New chiral molecular tweezers with a bis-Troeger's base skeleton

Article abstract of DOI:10.1021/jo0010882

A convenient synthesis of 5α,8α,14α,17α-5,17:8,14-dimethano- 5,8,14,17-tetraaza-5,6,7,8,13,14,17,18-octahydrodibenzo[e,e′] benzo[1,2-α:3,4-α′]dicyclooctene derivatives is described, and the compounds have been fully characterized by NMR; in some cases, the molecular structure has been determined by X-ray crystallography. These compounds represent the first examples of a new class of molecular tweezers.

Full text of DOI:10.1021/jo0010882

J . Org. Chem. 2001, 66, 1607-1611
1607
New Ch ir a l Molecu la r Tw eezer s w ith a Bis-Tr o1ger ’s Ba se
Sk eleton †
Carmen Pardo,*,‡ Esther Sesmilo,‡ Enrique Gutie´rrez-Puebla,§ Angeles Monge,§
J ose´ Elguero,| and Alain Fruchier
Departamento de Quı´mica Orga´nica I, Facultad de Ciencias Qu´ımicas, Universidad Complutense,
E-28040 Madrid, Spain, Instituto de Ciencia de Materiales, CSIC, Campus de Cantoblanco, E-28049
Madrid, Spain, Instituto de Quı´mica Me´dica, CSIC, J uan de la Cierva 3, E-28003 Madrid, Spain, and
Chimie Organique, ENSCM, 8, rue de l'Ecole Normale, F-34053 Montpellier Ce´dex 1, France
chpardo@eucmax.sim.ucm.es
Received J uly 18, 2000
A convenient synthesis of 5R,8R,14R,17R-5,17:8,14-dimethano-5,8,14,17-tetraaza-5,6,7,8,13,14,17,-
18-octahydrodibenzo[e,e′]benzo[1,2-a:3,4-a′]dicyclooctene derivatives is described, and the compounds
have been fully characterized by NMR; in some cases, the molecular structure has been determined
by X-ray crystallography. These compounds represent the first examples of a new class of molecular
tweezers.
In tr od u ction
Recognition of planar molecules based on noncovalent
interactions is of interest in host-guest chemistry. Mo-
lecular tweezers1 containing two aromatic chromophores
connected by a spacer unit are suitable receptors for
aromatic guests since they can hold the guest by the two
aromatic arms through π-stacking interactions. Harmata
et al.2 have described molecular tweezers derived from
Kagan’s ether, both achiral 1a and chiral 1b. Recently,
Fukazawa et al.3 have reported the synthesis of 2 and
related compounds formed by units of dioxa[2.2]-o-
cyclophane with an arrangement of the two terminal
aromatic rings in a face-to-face orientation in the syn
conformation. The lateral aromatic rings act as tweezers
toward π-electron-deficient compounds when at least one
of the terminal aromatic rings, Ar or Ar′, is larger than
benzene.
Tro¨ger’s base 3, first synthesized by Tro¨ger in 1887,4
is a concave chiral molecule, the chirality of which results
from the blocked configuration of the stereogenic nitrogen
atoms. Tro¨ger’s base and its analogues have been de-
scribed as “fascinating molecules”,5 and they provide
* To whom correspondence should be addressed.
†Dedicated to Professor J ose´ Luis Soto on the occasion of his 70th
birthday.
‡ Universidad Complutense.
§ Instituto de Ciencia de Materiales.
NSCM.
| Instituto de Qu´ımica Me´dica.
(1) (a) Zimmerman, S. C.; Mrksich, M.; Baloga, M. J . Am. Chem.
Soc. 1989, 111, 8528. (b) Zimmerman, S. C.; Wu, W. J . Am. Chem.
Soc. 1989, 111, 8054. (c) Zimmerman, S. C.; Van Zyl, C. M.; Hamilton,
G. S. J . Am. Chem. Soc. 1989, 111, 1373. (d) Zimmerman, S. C.
Tetrahedron Lett. 1988, 983. (e) Zimmerman, S. C.; Van Zyl, C. M. J .
Am. Chem. Soc. 1987, 109, 7894.
(2) (a) Harmata, M.; Barnes, C. L. Tetrahedron Lett. 1990, 31, 1825.
(b) Harmata, M.; Barnes, C. L. J . Am. Chem. Soc. 1990, 112, 5655. (c)
Fleischhauer, J .; Harmata, M.; Kahraman, M.; Koslowski, A.; Welch,
C. J . Tetrahedron Lett. 1997, 38, 8655.
(3) (a) Kurebayashi, H.; Sakaguchi, M.; Okajima, T.; Haino, T.; Usui,
S.; Fukazawa, Y. Tetrahedron Lett. 1999, 40, 5545. (b) Kurebayashi,
H.; Haino, T.; Fukazawa, Y. Tetrahedron Lett. 2000, 41, 477. (c)
Kurebayashi, H.; Fukazawa, Y. Chem. Lett. 2000, 530. (d) Kurebayashi,
H.; Haino, T.; Fukuzawa, Y. Tetrahedron Lett. 2000, 41, 477.
(4) Tro¨ger, J . J . Prakt. Chem. 1887, 36, 225.
relatively rigid chiral armatures for the construction of
chelating and biomimetic systems, which were essentially
developed thanks to the efforts of Wilcox and co-workers.6
Tro¨ger’s base and its analogues show a perpendicular
(5) Fascinating Molecules in Organic Chemistry; Vo¨gtle, F., Ed.;
J ohn Wiley: Chichester, 1992; p 237.
10.1021/jo0010882 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/13/2001

1608 J . Org. Chem., Vol. 66, No. 5, 2001
Pardo et al.
Sch em e 1a
a
Key: (i) H2/Pd 10%(C), CHCl3/EtOH, rt, 3 h; (ii) 6-nitroisatoic anhydride, THF, reflux, 3 h; (iii) 5-methyl-2-nitrobenzoic acid, DCC,
DMF, rt, 5 h; (iv) BH3-THF, reflux, 1 h; (v) 37% aqueous CH2O, 95% EtOH, 36% HCl, 90 °C, 24 h.
arrangement of the two aromatic rings,6a as in Kagan’s
ether, and could serve as starting compounds in the
synthesis of chiral molecular tweezers. Tro¨ger’s base
analogues are mostly derived from the reaction of form-
aldehyde with simple para-substituted anilines, but in
the past few years, new Tro¨ger’s base analogues derived
from heterocyclic compounds, such as phenanthroline,7
porphyrin,6h,8 azolyl-substituted anilines,9 acridines,10
benzophenanthroline,10 and various aminoheterocycles,11
have been reported, and some of them have been shown
to interact with DNA.7,10 In the course of our work on
the development of analogues of Tro¨ger’s bases, we report
in this paper the first example of molecular tweezers with
a bis-Tro¨ger’s base skeleton.
Resu lts a n d Discu ssion
We have synthesized the bis-Tro¨ger’s base analogues
4 and 5 (Scheme 1) starting from the unsymmetrical
Tro¨ger’s base 6 and following a synthetic pathway similar
to the procedure established by Wilcox et al. for the
synthesis of unsymmetrically substituted Tro¨ger’s bases.12
Base 612 was catalytically hydrogenated over 10%
palladium on charcoal, yielding amine 7 in almost
quantitative yield. The reaction of 7 with 6-nitroisatoic
anhydride13 in anhydrous THF afforded amide 8a in 65%
yield. Amide 8b was prepared in 66% yield by reaction
of 7 with 5-methyl-2-nitrobenzoic acid and dicyclohexyl-
carbodiimide (DCC) in anhydrous DMF and was then
hydrogenated over 10% palladium on charcoal, yielding
the amino derivative 10 in almost quantitative yield.
Amides 8a and 10 were reduced with BH3-THF in
anhydrous THF to the corresponding amines 9a and 9b
in 73% and 56% yields, respectively. All attempts to
reduce 8b to 9b in only one step using Ti4Cl/BH3 in
dimethoxyethane or in THF,14 conditions in which amides
and nitro compounds are reduced in high yields to
secondary and primary amines, respectively, failed.
Finally, cyclization of amines 9 by reaction with aqueous
formaldehyde in 95% ethanol and concentrated hydro-
chloric acid at 90 °C for 24 h yielded the corresponding
bis-Tro¨ger’s bases 4 and 5.
(6) For a recent review, see: (a) Demeunynck, M.; Tatiboue¨t, A.
Recent Developments in Tro¨ger’s Base Chemistry. In Progress in
Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon
Press: Oxford, 1999; Vol. 11, p1 and references therein, for example:
(b) Wilcox, C. S. Tetrahedron Lett. 1985, 26, 5749. (c) Wilcox, C. S.;
Cowart, M. D. Tetrahedron Lett. 1986, 27, 5563. (d) Cowart, M. D.;
Sucholeiki, I.; Bukownik, R. R.; Wilcox, C. S. J . Am. Chem. Soc. 1988,
110, 6204. (e) Adrian J r, J . C.; Wilcox, C. S. J . Am. Chem. Soc. 1989,
111, 8055. (f) Bond, D. R.; Scott, J . L. J . Chem. Soc., Perkin Trans. 2
1991, 47. (g) Adrian J r, J .; Wilcox, C. S. J . Am. Chem. Soc. 1992, 114,
1398. (h) Crossley, M. J .; Hambley, T. W.; Mackay, L. G.; Try, A. C.;
Walton, R. J . Chem. Soc., Chem. Commun. 1995, 1077. (i) Kim, E.-I.;
Paliwal, S.; Wilcox, C. S. J . Am. Chem. Soc. 1998, 120, 11192. (j)
Goswami, S.; Ghosh, K.; Dasgupta, S. J . Org. Chem. 2000, 65, 1907.
(k) Harmata, M.; Kahraman, M. Tetrahedron: Asymmetry 2000, 11,
2875.
Compound 9a affords, in a 63% yield, a 4:1 mixture of
stereoisomers 4a and 5a , which were separated by
chromatography. The reaction of cyclization to form the
(7) Yashima, E.; Akashi, M.; Miyauchi, N. Chem. Lett. 1991, 1017.
(8) Crossley, M. J .; Try, A. C.; Walton, R. Tetrahedron Lett. 1996,
37, 6807.
(9) Cerrada. L.; Cudero, J .; Elguero, J .; Pardo, C. J . Chem. Soc.,
Chem. Commun. 1993, 1713.
(10) (a) Tatiboue¨t, A.; Demeunynck, M.; Lhomme, J . Synth. Com-
mun. 1996, 26, 4375. (b) Salez, H.; Wardani, A.; Demeunynck, M.;
Tatiboue¨t, A.; Lhomme, J . Tetrahedron Lett. 1995, 36, 1271.
(11) Cudero, J .; Pardo, C.; Ramos, M.; Gutie´rrez-Puebla, E.; Monge,
A.; Elguero, J . Tetrahedron 1997, 53, 2233.
(12) Webb, T, H.; Wilcox, S. C. J . Org. Chem. 1990, 55, 363.
(13) Reissenweber, G.; Mangold, D. Angew. Chem., Int. Ed. Engl.
1980, 19, 222.
(14) Kano, S.; Tanaka, Y.; Sugino, E.; Hibino, S. Synthesis 1980,
695.

Chiral Molecular Tweezers
J . Org. Chem., Vol. 66, No. 5, 2001 1609
F igu r e 1. X-ray structure of 4a : ORTEP view.
new Tro¨ger’s base skeleton is stereo- and regioselective
and only one of the two possible regioisomers, as mixture
of the syn/anti stereoisomers 4a and 5a , was obtained
1
F igu r e 2.
and their structure was established by H NMR. In the
1H NMR spectra of both stereoisomers, the aromatic
protons of the central ring form an AB system with a
coupling constant of 8 Hz, corresponding to a J ortho. The
syn configuration of the major stereoisomer 4a was
determined by X-ray crystallography (Figure 1). When
the minor isomer 5a was placed in the above cyclization
conditions, an identical mixture (4:1) of 4a and 5a was
obtained. Therefore, the syn isomer is thermodynamically
more stable than the anti isomer, either because π-stack-
ing interaction between the lateral aromatic rings, which
are parallel, or due to differences in solvation between
the two isomers. The X-ray structure (Figure 1) shows
that the aromatic arms lie almost parallel with each other
(23.1°), with a distance between its centroids of 4.368(5)
Å. The central phenyl ring is almost orthogonal to the
external aromatic arms (p-methyl, 88.6°; p-nitro, 79.3°).
The molecular packing shows that in the c direction every
two molecules are intercalated each other in such a way
that the nitro-arm of one molecule is located between the
two arms of the front molecule with the nitro group
pointed to the central aromatic ring in an edge-to-face
interaction. The UV-vis spectrum of 4a in chloroform
shows a weak broad band at 700 nm that we tentatively
assign to a donor-acceptor interaction between the
external aromatic rings. In general, the formation of
Tro¨ger’s bases is sensitive to the steric hindrance and
the less hindered regioisomers are favored.15 The trans-
formation of 9a into the Tro¨ger’s bases 4a and 5a
requieres two molecules of formaldehyde, one for the
N-CH2-N bridge and the other to create the N-CH2-
C(Ar) bond. The formation of the gem-diamine bridge is
reversible as the isomerization 5a to 4a proved (the facile
racemization of Tro¨ger’s bases has the same explanation).6a
Since it is difficult to know in which order these two
reactions took place, we will assume that the bridge
N-CH2-N is already present before the deciding C-C
bond formation occur. There are four transition states,
that should resemble the intermediates depicted in
Figure 2, two correspond to an attack at the ortho
position, I1 and I2, and two to an attack at the para
F igu r e 3.
position, I3 and I4. The formation of bis-Tro¨ger’s bases
11 and 12 was not observed, although they seem to be
less hindered than regioisomer 4a . We propose that the
formation of the major isomer 4a corresponds to the
stabilizing π-stacking present in a transition state close
to I1 while in that corresponding to I3 the external
aromatic rings are too far apart to π stack. The anti
isomer 5a results from an equilibration of 4a in the
reaction conditions.
Compound 9b, in the same reaction conditions, af-
forded a complex reaction mixture from which a signifi-
cant quantity of 9b was recovered, and a sole stereoiso-
mer of the bis-Tro¨ger’s base was obtained in very low
yield. The reaction is also regioselective, and the assign-
ment of the structure as the more hindered regioisomer
1
5 was made on the basis of its H NMR spectrum. The
protons in the central aromatic ring are chemically
equivalent but NOE and NOESY experiments showed
that they are spatially close to the methylene protons
H-13n (H-18n) but not to H-6n (H-7n) (Figure 3). The
other pair of regioisomers, 13, should show NOE interac-
(15) Sucholeiki, I.; Lynch, V.; Phan, L.; Wilcox, C. S. J . Org. Chem.
1988, 53, 98.

1610 J . Org. Chem., Vol. 66, No. 5, 2001
Pardo et al.
room temperature under argon, was added portionwise amine
7 (0.891 g, 3.55 mmol), and the resulting mixture was refluxed
for 3 h until amine 7 disappeared, the progress of the reaction
being followed by TLC (eluent: hexane/ethyl acetate 3:7). The
reaction mixture was then cooled to room temperature and
poured into water; the mixture was extracted with ethyl
acetate (3 × 50 mL), the combined extracts were dried over
anhydrous MgSO4, and the solvent was evaporated under
reduced pressure. The crude product was then purified by flash
chromatography over silica gel. Elution with hexane/dichlo-
romethane (6/4) yielded pure 8a in 65% yield as an orange
solid: mp 250-253 °C; IR (KBr) ν 3385, 1655, 1622, 1589,
tions between the central aromatic protons H-7 (H-16)
and both pairs of endo protons H-9n (H-18n) and H-6n
(H-15n) (Figure 3).
The assignment of the structure to the anti stereoiso-
mer 5b was established by X-ray crystallography. The
central aromatic ring is also orthogonal to both external
aromatic rings (p-methyl, 83.4°; p-nitro, 75.6°) and the
planes defined by the external rings form an angle of
23.4°, similar to base 4a . The molecular packing shows
that the molecules are stacked along the c direction. The
low yield obtained in the cyclization reaction may be due
to the absence of stabilizing π-stacking interactions
between the external phenyl rings. Note that, contrary
to 4a , the lateral phenyl rings in 5b are identically
polarized.
1
1537, 1497, 1327 cm-1; H NMR (CDCl3) δ 2.24 (s, 3H), 4.15
(d, 1H, J ) 16.1), 4.19 (d, 1H, J ) 16.8), 4.35 (s, 2H), 4.70 (d,
1H, J ) 16.6), 4.72 (d, 1H, J ) 16.8), 6.47 (bs, 2H), 6.67 (d,
1H, J ) 9.3), 6.74 (bs, 1H), 6.99 (dd, 1H, J ) 8.3, 1.7), 7.07 (d,
1H, J ) 8.3), 7.18 (d, 1H, J ) 8.6), 7.27, 7.29 (dd, 1H, J ) 2.4),
7.83 (bs, 1H), 8.11 (dd, 1H, J ) 9.3, 2.4), 8.44 (d, 1H, J ) 2.4);
13C NMR (DMSO-d6) δ 20.54, 58.43, 58.58, 66.66, 113.75,
115.99 119.28, 120.43, 124.62, 124.80, 126.34, 127.19, 127.71,
127.81, 127.86, 128.18, 132.48, 134.15, 135.08, 144.40, 145.63,
155.29, 165.91. Anal. Calcd for C23H21N5O3: C, 66.49; H, 5.09;
N, 16.86. Found: C, 66.58; H, 4.85; N, 17.01.
Con clu sion
The successful synthesis of compounds 4a and 5a ,b
opens the way to the preparation of supramolecular boxes
and channels by addition of successive Tro¨ger’s bases,
by using larger spacers (phenantrenes instead of ben-
zenes) or by linking them through polyethylenoxy bridges
(bis-Tro¨gerophanes). All these approches are under way
in our group.
N-(5-Met h yl-2-n it r ob en zoyl)-8-a m in o-2-m et h yl-5,11-
m e t h a n o -5 ,6 ,1 1 ,1 2 -t e t r a h y d r o d i b e n z o [ b ,f ] [ 1 ,5 ] -
d ia zocin e (8b). To a stirred suspension of amine 7 (0.276 g,
1.10 mmol) and 5-methyl-2-nitrobenzoic acid (0.199 g, 1.10
mmol) in anhydrous DMF (1.2 mL), at 0 °C under argon, was
added slowly DCC (0.272 g, 1.32 mmol). The resulting mixture
was stirred at 0 °C for 15 min and then allowed to warm to
room temperature, and finally 0.25 mL of DMF was added.
The mixture was stirred at room temperature for 2.5 h, 0.25
mL of DMF was added, and the stirring was continued for
additional 2.5 h. The dicyclohexylurea precipitate was filtered
off and washed with dichloromethane. The combined organic
filtrate and CH2Cl2 wash were successively washed with
saturated aqueous NaHCO3 (3 × 50 mL) and water (10 × 50
mL). The organic layer was dried over anhydrous MgSO4,
evaporated under reduced pressure, and flash chromato-
graphed over silica gel. Elution with hexane/ethyl acetate
(4/6) afforded pure 8b in 66% yield as a pale yellow solid: mp
220-222 °C; IR (KBr) ν 3227, 3171, 3061, 1639, 1551, 1512,
1491, 1341, 837 cm -1; 1H NMR (CDCl3) δ 2.24 (s, 3H), 2.44 (s,
3H), 4.11 (d, 1H. J ) 17.1), 4.15 (d, 1H, J ) 17.0), 4.30 (s,
2H), 4.67 (d, 2H, J ) 16.6), 6.73 (bs, 1H), 6.98 (bd, 1H, J )
8.1), 7.04 (d, 1H, J ) 8.1), 7.10 (d, 1H, J ) 8.6), 7.19 (dd, 1H,
J ) 8.6, 2.2), 7.30, 7.32, 7.57 (bs, 1H), 7.94 (d, 1H, J ) 9.0);
13C NMR (DMSO-d6) δ 20.55, 20.95, 58.44, 58.57, 66.64, 117.89,
119.19, 124.44, 124.63, 125.05, 127.19, 127.76, 127.87, 128.46,
129.58, 131.06, 132.50, 133.10, 134.47, 144.30, 144.31, 145.35,
145.59, 164.08. Anal. Calcd for C24H22N4O3: C, 69.55; H, 5.35;
N, 13.52. Found: C, 69.47; H, 5.28; N, 13.61.
Exp er im en ta l Section
Melting points are uncorrected. 1H spectra were recorded
at 250, 300, and 400 MHz, and 13C NMR spectra were recorded
at 63, 75, and 100 MHz. 1H and 13C chemical shifts were
measured in ppm relative to internal Me4Si, and coupling
constants are expressed in Hz.
Gen er a l P r oced u r e for t h e H yd r ogen a t ion of Nit r o
Com p ou n d s. A solution of 1 mmol of the corresponding nitro
compound in 10 mL of chloroform and 40 mL of ethanol was
hydrogenated over 90 mg of Pd 10% (C) at 2 atm and room
temperature during 3 h. The reaction mixture was filtered
through Celite, the Celite was washed with ethyl acetate, and
the filtrate and washes were evaporated under reduced
pressure. The residual solid was dissolved in 30 mL of
chloroform, successively washed with 2 × 30 mL of 5% aqueous
NaOH and 30 mL of water, and then dried over anhydrous
MgSO4. The solvent was eliminated under reduced pressure,
and the almost pure amine was utilized without further
purification.
8-Am in o-2-m eth yl-5,11-m eth a n o-5,6,11,12-tetr a h yd r o-
d iben zo[b,f][1,5]d ia zocin e (7): yield 99%; mp 210-212 °C;
1
IR (KBr) ν 3398, 3325, 3207, 1614, 1497, 1207, 831 cm-1; H
NMR (CDCl3) δ 2.23 (s, 3H), 4.04 (d, 1H, J ) 16.6), 4.05 (d,
1H, J ) 16.6), 4.30 (s, 2H), 4.61 (d, 1H, J ) 16.6), 4.62 (d, 1H,
J ) 16.6), 6.22 (d, 1H, J ) 2.7), 6.52 (dd, 1H, J ) 8.5, 2.7),
6.72 (bs,1H,), 6.94 (d, 1H, J ) 8.5), 6.97 (dd, 1H, J ) 8.3, 1.5),
7.03 (d, 1H, J ) 8.3); 13C NMR δ 20.81, 58.60, 58.75, 67.18,
112.53, 114.99, 124.71, 125.77, 127.29, 127.62, 128.02, 128.63,
133.37, 139.30, 142.68, 145.44.
Gen er a l P r oced u r e for th e Red u ction of Am id es. To a
stirred solution of the corresponding amide (2.84 mmol) in
anhydrous THF (9.87 mL), at 0 °C under argon, was added
dropwise a 1.0 M solution of BH3-THF (14.20 mmol). The
mixture was refluxed for 1 h and then cooled to room
temperature. HCl (6 N, 9.70 mL) was added dropwise, and
the resulting mixture was stirred at room temperature for 1
h, basified with 6 N NaOH (pH ) 9), poured into water (50
mL), and extracted with chloroform (3 × 30 mL). The organic
extracts were dried over anhydrous MgSO4, evaporated under
reduced pressure, and flash chromatographed over silica gel.
N-(2-Am in o-5-n itr oben zyl)-8-am in o-2-m eth yl-5,11-m eth -
a n o-5,6,11,12-tetr a h yd r od iben zo[b,f][1,5]d ia zocin e (9a ).
Elution with hexane/ethyl acetate (1/9) yielded amide 8a (25%)
and pure 9a in 73% yield: mp 150-152 °C; IR (KBr) ν 3368,
3223, 1618, 1585, 1493, 1313, 831, 752 cm-1; 1H NMR (CDCl3)
δ 2.24 (s, 3H), 4.07 (d, 1H, J ) 17.1), 4.10 (d, 1H, J ) 17.1),
4.18 (s, 2H), 4.32 (s, 2H), 4.65 (d, 2H, J ) 16.6), 5.01 (bs, 2H),
6.28 (d, 1H, J ) 2.7), 6.59 (dd, 1H, J ) 8.0, 2.7), 6.63 (dt, 1H,
J ) 9.3, 1.7), 6.99 (dd, 1H, J ) 8.1, 2.0), 7.04 (d, 1H, J ) 8.6),
7.05 (d, 1H, J ) 8.1), 8.03 (1H, dd, J ) 2.5), 8.06; 13C NMR
(CDCl3) δ 20.83, 47.57, 58.60, 58.88, 67.16, 111.33, 114.30,
114.35, 121.48, 124.77, 125.56, 125.94, 126.28, 127.31, 127.52,
N-(2-Am in o-5-m eth ylben zoyl)-8-a m in o-2-m eth yl-5,11-
m e t h a n o -5 ,6 ,1 1 ,1 2 -t e t r a h y d r o d i b e n z o [ b ,f ] [ 1 ,5 ] -
d ia zocin e (10): yield 98%; mp 158-160 °C; IR (KBr) ν 3449,
1
3356, 1655, 1491, 1205, 829 cm-1, H NMR (CDCl3) δ 2.23 (s,
3H), 2.26 (s, 3H), 4.121 (d, 1H, J ) 16.4), 4.171 (d, 1H, J )
16.8), 4.32 (s, 2H), 4.67 (d, 1H, J ) 16.8), 4.69 (d, 1H, J )
16.6), 5.24 (bs, 2H), 6.63 (d, 1H, J ) 8.3), 6.72 (bs, 1H), 6.97
(dd, 1H, J ) 8.3, 1.7), 7.03 (d, 1H, J ) 8.3), 7.07 (d, 1H, J )
2.0), 7.12 (d, 1H, J ) 8.1), 7.20, 7.24, 7.26; 13C NMR (CDCl3)
δ 20.33, 20.80, 58.69, 58.76, 67.03, 116.41, 117.70, 119.00,
120.16, 124.72, 125.47, 126.07, 127.16, 127.21, 127.32, 128.20,
128.50, 133.53, 133.53, 133.69, 144.47, 145.20, 146.47, 167.43.
N -(2-Am in o-5-n it r ob e n zoyl)-8-a m in o-2-m e t h yl-5,11-
m e t h a n o -5 ,6 ,1 1 ,1 2 -t e t r a h y d r o d i b e n z o [ b ,f ] [ 1 ,5 ] -
d ia zocin e (8a ). To a stirred solution of 6-nitroisatoic anhy-
dride13 (1.000 g, 4.81 mmol) in anhydrous THF (9.2 mL), at

Chiral Molecular Tweezers
J . Org. Chem., Vol. 66, No. 5, 2001 1611
128.11, 128.78, 133.50, 138.59, 140.05, 144.07, 145.39, 152.31.
Anal. Calcd for C23H23N5O2: C, 68.81; H, 5.77; N, 17.44.
Found: C, 68.92; H, 5.61; N, 17.39.
122.82, 123.05, 128.87, 124.40, 124.82, 124.64, 124.88, 125.58,
127.36, 128.30, 134.13, 143.01, 143.72, 143.86, 144.93, 154.94;
HRMS (EI) calcd for C25H23N5O2 425.18516, found 425.18514.
2,11-Dim eth yl-5r,8â,14â,17r-5,17:8,14-d im eth a n o-5,8,-
14,17-tetr a a za -5,6,7,8,13,14,17,18-octa h yd r od iben zo[e,e′]-
ben zo[1,2-a :3,4-a ′]d icycloocten e (5b). Elution with hexane/
ethyl acetate (1/9) yielded impure 5b that was again flash
chromatographed; elution with dichloromethane/ethyl acetate
(6/4) yielded pure 5b in 6% yield: mp 278-80 °C; IR (KBr) ν
1497, 1474, 1261, 1094, 827, 800 cm-1; 1H NMR (CDCl3) δ 2.25
(s, 3H), 3.86 (d, 1H, J ) 16.6), 4.11 (d, 1H, J ) 16.8), 4.14 (dd,
1H, J ) 13.2, 1,5), 4.26 (d, 1H, J ) 13.2), 4.33 (d, 1H), 4.63 (d,
1H, J ) 16.8), 6.74 (bs, 1H), 6.99 (s, 1H), 7.00 (dd, 1H, J )
8.3, 1.7), 7.06 (d, 1H, J ) 8.3). 13C NMR (CDCl3) δ 20.88, 55.83,
58.15, 66.27, 124.31, 124.86, 127.32, 127.40, 128.24, 133.96,
143.51, 145.14; HRMS (EI) calcd for C26H26N4 394.21573, found
394.21451.
N-(2-Am in o-5-m et h ylb en zyl)-8-a m in o-2-m et h yl-5,11-
m e t h a n o -5 ,6 ,1 1 ,1 2 -t e t r a h y d r o d i b e n z o [ b ,f ] [ 1 ,5 ] -
d ia zocin e (9b ). Elution with hexane/ethyl acetate (3/7)
yielded amide 10 (13%), amine 7 (15%), and pure 9b in 56%
yield: mp 173-175 °C; IR (KBr) ν 3402, 1618, 1541, 1491,
1261, 1205, 820 cm-1 1H NMR (CDCl3) δ 2.25 (s, 6H), 3.74
;
(bs, 2H), 4.08 (d, 1H, J ) 16.6), 4.11 (s, 2H), 4.12 (d, 1H J )
16.6), 4.32 (s, 2H), 4.65 (d, 1H, J ) 16.6), 4.66 (d, 1H, J )
16.6), 6.25 (d, 1H, J ) 2.4), 6.57 (dd, 1H, J ) 8.5, 2.4), 6.62 (d,
1H, J ) 8.0), 6.74 (bs, 1H), 6.94 (bs, 1H), 6.97 (d, 1H), 6.99
(bd, 1H, J ) 8.1), 7.02, 7.06 (d, 1H, J ) 8.1); 13C NMR (CDCl3)
δ 20.30, 20.78, 47.36, 58.55, 58.88, 67.20, 110.50, 113.74,
115.99, 122.93, 124.72, 125.73, 127.29, 127.49, 127.50, 128.03,
128.52, 129.29, 130.56, 133.38, 138.88, 133.19, 145.03, 145.39.
Anal. Calcd for C24H26N4: C, 77.80; H, 7.07; N, 15.12. Found:
C, 77.63; H, 6.99; N, 15.21.
Cr ysta l Str u ctu r es of Com p ou n d s 4a a n d 5b. Crystal
of both compounds 4a and 5b were obtained from saturated
solutions in chloroform/96% ethanol. Those crystals showing
well-defined faced were mounted on a Bruker-Siemens Smart
diffractometer equipped with normal focus, 2.4 kW sealed tube
X-ray source (Molybdenum radiation, λ ) 0.710 67 Å) operating
at 50 kV and 20 mA. Compound 5b crystallized with a
disordered molecule of ethanol whose electron density has been
included in the crystal structure resolution. Data for each
crystal were collected over a quadrant, by combination of two
exposure sets, respectively. Each exposure of 10 s covers 0.3°
in ω. The unit cell dimensions were determined by least-
squares refinement using reflections with I > 20σ and 3°< θ
< 27° and 3°< θ < 32° for compounds 4a and 5b, respectively.
The crystal-to-detector distance was 4.5 cm. The first 50 frames
were recollected at the end of the data collection to monitor
crystal decay. The intensities were corrected for Lorentz and
polarization effects. Scattering factors for neutral atoms were
taken from the International Tables for X-ray Crystallogra-
phy.16 The structure was solved by Multan and Fourier
methods. Full-matrix least-squares refinement was carried out
Gen er al P r ocedu r e of For m ation of Bis-Tr o1ger ’s Bases.
To a stirred suspension of the corresponding amine 9 (4.47
mmol) in 95% ethanol (9.4 mL), at room temperature under
argon, were successively added 35-40% aqueous formaldehyde
(2.4 mL) and 36% HCl (2.3 mL). The mixture was stirred at
90 °C for 24 h, cooled to room temperature, and basified with
concentrated ammonia solution (pH ) 9). The alkaline solution
was extracted with methylene chloride (3 × 50 mL) and the
combined organic extracts were successively washed with
saturated aqueous solutions of NaHCO3 (100 mL) and NaCl
(100 mL). The organic layer was dried over anhydrous MgSO4,
evaporated under reduced pressure, and flash chromato-
graphed over silica gel.
2-Met h yl-11-n it r o-5r,8r,14r,17r-5,17:8,14-d im et h a n o-
5,8,14,17-t et r a a za -5,6,7,8,13,14,17,18-oct a h yd r od ib en zo-
[e,e′]ben zo[1,2-a :3,4-a ′]d icycloocten e (4a ). Elution with
ethyl acetate/dichloromethane (7/3) yielded the isomer 5a in
12% yield and then pure 4a in 50% yield.
4a : mp >230 °C dec; IR (KBr) ν 1610, 1582, 1512, 1495,
1
1475, 1340, 1215, 941, 744 cm-1; H NMR (CDCl3) δ 2.17 (s,
2
minimizing w(Fo - Fc2).17 The hydrogen atoms were in both
3H), 3.87 (d, 1H, J ) 17.0), 3.94 (d, 1H, J ) 16.8), 4.09 (d, 1H,
J ) 16.7), 4.18 (d, 1H, J ) 16.9), 4.19 (dd, 1H, J ) 12.5, 1.5,),
4.21 (dd, 1H, J ) 12.7, 1.1), 4.24 (dd, 1H, J ) 12.5, 1.2), 4.26
(dd, 1H, J ) 12.7, 1.6), 4.40 (d, 1H, J ) 17.0), 4.48 (d, 1H, J )
16.8), 4.64 (d, 1H. J ) 16.7), 4.69 (d, 1H, J ) 16.9), 6.69 (d,
1H, J ) 1.8), 6.94 (dd, 1H, J ) 8.1, 1.8), 7.00 (d, 1H, J ) 8.1),
7.01 (d, 1H, J ) 8.7), 7.04 (d, 1H, J ) 8.7), 7.20 (d, 1H, J )
8.9), 7.80 (d, 1H, J ) 2.6), 7.99 (dd, 1H, J ) 8.9, 2.6). 13C NMR
(CDCl3) δ 20.78, 55.79, 56.17, 57.75, 57.84, 66.34, 66.06,
122.85, 122.90, 124.17, 124.19, 124.72, 124.90, 125.11, 125.72,
127.04, 127.62, 128.14, 128.97, 133.61, 142.85, 143.72, 144.29,
145.59, 155.08; HRMS (EI) calcd for C25H23N5O2 425.18516,
found 425.18521.
cases located in Fourier synthesis and refined isotropically.
Refinement on F2 for all reflections. Weighted factors (Rw) and
all goodness of fit S are based on F2; conventional R factors
(R) are based on F.
Ack n ow led gm en t . Financial support from the
DGES, Ministerio de Educacio´n y Cultura of Spain
(Project No. PB96-0001-C01-01), is greatly acknowl-
edged.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 4a , 5a , and 5b. ORTEP structure of compound 5b.
Molecular packing in the crystal structure for compounds 4a
and 5b. Crystal data and structure refinement for compounds
4a and 5b. This material is available free of charge via the
Internet at http://pubs.acs.org.
5a : mp 185-187 °C; IR (KBr) ν 1610, 1580, 1514, 1474,
1333, 1221, 939, 839 cm-1 1H NMR (CDCl3) δ 2.25 (s, 3H),
;
3.87 (d, 1H, J ) 16.7), 3.95 (d, 1H, J ) 16.7), 4.12 (d, 1H, J )
16.8), 4.15 (dd, 1H, J ) 12.5, 1.7), 4.20 (s, 2H), 4.23 (d, 1H, J
) 16.8), 4.25 (dd, 1H, J ) 12.5, 1.5), 4.34 (d, 1H, J ) 16.7),
4.42 (d, 1H, J ) 16.7), 4.63 (d, 1H, J ) 16.8), 4.69 (d, 1H, J )
16.8), 6.75 (bs, 1H), 7.01 (dd, 1H, J ) 8.3, 1.7), 6.99 (d, 1H, J
) 8.7), 7.02 (d, 1H, J ) 8.7), 7.05 (d, 1H, J ) 8.3), 7.25 (d, 1H,
J )8.9), 7.87 (d, 1H, J ) 2.6), 8.06 (dd, 1H, J ) 8.9, 2.6), 13C
NMR (CDCl3) δ 20.88, 55.79, 56.20, 58.08, 58.17, 66.02, 66.28,
J O0010882
(16) International Tables for X-ray Crystallography; Kynoch Press:
Birmingham, 1974; Vol. IV, pp 78-98.
(17) SHELTXTL, Siemens Energy & Automation, Inc., Analytical
Instrumentation, 1996.