, 1651, 1514,
1131, 1072, 454 cm-1. The product was pure enough to be used
in the following step without further purification.
(R)-(+)-[2]Paracyclo[2](5,8)isoquinolinophan-1(2H)-
one [(R)-9]. Pulverized (R)-(-)-N-(2,2-dimethoxyethyl)-4-
carboxyamido[2.2]paracyclophane (3.4 g, 10.0 mmol) was
added in portions to vigorously stirred polyphosphoric acid (270
g) and preheated at 100 °C, and the resulting mixture was
allowed to react for 30 min before it was poured on triturated
ice. The aqueous phase was extracted with CHCl3 (3 × 50 mL),
and the collected organic phases were dried with Na2SO4. After
solvent, evaporation the gummy red product was washed with
diethyl ether and the residue was chromatographed on silica
gel (eluent, ethyl acetate/light petroleum 1:1.) to recover a
product that identified as (R)-(+)-[2]paracyclo[2](5,8)isoquino-
linophan-1-one (1.3 g, 47%) on the basis of the following
(R)-(+)-2-Bromo[2]paracyclo[2](5,8)quinolinophane
[(R)-7]. Quinolone (R)-6 (1.5 g, 4.4 mmol) was added to POBr3
(11.5 mL, 32.4 g, 0.11 mol), and the mixture was allowed to
react at 20 °C while stirring for 1 h. It was then poured on
ice, and the aqueous phase was cautiously neutralized with
NaHCO3 and extracted with CHCl3 (3 × 50 mL). The collected
organic phases were dried with Na2SO4, and the solvent was
evaporated at reduced pressure. Chromatography of the
residue on silica gel (eluent, light petroleum/diethyl ether 8:2)
spectroscopic and analytical characteristics. Mp: 238-240 °C.
allowed pure 2-bromoquinolinophane (R)-7 (1.1 g, 60%) to be
1
[R]20 ) +451 (c ) 0.5, CHCl3). H NMR δ: 11.01 (broad s, 1
1
isolated. Mp: 115-117 °C. [R]20 ) +94 (c ) 0.5, CHCl3). H
D
D
H), 7.17 (d, J ) 7.2 Hz, 1 H), 6.82-6.73 (AB system, J ) 7.5
Hz, 2 H), 6.56 (dd, J ) 7.9 and 1.8 Hz, 1 H), 6.48 (d, J ) 7.2
Hz, 1 H), 6.44 (dd, J ) 7.9 and 1.8 Hz, 1 H), 6.29 (dd, J ) 7.8
and 1.8 Hz, 1 H), 6.19 (dd, J ) 7.8 and 1.9 Hz, 1 H), 4.78 (ddd,
J ) 12.0, 9.5 and 1.9 Hz, 1 H), 3.60-3.53 (m, 1 H), 3.23-3.09
(m, 3 H), 3.03-2.93 (m, 3 H). 13C NMR δ: 164.1, 142.4, 140.6,
139.9, 138.1, 136.6, 135.9, 133.5, 133.2, 132.2, 129.9, 128.4,
127.6, 127.3, 104.6, 36.1, 34.4, 34.2, 33.1. IR νmax: 3674, 3407,
NMR δ: 7.76 (d, J ) 8.6 Hz, 1 H), 7.44 (d, J ) 8.6 Hz, 1 H),
6.96 (d, J ) 7.2 Hz, 1 H), 6.82 (d, J ) 7.2 Hz, 1 H), 6.45 (tight
AB system, J ) 7.0 Hz, 2 H) 5.75 (d, J ) 7.9 Hz, 1 H), 5.58 (d,
J ) 7.9 Hz, 1 H), 4.18 (ddd, J ) 12.5, 9.6 and 3.0 Hz, 1 H),
3.72-3.63 (m, 1 H), 3.16-2.76 (m, 6 H). 13C NMR δ: 150.1,
139.6, 139.5, 137.8, 137.7, 137.4, 135.1, 134.3, 132.7, 132.2,
131.7, 129.1, 128.8, 127.6, 124.4, 34.5, 34.5, 32.3, 31.4. IR
νmax: 3068, 3019, 2931, 1577, 1489, 1111, 465, 420 cm-1. Anal.
Calcd for C19H16BrN: C, 67.47; H, 4.77; N, 4.14. Found: C,
67.31; H, 4.59; 4.23.
3019, 2935, 2861, 1639, 1449, 1314, 1225, 1103, 871 cm-1
.
Anal. Calcd for C19H17NO: C, 82.88; H, 6.22; N, 5.09. Found:
C, 82.71; H, 6.28; 5.17.
(R,R)-(-)-2,2′-Bi([2]paracyclo[2](5,8)quinolinophane)
[(R,R)-1]. Zinc dust (0.07 g, 1.1 mmol) was added to a solution
of NiCl2‚6H2O (0.24 g, 1.0 mmol) and triphenylphosphine (1.0
g, 4.0 mmol) in DMF (5 mL), and the mixture was stirred at
50 °C for 1 h. (R)-(+)-2-Bromo[2]paracyclo[2](5,8)quinolinophane
[(R)-7] (0.4 g, 1.2 mmol) was added, and the mixture was
allowed to react at 50 °C for 30 min. The white precipitate
was filtered, washed first with DMF (5 mL) and then with CH3-
OH (5 mL), and dissolved in hot CHCl3 (250 mL). The solid
impurities were filtered off, and the solvent was evaporated
at reduced pressure. The resulting white solid was washed
with ethyl acetate and dried in a vacuum to recover pure 2,2′-
bi([2]paracyclo[2](5,8)quinolinophane) [(R,R)-1] (0.22 g, 72%).
(R)-(+)-1-Bromo[2]paracyclo[2](5,8)isoquinolino-
phane [(R)-10]. (R)-(+)-[2]paracyclo[2](5,8)isonolinophan-
1(2H)-one (0.8 g, 3.2 mmol) was allowed to react with POBr3
(10 mL) for 7 h at 100 °C. After cooling, the reaction mixture
was poured into triturated ice (100 g), and the resulting mash
was neutralized with 50% aqueous KOH and extracted with
diethyl ether (3 × 50 mL). The collected extracts were dried
with Na2SO4, and the solvent was evaporated at reduced
pressure. Chromatography of the remaining gummy product
on silica gel (eluent, ethyl acetate/petroleum ether 7:3) allowed
a reddish solid (0.3 g) to be isolated which was recrystallized
from ethanol after treatment with decolorizing carbon. A white
crystalline product was obtained which was identified as (R)-
1-bromo[2]paracyclo[2](5,8)isoquinolinophane (0.44 g, 45%) on
the basis of the following spectroscopic and analytical char-
Mp: 300 °C dec. [R]20 ) -10 (c ) 0.1, CHCl3). 1H NMR δ:
D
8.86 (d, J ) 8.6 Hz, 1 H), 8.17 (d, J ) 8.6 Hz, 1 H), 7.03 (d, J
) 7.2 Hz, 1 H), 6.86 (d, J ) 7.2 Hz, 1 H), 6.54 (tight AB system,
2 H), 5.77-5.72 (tight AB system, J ) 7.6 Hz, 2 H), 4.54 (tight
m, 1 H), 3.83 (m, 1 H), 3.21-2.91 (m, 6 H). 13C NMR δ: 153.3,
148.7, 139.4, 138.6, 137.7, 137.6, 133.8, 133.5, 132.6, 132.2,
131.6, 130.4, 128.8, 127.4, 118.0, 34.9, 34.6, 32.3, 31.9. IR
acteristics. Mp: 224-226 °C. [R]20 ) +193 (c ) 0.5, CHCl3).
D
1H NMR δ 7.77-7.43 (AB system, JAB ) 8.6 Hz, 2 H), 6.97-
6.81 (AB system, JAB ) 7.3 Hz, 2 H), 6.45 (s, 2 H), 5.75-5.57
(AB system, JAB ) 7.9 Hz, 2 H), 4.16 (ddd, J ) 12.2, 9.3, and
2.5 Hz, 1 H), 3.69-3.63 (m, 1 H), 3.16-2.90 (m, 5 H), 2.84-
2.70 (m, 1 H). 13C NMR δ: 141.6, 141.5, 141.0, 139.0, 137.6,
137.5, 136.9, 136.0, 134.7, 132.4, 131.5, 130.4, 129.6, 129.4,
νmax
:
3.68, 3034, 2932, 1592, 1498 cm-1. Anal. Calcd for
C38H32N2: C, 88.34; H, 6.24; N, 5.42. Found: C, 88.12; H, 6.31;
6.29.
J. Org. Chem, Vol. 70, No. 3, 2005 1017

Ricci et al.
118.1, 38.0, 34.9, 34.0, 32.5. IR νmax: 3020, 2941, 2863, 1588,
1311, 1222, 1212, 1056, 823 cm-1. Anal. Calcd for C19H16BrN:
C, 67.47; H, 4.77; N, 4.14. Found: C, 67.55; H, 4.69; 4.25.
(R,R)-(+)-1,1′-Bi([2]paracyclo[2](5,8)isoquinolino-
phane) [(R,R)-2]. Zinc dust (0.06 g, 0.9 mmol) was added to
a stirred solution of NiCl2‚6H2O (0.20 g, 1.0 mmol) and
triphenylphosphine (1.2 g, 4.6 mmol) in DMF (15 mL) at 50
°C. After 1 h, (R)-(+)-2-bromo-[2]paracyclo[2](5,8)quinolinophane
(0.4 g, 1.2 mmol) was added, and the mixture was allowed to
react at 50 °C for 1.5 h. H2O (50 mL) was added, and the
aqueous phase was acidified with 20% aqueous HCl (10 mL)
and extracted with diethyl ether (3 × 25 mL). Aqueous NaOH
(50%) was added to the aqueous phase and it was extracted
again with diethyl ether (3 × 25 mL). The collected organic
phases were dried with Na2SO4, and the solvent was
evaporated at reduced pressure. Chromatography of the
remaining solid on silica gel (eluent, 9:1 petroleum ether/
diethyl ether) allowed 130 mg (43%) of a white solid to be
recovered to which the structure of (R,R)-1,1′-bi([2]paracyclo-
[2](5,8)isoquinolinophane) was assigned on the basis of the
following spectroscopic and analytical properties. Mp: 280 °C
dec. [R]24 ) +414 (c ) 0.5, CHCl3), [R]30 ) +566 (c ) 0.05,
Hz, 1 H), 6.77 (d, J ) 7.2 Hz, 1 H), 6.45 (d, J ) 7.2 Hz, 1 H),
6.37 (dd, J ) 7.8 and 1.6 Hz, 1 H), 6.24 (dd, J ) 7.8 and 1.3
Hz, 1 H), 5.91 (dd, J ) 7.8 and 1.7 Hz, 1 H), 5.83 (dd, J ) 7.8
and 1.7 Hz, 1 H), 3.92-3.67 (m, 1 H), 3.18-2.93 (m, 3 H), 2.41
(t, J ) 11.1 Hz, 1 H), 2.32-2.25 (m, 1 H), 1.97-1.89 (m, 1 H),
0.86 (ddd, J ) 13.8, 9.6 and 1.7 Hz, 1 H). 13C NMR δ: 158.4,
142.0, 139.0, 138.9, 137.7, 137.0, 135.8, 134.4, 133.8, 131.9,
131.3, 130.3, 129.4, 129.2, 118.0, 35.6, 34.3, 34.2, 32.5. IR
νmax
:
3059, 3023, 2942, 1592, 1319 cm-1. Anal. Calcd for
C38H32N2: C, 88.34; H, 6.24; N, 5.42. Found: C, 88.15; H, 6.35;
5.58.
Acknowledgment. Financial support from Univer-
sita` della Basilicata, Universita` di Perugia, and MIUR
(COFIN 2004 contract no. 200403322) is gratefully
acknowledged.
Supporting Information Available: 1H and 13C NMR
spectra of all the reported new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
D
D
MeOH). 1H NMR δ: 8.82 (d, J ) 5.6 Hz, 1 H), 7.69 (d, J ) 5.6
JO048147M
1018 J. Org. Chem., Vol. 70, No. 3, 2005